@article {pmid40271071, year = {2025}, author = {Luo, H and Wei, S and Fu, S and Han, L}, title = {Role of Achyranthes aspera in neurodegenerative diseases: current evidence and future directions.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1511011}, doi = {10.3389/fphar.2025.1511011}, pmid = {40271071}, issn = {1663-9812}, abstract = {Neurodegenerative diseases are caused by the progressive degeneration of neurons and/or their myelin sheaths, ultimately leading to cognitive and motor dysfunction. Due to their complex pathogenesis and the limited efficacy of therapeutic drugs, these diseases have attracted significant attention. Achyranthes aspera, belongs to family Amaranthaceae, has been extensively used in the traditional and folk medicines for the treatment of various ailments. Modern research has revealed that Achyranthes aspera possesses various pharmacological effects, including cardiocerebrovascular protection, immune regulation, antioxidation, and anti-aging. Furthermore, the neuroprotective effects of Achyranthes aspera have been confirmed by numerous scientific studies. This review focuses on the primary pharmacological effects and mechanisms of Achyranthes aspera in the prevention and treatment of neurodegenerative diseases, as well as their potential application prospects. This review aims to provide insights into the potential clinical applications and research directions of Achyranthes aspera in neurodegenerative diseases.}, }
@article {pmid40267187, year = {2025}, author = {Guillaud, L and Garanzini, A and Zakhia, S and De la Fuente, S and Dimitrov, D and Boerner, S and Terenzio, M}, title = {Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.}, journal = {Science advances}, volume = {11}, number = {17}, pages = {eadq6077}, doi = {10.1126/sciadv.adq6077}, pmid = {40267187}, issn = {2375-2548}, mesh = {*Adenosine Triphosphate/metabolism ; Humans ; Animals ; *Protein Aggregation, Pathological/metabolism/pathology ; Mice ; *Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Axons/metabolism ; Viscosity ; Mitochondria/metabolism ; Protein Aggregates ; Parkinson Disease/metabolism/pathology ; DNA-Binding Proteins/metabolism ; Alzheimer Disease/metabolism/pathology ; }, abstract = {Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular adenosine triphosphate (ATP) regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondrial inhibition leads to axoterminal cytosol, synaptic vesicles, and active zone component condensation, modulating the functional organization of mouse glutamatergic synapses. Proteins involved in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) condensed and underwent ATP-dependent liquid phase separation in vitro. Human inducible pluripotent stem cell-derived neurons from patients with PD and ALS displayed reduced axoplasmic fluidity and decreased intracellular ATP. Last, nicotinamide mononucleotide treatment successfully rescued intracellular ATP levels and axoplasmic viscosity in neurons from patients with PD and ALS and reduced TAR DNA-binding protein 43 (TDP-43) aggregation in human motor neurons derived from a patient with ALS. Thus, our data suggest that the hydrotropic activity of ATP contributes to the regulation of neuronal homeostasis under both physiological and pathological conditions.}, }
@article {pmid40262868, year = {2025}, author = {Shi, Y and Wu, Z and Cheng, R and Zhang, L and Guo, X and Li, X and Bi, Y}, title = {The Trp-574-Leu mutations together with enhanced metabolism contribute to cross-resistance to ALS inhibiting herbicides in Fimbristylis littoralis.}, journal = {Pesticide biochemistry and physiology}, volume = {210}, number = {}, pages = {106385}, doi = {10.1016/j.pestbp.2025.106385}, pmid = {40262868}, issn = {1095-9939}, abstract = {Fimbristylis littoralis Gaudich., an important weed in Chinese paddy fields, has caused significant yield losses in rice and other crops. Acetolactate synthase (ALS) inhibitors, such as halosulfuron-methyl, are widely used for weed control. This study identified a highly resistant population (R23-1) of F. littoralis to halosulfuron-methyl, with an exceptionally high resistance index (RI) of 3441.66. The resistant mechanisms of F. littoralis to ALS inhibitors have not been reported previously. We employed a comprehensive approach to address this, including whole-plant bioassay, ALS target gene sequencing, molecular docking, synergistic tests with metabolic enzyme inhibitors, glutathione S-transferases (GSTs) activity assays, and cross-resistance testing. The results revealed the first report of a Trp-574-Leu mutation in the ALS gene of the R23-1 population, which significantly increased binding energy, as shown by molecular docking analysis. Synergistic tests demonstrated that the cytochrome P450 monooxygenase (P450) inhibitor piperonyl butoxide (PBO) and the GSTs inhibitor 4-chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) markedly enhanced the sensitivity of the R23-1 population to halosulfuron-methyl, with synergistic ratios of 4.11 and 8.15, respectively, while malathion had no effect. GST activity decreased in both populations after halosulfuron-methyl treatment, with the R23-1 population consistently showing significantly higher levels, peaking on day five. Furthermore, the R23-1 population demonstrated cross-resistance to multiple ALS inhibitors. These findings provide novel insights into the resistance mechanisms of F. littoralis and lay a theoretical foundation for developing effective strategies to mitigate or delay the evolution of resistance.}, }
@article {pmid40262277, year = {2025}, author = {Turner, N and Palmer, J and Faull, C and Davidson, S and Turner, MR and Wilson, E}, title = {Tracheostomy ventilation in ALS: healthcare practitioner perspectives on quality of life and implications for decision-making.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2025.2495014}, pmid = {40262277}, issn = {2167-9223}, abstract = {Objectives: This qualitative study aimed to increase understanding of how healthcare practitioners (HCPs) perceive quality of life for people with ALS who use tracheostomy ventilation (TV) and the extent to which such views inform discussions regarding future treatment and care. Methods: A thematic analysis was applied to data derived from online semi-structured interviews with a professionally diverse group of 24 HCPs with experience of supporting people with ALS to use TV. Results: Four main themes relating to TV use emerged: i) Positive benefits; ii) Risks and challenges; iii) Factors influencing HCP perspectives; iv) Concepts informing HCP discussions. HCPs acknowledged that TV has the potential to extend life but were concerned with prolonging a serious decline in physical and cognitive functioning. HCPs tried to identify the 'tipping point' between quantity and quality of life for the individual and their family, taking into account the likelihood of a higher burden of care. HCPs drew on prior experience to assess anticipated quality of life, yet most HCPs in the UK have limited experience of TV for this group. HCPs also drew on principles of person-centered care, patient autonomy and value for money to guide their approach to discussing TV. Conclusions: HCP experience of positive outcomes of TV can foster a more proactive approach to initiating conversations about its potential use. Sharing best practice and improving guidance for HCPs may support early and on-going future care planning and enable people with ALS to make choices which are informed and in their best interests.}, }
@article {pmid40261116, year = {2025}, author = {Shneider, NA and Nesta, AV and Rifai, OM and Yasek, J and Elyaman, W and Aziz-Zaman, S and Lyu, MA and Levy, SHS and Hoover, BN and Vlad, G and Huang, M and Zeng, K and Sadeghi, T and Reddy, A and Flowers, CR and Parmar, S}, title = {Clinical Safety and Preliminary Efficacy of Regulatory T Cells for ALS.}, journal = {NEJM evidence}, volume = {4}, number = {5}, pages = {EVIDoa2400249}, doi = {10.1056/EVIDoa2400249}, pmid = {40261116}, issn = {2766-5526}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Middle Aged ; *T-Lymphocytes, Regulatory/transplantation ; Female ; Male ; Aged ; Adult ; Biomarkers/blood ; Treatment Outcome ; Neurofilament Proteins/blood ; }, abstract = {BACKGROUND: Peripheral and neuroinflammation have been previously associated with progression in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease involving progressive loss of motor neurons. We hypothesize that regulatory T cell (Treg) therapy can resolve inflammation and preserve function in those patients with ALS.<br><br>METHODS: Participants with ALS received infusions of a fixed dose (100&#xd7;10[6] cells) of umbilical cord blood-derived, allogeneic, nonhuman leukocyte antigen-matched, cryopreserved Treg product (TREG), administered as four weekly infusions followed by six monthly infusions. No lymphodepletion, immunosuppression, or interleukin 2 was administered. The primary outcome was dose-limiting toxicity, including infusion reaction within 24 hours (as graded by National Cancer Institute - Common Terminology Criteria for Adverse Events, Version 4.0) and/or regimen-related death, or grade 3 or 4 cytokine release syndrome within 14 days postinfusion. We measured clinical response using the Revised ALS Functional Rating Scale (ALSFRS-R; range 0 to 48, with lower numbers indicating lower functional ability). Exploratory analyses measured serum and plasma neurofilament light (NfL) and inflammatory biomarkers.<br><br>RESULTS: Six participants with a median age of 48.5 years (range 27 to 66 years) and baseline ALSFRS-R score of 31.5 (range 23 to 43) were treated with a median of 11 (range 6 to 22) TREG infusions in an ambulatory setting. No dose-limiting toxicity was observed. In participants with sufficient data points (n=4), the mean ALSFRS-R slope of decline was -1.66&#xb1;1.03 points/month before treatment, -0.41&#xb1;0.45/month during treatment, and -0.60&#xb1;0.59/month posttreatment. Biomarkers including NfL and inflammatory markers MIP-1&#x3b4; (macrophage inflammatory protein-1 delta), CTACK (cutaneous T cell-attracting chemokine), and GRO&#x3b1; (growth-regulated oncogene alpha) exhibited different relationships with ALSFRS-R score between participants.<br><br>CONCLUSIONS: This study demonstrates the preliminary safety of "off-the-shelf", allogeneic Treg-cell therapy.}, }
@article {pmid40255098, year = {2025}, author = {Regnault, R and Kouach, M and Goossens, L and Thuru, X and Bailly, C and Goossens, JF}, title = {HR-MS Analysis of the Covalent Binding of Edaravone to 5-Formylpyrimidine Bases and a DNA Oligonucleotide Containing a 5-Formylcytidine Residue.}, journal = {Rapid communications in mass spectrometry : RCM}, volume = {39}, number = {14}, pages = {e10050}, doi = {10.1002/rcm.10050}, pmid = {40255098}, issn = {1097-0231}, support = {//Comit&#xe9; de l'Oise de la Ligue Contre le Cancer/ ; //French Ligue Against Cancer/ ; }, mesh = {Edaravone/chemistry ; *Mass Spectrometry/methods ; *Oligonucleotides/chemistry/metabolism ; *Pyrimidines/chemistry ; *DNA/chemistry ; *Cytidine/chemistry/analogs &amp; derivatives ; Cytosine/analogs &amp; derivatives ; }, abstract = {RATIONALE: Edaravone (EDA) is a radical scavenger and an antioxidant drug approved to treat amyotrophic lateral sclerosis and used as a research tool to explore treatment of neurodegenerative diseases and cancers. It is also a reactive agent, known as PMP (1-phenyl-3-methyl-5-pyrazolone), used for the analysis of polysaccharides composition. EDA can react with sugars and aromatic aldehydes. In this context, we have investigated the reactivity of EDA toward the biologically relevant formylated nucleobases, nucleosides, and an oligonucleotide containing a formylated residue.<br><br>METHODS: The formation of both mono- and bis-adducts between EDA and the formylated nucleobases (5-formyluracil (5fU) and 5-formylcytosine (5fC)) or the corresponding nucleosides 5-fdU and 5-fdC was characterized using high-resolution mass spectrometry (HR-MS). Similarly, the covalent binding of EDA to an 8-mer palindromic oligonucleotide d (TATG[*C]ATA) containing a single 5-fdC residue [*C] under physiological conditions was investigated using mass spectrometry.<br><br>RESULTS: For the first time, EDA is shown to react with formylated pyrimidines. Covalent and stable adducts were identified. EDA was found to react efficiently with the formylated oligonucleotide to generate mono- and bis-adducts. The rate of formation of the mono-adduct was five times higher than that of the bis-adduct. The reaction of EDA with aldehydic DNA modifications such as 5fU/5fC may have important consequences in terms of gene expression.<br><br>CONCLUSIONS: These observations raise implications for an epigenetic contribution to the mechanism of action of EDA. The biological implications of our in&#xa0;vitro results are discussed, notably in the frame of neurodegenerative diseases and cancers.}, }
@article {pmid40251832, year = {2025}, author = {Bresque, M and Esteve, D and Balmer, G and Hamilton, HL and Stephany, JS and Pehar, M and Vargas, MR}, title = {FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia.}, journal = {Glia}, volume = {}, number = {}, pages = {}, doi = {10.1002/glia.70023}, pmid = {40251832}, issn = {1098-1136}, support = {R01NS122973/NH/NIH HHS/United States ; R01NS132760/NH/NIH HHS/United States ; }, abstract = {Fatty acid binding proteins (FABPs) are a family of small proteins involved in fatty acid (FA) subcellular trafficking. In the adult central nervous system, FABP7, one of the members of this family, is highly expressed in astrocytes and participates in lipid metabolism, regulation of gene expression, and energy homeostasis. Reactive astrocytes in Alzheimer's disease and amyotrophic lateral sclerosis animal models upregulate FABP7 expression. This upregulation may contribute to the pro-inflammatory phenotype that astrocytes display during neurodegeneration and is detrimental for co-cultured neurons. Here, we explore how FABP7 expression modulates astrocyte response to inflammatory stimuli. Our results showed that silencing FABP7 expression in astrocyte cultures before treatment with different inflammatory stimuli decreases the expression of a luciferase reporter expressed under the control of NF-κB -response elements. Correspondingly, FABP7-silenced astrocytes display decreased nuclear translocation of the NF-κB-p65 subunit in response to these stimuli. Moreover, silencing FABP7 decreases the toxicity of stimulated astrocytes toward co-cultured motor neurons. Similar results were obtained after silencing FABP7 in human astrocytes differentiated from induced pluripotent stem cells. Finally, knockdown of astrocytic FABP7 expression in vivo reduces glial activation in the cerebral cortex of mice after systemic bacterial lipopolysaccharide (LPS) administration. In addition, whole transcriptome RNA sequencing analysis from the cerebral cortex of LPS-treated mice showed a differential inflammatory transcriptional profile, with attenuation of NF-κB-dependent transcriptional response after FABP7 knockdown. Together, our results highlight the potential of FABP7 as a target to modulate neuroinflammation in the central nervous system.}, }
@article {pmid40250093, year = {2025}, author = {Casiraghi, V and Pellegrini, E and Brusati, A and Peverelli, S and Invernizzi, S and Santangelo, S and Colombrita, C and Verde, F and Ticozzi, N and Silani, V and Ratti, A}, title = {Characterization of human healthy i[3] lower motor neurons exposed to CSF from ALS patients stratified by UNC13A and C9ORF72 genotype.}, journal = {Journal of the neurological sciences}, volume = {473}, number = {}, pages = {123508}, doi = {10.1016/j.jns.2025.123508}, pmid = {40250093}, issn = {1878-5883}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons. Neurodegeneration in ALS might be driven by proteotoxicity or neuroinflammation, which have also been proposed to be promoted by toxic components of the cerebrospinal fluid (CSF). We investigated the possible toxicity of ALS CSF on healthy induced pluripotent stem cells (iPSC)-derived integrated, inducible, and isogenic lower motor neurons (i[3]LMNs). CSFs were obtained from ALS patients homozygous for the risk UNC13A rs12608932 single nucleotide polymorphism (CC) and for the corresponding major allele (AA), ALS patients with C9ORF72 hexanucleotide repeat expansion, and individuals affected by normal pressure hydrocephalus as non-disease controls (ND). A chronic and low-dose sodium arsenite (ARS) treatment was used as positive control of oxidative stress. We found that 10 % ALS CSF treatment for 48 h was not sufficient to induce significant alterations in viability, autophagic flux, axonal degeneration, DNA damage, and Golgi apparatus integrity in healthy i[3]LMNs, in contrast to ARS treatment. Only UNC13A CC CSF significantly increased protein aggregation and Golgi apparatus fragments dimension. RNA-sequencing revealed that all ALS and ND CSFs induced expression changes of few genes, while chronic ARS deregulated the expression of thousands of genes, mostly involved in inflammation and synapse biology. In this work, we demonstrated that in our experimental settings only CSF from UNC13A CC patients induced some ALS-associated pathological features in healthy i[3]LMNs. Further studies will be required to elucidate the mechanistic link between the risk UNC13A genotype and CSF composition and toxicity.}, }
@article {pmid40244061, year = {2025}, author = {Tseriotis, VS and Liampas, A and Lazaridou, IZ and Karachrysafi, S and Vavougios, GD and Hadjigeorgiou, GM and Papamitsou, T and Kouvelas, D and Arnaoutoglou, M and Pourzitaki, C and Mavridis, T}, title = {Repulsive Guidance Molecule-A as a Therapeutic Target Across Neurological Disorders: An Update.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26073221}, pmid = {40244061}, issn = {1422-0067}, mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; *Nerve Tissue Proteins/metabolism/antagonists &amp; inhibitors/genetics ; *GPI-Linked Proteins/metabolism/antagonists &amp; inhibitors/genetics ; Molecular Targeted Therapy ; Neurodegenerative Diseases/metabolism/drug therapy ; }, abstract = {Repulsive guidance molecule-a (RGMa) has emerged as a significant therapeutic target in a variety of neurological disorders, including neurodegenerative diseases and acute conditions. This review comprehensively examines the multifaceted role of RGMa in central nervous system (CNS) pathologies such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuromyelitis optica spectrum disorder, spinal cord injury, stroke, vascular dementia, auditory neuropathy, and epilepsy. The mechanisms through which RGMa contributes to neuroinflammation, neuronal degeneration, and impaired axonal regeneration are herein discussed. Evidence from preclinical studies associate RGMa overexpression with negative outcomes, such as increased neuroinflammation and synaptic loss, while RGMa inhibition, particularly the use of agents like elezanumab, has shown promise in enhancing neuronal survival and functional recovery. RGMa's responses concerning immunomodulation and neurogenesis highlight its potential as a therapeutic avenue. We emphasize RGMa's critical role in CNS pathology and its potential to pave the way for innovative treatment strategies in neurological disorders. While preclinical findings are encouraging so far, further clinical trials are needed to validate the safety and efficacy of RGMa-targeted therapies.}, }
@article {pmid40237254, year = {2025}, author = {Russek, M and Peltner, J and Haenisch, B}, title = {Supplementing Single-Arm Trials with External Control Arms-Evaluation of German Real-World Data.}, journal = {Clinical pharmacology and therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1002/cpt.3684}, pmid = {40237254}, issn = {1532-6535}, abstract = {As single-arm trials (SATs) are increasingly used in pharmaceutical research, the validity of such study designs needs to be critically assessed. We characterize the feasibility of supplementing SATs with real-world data (RWD)-derived external control arms by determining the proportion of SATs on breast cancer and amyotrophic lateral sclerosis (ALS) for which an external control arm based on RWD can be constructed. The main outcome measure is the number and percentage of trials for which all important eligibility criteria and at least one primary endpoint could be identified in one of five German RWD sources. We surveyed all SATs concerning breast cancer or ALS treatment registered in the European Union's clinical trial registers between 2004 and 2023. Ten out of 379 breast cancer SATs and 2 of 11 ALS SATs could feasibly be supplemented with RWD-derived external control arms, if all important eligibility criteria and a primary endpoint have to be identifiable in the RWD source. Ninety-three breast cancer trials had at least one outcome ascertainable in a RWD source, and 35 trials had all important eligibility criteria recorded in a RWD source. Nine ALS trials had at least one primary endpoint ascertainable in RWD sources, and 2 had all important eligibility criteria recorded in a RWD source. Our study shows that SATs with RWD-derived external control arms will rarely be suitable to establish treatment effects of medicines in the current setting for the investigated phenotypes and that SATs should be designed with limitations of the source of external controls in mind.}, }
@article {pmid40235867, year = {2025}, author = {Sundararaju, U and Rajakumar, HK}, title = {Prognostic value of neutrophil-to-lymphocyte ratio in gastric cancer: Enhancing clinical relevance.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {4}, pages = {103128}, pmid = {40235867}, issn = {1948-5204}, abstract = {Gastric cancer (GC) is a leading cause of cancer-related deaths, highlighting the need for reliable prognostic biomarkers to guide treatment. Wei et al's systematic review and meta-analysis evaluates the neutrophil-to-lymphocyte ratio (NLR) as a potential biomarker for GC patients undergoing neoadjuvant chemotherapy. NLR is a simple and cost-effective measure of systemic inflammation that shows promise in predicting treatment response and survival outcomes, including overall survival and progression-free survival. However, variations in NLR thresholds and timing of measurements affect its accuracy and clinical utility. Moreover, the studies reviewed primarily involved Asian populations, which may limit the generalizability of the findings. To improve NLR's clinical relevance, future research should focus on standardizing NLR thresholds, refining measurement timing, and incorporating additional inflammatory markers like platelet-to-lymphocyte ratio and Glasgow prognostic score. Addressing confounders and including diverse patient populations will help improve NLR's reliability as a prognostic marker for GC.}, }
@article {pmid40229540, year = {2025}, author = {Ghimire, S and Kreilaus, F and Rosa Porto, R and Anderson, LL and Yerbury, JJ and Arnold, JC and Karl, T}, title = {Behavioural effects of oral cannabidiol (CBD) treatment in the superoxide dismutase 1 G93 A (SOD1[G93 A]) mouse model of amyotrophic lateral sclerosis.}, journal = {Psychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {40229540}, issn = {1432-2072}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting voluntary muscle movement as well as cognitive and other behavioural domains at later disease stages. No effective treatment for ALS is currently available. Elevated neuroinflammation, oxidative stress and alterations to the endocannabinoid system are evident in ALS. The phytocannabinoid cannabidiol (CBD) has anti-inflammatory and anti-oxidant properties. Thus, we evaluated the remedial effects of chronic oral cannabidiol (CBD) treatment on ALS-relevant behavioural domains in the copper-zinc superoxide dismutase 1 (SOD1) mouse model of ALS that carries a G93A mutation (SOD1[G93A]).<br><br>METHODS: Male and female SOD1[G93A] and wild&#xa0;type-like (WT) littermates were fed either a control (CHOW) or CBD-enriched chow diet (equivalent to a dose of 36 mg/kg per day) beginning from 10 weeks of age. Bodyweight and motor performance were recorded weekly from 11 to 19 weeks and open field behaviours at 12 and 18 weeks. Mice were also tested for prepulse inhibition (PPI), social behaviours, as well as fear-associated memory.<br><br>RESULTS: CBD treatment ameliorated the bodyweight loss in female SOD1[G93A] mice, tended to reinstate sociability in SOD1[G93A] males, strengthened social recognition memory in SOD1[G93A] females, and improved the PPI response in younger SOD1[G93A] females at higher prepulse intensities. CBD had no effect on motor impairments but instead reversed the anxiolytic-like phenotype of 12-week-old male SOD1[G93A] mice and decreased the acoustic startle response and strengthened cue freezing in male mice.<br><br>CONCLUSION: Thus, the current remedial oral dose of CBD delayed disease progression (inferred by bodyweight) in both male and female mice and improve specific cognitive deficits of SOD1[G93A] mice in a sex specific manner without altering the motor phenotype.}, }
@article {pmid40226510, year = {2025}, author = {Ufarry Alvarado, AJ and Zaidi Pons, MA and Plaza Hernández, J and Torres Ortiz, C}, title = {Improvements of Paraquat Treatment in Liquid Media for Behavior and Neurodegenerative Tests.}, journal = {microPublication biology}, volume = {2025}, number = {}, pages = {}, pmid = {40226510}, issn = {2578-9430}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a disease characterized by misfolded and aggregated proteins that have toxic effects on motor neurons. The missense mutation, G85R, of the sod-1 gene associated with ALS displays locomotor impairments in Caenorhadbitis elegans (C. elegans). We treated the sod-1 (G85R) strain with 0 and 2.5 mM Paraquat treatments in a liquid M9 buffer for 4 hours and in solid NGM media for 18 hours. In both methodologies, the locomotion defects and neurodegeneration were significantly increased with 2.5 mM Paraquat. Our work provides evidence of methodology that is more cost effective, rapid and reproducible to perform behavior and neurodegenerative assay in worms.}, }
@article {pmid40222103, year = {2025}, author = {Lum, JS and Brown, ML and Farrawell, NE and Bartlett, R and Chisholm, CG and Gorman, J and Dosseto, A and Dux, F and McInnes, LE and Ecroyd, H and McAlary, L and Crouch, PJ and Donnelly, PS and Yerbury, JJ}, title = {A polytherapy approach demonstrates therapeutic efficacy for the treatment of SOD1 associated amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {115}, number = {}, pages = {105692}, doi = {10.1016/j.ebiom.2025.105692}, pmid = {40222103}, issn = {2352-3964}, abstract = {BACKGROUND: SOD1 mutations are a significant contributor of familial amyotrophic lateral sclerosis (ALS) cases. SOD1 mutations increase the propensity for the protein to misfold and aggregate into insoluble proteinaceous deposits within motor neurons and neighbouring cells. The small molecule, CuATSM, has repeatedly shown in mouse models to be a promising therapeutic treatment for SOD1-associated ALS and is currently in Phase II/III clinical trials for the treatment of ALS. We have previously shown CuATSM stabilises various ALS-associated variants of the SOD1 protein, reducing misfolding and toxicity. Two additional FDA-approved small molecules, ebselen and telbivudine, have also been identified to reduce mutant SOD1 toxicity, providing additional potential therapeutic candidates that could be used in combination with CuATSM. Here, we aimed to investigate if CuATSM, ebselen and telbivudine (CET) polytherapy could improve on the therapeutic efficacy of CuATSM monotherapy for the treatment of SOD1-associated ALS.<br><br>METHODS: We utilised a 3D checkerboard approach to investigate whether a matrix of different concentrations CuATSM, ebselen and telbivudine could provide therapeutic improvements on cell survival, SOD1 folding and aggregation in SOD1[G93A]-transfected NSC-34&#xa0;cells, compared to CuATSM alone. To progress the preclinical development of CET polytherapy, we evaluated the bioavailability and safety of in&#xa0;vivo polytherapy administration. Furthermore, we assessed and compared the effects of CET- and CuATSM-treatment on disease onset, motor function, survival and neuropathological features in SOD1[G93A] mice.<br><br>FINDINGS: CET polytherapy reduced inclusion formation and increased cell survival of NSC-34&#xa0;cells overexpressing SOD1[G93A] compared to higher concentrations of CuATSM monotherapy. In addition, CET administration was bioavailable and tolerable in mice. CET treatment in SOD1[G93A] mice delayed disease onset, reduced motor impairments, and increased survival compared to vehicle- and CuATSM-treated mice. In line with these findings, biochemical analysis of lumbar spinal cords showed CET administration improved SOD1 folding, decreased misfolded SOD1 accumulation, and reduced motor neuron loss.<br><br>INTERPRETATION: These findings support CET polytherapy as an advantageous alternative compared to CuATSM monotherapy and highlight the potential of utilising small molecules targeting SOD1 as a polytherapy avenue for the treatment of SOD1-associated ALS.<br><br>FUNDING: This work was supported by a FightMND Drug Development Grant, an Australian National Health and Medical Research Council (NHMRC) Investigator Grant (No. 1194872) and a Motor Neuron Disease Research Institute of Australia Bill Gole Postdoctoral Fellowship.}, }
@article {pmid40216746, year = {2025}, author = {Rezaei, A and Kocsis-Jutka, V and Gunes, ZI and Zeng, Q and Kislinger, G and Bauernschmitt, F and Isilgan, HB and Parisi, LR and Kaya, T and Franzenburg, S and Koppenbrink, J and Knogler, J and Arzberger, T and Farny, D and Nuscher, B and Katona, E and Dhingra, A and Yang, C and Gouna, G and LaClair, KD and Janjic, A and Enard, W and Zhou, Q and Hagan, N and Ofengeim, D and Beltrán, E and Gokce, O and Simons, M and Liebscher, S and Edbauer, D}, title = {Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {3442}, pmid = {40216746}, issn = {2041-1723}, support = {390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 407495230//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 423957469//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 101057649//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; 101117710//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; }, mesh = {Animals ; Female ; Mice ; *Oligodendroglia/metabolism/drug effects ; *Lipid Metabolism/drug effects/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy/pathology ; *C9orf72 Protein/genetics/metabolism ; Disease Models, Animal ; Male ; Cholesterol/metabolism ; Humans ; *2-Hydroxypropyl-beta-cyclodextrin/pharmacology ; Mice, Transgenic ; Myelin Sheath/metabolism ; Spinal Cord/metabolism/pathology ; Longevity/drug effects/genetics ; }, abstract = {Clinical and genetic research links altered cholesterol metabolism with ALS development and progression, yet pinpointing specific pathomechanisms remain challenging. We investigated how cholesterol dysmetabolism interacts with protein aggregation, demyelination, and neuronal loss in ALS. Bulk RNAseq transcriptomics showed decreased cholesterol biosynthesis and increased cholesterol export in ALS mouse models (GA-Nes, GA-Camk2a GA-CFP, rNLS8) and patient samples (spinal cord), suggesting an adaptive response to cholesterol overload. Consequently, we assessed the efficacy of the cholesterol-binding drug 2-hydroxypropyl-β-cyclodextrin (CD) in a fast-progressing C9orf72 ALS mouse model with extensive poly-GA expression and myelination deficits. CD treatment normalized cholesteryl ester levels, lowered neurofilament light chain levels, and prolonged lifespan in female but not male GA-Nes mice, without impacting poly-GA aggregates. Single nucleus transcriptomics indicated that CD primarily affected oligodendrocytes, significantly restored myelin gene expression, increased density of myelinated axons, inhibited the disease-associated oligodendrocyte response, and downregulated the lipid-associated genes Plin4 and ApoD. These results suggest that reducing excess free cholesterol in the CNS could be a viable ALS treatment strategy.}, }
@article {pmid40213632, year = {2025}, author = {Dezawa, M}, title = {Macrophage- and pluripotent-like reparative Muse cells are unique endogenous stem cells distinct from other somatic stem cells.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {13}, number = {}, pages = {1553382}, pmid = {40213632}, issn = {2296-4185}, abstract = {Muse cells are endogenous reparative stem cells with dual characteristics: pluripotent-like and macrophage-like. They can be identified by the pluripotent surface marker stage-specific embryonic antigen-3-positive (SSEA-3 (+)) cells in the bone marrow, peripheral blood, and various organs, including the umbilical cord and amnion. Muse cells can differentiate into ectodermal, endodermal, and mesodermal lineage cells, self-renew, and selectively migrate to damaged sites by sensing one of the universal tissue damage signals, sphingosine-1-phosphate (S1P). At these sites, they phagocytose damaged/apoptotic cells and differentiate into the same cell type as the phagocytosed cells. In this manner, Muse cells replace damaged/apoptotic cells with healthy, functioning cells, thereby repairing tissues. Due to their specific immunosuppressive and immunotolerant mechanism, clinical trials have been conducted for acute myocardial infarction (AMI), subacute ischemic stroke, epidermolysis bullosa, amyotrophic lateral sclerosis (ALS), cervical spinal cord injury, neonatal hypoxic-ischemic encephalopathy (HIE), and COVID-19 acute respiratory distress syndrome. These trials involved the intravenous injection of ∼1.5 × 10[7] donor Muse cells without human leukocyte antigen (HLA) matching or immunosuppressant treatment, and they demonstrated safety and therapeutic efficacy. Thus, donor Muse cell treatment does not require gene manipulation, differentiation induction, or surgical intervention. These unique characteristics distinguish Muse cells from other somatic stem cells, such as mesenchymal stem cells, VSEL stem cells, and marrow-isolated adult multi-lineage inducible (MIAMI) cells.}, }
@article {pmid40209696, year = {2025}, author = {Hawas, Y and Hamad, AA and Meshref, M and Elbehary, M and Mohamed, RG and Elshahat, A and Mabrouk, MA and Nashwan, AJ and Fouda, BH}, title = {Clinical Features, Diagnostic Implications, And Outcomes of Amyotrophic Lateral Sclerosis and Myasthenia Gravis Overlap Syndrome: A Systematic Review.}, journal = {Medical principles and practice : international journal of the Kuwait University, Health Science Centre}, volume = {}, number = {}, pages = {1-18}, doi = {10.1159/000545806}, pmid = {40209696}, issn = {1423-0151}, abstract = {OBJECTIVE: This review aims to summarize the current evidence of reported myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) overlap syndrome regarding clinical and laboratory features, diagnostic implications, management, outcomes, and comorbid conditions to raise awareness among healthcare providers and aid in proper care provision.<br><br>METHODS: Recently, a few cases of an unusual association between both diseases have been reported. PubMed, Scopus, and Web of Science were searched from inception until May 2024 to identify eligible studies. After the screening and data extraction, 20 studies with 42 cases suffering from ALS and MG were included.<br><br>RESULTS: 42 cases were categorized into four groups as follows: The first group had 26 cases with MG onset (range 26-82 years) preceding ALS (range 46-83 years). The second group had 9 cases with ALS (range 34-89) preceding MG (range 40-89 years). The third group comprised 5 cases of ALS with positive acetylcholine receptor antibodies but without clinical manifestations of MG. The fourth group involved 2 cases of ALS with initial ocular symptoms that were unresponsive to MG treatments.<br><br>CONCLUSION: The onset of new ptosis or diplopia in ALS patients should prompt clinicians to consider the possibility of a coexisting condition or alternative diagnosis. Additionally, positive acetylcholine receptor antibodies alone are insufficient to diagnose MG if ALS coexists. In patients with ALS, repetitive nerve stimulation tests may be less sensitive for detecting MG. Thus, diagnosing MG in ALS patients should rely on clinical presentation and response to empirical treatment.}, }
@article {pmid40209306, year = {2025}, author = {Meanti, R and Bresciani, E and Rizzi, L and Molteni, L and Coco, S and Omeljaniuk, RJ and Torsello, A}, title = {Cannabinoid Receptor 2 (CB2R) as potential target for the pharmacological treatment of neurodegenerative diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {186}, number = {}, pages = {118044}, doi = {10.1016/j.biopha.2025.118044}, pmid = {40209306}, issn = {1950-6007}, abstract = {The endocannabinoid system (ECS) is a ubiquitous physiological system that plays a crucial role in maintaining CNS homeostasis and regulating its functions. It includes cannabinoid receptors (CBRs), endogenous cannabinoids (eCBs), and the enzymes responsible for their synthesis and degradation. In recent years, growing evidence has highlighted the therapeutic potential of the ECS and CBRs, in a wide range of severe diseases and pathological conditions, including Alzheimer's and Parkinson's diseases, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Huntington's Disease, HIV-1 associated neurocognitive disorders, neuropathic pain and migraine. Targeting the cannabinoid type 2 receptor (CB2R) has gained attention due to its ability to (i) mitigate neuroinflammatory responses, (ii) regulate mitochondrial function and (iii) provide trophic support, all without eliciting the psychotropic actions associated with CB1R activation. This review aims to explore the potential of CB2R modulation as a strategy for the prevention and treatment of neurologic disorders, exploring both preclinical and clinical findings.}, }
@article {pmid40205152, year = {2025}, author = {Mohan, M and Mannan, A and Singh, TG}, title = {Unravelling the role of protein kinase R (PKR) in neurodegenerative disease: a review.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {377}, pmid = {40205152}, issn = {1573-4978}, mesh = {Humans ; *eIF-2 Kinase/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics ; Animals ; Parkinson Disease/metabolism/genetics ; Huntington Disease/genetics/metabolism ; Alzheimer Disease/metabolism/genetics ; Mitochondria/metabolism ; }, abstract = {Protein Kinase R is an essential regulator of many cell activities and belongs to one of the largest and most functionally complex gene families. These are found all over the body, and by adding phosphate groups to the substrate proteins, they regulate their activity and coordinate the action of almost all cellular processes. Recent research has illuminated the involvement of PKR in the pathogenesis of neurodegenerative disorders (NDs), thereby expanding our understanding of intricate molecular mechanisms underlying disease progression. Through their inhibition or activation, they hold potential therapeutic targets for the pathogenesis or protection of NDs. In the case of AD (AD), PKR contributes to the protection or elevation of Aβ accumulation, neuroinflammation, synaptic plasticity alterations, and neuronal excitability. Similarly, in Parkinson's disease (PD), PKR again has a dual role in dopaminergic neuronal loss, gene mutations, and mitochondrial dysfunction via various pathways. Notably, neuronal excitotoxicity, as well as genetic mutations, have been linked to ALS. In Huntington's disease (HD), PKR is associated with decreased or increased mutated genes, striatal neuron degeneration, neuroinflammation, and excitotoxicity. This review emphasizes strategies that target PKR for the treatment of neurodegenerative disorders. Doing so offers valuable insights that can guide future research endeavors and the development of innovative therapeutic approaches.}, }
@article {pmid40200577, year = {2025}, author = {Winkelsas, A and Apfel, A and Johnson, B and Harmison, G and Perez, KD and Li, D and Cheung, VG and Grunseich, C}, title = {Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.}, journal = {HGG advances}, volume = {}, number = {}, pages = {100435}, doi = {10.1016/j.xhgg.2025.100435}, pmid = {40200577}, issn = {2666-2477}, abstract = {Amyotrophic lateral sclerosis 4 (ALS4) is an autosomal dominant motor neuron disease that is molecularly characterized by reduced R-loop levels and caused by pathogenic variants in senataxin (SETX). SETX encodes an RNA/DNA helicase that resolves three-stranded nucleic acid structures called R-loops. Currently, there are no disease-modifying therapies available for ALS4. Given that SETX is haplosufficient, removing the product of the mutated allele presents a potential therapeutic strategy. We designed a series of siRNAs to selectively target the RNA transcript from the ALS4 allele containing the c.1166T>C mutation (p.Leu389Ser). Transfection of HEK293 cells with siRNA and plasmids encoding either wild-type or mutant (Leu389Ser) epitope-tagged SETX revealed that three siRNAs specifically reduced mutant SETX protein levels while having minimal effect on the wild-type SETX protein. In ALS4 primary fibroblasts, siRNA treatment silenced the endogenous mutant SETX allele, while sparing the wild-type allele, and restored R-loop levels in patient cells. Our findings demonstrate that mutant SETX, differing from wild-type by a single nucleotide, can be effectively and specifically silenced by RNA interference.}, }
@article {pmid40198473, year = {2025}, author = {Seok, HY}, title = {Critical issues in the use of edaravone for the treatment of amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {40198473}, issn = {1590-3478}, abstract = {Edaravone, along with riluzole, is a key treatment for amyotrophic lateral sclerosis (ALS), with evidence supporting its efficacy in slowing disease progression, particularly in patients with early-stage ALS. Despite its approval and increasing clinical use, several critical questions about its use remain unanswered: Can edaravone be effective as monotherapy? Is it beneficial for patients who fall outside the inclusion criteria of pivotal trials? What is the optimal duration of treatment as ALS progresses? In addition, does edaravone provide clinical benefit to patients with familial ALS? Answering these questions is essential to optimize the use of edaravone in clinical practice and to further our understanding of its role in the treatment of ALS. This review synthesizes the current evidence to address these questions and identifies areas that require further investigation.}, }
@article {pmid40196899, year = {2025}, author = {Li, S and Pandat, T and Chi, B and Moon, D and Mas, M}, title = {Management Approaches to Spastic Gait Disorders.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28402}, pmid = {40196899}, issn = {1097-4598}, abstract = {Spastic gait presents clinically as the net mechanical consequence of neurological impairments of spasticity, weakness, and abnormal synergies and their interactions with the ground reaction force in patients with upper motor neuron syndromes and with some neuromuscular diseases. It is critical to differentiate whether the primary problem is weakness or spasticity, thus better understanding different phenotypes of spastic gait disorders. Pelvic girdle abnormality plays a pivotal role in determining the clinical presentation of gait disorders, since it determines the body vector and compensatory kinetic chain reactions in the knee and ankle joints. Knee joint abnormality can be a mechanical compensation for hip and/or ankle and foot abnormality. Diagnostic nerve blocks and instrumented gait analysis may be needed for diagnosing the underlying problems and developing an individualized plan of care. A wide spectrum of treatment options has been used to manage spastic gait disorders. Some are in early and investigational stages, such as neuromodulation modalities, while others are well-developed, such as therapeutic exercise, ankle-foot orthoses, botulinum toxin treatment, and surgical interventions. Physicians and other healthcare providers who manage spastic gait disorders should be familiar with these treatment options and should employ appropriate interventions concurrently rather than serially. The most effective treatments can be selected based on careful evaluation, inputs from patients, family, and therapists, along with appropriate goal setting. Treatment plans need to be re-evaluated for effectiveness, relevance, and in concordance with disease progress. This is particularly important for patients with progressive neuromuscular diseases such as amyotrophic lateral sclerosis.}, }
@article {pmid40196013, year = {2025}, author = {Viteri, JA and Kerr, NR and Brennan, CD and Kick, GR and Wang, M and Ketabforoush, A and Snyder, HK and Moore, PJ and Darvishi, FB and Dashtmian, AR and Ayyagari, SN and Rich, K and Zhu, Y and Arnold, WD}, title = {Targeting senescence in Amyotrophic Lateral Sclerosis: senolytic treatment improves neuromuscular function and preserves cortical excitability in a TDP-43Q331K mouse model.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-6081213/v1}, pmid = {40196013}, issn = {2693-5015}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron degeneration in the primary motor cortex (PMC) and spinal cord. Aging is a key factor in ALS onset and progression, with evidence suggesting that biological aging-a process involving cellular decline- far outpaces chronological aging in ALS. This promotes senescent cell accumulation-marked by irreversible cell-cycle arrest, impaired apoptosis, and chronic inflammation-disrupting tissue homeostasis and impairing neuronal support functions. Thus, targeting senescence presents a novel therapeutic strategy for ALS. Here, we investigated the senolytic combination Dasatinib and Quercetin (D&amp;Q) in TDP-43 [Q331K] ALS mice. D&amp;Q improved neuromuscular function and reduced plasma neurofilament light chain, a biomarker of axonal damage. The most pronounced improvement was the improved cortical excitability, accompanied by reductions in senescence and TDP-43 in the PMC. These findings highlight the potential of senolytics to mitigate ALS-related dysfunction, supporting their viability as a therapeutic strategy. *Jose A. Viteriab, Nathan R. Kerrab, and Charles D. Brennana are co-first authors.}, }
@article {pmid40188375, year = {2025}, author = {Prajapati, JL and Dhurandhar, Y and Singh, AP and Gupta, DK and Baghel, VS and Kushwaha, U and Namdeo, KP}, title = {Redox chemical delivery system: an innovative strategy for the treatment of neurodegenerative diseases.}, journal = {Expert opinion on drug delivery}, volume = {}, number = {}, pages = {}, doi = {10.1080/17425247.2025.2489558}, pmid = {40188375}, issn = {1744-7593}, abstract = {INTRODUCTION: It is anticipated that the prevalence of illnesses affecting the central nervous system (CNS) will rise significantly due to longer lifespans and changing demography. Age-related decline in brain function and neuronal death are features of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, which provide formidable treatment challenges. Because most therapeutic drugs cannot pass across the blood-brain barrier (BBB) to reach the brain, there are still few treatment alternatives available despite a great deal of research.<br><br>AREAS COVERED: This study explores the role of redox chemical delivery systems in CNS drug delivery and addresses challenges associated with neurodegenerative disease (ND). Redox Chemical Delivery System offers a promising approach to enhancing leveraging redox reactions that facilitate the transport of therapeutic agents across the BBB. Through the optimization of medication delivery pathways to the brain, this technology has the potential to greatly improve the treatment of ND.<br><br>EXPERT OPINION: As our understanding of the biological underpinnings of ND deepens, the potential for effective interventions increases. Refining drug delivery strategies, such as RCDS, is essential for advancing CNS therapies from research to clinical practice. These advancements could transform the management of ND, improving both treatment efficacy and patient outcomes.}, }
@article {pmid40187044, year = {2025}, author = {Fu, Y and Zhang, J and Qin, R and Ren, Y and Zhou, T and Han, B and Liu, B}, title = {Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases.}, journal = {Pharmacological reviews}, volume = {77}, number = {3}, pages = {100053}, doi = {10.1016/j.pharmr.2025.100053}, pmid = {40187044}, issn = {1521-0081}, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of "chasing and escaping" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.}, }
@article {pmid40185536, year = {2025}, author = {Uzgiris, AJ and Ladic, LA and Pfister, SX}, title = {Advances in neurofilament light chain analysis.}, journal = {Advances in clinical chemistry}, volume = {126}, number = {}, pages = {31-71}, doi = {10.1016/bs.acc.2025.01.006}, pmid = {40185536}, issn = {2162-9471}, mesh = {*Neurofilament Proteins/analysis ; Humans ; Biomarkers/analysis ; *Nervous System Diseases/diagnosis/metabolism ; }, abstract = {This chapter provides a comprehensive summary of clinical laboratory testing for neurofilament light chain (NfL) in neurologic disease. A primer on the NfL structure and function is presented with its potential use as a biomarker. The most widely utilized methods for NfL in biologic samples are highlighted and examined. Limitations of current knowledge are considered, as are outstanding questions related to dissemination and standardization of testing. Herein we focus on methods available today and those in development for clinical use. In the final section, a broad vision is presented of how NfL may be utilized in the future to improve diagnosis and treatment of neurologic diseases as well as for maintaining health.}, }
@article {pmid40181198, year = {2025}, author = {Manolopoulos, A and Yao, PJ and Kapogiannis, D}, title = {Extracellular vesicles: translational research and applications in neurology.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {40181198}, issn = {1759-4766}, abstract = {Over the past few decades, extensive basic, translational and clinical research has been devoted to deciphering the physiological and pathogenic roles of extracellular vesicles (EVs) in the nervous system. The presence of brain cell-derived EVs in the blood, carrying diverse cargoes, has enabled the development of predictive, diagnostic, prognostic, disease-monitoring and treatment-response biomarkers for various neurological disorders. In this Review, we consider how EV biomarkers can bring us closer to understanding the complex pathogenesis of neurological disorders such as Alzheimer disease, Parkinson disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis and multiple sclerosis. We describe how translational research on EVs might unfold bidirectionally, proceeding from basic to clinical studies but also in the opposite direction, with biomarker findings in the clinic leading to novel hypotheses that can be tested in the laboratory. We demonstrate the potential value of EVs across all stages of the therapeutic development pipeline, from identifying therapeutic targets to the use of EVs as reporters in model systems and biomarkers in clinical research. Finally, we discuss how the cargo and physicochemical properties of naturally occurring and custom-engineered EVs can be leveraged as novel treatments and vehicles for drug delivery, potentially revolutionizing neurotherapeutics.}, }
@article {pmid40180646, year = {2025}, author = {Temiz, K and Gul, A and Gov, E}, title = {5-Repurposed Drug Candidates Identified in Motor Neurons and Muscle Tissues with Amyotrophic Lateral Sclerosis by Network Biology and Machine Learning Based on Gene Expression.}, journal = {Neuromolecular medicine}, volume = {27}, number = {1}, pages = {24}, pmid = {40180646}, issn = {1559-1174}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Humans ; *Machine Learning ; *Motor Neurons/metabolism/drug effects ; *Drug Repositioning/methods ; Transcriptome ; Gene Expression Profiling ; *Muscle, Skeletal/metabolism ; Gene Regulatory Networks ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that leads to motor neuron degeneration, muscle weakness, and respiratory failure. Despite ongoing research, effective treatments for ALS are limited. This study aimed to apply network biology and machine learning (ML) techniques to identify novel repurposed drug candidates for ALS. In this study, we conducted a meta-analysis using 4 transcriptome data in ALS patients (including motor neuron and muscle tissue) and healthy controls. Through this analysis, we uncovered common shared differentially expressed genes (DEGs) separately for motor neurons and muscle tissue. Using common DEGs as proxies, we identified two distinct clusters of highly clustered differential co-expressed cluster genes: the 'Muscle Tissue Cluster' for muscle tissue and the 'Motor Neuron Cluster' for motor neurons. We then evaluated the performance of the nodes of these two modules to distinguish between diseased and healthy states with ML algorithms: KNN, SVM, and Random Forest. Furthermore, we performed drug repurposing analysis and text-mining analyses, employing the nodes of clusters as drug targets to identify novel drug candidates for ALS. The potential impact of the drug candidates on the expression of cluster genes was predicted using linear regression, SVR, Random Forest, Gradient Boosting, and neural network algorithms. As a result, we identified five novel drug candidates for the treatment of ALS: Nilotinib, Trovafloxacin, Apratoxin A, Carboplatin, and Clinafloxacin. These findings highlight the potential of drug repurposing in ALS treatment and suggest that further validation through experimental studies could lead to new therapeutic avenues.}, }
@article {pmid40176466, year = {2025}, author = {Zhang, Y and Robinson, K and Xia, Y and Sun, J}, title = {Synergistic Effects of Riluzole and Sodium Butyrate on Barrier Function and Disease Progression of Amyotrophic Lateral Sclerosis Through the Gut-Neuron Axis.}, journal = {Comprehensive Physiology}, volume = {15}, number = {2}, pages = {e70009}, pmid = {40176466}, issn = {2040-4603}, support = {R01DK114126/NH/NIH HHS/United States ; R01DK105118/NH/NIH HHS/United States ; R01DK134343/NH/NIH HHS/United States ; I01BX004824-06//U.S. Department of Veterans Affairs/ ; }, mesh = {Animals ; *Riluzole/pharmacology/therapeutic use/administration &amp; dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology ; Mice ; *Butyric Acid/pharmacology/therapeutic use ; Disease Progression ; *Neuroprotective Agents/pharmacology ; Male ; Mice, Transgenic ; Drug Synergism ; Disease Models, Animal ; *Neurons/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Emerging evidence has shown that gut-brain barrier dysfunction occurs at the early stages of ALS. Previous studies demonstrated that sodium butyrate significantly prolonged the life span of ALS mice. Riluzole is the first FDA-approved drug for ALS treatment. We hypothesize that Riluzole and sodium butyrate combined treatment further decreases aggregation of the h-SOD1[G93A], restores the gut-brain barrier function, and delays ALS progression. SOD1[G93A] mice (9-10-week-old) were treated with Riluzole (10 mg/kg, I.P. daily), sodium butyrate (2% in drinking water), or Riluzole and sodium butyrate combination for 6 weeks. The Riluzole/butyrate combination showed a significantly longer rotarod time, increased grip strength, and enhanced intestinal barrier, as compared with Riluzole or sodium butyrate-only treatment. More reduction of h-SOD1[G93A] aggregation was observed in the colon, spinal cord lumbar, and brain cortex with Riluzole and sodium butyrate combination, compared with Riluzole or sodium butyrate-only treatment. Tight junction proteins (ZO-1 and Claudin-5) significantly increased in the colon, spinal cord lumbar, and brain cortex of mice with Riluzole and sodium butyrate treatment. The Riluzole and sodium butyrate combination reduced serum lipopolysaccharides and h-SOD1[G93A] aggregation, and inflammatory cytokines more than those in Riluzole or sodium butyrate-only treatment. Overall, Riluzole and sodium butyrate treatment is more effective than either Riluzole or sodium butyrate-only in delaying ALS progress. It provides a potential therapeutic strategy and mechanism by restoring barrier function through the gut-brain axis for ALS.}, }
@article {pmid40170672, year = {2025}, author = {Schneck, D and Arguedas, A and Xenopoulos-Oddsson, A and Arcila-Londono, X and Lunetta, C and Wymer, J and Olney, N and Gwathmey, K and Ajroud-Driss, S and Hayat, G and Heiman-Patterson, T and Cerri, F and Fournier, C and Glass, J and Sherman, A and Fiecas, M and Walk, D}, title = {Time-to-event prediction in ALS using a landmark modeling approach, using the ALS Natural History Consortium dataset.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2025.2482943}, pmid = {40170672}, issn = {2167-9223}, abstract = {BACKGROUND AND OBJECTIVES: Times to clinically relevant events are a valuable outcome in observational and interventional studies, complementing linear outcomes such as functional rating scales and biomarkers. In ALS, there are several clinically relevant events. We developed dynamic prediction models for several of these times to events that can be used for clinical trial modeling and personal planning.<br><br>METHODS: Landmark time-to-event analysis was implemented to determine the effect of patient characteristics on disease progression. Longitudinal data from 1557 participants in the ALS Natural History Consortium dataset were used. Five outcomes in the ALS disease progression were considered: loss of ambulation, loss of speech, gastrostomy, noninvasive ventilation (NIV) use, and continuous NIV use. Covariates in our models include age at diagnosis, sex, onset location, riluzole use, diagnostic delay, ALSFRS-R scores at the landmark time, and ALSFRS-R rates of change from baseline. Internal and external validation techniques were used.<br><br>RESULTS: For each of our models and landmark times, we present risk prediction intervals for random sets of patient characteristics. We demonstrate our models' application for an individual's personal predicted time-to-event. Our internal and external validation metrics indicate good concordance and overall performance. The time to loss of speech models perform the best for each metric in terms of both internal and external validation.<br><br>DISCUSSION: Landmarking is an efficient, individualized risk prediction model that is intuitive for both clinicians and patients. Importantly, landmarking can be used for clinical trial modeling, personal planning, and development of real-world evidence of the impacts of treatment interventions.}, }
@article {pmid40169784, year = {2025}, author = {Simonini, C and Zucchi, E and Martinelli, I and Gianferrari, G and Lunetta, C and Sorarù, G and Trojsi, F and Pepe, R and Piras, R and Giacchino, M and Banchelli, F and Mandrioli, J}, title = {Neurodegenerative and neuroinflammatory changes in SOD1-ALS patients receiving tofersen.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {11034}, pmid = {40169784}, issn = {2045-2322}, support = {Ricerca Corrente funding scheme of the Italian Ministry of Health//Ministero della Salute/ ; Ricerca Finalizzata bando 2021 (RF-2021-12373036)//Ministero della Salute/ ; bando FAR 2021, Progetti di ricerca Interdisciplinari Mission Oriented, NEURALS project)//Universit&#xe0; Degli Studi di Modena e Reggio Emila/ ; Neurobiobanca di Modena//Fondazione Cassa di Risparmio di Modena/ ; }, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy/cerebrospinal fluid ; Middle Aged ; *Neurofilament Proteins/cerebrospinal fluid/blood ; *Biomarkers/blood/cerebrospinal fluid ; *Superoxide Dismutase-1 ; *alpha 1-Antitrypsin/blood ; Disease Progression ; Aged ; Adult ; Chitinase-3-Like Protein 1/blood/cerebrospinal fluid ; Neuroinflammatory Diseases/drug therapy ; }, abstract = {The initiation of tofersen, a new specific antisense oligonucleotide (ASO) for SOD1 pathology, marked a significant turning point for SOD1-ALS patients. While clinical trials and early access program studies reported a significant reduction in plasma and cerebrospinal fluid (CSF) neurofilament levels, neuroinflammation following prolonged treatment was never assessed. In this multicenter study, we evaluated a cohort of 18 SOD1-ALS patients treated with tofersen, analyzing correlations between biomarkers of neurodegeneration/neuroinflammation and clinical variables indicative of disease progression. NfL, NfH, CHI3L1, and Serpina1 levels in serum and CSF were determined by semi-automated immunoassays (Ella™ technology). Generalized linear mixed models were employed to investigate longitudinal trends of these biomarkers. Our data highlighted a progressive decrease in CSF neurofilament levels during tofersen treatment (MR = 0.97, 95% CI 0.94-0.99, p = 0.006 and MR = 0.98, 95% CI 0.95-1.00, p = 0.076 for NfL and NfH in CSF, respectively). Conversely, CSF levels of SerpinA1 and CHI3L1 increased over time (MR = 1.12, 95% CI 1.08-1.16, p < 0.0001 and MR = 1.039, 95% CI 1.015-1.062, p = 0.001 for SerpinA1 and CHI3L1 in CSF, respectively), but these modifications were most apparent after six and twelve months of therapy, respectively. Disease progression rate did not correlate with these biomarker trends. We observed a significant decrease in neurofilament levels during Tofersen treatment, alongside an increase in neuroinflammatory markers, potentially linked to an immune response triggered by ASO treatment. Given the limited data on tofersen's long-term efficacy in ALS due to its recent introduction, identifying biomarkers that predict clinical outcomes such as diminished therapeutic response or adverse effects is crucial. These biomarkers may help to better understand the underlying pathomechanisms of ALS and tofersen's role in modulating disease progression.}, }
@article {pmid40169538, year = {2025}, author = {Iyer, KA and Tenchov, R and Sasso, JM and Ralhan, K and Jotshi, J and Polshakov, D and Maind, A and Zhou, QA}, title = {Rare Diseases, Spotlighting Amyotrophic Lateral Sclerosis, Huntington's Disease, and Myasthenia Gravis: Insights from Landscape Analysis of Current Research.}, journal = {Biochemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.biochem.4c00722}, pmid = {40169538}, issn = {1520-4995}, abstract = {Rare diseases are a diverse group of disorders that, despite each individual condition's rarity, collectively affect a significant portion of the global population. Currently approximately 10,000 rare diseases exist globally, with 80% of these diseases being identified as having genetic origins. In this Review, we examine data from the CAS Content Collection to summarize scientific progress in the area of rare diseases. We examine the publication landscape in the area in an effort to provide insights into current advances and developments. We then discuss the evolution of key concepts in the field, genetic associations, as well as the major technologies and development pipelines of rare disease treatments. We focus our attention on three specific rare diseases: (i) amyotrophic lateral sclerosis, a terminal neurodegenerative disease affecting the central nervous system resulting in progressive loss of motor neurons that control voluntary muscles; (ii) Huntington's disease, another terminal neurodegenerative disease that causes progressive degeneration of nerve cells in the brain, with a wide impact on a person's functional abilities; and (iii) myasthenia gravis, a chronic autoimmune synaptopathy leading to skeletal muscle weakness. While the pathogenesis of these rare diseases is being elucidated, there is neither a cure nor preventative treatment available, only symptomatic treatment. The objective of the paper is to provide a broad overview of the evolving landscape of current knowledge on rare diseases and specifically on the biology and genetics of the three spotlighted diseases, to outline challenges and evaluate growth opportunities, an aim to further efforts in solving the remaining challenges.}, }
@article {pmid40169452, year = {2025}, author = {Hou, X and Jiang, J and Deng, M}, title = {Exploring epigenetic modifications as potential biomarkers and therapeutic targets in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {304}, pmid = {40169452}, issn = {1432-1459}, support = {82273915//National Natural Science Foundation of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Humans ; *Epigenesis, Genetic ; *Biomarkers/metabolism ; DNA Methylation ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. Whole-genome sequencing has identified many novel ALS-associated genes, but genetics alone cannot fully explain the onset of ALS and an effective treatment is still lacking. Moreover, we need more biomarkers for accurate diagnosis and assessment of disease prognosis. Epigenetics, which includes DNA methylation and hydroxymethylation, histone modifications, chromatin remodeling, and non-coding RNAs, influences gene transcription and expression by affecting chromatin accessibility and transcription factor binding without altering genetic information. These processes play a role in the onset and progression of ALS. Epigenetic targets can serve as potential biomarkers and more importantly, the reversibility of epigenetic changes supports their potential role as versatile therapeutic targets in ALS. This review summarized the alterations in different epigenetic modulations in ALS. Additionally, given the close association between aberrant metabolic profiles characterized by hypoxia and high glycolytic metabolism in ALS and epigenetic changes, we also integrate epigenetics with metabolomics. Finally, we discuss the application of therapies based on epigenetic mechanisms in ALS. Our data integration helps to identify potential diagnostic and prognostic biomarkers and support the development of new effective therapies.}, }
@article {pmid40166719, year = {2025}, author = {Xiong, J and Chen, X and Huang, K and Pan, Y}, title = {Successful Guselkumab Treatment in a Patient with Comorbid Psoriasis and Amyotrophic Lateral Sclerosis: A Case Study and Literature Review.}, journal = {Clinical, cosmetic and investigational dermatology}, volume = {18}, number = {}, pages = {735-741}, pmid = {40166719}, issn = {1178-7015}, abstract = {Psoriasis is genetically influenced and can be triggered by factors such as infections, stress, and lifestyle. Chronic plaque psoriasis, the most prevalent form, involves key roles for IL-17 and IL-23 in its pathogenesis. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons, resulting in muscle weakness and atrophy. Currently, there is no cure for ALS, and treatment is symptomatic, aimed at improving quality of life. The combination of psoriasis and ALS is relatively rare. Although biologic agents have shown remarkable efficacy in the treatment of chronic plaque psoriasis, we have not found any case reports regarding the use of biologic agents for treating psoriasis accompanied by ALS. Our study presents a patient with severe plaque psoriasis and ALS who exhibited a positive response to Guselkumab, without worsening of ALS symptoms, suggesting a promising therapeutic strategy. This could provide a treatment option for patients with psoriasis combined with ALS.We conducted a comprehensive review of the literature on the comorbidity of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and ALS, with plaque psoriasis. This review highlights the differential impact of treatment modalities. Specifically, we found that TNF-α inhibitors may have adverse effects in MS but could provide protective benefits in AD and PD. In ALS patients with psoriasis, IL-17A and IL-23 inhibitors, exemplified by Guselkumab, are suggested as a more suitable alternative due to their lower risk of worsening ALS symptoms.}, }
@article {pmid40163151, year = {2025}, author = {Wadan, AS and Shaaban, AH and El-Sadek, MZ and Mostafa, SA and Moshref, AS and El-Hussein, A and Ellakwa, DE and Mehanny, SS}, title = {Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {40163151}, issn = {1432-1912}, abstract = {Neurodegenerative disorders present significant challenges to modern medicine because of their complex etiology, pathogenesis, and progressive nature, which complicate practical treatment approaches. Mitochondrial dysfunction is an important contributor to the pathophysiology of various neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review paper examines the current literature highlighting the multifaceted functions of mitochondria, including energy production, calcium signaling, apoptosis regulation, mitochondrial biogenesis, mitochondrial dynamics, axonal transport, endoplasmic reticulum-mitochondrial interactions, mitophagy, mitochondrial proteostasis, and their crucial involvement in neuronal health. The literature emphasizes the increasing recognition of mitochondrial dysfunction as a critical factor in the progression of neurodegenerative disorders, marking a shift from traditional symptom management to innovative mitochondrial-based therapies. By discussing mitochondrial mechanisms, including mitochondrial quality control (MQC) processes and the impact of oxidative stress, this review highlights the need for novel therapeutic strategies to restore mitochondrial function, protect neuronal connections and integrity, and slow disease progression. This comprehensive review aims to provide insights into potential interventions that could transform the treatment landscape for neurodegenerative diseases, addressing symptoms and underlying pathophysiological changes.}, }
@article {pmid40162390, year = {2025}, author = {Xie, Y and Xie, H and Wang, RL}, title = {Enhancing palliative care in malignant obstructive jaundice: A critical care perspective on endoscopic biliary stenting.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {3}, pages = {103431}, pmid = {40162390}, issn = {1948-9366}, abstract = {This letter responds to Wang et al's recent publication on endoscopic biliary stenting for malignant obstructive jaundice (MOJ) by offering constructive feedback and suggestions for future research. We commend the authors for their comprehensive study design and execution, which included a clear delineation of study groups and a robust set of outcome measures. We suggest that future studies incorporate additional biomarkers, such as serum levels of liver enzymes and bilirubin, to provide a more nuanced understanding of liver function changes post-intervention. The study's focus on short-term survival rates is appreciated, but we recommend exploring longer-term follow-up periods to capture the full spectrum of survival outcomes. Additionally, the inclusion of quality of life assessments using validated instruments could offer a more holistic view of patient outcomes. From a critical care perspective, we advocate for the integration of advanced imaging techniques to better characterize biliary anatomy and potentially predict treatment response or complications. We believe that incorporating these suggestions could enhance the understanding of endoscopic biliary stenting's role in MOJ management and its impact on patient outcomes, influencing future clinical guidelines and practice.}, }
@article {pmid40161216, year = {2025}, author = {Scarcella, S and Brambilla, L and Quetti, L and Rizzuti, M and Melzi, V and Galli, N and Sali, L and Costamagna, G and Comi, GP and Corti, S and Gagliardi, D}, title = {Unveiling amyotrophic lateral sclerosis complexity: insights from proteomics, metabolomics and microbiomics.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf114}, pmid = {40161216}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is the most common motor neuron disease and manifests as a clinically and genetically heterogeneous neurodegenerative disorder mainly affecting the motor systems. To date, despite promising results and accumulating knowledge on the pathomechanisms of amyotrophic lateral sclerosis, a specific disease-modifying treatment is still not available. In vitro and in vivo disease models coupled with multiomics techniques have helped elucidate the pathomechanisms underlying this disease. In particular, omics approaches are powerful tools for identifying new potential disease biomarkers that may be particularly useful for diagnosis, prognosis and assessment of treatment response. In turn, these findings could support physicians in stratifying patients into clinically relevant subgroups for the identification of the best therapeutic targets. Here, we provide a comprehensive review of the most relevant literature highlighting the importance of proteomics approaches in determining the role of pathogenic misfolded/aggregated proteins and the molecular mechanisms involved in the pathogenesis and progression of amyotrophic lateral sclerosis. In addition, we explored new findings arising from metabolomic and lipidomic studies, which can aid to elucidate the intricate metabolic alterations underlying amyotrophic lateral sclerosis pathology. Moreover, we integrated these insights with microbiomics data, providing a thorough understanding of the interplay between metabolic dysregulation and microbial dynamics in disease progression. Indeed, a greater integration of these multiomics data could lead to a deeper understanding of disease mechanisms, supporting the development of specific therapies for amyotrophic lateral sclerosis.}, }
@article {pmid40157434, year = {2025}, author = {Pu, L and Steele, JR and Phillips, CR and Violi, JP and Rodgers, KJ}, title = {The cyanobacterial toxins BMAA and 2,4-DAB perturb the l-serine biosynthesis pathway and induce systemic changes in energy metabolism in human neuroblastoma cells: A proteomic study.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {106}, number = {}, pages = {106058}, doi = {10.1016/j.tiv.2025.106058}, pmid = {40157434}, issn = {1879-3177}, abstract = {Blue-green algae (cyanobacteria), an ancient phylum of bacteria, produce a wide array of secondary metabolites that are toxic to humans. Rapid growth of cyanobacteria in an aquatic environment can result in algal blooms capable of turning waterways green and increasing toxin levels in the environment. Cyanobacterial toxins were first linked to the high incidence of a complex neurodegenerative disorder reported on the island of Guam in the 1940s but more recently have been linked to clusters of sporadic amyotrophic lateral sclerosis (sALS) worldwide. The non-protein amino acid β-N-methylamino-L-alanine (BMAA) and its isomer L-2,4-diaminobutyric acid (2,4-DAB) are produced concurrently by most cyanobacterial species. We carried out proteomic analysis on human neuroblastoma cells treated with BMAA and 2,4-DAB to determine the underlying mechanisms of toxicity resulting from exposure to these cyanotoxins and identified significant changes in the l-serine biosynthesis pathway as well as pathways associated with energy production in the cell such as fatty acid ß-oxidation and glycolysis. The impact on the serine biosynthetic pathway was supported by demonstrating a significant decrease in both mRNA and protein levels of the enzyme 3-phosphoglycerate dehydrogenase (PHGDH) the first committed step in serine biosynthesis. PHGDH uses 3-phospho-D-glycerate (3PG) an intermediate in the glycolytic pathway as a substrate, and co-incubation of cells with l-serine restored expression levels of PHGDH as did cell pre-treatment with the glycolytic product pyruvate. This is the first study to link exposure to BMAA and 2,4-DAB to impairments in the l-serine biosynthesis pathway and broad disturbances in energy metabolism.}, }
@article {pmid40153582, year = {2025}, author = {Norata, D and Capone, F and Motolese, F and Marano, M and Rossi, M and Calandrelli, R and Sacchetti, M and Mantelli, F and Di Lazzaro, V and Pilato, F}, title = {1953-2023. Seventy Years of the Nerve Growth Factor: A Potential Novel Treatment in Neurological Diseases?.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.0573}, pmid = {40153582}, issn = {2152-5250}, abstract = {Rita Levi-Montalcini's 1953 discovery of nerve growth factor (NGF) in mouse sarcoma tumors marked a groundbreaking moment in neuroscience. NGF, a key signaling molecule, became the first identified neurotrophic factor, influencing the growth, differentiation, and survival of neurons in both peripheral and central nervous systems. NGF and related neurotrophic factors hold therapeutic potential for various neurological disorders, such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, amyotrophic lateral sclerosis, spinal cord injuries, neuropathies, traumatic brain injuries, and stroke. However, despite promising in vitro studies and animal models findings, NGF efficacy in patients remains unproven. Indeed, its use as a therapeutic agent faces challenges in delivery and clinical translation. This review delves into these challenges, exploring ongoing research on refined delivery methods, dosages, and safety profiles. Innovative strategies, including molecular mimicking, combination therapies, gene therapy, and coupling with neuromodulation techniques like transcranial magnetic stimulation and vagal nerve stimulation, are discussed. Incorporating nerve growth factor (NGF) into a comprehensive strategy may prove beneficial, particularly in non-neurodegenerative conditions such as stroke, trauma, and neuropathies. In these instances, NGF holds promise for promoting tissue regeneration and repair. Challenges persist in addressing the complexity of neurodegenerative pathologies for a combined therapeutic approach.}, }
@article {pmid40151753, year = {2025}, author = {Carqueja, I and Montenegro Sá, F and Monteiro, S}, title = {Ventricular Arrhythmias Caused by Left Main Coronary Artery Vasospasm: A Diagnostic Challenge in a Cardiac Arrest Victim.}, journal = {Cureus}, volume = {17}, number = {2}, pages = {e79554}, pmid = {40151753}, issn = {2168-8184}, abstract = {Sudden cardiac death (SCD) is a common cause of cardiovascular deaths. It may be caused by primary electrical diseases, cardiomyopathies, myocarditis, valvular heart diseases, or coronary artery disease (including acute coronary syndrome). Coronary artery vasospasm is defined as a transient total or subtotal coronary artery obstruction, associated with angina symptoms and ischemic findings on electrocardiogram (ECG). It is a cause of myocardial infarction, life-threatening arrhythmias, atrioventricular block, and SCD. A 55-year-old man presented to the hospital after an out-of-hospital cardiac arrest (OHCA). He had a previous history of cardiovascular risk factors, excessive alcohol intake, non-obstructive coronary artery disease, and paroxysmic atrial fibrillation. On the day of the OHCA, he had a sudden collapse while exercising, with ventricular fibrillation and return of spontaneous circulation (ROSC) after advanced life support (ALS). No ECG or echocardiographic anomalies were identified on hospital admission. The patient suffered three more episodes of cardiac arrest during the hospital stay, with atypical arrhythmic presentations. No ECG or echocardiographic abnormalities were observed after ROSC. The fourth cardiac arrest had concomitant segmental ST changes and de novoechocardiographic segmental motility abnormalities suggestive of left main coronary artery occlusion. These findings were transient, with a normal ECG and echocardiogram obtained one hour after ROSC. No electrolyte abnormalities or other causes of cardiac arrest were identified. The hypothesis of left main coronary vasospasm was raised as the likely diagnosis. Coronary artery vasospasm is a possible cause of major cardiac events. Diagnosis can be challenging due to the transient findings and varied manifestations, often in patients with normal coronary arteries. The correct diagnosis and treatment of coronary artery vasospasm can have a determinant effect on prognosis and mortality, as appropriate treatment can lead to prolonged event-free survival. Provocative coronary vasospasm tests performed in patients with atypical cardiovascular manifestations can allow for the timely diagnosis of vasospasm and avoid critical events. The authors aim to raise awareness of the different clinical presentations of coronary artery vasospasm and its consequences. The performance of provocative tests in selected patients should be considered to promote early diagnosis and potentially avoid major events.}, }
@article {pmid40151398, year = {2025}, author = {Roy, SM and Acquarone, E and Argyrousi, EK and Zhang, H and Staniszewski, A and Inoue, A and Ziarek, JJ and Arancio, O and Watterson, DM}, title = {Optimized 5-HT2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction.}, journal = {Alzheimer's &amp; dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70073}, pmid = {40151398}, issn = {2352-8737}, abstract = {INTRODUCTION: Neuropsychiatric syndromes such as anxiety and agitation are clinical presentations common to diverse neurodegenerative diseases and brain injury sequelae. They are a concern due to the impact on cognition, social interactions, and non-pharmacological treatments. Cognitive or behavioral disturbances occur at early disease stages and increase with disease progression. Coincident pathologies include the loss of serotonin (5-HT) neurons and appearance of neurofibrillary tangles in the raphe nucleus. Brain 5-HT2b receptor (5-HT2bR) levels are increased in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and post-stroke morbidity. HTR2B gene variants are implicated in psychiatric disorders. 5-HTRs are associated with atypical neurotropic drug mechanisms and behavioral dysfunction in drug abuse. The accumulating body of evidence suggests that selective 5-HT2bR inhibition might mitigate neuropsychiatric syndromes and the associated cognitive dysfunction. Atypical neurotropic drugs interact with a variety of monoamine receptors and outcomes are viewed as a combination of 5-HT and dopamine D2 receptor mediated actions. Clearly, there is a need for insight into precision 5-HT2bR inhibition as a potential pharmacological mechanism for treatment of neuropsychiatric syndromes and cognitive dysfunction associated with dementia.<br><br>METHODS: Strategic optimization of an atypical neurotropic drug was used to develop MW073, a highly selective and orally bioavailable inhibitor of 5-HT2bR activity and &#x3b2;-arrestin-1 recruitment that is devoid of dopamine receptor recognition and risk of 5-HT2bR agonist activity.<br><br>RESULTS: MW073 ameliorates amyloid and tau induction of behavioral dysfunction in preventive or disease stage intervention paradigms. Using MW073 as a standard of comparison, risperidone was shown to be a dose-dependent inhibitor 5-HT2bR activity and &#x3b2;-arrestin-1 recruitment.<br><br>DISCUSSION: Selective inhibition of 5-HT2bR activity is a viable mechanism for the treatment of neuropsychiatric syndromes with synaptic dysfunction as a root cause and is a previously unrealized pharmacodynamic mechanism potentially embedded in current neurotherapeutics.<br><br>HIGHLIGHTS: A new highly selective 5-HT2bR antagonist, MW073, is described and used as a reference standard.MW073 attenuates synaptic and behavioral dysfunctions an animal models of neuropsychatric syndromes.Risperidone is a dose dependent inhibitor of 5-HT2bR activity and arrestin recruitment.}, }
@article {pmid40150989, year = {2025}, author = {Matsumoto, S and Tateishi-Karimata, H and Ohyama, T and Sugimoto, N}, title = {Controlling the Local Conformation of RNA G-Quadruplex Results in Reduced RNA/Peptide Cytotoxic Accumulation Associated with C9orf72 ALS/FTD.}, journal = {Small methods}, volume = {}, number = {}, pages = {e2401630}, doi = {10.1002/smtd.202401630}, pmid = {40150989}, issn = {2366-9608}, abstract = {Repeat expansion of d(G4C2) in the noncoding region of the C9orf72 gene contributes to neurodegenerative diseases. The repeat expansion transcript r(G4C2) induces RNA/peptide accumulation, which, in turn, induces cytotoxicity and accelerates the development of neurodegenerative diseases. Such cytotoxic accumulation is triggered by peptide aggregation. Here, a technique is developed to prevent accumulation by regulating RNA interactions, assuming that RNA structure is important for peptide interactions. A screening method is used to identify compounds that suppress RNA accumulation of r(G4C2) repeats. The four compounds are identified with wide π-planes containing hydroxyl, methoxy, and cyclic ether groups that suppressed RNA accumulation. Interestingly, these compounds also suppressed RNA/peptide accumulation in neuroblastoma cells, indicating that RNA accumulation is a key regulator of RNA/peptide cytotoxic aggregate formation. In vitro and in silico physicochemical analyses reveal that these compounds bind to the loop region of the G-quadruplex via hydrogen bonds or CH-π interactions, resulting in an altered loop conformation. Importantly, these conformational changes inhibited RNA G-quadruplex associations. These results show that conformational changes are promising for controlling the interactions between G-quadruplexes and further RNA accumulation. These findings may be useful in the development of therapeutic strategies for the treatment of neurodegenerative diseases.}, }
@article {pmid40149599, year = {2025}, author = {Yang, W and Xiao, W and Liu, X and Li, H and Huang, T and Fan, D}, title = {Testosterone Supplementation: A Potential Therapeutic Strategy for Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {13}, number = {3}, pages = {}, pmid = {40149599}, issn = {2227-9059}, support = {82071426//National Natural Science Foundation of China/ ; }, abstract = {Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by the degeneration of spinal cord and brain neurons. Proteomics combined with Mendelian randomization (MR) is an effective method for finding disease treatment targets. Methods: We aimed to seek new therapeutic targets for ALS. A large-scale GWAS on proteomics (4907 circulatory protein) with 35,559 individuals was included as the exposure data; a GWAS with 138,086 ALS patients was used as the outcome data; we found that a high level of sex hormone-binding globulin (SHBG) is a risk factor by MR analysis. Colocalization analyses were used to validate the causality between SHBG and ALS further. Functional enrichment found a high level of SHBG was associated with a low level of bioavailable testosterone. Two-sample MR confirmed the association of SHBG (400,210 samples), bioavailable testosterone (367,289 samples), and ALS. Results: A high level of SHBG, and a low level of bioavailable testosterone are risk factors for ALS. Conclusions: A low level of bioavailable testosterone is a risk factor for ALS. Although our study is relatively limited and cannot fully confirm that testosterone supplementation has a therapeutic effect on ALS, it offers a promising direction for ALS therapy.}, }
@article {pmid40148057, year = {2025}, author = {De Marchi, F and Spinelli, EG and Bendotti, C}, title = {Neuroglia in neurodegeneration: Amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Handbook of clinical neurology}, volume = {210}, number = {}, pages = {45-67}, doi = {10.1016/B978-0-443-19102-2.00004-1}, pmid = {40148057}, issn = {0072-9752}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Frontotemporal Dementia/pathology ; *Neuroglia/pathology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases sharing significant pathologic and genetic overlap, leading to consider these diseases as a continuum in the spectrum of their pathologic features. Although FTD compromises only specific brain districts, while ALS involves both the nervous system and the skeletal muscles, several neurocentric mechanisms are in common between ALS and FTD. Also, recent research has revealed the significant involvement of nonneuronal cells, particularly glial cells such as astrocytes, oligodendrocytes, microglia, and peripheral immune cells, in disease pathology. This chapter aims to provide an extensive overview of the current understanding of the role of glia in the onset and advancement of ALS and FTD, highlighting the recent implications in terms of prognosis and future treatment options.}, }
@article {pmid40145977, year = {2025}, author = {Zhao, W and Liu, Z and Wu, J and Liu, A and Yan, J}, title = {Potential targets of microglia in the treatment of neurodegenerative diseases: mechanism and therapeutic implications.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-01343}, pmid = {40145977}, issn = {1673-5374}, abstract = {For diverse neurodegenerative disorders, microglial cells are activated. Furthermore, dysfunctional and hyperactivated microglia initiate mitochondrial autophagy, oxidative stress, and pathological protein accumulation, ending with neuroinflammation that exacerbates damage to dopaminergic neurons and contributes significantly to the pathology of neurodegenerative disorder. Microglial overactivation is closely associated with the secretion of pro-inflammatory cytokines, the phagocytosis of injured neurons, and the modulation of neurotoxic environments. This review summarizes the role of microglia neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, cortical degeneration, Lewy body dementia, and Huntington's disease. It also discusses novel forms of cell death such as ferroptosis, cuproptosis, disulfidptosis, and parthanatos (poly(adenosine diphosphate ribose) polymerase 1-dependent cell death), as well as the impact of regulatory factors related to microglial inflammation on microglial activation and neuroinflammation. The aim is to identify potential targets for microglial cell therapy in neurodegenerative diseases.}, }
@article {pmid40143051, year = {2025}, author = {Zou, Y and Zhang, J and Chen, L and Xu, Q and Yao, S and Chen, H}, title = {Targeting Neuroinflammation in Central Nervous System Diseases by Oral Delivery of Lipid Nanoparticles.}, journal = {Pharmaceutics}, volume = {17}, number = {3}, pages = {}, pmid = {40143051}, issn = {1999-4923}, support = {82100892//Hong Chen/ ; 82300929//Jing Zhang/ ; }, abstract = {Neuroinflammation within the central nervous system (CNS) is a primary characteristic of CNS diseases, such as Parkinson's disease, Alzheimer's disease (AD), amyotrophic lateral sclerosis, and mental disorders. The excessive activation of immune cells results in the massive release of pro-inflammatory cytokines, which subsequently induce neuronal death and accelerate the progression of neurodegeneration. Therefore, mitigating excessive neuroinflammation has emerged as a promising strategy for the treatment of CNS diseases. Despite advancements in drug discovery and the development of novel therapeutics, the effective delivery of these agents to the CNS remains a serious challenge due to the restrictive nature of the blood-brain barrier (BBB). This underscores the need to develop a novel drug delivery system. Recent studies have identified oral lipid nanoparticles (LNPs) as a promising approach to efficiently deliver drugs across the BBB and treat neurological diseases. This review aims to comprehensively summarize the recent advancements in the development of LNPs designed for the controlled delivery and therapeutic modulation of CNS diseases through oral administration. Furthermore, this review addresses the mechanisms by which these LNPs overcome biological barriers and evaluate their clinical implications and therapeutic efficacy in the context of oral drug delivery systems. Specifically, it focuses on LNP formulations that facilitate oral administration, exploring their potential to enhance bioavailability, improve targeting precision, and alleviate or manage the symptoms associated with a range of CNS diseases.}, }
@article {pmid40141987, year = {2025}, author = {Russo, A and Putaggio, S and Tellone, E and Calderaro, A and Cirmi, S and Laganà, G and Ficarra, S and Barreca, D and Patanè, GT}, title = {Emerging Ferroptosis Involvement in Amyotrophic Lateral Sclerosis Pathogenesis: Neuroprotective Activity of Polyphenols.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {6}, pages = {}, pmid = {40141987}, issn = {1420-3049}, mesh = {*Ferroptosis/drug effects ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy/genetics ; *Polyphenols/pharmacology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; Reactive Oxygen Species/metabolism ; Lipid Peroxidation/drug effects ; Oxidative Stress/drug effects ; Mitochondria/metabolism/drug effects ; Iron/metabolism ; }, abstract = {Neurodegenerative diseases are a group of diseases that share common features, such as the generation of misfolded protein deposits and increased oxidative stress. Among them, amyotrophic lateral sclerosis (ALS), whose pathogenesis is still not entirely clear, is a complex neurodegenerative disease linked both to gene mutations affecting different proteins, such as superoxide dismutase 1, Tar DNA binding protein 43, Chromosome 9 open frame 72, and Fused in Sarcoma, and to altered iron homeostasis, mitochondrial dysfunction, oxidative stress, and impaired glutamate metabolism. The purpose of this review is to highlight the molecular targets common to ALS and ferroptosis. Indeed, many pathways implicated in the disease are hallmarks of ferroptosis, a recently discovered type of iron-dependent programmed cell death characterized by increased reactive oxygen species (ROS) and lipid peroxidation. Iron accumulation results in mitochondrial dysfunction and increased levels of ROS, lipid peroxidation, and ferroptosis triggers; in addition, the inhibition of the Xc[-] system results in reduced cystine levels and glutamate accumulation, leading to excitotoxicity and the inhibition of GPx4 synthesis. These results highlight the potential involvement of ferroptosis in ALS, providing new molecular and biochemical targets that could be exploited in the treatment of the disease using polyphenols.}, }
@article {pmid40140966, year = {2025}, author = {Balaban, E and Köse, TE and Günaçar, DN and Naralan, ME and Gonca, M}, title = {Comparison of methods for detecting mandibular lingula and can antilingula be used in lingula mandibula detection?.}, journal = {BMC oral health}, volume = {25}, number = {1}, pages = {430}, pmid = {40140966}, issn = {1472-6831}, support = {02025001021255//Recep Tayyip Erdo&#x11f;an University Development Foundation/ ; 02025001021255//Recep Tayyip Erdo&#x11f;an University Development Foundation/ ; 02025001021255//Recep Tayyip Erdo&#x11f;an University Development Foundation/ ; 02025001021255//Recep Tayyip Erdo&#x11f;an University Development Foundation/ ; }, mesh = {Humans ; *Cone-Beam Computed Tomography ; Female ; Male ; Retrospective Studies ; Middle Aged ; Adult ; *Mandible/diagnostic imaging ; Aged ; Adolescent ; Aged, 80 and over ; Young Adult ; Orthognathic Surgical Procedures ; Anatomic Landmarks/diagnostic imaging ; Mandibular Nerve/diagnostic imaging/anatomy &amp; histology ; }, abstract = {OBJECTIVE: The aim of this study is to evaluate the relationship between anatomical reference points used during orthognathic surgery and to minimize the risks of iatrogenic neurovascular damage.<br><br>MATERIALS AND METHODS: This retrospective study included cone-beam computed tomography (CBCT) images involving the mandible from patients who visited Recep Tayyip Erdo&#x11f;an University Faculty of Dentistry between January 2018 and September 2023. The age range of the included individuals was set between 18 and 80 years. Horizontal and vertical distances between mandibular anatomical structures, such as the lingula mandibula (LM), mandibular foramen (MF), antilingula (AL), and surrounding structures were measured using CBCT software. Individuals with intraosseous pathology, insufficient image quality, or a history of surgical/orthodontic treatment were excluded from the study.<br><br>RESULTS: A total of 240 hemimandibles from 120 patients were analyzed (55.83% female, 44.17% male; mean age: 46.78&#x2009;&#xb1;&#x2009;15.30 years). Significant differences were identified in LM positions according to different AL types. The LM was found to be more inferior and posterior relative to hill and ridge type ALs, while it was more anterior relative to plateau type ALs. In 26.25% of mandibular rami, AL was not detected.<br><br>CONCLUSION: The position of the AL can serve as a guide in determining the osteotomy line during inferior vertical ramus osteotomy (IVRO). However, relying solely on AL as a reference point may increase the risk of inferior alveolar nerve (IAN) injury. Preoperative tomographic evaluations to determine the relationships among LM, MF, and AL can provide a safer approach in surgical planning, reduce complications, and help protect neurovascular structures.}, }
@article {pmid40138872, year = {2025}, author = {Liang, T and Jiang, T and Liang, Z and Li, L and Chen, Y and Chen, T and Yang, L and Zhang, N and Dong, B and Xie, X and Gu, B and Wu, Q}, title = {Gut microbiota-driven BCAA biosynthesis via Staphylococcus aureus -expressed acetolactate synthase impairs glycemic control in type 2 diabetes in South China.}, journal = {Microbiological research}, volume = {296}, number = {}, pages = {128145}, doi = {10.1016/j.micres.2025.128145}, pmid = {40138872}, issn = {1618-0623}, mesh = {*Diabetes Mellitus, Type 2/microbiology/metabolism ; *Gastrointestinal Microbiome/physiology ; *Staphylococcus aureus/enzymology/genetics/metabolism ; *Amino Acids, Branched-Chain/biosynthesis ; *Acetolactate Synthase/metabolism/genetics ; Humans ; Animals ; Mice ; China ; Male ; Insulin Resistance ; Female ; Middle Aged ; *Glycemic Control ; Blood Glucose ; Feces/microbiology ; Staphylococcal Infections/microbiology ; Metagenomics ; Prediabetic State/microbiology ; Metabolomics ; Insulin ; }, abstract = {An increase in branched-chain amino acid (BCAA) levels can result in insulin resistance at different stages of type 2 diabetes (T2D), however, the causes of this increase are unclear. We performed metagenomics and metabolomics profiling in patients with prediabetes (PDM), newly diagnosed diabetes (NDDM), and post-medication type 2 diabetes (P2DM) to investigate whether altered gut microbes and metabolites could explain the specific clinical characteristics of different disease stages of T2D. Here we identify acetolactate synthase (ALS) a BCAA biosynthesis enzyme in Staphylococcus aureus as a cause of T2D insulin resistance. Compared with healthy peoples, patients with PDM, NDDM, and P2DM groups, especially in P2DM group, have increased faecal numbers of S. aureus. We also demonstrated that insulin administration may be a risk factor for S. aureus infection in T2D. The presence of ALS-positive S. aureus correlated with the levels of BCAAs and was associated with an increased fasting blood glucose (FBG) and insulin resistance. Humanized microbiota transplantation experiment indicated that ALS contributes to disordered insulin resistance mediated by S. aureus. We also found that S. aureus phage can reduced the FBG levels and insulin resistance in db/db mice. The ALS-positive S. aureus are associated with insulin resistance in T2D, opening a new therapeutic avenue for the prevention or treatment of diabetes.}, }
@article {pmid40137226, year = {2025}, author = {Stella, R and Bertoli, A and Lopreiato, R and Peggion, C}, title = {A Twist in Yeast: New Perspectives for Studying TDP-43 Proteinopathies in S. cerevisiae.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {40137226}, issn = {2309-608X}, abstract = {TAR DNA-binding protein 43 kDa (TDP-43) proteinopathies are a group of neurodegenerative diseases (NDs) characterized by the abnormal accumulation of the TDP-43 protein in neurons and glial cells. These proteinopathies are associated with several NDs, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and some forms of Alzheimer's disease. Yeast models have proven valuable in ND research due to their simplicity, genetic tractability, and the conservation of many cellular processes shared with higher eukaryotes. For several decades, Saccharomyces cerevisiae has been used as a model organism to study the behavior and toxicity of TDP-43, facilitating the identification of genes and pathways that either exacerbate or mitigate its toxic effects. This review will discuss evidence showing that yeast models of TDP-43 exhibit defects in proteostasis, mitochondrial function, autophagy, and RNA metabolism, which are key features of TDP-43-related NDs. Additionally, we will explore how modulating proteins involved in these processes reduce TDP-43 toxicity, aiding in restoring normal TDP-43 function or preventing its pathological aggregation. These findings highlight potential therapeutic targets for the treatment of TDP-43-related diseases.}, }
@article {pmid40135721, year = {2025}, author = {Fayaz, MU and Wang, Q and Xu, M and Chen, D and Pan, F and Song, C}, title = {Compressive Strain-Induced Uphill Hydrogen Distribution in Strontium Ferrite Films.}, journal = {ACS applied materials &amp; interfaces}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsami.4c21825}, pmid = {40135721}, issn = {1944-8252}, abstract = {Hydrogen incorporation into metal oxides enhances their electrochemical properties, making them highly suitable for various energy conversion applications. The controlled distribution of hydrogen ions in material systems and their conduction at elevated temperatures have garnered significant attention for various energy storage and environmental monitoring applications, including fuel cells, smart windows, and sensor technologies. In this work, cost-effective, high-concentration hydrogen-doped SrFeO3-δ (HSrFeO3-δ) films were prepared under ambient conditions by treating Al(s)|SrFeO3-δ(s) films with KOH(aq), utilizing electron-proton codoping to investigate hydrogen distribution. The uphill hydrogen distributions in SrFeO3-δ films with compressive strain, in contrast to the density gradient behavior under tensile strain, suggest the fundamental role of the strain states in the hydrogen accommodation. Compressively strained films with a rich Al source follow an anomalous uphill feature of hydrogen distribution, highlighting their potential use as electrolyte for fuel cells. The strain significantly influences the structure, chemical lattice coupling, and consequently the ionic transport in SrFeO3-δ. Ionic conductivity measurements reveal that compressively strained HSrFeO3-δ films with uphill hydrogen distributions exhibit a significant ionic conductivity of 0.189 S/cm at 413 K, with an activation energy of approximately 0.29 eV, making them suitable for low-temperature electrochemical applications. These findings provide a promising approach for tuning material properties and valuable insights for building iontronic devices.}, }
@article {pmid40135631, year = {2024}, author = {Novy, C and Tysnes, OB and Busk, &#xd8;L and Jaioun, K and Holmøy, T and Holla, &#xd8;L and Høyer, H}, title = {Association of UNC13A with increased amyotrophic lateral sclerosis risk, bulbar onset, and lower motor neuron involvement in a Norwegian ALS cohort.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2024.2447922}, pmid = {40135631}, issn = {2167-9223}, abstract = {Objective: Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by the loss of motor neurons, has limited treatment options available. Treatments targeting specific ALS genes, including UNC13A, have attracted considerable attention. The UNC13A rs12608932 variant has been associated with an increased risk of ALS, shorter survival, and more frequent bulbar onset. Methods: In this study, we investigated the allele frequency of rs12608932 among 500 Norwegian ALS patients, divided into three groups: patients with a genetic cause, patients without a genetic cause, and the entire ALS population. The three groups were compared to two independent control groups. The patients carrying UNC13A genotypes AA, AC, and CC were further clinically characterized and compared using additive, recessive, and dominant models. Results: The frequency of the rs12608932 C allele was higher in the patients with ALS (0.438) than in the controls (0.365; p < 0.001). Among ALS patients without a known genetic cause, individuals with the CC genotype exhibited higher frequencies of bulbar onset (p = 0.015) and prominent lower motor neuron involvement (p = 0.007) than those with the AA and AC genotypes. Conclusions: The CC genotype of rs12608932 is associated with an increased risk of ALS. Additionally, it acts as a modifier of the ALS phenotype, increasing the risk of bulbar onset and dominant lower motor neuron involvement, specifically in patients without a genetic cause in known ALS genes.}, }
@article {pmid40135522, year = {2025}, author = {Bai, D and Fang, Y and Tian, J and Liao, Y and Liu, M and Pan, L}, title = {Tribenuron-methyl resistance in Capsella bursa-pastoris: the co-existence of ALS target enzyme mutation (Pro-197-Ser) and overexpression of GSTF12 and ADP/ATP carrier protein.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.8794}, pmid = {40135522}, issn = {1526-4998}, support = {//Scientific Research Fund of Hunan Provincial Education Department/ ; //National Natural Science Foundation of China/ ; //National Key Research and Development Program of China/ ; //China Agriculture Research System/ ; //Modern Agricultural Industrial Technology System of Hunan Province/ ; }, abstract = {BACKGROUND: Capsella bursa-pastoris, a prevalent wheat-field weed in China, demonstrates substantial resistance to tribenuron-methyl, a herbicide-targeting acetolactate synthase (ALS). Understanding weed herbicide-resistance mechanisms is crucial for managing resistant weed populations. However, the genes potentially involved in nontarget-site resistance (NTSR) in herbicide-resistant C. bursa-pastoris remain poorly understood and require further investigation. This research aimed to elucidate the resistance level and underlying mechanisms of a field population (R) from Shandong Province, China, to tribenuron-methyl.<br><br>RESULTS: Whole-plant bioassays revealed that the relative resistance index (RI) of the R population was 54-fold greater than that of the tribenuron-methyl-sensitive population (S). Additionally, treatment with the cytochrome P450 (CYP450) inhibitor malathion or the glutathione S-transferase (GST) inhibitor 4-Chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) partially mitigated the resistance of the R population to tribenuron-methyl. Sequencing of the ALS target enzyme identified a substitution of proline (CCT) at position 197 with serine (TCT). RNA sequencing combined with quantitative reverse transcription polymerase chain reaction (qRT-PCR) verification identified upregulation of a candidate GST gene (GSTF12) and an ADP/ATP carrier protein in the R population. Heterologous expression of the two candidate genes in yeast cells demonstrated enhanced growth in the presence of tribenuron-methyl.<br><br>CONCLUSION: We first identified that, in tribenuron-methyl-resistant C.&#x2009;bursa-pastoris, the Pro-197-Ser mutation in the ALS gene, along with GSTF12 and ADP/ATP carrier protein overexpression, jointly mediate its resistance. This enhances our understanding of herbicide-resistance mechanisms and offers a novel perspective for managing tribenuron-methyl-resistant weeds in agricultural practices. &#xa9; 2025 Society of Chemical Industry.}, }
@article {pmid40134643, year = {2025}, author = {Guo, YX and Yan, X and Liu, XC and Liu, YX and Liu, C}, title = {Artificial intelligence-driven strategies for managing renal and urinary complications in inflammatory bowel disease.}, journal = {World journal of nephrology}, volume = {14}, number = {1}, pages = {100825}, pmid = {40134643}, issn = {2220-6124}, abstract = {In this editorial, we discuss the article by Singh et al published in World Journal of Nephrology, stating the need for timely adjustments in inflammatory bowel disease (IBD) patients' long-term management plans. IBD is chronic and lifelong, with recurrence and remission cycles, including ulcerative colitis and Crohn's disease. It's exact etiology is unknown but likely multifactorial. Related to gut flora and immune issues. Besides intestinal symptoms, IBD can also affect various extraintestinal manifestations such as those involving the skin, joints, eyes and urinary system. The anatomical proximity of urinary system waste disposal to that of the alimentary canal makes early detection and the differentiation of such symptoms very difficult. Various studies show that IBD and it's first-line drugs have nephrotoxicity, impacting the patients' life quality. Existing guidelines give very few references for kidney lesion monitoring. Singh et al's plan aims to improve treatment management for IBD patients with glomerular filtration rate decline, specifically those at risk. Most of IBD patients are young and they need lifelong therapy. So early therapy cessation, taking into account drug side effects, can be helpful. Artificial intelligence-driven diagnosis and treatment has a big potential for management improvements in IBD and other chronic diseases.}, }
@article {pmid40129929, year = {2025}, author = {Liang, F and Sun, Y and Yang, J and Shen, Z and Wang, G and Zhu, J and Zhou, C and Xia, Y}, title = {Gut microbiome is associated with radiotherapy response in lung cancer patients with brain metastases.}, journal = {Frontiers in cellular and infection microbiology}, volume = {15}, number = {}, pages = {1562831}, pmid = {40129929}, issn = {2235-2988}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Lung Neoplasms/radiotherapy/pathology/microbiology ; Male ; Female ; Middle Aged ; *Brain Neoplasms/secondary/radiotherapy ; Aged ; *RNA, Ribosomal, 16S/genetics ; *Feces/microbiology ; *Bacteria/classification/isolation &amp; purification/genetics ; Treatment Outcome ; Adult ; }, abstract = {PURPOSE: To investigate the gut microbiome of lung cancer patients with brain metastases undergoing radiotherapy, identify key microorganisms associated with radiotherapy response, and evaluate their potential as biomarkers.<br><br>METHODS AND MATERIALS: This study enrolled 55 newly diagnosed lung cancer patients with brain metastases. Fecal samples were collected before radiotherapy and analyzed by 16S rRNA sequencing to assess the gut microbiome's composition and function. Patients were categorized into response (n=28) and non-response (n=27) groups based on treatment efficacy, and &#x3b1;-diversity, &#x3b2;-diversity, and functional pathways were compared between them. Linear Discriminant Analysis Effect Size was used to identify microbial features associated with treatment efficacy. Logistic regression analyses were performed to evaluate the predictive capacity of clinical and microbial factors for treatment outcomes.<br><br>RESULTS: No significant difference in &#x3b1;-diversity was observed between the groups (P > 0.05), but &#x3b2;-diversity differed significantly (P = 0.036). Twelve characteristic microorganisms were identified in the response group, including g_ Oscillibacter and g_ Blautia, and nine in the non-response group, such as f_ Desulfovibrionaceae and g_ Megamonas. Metabolic pathways associated with treatment response included ketone body metabolism and pathways related to amyotrophic lateral sclerosis. Multivariate analysis identified g_Flavonifractor (odds ratio [OR] = 6.680, P = 0.004), g_Negativibacillus (OR = 3.862, P = 0.014), C-reactive protein (OR = 1.054, P = 0.017), and systemic inflammation response index (OR = 1.367, P = 0.043) as independent predictors of radiotherapy response. The nomogram and microbiome models achieved area under the curve (AUC) values of 0.935 and 0.866, respectively, demonstrating excellent predictive performance. Decision curve analysis further confirmed these models provided significant net benefits across risk thresholds.<br><br>CONCLUSIONS: The composition and functional characteristics of the gut microbiome in lung cancer patients with brain metastases prior to radiotherapy are associated with therapeutic response and possess potential as predictive biomarkers. Further studies are warranted to validate these findings.}, }
@article {pmid40128823, year = {2025}, author = {Zhang, W and Huang, C and Yao, H and Yang, S and Jiapaer, Z and Song, J and Wang, X}, title = {Retrotransposon: an insight into neurological disorders from perspectives of neurodevelopment and aging.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {14}, pmid = {40128823}, issn = {2047-9158}, support = {2023TSYCCX0051//Tianshan Talent Training Program/ ; }, mesh = {Humans ; *Retroelements/genetics ; *Aging/genetics ; *Nervous System Diseases/genetics ; Animals ; }, abstract = {Neurological disorders present considerable challenges in diagnosis and treatment due to their complex and diverse etiology. Retrotransposons are a type of mobile genetic element that are increasingly revealed to play a role in these diseases. This review provides a detailed overview of recent developments in the study of retrotransposons in neurodevelopment, neuroaging, and neurological diseases. Retrotransposons, including long interspersed nuclear elements-1, Alu, SINE-VNTR-Alu, and endogenous retrovirus, play important regulatory roles in the development and aging of the nervous system. They have also been implicated in the pathological processes of several neurological diseases, including Alzheimer's disease, X-linked dystonia-parkinsonism, amyotrophic lateral sclerosis, autism spectrum disorder, and schizophrenia. Retrotransposons provide a new perspective for understanding the molecular mechanisms underlying neurological diseases and provide insights into diagnostic and therapeutic strategies of these diseases.}, }
@article {pmid40128246, year = {2025}, author = {Hu, X and Wei, M and Zhang, H and Yu, M and Wang, M and Zhou, B and Luo, Y and Li, B}, title = {The experience of pain symptoms in patients with amyotrophic lateral sclerosis: a qualitative study.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {10183}, pmid = {40128246}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology ; Middle Aged ; Male ; Female ; *Pain/psychology/etiology ; *Qualitative Research ; Aged ; Adult ; Adaptation, Psychological ; Pain Management/methods ; }, abstract = {ALS is a progressive neurodegenerative disease that has a serious impact on patients and their caregivers. For a long time in the past, ALS was considered a painless disease that was largely ignored by clinicians. Describing the complexity and needs of pain symptoms from the perspective of patients can provide the most intuitive direction for future research. The purpose of our research is to explore the experience of pain symptoms in patients with amyotrophic lateral sclerosis (ALS), provide reference for better understanding of pain symptoms in ALS patients. From April 2023 to May 2023, 27 patients experiencing pain symptoms in Peking University Third Hospital who met the diagnostic criteria of "Chinese Guidelines for the Diagnosis and Treatment of amyotrophic lateral sclerosis" were interviewed by means of objective sampling. The content analysis method was used to describe the pain changes since the disease (amyotrophic lateral sclerosis), the factors that aggravate the pain, the measures to cope with the pain and the needs. The interview results included 3 themes and 11 subthemes. (1) Pain is diverse: the type of pain, the time when pain occurs, the change in pain intensity, and the factors that aggravate pain; (2) Individualized pain coping measures: posture adjustment, medication, physical therapy, warmth, emotional regulation; (3) Patients lack of understanding of pain: insufficient source of knowledge, the single orientation of the solution. The nature, location and aggravating factors of pain in amyotrophic lateral sclerosis patients in China are complicated, which should be paid attention to by clinical staff and scientific researchers. The situation of pain management is not optimistic, and the pain of the vast majority of patients has not been effectively alleviated. It is necessary to realize the importance of self-management and care of others in coping with pain, and conduct further research in the future to find a breakthrough in pain relief, so as to strengthen pain intervention in clinical practice.}, }
@article {pmid40126464, year = {2025}, author = {Shefner, JM and Cudkowicz, ME and Genge, A and Hardiman, O and Al-Chalabi, A and Andrews, JA and Chio, A and Corcia, P and Couratier, P and de Carvalho, M and Heiman-Patterson, T and Henderson, RD and Ingre, C and Johnston, W and Ludolph, A and Maragakis, NJ and Miller, TM and Mora, JS and Petri, S and Simmons, Z and van den Berg, LH and Zinman, L and Kupfer, S and Malik, FI and Meng, L and Simkins, TJ and Wei, J and Wolff, AA and Rudnicki, SA and , }, title = {Reldesemtiv in Amyotrophic Lateral Sclerosis: Results From the COURAGE-ALS Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {40126464}, issn = {2168-6157}, abstract = {IMPORTANCE: Treatment options for amyotrophic lateral sclerosis (ALS) remain suboptimal. Results from a phase 2 study of reldesemtiv in ALS suggested that it may slow disease progression.<br><br>OBJECTIVE: To assess the effect of reldesemtiv vs placebo on functional outcomes in ALS.<br><br>A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (COURAGE-ALS) was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted at 83 ALS centers in 16 countries from August 2021 to July 2023. The first 24-week period was placebo controlled vs reldesemtiv. All participants received reldesemtiv during the second 24-week period with a 4-week follow-up. Two interim analyses were planned, the first for futility and the second for futility and possible resizing. This was a hybrid decentralized trial with approximately half the trial visits performed remotely and the remaining visits in the clinic. Eligible participants met criteria for definite, probable, or possible ALS with lower motor neuron signs by modified El Escorial Criteria, ALS symptoms for 24 months or less, ALS Functional Rating Scale-Revised (ALSFRS-R) total score of 44 or less, and forced vital capacity of greater than or equal to 65% of predicted.<br><br>INTERVENTIONS: Oral reldesemtiv, 300 mg, or placebo twice daily.<br><br>MAIN OUTCOMES AND MEASURES: The primary end point was change in ALSFRS-R total score from baseline to week 24.<br><br>RESULTS: Of the 696 participants screened, 207 were screen failures. A total of 486 participants (mean [SD] age, 59.4 [10.9] years; 309 male [63.6%]) were randomized to reldesemtiv (n&#x2009;=&#x2009;325) or placebo (n&#x2009;=&#x2009;161); 3 randomized patients were not dosed. The second interim analysis at 24 weeks after randomization included 256 participants. The data monitoring committee recommended that the trial should end due to futility, and the sponsor agreed. The mean (SE) group difference in the ALSFRS-R score from baseline to week 24 was -1.1 (0.53; 95% CI,&#x2009;-2.17 to -0.08; P&#x2009;=&#x2009;.04, favoring placebo). Given excess missing data from early termination, the combined assessment assumed greater importance; it, too, failed to show a benefit from treatment with reldesemtiv (win probability was 0.44 for reldesemtiv and 0.49 for placebo, with a win ratio of 0.91; 95% CI of win ratio,&#x2009;0.77-1.10; P&#x2009;=&#x2009;.11).<br><br>CONCLUSIONS AND RELEVANCE: This randomized clinical trial failed to demonstrate efficacy for reldesemtiv in slowing functional decline in ALS.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04944784.}, }
@article {pmid40125959, year = {2025}, author = {Gupta, U and Kumar, A and Alam, MI and Balaji, PG and Sharma, A and Yadav, AK}, title = {Synthesis and characterization of protein nanohybrid systems for the brain delivery of Riluzole.}, journal = {Therapeutic delivery}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/20415990.2025.2478805}, pmid = {40125959}, issn = {2041-6008}, abstract = {AIMS: Synthesis and Characterization of Protein NanoHybrid Systems for the Brain Delivery of Riluzole.<br><br>METHODS/MATERIALS: Fullerene is converted into carboxylated fullerene (CF) and then, prepared RZU-loaded BSA nanoparticles conjugated with CF.<br><br>RESULTS: The particle size and zeta potential of RZU-PNH were found to be 210&#x2009;&#xb1;&#x2009;1.15&#x2009;nm and -18.5&#x2009;&#xb1;&#x2009;0.615&#x2009;mV respectively, and entrapment efficiency and loading efficiency of RZU-PNH were found to be 98.8&#x2009;&#xb1;&#x2009;0.53% and 11.6&#x2009;&#xb1;&#x2009;0.43%, respectively. The XRD of the RZU-PNH shows the amorphism behavior and CD revealed that secondary structure of the protein mainly consists of &#x3b1;-helix and&#x3b2;-sheet. The MTT assay showed 88.60% and 90.84% cell viability in both SH-SY5Yand N2a cell lines at a concentration of 20&#x2009;&#x3bc;g/ml and also, no significant nasal ciliotoxicity was observed after incubation with RZU-PNH.<br><br>CONCLUSIONS: Obtained results indicated RZU-PNH formulation to treat amyotrophic lateral sclerosis.}, }
@article {pmid40125702, year = {2025}, author = {Madhavan, S and Deshmukh, S and Cummings, M and Doshi, A and Rezania, K and Freels, S and Sawa, G}, title = {Home-Based Tele-tDCS in Amyotrophic Lateral Sclerosis: Feasibility, Safety, and Preliminary Efficacy.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70038}, pmid = {40125702}, issn = {2328-9503}, support = {R21HD102722//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Transcranial direct current stimulation (tDCS) shows promise as a neuromodulatory intervention in various neurological disorders, but its application in ALS, particularly in a remote, home-based format, remains underexplored. This study investigates the feasibility, safety, and preliminary efficacy of remotely supervised tele-tDCS in ALS patients.<br><br>METHODS: This double-blinded pilot study included 14 spinal-onset ALS participants randomized into two groups: the intervention group received 72 tele-tDCS sessions over 24&#x2009;weeks, and the delayed-start group received 36 sham sessions followed by 36 tele-tDCS sessions. Stimulation was delivered at 2&#x2009;mA for 20&#x2009;min 3 times a week. Primary outcomes included feasibility, safety, and disease progression measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Adherence and adverse effects were monitored throughout.<br><br>RESULTS: Ten participants completed the study, with an overall compliance rate of 98.3%. No serious adverse events were reported, and mild side effects, like itching and tingling, were consistent with tDCS literature. The intervention group demonstrated a significantly slower decline in ALSFRS-R scores than the delayed-start group. At 24&#x2009;weeks, the intervention group had a mean ALSFRS-R change of -1.7, compared to -13.6 in the delayed-start group (p&#x2009;=&#x2009;0.0018). Additionally, the change in ALSFRS-R between pre- and mid-intervention significantly differed between groups (p&#x2009;=&#x2009;0.0071).<br><br>INTERPRETATION: Tele-tDCS was feasible, safe, and well-tolerated in individuals with ALS. Preliminary efficacy results suggest that tele-tDCS may slow disease progression, underscoring the potential of tele-tDCS as a promising home-based neuromodulatory intervention in ALS management.<br><br>TRIAL REGISTRATION: Clinical trial registration: NCT04866771.}, }
@article {pmid40124885, year = {2025}, author = {Dethier, C and Azirar, S and Verluyten, L and Boonen, H and Grosber, M and Gutermuth, J}, title = {Response to Fässler et al's "Successful treatment of refractory folliculitis decalvans with apremilast".}, journal = {JAAD case reports}, volume = {57}, number = {}, pages = {122-123}, pmid = {40124885}, issn = {2352-5126}, }
@article {pmid40116361, year = {2025}, author = {Li, C and Noonan, AM and Hays, J and Roychowdhury, S and Malalur, P and Elkhatib, R and Manne, A and Mittra, A and Rahman, S and Yan, L and Hill, K and Abbott, N and Phelps, M and Na, JY and Liang, B and Storts, H and Khan, M and Zhang, EH and Miles, W and Yildiz, V and Wei, L and Wang, JJ and Jin, N}, title = {Riluzole in Combination with mFOLFOX6 and Bevacizumab in Treating Patients with Metastatic Colorectal Cancer: A Phase 1 Clinical Trial.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-3964}, pmid = {40116361}, issn = {1557-3265}, abstract = {BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the US. 5-fluorouracil (5-FU)-based chemotherapies in combination with targeted agents remain the standard of care in patients with metastatic or locally advanced disease. New treatment strategies are needed for metastatic CRC patients with microsatellite stable disease. Preclinical studies showed that riluzole, an oral medicine for amyotrophic lateral sclerosis, inhibits glutamate release and synergizes with 5-FU to reduce cell viability in CRC cell lines.<br><br>METHODS: In this single-arm, phase 1 trial of riluzole in combination with mFOLFOX6/bevacizumab for patients with metastatic CRC, the riluzole dose started at 50 mg twice daily, escalating to 100 mg twice daily or de-escalating to 50 mg once daily. Patients received riluzole for 16 weeks in combination with mFOLOFX6/bevacizumab for 8 cycles. Patients then either continued mFOLFOX6/bevacizumab or switched therapy.<br><br>RESULTS: Twelve of the 14 patients enrolled were evaluable. All patients previously received FOLFOX, and 5 patients (41.7%) showed disease resistance to it. Two patients obtained partial responses, 9 had stable disease, and 1 had progressive disease. The objective response rate was 16.7%, and the disease control rate was 91.7%. The median duration of response was 4.9 months (95% CI 1.6-9.8). Median progression-free survival and overall survival were 4.89 and 12.98 months, respectively.<br><br>CONCLUSION: Our study showed that riluzole plus mFOLFOX6/bevacizumab is well tolerated in patients with metastatic CRC and may have clinical activity in patients whose disease is resistant to FOLFOX.}, }
@article {pmid40116017, year = {2025}, author = {Addy, G and Scirocco, E and Gelevski, D and Rohrer, M and Roderick, A and McCormack, M and Weiss Sadan, A and Scalia, J and Parikh, N and Giacomelli, E and Locatelli, M and Neel, DV and D'Agostino, D and Leite, A and Yu, H and Sherman, AV and Mock, J and Kalmes, A and Luppino, S and Babu, S and Berry, J and Cudkowicz, M and Paganoni, S}, title = {An Expanded Access Protocol of RNS60 in Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28398}, pmid = {40116017}, issn = {1097-4598}, support = {//The study drug was provided at no cost by Revalesio, and program costs were covered by philanthropic donations to the Sean M. Healey &amp; AMG Center for ALS/ ; }, abstract = {AIMS: RNS60 is an investigational product in clinical development for amyotrophic lateral sclerosis (ALS). RNS60 slowed disease progression in the ALS SOD1[G93A] mouse model and was safe and well tolerated both in an open-label pilot study and a randomized, placebo-controlled, multicenter phase 2 trial in people living with ALS. The objective of this ongoing expanded access protocol (EAP) was to provide RNS60 to people living with ALS who are ineligible for controlled clinical trials and to collect data on the safety and tolerability of dosing RNS60 via twice-daily nebulization rather than the previously studied daily nebulization with weekly intravenous administration.<br><br>METHODS: Eligible participants (&#x2265;&#x2009;18&#x2009;years old, diagnosed with ALS per investigator assessment, and ineligible for an ALS clinical trial testing RNS60) were treated with twice-daily nebulization of RNS60 at home. Safety was evaluated by the assessment of adverse events and routine safety labs.<br><br>RESULTS: A total of 84 participants have been treated with RNS60 via nebulization twice daily for up to 48&#x2009;months so far. The most common treatment-related adverse event was increased secretions [N&#x2009;=&#x2009;27 (32%)]. Serious adverse events (SAEs) [69 occurrences; N&#x2009;=&#x2009;38 (45%) with at least one SAE] and deaths [N&#x2009;=&#x2009;24 (28%)] were deemed not related to RNS60.<br><br>DISCUSSION: This EAP supports the benign side effect profile of RNS60 when administered via twice-daily nebulization and demonstrates the feasibility of long-term EAPs as a complementary approach to controlled trials in people with advanced ALS.}, }
@article {pmid40105291, year = {2025}, author = {Ozeki-Hayashi, R and Wilkinson, DJC}, title = {'An Unimaginable Challenge': A Cross-Cultural Qualitative Study of Ethics and Decision-Making Around Tracheostomy Ventilation in Patients with Amyotrophic Lateral Sclerosis.}, journal = {AJOB empirical bioethics}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/23294515.2025.2474928}, pmid = {40105291}, issn = {2329-4523}, abstract = {BACKGROUND: The rate of tracheostomy with invasive ventilation (TIV) for patients with Amyotrophic Lateral Sclerosis (ALS) varies widely. Previous studies have shown that doctors' values may affect decision-making. There have been no previous international qualitative comparisons of medical decision-making process for TIV or why practice varies.<br><br>METHODS: We conducted semi-structured in-depth interviews with 16 doctors actively involved in the management of ALS patients from Japan (n&#x2009;=&#x2009;7), the UK (n&#x2009;=&#x2009;5), and the US (n&#x2009;=&#x2009;4). We used three hypothetical cases to explore decision-making. Conversations were transcribed and thematically analyzed.<br><br>RESULTS: Our data reveals similarities but also marked differences in views between the US, the UK and Japan. Almost all participants stated that they ought to respect patient autonomy. However, their approaches varied. British participants wanted to (and felt that they should) respect patient autonomy, but they also believed that TIV was not a realistic option. US participants were likely to prioritize patient autonomy over other ethical principles, and Japanese participants were likely to limit patient autonomy indirectly. The option of TIV appeared to be heavily influenced by the availability of healthcare resources in all three countries. The high cost, limited availability and difficulty of treatment meant that particularly in the UK and the US, it is challenging to receive TIV even if patients wanted this.<br><br>CONCLUSIONS: Our study illustrates how the emphasis on autonomy varies along with variations in the way care is organized in the setting of highly resource intensive treatment and progressive severe disabling illness. There is a need to review elements of the decision-making process in all three countries. This includes the need for transparent, ideally centralized, decision-making guidelines about the provision of TIV. Although we investigated a rare neuromuscular disease, our results will be relevant to other diseases requiring highly resource-intensive treatment toward the end of life.}, }
@article {pmid40105198, year = {2025}, author = {Gotkine, M and Schoenfeld, DA and Cohen, I and Shefner, JM and Lerner, Y and Cohen, IR and Klein, C and Ovadia, E and Cudkowicz, ME and , }, title = {Akt Activation With IPL344 Treatment for Amyotrophic Lateral Sclerosis: First in Human, Open-Label Study.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28393}, pmid = {40105198}, issn = {1097-4598}, support = {//Immunity Pharma/ ; }, abstract = {INTRODUCTION/AIMS: Akt intracellular signal transduction pathway dysfunction has been reported in people with amyotrophic lateral sclerosis (ALS) providing a novel target for intervention in this devastating progressive disease. This first-in-human study evaluated the safety, tolerability, and preliminary efficacy of the Akt pathway activator, IPL344, in people with ALS.<br><br>METHODS: Nine participants with ALS and a progression rate >&#x2009;0.55 points/month on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) received open-label IPL344 treatment (once-daily) for up to 36&#x2009;months. Safety was assessed through adverse event (AE) reporting. Plasma neurofilament light chain (NfL) concentrations were measured before and after treatment. Clinical outcomes were compared to historical data.<br><br>RESULTS: The mean&#x2009;&#xb1;&#x2009;SD duration of IPL344 follow-up was 14.0&#x2009;&#xb1;&#x2009;12.5&#x2009;months. One participant developed drug hypersensitivity, two had central venous catheter-related AEs, and two had serious pneumonia AEs. The unadjusted mean&#x2009;&#xb1;&#x2009;SE slope of decline in ALSFRS-R was -0.53&#x2009;&#xb1;&#x2009;0.15 (48% slower progression vs. historical controls, p&#x2009;=&#x2009;0.028). Adjustment for disease stage and rate-indicating covariates indicated a 64% slower ALSFRS-R progression (p&#x2009;=&#x2009;0.034), with increased rather than reduced body weight (p&#x2009;=&#x2009;0.02). Eight of nine IPL344-treated participants had a significantly improved slope compared to the median slope of a matched control group (p&#x2009;=&#x2009;0.04). Plasma NfL concentrations were lowered by 27% (n&#x2009;=&#x2009;6). Unadjusted median survival for participants in the IPL344 group was 43.4&#x2009;months [95% CI: 20.5, NA] compared with 19.1&#x2009;months [17.4, 23.0] in the historical control group.<br><br>DISCUSSION: These preliminary data indicate that IPL344 was safe and well-tolerated, and possibly effective. Our findings may merit further investigation in a larger placebo-controlled clinical trial.}, }
@article {pmid40100917, year = {2025}, author = {Thau-Habermann, N and Gschwendtberger, T and Bodemer, C and Petri, S}, title = {Parthenolide regulates microglial and astrocyte function in primary cultures from ALS mice and has neuroprotective effects on primary motor neurons.}, journal = {PloS one}, volume = {20}, number = {3}, pages = {e0319866}, pmid = {40100917}, issn = {1932-6203}, mesh = {Animals ; *Microglia/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Sesquiterpenes/pharmacology ; *Motor Neurons/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; Mice ; *Astrocytes/drug effects/metabolism ; Cells, Cultured ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; }, abstract = {Over the last twenty years, the role of microgliosis and astrocytosis in the pathophysiology of neurodegenerative diseases has increasingly been recognized. Dysregulation of microglial and astrocyte properties and function has been described also in the fatal degenerative motor neuron disease amyotrophic lateral sclerosis (ALS). Microglia cells, the immune cells of the nervous system, can either have an immunonegative neurotoxic or immunopositive neuroprotective phenotype. The feverfew plant (Tanacetum parthenium) derived compound parthenolide has been found to be capable of interfering with microglial phenotype and properties. Positive treatment effects were shown in animal models of neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. Now we were able to show that PTL has a modulating effect on primary mouse microglia cells, both wild type and SOD1, causing them to adopt a more neuroprotective potential. Furthermore, we were able to show that PTL, through its positive effect on microglia, also has an indirect positive impact on motor neurons, although PTL itself has no direct effect on these primary motor neurons. The results of our study give reason to consider PTL as a drug candidate for ALS.}, }
@article {pmid40100796, year = {2025}, author = {Giroud, M and Kuhn, B and Steiner, S and Westwood, P and Mendel, M and Mani, A and Pinard, E and Haap, W and Grether, U and Caramenti, P and Rombach, D and Zambaldo, C and Ritter, M and Schmid, P and Gasser, C and Aregger, N and Séchet, N and Topp, A and Bilyard, M and Malnight-Alvarez, A and Plitzko, I and Hilbert, M and Kalayil, S and Burger, D and Bonardi, C and Saal, W and Haider, A and Wittwer, MB and Brigo, A and Benz, J and Keaney, J}, title = {Discovery of a Potent SARM1 Base-Exchange Inhibitor with In Vivo Efficacy.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {6}, pages = {6558-6575}, doi = {10.1021/acs.jmedchem.4c03127}, pmid = {40100796}, issn = {1520-4804}, mesh = {Animals ; *Armadillo Domain Proteins/antagonists &amp; inhibitors/metabolism ; Mice ; *Cytoskeletal Proteins/antagonists &amp; inhibitors/metabolism ; Humans ; Structure-Activity Relationship ; Drug Discovery ; Male ; }, abstract = {Sterile alpha and TIR Motif Containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD[+]) hydrolase that plays a central role in programmed axonal degeneration. Axonal degeneration has been linked to neurodegenerative and neurological disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and peripheral neuropathies. Therefore, developing potent and selective SARM1 inhibitors could be an effective strategy to treat these disorders. We present herein the structure-guided discovery of two novel SARM1 inhibitors, 7 and 35. Compounds 7 and 35 are potent inhibitors across assays and possess favorable ADMET properties. When tested in vivo, compound 7 showed efficacy after oral dosing in a mouse model of peripheral nerve injury by decreasing plasma neurofilament light (NfL) levels at 50 mg/kg compared with vehicle-treated control mice, holding promise for the treatment of neurodegenerative and neurological disorders.}, }
@article {pmid40099804, year = {2025}, author = {Zheng, W and Zhang, X and Chen, J and Luan, X and Wang, J and Zhang, L and Liu, K and Zhao, Y and Xu, Z}, title = {The Effect of Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex on the Amyotrophic Lateral Sclerosis Patients With Cognitive Impairment: A Double-Blinded, Randomized, and Sham Control Trial.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {31}, number = {3}, pages = {e70316}, pmid = {40099804}, issn = {1755-5949}, support = {20YF1436400//Shanghai Sailing program/ ; 23DZ2291500//Shanghai Science and Technology Innovation Action Plan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications/psychology ; *Transcranial Magnetic Stimulation/methods ; Double-Blind Method ; Male ; Female ; Middle Aged ; Aged ; *Cognitive Dysfunction/therapy/etiology/psychology ; *Dorsolateral Prefrontal Cortex/physiology ; Treatment Outcome ; Prefrontal Cortex ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. A large number of ALS patients have cognitive impairment. In this double-blinded, randomized, and sham-controlled study, we aimed to investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on ALS patients with cognitive impairment.<br><br>METHODS: A total of 90 ALS patients with cognitive impairment were recruited from two cohorts; 80 participants were randomly assigned in a 1:1 ratio to receive 10&#x2009;Hz rTMS or sham treatment on the bilateral dorsolateral prefrontal cortices (DLPFC) for 4 consecutive weeks. The patients were assessed by ECAS and ALSFRS-R scales. The Zarit care burden scale was administered to caregivers of ALS patients. The primary outcome measured was the rate of decline in the total ECAS score between pretreatment, 6&#x2009;months post-treatment, and 12&#x2009;months post-treatment. Secondary outcomes included the group difference in the slope of the Zarit score, ALSFRS-R total score, and the neurofilament light chain plasma levels.<br><br>RESULTS: The ECAS total score in the intention-to-treat population significantly changed from 79.74&#x2009;&#xb1;&#x2009;6.39 to 81.98&#x2009;&#xb1;&#x2009;6.51 and 79.22&#x2009;&#xb1;&#x2009;6.50 with rTMS intervention at the 6-month and 12-month follow-ups, respectively (p&#x2009;=&#x2009;0.031, p&#x2009;=&#x2009;0.042). The Zarit score also significantly decreased from 57.65&#x2009;&#xb1;&#x2009;3.42 to 52.24&#x2009;&#xb1;&#x2009;3.34 and 56.42&#x2009;&#xb1;&#x2009;3.41 at the 3-month and 6-month post-treatment time points, respectively (p&#x2009;=&#x2009;0.003, p&#x2009;=&#x2009;0.014). No significant differences were observed between the groups for other secondary endpoints. However, there was a trend of decreasing NF-L level rates in the treatment group over the first 6&#x2009;months' follow-up.<br><br>CONCLUSIONS: rTMS could yield short-term positive effects on the ALS patients subgroup with cognitive impairment and alleviate caregivers' burden. No improvement was observed in the severity of ALS and ALS plasma biomarkers.}, }
@article {pmid40099353, year = {2025}, author = {Giorgio, CM and Tancredi, V and Licata, G and Moscarella, E and Argenziano, G and Fulgione, E and Babino, G and Franzese, P and Di Brizzi, EV}, title = {Cutting-edge insights: LC-OCT and 5% cyclosporine for early lichen sclerosus treatment.}, journal = {Dermatology reports}, volume = {}, number = {}, pages = {}, doi = {10.4081/dr.2025.10279}, pmid = {40099353}, issn = {2036-7392}, abstract = {Dear Editor, Atrophic lichen sclerosus (ALS) is a chronic inflammatory dermatosis with significant morbidity, primarily affecting genital areas. The disease is often misdiagnosed or underdiagnosed, resulting in delayed treatment and progression to atrophic stages and permanent scars. While corticosteroids remain the first-line treatment, their long-term use may lead to adverse effects such as skin atrophy, prompting the need for alternative therapies. Cyclosporine, a calcineurin inhibitor, has shown efficacy in managing immune-mediated skin diseases and is delivered effectively through the Pentravan® vehicle. [...].}, }
@article {pmid40097762, year = {2025}, author = {Nabakhteh, S and Lotfi, A and Afsartaha, A and Khodadadi, ES and Abdolghaderi, S and Mohammadpour, M and Shokri, Y and Kiani, P and Ehtiati, S and Khakshournia, S and Khatami, SH}, title = {Nutritional Interventions in Amyotrophic Lateral Sclerosis: From Ketogenic Diet and Neuroprotective Nutrients to the Microbiota-Gut-Brain Axis Regulation.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40097762}, issn = {1559-1182}, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with significant challenges in diagnosis and treatment. Recent research has highlighted the complex nature of ALS, encompassing behavioral impairments in addition to its neurological manifestations. While several medications have been approved to slow disease progression, ongoing research is focused on identifying new therapeutic targets. The current review focuses on emerging therapeutic strategies and personalized approaches aimed at improving patient outcomes. Recent advancements highlight the importance of targeting additional pathways such as mitochondrial dysfunction and neuroinflammation to develop more effective treatments. Personalized medicine, including genetic testing and biomarkers, is proving valuable in stratifying patients and tailoring treatment options. Complementary therapies, such as nutritional interventions like the ketogenic diet and microbiome modulation, also show promise. This review emphasizes the need for a multidisciplinary approach that integrates early diagnosis, targeted treatments, and supportive care to address the multisystemic nature of ALS and improve the quality of life for patients.}, }
@article {pmid40097075, year = {2025}, author = {Cuevas, EP and Madruga, E and Valenzuela-Martínez, I and Ramírez, D and Gil, C and Nagaraj, S and Martin-Requero, A and Martinez, A}, title = {MicroRNA signature of lymphoblasts from amyotrophic lateral sclerosis patients as potential clinical biomarkers.}, journal = {Neurobiology of disease}, volume = {208}, number = {}, pages = {106871}, doi = {10.1016/j.nbd.2025.106871}, pmid = {40097075}, issn = {1095-953X}, abstract = {MicroRNAs (miRNAs) are a class of small, non-coding RNAs involved in different cellular functions that have emerged as key regulators of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). ALS is a fatal disease that lacks of not only effective treatments, but also presents delays in its diagnosis, since reliable clinical biomarkers are unavailable. In recent years, advancements in high-throughput sequencing strategies have led to the identification of novel ALS biomarkers, facilitating earlier diagnosis and assessment of treatment efficacy. Since immortalized lymphocytes obtained from peripheral blood are a suitable model to study pathological features of ALS, we employed these samples with the aim of characterize the dysregulated miRNAs in ALS patients. Next-generation sequencing (NGS) was utilized in order to analyze the expression profiles of miRNAs in immortalized lymphocytes from healthy controls, sporadic ALS (sALS), and familial ALS with mutations in superoxide dismutase 1 (SOD1-ALS). The screening analysis of the NGS data identified a set of dysregulated miRNAs, of which nine candidates were selected for qRT-PCR validation, identifying for the first time the possible importance of hsa-miR-6821-5p as a potential ALS biomarker. Furthermore, the up-regulated miRNAs identified are predicted to have direct or indirect interactions with genes closely related to ALS, such as SIGMAR1, HNRNPA1 and TARDBP. Additionally, by Metascape enrichment analysis, we found the VEGFA/VEGFR2 signaling pathway, previously implicated in neuroprotective effects in ALS, as a candidate pathway for further analyses.}, }
@article {pmid40095345, year = {2025}, author = {Dehghani, S and Ocakcı, O and Hatipoglu, PT and Özalp, VC and Tevlek, A}, title = {Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40095345}, issn = {1559-1182}, abstract = {Neurodegenerative diseases (NDs) like Alzheimer's, Parkinson's, and ALS rank among the most challenging global health issues, marked by substantial obstacles in early diagnosis and effective treatment. Current diagnostic techniques frequently demonstrate inadequate sensitivity and specificity, whilst conventional treatment strategies encounter challenges related to restricted bioavailability and insufficient blood-brain barrier (BBB) permeability. Recently, exosomes-nanoscale vesicles packed with proteins, RNAs, and lipids-have emerged as promising agents with the potential to reshape diagnostic and therapeutic approaches to these diseases. Unlike conventional drug carriers, they naturally traverse the BBB and can deliver bioactive molecules to affected neural cells. Their molecular cargo can influence cell signaling, reduce neuroinflammation, and potentially slow neurodegenerative progression. Moreover, exosomes serve as non-invasive biomarkers, enabling early and precise diagnosis while allowing real-time disease monitoring. Additionally, engineered exosomes, loaded with therapeutic molecules, enhance this capability by targeting diseased neurons and overcoming conventional treatment barriers. By offering enhanced specificity, reduced immunogenicity, and an ability to bypass physiological limitations, exosome-based strategies present a transformative advantage over existing diagnostic and therapeutic approaches. This review examines the multifaceted role of exosomes in NDDs, emphasizing their diagnostic capabilities, intrinsic therapeutic functions, and transformative potential as advanced treatment vehicles.}, }
@article {pmid40092960, year = {2025}, author = {Liu, Y and Li, XF}, title = {Characteristics and therapeutic strategies for familial gastrointestinal stromal tumors.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {3}, pages = {100463}, pmid = {40092960}, issn = {1948-5204}, abstract = {This editorial discusses Wang et al's article on familial gastrointestinal stromal tumors (GISTs). We read with great interest this article concerning the diagnosis, treatment, and post-treatment management of patients with familial GISTs. The actual incidence of GISTs may be underestimated due to diagnostic limitations and the long-term low-risk behavior of some GISTs. The molecular landscape of GISTs is primarily driven by mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. A subset of GISTs without these mutations known as wild-type GISTs, may harbor other rare mutations, impacting their response to targeted therapies. Clinically, patients with GISTs present with non-specific symptoms, often leading to delayed diagnosis. Genetic predispositions in familial GISTs provide insights into the genetic architecture and extragastrointestinal manifestations of GISTs. Management has evolved from surgical interventions to molecular-based therapies using tyrosine kinase inhibitors. The management of GISTs, especially in familial cases, requires a multidisciplinary approach. Cases of different gene mutations were reported in the same family, suggesting that incorporating genetic testing into routine clinical practice is crucial for the early identification of high-risk individuals and the implementation of tailored surveillance programs.}, }
@article {pmid40091916, year = {2025}, author = {Ansari, U and Wen, J and Karabala, M and Syed, B and Abed, I and Razick, DI and Lui, F}, title = {Analysis of Respiratory Muscle Strength Training in Amyotrophic Lateral Sclerosis (ALS) Patients: A Systematic Review.}, journal = {Cureus}, volume = {17}, number = {2}, pages = {e78903}, pmid = {40091916}, issn = {2168-8184}, abstract = {Respiratory muscle weakness is a significant contributor to morbidity and mortality in amyotrophic lateral sclerosis (ALS) patients. Respiratory muscle strength training (RMST) has emerged as a potential therapeutic approach to mitigate respiratory muscle weakness in ALS. Still, its efficacy and safety remain unclear due to conflicting evidence and methodological heterogeneity in existing studies. A systematic review was conducted across three databases (PubMed (United States National Library of Medicine, Bethesda, MD, USA), Embase (Elsevier, Amsterdam, Netherlands), and Cochrane Library (Cochrane, Alberta, Canada)) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to assess the effectiveness of RMST in ALS patients. Eligible studies included comparative studies for RMST, focusing on outcomes such as maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and ALS Functional Rating Scale (ALSFRS-R). Quality assessment was performed using the Cochrane Risk of Bias tool. This study included six studies, including 183 patients with a mean age of 58.0 years (49.6 to 63.2) and a mean follow-up time of 21.2 weeks (eight to 52). The average mean difference for ALSFRS-R (three studies), MIP (three studies), MEP (three studies), and FVC (two studies) were 2.062 (0.04 to 5.3), 2.285 (-8.145 to 10.8), 19.435 (10.86 to 21.7), and 7.23 (3.6 to 10.86), respectively. Complications related to RMST were poorly reported across studies. Secondary outcomes, such as depression scores, blood oxygen levels, and heart rate variability, showed promising trends but lacked consistency. Despite positive findings on respiratory muscle strength, RMST's efficacy in ALS management remains inconclusive. Challenges include methodological heterogeneity, limited sample sizes, and inadequate reporting of complications. Future research should focus on standardized protocols, larger sample sizes, longer follow-ups, and comprehensive assessment of adverse effects to clarify the role of RMST in ALS treatment.}, }
@article {pmid40090808, year = {2025}, author = {Rosina, M and Scaricamazza, S and Fenili, G and Nesci, V and Valle, C and Ferri, A and Paronetto, MP}, title = {Hidden players in the metabolic vulnerabilities of amyotrophic lateral sclerosis.}, journal = {Trends in endocrinology and metabolism: TEM}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tem.2025.02.004}, pmid = {40090808}, issn = {1879-3061}, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and rapidly progressive motor neuron disorder with a fatal outcome. Despite the remarkable progress in understanding ALS pathophysiology, which has significantly contributed to clinical trial design, ALS remains a rapidly disabling and life-shortening condition. The non-motor neuron features of ALS, including nutritional status, energy expenditure, and metabolic imbalance, are increasingly gaining attention. Indeed, the bioenergetic failure and mitochondrial dysfunction of patients with ALS impact not only the high energy-demanding motor neurons but also organs and brain areas long considered irrelevant to the disease. As such, here we discuss how considering energy balance in ALS is reshaping research on this disease, opening the path to novel targetable opportunities for its treatment.}, }
@article {pmid40089090, year = {2025}, author = {Men, J and Wang, X and Zhou, Y and Huang, Y and Zheng, Y and Wang, Y and Yang, S and Chen, N and Yan, N and Duan, X}, title = {Neurodegenerative diseases: Epigenetic regulatory mechanisms and therapeutic potential.}, journal = {Cellular signalling}, volume = {131}, number = {}, pages = {111715}, doi = {10.1016/j.cellsig.2025.111715}, pmid = {40089090}, issn = {1873-3913}, abstract = {Neurodegenerative diseases (NDDs) are a class of diseases in which the progressive loss of subtype-specific neurons leads to dysfunction. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), among others. Previous studies have demonstrated that the pathogenesis of NDDs involves various mechanisms, including genetic factors, oxidative stress, apoptosis, and the immune response. Recent studies have shown that epigenetic regulation mediates the interactions between DNA methylation, chromatin remodeling, histone modification, and non-coding RNAs, thus affecting gene transcription. A growing body of research links epigenetic modifications to crucial pathways involved in the occurrence and development of NDDs. Epigenetics has also been found to regulate and maintain nervous system function, and its imbalance is closely related to the occurrence and development of NDDs. The present review summarizes focuses on the role of epigenetic modifications in the pathogenesis of NDDs and provides an overview of the key genes regulated by DNA methylation, histone modification, and non-coding RNAs in NDDs. Further, the current research status of epigenetics in NDDs is summarized and the potential application of epigenetics in the clinical diagnosis and treatment of NDDs is discussed.}, }
@article {pmid40076771, year = {2025}, author = {Aguiar, B and Alfenim, AR and Machado, CS and Moreira, J and Pinto, M and Otero-Espinar, FJ and Borges, F and Fernandes, C}, title = {Exploring Nano-Delivery Systems to Enhance the Edaravone Performance in Amyotrophic Lateral Sclerosis Treatment.}, journal = {International journal of molecular sciences}, volume = {26}, number = {5}, pages = {}, pmid = {40076771}, issn = {1422-0067}, support = {2023.13291.PEX//Foundation for Science and tecnhology/ ; UIDB/00081/2020 (CIQUP)//Foundation for Science and Technology/ ; LA/P/0056/2020(IMS)//Foundation for Science and Technology/ ; 2021.04016.CEECIND/CP1655/CT0004//Foundation for Science and Technology/ ; IMPULSE: IMproving User experience, Long-term sustainability, and Services//EU-OPENSCREEN HORIZON-INFRA-2023-DEV-0/ ; 2020.08731.BD//Foundation for Science and Technology/ ; 2023.01250.BD//Foundation for Science and Technology/ ; 2024.00809.BD//Foundation for Science and Technology/ ; SFRH/BD/145637/2019//Foundation for Science and Technology/ ; }, mesh = {*Edaravone/pharmacology/chemistry/administration &amp; dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Nanoparticles/chemistry ; Drug Delivery Systems/methods ; Free Radical Scavengers/chemistry/pharmacology ; Drug Carriers/chemistry ; Nanoparticle Drug Delivery System/chemistry ; Polyethylene Glycols/chemistry ; }, abstract = {Edaravone is one of the treatment options for Amyotrophic Lateral Sclerosis, but its therapeutic efficacy is limited due to the incapacity to cross the blood-brain barrier, as well as its short life span and poor stability, which is ultimately caused by its tautomerism in physiological condions. This work presents an overview about the use of several nanoformulations based on polymeric, protein, lipidic, or hybrid structure as suitable and stable drug delivery systems for encapsulating edaravone. We also evaluated the functionalization of nanoparticles with pegylated chains using the polyethylene glycol or tocopherol polyethylene glycol succinate and the possibility of preparing polymeric nanoparticles at different pH (7.4, 9, and 11). Edaravone was sucessfully encapsulated in polymeric, lipid-polymer hybrid, and lipidic nanoparticles. The use of higher pH values in the synthesis of polymeric nanoparticles has led to a decrease in nanoparticle size and an increase in the percentage of encapsulation efficiency. However, the resulting nanoformulations are not stable. Only polymeric and hybrid nanoparticles showed good stability over 80 days of storage, mainly at 4 °C. Overall, the nanoformulations tested did not show cytotoxicity in the SH-SY5Y cell line except the nanostructured lipid carrier formulations that showed some cytotoxicity possibly due to lipidic peroxidation. In conclusion, this work shows that edaravone can be encapsulated in different nanocarriers that could act as an interesting alternative for the treatment of Amyotrophic Lateral Sclerosis.}, }
@article {pmid40069959, year = {2025}, author = {Chiò, A and Foucher, J and Gwathmey, KG and Ingre, C}, title = {Minimum clinically important difference for drug effectiveness in an area of patient-oriented therapeutic goals in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2475893}, pmid = {40069959}, issn = {2167-9223}, abstract = {Objective: In this review, we will examine the more common endpoints incorporated in randomized controlled trials (RCTs) and their strength of evidence, focusing on the definition of what constitutes a clinically meaningful change. We will also reflect on the perspective of patients and their families regarding the design of RCTs in amyotrophic lateral sclerosis (ALS). Methods: Authors performed a scoping review of the literature around clinical meaningfulness in the ALS field and the minimum clinically important difference to deem a treatment effective. Results: The use of survival as an RCT endpoint, as well as the ALS functional rating scale-revised slope, has been criticized, and their relevance for patients remains debated. Biomarkers are promising alternatives as surrogate endpoints, but currently, only cerebrospinal fluid and plasma neurofilaments have emerged as reliable and sensitive biomarkers of disease progression. Incorporating patients' preferences and priorities for their care when treatments are selected is important to minimize the burden of care and limit the potential harms of overtreatment. Patients' interest in and acceptance of a new therapy is also determined by its impact on their quality of life. Discussion and conclusion: While scientifically sound trials must be conducted, this must be balanced with patient expectations of limiting trial burden, duration and placebo usage. An important approach in uniting these diverging needs is the inclusion of people with ALS and their organizations to advise in the design and execution of clinical trials, facilitating the design of RCTs more focused on patients' expectations while retaining a high scientific rigor.}, }
@article {pmid40067821, year = {2025}, author = {,  and Berry, JD and Maragakis, NJ and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Stommel, EW and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, KJ and Simmons, Z and Miller, T and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, L and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, C and Ladha, S and Heiman-Patterson, T and Caress, J and Swenson, A and Peltier, A and Lewis, R and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, CE and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Glass, J and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Rynders, A and Evan, J and Evan, J and Hartford, A and Sepassi, M and Ho, KS and Glanzman, R and Greenberg, B and Hotchkin, MT and Paganoni, S and Cudkowicz, ME and , }, title = {CNM-Au8 in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.}, journal = {JAMA}, volume = {333}, number = {13}, pages = {1138-1149}, pmid = {40067821}, issn = {1538-3598}, abstract = {IMPORTANCE: Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD+, resulting in an increase of cellular adenosine triphosphate production.<br><br>OBJECTIVE: To determine the effects of CNM-Au8 on ALS disease progression.<br><br>CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n&#x2009;=&#x2009;120) or regimen-specific placebo (n&#x2009;=&#x2009;41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses.<br><br>INTERVENTIONS: Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n&#x2009;=&#x2009;61), CNM-Au8 30 mg daily (n&#x2009;=&#x2009;59), or matching placebo (n&#x2009;=&#x2009;41) for 24 weeks.<br><br>MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation.<br><br>RESULTS: Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n&#x2009;=&#x2009;120) vs placebo (n&#x2009;=&#x2009;163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]).<br><br>CONCLUSIONS AND RELEVANCE: No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04414345.}, }
@article {pmid40067755, year = {2025}, author = {,  and Shefner, JM and Oskarsson, B and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Heiman-Patterson, T and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, AV and Hall, M and Kittle, G and Berry, JD and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, K and Maragakis, NJ and Simmons, Z and Miller, TM and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, LA and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, CE and Ladha, S and Caress, JB and Swenson, A and Peltier, A and Lewis, RA and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, C and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Leitner, ML and Chen, K and Goldberg, YP and Cohen, Y and Geva, M and Hayden, MR and Paganoni, S and Cudkowicz, ME and , }, title = {Pridopidine in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.}, journal = {JAMA}, volume = {333}, number = {13}, pages = {1128-1137}, pmid = {40067755}, issn = {1538-3598}, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.<br><br>OBJECTIVE: To determine the effects of pridopidine, a &#x3c3;1-receptor agonist, in ALS.<br><br>Pridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.<br><br>INTERVENTIONS: Eligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n&#x2009;=&#x2009;121) or matching oral placebo (n&#x2009;=&#x2009;42) for a planned duration of 24 weeks.<br><br>MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.<br><br>RESULTS: Among 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR <1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n&#x2009;=&#x2009;121; placebo, n&#x2009;=&#x2009;163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).<br><br>CONCLUSIONS AND RELEVANCE: In this 24-week study, pridopidine did not impact the progression of ALS.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04615923.}, }
@article {pmid40067754, year = {2025}, author = {,  and Andrews, J and Paganoni, S and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Young, E and Chase, M and Pothier, L and Harkey, B and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Connolly, MR and Berry, JD and D'Agostino, D and Tustison, E and Giacomelli, E and Scirocco, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Heitzman, D and Ajroud-Driss, S and Appel, SH and Shroff, S and Katz, J and Felice, K and Maragakis, NJ and Simmons, Z and Goutman, SA and Olney, N and Miller, T and Fernandes, JA and Ilieva, H and Jawdat, O and Weiss, MD and Foster, L and Vu, T and Ladha, S and Owegi, MA and Newman, DS and Arcila-Londono, X and Jackson, CE and Swenson, A and Heiman-Patterson, T and Caress, J and Fee, D and Peltier, A and Lewis, R and Rosenfeld, J and Walk, D and Johnson, K and Elliott, M and Kasarskis, EJ and Rutkove, S and McIlduff, CE and Bedlack, R and Elman, L and Goyal, NA and Rezania, K and Twydell, P and Benatar, M and Glass, J and Cohen, JA and Jones, V and Zilliox, L and Wymer, JP and Beydoun, SR and Shah, J and Pattee, GL and Martinez-Thompson, J and Nayar, S and Granit, V and Donohue, M and Grossman, K and Campbell, DJ and Qureshi, IA and Cudkowicz, ME and Babu, S and , }, title = {Verdiperstat in Amyotrophic Lateral Sclerosis: Results From the Randomized HEALEY ALS Platform Trial.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {40067754}, issn = {2168-6157}, abstract = {IMPORTANCE: Myeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.<br><br>OBJECTIVE: To determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.<br><br>Verdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.<br><br>INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.<br><br>MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale-Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.<br><br>RESULTS: A total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability&#x2009;=&#x2009;0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, -23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.<br><br>CONCLUSIONS AND RELEVANCE: Results demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.<br><br>TRIAL REGISTRATION: Clinical Trial Identifiers: NCT04297683 and NCT04436510.}, }
@article {pmid40064496, year = {2025}, author = {Su, Y and Yang, F and Xie, JC and Zhang, C and Luo, RX and Li, WS and Liu, BL and Su, MZ}, title = {Electroacupuncture Neural Stimulation Mitigates Bladder Dysfunction and Mechanical Allodynia in Cyclophosphamide Induced Cystitis through Downregulation of the BDNF-TrkB Signaling Pathway.}, journal = {eNeuro}, volume = {12}, number = {3}, pages = {}, pmid = {40064496}, issn = {2373-2822}, abstract = {Central sensitization plays a critical role in bladder pain syndrome/interstitial cystitis (BPS/IC). Electroacupuncture (EA) nerve stimulation therapy has been broadly acknowledged as an effective means of alleviating chronic pathological pain. However, it remains to be explored whether EA is effective in mitigating pain-sensitive symptoms of BPS/IC and the mechanisms involved. This study aims to investigate the analgesic effect and mechanism of EA therapy. To achieve this goal, we employed several techniques: mechanical pain threshold tests to assess pain sensitivity, urodynamic studies to evaluate bladder function, Western blotting (WB) for protein analysis, immunofluorescence for visualizing, and transcriptomics. A rat cystitis model was established through a systemic intraperitoneal injection with cyclophosphamide (CYP). EA therapy was executed by stimulating the deep part of the hypochondriac point, where the 2nd-4th sacral nerves traverse. EA treatment was observed to effectively reduce mechanical allodynia, enhance urinary function, suppress the activation of microglial cells, and alleviate neuroinflammation. Additionally, EA demonstrated the capability to downregulate BDNF-TrkB signal transduction in the spinal dorsal horn. Transcriptome sequencing has indicated that EA therapy potentially inhibits excitatory neural transmission and modulates several pathways related to longevity. Furthermore, EA therapy has shown efficacy in treating conditions such as Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. In conclusion, by regulating the BDNF-TrkB signaling, EA nerve stimulation can effectively alleviate bladder dysfunction and mechanical allodynia in cyclophosphamide-induced cystitis model. Our research elucidates the underlying mechanisms of EA therapy in treating bladder dysfunction and offers new theoretical insights for addressing painful sensitization in BPS.Significance Statement Central sensitization is a major factor in bladder pain syndrome/interstitial cystitis (BPS/IC), making effective pain management crucial. This study explores the potential of electroacupuncture (EA) as a therapeutic approach to alleviate pain and improve bladder function in a rat model of BPS/IC induced by cyclophosphamide. Our findings demonstrate that EA therapy significantly reduces mechanical allodynia, enhances urinary function, and decreases neuroinflammation by modulating BDNF-TrkB signaling in the spinal dorsal horn. The research highlights EA's capability to inhibit excitatory neural transmission and provide relief in chronic pain conditions. These results offer new insights into the mechanisms of EA therapy, potentially improving treatment strategies for BPS/IC and similar pain syndromes.}, }
@article {pmid40064491, year = {2025}, author = {Izumi, Y and Nakayama, Y}, title = {[Communicating the Diagnosis of Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {3}, pages = {259-263}, doi = {10.11477/mf.188160960770030259}, pmid = {40064491}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; *Communication ; Patient Care Team ; }, abstract = {When explaining amyotrophic lateral sclerosis, family members, caregivers, and other professionals are encouraged to be present with the patient's consent. Patients' perceptions vary considerably depending on their condition, personality, and home environment; therefore, the content of the explanation should be carefully considered. If the patient did not fully understand or provide consent to participate, the explanation was repeated. Depending on the patient's level of understanding and acceptance, we provided step-by-step explanations. The patients were informed that the decision could change later, even after the treatment plan had been decided. In explanations involving a multidisciplinary team, each professional explains; however, it is also important for the team leader to understand the patient's perceptions.}, }
@article {pmid40061972, year = {2025}, author = {Yi, XM and Cai, HQ and Jiao, Y}, title = {Programmed cell death receptor 1 inhibitor Pembrolizumab in the treatment of advanced gastric cancer.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {2}, pages = {100257}, pmid = {40061972}, issn = {1948-9366}, abstract = {This editorial discusses Christodoulidis et al's article, which appeared in the most recent edition. The clinical trials have demonstrated the programmed cell death receptor 1 (PD-1) inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer (AGC). Pembrolizumab combined with chemotherapy can enhance its sensitivity, and further eliminate tumor cells that develop resistance to chemotherapy. The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis. The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy, and the safety is controllable. PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.}, }
@article {pmid40030015, year = {2025}, author = {Johnson, EA and Nowar, R and Viola, KL and Huang, W and Zhou, S and Bicca, MA and Zhu, W and Kranz, DL and Klein, WL and Silverman, RB}, title = {Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {10}, pages = {e2402117122}, pmid = {40030015}, issn = {1091-6490}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; R56 AG050492/AG/NIA NIH HHS/United States ; AG061708//HHS | National Institutes of Health (NIH)/ ; AG050492//HHS | National Institutes of Health (NIH)/ ; }, mesh = {*Amyloid beta-Peptides/metabolism ; Animals ; Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; Neurons/metabolism/drug effects ; Mice ; Hippocampus/metabolism/pathology ; Alzheimer Disease/metabolism/drug therapy/pathology ; Lysosomes/metabolism ; Protein Aggregation, Pathological/metabolism/drug therapy ; Autophagy/drug effects ; }, abstract = {Protein aggregation is a hallmark of neurodegenerative diseases, which connects these neuropathologies by a common phenotype. Various proteins and peptides form aggregates that are poorly degraded, and their ensuing pathological accumulation underlies these neurodegenerative diseases. Similarities may exist in the mechanisms responsible for the buildup of these aggregates. Therefore, therapeutics designed to treat one neurodegenerative disease may be beneficial to others. In ALS models, the compound NU-9 was previously shown to block neurodegeneration produced by aggregation-inducing mutations of SOD-1 and TDP-43 [B. Genç et al., Clin. Transl. Med. 11, e336 (2021)]. Here, we report that NU-9 also prevents the accumulation of amyloid beta oligomers (AβOs), small peptide aggregates that are instigators of Alzheimer's disease neurodegeneration [M. Tolar et al., Int. J. Mol. Sci. 22, 6355 (2021)]. AβO buildup was measured by immunofluorescence imaging of cultured hippocampal neurons exposed to exogenous monomeric Aβ. In this model, AβO buildup occurs via cathepsin L- and dynamin-dependent trafficking. This is prevented by NU-9 through a cellular mechanism that is cathepsin B- and lysosome-dependent, suggesting that NU-9 enhances the ability of endolysosomal trafficking to protect against AβO buildup. This possibility is strongly supported by a quantitative assay for autophagosomes that shows robust stimulation by NU-9. These results contribute additional understanding to the mechanisms of protein aggregation and suggest that multiple neurodegenerative diseases might be treatable by targeting common pathogenic mechanisms responsible for protein aggregation.}, }
@article {pmid40057669, year = {2025}, author = {Hatcher, H and Stankeviciute, S and Learn, C and Qu, AX}, title = {Regulatory, Translational, and Operational Considerations for the Incorporation of Biomarkers in Drug Development.}, journal = {Therapeutic innovation &amp; regulatory science}, volume = {}, number = {}, pages = {}, pmid = {40057669}, issn = {2168-4804}, abstract = {BACKGROUND: Biomarkers are an integral component in the drug development paradigm. According to the US Food and Drug Administration (FDA), a biomarker is "a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic intervention" (FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016-. Glossary. 2016 [Updated 2021 Nov 29, cited 2024 Apr 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK338448/ Co-published by National Institutes of Health (US), Bethesda (MD)). The European Medicines Agency (EMA) defines a biomarker as "an objective and quantifiable measure of a physiological process, pathological process or response to a treatment (excluding measurements of how an individual feels or functions" European Medicines Agency (EMA). Biomaker. 2020a. Available from: https://www.ema.europa.eu/en/glossary-terms/biomarker#:~:text=Biomarker-,Biomarker,an%20individual%20feels%20or%20functions . Several clinical biomarkers are well-documented and have been used routinely for decades in health care settings and have long been accepted as valid endpoints for drug approval (for example, blood pressure measurement as a biomarker for cardiovascular health) (European Medicines Agency (EMA). Assessment report, TAGRISSO. 2016. Available from: https://www.ema.europa.eu/en/documents/assessment-report/tagrisso-epar-public-assessment-report_en.pdf . Accessed 15 Apr 2024). Recently, novel biomarkers have been identified and validated to accelerate developing innovative therapies indicated for serious human diseases, for example targeted/immune therapies of cancer (Chen in Med Drug Discov 21:100174, 2024). As indicators of the efficacy of new pharmacological treatments or therapeutic interventions, biomarkers can improve clinical trial efficacy and reduce uncertainty in regulatory decision making (Bakker et al. in Clin Pharmacol Ther 112:69-80, 2022; Califf in Exp Biol Med 243:213-221, 2018; Parker et al. in Cancer Med 10:1955-1963, 2021).<br><br>METHODOLOGY: This article describes case studies of recent drug approvals that successfully leveraged validated and non-validated biomarkers (i.e., tofersen for the neurodegenerative disease amyotrophic lateral sclerosis (ALS) in adults; and osimertinib for treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC)).<br><br>CONCLUSIONS: Best practices for biomarker selection and strategies for health authority biomarker qualification programs are presented along with an overview of current limitations and challenges to optimizing biomarker applications along the drug development continuum from regulatory, translational, and operational perspectives.}, }
@article {pmid40056503, year = {2025}, author = {Zhan, A and Zhong, K and Zhang, K}, title = {Novel subcellular regulatory mechanisms of protein homeostasis and its implications in amyotrophic lateral sclerosis.}, journal = {Biochemical and biophysical research communications}, volume = {756}, number = {}, pages = {151582}, doi = {10.1016/j.bbrc.2025.151582}, pmid = {40056503}, issn = {1090-2104}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Proteostasis ; Animals ; Mitochondria/metabolism ; Protein Aggregates ; Homeostasis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disorder. Protein aggregates induce various forms of neuronal dysfunction and represent pathological hallmarks in ALS patients. Reducing protein aggregates could be a promising therapeutic strategy for ALS. While most studies have focused on cytoplasmic protein homeostasis, neurons adaptively reduce aggregates across subcellular compartments during stress through previously uncharacterized mechanisms. Here, we summarize novel compartment-specific proteostatic mechanisms: (1) the ERAD/RESET pathways, (2) HSPs-mediated nuclear sequestration, (3) mitochondrial aggregate import (MAGIC), (4) neurite-localized UPS/autophagosome and NMP, and (5) exopher-mediated extracellular disposal. These mechanisms collectively ensure cellular stress adaptation and provide novel therapeutic targets for ALS treatment.}, }
@article {pmid40044193, year = {2025}, author = {Ross, WT and Buday, S and Yakel, E and Khabele, D and Balls-Berry, J and As-Sanie, S and Colditz, G and Baumann, AA}, title = {Does interdisciplinary group care for the treatment of endometriosis improve pain interference: protocol for a pilot randomised controlled trial at an urban academic medical centre.}, journal = {BMJ open}, volume = {15}, number = {3}, pages = {e097372}, pmid = {40044193}, issn = {2044-6055}, support = {K23 HD110710/HD/NICHD NIH HHS/United States ; KL2 TR002346/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; Female ; Pilot Projects ; *Endometriosis/complications/therapy ; *Quality of Life ; *Pelvic Pain/therapy/etiology ; Academic Medical Centers ; Pain Management/methods ; Adult ; Randomized Controlled Trials as Topic ; Patient Care Team/organization &amp; administration ; Pain Measurement ; }, abstract = {INTRODUCTION: Endometriosis affects 10-15% of people assigned female at birth and can cause chronic pelvic pain and impair many domains of quality of life, such as fertility, mood and bladder, bowel and sexual function. Current treatments often fail, leading to recurrent pain and the need for reintervention. As endometriosis negatively affects many domains of life, a variety of non-pharmacological treatments modestly improve symptoms. To bundle these interventions into accessible packaging, our interdisciplinary team developed a novel endometriosis intervention titled 'Peer-Empowered Endometriosis Pain Support (PEEPS)', an 8-week integrative group care intervention. Here, we present the protocol for a pilot randomised controlled trial (RCT) to evaluate the effectiveness and implementation of PEEPS for people with endometriosis-associated pain refractory to surgical management. We hypothesise that patients who complete the PEEPS programme will show a greater decrease in pain interference in daily activities at intervention completion as compared with baseline than those in the education arm.<br><br>METHODS AND ANALYSIS: This is a hybrid type 1 effectiveness-implementation mixed-methods RCT in which 60 participants will be randomised using computer-generated random numbers stratified by group in the ratio 1:1 to PEEPS plus usual versus educational handout plus usual care. The primary outcome is change in pain interference from baseline to intervention completion. Secondary outcomes include change in pain interference from baseline to 6 months and 12 months postintervention, as well as change in other quality-of-life measures as measured by nine validated questionnaires from baseline to completion, 6 months and 12&#x2009;months. Proctor et al's Implementation Outcomes Framework will be used to evaluate acceptability, appropriateness and feasibility of PEEPS implementation, and the Consolidated Framework for Implementation Research will be used to guide the evaluation of barriers and facilitators of PEEPS at the patient and provider levels. Primary data analyses will follow the intention-to-treat principle. Descriptive statistics and two-sample t-tests for normally distributed values and Wilcoxon Rank-Sum test were performed for non-normally distributed values. Frequency analysis and Fisher's exact or &#x3c7;[2] tests will be used for categoric variables as appropriate. Longitudinal analysis of the primary and secondary outcomes will be conducted with a mixed-effects model to investigate the effect of PEEPS compared with education. Least square means (LSMs) and the corresponding 95% CIs at each timepoint, as well as LSM differences and 95% CIs between any post-baseline and baseline will be provided for the outcomes. ORs and 95% CIs will be calculated for categorical outcomes. Qualitative data will be collected in the form of open-ended feedback, focus groups with programme completers and semistructured interviews with participants who complete two or fewer sessions. The analysis will use an embedded design-experimental model in which quantitative and qualitative outcomes will occur concurrently with weight priority given to quantitative data.<br><br>ETHICS AND DISSEMINATION: This trial was approved by the Washington University in St. Louis Institutional Review Board (protocol 202402082) on 27 March 2024 and has low risk of harm to participants. All deidentified data from this project will be shared via Digital Commons@Becker. The findings of this study will be disseminated via scientific meetings and peer-reviewed journals. The results and conclusions will be summarised for patients and the public in common language using infographics to make the findings accessible. This pilot RCT will yield the effect size for PEEPS and generate implementation context and outcomes data to guide PEEPS application to real-world practice. If PEEPS proves to be effective, this study will inform adaptation and scaling to improve the lives of people with endometriosis through a non-hormonal, fertility-preserving approach.<br><br>TRIAL REGISTRATION NUMBER: ClinicalTrials.gov; NCT06549985.}, }
@article {pmid40041912, year = {2025}, author = {Dash, UC and Bhol, NK and Swain, SK and Samal, RR and Nayak, PK and Raina, V and Panda, SK and Kerry, RG and Duttaroy, AK and Jena, AB}, title = {Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {1}, pages = {15-34}, pmid = {40041912}, issn = {2211-3835}, abstract = {Neuroprotection is a proactive approach to safeguarding the nervous system, including the brain, spinal cord, and peripheral nerves, by preventing or limiting damage to nerve cells and other components. It primarily defends the central nervous system against injury from acute and progressive neurodegenerative disorders. Oxidative stress, an imbalance between the body's natural defense mechanisms and the generation of reactive oxygen species, is crucial in developing neurological disorders. Due to its high metabolic rate and oxygen consumption, the brain is particularly vulnerable to oxidative stress. Excessive ROS damages the essential biomolecules, leading to cellular malfunction and neurodegeneration. Several neurological disorders, including Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, multiple sclerosis, and ischemic stroke, are associated with oxidative stress. Understanding the impact of oxidative stress in these conditions is crucial for developing new treatment methods. Researchers are exploring using antioxidants and other molecules to mitigate oxidative stress, aiming to prevent or slow down the progression of brain diseases. By understanding the intricate interplay between oxidative stress and neurological disorders, scientists hope to pave the way for innovative therapeutic and preventive approaches, ultimately improving individuals' living standards.}, }
@article {pmid40038221, year = {2025}, author = {Mustafa, F and Mittal, S and Garg, D and Agarwal, A and Garg, A and Gupta, BK and Soneja, M and Srivastava, AK}, title = {HIV associated motor neuron disease (MND): A case series with systematic review of literature.}, journal = {Journal of neurovirology}, volume = {31}, number = {1}, pages = {1-15}, pmid = {40038221}, issn = {1538-2443}, mesh = {Humans ; *HIV Infections/drug therapy/complications/virology ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/virology/drug therapy/diagnostic imaging/pathology ; Female ; Adult ; *Motor Neuron Disease/virology/drug therapy ; Viral Load ; CD4 Lymphocyte Count ; Anti-HIV Agents/therapeutic use ; }, abstract = {Human immunodeficiency virus (HIV) associated motor neuron disease (MND) is very rare. HIV infection can cause an MND-like syndrome due to central nervous system (CNS) involvement de novo or during antiretroviral therapy (ART) due to CNS escape. We present two cases: one with a classic amyotrophic lateral sclerosis (ALS) phenotype, which was the manifestation of symptomatic CNS escape from ART, and the second with a primary lateral sclerosis (PLS) phenotype associated with underlying HIV infection. A systematic review of published literature of people living with HIV (PLHIV) who developed ALS/ MND was conducted using the PubMed, Embase, and Lilacs databases. A total of 91 cases were found, 89 of which were obtained from 37 articles, and two were included from our own case series. In patients with HIV-associated MND, 63 patients reviewed had a classic ALS phenotype followed by progressive muscular atrophy variant (12), progressive bulbar palsy (8), PLS (7) and bulbar onset ALS (1). Neuroimaging, electrophysiology, cerebrospinal fluid (CSF) analysis, CSF and serum HIV viral load, and CD4 count investigations were used for diagnosis. Following the initiation or modification of antiretroviral therapy (ART), approximately 70% exhibited an improvement or a stable disease course. HIV-associated MND is a rare condition that can occur in both ART-naive individuals and those on treatment. A proportion of cases (~ 70%) show improvement with ART. Accurate diagnosis requires the exclusion of opportunistic infections, which remains a critical yet challenging aspect of managing this condition.}, }
@article {pmid40033250, year = {2025}, author = {Lu, C and Huang, XX and Huang, M and Liu, C and Xu, J}, title = {Mendelian randomization of plasma proteomics identifies novel ALS-associated proteins and their GO enrichment and KEGG pathway analyses.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {82}, pmid = {40033250}, issn = {1471-2377}, mesh = {Humans ; *Mendelian Randomization Analysis/methods ; *Amyotrophic Lateral Sclerosis/genetics/blood ; *Proteomics/methods ; *Genome-Wide Association Study/methods ; *Biomarkers/blood ; Blood Proteins/genetics/analysis/metabolism ; Quantitative Trait Loci ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder with an increasing incidence rate. Despite advances in ALS research over the years, the precise etiology and pathogenic mechanisms remain largely elusive.<br><br>OBJECTIVE: To identify novel plasma proteins associated with ALS through Mendelian randomization methods in large-scale plasma proteomics and to provide potential biomarkers and therapeutic targets for ALS treatment.<br><br>METHODS: This study employed a large-scale plasma proteomic Mendelian randomization approach using genetic data from 80,610 individuals of European ancestry (including 20,806 ALS patients and 59,804 controls) derived from a genome-wide association study (GWAS). Protein quantitative trait loci (pQTLs) data were obtained from Ferkingstad et al. (2021), which measured 4,907 proteins in 35,559 Icelandic individuals. Multiple Mendelian randomization (MR) techniques were utilized, including weighted median, MR-Egger, Wald ratio, inverse-variance weighting (IVW), basic model, and weighted model. Heterogeneity was evaluated using Cochran's Q test. Horizontal pleiotropy was assessed through the MR-Egger intercept test and MR-PRESSO outlier detection. Sensitivity analysis was performed via leave-one-out analysis.<br><br>RESULTS: MR analysis revealed potential causal associations between 491 plasma proteins and ALS, identifying 19 novel plasma proteins significantly linked to the disease. Proteins such as C1QC, UMOD, SLITRK5, ASAP2, TREML2, DAPK2, ARHGEF10, POLM, SST, and SIGLEC1 showed positive correlations with ALS risk, whereas ADPGK, BTNL9, COLEC12, ADGRF5, FAIM, CRTAM, PRSS3, BAG5, and PSMD11 exhibited negative correlations. Reverse MR analyses confirmed that ALS negatively correlates with ADPGK and ADGRF5 expression. Enrichment analyses, including Gene Ontology (GO) functional analysis, indicated involvement in critical biological processes such as external encapsulating structure organization, extracellular matrix organization, chemotaxis, and taxis. KEGG pathway analysis highlighted significant enrichment in the PI3K-Akt signaling pathway, cytokine-cytokine receptor interactions, and axon guidance.<br><br>CONCLUSION: This study enhances the understanding of ALS pathophysiology and proposes potential biomarkers and mechanistic insights for therapeutic development. Future research should explore the clinical translation of these findings to improve ALS patient outcomes and quality of life.}, }
@article {pmid40030850, year = {2025}, author = {Hong, Z and Yi, S and Deng, M and Zhong, Y and Zhao, Y and Li, L and Zhou, H and Xiao, Y and Hu, X and Niu, L}, title = {Transcranial Focused Ultrasound Modifies Disease Progression in SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {IEEE transactions on ultrasonics, ferroelectrics, and frequency control}, volume = {72}, number = {2}, pages = {191-201}, doi = {10.1109/TUFFC.2024.3525143}, pmid = {40030850}, issn = {1525-8955}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/diagnostic imaging/genetics ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Ultrasonic Therapy/methods ; Superoxide Dismutase-1/genetics ; Disease Progression ; Muscle, Skeletal/physiopathology ; Male ; Motor Cortex ; Humans ; Elasticity Imaging Techniques ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressively worsening neurodegenerative condition with very few treatment options available. Ultrasound neuromodulation offers promising benefits for treating neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. However, the effects and underlying mechanisms of ultrasound neuromodulation on ALS remain unclear. A head-mounted ultrasound neuromodulation system was developed to noninvasively stimulate the motor cortex of symptomatic mice carrying the G93A human SOD1 mutation (SOD $1^{\text {G93A}}$) for four weeks. Motor performance was assessed through the rotarod locomotor test, grip strength test, and open field test. In addition, the effect of ultrasound stimulation on the elastic modulus of gastrocnemius muscle atrophy was measured using real-time shear wave elastography (SWE). Subsequently, the brain tissues of the mice were harvested. Gastrocnemius morphology was examined using hematoxylin-eosin and Gomori aldehyde-fuchsin (GAF) staining. The number of neurons and the phenotype of microglia in the motor cortex were observed by immunohistochemical analysis. Ultrasound therapy delayed disease onset by 10.7% and increased the lifespan by 6.7% in SOD $1^{\text {G93A}}$ mice by reduction of neuronal loss and enhancement of M2 microglia in the motor cortex. Furthermore, we found significant improvements in motor function for ultrasound-treated mice. More importantly, ultrasound stimulation ameliorated gastrocnemius muscle atrophy in the SOD $1^{\text {G93A}}$ mice. These results revealed the neuroprotective effects of ultrasound against the disease pathogenesis of SOD $1^{\text {G93A}}$ mice. Transcranial ultrasound neuromodulation provides an innovative tool for the intervention and treatment of neurodegenerative diseases.}, }
@article {pmid40029136, year = {2025}, author = {Revi, N and Nandeshwar, M and Harijan, D and Sankaranarayanan, SA and Joshi, M and Prabusankar, G and Rengan, AK}, title = {Acridine Benzimidazolium Derivatives Induced Protective Microglia Polarization and In Silico TDP-43 Interaction─Potential Implications for Amyotrophic Lateral Sclerosis.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {6}, pages = {1103-1116}, doi = {10.1021/acschemneuro.4c00791}, pmid = {40029136}, issn = {1948-7193}, mesh = {*Microglia/drug effects/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Animals ; *DNA-Binding Proteins/metabolism ; Benzimidazoles/pharmacology ; Neuroprotective Agents/pharmacology ; Mice ; Acridines/pharmacology ; Humans ; Molecular Docking Simulation ; }, abstract = {Abnormal protein aggregation and associated neuronal-glial cell cytotoxicity lead to a plethora of neurodegenerative disorders. Most of the earlier investigations on understanding neurodegenerative disease progression and cure focused on neuronal damage and restoration potential. With increased evidence on the role of glial cells like microglia and astrocytes in mediating these disorders, more studies are dedicated to understanding the role of inflammatory responses mediated by glial cells and how they lead to neuroinflammation. Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder caused by TDP-43 aggregation that affects motor neurons. Pro-inflammatory microglia are considered to aggravate the disorder condition. In the current study, a previously reported molecule with TDP-43 inhibition, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)imidazol-3-ium) dibromide salt (AIM4), is analyzed for its microglia polarization properties along with two other derivatives, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)benzoimidazol-3-ium) dibromide salt (ABA). The 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl) benzimidazol-3-ium) dibromide salt (ABA) display the increased ability to maintain microglial cells to anti-inflammatory state and TDP-43 binding as compared to 3,3'-(acridine-4,5-diylbis(methylene)) bis(carboxymethyl)imidazolium dibromide salt (AIM4). This was confirmed from total nitrite levels, mitochondria membrane potential analysis, and molecular docking studies. The selected pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) displayed decreased levels, and anti-inflammatory cytokines IL-4 and IL-10 displayed increased levels, however not very significantly, upon treatment with all acridine derivatives. The compounds were investigated on lipopolysaccharides (LPS)-triggered mouse microglial cells and Danio rerio embryos displaying no significant cytotoxicity and physiological changes (cardiac rhythm), respectively. In molecular docking studies, alanine at 315 mutated to glutamate of TDP-43 directly interacts with AIM4. However, π-σ interactions of the aromatic backbone of acridine in ABE and ABA with 313 phenylalanine of TDP-43 along with hydrogen bonds formed between 309, 310 glycine amino acids and imidazolium bromide side chains rendered a stronger binding of these acridine derivatives with the protein potentially inhibiting fibrillation. Conclusion: ABA, ABE, and AIM4 maintain microglia in an anti-inflammatory state. However, more studies are required to understand its interaction with TDP-43 and the mechanism of its anti-inflammatory nature.}, }
@article {pmid40027570, year = {2025}, author = {Giorgio, A and Ciracì, E and De Luca, M and Stella, G and Giorgio, V}, title = {Hepatic abscess and hydatid liver cyst: European infectious disease point of view.}, journal = {World journal of hepatology}, volume = {17}, number = {2}, pages = {103325}, pmid = {40027570}, issn = {1948-5182}, abstract = {This manuscript is based on a recent study by Pillay et al that was published in recently. Liver abscesses can be caused by rare potentially life-threatening infections of either bacterial or parasitic origin. The incidence rate in Europe is lower than in developing countries, but it is a major complication with high morbidity, particularly in immunocompromised patients. They are most frequently caused by Enterobacterales infections, but hypervirulent Klebsiella strains are an emerging problem in Western countries. Amoebiasis has been a public health problem in Europe, primarily imported from other endemic foci. At the same time, this infection is becoming an emerging disease, as the number of infected patients who have not traveled to endemic areas is rising. Treatment options for hydatid liver cyst include chemotherapy, open or laparoscopic surgery, percutaneous treatment (percutaneous aspiration, re-aspiration and injection and its modification) and ''wait and watch'' strategy. Most hydatid liver cyst patients in Pillay et al's study received surgical treatment, but several studies have confirmed the safety and efficacy of percutaneous aspiration, re-aspiration and injection.}, }
@article {pmid40025240, year = {2025}, author = {Maier, A and Kettemann, D and Weyen, U and Grehl, T and Schulte, PC and Steinbach, R and Rödiger, A and Weydt, P and Petri, S and Wolf, J and Grosskreutz, J and Koch, JC and Weishaupt, JH and Rosseau, S and Norden, J and Körtvélyessy, P and Koch, B and Holm, T and Hildebrandt, B and Schumann, P and Walter, B and Riitano, A and Münch, C and Meyer, T and Spittel, S}, title = {Provision, cough efficacy and treatment satisfaction of mechanical insufflation-exsufflation in a large multicenter cohort of patients with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {7360}, pmid = {40025240}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Cough ; Male ; Female ; *Insufflation/methods ; Middle Aged ; Aged ; *Patient Satisfaction ; Longitudinal Studies ; Treatment Outcome ; Germany ; }, abstract = {In patients with amyotrophic lateral sclerosis (ALS), mechanical insufflation-exsufflation (MI-E) addresses cough deficiency to achieve major therapeutic goals: improving costal muscle and joint function, reducing atelectasis through insufflation, and clearing bronchial secretions via exsufflation. Despite its perceived benefits, there is limited systematic research on MI-E provision, symptom alleviation, or patient satisfaction. The research platform Ambulanzpartner coordinated this longitudinal observational study conducted in 12 German ALS centers from July 2018 to September 2023. Patients were enrolled based on ALS-related cough deficiency requiring MI-E therapy. The study recorded provision, reasons for withholding MI-E, clinical parameters, therapy frequency, subjective cough deficiency, and symptomatic relief. Satisfaction with MI-E therapy was determined by the likelihood of recommendation. Out of 694 ALS patients indicated for MI-E, 527 (75.9%) received the therapy. The primary reason for non-provision was that the patient had died before provision (n = 66 of 167; 39.5%). These patients were significantly more affected as represented by higher progression rates and lower cough peak flows (CPF) at the time of MI-E indication (p < 0.05). Most patients who received MI-E used it daily (n = 290 of 370; 78.4%). Self-assessed cough deficiency correlated with clinical measurements, especially for patients with higher deficits. At follow-up visits, patients reported reduced cough deficiency (p < 0.001). Frequent MI-E use was linked to greater symptom relief and higher likelihood of recommending the therapy. This study highlights the symptomatic and palliative potential of MI-E therapy for ALS patients.}, }
@article {pmid40024955, year = {2025}, author = {Masood, S and Almas, MS and Hassan, SSU and Tahira, S and Fiaz, MH and Minhas, UEA and Zafar, HMQ and Masood, M}, title = {Safety and efficacy of arimoclomol in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {40024955}, issn = {1590-3478}, abstract = {OBJECTIVES: Amyotrophic Lateral Sclerosis (ALS) is a debilitating motor neuron disorder characterized by muscle weakness, atrophy, and spasticity. This meta-analysis aims to assess the safety and efficacy of Arimoclomol in patients with ALS.<br><br>METHOD: A comprehensive literature search was conducted on 3 databases to discover articles published up to August 2024. Included studies were randomized controlled trials (RCTs). Data was analysed using Review Manager (v5.4). Cochrane Risk of Bias-2 (RoB-2) was adopted to assess the quality of RCTs.<br><br>RESULTS: A total of 359 patients were analysed, with 239 individuals in the Arimoclomol group and 120 individuals in the placebo group. The pooled analysis of the primary outcome, change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score from baseline, did not demonstrate a statistically significant difference favoring the Arimoclomol group (MD&#x2009;=&#x2009;0.4495; 95% CI: -0.39, 1.27; p&#x2009;=&#x2009;0.30). Similarly, secondary outcomes, including the Combined Assessment of Function and Survival (CAFS) rank score (MD&#x2009;=&#x2009;1.00; 95% CI: -2.68, 4.67; p&#x2009;=&#x2009;0.60), increase in transaminases (RR&#x2009;=&#x2009;1.05; 95% CI: 0.19, 5.70; p&#x2009;=&#x2009;0.95), mortality rate (RR&#x2009;=&#x2009;0.86; 95% CI: 0.55, 1.34; p&#x2009;=&#x2009;0.50), and adverse events (RR&#x2009;=&#x2009;0.86; 95% CI: 0.55, 1.34; p&#x2009;=&#x2009;0.50), showed no statistically significant differences between the groups.<br><br>CONCLUSION: This study does not conclusively demonstrate that Arimoclomol has beneficial effects on ALS patients' physical functionality but shows promise for safety. Further clinical trials are needed to explore the neuroprotective effects of Arimoclomol in the treatment of ALS.}, }
@article {pmid40019593, year = {2025}, author = {Dobroniak, CC and Lesche, V and Olgemöller, U and Beck, P and Lehmann, W and Spering, C}, title = {Surgical strategy for chest wall reconstruction secondary to cardiopulmonary resuscitation versus post-traumatic.}, journal = {European journal of trauma and emergency surgery : official publication of the European Trauma Society}, volume = {51}, number = {1}, pages = {122}, pmid = {40019593}, issn = {1863-9941}, mesh = {Humans ; *Cardiopulmonary Resuscitation/methods ; Male ; Female ; Retrospective Studies ; Middle Aged ; *Thoracic Wall/injuries/surgery ; *Flail Chest/surgery/etiology ; *Rib Fractures/surgery ; *Sternum/injuries/surgery ; Germany ; Plastic Surgery Procedures/methods ; Aged ; Fracture Fixation, Internal/methods ; Adult ; Length of Stay/statistics &amp; numerical data ; Bone Plates ; }, abstract = {PURPOSE: In mechanically cardiopulmonary resuscitated (CPR) patients, chest compressions at the level of the 3rd to 5th rib on the sternum result in reproducibly similar injury patterns: parasternal osteochondral dissociation (OCS) on both sides in combination with a sternal fracture with or without an additional serial rib fracture in the anterolateral column (ALS). This injury biomechanically impairs physiological breathing, resulting in an inverse breathing pattern. Trauma patients, on the other hand, often show a mixed pattern depending on the location of the main energy. The aim of the study was to evaluate the surgical technique of chest wall reconstruction (CWR) using transsternal refixation of the 5th rib on both sides in combination with plate osteosynthesis of the sternum and to analyze its success in comparison to the surgical strategy of CWR in the context of a traumatic genesis.<br><br>METHOD: Data acquisition was performed using medical records of a Level I Trauma Centre in Germany and compare patients with radiologically or clinically diagnosed flail chest as a result of cardiopulmonary mechanical resuscitation (CPR). The retrospective study included patients in the period 2018-2023 after surgical CWR. The patients were either post-CPR (n&#x2009;=&#x2009;29; CPR) or trauma patients (n&#x2009;=&#x2009;36; trauma). The collective was described and analyzed using the digital patient file, as well as data on ICU stay and duration of ventilation or conversion to assisted ventilation modes, reason for chest wall instability, time of surgery, length of stay and mortality. As a long-term follow-up, body plethysmography was analyzed comparatively. Primary endpoints were mean length of stay in ICU, time to surgery, ventilator dependency and mortality rate. Secondary endpoints were time to transfer to rehabilitation, ventilation disorders and long term outcome.<br><br>RESULTS: In the period 65 patients (48&#xa0;m, 17w) were included, 29 of whom had been mechanically resuscitated (CPR), 36 formed to post-traumatic cohort (trauma). The CPR were significantly older (69 vs. 58 years; p-value 0.003). The duration from CPR to surgery was on average significantly longer than trauma to surgery (16.76 vs. 4.11 days). The mean length of stay in ICU were 30 days (trauma) and 45 days for CPR (significantly longer, p-value 0.0008). The mean duration of ventilation was 188&#xa0;h for trauma and 593&#xa0;h for CPR. Extubation or conversion to assisted, relevant de-escalating ventilation modes was possible in both groups after a mean of 38&#xa0;h post-OP. Among the CPR patients, 4 died in hospital (hospital mortality: CPR 20.7% vs. trauma 5.6%), 7 (30%) were transferred to an early clinical rehabilitation and 10 were discharged to home or follow-up treatment. In the case of trauma, 5 (14.7%) were transferred to an early clinical rehabilitation and 20 were discharged to home or follow-up treatment. Bodyplethysmography 6 months after CPR / trauma showed no differences in both collectives with regard to ventilation disorders. Diffusion was prolonged in both groups, presumably due to the healing process of lungs contusion. Both showed no restriction disorders.<br><br>CONCLUSION: Chest wall reconstruction, including plate osteosynthesis of the sternum in combination with transsternal fixation of the 5th rib on both sides can largely restore physiological respiratory mechanics immediately after surgery and accelerate the weaning success. In the management of patients after CPR, the initial diagnosis which had indicated resuscitation, is the main focus and can often be an obstacle to extubation. Nevertheless, independent breathing can be accelerated by restoring the biomechanics through early surgical treatment using CWR and saves long-term ICU stays with the potential for further complication and resource consumption. CWR forms the essential basis for early rehabilitation of the underlying cause of resuscitation. Ventilation disorders do not occur after surgical CWR, even during the course of the procedure.}, }
@article {pmid40017137, year = {2025}, author = {Lovett, A and Chary, S and Babu, S and Bruneteau, G and Glass, JD and Karlsborg, M and Ladha, S and Mayl, K and McDermott, C and Bucelli, RC and Chiò, A and Ferguson, TA and Cochrane, T and Fradette, S and Smirnakis, K and Inra, J and Malek, S and Fanning, L}, title = {Serious Neurologic Adverse Events in Tofersen Clinical Trials for Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28372}, pmid = {40017137}, issn = {1097-4598}, support = {//Biogen/ ; }, abstract = {INTRODUCTION/AIMS: Tofersen is approved for the treatment of amyotrophic lateral sclerosis (ALS) due to superoxide dismutase 1 mutations (SOD1-ALS). Here we report serious neurologic adverse events (AEs) that occurred in the tofersen clinical trials in people with SOD1-ALS.<br><br>METHODS: Serious neurologic AEs of myelitis, radiculitis, aseptic meningitis, and papilledema reported in the tofersen clinical trials are described. Serious AEs were defined according to International Conference for Harmonization guidelines, and neurologic AEs in clinical trials were diagnosed by investigators based on symptoms, clinical examination findings, and diagnostic workup.<br><br>RESULTS: Ten participants (approximately 7% of tofersen 100-mg-treated trial participants) experienced a total of 12 serious neurologic AEs-4 of myelitis, 2 of radiculitis, 2 of aseptic meningitis, and 4 of intracranial hypertension (ICH) and/or papilledema. All events but one resolved either spontaneously, with dosing interruption/modification, or with concomitant therapies. One event was ongoing but improved as of December 2022. While 3 events led to tofersen treatment discontinuation, all other participants were able to remain on treatment. No event was life-threatening or fatal.<br><br>DISCUSSION: Some antisense oligonucleotides (ASOs) have been described as having pro-inflammatory properties. Aseptic meningitis has been reported with nusinersen; however, myelitis, radiculitis, increased intracranial pressure, and papilledema have not been reported with ASO treatment. These neurologic AEs should be considered when assessing the overall benefit/risk of tofersen treatment for SOD1-ALS. Safety data from the open-label extension and expanded access program will continue to characterize these events and further inform the safety profile of tofersen in SOD1-ALS.}, }
@article {pmid40012174, year = {2025}, author = {Rajamanickam, G and Hu, Z and Liao, P}, title = {Targeting the TRPM4 Channel for Neurologic Diseases: Opportunity and Challenge.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {}, number = {}, pages = {10738584251318979}, doi = {10.1177/10738584251318979}, pmid = {40012174}, issn = {1089-4098}, abstract = {As a monovalent cation channel, the transient receptor potential melastatin 4 (TRPM4) channel is a unique member of the transient receptor potential family. Abnormal TRPM4 activity has been identified in various neurologic disorders, such as stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, amyotrophic lateral sclerosis, pathologic pain, and epilepsy. Following brain hypoxia/ischemia and inflammation, TRPM4 up-regulation and enhanced activity contribute to the cell death of neurons, vascular endothelial cells, and astrocytes. Enhanced ionic influx via TRPM4 leads to cell volume increase and oncosis. Depolarization of membrane potential following TRPM4 activation and interaction between TRPM4 and N-methyl-d-aspartate receptors exacerbate excitotoxicity during hypoxia. Importantly, TRPM4 expression and activity remain low in healthy neurons, making it an ideal drug target. Current approaches to inhibit or modulate the TRPM4 channel have various limitations that hamper the interpretation of TRPM4 physiology in the nervous system and potentially hinder their translation into therapy. In this review, we discuss the pathophysiologic roles of TRPM4 and the different inhibitors that modulate TRPM4 activity for potential treatment of neurologic diseases.}, }
@article {pmid40011745, year = {2025}, author = {Rödström, KEJ and Eymsh, B and Proks, P and Hayre, MS and Cordeiro, S and Mendez-Otalvaro, E and Madry, C and Rowland, A and Kopec, W and Newstead, S and Baukrowitz, T and Schewe, M and Tucker, SJ}, title = {Cryo-EM structure of the human THIK-1 K2P K[+] channel reveals a lower Y gate regulated by lipids and anesthetics.}, journal = {Nature structural &amp; molecular biology}, volume = {}, number = {}, pages = {}, pmid = {40011745}, issn = {1545-9985}, abstract = {THIK-1 (KCNK13) is a halothane-inhibited and anionic-lipid-activated two-pore domain (K2P) K[+] channel implicated in microglial activation and neuroinflammation, and a current target for the treatment of neurodegenerative disorders, for example Alzheimer's disease and amyothropic lateral sclerosis (ALS). However, compared to other K2P channels, little is known about the structural and functional properties of THIK-1. Here we present a 3.16-Å-resolution cryo-EM structure of human THIK-1 that reveals several distinct features, in particular, a tyrosine in M4 that contributes to a lower 'Y gate' that opens upon activation by physiologically relevant G-protein-coupled receptor and lipid signaling pathways. We demonstrate that linoleic acid bound within a modulatory pocket adjacent to the filter influences channel activity, and that halothane inhibition involves a binding site within the inner cavity, both resulting in conformational changes to the Y gate. Finally, the extracellular cap domain contains positively charged residues that line the ion exit pathway and contribute to the distinct biophysical properties of this channel. Overall, our results provide structural insights into THIK-1 function and identify distinct regulatory sites that expand its potential as a drug target for the modulation of microglial function.}, }
@article {pmid40011434, year = {2025}, author = {Gao, G and Shi, Y and Deng, HX and Krainc, D}, title = {Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1982}, pmid = {40011434}, issn = {2041-1723}, support = {R21 NS114765/NS/NINDS NIH HHS/United States ; NS114765//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS099623/NS/NINDS NIH HHS/United States ; R35 NS122257/NS/NINDS NIH HHS/United States ; NS122257//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS099623//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *Lipid Peroxidation ; *Ketoglutarate Dehydrogenase Complex/metabolism/genetics ; Humans ; *Mitochondria/metabolism ; *Parkinson Disease/metabolism/genetics ; Male ; Mice ; *alpha-Synuclein/metabolism/genetics ; *Disease Models, Animal ; *DNA-Binding Proteins/metabolism/genetics ; *Dopaminergic Neurons/metabolism/pathology ; Thioctic Acid/metabolism ; Transcription Factors/metabolism/genetics ; Mitochondrial Proteins/metabolism/genetics ; Mice, Knockout ; Ketoglutaric Acids/metabolism ; Brain/metabolism ; }, abstract = {Dysregulation of mitochondrial function has been implicated in Parkinson's disease (PD), but the role of mitochondrial metabolism in disease pathogenesis remains to be elucidated. Using an unbiased metabolomic analysis of purified mitochondria, we identified alterations in α-ketoglutarate dehydrogenase (KGDH) pathway upon loss of PD-linked CHCHD2 protein. KGDH, a rate-limiting enzyme complex in the tricarboxylic acid cycle, was decreased in CHCHD2-deficient male mouse brains and human dopaminergic neurons. This deficiency of KGDH led to elevated α-ketoglutarate and increased lipid peroxidation. Treatment of CHCHD2-deficient dopaminergic neurons with lipoic acid, a KGDH cofactor and antioxidant agent, resulted in decreased levels of lipid peroxidation and phosphorylated α-synuclein. CHCHD10, a close homolog of CHCHD2 that is primarily linked to amyotrophic lateral sclerosis/frontotemporal dementia, did not affect the KGDH pathway or lipid peroxidation. Together, these results identify KGDH metabolic pathway as a targetable mitochondrial mechanism for correction of increased lipid peroxidation and α-synuclein in Parkinson's disease.}, }
@article {pmid40010009, year = {2025}, author = {Mikuriya, S and Takegawa-Araki, T and Tamura, M}, title = {Edaravone mitigates TDP-43 mislocalization in human amyotrophic lateral sclerosis neurons with potential implication of the SIRT1-XBP1 pathway.}, journal = {Free radical biology &amp; medicine}, volume = {230}, number = {}, pages = {283-293}, doi = {10.1016/j.freeradbiomed.2025.01.012}, pmid = {40010009}, issn = {1873-4596}, mesh = {Humans ; *Edaravone/pharmacology ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *X-Box Binding Protein 1/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism/drug effects ; *Motor Neurons/metabolism/drug effects/pathology ; *Sirtuin 1/metabolism/genetics ; Signal Transduction/drug effects ; Free Radical Scavengers/pharmacology ; Neuroprotective Agents/pharmacology ; Endoplasmic Reticulum Stress/drug effects ; Gene Expression Regulation/drug effects ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss along with pathological mislocalization of TAR DNA-binding protein 43 (TDP-43), a protein implicated in RNA metabolism. Although edaravone, a free-radical scavenger, has been approved for ALS treatment, its precise mechanism of action is not fully understood, particularly in relation to TDP-43 pathology. Here, we investigated the effects of edaravone on induced pluripotent stem cell (iPSC)-derived motor neurons in a patient with ALS harboring a TDP-43 mutation. Our results demonstrated that edaravone significantly attenuated neurodegeneration, as evidenced by neurite preservation, neuronal cell death reduction, and correction of aberrant cytoplasmic localization of TDP-43. These neuroprotective effects were not observed with vitamin C, indicating a unique mechanism of action for edaravone, distinct from its antioxidative properties. RNA sequencing revealed that edaravone rapidly modulated gene expression, including protein quality control pathway, such as the ubiquitin-proteasome system. Further analysis identified X-box binding protein (XBP1), a key regulator of the endoplasmic reticulum stress response, as a critical factor in the therapeutic effects of edaravone. This study suggests that edaravone may offer a multifaceted therapeutic approach for ALS by targeting oxidative stress and TDP-43 mislocalization through distinct molecular pathways.}, }
@article {pmid40009414, year = {2025}, author = {Hamad, AA}, title = {Tofersen for Amyotrophic Lateral Sclerosis: Genetic Treatment With Precision Medicine: The Future of ALS Treatment.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {3}, pages = {117-119}, doi = {10.1097/CND.0000000000000517}, pmid = {40009414}, issn = {1537-1611}, }
@article {pmid40009238, year = {2025}, author = {Ruffo, P and Traynor, BJ and Conforti, FL}, title = {Advancements in genetic research and RNA therapy strategies for amyotrophic lateral sclerosis (ALS): current progress and future prospects.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {233}, pmid = {40009238}, issn = {1432-1459}, support = {ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/diagnosis ; Humans ; Genetic Therapy/methods ; }, abstract = {This review explores the intricate landscape of neurodegenerative disease research, focusing on Amyotrophic Lateral Sclerosis (ALS) and the intersection of genetics and RNA biology to investigate the causative pathogenetic basis of this fatal disease. ALS is a severe neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness and paralysis. Despite significant research advances, the exact cause of ALS remains largely unknown. Thanks to the application of next-generation sequencing (NGS) approaches, it was possible to highlight the fundamental role of rare variants with large effect sizes and involvement of portions of non-coding RNA, providing valuable information on risk prediction, diagnosis, and treatment of age-related diseases, such as ALS. Genetic research has provided valuable insights into the pathophysiology of ALS, leading to the development of targeted therapies such as antisense oligonucleotides (ASOs). Regulatory agencies in several countries are evaluating the commercialization of Qalsody (Tofersen) for SOD1-associated ALS, highlighting the potential of gene-targeted therapies. Furthermore, the emerging significance of microRNAs (miRNAs) and long RNAs are of great interest. MiRNAs have emerged as promising biomarkers for diagnosing ALS and monitoring disease progression. Understanding the role of lncRNAs in the pathogenesis of ALS opens new avenues for therapeutic intervention. However, challenges remain in delivering RNA-based therapeutics to the central nervous system. Advances in genetic screening and personalized medicine hold promise for improving the management of ALS. Ongoing clinical trials use genomic approaches for patient stratification and drug targeting. Further research into the role of non-coding RNAs in the pathogenesis of ALS and their potential as therapeutic targets is crucial to the development of effective treatments for this devastating disease.}, }
@article {pmid40008327, year = {2025}, author = {van Eijk, RPA and Steyn, FJ and Janse van Mantgem, MR and Schmidt, A and Meyjes, M and Allen, S and Daygon, DV and Loeffler, JP and Al-Chalabi, A and van den Berg, LH and Henderson, RD and Ngo, ST}, title = {An open-label Phase 2a study to assess the safety and tolerability of trimetazidine in patients with amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcaf063}, pmid = {40008327}, issn = {2632-1297}, abstract = {Metabolic imbalance is associated with amyotrophic lateral sclerosis progression. Impaired glucose oxidation and increased reliance on fatty acid oxidation contribute to reduced metabolic flexibility and faster disease progression in amyotrophic lateral sclerosis. We sought to evaluate the safety and tolerability, and explore the pharmacodynamic response of trimetazidine, a partial fatty acid oxidation inhibitor, on oxidative stress markers and energy expenditure in amyotrophic lateral sclerosis. The study was conducted between June 29, 2021 and May 24, 2023. People living with amyotrophic lateral sclerosis, recruited in Australia and the Netherlands, received open-label oral trimetazidine for 12 weeks after an initial 4-week lead-in period. The primary outcome measures were safety and tolerability, as well as the change from baseline in oxidative stress markers malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Secondary outcome measures were change from baseline in energy expenditure, amyotrophic lateral sclerosis functional rating scale-revised, and slow vital capacity (SVC). Linear mixed effects were used to estimate the mean difference in MDA and 8-OHdG between the on- and off-treatment periods. This trial is registered under ClinicalTrial.gov National Clinical Trial (NCT) number NCT04788745 and European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2020-005018-17. Twenty-one participants received trimetazidine; 19 (90%) completed the treatment period. Trimetazidine was well tolerated; there were 57 adverse events reported, of which 7 (11%) were deemed potentially drug-related, including hot flushes (2), nausea (2), paraesthesia (2) and fatigue (1). MDA was numerically lower during treatment [-0.29 uM; 95% confidence interval (CI) -0.90 to 0.33, P = 0.36]; 8-OHdG was significantly lower during treatment (-0.12 nM; 95% CI -0.23 to -0.01, P = 0.0245). The decrease in oxidative stress markers was accompanied by a reduction in resting energy expenditure (95 kcal, 95% CI 36.8-154, P = 0.0014). The absence of a placebo group prevented the interpretation of the clinical parameters. Oral trimetazidine was safe and well tolerated among patients with amyotrophic lateral sclerosis. This, combined with the significant reduction in markers of oxidative stress and resting energy expenditure, warrants a larger double-blind placebo-controlled efficacy study.}, }
@article {pmid40007904, year = {2025}, author = {Esteruelas, G and Ettcheto, M and Haro, I and Herrando-Grabulosa, M and Gaja-Capdevila, N and Gomara, MJ and Navarro, X and Espina, M and Souto, EB and Camins, A and García, ML and Sánchez-López, E}, title = {Novel Tissue-Specific Multifunctionalized Nanotechnological Platform Encapsulating Riluzole Against Motor Neuron Diseases.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {2273-2288}, pmid = {40007904}, issn = {1178-2013}, mesh = {*Riluzole/pharmacokinetics/pharmacology/chemistry/administration &amp; dosage ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Motor Neuron Disease/drug therapy ; Neuroprotective Agents/chemistry/pharmacokinetics/pharmacology/administration &amp; dosage ; Motor Neurons/drug effects ; Humans ; Nanoparticles/chemistry ; Polyethylene Glycols/chemistry/pharmacokinetics ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Mice ; Drug Carriers/chemistry/pharmacokinetics ; Blood-Brain Barrier/drug effects/metabolism ; Drug Delivery Systems/methods ; Tissue Distribution ; Peptides/chemistry/pharmacokinetics/administration &amp; dosage ; }, abstract = {BACKGROUND: Motor neuron diseases are neurological disorders characterized by progressive degeneration of upper and/or lower motor neurons. Amyotrophic Lateral Sclerosis (ALS) is the most common form of motor neuron diseases, where patients suffer progressive paralysis, muscle atrophy and finally death. Despite ALS severity, no treatment is safe and fully effective. In this area, Riluzole was the first drug approved and it constitutes the gold-standard for this pathology. However, to obtain suitable therapeutic efficacy, Riluzole requires high doses that are associated with severe adverse effects in other tissues. To attain Riluzole therapeutic efficacy avoiding other organs side-effects, new therapeutic strategies to enhance the delivery of Riluzole specifically to motor neurons constitute an unmet medical need. In this area, we have developed a novel multifunctional nanostructurated carrier to selectively deliver Riluzole to motor neurons.<br><br>RESULTS: This work develops and characterizes at in vitro and in vivo levels a tissue-targeted formulation of peptide and PEG-labelled PLGA nanoparticles encapsulating Riluzole. For this purpose, pVEC, a cell penetrating peptide able to increase transport through the blood-brain barrier, was attached to the nanoparticles surface. The multifunctionalized nanoparticles show suitable characteristics for the release of Riluzole in the central nervous system and were detected in motor neurons within 1 h after administration while significantly reducing the concentration of Riluzole in non-therapeutic organs responsible of side effects.<br><br>CONCLUSION: A novel drug delivery system has been developed and characterized, demonstrating enhanced CNS biodistribution of riluzole, which shows promise as efficient therapeutic tool for motor neuron diseases, including amyotrophic lateral sclerosis.}, }
@article {pmid40002740, year = {2025}, author = {Meng, K and Jia, H and Hou, X and Zhu, Z and Lu, Y and Feng, Y and Feng, J and Xia, Y and Tan, R and Cui, F and Yuan, J}, title = {Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies.}, journal = {Biomedicines}, volume = {13}, number = {2}, pages = {}, pmid = {40002740}, issn = {2227-9059}, support = {600791001//the Research Start-up Fund of Jining Medical University/ ; JYHL2021MS13//Research Fund for Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University/ ; 81700055//the National Natural Science Foundation of China/ ; Grant No. D2016021//Outstanding Talent Research Funding of Xuzhou Medical University/ ; BK20160229//Natural Science Foundation of Jiangsu Province/ ; tsqn201909147//Taishan Scholars Program of Shandong Province/ ; G2Y-kJS-SD-2023-097//Co-construction of Science and Technology Projects by the Science and Technology Department of the State Administration of Traditional Chinese Medicine/ ; }, abstract = {Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Recent studies have shown that mitochondria play a broad role in cell signaling, immune response, and metabolic regulation. For example, mitochondrial dysfunction is closely associated with the onset and progression of a variety of diseases, including ND, cardiovascular diseases, diabetes, and cancer. The dysfunction of energy metabolism, imbalance of mitochondrial dynamics, or abnormal mitophagy can lead to the imbalance of mitochondrial homeostasis, which can induce pathological reactions such as oxidative stress, apoptosis, and inflammation, damage the nervous system, and participate in the occurrence and development of degenerative nervous system diseases such as AD, PD, and ALS. In this paper, the latest research progress of this subject is detailed. The mechanisms of oxidative stress, mitochondrial homeostasis, and mitophagy-mediated ND are reviewed from the perspectives of β-amyloid (Aβ) accumulation, dopamine neuron damage, and superoxide dismutase 1 (SOD1) mutation. Based on the mechanism research, new ideas and methods for the treatment and prevention of ND are proposed.}, }
@article {pmid40001624, year = {2025}, author = {Ma, B and Ren, J and Qian, X}, title = {Study on the Polarization of Astrocytes in the Optic Nerve Head of Rats Under High Intraocular Pressure: In Vitro.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {12}, number = {2}, pages = {}, pmid = {40001624}, issn = {2306-5354}, support = {12472309 12072210//National Natural Science Foundation of China/ ; }, abstract = {Astrocytes, the most common glial cells in the optic nerve head (ONH), provide support and nutrition to retinal ganglion cells. This study aims to investigate the polarization types of astrocytes in the ONH of rats under high intraocular pressure (IOP) and explore signaling pathways potentially associated with different types of polarized astrocytes. The rat models with chronic high IOP were established. High IOP lasted for 2, 4, 6, and 8 weeks. Astrocytes were extracted from the ONH of rats using the tissue block cultivation method. Western blot was used to detect the expression of proteins associated with astrocyte polarization. Proteomics was employed to identify differential proteins associated with astrocyte polarization. Astrocytes polarized into A2 astrocytes after 2, 4, 6, and 8 weeks of high IOP, while polarization into A1 astrocytes began only after 8 weeks of high IOP. The differential proteins associated with A1 astrocyte polarization are primarily enriched in pathways of neurodegeneration with respect to multiple diseases, while the differential proteins associated with A2 astrocyte polarization are primarily enriched in pathways of spliceosome in amyotrophic lateral sclerosis. Our findings could provide a better understanding of the role of ONH astrocytes in the pathogenesis of glaucoma and offer new perspectives for glaucoma treatment.}, }
@article {pmid40001529, year = {2025}, author = {Onu, CJ and Adu, M and Chakkour, M and Kumar, V and Greenberg, ML}, title = {Inositol Phosphates and Synthesizing Enzymes: Implications in Neurodegenerative Disorders.}, journal = {Biomolecules}, volume = {15}, number = {2}, pages = {}, pmid = {40001529}, issn = {2218-273X}, support = {R01 GM125082/GM/NIGMS NIH HHS/United States ; R35 GM149271/GM/NIGMS NIH HHS/United States ; GM149271/GF/NIH HHS/United States ; GM125082/GF/NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Inositol Phosphates/metabolism ; Animals ; Parkinson Disease/metabolism ; Alzheimer Disease/metabolism ; Signal Transduction ; Inositol/metabolism ; }, abstract = {Inositol is a vital sugar molecule involved in numerous signaling pathways required for cellular homeostasis and cell survival. Myo-inositol and its phospho-derivatives, inositol phosphates (IPs), are the most prevalent forms of inositol found in living cells. They are involved in regulating ion channels, metabolic flux, stress response, and other key biological processes. While emerging research has highlighted the significant roles of inositol phosphates in immunity, cancer, and metabolic diseases, there is a lack of comprehensive reviews on their roles in psychiatric and neurological disorders. This review aims to fill that gap by analyzing the existing literature on the importance of inositol phosphates in severe psychiatric and neurological conditions such as Parkinson's disease, Alzheimer's disease, bipolar disorder, amyotrophic lateral sclerosis, schizophrenia, and Huntington's disease, underscoring the potential to pave the way for new treatment regimens for these debilitating disorders targeting inositol pathways.}, }
@article {pmid40000618, year = {2025}, author = {Ru, Q and Li, Y and Zhang, X and Chen, L and Wu, Y and Min, J and Wang, F}, title = {Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects.}, journal = {Bone research}, volume = {13}, number = {1}, pages = {27}, pmid = {40000618}, issn = {2095-4700}, support = {82071970//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82072506//National Natural Science Foundation of China (National Science Foundation of China)/ ; 31970689//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32330047//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2024AFB971//Natural Science Foundation of Hubei Province (Hubei Provincial Natural Science Foundation)/ ; }, mesh = {*Ferroptosis/physiology ; Humans ; *Homeostasis ; *Iron/metabolism ; *Muscular Diseases/metabolism/therapy/pathology/physiopathology ; Animals ; }, abstract = {The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.}, }
@article {pmid39998031, year = {2025}, author = {Burke, KM and Shea, C and Arulanandam, V and Sullivan, S and Ellrodt, AS and MacAdam, C and Carney, K and Casagrande, G and Christiansen, E and Paganoni, S}, title = {Cervical Collar Satisfaction and Functional Impact in Amyotrophic Lateral Sclerosis: A Survey Study.}, journal = {American journal of physical medicine &amp; rehabilitation}, volume = {}, number = {}, pages = {}, doi = {10.1097/PHM.0000000000002716}, pmid = {39998031}, issn = {1537-7385}, abstract = {OBJECTIVES: Many people with amyotrophic lateral sclerosis (ALS) develop cervical muscle weakness, often managed with cervical collars. Finding supportive and comfortable collars can be challenging. This study aimed to evaluate satisfaction with various collars and their impact on activities of daily living.<br><br>DESIGN: This electronic survey study collected demographic information, clinical status, and participant experiences with commonly used cervical collars.<br><br>RESULTS: Thirty-four participants (33 with ALS, 1 with primary lateral sclerosis) completed the survey, with 79% reporting neck weakness and 38% experiencing neck pain. Among those who tried cervical collars (65%), many had tried multiple options. The mean satisfaction across all collar types was 5.03 (SD = 2.92) out of 10.<br><br>CONCLUSION: These findings suggest current collars do not fully meet the needs of people living with ALS, emphasizing the importance of improved treatment options. Future research should explore innovative technologies to improve cervical support, function, and quality of life.}, }
@article {pmid39996130, year = {2025}, author = {Dilliott, AA and Costanzo, MC and Bandres-Ciga, S and Blauwendraat, C and Casey, B and Hoang, Q and Iwaki, H and Jang, D and Kim, JJ and Leonard, HL and Levine, KS and Makarious, M and Nguyen, TT and Rouleau, GA and Singleton, AB and Smadbeck, P and Solle, J and Vitale, D and Nalls, M and Flannick, J and Burtt, NP and Farhan, SMK}, title = {The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.}, journal = {Neurology. Genetics}, volume = {11}, number = {2}, pages = {e200246}, pmid = {39996130}, issn = {2376-7839}, abstract = {Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathologic mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across 10 different phenotypic groups, including neurologic conditions such as Alzheimer disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively use the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for patients with neurodegenerative disease.}, }
@article {pmid39995125, year = {2025}, author = {Kalinin, AP and Zubkova, ES and Menshikov, MY and Parfyonova, YV}, title = {ISR Modulators in Neurological Diseases.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X361653250213114821}, pmid = {39995125}, issn = {1875-6190}, abstract = {The dysfunction of different cells lies in the pathogenesis of neurological diseases and is usually associated with cellular stress. Various stressors trigger the integrated stress response (ISR) signaling, whose highly conserved mechanism is primarily aimed at protecting a stress-exposed cell to cope as safely as possible with such stressful conditions. On the contrary, if a cell is unable to cope with excessive stress, the ISR can induce apoptosis. The ISR mechanism, whose main stage is the inhibition of translation machinery in favor of the synthesis of specific proteins, including the transcription factors ATF3, ATF4, CEBPA, and CEBPB, which function only as dimers and determine the uniqueness of the ISR response in each individual case, thus ensures different outcomes of the ISR. Inhibition of global protein synthesis is achieved through phosphorylation of eIF2α by PERK, HRI, PKR, or GCN2. To date, a number of compounds have been developed that modulate the ISR, including activators and inhibitors of the abovementioned ISR kinases as well as modulators of p-eIF2α dephosphorylation. They target different ISR stages, allowing a broad ISR modulation strategy. At the same time, there are no drugs that are both exceptionally safe and effective for the treatment of several neurological diseases, so there is an urgent need for new approaches to the treatment of these disorders. In this review, we represent ISR signaling as an important participant in the pathogenesis of neurological diseases. We also describe how various ISR modulators may become a part of future therapies for these diseases.}, }
@article {pmid39992655, year = {2025}, author = {Liu, X and Shang, H and Wei, Q and Yao, X and Lian, L and Dang, J and Jia, R and Wu, Z and Li, H and Niu, Q and Cheng, X and Zou, Z and Chen, S and Zhang, M and Liu, Y and Liu, Y and Liu, Q and Huang, X and Wang, H and Feng, H and Wang, S and Fan, D and , }, title = {Tetramethylpyrazine Nitrone in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {8}, number = {2}, pages = {e2461055}, pmid = {39992655}, issn = {2574-3805}, mesh = {Humans ; Male ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Pyrazines/therapeutic use/adverse effects ; Double-Blind Method ; Aged ; Treatment Outcome ; China ; Nitrogen Oxides ; }, abstract = {IMPORTANCE: Tetramethylpyrazine nitrone has exhibited promising results in improving motor dysfunction in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).<br><br>OBJECTIVE: To evaluate the safety and efficacy of orally administered tetramethylpyrazine nitrone in patients with ALS.<br><br>This phase 2, multicenter, double-masked, placebo-controlled, randomized clinical trial was conducted from December 24, 2020, through July 14, 2023, in 11 centers in China, with a 180-day follow-up. Patients aged 45 to 70 years, with ALS onset within 2 years, ALS Functional Rating Scale-Revised (ALSFRS-R) scores of at least 2 points on each item, and forced vital capacity (FVC) of at least 80% were included. Patients experienced a 1- to 4-point decrease in ALSFRS-R score during a 3-month screening period.<br><br>INTERVENTIONS: Patients were randomly assigned 1:1:1 to receive low-dose tetramethylpyrazine nitrone (600 mg twice daily), high-dose tetramethylpyrazine nitrone (1200 mg twice daily), or placebo (twice daily) for 180 days.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was change in ALSFRS-R score (range of 0-48, with lower scores indicating worse function) from baseline to 180 days. The secondary outcomes were changes in FVC, grip strength, ALS Assessment Questionnaire-40 (ALSAQ-40) score, and end point events. Safety outcomes included adverse events.<br><br>RESULTS: A total of 155 patients (mean [SD] age, 55.0 [6.5] years; 115 men [74.2%]) were randomized (51 [32.9%] to the low-dose tetramethylpyrazine nitrone group, 52 [33.6%] to the high-dose tetramethylpyrazine nitrone group, and 52 [33.6%] to the placebo group). No significant differences were observed in ALSFRS-R score changes between low-dose tetramethylpyrazine nitrone (least squares [LS] mean difference, -0.89 points; 95% CI -3.25 to 1.48 points) and high-dose tetramethylpyrazine nitrone (LS mean difference, -0.20 points; 95% CI -2.48 to 2.07 points) compared with placebo. High-dose tetramethylpyrazine nitrone showed a significantly slower decline in grip strength at day 180 (LS mean difference, 2.46 kg; 95% CI, 0.15-4.76 kg). In a subgroup of patients younger than 65 years with slower disease progression, tetramethylpyrazine nitrone significantly attenuated the decline in grip strength (LS mean difference, 3.63 kg; 95% CI, 0.84-6.41 kg), bulbar scores (LS mean difference, 0.66 points; 95% CI, 0.03-1.29 points), and respiratory scores (LS mean difference, 0.54 points; 95% CI, 0.03-1.06 points). Adverse events were mostly mild or moderate, with no severe treatment-related adverse events or deaths.<br><br>CONCLUSIONS AND RELEVANCE: This randomized clinical trial demonstrates that tetramethylpyrazine nitrone is safe and well-tolerated in patients with ALS. There was no difference in the primary end point across the low-dose, high-dose, and placebo groups, with significant benefits in a subgroup of younger patients with slower disease progression.<br><br>TRIAL REGISTRATION: ChiCTR Identifier: ChiCTR2000039689.}, }
@article {pmid39987285, year = {2025}, author = {Fang, M and Zhou, Y and He, K and Lu, Y and Tao, F and Huang, H}, title = {Glucose Metabolic Reprogramming in Microglia: Implications for Neurodegenerative Diseases and Targeted Therapy.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39987285}, issn = {1559-1182}, support = {82204651//National Natural Science Foundation of China/ ; }, abstract = {As intrinsic immune cells in the central nervous system, microglia play a crucial role in maintaining brain homeostasis. Microglia can transition from homeostasis to various responsive states in reaction to different external stimuli, undergoing corresponding alterations in glucose metabolism. In neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), microglial glucose metabolic reprogramming is widespread. This reprogramming leads to changes in microglial function, exacerbating neuroinflammation and the accumulation of pathological products, thereby driving the progression of neurodegeneration. This review summarizes the specific alterations in glucose metabolism within microglia in AD, PD, ALS, and MS, as well as the corresponding treatments aimed at reprogramming glucose metabolism. Compounds that inhibit key glycolytic enzymes like hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2), or activate regulators of energy metabolism such as AMP-activated protein kinase (AMPK), have shown significant potential in the treatment of various neurodegenerative diseases. However, current research faces numerous challenges, including side effects and blood-brain barrier (BBB) penetration of compounds. Screening relevant drugs from natural products, especially flavonoids, is a reliable approach. On the one hand, longtime herbal medical practices provide a certain degree of assurance regarding clinical safety, and their chemical properties contribute to effective BBB permeability. On the other hand, the concurrent anti-tumor and anti-neuroinflammatory activities of flavonoids suggest that regulation of glucose metabolism reprogramming might be a potential common mechanism of action. Notably, considering the dynamic nature of microglial metabolism, there is an urgent need to develop technologies for real-time monitoring of glucose metabolism processes, which would significantly advance research in this field.}, }
@article {pmid39987111, year = {2025}, author = {Zeng, L and Yang, F and Xu, D and Zhou, J and Qiao, G and Wu, M and Li, C and Yu, Y and Qiu, Y and Liu, J}, title = {Actual needs of patients with amyotrophic lateral sclerosis: a qualitative study from Wuhan, China.}, journal = {BMC palliative care}, volume = {24}, number = {1}, pages = {50}, pmid = {39987111}, issn = {1472-684X}, support = {2023AFD160//Hubei Provincial Natural Science Foundation and Traditional Chinese Medicine Innovation and Development Joint/ ; 2024AFD279//Department of Science and Technology, Hubei Province, China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; China ; *Qualitative Research ; Male ; Middle Aged ; Female ; Aged ; Adult ; Needs Assessment ; Health Services Needs and Demand ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disorder that significantly impacts individuals and families. Previous research on ALS has predominantly focused on its pathophysiology, genetic factors, and potential therapeutic interventions. While these aspects are essential for understanding and treating the disease, there has been a growing recognition of the importance of studying patients' actual needs. Understanding these needs is vital for developing patient-centered care models that can enhance the well-being of ALS patients. However, existing studies on patients' needs are often limited in scope. Many are conducted in Western countries, and the results may not be directly applicable to patients in other cultural and socioeconomic contexts. China, with its large population and diverse cultural, economic, and healthcare landscapes, presents a unique setting for studying ALS patients' needs. At the same time, traditional Chinese medicine (TCM) practices are deeply ingrained in their healthcare system and may affect the way people with ALS seek treatment and manage their condition. Therefore, these differences may lead to differences in the actual needs of ALS patients in China. In conclusion, this qualitative study on the actual needs of ALS patients in China aims to bridge the gap in the existing research. By exploring these needs, it can provide valuable insights for healthcare providers, policymakers, and researchers, ultimately contributing to the improvement of care and quality of life for ALS patients in China.<br><br>METHOD: We carried out a qualitative study using an empirical phenomenological approach. Individual in-depth interviews were performed among 22 people with ALS from the motor neuron disease rehabilitation center of a tertiary Chinese medicine hospital in China, and the interview content was analyzed qualitatively. Interview recordings were converted to text content by NVivo 11.0 software and analyzed using Colaizzi's phenomenological method.<br><br>RESULT: Three main themes were identified in this study: (1) Demand for healthcare services, (2) Emotional requirements, (3) Functional requirements. In addition, 8 sub-themes were extracted as the actual needs of ALS patients.<br><br>CONCLUSION: This study is based on the real experience of ALS patients after diagnosis, and a deep understanding of these experiences can explore the actual needs of patients from many aspects and give reasonable advice and help. Given the particularity of the disease and the uncertainty of treatment, patients will have practical needs for relevant medical support, emotional requirements, physical functions, and other aspects during the period of illness, and the corresponding support is an effective measure to reduce the burden on patients.}, }
@article {pmid39985812, year = {2025}, author = {Filippi, M and Ghirelli, A and Spinelli, EG and Agosta, F}, title = {A comprehensive update on neuroimaging endpoints in amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {4}, pages = {397-413}, doi = {10.1080/14737175.2025.2470324}, pmid = {39985812}, issn = {1744-8360}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging ; Humans ; *Neuroimaging/methods ; *Magnetic Resonance Imaging/methods ; *Disease Progression ; *Positron-Emission Tomography/methods ; Biomarkers ; }, abstract = {INTRODUCTION: There are currently few treatments approved for amyotrophic lateral sclerosis (ALS). Additionally, there remains a significant unmet need for reliable, standardized biomarkers to assess endpoints in clinical trials. Magnetic resonance imaging (MRI)- and positron emission tomography (PET)-derived metrics could help in patient selection and stratification, shortening trial duration and reducing costs.<br><br>AREAS COVERED: This review focuses on the potential use of neuroimaging endpoints in the context of ALS therapeutic trials, providing insights on structural and functional neuroimaging, plexus and muscle alterations, glial involvement and neuroinflammation, envisioning how these surrogates of disease progression could be implemented in clinical trials. A PubMed search covering the past 15&#x2009;years was performed.<br><br>EXPERT OPINION: Neuroimaging is essential in understanding ALS pathophysiology, aiding in disease progression tracking and evaluating therapeutic interventions. High costs, limited accessibility, lack of standardization, and patient tolerability limit their use in routine ALS care. Addressing these obstacles is essential for fully harnessing neuroimaging potential in improving diagnostics and treatment in ALS.}, }
@article {pmid39982687, year = {2025}, author = {Loher, P and Londin, E and Ilieva, H and Pasinelli, P and Rigoutsos, I}, title = {Re-Analyses of Samples From Amyotrophic Lateral Sclerosis Patients and Controls Identify Many Novel Small RNAs With Diagnostic And Prognostic Potential.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39982687}, issn = {1559-1182}, abstract = {Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease for which accurate diagnostic and prognostic biomarkers are needed. Toward this goal, we reanalyzed two published collections of datasets generated from the plasma and serum of ALS patients and controls. We profiled these datasets for isoforms of microRNAs (miRNAs) known as isomiRs, transfer RNA-derived fragments (tRFs), and ribosomal RNA-derived fragments (rRFs), placing all remaining reads into a group labeled "not-itrs." We found that plasma and serum are rich in isomiRs (canonical, non-canonical, and non-templated), tRFs, rRFs, and members of an emerging class of small RNAs known as Y RNA-derived fragments (yRFs). In both analyzed collections, we found many isomiRs, tRFs, rRFs, and yRFs that are differentially abundant between patients and controls. We also performed a survival analysis that considered Riluzole treatment status, demographics (age at onset, age at enrollment, sex), and disease characteristics (ALSFRS, rD50, onset type) and found many of the differentially abundant small RNAs to be associated with survival time, with some of these associations being independent of Riluzole treatment. Unexpectedly, many not-itrs that did not map to the human genome mapped exactly to sequences from the SILVA database of ribosomal DNAs (rDNAs). Not-itrs from the plasma datasets mapped primarily to rDNAs from the order of Burkholderiales, and several of them were associated with patient survival. Not-itrs from the serum datasets also showed support for rDNA from Burkholderiales but a stronger support for rDNAs from the fungi group of the Nucletmycea taxon. The findings suggest that many previously unexplored small non-coding RNAs, including human isomiRs, tRFs, rRFs, and yRFs, could potentially serve as novel diagnostic and prognostic biomarkers for ALS.}, }
@article {pmid39981400, year = {2025}, author = {Yang, EJ and Lee, SH}, title = {Herbal Medicine Extracts Improve Motor Function by Anti-Inflammatory Activity in hSOD1[G93A] Animal Model.}, journal = {Mediators of inflammation}, volume = {2025}, number = {}, pages = {1999953}, pmid = {39981400}, issn = {1466-1861}, mesh = {Animals ; Mice ; *Mice, Transgenic ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; *Disease Models, Animal ; *Plant Extracts/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Muscle, Skeletal/drug effects/metabolism ; Paeonia/chemistry ; Male ; Oxidative Stress/drug effects ; Herbal Medicine ; Superoxide Dismutase/metabolism ; Motor Neurons/drug effects/metabolism ; Inflammation/drug therapy/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multicomplex neurodegenerative disorder characterized by motor neuron death, muscle atrophy, and respiratory failure. Owing to its multicomplex mechanisms and multifactorial nature in the skeletal muscle and spinal cord (SC), no effective therapy has been developed. However, herbal medicines, known for their multitarget properties, have demonstrated promising efficacy with limited side effects in treating various diseases. Specifically, Paeonia lactiflora Pallas has been demonstrated to exhibit analgesic, antidepressant, anti-inflammatory, and neuroprotective effects. However, the pharmacological mechanisms underlying the beneficial effects of P. lactiflora in hSOD1[G93A] animal models remain unexplored. Therefore, this study was conducted to investigate the multitarget effects of P. lactiflora in hSOD1[G93A] transgenic mice, an ALS model. Footprint tests, western blot assays, and immunohistochemical analysis were used to assess the effect of P. lactiflora on the tibia anterior (TA), gastrocnemius (GC), and SC. The results revealed that P. lactiflora augmented motor function and decreased motor neuron loss in hSOD1[G93A] mice. Furthermore, P. lactiflora significantly lowered the expression of proteins associated with inflammation and oxidative stress in the skeletal muscle (TA and GC) and SC. P. lactiflora also regulated autophagy function by reducing the levels of key markers, such as P62/sequestosome 1 (SQSTM1), microtubule-associated proteins 1A/1B light chain 3B, and SMAD family member 2, in the muscle and SC. Overall, P. lactiflora treatment improved motor function, prevented motor neuron death, and exhibited anti-inflammatory and antioxidative effects in the skeletal muscle and SC of ALS mouse models. These results suggest that P. lactiflora could serve as a promising multitarget therapeutic agent for systemic and multipathological diseases.}, }
@article {pmid39976261, year = {2025}, author = {Menendez-Gonzalez, M}, title = {Implementing a tridimensional diagnostic framework for personalized medicine in neurodegenerative diseases.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14591}, pmid = {39976261}, issn = {1552-5279}, support = {PI21/00467//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/diagnosis/genetics ; *Biomarkers ; Neuroimaging/methods ; }, abstract = {Neurodegenerative diseases (NDDs) pose a significant challenge in modern medicine due to their clinical heterogeneity, multifactorial etiologies, and frequent co-pathologies. Traditional diagnostic systems, based on clinical symptoms and post mortem findings, are limited in capturing the complex interactions among genetic, molecular, and neuroanatomical factors. This manuscript introduces a novel tridimensional diagnostic framework that integrates these factors across three key axes: etiology (genetic and environmental influences), molecular markers (primary and secondary biomarkers), and neuroanatomoclinical correlations. Through case studies, we demonstrate the framework's ability to synthesize incomplete datasets, stratify patients, and guide precision medicine. By incorporating omics technologies, neuroimaging, and AI-driven probabilistic modeling, the framework enhances diagnostic accuracy and clinical relevance. This approach may contribute to overcoming the limitations of traditional nosologies, offering a scalable and adaptable tool for both clinical practice and research and advancing the field of precision medicine in NDD management. HIGHLIGHTS: Tridimensional diagnostic system: We propose a new framework that incorporates three axes - etiology, molecular markers, and neuroanatomical-clinical correlations - to enhance diagnostic accuracy for NDDs. Personalized medicine: The tridimensional system enables the integration of genetic, molecular, and clinical data, allowing for highly personalized treatment strategies tailored to individual patients. Proteinopathies as key biomarkers: This diagnostic system emphasizes the use of primary proteinopathies (amyloid, tau, synuclein) and secondary biomarkers (eg, NfL, GFAP) to monitor disease progression and treatment efficacy. Addressing clinical heterogeneity: The framework accommodates the complexity and heterogeneity of NDDs, offering an adaptable diagnostic approach for classical conditions like Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and ALS. Case studies and real-world application: Practical case studies illustrate how this system can be implemented in clinical practice, enabling the combination of DMTs with symptomatic treatments.}, }
@article {pmid39967643, year = {2025}, author = {Abdel-Magid, AF}, title = {Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors as Potential Treatment for Several Inflammatory and Neurodegenerative Diseases.}, journal = {ACS medicinal chemistry letters}, volume = {16}, number = {2}, pages = {204-206}, pmid = {39967643}, issn = {1948-5875}, abstract = {The invention in this patent application relates to 2-amino-[1,2,4]triazolo[1,5-a]pyridin derivatives represented generally herein as formula 1. These compounds have activities as receptor-interacting protein kinase 1 (RIPK1) inhibitors and may potentially provide treatment and/or prophylaxis of inflammatory and neurodegenerative diseases associated with aberrant RIPK1 activity such as ulcerative colitis, Crohn's disease, psoriasis, NASH, heart failure, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease.}, }
@article {pmid39963928, year = {2025}, author = {Lomas, C and Dubey, RC and Perez-Alvarez, G and Lopez Hernandez, Y and Atmar, A and Arias, AY and Vashist, A and Aggarwal, S and Manickam, P and Lakshmana, MK and Vashist, A}, title = {Recent advances in nanotherapeutics for HIV-associated neurocognitive disorders and substance use disorders.}, journal = {Nanomedicine (London, England)}, volume = {20}, number = {6}, pages = {603-619}, pmid = {39963928}, issn = {1748-6963}, support = {R01 DA049657/DA/NIDA NIH HHS/United States ; R03 AG087475/AG/NIA NIH HHS/United States ; U01 ES033265/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/complications/drug therapy ; *Substance-Related Disorders ; *Blood-Brain Barrier/metabolism/drug effects ; Nanoparticles/chemistry ; Animals ; Neurocognitive Disorders/drug therapy/etiology ; Nanomedicine/methods ; AIDS Dementia Complex/drug therapy ; }, abstract = {Substance use disorders (SUD) and HIV-associated neurocognitive disorders (HAND) work synergistically as a significant cause of cognitive decline in adults and adolescents globally. Current therapies continue to be limited due to difficulties crossing the blood-brain barrier (BBB) leading to limited precision and effectiveness, neurotoxicity, and lack of co-treatment options for both HAND and SUD. Nanoparticle-based therapeutics have several advantages over conventional therapies including more precise targeting, the ability to cross the BBB, and high biocompatibility which decreases toxicity and optimizes sustainability. These advantages extend to other neurological disorders such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). This review summarizes recent advances in nanotechnology for application to HAND, SUD, and co-treatment, as well as other neurological disorders. This review also highlights the potential challenges these therapies face in clinical translation and long-term safety.}, }
@article {pmid39961673, year = {2025}, author = {Aryapadi, V and Trivedi, J}, title = {Atypical presentation of amyotrophic lateral sclerosis with SOD1-H47R mutation.}, journal = {BMJ case reports}, volume = {18}, number = {2}, pages = {}, doi = {10.1136/bcr-2024-263293}, pmid = {39961673}, issn = {1757-790X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Superoxide Dismutase-1/genetics ; Male ; *Mutation ; Middle Aged ; }, abstract = {Traditionally, amyotrophic lateral sclerosis (ALS) is recognised as a fatal neurodegenerative disease that typically emerges in the later decades of life, with a life expectancy of 2-5 years after symptom onset. We now understand that ALS exhibits a wide phenotypic clinical spectrum, significantly influenced by genetic factors. Here, we describe a patient with familial ALS carrying a heterozygous pathogenic H47R mutation of the superoxide dismutase 1 (SOD1) gene. His clinical presentation is atypical, with a slow progressive course, lower extremity weakness, and sparing of bulbar and respiratory function, consistent with the flail leg variant of ALS. The objective of this report is to increase awareness of atypical presentations of ALS and the diagnostic challenges they pose to clinicians. In addition to a description of the clinical case, we briefly discuss the new role of gene therapy in the treatment of familial ALS with SOD1 mutations.}, }
@article {pmid39960672, year = {2025}, author = {Paganoni, S and Fournier, CN and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Ajroud-Driss, S and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, AV and Shefner, JM and Hall, M and Kittle, G and Berry, JD and Babu, S and Andrews, J and Dagostino, D and Tustison, E and Giacomelli, E and Scirocco, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, K and Maragakis, NJ and Simmons, Z and Miller, TM and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, LA and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, CE and Ladha, S and Heiman-Patterson, T and Caress, JB and Swenson, A and Peltier, A and Lewis, R and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, C and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Glass, J and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Harvey, B and Patel, S and Mahoney, P and Duda, PW and Cudkowicz, ME and , }, title = {Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {8}, number = {2}, pages = {e2459058}, pmid = {39960672}, issn = {2574-3805}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Double-Blind Method ; Aged ; Treatment Outcome ; Edaravone/therapeutic use ; }, abstract = {IMPORTANCE: The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression.<br><br>OBJECTIVE: To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS.<br><br>Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens.<br><br>INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing.<br><br>MAIN OUTCOMES AND MEASURES: The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n&#x2009;=&#x2009;164).<br><br>RESULTS: Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority,&#x2009;0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified.<br><br>CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04297683.}, }
@article {pmid39958549, year = {2025}, author = {Zhang, Y}, title = {Enhancing rectal cancer liver metastasis prediction: Magnetic resonance imaging-based radiomics, bias mitigation, and regulatory considerations.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {2}, pages = {102151}, pmid = {39958549}, issn = {1948-5204}, abstract = {In this article, we comment on the article by Long et al published in the recent issue of the World Journal of Gastrointestinal Oncology. Rectal cancer patients are at risk for developing metachronous liver metastasis (MLM), yet early prediction remains challenging due to variations in tumor heterogeneity and the limitations of traditional diagnostic methods. Therefore, there is an urgent need for non-invasive techniques to improve patient outcomes. Long et al's study introduces an innovative magnetic resonance imaging (MRI)-based radiomics model that integrates high-throughput imaging data with clinical variables to predict MLM. The study employed a 7:3 split to generate training and validation datasets. The MLM prediction model was constructed using the training set and subsequently validated on the validation set using area under the curve (AUC) and dollar-cost averaging metrics to assess performance, robustness, and generalizability. By employing advanced algorithms, the model provides a non-invasive solution to assess tumor heterogeneity for better metastasis prediction, enabling early intervention and personalized treatment planning. However, variations in MRI parameters, such as differences in scanning resolutions and protocols across facilities, patient heterogeneity (e.g., age, comorbidities), and external factors like carcinoembryonic antigen levels introduce biases. Additionally, confounding factors such as diagnostic staging methods and patient comorbidities require further validation and adjustment to ensure accuracy and generalizability. With evolving Food and Drug Administration regulations on machine learning models in healthcare, compliance and careful consideration of these regulatory requirements are essential to ensuring safe and effective implementation of this approach in clinical practice. In the future, clinicians may be able to utilize data-driven, patient-centric artificial intelligence (AI)-enhanced imaging tools integrated with clinical data, which would help improve early detection of MLM and optimize personalized treatment strategies. Combining radiomics, genomics, histological data, and demographic information can significantly enhance the accuracy and precision of predictive models.}, }
@article {pmid39958442, year = {2025}, author = {Ozbey, D and Saribas, S and Kocazeybek, B}, title = {Gut microbiota in Crohn's disease pathogenesis.}, journal = {World journal of gastroenterology}, volume = {31}, number = {6}, pages = {101266}, pmid = {39958442}, issn = {2219-2840}, mesh = {Humans ; *Crohn Disease/microbiology/immunology/therapy ; *Gastrointestinal Microbiome ; *Fecal Microbiota Transplantation ; Treatment Outcome ; Intestinal Mucosa/microbiology/immunology/pathology ; Feces/microbiology ; Colon/microbiology/pathology/immunology ; Dysbiosis ; Ileum/microbiology/pathology/immunology ; Animals ; Colitis, Ulcerative/microbiology/therapy/immunology ; }, abstract = {Inflammatory bowel diseases (IBDs) are classified into two distinct types based on the area and severity of inflammation: Crohn's disease (CD) and ulcerative colitis. In CD, gut bacteria can infiltrate mesenteric fat, causing expansion known as creeping fat, which may limit bacterial spread and inflammation but can promote fibrosis. The gut bacteria composition varies depending on whether the colon or ileum is affected. Fecal microbiota transplantation (FMT) transfers feces from a healthy donor to restore gut microbiota balance, often used in IBD patients to reduce inflammation and promote mucosal repair. The use of FMT for CD remains uncertain, with insufficient evidence to fully endorse it as a definitive treatment. While some studies suggest it may improve symptoms, questions about the duration of these improvements and the need for repeated treatments persist. There is a pressing need for methods that provide long-term benefits, as highlighted by Wu et al's research.}, }
@article {pmid39954940, year = {2025}, author = {Satao, KS and Doshi, GM}, title = {Intercellular communication via exosomes: A new paradigm in the pathophysiology of neurodegenerative disorders.}, journal = {Life sciences}, volume = {365}, number = {}, pages = {123468}, doi = {10.1016/j.lfs.2025.123468}, pmid = {39954940}, issn = {1879-0631}, mesh = {*Exosomes/metabolism/physiology ; Humans ; *Neurodegenerative Diseases/metabolism/physiopathology/pathology ; *Cell Communication/physiology ; Animals ; }, abstract = {Neurodegenerative disorders are one of the leading causes of death and disability and pose a great economic burden on healthcare systems. Generally, these neurodegenerative disorders have a progressive deterioration in neural function and structure, and deposition of misfolded proteins commonly occurs, such as amyloid-β in AD and α-synuclein in PD. However, there exists a special class of exosomes, which acts like a transmitter and enhances communication between cells. The present review discusses the significant role of exosomes in neurodegenerative diseases, with a focus on Amyotrophic lateral Sclerosis (ALS), AD, PD, and Huntington's disease (HD). In this review, the biogenesis of exosomes is discussed from multivesicular bodies and onwards to their release into the extracellular environment. The present review focuses on recent data concerning the possible use of modified exosomes as ND therapy. Indeed, future work is needed to explain the processes driving exosome biogenesis and cargo selection, while opening new routes by the use of exosome-based therapeutics in neurodegenerative disease diagnosis and treatment.}, }
@article {pmid39954710, year = {2025}, author = {Nadeem, ZA and Ahmed, S}, title = {Amyotrophic lateral sclerosis and lovastatin: a promising treatment perspective.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-2}, doi = {10.1080/21678421.2025.2463943}, pmid = {39954710}, issn = {2167-9223}, }
@article {pmid39953725, year = {2025}, author = {Nishida, K and Sakashita, K and Futamura, N}, title = {Decision-making trends in therapeutic interventions for multiple system atrophy: a 24-year retrospective study.}, journal = {Movement disorders clinical practice}, volume = {}, number = {}, pages = {}, doi = {10.1002/mdc3.70000}, pmid = {39953725}, issn = {2330-1619}, support = {JPMH23FC1010//the Ministry of Health, Labour and Welfare, Japan/ ; }, abstract = {BACKGROUND: Managing multiple system atrophy (MSA) is challenging. While invasive interventions for amyotrophic lateral sclerosis are well-studied, those for MSA remain less explored.<br><br>OBJECTIVES: To explore factors influencing treatment choices and trends in advanced-stage MSA.<br><br>METHODS: A retrospective cohort study analyzed 128 MSA patients at Hyogo Chuo National Hospital, Japan, from 2000 to 2024, focusing on treatment period and age at onset.<br><br>RESULTS: Tracheostomy invasive ventilation (TIV) decreased after 2014 (26.9% vs. 9.2%; P&#x2009;=&#x2009;0.023). TIV-treated patients remained similarly young before and after 2014 (age at onset 52.7 vs. 54.5&#x2009;years; P&#x2009;=&#x2009;0.659) and tracheostomy was chosen by younger patients after 2014 (58.3 vs. 51.5&#x2009;years; P&#x2009;<&#x2009;0.001). Conversely, enteral nutrition increased in older patients (57.4 vs. 62.9&#x2009;years; P&#x2009;=&#x2009;0.011).<br><br>CONCLUSIONS: In Japanese MSA, preferences for invasive treatments shifted, with younger patients favoring TIV and tracheostomy, while older patients preferred less invasive options, emphasizing personalized care.}, }
@article {pmid39947630, year = {2025}, author = {Moreno-Martinez, L and Gaja-Capdevila, N and Mosqueira-Martín, L and Herrando-Grabulosa, M and Rodriguez-Gomez, L and Gonzalez-Imaz, K and Calvo, AC and Sagartzazu-Aizpurua, M and Moreno-García, L and Fuentes, JM and Acevedo-Arozena, A and Aizpurua, JM and Miranda, JI and López de Munain, A and Vallejo-Illarramendi, A and Navarro, X and Osta, R and Gil-Bea, FJ}, title = {Novel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1[G93A] amyotrophic lateral sclerosis (ALS) mice.}, journal = {British journal of pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bph.17448}, pmid = {39947630}, issn = {1476-5381}, support = {PID2022-140354OB-I00//Agencia Estatal de Investigaci&#xf3;n/ ; PID2020-119780RB-100//Agencia Estatal de Investigaci&#xf3;n/ ; IKERBASQUE/PP/2022/003//Ikerbasque, Basque Foundation for Science/ ; PIF19/184//Euskal Herriko Unibertsitatea/ ; PI2020/08-1//CIBER-CALS/ ; CB06/05/1105//Instituto de Salud Carlos III of Spain/ ; CB06/05/0041//Instituto de Salud Carlos III of Spain/ ; BIO19/ROCHE/017/BD//Roche Stop Fuga de Cerebros/ ; IT1732-22//Basque Government/ ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment options. ALS pathogenesis involves intricate processes within motor neurons, characterized by dysregulated Ca[2+] influx and buffering in early ALS-affected motor neurones. This study proposes the modulation of ryanodine receptors (RyRs), key mediators of intracellular Ca[2+], as a therapeutic target.<br><br>EXPERIMENTAL APPROACH: A novel class of novel FKBP12 ligands that show activity as cytosolic calcium modulators through stabilizing RyR channel activity, were tested in the superoxide dismutase 1 (SOD1)[G93A] mouse model of ALS. Different outcomes were used to assess treatment efficacy, including electrophysiology, histopathology, neuromuscular function and survival.<br><br>KEY RESULTS: Among the novel FKBP12 ligands, MP-010 was chosen for its central nervous system availability and favourable in vitro pharmaco-toxicological profile. Chronic administration of MP-010 to SOD1[G93A] mice produced preservation of motor nerve conduction, with the 61-mg&#xb7;kg[-1] dose significantly delaying the onset of motor impairment. This was accompanied by improved motor coordination, increased innervated endplates and significant preservation of motor neurones in the spinal cord of treated mice. Notably, MP-010 treatment significantly extended lifespan by an average of 10&#x2009;days compared to vehicle.<br><br>CONCLUSIONS AND IMPLICATIONS: FKBP12 ligands, particularly MP-010, exhibit promising neuroprotective effects in ALS, highlighting their potential as novel therapeutic agents. Further investigations into the molecular mechanisms and clinical translatability of these compounds are needed for their application in ALS treatment.}, }
@article {pmid39947279, year = {2025}, author = {Gelbenegger, G and Cheskes, S and Jilma, B and Zeitlinger, M and Lin, S and Drennan, IR and Jorda, A}, title = {Amiodarone dose in patients with shockable out-of-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {}, number = {}, pages = {110534}, doi = {10.1016/j.resuscitation.2025.110534}, pmid = {39947279}, issn = {1873-1570}, abstract = {BACKGROUND: Amiodarone is used in shockable out-of-hospital cardiac arrest (OHCA), but the ideal dose is unknown.<br><br>METHODS: This was an analysis from the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registry (2011-2015). Patients with shockable OHCA who received 5 or more defibrillation attempts and treatment with 300 or 450&#xa0;mg of amiodarone were included. Outcomes were ROSC at ED arrival, survival at hospital discharge, and favorable neurologic function at discharge. Group-differences were adjusted for using inverse probability weighting and a multiple logistic regression model.<br><br>RESULTS: The present study included 910 patients; 426 received amiodarone 300&#xa0;mg and 484 received amiodarone 450&#xa0;mg. The amiodarone 300&#xa0;mg group had a higher estimated probability of ROSC at ED arrival as compared with the amiodarone 450&#xa0;mg group (30.8% [95% CI, 26.6-35.1] vs 24.2% [95% CI, 20.5-27.9], respectively; adjusted probability difference, 6.6% (0.9-12.3), p&#xa0;=&#xa0;0.0234). The group differences in survival at hospital discharge (21.3% [95% CI, 17.2-25.4] vs 18.0% [95% CI, 14.6-21.5]; adjusted probability difference, 3.3% [-2.3-8.8]) and favorable neurologic outcome at discharge (16.5% [95% CI, 12.9-20.2] vs 12.7% [95% CI, 9.5-16.0]; adjusted probability difference, 3.8% [95% CI, -1.2-8.7]) did not reach statistical significance.<br><br>CONCLUSION: In patients with shockable OHCA who received 5 or more defibrillation attempts, a dose of amiodarone 300&#xa0;mg was associated with a similar survival compared with a total dose of amiodarone 450&#xa0;mg. Further study is needed to evaluate the need for a second administration of amiodarone in patients with shockable OHCA.}, }
@article {pmid39946662, year = {2025}, author = {Cordts, I and Fuetterer, C and Wachinger, A and von Heynitz, R and Kessler, T and Freigang, M and Quinten, AL and Bjelica, B and Brakemeier, S and Hobbiebrunken, E and Hagenacker, T and Petri, S and Koch, JC and Hahn, A and Lingor, P and Deschauer, M and Günther, R and Weiler, M and Haller, B and Feneberg, E}, title = {Long-Term Dynamics of CSF and Serum Neurofilament Light Chain in Adult Patients With 5q Spinal Muscular Atrophy Treated With Nusinersen.}, journal = {Neurology}, volume = {104}, number = {5}, pages = {e213371}, pmid = {39946662}, issn = {1526-632X}, mesh = {Humans ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Male ; Female ; Adult ; *Oligonucleotides/therapeutic use ; Retrospective Studies ; Middle Aged ; *Muscular Atrophy, Spinal/drug therapy/blood/cerebrospinal fluid ; *Biomarkers/blood/cerebrospinal fluid ; Young Adult ; }, abstract = {BACKGROUND AND OBJECTIVES: The availability of disease-modifying therapies for 5q-associated spinal muscular atrophy (SMA) has heightened the need to identify suitable biomarkers. This study investigates neurofilament light chain (NfL) concentrations during long-term nusinersen treatment in adult SMA.<br><br>METHODS: In a retrospective study of prospectively collected data, NfL concentrations in the CSF (cNfL) and serum (sNfL) were measured in patients with SMA from 8 German centers and in neurologic controls using a single-molecule array (Simoa) assay. NfL concentrations and clinical characteristics, including the clinical scores Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), were analyzed for defined treatment intervals (T1-T4 [loading phase until 4 months], T5-T8 [until 23 months], T9-T12 [until 37 months], and T13-T19 [until 60 months]). Linear mixed models with a random intercept were used to assess the changes in NfL levels during treatment, considering time and covariates as fixed effects.<br><br>RESULTS: One hundred thirteen adult patients with SMA (median age 35, 46% female), with a treatment duration of maximum 60 months, and 52 controls were included. At baseline, NfL concentrations were significantly higher in SMA {cNfL median, 585 (interquartile range [IQR] 428-787) pg/mL; sNfL, 11 (IQR 8-14) pg/mL} than in controls (cNfL, 420 [IQR 323-662] pg/mL; sNfL, 8 [IQR 6-12] pg/mL) (cNfL, p = 0.021; sNfL, p = 0.030). Median differences for all clinical scores were the highest for T5-T8 compared with the loading phase (&#x394; HFMSE, 0.6 [IQR 0.1-1.4], p = 0.017; &#x394; RULM, 0.9 [IQR 0.4-1.3], p < 0.001; &#x394; ALSFRS-R, 0.7 [IQR 0.4-1.0], p < 0.001), but not for subsequent intervals. Longitudinal analysis revealed a significant decrease of NfL concentrations during each treatment interval compared with the loading phase (p < 0.05, respectively) except for sNfL in T13-T19. Even among patients with no measurable clinical improvement (&#x394; HFMSE &#x2264; 0), more than 50% showed declining cNfL and sNfL levels up to T13-T19.<br><br>DISCUSSION: NfL decreased during nusinersen treatment, suggesting its potential as a pharmacodynamic response marker in adult SMA. However, in patients without detectable clinical improvement, our study cannot determine whether they represent a more sensitive outcome measure or are not clinically meaningful.}, }
@article {pmid39941101, year = {2025}, author = {Orywal, K and Socha, K and Iwaniuk, P and Kaczyński, P and Farhan, JA and Zoń, W and Łozowicka, B and Perkowski, M and Mroczko, B}, title = {Vitamins in the Prevention and Support Therapy of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39941101}, issn = {1422-0067}, support = {NdS/551580/2022/2022//Polish Ministry of Education and Science/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/prevention &amp; control/metabolism ; *Vitamins/therapeutic use ; Dietary Supplements ; Animals ; Alzheimer Disease/prevention &amp; control/metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), which are a consequence of the progressive loss of neuronal function and structure, cause significant cognitive impairment. The incidence of these diseases in the world's population is constantly increasing as a result of an aging population. Although genetic and environmental factors are most often mentioned as the pathogenetic factors of these diseases, increasing evidence points to the important role of proper nutrition in the prevention and support of the treatment of these disorders. A healthy, balanced diet can mitigate the risks associated with the risk factors mentioned above and slow the progression of the disease by reducing oxidative stress and inflammation. Vitamins B, D, E, C, K, and A have been shown to support cognitive functions and protect the nervous system. This review demonstrates the importance of vitamins in preventing and supporting the therapy of neurodegenerative diseases. Information regarding the health-promoting properties of these vitamins must be effectively communicated to consumers seeking to protect their health, particularly in the context of neurodegenerative diseases. Consequently, this review also examines the authorized health claims under EU food law related to these vitamins, assessing their role in promoting awareness of the vitamins' potential benefits for neuroprotection and the management of neurodegenerative diseases.}, }
@article {pmid39940966, year = {2025}, author = {Jamerlan, AM and Shim, KH and Sharma, N and An, SSA}, title = {Multimer Detection System: A Universal Assay System for Differentiating Protein Oligomers from Monomers.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39940966}, issn = {1422-0067}, support = {RS-2023-00251396//National Research Foundation of Korea/ ; 2021R1A6A1A03038996//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Protein Multimerization ; alpha-Synuclein/metabolism/chemistry ; Amyloid beta-Peptides/metabolism/chemistry ; Neurodegenerative Diseases/metabolism/diagnosis ; Protein Aggregates ; DNA-Binding Proteins/metabolism/chemistry ; tau Proteins/metabolism/chemistry ; Protein Aggregation, Pathological/metabolism ; }, abstract = {Depositions of protein aggregates are typical pathological hallmarks of various neurodegenerative diseases (NDs). For example, amyloid-beta (Aβ) and tau aggregates are present in the brain and plasma of patients with Alzheimer's disease (AD); α-synuclein in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); mutant huntingtin protein (Htt) in Huntington's disease (HD); and DNA-binding protein 43 kD (TDP-43) in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The same misfolded proteins can be present in multiple diseases in the form of mixed proteinopathies. Since there is no cure for all these diseases, understanding the mechanisms of protein aggregation becomes imperative in modern medicine, especially for developing diagnostics and therapeutics. A Multimer Detection System (MDS) was designed to distinguish and quantify the multimeric/oligomeric forms from the monomeric form of aggregated proteins. As the unique epitope of the monomer is already occupied by capturing or detecting antibodies, the aggregated proteins with multiple epitopes would be accessible to both capturing and detecting antibodies simultaneously, and signals will be generated from the oligomers rather than the monomers. Hence, MDS could present a simple solution for measuring various conformations of aggregated proteins with high sensitivity and specificity, which may help to explore diagnostic and treatment strategies for developing anti-aggregation therapeutics.}, }
@article {pmid39940644, year = {2025}, author = {Lee, AJB and Bi, S and Ridgeway, E and Al-Hussaini, I and Deshpande, S and Krueger, A and Khatri, A and Tsui, D and Deng, J and Mitchell, CS}, title = {Restoring Homeostasis: Treating Amyotrophic Lateral Sclerosis by Resolving Dynamic Regulatory Instability.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39940644}, issn = {1422-0067}, support = {U19 AG065169/AG/NIA NIH HHS/United States ; 1944247//National Science Foundation/ ; 253558//Chan Zuckerberg Initiative/ ; R35 GM152245/GM/NIGMS NIH HHS/United States ; R35GM152245/NH/NIH HHS/United States ; K01 NS069616/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy/pathology ; Animals ; *Homeostasis ; Mice ; *Mice, Transgenic ; *Disease Models, Animal ; Humans ; Disease Progression ; Superoxide Dismutase-1/genetics/metabolism ; Computer Simulation ; Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has an interactive, multifactorial etiology that makes treatment success elusive. This study evaluates how regulatory dynamics impact disease progression and treatment. Computational models of wild-type (WT) and transgenic SOD1-G93A mouse physiology dynamics were built using the first-principles-based first-order feedback framework of dynamic meta-analysis with parameter optimization. Two in silico models were developed: a WT mouse model to simulate normal homeostasis and a SOD1-G93A ALS model to simulate ALS pathology dynamics and their response to in silico treatments. The model simulates functional molecular mechanisms for apoptosis, metal chelation, energetics, excitotoxicity, inflammation, oxidative stress, and proteomics using curated data from published SOD1-G93A mouse experiments. Temporal disease progression measures (rotarod, grip strength, body weight) were used for validation. Results illustrate that untreated SOD1-G93A ALS dynamics cannot maintain homeostasis due to a mathematical oscillating instability as determined by eigenvalue analysis. The onset and magnitude of homeostatic instability corresponded to disease onset and progression. Oscillations were associated with high feedback gain due to hypervigilant regulation. Multiple combination treatments stabilized the SOD1-G93A ALS mouse dynamics to near-normal WT homeostasis. However, treatment timing and effect size were critical to stabilization corresponding to therapeutic success. The dynamics-based approach redefines therapeutic strategies by emphasizing the restoration of homeostasis through precisely timed and stabilizing combination therapies, presenting a promising framework for application to other multifactorial neurodegenerative diseases.}, }
@article {pmid39938752, year = {2025}, author = {Zhu, Y and Tian, M and Lu, S and Qin, Y and Zhao, T and Shi, H and Li, Z and Qin, D}, title = {The antioxidant role of aromatic plant extracts in managing neurodegenerative diseases: A comprehensive review.}, journal = {Brain research bulletin}, volume = {222}, number = {}, pages = {111253}, doi = {10.1016/j.brainresbull.2025.111253}, pmid = {39938752}, issn = {1873-2747}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Antioxidants/therapeutic use/pharmacology ; *Plant Extracts/therapeutic use/pharmacology ; *Oxidative Stress/drug effects ; Animals ; Flavonoids/therapeutic use/pharmacology ; Polyphenols/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative diseases (NDDs) are a class of cognitive and motor disorders including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), and others. They are caused by lesions in cells and tissues of the central nervous system, resulting in corresponding dysfunctions and consequent decline in cognitive and motor functions. Neural tissues are extremely vulnerable to oxidative stress, which plays critical biological roles in NDDs. Aromatic compounds are found extensively in natural plants and have substantial effects of anti-oxidative stress damage, which not only have a wide range of research applications in cosmetics, foods, etc., but are also frequently utilized in the treatment of various central nervous system diseases. This review summarizes the relevant oxidative stress mechanisms in NDDs (AD, PD, HD, and ALS) and reviews aromatic compounds such as polyphenols, terpenoids, and flavonoids that can be used in the management of neurodegenerative diseases, as well as their specific mechanisms of antioxidant action. This review will serve as a reference for future experimental studies on neurodegenerative illnesses while also offering fresh insights into clinical therapy.}, }
@article {pmid39936266, year = {2025}, author = {Denton, TT and Carter, GT and Goddard, M and Weiss, J and Weeks, DL and Weydt, P and Russo, EB and Weiss, MD}, title = {Amyotrophic Lateral Sclerosis, the Endocannabinoid System, and Exogenous Cannabinoids: Current State and Clinical Implications.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28359}, pmid = {39936266}, issn = {1097-4598}, abstract = {A unifying mechanistic cause for amyotrophic lateral sclerosis (ALS) remains uncertain. Multiple pathophysiological processes appear to occur simultaneously. Cannabinoids, including delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), and others found in cannabis, and cannabis extracts (CEs), appear to have activity in these pathogenic pathways, which have led to increasing interest in cannabinoids as therapeutic agents for ALS. The use of cannabinoids as a treatment strategy is substantiated by preclinical evidence suggesting a role for the endocannabinoid system (ECS) in ALS and other neurodegenerative disorders. Preclinical data indicate that cannabis and CEs have powerful antioxidative, anti-inflammatory, and neuroprotective effects in the SOD1[G93A] mouse model of ALS. The use of CEs in SOD1[G93A] murine models has been shown to prolong neuronal cell survival, which leads to delayed onset of the disease state, and slows progression of the disease. Although research in humans remains limited, a few studies suggest that cannabis and CBD, in humans, provide benefits for both motor symptoms, including rigidity, cramps, and fasciculations, and non-motor symptoms including sleep quality, pain, emotional state, quality of life, and depression. There remains a need for further, well-designed clinical trials to validate further the use of an individual cannabinoid, or a combination of cannabinoids, as a disease-modifying therapy for ALS.}, }
@article {pmid39933302, year = {2025}, author = {Li, H and Qiao, Z and Xiao, X and Cao, X and Li, Z and Liu, M and Jiao, Q and Chen, X and Du, X and Jiang, H}, title = {G protein-coupled receptors: A golden key to the treasure-trove of neurodegenerative diseases.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {46}, number = {}, pages = {155-168}, doi = {10.1016/j.clnu.2025.01.032}, pmid = {39933302}, issn = {1532-1983}, mesh = {Humans ; *Receptors, G-Protein-Coupled/metabolism ; *Neurodegenerative Diseases/drug therapy ; *Signal Transduction/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Animals ; Parkinson Disease/drug therapy/metabolism ; }, abstract = {G protein-coupled receptors (GPCRs) are a class of transmembrane proteins that distribute in various organs extensively. They can regulate physiological functions such as perception, neurotransmission and endocrinology through the synergies of signaling pathways. At present, Food and Drug Administration (FDA) have approved more than 500 drugs targeting GPCRs to treat a variety of conditions, including neurological diseases, gastrointestinal diseases and tumors. Conformational diversity and dynamic changes make GPCRs a star target for the treatment of neurodegenerative diseases. Moreover, GPCRs can also open biased signaling pathways for G protein and β-arrestin, which has unique functional selectivity and the possibility of overcoming side effects. Some studies believe that biased drugs will be the mainstream direction of drug innovation in the future. To disclose the essential role and research process of GPCRs in neurodegenerative diseases, we firstly reviewed several pivotal GPCRs and their mediated signaling pathways in Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Then we focused on the biased signaling pathway of GPCRs in these diseases. Finally, we updated the GPCR drugs under research for the treatment of neurodegenerative diseases in the clinical trials or approval. This review could provide valuable targets for precision therapy to cope with the dysfunction of neurodegenerative diseases in the future.}, }
@article {pmid39932195, year = {2025}, author = {Ruggieri, V and Scaricamazza, S and Bracaglia, A and D'Ercole, C and Parisi, C and D'Angelo, P and Proietti, D and Cappelletti, C and Macone, A and Lozanoska-Ochser, B and Bouchè, M and Latella, L and Valle, C and Ferri, A and Giordani, L and Madaro, L}, title = {Polyamine metabolism dysregulation contributes to muscle fiber vulnerability in ALS.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115123}, doi = {10.1016/j.celrep.2024.115123}, pmid = {39932195}, issn = {2211-1247}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Animals ; *Muscle Fibers, Skeletal/metabolism/pathology ; Mice ; *Polyamines/metabolism ; *Mice, Transgenic ; Disease Models, Animal ; Humans ; Homeostasis ; Superoxide Dismutase-1/metabolism/genetics ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing progressive paralysis due to motor neuron degeneration with no curative therapy despite extensive biomedical research. One of the primary targets of ALS is skeletal muscle, which undergoes profound functional changes as the disease progresses. To better understand how altered innervation interferes with muscle homeostasis during disease progression, we generated a spatial transcriptomics dataset of skeletal muscle in the SOD1[G93A] mouse model of ALS. Using this strategy, we identified polyamine metabolism as one of the main altered pathways in affected muscle fibers. By establishing a correlation between the vulnerability of muscle fibers and the dysregulation of this metabolic pathway, we show that disrupting polyamine homeostasis causes impairments similar to those seen in ALS muscle. Finally, we show that restoration of polyamine homeostasis rescues the muscle phenotype in SOD1[G93A] mice, opening new perspectives for the treatment of ALS.}, }
@article {pmid39928236, year = {2025}, author = {Kaspute, G and Ramanavicius, A and Prentice, U}, title = {Natural drug delivery systems for the treatment of neurodegenerative diseases.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {217}, pmid = {39928236}, issn = {1573-4978}, support = {S-MIP-24-111//Research Council of Lithuania (LMTLT)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Drug Delivery Systems/methods ; *Biological Products/administration &amp; dosage ; Blood-Brain Barrier/metabolism/drug effects ; Animals ; Liposomes ; Anti-Inflammatory Agents/administration &amp; dosage ; Nanoparticles/chemistry ; }, abstract = {Today, herbal drugs are prominent in the pharmaceutical industry due to their well-known therapeutic and side effects. Plant-based compounds often face limitations such as poor solubility, low bioavailability, and instability in physiological environments, restricting their therapeutic efficacy and delivery. Nanotechnology-based solutions, including nanoparticle formulations and advanced delivery systems like liposomes and transfersomes, address these issues by enhancing solubility, stability, bioavailability, and targeted delivery, thereby optimizing the therapeutic potential of phytoactive compounds. Neuroinflammation can be a cause of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, or amyotrophic lateral sclerosis. Consequently, there is a need for the optimal delivery of a pharmacological anti-inflammatory agents to the CNS. Thus, the non-invasive administration of a stable compound at a therapeutic concentration is needed to assure molecule crossing through the blood-brain barrier. Natural resources have more structural diversity and novelty than synthetic compounds, e.g. plant-derived drug products have higher molecular weights, incorporate more oxygen atoms, and are more complex. As a result, plant-derived products have unique features which can be used to effectively modulate neuroinflammation. Therefore, this review aims to identify herbal molecules capable of targeting neuroinflammation and present novel strategies for their efficient delivery.}, }
@article {pmid39910731, year = {2025}, author = {Singh, S and Khan, S and Khan, S and Ansari, O and Malhotra, N and Shukla, SK and Narang, J}, title = {Muscle Matters: Transforming Amyotrophic Lateral Sclerosis Diagnostics with Next-Gen Biosensors and Smart Detection.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {4}, pages = {563-587}, doi = {10.1021/acschemneuro.4c00664}, pmid = {39910731}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; *Biosensing Techniques/methods ; Electromyography/methods ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily targets the motor system, causing patients' speech and swallowing ability to rapidly deteriorate. Although ALS is usually classified into familial and sporadic forms, diagnosing it can be extremely difficult due to the absence of definitive biomarkers, often resulting in delays in diagnosis. Current diagnostic practices rely heavily on clinical assessments that indicate damage to both upper motor neurons (UMNs) and lower motor neurons (LMNs). This includes comprehensive physical examinations, electromyography (EMG) to assess neuromuscular function, and the exclusion of other similar conditions such as cervical spondylotic myelopathy, multifocal motor neuropathy, and Kennedy's disease through appropriate diagnostic procedures. The urgent need for specific biomarkers is critical for timely diagnosis and therapeutic advancements in ALS management. While many recent developments in research have not yet translated into direct patient benefits, the recognition of ALS as a complex disease is beginning to influence clinical practice significantly. Optimal management strategies emphasize on symptom control and improving the quality of life for patients within a holistic healthcare framework. This review provides a comprehensive overview of ALS, delving into its pathophysiology, clinical symptoms, and the latest advancements in detection methods that utilize traditional approaches, innovative biosensors, and smart diagnostic technologies. It discusses various treatment options available for ALS while exploring future developments that may enhance patient screening and improve clinical outcomes. By integrating assessments into the underlying mechanisms of the disease with cutting-edge diagnostic approaches, this review aims to contribute meaningfully to ongoing efforts to optimize ALS management and therapeutic strategies, ultimately improving patient care and outcomes.}, }
@article {pmid39907297, year = {2024}, author = {Čižek Sajko, M and Suklan, J and Osmanović, D and Peterlin, B}, title = {Translational Research on Polygenic Risk Scores in Common Neurodegenerative Diseases - A Scoping Review Protocol.}, journal = {Acta medica academica}, volume = {53}, number = {3}, pages = {303-308}, pmid = {39907297}, issn = {1840-2879}, mesh = {Humans ; Alzheimer Disease/genetics/diagnosis ; Amyotrophic Lateral Sclerosis/genetics ; Genetic Predisposition to Disease ; Genetic Risk Score ; *Multifactorial Inheritance ; Multiple Sclerosis/genetics ; *Neurodegenerative Diseases/genetics ; Parkinson Disease/genetics/diagnosis ; Research Design ; Risk Assessment ; Risk Factors ; *Translational Research, Biomedical ; Scoping Review as Topic ; }, abstract = {OBJECTIVE: The purpose of this protocol is to clearly describe the process for the scoping review we plan to conduct on the topic of polygenic risk scores (PRS) in common neurodegenerative diseases. We will present the review's objective, the strategy for evidence search, the data extraction and analysis procedure, and how the results will be presented.<br><br>METHODS: The inclusion criteria for the planned scoping review will focus on evidence sources that involve PRS applied to neurogenerative diseases such as Multiple sclerosis, Parkinson's disease, Alzheimer's disease, and Amyotrophic lateral sclerosis in any phase of translational research, from early development to clinical implementation. This includes its use in risk prediction, early diagnosis, prognosis, and treatment decision-making. The research questions were created based on the population, context, and concept framework. We will consider both peer-reviewed papers and grey literature published in English or German for inclusion. Two independent reviewers will search for information.<br><br>CONCLUISON: The findings from the scoping review will be presented descriptively and summarized according to the research questions to illustrate the current status of translational research on PRS in common neurodegenerative diseases.}, }
@article {pmid39902643, year = {2025}, author = {Abad-Yang, N and Raguseo, F and Di Michele, L and Patani, R and Di Antonio, M}, title = {The potential of multimolecular G-quadruplex structures for targeted treatment of Amyotrophic Lateral Sclerosis.}, journal = {Expert opinion on therapeutic targets}, volume = {29}, number = {1-2}, pages = {1-4}, doi = {10.1080/14728222.2025.2463361}, pmid = {39902643}, issn = {1744-7631}, }
@article {pmid39894843, year = {2025}, author = {Chen, L and Shen, Q and Liu, Y and Zhang, Y and Sun, L and Ma, X and Song, N and Xie, J}, title = {Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases.}, journal = {Signal transduction and targeted therapy}, volume = {10}, number = {1}, pages = {31}, pmid = {39894843}, issn = {2059-3635}, support = {32471049//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32170984//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32200802//National Natural Science Foundation of China (National Science Foundation of China)/ ; ZR2020YQ23//Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)/ ; ZR2024MC153//Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)/ ; }, mesh = {Humans ; *Iron/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; *Homeostasis ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Copper/metabolism ; Metals/metabolism ; Ferroptosis/genetics ; Oxidative Stress ; Zinc/metabolism ; Alzheimer Disease/metabolism/genetics/pathology/drug therapy ; Animals ; }, abstract = {As essential micronutrients, metal ions such as iron, manganese, copper, and zinc, are required for a wide range of physiological processes in the brain. However, an imbalance in metal ions, whether excessive or insufficient, is detrimental and can contribute to neuronal death through oxidative stress, ferroptosis, cuproptosis, cell senescence, or neuroinflammation. These processes have been found to be involved in the pathological mechanisms of neurodegenerative diseases. In this review, the research history and milestone events of studying metal ions, including iron, manganese, copper, and zinc in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), will be introduced. Then, the upstream regulators, downstream effector, and crosstalk of mental ions under both physiologic and pathologic conditions will be summarized. Finally, the therapeutic effects of metal ion chelators, such as clioquinol, quercetin, curcumin, coumarin, and their derivatives for the treatment of neurodegenerative diseases will be discussed. Additionally, the promising results and limitations observed in clinical trials of these metal ion chelators will also be addressed. This review will not only provide a comprehensive understanding of the role of metal ions in disease development but also offer perspectives on their modulation for the prevention or treatment of neurodegenerative diseases.}, }
@article {pmid39893487, year = {2025}, author = {Pilotto, F and Smeele, PH and Scheidegger, O and Diab, R and Schobesberger, M and Sierra-Delgado, JA and Saxena, S}, title = {Kaempferol enhances ER-mitochondria coupling and protects motor neurons from mitochondrial dysfunction and ER stress in C9ORF72-ALS.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {21}, pmid = {39893487}, issn = {2051-5960}, support = {725825//European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program/ ; 725825//European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program/ ; 725825//European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program/ ; }, mesh = {*Kaempferols/pharmacology ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics/drug therapy ; *Endoplasmic Reticulum Stress/drug effects ; Humans ; *Mitochondria/drug effects/metabolism/pathology ; *Motor Neurons/drug effects/metabolism/pathology ; Mice ; *Neuroprotective Agents/pharmacology ; *C9orf72 Protein/genetics/metabolism ; *Endoplasmic Reticulum/drug effects/metabolism ; Mice, Transgenic ; Male ; Female ; Mice, Inbred C57BL ; }, abstract = {Repeat expansions in the C9ORF72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Considerable progress has been made in identifying C9ORF72-mediated disease and resolving its underlying etiopathogenesis. The contributions of intrinsic mitochondrial deficits as well as chronic endoplasmic reticulum stress to the development of the C9ORF72-linked pathology are well established. Nevertheless, to date, no cure or effective therapy is available, and thus attempts to find a potential drug target, have received increasing attention. Here, we investigated the mode of action and therapeutic effect of a naturally occurring dietary flavanol, kaempferol in preclinical rodent and human models of C9ORF72-ALS. Notably, kaempferol treatment of C9ORF72-ALS human patient-derived motor neurons/neurons, resolved mitochondrial deficits, promoted resiliency against severe ER stress, and conferred neuroprotection. Treatment of symptomatic C9ORF72 mice with kaempferol, normalized mitochondrial calcium uptake, restored mitochondria function, and diminished ER stress. Importantly, in vivo, chronic kaempferol administration ameliorated pathological motor dysfunction and inhibited motor neuron degeneration, highlighting the translational potential of kaempferol. Lastly, in silico modelling identified a novel kaempferol target and mechanistically the neuroprotective mechanism of kaempferol is through the iP3R-VDAC1 pathway via the modulation of GRP75 expression. Thus, kaempferol holds great promise for treating neurodegenerative diseases where both mitochondrial and ER dysfunction are causally linked to the pathophysiology.}, }
@article {pmid39891383, year = {2025}, author = {Chen, M and Cui, H and Zhang, X and Ma, S and Guo, J and Liu, Z and Gu, D and Fan, Y}, title = {Super-Enhancer Protects Cells From Toxicity of C9orf72 Poly(proline-arginine) by Inducing the Expression of KPNA2/KPNB1.}, journal = {Cell biochemistry and function}, volume = {43}, number = {2}, pages = {e70053}, doi = {10.1002/cbf.70053}, pmid = {39891383}, issn = {1099-0844}, support = {//This work was supported by the National Natural Science Foundation of China (31970616, 82070505) and Jiangsu Provincial Natural Science Foundation (BK20211330)./ ; }, mesh = {*C9orf72 Protein/metabolism/genetics ; Humans ; beta Karyopherins/metabolism ; alpha Karyopherins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; }, abstract = {Hexanucleotide repeat expansions in C9orf72 are the most common genetic mutation associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Dipeptide repeat (DPR) proteins, such as poly(proline-arginine) (polyPR) generated from G4C2 repeat expansions, have been shown to be highly toxic. In this study, PR20 was labeled with fluorescein isothiocyanate (FITC) to track its cellular localization. Several cell lines demonstrated survival under PR20 treatment by sequestering PR20 in the cytoplasm. Treatment with JQ-1 or Ivermectin (Iver) translocated PR20 into the nucleus, leading to cell death. Mechanistically, KPNA2/KPNB1 interacted with PR20 in the cytoplasm and hindered PR20 from entering the cell nucleus. Genetic silencing of KPNA2/KPNB1 converted PR20-resistant cells into PR20-sensitive cells. Treatment with JQ1 significantly reduced the protein levels of KPNA2/KPNB1, allowing PR20 to enter the nucleus. Overexpression of KPNA2 or KPNB1 effectively blocked cell death induced by co-treatment with JQ-1 and PR20. Our results indicate that super-enhancers shield cells from PR20 toxicity by upregulating the expression of KPNA2/KPNB1.}, }
@article {pmid39886777, year = {2025}, author = {Alkhazaali-Ali, Z and Sahab-Negah, S and Boroumand, AR and Farkhad, NK and Khodadoust, MA and Ganjali, R and Tavakol-Afshari, J}, title = {Evaluation of Safety and Efficacy of Repeated Mesenchymal Stem Cell Transplantation in Patients with Amyotrophic Lateral Sclerosis (ALS) by Investigating Patient's Specific microRNAs as Novel Biomarkers: A Clinical Trial Study.}, journal = {Current stem cell research &amp; therapy}, volume = {}, number = {}, pages = {}, doi = {10.2174/011574888X330199250106081717}, pmid = {39886777}, issn = {2212-3946}, abstract = {BACKGROUND: Since there is currently no cure for amyotrophic lateral sclerosis (ALS), it is essential to search for diagnostic biomarkers and novel treatments to reduce the severity of this disease. One of these treatment approaches is stem cell transplantation.<br><br>OBJECTIVE: This study aims to evaluate the safety and efficacy of repeated transplantation of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with ALS by analyzing clinical and molecular data.<br><br>METHODS: This one-arm, single-center, open-label without a control group, prospective clinical trial, twenty-one confirmed ALS patients entered the study based on defined inclusion and exclusion criteria and underwent repeated stem cell transplantation (3 times BM-MSCs transplantation (1&#xd7;10^6, MSC/Kg BW per injection) concurrently intrathecally (IT) and intravenously (IV), with one-month interval). Clinical assessment using ALS functional rating scale-revised (ALSFRS) and forced vital capacity (FVC) values and also molecular investigation by evaluating specific microRNAs expression (mir206, 133a-3p, 338-3p) in patient's serum and Cerebra spinal fluid (CSF) samples were done three times during the 3-month follow-up period.<br><br>RESULT: No serious adverse effects were reported during the study. Besides, significant improvement in FVC when compared the baseline with the end of the research and the p-value was (0.036), and stability in ALSFRS was observed, and the p-value was (p=0.16) following stem cell transplantation in patients; also, the mentioned microRNA expression was non-significant (p > 0.05) as reported as well.<br><br>CONCLUSION: Our results demonstrated that repeated transplantation of BM-MSCs was a safe procedure in ALS patients, leading to delay in disease progression and improvement in clinical symptoms. Future studies are needed to confirm these results.}, }
@article {pmid39884579, year = {2025}, author = {Liu, WW and Wei, JC}, title = {Response to Vera et al's "Interleukin-23 inhibition associates with lower incidence of cardiovascular risk factor type diseases compared to biologic naïve patients with psoriasis: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.12.044}, pmid = {39884579}, issn = {1097-6787}, }
@article {pmid39882923, year = {2025}, author = {Koltsova, E and Smotraiev, R and Nehrii, A and Zhekeev, M and Ratnaweera, H}, title = {Mechanisms for removing phosphorus species through sequential coagulation using inorganic coagulants and organic polymers.}, journal = {Water science and technology : a journal of the International Association on Water Pollution Research}, volume = {91}, number = {2}, pages = {202-218}, pmid = {39882923}, issn = {0273-1223}, mesh = {*Phosphorus/chemistry ; *Polymers/chemistry ; Water Pollutants, Chemical/chemistry ; Water Purification/methods ; Alum Compounds/chemistry ; Waste Disposal, Fluid/methods ; }, abstract = {The need for stringent phosphorus removal from domestic wastewater is increasing to mitigate eutrophication, while efficient phosphate reuse is critical due to the global phosphate crisis. Combining aluminum sulfate (ALS) with high molecular weight organic polymers achieved 95-99% removal of particles, turbidity, and phosphates, reducing ALS usage by 40%. We propose mechanisms to explain the enhanced treatment efficiency. Particle and turbidity removal is more influenced by polymer charge density than molecular weight, while orthophosphate (OP) removal is linked to a change in zeta potential from negative to positive, allowing additional OP binding through complex formation with hydrolysis products and polymers. Enhanced phospholipid (PL) removal likely results from adsorption and neutralization of micelle PL charges by intermediate positively charged aluminum hydroxyphosphate ions. Higher PL removal with low ALS doses is attributed to a two-stage dosing process that optimizes coagulant and polymer dosages. The combined removal of OP and PL improves phosphorus bioavailability, increasing the sludge's fertilizer value.}, }
@article {pmid39880333, year = {2025}, author = {Izrael, M and Chebath, J and Molakandov, K and Revel, M}, title = {Clinical perspective on pluripotent stem cells derived cell therapies for the treatment of neurodegenerative diseases.}, journal = {Advanced drug delivery reviews}, volume = {218}, number = {}, pages = {115525}, doi = {10.1016/j.addr.2025.115525}, pmid = {39880333}, issn = {1872-8294}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Pluripotent Stem Cells ; Animals ; Cell- and Tissue-Based Therapy/methods ; Stem Cell Transplantation/methods ; Clinical Trials as Topic ; }, abstract = {Self-renewal capacity and potential to differentiate into almost any cell type of the human body makes pluripotent stem cells a valuable starting material for manufacturing of clinical grade cell therapies. Neurodegenerative diseases are characterized by gradual loss of structure or function of neurons, often leading to neuronal death. This results in gradual decline of cognitive, motor, and physiological functions due to the degeneration of the central nervous systems. Over the past two decades, comprehensive preclinical efficacy (proof-of-concept) and safety studies have led to the initiation of First-in-Human phase I-II clinical trials for a range of neurodegenerative diseases. In this review, we explore the fundamentals and challenges of neural-cell therapies derived from pluripotent stem cells for treating neurodegenerative diseases. Additionally, we highlight key preclinical investigations that paved the way for regulatory approvals of these trials. Furthermore, we provide an overview on progress and status of clinical trials done so far in treating neurodegenerative diseases such as spinal cord injury (SCI), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), as well as advances in retina diseases such as Stargardt disease (a.k.a fundus flavimaculatus), retinitis pigmentosa (RP) and age-related macular degeneration (AMD). These trials will pave the way for the development of new cell-based therapies targeting additional neurological conditions, including Alzheimer's disease and epilepsy.}, }
@article {pmid39879320, year = {2025}, author = {Guillot, SJ and Lang, C and Simonot, M and Beckett, D and Lulé, D and Balz, LT and Knehr, A and Stuart-Lopez, G and Vercruysse, P and Dieterlé, S and Weydt, P and Dorst, J and Kandler, K and Kassubek, J and Wassermann, L and Rouaux, C and Arthaud, S and Da Cruz, S and Luppi, PH and Roselli, F and Ludolph, AC and Dupuis, L and Bolborea, M}, title = {Early-onset sleep alterations found in patients with amyotrophic lateral sclerosis are ameliorated by orexin antagonist in mouse models.}, journal = {Science translational medicine}, volume = {17}, number = {783}, pages = {eadm7580}, doi = {10.1126/scitranslmed.adm7580}, pmid = {39879320}, issn = {1946-6242}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; *Orexins/metabolism ; *Disease Models, Animal ; Humans ; Sleep/drug effects ; Male ; Melanins/metabolism ; Mice ; Wakefulness/drug effects ; Female ; Motor Neurons/drug effects/pathology/metabolism ; Hypothalamic Hormones/metabolism ; Pituitary Hormones/metabolism ; Orexin Receptors/metabolism ; Superoxide Dismutase-1/metabolism/genetics ; Mice, Transgenic ; }, abstract = {Sleep alterations have been described in several neurodegenerative diseases yet are currently poorly characterized in amyotrophic lateral sclerosis (ALS). This study investigates sleep macroarchitecture and related hypothalamic signaling disruptions in ALS. Using polysomnography, we found that both patients with ALS as well as asymptomatic C9ORF72 and SOD1 mutation carriers exhibited increased wakefulness and reduced non-rapid eye movement sleep. Increased wakefulness correlated with diminished cognitive performance in both clinical cohorts. Similar changes in sleep macroarchitecture were observed in three ALS mouse models (Sod1[G86R], Fus[ΔNLS/+], and TDP43[Q331K]). A single oral administration of a dual-orexin receptor antagonist or intracerebroventricular delivery of melanin-concentrating hormone (MCH) through an osmotic pump over 15 days partially normalized sleep patterns in mouse models. MCH treatment did not extend the survival of Sod1[G86R] mice but did decrease the loss of lumbar motor neurons. These findings suggest MCH and orexin signaling as potential targets to treat sleep alterations that arise in early stages of the disease.}, }
@article {pmid39871563, year = {2025}, author = {Guo, J and Liu, XY and Yang, SS and Li, Q and Duan, Y and Zhu, SS and Zhou, K and Yan, YZ and Zeng, P}, title = {Roles of C/EBPβ/AEP in Neurodegenerative Diseases.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266357822250119172351}, pmid = {39871563}, issn = {1873-4294}, abstract = {In recent years, an increasing number of studies have shown that increased activation of aspartic endopeptidases (AEPs) is a common symptom in neurodegenerative diseases (NDDs). AEP cleaves amyloid precursor protein (APP), tau (microtubule-associated protein tau), α- synuclein (α-syn), SET (a 39-KDa phosphoprotein widely expressed in various tissues and localizes predominantly in the nucleus), and TAR DNA-binding protein 43 (TDP-43), and promotes their aggregation, contributing to Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) pathogenesis. Abundant evidence supports the notion that CCAAT/enhancer-binding protein β (C/EBPβ)/AEP may play an important role in NDDs. Developing its small molecule inhibitors is a promising treatment of NDDs. However, current research suggests that the pathophysiological mechanism of the C/EBPβ/AEP pathway is very complex in NDDs. This review summarizes the structure of C/EBPβ and AEP, their major physiological functions, potential pathogenesis, their small molecule inhibitors, and how C/EBPβ/AEP offers a novel pathway for the treatment of NDDs.}, }
@article {pmid39871559, year = {2025}, author = {Rani, S and Tuteja, M}, title = {Chaperones as Potential Pharmacological Targets for Treating Protein Aggregation Illness.}, journal = {Current protein &amp; peptide science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892037338028241230092414}, pmid = {39871559}, issn = {1875-5550}, abstract = {The three-dimensional structure of proteins, achieved through the folding of the nascent polypeptide chain in vivo, is largely facilitated by molecular chaperones, which are crucial for determining protein functionality. In addition to aiding in the folding process, chaperones target misfolded proteins for degradation, acting as a quality control system within the cell. Defective protein folding has been implicated in a wide range of clinical conditions, including neurodegenerative and metabolic disorders. It is now well understood that the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and Creutzfeldt-Jakob disease shares a common mechanism: the accumulation of misfolded proteins, which aggregate and become toxic to cells. Among the family of molecular chaperones, Heat Shock Proteins (HSPs) are highly expressed in response to cellular stress and play a pivotal role in preventing protein aggregation. Specific chaperones, particularly HSPs, are now recognized as critical in halting the accumulation and aggregation of misfolded proteins in these conditions. Consequently, these chaperones are increasingly considered promising pharmacological targets for the treatment of protein aggregation-related diseases. This review highlights research exploring the potential roles of specific molecular chaperones in disorders characterized by the accumulation of misfolded proteins.}, }
@article {pmid39868844, year = {2025}, author = {Elyaman, W and Stern, LJ and Jiang, N and Dressman, D and Bradley, P and Klatzmann, D and Bradshaw, EM and Farber, DL and Kent, SC and Chizari, S and Funk, K and Devanand, D and Thakur, KT and Raj, T and Dalahmah, OA and Sarkis, RA and Weiner, HL and Shneider, NA and Przedborski, S}, title = {Exploring the role of T cells in Alzheimer's and other neurodegenerative diseases: Emerging therapeutic insights from the T Cells in the Brain symposium.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14548}, pmid = {39868844}, issn = {1552-5279}, support = {T32 AI148099/AI/NIAID NIH HHS/United States ; P01 AI106697/AI/NIAID NIH HHS/United States ; R01AI137198/NH/NIH HHS/United States ; R13 AG090018/AG/NIA NIH HHS/United States ; R01 AG067581/AG/NIA NIH HHS/United States ; R01 AG076018/AG/NIA NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; T32AI148099-4/NH/NIH HHS/United States ; AI106697/NH/NIH HHS/United States ; R01 AG055422/AG/NIA NIH HHS/United States ; R01AG067581/NH/NIH HHS/United States ; R13AG090018-01/NH/NIH HHS/United States ; R01AG076018/NH/NIH HHS/United States ; AG R01AG055422/NH/NIH HHS/United States ; R35GM141457/NH/NIH HHS/United States ; R01 AI137198/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/immunology/therapy ; *Neurodegenerative Diseases/immunology/therapy ; *T-Lymphocytes/immunology ; Immunotherapy/methods ; Brain/pathology/immunology ; }, abstract = {This proceedings article summarizes the inaugural "T Cells in the Brain" symposium held at Columbia University. Experts gathered to explore the role of T cells in neurodegenerative diseases. Key topics included characterization of antigen-specific immune responses, T cell receptor (TCR) repertoire, microbial etiology in Alzheimer's disease (AD), and microglia-T cell crosstalk, with a focus on how T cells affect neuroinflammation and AD biomarkers like amyloid beta and tau. The symposium also examined immunotherapies for AD, including the Valacyclovir Treatment of Alzheimer's Disease (VALAD) trial, and two clinical trials leveraging regulatory T cell approaches for multiple sclerosis and amyotrophic lateral sclerosis therapy. Additionally, single-cell RNA/TCR sequencing of T cells and other immune cells provided insights into immune dynamics in neurodegenerative diseases. This article highlights key findings from the symposium and outlines future research directions to further understand the role of T cells in neurodegeneration, offering innovative therapeutic approaches for AD and other neurodegenerative diseases. HIGHLIGHTS: Researchers gathered to discuss approaches to study T cells in brain disorders. New technologies allow high-throughput screening of antigen-specific T cells. Microbial infections can precede several serious and chronic neurological diseases. Central and peripheral T cell responses shape neurological disease pathology. Immunotherapy can induce regulatory T cell responses in neuroinflammatory disorders.}, }
@article {pmid39865792, year = {2025}, author = {Murakami, E and Shibata, T and Tomemori, M and Kawai, G and Nakatani, K}, title = {The role of spatial arrangement of aromatic rings on the binding of N,N'-diheteroaryl guanidine ligands to the G2C4/G2C4 motif DNA.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {27}, number = {6}, pages = {3341-3350}, doi = {10.1039/d4cp03213f}, pmid = {39865792}, issn = {1463-9084}, mesh = {*DNA/chemistry/metabolism ; Ligands ; *Guanidine/chemistry/analogs &amp; derivatives ; Guanidines/chemistry ; Circular Dichroism ; Humans ; Surface Plasmon Resonance ; Hydrogen Bonding ; Nucleic Acid Conformation ; }, abstract = {Non-canonical DNA structures formed by aberrantly expanded repeat DNA are implicated in promoting repeat instability and the onset of repeat expansion diseases. Small molecules that target these disease-causing repeat DNAs hold promise as therapeutic agents for such diseases. Specifically, 1,3-di(quinolin-2-yl)guanidine (DQG) has been identified to bind to the disease-causing GGCCCC (G2C4) repeat DNA associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In this study, we investigate the structure-binding relationships between DQG analogs and double-stranded DNA (dsDNA) containing a G2C4/G2C4 unit. Our findings, derived from UV melting temperature, circular dichroism spectra, and surface plasmon resonance (SPR) analyses of DQG analogs, highlight the crucial role of the spatial arrangements of aromatic rings in binding to the G2C4/G2C4 unit. Among the tested DQG analogs, N,N'-di(quinazolin-2-yl)guanidine (DQzG) stands out for its ability to form seven planar conformers. These conformers enable ADD-DAA hydrogen bonding with cytosine and multiple spatial arrangements of aromatic rings, including those resembling DQG. Our binding analyses revealed that DQzG exhibits the highest affinity binding for the G2C4/G2C4 unit. NMR analysis of the DQzG-bound G2C4/G2C4-dsDNA further suggested that DQzG binds to the G2C4/G2C4 unit via hydrogen bonding. Moreover, SPR analysis demonstrated that DQzG binds more strongly to G2C4 repeat DNA compared to DQG. These results position DQzG as a promising lead compound for targeting the G2C4 repeat, offering potential therapeutic avenues for the treatment of ALS/FTD and other repeat expansion diseases.}, }
@article {pmid39863163, year = {2025}, author = {Kearney, CA and Needle, CD and Brinks, AL and Gutierrez, D and Lo Sicco, KI}, title = {Response to Sood et al's "Systemic Janus kinase inhibitor treatment for vitiligo: An evidence-based review".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.01.059}, pmid = {39863163}, issn = {1097-6787}, }
@article {pmid39863029, year = {2025}, author = {Liu, X and Li, T and Tu, X and Xu, M and Wang, J}, title = {Mitochondrial fission and fusion in neurodegenerative diseases:Ca[2+] signalling.}, journal = {Molecular and cellular neurosciences}, volume = {132}, number = {}, pages = {103992}, doi = {10.1016/j.mcn.2025.103992}, pmid = {39863029}, issn = {1095-9327}, mesh = {*Mitochondrial Dynamics ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Calcium Signaling/physiology ; Mitochondria/metabolism ; Endoplasmic Reticulum/metabolism ; Mitochondrial Proteins/metabolism/genetics ; }, abstract = {Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive loss of neuronal structure and function. The pathogenesis is intricate and involves a network of interactions among multiple causes and systems. Mitochondria and Ca[2+] signaling have long been considered to play important roles in the development of various NDs. Mitochondrial fission and fusion dynamics are important processes of mitochondrial quality control, ensuring the stability of mitochondrial structure and function. Mitochondrial fission and fusion imbalance and Ca[2+] signaling disorders can aggravate the disease progression of NDs. In this review, we explore the relationship between mitochondrial dynamics and Ca[2+] signaling in AD, PD, ALS, and HD, focusing on the roles of key regulatory proteins (Drp1, Fis1, Mfn1/2, and Opa1) and the association structures between mitochondria and the endoplasmic reticulum (MERCs/MAMs). We provide a detailed analysis of their involvement in the pathogenesis of these four NDs. By integrating these mechanisms, we aim to clarify their contributions to disease progression and offer insights into the development of therapeutic strategies that target mitochondrial dynamics and Ca[2+] signaling. We also examine the progress in drug research targeting these pathways, highlighting their potential as therapeutic targets in the treatment of NDs.}, }
@article {pmid39857761, year = {2025}, author = {Sun, C and Chen, Y and Xu, L and Wang, W and Zhang, N and Fournier, CN and Li, N and Fan, D}, title = {Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale as a Novel Tool to Measure Disease Progression.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, pmid = {39857761}, issn = {2227-9059}, support = {82001347//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; 81701067//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; }, abstract = {Background: A valuable outcome measure to monitor amyotrophic lateral sclerosis (ALS) disease progression is crucial in clinical trials. Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) is a novel questionnaire assessing ALS disability. Currently, there are no studies on the relationship between ROADS and ALS survival. This study explored the value of Chinese ROADS as a novel tool for measuring disease progression and the correlation between ROADS and ALS survival. Methods: A total of 170 ALS participants were included in this study. Clinical characteristics and baseline ROADS, ΔROADS, ALSFRS-R, and ΔFRS of patients were collected. Participants were followed for 18 months to assess time to tracheostomy and survival. Scales were collected every 3 to 6 months. We evaluated the association of baseline ROADS and ΔROADS with survival using Cox regression analyses. Linear mixed effects models were used to assess changes over time in ROADS and ALSFRS-R. Results: Multivariate Cox models confirmed that baseline ROADS positively correlated with ALS survival (HR = 0.95, p < 0.001), while baseline ΔROADS negatively correlated with survival (HR = 1.26, p < 0.001). Additionally, linear mixed effects models suggested that ROADS, similar to ALSFRS-R, declined significantly over time, but there was no significant difference between these two. Conclusions: Our study indicates that Chinese ROADS is strongly related to ALS survival. Changes in ROADS with disease progression are similar to those in ALSFRS-R. These findings support Chinese ROADS as a reliable outcome measure for clinical trials, potentially enhancing the dimension of evaluating treatment effectiveness in ALS trials.}, }
@article {pmid39857620, year = {2024}, author = {Frawley, L and Taylor, NT and Sivills, O and McPhillamy, E and To, TD and Wu, Y and Chin, BY and Wong, CY}, title = {Stem Cell Therapy for the Treatment of Amyotrophic Lateral Sclerosis: Comparison of the Efficacy of Mesenchymal Stem Cells, Neural Stem Cells, and Induced Pluripotent Stem Cells.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, pmid = {39857620}, issn = {2227-9059}, support = {Australian Government New Colombo Plan (NCP) scheme//Australian Government New Colombo Plan (NCP) scheme/ ; }, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a debilitating, incurable neurodegenerative disorder characterised by motor neuron death in the spinal cord, brainstem, and motor cortex. With an incidence rate of about 4.42 cases per 100,000 people annually, ALS severely impacts motor function and quality of life, causing progressive muscle atrophy, spasticity, paralysis, and eventually death. The cause of ALS is largely unknown, with 90% of cases being sporadic and 10% familial. Current research targets molecular mechanisms of inflammation, excitotoxicity, aggregation-prone proteins, and proteinopathy.<br><br>METHODS: This review evaluates the efficacy of three stem cell types in ALS treatment: mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs).<br><br>RESULTS: MSCs, derived from various tissues, show neuroprotective and regenerative qualities, with clinical trials suggesting potential benefits but limited by small sample sizes and non-randomised designs. NSCs, isolated from the fetal spinal cord or brain, demonstrate promise in animal models but face functional integration and ethical challenges. iPSCs, created by reprogramming patient-specific somatic cells, offer a novel approach by potentially replacing or supporting neurons. iPSC therapy addresses ethical issues related to embryonic stem cells but encounters challenges regarding genotoxicity and epigenetic irregularities, somatic cell sources, privacy concerns, the need for extensive clinical trials, and high reprogramming costs.<br><br>CONCLUSIONS: This research is significant for advancing ALS treatment beyond symptomatic relief and modest survival extensions to actively modifying disease progression and improving patient outcomes. Successful stem cell therapies could lead to new ALS treatments, slowing motor function loss and reducing symptom severity.}, }
@article {pmid39855275, year = {2025}, author = {Zhang, W and Zhang, L and Fu, S and Yan, R and Zhang, X and Song, J and Lu, Y}, title = {Roles of NLRC4 inflammasome in neurological disorders: Mechanisms, implications, and therapeutic potential.}, journal = {Pharmacology &amp; therapeutics}, volume = {267}, number = {}, pages = {108803}, doi = {10.1016/j.pharmthera.2025.108803}, pmid = {39855275}, issn = {1879-016X}, mesh = {Humans ; *Inflammasomes/metabolism ; Animals ; *Calcium-Binding Proteins/metabolism ; Nervous System Diseases/drug therapy/metabolism/immunology ; Neurodegenerative Diseases/drug therapy/metabolism ; Pyroptosis ; CARD Signaling Adaptor Proteins ; }, abstract = {The nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 4 (NLRC4) inflammasome, a vital component of the innate immune system, is known for defending against bacterial infections. However, recent insights have revealed its significant impact on neurological disorders. This comprehensive review discussed the mechanisms underlying the activation and regulation of the NLRC4 inflammasome, highlighting the complexity of its response to cellular stress and damage signals. The biological functions of NLRC4 were explored, particularly its influence on cytokine production and the induction of pyroptosis, a form of inflammatory cell death. This review further emphasized the role of the NLRC4 inflammasome in brain injuries and neurodegenerative disorders. In the realm of brain injuries such as stroke and traumatic brain injury, as well as in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, the NLRC4 inflammasome played a pivotal role in modulating neuroinflammatory responses, which was crucial for understanding the progression and potential therapeutic targeting of these conditions. The emerging role of NLRC4 in psychiatric disorders and its potential impact on glioma progression were also examined. Additionally, this review presented a thorough summary of the latest research on inhibitors that impeded the assembly and activation of the NLRC4 inflammasome, pointing to new therapeutic possibilities in neurological disorders. In conclusion, by integrating current knowledge on the activation and regulation of NLRC4 with its biological functions and clinical implications, this article underscored the importance of NLRC4 inflammasome in neurological pathologies, which opened new possibilities for the treatment of challenging neurological conditions.}, }
@article {pmid39854930, year = {2025}, author = {Drouet, C and Priou, P and Gagnadoux, F and Trzepizur, W}, title = {Constraints to the initiation of home non-invasive ventilation and short-term efficacy in different diagnostic groups (as a prelude to an ambulatory shift).}, journal = {Respiratory medicine and research}, volume = {87}, number = {}, pages = {101154}, doi = {10.1016/j.resmer.2025.101154}, pmid = {39854930}, issn = {2590-0412}, abstract = {INTRODUCTION: Non-invasive ventilation (NIV) is the reference treatment for chronic respiratory failure (CRF) due to impairment of the ventilatory system. Home initiation is increasingly practiced. To better support this ambulatory shift, we aimed to assess the implementation constraints and short-term efficacy according to different aetiologies of CRF.<br><br>METHODS: This retrospective study with cross-sectional and longitudinal analysis included patients initiated with NIV at Angers University Hospital. Patients were separated according to the following aetiologies: obesity hypoventilation syndrome (OHS), chronic obstruction pulmonary disease (COPD), amyotrophic lateral sclerosis (ALS), myopathy and chest wall disease. Implementation constraints were assessed by analysing the variability of NIV settings, the number of masks tried and the duration of hospitalisation. NIV effectiveness was assessed by measuring residual PaCO2 (arterial pressure in CO2), apnoea hypopnea index (AHIflow) and tidal volume (VT) (as displayed by the NIV software).<br><br>RESULTS: Between October 2020 and May 2022, 102 patients were started with NIV, including a majority of ALS patients. We found a moderate variability in NIV settings (pressure, slope, triggers, etc.) within the different etiological groups, particularly in ALS. On the other hand, ALS patients required more interface trials than other groups and often had unmet efficacy criteria at hospital discharge. Interestingly, longitudinal follow-up showed a progressive improvement in efficacy criteria, particularly in patients who were initially inadequately ventilated.<br><br>CONCLUSION: Each aetiological group has specific constraints in the initiation of NIV that should be considered when initiating NIV in the outpatient setting.}, }
@article {pmid39845577, year = {2025}, author = {Ludolph, A and Wiesenfarth, M}, title = {Tofersen and other antisense oligonucleotides in ALS.}, journal = {Therapeutic advances in neurological disorders}, volume = {18}, number = {}, pages = {17562864251313915}, pmid = {39845577}, issn = {1756-2856}, abstract = {The advent of antisense oligonucleotide (ASO) therapies in neurodegenerative disorders is associated with enormous hope. Nusinersen treatment was a breakthrough intervention in the recessive disease spinal muscular atrophy, and superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS) seems to be the paradigm disease in dominant degenerative diseases. The results of treatment with the ASO tofersen in SOD1-ALS show that the drug has a convincing beneficial effect on ALS caused by SOD1 mutations, that preclinical studies in rodents predicted the therapeutic effect in the human disease, and that clinical efficacy is associated with a specific sequence of effects of the drug on mechanistic and degenerative biomarkers and, subsequently, functional outcomes such as weight stabilization and ALSFRS-R. Therefore, the enthusiasm seems to be justified; but this should be followed by an attempt to obtain further insights with the goal to improve this therapy. In particular, the following issues are only partially resolved: Which mechanisms are responsible for the clinical effect following the downregulation of SOD1 protein by ASOs? Is long-term downregulation of SOD1 function associated with side effects? Is there an autoimmune response caused by this and other ASO? Is prevention of SOD1-associated ALS possible?}, }
@article {pmid39839897, year = {2025}, author = {Jiang, QR and Zeng, DW}, title = {Gut microbiota shifts in hepatitis B-related portal hypertension after transjugular intrahepatic portosystemic shunt: Mechanistic and clinical implications.}, journal = {World journal of gastroenterology}, volume = {31}, number = {3}, pages = {100752}, pmid = {39839897}, issn = {2219-2840}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Hypertension, Portal/diagnosis/etiology/microbiology ; *Portasystemic Shunt, Transjugular Intrahepatic/adverse effects ; *Hepatic Encephalopathy/etiology/microbiology/diagnosis ; *Liver Cirrhosis/microbiology/virology/diagnosis ; Hepatitis B virus/isolation &amp; purification ; Hepatitis B/diagnosis/complications/microbiology ; Dysbiosis ; Animals ; }, abstract = {In this article, we provide commentary on the recent article by Zhao et al. We focus on the shifts in the gut microbiota of patients with hepatitis B virus (HBV)-associated cirrhosis/portal hypertension (PH) following transjugular intrahepatic portosystemic shunt (TIPS) and the implications for understanding the mechanisms, diagnosis, and treatment. By comparing the gut microbiota composition and dynamic changes before and after TIPS in patients with and without hepatic encephalopathy, the authors found an increase in non-probiotic bacteria in those who developed hepatic encephalopathy post-TIPS, with Morganella species present only in the hepatic encephalopathy group. The gut microbiota changes post-TIPS among patients without the occurrence of hepatic encephalopathy suggest potential therapeutic benefits through prophylactic microbiome therapies. Furthermore, the specific gut microbiota alterations may hold promise to predict the risk of hepatic encephalopathy in individuals undergoing TIPS for HBV-related PH. Despite these promising findings, future studies are needed to address limitations, including a small sample size, a relatively short evaluation period for gut microbiota alterations, the absence of data on dynamic alterations in gut microbiota post-TIPS and their correlation with blood ammonia levels, and the lack of validation in animal models. In conclusion, Zhao et al's study has shed new light on the link of gut microbiota with post-TIPS hepatic encephalopathy, potentially through the intricate gut-liver axis, and has important clinical implications for improving the management of patients with HBV-related PH.}, }
@article {pmid39838927, year = {2025}, author = {Wang, Z and Sun, Y and Bai, Z and Li, M and Kong, D and Wu, G}, title = {Mitochondria-Related Genome-Wide Mendelian Randomization Identifies Putatively Causal Genes for Neurodegenerative Diseases.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {}, number = {}, pages = {}, doi = {10.1002/mds.30123}, pmid = {39838927}, issn = {1531-8257}, support = {SDQLQN2021-01//Qilu Young Scholars Program of Shandong University/ ; 202306352//Taishan Scholar Foundation of Shandong Province/ ; }, abstract = {BACKGROUND: Mitochondrial dysfunction is increasingly recognized as a key factor in neurodegenerative diseases (NDDs), underscoring the therapeutic potential of targeting mitochondria-related genes. This study aimed to identify novel biomarkers and drug targets for these diseases through a comprehensive analysis that integrated genome-wide Mendelian randomization (MR) with genes associated with mitochondrial function.<br><br>METHODS: Using existing publicly available genome-wide association studies (GWAS) summary statistics and comprehensive data on 1136 mitochondria-related genes, we initially identified a subset of genes related to mitochondrial function that exhibited significant associations with NDDs. We then conducted colocalization and summary-data-based Mendelian randomization (SMR) analyses using expression quantitative trait loci (eQTL) to validate the causal role of these candidate genes. Additionally, we assessed the druggability of the encoded proteins to prioritize potential therapeutic targets for further exploration.<br><br>RESULTS: Genetically predicted levels of 10 genes were found to be significantly associated with the risk of NDDs. Elevated DMPK and LACTB2 levels were associated with increased Alzheimer's disease risk. Higher expression of NDUFAF2, BCKDK, and MALSU1, along with lower TTC19, raised Parkinson's disease risk. Higher ACLY levels were associated with both amyotrophic lateral sclerosis and multiple sclerosis (MS) risks, while decreased MCL1, TOP3A, and VWA8 levels raised MS risk. These genes primarily impact mitochondrial function and energy metabolism. Notably, several druggable protein targets identified are being explored for potential NDDs treatment.<br><br>CONCLUSIONS: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in NDDs. Additionally, this study identified candidate genes that could serve as potential pharmacological targets for the prevention and treatment of NDDs. &#xa9; 2025 International Parkinson and Movement Disorder Society.}, }
@article {pmid39836043, year = {2025}, author = {Berry, JD and Hagan, M and Zhang, J and Liu, Y and Ciepielewska, M}, title = {Longer disease progression milestone-free time in people with amyotrophic lateral sclerosis treated versus not treated with intravenous edaravone: results from an administrative claims analysis.}, journal = {Journal of comparative effectiveness research}, volume = {14}, number = {2}, pages = {e240007}, pmid = {39836043}, issn = {2042-6313}, mesh = {Humans ; *Edaravone/therapeutic use/administration &amp; dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Disease Progression ; Male ; Female ; Retrospective Studies ; Middle Aged ; Aged ; Administration, Intravenous ; Insurance Claim Review ; Free Radical Scavengers/therapeutic use/administration &amp; dosage ; }, abstract = {Aim: To estimate time-to-progression milestones in people with amyotrophic lateral sclerosis (PALS) treated versus not treated with intravenous (IV) edaravone (Radicava[®] IV, Mitsubishi Tanabe Pharma America [MTPA], hereafter "IV edaravone") in a real-world setting. Background: IV edaravone is US FDA approved for the treatment of ALS and was shown in clinical trials to slow the rate of physical functional decline. Patients &amp; methods: This retrospective observational analysis included PALS continuously enrolled in Optum's Clinformatics[®] Data Mart between 8 August 2017 and 31 December 2021. Cases treated with IV edaravone and controls not treated with IV edaravone were propensity score matched for: age, sex, race, US region of residence, pre-index disease duration, insurance, riluzole prescription; and pre-index claims for cardiovascular disease, artificial nutrition/gastrostomy tube, noninvasive ventilation and all-cause hospitalization. The index date was the first IV edaravone claim for cases; for controls, the index date was randomly assigned after IV edaravone market availability. Restricted mean time lost was calculated for the following disease progression milestones: new use of canes/walkers/wheelchairs, artificial nutrition, noninvasive ventilation, invasive ventilation, speech-generating devices and hospice. Results: Cases (n = 395) were matched to controls (n = 395). Cases had less restricted mean time lost, indicating longer disease progression milestone-free time, for all disease progression milestones. From 0 to 24 months post index, more cases (n = 129) than controls (n = 103) reported no milestones and more controls (n = 232) than cases (n = 131) reported deaths. Conclusion: In a US-based real-world setting, IV edaravone-treated PALS had a longer time to disease progression milestone events and fewer deaths in 2 years compared with PALS not treated with IV edaravone.}, }
@article {pmid39835561, year = {2025}, author = {Rai, A and Shukla, S and Gupta, RK and Mishra, A}, title = {ALS: A Silent Slayer of Motor Neurons. Traditional Chinese Herbal Medicine as an Effective Therapy.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128329141241205063352}, pmid = {39835561}, issn = {1873-4286}, abstract = {Amyotrophic Lateral Sclerosis (ALS), is a progressive neurodegenerative disease characterized by motor symptoms, and cognitive impairment. The complexity in treating ALS arises from genetic and environmental factors, contributing to the gradual decline of lower and upper motor neurons. The anticipated pharmaceutical market valuation for ALS is projected to reach $1,038.94 million by 2032. This projection underscores the escalating impact of ALS on global healthcare systems. ALS prevalence is expected to surge to 376,674 cases by 2040. In 2022, India ranked among the top 3 Asian-Pacific nations, while North America dominated the global ALS market. Ongoing investigations explore the potential of neuroprotective drugs like riluzole and edaravone in ALS treatment. Recently approved drugs, Relyvrio (sodium phenylbutyrate and taurursodiol) and Tofersen (Qalsody) have completed the trials, and others are currently undergoing extensive clinical trials. Continuous research and exploration of therapeutic avenues, including gene therapy and neuroprotective treatments, are imperative to address the challenges posed by ALS and other neurodegenerative diseases. Traditional Chinese Medicine (TCM) approaches and clinical trials are being explored for treating ALS symptoms, targeting neuroinflammation, oxidative damage, and muscle weakness, showcasing the potential benefits of integrating traditional and modern approaches in ALS management.}, }
@article {pmid39835009, year = {2024}, author = {Frolov, A and D'sa, E and Henderson, C and Guzman, MA and Hayat, G and Martin, JR}, title = {Complex Genetic Framework in Familial Amyotrophic Lateral Sclerosis With a C9ORF72 Mutation: A Case Report.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e76027}, pmid = {39835009}, issn = {2168-8184}, abstract = {A significantly diverse clinical presentation of amyotrophic lateral sclerosis (ALS), even in its best-studied familial form, continues to hinder current efforts to develop effective disease-modifying drugs for the cure of this rapidly progressive, fatal neuromuscular disease. We have previously shown that clinical heterogeneity of sporadic ALS (sALS) could be explained, at least in part, by its polygenic nature as well as by the presence of mutated genes linked to non-ALS neurological diseases and genes known to mediate ALS-related pathologies. We hypothesized that a similar genetic framework could also be present in patients with familial ALS (fALS). To test this hypothesis, we conducted post-mortem genetic screening of an individual with fALS and a mutation in the C9ORF72 gene. C9ORF72 mutations are highly penetrant and are present in the majority of fALS patients. Genetic screening by whole exome sequencing (WES) on the next generation sequencing (NGS) Illumina platform (San Diego, CA, USA) followed by examination of the respective rare (minor allele frequency (MAF) ≤ 0.01) pathological/deleterious genetic variants yielded results consistent with our hypothesis of the presence of a complex genetic framework in fALS. Additional members of this genetic framework were identified when the low-frequency (0.01 < MAF < 0.05) pathological/deleterious genetic variants were analyzed with the low-frequency biallelic AHNAK2, GLI3, PTIRM1, and ZNF254 variants, warranting a closer look at their potentially important role in fALS as C9ORF72 genetic modifiers as well as their link to both neuromuscular disorders/ALS and cancer. Therefore, in addition to the current genetic screening using a standard panel of ALS-related genes, a supplementary screening by WES could be very beneficial for the development of personalized treatment of ALS patients as well as in search of the respective efficient disease-modifying drugs.}, }
@article {pmid39831022, year = {2025}, author = {Okpete, UE and Byeon, H}, title = {Brain-derived neurotrophic factor alterations and cognitive decline in schizophrenia: Implications for early intervention.}, journal = {World journal of psychiatry}, volume = {15}, number = {1}, pages = {102131}, pmid = {39831022}, issn = {2220-3206}, abstract = {This manuscript explores the recent study by Cui et al which assessed the interplay between inflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels in first-episode schizophrenia patients. The study revealed that higher levels of interleukin-6 and tumor necrosis factor-α correlated with reduced BDNF levels and poorer cognitive performance. Schizophrenia is a severe psychiatric disorder impacting approximately 1% of the global population, characterized by positive symptoms (hallucinations and delusions), negative symptoms (diminished motivation and cognitive impairments) and disorganized thoughts and behaviors. Emerging research highlights the role of BDNF as a potential biomarker for early diagnosis and therapeutic targeting. The findings from Cui et al's study suggest that targeting neuroinflammation and enhancing BDNF levels may improve cognitive outcomes. Effective treatment approaches involve a combination of pharmacological and non-pharmacological interventions tailored to individual patient needs. Hence, monitoring cognitive and neuroinflammatory markers is essential for improving patient outcomes and quality of life. Consequently, this manuscript highlights the need for an integrated approach to schizophrenia management, considering both clinical symptoms and underlying neurobiological changes.}, }
@article {pmid39828018, year = {2025}, author = {Sharma, D and Singh, V and Kumar, A and Singh, TG}, title = {Genistein: A promising ally in combating neurodegenerative disorders.}, journal = {European journal of pharmacology}, volume = {991}, number = {}, pages = {177273}, doi = {10.1016/j.ejphar.2025.177273}, pmid = {39828018}, issn = {1879-0712}, mesh = {*Genistein/pharmacology/therapeutic use ; Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Antioxidants/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative disorders arise when nerve cells in the brain or peripheral nervous system gradually lose functions and eventually die. Although certain therapies may alleviate some of the physical and mental symptoms associated with neurodegenerative disorders, hence slowing their progression, but no sure-shot treatment is currently available. It was shown that the rise in life expectancy and the number of elderly people in the community led to an increasing trend in the incidence and prevalence of neurodegenerative disease. Phytomolecules are demonstrating their effectiveness in combating, regression, and delaying various diseases. Genistein is one of soy isoflavone with antioxidant, anti-inflammatory, and estrogenic effects. Researchers demonstrated that Genistein treatment significantly reduced hyperglycemia, improved cognitive performance by modulating acetylcholinesterase activity and oxidative stress, and alleviated neuroinflammatory conditions in mice. This paper evaluates (in vivo and in vitro) various molecular targets of isoflavones and their ability to effectively counter several neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases and amyotrophic lateral sclerosis. In this review, we aim to provide an overview of the role that genistein plays in delaying the development of neurodegenerative disorders.}, }
@article {pmid39824655, year = {2025}, author = {Jia, M and Li, P and Yan, Y and Liu, X and Gao, L and Zhu, G and Chen, Z}, title = {Antimicrobial susceptibility and genomic characterization of Vibrio cholerae non-O1/non-O139 isolated from clinical and environmental samples in Jiaxing City, China.}, journal = {FEMS microbiology letters}, volume = {372}, number = {}, pages = {}, doi = {10.1093/femsle/fnaf009}, pmid = {39824655}, issn = {1574-6968}, support = {2024KY1697//Medical Science and Technology Project of Zhejiang Province/ ; 2023AY31028//Science and Technology Bureau of Jiaxing City/ ; }, mesh = {China ; Humans ; *Anti-Bacterial Agents/pharmacology ; *Multilocus Sequence Typing ; *Microbial Sensitivity Tests ; Vibrio cholerae non-O1/genetics/drug effects/isolation &amp; purification ; Genome, Bacterial ; Environmental Microbiology ; Virulence/genetics ; Cholera/microbiology ; Drug Resistance, Bacterial/genetics ; Genetic Variation ; Virulence Factors/genetics ; }, abstract = {Non-O1/non-O139 (NOVC) strains inhabit aquatic environments and sporadically induce human illnesses. This study involved the virulence and antimicrobial genetic characterization of 176 NOVC strains, comprising 25 from clinical samples and 151 from environmental sources, collected between 2021 and 2023. The antimicrobial susceptibility of the examined NOVC population was predominantly high, exhibiting only poor susceptibility to colistin, with 89.2% resistance. The examination of virulence genes revealed that the majority of strains were positive for glucose metabolism (als gene) (169/176, 96.0%). Through multilocus sequence typing, the 176 NOVC strains were categorised into 121 sequence types, 79 of which were novel. NOVC strains demonstrate significant genetic variability and frequently engage in recombination. This work offers genetic characterization of the pathogenicity and antimicrobial resistance of a NOVC community. Our findings offer insights that may aid in the development of preventative and treatment methods for this pathogen.}, }
@article {pmid39821843, year = {2025}, author = {Zhang, J and Guo, R and Zhou, Z and Fu, Z and Akogo, HY and Li, Y and Zhang, X and Wang, N and Liu, Y and Li, H and Feng, B and Cui, H and Ma, J}, title = {Neural Stem/Progenitor Cell Therapy in Patients and Animals with Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-analysis.}, journal = {Molecular neurobiology}, volume = {62}, number = {5}, pages = {6521-6536}, pmid = {39821843}, issn = {1559-1182}, support = {81801278//National Natural Science Foundation of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/pathology ; *Neural Stem Cells/transplantation ; Animals ; Humans ; *Stem Cell Transplantation/methods ; Treatment Outcome ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative malady that causes progressive degeneration and loss of motor neuron function in the brain and spinal cord, eventually resulting in muscular atrophy, paralysis, and death. Neural stem/progenitor cell (NSPC) transplantation can improve bodily function in animals and delay disease progression in patients with ALS. This paper summarizes and analyzes the efficacy and safety of neural stem/progenitor cell (NSPC) transplantation as a treatment for ALS, aiming to improve function and delay disease progression in patients. We present a summary of the pathogenic mechanism and causative genes associated with ALS and describe the mechanism and efficacy of NSPC treatment for ALS. We comprehensively searched for relevant English-language articles published between January 1, 2000 and October 1, 2023, across the following five medical databases: PubMed, EMBASE, OVID, Web of Science, and the Cochrane Library. We examined experimental indices of physical function in animals and patients who underwent stem cell transplantation. All statistical analyses were performed via Review Manager 5.4. The study comprised a total of 16 investigations, including 5 clinical studies and 11 animal studies and involving 66 patients and 203 animals. The meta-analysis revealed that the administration of NSPCs appeared to yield positive outcomes in clinical patients, as assessed by the ALS functional rating scale and forced vital capacity. Furthermore, improvements following cell injection were observed in the rotarod test results, the Basso-Beattie-Bresnahan Locomotor Rating Scale score, weight, and survival time. Our meta-analysis, which was grounded in randomized controlled trials, revealed that the transplantation of neural stem/progenitor cells (NSPCs), has potential effects on ALS patients, enhancing the physical function of animals and mitigating degenerative effects in individuals. These underscored the promise of NSPC therapy as a viable treatment option. We report that the transplantation of neural stem/progenitor cells (NSPCs) is promising for enhancing bodily function and slowing the progression of ALS in affected patients. In this review, we summarize the treatment of ALS with NSPCs, evaluating both its efficacy and safety. Through database searches, we identified 16 studies involving 66 patients and 203 animals and analyzed the experimental indices of physical function following stem cell transplantation. The meta-analysis results indicated a positive impact of NSPCs on the clinical conditions of patients and the behavior of animals. A meta-analysis of randomized controlled trials further supported the conclusion that NSPC transplantation has a beneficial effect on improving physical function and mitigating degeneration in ALS patients.}, }
@article {pmid39820267, year = {2025}, author = {Martinez-Thompson, JM and Mazurek, KA and Parra Cantu, C and Naddaf, E and Gogineni, V and Botha, H and Jones, DT and Laughlin, RS and Barnard, L and Staff, NP}, title = {Artificial intelligence models using F-wave responses predict amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf014}, pmid = {39820267}, issn = {1460-2156}, abstract = {Nerve conduction F-wave studies contain critical information about subclinical motor dysfunction which may be used to diagnose patients with amyotrophic lateral sclerosis (ALS). However, F-wave responses are highly variable in morphology, making waveform interpretation challenging. Artificial Intelligence techniques can extract time-frequency features to provide new insights into ALS diagnosis and prognosis. A retrospective analysis was performed on F-wave responses from 46,802 patients. Discrete wavelet transforms were applied to time-series waveform responses after stimulating ulnar, median, fibular, and tibial nerves. Wavelet coefficient statistics, onset age, sex, and BMI were features for training a Gradient Boosting Machine model on 40,095 (5,329 diagnosed with motor neuron disease). Model performance was tested on responses from 689 ALS patients meeting Gold Coast criteria and 689 age- and sex-matched controls. An exploratory analysis examined model performance on cohorts of patients with inclusion body myositis (IBM), cervical radiculopathy, lumbar radiculopathy, or peripheral neuropathy which can mimic ALS symptoms. Factors affecting survival were estimated through cox proportional hazards regression. The model trained using wavelet-features on the full waveform had 90% recall, 87% precision, and 88% accuracy. Similar model performance was measured using features only from the M-Wave or F-Wave. Classification probabilities for ALS patients were statistically different from the diagnoses mimicking ALS symptoms (p<0.001, ANOVA, Tukey's post-hoc), Higher model classification probabilities of ALS, older age at onset, and family history of ALS alone or with frontotemporal dementia were factors decreasing survival. Longer diagnostic delay and upper limb onset site were factors increasing survival. Model scores two standard deviations below the mean had 4 months increased survival (two standard deviations below had 3 months decreased survival). Artificial intelligence techniques extracted important information from F-wave responses to estimate a patient's likelihood of ALS and their survival risks. Although the model can make predictions at specific decision threshold as presented here, the true strength of such a model lies in its ability to provide probabilities about whether a patient is likely to have ALS compared to other mimicking diagnoses such as IBM, cervical or lumbar radiculopathy, or peripheral neuropathy. These probabilities provide clinicians with additional information they can use to make the final diagnosis with greater confidence and precision. Integrating such a model into the clinical workflow could help clinicians diagnose ALS sooner and manage treatment based on estimated survival, which may improve outcomes and patients' quality of life.}, }
@article {pmid39819742, year = {2025}, author = {Xu, B and Lei, X and Yang, Y and Yu, J and Chen, J and Xu, Z and Ye, K and Zhang, J}, title = {Peripheral proteinopathy in neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {2}, pmid = {39819742}, issn = {2047-9158}, support = {82020108012//National Natural Science Foundation of China/ ; 82371250//National Natural Science Foundation of China/ ; LY24H090006//Natural Science Foundation of Zhejiang Province/ ; LZ23H090002//Natural Science Foundation of Zhejiang Province/ ; 2024C03098//Key Research and Development Program of Zhejiang Province/ ; 2024SSYS0018//Key Research and Development Program of Zhejiang Province/ ; ZR2022QH177//Natural Science Foundation of Shandong Province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; alpha-Synuclein/metabolism ; }, abstract = {Proteinopathies in neurology typically refer to pathological changes in proteins associated with neurological diseases, such as the aggregation of amyloid β and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease and multiple system atrophy, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal dementia. Interestingly, these proteins are also commonly found in peripheral tissues, raising important questions about their roles in neurological disorders. Multiple studies have shown that peripherally derived pathological proteins not only travel to the brain through various routes, aggravating brain pathology, but also contribute significantly to peripheral dysfunction, highlighting their crucial impact on neurological diseases. Investigating how these peripherally derived proteins influence the progression of neurological disorders could open new horizons for achieving early diagnosis and treatment. This review summarizes the distribution, transportation pathways, and pathogenic mechanisms of several neurodegenerative disease-related pathological proteins in the periphery, proposing that targeting these peripheral pathological proteins could be a promising strategy for preventing and managing neurological diseases.}, }
@article {pmid39817131, year = {2025}, author = {Lampridis, S}, title = {Unraveling the landscape of pediatric pancreatic tumors: Insights from Japan.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {1}, pages = {101477}, pmid = {39817131}, issn = {1948-5204}, abstract = {Pediatric pancreatic tumors, though rare, pose significant diagnostic and management challenges. The recent, 22-year nationwide survey on pediatric pancreatic tumors in Japan by Makita et al offers valuable insights into this uncommon entity, revealing striking geographical variations and questioning current treatment paradigms. This editorial commentary analyzes the study's key findings, including the predominance of solid pseudopapillary neoplasms and their younger age of onset, which contrast sharply with Western data. It explores the implications for clinical practice and research, emphasizing the need for population-specific approaches to diagnosis and treatment. The revealed limited institutional experience and surgical management patterns prompt a reevaluation of optimal care delivery for these complex cases, suggesting benefits of centralizing healthcare services. Furthermore, the commentary advocates for international collaborative studies to elucidate the genetic, environmental, and lifestyle factors influencing the development and progression of pediatric pancreatic tumors across diverse populations. It also outlines future directions, calling for advancements in precision medicine and innovative care delivery models to improve global patient outcomes. Unraveling Makita et al's findings within the broader landscape of pediatric oncology can stimulate further research and clinical advancements in managing pancreatic and other rare tumors in children.}, }
@article {pmid39811452, year = {2024}, author = {Li, R and Bao, T and Li, B and Xia, P and Zhang, T and Zhang, H and Huang, F}, title = {Effectiveness and safety of traditional Chinese therapies intreating patients with amyotrophic lateral sclerosis: a protocol for systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1519513}, pmid = {39811452}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a chronic, progressive disease that affects both upper and lower motor neurons. Some physicians have used traditional Chinese therapies (TCT) to treat ALS. However, there has been no systematic review or meta-analysis to evaluate the effectiveness and safety of TCT interventions. This review aims to analyze the effects of TCT interventions for patients with amyotrophic lateral sclerosis.<br><br>METHODS AND ANALYSIS: This study will include randomized, non-randomized, and quasi-experimental clinical trials, with participants being any age Amyotrophic Lateral Sclerosis (ALS) patients who have undergone TCT treatment. Two researchers will independently search databases including CENTRAL, PubMed, PEDro, EMBASE, CNKI, CBM, and SPORTDiscus, without restrictions on language or publication date. These researchers will independently screen titles and abstracts and extract data from the included studies. If deemed suitable for meta-analysis, data synthesis will be conducted using Review Manager V.5.3 software; any discrepancies will be resolved by a third researcher. The meta-analysis will compare the effects of TCT with placebo or other interventions. The main endpoint evaluated was the decrease in the overall score of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; scoring from 0 to 48, where higher scores denote greater functionality) over a period of 24&#x202f;weeks. Additional endpoints included the reduction rates in isometric muscle power, levels of phosphorylated axonal neurofilament H subunits in plasma, and slow vital capacity measurements. Furthermore, the study monitored the duration until occurrence of death, tracheostomy, or the need for long-term ventilation, as well as the time until death, tracheostomy, long-term ventilation, or hospital admission.<br><br>ETHICS AND DISSEMINATION: Throughout the entire process of this systematic review, no personal information was used, hence ethical review is not required. The results of this meta-analysis will be disseminated through publication in peer-reviewed journals and/or conference presentations.}, }
@article {pmid39806490, year = {2025}, author = {Shen, Y and Zhang, X and Liu, S and Xin, L and Xuan, W and Zhuang, C and Chen, Y and Chen, B and Zheng, X and Wu, R and Lin, Y}, title = {CEST imaging combined with [1]H-MRS reveal the neuroprotective effects of riluzole by improving neurotransmitter imbalances in Alzheimer's disease mice.}, journal = {Alzheimer's research &amp; therapy}, volume = {17}, number = {1}, pages = {20}, pmid = {39806490}, issn = {1758-9193}, support = {240428226498013//Shantou Science and Technology Project/ ; 213769/SNSF_/Swiss National Science Foundation/Switzerland ; 82020108016//National Natural Science Foundation of China/ ; 82071973//National Natural Science Foundation of China/ ; 2023A1515010326//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2022ZDZX2020//Key Research Platform and Project of Guangdong University/ ; }, mesh = {Animals ; *Riluzole/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Neuroprotective Agents/pharmacology ; Mice ; *Mice, Transgenic ; *Glutamic Acid/metabolism ; *gamma-Aminobutyric Acid/metabolism ; Proton Magnetic Resonance Spectroscopy/methods ; Brain/drug effects/metabolism/diagnostic imaging ; Disease Models, Animal ; Male ; Magnetic Resonance Imaging/methods ; Neurotransmitter Agents/metabolism ; }, abstract = {BACKGROUND: The imbalance of glutamate (Glu) and gamma-aminobutyric acid (GABA) neurotransmitter system plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Riluzole is a Glu modulator originally approved for amyotrophic lateral sclerosis that has shown potential neuroprotective effects in various neurodegenerative disorders. However, whether riluzole can improve Glu and GABA homeostasis in AD brain and its related mechanism of action remain unknown. This study utilized chemical exchange saturation transfer (CEST) imaging combined with proton magnetic resonance spectroscopy ([1]H-MRS) to monitor the dynamic changes of Glu and GABA in riluzole-treated AD mice, aiming to evaluate the efficacy and mechanism of riluzole in AD treatment.<br><br>METHODS: GluCEST, GABACEST and [1]H-MRS were used to longitudinally monitor Glu and GABA levels in 3xTg AD mice treated with riluzole (12.5&#xa0;mg/kg/day) or vehicle for 20 weeks. Magnetic resonance measurements were performed at baseline, 6, 12, and 20 weeks post-treatment. Cognitive performance was assessed using the Morris Water Maze (MWM) at baseline, 10, and 20 weeks. At the study endpoint, immunohistochemistry, Nissl staining, and Western blot were used to evaluate the brain pathology, neuronal survival, and protein expression.<br><br>RESULTS: GluCEST, GABACEST and [1]H-MRS consistently revealed higher levels of Glu and GABA in the brain of riluzole-treated AD mice compared to untreated controls, which were associated with improvements in spatial learning and memory. The cognitive improvements significantly correlated with the increased GluCEST signals and Glu levels. Immunohistochemistry and Nissl staining demonstrated that riluzole treatment reduced amyloid-beta (A&#x3b2;) deposition, tau hyperphosphorylation, GFAP-positive astrocyte activation, and prevented neuronal loss. Moreover, riluzole upregulated the expression of excitatory amino acid transporter 2 (EAAT2), glutamic acid decarboxylase 65/67 (GAD65/67), and glutamine synthetase (GS), suggesting enhanced neurotransmitter metabolism.<br><br>CONCLUSIONS: CEST imaging combined with [1]H-MRS demonstrated the effectiveness of riluzole in modulating Glu- and GABA-related changes and improving cognitive function in 3xTg AD mice, potentially through regulating key proteins involved in neurotransmitter metabolism. These findings suggest riluzole as a therapeutic agent for Alzheimer's disease and highlight the utility of multimodal MR imaging in monitoring treatment response and exploring disease mechanisms.}, }
@article {pmid39801873, year = {2025}, author = {Kumar, AJ and Sathiyaseelan, N and Vinodh, JB and Vignesh, A and Rathi, NK}, title = {Recent Advances in Managing Ankylosing Spondylitis with Andersson Lesion: A Clinical Overview and Case Report.}, journal = {Journal of orthopaedic case reports}, volume = {15}, number = {1}, pages = {21-25}, pmid = {39801873}, issn = {2250-0685}, abstract = {INTRODUCTION: Ankylosing spondylitis (AS) is a chronic inflammatory disorder that primarily affects the spine and sacroiliac joints, leading to pain, stiffness, and progressive thoracolumbar kyphotic deformity. A key complication in advanced AS is the development of Andersson lesions (AL), degenerative vertebral lesions resulting from the disease's progression. These lesions can cause significant mechanical pain, often mistaken for the chronic discomfort associated with AS. The exact cause of AL remains unclear, with hypotheses ranging from spinal stress fractures to delays in the ankylosing process. Understanding AL's pathophysiology is essential for timely diagnosis and effective management.<br><br>CASE REPORT: A 52-year-old male presented with a 20-year history of diffuse abdominal pain, later developing insidious lower back pain over the past 2 months. The pain was aggravated by walking and prolonged standing. Physical examination revealed tenderness in the D11 region of the spine, with limited chest expansion and positive findings on the modified Schober's test. Radiographic studies showed irregularities and erosions at the D11-D12 vertebral levels, and magnetic resonance imaging confirmed the presence of an AL associated with asymmetrical bilateral sacroiliitis. The patient tested positive for human leukocyte antigen-B27, supporting a diagnosis of AS with an AL. Medical management, including methotrexate, sulfasalazine, non-steroidal anti-inflammatory drugs, and corticosteroids, led to significant pain reduction and improved mobility. The patient's condition remained stable with continued treatment over a 2-year follow-up period.<br><br>CONCLUSION: AL s are chronic, often overlooked complications of AS that can lead to spinal instability and neurological deficits if untreated. Early recognition and management are critical to preventing progressive kyphotic deformities and associated complications. While conservative treatment remains the cornerstone for managing AL, surgical intervention may be required in cases of severe pain, deformity, or neurological involvement. Understanding AL's presentation and treatment options is vital for improving patient outcomes in AS.}, }
@article {pmid39799559, year = {2025}, author = {Üremiş, N and Üremiş, MM}, title = {Oxidative/Nitrosative Stress, Apoptosis, and Redox Signaling: Key Players in Neurodegenerative Diseases.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {1}, pages = {e70133}, pmid = {39799559}, issn = {1099-0461}, support = {//This research was supported by the T&#xfc;rkiye Bilimsel ve Teknolojik Ara&#x15f;t&#x131;rma Kurumu (grant number: TUB1)./ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Apoptosis ; *Oxidative Stress ; *Nitrosative Stress ; *Oxidation-Reduction ; Animals ; *Signal Transduction ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases are significant health concerns that have a profound impact on the quality and duration of life for millions of individuals. These diseases are characterized by pathological changes in various brain regions, specific genetic mutations associated with the disease, deposits of abnormal proteins, and the degeneration of neurological cells. As neurodegenerative disorders vary in their epidemiological characteristics and vulnerability of neurons, treatment of these diseases is usually aimed at slowing disease progression. The heterogeneity of genetic and environmental factors involved in the process of neurodegeneration makes current treatment methods inadequate. However, the existence of common molecular mechanisms in the pathogenesis of these diseases may allow the development of new targeted therapeutic strategies. Oxidative and nitrosative stress damages membrane components by accumulating ROS and RNS and disrupting redox balance. This process results in the induction of apoptosis, which is important in the pathogenesis of neurodegenerative diseases through oxidative stress. Studies conducted using postmortem human samples, animal models, and cell cultures have demonstrated that oxidative stress, nitrosative stress, and apoptosis are crucial factors in the development of diseases such as Alzheimer's, Parkinson's, Multiple Sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. The excessive production of reactive oxygen and nitrogen species, elevated levels of free radicals, heightened mitochondrial stress, disturbances in energy metabolism, and the oxidation and nitrosylation of cellular macromolecules are recognized as triggers for neuronal cell death. Challenges in managing and treating neurodegenerative diseases require a better understanding of this field at the molecular level. Therefore, this review elaborates on the molecular mechanisms by which oxidative and nitrosative stress are involved in neuronal apoptosis.}, }
@article {pmid39799324, year = {2025}, author = {Freiha, J and Grand, E and Marshall, B and Arunchalam, R and Pinto, A and Osman, C}, title = {Amyotrophic lateral sclerosis in a patient with chronic lymphocytic leukaemia and drug related sarcoid-like reaction.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {16}, pmid = {39799324}, issn = {1471-2377}, mesh = {Humans ; Male ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/complications ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Sarcoidosis/diagnosis/complications ; Rituximab/therapeutic use/adverse effects ; Central Nervous System Diseases ; }, abstract = {Sarcoid-like reaction is an immunological reaction that can affect lymph nodes and organs but does not meet the diagnostic criteria for systemic sarcoidosis. Anti-CD20 auto-antibodies have been reported to be responsible for such reactions. There are several reported associations between Chronic lymphocytic leukaemia (CLL), Amyotrophic lateral sclerosis (ALS) and Sarcoid-like reactions (SLR). We report a case of ALS developing in a patient with treated CLL and drug related SLR one day after exposure to Venetoclax and Rituximab. A 60-year-old male presented with lower limb rash, left leg weakness followed by bulbar symptoms which progressed over 12-months. Workup demonstrated a Cerebrospinal fluid (CSF) pleocytosis and inguinal lymphadenopathy. Skin and inguinal lymph node biopsies showed non-necrotising granulomata. Electromyography met diagnostic criteria for ALS. He was treated for presumed neurosarcoidosis mimicking ALS. Despite prednisolone and infliximab treatment, the motor symptoms rapidly progressed; Hence, we made a clinical diagnosis of ALS. We discuss the diagnostic and treatment challenges of this case.}, }
@article {pmid39798853, year = {2025}, author = {Guan, D and Liang, C and Zheng, D and Liu, S and Luo, J and Cai, Z and Zhang, H and Chen, J}, title = {The role of mitochondrial remodeling in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {183}, number = {}, pages = {105927}, doi = {10.1016/j.neuint.2024.105927}, pmid = {39798853}, issn = {1872-9754}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; Mitochondrial Dynamics/physiology ; Energy Metabolism/physiology ; }, abstract = {Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.}, }
@article {pmid39796536, year = {2024}, author = {Cuffaro, F and Lamminpää, I and Niccolai, E and Amedei, A}, title = {Nutritional and Microbiota-Based Approaches in Amyotrophic Lateral Sclerosis: From Prevention to Treatment.}, journal = {Nutrients}, volume = {17}, number = {1}, pages = {}, pmid = {39796536}, issn = {2072-6643}, support = {PNRR-MAD-2022-12375798//Ministero della Salute/ ; PE0000006//Ministry of University and Research (MUR)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Gastrointestinal Microbiome ; *Dysbiosis/therapy ; Probiotics/therapeutic use ; Brain-Gut Axis/physiology ; Fecal Microbiota Transplantation ; Fatty Acids, Omega-3 ; Prebiotics/administration &amp; dosage ; Oxidative Stress ; Nutritional Status ; Diet, Mediterranean ; Antioxidants ; }, abstract = {Metabolic alterations, including hypermetabolism, lipid imbalances, and glucose dysregulation, are pivotal contributors to the onset and progression of Amyotrophic Lateral Sclerosis (ALS). These changes exacerbate systemic energy deficits, heighten oxidative stress, and fuel neuroinflammation. Simultaneously, gastrointestinal dysfunction and gut microbiota (GM) dysbiosis intensify disease pathology by driving immune dysregulation, compromising the intestinal barrier, and altering gut-brain axis (GBA) signaling, and lastly advancing neurodegeneration. Therapeutic and preventive strategies focused on nutrition offer promising opportunities to address these interconnected pathophysiological mechanisms. Diets enriched with antioxidants, omega-3 fatty acids, and anti-inflammatory compounds-such as the Mediterranean diet-have shown potential in reducing oxidative stress and systemic inflammation. Additionally, microbiota-targeted approaches, including probiotics, prebiotics, postbiotics, and fecal microbiota transplantation, are emerging as innovative tools to restore microbial balance, strengthen gut integrity, and optimize GBA function. This review highlights the critical need for personalized strategies integrating immunonutrition and microbiota modulation to slow ALS progression, improve quality of life, and develop preventive measures for neurodegenerative and neuroinflammatory diseases. Future research should prioritize comprehensive dietary and microbiota-based interventions to uncover their therapeutic potential and establish evidence-based guidelines for managing ALS and related disorders.}, }
@article {pmid39795334, year = {2024}, author = {Bhattacharya, S and Sen, MK and Hamouzová, K and Košnarová, P and Bharati, R and Menendez, J and Soukup, J}, title = {Pyroxsulam Resistance in Apera spica-venti: An Emerging Challenge in Crop Protection.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {1}, pages = {}, pmid = {39795334}, issn = {2223-7747}, support = {QL24010167//National Agency for Agricultural Research (NAZV)/ ; }, abstract = {Apera spica-venti, a prevalent weed in Czech winter wheat fields, has developed resistance to ALS-inhibiting herbicides due to their frequent use. This study reports a biotype of A. spica-venti resistant to pyroxsulam, with cross and multiple resistance to iodosulfuron, propoxycarbazone, pinoxaden, and chlortoluron. Dose-response experiments revealed high resistance of both R1 and R2 biotypes to pyroxsulam, with resistance factors (RF) of 6.69 and 141.65, respectively. Pre-treatment with malathion reduced RF by 2.40× and 1.25× in R1 and R2, indicating the potential involvement of cytochrome P450 (CytP450). NBD-Cl pre-treatment decreased RF only in R2, suggesting possible GST involvement. Gene analysis revealed no mutations (at previously reported sites) or overexpression in the acetolactate synthase (ALS) gene. However, a significant difference in ALS enzyme activity between resistant and susceptible biotypes points to target-site resistance mechanisms. Studies with [14]C-labeled pyroxsulam showed that reduced absorption and translocation were not likely resistance mechanisms. In summary, herbicide resistance in A. spica-venti appears to result from multiple mechanisms. Possible causes include target-site resistance from an unidentified ALS mutation (within coding or regulatory regions). Enhanced herbicide metabolism via CytP450s and GSTs is also a contributing factor. Further experimental validation is needed to confirm these mechanisms and fully understand the resistance. This evolution underscores the adaptive capacity of weed populations under herbicide pressure, emphasizing the need for alternative control strategies.}, }
@article {pmid39793633, year = {2025}, author = {Baker, RS and Wang, JT and Rouatbi, N and Lu, Y and Al-Adhami, T and Asker, D and Rahman, KM and Al-Chalabi, A and Forbes, B and Bansal, S and Al-Jamal, KT}, title = {Brain distribution study of [[14]C]-Riluzole following intranasal administration in mice.}, journal = {International journal of pharmaceutics}, volume = {670}, number = {}, pages = {125195}, doi = {10.1016/j.ijpharm.2025.125195}, pmid = {39793633}, issn = {1873-3476}, mesh = {Animals ; *Administration, Intranasal ; *Brain/metabolism ; Male ; Mice ; *Carbon Radioisotopes ; Tissue Distribution ; Biological Availability ; Tetrahydroisoquinolines/administration &amp; dosage/pharmacokinetics ; Blood-Brain Barrier/metabolism ; Administration, Oral ; Neuroprotective Agents/pharmacokinetics/administration &amp; dosage ; Acridines ; }, abstract = {Amyotrophic lateral sclerosis (ALS) presents a substantial challenge due to its complex nature, limited effective treatment options, and modest benefits from current therapies in slowing disease progression. This study explores the potential of intranasal (IN) delivery to enhance the CNS delivery of riluzole (RLZ), a standard ALS treatment which is subject to blood-brain barrier efflux mechanisms. Additionally, the impact of elacridar (ELC), an efflux pump inhibitor, on IN RLZ CNS bioavailability was examined. To quantify RLZ in vivo in mice, [[14]C]-RLZ was synthesised using an optimised one-pot method. [[14]C]-RLZ yield was 21.3 ± 3.4 %, measured by High Performance Liquid Chromatography (HPLC), with a specific activity of 40.4 ± 3.9 µCi/mg measured by HPLC and liquid scintillation counting. RLZ synthesis was verified using proton nuclear magnetic resonance ([1]H NMR), and liquid chromatography-mass spectrometry. IN RLZ (5 mg/kg) produced double the maximum brain levels (1.11 ± 0.34 % Injected Dose (ID)/brain) at 30 min as oral RLZ (5 mg/kg). The uptake of RLZ in the liver was reduced by half for intranasal administration compared to oral administration. Intravenous ELC (5 mg/kg) substantially increased brain levels of IN RLZ to 3.52 ± 0.62 % ID/g brain at 60 min post-administration, compared to 1.87 ± 0.33 % ID/g brain in the absence of the efflux pump inhibitor. However, increased concentrations were also observed in the liver and blood. These results indicate that intranasal delivery of RLZ enhances brain targeting and reduces liver accumulation compared to the oral route. Brain uptake of IN RLZ was enhanced further by ELC, although not selectively as accumulation in the liver or blood was also observed. Further metabolic research using Chromatography-Mass spectrometry (LC-MS) or NMR along with excretion studies are warranted for a more comprehensive understanding of the pharmacokinetics of IN RLZ and IN RLZ/ELC. Additionally, employing suitable ALS animal models is crucial for understanding RLZ's effects on disease progression, mechanism of action, efficacy, and potential side effects to aid further development.}, }
@article {pmid39792201, year = {2025}, author = {Fu, Z and Feng, B and Akogo, HY and Ma, J and Liu, Y and Quan, H and Zhang, X and Hou, Y and Zhang, X and Ma, J and Cui, H}, title = {Amyotrophic Lateral Sclerosis and Parkinson's Disease: Brain Tissue Transcriptome Analysis Reveals Interactions.}, journal = {Molecular neurobiology}, volume = {62}, number = {5}, pages = {6383-6396}, pmid = {39792201}, issn = {1559-1182}, support = {81801278//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Parkinson Disease/genetics/metabolism ; *Brain/metabolism/pathology ; *Gene Expression Profiling ; Gene Regulatory Networks ; Protein Interaction Maps/genetics ; Transcriptome/genetics ; MicroRNAs/genetics/metabolism ; Gene Ontology ; }, abstract = {This study utilises amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) human brain samples from the GEO database and employs differential expression gene (DEG) analysis to identify genes that are pivotal in both neurodegenerative diseases. Through in depth GO and KEGG enrichment analyses, we elucidated the biological functions and potential pathways associated with these DEGs. Furthermore, by constructing protein‒protein interaction networks, we highlight the significance of shared DEGs in both cellular physiology and disease contexts. Analysis of drug‒gene associations revealed potential therapeutic compounds linked to ALS and PD treatment. Additionally, we explored the interactions between transcription factors, miRNAs, and common DEGs, revealing aspects of gene regulatory networks. This study provides insights into the molecular mechanisms of ALS and PD, offering valuable contributions to ongoing research and potential therapeutic avenues.}, }
@article {pmid39786321, year = {2025}, author = {Kim, K and Kim, S and Katana, M and Terentyev, D and Radwański, PB and Munger, MA}, title = {Riluzole is associated with reduced risk of heart failure.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e70033}, pmid = {39786321}, issn = {1468-1331}, support = {R01HL14488/HL/NHLBI NIH HHS/United States ; R01 NS121234/NS/NINDS NIH HHS/United States ; R01 HL166604/HL/NHLBI NIH HHS/United States ; R01HL166604/HL/NHLBI NIH HHS/United States ; R01HL155378/HL/NHLBI NIH HHS/United States ; }, mesh = {*Riluzole/therapeutic use ; Humans ; *Heart Failure/epidemiology/drug therapy ; Male ; Female ; Aged ; Middle Aged ; Incidence ; Amyotrophic Lateral Sclerosis/epidemiology/drug therapy ; Aged, 80 and over ; Cohort Studies ; United States/epidemiology ; }, abstract = {BACKGROUND: Reduction of intracellular Na[+] accumulation through late Na[+] current inhibition has been recognized as a target for cardiac Ca[2+] handling which underlies myocardial contractility and relaxation in heart failure (HF). Riluzole, an Na[+] channel blocker with enhancement of Ca[2+]-activated K[+] channel function, used for management of amyotrophic lateral sclerosis (ALS), is effective in suppressing Ca[2+] leak and therefore may improve cardiac function.<br><br>OBJECTIVES: The study aim was to investigate whether riluzole lowers HF incidence.<br><br>METHODS: Rates of HF incident were compared using a commercial insurance and Medicare supplement claims databases. Patients with a filled riluzole prescription (treatment) between 06/2009 and 12/2019 were compared to those with no-riluzole (control). We excluded HF patients during the 180-day baseline period. Study endpoint was the first HF diagnosis from the index riluzole prescription or ALS diagnosis. HF onset was compared between the propensity score matched treatment and control cohorts.<br><br>RESULTS: The matched cohort consisted of 4060 pairs of riluzole/control patients. The 24-month cumulative incidence of HF onset for riluzole versus control patients was 4.96% versus 7.27%, calculating hazard ratio (HR) [95% CI, p-value] of 0.55 [0.40-0.76, p&#x2009;<&#x2009;0.01]. The HR estimates favoring riluzole over the ALS control were consistent across the 3&#x2009;months to 2-year follow-up. The clinically and statistically significant effect on HF onset was driven by the lower rate of HFrEF with the 2-year HR [95% CI] of 0.46 [0.21-0.99].<br><br>CONCLUSIONS: Riluzole is associated with a lower rate of HF onset, suggesting a potential prevention strategy for early management.}, }
@article {pmid39783196, year = {2025}, author = {Lee, I and Mitsumoto, H and Lee, S and Kasarskis, E and Rosenbaum, M and Factor-Litvak, P and Nieves, JW}, title = {Interaction between riluzole treatment and dietary glycemic index in the disease progression of amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {3}, pages = {491-498}, pmid = {39783196}, issn = {2328-9503}, support = {K23 NS131586/NS/NINDS NIH HHS/United States ; K23NS131586/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Riluzole/pharmacology/administration &amp; dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Male ; Female ; Middle Aged ; *Disease Progression ; *Glycemic Index/drug effects/physiology ; Aged ; *Neuroprotective Agents/pharmacology/administration &amp; dosage ; Cohort Studies ; Adult ; }, abstract = {OBJECTIVE: We examined whether riluzole treatment modifies the associations between the dietary glycemic index (GI) and load (GL) and disease progression in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Sporadic ALS patients in the Multicenter Cohort Study of Oxidative Stress who completed a baseline food frequency questionnaire were included (n&#x2009;=&#x2009;304). Interactions between baseline riluzole treatment and GI/GL on functional decline and tracheostomy-free survival were examined using linear regression and Cox proportional hazard models adjusted for covariates. Age, sex, disease duration, diagnostic certainty, body mass index, bulbar onset, revised ALS functional rating scale (ALSFRS-r) total score, and forced vital capacity, from baseline were included as covariates.<br><br>RESULTS: Baseline higher GI and GL were associated with less decline of ALSFRS-r total score at 3-month follow-up in the riluzole treatment group (RTG) but not in the no-riluzole group (NRG). When quartile groups were used, GI second [&#x3b2;&#x2009;=&#x2009;-1.9, 95% CI (-4.1, -0.2), p&#x2009;=&#x2009;0.07], third [&#x3b2;&#x2009;=&#x2009;-3.0, 95% CI (-5.1, -0.8), p&#x2009;<&#x2009;0.01] and fourth [&#x3b2;&#x2009;=&#x2009;-2.2, 95% CI (-4.3, -0.01), p&#x2009;<&#x2009;0.05] quartile groups were associated with less ALSFRS-r decline at 3-months compared to the first quartile group (GI&#x2009;<&#x2009;47.2) among the RTG. Similarly, GL fourth quartile group (GL&#x2009;>&#x2009;109.5) was associated with less ALSFRS-r decline at 3 months compared to the first quartile group [&#x3b2;&#x2009;=&#x2009;-2.6, 95% CI (-4.7, -0.5), p&#x2009;<&#x2009;0.05] among the RTG. In NRG, no statistically significant differences in ALSFRS-r decline were found among GI/GL quartile groups.<br><br>INTERPRETATION: High dietary GI and GL are associated with a slower functional decline only among ALS patients taking riluzole.}, }
@article {pmid39783194, year = {2025}, author = {Smith, SE and McCoy-Gross, K and Malcolm, A and Oranski, J and Markway, JW and Miller, TM and Bucelli, RC}, title = {Tofersen treatment leads to sustained stabilization of disease in SOD1 ALS in a "real-world" setting.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {2}, pages = {311-319}, pmid = {39783194}, issn = {2328-9503}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/physiopathology ; Male ; Female ; *Superoxide Dismutase-1/genetics ; Middle Aged ; Aged ; *Neurofilament Proteins/blood ; Disease Progression ; Muscle Strength/drug effects/physiology ; Adult ; }, abstract = {OBJECTIVE: Patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1 ALS) treated with tofersen have shown slowing of disease progression, and disease stabilization with recovery of function in some patients. We report our clinical experience with treating patients with SOD1 ALS and the effects of tofersen on outcome measures.<br><br>METHODS: This was a single-center observational study of patients with SOD1 ALS receiving treatment with tofersen. The effects of tofersen treatment on neurofilament levels, muscle strength, and clinical outcome measures were assessed. Several patients had outpatient neuromuscular rehabilitation in addition to tofersen treatment and we report changes in functional outcomes.<br><br>RESULTS: Seven SOD1 ALS patients received treatment at our institution. All patients showed robust and sustained declines in serum NfL and CSF pNFH (mean change serum NfL: -57.9%; mean change CSF pNFH: -67.6%). There was apparent disease stabilization as assessed by the ALSFRS-R total score, mean change 1.1 (SD&#x2009;=&#x2009;0.7). There was notable improvement in functional independence measured by the FIM motor score, mean change 5.13 points (SD&#x2009;=&#x2009;3.85).<br><br>INTERPRETATION: This study provides evidence that tofersen treatment in SOD1 ALS can lead to meaningful preservation of function and suggestions of sustained improvement in neurologic function in some patients, and strongly supports the role of neurofilaments as therapeutic biomarkers.}, }
@article {pmid39778888, year = {2025}, author = {Etxebeste-Mitxeltorena, M and Flores-Romero, H and Ramos-Inza, S and Masiá, E and Nenchova, M and Montesinos, J and Martinez-Gonzalez, L and Porras, G and Orzáez, M and Vicent, MJ and Gil, C and Area-Gomez, E and Garcia-Saez, AJ and Martinez, A}, title = {Modulation of Mitochondria-Endoplasmic Reticulum Contacts (MERCs) by Small Molecules as a New Strategy for Restoring Lipid Metabolism in an Amyotrophic Lateral Sclerosis Model.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {2}, pages = {1179-1194}, pmid = {39778888}, issn = {1520-4804}, support = {/ERC_/European Research Council/International ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Humans ; *Endoplasmic Reticulum/metabolism/drug effects ; *Mitochondria/metabolism/drug effects ; *Lipid Metabolism/drug effects ; *Small Molecule Libraries/pharmacology/chemistry ; Cholesterol/metabolism ; HCT116 Cells ; Mitochondria Associated Membranes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without effective treatment. The progressive motoneuron death in ALS is associated with alterations in lipid metabolism. As its regulation occurs in mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), modulation of mitochondria-ER contacts (MERCs) is emerging as a crucial factor in MAM formation and lipid metabolism control. Using the MERLIN biosensor in a high-throughput screening within the EU-OPENSCREEN ERIC, we discovered small molecules that increase MERCs in HCT116 cells, enhancing their ability to uptake cholesterol. We demonstrated that cholesterol trafficking is decreased in an ALS patient-derived cell model, and this trafficking is restored after treatment with the discovered MERC modulator 24. Electron microscopy revealed that treatment with compound 24 increases MERCs, promotes lipid droplet formation, and restores mitochondrial cristae. Overall, the brain-permeable MERC modulator, compound 24, may serve as a valuable pharmacological tool for studying MAM function and holds potential for in vivo studies in ALS and other MAM dysfunction diseases.}, }
@article {pmid39778593, year = {2025}, author = {Chen, Q and Chen, G and Wang, Q}, title = {Application of Network Pharmacology in the Treatment of Neurodegenerative Diseases with Traditional Chinese Medicine.}, journal = {Planta medica}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2512-8928}, pmid = {39778593}, issn = {1439-0221}, support = {2023AFB677//the Natural Science Foundation of Hubei Province/ ; 2024AFB578//the Natural Science Foundation of Hubei Province/ ; 2023LYYYGZRP0003//the Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology/ ; 2023LYYYSZRP0001//the Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology/ ; }, abstract = {In recent years, the incidence of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, has exhibited a steadily rising trend, which has posed a major challenge to the global public health. Traditional Chinese medicine, with its multicomponent and multitarget characteristics, offers a promising approach to treating neurodegenerative diseases. However, comprehensively elucidating the complex mechanisms underlying traditional Chinese medicine formulations remains challenging. As an emerging systems biology method, network pharmacology has provided a vital tool for revealing the multitarget mechanisms of traditional Chinese medicine through high-throughput technologies, molecular docking, and network analysis. This paper reviews the advancements in the application of network pharmacology in treating neurodegenerative diseases using traditional Chinese medicine, analyzes the current status of relevant databases and technological methods, discusses the limitations, and proposes future directions to promote the modernization of traditional Chinese medicine and the development of precision medicine.}, }
@article {pmid39775908, year = {2025}, author = {de Vries, E and Hagbohm, C and Ouellette, R and Granberg, T}, title = {Clinical 7 Tesla magnetic resonance imaging: Impact and patient value in neurological disorders.}, journal = {Journal of internal medicine}, volume = {297}, number = {3}, pages = {244-261}, pmid = {39775908}, issn = {1365-2796}, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Nervous System Diseases/diagnostic imaging ; Neuroimaging/methods ; }, abstract = {Magnetic resonance imaging (MRI) is a cornerstone of non-invasive diagnostics and treatment monitoring, particularly for diseases of the central nervous system. Although 1.5- and 3 Tesla (T) field strengths remain the clinical standard, the advent of 7 T MRI represents a transformative step forward, offering superior spatial resolution, contrast, and sensitivity for visualizing neuroanatomy, metabolism, and function. Recent innovations, including parallel transmission and deep learning-based reconstruction, have resolved many prior technical challenges of 7 T MRI, enabling its routine clinical use. This review examines the diagnostic impact, patient value, and practical considerations of 7 T MRI, emphasizing its role in facilitating earlier diagnoses and improving care in conditions, such as amyotrophic lateral sclerosis (ALS), epilepsy, multiple sclerosis (MS), dementia, parkinsonism, tumors, and vascular diseases. Based on insights from over 1200 clinical scans with a second-generation 7 T system, the review highlights disease-specific biomarkers such as the motor band sign in ALS and the new diagnostic markers in MS, the central vein sign, and paramagnetic rim lesions. The unparalleled ability of 7 T MRI to study neurological diseases ex vivo at ultra-high resolution is also explored, offering new opportunities to understand pathophysiology and identify novel treatment targets. Additionally, the review provides a clinical perspective on patient handling and safety considerations, addressing challenges and practicalities associated with clinical 7 T MRI. By bridging research and clinical practice, 7 T MRI has the potential to redefine neuroimaging and advance the understanding and management of complex neurological disorders.}, }
@article {pmid39774976, year = {2025}, author = {Naito, H and Nakamori, M and Toko, M and Hayashi, Y and Tazuma, T and Watanabe, T and Ishihara, K and Tachiyama, K and Yamazaki, Y and Maruyama, H}, title = {A single-center, single-arm, prospective, open-label, and comparative trial to evaluate the safety and tolerability profile of a 90-day oral L-arginine hydrochloride intervention for patients with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1120}, pmid = {39774976}, issn = {2045-2322}, support = {23K16642//Japan Society for the Promotion of Science/ ; NA//ALS Foundation, Japan ALS Association/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Administration, Oral ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Arginine/administration &amp; dosage/adverse effects/therapeutic use ; Nutritional Status ; Prospective Studies ; Treatment Outcome ; }, abstract = {Weight loss, a key indicator of malnutrition in amyotrophic lateral sclerosis (ALS) patients, negatively impacts patient prognosis. However, effective nutritional interventions have not been adequately established. Research in ALS model mice has shown that L-arginine can prolong survival; however, no human intervention studies have been conducted. We conducted a single-center, single-arm, prospective, open-label, and comparative trial to assess the safety and tolerability of L-arginine hydrochloride in ALS patients. ALS patients were administered 15 g/day L-arginine hydrochloride for 90 days. The primary outcome of safety was evaluated on days 45 and 90. The secondary outcome of efficacy was evaluated by measuring nutritional status, ALS Functional Rating Scale (ALSFRS) scores, and the occurrence of events such as the initiation of tracheostomy positive pressure ventilation (TPPV) and death. The study included 20 patients (40% female; mean age, 62.0 ± 6.9 years; median disease duration, 1.9 years). Six participants (30%) experienced treatment-emergent adverse events (TEAEs), including elevated creatine kinase levels, liver function test abnormalities, glucose tolerance issues, hyperammonemia, anorexia, dysgeusia, and vasculitis. No serious TEAEs were associated with L-arginine hydrochloride. Over the course of three months, the average changes in body weight, body mass index, and the ALSFRS score were - 0.37 kg, -1.1 kg/m[2], and - 1.7 points, respectively. There were no events requiring TPPV initiation or deaths. This study demonstrated that the oral administration of L-arginine hydrochloride over three months was well tolerated by ALS patients, with no serious TEAEs or deaths attributed to the study drug.Trial Registration number: Japan Registry of Clinical Trials (jRCTs061230001), first registered 11/04/2023.}, }
@article {pmid39771101, year = {2024}, author = {Chetverikova, D and Bakaeva, M and Starikov, S and Kendjieva, A and Chetverikov, S}, title = {The Influence of Plant Growth-Stimulating Bacteria on the Glutathione-S-Transferase Activity and the Toxic Effect of the Herbicide Metsulfuron-Methyl in Wheat and Canola Plants.}, journal = {Toxics}, volume = {12}, number = {12}, pages = {}, pmid = {39771101}, issn = {2305-6304}, support = {23-26-00097//Russian Science Foundation/ ; }, abstract = {The ability of some rhizosphere bacteria to mitigate herbicidal stress in cultivated plants may be useful in agriculture and bioremediation. There is poor understanding of how bacteria directly or through herbicide degradation affect the biochemical processes in plants exposed to sulfonylurea herbicides. In this study, treatment with a combination of herbicide metsulfuron-methyl (MSM) and bacteria (Pseudomonas protegens DA1.2 or P. chlororaphis 4CH) of wheat (Triticum aestivum L.) and canola (Brassica napus L.) plants was carried out. Activity of glutathione-S-transferase (GST), an important enzyme for the herbicide detoxification, and acetolactate synthase (ALS), a target for MSM in plants, was measured by spectrophotometric assays. MSM residues were analyzed using the HPLC-MS. Then, 24 h after bacterial treatment, GST activity increased by 75-91% in wheat and by 38-94% in canola. On the 30th day, a decrease in MSM in the soil associated with bacterial treatment was 54.6-79.7%. An increase in GST activity and acceleration of MSM degradation were accompanied by a decrease in inhibition of the ALS enzyme in plants, which indicated a mitigation of the toxic effect. The results obtained are evidence that rhizospheric bacteria can have beneficial effects on plants exposed to MSM due to the combination of abilities to directly affect detoxification enzymes in plants and degrade MSM in the soil.}, }
@article {pmid39770989, year = {2024}, author = {Pekdemir, B and Raposo, A and Saraiva, A and Lima, MJ and Alsharari, ZD and BinMowyna, MN and Karav, S}, title = {Mechanisms and Potential Benefits of Neuroprotective Agents in Neurological Health.}, journal = {Nutrients}, volume = {16}, number = {24}, pages = {}, pmid = {39770989}, issn = {2072-6643}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy ; Brain/drug effects/metabolism ; Animals ; Flavonoids/pharmacology/therapeutic use ; Apoptosis/drug effects ; Antioxidants/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {The brain contains many interconnected and complex cellular and molecular mechanisms. Injury to the brain causes permanent dysfunctions in these mechanisms. So, it continues to be an area where surgical intervention cannot be performed except for the removal of tumors and the repair of some aneurysms. Some agents that can cross the blood-brain barrier and reach neurons show neuroprotective effects in the brain due to their anti-apoptotic, anti-inflammatory and antioxidant properties. In particular, some agents act by reducing or modulating the accumulation of protein aggregates in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and prion disease) caused by protein accumulation. Substrate accumulation causes increased oxidative stress and stimulates the brain's immune cells, microglia, and astrocytes, to secrete proinflammatory cytokines. Long-term or chronic neuroinflammatory response triggers apoptosis. Brain damage is observed with neuronal apoptosis and brain functions are impaired. This situation negatively affects processes such as motor movements, memory, perception, and learning. Neuroprotective agents prevent apoptosis by modulating molecules that play a role in apoptosis. In addition, they can improve impaired brain functions by supporting neuroplasticity and neurogenesis. Due to the important roles that these agents play in central nervous system damage or neurodegenerative diseases, it is important to elucidate many mechanisms. This review provides an overview of the mechanisms of flavonoids, which constitute a large part of the agents with neuroprotective effects, as well as vitamins, neurotransmitters, hormones, amino acids, and their derivatives. It is thought that understanding these mechanisms will enable the development of new therapeutic agents and different treatment strategies.}, }
@article {pmid39769209, year = {2024}, author = {Xing, C and Chen, H and Bi, W and Lei, T and Hang, Z and Du, H}, title = {Targeting 5-HT Is a Potential Therapeutic Strategy for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769209}, issn = {1422-0067}, support = {32300682//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Serotonin/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; Alzheimer Disease/metabolism/drug therapy ; Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Parkinson Disease/metabolism/drug therapy ; Receptors, Serotonin/metabolism ; }, abstract = {There is increasing interest in the potential therapeutic role of 5-HT (serotonin) in the treatment of neurodegenerative diseases, which are characterized by the progressive degeneration and death of nerve cells. 5-HT is a vital neurotransmitter that plays a central role in regulating mood, cognition, and various physiological processes in the body. Disruptions in the 5-HT system have been linked to several neurological and psychiatric disorders, making it an attractive target for therapeutic intervention. Although the exact causes of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are not fully understood, researchers believe that regulating the 5-HT system could help alleviate symptoms and potentially slow the progression of these diseases. Here, we delve into the potential of harnessing 5-HT as a therapeutic target for the treatment of neurodegenerative diseases. It is important to note that the current clinical drugs targeting 5-HT are still limited in the treatment of these complex diseases. Therefore, further research and clinical trials are needed to evaluate the feasibility and effectiveness of its clinical application.}, }
@article {pmid39769187, year = {2024}, author = {O'Day, DH}, title = {The Search for a Universal Treatment for Defined and Mixed Pathology Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769187}, issn = {1422-0067}, mesh = {Animals ; Humans ; alpha-Synuclein/metabolism ; Alzheimer Disease/metabolism/pathology/drug therapy/therapy ; Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; Calmodulin/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; Parkinson Disease/metabolism/pathology/therapy ; Protein Glutamine gamma Glutamyltransferase 2 ; RNA-Binding Protein FUS/metabolism/genetics ; tau Proteins/metabolism ; Transglutaminases/metabolism ; }, abstract = {The predominant neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are rarely pure diseases but, instead, show a diversity of mixed pathologies. At some level, all of them share a combination of one or more different toxic biomarker proteins: amyloid beta (Aβ), phosphorylated Tau (pTau), alpha-synuclein (αSyn), mutant huntingtin (mHtt), fused in sarcoma, superoxide dismutase 1, and TAR DNA-binding protein 43. These toxic proteins share some common attributes, making them potentially universal and simultaneous targets for therapeutic intervention. First, they all form toxic aggregates prior to taking on their final forms as contributors to plaques, neurofibrillary tangles, Lewy bodies, and other protein deposits. Second, the primary enzyme that directs their aggregation is transglutaminase 2 (TGM2), a brain-localized enzyme involved in neurodegeneration. Third, TGM2 binds to calmodulin, a regulatory event that can increase the activity of this enzyme threefold. Fourth, the most common mixed pathology toxic biomarkers (Aβ, pTau, αSyn, nHtt) also bind calmodulin, which can affect their ability to aggregate. This review examines the potential therapeutic routes opened up by this knowledge. The end goal reveals multiple opportunities that are immediately available for universal therapeutic treatment of the most devastating neurodegenerative diseases facing humankind.}, }
@article {pmid39768371, year = {2024}, author = {Orlova, A and Malygin, Y and Gofman, A and Sotulenko, S and Gandalian, V and Kartashov, I and Brylev, L and Bolevich, S and Nikolic Turnic, T and Jakovljevic, V}, title = {Survival Prognostic Factors of Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {12}, pages = {}, pmid = {39768371}, issn = {2075-1729}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis is a neurodegenerative disease with high rates of disability and mortality. Non-invasive ventilation (NIV) is an effective method of treating patients, increasing life expectancy, but currently, predictors available to determine the best outcome of therapy in this category of patients are unknown. This systematic review aimed to determine the impact of prognostic factors on benefits from NIV application compared with non-NIV tools of treatment (invasive ventilation and standard care) in case of survival of ALS patients.<br><br>METHOD: We systematically sought relevant longitudinal cohort and case-control studies published in PubMed, CINAHL/EMBASE, Cochrane library, and Scopus.<br><br>RESULTS: We included seven prospective studies, published in 2010-2020, in the analysis. According to the evidence base available to date, NIV favors survival compared to non-NIV in patients with bulbar onset ALS. We obtained conflicting data on the significance of spinal onset and bulbar function. Survival depending on patient age, and also for spinal, cervical, and flail limb phenotypes during NIV therapy has not been sufficiently studied and needs further investigation.<br><br>CONCLUSIONS: The studies analyzed in this review allow us to state with confidence that NIV is effective in bulbar onset ALS, taking into account recommendations for duration of ventilation and the use of the full range of symptomatic therapy, including mechanically assisted coughing. The effectiveness of NIV on severe bulbar symptoms requires further research.}, }
@article {pmid39766450, year = {2024}, author = {Donaghy, R and Pioro, EP}, title = {Neurophysiologic Innovations in ALS: Enhancing Diagnosis, Monitoring, and Treatment Evaluation.}, journal = {Brain sciences}, volume = {14}, number = {12}, pages = {}, pmid = {39766450}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease of both upper motor neurons (UMNs) and lower motor neurons (LMNs) leading invariably to decline in motor function. The clinical exam is foundational to the diagnosis of the disease, and ordinal severity scales are used to track its progression. However, the lack of objective biomarkers of disease classification and progression delay clinical trial enrollment, muddle inclusion criteria, and limit accurate assessment of drug efficacy. Ultimately, biomarker evidence of therapeutic target engagement will support, and perhaps supplant, more traditional clinical trial outcome measures. Electrophysiology tools including nerve conduction study and electromyography (EMG) have already been established as diagnostic biomarkers of LMN degeneration in ALS. Additional understanding of the motor manifestations of disease is provided by motor unit number estimation, electrical impedance myography, and single-fiber EMG techniques. Dysfunction of UMN and non-motor brain areas is being increasingly assessed with transcranial magnetic stimulation, high-density electroencephalography, and magnetoencephalography; less common autonomic and sensory nervous system dysfunction in ALS can also be characterized. Although most of these techniques are used to explore the underlying disease mechanisms of ALS in research settings, they have the potential on a broader scale to noninvasively identify disease subtypes, predict progression rates, and assess physiologic engagement of experimental therapies.}, }
@article {pmid39764140, year = {2024}, author = {Akif, A and My Nguyen, TT and Liu, L and Xu, X and Kulkarni, A and Jiang, J and Zhang, Y and Hao, J}, title = {Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39764140}, issn = {2693-5015}, support = {R01 NS105787/NS/NINDS NIH HHS/United States ; R21 NS133895/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD.<br><br>METHODS: In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD + Vehicle, and VaD + AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50[th] day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1&#x3b2;), Tumor Necrosis Factor-alpha (TNF-&#x3b1;) and Interleukin-4 (IL-4) in the blood were measured using ELISA.<br><br>RESULTS: AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-&#x3b1; and IL-1&#x3b2; levels, while increasing the anti-inflammatory IL-4 level in the blood.<br><br>CONCLUSIONS: The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans.}, }
@article {pmid39762986, year = {2025}, author = {Berlowitz, DJ and Rowe, D and Howard, ME and Piper, A and Graco, M and Braat, S and Singh, B and Souza, TV and Lannin, N and McLean, A and Sawyer, A and Carey, KA and Ahamed, Y and , }, title = {Polysomnographic titration of non-invasive ventilation in motor neurone disease (3TLA): study protocol for a randomised controlled trial.}, journal = {Trials}, volume = {26}, number = {1}, pages = {10}, pmid = {39762986}, issn = {1745-6215}, mesh = {Humans ; *Noninvasive Ventilation/methods/adverse effects/instrumentation ; *Motor Neuron Disease/therapy/physiopathology ; *Polysomnography ; *Randomized Controlled Trials as Topic ; Treatment Outcome ; Australia ; Multicenter Studies as Topic ; Time Factors ; Sleep ; Respiratory Insufficiency/therapy/physiopathology ; Quality of Life ; }, abstract = {BACKGROUND: Non-invasive ventilation (NIV) uses positive pressure to assist people with respiratory muscle weakness or severe respiratory compromise to breathe. Most people use this treatment during sleep when breathing is most susceptible to instability. The benefits of using NIV in motor neurone disease (MND) are well-established. However, uptake and usage are low (~ 19%) and there is no consensus on how to best implement NIV in MND in Australia. Consequently, clinical practice models are highly variable. Our team has recently provided evidence that specific and individualised NIV titration using a sleep study (polysomnography; PSG) leads to better outcomes in people with MND. However, for this clinical practice model to result in sustained benefits, evidence of effectiveness across multiple sites, as well as culture and practice change, must occur.<br><br>METHODS: A two-arm, assessor-blinded, individual participant randomised controlled trial in MND care centres across Australia will be undertaken. Two-hundred and forty-four participants will be randomised (1:1) to either the intervention group (PSG-assisted commencement of NIV settings; PSG) or a control group (sham PSG). Participants will be asked to use their NIV device for 7&#xa0;weeks and will then return for follow-up assessments. Respiratory, sleep and patient-reported outcome measures will be collected at baseline and follow-up. The primary aim is to determine if the proportion of participants using NIV for&#x2009;>&#x2009;4&#xa0;h/day during the intervention period is higher in the PSG than the control group. A process evaluation, health economic evaluation and 12-month cohort follow-up will be undertaken and reported separately.<br><br>DISCUSSION: The results of this trial will demonstrate the effects of PSG-assisted titration of NIV on usage of NIV in people with MND. We hypothesise that the PSG intervention will improve synchrony between the user and the machine, which will lead to greater NIV usage compared to the control group.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT05136222. Registered on November 25, 2021.}, }
@article {pmid39759457, year = {2024}, author = {Ahmad, SR and Zeyaullah, M and Khan, MS and AlShahrani, AM and Altijani, AAG and Ali, H and Dawria, A and Mohieldin, A and Alam, MS and Mohamed, AOA}, title = {Pharmacogenomics for neurodegenerative disorders - a focused review.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1478964}, pmid = {39759457}, issn = {1663-9812}, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by the progressive degeneration of neuronal structure and function, leading to severe cognitive and motor impairments. These conditions present significant challenges to healthcare systems, and traditional treatments often fail to account for genetic variability among patients, resulting in inconsistent therapeutic outcomes. Pharmacogenomics aims to tailor medical treatments based on an individual's genetic profile, thereby improving therapeutic efficacy and reducing adverse effects. This focused review explores the genetic factors influencing drug responses in neurodegenerative diseases and the potential of pharmacogenomics to revolutionize their treatment. Key genetic markers, such as the APOE ε4 allele in AD and the CYP2D6 polymorphisms in PD, are highlighted for their roles in modulating drug efficacy. Additionally, advancements in pharmacogenomic tools, including genome-wide association studies (GWAS), next-generation sequencing (NGS), and CRISPR-Cas9, are discussed for their contributions to personalized medicine. The application of pharmacogenomics in clinical practice and its prospects, including ethical and data integration challenges, are also examined.}, }
@article {pmid39756374, year = {2025}, author = {Loap, P and Kirova, Y}, title = {Initial Characterization and Outcome Assessment of Anal Lymphomas in a Large-Size Contemporary Cohort: A Population-Based SEER Database Study (2000-2022).}, journal = {Acta haematologica}, volume = {}, number = {}, pages = {1-7}, doi = {10.1159/000541595}, pmid = {39756374}, issn = {1421-9662}, abstract = {INTRODUCTION: Anal lymphoma (AL) is a rare presentation of extranodal lymphomas, characterized by occurrence in the anal area and largely understudied due to its infrequency. This study aimed to address gaps in knowledge about AL's demographic and clinical profiles, treatments, and survival outcomes, leveraging data from the SEER program.<br><br>METHODS: We conducted a retrospective analysis of 79 AL cases identified in the SEER database from 2000 to 2022; 36 stage I AL cases were identified and defined as localized primary anal lymphoma (L-PAL). Data on demographics, tumor specifics, treatment modalities, and survival were analyzed using the Kaplan-Meier method and Cox proportional hazards models.<br><br>RESULTS: The majority of AL cases were diffuse large B-cell lymphoma (70.9%). Other notable subtypes included anaplastic T-cell lymphoma, marginal zone lymphoma, B-cell non-Hodgkin lymphoma, Burkitt lymphoma/leukemia (each accounting for 6.3%), followed by follicular lymphoma and mantle-cell lymphoma (each at 1.3%). AL primarily affected younger males (median age 50), with a significant majority being Caucasian. Initial stages (I and II) were more commonly observed, and treatments varied, with chemotherapy being most prevalent (67.1%), followed by radiation (30.4%) and surgery (30.4%). The 5- and 10-year overall survival (OS) rates were 59.4% and 44.1%, respectively, while the corresponding cancer-specific survival (CSS) rates were 67.9% and 58.0%, respectively. Age was a significant prognostic factor for OS but not for CSS. Radiotherapy tended to improve CSS in the AL population.<br><br>CONCLUSION: This research corresponds to the first in-depth analysis of AL, highlighting its distinct demographic patterns, clinical features, and responses to various treatments, distinguishing it from other types of anal cancers. Our results underscore the importance of developing specialized diagnostic and treatment strategies. To enhance our understanding and management of this uncommon form of lymphoma, future studies should aim for broader and more collaborative international research efforts.}, }
@article {pmid39753993, year = {2025}, author = {Cheng, L and Liu, Z and Shen, C and Xiong, Y and Shin, SY and Hwang, Y and Yang, SB and Chen, Z and Zhang, X}, title = {A Wonderful Journey: The Diverse Roles of Adenosine Deaminase Action on RNA 1 (ADAR1) in Central Nervous System Diseases.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {31}, number = {1}, pages = {e70208}, pmid = {39753993}, issn = {1755-5949}, support = {20224BAB216045//Youth Foundation of Natural Science Foundation of Jiangxi Province/ ; GJJ211812//Science and Technology Project Funded by the Education Department of Jiangxi Province/ ; GJJ211813//Science and Technology Project Funded by the Education Department of Jiangxi Province/ ; 202131084//Jiangxi Provincial Health Commission Science and Technology Plan Project/ ; 202211982//Jiangxi Provincial Health Commission Science and Technology Plan Project/ ; RZYB202201//Research project of Cognitive Science and Transdisciplinary Studies Center of Jiangxi Province/ ; 20224BAB206040//Provincial Natural Science Foundation of Jiangxi Province/ ; 202411843024//Foundation of Students' Platform for Innovation and Entrepreneurship Training Program/ ; S202411843050//Foundation of Students' Platform for Innovation and Entrepreneurship Training Program/ ; 2022B1010//Administration of Traditional Chinese Medicine of Jiangxi Province/ ; }, mesh = {*Adenosine Deaminase/genetics/metabolism ; Humans ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; *Central Nervous System Diseases/genetics/metabolism/therapy ; RNA Editing ; }, abstract = {BACKGROUND: Adenosine deaminase action on RNA 1 (ADAR1) can convert the adenosine in double-stranded RNA (dsRNA) molecules into inosine in a process known as A-to-I RNA editing. ADAR1 regulates gene expression output by interacting with RNA and other proteins; plays important roles in development, including growth; and is linked to innate immunity, tumors, and central nervous system (CNS) diseases.<br><br>RESULTS: In recent years, the role of ADAR1 in tumors has been widely discussed, but its role in CNS diseases has not been reviewed. It is worth noting that recent studies have shown ADAR1 has great potential in the treatment of neurodegenerative diseases, but the mechanisms are still unclear. Therefore, it is necessary to elaborate on the role of ADAR1 in CNS diseases.<br><br>CONCLUSIONS: Here, we focus on the effects and mechanisms of ADAR1 on CNS diseases such as Aicardi-AicardiGouti&#xe8;res syndrome, Alzheimer's disease, Parkinson's disease, glioblastoma, epilepsy, amyotrophic lateral sclerosis, and autism. We also evaluate the impact of ADAR1-based treatment strategies on these diseases, with a particular focus on the development and treatment strategies of new technologies such as microRNAs, nanotechnology, gene editing, and stem cell therapy. We hope to provide new directions and insights for the future development of ADAR1 gene editing technology in brain science and the treatment of CNS diseases.}, }
@article {pmid39753665, year = {2025}, author = {Quintanilla, CA and Fitzgerald, Z and Kashow, O and Radojicic, MS and Ulupinar, E and Bitlis, D and Genc, B and Andjus, P and van Drongelen, W and Ozdinler, PH}, title = {High-density multielectrode arrays bring cellular resolution to neuronal activity and network analyses of corticospinal motor neurons.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {732}, pmid = {39753665}, issn = {2045-2322}, support = {778405 "AUTOIGG"//EU H2020 MSCA RISE/ ; R01 AG061708/AG/NIA NIH HHS/United States ; 4242 "NIMOCHIP"//Science Fund of the Republic of Serbia/ ; R01AG061708-03/NH/NIH HHS/United States ; 5T32NS041234-18/NH/NIH HHS/United States ; }, mesh = {Animals ; *Motor Neurons/physiology ; Mice ; *Microelectrodes ; Motor Cortex/physiology ; Pyramidal Tracts/physiology ; Nerve Net/physiology ; Mice, Transgenic ; }, abstract = {Corticospinal motor neurons (CSMN), located in the motor cortex of the brain, are one of the key components of the motor neuron circuitry. They are in part responsible for the initiation and modulation of voluntary movement, and their degeneration is the hallmark for numerous diseases, such as amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia, and primary lateral sclerosis. Cortical hyperexcitation followed by in-excitability suggests the early involvement of cortical dysfunction in ALS pathology. However, a high-spatiotemporal resolution on our understanding of their functional health and connectivity is lacking. Here, we combine optical imaging with high-density microelectrode array (HD-MEA) system enabling single cell resolution and utilize UCHL1-eGFP mice to bring cell-type specificity to our understanding of the electrophysiological features of healthy CSMN, as they mature and form network connections with other cortical neurons, in vitro. This novel approach lays the foundation for future cell-type specific analyses of CSMN that are diseased due to different underlying causes with cellular precision, and it will allow the assessment of their functional response to compound treatment, especially for drug discovery efforts in upper motor neuron diseases.}, }
@article {pmid39744204, year = {2024}, author = {Morales-Galicia, AE and Ramírez-Mejía, MM and Ponciano-Rodriguez, G and Méndez-Sánchez, N}, title = {Revolutionizing the understanding of liver disease: Metabolism, function and future.}, journal = {World journal of hepatology}, volume = {16}, number = {12}, pages = {1365-1370}, pmid = {39744204}, issn = {1948-5182}, abstract = {The intersection between metabolic-associated steatotic liver disease (MASLD) and chronic hepatitis B virus (HBV) infection is an emerging area of research with significant implications for public health and clinical practice. Wang et al's study highlights the complexities of managing patients with concurrent MASLD and HBV. The findings revealed that patients with concurrent MASLD-HBV exhibited more severe liver inflammation and fibrosis, whereas those with HBV alone presented a better lipid profile. The growing recognition of metabolic dysfunction in liver disease, reflected in the shift from nonalcoholic liver disease to MASLD, demands updates to clinical guidelines, particularly for patients with dual etiologies. Understanding the biological interactions between MASLD and HBV could lead to novel therapeutic approaches, emphasizing the need for personalized treatment strategies. The coexistence of MASLD and HBV presents therapeutic challenges, particularly in managing advanced fibrosis and cirrhosis, which are more likely in these patients. The aim of this editorial is to analyze the interaction between MASLD and HBV, highlight the pathophysiological mechanisms that exacerbate liver disease when both conditions coexist, and discuss the clinical implications of the findings of Wang et al.}, }
@article {pmid39743546, year = {2025}, author = {Faller, KME and Chaytow, H and Gillingwater, TH}, title = {Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {2}, pages = {86-102}, pmid = {39743546}, issn = {1759-4766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism ; Animals ; }, abstract = {The motor neuron disease amyotrophic lateral sclerosis (ALS) is a devastating condition with limited treatment options. The past few years have witnessed a ramping up of translational ALS research, offering the prospect of disease-modifying therapies. Although breakthroughs using gene-targeted approaches have shown potential to treat patients with specific disease-causing mutations, the applicability of such therapies remains restricted to a minority of individuals. Therapies targeting more general mechanisms that underlie motor neuron pathology in ALS are therefore of considerable interest. ALS pathology is associated with disruption to a complex array of key cellular pathways, including RNA processing, proteostasis, metabolism and inflammation. This Review details attempts to restore cellular homeostasis by targeting these pathways in order to develop effective, broadly-applicable ALS therapeutics.}, }
@article {pmid39743032, year = {2025}, author = {Li, Y and Zhang, W and Zhang, Q and Li, Y and Xin, C and Tu, R and Yan, H}, title = {Oxidative stress of mitophagy in neurodegenerative diseases: Mechanism and potential therapeutic targets.}, journal = {Archives of biochemistry and biophysics}, volume = {764}, number = {}, pages = {110283}, doi = {10.1016/j.abb.2024.110283}, pmid = {39743032}, issn = {1096-0384}, mesh = {*Mitophagy ; Humans ; *Oxidative Stress/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; Animals ; *Antioxidants/metabolism/therapeutic use ; Mitochondria/metabolism ; }, abstract = {Neurodegenerative diseases are now significant chronic progressive neurological conditions that affect individuals' physical health. Oxidative stress is crucial in the development of these diseases. Among the various neurodegenerative diseases, mitochondrial damage has become a major factor in oxidative stress and disease advancement. During this process, oxidative stress and mitophagy plays an important role. In this paper, we introduced the role of mitophagy and oxidative stress in detail, and expounded the relationship between them. In addition, we summarized the pathogenesis of some neurodegenerative diseases and the mechanism of three antioxidants. The former includes AD, PD, HD and ALS, while the latter includes carnosine, adiponectin and resveratrol. Provide goals and directions for further research and treatment of neurodegenerative diseases. This review summarizes the impact of oxidative stress on neurodegenerative diseases by regulating mitophagy, provides a deeper understanding of their pathological mechanisms, and suggests potential new therapeutic targets.}, }
@article {pmid39736981, year = {2024}, author = {Zhang, Y and Li, N and Ge, Z and Li, F}, title = {Blood component therapy for dry eye disease: a systematic review and network meta-analysis.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1500160}, pmid = {39736981}, issn = {2296-858X}, abstract = {OBJECTIVE: Blood component therapy has shown promising potential as an emerging treatment for dry eye disease; however, it remains unclear which specific blood component is the most effective. This study aims to compare the efficacy of different blood components in the treatment of dry eye disease through a network meta-analysis, with the goal of providing the latest and most reliable evidence for clinical practice.<br><br>METHODS: We conducted a systematic search of the PubMed, Web of Science, Cochrane, Embase, and Scopus databases, with the search concluding on June 1, 2024. Two independent researchers performed literature screening, data extraction, and quality assessment.<br><br>RESULTS: A total of 16 randomized controlled trials (RCTs) involving 898 patients with dry eye disease were included. Six different blood components were utilized in treating dry eye disease, with platelet-rich plasma (PRP) being the most widely used. The results of the network meta-analysis indicated that platelet-rich plasma eye drops (PRPD) significantly outperformed artificial tears (AT) in improving the corneal fluorescein staining score (CFSS), while autologous serum (ALS) and umbilical cord serum (UCS) also demonstrated significantly better effects than AT in enhancing tear break-up time (TBUT). Additionally, ALS, PRP injection (PRPI), and PRPD showed significantly superior outcomes compared to AT in improving the ocular surface disease index (OSDI). However, no statistically significant differences were found among the various treatment modalities regarding their effects on Schirmer's I value, CFSS, TBUT, and OSDI. SUCRA analysis predicted that UCS was the most effective in improving Schirmer's I value and TBUT, while PRP excelled in enhancing CFSS and OSDI. Limitations such as publication bias and issues related to randomization, allocation concealment, and blinding may affect the reliability of the current findings.<br><br>CONCLUSION: Blood component therapy can significantly improve the pathological damage and ocular surface health in patients with dry eye disease. For those with aqueous-deficient dry eye, UCS may represent the optimal treatment option. In contrast, for patients with more severe corneal epithelial damage, PRP may offer a more effective therapeutic approach.<br><br>https://www.crd.york.ac.uk/PROSPERO/, CRD42024534091.}, }
@article {pmid39735276, year = {2024}, author = {Moyana, TN}, title = {Small cell lung carcinoma metastatic to the stomach: Commonly overlooked, limited treatment options.}, journal = {World journal of gastroenterology}, volume = {30}, number = {48}, pages = {5198-5204}, pmid = {39735276}, issn = {2219-2840}, mesh = {Humans ; *Small Cell Lung Carcinoma/therapy/secondary/pathology/diagnostic imaging ; *Stomach Neoplasms/pathology/therapy/diagnostic imaging ; *Lung Neoplasms/secondary/therapy/pathology/diagnostic imaging ; Prognosis ; Biomarkers, Tumor/analysis/metabolism ; Positron Emission Tomography Computed Tomography/methods ; Immune Checkpoint Inhibitors/therapeutic use ; Immunohistochemistry ; }, abstract = {Small cell lung carcinoma metastatic to the stomach, whether synchronous or metachronous, is a rare phenomenon accounting for < 0.5% of lung cancers. Hence it can be overlooked by clinicians resulting in delayed diagnosis. This manuscript comments on Yang et al's article which reported 3 such cases. The main diagnostic features are based on routine morphology comprised of small cells with hyperchromatic nuclei, scant cytoplasm, brisk mitoses and necrosis. This can be supplemented by immunohistochemistry demonstrating positivity for cytokeratin, thyroid transcription factor-1 and neuroendocrine markers as well as a high Ki-67 labelling index. Imaging modalities such as positron emission tomography/contrast computed tomography help to confirm lung origin and rule out the possibility of extra-pulmonary small cell carcinoma. The predominant mechanism of spread is most likely hematogeneous. Prognosis is generally poor since this represents stage 4 disease but survival can be improved by chemo/radiotherapy and palliative surgery in select cases. Though outcomes have not changed much in the last several decades, the recent Food and Drug Administration approval of immune checkpoint inhibitors was a significant milestone as was the delineation of small cell lung carcinoma molecular subtypes. Liquid biopsies are increasingly being used for biomarker studies in clinical trials to assess treatment response and prognosis.}, }
@article {pmid39728018, year = {2024}, author = {Jeyarajan, S and Ranjith, S and Veerapandian, R and Natarajaseenivasan, K and Chidambaram, P and Kumarasamy, A}, title = {Antibiofilm Activity of Epinecidin-1 and Its Variants Against Drug-Resistant Candida krusei and Candida tropicalis Isolates from Vaginal Candidiasis Patients.}, journal = {Infectious disease reports}, volume = {16}, number = {6}, pages = {1214-1229}, pmid = {39728018}, issn = {2036-7430}, support = {BT/PR2071/BBE/117/241/2016//Department of Biotechnology, India/ ; 311/RUSA(2.0)/2018//RUSA 2.0 Biological Sciences/ ; 01706/P6/2021//Tamil Nadu State Council for Higher Education (TANSCHE)/ ; ICMR-NET- 61754/2010//Indian Council of Medical Research/ ; }, abstract = {Background/Objective: Indwelling intrauterine contraceptive devices (IUDs) have surfaces that facilitate the attachment of Candida spp., creating a suitable environment for biofilm formation. Due to this, vulvovaginal candidiasis (VVC) is frequently linked to IUD usage, necessitating the prompt removal of these devices for effective treatment. In this study, we evaluated the susceptibility of antimicrobial peptides in vitro against biofilm forming, Amphotericin B (MIC50 > 2 mg L[-1]) resistant Candida krusei and Candida tropicalis isolated from IUD users who had signs of vaginal candidiasis (hemorrhage, pelvic pain, inflammation, itching, and vaginal discharge). Three antimicrobial peptides, namely, epinecidin-1 (epi-1) and its two variants, namely, variant-1 (Var-1) and variant-2 (Var-2), which were reported to have enhanced antibacterial activity were tested against IUD isolates (C. krusei and C. tropicalis) with pathogenic form of Candida albicans as control. Variants of epi-1, namely, Var-1 and Var-2 were created by substituting lysine in the place of histidine and alanine. Methods: The antimicrobial activity was measured using the microbroth dilution method to determine the minimum inhibitory concentration (MIC) of peptides against C. albicans, C. krusei and C. tropicalis. The MIC of each peptide was used for biofilm assay by Crystal violet staining, Scanning Electron Microscopy, and Reactive Oxygen Species (ROS) assay. To find the possible mechanism of anti-biofilm activity by the peptides, their ability to interact with Candida spp. cell membrane proteins such as Exo-β-(1,3)-Glucanase, Secreted Aspartic Proteinase (Sap) 1, and N-terminal Domain Adhesin: Als 9-2 were determined through PatchDock. Results: The MIC values of peptides: epi-1, var-1 and var-2 against C. albicans are 128 μg mL[-1], 64 μg mL[-1] and 32 μg mL[-1], C. tropicalis are 256 μg mL[-1], 64 μg mL[-1,] and 32 μg mL[-1] and C. krusei are 128 µg mL[-1], 128 µg mL[-1] and 64 µg mL[-1], respectively. Both the variants outperformed epi-1. Specifically for tested Candida spp., var-1 showed two- to four-fold enhancements and var-2 showed two- to eight-fold enhancements compared to epi-1. Electron microscopy confirmed that the mechanism of action involves pore formation thus inducing reactive oxygen species in Candida spp. cell membrane. Computational analysis showed that the peptides have a high tendency to interact with Candida spp. cell membrane proteins such as Exo-β-(1,3)-Glucanase, Secreted Aspartic Proteinase (Sap) 1, and N-terminal Domain Adhesin: Als 9-2, thereby preventing biofilm formation. Conclusions: The in vitro evidence supports the potential use of epi-1 and its variants to be used as an anti-biofilm agent to coat IUDs in the future for therapeutic purposes.}, }
@article {pmid39725771, year = {2024}, author = {Pagliari, E and Taiana, M and Manzini, P and Sali, L and Quetti, L and Bertolasi, L and Oldoni, S and Melzi, V and Comi, G and Corti, S and Nizzardo, M and Rizzo, F}, title = {Targeting STMN2 for neuroprotection and neuromuscular recovery in Spinal Muscular Atrophy: evidence from in vitro and in vivo SMA models.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {82}, number = {1}, pages = {29}, pmid = {39725771}, issn = {1420-9071}, support = {Craiplo Grant 2020-3623//Fondazione Cariplo/ ; 22739//SMA Europe Grant/ ; }, mesh = {Animals ; *Stathmin/metabolism/genetics ; *Muscular Atrophy, Spinal/therapy/genetics/pathology/metabolism ; Humans ; Mice ; *Disease Models, Animal ; *Motor Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism/cytology ; Neuromuscular Junction/metabolism/pathology ; Neuroprotection ; Dependovirus/genetics ; Genetic Therapy/methods ; }, abstract = {The development of ground-breaking Survival Motor Neuron (SMN) replacement strategies has revolutionized the field of Spinal Muscular Atrophy (SMA) research. However, the limitations of these therapies have now become evident, highlighting the need for the development of complementary targets beyond SMN replacement. To address these challenges, here we explored, in in vitro and in vivo disease models, Stathmin-2 (STMN2), a neuronal microtubule regulator implicated in neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), as a novel SMN-independent target for SMA therapy. Our findings revealed that STMN2 overexpression effectively restored axonal growth and outgrowth defects in induced pluripotent stem cell-(iPSC)-derived motor neurons (MNs) from SMA patients. Intracerebroventricular administration of adeno-associated virus serotype 9 (AAV9) carrying Stmn2 cDNA significantly ameliorated survival rates, motor functions, muscular and neuromuscular junction pathological features in SMA mice, mirrored by in vitro outcomes. Overall, this pioneering study not only provides insight into the therapeutic potential of STMN2 in SMA, but also suggests its broader applications for MN diseases, marking a substantial step forward in addressing the multifaceted challenges of neurological diseases treatment.}, }
@article {pmid39722495, year = {2024}, author = {García-Ramírez, Y and Cayuela-Fuentes, JM and Mira-Escolano, MP and Maceda-Roldán, LA and Mikulasova, E and Oliva-López, C and Sánchez-Escámez, A and Ciller-Montoya, P and Palomar-Rodríguez, JA}, title = {Characterization, epidemiology, and factors associated with evolution and survival in patients with amyotrophic lateral sclerosis in southeastern Spain, 2008-2021: a population-based study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/21678421.2024.2439454}, pmid = {39722495}, issn = {2167-9223}, abstract = {OBJECTIVE: To describe the epidemiology, characteristics, and factors associated with the evolution and survival in patients with amyotrophic lateral sclerosis (ALS) in a region of southeastern Spain.<br><br>METHODS: An observational study was carried out in people with a diagnosis of ALS in the period 2008-2021 who were registered in the Information System of Rare Diseases of the Region of Murcia (SIER). We calculated crude and standardized incidence rate (SIR) using European Standard Population of 2013 and point prevalence. The Kaplan-Meier method and the log-rank test were used to estimate and compare survival curves.<br><br>RESULTS: We identified 374 cases. The mean age at diagnosis was 66.5&#x2009;&#xb1;&#x2009;11.7 and 50.3% persons were spinal onset. Mean time from the onset of symptoms to diagnosis was 0.9&#x2009;&#xb1;&#x2009;1.0 years. The global SIR was 1.95/100,000 person-years (95%CI: 1.77-2.12), which was higher in men (ratio 1.34), and the point prevalence in 2021 was 4.57 per 100,000 (95% CI: 4.46-4.68). There were 297 deaths with a mean age of 69.8&#x2009;&#xb1;&#x2009;10.8. The median survival from clinical onset was 2 years (95%CI: 1.0-3.0). Factors associated with lower survival were bulbar onset (p&#x2009;<&#x2009;0.001), older age at the onset of symptoms (p&#x2009;<&#x2009;0.001), and the absence of riluzole treatment (p&#x2009;=&#x2009;0.003).<br><br>CONCLUSIONS: This study is one of few to evaluate the epidemiological, characteristics, and prognostic factors of ALS in Spain, with findings similar to previous population studies. The use of population-based registries offers reliable information on the magnitude, or evolution in these patients.}, }
@article {pmid39717968, year = {2024}, author = {Vergini, DE and Hadjipavlou-Litina, D}, title = {"A patent review on arachidonic acid lipoxygenase (LOX) inhibitors for the treatment of neurodegenerative diseases (2018-present)".}, journal = {Expert opinion on therapeutic patents}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/13543776.2024.2447067}, pmid = {39717968}, issn = {1744-7674}, abstract = {INTRODUCTION: Neuroinflammation is correlated to neurodegenerative diseases like Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Huntington Disease (HD), and Parkinson's disease (PD). A lot of recent research and patents are focused on the design and synthesis of arachidonic acid lipoxygenase (ALOX) inhibitors for the treatment of neurodegenerative diseases.<br><br>AREAS COVERED: The survey covers natural products, synthesis, hybrids, and assessments of biological effects in biological studies as ALOX inhibitors. A survey of patent publications from 2018 to present, taken from Google Scholar, Espanet, Web of Science, Drugbank, Scopus, or PubMed is analyzed.<br><br>EXPERT OPINION: The authors suggest that (i) numerous areas of biology-pharmacology need to be considered: selectivity, in vivo studies, toxicity, bioavailability, and drug-likeness, the mechanism of action in different animals and humans, evaluation of more efficient and selective biological tests; (ii) synthetic method outbalance in the discovery and production of ALOX inhibitors with greater selectivity. Several ALOX inhibitors show promising results for the treatment of neurological disorders. Their clinical evaluation will be critical to assess therapeutic utility. The compounds for which the mechanism of action and their bioavailability are well defined can be used as lead compounds for the treatment of neurodegenerative diseases.}, }
@article {pmid39715100, year = {2025}, author = {Wu, Y and Tian, X and Ma, J and Lin, Y and Ye, J and Wang, Y and Lu, J and Yin, W}, title = {Label-free discrimination analysis of breast cancer tumor and adjacent tissues of patients after neoadjuvant treatment using Raman spectroscopy: a diagnostic study.}, journal = {International journal of surgery (London, England)}, volume = {111}, number = {2}, pages = {1788-1800}, doi = {10.1097/JS9.0000000000002201}, pmid = {39715100}, issn = {1743-9159}, mesh = {Humans ; *Spectrum Analysis, Raman ; Female ; *Breast Neoplasms/therapy/pathology ; *Neoadjuvant Therapy ; Middle Aged ; Adult ; Aged ; Support Vector Machine ; Mastectomy, Segmental ; }, abstract = {BACKGROUND AND OBJECTIVE: Breast-conserving surgery (BCS) plays a crucial role in breast cancer treatment, with a primary focus on ensuring cancer-free surgical margins, particularly for patients undergoing neoadjuvant treatment. After neoadjuvant treatment, tumor regression can complicate the differentiation between breast cancer tumor and adjacent tissues. Raman spectroscopy, as a rapid and non-invasive optical technique, offers the advantage of providing detailed biochemical information and molecular signatures of internal molecular components in tissue samples. Despite its potential, there is currently no research on using label-free Raman spectroscopy to distinguish between breast cancer tumors and adjacent tissues after neoadjuvant treatment. This study intends to distinguish between tumor and adjacent tissues after neoadjuvant treatment in breast cancer through label-free Raman spectroscopy.<br><br>METHODS: In this study, the intraoperative frozen samples of breast cancer tumor and adjacent tissue were collected from patients who underwent neoadjuvant treatment during surgery. The samples were examined using Raman confocal microscopy, and Raman spectra were collected by LabSpec6 software. Spectra were preprocessed by Savitz-Golay filter, adaptive iterative reweighted penalized least squares and MinMax normalization method. The differences in Raman spectra between breast cancer tumor and adjacent tissues after neoadjuvant treatment were analyzed by Wilcoxon rank-sum test, with a Bonferroni correction for multiple comparisons. Based on the support vector machine (SVM) method in machine learning, a predictive model for classification was established in the total group and subgroups of different hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) status and Ki-67 expression level. The independent test set was used to evaluate the performance of the model, and the area under curve (AUC) of the receiver operating characteristic (ROC) curve, sensitivity, specificity and accuracy of different models were obtained.<br><br>RESULT: This study comprised 4260 Raman spectra of breast cancer tumor and adjacent frozen tissue samples from 142 breast cancer patients treated with neoadjuvant treatment. The Raman peaks associated with nucleotides and their metabolites in the Raman spectra of breast cancer tumor tissues were higher in intensities than those of adjacent tissues after neoadjuvant therapy (676 cm -1 : Bonferroni adjusted P <&#xa0;0.0001; 724 cm -1 : P <&#xa0;0.0001; 754 cm -1 : P <&#xa0;0.0001), and the Raman peaks from amide III bands were more intense (1271 cm -1 : P <&#xa0;0.01). Multivariate curve resolution-alternating least squares (MCR-ALS) decomposition of Raman spectra revealed reduced lipid content and increased collagen and nucleic acid content in breast cancer tumor tissues compared to adjacent tissues following neoadjuvant therapy. The predictive model based on the Raman spectral signature of breast cancer tumor and adjacent tissues after neoadjuvant treatment achieved an AUC of 0.98, with accuracy, sensitivity, and specificity values of 0.89, 0.97, and 0.83, respectively. The AUC of subgroup analysis according to different status of molecular pathological biomarkers was stably around 99%.<br><br>CONCLUSION: This study demonstrated that label-free Raman spectroscopy can differentiate tumor and adjacent tissues of breast cancer patients treated with neoadjuvant therapy thorough getting the panoramic perspective of the biochemical compounds for the first time. Our study provided a novel technique for determining the margin status in BCS in breast cancer following neoadjuvant treatment rapidly and precisely.}, }
@article {pmid39713159, year = {2024}, author = {Wang, YB and Jin, CZ}, title = {Roles of traditional Chinese medicine extracts in hyperuricemia and gout treatment: Mechanisms and clinical applications.}, journal = {World journal of gastroenterology}, volume = {30}, number = {47}, pages = {5076-5080}, pmid = {39713159}, issn = {2219-2840}, mesh = {*Hyperuricemia/drug therapy/blood ; Humans ; *Gout/drug therapy ; *Gastrointestinal Microbiome/drug effects ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Medicine, Chinese Traditional/methods ; *Uric Acid/blood/metabolism ; Gout Suppressants/therapeutic use ; Animals ; }, abstract = {In this manuscript, we comment on the article by Liu et al published in the recent issue of the journal. Hyperuricemia (HUA) has become the second most common metabolic disease after type 2 diabetes mellitus and is the most important risk factor for gout. This discussion focuses on the targets and clinical application value of traditional Chinese medicine (TCM) extracts in the treatment of HUA and gout, emphasizing the role of gut microbiota. Liu et al's study demonstrated that Poecilobdella manillensis protein extract alleviated HUA through multiple mechanisms, including inhibition of uric acid (UA) reabsorption, promotion of UA excretion, repair of intestinal barrier function, and regulation of gut microbiota and metabolome. Unlike the commonly used urate-lowering drugs such as allopurinol and febuxostat, which have clear and single targets, many TCMs have multi-target effects. However, the active components and mechanisms of TCMs are not fully understood, limiting their clinical application in the treatment of HUA and gout. Additionally, the role of gut microbiota in UA metabolic homeostasis needs to be further explored.}, }
@article {pmid39708835, year = {2024}, author = {Davalos, L and Kushlaf, H}, title = {Advances in Disease-Modifying Therapeutics for Chronic Neuromuscular Disorders.}, journal = {Seminars in respiratory and critical care medicine}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2463-3385}, pmid = {39708835}, issn = {1098-9048}, abstract = {Neuromuscular disorders can cause respiratory impairment by affecting the muscle fibers, neuromuscular junction, or innervation of respiratory muscles, leading to significant morbidity and mortality. Over the past few years, new disease-modifying therapies have been developed and made available for treating different neuromuscular disorders. Some of these therapies have remarkable effectiveness, resulting in the prevention and reduction of respiratory complications. For myasthenia gravis (MG), efgartigimod, ravulizumab, rozanolixizumab, and zilucoplan have been Food and Drug Administration (FDA)-approved for the treatment of acetylcholine receptor (AChR) antibody-positive generalized MG in the past 2 years. Rozanolixiumab is also approved for treating MG caused by muscle-specific tyrosine kinase (MuSK) antibodies. The new MG therapeutics target the complement system or block the neonatal fragment crystallizable (Fc) receptors (FcRn), leading to significant clinical improvement. For spinal muscular atrophy (SMA), nusinersen (intrathecal route) and risdiplam (oral route) modify the splicing of the SMN2 gene, increasing the production of normal survival motor neuron (SMN) protein. Onasemnogene abeparvovec is a gene replacement therapy that encodes a functional SMN protein. All SMA medications, particularly onasemnogene abeparvovec, have led to clinically meaningful improvement. For late-onset Pompe disease (LOPD), avalglucosidase alfa has shown a greater improvement in respiratory function, ambulation, and functional outcomes in comparison to alglucosidase alfa, and cipaglucosidase alfa combined with miglustat has shown improvement in respiratory and motor function in a cohort of enzyme replacement therapy-experienced LOPD patients. Amyotrophic lateral sclerosis (ALS) remains a challenge. The two most recent FDA-approved medications, namely sodium phenylbutyrate and tofersen, may slow down the disease by a few months in a selected population but do not stop the progression of the disease.}, }
@article {pmid39705668, year = {2024}, author = {Khandia, R and Gurjar, P and Priyanka,  and Romashchenko, V and Al-Hussain, SA and Zaki, MEA}, title = {Recent advances in stem cell therapy: efficacy, ethics, safety concerns, and future directions focusing on neurodegenerative disorders - a review.}, journal = {International journal of surgery (London, England)}, volume = {110}, number = {10}, pages = {6367-6381}, pmid = {39705668}, issn = {1743-9159}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation/methods ; }, abstract = {Neurodegeneration refers to the gradual loss of neurons and extensive changes in glial cells like tau inclusions in astrocytes and oligodendrocytes, α-synuclein inclusions in oligodendrocytes and SOD1 aggregates in astrocytes along with deterioration in the motor, cognition, learning, and behavior. Common neurodegenerative disorders are Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxia (SCA), and supranuclear palsy. There is a lack of effective treatment for neurodegenerative diseases, and scientists are putting their efforts into developing therapies against them. Stem cell therapy has emerged as a hope for neurodegenerative disorders since it is not only the damaged neurons that might be replaced, but other neuromodulators and neuroprotectors are secreted. Stem cell terminal differentiation before implantation ensures the implantation of correct cells and molecular markers like carbonic anhydrase II, CNPase (2',3'-cyclic nucleotide 3'-phosphohydrolase), myelin basic protein (MBP), and myelin oligodendrocyte glycoprotein (MOG) elucidate the differentiation. Secretion of various growth factors like epidermal growth factor (EGF), keratinocyte growth factor (KGF), vascular endothelial growth factor-α (VEGF-α), transforming growth factor (TGF), and macrophage inflammatory protein (MIP) supports cell survival, cell proliferation, blood vessel formation, axon regeneration, and neuroglial functional connection formation at the site of degeneration. Adverse effects of stem cell therapy, like teratogenicity and differentiation in different cells other than the desired one under the influence of microenvironment, are a few key concerns. Post-transplantation improved synaptic plasticity, apoptosis inhibition, and reduction in tau-phosphorylation and amyloid beta (Aβ) production has been observed in Alzheimer's patients. A large number of experimental, preclinical, and clinical studies have been conducted, and encouraging results have been obtained. The present review exhaustively discusses various kinds of stem cells, their usage in treating neurodegenerative disorders, limitations and challenges, and ethical issues related to stem cell therapy.}, }
@article {pmid39694549, year = {2024}, author = {Ma, YL and Qiu, T and Xu, XL and Wang, LX and Zhuang, PY}, title = {[Analysis of clinical characteristics of amyotrophic lateral sclerosis patients initially diagnosed with abnormal laryngeal function].}, journal = {Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery}, volume = {59}, number = {12}, pages = {1293-1298}, doi = {10.3760/cma.j.cn115330-20240630-00388}, pmid = {39694549}, issn = {1673-0860}, support = {82271155//National Natural Science Foundation of China/ ; 2020J011212//Fujian Provincial Natural Science Foundation/ ; }, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Adult ; Larynx/physiopathology ; }, abstract = {Objective: To study the laryngeal functional characteristics of patients with amyotrophic lateral sclerosis (ALS)disease diagnosed at the voice clinic. Methods: A retrospective analysis(case series study) was conducted on the laryngeal functional characteristics of 7 patients [2 males, 5 females, age ranged from 43 to 76(60.85±13.18)]with motor neuron disease who visited the voice clinic and were ultimately diagnosed by neurologists. The data included laryngostroboscopy, fiberoptic endoscopic examination of swallowing(FEES), acoustic analysis and laryngeal electromyography(LEMG). Descriptive methods were used for analysis. Results: ①There were 2 males and 5 females, with an average age of (60.85±13.18) years. They had previously visited the otolaryngology department more than twice, visit frequency with an average of 3.57 and an average diagnosis time of 12.28 months. The main complaints of the patient at the time of treatment were voice change, dysphagia or vocal fatigue. ②LEMG: Among 7 cases, 4 cases demonstrated neurogenic damage, all of which were bilateral, and 3 cases showed normal findings on examination. Spontaneous potentials (SP) were present in three cases for more than 6 months, with the longest duration being 24 months. Three cases exhibited the coexistence of spontaneous potential and reinnervated motor unit potentials (MUPs), and two cases showed bundle tremor potential.③Laryngostroboscopy revealed bilateral vocal fold asymmetry and glottic insufficiency in 7 cases, and decreased vocal cord movement in 4 cases, and vocal cord atrophy in 5 cases. FEES showed that 7 patients presented with mild to severe swallowing dysfunction, 3 cases had soft palate insufficiency and mild to severe food residues in the epiglottic valley and pyriform fossa. 1 case showed leakage and 1 case showed aspiration. Conclusions: Patients presenting with initial symptoms of abnormal laryngeal function should be vigilant for the possibility of motor neuron disease, especially when laryngostroboscopy reveals abnormal vocal fold movement and swallowing dysfunction. LEMG examination reveals bilateral neurogenic damage, prolonged spontaneous potential, coexistence of spontaneous potential and reinnervated MUPs, and the appearance of bundle tremor potential, which is beneficial for early detection of motor neuron disease.}, }
@article {pmid39686920, year = {2025}, author = {Sodagari, S and Sodagari, N}, title = {Examining vaccination-related adverse events in frequent neurodegenerative diseases.}, journal = {Brain, behavior, &amp; immunity - health}, volume = {43}, number = {}, pages = {100902}, pmid = {39686920}, issn = {2666-3546}, abstract = {This study investigates adverse events following vaccination in patients with four neurodegenerative diseases: Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, Multiple Sclerosis (MS), and Parkinson's disease. We applied advanced data processing techniques to analyze symptom patterns and severity scores across these disease groups. Patients were identified through filtering, and symptom clusters were extracted to group similar symptoms into distinct clusters, and severity scores were computed based on hospitalization and death reports. A chi-squared test was performed to assess the statistical significance of adverse event distributions among the diseases for different vaccines. The results reveal that ALS patients exhibit severe respiratory symptoms post-vaccination, while Alzheimer's patients report significant respiratory and gastrointestinal issues. MS patients commonly experience general symptoms such as fatigue, while Parkinson's patients face exacerbated motor symptoms. Notably, our analysis showed no significant difference in adverse event reporting rates between COVID-19 and pneumococcal vaccines across these disease groups. This research provides new insights into disease-specific responses to vaccines, emphasizing the importance of personalized monitoring and treatment strategies to mitigate risks and improve clinical outcomes in these vulnerable populations.}, }
@article {pmid39684324, year = {2024}, author = {Toader, C and Tataru, CP and Munteanu, O and Serban, M and Covache-Busuioc, RA and Ciurea, AV and Enyedi, M}, title = {Decoding Neurodegeneration: A Review of Molecular Mechanisms and Therapeutic Advances in Alzheimer's, Parkinson's, and ALS.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684324}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/therapy/metabolism/genetics ; *Parkinson Disease/therapy/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism ; Animals ; Neurodegenerative Diseases/therapy/metabolism/genetics ; Drug Delivery Systems ; Gene Editing ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS, and Huntington's, remain formidable challenges in medicine, with their relentless progression and limited therapeutic options. These diseases arise from a web of molecular disturbances-misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, and genetic mutations-that slowly dismantle neuronal integrity. Yet, recent scientific breakthroughs are opening new paths to intervene in these once-intractable conditions. This review synthesizes the latest insights into the underlying molecular dynamics of neurodegeneration, revealing how intertwined pathways drive the course of these diseases. With an eye on the most promising advances, we explore innovative therapies emerging from cutting-edge research: nanotechnology-based drug delivery systems capable of navigating the blood-brain barrier, gene-editing tools like CRISPR designed to correct harmful genetic variants, and stem cell strategies that not only replace lost neurons but foster neuroprotective environments. Pharmacogenomics is reshaping treatment personalization, enabling tailored therapies that align with individual genetic profiles, while molecular diagnostics and biomarkers are ushering in an era of early, precise disease detection. Furthermore, novel perspectives on the gut-brain axis are sparking interest as mounting evidence suggests that microbiome modulation may play a role in reducing neuroinflammatory responses linked to neurodegenerative progression. Taken together, these advances signal a shift toward a comprehensive, personalized approach that could transform neurodegenerative care. By integrating molecular insights and innovative therapeutic techniques, this review offers a forward-looking perspective on a future where treatments aim not just to manage symptoms but to fundamentally alter disease progression, presenting renewed hope for improved patient outcomes.}, }
@article {pmid39684197, year = {2024}, author = {García-González, N and Gonçalves-Sánchez, J and Gómez-Nieto, R and Gonçalves-Estella, JM and López, DE}, title = {Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684197}, issn = {1422-0067}, mesh = {Humans ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/therapy/genetics ; Animals ; Amyotrophic Lateral Sclerosis/therapy/genetics ; }, abstract = {This review explores recent advancements in gene therapy as a potential treatment for neurodegenerative diseases, focusing on intervention mechanisms, administration routes, and associated limitations. Following the PRISMA procedure guidelines, we systematically analyzed studies published since 2020 using the PICO framework to derive reliable conclusions. The efficacy of various gene therapies was evaluated for Parkinson's disease (n = 12), spinal muscular atrophy (n = 8), Huntington's disease (n = 3), Alzheimer's disease (n = 3), and amyotrophic lateral sclerosis (n = 6). For each condition, we assessed the therapeutic approach, curative or disease-modifying potential, delivery methods, advantages, drawbacks, and side effects. Results indicate that gene therapies targeting specific genes are particularly effective in monogenic disorders, with promising clinical outcomes expected in the near future. In contrast, in polygenic diseases, therapies primarily aim to promote cell survival. A major challenge remains: the translation of animal model success to human clinical application. Additionally, while intracerebral delivery methods enhance therapeutic efficacy, they are highly invasive. Despite these hurdles, gene therapy represents a promising frontier in the treatment of neurodegenerative diseases, underscoring the need for continued research to refine and personalize treatments for each condition.}, }
@article {pmid39681722, year = {2025}, author = {Weiner, HL}, title = {Immune mechanisms and shared immune targets in neurodegenerative diseases.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {2}, pages = {67-85}, pmid = {39681722}, issn = {1759-4766}, mesh = {Humans ; *Neurodegenerative Diseases/immunology/therapy ; Microglia/immunology ; Animals ; Immunotherapy/methods/trends ; Alzheimer Disease/immunology/therapy ; }, abstract = {The immune system plays a major part in neurodegenerative diseases. In some, such as multiple sclerosis, it is the primary driver of the disease. In others, such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, it has an amplifying role. Immunotherapeutic approaches that target the adaptive and innate immune systems are being explored for the treatment of almost all neurological diseases, and the targets and approaches are often common across diseases. Microglia are the primary immune cells in the brain that contribute to disease pathogenesis, and are consequently a common immune target for therapy. Other therapeutic approaches target components of the peripheral immune system, such as regulatory T cells and monocytes, which in turn act within the CNS. This Review considers in detail how microglia, monocytes and T cells contribute to the pathogenesis of multiple sclerosis, Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, and their potential as shared therapeutic targets across these diseases. The microbiome is also highlighted as an emerging therapeutic target that indirectly modulates the immune system. Therapeutic approaches being developed to target immune function in neurodegenerative diseases are discussed, highlighting how immune-based approaches developed to treat one disease could be applicable to multiple other neurological diseases.}, }
@article {pmid39678053, year = {2024}, author = {Finsterer, J and Mehri, S}, title = {The Causality Spectrum of Dropped Head Syndrome is Broad and Includes Myopathy, Neurodegenerative Disorders, and Varia.}, journal = {Noro psikiyatri arsivi}, volume = {61}, number = {4}, pages = {382-383}, pmid = {39678053}, issn = {1300-0667}, abstract = {Dropped head syndrome is a common complication of various neurological disorders. Most commonly, dropped head syndrome is due to primary or secondary myopathy. However, neurodegenerative diseases and various other conditions can also be complicated by dropped head syndrome. Among the primary myopathies, dropped head occurs most commonly in association with mitochondrial disorders, congenital myasthenic syndrome, and axial myopathies. Among the secondary myopathies, dropped occurs most commonly in association with inflammatory myopathies. Myasthenia is the most common transmission disorder associated with dropped head syndrome. The neurodegenerative disorder most commonly associated with dropped head syndrome is Parkinson syndrome. The diagnosis and treatment of dropped head syndrome from any cause requires a multidisciplinary approach. Outcome varies considerably but early diagnosis and early treatment are associated with a more favourable outcome.}, }
@article {pmid39674307, year = {2025}, author = {Pistolesi, A and Ranieri, G and Calvani, M and Guasti, D and Chiarugi, A and Buonvicino, D}, title = {Microglial suppression by myeloperoxidase inhibitor does not delay neurodegeneration in a mouse model of progressive multiple sclerosis.}, journal = {Experimental neurology}, volume = {385}, number = {}, pages = {115095}, doi = {10.1016/j.expneurol.2024.115095}, pmid = {39674307}, issn = {1090-2430}, mesh = {Animals ; *Microglia/drug effects/metabolism ; Mice ; *Peroxidase/metabolism ; *Multiple Sclerosis, Chronic Progressive/drug therapy ; *Disease Models, Animal ; Mice, Inbred NOD ; Female ; Enzyme Inhibitors/pharmacology/therapeutic use ; Piperidines/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; Nerve Degeneration/drug therapy/pathology ; Spinal Cord/drug effects/pathology/metabolism ; }, abstract = {Drugs able to efficiently counteract the progression of multiple sclerosis (MS) are still an unmet need. Numerous preclinical evidence indicates that reactive oxygen-generating enzyme myeloperoxidase (MPO), expressed by neutrophils and microglia, might play a key role in neurodegenerative disorders. Then, the MPO inhibition has been evaluated in clinical trials in Parkinson's and multiple system atrophy patients, and a clinical trial for the treatment of amyotrophic lateral sclerosis is underway. The effects of MPO inhibition on MS patients have not yet been explored. In the present study, by adopting the NOD mouse model of progressive MS (PMS), we evaluated the pharmacological effects of the MPO inhibitor verdiperstat (also known as AZD3241) on functional, immune, and mitochondrial parameters during disease evolution. We found that daily treatment with verdiperstat did not affect the pattern of progression as well as survival, despite its ability to reduce mitochondrial reactive oxygen species and microglia activation in the spinal cord of immunized mice. Remarkably, verdiperstat did not affect adaptive immunity, neutrophils invasion as well as mitochondrial derangement in the spinal cords of immunized mice. Data suggest that microglia suppression is not sufficient to prevent disease evolution, corroborating the hypothesis that immune-independent components drive neurodegeneration in progressive MS.}, }
@article {pmid39672208, year = {2025}, author = {Liu, Y and Wu, L and Peng, W and Mao, X}, title = {Glial polarization in neurological diseases: Molecular mechanisms and therapeutic opportunities.}, journal = {Ageing research reviews}, volume = {104}, number = {}, pages = {102638}, doi = {10.1016/j.arr.2024.102638}, pmid = {39672208}, issn = {1872-9649}, mesh = {Humans ; Animals ; *Nervous System Diseases/therapy ; *Neuroglia/metabolism/physiology ; Cell Polarity/physiology ; Astrocytes/metabolism/physiology ; }, abstract = {Glial cell polarization plays a pivotal role in various neurological disorders. In response to distinct stimuli, glial cells undergo polarization to either mitigate neurotoxicity or facilitate neural repair following injury, underscoring the importance of glial phenotypic polarization in modulating central nervous system function. This review presents an overview of glial cell polarization, focusing on astrocytes and microglia. It explores the involvement of glial polarization in neurological diseases such as Alzheimer's disease, Parkinson's disease, stroke, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis and meningoencephalitis. Specifically, it emphasizes the role of glial cell polarization in disease pathogenesis through mechanisms including neuroinflammation, neurodegeneration, calcium signaling dysregulation, synaptic dysfunction and immune response. Additionally, it summarizes various therapeutic strategies including pharmacological treatments, dietary supplements and cell-based therapies, aimed at modulating glial cell polarization to ameliorate brain dysfunction. Future research focused on the spatio-temporal manipulation of glial polarization holds promise for advancing precision diagnosis and treatment of neurological diseases.}, }
@article {pmid39670820, year = {2025}, author = {Lagiakos, HR and Zou, Y and Igawa, H and Therrien, E and Lawrenz, M and Kato, M and Svensson, M and Gray, F and Jensen, K and Dahlgren, MK and Pelletier, RD and Dingley, K and Bell, JA and Liu, Z and Jiang, Y and Zhou, H and Skene, RJ and Nie, Z}, title = {In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {3}, pages = {2720-2741}, doi = {10.1021/acs.jmedchem.4c02074}, pmid = {39670820}, issn = {1520-4804}, mesh = {Animals ; *Neurodegenerative Diseases/drug therapy ; Humans ; Mice ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use/chemical synthesis ; *Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis ; MAP Kinase Kinase Kinases/antagonists &amp; inhibitors/metabolism ; Neurons/drug effects/pathology/metabolism ; Drug Discovery ; Computer Simulation ; Structure-Activity Relationship ; Rats ; }, abstract = {Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge in silico tools. KAI-11101 displayed an excellent in vitro safety profile and showed neuroprotective properties in an ex vivo axon fragmentation assay as well as dose-dependent activity in a mouse PD model.}, }
@article {pmid39666202, year = {2024}, author = {van Eijk, RPA and van Loon, FT and van Unnik, JWJ and Weemering, DN and Seitidis, G and Mavridis, D and van den Berg, LH and Nikolakopoulos, S}, title = {Attrition and discontinuation in amyotrophic lateral sclerosis clinical trials: a meta-analysis.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {40}, pmid = {39666202}, issn = {1432-1459}, support = {EVIDENCE//Stichting ALS Nederland/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Randomized Controlled Trials as Topic ; Patient Dropouts/statistics &amp; numerical data ; }, abstract = {OBJECTIVES: Attrition due to adverse events and disease progression impacts the integrity and generalizability of clinical trials. The aim of this study is to provide evidence-based estimates of attrition for clinical trials in amyotrophic lateral sclerosis (ALS), and identify study-related predictors, through a comprehensive systematic review and meta-analysis.<br><br>METHODS: We systematically reviewed the literature to identify all randomized, placebo-controlled clinical trials in ALS and determined the number of patients who discontinued the study per randomized arm. Subsequently, we meta-analyzed attrition rates across studies, evaluated the difference between study arms, and explored the impact of study-level characteristics. Finally, a meta-regression model predicting study discontinuation for future clinical trials was translated into a web application.<br><br>RESULTS: In total, 60 randomized placebo-controlled clinical trials were included in the meta-analysis, randomizing 14,493 patients with ALS. Attrition varied significantly between studies, ranging from 3.1% to 75.7% of all randomized patients, with a pooled effect of 32.0% (90% prediction interval 6.1% to 66.3%). Attrition was similar between the intervention and placebo arm (odds ratio 1.08, 95% CI 0.89 to 1.31, p&#x2009;=&#x2009;0.43). The follow-up duration was identified as the sole study-level predictor (0.032, 95% CI 0.026 to 0.039, p&#x2009;<&#x2009;0.001), resulting in predicted attrition of 19.3% for 6-month, 36.4% for 12-month, and 55.6% for 18-month clinical trials.<br><br>CONCLUSIONS: ALS clinical trials encounter high attrition, which increases with the follow-up duration. These findings underscore the need to refine our strategies to manage attrition, preserving the integrity and generalizability of ALS clinical trials.}, }
@article {pmid39666071, year = {2024}, author = {de Boer, EMJ and de Vries, BS and Van Hecke, W and Mühlebner, A and Vincken, KL and Mol, CP and van Rheenen, W and Westeneng, HJ and Veldink, JH and Höglinger, GU and Morris, HR and Litvan, I and Raaphorst, J and Ticozzi, N and Corcia, P and Vandenberghe, W and Pijnenburg, YAL and Seelaar, H and Ingre, C and Van Damme, P and van den Berg, LH and van de Warrenburg, BPC and van Es, MA}, title = {Diagnosing primary lateral sclerosis: a clinico-pathological study.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {46}, pmid = {39666071}, issn = {1432-1459}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/diagnosis/pathology/genetics ; Autopsy ; Brain/pathology/diagnostic imaging ; Diagnosis, Differential ; *Motor Neuron Disease/diagnosis/pathology ; }, abstract = {BACKGROUND: Primary lateral sclerosis (PLS) is a rare motor neuron disease characterized by upper motor neuron degeneration, diagnosed clinically due to the absence of a (neuropathological) gold standard. Post-mortem studies, particularly TDP-43 pathology analysis, are limited.<br><br>METHODS: This study reports on 5 cases in which the diagnostic&#xa0;criteria for PLS were met, but in which neuropathology findings showed (partially) conflicting results. These discrepancies prompted us to perform a clinico-pathology study focussing on diagnostic challenges and accuracy in PLS. To this end, all cases were reviewed by an international panel of 11 experts using an e-module and structured questionnaires.<br><br>RESULTS: Autopsy exhibited neuropathological findings consistent with amyotrophic lateral sclerosis (ALS) in one case, while two cases exhibited similar, but more limited lower motor neuron involvement, hinting at PLS or ALS overlap. Another case displayed tau-pathology indicative of progressive supranuclear palsy. The final case displayed extensive myelin loss without a proteinopathy or a clear diagnosis. The expert panel identified 24 different ancillary investigations lacking across cases (e.g. genetic testing, DAT scans, neuropsychological evaluation), listed 28 differential diagnoses, and identified 13 different conditions as the most likely diagnosis. Autopsy results led panel members to change their final diagnosis in 42% of the cases.<br><br>CONCLUSIONS: This study underscores the diagnostic challenges posed by diverse underlying pathologies resulting in upper motor neuron phenotypes. Despite adhering to the same diagnostic criteria, consensus amongst experts was limited. Ensuring the diagnostic consistency is crucial for advancing understanding and treatment of PLS.&#xa0;Explicit guidelines for excluding potential mimics along with a neuropathological gold standard are imperative.}, }
@article {pmid39662855, year = {2025}, author = {Yang, ZF and Jiang, XC and Gao, JQ}, title = {Present insights into the progress in gene therapy delivery systems for central nervous system diseases.}, journal = {International journal of pharmaceutics}, volume = {669}, number = {}, pages = {125069}, doi = {10.1016/j.ijpharm.2024.125069}, pmid = {39662855}, issn = {1873-3476}, mesh = {Humans ; *Genetic Therapy/methods ; *Central Nervous System Diseases/therapy ; Animals ; *Gene Transfer Techniques ; *Genetic Vectors/administration &amp; dosage ; Dependovirus/genetics ; }, abstract = {Central nervous system (CNS) diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), spinal cord injury (SCI), and ischemic strokes and certain rare diseases, such as amyotrophic lateral sclerosis (ALS) and ataxia, present significant obstacles to treatment using conventional molecular pharmaceuticals. Gene therapy, with its ability to target previously "undruggable" proteins with high specificity and safety, is increasingly utilized in both preclinical and clinical research for CNS ailments. As our comprehension of the pathophysiology of these conditions deepens, gene therapy stands out as a versatile and promising strategy with the potential to both prevent and treat these diseases. Despite the remarkable progress in refining and enhancing the structural design of gene therapy agents, substantial obstacles persist in their effective and safe delivery within living systems. To surmount these obstacles, a diverse array of gene delivery systems has been devised and continuously improved. Notably, Adeno-Associated Virus (AAVs)-based viral gene vectors and lipid-based nanocarriers have each advanced the in vivo delivery of gene therapies to various extents. This review aims to concisely summarize the pathophysiological foundations of CNS diseases and to shed light on the latest advancements in gene delivery vector technologies. It discusses the primary categories of these vectors, their respective advantages and limitations, and their specialized uses in the context of gene therapy delivery.}, }
@article {pmid39662651, year = {2025}, author = {Keethedeth, N and Anantha Shenoi, R}, title = {Mitochondria-targeted nanotherapeutics: A new frontier in neurodegenerative disease treatment.}, journal = {Mitochondrion}, volume = {81}, number = {}, pages = {102000}, doi = {10.1016/j.mito.2024.102000}, pmid = {39662651}, issn = {1872-8278}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Mitochondria/drug effects/metabolism ; Drug Delivery Systems ; Nanoparticles/chemistry ; Animals ; }, abstract = {Mitochondria are the seat of cellular energy and play key roles in regulating several cellular processes such as oxidative phosphorylation, respiration, calcium homeostasis and apoptotic pathways. Mitochondrial dysfunction results in error in oxidative phosphorylation, redox imbalance, mitochondrial DNA mutations, and disturbances in mitochondrial dynamics, all of which can lead to several metabolic and degenerative diseases. A plethora of studies have provided evidence for the involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Hence mitochondria have been used as possible therapeutic targets in the regulation of neurodegenerative diseases. However, the double membranous structure of mitochondria poses an additional barrier to most drugs even if they are able to cross the plasma membrane. Most of the drugs acting on mitochondria also required very high doses to exhibit the desired mitochondrial accumulation and therapeutic effect which in-turn result in toxic effects. Mitochondrial targeting has been improved by direct conjugation of drugs to mitochondriotropic molecules like dequalinium (DQA) and triphenyl phosphonium (TPP) cations. But being cationic in nature, these molecules also exhibit toxicity at higher doses. In order to further improve the mitochondrial localization with minimal toxicity, TPP was conjugated with various nanomaterials like liposomes. inorganic nanoparticles, polymeric nanoparticles, micelles and dendrimers. This review provides an overview of the role of mitochondrial dysfunction in neurodegenerative diseases and various nanotherapeutic strategies for efficient targeting of mitochondria-acting drugs in these diseases.}, }
@article {pmid39659885, year = {2024}, author = {Wan, H and Qian, W and Wei, B and Tian, K and Chen, Z and Zhang, J and Chen, F}, title = {A bibliometric analysis of gene editing and amyotrophic lateral sclerosis (from 2004 to 2024).}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1499025}, pmid = {39659885}, issn = {1662-4548}, abstract = {OBJECTIVE: To learn more about gene editing and ALS, and to provide a comprehensive view of gene editing for further treatment of amyotrophic lateral sclerosis.<br><br>METHODS: We searched 1981 records from Web of Science core collection and Pubmed, Scopus, of which 1,292 records were obtained after exclusion. We then scientifically and metrologically analyzed these records for spatial and temporal distribution, author distribution, subject categories, subject distribution, references, and keywords using R, software CiteSpace and VOSviewer.<br><br>RESULTS: Our analysis provides basic information about research in the field, suggests that the field has stabilized over the past decade, and identifies potential partners for interested researchers. Current research in this area is focused on inflammatory mechanisms, immune mechanisms, related diseases, and associated cytokines in ALS.<br><br>CONCLUSION: RNA Editing, Antisense Bligonucleotide, and Glycine Receptor are cutting-edge research topics in this field, which is undergoing rapid development. We hope that this work will provide new ideas for advancing the scientific research and clinical application of ALS.}, }
@article {pmid39655696, year = {2025}, author = {Di Iacovo, A and D'Agostino, C and Bhatt, M and Romanazzi, T and Giovannardi, S and Cinquetti, R and Roseti, C and Bossi, E}, title = {The kinase LRRK2 is required for the physiological function and expression of the glial glutamate transporter EAAT2 (SLC1A2).}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16265}, pmid = {39655696}, issn = {1471-4159}, support = {860954//H2020 Marie Sk&#x142;odowska-Curie Actions/ ; }, mesh = {Animals ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics/metabolism/biosynthesis ; *Excitatory Amino Acid Transporter 2/metabolism/genetics/biosynthesis ; *Xenopus laevis ; Humans ; Oocytes/metabolism ; Female ; Neuroglia/metabolism ; }, abstract = {Neurotransmitter transporters (NTTs) control synaptic responses by modulating the concentration of neurotransmitters at the synaptic cleft. Glutamate is the most abundant excitatory neurotransmitter in the brain and needs to be finely tuned in time and space to maintain a healthy brain and precise neurotransmission. The glutamate transporter EAAT2 (SLC1A2) is primarily responsible for glutamate clearance. EAAT2 impairment has been associated with Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both monogenic and sporadic forms of PD, of which the common substitution Gly2019Ser is associated with a significant deficit in EAAT2 expression. The role of pathological mutants of the LRRK2 is intensively studied and reviewed. Here we have focused the attention on the physiological role of LRRK2 on EAAT2, comparing the activity of NTTs with or without the LRRK2 kinase. By heterologous expression in Xenopus laevis oocytes and two-electrode voltage clamp, the current amplitudes of the selected NTTs and kinetic parameters have been collected in the presence and absence of LRRK2. The results show that EAAT2 expression and function are impaired in the absence of the kinase and also under its pharmacological inhibition via MLi-2 treatment. LRRK2 stabilizes EAAT2 expression increasing the amount of transporter at the plasma membrane. Interestingly, the LRRK2 action is EAAT2-specific, as we observed no significant changes in the transport current amplitude and kinetic parameters obtained for the other excitatory and inhibitory NTTs studied. This study, for the first time, demonstrates the physiological importance of LRRK2 in EAAT2 function, highlighting the specificity of LRRK2-mediated modulation of EAAT2 and suggesting a potential role for the kinase as a checkpoint for preserving neurons from excitotoxicity. In brain conditions associated with impaired glutamate clearance, targeting LRRK2 for EAAT2 regulation may offer novel therapeutic opportunities.}, }
@article {pmid39655175, year = {2024}, author = {Palm, A and Ekström, M and Emilsson, &#xd6; and Ersson, K and Ljunggren, M and Sundh, J and Grote, L}, title = {Control of hypercapnia and mortality in home mechanical ventilation: the population-based DISCOVERY study.}, journal = {ERJ open research}, volume = {10}, number = {6}, pages = {}, pmid = {39655175}, issn = {2312-0541}, abstract = {BACKGROUND: Studies on the survival of patients with home mechanical ventilation (HMV) are sparse. We aimed to analyse the impact of controlled hypercapnia on survival over 27 years among patients with HMV in Sweden.<br><br>STUDY DESIGN AND METHODS: Population-based cohort study of adult patients starting HMV in the Swedish Registry for Respiratory Failure (Swedevox) during 1996-2022 cross-linked with the National Cause of Death registry. Mortality risk factors were analysed using crude and multivariable Cox regression models, including adjustments for anthropometrics, comorbidities, the underlying diagnosis causing chronic hypercapnic respiratory failure (CRF) and the control of hypercapnia (P aCO2 &#x2264;6.0&#x2005;kPa) at follow-up.<br><br>RESULTS: We included 10&#x2009;190 patients (50.1% women, age 62.9&#xb1;14.5&#x2005;years). Control of hypercapnia at follow-up after 1.3&#xb1;0.9&#x2005;years was associated with lower mortality, hazard ratio (HR) 0.74 (95% CI 0.68-0.80) and the association was strongest in those with pulmonary disease, restrictive thoracal disease (RTD), obesity hypoventilation syndrome (OHS) and amyotrophic lateral sclerosis (ALS). Predictors for increased mortality included age, Charlson Comorbidity Index, supplemental oxygen therapy and acute start of HMV therapy. Median survival varied between 0.8&#x2005;years (95% CI 0.8-0.9 (n=1401)) for ALS and 7.6&#x2005;years (95% CI 6.9-8.6 (n=1061)) for neuromuscular disease. Three-year survival decreased from 76% (95% CI 71-80) between 1996 and 1998 to 52% (95% CI 50-55) between 2017 and 2019. When adjusting for underlying diagnosis and age, the association between start year and decreased survival disappeared, HR 1.00 (95% CI 0.99-1.01).<br><br>CONCLUSION: Controlling P aCO2 is a key treatment goal for survival in HMV therapy. Survival differed markedly between diagnosis and age groups, and survival rates have declined as the patient group has aged.}, }
@article {pmid39654532, year = {2024}, author = {Dave, KD and Oskarsson, B and Yersak, J and Krauss, R and Heiman-Patterson, T and Lomen-Hoerth, C and Selig, WKD and Halpern Paul, I and Schaeffer, M and Garcia-Trujillo, B and Waldo, D and Thakur, N and Babu, S}, title = {Contributions of neurologists to diagnostic timelines of ALS and thinkALS as an early referral instrument for clinicians.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2432034}, pmid = {39654532}, issn = {2167-9223}, abstract = {Objectives: To evaluate neurologists and other clinicians' contributions to U.S. ALS diagnostic timelines. Background: Over the past two decades, the average time to ALS diagnosis in the U.S. has remained unchanged at 12 months. ALS patients see 3-4 clinicians prior to referral to an ALS specialist for diagnosis confirmation and/or treatment initiation. There is an urgent need to identify where delays occur, so that targeted clinician awareness may be raised about early suspicion and referrals. Methods: Review of Medicare claims database for health care utilization patterns by ALS beneficiaries during diagnostic journey. Survey of typical clinic wait times for new consultations reported by 75-78 ALS Certified Treatment Centers of Excellence (2019-2021). Results: During 2011-2021, 78,520 Medicare beneficiaries were diagnosed with ALS (T0). The mean (median) timelines between first neurologist ambulatory visit and T0, is 16.5 (11.0) months; mean ± SD for ALS/neuromuscular providers being 9.6 ± 12.6 months versus 16.7 ± 17.5 months for non-neuromuscular neurologists. During the 12-months preceding T0, an ALS patient undergoes median(max) 1.5(4.0) brain-MRIs, 1.6(6.0) spine-MRIs, and 1.3(4.0) electromyography studies. Greater than 75% of ALS centers consistently report ≤ 4 week wait times for new ALS consults. This study introduces "thinkALS," an easy-to-use clinical diagnostic and referral guide for non-ALS neurologists to tackle this challenge. Conclusions: This study is the first to provide metrics on how non-neuromuscular/ALS specialists contribute to ALS diagnostic timelines in the U.S.}, }
@article {pmid39645221, year = {2025}, author = {Bajpai, A and Bharathi, V and Patel, BK}, title = {Therapeutic targeting of the oxidative stress generated by pathological molecular pathways in the neurodegenerative diseases, ALS and Huntington's.}, journal = {European journal of pharmacology}, volume = {987}, number = {}, pages = {177187}, doi = {10.1016/j.ejphar.2024.177187}, pmid = {39645221}, issn = {1879-0712}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics ; *Antioxidants/pharmacology/therapeutic use ; *Huntington Disease/metabolism/drug therapy/pathology/genetics ; Molecular Targeted Therapy/methods ; Neurodegenerative Diseases/metabolism/drug therapy/pathology ; *Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative disorders are characterized by a progressive decline of specific neuronal populations in the brain and spinal cord, typically containing aggregates of one or more proteins. They can result in behavioral alterations, memory loss and a decline in cognitive and motor abilities. Various pathways and mechanisms have been outlined for the potential treatment of these diseases, where redox regulation is considered as one of the most common druggable targets. For example, in amyotrophic lateral sclerosis (ALS) with superoxide dismutase-1 (SOD1) pathology, there is a downregulation of the antioxidant response nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. TDP-43 proteinopathy in ALS is associated with elevated levels of reactive oxygen species and mitochondrial dyshomeostasis. In ALS with mutant FUS, poly ADP ribose polymerase-dependent X ray repair cross complementing 1/DNA-ligase recruitment to the sites of oxidative DNA damage is affected, thereby causing defects in DNA damage repair. Oxidative stress in Huntington's disease (HD) with mutant huntingtin accumulation manifests as protein oxidation, metabolic energetics dysfunction, metal ion dyshomeostasis, DNA damage and mitochondrial dysfunction. The impact of oxidative stress in the progression of these diseases further warrants studies into the role of antioxidants in their treatment. While an antioxidant, edaravone, has been approved for therapeutics of ALS, numerous antioxidant molecules failed to pass the clinical trials despite promising initial studies. In this review, we summarize the oxidative stress pathways and redox modulators that are investigated in ALS and HD using various models.}, }
@article {pmid39645085, year = {2025}, author = {Ediriweera, GR and Sivaram, AJ and Cowin, G and Brown, ML and McAlary, L and Lum, JS and Fletcher, NL and Robinson, L and Simpson, JD and Chen, L and Wasielewska, JM and Byrne, E and Finnie, JW and Manavis, J and White, AR and Yerbury, JJ and Thurecht, KJ and Vine, KL}, title = {Lipid nanoparticles and transcranial focused ultrasound enhance the delivery of SOD1 antisense oligonucleotides to the murine brain for ALS therapy.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {378}, number = {}, pages = {221-235}, doi = {10.1016/j.jconrel.2024.11.074}, pmid = {39645085}, issn = {1873-4995}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy ; *Oligonucleotides, Antisense/administration &amp; dosage ; *Superoxide Dismutase-1/genetics ; *Brain/metabolism ; *Mice, Inbred C57BL ; *Nanoparticles/administration &amp; dosage/chemistry ; *Mice, Transgenic ; Blood-Brain Barrier/metabolism ; Lipids/chemistry/administration &amp; dosage ; Male ; Motor Neurons/metabolism ; Mice ; Microbubbles ; Liposomes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with extremely limited therapeutic options. One key pathological feature of ALS is the abnormal accumulation of misfolded proteins within motor neurons. Hence, reducing the burden of misfolded protein has emerged as a promising therapeutic approach. Antisense oligonucleotides (ASOs) have the potential to effectively silence proteins with gain-of-function mutations, such as superoxide dismutase 1 (SOD1). However, ASO delivery to the central nervous system (CNS) is hindered by poor blood-brain barrier (BBB) penetration and the invasiveness of intrathecal administration. In the current study, we demonstrate effective systemic delivery of a next-generation SOD1 ASO (Tofersen) into the brain of wildtype and G93A-SOD1 transgenic C57BL/6 mice using calcium phosphate lipid nanoparticles (CaP lipid NPs). We show that transcranial focused ultrasound (FUS) with intravenously administered microbubbles can significantly enhance ASO-loaded nanoparticle delivery into the mouse brain. Magnetic resonance imaging (MRI) and immunohistological analysis showed reduced SOD1 expression in the FUS-exposed brain regions and increased motor neuron count in the spinal cord of treated mice suggesting decreased motor neuron degeneration. Importantly, the BBB opening was transient without evidence of structural changes, neuroinflammation or damage to the brain tissue, indicating that the treatment is well tolerated. Overall, our results highlight FUS-assisted nanoparticle delivery of ASOs as a promising non-invasive therapeutic strategy for the treatment of ALS and CNS diseases more broadly.}, }
@article {pmid39645043, year = {2025}, author = {Needle, C and Brinks, A and Shapiro, J and Lo Sicco, K}, title = {Response to Chen et al's "Emergence of Janus kinase inhibitors led to increase in proportion of severe alopecia areata patients receiving treatment: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {4}, pages = {e119-e120}, doi = {10.1016/j.jaad.2024.10.118}, pmid = {39645043}, issn = {1097-6787}, }
@article {pmid39640633, year = {2024}, author = {Nikafshan Rad, H and Su, Z and Trinh, A and Hakim Newton, MA and Shamsani, J and Nygc Als Consortium,  and Karim, A and Sattar, A}, title = {Amyotrophic lateral sclerosis diagnosis using machine learning and multi-omic data integration.}, journal = {Heliyon}, volume = {10}, number = {20}, pages = {e38583}, pmid = {39640633}, issn = {2405-8440}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex and rare neurodegenerative disorder characterized by significant genetic, molecular, and clinical heterogeneity. Despite numerous endeavors to discover the genetic factors underlying ALS, a significant number of these factors remain unknown. This knowledge gap highlights the necessity for personalized medicine approaches that can provide more comprehensive information for the purposes of diagnosis, prognosis, and treatment of ALS. This work utilizes an innovative approach by employing a machine learning-facilitated, multi-omic model to develop a more comprehensive knowledge of ALS. Through unsupervised clustering on gene expression profiles, 9,847 genes associated with ALS pathways are isolated and integrated with 7,699 genes containing rare, presumed pathogenic genomic variants, leading to a comprehensive amalgamation of 17,546 genes. Subsequently, a Variational Autoencoder is applied to distil complex biomedical information from these genes, culminating in the creation of the proposed Multi-Omics for ALS (MOALS) model, which has been designed to expose intricate genotype-phenotype interconnections within the dataset. Our meticulous investigation elucidates several pivotal ALS signaling pathways and demonstrates that MOALS is a superior model, outclassing other machine learning models based on single omic approaches such as SNV and RNA expression, enhancing accuracy by 1.7 percent and 6.2 percent, respectively. The findings of this study suggest that analyzing the relationships within biological systems can provide heuristic insights into the biological mechanisms that help to make highly accurate ALS diagnosis tools and achieve more interpretable results.}, }
@article {pmid39637982, year = {2024}, author = {Vallée, S and Deneux, V and Funaro, D and Marcoux, D and Powell, J and Hatami, A and Coulombe, J and Piram, M and McCuaig, CC}, title = {Long-term evolution of prepubertal-onset anogenital lichen sclerosus: A 35-year retrospective and cross-sectional study from a single tertiary care maternal and pediatric center.}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.09.086}, pmid = {39637982}, issn = {1097-6787}, abstract = {BACKGROUND: Anogenital lichen sclerosus (ALS) in children may persist after puberty with potential clinical repercussions.<br><br>OBJECTIVE: The purpose of this study was to evaluate postpubertal evolution of girls with ALS diagnosed in the prepubertal period based on physical examination, the persistence of functional symptoms, and the effect on quality of life.<br><br>METHODS: We retrospectively reviewed 65 cases of girls with prepubertal-onset ALS. Onset, signs/symptoms, photos, evolution, and treatment were collected from the medical records. Subsequently, 30 of these 65 patients were assessed for persistence of signs/symptoms by physical examination and/or standardized questionnaire.<br><br>RESULTS: Signs of active disease after puberty based on physical examination were present in 92% (N&#xa0;=&#xa0;23) of examined patients. A high proportion of cases with persistent ALS after puberty were asymptomatic (47%, N&#xa0;=&#xa0;14).<br><br>LIMITATIONS: This is a single-center retrospective study with a limited number of patients. Half of our original cohort could not be reached or declined a follow-up visit.<br><br>CONCLUSION: Prepubertal lichen sclerosus is a chronic condition that can be asymptomatic after puberty despite continued disease activity. We recommend long-term follow-up of patients with prepubertal ALS to prevent associated morbidity.}, }
@article {pmid39635310, year = {2024}, author = {Yuan, J and Zhang, YJ and Wen, W and Liu, XC and Chen, FL and Yang, Y}, title = {Afferent loop syndrome of a patient with recurrent fever: A case report.}, journal = {World journal of radiology}, volume = {16}, number = {11}, pages = {678-682}, pmid = {39635310}, issn = {1949-8470}, abstract = {BACKGROUND: Afferent loop syndrome (ALS) is a rare complication, Aoki et al reported that the incidence of distal gastrectomy in Billroth-II is 0.3%-1.0%. The clinical manifestations of ALS are atypical, which can manifest as severe abdominal pain, vomiting, obstructive jaundice, malnutrition, etc.<br><br>CASE SUMMARY: The patient was a 58-year-old man who complained of recurrent high fever for more than 1 week. Laboratory tests showed an increase in neutrophil ratio, procalcitonin, C-reactive protein, and abnormal liver function. Enhanced computed tomography scan of the abdomen showed small intestinal obstruction between the anastomosis of the gastrojejunum, bile duct, and pancreaticoduodenum. Gastroscopy revealed significant narrowing of the lumen 15 cm from the anastomosis into the afferent loop. After performing balloon dilation and placement of the nutrition tube, the patient did not experience further fever.<br><br>CONCLUSION: ALS is relatively rare after pancreaticoduodenectomy, and the treatment depends on the nature of the obstructive lesion. The traditional treatment method is surgery, and in recent years, endoscopy has provided a new treatment method for ALS.}, }
@article {pmid39634573, year = {2024}, author = {Braimah, RO and Taiwo, AO and Olasoji, HO and Legbo, JN and Amundson, M and Ibikunle, AA and Suleiman, IK and Bala, M and Ile-Ogedengbe, BO}, title = {Braimah-Taiwo et al New Classification System and Treatment Algorithm of Mandibulo-Maxillary Synostosis Related to Noma. Field Experience From Noma Children Hospital Sokoto, Nigeria.}, journal = {Craniomaxillofacial trauma &amp; reconstruction}, volume = {17}, number = {4}, pages = {279-290}, pmid = {39634573}, issn = {1943-3875}, abstract = {STUDY DESIGN: This was a retrospective study at Noma Children Hospital, Sokoto, Nigeria, from January 2018 to December 2021.<br><br>OBJECTIVE: The main objective of this appraisal was to present Braimah-Taiwo et al's new classification system for mandibulo-maxillary synostosis secondary to noma and also to provide a guide to their treatment.<br><br>METHODS: Noma with mandibulo-maxillary synostosis was the main inclusion criteria. Excluded were cases of acute noma and noma without mandibulo-maxillary synostosis. Data retrieved include demographics of patients and extent of bony ankylosis and mandibulo-maxillary synostosis.<br><br>RESULTS: A total of 64 patients (30 (46.9%) males and 34 (53.1%) females) were managed. Ages ranged from 6 to 40 years with mean &#xb1; SD (18.2 &#xb1; 7.6) years. Regarding the new classification system of mandibulo-maxillary synostosis, 6 (9.4%) patients presented with Type 1 (Mild joint obliteration)&#xb1;Soft tissue scarring, 24 (37.5%) presented with Type II (Total joint obliteration)&#xb1;Soft tissue scarring, 21 (32.8%) presented with Type III (Coronoid, zygoma and maxilla) &#xb1;Soft tissue scarring, 4 (6.3%) presented with Type IV (Condyle, glenoid fossa, coronoid, sigmoid notch and zygoma) &#xb1;Soft tissue scarring, 7 (10.9%) presented with Type V (Condyle, glenoid fossa, coronoid, sigmoid notch, zygoma and pterygo-maxilla) &#xb1;Soft tissue scarring, while 2 (3.1%) patients presented with Type VI (condyle, glenoid fossa, coronoid, sigmoid notch, zygoma, pterygo-maxilla and the orbit) &#xb1;Soft tissue scarring.<br><br>CONCLUSIONS: Pattern of tissue destruction in noma patients is complex involving both soft and hard tissues. This new classification will guide surgeons in the effective management of these patients.}, }
@article {pmid39633896, year = {2024}, author = {Bhaskaran, S and Piekarz, KM and Brown, J and Yang, B and Ocañas, SR and Wren, JD and Georgescu, C and Bottoms, C and Murphy, A and Thomason, J and Saunders, D and Smith, N and Towner, R and Van Remmen, H}, title = {The nitrone compound OKN-007 delays motor neuron loss and disease progression in the G93A mouse model of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1505369}, pmid = {39633896}, issn = {1662-4548}, abstract = {Our study investigated the therapeutic potential of OKN-007 in the SOD1 G93A mouse model of amyotrophic lateral sclerosis (ALS). The impact of OKN-007, known for its antioxidant, anti-inflammatory, and neuroprotective properties, was tested at two doses (150 mg/kg and 300 mg/kg) at onset and late-stage disease. Results demonstrated a significant delay in disease progression at both doses, with treated mice showing a slower advance to early disease stages compared to untreated controls. Motor neuron counts in the lumbar spinal cord were notably higher in OKN-007 treated mice at the time of disease onset, suggesting neuroprotection. Additionally, OKN-007 reduced microglial activation and preserved reduced neuromuscular junction fragmentation, although it did not significantly alter the increase in astrocyte number or the decline in hindlimb muscle mass. MR spectroscopy (MRS) revealed improved spinal cord perfusion and normalized myo-inositol levels in treated mice, supporting reduced neuroinflammation. While the expression of several proteins associated with inflammation is increased in spinal cord extracts from G93A mice, OKN-007 dampened the expression of IL-1β, IL-1ra and IL-1α. Despite its promising effects on early-stage disease progression, in general, the beneficial effects of OKN-007 diminished over longer treatment durations. Further, we found no improvement in muscle atrophy or weakness phenotypes in OKN-007 treated G93A mice, and no effect on mitochondrial function or lifespan. Overall, our findings suggest that OKN-007 holds potential as a disease-modifying treatment for ALS, although further research is needed to optimize dosing regimens and understand its long-term effects.}, }
@article {pmid39633494, year = {2024}, author = {Ko, VI and Ong, K and Kwon, DY and Li, X and Pietrasiewicz, A and Harvey, JS and Lulla, M and Bhat, G and Cleveland, DW and Ravits, JM}, title = {CK1δ/ε-mediated TDP-43 phosphorylation contributes to early motor neuron disease toxicity in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {187}, pmid = {39633494}, issn = {2051-5960}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Phosphorylation ; *DNA-Binding Proteins/metabolism/genetics ; *Casein Kinase Idelta/metabolism/genetics ; *Casein Kinase 1 epsilon/metabolism/genetics ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Humans ; Motor Neurons/metabolism/pathology/drug effects ; Mice, Inbred C57BL ; Male ; Mice, Knockout ; }, abstract = {Hyperphosphorylated TDP-43 aggregates in the cytoplasm of motor neurons is a neuropathological signature of amyotrophic lateral sclerosis (ALS). These aggregates have been proposed to possess a toxic disease driving role in ALS pathogenesis and progression, however, the contribution of phosphorylation to TDP-43 aggregation and ALS disease mechanisms remains poorly understood. We've previously shown that CK1δ and CK1ε phosphorylate TDP-43 at disease relevant sites, and that genetic reduction and chemical inhibition could reduce phosphorylated TDP-43 (pTDP-43) levels in cellular models. In this study, we advanced our findings into the hTDP-43-ΔNLS in vivo mouse model of ALS and TDP-43 proteinopathy. This mouse model possesses robust disease-relevant features of ALS, including TDP-43 nuclear depletion, cytoplasmic pTDP-43 accumulation, motor behavior deficits, and shortened survival. We tested the effect of homozygous genetic deletion of Csnk1e in the hTDP-43-ΔNLS mouse model and observed a delay in the formation of pTDP-43 without significant ultimate rescue of TDP-43 proteinopathy or disease progression. Homozygous genetic deletion of Csnk1d is lethal in mice, and we were unable to test the role of CK1δ alone. We then targeted both CK1δ and CK1ε kinases by way of CK1δ/ε-selective PF-05236216 inhibitor in the hTDP-43-ΔNLS mouse model, reasoning that inhibiting CK1ε alone would be insufficient as shown by our Csnk1e knockout mouse model study. Treated mice demonstrated reduced TDP-43 phosphorylation, lowered Nf-L levels, and improved survival in the intermediate stages. The soluble TDP-43 may have been more amenable to the inhibitor treatment than insoluble TDP-43. However, the treatments did not result in improved functional measurements or in overall survival. Our results demonstrate that phosphorylation contributes to neuronal toxicity and suggest CK1δ/ε inhibition in combination with other therapies targeting TDP-43 pathology could potentially provide therapeutic benefit in ALS.}, }
@article {pmid39631325, year = {2024}, author = {Zhang, Y and Liu, Q and Xie, H and Zhang, W and Lin, X and Zhang, H and Yu, H and Ma, Y and Zhang, C and Geng, H and Shi, N and Cui, L and Li, B and Li, YF}, title = {Fecal microbiota transplantation as an effective way in treating methylmercury-poisoned rats.}, journal = {The Science of the total environment}, volume = {957}, number = {}, pages = {177850}, doi = {10.1016/j.scitotenv.2024.177850}, pmid = {39631325}, issn = {1879-1026}, mesh = {Animals ; *Methylmercury Compounds/metabolism ; *Fecal Microbiota Transplantation ; Rats ; *Gastrointestinal Microbiome ; Male ; Feces/microbiology ; }, abstract = {Methylmercury (MeHg) can cause devastating neurotoxicity in animals and human beings. Gut microbiota dysbiosis has been found in MeHg-poisoned animals. Fecal microbiota transplantation (FMT) has been shown to improve clinical outcomes in a variety of diseases such as epilepsy, amyotrophic lateral sclerosis (ALS) and autism. The aim of this study was to investigate the effects of FMT on MeHg-poisoned rats. FMT treatment was applied to MeHg-poisoned rats for 14 days. The neurobehavior, weight changes, dopamine (DA), the total Hg and MeHg level were evaluated. Besides, the gut microbiota and metabolites change in feces were also checked. It was found that FMT helped weight gain, alleviated the neurological disorders, enhanced fecal mercury excretion and MeHg demethylation, reconstructed gut microbiome and promoted the production of gut-brain axis related-metabolites in MeHg-poisoned rats. This study elaborates on the therapeutic efficacy of FMT in treating of MeHg-poisoned rats, which sheds lights on the treatment of neurological diseases like Minamata Disease and even Parkinson's Disease.}, }
@article {pmid39629626, year = {2025}, author = {Boutin, RCT and Shobeirian, F and Adam, S and Lehman, A and Salvarinova, R and Friedman, JM}, title = {Immune Dysregulation in a Child With SOD1-Related Neurological Disease.}, journal = {American journal of medical genetics. Part A}, volume = {197}, number = {4}, pages = {e63949}, doi = {10.1002/ajmg.a.63949}, pmid = {39629626}, issn = {1552-4833}, support = {//Mining for Miracles (BCCH Foundation)/ ; //Genome British Columbia/ ; }, mesh = {Humans ; Male ; *Superoxide Dismutase-1/genetics ; *Homozygote ; Young Adult ; Child ; Nervous System Diseases/genetics/pathology ; Phenotype ; Mutation/genetics ; Quadriplegia/genetics/pathology ; }, abstract = {Spastic tetraplegia and axial hypotonia (STAHP) associated with biallelic SOD1 deficiency is a recently described neurological disorder affecting children. Five studies have described a total of nine cases thus far, all characterized by the onset of progressive spastic tetraplegia beginning before 2 years of age. All but two of these cases are associated with homozygosity for the same genetic variant (NM_000454.4:c.335dupG; NP_000445.1:p.Cys112Trpfs*11) that leads to a non-functional enzyme product. More recently, a homozygous 3-base pair in-frame deletion (NM_000454.5: c.357_357+2delGGT) and a truncating frameshift variant (NM_000454.5: c.52_56del5ins154) in SOD1 have been described in similarly affected patients lacking SOD1 activity. Here we expand on the neurological and extra-neuronal phenotypes of STAHP in a patient with a novel homozygous SOD1 variant predicted to result in disrupted calcium- and zinc-binding activity of the encoded enzyme. We describe a 19-year-old male born to consanguineous parents who is homozygous for an NM_000454.4:c.369_371del SOD1 variant. The patient had progressive neuromuscular degeneration with onset before 1 year of age, consistent with a diagnosis of STAHP. Brain MRI at 7 years of age showed cerebellar atrophy, as has previously been described in this condition, as well as small optic nerves and a hypoplastic optic chiasm, which have not been reported previously. Our patient also exhibited clinical features of immune dysregulation with treatment-refractory inflammatory bowel disease, asthma, recurrent infections, and dermatitis. Overall, the early-onset progressive neurological disorder in our patient, found in association with homozygosity for an SOD1 variant that is predicted to result in impaired function of the transcribed protein, is consistent with a diagnosis of STAHP. Our patient also demonstrates optic atrophy and disrupted immune homeostasis, which have not been previously described as part of this condition. Taken together with previous case studies in children carrying loss-of-function variants of SOD1, this case highlights a possible role for antioxidant therapy in slowing disease progression in patients lacking SOD1 activity. These cases also draw attention to the need for careful consideration of possible harmful neuronal and extra-neuronal complications of proposed SOD1 knockdown therapies against ALS.}, }
@article {pmid39628659, year = {2024}, author = {Ye, Q and Li, X and Gao, W and Gao, J and Zheng, L and Zhang, M and Yang, F and Li, H}, title = {Role of Rho-associated kinases and their inhibitor fasudil in neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1481983}, pmid = {39628659}, issn = {1662-4548}, abstract = {Neurodegenerative diseases (NDDs) are prevalent in the elderly. The pathogenesis of NDDs is complex, and currently, there is no cure available. With the increase in aging population, over 20 million people are affected by common NDDs alone (Alzheimer's disease and Parkinson's disease). Therefore, NDDs have profound negative impacts on patients, their families, and society, making them a major global health concern. Rho-associated kinases (ROCKs) belong to the serine/threonine protein kinases family, which modulate diverse cellular processes (e.g., apoptosis). ROCKs may elevate the risk of various NDDs (including Huntington's disease, Parkinson's disease, and Alzheimer's disease) by disrupting synaptic plasticity and promoting inflammatory responses. Therefore, ROCK inhibitors have been regarded as ideal therapies for NDDs in recent years. Fasudil, one of the classic ROCK inhibitor, is a potential drug for treating NDDs, as it repairs nerve damage and promotes axonal regeneration. Thus, the current review summarizes the relationship between ROCKs and NDDs and the mechanism by which fasudil inhibits ROCKs to provide new ideas for the treatment of NDDs.}, }
@article {pmid39627617, year = {2024}, author = {Wiersema, AF and Rennenberg, A and Smith, G and Varderidou-Minasian, S and Pasterkamp, RJ}, title = {Shared and distinct changes in the molecular cargo of extracellular vesicles in different neurodegenerative diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {479}, pmid = {39627617}, issn = {1420-9071}, support = {XS grant//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; GoALS//Stichting ALS Nederland/ ; TOTALS//Stichting ALS Nederland/ ; MUSALS//Stichting ALS Nederland/ ; ATAXALS//Stichting ALS Nederland/ ; MAXOMOD//E-rare3/ ; INTEGRALS//Rare-3/ ; TRIAGE//JPND/ ; }, mesh = {Animals ; Humans ; Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Biomarkers/analysis/metabolism ; *Cell Communication ; *Extracellular Vesicles/metabolism ; MicroRNAs/metabolism/genetics ; *Neurodegenerative Diseases/diagnosis/metabolism/pathology ; Parkinson Disease/metabolism/pathology ; tau Proteins/metabolism ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) affect millions of people worldwide. Curative treatment for these neurodegenerative disorders is still lacking and therefore a further understanding of their cause and progression is urgently needed. Extracellular vesicles (EVs) are nanosized vesicles loaded with cargo, such as proteins and miRNAs, that are released by cells and play an important role in intercellular communication. Intercellular communication through EVs can contribute to the spread of pathological proteins, such as amyloid-beta and tau, or cause pathogenesis through other mechanisms. In addition, EVs may serve as potential biomarkers for diagnosis and for monitoring disease progression. In this review, we summarize and discuss recent advances in our understanding of the role of EVs in AD, ALS an PD with an emphasis on dysregulated cargo in each disease. We highlight shared dysregulated cargo between these diseases, discuss underlying pathways, and outline future implications for therapeutic strategies.}, }
@article {pmid39624969, year = {2024}, author = {Yuan, D and Jiang, S and Xu, R}, title = {Clinical features and progress in diagnosis and treatment of amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2399962}, pmid = {39624969}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy/epidemiology/genetics ; Humans ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the central nervous system. Despite a large number of studies, the current prognosis of ALS is still not ideal. This article briefly describes the clinical features including epidemiology, genetic structure and clinical manifestations, as well as the progress of new diagnostic criteria and treatment of ALS. Meanwhile, we also discussed further both developments and improvements to enhance understanding and accelerating the introduction of the effective treatments of ALS.}, }
@article {pmid39623504, year = {2024}, author = {Gupta, R and Bhandari, M and Grover, A and Al-Shehari, T and Kadrie, M and Alfakih, T and Alsalman, H}, title = {Predictive modeling of ALS progression: an XGBoost approach using clinical features.}, journal = {BioData mining}, volume = {17}, number = {1}, pages = {54}, pmid = {39623504}, issn = {1756-0381}, support = {RSP2024R244//King Saud University/ ; }, abstract = {This research presents a predictive model aimed at estimating the progression of Amyotrophic Lateral Sclerosis (ALS) based on clinical features collected from a dataset of 50 patients. Important features included evaluations of speech, mobility, and respiratory function. We utilized an XGBoost regression model to forecast scores on the ALS Functional Rating Scale (ALSFRS-R), achieving a training mean squared error (MSE) of 0.1651 and a testing MSE of 0.0073, with R[2] values of 0.9800 for training and 0.9993 for testing. The model demonstrates high accuracy, providing a useful tool for clinicians to track disease progression and enhance patient management and treatment strategies.}, }
@article {pmid39622292, year = {2025}, author = {Ojo, O and Boateng, J and Pacella, R and Hanrahan, A and Essex, R and Dibley, L}, title = {Factors Influencing the Care and Management of Diabetic Foot Ulcers: A Scoping Review.}, journal = {Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists}, volume = {31}, number = {3}, pages = {380-389}, doi = {10.1016/j.eprac.2024.11.010}, pmid = {39622292}, issn = {1530-891X}, mesh = {Humans ; *Diabetic Foot/therapy ; Patient Education as Topic ; Health Knowledge, Attitudes, Practice ; Health Personnel ; Communication ; Disease Management ; }, abstract = {OBJECTIVE: The objective of this scoping review is to explore the experiences of patients' and healthcare practitioners on the factors that influence the care and management of diabetes-related foot ulcers (DFUs).<br><br>METHODS: Levac et&#xa0;al's 6-stage framework and the Preferred Reporting Items for Systematic Review and Meta-analysis extension for scoping reviews, guided the review. The SPIDER tool was used to define key elements of the review question. Searches for relevant articles were conducted in electronic databases (PUBMED, CINAHL, AMED, Embase, Cochrane Database of Systematic Reviews, and PsycINFO), Google Scholar, and hand searches of reference lists.<br><br>RESULTS: Eight articles met the inclusion criteria and were included in the review. Three themes were identified: Communication and Education about DFUs; Challenges of managing DFUs; and Barriers to treatment and management. The themes are presented as a narrative synthesis.<br><br>CONCLUSION: Inadequate knowledge of diabetic foot care by patients and inconsistent communication by healthcare professionals were primary factors affecting the effective management of diabetes-related foot ulcers. Consistent, patient-focused education that is supported by knowledgeable health care professionals should form the foundation of effective diabetic foot ulcer care.}, }
@article {pmid39621188, year = {2025}, author = {Gerometta, M and Henderson, RD and Friend, R and Cooper, LT and Zhao, J and Boyd, AW and Bartlett, PF}, title = {Evaluation of NUN-004, a Novel Engineered Ephrin Antagonist, in Healthy Volunteers and Patients with Amyotrophic Lateral Sclerosis: A Phase I/Ib, Open-Label, Escalating Dose and Extended Access Study.}, journal = {Clinical drug investigation}, volume = {45}, number = {1}, pages = {17-28}, pmid = {39621188}, issn = {1179-1918}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Adult ; Aged ; Healthy Volunteers ; Dose-Response Relationship, Drug ; Young Adult ; }, abstract = {BACKGROUND: Erythropoietin-producing hepatocellular carcinoma A4 (EphA4) is implicated in the pathophysiology of amyotrophic lateral sclerosis. EphA4 fusion protein (EphA4-Fc) inhibits EphA4 function in vivo but is too short-lived for prolonged therapy. NUN-004 (mEphA4-Fc) is a modified EphA4-Fc engineered for an extended half-life.<br><br>OBJECTIVE: This first-in-human phase I/Ib study evaluated the safety, tolerability, pharmacokinetics, immunogenicity and efficacy of NUN-004 in healthy volunteers and patients with amyotrophic lateral sclerosis.<br><br>METHODS: In this open-label study, Part 1 enrolled 20 healthy volunteers in five single ascending dose cohorts (1, 3, 10, 20 and 30 mg/kg), followed by Part 2, which enrolled eight patients with amyotrophic lateral sclerosis in two multiple ascending dose cohorts (cycle 1: 15 and 30 mg/kg) who could continue into an extended access phase (cycles 2-6: 15 mg/kg) for a total of 6 months' treatment. All participants received intravenous NUN-004; multiple dosing was administered weekly in 28-day cycles. Primary endpoints included safety assessments, single-dose and multiple-dose pharmacokinetics, and anti-drug antibodies. Efficacy assessments were Amyotrophic Lateral Sclerosis Function Rating Score Revised (ALSFRS-R) and forced vital capacity.<br><br>RESULTS: NUN-004 was well tolerated, with no serious adverse events or discontinuations. NUN-004 exposure generally increased with dose. Single-dose half-life was 111.7 (&#xb1; 22.8) h in healthy volunteers (n = 20) and 74.4 (&#xb1; 19.4) h in patients (n = 6). Steady state was observed in patients by day 8. Steady-state half-life (cycle 1 doses 2-4) was 83.7 (&#xb1; 26.6) to 101.1 (&#xb1; 46.0) h. No antibody response was observed. ALSFRS-R showed a slight improvement (+0.09 points/month) to cycle 4 and a slight decline (-0.35 points/month) over the whole study. Forced vital capacity trends were consistent with ALSFRS-R.<br><br>CONCLUSIONS: This study supports the safety, tolerability and extended half-life of NUN-004, and provides preliminary evidence for its ability to ameliorate disease progression in an amyotrophic lateral sclerosis cohort.<br><br>CLINICAL TRIAL REGISTRATION: Registered on ANZCTR under identifier ACTRN12621000514808 (3 May, 2021).}, }
@article {pmid39612826, year = {2025}, author = {Xu, H and Cheng, J and Leng, Q and Cao, R and Su, W and Sun, L and Xue, F and Han, Y and Wu, R}, title = {Characterization of acetolactate synthase genes and resistance mechanisms of multiple herbicide resistant Lolium multiflorum.}, journal = {Plant physiology and biochemistry : PPB}, volume = {219}, number = {}, pages = {109324}, doi = {10.1016/j.plaphy.2024.109324}, pmid = {39612826}, issn = {1873-2690}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Plant Proteins/genetics/metabolism ; *Lolium/genetics/enzymology/drug effects ; Imidazoles/pharmacology ; Genes, Plant ; }, abstract = {Combining imidazolinone-tolerant wheat with imazamox presents an effective solution to combat weed resistance. However, Lolium multiflorum, a troublesome resistant weed infesting wheat fields, may have developed resistance to imazamox, and the potential resistance mechanisms are intriguing. In this study, we explored the susceptibility of L. multiflorum to imazamox and investigated the resistance mechanisms, including the contribution of the target enzyme acetolactate synthase (ALS) to resistance and the presence of non-target-site resistance (NTSR). Eight L. multiflorum populations suspected of being resistant to imazamox were collected, and six populations exhibited resistance, ranging from 2.45-fold to 16.32-fold. The LmALS1 gene from susceptible population D3 plants and multiple copies of the LmALS gene (LmALS1, LmALS2, LmALS2α, LmALS3, LmALS3α, LmALS3β) from resistant populations D5 and D8 plants were separately amplified. Two mutations (Pro/Gln197 to Thr, Trp574 to Leu) were found in LmALS1 in the resistant populations. Compared to D3, LmALS1 was overexpressed in D5 but not in D8. The presence of LmALS1 mutants (LmALS1-Thr197 and LmALS1- Leu574), along with LmALS2, LmALS3, and their subunits, contribute to the resistance phenotype by increasing bonding energies, weakening hydrogen bonds, or decreasing protein binding pocket volumes and surface area. Additionally, D5 and D8 populations exhibited multiple resistance (>40-fold) to three other ALS inhibitors: pyroxsulam, flucarbazone-sodium, and mesosulfuron-methyl. Pre-treatment with malathion and 4-chloro-7-nitrobenzoxadiazole (cytochrome P450 monooxygenase and glutathione S-transferase inhibitors respectively) reversed the resistance of the D8 population and partially reversed the resistance of the D5 population to imazamox. This study characterizes ALS genes and extends our knowledge into the ALS resistance mechanisms involved in L. multiflorum. It also deepens our understanding of the complex diversification resistance mechanisms, thereby facilitating advances in weed resistance management strategies in wheat fields.}, }
@article {pmid39611137, year = {2024}, author = {Valančius, D and Burnytė, B and Masaitienė, R and Morkūnienė, A and Klimašauskienė, A}, title = {Rapidly Progressing and Early-Onset Forms of Amyotrophic Lateral Sclerosis Caused by a Novel SOD1 Variant in a Lithuanian Family.}, journal = {Neurology. Genetics}, volume = {10}, number = {6}, pages = {e200217}, pmid = {39611137}, issn = {2376-7839}, abstract = {OBJECTIVES: To describe a novel familial variant of superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS) in a Lithuanian family, highlighting its variable progression and implications for treatment inclusion criteria.<br><br>METHODS: This study presents the clinical and genetic findings of a family with the novel SOD1 variant, including one member diagnosed with early-onset ALS (onset <40 years) and one with a particularly rapidly progressing course of ALS.<br><br>RESULTS: The SOD1 variant NM_000454.5:c.446T>C, NP_000445.1:p.(Val149Ala) was identified in affected family members and 4 asymptomatic members aged 32-56 years. We present detailed disease course of the affected family members obtained during follow-up. Clinically, this variant is associated with variable disease progression, with the time from symptom onset to death ranging from 5 to 77 months.<br><br>DISCUSSION: The novel SOD1 variant p.Val149Ala in this Lithuanian family causes ALS of variable onset and course, including a case of early-onset ALS and one case of rapidly progressing ALS, necessitating recognition by the scientific community and development of tailored therapeutic approaches.}, }
@article {pmid39604641, year = {2025}, author = {Mi, Y and Zhang, P and Hou, X and Ding, Y and Wang, Y and Du, H and Deng, M}, title = {A rare genetic variant in APEX1 is associated with familial amyotrophic lateral sclerosis with slow progression.}, journal = {Acta neurologica Belgica}, volume = {125}, number = {1}, pages = {191-203}, pmid = {39604641}, issn = {2240-2993}, support = {No. 82273915//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; *DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics ; *Disease Progression ; *Pedigree ; Adult ; Aged ; Mutation, Missense/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of motor neurons and progressive muscle weakness. We aimed to identify the pathogenic genetic variants in familial ALS (fALS) pedigrees and to elucidate their impact on the disease phenotype. Through the analysis of whole-genome sequencing data of 34 fALS probands that screened negative for mutations in the most common ALS-causing genes, we identified a rare missense variant in APEX1 (NM_001641.4: c.22G > A, p.Gly8Arg) associated with ALS in one pedigree. Fluorescence microscopy images using green fluorescent protein (GFP)-fusion proteins suggested that this amino acid substitution could cause an impairment in nuclear localization of the protein. We described the clinical characteristics of this cohort analyzed and found that patients carrying this variant exhibit lower motor neuron onset and prolonged survival. The relation between APEX1 and ALS occurrence has been elusive despite evidence of a neuroprotective role for the gene. This study provides evidence linking an APEX1 variant with fALS and information on the distinct clinical manifestation. This study contributes to the understanding of the genetic basis of ALS, as well as a potential mechanism leading to loss of neurons, highlighting possible opportunities of targeted treatment harnessing the DNA repair process or ameliorating the oxidative stress.}, }
@article {pmid39603574, year = {2024}, author = {Wen, J and Li, Y and Qin, Y and Yan, L and Zhang, K and Li, A and Wang, Z and Yu, F and Lai, J and Yang, W and Liu, YU and Qin, D and Su, H}, title = {Lycorine protects motor neurons against TDP-43 proteinopathy-induced degeneration in cross-species models with amyotrophic lateral sclerosis.}, journal = {Pharmacological research}, volume = {210}, number = {}, pages = {107518}, doi = {10.1016/j.phrs.2024.107518}, pmid = {39603574}, issn = {1096-1186}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Phenanthridines/pharmacology/therapeutic use ; *Amaryllidaceae Alkaloids/pharmacology/therapeutic use ; *Caenorhabditis elegans/drug effects/metabolism ; *Motor Neurons/drug effects/pathology/metabolism ; Humans ; *Disease Models, Animal ; TDP-43 Proteinopathies/drug therapy/metabolism/pathology ; DNA-Binding Proteins/metabolism/genetics ; Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; }, abstract = {Aggregation of TAR-DNA binding protein-43 (TDP-43) is a pathological feature present in nearly 97 % cases of amyotrophic lateral sclerosis (ALS), making it an attractive target for pathogenic studies and drug screening. Here, we have performed a high-throughput screening of 1500 compounds from a natural product library and identified that lycorine, a naturally occurring alkaloid, significantly decreases the level of TDP-43[A315T] in a cellular model. We further demonstrate that lycorine reduces the level of TDP-43[A315T] both through inhibiting its synthesis and by promoting its degradation by the ubiquitin-proteasome system (UPS). Importantly, treatment with lycorine significantly attenuates TDP-43 proteinopathy and improves functional recovery in TDP-43[A315T]-expressing Caenorhabditis elegans and mouse models. These findings suggest that lycorine is a promising lead compound that has therapeutic potential for ALS.}, }
@article {pmid39598374, year = {2024}, author = {Li, Y and Fu, J and Wang, H}, title = {Advancements in Targeting Ion Channels for the Treatment of Neurodegenerative Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {11}, pages = {}, pmid = {39598374}, issn = {1424-8247}, support = {2023YFF1205500//National Key Research and Development Program of China/ ; 82471465//NSFC/ ; C2024202005//Distinguished Young Scholars Science Fund of the Natural Science Foundation of Hebei Province/ ; JZX2023002//Technology Project of Hebei Education Department/ ; 22JCQNJC01110//Tianjin Applied Basic Research Project/ ; 236Z2602G, 246Z2605G, 236Z2401G//the central government guides local funds for science and technology development for Hebei Province/ ; NV20230015//The Key Laboratory of Neural and Vascular Biology, Ministry of Education/ ; }, abstract = {Ion channels are integral membrane proteins embedded in biological membranes, and they comprise specific proteins that control the flow of ion transporters in and out of cells, playing crucial roles in the biological functions of different cells. They maintain the homeostasis of water and ion metabolism by facilitating ion transport and participate in the physiological processes of neurons and glial cells by regulating signaling pathways. Neurodegenerative diseases are a group of disorders characterized by the progressive loss of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Despite significant progress in understanding the pathophysiological processes of various neurological diseases in recent years, effective treatments for mitigating the damage caused by these diseases remain inadequate. Increasing evidence suggests that ion channels are closely associated with neuroinflammation; oxidative stress; and the characteristic proteins in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Therefore, studying the pathogenic mechanisms closely related to ion channels in neurodegenerative diseases can help identify more effective therapeutic targets for treating neurodegenerative diseases. Here, we discuss the progress of research on ion channels in different neurodegenerative diseases and emphasize the feasibility and potential of treating such diseases from the perspective of ion channels.}, }
@article {pmid39595812, year = {2024}, author = {Zhang, S and Yang, Y and Lv, X and Zhou, X and Zhao, W and Meng, L and Zhu, S and Zhang, Z and Wang, Y}, title = {Exosome Cargo in Neurodegenerative Diseases: Leveraging Their Intercellular Communication Capabilities for Biomarker Discovery and Therapeutic Delivery.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595812}, issn = {2076-3425}, support = {82171871//National Natural Science Foundation of China/ ; BK20230488//Youth Fund Project of the Jiangsu Province Basic Research Program (Natural Science Foundation)/ ; None//Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)/ ; }, abstract = {The inexorable progression of neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, is closely related to irreversible brain decline. Accurately characterizing pathophysiological features and identifying reliable biomarkers for early diagnosis and optimized treatment are critical. Hindered by the blood-brain barrier (BBB), obtaining sensitive monitoring indicators for disease progression and achieving efficient drug delivery remain significant challenges. Exosomes, endogenous nanoscale vesicles that carry key bioactive substances, reflect the intracellular environment and play an important role in cell signaling. They have shown promise in traversing the BBB, serving dual roles as potential biomarkers for NDs and vehicles for targeted drug delivery. However, the specific mechanisms by which exosome influence NDs are not fully understood, necessitating further investigation into their attributes and functionalities in the context of NDs. This review explores how exosomes mediate multifaceted interactions, particularly in exacerbating pathogenic processes such as oxidative stress, neuronal dysfunction, and apoptosis integral to NDs. It provides a comprehensive analysis of the profound impact of exosomes under stress and disease states, assessing their prospective utility as biomarkers and drug delivery vectors, offering new perspectives for tackling these challenging diseases.}, }
@article {pmid39594452, year = {2024}, author = {Dibwe, DF and Oba, S and Monde, S and Hui, SP}, title = {Inhibition of Accumulation of Neutral Lipids and Their Hydroperoxide Species in Hepatocytes by Bioactive Allium sativum Extract.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {39594452}, issn = {2076-3921}, abstract = {Our ongoing research suggests that extracts from plant-based foods inhibit the accumulation of lipid droplets (LDs) and oxidized lipid droplets (oxLDs) in liver cells. These findings suggest their potential use in the alleviation of metabolic dysfunction-associated fatty liver disease (MAFLD) and its most severe manifestation, metabolic dysfunction-associated steatohepatitis (MASH). Allium extracts (ALs: AL1-AL9) were used to assess their ability to reduce lipid droplet accumulation (LDA) and oxidized lipid droplet accumulation (oxLDA) by inhibiting neutral lipid accumulation and oxidation in LD. Among the tested Allium extracts, AL1, AL3, and AL6 demonstrated substantial inhibitory effects on the LDA. Furthermore, AL1 extract showed real-time inhibition of LDA in HepG2 cells in DMEM supplemented with oleic acid (OA) within 12 h of treatment. Our lipidomic approach was used to quantify the accumulation and inhibition of intracellular triacylglycerol (TAG) and oxidized TAG hydroperoxide [TG (OOH) n = 3] species in hepatocytes under OA and linoleic acid loading conditions. These results suggest that Allium-based foods inhibit LD accumulation by decreasing intracellular lipids and lipid hydroperoxides in the hepatocytes. The metabolomic analysis of AL1-the bioactive LDAI extract-using both LC-MS/MS and 1D-NMR [[1]H, [13]C, and Dept (135 and 90)] approaches revealed that AL1 contains mainly carbohydrates and glucoside metabolites, including iridoid glucosides, as well as minor amino acids, organosulfur compounds, and organic acids such as the antioxidant ascorbic acid (KA2 = S13), and their derivatives, suggesting that AL1 could be a potential resource for the development of functional foods and in drug discovery targeting MAFLD/MASH and other related diseases.}, }
@article {pmid39591907, year = {2024}, author = {Bajpai, A and Bharathi, V and Kumawat, R and Tomar, RS and Patel, BK}, title = {Activation of the yeast MAP kinase, Slt2, protects against TDP-43 and TDP-25 toxicity in the Saccharomyces cerevisiae proteinopathy model.}, journal = {Biochemical and biophysical research communications}, volume = {741}, number = {}, pages = {151062}, doi = {10.1016/j.bbrc.2024.151062}, pmid = {39591907}, issn = {1090-2104}, mesh = {*Saccharomyces cerevisiae/metabolism/genetics ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Unfolded Protein Response/drug effects ; *Mitogen-Activated Protein Kinases/metabolism/genetics ; TDP-43 Proteinopathies/metabolism/genetics/pathology ; Humans ; Enzyme Activation ; Oxidative Stress/drug effects ; }, abstract = {TDP-43 proteinopathy is observed in human neurodegenerative diseases like ALS. Heterologous TDP-43 expression in the yeast model also mimics several proteinopathy features such as cytotoxicity, cytoplasmic mis-localization and oxidative stress. Among the pathways implicated in modulating the TDP-43 toxicity in yeast, the unfolded protein response (UPR) activation was also identified. Here, we examine the role of stress-regulated yeast MAP kinase, Slt2, which also links cellular stress with UPR activation, in modulating the toxicities of the full-length TDP-43 and its 25 kDa C-terminal fragment, TDP-25. We find enhancement in the cytotoxicity of TDP-43, as well as TDP-25, in the yeast cells deleted for the MAP kinase, Slt2, but not in those lacking other yeast MAP kinases, Kss1 and Fus3. Unlike in the wild-type yeast, upon treatment with an antioxidant N-acetyl cysteine, the TDP-43 toxicity could not be mitigated in the slt2Δ yeast but the TDP-25 toxicity was significantly rescued suggesting oxidative stress as an important contributor to the TDP-25 toxicity. Notably, TDP-43 as well as TDP-25 expressions could cause significant phosphorylation of Slt2 suggesting activation of this MAP Kinase due to their toxicities. Interestingly, in the slt2Δ cells, lacking the MAP Kinase activity, a treatment with low concentrations of an UPR activator molecule, DTT, caused significant reduction in the toxicities of both TDP-43 as well as TDP-25. Taken together, these findings suggest that TDP-43 and TDP-25 toxicity-induced stress-mediated activation of the MAP kinase Slt2 helps in mitigating their toxicities in the yeast model possibly through UPR activation.}, }
@article {pmid39589881, year = {2024}, author = {Jean Gregoire, M and Sirtori, R and Donatelli, L and Morgan Potts, E and Collins, A and Zamor, D and Katenka, N and Fallini, C}, title = {Early disruption of the CREB pathway drives dendritic morphological alterations in FTD/ALS cortical neurons.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {49}, pages = {e2406998121}, pmid = {39589881}, issn = {1091-6490}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; Early Career Development Award//RI-INBRE/ ; R01NS116143//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; P20GM103430//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 NS116143/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Dendrites/metabolism ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Frontotemporal Dementia/metabolism/genetics/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Neurons/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Signal Transduction ; C9orf72 Protein/genetics/metabolism ; Phosphorylation ; Cerebral Cortex/metabolism/pathology ; }, abstract = {Synaptic loss and dendritic degeneration are common pathologies in several neurodegenerative diseases characterized by progressive cognitive and/or motor decline, such as Alzheimer's disease (AD) and frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). An essential regulator of neuronal health, the cAMP-dependent transcription factor CREB positively regulates synaptic growth, learning, and memory. Phosphorylation of CREB by protein kinase A (PKA) and other cellular kinases promotes neuronal survival and maturation via transcriptional activation of a wide range of downstream target genes. CREB pathway dysfunction has been strongly implicated in AD pathogenesis, and recent data suggest that impaired CREB activation may contribute to disease phenotypes in FTD/ALS as well. However, the mechanisms behind reduced CREB activity in FTD/ALS pathology are not clear. In this study, we found that cortical-like neurons derived from iPSC lines carrying the hexanucleotide repeat expansion in the C9ORF72 gene, a common genetic cause of FTD/ALS, displayed a diminished activation of CREB, resulting in decreased dendritic and synaptic health. Importantly, we determined such impairments to be mechanistically linked to an imbalance in the ratio of regulatory and catalytic subunits of the CREB activator PKA and to be conserved in C9-ALS patient's postmortem tissue. Modulation of cAMP upstream of this impairment allowed for a rescue of CREB activity and an amelioration of dendritic morphology and synaptic protein levels. Our data elucidate the mechanism behind early CREB pathway dysfunction and discern a feasible therapeutic target for the treatment of FTD/ALS and possibly other neurodegenerative diseases.}, }
@article {pmid39589160, year = {2025}, author = {Wang, Y and Li, D and Xu, K and Wang, G and Zhang, F}, title = {Copper homeostasis and neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3124-3143}, pmid = {39589160}, issn = {1673-5374}, abstract = {Copper, one of the most prolific transition metals in the body, is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations. Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins, including copper transporters (CTR1 and CTR2), the two copper ion transporters the Cu -transporting ATPase 1 (ATP7A) and Cu-transporting beta (ATP7B), and the three copper chaperones ATOX1, CCS, and COX17. Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue. Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins, including ceruloplasmin and metallothionein, is involved in the pathogenesis of neurodegenerative disorders. However, the exact mechanisms underlying these processes are not known. Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress. Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction. Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation, with elevated levels activating several critical inflammatory pathways. Additionally, copper can bind aberrantly to several neuronal proteins, including alpha-synuclein, tau, superoxide dismutase 1, and huntingtin, thereby inducing neurotoxicity and ultimately cell death. This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases, with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis. By synthesizing the current findings on the functions of copper in oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders, such as Wilson's disease, Menkes' disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine, and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline, along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.}, }
@article {pmid39588282, year = {2024}, author = {Dash, BP and Freischmidt, A and Helferich, AM and Ludolph, AC and Andersen, PM and Weishaupt, JH and Hermann, A}, title = {Upregulated miR-10b-5p as a potential miRNA signature in amyotrophic lateral sclerosis patients.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1457704}, pmid = {39588282}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset disease marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Death in most patients usually occurs within 2-4 years after symptoms onset. Despite promising progress in delineating underlying mechanisms, such as disturbed proteostasis, DNA/RNA metabolism, splicing or proper nucleocytoplasmic shuttling, there are no effective therapies for the vast majority of cases. A reason for this might be the disease heterogeneity and lack of substantial clinical and molecular biomarkers. The identification and validation of such pathophysiology driven biomarkers could be useful for early diagnosis and treatment stratification. Recent advances in next generation RNA-sequencing approaches have provided important insights to identify key changes of non-coding RNAs (ncRNAs) implicated with ALS disease. Especially, microRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression to target several genes/pathways by degrading messenger RNAs (mRNAs) or repressing levels of gene expression. In this study, we expand our previous work to identify top-regulated differentially expressed (DE)-miRNAs by combining different normalizations to search for important and generalisable pathomechanistic dysregulations in ALS as putative novel biomarkers of the disease. For this we performed a consensus pipeline of existing datasets to investigate the transcriptomic profile (mRNAs and miRNAs) of MN cell lines from iPSC-derived SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to identify potential signatures and their related pathways associated with neurodegeneration. Transcriptional profiling of miRNA-mRNA interactions from MN cell lines in ALS patients revealed differential expression of genes showed greater vulnerability to KEAP1-NRF2 stress response pathway, sharing a common molecular denominator linked to both disease conditions. We also reported that mutations in above genes led to significant upregulation of the top candidate miR-10b-5p, which we could validate in immortalized lymphoblast cell lines (LCLs) derived from sporadic and familial ALS patients and postmortem tissues of familial ALS patients. Collectively, our findings suggest that miRNA analysis simultaneously performed in various human biological samples may reveal shared miRNA profiles potentially useful as a biomarker of the disease.}, }
@article {pmid39585060, year = {2024}, author = {Magni, E and Hochsprung, A and Cáceres-Matos, R and Pabón-Carrasco, M and Heredia-Camacho, B and Solís-Marcos, I and Luque-Moreno, C}, title = {Effects of Respiratory Training on Pulmonary Function, Cough, and Functional Independence in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Neurology international}, volume = {16}, number = {6}, pages = {1332-1342}, pmid = {39585060}, issn = {2035-8385}, abstract = {BACKGROUND: Respiratory complications in patients with amyotrophic lateral sclerosis (ALS), due to the involvement of respiratory muscles, are the leading cause of death, and respiratory physiotherapy (RP) focuses on addressing these complications.<br><br>OBJECTIVES: The objective was to evaluate the effectiveness of an RP intervention that combines the four specific techniques (inspiratory muscle training, lung volume recruitment, manually assisted coughing, and diaphragmatic breathing training) in patients with ALS.<br><br>METHODS: A quasi-experimental study was carried out, and a specific RP programme was implemented in 15 patients with ALS (12 sessions, 30 min/session, one session/week, duration of three months), based on directed ventilation techniques, lung volume recruitment, manually assisted coughing, and the use of incentive spirometry and a cough assist device, along with a daily home exercise programme. Respiratory functions were assessed (pre- and post-intervention, with follow-up at three months) using Forced Vital Capacity (FVC) and Peak Expiratory Cough Flow (PECF); functionality was assessed using the Revised ALS Functional Rating Scale (ALSFRS-R) and the Modified Barthel Index by Granger.<br><br>RESULTS: FVC experienced an increase after three months of the intervention initiation (p = 0.30), which was not sustained at the three-month follow-up after the intervention ended. All other variables remained practically constant after treatment, with their values decreasing at follow-up.<br><br>CONCLUSION: A specific RP intervention could have beneficial effects on respiratory functions, potentially preventing pulmonary infections and hospitalisations in patients with ALS. It may improve FVC and help stabilize the patient's functional decline. Considering the progressive and degenerative nature of the disease, this finding could support the usefulness of these techniques in maintaining respiratory function.}, }
@article {pmid39578404, year = {2025}, author = {Phrathep, DD and Abdo, Z and Tadros, M and Lewandowski, E and Evans, J}, title = {The role of osteopathic manipulative treatment for dystonia: a literature review.}, journal = {Journal of osteopathic medicine}, volume = {125}, number = {4}, pages = {203-211}, pmid = {39578404}, issn = {2702-3648}, mesh = {Humans ; *Manipulation, Osteopathic/methods ; *Dystonia/therapy ; }, abstract = {CONTEXT: Dystonia is a movement disorder that causes involuntary muscle contractions leading to abnormal movements and postures, such as twisting. Dystonia is the third most common movement disorder in the United States, with as many as 250,000 people affected. Because of its complexity, dystonia presents a significant challenge in terms of management and treatment. Despite limited research, osteopathic manipulative treatment (OMT) has been considered as an adjunctive treatment due to its inexpensive and noninvasive nature, as opposed to other modalities such as botulinum toxin injections, deep brain stimulation (DBS), and transcranial magnetic stimulation, which are often expensive and inaccessible. OMT treatments performed in case studies and series such as balanced ligamentous tension/articular ligamentous strain (BLT/ALS), muscle energy (ME), high-velocity low-amplitude (HVLA), and myofascial release (MFR) have shown reduction of pain and muscle hypertonicity, including in patients with dystonia.<br><br>OBJECTIVES: The studies reviewed in this paper provide a snapshot of the literature regarding the current evidence of OMT's role for dystonia.<br><br>METHODS: A medical reference librarian conducted a thorough literature search across multiple databases including PubMed and Google Scholar to find articles relevant to the use of OMT for dystonia. The search employed a combination of Medical Subject Headings (MeSH) terms and keywords related to osteopathic medicine and dystonia to ensure precise retrieval of relevant articles within the last 20 years. Despite limited research on the topic, all four relevant reports found in the literature were selected for review.<br><br>RESULTS: Of the four relevant reports, case series and studies highlighted the potential benefits of OMT in managing dystonia, particularly cervical dystonia and foot dystonia. OMT has shown promising results addressing pain, stiffness, and impaired motor function. In cases of foot dystonia in Parkinson's disease, OMT has helped improve gait and reduce pain by targeting somatic dysfunctions (SDs) associated with dystonia, such as abnormalities in foot progression angle (FPA) and musculoskeletal imbalances. Also, OMT has been found to alleviate symptoms of cervical dystonia, including tremors, muscle spasms, and neck stiffness. These interventions performed in case studies and series led to improvements in gait biomechanics in foot dystonia and overall symptom severity in patients with cervical dystonia.<br><br>CONCLUSIONS: Currently, botulinum toxin, oral medications, physical therapy, and rehabilitation are commonly utilized in managing dystonia. The studies reviewed in this paper suggest that these treatments may lead to improvements in pain and muscle hypertonicity in patients with dystonia. It is important to investigate whether factors such as the type of dystonia (eg, focal vs. segmental) and its underlying cause (eg, idiopathic, trauma, infection, autoimmune, medication side effects) influence treatment outcomes. Further research is recommended to explore the role of OMT in managing dystonia.}, }
@article {pmid39577830, year = {2024}, author = {Morikawa, K and Izumiya, Y and Takashio, S and Kawano, Y and Oguni, T and Kuyama, N and Oike, F and Yamamoto, M and Tabata, N and Ishii, M and Hanatani, S and Hoshiyama, T and Kanazawa, H and Matsuzawa, Y and Usuku, H and Yamamoto, E and Ueda, M and Tsujita, K}, title = {Early experience with daratumumab-containing regimens in patients with light-chain cardiac amyloidosis.}, journal = {Journal of cardiology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jjcc.2024.11.003}, pmid = {39577830}, issn = {1876-4738}, abstract = {BACKGROUND: Immunoglobulin light-chain (AL) amyloidosis is a lethal condition resulting from misfolded immunoglobulin ALs produced by clonal CD38-positive plasma cells. Treatment with daratumumab, an anti-human CD38 monoclonal antibody, led to higher frequencies of complete hematologic response and better clinical outcomes compared with conventional treatment. This study sought to evaluate the survival benefit of daratumumab-containing regimens in patients with AL cardiac amyloidosis.<br><br>METHODS AND RESULTS: We examined 65 consecutive patients with AL cardiac amyloidosis (mean age: 67.2&#x202f;&#xb1;&#x202f;10.4&#x202f;years, male: 69&#x202f;%) who underwent chemotherapy. We divided patients into a daratumumab group, which used daratumumab-containing regimens before second-line treatment (n&#x202f;=&#x202f;32), and a conventional treatment group (n&#x202f;=&#x202f;33). Compared with the conventional treatment group, the daratumumab group tended to be older, but there were no significant differences between groups in biomarkers and echocardiographic parameters. A total of 26 patients (40&#x202f;%) died (median follow-up duration: 395&#x202f;days). Kaplan-Meier survival analysis showed that the daratumumab group had significantly lower mortality compared with the conventional treatment group (p&#x202f;=&#x202f;0.04; log-rank test). Cox hazard analysis revealed that use of daratumumab-containing regimens was associated with lower mortality after adjustment for the revised Mayo staging of AL amyloidosis (hazard ratio: 0.32; 95&#x202f;% confidence interval: 0.12 to 0.85; p&#x202f;=&#x202f;0.02).<br><br>CONCLUSION: Daratumumab-containing regimens may be associated with improved survival in patients with AL cardiac amyloidosis.}, }
@article {pmid39577228, year = {2025}, author = {Sojdeh, S and Safarkhani, M and Daneshgar, H and Aldhaher, A and Heidari, G and Nazarzadeh Zare, E and Iravani, S and Zarrabi, A and Rabiee, N}, title = {Promising breakthroughs in amyotrophic lateral sclerosis treatment through nanotechnology's unexplored frontier.}, journal = {European journal of medicinal chemistry}, volume = {282}, number = {}, pages = {117080}, doi = {10.1016/j.ejmech.2024.117080}, pmid = {39577228}, issn = {1768-3254}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Nanotechnology ; Genetic Therapy ; Animals ; Drug Delivery Systems ; Neuroprotective Agents/chemistry/therapeutic use/pharmacology ; }, abstract = {This review explores the transformative potential of nanotechnology in the treatment and diagnosis of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder characterized by motor neuron degeneration, muscle weakness, and eventual paralysis. Nanotechnology offers innovative solutions across various domains, including targeted drug delivery, neuroprotection, gene therapy and editing, biomarker detection, advanced imaging techniques, and tissue engineering. By enhancing the precision and efficacy of therapeutic interventions, nanotechnology facilitates key advancements such as crossing the blood-brain barrier, targeting specific cell types, achieving sustained therapeutic release, and enabling combination therapies tailored to the complex pathophysiology of ALS. Despite its immense promise, the clinical translation of these approaches faces challenges, including potential cytotoxicity, biocompatibility, and regulatory compliance, which must be addressed through rigorous research and testing. This review emphasizes the application of nanotechnology in targeted drug delivery and gene therapy/editing for ALS, drawing on the author's prior work with various nanotechnological platforms to illustrate strategies for overcoming similar obstacles in drug and gene delivery. By bridging the gap between cutting-edge technology and clinical application, this article aims to highlight the vital role of nanotechnology in shaping the future of ALS treatment.}, }
@article {pmid39570667, year = {2024}, author = {Burks, CA and Brenner, MJ}, title = {Commentary on Von Sneidern et al's "Evaluation and Treatment of Acute Facial Palsy: Opportunities for Optimization at a Single Institution."-Bridging the Gap Between Guidelines and Practice.}, journal = {Facial plastic surgery &amp; aesthetic medicine}, volume = {}, number = {}, pages = {}, doi = {10.1089/fpsam.2024.0263}, pmid = {39570667}, issn = {2689-3622}, }
@article {pmid39570437, year = {2025}, author = {Maity, D and Kaundal, RK}, title = {Exploring dysregulated miRNAs in ALS: implications for disease pathogenesis and early diagnosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {4}, pages = {1661-1686}, pmid = {39570437}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Humans ; *MicroRNAs/genetics/metabolism ; *Early Diagnosis ; Biomarkers/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor neuron degeneration, leading to muscle weakness and paralysis, with no effective treatments available. Early diagnosis could slow disease progression and optimize treatment. MicroRNAs (miRNAs) are being investigated as potential biomarkers due to their regulatory roles in cellular processes and stability in biofluids. However, variability across studies complicates their diagnostic utility in ALS. This study aims to identify significantly dysregulated miRNAs in ALS through meta-analysis to elucidate disease mechanisms and improve diagnostic strategies.<br><br>METHODS: We systematically searched PubMed, Google Scholar, and the Cochrane Library, following predefined inclusion and exclusion criteria. The primary effect measure was the standardized mean difference (SMD) with a 95% confidence interval, analyzed using a random-effects model. Additionally, we used network pharmacology to examine the targets of dysregulated miRNAs and their roles in ALS pathology.<br><br>RESULTS: Analysing 34 studies, we found significant upregulation of hsa-miR-206, hsa-miR-133b, hsa-miR-23a, and hsa-miR-338-3p, and significant downregulation of hsa-miR-218, hsa-miR-21-5p, and hsa-let-7b-5p in ALS patients. These miRNAs are involved in ALS pathophysiology, including stress granule formation, nuclear pore complex, SMCR8 and Sig1R dysfunction, histone methyltransferase complex alterations, and MAPK signaling perturbation, highlighting their critical role in ALS progression.<br><br>CONCLUSION: This study identifies several dysregulated miRNAs in ALS patients, offering insights into their role in the disease and potential as diagnostic biomarkers. These findings enhance our understanding of ALS mechanisms and may inform future diagnostic strategies. Validating these results and exploring miRNA-based interventions are crucial for improving ALS diagnosis and treatment outcomes.}, }
@article {pmid39569650, year = {2025}, author = {Luo, S and Wang, X and Ma, B and Liu, D and Li, L and Wang, L and Ding, N and Zou, L and Wang, J and Pan, J and Sang, D and Zhou, H and Qu, H and Lu, Y and Yang, L}, title = {Therapeutic potential of simvastatin in ALS: Enhanced axonal integrity and motor neuron survival through Apoa4 and Alb modulation.}, journal = {Biomolecules &amp; biomedicine}, volume = {25}, number = {3}, pages = {632-647}, doi = {10.17305/bb.2024.11218}, pmid = {39569650}, issn = {2831-090X}, mesh = {*Simvastatin/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism/genetics ; Animals ; *Motor Neurons/drug effects/pathology/metabolism ; *Mice, Transgenic ; Mice ; *Axons/drug effects/pathology ; *Mice, Inbred C57BL ; Disease Models, Animal ; Superoxide Dismutase/metabolism/genetics ; Cell Survival/drug effects ; Spinal Cord/drug effects/pathology/metabolism ; Male ; Apolipoproteins A ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using hematoxylin and eosin staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression.}, }
@article {pmid39567497, year = {2024}, author = {Zhu, Z and Song, M and Ren, J and Liang, L and Mao, G and Chen, M}, title = {Copper homeostasis and cuproptosis in central nervous system diseases.}, journal = {Cell death &amp; disease}, volume = {15}, number = {11}, pages = {850}, pmid = {39567497}, issn = {2041-4889}, mesh = {Humans ; *Copper/metabolism ; *Homeostasis ; *Central Nervous System Diseases/metabolism/pathology ; Animals ; }, abstract = {Copper (Cu), an indispensable micronutrient for the sustenance of living organisms, contributes significantly to a vast array of fundamental metabolic processes. The human body maintains a relatively low concentration of copper, which is mostly found in the bones, liver, and brain. Despite its low concentration, Cu plays a crucial role as an indispensable element in the progression and pathogenesis of central nervous system (CNS) diseases. Extensive studies have been conducted in recent years on copper homeostasis and copper-induced cell death in CNS disorders, including glioma, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease, and stroke. Cuproptosis, a novel copper-induced cell death pathway distinct from apoptosis, necrosis, pyroptosis, and ferroptosis, has been identified as potentially intricately linked to the pathogenic mechanisms underlying various CNS diseases. Therefore, a systematic review of copper homeostasis and cuproptosis and their relationship with CNS disorders could deepen our understanding of the pathogenesis of these diseases. In addition, it may provide new insights and strategies for the treatment of CNS disorders.}, }
@article {pmid39564171, year = {2024}, author = {Byeon, H}, title = {Holistic approaches to mitigating psychological distress in gynecological cancer patients.}, journal = {World journal of psychiatry}, volume = {14}, number = {11}, pages = {1766-1771}, pmid = {39564171}, issn = {2220-3206}, abstract = {This article delves into the psychological impact of gynecological malignancies and suggests pathways to improve the quality of life (QoL) for affected patients. Building on Shang et al's comprehensive analysis, this piece integrates insights from various studies to highlight the profound influence of psychological and physical symptoms on patients undergoing treatment for gynecological cancers. The study underscores that anxiety and depression significantly exacerbate the disease's toll. Factors such as physical exercise and digital and interactive health interventions show promise in mitigating these adverse effects. The article emphasizes the necessity for a holistic care approach that addresses both physical and emotional needs. Recommendations include enhanced training for healthcare providers, public awareness campaigns, streamlined diagnostic pathways, and improved access to specialist care. These integrated strategies aim to ensure that women facing gynecological cancers can maintain an optimal QoL through comprehensive and multidisciplinary care models.}, }
@article {pmid39563026, year = {2025}, author = {Hawley, ZCE and Pardo, ID and Cao, S and Zavodszky, MI and Casey, F and Ferber, K and Luo, Y and Hana, S and Chen, SK and Doherty, J and Costa, R and Cullen, P and Liu, Y and Carlile, TM and Chowdhury, T and Doyle, B and Clarner, P and Mangaudis, K and Guilmette, E and Bourque, S and Koske, D and Nadella, MVP and Trapa, P and Hawes, ML and Raitcheva, D and Lo, SC}, title = {Dorsal root ganglion toxicity after AAV intra-CSF delivery of a RNAi expression construct into non-human primates and mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {1}, pages = {215-234}, pmid = {39563026}, issn = {1525-0024}, mesh = {Animals ; *Dependovirus/genetics ; Mice ; *MicroRNAs/genetics ; *Ganglia, Spinal/metabolism ; *Genetic Vectors/administration &amp; dosage/genetics ; *RNA Interference ; Superoxide Dismutase-1/genetics ; Humans ; Neurons/metabolism ; Male ; }, abstract = {Dorsal root ganglion (DRG) toxicity has been consistently reported as a potential safety concern after delivery of adeno-associated viruses (AAVs) containing gene-replacement vectors but has yet to be reported for RNAi-based vectors. Here, we report DRG toxicity after AAV intra-CSF delivery of an RNAi expression construct-artificial microRNA targeting superoxide dismutase 1 (SOD1)-in non-human primates (NHPs) and provide evidence that this can be recapitulated within mice. Histopathology evaluation showed that NHPs and mice develop DRG toxicity after AAV delivery, including DRG neuron degeneration and necrosis and nerve-fiber degeneration that were associated with increases in cerebrospinal fluid (CSF) and serum phosphorylated neurofilament heavy chain (pNF-H). RNA-sequencing analysis of DRGs showed that dysregulated pathways were preserved between NHPs and mice, including increases in innate/adaptive immune responses and decreases in mitochondrial- and neuronal-related genes, following AAV treatment. Finally, endogenous miR-21-5p was upregulated in DRGs of AAV-treated NHPs and mice. Increases in miR-21-5p were also identified within the CSF of NHPs, which significantly correlated with pNF-H, implicating miR-21-5p as a potential biomarker of DRG toxicity in conjunction with other molecular analytes. This work highlights the importance of assessing safety concerns related to DRG toxicity when developing RNAi-based AAV vectors for therapeutic purposes.}, }
@article {pmid39562997, year = {2024}, author = {Zheng, W and Xia, T and Zhang, X and Han, J and Li, Y and Tian, N and Zheng, G and Wang, J and Peng, Y and Yao, D and Long, F}, title = {Tailoring Multifunctional Amine Salts Based on Anisole Liquid Soaking for Fabricating Efficient and Stable Perovskite Solar Cells.}, journal = {ACS applied materials &amp; interfaces}, volume = {16}, number = {48}, pages = {66643-66654}, doi = {10.1021/acsami.4c12455}, pmid = {39562997}, issn = {1944-8252}, abstract = {The post-treatment based on spin-coating (SC) organic amine salts is commonly used for surface modification of perovskite films to eliminate defects. However, there is still a lack of systematic study and a unified understanding of the functions and mechanisms of different organic amine salts. The SC method is also not conducive to the industrialization of solar cells. In this work, we study three different organic amine salts, and a passivation strategy for perovskite films based on green anisole liquid soaking (ALS) has been developed. Phenylethylammonium iodide (PEAI), diethylamine hydroiodide (DEAI), and guanidine hydroiodide (GAI) organic amine salt passivators are selected to modify perovskite films, and their effect and working mechanism are also systematically estimated. It is found that PEAI passivates shallow-level defects on the surface of perovskite films, while DEAI incorporates into the perovskite lattice to suppress point defects, and GAI eliminates excess PbI2 residuals in perovskite films. These three organic-amine-salt-modified devices achieve enhanced power conversion efficiencies (PCE) of 21.82% (PEAI-ALS), 21.74% (DEAI-ALS), and 22.21% (GAI-ALS), which is much higher than that of the pristine device without treatment (19.95%). The PCE of the PEAI-ALS device retains nearly 94% of the initial efficiency after 1200 h in unpackaged conditions and about 40% ambient humidity, achieving the best stability performance. Particularly, the PEAI-ALS device has the best comprehensive performance in efficiency and stability. And PEAI is estimated by the SC method and ALS method, and it is found that the PEAI-ALS device achieves a higher PCE compared to the PEAI-SC device (21.51%). We believe that the post-treatment based on a combination of appropriate amine salts and ALS enables a universal approach for fabrication of perovskite solar cells with enhanced photovoltaic performance.}, }
@article {pmid39556113, year = {2025}, author = {Yeganeh Markid, T and Pourahmadiyan, A and Hamzeh, S and Sharifi-Bonab, M and Asadi, MR and Jalaiei, A and Rezazadeh, M and Ghafouri-Fard, S}, title = {A special focus on polyadenylation and alternative polyadenylation in neurodegenerative diseases: A systematic review.}, journal = {Journal of neurochemistry}, volume = {169}, number = {2}, pages = {e16255}, doi = {10.1111/jnc.16255}, pmid = {39556113}, issn = {1471-4159}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics ; *Polyadenylation ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) are one of the prevailing conditions characterized by progressive neuronal loss. Polyadenylation (PA) and alternative polyadenylation (APA) are the two main post-transcriptional events that regulate neuronal gene expression and protein production. This systematic review analyzed the available literature on the role of PA and APA in NDDs, with an emphasis on their contributions to disease development. A comprehensive literature search was performed using the PubMed, Scopus, Cochrane, Google Scholar, Embase, Web of Science, and ProQuest databases. The search strategy was developed based on the framework introduced by Arksey and O'Malley and supplemented by the inclusion and exclusion criteria. The study selection was performed by two independent reviewers. Extraction and data organization were performed in accordance with the predefined variables. Subsequently, quantitative and qualitative analyses were performed. Forty-seven studies were included, related to a variety of NDDs, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Disease induction was performed using different models, including human tissues, animal models, and cultured cells. Most investigations were related to PA, although some were related to APA or both. Amyloid precursor protein (APP), Tau, SNCA, and STMN2 were the major genes identified; most of the altered PA patterns were related to mRNA stability and translation efficiency. This review particularly underscores the key roles of PA and APA in the pathogenesis of NDDs through their mechanisms that contribute to gene expression dysregulation, protein aggregation, and neuronal dysfunction. Insights into these mechanisms may lead to new therapeutic strategies focused on the modulation of PA and APA activities. Further research is required to investigate the translational potential of targeting these pathways for NDD treatment.}, }
@article {pmid39552508, year = {2025}, author = {Zhong, R and Dionela, DLA and Kim, NH and Harris, EN and Geisler, JG and Wei-LaPierre, L}, title = {Micro-Doses of DNP Preserve Motor and Muscle Function with a Period of Functional Recovery in Amyotrophic Lateral Sclerosis Mice.}, journal = {Annals of neurology}, volume = {97}, number = {3}, pages = {542-557}, pmid = {39552508}, issn = {1531-8249}, support = {R56 NS117429/NS/NINDS NIH HHS/United States ; NS99545/NS/NINDS NIH HHS/United States ; R01 NS127858/NS/NINDS NIH HHS/United States ; R21 NS099545/NS/NINDS NIH HHS/United States ; NS117429/NS/NINDS NIH HHS/United States ; NS127858/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; *2,4-Dinitrophenol/pharmacology ; Mice ; *Muscle, Skeletal/drug effects/physiopathology ; *Mice, Transgenic ; *Disease Models, Animal ; *Recovery of Function/drug effects/physiology ; Muscle Contraction/drug effects/physiology ; Male ; Uncoupling Agents/pharmacology ; Motor Neurons/drug effects ; Neuromuscular Junction/drug effects ; }, abstract = {OBJECTIVE: Mitochondrial dysfunction is one of the earliest pathological events observed in amyotrophic lateral sclerosis (ALS). The aim of this study is to evaluate the therapeutic efficacy of 2,4-dinitrophenol (DNP), a mild mitochondrial uncoupler, in an ALS mouse model to provide preclinical proof-of-concept evidence of using DNP as a potential therapeutic drug for ALS.<br><br>METHODS: hSOD1[G93A] mice were treated with 0.5-1.0&#x2009;mg/kg DNP through daily oral gavage from presymptomatic stage or disease onset until 18&#x2009;weeks old. Longitudinal behavioral studies were performed weekly or biweekly from 6 to 18&#x2009;weeks old. In situ muscle contraction measurements in extensor digitorum longus muscles were conducted to evaluate the preservation of contractile force and motor unit numbers in hSOD1[G93A] mice following DNP treatment. Muscle innervation and inflammatory markers were assessed using immunostaining. Extent of protein oxidation and activation of Akt pathway were also examined.<br><br>RESULTS: DNP delayed disease onset; improved motor coordination and muscle performance in vivo; preserved muscle contractile function, neuromuscular junction morphology, and muscle innervation; and reduced inflammation and protein oxidation at 18&#x2009;weeks old in hSOD1[G93A] mice. Strikingly, symptomatic hSOD1[G93A] mice exhibited a period of recovery in running ability at 20&#x2009;cm/s several weeks after 2,4-dinitrophenol treatment started at disease onset, offering the first observation in disease phenotype reversal using a small molecule.<br><br>INTERPRETATION: Our results strongly support that micro-dose DNP may be used as a potential novel treatment for ALS patients, with a possibility for recovery, when used at optimal doses and time of intervention. ANN NEUROL 2025;97:542-557.}, }
@article {pmid39547816, year = {2024}, author = {Salmerón-Mendoza, AN and Aguilar-Vázquez, CA and Aguilar-Castillo, SJ}, title = {[Electromyography in atypical variants of motor neuron disease: a case series].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {62}, number = {4}, pages = {1-6}, doi = {10.5281/zenodo.11397347}, pmid = {39547816}, issn = {2448-5667}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Electromyography ; Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Adult ; Aged, 80 and over ; Motor Neuron Disease/diagnosis/physiopathology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both the upper and lower motor neurons, it has a heterogeneous clinical presentation, there are atypical variants that differ from the classic form of the disease. The criteria for diagnosis have evolved over time, with the support of electromyography (EMG), we present a patient series with these variants in which EMG was crucial to make the diagnosis.<br><br>CLINICAL CASES: Six cases are described with atypical presentation of motor neuron disease, for the isolated bulbar ALS phenotype, three cases are reported: two male patients (68 and 62 years old) and one woman (33 years old), with initial symptoms in the bulbar segment and late progression. to a second segment, corroborating characteristic findings by EMG. For the variant of Vulpian-Bernhardt syndrome (VBS), two male patients aged 82 and 72 years are reported, with initial symptoms in the thoracic segment with electromyographic support for the diagnosis; Finally, a case of amyotrophic diplegia of the legs (APD) is described in a 50-year-old female patient with symptoms isolated to the pelvic limbs, with a slow clinical evolution, corroborated by EMG with involvement of other spinal segments.<br><br>CONCLUSIONS: ALS a spectrum of motor neuron disease, a neurodegenerative disease of the CNS, without curative treatment and one with a fatal outcome, the diagnosis of ELA is complex and becomes more complex for atypical phenotypes, as observed in the presented cases EMG is an essential part of the approach and part of the diagnostic criteria.}, }
@article {pmid39545975, year = {2024}, author = {Eickhoff, C and Schöne-Seifert, B and Kettemann, D and Bormann, E and Grehl, T and Boentert, M and Koch, JC and Schmitt, C and Schrank, B and Schröter, C and Meyer, T}, title = {[End of life perspectives: a systematic survey of patients with amyotrophic lateral sclerosis].}, journal = {Der Nervenarzt}, volume = {95}, number = {12}, pages = {1131-1138}, pmid = {39545975}, issn = {1433-0407}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/psychology ; Humans ; Male ; Female ; Middle Aged ; *Terminal Care/psychology ; Aged ; *Advance Directives/psychology ; Surveys and Questionnaires ; Germany ; Adult ; Aged, 80 and over ; Noninvasive Ventilation ; Palliative Care ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease that still has to be primarily treated symptomatically or palliatively. It is therefore all the more important, in addition to initiating treatment, such as percutaneous endoscopic gastrostomy (PEG), noninvasive ventilation therapy (NIVT) and invasive ventilation therapy via tracheotomy (IVT), to discuss the possible termination of these measures early on.<br><br>QUESTION: What is the importance of advance directives for those affected and where are possible deficits in therapy planning for the end of life?<br><br>MATERIAL AND METHOD: Between March 2017 and January 2019 patients with a&#xa0;clinically confirmed diagnosis of ALS at six treatment centers were asked to fill out a&#xa0;questionnaire. A&#xa0;total of 328 people returned the completed forms.<br><br>RESULTS: Of the participants 72% had already made an advance directive (AD), 25% planned to fill one out and only 3% refused to do so. In composing the AD most patients (90%) had support, although 56% lacked medical counselling and only 18% had drawn up the will together with the doctor and relatives, with the majority of the rest also wanting support from a&#xa0;doctor. A&#xa0;total of 37% of all patients wanted a&#xa0;contact person to talk about their illness but only 40% of them had such a&#xa0;contact person. Of the patients 22% stated that they had considered suicide and of these only 55% stated that they had no contact person for the psychological stress caused by the illness but 31% wished to have such a&#xa0;person.<br><br>DISCUSSION AND CONCLUSION: A&#xa0;coordinated care of ALS patients, which also takes the psychosocial aspects into account is urgently needed.}, }
@article {pmid39542176, year = {2024}, author = {Tian, Z and Zhang, Q and Wang, L and Li, M and Li, T and Wang, Y and Cao, Z and Jiang, X and Luo, P}, title = {Progress in the mechanisms of pain associated with neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102579}, doi = {10.1016/j.arr.2024.102579}, pmid = {39542176}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Pain/physiopathology/metabolism/etiology ; Animals ; Neuroinflammatory Diseases ; }, abstract = {Neurodegenerative diseases (NDDs) represent a class of neurological disorders characterized by the progressive degeneration or loss of neurons, impacting millions of individuals globally. In addition to the typical manifestations, pain is a prevalent symptom associated with NDDs, seriously impacting the quality of life for patients. The pathogenesis of pain associated with NDDs is intricate and multifaceted. Currently, the clinical management of NDDs-related pain symptoms predominantly relies on conventional pharmacological agents or physical therapy. However, these approaches often fail to produce satisfactory outcomes. This article summarizes the underlying mechanisms of major NDDs-associated pain: Neuroinflammation, Brain and spinal cord dysfunctions, Mitochondrial dysfunction, Risk gene and pathological protein, as well as Receptor, channel, and neurotransmitter. While numerous studies have investigated the downstream pathological processes associated with these mechanisms, there remains a significant gap in identifying the key initiating factors. Specifically, there is insufficient evidence for the upstream elements that activate microglia and astrocytes in neuroinflammation leading to pain in NDDs. Likewise, there is an absence of upstream factors elucidating how dysfunctions in the brain and spinal cord, as well as mitochondrial impairments, contribute to the development of pain. Furthermore, the specific mechanisms through which hallmark pathological proteins related to NDDs contribute to these pathological processes remain inadequately understood. The objective of this article is to synthesize the existing mechanisms underlying pain associated with NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Schizophrenia, Amyotrophic lateral sclerosis, and Multiple sclerosis, while also identifying gaps and deficiencies in these mechanisms. This paper offers insights for future research trajectories. Given the intricate pathogenesis of NDDs-related pain, it emphasizes that a promising short-term strategy is combination therapy-intervening concurrently in multiple pathological processes-akin to the cocktail approach utilized in treating acquired immunodeficiency syndrome (AIDS). For long-term advancements, achieving breakthroughs in the treatment of the NDDs themselves will remain essential for alleviating accompanying pain symptoms.}, }
@article {pmid39538364, year = {2025}, author = {Terra, R and Éthier, V and Busque, L and Morin-Quintal, A and D'Angelo, G and Hébert, J and Wang, X and Lépine, G and LeBlanc, R and Bergeron, J}, title = {Improved identification of clinically relevant Acute Leukemia subtypes using standardized EuroFlow panels versus non-standardized approach.}, journal = {Cytometry. Part B, Clinical cytometry}, volume = {108}, number = {2}, pages = {116-127}, doi = {10.1002/cyto.b.22213}, pmid = {39538364}, issn = {1552-4957}, support = {//BD Biosciences/ ; }, mesh = {Humans ; *Flow Cytometry/methods ; *Immunophenotyping/methods ; *Leukemia, Myeloid, Acute/diagnosis/pathology ; Adult ; Male ; Female ; Middle Aged ; Aged ; Dendritic Cells/pathology ; Adolescent ; Young Adult ; Aged, 80 and over ; Cell Differentiation ; Child ; Mutation/genetics ; }, abstract = {Rare acute leukemia (AL) components or subtypes such as blastic plasmacytoid dendritic cell neoplasm (BPDCN) or early T-cell precursor acute Lymphoblastic Leukemia (ETP-ALL) can be difficult to detect by routine flow cytometry due to their immunophenotypes overlapping with other poorly differentiated AL. We hypothesized that using standardized EuroFlow™ Consortium approach could better diagnose such entities among cases that previously classified as acute myeloid leukemia (AML)-M0, AML with minimal differentiation, AML with myelodysplasia-related changes without further lineage differentiation, and AL of ambiguous lineage. In order to confirm this hypothesis and assess whether these AL subtypes such as BPDCN and ETP-ALL had previously gone undetected, we reanalyzed 49 banked cryopreserved sample cases using standardized EuroFlow™ Consortium panels. We also performed target sequencing to capture the mutational commonalities between these AL subtypes. Reanalysis led to revised or refined diagnoses for 23 cases (47%). Of these, five diagnoses were modified, uncovering 3 ETP-ALL and 2 typical BPDCN cases. In 12 AML cases, a variable proportion of immature plasmacytoid dendritic cell and/or monocytic component was newly identified. In one AML case, we have identified a megakaryoblastic differentiation. Finally, in five acute lymphoblastic leukemia (ALL) cases, we were able to more precisely determine the maturation stage. The application of standardized EuroFlow flow cytometry immunophenotyping improves the diagnostic accuracy of ALs and could impact treatment decisions.}, }
@article {pmid39538124, year = {2024}, author = {Sun, Y and Hu, S and Lan, Y and Wang, R and Wei, S and Huang, H and Cui, H and Li, X and Huang, Z}, title = {Investigation of resistance mechanisms to flucarbazone-sodium in wild oat (Avena fatua L.) from China.}, journal = {BMC plant biology}, volume = {24}, number = {1}, pages = {1073}, pmid = {39538124}, issn = {1471-2229}, mesh = {*Avena/genetics/drug effects ; China ; Herbicide Resistance/genetics ; Herbicides/pharmacology ; Plant Proteins/genetics/metabolism ; Gene Expression Regulation, Plant/drug effects ; Plant Weeds/genetics/drug effects ; }, abstract = {BACKGROUND: Wild oat (Avena fatua L.) is a self-pollinating, allohexaploid species in the family Gramineae (grasses), which is a malignant weed that mainly harms crops such as wheat. In recent years, a decline in the control efficiency of flucarbazone-sodium against wild oat has occurred in some regions of China.<br><br>RESULTS: We identified an ALS-resistant A. fatua population (R population). Whole-plant response assays revealed that the R population exhibited a moderate level of resistance (5.9-fold) to flucarbazone-sodium. Pre-treatment with malathion significantly reduced flucarbazone-sodium resistance in the R population. The known mutation sites and ALS gene relative expression that confer resistance to ALS inhibitor herbicides were not found in R population. Following flucarbazone-sodium treatment, the expression of eight genes related to metabolic enzymes was investigated using quantitative real-time PCR (qRT-PCR). CYP92A6 and the Aldo/keto reductase family were highly expressed in the R population after the application of flucarbazone-sodium.<br><br>CONCLUSIONS: The mechanism of flucarbazone-sodium resistance in A. fatua is mediated by NTSR, nor TSR. Two genes, CYP92A6 and the Aldo/keto reductase family, were discovered to be possibly related in the metabolism of NTSR in the A. fatua population, justifying more functional studies. The results will serve as a data resource for further studies on the molecular mechanisms of A. fatua to flucarbazone-sodium.}, }
@article {pmid39536963, year = {2025}, author = {Casiraghi, V and Sorce, MN and Santangelo, S and Invernizzi, S and Bossolasco, P and Lattuada, C and Battaglia, C and Venturin, M and Silani, V and Colombrita, C and Ratti, A}, title = {Modeling of TDP-43 proteinopathy by chronic oxidative stress identifies rapamycin as beneficial in ALS patient-derived 2D and 3D iPSC models.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {115057}, doi = {10.1016/j.expneurol.2024.115057}, pmid = {39536963}, issn = {1090-2430}, mesh = {Humans ; *Induced Pluripotent Stem Cells/drug effects ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/drug therapy ; *Oxidative Stress/drug effects/physiology ; *Sirolimus/pharmacology ; *TDP-43 Proteinopathies/pathology/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Arsenites/toxicity/pharmacology ; Sodium Compounds/toxicity/pharmacology ; Motor Neurons/drug effects/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized neuropathologically by TDP-43 proteinopathy with loss of TDP-43 nuclear splicing activity and formation of cytoplasmic TDP-43 aggregates. The lack of suitable experimental models of TDP-43 proteinopathy has hampered the discovery of effective therapies. We already showed that chronic and mild oxidative insult by sodium arsenite (ARS) triggered TDP-43 cytoplasmic aggregation and stress granules (SGs) formation in ALS patient-derived fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs). However, whether this insult induces a reduction of TDP-43 splicing activity in the nucleus, thus recapitulating both gain and loss of function pathomechanisms, still remains to be determined. In this study we first showed that chronic ARS in human neuroblastoma cells triggered TDP-43 cytoplasmic mislocalization, SGs formation and defective splicing of TDP-43 target genes UNC13A and POLDIP3 as functional readouts of TDP-43 proteinopathy. Additionally, a dysregulation of autophagy and senescence markers was observed in this condition. In a preliminary drug screening approach with autophagy-promoting drugs, namely rapamycin, lithium carbonate and metformin, only rapamycin prevented ARS-induced loss of TDP-43 splicing activity. We then demonstrated that, in addition to TDP-43 cytoplasmic aggregation, chronic ARS triggered TDP-43 loss of splicing activity also in ALS patient-derived primary fibroblasts and iPSC-MNs and that rapamycin was beneficial to reduce these TDP-43 pathological features. By switching to a neuro-glial 3D in vitro model, we observed that treatment of ALS iPSC-brain organoids with chronic ARS also induced a defective TDP-43 splicing activity which was prevented by rapamycin. Collectively, we established different human cell models of TDP-43 proteinopathy which recapitulate TDP-43 gain and loss of function, prevented by rapamycin administration. Human neuroblastoma cells and patient-derived fibroblasts and 2D- and 3D-iPSC models exposed to chronic oxidative stress represent therefore suitable in vitro platforms for future drug screening approaches in ALS.}, }
@article {pmid39536438, year = {2024}, author = {Henderson, NL and Ortiz-Olguin, E and Bourne, G and Pywell, C and Rose, JB and Williams, GR and Nipp, RD and Rocque, GB}, title = {Implementation of ePROs Into Multidisciplinary Tumor Board Discussions for Patients With Pancreatic Cancer: The INSPIRE Intervention.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {9}, pages = {602-609}, doi = {10.6004/jnccn.2024.7052}, pmid = {39536438}, issn = {1540-1413}, mesh = {Humans ; *Pancreatic Neoplasms/therapy ; Female ; Male ; *Patient Reported Outcome Measures ; Aged ; Middle Aged ; Patient Care Team/standards ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: The incorporation of electronic patient-reported outcomes (ePROs), such as the Geriatric Assessment (GA) and treatment preferences, into decision-making for pancreatic cancer has been limited by clinician- and system-level barriers concerning workflow. We hypothesized that ePRO inclusion within multidisciplinary tumor boards (MDTBs) would circumvent barriers and provide a venue for systematic consideration of critical patient-provided information.<br><br>PATIENTS AND METHODS: The INtegrating Systematic PatIent-Reported Evaluations (INSPIRE) intervention consists of (1) patient survey completion, including GA and patient preferences, and (2) screensharing patient ePROs during MDTBs. Proctor et al's implementation outcomes were assessed, with penetration (the proportion of consented patients who were presented at MDTBs) acting as the primary outcome (considered successful at 70%). Secondary outcomes included adoption, feasibility, acceptability, appropriateness, cost, and sustainability, assessed by clinician post-MDTB exit surveys, clinician postintervention surveys, clinician postintervention semistructured interviews, and time-coding analysis of recorded and transcribed historical (November 2021-February 2022) and intervention (September 2022-June 2023) MDTBs.<br><br>RESULTS: A total of 50 patients completed surveys and all were presented at MDTBs (penetration=100%). All eligible clinicians (n=9) enrolled patients (adoption=100%) and reported that ePROs were useful in 90% and led to a change in treatment plan in 30% of cases. In postintervention surveys and interviews, clinicians primarily responded positively to feasibility, acceptability, and appropriateness questions. Time-coding analysis found a modest time cost of an additional 51.1 seconds in mean discussion time-per-patient between preintervention (mean [SD], 172.7 [111.4] seconds) and intervention patients (mean [SD], 223.8 [107.1] seconds); 86% of clinicians reported the intervention did not take too much time. All surveyed clinicians reported interest in continuing the intervention and suggested adaptations to further promote sustainability.<br><br>CONCLUSIONS: The integration of ePROs into pancreatic MDTBs was feasible and acceptable, providing a potential approach to increase the utilization of ePROs by clinical teams in their management of patients with pancreatic cancer.}, }
@article {pmid39535924, year = {2024}, author = {Hannestad, J and Smith, S and Lam, A and Hurt, J and Harada, N and Kim, R and Das, A and Brunello, J and Whitaker, G and Chalmers, D and Senjoti, F and Lin, W and Coghill, J and Bansal, Y and Sidhu, S and Zann, V and Liu, E}, title = {A randomized, placebo-controlled first-in-human study of oral TQS-168 in healthy volunteers: Assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect.}, journal = {Clinical and translational science}, volume = {17}, number = {11}, pages = {e70064}, pmid = {39535924}, issn = {1752-8062}, mesh = {Humans ; Male ; *Food-Drug Interactions ; Adult ; Administration, Oral ; *Healthy Volunteers ; Young Adult ; Middle Aged ; Area Under Curve ; Double-Blind Method ; Dose-Response Relationship, Drug ; Methylcellulose/administration &amp; dosage/analogs &amp; derivatives/chemistry ; Spray Drying ; Suspensions ; Cross-Over Studies ; Placebos/administration &amp; dosage ; }, abstract = {TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach. Dosing in the SAD part was initiated with a crystalline methylcellulose (MC) suspension, and then spray-dried dispersion (SDD) and hot-melt extrusion (HME) suspensions were evaluated. The HME and SDD formulations showed two and fourfold higher exposure than the MC suspension, respectively, and the SDD formulation was selected for progression to subsequent SAD and MAD cohorts, in which there was further investigation of the food effect on exposure in addition to assessments of safety, tolerability, PK, and PD. Cmax and AUC plasma exposures of TQS-168 were supra-proportional at higher doses, irrespective of formulation. Median Tmax for TQS-168 occurred between 0.5 and 4.0 h post-dose and occurred later with higher doses. Geometric mean half-lives (T1/2) for TQS-168 were independent of formulation and food, ranging from 3.2 to 10.5 h following single doses and 4.1 to 7.3 h following multiple doses. Food blunted TQS-168 Cmax but had minimal impact on AUC. TQS-168 was considered to be safe and generally well tolerated following single and multiple oral doses. The SDD formulation was selected for future patient studies.}, }
@article {pmid39531940, year = {2024}, author = {Pioro, EP and Brooks, BR and Liu, Y and Zhang, J and Apple, S}, title = {Efficacy of Radicava® IV (intravenous edaravone) in subjects with differing trajectories of disease progression in amyotrophic lateral sclerosis: Use of a novel statistical approach for post hoc analysis of a pivotal phase 3 clinical trial.}, journal = {Journal of the neurological sciences}, volume = {467}, number = {}, pages = {123290}, doi = {10.1016/j.jns.2024.123290}, pmid = {39531940}, issn = {1878-5883}, mesh = {Humans ; *Edaravone/therapeutic use/administration &amp; dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Disease Progression ; Male ; Female ; Middle Aged ; Aged ; Treatment Outcome ; Double-Blind Method ; Free Radical Scavengers/therapeutic use/administration &amp; dosage ; Administration, Intravenous ; }, abstract = {INTRODUCTION: Subjects with amyotrophic lateral sclerosis (ALS) treated with Radicava® (edaravone) IV (intravenous; Mitsubishi Tanabe Pharma America [MTPA], hereafter "MTPA IV edaravone") in Study MCI186-19 had a significantly slower physical functional decline vs placebo-treated subjects as measured by the revised ALS Functional Rating Scale (ALSFRS-R) and analyzed by the linear mixed model for repeated measures (MMRM). This Study 19 post hoc analysis of MTPA IV edaravone-treated and placebo-treated subjects evaluated linear and nonlinear latent class mixed models defining trajectories based on identifying the model with the lowest Bayesian information criterion. The best model differentiated 4 nonlinear trajectories in ALS subjects. ALSFRS-R total score in MTPA IV edaravone-treated and placebo-treated subjects was evaluated for these 4 nonlinear latent class trajectory groups.<br><br>METHODS: Disease trajectories of MCI186-19 MTPA IV edaravone-treated or placebo-treated ALS subjects who completed the double-blind period were investigated using latent class analysis (LCA) statistical models to identify potential unique nonlinear ALSFRS-R disease trajectories.<br><br>RESULTS: ALSFRS-R trajectories revealed 4 unique nonlinear trajectory latent classes per treatment group in MTPA IV edaravone-treated and placebo-treated ALS subjects completing the MCI186-19 double-blind period. Latent classes 2-4 had statistically significant slowing of ALSFRS-R total score decline in the predicted nonlinear trajectories of MTPA IV edaravone-treated vs placebo-treated ALS subjects.<br><br>CONCLUSIONS: This post hoc analysis suggests MTPA IV edaravone treatment results in slower ALSFRS-R decline vs placebo in most predicted nonlinear trajectories. LCA is a novel approach that may benefit future trial analyses.}, }
@article {pmid39523617, year = {2024}, author = {Iguchi, Y and Katsuno, M}, title = {[Current Status of Drug Development for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1241-1249}, doi = {10.11477/mf.1416202766}, pmid = {39523617}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Drug Development ; Clinical Trials as Topic ; Animals ; Riluzole/therapeutic use ; Neuroprotective Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease of motor neuron. Although riluzole and edaravone have been approved for the treatment of ALS, it remains a lethal disease that causes rapid motor impairment, and there is an urgent need to develop more effective treatments. Advances in understanding the pathomechanisms of ALS, efficient clinical trial design, and research support programs have led to many clinical trials for ALS both domestically and internationally.}, }
@article {pmid39523616, year = {2024}, author = {Ishiguro, T and Nagata, T and Yokota, T}, title = {[Current Landscape of Tofersen in SOD-1-associated Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1233-1239}, doi = {10.11477/mf.1416202765}, pmid = {39523616}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; Humans ; *Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Since the identification, in 1993, of the causative gene for familial amyotrophic lateral sclerosis (ALS), which is associated with SOD1 mutations, research has focused on the pathogenesis and therapeutics of ALS for more than 30 years. Tofersen, a highly anticipated gene-specific therapy that has been aligned with the disease-specific pathology, has been approved for marketing by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) However, as significant data on tofersen's safety and efficacy are required, the evaluation of this treatment is ongoing. This paper introduces the current clinical and commercial status of Tofersen, along with expectations for its approval in Japan.}, }
@article {pmid39523615, year = {2024}, author = {Ogino, M}, title = {[Palliative Care for Persons with Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1225-1232}, doi = {10.11477/mf.1416202764}, pmid = {39523615}, issn = {1881-6096}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Analgesics, Opioid/administration &amp; dosage ; Japan ; *Palliative Care ; }, abstract = {Palliative care in Japan is available mainly for patients with cancer, and palliative care specialists do not have sufficient experience with management of palliation in persons with amyotrophic lateral sclerosis (ALS). Treatment of ALS symptoms is an important component of palliative care, and it is important that neurologists and home care physicians familiarize themselves with palliative care for ALS in consultation with palliative care specialists. Notably, the use of opioids at the end of life differs from that of pain relief for cancer. Physicians should be mindful that opioids are not a perfect solution for palliative care of persons with ALS.}, }
@article {pmid39523614, year = {2024}, author = {Yamakawa, I and Urushitani, M}, title = {[Gold Coast Criteria: A New Diagnostic Paradigm in the Era of Disease-Modifying Therapy for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1217-1223}, doi = {10.11477/mf.1416202763}, pmid = {39523614}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Humans ; }, abstract = {Significant progress has been made in the development of disease-modifying drugs for amyotrophic lateral sclerosis (ALS), with the introduction of tofersen, an antisense oligonucleotide drug for familial ALS, marking a turning point in the treatment. These drugs are most effective when administered early in the disease course, highlighting the need for improved diagnostic sensitivity. The 2020 Gold Coast Diagnostic Criteria allow ALS diagnosis in cases without upper motor neuron symptoms, potentially increasing early detection rates. However, careful differential diagnoses are necessary when applying these criteria to maintain diagnostic specificity. This review outlines the key points to consider when using the Gold Coast Criteria, balancing the need for an early diagnosis with caution to avoid overdiagnosis.}, }
@article {pmid39523613, year = {2024}, author = {Fukutake, T}, title = {[Diagnosis, Notification, and Managements of ALS: A Personal Perspective from 40 years of Experience as a Clinical Neurologist].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1205-1216}, doi = {10.11477/mf.1416202762}, pmid = {39523613}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Humans ; *Neurologists ; Female ; Middle Aged ; Male ; Aged ; }, abstract = {This narrative summary presents the author's 40-year experience as a clinical neurologist who treated patients with amyotrophic lateral sclerosis (ALS). Five representative cases from the author's first 20 years at Chiba University Hospital and its affiliated hospitals were selected, including a patient of respiratory-onset who was ignorantly extubated by a female relative for patient's distress to the intratracheal tube. Based on the latter 20 years of experience at the author's current hospital, the author first describes a famous patient with ALS who was being treated at this medical center before the author was assigned to this hospital and fought against ALS for 31 years before eventually succumbing to total locked-in syndrome. Thereafter, the author has summarized the ages, sex, phenotypes, comorbidities, responses to the available treatment options, and total number of years that have elapsed for the 24 patients that the author initially examined in the outpatient clinic. In terms of diagnostic delay, the author describes "foot drop" in patients who developed lower limb symptoms, and hoarseness in those who developed bulbar palsy. Furthermore, the author discusses issues regarding family caregiving capacity, patient's and families' understanding of notification, and medical management (i.e., medications, rehabilitation for ADL, nutrition and respiration, complications of frontotemporal dementia, and medical cooperation with other clinics and hospitals).}, }
@article {pmid39522723, year = {2025}, author = {Nardone, V and Esposito, A and D'Ippolito, E and Argenziano, G and Reginelli, A and Troiani, T}, title = {Response to Sajid et al's "Response to Valerio Nardone et al's 'Previous radiotherapy increases the efficacy of cemiplimab in the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma: A retrospective analysis'".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e55-e56}, doi = {10.1016/j.jaad.2024.10.058}, pmid = {39522723}, issn = {1097-6787}, }
@article {pmid39522697, year = {2024}, author = {Gao, L and Yang, XN and Dong, YX and Han, YJ and Zhang, XY and Zhou, XL and Liu, Y and Liu, F and Fang, JS and Ji, JL and Gao, ZR and Qin, XM}, title = {The potential therapeutic strategy in combating neurodegenerative diseases: Focusing on natural products.}, journal = {Pharmacology &amp; therapeutics}, volume = {264}, number = {}, pages = {108751}, doi = {10.1016/j.pharmthera.2024.108751}, pmid = {39522697}, issn = {1879-016X}, mesh = {Humans ; *Biological Products/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and Multiple sclerosis (MS), pose a significant global health challenge due to their intricate pathology and limited therapeutic interventions. Natural products represent invaluable reservoirs for combating these neurodegenerative diseases by targeting key pathological hallmarks such as protein aggregation, synaptic dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, inflammation, and neuronal cell death. This review provides an in-depth analysis of the mechanisms and therapeutic targets of natural products for their neuroprotective effects. Furthermore, it elucidates the current progress of clinical trials investigating the potential of natural products in delaying neurodegeneration. The objective of this review is to enhance the comprehension of natural products in the prevention and treatment of neurodegenerative diseases, offering new insights and potential avenues for future pharmaceutical research.}, }
@article {pmid39521994, year = {2024}, author = {Liang, H and Zhou, X and Zhang, J and Xu, W and Liu, Y and Wang, X and Hu, Y and Xu, R and Li, X}, title = {The therapeutic potential of Apigenin in amyotrophic lateral sclerosis through ALDH1A2/Nrf2/ARE signaling.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {30}, number = {1}, pages = {206}, pmid = {39521994}, issn = {1528-3658}, support = {81960244//National Natural Science Foundation of China/ ; 20212BAB216026//Jiangxi Natural Science Foundation/ ; 202110016//Science and Technology Plan of Jiangxi Provincial Health Commission/ ; 2022B975//Science and Technology Plan of Jiangxi Provincial Administration of Traditional Chinese Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; Animals ; *Apigenin/pharmacology/therapeutic use ; Mice ; *Signal Transduction/drug effects ; *Mice, Transgenic ; *Disease Models, Animal ; *NF-E2-Related Factor 2/metabolism/genetics ; Oxidative Stress/drug effects ; Aldehyde Dehydrogenase 1 Family/metabolism/genetics ; Humans ; Apoptosis/drug effects ; Retinal Dehydrogenase/metabolism/genetics ; Cell Line ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss leading to muscle weakness and atrophy. Apigenin (APG), known for its antioxidant properties, holds potential as a therapeutic compound in ALS.<br><br>METHODS: We used the Tg(SOD1*G93A)1Gur/J transgenic mouse model of ALS to investigate the therapeutic effects of APG. Key measured included motor function via the ALSTDI score, molecular markers of oxidative stress (OS) and apoptosis in spinal cord tissues. Techniques used included pathological, Western blotting, flow cytometry, and qRT-PCR to assess the effect of ALDH1A2.<br><br>RESULTS: APG treatment attenuated weight loss and improved motor function scores in ALS mice compared to untreated ALS models. Molecular analyses revealed a significant upregulation of ALDH1A2 in APG-treated groups, along with a reduction in markers of OS and apoptosis. In vitro studies in NSC34 cells further confirmed the protective effects of APG against SOD1*G93A mutation-induced cytotoxicity. In addition, suppression of ALDH1A2 by shRNA exacerbated disease markers that were ameliorated by APG treatment.<br><br>CONCLUSIONS: Our results suggest that APG attenuates the progression of ALS pathology by regulating OS and apoptosis through ALDH1A2. These results support further investigation of APG as a potential therapeutic agent for the treatment of ALS.}, }
@article {pmid39521135, year = {2025}, author = {Sajid, SL and Ur Rehman, MA and Sajid, SA and Shahid, N}, title = {Response to Valerio Nardone et al's "Previous radiotherapy increases the efficacy of cemiplimab in the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma: A retrospective analysis".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e53-e54}, doi = {10.1016/j.jaad.2024.08.084}, pmid = {39521135}, issn = {1097-6787}, }
@article {pmid39520580, year = {2024}, author = {Hyldgaard Andersen, S and Harsløf, S and Tøttrup, A}, title = {Laparoscopic ileopexy for afferent loop syndrome after restorative proctocolectomy-a retrospective case series.}, journal = {International journal of colorectal disease}, volume = {39}, number = {1}, pages = {180}, pmid = {39520580}, issn = {1432-1262}, mesh = {Humans ; *Proctocolectomy, Restorative/adverse effects ; *Laparoscopy/adverse effects ; Female ; Male ; Retrospective Studies ; Middle Aged ; Adult ; *Afferent Loop Syndrome/surgery/etiology ; *Ileum/surgery ; Aged ; Treatment Outcome ; Postoperative Complications/etiology/surgery ; }, abstract = {BACKGROUND: To study the effect of laparoscopic ileopexy in patients with afferent-loop syndrome (ALS) after restorative proctocolectomy (RP).<br><br>METHOD: Ileopexy has been the treatment of choice in patients with ALS for the last 5&#xa0;years at our department. All patients who had undergone ileopexy for ALS between January 2019 and August 2023 were identified. Data were extracted from the medical records. All patients were contacted and asked standardized questions regarding symptoms of ALS. A symptom score was calculated and compared before surgery and at the last follow-up.<br><br>RESULTS: Ten patients, who had undergone ileopexy for ALS, were identified. Eight of these (80%) had been admitted with small bowel obstruction due to ALS. The remaining 2 patients had other symptoms indicative of ALS. In all patients, ileopexy was immediately effective in reducing symptoms. Symptoms recurred after 16.5&#xa0;weeks (2-80) in 8 patients. Repeat laparoscopy showed that the ileopexy had slipped in 6 of these. Six had a new ileopexy with mesh. Later, one of these developed recurrent symptoms and had a new mesh ileopexy performed. No mesh complications were seen. Symptom score was reduced from 6.5 (1-9) to 2 (0-7) (p&#x2009;=&#x2009;0.02) at the last follow-up.<br><br>CONCLUSIONS: In this study, ileopexy is effective in reducing symptoms of ALS after RP. In a high proportion of patients, it is necessary to use mesh to ensure long-term fixation of the ileum.}, }
@article {pmid39513379, year = {2025}, author = {Simkins, TJ and Kupfer, S and Malik, FI and Meng, L and Rudnicki, SA and Wei, J and Shefner, JM and Bowser, R}, title = {Plasma neurofilament analysis in VITALITY-ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {103-112}, doi = {10.1080/21678421.2024.2423707}, pmid = {39513379}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/drug therapy ; Middle Aged ; Double-Blind Method ; *Neurofilament Proteins/blood ; Aged ; *Disease Progression ; Biomarkers/blood ; Longitudinal Studies ; Adult ; Intermediate Filaments/metabolism ; }, abstract = {OBJECTIVE: To evaluate correlations between neurofilament (Nf) concentrations and clinical characteristics and disease progression using a large longitudinal dataset from VITALITY-ALS (ClinicalTrials.gov identifier: NCT02496767), a 48-week, randomized, double-blind, placebo-controlled clinical trial of tirasemtiv in people with ALS (pALS).<br><br>METHODS: Plasma was collected at baseline and every 8 weeks thereafter. Results were compared between treatment groups and evaluated by clinical characteristics and over time. Pearson's correlation coefficients (r) were calculated to evaluate associations between Nf concentrations and slow vital capacity (SVC), Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score, and pre-study/in-study rates of disease progression (psRDP/isRDP).<br><br>RESULTS: Nf measurements were available from 101 placebo- and 161 tirasemtiv-treated people with ALS (pALS). There were no significant differences in Nf between placebo and tirasemtiv groups at any time point; further analyses grouped all samples. At baseline, Nf concentration did not differ by multiple clinical characteristics. Baseline Nf light chain (NfL) concentration correlated with the psRDP (r&#xa0;=&#xa0;0.50, p&#xa0;<&#xa0;0.001) and isRDP (r&#xa0;=&#xa0;0.53, p&#xa0;<&#xa0;0.0001). Phosphorylated Nf heavy chain (pNfH) demonstrated a similar, but less robust, pattern of results. Baseline Nf concentration correlated with change in SVC and ALSFRS-R score over time. Plasma pNfH concentration continuously decreased over time. There was no meaningful change in plasma NfL concentration over the study period.<br><br>CONCLUSIONS: In this large longitudinal study, baseline NfL concentration correlated with multiple markers of disease progression. The findings suggest Nfs show promise primarily as prognostic markers for pALS, particularly for those with rapid disease progression.}, }
@article {pmid39511965, year = {2025}, author = {Bhai, S and Levine, T and Moore, D and Bowser, R and Heim, AJ and Walsh, M and Shibani, A and Simmons, Z and Grogan, J and Goyal, NA and Govindarajan, R and Hussain, Y and Papsdorf, T and Schwasinger-Schmidt, T and Olney, N and Goslin, K and Pulley, M and Kasarskis, E and Weiss, M and Katz, SW and Moser, S and Jabari, D and Jawdat, O and Statland, J and Dimachkie, MM and Barohn, R and , }, title = {A 40-week phase 2B randomized, multicenter, double-blind, placebo-controlled study evaluating the safety and efficacy of memantine in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {71}, number = {1}, pages = {63-72}, pmid = {39511965}, issn = {1097-4598}, support = {R01 FD003937/FD/FDA HHS/United States ; R01FD003937//FDA-OPD/ ; //U.S. Food and Drug Administration/ ; }, mesh = {Humans ; *Memantine/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Double-Blind Method ; Middle Aged ; Aged ; Adult ; Aged, 80 and over ; *Disease Progression ; Treatment Outcome ; Young Adult ; Excitatory Amino Acid Antagonists/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with no known cure, limited treatment options with minimal benefits, and significant unmet need for disease modifying therapies.<br><br>AIMS: This study investigated memantine's impact on ALS progression, with an additional focus on the effects of memantine on cognitive and behavioral changes associated with the disease.<br><br>METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted from December 2018 to September 2020. ALS patients were enrolled in-person and remotely across 13 sites in the United States. Participants were randomized to memantine (20&#x2009;mg twice daily) or placebo in a 2:1 ratio and completed 36&#x2009;weeks of treatment. The primary outcome of disease progression was assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and blood was collected for biomarker analysis.<br><br>RESULTS: Of the 99 participants enrolled in the study, 89 were randomized to memantine or placebo (ages 24-83&#x2009;years, male-to-female ratio ~3:2). Fifty-two participants completed the study treatment with no significant differences in disease progression, biomarker changes (including neurofilament light chain [NfL]), or neuropsychiatric testing noted between the groups. Initial NfL values correlated with the rate of ALSFRS-R decline.<br><br>DISCUSSION: In this study, memantine did not impact ALS disease progression or neuropsychiatric symptoms. Trials with remote enrollment may help trial participation and success.}, }
@article {pmid39509425, year = {2024}, author = {Deng, YC and Liu, JW and Ting, HC and Kuo, TC and Chiang, CH and Lin, EY and Harn, HJ and Lin, SZ and Chang, CY and Chiou, TW}, title = {n-Butylidenephthalide recovered calcium homeostasis to ameliorate neurodegeneration of motor neurons derived from amyotrophic lateral sclerosis iPSCs.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0311573}, pmid = {39509425}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; *Induced Pluripotent Stem Cells/metabolism/drug effects ; Humans ; *Motor Neurons/drug effects/metabolism/pathology ; *Calcium/metabolism ; *Homeostasis/drug effects ; *Superoxide Dismutase-1/genetics/metabolism ; *Phthalic Anhydrides/pharmacology ; Cell Differentiation/drug effects ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that causes muscle atrophy and primarily targets motor neurons (MNs). Approximately 20% of familial ALS cases are caused by gain-of-function mutations in superoxide dismutase 1 (SOD1), leading to MN degeneration and ion channel dysfunction. Previous studies have shown that n-Butylidenephthalide (BP) delays disease progression and prolongs survival in animal models of ALS. However, no studies have been conducted on models from human sources. Herein, we examined the protective efficacy of BP on MNs derived from induced pluripotent stem cells (iPSCs) of an ALS patient harboring the SOD1G85R mutation as well as on those derived from genetically corrected iPSCs (SOD1G85G). Our results demonstrated that the motor neurons differentiated from iPSC with SOD1G85R mutation exhibited characteristics of neuron degeneration (as indicated by the reduction of neurofilament expression) and ion channel dysfunction (in response to potassium chloride (KCl) and L-glutamate stimulation), in contrast to those derived from the gene corrected iPSC (SOD1G85G). Meanwhile, BP treatment effectively restored calcium ion channel function by reducing the expression of glutamate receptors including glutamate ionotropic receptor AMPA type subunit 3 (GluR3) and glutamate ionotropic receptor NMDA type subunit 1 (NMDAR1). Additionally, BP treatment activated autophagic pathway to attenuate neuron degeneration. Overall, this study supports the therapeutic effects of BP on ALS patient-derived neuron cells, and suggests that BP may be a promising candidate for future drug development.}, }
@article {pmid39503018, year = {2024}, author = {Rennie, O and Sharma, M and Helwa, N}, title = {Hepatobiliary anastomotic leakage: a narrative review of definitions, grading systems, and consequences of leaks.}, journal = {Translational gastroenterology and hepatology}, volume = {9}, number = {}, pages = {70}, pmid = {39503018}, issn = {2415-1289}, abstract = {BACKGROUND AND OBJECTIVE: Hepatobiliary diseases are a longstanding and significant medical challenge which, despite advances in surgical techniques, still carry risks for postoperative complications such as anastomotic leaks (ALs), which can include both postoperative pancreatic fistula (POPF) and bile leaks (BL). These complications incur significant human and economic costs on all those involved, including the patient, healthcare providers, and hospital systems. The aim of this study was to construct a narrative review of literature surrounding definitions and grading systems for ALs in the context of hepato-pancreato-biliary (HPB) procedures, and consequences of POPF and BL.<br><br>METHODS: A literature review was conducted by examining databases including PubMed, Web of Science, OVID Embase, Google Scholar, and Cochrane library databases. Searches were performed with the following search criteria: (((((((anastomosis) OR (anastomotic leak*)) OR (postoperative pancreatic fistula)) OR (bile leak*)) OR (pancreaticoduodenectomy)) OR (whipple)) AND ((hepatobiliary) OR (hepato-pancreato-biliary)) AND ((definition) OR (grading system*) OR (consequences) OR (outcomes) OR (risk factor*) OR (morbidity) OR (mortality))). Publications that were retrieved underwent further assessment to ensure other relevant publications were identified and included.<br><br>KEY CONTENT AND FINDINGS: A universally accepted definition and grading system for POPF and BL continues to be lacking, leading to variability in reported incidence in the literature. Various groups have worked to publish guidelines for defining and grading POPF and BL, with the International Study Group in Pancreatic Surgery (ISGPS) and International Study Group for Liver Surgery (ISGLS) definitions the current most recommended definitions for POPF and BL, respectively. The burden of AL on patients, healthcare providers, and hospitals is well documented in evidence from leak consequences, such as increased morbidity and mortality, higher reoperation rates, and increased readmission rates, among others.<br><br>CONCLUSIONS: AL remains a significant challenge in HPB surgery, despite medical advancements. Understanding the progress made in defining and grading leaks, as well as the range of negative outcomes that arise from AL, is crucial in improving patient care, reduce surgical mortality, and drive further advancements in earlier detection and treatment of AL.}, }
@article {pmid39494653, year = {2025}, author = {Springer, SA}, title = {Commentary on Gregory et al.: Fear of precipitated opioid withdrawal should not prevent buprenorphine initiation.}, journal = {Addiction (Abingdon, England)}, volume = {120}, number = {1}, pages = {21-22}, pmid = {39494653}, issn = {1360-0443}, support = {DP1 DA056106/DA/NIDA NIH HHS/United States ; NIDA DP1DA056106/DA/NIDA NIH HHS/United States ; }, abstract = {Provision of buprenorphine treatment for opioid use disorder is often stymied by clinicians’ concerns for precipitated opioid withdrawal. Gregory et al’s systematic review identified a low level of precipitated withdrawal with buprenorphine induction even among persons who reported fentanyl use. Evidence, not fear should guide treatment.}, }
@article {pmid39494098, year = {2024}, author = {Xu, AX and Zhao, ZF and Zhu, L and Zhang, YH and Li, Y and Wei, YF and Zhang, BY and Jiang, B and Gao, TZ and Li, MS and Liu, JY}, title = {Promise and challenges of traditional Chinese medicine, specifically Calculus bovis, in liver cancer treatment.}, journal = {World journal of gastroenterology}, volume = {30}, number = {40}, pages = {4380-4385}, pmid = {39494098}, issn = {2219-2840}, mesh = {Humans ; Drugs, Chinese Herbal/therapeutic use ; *Liver Neoplasms/therapy/pathology/mortality ; *Medicine, Chinese Traditional/methods ; Neoplasm Staging ; Quality of Life ; Treatment Outcome ; }, abstract = {Liver cancer, one of the most common malignancies worldwide, ranks sixth in incidence and third in mortality. Liver cancer treatment options are diverse, including surgical resection, liver transplantation, percutaneous ablation, transarterial chemoembolization, radiotherapy, chemotherapy, targeted therapy, immunotherapy, and traditional Chinese medicine (TCM). A multidisciplinary team (MDT) is essential to customize treatment plans based on tumor staging, liver function, and performance status (PS), ensuring individualized patient care. Treatment decisions require a MDT to tailor strategies based on tumor staging, liver function, and PS, ensuring personalized care. The approval of new first-line and second-line drugs and the establishment of standard treatments based on immune checkpoint inhibitors have significantly expanded treatment options for advanced liver cancer, improving overall prognosis. However, many patients do not respond effectively to these treatments and ultimately succumb to the disease. Modern oncology treatments, while extending patient survival, often come with severe side effects, resistance, and damage to the body, negatively impacting quality of life. Huang et al's study published at World Journal of Gastroenterology rigorously validates the anticancer properties of Calculus bovis, enhancing our understanding of TCM and contributing to new liver cancer treatment strategies. For over 5000 years, TCM has been used in East Asian countries like China to treat various diseases, including liver conditions. Analysis of real-world clinical data suggests that for patients with advanced-stage tumors lacking effective treatments, integrated TCM therapies could provide significant breakthroughs.}, }
@article {pmid39491718, year = {2024}, author = {Sharma, R and Khan, Z and Mehan, S and Das Gupta, G and Narula, AS}, title = {Unraveling the multifaceted insights into amyotrophic lateral sclerosis: Genetic underpinnings, pathogenesis, and therapeutic horizons.}, journal = {Mutation research. Reviews in mutation research}, volume = {794}, number = {}, pages = {108518}, doi = {10.1016/j.mrrev.2024.108518}, pmid = {39491718}, issn = {1388-2139}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Mutation/genetics ; RNA-Binding Protein FUS/genetics ; C9orf72 Protein/genetics ; Animals ; Superoxide Dismutase-1/genetics ; DNA-Binding Proteins/genetics ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS), a progressive neurodegenerative disease, primarily impairs upper and lower motor neurons, leading to debilitating motor dysfunction and eventually respiratory failure, widely known as Lou Gehrig's disease. ALS presents with diverse symptomatology, including dysarthria, dysphagia, muscle atrophy, and hyperreflexia. The prevalence of ALS varies globally, with incidence rates ranging from 1.5 to 3.8 per 100,000 individuals, significantly affecting populations aged 45-80. A complex interplay of genetic and environmental factors underpins ALS pathogenesis. Key genetic contributors include mutations in chromosome 9 open reading frame 72 (C9ORF72), superoxide dismutase type 1 (SOD1), Fusedin sarcoma (FUS), and TAR DNA-binding protein (TARDBP) genes, accounting for a considerable fraction of both familial (fALS) and sporadic (sALS) cases. The disease mechanism encompasses aberrant protein folding, mitochondrial dysfunction, oxidative stress, excitotoxicity, and neuroinflammation, contributing to neuronal death. This review consolidates current insights into ALS's multifaceted etiology, highlighting the roles of environmental exposures (e.g., toxins, heavy metals) and their interaction with genetic predispositions. We emphasize the polygenic nature of ALS, where multiple genetic variations cumulatively influence disease susceptibility and progression. This aspect underscores the challenges in ALS diagnosis, which currently lacks specific biomarkers and relies on symptomatology and familial history. Therapeutic strategies for ALS, still in nascent stages, involve symptomatic management and experimental approaches targeting molecular pathways implicated in ALS pathology. Gene therapy, focusing on specific ALS mutations, and stem cell therapy emerge as promising avenues. However, effective treatments remain elusive, necessitating a deeper understanding of ALS's genetic architecture and the development of targeted therapies based on personalized medicine principles. This review aims to provide a comprehensive understanding of ALS, encouraging further research into its complex genetic underpinnings and the development of innovative, effective treatment modalities.}, }
@article {pmid39491419, year = {2023}, author = {Talebi, M and Sadoughi, MM and Ayatollahi, SA and Ainy, E and Kiani, R and Zali, A and Miri, M}, title = {Therapeutic potentials of cannabidiol: Focus on the Nrf2 signaling pathway.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {168}, number = {}, pages = {115805}, doi = {10.1016/j.biopha.2023.115805}, pmid = {39491419}, issn = {1950-6007}, abstract = {Cannabidiol (CBD), a cannabinoid that does not create psychoactive activities, has been identified as having a multitude of therapeutic benefits. This study delves into the chemical properties, pharmacokinetics, safety and toxicity, pharmacological effects, and most importantly, the association between the therapeutic potential of CBD and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The relationship between Nrf2 and CBD is closely linked to certain proteins that are associated with cardiovascular dysfunctions, cancers, and neurodegenerative conditions. Specifically, Nrf2 is connected to the initiation and progression of diverse health issues, including nephrotoxicity, bladder-related diseases, oral mucositis, cancers, obesity, myocardial injury and angiogenesis, skin-related inflammations, psychotic disorders, neuropathic pain, Huntington's disease, Alzheimer's disease, Parkinson's disease, neuroinflammation, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. The association between CBD and Nrf2 is a zone of great interest in the medical field, as it has the potential to significantly impact the treatment and prevention of wide-ranging health conditions. Additional investigation is necessary to entirely apprehend the mechanisms underlying this crucial interplay and to develop effective therapeutic interventions.}, }
@article {pmid39490684, year = {2024}, author = {Liu, YJ and Lee, CW and Liao, YC and Huang, JJ and Kuo, HC and Jih, KY and Lee, YC and Chern, Y}, title = {The role of adiponectin-AMPK axis in TDP-43 mislocalization and disease severity in ALS.}, journal = {Neurobiology of disease}, volume = {202}, number = {}, pages = {106715}, doi = {10.1016/j.nbd.2024.106715}, pmid = {39490684}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; *Adiponectin/metabolism ; *DNA-Binding Proteins/metabolism ; Male ; Female ; Middle Aged ; *AMP-Activated Protein Kinases/metabolism ; Aged ; Motor Neurons/metabolism ; Severity of Illness Index ; }, abstract = {Hypermetabolism is a prominent characteristic of ALS patients. Aberrant activation of AMPK, an energy sensor regulated by adiponectin, is known to cause TDP-43 mislocalization, an early event in ALS pathogenesis. This study aims to evaluate the association between key energy mediators and clinical severity in ALS patients. We found that plasma adiponectin levels were significantly higher in ALS patients with ALSFRS-R scores below 38 compared to controls (p = 0.047). Additionally, adiponectin concentration was inversely correlated with ALSFRS-R scores (p = 0.021). Immunofluorescence staining of PBMCs revealed negative associations between AMPK activation, TDP-43 mislocalization, and ALSFRS-R scores. We then examined the hypothesis that adiponectin may activate the AMPK-TDP-43 axis in motor neurons. Our results demonstrated that adiponectin treatment of NSC34 cells and HiPSC-MNs induced AMPK activation and TDP-43 mislocalization in an adiponectin receptor-dependent manner. Collectively, these findings suggest that elevated plasma adiponectin may enhance AMPK activation, leading to TDP-43 mislocalization in both PBMCs and motor neurons of ALS patients. This highlights the potential involvement of the adiponectin-AMPK-TDP-43 axis in the dysregulated energy balance observed in ALS.}, }
@article {pmid39486809, year = {2024}, author = {Van Loon, FT and Seitidis, G and Mavridis, D and van Unnik, JWJ and Weemering, DN and van den Berg, LH and Bethani, I and Nikolakopoulos, S and van Eijk, RPA}, title = {Living systematic review and comprehensive network meta-analysis of ALS clinical trials: study protocol.}, journal = {BMJ open}, volume = {14}, number = {10}, pages = {e087970}, pmid = {39486809}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Clinical Trials as Topic ; Disease Progression ; Network Meta-Analysis ; Research Design ; Systematic Reviews as Topic ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurogenerative disease with no effective treatment to date. Despite numerous clinical trials, the majority of studies have been futile in their effort to significantly alter the course of the disease. However, these studies may still provide valuable information for identifying patient subgroups and generating new hypotheses for future research. Additionally, synthesising evidence from these studies may help overcome the limitations of individual studies. Network meta-analysis may refine the assessment of efficacy in specific patient subgroups, evaluate intervention characteristics such as mode of administration or biological mechanisms of action, and rank order promising therapeutic areas of interest. Therefore, we aim to synthesise the available evidence from ALS clinical trials.<br><br>METHODS AND ANALYSIS: We will conduct a systematic review to identify all clinical trials that assessed disease-modifying pharmaceutical therapies, cell therapies, or supplements in patients with ALS. Outcomes of interest are clinical disease progression outcomes and survival. We will conduct this search in the period Q4 2024 in three databases: PubMed, Embase and ClinicalTrials.gov for studies from 1999 to 2023. Individual patient data and aggregate data will be collected and subsequentially synthesised in meta-analytical models. The final model will be presented as an open-source web application with biannual updates of the underlying data, thereby providing a 'living' overview of the ALS clinical trial landscape.<br><br>ETHICS AND DISSEMINATION: No ethics approvals are required. Findings will be presented at relevant conferences and submitted to peer-reviewed journals. Data will be stored anonymously in secure repositories.}, }
@article {pmid39480764, year = {2024}, author = {Perrin, S and Ladha, S and Maragakis, N and Rivner, MH and Katz, J and Genge, A and Olney, N and Lange, D and Heitzman, D and Bodkin, C and Jawdat, O and Goyal, NA and Bornstein, JD and Mak, C and Appel, SH and Paganoni, S}, title = {Safety and tolerability of tegoprubart in patients with amyotrophic lateral sclerosis: A Phase 2A clinical trial.}, journal = {PLoS medicine}, volume = {21}, number = {10}, pages = {e1004469}, pmid = {39480764}, issn = {1549-1676}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/immunology ; Male ; Middle Aged ; Female ; Aged ; Adult ; CD40 Ligand/blood ; Biomarkers/blood ; Antibodies, Monoclonal, Humanized/adverse effects/administration &amp; dosage/therapeutic use/pharmacokinetics ; Antibodies, Monoclonal/adverse effects/administration &amp; dosage/therapeutic use ; Neurofilament Proteins/blood ; Dose-Response Relationship, Drug ; Treatment Outcome ; Disease Progression ; Imidazoles ; Pyrazines ; }, abstract = {BACKGROUND: The interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS).<br><br>METHODS AND FINDINGS: In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation.<br><br>CONCLUSIONS: Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS.<br><br>TRIAL REGISTRATION: Clintrials.gov ID:NCT04322149.}, }
@article {pmid39473490, year = {2024}, author = {Fei, Y and Ding, Y}, title = {The role of ferroptosis in neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1475934}, pmid = {39473490}, issn = {1662-5102}, abstract = {Ferroptosis represents an iron[-] and lipid peroxidation (LPO)-mediated form of regulated cell death (RCD). Recent evidence strongly suggests the involvement of ferroptosis in various neurodegenerative diseases (NDs), particularly Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), among others. The treatment of ferroptosis poses both opportunities and challenges in the context of ND. This review provides a comprehensive overview of characteristic features, induction and inhibition of ferroptosis, highlighting the ferroptosis inhibitor and the underlying mechanisms responsible for its occurrence. Moreover, the review explores how these mechanisms contribute to the pathogenesis and progression of major neurodegenerative disorders. Additionally, it presents novel insights into the role of ferroptosis in ND and summarizes recent advancements in the development of therapeutic approaches targeting ferroptosis. These insights and advancements hold potential to guide future strategies aimed at effectively managing these debilitating medical conditions.}, }
@article {pmid39473221, year = {2024}, author = {Ito, D and Okada, K}, title = {Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {12}, pages = {3054-3063}, pmid = {39473221}, issn = {2328-9503}, support = {21H02812//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; *Oligonucleotides, Antisense/administration &amp; dosage/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Antisense oligonucleotides, which are used to silence target genes, are gaining attention as a novel drug discovery modality for proteinopathies. However, while clinical trials for neurodegenerative diseases like amyotrophic lateral sclerosis have been conducted in recent years, the results have not always been favorable. The results from a Phase III trial of the antisense oligonucleotide, that is, tofersen, which targets SOD1 mRNA, showed decreased levels of cerebrospinal fluid SOD1 and plasma neurofilament light chain but no improvements in primary clinical endpoint. Moreover, case reports pertaining to patients with amyotrophic lateral sclerosis carrying FUS and C9orf72 mutations who received antisense oligonucleotide-based treatments have demonstrated a notable reduction in the targeted protein (thus providing the proof of mechanism) but with no discernible clinical benefits. There are several possible reasons why antisense oligonucleotides knockdown fails to achieve proof of concept, which need to be addressed: on-target adverse effects resulting from the loss of function of target gene and irreversible neuronal death cascade due to toxic protein accumulation, among other factors. This review provides an overview of the current status and discusses the prospects of antisense oligonucleotides treatment for amyotrophic lateral sclerosis.}, }
@article {pmid39470847, year = {2025}, author = {Jellinger, KA}, title = {Mild cognitive impairment in amyotrophic lateral sclerosis: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {132}, number = {3}, pages = {357-368}, pmid = {39470847}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {Humans ; *Cognitive Dysfunction/etiology/physiopathology/metabolism/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/complications/metabolism/physiopathology ; Brain/diagnostic imaging/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal multi-system neurodegenerative disorder with no effective treatment or cure. Although primarily characterized by motor degeneration, cognitive dysfunction is an important non-motor symptom that has a negative impact on patient and caregiver burden. Mild cognitive deficits are present in a subgroup of non-demented patients with ALS, often preceding motor symptoms. Detailed neuropsychological assessments reveal deficits in a variety of cognitive domains, including those of verbal fluency and retrieval, language, executive function, attention and verbal memory. Mild cognitive impairment (MCI), a risk factor for developing dementia, affects between 10% and over 50% of ALS patients. Neuroimaging revealed atrophy of frontal and temporal cortices, disordered white matter Integrity, volume reduction in amygdala and thalamus, hypometabolism in the frontal and superior temporal gyrus and anterior insula. Neuronal loss in non-motor brain areas, associated with TDP-43 deposition, one of the morphological hallmarks of ALS, is linked to functional disruption of frontostriatal and frontotemporo-limbic connectivities as markers for cognitive deficits in ALS, the pathogenesis of which is still poorly understood. Early diagnosis by increased cerebrospinal fluid or serum levels of neurofilament light/heavy chain or glial fibrillary acidic protein awaits confirmation for MCI in ALS. These fluid biomarkers and early detection of brain connectivity signatures before structural changes will be helpful not only in establishing early premature diagnosis but also in clarifying the pathophysiological mechanisms of MCI in ALS, which might serve as novel targets for prohibition/delay and future adequate treatment of this debilitating disorder.}, }
@article {pmid39468607, year = {2024}, author = {Liu, C and Wu, Y and Wang, F and Sun, S and Wei, J and Tao, L}, title = {Cost-utility analysis for sublingual versus intravenous edaravone in the treatment of amyotrophic lateral sclerosis.}, journal = {Orphanet journal of rare diseases}, volume = {19}, number = {1}, pages = {400}, pmid = {39468607}, issn = {1750-1172}, mesh = {*Edaravone/therapeutic use/economics/administration &amp; dosage ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/economics ; *Cost-Benefit Analysis ; Administration, Sublingual ; Antipyrine/analogs &amp; derivatives/therapeutic use/economics/administration &amp; dosage ; Free Radical Scavengers/therapeutic use/economics/administration &amp; dosage ; Administration, Intravenous ; Male ; }, abstract = {BACKGROUND: Edaravone has been widely used in amyotrophic lateral sclerosis (ALS) treatment, and a sublingual (SL) tablet has been developed to offer a more convenient alternative for injection. We present a cost-utility analysis to comprehensively evaluate the costs and health outcomes of oral and intravenous edaravone for the treatment of ALS in Chinese medical context.<br><br>METHODS: Cost-utility analysis of SL tablets of edaravone versus intravenous edaravone at home was performed by constructing a 20-year Markov model of ALS stage 1-4 and death. The data were extracted from the literature with model assumptions. Typical sensitivity analysis and scenario analysis for administering SL tablets at home versus intravenous tablets at the hospital were performed.<br><br>RESULTS: In the base case analysis, with SL tablets and intravenous injections both at home, the model estimated an additional cost of &#xa5;12,670.04 and an additional 0.034 QALYs over 20&#xa0;years (life time) of modeling analysis, and the ICER was &#xa5;372,648.24 per QALY. However, in the scenario of intravenous administration at the hospital, SL tablet was demonstrated dominance to intravenous injection.<br><br>CONCLUSIONS: Using 3 times the GDP per capita of China in 2023 as the threshold, the SL tablet edaravone was not cost-effective in the context of home treatment for both formulationst, but was dominance to intravenous injection in hospital treatment. The results highlighted the importance of treatment context for health economic analysis.}, }
@article {pmid39464461, year = {2024}, author = {Karunakaran, V and Dadgar, S and Paidi, SK and Mordi, AF and Lowe, WA and Mim, UM and Ivers, JD and Rodriguez Troncoso, JI and McPeake, JA and Fernandes, A and Tripathi, SD and Barman, I and Rajaram, N}, title = {Investigating In Vivo Tumor Biomolecular Changes Following Radiation Therapy Using Raman Spectroscopy.}, journal = {ACS omega}, volume = {9}, number = {42}, pages = {43025-43033}, pmid = {39464461}, issn = {2470-1343}, support = {P20 GM139768/GM/NIGMS NIH HHS/United States ; P41 EB015871/EB/NIBIB NIH HHS/United States ; R01 CA238025/CA/NCI NIH HHS/United States ; R15 CA238861/CA/NCI NIH HHS/United States ; }, abstract = {Treatment resistance is a major bottleneck in the success of cancer therapy. Early identification of the treatment response or lack thereof in patients can enable an earlier switch to alternative treatment strategies that can enhance response rates. Here, Raman spectroscopy was applied to monitor early tumor biomolecular changes in sensitive (UM-SCC-22B) and resistant (UM-SCC-47) head and neck tumor xenografts for the first time in in vivo murine tumor models in response to radiation therapy. We used a validated multivariate curve resolution-alternating least-squares (MCR-ALS) model to resolve complex multicomponent Raman spectra into individual pure spectra and their respective contributions. We observed a significant radiation-induced increase in the contributions of lipid-like species (p = 0.0291) in the radiation-sensitive UM-SCC-22B tumors at 48 h following radiation compared to the nonradiated baseline (prior to commencing treatment). We also observed an increase in the contribution of collagen-like species in the radiation-resistant UM-SCC-47 tumors at 24 h following radiation compared to the nonradiated baseline (p = 0.0125). In addition to the in vivo analysis, we performed ex vivo confocal Raman microscopic imaging of frozen sections derived from the same tumors. A comparison of all control and treated tumors revealed similar trends in the contributions of lipid-like and collagen-like species in both in vivo and ex vivo measurements; however, when evaluated as a function of time, longitudinal trends in the scores of collagen-like and lipid-like components were not consistent between the two data sets, likely due to sample numbers and differences in sampling depth at which information is obtained. Nevertheless, this study demonstrates the potential of fiber-based Raman spectroscopy for identifying early tumor microenvironmental changes in response to clinical doses of radiation therapy.}, }
@article {pmid39462586, year = {2024}, author = {Kurita, H and Hirasawa, N and Yabe, S and Okuda, A and Murakami, T and Ohuchi, K and Ogata, A and Yoshioka, H and Kakita, A and Hozumi, I and Inden, M}, title = {MicroRNA-5572 Is Associated with Endoplasmic Reticulum Stress Responses in Low Zinc Treated and SOD1 G85R-Transfected HEK293 Cells.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {47}, number = {10}, pages = {1717-1725}, doi = {10.1248/bpb.b24-00418}, pmid = {39462586}, issn = {1347-5215}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Endoplasmic Reticulum Stress/drug effects/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; *Zinc/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; HEK293 Cells ; Transfection ; Tunicamycin/toxicity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fetal neurodegenerative disease. The mechanism of sporadic ALS onset remains unclarified in detail. Disruption of zinc homeostasis could be related to sporadic ALS. Previously, we first reported miR-5572 as a microRNA (miRNA) among those identified in the spinal cords of patients with sporadic ALS. However, since its function in ALS remained unknown, this study further examined the role of miR-5572 in low-zinc status and ALS model cells which transfected with causative gene, Cu/Zn superoxide dismutase 1 (SOD1) G85R mutant vector. The miR-5572 level was increased by low-zinc condition accompanied by increase of endoplasmic reticulum (ER) stress. In addition, increase of miR-5572 enhanced the cellular toxicity induced by low-zinc treatment. The expression of miR-5572 was also increased, which was accompanied by an increase of ER stress markers associated with SOD1 aggregation formation. Cell death and ER stress makers levels induced by tunicamycin treatment were further increased in miR-5572 mimic-transfected cells. This study showed that miR-5572 exacerbated ER stress toxicity associated with low-zinc status and mutant SOD1 aggregates in ALS.}, }
@article {pmid39461864, year = {2024}, author = {Imamura, K and Izumi, Y and Egawa, N and Ayaki, T and Nagai, M and Nishiyama, K and Watanabe, Y and Murakami, T and Hanajima, R and Kataoka, H and Kiriyama, T and Nanaura, H and Sugie, K and Hirayama, T and Kano, O and Nakamori, M and Maruyama, H and Haji, S and Fujita, K and Atsuta, N and Tatebe, H and Tokuda, T and Takahashi, N and Morinaga, A and Tabuchi, R and Oe, M and Kobayashi, M and Lobello, K and Morita, S and Sobue, G and Takahashi, R and Inoue, H}, title = {Protocol for a phase 2 study of bosutinib for amyotrophic lateral sclerosis using real-world data: induced pluripotent stem cell-based drug repurposing for amyotrophic lateral sclerosis medicine (iDReAM) study.}, journal = {BMJ open}, volume = {14}, number = {10}, pages = {e082142}, pmid = {39461864}, issn = {2044-6055}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Aniline Compounds/therapeutic use ; Clinical Trials, Phase II as Topic ; *Drug Repositioning ; Induced Pluripotent Stem Cells ; Japan ; Multicenter Studies as Topic ; *Nitriles/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; *Quinolines/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive, severe neurodegenerative disease caused by motor neuron death. Development of a medicine for ALS is urgently needed, and induced pluripotent cell-based drug repurposing identified a Src/c-Abl inhibitor, bosutinib, as a candidate for molecular targeted therapy of ALS. A phase 1 study confirmed the safety and tolerability of bosutinib in a 12-week treatment of ALS patients. The objectives of this study are to evaluate the efficacy and longer-term safety of bosutinib in ALS patients.<br><br>METHODS AND ANALYSIS: An open-label, multicentre phase 2 study was designed. The study consisted of a 12-week observation period, a 1-week transitional period, a 24-week study treatment period and a 4-week follow-up period. Following the transitional period, patients whose total Revised ALS Functional Rating Scale (ALSFRS-R) score declined by 1 to 4 points during the 12-week observation period were to receive bosutinib for 24 weeks. In this study, 25 ALS patients will be enrolled; patients will be randomly assigned to the following groups: 12 patients in the 200&#x2009;mg quaque die (QD) group and 13 patients in the 300&#x2009;mg QD group of bosutinib. The safety and exploratory efficacy of bosutinib in ALS patients for 24 weeks will be assessed. Efficacy using the ALSFRS-R score will be compared with the external published data from an edaravone study (MCI186-19) and registry data from a multicentre ALS cohort study, the Japanese Consortium for Amyotrophic Lateral Sclerosis Research.<br><br>ETHICS AND DISSEMINATION: This study was approved by the ethics committees of Kyoto University, Tokushima University, Kitasato University, Tottori University, Nara Medical University School of Medicine, Toho University and Hiroshima University. The findings will be disseminated in peer-reviewed journals and at scientific conferences.<br><br>TRIAL REGISTRATION NUMBER: jRCT2051220002; Pre-results, NCT04744532; Pre-results.}, }
@article {pmid39459490, year = {2024}, author = {Banciu, C and Chiriac, S and Pojoga, C and Marian, L and Fabian, A and Gogulescu, A and Simu, M and Parvanescu, R and Mioc, A and Racoviceanu, R and Munteanu, A}, title = {An Uncommon Overlap Syndrome Between Ankylosing Spondylitis and Amyotrophic Lateral Sclerosis-Case Report.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {10}, pages = {}, pmid = {39459490}, issn = {1648-9144}, support = {//"Victor Babes" University of Medicine and Pharmacy Timisoara/ ; }, mesh = {Humans ; *Spondylitis, Ankylosing/complications/drug therapy ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Middle Aged ; Etanercept/therapeutic use ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors ; Syndrome ; }, abstract = {This case report describes an uncommon overlap syndrome between ankylosing spondylitis (AS) and amyotrophic lateral sclerosis (ALS). Initially, the patient was diagnosed with AS, for which he received various specific treatments, including TNF-α inhibitors. After five years of treatment with TNF-α inhibitor etanercept, the patient was referred for a full neurological assessment after he reported balance disturbances, postural instability, muscle weakness, and other neurological symptoms that indicated the presence of a neurological disorder. After a thorough investigation, the patient was diagnosed with ALS. This case report aims to contribute to the limited literature by providing a detailed case study regarding the crosstalk between AS and ALS while also exploring the potential underlying mechanisms and the possible link between TNF-α inhibitors therapy and ALS.}, }
@article {pmid39459030, year = {2024}, author = {Al-Khayri, JM and Ravindran, M and Banadka, A and Vandana, CD and Priya, K and Nagella, P and Kukkemane, K}, title = {Amyotrophic Lateral Sclerosis: Insights and New Prospects in Disease Pathophysiology, Biomarkers and Therapies.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {10}, pages = {}, pmid = {39459030}, issn = {1424-8247}, support = {GRANT0000//Deanship of Scientific Research, King Faisal University/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disorder marked by the gradual loss of motor neurons, leading to significant disability and eventual death. Despite ongoing research, there are still limited treatment options, underscoring the need for a deeper understanding of the disease's complex mechanisms and the identification of new therapeutic targets. This review provides a thorough examination of ALS, covering its epidemiology, pathology, and clinical features. It investigates the key molecular mechanisms, such as protein aggregation, neuroinflammation, oxidative stress, and excitotoxicity that contribute to motor neuron degeneration. The role of biomarkers is highlighted for their importance in early diagnosis and disease monitoring. Additionally, the review explores emerging therapeutic approaches, including inhibitors of protein aggregation, neuroinflammation modulators, antioxidant therapies, gene therapy, and stem cell-based treatments. The advantages and challenges of these strategies are discussed, with an emphasis on the potential for precision medicine to tailor treatments to individual patient needs. Overall, this review aims to provide a comprehensive overview of the current state of ALS research and suggest future directions for developing effective therapies.}, }
@article {pmid39458929, year = {2024}, author = {Giannakou, M and Akrani, I and Tsoka, A and Myrianthopoulos, V and Mikros, E and Vorgias, C and Hatzinikolaou, DG}, title = {Discovery of Novel Inhibitors against ALS-Related SOD1(A4V) Aggregation through the Screening of a Chemical Library Using Differential Scanning Fluorimetry (DSF).}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {10}, pages = {}, pmid = {39458929}, issn = {1424-8247}, support = {MIS-5000432//state scholarship foundation (GR)/ ; }, abstract = {BACKGROUND: Cu/Zn Superoxide Dismutase 1 (SOD1) is a 32 kDa cytosolic dimeric metalloenzyme that neutralizes superoxide anions into oxygen and hydrogen peroxide. Mutations in SOD1 are associated with ALS, a disease causing motor neuron atrophy and subsequent mortality. These mutations exert their harmful effects through a gain of function mechanism, rather than a loss of function. Despite extensive research, the mechanism causing selective motor neuron death still remains unclear. A defining feature of ALS pathogenesis is protein misfolding and aggregation, evidenced by ubiquitinated protein inclusions containing SOD1 in affected motor neurons. This work aims to identify compounds countering SOD1(A4V) misfolding and aggregation, which could potentially aid in ALS treatment.<br><br>METHODS: The approach employed was in vitro screening of a library comprising 1280 pharmacologically active compounds (LOPAC[&#xae;]) in the context of drug repurposing. Using differential scanning fluorimetry (DSF), these compounds were tested for their impact on SOD1(A4V) thermal stability.<br><br>RESULTS AND CONCLUSIONS: Dimer stability was the parameter chosen as the criterion for screening, since the dissociation of the native SOD1 dimer is the step prior to its in vitro aggregation. The screening revealed one compound raising protein-ligand Tm by 6 &#xb0;C, eleven inducing a higher second Tm, suggesting a stabilization effect, and fourteen reducing Tm from 10 up to 26 &#xb0;C, suggesting possible interactions or non-specific binding.}, }
@article {pmid39457680, year = {2024}, author = {McGrath, MS and Zhang, R and Bracci, PM and Azhir, A and Forrest, BD}, title = {Systemic Innate Immune System Restoration as a Therapeutic Approach for Neurodegenerative Disease: Effects of NP001 on Amyotrophic Lateral Sclerosis (ALS) Progression.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457680}, issn = {2227-9059}, support = {Neuvivo-NP001//Neuvivo, Inc./ ; }, abstract = {BACKGROUND/OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a diagnosis that incorporates a heterogeneous set of neurodegenerative processes into a single progressive and uniformly fatal disease making the development of a uniformly applicable therapeutic difficult. Recent multinational ALS natural history incidence studies have identified systemic chronic activation of the innate immune system as a major risk factor for developing ALS. Persistent immune activation in patients with ALS leads to loss of muscle and lowering of serum creatinine. The goal of the current study was to test whether the slowing of nerve and muscle destruction in NP001-treated ALS patients compared with controls in phase 2 studies would lead to extension of survival.<br><br>METHODS: Phase 2 clinical studies with NP001, an intravenously administered form of the innate immune system regulator NaClO2, are now reporting long-term survival benefits for drug recipients vs. placebo controls after only six months of intermittent treatment. As a prodrug, NP001 is converted by macrophages to taurine chloramine, a long-lived regulator of inflammation. We performed a pooled analysis of all patients who had completed the studies in two six-month NP001 phase 2 trials. Changes in respiratory vital capacity and the muscle mass product, creatinine, defined treated patients who, compared to placebo, had up to a year of extended survival.<br><br>CONCLUSIONS: The observed longer survival in ALS patients with the greatest inflammation-associated muscle loss provides further evidence that ALS is a disease of ongoing innate immune dysfunction and that NP001 is a disease-modifying drug with sustained clinical activity.}, }
@article {pmid39457678, year = {2024}, author = {Forrest, BD and Goyal, NA and Fleming, TR and Bracci, PM and Brett, NR and Khan, Z and Robinson, M and Azhir, A and McGrath, M}, title = {The Effectiveness of NP001 on the Long-Term Survival of Patients with Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457678}, issn = {2227-9059}, support = {01//Neuvivo, Inc./ ; }, abstract = {BACKGROUND/OBJECTIVES: The aim of this study was to estimate the effect of a 6 months' treatment course of the innate immune modulator NP001 (a pH-adjusted intravenous formulation of purified sodium chlorite), on disease progression, as measured by overall survival (OS) in patients with amyotrophic lateral sclerosis.<br><br>METHODS: Blinded survival data were retrospectively collected for 268 of the 273 patients who had participated in two phase 2 placebo-controlled clinical trials of NP001 (ClinicalTrials.gov: NCT01281631 and NCT02794857) and received at least one dose of either 1 mg/kg or 2 mg/kg of NP001 as chlorite based on actual body weight, or placebo. Kaplan-Meier methods were used on the intent-to-treat population to estimate survival probabilities.<br><br>RESULTS: In the overall population, the median OS was 4.8 months (2.7 years [95% CI: 2.3, 3.5] in the 2 mg/kg NP001group and 2.3 years [95% CI: 1.8, 2.9] in the placebo group). Hazard ratio (HR): 0.77 (95% CI: 0.57, 1.03), p = 0.073. Among patients aged &#x2264; 65 years, the median OS for the 2 mg/kg NP001 group was 10.8 months (3.3 years [95% CI: 2.4, 3.8] in the 2 mg/kg NP001 group and 2.4 years [95% CI: 1.7, 3.3] in the placebo group). HR: 0.69 (95% CI: 0.50, 0.95). No differences were observed in the 1 mg/kg NP001 group or in patients aged > 65 years.<br><br>CONCLUSIONS: The findings from this study suggest that a 6 months' treatment course of NP001 resulted in a 4.8-month increase in overall survival in patients with ALS. The findings from this study indicate that targeting inflammation associated with the innate immune system may provide a pathway for new therapeutic options for the treatment of ALS.}, }
@article {pmid39457513, year = {2024}, author = {Montiel-Troya, M and Mohamed-Mohamed, H and Pardo-Moreno, T and González-Díaz, A and Ruger-Navarrete, A and de la Mata Fernández, M and Tovar-Gálvez, MI and Ramos-Rodríguez, JJ and García-Morales, V}, title = {Advancements in Pharmacological Interventions and Novel Therapeutic Approaches for Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457513}, issn = {2227-9059}, support = {PID2019-110960GB-I00//Ministry of Science and Innovation, Spain./ ; }, abstract = {(1) Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which the patient suffers from an affection of both upper and lower motor neurons at the spinal and brainstem level, causing a progressive paralysis that leads to the patient's demise. Gender is also considered a predisposing risk factor for developing the disease. A brief review of the pathophysiological mechanisms of the disease is also described in this work. Despite the fact that a cure for ALS is currently unknown, there exists a variety of pharmacological and non-pharmacological therapies that can help reduce the progression of the disease over a certain period of time and alleviate symptoms. (2) We aim to analyze these pharmacological and non-pharmacological therapies through a systematic review. A comprehensive, multidisciplinary approach to treatment is necessary. (3) Drugs such as riluzole, edaravone, and sodium phenylbutyrate, among others, have been investigated. Additionally, it is important to stay updated on research on new drugs, such as masitinib, from which very good results have been obtained. (4) Therapies aimed at psychological support, speech and language, and physical therapy for the patient are also available, which increase the quality of life of the patients.}, }
@article {pmid39457505, year = {2024}, author = {Seta, Y and Kimura, K and Masahiro, G and Tatsumori, K and Murakami, Y}, title = {SHED-CM: The Safety and Efficacy of Conditioned Media from Human Exfoliated Deciduous Teeth Stem Cells in Amyotrophic Lateral Sclerosis Treatment: A Retrospective Cohort Analysis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457505}, issn = {2227-9059}, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive and irreversible neurodegenerative disease with limited treatment options. Advances in regenerative medicine have opened up new treatment options. The primary and exploratory objectives of this retrospective cohort study were to evaluate the safety and efficacy of stem cells from human exfoliated deciduous teeth-conditioned media (SHED-CM).<br><br>METHODS: Safety assessments included adverse events, vital signs, and laboratory test changes before and after administration, and efficacy was measured using the ALS Functional Rating Scale-Revised (ALSFRS-R), grip strength, and forced vital capacity in 24 patients with ALS treated at a single facility between 1 January 2022, and 30 November 2023.<br><br>RESULTS: While ALSFRS-R scores typically decline over time, the progression rate in this cohort was slower, suggesting a potential delay in disease progression. Alternatively, improvements in muscle strength and mobility were observed in some patients. Although adverse events were reported in only 3% of cases (no serious allergic reactions), the treatment-induced changes in vital signs and laboratory results were not clinically significant.<br><br>CONCLUSIONS: The SHED-CM treatment is a safe and potentially effective therapeutic option for patients with ALS. Further research is needed to optimize the SHED-CM treatment; however, this study lays the groundwork for future exploration of regenerative therapies for ALS.}, }
@article {pmid39457466, year = {2024}, author = {Moriyama, H and Yokota, T}, title = {Recent Progress of Antisense Oligonucleotide Therapy for Superoxide-Dismutase-1-Mutated Amyotrophic Lateral Sclerosis: Focus on Tofersen.}, journal = {Genes}, volume = {15}, number = {10}, pages = {}, pmid = {39457466}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; Humans ; *Superoxide Dismutase-1/genetics ; *Oligonucleotides, Antisense/therapeutic use/genetics ; *Mutation ; Animals ; Oligonucleotides/therapeutic use/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a refractory neurodegenerative disease characterized by the degeneration and loss of motor neurons, typically resulting in death within five years of onset. There have been few effective treatments, making the development of robust therapies an urgent challenge. Genetic mutations have been identified as contributors to ALS, with mutations in superoxide dismutase 1 (SOD1), which neutralizes the harmful reactive oxygen species superoxide, accounting for approximately 2% of all ALS cases. To counteract the toxic gain of function caused by SOD1 mutations, therapeutic strategies aimed at suppressing SOD1 gene expression have shown promise. Antisense oligonucleotide (ASO) is an artificially synthesized, short, single-stranded DNA/RNA molecule that binds to target RNA to alter gene expression, representing a next-generation therapeutic approach. In 2023, tofersen became the first ASO drug approved by the FDA for ALS. Administered intrathecally, tofersen specifically binds to SOD1 mRNA, inhibiting the production of toxic SOD1 protein, thereby improving biomarkers of ALS. The long-term efficacy and safety of tofersen require further validation, and the development of more optimized treatment protocols is essential. A series of studies and therapeutic developments related to SOD1 mutations have advanced the understanding of ALS pathophysiology and significantly contributed to treatment strategies for central nervous system disorders. This review focuses on an overview of SOD1 mutations and the development process of tofersen, aiming to deepen the understanding of advancements in ALS research and discuss future challenges and directions for ASO therapy.}, }
@article {pmid39455931, year = {2024}, author = {Martínez, P and Silva, M and Abarzúa, S and Tevy, MF and Jaimovich, E and Constantine-Paton, M and Bustos, FJ and van Zundert, B}, title = {Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {30}, number = {1}, pages = {185}, pmid = {39455931}, issn = {1528-3658}, support = {1181645//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; DI-06-24/REG//UNAB/ ; 1221745//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; 21151265//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; R01-638 EY014420//National Institute of Mental Health and Neurosciences/ ; R01-EY014074//National Institute of Mental Health and Neurosciences/ ; R03 EY014420/EY/NEI NIH HHS/United States ; 1151293//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; 13220203 explorador//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; NCN2023_32//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; }, mesh = {Animals ; *Muscle Fibers, Skeletal/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Mitochondria/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Humans ; *Mice, Transgenic ; *Axonal Transport ; Cell Death ; Disease Models, Animal ; Mutation ; Cells, Cultured ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1[G93A] (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2 + transients and reactive oxygen species (i.e., H2O2). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.}, }
@article {pmid39454934, year = {2025}, author = {Takeda, T and Her, YR and Kim, JK and Jha, NN and Monani, UR}, title = {A variant of the Hspa8 synaptic chaperone modifies disease in a SOD1[G86R] mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {115024}, pmid = {39454934}, issn = {1090-2430}, support = {R01 NS104218/NS/NINDS NIH HHS/United States ; R01 NS123292/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Disease Models, Animal ; *Mice, Transgenic ; *HSC70 Heat-Shock Proteins/metabolism/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Motor Neurons/pathology/metabolism ; Humans ; Mutation ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relatively common and invariably fatal, paralyzing motor neuron disease for which there are few treatment options. ALS is frequently associated with ubiquitin-positive motor neuronal aggregates, a pathology suggestive of perturbed proteostasis. Indeed, cellular chaperones, which are involved in protein trafficking and degradation often underlie familial ALS. Spinal muscular atrophy (SMA) is a second, common paralytic condition resulting from motor neuron loss and muscle atrophy. While SMA is now effectively treated, mechanisms underlying motor neuron degeneration in the disease remain far from clear. To address mechanistic questions about SMA, we recently identified a genetic modifier of the disease. The factor, a G470R variant in the constitutively expressed cellular chaperone, Hspa8, arrested motor neuron loss, prevented the abnormal accumulation of neurofilament aggregates at nerve terminals and suppressed disease. Hspa8 is best known for its role in autophagy. Amongst its many clients is the ALS-associated superoxide dismutase 1 (SOD1) protein. Given its suppression of the SMA phenotype, we tested potential disease-mitigating effects of Hspa8[G470R] in a mutant SOD1 mouse model of ALS. Unexpectedly, disease in mutant SOD1 mice expressing the G470R variant was aggravated. Motor performance of the mice deteriorated, muscle atrophy worsened, and lifespan shrunk even further. Paradoxically, SOD1 protein in spinal cord tissue of the mice was dramatically reduced. Our results suggest that Hspa8 modulates the ALS phenotype. However, rather than mitigating disease, the G470R variant exacerbates it.}, }
@article {pmid39451396, year = {2024}, author = {Yang, CH and Huang, JL and Tsai, LK and Taniar, D and Pai, TW}, title = {An Effective DNA Methylation Biomarker Screening Mechanism for Amyotrophic Lateral Sclerosis (ALS) Based on Comorbidities and Gene Function Analysis.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {39451396}, issn = {2306-5354}, support = {MOST 111-2221-E-027-113-414 MY2//National Science and Technology Council (Taiwan)/ ; NSTC113-2221-E-027-109//National Science and Technology Council (Taiwan)/ ; MOST104-2321-B-019-009//National Science and Technology Council (Taiwan)/ ; }, abstract = {This study used epigenomic methylation differential expression analysis to identify primary biomarkers in patients with amyotrophic lateral sclerosis (ALS). We combined electronic medical record datasets from MIMIC-IV (United States) and NHIRD (Taiwan) to explore ALS comorbidities in depth and discover any comorbidity-related biomarkers. We also applied word2vec to these two clinical diagnostic medical databases to measure similarities between ALS and other similar diseases and evaluated the statistical assessment of the odds ratio to discover significant comorbidities for ALS subjects. Important and representative DNA methylation biomarker candidates could be effectively selected by cross-comparing similar diseases to ALS, comorbidity-related genes, and differentially expressed methylation loci for ALS subjects. The screened epigenomic and comorbidity-related biomarkers were clustered based on their genetic functions. The candidate DNA methylation biomarkers associated with ALS were comprehensively discovered. Gene ontology annotations were then applied to analyze and cluster the candidate biomarkers into three different groups based on gene function annotations. The results showed that a potential testing kit for ALS detection can be composed of SOD3, CACNA1H, and ERBB4 for effective early screening of ALS using blood samples. By developing an effective DNA methylation biomarker screening mechanism, early detection and prophylactic treatment of high-risk ALS patients can be achieved.}, }
@article {pmid39451238, year = {2024}, author = {Crescioli, C and Paronetto, MP}, title = {The Emerging Role of Phosphodiesterase 5 Inhibition in Neurological Disorders: The State of the Art.}, journal = {Cells}, volume = {13}, number = {20}, pages = {}, pmid = {39451238}, issn = {2073-4409}, mesh = {Humans ; *Phosphodiesterase 5 Inhibitors/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy ; Animals ; Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; Neuroinflammatory Diseases/drug therapy/metabolism ; }, abstract = {Growing evidence suggests that neuroinflammation is not just a consequence of neurodegeneration in pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease or Amyotrophic lateral sclerosis, but it is rather a determinant factor, which plays a pivotal role in the onset and progression of these disorders. Neuroinflammation can affect cells and processes in the central nervous system (CNS) as well as immune cells, and might precede protein aggregation, which is a hallmark of the neurodegenerative process. Standard treatment methods are far from being able to counteract inflammation and delay neurodegeneration. Remarkably, phosphodiesterase 5 inhibitors (PDE5is), which represent potent vasoactive drugs used as a first-line treatment for erectile dysfunction (ED), display important anti-inflammatory effects through cyclic guanosine monophosphate (cGMP) level stabilization. Since PDE5 hydrolyzes cGMP, several studies positioned PDE5 as a therapeutic target, and more specifically, PDE5is as potential alternative strategies for the treatment of a variety of neurological disorders. Indeed, PDE5is can limit neuroinflammation and enhance synaptic plasticity, with beneficial effects on cognitive function and memory. The aim of this review is to provide an overview of some of the main processes underlying neuroinflammation and neurodegeneration which may be potential targets for PDE5is, focusing on sildenafil, the most extensively studied. Current strategies using PDEis for the treatment of neurodegenerative diseases will be summarized.}, }
@article {pmid39449457, year = {2024}, author = {Rosa, D and Ingrande, L and Marcomini, I and Poliani, A and Villa, G and Sodano, M and Manara, DF}, title = {Perceived Pain in People Living with Amyotrophic Lateral Sclerosis-A Scoping Review.}, journal = {Nursing reports (Pavia, Italy)}, volume = {14}, number = {4}, pages = {3023-3039}, pmid = {39449457}, issn = {2039-4403}, abstract = {(1) Background: Pain is a common symptom in patients with Amyotrophic Lateral Sclerosis (ALS). There are no evidence-based pharmacological treatments for pain in ALS; recommendations are based on guidelines for chronic non-oncological pain and clinical experience. The aim is to map the literature on how people with ALS experience pain, and how this affects their daily activities and social relationships. (2) Methods: This scoping review included studies concerning patients with spinal/bulbar ALS aged ≥ 18 years who experience pain, focusing on perception, characteristics, treatment, and impact on quality of life. Temporal and linguistic criteria were applied when searching the MEDLINE, CINAHL, and SCOPUS databases. (3) Results: The management of pain in these patients is complex and involves the use of anti-inflammatory drugs, analgesics, and opioids. Pain is associated with other conditions such as depression and anxiety, which contribute to a deterioration in the quality of life. Moreover, pain may also negatively influence patient compliance with prescribed treatment regimens and the quality of care they perceive themselves to be receiving. (4) Conclusions: It is of the most importance to identify effective ways to assess and treat this issue, with health care professionals taking an active role in this process.}, }
@article {pmid39448670, year = {2024}, author = {Stankiewicz-Kosyl, M and Wińska-Krysiak, M and Wrochna, M and Haliniarz, M and Marcinkowska, K}, title = {Regional diversity of the ALS gene and hormesis due to tribenuron-methyl in Centaurea cyanus L.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {25197}, pmid = {39448670}, issn = {2045-2322}, support = {BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; }, mesh = {*Acetolactate Synthase/genetics ; *Hormesis ; *Herbicides/pharmacology ; *Centaurea/genetics ; Arylsulfonates/pharmacology ; Herbicide Resistance/genetics ; Mutation ; Poland ; Plant Proteins/genetics ; Genetic Variation ; }, abstract = {Centaurea cyanus L. is a common field weed in Eastern Europe but only in Poland biotypes of this species with resistance to acetolactate synthase (ALS) inhibitors have been confirmed. This phenomenon is constantly developing and spreading to consecutive regions of Poland. This study aimed to assess the response of selected Polish C. cyanus populations to tribenuron-methyl and to analyse the genetic variability of the ALS gene of C. cyanus populations resistant to ALS inhibitors. Between 2017 and 2021, 13 seed samples were collected from eastern Poland and a dose-response study with tribenuron-methyl was performed. Eleven populations resistant to tribenuron-methyl were identified. All populations from this study as well as 6 additional resistant populations characterised in the previous dose-response studies were subjected to molecular analysis of the ALS gene. Target-site resistance due to mutations P197S, P197Q, P197T and P197A were identified in 8 populations from Warmia-Masuria and Podlaskie provinces. This is the first case of target-site resistance (TSR) in C. cyanus confirmed by sequencing of the ALS gene. Moreover in some resistant plants, ten changes in the amino acid ALS sequence were identified in comparison to those in the susceptible ones. In none of the populations were all mutations detected in the same individual. The highest frequency of mutations was detected in Warmia-Masuria province. Some C. cyanus populations resistant to ALS inhibitors showed hormesis effect concerning shoot fresh weight after tribenuron-methyl treatment. Stimulation due to half the recommended dose of tribenuron-methyl was the highest and the difference between untreated and treated plants was statistically significant in two populations from Warmia-Masuria and in one from Podlaskie province.}, }
@article {pmid39439710, year = {2024}, author = {Kelser, BM and Teichner, EM and Subtirelu, RC and Hoss, KN}, title = {A review of proposed mechanisms for neurodegenerative disease.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1370580}, pmid = {39439710}, issn = {1663-4365}, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) affect millions and present significant challenges in healthcare and treatment costs. The debate in the field pivots around two hypotheses: synaptic spread and selective vulnerability. Pioneers like Virginia Lee and John Trojanowski have been instrumental in identifying key proteins (tau, alpha-synuclein, TDP-43) central to these diseases. The synaptic spread hypothesis suggests a cell-to-cell propagation of pathogenic proteins across neuronal synapses, influencing disease progression, with studies highlighting the role of proteins like alpha-synuclein and amyloid-beta in this process. In contrast, the selective vulnerability hypothesis proposes inherent susceptibility of certain neurons to degeneration due to factors like metabolic stress, leading to protein aggregation. Recent advancements in neuroimaging, especially PET/MRI hybrid imaging, offer new insights into these mechanisms. While both hypotheses offer substantial evidence, their relative contributions to neurodegenerative processes remain to be fully elucidated. This uncertainty underscores the necessity for continued research, with a focus on these hypotheses, to develop effective treatments for these devastating diseases.}, }
@article {pmid39437787, year = {2024}, author = {Saez-Atienzar, S and Souza, CDS and Chia, R and Beal, SN and Lorenzini, I and Huang, R and Levy, J and Burciu, C and Ding, J and Gibbs, JR and Jones, A and Dewan, R and Pensato, V and Peverelli, S and Corrado, L and van Vugt, JJFA and van Rheenen, W and Tunca, C and Bayraktar, E and Xia, M and ,  and ,  and ,  and ,  and Iacoangeli, A and Shatunov, A and Tiloca, C and Ticozzi, N and Verde, F and Mazzini, L and Kenna, K and Al Khleifat, A and Opie-Martin, S and Raggi, F and Filosto, M and Piccinelli, SC and Padovani, A and Gagliardi, S and Inghilleri, M and Ferlini, A and Vasta, R and Calvo, A and Moglia, C and Canosa, A and Manera, U and Grassano, M and Mandrioli, J and Mora, G and Lunetta, C and Tanel, R and Trojsi, F and Cardinali, P and Gallone, S and Brunetti, M and Galimberti, D and Serpente, M and Fenoglio, C and Scarpini, E and Comi, GP and Corti, S and Del Bo, R and Ceroni, M and Pinter, GL and Taroni, F and Bella, ED and Bersano, E and Curtis, CJ and Lee, SH and Chung, R and Patel, H and Morrison, KE and Cooper-Knock, J and Shaw, PJ and Breen, G and Dobson, RJB and Dalgard, CL and ,  and Scholz, SW and Al-Chalabi, A and van den Berg, LH and McLaughlin, R and Hardiman, O and Cereda, C and Sorarù, G and D'Alfonso, S and Chandran, S and Pal, S and Ratti, A and Gellera, C and Johnson, K and Doucet-O'Hare, T and Pasternack, N and Wang, T and Nath, A and Siciliano, G and Silani, V and Başak, AN and Veldink, JH and Camu, W and Glass, JD and Landers, JE and Chiò, A and Sattler, R and Shaw, CE and Ferraiuolo, L and Fogh, I and Traynor, BJ}, title = {Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data.}, journal = {Cell genomics}, volume = {4}, number = {11}, pages = {100679}, pmid = {39437787}, issn = {2666-979X}, support = {R35 NS127253/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Drug Repositioning ; *Frontotemporal Dementia/genetics/drug therapy ; Genomics/methods ; Riluzole/therapeutic use ; Male ; Female ; Neuroprotective Agents/therapeutic use/pharmacology ; DNA Repeat Expansion/genetics ; }, abstract = {Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these bottlenecks. Our drug-repurposing screen, based on gene- and expression-pattern matching and information about the genetic variants influencing onset age among C9orf72 carriers, identified acamprosate, a γ-aminobutyric acid analog, as a potentially repurposable treatment for patients carrying C9orf72 repeat expansions. We validated its neuroprotective effect in cell models and showed comparable efficacy to riluzole, the current standard of care. Our work highlights the potential value of genomics in repurposing drugs in situations where the underlying pathomechanisms are inherently complex. VIDEO ABSTRACT.}, }
@article {pmid39436867, year = {2025}, author = {Firozjae, AA and Shiran, MR and Rashidi, M}, title = {The neuropharmacological and clinical effects of lutein: a systematic review.}, journal = {Hormone molecular biology and clinical investigation}, volume = {46}, number = {1}, pages = {27-38}, pmid = {39436867}, issn = {1868-1891}, mesh = {*Lutein/pharmacology/therapeutic use ; Humans ; *Neurodegenerative Diseases/drug therapy ; Alzheimer Disease/drug therapy ; }, abstract = {OBJECTIVES: Neurodegenerative diseases are defined by specific protein accumulation and anatomic vulnerability leading to neuronal loss. Some studies have shown that lutein may have an effect on neurodegenerative diseases. As most of the neurodegenerative diseases don't have certain cure and therapies focus on symptom control, Lutein may be a complementary treatment. Due to controversies in studies investigating lutein effect on neurodegenerative diseases, we decided to perform a systematic review on these studies.<br><br>METHODS: A systematic search was carried out in the available databases. We used all MeSH terms and relevant keywords. Studies that reported relationship between lutein and any neurodegenerative disease were included.<br><br>RESULTS: We found 278 studies. After removing duplicates, screening by titles and abstracts and excluding irrelevant papers, 17 articles were included in this study. Fourteen studies investigated Alzheimer's disease, 2 studies Parkinson's disease and 1 study Amyotrophic lateral sclerosis. 1/17 study found that high serum levels of lutein at baseline were associated with a lower risk of AD mortality and lutein effect on lipid profile have been investigated in 2/17 studies. Also, 1/17 study has been shown that high intake of lutein may reduce the risk of ALS progression.<br><br>CONCLUSIONS: 4/17 studies confirm that lutein can improve cognitive function. 8/17 studies demonstrate a reduction in&#xa0;the progression of AD, and 2/17 studies indicate an improvement in lipid profiles. However, some studies did not find any significant associations. Additionally, there is a limited number of studies investigating the effects of lutein on other neurodegenerative diseases.}, }
@article {pmid39435635, year = {2025}, author = {Yang, X and Gao, X and Jiang, X and Yue, K and Luo, P}, title = {Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3076-3094}, pmid = {39435635}, issn = {1673-5374}, abstract = {Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases. Owing to their therapeutic properties and ability to cross the blood-brain barrier, extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions, including ischemic stroke, traumatic brain injury, neurodegenerative diseases, glioma, and psychosis. However, the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body. To address these limitations, multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles, thereby enabling the delivery of therapeutic contents to specific tissues or cells. Therefore, this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles, exploring their applications in treating traumatic brain injury, ischemic stroke, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, glioma, and psychosis. Additionally, we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases. This review offers new insights for developing highly targeted therapies in this field.}, }
@article {pmid39431591, year = {2024}, author = {Sheers, NL and Hannan, LM and Rautela, L and Graco, M and Jones, J and Retica, S and Saravanan, K and Burgess, N and McGaw, R and Donovan, A and Clohessy, T and Chao, C and Charles, C and Howard, ME and Berlowitz, DJ}, title = {NIV@Home: a pilot randomized controlled trial of in-home noninvasive ventilation initiation compared to a single-day admission model.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2416668}, pmid = {39431591}, issn = {2167-9223}, abstract = {Objective: Noninvasive ventilation (NIV) is the primary treatment for respiratory insufficiency in neuromuscular disease. NIV implementation is usually conducted within hospitals; however, in-home implementation with intensive follow-up is an effective alternative. This pilot study aimed to assess model feasibility, acceptability, and NIV usage at 12-weeks after a single visit in-home implementation of NIV with remote monitoring follow-up (NIV@Home) compared to an in-hospital day admission NIV initiation plus planned polysomnography (Usual care). Methods: A single-blinded randomized controlled trial (www.anzctr.org.au ACTRN12620000682943) of adults with neuromuscular disease referred for NIV implementation. Participants were stratified by disease (MND or Other diagnoses) and bulbar symptoms before randomization to NIV@Home or Usual care, with follow-up at 12-weeks. The primary outcome was NIV usage. Secondary outcomes included feasibility, health-related quality of life, symptoms, carer burden, and NIV experience (semi-structured qualitative interviews). Results: Twenty-three participants (MND bulbar = 9, MND non-bulbar = 11, Other = 3) were randomized (NIV@Home = 9). No statistical differences were observed in the percentage of MND participants using NIV for >4 hours/day (NIV@Home = 33% vs. Usual care = 60%, p = 0.370), average use (NIV@Home = 2.4 [1.5-9.3] vs. 5.3 [1.8-7.0] hours/day, p = 0.568), or secondary outcomes. In-home NIV implementation was feasible and safe but took more therapist time (NIV@Home = 278 [270-305] vs. 172 [130-200] minutes, p < 0.001). Participants in the NIV@Home group reported substantial advantages to receiving care in home. Conclusion: In-home NIV implementation is feasible and acceptable to people with MND but requires more therapist time. Larger studies are required to determine whether there are clinically important differences between this model of NIV initiation and a traditional hospital-based model.}, }
@article {pmid39424560, year = {2024}, author = {Koch, JC and Leha, A and Bidner, H and Cordts, I and Dorst, J and Günther, R and Zeller, D and Braun, N and Metelmann, M and Corcia, P and De La Cruz, E and Weydt, P and Meyer, T and Großkreutz, J and Soriani, MH and Attarian, S and Weishaupt, JH and Weyen, U and Kuttler, J and Zurek, G and Rogers, ML and Feneberg, E and Deschauer, M and Neuwirth, C and Wuu, J and Ludolph, AC and Schmidt, J and Remane, Y and Camu, W and Friede, T and Benatar, M and Weber, M and Lingor, P and , }, title = {Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1133-1146}, doi = {10.1016/S1474-4422(24)00373-9}, pmid = {39424560}, issn = {1474-4465}, mesh = {Humans ; *1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs &amp; derivatives/therapeutic use/pharmacology/adverse effects ; Middle Aged ; Male ; Double-Blind Method ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; Aged ; Adult ; *rho-Associated Kinases/antagonists &amp; inhibitors ; *Protein Kinase Inhibitors/adverse effects/therapeutic use/administration &amp; dosage ; Treatment Outcome ; Aged, 80 and over ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis.<br><br>METHODS: ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18-80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6-24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed.<br><br>FINDINGS: Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1&#xb7;00 (95% CI 0&#xb7;91 to 1&#xb7;00) with placebo, 1&#xb7;00 (0&#xb7;89 to 1&#xb7;00) with fasudil 30 mg, and 1&#xb7;00 (0&#xb7;90 to 1&#xb7;00) with fasudil 60 mg; the difference in proportions was 0&#xb7;00 (95% CI -0&#xb7;11 to 0&#xb7;10; p>0&#xb7;99) for fasudil 30 mg versus placebo and 0&#xb7;00 (-0&#xb7;10 to 0&#xb7;10; p>0&#xb7;99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0&#xb7;93 (95% CI 0&#xb7;81 to 0&#xb7;99) with placebo, 1&#xb7;00 (0&#xb7;90 to 1&#xb7;00) with fasudil 30 mg, and 0&#xb7;90 (0&#xb7;76 to 0&#xb7;97) with fasudil 60 mg; the difference in proportions was 0&#xb7;07 (95% CI -0&#xb7;05 to 0&#xb7;20; p=0&#xb7;25) for fasudil 30 mg versus placebo, and -0&#xb7;03 (-0&#xb7;18 to 0&#xb7;10; p=0&#xb7;70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group.<br><br>INTERPRETATION: Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug.<br><br>FUNDING: Framework of the E-Rare Joint Transnational Call 2016 "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases".}, }
@article {pmid39422938, year = {2024}, author = {Pappolla, MA and Wu, P and Fang, X and Poeggeler, B and Sambamurti, K and Wisniewski, T and Perry, G}, title = {Stem Cell Interventions in Neurology: From Bench to Bedside.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {101}, number = {s1}, pages = {S395-S416}, doi = {10.3233/JAD-230897}, pmid = {39422938}, issn = {1875-8908}, mesh = {Humans ; Animals ; *Stem Cell Transplantation/methods/trends ; Nervous System Diseases/therapy ; Neurology/trends/methods ; Translational Research, Biomedical/trends ; Neural Stem Cells/transplantation ; }, abstract = {Stem cell therapies are progressively redefining the treatment landscape for a spectrum of neurological and age-related disorders. This review discusses the molecular and functional attributes of stem cells, emphasizing the roles of neural stem cells and mesenchymal stem cells in the context of neurological diseases such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, Parkinson's disease, and Alzheimer's disease. The review also explores the potential of stem cells in addressing the aging process. The paper analyzes stem cells' intrinsic properties of self-renewal, differentiation, and paracrine effects, alongside the importance of laboratory-modified stem cells like induced pluripotent stem cells and transgenic stem cells. Insights into disease-specific stem cell treatments are offered, reviewing both successes and challenges in the field. This includes the translational difficulties from rodent studies to human trials. The review concludes by acknowledging the uncharted territories that warrant further investigation, emphasizing the potential roles of stem cell-derived exosomes and indole-related molecules, and aiming at providing a basic understanding of stem cell therapies.}, }
@article {pmid39420987, year = {2024}, author = {Sun, H and Tang, Q and Yan, X and Xie, W and Xu, Y and Zhang, W}, title = {Cathepsins and neurological diseases: a Mendelian randomization study.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1454369}, pmid = {39420987}, issn = {1662-4548}, abstract = {BACKGROUND: The causal relationship between cathepsins and neurological diseases remains uncertain. To address this, we utilized a two-sample Mendelian randomization (MR) approach to assess the potential causal effect of cathepsins on the development of neurological diseases.<br><br>METHODS: This study conducted a two-sample two-way MR study using pooled data from published genome-wide association studies to evaluate the relationship between 10 cathepsins (B, D, E, F, G, H, L2, O, S, and Z) and 7 neurological diseases, which included ischemic stroke, cerebral hemorrhage, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and epilepsy. The analysis employed various methods such as inverse variance weighting (IVW), weighted median, MR Egger regression, MR pleiotropy residual sum and outlier, Cochran Q statistic, and leave-one-out analysis.<br><br>RESULTS: We found a causal relationship between cathepsins and neurological diseases, including Cathepsin B and Parkinson's disease (IVW odds ratio (OR): 0.89, 95% confidence interval (CI): 0.83, 0.95, p&#x2009;=&#x2009;0.001); Cathepsin D and Parkinson's disease (OR: 0.80, 95%CI: 0.68, 0.95, p&#x2009;=&#x2009;0.012); Cathepsin E and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.09, p&#x2009;=&#x2009;0.015); Cathepsin O and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.10, p&#x2009;=&#x2009;0.021). Reverse MR analyses revealed that multiple sclerosis and Cathepsin E (OR: 1.05, 95%CI: 1.01, 1.10, p&#x2009;=&#x2009;0.030). There is currently no significant relationship has been found between other cathepsins and neurological diseases.<br><br>CONCLUSION: Our study reveals a causal relationship between Cathepsins B, D, E, and O and neurological diseases, offering valuable insights for research aimed at improving the diagnosis and treatment of such conditions.}, }
@article {pmid39419433, year = {2025}, author = {Majumder, P and Hsu, TI and Hu, CJ and Huang, JK and Lee, YC and Hsieh, YC and Ahsan, A and Huang, CC}, title = {Potential role of solid lipid curcumin particle (SLCP) as estrogen replacement therapy in mitigating TDP-43-related neuropathy in the mouse model of ALS disease.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {114999}, doi = {10.1016/j.expneurol.2024.114999}, pmid = {39419433}, issn = {1090-2430}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mice ; Female ; *Disease Models, Animal ; Male ; *DNA-Binding Proteins/metabolism/genetics ; *Estrogen Replacement Therapy/methods ; *Curcumin/pharmacology/administration &amp; dosage/therapeutic use ; Mice, Transgenic ; Aromatase/metabolism ; Estradiol/pharmacology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) was first identified in 1869, but it wasn't until the 2014 Ice Bucket Challenge that widespread attention was drawn to the disease. Since then, substantial research has been dedicated to developing treatments for ALS. Despite this, only three drugs - riluzole, edaravone and AMX0035, have been approved for clinical use, and they can only temporarily alleviate mild symptoms without significant disease modification or cure. Therefore, there remains a critical unmet need to identify disease modifying or curative therapies for ALS. The higher incidence and more severe progression of ALS and FTLD (frontotemporal lobar degeneration) observed in men and postmenopausal woman compared to young women suggests that sex hormones may significantly influence disease onset and progression. In both animal models and human clinical studies, 17β estradiol (E2) has been shown to delay and improve the outcomes of many neurodegenerative diseases. Here, we examined the role of TDP-43 in the regulation of estrogen-related enzymes, CYP19A1 and CYP3A4. In addition, we examined the impact of curcumin on the regulation of estrogen E2 levels and TDP-43-associated neuropathy as a potential therapeutic strategy for the treatment of FTLD and ALS.<br><br>METHODS: Prp-TDP-43[A315T] mice was used as a model of ALS/FTLD to examine the expression patterns of E2 and its biosynthesis and degradation enzymes, CYP19A1 and CYP3A4. Moreover, the molecular mechanisms and the potency of solid lipid curcumin particles (SLCP) as an E2 replacement therapy for TDP-43 associated neuropathy was analyzed. We further examined the survival rates and the pathological TDP43 patterns in female and male Prp-TDP-43[A315T] mice administrated with or without SLCP. In addition, the changed expression levels of enzymes corresponding to E2 biosynthesis and degradation in the spinal cord of female and male Prp-TDP-43[A315T] mice with or without SLCP were determined.<br><br>RESULTS: We found that in addition to E2, the expression patterns of CYP19A1 and CYP3A4 proteins differed between Prp-TDP-43[A315T] mice compared to wild-type control, suggesting that toxic phosphorylated TDP43 oligomers may disrupt the balance between CYP19A1 and CYP3A4 expression, leading to reduced estrogen biosynthesis and accelerated degradation. In addition, we found that oral administration of SLCP prolonged the survival rates in female Prp-TDP-43[A315T] mice and significantly reduced the pathological insoluble phosphorylated TDP-43 species. Furthermore, SLCP attenuated disease progression associated with TDP-43-related neuropathies through modulating estrogen biosynthesis and the activity of CYP450 enzymes.<br><br>CONCLUSIONS: Our results showed that Prp-TDP-43[A315T] mice exhibit altered estradiol levels. Moreover, we demonstrated the efficacy of SLCP as an estrogen replacement therapy in mitigating TDP-43-associated disease progression and pathogenesis. These findings suggest that SLCP could be a promising strategy to induce E2 expression for the treatment of ALS and FTLD.}, }
@article {pmid39418491, year = {2025}, author = {Kumar, R and Ghai, S and Finelli, A and Klotz, L and Kinnaird, A and Mannas, M and Bhindi, B and Sanchez-Salas, R and Anidjar, M and Ahmad, A and Chin, J and Inman, B and Perlis, N}, title = {The use of focal therapy for the treatment of prostate cancer in Canada Where are we, how did we get here, and where are we going?.}, journal = {Canadian Urological Association journal = Journal de l'Association des urologues du Canada}, volume = {19}, number = {2}, pages = {63-72}, pmid = {39418491}, issn = {1911-6470}, abstract = {INTRODUCTION: Focal therapy is an emerging treatment for localized prostate cancer (PCa). The objectives of this review were to: 1) review how focal therapies are regulated and approved; 2) summarize the scope and quality of the literature regarding safety, efficacy, and side-effects; and 3) outline ongoing clinical trials of focal therapy in Canada.<br><br>METHODS: Using the PRISMA framework for scoping reviews, we searched PubMed, Embase, and Cochrane from 2021-2024, complementing Hopstaken et al's search up to 2020. We focused on studies reporting functional and oncologic outcomes. Additionally, we examined the FDA database for regulatory details and ongoing trials in Canada via ClinicalTrials.gov.<br><br>RESULTS: FDA approval for prostate tissue ablation was granted to high-intensity focused ultrasound (HIFU) in 2015 via the de novo pathway; other therapies followed the 510(k) route, citing equivalence to predicate devices. Most studies are in early stages, primarily single-arm, prospective cohort designs. Oncologic outcomes like cancer detection and survival rates, alongside functional data, such as adverse events and erectile function, were assessed. Recurrence-free survival at 48 months ranged from 58-92%, pad-free rates were greater than 95%, and rates of new-onset erectile dysfunction were variable, ranging from no change to 50%. Rates of serious adverse events were low, ranging from 0-14%. Three Canadian clinical trials are actively enrolling participants, and five private clinics were found offering private HIFU, irreversible electroporation, or transurethral ultrasound ablation.<br><br>CONCLUSIONS: Focal therapy technologies have gained regulatory approval for prostate tissue ablation, and aside from provincial support for cryoablation in Alberta, are available to Canadians through private payment or clinical trials. Many studies demonstrate promising cancer control and impressive functional outcomes but are limited by their short followup and lack of comparator group. Clinical trial or registry participation should be prioritized to ensure an evidence-based integration into current prostate cancer treatment approaches.}, }
@article {pmid39416141, year = {2024}, author = {Winkelsas, A and Apfel, A and Johnson, B and Harmison, G and Li, D and Cheung, V and Grunseich, C}, title = {Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39416141}, issn = {2692-8205}, support = {R21 ES034919/ES/NIEHS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis 4 (ALS4) is an autosomal dominant motor neuron disease that is molecularly characterized by reduced R-loop levels and caused by pathogenic variants in senataxin (SETX). SETX encodes an RNA/DNA helicase that resolves three-stranded nucleic acid structures called R-loops. Currently, there are no disease-modifying therapies available for ALS4. Given that SETX is haplosufficient, removing the product of the mutated allele presents a potential therapeutic strategy. We designed a series of siRNAs to selectively target the RNA transcript from the ALS4 allele containing the c.1166T>C mutation (p.Leu389Ser). Transfection of HEK293 cells with siRNA and plasmids encoding either wild-type or mutant (Leu389Ser) epitope tagged SETX revealed that three siRNAs specifically reduced mutant SETX protein levels without affecting the wild-type SETX protein. In ALS4 primary fibroblasts, siRNA treatment silenced the endogenous mutant SETX allele, while sparing the wild-type allele, and restored R-loop levels in patient cells. Our findings demonstrate that mutant SETX, differing from wild-type by a single nucleotide, can be effectively and specifically silenced by RNA interference, highlighting the potential of allele-specific siRNA as a therapeutic approach for ALS4.}, }
@article {pmid39412921, year = {2024}, author = {Bahador, M and Soltaninejad, S and Mobasheri, M}, title = {Correlation of new two-dimensional geometrical parameters to lung and heart dose-volume parameters in breast cancer radiation therapy.}, journal = {Journal of cancer research and therapeutics}, volume = {20}, number = {5}, pages = {1570-1577}, doi = {10.4103/jcrt.jcrt_2351_23}, pmid = {39412921}, issn = {1998-4138}, mesh = {Humans ; Female ; *Heart/radiation effects/diagnostic imaging ; *Radiotherapy Dosage ; *Radiotherapy Planning, Computer-Assisted/methods ; *Lung/radiation effects/diagnostic imaging/pathology ; *Breast Neoplasms/radiotherapy/pathology ; *Organs at Risk/radiation effects ; Tomography, X-Ray Computed/methods ; ROC Curve ; Middle Aged ; }, abstract = {OBJECTIVE: To develop new two-dimensional geometric parameters for pulmonary and cardiac dose estimation in left-sided breast cancer radiation therapy without dose-volume histogram (DVH).<br><br>METHODS: On the CT image of 90 patients with left breast cancer, treatment planning was performed using two opposed tangent fields with/without supraclavicular. The field-in-field technique and 6MV photons were used. From DVH dosimetric parameters of mean dose, Vx (x (Gy) =5, 10, 15, 20, 30, 40, 50) were calculated, and from heart and lung outlines on the beam's eye view, new geometric parameters of percent of lung area in tangent and supraclavicular fields (%area of the lung in the tangent (ALT), %ALS) and percent of heart in tangent field (%area of the heart in the tangent (AHT)) were measured. Correlation, regression, and diagnostic performance by receiver operating characteristic curve (ROC) were investigated for statistical analysis.<br><br>RESULTS: The Pearson coefficient between %ALT and Vx (x = 10, 15, 20, 30, 40) show strong correlation in patient treatment with only opposed tangents (>0.85) and weaker in treatment by opposed tangents with supraclavicular (0.56-0.88), the %ALS indicate weak correlation (<0.5) and %AHT show strong correlation (0.93-0.98). The regression analysis shows a positive relation between %ALT and mean dose (R2 = 0.8), V20Gy (R2 = 0.9) in the lung (tangent treatment), and between %AHT and mean dose (R2 = 0.9), V20Gy (R2 = 1.0) in the heart. The ROC analysis shows by %ALT <20.3 for treatment by just opposed fields, %ALT <22.1% for treatment tangents with supra, and %AHT <11.6%, practical lung and heart dose constraints are addressed.<br><br>CONCLUSION: The proposed geometric parameters could replace previous one-dimensional maximum and central distances for predicting doses to lung and heart.<br><br>ADVANCES IN KNOWLEDGE: This study presents simple geometric parameters that could estimate pulmonary and cardiac dose in left breast cancer treatment from a 2D radiograph.}, }
@article {pmid39411168, year = {2024}, author = {An, D and Han, J and Fang, P and Bu, Y and Ji, G and Liu, M and Deng, J and Song, X}, title = {Evidence for the potential role of m6A modification in regulating autophagy in models of amyotrophic lateral sclerosis.}, journal = {CytoJournal}, volume = {21}, number = {}, pages = {33}, pmid = {39411168}, issn = {0974-5963}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. Research indicates that N6-methyladenosine (m6A) modification plays a crucial role in cellular autophagy during ALS development. This study investigates the role of autophagy in ALS, with a focus on the effect of messenger ribonucleic acid m6A methylation modification on disease progression.<br><br>MATERIAL AND METHODS: We compared m6A levels and regulatory molecule expressions in transgenic superoxide dismutase (SOD1)-G93A and non-transgenic mice, categorized into end-stage and control groups, using quantitative polymerase chain reaction and Western blotting. The NSC-34 cell line, which was modified to model ALS, enabled the investigation of apoptosis, autophagy, and autophagy disruption through terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assays, Western blotting, and fluorescent staining.<br><br>RESULTS: Our findings indicate significantly elevated m6A methylation levels in ALS mice (0.262 &#xb1; 0.005) compared with the controls (0.231 &#xb1; 0.003) and in the ALS model cells (0.242&#xb1;0.005) relative to those belonging to the wild-type control group (0.183 &#xb1; 0.007). Furthermore, the proteins involved in m6A RNA modification differed between groups, which suggest impaired autophagy flux in the ALS models.<br><br>CONCLUSION: These results suggest that m6A methylation may accelerate ALS progression through the disruption of autophagic processes. Our study underscores the role of m6A methylation in the pathology of ALS and proposes the targeting of m6A methylation as a potential therapeutic strategy for disease treatment. Although this study primarily used transgenic SOD1-G93A mice and NSC-34 cell models to investigate ALS pathology, potential differences in disease mechanisms between animal models and humans must be considered. Although a correlation was detected between m6A methylation levels and autophagy disruption in ALS, the study primarily established an association rather than provided detailed mechanistic insights.}, }
@article {pmid39408720, year = {2024}, author = {Du, X and Dong, Q and Zhu, J and Li, L and Yu, X and Liu, R}, title = {Rutin Ameliorates ALS Pathology by Reducing SOD1 Aggregation and Neuroinflammation in an SOD1-G93A Mouse Model.}, journal = {International journal of molecular sciences}, volume = {25}, number = {19}, pages = {}, pmid = {39408720}, issn = {1422-0067}, support = {XDB39050600//Strategic Priority Research Program of Chinese Academy of Sciences/ ; 82150107//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Rutin/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; Mice ; *Superoxide Dismutase-1/metabolism/genetics ; *Disease Models, Animal ; *Mice, Transgenic ; *Spinal Cord/drug effects/metabolism/pathology ; Motor Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/pharmacology/therapeutic use ; Neuroinflammatory Diseases/drug therapy/metabolism ; Humans ; Protein Aggregation, Pathological/drug therapy/metabolism ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of motor neurons, with limited effective treatments. Recently, the exploration of natural products has unveiled their potential in exerting neuroprotective effects, offering a promising avenue for ALS therapy. In this study, the therapeutic effects of rutin, a natural flavonoid glycoside with neuroprotective properties, were evaluated in a superoxide dismutase 1 (SOD1)-G93A mouse model of ALS. We showed that rutin reduced the level of SOD1 aggregation and diminished glial cell activation in spinal cords and brainstems, resulting in significantly improved motor function and motor neuron restoration in SOD1-G93A mice. Our findings indicated that rutin's multi-targeted approach to SOD1-related pathology makes it a promising candidate for the treatment of ALS.}, }
@article {pmid39402174, year = {2025}, author = {Jellinger, KA}, title = {The spectrum of behavioral disorders in amyotrophic lateral sclerosis: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {132}, number = {2}, pages = {217-236}, pmid = {39402174}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/complications ; Humans ; *Mental Disorders/physiopathology/etiology ; Brain/physiopathology ; }, abstract = {Behavioral disorders, with an average prevalence of 30-60% are important non-motor symptoms in amyotrophic lateral sclerosis (ALS) that have a negative impact on prognosis, management and quality of life, yet the underlying neurobiology is poorly understood. Among people with ALS, apathy, fatigue, anxiety, irritability and other behavioral symptoms are the most prominent, although less frequent than cognitive impairment. The present review explores the current understanding of behavioral changes in ALS with particular emphasis on our current knowledge about their structural and functional brain correlates, substantiating a multisystem degeneration with particular dysfunction of frontal-subcortical circuits and dysfunction of fronto-striatal, frontotemporal and other essential brain systems. The natural history of behavioral dysfunctions in ALS and their relationship to frontotemporal lobe degeneration (FTLD) are not fully understood, although they form a clinical continuum, suggesting a differential vulnerability of non-motor brain networks, ALS being considered a brain network disorder. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of behavioral impairment in ALS. Treatment of both ALS and co-morbid behavioral disorders is a multidisciplinary task, but whereas no causal or disease-modifying therapies for ALS are available, symptomatic treatment of a variety of behavioral symptoms plays a pivotal role in patient care, although the management of behavioral symptoms in clinical care still remains limited.}, }
@article {pmid39401249, year = {2024}, author = {Pérez de la Lastra Aranda, C and Tosat-Bitrián, C and Porras, G and Dafinca, R and Muñoz-Torrero, D and Talbot, K and Martín-Requero, &#xc1; and Martínez, A and Palomo, V}, title = {Proteome Aggregation in Cells Derived from Amyotrophic Lateral Sclerosis Patients for Personalized Drug Evaluation.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {21}, pages = {3945-3953}, doi = {10.1021/acschemneuro.4c00328}, pmid = {39401249}, issn = {1948-7193}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy/pathology ; *Proteome/metabolism ; Precision Medicine/methods ; Motor Neurons/metabolism/drug effects ; Lymphocytes/metabolism/drug effects ; Protein Aggregates/drug effects/physiology ; Induced Pluripotent Stem Cells/metabolism/drug effects ; Protein Aggregation, Pathological/metabolism ; DNA-Binding Proteins/metabolism ; Drug Evaluation, Preclinical/methods ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that currently lacks effective therapy. Given the heterogeneity of clinical and molecular profiles of ALS patients, personalized diagnostics and pathological characterization represent a powerful strategy to optimize patient stratification, thereby enabling personalized treatment. Immortalized lymphocytes from sporadic and genetic ALS patients recapitulate some pathological hallmarks of the disease, facilitating the fundamental task of drug screening. However, the molecular aggregation of ALS has not been characterized in this patient-derived cellular model. Indeed, protein aggregation is one of the most prominent features of neurodegenerative diseases, and therefore, models to test drugs against personalized pathological aggregation could help discover improved therapies. With this work, we aimed to characterize the aggregation profile of ALS immortalized lymphocytes and test several drug candidates with different mechanisms of action. In addition, we have evaluated the molecular aggregation in motor neurons derived from two hiPSC cell lines corresponding to ALS patients with different mutations in TARDBP. The results provide valuable insight into the different characterization of sporadic and genetic ALS patients' immortalized lymphocytes, their differential response to drug treatment, and the usefulness of proteome homeostasis characterization in patients' cells.}, }
@article {pmid39400020, year = {2024}, author = {Ali, A and A Emad, N and Sultana, N and Waheed, A and Aqil, M and Sultana, Y and Mujeeb, M}, title = {Navigating into the Paradigm of Nose-to-brain Delivery of Nanotherapeutics and their Repurposing as Nanotheranostics for Neurodegenerative Diseases.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273319597240927044906}, pmid = {39400020}, issn = {1996-3181}, abstract = {Repurposing drugs for neurodegenerative diseases using the nose-to-brain route of administration is an intriguing concept with potential benefits. The nose-to-brain route involves delivering drugs directly to the brain via the olfactory or trigeminal pathways, bypassing the blood-brain barrier, which can improve drug efficacy and reduce systemic side effects. Treatment of numerous neurodegenerative diseases such as Multiple sclerosis, Amyotrophic lateral sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases has been attempted using this route of administration. These drugs may include neuroprotective agents, anti-inflammatory drugs, antioxidants, or diseasemodifying therapies. Nanotheranostics, which integrates therapeutic and diagnostic functions in a nanosystem, improves treatment precision and efficacy. Repurposing nanotherapeutics as nanotheranostics for neurodegenerative diseases through the nose-to-brain route of administration holds great potential for both diagnosis and treatment. This review highlights the various mechanisms engaged in transporting nanocarriers from nose-to-brain and the proposed fate of these nanocarriers using different live imaging techniques. Additionally, the discussion covers the recent combinatorial therapeutic approaches and theranostic applications of various nanocarriers used for neurodegenerative diseases through the nose-to-brain. Toxicity to the CNS and nasal mucosa and regulatory considerations about these delivery systems are also deliberated. Overall, repurposed nanoparticles designed as nanotheranostic agents offer a versatile platform for precise diagnosis, targeted therapy, and personalized management of neurodegenerative diseases, holding great promise for improving patient care and advancing our understanding of these complex disorders.}, }
@article {pmid39392186, year = {2025}, author = {Corcia, P and Piras, R and Lunetta, C}, title = {Why is the treatment and management of amyotrophic lateral sclerosis so difficult?.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {1}, pages = {1-3}, doi = {10.1080/14737175.2024.2415002}, pmid = {39392186}, issn = {1744-8360}, }
@article {pmid39386447, year = {2024}, author = {Rodemer, W and Ra, I and Jia, E and Gujral, J and Zhang, B and Hoxha, K and Xing, B and Mehta, S and Farag, M and Porta, S and Jensen, FE and Talos, DM and Lee, VM}, title = {Hyperexcitability precedes CA3 hippocampal neurodegeneration in a dox-regulatable TDP-43 mouse model of ALS-FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.09.24.612703}, pmid = {39386447}, issn = {2692-8205}, abstract = {UNLABELLED: Neuronal hyperexcitability is a hallmark of amyotrophic lateral sclerosis (ALS) but its relationship with the TDP-43 aggregates that comprise the predominant pathology in over 90% of ALS cases remains unclear. Emerging evidence in tissue and slice culture models indicate that TDP-43 pathology induces neuronal hyperexcitability suggesting it may be responsible for the excitotoxicity long believed to be a major driver of ALS neuron death. Here, we characterized hyperexcitability and neurodegeneration in the hippocampus of doxycycline-regulatable rNLS8 mice (NEFH-tTA x tetO-hTDP-43ΔNLS), followed by treatment with AAV encoded DREADDs and anti-seizure medications to measure the effect on behavioral function and neurodegeneration. We found that approximately half of the CA3 neurons in the dorsal hippocampus are lost between 4 and 6 weeks after TDP-43ΔNLS induction. Neurodegeneration was preceded by selective hyperexcitability in the mossy fiber - CA3 circuit, leading us to hypothesize that glutamate excitotoxicity may be a significant contributor to neurodegeneration in this model. Interestingly, hippocampal injection of AAV encoded inhibitory DREADDs (hM4Di) and daily activation with CNO ligand rescued anxiety deficits on elevated zero maze (EZM) but did not reduce neurodegeneration. Therapeutic doses of the anti-seizure medications, valproic acid and levetiracetam, did not improve behavior or prevent neurodegeneration. These results highlight the complexity of TDP-43 - induced alterations to neuronal excitability and suggest that whereas targeting hyperexcitability can meliorate some behavioral deficits, it may not be sufficient to halt or slow neurodegeneration in TDP-43-related proteinopathies.<br><br>SIGNIFICANCE STATEMENT: Cytoplasmic aggregates of TAR DNA Binding Protein 43 (TDP-43) are the predominant pathology in over 90% of Amyotrophic lateral sclerosis (ALS) and the majority of frontotemporal lobar degeneration (FTLD-TDP) cases. Understanding how TDP-43 pathology promotes neurodegeneration may lead to therapeutic strategies to slow disease progression in humans. Recent reports in mouse and cell culture models suggest loss-of-normal TDP-43 function may drive neuronal hyperexcitability, a key physiological hallmark of ALS and possible contributor to neurodegeneration. In this study, we identified region-specific hyperexcitability that precedes neurodegeneration in the inducible rNLS8 TDP-43 mouse model. Suppressing hyperexcitability with chemogenetics improved behavioral function but did not reduce hippocampal neuron loss. Anti-seizure medications had no beneficial effects suggesting directly targeting hyperexcitability may not be therapeutically effective.}, }
@article {pmid39382075, year = {2025}, author = {Liang, B and Khan, M and Storts, H and Zhang, EH and Zheng, X and Xing, X and Claybon, H and Wilson, J and Li, C and Jin, N and Fishel, R and Miles, WO and Wang, JJ}, title = {Riluzole Enhancing Anti-PD-1 Efficacy by Activating cGAS/STING Signaling in Colorectal Cancer.}, journal = {Molecular cancer therapeutics}, volume = {24}, number = {1}, pages = {131-140}, pmid = {39382075}, issn = {1538-8514}, support = {R01 CA251753/CA/NCI NIH HHS/United States ; R01 CA208063/CA/NCI NIH HHS/United States ; R01CA215389//National Cancer Institute (NCI)/ ; P30 CA016058/CA/NCI NIH HHS/United States ; R01 CA215389/CA/NCI NIH HHS/United States ; R01 CA067007/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Nucleotidyltransferases/metabolism ; *Colorectal Neoplasms/drug therapy/metabolism/pathology ; Mice ; *Membrane Proteins/metabolism ; Humans ; *Signal Transduction/drug effects ; *Programmed Cell Death 1 Receptor/antagonists &amp; inhibitors/metabolism ; *Riluzole/pharmacology/therapeutic use ; CD8-Positive T-Lymphocytes/drug effects/immunology/metabolism ; Cell Line, Tumor ; Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; }, abstract = {Colorectal cancer is the second leading cause of cancer mortality in the United States. Although immune checkpoint blockade therapies including anti-PD-1/PD-L1 have been successful in treating a subset of patients with colorectal cancer, the response rates remain low. We have found that riluzole, a well-tolerated FDA-approved oral medicine for treating amyotrophic lateral sclerosis, increased intratumoral CD8+ T cells and suppressed tumor growth of colon cancer cells in syngeneic immune-competent mice. Riluzole-mediated tumor suppression was dependent on the presence of CD8+ T cells. Riluzole activates the cytosolic DNA sensing cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway in colon cancer cells, resulting in increased expression of IFNβ and IFNβ-regulated genes including CXCL10. Inhibition of ataxia telangiectasia mutated (ATM), but not ATM-related, resulted in a synergistic increase in IFNβ expression, suggesting that riluzole induces ATM-mediated damage response that contributes to cGAS/STING activation. Depletion of cGAS or STING significantly attenuated riluzole-induced expression of IFNβ and CXCL10 as well as increase of intratumoral CD8+ T cells and suppression of tumor growth. These results indicate that riluzole-mediated tumor infiltration of CD8+ T cells and attenuation of tumor growth is dependent on tumor cell-intrinsic STING activation. To determine whether riluzole treatment primes the tumor microenvironment for immune checkpoint modulation, riluzole was combined with anti-PD-1 treatment. This combination showed greater efficacy than either single agent and strongly suppressed tumor growth in vivo. Taken together, our studies indicate that riluzole activates cGAS/STING-mediated innate immune responses, which might be exploited to sensitize colorectal tumors to anti-PD-1/PD-L1 therapies.}, }
@article {pmid39378530, year = {2025}, author = {Meng, T and Wu, W and Wang, B and Li, C and Li, J and Liu, J and Wang, J and Qie, R}, title = {Treating chronic pulmonary heart disease with traditional Chinese medicine: Systematic evaluation and mechanistic insights into the resolving phlegm and activating blood approach.}, journal = {Heart &amp; lung : the journal of critical care}, volume = {69}, number = {}, pages = {111-126}, doi = {10.1016/j.hrtlng.2024.09.017}, pmid = {39378530}, issn = {1527-3288}, mesh = {Humans ; Chronic Disease ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Medicine, Chinese Traditional/methods ; *Pulmonary Heart Disease/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Chronic Pulmonary Heart Disease (CPHD) significantly impacts global health, especially among middle-aged and older adults. In China, the Traditional Chinese Medicine (TCM) technique of Resolving Phlegm and Activating Blood (RPAB) is widely used to treat CPHD, although high-quality evidence supporting its efficacy remains limited.<br><br>OBJECTIVES: The purpose of this study was to rigorously assess the clinical efficacy of RPAB for CPHD and elucidate the mechanisms underlying its primary herbal components.<br><br>METHODS: Through a detailed search of literature in both Chinese and English and strict inclusion and exclusion criteria, 18 randomized controlled trials (RCTs) were selected for meta-analysis. We identified RPAB's core herbal combinations using association rule analysis. This method statistically analyzes the frequency and correlation of herbal medicine usage. We then analyzed the chemical components of these combinations and investigated their potential intervention mechanisms on CPHD through network pharmacology.<br><br>RESULTS: The combination of RPAB with Western medicine was superior to Western medicine alone in improving blood gas analysis and pulmonary function and reducing plasma viscosity in CPHD patients. The core herbal combination identified was Astragalus membranaceus (Fisch.) Bunge, Ligusticum chuanxiong Hort. ex S. H. Qiu &amp; al., and Stellaria alsine Grimm (ALS). This combination targeted 588 therapeutic and 27 core targets. It influenced ten core compounds across 34 pathways, primarily through the chemokine signaling pathway and the JAK-STAT signaling pathway.<br><br>CONCLUSION: RPAB with Western medicine significantly improves CPHD treatment outcomes. The study highlights the therapeutic potential of the ALS combination, which operates through multiple pathways to remodel pulmonary arteries, decrease inflammation, and lessen oxidative stress. These insights support the clinical application of RPAB in CPHD treatment and open new avenues for research and therapeutic development.}, }
@article {pmid39373990, year = {2024}, author = {Appel, SH and Thonhoff, JR}, title = {Barriers to Tofersen Therapy for Variant SOD1-Mediated ALS.}, journal = {JAMA neurology}, volume = {81}, number = {12}, pages = {1239-1240}, doi = {10.1001/jamaneurol.2024.3331}, pmid = {39373990}, issn = {2168-6157}, }
@article {pmid39370211, year = {2024}, author = {Kajitani, GS and Xavier, G and Villena-Rueda, BE and Karia, BTR and Santoro, ML}, title = {Extracellular vesicles in neurodegenerative, mental, and other neurological disorders: Perspectives into mechanisms, biomarker potential, and therapeutic implications.}, journal = {Current topics in membranes}, volume = {94}, number = {}, pages = {299-336}, doi = {10.1016/bs.ctm.2024.06.002}, pmid = {39370211}, issn = {1063-5823}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; *Biomarkers/metabolism ; Mental Disorders/metabolism/drug therapy/therapy ; Animals ; Nervous System Diseases/metabolism/pathology ; }, abstract = {Extracellular vesicles (EVs) are produced, secreted, and targeted by most human cells, including cells that compose nervous system tissues. EVs carry several types of biomolecules, such as lipids, proteins and microRNA, and can function as signaling agents in physiological and pathological processes. In this chapter, we will focus on EVs and their cargo secreted by brain cells, especially neurons and glia, and how these aspects are affected in pathological conditions. The chapter covers neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, as well as several psychiatric disorders, namely schizophrenia, autism spectrum disorder and major depressive disorder. This chapter also addresses other types of neurological dysfunctions, epilepsy and traumatic brain injury. EVs can cross the blood brain barrier, and thus brain EVs may be detected in more accessible peripheral tissue, such as circulating blood. Alterations in EV composition and contents can therefore impart valuable clues into the molecular etiology of these disorders, and serve biomarkers regarding disease prevalence, progression and treatment. EVs can also be used to carry drugs and biomolecules into brain tissue, considered as a promising drug delivery agent for neurological diseases. Therefore, although this area of research is still in its early development, it offers great potential in further elucidating and in treating neurological disorders.}, }
@article {pmid39368746, year = {2024}, author = {Sharma, R and Mehan, S and Khan, Z and Das Gupta, G and Narula, AS}, title = {Therapeutic potential of oleanolic acid in modulation of PI3K/Akt/mTOR/STAT-3/GSK-3β signaling pathways and neuroprotection against methylmercury-induced neurodegeneration.}, journal = {Neurochemistry international}, volume = {180}, number = {}, pages = {105876}, doi = {10.1016/j.neuint.2024.105876}, pmid = {39368746}, issn = {1872-9754}, mesh = {Animals ; *Oleanolic Acid/pharmacology/therapeutic use ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; Male ; *Methylmercury Compounds/toxicity ; *Glycogen Synthase Kinase 3 beta/metabolism ; *TOR Serine-Threonine Kinases/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Phosphatidylinositol 3-Kinases/metabolism ; Rats, Wistar ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Neuroprotection/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that gradually deteriorates motor neurons, leading to demyelination, muscle weakness, and eventually respiratory failure. The disease involves several pathological processes, such as increased glutamate levels, mitochondrial dysfunction, and persistent neuroinflammation, often exacerbated by environmental toxins like mercury. This study explores the therapeutic potential of Olea europaea active phytoconstituents oleanolic acid (OLA) against ALS by targeting the overactivated PI3K/Akt/mTOR/STAT-3/GSK-3β signalling pathways. Methods involved in-silico studies, in vitro and in vivo experiments in which varying doses of methylmercury 5 mg/kg, p.o. and OLA (100 and 200 mg/kg, i.p.) were administered to rats for 42 days. Behavioural assessments, gross morphological, histopathological, and neurochemical parameters were measured in cerebrospinal fluid (CSF), blood plasma, and brain homogenates (cerebral cortex, hippocampus, striatum, midbrain, cerebellum) along with complete blood count (CBC) analysis. Results revealed OLA's significant neuroprotective properties. OLA effectively modulated targeted pathways, reducing pro-inflammatory cytokines, restoring normal levels of myelin basic protein (MBP) and neurofilament light chain (NEFL), and reducing histopathological changes. Gross pathological studies indicated less tissue damage, while CBC analysis showed improved hematology parameters. Additionally, the combination of OLA and edaravone (10 mg/kg, i.p.) demonstrated enhanced efficacy, improving motor functions and extending survival in ALS model rats. In conclusion, OLA exhibits significant therapeutic potential for ALS, acting as a potent modulator of key pathological signaling pathways. The findings suggest the feasibility of integrating OLA into existing treatment regimens, potentially improving clinical outcomes for ALS patients. However, further research must validate these findings in human clinical trials.}, }
@article {pmid39368179, year = {2025}, author = {Brito, ALB and Cardoso, IF and Viegas, LP and Fausto, R}, title = {Semi-quantitative chemometric models for characterization of mixtures of sugars using infrared spectral data.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {326}, number = {}, pages = {125225}, doi = {10.1016/j.saa.2024.125225}, pmid = {39368179}, issn = {1873-3557}, mesh = {*Chemometrics/methods ; *Models, Chemical ; *Sugars/analysis ; Spectrophotometry, Infrared ; Principal Component Analysis ; Multivariate Analysis ; Least-Squares Analysis ; }, abstract = {Sugars (saccharides) are sweet-tasting carbohydrates that are abundant in foods and play very important roles in living organisms, particularly as sources and stores of energy, and as structural elements in cellular membranes. They are desirable therapeutic targets, as they participate in multiple metabolic processes as fundamental elements. However, the physicochemical characterization of sugars is a challenging task, mostly due to the structural similarity shared by the large diversity of compounds of this family. The need for fast, accurate enough, and cost-effective analytical methods for these substances is of extreme relevance, in particular because of the recently increasing importance of carbohydrates in Medicine and food industry. With this in view, this work focused on the development of chemometric models for semi-quantitative analysis of samples of different types of sugars (glucose, galactose, mannitol, sorbose and fructose) using infrared spectra as data, as an example of application of a novel approach, where the Principal Component Analysis (PCA) score plots are used to estimate the composition (weight-%) of the mixtures of the sugars. In these plots, polygonal geometric shapes emerge in the vectorial space of the most significant principal components, that allow grouping different types of samples on the vertices, edges, faces and interior of the polygons according to the composition of the samples. This approach was applied successfully to mixtures of up to 5 sugars and shown to appropriately extract the compositional information from the hyper-redundant complex spectral data. Thought the method has been applied here to a specific problem, it shall be considered as a general procedure for the semi-quantitative analysis of other types of mixtures and applicable to other types of data reflecting their composition. In fact, the methodology appears as an efficient tool to solve three main general problems: (i) use hyper-redundant (in variables) data, as spectral information, directly and with minimum pre-treatment, to evaluate semi-quantitatively the composition of mixtures; (ii) do this for systems which produce data that can be considered rather similar; and (iii) do it for a number of substances present in the mixtures that might be greater than that usually considered in chemistry, which in general is limited to 3 components. In addition, this work also demonstrates that, similarly to the developed analysis based on the PCA score plots, the Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS) chemometric method can also be used successfully for the qualitative (when used without any previous knowledge of the components present in the samples) or semi-quantitative (when the pure components spectral profiles are provided as references) analyses of mixtures of (at least) up to 5 distinct sugars.}, }
@article {pmid39367309, year = {2024}, author = {Makled, AF and Ali, SAM and Labeeb, AZ and Salman, SS and Shebl, DZM and Hegazy, SG and Sabal, MS}, title = {Characterization of Candida species isolated from clinical specimens: insights into virulence traits, antifungal resistance and molecular profiles.}, journal = {BMC microbiology}, volume = {24}, number = {1}, pages = {388}, pmid = {39367309}, issn = {1471-2180}, mesh = {Humans ; *Candida/genetics/pathogenicity/drug effects/isolation &amp; purification/classification ; *Drug Resistance, Fungal/genetics ; *Antifungal Agents/pharmacology ; *Virulence Factors/genetics ; *Candidiasis/microbiology ; *Biofilms/growth &amp; development ; *Microbial Sensitivity Tests ; Virulence/genetics ; Multiplex Polymerase Chain Reaction ; Male ; Female ; Adult ; Middle Aged ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Candida species have emerged as a significant cause of opportunistic infections. Alongside the expression of various virulence factors, the rise of antifungal resistance among Candida species presents a considerable clinical challenge.<br><br>AIM: This study aimed to identify different Candida species isolated from clinical specimens, evaluate their antifungal sensitivity patterns, identify key genes regulating virulence mechanisms using multiplex PCR and to assess any correlation between their virulence profiles and antifungal resistance patterns.<br><br>METHOD: A total of 100 Candida spp. was isolated from 630 different clinical specimens and identified to the species level. Their antifungal susceptibility was phenotypically evaluated in accordance with CLSI guidelines using the Vitek-2 Compact System. Virulence markers, including biofilm formation capacity, protease production, melanin production, coagulase production and hemolysin production, were also phenotypically detected. The genetic determinants for biofilm formation and extracellular hydrolytic enzymes were assessed using a multiplex PCR assay.<br><br>RESULTS: The prevalence of Candida spp. was 15.9%, with C. albicans (48%) and C. glabrata (16%) being the most common. C. albicans showed the highest virulence, with strong biofilm formation, and high proteinase and melanin production. Multiplex PCR revealed Hlp in 22.0%, Hwp in 80.0%, Als in 56.0%, and Sap genes in 56.0% of isolates. Virulence genes were more common in C. albicans than in non-albicans Candida (NAC). Resistance patterns significantly correlated with virulence profiles, with notable associations between flucytosine resistance and the presence of Hlp and Hwp genes.<br><br>CONCLUSION: The significant correlation between virulent markers such as germination, coagulase, hemolysin production and resistance patterns among different Candida isolates is crucial for predicting the severity and outcomes of Candida infections. This understanding aids in guiding tailored treatment strategies.}, }
@article {pmid39362869, year = {2024}, author = {Ma, YY and Li, X and Yu, ZY and Luo, T and Tan, CR and Bai, YD and Xu, G and Sun, BD and Bu, XL and Liu, YH and Jin, WS and Gao, YQ and Zhou, XF and Liu, J and Wang, YJ}, title = {Oral antioxidant edaravone protects against cognitive deficits induced by chronic hypobaric hypoxia at high altitudes.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {415}, pmid = {39362869}, issn = {2158-3188}, support = {92249305//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; *Edaravone/pharmacology/administration &amp; dosage ; *Cognitive Dysfunction/etiology/drug therapy/prevention &amp; control ; Mice ; *Oxidative Stress/drug effects ; Male ; *Hypoxia/complications/drug therapy/metabolism ; *Altitude ; Antioxidants/pharmacology/administration &amp; dosage ; Mice, Inbred C57BL ; Administration, Oral ; Hippocampus/drug effects/metabolism ; Disease Models, Animal ; Free Radical Scavengers/administration &amp; dosage/pharmacology ; Brain/drug effects/metabolism ; }, abstract = {Chronic hypobaric hypoxia at high altitudes can impair cognitive functions, especially causing deficits in learning and memory, which require therapeutic intervention. Here, we showed that mice subjected to hypobaric hypoxia (simulating an altitude of 5000 m) for one month experienced significant cognitive impairment, accompanied by increased biomarker levels of oxidative stress in the brain and blood. Oral administration of a novel formulation of edaravone, a free radical scavenger approved for the treatment of ischaemic stroke and amyotrophic lateral sclerosis, significantly alleviated oxidative stress and cognitive impairments caused by chronic hypobaric hypoxia. Furthermore, oral edaravone treatment also mitigated neuroinflammation and restored hippocampal neural stem cell exhaustion. Additionally, periostin (Postn) is vital in the cognitive deficits caused by chronic hypobaric hypoxia and may be a molecular target of edaravone. In conclusion, our results suggest that oxidative stress plays a crucial role in the cognitive deficits caused by chronic hypobaric hypoxia and that oral edaravone is a potential medicine for protecting against cognitive deficits caused by chronic hypobaric hypoxia in high-altitude areas.}, }
@article {pmid39360074, year = {2024}, author = {Puri, SN and Raghuveer, R and Jachak, S and Tikhile, P}, title = {Exploring the Impact of Personalized Physical Therapy on a Patient With Motor Neuron Disorder: A Case Study.}, journal = {Cureus}, volume = {16}, number = {9}, pages = {e68373}, pmid = {39360074}, issn = {2168-8184}, abstract = {This case study examines the effect of a tailor-made physiotherapy regimen on an 85-year-old male patient who was suffering from bulbar motor neuron disease (MND) and had a history of stroke and COVID-19. The physiotherapy plan was designed to strategically address the patient's respiratory issues, generalized weakness affecting limb muscles, and speech and swallowing difficulties. Frequent evaluations made it possible to adjust the treatment plan, emphasizing a holistic strategy to improve the patient's overall quality of life. Improvements in scores on multiple functional scales and manual muscle testing were shown by outcome measures and follow-up evaluations. This case emphasizes how important customized physiotherapy is for maximizing functional outcomes and enhancing the quality of life for patients dealing with the complicated conditions of bulbar MND.}, }
@article {pmid39355247, year = {2024}, author = {Yang, JL and Wu, JY and Liu, JJ and Zheng, GQ}, title = {Herbal medicines for SOD1[G93A] mice of amyotrophic lateral sclerosis: preclinical evidence and possible immunologic mechanism.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1433929}, pmid = {39355247}, issn = {1664-3224}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/immunology/genetics ; Animals ; Mice ; *Disease Models, Animal ; Mice, Transgenic ; Humans ; Superoxide Dismutase-1/genetics ; Herbal Medicine ; }, abstract = {Currently, there is no cure or effective treatment for Amyotrophic Lateral Sclerosis (ALS). The mechanisms underlying ALS remain unclear, with immunological factors potentially playing a significant role. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), a systematic review of preclinical studies was conducted, searching seven databases including PubMed, covering literature from the inception of the databases to April 10, 2024. Methodological quality of the included literature was assessed using CAMARADES, while the risk of bias in the included studies was evaluated using SYRCLE's ROB tool. Review Manager 5.4.1 statistical software was used for meta-analysis of the outcomes. The scoping review followed the Joanna Briggs Institute Methodological Guidelines and reporting of this review followed the PRISMA-extension for Scoping Reviews (PRISMA -ScR) checklist to explore the immunological mechanisms of Herbal Medicine (HM) in treating ALS. This systematic review and meta-analysis involved 18 studies with a total of 443 animals. The studies scored between 4 to 8 for methodological quality and 3 to 7 for risk of bias, both summing up to 10.A remarkable effects of HM in ALS mice, including onset time(Standardized Mean Difference(SMD): 1.75, 95% Confidence Interval(CI) (1.14 ~ 2.36), Z = 5.60, P < 0.01), survival time(SMD = 1.42, 95% CI (0.79 ~ 2.04), Z = 4.44, P < 0.01), stride length(SMD=1.90, 95% CI (1.21 to 2.59), Z = 5.39, P < 0.01) and duration time (Mean Difference(MD)=6.79, 95% CI [-0.28, 13.87], Z=1.88, P =0.06), showing HM's certain efficiency in treating ALS mice. The scoping review ultimately included 35 articles for review. HMs may treat ALS through mechanisms such as combating oxidative stress, excitatory amino acid toxicity, and calcium cytotoxicity, understanding and exploring the mechanisms will bring hope to patients. Individual herbs and their formulations within HM address ALS through a variety of immune pathways, including safeguarding the blood-brain barrier, countering neuroinflammation, impeding complement system activation, mitigating natural killer cell toxicity, and regulating T cell-mediated immune pathways. The preclinical evidence supports the utilization of HM as a conventional treatment for ALS mice. Growing evidence indicates that HM may potentially delay neurological degeneration in ALS by activating diverse signaling pathways, especially immune pathways.}, }
@article {pmid39352708, year = {2024}, author = {Crose, JJ and Crose, A and Ransom, JT and Lightner, AL}, title = {Bone marrow mesenchymal stem cell-derived extracellular vesicle infusion for amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {3-4}, pages = {111-117}, pmid = {39352708}, issn = {1758-2032}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Extracellular Vesicles ; Male ; Middle Aged ; Female ; Pilot Projects ; Aged ; Mesenchymal Stem Cells ; Mesenchymal Stem Cell Transplantation/methods ; Infusions, Intravenous ; Adult ; Treatment Outcome ; }, abstract = {Background: In this pilot safety study, we hypothesized that a human bone marrow stem cell-derived extracellular vesicle (hBM-MSC EV) investigational product (IP) would be safe and exhibit potential efficacy in amyotrophic lateral sclerosis (ALS) patients.Methods: Ten ALS patients received two 10-ml intravenous infusions of the IP given 1 month apart and evaluated over 3 months.Results: There were no serious adverse events or adverse events related to the IP and 30% of subjects' ALS functional rating scale-revised (ALSFRS-R) scores did not decline.Conclusion: HBM-MSC EVs appear safe in ALS patients. This early investigation suggests a controlled study of EVs for the treatment of ALS is warranted.}, }
@article {pmid39347334, year = {2024}, author = {Aljehani, NS and Al-Gunaid, ST and Hobani, AH and Alhinti, MF and Khubrani, YA and Abu-Hamoud, LM and Alrayes, AA and Alharbi, LB and Sultan, AA and Turkistani, DA and Naiser, SS and Albraik, L and Alakel, AM and Alotaibi, M and Asiri, AY}, title = {Ultrasound Blood-Brain Barrier Opening and Aducanumab in Alzheimer's Disease: A Systematic Review and Meta-Analysis.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e68008}, pmid = {39347334}, issn = {2168-8184}, abstract = {The blood-brain barrier (BBB) presents a significant challenge in treating Alzheimer's disease, as it restricts the delivery of therapeutic medications to brain tissue. Reversible breaking of the BBB using low-intensity focused ultrasound guided by magnetic resonance imaging (MRI) may benefit patients with Alzheimer's disease and other neurological illnesses, such as brain tumors, amyotrophic lateral sclerosis, and Parkinson's disease. This systematic study and meta-analysis aimed to assess aducanumab and the ultrasonography of BBB opening in Alzheimer's patients. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), the study was conducted by searching six digital repositories for relevant scholarly literature, focusing on English papers published between 2015 and 2024; the data was extracted using an Excel sheet, and data was analyzed using Revman 5.4.1 software. The study's findings indicate that the groups receiving ultrasound and aducanumab treatment benefited from it; however, overall, the effect was not statistically significant (P=0.29) at 95% CI 0.86 (0.75, 1.00). With regard to side effects, the results indicate that the treatment had fewer side effects compared to the control group; however, the difference was not statistically significant (p=0.94) at 95% CI 0.93 (0.70, 1.22). The study found a positive effect of ultrasound and aducanumab on the treatment groups, but it was not statistically significant. The control group had less side effects than the treatment group. Therefore, future studies should focus on the quantity or combination of the drug that yields more effective results.}, }
@article {pmid39346681, year = {2024}, author = {Fisher, RMA and Torrente, MP}, title = {Histone post-translational modification and heterochromatin alterations in neurodegeneration: revealing novel disease pathways and potential therapeutics.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1456052}, pmid = {39346681}, issn = {1662-5099}, support = {R15 NS125394/NS/NINDS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), Frontotemporal Dementia (FTD), and Amyotrophic lateral sclerosis (ALS) are complex and fatal neurodegenerative diseases. While current treatments for these diseases do alleviate some symptoms, there is an imperative need for novel treatments able to stop their progression. For all of these ailments, most cases occur sporadically and have no known genetic cause. Only a small percentage of patients bear known mutations which occur in a multitude of genes. Hence, it is clear that genetic factors alone do not explain disease occurrence. Chromatin, a DNA-histone complex whose basic unit is the nucleosome, is divided into euchromatin, an open form accessible to the transcriptional machinery, and heterochromatin, which is closed and transcriptionally inactive. Protruding out of the nucleosome, histone tails undergo post-translational modifications (PTMs) including methylation, acetylation, and phosphorylation which occur at specific residues and are connected to different chromatin structural states and regulate access to transcriptional machinery. Epigenetic mechanisms, including histone PTMs and changes in chromatin structure, could help explain neurodegenerative disease processes and illuminate novel treatment targets. Recent research has revealed that changes in histone PTMs and heterochromatin loss or gain are connected to neurodegeneration. Here, we review evidence for epigenetic changes occurring in AD, PD, and FTD/ALS. We focus specifically on alterations in the histone PTMs landscape, changes in the expression of histone modifying enzymes and chromatin remodelers as well as the consequences of these changes in heterochromatin structure. We also highlight the potential for epigenetic therapies in neurodegenerative disease treatment. Given their reversibility and pharmacological accessibility, epigenetic mechanisms provide a promising avenue for novel treatments. Altogether, these findings underscore the need for thorough characterization of epigenetic mechanisms and chromatin structure in neurodegeneration.}, }
@article {pmid39344189, year = {2025}, author = {Khorshidi, Z and Adibi, I and Ghasemi, M}, title = {Association between cerebrospinal fluid chitotriosidase level and amyotrophic lateral sclerosis: a systematic review.}, journal = {Hormone molecular biology and clinical investigation}, volume = {46}, number = {1}, pages = {13-19}, pmid = {39344189}, issn = {1868-1891}, mesh = {*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Humans ; *Hexosaminidases/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; }, abstract = {INTRODUCTION: One of the fatal and debilitating neurodegenerative diseases is amyotrophic lateral sclerosis (ALS). Increasing age is one of the risk factors of ALS. Considering that the elderly population in the world is increasing, it is very important to identify useful and effective diagnostic and treatment methods. The purpose of this systematic review is to determine the relationship between chitotriosidase (CHIT1) level and ALS disorder.<br><br>CONTENT: Keywords "Amyotrophic Lateral Sclerosis", "Gehrig* Disease", "Charcot Disease", "Guam Disease", ALS, CHIT1 and chitotriosidase were searched in PubMed, Scopus, Web of Science and Science Direct databases without time limit on September 2023. Hundred twenty studies were obtained by searching, and finally, 14 studies were included in this study using the inclusion and exclusion criteria. In all 14 selected studies, the level of biomarker CHIT1 in the CSF of ALS patients was significantly higher than that of healthy control and disease control groups. But, in 8 studies that included 3 groups, no significant difference was observed between the CHIT1 levels in the two control groups. Six studies have reported the amount of CHIT1 level quantitatively. Among these 6 studies, in 5 studies CHIT1 level in disease control was higher than healthy control (not significant) and in only one study CHIT1 level was higher in healthy control compared to disease control (not significant).<br><br>SUMMARY AND OUTLOOK: In all 14 studies, a multifold increase in CHIT1 levels has been observed in patients compared to healthy and disease control groups. Therefore, based on the findings of the studies, this study confirms the relationship between CHIT1 increase and ALS disorder.}, }
@article {pmid39343990, year = {2024}, author = {Xia, L and Qiu, Y and Li, J and Xu, M and Dong, Z}, title = {The Potential Role of Artemisinins Against Neurodegenerative Diseases.}, journal = {The American journal of Chinese medicine}, volume = {52}, number = {6}, pages = {1641-1660}, doi = {10.1142/S0192415X24500642}, pmid = {39343990}, issn = {1793-6853}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Artemisinins/pharmacology ; *Neuroprotective Agents/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Parkinson Disease/drug therapy/metabolism ; Ferroptosis/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy ; Huntington Disease/drug therapy/metabolism ; Autophagy/drug effects ; }, abstract = {Artemisinin (ART) and its derivatives, collectively referred to as artemisinins (ARTs), have been approved for the treatment of malaria for decades. ARTs are converted into dihydroartemisinin (DHA), the only active form, which is reductive in vivo. In this review, we provide a brief overview of the neuroprotective potential of ARTs and the underlying mechanisms on several of the most common neurodegenerative diseases, particularly considering their potential application in those associated with cognitive and motor impairments including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). ARTs act as autophagy balancers to alleviate AD and PD. They inhibit neuroinflammatory responses by regulating phosphorylation of signal transduction proteins, such as AKT, PI3K, ERK, NF-κB, p38 MAPK, IκBα. In addition, ARTs regulate GABAergic signaling in a dose-dependent manner. Although they competitively inhibit the binding of gephyrin to GABAergic receptors, low doses of ARTs enhance GABAergic signaling. ARTs can also inhibit ferroptosis, activate the Akt/Bcl-2, AMPK, or ERK/CREB pathways to reduce oxidative stress, and maintain mitochondrial homeostasis, protecting neurons from oxidative stress injury. More importantly, ARTs structurally combine with and suppress β-Amyloid (A[Formula: see text]-induced neurotoxicity, reduce P-tau, and maintain O-GlcNAcylation/Phosphorylation balance, leading to relieved pathological changes in neurodegenerative diseases. Collectively, these natural properties endow ARTs with unique potential for application in neurodegenerative diseases.}, }
@article {pmid39343443, year = {2024}, author = {O'Brien, D and Shaw, PJ}, title = {New developments in the diagnosis and management of motor neuron disease.}, journal = {British medical bulletin}, volume = {152}, number = {1}, pages = {4-15}, doi = {10.1093/bmb/ldae010}, pmid = {39343443}, issn = {1471-8391}, support = {NIHR 203321//NIHR Sheffield Biomedical Research Centre/ ; 972-797//AMBRoSIA Biosampling Programme/ ; 764-780//MNDA (Sheffield Care and Research Centre for Motor Neuron Disorders/ ; }, mesh = {Humans ; *Motor Neuron Disease/therapy/diagnosis ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {INTRODUCTION: Motor neuron disease (MND) is a devastating neurodegenerative disease characterized by progressive muscle weakness.<br><br>SOURCES OF DATA: PubMed, MEDLINE, and Cochrane databases were searched for articles to March 2024. Searches involved the terms 'motor neuron disease' or 'amyotrophic lateral sclerosis' and 'epidemiology', 'diagnosis', 'clinical', 'genetic', 'management', 'treatment', or 'trial'.<br><br>AREAS OF AGREEMENT: Evidence-based management involves riluzole, multidisciplinary care, provision of noninvasive ventilation and gastrostomy, and symptomatic treatments. Tofersen should be offered to treat SOD1-MND.<br><br>AREAS OF CONTROVERSY: Edaravone and Relyvrio are approved treatments in the USA, but insufficient evidence was found to support approval in the UK and Europe.<br><br>GROWING POINTS: The discovery of neurofilaments as MND biomarkers, growth of platform trials and development of novel therapies provide optimism for more powerful neuroprotective therapies.<br><br>Further work should focus on the elucidation of environmental causes of MND, gene-environment interactions, and advanced cellular models of disease.}, }
@article {pmid39341837, year = {2024}, author = {Hollingworth, D and Thomas, F and Page, DA and Fouda, MA and De Castro, RL and Sula, A and Mykhaylyk, VB and Kelly, G and Ulmschneider, MB and Ruben, PC and Wallace, BA}, title = {Structural basis for the rescue of hyperexcitable cells by the amyotrophic lateral sclerosis drug Riluzole.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8426}, pmid = {39341837}, issn = {2041-1723}, support = {BB/105581//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; CC1078/ARC_/Arthritis Research UK/United Kingdom ; mutiple grants//Diamond Light Source/ ; /WT_/Wellcome Trust/United Kingdom ; BB/V0183511//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; CF2-100001//Rosetrees Trust/ ; BB/S017844//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; studentship//Wellcome Trust (Wellcome)/ ; }, mesh = {*Riluzole/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; Humans ; *Neuroprotective Agents/pharmacology ; Voltage-Gated Sodium Channels/metabolism/chemistry ; HEK293 Cells ; Animals ; Sodium/metabolism ; Motor Neurons/drug effects/metabolism ; }, abstract = {Neuronal hyperexcitability is a key element of many neurodegenerative disorders including the motor neuron disease Amyotrophic Lateral Sclerosis (ALS), where it occurs associated with elevated late sodium current (INaL). INaL results from incomplete inactivation of voltage-gated sodium channels (VGSCs) after their opening and shapes physiological membrane excitability. However, dysfunctional increases can cause hyperexcitability-associated diseases. Here we reveal the atypical binding mechanism which explains how the neuroprotective ALS-treatment drug riluzole stabilises VGSCs in their inactivated state to cause the suppression of INaL that leads to reversed cellular overexcitability. Riluzole accumulates in the membrane and enters VGSCs through openings to their membrane-accessible fenestrations. Riluzole binds within these fenestrations to stabilise the inactivated channel state, allowing for the selective allosteric inhibition of INaL without the physical block of Na[+] conduction associated with traditional channel pore binding VGSC drugs. We further demonstrate that riluzole can reproduce these effects on a disease variant of the non-neuronal VGSC isoform Nav1.4, where pathologically increased INaL is caused directly by mutation. Overall, we identify a model for VGSC inhibition that produces effects consistent with the inhibitory action of riluzole observed in models of ALS. Our findings will aid future drug design and supports research directed towards riluzole repurposing.}, }
@article {pmid39341656, year = {2024}, author = {Paris, A and Lakatos, A}, title = {Cell and gene therapy for amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {205}, number = {}, pages = {217-241}, doi = {10.1016/B978-0-323-90120-8.00017-4}, pmid = {39341656}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; *Genetic Therapy/methods ; Animals ; Cell- and Tissue-Based Therapy/methods/trends ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disorder with rapidly progressive skeletal muscle weakness, which can also cause a variable cognitive deficit. Genetic causes are only identified in approximately 10% of all cases, with complex genotype-phenotype associations, making it challenging to identify treatment targets. What further hampers therapeutic development is a broad heterogeneity in mechanisms, possible targets, and disturbances across various cell types, aside from the cortical and spinal motor neurons that lie at the heart of the pathology of ALS. Over the last decade, significant progress in biotechnologic techniques, cell and ribonucleic acid (RNA) engineering, animal models, and patient-specific human stem cell and organoid models have accelerated both mechanistic and therapeutic discoveries. The growing number of clinical trials mirrors this. This chapter reviews the current state of human preclinical models supporting trial strategies as well as recent clinical cell and gene therapy approaches.}, }
@article {pmid39341507, year = {2024}, author = {Sivalingam, AM}, title = {Advances in understanding biomarkers and treating neurological diseases - Role of the cerebellar dysfunction and emerging therapies.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102519}, doi = {10.1016/j.arr.2024.102519}, pmid = {39341507}, issn = {1872-9649}, mesh = {Humans ; *Biomarkers/metabolism ; Animals ; *Cerebellar Diseases/therapy/diagnosis/metabolism/genetics ; Genetic Therapy/methods/trends ; Nervous System Diseases/therapy/diagnosis/metabolism ; Cerebellum/metabolism/pathology ; }, abstract = {Cerebellar dysfunction is increasingly recognized as a critical factor in various neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Research has revealed distinct cerebellar atrophy patterns in conditions such as AD and multiple system atrophy, and studies in mice have highlighted its impact on motor control and cognitive functions. Emerging research into autism spectrum disorder (ASD) has identified key targets, such as elevated levels of chemokine receptors and ZIC family genes. Biomarkers, including cerebrospinal fluid (CSF), genetic markers, and advances in AI and bioinformatics, are enhancing early diagnosis and personalized treatment across neurodegenerative disorders. Notable advancements include improved diagnostic tools, gene therapy, and novel clinical trials. Despite progress, challenges such as the bloodbrain barrier and neuroinflammation persist. Current therapies for AD, PD, HD, and ALS, including antisense oligonucleotides and stem cell treatments, show promise but require further investigation. A comprehensive approach that integrates diagnostic methods and innovative therapies is essential for effective management and improved patient outcomes.}, }
@article {pmid39340928, year = {2024}, author = {Dahl, R and Bezprozvanny, I}, title = {SERCA pump as a novel therapeutic target for treating neurodegenerative disorders.}, journal = {Biochemical and biophysical research communications}, volume = {734}, number = {}, pages = {150748}, doi = {10.1016/j.bbrc.2024.150748}, pmid = {39340928}, issn = {1090-2104}, support = {R01 AG071310/AG/NIA NIH HHS/United States ; R56 AG078337/AG/NIA NIH HHS/United States ; R42 AG062001/AG/NIA NIH HHS/United States ; }, mesh = {*Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; Humans ; Animals ; Disease Models, Animal ; Allosteric Regulation/drug effects ; Molecular Targeted Therapy/methods ; *Neuroprotective Agents/pharmacology/therapeutic use ; Calcium Signaling/drug effects ; Calcium/metabolism ; }, abstract = {The neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and Spinocerebellar ataxias (SCAs), present an enormous medical, social, financial and scientific problem. Despite intense research into the causes of these disorders, only marginal progress has been made in the clinic and no cures exist for any of them. Most of the scientific effort has been focused on identification of the major causes of these diseases and on developing ways to target them, such as targeting amyloid accumulation for AD or targeting expression of mutant Huntingtin for HD. Calcium (Ca[2+]) signaling has long been proposed to play an important role in the pathogenesis of neurodegenerative disorders, but blockers of Ca[2+] channels and Ca[2+] signaling proteins have not been translated to clinic primarily due to side effects related to the important roles of target molecules for these compounds at the peripheral tissues. In this review article, we would like to discuss an idea that recently identified positive allosteric modulators (PAMs) of the sarco-endoplasmic reticulum calcium (SERCA) pump may provide a promising approach to develop therapeutic compounds for treatment of these disorders. This hypothesis is supported by the preclinical data obtained with animal models of AD and PD. The first critical test of this idea will be an imminent phase I study that will offer an opportunity to evaluate potential side effects of this class of compounds in humans.}, }
@article {pmid39338563, year = {2024}, author = {Dow, CT and Pierce, ES and Sechi, LA}, title = {Mycobacterium paratuberculosis: A HERV Turn-On for Autoimmunity, Neurodegeneration, and Cancer?.}, journal = {Microorganisms}, volume = {12}, number = {9}, pages = {}, pmid = {39338563}, issn = {2076-2607}, abstract = {Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV-promoting pathological conditions, including the development of autoimmunity, neurodegenerative disease and cancer. What infections trigger HERV activation? Mycobacterium avium subspecies paratuberculosis (MAP) is a pluripotent driver of human disease. Aside from granulomatous diseases, Crohn's disease, sarcoidosis and Blau syndrome, MAP is associated with autoimmune disease: type one diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis (RA) and autoimmune thyroiditis. MAP is also associated with Alzheimer's disease (AD) and Parkinson's disease (PD). Autoimmune diabetes, MS and RA are the diseases with the strongest MAP/HERV association. There are several other diseases associated with HERV activation, including diseases whose epidemiology and/or pathology would prompt speculation for a causal role of MAP. These include non-solar uveal melanoma, colon cancer, glioblastoma and amyotrophic lateral sclerosis (ALS). This article further points to MAP infection as a contributor to autoimmunity, neurodegenerative disease and cancer via the un-silencing of HERV. We examine the link between the ever-increasing number of MAP-associated diseases and the MAP/HERV intersection with these diverse medical conditions, and propose treatment opportunities based upon this association.}, }
@article {pmid39337908, year = {2024}, author = {Wang, R and Chen, L and Zhang, Y and Sun, B and Liang, M}, title = {Expression Changes of miRNAs in Humans and Animal Models of Amyotrophic Lateral Sclerosis and Their Potential Application for Clinical Diagnosis.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {9}, pages = {}, pmid = {39337908}, issn = {2075-1729}, support = {YJXJ-JZ-2021-0014//Scientific Research Project of Beijing Yicheng Cooperative Development Foundation in 2021-Public welfare projects of rare disease related topics/ ; KM202310858001//R&amp;D Program of Beijing Municipal Education Commission/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease. Current detection methods can only confirm the diagnosis at the onset of the disease, missing the critical window for early treatment. Recent studies using animal models have found that detecting changes in miRNA sites can predict the onset and severity of the disease in its early stages, facilitating early diagnosis and treatment. miRNAs show expression changes in motor neurons that connect the brain, spinal cord, and brain stem, as well as in the skeletal muscle in mouse models of ALS. Clinically, expression changes in some miRNAs in patients align with those in mouse models, such as the upregulation of miR-29b in the brain and the upregulation of miR-206 in the skeletal muscle. This study provides an overview of some miRNA study findings in humans as well as in animal models, including SOD1, FUS, TDP-43, and C9orf72 transgenic mice and wobbler mice, highlighting the potential of miRNAs as diagnostic markers for ALS. miR-21 and miR-206 are aberrantly expressed in both mouse model and patient samples, positioning them as key potential diagnostic markers in ALS. Additionally, miR-29a, miR-29b, miR-181a, and miR-142-3p have shown aberrant expression in both types of samples and show promise as clinical targets for ALS. Finally, miR-1197 and miR-486b-5p have been recently identified as aberrantly expressed miRNAs in mouse models for ALS, although further studies are needed to determine their viability as diagnostic targets.}, }
@article {pmid39337696, year = {2024}, author = {Niazi, SK}, title = {Bioavailability as Proof to Authorize the Clinical Testing of Neurodegenerative Drugs-Protocols and Advice for the FDA to Meet the ALS Act Vision.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337696}, issn = {1422-0067}, mesh = {Humans ; *United States Food and Drug Administration ; United States ; *Drug Approval ; *Biological Availability ; *Amyotrophic Lateral Sclerosis/drug therapy ; Neurodegenerative Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; Clinical Trials as Topic ; }, abstract = {Although decades of intensive drug discovery efforts to treat neurodegenerative disorders (NDs) have failed, around half a million patients in more than 2000 studies continue being tested, costing over USD 100 billion, despite the conclusion that even those drugs which have been approved have no better effect than a placebo. The US Food and Drug Administration (FDA) has established multiple programs to innovate the treatment of rare diseases, particularly NDs, providing millions of USD in funding primarily by encouraging novel clinical trials to account for issues related to study sizes and adopting multi-arm studies to account for patient dropouts. Instead, the FDA should focus on the primary reason for failure: the poor bioavailability of drugs reaching the brain (generally 0.1% at most) due to the blood-brain barrier (BBB). There are several solutions to enhance entry into the brain, and the FDA must require proof of significant entry into the brain as the prerequisite to approving Investigational New Drug (IND) applications. The FDA should also rely on factors other than biomarkers to confirm efficacy, as these are rarely relevant to clinical use. This study summarizes how the drugs used to treat NDs can be made effective and how the FDA should change its guidelines for IND approval of these drugs.}, }
@article {pmid39337560, year = {2024}, author = {Malaguarnera, M and Cabrera-Pastor, A}, title = {Emerging Role of Extracellular Vesicles as Biomarkers in Neurodegenerative Diseases and Their Clinical and Therapeutic Potential in Central Nervous System Pathologies.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337560}, issn = {1422-0067}, support = {PI23/00204//Instituto de Salud Carlos III (ISCIII) through the project "PI23/00204" and co-funded by the European Union; and Conselleria de Educaci&#xf3;n/Innovaci&#xf3;n, Universidades, Ciencia y Sociedad Digital, subvenciones para la realizaci&#xf3;n de proyectos de I+D+i desarro/ ; CIGE/083//This research was funded by Instituto de Salud Carlos III (ISCIII) through the project "PI23/00204" and co-funded by the European Union; and Conselleria de Educaci&#xf3;n/Innovaci&#xf3;n, Universidades, Ciencia y Sociedad Digital, subvenciones para la realizaci&#xf3;n d/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/therapy/metabolism/diagnosis ; Animals ; Central Nervous System Diseases/metabolism/therapy/diagnosis ; Blood-Brain Barrier/metabolism ; }, abstract = {The emerging role of extracellular vesicles (EVs) in central nervous system (CNS) diseases is gaining significant interest, particularly their applications as diagnostic biomarkers and therapeutic agents. EVs are involved in intercellular communication and are secreted by all cell types. They contain specific markers and a diverse cargo such as proteins, lipids, and nucleic acids, reflecting the physiological and pathological state of their originating cells. Their reduced immunogenicity and ability to cross the blood-brain barrier make them promising candidates for both biomarkers and therapeutic agents. In the context of CNS diseases, EVs have shown promise as biomarkers isolable from different body fluids, providing a non-invasive method for diagnosing CNS diseases and monitoring disease progression. This makes them useful for the early detection and monitoring of diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, where specific alterations in EVs content can be detected. Additionally, EVs derived from stem cells show potential in promoting tissue regeneration and repairing damaged tissues. An evaluation has been conducted on the current clinical trials studying EVs for CNS diseases, focusing on their application, treatment protocols, and obtained results. This review aims to explore the potential of EVs as diagnostic markers and therapeutic carriers for CNS diseases, highlighting their significant advantages and ongoing clinical trials evaluating their efficacy.}, }
@article {pmid39337251, year = {2024}, author = {Escudier, O and Zhang, Y and Whiting, A and Chazot, P}, title = {Evaluation of a Synthetic Retinoid, Ellorarxine, in the NSC-34 Cell Model of Motor Neuron Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337251}, issn = {1422-0067}, mesh = {Animals ; Mice ; *Neuroprotective Agents/pharmacology ; Retinoids/pharmacology ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Cell Line ; Humans ; Receptors, AMPA/metabolism ; Motor Neurons/drug effects/metabolism/pathology ; Benzoates/pharmacology ; Motor Neuron Disease/drug therapy/metabolism/pathology ; Calcium/metabolism ; Neurites/drug effects/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease worldwide and is characterized by progressive muscle atrophy. There are currently two approved treatments, but they only relieve symptoms briefly and do not cure the disease. The main hindrance to research is the complex cause of ALS, with its pathogenesis not yet fully elucidated. Retinoids (vitamin A derivatives) appear to be essential in neuronal cells and have been implicated in ALS pathogenesis. This study explores 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxalin-2-yl)ethylnyl]benzoic acid (Ellorarxine, or DC645 or NVG0645), a leading synthetic retinoic acid, discussing its pharmacological mechanisms, neuroprotective properties, and relevance to ALS. The potential therapeutic effect of Ellorarxine was analyzed in vitro using the WT and SOD1G93A NSC-34 cell model of ALS at an administered concentration of 0.3-30 nM. Histological, functional, and biochemical analyses were performed. Elorarxine significantly increased MAP2 expression and neurite length, increased AMPA receptor GluA2 expression and raised intracellular Ca[2+] baseline, increased level of excitability, and reduced Ca[2+] spike during depolarization in neurites. Ellorarxine also displayed both antioxidant and anti-inflammatory effects. Overall, these results suggest Ellorarxine shows relevance and promise as a novel therapeutic strategy for treatment of ALS.}, }
@article {pmid39330700, year = {2024}, author = {Everett, WH and Bucelli, RC}, title = {Tofersen for SOD1 ALS.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {5}, pages = {149-160}, pmid = {39330700}, issn = {1758-2032}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Oligonucleotides/therapeutic use ; *Superoxide Dismutase-1/antagonists &amp; inhibitors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition affecting the motor system. The heterogenous nature of ALS complicates trial design. Genetic forms of ALS present an opportunity to intervene in a less heterogeneous population. ALS associated with gain of function mutations in SOD1 make 'knock-down' strategies an attractive therapeutic approach. Tofersen, an antisense oligonucleotide that reduces expression of SOD1 via RNAase mediated degradation of SOD1 mRNA, has shown robust effects on ALS biomarkers. While a Phase III trial of tofersen failed to meet its primary end point, open label extension data suggests that tofersen slows progression of SOD1 ALS.}, }
@article {pmid39328135, year = {2024}, author = {Sharma, S and Mehan, S and Khan, Z and Tiwari, A and Kumar, A and Gupta, GD and Narula, AS and Kalfin, R}, title = {Exploring the Neuroprotective Potential of Icariin through Modulation of Neural Pathways in the Treatment of Neurological Diseases.}, journal = {Current molecular medicine}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115665240317650240924041923}, pmid = {39328135}, issn = {1875-5666}, abstract = {Neuropathological diseases involve the death of neurons and the aggregation of proteins with altered properties in the brain. Proteins are used at the molecular level to categorize neurodegenerative disorders, emphasizing the importance of protein-processing mechanisms in their development. Natural herbal phytoconstituents, such as icariin, have addressed these neurological complications. Icariin, the principal compound in Epimedium, has been studied for its antineuroinflammatory, anti-oxidative, and antiapoptotic properties. Recent scientific investigations have shown that icariin exhibits promising therapeutic and preventive properties for mental and neurodegenerative disorders. In preclinical, icariin has been shown to inhibit amyloid development and reduce the expression of APP and BACE-1. Previous preclinical studies have demonstrated that icariin can regulate proinflammatory responses in neurological conditions like Parkinson's disease, depression, cerebral ischemia, ALS, and multiple sclerosis. Studies have shown that icariin possesses neuroprotective properties by modulating signaling pathways and crossing the blood-brain barrier, suggesting its potential to address various neurocomplications. This review aims to establish a foundation for future clinical investigations by examining the existing literature on icariin and exploring its potential therapeutic implications in treating neurodegenerative disorders and neuropsychiatric conditions. Future research may address numerous concerns and yield captivating findings with far-reaching implications for various aspects of icariin.}, }
@article {pmid39316747, year = {2024}, author = {de Calbiac, H and Renault, S and Haouy, G and Jung, V and Roger, K and Zhou, Q and Campanari, ML and Chentout, L and Demy, DL and Marian, A and Goudin, N and Edbauer, D and Guerrera, C and Ciura, S and Kabashi, E}, title = {Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.}, journal = {Autophagy}, volume = {20}, number = {10}, pages = {2164-2185}, pmid = {39316747}, issn = {1554-8635}, mesh = {*Motor Neurons/metabolism/pathology ; Animals ; *C9orf72 Protein/genetics/metabolism ; *Zebrafish ; *Mitophagy/genetics ; *Apoptosis/genetics ; Humans ; *Autophagy/genetics/physiology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Dipeptides/pharmacology/metabolism ; Loss of Function Mutation/genetics ; Mitochondria/metabolism ; Disease Models, Animal ; }, abstract = {The GGGGCC hexanucleotide repeat expansion (HRE) of the C9orf72 gene is the most frequent cause of amyotrophic lateral sclerosis (ALS), a devastative neurodegenerative disease characterized by motor neuron degeneration. C9orf72 HRE is associated with lowered levels of C9orf72 expression and its translation results in the production of dipeptide-repeats (DPRs). To recapitulate C9orf72-related ALS disease in vivo, we developed a zebrafish model where we expressed glycine-proline (GP) DPR in a c9orf72 knockdown context. We report that C9orf72 gain- and loss-of-function properties act synergistically to induce motor neuron degeneration and paralysis with poly(GP) accumulating preferentially within motor neurons along with Sqstm1/p62 aggregation indicating macroautophagy/autophagy deficits. Poly(GP) levels were shown to accumulate upon c9orf72 downregulation and were comparable to levels assessed in autopsy samples of patients carrying C9orf72 HRE. Chemical boosting of autophagy using rapamycin or apilimod, is able to rescue motor deficits. Proteomics analysis of zebrafish-purified motor neurons unravels mitochondria dysfunction confirmed through a comparative analysis of previously published C9orf72 iPSC-derived motor neurons. Consistently, 3D-reconstructions of motor neuron demonstrate that poly(GP) aggregates colocalize to mitochondria, thus inducing their elongation and swelling and the failure of their processing by mitophagy, with mitophagy activation through urolithin A preventing locomotor deficits. Finally, we report apoptotic-related increased amounts of cleaved Casp3 (caspase 3, apoptosis-related cysteine peptidase) and rescue of motor neuron degeneration by constitutive inhibition of Casp9 or treatment with decylubiquinone. Here we provide evidence of key pathogenic steps in C9ALS-FTD that can be targeted through pharmacological avenues, thus raising new therapeutic perspectives for ALS patients.}, }
@article {pmid39315251, year = {2024}, author = {Maitra, S and Baek, M and Choe, YJ and Kim, NC}, title = {FDA-approved PDE4 inhibitors alleviate the dominant toxicity of ALS-FTD-associated CHCHD10S59L by reducing the PINK1/Parkin pathway.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39315251}, issn = {2693-5015}, support = {R56 NS112296/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing CHCHD10[S59L], and human cell models expressing CHCHD10[S59L], we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10[S59L]. Evidences using in vitro, in vivo genetic, and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10[S59L]-induced diseases.<br><br>METHODS: An in vivo human cell culture and in vivo Drosophila models expressing CHCHD10[S59L] mutant were utilized in this study to evaluate the effect of PDE4 inhibitors in PINK-parkin mediated cytotoxicity through immunohistochemical and seahorse assays. Data were analysed using one-way ANOVA and post-hoc Dunnett's test for statistical significance.<br><br>RESULTS: We investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10[S59L]-induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10[S59L]-induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H[S81L]. Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10[S59L].<br><br>CONCLUSION: These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10[S59L]-induced ALS-FTD and possibly other related diseases, and that disease treatment with PDE4 inhibitors should include careful consideration of the PINK1/Parkin pathway, as it is generally recognized as a protective pathway.}, }
@article {pmid39314138, year = {2025}, author = {Lv, Y and Li, H}, title = {Blood diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {9}, pages = {2556-2570}, pmid = {39314138}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited. The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain, brainstem, and spinal cord, as well as abnormal protein deposition in the cytoplasm of neurons and glial cells. The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid, blood, and even urine. Among these biomarkers, neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system, while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles. Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity. However, there are challenges in using neurofilament light chain to differentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury. Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment, oxygen saturation, and the glomerular filtration rate. TAR DNA-binding protein 43, a pathological protein associated with amyotrophic lateral sclerosis, is emerging as a promising biomarker, particularly with advancements in exosome-related research. Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers; however, they show potential in predicting disease prognosis. Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years, the quest for definitive diagnostic and prognostic biomarkers remains a formidable challenge. This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.}, }
@article {pmid39313512, year = {2024}, author = {Khan, AF and Iturria-Medina, Y}, title = {Beyond the usual suspects: multi-factorial computational models in the search for neurodegenerative disease mechanisms.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {386}, pmid = {39313512}, issn = {2158-3188}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/physiopathology ; *Neuroimaging/methods ; *Brain/diagnostic imaging/physiopathology ; Disease Progression ; Biomarkers ; Alzheimer Disease/diagnostic imaging/physiopathology ; Computer Simulation ; }, abstract = {From Alzheimer's disease to amyotrophic lateral sclerosis, the molecular cascades underlying neurodegenerative disorders remain poorly understood. The clinical view of neurodegeneration is confounded by symptomatic heterogeneity and mixed pathology in almost every patient. While the underlying physiological alterations originate, proliferate, and propagate potentially decades before symptomatic onset, the complexity and inaccessibility of the living brain limit direct observation over a patient's lifespan. Consequently, there is a critical need for robust computational methods to support the search for causal mechanisms of neurodegeneration by distinguishing pathogenic processes from consequential alterations, and inter-individual variability from intra-individual progression. Recently, promising advances have been made by data-driven spatiotemporal modeling of the brain, based on in vivo neuroimaging and biospecimen markers. These methods include disease progression models comparing the temporal evolution of various biomarkers, causal models linking interacting biological processes, network propagation models reproducing the spatial spreading of pathology, and biophysical models spanning cellular- to network-scale phenomena. In this review, we discuss various computational approaches for integrating cross-sectional, longitudinal, and multi-modal data, primarily from large observational neuroimaging studies, to understand (i) the temporal ordering of physiological alterations, i(i) their spatial relationships to the brain's molecular and cellular architecture, (iii) mechanistic interactions between biological processes, and (iv) the macroscopic effects of microscopic factors. We consider the extents to which computational models can evaluate mechanistic hypotheses, explore applications such as improving treatment selection, and discuss how model-informed insights can lay the groundwork for a pathobiological redefinition of neurodegenerative disorders.}, }
@article {pmid39313211, year = {2025}, author = {Rahimi, M and Al Masry, Z and Templeton, JM and Schneider, S and Poellabauer, C}, title = {A Comprehensive Multifunctional Approach for Measuring Parkinson's Disease Severity.}, journal = {Applied clinical informatics}, volume = {16}, number = {1}, pages = {11-23}, pmid = {39313211}, issn = {1869-0327}, mesh = {Humans ; *Parkinson Disease/diagnosis/physiopathology ; Male ; Female ; *Severity of Illness Index ; Aged ; Middle Aged ; Neuropsychological Tests ; Machine Learning ; }, abstract = {OBJECTIVES: This research study aims to advance the staging of Parkinson's disease (PD) by incorporating machine learning to assess and include a broader multifunctional spectrum of neurocognitive symptoms in the staging schemes beyond motor-centric assessments. Specifically, we provide a novel framework to modernize and personalize PD staging more objectively by proposing a hybrid feature scoring approach.<br><br>METHODS: &#x2003;We recruited 37 individuals diagnosed with PD, each of whom completed a series of tablet-based neurocognitive tests assessing motor, memory, speech, executive functions, and tasks ranging in complexity from single to multifunctional. Then, the collected data were used to develop a hybrid feature scoring system to calculate a weighted vector for each function. We evaluated the current PD staging schemes and developed a new approach based on the features selected and extracted using random forest and principal component analysis.<br><br>RESULTS: &#x2003;Our findings indicate a substantial bias in current PD staging systems toward fine motor skills, that is, other neurological functions (memory, speech, executive function, etc.) do not map into current PD stages as well as fine motor skills do. The results demonstrate that a more accurate and personalized assessment of PD severity could be achieved by including a more exhaustive range of neurocognitive functions in the staging systems either by involving multiple functions in a unified staging score or by designing a function-specific staging system.<br><br>CONCLUSION: &#x2003;The proposed hybrid feature score approach provides a comprehensive understanding of PD by highlighting the need for a staging system that covers various neurocognitive functions. This approach could potentially lead to more effective, objective, and personalized treatment strategies. Further, this proposed methodology could be adapted to other neurodegenerative conditions such as Alzheimer's disease or amyotrophic lateral sclerosis.}, }
@article {pmid39311426, year = {2024}, author = {Azzolino, D and Piras, R and Zulueta, A and Lucchi, T and Lunetta, C}, title = {Amyotrophic lateral sclerosis as a disease model of sarcopenia.}, journal = {Age and ageing}, volume = {53}, number = {9}, pages = {}, doi = {10.1093/ageing/afae209}, pmid = {39311426}, issn = {1468-2834}, mesh = {Humans ; *Sarcopenia/physiopathology/diagnosis ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; *Muscle, Skeletal/pathology/physiopathology ; Aging/pathology ; Animals ; Age Factors ; Aged ; Risk Factors ; }, abstract = {Sarcopenia, the progressive decline of muscle mass and function, has traditionally been viewed as an age-related process leading to a broad range of adverse outcomes. However, it has been widely reported that sarcopenia can occur earlier in life in association with various conditions (i.e. disease-related sarcopenia), including neuromuscular disorders. As early as 2010, the European Working Group on Sarcopenia in Older People included neurodegenerative diseases characterised by motor neuron loss among the mechanisms underlying sarcopenia. Despite some differences in pathogenetic mechanisms, both amyotrophic lateral sclerosis (ALS) and age-related sarcopenia share common characteristics, such as the loss of motor units and muscle fibre atrophy, oxidative stress, mitochondrial dysfunction and inflammation. The histology of older muscle shows fibre size heterogeneity, fibre grouping and a loss of satellite cells, similar to what is observed in ALS patients. Regrettably, the sarcopenic process in ALS patients has been largely overlooked, and literature on the condition in this patient group is very scarce. Some instruments used for the assessment of sarcopenia in older people could also be applied to ALS patients. At this time, there is no approved specific pharmacological treatment to reverse damage to motor neurons or cure ALS, just as there is none for sarcopenia. However, some agents targeting the muscle, like myostatin and mammalian target of rapamycin inhibitors, are under investigation both in the sarcopenia and ALS context. The development of new therapeutic agents targeting the skeletal muscle may indeed be beneficial to both ALS patients and older people with sarcopenia.}, }
@article {pmid39311315, year = {2025}, author = {Ortiz-Corredor, F and Correa-Arrieta, C and Forero Diaz, JJ and Castellar-Leones, S and Gil-Salcedo, A}, title = {Profiles of disease progression and predictors of mortality in Colombian patients with amyotrophic lateral sclerosis: a comprehensive longitudinal study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {141-148}, doi = {10.1080/21678421.2024.2405587}, pmid = {39311315}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis ; *Disease Progression ; Colombia/epidemiology ; Male ; Female ; Middle Aged ; Longitudinal Studies ; Aged ; Retrospective Studies ; Adult ; Prognosis ; }, abstract = {OBJECTIVE: This study aimed to assess the prognostic value of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) in predicting mortality and characterizing disease progression patterns in ALS patients in Colombia.<br><br>METHODS: We conducted a retrospective longitudinal analysis of 537 ALS patients from the Roosevelt Institute Rehabilitation Service between October 2008 and October 2022. The study excluded nine patients due to incomplete data, resulting in 528 individuals in the analysis. ALS diagnoses were confirmed using the revised El Escorial and Gold Coast criteria. Disease progression was assessed using the ALSFRS-R, and mortality data were sourced from follow-up calls and a national database. Statistical analysis included Cox proportional hazards models to identify mortality predictors and Growth Mixture Modeling (GMM) to explore ALS progression trajectories.<br><br>RESULTS: The majority of the cohort (63.8%) deceased within the 84-month follow-up period. Survival analysis revealed that each point increase in the ALSFRS-R rate was associated with a 2.22-fold (95% CI =1.99-2.48, p&#x2009;<&#x2009;0.001) increased risk of mortality. In the population with data from two clinical visits, the ALSFRS-R rate based on initial assessments predicted mortality more effectively over 36 months than the rate based on two evaluations. GMM identified three distinct progression trajectories: slow, intermediate, and rapid decliners.<br><br>CONCLUSIONS: The ALSFRS-R rate, derived from self-reported symptom onset, significantly predicts mortality, underscoring its value in clinical assessments. This study highlights the heterogeneity in disease progression among Colombian ALS patients, indicating the necessity for personalized treatment approaches based on individual progression trajectories. Further studies are needed to refine these predictive models and improve patient management and outcomes.}, }
@article {pmid39307154, year = {2024}, author = {Pal, S and Chataway, J and Swingler, R and Macleod, MR and Carragher, NO and Hardingham, G and Selvaraj, BT and Smith, C and Wong, C and Newton, J and Lyle, D and Stenson, A and Dakin, RS and Ihenacho, A and Colville, S and Mehta, AR and Stallard, N and Carpenter, JR and Parker, RA and Keerie, C and Weir, CJ and Virgo, B and Morris, S and Waters, N and Gray, B and MacDonald, D and MacDonald, E and Parmar, MKB and Chandran, S and , }, title = {Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1097-1107}, doi = {10.1016/S1474-4422(24)00326-0}, pmid = {39307154}, issn = {1474-4465}, mesh = {Humans ; *Trazodone/therapeutic use/pharmacology ; Male ; Middle Aged ; Female ; Aged ; *Memantine/therapeutic use ; Double-Blind Method ; *Motor Neuron Disease/drug therapy ; Treatment Outcome ; Adult ; }, abstract = {BACKGROUND: Motor neuron disease represents a group of progressive and incurable diseases that are characterised by selective loss of motor neurons, resulting in an urgent need for rapid identification of effective disease-modifying therapies. The MND SMART trial aims to test the safety and efficacy of promising interventions efficiently and definitively against a single contemporaneous placebo control group. We now report results of the stage two interim analysis for memantine and trazodone.<br><br>METHODS: MND SMART is an investigator-led, phase 3, double-blind, placebo-controlled, multiarm, multistage, randomised, adaptive platform trial recruiting at 20 hospital centres in the UK. Individuals older than 18 years with a confirmed diagnosis of either amyotrophic lateral sclerosis classified by the revised El Escorial criteria, primary lateral sclerosis, progressive muscular atrophy, or progressive bulbar palsy, regardless of disease duration, were eligible for screening. Participants were randomised (1:1:1) to receive oral trazodone 200 mg once a day, oral memantine 20 mg once a day, or matched placebo using a computer-generated minimisation algorithm delivered via a secure web-based system. Co-primary outcome measures were clinical functioning, measured by rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R), and survival. Comparisons were conducted in four stages, with predefined criteria for stopping at the end of stages one and two. We report interim analysis from the stage two results, which was done when 100 participants per group (excluding long survivors, defined as >8 years since diagnosis at baseline) completed a minimum of 12 months of follow-up for the candidate investigational medicinal products. The trial is registered on the European Clinical Trials Registry, 2019-000099-41, and ClinicalTrials.gov, NCT04302870, and is ongoing.<br><br>FINDINGS: Between Feb 27, 2020, and July 24, 2023 (database lock for interim analysis two), 554 people with a motor neuron disease were randomly allocated to memantine (183 [33%]), trazodone (185 [33%]), or placebo (186 [34%]). The primary interim analysis population comprised 530 participants, of whom 175 (33%) had been allocated memantine, 175 (33%) had been allocated trazodone, and 180 (34%) had been allocated placebo. Over 12 months of follow-up, the mean rate of change per month in ALSFRS-R was -0&#xb7;650 for memantine, -0&#xb7;625 for trazodone, and -0&#xb7;655 for placebo (memantine versus placebo estimated mean difference 0&#xb7;033, one-sided 90% CI lower level -0&#xb7;085; one-sided p=0&#xb7;36; trazodone vs placebo: 0&#xb7;065, -0&#xb7;051; one-sided p=0&#xb7;24). The one-sided p values were both above the significance threshold of 10%, indicating that neither memantine nor trazodone groups met the criteria for continuation. There were 483 participants with at least one adverse event (145 [77%] on placebo, 170 [91%] on memantine, and 168 [90%] on trazodone). There were 88 participants with at least one serious adverse event (37 [20%] on memantine, 27 [14%] on trazodone, and 24 [13%] on placebo). A total of 11 serious adverse event led to treatment discontinuation. There was no survival difference between comparisons, with 49 deaths in the memantine group, 52 deaths in the trazodone group, and 48 deaths in the placebo group.<br><br>INTERPRETATION: Neither memantine nor trazodone improved efficacy outcomes compared with placebo. This result is sufficiently powered to warrant no further testing of trazodone or memantine in motor neuron disease at the doses evaluated in this study. The multiarm multistage design shows important benefits in reducing the time, cost, and participant numbers to reach a definitive result.<br><br>FUNDING: The Euan MacDonald Centre, MND Scotland, My Name'5 Doddie Foundation, and Baillie Gifford.}, }
@article {pmid39307005, year = {2024}, author = {Austin, JM and Bailey, R and Velazquez, SG and Sainath, H and Jackson, C}, title = {Clinical effectiveness of medical marijuana in patients with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123243}, doi = {10.1016/j.jns.2024.123243}, pmid = {39307005}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; *Medical Marijuana/therapeutic use ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Treatment Outcome ; Disease Progression ; Cohort Studies ; Adult ; Anxiety/drug therapy/etiology ; }, abstract = {Following legalization, Medical Marijuana (MM), has been used to treat the symptoms of Amyotrophic Lateral Sclerosis (ALS), yet data regarding Medical Marijuana's efficacy is lacking. Thus, we conducted a retrospective cohort study to assess Medical Marijuana's impact on ALS symptoms and progression. We reviewed the charts of all ALS patients treated in our clinic over a two-year period to collect data related to the primary outcome measures of symptoms of pain, poor appetite, anxiety, spasticity, insomnia, ALSFRS-R score, BMI, and MM use. Two groups were defined: a control group with target symptoms but no MM prescription, and a test group that filled a MM prescription, including a subgroup on MM for ≥3 visits. Outcomes were correlations between MM usage and symptom prevalence, and between MM usage and BMI and ALSFRS-R decline slope, analyzed using descriptive statistics and qualitative analysis via local regression. Data included 344 ALS patients. We found MM use correlated with alleviation of pain, poor appetite, and anxiety in the short term, but not with spasticity or insomnia. There was no correlation between MM use BMI maintenance. Notably, MM usage correlated with faster ALS progression, although patients using MM exhibited higher symptom burden and progressed faster than controls even pre-MM prescription. In conclusion, MM shows correlation with managing pain, poor appetite, and short-term anxiety in ALS, but is also correlated with faster disease progression based on ALSFRS-R scores. We suggest a multi-center, randomized controlled trial to evaluate both the clinical efficacy and safety of MM in the treatment of ALS.}, }
@article {pmid39297377, year = {2024}, author = {Akyuz, E and Aslan, FS and Gokce, E and Ilmaz, O and Topcu, F and Kakac, S}, title = {Extracellular vesicle and CRISPR gene therapy: Current applications in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.}, journal = {The European journal of neuroscience}, volume = {60}, number = {8}, pages = {6057-6090}, doi = {10.1111/ejn.16541}, pmid = {39297377}, issn = {1460-9568}, mesh = {Humans ; *Genetic Therapy/methods ; *Extracellular Vesicles/metabolism/genetics ; *CRISPR-Cas Systems ; *Huntington Disease/therapy/genetics ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Parkinson Disease/therapy/genetics ; *Alzheimer Disease/therapy/genetics ; Animals ; Gene Editing/methods ; Neurodegenerative Diseases/therapy/genetics ; }, abstract = {Neurodegenerative diseases are characterized by progressive deterioration of the nervous system. Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are prominently life-threatening examples of neurodegenerative diseases. The complexity of the pathophysiology in neurodegenerative diseases causes difficulties in diagnosing. Although the drugs temporarily help to correct specific symptoms including memory loss and degeneration, a complete treatment has not been found yet. New therapeutic approaches have been developed to understand and treat the underlying pathogenesis of neurodegenerative diseases. With this purpose, clustered-regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas) technology has recently suggested a new treatment option. Editing of the genome is carried out by insertion and deletion processes on DNA. Safe delivery of the CRISPR/Cas system to the targeted cells without affecting surrounding cells is frequently investigated. Extracellular vesicles (EVs), that is exosomes, have recently been used in CRISPR/Cas studies. In this review, CRISPR/Cas and EV approaches used for diagnosis and/or treatment in AD, PD, ALS, and HD are reviewed. CRISPR/Cas and EV technologies, which stand out as new therapeutic approaches, may offer a definitive treatment option in neurodegenerative diseases.}, }
@article {pmid39305312, year = {2024}, author = {Torres, P and Rico-Rios, S and Ceron-Codorniu, M and Santacreu-Vilaseca, M and Seoane-Miraz, D and Jad, Y and Ayala, V and Mariño, G and Beltran, M and Miralles, MP and Andrés-Benito, P and Fernandez-Irigoyen, J and Santamaria, E and López-Otín, C and Soler, RM and Povedano, M and Ferrer, I and Pamplona, R and Wood, MJA and Varela, MA and Portero-Otin, M}, title = {TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {45}, pmid = {39305312}, issn = {1432-0533}, support = {PI 20-00155//Instituto de Salud Carlos III/ ; 23-00176//Instituto de Salud Carlos III/ ; Programa Margarita Salas//Ministerio de Universidades/ ; SGR//Departament d'Innovaci&#xf3;, Universitats i Empresa, Generalitat de Catalunya/ ; Ayuda Unzue//Fundaci&#xf3;n Luzon/ ; }, mesh = {Animals ; *Autophagy-Related Proteins/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; *Microtubule-Associated Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Cysteine Endopeptidases/metabolism/genetics ; Male ; Spinal Cord/metabolism/pathology ; Autophagy/physiology ; Mice, Knockout ; RNA Splicing/genetics ; Female ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Oligonucleotides, Antisense/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including ATG4B, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), Atg4b depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and atg4b[-/-] mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore ATG4B mRNA in TARDBP knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases.}, }
@article {pmid39300071, year = {2024}, author = {Castelli, S and Desideri, E and Laureti, L and Felice, F and De Cristofaro, A and Scaricamazza, S and Lazzarino, G and Ciriolo, MR and Ciccarone, F}, title = {N-acetylaspartate promotes glycolytic-to-oxidative fiber-type switch and resistance to atrophic stimuli in myotubes.}, journal = {Cell death &amp; disease}, volume = {15}, number = {9}, pages = {686}, pmid = {39300071}, issn = {2041-4889}, support = {GR-2019-1236998//Ministero della Salute (Ministry of Health, Italy)/ ; MNESYS PNRR - MUR PE00000006//Ministero della Salute (Ministry of Health, Italy)/ ; }, mesh = {Animals ; *Glycolysis/drug effects ; *Muscle Fibers, Skeletal/metabolism/drug effects ; Mice ; *Aspartic Acid/metabolism/analogs &amp; derivatives ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; Oxidation-Reduction ; Cell Line ; Mice, Transgenic ; }, abstract = {N-acetylaspartate (NAA) is a neuronal metabolite that can be extruded in extracellular fluids and whose blood concentration increases in several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Aspartoacylase (ASPA) is the enzyme responsible for NAA breakdown. It is abundantly expressed in skeletal muscle and most other human tissues, but the role of NAA catabolism in the periphery is largely neglected. Here we demonstrate that NAA treatment of differentiated C2C12 muscle cells increases lipid turnover, mitochondrial biogenesis and oxidative metabolism at the expense of glycolysis. These effects were ascribed to NAA catabolism, as CRISPR/Cas9 ASPA KO cells are insensitive to NAA administration. Moreover, the metabolic switch induced by NAA was associated with an augmented resistance to atrophic stimuli. Consistently with in vitro results, SOD1-G93A ALS mice show an increase in ASPA levels in those muscles undergoing the glycolytic to oxidative switch during the disease course. The impact of NAA on the metabolism and resistance capability of myotubes supports a role for this metabolite in the phenotypical adaptations of skeletal muscle in neuromuscular disorders.}, }
@article {pmid39296960, year = {2024}, author = {Keilholz, AN and Pathak, I and Smith, CL and Osman, KL and Smith, L and Oti, G and Golzy, M and Ma, L and Lever, TE and Nichols, NL}, title = {Tongue exercise ameliorates structural and functional upper airway deficits in a rodent model of hypoglossal motor neuron loss.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1441529}, pmid = {39296960}, issn = {1664-2295}, abstract = {INTRODUCTION: Tongue weakness and atrophy can lead to deficits in the vital functions of breathing and swallowing in patients with motor neuron diseases (MNDs; e.g., amyotrophic lateral sclerosis (ALS) and pseudobulbar palsy), often resulting in aspiration pneumonia, respiratory failure, and death. Available treatments for patients with MNDs are largely palliative; thus, there is a critical need for therapies targeting preservation of upper airway function and suggesting a role for tongue exercise in patients with MNDs. Here, we leveraged our inducible rodent model of hypoglossal (XII) motor neuron degeneration to investigate the effects of a strength endurance tongue exercise program on upper airway structure and function. Our model was created through intralingual injection of cholera toxin B conjugated to saporin (CTB-SAP) into the genioglossus muscle of the tongue to induce targeted death of XII motor neurons.<br><br>METHODS: Rats in this study were allocated to 4 experimental groups that received intralingual injection of either CTB-SAP or unconjugated CTB + SAP (i.e., control) +/- tongue exercise. Following tongue exercise exposure, we evaluated the effect on respiratory function (via plethysmography), macrostructure [via magnetic resonance imaging (MRI) of the upper airway and tongue], and ultrafine structure [via ex vivo magnetic resonance spectroscopy (MRS) of the tongue] with a focus on lipid profiles.<br><br>RESULTS: Results showed that sham exercise-treated CTB-SAP rats have evidence of upper airway restriction (i.e., reduced airflow) and structural changes present in the upper airway (i.e., airway compression) when compared to CTB-SAP + exercise rats and control rats +/- tongue exercise, which was ameliorated with tongue exercise. Additionally, CTB-SAP + sham exercise rats have evidence of increased lipid expression in the tongue consistent with previously observed tongue hypertrophy when compared to CTB-SAP + exercise rats or control rats +/- tongue exercise.<br><br>CONCLUSION: These findings provide further evidence that a strength endurance tongue exercise program may be a viable therapeutic treatment option in patients with XII motor neuron degeneration in MNDs such as ALS. Future directions will focus on investigating the underlying mechanism responsible for tongue exercise-induced plasticity in the hypoglossal-tongue axis, particularly inflammatory associated factors such as BDNF.}, }
@article {pmid39293800, year = {2024}, author = {Gao, J and Chai, N and Wang, T and Han, Z and Chen, J and Lin, G and Wu, Y and Bi, L}, title = {A new technique of percutaneous minimally invasive surgery assisted by magnetic resonance neurography.}, journal = {Bone &amp; joint open}, volume = {5}, number = {9}, pages = {776-784}, pmid = {39293800}, issn = {2633-1462}, abstract = {AIMS: In order to release the contracture band completely without damaging normal tissues (such as the sciatic nerve) in the surgical treatment of gluteal muscle contracture (GMC), we tried to display the relationship between normal tissue and contracture bands by magnetic resonance neurography (MRN) images, and to predesign a minimally invasive surgery based on the MRN images in advance.<br><br>METHODS: A total of 30 patients (60 hips) were included in this study. MRN scans of the pelvis were performed before surgery. The contracture band shape and external rotation angle (ERA) of the proximal femur were also analyzed. Then, the minimally invasive GMC releasing surgery was performed based on the images and measurements, and during the operation, incision lengths, surgery duration, intraoperative bleeding, and complications were recorded; the time of the first postoperative off-bed activity was also recorded. Furthermore, the patients' clinical functions were evaluated by means of Hip Outcome Score (HOS) and Ye et al's objective assessments, respectively.<br><br>RESULTS: The contracture bands exhibited three typical types of shape - feather-like, striped, and mixed shapes - in MR images. Guided by MRN images, we designed minimally invasive approaches directed to each hip. These approaches resulted in a shortened incision length in each hip (0.3 cm (SD 0.1)), shorter surgery duration (25.3 minutes (SD 5.8)), less intraoperative bleeding (8.0 ml (SD 3.6)), and shorter time between the end of the operation and the patient's first off-bed activity (17.2 hours (SD 2.0)) in each patient. Meanwhile, no serious postoperative complications occurred in all patients. The mean HOS-Sports subscale of patients increased from 71.0 (SD 5.3) to 94.83 (SD 4.24) at six months postoperatively (p < 0.001). The follow-up outcomes from all patients were "good" and "excellent", based on objective assessments.<br><br>CONCLUSION: Preoperative MRN analysis can be used to facilitate the determination of the relationship between contracture band and normal tissues. The minimally invasive surgical design via MRN can avoid nerve damage and improve the release effect.}, }
@article {pmid39292705, year = {2024}, author = {Minnella, A and McCusker, KP and Amagata, A and Trias, B and Weetall, M and Latham, JC and O'Neill, S and Wyse, RK and Klein, MB and Trimmer, JK}, title = {Targeting ferroptosis with the lipoxygenase inhibitor PTC-041 as a therapeutic strategy for the treatment of Parkinson's disease.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0309893}, pmid = {39292705}, issn = {1932-6203}, mesh = {Animals ; *Ferroptosis/drug effects ; *Lipoxygenase Inhibitors/pharmacology/therapeutic use ; Humans ; *Parkinson Disease/drug therapy/metabolism/pathology ; Rats ; Mice ; alpha-Synuclein/metabolism ; Lipid Peroxidation/drug effects ; Neurons/drug effects/metabolism/pathology ; Fibroblasts/drug effects/metabolism ; Arachidonate 15-Lipoxygenase/metabolism ; Cells, Cultured ; Male ; }, abstract = {Parkinson's disease is the second most common neurodegenerative disorder, affecting nearly 10 million people worldwide. Ferroptosis, a recently identified form of regulated cell death characterized by 15-lipoxygenase-mediated hydroperoxidation of membrane lipids, has been implicated in neurodegenerative disorders including amyotrophic lateral sclerosis and Parkinson's disease. Pharmacological inhibition of 15 -lipoxygenase to prevent iron- and lipid peroxidation-associated ferroptotic cell death is a rational strategy for the treatment of Parkinson's disease. We report here the characterization of PTC-041 as an anti-ferroptotic reductive lipoxygenase inhibitor developed for the treatment of Parkinson's disease. In these studies, PTC-041 potently protects primary human Parkinson's disease patient-derived fibroblasts from lipid peroxidation and subsequent ferroptotic cell death and prevents ferroptosis-related neuronal loss and astrogliosis in primary rat neuronal cultures. Additionally, PTC-041 prevents ferroptotic-mediated α-synuclein protein aggregation and nitrosylation in vitro, suggesting a potential role for anti-ferroptotic lipoxygenase inhibitors in mitigating pathogenic aspects of synucleinopathies such as Parkinson's disease. We further found that PTC-041 protects against synucleinopathy in vivo, demonstrating that PTC-041 treatment of Line 61 transgenic mice protects against α-synuclein aggregation and phosphorylation as well as prevents associated neuronal and non-neuronal cell death. Finally, we show that. PTC-041 protects against 6-hydroxydopamine-induced motor deficits in a hemiparkinsonian rat model, further validating the potential therapeutic benefits of lipoxygenase inhibitors in the treatment of Parkinson's disease.}, }
@article {pmid39292682, year = {2024}, author = {Tang, X and Li, Q and Huang, G and Pei, X and Chen, Z and Huang, Y and Zhao, S and Guo, T and Liu, Z}, title = {Immediate efficacy of auricular acupuncture combined with active exercise in the treatment of acute lumbar sprains in 10 minutes: Protocol of a randomized controlled trial.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0308801}, pmid = {39292682}, issn = {1932-6203}, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Acupuncture, Ear/methods ; Combined Modality Therapy ; *Exercise Therapy/methods ; Low Back Pain/therapy ; Lumbar Vertebrae/physiopathology ; Lumbosacral Region ; Pain Measurement ; Prospective Studies ; Range of Motion, Articular ; Sprains and Strains/therapy ; Treatment Outcome ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Acute lumbar sprain (ALS) is common musculoskeletal disorder characterized by severe low back pain and activity limitation, which significantly impacts the patient's work and life. Immediate relief of pain and restoration of mobility in a short period of time are the main needs of patients when they visit the clinic. This study aims to evaluate the immediate efficacy of this combined treatment for ALS within 10 minutes.<br><br>METHODS: This is a single-center, prospective, randomized clinical trial. 128 eligible patients with ALS will be randomly allocated in a 1:1 ratio to either the auricular acupuncture (AA) group or the sham auricular acupuncture (SAA) group. All patients will receive a single 10-minute treatment. The primary outcome will be the change in pain intensity after 10 minutes of treatment. The secondary outcomes include changes in pain intensity at other time points (2, 5 minutes), changes in lumbar range of motion (ROM) at different time points, blinded assessment, treatment effect expectancy scale evaluation, and treatment satisfaction scale evaluation. All participants will be included in the analysis according to the intention-to-treat principle.<br><br>DISCUSSION: This is the first randomized controlled trial to assess the immediate efficacy of AA combined with active exercise for ALS. The findings of this study are expected to provide a simple and rapid treatment for ALS in clinical.<br><br>TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2400083740. Registered 30 April 2024.}, }
@article {pmid39292338, year = {2024}, author = {Zhang, H and Gao, C and Yang, D and Nie, L and He, K and Chen, C and Li, S and Huang, G and Zhou, L and Huang, X and Wu, D and Liu, J and Huang, Z and Wang, J and Li, W and Zhang, Z and Yang, X and Zou, L}, title = {Urolithin a Improves Motor Dysfunction Induced by Copper Exposure in SOD1[G93A] Transgenic Mice Via Activation of Mitophagy.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39292338}, issn = {1559-1182}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease pathologically characterized by selective degeneration of motor neurons resulting in a catastrophic loss of motor function. The present study aimed to investigate the effect of copper (Cu) exposure on progression of ALS and explore the therapeutic effect and mechanism of Urolithin A (UA) on ALS. 0.13 PPM copper chloride drinking water was administrated in SOD1[G93A] transgenic mice at 6 weeks, UA at a dosage of 50 mg/kg/day was given for 6 weeks after a 7-week Cu exposure. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes and microglia in the spinal cord were evaluated by H&amp;E, Masson, Sirius Red, Nissl and Immunohistochemistry Staining. Proteomics analysis, Western blotting and ELISA were conducted to detect protein expression. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit. Cu-exposure worsened motor function, promoted muscle fibrosis, loss of motor neurons, and astrocyte and microglial activation. It also induced abnormal changes in mitochondria-related biological processes, leading to a significant reduction in ATP levels and an increase in MDA levels. Upregulation of P62 and downregulation of Parkin, PINK1, and LAMP1 were revealed in SOD1[G93A] mice with Cu exposure. Administration of UA activated mitophagy, modulated mitochondria dysfunction, reduced neuroinflammation, and improved gastrocnemius muscle atrophy and motor dysfunction in SOD1[G93A] mice with Cu exposure. Mitophagy plays critical role in ALS exacerbated by Cu exposure. UA administration may be a promising treatment strategy for ALS.}, }
@article {pmid39291166, year = {2024}, author = {Gianferrari, G and Cuoghi Costantini, R and Crippa, V and Carra, S and Bonetto, V and Pansarasa, O and Cereda, C and Zucchi, E and Martinelli, I and Simonini, C and Vicini, R and Fini, N and Trojsi, F and Passaniti, C and Ticozzi, N and Doretti, A and Diamanti, L and Fiamingo, G and Conte, A and Dalla Bella, E and D'Errico, E and Scarian, E and Pasetto, L and Antoniani, F and Galli, V and Casarotto, E and ,  and D'Amico, R and Poletti, A and Mandrioli, J}, title = {Colchicine treatment in amyotrophic lateral sclerosis: safety, biological and clinical effects in a randomized clinical trial.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae304}, pmid = {39291166}, issn = {2632-1297}, abstract = {In preclinical studies, the anti-inflammatory drug colchicine, which has never been tested in amyotrophic lateral sclerosis, enhanced the expression of autophagy factors and inhibited accumulation of transactive response DNA-binding protein 43 kDa, a known histopathological marker of amyotrophic lateral sclerosis. This multicentre, randomized, double-blind trial enrolled patients with probable or definite amyotrophic lateral sclerosis who experienced symptom onset within the past 18 months. Patients were randomly assigned in a 1:1:1 ratio to receive colchicine at a dose of 0.005 mg/kg/day, 0.01 mg/kg/day or placebo for a treatment period of 30 weeks. The number of positive responders, defined as patients with a decrease lesser than 4 points in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised total score during the 30-week treatment period, was the primary outcome. Disease progression, survival, safety and quality of life at the end of treatment were the secondary clinical outcomes. Secondary biological outcomes included changes from baseline to treatment end of stress granule and autophagy responses, transactive response DNA-binding protein 43 kDa, neurofilament accumulation and extracellular vesicle secretion, between the colchicine and placebo groups. Fifty-four patients were randomized to receive colchicine (n = 18 for each colchicine arm) or placebo (n = 18). The number of positive responders did not differ between the placebo and colchicine groups: 2 out of 18 patients (11.1%) in the placebo group, 5 out of 18 patients (27.8%) in the colchicine 0.005 mg/kg/day group (odds ratio = 3.1, 97.5% confidence interval 0.4-37.2, P = 0.22) and 1 out of 18 patients (5.6%) in the colchicine 0.01 mg/kg/day group (odds ratio = 0.5, 97.5% confidence interval 0.01-10.2, P = 0.55). During treatment, a slower Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised decline was detected in patients receiving colchicine 0.005 mg/kg/day (mean difference = 0.53, 97.5% confidence interval 0.07-0.99, P = 0.011). Eight patients experienced adverse events in placebo arm (44.4%), three in colchicine 0.005 mg/kg/day (16.7%) and seven in colchicine 0.01 mg/kg/day arm (35.9%). The differences in adverse events were not statistically significant. In conclusion, colchicine treatment was safe for amyotrophic lateral sclerosis patients. Further studies are required to better understand mechanisms of action and clinical effects of colchicine in this condition.}, }
@article {pmid39286440, year = {2024}, author = {Kew, SYN and Mok, SY and Goh, CH}, title = {Machine learning and brain-computer interface approaches in prognosis and individualized care strategies for individuals with amyotrophic lateral sclerosis: A systematic review.}, journal = {MethodsX}, volume = {13}, number = {}, pages = {102765}, pmid = {39286440}, issn = {2215-0161}, abstract = {Amyotrophic lateral sclerosis (ALS) characterized by progressive degeneration of motor neurons is a debilitating disease, posing substantial challenges in both prognosis and daily life assistance. However, with the advancement of machine learning (ML) which is renowned for tackling many real-world settings, it can offer unprecedented opportunities in prognostic studies and facilitate individuals with ALS in motor-imagery tasks. ML models, such as random forests (RF), have emerged as the most common and effective algorithms for predicting disease progression and survival time in ALS. The findings revealed that RF models had an excellent predictive performance for ALS, with a testing R2 of 0.524 and minimal treatment effects of 0.0717 for patient survival time. Despite significant limitations in sample size, with a maximum of 18 participants, which may not adequately reflect the population diversity being studied, ML approaches have been effectively applied to ALS datasets, and numerous prognostic models have been tested using neuroimaging data, longitudinal datasets, and core clinical variables. In many literatures, the constraints of ML models are seldom explicitly enunciated. Therefore, the main objective of this research is to provide a review of the most significant studies on the usage of ML models for analyzing ALS. This review covers a variation of ML algorithms involved in applications in ALS prognosis besides, leveraging ML to improve the efficacy of brain-computer interfaces (BCIs) for ALS individuals in later stages with restricted voluntary muscular control. The key future advances in individualized care and ALS prognosis may include the advancement of more personalized care aids that enable real-time input and ongoing validation of ML in diverse healthcare contexts.}, }
@article {pmid39283513, year = {2024}, author = {Koopmann, A and Hoffmann, S and Riegler, A and Cordes, J and Kiefer, F}, title = {[Factors influencing hospital readmission rates in alcohol use disorder].}, journal = {Der Nervenarzt}, volume = {}, number = {}, pages = {}, pmid = {39283513}, issn = {1433-0407}, abstract = {BACKGROUND: According to data from the Federal Statistical Office, the diagnosis of alcohol use disorder (AUD) (F 10) is the second most common main diagnosis for hospital treatment. Those affected by this disorder are often repeatedly hospitalized at short intervals due to relapses; however, little is known about the factors that influence readmission rates after initial treatment.<br><br>AIM OF THE STUDY: The aim of this retrospective analysis is to analyze the effects of treatment type (qualified withdrawal treatment&#xa0;(QE) versus physical detoxification) and discharge mode on the probability of readmission in alcohol-dependent patients after inpatient treatment.<br><br>MATERIAL AND METHODS: Data from 981 male and female alcohol-dependent patients who completed either qualified withdrawal treatment (QE) (68% men; mean age&#xa0;47.6 years) or inpatient detoxification (74% men; mean age&#xa0;48.0 years) were analyzed. Predictors of regular discharge were determined separately for both types of treatment using stepwise logistic regression.<br><br>RESULTS: Patients who had completed a&#xa0;qualified withdrawal treatment were significantly more likely to be regularly discharged. Regular completion of the qualified withdrawal treatment (QE) led to a&#xa0;relative reduction in the readmission rate of 25.64% within 1 year compared to a&#xa0;physical detoxification.<br><br>CONCLUSION: In order to prevent readmission and chronic courses of alcohol use disorder (AUD), qualified withdrawal treatment should always be recommended to affected patients instead of physical detoxification. Aktuelle Daten des Statistischen Bundesamtes f&#xfc;r das Jahr 2022 zeigen, dass die Diagnose "Psychische und Verhaltensst&#xf6;rungen durch Alkohol (F&#xa0;10.X)" die zweith&#xe4;ufigste Hauptdiagnose bei Krankenhausbehandlungen darstellt [13]. Im Gesundheitssystem entstehen durch dieses Erkrankungsbild und seine somatischen und psychischen Folgeerkrankungen j&#xe4;hrlich ca.&#xa0;10&#x202f;Mrd. &#x20ac; direkte Kosten [13]. Dieser Sachverhalt wird dadurch kontrastiert, dass die Krankenkassen die qualifizierte Entzugsbehandlung (QE) als leitliniengerechte Goldstandardtherapie [4] wiederholt infrage stellen [10].}, }
@article {pmid39278909, year = {2024}, author = {Reis, ALG and Maximino, JR and Lage, LAPC and Gomes, HR and Pereira, J and Brofman, PRS and Senegaglia, AC and Rebelatto, CLK and Daga, DR and Paiva, WS and Chadi, G}, title = {Proteomic analysis of cerebrospinal fluid of amyotrophic lateral sclerosis patients in the presence of autologous bone marrow derived mesenchymal stem cells.}, journal = {Stem cell research &amp; therapy}, volume = {15}, number = {1}, pages = {301}, pmid = {39278909}, issn = {1757-6512}, support = {401922/2014-6//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 836458/2016//Minist&#xe9;rio da Sa&#xfa;de/ ; 1701/22//Financiadora de Estudos e Projetos/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/therapy/metabolism ; Apolipoprotein A-I/cerebrospinal fluid/metabolism ; Apolipoproteins E/metabolism/genetics/cerebrospinal fluid ; Bone Marrow Cells/metabolism ; *Mesenchymal Stem Cell Transplantation/methods ; *Mesenchymal Stem Cells/metabolism ; Protein Interaction Maps ; *Proteomics/methods ; *Transplantation, Autologous ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressive motoneuron degenerative disorder. There are still no drugs capable of slowing disease evolution or improving life quality of ALS patients. Thus, autologous stem cell therapy has emerged as an alternative treatment regime to be investigated in clinical ALS.<br><br>METHOD: Using Proteomics and Protein-Protein Interaction Network analyses combined with bioinformatics, the possible cellular mechanisms and molecular targets related to mesenchymal stem cells (MSCs, 1&#x2009;&#xd7;&#x2009;10[6] cells/kg, intrathecally in the lumbar region of the spine) were investigated in cerebrospinal fluid (CSF) of ALS patients who received intrathecal infusions of autologous bone marrow-derived MSCs thirty days after cell therapy. Data are available via ProteomeXchange with identifier PXD053129.<br><br>RESULTS: Proteomics revealed 220 deregulated proteins in CSF of ALS subjects treated with MSCs compared to CSF collected from the same patients prior to MSCs infusion. Bioinformatics enriched analyses highlighted events of Extracellular matrix and Cell adhesion molecules as well as related key targets APOA1, APOE, APP, C4A, C5, FGA, FGB, FGG and PLG in the CSF of cell treated ALS subjects.<br><br>CONCLUSIONS: Extracellular matrix and cell adhesion molecules as well as their related highlighted components have emerged as key targets of autologous MSCs in CSF of ALS patients.<br><br>TRIAL REGISTRATION: Clinicaltrial.gov identifier NCT0291768. Registered 28 September 2016.}, }
@article {pmid39277366, year = {2024}, author = {Weng, WF and Yao, X and Zhao, M and Fang, Z and Yang, S and Ruan, JJ}, title = {Novel mutations in acetolactate synthase confer high levels of resistance to tribenuron-methyl in Fagopyrum tataricum.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106039}, doi = {10.1016/j.pestbp.2024.106039}, pmid = {39277366}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Fagopyrum/genetics/drug effects ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Arylsulfonates/pharmacology ; *Mutation ; Plant Proteins/genetics/metabolism ; }, abstract = {Tartary buckwheat (Fagopyrum tataricum) field weeds are rich in species, with many weeds causing reduced quality, yield, and crop failure. The selection of herbicide-resistant Tartary buckwheat varieties, while applying low-toxicity and efficient herbicides as a complementary weed control system, is one way to improve Tartary buckwheat yield and quality. Therefore, the development of herbicide-resistant varieties is important for the breeding of Tartary buckwheat. In this experiment, 50 mM ethyl methyl sulfonate solution was used to treat Tartary buckwheat seeds (M1) and then planted in the field. Harvested seeds (M2) were planted in the experiment field of Guizhou University, and when seedlings had 5-7 leaves, the seedlings were sprayed with 166 mg/L tribenuron-methyl (TBM). A total of 15 resistant plants were obtained, of which three were highly resistant. Using the homologous cloning method, an acetolactate synthase (ALS) gene encoding 547 amino acids was identified in Tartary buckwheat. A GTG (valine) to GGA (glycine) mutation (V409G) occurred at position 409 of the ALS gene in the high tribenuron-methyl resistant mutant sm113. The dm36 mutant harbored a double mutation, a deletion mutation at position 405, and a GTG (valine) to GGA (glycine) mutation (V411G) at position 411. The dm110 mutant underwent a double mutation: an ATG (methionine) to AGG (arginine) mutation (M333R) at position 333 and an insertion mutation at position 372. The synthesis of Chl a, Chl b, total Chl, and Car was significantly inhibited by TBM treatment. TBM was more efficient at suppressing the growth of wild-type plants than that of mutant plants. Antioxidant enzyme activities such as ascorbate peroxidase, peroxidase, and superoxide dismutase were significantly higher in resistant plants than in wild-type after spraying with TBM; malondialdehyde content was significantly lower than in wild-type plants after spraying with TBM. Plants with a single-site mutation in the ALS gene could survive, but their growth was affected by herbicide application. In contrast, plants with dual-site mutations in the ALS gene were not affected, indicating that plants with dual-site mutations in the ALS gene showed higher levels of resistance than plants with a single-site mutation in the ALS gene.}, }
@article {pmid39268612, year = {2025}, author = {Meyer, T and Schumann, P and Grehl, T and Weyen, U and Petri, S and Rödiger, A and Steinbach, R and Grosskreutz, J and Bernsen, S and Weydt, P and Wolf, J and Günther, R and Vidovic, M and Baum, P and Metelmann, M and Weishaupt, JH and Streubel, B and Kasper, DC and Koc, Y and Kettemann, D and Norden, J and Schmitt, P and Walter, B and Münch, C and Spittel, S and Maier, A and Körtvélyessy, P}, title = {SOD1 gene screening in ALS - frequency of mutations, patients' attitudes to genetic information and transition to tofersen treatment in a multi-center program.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {162-171}, doi = {10.1080/21678421.2024.2401131}, pmid = {39268612}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/diagnosis ; *Superoxide Dismutase-1/genetics ; Male ; Female ; *Genetic Testing/methods ; Middle Aged ; *Mutation/genetics ; Aged ; Adult ; C9orf72 Protein/genetics ; Germany ; RNA-Binding Protein FUS/genetics ; DNA-Binding Proteins ; }, abstract = {OBJECTIVE: To report the frequency of pathogenic SOD1 gene variants in a screening program in amyotrophic lateral sclerosis (ALS), and the clinical practice of transition to an expanded access program (EAP) of tofersen treatment.<br><br>METHODS: From October 2021 to February 2024, at 11 ALS centers in Germany genetic testing for SOD1, FUS, TARDBP, and C9orf72 was performed. Patients were offered to opt for notification either about all genetic variants or SOD1 variants relevant for tofersen therapy. The transition to the EAP with tofersen was assessed.<br><br>RESULTS: 1935 patients were screened (94.7% sporadic ALS). 48.8% (n&#x2009;=&#x2009;928) opted for notification of treatment-relevant information. Genetic variants were found as follows: SOD1 (likely) pathogenic variants (class 4/5) 1.8% (n&#x2009;=&#x2009;34), variants of unknown significance (class 3) 0.8% (n&#x2009;=&#x2009;16), FUS (class 4/5) 0.9% (n&#x2009;=&#x2009;17), TARDBP (class 4/5) 1.3% (n&#x2009;=&#x2009;25), C9orf72 hexanucleotide repeat expansion 7.0% (n&#x2009;=&#x2009;135). In SOD1-ALS (encompassing class 3-5 variants, n&#x2009;=&#x2009;50), 68.0% (n&#x2009;=&#x2009;34) reported a negative family history. 74.0% (n&#x2009;=&#x2009;37) of SOD1-ALS patients - which represent 1.9% of all participants of the screening program - were transitioned to tofersen. Median duration from start of genetic testing to treatment was 94 days (57 to 295 days). Eight patients declined treatment whereas five individuals died before initiation of therapy.<br><br>CONCLUSION: The finding of SOD1 variants in patients with a negative family history underscores the need for a broad genetic screening in ALS. In SOD1-ALS, the treatment option with tofersen was mostly utilized. The wide range in the transition time to tofersen calls for a SOD1-ALS management program.}, }
@article {pmid39273435, year = {2024}, author = {Di Chiano, M and Sallustio, F and Fiocco, D and Rocchetti, MT and Spano, G and Pontrelli, P and Moschetta, A and Gesualdo, L and Gadaleta, RM and Gallone, A}, title = {Psychobiotic Properties of Lactiplantibacillus plantarum in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {17}, pages = {}, pmid = {39273435}, issn = {1422-0067}, support = {1062//PON "RICERCA E INNOVAZIONE" 2014-2020-Innovazione/ ; Call for tender No. 341 of 15 March 2022 of Italian Ministry of University and Research funded by the European Union - Next Generation EU//National Recovery and Resilience Plan (NRRP)/ ; Concession Decree No. 1550 of 11 October 2022 adopted by the Italian Ministry of University and Research, CUP D93C22000890001//Italian Ministry of University and Research, CUP D93C22000890001/ ; Codice progetto n. 2022H9MPZ5//MIUR- PRIN Progetti di Ricerca di Rilevante Interesse Nazionale 2022/ ; Id. 23239//AIRC IG 2019/ ; Call for tender No. 3138 of 16/12/2021 of Italian Ministry of University and Research funded by the European Union//National Recovery and Resilience Plan (NRRP)/ ; Project code: CN00000041, CUP H93C22000430007//NextGenerationEU/ ; PNRR-MR1-2022-12376395//European Union - Next Generation EU - PNRR M6C2/ ; "POFACS" - ARS01_00640 -", D.D. 1211/2020 and 1104/2021//Italian Ministry of University and Research (MIUR)/ ; PRA-HE 2021//University of Foggia/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/microbiology/metabolism ; *Gastrointestinal Microbiome ; *Probiotics/therapeutic use ; Dysbiosis/microbiology ; Brain-Gut Axis ; Animals ; }, abstract = {Neurodegenerative disorders are the main cause of cognitive and physical disabilities, affect millions of people worldwide, and their incidence is on the rise. Emerging evidence pinpoints a disturbance of the communication of the gut-brain axis, and in particular to gut microbial dysbiosis, as one of the contributors to the pathogenesis of these diseases. In fact, dysbiosis has been associated with neuro-inflammatory processes, hyperactivation of the neuronal immune system, impaired cognitive functions, aging, depression, sleeping disorders, and anxiety. With the rapid advance in metagenomics, metabolomics, and big data analysis, together with a multidisciplinary approach, a new horizon has just emerged in the fields of translational neurodegenerative disease. In fact, recent studies focusing on taxonomic profiling and leaky gut in the pathogenesis of neurodegenerative disorders are not only shedding light on an overlooked field but are also creating opportunities for biomarker discovery and development of new therapeutic and adjuvant strategies to treat these disorders. Lactiplantibacillus plantarum (LBP) strains are emerging as promising psychobiotics for the treatment of these diseases. In fact, LBP strains are able to promote eubiosis, increase the enrichment of bacteria producing beneficial metabolites such as short-chain fatty acids, boost the production of neurotransmitters, and support the homeostasis of the gut-brain axis. In this review, we summarize the current knowledge on the role of the gut microbiota in the pathogenesis of neurodegenerative disorders with a particular focus on the benefits of LBP strains in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, autism, anxiety, and depression.}, }
@article {pmid39264833, year = {2024}, author = {Su, B and He, Z and Liu, J and Li, M and Huang, X}, title = {Mangiferin activates the nuclear factor erythroid 2-related factor pathway to protect SOD1-G93A induced NSC-34 motor neurons from oxidative stress and apoptosis.}, journal = {Journal of biochemical and molecular toxicology}, volume = {38}, number = {10}, pages = {e23849}, doi = {10.1002/jbt.23849}, pmid = {39264833}, issn = {1099-0461}, mesh = {*Xanthones/pharmacology ; *NF-E2-Related Factor 2/metabolism/genetics ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; Mice ; Animals ; *Motor Neurons/metabolism/drug effects/pathology ; *Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; Cell Line ; Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Humans ; NAD(P)H Dehydrogenase (Quinone)/metabolism/genetics ; }, abstract = {One of the main factors in the pathophysiology of amyotrophic lateral sclerosis is oxidative stress. Mangiferin (MF), a natural plant polyphenol, has anti-inflammatory and antioxidant effects. The aim of our study was to investigate the protective effects and mechanisms of MF in the hSOD1-G93A ALS cell model. Our result revealed that MF treatment reduced the generation of reactive oxygen species (ROS) and malondialdehyde (MDA), decreased oxidative damage, and reduced apoptosis. Additionally, it was observed that MF significantly increased the synthesis of the antioxidant genes hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase 1, which are downstream of the Nrf2 signaling pathway, and increased the expression and activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 knockdown greatly promoted apoptosis, which was reversed by MF treatment. To summarize, MF promoted the Nrf2 pathway and scavenged MDA and ROS to protect the ALS cell model.}, }
@article {pmid39257530, year = {2024}, author = {Baird, MC and Likhite, SB and Vetter, TA and Caporale, JR and Girard, HB and Roussel, FS and Howard, AE and Schwartz, MK and Reed, AR and Kaleem, A and Zhang, X and Meyer, KC}, title = {Combination AAV therapy with galectin-1 and SOD1 downregulation demonstrates superior therapeutic effect in a severe ALS mouse model.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {32}, number = {3}, pages = {101312}, pmid = {39257530}, issn = {2329-0501}, abstract = {Neuroinflammation is a miscreant in accelerating progression of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, treatments targeting neuroinflammation alone have led to disappointing results in clinical trials. Both neuronal and non-neuronal cell types have been implicated in the pathogenesis of ALS, and multiple studies have shown correction of each cell type has beneficial effects on disease outcome. Previously, we shown that AAV9-mediated superoxide dismutase 1 (SOD1) suppression in motor neurons and astrocytes significantly improves motor function and extends survival in ALS mouse models. Despite neuron and astrocyte correction, ALS mice still succumb to death with microgliosis observed in endpoint tissue. Therefore, we hypothesized that the optimal therapeutic approach will target and simultaneously correct motor neurons, astrocytes, and microglia. Here, we developed a novel approach to indirectly target microglia with galectin-1 (Gal1) and combined this with our previously established AAV9.SOD1.short hairpin RNA treatment. We show Gal1 conditioning of SOD1 [G93A] microglia decreases inflammatory markers and rescues motor neuron death in vitro. When paired with SOD1 downregulation, we found a synergistic effect of combination treatment in vivo and show a significant extension of survival of SOD1 [G93A] mice over SOD1 suppression alone. These results highlight the importance of targeting inflammatory microglia as a critical component in future therapeutic development.}, }
@article {pmid39254548, year = {2025}, author = {Zhang, M and Xiang, C and Niu, R and He, X and Luo, W and Liu, W and Gu, R}, title = {Liposomes as versatile agents for the management of traumatic and nontraumatic central nervous system disorders: drug stability, targeting efficiency, and safety.}, journal = {Neural regeneration research}, volume = {20}, number = {7}, pages = {1883-1899}, pmid = {39254548}, issn = {1673-5374}, abstract = {Various nanoparticle-based drug delivery systems for the treatment of neurological disorders have been widely studied. However, their inability to cross the blood-brain barrier hampers the clinical translation of these therapeutic strategies. Liposomes are nanoparticles composed of lipid bilayers, which can effectively encapsulate drugs and improve drug delivery across the blood-brain barrier and into brain tissue through their targeting and permeability. Therefore, they can potentially treat traumatic and nontraumatic central nervous system diseases. In this review, we outlined the common properties and preparation methods of liposomes, including thin-film hydration, reverse-phase evaporation, solvent injection techniques, detergent removal methods, and microfluidics techniques. Afterwards, we comprehensively discussed the current applications of liposomes in central nervous system diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, and brain tumors. Most studies related to liposomes are still in the laboratory stage and have not yet entered clinical trials. Additionally, their application as drug delivery systems in clinical practice faces challenges such as drug stability, targeting efficiency, and safety. Therefore, we proposed development strategies related to liposomes to further promote their development in neurological disease research.}, }
@article {pmid39251025, year = {2025}, author = {Del Rosso, JQ and Zaenglein, A and Callender, V and Schlosser, B and Graber, E and Keri, J and Weiss, J}, title = {Response to Reynolds et al's "Guidelines of care for the management of acne vulgaris".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {1}, pages = {e15}, doi = {10.1016/j.jaad.2024.07.1528}, pmid = {39251025}, issn = {1097-6787}, }
@article {pmid39242252, year = {2024}, author = {Benmoussa, A and Assernannas, I and Maatoui-Belabbes, H and Dahmaoui, N and Qachouh, M and Cherkaoui, S and Lamchaheb, M and Rachid, M and Madani, A and Khoubila, N}, title = {[Acquired bone marrow aplasia in children and young adults under the age of 30: Experience of the Pediatric Hematology and Oncology Department of the 20 August Hospital, Casablanca].}, journal = {Bulletin du cancer}, volume = {111}, number = {10}, pages = {944-954}, doi = {10.1016/j.bulcan.2024.06.010}, pmid = {39242252}, issn = {1769-6917}, mesh = {Humans ; Male ; Female ; Infant ; Child, Preschool ; Child ; Adolescent ; Adult ; *Anemia, Aplastic/mortality/therapy ; Morocco/epidemiology ; Retrospective Studies ; Prognosis ; Time-to-Treatment ; *Cyclosporine/therapeutic use ; *Antilymphocyte Serum/therapeutic use ; *Hematopoietic Stem Cell Transplantation ; Treatment Outcome ; Delayed Diagnosis ; }, abstract = {Bone marrow aplasia is a rare and serious hematologic disorder. Although benign, it is a hematologic disorder whose prognosis can be poor and whose spontaneous development can be fatal. Treatment is long, difficult and costly. In developing countries, the mortality rate is high due to the difficulties of therapeutic management, both supportive and specific. We conducted a retrospective study of 92 cases of AM identified in the Pediatric Hematology and Oncology Department of the 20 Août University Hospital in Casablanca over a 10-year period (January 2010-January 2020). In this work, we present an overview of the situation and highlight the difficulties encountered in the management of AM in the Pediatric Hematology and Oncology Department of the University Hospital of Casablanca. In our study, the mean age was 19 years, ranging from 3 months to 29 years, with a peak in the 15-20 age group. The sex ratio (M/F) was 2.06, with a male predominance of 67%. In our series, only 35% of patients had complete bone marrow failure. An anemic syndrome was present in 92% of patients, and hemorrhagic and infectious syndromes were present in 70% and 41% of patients, respectively. The median time from diagnosis to treatment was 82 days. According to the Camitta score, 31% of our patients had mild AM, 41% had severe AM, and 28% had very severe AM. After etiologic evaluation, we concluded that 90% of the patients had idiopathic bone marrow aplasia, 2% had constitutional bone marrow aplasia, and 8% of the patients were suspected to have secondary bone marrow aplasia: post-hepatitis (3 cases), toxic (2 cases), drug-induced (1 case), and aplastic PNH (1 case). Mortality in the first three months after diagnosis was 21%. Sixty-nine percent of our patients received specific treatment: 28 were treated with cyclosporin (CIS) alone as first-line therapy, 20 received a combination of antilymphocyte serum (ALS) and cyclosporin, 2 received hematopoietic stem cell transplantation (HSCT), while 3 were treated with androgens alone. The overall response rate was 30% with CIS, 42% with ALS+CIS and 100% with HSCT. In our study, the overall death rate was 44%, while the one-year survival rate was 40%. It is important to note that septic shock was the leading cause of death (53% of deaths), followed by hemorrhagic shock (24%). This highlights the lack of hemodynamic resuscitation and symptomatic treatment. Our multivariate study defined the following risk factors as predictive of worse survival: age greater than 16 years (RR: 3.28; CI: 1.29-8.33; P=0.012), PNN less than 200 or very severe bone marrow aplasia (RR: 3.01; 1.1-8.08; P=0.028), and failure to receive any specific treatment (RR: 4.07; 1.77-9.35; P=0.0003). The high overall mortality in our series was due to several factors: inaccessibility to effective therapies, delayed diagnosis, failure to initiate specific treatment, inadequate symptomatic treatment, and geographical and financial inaccessibility.}, }
@article {pmid39239063, year = {2024}, author = {Pezeshgi, S and Ghaderi, S and Mohammadi, S and Karimi, N and Ziaadini, B and Mohammadi, M and Fatehi, F}, title = {Diffusion tensor imaging biomarkers and clinical assessments in amyotrophic lateral sclerosis (ALS) patients: an exploratory study.}, journal = {Annals of medicine and surgery (2012)}, volume = {86}, number = {9}, pages = {5080-5090}, pmid = {39239063}, issn = {2049-0801}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Biomarkers are needed to improve diagnosis, gauge progression, and evaluate treatment. Diffusion tensor imaging (DTI) is a promising biomarker for detecting microstructural alterations in the white matter tracts. This study aimed to assess DTI metrics as biomarkers and to examine their relationship with clinical assessments in patients with ALS. Eleven patients with ALS and 21 healthy controls (HCs) underwent 3T MRI with DTI. DTI metrics, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), were compared between key motor and extra-motor tract groups. Group comparisons and correlations between DTI metrics also correlated with clinical scores of disability (ALSFRS-R), muscle strength (dynamometry), and motor unit loss (MUNIX). Widespread differences were found between patients with ALS and HCs in DTI metrics, including decreased FA and increased diffusivity metrics. However, MD and RD are more sensitive metrics for detecting white matter changes in patients with ALS. Significant interhemispheric correlations between the tract DTI metrics were also observed. DTI metrics showed symmetry between the hemispheres and correlated with the clinical assessments. MD, RD, and AD increases significantly correlated with lower ALSFRS-R and MUNIX scores and weaker dynamometry results. DTI reveals microstructural damage along the motor and extra-motor regions in ALS patients. DTI metrics can serve as quantitative neuroimaging biomarkers for diagnosis, prognosis, monitoring of progression, and treatment. Combined analysis of imaging, electrodiagnostic, and functional biomarkers shows potential for characterizing disease pathophysiology and progression.}, }
@article {pmid39236857, year = {2024}, author = {Reiter, RJ and Sharma, RN and Manucha, W and Rosales-Corral, S and Almieda Chuffa, LG and Loh, D and Luchetti, F and Balduini, W and Govitrapong, P}, title = {Dysfunctional mitochondria in age-related neurodegeneration: Utility of melatonin as an antioxidant treatment.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102480}, doi = {10.1016/j.arr.2024.102480}, pmid = {39236857}, issn = {1872-9649}, mesh = {*Melatonin/metabolism/pharmacology/therapeutic use ; Humans ; *Antioxidants/pharmacology/therapeutic use ; *Mitochondria/metabolism/drug effects ; *Aging/metabolism/drug effects ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; Oxidative Stress/drug effects ; }, abstract = {Mitochondria functionally degrade as neurons age. Degenerative changes cause inefficient oxidative phosphorylation (OXPHOS) and elevated electron leakage from the electron transport chain (ETC) promoting increased intramitochondrial generation of damaging reactive oxygen and reactive nitrogen species (ROS and RNS). The associated progressive accumulation of molecular damage causes an increasingly rapid decline in mitochondrial physiology contributing to aging. Melatonin, a multifunctional free radical scavenger and indirect antioxidant, is synthesized in the mitochondrial matrix of neurons. Melatonin reduces electron leakage from the ETC and elevates ATP production; it also detoxifies ROS/RNS and via the SIRT3/FOXO pathway it upregulates activities of superoxide dismutase 2 and glutathione peroxidase. Melatonin also influences glucose processing by neurons. In neurogenerative diseases, neurons often adopt Warburg-type metabolism which excludes pyruvate from the mitochondria causing reduced intramitochondrial acetyl coenzyme A production. Acetyl coenzyme A supports the citric acid cycle and OXPHOS. Additionally, acetyl coenzyme A is a required co-substrate for arylalkylamine-N-acetyl transferase, which rate limits melatonin synthesis; therefore, melatonin production is diminished in cells that experience Warburg-type metabolism making mitochondria more vulnerable to oxidative stress. Moreover, endogenously produced melatonin diminishes during aging, further increasing oxidative damage to mitochondrial components. More normal mitochondrial physiology is preserved in aging neurons with melatonin supplementation.}, }
@article {pmid39233624, year = {2024}, author = {Garnier, M and Camdessanché, JP and Cassereau, J and Codron, P}, title = {From suspicion to diagnosis: exploration strategy for suspected amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2398199}, pmid = {39233624}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; Diagnosis, Differential ; Electromyography/methods ; }, abstract = {The diagnosis of amyotrophic lateral sclerosis (ALS) is based on evidence of upper and lower motor neuron degeneration in the bulbar, cervical, thoracic, and lumbar regions in a patient with progressive motor weakness, in the absence of differential diagnosis. Despite these well-defined criteria, ALS can be difficult to diagnose, given the wide variety of clinical phenotypes. Indeed, the central or peripheral location of the disease varies with a spectrum ranging from predominantly central to exclusively peripheral, symptoms can be extensive or limited to the limbs, bulbar area or respiratory muscles, and the duration of the disease may range from a few months to several decades. In the absence of a specific test, the diagnostic strategy relies on clinical, electrophysiological, biological and radiological investigations to confirm the disease and exclude ALS mimics. The main challenge is to establish a diagnosis based on robust clinical and paraclinical evidence without delaying treatment initiation by increasing the number of additional tests. This approach requires a thorough knowledge of the phenotypes of ALS and its main differential diagnoses.}, }
@article {pmid39233146, year = {2024}, author = {Wang, H and Liu, S and Sun, Y and Chen, C and Hu, Z and Li, Q and Long, J and Yan, Q and Liang, J and Lin, Y and Yang, S and Lin, M and Liu, X and Wang, H and Yu, J and Yi, F and Tan, Y and Yang, Y and Chen, N and Ai, Q}, title = {Target modulation of glycolytic pathways as a new strategy for the treatment of neuroinflammatory diseases.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102472}, doi = {10.1016/j.arr.2024.102472}, pmid = {39233146}, issn = {1872-9649}, mesh = {Humans ; *Glycolysis/physiology ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Animals ; Aging/metabolism ; }, abstract = {Neuroinflammation is an innate and adaptive immune response initiated by the release of inflammatory mediators from various immune cells in response to harmful stimuli. While initially beneficial and protective, prolonged or excessive neuroinflammation has been identified in clinical and experimental studies as a key pathological driver of numerous neurological diseases and an accelerant of the aging process. Glycolysis, the metabolic process that converts glucose to pyruvate or lactate to produce adenosine 5'-triphosphate (ATP), is often dysregulated in many neuroinflammatory disorders and in the affected nerve cells. Enhancing glucose availability and uptake, as well as increasing glycolytic flux through pharmacological or genetic manipulation of glycolytic enzymes, has shown potential protective effects in several animal models of neuroinflammatory diseases. Modulating the glycolytic pathway to improve glucose metabolism and ATP production may help alleviate energy deficiencies associated with these conditions. In this review, we examine six neuroinflammatory diseases-stroke, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and depression-and provide evidence supporting the role of glycolysis in their treatment. We also explore the potential link between inflammation-induced aging and glycolysis. Additionally, we briefly discuss the critical role of glycolysis in three types of neuronal cells-neurons, microglia, and astrocytes-within physiological processes. This review highlights the significance of glycolysis in the pathology of neuroinflammatory diseases and its relevance to the aging process.}, }
@article {pmid39225243, year = {2024}, author = {Liang, J and Zhu, Y and Liu, S and Kuang, B and Tian, Z and Zhang, L and Yang, S and Lin, M and Chen, N and Liu, X and Ai, Q and Yang, Y}, title = {Progress of Exosomal MicroRNAs and Traditional Chinese Medicine Monomers in Neurodegenerative Diseases.}, journal = {Phytotherapy research : PTR}, volume = {38}, number = {11}, pages = {5323-5349}, doi = {10.1002/ptr.8322}, pmid = {39225243}, issn = {1099-1573}, support = {//The Key Discipline of Biological Engineering of Hunan University of Chinese Medicine [2018] No. 3/ ; 22JBZ052//Hunan University of Chinese Medicine Discipline Construction Project/ ; 202329-2//Key Project of Changsha Hospital for Maternal &amp; Child Health Care Affiliated to Hunan Normal University/ ; 2021JJ30512//Hunan Natural Science Foundation/ ; 2022JJ40313//Hunan Natural Science Foundation/ ; 2022JJ40456//Hunan Natural Science Foundation/ ; 2023JJ60126//Hunan Natural Science Foundation/ ; 2023JJ60471//Hunan Natural Science Foundation/ ; 21B0354//Outstanding Youth Project of Hunan Education Department/ ; B2023061//Scientific Research Project of Hunan Provincial Administration of Traditional Chinese Medicine/ ; //Hunan University of Chinese Medicine First-class Disciple Construction Project of Chinese Material Medica/ ; kq2014091//Changsha Natural Science Foundation/ ; kq2202269//Changsha Natural Science Foundation/ ; //The First-class Discipline Construction Project of Chemical Engineering and Technology of Hunan University of Traditional Chinese Medicine/ ; 212010//Special Scientific and Technological Project for Comprehensive Utilization of Ampelopsis grossedentata Resources of Hunan Qiankun Biotechnology Co., Ltd/ ; 2019xjjj001//Key Project of Hunan University of Chinese Medicine School level Scientific Research Fund/ ; 2021XJJJ028//Key Project of Hunan University of Chinese Medicine School level Scientific Research Fund/ ; U2202214//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Exosomes/metabolism ; *MicroRNAs/genetics ; *Neurodegenerative Diseases/drug therapy ; *Medicine, Chinese Traditional/methods ; Drugs, Chinese Herbal/pharmacology ; Animals ; }, abstract = {Exosomes, extracellular vesicles secreted by various cells, actively participate in intercellular communication by facilitating the exchange of crucial molecular information such as DNA, RNA, and lipids. Within this intricate network, microRNAs, endogenous non-coding small RNAs, emerge as pivotal regulators of post-transcriptional gene expression, significantly influencing the development of neurodegenerative diseases. The historical prominence of traditional Chinese medicine (TCM) in clinical practice in China underscores its enduring significance. Notably, TCM monomers, serving as active constituents within herbal medicine, assume a critical role in the treatment of neurodegenerative diseases, particularly in mitigating oxidative stress, inhibiting apoptosis, and reducing inflammation. This comprehensive review aims to delineate the specific involvement of exosomal microRNAs in various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and amyotrophic lateral sclerosis. Furthermore, the exploration extends to the application of TCM monomers, elucidating their efficacy as therapeutic agents in these conditions. Additionally, the review examines the utilization of exosomes as drug delivery carriers in the context of neurodegenerative diseases, providing a nuanced understanding of the potential synergies between TCM and modern therapeutic approaches. This synthesis of knowledge aims to contribute to the advancement of our comprehension of the intricate molecular mechanisms underlying neurodegeneration and the potential therapeutic avenues offered by TCcom interventions.}, }
@article {pmid39218769, year = {2024}, author = {Sun, J and Zhang, Y}, title = {Microbiome and micronutrient in ALS: From novel mechanisms to new treatments.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {6}, pages = {e00441}, pmid = {39218769}, issn = {1878-7479}, support = {I01 BX004824/BX/BLRD VA/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; R01 DK134343/DK/NIDDK NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/microbiology/metabolism/therapy ; Humans ; *Micronutrients/metabolism ; *Gastrointestinal Microbiome/physiology ; Animals ; Dysbiosis ; Microbiota/physiology ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disorder. Despite extensive studies, it remains challenging to treat ALS. Recent ALS studies have shown dysbiosis (e.g., loss of microbial diversity and beneficial function in the gut microbiota) is correlated with intestinal inflammation and change of intestinal integrity in ALS. The novel concepts and the roles of microbiome and microbial metabolites through the gut-microbiome-neuron axis in ALS pathogenesis have been slowly recognized by the neurology research field. Here, we will discuss the recent progress of microbiome, including bacteria, fungi, and viruses, in the ALS research. We will discuss our understanding of microbial metabolites in ALS. Micronutrition refers to the intake of essential vitamins, minerals, and other micronutrients. We will summarize the literation related to micronutrition and ALS. Furthermore, we will consider the mutual interactions of microbiome and micronutrition in the ALS progression and treatment. We further propose that the mechanistic and translational studies that shift from suspension of disbelief to cogent ingenuity, and from bench study to bed-side application, should allow new strategies of diagnosis and treatment for ALS.}, }
@article {pmid39218010, year = {2024}, author = {Shojaie, A and Al Khleifat, A and Garrahy, S and Habash-Bailey, H and Thomson, R and Opie-Martin, S and Javidnia, S and Leigh, PN and Al-Chalabi, A}, title = {Investigating the impact of socioeconomic status on amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {702-707}, pmid = {39218010}, issn = {2167-9223}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/economics ; Male ; Female ; Middle Aged ; *Social Class ; Aged ; Adult ; Age of Onset ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the gradual death of motor neurons in the brain and spinal cord, leading to fatal paralysis. Socioeconomic status (SES) is a measure of an individual's shared economic and social status, which has been shown to have an association with health outcomes. Understanding the impact of SES on health conditions is crucial, as it can influence and be influenced by health-related variables. The role of socioeconomic status in influencing the risk and progression of ALS has not been established, and understanding the various factors that impact ALS is important in developing strategies for treatment and prevention. To investigate this relationship, we recruited 413 participants with definite, probable, or possible ALS according to the El Escorial criteria, from three tertiary centers in London, Sheffield, and Birmingham. Logistic regression was used to examine the association between case-control status, socioeconomic criteria, and ALS risk. Linear regression was used to examine the association between age of onset and socioeconomic variables. Two sensitivity analyses were performed, one using an alternative occupational classifier, and the other using Mendelian Randomization analysis to examine association. There was no significant relationship between any variables and ALS risk. We found an inverse relationship between mean lifetime salary and age of ALS onset (Beta = -0.157, p = 0.011), but no effect of education or occupation on the age of onset. The finding was confirmed in both sensitivity analyses and in Mendelian Randomization. We find that a higher salary is associated with a younger age of ALS onset taking into account sex, occupation, years of education, and clinical presentation.}, }
@article {pmid39217855, year = {2024}, author = {Zhang, J and Chen, K and Chen, Y and Hua, L and Chen, S and Chen, X and Zou, L and Li, S and Yang, X and Shen, Y}, title = {Pathology reduction and motor behavior improvement associated with ultrasound-mediated delivery of arctiin to the motor cortex in a mutant SOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {Ultrasonics}, volume = {144}, number = {}, pages = {107449}, doi = {10.1016/j.ultras.2024.107449}, pmid = {39217855}, issn = {1874-9968}, mesh = {Animals ; Male ; Mice ; *Amyotrophic Lateral Sclerosis ; *Disease Models, Animal ; Drug Delivery Systems ; Furans/pharmacology/administration &amp; dosage ; Glucosides/pharmacology/administration &amp; dosage ; *Mice, Transgenic ; Microbubbles ; *Motor Cortex/drug effects/physiopathology ; Mutation ; Superoxide Dismutase-1/genetics ; Ultrasonic Therapy/methods ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is marked by the deterioration of both cortical and spinal cord motor neurons. Despite the underlying causes of the disease remain elusive, there has been a growing attention on the well-being of cortical motor neurons in recent times. Focused ultrasound combined with microbubbles (FUS/MB) for opening the blood-brain barrier (BBB) provides a means for drug delivery to specific brain regions, holding significant promise for the treatment of neurological disorders.<br><br>OBJECTIVES: We aim to explore the outcomes of FUS/MB-mediated delivery of arctiin (Arc), a natural compound with anti-inflammatory activities, to the cerebral motor cortex area by using a transgenic ALS mouse model.<br><br>METHODS: The ALS mouse model with the SOD1[G93A] mutation was used and subjected to daily Arc administration with FUS/MB treatment twice a week. After six-week treatments, the motor performance was assessed by grip strength, wire hanging, and climbing-pole tests. Mouse brains, spinal cords and gastrocnemius muscle were harvested for histological staining.<br><br>RESULTS: Compared with the mice given Arc administration only, the combined treatments of FUS/MB with Arc induced further mitigation of the motor function decline, accompanied by improved health of the gastrocnemius muscle. Furthermore, notable neuroprotective effect was evidenced by the amelioration of motor neuron failure in the cortex and lumbar spinal cord.<br><br>CONCLUSION: These preliminary results indicated that the combined treatment of FUS/MB and arctiin exerted a potentially beneficial effect on neuromuscular function in the ALS disease.}, }
@article {pmid39211392, year = {2024}, author = {Matsuo, K and Nagamatsu, J and Nagata, K and Umeda, R and Shiota, T and Morimoto, S and Suzuki, N and Aoki, M and Okano, H and Nakamori, M and Nishihara, H}, title = {Establishment of a novel amyotrophic lateral sclerosis patient (TARDBP [N345K/+])-derived brain microvascular endothelial cell model reveals defective Wnt/β-catenin signaling: investigating diffusion barrier dysfunction and immune cell interaction.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1357204}, pmid = {39211392}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a major neurodegenerative disease for which there is currently no curative treatment. The blood-brain barrier (BBB), multiple physiological functions formed by mainly specialized brain microvascular endothelial cells (BMECs), serves as a gatekeeper to protect the central nervous system (CNS) from harmful molecules in the blood and aberrant immune cell infiltration. The accumulation of evidence indicating that alterations in the peripheral milieu can contribute to neurodegeneration within the CNS suggests that the BBB may be a previously overlooked factor in the pathogenesis of ALS. Animal models suggest BBB breakdown may precede neurodegeneration and link BBB alteration to the disease progression or even onset. However, the lack of a useful patient-derived model hampers understanding the pathomechanisms of BBB dysfunction and the development of BBB-targeted therapies. In this study, we differentiated BMEC-like cells from human induced pluripotent stem cells (hiPSCs) derived from ALS patients to investigate BMEC functions in ALS patients. TARDBP [N345K/+] carrying patient-derived BMEC-like cells exhibited increased permeability to small molecules due to loss of tight junction in the absence of neurodegeneration or neuroinflammation, highlighting that BMEC abnormalities in ALS are not merely secondary consequences of disease progression. Furthermore, they exhibited increased expression of cell surface adhesion molecules like ICAM-1 and VCAM-1, leading to enhanced immune cell adhesion. BMEC-like cells derived from hiPSCs with other types of TARDBP gene mutations (TARDBP [K263E/K263E] and TARDBP [G295S/G295S]) introduced by genome editing technology did not show such BMEC dysfunction compared to the isogenic control. Interestingly, transactive response DNA-binding protein 43 (TDP-43) was mislocalized to cytoplasm in TARDBP [N345K/+] carrying model. Wnt/β-catenin signaling was downregulated in the ALS patient (TARDBP [N345K/+])-derived BMEC-like cells and its activation rescued the leaky barrier phenotype and settled down VCAM-1 expressions. These results indicate that TARDBP [N345K/+] carrying model recapitulated BMEC abnormalities reported in brain samples of ALS patients. This novel patient-derived BMEC-like cell is useful for the further analysis of the involvement of vascular barrier dysfunctions in the pathogenesis of ALS and for promoting therapeutic drug discovery targeting BMEC.}, }
@article {pmid39207717, year = {2024}, author = {Ling, Y and Crotti, A}, title = {Emerging Microglial Therapies and Targets in Clinical Trial.}, journal = {Advances in neurobiology}, volume = {37}, number = {}, pages = {623-637}, pmid = {39207717}, issn = {2190-5215}, mesh = {*Microglia/metabolism ; Humans ; Clinical Trials as Topic ; Neurodegenerative Diseases/drug therapy/therapy/metabolism ; Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Modulation of microglia function for treatment of neurodegenerative and neuropsychiatric disorders is an emerging field of neuroscience drug development. This is largely attributed to human genetic association studies combined with biological evidence indicating that the innate immune system acts as a causal contributor superimposed on the reactive component of neuronal loss in neurological dysfunction. The identification of disease risk gene variants that encode immune-modulatory proteins in microglia provides tools to evaluate how microglia cellular function or dysfunction affect neuronal health. The development of clinical stage therapeutic compounds that modify myeloid cell function enables us to investigate how modulating microglia function could become a transformational approach to mitigate neurological disorders. Improving our ability to boost microglia-promoting homeostatic and reparative functions hopefully will translate into achieving a better outcome for patients affected by neurological diseases. In this chapter, we aim to provide an overview of the microglial emerging therapies and targets being studied in current clinical trials.}, }
@article {pmid39207520, year = {2024}, author = {Bjelica, B and Petri, S}, title = {Narrative review of diagnosis, management and treatment of dysphagia and sialorrhea in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6508-6513}, pmid = {39207520}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/diagnosis ; *Sialorrhea/etiology/therapy/diagnosis ; *Deglutition Disorders/etiology/therapy/diagnosis/physiopathology ; Disease Management ; }, abstract = {The degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) frequently leads bulbar symptoms like dysarthria, dysphagia, and sialorrhea, in approximately one-third of cases being the initial symptom. Throughout the disease, more than two-thirds of ALS patients experience dysphagia, regardless of the region of onset. In this review, we aimed to offer an updated overview of dysphagia and sialorrhea in ALS, covering its diagnosis, monitoring, and treatment in clinical practice. Regular assessment of dysphagia and sialorrhea during each patient visit is essential and should be a standard aspect of ALS care. Early discussion of potential treatments such as high-calorie diets or percutaneous endoscopic gastrostomy (PEG) is crucial. Furthermore, this review highlights and discusses potential areas for improvement in both clinical practice and research.}, }
@article {pmid39206899, year = {2024}, author = {Ma, J and Liu, J and Chen, S and Zhang, W and Wang, T and Cao, M and Yang, Y and Du, Y and Cui, G and Du, Z}, title = {Understanding the Mechanism of Ferroptosis in Neurodegenerative Diseases.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {29}, number = {8}, pages = {291}, doi = {10.31083/j.fbl2908291}, pmid = {39206899}, issn = {2768-6698}, support = {81602893//National Natural Science Foundation of China (NSFC)/ ; ZR2015YL049//Natural Science Foundation of Shandong Province/ ; ZR2021MH218//Natural Science Foundation of Shandong Province/ ; ZR2022MH184//Natural Science Foundation of Shandong Province/ ; 202104020224//Shandong Province Medical and Health Technology Development Plan/ ; 202312010854//Shandong Province Medical and Health Technology Development Plan/ ; Z-2023114//Shandong Province Traditional Chinese Medicine Science and Technology Plan/ ; 202328074//Jinan Science and Technology Plan/ ; }, mesh = {*Ferroptosis/physiology ; Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Iron/metabolism ; Animals ; Neurons/metabolism/pathology ; }, abstract = {Neurodegenerative disorders are typified by the progressive degeneration and subsequent apoptosis of neuronal cells. They encompass a spectrum of conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), epilepsy, brian ischemia, brian injury, and neurodegeneration with brain iron accumulation (NBIA). Despite the considerable heterogeneity in their clinical presentation, pathophysiological underpinning and disease trajectory, a universal feature of these disorders is the functional deterioration of the nervous system concomitant with neuronal apoptosis. Ferroptosis is an iron (Fe)-dependent form of programmed cell death that has been implicated in the pathogenesis of these conditions. It is intricately associated with intracellular Fe metabolism and lipid homeostasis. The accumulation of Fe is observed in a variety of neurodegenerative diseases and has been linked to their etiology and progression, although its precise role in these pathologies has yet to be elucidated. This review aims to elucidate the characteristics and regulatory mechanisms of ferroptosis, its association with neurodegenerative diseases, and recent advances in ferroptosis-targeted therapeutic strategies. Ferroptosis may therefore be a critical area for future research into neurodegenerative diseases.}, }
@article {pmid39204338, year = {2024}, author = {O'Neill, R and Yoo, O and Burcham, P and Lim, LY}, title = {Edaravone for the Treatment of Motor Neurone Disease: A Critical Review of Approved and Alternative Formulations against a Proposed Quality Target Product Profile.}, journal = {Pharmaceutics}, volume = {16}, number = {8}, pages = {}, pmid = {39204338}, issn = {1999-4923}, support = {000990//Australian Government Research Training Program, Stan Perron Charitable Foundation/ ; }, abstract = {Edaravone is one of two main drugs for treating motor neurone disease (MND). This review proposes a specific quality target product profile (QTPP) for edaravone following an appraisal of the issues accounting for the poor clinical uptake of the approved IV and oral liquid edaravone formulations. This is followed by a review of the alternative oral formulations of edaravone described in the published patent and journal literature against the QTPP. A total of 14 texts published by six research groups on 18 novel oral formulations of edaravone for the treatment of MND have been reviewed. The alternative oral formulations included liquid and solid formulations developed with cyclodextrins, lipids, surfactants, co-surfactants, alkalising agents, tablet excipients, and co-solvents. Most were intended to deliver edaravone for drug absorption in the lower gastrointestinal tract (GIT); however, there were also four formulations targeting the oral mucosal absorption of edaravone to avoid first-pass metabolism. All the novel formulations improved the aqueous solubility, stability, and oral bioavailability (BA) of edaravone compared to an aqueous suspension of edaravone. A common limitation of the published formulations is the lack of MND-patient-centred data. Except for TW001, no other formulations have been trialled in MND patients. To meet the QTPP of an oral edaravone formulation for MND patients, it is recommended that a tablet of appropriate size and with acceptable taste and stability be designed for the effective sublingual or buccal absorption of edaravone. This tablet should be designed with input from the MND community.}, }
@article {pmid39201793, year = {2024}, author = {Martin, LJ and Koh, SJ and Price, A and Park, D and Kim, BW}, title = {Nuclear Localization of Human SOD1 in Motor Neurons in Mouse Model and Patient Amyotrophic Lateral Sclerosis: Possible Links to Cholinergic Phenotype, NADPH Oxidase, Oxidative Stress, and DNA Damage.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201793}, issn = {1422-0067}, support = {NS34100/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Cell Nucleus/metabolism ; Disease Models, Animal ; *DNA Damage ; *Induced Pluripotent Stem Cells/metabolism ; Mice, Transgenic ; *Motor Neurons/metabolism/pathology ; NADPH Oxidases/metabolism/genetics ; *Oxidative Stress ; Phenotype ; Spinal Cord/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease that causes degeneration of motor neurons (MNs) and paralysis. ALS can be caused by mutations in the gene that encodes copper/zinc superoxide dismutase (SOD1). SOD1 is known mostly as a cytosolic antioxidant protein, but SOD1 is also in the nucleus of non-transgenic (tg) and human SOD1 (hSOD1) tg mouse MNs. SOD1's nuclear presence in different cell types and subnuclear compartmentations are unknown, as are the nuclear functions of SOD1. We examined hSOD1 nuclear localization and DNA damage in tg mice expressing mutated and wildtype variants of hSOD1 (hSOD1-G93A and hSOD1-wildtype). We also studied ALS patient-derived induced pluripotent stem (iPS) cells to determine the nuclear presence of SOD1 in undifferentiated and differentiated MNs. In hSOD1-G93A and hSOD1-wildtype tg mice, choline acetyltransferase (ChAT)-positive MNs had nuclear hSOD1, but while hSOD1-wildtype mouse MNs also had nuclear ChAT, hSOD1-G93A mouse MNs showed symptom-related loss of nuclear ChAT. The interneurons had preserved parvalbumin nuclear positivity in hSOD1-G93A mice. hSOD1-G93A was seen less commonly in spinal cord astrocytes and, notably, oligodendrocytes, but as the disease emerged, the oligodendrocytes had increased mutant hSOD1 nuclear presence. Brain and spinal cord subcellular fractionation identified mutant hSOD1 in soluble nuclear extracts of the brain and spinal cord, but mutant hSOD1 was concentrated in the chromatin nuclear extract only in the spinal cord. Nuclear extracts from mutant hSOD1 tg mouse spinal cords had altered protein nitration, footprinting peroxynitrite presence, and the intact nuclear extracts had strongly increased superoxide production as well as the active NADPH oxidase marker, p47phox. The comet assay showed that MNs from hSOD1-G93A mice progressively (6-14 weeks of age) accumulated DNA single-strand breaks. Ablation of the NCF1 gene, encoding p47phox, and pharmacological inhibition of NADPH oxidase with systemic treatment of apocynin (10 mg/kg, ip) extended the mean lifespan of hSOD1-G93A mice by about 25% and mitigated genomic DNA damage progression. In human postmortem CNS, SOD1 was found in the nucleus of neurons and glia; nuclear SOD1 was increased in degenerating neurons in ALS cases and formed inclusions. Human iPS cells had nuclear SOD1 during directed differentiation to MNs, but mutant SOD1-expressing cells failed to establish wildtype MN nuclear SOD1 levels. We conclude that SOD1 has a prominent nuclear presence in the central nervous system, perhaps adopting aberrant contexts to participate in ALS pathobiology.}, }
@article {pmid39200200, year = {2024}, author = {Yoo, JK and Kwon, SH and Yoon, SH and Lee, JE and Jeon, JE and Chung, JH and Lee, SY}, title = {Preservation of Vocal Function in Amyotrophic Lateral Sclerosis (ALS) Patients Following Percutaneous Dilatational Tracheostomy (PDT) and Adjuvant Therapies.}, journal = {Biomedicines}, volume = {12}, number = {8}, pages = {}, pmid = {39200200}, issn = {2227-9059}, abstract = {UNLABELLED: The study aimed to evaluate the efficacy of percutaneous dilatational tracheostomy (PDT) combined with adjuvant therapies in preserving vocal function in amyotrophic lateral sclerosis (ALS) patients.<br><br>METHODS: We performed a retrospective analysis of 47 ALS patients who underwent PDT at the Rodem Hospital from 2021 to 2023. Post-operatively, these patients were provided with a comprehensive treatment plan that included regenerative injection therapy, low-frequency electrical stimulation, respiratory rehabilitation, and swallowing rehabilitation therapy. Additionally, a balloon reduction program was implemented for effective tracheostomy tube (T-tube) management. The preservation of vocal functions was evaluated 4 weeks following the procedure.<br><br>RESULTS: While some patients maintained or slightly improved their ALSFRS-R speech scores, the overall trend indicated a decrease in speech scores post-PDT. This suggests that PDT in combination with adjuvant therapies may not universally improve vocal function, but can help maintain it in certain cases.<br><br>CONCLUSIONS: Our findings indicate that PDT combined with mesotherapy, low-frequency electrical stimulation, and swallowing rehabilitation therapy may play a role in maintaining vocal function in limb type ALS patients, though further research is needed to optimize patient management and to validate these results.}, }
@article {pmid39198773, year = {2024}, author = {Lei, Y and Zhang, X and Liu, H and Xu, Z and Xu, P}, title = {Amyotrophic lateral sclerosis associated with Sjögren's syndrome: a case report.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {300}, pmid = {39198773}, issn = {1471-2377}, mesh = {Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/drug therapy/pathology ; *Sjogren's Syndrome/complications/diagnosis/drug therapy/pathology ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a chronic and progressive neurodegenerative disorder with an unknown cause. The development of amyotrophic lateral sclerosis (ALS) is believed to be linked to an immune response. Monocytes/macrophages and T cells are key players in the disease's advancement. Monitoring levels of cytokines in the blood can help forecast patient outcomes, while immunotherapy shows promise in alleviating symptoms for certain individuals.<br><br>CASE PRESENTATION: A 56-year-old male patient was admitted to the hospital due to progressive limb weakness persisting for eight months. The neurological examination revealed impairments in both upper and lower motor neurons, as well as sensory anomalies, without corresponding signs. Electrophysiological examination results indicated extensive neuronal damage and multiple peripheral nerve impairments, thereby the diagnosis was ALS. One month ago, the patient began experiencing symptoms of dry mouth and a bitter taste. Following tests for rheumatic immune-related antibodies and a lip gland biopsy, a diagnosis of Sj&#xf6;gren's syndrome (SS) was proposed. Despite treatment with medications such as hormones (methylprednisolone), immunosuppressants (hydroxychloroquine sulfate), and riluzole, the symptoms did not significantly improve, but also did not worsen.<br><br>CONCLUSION: It is recommended to include screening for SS in the standard assessment of ALS. Furthermore, research should focus on understanding the immune mechanisms involved in ALS, providing new insights for the diagnosis and treatment of ALS in conjunction with SS.}, }
@article {pmid39197801, year = {2025}, author = {Zhan, Y and Huang, J and Tang, X and Du, B and Yang, B}, title = {Semen Strychni Pulveratum and vomicine alleviate neuroinflammation in amyotrophic lateral sclerosis through cGAS-STING-TBK1 pathway.}, journal = {Journal of ethnopharmacology}, volume = {336}, number = {}, pages = {118741}, doi = {10.1016/j.jep.2024.118741}, pmid = {39197801}, issn = {1872-7573}, mesh = {Animals ; *Protein Serine-Threonine Kinases/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mice ; *Membrane Proteins/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Nucleotidyltransferases/metabolism ; Male ; Signal Transduction/drug effects ; Mice, Transgenic ; Neuroinflammatory Diseases/drug therapy ; Spinal Cord/drug effects/metabolism/pathology ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fetal neuromuscular disorder characterized by the gradual deterioration of motor neurons. Semen Strychni pulveratum (SSP), a processed version of Semen Strychni (SS) powder, is widely used to treat ALS in China. Vomicine is one of the most primary components of SS. However, their pharmacological effects and mechanisms for ALS remain elusive.<br><br>AIM OF THE STUDY: This study aimed to evaluate the neuroprotective and anti-neuroinflammatory effects of SSP and vomicine, as well as to explore their protective roles in ALS and the underlying mechanisms.<br><br>MATERIALS AND METHODS: In vivo, 8-week-old hSOD1-WT mice and hSOD1-G93A mice were orally administered different concentrations of SSP (SSP-L&#xa0;=&#xa0;5.46&#xa0;mg/ml, SSP-M&#xa0;=&#xa0;10.92&#xa0;mg/ml or SSP-H&#xa0;=&#xa0;16.38&#xa0;mg/ml) once every other day for 8 weeks. A series of experiments, including body weight measurement, footprint tests, Hematoxylin &amp; Eosin staining, and Nissl staining, were performed to evaluate the preventive effect of SSP. Immunofluorescence staining, western blotting, and RT-qPCR were subsequently performed to evaluate activation of the cGAS-STING-TBK1 pathway in the spinal cord. In vitro, hSOD1[G93A] NSC-34&#xa0;cells were treated with vomicine to further explore the pharmacological mechanism of vomicine in the treatment of ALS via the cGAS-STING-TBK1 pathway.<br><br>RESULTS: SSP improved motor function, body weight loss, gastrocnemius muscle atrophy, and motor neuron loss in the spine and cortex of hSOD1-G93A mice. Furthermore, the cGAS-STING-TBK1 pathway was activated in the spinal cord of hSOD1-G93A mice, with activation predominantly observed in neurons and microglia. However, the levels of cGAS, STING, and pTBK1 proteins and cGAS, IRF3, IL-6, and IL-1&#x3b2; mRNA were reversed following intervention with SSP. Vomicine not only downregulated the levels of cGAS, TBK1, IL-6 and IFN-&#x3b2; mRNA, but also the levels of cGAS and STING protein in hSOD1[G93A] NSC-34&#xa0;cells.<br><br>CONCLUSION: This study demonstrated that SSP and vomicine exert neuroprotective and anti-neuroinflammatory effects in the treatment of ALS. SSP and vomicine may reduce neuroinflammation by regulating the cGAS-STING-TBK1 pathway, and could thereby play a role in ALS treatment.}, }
@article {pmid39194682, year = {2024}, author = {Sacharczuk, M and Mickael, ME and Kubick, N and Kamińska, A and Horbańczuk, JO and Atanasov, AG and Religa, P and Ławiński, M}, title = {The Current Landscape of Hypotheses Describing the Contribution of CD4+ Heterogeneous Populations to ALS.}, journal = {Current issues in molecular biology}, volume = {46}, number = {8}, pages = {7846-7861}, pmid = {39194682}, issn = {1467-3045}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a poorly understood and fatal disease. It has a low prevalence and a 2-4 year survival period. Various theories and hypotheses relating to its development process have been proposed, albeit with no breakthrough in its treatment. Recently, the role of the adaptive immune system in ALS, particularly CD4+ T cells, has begun to be investigated. CD4+ T cells are a heterogeneous group of immune cells. They include highly pro-inflammatory types such as Th1 and Th17, as well as highly anti-inflammatory cells such as Tregs. However, the landscape of the role of CD4+ T cells in ALS is still not clearly understood. This review covers current hypotheses that elucidate how various CD4+ T cells can contribute to ALS development. These hypotheses include the SWITCH model, which suggests that, in the early stages of the disease, Tregs are highly capable of regulating the immune response. However, in the later stages of the disease, it seems that pro-inflammatory cells such as Th1 and Th17 are capable of overwhelming Treg function. The reason why this occurs is not known. Several research groups have proposed that CD4+ T cells as a whole might experience aging. Others have proposed that gamma delta T cells might directly target Tregs. Additionally, other research groups have argued that less well-known CD4+ T cells, such as Emoes+ CD4+ T cells, may be directly responsible for neuron death by producing granzyme B. We propose that the ALS landscape is highly complicated and that there is more than one feasible hypothesis. However, it is critical to take into consideration the differences in the ability of different populations of CD4+ T cells to infiltrate the blood-brain barrier, taking into account the brain region and the time of infiltration. Shedding more light on these still obscure factors can help to create a personalized therapy capable of regaining the balance of power in the battle between the anti-inflammatory and pro-inflammatory cells in the central nervous system of ALS patients.}, }
@article {pmid39193833, year = {2025}, author = {Jalaiei, A and Asadi, MR and Daneshmandpour, Y and Rezazadeh, M and Ghafouri-Fard, S}, title = {Clinical, molecular, physiologic, and therapeutic feature of patients with CHRNA4 and CHRNB2 deficiency: A systematic review.}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16200}, doi = {10.1111/jnc.16200}, pmid = {39193833}, issn = {1471-4159}, mesh = {Humans ; *Receptors, Nicotinic/genetics ; Mutation/genetics ; Neurodegenerative Diseases/genetics/metabolism ; }, abstract = {The α4β2 nAChRs are crucial ion channels that control neurotransmitter release and play a role in various physiologic and pathologic processes. CHRNA4 encodes the α4-nAChRs, while CHRNB2 encodes the β2-nAChRs. Recent studies have found different variants of α4β2-nAChRs in individuals with conditions such as AD, ADHD, ALS, PD, and brain abnormalities. We conducted a scoping review following a six-stage methodology structure and adhering to PRISMA guidelines. We systematically reviewed articles using relevant keywords up to October 2, 2023. In this summary, we cover the clinical symptoms reported, the genes and protein structure of CHRNA4 and CHRNB2, mutations in these genes, inheritance patterns, the functional impact of mutations and polymorphisms in CHRNA4 and CHRNB2, and the epidemiology of these diseases. Recent research indicates that nAChRs may play a significant role in neurodegenerative disorders, possibly impacting neuronal function through yet undiscovered regulatory pathways. Studying how nAChRs interact with disease-related aggregates in neurodegenerative conditions may lead to new treatment options for these disorders.}, }
@article {pmid39192797, year = {2024}, author = {Luo, RC and Wu, XY and Yu, WW and Zheng, YJ and Wang, D}, title = {[Research progress on the relationship between TRAF6 and neurodegenerative diseases].}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {76}, number = {4}, pages = {653-662}, pmid = {39192797}, issn = {0371-0874}, mesh = {Animals ; Humans ; Alzheimer Disease/metabolism/etiology ; Amyotrophic Lateral Sclerosis/metabolism/physiopathology/genetics/etiology ; Multiple Sclerosis/metabolism/physiopathology/etiology ; *Neurodegenerative Diseases/metabolism/etiology ; Parkinson Disease/metabolism/physiopathology ; *TNF Receptor-Associated Factor 6/metabolism/genetics/physiology ; Ubiquitination ; }, abstract = {Given the increasing trend of aging population in the world, neurodegenerative diseases (NDDs), a common type of diseases that mostly occur in the elderly, have attracted much more attention. It has been shown that tumor necrosis factor receptor-associated factor 6 (TRAF6) is involved in the regulation of neuroinflammation, an important pathological feature of NDDs, and affects the occurrence and development of NDDs. Most importantly, the regulatory effect of TRAF6 is related to its ubiquitination. Therefore, in the present paper, the molecular structure, biological function, and ubiquitination mechanism of TRAF6, and its relationship with some common NDDs, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, were analyzed and summarized. The possible molecular mechanisms by which TRAF6 regulates the occurrence of NDDs were also elucidated, providing a theoretical basis for exploring the etiology and treatment of NDDs.}, }
@article {pmid39190906, year = {2024}, author = {Yu, J and Chen, S and Zhang, H and Zhang, S and Dong, D}, title = {Patterns of the Health and Economic Burden of 33 Rare Diseases in China: Nationwide Web-Based Study.}, journal = {JMIR public health and surveillance}, volume = {10}, number = {}, pages = {e57353}, pmid = {39190906}, issn = {2369-2960}, mesh = {Humans ; China/epidemiology ; *Rare Diseases/epidemiology/economics ; Male ; Adult ; Female ; Cross-Sectional Studies ; Middle Aged ; *Cost of Illness ; Adolescent ; Child ; *Internet ; Child, Preschool ; Young Adult ; Surveys and Questionnaires ; Aged ; Infant ; }, abstract = {BACKGROUND: Rare diseases (RDs) affect millions of individuals collectively worldwide, contributing to significant burdens on patients and families in various aspects. However, there is a lack of evidence on the underlying patterns of burdens among diverse RDs for informing targeted social and health policies to address the unmet needs of this vulnerable population.<br><br>OBJECTIVE: This study aimed to examine the underlying patterns of the health and economic burden of 33 different RDs in China and identify the potential determinants.<br><br>METHODS: A nationwide internet-based cross-sectional survey was conducted in China between 2019 and 2020. Physical and mental health burden was measured by health-related quality of life. Economic burden was evaluated based on the proportions of direct medical, direct nonmedical, and indirect costs relative to household income. We used cluster analysis to identify patterns of health and economic burdens and conducted multinomial logistic regression to explore potential predictors of cluster membership.<br><br>RESULTS: The study included 8454 adults and 8491 children affected by 33 RDs. The following 3 clusters were identified: "extremely high burden" (representing 92/8454, 1.1% and 19/8491, 0.2% of adult and pediatric patients, respectively), "overall high burden" (5933/8454, 70.2% and 4864/8491, 57.3%, respectively), and "overall low burden" (2429/8454, 28.7% and 3608/8491, 42.5%, respectively). Wilson disease, Marfan syndrome, and Langerhans cell histiocytosis more likely resulted in an "extremely high burden" than others. Poverty was significantly associated with being in this extremely high burden group. Diseases causing neuromuscular symptoms and requiring long-term treatment (eg, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Dravet syndrome) were prevalent in the "overall high burden" group. Key predictors of this group included older age, lower socioeconomic status, diagnostic delay, and comorbidity.<br><br>CONCLUSIONS: This study provides novel and valuable evidence on the burden of RDs in developing regions like China. The findings reveal significant disparities in the impact of RDs, emphasizing the need for targeted health care interventions and policies.}, }
@article {pmid39187176, year = {2025}, author = {Althobaiti, NA}, title = {Heavy metals exposure and Alzheimer's disease: Underlying mechanisms and advancing therapeutic approaches.}, journal = {Behavioural brain research}, volume = {476}, number = {}, pages = {115212}, doi = {10.1016/j.bbr.2024.115212}, pmid = {39187176}, issn = {1872-7549}, mesh = {Humans ; *Alzheimer Disease/chemically induced ; *Metals, Heavy/adverse effects ; Animals ; Oxidative Stress/drug effects/physiology ; Environmental Exposure/adverse effects ; Brain/drug effects/metabolism ; }, abstract = {Heavy metals such as lead, cadmium, mercury, and arsenic are prevalent in the environment due to both natural and anthropogenic sources, leading to significant public health concerns. These heavy metals are known to cause damage to the nervous system, potentially leading to a range of neurological conditions including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and attention-deficit hyperactivity disorder (ADHD). The present study examines the complex relationship between heavy metal exposure and AD, focusing on the underlying mechanisms of toxicity and potential therapeutic approaches. This review article highlights how these metals can impair brain function through mechanisms such as oxidative stress, inflammation, and neurotransmitter disruption, ultimately contributing to neurodegenerative diseases like AD. It also addresses the challenges in diagnosing heavy metal-induced cognitive impairments and emphasizes the need for further research to explore effective treatment strategies and preventive measures against heavy metal exposure.}, }
@article {pmid39185360, year = {2024}, author = {Di Lazzaro, V and Ranieri, F and Doretti, A and Boscarino, M and Maderna, L and Colombo, E and Soranna, D and Zambon, A and Ticozzi, N and Musumeci, G and Capone, F and Silani, V}, title = {Transcranial static magnetic stimulation for amyotrophic lateral sclerosis: a bicentric, randomised, double-blind placebo-controlled phase 2 trial.}, journal = {The Lancet regional health. Europe}, volume = {45}, number = {}, pages = {101019}, pmid = {39185360}, issn = {2666-7762}, abstract = {BACKGROUND: Enhanced glutamatergic transmission leading to motor neuron death is considered the major pathophysiological mechanism of amyotrophic lateral sclerosis (ALS). Motor cortex excitability can be suppressed by transcranial static magnetic stimulation (tSMS), thus tSMS can be evaluated as a potential treatment for ALS. The aim of present study was to investigate the efficacy and safety of tSMS in ALS.<br><br>METHODS: In this phase 2 trial, we randomly assigned ALS patients to receive daily tSMS or placebo stimulation over a period of 6 months. For each participant we calculated mean disease monthly progression rate (MPR) as the variation of the total ALS Functional Rating Scale-Revised (ALSRFS-R) score, before the beginning of the treatment (over a period of at least three months) and over the six-month treatment period. The primary efficacy outcome was the difference in MPR before and after the beginning of treatment. Secondary outcomes included safety and tolerability, compliance, and changes in corticospinal output. A long-term follow-up of 18 months was performed in all patients who completed the six-month treatment considering a composite endpoint event (tracheostomy or death). Trial registered at ClinicalTrials.gov, ID: NCT04393467, status: closed.<br><br>FINDINGS: Forty participants were randomly assigned to real (n&#xa0;=&#xa0;21) or placebo stimulation (n&#xa0;=&#xa0;19). Thirty-two participants (18 real and 14 placebo) completed the 6-month treatment. The MPR did not show statistically significant differences between the two arms during the pre-treatment (mean&#xa0;&#xb1;&#xa0;Standard deviation; Real: 1.02&#xa0;&#xb1;&#xa0;0.62, Sham: 1.02&#xa0;&#xb1;&#xa0;0.57, p-value&#xa0;=&#xa0;1.00) and treatment period (Real: 0.90&#xa0;&#xb1;&#xa0;0.55, Sham: 0.94&#xa0;&#xb1;&#xa0;0.55, p-value&#xa0;=&#xa0;0.83). Results for secondary clinical endpoints showed that the treatment is feasible and safe, being compliance with tSMS high. The change in corticospinal output did not differ significantly between the two groups. At the end of the long-term follow-up of 18 months, patients of real group had a statistically significant higher tracheostomy-free survival compared with patients of placebo group (Hazard Ratio&#xa0;=&#xa0;0.27 95% Confidence interval 0.09-0.80, p-value&#xa0;=&#xa0;0.019).<br><br>INTERPRETATION: tSMS did not modify disease progression during the 6 months of treatment. However, long-term follow-up revealed a substantial increase in tracheostomy free survival in patients treated with real stimulation supporting the evaluation of tSMS in larger and more prolonged studies.<br><br>FUNDING: The "Fondazione 'Nicola Irti' per le opere di carit&#xe0; e di cultura", Rome, Italy, supported present study.}, }
@article {pmid39184484, year = {2024}, author = {Ozceylan, O and Sezgin-Bayindir, Z}, title = {Current Overview on the Use of Nanosized Drug Delivery Systems in the Treatment of Neurodegenerative Diseases.}, journal = {ACS omega}, volume = {9}, number = {33}, pages = {35223-35242}, pmid = {39184484}, issn = {2470-1343}, abstract = {Neurodegenerative diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, prion disease, and Huntington's disease, present a growing health concern as human life expectancy increases. Despite this, effective treatments to halt disease progression remain elusive due to various factors, including challenges in drug delivery across physiological barriers like the blood-brain barrier and patient compliance issues leading to treatment discontinuation. In response, innovative treatment approaches leveraging noninvasive techniques with higher patient compliance are emerging as promising alternatives. This Review aims to synthesize current treatment options and the challenges encountered in managing neurodegenerative diseases, while also exploring innovative treatment modalities. Specifically, noninvasive strategies such as intranasal administration and nanosized drug delivery systems are gaining prominence for their potential to enhance treatment efficacy and patient adherence. Nanosized drug delivery systems, including liposomes, polymeric micelles, and nanoparticles, are evaluated within the context of outstanding studies. The advantages and disadvantages of these approaches are discussed, providing insights into their therapeutic potential and limitations. Through this comprehensive examination, this Review contributes to the ongoing discourse surrounding the development of effective treatments for neurodegenerative diseases.}, }
@article {pmid39184100, year = {2024}, author = {Sikirzhytskaya, A and Tyagin, I and Sutton, SS and Wyatt, MD and Safro, I and Shtutman, M}, title = {AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-4750719/v1}, pmid = {39184100}, issn = {2693-5015}, abstract = {Neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing.}, }
@article {pmid39182589, year = {2024}, author = {Pupillo, E and Bianchi, E and Bonetto, V and Pasetto, L and Bendotti, C and Paganoni, S and Mandrioli, J and Mazzini, L and , }, title = {Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis.}, journal = {Brain, behavior, and immunity}, volume = {122}, number = {}, pages = {456-462}, doi = {10.1016/j.bbi.2024.08.044}, pmid = {39182589}, issn = {1090-2139}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology ; Male ; Female ; Middle Aged ; Double-Blind Method ; Vital Capacity ; Aged ; *Disease Progression ; Biomarkers/blood ; Treatment Outcome ; Adult ; Neurofilament Proteins ; }, abstract = {BACKGROUND: Positive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS).<br><br>OBJECTIVE: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation.<br><br>STUDY DESIGN AND SETTINGS: A randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial's last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated.<br><br>RESULTS: Mean duration of follow-up was 2.8&#xa0;years. Long-term median survival was six months longer in the RNS60 group (p&#xa0;=&#xa0;0.0519). Baseline FVC, and rates of FVC decline during the first 4&#xa0;weeks of trial participation, were balanced between the active and placebo treatment arms. After 6&#xa0;months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7&#xa0;years in slow FVC progressors; 1.6&#xa0;years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL - RNS60 group; 3.3&#xa0;years in low NfL - placebo group; 1.9&#xa0;years in high NfL - RNS60 group; 1.8&#xa0;years in high NfL - placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7&#xa0;years in low MCP-1 - RNS60 group; 2.3&#xa0;years in low MCP-1 - placebo group; 2.8&#xa0;years in high MCP-1 - RNS60 group; 2.6&#xa0;years in high MCP-1 - placebo group) levels at baseline.<br><br>CONCLUSIONS AND RELEVANCE: In this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug's effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival.<br><br>TRIAL REGISTRATION: Study preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.}, }
@article {pmid39182251, year = {2024}, author = {Peng, Y and Liu, G and Li, S and Li, Z and Song, J}, title = {A machine learning system for artificial ligaments with desired mechanical properties in ACL reconstruction applications.}, journal = {Journal of the mechanical behavior of biomedical materials}, volume = {159}, number = {}, pages = {106691}, doi = {10.1016/j.jmbbm.2024.106691}, pmid = {39182251}, issn = {1878-0180}, mesh = {*Machine Learning ; *Mechanical Phenomena ; *Anterior Cruciate Ligament Reconstruction/methods ; Materials Testing ; Humans ; Anterior Cruciate Ligament/surgery ; Neural Networks, Computer ; Biomechanical Phenomena ; Ligaments/surgery ; Artificial Organs ; Mechanical Tests ; }, abstract = {The anterior cruciate ligament is one of the important tissues to maintain the stability of the human knee joint, but it is difficult for this ligament to self-heal after injury. Consequently, transplantation of artificial ligaments (ALs) has gained widespread attention as an important alternative treatment method in recent years. However, accurately predicting the intricate mechanical properties of ALs remains a formidable challenge, particularly when employing theoretical frameworks such as braiding theory. This obstacle presents a significant impediment to achieving optimal AL design. Therefore, in this study, a high-precision machine learning model based on an artificial neural network was developed to rapidly and accurately predict the mechanical properties of ALs. The results showed that the proposed model achieved a reduction of 45.22% and 50.17% in the normalized root mean square error on the testing set when compared to traditional machine learning models (Random Forest and Support Vector Machine), demonstrating its higher accuracy. In addition, the design of ALs with desired mechanical properties was achieved by optimizing the braiding parameters, and its effectiveness was verified through experiments. The mechanical properties of the prepared ALs were able to fully meet the desired targets and were at least 2% higher. Finally, the influence weights of different braiding parameters on the mechanical properties of ALs were analyzed by feature importance.}, }
@article {pmid39181624, year = {2024}, author = {Mousele, C and Holden, D and Gnanapavan, S}, title = {Neurofilaments in neurologic disease.}, journal = {Advances in clinical chemistry}, volume = {123}, number = {}, pages = {65-128}, doi = {10.1016/bs.acc.2024.06.010}, pmid = {39181624}, issn = {2162-9471}, mesh = {Humans ; *Nervous System Diseases/pathology/metabolism/diagnosis ; *Biomarkers ; Neurofilament Proteins/cerebrospinal fluid/metabolism ; Intermediate Filaments/metabolism ; Animals ; }, abstract = {Neurofilaments (NFs), major cytoskeletal constituents of neurons, have emerged as universal biomarkers of neuronal injury. Neuroaxonal damage underlies permanent disability in various neurological conditions. It is crucial to accurately quantify and longitudinally monitor this damage to evaluate disease progression, evaluate treatment effectiveness, contribute to novel treatment development, and offer prognostic insights. Neurofilaments show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. New assays with high sensitivity allow reliable measurement of neurofilaments in body fluids and open avenues to investigate their role in neurological disorders. This book chapter will delve into the evolving landscape of neurofilaments, starting with their structure and cellular functions within neurons. It will then provide a comprehensive overview of their broad clinical value as biomarkers in diseases affecting the central or peripheral nervous system.}, }
@article {pmid39180957, year = {2024}, author = {Harkins, AL and Ambegaokar, PP and Keeler, AM}, title = {Immune responses to central nervous system directed adeno-associated virus gene therapy: Does direct CNS delivery make a difference?.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {4}, pages = {e00435}, pmid = {39180957}, issn = {1878-7479}, mesh = {Humans ; *Dependovirus/genetics/immunology ; *Genetic Therapy/methods ; *Genetic Vectors/immunology/administration &amp; dosage ; Animals ; Central Nervous System/immunology ; Gene Transfer Techniques ; Central Nervous System Diseases/therapy/immunology ; }, abstract = {Adeno-associated virus (AAV) mediated gene therapy is a leading gene delivery platform with potential to transform the landscape of treatment for neurological disorders. While AAV is deemed non-immunogenic compared to other viral vectors, adverse immune reactions have been observed in the clinic, raising concerns. As the central nervous system (CNS) has a tightly regulated immune system, characterized by a degree of tolerance, it has been considered a unique target for AAV gene therapy. AAV vectors have shown promising results for the treatment of several CNS disorders including Spinal Muscular Atrophy, Giant Axonal Neuropathy, Amyotrophic Lateral Sclerosis, Tay Sachs Disease, Parkinson's Disease, and others, demonstrating safety and success. The Food and Drug Administration (FDA) approval of Zolgensma and European Medicines Agency (EMA) approval of Upstaza, for Spinal Muscular Atrophy (SMA) and Aromatic l-amino acid decarboxylase deficiency (AADC) respectively, represent this success, all while highlighting significant differences in immune responses to AAV, particularly with regards to therapeutic administration route. AAV therapies like Upstaza that are injected directly into the immune-specialized brain have been characterized by mild immune response profiles and minor adverse events, whereas therapies like Zolgensma that are injected systemically demonstrate more robust immune stimulation and off-target toxicities. Despite these contrasting parallels, these therapeutics and others in the clinic have demonstrated clinical benefit for patients, warranting further exploration of immune responses to CNS-directed AAV clinical trials. Thus, in this review, we discuss effects of different routes of AAV administration on eliciting local and peripheral immune responses specifically observed in CNS-targeted trials.}, }
@article {pmid39180748, year = {2024}, author = {Liu, Z and Zhang, H and Lu, K and Chen, L and Zhang, Y and Xu, Z and Zhou, H and Sun, J and Xu, M and Ouyang, Q and Thompson, GJ and Yang, Y and Su, N and Cai, X and Cao, L and Zhao, Y and Jiang, L and Zheng, Y and Zhang, X}, title = {Low-intensity pulsed ultrasound modulates disease progression in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {Cell reports}, volume = {43}, number = {9}, pages = {114660}, doi = {10.1016/j.celrep.2024.114660}, pmid = {39180748}, issn = {2211-1247}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy/metabolism ; *Disease Models, Animal ; Mice ; *Disease Progression ; *Ultrasonic Waves ; *Mice, Transgenic ; *Motor Cortex/pathology/metabolism ; TRPV Cation Channels/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Cerebrovascular Circulation ; Ultrasonic Therapy/methods ; Mice, Inbred C57BL ; Male ; Endothelial Cells/metabolism ; Motor Neurons/pathology/metabolism ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord, and there are no effective drug treatments. Low-intensity pulsed ultrasound (LIPUS) has garnered attention as a promising noninvasive neuromodulation method. In this study, we investigate its effects on the motor cortex and underlying mechanisms using the SOD1[G93A] mouse model of ALS. Our results show that LIPUS treatment delays disease onset and prolongs lifespan in ALS mice. LIPUS significantly increases cerebral blood flow in the motor cortex by preserving vascular endothelial cell integrity and increasing microvascular density, which may be mediated via the ion channel TRPV4. RNA sequencing analysis reveals that LIPUS substantially reduces the expression of genes associated with neuroinflammation. These findings suggest that LIPUS applied to the motor cortex may represent a potentially effective therapeutic tool for the treatment of ALS.}, }
@article {pmid39180568, year = {2024}, author = {Yang, J and Tang, C}, title = {Causal relationship between imaging-derived phenotypes and neurodegenerative diseases: a Mendelian randomization study.}, journal = {Mammalian genome : official journal of the International Mammalian Genome Society}, volume = {35}, number = {4}, pages = {711-723}, pmid = {39180568}, issn = {1432-1777}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/diagnostic imaging ; *Phenotype ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging ; Alzheimer Disease/genetics/diagnostic imaging ; Frontotemporal Dementia/genetics/diagnostic imaging/pathology ; Parkinson Disease/genetics/diagnostic imaging ; Brain/diagnostic imaging/pathology/metabolism ; Multiple Sclerosis/genetics/diagnostic imaging ; Neuroimaging/methods ; }, abstract = {Neurodegenerative diseases are incurable conditions that lead to gradual and progressive deterioration of brain function in patients. With the aging population, the prevalence of these diseases is expected to increase, posing a significant economic burden on society. Imaging techniques play a crucial role in the diagnosis and monitoring of neurodegenerative diseases. This study utilized a two-sample Mendelian randomization (MR) analysis to assess the causal relationship between different imaging-derived phenotypes (IDP) in the brain and neurodegenerative diseases. Multiple MR methods were employed to minimize bias and obtain reliable estimates of the potential causal relationship between the variable exposures of interest and the outcomes. The study found potential causal relationships between different IDPs and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and frontotemporal dementia (FTD). Specifically, the study identified potential causal relationships between 2 different types of IDPs and AD, 8 different types of IDPs and PD, 11 different types of imaging-derived phenotypes and ALS, 1 type of IDP and MS, and 1 type of IDP and FTD. This study provides new insights for the prevention, diagnosis, and treatment of neurodegenerative diseases, offering important clues for understanding the pathogenesis of these diseases and developing relevant intervention strategies.}, }
@article {pmid39180054, year = {2024}, author = {Spittel, S and Meyer, T and Weyen, U and Grehl, T and Weydt, P and Steinbach, R and Petri, S and Baum, P and Metelmann, M and Sperfeld, AD and Kettemann, D and Norden, J and Rödiger, A and Ilse, B and Grosskreutz, J and Hildebrandt, B and Walter, B and Münch, C and Maier, A}, title = {User expectations and experiences of an assistive robotic arm in amyotrophic lateral sclerosis: a multicenter observational study.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {42}, pmid = {39180054}, issn = {2524-3489}, abstract = {OBJECTIVE: Robotic arms are innovative assistive devices for ALS patients with progressive motor deficits of arms and hands. The objective was to explore the patients´ expectations towards a robotic arm system and to assess the actual experiences after the provision of the device.<br><br>METHODS: A prospective observational study was conducted at 9 ALS centers in Germany. ALS-related functional deficits were assessed using the ALS-Functional Rating Scale-revised (ALSFRS-R). Motor deficit of the upper limbs was determined using a subscore of three arm-related items of the ALSFRS-R (items 4-6; range 0-12 points). User expectations before provision (expectation group, n&#x2009;=&#x2009;85) and user experiences after provision (experience group, n&#x2009;=&#x2009;14) with the device (JACO Assistive Robotic Device, Kinova, Boisbriand, QC, Canada) were assessed.<br><br>RESULTS: In the total cohort, mean ALSFRS-R subscore for arm function was 1.7 (SD: 2.0, 0-9) demonstrating a severe functional deficit of the upper limbs. In the expectation group (n&#x2009;=&#x2009;85), the following use cases of the robotic arm have been prioritized: handling objects (89%), close-body movements (88%), pressing buttons (87%), serving drinks (86%), and opening cabinets and doors (85%). In the experience group (n&#x2009;=&#x2009;14), handling objects (79%), serving drinks (79%), near-body movements (71%), pushing buttons (71%), serving food (64%), and opening doors (64%) were the most frequent used cases. Most patients used the device daily (71.4%, n&#x2009;=&#x2009;10), and 28.6% (n&#x2009;=&#x2009;4) several times a week. All patients of the experience group found the device helpful, felt safe while using the device, and were satisfied with its reliability. NPS of the assistive robotic arm revealed 64% "promoters" (strong recommendation), 29% "indifferents" (uncertain recommendation) and 7% "detractors" (no recommendation). Total NPS was&#x2009;+&#x2009;57 demonstrating strong patient satisfaction.<br><br>CONCLUSIONS: Initiation of procurement with a robotic assistive arm was confined to patients with severe functional deficit of the upper limbs. User experience underlined the wide spectrum of use cases of assistive robotic arms in ALS. The positive user experience together with high satisfaction underscore that robotic arm systems serve as a valuable treatment option in ALS patients with severe motor deficits of the arms.}, }
@article {pmid39177131, year = {2024}, author = {Sheremeta, CL and Yarlagadda, S and Smythe, ML and Noakes, PG}, title = {Prostaglandins in the Inflamed Central Nervous System: Potential Therapeutic Targets.}, journal = {Current drug targets}, volume = {25}, number = {13}, pages = {885-908}, pmid = {39177131}, issn = {1873-5592}, support = {Project grant,//Muscular Dystrophy Association/ ; }, mesh = {Humans ; *Prostaglandins/metabolism ; Animals ; *Central Nervous System/metabolism/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Signal Transduction/drug effects ; Multiple Sclerosis/drug therapy/metabolism ; Inflammation/drug therapy/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Central Nervous System Diseases/drug therapy/metabolism ; }, abstract = {The global burden of neurological disorders is evident, yet there remains limited efficacious therapeutics for their treatment. There is a growing recognition of the role of inflammation in diseases of the central nervous system (CNS); among the numerous inflammatory mediators involved, prostaglandins play a crucial role. Prostaglandins are small lipid mediators derived from arachidonic acid via multi-enzymatic pathways. The actions of prostaglandins are varied, with each prostaglandin having a specific role in maintaining homeostasis. In the CNS, prostaglandins can have neuroprotective or neurotoxic properties depending on their specific G-protein receptor. These G-protein receptors have varying subfamilies, tissue distribution, and signal transduction cascades. Further studies into the impact of prostaglandins in CNS-based diseases may contribute to the clarification of their actions, hopefully leading to the development of efficacious therapeutic strategies. This review focuses on the roles played by prostaglandins in neural degeneration, with a focus on Alzheimer's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis in both preclinical and clinical settings. We further discuss current prostaglandin-related agonists and antagonists concerning suggestions for their use as future therapeutics.}, }
@article {pmid39176177, year = {2024}, author = {Al Dera, H and AlQahtani, B}, title = {Molecular mechanisms and antisense oligonucleotide therapies of familial amyotrophic lateral sclerosis.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {3}, pages = {102271}, pmid = {39176177}, issn = {2162-2531}, abstract = {Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, presents considerable challenges in both diagnosis and treatment. It is categorized into sporadic and familial amyotrophic lateral sclerosis (fALS); the latter accounts for approximately 10% of cases and is primarily inherited in an autosomal dominant manner. This review summarizes the molecular genetics of fALS, highlighting key mutations that contribute to its pathogenesis, such as mutations in SOD1, FUS, and C9orf72. Central to this discourse is exploring antisense oligonucleotides (ASOs) that target these genetic aberrations, providing a promising therapeutic strategy. This review provides a detailed overview of the molecular mechanisms underlying fALS and the potential therapeutic value of ASOs, offering new insights into treating neurodegenerative diseases.}, }
@article {pmid39174305, year = {2025}, author = {Mohamed Yusoff, AA and Mohd Khair, SZN}, title = {Unraveling mitochondrial dysfunction: comprehensive perspectives on its impact on neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {36}, number = {1}, pages = {53-90}, pmid = {39174305}, issn = {2191-0200}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Mitochondria/metabolism ; Animals ; Mitochondrial Dynamics/physiology ; Mitochondrial Diseases/metabolism ; Mitophagy/physiology ; }, abstract = {Neurodegenerative diseases represent a significant challenge to modern medicine, with their complex etiology and progressive nature posing hurdles to effective treatment strategies. Among the various contributing factors, mitochondrial dysfunction has emerged as a pivotal player in the pathogenesis of several neurodegenerative disorders. This review paper provides a comprehensive overview of how mitochondrial impairment contributes to the development of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, driven by bioenergetic defects, biogenesis impairment, alterations in mitochondrial dynamics (such as fusion or fission), disruptions in calcium buffering, lipid metabolism dysregulation and mitophagy dysfunction. It also covers current therapeutic interventions targeting mitochondrial dysfunction in these diseases.}, }
@article {pmid39173710, year = {2025}, author = {Weber, MP and Strobel, RJ and Norman, AV and Kareddy, A and Young, A and Young, S and El Moheb, M and Noona, SWW and Wisniewski, AM and Quader, M and Mazzeffi, M and Yarboro, LT and Teman, NR}, title = {Cardiac Surgical Unit-Advanced Life Support-certified centers are associated with improved failure to rescue after cardiac arrest: A propensity score-matched analysis.}, journal = {The Journal of thoracic and cardiovascular surgery}, volume = {169}, number = {4}, pages = {1271-1281}, doi = {10.1016/j.jtcvs.2024.08.014}, pmid = {39173710}, issn = {1097-685X}, mesh = {Humans ; *Heart Arrest/mortality/therapy ; Female ; Male ; *Propensity Score ; Middle Aged ; Aged ; *Certification ; Retrospective Studies ; Advanced Cardiac Life Support/standards ; Failure to Rescue, Health Care/statistics &amp; numerical data ; Patient Readmission/statistics &amp; numerical data ; Cardiac Surgical Procedures/adverse effects/mortality ; Risk Factors ; Time Factors ; Risk Assessment ; }, abstract = {OBJECTIVE: The impact of Cardiac Surgical Unit-Advanced Life Support (CSU-ALS) training on failure to rescue after cardiac arrest (FTR-CA) is unknown. We hypothesized that institutional CSU-ALS certification would be associated with lower FTR-CA.<br><br>METHODS: Patients undergoing Society of Thoracic Surgeons index operations from 2020 to 2023 from a regional collaborative were analyzed. Each institution was surveyed regarding its status as a CSU-ALS-certified center. Patients stratified by CSU-ALS certification were 1:1 propensity score matched with subsequent multivariable model reviewing associations with FTR-CA.<br><br>RESULTS: A total of 12,209 patients were included in the study period across 15 institutions. Eight centers reported CSU-ALS certification. After propensity score matching, 2 patient cohorts were formed (n&#xa0;=&#xa0;3557). Patients at CSU-ALS centers had greater rates of intensive care unit readmission (3.9% vs 2.3%, P&#xa0;<&#xa0;.01) and total operating room time (340&#xa0;minutes vs 323&#xa0;minutes, P&#xa0;<&#xa0;.01). Hospital readmission was less likely in the CSU-ALS centers (9.0% vs 10.1%, P&#xa0;<&#xa0;.01). There was no difference in the rate of postoperative cardiac arrest (1.8% vs 2.2%, P&#xa0;=&#xa0;.24) or operative mortality (2.5% vs 2.9%, P&#xa0;=&#xa0;.30). After risk adjustment, CSU-ALS centers (odds ratio, 0.30; 95% confidence interval, 0.12-0.72, P&#xa0;<&#xa0;.01) and greater-volume centers (odds ratio, 0.15; confidence interval, 0.03-0.74, P&#xa0;=&#xa0;.02) had reduced odds of FTR-CA.<br><br>CONCLUSIONS: Centers with CSU-ALS certification are associated with a lower risk-adjusted likelihood of FTR-CA. This highlights the importance of well-trained staff and treatment algorithms in the care of patients postcardiac surgery.}, }
@article {pmid39170988, year = {2024}, author = {Baroni, LM and Funari, MP and So Taa Kum, A and Bestetti, AM and de Oliveira, LB and de Carvalho, MF and Franzini, TAP and de Moura, DTH and Bernardo, WM and de Moura, EGH}, title = {Endoscopic Versus Surgical Treatment for Ampullary Lesions: A Systematic Review With Meta-Analysis.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e65076}, pmid = {39170988}, issn = {2168-8184}, abstract = {Ampullary lesions (ALs) can be treated through either an endoscopic approach (EA) or a surgical approach (SA). However, it is important to note that EAs carry a significant risk of incomplete resection, while opting for surgical interventions can result in substantial morbidity. We performed a systematic review and meta-analysis for R0 resection, recurrence, adverse events in general, major adverse events, mortality, and length of hospital stay between SAs and EAs. Electronic databases were searched from inception to 2023. We identified nine independent studies. The risk difference was -0.32 (95% CI: -0.50, -0.15; p <0.001) for R0, 0.12 (95% CI: 0.06, 0.19; p < 0.001) for recurrence, -0.22 (95% CI: -0.43, 0.00; p 0.05) for overall adverse events, -0.11 (95% CI: -0.32, 0.10; p = 0.31) for major complications, -0.01 (95% CI: -0.02, 0.01; p = 0.43) for mortality, and -14.69 (95% CI: -19.91, -9.47; p < 0.001) for length of hospital stay. As expected, our data suggest a higher complete resection rate and lower recurrence from surgical interventions, but this is associated with an elevated risk of adverse events and a longer hospital stay.}, }
@article {pmid39170265, year = {2024}, author = {Pain, O and Jones, A and Al Khleifat, A and Agarwal, D and Hramyka, D and Karoui, H and Kubica, J and Llewellyn, DJ and Ranson, JM and Yao, Z and Iacoangeli, A and Al-Chalabi, A}, title = {Harnessing transcriptomic signals for amyotrophic lateral sclerosis to identify novel drugs and enhance risk prediction.}, journal = {Heliyon}, volume = {10}, number = {15}, pages = {e35342}, pmid = {39170265}, issn = {2405-8440}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. This study integrates common genetic association results from the latest ALS genome-wide association study (GWAS) summary statistics with functional genomic annotations with the aim of providing mechanistic insights into ALS risk loci, inferring drug repurposing opportunities, and enhancing prediction of ALS risk and clinical characteristics.<br><br>METHODS: Genes associated with ALS were identified using GWAS summary statistic methodology including SuSiE SNP-based fine-mapping, and transcriptome- and proteome-wide association study (TWAS/PWAS) analyses. Using several approaches, gene associations were integrated with the DrugTargetor drug-gene interaction database to identify drugs that could be repurposed for the treatment of ALS. Furthermore, ALS gene associations from TWAS were combined with observed blood expression in two external ALS case-control datasets to calculate polytranscriptomic scores and evaluate their utility for prediction of ALS risk and clinical characteristics, including site of onset, age at onset, and survival.<br><br>RESULTS: SNP-based fine-mapping, TWAS and PWAS identified 118 genes associated with ALS, with TWAS and PWAS providing novel mechanistic insights. Drug repurposing analyses identified six drugs significantly enriched for interactions with ALS associated genes, though directionality could not be determined. Additionally, drug class enrichment analysis showed gene signatures linked to calcium channel blockers may reduce ALS risk, whereas antiepileptic drugs may increase ALS risk. Across the two observed expression target samples, ALS polytranscriptomic scores significantly predicted ALS risk (R [2]&#xa0;=&#xa0;5.1&#xa0;%; p-value&#xa0;=&#xa0;3.2&#xa0;&#xd7;&#xa0;10[-27]) and clinical characteristics.<br><br>CONCLUSIONS: Functionally-informed analyses of ALS GWAS summary statistics identified novel mechanistic insights into ALS aetiology, highlighted several therapeutic research avenues, and enabled statistically significant prediction of ALS risk.}, }
@article {pmid39168358, year = {2024}, author = {Ueno, Y and Morishima, Y and Hata, T and Shindo, A and Murata, H and Saito, T and Nakamura, Y and Shindo, K}, title = {Current progress in microRNA profiling of circulating extracellular vesicles in amyotrophic lateral sclerosis: A systematic review.}, journal = {Neurobiology of disease}, volume = {200}, number = {}, pages = {106639}, doi = {10.1016/j.nbd.2024.106639}, pmid = {39168358}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/diagnosis ; Biomarkers/blood ; *Extracellular Vesicles/metabolism/genetics ; *MicroRNAs/blood/genetics ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons, leading to death resulting mainly from respiratory failure, for which there is currently no curative treatment. Underlying pathological mechanisms for the development of ALS are diverse and have yet to be elucidated. Non-invasive testing to isolate circulating molecules including microRNA to diagnose ALS has been reported, but circulating extracellular vesicle (EV)-derived microRNA has not been fully studied in the ALS population.<br><br>METHODS: A systematic literature review to explore studies investigating the profile of microRNAs in EVs from blood samples of ALS patients was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline.<br><br>RESULTS: Eleven studies including a total of 263 patients with ALS were included in the present systematic review. The majority of patients had sporadic ALS, though a small number of patients with ALS having genetic mutations were included. Seven studies used plasma-derived EVs, and the remaining four studies used serum-derived EVs. RNA sequencing or microarrays were used in eight studies, and quantitative PCR was used in eight studies, of which five studies used RNA sequencing or microarrays for screening and quantitative PCR for validation. There was overlap of miR-199a-3p and miR-199a-5p in three studies.<br><br>CONCLUSIONS: Overall, the systematic review addressed the current advances in the profiling of microRNAs in circulating EVs of ALS patients. Blood samples, isolation of EVs, and microRNA analysis were diverse. Although there was an overlap of miR-199a-3p and miR-199a-5p, collection of further evidence is warranted.}, }
@article {pmid39162129, year = {2024}, author = {Mazzini, L and De Marchi, F and Buzanska, L and Follenzi, A and Glover, JC and Gelati, M and Lombardi, I and Maioli, M and Mesa-Herrera, F and Mitrečić, D and Olgasi, C and Pivoriūnas, A and Sanchez-Pernaute, R and Sgromo, C and Zychowicz, M and Vescovi, A and Ferrari, D}, title = {Current status and new avenues of stem cell-based preclinical and therapeutic approaches in amyotrophic lateral sclerosis.}, journal = {Expert opinion on biological therapy}, volume = {24}, number = {9}, pages = {933-954}, doi = {10.1080/14712598.2024.2392307}, pmid = {39162129}, issn = {1744-7682}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; Animals ; *Stem Cell Transplantation ; Disease Models, Animal ; Clinical Trials as Topic ; }, abstract = {INTRODUCTION: Cell therapy development represents a critical challenge in amyotrophic lateral sclerosis (ALS) research. Despite more than 20 years of basic and clinical research, no definitive safety and efficacy results of cell-based therapies for ALS have been published.<br><br>AREAS COVERED: This review summarizes advances using stem cells (SCs) in pre-clinical studies to promote clinical translation and in clinical trials to treat ALS. New technologies have been developed and new experimental in vitro and animal models are now available to facilitate pre-clinical research in this field and to determine the most promising approaches to pursue in patients. New clinical trial designs aimed at developing personalized SC-based treatment with biological endpoints are being defined.<br><br>EXPERT OPINION: Knowledge of the basic biology of ALS and on the use of SCs to study and potentially treat ALS continues to grow. However, a consensus has yet to emerge on how best to translate these results into therapeutic applications. The selection and follow-up of patients should be based on clinical, biological, and molecular criteria. Planning of SC-based clinical trials should be coordinated with patient profiling genetically and molecularly to achieve personalized treatment. Much work within basic and clinical research is still needed to successfully transition SC therapy in ALS.}, }
@article {pmid39156432, year = {2024}, author = {Kaye, AD and Sala, KR and Dethloff, D and Norton, M and Moss, C and Plessala, MJ and Derouen, AG and Lopez Torres, Y and Kim, J and Tirumala, S and Shekoohi, S and Varrassi, G}, title = {The Evolving Use of Gold Nanoparticles as a Possible Reversal Agent for the Symptoms of Neurodegenerative Diseases: A Narrative Review.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64846}, pmid = {39156432}, issn = {2168-8184}, abstract = {Neurodegenerative diseases are broadly hallmarked by impaired energy metabolism and toxic intracellular accumulations such as damaged organelles or reactive oxygen species (ROS). Gold nanoparticles readily cross the blood-brain barrier and increase nicotinamide adenine dinucleotide + hydrogen (NADH) oxidation to nicotinamide adenine dinucleotide (NAD+), which is vital for intracellular energy generation, cellular repair, and protection from ROS. Thus, the use of gold nanoparticles to treat and potentially reverse cellular injury seen in neurodegenerative disease has been an area of ongoing research. This systematic review explores current literature regarding the use of gold nanoparticle therapy in the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). In vitro studies of CNM-Au8 (Clene Nanomedicine, Salt Lake City, UT) have been shown to reduce TDP-43 aggregates associated with ALS. These studies also exhibited the neuroprotective effects of CNM-Au8 in rat primary neurons exposed to amyloid-beta peptides, which are associated with Alzheimer's disease. In animal models of MS, oral delivery of CNM-Au8 was demonstrated to produce robust and significant remyelination activity, oligodendrocyte maturation, and expression of myelin markers. In these same MS animal models, CNM-Au8 improved the motor function of cuprizone-treated mice in both open-field and kinematic gait studies. Recent phase II trials of CNM-Au8 in 13 patients with Parkinson's disease and 11 patients with stable relapsing MS demonstrated a statistically significant increase in the NAD+/NADH ratio across two cohorts. As the current data repeatedly suggest, these gold nanoparticles are efficacious for the treatment and reversal of symptoms across these varying neurodegenerative pathologies. Further opportunities exist for increasing human trials and eventually incorporating this new technology into existing treatment regimens.}, }
@article {pmid39154890, year = {2024}, author = {Brebner, C and Asamoah-Boaheng, M and Zaidel, B and Yap, J and Scheuermeyer, F and Mok, V and Hutton, J and Meckler, G and Schlamp, R and Christenson, J and Grunau, B}, title = {The association of intravenous vs. humeral-intraosseous vascular access with patient outcomes in adult out-of-hospital cardiac arrests.}, journal = {Resuscitation}, volume = {202}, number = {}, pages = {110360}, doi = {10.1016/j.resuscitation.2024.110360}, pmid = {39154890}, issn = {1873-1570}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; *Infusions, Intraosseous/methods ; Middle Aged ; *Cardiopulmonary Resuscitation/methods ; *Registries ; Aged ; Humerus ; Emergency Medical Services/methods ; Treatment Outcome ; Adult ; Propensity Score ; }, abstract = {AIM: While intravenous (IV) vascular access for out-of-hospital cardiac arrest (OHCA) resuscitation is standard, humeral-intraosseous (IO) access is commonly used, despite few supporting data. We investigated the association between IV vs. humeral-IO and outcomes.<br><br>METHODS: We utilized BC Cardiac Arrest Registry data, including adult OHCA where the first-attempted intra-arrest vascular access route performed by advanced life support (ALS)-trained paramedics was IV or humeral-IO. We fit a propensity-score adjusted model with inverse probability treatment weighting to estimate the association between IV vs. humeral-IO routes and favorable neurological outcomes (CPC 1-2) and survival at hospital discharge. We repeated models within subgroups defined by initial cardiac rhythm.<br><br>RESULTS: We included 2,112 cases; the first-attempted route was IV (n&#xa0;=&#xa0;1,575) or humeral-IO (n&#xa0;=&#xa0;537). Time intervals from ALS-paramedic on-scene arrival to vascular access (6.6 vs. 6.9&#xa0;min) and epinephrine administration (9.0 vs. 9.3&#xa0;min) were similar between IV and IO groups, respectively. Among IV and humeral-IO groups, 98 (6.2%) and 20 (3.7%) had favorable neurological outcomes. Compared to humeral-IO, an IV-first approach was associated with improved hospital-discharge favorable neurological outcomes (AOR 1.7; 95% CI 1.1-2.7) and survival (AOR 1.5; 95% CI 1.0-2.3). Among shockable rhythm cases, an IV-first approach was associated with improved favorable neurological outcomes (AOR 4.2; 95% CI 2.1-8.2), but not among non-shockable rhythm cases (AOR 0.73; 95% CI 0.39-1.4).<br><br>CONCLUSION: An IV-first approach, compared to humeral-IO, for intra-arrest resuscitation was associated with an improved odds of favorable neurological outcomes and survival to hospital discharge. This association was seen among an initial shockable rhythm, but not non-shockable rhythm, subgroups.}, }
@article {pmid39154745, year = {2024}, author = {Vu, D and Park, M and Alhusayen, R}, title = {Response to Chawla et al, "Response to Vu et al's "Efficacy of moxifloxacin as a mono-antibiotic therapy for hidradenitis suppurativa: A retrospective cohort study"".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {6}, pages = {e177-e178}, doi = {10.1016/j.jaad.2024.08.013}, pmid = {39154745}, issn = {1097-6787}, }
@article {pmid39153378, year = {2024}, author = {Maramai, S and Saletti, M and Paolino, M and Giuliani, G and Cazzola, J and Spaiardi, P and Talpo, F and Frosini, M and Pifferi, A and Ballarotto, M and Carotti, A and Poggialini, F and Vagaggini, C and Dreassi, E and Giorgi, G and Dondio, G and Cappelli, A and Rosario Biella, G and Anzini, M}, title = {Novel multitarget directed ligands inspired by riluzole: A serendipitous synthesis of substituted benzo[b][1,4]thiazepines potentially useful as neuroprotective agents.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {112}, number = {}, pages = {117872}, doi = {10.1016/j.bmc.2024.117872}, pmid = {39153378}, issn = {1464-3391}, mesh = {Animals ; Humans ; Dose-Response Relationship, Drug ; Ligands ; Molecular Structure ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; *Riluzole/pharmacology/chemical synthesis/chemistry ; Structure-Activity Relationship ; Thiazepines/chemical synthesis/chemistry/pharmacology ; }, abstract = {Riluzole, the first clinically approved treatment for amyotrophic lateral sclerosis (ALS), represents a successful example of a drug endowed with a multimodal mechanism of action. In recent years, different series of riluzole-based compounds have been reported, including several agents acting as Multi-Target-Directed Ligands (MTLDs) endowed with neuroprotective effects. Aiming at identical twin structures inspired by riluzole (2a-c), a synthetic procedure was planned, but the reactivity of the system took a different path, leading to the serendipitous isolation of benzo[b][1,4]thiazepines 3a-c and expanded intermediates N-cyano-benzo[b][1,4]thiazepines 4a-c, which were fully characterized. The newly obtained structures 3a-c, bearing riluzole key elements, were initially tested in an in vitro ischemia/reperfusion injury protocol, simulating the cerebral stroke. Results identified compound 3b as the most effective in reverting the injury caused by an ischemia-like condition, and its activity was comparable, or even higher than that of riluzole, exhibiting a concentration-dependent neuroprotective effect. Moreover, derivative 3b completely reverted the release of Lactate Dehydrogenase (LDH), lowering the values to those of the control slices. Based on its very promising pharmacological properties, compound 3b was then selected to assess its effects on voltage-dependent Na[+] and K[+] currents. The results indicated that derivative 3b induced a multifaceted inhibitory effect on voltage-gated currents in SH-SY5Y differentiated neurons, suggesting its possible applications in epilepsy and stroke management, other than ALS. Accordingly, brain penetration was also measured for 3b, as it represents an elegant example of a MTDL and opens the way to further ex-vivo and/or in-vivo characterization.}, }
@article {pmid39153346, year = {2025}, author = {Khazaei, K and Roshandel, P and Parastar, H}, title = {Visible-short wavelength near infrared hyperspectral imaging coupled with multivariate curve resolution-alternating least squares for diagnosis of breast cancer.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {324}, number = {}, pages = {124966}, doi = {10.1016/j.saa.2024.124966}, pmid = {39153346}, issn = {1873-3557}, mesh = {Humans ; Female ; *Breast Neoplasms/diagnosis ; Least-Squares Analysis ; *Principal Component Analysis ; *Spectroscopy, Near-Infrared/methods ; *Hyperspectral Imaging/methods ; Multivariate Analysis ; Discriminant Analysis ; }, abstract = {This study investigates the application of visible-short wavelength near-infrared hyperspectral imaging (Vis-SWNIR HSI) in the wavelength range of 400-950 nm and advanced chemometric techniques for diagnosing breast cancer (BC). The research involved 56 ex-vivo samples encompassing both cancerous and non-cancerous breast tissue from females. First, HSI images were analyzed using multivariate curve resolution-alternating least squares (MCR-ALS) to exploit pure spatial and spectral profiles of active components. Then, the MCR-ALS resolved spatial profiles were arranged in a new data matrix for exploration and discrimination between benign and cancerous tissue samples using principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA). The PLS-DA classification accuracy of 82.1 % showed the potential of HSI and chemometrics for non-invasive detection of BC. Additionally, the resolved spectral profiles by MCR-ALS can be used to track the changes in the breast tissue during cancer and treatment. It is concluded that the proposed strategy in this work can effectively differentiate between cancerous and non-cancerous breast tissue and pave the way for further studies and potential clinical implementation of this innovative approach, offering a promising avenue for improving early detection and treatment outcomes in BC patients.}, }
@article {pmid39147172, year = {2024}, author = {Acton, S and O'Donnell, MM and Periyasamy, K and Dixit, B and Eishingdrelo, H and Hill, C and Paul Ross, R and Chesnel, L}, title = {LPA3 agonist-producing Bacillus velezensis ADS024 is efficacious in multiple neuroinflammatory disease models.}, journal = {Brain, behavior, and immunity}, volume = {121}, number = {}, pages = {384-402}, doi = {10.1016/j.bbi.2024.08.024}, pmid = {39147172}, issn = {1090-2139}, mesh = {*Bacillus/metabolism ; Animals ; Mice ; Humans ; *Neuroinflammatory Diseases/metabolism ; Disease Models, Animal ; Mice, Inbred C57BL ; Multiple Sclerosis/metabolism ; Male ; Encephalomyelitis, Autoimmune, Experimental/metabolism ; Anti-Inflammatory Agents/pharmacology ; }, abstract = {Neuroinflammation is a common component of neurological disorders. In the gut-brain-immune axis, bacteria and their metabolites are now thought to play a role in the modulation of the nervous and immune systems which may impact neuroinflammation. In this respect, commensal bacteria of humans have recently been shown to produce metabolites that mimic endogenous G-protein coupled receptor (GPCR) ligands. To date, it has not been established whether plant commensal bacteria, which may be ingested by animals including humans, can impact the gut-brain-immune axis via GPCR agonism. We screened an isopropanol (IPA) extract of the plant commensal Bacillus velezensis ADS024, a non-engrafting live biotherapeutic product (LBP) with anti-inflammatory properties isolated from human feces, against a panel of 168 GPCRs and identified strong agonism of the lysophosphatidic acid (LPA) receptor LPA3. The ADS024 IPA extracted material (ADS024-IPA) did not agonize LPA2, and only very weakly agonized LPA1. The agonism of LPA3 was inhibited by the reversible LPA1/3 antagonist Ki16425. ADS024-IPA signaled downstream of LPA3 through G-protein-induced calcium release, recruitment of β-arrestin, and recruitment of the neurodegeneration-associated proteins 14-3-3γ, ε and ζ but did not recruit the β isoform. Since LPA3 agonism was previously indirectly implicated in the reduction of pathology in models of Parkinson's disease (PD) and multiple sclerosis (MS) by use of the nonselective antagonist Ki16425, and since we identified an LPA3-specific agonist within ADS024, we sought to examine whether LPA3 might indeed be part of a broad underlying mechanism to control neuroinflammation. We tested oral treatment of ADS024 in multiple models of neuroinflammatory diseases using three models of PD, two models of MS, and a model each of amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and chemo-induced peripheral neuropathy (CIPN). ADS024 treatment improved model-specific functional effects including improvements in motor movement, breathing and swallowing, and allodynia suggesting that ADS024 treatment impacted a universal underlying neuroinflammatory mechanism regardless of the initiating cause of disease. We used the MOG-EAE mouse model to examine early events after disease initiation and found that ADS024 attenuated the increase in circulating lymphocytes and changes in neutrophil subtypes, and ADS024 attenuated the early loss of cell-surface LPA3 receptor expression on circulating white blood cells. ADS024 efficacy was partially inhibited by Ki16425 in vivo suggesting LPA3 may be part of its mechanism. Altogether, these data suggest that ADS024 and its LPA3 agonism activity should be investigated further as a possible treatment for diseases with a neuroinflammatory component.}, }
@article {pmid39145609, year = {2024}, author = {Adil, O and Adeyeye, C and Shamsi, MH}, title = {Electrografted Laser-Induced Graphene: Direct Detection of Neurodegenerative Disease Biomarker in Cerebrospinal Fluid.}, journal = {ACS sensors}, volume = {9}, number = {9}, pages = {4748-4757}, doi = {10.1021/acssensors.4c01150}, pmid = {39145609}, issn = {2379-3694}, mesh = {*Graphite/chemistry ; Humans ; *Biomarkers/cerebrospinal fluid ; *Electrochemical Techniques/methods ; *Lasers ; Immunoassay/methods ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Electrodes ; Neurodegenerative Diseases/cerebrospinal fluid/diagnosis ; Limit of Detection ; Biosensing Techniques/methods ; }, abstract = {There are more than 50 neurodegenerative disorders, and amyotrophic lateral sclerosis (ALS) is one of the most common disorders that poses diagnostic and treatment challenges. The poly glycine-proline (polyGP) dipeptide repeat is a toxic protein that has been recognized as a pharmacodynamic biomarker of C9orf72-associated (c9+) ALS, a subtype of ALS that originates from genetic mutation. Early detection of polyGP will help healthcare providers start timely gene therapy. Herein, we developed a label-free electrochemical immunoassay for the simple detection of polyGP in unprocessed cerebrospinal fluid (CSF) samples collected from ALS patients in the National ALS Biorepository. For the first time, an electrografted laser-induced graphene (E-LIG) electrode system was employed in a sandwich format to detect polyGP using a label-free electrochemical impedance technique. The results show that the E-LIG-modified surface exhibited high sensitivity and selectivity in buffer and CSF media with limit of detection values of 0.19 and 0.27 ng/mL, respectively. The precision of the calibration model was better in CSF than in the buffer. The E-LIG immunosensor can easily select polyGP targets in the presence of other dipeptide proteins translated from the c9 gene. Further study with CSF samples from ALS patients demonstrated that the label-free E-LIG-based immunosensor not only quantified polyGP in the complex CSF matrix but also distinguished between c9+ and non-c9- ALS patients.}, }
@article {pmid39144569, year = {2024}, author = {Choudhury, C and Egleton, JE and Butcher, NJ and Russell, AJ and Minchin, RF}, title = {Small Molecule Inhibitors of Arylamine N-Acetyltransferase 1 Attenuate Cellular Respiration.}, journal = {ACS pharmacology &amp; translational science}, volume = {7}, number = {8}, pages = {2326-2332}, pmid = {39144569}, issn = {2575-9108}, abstract = {Arylamine N-acetyltransferase 1 (NAT1) expression has been shown to attenuate mitochondrial function, suggesting it is a promising drug target in diseases of mitochondrial dysfunction. Here, several second-generation naphthoquinones have been investigated as small molecule inhibitors of NAT1. The results show that the compounds inhibit both in vitro and in whole cells. A lead compound (Cmp350) was further investigated for its ability to alter mitochondrial metabolism in MDA-MB-231 cells. At concentrations that inhibited NAT1 by over 85%, no overt toxicity was observed. Moreover, the inhibitor decreased basal respiration and reserve respiratory capacity without affecting ATP production. Cells treated with Cmp350 were almost exclusively dependent on glucose as a fuel source. We postulate that Cmp350 is an excellent lead compound for the development of NAT1-targeted inhibitors as both experimental tools and therapeutics in the treatment of hypermetabolic diseases such as amyotrophic lateral sclerosis, cancer cachexia, and sepsis.}, }
@article {pmid39141064, year = {2024}, author = {Wiesenfarth, M and Forouhideh-Wiesenfarth, Y and Elmas, Z and Parlak, &#xd6; and Weiland, U and Herrmann, C and Schuster, J and Freischmidt, A and Müller, K and Siebert, R and Günther, K and Fröhlich, E and Knehr, A and Simak, T and Bachhuber, F and Regensburger, M and Petri, S and Klopstock, T and Reilich, P and Schöberl, F and Schumann, P and Körtvélyessy, P and Meyer, T and Ruf, WP and Witzel, S and Tumani, H and Brenner, D and Dorst, J and Ludolph, AC}, title = {Clinical characterization of common pathogenic variants of SOD1-ALS in Germany.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6667-6679}, pmid = {39141064}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Superoxide Dismutase-1/genetics ; Male ; Female ; Germany ; Middle Aged ; Aged ; *Disease Progression ; Mutation ; Adult ; Phenotype ; }, abstract = {Pathogenic variants in the Cu/Zn superoxide dismutase (SOD1) gene can be detected in approximately 2% of sporadic and 11% of familial amyotrophic lateral sclerosis (ALS) patients in Europe. We analyzed the clinical phenotypes of 83 SOD1-ALS patients focusing on patients carrying the most frequent (likely) pathogenic variants (R116G, D91A, L145F) in Germany. Moreover, we describe the effect of tofersen treatment on ten patients carrying these variants. R116G patients showed the most aggressive course of disease with a median survival of 22.0 months compared to 198.0 months in D91A and 87.0 months in L145F patients (HR 7.71, 95% CI 2.89-20.58 vs. D91A; p < 0.001 and HR 4.25, 95% CI 1.55-11.67 vs. L145F; p = 0.02). Moreover, R116G patients had the fastest median ALSFRS-R progression rate with 0.12 (IQR 0.07-0.20) points lost per month. Median diagnostic delay was 10.0 months (IQR 5.5-11.5) and therefore shorter compared to 57.5 months (IQR 14.0-83.0) in D91A (p < 0.001) and 21.5 months (IQR 5.8-38.8) in L145F (p = 0.21) carriers. As opposed to D91A carriers (50.0%), 96.2% of R116G (p < 0.001) and 100.0% of L145F (p = 0.04) patients reported a positive family history. During tofersen treatment, all patients showed a reduction of neurofilament light chain (NfL) serum levels, independent of the SOD1 variant. Patients with SOD1-ALS carrying R116G, D91A, or L145F variants show commonalities, but also differences in their clinical phenotype, including a faster progression rate with shorter survival in R116G, and a comparatively benign disease course in D91A carriers.}, }
@article {pmid39139642, year = {2024}, author = {Liu, X and Li, Y and Huang, L and Kuang, Y and Wu, X and Ma, X and Zhao, B and Lan, J}, title = {Unlocking the therapeutic potential of P2X7 receptor: a comprehensive review of its role in neurodegenerative disorders.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1450704}, pmid = {39139642}, issn = {1663-9812}, abstract = {The P2X7 receptor (P2X7R), an ATP-gated ion channel, has emerged as a crucial player in neuroinflammation and a promising therapeutic target for neurodegenerative disorders. This review explores the current understanding of P2X7R's structure, activation, and physiological roles, focusing on its expression and function in microglial cells. The article examines the receptor's involvement in calcium signaling, microglial activation, and polarization, as well as its role in the pathogenesis of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. The review highlights the complex nature of P2X7R signaling, discussing its potential neuroprotective and neurotoxic effects depending on the disease stage and context. It also addresses the development of P2X7R antagonists and their progress in clinical trials, identifying key research gaps and future perspectives for P2X7R-targeted therapy development. By providing a comprehensive overview of the current state of knowledge and future directions, this review serves as a valuable resource for researchers and clinicians interested in exploring the therapeutic potential of targeting P2X7R for the treatment of neurodegenerative disorders.}, }
@article {pmid39138578, year = {2024}, author = {Wasielewska, JM and Chaves, JCS and Cabral-da-Silva, MC and Pecoraro, M and Viljoen, SJ and Nguyen, TH and Bella, V and Oikari, LE and Ooi, L and White, AR}, title = {A patient-derived amyotrophic lateral sclerosis blood-brain barrier model for focused ultrasound-mediated anti-TDP-43 antibody delivery.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {65}, pmid = {39138578}, issn = {2045-8118}, support = {PhD Scholarship//University of Queensland/ ; PhD Top-Up Scholarship//QIMR Berghofer Medical Research Institute/ ; APP1125796 and 1118452//National Health and Medical Research Council/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; *Microbubbles ; *DNA-Binding Proteins/metabolism ; Drug Delivery Systems/methods ; Endothelial Cells/metabolism ; Antibodies/administration &amp; dosage ; Ultrasonic Waves ; Cells, Cultured ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with minimally effective treatment options. An important hurdle in ALS drug development is the non-invasive therapeutic access to the motor cortex currently limited by the presence of the blood-brain barrier (BBB). Focused ultrasound and microbubble (FUS[+ MB]) treatment is an emerging technology that was successfully used in ALS patients to temporarily open the cortical BBB. However, FUS[+ MB]-mediated drug delivery across ALS patients' BBB has not yet been reported. Similarly, the effects of FUS[+ MB] on human ALS BBB cells remain unexplored.<br><br>METHODS: Here we established the first FUS[+&#x2009;MB]-compatible, fully-human ALS patient-cell-derived BBB model based on induced brain endothelial-like cells (iBECs) to study anti-TDP-43 antibody delivery and FUS[+&#x2009;MB] bioeffects in vitro.<br><br>RESULTS: Generated ALS iBECs recapitulated disease-specific hallmarks of BBB pathology, including reduced BBB integrity and permeability, and TDP-43 proteinopathy. The results also identified differences between sporadic ALS and familial (C9orf72 expansion carrying) ALS iBECs reflecting patient heterogeneity associated with disease subgroups. Studies in these models revealed successful ALS iBEC monolayer opening in vitro with no adverse cellular effects of FUS[+&#x2009;MB] as reflected by lactate dehydrogenase (LDH) release viability assay and the lack of visible monolayer damage or morphology change in FUS[+&#x2009;MB] treated cells. This was accompanied by the molecular bioeffects of FUS[+&#x2009;MB] in ALS iBECs including changes in expression of tight and adherens junction markers, and drug transporter and inflammatory mediators, with sporadic and C9orf72 ALS iBECs generating transient specific responses. Additionally, we demonstrated an effective increase in the delivery of anti-TDP-43 antibody with FUS[+&#x2009;MB] in C9orf72 (2.7-fold) and sporadic (1.9-fold) ALS iBECs providing the first proof-of-concept evidence that FUS[+&#x2009;MB] can be used to enhance the permeability of large molecule therapeutics across the BBB in a human ALS in vitro model.<br><br>CONCLUSIONS: Together, this study describes the first characterisation of cellular and molecular responses of ALS iBECs to FUS[+&#x2009;MB] and provides a fully-human platform for FUS[+&#x2009;MB]-mediated drug delivery screening on an ALS BBB in vitro model.}, }
@article {pmid39135084, year = {2024}, author = {Ma, H and Zhu, M and Chen, M and Li, X and Feng, X}, title = {The role of macrophage plasticity in neurodegenerative diseases.}, journal = {Biomarker research}, volume = {12}, number = {1}, pages = {81}, pmid = {39135084}, issn = {2050-7771}, support = {PX2023037//Beijing Municipal Administration of Hospitals Incubating Program/ ; }, abstract = {Tissue-resident macrophages and recruited macrophages play pivotal roles in innate immunity and the maintenance of brain homeostasis. Investigating the involvement of these macrophage populations in eliciting pathological changes associated with neurodegenerative diseases has been a focal point of research. Dysregulated states of macrophages can compromise clearance mechanisms for pathological proteins such as amyloid-β (Aβ) in Alzheimer's disease (AD) and TDP-43 in Amyotrophic lateral sclerosis (ALS). Additionally, recent evidence suggests that abnormalities in the peripheral clearance of pathological proteins are implicated in the pathogenesis and progression of neurodegenerative diseases. Furthermore, numerous genome-wide association studies have linked genetic risk factors, which alter the functionality of various immune cells, to the accumulation of pathological proteins. This review aims to unravel the intricacies of macrophage biology in both homeostatic conditions and neurodegenerative disorders. To this end, we initially provide an overview of the modifications in receptor and gene expression observed in diverse macrophage subsets throughout development. Subsequently, we outlined the roles of resident macrophages and recruited macrophages in neurodegenerative diseases and the progress of targeted therapy. Finally, we describe the latest advances in macrophage imaging methods and measurement of inflammation, which may provide information and related treatment strategies that hold promise for informing the design of future investigations and therapeutic interventions.}, }
@article {pmid39134696, year = {2024}, author = {Visser, BS and Lipiński, WP and Spruijt, E}, title = {The role of biomolecular condensates in protein aggregation.}, journal = {Nature reviews. Chemistry}, volume = {8}, number = {9}, pages = {686-700}, pmid = {39134696}, issn = {2397-3358}, mesh = {Humans ; *Biomolecular Condensates/metabolism/chemistry ; *Protein Aggregates ; Neurodegenerative Diseases/metabolism ; Amyloid/metabolism/chemistry ; Protein Aggregation, Pathological/metabolism ; Proteins/chemistry/metabolism ; }, abstract = {There is an increasing amount of evidence that biomolecular condensates are linked to neurodegenerative diseases associated with protein aggregation, such as Alzheimer's disease and amyotrophic lateral sclerosis, although the mechanisms underlying this link remain elusive. In this Review, we summarize the possible connections between condensates and protein aggregation. We consider both liquid-to-solid transitions of phase-separated proteins and the partitioning of proteins into host condensates. We distinguish five key factors by which the physical and chemical environment of a condensate can influence protein aggregation, and we discuss their relevance in studies of protein aggregation in the presence of biomolecular condensates: increasing the local concentration of proteins, providing a distinct chemical microenvironment, introducing an interface wherein proteins can localize, changing the energy landscape of aggregation pathways, and the presence of chaperones in condensates. Analysing the role of biomolecular condensates in protein aggregation may be essential for a full understanding of amyloid formation and offers a new perspective that can help in developing new therapeutic strategies for the prevention and treatment of neurodegenerative diseases.}, }
@article {pmid39130445, year = {2024}, author = {Phipps, AJ and Dwyer, S and Collins, JM and Kabir, F and Atkinson, RA and Chowdhury, MA and Matthews, L and Dixit, D and Terry, RS and Smith, J and Gueven, N and Bennett, W and Cook, AL and King, AE and Perry, S}, title = {HDAC6 inhibition as a mechanism to prevent neurodegeneration in the mSOD1[G93A] mouse model of ALS.}, journal = {Heliyon}, volume = {10}, number = {14}, pages = {e34587}, pmid = {39130445}, issn = {2405-8440}, abstract = {The loss of upper and lower motor neurons, and their axons is central to the loss of motor function and death in amyotrophic lateral sclerosis (ALS). Due to the diverse range of genetic and environmental factors that contribute to the pathogenesis of ALS, there have been difficulties in developing effective therapies for ALS. One emerging dichotomy is that protection of the neuronal cell soma does not prevent axonal vulnerability and degeneration, suggesting the need for targeted therapeutics to prevent axon degeneration. Post-translational modifications of protein acetylation can alter the function, stability and half-life of individual proteins, and can be enzymatically modified by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance of post-translational microtubule acetylation has been suggested as a mechanism to stabilize axons, prevent axonal loss and neurodegeneration in ALS. This study used an orally dosed potent HDAC6 inhibitor, ACY-738, prevent deacetylation and stabilize microtubules in the mSOD1[G93A] mouse model of ALS. Co-treatment with riluzole was performed to determine any effects or drug interactions and potentially enhance preclinical research translation. This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1[G93A] mice, reduced lower motor neuron degeneration in female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS.}, }
@article {pmid39126203, year = {2024}, author = {Tabuchi, R and Momozawa, Y and Hayashi, Y and Noma, H and Ichijo, H and Fujisawa, T}, title = {SoDCoD: a comprehensive database of Cu/Zn superoxide dismutase conformational diversity caused by ALS-linked gene mutations and other perturbations.}, journal = {Database : the journal of biological databases and curation}, volume = {2024}, number = {}, pages = {0}, pmid = {39126203}, issn = {1758-0463}, support = {JP21H04760 JP22H04636 JP22H04804 JP22K06610 JP23K14143//Japan Society for the Promotion of Science/ ; JP21gm5010001//Japan Agency for Medical Research and Development/ ; //SERIKA FUND/ ; 2023-ISMCRP-2033//the ISM Cooperative Research Program/ ; //the researcher exchange promotion program of ROIS (Research Organization of Information and Systems)/ ; JPMJMS2022-18//Japan Science and Technology Agency/ ; JP21H04760 JP22H04636 JP22H04804 JP22K06610 JP23K14143//Japan Society for the Promotion of Science/ ; JP21gm5010001//Japan Agency for Medical Research and Development/ ; //SERIKA FUND/ ; 2023-ISMCRP-2033//the ISM Cooperative Research Program/ ; //the researcher exchange promotion program of ROIS (Research Organization of Information and Systems)/ ; JPMJMS2022-18//Japan Science and Technology Agency/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/enzymology ; Humans ; *Mutation ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; Databases, Protein ; Protein Conformation ; Databases, Genetic ; Superoxide Dismutase/genetics/chemistry/metabolism ; }, abstract = {A structural alteration in copper/zinc superoxide dismutase (SOD1) is one of the common features caused by amyotrophic lateral sclerosis (ALS)-linked mutations. Although a large number of SOD1 variants have been reported in ALS patients, the detailed structural properties of each variant are not well summarized. We present SoDCoD, a database of superoxide dismutase conformational diversity, collecting our comprehensive biochemical analyses of the structural changes in SOD1 caused by ALS-linked gene mutations and other perturbations. SoDCoD version 1.0 contains information about the properties of 188 types of SOD1 mutants, including structural changes and their binding to Derlin-1, as well as a set of genes contributing to the proteostasis of mutant-like wild-type SOD1. This database provides valuable insights into the diagnosis and treatment of ALS, particularly by targeting conformational alterations in SOD1. Database URL: https://fujisawagroup.github.io/SoDCoDweb/.}, }
@article {pmid39126144, year = {2024}, author = {Briones, MRS and Campos, JH and Ferreira, RC and Schneper, L and Santos, IM and Antoneli, FM and ,  and Broach, JR}, title = {Mitochondrial genome variants associated with amyotrophic lateral sclerosis and their haplogroup distribution.}, journal = {Muscle &amp; nerve}, volume = {70}, number = {4}, pages = {862-872}, pmid = {39126144}, issn = {1097-4598}, support = {//Tow Foundation/ ; //NIH/ ; 2013/07838-0//FAPESP/ ; 2014/25602-6//FAPESP/ ; //CAPES/ ; 303912/2017-0//CNPq/ ; T32 LM012415/LM/NLM NIH HHS/United States ; 19-SI-459//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genome, Mitochondrial/genetics ; Male ; Female ; *Genome-Wide Association Study ; Middle Aged ; Haplotypes ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease/genetics ; Aged ; Genetic Variation/genetics ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) may be familial or sporadic, and twin studies have revealed that even sporadic forms have a significant genetic component. Variants in 55 nuclear genes have been associated with ALS and although mitochondrial dysfunction is observed in ALS, variants in mitochondrial genomes (mitogenomes) have not yet been tested for association with ALS. The aim of this study was to determine whether mitogenome variants are associated with ALS.<br><br>METHODS: We conducted a genome-wide association study (GWAS) in mitogenomes of 1965 ALS patients and 2547 controls.<br><br>RESULTS: We identified 51 mitogenome variants with p values <10[-7], of which 13 had odds ratios (ORs) >1, in genes RNR1, ND1, CO1, CO3, ND5, ND6, and CYB, while 38 variants had OR <1 in genes RNR1, RNA2, ND1, ND2, CO2, ATP8, ATP6, CO3, ND3, ND4, ND5, ND6, and CYB. The frequencies of haplogroups H, U, and L, the most frequent in our ALS data set, were the same in different onset sites (bulbar, limb, spinal, and axial). Also, intra-haplogroup GWAS revealed unique ALS-associated variants in haplogroups L and U.<br><br>DISCUSSION: Our study shows that mitogenome single nucleotide variants (SNVs) are associated with ALS and suggests that these SNVs could be included in routine genetic testing for ALS and that mitochondrial replacement therapy has the potential to serve as a basis for ALS treatment.}, }
@article {pmid39122743, year = {2024}, author = {Shin, B and Kwon, Y and Mittaz, M and Kim, H and Xu, X and Kim, E and Lee, YJ and Lee, J and Yeo, WH and Choo, HJ}, title = {All-in-one wearable drug efficacy assessment systems for bulbar muscle function using amyotrophic lateral sclerosis animal models.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {6803}, pmid = {39122743}, issn = {2041-1723}, support = {R21 EB031535/EB/NIBIB NIH HHS/United States ; UL1 TR002378/TR/NCATS NIH HHS/United States ; R21EB031535//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/drug therapy ; Animals ; *Disease Models, Animal ; *Wearable Electronic Devices ; *Electromyography/methods ; Drug Evaluation, Preclinical ; Deglutition Disorders/physiopathology/etiology ; Muscle, Skeletal/drug effects/physiopathology/innervation ; Humans ; Male ; Motor Neurons/drug effects/physiology ; Rats ; }, abstract = {Preclinical studies are crucial for developing amyotrophic lateral sclerosis drugs. Current FDA-approved drugs have been created by monitoring limb muscle function and histological analysis of amyotrophic lateral sclerosis model animals. Drug candidates for this disease have yet to be tested for bulbar-onset type due to the limitations of traditional preclinical tools: excessive animal use and discrete detection of disease progress. Here, our study introduces an all-in-one, wireless, integrated wearable system for facilitating continuous drug efficacy assessment of dysphagia-related muscles in animals during natural eating behaviors. By incorporating a kirigami-based strain-isolation mechanism, this device mounted on the skin of animals mitigates electromyography signal contamination caused by unpredictable animal movements. Our findings indicate this system, measuring the progression of motor neuron denervation, offers high precision in monitoring drug effects on dysphagia-responsible bulbar muscles. This study paves the way for more humane and efficient approaches to developing treatment solutions for degenerative neuromuscular diseases.}, }
@article {pmid39119372, year = {2024}, author = {Maristany, AJ and Sa, BC and Murray, C and Subramaniam, AB and Oldak, SE}, title = {Psychiatric Manifestations of Neurological Diseases: A Narrative Review.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64152}, pmid = {39119372}, issn = {2168-8184}, abstract = {Neurological diseases often manifest with psychiatric symptoms, profoundly impacting patients' well-being and treatment outcomes. This comprehensive review examines the psychiatric manifestations associated with Alzheimer's disease, frontotemporal dementia (FTD), Parkinson's disease, multiple sclerosis (MS), stroke, epilepsy, Huntington's disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and multiple system atrophy (MSA). Key psychiatric symptoms include agitation, depression, anxiety, apathy, hallucinations, impulsivity, and aggression across these diseases. In addition, ethical considerations in treating these symptoms are paramount, particularly regarding genetic testing implications, end-of-life discussions, informed consent, and equitable access to innovative treatments. Effective management necessitates interdisciplinary collaboration, personalized interventions, and a focus on patient autonomy. Understanding the psychiatric burden of neurological diseases is crucial for enhancing patients' quality of life. Further research is needed to elucidate underlying mechanisms and develop targeted interventions. This review underscores the importance of comprehensive assessment and ethical treatment practices to address psychiatric manifestations effectively.}, }
@article {pmid39116956, year = {2024}, author = {Yang, N and Shi, L and Xu, P and Ren, F and Li, C and Qi, X}, title = {Identification of potential drug targets for amyotrophic lateral sclerosis by Mendelian randomization analysis based on brain and plasma proteomics.}, journal = {Experimental gerontology}, volume = {195}, number = {}, pages = {112538}, doi = {10.1016/j.exger.2024.112538}, pmid = {39116956}, issn = {1873-6815}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/drug therapy ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Proteomics/methods ; *Brain/metabolism ; *Protein Interaction Maps ; Anoctamins/genetics ; Bayes Theorem ; Blood Proteins/analysis/metabolism ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic lateral sclerosis as a fatal neurodegenerative disease currently lacks effective therapeutic agents. Thus, finding new therapeutic targets to drive disease treatment is necessary. In this study, we utilized brain and plasma proteins as genetic instruments obtained from genome-wide association studies to conduct a Mendelian randomization analysis to identify potential drug targets for amyotrophic lateral sclerosis. Additionally, we validated our results externally using other datasets. We also used Bayesian co-localization analysis and phenotype scanning. Furthermore, we constructed a protein-protein interaction network to elucidate potential correlations between the identified proteins and existing targets. Mendelian randomization analysis indicated that elevated levels of ANO5 (OR = 1.30; 95 % CI, 1.14-1.49; P = 1.52E-04), SCFD1 (OR = 3.82; 95 % CI, 2.39-6.10; P = 2.19E-08), and SIGLEC9 (OR = 1.05; 95% CI, 1.03-1.07; P = 4.71E-05) are associated with an increased risk of amyotrophic lateral sclerosis, with external validation supporting these findings. Co-localization analysis confirmed that ANO5, SCFD1, and SIGLEC9 (coloc.abf-PPH4 = 0.848, 0.984, and 0.945, respectively) shared the same variant with amyotrophic lateral sclerosis, further substantiating potential role of these proteins as a therapeutic target. There are interactive relationships between the potential proteins and existing targets of amyotrophic lateral sclerosis. Our findings suggested that elevated levels of ANO5, SCFD1, and SIGLEC9 are connected with an increased risk of amyotrophic lateral sclerosis and might be promising therapeutic targets. However, further exploration is necessary to fully understand the underlying mechanisms involved.}, }
@article {pmid39116263, year = {2024}, author = {Aguilar-Vázquez, CA and Aguilar-Castillo, SJ and Raymundo-Carrillo, AD}, title = {[Electrodiagnostic support in an atypical form of amyotrophic lateral sclerosis (Vulpian-Bernhardt syndrome)].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {62}, number = {1}, pages = {1-8}, doi = {10.5281/zenodo.10278187}, pmid = {39116263}, issn = {2448-5667}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/mortality/therapy ; *Electrodiagnosis/methods ; }, abstract = {BACKGROUND: Vulpian-Bernhardt syndrome is an atypical form of the motor neuron disease described since the 19th century. The importance of a timely diagnosis lies in the increased survival present in this variant. Due to the clinical rarity and complex diagnosis we report a clinical case of this disease, which is why we describe the typical clinical presentation, the diagnostic approach, and we make a bibliographic review of this neurodegenerative disorder as well.<br><br>CLINICAL CASE: Latin American man whose clinical case onset was characterized by thoracic asymmetric and increasing limb weakness, showing affection from distal to proximal upper limbs area. Subsequently, symptoms worsened to the point of limiting day-to-day activities and conditioning patient's physical independence. Physical examination was consistent with motor neuron disease. Nerve conduction studies were performed and confirmed findings compatible with motor neuron involvement limited to thoracic limbs.<br><br>CONCLUSION: Vulpian-Bernhardt syndrome is an uncommon form of motor neuron disease. Due to the rarity of its presentation, it is frequent to confuse clinical profile even for trained physicians. The importance of electrodiagnosis relies in identifying the neurogenic origin of the disease, as well as the active denervation and reinnervation data. Considering that with this syndrome patients have a longer survival than with the classic form of amyotrophic lateral sclerosis, it is important to have a clear diagnosis approach in order to provide a better quality of life and supportive treatment.}, }
@article {pmid39111227, year = {2024}, author = {Torghabeh, FA and Moghadam, EA and Hosseini, SA}, title = {Simultaneous time-frequency analysis of gait signals of both legs in classifying neurodegenerative diseases.}, journal = {Gait &amp; posture}, volume = {113}, number = {}, pages = {443-451}, doi = {10.1016/j.gaitpost.2024.07.302}, pmid = {39111227}, issn = {1879-2219}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/physiopathology ; *Gait Analysis/methods ; Gait Disorders, Neurologic/classification/diagnosis/physiopathology/etiology ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/classification ; Wavelet Analysis ; Male ; Female ; Middle Aged ; Parkinson Disease/diagnosis/physiopathology/classification ; Deep Learning ; Signal Processing, Computer-Assisted ; Case-Control Studies ; Huntington Disease/physiopathology/diagnosis/classification ; Aged ; }, abstract = {BACKGROUND: Neurodegenerative diseases (NDDs) pose significant challenges due to their debilitating nature and limited therapeutic options. Accurate and timely diagnosis is crucial for optimizing patient care and treatment strategies. Gait analysis, utilizing wearable sensors, has shown promise in assessing motor abnormalities associated with NDDs.<br><br>RESEARCH QUESTION: Research Question 1 To what extent can analyzing the interaction of both limbs in the time-frequency domain serve as a suitable methodology for accurately classifying NDDs? Research Question 2 How effective is the utilization of color-coded images, in conjunction with deep transfer learning models, for the classification of NDDs?<br><br>METHODS: GaitNDD database was used, comprising recordings from patients with Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, and healthy controls. The gait signals underwent signal preparation, wavelet coherence analysis, and principal component analysis for feature enhancement. Deep transfer learning models (AlexNet, GoogLeNet, SqueezeNet) were employed for classification. Performance metrics, including accuracy, sensitivity, specificity, precision, and F1 score, were evaluated using 5-fold cross-validation.<br><br>RESULTS: The classification performance of the models varied depending on the time window used. For 5-second gait signal segments, AlexNet achieved an accuracy of 95.91&#x202f;%, while GoogLeNet and SqueezeNet achieved accuracies of 96.49&#x202f;% and 92.73&#x202f;%, respectively. For 10-second segments, AlexNet outperformed other models with an accuracy of 99.20&#x202f;%, while GoogLeNet and SqueezeNet achieved accuracies of 96.75&#x202f;% and 95.00&#x202f;%, respectively. Statistical tests confirmed the significance of the extracted features, indicating their discriminative power for classification.<br><br>SIGNIFICANCE: The proposed method demonstrated superior performance compared to previous studies, offering a non-invasive and cost-effective approach for the automated diagnosis of NDDs. By analyzing the interaction between both legs during walking using wavelet coherence, and utilizing deep transfer learning models, accurate classification of NDDs was achieved.}, }
@article {pmid39106020, year = {2024}, author = {Mirmotahari, SA and Aliomrani, M and Hassanzadeh, F and Sirous, H and Rostami, M}, title = {Hybrid derivatives containing dimethyl fumarate and benzothiazole scaffolds for the potential treatment of multiple sclerosis; in silico &amp; in vivo study.}, journal = {Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences}, volume = {32}, number = {2}, pages = {599-615}, pmid = {39106020}, issn = {2008-2231}, mesh = {*Dimethyl Fumarate/pharmacology/chemistry ; *Multiple Sclerosis/drug therapy ; Animals ; *Molecular Docking Simulation ; *Benzothiazoles/chemistry/pharmacology ; *Riluzole/pharmacology/chemistry ; Mice ; *Mice, Inbred C57BL ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors/metabolism ; Male ; Cuprizone ; Disease Models, Animal ; Computer Simulation ; Neuroprotective Agents/pharmacology/chemistry ; Remyelination/drug effects ; }, abstract = {BACKGROUND: Multiple Sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease of the CNS. Riluzole and dimethyl fumarate (DMF) are two FDA-approved drugs to treat amyotrophic lateral sclerosis (ALS) and MS. Riluzole (a benzothiazole derivative) inhibits glutamate release from nerve terminals by antagonizing the N-Methyl-D-Aspartate (NMDA) receptor, and DMF upregulates anti-oxidative pathways.<br><br>OBJECTIVES: Herein, using molecular hybridization strategy, we synthesized some new hybrid structures of Riluzole and DMF through some common successive synthetic pathways for evaluating their potential activity for remyelination in MS treatment.<br><br>METHODS: Molecular docking experiments assessed the binding affinity of proposed structures to the NMDA active site. The designed structures were synthesized and purified based on well-known chemical synthesis procedures. Afterward, in vivo&#xa0;evaluation for their activity was done in the C57Bl/6 Cuprizone-induced demyelination MS model.<br><br>RESULTS AND CONCLUSION: The proposed derivatives were recognized to be potent enough based on docking studies (&#x394;Gbind of all derivatives were -7.2 to -7.52 compare to the Ifenprodil (-6.98) and Riluzole (-4.42)). The correct structures of desired derivatives were confirmed using spectroscopic methods. Based on&#xa0;in vivo&#xa0;studies, D4 and D6 derivatives exhibited the best pharmacological results, although only D6 showed a statistically significant difference compared to the control. Also, for D4 and D6 derivatives, myelin staining confirmed reduced degeneration in the corpus callosum. Consequently,&#xa0;D4 and D6&#xa0;derivatives are promising candidates for developing new NMDA antagonists with therapeutic value against MS disorders.}, }
@article {pmid39104562, year = {2024}, author = {Haikal, A and Ali, AR}, title = {Chemical composition and toxicity studies on Lantana camara L. flower essential oil and its in silico binding and pharmacokinetics to superoxide dismutase 1 for amyotrophic lateral sclerosis (ALS) therapy.}, journal = {RSC advances}, volume = {14}, number = {33}, pages = {24250-24264}, pmid = {39104562}, issn = {2046-2069}, abstract = {Using the gas chromatography mass spectrometry method, the chemical components of essential oil from flowers of Lantana camara growing in Egypt are analyzed. Through this investigation, 22 chemicals from floral oil were identified. Most of the oil is made up of sesquiterpene caryophyllene (15.51%) and monoterpene sabinene (14.90%). When the oil's composition was compared to oils extracted from the same plant on several continents, we observed that the essential components were largely the same with some difference in proportions and some compounds due to geographical differences. A molecular docking study of essential oil components was conducted with human superoxide dismutase 1, a target involved in the pathophysiology of amyotrophic lateral sclerosis (ALS). Isospathulenol showed a comparable docking score to the reference ligand bound to the dismutase enzyme. Isospathulenol showed a reasonable drug score with some safety concerns. In addition, isospathulenol is predicted to have high GI absorption, good permeability through the blood-brain barrier and reasonable bioavailability score with ease access to synthetic modifications. In addition, the same compound is devoid from any violation to Lipinski rules or any PAINS alerts. This may establish the promising characteristics of such a compound to be optimized into potential drug candidates for treatment of ALS.}, }
@article {pmid39091098, year = {2024}, author = {Annetta, MG and Barbato, G and Pisciaroli, E and Marche, B and Sabatelli, M and Pittiruti, M}, title = {Central venous catheter-related thrombosis in patients with amyotrophic lateral sclerosis.}, journal = {The journal of vascular access}, volume = {}, number = {}, pages = {11297298241262821}, doi = {10.1177/11297298241262821}, pmid = {39091098}, issn = {1724-6032}, abstract = {BACKGROUND: Central venous catheterization may be required in patients with amyotrophic lateral sclerosis (ALS) for parenteral nutrition, antibiotic treatment, or blood sampling. Different venous access devices can be taken into consideration-centrally inserted central catheters (CICC), peripherally inserted central catheters (PICC), and femorally inserted central catheters (FICCs)-depending on the clinical conditions of the patients. Regardless of the type of access, the presence of paraplegia or tetraplegia is commonly considered a risk factor for catheter-related thrombosis (CRT).<br><br>METHOD: This retrospective study analyzes the rate of CRT and other non-infectious complications associated with central venous access in a cohort of 115 patients with paraplegia or tetraplegia, most of them affected by ALS (n&#x2009;=&#x2009;109).<br><br>RESULTS: In a period of 34&#x2009;months, from January 2021 to October 2023, we inserted 75 FICCs, 29 CICCs, and 11 PICCs. PICCs were inserted only in patients with preserved motility of the upper limbs. All devices were inserted by trained operators adopting appropriate insertion bundles. We had no immediate or early complication. Though antithrombotic prophylaxis was adopted only in 61.7% of patients, we had no symptomatic CRT. Other non-infectious complications were infrequent (4 out of 115 patients).<br><br>CONCLUSION: These results suggest (a) that the presence of paraplegia or tetraplegia is not necessarily associated with an increased risk of CRT, (b) that the adoption of well-designed insertion bundles plays a key role in minimizing non-infectious complications, and (c) that the insertion of FICCs by direct cannulation of the superficial femoral vein at mid-thigh in paraplegic/tetraplegic patients may have the same advantages which have been described in the general population.}, }
@article {pmid39088003, year = {2024}, author = {Lai, HJ and Kuo, YC and Ting, CH and Yang, CC and Kao, CH and Tsai, YC and Chao, CC and Hsueh, HW and Hsieh, PF and Chang, HY and Wang, IF and Tsai, LK}, title = {Increase of HCN current in SOD1-associated amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {12}, pages = {4240-4253}, doi = {10.1093/brain/awae248}, pmid = {39088003}, issn = {1460-2156}, support = {108-2314-B-002-082-MY3//Ministry of Science and Technology, ROC/ ; MQ999//National Taiwan University Hospital/ ; 112-BIH001//National Taiwan University Hospital Hsinchu branch/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Animals ; *Superoxide Dismutase-1/genetics ; Mice ; Male ; Female ; *Mice, Transgenic ; *Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics/metabolism ; Middle Aged ; Aged ; Axons/metabolism ; Disease Models, Animal ; Potassium Channels/metabolism/genetics ; Adult ; }, abstract = {The clinical manifestations of sporadic amyotrophic lateral sclerosis (ALS) vary widely. However, the current classification of ALS is based mainly on clinical presentations, and the roles of electrophysiological and biomedical biomarkers remain limited. Herein, we investigated a group of patients with sporadic ALS and an ALS mouse model with superoxide dismutase 1 (SOD1)/G93A transgenes using nerve excitability tests (NETs) to investigate axonal membrane properties and chemical precipitation, followed by ELISA analysis to measure plasma misfolded protein levels. Six of 19 patients (31.6%) with sporadic ALS had elevated plasma misfolded SOD1 protein levels. In sporadic ALS patients, only those with elevated misfolded SOD1 protein levels showed an increased inward rectification in the current-voltage threshold curve and an increased threshold reduction in the hyperpolarizing threshold electrotonus in the NET study. Two familial ALS patients with SOD1 mutations also exhibited similar electrophysiological patterns of NET. For patients with sporadic ALS showing significantly increased inward rectification in the current-voltage threshold curve, we noted an elevation in plasma misfolded SOD1 level, but not in total SOD1, misfolded C9orf72 or misfolded phosphorylated TDP43 levels. Computer simulations demonstrated that the aforementioned axonal excitability changes are likely to be associated with an increase in hyperpolarization-activated cyclic nucleotide-gated (HCN) current. In SOD1/G93A mice, NET also showed an increased inward rectification in the current-voltage threshold curve, which could be reversed by a single injection of the HCN channel blocker, ZD7288. Daily treatment of SOD1/G93A mice with ZD7288 partly prevented the early motor function decline and spinal motor neuron death. In summary, sporadic ALS patients with elevated plasma misfolded SOD1 exhibited similar patterns of motor axonal excitability changes to familial ALS patients and ALS mice with mutant SOD1, suggesting the existence of SOD1-associated sporadic ALS. The observed NET pattern of increased inward rectification in the current-voltage threshold curve was attributable to an elevation in the HCN current in SOD1-associated ALS.}, }
@article {pmid39084789, year = {2024}, author = {Wang, H and Zhang, Y and Ren, Y and Liu, Y and Feng, Z and Dong, L}, title = {Mechanism of multiple resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon in Avena fatua L. from China.}, journal = {Pesticide biochemistry and physiology}, volume = {203}, number = {}, pages = {105985}, doi = {10.1016/j.pestbp.2024.105985}, pmid = {39084789}, issn = {1095-9939}, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Oxazoles/pharmacology ; China ; *Phenylurea Compounds/pharmacology ; *Acetyl-CoA Carboxylase/genetics/metabolism ; *Propionates/pharmacology ; *Acetolactate Synthase/genetics/metabolism ; Poaceae/drug effects ; Phenylpropionates/pharmacology ; Plant Proteins/genetics/metabolism ; Sulfonylurea Compounds ; }, abstract = {Avena fatua L. is one of the most damaging and malignant weeds in wheat fields in China. Fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon, which belong to Acetyl-CoA carboxylase- (ACCase), acetolactate synthase- (ALS), and photosystem II- (PS II) inhibitors, respectively, are commonly used in wheat fields and have a long history of use on A. fatua. An A. fatua population (R) resistant to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon was collected from a wheat field in 2020. This study explored the mechanisms of target site resistance (TSR) and non-target site resistance (NTSR) in the multi-resistant A. fatua. Whole-plant bioassays showed that the R population had evolved high resistance to fenoxaprop-P-ethyl and moderate resistance to mesosulfuron-methyl and isoproturon. However, no mutations were detected in the ACCase, ALS, or psbA genes in the R population. In addition, the ACCase and ALS gene expression levels in the R group were significantly higher than those in the susceptible population (S) after treatment with fenoxaprop-P-ethyl or mesosulfuron-methyl. In vitro ACCase and ALS activity assays showed that ACCase and ALS from the R population were insensitive to fenoxaprop and mesosulfuron-methyl, respectively, with resistance indices 6.12-fold and 17.46-fold higher than those of the S population. Furthermore, pretreatment with P450 inhibitors significantly (P < 0.05) reversed the multi-resistant A. fatua's resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon. Sethoxydim, flucarbazone‑sodium, chlortoluron, and cypyrafluone were effective in controlling multi-resistance A. fatua. Therefore, the overexpression of ACCase and ALS to synthesize sufficient herbicide-targeting proteins, along with P450-mediated metabolism, conferred resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon in the R population.}, }
@article {pmid39084211, year = {2024}, author = {Sharma, S and Gilberto, VS and Rask, J and Chatterjee, A and Nagpal, P}, title = {Inflammasome-Inhibiting Nanoligomers Are Neuroprotective against Space-Induced Pathology in Healthy and Diseased Three-Dimensional Human Motor and Prefrontal Cortex Brain Organoids.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {16}, pages = {3009-3021}, doi = {10.1021/acschemneuro.4c00160}, pmid = {39084211}, issn = {1948-7193}, mesh = {Humans ; *Prefrontal Cortex/drug effects/metabolism ; *Organoids/drug effects ; *Inflammasomes/metabolism ; Neuroprotective Agents/pharmacology ; Space Flight ; Weightlessness ; Neurodegenerative Diseases ; Alzheimer Disease/pathology/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Frontotemporal Dementia/metabolism ; }, abstract = {The microgravity and space environment has been linked to deficits in neuromuscular and cognitive capabilities, hypothesized to occur due to accelerated aging and neurodegeneration in space. While the specific mechanisms are still being investigated, spaceflight-associated neuropathology is an important health risk to astronauts and space tourists and is being actively investigated for the development of appropriate countermeasures. However, such space-induced neuropathology offers an opportunity for accelerated screening of therapeutic targets and lead molecules for treating neurodegenerative diseases. Here, we show a proof-of-concept high-throughput target screening (on Earth), target validation, and mitigation of microgravity-induced neuropathology using our Nanoligomer platform, onboard the 43-day SpaceX CRS-29 mission to the International Space Station. First, comparing 3D healthy and diseased prefrontal cortex (PFC, for cognition) and motor neuron (MN, for neuromuscular function) organoids, we assessed space-induced pathology using biomarkers relevant to Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Both healthy and diseased PFC and MN organoids showed significantly enhanced neurodegeneration in space, as measured through relevant disease biomarkers, when compared to their respective Earth controls. Second, we tested the top two lead molecules, NI112 that targeted NF-κB and NI113 that targeted IL-6. We observed that these Nanoligomers significantly mitigate the AD, FTD, and ALS relevant biomarkers like amyloid beta-42 (Aβ42), phosphorylated tau (pTau), Kallikrein (KLK-6), Tar DNA-binding protein 43 (TDP-43), and others. Moreover, the 43-day Nanoligomer treatment of these brain organoids did not appear to cause any observable toxicity or safety issues in the target organoid tissue, suggesting good tolerability for these molecules in the brain at physiologically relevant doses. Together, these results show significant potential for both the development and translation of NI112 and NI113 molecules as potential neuroprotective countermeasures for safer space travel and demonstrate the usefulness of the space environment for rapid, high-throughput screening of targets and lead molecules for clinical translation. We assert that the use of microgravity in drug development and screening may ultimately benefit millions of patients suffering from debilitating neurodegenerative diseases on Earth.}, }
@article {pmid39072497, year = {2025}, author = {Alonso, JP and Ini, N and Villarejo, A and Belizán, M and Roberti, J}, title = {Amyotrophic lateral sclerosis in Argentina: unveiling the burden of treatment through patient and caregiver perspectives.}, journal = {Disability and rehabilitation}, volume = {47}, number = {7}, pages = {1828-1835}, doi = {10.1080/09638288.2024.2385732}, pmid = {39072497}, issn = {1464-5165}, mesh = {Humans ; Argentina ; *Caregivers/psychology ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Male ; Female ; Middle Aged ; *Qualitative Research ; *Cost of Illness ; Aged ; *Interviews as Topic ; Adult ; Activities of Daily Living ; COVID-19/epidemiology ; }, abstract = {PURPOSE: To examine the burden of treatment (BoT) experienced by people with Amyotrophic Lateral Sclerosis (ALS) in Argentina.<br><br>METHODS: Qualitative methodological design based on semi-structured interviews. Nineteen semi-structured interviews were conducted (PwALS = 7, informal caregivers= 12). The interview guides were designed based on the literature and BoT theory. Data were analysed following a framework analysis approach.<br><br>RESULTS: The research highlighted the arduous journey toward obtaining a diagnosis, marked by delays influenced by healthcare system inefficiencies, lack of disease awareness and pandemic-related anxiety. Receiving the diagnosis was a destabilising experience, triggering the need to reframe self-identity, a new reality. As the disease progressed, patients encountered significant challenges in their daily activities and basic tasks, affecting their ability to work, communicate, and manage personal care. The burden extended beyond the patients to their primary caregivers. Access to specialised care, bureaucratic complexities in securing treatment, and the financial impact of managing the disease posed substantial challenges.<br><br>CONCLUSION: The findings offer valuable insights into the experiences of PwALS and their caregivers in Argentina. They underscore the need for increased disease awareness, improved access to specialised care, and enhanced support networks to alleviate the burdens PwALS and their families face.}, }
@article {pmid39062967, year = {2024}, author = {Kisielewska, M and Filipski, M and Sebastianka, K and Karaś, D and Molik, K and Choromańska, A}, title = {Investigation into the Neuroprotective and Therapeutic Potential of Plant-Derived Chk2 Inhibitors.}, journal = {International journal of molecular sciences}, volume = {25}, number = {14}, pages = {}, pmid = {39062967}, issn = {1422-0067}, mesh = {*Checkpoint Kinase 2/metabolism/antagonists &amp; inhibitors ; Humans ; Animals ; Protein Kinase Inhibitors/pharmacology/therapeutic use/chemistry ; Neuroprotective Agents/pharmacology/therapeutic use ; Neoplasms/drug therapy ; DNA Damage/drug effects ; DNA Repair/drug effects ; }, abstract = {Nature provides us with a rich source of compounds with a wide range of applications, including the creation of innovative drugs. Despite advancements in chemically synthesized therapeutics, natural compounds are increasingly significant, especially in cancer treatment, a leading cause of death globally. One promising approach involves the use of natural inhibitors of checkpoint kinase 2 (Chk2), a critical regulator of DNA repair, cell cycle arrest, and apoptosis. Chk2's activation in response to DNA damage can lead to apoptosis or DNA repair, influencing glycolysis and mitochondrial function. In cancer therapy, inhibiting Chk2 can disrupt DNA repair and cell cycle progression, promoting cancer cell death and enhancing the efficacy of radiotherapy and chemotherapy. Additionally, Chk2 inhibitors can safeguard non-cancerous cells during these treatments by inhibiting p53-dependent apoptosis. Beyond oncology, Chk2 inhibition shows potential in treating hepatitis C virus (HCV) infections, as the virus relies on Chk2 for RNA replication in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), in which DNA damage plays a crucial role. Plant-derived Chk2 inhibitors, such as artemetin, rhamnetin, and curcumin, offer a promising future for treating various diseases with potentially milder side effects and broader metabolic impacts compared to conventional therapies. The review aims to underscore the immense potential of natural Chk2 inhibitors in various therapeutic contexts, particularly in oncology and the treatment of other diseases involving DNA damage and repair mechanisms. These natural Chk2 inhibitors hold significant promise for revolutionizing the landscape of cancer treatment and other diseases. Further research into these compounds could lead to the development of innovative therapies that offer hope for the future with fewer side effects and enhanced efficacy.}, }
@article {pmid39062592, year = {2024}, author = {Gao, J and Sterling, E and Hankin, R and Sikal, A and Yao, Y}, title = {Therapeutics Targeting Skeletal Muscle in Amyotrophic Lateral Sclerosis.}, journal = {Biomolecules}, volume = {14}, number = {7}, pages = {}, pmid = {39062592}, issn = {2218-273X}, support = {W81XWH2210261//United States Department of Defense/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/therapy ; Humans ; *Muscle, Skeletal/metabolism/pathology ; Animals ; Neuromuscular Junction/metabolism/pathology ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neuromuscular disease characterized by progressive motor neuron degeneration, neuromuscular junction dismantling, and muscle wasting. The pathological and therapeutic studies of ALS have long been neurocentric. However, recent insights have highlighted the significance of peripheral tissue, particularly skeletal muscle, in disease pathology and treatment. This is evidenced by restricted ALS-like muscle atrophy, which can retrogradely induce neuromuscular junction and motor neuron degeneration. Moreover, therapeutics targeting skeletal muscles can effectively decelerate disease progression by modulating muscle satellite cells for muscle repair, suppressing inflammation, and promoting the recovery or regeneration of the neuromuscular junction. This review summarizes and discusses therapeutic strategies targeting skeletal muscles for ALS treatment. It aims to provide a comprehensive reference for the development of novel therapeutics targeting skeletal muscles, potentially ameliorating the progression of ALS.}, }
@article {pmid39061876, year = {2024}, author = {Magalhães, RSS and Monteiro Neto, JR and Ribeiro, GD and Paranhos, LH and Eleutherio, ECA}, title = {Trehalose Protects against Superoxide Dismutase 1 Proteinopathy in an Amyotrophic Lateral Sclerosis Model.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {7}, pages = {}, pmid = {39061876}, issn = {2076-3921}, support = {PROBRAL 88881.371325/2019-01//Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior (CAPES)/ ; CNE 201.174/2022 and Posdoc Nota 10 202.267/2019//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; Universal 401780/2023-6//National Council for Scientific and Technological Development/ ; }, abstract = {This work aimed to study the effect of trehalose in protecting cells against Sod1 proteinopathy associated with amyotrophic lateral sclerosis (ALS). Humanized yeast cells in which native Sod1 was replaced by wild-type human Sod1 or an ALS mutant (WT-A4V Sod1 heterodimer) were used as the experimental model. Cells were treated with 10% trehalose (p/v) before or after the appearance of hSod1 proteinopathy induced by oxidative stress. In both conditions, trehalose reduced the number of cells with Sod1 inclusions, increased Sod1 activity, and decreased the levels of intracellular oxidation, demonstrating that trehalose avoids Sod1 misfolding and loss of function in response to oxidative stress. The survival rates of ALS Sod1 cells stressed in the presence of trehalose were 60% higher than in their absence. Treatment with trehalose after the appearance of Sod1 inclusions in cells expressing WT Sod1 doubled longevity; after 5 days, non-treated cells did not survive, but 15% of cells treated with sugar were still alive. Altogether, our results emphasize the potential of trehalose as a novel therapy, which might be applied preventively in ALS patients with a family history of the disease or after diagnosis in ALS patients who discover the disease following the first symptoms.}, }
@article {pmid39059407, year = {2024}, author = {van den Berg, LH and Rothstein, JD and Shaw, PJ and Babu, S and Benatar, M and Bucelli, RC and Genge, A and Glass, JD and Hardiman, O and Libri, V and Mobach, T and Oskarsson, B and Pattee, GL and Ravits, J and Shaw, CE and Weber, M and Zinman, L and Jafar-Nejad, P and Rigo, F and Lin, L and Ferguson, TA and Gotter, AL and Graham, D and Monine, M and Inra, J and Sinks, S and Eraly, S and Garafalo, S and Fradette, S}, title = {Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study.}, journal = {The Lancet. Neurology}, volume = {23}, number = {9}, pages = {901-912}, doi = {10.1016/S1474-4422(24)00216-3}, pmid = {39059407}, issn = {1474-4465}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Double-Blind Method ; *C9orf72 Protein/genetics ; *Oligonucleotides, Antisense/pharmacokinetics/administration &amp; dosage/adverse effects/pharmacology ; Aged ; Adult ; Dose-Response Relationship, Drug ; }, abstract = {BACKGROUND: Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS.<br><br>METHODS: This phase 1, randomised controlled trial was done at 22 sites in six countries (Canada, Ireland, Netherlands, Switzerland, UK, and USA). Adults with ALS and a pathogenic repeat expansion in C9orf72 were randomly assigned within six cohorts, via Interactive Response Technology in a 3:1 ratio per cohort, to receive BIIB078 (5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg in cohorts 1-6, respectively) or placebo, via an intrathecal bolus injection. The treatment period consisted of three loading doses of study treatment, administered approximately once every 2 weeks, followed by monthly maintenance doses during a treatment period of about 3 months for cohorts 1-3 and about 6 months for cohorts 4-6. Patients and investigators were masked to treatment assignment. The primary endpoint was the incidence of adverse events and serious adverse events. This trial was registered with ClinicalTrials.gov (NCT03626012) and is completed.<br><br>FINDINGS: Between Sept 10, 2018, and Nov 17, 2021, 124 patients were screened for inclusion in the study. 18 patients were excluded and 106 participants were enrolled and randomly assigned to receive 5 mg (n=6), 10 mg (n=9), 20 mg (n=9), 35 mg (n=19), 60 mg (n=18), or 90 mg (n=18) of BIIB078, or placebo (n=27). 58 (55%) of 106 patients were female. All patients received at least one dose of study treatment and were included in all analyses. All participants had at least one adverse event; most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. The most common adverse events in BIIB078-treated participants were falls, procedural pain, headache, and post lumbar puncture syndrome. 14 (18%) of 79 patients who received any dose of BIIB078 reported serious adverse events, compared with nine (33%) of 27 patients who received placebo. Five participants who received BIIB078 and three participants who received placebo had fatal adverse events: respiratory failure in a participant who received 10 mg BIIB078, ALS worsening in two participants who received 35 mg BIIB078, traumatic intracerebral haemorrhage in one participant who received 35 mg BIIB078, pulmonary embolism in one participant who received 60 mg BIIB078, and respiratory failure in three participants who received placebo. All deaths were assessed as not related to the study treatment by the reporting investigator.<br><br>INTERPRETATION: On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS.<br><br>FUNDING: Biogen.}, }
@article {pmid39054501, year = {2024}, author = {Rahimi Darehbagh, R and Seyedoshohadaei, SA and Ramezani, R and Rezaei, N}, title = {Stem cell therapies for neurological disorders: current progress, challenges, and future perspectives.}, journal = {European journal of medical research}, volume = {29}, number = {1}, pages = {386}, pmid = {39054501}, issn = {2047-783X}, mesh = {Humans ; *Nervous System Diseases/therapy ; *Stem Cell Transplantation/methods/trends ; Animals ; Cell- and Tissue-Based Therapy/methods/trends ; Neural Stem Cells/transplantation/physiology ; }, abstract = {Stem cell-based therapies have emerged as a promising approach for treating various neurological disorders by harnessing the regenerative potential of stem cells to restore damaged neural tissue and circuitry. This comprehensive review provides an in-depth analysis of the current state of stem cell applications in primary neurological conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other related disorders. The review begins with a detailed introduction to stem cell biology, discussing the types, sources, and mechanisms of action of stem cells in neurological therapies. It then critically examines the preclinical evidence from animal models and early human trials investigating the safety, feasibility, and efficacy of different stem cell types, such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs). While ESCs have been studied extensively in preclinical models, clinical trials have primarily focused on adult stem cells such as MSCs and NSCs, as well as iPSCs and their derivatives. We critically assess the current state of research for each cell type, highlighting their potential applications and limitations in different neurological conditions. The review synthesizes key findings from recent, high-quality studies for each neurological condition, discussing cell manufacturing, delivery methods, and therapeutic outcomes. While the potential of stem cells to replace lost neurons and directly reconstruct neural circuits is highlighted, the review emphasizes the critical role of paracrine and immunomodulatory mechanisms in mediating the therapeutic effects of stem cells in most neurological disorders. The article also explores the challenges and limitations associated with translating stem cell therapies into clinical practice, including issues related to cell sourcing, scalability, safety, and regulatory considerations. Furthermore, it discusses future directions and opportunities for advancing stem cell-based treatments, such as gene editing, biomaterials, personalized iPSC-derived therapies, and novel delivery strategies. The review concludes by emphasizing the transformative potential of stem cell therapies in revolutionizing the treatment of neurological disorders while acknowledging the need for rigorous clinical trials, standardized protocols, and multidisciplinary collaboration to realize their full therapeutic promise.}, }
@article {pmid39054363, year = {2024}, author = {Weishaupt, JH and Körtvélyessy, P and Schumann, P and Valkadinov, I and Weyen, U and Hesebeck-Brinckmann, J and Weishaupt, K and Endres, M and Andersen, PM and Regensburger, M and Dreger, M and Koch, JC and Conrad, J and Meyer, T}, title = {Tofersen decreases neurofilament levels supporting the pathogenesis of the SOD1 p.D91A variant in amyotrophic lateral sclerosis patients.}, journal = {Communications medicine}, volume = {4}, number = {1}, pages = {150}, pmid = {39054363}, issn = {2730-664X}, abstract = {BACKGROUND: Since the antisense oligonucleotide tofersen has recently become available for the treatment of amyotrophic lateral sclerosis (ALS) caused by mutations in SOD1, determining the causality of the over 230 SOD1 variants has become even more important. The most common SOD1 variant worldwide is p.D91A (c.272A > C), whose causality for ALS is contested when in a heterozygous state. The reason is the high allele frequency of SOD1[D91A] in Europe, exceeding 1% in Finno-Scandinavia.<br><br>METHODS: We present the clinical disease course and serum neurofilament light chain (NfL) results of treating 11 patients either homo- or heterozygous for the SOD1[D91A] allele for up to 16 months with tofersen.<br><br>RESULTS: Tofersen decreases serum neurofilament levels (sNFL), which are associated with the ALS progression rate, in the 6 ALS patients homozygous for SOD1[D91A]. We observe significantly lower sNfL levels in the 5 patients heterozygous for SOD1[D91A]. The results indicate that both mono- and bi-allelic SOD1[D91A] are causally relevant targets, with a possibly reduced effect size of SOD1[D91Ahet].<br><br>CONCLUSIONS: The finding is relevant for decision making regarding tofersen treatment, patient counseling and inclusion of SOD1[D91A] patients in drug trials. As far as we are aware, the approach is conceptually new since it provides evidence for the causality of an ALS variant based on a biomarker response to gene-specific treatment.}, }
@article {pmid39050823, year = {2024}, author = {Min, JH and Sarlus, H and Harris, RA}, title = {Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1408159}, pmid = {39050823}, issn = {1662-5099}, abstract = {The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease.}, }
@article {pmid39039445, year = {2024}, author = {Jonsdottir, G and Haraldsdottir, E and Vilhjalmsson, R and Sigurdardottir, V and Hjaltason, H and Klinke, ME and Tryggvadottir, GB and Jonsdottir, H}, title = {Transition to end-of-life care in patients with neurological diseases in an acute hospital ward.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {253}, pmid = {39039445}, issn = {1471-2377}, support = {71545//The Icelandic Nurses&#xb4; Association/ ; }, mesh = {Humans ; Male ; *Terminal Care/methods/statistics &amp; numerical data ; Female ; Aged ; Middle Aged ; Retrospective Studies ; *Nervous System Diseases/therapy/diagnosis/epidemiology ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/therapy/diagnosis/mortality ; }, abstract = {BACKGROUND: Transitioning to end-of-life care and thereby changing the focus of treatment directives from life-sustaining treatment to comfort care is important for neurological patients in advanced stages. Late transition to end-of-life care for neurological patients has been described previously.<br><br>OBJECTIVE: To investigate whether previous treatment directives, primary medical diagnoses, and demographic factors predict the transition to end-of-life care and time to eventual death in patients with neurological diseases in an acute hospital setting.<br><br>METHOD: All consecutive health records of patients diagnosed with stroke, amyotrophic lateral sclerosis (ALS), and Parkinson's disease or other extrapyramidal diseases (PDoed), who died in an acute neurological ward between January 2011 and August 2020 were retrieved retrospectively. Descriptive statistics and multivariate Cox regression were used to examine the timing of treatment directives and death in relation to medical diagnosis, age, gender, and marital status.<br><br>RESULTS: A total of 271 records were involved in the analysis. Patients in all diagnostic categories had a treatment directive for end-of-life care, with patients with haemorrhagic stroke having the highest (92%) and patients with PDoed the lowest (73%) proportion. Cox regression identified that the likelihood of end-of-life care decision-making was related to advancing age (HR&#x2009;=&#x2009;1.02, 95% CI: 1.007-1.039, P&#x2009;=&#x2009;0.005), ischaemic stroke (HR&#x2009;=&#x2009;1.64, 95% CI: 1.034-2.618, P&#x2009;=&#x2009;0.036) and haemorrhagic stroke (HR&#x2009;=&#x2009;2.04, 95% CI: 1.219-3.423, P&#x2009;=&#x2009;0.007) diagnoses. End-of-life care decision occurred from four to twenty-two days after hospital admission. The time from end-of-life care decision to death was a median of two days. Treatment directives, demographic factors, and diagnostic categories did not increase the likelihood of death following an end-of-life care decision.<br><br>CONCLUSIONS: Results show not only that neurological patients transit late to end-of-life care but that the timeframe of the decision differs between patients with acute neurological diseases and those with progressive neurological diseases, highlighting the particular significance of the short timeframe of patients with the progressive neurological diseases ALS and PDoed. Different trajectories of patients with neurological diseases at end-of-life should be further explored and clinical guidelines expanded to embrace the high diversity in neurological patients.}, }
@article {pmid39033904, year = {2024}, author = {Lu, XY and Li, MQ and Li, YT and Yao, JY and Zhang, LX and Zeng, ZH and Yu-Liu,  and Chen, ZR and Li, CQ and Zhou, XF and Li, F}, title = {Oral edaravone ameliorates behavioral deficits and pathologies in a valproic acid-induced rat model of autism spectrum disorder.}, journal = {Neuropharmacology}, volume = {258}, number = {}, pages = {110089}, doi = {10.1016/j.neuropharm.2024.110089}, pmid = {39033904}, issn = {1873-7064}, mesh = {Animals ; *Valproic Acid/pharmacology/administration &amp; dosage ; *Edaravone/pharmacology ; *Autism Spectrum Disorder/drug therapy/chemically induced ; *Disease Models, Animal ; Female ; *Oxidative Stress/drug effects ; Male ; Administration, Oral ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Brain/drug effects/metabolism/pathology ; Prenatal Exposure Delayed Effects/chemically induced ; Free Radical Scavengers/pharmacology/administration &amp; dosage/therapeutic use ; Dose-Response Relationship, Drug ; Stereotyped Behavior/drug effects ; Behavior, Animal/drug effects ; Social Interaction/drug effects ; }, abstract = {Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies.}, }
@article {pmid39031772, year = {2024}, author = {Meyer, T and Schumann, P and Weydt, P and Petri, S and Weishaupt, JH and Weyen, U and Koch, JC and Günther, R and Regensburger, M and Boentert, M and Wiesenfarth, M and Koc, Y and Kolzarek, F and Kettemann, D and Norden, J and Bernsen, S and Elmas, Z and Conrad, J and Valkadinov, I and Vidovic, M and Dorst, J and Ludolph, AC and Hesebeck-Brinckmann, J and Spittel, S and Münch, C and Maier, A and Körtvélyessy, P}, title = {Clinical and patient-reported outcomes and neurofilament response during tofersen treatment in SOD1-related ALS-A multicenter observational study over 18 months.}, journal = {Muscle &amp; nerve}, volume = {70}, number = {3}, pages = {333-345}, doi = {10.1002/mus.28182}, pmid = {39031772}, issn = {1097-4598}, support = {(H4017703513237604)//Boris Canessa ALS Stiftung (D&#xfc;sseldorf, Germany) and Martin Herrenknecht Fonds for ALS Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Male ; Female ; *Patient Reported Outcome Measures ; Middle Aged ; Aged ; *Superoxide Dismutase-1/genetics ; *Neurofilament Proteins/blood ; Treatment Outcome ; Disease Progression ; Adult ; Oligonucleotides/therapeutic use ; }, abstract = {INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (SOD1-ALS), tofersen received accelerated approval in the United States and is available via expanded access programs (EAP) outside the United States. This multicenter study investigates clinical and patient-reported outcomes (PRO) and serum neurofilament light chain (sNfL) during tofersen treatment in an EAP in Germany.<br><br>METHODS: Sixteen SOD1-ALS patients receiving tofersen for at least 6&#x2009;months were analyzed. The ALS progression rate (ALS-PR), as measured by the monthly change of the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity (SVC), and sNfL were investigated. PRO included the Measure Yourself Medical Outcome Profile (MYMOP2), Treatment Satisfaction Questionnaire for Medication (TSQM-9), and Net Promoter Score (NPS).<br><br>RESULTS: Mean tofersen treatment was 11&#x2009;months (6-18&#x2009;months). ALS-PR showed a mean change of -0.2 (range 0 to -1.1) and relative reduction by 25%. Seven patients demonstrated increased ALSFRS-R. SVC was stable (mean 88%, range -15% to +28%). sNfL decreased in all patients except one heterozygous D91A-SOD1 mutation carrier (mean change of sNfL -58%, range -91 to +27%, p&#x2009;<&#x2009;.01). MYMOP2 indicated improved symptom severity (n&#x2009;=&#x2009;10) or yet perception of partial response (n&#x2009;=&#x2009;6). TSQM-9 showed high global treatment satisfaction (mean 83, SD 16) although the convenience of drug administration was modest (mean 50, SD 27). NPS revealed a very high recommendation rate for tofersen (NPS +80).<br><br>DISCUSSION: Data from this EAP supported the clinical and sNfL response to tofersen in SOD1-ALS. PRO suggested a favorable patient perception of tofersen treatment in clinical practice.}, }
@article {pmid39025824, year = {2024}, author = {Lorenc, T and Khouja, C and Harden, M and Fulbright, H and Thomas, J}, title = {Defensive healthcare practice: systematic review of qualitative evidence.}, journal = {BMJ open}, volume = {14}, number = {7}, pages = {e085673}, pmid = {39025824}, issn = {2044-6055}, mesh = {Humans ; *Qualitative Research ; *Defensive Medicine ; Attitude of Health Personnel ; }, abstract = {OBJECTIVE: To synthesise qualitative evidence on clinicians' views and experiences of defensive practice.<br><br>DESIGN: Systematic review of qualitative data.<br><br>DATA SOURCES: MEDLINE, Embase, PsycINFO, AMED, Maternity and Infant Care, CINAHL, ASSIA, Sociological Abstracts, Proquest Dissertations &amp; Theses and PROSPERO were searched from 2000 to October 2023.<br><br>ELIGIBILITY CRITERIA: We included English-language studies of clinicians which reported qualitative data on the impact of litigation or complaints on clinical practice.<br><br>DATA EXTRACTION AND SYNTHESIS: We coded findings data line by line using a grounded theory approach. We assessed quality using Hawker et al's tool and synthesised data thematically.<br><br>RESULTS: 17 studies were included. Participants identify a range of clinical decisions which may be defensively motivated, relating to diagnosis and documentation as well as to treatment. Defensive practice often relates to a diffuse sense of risk rather than the direct threat of litigation and may overlap with other motivations, such as perceived pressure from patients or the desire to avoid harm. Defensive practice is seen to be harmful in many ways, but again, these perceptions may gain force from broader narratives of mistrust and disempowerment, as much as from the risk of litigation.<br><br>CONCLUSIONS: The idea of defensive practice, as enacted, is more complex than some theoretical accounts suggest and may often function to express broader concerns about the work of clinical care. The qualitative evidence calls into question the view of defensive practice as a key mediator linking litigation risk to inappropriate treatment and excess costs.}, }
@article {pmid39022351, year = {2024}, author = {Corvino, A and Caliendo, G and Fiorino, F and Frecentese, F and Valsecchi, V and Lombardi, G and Anzilotti, S and Andreozzi, G and Scognamiglio, A and Sparaco, R and Perissutti, E and Severino, B and Gargiulo, M and Santagada, V and Pignataro, G}, title = {Newly Synthesized Indolylacetic Derivatives Reduce Tumor Necrosis Factor-Mediated Neuroinflammation and Prolong Survival in Amyotrophic Lateral Sclerosis Mice.}, journal = {ACS pharmacology &amp; translational science}, volume = {7}, number = {7}, pages = {1996-2005}, pmid = {39022351}, issn = {2575-9108}, abstract = {The debilitating neurodegenerative disease known as amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons (MNs) in the brain, spinal cord, and motor cortex. The ALS neuroinflammatory component is being characterized and includes the overexpression of mediators, such as inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α). Currently, there are no effective treatments for ALS. Indeed, riluzole, an N-methyl-D-aspartate (NMDA) glutamate receptor blocker, and edaravone, a reactive oxygen species (ROS) scavenger, are currently the sole two medications approved for ALS treatment. However, their efficacy in extending life expectancy typically amounts to only a few months. In order to improve the medicaments for the treatment of neurodegenerative diseases, preferably ALS, novel substituted 2-methyl-3-indolylacetic derivatives (compounds II-IV) were developed by combining the essential parts of two small molecules, namely, the opioids containing a 4-piperidinyl ring with indomethacin, previously shown to be efficacious in different experimental models of neuroinflammation. The synthesized compounds were evaluated for their potential capability of slowing down neurodegeneration associated with ALS progression in preclinical models of the disease in vitro and in vivo. Notably, we produced data to demonstrate that the treatment with the newly synthesized compound III: (1) prevented the upregulation of TNF-α observed in BV-2 microglial cells exposed to the toxin lipopolysaccharides (LPS), (2) preserved SHSY-5Y cell survival exposed to β-N-methylamino-l-alanine (L-BMAA) neurotoxin, and (3) mitigated motor symptoms and improved survival rate of SOD1G93A ALS mice. In conclusion, the findings of the present work support the potential of the synthesized indolylacetic derivatives II-IV in ALS treatment. Indeed, in the attempt to realize an association between two active molecules, we assumed that the combination of the indispensable moieties of two small molecules (the opioids containing a 4-piperidinyl ring with the FANS indomethacin) might lead to new medicaments potentially useful for the treatment of amyotrophic lateral sclerosis.}, }
@article {pmid39020237, year = {2024}, author = {Yuan, ZL and Ren, J and Huang, ML and Qi, YF and Gao, X and Sun, YY and He, YL and Zhu, L and Xue, HD}, title = {A new magnetic resonance imaging-based PUMCH classification system for congenital cervical malformations: devising a standardised diagnosis pathway.}, journal = {Insights into imaging}, volume = {15}, number = {1}, pages = {177}, pmid = {39020237}, issn = {1869-4101}, support = {2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; 2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; 2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; 2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; }, abstract = {OBJECTIVES: To develop an innovative magnetic resonance imaging (MRI)-based PUMCH (Peking Union Medical College Hospital) classification system aimed at standardising the diagnosis of congenital cervical malformations (CCMs) by identifying their distinctive MRI features.<br><br>METHODS: Seventy-nine consecutive patients with CCM underwent pre-treatment pelvic MRI; three experienced gynaecological radiologists retrospectively analysed these images. Qualitative assessments included Rock et al's classification; PUMCH classification; haematometra; cervical signal features; ovarian endometriosis; haematosalpinx; and uterine, vaginal, urinary, and musculoskeletal malformations. Quantitative assessments involved the uterine volume, sagittal cervical length, and maximum ovarian cross-sectional area. The surgical treatment types were also recorded. Statistical methods were used to incorporate differences in clinical features and surgical methods into our classification.<br><br>RESULTS: Morphologically, CCMs were categorised into three types: type I (53%) was characterised by the presence of a cervix with visible cervical canals; type II (23%) featured an existing cervix with concealed cervical canals; and type III (24%) indicated cervical aplasia, which involves a blind end in the lower part of the uterine corpus. Haematometra was significantly more prevalent in patients with type I CCM than in those with type II (p&#x2009;<&#x2009;0.001). There were three cervical signal patterns: no signal (27%), no evident layer differentiation (21%), and multi-layer differentiation with haematocele (52%). Most patients (94%) had complete vaginal atresia. Type I CCM patients had a higher likelihood of regaining normal uterovaginal anatomy compared to types II and III.<br><br>CONCLUSIONS: Our proposed PUMCH classification system has a high potential for enhancing the efficiency of clinical diagnosis among patients with CCM.<br><br>CRITICAL RELEVANCE STATEMENT: The proposed new PUMCH classification promised to elevate the conventional diagnostic trajectory for congenital cervical malformations, offering a valuable framework to refine the selection and planning of surgical interventions, thereby enhancing overall clinical efficacy.<br><br>KEY POINTS: Effective classification of congenital cervical malformations is desirable to optimise the diagnostic process. We presented a PUMCH classification of congenital cervical malformations using pelvic MRI. The new classification significantly aids clinical triage for congenital cervical malformations.}, }
@article {pmid39019674, year = {2024}, author = {Georges, M and Perez, T and Rabec, C and Jacquin, L and Finet-Monnier, A and Ramos, C and Patout, M and Attali, V and Amador, M and Gonzalez-Bermejo, J and Salachas, F and Morelot-Panzini, C}, title = {[Proposals from a French expert panel for respiratory care in ALS patients].}, journal = {Revue des maladies respiratoires}, volume = {41}, number = {8}, pages = {620-637}, doi = {10.1016/j.rmr.2024.06.006}, pmid = {39019674}, issn = {1776-2588}, mesh = {*Amyotrophic Lateral Sclerosis/complications/therapy ; Humans ; France/epidemiology ; *Noninvasive Ventilation/methods/standards/instrumentation ; *Respiratory Insufficiency/therapy/etiology ; Respiratory Therapy/methods/standards ; Quality of Life ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive diaphragm weakness and deteriorating lung function. Bulbar involvement and cough weakness contribute to respiratory morbidity and mortality. ALS-related respiratory failure significantly affects quality of life and is the leading cause of death. Non-invasive ventilation (NIV), which is the main recognized treatment for alleviating the symptoms of respiratory failure, prolongs survival and improves quality of life. However, the optimal timing for the initiation of NIV is still a matter of debate. NIV is a complex intervention. Multiple factors influence the efficacy of NIV and patient adherence. The aim of this work was to develop practical evidence-based advices to standardize the respiratory care of ALS patients in French tertiary care centres.<br><br>METHODS: For each proposal, a French expert panel systematically searched an indexed bibliography and prepared a written literature review that was then shared and discussed. A combined draft was prepared by the chairman for further discussion. All of the proposals were unanimously approved by the expert panel.<br><br>RESULTS: The French expert panel updated the criteria for initiating NIV in ALS patients. The most recent criteria were established in 2005. Practical advice for NIV initiation were included and the value of each tool available for NIV monitoring was reviewed. A strategy to optimize NIV parameters was suggested. Revisions were also suggested for the use of mechanically assisted cough devices in ALS patients.<br><br>CONCLUSION: Our French expert panel proposes an evidence-based review to update the respiratory care recommendations for ALS patients in daily practice.}, }
@article {pmid39017978, year = {2025}, author = {Vinceti, M and Urbano, T and Filippini, T and Bedin, R and Simonini, C and Sorarù, G and Trojsi, F and Michalke, B and Mandrioli, J}, title = {Changes in Cerebrospinal Fluid Concentrations of Selenium Species Induced by Tofersen Administration in Subjects with Amyotrophic Lateral Sclerosis Carrying SOD1 Gene Mutations.}, journal = {Biological trace element research}, volume = {203}, number = {4}, pages = {2355-2364}, pmid = {39017978}, issn = {1559-0720}, support = {"PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Universit&#xe0; e della Ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/drug therapy/genetics ; *Selenium/cerebrospinal fluid ; *Superoxide Dismutase-1/genetics/cerebrospinal fluid ; Male ; *Mutation ; Female ; Middle Aged ; Aged ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the brain and spinal cord motor neurons. On 25 April 2023, the drug tofersen, an antisense oligonucleotide, received the US Food and Drug Administration approval for treating ALS in adults carrying mutations of the SOD1 gene. We aimed at assessing whether cerebrospinal fluid concentrations of selenium, an element of both toxicological and nutritional interest possibly involved in disease etiology and progression, are modified by tofersen administration. We determined concentrations of selenium species by anion exchange chromatography hyphenated to inductively coupled plasma-dynamic reaction cell-mass spectrometry and overall selenium by using inductively coupled plasma sector-field mass spectrometry, at baseline and 6 months after active tofersen treatment in ten Italian ALS patients carrying the SOD1 gene mutation. Concentrations of total selenium and many selenium species substantially increased after the intervention, particularly of inorganic (tetravalent and hexavalent) selenium and of the organic species selenomethionine and a compound co-eluting with the selenocystine standard. Overall, these findings suggest that tofersen treatment markedly alters selenium status and probably the redox status within the central nervous system, possibly due to a direct effect on neurons and/or the blood-brain barrier. Further studies are required to investigate the biological and clinical relevance of these findings and how they might relate to the pharmacological effects of the drug and to disease progression.}, }
@article {pmid39007083, year = {2024}, author = {Chidambaram, SB and Anand, N and Varma, SR and Ramamurthy, S and Vichitra, C and Sharma, A and Mahalakshmi, AM and Essa, MM}, title = {Superoxide dismutase and neurological disorders.}, journal = {IBRO neuroscience reports}, volume = {16}, number = {}, pages = {373-394}, pmid = {39007083}, issn = {2667-2421}, abstract = {Superoxide dismutase (SOD) is a common antioxidant enzyme found majorly in living cells. The main physiological role of SOD is detoxification and maintain the redox balance, acts as a first line of defence against Reactive nitrogen species (RNS), Reactive oxygen species (ROS), and other such potentially hazardous molecules. SOD catalyses the conversion of superoxide anion free radicals (O 2 -.) into molecular oxygen (O 2) and hydrogen peroxide (H 2O 2) in the cells. Superoxide dismutases (SODs) are expressed in neurons and glial cells throughout the CNS both intracellularly and extracellularly. Endogenous oxidative stress (OS) linked with enlarged production of reactive oxygen metabolites (ROMs), inflammation, deregulation of redox balance, mitochondrial dysfunction and bioenergetic crisis are found to be prerequisite for neuronal loss in neurological diseases. Clinical and genetic studies indicate a direct correlation between mutations in SOD gene and neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), Parkinson's Disease (PD) and Alzheimer's Disease (AD). Therefore, inhibitors of OS are considered as an optimistic approach to prevent neuronal loss. SOD mimetics like Metalloporphyrin Mn (II)-cyclic polyamines, Nitroxides and Mn (III)- Salen complexes are designed and used as therapeutic extensively in the treatment of neurological disorders. SODs and SOD mimetics are promising future therapeutics in the field of various diseases with OS-mediated pathology.}, }
@article {pmid39006764, year = {2024}, author = {Yang, C and Liu, G and Chen, X and Le, W}, title = {Cerebellum in Alzheimer's disease and other neurodegenerative diseases: an emerging research frontier.}, journal = {MedComm}, volume = {5}, number = {7}, pages = {e638}, pmid = {39006764}, issn = {2688-2663}, abstract = {The cerebellum is crucial for both motor and nonmotor functions. Alzheimer's disease (AD), alongside other dementias such as vascular dementia (VaD), Lewy body dementia (DLB), and frontotemporal dementia (FTD), as well as other neurodegenerative diseases (NDs) like Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias (SCA), are characterized by specific and non-specific neurodegenerations in central nervous system. Previously, the cerebellum's significance in these conditions was underestimated. However, advancing research has elevated its profile as a critical node in disease pathology. We comprehensively review the existing evidence to elucidate the relationship between cerebellum and the aforementioned diseases. Our findings reveal a growing body of research unequivocally establishing a link between the cerebellum and AD, other forms of dementia, and other NDs, supported by clinical evidence, pathological and biochemical profiles, structural and functional neuroimaging data, and electrophysiological findings. By contrasting cerebellar observations with those from the cerebral cortex and hippocampus, we highlight the cerebellum's distinct role in the disease processes. Furthermore, we also explore the emerging therapeutic potential of targeting cerebellum for the treatment of these diseases. This review underscores the importance of the cerebellum in these diseases, offering new insights into the disease mechanisms and novel therapeutic strategies.}, }
@article {pmid39006715, year = {2024}, author = {Suleiman Khoury, Z and Sohail, F and Wang, J and Mendoza, M and Raake, M and Tahoor Silat, M and Reddy Bathinapatta, M and Sadeghzadegan, A and Meghana, P and Paul, J}, title = {Neuroinflammation: A Critical Factor in Neurodegenerative Disorders.}, journal = {Cureus}, volume = {16}, number = {6}, pages = {e62310}, pmid = {39006715}, issn = {2168-8184}, abstract = {This review offers a comprehensive review of the signals and the paramount role neuroinflammation plays in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The study explores the sophisticated interactions between microglial, astrocytic, and dendritic cells and how neuroinflammation affects long-term neuronal damage and dysfunction. There are specific pathways related to the mentioned inflammatory processes, including Janus kinases/signal transducer and activator of transcriptions, nuclear factor-κB, and mitogen-activated protein kinases pathways. Neuroinflammation is argued to be a double-edged sword, being not only a protective agent that prevents further neuron damage but also the causative factor in more cell injury development. This concept of contrasting inflammation with neuroprotection advocates for the use of therapeutic techniques that seek to modulate neuroinflammatory responses as part of the neurodegeneration treatment. The recent research findings are integrated with the established knowledge to help present a comprehensive image of neuroinflammation's impact on neurodegenerative diseases and its implications for future therapy.}, }
@article {pmid39002811, year = {2024}, author = {Huin, V and Blum, D and Delforge, V and Cailliau, E and Djeziri, S and Dujardin, K and Genet, A and Viard, R and Attarian, S and Bruneteau, G and Cassereau, J and Genestet, S and Kaminsky, AL and Soriani, MH and Lefilliatre, M and Couratier, P and Pittion-Vouyovitch, S and Esselin, F and De La Cruz, E and Guy, N and Kolev, I and Corcia, P and Cintas, P and Desnuelle, C and Buée, L and Danel-Brunaud, V and Devos, D and Rolland, AS}, title = {Caffeine consumption outcomes on amyotrophic lateral sclerosis disease progression and cognition.}, journal = {Neurobiology of disease}, volume = {199}, number = {}, pages = {106603}, doi = {10.1016/j.nbd.2024.106603}, pmid = {39002811}, issn = {1095-953X}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; Basic Helix-Loop-Helix Transcription Factors ; *Caffeine ; Central Nervous System Stimulants/therapeutic use ; Cognition/physiology/drug effects ; Cognitive Dysfunction/genetics ; Cytochrome P-450 CYP1A1/genetics ; *Cytochrome P-450 CYP1A2/genetics ; *Disease Progression ; *Polymorphism, Single Nucleotide ; Prospective Studies ; *Receptor, Adenosine A2A/genetics ; Receptors, Aryl Hydrocarbon/genetics ; Riluzole/therapeutic use ; }, abstract = {Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.}, }
@article {pmid38999592, year = {2024}, author = {Li, Q and Wang, H and Yu, J and Zhang, W and Guo, W and Liu, Y}, title = {Metabolism-Based Herbicide Resistance to Mesosulfuron-methyl and Identification of Candidate Genes in Bromus japonicus.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {13}, pages = {}, pmid = {38999592}, issn = {2223-7747}, support = {23JCQNJC00450//Tianjin Natural Science Foundation/ ; 2021CXGC010811//Key R&amp;D Program of Shandong Province, China/ ; }, abstract = {The evolved resistance of Bromus japonicus Houtt. to ALS-inhibiting herbicides is well established. Previous studies have primarily focused on target-site resistance; however, non-target-site resistance has not been well characterized. This investigation demonstrated that ALS gene sequencing did not detect any previously known resistance mutations in a mesosulfuron-methyl-resistant (MR) population, and notably, treatment with the P450 monooxygenase (P450) inhibitor malathion markedly heightened susceptibility to mesosulfuron-methyl. Utilizing UPLC-MS/MS analysis confirmed elevated mesosulfuron-methyl metabolism in MR plants. The integration of Isoform Sequencing (Iso-Seq) and RNA Sequencing (RNA-Seq) facilitated the identification of candidate genes associated with non-target sites in a subpopulation with two generations of herbicide selection. Through qRT-PCR analysis, 21 differentially expressed genes were characterized, and among these, 10 genes (comprising three P450s, two glutathione S-transferases, one glycosyltransferase, two ATP-binding cassette transporters, one oxidase, and one hydrolase) exhibited constitutive upregulation in resistant plants. Our findings substantiated that increased herbicide metabolism is a driving force behind mesosulfuron-methyl resistance in this B. japonicus population.}, }
@article {pmid38999371, year = {2024}, author = {Dell'Anna, G and Fanti, L and Fanizza, J and Barà, R and Barchi, A and Fasulo, E and Elmore, U and Rosati, R and Annese, V and Laterza, L and Fuccio, L and Azzolini, F and Danese, S and Mandarino, FV}, title = {VAC-Stent in the Treatment of Post-Esophagectomy Anastomotic Leaks: A New "Kid on the Block" Who Marries the Best of Old Techniques-A Review.}, journal = {Journal of clinical medicine}, volume = {13}, number = {13}, pages = {}, pmid = {38999371}, issn = {2077-0383}, abstract = {Esophagectomy, while a pivotal treatment for esophageal cancer, is not without adverse events. Among these, anastomotic leak (AL) is the most feared complication, threatening patient lives and incurring significant healthcare costs. The management of AL is complex and lacks standardization. Given the high morbidity and mortality rates associated with redo-surgery, which poses risks for already fragile patients, various endoscopic treatments have been developed over time. Self-expandable metallic stents (SEMSs) were the most widely used treatment until the early 2000s. The mechanism of action of SEMSs includes covering the wall defect, protecting it from secretions, and promoting healing. In 2010, endoscopic vacuum therapy (EVT) emerged as a viable alternative for treating ALs, quickly gaining acceptance in clinical practice. EVT involves placing a dedicated sponge under negative pressure inside or adjacent to the wall defect, aiming to clear the leak and promote granulation tissue formation. More recently, the VAC-Stent entered the scenario of endoscopic treatment of post-esophagectomy ALs. This device combines a fully covered SEMS with an integrated EVT sponge, blending the ability of SEMSs to exclude defects and maintain the patency of the esophageal lumen with the capacity of EVT to aspirate secretions and promote the formation of granulation tissue. Although the literature on this new device is not extensive, early results from the application of VAC-Stent have shown promising outcomes. This review aims to synthesize the preliminary efficacy and safety data on the device, thoroughly analyze its advantages over traditional techniques and disadvantages, explore areas for improvement, and propose future directions.}, }
@article {pmid38997748, year = {2024}, author = {Kato, C and Ueda, K and Morimoto, S and Takahashi, S and Nakamura, S and Ozawa, F and Ito, D and Daté, Y and Okada, K and Kobayashi, N and Nakahara, J and Okano, H}, title = {Proteomic insights into extracellular vesicles in ALS for therapeutic potential of Ropinirole and biomarker discovery.}, journal = {Inflammation and regeneration}, volume = {44}, number = {1}, pages = {32}, pmid = {38997748}, issn = {1880-9693}, support = {JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; }, abstract = {BACKGROUND: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs.<br><br>METHODS: We collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment.<br><br>RESULTS: The findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search.<br><br>CONCLUSIONS: Despite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.}, }
@article {pmid38996764, year = {2024}, author = {Montero, AS and Aliouat, I and Ribon, M and Canney, M and Goldwirt, L and Mourah, S and Berriat, F and Lobsiger, CS and Pradat, PF and Salachas, F and Bruneteau, G and Carpentier, A and Boillée, S}, title = {Effect of ultrasound-mediated blood-spinal cord barrier opening on survival and motor function in females in an amyotrophic lateral sclerosis mouse model.}, journal = {EBioMedicine}, volume = {106}, number = {}, pages = {105235}, pmid = {38996764}, issn = {2352-3964}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/therapy ; Female ; *Disease Models, Animal ; Mice ; *Spinal Cord/metabolism ; *Blood-Brain Barrier/metabolism ; *Insulin-Like Growth Factor I/metabolism ; Mice, Transgenic ; Humans ; Motor Neurons/metabolism ; Ultrasonic Waves ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. The limited efficacy of recent therapies in clinical development may be linked to lack of drug penetration to the affected motor neurons due to the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB).<br><br>METHODS: In this work, the safety and efficacy of repeated short transient opening of the BSCB by low intensity pulsed ultrasound (US, sonication) was studied in females of an ALS mouse model (B6.Cg-Tg(SOD1&#x2217;G93A)1Gur/J). The BSCB was disrupted using a 1&#xa0;MHz ultrasound transducer coupled to the spinal cord, with and without injection of insulin-like growth factor 1 (IGF1), a neurotrophic factor that has previously shown efficacy in ALS models.<br><br>FINDINGS: Results in wild-type (WT) animals demonstrated that the BSCB can be safely disrupted and IGF1 concentrations significantly enhanced after a single session of transient BSCB disruption (176&#xa0;&#xb1;&#xa0;32&#xa0;&#x3bc;g/g vs. 0.16&#xa0;&#xb1;&#xa0;0.008&#xa0;&#x3bc;g/g, p&#xa0;<&#xa0;0.0001). Five repeated weekly US sessions performed in female ALS mice demonstrated a survival advantage in mice treated with IGF1 and US (US IGF1) compared to treatment with IGF1 alone (176 vs. 166 days, p&#xa0;=&#xa0;0.0038). Surprisingly, this survival advantage was also present in mice treated with US alone vs. untreated mice (178.5 vs. 166.5 days, p&#xa0;=&#xa0;0.0061). Muscle strength did not show difference among the groups. Analysis of glial cell immunoreactivity and microglial transcriptome showing reduced cell proliferation pathways, in addition to lymphocyte infiltration, suggested that the beneficial effect of US or US IGF1 could act through immune cell modulation.<br><br>INTERPRETATION: These results show the first step towards a possible beneficial impact of transient BSCB opening for ALS therapy and suggest implication of immune cells.<br><br>FUNDING: Fondation pour la Recherche M&#xe9;dicale (FRM). Investissements d'avenirANR-10-IAIHU-06, Soci&#xe9;t&#xe9; Fran&#xe7;aise de Neurochirurgie (SFNC), Fond d'&#xe9;tude et de Recherche du Corps Medical (FERCM), Aide &#xe0; la Recherche des Maladies du Cerveau (ARMC), SLA Fondation Recherche (SLAFR), French Ministry for High Education and Research (MENR), Carthera, Laboratoire de Recherche en Technologies Chirurgicales Avanc&#xe9;es (LRTCA).}, }
@article {pmid38996643, year = {2024}, author = {Sheehan, Y and Cochrane, A and Treloar, C and Grebely, J and Tedla, N and Lloyd, AR and Lafferty, L}, title = {Understanding hepatitis C virus (HCV) health literacy and educational needs among people in prison to enhance HCV care in prisons.}, journal = {The International journal on drug policy}, volume = {130}, number = {}, pages = {104516}, doi = {10.1016/j.drugpo.2024.104516}, pmid = {38996643}, issn = {1873-4758}, mesh = {Humans ; Male ; *Health Literacy ; *Hepatitis C ; *Prisoners/psychology ; Adult ; Australia ; *Prisons ; Middle Aged ; Health Knowledge, Attitudes, Practice ; Substance Abuse, Intravenous ; }, abstract = {BACKGROUND: Hepatitis C virus (HCV) is a significant concern within prison populations. Provision of HCV testing and treatment for people in prison is expanding and a key component of global elimination efforts. Despite growing service availability, several challenges remain in HCV testing and treatment engagement during incarceration. The PIVOT study demonstrated that a 'one-stop-shop' intervention (point-of-care HCV RNA testing, Fibroscan®, nurse-led clinical assessment, and fast-tracked direct-acting antiviral prescription) enhanced HCV testing and treatment at a reception prison in Australia. Utilising Squier et al's Health Literacy Skills Framework, this analysis aimed to understand HCV health literacy and educational needs among people at a reception prison in Australia.<br><br>METHODS: Semi-structured interviews were conducted with twenty-four male PIVOT study participants. Purposive sampling ensured comparable representation of those with: 1) prior HCV testing history (standard pathology / no prior testing), and 2) injecting drug use history (IDU; ever / never).<br><br>RESULTS: Varied HCV health literacy levels and educational needs were evident amongst people in prison. Whilst those with multiple incarceration episodes and IDU history (prior knowledge) appeared to have stronger HCV health literacy than those without, substantial gaps in HCV health literacy were evident. Knowledge of HCV transmission risks in prison was high, and most understood the importance of HCV testing and treatment in prison (comprehension), but ability to engage with HCV testing and treatment services, participation in safe injecting behaviours (health-related behaviours), and knowledge of re-infection and re-treatment, within the context of the prison environment, were suboptimal. There was a general desire for increased HCV education in prison.<br><br>CONCLUSION: Gaps in HCV health literacy among people in prison were evident, indicating opportunities for improvement. A targeted HCV education program for people in prison, addressing the gaps identified in this analysis, may enhance HCV testing, treatment, and prevention by fostering stronger HCV health literacy among people in prison.}, }
@article {pmid38990927, year = {2024}, author = {Srinivasan, V and Homer, V and Barton, D and Clutterbuck-James, A and Jenkins, S and Potter, C and Brock, K and Logan, A and Smith, D and Bruce, L and Nagy, Z and Bach, SP}, title = {A low molecular weight dextran sulphate, ILB®, for the treatment of amyotrophic lateral sclerosis (ALS): An open-label, single-arm, single-centre, phase II trial.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0291285}, pmid = {38990927}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Aged ; Prospective Studies ; Treatment Outcome ; Adult ; Neuroprotective Agents/therapeutic use/administration &amp; dosage/adverse effects ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig´s disease, is a rare neurological condition and is the most common motor neurone disease. It is a fatal disease with specific loss of motor neurons in the spinal cord, brain stem, and motor cortex leading to progressive paralysis and usually death within five years of diagnosis. There remains no cure for ALS, and management is focused on a combination of neuroprotective medication, respiratory support, and management by multidisciplinary clinics.<br><br>PATIENTS AND METHODS: This prospective, single-arm, open-label phase II clinical trial of sustained weekly administration of 2 mg/kg ILB&#xae; (a low-molecular weight dextran sulphate) was conducted in a single UK hospital. Eligible patients were at least 18 years and had a definite diagnosis of ALS according to El Escorial Criteria. The co-primary outcomes were safety, tolerability, and quantity of ILB&#xae; administered. EudraCT number. 2018-000668-28.<br><br>FINDINGS: Between 18-Apr-2019 and 27-Mar-2020, 11 patients were recruited and treated for up to 38 weeks. There were no treatment terminations or withdrawals. One serious adverse event was reported, which was not related to ILB&#xae; and resolved without sequalae. 270 mild/moderate adverse events were reported with no intolerable events occurring during the trial. The total number of ILB&#xae; treatments administered per patient ranged from 4 to 38, with a cumulative dose ranging from 745 to 6668 mg. As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and treatment was suspended early in Mar-2020. At the long-term follow-up, three patients had died after the trial was halted, between 53 and 62 weeks after their final ILB&#xae; injection.<br><br>INTERPRETATION: Long-term weekly ILB&#xae; injections of 2 mg/kg was well tolerated and had an acceptable safety profile in patients with ALS.<br><br>TRIAL REGISTRATION: EudraCT: 2018-000668-28. clinicaltrials.gov: NCT03705390. This trial adheres to the principles of GCP in the design, conduct, recording and reporting of clinical trials as listed in part 2, "Conditions and Principles which apply to all Clinical Trials" under the header "Principles based on Articles 2 to 5 of the EU GCP Directive" in the Medicines for Human Use Clinical Trials Regulations (as amended in SI 2006/1928). For clarity, the study did not conform to all aspects of the International Conference on Harmonisation (ICH) E6 R2 Guidelines for GCP (also known as 'ICH GCP'). Of note, we did not use an external database, perform 100% source data verification, and only primary outcome data were analysed in parallel by a second, independent statistician.}, }
@article {pmid38975145, year = {2024}, author = {Zhang, J and Xie, D and Jiao, D and Zhou, S and Liu, S and Ju, Z and Hu, L and Qi, L and Yao, C and Zhao, C}, title = {From inflammatory signaling to neuronal damage: Exploring NLR inflammasomes in ageing neurological disorders.}, journal = {Heliyon}, volume = {10}, number = {12}, pages = {e32688}, pmid = {38975145}, issn = {2405-8440}, abstract = {The persistence of neuronal degeneration and damage is a major obstacle in ageing medicine. Nucleotide-binding oligomerization domain (NOD)-like receptors detect environmental stressors and trigger the maturation and secretion of pro-inflammatory cytokines that can cause neuronal damage and accelerate cell death. NLR (NOD-like receptors) inflammasomes are protein complexes that contain NOD-like receptors. Studying the role of NLR inflammasomes in ageing-related neurological disorders can provide valuable insights into the mechanisms of neurodegeneration. This includes investigating their activation of inflammasomes, transcription, and capacity to promote or inhibit inflammatory signaling, as well as exploring strategies to regulate NLR inflammasomes levels. This review summarizes the use of NLR inflammasomes in guiding neuronal degeneration and injury during the ageing process, covering several neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and peripheral neuropathies. To improve the quality of life and slow the progression of neurological damage, NLR-based treatment strategies, including inhibitor-related therapies and physical therapy, are presented. Additionally, important connections between age-related neurological disorders and NLR inflammasomes are highlighted to guide future research and facilitate the development of new treatment options.}, }
@article {pmid38973130, year = {2025}, author = {Corcia, P and Guy, N and Pradat, PF and Soriani, MH and Verschueren, A and Couratier, P}, title = {Treatment continuity of amyotrophic lateral sclerosis with available riluzole formulations: state of the art and current challenges in a 'real-world' setting.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {15-21}, doi = {10.1080/21678421.2024.2375330}, pmid = {38973130}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/complications ; *Riluzole/therapeutic use ; Humans ; *Neuroprotective Agents/therapeutic use ; Deglutition Disorders/drug therapy/etiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare multisystem neurodegenerative disease leading to death due to respiratory failure. Riluzole was the first disease modifying treatment approved in ALS. Randomized clinical trials showed a significant benefit of riluzole on survival in the months following randomization, with a good safety profile. 'Real-world' studies suggested that the survival benefit of riluzole is substantially greater, with an extended survival ranging between 6 and 19 months. The main limiting associated adverse effects of riluzole are non-severe gastrointestinal complications and an elevation of liver enzymes, observed in 10% of patients. While different classes of drugs have been approved in some countries, riluzole remains the gold standard of therapy. Dysphagia induced by ALS is a major challenge for food intake and riluzole administration. Tablet crushing is associated with a loss of drug intake and a risk of powder aspiration, which jeopardizes the benefits of riluzole. Riluzole oral suspension (ROS) and oral film (ROF) allow riluzole intake in patients with dysphagia. Both formulations are bioequivalent to riluzole tablets with a good safety profile albeit transient oral hypoaesthesia. In case of severe dysphagia, ROS can be used with percutaneous endoscopic gastrostomy. ROF, the last approved formulation, requires low swallowing capacities and may contribute to maintain the efficacy of riluzole when tablets are inadequate according to patient's status and/or preferences. To optimize treatment continuity in newly diagnosed patients, the expected psychological impact of formulation switching that may be perceived as the sign of disease progression should be anticipated.}, }
@article {pmid38972779, year = {2024}, author = {Pelaez, MC and Fiore, F and Larochelle, N and Dabbaghizadeh, A and Comaduran, MF and Arbour, D and Minotti, S and Marcadet, L and Semaan, M and Robitaille, R and Nalbantoglu, JN and Sephton, CF and Durham, HD}, title = {Reversal of cognitive deficits in FUS[R521G] amyotrophic lateral sclerosis mice by arimoclomol and a class I histone deacetylase inhibitor independent of heat shock protein induction.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {5}, pages = {e00388}, pmid = {38972779}, issn = {1878-7479}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Mice ; *Mice, Transgenic ; Heat-Shock Proteins/genetics/metabolism ; Hydroxylamines/pharmacology/therapeutic use ; Cognitive Dysfunction/drug therapy/metabolism ; Disease Models, Animal ; Spinal Cord/drug effects/metabolism ; Humans ; Mice, Inbred C57BL ; }, abstract = {Protein misfolding and mislocalization are common to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Maintaining proteostasis through induction of heat shock proteins (HSP) to increase chaperoning capacity is a rational therapeutic strategy in the treatment of ALS. However, the threshold for upregulating stress-inducible HSPs remains high in neurons, presenting a therapeutic obstacle. This study used mouse models expressing the ALS variants FUS[R521G] or SOD1[G93A] to follow up on previous work in cultured motor neurons showing varied effects of the HSP co-inducer, arimoclomol, and class I histone deacetylase (HDAC) inhibitors on HSP expression depending on the ALS variant being expressed. As in cultured neurons, neither expression of the transgene nor drug treatments induced expression of HSPs in cortex, spinal cord or muscle of FUS[R521G] mice, indicating suppression of the heat shock response. Nonetheless, arimoclomol, and RGFP963, restored performance on cognitive tests and improved cortical dendritic spine densities. In SOD1[G93A] mice, multiple HSPs were upregulated in hindlimb skeletal muscle, but not in lumbar spinal cord with the exception of HSPB1 associated with astrocytosis. Drug treatments improved contractile force but reduced the increase in HSPs in muscle rather than facilitating their expression. The data point to mechanisms other than amplification of the heat shock response underlying recovery of cognitive function in ALS-FUS mice by arimoclomol and class I HDAC inhibition and suggest potential benefits in counteracting cognitive impairment in ALS, frontotemporal dementia and related disorders.}, }
@article {pmid38972199, year = {2024}, author = {Rosén, C and Mitre, B and Nellgård, B and Axelsson, M and Constantinescu, R and Andersen, PM and Dalla, K and Blennow, K and Nilsson, G and Zetterberg, H and Rosén, H}, title = {High levels of neurofilament light and YKL-40 in cerebrospinal fluid are related to poor outcome in ALS.}, journal = {Journal of the neurological sciences}, volume = {463}, number = {}, pages = {123112}, doi = {10.1016/j.jns.2024.123112}, pmid = {38972199}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis/blood ; *Chitinase-3-Like Protein 1/cerebrospinal fluid/blood ; Female ; Male ; *Neurofilament Proteins/cerebrospinal fluid ; Middle Aged ; Aged ; *Biomarkers/cerebrospinal fluid ; Glial Fibrillary Acidic Protein/cerebrospinal fluid ; Disease Progression ; Adult ; Membrane Glycoproteins ; Receptors, Immunologic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease without effective treatment. No pathognomonic test can diagnose ALS in sporadic cases. Routine investigation in suspected cases includes neurological examination, imaging of the brain and spine and electromyography supported by blood and cerebrospinal fluid (CSF) analyses. The ALS diagnosis is made by clinical judgement and results from examinations. We aimed to study if the CSF biomarkers neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), YKL-40, soluble amyloid precursor protein (sAPP) α and β, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with ALS diagnosis and could predict disease progression. Eighty-one patients with suspected ALS were included after referral to the neurological clinic at Sahlgrenska University Hospital. Fifty-nine patients were diagnosed having ALS, while 22 patients were given alternative diagnoses and labeled ALS mimics. Finally, 25 age-matched neurologically intact individuals were used as controls. ALS patients had significantly higher CSF levels of NFL than controls and mimics. Levels of YKL-40 and GFAP were significantly higher in ALS patients compared with controls. No difference was found between study groups when comparing levels of sAPPα, sAPPβ and sTREM2. Further, elevated levels of NFL and YKL-40 were associated with an increased hazard of death and the annual decline in ALSFRS-R. We also found that patients with elevated levels of both NFL and YKL-40 had a particularly poor prognosis. The results demonstrate the usefulness of CSF biomarkers in the diagnosis and prognostication of ALS.}, }
@article {pmid38969143, year = {2024}, author = {Jha, SK and Nelson, VK and Suryadevara, PR and Panda, SP and Pullaiah, CP and Nuli, MV and Kamal, M and Imran, M and Ausali, S and Abomughaid, MM and Srivastava, R and Deka, R and Pritam, P and Gupta, N and Shyam, H and Singh, IK and Pandey, BW and Dewanjee, S and Jha, NK and Jafari, SM}, title = {Cannabidiol and neurodegeneration: From molecular mechanisms to clinical benefits.}, journal = {Ageing research reviews}, volume = {100}, number = {}, pages = {102386}, doi = {10.1016/j.arr.2024.102386}, pmid = {38969143}, issn = {1872-9649}, mesh = {Humans ; *Cannabidiol/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis are severe and life-threatening conditions in which significant damage of functional neurons occurs to produce psycho-motor malfunctions. NDs are an important cause of death in the elderly population worldwide. These disorders are commonly associated with the progression of age, oxidative stress, and environmental pollutants, which are the major etiological factors. Abnormal aggregation of specific proteins such as α-synuclein, amyloid-β, huntingtin, and tau, and accumulation of the associated oligomers in neurons are the hallmark pathological features of NDs. Existing therapeutic options for NDs are only symptomatic relief and do not address root-causing factors, such as protein aggregation, oxidative stress, and neuroinflammation. Cannabidiol (CBD) is a non-psychotic natural cannabinoid obtained from Cannabis sativa that possesses multiple pharmacological actions, including antioxidant, anti-inflammatory, and neuroprotective effects in various NDs and other neurological disorders both in vitro and in vivo. CBD has gained attention as a promising drug candidate for the management of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, by inhibiting protein aggregation, free radicals, and neuroinflammation. In parallel, CBD has shown positive results in other neurological disorders, such as epilepsy, depression, schizophrenia, and anxiety, as well as adjuvant treatment with existing standard therapeutic agents. Hence, the present review focuses on exploring the possible molecular mechanisms in controlling various neurological disorders as well as the clinical applications of CBD in NDs including epilepsy, depression and anxiety. In this way, the current review will serve as a standalone reference for the researchers working in this area.}, }
@article {pmid38967881, year = {2024}, author = {Rojas-López, JC and Estrada-Gualdron, PI and Ramírez-Guerrero, S and Velásquez-Cárdenas, MJ and Redondo-Escobar, J and Vargas-Arenas, S and Palacios-Sánchez, L and Palacios-Espinosa, X}, title = {Efficacy of pain management strategies in adults with Amyotrophic Lateral Sclerosis (ALS): A Systematic Review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {12}, pages = {5591-5604}, pmid = {38967881}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Pain Management/methods ; Adult ; Pain/etiology/drug therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness. Presence of pain in ALS patients is heterogeneously reported in studies, and mostly underrepresented in symptom scales. The aim of this study is to evaluate the efficacy of pharmacological and non-pharmacological therapeutic modalities for pain management in patients with ALS. A systematic review was conducted in four databases; PubMed, Scopus, Clinicaltrials.gov, and Cochrane-Ovid. Five randomized controlled clinical trials were included regarding pharmacological and non-pharmacological pain management interventions in adult patients with confirmed diagnosis of ALS in whom pain was objectively evaluated. Risk of bias assessment was evaluated using the RoB2.0 tool. Eligible studies were reported as a descriptive analysis. This systematic review was registered with PROSPERO ID: CRD42024495009. Five clinical trials regarding pain management strategies in ALS were eligible for analysis. Two out of five were non-pharmacological approaches whilst the remaining three provided pharmacological therapies. Of these, Mexiletine was efficient in terms of pain relief, particularly between 600 and 900 mg per day, whereas Mecasin showed no pain relief at both, high and low doses. Non-pharmacological therapies, such as exercise and osteopathic manual treatment also lacked efficacy in regard to pain management. Clinical trials focusing on pain management strategies for ALS patients are limited. Medical professionals, understandably focused on immediate life-threatening aspects, may inadvertently sideline the nuanced and intricate dimension of pain experienced by patients with ALS.}, }
@article {pmid38960473, year = {2024}, author = {R, HC and Datta, A and S, UK and Zayed, H and D, TK and C, GPD}, title = {Decoding genetic and pathophysiological mechanisms in amyotrophic lateral sclerosis and primary lateral sclerosis: A comparative study of differentially expressed genes and implicated pathways in motor neuron disorders.}, journal = {Advances in protein chemistry and structural biology}, volume = {141}, number = {}, pages = {177-201}, doi = {10.1016/bs.apcsb.2023.12.008}, pmid = {38960473}, issn = {1876-1631}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Gene Expression Profiling ; Motor Neuron Disease/genetics/metabolism ; }, abstract = {Motor Neuron Disorders (MNDs), characterized by the degradation and loss of function of motor neurons, are recognized as fatal conditions with limited treatment options and no known cure. The present study aimed to identify the pathophysiological functions and affected genes in patients with MNDs, specifically Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS). The GSE56808 dataset comprised three sample groups: six patients diagnosed with ALS (GSM1369650, GSM1369652, GSM1369654, GSM1369656, GSM1369657, GSM1369658), five patients diagnosed with PLS (GSM1369648, GSM1369649, GSM1369653, GSM1369655, GSM1369659), and six normal controls (GSM1369642, GSM1369643, GSM1369644, GSM1369645, GSM1369646, and GSM1369647). The application of computational analysis of microarray gene expression profiles enabled us to identify 346 significantly differentially expressed genes (DEGs), 169 genes for the ALS sample study, and 177 genes for the PLS sample study. Enrichment was carried out using MCODE, a Cytoscape plugin. Functional annotation of DEGs was carried out via ClueGO/CluePedia (v2.5.9) and further validated via the DAVID database. NRP2, SEMA3D, ROBO3 and, CACNB1, CACNG2 genes were identified as the gene of interest for ALS and PLS sample groups, respectively. Axonal guidance (GO:0007411) and calcium ion transmembrane transport (GO:0070588) were identified to be some of the significantly dysregulated gene ontology (GO) terms, with arrhythmogenic right ventricular cardiomyopathy (KEGG:05412) to be the top relevant KEGG pathway which is affected in MND patients. ROBO3 gene was observed to have distinctive roles in ALS and PLS-affected patients, hinting towards the differential progression of ALS from PLS. The insights derived from our comprehensive analysis accentuate the distinct variances in the underlying molecular pathogenesis of ALS and PLS. Further research should investigate the mechanistic roles of the identified DEGs and molecular pathways, leading to potential targeted therapies for ALS and PLS.}, }
@article {pmid38960099, year = {2024}, author = {Bhandari, UR and Danish, SM and Ahmad, S and Ikram, M and Nadaf, A and Hasan, N and Kesharwani, P and Ahmad, FJ}, title = {New opportunities for antioxidants in amelioration of neurodegenerative diseases.}, journal = {Mechanisms of ageing and development}, volume = {221}, number = {}, pages = {111961}, doi = {10.1016/j.mad.2024.111961}, pmid = {38960099}, issn = {1872-6216}, mesh = {Humans ; *Antioxidants/pharmacology/therapeutic use ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Oxidative Stress/drug effects ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {This comprehensive review elucidates the critical role of antioxidants to mitigate oxidative stress, a common denominator in an array of neurodegenerative disorders. Oxidative stress-induced damage has been linked to the development of diseases such as Alzheimer's, Parkinson's, Huntington's disease and amyotrophic lateral sclerosis. This article examines a wide range of scientific literature and methodically delineates the several methods by which antioxidants exercise their neuroprotective benefits. It also explores into the complex relationship between oxidative stress and neuroinflammation, focusing on how antioxidants can alter signaling pathways and transcription factors to slow neurodegenerative processes. Key antioxidants, such as vitamins C and E, glutathione, and polyphenolic compounds, are tested for their ability to combat reactive oxygen and nitrogen species. The dual character of antioxidants, which operate as both direct free radical scavengers and regulators of cellular redox homeostasis, is investigated in terms of therapeutic potential. Furthermore, the study focuses on new antioxidant-based therapy techniques and their mechanisms including Nrf-2, PCG1α, Thioredoxin etc., which range from dietary interventions to targeted antioxidant molecules. Insights into ongoing clinical studies evaluating antioxidant therapies in neurodegenerative illnesses offer an insight into the translational potential of antioxidant research. Finally, this review summarizes our present understanding of antioxidant processes in neurodegenerative illnesses, providing important possibilities for future study and treatment development.}, }
@article {pmid38951798, year = {2024}, author = {Pottinger, TD and Motelow, JE and Povysil, G and Moreno, CAM and Ren, Z and Phatnani, H and ,  and Aitman, TJ and Santoyo-Lopez, J and ,  and Mitsumoto, H and ,  and ,  and ,  and Goldstein, DB and Harms, MB}, title = {Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.}, journal = {BMC genomics}, volume = {25}, number = {1}, pages = {651}, pmid = {38951798}, issn = {1471-2164}, support = {P01 AG007232/AG/NIA NIH HHS/United States ; U19 AI067854/AI/NIAID NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; UM1 AI100645/AI/NIAID NIH HHS/United States ; T32 HL144442/HL/NHLBI NIH HHS/United States ; }, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics ; Ethnicity/genetics ; Genetic Predisposition to Disease ; Genetic Variation ; European People ; East Asian People ; African People ; Hispanic or Latino ; Middle Eastern People ; South Asian People ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.<br><br>METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic&#xa0;cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.<br><br>RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR&#x2009;=&#x2009;19.18, p&#x2009;=&#x2009;3.67&#x2009;&#xd7;&#x2009;10[-39]; OR&#x2009;=&#x2009;4.73, p&#x2009;=&#x2009;2&#x2009;&#xd7;&#x2009;10[-10]; OR&#x2009;=&#x2009;2.3, p&#x2009;=&#x2009;7.49&#x2009;&#xd7;&#x2009;10[-9], respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p&#x2009;=&#x2009;4.88&#x2009;&#xd7;&#x2009;10[-7]), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR&#x2009;=&#x2009;10.08, p&#x2009;=&#x2009;3.62&#x2009;&#xd7;&#x2009;10[-16]). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p&#x2009;=&#x2009;8.38&#x2009;&#xd7;&#x2009;10[-6]).<br><br>CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.}, }
@article {pmid38948094, year = {2024}, author = {Haider, KH}, title = {Priming mesenchymal stem cells to develop "super stem cells".}, journal = {World journal of stem cells}, volume = {16}, number = {6}, pages = {623-640}, pmid = {38948094}, issn = {1948-0210}, abstract = {The stem cell pre-treatment approaches at cellular and sub-cellular levels encompass physical manipulation of stem cells to growth factor treatment, genetic manipulation, and chemical and pharmacological treatment, each strategy having advantages and limitations. Most of these pre-treatment protocols are non-combinative. This editorial is a continuum of Li et al's published article and Wan et al's editorial focusing on the significance of pre-treatment strategies to enhance their stemness, immunoregulatory, and immunosuppressive properties. They have elaborated on the intricacies of the combinative pre-treatment protocol using pro-inflammatory cytokines and hypoxia. Applying a well-defined multi-pronged combinatorial strategy of mesenchymal stem cells (MSCs), pre-treatment based on the mechanistic understanding is expected to develop "Super MSCs", which will create a transformative shift in MSC-based therapies in clinical settings, potentially revolutionizing the field. Once optimized, the standardized protocols may be used with slight modifications to pre-treat different stem cells to develop "super stem cells" with augmented stemness, functionality, and reparability for diverse clinical applications with better outcomes.}, }
@article {pmid38946579, year = {2024}, author = {Trucco, AP and Backhouse, T and Mioshi, E}, title = {Describing and assessing behavioural symptoms in amyotrophic lateral sclerosis with and without frontotemporal dementia: a scoping review.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {603-610}, pmid = {38946579}, issn = {1473-6551}, mesh = {Humans ; *Frontotemporal Dementia/psychology/physiopathology/diagnosis ; *Amyotrophic Lateral Sclerosis/psychology/complications/diagnosis ; Behavioral Symptoms/etiology/diagnosis ; }, abstract = {PURPOSE OF REVIEW: Alongside motor and cognitive symptoms, amyotrophic lateral sclerosis (ALS) and ALS with frontotemporal dementia (ALSFTD) present with behavioural symptoms, which can be challenging for all affected by the disease. A scoping review of studies published between 2011 and 2024 was conducted to present the breadth of behavioural symptoms in ALS and ALSFTD, explore how they are described and assessed, and identify patterns in the literature.<br><br>FINDINGS: This scoping review identified 3939 articles, with 111/3939 meeting eligibility criteria. Most studies were from Australia (23.22%), Italy (16.94%) and the UK (14.29%); 75.67% were cross-sectional. Sample size ranged from 1 to 1013, as case studies were included. Overall mean age (100/111 studies) was 61.32 (SD&#x200a;=&#x200a;4.15). Proportion of male patients (reported 102/111 studies) was 61.49%; mean disease duration (reported in 86/111 records) was 32.63&#x200a;months (SD&#x200a;=&#x200a;24.72). Papers described a broad range of behavioural symptoms (465 examples), which were thematically collated into seven categories: disinhibition (27.74%), apathy (25.16%), perseverative/compulsive behaviours (17.42%), hyperorality (10.53%), loss of sympathy or empathy (8.6%), psychotic symptoms (7.74%), and loss of insight about disease and changes (2.8%). Most studies (78.37%) used validated behavioural assessments that elicited carer's perspectives.<br><br>SUMMARY: Despite extensive evidence of behavioural symptoms in ALS, implementation of assessments and management of behavioural symptoms in clinical care remain limited. Clinicians must assess behavioural symptoms, as these can negatively affect disease prognosis, patient treatment engagement and increase family distress. Measures capturing carers' perspectives through interviews are ideal as they can reveal anosognosia, lack of sympathy and lack of empathy.}, }
@article {pmid38944367, year = {2024}, author = {Wankhede, NL and Rajendra Kopalli, S and Dhokne, MD and Badnag, DJ and Chandurkar, PA and Mangrulkar, SV and Shende, PV and Taksande, BG and Upaganlawar, AB and Umekar, MJ and Koppula, S and Kale, MB}, title = {Decoding mitochondrial quality control mechanisms: Identifying treatment targets for enhanced cellular health.}, journal = {Mitochondrion}, volume = {78}, number = {}, pages = {101926}, doi = {10.1016/j.mito.2024.101926}, pmid = {38944367}, issn = {1872-8278}, mesh = {Humans ; *Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; Animals ; }, abstract = {Mitochondria are singular cell organelles essential for many cellular functions, which includes responding to stress, regulating calcium levels, maintaining protein homeostasis, and coordinating apoptosis response. The vitality of cells, therefore, hinges on the optimal functioning of these dynamic organelles. Mitochondrial Quality Control Mechanisms (MQCM) play a pivotal role in ensuring the integrity and functionality of mitochondria. Perturbations in these mechanisms have been closely associated with the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Compelling evidence suggests that targeting specific pathways within the MQCM could potentially offer a therapeutic avenue for rescuing mitochondrial integrity and mitigating the progression of neurodegenerative diseases. The intricate interplay of cellular stress, protein misfolding, and impaired quality control mechanisms provides a nuanced understanding of the underlying pathology. Consequently, unravelling the specific MQCM dysregulation in neurodegenerative disorders becomes paramount for developing targeted therapeutic strategies. This review delves into the impaired MQCM pathways implicated in neurodegenerative disorders and explores emerging therapeutic interventions. By shedding light on pharmaceutical and genetic manipulations aimed at restoring MQCM efficiency, the discussion aims to provide insights into novel strategies for ameliorating the progression of neurodegenerative diseases. Understanding and addressing mitochondrial quality control mechanisms not only underscore their significance in cellular health but also offer a promising frontier for advancing therapeutic approaches in the realm of neurodegenerative disorders.}, }
@article {pmid38942541, year = {2024}, author = {Shukla, H and John, D and Banerjee, S and Tiwari, AK}, title = {Drug repurposing for neurodegenerative diseases.}, journal = {Progress in molecular biology and translational science}, volume = {207}, number = {}, pages = {249-319}, doi = {10.1016/bs.pmbts.2024.03.035}, pmid = {38942541}, issn = {1878-0814}, mesh = {Humans ; *Drug Repositioning ; *Neurodegenerative Diseases/drug therapy ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) are neuronal problems that include the brain and spinal cord and result in loss of sensory and motor dysfunction. Common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS) etc. The occurrence of these diseases increases with age and is one of the challenging problems among elderly people. Though, several scientific research has demonstrated the key pathologies associated with NDDs still the underlying mechanisms and molecular details are not well understood and need to be explored and this poses a lack of effective treatments for NDDs. Several lines of evidence have shown that NDDs have a high prevalence and affect more than a billion individuals globally but still, researchers need to work forward in identifying the best therapeutic target for NDDs. Thus, several researchers are working in the directions to find potential therapeutic targets to alter the disease pathology and treat the diseases. Several steps have been taken to identify the early detection of the disease and drug repurposing for effective treatment of NDDs. Moreover, it is logical that current medications are being evaluated for their efficacy in treating such disorders; therefore, drug repurposing would be an efficient, safe, and cost-effective way in finding out better medication. In the current manuscript we discussed the utilization of drugs that have been repurposed for the treatment of AD, PD, HD, MS, and ALS.}, }
@article {pmid38935506, year = {2024}, author = {Halim, DO and Krishnan, G and Hass, EP and Lee, S and Verma, M and Almeida, S and Gu, Y and Kwon, DY and Fazzio, TG and Gao, FB}, title = {The exocyst subunit EXOC2 regulates the toxicity of expanded GGGGCC repeats in C9ORF72-ALS/FTD.}, journal = {Cell reports}, volume = {43}, number = {7}, pages = {114375}, pmid = {38935506}, issn = {2211-1247}, support = {RF1 NS101986/NS/NINDS NIH HHS/United States ; R21 NS119952/NS/NINDS NIH HHS/United States ; R01 HD104971/HD/NICHD NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; R21 NS112766/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *DNA Repeat Expansion/genetics ; Motor Neurons/metabolism/pathology ; }, abstract = {GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this genetic mutation leads to neurodegeneration remains largely unknown. Using CRISPR-Cas9 technology, we deleted EXOC2, which encodes an essential exocyst subunit, in induced pluripotent stem cells (iPSCs) derived from C9ORF72-ALS/FTD patients. These cells are viable owing to the presence of truncated EXOC2, suggesting that exocyst function is partially maintained. Several disease-relevant cellular phenotypes in C9ORF72 iPSC-derived motor neurons are rescued due to, surprisingly, the decreased levels of dipeptide repeat (DPR) proteins and expanded G4C2 repeats-containing RNA. The treatment of fully differentiated C9ORF72 neurons with EXOC2 antisense oligonucleotides also decreases expanded G4C2 repeats-containing RNA and partially rescued disease phenotypes. These results indicate that EXOC2 directly or indirectly regulates the level of G4C2 repeats-containing RNA, making it a potential therapeutic target in C9ORF72-ALS/FTD.}, }
@article {pmid38929462, year = {2024}, author = {De Marchi, I and Buffone, F and Mauro, A and Bruini, I and Vismara, L}, title = {Manual Therapy of Dysphagia in a Patient with Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {6}, pages = {}, pmid = {38929462}, issn = {1648-9144}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Male ; *Deglutition Disorders/etiology/therapy ; Middle Aged ; Manipulation, Osteopathic/methods ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable rare neurodegenerative condition, with 45% of cases showing the symptom of dysphagia; its clinical signs are atrophy, weakness, and fasciculations of the facial muscles, tongue, and pharynx. Furthermore, dysphagia is the main cause of aspiration pneumonia. The traditional treatment for dysphagia varies based on the patient's difficulty of swallowing. The initial phase consists of dietary consistency adjustments, progressing to alternatives like nasogastric tubes or percutaneous endoscopic gastrostomy (PEG) in advanced stages. Osteopathic manipulative treatment (OMT) is a complementary 'hands-on' approach that has already shown positive results as an add-on therapy in various health conditions. This study is a case report of a man diagnosed with ALS with initial dysphagia, managed with a protocol that extraordinarily included OMT. The patient showed somatic dysfunctions in the mediastinal region, upper cervical region, and occipital area which are all anatomically related to the nervous system, especially the glossopharyngeal reflex. At the end of the rehabilitation protocol, there was a reduction in the swallowing problems measured with Strand Scale and swallowing tests, and the patient reported an improved psycho-physical well-being assessed with the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40). Instead, the neurological function measured with ALSFRS-S remained stable. Although the nature of this study design prevents any causal assumption, the positive results should lead to future randomized controlled trials to assess the effectiveness of OMT as an adjunctive therapeutic proposal to improve the health of ALS patients.}, }
@article {pmid38928874, year = {2024}, author = {Szulc, A and Wiśniewska, K and Żabińska, M and Gaffke, L and Szota, M and Olendzka, Z and Węgrzyn, G and Pierzynowska, K}, title = {Effectiveness of Flavonoid-Rich Diet in Alleviating Symptoms of Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {12}, pages = {}, pmid = {38928874}, issn = {2304-8158}, support = {533-0C20-GS0D-24//University of Gdansk/ ; }, abstract = {Over the past decades, there has been a significant increase in the burden of neurological diseases, including neurodegenerative disorders, on a global scale. This is linked to a widespread demographic trend in which developed societies are aging, leading to an increased proportion of elderly individuals and, concurrently, an increase in the number of those afflicted, posing one of the main public health challenges for the coming decades. The complex pathomechanisms of neurodegenerative diseases and resulting varied symptoms, which differ depending on the disease, environment, and lifestyle of the patients, make searching for therapies for this group of disorders a formidable challenge. Currently, most neurodegenerative diseases are considered incurable. An important aspect in the fight against and prevention of neurodegenerative diseases may be broadly understood lifestyle choices, and more specifically, what we will focus on in this review, a diet. One proposal that may help in the fight against the spread of neurodegenerative diseases is a diet rich in flavonoids. Flavonoids are compounds widely found in products considered healthy, such as fruits, vegetables, and herbs. Many studies indicated not only the neuroprotective effects of these compounds but also their ability to reverse changes occurring during the progression of diseases such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis. Here, we present the main groups of flavonoids, discussing their characteristics and mechanisms of action. The most widely described mechanisms point to neuroprotective functions due to strong antioxidant and anti-inflammatory effects, accompanied with their ability to penetrate the blood-brain barrier, as well as the ability to inhibit the formation of protein aggregates. The latter feature, together with promoting removal of the aggregates is especially important in neurodegenerative diseases. We discuss a therapeutic potential of selected flavonoids in the fight against neurodegenerative diseases, based on in vitro studies, and their impact when included in the diet of animals (laboratory research) and humans (population studies). Thus, this review summarizes flavonoids' actions and impacts on neurodegenerative diseases. Therapeutic use of these compounds in the future is potentially possible but depends on overcoming key challenges such as low bioavailability, determining the therapeutic dose, and defining what a flavonoid-rich diet is and determining its potential negative effects. This review also suggests further research directions to address these challenges.}, }
@article {pmid38925911, year = {2024}, author = {De La Cruz, E and Esselin, F and Polge, A and Mouzat, K and Guissart, C}, title = {Most SOD1 mutations are pathogenic, and their identification can lead to early access to treatment.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {12}, pages = {1219-1220}, doi = {10.1136/jnnp-2024-333939}, pmid = {38925911}, issn = {1468-330X}, }
@article {pmid38924779, year = {2024}, author = {Bratches, RWR and Cohen, J and Carpenter-Song, E and Mistler, L and Barr, PJ}, title = {The Feasibility and Acceptability of Sharing Video Recordings of Amyotrophic Lateral Sclerosis Clinical Encounters With Patients and Their Caregivers: Pilot Randomized Clinical Trial.}, journal = {JMIR formative research}, volume = {8}, number = {}, pages = {e57519}, pmid = {38924779}, issn = {2561-326X}, support = {T32 HS013852/HS/AHRQ HHS/United States ; }, abstract = {BACKGROUND: Multidisciplinary clinics (MDCs) provide benefits to patients with amyotrophic lateral sclerosis (ALS) and their caregivers, but MDC visits are information-heavy and can last 4 hours, with patients and caregivers meeting with multiple specialists within each MDC visit. There are questions about the effectiveness of current methods of sharing information from MDCs with patients. Video recordings are a promising new method of sharing information that may allow patients and caregivers to revisit the MDC and remind them of clinical recommendations and conversations.<br><br>OBJECTIVE: The objective of this trial is to determine the feasibility and acceptability of sharing information through video recordings of ALS MDC visits with patients and caregivers.<br><br>METHODS: This study was a randomized, controlled pilot trial with 3 months of follow-up from April 2021 to March 2022 in a rural multidisciplinary neurology clinic. We recruited patients with ALS, their caregivers, and their clinicians. Patients and their caregivers were randomized to either receive their normal after-visit summary (treatment as usual) or to receive their normal after-visit summary and a video recording of their MDC visit (video). Each specialist visit had its own recording and was accessible by patients and caregivers using a secure web-based platform called HealthPAL over a 3-month follow-up period. Primary study outcomes were feasibility and acceptability of the video intervention measured by recruitment rate (target: 70%), percentage of participants watching videos (target: 75%), and the Feasibility of Intervention Measure and Acceptability of Intervention Measure (targets: 3/5). We hypothesized that video recording would be feasible and acceptable to patients and their caregivers.<br><br>RESULTS: Of the 30 patients approached, 24 were recruited, while all caregivers (n=21) and clinicians (n=34) approached were recruited. A total of 144 specialist visits were recorded, approximately 12 specialist visits at a median of one MDC visit per patient. Of the recorded patients, 75% (9/12) viewed videos. High median intervention feasibility (4, SD 0.99) and acceptability (4, SD 1.22) of intervention measures were reported by patients and caregivers in the intervention arm. High median intervention feasibility (5, SD 0.21) and acceptability (4.88, SD 0.4) were reported by clinicians. Of the 24 patients, 50% (n=12) did not complete a 3-month follow-up, primarily due to death (n=10).<br><br>CONCLUSIONS: Video recording is highly feasible and acceptable for patients, caregivers, and clinicians at a rural ALS clinic. Our level of attrition is a useful benchmark for future studies in MDC populations. Despite high rates of patient death, 1-week assessments highlight the value of recordings for both patients and caregivers.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT04719403; https://clinicaltrials.gov/study/NCT04719403.}, }
@article {pmid38924633, year = {2024}, author = {Wolf, J and Buckley, GJ and Rozanski, EA and Fletcher, DJ and Boller, M and Burkitt-Creedon, JM and Weigand, KA and Crews, M and Fausak, ED and , }, title = {2024 RECOVER Guidelines: Advanced Life Support. Evidence and knowledge gap analysis with treatment recommendations for small animal CPR.}, journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)}, volume = {34 Suppl 1}, number = {}, pages = {44-75}, doi = {10.1111/vec.13389}, pmid = {38924633}, issn = {1476-4431}, support = {//Zoetis Animal Health/ ; //Boehringer Ingelheim Animal Health/ ; }, mesh = {Animals ; Dogs ; Cats ; *Dog Diseases/therapy/drug therapy ; Cardiopulmonary Resuscitation/veterinary/standards ; Cat Diseases/therapy/drug therapy ; Veterinary Medicine/standards ; Heart Arrest/veterinary/therapy ; }, abstract = {OBJECTIVE: To systematically review the evidence and devise clinical recommendations on advanced life support (ALS) in dogs and cats and to identify critical knowledge gaps.<br><br>DESIGN: Standardized, systematic evaluation of literature pertinent to ALS following Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Prioritized questions were each reviewed by Evidence Evaluators, and findings were reconciled by ALS Domain Chairs and Reassessment Campaign on Veterinary Resuscitation (RECOVER) Co-Chairs to arrive at treatment recommendations commensurate to quality of evidence, risk:benefit relationship, and clinical feasibility. This process was implemented using an Evidence Profile Worksheet for each question that included an introduction, consensus on science, treatment recommendations, justification for these recommendations, and important knowledge gaps. A draft of these worksheets was distributed to veterinary professionals for comment for 4&#xa0;weeks prior to finalization.<br><br>SETTING: Transdisciplinary, international collaboration in university, specialty, and emergency practice.<br><br>RESULTS: Seventeen questions pertaining to vascular access, vasopressors in shockable and nonshockable rhythms, anticholinergics, defibrillation, antiarrhythmics, and adjunct drug therapy as well as open-chest CPR were reviewed. Of the 33 treatment recommendations formulated, 6 recommendations addressed the management of patients with nonshockable arrest rhythms, 10 addressed shockable rhythms, and 6 provided guidance on open-chest CPR. We recommend against high-dose epinephrine even after prolonged CPR and suggest that atropine, when indicated, is used only once. In animals with a shockable rhythm in which initial defibrillation was unsuccessful, we recommend doubling the defibrillator dose once and suggest vasopressin (or epinephrine if vasopressin is not available), esmolol, lidocaine in dogs, and/or amiodarone in cats.<br><br>CONCLUSIONS: These updated RECOVER ALS guidelines clarify the approach to refractory shockable rhythms and prolonged CPR. Very low quality of evidence due to absence of clinical data in dogs and cats continues to compromise the certainty with which recommendations can be made.}, }
@article {pmid38924627, year = {2024}, author = {Burkitt-Creedon, JM and Boller, M and Fletcher, DJ and Brainard, BM and Buckley, GJ and Epstein, SE and Fausak, ED and Hopper, K and Lane, SL and Rozanski, EA and Wolf, J}, title = {2024 RECOVER Guidelines: Updated treatment recommendations for CPR in dogs and cats.}, journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)}, volume = {34 Suppl 1}, number = {}, pages = {104-123}, doi = {10.1111/vec.13391}, pmid = {38924627}, issn = {1476-4431}, support = {//Boehringer Ingelheim Animal Health/ ; //Zoetis Animal Health/ ; }, mesh = {Dogs ; Animals ; Cats ; *Cardiopulmonary Resuscitation/veterinary/standards/methods ; *Cat Diseases/therapy ; Dog Diseases/therapy ; Heart Arrest/veterinary/therapy ; }, abstract = {OBJECTIVE: After the 2012 Reassessment Campaign on Veterinary Resuscitation (RECOVER) CPR Guidelines, this is an update of evidence-based consensus guidelines for Basic Life Support (BLS), advanced life support (ALS), and periarrest monitoring.<br><br>DESIGN: These RECOVER CPR Guidelines were generated using a modified version of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for evidence evaluation and translation of this evidence into clear and actionable clinical instructions. Prioritized clinical questions in the Population, Intervention, Comparator, and Outcome (PICO) format were used as the basis to conduct systematic literature searches by information specialists, to extract information from relevant publications, to assess this evidence for quality, and finally to translate the findings into treatment recommendations. These recommendations were reviewed by the RECOVER writing group and opened for comment by veterinary professionals for 4&#xa0;weeks.<br><br>SETTING: Transdisciplinary, international collaboration in university, specialty, and emergency practice.<br><br>RESULTS: A total of 40 worksheets were prepared to evaluate questions across the 3 domains of BLS, ALS and Monitoring, resulting in 90 individual treatment recommendations. High-dose epinephrine is no longer recommended, and atropine, if used, is only administered once. Bag-mask ventilation is prioritized over mouth-to-nose ventilation in nonintubated animals. In addition, an algorithm for initial assessment, an updated CPR algorithm, a rhythm diagnosis tool, and an updated drug dosing table are provided.<br><br>CONCLUSIONS: While the majority of the BLS and ALS recommendations remain unchanged, some noteworthy changes were made due to new evidence that emerged over the past 10&#xa0;years. Indirectness of evidence remains the largest impediment to the certainty of guidelines formulation and underscores an urgent need for more studies in the target species of dogs and cats.}, }
@article {pmid38924023, year = {2024}, author = {Spoden, C and Wenzel, O and Erdmann, A and Neitzke, G and Hirschberg, I}, title = {Coping and end-of-life decision-making in ALS: A qualitative interview study.}, journal = {PloS one}, volume = {19}, number = {6}, pages = {e0306102}, pmid = {38924023}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Male ; Female ; Middle Aged ; *Adaptation, Psychological ; *Decision Making ; *Terminal Care/psychology ; Aged ; *Qualitative Research ; Adult ; Germany ; Interviews as Topic ; }, abstract = {How do people with amyotrophic lateral sclerosis (PALS) deal with their diagnosis and engage in end-of-life decision-making? What informational or supportive needs do they have for counselling about life-sustaining treatment and end-of-life care? Which correlating conditions and influences relate to these needs and how do they connect to the wish to die or wish to live? We conducted a qualitative interview study with 13 people with ALS in Germany from March 2019 to April 2021. Data collection and analysis followed a grounded theory-based approach and revealed close relationships between coping, informational needs and the preparedness for decision-making. We identified the coping strategies 'avoid thinking about end-of-life' and its counterpart, 'planning ahead to be well-prepared,' and differentiated the latter into the patterns 'withdrawing from life and taking precautions against life-prolongation' and 'searching for a new meaning in life and preparing for life-sustaining treatment'. The approaches are based on individual perceptions, attitudes and motives and can be positively/negatively reinforced by healthcare professionals (HCP), family and other interpersonal networks, but also by disease progression and in reaction to health care services. Type and degree of needs concerning information and counselling differed according to coping strategies. These strategies may vary over time, resulting in different support needs. Our findings signify that deep insight is needed into PALS' coping processes to understand their decision-making about life-sustaining treatment. Healthcare professionals should be sensitive to illness experiences beyond medical aspects and foster coping as a biographical process to better support people with ALS.}, }
@article {pmid38923364, year = {2024}, author = {Yang, XD and Gong, B and Chen, W and Chen, JJ and Qian, C and Lu, R and Min, Y and Jiang, T and Li, L and Yu, HQ}, title = {In Situ Quantitative Monitoring of Adsorption from Aqueous Phase by UV-vis Spectroscopy: Implication for Understanding of Heterogeneous Processes.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {11}, number = {32}, pages = {e2402732}, pmid = {38923364}, issn = {2198-3844}, support = {//Program for Changjiang Scholars and Innovative Research Team in University/ ; 51821006//National Natural Science Foundation of China/ ; 52027815//National Natural Science Foundation of China/ ; 52192684//National Natural Science Foundation of China/ ; 22276217//National Natural Science Foundation of China/ ; }, abstract = {The development of in situ techniques to quantitatively characterize the heterogeneous reactions is essential for understanding physicochemical processes in aqueous phase. In this work, a new approach coupling in situ UV-vis spectroscopy with a two-step algorithm strategy is developed to quantitatively monitor heterogeneous reactions in a compact closed-loop incorporation. The algorithm involves the inverse adding-doubling method for light scattering correction and the multivariate curve resolution-alternating least squares (MCR-ALS) method for spectral deconvolution. Innovatively, theoretical spectral simulations are employed to connect MCR-ALS solutions with chemical molecular structural evolution without prior information for reference spectra. As a model case study, the aqueous adsorption kinetics of bisphenol A onto polyamide microparticles are successfully quantified in a one-step UV-vis spectroscopic measurement. The practical applicability of this approach is confirmed by rapidly screening a superior adsorbent from commercial materials for antibiotic wastewater adsorption treatment. The demonstrated capabilities are expected to extend beyond monitoring adsorption systems to other heterogeneous reactions, significantly advancing UV-vis spectroscopic techniques toward practical integration into automated experimental platforms for probing aqueous chemical processes and beyond.}, }
@article {pmid38922880, year = {2025}, author = {Goldschmidt-Clermont, PJ and Khan, A and Jimsheleishvili, G and Graham, P and Brooks, A and Silvera, R and Goldschmidt, AJP and Pearse, DD and Dietrich, WD and Levi, AD and Guest, JD}, title = {Treating amyotrophic lateral sclerosis with allogeneic Schwann cell-derived exosomal vesicles: a case report.}, journal = {Neural regeneration research}, volume = {20}, number = {4}, pages = {1207-1216}, pmid = {38922880}, issn = {1673-5374}, abstract = {Schwann cells are essential for the maintenance and function of motor neurons, axonal networks, and the neuromuscular junction. In amyotrophic lateral sclerosis, where motor neuron function is progressively lost, Schwann cell function may also be impaired. Recently, important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported. This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles, marking, to our knowledge, the first instance of such treatment. An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis. After initial diagnosis, the patient underwent a combination of generic riluzole, sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis, and taurursodiol. The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function. We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired (senescent) and that exposure of the patient's Schwann cells to allogeneic Schwann cell-derived exosomal vesicles, cultured expanded from a cadaver donor improved their growth capacity in vitro. After a period of observation lasting 10 weeks, during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored, the patient received weekly consecutive infusions of 1.54 × 10 12 (×2), and then consecutive infusions of 7.5 × 10 12 (×6) allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco's phosphate-buffered saline. None of the infusions were associated with adverse events such as infusion reactions (allergic or otherwise) or changes in vital signs. Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend. A more sensitive in-house assay suggested possible inflammasome activation during the disease course. A trend for clinical stabilization was observed during the infusion period. Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles. Initial findings suggest that this approach is safe.}, }
@article {pmid38920997, year = {2024}, author = {Nowak, I and Paździor, M and Sarna, R and Madej, M}, title = {Molecular Mechanisms in the Design of Novel Targeted Therapies for Neurodegenerative Diseases.}, journal = {Current issues in molecular biology}, volume = {46}, number = {6}, pages = {5436-5453}, pmid = {38920997}, issn = {1467-3045}, abstract = {Neurodegenerative diseases are a diverse group of diseases characterized by a progressive loss of neurological function due to damage to nerve cells in the central nervous system. In recent years, there has been a worldwide increase in the expanding associated with increasing human life expectancy. Molecular mechanisms control many of the essential life processes of cells, such as replication, transcription, translation, protein synthesis and gene regulation. These are complex interactions that form the basis for understanding numerous processes in the organism and developing new diagnostic and therapeutic approaches. In the context of neurodegenerative diseases, molecular basis refers to changes at the molecular level that cause damage to or degeneration of nerve cells. These may include protein aggregates leading to pathological structures in brain cells, impaired protein transport in nerve cells, mitochondrial dysfunction, inflammatory processes or genetic mutations that impair nerve cell function. New medical therapies are based on these mechanisms and include gene therapies, reduction in inflammation and oxidative stress, and the use of miRNAs and regenerative medicine. The aim of this study was to bring together the current state of knowledge regarding selected neurodegenerative diseases, presenting the underlying molecular mechanisms involved, which could be potential targets for new forms of treatment.}, }
@article {pmid38915796, year = {2024}, author = {Thonhoff, JR and Beers, DR and Zhao, W and Faridar, A and Thome, A and Wen, S and Zhang, A and Wang, J and Appel, SH}, title = {A phase 1 proof-of-concept study evaluating safety, tolerability, and biological marker responses with combination therapy of CTLA4-Ig and interleukin-2 in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1415106}, pmid = {38915796}, issn = {1664-2295}, abstract = {OBJECTIVE: To determine whether a combination therapy with abatacept (CTLA4-Ig) and interleukin-2 (IL-2) is safe and suppresses markers of oxidative stress, inflammation, and degeneration in ALS.<br><br>METHODS: In this open-label study, four participants with ALS received subcutaneous injections of low dose IL-2 (1&#x2009;&#xd7;&#x2009;10[6] IU/injection/day) for 5 consecutive days every 2&#x2009;weeks and one subcutaneous injection of CTLA4-Ig (125&#x2009;mg/mL/injection) every 2&#x2009;weeks coinciding with the first IL-2 injection of each treatment cycle. Participants received a total of 24 treatment cycles during the first 48&#x2009;weeks in this 56-week study. They were closely monitored for treatment-emergent adverse events (TEAEs) and disease progression with the ALSFRS-R. Phenotypic changes within T cell populations and serum biological markers of oxidative stress [4-hydroxynonenal (4-HNE) and oxidized-LDL (ox-LDL)], inflammation (IL-18), and structural neuronal degeneration [neurofilament light chain (Nf-L)] were assessed longitudinally.<br><br>RESULTS: CTLA4-Ig/IL-2 therapy was safe and well-tolerated in all four participants over the 56-week study. During the first 24&#x2009;weeks, the average rate of change in the ALSFRS-R was +0.04 points/month. Over the 48-week treatment period, the average rate of change was -0.13 points/month with one participant improving by 0.9 points/month while the other three participants experienced an average decrease of -0.47 points/month, which is slower than the average&#x2009;-&#x2009;1.1 points/month prior to initiation of therapy. Treg suppressive function and numbers increased during treatment. Responses in the biological markers during the first 16&#x2009;weeks coincided with minimal clinical progression. Mean levels of 4-HNE decreased by 30%, ox-LDL decreased by 19%, IL-18 decreased by 23%, and Nf-L remained the same, on average, in all four participants. Oxidized-LDL levels decreased in all four participants, 4-HNE and IL-18 levels decreased in three out of four participants, and Nf-L decreased in two out of four participants.<br><br>CONCLUSION: The combination therapy of CTLA4-Ig and IL-2 in ALS is safe and well-tolerated with promising results of clinical efficacy and suppression of biomarkers of oxidative stress, neuroinflammation and neuronal degeneration. In this open-label study, the efficacy as measured by the ALSFRS-R and corresponding biomarkers suggests the therapeutic potential of this treatment and warrants further study in a phase 2 double-blind, placebo-controlled trial.<br><br>CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT06307301.}, }
@article {pmid38914784, year = {2024}, author = {Sang, A and Zhuo, S and Bochanis, A and Manautou, JE and Bahal, R and Zhong, XB and Rasmussen, TP}, title = {Mechanisms of Action of the US Food and Drug Administration-Approved Antisense Oligonucleotide Drugs.}, journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy}, volume = {38}, number = {4}, pages = {511-526}, pmid = {38914784}, issn = {1179-190X}, support = {R01 HL147028/HL/NHLBI NIH HHS/United States ; R35 GM140862/GM/NIGMS NIH HHS/United States ; R35GM140862/GM/NIGMS NIH HHS/United States ; R01HL147028/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use/pharmacology ; United States ; *United States Food and Drug Administration ; *Drug Approval ; RNA, Messenger/genetics/metabolism ; Animals ; RNA Splicing/drug effects ; }, abstract = {Antisense oligonucleotides (ASOs) are single stranded nucleic acids that target RNA. The US Food and Drug Administration has approved ASOs for several diseases. ASOs utilize three principal modes of action (MOA). The first MOA is initiated by base-pairing between the ASO and its target mRNA, followed by RNase H-dependent mRNA degradation. The second MOA is triggered by ASOs that occlude splice acceptor sites in pre-mRNAs leading to skipping of a mutation-bearing exon. The third MOA involves ASOs that sterically hinder mRNA function, often inhibiting translation. ASOs contain a variety of modifications to the sugar-phosphate backbone and bases that stabilize the ASO or render them resistant to RNase activity. RNase H-dependent ASOs include inotersen and eplontersen (for hereditary transthyretin amyloidosis), fomiversen (for opportunistic cytomegalovirus infection), mipomersen (for familial hypercholesterolemia), and tofersen [for amyotrophic lateral sclerosis (ALS)]. Splice modulating ASOs include nursinersen (for spinal muscular atrophy) and eteplirsen, golodirsen, viltolarsen, and casimersen (all for the treatment of Duchenne muscular dystrophy). In addition, a designer ASO, milasen, was used to treat a single individual afflicted with Batten disease. Since ASO design relies principally upon knowledge of mRNA sequence, the bench to bedside pipeline for ASOs is expedient compared with protein-directed drugs. [Graphical abstract available.].}, }
@article {pmid38914219, year = {2024}, author = {Asahina, R and Takahashi, M and Takano, H and Yao, R and Abe, M and Goshima, Y and Ohshima, T}, title = {The role of CRMP4 in LPS-induced neuroinflammation.}, journal = {Brain research}, volume = {1841}, number = {}, pages = {149094}, doi = {10.1016/j.brainres.2024.149094}, pmid = {38914219}, issn = {1872-6240}, mesh = {Animals ; *Lipopolysaccharides/pharmacology ; *Microglia/metabolism/drug effects ; *Mice, Knockout ; *Nerve Tissue Proteins/metabolism/genetics ; Mice ; *Neuroinflammatory Diseases/metabolism/chemically induced ; Inflammation/metabolism/chemically induced ; Interleukin-10/metabolism ; Substantia Nigra/metabolism/drug effects ; Mice, Inbred C57BL ; Corpus Striatum/metabolism/drug effects ; Male ; Microfilament Proteins/metabolism ; Arginase/metabolism ; }, abstract = {Neuroinflammation has been gaining attention as one of the potential causes of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis in recent years. The suppression of excessive proinflammatory responses is expected to be a target for the treatment and prevention of neurodegenerative diseases. Collapsin response mediator protein 4 (CRMP4) is involved in cytoskeleton-associated axonal guidance in the developing brain. Recently, the involvement of CRMP4 in several pathological conditions, including inflammation induced by lipopolysaccharide (LPS), a widely used inflammatory molecule, has been reported. However, the role of CRMP4 in LPS-induced inflammation in vivo remains largely unknown. In this study, we generated microglia-specific CRMP4 knockout mice for the first time and examined the role of CRMP4 in an LPS-induced brain inflammation model. We found that microglia after LPS injection in substantia nigra was significantly reduced in Crmp4[-/-] mice compared to Crmp4[+/+]mice. The increased expression of IL-10 in striatum samples was downregulated in Crmp4[-/-] mice. A significant reduction in Iba1 expression was also observed in microglia-specific Crmp4 knockout mice compared with that in control mice. In contrast, the expression of IL-10 did not change in these mice, whereas arginase 1 (Arg1) expression was significantly suppressed. These results demonstrate the involvement of CRMP4 in LPS-induced inflammation in vivo, that CRMP4 suppresses microglial proliferation in a cell-autonomous manner.}, }
@article {pmid38914173, year = {2024}, author = {Tortarolo, M and Re Cecconi, AD and Camporeale, L and Margotta, C and Nardo, G and Pasetto, L and Bonetto, V and Galbiati, M and Crippa, V and Poletti, A and Piccirillo, R and Bendotti, C}, title = {Sunitinib-mediated inhibition of STAT3 in skeletal muscle and spinal cord does not affect the disease in a mouse model of ALS.}, journal = {Neurobiology of disease}, volume = {199}, number = {}, pages = {106576}, doi = {10.1016/j.nbd.2024.106576}, pmid = {38914173}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; *Sunitinib/pharmacology ; *Muscle, Skeletal/drug effects/metabolism/pathology ; *STAT3 Transcription Factor/metabolism/antagonists &amp; inhibitors ; *Mice, Transgenic ; *Indoles/pharmacology ; Mice ; *Disease Models, Animal ; *Spinal Cord/metabolism/drug effects/pathology ; *Mice, Inbred C57BL ; *Pyrroles/pharmacology ; Superoxide Dismutase/metabolism/genetics ; Muscular Atrophy/metabolism/pathology ; Motor Neurons/drug effects/metabolism/pathology ; Disease Progression ; }, abstract = {Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A transgenic mice expressing the same amount of mutant SOD1 but with different genetic backgrounds, C57BL/6JOlaHsd and 129S2/SvHsd, show slow and rapid muscle wasting and disease progression, respectively. Here, we investigated the different molecular mechanisms underlying muscle atrophy. Although both strains showed similar denervation-induced degradation of muscle proteins, only the rapidly progressing mice exhibited early and sustained STAT3 activation that preceded atrophy in gastrocnemius muscle. We therefore investigated the therapeutic potential of sunitinib, a tyrosine kinase inhibitor known to inhibit STAT3 and prevent cancer-induced muscle wasting. Although sunitinib treatment reduced STAT3 activation in the gastrocnemius muscle and lumbar spinal cord, it did not preserve spinal motor neurons, improve neuromuscular impairment, muscle atrophy and disease progression in the rapidly progressing SOD1-G93A mice. Thus, the effect of sunitinib is not equally positive in different diseases associated with muscle wasting. Moreover, given the complex role of STAT3 in the peripheral and central compartments of the neuromuscular system, the present study suggests that its broad inhibition may lead to opposing effects, ultimately preventing a potential positive therapeutic action in ALS.}, }
@article {pmid38909349, year = {2024}, author = {Ketabforoush, A and Faghihi, F and Azedi, F and Ariaei, A and Habibi, MA and Khalili, M and Ashtiani, BH and Joghataei, MT and Arnold, WD}, title = {Sodium Phenylbutyrate and Tauroursodeoxycholic Acid: A Story of Hope Turned to Disappointment in Amyotrophic Lateral Sclerosis Treatment.}, journal = {Clinical drug investigation}, volume = {44}, number = {7}, pages = {495-512}, pmid = {38909349}, issn = {1179-1918}, mesh = {Humans ; *Taurochenodeoxycholic Acid/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; *Phenylbutyrates/therapeutic use/pharmacology ; Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {The absence of a definitive cure for amyotrophic lateral sclerosis (ALS) emphasizes the crucial need to explore new and improved treatment approaches for this fatal, progressive, and disabling neurodegenerative disorder. As at the end of 2023, five treatments - riluzole, edaravone, dextromethorphan hydrobromide + quinidine sulfate (DHQ), tofersen, and sodium phenylbutyrate-tauroursodeoxycholic acid (PB-TUDCA) - were FDA approved for the treatment of patients with ALS. Among them PB-TUDCA has been shown to impact DNA processing impairments, mitochondria dysfunction, endoplasmic reticulum stress, oxidative stress, and pathologic folded protein agglomeration defects, which have been associated with ALS pathophysiology. The Phase 2 CENTAUR trial demonstrated significant impact of PB-TUDCA on the ALS Functional Rating Scale-Revised (ALSFRS-R) risk of death, hospitalization, and the need for tracheostomy or permanent assisted ventilation in patients with ALS based on post hoc analyses. More recently, contrasting with the CENTAUR trial results, results from the Phase 3 PHOENIX trial (NCT05021536) showed no change in ALSFRS-R total score at 48 weeks. Consequently, the sponsor company initiated the process with the US FDA and Health Canada to voluntarily withdraw the marketing authorizations for PB-TUDCA. In the present article, we review ALS pathophysiology, with a focus on PB-TUDCA's proposed mechanisms of action and recent clinical trial results and discuss the implications of conflicting trial data for ALS and other neurological disorders.}, }
@article {pmid38909342, year = {2024}, author = {Réginault, T and Wibart, P and Mathis, S and Le Masson, G and Pillet, O and Grassion, L}, title = {Factors associated with survival after early at-home NIV initiation in ALS patients.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5590-5597}, pmid = {38909342}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/mortality/physiopathology ; Male ; Female ; *Noninvasive Ventilation ; Middle Aged ; Retrospective Studies ; Aged ; Respiratory Insufficiency/therapy/mortality/etiology ; Home Care Services ; }, abstract = {BACKGROUND: The initiation of early non-invasive ventilation (NIV) often involves a careful balance between tolerance and effectiveness. In amyotrophic lateral sclerosis (ALS) patients, the establishment of a strategy, including the decision to focus on adhering to a cut-off, setting specific targets, or correcting all events, is crucial.<br><br>OBJECTIVE: To identify factors at 1&#xa0;month after early at-home NIV initiation that are associated with improved survival in ALS patients. We explored the impacts of adherence (ADH), quality of treatment, and NIV parameters at 1&#xa0;month after early at-home NIV initiation on patient survival.<br><br>METHODS: We conducted a retrospective study of 184 ALS patients at the Bordeaux ALS Centre for whom NIV was initiated between September 2017 and June 2021, and we collected data for a minimum period of 2&#xa0;years after the last patient included. The primary outcome was the risk of death according to baseline characteristics of our population and the NIV parameters and monitoring during the early NIV initiation period. The secondary outcomes were association with NIV ADH during the early NIV initiation period on prognosis, and NIV ADH cut-off for good versus poor prognosis.<br><br>RESULTS: Among the 178 ALS patients analysed, we found that quality of NIV treatment and device settings did not significantly influence prognosis. However, low ADH was significantly associated with a higher risk of death. The use of NIV for&#x2009;>&#x2009;5&#xa0;h/day during the early NIV initiation period was linked to a decreased risk of death [hazard ratio&#x2009;=&#x2009;0.4; 95% confidence interval: 0.27-0.9].<br><br>CONCLUSION: The use of NIV for&#x2009;>&#x2009;5&#xa0;h/day during the early NIV initiation period was associated with increased survival.}, }
@article {pmid38906677, year = {2024}, author = {Au, WH and Miller-Fleming, L and Sanchez-Martinez, A and Lee, JA and Twyning, MJ and Prag, HA and Raik, L and Allen, SP and Shaw, PJ and Ferraiuolo, L and Mortiboys, H and Whitworth, AJ}, title = {Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes in C9orf72 ALS/FTD models.}, journal = {Life science alliance}, volume = {7}, number = {9}, pages = {}, pmid = {38906677}, issn = {2575-1077}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Oxidative Stress ; *NF-E2-Related Factor 2/metabolism/genetics ; *C9orf72 Protein/genetics/metabolism ; *Mitochondria/metabolism ; Animals ; *Disease Models, Animal ; *Kelch-Like ECH-Associated Protein 1/metabolism/genetics ; Humans ; *Signal Transduction ; *Frontotemporal Dementia/genetics/metabolism ; *Phenotype ; Drosophila Proteins/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Mitophagy/genetics ; Dimethyl Fumarate/pharmacology ; Male ; }, abstract = {Mitochondrial dysfunction is a common feature of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or consequence of the pathogenic process. Analysing multiple aspects of mitochondrial biology across several Drosophila models of C9orf72-ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue C9orf72 locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of Keap1 or pharmacological inhibition by dimethyl fumarate significantly rescued the C9orf72-related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in C9orf72 patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to C9orf72 pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for C9orf72-related ALS/FTD.}, }
@article {pmid38904729, year = {2024}, author = {Portes E Silva, KR and Nogueira, EM and Jesus Mendes, AL and Pena, ALB and Simões E Silva, AC}, title = {The potential role of renin angiotensin system in acute leukemia: a narrative review.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {775}, pmid = {38904729}, issn = {1573-4978}, support = {304496/2023-5//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; }, mesh = {Humans ; *Renin-Angiotensin System/physiology ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism/pathology ; *Angiotensin II/metabolism ; Leukemia, Myeloid, Acute/metabolism/pathology ; Signal Transduction ; Angiotensin I/metabolism ; Neovascularization, Pathologic/metabolism ; Animals ; Peptide Fragments/metabolism ; }, abstract = {Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.}, }
@article {pmid38898231, year = {2024}, author = {Gao, J and Gunasekar, S and Xia, ZJ and Shalin, K and Jiang, C and Chen, H and Lee, D and Lee, S and Pisal, ND and Luo, JN and Griciuc, A and Karp, JM and Tanzi, R and Joshi, N}, title = {Gene therapy for CNS disorders: modalities, delivery and translational challenges.}, journal = {Nature reviews. Neuroscience}, volume = {25}, number = {8}, pages = {553-572}, pmid = {38898231}, issn = {1471-0048}, mesh = {Humans ; *Genetic Therapy/methods/trends ; *Central Nervous System Diseases/therapy/genetics ; Animals ; Translational Research, Biomedical/methods ; Gene Transfer Techniques/trends ; }, abstract = {Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.}, }
@article {pmid38896262, year = {2024}, author = {Shen, D and Yang, X and He, D and Zhang, K and Liu, S and Sun, X and Li, J and Cai, Z and Liu, M and Zhang, X and Liu, Q and Cui, L}, title = {Clinical and genetic characteristics of 1672 cases of amyotrophic lateral sclerosis in China: a single-center retrospective study.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5541-5548}, pmid = {38896262}, issn = {1432-1459}, support = {XDB39040100//Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; 2022-PUMCH-B-017//High-level Hospital Construction Project of Guangdong Provincial People's Hospital/ ; 2022YFC2703904//Key Technologies Research and Development Program/ ; 2021-I2M-1-034//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 81971293//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Male ; Middle Aged ; Female ; Adult ; Aged ; Young Adult ; Adolescent ; Aged, 80 and over ; China/epidemiology ; Retrospective Studies ; *C9orf72 Protein/genetics ; Age of Onset ; Mutation ; Phenotype ; Exome Sequencing ; Genotype ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. In recent years, continuous discoveries of new ALS-causing genes have enhanced the understanding of the genotype-phenotype relationship in ALS, aiding in disease progression prediction and providing a more comprehensive basis for genetic diagnosis.<br><br>METHODS: A total of 1672 ALS patients who visited the Neurology Department of Peking Union Medical College Hospital between January 2014 and December 2022 and met the revised El Escorial diagnostic criteria were included. Clinical data were collected, whole exome sequencing and dynamic mutation screening of the C9ORF72 gene were performed, and the clinical phenotypes and genotypes of the patients were analyzed.<br><br>RESULTS: The average age of onset for the 1672 ALS patients was 52.6&#x2009;&#xb1;&#x2009;11.2&#xa0;years (range 17-85&#xa0;years), with a median disease duration of 14&#xa0;months at the time of visit (interquartile range 9-24&#xa0;months, range 2-204&#xa0;months). The male to female ratio was 833:839. The patients included 297 (17.8%) with bulbar onset, 198 (11.8%) with flail arm/leg syndrome, 89 (5.3%) with familial ALS, and 52 (3.1%) with concomitant frontotemporal dementia (FTD). Pathogenic variants associated with ALS were detected in 175 patients (10.5% of the cohort), with the most common mutations being SOD1, FUS, and ANXA11. Among patients with familial ALS, 56.2% (50/89) had genetic mutations, compared to 7.9% (125/1583) in sporadic ALS cases. From the perspective of phenotype-genotype correlation, (1) In ALS-FTD patients, the most common genetic mutations were ANXA11 and C9ORF72 repeat expansions. Patients with flail arm/leg syndrome more frequently carried mutations in SOD1, ANXA11, and hnRNPA1; (2) Despite genetic heterogeneity, it was observed that mutations in FUS and NEK1 were more common in males, and patients with FUS mutations had a younger age of onset; mutations in SOD1 and SQSTM1 were more likely to present with lower limb onset.<br><br>CONCLUSION: This study provides comprehensive data on the genetic characteristics of ALS patients in China through large-scale clinical data and genetic analysis of 1672 cases. Differences in age of onset, onset site, and clinical phenotype among ALS patients with different genotypes can help clinicians better predict disease progression and provide a basis for precise diagnosis and individualized treatment.}, }
@article {pmid38895672, year = {2024}, author = {Deng, J and Sun, WT and Gong, K and Wang, LP and Li, FZ}, title = {Internal limiting membrane peeling combined with silicone oil or air tamponade for highly myopic foveoschisis.}, journal = {International journal of ophthalmology}, volume = {17}, number = {6}, pages = {1079-1085}, pmid = {38895672}, issn = {2222-3959}, abstract = {AIM: To compare the efficacy of pars plana vitrectomy (PPV) combined with internal limiting membrane (ILM) and silicone oil or sterile air tamponade for the treatment of myopic foveoschisis (MF) in highly myopic eyes.<br><br>METHODS: This retrospective study included 48 myopic eyes of 40 patients with MF and axial lengths (ALs) ranging from 26-32 mm treated between January 2020 and January 2022. All patients were underwent PPV combined with ILM peeling followed by sterile air or silicone oil tamponade and followed up at least 12mo. Based on the features on spectral-domain optical coherence tomography (SD-OCT), the eyes were divided into the MF-only group (Group A, n=15 eyes), MF with central foveal detachment group (Group B, n=20 eyes), and MF with lamellar macular hole group (Group C, n=13 eyes). According to AL, eyes were further divided into three groups: Group D (26.01-28.00 mm, n=12 eyes), Group E (28.01-30.00 mm, n=26 eyes), and Group F (30.01-32.00 mm, n=10 eyes). The best-corrected visual acuity (BCVA), central foveal thickness (CFT), and complications were recorded.<br><br>RESULTS: The patients included 16 males and 24 females with the mean age of 56&#xb1;9.82y. The BCVA and CFT improved in all groups after surgery (P<0.01), while there was no significant difference of the CFT in Group A, B, and C postoperatively (P>0.05). The intergroup differences of BCVA and CFT postoperatively were statistically significant in Group D, E, and F. Twenty eyes were injected with sterile air, and 28 eyes were injected with silicone oil for tamponade based on the AL. However, there was no statistically significant difference among Groups D, E, and F in terms of the results of sterile air or silicone oil tamponade. The mean recovery time was 5.9mo for MF patients subjected to silicone oil tamponade and 7.7mo for patients subjected to sterile air tamponade, and the difference was not statistically significant.<br><br>CONCLUSION: PPV and ILM peeling combined with silicone oil or sterile air tamponade can achieve good results for MF in highly myopic eyes with ALs&#x2264;32 mm.}, }
@article {pmid38895485, year = {2024}, author = {Sikirzhytskaya, A and Tyagin, I and Sutton, SS and Wyatt, MD and Safro, I and Shtutman, M}, title = {AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.06.597745}, pmid = {38895485}, issn = {2692-8205}, abstract = {UNLABELLED: Neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing.<br><br>AUTHOR SUMMARY: This manuscript outlines our project involving the application of AGATHA, an AI-based literature mining tool, to discover drugs with the potential for repurposing in the context of neurocognitive disorders. The primary objective is to identify connections between approved medications and specific health conditions through advanced statistical analysis, including techniques like Partial Least Squares Discriminant Analysis (PLSDA) and unsupervised clustering. The methodology involves grouping scientific terms related to different health conditions and genes, followed by building discrimination models to extract lists of disease-specific genes. These genes are then analyzed through pathway analysis to select candidates for drug repurposing.}, }
@article {pmid38895204, year = {2024}, author = {Maitra, S and Baek, M and Choe, YJ and Kim, NC}, title = {FDA-approved PDE4 inhibitors reduce the dominant toxicity of ALS-FTD-associated CHCHD10 [S59L].}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.04.597429}, pmid = {38895204}, issn = {2692-8205}, abstract = {Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10(CHCHD10) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing C2C10H [S81L] , and human cell models expressing CHCHD10 [S59L] , we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10 [S59L] . Evidences using in vitro/ in vivo genetic and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10 [S59L] -induced diseases. Therefore, we have investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10 [S59L] -induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10 [S59L] -induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H [S81L] . Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10 [S59L] . These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10 [S59L] -induced ALS-FTD and possibly other related diseases.}, }
@article {pmid38891895, year = {2024}, author = {Dabrowska, S and Turano, E and Scambi, I and Virla, F and Nodari, A and Pezzini, F and Galiè, M and Bonetti, B and Mariotti, R}, title = {A Cellular Model of Amyotrophic Lateral Sclerosis to Study the Therapeutic Effects of Extracellular Vesicles from Adipose Mesenchymal Stem Cells on Microglial Activation.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38891895}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/metabolism/pathology ; *Extracellular Vesicles/metabolism ; *Microglia/metabolism ; *Mesenchymal Stem Cells/metabolism ; Humans ; *Superoxide Dismutase-1/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Cell Line ; Adipose Tissue/cytology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons (MNs) in the brain and spinal cord, leading to progressive paralysis and death. Increasing evidence indicates that neuroinflammation plays an important role in ALS's pathogenesis and disease progression. Neuroinflammatory responses, primarily driven by activated microglia and astrocytes, and followed by infiltrating peripheral immune cells, contribute to exacerbate/accelerate MN death. In particular, the role of the microglia in ALS remains unclear, partly due to the lack of experimental models that can fully recapitulate the complexity of ALS's pathology. In this study, we developed and characterized a microglial cell line, SIM-A9-expressing human mutant protein Cu[+]/Zn[+] superoxide dismutase_1 (SIM-A9hSOD1(G93A)), as a suitable model in vitro mimicking the microglia activity in ALS. The expression of hSOD1(G93A) in SIM-A9 cells induced a change in their metabolic activity, causing polarization into a pro-inflammatory phenotype and enhancing reactive oxygen species production, which is known to activate cell death processes and apoptosis. Afterward, we used our microglial model as an experimental set-up to investigate the therapeutic action of extracellular vesicles isolated from adipose mesenchymal stem cells (ASC-EVs). ASC-EVs represent a promising therapeutic treatment for ALS due to their neuroprotective and immunomodulatory properties. Here, we demonstrated that treatment with ASC-EVs is able to modulate activated ALS microglia, reducing their metabolic activity and polarizing their phenotype toward an anti-inflammatory one through a mechanism of reduction of reactive oxygen species.}, }
@article {pmid38891791, year = {2024}, author = {Tokuda, E and Sakashita, Y and Tokoro, N and Date, A and Kosuge, Y and Miyasaka, T}, title = {MS785-MS27 Reactive Misfolded/Non-Native Zn-Deficient SOD1 Species Exhibit Cytotoxicity and Adopt Heterozygous Conformations in Motor Neurons.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38891791}, issn = {1422-0067}, support = {2022-2025//The Takeda Science Foundation/ ; }, mesh = {Animals ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Motor Neurons/metabolism/pathology ; Mice ; *Zinc/metabolism/deficiency ; *Protein Folding ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Mutation ; Mice, Transgenic ; Heterozygote ; Protein Conformation ; }, abstract = {Misfolding of superoxide dismutase-1 (SOD1) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) with SOD1 mutations. The development of antibodies specific for misfolded SOD1 deepens our understanding of how the protein participates in ALS pathogenesis. Since the term "misfolding" refers to various disordered conformers other than the natively folded one, which misfolded species are recognized by specific antibodies should be determined. Here, we molecularly characterized the recognition by MS785-MS27, an antibody cocktail experimentally confirmed to recognize over 100 ALS-linked SOD1 mutants. Indirect ELISA revealed that the antibody cocktail recognized Zn-deficient wild-type and mutated SOD1 species. It also recognized conformation-disordered wild-type and mutated SOD1 species, such as unfolded and oligomeric forms, but had less affinity for the aggregated form. Antibody-reactive SOD1 exhibited cytotoxicity to a motor neuron cell model, which was blocked by Zn treatment with Zn-deficient SOD1. Immunohistochemistry revealed antibody-reactive SOD1 mainly in spinal motor neurons of SOD1[G93A] mice throughout the disease course, and the distribution after symptomatic stages differed from that of other misfolded SOD1 species. This suggests that misfolded/non-native SOD1 species exist as heterogeneous populations. In conclusion, MS785-MS27 recognizes various conformation-disordered SOD1 species lacking the Zn ion.}, }
@article {pmid38891289, year = {2024}, author = {Idziak, R and Waligóra, H and Majchrzak, L and Szulc, P}, title = {Multifunctional Adjuvants Affect Sulfonylureas with Synthetic Auxin Mixture in Weed and Maize Grain Yield.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {38891289}, issn = {2223-7747}, abstract = {A field study in the years 2017-2019 was carried out to evaluate the impact of novel adjuvant formulations on the efficacy of sulfonylurea and synthetic auxin herbicides. Treatments included nicosulfuron + rimsulfuron + dicamba (N+R+D) at full and reduced rates with three multicomponent (TEST-1, TEST-2, TEST-3) as well as standard (MSO, S) adjuvants. In this greenhouse study, Echinochloa crus-galli seeds were planted and treated with N+R+D at 2-3 leaf stages. The water with the desired pH (4, 7, and 9) for the preparation of the spray liquid was prepared by incorporating citric acid or K3PO4 to either lower or raise the pH of the water. Adjuvant TEST-1 added to the spray liquid at pH 4 increased the effectiveness to 68%, TEST-2 to 81%, and TEST-3 to 80%, compared to 73% and 66% with the MSO and S. The efficacy of N+R+D at pH 7 with TEST-1 increased to 83%, TEST-2 to 82%, and TEST-3 to 77%, but with MSO, it increased to 81%, and 71% with S. Adjuvants TEST-1, TEST-2, and TEST-3 in the liquid at pH 9 increased efficacy to 76 and 80%, compared to 79 and 63% with MSO or S adjuvants. N+R+D applied with TEST-1, TEST-2, and TEST-3 provided greater weed control than herbicides with surfactant (S) and similar or even better than with standard methylated seed oil (MSO) adjuvants. Maize grain yield after herbicide-with-tested-adjuvant application was higher than from an untreated check, and comparable to yield from herbicide-with-MSO treatment, but higher than from S treatment.}, }
@article {pmid38891059, year = {2024}, author = {Dashtmian, AR and Darvishi, FB and Arnold, WD}, title = {Chronological and Biological Aging in Amyotrophic Lateral Sclerosis and the Potential of Senolytic Therapies.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891059}, issn = {2073-4409}, support = {1R01AG067758, R01AG078129, and R01AG067758-02S2//national institute of health/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/therapy ; Humans ; *Aging/pathology ; Senotherapeutics/pharmacology/therapeutic use ; Animals ; Cellular Senescence ; Mitochondria/metabolism/pathology ; DNA Damage ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a group of sporadic and genetic neurodegenerative disorders that result in losses of upper and lower motor neurons. Treatment of ALS is limited, and survival is 2-5 years after disease onset. While ALS can occur in younger individuals, the risk significantly increases with advancing age. Notably, both sporadic and genetic forms of ALS share pathophysiological features overlapping hallmarks of aging including genome instability/DNA damage, mitochondrial dysfunction, inflammation, proteostasis, and cellular senescence. This review explores chronological and biological aging in the context of ALS onset and progression. Age-related muscle weakness and motor unit loss mirror aspects of ALS pathology and coincide with peak ALS incidence, suggesting a potential link between aging and disease development. Hallmarks of biological aging, including DNA damage, mitochondrial dysfunction, and cellular senescence, are implicated in both aging and ALS, offering insights into shared mechanisms underlying disease pathogenesis. Furthermore, senescence-associated secretory phenotype and senolytic treatments emerge as promising avenues for ALS intervention, with the potential to mitigate neuroinflammation and modify disease progression.}, }
@article {pmid38891021, year = {2024}, author = {Nguyen, L}, title = {Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891021}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/drug therapy ; Animals ; C9orf72 Protein/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a motor neuron disease. In ALS, upper and lower motor neurons in the brain and spinal cord progressively degenerate during the course of the disease, leading to the loss of the voluntary movement of the arms and legs. Since its first description in 1869 by a French neurologist Jean-Martin Charcot, the scientific discoveries on ALS have increased our understanding of ALS genetics, pathology and mechanisms and provided novel therapeutic strategies. The goal of this review article is to provide a comprehensive summary of the recent findings on ALS mechanisms and related therapeutic strategies to the scientific audience. Several highlighted ALS research topics discussed in this article include the 2023 FDA approved drug for SOD1 ALS, the updated C9orf72 GGGGCC repeat-expansion-related mechanisms and therapeutic targets, TDP-43-mediated cryptic splicing and disease markers and diagnostic and therapeutic options offered by these recent discoveries.}, }
@article {pmid38891002, year = {2024}, author = {Genchi, G and Lauria, G and Catalano, A and Carocci, A and Sinicropi, MS}, title = {Neuroprotective Effects of Curcumin in Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {38891002}, issn = {2304-8158}, abstract = {Curcumin, a hydrophobic polyphenol extracted from the rhizome of Curcuma longa, is now considered a candidate drug for the treatment of neurological diseases, including Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and prion disease, due to its potent anti-inflammatory, antioxidant potential, anticancerous, immunomodulatory, neuroprotective, antiproliferative, and antibacterial activities. Traditionally, curcumin has been used for medicinal and dietary purposes in Asia, India, and China. However, low water solubility, poor stability in the blood, high rate of metabolism, limited bioavailability, and little capability to cross the blood-brain barrier (BBB) have limited the clinical application of curcumin, despite the important pharmacological activities of this drug. A variety of nanocarriers, including liposomes, micelles, dendrimers, cubosome nanoparticles, polymer nanoparticles, and solid lipid nanoparticles have been developed with great success to effectively deliver the active drug to brain cells. Functionalization on the surface of nanoparticles with brain-specific ligands makes them target-specific, which should significantly improve bioavailability and reduce harmful effects. The aim of this review is to summarize the studies on curcumin and/or nanoparticles containing curcumin in the most common neurodegenerative diseases, highlighting the high neuroprotective potential of this nutraceutical.}, }
@article {pmid38889403, year = {2024}, author = {Zhu, Y and Wang, F and Xia, Y and Wang, L and Lin, H and Zhong, T and Wang, X}, title = {Research progress on astrocyte-derived extracellular vesicles in the pathogenesis and treatment of neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {8}, pages = {855-875}, pmid = {38889403}, issn = {2191-0200}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; *Astrocytes/metabolism ; Animals ; Cell Communication/physiology ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), pose significant global health risks and represent a substantial public health concern in the contemporary era. A primary factor in the pathophysiology of these disorders is aberrant accumulation and aggregation of pathogenic proteins within the brain and spinal cord. Recent investigations have identified extracellular vesicles (EVs) in the central nervous system (CNS) as potential carriers for intercellular transport of misfolded proteins associated with neurodegenerative diseases. EVs are involved in pathological processes that contribute to various brain disorders including neurodegenerative disorders. Proteins linked to neurodegenerative disorders are secreted and distributed from cell to cell via EVs, serving as a mechanism for direct intercellular communication through the transfer of biomolecules. Astrocytes, as active participants in CNS intercellular communication, release astrocyte-derived extracellular vesicles (ADEVs) that are capable of interacting with diverse target cells. This review primarily focuses on the involvement of ADEVs in the development of neurological disorders and explores their potential dual roles - both advantageous and disadvantageous in the context of neurological disorders. Furthermore, this review examines the current studies investigating ADEVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases. The prospects and challenges associated with the application of ADEVs in clinical settings were also comprehensively reviewed.}, }
@article {pmid38887384, year = {2024}, author = {Tang, X and Li, Q and Huang, G and Chen, Z and Huang, Y and Pei, X and Zhao, S and Liu, Z and Guo, T and Liang, F}, title = {Immediate Efficacy of Contralateral Acupuncture on SI3 Combined with Active Exercise for Acute Lumbar Sprains: Protocol for a Randomized Controlled Trial.}, journal = {Journal of pain research}, volume = {17}, number = {}, pages = {2099-2110}, pmid = {38887384}, issn = {1178-7090}, abstract = {PURPOSE: Acute lumbar sprain (ALS) is a common clinical disease characterized by persistent intolerable low back pain and limitation of movement, and quick pain relief and restoration of mobility in a short time are the main needs of patients when they visit the clinic. This study aims to evaluate the immediate efficacy of contralateral acupuncture (CAT) on SI3 combined with active exercise in treating ALS.<br><br>METHODS AND ANALYSIS: This study is a randomized controlled trial which will recruit 118 eligible participants aged 18 to 55 years with ALS at the Second Affiliated Hospital of Yunnan University of Chinese Medicine between March 2024 and December 2026. Participants will be randomly assigned to the acupuncture group or the sham-acupuncture group in a 1:1 ratio. The acupuncture group will receive a 10-minute acupuncture treatment combined with active exercise, while the sham-acupuncture group will receive a 10-minute sham acupuncture treatment combined with active exercise. Randomization will use a computer-generated sequence with allocation concealed in opaque envelopes. The primary outcome will be the pain visual analogue scale (VAS) scores after 10 minutes of treatment. Secondary outcomes will include the pain VAS scores at other time points (2, 4, 6, and 8 minutes post-treatment), the lumbar range of motion (ROM) scores at various time points, blinded assessment, the treatment effect expectancy scale, and the rescue analgesia rate. The analysis will follow the intention-to-treat principle. The primary outcome will be analyzed using ANCOVA, and secondary outcomes with repeated measures ANOVA. The rescue analgesia rate will be assessed using either the &#x3c7;[2] test or Fisher's exact test.<br><br>DISCUSSION: This study is the first randomized controlled trial to assess the immediate efficacy of CAT in combination with active exercise for ALS. This study will provide a simple, rapid, and effective treatment for the clinical management of ALS.}, }
@article {pmid38886938, year = {2025}, author = {Helmold, BR and Ahrens, A and Fitzgerald, Z and Ozdinler, PH}, title = {Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets.}, journal = {Neural regeneration research}, volume = {20}, number = {3}, pages = {725-739}, pmid = {38886938}, issn = {1673-5374}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; }, abstract = {Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein-protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as "causative" for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration-approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.}, }
@article {pmid38885838, year = {2024}, author = {López Sanz, P and Azaña Defez, JM}, title = {Is ILVEN a misnomer? Proposal of MALID as an accurate nomenclature. Response to Polubothu et al's "ILVEN should be genotyped to direct treatment and genetic counselling".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e107-e108}, doi = {10.1016/j.jaad.2024.05.084}, pmid = {38885838}, issn = {1097-6787}, mesh = {Humans ; *Terminology as Topic ; *Genetic Counseling ; Genotype ; }, }
@article {pmid38878774, year = {2024}, author = {Kumbier, K and Roth, M and Li, Z and Lazzari-Dean, J and Waters, C and Hammerlindl, S and Rinaldi, C and Huang, P and Korobeynikov, VA and ,  and Phatnani, H and Shneider, N and Jacobson, MP and Wu, LF and Altschuler, SJ}, title = {Identifying FUS amyotrophic lateral sclerosis disease signatures in patient dermal fibroblasts.}, journal = {Developmental cell}, volume = {59}, number = {16}, pages = {2134-2142.e6}, doi = {10.1016/j.devcel.2024.05.011}, pmid = {38878774}, issn = {1878-1551}, support = {R01 NS106236/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Fibroblasts/metabolism/pathology ; *RNA-Binding Protein FUS/metabolism/genetics ; Mutation/genetics ; Male ; Female ; Skin/pathology/metabolism ; Machine Learning ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, highly heterogeneous neurodegenerative disease, underscoring the importance of obtaining information to personalize clinical decisions quickly after diagnosis. Here, we investigated whether ALS-relevant signatures can be detected directly from biopsied patient fibroblasts. We profiled familial ALS (fALS) fibroblasts, representing a range of mutations in the fused in sarcoma (FUS) gene and ages of onset. To differentiate FUS fALS and healthy control fibroblasts, machine-learning classifiers were trained separately on high-content imaging and transcriptional profiles. "Molecular ALS phenotype" scores, derived from these classifiers, captured a spectrum from disease to health. Interestingly, these scores negatively correlated with age of onset, identified several pre-symptomatic individuals and sporadic ALS (sALS) patients with FUS-like fibroblasts, and quantified "movement" of FUS fALS and "FUS-like" sALS toward health upon FUS ASO treatment. Taken together, these findings provide evidence that non-neuronal patient fibroblasts can be used for rapid, personalized assessment in ALS.}, }
@article {pmid38878554, year = {2024}, author = {Mincic, AM and Antal, M and Filip, L and Miere, D}, title = {Modulation of gut microbiome in the treatment of neurodegenerative diseases: A systematic review.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {43}, number = {7}, pages = {1832-1849}, doi = {10.1016/j.clnu.2024.05.036}, pmid = {38878554}, issn = {1532-1983}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Neurodegenerative Diseases/microbiology/therapy ; *Probiotics/administration &amp; dosage/therapeutic use ; *Prebiotics/administration &amp; dosage ; *Dysbiosis/therapy/microbiology ; Animals ; Fecal Microbiota Transplantation ; }, abstract = {BACKGROUND AND AIMS: Microbiota plays an essential role in maintaining body health, through positive influences on metabolic, defensive, and trophic processes and on intercellular communication. Imbalance in intestinal flora, with the proliferation of harmful bacterial species (dysbiosis) is consistently reported in chronic illnesses, including neurodegenerative diseases (ND). Correcting dysbiosis can have a beneficial impact on the symptoms and evolution of ND. This review examines the effects of microbiota modulation through administration of probiotics, prebiotics, symbiotics, or prebiotics' metabolites (postbiotics) in patients with ND like multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).<br><br>METHODS: PubMed, Web of Science, Medline databases and ClinicalTrials.gov registry searches were performed using pre-/pro-/postbiotics and ND-related terms. Further references were obtained by checking relevant articles.<br><br>RESULTS: Although few compared to animal studies, the human studies generally show positive effects on disease-specific symptoms, overall health, metabolic parameters, on oxidative stress and immunological markers. Therapy with probiotics in various forms (mixtures of bacterial strains, fecal microbiota transplant, diets rich in fermented foods) exert favorable effects on patients' mental health, cognition, and quality of life, targeting pathogenetic ND mechanisms and inducing reparatory mechanisms at the cellular level. More encouraging results have been observed in prebiotic/postbiotic therapy in some ND.<br><br>CONCLUSIONS: The effects of probiotic-related interventions depend on the patients' ND stage and pre-existing allopathic medication. Further studies on larger cohorts and long term comprehensive neuropsychiatric, metabolic, biochemical testing, and neuroimaging monitoring are necessary to optimize therapeutic protocols in ND.}, }
@article {pmid38878150, year = {2025}, author = {Wang, F and Wen, H and Liu, L and Aisa, HA and Xin, X}, title = {A Pair of Epimers of Lignan Alleviate Neuroinflammatory Effects by Modulating iNOS/COX-2 and MAPK/NF-κB Signaling Pathways.}, journal = {Inflammation}, volume = {48}, number = {1}, pages = {361-371}, pmid = {38878150}, issn = {1573-2576}, support = {2020YFE0205600//the National Key Research and Development Program of China/ ; U1703235//the National Natural Science Foundation of China/ ; }, mesh = {*Lignans/pharmacology ; *Cyclooxygenase 2/metabolism ; Animals ; *NF-kappa B/metabolism ; *Nitric Oxide Synthase Type II/metabolism ; Mice ; *Anti-Inflammatory Agents/pharmacology/chemistry ; MAP Kinase Signaling System/drug effects ; Signal Transduction/drug effects ; Artemisia/chemistry ; Cell Line ; Neuroinflammatory Diseases/drug therapy/metabolism ; Lipopolysaccharides ; Microglia/drug effects/metabolism ; }, abstract = {Neuroinflammation is a causative factor in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Previous studies have shown that Artemisia mongolica has anti-inflammatory properties. Aschantin (AM3) has been shown to have anti-inflammatory effects. However, the mechanism of AM3 and its epimer epi-aschantin (AM2) remains controversial. Therefore, the present study explored the mechanism of neuroinflammation by AM2 and AM3 and attempted to reveal the relationship between the structure of AM2 and AM3 and anti-neuroinflammatory activity. We isolated for the first time 12 lignans from A. mongolica that inhibited NO content at 10 μM in LPS-stimulated BV2 cells. Among them, epi-aschantin (AM2) and Aschantin (AM3) showed significant inhibition in NO screening. With further studies, we found that both AM2 and AM3 effectively inhibited the overproduction of NO, PGE2, IL-6, TNF-α and MCP-1, as well as the overexpression of COX-2 and iNOS. Mechanistic studies have shown AM2 and AM3 significantly inhibited the phosphorylation of ERK, JNK and P-38 in the MAPK signaling pathway and p-IκBα,p-p65 and blocked p65 entry into the nucleus. The results suggested that the pair of epimers (AM2 and AM3) can be used as potential therapeutic agents in the treatment of various brain disorders and that structural differences do not differ in anti-neuroinflammatory effects.}, }
@article {pmid38875517, year = {2024}, author = {Michielsen, A and van Veenhuijzen, K and Janse van Mantgem, MR and van Es, MA and Veldink, JH and van Eijk, RPA and van den Berg, LH and Westeneng, HJ}, title = {Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209603}, pmid = {38875517}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Hypothalamus/diagnostic imaging/metabolism/pathology ; *Magnetic Resonance Imaging ; Aged ; Cross-Sectional Studies ; Longitudinal Studies ; Disease Progression ; Cognition/physiology ; Adult ; Energy Metabolism/physiology ; }, abstract = {BACKGROUND AND OBJECTIVES: Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood. Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior. We evaluated, therefore, hypothalamic neurodegeneration in ALS and explored the relationship between hypothalamic volumes and dysregulation of energy metabolism, cognitive and behavioral changes, disease progression, and survival.<br><br>METHODS: Patients with ALS and population-based controls were included for this cross-sectional and longitudinal MRI study. The hypothalamus was segmented into 5 subregions and their volumes were calculated. Linear (mixed) models, adjusted for age, sex, and total intracranial volume, were used to compare hypothalamic volumes between groups and to analyze associations with metabolism, cognition, behavior, and disease progression. Cox proportional hazard models were used to investigate the relationship of hypothalamic volumes with survival. Permutation-based corrections for multiple hypothesis testing were applied to all analyses to control the family-wise error rate.<br><br>RESULTS: Data were available for 564 patients with ALS and 356 controls. The volume of the anterior superior subregion of the hypothalamus was smaller in patients with ALS than in controls (&#x3b2; = -0.70 [-1.15 to -0.25], p = 0.013). Weight loss, memory impairments, and behavioral disinhibition were associated with a smaller posterior hypothalamus (&#x3b2; = -4.79 [-8.39 to -2.49], p = 0.001, &#x3b2; = -10.14 [-15.88 to -4.39], p = 0.004, and &#x3b2; = -12.09 [-18.83 to -5.35], p = 0.003, respectively). Furthermore, the volume of this subregion decreased faster over time in patients than in controls (&#x3b2; = -0.25 [0.42 to -0.09], p = 0.013), and a smaller volume of this structure was correlated with shorter survival (hazard ratio = 0.36 [0.21-0.61], p = 0.029).<br><br>DISCUSSION: We obtained evidence for hypothalamic involvement in ALS, specifically marked by atrophy of the anterior superior subregion. Moreover, we found that atrophy of the posterior hypothalamus was associated with weight loss, memory dysfunction, behavioral disinhibition, and survival, and that this subregion deteriorated faster in patients with ALS than in controls. These findings improve our understanding of nonmotor involvement in ALS and could contribute to the identification of new treatment targets for this devastating disease.}, }
@article {pmid38873369, year = {2024}, author = {Hong, J and Kim, GC and Cha, JG and Park, J and Park, B and Park, SY and Kim, SU}, title = {Transcholecystic Duodenal Drainage as an Alternative Decompression Method for Afferent Loop Syndrome: Two Case Reports.}, journal = {Journal of the Korean Society of Radiology}, volume = {85}, number = {3}, pages = {661-667}, pmid = {38873369}, issn = {2951-0805}, abstract = {Afferent loop syndrome (ALS) is a rare complication of gastrectomies and gastrointestinal reconstruction. This can predispose patients to fatal conditions, such as cholangitis, pancreatitis, and duodenal perforation with peritonitis. Therefore, emergency decompression is necessary to prevent these complications. Herein, we report two cases in which transcholecystic duodenal drainage, an alternative decompression treatment, was performed in ALS patients without bile duct dilatation. Two patients who underwent distal gastrectomy with Billroth II anastomosis sought consultation in an emergency department for epigastric pain and vomiting. On CT, ALS with acute pancreatitis was diagnosed. However, biliary access could not be achieved because of the absence of bile duct dilatation. To overcome this problem, a duodenal drainage catheter was placed to decompress the afferent loop after traversing the cystic duct via a transcholecystic approach. The patients were discharged without additional surgical treatment 2 weeks and 1 month after drainage.}, }
@article {pmid38872258, year = {2024}, author = {Xiong, B and Yang, C and Yang, X and Luo, S and Li, S and Chen, C and He, K and Nie, L and Li, P and Li, S and Huang, H and Liu, J and Zhang, Z and Xie, Y and Zou, L and Yang, X}, title = {Arctigenin derivative A-1 ameliorates motor dysfunction and pathological manifestations in SOD1[G93A] transgenic mice via the AMPK/SIRT1/PGC-1α and AMPK/SIRT1/IL-1β/NF-κB pathways.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {30}, number = {6}, pages = {e14692}, pmid = {38872258}, issn = {1755-5949}, support = {SZSM201611090//Sanming Project of Medicine in Shenzhen/ ; 82171583//National Natural Science Foundation of China/ ; JCYJ20200109144418639//The Key Basic Research Program of Shenzhen Science and Technology Innovation Commission/ ; JCYJ20200109150717745//The Key Basic Research Program of Shenzhen Science and Technology Innovation Commission/ ; SZXK069//Shenzhen Key Medical Discipline Construction Fund/ ; }, mesh = {Animals ; *Mice, Transgenic ; *Sirtuin 1/metabolism ; Mice ; *NF-kappa B/metabolism ; *AMP-Activated Protein Kinases/metabolism ; *Furans/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; *Interleukin-1beta/metabolism ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Lignans/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; Male ; Motor Neurons/drug effects/pathology/metabolism ; Spinal Cord/drug effects/pathology/metabolism ; }, abstract = {AIM: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive death of upper and lower motor neurons, leading to generalized muscle atrophy, paralysis, and even death. Mitochondrial damage and neuroinflammation play key roles in the pathogenesis of ALS. In the present study, the efficacy of A-1, a derivative of arctigenin with AMP-activated protein kinase (AMPK) and silent information regulator 1 (SIRT1) activation for ALS, was investigated.<br><br>METHODS: A-1 at 33.3&#x2009;mg/kg was administrated in SOD1[G93A] transgenic mice orally from the 13th week for a 6-week treatment period. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes, and microglia in the spinal cord were evaluated by H&amp;E, Masson, Sirius Red, Nissl, and immunohistochemistry staining. Protein expression was detected with proteomics analysis, Western blotting, and ELISA. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit.<br><br>RESULTS: A-1 administration in SOD1[G93A] mice enhanced mobility, decreased skeletal muscle atrophy and fibrosis, mitigated loss of spinal motor neurons, and reduced glial activation. Additionally, A-1 treatment improved mitochondrial function, evidenced by elevated ATP levels and increased expression of key mitochondrial-related proteins. The A-1 treatment group showed decreased levels of IL-1&#x3b2;, pI&#x3ba;B&#x3b1;/I&#x3ba;B&#x3b1;, and pNF-&#x3ba;B/NF-&#x3ba;B.<br><br>CONCLUSIONS: A-1 treatment reduced motor neuron loss, improved gastrocnemius atrophy, and delayed ALS progression through the AMPK/SIRT1/PGC-1&#x3b1; pathway, which promotes mitochondrial biogenesis. Furthermore, the AMPK/SIRT1/IL-1&#x3b2;/NF-&#x3ba;B pathway exerted neuroprotective effects by reducing neuroinflammation. These findings suggest A-1 as a promising therapeutic approach for ALS.}, }
@article {pmid38869826, year = {2024}, author = {Wang, H and Zeng, R}, title = {Aberrant protein aggregation in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {4826-4851}, pmid = {38869826}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates/physiology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease. As its pathological mechanisms are not well understood, there are no efficient therapeutics for it at present. While it is highly heterogenous both etiologically and clinically, it has a common salient hallmark, i.e., aberrant protein aggregation (APA). The upstream pathogenesis and the downstream effects of APA in ALS are sophisticated and the investigation of this pathology would be of consequence for understanding ALS. In this paper, the pathomechanism of APA in ALS and the candidate treatment strategies for it are discussed.}, }
@article {pmid38867220, year = {2024}, author = {Jia, Q and Song, Y and Zhang, C and Li, M and Feng, L and Sugimoto, K and Zhang, X and Liu, J and Gao, Y}, title = {Reasons and experience for patients with amyotrophic lateral sclerosis using traditional Chinese medicine: a CARE-TCM based mixed method study.}, journal = {BMC complementary medicine and therapies}, volume = {24}, number = {1}, pages = {231}, pmid = {38867220}, issn = {2662-7671}, support = {QN2021110001L//National Foreign Expert Project/ ; 2018, 12//Chinese Medicine Inheritance and Innovation Talent Project Leading Talent Support Program of National Traditional Chinese Medicine/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Medicine, Chinese Traditional/methods ; Female ; Male ; Middle Aged ; Surveys and Questionnaires ; Aged ; China ; Adult ; Quality of Life ; Qualitative Research ; }, abstract = {BACKGROUND AND AIM: Traditional Chinese medicine (TCM) is widely used by patients with amyotrophic lateral sclerosis (ALS). However, their reasons and experience in using TCM have received insufficient attention. Therefore, we conducted a mixed method study to gain insights into this issue.<br><br>MATERIALS AND METHODS: This study was conducted on the basis of the China Amyotrophic Lateral Sclerosis Registry of Patients with Traditional Chinese Medicine (CARE-TCM). Data were collected from Dongzhimen Hospital through a mixed method approach, including a questionnaire and a semi-structured interview. Patients with ALS who were using TCM when they were initially registered with CARE-TCM and who had been followed-up for over six months were recruited. The questionnaires' outcomes were statistically outlined, and the interview transcripts were thematically analysed to identify themes and sub-themes.<br><br>RESULTS: Fifty-two and sixteen patients were included in the questionnaire and semi-structured interview groups, respectively. Patients used TCM with the hope of regulating their body holistically to improve nonmotor symptoms and quality of life (QOL). Those who recognised TCM as ineffective tended to discontinue it after a three-month trial period. Although quality was a major concern, herbal medicine (HM) was the most frequently used modality among all participants (n&#x2009;=&#x2009;52), with the majority (n&#x2009;=&#x2009;44, 84.6%) continuing to use it. Patients emphasised in-person consultations as a crucial part of TCM treatment. However, the disability caused by disease often made this interaction unattainable.<br><br>CONCLUSION: Nonmotor symptoms and QOL hold substantial importance for patients with ALS using TCM. HM is a more suitable modality than other TCM treatment modalities, but patients are facing challenges in seeking HM treatment. It is necessary to promote the implementation of hierarchical diagnosis and treatment, thus making TCM more accessible.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04885374 (registered on May 13, 2021).}, }
@article {pmid38864944, year = {2024}, author = {Wang, LY and Zhang, L and Bai, XY and Qiang, RR and Zhang, N and Hu, QQ and Cheng, JZ and Yang, YL and Xiang, Y}, title = {The Role of Ferroptosis in Amyotrophic Lateral Sclerosis Treatment.}, journal = {Neurochemical research}, volume = {49}, number = {10}, pages = {2653-2667}, pmid = {38864944}, issn = {1573-6903}, mesh = {*Ferroptosis/drug effects/physiology ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; Humans ; Animals ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; Iron/metabolism ; Antioxidants/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a challenging treatment landscape, due to its complex pathogenesis and limited availability of clinical drugs. Ferroptosis, an iron-dependent form of programmed cell death (PCD), stands distinct from apoptosis, necrosis, autophagy, and other cell death mechanisms. Recent studies have increasingly highlighted the role of iron deposition, reactive oxygen species (ROS) accumulation, oxidative stress, as well as systemic Xc- and glutamate accumulation in the antioxidant system in the pathogenesis of amyotrophic lateral sclerosis. Therefore, targeting ferroptosis emerges as a promising strategy for amyotrophic lateral sclerosis treatment. This review introduces the regulatory mechanism of ferroptosis, the relationship between amyotrophic lateral sclerosis and ferroptosis, and the drugs used in the clinic, then discusses the current status of amyotrophic lateral sclerosis treatment, hoping to provide new directions and targets for its treatment.}, }
@article {pmid38860943, year = {2024}, author = {Zhang, Y and Xia, Y and Sun, J}, title = {Probiotics and microbial metabolites maintain barrier and neuromuscular functions and clean protein aggregation to delay disease progression in TDP43 mutation mice.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2363880}, pmid = {38860943}, issn = {1949-0984}, support = {I01 BX004824/BX/BLRD VA/United States ; R01 DK105118/DK/NIDDK NIH HHS/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; R01 DK134343/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy ; Blood-Brain Barrier/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Disease Progression ; *DNA-Binding Proteins/metabolism/genetics ; *Gastrointestinal Microbiome ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Neuroglia/metabolism ; *Probiotics/administration &amp; dosage/pharmacology ; Spinal Cord/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. The ALS mice expressing human mutant of transactive response DNA binding protein of 43 kDa (hmTDP43) showed intestinal dysfunction before neuromuscular symptoms. We hypothesize that restoring the intestinal and microbial homeostasis with a bacterial metabolite or probiotics delays the ALS disease onset. We investigate the pathophysiological changes in the intestine and neurons, intestinal and blood-brain barriers, and inflammation during the ALS progression. We then cultured enteric glial cells (EGCs) isolated from TDP43 mice for mechanistic studies. TDP43 mice had significantly decreased intestinal mobility, increased permeability, and weakened muscle, compared with the age-matched wild-type mice. We observed increased hmTDP43 and Glial fibrillary acidic protein (GFAP), and decreased expression of α-smooth muscle actin (α-SMA), tight junction proteins (ZO-1 and Claudin-5) in the colon, spinal cord, and brain in TDP43 mice. TDP43 mice had reduced Butyryl-coenzyme A CoA transferase, decreased butyrate-producing bacteria Butyrivibrio fibrisolvens, and increased Bacteroides fragilis, compared to the WT mice. Serum inflammation cytokines (IL-6, IL-17, and IFN-γ) and LPS were elevated in TDP43 mice. EGCs from TDP43 mice showed aggregation of hmTDP43 associated with increased GFAP and ionized calcium-binding adaptor molecule (IBA1, a microglia marker). TDP43 mice treated with butyrate or probiotic VSL#3 had significantly increased rotarod time, increased intestinal mobility and decreased permeability, compared to the untreated group. Butyrate or probiotics treatment decreased the expression of GFAP, TDP43, and increased α-SMA, ZO-1, and Claudin-5 in the colon, spinal cord, and brain. Also, butyrate or probiotics treatment enhanced the Butyryl-coenzyme A CoA transferase, Butyrivibrio fibrisolvens, and reduced inflammatory cytokines in TDP43 mice. The TDP43 EGCs treated with butyrate or probiotics showed reduced GFAP, IBA1, and TDP43 aggregation. Restoring the intestinal and microbial homeostasis by beneficial bacteria and metabolites provide a potential therapeutic strategy to treat ALS.}, }
@article {pmid38859699, year = {2024}, author = {Finsterer, J and Strobl, W}, title = {Gastrointestinal involvement in neuromuscular disorders.}, journal = {Journal of gastroenterology and hepatology}, volume = {39}, number = {10}, pages = {1982-1993}, doi = {10.1111/jgh.16650}, pmid = {38859699}, issn = {1440-1746}, mesh = {Humans ; *Neuromuscular Diseases/complications/etiology ; *Gastrointestinal Diseases/etiology/therapy/diagnosis ; Myotonic Dystrophy/complications/diagnosis/physiopathology ; Mitochondrial Diseases/complications ; }, abstract = {Although not often discussed, many of the neuromuscular disorders (NMDs) affect the gastrointestinal tract (GIT). Depending on the type of NMD, the prevalence of GIT involvement ranges from <5% (e.g. hereditary neuropathies, myofibrillar myopathies) to 100% (e.g. MNGIE, OPMD). Particularly in NMDs with multisystem affection, involvement of the GIT can dominate the clinical presentation or at least make up a significant part of the clinical picture. The most prominent representatives of NMDs with multisystem involvement are the mitochondrial disorders (MIDs) and the myotonic dystrophies. The best known syndromic MIDs with GIT involvement are MNGIE, MELAS, Leigh, and Pearson syndromes. Among neuropathies, GIT involvement is most commonly found in ALS and GBS. GIT involvement may also be a feature of myasthenia. The clinical manifestations of GIT involvement are diverse and can affect the entire GIT, from the teeth to the rectum, including the liver and pancreas. The most well-known clinical manifestations of GIT involvement are dysphagia, nausea, vomiting, reflux, hollow organ dysmotility, hepatopathy, diabetes, diarrhea, constipation, and fecal incontinence. Even if treatment can usually only be symptomatic, the therapeutic options are diverse, are often effective, and can significantly and beneficially influence the course of the underlying NMD.}, }
@article {pmid38856890, year = {2024}, author = {Tripathi, S and Bhawana, }, title = {Epigenetic Orchestration of Neurodegenerative Disorders: A Possible Target for Curcumin as a Therapeutic.}, journal = {Neurochemical research}, volume = {49}, number = {9}, pages = {2319-2335}, pmid = {38856890}, issn = {1573-6903}, mesh = {*Curcumin/therapeutic use/pharmacology ; Humans ; *Epigenesis, Genetic/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism/genetics ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; Mitochondria/metabolism/drug effects ; Oxidative Stress/drug effects ; }, abstract = {Epigenetic modulations play a major role in gene expression and thus are responsible for various physiological changes including age-associated neurological disorders. Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), although symptomatically different, may share common underlying mechanisms. Most neurodegenerative diseases are associated with increased oxidative stress, aggregation of certain proteins, mitochondrial dysfunction, inactivation/dysregulation of protein degradation machinery, DNA damage and cell excitotoxicity. Epigenetic modulations has been reported to play a significant role in onset and progression of neurodegenerative diseases by regulating these processes. Previous studies have highlighted the marked antioxidant and neuroprotective abilities of polyphenols such as curcumin, by increased activity of detoxification systems like superoxide dismutase (SOD), catalase or glutathione peroxidase. The role of curcumin as an epigenetic modulator in neurological disorders and neuroinflammation apart from other chronic diseases have also been reported by a few groups. Nonetheless, the evidences for the role of curcumin mediated epigenetic modulation in its neuroprotective ability are still limited. This review summarizes the current knowledge of the role of mitochondrial dysfunction, epigenetic modulations and mitoepigenetics in age-associated neurological disorders such as PD, AD, HD, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), and describes the neuroprotective effects of curcumin in the treatment and/or prevention of these neurodegenerative diseases by regulation of the epigenetic machinery.}, }
@article {pmid38856793, year = {2025}, author = {Kumari, S and Kamiya, A and Karnik, SS and Rohilla, S and Dubey, SK and Taliyan, R}, title = {Novel Gene Therapy Approaches for Targeting Neurodegenerative Disorders: Focusing on Delivering Neurotrophic Genes.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {386-411}, pmid = {38856793}, issn = {1559-1182}, mesh = {Humans ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/therapy/genetics ; Animals ; *Nerve Growth Factors/genetics ; Gene Transfer Techniques ; Genetic Vectors ; }, abstract = {Neurodegenerative illnesses (NDDs) like Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, spinal muscular atrophy, and Huntington's disease have demonstrated considerable potential for gene therapy as a viable therapeutic intervention. NDDs are marked by the decline of neurons, resulting in changes in both behavior and pathology within the body. Strikingly, only symptomatic management is available without a cure for the NDDs. There is an unmet need for a permanent therapeutic approach. Many studies have been going on to target the newer therapeutic molecular targets for NDDs including gene-based therapy. Gene therapy has the potential to provide therapeutic benefits to a large number of patients with NDDs by offering mechanisms including neuroprotection, neuro-restoration, and rectification of pathogenic pathways. Gene therapy is a medical approach that aims to modify the biological characteristics of living cells by controlling the expression of specific genes in certain neurological disorders. Despite being the most complex and well-protected organ in the human body, there is clinical evidence to show that it is possible to specifically target the central nervous system (CNS). This provides hope for the prospective application of gene therapy in treating NDDs in the future. There are several advanced techniques available for using viral or non-viral vectors to deliver the therapeutic gene to the afflicted region. Neurotrophic factors (NTF) in the brain are crucial for the development, differentiation, and survival of neurons in the CNS, making them important in the context of various neurological illnesses. Gene delivery of NTF has the potential to be used as a therapeutic approach for the treatment of neurological problems in the brain. This review primarily focuses on the methodologies employed for delivering the genes of different NTFs to treat neurological disorders. These techniques are currently being explored as a viable therapeutic approach for neurodegenerative diseases. The article exclusively addresses gene delivery approaches and does not cover additional therapy strategies for NDDs. Gene therapy offers a promising alternative treatment for NDDs by stimulating neuronal growth instead of solely relying on symptom relief from drugs and their associated adverse effects. It can serve as a long-lasting and advantageous treatment choice for the management of NDDs. The likelihood of developing NDDs increases with age as a result of neuronal degradation in the brain. Gene therapy is an optimal approach for promoting neuronal growth through the introduction of nerve growth factor genes.}, }
@article {pmid38855716, year = {2024}, author = {Morganroth, J and Bardakjian, TM and Dratch, L and Quinn, CC and Elman, LB}, title = {Enhancing Clinical Infrastructure for the Delivery of Intrathecal and Genetic Therapies: A Qalsody (Tofersen) Model for Patients With SOD1-ALS.}, journal = {Neurology. Clinical practice}, volume = {14}, number = {4}, pages = {e200303}, pmid = {38855716}, issn = {2163-0402}, abstract = {BACKGROUND: Qalsody (tofersen), an intrathecal therapy (IT) antisense oligonucleotide (ASO), was granted accelerated approval by the Food and Drug Administration for the treatment of SOD1-mediated amyotrophic lateral sclerosis (ALS) on April 25, 2023. Academic centers need to be prepared for expedited drug delivery. The purpose of this model was to predict the number of SOD1-ALS patients whom we expect to see at our center at the time of Qalsody approval and to use it to extrapolate to a model for a hypothetical sporadic IT ALS therapy.<br><br>RECENT FINDINGS: We predicted that 6 symptomatic and 14 presymptomatic SOD1 patients would come to our center, whereas a sporadic therapy would generate 108 patients, creating excess office visits, lumbar punctures, and genetic counseling visits.<br><br>IMPLICATIONS FOR PRACTICE: As new therapies for neurologic diseases come to market, preparing for increased office volume and complex drug delivery are essential for optimal care.}, }
@article {pmid38853922, year = {2024}, author = {Dilliott, AA and Costanzo, MC and Bandres-Ciga, S and Blauwendraat, C and Casey, B and Hoang, Q and Iwaki, H and Jang, D and Kim, JJ and Leonard, HL and Levine, KS and Makarious, M and Nguyen, TT and Rouleau, GA and Singleton, AB and Smadbeck, P and Solle, J and Vitale, D and Nalls, MA and Flannick, J and Burtt, NP and Farhan, SMK}, title = {The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38853922}, abstract = {Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathological mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across ten different phenotypic groups, including neurological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use-cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open-science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for neurodegenerative disease patients.}, }
@article {pmid38852112, year = {2024}, author = {Leighton, DJ and Ansari, M and Newton, J and Cleary, E and Stephenson, L and Beswick, E and Carod Artal, J and Davenport, R and Duncan, C and Gorrie, GH and Morrison, I and Swingler, R and Deary, IJ and Porteous, M and Chandran, S and Pal, S and , }, title = {Genotypes and phenotypes of motor neuron disease: an update of the genetic landscape in Scotland.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5256-5266}, pmid = {38852112}, issn = {1432-1459}, support = {CAF/MND/15/01//Chief Scientist Office, Scottish Government Health and Social Care Directorate/ ; CAF/MND/15/01//MND Scotland/ ; CAF/MND/15/01/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; Scotland/epidemiology ; *Motor Neuron Disease/genetics/epidemiology ; Male ; Female ; Middle Aged ; Aged ; *Phenotype ; *C9orf72 Protein/genetics ; Genotype ; Adult ; DNA Repeat Expansion/genetics ; Cohort Studies ; Aged, 80 and over ; Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: Using the Clinical Audit Research and Evaluation of Motor Neuron Disease (CARE-MND) database and the Scottish Regenerative Neurology Tissue Bank, we aimed to outline the genetic epidemiology and phenotypes of an incident cohort of people with MND (pwMND) to gain a realistic impression of the genetic landscape and genotype-phenotype associations.<br><br>METHODS: Phenotypic markers were identified from the CARE-MND platform. Sequence analysis of 48 genes was undertaken. Variants were classified using a structured evidence-based approach. Samples were also tested for C9orf72 hexanucleotide expansions using repeat-prime PCR methodology.<br><br>RESULTS: 339 pwMND donated a DNA sample: 44 (13.0%) fulfilled criteria for having a pathogenic variant/repeat expansion, 53.5% of those with a family history of MND and 9.3% of those without. The majority (30 (8.8%)) had a pathogenic C9orf72 repeat expansion, including two with intermediate expansions. Having a C9orf72 expansion was associated with a significantly lower Edinburgh Cognitive and Behavioural ALS Screen ALS-Specific score (p&#x2009;=&#x2009;0.0005). The known pathogenic SOD1 variant p.(Ile114Thr), frequently observed in the Scottish population, was detected in 9 (2.7%) of total cases but in 17.9% of familial cases. Rare variants were detected in FUS and NEK1. One individual carried both a C9orf72 expansion and SOD1 variant.<br><br>CONCLUSIONS: Our results provide an accurate summary of MND demographics and genetic epidemiology. We recommend early genetic testing of people with cognitive impairment to ensure that C9orf72 carriers are given the best opportunity for informed treatment planning. Scotland is enriched for the SOD1 p.(Ile114Thr) variant and this has significant implications with regards to future genetically-targeted treatments.}, }
@article {pmid38850875, year = {2024}, author = {Coen, M and Benyamine, A and Delmont, E and Kaplanski, G and Bouabdallah, R and Xerri, L and Attarian, S and Serratrice, J}, title = {Tell-tale immune-related neurological syndromes: Should we look for and underlying low-grade B-cell lymphoma? A retrospective study on 12 cases.}, journal = {Pathology, research and practice}, volume = {260}, number = {}, pages = {155377}, doi = {10.1016/j.prp.2024.155377}, pmid = {38850875}, issn = {1618-0631}, mesh = {Humans ; Retrospective Studies ; Male ; Female ; Middle Aged ; *Lymphoma, B-Cell/pathology/immunology ; Aged ; Adult ; }, abstract = {INTRODUCTION: Immune-related neurological syndromes (affecting both the central and peripheral nervous system, as well as the neuromuscular junction) can associate with low-grade B-cell lymphomas.<br><br>METHODS: We conducted a retrospective study on the records of patients with miscellaneous immune-related neuropathies followed by the "Referral Centre for Neuromuscular Diseases and ALS" in collaboration with the Services of Internal Medicine and Hematology (La Timone Hospital, and the Paoli Calmettes-Insitute, Marseille, France; Geneva University Hospitals, Geneva, Switzerland). Clinical, biological, immunological and histological work-up was carried out and data collected.<br><br>RESULTS: We identified 12 patients with neurological syndromes and atypical presentation/course. In all these patients multiple autoantibodies were found. This prompted us to perform thorough hematologic investigations, that led to the diagnosis of different type of Low-Grade B-Cell lymphomas [i.e. marginal zone lymphomas with lymphoplasmacytic differentiation (n=3), splenic marginal area lymphoma with secondary lymph node invasion (n=1), unclassified marginal area lymphomas (n=8)]. Treatment of the underling lymphoma resulted in an improvement (n=8) or stabilization (n=4) of neurological disease.<br><br>CONCLUSION: Atypical presentation of immune-related neurological syndromes, as well as the presence of antibodies with different antigenic targets should be regarded as "warning signs" and raise the suspicion of a paraneoplastic origin sustained by an underlying low-grade B-cell lymphoma that should be actively sought and treated. Close collaboration between internists, neurologists and hematologists allows for the appropriate management of each case.}, }
@article {pmid38848664, year = {2024}, author = {Morioka, D and Sagisaka, R and Nakagawa, K and Takahashi, H and Tanaka, H}, title = {Effect of timing of advanced life support on out-of-hospital cardiac arrests at home.}, journal = {The American journal of emergency medicine}, volume = {82}, number = {}, pages = {94-100}, doi = {10.1016/j.ajem.2024.05.021}, pmid = {38848664}, issn = {1532-8171}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; Retrospective Studies ; Aged ; *Epinephrine/administration &amp; dosage/therapeutic use ; Japan/epidemiology ; Middle Aged ; *Emergency Medical Services ; *Advanced Cardiac Life Support/methods ; Intubation, Intratracheal/statistics &amp; numerical data ; Time-to-Treatment/statistics &amp; numerical data ; Aged, 80 and over ; Registries ; Time Factors ; Return of Spontaneous Circulation ; Cardiopulmonary Resuscitation/methods ; }, abstract = {AIM: In cases of out-of-hospital cardiac arrests (OHCA) occurring at home, Japanese emergency medical services personnel decide whether to provide treatment on the scene or during transport based on their judgment. This study aimed to evaluate the association between the timing of advanced life support (ALS) (i.e., endotracheal intubation [ETI] or adrenaline administration) for OHCA at home and prognosis.<br><br>METHOD: This retrospective cohort study used data from the Japan Utstein Registry and emergency transport data collected from patients who underwent pre-hospital ETI (n&#xa0;=&#xa0;6806) and received adrenaline (n&#xa0;=&#xa0;22,636) between 2016 and 2019. The timing of ETI or adrenaline administration was determined as "on the scene" or "in the ambulance." Multiple logistic regression analysis was used to estimate the association among the timing of ALS implementation, pre-hospital return of spontaneous circulation (ROSC), and survival at 1&#xa0;month.<br><br>RESULT: ETI on the scene was significantly positively associated with pre-hospital ROSC (adjusted odds ratio [AOR], 1.81; 95% confidence interval [CI], 1.57-2.09) and survival at 1&#xa0;month (AOR, 1.81; 95% CI, 1.47-2.23). Adrenaline administration on the scene was significantly positively associated with pre-hospital ROSC (AOR, 2.51; 95% CI, 2.33-2.70) and survival at 1&#xa0;month (AOR, 2.13; 95% CI, 1.89-2.40).<br><br>CONCLUSION: Our analysis suggests performing ALS on the scene was associated with pre-hospital ROSC and survival at 1&#xa0;month. Further efforts are needed to increase the rate of ALS implementation on the scene by emergency life-saving technicians.}, }
@article {pmid38848044, year = {2025}, author = {Samalia, P and Niederer, R}, title = {Letter to the Editor: Comment on Raad et al's "Adalimumab for the Treatment of Non-Infectious Uveitis: A Real Life Experience".}, journal = {Ocular immunology and inflammation}, volume = {33}, number = {3}, pages = {377}, doi = {10.1080/09273948.2024.2362879}, pmid = {38848044}, issn = {1744-5078}, }
@article {pmid38840222, year = {2024}, author = {Provasek, VE and Kodavati, M and Kim, B and Mitra, J and Hegde, ML}, title = {TDP43 interacts with MLH1 and MSH6 proteins in a DNA damage-inducible manner.}, journal = {Molecular brain}, volume = {17}, number = {1}, pages = {32}, pmid = {38840222}, issn = {1756-6606}, support = {RF1 NS112719/NS/NINDS NIH HHS/United States ; RF1NS112719/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism ; *MutL Protein Homolog 1/metabolism ; *DNA Damage ; *Protein Binding/drug effects ; Cell Line, Tumor ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Neurons/metabolism ; Middle Aged ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double-strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that the TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complementary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 h treatment of 10 μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS-affected neurons.}, }
@article {pmid38835175, year = {2024}, author = {Barclay, G and Barbato, M and Yerbury, R and Harnish, L and Miranda, N}, title = {Bispectral Index monitoring of palliative sedation for home withdrawal of tracheostomy ventilation: A case report.}, journal = {Palliative medicine}, volume = {38}, number = {7}, pages = {755-758}, doi = {10.1177/02692163241257580}, pmid = {38835175}, issn = {1477-030X}, mesh = {Humans ; Male ; *Consciousness Monitors ; Deep Sedation ; *Hypnotics and Sedatives/administration &amp; dosage/therapeutic use ; Motor Neuron Disease/therapy ; *Palliative Care ; *Respiration, Artificial ; Tracheostomy ; *Withholding Treatment ; }, abstract = {BACKGROUND: Tracheostomy ventilation in motor neurone disease is an uncommon life-sustaining treatment. Best practice is having a plan for ventilation withdrawal, but the literature to guide practice is limited. Case reports have documented standard doses of opioids and benzodiazepines used for sedation in such cases.<br><br>CASE: A 49-year-old man was diagnosed with motor neurone disease in 2016. He commenced tracheostomy ventilation in 2018. In 2022 and 2023, planning was undertaken, at the patient's request, for withdrawal of tracheostomy ventilation at home, when he was no longer able to communicate with technology.<br><br>CASE PLANNING: Planning included Bispectral Index monitoring prior to cessation of ventilation, ensuring this only occurred when deep sedation was achieved. After ventilation withdrawal in 2023, a retrospective review of medications given and his level of sedation on monitoring was undertaken, with family consent.<br><br>OUTCOME: Ventilation withdrawal was initiated after deep sedation was achieved, 6&#x2009;h after commencing subcutaneous infusions of morphine, midazolam, clonazepam and phenobarbital.<br><br>LESSONS: Doses required to achieve acceptable sedation exceeded literature reports. Achieving deep sedation was a longer than expected process.<br><br>CONCLUSION: More research using an objective measure of sedation is required, as clinical assessment of sedation in this context is compromised.}, }
@article {pmid38833116, year = {2024}, author = {Mubeen, H and Masood, A and Zafar, A and Khan, ZQ and Khan, MQ and Nisa, AU}, title = {Insights into AlphaFold's breakthrough in neurodegenerative diseases.}, journal = {Irish journal of medical science}, volume = {193}, number = {5}, pages = {2577-2588}, pmid = {38833116}, issn = {1863-4362}, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology ; Artificial Intelligence ; Deep Learning ; Parkinson Disease ; Alzheimer Disease ; Algorithms ; Frontotemporal Dementia/genetics ; }, abstract = {Neurodegenerative diseases (ND) are disorders of the central nervous system (CNS) characterized by impairment in neurons' functions, and complete loss, leading to memory loss, and difficulty in learning, language, and movement processes. The most common among these NDs are Alzheimer's disease (AD) and Parkinson's disease (PD), although several other disorders also exist. These are frontotemporal dementia (FTD), amyotrophic lateral syndrome (ALS), Huntington's disease (HD), and others; the major pathological hallmark of NDs is the proteinopathies, either of amyloid-β (Aβ), tauopathies, or synucleinopathies. Aggregation of proteins that do not undergo normal configuration, either due to mutations or through some disturbance in cellular pathway contributes to the diseases. Artificial Intelligence (AI) and deep learning (DL) have proven to be successful in the diagnosis and treatment of various congenital diseases. DL approaches like AlphaFold (AF) are a major leap towards success in CNS disorders. This 3D protein geometry modeling algorithm developed by DeepMind has the potential to revolutionize biology. AF has the potential to predict 3D-protein confirmation at an accuracy level comparable to experimentally predicted one, with the additional advantage of precisely estimating protein interactions. This breakthrough will be beneficial to identify diseases' advancement and the disturbance of signaling pathways stimulating impaired functions of proteins. Though AlphaFold has solved a major problem in structural biology, it cannot predict membrane proteins-a beneficial approach for drug designing.}, }
@article {pmid38832321, year = {2024}, author = {Patel, JS and McCall, NS and Thomas, M and Zhou, J and Higgins, KA and Bradley, JD and Tian, S and McDonald, MW and Kesarwala, AH and Stokes, WA}, title = {Immune System Dose With Proton Versus Photon Radiotherapy for Treatment of Locally Advanced NSCLC.}, journal = {International journal of particle therapy}, volume = {12}, number = {}, pages = {100016}, pmid = {38832321}, issn = {2331-5180}, abstract = {PURPOSE: Emerging data have illuminated the impact of effective radiation dose to immune cells (EDIC) on outcomes in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) treated with intensity-modulated radiotherapy (IMRT). Hypothesizing that intensity-modulated proton therapy (IMPT) may reduce EDIC versus IMRT, we conducted a dosimetric analysis of patients treated at our institution.<br><br>MATERIALS AND METHODS: Data were retrospectively collected for 12 patients with locally advanced, unresectable NSCLC diagnosed between 2019 and 2021 who had physician-approved IMRT and IMPT plans. Data to calculate EDIC from both Jin et al (PMID: 34944813) and Ladbury et al's (PMID: 31175902) models were abstracted. Paired t tests were utilized to compare the difference in mean EDIC between IMPT and IMRT plans.<br><br>RESULTS: IMPT decreased EDIC for 11 of 12 patients (91.7%). The mean EDIC per the Jin model was significantly lower with IMPT than IMRT (3.04 GyE vs 4.99&#xa0;Gy, P&#xa0;<&#xa0;.001). Similarly, the mean EDIC per the Ladbury model was significantly lower with IMPT than IMRT (4.50 GyE vs 7.60&#xa0;Gy, P&#xa0;<&#xa0;.002). Modeled 2-year&#xa0;overall&#xa0;survival was significantly longer with IMPT than IMRT (median 71% vs 63%; P&#xa0;=&#xa0;.03).<br><br>CONCLUSION: IMPT offers a statistically significant reduction in EDIC compared to IMRT. Given the emergence of EDIC as a modifiable prognostic factor in treatment planning, our dosimetric study highlights a potential role for IMPT to address an unmet need in improving oncologic outcomes in patients with locoregionally advanced NSCLC.}, }
@article {pmid38830181, year = {2024}, author = {Weemering, DN and Beelen, A and Kliest, T and van Leeuwen, LAG and van den Berg, LH and van Eijk, RPA}, title = {Trial Participation in Neurodegenerative Diseases: Barriers and Facilitators: A Systematic Review and Meta-Analysis.}, journal = {Neurology}, volume = {103}, number = {1}, pages = {e209503}, pmid = {38830181}, issn = {1526-632X}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Clinical Trials as Topic ; *Patient Participation ; Patient Selection ; }, abstract = {BACKGROUND AND OBJECTIVES: Clinical trials in neurodegenerative diseases often encounter selective enrollment and under-representation of certain patient populations. This delays drug development and substantially limits the generalizability of clinical trial results. To inform recruitment and retention strategies, and to better understand the generalizability of clinical trial populations, we investigated which factors drive participation.<br><br>METHODS: We reviewed the literature systematically to identify barriers to and facilitators of trial participation in 4 major neurodegenerative disease areas: Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease. Inclusion criteria included original research articles published in a peer-reviewed journal and evaluating barriers to and/or facilitators of participation in a clinical trial with a drug therapy (either symptomatic or disease-modifying). The Critical Appraisal Skills Program checklist for qualitative studies was used to assess and ensure the quality of the studies. Qualitative thematic analyses were employed to identify key enablers of trial participation. Subsequently, we pooled quantitative data of each enabler using meta-analytical models.<br><br>RESULTS: Overall, we identified 36 studies, enrolling a cumulative sample size of 5,269 patients, caregivers, and health care professionals. In total, the thematic analysis resulted in 31 unique enablers of trial participation; the key factors were patient-related (own health benefit and altruism), study-related (treatment and study burden), and health care professional-related (information availability and patient-physician relationship). When meta-analyzed across studies, responders reported that the reason to participate was mainly driven by (1) the relationship with clinical staff (70% of the respondents; 95% CI 53%-83%), (2) the availability of study information (67%, 95% CI 38%-87%), and (3) the use or absence of a placebo or sham-control arm (53% 95% CI 32%-72%). There was, however, significant heterogeneity between studies (all p < 0.001).<br><br>DISCUSSION: We have provided a comprehensive list of reasons why patients participate in clinical trials for neurodegenerative diseases. These results may help to increase participation rates, better inform patients, and facilitate patient-centric approaches, thereby potentially reducing selection mechanisms and improving generalizability of trial results.}, }
@article {pmid38829866, year = {2024}, author = {Laurido-Soto, OJ and Faust, IM and Nielsen, SS and Racette, BA}, title = {Adherence to practice parameters in Medicare beneficiaries with amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {6}, pages = {e0304083}, pmid = {38829866}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Medicare ; Male ; Female ; United States ; Aged ; Retrospective Studies ; Aged, 80 and over ; Guideline Adherence/statistics &amp; numerical data ; Middle Aged ; Practice Patterns, Physicians'/statistics &amp; numerical data ; }, abstract = {OBJECTIVE: Physician adherence to evidence-based clinical practice parameters impacts outcomes of amyotrophic lateral sclerosis (ALS) patients. We sought to investigate compliance with the 2009 practice parameters for treatment of ALS patients in the United States, and sociodemographic and provider characteristics associated with adherence.<br><br>METHODS: In this population-based, retrospective cohort study of incident ALS patients in 2009-2014, we included all Medicare beneficiaries age &#x2265;20 with &#x2265;1 International Classification of Diseases, Ninth Revision, Clinical Modification ALS code (335.20) in 2009 and no prior years (N = 8,575). Variables of interest included race/ethnicity, sex, age, urban residence, Area Deprivation Index (ADI), and provider specialty (neurologist vs. non-neurologist). Outcomes were use of practice parameters, which included feeding tubes, non-invasive ventilation (NIV), riluzole, and receiving care from a neurologist.<br><br>RESULTS: Overall, 42.9% of patients with ALS received neurologist care. Black beneficiaries (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.47-0.67), older beneficiaries (OR 0.964, 95% CI 0.961-0.968 per year), and those living in disadvantaged areas (OR 0.70, 95% CI 0.61-0.80) received less care from neurologists. Overall, only 26.7% of beneficiaries received a feeding tube, 19.2% NIV, and 15.3% riluzole. Neurologist-treated patients were more likely to receive interventions than other ALS patients: feeding tube (OR 2.80, 95% CI 2.52-3.11); NIV (OR 10.8, 95% CI 9.28-12.6); and riluzole (OR 7.67, 95% CI 6.13-9.58), after adjusting for sociodemographics. These associations remained marked and significant when we excluded ALS patients who subsequently received a code for other diseases that mimic ALS.<br><br>CONCLUSIONS: ALS patients treated by neurologists received care consistent with practice parameters more often than those not treated by a neurologist. Black, older, and disadvantaged beneficiaries received less care consistent with the practice parameters.}, }
@article {pmid38829511, year = {2025}, author = {Jiang, S and Xu, R}, title = {The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {221-232}, pmid = {38829511}, issn = {1559-1182}, support = {30560042//National Natural Science Foundation of China/ ; 81160161//National Natural Science Foundation of China/ ; 81360198//National Natural Science Foundation of China/ ; 82160255//National Natural Science Foundation of China/ ; GJJ13198//Education Department of Jiangxi Province/ ; GJJ170021//Education Department of Jiangxi Province/ ; 20192BAB205043//Jiangxi Provincial Department of Science and Technology/ ; 20181019//Health and Family Planning Commission of Jiangxi Province/ ; 202210002//Health and Family Planning Commission of Jiangxi Province/ ; 202310119//Health and Family Planning Commission of Jiangxi Province/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/microbiology/pathology/physiopathology ; Autophagy/physiology ; Dysbiosis/complications/microbiology/physiopathology ; Extracellular Vesicles/metabolism ; Gastrointestinal Microbiome/physiology ; Mitochondria/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease mainly characterized by the accumulation of ubiquitinated proteins in the affected motor neurons. At present, the accurate pathogenesis of ALS remains unclear and there are still no effective treatment measures for ALS. The potential pathogenesis of ALS mainly includes the misfolding of some pathogenic proteins, the genetic variation, mitochondrial dysfunction, autophagy disorders, neuroinflammation, the misregulation of RNA, the altered axonal transport, and gut microbial dysbiosis. Exploring the pathogenesis of ALS is a critical step in searching for the effective therapeutic approaches. The current studies suggested that the genetic variation, gut microbial dysbiosis, the activation of glial cells, and the transportation disorder of extracellular vesicles may play some important roles in the pathogenesis of ALS. This review conducts a systematic review of these current potential promising topics closely related to the pathogenesis of ALS; it aims to provide some new evidences and clues for searching the novel treatment measures of ALS.}, }
@article {pmid38829431, year = {2024}, author = {Sabatelli, M and Cerri, F and Zuccarino, R and Patanella, AK and Bernardo, D and Bisogni, G and Tanel, R and Sansone, V and Filosto, M and Lattante, S and Martello, F and Doronzio, PN and Stano, S and Zanfini, BA and Coccia, M and Costantini, EM and Lizio, A and Lucioli, G and Padovani, A and Merlini, GP and Conte, A}, title = {Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5177-5186}, pmid = {38829431}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/blood ; Male ; Female ; Middle Aged ; Aged ; *Superoxide Dismutase-1/genetics ; Neurofilament Proteins/blood/cerebrospinal fluid ; Disease Progression ; Adult ; Retrospective Studies ; Treatment Outcome ; Cohort Studies ; }, abstract = {BACKGROUND: In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant.<br><br>METHODS: In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48&#xa0;weeks (median period of 84&#xa0;weeks, range 48-108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1&#xa0;year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients.<br><br>RESULTS: Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p&#x2009;=&#x2009;0.023 and p&#x2009;=&#x2009;0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy.<br><br>CONCLUSIONS: Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients.}, }
@article {pmid38826483, year = {2024}, author = {Provasek, VE and Kodavati, M and Kim, B and Mitra, J and Hegde, ML}, title = {TDP43 Interacts with MLH1 and MSH6 Proteins in A DNA Damage-Inducible Manner.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38826483}, issn = {2693-5015}, support = {R35 CA220430/CA/NCI NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; P01 CA092584/CA/NCI NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complimentary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 hr treatment of 10μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS affected neurons.}, }
@article {pmid38826246, year = {2024}, author = {Martínez, P and Silva, M and Abarzúa, S and Tevy, MF and Jaimovich, E and Constantine-Paton, M and Bustos, FJ and van Zundert, B}, title = {Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.05.24.595817}, pmid = {38826246}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1 [G93A] (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2+ transients and reactive oxygen species (i.e., H 2 O 2). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.}, }
@article {pmid38825034, year = {2024}, author = {Fang, T and Pacut, P and Bose, A and Sun, Y and Gao, J and Sivakumar, S and Bloom, B and Nascimento Andrade, EI and Trombetta, B and Ghasemi, M}, title = {Clinical and genetic factors affecting diagnostic timeline of amyotrophic lateral sclerosis: a 15-year retrospective study.}, journal = {Neurological research}, volume = {46}, number = {9}, pages = {859-867}, doi = {10.1080/01616412.2024.2362578}, pmid = {38825034}, issn = {1743-1328}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Genetic Testing/methods ; Adult ; Delayed Diagnosis ; Time Factors ; }, abstract = {OBJECTIVES: Amyotrophic Lateral Sclerosis (ALS) diagnosis can take 10-16 months from symptom onset, leading to delays in treatment and patient counselling. We studied the impact of clinical and genetic risk factors on the diagnostic timeline of ALS.<br><br>METHODS: Baseline characteristics, family history, gene testing, onset location, time from symptom onset to diagnosis, and time from first doctor visit to suspected ALS was collected. We used multiple regression to assess the interaction of these factors on ALS diagnostic timeline. We analysed a subgroup of patients with genetic testing and compared positive or negative tests, sporadic or familial and ALS-related genes to time for diagnosis.<br><br>RESULTS: Four hundred and forty-eight patients diagnosed with ALS at the University of Massachusetts Chan Medical Center between January 2007 and December 2021 were analysed. The median time to ALS diagnosis was 12&#x2009;months and remained unchanged from 2007 to 2021 (p&#x2009;=&#x2009;0.20). Diagnosis was delayed in patients with sporadic compared with familial ALS (mean months [standard deviation], 16.5[13.5] and 11.2[8.5], p&#x2009;<&#x2009;0.001); cognitive onset (41[21.26]) had longer time to diagnosis than bulbar (11.9[8.2]), limb (15.9[13.2]), respiratory (19.7[13.9]) and ALS with multiple onset locations (20.77[15.71], p&#x2009;<&#x2009;0.001). One hundred and thirty-four patients had gene testing and 32 tested positive (23.8%). Gene testing (p&#x2009;=&#x2009;0.23), a positive genetic test (p&#x2009;=&#x2009;0.16), different ALS genes (p&#x2009;=&#x2009;0.25) and sporadic (p&#x2009;=&#x2009;0.92) or familial (p&#x2009;=&#x2009;0.85) ALS testing positive for ALS genes did not influence time to diagnosis.<br><br>DISCUSSION: Time for ALS diagnosis remained unchanged from 2007 to 2021, bulbar-onset and familial ALS made for faster diagnosis.}, }
@article {pmid38823229, year = {2024}, author = {Roman-Pognuz, E and Rigutti, S and Colussi, G and Lena, E and Bonsano, M and Lucangelo, U}, title = {Acute esophageal necrosis following cardiac arrest: A rare and lethal syndrome with diagnostic challenges.}, journal = {International journal of surgery case reports}, volume = {120}, number = {}, pages = {109751}, pmid = {38823229}, issn = {2210-2612}, abstract = {Acute esophageal necrosis (AEN) is a condition characterized by the necrosis of the distal portion of the esophageal mucosa. Risk factors predisposing to this condition are associated to compromised vascular perfusion (e.g. diabetes mellitus, chronic kidney disease, advanced age, and hypertension, shock states). Complications of AEN can be severe including UGI stricture, perforation and overall increased mortality. The true incidence of AEN remains uncertain due to potential subclincal presentations and early resolution.<br><br>CASE PRESENTATION: The case outlined involves a 66-years-old obese male with history of alcoholism and lymph-edema of the left leg who presented to the emergency department with hematemesis, haemodynamic instability and impaired consciousness. Shortly after initial assessment, the patient went into cardiac arrest with pulse-less electrical activity (PEA). Return of spontaneous circulation (ROSC) was achieved following instigation of ALS protocol, fluid resuscitation and the administration of a total of 5&#xa0;mg of adrenaline. Following stabilization, a CT scan was performed which reported a moderately enlarged esophagus with a thickened wall, liquid hypodense material within the esophagus and stomach, and liver cirrhosis. The emergent esophagogastroduodenoscopy (EGDS) revealed extensive mucosal findings indicative of diffuse necrosis with initial scarring, which was later diagnosed as AEN. The patient unfortunately deceased in ICU after developing progression of the AEN, post-cardiac arrest syndrome and liver failure.<br><br>CLINICAL DISCUSSION: The presented case highlights several crucial clinical issues and management problems related to AEN. To diagnose AEN, EGDS is still the gold-standard since it allows direct inspection of the esophageal mucosal layer. The management of AEN necessitates a multidisciplinary approach that includes aggressive resuscitation, treatment of underlying comorbidities, and supportive care (e.g. proton pump inhibitors). The mortality rate for AEN remains high despite improvements in diagnosis and treatment highlighting the need to recognize this condition early and intervene promptly in the patients affected. Moreover, long-term sequelae like stricture formation of the esophagus and impaired esophageal motility may contribute to morbidity requiring continuos monitoring. Therefore, to optimize outcomes while reducing complications among affected patients, prompt identification associated with appropriate medical measures are essential. More research needs to be done aiming to better understand the pathophysiology of AEN thereby identifying strategies for its prevention or cure.<br><br>CONCLUSIONS: AEN is a rare syndrome characterized by upper gastrointestinal bleeding and hypoxic damage of the esophageal mucosa, often associated with ischemia, gastric outlet obstruction, and compromised protective barriers. Treatment involves aggressive resuscitation, proton pump inhibitors, and monitoring for infection or perforation. However, despite intensive efforts, the mortality rate for AEN remains high at 32&#xa0;%.}, }
@article {pmid38822985, year = {2024}, author = {Faysal, M and Dehbia, Z and Zehravi, M and Sweilam, SH and Haque, MA and Kumar, KP and Chakole, RD and Shelke, SP and Sirikonda, S and Nafady, MH and Khan, SL and Nainu, F and Ahmad, I and Emran, TB}, title = {Flavonoids as Potential Therapeutics Against Neurodegenerative Disorders: Unlocking the Prospects.}, journal = {Neurochemical research}, volume = {49}, number = {8}, pages = {1926-1944}, pmid = {38822985}, issn = {1573-6903}, mesh = {*Flavonoids/therapeutic use/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Antioxidants/therapeutic use/pharmacology ; }, abstract = {Neurodegeneration, the decline of nerve cells in the brain, is a common feature of neurodegenerative disorders (NDDs). Oxidative stress, a key factor in NDDs such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease can lead to neuronal cell death, mitochondria impairment, excitotoxicity, and Ca[2+] stress. Environmental factors compromising stress response lead to cell damage, necessitating novel therapeutics for preventing or treating brain disorders in older individuals and an aging population. Synthetic medications offer symptomatic benefits but can have adverse effects. This research explores the potential of flavonoids derived from plants in treating NDDs. Flavonoids compounds, have been studied for their potential to enter the brain and treat NDDs. These compounds have diverse biological effects and are currently being explored for their potential in the treatment of central nervous system disorders. Flavonoids have various beneficial effects, including antiviral, anti-allergic, antiplatelet, anti-inflammatory, anti-tumor, anti-apoptotic, and antioxidant properties. Their potential to alleviate symptoms of NDDs is significant.}, }
@article {pmid38819717, year = {2024}, author = {Tappenden, P and Hardiman, O and Kwon, SH and Mon-Yee, M and Galvin, M and McDermott, C and , }, title = {A Model-Based Economic Evaluation of Hypothetical Treatments for Amyotrophic Lateral Sclerosis in the UK: Implications for Pricing of New and Emerging Health Technologies.}, journal = {PharmacoEconomics}, volume = {42}, number = {9}, pages = {1003-1016}, pmid = {38819717}, issn = {1179-2027}, mesh = {*Amyotrophic Lateral Sclerosis/economics/therapy/drug therapy ; Humans ; *Cost-Benefit Analysis ; *Quality-Adjusted Life Years ; United Kingdom ; *Models, Economic ; Disease Progression ; Biomedical Technology/economics ; Technology Assessment, Biomedical ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease which leads to loss of muscle function and paralysis. Historically, clinical drug development has been unsuccessful, but promising disease-modifying therapies (DMTs) may be on the horizon.<br><br>OBJECTIVES: The aims of this study were to estimate survival, quality-adjusted life-years (QALYs) and costs under current care, and to explore the conditions under which new therapies might be considered cost effective.<br><br>METHODS: We developed a health economic model to evaluate the cost effectiveness of future ALS treatments from a UK National Health Service and Personal Social Services perspective over a lifetime horizon using data from the ALS-CarE study. Costs were valued at 2021/22 prices. Two hypothetical interventions were evaluated: a DMT which delays progression and mortality, and a symptomatic therapy which improves utility only. Sensitivity analysis was conducted to identify key drivers of cost effectiveness.<br><br>RESULTS: Starting from King's stage 2, patients receiving current care accrue an estimated 2.27 life-years, 0.75 QALYs and lifetime costs of &#xa3;68,047. Assuming a 50% reduction in progression rates and a UK-converted estimate of the price of edaravone, the incremental cost-effectiveness ratio for a new DMT versus current care is likely to exceed &#xa3;735,000 per QALY gained. Symptomatic therapies may be more likely to achieve acceptable levels of cost effectiveness.<br><br>CONCLUSIONS: Regardless of efficacy, DMTs may struggle to demonstrate cost effectiveness, even at a low price. The cost effectiveness of DMTs is likely to be strongly influenced by drug price, the magnitude and durability of relative treatment effects, treatment starting/stopping rules and any additional utility benefits over current care.}, }
@article {pmid38819491, year = {2024}, author = {Juarez, D and Handal-Silva, A and Morán-Perales, JL and Torres-Cifuentes, DM and Flores, G and Treviño, S and Moreno-Rodriguez, A and Guevara, J and Diaz, A}, title = {New insights into sodium phenylbutyrate as a pharmacotherapeutic option for neurological disorders.}, journal = {Synapse (New York, N.Y.)}, volume = {78}, number = {4}, pages = {e22301}, doi = {10.1002/syn.22301}, pmid = {38819491}, issn = {1098-2396}, support = {IN214117//PAPITT-UNAM/ ; DIFA-NAT24-G//Vicerrector&#xed;a de Investigaci&#xf3;n y Estudios de Posgrado, Benem&#xe9;rita Universidad Aut&#xf3;noma de Puebla/ ; TEMS-NAT24-G//Vicerrector&#xed;a de Investigaci&#xf3;n y Estudios de Posgrado, Benem&#xe9;rita Universidad Aut&#xf3;noma de Puebla/ ; }, mesh = {Humans ; *Phenylbutyrates/therapeutic use/pharmacology ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Neurological disorders (NDs) are diseases of the central and peripheral nervous systems that affect more than one billion people worldwide. The risk of developing an ND increases with age due to the vulnerability of the different organs and systems to genetic, environmental, and social changes that consequently cause motor and cognitive deficits that disable the person from their daily activities and individual and social productivity. Intrinsic factors (genetic factors, age, gender) and extrinsic factors (addictions, infections, or lifestyle) favor the persistence of systemic inflammatory processes that contribute to the evolution of NDs. Neuroinflammation is recognized as a common etiopathogenic factor of ND. The study of new pharmacological options for the treatment of ND should focus on improving the characteristic symptoms and attacking specific molecular targets that allow the delay of damage processes such as neuroinflammation, oxidative stress, cellular metabolic dysfunction, and deregulation of transcriptional processes. In this review, we describe the possible role of sodium phenylbutyrate (NaPB) in the pathogenesis of Alzheimer's disease, hepatic encephalopathy, aging, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis; in addition, we describe the mechanism of action of NaPB and its beneficial effects that have been shown in various in vivo and in vitro studies to delay the evolution of any ND.}, }
@article {pmid38818523, year = {2024}, author = {Shen, J and Wang, X and Wang, M and Zhang, H}, title = {Potential molecular mechanism of exercise reversing insulin resistance and improving neurodegenerative diseases.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1337442}, pmid = {38818523}, issn = {1664-042X}, abstract = {Neurodegenerative diseases are debilitating nervous system disorders attributed to various conditions such as body aging, gene mutations, genetic factors, and immune system disorders. Prominent neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Insulin resistance refers to the inability of the peripheral and central tissues of the body to respond to insulin and effectively regulate blood sugar levels. Insulin resistance has been observed in various neurodegenerative diseases and has been suggested to induce the occurrence, development, and exacerbation of neurodegenerative diseases. Furthermore, an increasing number of studies have suggested that reversing insulin resistance may be a critical intervention for the treatment of neurodegenerative diseases. Among the numerous measures available to improve insulin sensitivity, exercise is a widely accepted strategy due to its convenience, affordability, and significant impact on increasing insulin sensitivity. This review examines the association between neurodegenerative diseases and insulin resistance and highlights the molecular mechanisms by which exercise can reverse insulin resistance under these conditions. The focus was on regulating insulin resistance through exercise and providing practical ideas and suggestions for future research focused on exercise-induced insulin sensitivity in the context of neurodegenerative diseases.}, }
@article {pmid38807021, year = {2024}, author = {Rahimian, S and Najafi, H and Webber, CA and Jalali, H}, title = {Advances in Exosome-Based Therapies for the Repair of Peripheral Nerve Injuries.}, journal = {Neurochemical research}, volume = {49}, number = {8}, pages = {1905-1925}, pmid = {38807021}, issn = {1573-6903}, mesh = {*Exosomes/metabolism/transplantation ; Humans ; *Peripheral Nerve Injuries/therapy/metabolism ; Animals ; Nerve Regeneration/physiology ; }, abstract = {Peripheral nerve injuries (PNIs) are the term used to describe injuries that occur to the nerve fibers of the peripheral nervous system (PNS). Such injuries may be caused by trauma, infection, or aberrant immunological response. Although the peripheral nervous system has a limited capacity for self-repair, in cases of severe damage, this process is either interrupted entirely or is only partially completed. The evaluation of variables that promote the repair of peripheral nerves has consistently been a focal point. Exosomes are a subtype of extracellular vesicles that originate from cellular sources and possess abundant proteins, lipids, and nucleic acids, play a critical role in facilitating intercellular communication. Due to their modifiable composition, they possess exceptional capabilities as carriers for therapeutic compounds, including but not limited to mRNAs or microRNAs. Exosome-based therapies have gained significant attention in the treatment of several nervous system diseases due to their advantageous properties, such as low toxicity, high stability, and limited immune system activation. The objective of this review article is to provide an overview of exosome-based treatments that have been developed in recent years for a range of PNIs, including nerve trauma, diabetic neuropathy, amyotrophic lateral sclerosis (ALS), glaucoma, and Guillain-Barre syndrome (GBS). It was concluded that exosomes could provide favorable results in the improvement of peripheral PNIs by facilitating the transfer of regenerative factors. The development of bioengineered exosome therapy for PNIs should be given more attention to enhance the efficacy of exosome treatment for PNIs.}, }
@article {pmid38805053, year = {2024}, author = {Bjelica, B and Bartels, MB and Hesebeck-Brinckmann, J and Petri, S}, title = {Non-motor symptoms in patients with amyotrophic lateral sclerosis: current state and future directions.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {3953-3977}, pmid = {38805053}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of both upper and lower motor neurons. A defining histopathological feature in approximately 97% of all ALS cases is the accumulation of phosphorylated trans-activation response (TAR) DNA-binding protein 43 protein (pTDP-43) aggregates in the cytoplasm of neurons and glial cells within the central nervous system. Traditionally, it was believed that the accumulation of TDP-43 aggregates and subsequent neurodegeneration primarily occurs in motor neurons. However, contemporary evidence suggests that as the disease progresses, other systems and brain regions are also affected. Despite this, there has been a limited number of clinical studies assessing the non-motor symptoms in ALS patients. These studies often employ various outcome measures, resulting in a wide range of reported frequencies of non-motor symptoms in ALS patients. The importance of assessing the non-motor symptoms reflects in a fact that they have a significant impact on patients' quality of life, yet they frequently go underdiagnosed and unreported during clinical evaluations. This review aims to provide an up-to-date overview of the current knowledge concerning non-motor symptoms in ALS. Furthermore, we address their diagnosis and treatment in everyday clinical practice.}, }
@article {pmid38802175, year = {2024}, author = {Malaspina, A}, title = {Use of biomarkers in clinical trials and future developments that will help identify novel biomarkers.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {171-207}, doi = {10.1016/bs.irn.2024.04.010}, pmid = {38802175}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/genetics/metabolism/drug therapy ; *Biomarkers ; *Clinical Trials as Topic/methods ; }, abstract = {Engineering new solutions for therapeutic benefit in Amyotrophic Lateral Sclerosis (ALS) has proved a difficult task to accomplish. This is largely the reflection of complexities at multiple levels, that require solutions to improve cost-effectiveness and outcomes. The main obstacle related to the condition's clinical heterogeneity, chiefly the broad difference in survival observed among ALS patients, imposes large populations studies and long follow-up to evaluate any efficacy. The emerging solution is composite clinical and biological parameters enabling prognostic stratification into homogeneous phenotypes for more affordable studies. From a therapeutic development perspective, the choice of a medicinal product requires the availability of treatment-specific biomarkers of target engagement to identify off-target effects based on the compound's putative modality of action. More importantly, there are no established biomarkers of treatment response that can complement clinical outcome measures and support futility and end of treatment analyses of efficacy. Ultimately the onus rests on the development of biomarkers encompassing the unmet needs of clinical trial design, from inclusion to efficacy. These readouts of the pathological process may be used in combination with clinical and paraclinical outcome measured, significantly reducing the time and financial burden of clinical studies. Progress towards a biomarker-driven clinical trial design in ALS has been possible thanks to the accurate detection of neurofilaments and of other immunological mediators in biological fluids with the disease progression, a step change enabling the testing of novel therapeutic agents in a new clinical trial setting. However, further progress remains to be made to find treatment specific target engagement biomarkers along with readouts of treatment response that can be reliably applied to all emerging therapies and clinical studies. Here we will cover the basic notions of biomarker development in ALS clinical trials, the most crucial unanswered questions and the unmet needs in the ALS biomarkers space.}, }
@article {pmid38802174, year = {2024}, author = {Hobson, E and McDermott, C}, title = {Advances in symptom management and in monitoring disease progression in motor neuron disease.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {119-169}, doi = {10.1016/bs.irn.2024.04.004}, pmid = {38802174}, issn = {2162-5514}, mesh = {Humans ; *Motor Neuron Disease/therapy/physiopathology ; *Disease Progression ; Disease Management ; Quality of Life ; }, abstract = {The aim of supportive management of motor neuron disease is to improve survival, promote good quality of life and patient independence and autonomy whilst preparing for future progression and the end of life. Multidisciplinary specialist care aims to address the multifaceted and interacting biopsychosocial problems associated with motor neuron disease that leads to proven benefits in both survival and quality of life. This chapter will explore principles, structure and details of treatment options, and make recommendations for practice and for future research.}, }
@article {pmid38791160, year = {2024}, author = {Bocheva, G and Bakalov, D and Iliev, P and Tafradjiiska-Hadjiolova, R}, title = {The Vital Role of Melatonin and Its Metabolites in the Neuroprotection and Retardation of Brain Aging.}, journal = {International journal of molecular sciences}, volume = {25}, number = {10}, pages = {}, pmid = {38791160}, issn = {1422-0067}, mesh = {*Melatonin/metabolism/pharmacology/therapeutic use ; Humans ; *Brain/metabolism/drug effects ; *Aging/metabolism/drug effects ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Neuroprotection/drug effects ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Kynuramine/metabolism/analogs &amp; derivatives ; }, abstract = {While primarily produced in the pineal gland, melatonin's influence goes beyond its well-known role in regulating sleep, nighttime metabolism, and circadian rhythms, in the field of chronobiology. A plethora of new data demonstrates melatonin to be a very powerful molecule, being a potent ROS/RNS scavenger with anti-inflammatory, immunoregulatory, and oncostatic properties. Melatonin and its metabolites exert multiple beneficial effects in cutaneous and systemic aging. This review is focused on the neuroprotective role of melatonin during aging. Melatonin has an anti-aging capacity, retarding the rate of healthy brain aging and the development of age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. Melatonin, as well as its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), can reduce oxidative brain damage by shielding mitochondria from dysfunction during the aging process. Melatonin could also be implicated in the treatment of neurodegenerative conditions, by modifying their characteristic low-grade neuroinflammation. It can either prevent the initiation of inflammatory responses or attenuate the ongoing inflammation. Drawing on the current knowledge, this review discusses the potential benefits of melatonin supplementation in preventing and managing cognitive impairment and neurodegenerative diseases.}, }
@article {pmid38790979, year = {2024}, author = {Mishra, PS and Phaneuf, D and Boutej, H and Picher-Martel, V and Dupre, N and Kriz, J and Julien, JP}, title = {Inhibition of NF-κB with an Analog of Withaferin-A Restores TDP-43 Homeostasis and Proteome Profiles in a Model of Sporadic ALS.}, journal = {Biomedicines}, volume = {12}, number = {5}, pages = {}, pmid = {38790979}, issn = {2227-9059}, support = {143275/CAPMC/CIHR/Canada ; 231575//Canada Research Chairs/ ; }, abstract = {The current knowledge on pathogenic mechanisms in amyotrophic lateral sclerosis (ALS) has widely been derived from studies with cell and animal models bearing ALS-linked genetic mutations. However, it remains unclear to what extent these disease models are of relevance to sporadic ALS. Few years ago, we reported that the cerebrospinal fluid (CSF) from sporadic ALS patients contains toxic factors for disease transmission in mice via chronic intracerebroventricular (i.c.v.) infusion. Thus a 14-day i.c.v. infusion of pooled CSF samples from ALS cases in mice provoked motor impairment as well as ALS-like pathological features. This offers a unique paradigm to test therapeutics in the context of sporadic ALS disease. Here, we tested a new Withaferin-A analog (IMS-088) inhibitor of NF-κB that was found recently to mitigate disease phenotypes in mouse models of familial disease expressing TDP-43 mutant. Our results show that oral intake of IMS-088 ameliorated motor performance of mice infused with ALS-CSF and it alleviated pathological changes including TDP-43 proteinopathy, neurofilament disorganization, and neuroinflammation. Moreover, CSF infusion experiments were carried out with transgenic mice having neuronal expression of tagged ribosomal protein (hNfL-RFP mice), which allowed immunoprecipitation of neuronal ribosomes for analysis by mass spectrometry of the translational peptide signatures. The results indicate that treatment with IMS-088 prevented many proteomic alterations associated with exposure to ALS-CSF involving pathways related to cytoskeletal changes, inflammation, metabolic dysfunction, mitochondria, UPS, and autophagy dysfunction. The effective disease-modifying effects of this drug in a mouse model based on i.c.v. infusion of ALS-CSF suggest that the NF-κB signaling pathway represents a compelling therapeutic target for sporadic ALS.}, }
@article {pmid38785754, year = {2024}, author = {Alkhazaali-Ali, Z and Sahab-Negah, S and Boroumand, AR and Farkhad, NK and Khodadoust, MA and Tavakol-Afshari, J}, title = {Evaluation of the Safety and Efficacy of Repeated Mesenchymal Stem Cell Transplantations in ALS Patients by Investigating Patients' Specific Immunological and Biochemical Biomarkers.}, journal = {Diseases (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {38785754}, issn = {2079-9721}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable disease. There are vigorous attempts to develop treatments to reduce the effects of this disease, and among these treatments is the transplantation of stem cells. This study aimed to retrospectively evaluate a mesenchymal stem cell (MSC) therapy cohort as a promising novel treatment modality by estimating some additional new parameters, such as immunological and biochemical factors.<br><br>METHODS: This study was designed as an open-label, one-arm cohort retrospective study to evaluate potential diagnostic biomarkers of repeated infusions of autologous-bone marrow-derived mesenchymal stem cells (BM-MSCs) in 15 confirmed patients with ALS, administered at a dose of 1 &#xd7; 106 cells/kg BW with a one-month interval, in equal amounts in both an intravenous (IV) and intrathecal (IT) capacity simultaneously, via various biochemical (iron (Fe), ferritin, total-iron-binding capacity (TIBC), transferrin, and creatine kinase (CK)) and immunological parameters (tumor necrosis factor-alpha (TNF-&#x3b1;), neurofilament light chain (NFL), and glial-cell-derived neurotrophic factor (GDNF) levels, evaluated during the three-month follow-up period in serum and cerebrospinal fluid (CSF).<br><br>RESULTS: Our study indicated that, in the case of immunological biomarkers, TNF-&#x3b1; levels in the CSF showed a significant decrease at month three after transplantation compared with levels at month zero, and the p-value was p < 0.01. No statistically significant changes were observed for other immunological as well as biochemical parameters and a p-value of p > 0.05.<br><br>CONCLUSIONS: These results can indicate the potential benefit of stem cell transfusion in patients with ALS and suggest some diagnostic biomarkers. Several studies are required to approve these results.}, }
@article {pmid38784093, year = {2024}, author = {Chen, W and Liu, X and Wan, P and Chen, Z and Chen, Y}, title = {Anti-artifacts techniques for neural recording front-ends in closed-loop brain-machine interface ICs.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1393206}, pmid = {38784093}, issn = {1662-4548}, abstract = {In recent years, thanks to the development of integrated circuits, clinical medicine has witnessed significant advancements, enabling more efficient and intelligent treatment approaches. Particularly in the field of neuromedical, the utilization of brain-machine interfaces (BMI) has revolutionized the treatment of neurological diseases such as amyotrophic lateral sclerosis, cerebral palsy, stroke, or spinal cord injury. The BMI acquires neural signals via recording circuits and analyze them to regulate neural stimulator circuits for effective neurological treatment. However, traditional BMI designs, which are often isolated, have given way to closed-loop brain-machine interfaces (CL-BMI) as a contemporary development trend. CL-BMI offers increased integration and accelerated response speed, marking a significant leap forward in neuromedicine. Nonetheless, this advancement comes with its challenges, notably the stimulation artifacts (SA) problem inherent to the structural characteristics of CL-BMI, which poses significant challenges on the neural recording front-ends (NRFE) site. This paper aims to provide a comprehensive overview of technologies addressing artifacts in the NRFE site within CL-BMI. Topics covered will include: (1) understanding and assessing artifacts; (2) exploring the impact of artifacts on traditional neural recording front-ends; (3) reviewing recent technological advancements aimed at addressing artifact-related issues; (4) summarizing and classifying the aforementioned technologies, along with an analysis of future trends.}, }
@article {pmid38782015, year = {2024}, author = {Benatar, M and Hansen, T and Rom, D and Geist, MA and Blaettler, T and Camu, W and Kuzma-Kozakiewicz, M and van den Berg, LH and Morales, RJ and Chio, A and Andersen, PM and Pradat, PF and Lange, D and Van Damme, P and Mora, G and Grudniak, M and Elliott, M and Petri, S and Olney, N and Ladha, S and Goyal, NA and Meyer, T and Hanna, MG and Quinn, C and Genge, A and Zinman, L and Jabari, D and Shoesmith, C and Ludolph, AC and Neuwirth, C and Nations, S and Shefner, JM and Turner, MR and Wuu, J and Bennett, R and Dang, H and Sundgreen, C and , }, title = {Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {7}, pages = {687-699}, doi = {10.1016/S1474-4422(24)00134-0}, pmid = {38782015}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Double-Blind Method ; Middle Aged ; Aged ; *Neuroprotective Agents/therapeutic use/adverse effects ; Treatment Outcome ; Adult ; Hydroxylamines/therapeutic use/adverse effects/pharmacology ; Oxadiazoles/therapeutic use/adverse effects ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.<br><br>METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.<br><br>FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57&#xb7;6 years (SD 10&#xb7;9). CAFS score over 76 weeks did not differ between groups (mean 0&#xb7;51 [SD 0&#xb7;29] in the arimoclomol group vs 0&#xb7;49 [0&#xb7;28] in the placebo group; p=0&#xb7;62). Cliff's delta comparing the two groups was 0&#xb7;039 (95% CI -0&#xb7;116 to 0&#xb7;194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).<br><br>INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.<br><br>FUNDING: Orphazyme.}, }
@article {pmid38778595, year = {2025}, author = {Jayaprakash, B and Savira, M and Mahmood, AAR and Prasanna, M}, title = {The Role of Stem Cell Therapies in the Treatment of Neurodegenerative Diseases.}, journal = {Current stem cell research &amp; therapy}, volume = {20}, number = {2}, pages = {146-165}, doi = {10.2174/011574888X313112240510160102}, pmid = {38778595}, issn = {2212-3946}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation/methods ; Animals ; Neural Stem Cells/transplantation ; Parkinson Disease/therapy ; }, abstract = {Cellular replacement therapy and genetic transfer in injured brains provide new pathways for treating human neurological illnesses. Current progress in the field focuses on the production of neurons and glial cells from many types of stem cells, such as embryonic, induced pluripotent, mesenchymal, and neural stem cells. This has led to a significant increase in research on brain transplantation treatments. Extended neurodegeneration results in the progressive decline of certain neuronal subtypes or whole neuronal cells. An analysis of the progress made in induced pluripotent and mesenchymal stem cells reveals their significant promise in disease modeling, regeneration, and medication screening. The requirement for stem cells in neurodegenerative disease studies has been crucial in recent years. Stem cells provide the potential for replacing impaired neurons, comprehending disease needs modeling, and creating efficient treatments, but they have many challenges in culturing and acceptability to the host immune cells. The need to use their potential in discovering novel therapies for diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis leads to promising therapy. This review examines the function of stem cells in the pathogenesis and treatment of Huntington's disease, Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review further examines hurdles such as immunological reactions and delivery systems intending to overcome these problems. This article offers a detailed viewpoint on the use of stem cell-based nanotherapies as revolutionary treatments for various neurological illnesses.}, }
@article {pmid38778483, year = {2024}, author = {Yan, J and Chen, H and Zhang, Y and Peng, L and Wang, Z and Lan, X and Yu, S and Yang, Y}, title = {Fecal microbiota transplantation significantly improved respiratory failure of amyotrophic lateral sclerosis.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2353396}, pmid = {38778483}, issn = {1949-0984}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/microbiology ; Bacteroides ; Faecalibacterium prausnitzii ; *Fecal Microbiota Transplantation ; Feces/microbiology ; Gastrointestinal Microbiome ; Respiration, Artificial ; *Respiratory Insufficiency/therapy/microbiology ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to respiratory failure, and eventually death. However, there is a lack of effective treatments for ALS. Here we report the results of fecal microbiota transplantation (FMT) in two patients with late-onset classic ALS with a Japan ALS severity classification of grade 5 who required tracheostomy and mechanical ventilation. In both patients, significant improvements in respiratory function were observed following two rounds of FMT, leading to weaning off mechanical ventilation. Their muscle strength improved, allowing for assisted standing and mobility. Other notable treatment responses included improved swallowing function and reduced muscle fasciculations. Metagenomic and metabolomic analysis revealed an increase in beneficial Bacteroides species (Bacteroides stercoris, Bacteroides uniformis, Bacteroides vulgatus), and Faecalibacterium prausnitzii after FMT, as well as elevated levels of metabolites involved in arginine biosynthesis and decreased levels of metabolites involved in branched-chain amino acid biosynthesis. These findings offer a potential rescue therapy for ALS with respiratory failure and provide new insights into ALS in general.}, }
@article {pmid38775852, year = {2024}, author = {Ebrahimi, P and Davoudi, E and Sadeghian, R and Zadeh, AZ and Razmi, E and Heidari, R and Morowvat, MH and Sadeghian, I}, title = {In vivo and ex vivo gene therapy for neurodegenerative diseases: a promise for disease modification.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {397}, number = {10}, pages = {7501-7530}, pmid = {38775852}, issn = {1432-1912}, support = {29849//Shiraz University of Medical Sciences/ ; }, mesh = {Humans ; *Genetic Therapy/methods ; Animals ; *Neurodegenerative Diseases/therapy/genetics ; Gene Editing/methods ; }, abstract = {Neurodegenerative diseases (NDDs), including AD, PD, HD, and ALS, represent a growing public health concern linked to aging and lifestyle factors, characterized by progressive nervous system damage leading to motor and cognitive deficits. Current therapeutics offer only symptomatic management, highlighting the urgent need for disease-modifying treatments. Gene therapy has emerged as a promising approach, targeting the underlying pathology of diseases with diverse strategies including gene replacement, gene silencing, and gene editing. This innovative therapeutic approach involves introducing functional genetic material to combat disease mechanisms, potentially offering long-term efficacy and disease modification. With advancements in genomics, structural biology, and gene editing tools such as CRISPR/Cas9, gene therapy holds significant promise for addressing the root causes of NDDs. Significant progress in preclinical and clinical studies has demonstrated the potential of in vivo and ex vivo gene therapy to treat various NDDs, offering a versatile and precise approach in comparison to conventional treatments. The current review describes various gene therapy approaches employed in preclinical and clinical studies for the treatment of NDDs, including AD, PD, HD, and ALS, and addresses some of the key translational challenges in this therapeutic approach.}, }
@article {pmid38775303, year = {2024}, author = {Zhang, J and Yang, F and Li, M and Zhu, Y and Huang, X}, title = {Quantitative evaluation of factors influencing the 3 Hz repetitive nerve stimulation test in patients with amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {70}, number = {2}, pages = {194-203}, doi = {10.1002/mus.28165}, pmid = {38775303}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; Aged ; Adult ; Electric Stimulation/methods ; Neuromuscular Junction/physiopathology ; Electromyography/methods ; }, abstract = {INTRODUCTION/AIMS: Previous studies have suggested that treatments targeting the neuromuscular junction (NMJ) may play a role in the treatment of amyotrophic lateral sclerosis (ALS). However, factors impacting repetitive nerve stimulation (RNS), a technique to evaluate NMJ function, have yet to be fully elucidated. We aimed to identify independent factors contributing to the decremental response of the accessory nerve and evaluated its value in ALS clinical practice.<br><br>METHODS: A total of 626 patients who were diagnosed with ALS and underwent 3&#x2009;Hz RNS tests on the accessory nerve were enrolled. Data on their clinical and electrophysiological indicators were divided into a training set (collected from June 2016 to December 2022) and a test set (collected from January to August 2023). Stepwise regression was used in independent variable selection and model building.<br><br>RESULTS: Forty-two percent of patients had a decrement larger than 10% and 24% had a decrement larger than 15%. Onset age, sex, onset site, forced vital capacity (FVC) and motor unit potential (MUP) duration were independent factors contributing to the results of the RNS test. MUP duration had the greatest impact on decremental response, followed by FVC and onset age. The decremental response in females was larger than in males. Upper limb onset was found to contribute more to the decrement than lower limb or bulbar onset.<br><br>DISCUSSION: In patients with ALS, NMJ safety factor is reduced during re-innervation. Decremental response is affected by multiple factors, which needs to be considered in clinical trials targeting the NMJ in these patients.}, }
@article {pmid38774156, year = {2024}, author = {Canella, C and Braun, C and Witt, CM}, title = {Developing a digital mind body medicine supportive care intervention for people with amyotrophic lateral sclerosis using stakeholder engagement and design thinking.}, journal = {Digital health}, volume = {10}, number = {}, pages = {20552076241255928}, pmid = {38774156}, issn = {2055-2076}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis disease (ALS) is also called the disease of a thousand farewells. Consequently, it is important to offer supportive care interventions that can be applied continuously during the whole course of the disease. People with ALS are interested in complementary and integrative medicine. Due to ALS' progressive nature, digital solutions might be most feasible and accessible for people with ALS in the long-term.<br><br>OBJECTIVES: In our study, we explored with stakeholders which digital complementary and integrative medicine interventions and formats are considered as supportive for people with ALS, and which settings are needed by the people with ALS to incorporate the interventions in everyday life.<br><br>METHODS: We used a participatory research approach and conducted a stakeholder engagement process, applying a design thinking process with qualitative research methods (interviews, workshops).<br><br>RESULTS: Due to the unpredictable course of the disease on their loss of abilities, people with ALS welcome online settings because they are accessible and easy to implement in their daily life. Stakeholders considered the following implementation factors for a complementary and integrative medicine intervention as essential: short-term realization of planned interventions, short duration of interventions, and user-friendliness in terms of accessibility and applicability. Concerning the complementary and integrative medicine interventions, the people with ALS preferred mind body medicine interventions, such as breathing, mindfulness and relaxation exercises.<br><br>CONCLUSIONS: Short-term treatment intervals and short online mind body medicine interventions align with the needs of people with ALS. The complementary and integrative medicine interventions as well as the digital infrastructure must meet the special accessibility and applicability needs of people with ALS.}, }
@article {pmid38772930, year = {2024}, author = {Kherbek, H and Itoh, CY and Daley, C and Eggers, SD and Hinson, S and Sarker, P and Staff, NP and Pittock, SJ and Dubey, D}, title = {Clinical and serological insights into paraneoplastic brachial amyotrophic diplegia.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {4620-4627}, pmid = {38772930}, issn = {1432-1459}, support = {238183//State of Minnesota's David J. Tomassoni ALS Research Grant Program/ ; }, mesh = {Humans ; Male ; Middle Aged ; Retrospective Studies ; Aged ; Female ; *Paraneoplastic Syndromes, Nervous System/immunology/diagnosis/blood ; Adult ; Autoantibodies/blood ; Brachial Plexus Neuropathies/etiology/diagnosis/physiopathology ; Carrier Proteins ; }, abstract = {BACKGROUND: Brachial amyotrophic diplegia (BAD) is typically linked to a neurodegenerative etiology such as amyotrophic lateral sclerosis (ALS). Clinical and serological characterizations of paraneoplastic neurologic syndromes resembling BAD are limited.<br><br>METHODS: A retrospective chart review of patients with BAD-like presentations was conducted. Clinical/paraclinical features of paraneoplastic BAD and neurodegenerative BAD cases were compared.<br><br>RESULTS: Between 2017 and 2023, 13 cases of BAD were identified, of these 10 were neurodegenerative BAD (ALS variant), and 3 cases associated with paraneoplastic autoimmunity. An additional paraneoplastic BAD case diagnosed in 2005 was included. LUZP4-IgG was detected in all four paraneoplastic cases, with coexisting KLHL11-IgG in three cases and ANNA1 (anti-Hu)-IgG in one case. Out of the four paraneoplastic cases, two patients had seminoma, while the remaining two had limited cancer investigation. Three patients exhibited bi-brachial weakness as the initial symptom before the onset of brainstem symptoms or seizures. Compared to BAD patients with a neurodegenerative etiology, a higher proportion of paraneoplastic cases had ataxia (75% vs 0%, p&#x2009;=&#x2009;0.011). Other clinical features only detected in the paraneoplastic BAD group were vertigo (n&#x2009;=&#x2009;2), hearing loss (n&#x2009;=&#x2009;2) and ophthalmoplegia (n&#x2009;=&#x2009;2). Electrodiagnostic studies in these patients revealed cervical myotome involvement, supportive of motor neuronopathy. All paraneoplastic cases but none of the neurodegenerative BAD cases exhibited inflammatory cerebrospinal fluid (CSF) findings (lymphocytic pleocytosis and/or supernumerary oligoclonal bands; p&#x2009;=&#x2009;0.067). Despite the administration of immunotherapy and/or cancer treatment, none of the paraneoplastic patients reported clinical improvement.<br><br>DISCUSSION: BAD or bi-brachial neurogenic weakness is a rare phenotypic presentation associated with paraneoplastic autoimmunity. Co-existing features of brainstem dysfunction or cerebellar ataxia should prompt further paraneoplastic evaluation. Common serological and cancer associations among these cases include LUZP4-IgG and KLHL11-IgG, along with testicular germ cell tumors, respectively.}, }
@article {pmid38771698, year = {2024}, author = {Alarcan, H and Bruno, C and Emond, P and Raoul, C and Vourc'h, P and Corcia, P and Camu, W and Veyrune, JL and Garlanda, C and Locati, M and Juntas-Morales, R and Saker, S and Suehs, C and Masseguin, C and Kirby, J and Shaw, P and Malaspina, A and De Vos, J and Al-Chalabi, A and Leigh, PN and Tree, T and Bensimon, G and Blasco, H}, title = {Pharmacometabolomics applied to low-dose interleukin-2 treatment in amyotrophic lateral sclerosis.}, journal = {Annals of the New York Academy of Sciences}, volume = {1536}, number = {1}, pages = {82-91}, doi = {10.1111/nyas.15147}, pmid = {38771698}, issn = {1749-6632}, support = {//National&#xa0;Institute of Health and Medical Research/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; *Interleukin-2/administration &amp; dosage/metabolism ; *Metabolomics/methods ; *T-Lymphocytes, Regulatory/metabolism/drug effects/immunology ; Male ; Middle Aged ; Female ; Kynurenine/metabolism ; Aged ; Metabolome/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld-IL-2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL-2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points for the treatment group (average error rate of 42%). Among the important metabolites, kynurenine increased between D1 and D64, followed by a reduction at D85. The percentage increase of Treg number from D1 to D64, as predicted by the metabolome at D1, was highly correlated with the observed value. This study provided a proof of concept for metabolic characterization of the effect of ld-IL-2 in ALS. These data could present advances toward a personalized medicine approach and present pharmacometabolomics as a key tool to complement genomic and transcriptional data for drug characterization, leading to systems pharmacology.}, }
@article {pmid38761668, year = {2024}, author = {Silani, V}, title = {Continuity of treatment in ALS: Benefits and challenges of maintaining riluzole over the course of the disease.}, journal = {Journal of the neurological sciences}, volume = {461}, number = {}, pages = {123038}, doi = {10.1016/j.jns.2024.123038}, pmid = {38761668}, issn = {1878-5883}, mesh = {Humans ; *Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neuroprotective Agents/therapeutic use ; Male ; Female ; Middle Aged ; }, }
@article {pmid38760174, year = {2024}, author = {Pal, A and Grossmann, D and Glaß, H and Zimyanin, V and Günther, R and Catinozzi, M and Boeckers, TM and Sterneckert, J and Storkebaum, E and Petri, S and Wegner, F and Grill, SW and Pan-Montojo, F and Hermann, A}, title = {Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.}, journal = {Life science alliance}, volume = {7}, number = {8}, pages = {}, pmid = {38760174}, issn = {2575-1077}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *RNA-Binding Protein FUS/metabolism/genetics ; *Glycolates/metabolism/pharmacology ; *Mitochondria/metabolism ; *Protein Deglycase DJ-1/metabolism/genetics ; *Lactic Acid/metabolism ; *Superoxide Dismutase-1/metabolism/genetics ; Membrane Potential, Mitochondrial ; Motor Neurons/metabolism ; Lysosomes/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.}, }
@article {pmid38759931, year = {2024}, author = {Guo, X and Zhang, Z and Gu, J and Ke, P and Liu, J and Meng, Y and Zheng, W and Que, W and Fan, R and Luo, J and Xiao, F}, title = {FUDNC1-dependent mitophagy ameliorate motor neuron death in an amyotrophic lateral sclerosis mouse model.}, journal = {Neurobiology of disease}, volume = {197}, number = {}, pages = {106534}, doi = {10.1016/j.nbd.2024.106534}, pmid = {38759931}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Mitophagy/physiology ; *Motor Neurons/metabolism/pathology ; *Mice, Transgenic ; Mice ; *Disease Models, Animal ; *Mitochondrial Proteins/metabolism/genetics ; Membrane Proteins/metabolism/genetics ; Humans ; Spinal Cord/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, yet effective treatment is lacking. Moreover, the underlying pathomechanisms of ALS remain unclear, with impaired mitophagy function being increasingly recognized as a contributing factor. FUN14 domain-containing protein 1 (FUNDC1) is an autophagy receptor localized to the outer mitochondrial membrane and a mitochondrial membrane protein that mediates mitophagy and therefore considered as important factor in neurodegenerative diseases. However, its specific role in ALS is not yet clear. Therefore, this study aimed to investigate the regulatory role of FUNDC1 in ALS and determine its regulatory mechanisms. ALS transgenic mice were obtained and maintained under standard conditions. Cell lines were generated by stable transfection with hSOD1[G93A] or control vectors. Mice received intrathecal injections of AAV9 vectors expressing FUNDC1 or EGFP. Motor function was assessed through behavioral tests, and histological and immunostaining analyses were performed. Colocalization analysis was conducted in transfected cells, and protein expression was evaluated via western blotting. We first observed that FUNDC1 was significantly downregulated in the spinal cord tissues of SOD1[G93A] mice. FUNDC1 overexpression considerably improved locomotor activity and prolonged survival time in SOD1[G93A] mice. Mechanistically, reduced expression of FUNDC1 resulted in decreased mitophagy, as indicated by decreased recruitment through LC3 in SOD1[G93A] mice and cellular models. Consequently, this led to increased mitochondrial accumulation and cell apoptosis, exacerbating the ALS phenotype. Furthermore, we identified transcription factor FOXD3 as an essential upstream factor of FUNDC1, resulting in reduced transcription of FUNDC1 in ALS lesions. This study suggests a novel strategy of targeting FUNDC1-mediated mitophagy for developing therapeutic interventions to mitigate disease progression and improve outcomes for ALS patients.}, }
@article {pmid38759454, year = {2024}, author = {Wei, Y and Zhong, S and Yang, H and Wang, X and Lv, B and Bian, Y and Pei, Y and Xu, C and Zhao, Q and Wu, Y and Luo, D and Wang, F and Sun, H and Chen, Y}, title = {Current therapy in amyotrophic lateral sclerosis (ALS): A review on past and future therapeutic strategies.}, journal = {European journal of medicinal chemistry}, volume = {272}, number = {}, pages = {116496}, doi = {10.1016/j.ejmech.2024.116496}, pmid = {38759454}, issn = {1768-3254}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the first and second motoneurons (MNs), associated with muscle weakness, paralysis and finally death. The exact etiology of the disease still remains unclear. Currently, efforts to develop novel ALS treatments which target specific pathomechanisms are being studied. The mechanisms of ALS pathogenesis involve multiple factors, such as protein aggregation, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, apoptosis, inflammation etc. Unfortunately, to date, there are only two FDA-approved drugs for ALS, riluzole and edavarone, without curative treatment for ALS. Herein, we give an overview of the many pathways and review the recent discovery and preclinical characterization of neuroprotective compounds. Meanwhile, drug combination and other therapeutic approaches are also reviewed. In the last part, we analyze the reasons of clinical failure and propose perspective on the treatment of ALS in the future.}, }
@article {pmid38758193, year = {2024}, author = {Oliveira Santos, M and de Carvalho, M}, title = {Profiling tofersen as a treatment of superoxide dismutase 1 amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {24}, number = {6}, pages = {549-553}, doi = {10.1080/14737175.2024.2355983}, pmid = {38758193}, issn = {1744-8360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Oligonucleotides/therapeutic use ; Oligonucleotides, Antisense/therapeutic use ; Biomarkers/blood ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disorder with a fatal outcome 3-5 years after disease onset due to respiratory complications. Superoxide dismutase 1 (SOD1) mutations are found in about 2% of all patients. Tofersen is a novel oligonucleotide antisense drug specifically developed to treat SOD1-ALS patients.<br><br>AREAS COVERED: Our review covers and discusses tofersen pharmacological properties and its phase I/II and III clinical trials results. Other available drugs and their limitations are also addressed.<br><br>EXPERT OPINION: VALOR study failed to meet the primary endpoint (change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale score from baseline to week 28, tofersen arm vs. placebo), but a significant reduction in plasma neurofilament light chain (NfL) levels was observed in tofersen arm (60% vs. 20%). PrefALS study has proposed plasma NfL has a potential biomarker for presymptomatic treatment, since it increases 6-12&#x2009;months before phenoconversion. There is probably a delay between plasma NfL reduction and the clinical benefit. ATLAS study will allow more insights regarding tofersen clinical efficacy in disease progression rate, survival, and even disease onset delay in presymptomatic SOD1 carriers.}, }
@article {pmid38758158, year = {2024}, author = {Zou, X and Shi, Y and Zhang, T and Huang, A and Cui, H and Wang, T}, title = {Electroacupuncture Combined with Chinese Herbal Medicine, Qidong Huoluo Granule, for Amyotrophic Lateral Sclerosis: An 8-Month Case Report.}, journal = {Alternative therapies in health and medicine}, volume = {}, number = {}, pages = {}, pmid = {38758158}, issn = {1078-6791}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult neurodegenerative disorder characterized by progressive muscle weakness and eventual paralysis, for which there is currently no curative treatment. Mainstream medical interventions primarily focus on providing supportive care. However, acupuncture offers promising avenues for alleviating symptoms and enhancing quality of life. Specific acupuncture points are targeted to address bulbar paralysis as well as paralysis affecting the upper and lower extremities.<br><br>OBJECTIVE: To investigate the efficacy of electroacupuncture combined with Chinese herbal medicine in delaying disease progression and alleviating symptoms of bulbar paralysis in patients with ALS.<br><br>CASE PRESENTATION: A 51-year-old male presented with a 4-year and 8-month history of weakness in his left arm and both legs, accompanied by muscle cramps and diminished coordination, which had rapidly worsened over the past year. ALS was diagnosed, and the patient was initiated on oral Riluzole (50 mg) and Qidong Huoluo granule, a Chinese herbal compound, administered twice daily. Concurrently, he underwent acupuncture treatment sessions twice weekly for over 8 months.<br><br>RESULTS: Following acupuncture therapy, the patient experienced gradual stabilization of symptoms, notably improvement in swallowing function. The combination of electroacupuncture and Qidong Huoluo granule resulted in sustained clinical enhancements post-treatment, including improvements in speech, coughing, articulation, and breathing.<br><br>CONCLUSION: Electroacupuncture therapy demonstrates the potential to slow disease progression and ameliorate symptoms of bulbar paralysis in ALS patients. However, further robust clinical research is imperative to explain the precise therapeutic role of electroacupuncture in managing this debilitating condition. Continued investigation into the efficacy and safety profile of electroacupuncture holds promise for advancing treatment modalities for ALS.}, }
@article {pmid38756356, year = {2024}, author = {Rennie, O and Sharma, M and Helwa, N}, title = {Colorectal anastomotic leakage: a narrative review of definitions, grading systems, and consequences of leaks.}, journal = {Frontiers in surgery}, volume = {11}, number = {}, pages = {1371567}, pmid = {38756356}, issn = {2296-875X}, abstract = {BACKGROUND: Anastomotic leaks (ALs) are a significant and feared postoperative complication, with incidence of up to 30% despite advances in surgical techniques. With implications such as additional interventions, prolonged hospital stays, and hospital readmission, ALs have important impacts at the level of individual patients and healthcare providers, as well as healthcare systems as a whole. Challenges in developing unified definitions and grading systems for leaks have proved problematic, despite acknowledgement that colorectal AL is a critical issue in intestinal surgery with serious consequences. The aim of this study was to construct a narrative review of literature surrounding definitions and grading systems for ALs, and consequences of this postoperative complication.<br><br>METHODS: A literature review was conducted by examining databases including PubMed, Web of Science, OVID Embase, Google Scholar, and Cochrane library databases. Searches were performed with the following keywords: anastomosis, anastomotic leak, colorectal, surgery, grading system, complications, risk factors, and consequences. Publications that were retrieved underwent further assessment to ensure other relevant publications were identified and included.<br><br>RESULTS: A universally accepted definition and grading system for ALs continues to be lacking, leading to variability in reported incidence in the literature. Additional factors add to variability in estimates, including differences in the anastomotic site and institutional/individual differences in operative technique. Various groups have worked to publish guidelines for defining and grading AL, with the International Study Group of Rectal Cancer (ISGRC/ISREC) definition the current most recommended universal definition for colorectal AL. The burden of AL on patients, healthcare providers, and hospitals is well documented in evidence from leak consequences, such as increased morbidity and mortality, higher reoperation rates, and increased readmission rates, among others.<br><br>CONCLUSIONS: Colorectal AL remains a significant challenge in intestinal surgery, despite medical advancements. Understanding the progress made in defining and grading leaks, as well as the range of negative outcomes that arise from AL, is crucial in improving patient care, reduce surgical mortality, and drive further advancements in earlier detection and treatment of AL.}, }
@article {pmid38751168, year = {2024}, author = {Raffaele, S and Nguyen, N and Milanese, M and Mannella, FC and Boccazzi, M and Frumento, G and Bonanno, G and Abbracchio, MP and Bonifacino, T and Fumagalli, M}, title = {Montelukast improves disease outcome in SOD1[G93A] female mice by counteracting oligodendrocyte dysfunction and aberrant glial reactivity.}, journal = {British journal of pharmacology}, volume = {181}, number = {18}, pages = {3303-3326}, doi = {10.1111/bph.16408}, pmid = {38751168}, issn = {1476-5381}, support = {GPR17ALS-1//AriSLA ETS - Fondazione Italiana di ricerca per la SLA/ ; 2017NSXP8J//Italian Ministry of University and Research (MUR)/ ; PE0000006//#NEXTGENERATIONEU (NGEU) and the Italian Ministry of University and Research (MUR), NRRP - National Recovery and Resilience Plan/ ; //Foundation Bellandi Bernardoni/ ; }, mesh = {Animals ; Female ; *Cyclopropanes/pharmacology ; *Quinolines/pharmacology ; *Acetates/pharmacology/therapeutic use ; *Oligodendroglia/drug effects/metabolism/pathology ; *Sulfides/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; *Mice, Transgenic ; Mice ; Male ; Receptors, Leukotriene/metabolism/genetics ; Receptors, G-Protein-Coupled/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; Spinal Cord/drug effects/metabolism/pathology ; Microglia/drug effects/metabolism/pathology ; Nerve Tissue Proteins ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron (MN) loss and consequent muscle atrophy, for which no effective therapies are available. Recent findings reveal that disease progression is fuelled by early aberrant neuroinflammation and the loss of oligodendrocytes with neuroprotective and remyelinating properties. On this basis, pharmacological interventions capable of restoring a pro-regenerative local milieu and re-establish proper oligodendrocyte functions may be beneficial.<br><br>EXPERIMENTAL APPROACH: Here, we evaluated the in vivo therapeutic effects of montelukast (MTK), an antagonist of the oligodendroglial G protein-coupled receptor 17 (GPR17) and of cysteinyl-leukotriene receptor 1 (CysLT1R) receptors on microglia and astrocytes, in the SOD1[G93A] ALS mouse model. We chronically treated SOD1[G93A] mice with MTK, starting from the early symptomatic disease stage. Disease progression was assessed by behavioural and immunohistochemical approaches.<br><br>KEY RESULTS: Oral MTK treatment significantly extended survival probability, delayed body weight loss and ameliorated motor functionalityonly in female SOD1[G93A] mice. Noteworthy, MTK significantly restored oligodendrocyte maturation and induced significant changes in the reactive phenotype and morphological features of microglia/macrophages and astrocytes in the spinal cord of female SOD1[G93A] mice, suggesting enhanced pro-regenerative functions. Importantly, concomitant MN preservation has been detected after MTK administration. No beneficial effects were observed in male mice, highlighting a sex-based difference in the protective activity of MTK.<br><br>CONCLUSIONS AND IMPLICATIONS: Our results provide the first preclinical evidence indicating that repurposing of MTK, a safe and marketed anti-asthmatic drug, may be a promising sex-specific strategy for personalized ALS treatment.}, }
@article {pmid38749729, year = {2025}, author = {Kunieda, K and Hayashi, Y and Fujishima, I and Shimohata, T}, title = {Weight and Muscle Mass Loss Associated with Acute Disease Can Be Reversed with Appropriate Nutrition Therapy and Exercise in a Patient with Amyotrophic Lateral Sclerosis.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {64}, number = {1}, pages = {133-136}, pmid = {38749729}, issn = {1349-7235}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/complications/rehabilitation/therapy/diet therapy/physiopathology ; Aged, 80 and over ; *Exercise Therapy/methods ; *Weight Loss/physiology ; Nutrition Therapy/methods ; Acute Disease ; Deglutition Disorders/etiology/rehabilitation/therapy/physiopathology ; Muscle Strength/physiology ; Body Composition ; Treatment Outcome ; }, abstract = {Nutritional interventions targeting weight loss are useful for the treatment of amyotrophic lateral sclerosis (ALS). However, the changes in body composition after nutritional intervention remain unclear. We herein present a patient with ALS who experienced an increased weight and muscle mass owing to nutritional therapy and physical exercise. An 86-year-old man presented with dysphagia and dysarthria. The patient was diagnosed with bulbar-type ALS. As weight loss progressed, a gastrostomy was performed. After 21 months of disease onset, gastrointestinal bleeding due to a bumper ulcer led to further weight loss (from 40.2 kg to 36.8 kg). The patient experienced difficulty walking and ingesting food orally. Although the total daily energy expenditure (TDEE) was estimated to be 1,122 kcal/day, an intake of 1,500 kcal/day beyond the calculated TDEE was administered. The patient continued to perform daily voluntary exercises in addition to his usual rehabilitation. After 5 months, his weight increased from 36.8 kg to 40.4 kg. Muscle mass increased from 25.1 kg to 30.1 kg, as measured using a multifrequency bioelectrical impedance device. Muscle strength improved from 8.5/10.0 kg to 15.0/18.0 kg in grip strength and from 15.2 kPa to 20.4 kPa in tongue pressure. The patient's physical and swallowing functions also improved. In patients with ALS, a decreased body weight and muscle mass due to acute disease may be improved by appropriate nutritional therapy and physical exercise.}, }
@article {pmid38747109, year = {2024}, author = {Bender, J and Kojeku, T and Preece, E}, title = {Grading lumbar foraminal stenosis - Interrater agreement of radiologists and radiology trainees before and after education of a standardised grading scale.}, journal = {Journal of medical imaging and radiation oncology}, volume = {68}, number = {5}, pages = {511-515}, doi = {10.1111/1754-9485.13669}, pmid = {38747109}, issn = {1754-9485}, mesh = {Humans ; *Spinal Stenosis/diagnostic imaging ; *Lumbar Vertebrae/diagnostic imaging ; *Observer Variation ; *Magnetic Resonance Imaging/methods ; *Radiologists ; Severity of Illness Index ; Radiology/education ; Reproducibility of Results ; Clinical Competence ; Male ; }, abstract = {INTRODUCTION: Lumbar foraminal stenosis is a key contributor to low back pain. Imaging, particularly MRI, is commonly used in the assessment of foraminal stenosis, contributing to treatment planning. The adoption of a standardised grading system to try and improve inter-rater agreement is thought to be of importance. Our study aims to assess the variability of grading lumbar foraminal stenosis amongst reporting doctors, determine whether education about a validated grading scale increases agreement, and determine if these changes persist over time.<br><br>METHODS: A single-site study involving MRI reporting registrars/radiologists was performed. Participants were shown select MRI images and asked to grade the degree of stenosis in each on a 4-point scale. Subsequently, they were educated about Lee et&#xa0;al's grading system and asked to re-grade the cases 1 and 6&#x2009;weeks later. The level of agreement was calculated using Gwet's AC1 coefficient and Krippendorff's Alpha.<br><br>RESULTS: The baseline level of agreement was substantial (AC1&#x2009;=&#x2009;0.71). This decreased to a moderate level of agreement post-intervention (AC1&#x2009;=&#x2009;0.575 at 1-week, P-value 0.033 and AC1&#x2009;=&#x2009;0.598 at 6&#x2009;weeks, P-value 0.012). A grading of severe stenosis was 21% more likely 6&#x2009;weeks post-education.<br><br>CONCLUSION: The baseline agreement at our institution was substantial, thought to be due to the single-centre nature of the study. Moderate agreement was achieved after education regarding the Lee et&#xa0;al.'s scale, in-line with other studies, with changes maintained at 6&#x2009;weeks, showing retention of the scale parameters. Grading of severe stenosis was more common post intervention.}, }
@article {pmid38743390, year = {2024}, author = {Vignolo, M and Zuccarino, R and Truffelli, R and Gemelli, C and Giove, E and Ferraro, PM and Manunza, D and Trinchero, C and Cipollina, I and Lungu, M and Lizio, A and Gragnano, G and Cabona, C and Pardini, M and Caponnetto, C and Rao, F}, title = {Dog-assisted physiotherapy in amyotrophic lateral sclerosis: a randomized controlled pilot study.}, journal = {European journal of physical and rehabilitation medicine}, volume = {60}, number = {3}, pages = {470-476}, pmid = {38743390}, issn = {1973-9095}, mesh = {Humans ; Pilot Projects ; *Amyotrophic Lateral Sclerosis/rehabilitation ; Male ; Female ; Middle Aged ; *Animal Assisted Therapy/methods ; Aged ; *Physical Therapy Modalities ; Animals ; Dogs ; Treatment Outcome ; }, abstract = {BACKGROUND: Animal-assisted therapy (AAT) is an intervention in which the animal acts as a co-therapist. It has been mainly used in the context of patients with dementia, showing positive effects on psychological symptoms, but its potential as a physiotherapy treatment for patients with neuromuscular disorders, amyotrophic lateral sclerosis (ALS) in particular, has not yet been investigated.<br><br>AIM: The aim of the study was to evaluate the impact of AAT, specifically of dog-assisted therapy, on motor functions and psychological status in patients with ALS.<br><br>DESIGN: This study was a randomized controlled pilot study.<br><br>SETTING: The study was carried out at the Rehabilitation Unit NEuroMuscular Omnicenter (NEMO) of Arenzano, Genoa.<br><br>POPULATION: Sixty hospitalized ALS patients were enrolled.<br><br>METHODS: All patients ran a regular two-weeks neurorehabilitation program twice a day. For three days a week, in place of the morning traditional treatment, the AAT group performed a rehabilitation session with a simultaneous interaction with the therapy-dog, while the control group performed a traditional rehabilitation session. The outcome measures were the Timed Up and Go Test, the Short Physical Performance Battery (SPPB), the Six Minutes Walk Test, the Ten Meters walking Test and the Hospital Anxiety and Depression Scale.<br><br>RESULTS: Both groups showed an amelioration in motor scales. However, SPPB subscales as well as HADS scores showed a statistically significant improvement only in the AAT group (P values from <0.0001 to 0.0004). Additionally, across almost all motor and psychological measures, post-treatments values were significantly better for the AAT group (P values from <0.0001 to 0.01).<br><br>CONCLUSIONS: The obtained results not only suggest that AAT is comparable to traditional physiotherapy treatments, but also evidence that this type of treatment has greater beneficial effects on motor and psychological symptoms in patients with ALS.<br><br>This study provides first evidence that AAT is a powerful rehabilitation strategy in patients with ALS, improving both motor and psychological symptoms, and therefore possibly ameliorating quality of life.}, }
@article {pmid38741492, year = {2024}, author = {Kanda, S and Kanda, T}, title = {[Multifocal Motor Neuropathy].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {5}, pages = {526-533}, doi = {10.11477/mf.1416202639}, pmid = {38741492}, issn = {1881-6096}, mesh = {Humans ; *Polyneuropathies/physiopathology/diagnosis ; Immunoglobulins, Intravenous/therapeutic use/administration &amp; dosage ; }, abstract = {Multifocal motor neuropathy (MMN), an acquired chronic progressive immune-mediated motor neuropathy, is characterized by asymmetrical distal upper limb muscle weakness and muscle atrophy without sensory impairment. Differentiation from amyotrophic lateral sclerosis is usually challenging, and electrophysiological studies show multifocal conduction blocks. Immunoglobulin (Ig)M GM1 antibodies are detected in approximately 50% of patients. In contrast to chronic inflammatory demyelinating polyneuropathy, corticosteroids are ineffective for management of MMN, and IVIg is the sole established treatment.}, }
@article {pmid38741111, year = {2024}, author = {Maresova, P and Rezny, L and Bauer, P and Valko, M and Kuca, K}, title = {Nonpharmacological intervention therapies for dementia: potential break-even intervention price and savings for selected risk factors in the European healthcare system.}, journal = {BMC public health}, volume = {24}, number = {1}, pages = {1293}, pmid = {38741111}, issn = {1471-2458}, support = {ERDF No. CZ.02.1.01/0.0/0.0/18_069/0010054-IT4Neuro(degeneration)//Ministry of Education Youth and Sports/ ; Excellence 2022//UHK FIM/ ; }, mesh = {Humans ; *Dementia/economics/epidemiology/prevention &amp; control ; Risk Factors ; Europe/epidemiology ; Cost Savings ; Aged ; Health Care Costs/statistics &amp; numerical data ; Models, Theoretical ; Male ; Female ; Prevalence ; Aged, 80 and over ; Middle Aged ; }, abstract = {BACKGROUND: New effective treatments for dementia are lacking, and early prevention focusing on risk factors of dementia is important. Non-pharmacological intervention therapies aimed at these factors may provide a valuable tool for reducing the incidence of dementia. This study focused on the development of a mathematical model to predict the number of individuals with neurodegenerative diseases, specifically Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis. Scenarios for non-pharmacological intervention therapies based on risk factor reduction were also assessed. The estimated total costs and potential cost savings from societal were included.<br><br>METHODS: Based on demographic and financial data from the EU, a mathematical model was developed to predict the prevalence and resulting care costs of neurodegenerative diseases in the population. Each disease (Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis) used parameters that included prevalence, incidence, and death risk ratio, and the simulation is related to the age of the cohort and the disease stage.<br><br>RESULTS: A replicable simulation for predicting the prevalence and resulting cost of care for neurodegenerative diseases in the population exhibited an increase in treatment costs from 267&#xa0;billion EUR in 2021 to 528&#xa0;billion EUR by 2050 in the EU alone. Scenarios related to the reduction of the prevalence of dementia by up to 20% per decade led to total discounted treatment cost savings of up to 558&#xa0;billion EUR.<br><br>CONCLUSION: The model indicates the magnitude of the financial burden placed on EU healthcare systems due to the growth in the population prevalence of neurodegenerative diseases in the coming decades. Lifestyle interventions based on reducing the most common risk factors could serve as a prevention strategy to reduce the incidence of dementia with substantial cost-savings potential. These findings could support the implementation of public health approaches throughout life to ultimately prevent premature mortality and promote a healthier and more active lifestyle in older individuals.}, }
@article {pmid38739991, year = {2024}, author = {Li, X and Liu, N and Wu, D and Li, SC and Wang, Q and Zhang, DW and Song, LL and Huang, M and Chen, X and Li, W}, title = {Hippocampal transcriptomic analyses reveal the potential antiapoptotic mechanism of a novel anticonvulsant agent Q808 on pentylenetetrazol-induced epilepsy in rats.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {175}, number = {}, pages = {116746}, doi = {10.1016/j.biopha.2024.116746}, pmid = {38739991}, issn = {1950-6007}, mesh = {Animals ; *Pentylenetetrazole ; *Hippocampus/drug effects/metabolism/pathology ; *Apoptosis/drug effects ; *Anticonvulsants/pharmacology ; Male ; *Transcriptome/drug effects ; *Epilepsy/drug therapy/chemically induced/genetics ; *Gene Expression Profiling/methods ; Rats ; *Rats, Sprague-Dawley ; Disease Models, Animal ; Neurons/drug effects/metabolism/pathology ; Seizures/chemically induced/genetics/drug therapy ; }, abstract = {Brain apoptosis is one of the main causes of epileptogenesis. The antiapoptotic effect and potential mechanism of Q808, an innovative anticonvulsant chemical, have never been reported. In this study, the seizure stage and latency to reach stage 2 of pentylenetetrazol (PTZ) seizure rat model treated with Q808 were investigated. The morphological change and neuronal apoptosis in the hippocampus were detected by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, respectively. The hippocampal transcriptomic changes were observed using RNA sequencing (RNA-seq). The expression levels of hub genes were verified by quantitative reverse-transcription PCR (qRT-PCR). Results revealed that Q808 could allay the seizure score and prolong the stage 2 latency in seizure rats. The morphological changes of neurons and the number of apoptotic cells in the DG area were diminished by Q808 treatment. RNA-seq analysis revealed eight hub genes, including Map2k3, Nfs1, Chchd4, Hdac6, Siglec5, Slc35d3, Entpd1, and LOC103690108, and nine hub pathways among the control, PTZ, and Q808 groups. Hub gene Nfs1 was involved in the hub pathway sulfur relay system, and Map2k3 was involved in the eight remaining hub pathways, including Amyotrophic lateral sclerosis, Cellular senescence, Fc epsilon RI signaling pathway, GnRH signaling pathway, Influenza A, Rap1 signaling pathway, TNF signaling pathway, and Toll-like receptor signaling pathway. qRT-PCR confirmed that the mRNA levels of these hub genes were consistent with the RNA-seq results. Our findings might contribute to further studies exploring the new apoptosis mechanism and actions of Q808.}, }
@article {pmid38735299, year = {2024}, author = {Gould, RL and McDermott, CJ and Thompson, BJ and Rawlinson, CV and Bursnall, M and Bradburn, M and Kumar, P and Turton, EJ and White, DA and Serfaty, MA and Graham, CD and McCracken, LM and Goldstein, LH and Al-Chalabi, A and Orrell, RW and Williams, T and Noad, R and Baker, I and Faull, C and Lambert, T and Chhetri, SK and Ealing, J and Hanratty, A and Radunovic, A and Gunawardana, N and Meadows, G and Gorrie, GH and Young, T and Lawrence, V and Cooper, C and Shaw, PJ and Howard, RJ and , }, title = {Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK.}, journal = {Lancet (London, England)}, volume = {403}, number = {10442}, pages = {2381-2394}, doi = {10.1016/S0140-6736(24)00533-6}, pmid = {38735299}, issn = {1474-547X}, support = {NIHR202421//NIHR/ ; }, mesh = {Humans ; *Quality of Life ; *Acceptance and Commitment Therapy/methods ; Male ; Female ; Middle Aged ; *Motor Neuron Disease/therapy/psychology ; United Kingdom ; Aged ; Treatment Outcome ; }, abstract = {BACKGROUND: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease.<br><br>METHODS: We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391).<br><br>FINDINGS: Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63&#xb7;1 years (SD 11&#xb7;0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0&#xb7;66 [95% CI 0&#xb7;22-1&#xb7;10]; d=0&#xb7;46 [0&#xb7;16-0&#xb7;77]; p=0&#xb7;0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention.<br><br>INTERPRETATION: ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services.<br><br>FUNDING: National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association.}, }
@article {pmid38734896, year = {2024}, author = {Sun, S and Shen, Y and Zhang, X and Ding, N and Xu, Z and Zhang, Q and Li, L}, title = {The MuSK agonist antibody protects the neuromuscular junction and extends the lifespan in C9orf72-ALS mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {32}, number = {7}, pages = {2176-2189}, pmid = {38734896}, issn = {1525-0024}, mesh = {Animals ; *Neuromuscular Junction/metabolism/drug effects ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy ; *C9orf72 Protein/genetics/metabolism ; Humans ; *Disease Models, Animal ; *Receptor Protein-Tyrosine Kinases/metabolism/genetics ; Longevity/drug effects ; Motor Neurons/metabolism/drug effects ; Agrin/metabolism/genetics ; Mice, Transgenic ; Antibodies/pharmacology ; Receptors, Cholinergic/metabolism/genetics ; LDL-Receptor Related Proteins/metabolism/genetics ; }, abstract = {The disassembly of the neuromuscular junction (NMJ) is an early event in amyotrophic lateral sclerosis (ALS), ultimately leading to motor dysfunction and lethal respiratory paralysis. The hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most common genetic mutation, and the dipeptide repeat (DPR) proteins have been shown to cause neurodegeneration. While no drugs can treat ALS patients efficiently, new treatment strategies are urgently needed. Here, we report that a MuSK agonist antibody alleviates poly-PR-induced NMJ deficits in C9orf72-ALS mice. The HB9-PR[F/F] mice, which express poly-PR proteins in motor neurons, exhibited impaired motor behavior and NMJ deficits. Mechanistically, poly-PR proteins interacted with Agrin to disrupt the interaction between Agrin and Lrp4, leading to attenuated activation of MuSK. Treatment with a MuSK agonist antibody rescued NMJ deficits, and extended the lifespan of C9orf72-ALS mice. Moreover, impaired NMJ transmission was observed in C9orf72-ALS patients. These findings identify the mechanism by which poly-PR proteins attenuate MuSK activation and NMJ transmission, highlighting the potential of promoting MuSK activation with an agonist antibody as a therapeutic strategy to protect NMJ function and prolong the lifespan of ALS patients.}, }
@article {pmid38732027, year = {2024}, author = {Cantara, S and Simoncelli, G and Ricci, C}, title = {Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade.}, journal = {International journal of molecular sciences}, volume = {25}, number = {9}, pages = {}, pmid = {38732027}, issn = {1422-0067}, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use ; *Motor Neuron Disease/genetics/therapy ; Animals ; Muscular Atrophy, Spinal/therapy/genetics ; Amyotrophic Lateral Sclerosis/genetics/therapy ; }, abstract = {Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.}, }
@article {pmid38731036, year = {2024}, author = {Ueha, R and Miura, C and Matsumoto, N and Sato, T and Goto, T and Kondo, K}, title = {Vocal Fold Motion Impairment in Neurodegenerative Diseases.}, journal = {Journal of clinical medicine}, volume = {13}, number = {9}, pages = {}, pmid = {38731036}, issn = {2077-0383}, abstract = {Vocal fold motion impairment (VFMI) is the inappropriate movement of the vocal folds during respiration, leading to vocal fold adduction and/or abduction problems and causing respiratory and vocal impairments. Neurodegenerative diseases (NDDs) are a wide range of disorders characterized by progressive loss of neurons and deposition of altered proteins in the brain and peripheral organs. VFMI may be unrecognized in patients with NDDs. VFMI in NDDs is caused by the following: laryngeal muscle weakness due to muscular atrophy, caused by brainstem and motor neuron degeneration in amyotrophic lateral sclerosis; hyperactivity of laryngeal adductors in Parkinson's disease; and varying degrees of laryngeal adductor hypertonia and abductor paralysis in multiple system atrophy. Management of VFMI depends on whether there is a presence of glottic insufficiency or insufficient glottic opening with/without severe dysphagia. VFMI treatment options for glottic insufficiency range from surgical interventions, including injection laryngoplasty and medialization thyroplasty, to behavioral therapies; for insufficient glottic opening, various options are available based on the severity and underlying cause of the condition, including continuous positive airway pressure therapy, botulinum toxin injection, tracheostomy, vocal fold surgery, or a combination of interventions. In this review, we outline the mechanisms, clinical features, and management of VFMI in NDDs and provide a guide for physicians who may encounter these clinical features in their patients. NDDs are always progressive; hence, timely evaluation, proper diagnosis, and appropriate management of the patient will greatly affect their vocal, respiratory, and swallowing functions as well as their quality of life.}, }
@article {pmid38721118, year = {2024}, author = {Lu, L and Deng, Y and Xu, R}, title = {Current potential therapeutics of amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1402962}, pmid = {38721118}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating motor neurological disorder for which there is still no cure. The disease seriously jeopardizes the health and lifespan of adult populations. The authors extensively retrieved the current literature about clinical and experimental ALS treatments. Based on them, this review primarily focused on summarizing the current potential clinical usage and trialing therapeutics of ALS. Currently, the clinical ALS treatments have focused primarily on relieving symptoms to improve the quality of life yet. There are a number of therapeutic approaches such as medicine, gene therapy, neuron protectants, combination therapy and stem cells. Among them, Stem cells including embryonic stem cells, mesenchymal stem cells, neural stem cells, and many other types of stem cells have been used in ALS treatment, and although the short-term efficacy is good, it is worth exploring whether this improved efficacy leads to prolonged patient survival. In addition, the supportive treatments also exert an important effect on improving the quality of life and prolong the survival of ALS patients in absence of effectively care for stopping or reversing the progression of ALS.}, }
@article {pmid38720896, year = {2024}, author = {Zong, J and Yang, Y and Wang, H and Zhang, H and Yang, X and Yang, X}, title = {The two-directional prospective association between inflammatory bowel disease and neurodegenerative disorders: a systematic review and meta-analysis based on longitudinal studies.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1325908}, pmid = {38720896}, issn = {1664-3224}, mesh = {Humans ; *Inflammatory Bowel Diseases/complications ; *Neurodegenerative Diseases/epidemiology/etiology ; Longitudinal Studies ; Risk Factors ; Prospective Studies ; }, abstract = {OBJECTIVE: Previous studies reported possible connections between inflammatory bowel disease (IBD) and several neurodegenerative disorders. However, the comprehensive relationships between IBD and various neurodegenerative disorders were not summarized. We executed a meta-analysis of longitudinal studies to provide an estimate of the strength of the two-directional prospective association between IBD and neurodegenerative disorders.<br><br>METHODS: We accomplished a thorough bibliographic search of PubMed, Web of Science, Embase, PsycINFO, and Cochrane Library databases until June 2023 to locate relevant longitudinal studies. The extracted data were then analyzed via meta-analysis using either a fixed or random effects model.<br><br>RESULTS: The final analysis encompassed 27 studies. Individuals with IBD faced an increased risk of developing four neurodegenerative disorders than the general public, namely, Alzheimer's disease (hazard ratio[HR] = 1.35, 95% confidence interval [CI]: 1.03-1.77, P=0.031), dementia (HR =1.24, 95% CI: 1.13-1.36, P<0.001), multiple sclerosis (HR =2.07, 95% CI:1.42-3.02, P<0.001) and Parkinson's disease (HR =1.23, 95% CI:1.10-1.38, P<0.001). Two articles reported an increased incidence of amyotrophic lateral sclerosis or multiple system atrophy in IBD patients. Three studies investigated the prospective association between multiple sclerosis and IBD, revealing an elevated risk of the latter in patients with the former. (HR=1.87, 95% CI:1.66-2.10, P<0.001).<br><br>INTERPRETATION: These findings verified the two-directional relationship between the brain-gut axis, specifically demonstrating a heightened risk of various neurodegenerative diseases among IBD patients. It may be profitable to prepare screening strategies for IBD patients to find neurodegenerative diseases during the long-term course of treatment for IBD with a view to potential earlier diagnosis and treatment of neurodegenerative diseases, reducing public health and social burden.<br><br>PROSPERO (CRD42023437553).}, }
@article {pmid38719860, year = {2024}, author = {Cusaro, CM and Capelli, E and Picco, AM and Brusoni, M}, title = {Incidence of resistance to ALS and ACCase inhibitors in Echinochloa species and soil microbial composition in Northern Italy.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {10544}, pmid = {38719860}, issn = {2045-2322}, support = {ECS00000036//MUR - M4C2 1.5 of PNRR funded by the European Union - NextGenerationEU/ ; }, mesh = {*Soil Microbiology ; Italy/epidemiology ; *Herbicide Resistance ; *Herbicides/pharmacology ; *Acetolactate Synthase/antagonists &amp; inhibitors/genetics ; *Echinochloa/drug effects ; *Acetyl-CoA Carboxylase/genetics/antagonists &amp; inhibitors ; Plant Weeds/drug effects ; Microbiota/drug effects ; Biodiversity ; Bacteria/drug effects/genetics/isolation &amp; purification/classification ; Soil/chemistry ; Fungi/drug effects/isolation &amp; purification/genetics ; }, abstract = {The increasing amount of weeds surviving herbicide represents a very serious problem for crop management. The interaction between microbial community of soil and herbicide resistance, along with the potential evolutive consequences, are still poorly known and need to be investigated to better understand the impact on agricultural management. In our study, we analyzed the microbial composition of soils in 32 farms, located in the Northern Italy rice-growing area (Lombardy) with the aim to evaluate the relationship between the microbial composition and the incidence of resistance to acetolactate synthase (ALS) and acetyl-CoA carboxylase (ACCase) inhibiting herbicides in Echinochloa species. We observed that the coverage of weeds survived herbicide treatment was higher than 60% in paddy fields with a low microbial biodiversity and less than 5% in those with a high microbial biodiversity. Fungal communities showed a greater reduction in richness than Bacteria. In soils with a reduced microbial diversity, a significant increase of some bacterial and fungal orders (i.e. Lactobacillales, Malasseziales and Diaporthales) was observed. Interestingly, we identified two different microbial profiles linked to the two conditions: high incidence of herbicide resistance (H-HeR) and low incidence of herbicide resistance (L-HeR). Overall, the results we obtained allow us to make hypotheses on the greater or lesser probability of herbicide resistance occurrence based on the composition of the soil microbiome and especially on the degree of biodiversity of the microbial communities.}, }
@article {pmid38718295, year = {2024}, author = {Huang, J and Fu, Y and Wang, A and Shi, K and Peng, Y and Yi, Y and Yu, R and Gao, J and Feng, J and Jiang, G and Song, Q and Jiang, J and Chen, H and Gao, X}, title = {Brain Delivery of Protein Therapeutics by Cell Matrix-Inspired Biomimetic Nanocarrier.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {36}, number = {31}, pages = {e2405323}, doi = {10.1002/adma.202405323}, pmid = {38718295}, issn = {1521-4095}, support = {2022YFC2502800//National Key Research and Development Program of China/ ; 2023ZKZD21//Innovation Program of Shanghai Municipal Education Commission/ ; 81973272//National Natural Science Foundation of China/ ; 92068111//National Natural Science Foundation of China/ ; 81801212//National Natural Science Foundation of China/ ; 23S41900100//Shanghai Science and Technology Development Foundation/ ; 22QA1405000//Shanghai Science and Technology Development Foundation/ ; 21XD1422200//Shanghai Science and Technology Development Foundation/ ; SHSMU-ZDCX20211201//Innovative Research Team of High-Level Local Universities in Shanghai/ ; }, mesh = {Animals ; Mice ; *Biomimetic Materials/chemistry ; *Drug Carriers/chemistry ; *Blood-Brain Barrier/metabolism ; *Hyaluronic Acid/chemistry ; *Catalase/metabolism/chemistry ; *Brain/metabolism ; Nanoparticles/chemistry ; Protamines/chemistry ; Amyotrophic Lateral Sclerosis/drug therapy ; Disease Models, Animal ; Humans ; Brain Injuries/drug therapy/metabolism ; Biomimetics/methods ; }, abstract = {Protein therapeutics are anticipated to offer significant treatment options for central nervous system (CNS) diseases. However, the majority of proteins are unable to traverse the blood-brain barrier (BBB) and reach their CNS target sites. Inspired by the natural environment of active proteins, the cell matrix components hyaluronic acid (HA) and protamine (PRTM) are used to self-assemble with proteins to form a protein-loaded biomimetic core and then incorporated into ApoE3-reconstituted high-density lipoprotein (rHDL) to form a protein-loaded biomimetic nanocarrier (Protein-HA-PRTM-rHDL). This cell matrix-inspired biomimetic nanocarrier facilitates the penetration of protein therapeutics across the BBB and enables their access to intracellular target sites. Specifically, CAT-HA-PRTM-rHDL facilitates rapid intracellular delivery and release of catalase (CAT) via macropinocytosis-activated membrane fusion, resulting in improved spatial learning and memory in traumatic brain injury (TBI) model mice (significantly reduces the latency of TBI mice and doubles the number of crossing platforms), and enhances motor function and prolongs survival in amyotrophic lateral sclerosis (ALS) model mice (extended the median survival of ALS mice by more than 10 days). Collectively, this cell matrix-inspired nanoplatform enables the efficient CNS delivery of protein therapeutics and provides a novel approach for the treatment of CNS diseases.}, }
@article {pmid38712849, year = {2024}, author = {Ludolph, AC and Corcia, P and Desnuelle, C and Heiman-Patterson, T and Mora, JS and Mansfield, CD and Couratier, P}, title = {Categorization of the amyotrophic lateral sclerosis population via the clinical determinant of post-onset ΔFS for study design and medical practice.}, journal = {Muscle &amp; nerve}, volume = {70}, number = {1}, pages = {36-41}, doi = {10.1002/mus.28101}, pmid = {38712849}, issn = {1097-4598}, support = {//AB Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Clinical Trials as Topic/methods ; Disease Progression ; Outcome Assessment, Health Care/standards ; *Research Design ; Severity of Illness Index ; }, abstract = {The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) has become the most widely utilized measure of disease severity in patients with ALS, with change in ALSFRS-R from baseline being a trusted primary outcome measure in ALS clinical trials. This is despite the scale having several established limitations, and although alternative scales have been proposed, it is unlikely that these will displace ALSFRS-R in the foreseeable future. Here, we discuss the merits of delta FS (ΔFS), the slope or rate of ALSFRS-R decline over time, as a relevant tool for innovative ALS study design, with an as yet untapped potential for optimization of drug effectiveness and patient management. In our view, categorization of the ALS population via the clinical determinant of post-onset ΔFS is an important study design consideration. It serves not only as a critical stratification factor and basis for patient enrichment but also as a tool to explore differences in treatment response across the overall population; thereby, facilitating identification of responder subgroups. Moreover, because post-onset ΔFS is derived from information routinely collected as part of standard patient care and monitoring, it provides a suitable patient selection tool for treating physicians. Overall, post-onset ΔFS is a very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design.}, }
@article {pmid38711616, year = {2024}, author = {Chen, L and Chen, G and Zhang, M and Zhang, X}, title = {Modeling sporadic juvenile ALS in iPSC-derived motor neurons explores the pathogenesis of FUS[R503fs] mutation.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1364164}, pmid = {38711616}, issn = {1662-5102}, abstract = {INTRODUCTION: Fused in sarcoma (FUS) mutations represent the most common genetic etiology of juvenile amyotrophic lateral sclerosis (JALS), for which effective treatments are lacking. In a prior report, we identified a novel FUS mutation, c.1509dupA: p. R503fs (FUSR503fs), in a sporadic JALS patient.<br><br>METHODS: The physicochemical properties and structure of FUSR503fs protein were analyzed by software: Multi-electrode array (MEA) assay, calcium activity imaging assay and transcriptome analysis were used to explore the pathophysiological mechanism of iPSC derived motor neurons.<br><br>RESULTS: Structural analysis and predictions regarding physical and chemical properties of this mutation suggest that the reduction of phosphorylation and glycosylation sites, along with alterations in the amino acid sequence, may contribute to abnormal FUS accumulation within the cytoplasm and nucleus of induced pluripotent stem cell- derived motor neurons (MNs). Multi-electrode array and calcium activity imaging indicate diminished spontaneous electrical and calcium activity signals in MNs harboring the FUS[R503fs] mutation. Transcriptomic analysis reveals upregulation of genes associated with viral infection and downregulation of genes involved in neural function maintenance, such as the ATP6V1C2 gene. Treatment with ropinirole marginally mitigates the electrophysiological decline in FUS[R503fs] MNs, suggesting the utility of this cell model for mechanistic exploration and drug screening.<br><br>DISCUSSION: iPSCs-derived motor neurons from JALS patients are promising tools for drug screening. The pathological changes in motor neurons of FUS[R503fs] may occur earlier than in other known mutation types that have been reported.}, }
@article {pmid38703766, year = {2024}, author = {Alfahel, L and Gschwendtberger, T and Kozareva, V and Dumas, L and Gibbs, R and Kertser, A and Baruch, K and Zaccai, S and Kahn, J and Thau-Habermann, N and Eggenschwiler, R and Sterneckert, J and Hermann, A and Sundararaman, N and Vaibhav, V and Van Eyk, JE and Rafuse, VF and Fraenkel, E and Cantz, T and Petri, S and Israelson, A}, title = {Targeting low levels of MIF expression as a potential therapeutic strategy for ALS.}, journal = {Cell reports. Medicine}, volume = {5}, number = {5}, pages = {101546}, pmid = {38703766}, issn = {2666-3791}, mesh = {*Macrophage Migration-Inhibitory Factors/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology ; Animals ; Humans ; *Motor Neurons/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Induced Pluripotent Stem Cells/metabolism ; Intramolecular Oxidoreductases/metabolism/genetics ; Mice, Transgenic ; Dependovirus/genetics ; Disease Models, Animal ; Male ; Mutation/genetics ; Female ; Protein Folding ; }, abstract = {Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neuron (MN) loss. We previously discovered that macrophage migration inhibitory factor (MIF), whose levels are extremely low in spinal MNs, inhibits mutant SOD1 misfolding and toxicity. In this study, we show that a single peripheral injection of adeno-associated virus (AAV) delivering MIF into adult SOD1[G37R] mice significantly improves their motor function, delays disease progression, and extends survival. Moreover, MIF treatment reduces neuroinflammation and misfolded SOD1 accumulation, rescues MNs, and corrects dysregulated pathways as observed by proteomics and transcriptomics. Furthermore, we reveal low MIF levels in human induced pluripotent stem cell-derived MNs from familial ALS patients with different genetic mutations, as well as in post mortem tissues of sporadic ALS patients. Our findings indicate that peripheral MIF administration may provide a potential therapeutic mechanism for modulating misfolded SOD1 in vivo and disease outcome in ALS patients.}, }
@article {pmid38698397, year = {2024}, author = {Wilson, E and Palmer, J and Armstrong, A and Messer, B and Presswood, E and Faull, C}, title = {End of life decision making when home mechanical ventilation is used to sustain breathing in Motor Neurone Disease: patient and family perspectives.}, journal = {BMC palliative care}, volume = {23}, number = {1}, pages = {115}, pmid = {38698397}, issn = {1472-684X}, support = {Anne McLaren Research Fellowship//University of Nottingham/ ; }, mesh = {Humans ; *Motor Neuron Disease/psychology/therapy/complications ; *Decision Making ; Male ; Female ; Middle Aged ; *Qualitative Research ; *Respiration, Artificial/methods/psychology ; Aged ; *Terminal Care/methods/psychology ; *Family/psychology ; United Kingdom ; Adult ; Aged, 80 and over ; Home Care Services/standards ; }, abstract = {BACKGROUND: Motor Neurone Disease (MND) leads to muscle weakening, affecting movement, speech, and breathing. Home mechanical ventilation, particularly non-invasive ventilation (NIV), is used to alleviate symptoms and support breathing in people living with MND. While home mechanical ventilation can alleviate symptoms and improve survival, it does not slow the progression of MND. This study addresses gaps in understanding end-of-life decision-making in those dependent on home mechanical ventilation, considering the perspectives of patients, family members, and bereaved families.<br><br>METHODS: A UK-wide qualitative study using flexible interviews to explore the experiences of people living with MND (n&#x2009;=&#x2009;16), their family members (n&#x2009;=&#x2009;10), and bereaved family members (n&#x2009;=&#x2009;36) about the use of home mechanical ventilation at the end of life.<br><br>RESULTS: Some participants expressed a reluctance to discuss end-of-life decisions, often framed as a desire to "live for the day" due to the considerable uncertainty faced by those with MND. Participants who avoided end-of-life discussions often engaged in 'selective decision-making' related to personal planning, involving practical and emotional preparations. Many faced challenges in hypothesising about future decisions given the unpredictability of the disease, opting to make 'timely decisions' as and when needed. For those who became dependent on ventilation and did not want to discuss end of life, decisions were often 'defaulted' to others, especially once capacity was lost. 'Proactive decisions', including advance care planning and withdrawal of treatment, were found to empower some patients, providing a sense of control over the timing of their death. A significant proportion lacked a clear understanding of the dying process and available options.<br><br>CONCLUSIONS: The study highlights the complexity and evolution of decision-making, often influenced by the dynamic and uncertain nature of MND. The study emphasises the need for a nuanced understanding of decision-making in the context of MND.}, }
@article {pmid38697285, year = {2024}, author = {Tuerxun, K and Tang, RH and Abudoumijiti, A and Yusupu, Z and Aikebaier, A and Mijiti, S and Ibrahim, I and Cao, YL and Yasheng, A and Wu, YQ}, title = {Comparative proteomics analysis of samples from hepatic cystic echinococcosis patients using data-independent acquisition approach.}, journal = {Journal of proteomics}, volume = {301}, number = {}, pages = {105191}, doi = {10.1016/j.jprot.2024.105191}, pmid = {38697285}, issn = {1876-7737}, mesh = {*Proteomics/methods ; Humans ; *Echinococcus granulosus/metabolism ; Animals ; Helminth Proteins/metabolism/analysis ; Echinococcosis, Hepatic/metabolism/parasitology ; Proteome/analysis/metabolism ; }, abstract = {Cystic echinococcosis is a zoonotic disease resulting from infection caused by the larval stage of Echinococcus granulosus. This study aimed to assess the specific proteins that are potential candidates for the development of a vaccine against E. granulosus. The data-independent acquisition approach was employed to identify differentially expressed proteins (DEPs) in E. granulosus samples. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was employed to identify several noteworthy proteins. Results: The DEPs in E. granulosus samples were identified (245 pericystic wall vs. parasite-free yellowish granuloma (PYG, 1725 PY vs. PYG, 2274 PN vs. PYG). Further examination of these distinct proteins revealed their predominant enrichment in metabolic pathways, amyotrophic lateral sclerosis, and neurodegeneration-associated pathways. Notably, among these DEPs, SH3BGRL, MST1, TAGLN2, FABP5, UBE2V2, and RARRES2 exhibited significantly higher expression levels in the PYG group compared with the PY group (P < 0.05). The findings may contribute to the understanding of the pathological mechanisms underlying echinococcosis, providing valuable insights into the development of more effective diagnostic tools, treatment modalities, and preventive strategies. SIGNIFICANCE: CE is a major public health hazard in the western regions of China, Central Asia, South America, the Mediterranean countries, and eastern Africa. Echinococcus granulosus is responsible for zoonotic disease through infection Our analysis focuses on the proteins in various samples by data-dependent acquisition (DIA) for proteomic analysis. The importance of this research is to develop new strategies and targets to protect against E. granulosus infections in humans.}, }
@article {pmid38694387, year = {2024}, author = {Arora, H and Javed, B and Kutikuppala, LVS and Chaurasia, M and Khullar, K and Kannan, S and Golla, V}, title = {ST2 levels and neurodegenerative diseases: is this a significant relation?.}, journal = {Annals of medicine and surgery (2012)}, volume = {86}, number = {5}, pages = {2812-2817}, pmid = {38694387}, issn = {2049-0801}, abstract = {Interleukin-33 (IL-33), belonging to the interleukin-1 cytokine family, has a decoy receptor soluble ST2 (sST2). IL-33 is found in oligodendrocytes and astrocytes and is involved in central nervous system healing and repair, whereas ST2 is found in microglia and astrocytes. Some studies have found a link between changes in the IL-33/ST2 pathway and neurodegenerative disorders. This review article investigates the relationship between the interleukin-33 (IL-33)/ST2 pathway and neurodegenerative disorders. It was discovered that soluble st2 levels were increased. Furthermore, IL-33 levels were found to be lower in many neurodegenerative diseases such as Alzheimer's and amyotrophic lateral sclerosis (ALS). The association with other disorders, such as ankylosing spondylitis, multiple sclerosis, and systemic lupus erythematosus (SLE), was also observed. Various studies suggest that ST2/IL-33 signalling may be pivotal in the disease modulation of neurodegenerative disorders. The serum sST2 level test can be useful in determining the inflammatory status and severity of illness in many neurodegenerative disorders. In this review, we will discuss recent findings concerning the interleukin-33 (IL-33)/ST2 pathway and its role in the diagnosis and treatment of diseases with neurodegeneration.}, }
@article {pmid38691665, year = {2024}, author = {Singh, P and Belliveau, P and Towle, J and Neculau, AE and Dima, L}, title = {Edaravone Oral Suspension: A Neuroprotective Agent to Treat Amyotrophic Lateral Sclerosis.}, journal = {American journal of therapeutics}, volume = {31}, number = {3}, pages = {e258-e267}, doi = {10.1097/MJT.0000000000001742}, pmid = {38691665}, issn = {1536-3686}, mesh = {*Edaravone/administration &amp; dosage/pharmacology/therapeutic use ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neuroprotective Agents/administration &amp; dosage/therapeutic use/adverse effects ; Administration, Oral ; Suspensions ; Biological Availability ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration of nerve cells within the brain and spinal cord. Early symptoms include limb weakness, twitching or muscle cramping, and slurred speech. As the disease progresses, difficulty breathing, swallowing, and paralysis can lead to death. Currently, there are no medications that cure ALS, and guidelines recommend treatments focused on symptom management. Intravenous (IV) edaravone was approved by the US Food and Drug Administration (FDA) in 2017 as a treatment to slow the progression of ALS. In May 2022, the FDA approved an oral suspension (ORS) formulation of edaravone.<br><br>MECHANISM OF ACTION: The mechanism of action of edaravone is not well defined. However, its neuroprotective effects are thought to result from antioxidant properties occurring through elimination of free radicals.<br><br>PHARMACOKINETICS: Edaravone ORS (105 mg) has a bioavailability of 57% when compared with edaravone IV (60 mg). The ORS should be taken on an empty stomach in the morning, with water and no food or beverages, for 1 hour. Edaravone is bound to albumin (92%), has a mean volume of distribution of 63.1 L, a half-life of 4.5-9 hours, and a total clearance of 35.9 L/h after intravenous administration. Edaravone is metabolized into nonactive sulfate and glucuronide conjugates.<br><br>CLINICAL TRIALS: The FDA approval was based on studies of the pharmacokinetics, safety, tolerability, and bioavailability of edaravone ORS. A phase III, global, multicenter, open-label safety study was conducted on edaravone ORS in 185 patients with ALS over 48 weeks. The most reported treatment-emergent adverse events were falls, muscular weakness, and constipation. Serious treatment-emergent adverse events included disease worsening, dysphagia, dyspnea, and respiratory failure.<br><br>THERAPEUTIC ADVANCE: Oral edaravone is an ALS treatment that can be self-administered or administered by a caregiver, precluding the need for administration by a health care professional in an institutional setting.}, }
@article {pmid38685454, year = {2024}, author = {Gadri, Y and Avneri, A and Peleg, Z}, title = {Induced mutation in the SiALS gene offers new weed management opportunities for sesame crop.}, journal = {Plant science : an international journal of experimental plant biology}, volume = {345}, number = {}, pages = {112104}, doi = {10.1016/j.plantsci.2024.112104}, pmid = {38685454}, issn = {1873-2259}, mesh = {*Weed Control/methods ; *Herbicide Resistance/genetics ; *Sesamum/genetics/growth &amp; development ; *Herbicides/pharmacology ; Acetolactate Synthase/genetics ; Plant Weeds/genetics/drug effects ; Plant Proteins/genetics/metabolism ; Mutation ; Crops, Agricultural/genetics/growth &amp; development ; }, abstract = {Weeds are the primary biotic constraint affecting sesame growth and production. Here, we applied EMS mutagenesis to an elite sesame cultivar and discovered a novel point mutation in the sesame SiALS gene conferring resistance to imidazolinone, a group of acetolactate-synthase (ALS)-inhibitors. The mutant line exhibited high resistance to imazamox, an ALS-inhibitor, with hybrid plants displaying an intermediate response. Field-based validation confirmed the mutant line's substantial resistance, leading to a significantly higher yield under imazamox treatment. Under pre-emergence application of imazapic, the mutant plants sustained growth, whereas wild-type and weed were effectively controlled. Field trials using s-metolachlor and imazapic combined resulted in weed-free plots compared to untreated controls. Consequently, this treatment showed a significantly greater yield (2280 vs. 880 Kg ha[-1]) than the commercial practice (s-metolachlor). Overall, our study unveils the potential of utilizing this point mutation in sesame breeding programs, offering new opportunities for integrated weed management strategies for sesame cultivation. Developing herbicide-resistant crop plants holds promise for supporting sustainable production and addressing the challenges of weed infestations in sesame farming.}, }
@article {pmid38681726, year = {2024}, author = {Grzanka, M and Joniec, A and Rogulski, J and Sobiech, &#x141; and Idziak, R and Loryś, B}, title = {Impact of novel herbicide based on synthetic auxins and ALS inhibitor on weed control.}, journal = {Open life sciences}, volume = {19}, number = {1}, pages = {20220868}, pmid = {38681726}, issn = {2391-5412}, abstract = {Delayed sowing of winter cereals or unfavorable weather conditions in autumn may make it impossible to carry out herbicide treatment in autumn. In such cases, weed control should be started in the spring. During this time, the plantation should be protected as effectively as possible because the weeds are at an advanced stage of growth. Therefore, they are less sensitive to applied herbicides. In the treatment, it is worth using a mixture of different mechanisms of action. Studies were conducted to evaluate the effectiveness of a band of tribenuron-methyl, and MCPA applied as soluble granules in spring control of dicotyledonous in winter cereals. The biological efficacy of herbicides was estimated in the 25 field experiments on winter cereals in Poland. Postemergence, a spring application of tribenuron-methyl + MCPA, effectively controls the majority of weed species present in spring: Anthemis arvensis, Brassica napus, Capsella bursa-pastoris, Centaurea cyanus, Lamium purpureum, Matricaria chamomilla, Tripleurospermum inodorum, Stellaria media and Thlaspi arvense. Satisfactory control was confirmed for Veronica persica, Viola arvensis, and Galium aparine. Tribenuron-methyl with MCPA is recommended for application to winter cereals in spring. To prevent the development of resistance in weeds, it is advantageous to combine two active substances.}, }
@article {pmid38678262, year = {2024}, author = {Xu, C and Mei, Y and Yang, R and Luo, Q and Zhang, J and Kou, X and Hu, J and Wang, Y and Li, Y and Chen, R and Zhang, Z and Yao, Y and Sima, J}, title = {Edaravone Dexborneol mitigates pathology in animal and cell culture models of Alzheimer's disease by inhibiting neuroinflammation and neuronal necroptosis.}, journal = {Cell &amp; bioscience}, volume = {14}, number = {1}, pages = {55}, pmid = {38678262}, issn = {2045-3701}, support = {82173804//National Natural Science Foundation of China/ ; 82001144//National Natural Science Foundation of China/ ; 3150120042//High-Level Talents Start-up Funding of China Pharmaceutical University/ ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with limited disease-modifying treatments. Drug repositioning strategy has now emerged as a promising approach for anti-AD drug discovery. Using 5×FAD mice and Aβ-treated neurons in culture, we tested the efficacy of Y-2, a compounded drug containing the antioxidant Edaravone (Eda), a pyrazolone and (+)-Borneol, an anti-inflammatory diterpenoid from cinnamon, approved for use in amyotrophic lateral sclerosis patients.<br><br>RESULTS: We examined effects of Y-2 versus Eda alone by i.p. administered in 8-week-old 5&#xd7;FAD mice (females) for 4 months by comparing cognitive function, A&#x3b2; pathologies, neuronal necroptosis and neuroinflammation. Using primary neurons and astrocytes, as well as neuronal and astrocytic cell lines, we elucidated the molecular mechanisms of Y-2 by examining neuronal injury, astrocyte-mediated inflammation and necroptosis. Here, we find that Y-2 improves cognitive function in AD mice. Histopathological data show that Y-2, better than Eda alone, markedly ameliorates A&#x3b2; pathologies including A&#x3b2; burden, astrogliosis/microgliosis, and Tau phosphorylation. In addition, Y-2 reduces A&#x3b2;-induced neuronal injury including neurite damage, mitochondrial impairment, reactive oxygen species production and NAD[+] depletion. Notably, Y-2 inhibits astrocyte-mediated neuroinflammation and attenuates TNF-&#x3b1;-triggered neuronal necroptosis in cell cultures and AD mice. RNA-seq further demonstrates that Y-2, compared to Eda, indeed upregulates anti-inflammation pathways in astrocytes.<br><br>CONCLUSIONS: Our findings infer that Y-2, better than Eda alone, mitigates AD pathology and may provide a potential drug candidate for AD treatment.}, }
@article {pmid38677733, year = {2024}, author = {Keul, J and Sperling, S and Rohde, V and Mielke, D and Ninkovic, M}, title = {Riluzole Reverses a Number of Undesirable Effects of Dexamethasone in Glioblastoma Cells.}, journal = {Anticancer research}, volume = {44}, number = {5}, pages = {1829-1835}, doi = {10.21873/anticanres.16984}, pmid = {38677733}, issn = {1791-7530}, mesh = {*Riluzole/pharmacology ; Humans ; *Glioblastoma/drug therapy/pathology/metabolism ; *Dexamethasone/pharmacology ; *Cell Movement/drug effects ; Cell Line, Tumor ; Brain Neoplasms/drug therapy/pathology/metabolism ; Cell Survival/drug effects ; }, abstract = {BACKGROUND/AIM: Glioblastoma multiforme (GBM)-induced oedema is a major cause of morbidity and mortality among patients with GBM. Dexamethasone (Dex) is the most common corticosteroid used pre-operatively to control cerebral oedema in patients with GBM. Dex is associated with many side effects, and shorter overall survival and progression-free survival of patients with GBM. These negative effects of Dex highlight the need for combinational therapy. Riluzole (Ril), a drug used to treat amyotrophic lateral sclerosis (ALS), is thought to have potential as a treatment for various cancers, with clinical trials underway. Here, we investigated whether Ril could reverse some of the undesirable effects of Dex.<br><br>MATERIALS AND METHODS: The effect of Dex, Ril, and Ril-Dex treatment on cell migration was monitored using the xCELLigence system. Cell viability assays were performed using 3-(4, 5-dimethylthiazol)-2, 5-diphenyltetrazolium bromide (MTT). The expression of genes involved in migration, glucose metabolism, and stemness was examined using real-time polymerase chain reaction (PCR).<br><br>RESULTS: Pre-treating GBM cells with Ril reduced Dex-induced cell migration and altered Dex-induced effects on cell invasion, stem cell, and glucose metabolism markers. Furthermore, Ril remained effective in killing GBM cells in combination with Dex.<br><br>CONCLUSION: Ril, which acts as an anti-tumorigenic drug, mediates some of the negative effects of Dex; therefore, it could be a potential drug to manage the side effects of Dex therapy in GBM.}, }
@article {pmid38676672, year = {2024}, author = {Kutlubaev, MA}, title = {[Promising approaches to the pathogenetic therapy of amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {4}, pages = {13-21}, doi = {10.17116/jnevro202412404113}, pmid = {38676672}, issn = {1997-7298}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Neuroprotective Agents/therapeutic use ; Genetic Therapy ; Antioxidants/therapeutic use ; Stem Cell Transplantation ; Gastrointestinal Microbiome ; Immunologic Factors/therapeutic use ; Immunomodulating Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis is a severe incurable disease of the nervous system. Currently only methods of palliative care for the patients with this disease are available. Few medications for the pathogenetic therapy are registered in some countries, i.e. riluzole, edaravon, sodium phenylbutyrate/taurursodiol as well as tofersen (conditionally). Their efficacy is relatively low. The main directions in the development of pathogenetic therapy of ALS include gene therapy, use of stem cells, immunomodulators, agents affecting gut microbiota. A search is also underway for low-molecular compounds with neuroprotective and antioxidant properties. Perspective direction is prevention of ALS. This will be possible when biomarkers for identification of patients in pre-manifest/prodromal stage are detected.}, }
@article {pmid38676303, year = {2024}, author = {Zhao, W and Wang, R and Chen, M}, title = {Clinical analysis of air-leak syndrome following allogeneic hematopoietic stem cell transplantation in pediatric patients.}, journal = {Pediatric blood &amp; cancer}, volume = {71}, number = {7}, pages = {e31008}, doi = {10.1002/pbc.31008}, pmid = {38676303}, issn = {1545-5017}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Male ; Female ; Retrospective Studies ; Child ; Child, Preschool ; Adolescent ; Infant ; Prognosis ; Survival Rate ; Follow-Up Studies ; Transplantation, Homologous ; Bronchiolitis Obliterans/etiology/mortality/therapy ; Pneumonia/etiology/mortality ; }, abstract = {BACKGROUND: Air-leak syndrome (ALS) is considered as an independent risk factor for poor prognosis in adult patients who had received hematopoietic stem cell transplantation (HSCT), and the 5-year overall survival (OS) of ALS is less than 30%. However, the clinical features of ALS among post-transplant pediatric patients have rarely been explored.<br><br>PROCEDURES: We retrospectively reviewed 2206 pediatric patients who had received an allo-HSCT between January 2013 and December 2019 at the Hebei Yanda Lu Daopei Hospital, and analyzed the role of ALS in prognosis following HSCT.<br><br>RESULTS: In our research, ALS was divided into two categories: 15 cases of bronchiolitis obliterans syndrome (BOS) and 13 cases of idiopathic pneumonia syndrome (IPS). Following treatment of the ALS, 18 patients survived (18/28, 64.3%), and 10 patients died of respiratory failure or infection (10/28, 35.7%).<br><br>CONCLUSIONS: The OS of ALS in Hebei Yanda Lu Daopei Hospital is significantly higher than others, and they were cited to be related to early diagnosis and timely FAM treatment in previous reports.}, }
@article {pmid38674921, year = {2024}, author = {Wang, W and Pan, D and Liu, Q and Chen, X and Wang, S}, title = {L-Carnitine in the Treatment of Psychiatric and Neurological Manifestations: A Systematic Review.}, journal = {Nutrients}, volume = {16}, number = {8}, pages = {}, pmid = {38674921}, issn = {2072-6643}, mesh = {Humans ; *Carnitine/therapeutic use ; Dietary Supplements ; *Mental Disorders/drug therapy ; *Nervous System Diseases/drug therapy ; }, abstract = {OBJECTIVE: L-carnitine (LC), a vital nutritional supplement, plays a crucial role in myocardial health and exhibits significant cardioprotective effects. LC, being the principal constituent of clinical-grade supplements, finds extensive application in the recovery and treatment of diverse cardiovascular and cerebrovascular disorders. However, controversies persist regarding the utilization of LC in nervous system diseases, with varying effects observed across numerous mental and neurological disorders. This article primarily aims to gather and analyze database information to comprehensively summarize the therapeutic potential of LC in patients suffering from nervous system diseases while providing valuable references for further research.<br><br>METHODS: A comprehensive search was conducted in PubMed, Web Of Science, Embase, Ovid Medline, Cochrane Library and Clinicaltrials.gov databases. The literature pertaining to the impact of LC supplementation on neurological or psychiatric disorders in patients was reviewed up until November 2023. No language or temporal restrictions were imposed on the search.<br><br>RESULTS: A total of 1479 articles were retrieved, and after the removal of duplicates through both automated and manual exclusion processes, 962 articles remained. Subsequently, a meticulous re-screening led to the identification of 60 relevant articles. Among these, there were 12 publications focusing on hepatic encephalopathy (HE), while neurodegenerative diseases (NDs) and peripheral nervous system diseases (PNSDs) were represented by 9 and 6 articles, respectively. Additionally, stroke was addressed in five publications, whereas Raynaud's syndrome (RS) and cognitive disorder (CD) each had three dedicated studies. Furthermore, migraine, depression, and amyotrophic lateral sclerosis (ALS) each accounted for two publications. Lastly, one article was found for other symptoms under investigation.<br><br>CONCLUSION: In summary, LC has demonstrated favorable therapeutic effects in the management of HE, Alzheimer's disease (AD), carpal tunnel syndrome (CTS), CD, migraine, neurofibromatosis (NF), PNSDs, RS, and stroke. However, its efficacy appears to be relatively limited in conditions such as ALS, ataxia, attention deficit hyperactivity disorder (ADHD), depression, chronic fatigue syndrome (CFS), Down syndrome (DS), and sciatica.}, }
@article {pmid38666665, year = {2024}, author = {Forsberg, K and Karlsborg, M and Salvesen, L and Svenstrup, K and Winroth, I and Berntsson, H and M Andersen, P}, title = {[SOD1 gene therapy delays ALS disease progression].}, journal = {Lakartidningen}, volume = {121}, number = {}, pages = {}, pmid = {38666665}, issn = {1652-7518}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; *Superoxide Dismutase-1/genetics ; *Genetic Therapy ; *Disease Progression ; Male ; Middle Aged ; Mutation ; Oligonucleotides, Antisense/therapeutic use/administration &amp; dosage ; Oligonucleotides/therapeutic use/administration &amp; dosage ; }, abstract = {We present a patient with familial amyotrophic lateral sclerosis caused by an aggressive A4S mutation in the SOD1 gene. In 2020, the patient was enrolled in the VALOR SOD1 gene therapy phase-3 trial. At screening, the ALSFRS-R score was 41 (48 is normal) and the level of CSF-neurofilament L (an indicator of ongoing neuronal damage) was 11 000 ng/L (ref <650 ng/L). In the four years following enrollment, the patient received monthly intrathecal treatment with tofersen, an antisense oligonucleotide compound that inhibits SOD1 protein expression and hence lowers the synthesis of toxic SOD1 protein species. Side effects have been minimal and mostly attributed to the spinal taps. The patient remains ambulatory with an active social lifestyle. The ALSFRS-R score has in the past 18 months stabilized around 35-37, CSF-NfL is 1 290 ng/L and plasma-NfL is 12 (reference <13). This is the first documented arresting intervention in a patient with ALS in Sweden.}, }
@article {pmid38666601, year = {2024}, author = {Officer, L and Armon, C and Barkhaus, P and Beauchamp, M and Benatar, M and Bertorini, T and Bowser, R and Bromberg, M and Brown, A and Carbunar, OM and Carter, GT and Crayle, J and Denson, K and Feldman, E and Fullam, T and Heiman-Patterson, T and Jackson, C and Jhooty, S and Levinson, D and Li, X and Linares, A and Mallon, E and Mascias Cadavid, J and Mcdermott, C and Mushannen, T and Ostrow, L and Patel, R and Pattee, G and Ratner, D and Sun, Y and Sladky, J and Wicks, P and Bedlack, R}, title = {ALSUntangled #75: Portable neuromodulation stimulator therapy.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {648-652}, doi = {10.1080/21678421.2024.2346825}, pmid = {38666601}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Electric Stimulation Therapy/methods/instrumentation ; }, abstract = {Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment.}, }
@article {pmid38663103, year = {2024}, author = {Nozal, V and Fernández-Gómez, P and García-Rubia, A and Martínez-González, L and Cuevas, EP and Carro, E and Palomo, V and Martínez, A}, title = {Designing multitarget ligands for neurodegenerative diseases with improved permeability trough PLGA nanoencapsulation.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {175}, number = {}, pages = {116626}, doi = {10.1016/j.biopha.2024.116626}, pmid = {38663103}, issn = {1950-6007}, mesh = {*Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Ligands ; Humans ; *Blood-Brain Barrier/metabolism/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Permeability ; Nanoparticles/chemistry ; Drug Design ; Drug Compounding ; Amyloid beta-Peptides/metabolism ; Animals ; tau Proteins/metabolism ; }, abstract = {Multitarget ligands (MTLs) have emerged as an interesting alternative for addressing complex multifactorial pathologies such as neurodegenerative diseases. However, a common challenge associated with these compounds is often their high molecular weight and low solubility, which becomes a hurdle when trying to permeate over the blood-brain barrier (BBB). In this study, we have designed two new MTLs that modulate three pharmacological targets simultaneously (tau, beta-amyloid and TAR DNA-binding protein 43). To enhance their brain penetration, we have formulated organic polymeric nanoparticles using poly(lactic-co-glycolic acid). The characterization of the formulations, evaluation of their permeability through an in vitro BBB model, and assessment of their activity on disease-representative cellular models, such as Alzheimer's disease and amyotrophic lateral sclerosis, have been conducted. The results demonstrate the potential of the new MTLs and their nanoparticle encapsulation for the treatment of neurodegenerative diseases.}, }
@article {pmid38662766, year = {2024}, author = {Stikvoort García, DJL and Goedee, HS and van Eijk, RPA and van Schelven, LJ and van den Berg, LH and Sleutjes, BTHM}, title = {Revisiting distinct nerve excitability patterns in patients with amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {8}, pages = {2842-2853}, pmid = {38662766}, issn = {1460-2156}, support = {AV20180012//Dutch ALS Foundation/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Male ; Female ; Middle Aged ; Aged ; *Motor Neurons/physiology ; Adult ; Action Potentials/physiology ; Principal Component Analysis ; Axons/physiology ; Membrane Potentials/physiology ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease, characterized by loss of central and peripheral motor neurons. Although the disease is clinically and genetically heterogeneous, axonal hyperexcitability is a commonly observed feature that has been suggested to reflect an early pathophysiological step linked to the neurodegenerative cascade. Therefore, it is important to clarify the mechanisms causing axonal hyperexcitability and how these relate to the clinical characteristics of patients. Measures derived directly from a nerve excitability recording are frequently used as study end points, although their biophysical basis is difficult to deduce. Mathematical models can aid in the interpretation but are reliable only when applied to group-averaged recordings. Consequently, model estimates of membrane properties cannot be compared with clinical characteristics or treatment effects in individual patients, posing a considerable limitation in heterogeneous diseases, such as amyotrophic lateral sclerosis. To address these challenges, we revisited nerve excitability using a new pattern analysis-based approach (principal component analysis). We evaluated disease-specific patterns of excitability changes and established their biophysical origins. Based on the observed patterns, we developed new compound measures of excitability that facilitate the implementation of this approach in clinical settings. We found that excitability changes in amyotrophic lateral sclerosis patients (n = 161, median disease duration = 11 months) were characterized by four unique patterns compared with controls (n = 50, age and sex matched). These four patterns were best explained by changes in resting membrane potential (modulated by Na+/K+ currents), slow potassium and sodium currents (modulated by their gating kinetics) and refractory properties of the nerve. Consequently, we were able to show that altered gating of slow potassium channels was associated with, and predictive of, the rate of progression of the disease on the amyotrophic lateral sclerosis functional rating scale. Based on these findings, we designed four composite measures that capture these properties to facilitate implementation outside this study. Our findings demonstrate that changes in nerve excitability in patients with amyotrophic lateral sclerosis are dominated by four distinct patterns, each with a distinct biophysical origin. Based on this new approach, we provide evidence that altered slow potassium-channel function might play a role in the rate of disease progression. The magnitudes of these patterns, quantified using a similar approach or our new composite measures, have potential as efficient measures to study membrane properties directly in amyotrophic lateral sclerosis patients, and thus aid prognostic stratification and trial design.}, }
@article {pmid38661532, year = {2024}, author = {Li, A and Yi, J and Li, X and Dong, L and Ostrow, LW and Ma, J and Zhou, J}, title = {Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {38661532}, issn = {2050-084X}, support = {R01 NS105621/NS/NINDS NIH HHS/United States ; R01 AG071676/AG/NIA NIH HHS/United States ; R01NS105621/NH/NIH HHS/United States ; R01AG071676/NH/NIH HHS/United States ; R01NS129219/NH/NIH HHS/United States ; R01 NS129219/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Neuromuscular Junction/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Mice ; *Satellite Cells, Skeletal Muscle/metabolism ; *Disease Models, Animal ; *Transcriptome ; Mice, Transgenic ; Oculomotor Muscles/innervation/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder characterized by progressive weakness of almost all skeletal muscles, whereas extraocular muscles (EOMs) are comparatively spared. While hindlimb and diaphragm muscles of end-stage SOD1G93A (G93A) mice (a familial ALS mouse model) exhibit severe denervation and depletion of Pax7[+]satellite cells (SCs), we found that the pool of SCs and the integrity of neuromuscular junctions (NMJs) are maintained in EOMs. In cell sorting profiles, SCs derived from hindlimb and diaphragm muscles of G93A mice exhibit denervation-related activation, whereas SCs from EOMs of G93A mice display spontaneous (non-denervation-related) activation, similar to SCs from wild-type mice. Specifically, cultured EOM SCs contain more abundant transcripts of axon guidance molecules, including Cxcl12, along with more sustainable renewability than the diaphragm and hindlimb counterparts under differentiation pressure. In neuromuscular co-culture assays, AAV-delivery of Cxcl12 to G93A-hindlimb SC-derived myotubes enhances motor neuron axon extension and innervation, recapitulating the innervation capacity of EOM SC-derived myotubes. G93A mice fed with sodium butyrate (NaBu) supplementation exhibited less NMJ loss in hindlimb and diaphragm muscles. Additionally, SCs derived from G93A hindlimb and diaphragm muscles displayed elevated expression of Cxcl12 and improved renewability following NaBu treatment in vitro. Thus, the NaBu-induced transcriptomic changes resembling the patterns of EOM SCs may contribute to the beneficial effects observed in G93A mice. More broadly, the distinct transcriptomic profile of EOM SCs may offer novel therapeutic targets to slow progressive neuromuscular functional decay in ALS and provide possible 'response biomarkers' in pre-clinical and clinical studies.}, }
@article {pmid38655443, year = {2024}, author = {Zubair, AS and Saab, L and Scharer, K and Khokhar, B}, title = {Patients' experiences with methylcobalamin injections in amyotrophic lateral sclerosis.}, journal = {Brain circulation}, volume = {10}, number = {1}, pages = {60-66}, pmid = {38655443}, issn = {2455-4626}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with no definitive treatment. Vitamin B12 is not a Food and Drug Administration-approved treatment in the United States, although it has been prescribed off-label as ultra-high-dose methylcobalamin, which has been shown to be safe and effective in slowing functional decline in patients with ALS. This study evaluates the impact of Vitamin B12 injections on the quality of life of five patients.<br><br>METHODS: Semi-structured interviews were conducted with the patients and caregivers. The data was carefully read, coded, and organized into themes and sub-themes by two independent researchers.<br><br>RESULTS: The study found four themes and 11 subthemes from the data, including initial circumstances, administration of the injection, subjective experience with Vitamin B12, and outcomes and expectations. All participants recognized some benefits from Vitamin B12 injections, specifically increased energy, reduced fatigue, and improved balance. However, some patients had difficulty monitoring its specific effect due to the progressive nature of the disease.<br><br>DISCUSSION: The flexibility offered by this intervention is beneficial for patients with declining mobility and strength who wish to adapt their treatment to their schedule. This work is a modest call to fill the existing gap in the literature and push for more randomized controlled trials investigating and clarifying the effects of Vitamin B12 injections on disease progression, muscle function, and quality of life in a small but diverse pool of patients with ALS.}, }
@article {pmid38647433, year = {2024}, author = {Mousavi, H and Rimaz, M and Zeynizadeh, B}, title = {Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {9}, pages = {1828-1881}, doi = {10.1021/acschemneuro.4c00055}, pmid = {38647433}, issn = {1948-7193}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Molecular Docking Simulation/methods ; Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; Heterocyclic Compounds, 2-Ring/pharmacology/chemical synthesis/chemistry ; Structure-Activity Relationship ; }, abstract = {Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome and (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a-h), and hydrazine monohydrate (NH2NH2•H2O) for the regioselective preparation of some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a-h). After synthesis and characterization of the mentioned cinnolines (3a-h), the in silico multi-targeting inhibitory properties of these heterocyclic scaffolds have been investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2[(G2019S)], hGSK-3β, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, and hDHODH, which have confirmed their functions and roles in the neurodegenerative diseases (NDs), based on molecular docking studies, and the obtained results were compared with a wide range of approved drugs and well-known (with IC50, EC50, etc.) compounds. In addition, in silico ADMET prediction analysis was performed to examine the prospective drug properties of the synthesized heterocyclic compounds (3a-h). The obtained results from the molecular docking studies and ADMET-related data demonstrated that these series of 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines (3a-h), especially hit ones, can really be turned into the potent core of new drugs for the treatment of neurodegenerative diseases (NDs), and/or due to the having some reactionable locations, they are able to have further organic reactions (such as cross-coupling reactions), and expansion of these compounds (for example, with using other types of aryl(or heteroaryl)glyoxal monohydrates) makes a new avenue for designing novel and efficient drugs for this purpose.}, }
@article {pmid38646691, year = {2024}, author = {Flynn, MB and Flynn, JF and Palacios, AM}, title = {Capitalizing on Hope: Questionable Marketing Approval and Pricing of a New ALS Drug.}, journal = {International journal of social determinants of health and health services}, volume = {54}, number = {4}, pages = {405-411}, doi = {10.1177/27551938241247778}, pmid = {38646691}, issn = {2755-1946}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/economics ; Humans ; *Drug Approval ; United States ; United States Food and Drug Administration ; Cost-Benefit Analysis ; }, abstract = {Regulatory agencies must balance patient demands to access new treatments for fatal diseases with limited treatment options while ensuring drug safety and efficacy. However, questionable U.S. regulatory actions resulted in the early approval of AMX0035 to treat amyotrophic lateral sclerosis (ALS) by reconvening advisory commissions to obtain positive decisions and designating the drug as a new molecular entity. Data from one randomized clinical trial suggests minimal delays in disease progression and longer survivability, but debate remains about the lack of confirmatory evidence of effectiveness owing to study limitations. A patient's decision-making process details the experience of using the drug, including perspectives on access, cost, effectiveness, and adverse effects. In line with the "nichebuster" business model, the drugmaker, Amylyx Pharmaceuticals, is charging US$158,000/year/patient and thus forecast to turn a profit on a drug with debatable clinical effectiveness prior to completing a Phase 3 trial. Early marketing approval, despite community demands, is unnecessary and may have reduced access because of the end of a compassionate use program, and the high price tag results in restricted coverage and high out-of-pocket costs. Also, the drug's key ingredients are available as a generic and a supplement.}, }
@article {pmid38644578, year = {2024}, author = {Yao, Q and Long, C and Yi, P and Zhang, G and Wan, W and Rao, X and Ying, J and Liang, W and Hua, F}, title = {C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {30}, number = {4}, pages = {e14721}, pmid = {38644578}, issn = {1755-5949}, support = {jxsq2019201023//Jiangxi Province "Double Thousand Plan"/ ; 82060219//National Natural Science Foundation of China/ ; 82271234//National Natural Science Foundation of China/ ; 20212ACB216009//Natural Science Foundation of Jiangxi Province/ ; 20212BAB216048//Natural Science Foundation of Jiangxi Province/ ; 2019YNTD12003//Youth Team Project of the Second Affiliated Hospital of Nanchang University/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *CCAAT-Enhancer-Binding Protein-beta/metabolism/genetics ; *Disease Progression ; Animals ; Amyloid beta-Peptides/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment.<br><br>AIMS: Several studies have demonstrated an elevation in the expression level of C/EBP&#x3b2; among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBP&#x3b2; expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBP&#x3b2; can be a new therapeutic target for AD.<br><br>METHODS: A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded.<br><br>RESULTS: Overexpression of C/EBP&#x3b2; exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including &#x3b4;-secretase, apolipoprotein E4 (APOE4), acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO).<br><br>DISCUSSION: The correlation between overexpression of C/EBP&#x3b2; and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBP&#x3b2; regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBP&#x3b2; overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS).<br><br>CONCLUSION: The overexpression of C/EBP&#x3b2; accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBP&#x3b2; plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBP&#x3b2; could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.}, }
@article {pmid38630299, year = {2024}, author = {Wolff, A and Demleitner, AF and Feneberg, E and Lingor, P}, title = {[Smell the smoke before one sees the fire-The oligosymptomatic prodromal phase of neurodegenerative diseases].}, journal = {Der Nervenarzt}, volume = {95}, number = {8}, pages = {689-696}, pmid = {38630299}, issn = {1433-0407}, mesh = {*Neurodegenerative Diseases/diagnosis ; *Prodromal Symptoms ; Humans ; *Early Diagnosis ; *Biomarkers/blood ; Disease Progression ; }, abstract = {BACKGROUND: With the increasing development of disease-modifying causative treatment, the importance of early diagnosis and detection of asymptomatic or oligosymptomatic early stages of neurodegenerative diseases is increasing.<br><br>OBJECTIVE: Presentation of early stages of neurodegenerative diseases, diagnostic procedures for the early detection and possible treatment consequences.<br><br>MATERIAL AND METHODS: Selective literature search, discussion of basic research and expert recommendations.<br><br>RESULTS: Many neurodegenerative diseases have a&#xa0;prodromal phase preceding the manifest disease that can be diagnosed with current criteria. In this prodromal phase, those affected are often oligosymptomatic but in some cases can already be identified using biomarkers. These developments are already taken into account in diagnostic criteria for some of these prodromal phases. The prodromal phase, in turn, is preceded by an asymptomatic phase which, however, already shows molecular changes and can be identified by biomarkers in some diseases. The early identification and stratification of patients is particularly important when planning studies for disease-modifying treatment, and biomarkers are already being used in clinical trials for this purpose.<br><br>DISCUSSION: Biomarker-based identification of individuals in the prodromal phase of neurodegenerative diseases is already possible for some entities. People who show the first signs of a&#xa0;neurodegenerative disease can be referred to centers for clinical trials and observational studies.}, }
@article {pmid38623278, year = {2024}, author = {Inci, OK and Basırlı, H and Can, M and Yanbul, S and Seyrantepe, V}, title = {Gangliosides as Therapeutic Targets for Neurodegenerative Diseases.}, journal = {Journal of lipids}, volume = {2024}, number = {}, pages = {4530255}, pmid = {38623278}, issn = {2090-3030}, abstract = {Gangliosides, sialic acid-containing glycosphingolipids, are abundant in cell membranes and primarily involved in controlling cell signaling and cell communication. The altered ganglioside pattern has been demonstrated in several neurodegenerative diseases, characterized during early-onset or infancy, emphasizing the significance of gangliosides in the brain. Enzymes required for the biosynthesis of gangliosides are linked to several devastating neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP). In this review, we summarized not only the critical roles of biosynthetic enzymes and their inhibitors in ganglioside metabolism but also the efficacy of treatment strategies of ganglioside to address their significance in those diseases.}, }
@article {pmid38621743, year = {2024}, author = {Rezvykh, A and Shteinberg, D and Bronovitsky, E and Ustyugov, A and Funikov, S}, title = {Animal Models of FUS-Proteinopathy: A Systematic Review.}, journal = {Biochemistry. Biokhimiia}, volume = {89}, number = {Suppl 1}, pages = {S34-S56}, doi = {10.1134/S0006297924140037}, pmid = {38621743}, issn = {1608-3040}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; RNA-Binding Protein FUS/genetics/metabolism ; Motor Neurons/metabolism/pathology ; Cytoplasm/metabolism ; Mutation ; Disease Models, Animal ; }, abstract = {Mutations that disrupt the function of the DNA/RNA-binding protein FUS could cause amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. One of the key features in ALS pathogenesis is the formation of insoluble protein aggregates containing aberrant isoforms of the FUS protein in the cytoplasm of upper and lower motor neurons. Reproduction of human pathology in animal models is the main tool for studying FUS-associated pathology and searching for potential therapeutic agents for ALS treatment. In this review, we provide a systematic analysis of the role of FUS protein in ALS pathogenesis and an overview of the results of modelling FUS-proteinopathy in animals.}, }
@article {pmid38614367, year = {2024}, author = {Roghani, AK and Garcia, RI and Roghani, A and Reddy, A and Khemka, S and Reddy, RP and Pattoor, V and Jacob, M and Reddy, PH and Sehar, U}, title = {Treating Alzheimer's disease using nanoparticle-mediated drug delivery strategies/systems.}, journal = {Ageing research reviews}, volume = {97}, number = {}, pages = {102291}, doi = {10.1016/j.arr.2024.102291}, pmid = {38614367}, issn = {1872-9649}, support = {R01 AG069333/AG/NIA NIH HHS/United States ; RF1 AG079264/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Drug Delivery Systems/methods ; Animals ; *Blood-Brain Barrier/drug effects/metabolism ; *Nanoparticles/administration &amp; dosage ; Nanoparticle Drug Delivery System ; }, abstract = {The administration of promising medications for the treatment of neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) is significantly hampered by the blood-brain barrier (BBB). Nanotechnology has recently come to light as a viable strategy for overcoming this obstacle and improving drug delivery to the brain. With a focus on current developments and prospects, this review article examines the use of nanoparticles to overcome the BBB constraints to improve drug therapy for AD The potential for several nanoparticle-based approaches, such as those utilizing lipid-based, polymeric, and inorganic nanoparticles, to enhance drug transport across the BBB are highlighted. To shed insight on their involvement in aiding effective drug transport to the brain, methods of nanoparticle-mediated drug delivery, such as surface modifications, functionalization, and particular targeting ligands, are also investigated. The article also discusses the most recent findings on innovative medication formulations encapsulated within nanoparticles and the therapeutic effects they have shown in both preclinical and clinical testing. This sector has difficulties and restrictions, such as the need for increased safety, scalability, and translation to clinical applications. However, the major emphasis of this review aims to provide insight and contribute to the knowledge of how nanotechnology can potentially revolutionize the worldwide treatment of NDDs, particularly AD, to enhance clinical outcomes.}, }
@article {pmid38612804, year = {2024}, author = {Giri, PM and Banerjee, A and Ghosal, A and Layek, B}, title = {Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications.}, journal = {International journal of molecular sciences}, volume = {25}, number = {7}, pages = {}, pmid = {38612804}, issn = {1422-0067}, support = {P20 GM109024/GM/NIGMS NIH HHS/United States ; 2P20M109024/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Neuroinflammatory Diseases ; Inflammation/therapy ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; Central Nervous System ; }, abstract = {Neurodegenerative disorders (NDs) have become increasingly common during the past three decades. Approximately 15% of the total population of the world is affected by some form of NDs, resulting in physical and cognitive disability. The most common NDs include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although NDs are caused by a complex interaction of genetic, environmental, and lifestyle variables, neuroinflammation is known to be associated with all NDs, often leading to permanent damage to neurons of the central nervous system. Furthermore, numerous emerging pieces of evidence have demonstrated that inflammation not only supports the progression of NDs but can also serve as an initiator. Hence, various medicines capable of preventing or reducing neuroinflammation have been investigated as ND treatments. While anti-inflammatory medicine has shown promising benefits in several preclinical models, clinical outcomes are often questionable. In this review, we discuss various NDs with their current treatment strategies, the role of neuroinflammation in the pathophysiology of NDs, and the use of anti-inflammatory agents as a potential therapeutic option.}, }
@article {pmid38610192, year = {2024}, author = {Papadopoulou, M and Papapostolou, A and Dimakopoulos, R and Salakou, S and Koropouli, E and Fanouraki, S and Bakola, E and Moschovos, C and Tsivgoulis, G}, title = {Non-Pharmacological Interventions on Pain in Amyotrophic Lateral Sclerosis Patients: A Systematic Review and Meta-Analysis.}, journal = {Healthcare (Basel, Switzerland)}, volume = {12}, number = {7}, pages = {}, pmid = {38610192}, issn = {2227-9032}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motor neurons. Some ALS patients exhibit concomitant nonmotor signs; thus, ALS is considered a multisystemic disorder. Pain is an important nonmotor symptom. Observational and case-control studies report high frequency of pain in ALS patients and it has been correlated with depression and quality of life. There are no specific scales for the assessment of pain and no randomized controlled trials (RCTs) regarding the drug management of pain in ALS.<br><br>AIM: To systematically review the evidence for the nonpharmacological interventions (NPIs) in relieving pain in ALS, on March 2024, we searched the following databases: Pubmed, Scopus, Web of Science, and Cochrane. We also checked the bibliographies of trials identified to include further published or unpublished trials.<br><br>MAIN RESULTS: A total of 1003 records were identified. Finally, five RCTs including 131 patients (64 in the intervention group and 67 in the control group) were included for meta-analysis. The interventions of the included RCTs consisted of muscle exercise, combined aerobics-strength intervention, and osteopathic manual treatment. The meta-analysis did not find a statistically significant difference in favor of NPIs for alleviating pain in ALS patients.<br><br>CONCLUSIONS: ALS has a fulminant course and irreversibly leads to death. Pain in ALS patients, although a common nonmotor symptom, is often unrecognized and undertreated, and this is underlined by the lack of any RCTs on drug therapy for pain. Albeit NPIs are considered safe, as adverse effects are rarely reported, this systematic review did not provide sufficient evidence for a beneficial effect on pain. The scarceness of relevant literature highlights the need for future studies, with larger samples, more homogeneous in terms of interventions and population characteristics (stage of disease), and better choice of measurement scales to further investigate the efficacy, if any, of various pain interventions in ALS patients.}, }
@article {pmid38610012, year = {2024}, author = {Liu, X and Shen, L and Wan, M and Xie, H and Wang, Z}, title = {Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles.}, journal = {Journal of nanobiotechnology}, volume = {22}, number = {1}, pages = {170}, pmid = {38610012}, issn = {1477-3155}, support = {82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 2020YFC2008500//National Key R&amp;D Program of China/ ; }, mesh = {Humans ; Prospective Studies ; *Extracellular Vesicles ; *Exosomes ; *Parkinson Disease ; *Alzheimer Disease ; }, abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis epitomize a class of insidious and relentless neurological conditions that are difficult to cure. Conventional therapeutic regimens often fail due to the late onset of symptoms, which occurs well after irreversible neurodegeneration has begun. The integrity of the blood-brain barrier (BBB) further impedes efficacious drug delivery to the central nervous system, presenting a formidable challenge in the pharmacological treatment of NDDs. Recent scientific inquiries have shifted focus toward the peripheral biological systems, investigating their influence on central neuropathology through the lens of extracellular vesicles (EVs). These vesicles, distinguished by their ability to breach the BBB, are emerging as dual operatives in the context of NDDs, both as conveyors of pathogenic entities and as prospective vectors for therapeutic agents. This review critically summarizes the burgeoning evidence on the role of extracerebral EVs, particularly those originating from bone, adipose tissue, and gut microbiota, in modulating brain pathophysiology. It underscores the duplicity potential of peripheral EVs as modulators of disease progression and suggests their potential as novel vehicles for targeted therapeutic delivery, positing a transformative impact on the future landscape of NDD treatment strategies. Search strategy A comprehensive literature search was conducted using PubMed, Web of Science, and Scopus from January 2000 to December 2023. The search combined the following terms using Boolean operators: "neurodegenerative disease" OR "Alzheimer's disease" OR "Parkinson's disease" OR "Amyotrophic lateral sclerosis" AND "extracellular vesicles" OR "exosomes" OR "outer membrane vesicles" AND "drug delivery systems" AND "blood-brain barrier". MeSH terms were employed when searching PubMed to refine the results. Studies were included if they were published in English, involved human subjects, and focused on the peripheral origins of EVs, specifically from bone, adipose tissue, and gut microbiota, and their association with related diseases such as osteoporosis, metabolic syndrome, and gut dysbiosis. Articles were excluded if they did not address the role of EVs in the context of NDDs or did not discuss therapeutic applications. The titles and abstracts of retrieved articles were screened using a dual-review process to ensure relevance and accuracy. The reference lists of selected articles were also examined to identify additional relevant studies.}, }
@article {pmid38609644, year = {2024}, author = {Khalil, M and Teunissen, CE and Lehmann, S and Otto, M and Piehl, F and Ziemssen, T and Bittner, S and Sormani, MP and Gattringer, T and Abu-Rumeileh, S and Thebault, S and Abdelhak, A and Green, A and Benkert, P and Kappos, L and Comabella, M and Tumani, H and Freedman, MS and Petzold, A and Blennow, K and Zetterberg, H and Leppert, D and Kuhle, J}, title = {Neurofilaments as biomarkers in neurological disorders - towards clinical application.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {5}, pages = {269-287}, pmid = {38609644}, issn = {1759-4766}, mesh = {Humans ; *Biomarkers/metabolism/blood ; *Intermediate Filaments/metabolism ; *Nervous System Diseases/diagnosis/metabolism/blood ; *Neurofilament Proteins/blood/metabolism ; }, abstract = {Neurofilament proteins have been validated as specific body fluid biomarkers of neuro-axonal injury. The advent of highly sensitive analytical platforms that enable reliable quantification of neurofilaments in blood samples and simplify longitudinal follow-up has paved the way for the development of neurofilaments as a biomarker in clinical practice. Potential applications include assessment of disease activity, monitoring of treatment responses, and determining prognosis in many acute and chronic neurological disorders as well as their use as an outcome measure in trials of novel therapies. Progress has now moved the measurement of neurofilaments to the doorstep of routine clinical practice for the evaluation of individuals. In this Review, we first outline current knowledge on the structure and function of neurofilaments. We then discuss analytical and statistical approaches and challenges in determining neurofilament levels in different clinical contexts and assess the implications of neurofilament light chain (NfL) levels in normal ageing and the confounding factors that need to be considered when interpreting NfL measures. In addition, we summarize the current value and potential clinical applications of neurofilaments as a biomarker of neuro-axonal damage in a range of neurological disorders, including multiple sclerosis, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, stroke and cerebrovascular disease, traumatic brain injury, and Parkinson disease. We also consider the steps needed to complete the translation of neurofilaments from the laboratory to the management of neurological diseases in clinical practice.}, }
@article {pmid38606777, year = {2024}, author = {Babu, S and Nicholson, KA and Rothstein, JD and Swenson, A and Sampognaro, PJ and Pant, P and Macklin, EA and Spruill, S and Paganoni, S and Gendron, TF and Prudencio, M and Petrucelli, L and Nix, D and Landrette, S and Nkrumah, E and Fandrick, K and Edwards, J and Young, PR}, title = {Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {9}, pages = {2998-3008}, doi = {10.1093/brain/awae109}, pmid = {38606777}, issn = {1460-2156}, support = {//OrphAI Therapeutics/ ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Double-Blind Method ; Adult ; Aged ; *C9orf72 Protein/genetics ; Pyrazoles/therapeutic use/pharmacokinetics ; Treatment Outcome ; Biomarkers/blood ; Hydrazones ; Morpholines ; Pyrimidines ; }, abstract = {Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured. Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by >2.5-fold (P < 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P < 0.001), indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.}, }
@article {pmid38603949, year = {2024}, author = {Shin-Yi Lin, C and Howells, J and Rutkove, S and Nandedkar, S and Neuwirth, C and Noto, YI and Shahrizaila, N and Whittaker, RG and Bostock, H and Burke, D and Tankisi, H}, title = {Neurophysiological and imaging biomarkers of lower motor neuron dysfunction in motor neuron diseases/amyotrophic lateral sclerosis: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {162}, number = {}, pages = {91-120}, doi = {10.1016/j.clinph.2024.03.015}, pmid = {38603949}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; *Motor Neurons/physiology ; *Motor Neuron Disease/physiopathology/diagnostic imaging/diagnosis ; *Biomarkers ; *Electromyography/methods ; *Neural Conduction/physiology ; }, abstract = {This chapter discusses comprehensive neurophysiological biomarkers utilised in motor neuron disease (MND) and, in particular, its commonest form, amyotrophic lateral sclerosis (ALS). These encompass the conventional techniques including nerve conduction studies (NCS), needle and high-density surface electromyography (EMG) and H-reflex studies as well as novel techniques. In the last two decades, new methods of assessing the loss of motor units in a muscle have been developed, that are more convenient than earlier methods of motor unit number estimation (MUNE),and may use either electrical stimulation (e.g. MScanFit MUNE) or voluntary activation (MUNIX). Electrical impedance myography (EIM) is another novel approach for the evaluation that relies upon the application and measurement of high-frequency, low-intensity electrical current. Nerve excitability techniques (NET) also provide insights into the function of an axon and reflect the changes in resting membrane potential, ion channel dysfunction and the structural integrity of the axon and myelin sheath. Furthermore, imaging ultrasound techniques as well as magnetic resonance imaging are capable of detecting the constituents of morphological changes in the nerve and muscle. The chapter provides a critical description of the ability of each technique to provide neurophysiological insight into the complex pathophysiology of MND/ALS. However, it is important to recognise the strengths and limitations of each approach in order to clarify utility. These neurophysiological biomarkers have demonstrated reliability, specificity and provide additional information to validate and assess lower motor neuron dysfunction. Their use has expanded the knowledge about MND/ALS and enhanced our understanding of the relationship between motor units, axons, reflexes and other neural circuits in relation to clinical features of patients with MND/ALS at different stages of the disease. Taken together, the ultimate goal is to aid early diagnosis, distinguish potential disease mimics, monitor and stage disease progression, quantify response to treatment and develop potential therapeutic interventions.}, }
@article {pmid38601118, year = {2024}, author = {Patel, GD and Liu, L and Li, A and Yang, YH and Shen, CC and Brand-Saberi, B and Yang, X}, title = {Mesenchymal stem cell-based therapies for treating well-studied neurological disorders: a systematic review.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1361723}, pmid = {38601118}, issn = {2296-858X}, abstract = {BACKGROUND: Millions of people across the globe are affected by conditions like Amyotrophic Lateral Sclerosis (ALS), Parkinson's Disease (PD), Multiple Sclerosis (MS), Spinal Cord Injury (SCI), and Traumatic Brain Injury (TBI), although most occurrences are common in the elderly population. This systematic review aims to highlight the safety of the procedures, their tolerability, and efficacy of the available therapies conducted over the years using mesenchymal stem cells (MSCs) in treating the neurological conditions mentioned above.<br><br>METHODS: PubMed was used to search for published data from clinical trials performed using mesenchymal stem cells. Studies that provided the necessary information that mentioned the efficacy and adverse effects of the treatment in patients were considered for this review.<br><br>RESULTS: In total, 43 manuscripts were selected after a strategic search, and these studies have been included in this systematic review. Most included studies reported the safety of the procedures used and the treatment's good tolerability, with mild adverse events such as fever, headache, mild pain at the injection site, or nausea being common. A few studies also reported death of some patients, attributed to the progression of the disease to severe stages before the treatment. Other severe events, such as respiratory or urinary infections reported in some studies, were not related to the treatment. Different parameters were used to evaluate the efficacy of the treatment based on the clinical condition of the patient.<br><br>CONCLUSION: Mesenchymal stem cells transplantation has so far proven to be safe and tolerable in select studies and patient types. This systematic review includes the results from the 43 selected studies in terms of safety and tolerability of the procedures, and several adverse events and therapeutic benefits during the follow-up period after administration of MSCs.}, }
@article {pmid38600725, year = {2024}, author = {Madhubala, D and Patra, A and Khan, MR and Mukherjee, AK}, title = {Phytomedicine for neurodegenerative diseases: The road ahead.}, journal = {Phytotherapy research : PTR}, volume = {38}, number = {6}, pages = {2993-3019}, doi = {10.1002/ptr.8192}, pmid = {38600725}, issn = {1099-1573}, support = {//IASST/ ; EMR/2017/001829//Science and Engineering Research Board/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Catechin/analogs &amp; derivatives/therapeutic use/pharmacology ; *Phytotherapy ; Curcumin/therapeutic use/pharmacology ; Quercetin/pharmacology/therapeutic use ; Animals ; Cannabinoids/therapeutic use/pharmacology ; Apigenin/pharmacology/therapeutic use ; Blood-Brain Barrier/drug effects ; Phytochemicals/pharmacology/therapeutic use ; Plant Extracts/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative disorders (NDs) are among the most common causes of death across the globe. NDs are characterized by progressive damage to CNS neurons, leading to defects in specific brain functions such as memory, cognition, and movement. The most common NDs are Parkinson's, Alzheimer's, Huntington's, and amyotrophic lateral sclerosis (ALS). Despite extensive research, no therapeutics or medications against NDs have been proven to be effective. The current treatment of NDs involving symptom-based targeting of the disease pathogenesis has certain limitations, such as drug resistance, adverse side effects, poor blood-brain barrier permeability, and poor bioavailability of drugs. Some studies have shown that plant-derived natural compounds hold tremendous promise for treating and preventing NDs. Therefore, the primary objective of this review article is to critically analyze the properties and potency of some of the most studied phytomedicines, such as quercetin, curcumin, epigallocatechin gallate (EGCG), apigenin, and cannabinoids, and highlight their advantages and limitations for developing next-generation alternative treatments against NDs. Further extensive research on pre-clinical and clinical studies for developing plant-based drugs against NDs from bench to bedside is warranted.}, }
@article {pmid38600555, year = {2024}, author = {Liu, Y and Yan, D and Yang, L and Chen, X and Hu, C and Chen, M}, title = {Stathmin 2 is a potential treatment target for TDP-43 proteinopathy in amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {20}, pmid = {38600555}, issn = {2047-9158}, support = {2023A1515010477//Guangdong Basic and Applied Basic Research Foundation/ ; 32000690//National Natural Science Foundation of China/ ; 2019B030335001//The Key-Area Research and Development Program of Guangdong Province,China/ ; 2023-Z04-103//The Key Medical and Health Projects of Panyu District Science and Technology Plan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; DNA-Binding Proteins/genetics ; *Stathmin/antagonists &amp; inhibitors ; *TDP-43 Proteinopathies/drug therapy ; }, }
@article {pmid38596495, year = {2024}, author = {Dirjayanto, VJ and Audrey, J and Simadibrata, DM}, title = {Vonoprazan-amoxicillin dual regimen with Saccharomyces boulardii as a rescue therapy for Helicobacter pylori: Current perspectives and implications.}, journal = {World journal of gastroenterology}, volume = {30}, number = {10}, pages = {1280-1286}, pmid = {38596495}, issn = {2219-2840}, mesh = {Humans ; Amoxicillin/therapeutic use ; Anti-Bacterial Agents/adverse effects ; *Helicobacter pylori ; *Saccharomyces boulardii ; *Helicobacter Infections/drug therapy ; Clarithromycin/therapeutic use ; Drug Therapy, Combination ; Proton Pump Inhibitors/adverse effects ; H(+)-K(+)-Exchanging ATPase ; Ions/pharmacology/therapeutic use ; Treatment Outcome ; *Pyrroles ; *Sulfonamides ; }, abstract = {Yu et al's study in the World Journal of Gastroenterology (2023) introduced a novel regimen of Vonoprazan-amoxicillin dual therapy combined with Saccharomyces boulardii (S. boulardii) for the rescue therapy against Helicobacter pylori (H. pylori), a pathogen responsible for peptic ulcers and gastric cancer. Vonoprazan is a potassium-competitive acid blocker renowned for its rapid and long-lasting acid suppression, which is minimally affected by mealtime. Compared to proton pump inhibitors, which bind irreversibly to cysteine residues in the H[+]/K[+]-ATPase pump, Vonoprazan competes with the K[+] ions, prevents the ions from binding to the pump and blocks acid secretion. Concerns with increasing antibiotic resistance, effects on the gut microbiota, patient compliance, and side effects have led to the advent of a dual regimen for H. pylori. Previous studies suggested that S. boulardii plays a role in stabilizing the gut barrier which improves H. pylori eradication rate. With an acceptable safety profile, the dual-adjunct regimen was effective regardless of prior treatment failure and antibiotic resistance profile, thereby strengthening the applicability in clinical settings. Nonetheless, S. boulardii comes in various formulations and dosages, warranting further exploration into the optimal dosage for supplementation in rescue therapy. Additionally, larger, randomized, double-blinded controlled trials are warranted to confirm these promising results.}, }
@article {pmid38596406, year = {2024}, author = {Tanaka, Y and Kozuma, L and Hino, H and Takeya, K and Eto, M}, title = {Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic flux.}, journal = {Biochemistry and biophysics reports}, volume = {38}, number = {}, pages = {101705}, pmid = {38596406}, issn = {2405-5808}, abstract = {(Macro)autophagy is a cellular degradation system for unnecessary materials, such as aggregate-prone TDP-43, a central molecule in neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Abemaciclib (Abe) and vacuolin-1 (Vac) treatments are known to induce vacuoles characterized by an autophagosome and a lysosome component, suggesting that they facilitate autophagosome-lysosome fusion. However, it remains unknown whether Abe and Vac suppress the accumulation of aggregate-prone TDP-43 by accelerating autophagic flux. In the present study, the Abe and Vac treatment dose-dependently reduced the GFP/RFP ratio in SH-SY5Y neuroblastoma cells stably expressing the autophagic flux marker GFP-LC3-RFP-LC3ΔG. Abe and Vac also increased the omegasome marker GFP-ATG13 signal and the autophagosome marker mCherry-LC3 localized to the lysosome marker LAMP1-GFP. The Abe and Vac treatment decreased the intracellular level of the lysosome marker LAMP1-GFP in SH-SY5Y cells stably expressing LAMP1-GFP, but did not increase the levels of LAMP1-GFP, the autophagosome marker LC3-II, or the multivesicular body marker TSG101 in the extracellular vesicle-enriched fraction. Moreover, Abe and Vac treatment autophagy-dependently inhibited GFP-tagged aggregate-prone TDP-43 accumulation. The results of a PI(3)P reporter assay using the fluorescent protein tagged-2 × FYVE and LAMP1-GFP indicated that Abe and Vac increased the intensity of the PI(3)P signal on lysosomes. A treatment with the VPS34 inhibitor wortmannin (WM) suppressed Abe-/Vac-facilitated autophagic flux and the degradation of GFP-tagged aggregate-prone TDP-43. Collectively, these results suggest that Abe and Vac degrade aggregate-prone TDP-43 by accelerating autophagosome formation and autophagosome-lysosome fusion through the formation of PI(3)P.}, }
@article {pmid38593477, year = {2024}, author = {Lindborg, SR and Goyal, NA and Katz, J and Burford, M and Li, J and Kaspi, H and Abramov, N and Boulanger, B and Berry, JD and Nicholson, K and Mozaffar, T and Miller, R and Jenkins, L and Baloh, RH and Lewis, R and Staff, NP and Owegi, MA and Dagher, B and Blondheim-Shraga, NR and Gothelf, Y and Levy, YS and Kern, R and Aricha, R and Windebank, AJ and Bowser, R and Brown, RH and Cudkowicz, ME}, title = {Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes.}, journal = {Muscle &amp; nerve}, volume = {69}, number = {6}, pages = {719-729}, doi = {10.1002/mus.28093}, pmid = {38593477}, issn = {1097-4598}, support = {//California Institute for Regenerative Medicine/ ; //I AM ALS/ ; //ALS Association/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/drug therapy/diagnosis ; *Biomarkers/cerebrospinal fluid ; Double-Blind Method ; *Neurofilament Proteins/cerebrospinal fluid ; Treatment Outcome ; }, abstract = {INTRODUCTION/AIMS: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint.<br><br>METHODS: A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty-five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale-Revised (ALSFRS-R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS-R.<br><br>RESULTS: We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel-treated participants (baseline NfL, baseline latency-associated peptide/transforming growth factor beta1 [LAP/TGF&#x3b2;1], change galectin-1, all p&#x2009;<&#x2009;.01), with baseline NfL and LAP/TGF&#x3b2;1 remaining (p&#x2009;<&#x2009;.05) when disease characteristics (p&#x2009;<&#x2009;.005) were incorporated. Change from baseline to the last measurement showed debamestrocel-driven reductions in NfL were associated with less decline in ALSFRS-R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p&#x2009;=&#x2009;.037).<br><br>DISCUSSION: Following debamestrocel treatment, many biomarkers showed increases (anti-inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed.}, }
@article {pmid38585774, year = {2024}, author = {Yu, M and Xu, J and Dutta, R and Trapp, B and Pieper, AA and Cheng, F}, title = {Network medicine informed multi-omics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38585774}, issn = {2692-8205}, support = {R21 AG083003/AG/NIA NIH HHS/United States ; R01 AG082118/AG/NIA NIH HHS/United States ; R56 AG074001/AG/NIA NIH HHS/United States ; RF1 AG082211/AG/NIA NIH HHS/United States ; R01 AG084250/AG/NIA NIH HHS/United States ; RF1 NS133812/NS/NINDS NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; R01 AG066707/AG/NIA NIH HHS/United States ; R01 AG076448/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. To date, the challenge to establishing effective treatment for ALS remains formidable, partly due to inadequate translation of existing human genetic findings into actionable ALS-specific pathobiology for subsequent therapeutic development. This study evaluates the feasibility of network medicine methodology via integrating human brain-specific multi-omics data to prioritize drug targets and repurposable treatments for ALS. Using human brain-specific genome-wide quantitative trait loci (x-QTLs) under a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in various known ALS pathobiological pathways, including regulation of T cell activation, monocyte differentiation, and lymphocyte proliferation. Specifically, we leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on brain-specific expression quantitative trait loci (QTL) (eQTL), protein QTLs (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Applying network proximity analysis of predicted ALS-associated gene-coding targets and existing drug-target networks under the human protein-protein interactome (PPI) model, we identified a set of potential repurposable drugs (including Diazoxide, Gefitinib, Paliperidone, and Dimethyltryptamine) for ALS. Subsequent validation established preclinical and clinical evidence for top-prioritized repurposable drugs. In summary, we presented a network-based multi-omics framework to identify potential drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.}, }
@article {pmid38585517, year = {2023}, author = {Firstenfeld, AJ and Listorti, J and Jalaff, N and Loaiza Orozco, CP and Navarrete Gosdenovich, F and Schurr, T}, title = {Add-on treatment with Cerebrolysin improves clinical symptoms in patients with ALS: results from a prospective, single-center, placebo-controlled, randomized, double-blind, phase II study.}, journal = {Journal of medicine and life}, volume = {16}, number = {12}, pages = {1750-1755}, pmid = {38585517}, issn = {1844-3117}, mesh = {Humans ; *Amino Acids ; *Amyotrophic Lateral Sclerosis/drug therapy/diagnosis ; *Neuroprotective Agents/therapeutic use ; Prospective Studies ; Riluzole/therapeutic use ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and progressive neurodegenerative disease with limited treatment options available. Cerebrolysin is a drug candidate for the treatment of ALS because of its neuroprotective and neuroregenerative effects. We initiated a pilot clinical study of a combination of Cerebrolysin and riluzole to assess the therapeutic benefit of Cerebrolysin as an add-on treatment on clinical signs and symptoms in outpatients with ALS. Twenty patients with a clinically definitive diagnosis of ALS were enrolled and randomly assigned in a 1:1 ratio to receive Cerebrolysin or placebo. All patients received 50 mg of riluzole PO twice daily as a standard treatment. Patients in the Cerebrolysin group received intravenous injections of 10 mL of Cerebrolysin once daily, five days a week for the first month and three days a week for the next two months. Analysis of the ALS Functional Rating Scale - revised at Month 1 (primary outcome measure), showed a significant treatment effect in favor of Cerebrolysin with a 2.3-point improvement from baseline to Month 1 compared to a 0.9-point decrease in patients on placebo (P=0.005). The effect was maintained over the three-month study period, and the beneficial effect of Cerebrolysin over placebo was also evident in the secondary outcome measures. The safety analysis showed that the combination of riluzole and Cerebrolyisn was well tolerated. Our results demonstrate for the first time a significant clinical effect of Cerebrolysin in improving functional outcomes in patients with ALS and suggest that Cerebrolysin has potential as a novel therapeutic option for ALS.}, }
@article {pmid38582030, year = {2024}, author = {van Unnik, JWJ and Meyjes, M and Janse van Mantgem, MR and van den Berg, LH and van Eijk, RPA}, title = {Remote monitoring of amyotrophic lateral sclerosis using wearable sensors detects differences in disease progression and survival: a prospective cohort study.}, journal = {EBioMedicine}, volume = {103}, number = {}, pages = {105104}, pmid = {38582030}, issn = {2352-3964}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis/physiopathology ; Male ; Female ; *Disease Progression ; *Wearable Electronic Devices ; Middle Aged ; Prospective Studies ; Aged ; Accelerometry/instrumentation ; Prognosis ; Remote Sensing Technology/instrumentation/methods ; Adult ; }, abstract = {BACKGROUND: There is an urgent need for objective and sensitive measures to quantify clinical disease progression and gauge the response to treatment in clinical trials for amyotrophic lateral sclerosis (ALS). Here, we evaluate the ability of an accelerometer-derived outcome to detect differential clinical disease progression and assess its longitudinal associations with overall survival in patients with ALS.<br><br>METHODS: Patients with ALS wore an accelerometer on the hip for 3-7 days, every 2-3 months during a multi-year observation period. An accelerometer-derived outcome, the Vertical Movement Index (VMI), was calculated, together with predicted disease progression rates, and jointly analysed with overall survival. The clinical utility of VMI was evaluated using comparisons to patient-reported functionality, while the impact of various monitoring schemes on empirical power was explored through simulations.<br><br>FINDINGS: In total, 97 patients (70.1% male) wore the accelerometer for 1995 days, for a total of 27,701&#xa0;h. The VMI was highly discriminatory for predicted disease progression rates, revealing faster rates of decline in patients with a worse predicted prognosis compared to those with a better predicted prognosis (p&#xa0;<&#xa0;0.0001). The VMI was strongly associated with the hazard for death (HR 0.20, 95% CI: 0.09-0.44, p&#xa0;<&#xa0;0.0001), where a decrease of 0.19-0.41 unit was associated with reduced ambulatory status. Recommendations for future studies using accelerometery are provided.<br><br>INTERPRETATION: The results serve as motivation to incorporate accelerometer-derived outcomes in clinical trials, which is essential for further validation of these markers to meaningful endpoints.<br><br>FUNDING: Stichting ALS Nederland (TRICALS-Reactive-II).}, }
@article {pmid38570095, year = {2024}, author = {Wiblin, L}, title = {An introduction to neuropalliative care: A growing need.}, journal = {Clinical medicine (London, England)}, volume = {24}, number = {2}, pages = {100038}, pmid = {38570095}, issn = {1473-4893}, mesh = {Humans ; *Palliative Care/methods ; *Quality of Life ; Motor Neuron Disease/therapy/psychology ; }, abstract = {Palliative care (PC) defined as 'an approach improving the quality of life of patients and their families facing problems associated with life-limiting illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual' aims to enhance the improve the remaining time that patients have, emphasising choice for patients and families.[1] Patients with neurological disease such as Parkinson's (PD) and motor neurone disease (MND) benefit from PC earlier in disease with increasing emphasis over time. Understanding and communicating uncertain trajectories, honest prognostic communication when patients are ready and careful symptom control has been shown to enhance quality of life in patients and caregivers, giving greater autonomy to these patients when supported in decision-making by a palliative approach. Although obstacles to palliative care are frequent, there are strategies which can help overcome them.}, }
@article {pmid38568044, year = {2024}, author = {Calvo, A and Moglia, C and Canosa, A and Manera, U and Vasta, R and Grassano, M and Daviddi, M and De Mattei, F and Matteoni, E and Gallone, S and Brunetti, M and Sbaiz, L and Cabras, S and Peotta, L and Palumbo, F and Iazzolino, B and Mora, G and Chiò, A}, title = {High Frequency of Cognitive and Behavioral Impairment in Amyotrophic Lateral Sclerosis Patients with SOD1 Pathogenic Variants.}, journal = {Annals of neurology}, volume = {96}, number = {1}, pages = {150-158}, doi = {10.1002/ana.26928}, pmid = {38568044}, issn = {1531-8249}, support = {RF-2016-02362405//Ministero della Salute/ ; 101017598//HORIZON EUROPE Health/ ; 2017SNW5MB//Ministero dell'Universit&#xe0; e della Ricerca/ ; 259867//FP7 Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/psychology/complications ; Male ; Female ; *Superoxide Dismutase-1/genetics ; Aged ; Middle Aged ; *Cognitive Dysfunction/genetics/psychology ; Adult ; }, abstract = {OBJECTIVE: While the cognitive-behavioral characteristics of amyotrophic lateral sclerosis (ALS) patients carrying C9orf72 pathological repeat expansion have been extensively studied, our understanding of those carrying SOD1 variants is mostly based on case reports. The aim of this paper is to extensively explore the cognitive-behavioral characteristics of a cohort of ALS patients carrying pathogenetic variants of SOD1 gene, comparing them to patients without pathogenetic variants of 46 ALS-related genes (wild-type [WT]-ALS) and healthy controls.<br><br>METHODS: All ALS patients seen at the Turin ALS expert center in the 2009-2021 period who underwent both cognitive/behavioral and extensive genetic testing were eligible to be included in the study. Only patients with SOD1 pathogenetic variants (n&#x2009;=&#x2009;28) (SOD1-ALS) and WT-ALS (n&#x2009;=&#x2009;829) were enrolled in the study. A series of 129 controls was also included.<br><br>RESULTS: Among the 28 SOD1-ALS patients, 16 (57.1%) had normal cognitive function, 5 (17.9%) isolated cognitive impairment (ALSci) (17.9%), 6 (21.4%) isolated behavioral impairment (ALSbi), 1 (3.6%) cognitive and behavioral impairment (ALScbi), and no one ALS-FTD. SOD1-ALS performed worse than controls in all explored domains, in particular Social Cognition and Language domains. SOD1-ALS patients had similar scores in all tests compared to WT-ALS, except the Story-based Empathy Task (SET), where they performed worse.<br><br>INTERPRETATION: Cognitive-behavioral impairment is much more common in SOD1 patients than previously assumed. SOD1-ALS are characterized by a more frequent impairment of Social Cognition and, less markedly, of Language domains. These findings have relevant implication both in the clinical and in the research setting, also considering recently approved treatment for SOD1-ALS. ANN NEUROL 2024;96:150-158.}, }
@article {pmid38567799, year = {2024}, author = {Wang, XJ and Cornell, PY and Belanger, E and Thomas, KS}, title = {Do end-of-life outcomes differ by assisted living memory-care designation?.}, journal = {Journal of the American Geriatrics Society}, volume = {72}, number = {8}, pages = {2491-2499}, pmid = {38567799}, issn = {1532-5415}, support = {R01 AG057746/AG/NIA NIH HHS/United States ; R01 AG066902/AG/NIA NIH HHS/United States ; R01AG066902/AG/NIA NIH HHS/United States ; R01AG057746/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Assisted Living Facilities/statistics &amp; numerical data ; Aged, 80 and over ; United States ; *Terminal Care/statistics &amp; numerical data ; Aged ; *Medicare/statistics &amp; numerical data ; Prospective Studies ; *Hospice Care/statistics &amp; numerical data ; Alzheimer Disease/mortality/therapy ; Dementia/mortality/therapy ; }, abstract = {BACKGROUND: Residential care/assisted living (RC/AL) is an increasingly common place of end-of-life care for persons with Alzheimer's disease and related dementia (ADRD), who have unique care needs as their health declines. Approximately 22% of RC/ALs provide specialized memory care (memory-care RC/AL). Understanding how end-of-life outcomes differ by memory care among residents with ADRD could facilitate aging/dying in place for this population. The objective of this paper is to examine if end-of-life outcomes (i.e., mortality, hospice use, and number of days receiving hospice in the last month of life) differ between residents with ADRD who moved to memory-care RC/AL, compared with residents with ADRD who moved to RC/AL without memory care (general RC/AL).<br><br>METHODS: Prospective cohort of 15,152 fee-for-service Medicare beneficiaries with ADRD who moved to large RC/AL (>&#x2009;=&#x2009;25 beds) between 2016 and 2018. We used inverse probability treatment weighting to account for observable differences between memory-care and general RC/AL residents. Two-part models estimated the difference by memory care in the number of days receiving hospice care in the last months of life among RC/AL decedents.<br><br>RESULTS: The unadjusted mortality rates were 13.4% in general RC/AL and 15.8% in memory-care RC/AL with an adjusted difference of 1.3 percentage points higher mortality among memory-care RC/AL residents (p&#x2009;=&#x2009;0.04). Hospice use was 8% and 10.6% among general and memory-care RC/AL residents, respectively, with an adjusted difference of 1.4 percentage points (p&#x2009;=&#x2009;0.01) higher in memory care. Two-part models showed that decedents in memory-care RC/AL spent about 1.4 more days receiving hospice care in the last month of life (p&#x2009;=&#x2009;0.02).<br><br>CONCLUSION: We find a higher mortality rate and higher rate of hospice use among memory-care RC/AL residents. These findings suggest that memory care may attract residents closer to the end of life and/or promote hospice use at the end of life.}, }
@article {pmid38565200, year = {2024}, author = {Stierwalt, J and Stierwalt, JAG and Clark, H and Burda, A and Benavidez Kiley, H and Collins, E and Kortemeyer, M and Miller, E and Peckenschneider, G and Schieltz, E and Shah, Y and Simon, K}, title = {Factors Affecting Performance on a Screening Tool in Persons with Amyotrophic Lateral Sclerosis.}, journal = {Seminars in speech and language}, volume = {45}, number = {3}, pages = {228-241}, doi = {10.1055/s-0044-1785447}, pmid = {38565200}, issn = {1098-9056}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications ; Male ; Female ; Middle Aged ; Aged ; Retrospective Studies ; Cognitive Dysfunction/diagnosis ; Neuropsychological Tests ; Frontotemporal Dementia/diagnosis/psychology ; Adult ; Aged, 80 and over ; }, abstract = {Persons with amyotrophic lateral sclerosis (PALS) are at risk of developing cognitive impairments and frontotemporal dementia (FTD). This study examined the relationship between performance of the ALS-Cognitive Behavioral Screen (ALS-CBS) and the demographic parameters of sex, education, time post-ALS diagnosis, and severity of symptoms. Data were collected retrospectively from 69 participants seen at the Mayo Clinic. Correlations were conducted on the ALS-CBS total scores and subsection scores and the above listed parameters; t-tests were conducted between participant subgroups. No statistically significant relationships or differences occurred between the ALS-CBS or its subsections and the variables measured with exception of age and the attention subsection. Older participants had lower ALS-CBS attention subsection scores. Based on the ALS-CBS scores, most participants had some degree of cognitive impairments: 43 had suspected cognitive impairment, 8 had suspected FTD; 18 fell within the normal range of cognitive function. Overall, the variables of sex, education, time post-diagnosis, and severity of symptoms do not appear to influence ALS-CBS scores. It is recommended cognitive screenings be completed for all PALS due to the high risk for developing cognitive impairments and FTD. Such knowledge can help clinicians develop assessment and treatment plans.}, }
@article {pmid38564446, year = {2024}, author = {Kinnear, EE and Beales, D and Paton, A and Challice, S}, title = {Making a difference: neurological support in the community.}, journal = {British journal of community nursing}, volume = {29}, number = {4}, pages = {190-194}, doi = {10.12968/bjcn.2024.29.4.190}, pmid = {38564446}, issn = {1462-4753}, mesh = {Humans ; Quality of Life ; *Nervous System Diseases/therapy ; *Parkinson Disease/therapy ; *Multiple Sclerosis/therapy ; *Stroke ; }, abstract = {Nearly 3 million people in the UK have a neurological condition; stroke, traumatic brain injury, Parkinson's disease, multiple sclerosis, brain tumour, motor neurone disease, among others - all affecting the person for the rest of their life. The NHS provides treatment at the onset of a condition but after that, there is a huge need for ongoing support. Research shows that those who are supported and know more about their condition are less likely to have to call on further in-hospital and GP care. There is enormous scope for improving the quality of life for those with neurological conditions. The right support-therapeutic and social-makes all the difference. The book, which this article is based on, shows how those with neurological conditions benefit from integrated ongoing support provided in the local community and self-help, and how lives can be improved. It explains good practice and encouraging methods in the support and treatment of those with life changing conditions.}, }
@article {pmid38563162, year = {2024}, author = {Pastora, LE and Namburu, NS and Arora, K and Christov, PP and Wilson, JT}, title = {STING-Pathway Inhibiting Nanoparticles (SPINs) as a Platform for Treatment of Inflammatory Diseases.}, journal = {ACS applied bio materials}, volume = {7}, number = {8}, pages = {4867-4878}, pmid = {38563162}, issn = {2576-6422}, support = {T32 DK101003/DK/NIDDK NIH HHS/United States ; P30 DK058404/DK/NIDDK NIH HHS/United States ; }, mesh = {*Membrane Proteins/metabolism/antagonists &amp; inhibitors ; *Nanoparticles/chemistry ; Animals ; Mice ; Inflammation/drug therapy ; Humans ; Biocompatible Materials/chemistry/pharmacology ; Particle Size ; Materials Testing ; Nucleotidyltransferases/antagonists &amp; inhibitors/metabolism ; Signal Transduction/drug effects ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; }, abstract = {Aberrant activation of the cyclic GMP-AMP synthase (cGAS)/Stimulator of Interferon Genes (STING) pathway has been implicated in the development and progression of a myriad of inflammatory diseases including colitis, nonalcoholic steatohepatitis, amyotrophic lateral sclerosis (ALS), and age-related macular degeneration. Thus, STING pathway inhibitors could have therapeutic application in many of these inflammatory conditions. The cGAS inhibitor RU.521 and the STING inhibitor H-151 have shown promise as therapeutics in mouse models of colitis, ALS, and more. However, these agents require frequent high-dose intraperitoneal injections, which may limit translatability. Furthermore, long-term use of systemically administered cGAS/STING inhibitors may leave patients vulnerable to viral infections and cancer. Thus, localized or targeted inhibition of the cGAS/STING pathway may be an attractive, broadly applicable treatment for a variety of STING pathway-driven ailments. Here we describe STING-Pathway Inhibiting Nanoparticles (SPINS)-poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with RU.521 and H-151-as a platform for enhanced and sustained inhibition of cGAS/STING signaling. We demonstrate that SPINs are equally or more effective at inhibiting type-I interferon responses induced by cytosolic DNA than free H-151 or RU.521. Additionally, we describe a SPIN formulation in which PLGA is coemulsified with poly(benzoyloxypropyl methacrylamide) (P(HPMA-Bz)), which significantly improves drug loading and allows for tunable release of H-151 over a period of days to over a week by varying P(HPMA-Bz) content. Finally, we find that all SPIN formulations were as potent or more potent in inhibiting cGAS/STING signaling in primary murine macrophages, resulting in decreased expression of inflammatory M1-like macrophage markers. Therefore, our study provides an in vitro proof-of-concept for nanoparticle delivery of STING pathway inhibitors and positions SPINs as a potential platform for slowing or reversing the onset or progression of cGAS/STING-driven inflammatory conditions.}, }
@article {pmid38563056, year = {2024}, author = {Umar, TP and Jain, N and Papageorgakopoulou, M and Shaheen, RS and Alsamhori, JF and Muzzamil, M and Kostiks, A}, title = {Artificial intelligence for screening and diagnosis of amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {425-436}, doi = {10.1080/21678421.2024.2334836}, pmid = {38563056}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Humans ; *Artificial Intelligence ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurological disease that leads to progressive motor function degeneration. Diagnosing ALS is challenging due to the absence of a specific detection test. The use of artificial intelligence (AI) can assist in the investigation and treatment of ALS.<br><br>METHODS: We searched seven databases for literature on the application of AI in the early diagnosis and screening of ALS in humans. The findings were summarized using random-effects summary receiver operating characteristic curve. The risk of bias (RoB) analysis was carried out using QUADAS-2 or QUADAS-C tools.<br><br>RESULTS: In the 34 analyzed studies, a meta-prevalence of 47% for ALS was noted. For ALS detection, the pooled sensitivity of AI models was 94.3% (95% CI - 63.2% to 99.4%) with a pooled specificity of 98.9% (95% CI - 92.4% to 99.9%). For ALS classification, the pooled sensitivity of AI models was 90.9% (95% CI - 86.5% to 93.9%) with a pooled specificity of 92.3% (95% CI - 84.8% to 96.3%). Based on type of input for classification, the pooled sensitivity of AI models for gait, electromyography, and magnetic resonance signals was 91.2%, 92.6%, and 82.2%, respectively. The pooled specificity for gait, electromyography, and magnetic resonance signals was 94.1%, 96.5%, and 77.3%, respectively.<br><br>CONCLUSIONS: Although AI can play a significant role in the screening and diagnosis of ALS due to its high sensitivities and specificities, concerns remain regarding quality of evidence reported in the literature.}, }
@article {pmid38561605, year = {2024}, author = {Singh, K and Gupta, JK and Kumar, S and Soni, U}, title = {A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Bioactive Peptides.}, journal = {Current protein &amp; peptide science}, volume = {25}, number = {7}, pages = {507-526}, pmid = {38561605}, issn = {1875-5550}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Peptides/therapeutic use/chemistry/pharmacology ; Animals ; Alzheimer Disease/drug therapy/metabolism/pathology ; Parkinson Disease/drug therapy/metabolism/pathology ; Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; Oxidative Stress/drug effects ; Huntington Disease/drug therapy/metabolism/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Cholinesterase Inhibitors/therapeutic use/pharmacology/chemistry ; }, abstract = {Neurodegenerative disorders, which include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a significant and growing global health challenge. Current therapies predominantly focus on symptom management rather than altering disease progression. In this review, we discuss the major therapeutic strategies in practice for these disorders, highlighting their limitations. For AD, the mainstay treatments are cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. For PD, dopamine replacement therapies, including levodopa, are commonly used. HD is managed primarily with symptomatic treatments, and reusable extends survival in ALS. However, none of these therapies halts or substantially slows the neurodegenerative process. In contrast, this review highlights emerging research into bioactive peptides as potential therapeutic agents. These naturally occurring or synthetically designed molecules can interact with specific cellular targets, potentially modulating disease processes. Preclinical studies suggest that bioactive peptides may mitigate oxidative stress, inflammation, and protein misfolding, which are common pathological features in neurodegenerative diseases. Clinical trials using bioactive peptides for neurodegeneration are limited but show promising initial results. For instance, hemiacetal, a γ-secretase inhibitor peptide, has shown potential in AD by reducing amyloid-beta production, though its development was discontinued due to side effects. Despite these advancements, many challenges remain, including identifying optimal peptides, confirming their mechanisms of action, and overcoming obstacles related to their delivery to the brain. Future research should prioritize the discovery and development of novel bioactive peptides and improve our understanding of their pharmacokinetics and pharmacodynamics. Ultimately, this approach may lead to more effective therapies for neurodegenerative disorders, moving beyond symptom management to potentially modify the course of these devastating diseases.}, }
@article {pmid38560980, year = {2024}, author = {Xiang, SR and Ma, Q and Dong, J and Ren, YF and Lin, JZ and Zheng, C and Xiao, P and You, FM}, title = {Contrasting Effects of Music Therapy and Aromatherapy on Perioperative Anxiety: A Systematic Review and Meta-Analysis.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {278-291}, doi = {10.1159/000538425}, pmid = {38560980}, issn = {2504-2106}, mesh = {*Aromatherapy ; *Music Therapy ; Humans ; *Anxiety/therapy ; Heart Rate ; }, abstract = {INTRODUCTION: Music therapy and aromatherapy have been demonstrated effective for perioperative anxiety. However, the available studies have indicated discordant results about which adjunct treatment is better for perioperative anxiety. Therefore, we conducted this meta-analysis to explore the contrasting effects between them.<br><br>METHODS: Six electronic databases were searched for clinical trials evaluating the efficacy of music therapy compared with aromatherapy in alleviating perioperative anxiety. The primary outcome was the postintervention anxiety level. Secondary outcomes included differences in blood pressure and heart rate before and after the intervention as well as pain scores at intraoperative and postoperative time points. The study protocol was registered on PROSPERO (CRD42021249737).<br><br>RESULTS: Twelve studies (894 patients) were included. The anxiety level showed no statistically significant difference (SMD, 0.28; 95% CI: -0.12, 0.68; p = 0.17). The analysis of blood pressure and heart rate also did not identify statistically significant differences. Notably, the pain scores at the intraoperative time point suggested that aromatherapy was superior to music therapy (WMD, 0.29 cm; 95% CI: 0.05, 0.52; p = 0.02), while those at 4 h after surgery indicated the opposite results (WMD, -0.48 cm; 95% CI: -0.60, -0.36; p < 0.001).<br><br>CONCLUSION: Low-to-moderate quality evidence suggests that music therapy and aromatherapy have similar potential to relieve perioperative anxiety. The potential data indicate that the two therapies have different benefits in intervention duration and age distribution. More direct high-quality comparisons are encouraged in the future to verify this point.<br><br>UNLABELLED: <title>Einleitung</title>Musik- und Aromatherapie haben sich bei perioperativen Angstzust&#xe4;nden als wirksam erwiesen. Die verf&#xfc;gbaren Studien zeigten jedoch widerspr&#xfc;chliche Ergebnisse zur Frage, welche adjuvante Therapie bei perioperativen Angstzust&#xe4;nden besser ist. Daher f&#xfc;hrten wir die vorliegende Metaanalyse durch, um die unterschiedlichen Effekte der beiden Therapien zu untersuchen.<title>Methoden</title>Sechs (6) elektronische Datenbanken wurden nach klinischen Studien zur Wirksamkeit von Musiktherapie im Vergleich zur Aromatherapie bei der Linderung perioperativer Angstzust&#xe4;nde durchsucht. Prim&#xe4;res Zielkriterium war das Angstniveau nach der Intervention. Die sekund&#xe4;ren Zielkriterien umfassten die Unterschiede bei Blutdruck und Herzfrequenz vor und nach der Intervention sowie die Schmerz-Scores zu intra- und postoperativen Zeitpunkten. Das Studienprotokoll wurde auf PROSPERO (CRD42021249737) registriert.<title>Ergebnisse</title>Zw&#xf6;lf (12) Studien (894 Patienten) wurden eingeschlossen. Das Angstniveau zeigte keinen statistisch signifikanten Unterschied (SMD, 0,28; 95%-KI: &#x2212;0,12, 0,68, <italic>p</italic>&#xa0;=&#xa0;0,17) und auch die Analyse von Blutdruck und Herzfrequenz ergab keine statistisch signifikanten Unterschiede. Insbesondere die Schmerz-Scores zum intraoperativen Zeitpunkt sprachen daf&#xfc;r, dass die Aromatherapie gegen&#xfc;ber der Musiktherapie &#xfc;berlegen war (WMD, 0,29&#xa0;cm; 95%-KI: 0,05, 0,52; <italic>p&#xa0;</italic>=&#xa0;0,02), w&#xe4;hrend die Werte 4 Stunden nach der Operation gegenteilige Ergebnisse zeigten (WMD, &#x2212;0,48 cm; 95%-KI: &#x2212;0,60, &#x2212;0,36, <italic>p</italic>&#xa0;<&#xa0;0,001).<title>Schlussfolgerung</title>Evidenzen von geringer bis m&#xe4;ssiger Qualit&#xe4;t deuten darauf hin, dass Musik- und Aromatherapie ein vergleichbares Potenzial bei der Linderung perioperativer &#xc4;ngste besitzen. Die potenziellen Daten zeigen, dass die beiden Therapien unterschiedliche Vorteile hinsichtlich Interventionsdauer und Altersverteilung haben. K&#xfc;nftig sollten mehr direkte und qualitativ hochwertige Vergleiche durchgef&#xfc;hrt werden, um diesen Aspekt zu &#xfc;berpr&#xfc;fen.}, }
@article {pmid38560897, year = {2024}, author = {Minatoguchi, S and Fujita, Y and Niizuma, K and Tominaga, T and Yamashita, T and Abe, K and Dezawa, M}, title = {Donor Muse Cell Treatment Without HLA-Matching Tests and Immunosuppressant Treatment.}, journal = {Stem cells translational medicine}, volume = {13}, number = {6}, pages = {532-545}, pmid = {38560897}, issn = {2157-6580}, support = {//New Energy and Industrial Technology Development Organization/ ; //Japan Agency for Medical Research and Development/ ; //Ministry of Education, Culture, Sports, Science and Technology/ ; //Japan Society for the Promotion of Science/ ; //SENSHIN Medical Research Foundation/ ; //Life Science Institute Inc/ ; }, mesh = {Humans ; *Mesenchymal Stem Cells/cytology/metabolism ; Mesenchymal Stem Cell Transplantation/methods ; Immunosuppressive Agents/pharmacology/therapeutic use ; HLA Antigens/metabolism ; Cell Differentiation ; Animals ; Histocompatibility Testing/methods ; }, abstract = {The strength of stem cell therapy is the regeneration of tissues by synergistic pleiotropic effects. Among many stem cell types, mesenchymal stem cells (MSCs) that are comprised of heterogenous population are widely used for clinical applications with the expectation of pleiotropic bystander effects. Muse cells are pluripotent-like/macrophage-like stem cells distributed in the bone marrow, peripheral blood, and organ connective tissues as cells positive for the pluripotent surface marker stage-specific-embryonic antigen -3. Muse cells comprise ~1% to several percent of MSCs. While Muse cells and MSCs share several characteristics, such as mesenchymal surface marker expression and their bystander effects, Muse cells exhibit unique characteristics not observed in MSCs. These unique characteristics of Muse cells include selective homing to damaged tissue after intravenous injection rather than being trapped in the lung like MSCs, replacement of a wide range of damaged/apoptotic cells by differentiation through phagocytosis, and long-lasting immunotolerance for donor cell use. In this review, we focus on the basic properties of Muse cells clarified through preclinical studies and clinical trials conducted by intravenous injection of donor-Muse cells without HLA-matching tests or immunosuppressant treatment. MSCs are considered to differentiate into osteogenic, chondrogenic, and adipogenic cells, whereas the range of their differentiation has long been debated. Muse cells may provide clues to the wide-ranging differentiation potential of MSCs that are observed with low frequency. Furthermore, the utilization of Muse cells may provide a novel strategy for clinical treatment.}, }
@article {pmid38559706, year = {2024}, author = {Bhor, S and Tonny, SH and Dinesh, S and Sharma, S}, title = {Computational screening of damaging nsSNPs in human SOD1 genes associated with amyotrophic lateral sclerosis identifies destabilising effects of G38R and G42D mutations through in silico evaluation.}, journal = {In silico pharmacology}, volume = {12}, number = {1}, pages = {20}, pmid = {38559706}, issn = {2193-9616}, abstract = {Amyotrophic lateral sclerosis (ALS), a complicated neurodegenerative disorder affected by hereditary and environmental variables, is a condition. In this study, the genetic makeup of ALS is investigated, with a focus on the SOD1 gene's single-nucleotide polymorphisms (SNPs) and their ability to affect disease risk. Eleven high-risk missense variations that may impair the functionality of the SOD1 protein were discovered after a thorough examination of SNPs in the SOD1 gene. These mutations were chosen using a variety of prediction approaches, highlighting their importance in the aetiology of ALS. Notably, it was discovered that the stability of the SOD1 wild-type protein structure was compromised by the G38R and G42D SOD1 variants. Additionally, Edaravone, a possible ALS medication, showed a greater affinity for binding mutant SOD1 structures, pointing to potential personalised treatment possibilities. The high-risk SNPs discovered in this investigation seem to have functional effects, especially on the stability of proteins and their interactions with other molecules. This study clarifies the complex genetics of ALS and offers insights into how these genetic variations may affect the effectiveness of therapeutic interventions, particularly in the context of edaravone. In this study advances our knowledge of the genetic mechanisms causing ALS vulnerability and prospective therapeutic strategies. Future studies are necessary to confirm these results and close the gap between individualised clinical applications and improved ALS care.}, }
@article {pmid38551974, year = {2024}, author = {Jiménez-García, AM and Bonnel, G and Álvarez-Mota, A and Arias, N}, title = {Current perspectives on neuromodulation in ALS patients: A systematic review and meta-analysis.}, journal = {PloS one}, volume = {19}, number = {3}, pages = {e0300671}, pmid = {38551974}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Quality of Life ; *Neurodegenerative Diseases ; Exercise Therapy/methods ; Muscle Spasticity ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, resulting in muscle weakness, paralysis, and eventually patient mortality. In recent years, neuromodulation techniques have emerged as promising potential therapeutic approaches to slow disease progression and improve the quality of life of ALS patients. A systematic review was conducted until August 8, 2023, to evaluate the neuromodulation methods used and their potential in the treatment of ALS. The search strategy was applied in the Cochrane Central database, incorporating results from other databases such as PubMed, Embase, CTgov, CINAHL, and ICTRP. Following the exclusion of papers that did not fulfil the inclusion criteria, a total of 2090 records were found, leaving a total of 10 studies. R software was used to conduct meta-analyses based on the effect sizes between the experimental and control groups. This revealed differences in muscle stretch measures with manual muscle testing (p = 0.012) and resting motor threshold (p = 0.0457), but not with voluntary isometric contraction (p = 0.1883). The functionality of ALS was also different (p = 0.007), but not the quality of life. Although intracortical facilitation was not seen in motor cortex 1 (M1) (p = 0.1338), short-interval intracortical inhibition of M1 was significant (p = 0.0001). BDNF showed no differences that were statistically significant (p = 0.2297). Neuromodulation-based treatments are proposed as a promising therapeutic approach for ALS that can produce effects on muscle function, spasticity, and intracortical connections through electrical, magnetic, and photonic stimulation. Photobiomodulation stands out as an innovative approach that uses specific wavelengths to influence mitochondria, with the aim of improving mitochondrial function and reducing excitotoxicity. The lack of reliable placebo controls and the variation in stimulation frequency are some of the drawbacks of neuromodulation.}, }
@article {pmid38542497, year = {2024}, author = {Nemeth, C and Banik, NL and Haque, A}, title = {Disruption of Neuromuscular Junction Following Spinal Cord Injury and Motor Neuron Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {6}, pages = {}, pmid = {38542497}, issn = {1422-0067}, support = {R21 NS118393/NS/NINDS NIH HHS/United States ; I01 BX001262/BX/BLRD VA/United States ; 1R21NS118393-01/NH/NIH HHS/United States ; I01 BX004269/BX/BLRD VA/United States ; I01 BX006101/BX/BLRD VA/United States ; IK6 BX005964/BX/BLRD VA/United States ; }, mesh = {Humans ; Neuromuscular Junction/metabolism ; Motor Neurons/metabolism ; Muscle Fibers, Skeletal/metabolism ; Spinal Cord/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *Spinal Cord Injuries/metabolism ; }, abstract = {The neuromuscular junction (NMJ) is a crucial structure that connects the cholinergic motor neurons to the muscle fibers and allows for muscle contraction and movement. Despite the interruption of the supraspinal pathways that occurs in spinal cord injury (SCI), the NMJ, innervated by motor neurons below the injury site, has been found to remain intact. This highlights the importance of studying the NMJ in rodent models of various nervous system disorders, such as amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). The NMJ is also involved in myasthenic disorders, such as myasthenia gravis (MG), and is vulnerable to neurotoxin damage. Thus, it is important to analyze the integrity of the NMJ in rodent models during the early stages of the disease, as this may allow for a better understanding of the condition and potential treatment options. The spinal cord also plays a crucial role in the functioning of the NMJ, as the junction relays information from the spinal cord to the muscle fibers, and the integrity of the NMJ could be disrupted by SCI. Therefore, it is vital to study SCI and muscle function when studying NMJ disorders. This review discusses the formation and function of the NMJ after SCI and potential interventions that may reverse or improve NMJ dysfunction, such as exercise, nutrition, and trophic factors.}, }
@article {pmid38542223, year = {2024}, author = {Salvatori, I and Nesci, V and Spalloni, A and Marabitti, V and Muzzi, M and Zenuni, H and Scaricamazza, S and Rosina, M and Fenili, G and Goglia, M and Boffa, L and Massa, R and Moreno, S and Mercuri, NB and Nazio, F and Longone, P and Ferri, A and Valle, C}, title = {Trimetazidine Improves Mitochondrial Dysfunction in SOD1[G93A] Cellular Models of Amyotrophic Lateral Sclerosis through Autophagy Activation.}, journal = {International journal of molecular sciences}, volume = {25}, number = {6}, pages = {}, pmid = {38542223}, issn = {1422-0067}, support = {CNR IFT DBA.AD005.225 -NUTRAGE- FOE2021//National Research Council/ ; RF-2019-12369105//Ministero della Salute/ ; HyperALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; 'Unraveling the protective effects of NOS1AP in the rescue of TDP-43 loss of function pathological mechanisms//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; Ref. 27019//Italian Association for Cancer Research/ ; Prot. GeCoWEB n. A0375-2020- 36668//Regione Lazio/ ; The Grant of Excellence Departments 2023-2027//Ministero dell'Universit&#xe0; e Ricerca Italy/ ; }, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/metabolism ; *Trimetazidine/pharmacology/therapeutic use ; Mice, Transgenic ; Leukocytes, Mononuclear/metabolism ; Superoxide Dismutase/metabolism ; Autophagy ; *Mitochondrial Diseases ; Disease Models, Animal ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is considered the prototype of motor neuron disease, characterized by motor neuron loss and muscle waste. A well-established pathogenic hallmark of ALS is mitochondrial failure, leading to bioenergetic deficits. So far, pharmacological interventions for the disease have proven ineffective. Trimetazidine (TMZ) is described as a metabolic modulator acting on different cellular pathways. Its efficacy in enhancing muscular and cardiovascular performance has been widely described, although its molecular target remains elusive. We addressed the molecular mechanisms underlying TMZ action on neuronal experimental paradigms. To this aim, we treated murine SOD1[G93A]-model-derived primary cultures of cortical and spinal enriched motor neurons, as well as a murine motor-neuron-like cell line overexpressing SOD1[G93A], with TMZ. We first characterized the bioenergetic profile of the cell cultures, demonstrating significant mitochondrial dysfunction that is reversed by acute TMZ treatments. We then investigated the effect of TMZ in promoting autophagy processes and its impact on mitochondrial morphology. Finally, we demonstrated the effectiveness of TMZ in terms of the mitochondrial functionality of ALS-rpatient-derived peripheral blood mononuclear cells (PBMCs). In summary, our results emphasize the concept that targeting mitochondrial dysfunction may represent an effective therapeutic strategy for ALS. The findings demonstrate that TMZ enhances mitochondrial performance in motor neuron cells by activating autophagy processes, particularly mitophagy. Although further investigations are needed to elucidate the precise molecular pathways involved, these results hold critical implications for the development of more effective and specific derivatives of TMZ for ALS treatment.}, }
@article {pmid38538275, year = {2024}, author = {Ceccarelli, L and Verriello, L and Pauletto, G and Valente, M and Spadea, L and Salati, C and Zeppieri, M and Ius, T}, title = {The Role of Human Pluripotent Stem Cells in Amyotrophic Lateral Sclerosis: From Biological Mechanism to Practical Implications.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {29}, number = {3}, pages = {114}, doi = {10.31083/j.fbl2903114}, pmid = {38538275}, issn = {2768-6698}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Motor Neurons/metabolism ; *Pluripotent Stem Cells/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, characterized by progressive loss of both upper and lower motor neurons, resulting in clinical features such as muscle weakness, paralysis, and ultimately, respiratory failure. Nowadays, there is not effective treatment to reverse the progression of the disease, that leads to death within 3-5 years after the onset. Nevertheless, the induced pluripotent stem cells (iPS) technology could be the answer, providing disease modelling, drug testing, and cell-based therapies for this pathology. The aim of this work was to conduct a literature review of the past 5 years about the role of iPS in ALS, to better define the neurobiological mechanisms involved in the pathogenesis and the potential future therapies. The review also deals with advanced and currently available technologies used to reprogram cell lines and generate human motor neurons in vitro, which represent the source to study the pathological processes, the relationship between phenotype and genotype, the disease progression and the potential therapeutic targets of these group of disorders. Specific treatment options with stem cells involve Advance Gene Editing Technology, neuroprotective agents, and cells or exosomes transplantation, aimed to replace dead or damaged nerve cells. In summary, this review comprehensively addresses the role of human pluripotent stem cells (hPSCs) in motor neuron diseases (MND), with a focus on physiopathology, diagnostic and prognostic implications, specific and potential future treatment options. Understanding the biological mechanisms and practical implications of hPSCs in MND is crucial for advancing therapeutic strategies and improving outcomes for patients affected by these devastating diseases.}, }
@article {pmid38533934, year = {2024}, author = {Deutsch, AJ}, title = {PICking out progressive PIC alterations in amyotrophic lateral sclerosis.}, journal = {Journal of neurophysiology}, volume = {131}, number = {5}, pages = {822-824}, pmid = {38533934}, issn = {1522-1598}, support = {NS091836//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS131816/NS/NINDS NIH HHS/United States ; R01 AG067758/AG/NIA NIH HHS/United States ; AG067758//HHS | NIH | National Institute on Aging (NIA)/ ; R01 NS091836/NS/NINDS NIH HHS/United States ; NS131816//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Humans ; *Motor Neurons/physiology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motoneuron death. Alterations to motoneuron excitability in ALS are suspected to contribute to motoneuron degeneration. Therefore, mechanisms underlying changes in motoneuron excitability are being thoroughly investigated. A recent publication from Trajano et al. (Trajano GS, Orssatto LB, McCombe PA, Rivlin W, Tang L, Henderson RD. J Physiol 601: 4723-4735, 2023) examined temporal changes to persistent inward currents (PICs) in ALS patients. They show that delta frequency (ΔF, an estimate of PICs) has opposite temporal trends in stronger and weaker muscles of ALS patients. This study is very important to aid in the understanding of disease mechanisms. This Neuro Forum article explores some important considerations for interpreting the results of this study, including treatment effects, potential sex differences, and a lack of comparison to healthy individuals.}, }
@article {pmid38533300, year = {2024}, author = {Moskvin, SV}, title = {A brief literature review of low-level laser therapy for treating amyotrophic lateral sclerosis and confirmation of its effectiveness.}, journal = {BioMedicine}, volume = {14}, number = {1}, pages = {1-9}, pmid = {38533300}, issn = {2211-8020}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a steadily progressive course due to the death of central and peripheral motor neurons responsible for voluntary movements. Low-level laser therapy (LLLT) is a treatment method unique in its universality and efficacy, particularly for neurodegenerative diseases.<br><br>METHODS: In this review, we discuss the effect and application of LLLT in the treatment of ALS. A literature search for English and Russian publications for the keywords "Amyotrophic Lateral Sclerosis", "Low-Level Laser Therapy" was performed using PubMed, Scopus, Google Scholar, Web of Science and Russian Science Citation Index (RSCI) databases.<br><br>RESULTS: The article provided a brief literature review, substantiated the potential use of low-level laser therapy for ALS. The particular techniques of LLLT were developed.<br><br>CONCLUSION: Based on the results of several studies and many years of successful experience with low-level laser therapy in Russia we conclude that a LLLT technique, including intravenous laser blood illumination (ILBI), noninvasive laser blood illumination (NLBI), and local exposure, is a promising treatment method for ALS.}, }
@article {pmid38531340, year = {2024}, author = {Lee, KH and Kim, MH and Kim, J and Nam, HJ}, title = {Acupuncture for Tinnitus: A Scoping Review of Clinical Studies.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {292-301}, pmid = {38531340}, issn = {2504-2106}, mesh = {Humans ; *Acupuncture Therapy/methods ; *Tinnitus/therapy ; Randomized Controlled Trials as Topic ; Acupuncture Points ; }, abstract = {BACKGROUND: Acupuncture treatment for tinnitus has received attention owing to its potential as an alternative to conventional treatment modalities. We conducted a scoping review to identify detailed information on acupuncture treatment methods used in clinical studies and to provide useful information for practitioners, patients, and researchers.<br><br>METHODS: MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Oriental Medicine Advanced Searching Integrated System (OASIS), Korean Research Information Sharing Service (RISS), DataBase Periodical Information Academic (DBPIA), and the China National Knowledge Infrastructure (CNKI) were searched from their inception to December 2023. This review included single-arm trials, open-label randomized controlled trials (RCTs), and double-blind RCTs using needle-type acupuncture to treat tinnitus in English, Chinese, and Korean. We investigated basic and detailed information on the acupuncture treatment methods, assessment methods, and study outcomes. Network analysis was also conducted to evaluate the centrality between acupoints in the double-blind RCTs.<br><br>RESULTS: We included 106 articles. There were 11 single-arm trials, 90 open-label RCTs, and 5 double-blind RCTs. Most (89.6%) of these studies were conducted in China. Manual acupuncture was the most common type of acupuncture in treatment group. A total of 119 acupuncture points were used 1,138 times. The most frequently used acupoints were local points around the ear (TE17, GB2, SI19, and TE21). Both local and distant acupoints were used simultaneously in these studies. The treatment duration of 20-39 days, 10 to 19 sessions of treatment, the mean acupuncture duration of 30 min, needle diameter of 0.30 mm &#xd7; 40 mm, and needling depth over 30 mm and less than 50 mm were confirmed as the most common.<br><br>CONCLUSION: These study outcomes will enable future acupuncture studies on tinnitus to perform more effective and standardized acupuncture treatments in selecting acupoints and procedures. Furthermore, the study has implications for informing clinicians and students about more impactful acupuncture strategies for addressing tinnitus.<br><br>UNLABELLED: <title>Hintergrund</title>Die Anwendung von Akupunktur bei Tinnitus erh&#xe4;lt seit einiger Zeit Aufmerksamkeit als potenzielle Alternative zu konventionellen Behandlungsmodalit&#xe4;ten. Wir f&#xfc;hrten einen Scoping-Review durch, um detaillierte Informationen zu den in klinischen Studien angewandten Akupunktur-Behandlungsmethoden zu sammeln und n&#xfc;tzliche Informationen f&#xfc;r Praktiker, Patienten und Forscher bereitzustellen.<title>Methoden</title>MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Oriental Medicine Advanced Searching Integrated System (OASIS), Korean Research Information Sharing Service (RISS), DataBase Periodical Information Academic (DBPIA) und die China National Knowledge Infrastructure (CNKI) wurden von ihrem jeweiligen Beginn bis Dezember 2023 durchsucht. In diese &#xdc;bersichtsarbeit wurden einarmige Studien, offene, randomisierte, kontrollierte Studien (RCTs) sowie doppelt verblindete RCTs zu Nadel-Akupunktur zur Behandlung von Tinnitus in englischer, chinesischer und koreanischer Sprache einbezogen. Wir untersuchten grundlegende und detaillierte Informationen zu den Akupunktur-Behandlungsmethoden, Untersuchungsmethoden und Studienergebnissen. Au&#xdf;erdem wurden Netzwerkanalysen zur Beurteilung der Zentralit&#xe4;t zwischen Akupunkten in den doppelt verblindeten RCTs durchgef&#xfc;hrt.<title>Ergebnisse</title>106 Artikel wurden eingeschlossen. Sie behandelten 11 einarmige Studien, 90 offene RCTs und 5 doppelt verblindete RCTs. Die meisten (89,6%) dieser Studien waren in China durchgef&#xfc;hrt worden. Manuelle Akupunktur war die h&#xe4;ufigste Form der Akupunktur in den Behandlungsgruppen. 119 Akupunkturpunkte wurden insgesamt 1&#x2019;138 Mal verwendet. Die am h&#xe4;ufigsten verwendeten Akupunkte waren lokale Punkte im Bereich des Ohrs (TE17, GB2, SI19 und TE21). Jedoch wurden in den Studien lokale und entfernte Akupunkte gleichzeitig angewendet. Au&#xdf;erdem wurde festgestellt, dass die Behandlungsdauer am h&#xe4;ufigsten 20 bis 39 Tage betrug, die Zahl der Sitzungen 10 bis 19, die mittlere Akupunkturdauer 30 Minuten, die Nadelgr&#xf6;&#xdf;e 0.30 mm &#xd7; 40 mm und die Einstichtiefe zwischen 30 mm und weniger als 50 mm.<title>Schlussfolgerung</title>Diese Studienergebnisse bieten eine Grundlage f&#xfc;r k&#xfc;nftige Studien zu Akupunktur bei Tinnitus, um durch die Auswahl der Akupunkte und Verfahren wirksamere und standardisierte Akupunkturbehandlungen durchzuf&#xfc;hren. Dar&#xfc;ber hinaus hat die Studie Implikationen f&#xfc;r die Aufkl&#xe4;rung von Praktikern und Sch&#xfc;lern &#xfc;ber wirkungsvollere Akupunkturstrategien zur Behandlung von Tinnitus.}, }
@article {pmid38526287, year = {2024}, author = {Chen, W and Jiang, S and Li, S and Li, C and Xu, R}, title = {OSMR is a potential driver of inflammation in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {11}, pages = {2513-2521}, pmid = {38526287}, issn = {1673-5374}, abstract = {JOURNAL/nrgr/04.03/01300535-202419110-00031/figure1/v/2024-03-08T184507Z/r/image-tiff Amyotrophic lateral sclerosis is a neurodegenerative disease, and the molecular mechanism underlying its pathology remains poorly understood. However, inflammation is known to play an important role in the development of this condition. To identify driver genes that affect the inflammatory response in amyotrophic lateral sclerosis, as well as potential treatment targets, it is crucial to analyze brain tissue samples from patients with both sporadic amyotrophic lateral sclerosis and C9orf72-related amyotrophic lateral sclerosis. Therefore, in this study we used a network-driven gene analysis tool, NetBID2.0, which is based on SJARACNe, a scalable algorithm for the reconstruction of accurate cellular networks, to experimentally analyze sequencing data from patients with sporadic amyotrophic lateral sclerosis. The results showed that the OSMR gene is pathogenic in amyotrophic lateral sclerosis and participates in the progression of amyotrophic lateral sclerosis by mediating the neuroinflammatory response. Furthermore, there were differences in OSMR activity and expression between patients with sporadic amyotrophic lateral sclerosis and those with C9orf72-related amyotrophic lateral sclerosis. These findings suggest that OSMR may be a diagnostic and prognostic marker for amyotrophic lateral sclerosis.}, }
@article {pmid38524401, year = {2024}, author = {Pota, V and Sansone, P and De Sarno, S and Aurilio, C and Coppolino, F and Barbarisi, M and Barbato, F and Fiore, M and Cosenza, G and Passavanti, MB and Pace, MC}, title = {Amyotrophic Lateral Sclerosis and Pain: A Narrative Review from Pain Assessment to Therapy.}, journal = {Behavioural neurology}, volume = {2024}, number = {}, pages = {1228194}, pmid = {38524401}, issn = {1875-8584}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Pain Measurement ; Quality of Life ; *Neurodegenerative Diseases/complications ; Pain/drug therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent neurodegenerative disease of the motor system that affects upper and lower motor neurons, leading to progressive muscle weakness, spasticity, atrophy, and respiratory failure, with a life expectancy of 2-5 years after symptom onset. In addition to motor symptoms, patients with ALS have a multitude of nonmotor symptoms; in fact, it is currently considered a multisystem disease. The purpose of our narrative review is to evaluate the different types of pain, the correlation between pain and the disease's stages, the pain assessment tools in ALS patients, and the available therapies focusing above all on the benefits of cannabis use. Pain is an underestimated and undertreated symptom that, in the last few years, has received more attention from research because it has a strong impact on the quality of life of these patients. The prevalence of pain is between 15% and 85% of ALS patients, and the studies on the type and intensity of pain are controversial. The absence of pain assessment tools validated in the ALS population and the dissimilar study designs influence the knowledge of ALS pain and consequently the pharmacological therapy. Several studies suggest that ALS is associated with changes in the endocannabinoid system, and the use of cannabis could slow the disease progression due to its neuroprotective action and act on pain, spasticity, cramps, sialorrhea, and depression. Our research has shown high patients' satisfaction with the use of cannabis for the treatment of spasticity and related pain. However, especially due to the ethical problems and the lack of interest of pharmaceutical companies, further studies are needed to ensure the most appropriate care for ALS patients.}, }
@article {pmid38516735, year = {2024}, author = {Li, X and Bedlack, R}, title = {Evaluating emerging drugs in phase II &amp; III for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert opinion on emerging drugs}, volume = {29}, number = {2}, pages = {93-102}, doi = {10.1080/14728214.2024.2333420}, pmid = {38516735}, issn = {1744-7623}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Humans ; *Drug Development ; *Drugs, Investigational/pharmacology ; Animals ; *Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Drug Design ; Molecular Targeted Therapy ; Research Design ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis is a rapidly progressive motor neuron disorder causing severe disability and premature death. Owing to the advances in uncovering ALS pathophysiology, efficient clinical trial design and research advocacy program, several disease-modifying drugs have been approved for treating ALS. Despite this progress, ALS remains a rapidly disabling and life shortening condition. There is a critical need for more effective therapies.<br><br>AREAS COVERED: Here, we reviewed the emerging ALS therapeutics undergoing phase II &amp; III clinical trials. To identify the investigational drugs, we searched ALS and phase II/III trials that are active and recruiting or not yet recruiting on clinicaltrials.gov and Pharmaprojects database.<br><br>EXPERT OPINION: The current pipeline is larger and more diverse than ever, with drugs targeting potential genetic and retroviral causes of ALS and drugs targeting a wide array of downstream pathways, including RNA metabolism, protein aggregation, integrated stress response and neuroinflammation.We remain most excited about those that target direct causes of ALS, e.g. antisense oligonucleotides targeting causative genes. Drugs that eliminate abnormal protein aggregates are also up-and-coming. Eventually, because of the heterogeneity of ALS pathophysiology, biomarkers that determine which biological events are most important for an individual ALS patient are needed.}, }
@article {pmid38515787, year = {2024}, author = {Wang, L and Fang, X and Ling, B and Wang, F and Xia, Y and Zhang, W and Zhong, T and Wang, X}, title = {Research progress on ferroptosis in the pathogenesis and treatment of neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1359453}, pmid = {38515787}, issn = {1662-5102}, abstract = {Globally, millions of individuals are impacted by neurodegenerative disorders including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD). Although a great deal of energy and financial resources have been invested in disease-related research, breakthroughs in therapeutic approaches remain elusive. The breakdown of cells usually happens together with the onset of neurodegenerative diseases. However, the mechanism that triggers neuronal loss is unknown. Lipid peroxidation, which is iron-dependent, causes a specific type of cell death called ferroptosis, and there is evidence its involvement in the pathogenic cascade of neurodegenerative diseases. However, the specific mechanisms are still not well known. The present article highlights the basic processes that underlie ferroptosis and the corresponding signaling networks. Furthermore, it provides an overview and discussion of current research on the role of ferroptosis across a variety of neurodegenerative conditions.}, }
@article {pmid38515326, year = {2024}, author = {Lee, DY and Kwon, YN and Lee, K and Kim, SJ and Sung, JJ}, title = {Dual effects of TGF-β inhibitor in ALS - inhibit contracture and neurodegeneration.}, journal = {Journal of neurochemistry}, volume = {168}, number = {9}, pages = {2495-2514}, doi = {10.1111/jnc.16102}, pmid = {38515326}, issn = {1471-4159}, support = {2018R1A5A2025964//National Research Foundation of Korea (NRF) Grant/ ; 2019M3C7A1031867//National Research Foundation of Korea (NRF) Grant/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; Mice ; *Transforming Growth Factor beta/metabolism/antagonists &amp; inhibitors ; *Contracture/drug therapy/prevention &amp; control ; Mice, Transgenic ; Male ; Mice, Inbred C57BL ; Piperidines/pharmacology/therapeutic use ; Humans ; }, abstract = {As persistent elevation of transforming growth factor-β (TGF-β) promotes fibrosis of muscles and joints and accelerates disease progression in amyotrophic lateral sclerosis (ALS), we investigated whether inhibition of TGF-β would be effective against both exacerbations. The effects of TGF-β and its inhibitor on myoblasts and fibroblasts were tested in vitro and confirmed in vivo, and the dual action of a TGF-β inhibitor in ameliorating the pathogenic role of TGF-β in ALS mice was identified. In the peripheral neuromuscular system, fibrosis in the muscles and joint cavities induced by excessive TGF-β causes joint contracture and muscular degeneration, which leads to motor dysfunction. In an ALS mouse model, an increase in TGF-β in the central nervous system (CNS), consistent with astrocyte activity, was associated with M1 microglial activity and pro-inflammatory conditions, as well as with neuronal cell death. Treatment with the TGF-β inhibitor halofuginone could prevent musculoskeletal fibrosis, resulting in the alleviation of joint contracture and delay of motor deterioration in ALS mice. Halofuginone could also reduce glial cell-induced neuroinflammation and neuronal apoptosis. These dual therapeutic effects on both the neuromuscular system and the CNS were observed from the beginning to the end stages of ALS; as a result, treatment with a TGF-β inhibitor from the early stage of disease delayed the time of symptom exacerbation in ALS mice, which led to prolonged survival.}, }
@article {pmid38511649, year = {2024}, author = {Craig, RA and De Vicente, J and Estrada, AA and Feng, JA and Lexa, KW and Canet, MJ and Dowdle, WE and Erickson, RI and Flores, BN and Haddick, PCG and Kane, LA and Lewcock, JW and Moerke, NJ and Poda, SB and Sweeney, Z and Takahashi, RH and Tong, V and Wang, J and Yulyaningsih, E and Solanoy, H and Scearce-Levie, K and Sanchez, PE and Tang, L and Xu, M and Zhang, R and Osipov, M}, title = {Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases.}, journal = {Journal of medicinal chemistry}, volume = {67}, number = {7}, pages = {5758-5782}, doi = {10.1021/acs.jmedchem.3c02422}, pmid = {38511649}, issn = {1520-4804}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mutation ; Eukaryotic Initiation Factor-2B/genetics/metabolism ; Brain/metabolism ; *Leukoencephalopathies/metabolism ; }, abstract = {Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and stress granule formation in response to cellular insult. Modulation of the ISR has been proposed as a therapeutic strategy for treatment of neurodegenerative diseases such as vanishing white matter (VWM) disease and amyotrophic lateral sclerosis (ALS) based on its ability to improve cellular homeostasis and prevent neuronal degeneration. Herein, we report the small-molecule discovery campaign that identified potent, selective, and CNS-penetrant eIF2B activators using both structure- and ligand-based drug design. These discovery efforts culminated in the identification of DNL343, which demonstrated a desirable preclinical drug profile, including a long half-life and high oral bioavailability across preclinical species. DNL343 was progressed into clinical studies and is currently undergoing evaluation in late-stage clinical trials for ALS.}, }
@article {pmid38511059, year = {2024}, author = {Casado Gama, H and Amorós, MA and Andrade de Araújo, M and Sha, CM and Vieira, MPS and Torres, RGD and Souza, GF and Junkes, JA and Dokholyan, NV and Leite Góes Gitaí, D and Duzzioni, M}, title = {Systematic review and meta-analysis of dysregulated microRNAs derived from liquid biopsies as biomarkers for amyotrophic lateral sclerosis.}, journal = {Non-coding RNA research}, volume = {9}, number = {2}, pages = {523-535}, pmid = {38511059}, issn = {2468-0540}, abstract = {The discovery of disease-specific biomarkers, such as microRNAs (miRNAs), holds the potential to transform the landscape of Amyotrophic Lateral Sclerosis (ALS) by facilitating timely diagnosis, monitoring treatment response, and accelerating drug discovery. Such advancement could ultimately improve the quality of life and survival rates for ALS patients. Despite more than a decade of research, no miRNA biomarker candidate has been translated into clinical practice. We conducted a systematic review and meta-analysis to quantitatively synthesize data from original studies that analyzed miRNA expression from liquid biopsies via PCR and compared them to healthy controls. Our analysis encompasses 807 miRNA observations from 31 studies, stratified according to their source tissue. We identified consistently dysregulated miRNAs in serum (hsa-miR-3665, -4530, -4745-5p, -206); blood (hsa-miR-338-3p, -183-5p); cerebrospinal fluid (hsa-miR-34a-3p); plasma (hsa-miR-206); and neural-enriched extracellular vesicles from plasma (hsa-miR-146a-5p, -151a-5p, -10b-5p, -29b-3p, and -4454). The meta-analyses provided further support for the upregulation of hsa-miR-206, hsa-miR-338-3p, hsa-miR-146a-5p and hsa-miR-151a-5p, and downregulation of hsa-miR-183-5p, hsa-miR-10b-5p, hsa-miR-29b-3p, and hsa-miR-4454 as consistent indicators of ALS across independent studies. Our findings provide valuable insights into the current understanding of miRNAs' dysregulated expression in ALS patients and on the researchers' choices of methodology. This work contributes to the ongoing efforts towards discovering disease-specific biomarkers.}, }
@article {pmid38510000, year = {2024}, author = {Ditan, ID and Turalde, CWR}, title = {Treatment gaps in the care of amyotrophic lateral sclerosis in the Philippines: A scoping review.}, journal = {Heliyon}, volume = {10}, number = {6}, pages = {e27944}, pmid = {38510000}, issn = {2405-8440}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease affecting both the upper and lower motor neurons. Much of the management of ALS is supportive with the goal of maximizing patient quality of life. While the Philippines was participative in the "Ice Bucket Challenge" in 2014, it is up for investigation whether substantial changes occurred to improve healthcare for ALS patients. This study aims to evaluate the treatment gaps in the management of ALS in the Philippines through a scoping review. Data on epidemiology, health systems, and pharmacotherapy available regarding ALS in the local setting were synthesized. Nine articles were included. As of July 2023, there were only four indexed studies on ALS from the Philippines. Five of the included articles investigated ALS in Filipino populations but were not authored by Filipinos nor affiliated with Philippine institutions. The available literature showed a distinct lack of local ALS epidemiologic data, as well as limited availability in diagnostic centers, medications, health financing options, and digestible information for Filipinos. The limitations in managing ALS in the country are multifactorial - from political, medical, and social. It is imperative to establish a national database, financing systems, support groups, and accessible diagnostic centers for ALS patients.}, }
@article {pmid38508480, year = {2024}, author = {Bager, P and Hvas, CL and Dahlerup, JF}, title = {Severe Fatigue in Inflammatory Bowel Disease: Dopaminergic Therapy With Modafinil or Vitamin Therapy With Thiamine.}, journal = {Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association}, volume = {22}, number = {11}, pages = {2348-2349}, doi = {10.1016/j.cgh.2024.03.002}, pmid = {38508480}, issn = {1542-7714}, mesh = {Humans ; *Modafinil/therapeutic use ; *Fatigue/drug therapy ; *Inflammatory Bowel Diseases/drug therapy/complications ; *Thiamine/therapeutic use ; Treatment Outcome ; Male ; Female ; Middle Aged ; }, abstract = {We found Moulton et al's[1] illustrative case series of 10 patients with inflammatory bowel disease (IBD) and chronic fatigue, all presenting with depression, particularly interesting. [1] Among the patients, 8 previously had undergone treatment with multiple psychotropic medications, and 2 had active IBD as indicated by increased fecal calprotectin levels. Remarkably, all 10 patients responded positively to open-label treatment with modafinil, a central nervous system stimulant that blocks dopamine reuptake transport, which resulted in an impressive improvement in their fatigue symptoms. At baseline, the self-reported mean fatigue score was 16, measured on the IBD Fatigue Assessment Scale (IBD-FAS), which ranges up to 20, and with levels higher than 11 indicating severe fatigue. After 6 months of modafinil treatment, the mean fatigue score was 6.7.[1].}, }
@article {pmid38504592, year = {2024}, author = {Hamilton, HL and Akther, M and Anis, S and Colwell, CB and Vargas, MR and Pehar, M}, title = {Nicotinamide Adenine Dinucleotide Precursor Supplementation Modulates Neurite Complexity and Survival in Motor Neurons from Amyotrophic Lateral Sclerosis Models.}, journal = {Antioxidants &amp; redox signaling}, volume = {41}, number = {7-9}, pages = {573-589}, pmid = {38504592}, issn = {1557-7716}, support = {R01 NS089640/NS/NINDS NIH HHS/United States ; R01 NS100835/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *Motor Neurons/metabolism/pathology/drug effects ; Mice ; Humans ; *Disease Models, Animal ; *NAD/metabolism ; *Induced Pluripotent Stem Cells/metabolism/cytology ; *Neurites/metabolism/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Nicotinamide Mononucleotide/pharmacology/metabolism ; Neuroprotective Agents/pharmacology ; DNA-Binding Proteins/metabolism/genetics ; Cell Survival/drug effects ; Dietary Supplements ; }, abstract = {Aims: Increasing nicotinamide adenine dinucleotide (NAD[+]) availability has been proposed as a therapeutic approach to prevent neurodegeneration in amyotrophic lateral sclerosis (ALS). Accordingly, NAD[+] precursor supplementation appears to exert neuroprotective effects in ALS patients and mouse models. The mechanisms mediating neuroprotection remain uncertain but could involve changes in multiple cell types. We investigated a potential direct effect of the NAD[+] precursor nicotinamide mononucleotide (NMN) on the health of cultured induced pluripotent stem cell (iPSC)-derived human motor neurons and in motor neurons isolated from two ALS mouse models, that is, mice overexpressing wild-type transactive response DNA binding protein-43 (TDP-43) or the ALS-linked human superoxide dismutase 1 with the G93A mutation (hSOD1[G93A]). Results: NMN treatment increased the complexity of neuronal processes in motor neurons isolated from both mouse models and in iPSC-derived human motor neurons. In addition, NMN prevented neuronal death induced by trophic factor deprivation. In mouse and human motor neurons expressing ALS-linked mutant superoxide dismutase 1, NMN induced an increase in glutathione levels, but this effect was not observed in nontransgenic or TDP-43 overexpressing motor neurons. In contrast, NMN treatment normalized the TDP-43 cytoplasmic mislocalization induced by its overexpression. Innovation: NMN can directly act on motor neurons to increase the growth and complexity of neuronal processes and prevent the death induced by trophic factor deprivation. Conclusion: Our results support a direct beneficial effect of NAD[+] precursor supplementation on the maintenance of the neuritic arbor in motor neurons. Importantly, this was observed in motor neurons isolated from two different ALS models, with and without involvement of TDP-43 pathology, supporting its therapeutic potential in sporadic and familial ALS. Antioxid. Redox Signal. 41, 573-589.}, }
@article {pmid38504285, year = {2024}, author = {Papaiz, F and Dourado, MET and de Medeiros Valentim, RA and Pinto, R and de Morais, AHF and Arrais, JP}, title = {Ensemble-imbalance-based classification for amyotrophic lateral sclerosis prognostic prediction: identifying short-survival patients at diagnosis.}, journal = {BMC medical informatics and decision making}, volume = {24}, number = {1}, pages = {80}, pmid = {38504285}, issn = {1472-6947}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Prognosis ; Machine Learning ; }, abstract = {Prognosticating Amyotrophic Lateral Sclerosis (ALS) presents a formidable challenge due to patients exhibiting different onset sites, progression rates, and survival times. In this study, we have developed and evaluated Machine Learning (ML) algorithms that integrate Ensemble and Imbalance Learning techniques to classify patients into Short and Non-Short survival groups based on data collected during diagnosis. We aimed to identify individuals at high risk of mortality within 24 months of symptom onset through analysis of patient data commonly encountered in daily clinical practice. Our Ensemble-Imbalance approach underwent evaluation employing six ML algorithms as base classifiers. Remarkably, our results outperformed those of individual algorithms, achieving a Balanced Accuracy of 88% and a Sensitivity of 96%. Additionally, we used the Shapley Additive Explanations framework to elucidate the decision-making process of the top-performing model, pinpointing the most important features and their correlations with the target prediction. Furthermore, we presented helpful tools to visualize and compare patient similarities, offering valuable insights. Confirming the obtained results, our approach could aid physicians in devising personalized treatment plans at the time of diagnosis or serve as an inclusion/exclusion criterion in clinical trials.}, }
@article {pmid38499161, year = {2024}, author = {Bashir, S and Aiman, A and Shahid, M and Chaudhary, AA and Sami, N and Basir, SF and Hassan, I and Islam, A}, title = {Amyloid-induced neurodegeneration: A comprehensive review through aggregomics perception of proteins in health and pathology.}, journal = {Ageing research reviews}, volume = {96}, number = {}, pages = {102276}, doi = {10.1016/j.arr.2024.102276}, pmid = {38499161}, issn = {1872-9649}, mesh = {Humans ; Amyloid/metabolism ; *Amyloidosis/metabolism ; *Neurodegenerative Diseases/metabolism ; *Parkinson Disease/metabolism ; Amyloidogenic Proteins ; Perception ; }, abstract = {Amyloidosis of protein caused by fibrillation and aggregation are some of the most exciting new edges not only in protein sciences but also in molecular medicines. The present review discusses recent advancements in the field of neurodegenerative diseases and therapeutic applications with ongoing clinical trials, featuring new areas of protein misfolding resulting in aggregation. The endogenous accretion of protein fibrils having fibrillar morphology symbolizes the beginning of neuro-disorders. Prognostic amyloidosis is prominent in numerous degenerative infections such as Alzheimer's and Parkinson's disease, Amyotrophic lateral sclerosis (ALS), etc. However, the molecular basis determining the intracellular or extracellular evidence of aggregates, playing a significant role as a causative factor in neurodegeneration is still unclear. Structural conversions and protein self-assembly resulting in the formation of amyloid oligomers and fibrils are important events in the pathophysiology of the disease. This comprehensive review sheds light on the evolving landscape of potential treatment modalities, highlighting the ongoing clinical trials and the potential socio-economic impact of novel therapeutic interventions in the realm of neurodegenerative diseases. Furthermore, many drugs are undergoing different levels of clinical trials that would certainly help in treating these disorders and will surely improve the socio-impact of human life.}, }
@article {pmid38498721, year = {2024}, author = {Kertesz, A and Finger, E and Munoz, DG}, title = {Progress in Primary Progressive Aphasia: A Review.}, journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology}, volume = {37}, number = {1}, pages = {3-12}, pmid = {38498721}, issn = {1543-3641}, mesh = {Humans ; *Frontotemporal Dementia/diagnosis/genetics ; *Supranuclear Palsy, Progressive/genetics/pathology ; Syndrome ; *Aphasia, Primary Progressive ; }, abstract = {We present a review of the definition, classification, and epidemiology of primary progressive aphasia (PPA); an update of the taxonomy of the clinical syndrome of PPA; and recent advances in the neuroanatomy, pathology, and genetics of PPA, as well as the search for biomarkers and treatment. PPA studies that have contributed to concepts of language organization and disease propagation in neurodegeneration are also reviewed. In addition, the issues of heterogeneity versus the relationships of the clinical phenotypes and their relationship to biological, pathological, and genetic advances are discussed, as is PPA's relationship to other conditions such as frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, Pick disease, and amyotrophic lateral sclerosis. Arguments are presented in favor of considering these conditions as one entity versus many.}, }
@article {pmid38493058, year = {2024}, author = {Milani, M and Della Valle, I and Rossi, S and Fabbrizio, P and Margotta, C and Nardo, G and Cozzolino, M and D'Ambrosi, N and Apolloni, S}, title = {Neuroprotective effects of niclosamide on disease progression via inflammatory pathways modulation in SOD1-G93A and FUS-associated amyotrophic lateral sclerosis models.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {3}, pages = {e00346}, pmid = {38493058}, issn = {1878-7479}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Disease Models, Animal ; *Disease Progression ; Inflammation/drug therapy ; Mice, Transgenic ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Niclosamide/pharmacology/therapeutic use ; RNA-Binding Protein FUS/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease influenced by genetic, epigenetic, and environmental factors, resulting in dysfunction in cellular and molecular pathways. The limited efficacy of current treatments highlights the need for combination therapies targeting multiple aspects of the disease. Niclosamide, an anthelminthic drug listed as an essential medicine, has been repurposed in clinical trials for different diseases due to its anti-inflammatory and anti-fibrotic properties. Niclosamide can inhibit various molecular pathways (e.g., STAT3, mTOR) that are dysregulated in ALS, suggesting its potential to disrupt these altered mechanisms associated with the pathology. We administered niclosamide intraperitoneally to two transgenic murine models, SOD1-G93A and FUS mice, mimicking key pathological processes of ALS. The treatment was initiated at the onset of symptoms, and we assessed disease progression by neurological scores, rotarod and wire tests, and monitored survival. Furthermore, we investigated cellular and molecular mechanisms affected by niclosamide in the spinal cord and muscle of ALS mice. In both models, the administration of niclosamide resulted in a slowdown of disease progression, an increase in survival rates, and an improvement in tissue pathology. This was characterised by reduced gliosis, motor neuron loss, muscle atrophy, and inflammatory pathways. Based on these results, our findings demonstrate that niclosamide can impact multiple pathways involved in ALS. This multi-targeted approach leads to a slowdown in the progression of the disease, positioning niclosamide as a promising candidate for repurposing in the treatment of ALS.}, }
@article {pmid38489867, year = {2024}, author = {Tausendfreund, O and Bidlingmaier, M and Martini, S and Müller, K and Rippl, M and Schilbach, K and Schmidmaier, R and Drey, M}, title = {Growth hormone treatment in aged patients with comorbidities: A systematic review.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {75}, number = {}, pages = {101584}, doi = {10.1016/j.ghir.2024.101584}, pmid = {38489867}, issn = {1532-2238}, mesh = {Aged ; Humans ; Comorbidity ; Growth Hormone ; *Human Growth Hormone/adverse effects/therapeutic use ; Insulin-Like Growth Factor I ; Quality of Life ; Randomized Controlled Trials as Topic ; *Aging/pathology ; }, abstract = {OBJECTIVE: Hormonal substitution with growth hormone in aged patients remains a debated research topic and is rarely initiated in clinical practice. This reluctance may originate from concerns about adverse effects and the uncritical use as an anti-aging agent. Nevertheless, beneficial effects for selected patients suffering from certain acute and chronic illnesses could justify its use at an advanced age. This systematic review analyzes randomized controlled studies of GH interventions in older patients with different comorbidities to assess both, beneficial and harmful effects.<br><br>DESIGN: A systematic search strategy was implemented to identify relevant studies from PubMed, MEDLINE, and The Cochrane Library.<br><br>INCLUSION CRITERIA: participants aged over 65&#xa0;years, randomized controlled trials involving human growth hormone (GH) and presence of at least one additional comorbidity independent of a flawed somatotropic axis.<br><br>RESULTS: The eight eligible studies encompassed various comorbidities including osteoporosis, frailty, chronic heart failure, hip fracture, amyotrophic lateral sclerosis and hemodialysis. Outcomes varied, including changes in body composition, physical performance, strength, bone mineral density, cardiovascular parameters, quality of life and housing situation. Study protocols differed greatly in GH application frequency (daily, 2nd day or 3&#xd7;/week), doses (0.41&#xa0;mg-2.6&#xa0;mg; mean 1.3&#xa0;mg per 60&#xa0;kg patient) and duration (1-12&#xa0;months; mean 7&#xa0;months). Mild dose-related side effects were reported, alongside noticeable positive impacts particularly on body composition, functionality, and quality of life.<br><br>CONCLUSION: Despite limited evidence, GH treatment might offer diverse benefits with few adverse effects. Further research with IGF-I dependent indication and clear outcomes, incorporating IGF-I dependent GH titration in older adults is warranted.}, }
@article {pmid38487578, year = {2024}, author = {Cortes-Flores, H and Torrandell-Haro, G and Brinton, RD}, title = {Association between CNS-active drugs and risk of Alzheimer's and age-related neurodegenerative diseases.}, journal = {Frontiers in psychiatry}, volume = {15}, number = {}, pages = {1358568}, pmid = {38487578}, issn = {1664-0640}, support = {P01 AG026572/AG/NIA NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; R01 AG057931/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVE: As neuropsychiatric conditions can increase the risk of age-related neurodegenerative diseases (NDDs), the impact of CNS-active drugs on the risk of developing Alzheimer's Disease (AD), non-AD dementia, Multiple Sclerosis (MS), Parkinson's Disease (PD) and Amyotrophic Lateral Sclerosis (ALS) was investigated.<br><br>RESEARCH DESIGN AND METHODS: A retrospective cohort analysis of a medical claims dataset over a 10 year span was conducted in patients aged 60 years or older. Participants were propensity score matched for comorbidity severity and demographic parameters. Relative risk (RR) ratios and 95% confidence intervals (CI) were determined for age-related NDDs. Cumulative hazard ratios and treatment duration were determined to assess the association between CNS-active drugs and NDDs at different ages and treatment duration intervals.<br><br>RESULTS: In 309,128 patients who met inclusion criteria, exposure to CNS-active drugs was associated with a decreased risk of AD (0.86% vs 1.73%, RR: 0.50; 95% CI: 0.47-0.53; p <.0001) and all NDDs (3.13% vs 5.76%, RR: 0.54; 95% CI: 0.53-0.56; p <.0001). Analysis of impact of drug class on risk of AD indicated that antidepressant, sedative, anticonvulsant, and stimulant medications were associated with significantly reduced risk of AD whereas atypical antipsychotics were associated with increased AD risk. The greatest risk reduction for AD and NDDs occurred in patients aged 70 years or older with a protective effect only in patients with long-term therapy (>3 years). Furthermore, responders to these therapeutics were characterized by diagnosed obesity and higher prescriptions of anti-inflammatory drugs and menopausal hormonal therapy, compared to patients with a diagnosis of AD (non-responders). Addition of a second CNS-active drug was associated with greater reduction in AD risk compared to monotherapy, with the combination of a Z-drug and an SNRI associated with greatest AD risk reduction.<br><br>CONCLUSION: Collectively, these findings indicate that CNS-active drugs were associated with reduced risk of developing AD and other age-related NDDs. The exception was atypical antipsychotics, which increased risk. Potential use of combination therapy with atypical antipsychotics could mitigate the risk conferred by these drugs. Evidence from these analyses advance precision prevention strategies to reduce the risk of age-related NDDs in persons with neuropsychiatric disorders.}, }
@article {pmid38487369, year = {2024}, author = {Fagnani, E and Bonì, F and Seneci, P and Gornati, D and Muzio, L and Mastrangelo, E and Milani, M}, title = {Stabilization of the retromer complex: Analysis of novel binding sites of bis-1,3-phenyl guanylhydrazone 2a to the VPS29/VPS35 interface.}, journal = {Computational and structural biotechnology journal}, volume = {23}, number = {}, pages = {1088-1093}, pmid = {38487369}, issn = {2001-0370}, abstract = {The stabilization of the retromer protein complex can be effective in the treatment of different neurological disorders. Following the identification of bis-1,3-phenyl guanylhydrazone 2a as an effective new compound for the treatment of amyotrophic lateral sclerosis, in this work we analyze the possible binding sites of this molecule to the VPS35/VPS29 dimer of the retromer complex. Our results show that the affinity for different sites of the protein assembly depends on compound charge and therefore slight changes in the cell microenvironment could promote different binding states. Finally, we describe a novel binding site located in a deep cleft between VPS29 and VPS35 that should be further explored to select novel molecular chaperones for the stabilization of the retromer complex.}, }
@article {pmid38483107, year = {2024}, author = {Adari, MD and Pandian, BA and Gaines, TA and Prasad, PV and Jugulam, M}, title = {Confirmation and characterization of the first case of acetolactate synthase (ALS)-inhibitor resistance in Japanese brome (Bromus japonicus) in the US.}, journal = {Pest management science}, volume = {80}, number = {8}, pages = {3717-3725}, doi = {10.1002/ps.8074}, pmid = {38483107}, issn = {1526-4998}, mesh = {*Acetolactate Synthase/genetics/antagonists &amp; inhibitors/metabolism ; *Bromus/enzymology/drug effects/genetics ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Kansas ; *Plant Proteins/genetics/metabolism/antagonists &amp; inhibitors ; Plant Weeds/drug effects/genetics/enzymology ; }, abstract = {BACKGROUND: Japanese brome (Bromus japonicus Thumb.) is one of the problematic annual weeds in winter wheat (Triticum aestivum L.) and is generally controlled by acetolactate synthase (ALS) inhibitors. Repeated use of the ALS inhibitor propoxycarbazone-Na resulted in the evolution of resistance to this herbicide in three B. japonicus populations, i.e., R1, R2, and R3 in Kansas (KS). However, the level of resistance and mechanism conferring resistance in these populations is unknown. The objectives of this research were to (i) evaluate the level of resistance to propoxycarbazone-Na in R1, R2, and R3 in comparison with a known susceptible population (S1), (ii) investigate the mechanism of resistance involved in conferring ALS-inhibitor resistance, and (iii) investigate the cross-resistance to other ALS inhibitors.<br><br>RESULTS: Dose-response (0 to 16x; x&#x2009;=&#x2009;44&#x2009;g ai ha[-1] of propoxycarbazone-Na) assay indicated 167, 125, and 667-fold resistance in R1, R2 and R3 populations, respectively, compared to S1 population. ALS gene sequencing confirmed the mutations resulting in amino acid substitutions, i.e., Pro-197-Thr (R3, R1)/Ser (R2, R1) bestowing resistance to these ALS inhibitors. Such amino acid substitutions also showed differential cross-resistance to sulfosulfuron, mesosulfuron-methyl, pyroxsulam, and imazamox among resistant populations. Pretreatment with malathion (a cytochrome P450 enzyme-inhibitor) followed by imazamox treatment suggested cross-resistance to this herbicide possibly via metabolism only in R3 population.<br><br>CONCLUSION: Overall, these results confirm the first case of target-site based resistance to ALS inhibitors in B. japonicus in the US, highlighting the need for exploring herbicides with alternative modes of action to enhance weed control in winter wheat. &#xa9; 2024 Society of Chemical Industry.}, }
@article {pmid38481899, year = {2024}, author = {El-Ghanem, M and Abdulrazeq, H and Brasiliense, L and Abbad, H and Aguilar-Salinas, P and Al-Mufti, F and Dumont, T}, title = {Outcomes of Mechanical Thrombectomy in Patients With Neurological Disorders: A National Inpatient Sample Database Analysis.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e54063}, pmid = {38481899}, issn = {2168-8184}, abstract = {INTRODUCTION: Mechanical thrombectomy (MT) has changed the standard of care for patients presenting with acute ischemic stroke (AIS). The window of treatment has significantly increased the number of patients who would benefit from intervention and operators may be confronted with patients harboring preexistent neurological disorders. Still, the epidemiology of patients with AIS and neurological disorders has not been established.<br><br>METHODS: This is a retrospective study,&#xa0;which utilizes data from the National Inpatient Sample (NIS) between 2012 and 2016. Patients with the major neurological comorbidities in the study were included: Alzheimer's dementia (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and myasthenia gravis (MG). These patients were divided into groups and analyzed based on discharged home status, length of hospital stay (LOS), and inpatient mortality. These outcomes were also compared between patients who underwent MT versus those who did not.<br><br>RESULTS: In this study, 460,070 patients with AIS were identified and included. MT was performed less often when the patient had a neurological diagnosis compared to those without a&#xa0;neurological disease (p<0.0001). However, patients with AIS who&#xa0;have underlying neurological disorders such as AD, PD, and MS&#xa0;have shown similar outcomes after MT to those who do not have these disorders.<br><br>CONCLUSION: Patients with preexisting neurological disorders were less likely to undergo MT. Further studies are required to elucidate the implications of having a neurological disorder in the setting of an AIS.}, }
@article {pmid38477419, year = {2024}, author = {de Fátima Dos Santos Sampaio, M and de Paiva, YB and Sampaio, TB and Pereira, MG and Coimbra, NC}, title = {Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson's disease and in comorbidity with psychiatric disorders.}, journal = {Basic &amp; clinical pharmacology &amp; toxicology}, volume = {134}, number = {5}, pages = {574-601}, doi = {10.1111/bcpt.13997}, pmid = {38477419}, issn = {1742-7843}, support = {2014/11869-0//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 2020/15050-7//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; PDJ grant 155489/2018-6//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; Research Grant (NAP-USP-NuPNE; process IaPq2012-15//Universidade de S&#xe3;o Paulo/ ; 374/2022//Funda&#xe7;&#xe3;o de Apoio ao Ensino, Pesquisa e Assist&#xea;ncia do Hospital das Cl&#xed;nicas da Faculdade de Medicina de Ribeir&#xe3;o Preto da Universidade de S&#xe3;o Paulo/ ; 302605/2021-5//CNPq/ ; 301341/2015-0//CNPq/ ; 301905/2010-0//CNPq/ ; 155489/2018-6//CNPq/ ; }, mesh = {Humans ; *Cannabidiol/pharmacology/therapeutic use ; *Parkinson Disease/drug therapy ; *Multiple Sclerosis/drug therapy ; Receptor, Serotonin, 5-HT1A/therapeutic use ; *Cannabinoids/pharmacology/therapeutic use ; *Epilepsy/drug therapy ; *Mental Disorders/drug therapy ; Comorbidity ; }, abstract = {Studies have demonstrated the neuroprotective effect of cannabidiol (CBD) and other Cannabis sativa L. derivatives on diseases of the central nervous system caused by their direct or indirect interaction with endocannabinoid system-related receptors and other molecular targets, such as the 5-HT1A receptor, which is a potential pharmacological target of CBD. Interestingly, CBD binding with the 5-HT1A receptor may be suitable for the treatment of epilepsies, parkinsonian syndromes and amyotrophic lateral sclerosis, in which the 5-HT1A serotonergic receptor plays a key role. The aim of this review was to provide an overview of cannabinoid effects on neurological disorders, such as epilepsy, multiple sclerosis and Parkinson's diseases, and discuss their possible mechanism of action, highlighting interactions with molecular targets and the potential neuroprotective effects of phytocannabinoids. CBD has been shown to have significant therapeutic effects on epilepsy and Parkinson's disease, while nabiximols contribute to a reduction in spasticity and are a frequent option for the treatment of multiple sclerosis. Although there are multiple theories on the therapeutic potential of cannabinoids for neurological disorders, substantially greater progress in the search for strong scientific evidence of their pharmacological effectiveness is needed.}, }
@article {pmid38474719, year = {2024}, author = {Noor Eddin, A and Alfuwais, M and Noor Eddin, R and Alkattan, K and Yaqinuddin, A}, title = {Gut-Modulating Agents and Amyotrophic Lateral Sclerosis: Current Evidence and Future Perspectives.}, journal = {Nutrients}, volume = {16}, number = {5}, pages = {}, pmid = {38474719}, issn = {2072-6643}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Dysbiosis/etiology ; *Gastrointestinal Microbiome/physiology ; *Microbiota ; Disease Progression ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a highly fatal neurodegenerative disorder characterized by the progressive wasting and paralysis of voluntary muscle. Despite extensive research, the etiology of ALS remains elusive, and effective treatment options are limited. However, recent evidence implicates gut dysbiosis and gut-brain axis (GBA) dysfunction in ALS pathogenesis. Alterations to the composition and diversity of microbial communities within the gut flora have been consistently observed in ALS patients. These changes are often correlated with disease progression and patient outcome, suggesting that GBA modulation may have therapeutic potential. Indeed, targeting the gut microbiota has been shown to be neuroprotective in several animal models, alleviating motor symptoms and mitigating disease progression. However, the translation of these findings to human patients is challenging due to the complexity of ALS pathology and the varying diversity of gut microbiota. This review comprehensively summarizes the current literature on ALS-related gut dysbiosis, focusing on the implications of GBA dysfunction. It delineates three main mechanisms by which dysbiosis contributes to ALS pathology: compromised intestinal barrier integrity, metabolic dysfunction, and immune dysregulation. It also examines preclinical evidence on the therapeutic potential of gut-microbiota-modulating agents (categorized as prebiotics, probiotics, and postbiotics) in ALS.}, }
@article {pmid38474416, year = {2024}, author = {Tzeplaeff, L and Jürs, AV and Wohnrade, C and Demleitner, AF}, title = {Unraveling the Heterogeneity of ALS-A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials.}, journal = {Cells}, volume = {13}, number = {5}, pages = {}, pmid = {38474416}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Treatment Outcome ; Clinical Trials as Topic ; }, abstract = {Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be a single disease entity but rather may represent a clinical syndrome, with diverse genetic and molecular causes, histopathological alterations, and subsequent clinical presentations contributing to its complexity and variability among individuals. Defining a way to subcluster ALS patients is becoming a central endeavor in the field. Identifying specific clusters and applying them in clinical trials could enable the development of more effective treatments. This review aims to summarize the available data on heterogeneity in ALS with regard to various aspects, e.g., clinical, genetic, and molecular.}, }
@article {pmid38473944, year = {2024}, author = {Scarian, E and Viola, C and Dragoni, F and Di Gerlando, R and Rizzo, B and Diamanti, L and Gagliardi, S and Bordoni, M and Pansarasa, O}, title = {New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {5}, pages = {}, pmid = {38473944}, issn = {1422-0067}, support = {Ricerca Corrente 2022-2024//Ministero della Salute/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Oxidative Stress/physiology ; Antioxidants/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Inflammation/drug therapy ; }, abstract = {Oxidative stress (OS) and inflammation are two important and well-studied pathological hallmarks of neurodegenerative diseases (NDDs). Due to elevated oxygen consumption, the high presence of easily oxidizable polyunsaturated fatty acids and the weak antioxidant defenses, the brain is particularly vulnerable to oxidative injury. Uncertainty exists over whether these deficits contribute to the development of NDDs or are solely a consequence of neuronal degeneration. Furthermore, these two pathological hallmarks are linked, and it is known that OS can affect the inflammatory response. In this review, we will overview the last findings about these two pathways in the principal NDDs. Moreover, we will focus more in depth on amyotrophic lateral sclerosis (ALS) to understand how anti-inflammatory and antioxidants drugs have been used for the treatment of this still incurable motor neuron (MN) disease. Finally, we will analyze the principal past and actual clinical trials and the future perspectives in the study of these two pathological mechanisms.}, }
@article {pmid38471489, year = {2024}, author = {D'Souza, A and Zink, K and Langhorst, J and Wildner, M and Stupp, C and Keil, T}, title = {How Effective Is Drinking Natural Mineral Water against Heartburn from Functional Dyspepsia, Gastroesophageal Reflux Disease, or Other Causes? A Systematic Review of Clinical Intervention Studies.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {253-265}, pmid = {38471489}, issn = {2504-2106}, mesh = {Humans ; *Mineral Waters/therapeutic use ; *Gastroesophageal Reflux/therapy/drug therapy ; *Heartburn/drug therapy ; *Dyspepsia/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: For centuries, spring and other natural waters have been recommended as external or internal remedies for numerous diseases. For studies that examined the effects of drinking mineral waters against heartburn, gastroesophageal reflux disease (GERD), or functional dyspepsia, a systematic review is lacking.<br><br>OBJECTIVES: The main aim of this systematic review was to examine the effects of drinking natural mineral waters on heartburn from various causes by identifying all published intervention studies and critically appraising their methods as well as summarizing their results.<br><br>METHODS: We systematically searched the largest medical literature database MEDLINE, further relevant web sources, and gray literature for randomized and nonrandomized trials, with or without control groups, up to September 2021 and no language restrictions. Further inclusion criteria were adult patients with heartburn, drinking cure with natural mineral water as the intervention, compared to no or other interventions (care-as-usual, waiting list). We defined the reduction of heartburn symptoms and duration of disease episodes as primary and quality of life as secondary outcomes. Two reviewers independently carried out the study quality assessments (risk of bias) using the National Institutes of Health-Study Quality Assessment Tools.<br><br>RESULTS: Nine trials comprising 393 patients from Italy, Russia, Ukraine, and Germany fulfilled all inclusion criteria. We identified three randomized controlled trials (all with poor methodological quality), plus six before-after (pre/post) intervention studies without a control group. The intervention groups of the three comparative trials seemed to show a stronger reduction of self-reported heartburn symptoms, and duration of heartburn episodes than the respective control groups; however, they all had poor methodological quality.<br><br>CONCLUSION: Based on the best available evidence of clinical studies, we cannot recommend or advise against drinking natural mineral waters as a treatment for heartburn. The potential benefits of natural mineral waters that were reported in some studies with a lower evidence level (e.g., lacking a control group) should be verified by good quality randomized clinical trials with adequate comparison groups and longer follow-up periods.<br><br>UNLABELLED: <title>Hintergrund</title>Seit Jahrhunderten werden Quell- und andere nat&#xfc;rliche W&#xe4;sser als &#xe4;u&#xdf;erliche oder innerliche Heilmittel f&#xfc;r zahlreiche Krankheiten empfohlen. F&#xfc;r Studien, die die Wirkung des Trinkens von Mineralwasser gegen Sodbrennen, gastro&#xf6;sophageale Refluxkrankheit (GERD) oder funktionelle Dyspepsie untersuchten, fehlt eine systematische &#xdc;bersicht.<title>Zielsetzung</title>Das Hauptziel dieser systematischen &#xdc;bersichtsarbeit war es, die Auswirkungen von Trinkkuren mit nat&#xfc;rlichen Mineralw&#xe4;ssern auf Sodbrennen verschiedener Ursachen zu untersuchen, indem alle ver&#xf6;ffentlichten Interventionsstudien identifiziert und ihre Methoden kritisch bewertet sowie ihre Ergebnisse zusammengefasst wurden.<title>Methoden</title>Wir durchsuchten systematisch die gr&#xf6;&#xdf;te medizinische Literaturdatenbank MEDLINE, weitere relevante Internetquellen und graue Literatur nach randomisierten und nicht-randomisierten Studien, mit oder ohne Kontrollgruppen, bis September 2021 und ohne sprachliche Einschr&#xe4;nkungen. Weitere Einschlusskriterien waren erwachsene Patienten mit Sodbrennen, Trinkkur mit nat&#xfc;rlichem Mineralwasser als Intervention, im Vergleich zu keiner oder anderen Interventionen (care-as-usual, Warteliste). Wir definierten die Abnahme der Symptome des Sodbrennens und die Dauer der Krankheitsepisoden als prim&#xe4;re und die Lebensqualit&#xe4;t als sekund&#xe4;re Endpunkte. Zwei Gutachter bewerteten unabh&#xe4;ngig voneinander die Qualit&#xe4;t der Studien (Verzerrungsrisiko) anhand der National Institutes of Health-Study Quality Assessment Tools.<title>Ergebnisse</title>Neun Studien mit 393 Patienten aus Italien, Russland, der Ukraine und Deutschland erf&#xfc;llten alle Einschlusskriterien. Wir identifizierten drei randomisierte kontrollierte Studien (alle mit schlechter methodischer Qualit&#xe4;t) sowie sechs Vorher-Nachher-Studien (Pr&#xe4;-/Post-Studien) ohne Kontrollgruppe. Die Interventionsgruppen der drei randomisierten Vergleichsstudien schienen eine st&#xe4;rkere Verringerung der selbstberichteten Symptome und der Dauer der Episoden des Sodbrennens zu zeigen als die jeweiligen Kontrollgruppen, allerdings waren sie alle von schlechter methodischer Qualit&#xe4;t.<title>Schlussfolgerung</title>Auf der Grundlage der besten verf&#xfc;gbaren Belege aus klinischen Studien k&#xf6;nnen wir das Trinken nat&#xfc;rlicher Mineralw&#xe4;sser zur Behandlung von Sodbrennen weder empfehlen noch davon abraten. Die potenziellen Vorteile nat&#xfc;rlicher Mineralw&#xe4;sser, die in einigen Studien mit geringerer Evidenz (z. B. ohne Kontrollgruppe) berichtet wurden, sollten durch qualitativ hochwertige randomisierte klinische Studien mit angemessenen Vergleichsgruppen und l&#xe4;ngeren Nachbeobachtungszeitr&#xe4;umen &#xfc;berpr&#xfc;ft werden.}, }
@article {pmid38470068, year = {2024}, author = {Van Damme, P and Al-Chalabi, A and Andersen, PM and Chiò, A and Couratier, P and De Carvalho, M and Hardiman, O and Kuźma-Kozakiewicz, M and Ludolph, A and McDermott, CJ and Mora, JS and Petri, S and Probyn, K and Reviers, E and Salachas, F and Silani, V and Tysnes, OB and van den Berg, LH and Villanueva, G and Weber, M}, title = {European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).}, journal = {European journal of neurology}, volume = {31}, number = {6}, pages = {e16264}, pmid = {38470068}, issn = {1468-1331}, support = {//ERN Euro-NMD/ ; //European Academy of Neurology/ ; //ALS Liga Belgium/ ; //EUpALS/ ; //ENCALS/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Europe ; Neurology/standards/methods ; Neuromuscular Diseases/therapy ; }, abstract = {BACKGROUND: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS).<br><br>METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available.<br><br>RESULTS: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management.<br><br>CONCLUSIONS: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available.}, }
@article {pmid38467696, year = {2024}, author = {Hilton, JBW and Kysenius, K and Liddell, JR and Mercer, SW and Paul, B and Beckman, JS and McLean, CA and White, AR and Donnelly, PS and Bush, AI and Hare, DJ and Roberts, BR and Crouch, PJ}, title = {Evidence for disrupted copper availability in human spinal cord supports Cu[II](atsm) as a treatment option for sporadic cases of ALS.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {5929}, pmid = {38467696}, issn = {2045-2322}, mesh = {Humans ; Mice ; Animals ; Copper/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Mice, Transgenic ; Spinal Cord/metabolism ; Ceruloplasmin/metabolism ; Disease Models, Animal ; *Thiosemicarbazones ; *Coordination Complexes ; }, abstract = {The copper compound Cu[II](atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Cu[II](atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~ 2% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for Cu[II](atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for Cu[II](atsm) involving copper availability may also be pertinent to sporadic cases of ALS.}, }
@article {pmid38466738, year = {2024}, author = {Pelletier, C and Shaw, S and Alsayegh, S and Brown, AJP and Lorenz, A}, title = {Candida auris undergoes adhesin-dependent and -independent cellular aggregation.}, journal = {PLoS pathogens}, volume = {20}, number = {3}, pages = {e1012076}, pmid = {38466738}, issn = {1553-7374}, support = {MR/M026663/1/MRC_/Medical Research Council/United Kingdom ; MR/M026663/2/MRC_/Medical Research Council/United Kingdom ; MR/V033417/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Antifungal Agents/therapeutic use ; *Candida/genetics ; Candida auris ; Virulence ; Drug Resistance, Fungal ; Adhesins, Bacterial/metabolism ; Microbial Sensitivity Tests ; }, abstract = {Candida auris is a fungal pathogen of humans responsible for nosocomial infections with high mortality rates. High levels of resistance to antifungal drugs and environmental persistence mean these infections are difficult to treat and eradicate from a healthcare setting. Understanding the life cycle and the genetics of this fungus underpinning clinically relevant traits, such as antifungal resistance and virulence, is of the utmost importance to develop novel treatments and therapies. Epidemiological and genomic studies have identified five geographical clades (I-V), which display phenotypic and genomic differences. Aggregation of cells, a phenotype primarily of clade III strains, has been linked to reduced virulence in some infection models. The aggregation phenotype has thus been associated with conferring an advantage for (skin) colonisation rather than for systemic infection. However, strains with different clade affiliations were compared to infer the effects of different morphologies on virulence. This makes it difficult to distinguish morphology-dependent causes from clade-specific or even strain-specific genetic factors. Here, we identify two different types of aggregation: one induced by antifungal treatment which is a result of a cell separation defect; and a second which is controlled by growth conditions and only occurs in strains with the ability to aggregate. The latter aggregation type depends on an ALS-family adhesin which is differentially expressed during aggregation in an aggregative C. auris strain. Finally, we demonstrate that macrophages cannot clear aggregates, suggesting that aggregation might after all provide a benefit during systemic infection and could facilitate long-term persistence in the host.}, }
@article {pmid38455726, year = {2024}, author = {Liu, L and Wu, L and Li, Z and Fang, Y and Ju, B and Zhang, S and Bai, L and Pan, L}, title = {The Pro-197-Thr mutation in the ALS gene confers novel resistance patterns to ALS-inhibiting herbicides in Bromus japonicus in China.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1348815}, pmid = {38455726}, issn = {1664-462X}, abstract = {INTRODUCTION: Bromus japonicus is one of the most notorious agricultural weeds in China. The long-term use of ALS-inhibiting herbicides has led to rapid evolution of herbicide resistance in B. japonicus. B. japonicus population (BJ-R) surviving mesosulfuron-methyl treatment was collected from wheatland. Here, we aimed to confirm the resistance mechanisms in this putative resistant population.<br><br>METHODS: The dose-reponse tests were used to test the resistance level of the B. japonicus to ALS-inhibiting herbicides. Pretreatment with P450 and GST inhibitors and GST activity assays were used to determine whether P450 or GST was involved in the resistance of the BJ-R population. Sanger sequencing was used to analyse the ALS mutation of the BJ-R population. RT-qPCR was used to confirm the the expression levels of the ALS gene in mesosulfuron-methyl -resistant (BJ-R) and-susceptible (BJ-S) B. japonicus. An in vitro ALS activity assay was used to determine the ALS activity of the BJ-R and BJ-S populations. Homology modelling and docking were used to determine the binding energy of the BJ-R and BJ-S populations with ALS-inhibiting herbicides.<br><br>RESULTS: B. japonicus population (BJ-R) was confirmed to be 454- and 2.7-fold resistant to the SU herbicides mesosulfuron-methyl and nicosulfuron, and 7.3-, 2.3-, 1.1- and 10.8-fold resistant to the IMI herbicide imazamox, the TP herbicide penoxsulam, the PTB herbicide pyribenzoxim and the SCT herbicide flucarbazone-sodium, respectively, compared with its susceptible counterpart (BJ-S). Neither a P450 inhibitor nor a GST inhibitor could reverse the level of resistance to mesosulfuron-methyl in BJ-R. In addition, no significant differences in GST activity were found between the BJ-R and BJ-S. ALS gene sequencing revealed a Pro-197-Thr mutation in BJ-R, and the gene expression had no significant differences between the BJ-R and BJ-S. The ALS activity of BJ-R was 106-fold more tolerant to mesosulfuron-methyl than that of BJ-S. Molecular docking showed that the binding energy of the ALS active site and mesosulfuron-methyl was changed from -6.67 to -4.57 kcal mol[-1] due to the mutation at position 197.<br><br>DISCUSSION: These results suggested that the Pro-197-Thr mutation was the main reason for the high resistance level of BJ-R to mesosulfuron-methyl. Unlike previous reports of the cross-resistance pattern conferred by this mutation, we firstly documented that the Pro-197-Thr mutation confers broad cross-resistance spectrums to ALS-inhibiting herbicides in B. japonicus.}, }
@article {pmid38452377, year = {2024}, author = {Rajabi, D and Khanmohammadi, S and Rezaei, N}, title = {The role of long noncoding RNAs in amyotrophic lateral sclerosis.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {5}, pages = {533-547}, pmid = {38452377}, issn = {2191-0200}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *RNA, Long Noncoding/genetics/metabolism ; Animals ; RNA-Binding Protein FUS/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a poor prognosis leading to death. The diagnosis and treatment of ALS are inherently challenging due to its complex pathomechanism. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides involved in different cellular processes, incisively gene expression. In recent years, more studies have been conducted on lncRNA classes and interference in different disease pathologies, showing their promising contribution to diagnosing and treating neurodegenerative diseases. In this review, we discussed the role of lncRNAs like NEAT1 and C9orf72-as in ALS pathogenesis mechanisms caused by mutations in different genes, including TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), superoxide dismutase type 1 (SOD1). NEAT1 is a well-established lncRNA in ALS pathogenesis; hence, we elaborate on its involvement in forming paraspeckles, stress response, inflammatory response, and apoptosis. Furthermore, antisense lncRNAs (as-lncRNAs), a key group of transcripts from the opposite strand of genes, including ZEB1-AS1 and ATXN2-AS, are discussed as newly identified components in the pathology of ALS. Ultimately, we review the current standing of using lncRNAs as biomarkers and therapeutic agents and the future vision of further studies on lncRNA applications.}, }
@article {pmid38447450, year = {2024}, author = {Malacarne, C and Giagnorio, E and Chirizzi, C and Cattaneo, M and Saraceno, F and Cavalcante, P and Bonanno, S and Mantegazza, R and Moreno-Manzano, V and Lauria, G and Metrangolo, P and Bombelli, FB and Marcuzzo, S}, title = {FM19G11-loaded nanoparticles modulate energetic status and production of reactive oxygen species in myoblasts from ALS mice.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {173}, number = {}, pages = {116380}, doi = {10.1016/j.biopha.2024.116380}, pmid = {38447450}, issn = {1950-6007}, mesh = {Mice ; Animals ; Superoxide Dismutase-1/metabolism ; Reactive Oxygen Species/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neurodegenerative Diseases/pathology ; Myoblasts/metabolism ; *Nanoparticles ; Atrophy/pathology ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase/metabolism ; *Benzamides ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Considerable evidence indicates that early skeletal muscle atrophy plays a crucial role in the disease pathogenesis, leading to an altered muscle-motor neuron crosstalk that, in turn, may contribute to motor neuron degeneration. Currently, there is no effective treatment for ALS, highlighting the need to dig deeper into the pathological mechanisms for developing innovative therapeutic strategies. FM19G11 is a novel drug able to modulate the global cellular metabolism, but its effects on ALS skeletal muscle atrophy and mitochondrial metabolism have never been evaluated, yet. This study investigated whether FM19G11-loaded nanoparticles (NPs) may affect the bioenergetic status in myoblasts isolated from G93A-SOD1 mice at different disease stages. We found that FM19G1-loaded NP treatment was able to increase transcriptional levels of Akt1, Akt3, Mef2a, Mef2c and Ucp2, which are key genes associated with cell proliferation (Akt1, Akt3), muscle differentiation (Mef2c), and mitochondrial activity (Ucp2), in G93A-SOD1 myoblasts. These cells also showed a significant reduction of mitochondrial area and networks, in addition to decreased ROS production after treatment with FM19G11-loaded NPs, suggesting a ROS clearance upon the amelioration of mitochondrial dynamics. Our overall findings demonstrate a significant impact of FM19G11-loaded NPs on muscle cell function and bioenergetic status in G93A-SOD1 myoblasts, thus promising to open new avenues towards possible adoption of FM19G11-based nanotherapies to slow muscle degeneration in the frame of ALS and muscle disorders.}, }
@article {pmid38445369, year = {2024}, author = {Nishimura, K and Sanchez-Molano, J and Kerr, N and Pressman, Y and Silvera, R and Khan, A and Gajavelli, S and Bramlett, HM and Dietrich, WD}, title = {Beneficial Effects of Human Schwann Cell-Derived Exosomes in Mitigating Secondary Damage After Penetrating Ballistic-Like Brain Injury.}, journal = {Journal of neurotrauma}, volume = {41}, number = {21-22}, pages = {2395-2412}, pmid = {38445369}, issn = {1557-9042}, support = {R37 NS133195/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Rats, Sprague-Dawley ; Male ; Rats ; *Exosomes/metabolism/transplantation ; Humans ; *Schwann Cells/metabolism ; *Head Injuries, Penetrating ; }, abstract = {There is a growing body of evidence that the delivery of cell-derived exosomes normally involved in intracellular communication can reduce secondary injury mechanisms after brain and spinal cord injury and improve outcomes. Exosomes are nanometer-sized vesicles that are released by Schwann cells and may have neuroprotective effects by reducing post-traumatic inflammatory processes as well as promoting tissue healing and functional recovery. The purpose of this study was to evaluate the beneficial effects of human Schwann-cell exosomes (hSC-Exos) in a severe model of penetrating ballistic-like brain injury (PBBI) in rats and investigate effects on multiple outcomes. Human Schwann cell processing protocols followed Current Good Manufacturing Practices (cGMP) with exosome extraction and purification steps approved by the Food and Drug Administration for an expanded access single ALS patient Investigational New Drug. Anesthetized male Sprague-Dawley rats (280-350g) underwent PBBI surgery or Sham procedures and, starting 30 min after injury, received either a dose of hSC-Exos or phosphate-buffered saline through the jugular vein. At 48h after PBBI, flow cytometry analysis of cortical tissue revealed that hSC-Exos administration reduced the number of activated microglia and levels of caspase-1, a marker of inflammasome activation. Neuropathological analysis at 21 days showed that hSC-Exos treatment after PBBI significantly reduced overall contusion volume and decreased the frequency of Iba-1 positive activated and amoeboid microglia by immunocytochemical analysis. This study revealed that the systemic administration of hSC-Exos is neuroprotective in a model of severe TBI and reduces secondary inflammatory injury mechanisms and histopathological damage. The administration of hSC-Exos represents a clinically relevant cell-based therapy to limit the detrimental effects of neurotrauma or other progressive neurological injuries by impacting multiple pathophysiological events and promoting neurological recovery.}, }
@article {pmid38443977, year = {2024}, author = {Duan, QQ and Wang, H and Su, WM and Gu, XJ and Shen, XF and Jiang, Z and Ren, YL and Cao, B and Li, GB and Wang, Y and Chen, YP}, title = {TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro.}, journal = {BMC medicine}, volume = {22}, number = {1}, pages = {96}, pmid = {38443977}, issn = {1741-7015}, support = {2022YFC2703101//the National Key Research and Development Program of China/ ; 2021YFS0051//Sichuan Province Science and Technology Support Program/ ; 2023YFS0269//Sichuan Province Science and Technology Support Program/ ; 81971188//the National Natural Science Fund of China/ ; 2022NSFSC0749//the National Natural Science Fund of Sichuan/ ; 2023HXFH032//the 1&#xb7;3&#xb7;5 project for disciplines of excellence Clinical Research Fund, West China Hospital, Sichuan University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Drug Repositioning ; Mendelian Randomization Analysis ; Protein Serine-Threonine Kinases/genetics ; *Aminopyridines ; }, abstract = {BACKGROUND: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment.<br><br>METHODS: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models.<br><br>RESULTS: Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation.<br><br>CONCLUSIONS: Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.}, }
@article {pmid38435120, year = {2024}, author = {Duan, C and Kang, M and Pan, X and Gan, Z and Huang, V and Li, G and Place, RF and Li, LC}, title = {Intrathecal administration of a novel siRNA modality extends survival and improves motor function in the SOD1[G93A] ALS mouse model.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {1}, pages = {102147}, pmid = {38435120}, issn = {2162-2531}, abstract = {Antisense oligonucleotides (ASOs) were the first modality to pioneer targeted gene knockdown in the treatment of amyotrophic lateral sclerosis (ALS) caused by mutant superoxide dismutase 1 (SOD1). RNA interference (RNAi) is another mechanism of gene silencing in which short interfering RNAs (siRNAs) effectively degrade complementary transcripts. However, delivery to extrahepatic tissues like the CNS has been a bottleneck in the clinical development of RNAi. Herein, we identify potent siRNA duplexes for the knockdown of human SOD1 in which medicinal chemistry and conjugation to an accessory oligonucleotide (ACO) enable activity in CNS tissues. Local delivery via intracerebroventricular or intrathecal injection into SOD1[G93A] mice delayed disease progression and extended animal survival with superior efficacy compared with an ASO resembling tofersen in sequence and chemistry. Treatment also prevented disease-related declines in motor function, including improvements in animal mobility, muscle strength, and coordination. The ACO itself does not target any specific complementary nucleic acid sequence; rather, it imparts benefits conducive to bioavailability and delivery through its chemistry. The complete conjugate (i.e., siRNA-ACO) represents a novel modality for delivery of duplex RNA (e.g., siRNA) to the CNS that is currently being tested in the clinic for treatment of ALS.}, }
@article {pmid38431841, year = {2024}, author = {Gao, C and Shi, Q and Pan, X and Chen, J and Zhang, Y and Lang, J and Wen, S and Liu, X and Cheng, TL and Lei, K}, title = {Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis.}, journal = {Cell reports}, volume = {43}, number = {3}, pages = {113892}, doi = {10.1016/j.celrep.2024.113892}, pmid = {38431841}, issn = {2211-1247}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology ; Proteins/genetics ; Dipeptides/pharmacology/metabolism ; DNA Repeat Expansion ; }, abstract = {Hexanucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Due to the lack of trunk neuromuscular organoids (NMOs) from ALS patients' induced pluripotent stem cells (iPSCs), an organoid system was missing to model the trunk spinal neuromuscular neurodegeneration. With the C9orf72 ALS patient-derived iPSCs and isogenic controls, we used an NMO system containing trunk spinal cord neural and peripheral muscular tissues to show that the ALS NMOs could model peripheral defects in ALS, including contraction weakness, neural denervation, and loss of Schwann cells. The neurons and astrocytes in ALS NMOs manifested the RNA foci and dipeptide repeat proteins. Acute treatment with the unfolded protein response inhibitor GSK2606414 increased the glutamatergic muscular contraction 2-fold and reduced the dipeptide repeat protein aggregation and autophagy. This study provides an organoid system for spinal neuromuscular pathologies in ALS and its application for drug testing.}, }
@article {pmid38431830, year = {2024}, author = {Li, R and Han, X and Wang, Q and Wang, C and Jing, W and Zhang, H and Wang, J and Pan, W}, title = {Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 3: Alleviation of hypoxia, muscle-wasting, and modulation of redox functions in amyotrophic lateral sclerosis.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {62}, number = {4}, pages = {169-177}, doi = {10.5414/CP204520}, pmid = {38431830}, issn = {0946-1965}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/diagnosis ; Medicine, Chinese Traditional ; Network Pharmacology ; Treatment Outcome ; Hypoxia ; Cholecalciferol ; Muscles ; Disease Progression ; }, abstract = {OBJECTIVE: The aim of this clinical study is to obtain evidence for the clinical efficacy of Bu-Shen-Jian-Pi formula (BSJP), a traditional Chinese medicine, used for the treatment of amyotrophic lateral sclerosis, a relatively rare, progressive and usually fatal disease possibly associated with alterations in tissue redox status, hypoxia, and muscular injury.<br><br>BACKGROUND: The active agents in BSJP formula[&#x2020;] causing apoptosis, modulation of redox changes, and alterations in the immune status have been studied previously by us using cell cultures. The findings from these investigations have been incorporated into pharmacology databases employed in our analysis of BSJP using network pharmacology analysis/artifical intelligence. This information has been used here in the design of the investigation and to optimize evaluation of the clinical efficacy and usefulness of this herbal medicine, as far as possible using evidence-based medicine criteria.<br><br>MATERIALS AND METHODS: The design of the study was a randomized multi-center, controlled clinical trial in 127 patients with confirmed diagnoses of amyotrophic lateral sclerosis. Patients and investigator were double-blinded. Clinical efficacy was determined using the Amyotrophic Lateral Sclerosis Symptom Score in Integrative Treatment Scale (ALS-SSIT) and the Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R), together with tests of limb muscle strength using the manual muscle test (MMT), forced vital capacity (FVC), and clinical chemistry laboratory tests over a 20-week observation period.<br><br>RESULTS: The scores of ALS-SSIT in the BSJP group increased significantly (22%) after treatment. The ALSFRS-R score in the BSJP group decreased significantly after treatment (19%). The rate of decrease in muscle function (MMT score) in most BSJP patients was lower than that in the control group, where the differences in the scores for the trapezius and triceps brachii were statistically significant compared to the control group. The fall in FVC in the BJSP group was significantly slower than in the control group. There were no marked differences observed in the frequency of side effects. Serum vitamin D3 levels in the BSJP group showed greater increases compared to the control group.<br><br>CONCLUSION: BSJP treatment reduced the rate of progression of amyotrophic lateral sclerosis according to the ALS-SSITS and ALSFRS scores and significantly reduced the rate of deterioration in muscle function in the limbs of amyotrophic lateral sclerosis patients. The modes of action of BSJP in treating amyotrophic lateral sclerosis are probably diverse and multi targeted, some of which may involve regulation of serum vitamin D3 and alleviation of the impairments in liver and kidney function.}, }
@article {pmid38431829, year = {2024}, author = {Yuan, W and Lin, J and Wang, J and Wang, C and Shan, Y and Jing, W and Fei, Z and Pan, W}, title = {Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 2: Modulation of hypoxia, redox status, and mitochondrial protection in a neuroblastoma cell line, SH-SY5Y.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {62}, number = {4}, pages = {162-168}, doi = {10.5414/CP204505}, pmid = {38431829}, issn = {0946-1965}, mesh = {Humans ; *Medicine, Chinese Traditional ; Kaempferols/pharmacology ; Cell Line, Tumor ; Network Pharmacology ; *Neuroblastoma/drug therapy/metabolism ; Oxidation-Reduction ; Hypoxia/drug therapy ; Treatment Outcome ; }, abstract = {OBJECTIVE: To examine the mitochondrial protective effects of icariin, naringenin, kaempferol, and formononetin, potentially active agents in Bu-Shen-Jian-Pi formula (BSJP) identified using network pharmacology analysis.<br><br>MATERIALS AND METHODS: Mitochondrial protection activity was determined using a hypoxia-reoxygenation in vitro model based on the neuroblastoma cell line SH-SY5Y and measurements of anti-ferroptotic activity.<br><br>RESULTS: Icariin, naringenin, kaempferol, and formononetin showed mitochondrial protective activity involving diverse signaling pathways. The cytoprotective effects of formononetin depended on the inhibition of ferroptosis. Hypoxia-reoxygenation stimulation induced ferroptosis in SH-SY5Y cells.<br><br>DISCUSSION: Ferroptosis is a key mechanism in nervous system diseases and is associated with hypoxia-reoxygenation injury. Naringenin and kaempferol were devoid of anti-ferroptotic activity.<br><br>CONCLUSION: Evidence has been obtained showing that the core components: icariin, naringenin, kaempferol, and formononetin in BSJP formula have anti-hypoxic and mitochondrial protective activity of potential clinical importance in the treatment of amyotrophic lateral sclerosis and patients with symptoms of hypoxia.}, }
@article {pmid38429929, year = {2024}, author = {Schuster, KH and Zalon, AJ and DiFranco, DM and Putka, AF and Stec, NR and Jarrah, SI and Naeem, A and Haque, Z and Zhang, H and Guan, Y and McLoughlin, HS}, title = {ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {32}, number = {5}, pages = {1359-1372}, pmid = {38429929}, issn = {1525-0024}, support = {R01 NS122751/NS/NINDS NIH HHS/United States ; R35 GM133346/GM/NIGMS NIH HHS/United States ; U01 NS106670/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Oligodendroglia/metabolism ; Mice ; *Machado-Joseph Disease/genetics/therapy/pathology/metabolism ; *Oligonucleotides, Antisense ; *Disease Models, Animal ; *Ataxin-3/genetics/metabolism ; Humans ; Repressor Proteins/genetics/metabolism ; Mice, Transgenic ; }, abstract = {Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia. Currently, no preventive or disease-modifying treatments exist for this progressive neurodegenerative disorder, although efforts using gene silencing approaches are under clinical trial investigation. The disease is caused by a CAG repeat expansion in the mutant gene, ATXN3, producing an enlarged polyglutamine tract in the mutant protein. Similar to other paradigmatic neurodegenerative diseases, studies evaluating the pathogenic mechanism focus primarily on neuronal implications. Consequently, therapeutic interventions often overlook non-neuronal contributions to disease. Our lab recently reported that oligodendrocytes display some of the earliest and most progressive dysfunction in SCA3 mice. Evidence of disease-associated oligodendrocyte signatures has also been reported in other neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. Here, we assess the effects of anti-ATXN3 antisense oligonucleotide (ASO) treatment on oligodendrocyte dysfunction in premanifest and symptomatic SCA3 mice. We report a severe, but modifiable, deficit in oligodendrocyte maturation caused by the toxic gain-of-function of mutant ATXN3 early in SCA3 disease that is transcriptionally, biochemically, and functionally rescued with anti-ATXN3 ASO. Our results highlight the promising use of an ASO therapy across neurodegenerative diseases that requires glial targeting in addition to affected neuronal populations.}, }
@article {pmid38428880, year = {2024}, author = {Hu, CJ and Chen, PC and Padmanabhan, N and Zahn, A and Ho, CM and Wang, K and Yen, Y}, title = {A new potential therapeutic approach for ALS: A case report with NGS analysis.}, journal = {Medicine}, volume = {103}, number = {9}, pages = {e37401}, pmid = {38428880}, issn = {1536-5964}, mesh = {Humans ; Male ; Aged ; Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/genetics ; Artificial Intelligence ; Treatment Outcome ; *Hypotension/drug therapy ; }, abstract = {RATIONALE: Amyotrophic lateral sclerosis (ALS) poses a significant clinical challenge due to its rapid progression and limited treatment options, often leading to deadly outcomes. Looking for effective therapeutic interventions is critical to improve patient outcomes in ALS.<br><br>PATIENT CONCERNS: The patient, a 75-year-old East Asian male, manifested an insidious onset of right-hand weakness advancing with dysarthria. Comprehensive Next-generation sequencing analysis identified variants in specific genes consistent with ALS diagnosis.<br><br>DIAGNOSES: ALS diagnosis is based on El Escorial diagnostic criteria.<br><br>INTERVENTIONS: This study introduces a novel therapeutic approach using artificial intelligence phenotypic response surface (AI-PRS) technology to customize personalized drug-dose combinations for ALS. The patient underwent a series of phases of AI-PRS-assisted trials, initially incorporating a 4-drug combination of Ibudilast, Riluzole, Tamoxifen, and Ropinirole. Biomarkers and regular clinical assessments, including nerve conduction velocity, F-wave, H-reflex, electromyography, and motor unit action potential, were monitored to comprehensively evaluate treatment efficacy.<br><br>OUTCOMES: Neurophysiological assessments supported the ALS diagnosis and revealed the co-presence of diabetic polyneuropathy. Hypotension during the trial necessitated an adaptation to a 2-drug combinational trial (ibudilast and riluzole). Disease progression assessment shifted exclusively to clinical tests of muscle strength, aligning with the patient's well-being.<br><br>LESSONS: The study raises the significance of personalized therapeutic strategies in ALS by AI-PRS. It also emphasizes the adaptability of interventions based on patient-specific responses. The encountered hypotension incident highlights the importance of attentive monitoring and personalized adjustments in treatment plans. The described therapy using AI-PRS, offering personalized drug-dose combinations technology is a potential approach in treating ALS. The promising outcomes warrant further evaluation in clinical trials for searching a personalized, more effective combinational treatment for ALS patients.}, }
@article {pmid38428228, year = {2024}, author = {Masroor, A and Zaidi, N and Nabi, F and Malik, S and Zehra, S and Arjmand, F and Naseem, N and Khan, RH}, title = {Biophysical insight into anti-amyloidogenic nature of novel ionic Co(II)(phen)(H2O)4][+][glycinate][-] chemotherapeutic drug candidate against human lysozyme aggregation.}, journal = {Biophysical chemistry}, volume = {308}, number = {}, pages = {107214}, doi = {10.1016/j.bpc.2024.107214}, pmid = {38428228}, issn = {1873-4200}, mesh = {Humans ; *Amyloid/chemistry ; Muramidase/chemistry ; Molecular Docking Simulation ; *Amyloidosis/drug therapy/metabolism ; Dynamic Light Scattering ; Protein Aggregates ; }, abstract = {In the recent past, there has been an ever-increasing interest in the search for metal-based therapeutic drug candidates for protein misfolding disorders (PMDs) particularly neurodegenerative disorders such as Alzheimer's, Parkinson's, Prion's diseases, and amyotrophic lateral sclerosis. Also, different amyloidogenic variants of human lysozyme (HL) are involved in hereditary systemic amyloidosis. Metallo-therapeutic agents are extensively studied as antitumor agents, however, they are relatively unexplored for the treatment of non-neuropathic amyloidoses. In this work, inhibition potential of a novel ionic cobalt(II) therapeutic agent (CoTA) of the formulation [Co(phen)(H2O)4][+][glycinate][-] is evaluated against HL fibrillation. Various biophysical techniques viz., dye-binding assays, dynamic light scattering (DLS), differential scanning calorimetry (DSC), electron microscopy, and molecular docking experiments validate the proposed mechanism of inhibition of HL fibrillation by CoTA. The experimental corroborative results of these studies reveal that CoTA can suppress and slow down HL fibrillation at physiological temperature and pH. DLS and 1-anilino-8-naphthalenesulfonate (ANS) assay show that reduced fibrillation in the presence of CoTA is marked by a significant decrease in the size and hydrophobicity of the aggregates. Fluorescence quenching and molecular docking results demonstrate that CoTA binds moderately to the aggregation-prone region of HL (Kb = 6.6 × 10[4] M[-1]), thereby, inhibiting HL fibrillation. In addition, far-UV CD and DSC show that binding of CoTA to HL does not cause any change in the stability of HL. More importantly, CoTA attenuates membrane damaging effects of HL aggregates against RBCs. This study identifies inorganic metal complexes as a therapeutic intervention for systemic amyloidosis.}, }
@article {pmid38428126, year = {2024}, author = {Wahbeh, F and Restifo, D and Laws, S and Pawar, A and Parikh, NS}, title = {Impact of tobacco smoking on disease-specific outcomes in common neurological disorders: A scoping review.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {122}, number = {}, pages = {10-18}, pmid = {38428126}, issn = {1532-2653}, support = {K23 AG073524/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Smoking Cessation ; Smoking/adverse effects/epidemiology ; Tobacco Smoking ; *Stroke/epidemiology/etiology/therapy ; *Multiple Sclerosis ; }, abstract = {Although the association of smoking with the risk of incident neurological disorders is well established, less is known about the impact of smoking and smoking cessation on outcomes of these conditions. The objective of this scoping review was to synthesize what is known about the impact of smoking and smoking cessation on disease-specific outcomes for seven common neurological disorders. We included 67 studies on the association of smoking and smoking cessation on disease-specific outcomes. For multiple sclerosis, smoking was associated with greater clinical and radiological disease progression, relapses, risk for disease-related death, cognitive decline, and mood symptoms, in addition to reduced treatment effectiveness. For stroke and transient ischemic attack, smoking was associated with greater rates of stroke recurrence, post-stroke cardiovascular outcomes, post-stroke mortality, post-stroke cognitive impairment, and functional impairment. In patients with cognitive impairment and dementia, smoking was associated with faster cognitive decline, and smoking was also associated with greater cognitive decline in Parkinson's disease, but not motor symptom worsening. Patients with amyotrophic lateral sclerosis who smoked faced increased mortality. Last, in patients with cluster headache, smoking was associated with more frequent and longer cluster attack periods. Conversely, for multiple sclerosis and stroke, smoking cessation was associated with improved disease-specific outcomes. In summary, whereas smoking is detrimentally associated with disease-specific outcomes in common neurological conditions, there is growing evidence that smoking cessation may improve outcomes. Effective smoking cessation interventions should be leveraged in the management of common neurological disorders to improve patient outcomes.}, }
@article {pmid38427990, year = {2024}, author = {El-Hajj, VG and Daller, C and Fletcher-Sandersjöö, A and Gharios, M and Bydon, M and Söderman, M and Jabbour, P and Edström, E and Elmi-Terander, A and Arnberg, F}, title = {The negative impact of treatment delays on the long-term neurological outcomes of spinal dural arteriovenous fistulas: a longitudinal cohort study.}, journal = {Neurosurgical focus}, volume = {56}, number = {3}, pages = {E14}, doi = {10.3171/2023.12.FOCUS23703}, pmid = {38427990}, issn = {1092-0684}, mesh = {Humans ; Male ; Aged ; Female ; Cohort Studies ; Longitudinal Studies ; Retrospective Studies ; *Treatment Delay ; *Central Nervous System Vascular Malformations/complications/surgery ; }, abstract = {OBJECTIVE: Dural arteriovenous fistulas are rare vascular malformations that affect the brain and spinal cord. Spinal dural arteriovenous fistulas (sdAVFs) are the most frequently encountered vascular malformation affecting the spinal cord. The object of this study was to evaluate the impact of treatment delays on the long-term neurological outcomes of either open surgical or interventional treatment of sdAVFs.<br><br>METHODS: In this retrospective, population-based cohort study, the authors examined consecutive patients with diagnosed sdAVFs at a tertiary care center between 2005 and 2020. Patients were assessed using the Aminoff-Logue disability scale (ALS) at various time points including symptom onset, primary care visit, first specialist outpatient visit, as well as both short and long-term follow-ups. The postoperative long-term ALS gait and bladder grades constituted the primary outcomes of the study.<br><br>RESULTS: Among the 34 patients included in the study, the median age was 65 years, and there was a male predominance (71%). Most lesions were in the lumbar region (47%). Significant worsening in ALS gait and bladder grades was observed preoperatively, followed by postoperative improvements (p < 0.05). There was no difference in outcomes between surgical and endovascular treatments. Older age (OR 1.10, 95% CI 1.03-1.17, p = 0.007), worse preoperative ALS gait grades (OR 5.12, 95% CI 2.18-12.4, p < 0.001), and longer time from first specialist outpatient visit to first treatment (OR 1.00, 95% CI 1.00-1.01, p = 0.040) were independently associated with worse long-term gait outcomes. Only the preoperative ALS bladder score was a predictor of worse long-term bladder function (OR 92.7, 95% CI 28.0-306.7, p < 0.001).<br><br>CONCLUSIONS: Both surgical and endovascular treatments for sdAVFs led to significant neurological improvements. However, treatment delays were associated with less favorable long-term outcomes. Prompt diagnosis and early intervention prior to symptom progression may enhance recovery and help to preserve neurological function.}, }
@article {pmid38427252, year = {2024}, author = {Rajaratnam, S and Pradhan, SS and Naik, AA and Sivaramakrishnan, V}, title = {Integrated Multi-Omics Analysis and Validation in Yeast Model of Amyotrophic Lateral Sclerosis.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2761}, number = {}, pages = {397-419}, pmid = {38427252}, issn = {1940-6029}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Saccharomyces cerevisiae/genetics ; Multiomics ; Software ; Gene Expression Profiling ; }, abstract = {Transcriptomics is a complex process that involves raw data extraction, normalization, differential gene expression, and analysis. The Gene Expression Omnibus (GEO) database at the National Center for Biotechnology Information (NCBI) is a repository of experimental datasets. Amyotrophic lateral sclerosis (ALS) datasets are deposited by various scientists and research investigators to expand the horizon of scientific knowledge. R-statistical tools are the most common ways for conducting these kinds of studies. The first step is the identification of appropriate datasets. Since the raw data is available in a variety of formats, a large array of software is used for extraction and analysis. Normalization is conducted for the datasets using NetworkAnalyst. Differential analysis is further conducted on the normalized data to identify significantly enriched genes. The significant genes are then grouped into pathways. The results were validated using yeast model of ALS in which the yeast is transformed with ALS plasmids encoding genes associated with ALS. The resulting GFP-tagged protein aggregates are imaged using fluorescence microscopy and subsequently validated using filter retardation assay and quantified using ImageJ software. Functional role of different genes is studied using metabolite treatment and knockout studies.}, }
@article {pmid38421827, year = {2024}, author = {Zhang, Y and Li, Y and Bin, S and Cheng, X and Niu, Q}, title = {A Neglected Gene: The Role of the ANG Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {16}, number = {1}, pages = {13-32}, pmid = {38421827}, issn = {2152-5250}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with a poor prognosis. To date, more than 40 ALS-related genes have been identified. However, there is still a lack of targeted therapeutic drugs for the treatment of ALS, especially for patients with acute onset and severe disease. A series of studies reported missense heterozygous mutations with loss of function in the coding region of the ANG gene in ALS patients. ANG deficiency is related to the pathogenesis of ALS, but the underlying mechanism has not been determined. This article aimed to synthesize and consolidate the knowledge of the pathological mechanism of ALS induced by ANG mutation and provide a theoretical basis for ALS diagnosis and targeted therapy. This article further delves into the mechanisms underlying the current understanding of the structure and function of the ANG gene, the association between ANG and ALS, and its pathogenesis. Mutations in ANG may lead to the development of ALS through the loss of neuroprotective function, induction of oxidative stress, or inhibition of rRNA synthesis. ANG mutations and genetic and environmental factors may cause disease heterogeneity and more severe disease than in ALS patients with the wild-type gene. Exploring this mechanism is expected to provide a new approach for ALS treatment through increasing ANG expression or angiogenin activity. However, the related study is still in its infancy; therefore, this article also highlights the need for further exploration of the application of ANG gene mutations in clinical trials and animal experiments is needed to achieve improved early diagnosis and treatment of ALS.}, }
@article {pmid38416402, year = {2024}, author = {Wolff, AW and Peine, J and Höfler, J and Zurek, G and Hemker, C and Lingor, P}, title = {SAFE-ROCK: A Phase I Trial of an Oral Application of the ROCK Inhibitor Fasudil to Assess Bioavailability, Safety, and Tolerability in Healthy Participants.}, journal = {CNS drugs}, volume = {38}, number = {4}, pages = {291-302}, pmid = {38416402}, issn = {1179-1934}, support = {2017_T05//Else Kr&#xf6;ner-Fresenius-Stiftung/ForTra GmbH/ ; }, mesh = {Male ; Humans ; Female ; *rho-Associated Kinases ; Biological Availability ; Healthy Volunteers ; *Protein Kinase Inhibitors/adverse effects ; Chronic Disease ; Administration, Oral ; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/*analogs &amp; derivatives ; }, abstract = {BACKGROUND: The intravenous (IV) formulation of Rho-kinase (ROCK) inhibitor fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995. Additionally, fasudil has shown promising preclinical results for various chronic diseases, including neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and dementia, in which long-term intravenous (IV) administration might not be suitable.<br><br>OBJECTIVE: The objective of this study was to assess the absolute bioavailability of oral, in comparison to IV, application of the approved formulation of fasudil (ERIL&#xae;) and to evaluate the safety and tolerability of the oral application of fasudil.<br><br>METHODS: This was a phase I, single-center, open-label, randomized, two period cross-over clinical trial in healthy women and men. By applying a cross-over design, each subject served as their own control. Two treatments were investigated, separated by a wash out phase of at least 3 days. Oral fasudil was administered once on day 1 to assess pharmacokinetics and three times on day 2, at an interval of 8 &#xb1; 1 h, to assess safety and gastrointestinal tolerability. For pharmacometrics of IV fasudil, it was administered once on day 1. Plasma profiles of fasudil and its active metabolite hydroxyfasudil after oral or IV administration were measured by liquid chromatography electrospray tandem mass spectrometry. Tolerability was assessed as proportion of subjects without significant drug intolerance, and safety was assessed by the proportion of subjects without clinical or laboratory treatment-associated serious adverse events. Gastrointestinal safety was assessed by applying the gastrointestinal symptom rating scale (GSRS).<br><br>RESULTS: Fourteen subjects aged 30-70 years were included in this trial. After oral administration, fasudil concentrations in blood were mostly very low [1.4 g/L; coefficient of variation (CV) 41.0%]. After IV application, the peak concentration was 100.6 &#xb5;g/L (CV 74.2%); however, a high variance in peak concentrations were assessed for both treatments. The maximal concentrations of hydroxyfasudil in blood were similar after oral and IV treatment [111.6 &#xb5;g/L (CV 24.1%) and 108.4 &#xb5;g/L (CV 19.7%), respectively]. Exposure of hydroxyfasudil (assessed as AUC0-tz) differed between both treatments, with 449 &#xb5;g &#xd7; h/L after IV treatment and 309 &#xb5;g &#xd7; h/L after oral treatment. Therefore, the absolute bioavailability of hydroxyfasudil after the oral treatment was approximately 69% of the IV treatment. No serious adverse events (SAEs) occurred during this trial, and good tolerability of oral fasudil (90 mg/day) was documented.<br><br>CONCLUSIONS: Oral fasudil was generally well tolerated in the studied population, and no safety concerns were identified. However, systemic bioavailability of oral hydroxyfasudil corresponded to 69%, and dose adjustments need to considered. The results presented here lay grounds for future trials of fasudil in chronic diseases, which require an oral long-term application. This trial was registered with EudraCT (no. 2019-001805-26).}, }
@article {pmid38413232, year = {2024}, author = {Chun, C and Lee, JH and Bothwell, M and Nghiem, P and Smith, AST and Mack, DL}, title = {Human Motor Neurons Elicit Pathological Hallmarks of ALS and Reveal Potential Biomarkers of the Disease in Response to Prolonged IFNγ Exposure.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {44}, number = {16}, pages = {}, pmid = {38413232}, issn = {1529-2401}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; R03 TR004009/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; B7-H1 Antigen/metabolism ; Biomarkers ; DNA-Binding Proteins/genetics ; *Induced Pluripotent Stem Cells/metabolism ; Interferon-gamma/metabolism/pharmacology ; Motor Neurons/drug effects/metabolism/pathology ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder marked by progressive motor neuron degeneration and muscle denervation. A recent transcriptomic study integrating a wide range of human ALS samples revealed that the upregulation of p53, a downstream target of inflammatory stress, is commonly detected in familial and sporadic ALS cases by a mechanism linked to a transactive response DNA-binding protein 43 (TDP-43) dysfunction. In this study, we show that prolonged interferon-gamma (IFNγ) treatment of human induced pluripotent stem cell-derived spinal motor neurons results in a severe cytoplasmic aggregation of TDP-43. TDP-43 dysfunction resulting from either IFNγ exposure or an ALS-associated TDP-43 mutation was associated with the activation of the p53 pathway. This was accompanied by the hyperactivation of neuronal firing, followed by the complete loss of their electrophysiological function. Through a comparative single-cell transcriptome analysis, we have identified significant alterations in ALS-associated genes in motor neurons exposed to IFNγ, implicating their direct involvement in ALS pathology. Interestingly, IFNγ was found to induce significant levels of programmed death-ligand 1 (PD-L1) expression in motor neurons without affecting the levels of any other immune checkpoint proteins. This finding suggests a potential role of excessive PD-L1 expression in ALS development, given that PD-L1 was recently reported to impair neuronal firing ability in mice. Our findings suggest that exposing motor neurons to IFNγ could directly derive ALS pathogenesis, even without the presence of the inherent genetic mutation or functional glia component. Furthermore, this study provides a comprehensive list of potential candidate genes for future immunotherapeutic targets with which to treat sporadic forms of ALS, which account for 90% of all reported cases.}, }
@article {pmid38410712, year = {2024}, author = {Moretti, A and Pietersen, PI and Hassan, M and Shafiek, H and Prosch, H and Tarnoki, AD and Annema, JT and Munavvar, M and Bonta, PI and de Wever, W and Juul, AD}, title = {ERS International Congress 2023: highlights from the Clinical Techniques, Imaging and Endoscopy Assembly.}, journal = {ERJ open research}, volume = {10}, number = {1}, pages = {}, pmid = {38410712}, issn = {2312-0541}, abstract = {The Clinical Techniques, Imaging and Endoscopy Assembly is involved in the diagnosis and treatment of several pulmonary diseases, as demonstrated at the 2023 European Respiratory Society (ERS) International Congress in Milan, Italy. From interventional pulmonology, the congress included several exciting results for the use of bronchoscopy in lung cancer, including augmented fluoroscopy, robotic-assisted bronchoscopy and cryobiopsies. In obstructive lung disease, the latest results on bronchoscopic treatment of emphysema with hyperinflation and chronic bronchitis were presented. Research on using cryobiopsies to diagnose interstitial lung disease was further explored, with the aims of elevating diagnostic yield and minimising risk. For imaging, the latest updates in using artificial intelligence to overcome the increased workload of radiologists were of great interest. Novel imaging in sarcoidosis explored the use of magnetic resonance imaging, photon-counting computed tomography and positron emission tomography/computed tomography in the diagnostic work-up. Lung cancer screening is still a hot topic and new results were presented regarding incorporation of biomarkers, identifying knowledge gaps and improving screening programmes. The use of ultrasound in respiratory medicine is an expanding field, which was demonstrated by the large variety in studies presented at the 2023 ERS Congress. Ultrasound of the diaphragm in patients with amyotrophic lateral sclerosis and myasthenia gravis was used to assess movements and predict respiratory fatigue. Furthermore, studies using ultrasound to diagnose or monitor pulmonary disease were presented. The congress also included studies regarding the training and assessment of competencies as an important part of implementing ultrasound in clinical practice.}, }
@article {pmid38405076, year = {2024}, author = {Dittlau, KS and Chandrasekaran, A and Freude, K and Van Den Bosch, L}, title = {Generation of Human Induced Pluripotent Stem Cell (hiPSC)-Derived Astrocytes for Amyotrophic Lateral Sclerosis and Other Neurodegenerative Disease Studies.}, journal = {Bio-protocol}, volume = {14}, number = {4}, pages = {e4936}, pmid = {38405076}, issn = {2331-8325}, abstract = {Astrocytes are increasingly recognized for their important role in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). In ALS, astrocytes shift from their primary function of providing neuronal homeostatic support towards a reactive and toxic role, which overall contributes to neuronal toxicity and cell death. Currently, our knowledge on these processes is incomplete, and time-efficient and reproducible model systems in a human context are therefore required to understand and therapeutically modulate the toxic astrocytic response for future treatment options. Here, we present an efficient and straightforward protocol to generate human induced pluripotent stem cell (hiPSC)-derived astrocytes implementing a differentiation scheme based on small molecules. Through an initial 25 days, hiPSCs are differentiated into astrocytes, which are matured for 4+ weeks. The hiPSC-derived astrocytes can be cryopreserved at every passage during differentiation and maturation. This provides convenient pauses in the protocol as well as cell banking opportunities, thereby limiting the need to continuously start from hiPSCs. The protocol has already proven valuable in ALS research but can be adapted to any desired research field where astrocytes are of interest. Key features • This protocol requires preexisting experience in hiPSC culturing for a successful outcome. • The protocol relies on a small molecule differentiation scheme and an easy-to-follow methodology, which can be paused at several time points. • The protocol generates >50 × 10[6] astrocytes per differentiation, which can be cryopreserved at every passage, ensuring a large-scale experimental output.}, }
@article {pmid38399543, year = {2024}, author = {Karagul, S and Senol, S and Karakose, O and Uzunoglu, K and Kayaalp, C}, title = {One Anastomosis Gastric Bypass versus Roux-en-Y Gastric Bypass: A Randomized Prospective Trial.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {2}, pages = {}, pmid = {38399543}, issn = {1648-9144}, mesh = {Humans ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged ; *Gastric Bypass/methods ; Prospective Studies ; *Obesity, Morbid/surgery ; Comorbidity ; Weight Loss ; Retrospective Studies ; }, abstract = {Background and Objectives: One anastomosis gastric bypass (OAGB) and Roux-en-Y gastric bypass (RYGB) surgeries are effective methods used in bariatric surgery. There are limited randomized studies comparing these procedures over more than 2 years. Here, we aimed to compare the 3-year results of two bariatric procedures. Materials and Methods: Patients included in this randomized prospective study were compared in OAGB and RYGB groups. A total of 55 patients, aged between 18 and 65, were eligible for the study. Thirteen patients who did not accept randomization were excluded. Patients were evaluated at 6, 12, 24, and 36 months postoperatively. Results: Three patients were excluded from the study due to loss of communication during the clinical follow-up and one due to death by amyotrophic lateral sclerosis, which started in the eighth month after surgery. The study was completed with a total of 38 patients (OAGB; n = 20, RYGB; n = 18). Patients in the two groups were similar in terms of age, gender, body mass index (BMI), and obesity-related comorbidities. At the end of 3-year follow-up, BMI in the OAGB and RYGB groups was 28.80 ± 4.53 kg/m[2] and 29.17 ± 5.36 kg/m[2], respectively (p = 0.822). Percentage total weight loss (TWL%) was similar. No significant differences were found between the groups regarding percentage excess weight loss (EWL%). Remission of comorbidities was similar. De novo refluxes developed in four OAGB patients; there were no occurrences of these in RYGB patients (p = 0.066). Conclusions: Both OAGB and RYGB are effective in the treatment of morbid obesity. The two procedures are similarly successful in terms of obesity-related comorbidities.}, }
@article {pmid38399458, year = {2024}, author = {Al Shaer, D and Al Musaimi, O and Albericio, F and de la Torre, BG}, title = {2023 FDA TIDES (Peptides and Oligonucleotides) Harvest.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {2}, pages = {}, pmid = {38399458}, issn = {1424-8247}, abstract = {A total of nine TIDES (pepTIDES and oligonucleoTIDES) were approved by the FDA during 2023. The four approved oligonucleotides are indicated for various types of disorders, including amyotrophic lateral sclerosis, geographic atrophy, primary hyperoxaluria type 1, and polyneuropathy of hereditary transthyretin-mediated amyloidosis. All oligonucleotides show chemically modified structures to enhance their stability and therapeutic effectiveness as antisense or aptamer oligomers. Some of them demonstrate various types of conjugation to driving ligands. The approved peptides comprise various structures, including linear, cyclic, and lipopeptides, and have diverse applications. Interestingly, the FDA has granted its first orphan drug designation for a peptide-based drug as a highly selective chemokine antagonist. Furthermore, Rett syndrome has found its first-ever core symptoms treatment, which is also peptide-based. Here, we analyze the TIDES approved in 2023 on the basis of their chemical structure, medical target, mode of action, administration route, and common adverse effects.}, }
@article {pmid38399373, year = {2024}, author = {Cha, Y and Kagalwala, MN and Ross, J}, title = {Navigating the Frontiers of Machine Learning in Neurodegenerative Disease Therapeutics.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {2}, pages = {}, pmid = {38399373}, issn = {1424-8247}, abstract = {Recent advances in machine learning hold tremendous potential for enhancing the way we develop new medicines. Over the years, machine learning has been adopted in nearly all facets of drug discovery, including patient stratification, lead discovery, biomarker development, and clinical trial design. In this review, we will discuss the latest developments linking machine learning and CNS drug discovery. While machine learning has aided our understanding of chronic diseases like Alzheimer's disease and Parkinson's disease, only modest effective therapies currently exist. We highlight promising new efforts led by academia and emerging biotech companies to leverage machine learning for exploring new therapies. These approaches aim to not only accelerate drug development but to improve the detection and treatment of neurodegenerative diseases.}, }
@article {pmid38391754, year = {2024}, author = {Leão Batista Simões, J and Webler Eichler, S and Raitz Siqueira, ML and de Carvalho Braga, G and Bagatini, MD}, title = {Amyotrophic Lateral Sclerosis in Long-COVID Scenario and the Therapeutic Potential of the Purinergic System in Neuromodulation.}, journal = {Brain sciences}, volume = {14}, number = {2}, pages = {}, pmid = {38391754}, issn = {2076-3425}, support = {Proj. No 404256/2021-0 and 310606/2021-7).//National Council for Scientific and Technological Development/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) involves the degeneration of motor neurons and debilitating and possibly fatal symptoms. The COVID-19 pandemic directly affected the quality of life of this group, and the SARS-CoV-2 infection accelerated the present neuroinflammatory process. Furthermore, studies indicate that the infection may have led to the development of the pathology. Thus, the scenario after this pandemic presents "long-lasting COVID" as a disease that affects people who have been infected. From this perspective, studying the pathophysiology behind ALS associated with SARS-CoV-2 infection and possible supporting therapies becomes necessary when we understand the impact on the quality of life of these patients. Thus, the purinergic system was trained to demonstrate how its modulation can add to the treatment, reduce disease progression, and result in better prognoses. From our studies, we highlight the P2X7, P2X4, and A2AR receptors and how their activity can directly influence the ALS pathway.}, }
@article {pmid38390945, year = {2024}, author = {Fukatsu, S and Sashi, H and Shirai, R and Takagi, N and Oizumi, H and Yamamoto, M and Ohbuchi, K and Miyamoto, Y and Yamauchi, J}, title = {Rab11a Controls Cell Shape via C9orf72 Protein: Possible Relationships to Frontotemporal Dementia/Amyotrophic Lateral Sclerosis (FTDALS) Type 1.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {31}, number = {1}, pages = {100-116}, pmid = {38390945}, issn = {1873-149X}, abstract = {Abnormal nucleotide insertions of C9orf72, which forms a complex with Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8) protein and WD repeat-containing protein 41 (WDR41) protein, are associated with an autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 1 (FTDALS1). The differentially expressed in normal and neoplastic cells (DENN) domain-containing C9orf72 and its complex with SMCR8 and WDR41 function as a guanine-nucleotide exchange factor for Rab GTP/GDP-binding proteins (Rab GEF, also called Rab activator). Among Rab proteins serving as major effectors, there exists Rab11a. However, it remains to be established which Rab protein is related to promoting or sustaining neuronal morphogenesis or homeostasis. In this study, we describe that the knockdown of Rab11a decreases the expression levels of neuronal differentiation marker proteins, as well as the elongation of neurite-like processes, using N1E-115 cells, a well-utilized neuronal differentiation model. Similar results were obtained in primary cortical neurons. In contrast, the knockdown of Rab11b, a Rab11a homolog, did not significantly affect their cell morphological changes. It is of note that treatment with hesperetin, a citrus flavonoid (also known as Vitamin P), recovered the neuronal morphological phenotypes induced by Rab11a knockdown. Also, the knockdown of Rab11a or Rab11b led to a decrease in glial marker expression levels and in morphological changes in FBD-102b cells, which serve as the oligodendroglial differentiation model. Rab11a is specifically involved in the regulation of neuronal morphological differentiation. The knockdown effect mimicking the loss of function of C9orf72 is reversed by treatment with hesperetin. These findings may reveal a clue for identifying one of the potential molecular and cellular phenotypes underlying FTDALS1.}, }
@article {pmid38389786, year = {2024}, author = {Berthiaume, AA and Reda, SM and Kleist, KN and Setti, SE and Wu, W and Johnston, JL and Taylor, RW and Stein, LR and Moebius, HJ and Church, KJ}, title = {ATH-1105, a small-molecule positive modulator of the neurotrophic HGF system, is neuroprotective, preserves neuromotor function, and extends survival in preclinical models of ALS.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1348157}, pmid = {38389786}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disorder, primarily affects the motor neurons of the brain and spinal cord. Like other neurodegenerative conditions, ongoing pathological processes such as increased inflammation, excitotoxicity, and protein accumulation contribute to neuronal death. Hepatocyte growth factor (HGF) signaling through the MET receptor promotes pro-survival, anti-apoptotic, and anti-inflammatory effects in multiple cell types, including the neurons and support cells of the nervous system. This pleiotropic system is therefore a potential therapeutic target for treatment of neurodegenerative disorders such as ALS. Here, we test the effects of ATH-1105, a small-molecule positive modulator of the HGF signaling system, in preclinical models of ALS.<br><br>METHODS: In vitro, the impact of ATH-1105 on HGF-mediated signaling was assessed via phosphorylation assays for MET, extracellular signal-regulated kinase (ERK), and protein kinase B (AKT). Neuroprotective effects of ATH-1105 were evaluated in rat primary neuron models including spinal motor neurons, motor neuron-astrocyte cocultures, and motor neuron-human muscle cocultures. The anti-inflammatory effects of ATH-1105 were evaluated in microglia- and macrophage-like cell systems exposed to lipopolysaccharide (LPS). In vivo, the impact of daily oral treatment with ATH-1105 was evaluated in Prp-TDP43[A315T] hemizygous transgenic ALS mice.<br><br>RESULTS: In vitro, ATH-1105 augmented phosphorylation of MET, ERK, and AKT. ATH-1105 attenuated glutamate-mediated excitotoxicity in primary motor neurons and motor neuron- astrocyte cocultures, and had protective effects on motor neurons and neuromuscular junctions in motor neuron-muscle cocultures. ATH-1105 mitigated LPS-induced inflammation in microglia- and macrophage-like cell systems. In vivo, ATH-1105 treatment resulted in improved motor and nerve function, sciatic nerve axon and myelin integrity, and survival in ALS mice. Treatment with ATH-1105 also led to reductions in levels of plasma biomarkers of inflammation and neurodegeneration, along with decreased pathological protein accumulation (phospho-TDP-43) in the sciatic nerve. Additionally, both early intervention (treatment initiation at 1 month of age) and delayed intervention (treatment initiation at 2 months of age) with ATH-1105 produced benefits in this preclinical model of ALS.<br><br>DISCUSSION: The consistent neuroprotective and anti-inflammatory effects demonstrated by ATH-1105 preclinically provide a compelling rationale for therapeutic interventions that leverage the positive modulation of the HGF pathway as a treatment for ALS.}, }
@article {pmid38384337, year = {2024}, author = {Wiesenfarth, M and Dorst, J and Brenner, D and Elmas, Z and Parlak, &#xd6; and Uzelac, Z and Kandler, K and Mayer, K and Weiland, U and Herrmann, C and Schuster, J and Freischmidt, A and Müller, K and Siebert, R and Bachhuber, F and Simak, T and Günther, K and Fröhlich, E and Knehr, A and Regensburger, M and German, A and Petri, S and Grosskreutz, J and Klopstock, T and Reilich, P and Schöberl, F and Hagenacker, T and Weyen, U and Günther, R and Vidovic, M and Jentsch, M and Haarmeier, T and Weydt, P and Valkadinov, I and Hesebeck-Brinckmann, J and Conrad, J and Weishaupt, JH and Schumann, P and Körtvélyessy, P and Meyer, T and Ruf, WP and Witzel, S and Senel, M and Tumani, H and Ludolph, AC}, title = {Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program.}, journal = {EClinicalMedicine}, volume = {69}, number = {}, pages = {102495}, pmid = {38384337}, issn = {2589-5370}, abstract = {BACKGROUND: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated.<br><br>METHODS: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events.<br><br>FINDINGS: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR&#xa0;-0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0&#xa0;pg/ml (IQR 37.0-147.0&#xa0;pg/ml; n&#xa0;=&#xa0;23) to 36.0&#xa0;pg/ml (IQR 22.0-65.0&#xa0;pg/ml; n&#xa0;=&#xa0;23; p&#xa0;=&#xa0;0.02), median pNfH in CSF from 2226&#xa0;pg/ml (IQR 1061-6138&#xa0;pg/ml; n&#xa0;=&#xa0;18) to 1151&#xa0;pg/ml (IQR 521-2360&#xa0;pg/ml; n&#xa0;=&#xa0;18; p&#xa0;=&#xa0;0.02). In the CSF, we detected a pleocytosis in 73% of patients (11&#xa0;of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported.<br><br>INTERPRETATION: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction.<br><br>FUNDING: No funding was received towards this study.}, }
@article {pmid38383503, year = {2024}, author = {Vidovic, M and Menschikowski, M and Freigang, M and Lapp, HS and Günther, R}, title = {Macrophage inclusions in cerebrospinal fluid following treatment initiation with antisense oligonucleotide therapies in motor neuron diseases.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {11}, pmid = {38383503}, issn = {2524-3489}, abstract = {5q-associated spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are two distinct neurological disorders leading to degeneration of lower motor neurons. The antisense oligonucleotides (ASOs) nusinersen and tofersen are novel disease-modifying agents for these diseases, respectively. In the context of ASO treatment, the cytological characteristics and composition of cerebrospinal fluid (CSF) have recently garnered particular interest. This report presents a case series of CSF cytology findings in two patients with SMA and ALS revealing comparable unspecified macrophage inclusions following treatment initiation with nusinersen and tofersen. Yet, the presence of these "asophages" in the treatment course of two different ASOs is of unclear significance. While both treatments have been well tolerated, this phenomenon warrants attention, given the long-term nature of these treatments.}, }
@article {pmid38382884, year = {2024}, author = {Jiao, LL and Dong, HL and Liu, MM and Wu, PL and Cao, Y and Zhang, Y and Gao, FG and Zhu, HY}, title = {The potential roles of salivary biomarkers in neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {193}, number = {}, pages = {106442}, doi = {10.1016/j.nbd.2024.106442}, pmid = {38382884}, issn = {1095-953X}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; Reproducibility of Results ; *Parkinson Disease/metabolism ; *Alzheimer Disease ; *Huntington Disease/diagnosis ; Biomarkers ; }, abstract = {Current research efforts on neurodegenerative diseases are focused on identifying novel and reliable biomarkers for early diagnosis and insight into disease progression. Salivary analysis is gaining increasing interest as a promising source of biomarkers and matrices for measuring neurodegenerative diseases. Saliva collection offers multiple advantages over the currently detected biofluids as it is easily accessible, non-invasive, and repeatable, allowing early diagnosis and timely treatment of the diseases. Here, we review the existing findings on salivary biomarkers and address the potential value in diagnosing neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Based on the available research, β-amyloid, tau protein, α-synuclein, DJ-1, Huntington protein in saliva profiles display reliability and validity as the biomarkers of neurodegenerative diseases.}, }
@article {pmid38382647, year = {2024}, author = {Huang, TN and Shih, YT and Yen, TL and Hsueh, YP}, title = {Vcp overexpression and leucine supplementation extend lifespan and ameliorate neuromuscular junction phenotypes of a SOD1G93A-ALS mouse model.}, journal = {Human molecular genetics}, volume = {33}, number = {11}, pages = {935-944}, pmid = {38382647}, issn = {1460-2083}, support = {AS-CFII-108-104//Transgenic Core Facility/ ; //Animal Facility of the Institute of Molecular Biology, Academia Sinica/ ; }, mesh = {Animals ; *Valosin Containing Protein/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Disease Models, Animal ; Mice ; *Neuromuscular Junction/metabolism ; Female ; Male ; *Longevity/genetics ; *Mice, Transgenic ; *Leucine/pharmacology/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Phenotype ; Superoxide Dismutase/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; Humans ; Adenosine Triphosphatases/genetics/metabolism ; }, abstract = {Many genes with distinct molecular functions have been linked to genetically heterogeneous amyotrophic lateral sclerosis (ALS), including SuperOxide Dismutase 1 (SOD1) and Valosin-Containing Protein (VCP). SOD1 converts superoxide to oxygen and hydrogen peroxide. VCP acts as a chaperon to regulate protein degradation and synthesis and various other cellular responses. Although the functions of these two genes differ, in the current report we show that overexpression of wild-type VCP in mice enhances lifespan and maintains the size of neuromuscular junctions (NMJs) of both male and female SOD1G93A mice, a well-known ALS mouse model. Although VCP exerts multiple functions, its regulation of ER formation and consequent protein synthesis has been shown to play the most important role in controlling dendritic spine formation and social and memory behaviors. Given that SOD1 mutation results in protein accumulation and aggregation, it may direct VCP to the protein degradation pathway, thereby impairing protein synthesis. Since we previously showed that the protein synthesis defects caused by Vcp deficiency can be improved by leucine supplementation, to confirm the role of the VCP-protein synthesis pathway in SOD1-linked ALS, we applied leucine supplementation to SOD1G93A mice and, similar to Vcp overexpression, we found that it extends SOD1G93A mouse lifespan. In addition, the phenotypes of reduced muscle strength and fewer NMJs of SOD1G93A mice are also improved by leucine supplementation. These results support the existence of crosstalk between SOD1 and VCP and suggest a critical role for protein synthesis in ASL. Our study also implies a potential therapeutic treatment for ALS.}, }
@article {pmid38378992, year = {2024}, author = {Song, M and Qiang, Y and Zhao, X and Song, F}, title = {Cyclin-dependent Kinase 5 and Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {61}, number = {10}, pages = {7287-7302}, pmid = {38378992}, issn = {1559-1182}, mesh = {Humans ; *Neurodegenerative Diseases/enzymology/metabolism ; *Cyclin-Dependent Kinase 5/metabolism ; Animals ; Oxidative Stress/physiology ; Mitochondria/metabolism ; }, abstract = {Neurodegenerative diseases are a group of diseases characterized by the progressive loss of neurons, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. These diseases have a high incidence and mortality rate globally, placing a heavy burden on patients and their families. The pathogenesis of neurodegenerative diseases is complex, and there are no effective treatments at present. Cyclin-dependent kinase 5 is a proline-directed serine/threonine protein kinase that is closely related to the development and function of the nervous system. Under physiological conditions, it is involved in regulating the process of neuronal proliferation, differentiation, migration, and synaptic plasticity. Moreover, there is increasing evidence that cyclin-dependent kinase 5 also plays an important role in the pathogenesis of neurodegenerative diseases. In this review, we address the biological characteristics of cyclin-dependent kinase 5 and its role in neurodegenerative diseases. In particular, this review highlights the underlying mechanistic linkages between cyclin-dependent kinase 5 and mitochondrial dysfunction, oxidative stress and neuroinflammation in the context of neurodegeneration. Finally, we also summarize the currently available cyclin-dependent kinase 5 inhibitors and their prospects for the treatment of neurodegenerative diseases. Taken together, a better understanding of the molecular mechanisms of cyclin-dependent kinase 5 involved in neurodegenerative diseases can lead to the development of new strategies for the prevention and treatment of these devastating diseases.}, }
@article {pmid38372421, year = {2024}, author = {Miquel, E and Villarino, R and Martínez-Palma, L and Cassina, A and Cassina, P}, title = {Pyruvate dehydrogenase kinase 2 knockdown restores the ability of amyotrophic lateral sclerosis-linked SOD1G93A rat astrocytes to support motor neuron survival by increasing mitochondrial respiration.}, journal = {Glia}, volume = {72}, number = {5}, pages = {999-1011}, doi = {10.1002/glia.24516}, pmid = {38372421}, issn = {1098-1136}, support = {//Programa de Desarrollo de las Ciencias B&#xe1;sicas (PEDECIBA)/ ; FCE_1_2019_1_156461//Agencia Nacional de Investigaci&#xf3;n e Innovaci&#xf3;n/ ; }, mesh = {Animals ; Rats ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Astrocytes/metabolism ; Cells, Cultured ; Disease Models, Animal ; Motor Neurons/metabolism ; *Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics/metabolism ; Respiration ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration. Various studies using cellular and animal models of ALS indicate that there is a complex interplay between MN and neighboring non-neuronal cells, such as astrocytes, resulting in noncell autonomous neurodegeneration. Astrocytes in ALS exhibit a lower ability to support MN survival than nondisease-associated ones, which is strongly correlated with low-mitochondrial respiratory activity. Indeed, pharmacological inhibition of pyruvate dehydrogenase kinase (PDK) led to an increase in the mitochondrial oxidative phosphorylation pathway as the primary source of cell energy in SOD1G93A astrocytes and restored the survival of MN. Among the four PDK isoforms, PDK2 is ubiquitously expressed in astrocytes and presents low expression levels in neurons. Herein, we hypothesize whether selective knockdown of PDK2 in astrocytes may increase mitochondrial activity and, in turn, reduce SOD1G93A-associated toxicity. To assess this, cultured neonatal SOD1G93A rat astrocytes were incubated with specific PDK2 siRNA. This treatment resulted in a reduction of the enzyme expression with a concomitant decrease in the phosphorylation rate of the pyruvate dehydrogenase complex. In addition, PDK2-silenced SOD1G93A astrocytes exhibited restored mitochondrial bioenergetics parameters, adopting a more complex mitochondrial network. This treatment also decreased lipid droplet content in SOD1G93A astrocytes, suggesting a switch in energetic metabolism. Significantly, PDK2 knockdown increased the ability of SOD1G93A astrocytes to support MN survival, further supporting the major role of astrocyte mitochondrial respiratory activity in astrocyte-MN interactions. These results suggest that PDK2 silencing could be a cell-specific therapeutic tool to slow the progression of ALS.}, }
@article {pmid38366598, year = {2024}, author = {Ke, YD and van Hummel, A and Au, C and Chan, G and Lee, WS and van der Hoven, J and Przybyla, M and Deng, Y and Sabale, M and Morey, N and Bertz, J and Feiten, A and Ippati, S and Stevens, CH and Yang, S and Gladbach, A and Haass, NK and Kril, JJ and Blair, IP and Delerue, F and Ittner, LM}, title = {Targeting 14-3-3θ-mediated TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal dementia mice.}, journal = {Neuron}, volume = {112}, number = {8}, pages = {1249-1264.e8}, doi = {10.1016/j.neuron.2024.01.022}, pmid = {38366598}, issn = {1097-4199}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/metabolism ; Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by cytoplasmic deposition of the nuclear TAR-binding protein 43 (TDP-43). Although cytoplasmic re-localization of TDP-43 is a key event in the pathogenesis of ALS/FTD, the underlying mechanisms remain unknown. Here, we identified a non-canonical interaction between 14-3-3θ and TDP-43, which regulates nuclear-cytoplasmic shuttling. Neuronal 14-3-3θ levels were increased in sporadic ALS and FTD with TDP-43 pathology. Pathogenic TDP-43 showed increased interaction with 14-3-3θ, resulting in cytoplasmic accumulation, insolubility, phosphorylation, and fragmentation of TDP-43, resembling pathological changes in disease. Harnessing this increased affinity of 14-3-3θ for pathogenic TDP-43, we devised a gene therapy vector targeting TDP-43 pathology, which mitigated functional deficits and neurodegeneration in different ALS/FTD mouse models expressing mutant or non-mutant TDP-43, including when already symptomatic at the time of treatment. Our study identified 14-3-3θ as a mediator of cytoplasmic TDP-43 localization with implications for ALS/FTD pathogenesis and therapy.}, }
@article {pmid38360060, year = {2024}, author = {El-Ghazouly, DE and Yassien, RI}, title = {Bisphosphonate's effect on the tongue in adult male albino rats and the possible protective role of rutin: light and scanning electron microscopic study.}, journal = {Anatomy &amp; cell biology}, volume = {57}, number = {1}, pages = {129-142}, pmid = {38360060}, issn = {2093-3665}, abstract = {Alendronate sodium (ALS) is a nitrogen-containing bisphosphonate used for the treatment of different bone disorders. However, its adverse effect on oral soft tissue has been detected. Rutin (RUT) is natural flavonoid with antioxidant and anti-inflammatory properties. This work aimed to investigate the possible effect of ALS on the tongue of adult male albino rats and to evaluate the possible protective role of RUT. Forty adult male albino rats were equally divided into four groups: group I (control), group II (RUT): Received RUT 50 mg/kg, group III (ALS): Received ALS 1 mg/kg, group IV (ALS+RUT): Received ALS and RUT with the same doses as pervious groups. The drugs were given once daily for 5 weeks. Tongue specimens were taken and processed for light and scanning electron microscopic inspection. ALS treated group revealed structural changes in the tongue in the form of decrease in the height of the filiform papillae with blunt ends, marked atrophy in some papillae with areas of focal loss, loss of some epithelial cells, pyknotic nuclei and cytoplasmic vacuoles in some epithelial cells. The lamina propria showed inflammatory cellular infiltration with congested blood vessels. Statistically, there were highly significant decrease in the number of proliferating cell nuclear antigen immunopositive cells, area percentage of Bcl-2 immunoexpression and highly significant increase in the collagen content compared to control group. Administration of RUT with ALS minimizes these changes. RUT protected the rat tongue against the histological and immunohistochemical changes induced by ALS through its antioxidant and anti-inflammatory properties.}, }
@article {pmid38359044, year = {2024}, author = {Vieira, FG and Tassinari, VR and Kidd, JD and Moreno, A and Thompson, K and Perrin, S and Gill, A and Hatzipetros, T}, title = {PERK modulation, with GSK2606414, Sephin1 or salubrinal, failed to produce therapeutic benefits in the SOD1G93A mouse model of ALS.}, journal = {PloS one}, volume = {19}, number = {2}, pages = {e0292190}, pmid = {38359044}, issn = {1932-6203}, mesh = {Mice ; Humans ; Animals ; *Guanabenz/pharmacology/therapeutic use/*analogs &amp; derivatives ; eIF-2 Kinase/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Clonidine ; Unfolded Protein Response ; Adrenergic alpha-2 Receptor Agonists ; Adenine/*analogs &amp; derivatives ; *Cinnamates ; *Indoles ; Thiourea/*analogs &amp; derivatives ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has been linked to overactivity of the protein kinase RNA-like ER kinase (PERK) branch of the unfolded protein response (UPR) pathway, both in ALS patients and mouse models. However, attempts to pharmacologically modulate PERK for therapeutic benefit have yielded inconsistent and often conflicting results. This study sought to address these discrepancies by comprehensively evaluating three commonly used, CNS-penetrant, PERK modulators (GSK2606414, salubrinal, and Sephin1) in the same experimental models, with the goal of assessing the viability of targeting the PERK pathway as a therapeutic strategy for ALS. To achieve this goal, a tunicamycin-challenge assay was developed using wild-type mice to monitor changes in liver UPR gene expression in response to PERK pathway modulation. Subsequently, multiple dosing regimens of each PERK modulator were tested in standardized, well-powered, gender-matched, and litter-matched survival efficacy studies using the SOD1G93A mouse model of ALS. The alpha-2-adrenergic receptor agonist clonidine was also tested to elucidate the results obtained from the Sephin1, and of the previously reported guanabenz studies, by comparing the effects of presence or absence of α-2 agonism. The results revealed that targeting PERK may not be an ideal approach for ALS treatment. Inhibiting PERK with GSK2606414 or activating it with salubrinal did not confer therapeutic benefits. While Sephin1 showed some promising therapeutic effects, it appears that these outcomes were mediated through PERK-independent mechanisms. Clonidine also produced some favorable therapeutic effects, which were unexpected and not linked to the UPR. In conclusion, this study highlights the challenges of pharmacologically targeting PERK for therapeutic purposes in the SOD1G93A mouse model and suggests that exploring other targets within, and outside, the UPR may be more promising avenues for ALS treatment.}, }
@article {pmid38358553, year = {2024}, author = {Brakemeier, S and Lipka, J and Schlag, M and Kleinschnitz, C and Hagenacker, T}, title = {Risdiplam improves subjective swallowing quality in non-ambulatory adult patients with 5q-spinal muscular atrophy despite advanced motor impairment.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2649-2657}, pmid = {38358553}, issn = {1432-1459}, mesh = {Humans ; Male ; Female ; Middle Aged ; Adult ; *Deglutition Disorders/etiology/physiopathology/drug therapy ; Pyrimidines/therapeutic use/pharmacology ; Aged ; Spinal Muscular Atrophies of Childhood/drug therapy/physiopathology/complications ; Treatment Outcome ; Deglutition/physiology/drug effects ; Prospective Studies ; Muscular Atrophy, Spinal/drug therapy/physiopathology ; Young Adult ; *Azo Compounds ; }, abstract = {BACKGROUND: 5q-associated spinal muscular atrophy (SMA) is characterized by the progressive loss of motor neurons with consecutive weakness and atrophy of the limb, respiratory, and bulbar muscles. While trunk and limb motor function improve or stabilize in adults with SMA under nusinersen and risdiplam treatment, the efficacy on bulbar function in this age group of patients remains uncertain. However, it is important to assess bulbar dysfunction, which frequently occurs in the disease course and is associated with increased morbidity and mortality.<br><br>METHODS: Bulbar function was evaluated prospectively in 25 non-ambulatory adults with type 2 and 3 SMA before and 4 and 12&#xa0;months after risdiplam treatment initiation using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (b-ALSFRS-R). Extremity function was assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM).<br><br>RESULTS: Subjective swallowing quality, measured with the SSQ, improved after 12 months of therapy with risdiplam. For the b-ALSFRS-R, a non-significant trend towards improvement was observed. The RULM score improved after 12 months of risdiplam therapy, but not the HFMSE score. HFMSE and RULM scores did not correlate with the SSQ but the b-ALSFRS-R score at baseline.<br><br>CONCLUSIONS: The improvement in subjective swallowing quality under risdiplam treatment, despite an advanced disease stage with severe motor deficits, strengthens the importance of a standardized bulbar assessment in addition to established motor scores. This may reveal relevant treatment effects and help individualize treatment decisions in the future.}, }
@article {pmid38352376, year = {2024}, author = {Amado, DA and Robbins, AB and Smith, AR and Whiteman, KR and Chillon Bosch, G and Chen, Y and Fuller, JA and Izda, A and Nelson, S and Dichter, AI and Monteys, AM and Davidson, BL}, title = {AAV-based delivery of RNAi targeting Ataxin-2 improves survival, strength, and pathology in mouse models of rapidly and slowly progressive sporadic ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.01.31.578314}, pmid = {38352376}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron death due to nuclear loss and cytoplasmic aggregation of the splice factor TDP-43. Pathologic TDP-43 associates with stress granules (SGs) and downregulating the SG-associated protein Ataxin-2 (Atxn2) using antisense oligonucleotides (ASO) prolongs survival in the TAR4/4 sporadic ALS mouse model, a strategy now in clinical trials. Here, we used AAV-mediated RNAi delivery to achieve lasting and targeted Atxn2 knockdown after a single injection. To achieve this, a novel AAV with improved transduction potency of our target cells was used to deliver Atxn2 -targeting miRNAs. Mouse dosing studies demonstrated 55% Atxn2 knockdown in frontal cortex and 25% knockdown throughout brainstem and spinal cord after intracerebroventricular injection at a dose 40x lower than used in other recent studies. In TAR4/4 mice, miAtxn2 treatment increased mean and median survival by 54% and 45% respectively (p<0.0003). Mice showed robust improvement across strength-related measures ranging from 24-75%. Interestingly, treated mice showed increased vertical activity above wildtype, suggesting unmasking of an FTD phenotype with improved strength. Histologically, lower motor neuron survival improved with a concomitant reduction in CNS inflammatory markers. Additionally, phosphorylated TDP-43 was reduced to wildtype levels. Bulk RNA sequencing revealed correction of 153 genes in the markedly dysregulated transcriptome of mutant mice, several of which are described in the human ALS literature. In slow progressing hemizygous mice, treatment rescued weight loss and improved gait at late time points. Cumulatively the data support the utility of AAV-mediated RNAi against Atxn2 as a robust and translatable treatment strategy for sporadic ALS.}, }
@article {pmid38349516, year = {2024}, author = {Xin, Z and Xin, C and Huo, J and Liu, Q and Dong, H and Li, R and Liu, Y}, title = {Neuroprotective Effect of a Multistrain Probiotic Mixture in SOD1[G93A] Mice by Reducing SOD1 Aggregation and Targeting the Microbiota-Gut-Brain Axis.}, journal = {Molecular neurobiology}, volume = {61}, number = {12}, pages = {10051-10071}, pmid = {38349516}, issn = {1559-1182}, support = {H2021206310//the Natural Science Foundation of Hebei Province/ ; zh2018004//the Key Project of Technical Health Research and Achievement Transformation of Hebei Provincial Department of Health/ ; }, mesh = {Animals ; *Probiotics/pharmacology ; *Gastrointestinal Microbiome/drug effects ; *Superoxide Dismutase-1/metabolism/genetics ; *Mice, Transgenic ; *Neuroprotective Agents/pharmacology ; *Amyotrophic Lateral Sclerosis/pathology ; Brain-Gut Axis/drug effects/physiology ; Mice ; Autophagy/drug effects ; Brain/drug effects/metabolism ; Spinal Cord/drug effects/metabolism/pathology ; Protein Aggregates/drug effects ; Mice, Inbred C57BL ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the selective loss of motor neurons. A bidirectional communication system known as the "microbiota-gut-brain" axis has a regulatory function in neurodegenerative disorders. The impact of probiotics on ALS through the "microbiota-gut-brain" axis remains uncertain. A longitudinal investigation was conducted to examine the alterations in the structure of the ileum and colon in mutant superoxide dismutase 1 (SOD1[G93A]) transgenic mice models of ALS by using immunofluorescence and Western blotting. Subsequently, the mice were administered a multistrain probiotic mixture (LBE) or vehicle orally, starting from 60 days of age until the terminal stage of the disease. The effects of these agents on the behavior, gut microbiota, microbial metabolites, and pathological processes of the spinal and intestine of SOD1[G93A] mice were analyzed, with a focus on exploring potential protective mechanisms. SOD1[G93A] mice exhibit various structural abnormalities in the intestine. Oral administration of LBE improved the proinflammatory response, reduced aberrant superoxide dismutase 1 (SOD1) aggregation, and protected neuronal cells in the intestine and spinal cord of SOD1[G93A] mice. Furthermore, LBE treatment resulted in a change in intestinal microbiota, an increase in short-chain fatty acid levels, and an enhancement in autophagy flux. SOD1[G93A] mice exhibited various structural abnormalities in the intestine. LBE can improve the proinflammatory response, reduce aberrant SOD1 aggregation, and protect neuronal cells in the spinal cord and intestine of SOD1[G93A] mice. The positive effect of LBE can be attributed to increased short-chain fatty acids and enhanced autophagy flux.}, }
@article {pmid38349395, year = {2024}, author = {Soni, S and Lukhey, MS and Thawkar, BS and Chintamaneni, M and Kaur, G and Joshi, H and Ramniwas, S and Tuli, HS}, title = {A current review on P2X7 receptor antagonist patents in the treatment of neuroinflammatory disorders: a patent review on antagonists.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {397}, number = {7}, pages = {4643-4656}, pmid = {38349395}, issn = {1432-1912}, mesh = {*Patents as Topic ; Humans ; *Receptors, Purinergic P2X7/metabolism ; *Purinergic P2X Receptor Antagonists/therapeutic use/pharmacology ; Animals ; *Neuroinflammatory Diseases/drug therapy ; }, abstract = {Chronic inflammation is defined by an activated microglial state linked to all neurological disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (a motor neuron disease that affects the brain and spinal cord). P2X7 receptors (P2X7R) are ATP-activated ion-gated channels present on microglial surfaces. Prolonged ATP release under pathological settings results in sustained P2X7R activation, which leads to inflammasome development and cytokine release. P2X7R and its enabling roles have recently been linked to neurodegenerative diseases, making it a potential research subject. This research provides an overview of current patents for chemicals, biologics, and medicinal applications. The World Intellectual Property Organization (WIPO), European Patent Office (EPO, Espacenet), and the United States Patent and Trademark Office (USPTO) databases were searched for patents using the keywords "P2X7R and Neuroinflammation." During the study period from 2015 to 2021, 103 patents were examined. The countries that protected these innovations were the United States, PCT (Patent Cooperation Treaty states), Europe, Canada, Australia, and India. Janssen Pharmaceutica NV had the most applications, followed by Acetelion Pharmaceuticals LTD., Renovis Inc., Kelly Michael G, Kincaid Jhon, Merck Patent GMBH, H Lundbeck A/S, and many more. The P2X7R is a possible diagnostic and therapeutic target for cancer, pain disorders, and inflammation. For P2X7 R, several compounds have been discovered and are presently the subject of clinical trial investigations. This study featured patents for P2X7R antagonists, which help treat conditions including neuroinflammation.}, }
@article {pmid38347638, year = {2024}, author = {Li, W and Li, HL and Wang, JZ and Liu, R and Wang, X}, title = {Abnormal protein post-translational modifications induces aggregation and abnormal deposition of protein, mediating neurodegenerative diseases.}, journal = {Cell &amp; bioscience}, volume = {14}, number = {1}, pages = {22}, pmid = {38347638}, issn = {2045-3701}, support = {92049107//National Natural Science Foundation of China/ ; 82071440//National Natural Science Foundation of China/ ; 31929002//National Natural Science Foundation of China/ ; }, abstract = {Protein post-translational modifications (PPTMs) refer to a series of chemical modifications that occur after the synthesis of protein. Proteins undergo different modifications such as phosphorylation, acetylation, ubiquitination, and so on. These modifications can alter the protein's structure, function, and interaction, thereby regulating its biological activity. In neurodegenerative diseases, several proteins undergo abnormal post-translational modifications, which leads to aggregation and abnormal deposition of protein, thus resulting in neuronal death and related diseases. For example, the main pathological features of Alzheimer's disease are the aggregation of beta-amyloid protein and abnormal phosphorylation of tau protein. The abnormal ubiquitination and loss of α-synuclein are related to the onset of Parkinson's disease. Other neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis, and so on are also connected with abnormal PPTMs. Therefore, studying the abnormal PPTMs in neurodegenerative diseases is critical for understanding the mechanism of these diseases and the development of significant therapeutic strategies. This work reviews the implications of PPTMs in neurodegenerative diseases and discusses the relevant therapeutic strategies.}, }
@article {pmid38347315, year = {2024}, author = {Huang, SL and Shen, YL and Peng, WY and Ye, K and Zheng, H}, title = {Edaravone for patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Acta neurologica Belgica}, volume = {124}, number = {3}, pages = {895-904}, pmid = {38347315}, issn = {2240-2993}, support = {no. 2021JDTD0007//Sichuan Province Science and Technology Support Program/ ; }, mesh = {*Edaravone/therapeutic use ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Free Radical Scavengers/therapeutic use ; Randomized Controlled Trials as Topic/methods ; Treatment Outcome ; }, abstract = {BACKGROUND AND OBJECTIVE: The effectiveness and long-term efficacy of edaravone, a recommended treatment for amyotrophic lateral sclerosis (ALS), has not been examined in real-world settings. This study aims to evaluate the effectiveness and long-term efficacy of edaravone.<br><br>METHODS: The OVID Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases were searched for articles published between January 1, 2000, and May 1, 2023. Two investigators independently screened the retrieved articles for randomized controlled trials (RCTs), cohort studies, or single-arm trials that evaluated the effect of edaravone on amyotrophic lateral sclerosis (ALS). The risk of bias was evaluated using the revised Cochrane Risk-of-Bias (RoB 2.0) tool for randomized controlled trials (RCTs) and the Risk-of-Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies. The primary outcome was the ALSFRS-R score assessed at month 6, with secondary outcomes including the ALSFRS-R scores evaluated at months 9, 12, and 18, forced vital capacity (FVC), and adverse events. The certainty of evidence was assessed using the GRADE approach.<br><br>RESULTS: The analysis included 16 studies with a total of 4828 participants. Among these, four were randomized controlled trials (RCTs) and 12 were observational studies. Of the RCTs, four were rated as having a low risk of bias, while six of the observational studies were rated as having a low risk of bias. Edaravone was associated with slightly slower progression in the reduction of ALSFRS-R score at month 6 compared to placebo (mean difference 1.01, 95%CI -0.87 to 3.09, p&#x2009;=&#x2009;0.293), as shown by evidence from RCTs. However, observational studies did not show any benefit of adding edaravone to routine practice (mean difference 1.85, 95%CI -2.05 to 5.75, p&#x2009;=&#x2009;0.352). The change from baseline in ALSFRS-R score was -2.1, -4.04, -7.5, -6.82, and -7.9 at months 3, 6, 9, 12, and 18, respectively. The GRADE assessment indicated moderate certainty for evidence from RCTs, while evidence from observational studies had very low certainty.<br><br>CONCLUSION: Due to the limited number of studies and confounding issues in observational studies, further examination of the added benefits of edaravone to routine practice is necessary through RCTs, particularly regarding its long-term efficacy.}, }
@article {pmid38339026, year = {2024}, author = {Potenza, RL and Armida, M and Popoli, P}, title = {Can Some Anticancer Drugs Be Repurposed to Treat Amyotrophic Lateral Sclerosis? A Brief Narrative Review.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38339026}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Motor Neuron Disease ; *Antineoplastic Agents/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare progressive motor neuron disease that, due to its high complexity, still lacks effective treatments. Development of a new drug is a highly costly and time-consuming process, and the repositioning of approved drugs can represent an efficient strategy to provide therapeutic opportunities. This is particularly true for rare diseases, which are characterised by small patient populations and therefore attract little commercial interest. Based on the overlap between the biological background of cancer and neurodegeneration, the repurposing of antineoplastic drugs for ALS has been suggested. The objective of this narrative review was to summarise the current experimental evidence on the use of approved anticancer drugs in ALS. Specifically, anticancer drugs belonging to different classes were found to act on mechanisms involved in the ALS pathogenesis, and some of them proved to exert beneficial effects in ALS models. However, additional studies are necessary to confirm the real therapeutic potential of anticancer drugs for repositioning in ALS treatment.}, }
@article {pmid38338912, year = {2024}, author = {Duranti, E and Cordani, N and Villa, C}, title = {Edaravone: A Novel Possible Drug for Cancer Treatment?.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38338912}, issn = {1422-0067}, mesh = {Humans ; Edaravone/therapeutic use ; *Neuroprotective Agents/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy ; Antioxidants/therapeutic use ; *Neoplasms/drug therapy/chemically induced ; Free Radical Scavengers/pharmacology ; }, abstract = {Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances in cancer therapy, there has been a growing interest in drug repurposing, which involves exploring new uses for medications that are already approved for clinical use. One such medication is edaravone, which is currently used to manage patients with cerebral infarction and amyotrophic lateral sclerosis. Due to its antioxidant and anti-inflammatory properties, edaravone has also been investigated for its potential activities in treating cancer, notably as an anti-proliferative and cytoprotective drug against side effects induced by traditional cancer therapies. This comprehensive review aims to provide updates on the various applications of edaravone in cancer therapy. It explores its potential as a standalone antitumor drug, either used alone or in combination with other medications, as well as its role as an adjuvant to mitigate the side effects of conventional anticancer treatments.}, }
@article {pmid38337058, year = {2024}, author = {Choi, BJ and Park, MH and Jin, HK and Bae, JS}, title = {Acid sphingomyelinase as a pathological and therapeutic target in neurological disorders: focus on Alzheimer's disease.}, journal = {Experimental &amp; molecular medicine}, volume = {56}, number = {2}, pages = {301-310}, pmid = {38337058}, issn = {2092-6413}, mesh = {Animals ; Humans ; Mice ; *Alzheimer Disease/drug therapy ; Brain ; *Multiple Sclerosis ; *Nervous System Diseases ; Sphingomyelin Phosphodiesterase/genetics ; }, abstract = {Over the past decade, numerous studies have highlighted the importance of acid sphingomyelinase (ASM) in disease treatment in humans. This enzyme functions primarily to generate ceramide, maintain the cellular membrane, and regulate cellular function. However, in the blood and brain of patients with neurological disorders, including major depression, ischemic stroke, amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer's disease (AD), elevated ASM levels significantly suggest disease onset or progression. In these diseases, increased ASM is profoundly involved in neuronal death, abnormal autophagy, neuroinflammation, blood-brain barrier disruption, hippocampal neurogenesis loss, and immune cell dysfunction. Moreover, genetic and pharmacological inhibition of ASM can prevent or ameliorate various diseases. The therapeutic effects of ASM inhibition have prompted the urgent need to develop ASM inhibitors, and several ASM inhibitors have been identified. In this review, we summarize the current knowledge on the critical roles and mechanisms of ASM in brain cells and blood that are associated with different neuropathological features, especially those observed in AD. Furthermore, we elucidate the potential possibility and limitations of existing ASM-targeting drugs according to experimental studies in neurological disorder mouse models.}, }
@article {pmid38336286, year = {2024}, author = {Lomeli, N and Pearre, DC and Cruz, M and Di, K and Ricks-Oddie, JL and Bota, DA}, title = {Cisplatin induces BDNF downregulation in middle-aged female rat model while BDNF enhancement attenuates cisplatin neurotoxicity.}, journal = {Experimental neurology}, volume = {375}, number = {}, pages = {114717}, pmid = {38336286}, issn = {1090-2430}, support = {TL1 TR001415/TR/NCATS NIH HHS/United States ; T32 NS082174/NS/NINDS NIH HHS/United States ; R01 CA263806/CA/NCI NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; T32 CA060396/CA/NCI NIH HHS/United States ; P30 CA062203/CA/NCI NIH HHS/United States ; K08 NS072234/NS/NINDS NIH HHS/United States ; }, mesh = {Rats ; Animals ; Female ; *Cisplatin/toxicity ; *Brain-Derived Neurotrophic Factor/metabolism ; Rats, Sprague-Dawley ; Down-Regulation ; Quality of Life ; Riluzole/pharmacology ; Hippocampus/metabolism ; Disks Large Homolog 4 Protein ; }, abstract = {Cancer-related cognitive impairments (CRCI) are neurological complications associated with cancer treatment, and greatly affect cancer survivors' quality of life. Brain-derived neurotrophic factor (BDNF) plays an essential role in neurogenesis, learning and memory. The reduction of BDNF is associated with the decrease in cognitive function in various neurological disorders. Few pre-clinical studies have reported on the effects of chemotherapy and medical stress on BDNF levels and cognition. The present study aimed to compare the effects of medical stress and cisplatin on serum BDNF levels and cognitive function in 9-month-old female Sprague Dawley rats to age-matched controls. Serum BDNF levels were collected longitudinally during cisplatin treatment, and cognitive function was assessed by novel object recognition (NOR) 14 weeks post-cisplatin initiation. Terminal BDNF levels were collected 24 weeks after cisplatin initiation. In cultured hippocampal neurons, we screened three neuroprotective agents, riluzole (an approved treatment for amyotrophic lateral sclerosis), as well as the ampakines CX546 and CX1739. We assessed dendritic arborization by Sholl analysis and dendritic spine density by quantifying postsynaptic density-95 (PSD-95) puncta. Cisplatin and exposure to medical stress reduced serum BDNF levels and impaired object discrimination in NOR compared to age-matched controls. Pharmacological BDNF augmentation protected neurons against cisplatin-induced reductions in dendritic branching and PSD-95. Ampakines (CX546 and CX1739) and riluzole did not affect the antitumor efficacy of cisplatin in vitro. In conclusion, we established the first middle-aged rat model of cisplatin-induced CRCI, assessing the contribution of medical stress and longitudinal changes in BDNF levels on cognitive function, although future studies are warranted to assess the efficacy of BDNF enhancement in vivo on synaptic plasticity. Collectively, our results indicate that cancer treatment exerts long-lasting changes in BDNF levels, and support BDNF enhancement as a potential preventative approach to target CRCI with therapeutics that are FDA approved and/or in clinical study for other indications.}, }
@article {pmid38334818, year = {2024}, author = {Hoek, AG and Dal Canto, E and Wenker, E and Bindraban, N and Handoko, ML and Elders, PJM and Beulens, JWJ}, title = {Epidemiology of heart failure in diabetes: a disease in disguise.}, journal = {Diabetologia}, volume = {67}, number = {4}, pages = {574-601}, pmid = {38334818}, issn = {1432-0428}, support = {91718304/ZONMW_/ZonMw/Netherlands ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/epidemiology/complications ; *Heart Failure/epidemiology/physiopathology ; Incidence ; Prevalence ; Stroke Volume/physiology ; Ventricular Dysfunction, Left/epidemiology/physiopathology ; Echocardiography ; }, abstract = {Left ventricular diastolic dysfunction (LVDD) without symptoms, and heart failure (HF) with preserved ejection fraction (HFpEF) represent the most common phenotypes of HF in individuals with type 2 diabetes mellitus, and are more common than HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF) and left ventricular systolic dysfunction (LVSD) in these individuals. However, diagnostic criteria for HF have changed over the years, resulting in heterogeneity in the prevalence/incidence rates reported in different studies. We aimed to give an overview of the diagnosis and epidemiology of HF in type 2 diabetes, using both a narrative and systematic review approach; we focus narratively on diagnosing (using the 2021 European Society of Cardiology [ESC] guidelines) and screening for HF in type 2 diabetes. We performed an updated (2016-October 2022) systematic review and meta-analysis of studies reporting the prevalence and incidence of HF subtypes in adults ≥18 years with type 2 diabetes, using echocardiographic data. Embase and MEDLINE databases were searched and data were assessed using random-effects meta-analyses, with findings presented as forest plots. From the 5015 studies found, 209 were screened using the full-text article. In total, 57 studies were included, together with 29 studies that were identified in a prior meta-analysis; these studies reported on the prevalence of LVSD (n=25 studies, 24,460 individuals), LVDD (n=65 studies, 25,729 individuals), HFrEF (n=4 studies, 4090 individuals), HFmrEF (n=2 studies, 2442 individuals) and/or HFpEF (n=8 studies, 5292 individuals), and on HF incidence (n=7 studies, 17,935 individuals). Using Hoy et al's risk-of-bias tool, we found that the studies included generally had a high risk of bias. They showed a prevalence of 43% (95% CI 37%, 50%) for LVDD, 17% (95% CI 7%, 35%) for HFpEF, 6% (95% CI 3%, 10%) for LVSD, 7% (95% CI 3%, 15%) for HFrEF, and 12% (95% CI 7%, 22%) for HFmrEF. For LVDD, grade I was found to be most prevalent. Additionally, we reported a higher incidence rate of HFpEF (7% [95% CI 4%, 11%]) than HFrEF 4% [95% CI 3%, 7%]). The evidence is limited by the heterogeneity of the diagnostic criteria over the years. The systematic section of this review provides new insights on the prevalence/incidence of HF in type 2 diabetes, unveiling a large pre-clinical target group with LVDD/HFpEF in which disease progression could be halted by early recognition and treatment.Registration PROSPERO ID CRD42022368035.}, }
@article {pmid38334639, year = {2024}, author = {Cunha-Oliveira, T and Montezinho, L and Simões, RF and Carvalho, M and Ferreiro, E and Silva, FSG}, title = {Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {3}, pages = {}, pmid = {38334639}, issn = {2073-4409}, support = {PTDC/MED-FAR/29391/2017//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; POCI-01-0145-FEDER-029391//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; PTDC/BTM-SAL/29297/2017//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; POCI-01-0145-FEDER-029297//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; PTDC/BTM-ORG/0055/2021//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; DL57/2016/CP1448/CT0016//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; CEECIND/00322/2017//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; 2022.00011.CEECIND//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; UIDP/04539/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; UIDB/04539/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; UIDB/00081/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; Motor Neurons/pathology ; Apoptosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, for which current treatment options are limited. Recent studies have shed light on the role of mitochondria in ALS pathogenesis, making them an attractive therapeutic intervention target. This review contains a very comprehensive critical description of the involvement of mitochondria and mitochondria-mediated mechanisms in ALS. The review covers several key areas related to mitochondria in ALS, including impaired mitochondrial function, mitochondrial bioenergetics, reactive oxygen species, metabolic processes and energy metabolism, mitochondrial dynamics, turnover, autophagy and mitophagy, impaired mitochondrial transport, and apoptosis. This review also highlights preclinical and clinical studies that have investigated various mitochondria-targeted therapies for ALS treatment. These include strategies to improve mitochondrial function, such as the use of dichloroacetate, ketogenic and high-fat diets, acetyl-carnitine, and mitochondria-targeted antioxidants. Additionally, antiapoptotic agents, like the mPTP-targeting agents minocycline and rasagiline, are discussed. The paper aims to contribute to the identification of effective mitochondria-targeted therapies for ALS treatment by synthesizing the current understanding of the role of mitochondria in ALS pathogenesis and reviewing potential convergent therapeutic interventions. The complex interplay between mitochondria and the pathogenic mechanisms of ALS holds promise for the development of novel treatment strategies to combat this devastating disease.}, }
@article {pmid38332489, year = {2024}, author = {Dandl, S and Bender, A and Hothorn, T}, title = {Heterogeneous treatment effect estimation for observational data using model-based forests.}, journal = {Statistical methods in medical research}, volume = {33}, number = {3}, pages = {392-413}, pmid = {38332489}, issn = {1477-0334}, mesh = {Humans ; *Treatment Effect Heterogeneity ; Riluzole ; *Amyotrophic Lateral Sclerosis ; Linear Models ; }, abstract = {The estimation of heterogeneous treatment effects has attracted considerable interest in many disciplines, most prominently in medicine and economics. Contemporary research has so far primarily focused on continuous and binary responses where heterogeneous treatment effects are traditionally estimated by a linear model, which allows the estimation of constant or heterogeneous effects even under certain model misspecifications. More complex models for survival, count, or ordinal outcomes require stricter assumptions to reliably estimate the treatment effect. Most importantly, the noncollapsibility issue necessitates the joint estimation of treatment and prognostic effects. Model-based forests allow simultaneous estimation of covariate-dependent treatment and prognostic effects, but only for randomized trials. In this paper, we propose modifications to model-based forests to address the confounding issue in observational data. In particular, we evaluate an orthogonalization strategy originally proposed by Robinson (1988, Econometrica) in the context of model-based forests targeting heterogeneous treatment effect estimation in generalized linear models and transformation models. We found that this strategy reduces confounding effects in a simulated study with various outcome distributions. We demonstrate the practical aspects of heterogeneous treatment effect estimation for survival and ordinal outcomes by an assessment of the potentially heterogeneous effect of Riluzole on the progress of Amyotrophic Lateral Sclerosis.}, }
@article {pmid38330934, year = {2024}, author = {Yang, L and Li, Y and Zhang, S and Qian, H and Xu, W and Yu, J}, title = {Efficacy of Acupuncture Combined with Traditional Chinese Medicine Fumigation Therapy in Sequelae of Pelvic Inflammatory Disease: A Systematic Review and Meta-Analysis.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {175-186}, doi = {10.1159/000536101}, pmid = {38330934}, issn = {2504-2106}, abstract = {BACKGROUND AND OBJECTIVE: Acupuncture combined with traditional Chinese medicine fumigation is increasingly being used in treating sequelae of pelvic inflammatory disease (SPID). However, there is a lack of meta-analysis on the effectiveness of acupuncture combined with traditional Chinese medicine fumigation in treating SPID. The aim of this study was to assess the feasibility of combining acupuncture with traditional Chinese medicine fumigation in the treatment of SPID.<br><br>METHODS: We searched eight databases for studies on acupuncture combined with traditional Chinese medicine fumigation for the treatment of SPID from the date of establishment to October 29, 2022. We assessed the quality of included studies by using the Cochrane bias risk tool. Pooled results were expressed as risk ratios (RRs), with a 95% confidence interval (CI). In addition, we identified sources of heterogeneity by sensitivity analysis, assessed publication bias by Egger's test, and assessed the quality of the evidence by Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). All statistical analyses were performed by Review Manager 5.3 and Stata 14.<br><br>RESULTS: Finally, seven studies with a total of 663 participants were included. We found a significant difference in the total effective rate in the acupuncture combined with the fumigation group compared with the acupuncture group in the treatment of SPID (RR = 1.17, 95% CI [1.09, 1.25], p = 0.0001 < 0.05; I2 = 0%; 6 trials), and a significant difference in the total effective rate in the acupuncture combined with fumigation group compared with the fumigation group in the treatment of SPID (RR = 1.42, 95% CI [1.21, 1.66], p = 0.0001 < 0.05; 5 trials).<br><br>CONCLUSION: The clinical efficacy of acupuncture combined with herbal fumigation in the treatment of SPID is relatively good. Larger scale studies are needed in the future.<br><br>UNLABELLED: <title>Hintergrund und Ziel</title>Akupunktur in Kombination mit Fumigation, einem Verfahren der Traditionellen Chinesischen Medizin, wird zunehmend in der Behandlung von Folgeerscheinungen von Beckenentz&#xfc;ndungen (SPID; <italic>sequelae of pelvic inflammatory disease</italic>) eingesetzt. Es mangelt jedoch an Metaanalysen zur Wirksamkeit der Akupunktur in Kombination mit Fumigation gem&#xe4;&#xdf; der Traditionellen Chinesischen Medizin in der Behandlung von SPID. Das Ziel dieser Studie ist die Beurteilung der Machbarkeit der Kombination aus Akupunktur und Fumigation gem&#xe4;&#xdf; der Traditionellen Chinesischen Medizin in der Behandlung von SPID.<title>Methoden</title>Wir durchsuchten acht Datenbanken nach Studien zur Akupunktur in Kombination mit Fumigation gem&#xe4;&#xdf; der Traditionellen Chinesischen Medizin in der Behandlung von Folgeerscheinungen von SPID von der Einrichtung bis zum 29. Oktober 2022. Wir beurteilten die Qualit&#xe4;t der eingeschlossenen Studien mit dem Cochrane-Tool zur Bewertung des Bias-Risikos. Die gepoolten Ergebnisse wurden als Risikoquotient (RR; <italic>risk ratio</italic>) mit 95%-Konfidenzintervall (KI) ausgedr&#xfc;ckt. Zus&#xe4;tzlich identifizierten wir Quellen f&#xfc;r Heterogenit&#xe4;t mittels Sensitivit&#xe4;tsanalyse, beurteilten den Publikations-Bias mittels Egger-Test und bewerteten die Qualit&#xe4;t der Evidenz nach Grad der Empfehlungsst&#xe4;rke, Beurteilung, Entwicklung und Evaluierung (GRADE). Alle statistischen Analysen erfolgten mit Review Manager 5.3 und Stata 14.<title>Ergebnisse</title>Im Endeffekt wurden 7 Studien mit insgesamt 663 Teilnehmern eingeschlossen. Wir fanden einen signifikanten Unterschied in der Gesamt-Effektivit&#xe4;tsrate bei der Gruppe, die zur Behandlung von SPID Akupunktur in Kombination mit Fumigation erhielt, im Vergleich zur reinen Akupunkturgruppe (RR = 1,17; 95%-KI [1,09; 1,25]; <italic>p</italic> = 0,0001 < 0,05; <italic>I</italic>2-Wert = 0%; 6 Studien), und einen signifikanten Unterschied in der Gesamt-Effektivit&#xe4;tsrate bei der Gruppe, die zur Behandlung von SPID Akupunktur in Kombination mit Fumigation erhielt, im Vergleich zur reinen Fumigationsgruppe (RR = 1,42; 95%-KI [1,21; 1,66]; <italic>p</italic> = 0,0001 < 0,05; 5 Studien).<title>Schlussfolgerung</title>Die klinische Wirksamkeit der Akupunktur in Kombination mit Kr&#xe4;uter-Fumigation zur Behandlung von SPID ist relativ gut. Zuk&#xfc;nftig sind gr&#xf6;&#xdf;ere Studien erforderlich.}, }
@article {pmid38330924, year = {2024}, author = {Leedasawat, P and Sangvatanakul, P and Tungsukruthai, P and Kamalashiran, C and Phetkate, P and Patarajierapun, P and Sriyakul, K}, title = {The Efficacy and Safety of Chinese Eye Exercise of Acupoints in Dry Eye Patients: A Randomized Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {149-159}, doi = {10.1159/000536516}, pmid = {38330924}, issn = {2504-2106}, abstract = {INTRODUCTION: Dry eye disorder (DED) is a growing global issue linked to excessive digital screen time. Chinese eye exercise of acupoint (CEA), a set of self-massages on shared Chinese acupuncture (CA), has been used to reduce visual-related ocular symptoms and possibly as an alternative treatment for DED. This study aimed to assess the efficacy and safety of CEA.<br><br>METHODS: A single-blind randomized controlled trial was conducted at Thammasat University Hospital in Thailand, recruiting 56 participants aged 20-60 years, equally divided into two groups: the treatment group with CEA and the control group with standard lid hygiene treatment (STD). The intervention program lasted 12 weeks.<br><br>MAIN OUTCOME MEASURES: Ocular Surface Disease Index (OSDI), tear break-up time (TBUT), Schirmer-I test (SIT), corneal surface staining (CSS), and self-recorded forms for safety and adverse effects were measured at baseline, week 4, and week 12. An independent sample t test, paired t test, and repeated measures (ANOVA) were used to compare results between both groups, study visits, and primary and secondary outcome measurements, respectively. The p values <0.05 were considered statistically significant.<br><br>RESULTS: The characteristics were not statistically different between both groups at the baseline. The mean OSDI scores were significantly reduced in both groups at week 4 and week 12 compared to baseline (p value <0.05). Additionally, both CEA and STD showed significant improvement in TBUT and SIT (p value <0.05). CSS was significantly improved only in the CEA groups (p value <0.05). No significant differences were observed between the study groups, except for SIT at week 12 (p value <0.05). For the safety, there were no adverse side effects in either group.<br><br>CONCLUSION: CEA seemed to be as effective as STD in improving the OSDI, TBUT, and SIT of DED without causing any side effects.<br><br>UNLABELLED: <title>Einleitung</title>Das Trockene Auge (Dry eye disorder, DED) ist weltweit ein zunehmendes Problem, das mit &#xfc;berm&#xe4;ssiger Bildschirmarbeit zusammenh&#xe4;ngt. Die chinesische Augen&#xfc;bung der Akupunkturpunkte (Chinese eye exercise of acupoint, CEA), eine Reihe von Selbstmassagen an gemeinsamen CA-Akupunkturpunkten, wird zur Linderung visusbezogener Augensymptome und als m&#xf6;gliche alternative Behandlung f&#xfc;r DED eingesetzt. Mit dieser Studie sollte die Wirksamkeit und Sicherheit von CEA bewertet werden.<title>Methoden</title>Am Thammasat-Universit&#xe4;tsklinikum in Thailand wurde eine einfach verblindete, randomisierte, kontrollierte Studie mit 56 Teilnehmern im Alter von 20 bis 60 Jahren durchgef&#xfc;hrt, die zu gleichen Teilen zwei Gruppen zugewiesen wurden: die Behandlungsgruppe mit CEA und die Kontrollgruppe, die die Standard-Lidhygienebehandlung erhielt (STD). Das Interventionsprogramm dauerte 12 Wochen. Die Haupt-Zielkriterien, der Ocular Surface Disease Index (OSDI), die Tr&#xe4;nenfilmaufreisszeit (tear break-up time, TBUT), der Schirmer-I-Test (SIT), das Corneal Surface Staining (CSS) und Selbstauskunftsformulare zur Sicherheit und zu unerw&#xfc;nschten Wirkungen wurden zu Beginn der Behandlung, in Woche 4 und in Woche 12 ermittelt. F&#xfc;r den Vergleich der Ergebnisse zwischen den beiden Gruppen, den Studienvisiten bzw. den prim&#xe4;ren und sekund&#xe4;ren Zielkriterien wurden ein <italic>t</italic> Test f&#xfc;r unabh&#xe4;ngige Stichproben, ein <italic>t</italic> Test f&#xfc;r paarige Stichproben und eine ANOVA mit Messwiederholungen verwendet. <italic>p</italic>-Werte <0,05 galten als statistisch signifikant.<title>Ergebnisse</title>Hinsichtlich der Merkmale bestand zwischen den beiden Gruppen kein statistischer Unterschied bei Studienbeginn. In beiden Gruppen fielen die mittleren OSDI-Scores in Woche 4 und Woche 12 im Vergleich zum Ausgangswert signifikant geringer aus (<italic>p</italic>-Wert <0,05). Dar&#xfc;ber hinaus zeigten sowohl die CEA- als auch die STD-Gruppe eine signifikante Verbesserung der TBUT- und SIT-Werte (<italic>p</italic>-Wert <0,05). Das CSS verbesserte sich nur in der CEA-Gruppe signifikant (<italic>p</italic>-Wert <0,05). Zwischen den Studiengruppen waren keine signifikanten Unterschiede zu beobachten, ausser beim SIT in Woche 12 (<italic>p</italic>-Wert <0,05). Was die Sicherheit betrifft, so traten in beiden Gruppen keine unerw&#xfc;nschten Nebenwirkungen auf.<title>Schlussfolgerung</title>Die CEA schien die OSDI-, TBUT- und SIT-Werte bei DED ebenso wirksam zu verbessern wie die Standardbehandlung, ohne Nebenwirkungen zu verursachen.}, }
@article {pmid38330475, year = {2024}, author = {Stavros, K}, title = {Genetic Myelopathies.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {30}, number = {1}, pages = {119-132}, pmid = {38330475}, issn = {1538-6899}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Muscular Atrophy, Spinal/diagnosis ; *Spastic Paraplegia, Hereditary/diagnosis ; *Spinal Cord Diseases/diagnosis/genetics/therapy ; }, abstract = {OBJECTIVE: This article provides an overview of genetic myelopathies, a diverse group of inherited, degenerative conditions that may be broadly categorized as motor neuron disorders, disorders of spinocerebellar degeneration, leukodystrophies, and hereditary spastic paraplegia. Clinical examples from each category are provided to illustrate the spectrum of genetic myelopathies and their distinguishing features that aid in differentiating genetic myelopathies from potentially treatable acquired causes of myelopathy.<br><br>LATEST DEVELOPMENTS: Advances in genetic testing have vastly enhanced current knowledge of genetic myelopathies and the ability to diagnose and provide appropriate counseling to patients and their families. However, potential health care disparities in access to genetic testing is a topic that must be further explored. Although treatment for most of these conditions is typically supportive, there have been recent therapeutic breakthroughs in treatments for amyotrophic lateral sclerosis, spinal muscular atrophy, and Friedreich ataxia.<br><br>ESSENTIAL POINTS: Genetic myelopathies may present with chronic and progressive symptoms, a family history of similar symptoms, and involvement of other structures outside of the spinal cord. Imaging often shows spinal cord atrophy, but cord signal change is rare. Exclusion of reversible causes of myelopathy is a key step in the diagnosis. There are many different causes of genetic myelopathies, and in some cases, symptoms may overlap, which underscores the utility of genetic testing in confirming the precise underlying neurologic condition.}, }
@article {pmid38325473, year = {2024}, author = {Xu, Y and Nie, J and Lu, C and Hu, C and Chen, Y and Ma, Y and Huang, Y and Lu, L}, title = {Effects and mechanisms of bisphenols exposure on neurodegenerative diseases risk: A systemic review.}, journal = {The Science of the total environment}, volume = {919}, number = {}, pages = {170670}, doi = {10.1016/j.scitotenv.2024.170670}, pmid = {38325473}, issn = {1879-1026}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/chemically induced ; *Alzheimer Disease ; *Parkinson Disease/etiology/metabolism ; Brain/metabolism ; Oxidative Stress/physiology ; }, abstract = {Environmental bisphenols (BPs) pose a global threat to human health because of their extensive use as additives in plastic products. BP residues are increasing in various environmental media (i.e., water, soil, and indoor dust) and biological and human samples (i.e., serum and brain). Both epidemiological and animal studies have determined an association between exposure to BPs and an increased risk of neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis), including cognitive abnormalities and behavioral disturbances. Hence, understanding the biological responses to different BPs is essential for prevention, and treatment. This study provides an overview of the underlying pathogenic molecular mechanisms as a valuable basis for understanding neurodegenerative disease responses to BPs, including accumulation of misfolded proteins, reduction of tyrosine hydroxylase and dopamine, abnormal hormone signaling, neuronal death, oxidative stress, calcium homeostasis, and inflammation. These findings provide new insights into the neurotoxic potential of BPs and ultimately contribute to a comprehensive health risk evaluation.}, }
@article {pmid38325382, year = {2024}, author = {Yan, J and Wang, YM and Hellwig, A and Bading, H}, title = {TwinF interface inhibitor FP802 stops loss of motor neurons and mitigates disease progression in a mouse model of ALS.}, journal = {Cell reports. Medicine}, volume = {5}, number = {2}, pages = {101413}, pmid = {38325382}, issn = {2666-3791}, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology ; Superoxide Dismutase/metabolism/pharmacology/therapeutic use ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Disease Models, Animal ; Disease Progression ; *TRPM Cation Channels ; }, abstract = {Toxic signaling by extrasynaptic NMDA receptors (eNMDARs) is considered an important promoter of amyotrophic lateral sclerosis (ALS) disease progression. To exploit this therapeutically, we take advantage of TwinF interface (TI) inhibition, a pharmacological principle that, contrary to classical NMDAR pharmacology, allows selective elimination of eNMDAR-mediated toxicity via disruption of the NMDAR/TRPM4 death signaling complex while sparing the vital physiological functions of synaptic NMDARs. Post-disease onset treatment of the SOD1[G93A] ALS mouse model with FP802, a modified TI inhibitor with a safe pharmacology profile, stops the progressive loss of motor neurons in the spinal cord, resulting in a reduction in the serum biomarker neurofilament light chain, improved motor performance, and an extension of life expectancy. FP802 also effectively blocks NMDA-induced death of neurons in ALS patient-derived forebrain organoids. These results establish eNMDAR toxicity as a key player in ALS pathogenesis. TI inhibitors may provide an effective treatment option for ALS patients.}, }
@article {pmid38318860, year = {2024}, author = {Jhooty, S and Barkhaus, P and Brown, A and Mascias Cadavid, J and Carter, GT and Crayle, J and Heiman-Patterson, T and Li, X and Mallon, E and Mcdermott, C and Mushannen, T and Pattee, G and Ratner, D and Wicks, P and Wiedau, M and Bedlack, R}, title = {ALSUntangled #74: Withania Somnifera (Ashwagandha).}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {805-808}, doi = {10.1080/21678421.2024.2311721}, pmid = {38318860}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Withania ; Animals ; *Plant Extracts/therapeutic use ; Phytotherapy/methods ; }, abstract = {ALSUntangled reviews alternative and off-label treatments on behalf of people with ALS (PALS) who ask about them. Here, we review withania somnifera (WS) commonly known as ashwagandha or winter cherry. WS has plausible mechanisms for slowing ALS progression because of its effects on inflammation, oxidative stress, autophagy, mitochondrial function, and apoptosis. Preclinical trials demonstrate that WS slows disease progression in multiple different animal models of ALS. Of the five individuals we found who described using WS for their ALS, two individuals reported moderate benefit while none reported experiencing any significant side effects. There is currently one clinical trial using WS to treat PALS; the results are not yet published. There are no serious side effects associated with WS and the associated cost of this treatment is low. Based on the above information, WS appears to us to be a good candidate for future ALS trials.}, }
@article {pmid38318827, year = {2024}, author = {Motamedy, S and Soltani, B and Kameshki, H and Kermani, AA and Amleshi, RS and Nazeri, M and Shabani, M}, title = {The Therapeutic Potential and Molecular Mechanisms Underlying the Neuroprotective Effects of Sativex[®] - A Cannabis-derived Spray.}, journal = {Mini reviews in medicinal chemistry}, volume = {24}, number = {15}, pages = {1427-1448}, pmid = {38318827}, issn = {1875-5607}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/chemistry ; *Cannabidiol/pharmacology/therapeutic use/chemistry ; *Plant Extracts/chemistry/pharmacology ; *Dronabinol/pharmacology/chemistry/therapeutic use ; Animals ; Multiple Sclerosis/drug therapy ; Cannabis/chemistry ; Drug Combinations ; }, abstract = {Sativex is a cannabis-based medicine that comes in the form of an oromucosal spray. It contains equal amounts of Δ9-tetrahydrocannabinol and cannabidiol, two compounds derived from cannabis plants. Sativex has been shown to have positive effects on symptoms of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and sleep disorders. It also has analgesic, antiinflammatory, antitumoral, and neuroprotective properties, which make it a potential treatment option for other neurological disorders. The article reviews the results of recent preclinical and clinical studies that support the therapeutic potential of Sativex and the molecular mechanisms behind its neuroprotective benefits in various neurological disorders. The article also discusses the possible advantages and disadvantages of using Sativex as a neurotherapeutic agent, such as its safety, efficacy, availability, and legal status.}, }
@article {pmid38317225, year = {2024}, author = {Liddell, JR and Hilton, JBW and Kysenius, K and Billings, JL and Nikseresht, S and McInnes, LE and Hare, DJ and Paul, B and Mercer, SW and Belaidi, AA and Ayton, S and Roberts, BR and Beckman, JS and McLean, CA and White, AR and Donnelly, PS and Bush, AI and Crouch, PJ}, title = {Microglial ferroptotic stress causes non-cell autonomous neuronal death.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {14}, pmid = {38317225}, issn = {1750-1326}, mesh = {Mice ; Animals ; Humans ; Microglia/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/metabolism ; *Neurodegenerative Diseases/metabolism ; Cell Death ; Disease Models, Animal ; }, abstract = {BACKGROUND: Ferroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved.<br><br>METHODS: To elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). We utilised the SOD1[G37R] mouse model of ALS and a CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo.<br><br>RESULTS: We found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from human cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Further, we show the molecular correlation between ferroptosis and neurotoxic astrocytes evident in human ALS-affected spinal cord is recapitulated in the SOD1[G37R] mouse model where treatment with a CNS-permeant ferroptosis inhibitor, Cu[II](atsm), ameliorated these markers and was neuroprotective.<br><br>CONCLUSIONS: By showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease.}, }
@article {pmid38314348, year = {2023}, author = {Watts, ME and Giadone, RM and Ordureau, A and Holton, KM and Harper, JW and Rubin, LL}, title = {Analyzing the ER stress response in ALS patient derived motor neurons identifies druggable neuroprotective targets.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1327361}, pmid = {38314348}, issn = {1662-5102}, support = {F32 AG079593/AG/NIA NIH HHS/United States ; R01 NS083524/NS/NINDS NIH HHS/United States ; R01 NS110395/NS/NINDS NIH HHS/United States ; R37 NS083524/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron (MN) disease with severely limited treatment options. Identification of effective treatments has been limited in part by the lack of predictive animal models for complex human disorders. Here, we utilized pharmacologic ER stressors to exacerbate underlying sensitivities conferred by ALS patient genetics in induced pluripotent stem cell (iPSC)-derived motor neurons (MNs). In doing so, we found that thapsigargin and tunicamycin exposure recapitulated ALS-associated degeneration, and that we could rescue this degeneration via MAP4K4 inhibition (MAP4K4i). We subsequently identified mechanisms underlying MAP4K4i-mediated protection by performing phosphoproteomics on iPSC-derived MNs treated with ER stressors ±MAP4K4i. Through these analyses, we found JNK, PKC, and BRAF to be differentially modulated in MAP4K4i-protected MNs, and that inhibitors to these proteins could also rescue MN toxicity. Collectively, this study highlights the value of utilizing ER stressors in ALS patient MNs to identify novel druggable targets.}, }
@article {pmid38314277, year = {2024}, author = {Mohan, S and Alhazmi, HA and Hassani, R and Khuwaja, G and Maheshkumar, VP and Aldahish, A and Chidambaram, K}, title = {Role of ferroptosis pathways in neuroinflammation and neurological disorders: From pathogenesis to treatment.}, journal = {Heliyon}, volume = {10}, number = {3}, pages = {e24786}, pmid = {38314277}, issn = {2405-8440}, abstract = {Ferroptosis is a newly discovered non-apoptotic and iron-dependent type of cell death. Ferroptosis mainly takes place owing to the imbalance of anti-oxidation and oxidation in the body. It is regulated via a number of factors and pathways both inside and outside the cell. Ferroptosis is closely linked with brain and various neurological disorders (NDs). In the human body, the brain contains the highest levels of polyunsaturated fatty acids, which are known as lipid peroxide precursors. In addition, there is also a connection of glutathione depletion and lipid peroxidation with NDs. There is growing evidence regarding the possible link between neuroinflammation and multiple NDs, such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and stroke. Recent studies have demonstrated that disruptions of lipid reactive oxygen species (ROS), glutamate excitatory toxicity, iron homeostasis, and various other manifestations linked with ferroptosis can be identified in various neuroinflammation-mediated NDs. It has also been reported that damage-associated molecular pattern molecules including ROS are generated during the events of ferroptosis and can cause glial activation via activating neuroimmune pathways, which subsequently leads to the generation of various inflammatory factors that play a role in various NDs. This review summarizes the regulation pathways of ferroptosis, the link between ferroptosis as well as inflammation in NDs, and the potential of a range of therapeutic agents that can be used to target ferroptosis and inflammation in the treatment of neurological disorders.}, }
@article {pmid38308282, year = {2024}, author = {Cai, R and Yang, J and Wu, L and Liu, Y and Wang, X and Zheng, Q and Li, L}, title = {Accelerating drug development for amyotrophic lateral sclerosis: construction and application of a disease course model using historical placebo group data.}, journal = {Orphanet journal of rare diseases}, volume = {19}, number = {1}, pages = {40}, pmid = {38308282}, issn = {1750-1172}, support = {82174229//the National Natural Science Funds of China/ ; 2022YFC3502000//China national key research and development program/ ; ZY [2021-2023]-0401//Shanghai 3-year Action Plan for Inheritance, Innovation, and Development of traditional Chinese Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Drug Development ; *Riluzole/therapeutic use ; Male ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an irreversible degenerative disease. Placebo-controlled randomized trials are currently the main trial design to assess the clinical efficacy of drugs for ALS treatment. The aim of this study was to establish models to quantitatively describe the course of ALS, explore influencing factors, and provide the necessary information for ALS drug development.<br><br>METHODS: We conducted a comprehensive search of PubMed and the Cochrane Library Central Register for placebo-controlled trials that evaluated treatments for ALS. From these trials, we extracted the clinical and demographic characteristics of participants in the placebo group, as well as outcome data, which encompassed overall survival (OS) and Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores, at various time points.<br><br>RESULTS: In total, 47 studies involving 6118 participants were included. Disease duration and the proportion of patients receiving riluzole were identified as significant factors influencing OS in the placebo group. Specifically, the median OS was 35.5&#xa0;months for a disease duration of 9&#xa0;months, whereas it was 20.0&#xa0;months for a disease duration of 36&#xa0;months. Furthermore, for every 10% increase in the proportion of patients treated with riluzole (100&#xa0;mg daily), there was an association with a median OS extension of approximately 0.4&#xa0;months. The estimated time for the ALSFRS-R score in the placebo group to decrease to 50% of its maximum effect from baseline level was approximately 17.5&#xa0;months, and the time to reach a plateau was about 40&#xa0;months.<br><br>CONCLUSIONS: The established disease course model of the historical placebo group is valuable in the decision-making process for the clinical development of ALS drugs. It serves not only as an external control to evaluate the efficacy of the tested drug in single-arm trials but also as prior information that aids in accurately estimating the posterior distribution of the disease course in the placebo group during small-sample clinical trials.}, }
@article {pmid38292603, year = {2024}, author = {Weerawarna, PM and Schiefer, IT and Soares, P and Fox, S and Morimoto, RI and Melani, RD and Kelleher, NL and Luan, CH and Silverman, RB}, title = {Target Identification of a Class of Pyrazolone Protein Aggregation Inhibitor Therapeutics for Amyotrophic Lateral Sclerosis.}, journal = {ACS central science}, volume = {10}, number = {1}, pages = {87-103}, pmid = {38292603}, issn = {2374-7943}, support = {P41 GM108569/GM/NIGMS NIH HHS/United States ; R01 AG061708/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure, and current treatment options are very limited. Previously, we performed a high-throughput screen to identify small molecules that inhibit protein aggregation caused by a mutation in the gene that encodes superoxide dismutase 1 (SOD1), which is responsible for about 25% of familial ALS. This resulted in three hit series of compounds that were optimized over several years to give three compounds that were highly active in a mutant SOD1 ALS model. Here we identify the target of two of the active compounds (6 and 7) with the use of photoaffinity labeling, chemical biology reporters, affinity purification, proteomic analysis, and fluorescent/cellular thermal shift assays. Evidence is provided to demonstrate that these two pyrazolone compounds directly interact with 14-3-3-E and 14-3-3-Q isoforms, which have chaperone activity and are known to interact with mutant SOD1[G93A] aggregates and become insoluble in the subcellular JUNQ compartment, leading to apoptosis. Because protein aggregation is the hallmark of all neurodegenerative diseases, knowledge of the target compounds that inhibit protein aggregation allows for the design of more effective molecules for the treatment of ALS and possibly other neurodegenerative diseases.}, }
@article {pmid38289969, year = {2024}, author = {Hossain, MA and Sarin, R and Donnelly, DP and Miller, BC and Weiss, A and McAlary, L and Antonyuk, SV and Salisbury, JP and Amin, J and Conway, JB and Watson, SS and Winters, JN and Xu, Y and Alam, N and Brahme, RR and Shahbazian, H and Sivasankar, D and Padmakumar, S and Sattarova, A and Ponmudiyan, AC and Gawde, T and Verrill, DE and Yang, W and Kannapadi, S and Plant, LD and Auclair, JR and Makowski, L and Petsko, GA and Ringe, D and Agar, NYR and Greenblatt, DJ and Ondrechen, MJ and Chen, Y and Yerbury, JJ and Manetsch, R and Hasnain, SS and Brown, RH and Agar, JN}, title = {Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS.}, journal = {PLoS biology}, volume = {22}, number = {1}, pages = {e3002462}, pmid = {38289969}, issn = {1545-7885}, support = {P30 GM124166/GM/NIGMS NIH HHS/United States ; R01 NS065263/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Cysteine/genetics ; Mutation ; Superoxide Dismutase/genetics/chemistry/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, "S-XL6," was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A's in vivo half-life; and that S-XL6 crosses the blood-brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS.}, }
@article {pmid38288843, year = {2024}, author = {Fatima, J and Siddique, YH}, title = {Application of Nanocomposites and Nanoparticles in Treating Neurodegenerative Disorders.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {23}, number = {10}, pages = {1217-1233}, pmid = {38288843}, issn = {1996-3181}, support = {211610179057//University Grants Commission/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Nanoparticles/therapeutic use ; *Nanocomposites/therapeutic use ; Animals ; Drug Delivery Systems/methods ; Blood-Brain Barrier/drug effects/metabolism ; Neuroprotective Agents/therapeutic use ; }, abstract = {Neurodegenerative diseases represent a formidable global health challenge, affecting millions and imposing substantial burdens on healthcare systems worldwide. Conditions, like Alzheimer's, Parkinson's, and Huntington's diseases, among others, share common characteristics, such as neuronal loss, misfolded protein aggregation, and nervous system dysfunction. One of the major obstacles in treating these diseases is the presence of the blood-brain barrier, limiting the delivery of therapeutic agents to the central nervous system. Nanotechnology offers promising solutions to overcome these challenges. In Alzheimer's disease, NPs loaded with various compounds have shown remarkable promise in preventing amyloid-beta (Aβ) aggregation and reducing neurotoxicity. Parkinson's disease benefits from improved dopamine delivery and neuroprotection. Huntington's disease poses its own set of challenges, but nanotechnology continues to offer innovative solutions. The promising developments in nanoparticle-based interventions for neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), have offered new avenues for effective treatment. Nanotechnology represents a promising frontier in biomedical research, offering tailored solutions to the complex challenges posed by neurodegenerative diseases. While much progress has been made, ongoing research is essential to optimize nanomaterial designs, improve targeting, and ensure biocompatibility and safety. Nanomaterials possess unique properties that make them excellent candidates for targeted drug delivery and neuroprotection. They can effectively bypass the blood-brain barrier, opening doors to precise drug delivery strategies. This review explores the extensive research on nanoparticles (NPs) and nanocomposites in diagnosing and treating neurodegenerative disorders. These nanomaterials exhibit exceptional abilities to target neurodegenerative processes and halt disease progression.}, }
@article {pmid38286832, year = {2024}, author = {Lu, J and He, AX and Jin, ZY and Zhang, M and Li, ZX and Zhou, F and Ma, L and Jin, HM and Wang, JY and Shen, X}, title = {Desloratadine alleviates ALS-like pathology in hSOD1[G93A] mice via targeting 5HTR2A on activated spinal astrocytes.}, journal = {Acta pharmacologica Sinica}, volume = {45}, number = {5}, pages = {926-944}, pmid = {38286832}, issn = {1745-7254}, mesh = {Animals ; *Astrocytes/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Spinal Cord/drug effects/pathology/metabolism ; Mice ; *Mice, Transgenic ; *Superoxide Dismutase-1/genetics/metabolism ; *Loratadine/*analogs &amp; derivatives/pharmacology/therapeutic use ; Humans ; Receptor, Serotonin, 5-HT2A/metabolism ; Disease Models, Animal ; Male ; Serotonin 5-HT2 Receptor Antagonists/pharmacology/therapeutic use ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive loss of motor neurons in the spinal cord, cerebral cortex and brain stem. ALS is characterized by gradual muscle atrophy and dyskinesia. The limited knowledge on the pathology of ALS has impeded the development of therapeutics for the disease. Previous studies have shown that autophagy and astrocyte-mediated neuroinflammation are involved in the pathogenesis of ALS, while 5HTR2A participates in the early stage of astrocyte activation, and 5HTR2A antagonism may suppress astrocyte activation. In this study, we evaluated the therapeutic effects of desloratadine (DLT), a selective 5HTR2A antagonist, in human SOD1[G93A] (hSOD1[G93A]) ALS model mice, and elucidated the underlying mechanisms. HSOD1[G93A] mice were administered DLT (20 mg·kg[-1]·d[-1], i.g.) from the age of 8 weeks for 10 weeks or until death. ALS onset time and lifespan were determined using rotarod and righting reflex tests, respectively. We found that astrocyte activation accompanying with serotonin receptor 2 A (5HTR2A) upregulation in the spinal cord was tightly associated with ALS-like pathology, which was effectively attenuated by DLT administration. We showed that DLT administration significantly delayed ALS symptom onset time, prolonged lifespan and ameliorated movement disorders, gastrocnemius injury and spinal motor neuronal loss in hSOD1[G93A] mice. Spinal cord-specific knockdown of 5HTR2A by intrathecal injection of adeno-associated virus9 (AAV9)-si-5Htr2a also ameliorated ALS pathology in hSOD1[G93A] mice, and occluded the therapeutic effects of DLT administration. Furthermore, we demonstrated that DLT administration promoted autophagy to reduce mutant hSOD1 levels through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocyte neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1[G93A] mice. In summary, 5HTR2A antagonism shows promise as a therapeutic strategy for ALS, highlighting the potential of DLT in the treatment of the disease. DLT as a 5HTR2A antagonist effectively promoted autophagy to reduce mutant hSOD1 level through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocytic neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1[G93A] mice.}, }
@article {pmid38286113, year = {2024}, author = {Dutta, A and Manna, A and Ghosh, S and Mundle, M and Saha, M and Gourav, K and Maiti, S and Chattopadhyay, B}, title = {Prespecified Homeopathic Medicines in the Prevention of Confirmed and Suspected Cases of COVID-19: A Community-Based, Double-Blind, Randomized, Placebo-Controlled Prophylaxis Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {140-148}, doi = {10.1159/000536395}, pmid = {38286113}, issn = {2504-2106}, abstract = {INTRODUCTION: Homeopathic medicines have been used for decades in the prevention and treatment of infectious diseases. However, the preventive efficacy of specific homeopathic medicines in COVID-19 is not well characterized. This study aimed to evaluate the comparative efficacy of prespecified homeopathic medicines in preventing COVID-19.<br><br>METHODS: A community-based, double-blind, randomized, placebo-controlled trial was conducted on 4,034 participants residing in Ward No. 27 of the Howrah Municipal Corporation in India. Participants were randomized to receive one of three prespecified homeopathic medicines [Influenzinum 30C, Arsenicum album 30C, Anas barbariae hepatis et cordis extractum 200K (Oscillococcinum&#xae;)], or placebo. The outcomes were the incidence of laboratory-confirmed and suspected cases of COVID-19 during a follow-up period of 1 month.<br><br>RESULTS: During the follow-up period, a total of 13 new laboratory-confirmed COVID-19 cases were reported in the study population. Among these, 5 cases in Influenzinum group, 2 cases in Arsenicum album group, 1 case in Oscillococcinum&#xae; group, and 5 cases in Placebo group were reported. On the other hand, number of suspected COVID-19 cases was significantly less in all the three homeopathic medicine groups compared to placebo. The least number of suspected cases reported in the Oscillococcinum&#xae; group (aOR: 0.058; 95% confidence interval [CI]: 0.029, 0.114), followed by the Arsenicum album (aOR: 0.337; 95% CI: 0.238, 0.475) and Influenzinum (aOR: 0.539; 95% CI: 0.401, 0.726) groups.<br><br>CONCLUSION: Prespecified homeopathic medicines, particularly Oscillococcinum&#xae; and Arsenicum album 30C, may have a role in preventing COVID-19, especially in reducing the incidence of suspected or COVID-19-like respiratory illnesses. However, the result failed to demonstrate a statistically significant difference in the occurrence of confirmed cases of COVID-19 between the study groups. Further research is needed to evaluate the efficacy of these medicines in different populations and settings.<br><br>UNLABELLED: <title>Einleitung</title>Hom&#xf6;opathische Arzneimittel werden seit Jahrzehnten zur Pr&#xe4;vention und Behandlung von Infektionskrankheiten eingesetzt. Die Wirksamkeit spezifischer hom&#xf6;opathischer Arzneimittel zur Prophylaxe von COVID-19 ist jedoch nicht gut untersucht. Mit dieser Studie sollte die vergleichende Wirksamkeit spezifischer hom&#xf6;opathischer Arzneimittel bei der Pr&#xe4;vention von COVID-19 untersucht werden.<title>Methoden</title>Es handelte sich um eine gemeindebasierte, doppelblinde, randomisierte, placebokontrollierte Studie mit 4.034 Teilnehmern, die im Bezirk Nr. 27 der Howrah Municipal Corporation in Indien lebten. Die Teilnehmer erhielten randomisiert eines von drei zuvor festgelegten hom&#xf6;opathischen Arzneimitteln [<italic>Influenzinum</italic> 30C, <italic>Arsenicum album</italic> 30C, <italic>Anas barbariae hepatis et cordis extractum</italic> 200K (Oscillococcinum&#xae;)] oder Placebo. Zielkriterien waren die Inzidenz von laborchemisch best&#xe4;tigten und vermuteten COVID-19-F&#xe4;llen w&#xe4;hrend des Follow-up-Zeitraums von einem Monat.<title>Ergebnisse</title>W&#xe4;hrend des Follow-up-Zeitraums wurden insgesamt 13 neue, laborchemisch best&#xe4;tigte COVID-19-F&#xe4;lle in der Studienpopulation berichtet, davon 5 F&#xe4;lle in der <italic>Influenzinum</italic>-Gruppe, 2 F&#xe4;lle in der <italic>Arsenicum album</italic>-Gruppe, 1 Fall in der Oscillococcinum&#xae;-Gruppe und 5 F&#xe4;lle in der Placebo-Gruppe. Demgegen&#xfc;ber fiel Zahl der COVID-19-Verdachtsf&#xe4;lle in allen drei hom&#xf6;opathischen Arzneimittelgruppen signifikant geringer aus als in der Placebogruppe. Die wenigsten Verdachtsf&#xe4;lle wurden in der Oscillococcinum&#xae;-Gruppe berichtet (aOR: 0.058; 95%-KI: 0.029, 0.114), gefolgt von der <italic>Arsenicum album</italic>- (aOR: 0.337; 95%-KI: 0.238, 0.475) und der <italic>Influenzinum</italic>- (aOR: 0.539; 95%-KI: 0.401, 0.726) Gruppe.<title>Schlussfolgerung</title>Spezifische hom&#xf6;opathische Arzneimittel, insbesondere Oscillococcinum&#xae; und <italic>Arsenicum album</italic> 30C, k&#xf6;nnten bei der Pr&#xe4;vention von COVID-19 eine Rolle spielen, vor allem bei der Senkung der Inzidenz von COVID-19-Verdachtsf&#xe4;llen oder COVID-19-&#xe4;hnlichen Atemwegserkrankungen. Allerdings war kein statistisch signifikanter Unterschied im Auftreten von best&#xe4;tigten COVID-19-F&#xe4;llen zwischen den Studiengruppen nachweisbar. Weitere Untersuchungen sind erforderlich, um die Wirksamkeit dieser Arzneimittel in verschiedenen Populationen und Umgebungen zu bewerten.}, }
@article {pmid38286111, year = {2024}, author = {Wang, M and Wang, T and Gu, F}, title = {Efficacy of Huanglian Jiedu Decoction for Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {187-200}, doi = {10.1159/000536453}, pmid = {38286111}, issn = {2504-2106}, abstract = {OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder, and there is an increasing interest in the potential benefits of traditional Chinese medicine, such as Huanglian Jiedu decoction (HJD), for its management. This meta-analysis aimed to determine the efficacy and safety of HJD in the treatment of T2DM.<br><br>METHODS: A systematic review was conducted across six databases including PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang, from their inception to August 24, 2023. We focused on randomized controlled trials (RCTs) that evaluated HJD as both a monotherapy and in combination treatments for T2DM patients. Data analysis was performed using RevMan 5.3 and Stata 17.0, with evaluations for heterogeneity and publication bias. Additionally, subgroup analyses were stratified based on the duration of treatment.<br><br>RESULTS: A total of 40 studies involving 3,934 participants were included in the meta-analysis. Both HJD monotherapy and combined with other therapies significantly reduced hemoglobin A1C (HbA1c) fasting blood glucose (FBG) and 2-h postprandial glucose (2hPG) levels, as well as improved insulin resistance. Furthermore, combination therapy enhanced the efficacy rate and favorably altered lipid profiles, including increasing HDL-C and decreasing LDL-C, TC, and TG levels. It was worth noting that the results of the subgroup analysis indicated that, in terms of reducing HbA1c and 2hPG, the efficacy of HJD alone for a duration of less than 3 months was found to be potentially superior to that observed in treatments exceeding 3 months. Adverse event assessment suggested that HJD did not increase the incidence of side effects, including diarrhea, affirming its safety.<br><br>CONCLUSION: HJD appears to be an effective and safe alternative or adjunctive therapy for T2DM, showing significant improvements in glycemic control and lipid profiles without increasing adverse events. Further rigorous, multicenter RCTs outside China are warranted to validate these findings.<br><br>UNLABELLED: <title>Ziel</title>Diabetes mellitus Typ 2 (DMT2) ist eine weit verbreitete Stoffwechselerkrankung, und es besteht ein steigendes Interesse an den potenziellen Vorteilen der traditionellen chinesischen Medizin, wie beispielsweise Huanglian Jiedu-Dekokt (HJD), zu seiner Behandlung. Mit dieser Metaanalyse sollten die Wirksamkeit und Sicherheit von HJD zur Behandlung von DMT2 ermittelt werden.<title>Methoden</title>Es wurde eine systematische Recherche in sechs Datenbanken durchgef&#xfc;hrt, darunter PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure (CNKI) und Wanfang, f&#xfc;r die Zeit vom Beginn der Datenbank bis zum 24. August 2023. Dabei lag unser Hauptaugenmerk auf randomisierten kontrollierten Studien (RCTs), die HJD sowohl als Monotherapie als auch in Kombinationstherapien bei Patienten mit DMT2 untersuchten. Die Datenanalyse erfolgte mithilfe von RevMan 5.3 und Stata 17.0 mit Untersuchungen auf Heterogenit&#xe4;t und Publikationsverzerrungen. Dar&#xfc;ber hinaus wurden Subgruppenanalysen stratifiziert nach Behandlungsdauer durchgef&#xfc;hrt.<title>Ergebnisse</title>Insgesamt wurden 40 Studien mit 3.934 Teilnehmern in die Metaanalyse eingeschlossen. HJD f&#xfc;hrte sowohl als Monotherapie als auch in Kombination mit anderen Therapien zu einer signifikanten Senkung des HbA1c-N&#xfc;chternblutzuckerspiegels (fasting blood glucose, FBG) und der postprandialen Blutzuckerwerte 2 Stunden nach dem Essen (2-h postprandial glucose, 2hPG) sowie zu einer Verbesserung der Insulinresistenz. Dar&#xfc;ber hinaus verbesserte die Kombinationstherapie die Wirksamkeitsrate und f&#xfc;hrte zu einer positiven Ver&#xe4;nderung der Lipidprofile, die eine Erh&#xf6;hung der HDL-Cholesterinwerte und eine Senkung der LDL-, Gesamtcholesterin- und Trigylceridwerte einschloss. Erw&#xe4;hnenswert ist, dass nach den Ergebnissen der Subgruppenanalyse die Wirksamkeit von HJD als Monotherapie in Hinblick auf die Senkung der HbA1c- und 2hPG-Werte bei einer Behandlungsdauer von weniger als drei Monaten gegen&#xfc;ber derjenigen von Behandlungen, die l&#xe4;nger als drei Monate dauerten, potenziell &#xfc;berlegen war. Die Bewertung der unerw&#xfc;nschten Ereignisse zeigte, dass HJD nicht zu einem Anstieg der Nebenwirkungen wie Durchfall f&#xfc;hrte, was seine Sicherheit best&#xe4;tigte.<title>Schlussfolgerung</title>HJD scheint eine wirksame und sichere Alternative oder Zusatztherapie bei DMT2 zu sein, die signifikante Verbesserungen der Blutzuckerkontrolle und der Lipidprofile ohne Zunahme der unerw&#xfc;nschten Ereignisse bewirkt. Weitere rigorose, multizentrische RCTs au&#xdf;erhalb Chinas sind erforderlich, um diese Ergebnisse zu validieren.}, }
@article {pmid38284068, year = {2024}, author = {Sunildutt, N and Ahmed, F and Chethikkattuveli Salih, AR and Lim, JH and Choi, KH}, title = {Integrating Transcriptomic and Structural Insights: Revealing Drug Repurposing Opportunities for Sporadic ALS.}, journal = {ACS omega}, volume = {9}, number = {3}, pages = {3793-3806}, pmid = {38284068}, issn = {2470-1343}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disorder characterized by the loss of upper and lower motor neurons, resulting in debilitating muscle weakness and atrophy. Currently, there are no effective treatments available for ALS, posing significant challenges in managing the disease that affects approximately two individuals per 100,000 people annually. To address the urgent need for effective ALS treatments, we conducted a drug repurposing study using a combination of bioinformatics tools and molecular docking techniques. We analyzed sporadic ALS-related genes from the GEO database and identified key signaling pathways involved in sporadic ALS pathogenesis through pathway analysis using DAVID. Subsequently, we utilized the Clue Connectivity Map to identify potential drug candidates and performed molecular docking using AutoDock Vina to evaluate the binding affinity of short-listed drugs to key sporadic ALS-related genes. Our study identified Cefaclor, Diphenidol, Flubendazole, Fluticasone, Lestaurtinib, Nadolol, Phenamil, Temozolomide, and Tolterodine as potential drug candidates for repurposing in sporadic ALS treatment. Notably, Lestaurtinib demonstrated high binding affinity toward multiple proteins, suggesting its potential as a broad-spectrum therapeutic agent for sporadic ALS. Additionally, docking analysis revealed NOS3 as the gene that interacts with all the short-listed drugs, suggesting its possible involvement in the mechanisms underlying the therapeutic potential of these drugs in sporadic ALS. Overall, our study provides a systematic framework for identifying potential drug candidates for sporadic ALS therapy and highlights the potential of drug repurposing as a promising strategy for discovering new therapies for neurodegenerative diseases.}, }
@article {pmid38270442, year = {2024}, author = {Smith, R and Hovren, H and Bowser, R and Bakkar, N and Garruto, R and Ludolph, A and Ravits, J and Gaertner, L and Murphy, D and Lebovitz, R}, title = {Misfolded alpha-synuclein in amyotrophic lateral sclerosis: Implications for diagnosis and treatment.}, journal = {European journal of neurology}, volume = {31}, number = {4}, pages = {e16206}, pmid = {38270442}, issn = {1468-1331}, mesh = {Humans ; *alpha-Synuclein/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Lewy Bodies/metabolism/pathology ; Superoxide Dismutase-1 ; }, abstract = {BACKGROUND: Alpha-synuclein (α-Syn) oligomers and fibrils have been shown to augment the aggregation of TAR DNA-binding Protein 43 (TDP-43) monomers in vitro, supporting the idea that TDP-43 proteinopathies such as ALS may be modulated by the presence of toxic forms of α-Syn. Recently, parkinsonian features were reported in a study of European patients and Lewy bodies have been demonstrated pathologically in a similar series of patients. Based on these and other considerations, we sought to determine whether seed-competent α-Syn can be identified in spinal fluid of patients with ALS including familial, sporadic, and Guamanian forms of the disease.<br><br>METHODS: Based on the finding that &#x3b1;-Syn has been found to be a prion-like protein, we have utilized a validated &#x3b1;-Synuclein seed amplification assay to determine if seed-competent &#x3b1;-Syn could be detected in the spinal fluid of patients with ALS.<br><br>RESULTS: Toxic species of &#x3b1;-Syn were detected in CSF in 18 of 127 ALS patients, 5 of whom were from Guam. Two out of twenty six samples from patients with C9orf72 variant ALS had positive seed-amplification assays (SAAs). No positive tests were noted in superoxide dismutase type 1 ALS subjects (n&#x2009;=&#x2009;14). The SAA was negative in 31 control subjects.<br><br>CONCLUSIONS: Our findings suggest that a sub-group of ALS occurs in which self-replicating &#x3b1;-Syn is detectable and likely contributes to its pathogenesis. This finding may have implications for the diagnosis and treatment of this disorder.}, }
@article {pmid38267984, year = {2024}, author = {Irwin, KE and Sheth, U and Wong, PC and Gendron, TF}, title = {Fluid biomarkers for amyotrophic lateral sclerosis: a review.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {9}, pmid = {38267984}, issn = {1750-1326}, support = {R01 NS095969/NS/NINDS NIH HHS/United States ; T32 GM136577/GM/NIGMS NIH HHS/United States ; P01NS084974/NH/NIH HHS/United States ; U19AG063911/NH/NIH HHS/United States ; RF1 NS095969/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Neurodegenerative Diseases ; Biomarkers ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Presently, three FDA-approved drugs are available to help slow functional decline for patients with ALS, but no cure yet exists. With an average life expectancy of only two to five years after diagnosis, there is a clear need for biomarkers to improve the care of patients with ALS and to expedite ALS treatment development. Here, we provide a review of the efforts made towards identifying diagnostic, prognostic, susceptibility/risk, and response fluid biomarkers with the intent to facilitate a more rapid and accurate ALS diagnosis, to better predict prognosis, to improve clinical trial design, and to inform interpretation of clinical trial results. Over the course of 20 + years, several promising fluid biomarker candidates for ALS have emerged. These will be discussed, as will the exciting new strategies being explored for ALS biomarker discovery and development.}, }
@article {pmid38265475, year = {2024}, author = {Xiang, Y and Song, X and Long, D}, title = {Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases.}, journal = {Archives of toxicology}, volume = {98}, number = {3}, pages = {579-615}, pmid = {38265475}, issn = {1432-0738}, support = {81673227//National Natural Science Foundation of China/ ; 2020JJ4080//Natural Science Foundation of&#xa0;Hunan Province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases ; NF-E2-Related Factor 2/metabolism ; *Ferroptosis ; Oxidative Stress/physiology ; Antioxidants/metabolism ; }, abstract = {This article provides an overview of the background knowledge of ferroptosis in the nervous system, as well as the key role of nuclear factor E2-related factor 2 (Nrf2) in regulating ferroptosis. The article takes Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) as the starting point to explore the close association between Nrf2 and ferroptosis, which is of clear and significant importance for understanding the mechanism of neurodegenerative diseases (NDs) based on oxidative stress (OS). Accumulating evidence links ferroptosis to the pathogenesis of NDs. As the disease progresses, damage to the antioxidant system, excessive OS, and altered Nrf2 expression levels, especially the inhibition of ferroptosis by lipid peroxidation inhibitors and adaptive enhancement of Nrf2 signaling, demonstrate the potential clinical significance of Nrf2 in detecting and identifying ferroptosis, as well as targeted therapy for neuronal loss and mitochondrial dysfunction. These findings provide new insights and possibilities for the treatment and prevention of NDs.}, }
@article {pmid38264389, year = {2023}, author = {Gouveia, C and Araújo, L and Freitas, S and Correia, J and Passos, V and Camacho, G and Gomes, L and Fragoeiro, H and Camacho, C and Chambino, B}, title = {A Palliative Care Approach to Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {15}, number = {12}, pages = {e51048}, pmid = {38264389}, issn = {2168-8184}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a degenerative disease characterized by motor dysfunction. Currently, treatment options are limited and management is based mostly on symptom control and quality of life optimization, so palliative care plays a fundamental role. Our objective was to characterize the ALS population in Madeira Island that was referenced and/or followed by a palliative care unit over a five-year period.<br><br>METHODS: Longitudinal, retrospective, descriptive, and observational study to analyze patients with ALS who were referred and/or followed by a palliative care unit during a five-year period, between 2017 and 2021. Patient's medical electronic and physical records were analyzed to gather data. Descriptive and inferential statistical analysis was done using Microsoft Excel and Statistical Package for the Social Sciences (version 28.0.1).<br><br>RESULTS: During this five-year period, a total of 38 patients were diagnosed with ALS in Madeira Island and&#xa0;23 (60.53%) were referred to palliative care. Three patients died before assessment, so 20 (50.63%) were followed by the palliative care team. They had a median life expectancy of 425 days and the median time spent in palliative care was 137 days. Of this population, 56.52% (n=13) was male with an average age of 64 years. The median period from diagnosis to referral was 167 days, with most referrals being made by family medicine (39.13%; n=9) motivated by uncontrolled symptoms (95.65%; n=22).&#xa0;The median period from referral to first assessment by a palliative care physician was 19 days. The Palliative Performance Scale (PPS) and Confusion Assessment Method (CAM) applied on the first visit had a median score of 40% in the former and was negative in 95.00% (n=19) of patients in the latter. Advanced care directives were present in 55.00% (n=11) of patients and all provided care was in accordance with the patient's wishes. The most common symptoms were dysphagia, dyspnea, pain, anxiety, and sialorrhea. The most used drugs were morphine, riluzole, butylscopolamine, bisacodyl, and midazolam. As for other interventions, 55.00% (n=11) of patients underwent noninvasive ventilation (NIV), 15.00% (n=3) were submitted to percutaneous endoscopic gastrostomy (PEG), and one patient (5.00%) was nasogastrically intubated. The death rate was 95.00% (n=19) with 73.68% (n=14) of deaths occurring in the palliative care unit.<br><br>CONCLUSION: Literature has shown that there are many advantages to the early inclusion of palliative care in ALS management, achieving effective symptom control and greater quality of life, but also reducing caregiver burden. However, in this study, we found that referrals to palliative care were late and included mostly cases of advanced disease with uncontrolled symptoms.}, }
@article {pmid38262101, year = {2024}, author = {Masegosa, VM and Navarro, X and Herrando-Grabulosa, M}, title = {ICA-27243 improves neuromuscular function and preserves motoneurons in the transgenic SOD1[G93A] mice.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {2}, pages = {e00319}, pmid = {38262101}, issn = {1878-7479}, mesh = {Mice ; Animals ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases ; Motor Neurons ; Spinal Cord ; Disease Models, Animal ; Superoxide Dismutase ; *Benzamides ; *Pyridines ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the death of upper and lower motor neurons (MNs). Excessive neuronal excitability has been implicated in MN degeneration; thus, modulation of hyperexcitability appears as a promising therapeutic strategy. Potassium channels are attractive targets since they can be activated at subthreshold voltages and can regulate neuronal excitability. In this study, we assayed the effects of N-(6-Chloro-pyridin-3-yl)-3,4-difluorobenzamide compound, known as ICA-27243, as a potential treatment for ALS. ICA-27243 is a highly selective Kv7.2/7.3 opener used mainly in epilepsy models. In the in vitro model of spinal cord organotypic cultures (SCOCs) exposed to acute excitotoxicity, ICA-27243 prevented MN degeneration at a dose-of 10 μM. Administration of ICA-27243 to transgenic SOD1[G93A] ALS mice improved the decline of neuromuscular function, maintained locomotion and coordination in the rotarod, decreased spinal MN death and attenuated glial reactivity. In conclusion, we report here for the first time that ICA-27243 is an effective treatment for ALS, emphasizing the potential of targeting Kv channels to reduce neuronal hyperexcitability.}, }
@article {pmid38261982, year = {2024}, author = {Moglia, C and Calvo, A and Canosa, A and Manera, U and Vasta, R and Di Pede, F and Daviddi, M and Matteoni, E and Brunetti, M and Sbaiz, L and Cabras, S and Gallone, S and Grassano, M and Peotta, L and Palumbo, F and Mora, G and Iazzolino, B and Chio, A}, title = {Cognitive and Behavioral Features of Patients With Amyotrophic Lateral Sclerosis Who Are Carriers of the TARDBP Pathogenic Variant.}, journal = {Neurology}, volume = {102}, number = {4}, pages = {e208082}, pmid = {38261982}, issn = {1526-632X}, mesh = {Aged ; Female ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis ; *Apathy ; Cognition ; *Frontotemporal Dementia ; Memory, Short-Term ; Male ; }, abstract = {BACKGROUND AND OBJECTIVES: TARDBP patients are considered particularly prone to cognitive involvement, but no systematic studies of cognitive impairment in TARDBP patients are available. The aim of this article was to depict in depth the cognitive-behavioral characteristics of a cohort of patients with amyotrophic lateral sclerosis (ALS) carrying TARDBP pathogenetic variants followed by an ALS referral center.<br><br>METHODS: We enrolled all patients with ALS seen at the Turin ALS expert center in the 2009-2021 period who underwent extensive genetic testing and a neuropsychological battery encompassing executive function, verbal memory, language, visual memory, visuoconstructive abilities, attention/working memory, psychomotor speed, nonverbal intelligence, cognitive flexibility, social cognition, and behavior. Tests were compared with the Mann-Whitney U test on age-corrected, sex-corrected, and education-corrected scores. Cognition was classified as normal (ALS-CN); isolated cognitive impairment (ALSci), that is, evidence of executive and/or language dysfunction; isolated behavioral impairment (ALSbi), that is, identification of apathy; cognitive and behavioral impairment (ALScbi), that is, evidence meeting the criteria for both ALSci and ALSbi; and frontotemporal dementia (ALS-FTD).<br><br>RESULTS: This study includes 33 patients with TARDBP pathogenetic variants (TARDBP-ALS) (median age 61 years [interquartile range (IQR) 53-67], 8 female [24.2%]) and 928 patients with ALS not carrying the pathogenic variant (WT-ALS) (median age 67 years [IQR 59-74], 386 female [41.6%]). TARDBP-ALS cases were also compared with 129 matched controls (median age 66 years [IQR 57.5-71.5], 55 female [42.6%]). TARDBP-ALS and WT-ALS patients were cognitively classified as ALS-CN (54% vs 58.8%, respectively), ALSci (21.2% vs 18.3%), ALSci (9.1% vs 9.5%), ALScbi (6.1% vs 6.0%), and ALS-FTD (9.1 vs 6.7%), with no significant difference (p = 0.623). Compared with controls, TARDBP-ALS had a worse performance in executive functions, visual memory, visuoconstructive abilities, verbal fluency, and the apathy behavioral component of FrSBe. The scores of performed tests, including all Edinburgh Cognitive and Behavioral ALS Screen subdomains, were similar in TARDBP-ALS and WT-ALS.<br><br>DISCUSSION: TARDBP-ALS patients were significantly more impaired than controls in most examined domains but do not show any specific pattern of cognitive impairment compared with WT-ALS. Our findings are relevant both clinically, considering the effect of cognitive impairment on patients' decision-making and caregivers' burden, and in designing clinical trials for the treatment of patients carrying TARDBP pathogenetic variants.}, }
@article {pmid38260713, year = {2023}, author = {Geraci, J and Bhargava, R and Qorri, B and Leonchyk, P and Cook, D and Cook, M and Sie, F and Pani, L}, title = {Machine learning hypothesis-generation for patient stratification and target discovery in rare disease: our experience with Open Science in ALS.}, journal = {Frontiers in computational neuroscience}, volume = {17}, number = {}, pages = {1199736}, pmid = {38260713}, issn = {1662-5188}, abstract = {INTRODUCTION: Advances in machine learning (ML) methodologies, combined with multidisciplinary collaborations across biological and physical sciences, has the potential to propel drug discovery and development. Open Science fosters this collaboration by releasing datasets and methods into the public space; however, further education and widespread acceptance and adoption of Open Science approaches are necessary to tackle the plethora of known disease states.<br><br>MOTIVATION: In addition to providing much needed insights into potential therapeutic protein targets, we also aim to demonstrate that small patient datasets have the potential to provide insights that usually require many samples (>5,000). There are many such datasets available and novel advancements in ML can provide valuable insights from these patient datasets.<br><br>PROBLEM STATEMENT: Using a public dataset made available by patient advocacy group AnswerALS and a multidisciplinary Open Science approach with a systems biology augmented ML technology, we aim to validate previously reported drug targets in ALS and provide novel insights about ALS subpopulations and potential drug targets using a unique combination of ML methods and graph theory.<br><br>METHODOLOGY: We use NetraAI to generate hypotheses about specific patient subpopulations, which were then refined and validated through a combination of ML techniques, systems biology methods, and expert input.<br><br>RESULTS: We extracted 8 target classes, each comprising of several genes that shed light into ALS pathophysiology and represent new avenues for treatment. These target classes are broadly categorized as inflammation, epigenetic, heat shock, neuromuscular junction, autophagy, apoptosis, axonal transport, and excitotoxicity. These findings are not mutually exclusive, and instead represent a systematic view of ALS pathophysiology. Based on these findings, we suggest that simultaneous targeting of ALS has the potential to mitigate ALS progression, with the plausibility of maintaining and sustaining an improved quality of life (QoL) for ALS patients. Even further, we identified subpopulations based on disease onset.<br><br>CONCLUSION: In the spirit of Open Science, this work aims to bridge the knowledge gap in ALS pathophysiology to aid in diagnostic, prognostic, and therapeutic strategies and pave the way for the development of personalized treatments tailored to the individual's needs.}, }
@article {pmid38256050, year = {2024}, author = {Bruno, A and Milillo, C and Anaclerio, F and Buccolini, C and Dell'Elice, A and Angilletta, I and Gatta, M and Ballerini, P and Antonucci, I}, title = {Perinatal Tissue-Derived Stem Cells: An Emerging Therapeutic Strategy for Challenging Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {2}, pages = {}, pmid = {38256050}, issn = {1422-0067}, mesh = {Female ; Pregnancy ; Humans ; *Neurodegenerative Diseases/therapy ; *Alzheimer Disease ; *Huntington Disease/therapy ; *Parkinson Disease/therapy ; Stem Cells ; }, abstract = {Over the past 20 years, stem cell therapy has been considered a promising option for treating numerous disorders, in particular, neurodegenerative disorders. Stem cells exert neuroprotective and neurodegenerative benefits through different mechanisms, such as the secretion of neurotrophic factors, cell replacement, the activation of endogenous stem cells, and decreased neuroinflammation. Several sources of stem cells have been proposed for transplantation and the restoration of damaged tissue. Over recent decades, intensive research has focused on gestational stem cells considered a novel resource for cell transplantation therapy. The present review provides an update on the recent preclinical/clinical applications of gestational stem cells for the treatment of protein-misfolding diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). However, further studies should be encouraged to translate this promising therapeutic approach into the clinical setting.}, }
@article {pmid38250776, year = {2024}, author = {Du, P and Zhang, X and Lian, X and Hölscher, C and Xue, G}, title = {O-GlcNAcylation and Its Roles in Neurodegenerative Diseases.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {97}, number = {3}, pages = {1051-1068}, doi = {10.3233/JAD-230955}, pmid = {38250776}, issn = {1875-8908}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Protein Processing, Post-Translational ; Proteins/metabolism ; *Alzheimer Disease/pathology ; Acetylglucosamine/metabolism ; Disease Progression ; N-Acetylglucosaminyltransferases/metabolism ; }, abstract = {As a non-classical post-translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is widely found in human organ systems, particularly in our brains, and is indispensable for healthy cell biology. With the increasing age of the global population, the incidence of neurodegenerative diseases is increasing, too. The common characteristic of these disorders is the aggregation of abnormal proteins in the brain. Current research has found that O-GlcNAcylation dysregulation is involved in misfolding or aggregation of these abnormal proteins to mediate disease progression, but the specific mechanism has not been defined. This paper reviews recent studies on O-GlcNAcylation's roles in several neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, Machado-Joseph's disease, and giant axonal neuropathy, and shows that O-GlcNAcylation, as glucose metabolism sensor, mediating synaptic function, participating in oxidative stress response and signaling pathway conduction, directly or indirectly regulates characteristic pathological protein toxicity and affects disease progression. The existing results suggest that targeting O-GlcNAcylation will provide new ideas for clinical diagnosis, prevention, and treatment of neurodegenerative diseases.}, }
@article {pmid38249592, year = {2023}, author = {Jiang, Q and Guo, Y and Yang, T and Li, S and Hou, Y and Lin, J and Xiao, Y and Ou, R and Wei, Q and Shang, H}, title = {Cystatin C is associated with poor survival in amyotrophic lateral sclerosis patients.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1309568}, pmid = {38249592}, issn = {1662-4548}, abstract = {BACKGROUND: Cystatin C (CysC) levels in amyotrophic lateral sclerosis (ALS) have been found changes, however, the associations between serum CysC levels and the progression and survival of ALS remain largely unknown.<br><br>METHODS: A total of 1,086 ALS patients and 1,026 sex-age matched healthy controls (HCs) were enrolled in this study. Serum CysC, other renal function, and metabolic parameters were measured. Correlation analysis and binary logistic regression were used to explore the factors related to serum CysC. Kaplan-Meier curve and Cox regression model were used for survival analysis.<br><br>RESULTS: CysC levels were significantly higher in ALS patients compared to HCs (0.94 vs. 0.85&#x2009;mg/L, p&#x2009;<&#x2009;0.001). Compared with ALS patients with lower CysC levels, those with higher CysC levels had an older age of onset, significantly lower ALSFRS-R scores (40.1 vs. 41.3, p&#x2009;<&#x2009;0.001), a faster disease progression rate (0.75 vs. 0.67, p&#x2009;=&#x2009;0.011), and lower frontal lobe function scores (15.8 vs. 16.1, p&#x2009;=&#x2009;0.020). In the correlation analysis, CysC levels were significantly negatively correlated with ALSFRS-R scores (r&#x2009;=&#x2009;-0.16, p&#x2009;<&#x2009;0.001). Additionally, ALS patients with higher CysC levels had significantly shorter survival time (40.0 vs. 51.8, p&#x2009;<&#x2009;0.001) compared to patients with lower CysC levels. Higher CysC levels were associated with a higher risk of death in Cox analysis (HR: 1.204, 95% CI: 1.012-1.433). However, when treatment was included in the model, the result was no longer significant.<br><br>CONCLUSION: CysC levels in ALS patients were higher compared to HCs. Higher CysC levels were associated with greater disease severity, faster progression rate and shorter survival, needing early intervention.}, }
@article {pmid38249293, year = {2023}, author = {Krishnamurthy, K and Pradhan, RK}, title = {Emerging perspectives of synaptic biomarkers in ALS and FTD.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1279999}, pmid = {38249293}, issn = {1662-5099}, abstract = {Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are debilitating neurodegenerative diseases with shared pathological features like transactive response DNA-binding protein of 43 kDa (TDP-43) inclusions and genetic mutations. Both diseases involve synaptic dysfunction, contributing to their clinical features. Synaptic biomarkers, representing proteins associated with synaptic function or structure, offer insights into disease mechanisms, progression, and treatment responses. These biomarkers can detect disease early, track its progression, and evaluate therapeutic efficacy. ALS is characterized by elevated neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) and blood, correlating with disease progression. TDP-43 is another key ALS biomarker, its mislocalization linked to synaptic dysfunction. In FTD, TDP-43 and tau proteins are studied as biomarkers. Synaptic biomarkers like neuronal pentraxins (NPs), including neuronal pentraxin 2 (NPTX2), and neuronal pentraxin receptor (NPTXR), offer insights into FTD pathology and cognitive decline. Advanced technologies, like machine learning (ML) and artificial intelligence (AI), aid biomarker discovery and drug development. Challenges in this research include technological limitations in detection, variability across patients, and translating findings from animal models. ML/AI can accelerate discovery by analyzing complex data and predicting disease outcomes. Synaptic biomarkers offer early disease detection, personalized treatment strategies, and insights into disease mechanisms. While challenges persist, technological advancements and interdisciplinary efforts promise to revolutionize the understanding and management of ALS and FTD. This review will explore the present comprehension of synaptic biomarkers in ALS and FTD and discuss their significance and emphasize the prospects and obstacles.}, }
@article {pmid38249102, year = {2024}, author = {Bakaeva, M and Chetverikov, S and Starikov, S and Kendjieva, A and Khudaygulov, G and Chetverikova, D}, title = {Effect of Plant Growth-Promoting Bacteria on Antioxidant Status, Acetolactate Synthase Activity, and Growth of Common Wheat and Canola Exposed to Metsulfuron-Methyl.}, journal = {Journal of xenobiotics}, volume = {14}, number = {1}, pages = {79-95}, pmid = {38249102}, issn = {2039-4713}, support = {23-26-00097//Russian Science Foundation/ ; }, abstract = {Metsulfuron-methyl, a widely used herbicide, could cause damage to the sensitive plants in crop-rotation systems at extremely low levels in the soil. The potential of plant growth-promoting bacteria (PGPB) for enhancing the resistance of plants against herbicide stress has been discovered recently. Therefore, it is poorly understood how physiological processes occur in plants, while PGPB reduce the phytotoxicity of herbicides for agricultural crops. In greenhouse studies, the effect of strains Pseudomonas protegens DA1.2 and Pseudomonas chlororaphis 4CH on oxidative damage, acetolactate synthase (ALS), enzymatic and non-enzymatic antioxidants in canola (Brassica napus L.), and wheat (Triticum aestivum L.) were investigated under two levels (0.05 and 0.25 mg∙kg[-1]) of metsulfuron-methyl using spectrophotometric assays. The inoculation of herbicide-exposed wheat with bacteria significantly increased the shoots fresh weight (24-28%), amount of glutathione GSH (60-73%), and flavonoids (5-14%), as well as activity of ascorbate peroxidase (129-140%), superoxide dismutase SOD (35-49%), and ALS (50-57%). Bacterial treatment stimulated the activity of SOD (37-94%), ALS (65-73%), glutathione reductase (19-20%), and the accumulation of GSH (61-261%), flavonoids (17-22%), and shoots weight (27-33%) in herbicide-exposed canola. Simultaneous inoculation prevented lipid peroxidation induced by metsulfuron-methyl in sensitive plants. Based on the findings, it is possible that the protective role of bacterial strains against metsulfuron-metil is linked to antioxidant system activation.}, }
@article {pmid38244886, year = {2024}, author = {DSouza, AA and Kulkarni, P and Ferris, CF and Amiji, MM and Bleier, BS}, title = {Mild repetitive TBI reduces brain-derived neurotrophic factor (BDNF) in the substantia nigra and hippocampus: A preclinical model for testing BDNF-targeted therapeutics.}, journal = {Experimental neurology}, volume = {374}, number = {}, pages = {114696}, pmid = {38244886}, issn = {1090-2430}, support = {P30 EY003790/EY/NEI NIH HHS/United States ; R01 NS108968/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Female ; Male ; Rats ; *Brain Concussion/complications ; *Brain Injuries, Traumatic/drug therapy/complications ; Brain-Derived Neurotrophic Factor/metabolism ; Hippocampus/metabolism ; Substantia Nigra/metabolism ; }, abstract = {Clinical studies have consistently shown that neurodegenerative diseases (NDs) such as Parkinson's disease, Alzheimer's disease, Amyotrophic Lateral Sclerosis, and Huntington's disease show absent or low levels of brain-derived neurotrophic factor (BDNF). Despite this relationship between BDNF and ND, only a few ND animal models have been able to recapitulate the low BDNF state, thereby hindering research into the therapeutic targeting of this important neurotrophic factor. In order to address this unmet need, we sought to develop a reproducible model of BDNF reduction by inducing traumatic brain injury (TBI) using a closed head momentum exchange injury model in mature 9-month-old male and female rats. Head impacts were repetitive and varied in intensity from mild to severe. BDNF levels, as assessed by ELISA, were significantly reduced in the hippocampus of both males and females as well as in the substantia nigra of males 12 days after mild TBI. However, we observed significant sexual dimorphism in multiple sequelae, including magnetic resonance imaging-determined vasogenic edema, astrogliosis (GFAP-activation), and microgliosis (Iba1 activation). This study provides an opportunity to investigate the mechanism of BDNF reduction in rodent models and provides a reliable paradigm to test BDNF-targeted therapeutics for the treatment of ND.}, }
@article {pmid38240416, year = {2024}, author = {Schuster, J and Dreyhaupt, J and Mönkemöller, K and Dupuis, L and Dieterlé, S and Weishaupt, JH and Kassubek, J and Petri, S and Meyer, T and Grosskreutz, J and Schrank, B and Boentert, M and Emmer, A and Hermann, A and Zeller, D and Prudlo, J and Winkler, AS and Grehl, T and Heneka, MT and Johannesen, S and Göricke, B and Witzel, S and Dorst, J and Ludolph, AC and , }, title = {In-depth analysis of data from the RAS-ALS study reveals new insights in rasagiline treatment for amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {4}, pages = {e16204}, pmid = {38240416}, issn = {1468-1331}, support = {//Teva Pharmaceutical Industries/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Indans/therapeutic use ; Disease Progression ; }, abstract = {BACKGROUND AND PURPOSE: In 2016, we concluded a randomized controlled trial testing 1 mg rasagiline per day add-on to standard therapy in 252 amyotrophic lateral sclerosis (ALS) patients. This article aims at better characterizing ALS patients who could possibly benefit from rasagiline by reporting new subgroup analysis and genetic data.<br><br>METHODS: We performed further exploratory in-depth analyses of the study population and investigated the relevance of single nucleotide polymorphisms (SNPs) related to the dopaminergic system.<br><br>RESULTS: Placebo-treated patients with very slow disease progression (loss of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R] per month before randomization of &#x2264;0.328 points) showed a per se survival probability after 24&#x2009;months of 0.85 (95% confidence interval&#x2009;=&#x2009;0.65-0.94). The large group of intermediate to fast progressing ALS patients showed a prolonged survival in the rasagiline group compared to placebo after 6 and 12&#x2009;months (p&#x2009;=&#x2009;0.02, p&#x2009;=&#x2009;0.04), and a reduced decline of ALSFRS-R after 18&#x2009;months (p&#x2009;=&#x2009;0.049). SNP genotypes in the MAOB gene and DRD2 gene did not show clear associations with rasagiline treatment effects.<br><br>CONCLUSIONS: These results underline the need to consider individual disease progression at baseline in future ALS studies. Very slow disease progressors compromise the statistical power of studies with treatment durations of 12-18&#x2009;months using clinical endpoints. Analysis of MAOB and DRD2 SNPs revealed no clear relationship to any outcome parameter. More insights are expected from future studies elucidating whether patients with DRD2CC genotype (Rs2283265) show a pronounced benefit from treatment with rasagiline, pointing to the opportunities precision medicine could open up for ALS patients in the future.}, }
@article {pmid38235844, year = {2024}, author = {Zhang, L and Li, Y and Niu, J and Hu, N and Ding, J and Cui, L and Liu, M}, title = {Neuromuscular ultrasound in combination with nerve conduction studies helps identify inflammatory motor neuropathies from lower motor neuron syndromes.}, journal = {European journal of neurology}, volume = {31}, number = {4}, pages = {e16202}, pmid = {38235844}, issn = {1468-1331}, support = {CIFMS 2021-I2M-1-003//CAMS Innovation Fund for Medical Sciences/ ; 2022-PUMCH-B-017//National High Level Hospital Clinical Research Funding/ ; 2016YFC0905103//National Key Research and Development Program of China/ ; grant XDB39040000//the Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/therapy ; Nerve Conduction Studies ; Neural Conduction/physiology ; Motor Neurons ; *Polyneuropathies ; *Motor Neuron Disease ; }, abstract = {BACKGROUND AND PURPOSE: Identifying patients with inflammatory motor neuropathies (IMNs) is warranted since effective treatments are available and the prognosis of these patients differs from that of amyotrophic lateral sclerosis patients.<br><br>METHODS: Between January 2019 and May 2022, 102 consecutive treatment-na&#xef;ve lower motor neuron syndrome (LMNS) patients were recruited; these patients were suspected of having multifocal motor neuropathy, pure motor chronic inflammatory demyelinating polyneuropathy or amyotrophic lateral sclerosis with initial lower motor neuron presentation. Neuromuscular ultrasound (US) and nerve conduction studies (NCSs) were conducted at baseline. Relevant diagnostic investigations were performed if clinically warranted. The proposed US evidence of IMN was as follows: (i) nerve enlargement at &#x2265;1 of the predetermined sites or (ii) absence of high intensity fasciculations in predefined muscle groups. Final diagnoses were made by experienced physicians after a prolonged follow-up period (&#x2265;12&#x2009;months). IMN patients were defined as LMNS patients who experienced convincing improvements in response to immunotherapies. IMN patients without electrodiagnostic demyelinating features were diagnosed with treatment-responsive LMNS (TR-LMNS).<br><br>RESULTS: In total, 16 patients were classified as IMN, including nine chronic inflammatory demyelinating polyneuropathy/multifocal motor neuropathy patients and seven TR-LMNS patients. Six TR-LMNS patients were identified by neuromuscular US. The sensitivity and specificity of NCSs, nerve US and muscle US were 56.3% and 100%, 43.8% and 90.7% and 68.8% and 97.7%, respectively. When these three modalities were combined, the sensitivity and specificity were 93.8% and 88.4%, respectively.<br><br>CONCLUSION: Neuromuscular US studies are supplementary modalities to NCSs, and the combined use of these techniques might improve the identification of IMNs in LMNS patients.}, }
@article {pmid38235589, year = {2024}, author = {Gebrehiwet, P and Aggarwal, S and Topaloglu, O and Chiò, A}, title = {Feasibility assessment of using the MiToS staging system for conducting economic evaluation in amyotrophic lateral sclerosis.}, journal = {Expert review of pharmacoeconomics &amp; outcomes research}, volume = {24}, number = {3}, pages = {447-458}, doi = {10.1080/14737167.2024.2306819}, pmid = {38235589}, issn = {1744-8379}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Cost-Benefit Analysis ; Feasibility Studies ; Mitochondria Associated Membranes ; Disease Progression ; Quality-Adjusted Life Years ; }, abstract = {OBJECTIVES: This study assessed the feasibility of using the Milano-Torino staging (MiToS) system for conducting economic evaluation to measure health outcomes in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: A Markov model was developed using the MiToS system and evaluated with a hypothetical treatment versus standard of care. Health utilities and transition probabilities were derived from the literature. Four-time horizons (1, 5, 10, and 20&#x2009;years) were examined. Treatment effects of 20-35% relative risk reduction (RRR) of progressing to the next MiToS stage were assessed. Three patient distribution scenarios were tested: (1) all patients began in stage 0; (2) patient distribution based on real-world TONiC study; (3) distribution based on the PRO-ACT database. Health outcomes (quality-adjusted life-years [QALYs], life-years [LYs]) were reported with a 3% discount rate.<br><br>RESULTS: A time horizon of 10&#x2009;years fully captured treatment benefits: incremental QALYs were 0.28-0.60, 0.21-0.45, and 0.26-0.55 for scenarios 1-3, respectively; incremental LYs were 0.56-1.17, 0.46-0.97, and 0.53-1.11, respectively.<br><br>CONCLUSION: MiToS-based staging can be used for conducting economic analyses in ALS. Estimated incremental QALY and LY gains were meaningful within the context of ALS, for hypothetical treatments with RRR of 20-35%.}, }
@article {pmid38229740, year = {2024}, author = {Rosse, G}, title = {Novel Pyrazolopyridine Inhibitors of Monoacylglycerol Lipase for the Treatment of Neurodegenerative Diseases and Neuroinflammation.}, journal = {ACS medicinal chemistry letters}, volume = {15}, number = {1}, pages = {19-20}, pmid = {38229740}, issn = {1948-5875}, abstract = {This work highlights the use of bicyclic heterocyclic compounds as monoacylglycerol lipase inhibitors potentially in the treatment of Alzheimer's disease, Parkinson's disease, ALS, traumatic brain injury, and multiple sclerosis.}, }
@article {pmid38225089, year = {2024}, author = {Unan, R and Azapoglu, O and Deligoz, &#x130; and Mennan, H and Al-Khatib, K}, title = {Gene flow and spontaneous mutations are responsible for imidazolinone herbicide-resistant weedy rice (Oryza sativa L.).}, journal = {Pesticide biochemistry and physiology}, volume = {198}, number = {}, pages = {105746}, doi = {10.1016/j.pestbp.2023.105746}, pmid = {38225089}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology ; *Oryza/genetics ; Gene Flow ; Plant Weeds/genetics ; Herbicide Resistance/genetics ; Mutation ; }, abstract = {For more than two decades, weedy rice (Oryza sativa L.) has been controlled in rice fields by using imidazolinone (IMI) herbicide-resistant rice technology (Clearfield®). Outcrossing in weedy rice populations and spontaneous mutations are potential problems with herbicide-resistant crop management technologies, such as the IMI-resistant rice. The aim of this study was to characterize the mechanism of IMI herbicide resistance in weedy rice through dose-response bioassay study and evaluating amino acid substitutions in acetolactate synthase (ALS) protein. A total of 118 suspected IMI-resistant weedy rice samples, which survived in the field after an IMI herbicide application, were collected at harvest time from Türkiye in 2020 and 2021. Single-dose imazamox application experiment revealed that 38 plants survived herbicide treatment. The imazamox resistance of the surviving plants was confirmed by dose-response experiment. ALS gene region underwent a sanger DNA partial sequencing. No substitution was found in 10 samples, however, amino acid substitutions were found in 26 samples with S563N, one sample with S653T, and one sample with E630D. The S653N point is the same substitution point that serves as the origin of resistance for the Clearfield® rice varieties that are commonly cultivated in the region. It has been hypothesized that the gene flow from IMI-resistant rice may be the cause of resistance in the IMI resistant weedy rice samples with S653N. The other substitution, S653T, were considered spontaneous mutation to IMI resistance. Interestingly, the S653T mutation was detected for the first time in weedy rice. The mechanism of resistance of 10 resistant weedy rice was not confirmed in this study, however, it may be a non-target resistance or another mutation point in target site, but evidently, they did not acquire resistance by gene flow from IMI-resistant rice. It has been concluded that the effectiveness of IMI-resistant rice technology in controlling weedy rice has drastically decreased due to possible gene flow, spontaneous mutation and non-target resistance. In addition to cultural controls like clean seed, clean machinery and crop rotation, other herbicide-tolerant rice systems such as Provisia® and Roxy-RPS® rice are needed to create a diverse weedy rice management ensemble available for rice production and move towards sustainable rice farming.}, }
@article {pmid38225062, year = {2024}, author = {Xu, X and Zhao, B and Li, B and Shen, B and Qi, Z and Wang, J and Cui, H and Chen, S and Wang, G and Liu, X}, title = {Trp-574-Leu mutation and metabolic resistance by cytochrome P450 gene conferred high resistance to ALS-inhibiting herbicides in Descurainia sophia.}, journal = {Pesticide biochemistry and physiology}, volume = {198}, number = {}, pages = {105708}, doi = {10.1016/j.pestbp.2023.105708}, pmid = {38225062}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/antagonists &amp; inhibitors/metabolism ; *Arylsulfonates ; *Brassicaceae/drug effects/genetics ; Cytochrome P-450 Enzyme System/genetics ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Mutation ; }, abstract = {Descurainia sophia (flixweed) is a troublesome weed in winter wheat fields in North China. Resistant D. sophia populations with different acetolactate synthetase (ALS) mutations have been reported in recent years. In addition, metabolic resistance to ALS-inhibiting herbicides has also been identified. In this study, we collected and purified two resistant D. sophia populations (R1 and R2), which were collected from winter wheat fields where tribenuron-methyl provided no control of D. sophia at 30 g a.i. ha[-1]. Whole plant bioassay and ALS activity assay results showed the R1 and R2 populations had evolved high-level resistance to tribenuron-methyl and florasulam and cross-resistance to imazethapyr and pyrithiobac‑sodium. The two ALS genes were cloned from the leaves of R1 and R2 populations, ALS1 (2004 bp) and ALS2 (1998 bp). A mutation of Trp 574 to Leu in ALS1 was present in both R1 and R2. ALS1 and ALS2 were cloned from R1 and R2 populations respectively and transferred into Arabidopsis thaliana. Homozygous T3 transgenic seedlings with ALS1 of R1 or R2 were resistant to ALS-inhibiting herbicides and the resistant levels were the same. Transgenic seedlings with ALS2 from R1 or R2 were susceptible to ALS-inhibiting herbicides. Treatment with cytochrome P450 inhibitor malathion decreased the resistant levels to tribenuron-methyl in R1 and R2. RNA-Seq was used to identify target cytochrome P450 genes possibly involved in resistance to ALS-inhibiting herbicides. There were five up-regulated differentially expressed cytochrome P450 genes: CYP72A15, CYP83B1, CYP81D8, CYP72A13 and CYP71A12. Among of them, CYP72A15 had the highest expression level in R1 and R2 populations. The R1 and R2 populations of D. sophia have evolved resistance to ALS-inhibiting herbicides due to Trp 574 Leu mutation in ALS1 and possibly other mechanisms. The resistant function of CYP72A15 needs further research.}, }
@article {pmid38218903, year = {2024}, author = {Lee, MH and Kang, S and Um, KH and Lee, SW and Hwang, H and Baek, K and Choi, JW}, title = {Brain-targeted delivery of neuroprotective survival gene minimizing hematopoietic cell contamination: implications for Parkinson's disease treatment.}, journal = {Journal of translational medicine}, volume = {22}, number = {1}, pages = {53}, pmid = {38218903}, issn = {1479-5876}, support = {NRF-2017R1A5A2014768//Ministry of Science and ICT, South Korea/ ; NRF-2022R1A2C2009281//Ministry of Science and ICT, South Korea/ ; NRF-2019R1A2C1006752//Ministry of Science and ICT, South Korea/ ; 21153MFDS601//Ministry of Food and Drug Safety/ ; }, mesh = {Animals ; *Parkinson Disease/genetics/therapy ; Leukocytes, Mononuclear ; Brain/metabolism ; Genetic Therapy/methods ; Transgenes ; Genetic Vectors ; Dependovirus/genetics ; }, abstract = {BACKGROUND: Neurodegenerative diseases, including Parkinson's disease, Amyotropic Lateral Sclerosis (ALS) and Alzheimer's disease, present significant challenges for therapeutic development due to drug delivery restrictions and toxicity concerns. Prevailing strategies often employ adeno-associated viral (AAV) vectors to deliver neuroprotective survival genes directly into the central nervous system (CNS). However, these methods have been limited by triggering immunogenic responses and risk of tumorigenicity, resulting from overexpression of survival genes in peripheral blood mononuclear cells (PBMC), thereby increasing the risk of tumorigenicity in specific immune cells. Thus, by coding selectively suppressive microRNA (miRNA) target sequences in AAV genome, we designed CNS-targeted neuroprotective gene expression vector system without leakage to blood cells.<br><br>METHODS: To minimize the potential for transgene contamination in the blood, we designed a CNS-specific AAV system. Our system utilized a self-complementary AAV (scAAV), encoding a quadruple repeated target sequence of the hematopoietic cell-specific miR142-3p at the 3' untranslated region (UTR). As a representative therapeutic survival gene for Parkinson's disease treatment, we integrated DX2, an antagonistic splice variant of the apoptotic gene AIMP2, known to be implicated in Parkinson's disease, into the vector.<br><br>RESULTS: This configuration ensured that transgene expression was stringently localized to the CNS, even if the vector found its way into the blood cells. A single injection of scAAV-DX2 demonstrated marked improvement in behavior and motor activity in animal models of Parkinson's disease induced by either Rotenone or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Importantly, comprehensive preclinical data adhering to Good Laboratory Practice (GLP) standards revealed no adverse effects in the treated animals.<br><br>CONCLUSIONS: Our CNS-specific vector system, which encodes a survival transgene DX2, signifies a promising avenue for safe gene therapy, avoiding unintended expression of survival gene in blood cells, applicable to various neurodegenerative diseases.}, }
@article {pmid38218077, year = {2024}, author = {Di Lazzaro, V and Ranieri, F and Bączyk, M and de Carvalho, M and Dileone, M and Dubbioso, R and Fernandes, S and Kozak, G and Motolese, F and Ziemann, U}, title = {Novel approaches to motoneuron disease/ALS treatment using non-invasive brain and spinal stimulation: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {158}, number = {}, pages = {114-136}, doi = {10.1016/j.clinph.2023.12.012}, pmid = {38218077}, issn = {1872-8952}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; *Transcranial Direct Current Stimulation ; *Motor Neuron Disease/diagnosis/therapy ; Motor Neurons/physiology ; Brain ; Transcranial Magnetic Stimulation/methods ; }, abstract = {Non-invasive brain stimulation techniques have been exploited in motor neuron disease (MND) with multifold objectives: to support the diagnosis, to get insights in the pathophysiology of these disorders and, more recently, to slow down disease progression. In this review, we consider how neuromodulation can now be employed to treat MND, with specific attention to amyotrophic lateral sclerosis (ALS), the most common form with upper motoneuron (UMN) involvement, taking into account electrophysiological abnormalities revealed by human and animal studies that can be targeted by neuromodulation techniques. This review article encompasses repetitive transcranial magnetic stimulation methods (including low-frequency, high-frequency, and pattern stimulation paradigms), transcranial direct current stimulation as well as experimental findings with the newer approach of trans-spinal direct current stimulation. We also survey and discuss the trials that have been performed, and future perspectives.}, }
@article {pmid38216448, year = {2024}, author = {Van Daele, SH and Masrori, P and Van Damme, P and Van Den Bosch, L}, title = {The sense of antisense therapies in ALS.}, journal = {Trends in molecular medicine}, volume = {30}, number = {3}, pages = {252-262}, doi = {10.1016/j.molmed.2023.12.003}, pmid = {38216448}, issn = {1471-499X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; Oligonucleotides, Antisense/therapeutic use ; RNA Splicing ; }, abstract = {Treatment of patients with amyotrophic lateral sclerosis (ALS) has entered a new era now that encouraging results about antisense oligonucleotides (ASOs) are becoming available and a first ASO therapy for ALS has been approved by the FDA. Moreover, there is hope not only that ALS can be stopped but also that symptoms can be reversed. Until now, degrading ASOs seemed to be successful mostly for rarer forms of familial ALS. However, the first attempts to correct mis-splicing events in sporadic ALS are underway, as well as a clinical trial examining interference with a genetic modifier. In this review, we discuss the current status of using ASOs in ALS and the possibilities and pitfalls of this therapeutic strategy.}, }
@article {pmid38203300, year = {2023}, author = {Wei, J and Wong, LC and Boland, S}, title = {Lipids as Emerging Biomarkers in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {1}, pages = {}, pmid = {38203300}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; *Alzheimer Disease/diagnosis ; *Parkinson Disease ; Biomarkers ; Monoglycerides ; }, abstract = {Biomarkers are molecules that can be used to observe changes in an individual's biochemical or medical status and provide information to aid diagnosis or treatment decisions. Dysregulation in lipid metabolism in the brain is a major risk factor for many neurodegenerative disorders, including frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Thus, there is a growing interest in using lipids as biomarkers in neurodegenerative diseases, with the anionic phospholipid bis(monoacylglycerol)phosphate and (glyco-)sphingolipids being the most promising lipid classes thus far. In this review, we provide a general overview of lipid biology, provide examples of abnormal lysosomal lipid metabolism in neurodegenerative diseases, and discuss how these insights might offer novel and promising opportunities in biomarker development and therapeutic discovery. Finally, we discuss the challenges and opportunities of lipid biomarkers and biomarker panels in diagnosis, prognosis, and/or treatment response in the clinic.}, }
@article {pmid38202163, year = {2023}, author = {Ueha, R and Cotaoco, C and Kondo, K and Yamasoba, T}, title = {Management and Treatment for Dysphagia in Neurodegenerative Disorders.}, journal = {Journal of clinical medicine}, volume = {13}, number = {1}, pages = {}, pmid = {38202163}, issn = {2077-0383}, abstract = {Patients with neurodegenerative disorders (NDDs) often experience functional dysphagia, which may involve dysfunction in a specific phase of swallowing or in the entire process. This review outlines the approach to dysphagia in the setting of NDDs. Distinguishing the etiology of dysphagia can be difficult, and it is important to always look out for signs pointing to NDD as the cause. Thorough diagnostic work-up is essential, and it includes a comprehensive history and physical examination, alongside swallowing function tests, such as fiberoptic endoscopic evaluation of swallowing, videofluoroscopic swallowing study, and high-resolution manometry. Management requires a multidisciplinary approach with a treatment plan tailored to each patient. This involves dietary guidance, swallowing rehabilitation, and surgery in cases in which improvement with rehabilitation is inadequate. Surgery may involve altering certain pharyngolaryngeal structures to facilitate swallowing and reduce the risk of aspiration (swallowing improvement surgery) or separating the airway and digestive tract while sacrificing laryngeal function, with the main goal of preventing aspiration (aspiration prevention surgery). Proper management stems from recognizing the impact of these disorders on swallowing and consistently finding ways to improve the quality of life of patients.}, }
@article {pmid38201932, year = {2023}, author = {Sharma, H and Sharma, N and An, SSA}, title = {Unique Bioactives from Zombie Fungus (Cordyceps) as Promising Multitargeted Neuroprotective Agents.}, journal = {Nutrients}, volume = {16}, number = {1}, pages = {}, pmid = {38201932}, issn = {2072-6643}, support = {RS-2023-00251396 and 2021R1A6A1A03038996//National Research Foundation of Korea/ ; }, mesh = {*Neuroprotective Agents/pharmacology ; *Cordyceps ; *Agaricales ; Neuroprotection ; Adenosine ; }, abstract = {Cordyceps, also known as "zombie fungus", is a non-poisonous mushroom that parasitizes insects for growth and development by manipulating the host system in a way that makes the victim behave like a "zombie". These species produce promising bioactive metabolites, like adenosine, β-glucans, cordycepin, and ergosterol. Cordyceps has been used in traditional medicine due to its immense health benefits, as it boosts stamina, appetite, immunity, longevity, libido, memory, and sleep. Neuronal loss is the typical feature of neurodegenerative diseases (NDs) (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS)) and neurotrauma. Both these conditions share common pathophysiological features, like oxidative stress, neuroinflammation, and glutamatergic excitotoxicity. Cordyceps bioactives (adenosine, N[6]-(2-hydroxyethyl)-adenosine, ergosta-7, 9 (11), 22-trien-3β-ol, active peptides, and polysaccharides) exert potential antioxidant, anti-inflammatory, and anti-apoptotic activities and display beneficial effects in the management and/or treatment of neurodegenerative disorders in vitro and in vivo. Although a considerable list of compounds is available from Cordyceps, only a few have been evaluated for their neuroprotective potential and still lack information for clinical trials. In this review, the neuroprotective mechanisms and safety profile of Cordyceps extracts/bioactives have been discussed, which might be helpful in the identification of novel potential therapeutic entities in the future.}, }
@article {pmid38200398, year = {2024}, author = {Stenson, K and Fecteau, TE and O'Callaghan, L and Bryden, P and Mellor, J and Wright, J and Earl, L and Thomas, O and Iqbal, H and Barlow, S and Parvanta, S}, title = {Health-related quality of life across disease stages in patients with amyotrophic lateral sclerosis: results from a real-world survey.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2390-2404}, pmid = {38200398}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology/complications ; *Quality of Life ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; *Disease Progression ; Aged ; Adult ; Severity of Illness Index ; Surveys and Questionnaires ; Caregivers/psychology ; Neurologists ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by a rapid disease course, with disease severity being associated with declining health-related quality of life (HRQoL) in persons living with ALS (pALS). The main objective of this study was to assess the impact of disease progression on HRQoL across King's, Milano-Torino Staging (MiToS), and physician-judgement clinical staging. Additionally, we evaluated the impact of the disease on the HRQoL of care partners (cALS).<br><br>METHODS: Data were sourced from the Adelphi ALS Disease Specific Programme (DSP)&#x2122;, a cross-sectional survey of neurologists, pALS and cALS presenting in a real-world clinical setting between July 2020 and March 2021 in Europe and the United States.<br><br>RESULTS: Neurologists (n&#x2009;=&#x2009;142) provided data for 880 pALS. There were significant negative correlations between all three clinical staging systems and EuroQol (European Quality of Life) Five Dimension Five Level Scale (EQ-5D-5L) utility scores and visual analogue scale (VAS) ratings. Although not all differences were significant, 5-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5) scores showed a stepwise increase in HRQoL impairment at each stage of the disease regardless of the staging system. At later stages, high levels of fatigue and substantial activity impairment were reported. As pALS disease states progressed, cALS also experienced a decline in&#xa0;HRQoL and increased burden.<br><br>CONCLUSIONS: Across outcomes, pALS and cALS generally reported worse outcomes at later stages of the disease, highlighting an unmet need in this population for strategies to maximise QoL despite disease progression. Recognition and treatment of symptoms such as pain and fatigue may lead to improved outcomes for pALS and cALS.}, }
@article {pmid38198547, year = {2024}, author = {Perlegos, AE and Durkin, J and Belfer, SJ and Rodriguez, A and Shcherbakova, O and Park, K and Luong, J and Bonini, NM and Kayser, MS}, title = {TDP-43 impairs sleep in Drosophila through Ataxin-2-dependent metabolic disturbance.}, journal = {Science advances}, volume = {10}, number = {2}, pages = {eadj4457}, pmid = {38198547}, issn = {2375-2548}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; T32 HL007953/HL/NHLBI NIH HHS/United States ; P40 OD018537/OD/NIH HHS/United States ; F31 AG063470/AG/NIA NIH HHS/United States ; T32 MH014654/MH/NIMH NIH HHS/United States ; R01 AG071777/AG/NIA NIH HHS/United States ; R56 AG071777/AG/NIA NIH HHS/United States ; R01 GM084947/GM/NIGMS NIH HHS/United States ; F30 AG058409/AG/NIA NIH HHS/United States ; P40 OD010949/OD/NIH HHS/United States ; F32 NS117785/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis ; Ataxin-2 ; DNA-Binding Proteins/genetics ; Drosophila ; *Neurodegenerative Diseases ; }, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia are associated with substantial sleep disruption, which may accelerate cognitive decline and brain degeneration. Here, we define a role for trans-activation response element (TAR) DNA binding protein 43 (TDP-43), a protein associated with human neurodegenerative disease, in regulating sleep using Drosophila. Expression of TDP-43 severely disrupts sleep, and the sleep deficit is rescued by Atx2 knockdown. Brain RNA sequencing revealed that Atx2 RNA interference regulates transcripts enriched for small-molecule metabolic signaling in TDP-43 brains. Focusing on these Atx2-regulated genes, we identified suppressors of the TDP-43 sleep phenotype enriched for metabolism pathways. Knockdown of Atx2 or treatment with rapamycin attenuated the sleep phenotype and mitigated the disruption of small-molecule glycogen metabolism caused by TDP-43. Our findings provide a connection between toxicity of TDP-43 and sleep disturbances and highlight key aspects of metabolism that interplay with TDP-43 toxicity upon Atx2 rescue.}, }
@article {pmid38196621, year = {2023}, author = {Pottinger, TD and Motelow, JE and Povysil, G and Moreno, CAM and Ren, Z and Phatnani, H and ,  and Aitman, TJ and Santoyo-Lopez, J and ,  and Mitsumoto, H and ,  and Goldstein, DB and Harms, MB}, title = {Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38196621}, issn = {2693-5015}, support = {K01 MH098126/MH/NIMH NIH HHS/United States ; RC2 MH089915/MH/NIMH NIH HHS/United States ; P01 HD080642/HD/NICHD NIH HHS/United States ; R01 MH097971/MH/NIMH NIH HHS/United States ; RC2 NS070344/NS/NINDS NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UM1 AI100645/AI/NIAID NIH HHS/United States ; P30 AG028377/AG/NIA NIH HHS/United States ; U54 NS078059/NS/NINDS NIH HHS/United States ; P01 AG007232/AG/NIA NIH HHS/United States ; MC_PC_15080/MRC_/Medical Research Council/United Kingdom ; RF1 AG054023/AG/NIA NIH HHS/United States ; R01 HD048805/HD/NICHD NIH HHS/United States ; U01 HG007672/HG/NHGRI NIH HHS/United States ; U01 NS053998/NS/NINDS NIH HHS/United States ; U01 NS077303/NS/NINDS NIH HHS/United States ; U19 AI067854/AI/NIAID NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; R01 ES016348/ES/NIEHS NIH HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 30,000 people in the United States. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms, such as antisense oligonucleotides, continue to develop, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.<br><br>METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger cohort of 6,970 ALS patients from a large multi-ethnic cohort as well as 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.<br><br>RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR=19.18, p = 3.67 &#xd7; 10[-39]; OR=4.73, p = 2 &#xd7; 10[-10]; OR=2.3, p = 7.49 &#xd7; 10[-9], respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 &#xd7; 10[-7]), was protective for ALS in this model. An intolerant domain based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR=10.08, p = 3.62 &#xd7; 10[-16]). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p=8.38 &#xd7; 10[-6]).<br><br>CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, rare variant burden testing validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.}, }
@article {pmid38188011, year = {2023}, author = {Ansari, U and Chen, V and Sedighi, R and Syed, B and Muttalib, Z and Ansari, K and Ansari, F and Nadora, D and Razick, D and Lui, F}, title = {Role of the UNC13 family in human diseases: A literature review.}, journal = {AIMS neuroscience}, volume = {10}, number = {4}, pages = {388-400}, pmid = {38188011}, issn = {2373-7972}, abstract = {This literature review explores the pivotal roles of the Uncoordinated-13 (UNC13) protein family, encompassing UNC13A, UNC13B, UNC13C, and UNC13D, in the pathogenesis of various human diseases. These proteins, which are evolutionarily conserved and crucial for synaptic vesicle priming and exocytosis, have been implicated in a range of disorders, spanning from neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) to immune-related conditions such as familial hemophagocytic lymphohistiocytosis (FHL). The involvement of UNC13A in neurotransmitter release and synaptic plasticity is linked to ALS and FTD, with genetic variations affecting disease progression. UNC13B, which is closely related to UNC13A, plays a role in autism spectrum disorders (ASD), epilepsy, and schizophrenia. UNC13C is implicated in oral squamous cell carcinoma (OSCC) and hepatocellular carcinoma (HCC), and has a neuroprotective role in Alzheimer's disease (AD). UNC13D has an essential role in immune cell function, making it a key player in FHL. This review highlights the distinct molecular functions of each UNC13 family member and their implications in disease contexts, shedding light on potential therapeutic strategies and avenues for future research. Understanding these proteins' roles offers new insights into the management and treatment of neurological and immunological disorders.}, }
@article {pmid38187158, year = {2023}, author = {Yang, J and Liu, T and Zhang, L and Li, X and Du, FP and Liu, Q and Dong, H and Liu, Y}, title = {Eosinophils at diagnosis are elevated in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1289467}, pmid = {38187158}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare, devastating neurodegenerative disease that affects upper and lower motor neurons. To date, no effective treatment or reliable biomarker for ALS has been developed. In recent years, many factors have been proposed as possible biomarkers of ALS; however, no consensus has been reached. Therefore, a reliable biomarker is urgently needed. Eosinophils may play a crucial role in healthy humans and diseases, and serve as a biomarker for many chronic diseases.<br><br>METHODS: Routine blood test results were collected from 66 healthy controls and 59 patients with ALS. The percentages and total numbers of each cell population were analyzed, and the correlation between these indicators and patient ALS functional rating scale-revised (ALSFRS-R) score or disease progression rate (&#x394;FS score) was analyzed.<br><br>RESULTS: Compared to healthy controls, the number of blood leukocytes, neutrophils, monocytes, and basophils was significantly decreased in patients with ALS (p&#x2009;=&#x2009;0.002, p&#x2009;=&#x2009;0.001, p&#x2009;=&#x2009;0.049, and p&#x2009;<&#x2009;0.0001, respectively). There was an increase in the number of eosinophils (p&#x2009;<&#x2009;0.0001), but no difference in the number of lymphocytes between patients with ALS and healthy controls was found (p&#x2009;=&#x2009;0.563). Compared to healthy controls, the percentage of neutrophils was decreased and the percentage of lymphocytes and eosinophils was increased in patients with ALS (p&#x2009;=&#x2009;0.01, p&#x2009;=&#x2009;0.012, and p&#x2009;=&#x2009;0.001, respectively). There was no difference between patients with ALS and healthy controls in the percentage of monocytes and basophils (p&#x2009;=&#x2009;0.622 and p&#x2009;=&#x2009;0.09, respectively). However, only the percentage and number of eosinophils had a correlation with the &#x394;FS score. Further multivariate analysis revealed a significant correlation between the disease duration, eosinophil count and percentage, and the disease progression rate (p&#x2009;<&#x2009;0.0001, p&#x2009;=&#x2009;0.048, and p&#x2009;=&#x2009;0.023, respectively). The neutrophil-to-eosinophil ratio (NER), lymphocyte-to-eosinophil ratio (LER), and monocyte-to-eosinophil ratio (MER) were significantly lower in patients with ALS than in healthy controls. However, only the LER was significantly correlated with the &#x394;FS score.<br><br>CONCLUSION: These observations implicate neutrophils, lymphocytes, and eosinophils as important factors, and increasing eosinophil counts were negatively correlated with the &#x394;FS score in patients with ALS.}, }
@article {pmid38185999, year = {2024}, author = {Liu, Z and Qiang, Y and Shan, S and Wang, S and Song, F}, title = {Carbon disulfide induces accumulation of TDP-43 in the cytoplasm and mitochondrial dysfunction in rat spinal cords.}, journal = {Cerebral cortex (New York, N.Y. : 1991)}, volume = {34}, number = {2}, pages = {}, doi = {10.1093/cercor/bhad526}, pmid = {38185999}, issn = {1460-2199}, support = {82173552//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Rats ; Animals ; *Carbon Disulfide/metabolism ; *Neuroblastoma/metabolism/pathology ; Cytoplasm/metabolism ; DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/chemically induced/pathology ; Spinal Cord/pathology ; *Neurodegenerative Diseases/metabolism ; *Mitochondrial Diseases/metabolism/pathology ; }, abstract = {The relationship between environmental neurotoxicant exposure and neurodegenerative diseases is being extensively investigated. Carbon disulfide, a classic neurotoxicant and prototype of dithiocarbamates fungicides and anti-inflammatory agents, has been detected in urban adults, raising questions about whether exposure to carbon disulfide is associated with a high incidence of neurodegenerative diseases. Here, using rat models and SH-SY5Y cells, we investigated the possible mechanistic linkages between carbon disulfide neurotoxicity and the expression of TDP-43 protein, a marker of amyotrophic lateral sclerosis/frontotemporal lobar degeneration. Our results showed that rats exhibited severe dyskinesia and increased TDP-43 expression in the spinal cord following carbon disulfide exposure. Moreover, carbon disulfide exposure induced abnormal cytoplasmic localization and phosphorylation of TDP-43 in motor neurons. Importantly, carbon disulfide treatment led to the accumulation of TDP-43 in the mitochondria of motor neurons and resulted in subsequent mitochondrial damage, including mitochondrial structural disruption, mitochondrial respiratory chain complex I inhibition, and impaired VCP/p97-dependent mitophagy. In summary, our study provides support for carbon disulfide exposure-mediated TDP-43 mislocalization and mitochondrial dysfunction, contributes to understanding the pathogenesis of environmental neurotoxin-induced neurodegeneration, and provides inspiration for potential therapeutic strategies.}, }
@article {pmid38185101, year = {2024}, author = {Huber, T and Krüerke, D and Simões-Wüst, AP}, title = {How Physicians and Nursing Staff Perceive Effectiveness and Tolerability of Bryophyllum Preparations: An Online Survey in an Anthroposophic Hospital.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {116-123}, pmid = {38185101}, issn = {2504-2106}, abstract = {BACKGROUND: Bryophyllum preparations are widely used in anthroposophic medicine, most often for mental and behavioural disorders. Three prospective studies have revealed positive effects of Bryophyllum pinnatum on sleep quality, and various trials have shown very good tolerability. Results from animal models have indicated CNS depressant and anxiolytic effects. This survey was conducted at the hospital "Klinik Arlesheim" in Switzerland to find out how the physicians and the nursing staff perceive the effectiveness and the tolerability of the Bryophyllum preparations they most frequently use.<br><br>DESIGN: Internal, anonymous online survey of healthcare professionals (April 8-May 31, 2022). The questionnaire comprised 105 multiple-choice questions. Answering the questions was taken as consent to participate in the survey.<br><br>PARTICIPANTS AND METHODS: All physicians and nursing staff with a valid email address at the hospital "Klinik Arlesheim AG" were invited via email to participate in this REDCap survey. The data were analysed descriptively.<br><br>RESULTS: Out of 266 invited participants, 48 answered some and 36 answered all questions (response rate between 18.0% and 13.5%). The participants had long experience with Bryophyllum preparations and were comprised approximately equal numbers of physicians and nursing staff. Various Bryophyllum preparations from the hospital's own production and Wala Heilmittel GmbH (in both cases produced from the species B. daigremontianum) and from Weleda AG (species B. pinnatum) were used. The indications for which most participants had prescribed or administered Bryophyllum preparations "very frequently" were anxiety, sleep disorders, crisis situations in oncology, posttraumatic stress disorder, benzodiazepine dependence/withdrawal, and depression. Improvements such as relief from restlessness, decreased anxiety, balance, easier falling asleep, better sleeping through, increased resilience, mood elevation, and less urge to move one's legs were reported "frequently" or "very frequently." Almost all participants agreed that Bryophyllum can be used to reduce the intake of synthetic sedatives or psychotropic drugs, but only approximately half believed that it could replace them. The majority of participants mentioned good tolerability of the various products, but a few reported occasional stomach or intestinal irritation, daytime fatigue, drowsiness, diarrhoea, and nausea.<br><br>CONCLUSION: Bryophyllum preparations are perceived as helpful in the treatment of various mental disorders, particularly anxiety, and are generally well tolerated. Most of these preparations are used for indications that have not yet been clinically investigated.<br><br>UNLABELLED: <title>Hintergrund</title><italic>Bryophyllum</italic>-Pr&#xe4;parate werden in der Anthroposophischen Medizin sehr h&#xe4;ufig zur Behandlung von psychischen und Verhaltensst&#xf6;rungen eingesetzt. Drei prospektive Studien zeigten zudem positive Wirkungen von <italic>Bryophyllum pinnatum</italic> (<italic>BP</italic>) auf die Schlafqualit&#xe4;t. Auch die Vertr&#xe4;glichkeit wurde in allen bisherigen Studien als sehr gut bewertet. In Tiermodellen wurden ZNS-depressive und anxiolytische Effekte von BP festgestellt. Die hier durchgef&#xfc;hrte Umfrage fand an der Klinik Arlesheim (Schweiz) statt. Sie diente dazu herauszufinden, wie &#xc4;rztinnen und &#xc4;rzte sowie das Pflegepersonal die Wirksamkeit und Vertr&#xe4;glichkeit der von ihnen am h&#xe4;ufigsten verwendeten <italic>Bryophyllum</italic>-Pr&#xe4;parate wahrnehmen.<title>Design</title>Interne, anonyme, Online-Befragung unter &#xe4;rztlichen und pflegerischen Fachkr&#xe4;ften (8. April&#x2013;31. Mai 2022). Der Fragebogen umfasste 105 Multiple-Choice-Fragen. Die Beantwortung der Fragen wurde als Zustimmung zur Teilnahme an der Umfrage interpretiert.<title>Teilnehmende und Methoden</title>Alle &#xc4;rztinnen, &#xc4;rzte und Pflegefachpersonen mit einer g&#xfc;ltigen E-Mail-Adresse der &#x201c;Klinik Arlesheim AG&#x201d; wurden per E-Mail eingeladen, an dieser REDCap-Umfrage teilzunehmen. Die Daten wurden deskriptiv ausgewertet.<title>Ergebnisse</title>Von den 266 eingeladenen Teilnehmenden beantworteten 48 einige und 36 alle Fragen (Antwortquote zwischen 18.0% und 13.5%). Die Teilnehmenden hatten langj&#xe4;hrige Erfahrung mit <italic>Bryophyllum</italic>-Pr&#xe4;paraten und setzten sich etwa zu gleichen Teilen aus &#xe4;rztlichen und pflegerischen Fachkr&#xe4;ften zusammen. Die Resultate zeigen, dass verschiedenste Bryophyllum-Pr&#xe4;parate aus klinikeigener Herstellung, von der Wala Heilmittel GmbH (Art <italic>B. daigremontianum</italic>) und von der Weleda AG (Art <italic>B. pinnatum</italic>) verwendet werden. Zu den Indikationen, bei denen die meisten Teilnehmenden <italic>Bryophyllum</italic>-Pr&#xe4;parate &#x201c;sehr h&#xe4;ufig&#x201d; verordnet oder angewendet haben, geh&#xf6;ren Angstzust&#xe4;nde, Schlafst&#xf6;rungen, Krisensituationen in der Onkologie, Posttraumatische Belastungsst&#xf6;rung, Benzodiazepin-Abh&#xe4;ngigkeit/Entzug und Depressionen. Gesundheitsverbesserungen wie Linderung von Unruhe, verminderte Angst, Ausgeglichenheit, leichteres Einschlafen, besseres Durchschlafen, erh&#xf6;hte Belastbarkeit, Stimmungsaufhellung und weniger Drang, die Beine zu bewegen, wurden als &#x201c;h&#xe4;ufig&#x201d; oder &#x201c;sehr h&#xe4;ufig&#x201d; angegeben. Fast alle Teilnehmenden waren sich einig, dass <italic>Bryophyllum</italic> verwendet werden kann, um die Einnahme von synthetischen Beruhigungsmitteln oder Psychopharmaka zu reduzieren, aber nur etwa die H&#xe4;lfte gab an, dass es diese ersetzen kann. Die Mehrheit der Teilnehmenden spricht von einer guten Vertr&#xe4;glichkeit der verschiedenen Produkte. Einige wenige berichteten von gelegentlicher Magen- oder Darmreizung, Tagesm&#xfc;digkeit, Schl&#xe4;frigkeit, Durchfall und &#xdc;belkeit.<title>Schlussfolgerung</title><italic>Bryophyllum</italic>-Pr&#xe4;parate werden als hilfreich bei der Behandlung verschiedener psychischen St&#xf6;rungen, insbesondere bei Angstzust&#xe4;nden, angesehen und im Allgemeinen gut vertragen. Die meisten der angegebenen Pr&#xe4;parate werden f&#xfc;r Indikationen verwendet, die noch nicht klinisch untersucht worden sind.}, }
@article {pmid38180612, year = {2024}, author = {Lin, CY and Wu, HE and Weng, EF and Wu, HC and Su, TP and Wang, SM}, title = {Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB.}, journal = {Molecular neurobiology}, volume = {61}, number = {8}, pages = {5282-5294}, pmid = {38180612}, issn = {1559-1182}, mesh = {*Sigma-1 Receptor ; *Fluvoxamine/pharmacology ; *Receptors, sigma/metabolism ; *Autophagy/drug effects ; *Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Humans ; *Active Transport, Cell Nucleus/drug effects ; Animals ; Mice ; Cell Nucleus/metabolism/drug effects ; C9orf72 Protein/metabolism/genetics ; Cell Line ; }, abstract = {Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alzheimer's disease. Nevertheless, the mechanisms underlying Sigma-1R activation and its effect on (G4C2)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and stabilize the protein expression of Pom121 in (G4C2)31-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In C9orf72-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (G4C2)31-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, fluvoxamine may act as a promising repurposed medicine for patients with C9orf72-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G4C2)31-RNA-expressing NSC34 cells.}, }
@article {pmid38180358, year = {2024}, author = {Ferguson, R and van Es, MA and van den Berg, LH and Subramanian, V}, title = {Neural stem cell homeostasis is affected in cortical organoids carrying a mutation in Angiogenin.}, journal = {The Journal of pathology}, volume = {262}, number = {4}, pages = {410-426}, doi = {10.1002/path.6244}, pmid = {38180358}, issn = {1096-9896}, support = {084562/Z/07/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics/pathology ; *Neural Stem Cells/metabolism ; Mutation ; Homeostasis ; *Ribonuclease, Pancreatic ; }, abstract = {Mutations in Angiogenin (ANG) and TARDBP encoding the 43 kDa transactive response DNA binding protein (TDP-43) are associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). ANG is neuroprotective and plays a role in stem cell dynamics in the haematopoietic system. We obtained skin fibroblasts from members of an ALS-FTD family, one with mutation in ANG, one with mutation in both TARDBP and ANG, and one with neither mutation. We reprogrammed these fibroblasts to induced pluripotent stem cells (iPSCs) and generated cortical organoids as well as induced stage-wise differentiation of the iPSCs to neurons. Using these two approaches we investigated the effects of FTD-associated mutations in ANG and TARDBP on neural precursor cells, neural differentiation, and response to stress. We observed striking neurodevelopmental defects such as abnormal and persistent rosettes in the organoids accompanied by increased self-renewal of neural precursor cells. There was also a propensity for differentiation to later-born neurons. In addition, cortical neurons showed increased susceptibility to stress, which is exacerbated in neurons carrying mutations in both ANG and TARDBP. The cortical organoids and neurons generated from patient-derived iPSCs carrying ANG and TARDBP gene variants recapitulate dysfunctions characteristic of frontotemporal lobar degeneration observed in FTD patients. These dysfunctions were ameliorated upon treatment with wild type ANG. In addition to its well-established role during the stress response of mature neurons, ANG also appears to play a role in neural progenitor dynamics. This has implications for neurogenesis and may indicate that subtle developmental defects play a role in disease susceptibility or onset. © 2024 The Authors. The Journal of Pathology published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.}, }
@article {pmid38179776, year = {2023}, author = {Yang, EJ and Lee, SH}, title = {Anti-Inflammatory Effects of Chaenomeles sinensis Extract in an ALS Animal Model.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {28}, number = {12}, pages = {326}, doi = {10.31083/j.fbl2812326}, pmid = {38179776}, issn = {2768-6698}, support = {NRF-2020R1A2C2006703//National Research Foundation of Korea, South Korea/ ; KSN2212010//KIOM, South Korea/ ; C18040//KIOM, South Korea/ ; }, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Mice, Transgenic ; Disease Models, Animal ; Spinal Cord ; *Rosaceae/chemistry ; Antioxidants/pharmacology/therapeutic use ; Plant Extracts/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a systemic disease with multiple pathological effects, including neuroinflammation, oxidative stress, autophagy, mitochondrial dysfunction, and endoplasmic reticulum stress. Despite many studies seeking to identify and develop effective therapies, effective ALS treatment has yet to be approved. Hence, patients with ALS ultimately experience muscle atrophy and loss of motor neurons. Herbal medicines have been used to treat numerous diseases by modulating multiple biological processes and exerting pharmacological effects, including anti-inflammatory and antioxidant properties. In particular, Chaenomeles sinensis Koehne (CS) exhibits anti-hyperuricemic and nephroprotective effects and is used to treat anaphylaxis, viral infections, and neurodegenerative diseases, such as Alzheimer's disease. This study monitored the effects of CS supplementation on muscle function and motor neurons in hSOD1G93A mice, an established ALS animal model.<br><br>METHODS: Body weight measurements and behavioral tests were performed; additionally, western blotting and immunohistochemistry analyses were conducted using the mice gastrocnemius, tibialis anterior, and spinal cord.<br><br>RESULTS: CS augmented anti-inflammatory and antioxidant effects in the muscle and spinal cord of hSOD1G93A mice. Furthermore, CS improved motor function and regulated autophagy in the muscles of the hSOD1G93A mice.<br><br>CONCLUSIONS: CS might represent a promising supplement for improving motor function and delaying ALS progression. However, its development for clinical use warrants further investigation.}, }
@article {pmid38178841, year = {2023}, author = {Zhao, S and Chen, R and Gao, Y and Lu, Y and Bai, X and Zhang, J}, title = {Fundamental roles of the Optineurin gene in the molecular pathology of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1319706}, pmid = {38178841}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons (MNs) in the brain and spinal cord. It is caused by multiple factors, including mutations in any one of several specific genes. Optineurin (OPTN) mutation is an essential cause of some familial and sporadic ALS. Besides, as a multifunctional protein, OPTN is highly expressed and conserved in the central nervous system. OPTN exerts its functions by interacting with various proteins, often acting as an adaptor to provide a link between two or more core proteins related to autophagy and inflammation, etc. OPTN mutation mainly results in its function deficiency, which alters these interactions, leading to functional impairment in many processes. Meanwhile, OPTN immunopositive inclusions are also confirmed in the cases of ALS due to C9ORF72, FUS, TARDBP, and SOD1 mutations. Therefore, OPTN gene may play fundamental roles in the molecular pathology of ALS in addition to OPTN mutation. In this review, we summarize the recent advances in the ALS pathology of OPTN defect, such as mitophagy disorder, neuroinflammation, neuronal axonal degeneration, vesicular transport dysfunction, etc., which will provide a reference for research on the pathogenesis and treatment of ALS.}, }
@article {pmid38177242, year = {2024}, author = {Shi, Y and Huang, L and Dong, H and Yang, M and Ding, W and Zhou, X and Lu, T and Liu, Z and Zhou, X and Wang, M and Zeng, B and Sun, Y and Zhong, S and Wang, B and Wang, W and Yin, C and Wang, X and Wu, Q}, title = {Decoding the spatiotemporal regulation of transcription factors during human spinal cord development.}, journal = {Cell research}, volume = {34}, number = {3}, pages = {193-213}, pmid = {38177242}, issn = {1748-7838}, support = {81891001//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32122037//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; Humans ; *Transcription Factors/genetics ; *Amyotrophic Lateral Sclerosis ; Neurogenesis ; Central Nervous System ; }, abstract = {The spinal cord is a crucial component of the central nervous system that facilitates sensory processing and motor performance. Despite its importance, the spatiotemporal codes underlying human spinal cord development have remained elusive. In this study, we have introduced an image-based single-cell transcription factor (TF) expression decoding spatial transcriptome method (TF-seqFISH) to investigate the spatial expression and regulation of TFs during human spinal cord development. By combining spatial transcriptomic data from TF-seqFISH and single-cell RNA-sequencing data, we uncovered the spatial distribution of neural progenitor cells characterized by combinatorial TFs along the dorsoventral axis, as well as the molecular and spatial features governing neuronal generation, migration, and differentiation along the mediolateral axis. Notably, we observed a sandwich-like organization of excitatory and inhibitory interneurons transiently appearing in the dorsal horns of the developing human spinal cord. In addition, we integrated data from 10× Visium to identify early and late waves of neurogenesis in the dorsal horn, revealing the formation of laminas in the dorsal horns. Our study also illuminated the spatial differences and molecular cues underlying motor neuron (MN) diversification, and the enrichment of Amyotrophic Lateral Sclerosis (ALS) risk genes in MNs and microglia. Interestingly, we detected disease-associated microglia (DAM)-like microglia groups in the developing human spinal cord, which are predicted to be vulnerable to ALS and engaged in the TYROBP causal network and response to unfolded proteins. These findings provide spatiotemporal transcriptomic resources on the developing human spinal cord and potential strategies for spinal cord injury repair and ALS treatment.}, }
@article {pmid38174670, year = {2023}, author = {Maksymowicz-Śliwińska, A and Lulé, D and Nieporęcki, K and Ciećwierska, K and Ludolph, AC and Kuźma-Kozakiewicz, M}, title = {Attitudes of caregivers towards prolonging and shortening life in advanced stages of amyotrophic lateral sclerosis.}, journal = {Folia neuropathologica}, volume = {61}, number = {4}, pages = {349-359}, doi = {10.5114/fn.2023.130444}, pmid = {38174670}, issn = {1509-572X}, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/therapy ; Quality of Life ; Caregivers ; Death ; Disease Progression ; }, abstract = {INTRODUCTION: Inevitable disease progression in amyotrophic lateral sclerosis (ALS) forces patients and their caregivers (CGs) to reflect on end-of-life treatment. The CGs are often heavily burdened with their role of surrogate decision-makers. The aim of the study was to analyze attitudes of CGs and presumable attitudes of ALS patients from the CGs' perspective towards palliative care in advanced disease stages.<br><br>MATERIAL AND METHODS: One hundred and sixty four CGs from Germany and Poland were interviewed regarding their own preferences and patients' ideational attitudes towards life-prolonging (invasive and non-invasive ventilation, tube feeding) and life-shortening methods (termination of measures, active measures if permitted by law). The data were correlated with patient- and CG-related factors: demographic and clinical data, care commitment, depression and quality of life (QoL).<br><br>RESULTS: The CGs were mostly female spouses of ALS patients, with secondary/higher education. Nearly 70% (81% in Poland, 57% in Germany; p = 0.0001) reported positive attitudes towards life-prolonging methods, which positively correlated with religiousness and negatively with patients' age. Approximately 40% of CGs (25% and 51% respectively; p = 0.001) reported positive attitudes towards life-shortening methods. It positively correlated with time since diagnosis and negatively with the CG's QoL, religiosity and religious/spiritual faith as factors that significantly influenced end-of-life decisions. There was a strongly positive correlation between CGs' positive attitudes towards life-shortening methods and presumed positive patients' attitudes assessed by their CGs (p < 0.000001).<br><br>CONCLUSIONS: Although attitudes towards treatment differed between countries, the CGs of ALS patients were generally positive towards life-prolonging treatment. A greater acceptance of life-shortening methods in the case of longer disease duration and poorer QoL may indicate worse coping with disease progression and weaker adaptation mechanisms in CGs compared to those previously reported in ALS patients. A close resemblance of the CGs' answers to probable patients' attitudes reported by the CGs indicates that many GCs might actually express their own culturally shaped attitudes towards end-of-life methods. In light of earlier-reported discrepancies between presumed opinions of the CGs and of patients themselves, a greater focus should be placed on thorough discussions on future treatment options with ALS patients in the presence of their CGs, to stay in line with the patient's authentic will.}, }
@article {pmid38158673, year = {2023}, author = {Luo, S and Yang, L and Ma, B and Wang, X and Lu, Y and Ma, S and Wang, D and Qu, H and Zou, L}, title = {Explore the pharmacological basis of ShengJiYiSui decoction in the treatment of amyotrophic lateral sclerosis based on network pharmacology and molecular docking technology.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {69}, number = {13}, pages = {156-161}, doi = {10.14715/cmb/2023.69.13.24}, pmid = {38158673}, issn = {1165-158X}, mesh = {Humans ; Network Pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Molecular Docking Simulation ; Phosphatidylinositol 3-Kinases/genetics ; Proto-Oncogene Proteins c-akt ; Medicine, Chinese Traditional ; Technology ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative illnesses have long been handled clinically by traditional Chinese medicine. This study is the first time to explore the pharmacological basis of application in amyotrophic lateral sclerosis (ALS) through network pharmacology and molecular docking techniques. In the present investigation, the TCMSP database and HIT2 database were examined for 9 TCM constituents of Sheng Ji Yu Sui Decoction (SJYSD), and the desired sites for the components were searched in the Drugbank database. and the Sjysd-target network was constructed. Associated targets for Amyotrophic lateral sclerosis (ALS) were then retrieved and collected in the OMIM, TTD, Genecards and DisGeNET databases. Protein-protein interaction and enrichment analysis were performed for the common targets of drugs and diseases, and molecular anchoring for the chosen core targets and related molecules was carried out. The results showed that SJYSD had 100 active compounds corresponding to 598 targets. ALS has a total of 5,325 genes. SJYSD and ALS share 163 genes, and these targets involve PI3K-AKT signaling, p53 signaling and IL-17 signaling, etc. The core components of luteolin and quercetin were discovered and may be used to treat ALS by regulating PI3K-AKT signaling pathway by HSP90AB1 protein.}, }
@article {pmid38157654, year = {2024}, author = {Halseth, M and Mahoney, R and Hsiou, J and Jones, HN and Kimonis, V}, title = {Remote respiratory resistance exercise training improves respiratory function in individuals with VCP multisystem proteinopathy.}, journal = {Neuromuscular disorders : NMD}, volume = {34}, number = {}, pages = {68-74}, doi = {10.1016/j.nmd.2023.12.001}, pmid = {38157654}, issn = {1873-2364}, mesh = {Adult ; Humans ; Valosin Containing Protein/genetics ; *Resistance Training ; *Muscular Diseases ; Respiration ; *Frontotemporal Dementia ; *Amyotrophic Lateral Sclerosis ; Mutation ; Cell Cycle Proteins/genetics ; }, abstract = {Valosin-containing protein (VCP) disease is an autosomal dominant multisystem proteinopathy associated with hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Myopathy frequently results in respiratory muscle weakness, leading to early mortality due to respiratory failure. We investigated the effects of a remotely administered inspiratory muscle training program in individuals with VCP disease. Nine adults with VCP mutation-positive familial myopathy without evidence of dementia were recruited for a 40-week remotely administered study. Baseline performance was established during the first 8 weeks, followed by 32 weeks of inspiratory muscle training. The primary outcome was maximum inspiratory pressure (MIP). The secondary and exploratory endpoints included spirometry, grip strength, Inclusion Body Myopathy Functional Rating Scale (IBMFRS), Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS), timed up and go, and six-minute walk test (6MWT). During the treatment phase, MIP increased significantly by a weekly mean of 0.392cm. H2O (p=0.023). In contrast, grip strength and ALSFRS significantly decreased by 0.088 lbs. (p=0.031) and 0.043 points (p=0.004) per week, respectively, as expected from the natural progression of this disease. A remotely administered inspiratory muscle training program is therefore feasible, safe, and well-tolerated in individuals with VCP disease and results in improved inspiratory muscle strength.}, }
@article {pmid38157256, year = {2023}, author = {Kang, Q and Jiang, S and Min, J and Hu, F and Xu, R}, title = {Parvalbumin interneurons dysfunction is potentially associated with FαMNs decrease and NRG1-ErbB4 signaling inhibition in spinal cord in amyotrophic lateral sclerosis.}, journal = {Aging}, volume = {15}, number = {24}, pages = {15324-15339}, pmid = {38157256}, issn = {1945-4589}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; *Interneurons/metabolism ; Matrix Metalloproteinase 9/metabolism ; Mice, Transgenic ; Parvalbumins/metabolism ; Receptor, ErbB-4/genetics/metabolism ; Neuregulin-1/genetics/metabolism ; }, abstract = {OBJECTIVE: To investigate the alteration of PV interneurons in ALS mainly focusing its dynamic changes and its relationship with motor neurons and ErbB4 signaling.<br><br>METHODS: SOD1G93A mice were used as ALS model. ALS animals were divided into different groups according to birth age: symptomatic prophase (50~60 days), symptomatic phase (90~100 days), and symptomatic progression (130~140 days). Immunofluorescence was performed for measurement of PV-positive interneurons, MMP-9, ChAT, NeuN and ErbB4. RT-qPCR and western blot were used to determine the expression of PV and MMP-9.<br><br>RESULTS: PV expression was remarkably higher in the anterior horn of gray matter compared with posterior horn and area in the middle of gray matter in control mice. In ALS mice, PV, MMP-9 and ErbB4 levels were gradually decreased along with onset. PV, MMP-9 and ErbB4 levels in ALS mice were significantly down-regulated than control mice after onset, indicating the alteration of PV interneurons, F&#x3b1;MNs and ErbB4. S&#x3b1;MNs levels only decreased remarkably at symptomatic progression in ALS mice compared with control mice, while &#x3b3;MNs levels showed no significant change during whole period in all mice. MMP-9 and ErbB4 were positively correlated with PV. NRG1 treatment significantly enhanced the expression of ErBb4, PV and MMP-9 in ALS mice.<br><br>CONCLUSION: PV interneurons decrease is along with F&#x3b1;MNs and ErbB4 decrease in ALS mice.}, }
@article {pmid38151482, year = {2024}, author = {Taha, MA and Morren, JA}, title = {The role of artificial intelligence in electrodiagnostic and neuromuscular medicine: Current state and future directions.}, journal = {Muscle &amp; nerve}, volume = {69}, number = {3}, pages = {260-272}, doi = {10.1002/mus.28023}, pmid = {38151482}, issn = {1097-4598}, mesh = {Humans ; *Artificial Intelligence ; Machine Learning ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Brain ; Electromyography ; }, abstract = {The rapid advancements in artificial intelligence (AI), including machine learning (ML), and deep learning (DL) have ushered in a new era of technological breakthroughs in healthcare. These technologies are revolutionizing the way we utilize medical data, enabling improved disease classification, more precise diagnoses, better treatment selection, therapeutic monitoring, and highly accurate prognostication. Different ML and DL models have been used to distinguish between electromyography signals in normal individuals and those with amyotrophic lateral sclerosis and myopathy, with accuracy ranging from 67% to 99.5%. DL models have also been successfully applied in neuromuscular ultrasound, with the use of segmentation techniques achieving diagnostic accuracy of at least 90% for nerve entrapment disorders, and 87% for inflammatory myopathies. Other successful AI applications include prediction of treatment response, and prognostication including prediction of intensive care unit admissions for patients with myasthenia gravis. Despite these remarkable strides, significant knowledge, attitude, and practice gaps persist, including within the field of electrodiagnostic and neuromuscular medicine. In this narrative review, we highlight the fundamental principles of AI and draw parallels with the intricacies of human brain networks. Specifically, we explore the immense potential that AI holds for applications in electrodiagnostic studies, neuromuscular ultrasound, and other aspects of neuromuscular medicine. While there are exciting possibilities for the future, it is essential to acknowledge and understand the limitations of AI and take proactive steps to mitigate these challenges. This collective endeavor holds immense potential for the advancement of healthcare through the strategic and responsible integration of AI technologies.}, }
@article {pmid38148559, year = {2024}, author = {Gautam, S and Latif, S and Kang, YS}, title = {Effect of Various Pathological Conditions on Nitric Oxide Level and L-Citrulline Uptake in Motor Neuron-Like (NSC-34) Cell Lines.}, journal = {Biomolecules &amp; therapeutics}, volume = {32}, number = {1}, pages = {154-161}, pmid = {38148559}, issn = {1976-9148}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder that causes progressive paralysis. L-Citrulline is a non-essential neutral amino acid produced by L-arginine via nitric oxide synthase (NOS). According to previous studies, the pathogenesis of ALS entails glutamate toxicity, oxidative stress, protein misfolding, and neurofilament disruption. In addition, L-citrulline prevents neuronal cell death in brain ischemia; therefore, we investigated the change in the transport of L-citrulline under various pathological conditions in a cell line model of ALS. We examined the uptake of [[14]C]L-citrulline in wild-type (hSOD1wt/WT) and mutant NSC-34/ SOD1[G93A] (MT) cell lines. The cell viability was determined via MTT assay. A transport study was performed to determine the uptake of [[14]C]L-citrulline. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed to determine the expression levels of rat large neutral amino acid transported 1 (rLAT1) in ALS cell lines. Nitric oxide (NO) assay was performed using Griess reagent. L-Citrulline had a restorative effect on glutamate induced cell death, and increased [[14]C]L-citrulline uptake and mRNA levels of the large neutral amino acid transporter (LAT1) in the glutamate-treated ALS disease model (MT). NO levels increased significantly when MT cells were pretreated with glutamate for 24 h and restored by co-treatment with L-citrulline. Co-treatment of MT cells with L-arginine, an NO donor, increased NO levels. NSC-34 cells exposed to high glucose conditions showed a significant increase in [[14]C]L-citrulline uptake and LAT1 mRNA expression levels, which were restored to normal levels upon co-treatment with unlabeled L-citrulline. In contrast, exposure of the MT cell line to tumor necrosis factor alpha, lipopolysaccharides, and hypertonic condition decreased the uptake significantly which was restored to the normal level by co-treating with unlabeled L-citrulline. L-Citrulline can restore NO levels and cellular uptake in ALS-affected cells with glutamate cytotoxicity, pro-inflammatory cytokines, or other pathological states, suggesting that L-citrulline supplementation in ALS may play a key role in providing neuroprotection.}, }
@article {pmid38143551, year = {2023}, author = {Kasindi, A and Carstarphen, KJ}, title = {Bulbar Onset Amyotrophic Lateral Sclerosis in an African American Older Adult.}, journal = {Ochsner journal}, volume = {23}, number = {4}, pages = {353-356}, pmid = {38143551}, issn = {1524-5012}, abstract = {Background: Amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease, affects the motor tracts and anterior horn cells of the spinal cord, causing both upper and lower motor neuron dysfunction. ALS typically involves progressive peripheral weakness and mobility issues. Case Report: An African American male in his early 70s presented to his primary care provider (PCP) with bulbar weakness and urinary tract symptoms. At presentation, and even later in the disease course, he ambulated well and did not report any limb issues. After some months of worsening symptoms of dyspnea, dysarthria, dysphagia, and urinary incontinence, a diagnosis of ALS was made via collaborative work between the PCP, a medical student, and various medical specialists including a neurosurgeon and neurologist. Because of the absence of limb abnormalities, the patient had difficulty accepting a diagnosis of ALS, thus delaying treatment onset. Conclusion: Clinicians must consider the patient's presentation holistically so that they do not miss insidious, complex, or unique presentations. ALS can present with bulbar symptoms early in the disease course with no upper motor neuron/lower motor neuron involvement. Older adult African American males can present with ALS. Mistrust of health care systems and resistance to science based on religious beliefs can impact patient acceptance of diagnoses and engagement in treatments. Having a long-term relationship with a PCP who also represents the patient's community can influence patient willingness to accept diagnoses, especially those that are life-limiting.}, }
@article {pmid38135852, year = {2024}, author = {Huang, J and Yu, Y and Pang, D and Li, C and Wei, Q and Cheng, Y and Cui, Y and Ou, R and Shang, H}, title = {Lnc-HIBADH-4 Regulates Autophagy-Lysosome Pathway in Amyotrophic Lateral Sclerosis by Targeting Cathepsin D.}, journal = {Molecular neurobiology}, volume = {61}, number = {7}, pages = {4768-4782}, pmid = {38135852}, issn = {1559-1182}, support = {81871000//National Natural Science Foundation of China/ ; 82101485//National Natural Science Foundation of China/ ; 2022ZYD0051//Sichuan Province Science and Technology Support Program/ ; No.2022NSFSC0750//Sichuan Province Science and Technology Support Program/ ; }, mesh = {Humans ; *Autophagy/physiology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; *Lysosomes/metabolism ; *Cathepsin D/metabolism/genetics ; Male ; Female ; Signal Transduction ; MicroRNAs/genetics/metabolism ; Apoptosis/genetics ; Middle Aged ; Cell Proliferation ; Down-Regulation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most prevalent and lethal class of severe motor neuron diseases (MND) with no efficacious treatment. The pathogenic mechanisms underlying ALS remain unclear. Nearly 90% of patients exhibit sporadic onset (sALS). Therefore, elucidating the pathophysiology of ALS is imperative. Long non-coding RNA (lncRNA) is a large class of non-coding RNAs that regulate transcription, translation, and post-translational processes. LncRNAs contribute to the pathogenesis of diverse neurodegenerative disorders and hold promise as targets for interference in the realm of neurodegeneration. However, the mechanisms of which lncRNAs are involved in ALS have not been thoroughly investigated. We identified and validated a downregulated lncRNA, lnc-HIBADH-4, in ALS which correlated with disease severity and overall survival. Lnc-HIBADH-4 acted as a "molecular sponge" regulating lysosomal function through the lnc-HIBADH-4/miR-326/CTSD pathway, thereby impacting autophagy-lysosome dynamics and the levels of cell proliferation and apoptosis. Therefore, this study discovered and revealed the role of lnc-HIBADH-4 in the pathogenesis of ALS. With further research, lnc-HIBADH-4 is expected to provide a new biomarker in the diagnosis and treatment of ALS.}, }
@article {pmid38129934, year = {2023}, author = {Marriott, H and Kabiljo, R and Hunt, GP and Khleifat, AA and Jones, A and Troakes, C and ,  and ,  and Pfaff, AL and Quinn, JP and Koks, S and Dobson, RJ and Schwab, P and Al-Chalabi, A and Iacoangeli, A}, title = {Unsupervised machine learning identifies distinct ALS molecular subtypes in post-mortem motor cortex and blood expression data.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {208}, pmid = {38129934}, issn = {2051-5960}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; Motor Neurone Disease Association/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Unsupervised Machine Learning ; *Motor Cortex/metabolism ; Brain/pathology ; Autopsy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) displays considerable clinical and genetic heterogeneity. Machine learning approaches have previously been utilised for patient stratification in ALS as they can disentangle complex disease landscapes. However, lack of independent validation in different populations and tissue samples have greatly limited their use in clinical and research settings. We overcame these issues by performing hierarchical clustering on the 5000 most variably expressed autosomal genes from motor cortex expression data of people with sporadic ALS from the KCL BrainBank (N = 112). Three molecular phenotypes linked to ALS pathogenesis were identified: synaptic and neuropeptide signalling, oxidative stress and apoptosis, and neuroinflammation. Cluster validation was achieved by applying linear discriminant analysis models to cases from TargetALS US motor cortex (N = 93), as well as Italian (N = 15) and Dutch (N = 397) blood expression datasets, for which there was a high assignment probability (80-90%) for each molecular subtype. The ALS and motor cortex specificity of the expression signatures were tested by mapping KCL BrainBank controls (N = 59), and occipital cortex (N = 45) and cerebellum (N = 123) samples from TargetALS to each cluster, before constructing case-control and motor cortex-region logistic regression classifiers. We found that the signatures were not only able to distinguish people with ALS from controls (AUC 0.88 ± 0.10), but also reflect the motor cortex-based disease process, as there was perfect discrimination between motor cortex and the other brain regions. Cell types known to be involved in the biological processes of each molecular phenotype were found in higher proportions, reinforcing their biological interpretation. Phenotype analysis revealed distinct cluster-related outcomes in both motor cortex datasets, relating to disease onset and progression-related measures. Our results support the hypothesis that different mechanisms underpin ALS pathogenesis in subgroups of patients and demonstrate potential for the development of personalised treatment approaches. Our method is available for the scientific and clinical community at https://alsgeclustering.er.kcl.ac.uk .}, }
@article {pmid38127305, year = {2023}, author = {Lester, EG and Vitolo, OV and Flaherty, A and Beaussant, Y and Cramer, M and Harley, R and Cohen, JN}, title = {"When Will All of This End?": A 65-Year-Old Man With Amyotrophic Lateral Sclerosis and Psychiatric Distress.}, journal = {The Journal of clinical psychiatry}, volume = {85}, number = {1}, pages = {}, doi = {10.4088/JCP.23ct15038}, pmid = {38127305}, issn = {1555-2101}, mesh = {Aged ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/therapy ; *Cognitive Behavioral Therapy ; Psychotherapy ; *Psychological Distress ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) are impacted both physically and psychiatrically during their illness. Emotional distress (ie, anxiety, depression, stress) is common in patients diagnosed with ALS, as prognosis is poor and there are very few effective treatments. The progression of symptoms is unpredictable, and all cases are terminal. Neuropsychiatric symptoms are also increasingly recognized as part of ALS symptomatology. There are currently no empirically supported interventions or best practices for adjustment to ALS. This case presents both the psychological and pharmacologic aspects of caring for a patient with ALS. Psychotherapy utilized a cognitive behavioral therapy-informed approach, and pharmacotherapy was tailored to the specific needs of the patient. We explore how these approaches impacted our patient, as well as how ALS-specific challenges presented throughout the course of treatment.}, }
@article {pmid38112783, year = {2024}, author = {Libonati, L and Cambieri, C and Colavito, D and Moret, F and D'Andrea, E and Del Giudice, E and Leon, A and Inghilleri, M and Ceccanti, M}, title = {Genetics screening in an Italian cohort of patients with Amyotrophic Lateral Sclerosis: the importance of early testing and its implication.}, journal = {Journal of neurology}, volume = {271}, number = {4}, pages = {1921-1936}, pmid = {38112783}, issn = {1432-1459}, mesh = {Humans ; Mutation ; *Amyotrophic Lateral Sclerosis/epidemiology ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; *Neurodegenerative Diseases ; Italy ; Heat-Shock Proteins/genetics ; Molecular Chaperones/genetics ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with an elusive etiology. While environmental factors have been considered, familial ALS cases have raised the possibility of genetic involvement. This genetic connection is increasingly evident, even in patients with sporadic ALS. We allowed access to the genetic test to all patients attending our clinic to identify the prevalence and the role of genetic variants in the development of the disease and to identify patients with potentially treatable forms of the disease.<br><br>MATERIALS AND METHODS: 194 patients with probable or definite ALS, were enrolled. A comprehensive genetic testing was performed, including sequencing all exons of the SOD1 gene and testing for hexanucleotide intronic repeat expansions (G4C2) in the C9orf72 gene using fluorescent repeat-primed PCR (RP-PCR). Whole Exome NGS Sequencing (WES) was performed, followed by an in silico multigene panel targeting neuromuscular diseases, spastic paraplegia, and motor distal neuropathies. We conducted statistical analyses to compare different patient groups.<br><br>RESULTS: Clinically significant pathogenetic variants were detected in 14.43% of cases. The highest prevalence of pathogenetic variants was observed in fALS patients, but a substantial proportion of sALS patients also displayed at least one variant, either pathogenetic or of uncertain significance (VUS). The most observed pathogenetic variant was the expansion of the C9orf72 gene, which was associated with a shorter survival. SOD1 variants were found in 1.6% of fALS and 2.5% of sALS patients.<br><br>DISCUSSION: The study reveals a significant number of ALS patients carrying pathogenic or likely pathogenic variants, with a higher prevalence in familial ALS cases. The expansion of the C9orf72 gene emerges as the most common genetic cause of ALS, affecting familial and sporadic cases. Additionally, SOD1 variants are detected at an unexpectedly higher rate, even in patients without a familial history of ALS, underscoring the crucial role of genetic testing in treatment decisions and potential participation in clinical trials. We also investigated variants in genes such as TARDBP, FUS, NEK1, TBK1, and DNAJC7, shedding light on their potential involvement in ALS. These findings underscore the complexity of interpreting variants of uncertain significance (VUS) and their ethical implications in patient communication and genetic counseling for patients' relatives.<br><br>CONCLUSION: This study emphasizes the diverse genetic basis of ALS and advocates for integrating comprehensive genetic testing into diagnostic protocols. The evolving landscape of genetic therapies requires identifying all eligible patients transcending traditional familial boundaries. The presence of VUS highlights the multifaceted nature of ALS genetics, prompting further exploration of complex interactions among genetic variants, environmental factors, and disease development.}, }
@article {pmid38112345, year = {2024}, author = {Battaglini, M and Marino, A and Montorsi, M and Carmignani, A and Ceccarelli, MC and Ciofani, G}, title = {Nanomaterials as Microglia Modulators in the Treatment of Central Nervous System Disorders.}, journal = {Advanced healthcare materials}, volume = {13}, number = {12}, pages = {e2304180}, doi = {10.1002/adhm.202304180}, pmid = {38112345}, issn = {2192-2659}, mesh = {*Microglia/drug effects/metabolism ; Humans ; *Nanostructures/chemistry ; Animals ; *Central Nervous System Diseases/drug therapy/metabolism ; Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {Microglia play a pivotal role in the central nervous system (CNS) homeostasis, acting as housekeepers and defenders of the surrounding environment. These cells can elicit their functions by shifting into two main phenotypes: pro-inflammatory classical phenotype, M1, and anti-inflammatory alternative phenotype, M2. Despite their pivotal role in CNS homeostasis, microglia phenotypes can influence the development and progression of several CNS disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, ischemic stroke, traumatic brain injuries, and even brain cancer. It is thus clear that the possibility of modulating microglia activation has gained attention as a therapeutic tool against many CNS pathologies. Nanomaterials are an unprecedented tool for manipulating microglia responses, in particular, to specifically target microglia and elicit an in situ immunomodulation activity. This review focuses the discussion on two main aspects: analyzing the possibility of using nanomaterials to stimulate a pro-inflammatory response of microglia against brain cancer and introducing nanostructures able to foster an anti-inflammatory response for treating neurodegenerative disorders. The final aim is to stimulate the analysis of the development of new microglia nano-immunomodulators, paving the way for innovative and effective therapeutic approaches for the treatment of CNS disorders.}, }
@article {pmid38110502, year = {2023}, author = {Ludolph, AC and Grandjean, H and Reviers, E and De Micheli, V and Bianchi, C and Cardosi, L and Russ, H and Silani, V}, title = {The preferences of people with amyotrophic lateral sclerosis on riluzole treatment in Europe.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {22497}, pmid = {38110502}, issn = {2045-2322}, mesh = {Humans ; Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Suspensions ; Europe ; *Airway Obstruction ; Tablets ; *Neuroprotective Agents ; }, abstract = {The Patient Preference Survey aims to understand unmet needs related to riluzole management in people with Amyotrophic Lateral Sclerosis (ALS) and to identify which characteristics of a new formulation could better match their preferences. The survey involved 117 people with ALS (PALS) treated with riluzole in four European countries. The dysphagic PALS were least satisfied with the riluzole tablet and oral suspension and with ease in self-administration; up to 68% of respondents postponed or missed the treatment due to swallowing difficulties and need of caregiver assistance. Overall, 51% of tablet and 53% of oral suspension users regularly crushed or mixed riluzole with beverages, respectively; PALS who always manipulated riluzole showed low satisfaction with the formulation and considered the risk of choking and pneumonia the most worrisome event. The survey evaluated the driving factors in choosing/switching the therapy: 67% of PALS declared a low risk of choking. The research finally evaluated which attributes of a new formulation would be preferred: the most relevant were ease of use (4.3/5), convenient/portable packaging (4.0/5) and oral-dissolving properties without tongue motility (3.9/5). The Patient Preference Survey suggests that patients have several unmet needs and preferences that could be addressed by a different formulation, e.g. using oral film technologies.}, }
@article {pmid38110144, year = {2024}, author = {Hafner, C and Manschein, V and Klaus, DA and Schaubmayr, W and Tiboldi, A and Scharner, V and Gleiss, A and Thal, B and Krammel, M and Hamp, T and Willschke, H and Hermann, M}, title = {Live stream of prehospital point-of-care ultrasound during cardiopulmonary resuscitation - A feasibility trial.}, journal = {Resuscitation}, volume = {194}, number = {}, pages = {110089}, doi = {10.1016/j.resuscitation.2023.110089}, pmid = {38110144}, issn = {1873-1570}, support = {21044//Medical Scientific Fund of the Mayor of the City of Vienna/ ; }, mesh = {Humans ; *Cardiopulmonary Resuscitation/methods ; *Emergency Medical Services/methods ; Feasibility Studies ; *Out-of-Hospital Cardiac Arrest/diagnostic imaging/therapy ; Point-of-Care Systems ; }, abstract = {BACKGROUND: Current resuscitation guidelines recommend that skilled persons could use ultrasound to detect reversible causes during cardiopulmonary resuscitation (CPR) where the examination can be safely integrated into the Advanced Life Support (ALS) algorithm. However, in a prehospital setting performing and rapidly interpreting ultrasound can be challenging for physicians. Implementing remote, expert-guided, and real-time transmissions of ultrasound examinations offers the opportunity for tele-support, even during an out-of-hospital cardiac arrest (OHCA). The aim of this feasibility study was to evaluate the impact of tele-supported ultrasound in ALS on hands-off time during an OHCA.<br><br>METHODS: In an urban setting, physicians performed point-of-care ultrasound (POCUS) on patients during OHCA using a portable device, either with tele-support (n&#xa0;=&#xa0;30) or without tele-support (n&#xa0;=&#xa0;12). Where tele-support was used, the ultrasound image was transmitted via a remote real-time connection to an on-call specialist in anaesthesia and intensive care medicine with an advanced level of critical care ultrasound expertise. The primary safety endpoint of this study was to evaluate whether POCUS can be safely integrated into the algorithm, and to provide an analysis of hands-off time before, during, and after POCUS during OHCA.<br><br>RESULTS: In all 42 cases it was possible to perform POCUS during regular rhythm analyses, and no additional hands-off time was required. In 40 of these 42 cases, the physicians were able to perform POCUS during a single regular rhythm analysis, with two periods required only in two cases. The median hands-off time during these rhythm analyses for POCUS with tele-support was 10 (8-13) seconds, and 11 (9-14) seconds for POCUS without tele-support. Furthermore, as a result of POCUS, in a quarter of all cases the physician on scene altered their diagnosis of the primary suspected cause of cardiac arrest, leading to a change in treatment strategy.<br><br>CONCLUSIONS: This feasibility study demonstrated that POCUS with tele-support can be safely performed during OHCA in an urban environment. Trial Registration (before patient enrolment): ClinicalTrials.gov, NCT04817475.}, }
@article {pmid38108952, year = {2024}, author = {Xiao, X and Rui, Y and Jin, Y and Chen, M}, title = {Relationship of Sleep Disorder with Neurodegenerative and Psychiatric Diseases: An Updated Review.}, journal = {Neurochemical research}, volume = {49}, number = {3}, pages = {568-582}, pmid = {38108952}, issn = {1573-6903}, support = {82371541//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Alzheimer Disease/metabolism ; Brain/metabolism ; *Huntington Disease/metabolism ; *Sleep Wake Disorders/metabolism ; }, abstract = {Sleep disorders affect many people worldwide and can accompany neurodegenerative and psychiatric diseases. Sleep may be altered before the clinical manifestations of some of these diseases appear. Moreover, some sleep disorders affect the physiological organization and function of the brain by influencing gene expression, accelerating the accumulation of abnormal proteins, interfering with the clearance of abnormal proteins, or altering the levels of related hormones and neurotransmitters, which can cause or may be associated with the development of neurodegenerative and psychiatric diseases. However, the detailed mechanisms of these effects are unclear. This review mainly focuses on the relationship between and mechanisms of action of sleep in Alzheimer's disease, depression, and anxiety, as well as the relationships between sleep and Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This summary of current research hotspots may provide researchers with better clues and ideas to develop treatment solutions for neurodegenerative and psychiatric diseases associated with sleep disorders.}, }
@article {pmid38105307, year = {2024}, author = {Hamad, AA and Amer, BE and Hawas, Y and Mabrouk, MA and Meshref, M}, title = {Masitinib as a neuroprotective agent: a scoping review of preclinical and clinical evidence.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {1861-1873}, pmid = {38105307}, issn = {1590-3478}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; *Benzamides/pharmacology/therapeutic use ; *Thiazoles/pharmacology/therapeutic use ; *Piperidines/pharmacology/therapeutic use ; *Pyridines/pharmacology/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; }, abstract = {OBJECTIVES: Masitinib, originally developed as a tyrosine kinase inhibitor for cancer treatment, has shown potential neuroprotective effects in various neurological disorders by modulating key pathways implicated in neurodegeneration. This scoping review aimed to summarize the current evidence of masitinib's neuroprotective activities from preclinical to clinical studies.<br><br>METHODS: This scoping review was conducted following the guidelines described by Arksey and O'Malley and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The inclusion criteria covered all original studies reporting on the neuroprotective effects of masitinib, including clinical studies, animal studies, and in vitro studies.<br><br>RESULTS: A total of 16 studies met the inclusion criteria and were included in the review. These comprised five randomized controlled trials (RCTs), one post-hoc analysis study, one case report, and nine animal studies. The RCTs focused on Alzheimer's disease (two studies), multiple sclerosis (two studies), and amyotrophic lateral sclerosis (one study). Across all included studies, masitinib consistently demonstrated neuroprotective properties. However, the majority of RCTs reported concerns regarding the safety profile of masitinib. Preclinical studies revealed the neuroprotective mechanisms of masitinib, which include inhibition of certain kinases interfering with cell proliferation and survival, reduction of neuroinflammation, and exhibition of antioxidant activity.<br><br>CONCLUSION: The current evidence suggests a promising therapeutic benefit of masitinib in neurodegenerative diseases. However, further research is necessary to validate and expand upon these findings, particularly regarding the precise mechanisms through which masitinib exerts its therapeutic effects. Future studies should also focus on addressing the safety concerns associated with masitinib use.}, }
@article {pmid38100267, year = {2024}, author = {Qi, S and Peng, Y and Wang, G and Zhang, X and Liu, M and He, L}, title = {A tale of dual functions of SERF family proteins in regulating amyloid formation.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {25}, number = {5}, pages = {e202300727}, doi = {10.1002/cbic.202300727}, pmid = {38100267}, issn = {1439-7633}, support = {2018YFE0202301//National Key R&amp;D Program of China/ ; 2018YFE0202300//National Key R&amp;D Program of China/ ; 22174151//National Natural Sciences Foundation of China/ ; 21991080//National Natural Sciences Foundation of China/ ; XDB0540000//Strategic Priority Research Program of the Chinese Academy of Sciences/ ; 2023AFA041//Hubei Provincial Natural Science Foundation of China/ ; }, mesh = {Animals ; Caenorhabditis elegans ; *Neurodegenerative Diseases ; Amyloidogenic Proteins ; Amyloid beta-Peptides ; *Alzheimer Disease ; *Caenorhabditis elegans Proteins ; }, abstract = {The abnormal aggregation of proteins is a significant pathological hallmark of diseases, such as the amyloid formation associated with fused in sarcoma protein (FUS) in frontotemporal lobar degeneration and amyotrophic lateral sclerosis diseases. Understanding which cellular components and how these components regulate the process of abnormal protein aggregation in living organisms is crucial for the prevention and treatment of neurodegenerative diseases. MOAG-4/SERF is a conserved family of proteins with rich positive charged residues, which was initially identified as an enhancer for the formation of amyloids in C. elegans. Knocking out SERF impedes the amyloid formation of various proteins, including α-synuclein and β-amyloid, which are linked to Parkinson's and Alzheimer's diseases, respectively. However, recent studies revealed SERF exhibited dual functions, as it could both promote and inhibit the fibril formation of the neurodegenerative disease-related amyloidogenic proteins. The connection between functions and structure basis of SERF in regulating the amyloid formation is still unclear. This review will outline the hallmark proteins in neurodegenerative diseases, summarize the contradictory role of the SERF protein family in promoting and inhibiting the aggregation of neurodegenerative proteins, and finally explore the potential structural basis and functional selectivity of the SERF protein.}, }
@article {pmid38093670, year = {2024}, author = {Oliveira Santos, M and Swash, M and de Carvalho, M}, title = {Current challenges in primary lateral sclerosis diagnosis.}, journal = {Expert review of neurotherapeutics}, volume = {24}, number = {1}, pages = {45-53}, doi = {10.1080/14737175.2023.2295010}, pmid = {38093670}, issn = {1744-8360}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis ; *Motor Neuron Disease/diagnosis ; Neuroimaging ; Diagnosis, Differential ; Biomarkers ; Multicenter Studies as Topic ; }, abstract = {INTRODUCTION: Primary lateral sclerosis (PLS) is a rare, adult-onset and slowly progressive motor neuron disorder whose clinical core is characterized by upper motor neuron (UMN) dysfunction. Its formal diagnosis is clinically based and disease duration-dependent. Differentiating PLS from other disorders involving UMN can be challenging, particularly in the early stages.<br><br>AREAS COVERED: Our review covers and discusses different aspects of the PLS field, including the diagnostic criteria and its limitations, its differential diagnosis and their major pitfalls, and the actual role of neurophysiology, neuroimaging, genetics, and molecular biomarkers. Symptomatic treatment of the different manifestations is also addressed. The authors searched MEDLINE and Scopus. They also searched the reference lists of articles identified by our search strategy and reviewed and selected those deemed relevant. They selected papers and studies based on the quality of the report, significance of the findings, and on the author's critical appraise and expertise.<br><br>EXPERT OPINION: It is important to investigate novel molecular biomarkers and plan multicenter clinical trials for PLS. However, this will require a large international project to recruit enough patients, particularly given the diagnostic uncertainty of the current clinical criteria. A better understanding of PLS pathophysiology is crucial for designing disease-targeted therapies.}, }
@article {pmid38090405, year = {2023}, author = {Gupta, D and Vagha, S and Dhingra, H and Shirsath, H}, title = {Advances in Understanding and Treating Amyotrophic Lateral Sclerosis (ALS): A Comprehensive Review.}, journal = {Cureus}, volume = {15}, number = {11}, pages = {e48691}, pmid = {38090405}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a deadly CNS neurodegenerative disease. The way ALS is now managed, from diagnosis to prognosis, is still not ideal despite many studies. Early diagnosis can help ALS patients live longer since prompt treatment can halt the disease's development. Two medications, riluzole and edaravone, have recently been licensed for use in therapy, and they very slightly increase life expectancy. Still, a lot of cutting-edge experimental medications are being developed. In the following article, we give a synopsis of the innovative medications and genetic remodeling that have emerged recently and help to halt the course of the illness. Studies have also been conducted on a few symptomatic and rehabilitative therapies that enhance the quality of life for ALS patients.}, }
@article {pmid38087359, year = {2023}, author = {Nayab, DE and Din, FU and Ali, H and Kausar, WA and Urooj, S and Zafar, M and Khan, I and Shabbir, K and Khan, GM}, title = {Nano biomaterials based strategies for enhanced brain targeting in the treatment of neurodegenerative diseases: an up-to-date perspective.}, journal = {Journal of nanobiotechnology}, volume = {21}, number = {1}, pages = {477}, pmid = {38087359}, issn = {1477-3155}, support = {20-14604/NRPU/R&amp;D/HEC/2021//Higher Education Commision, Pakistan/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Brain ; Blood-Brain Barrier ; Drug Delivery Systems/methods ; Nanotechnology ; }, abstract = {Neurons and their connecting axons gradually degenerate in neurodegenerative diseases (NDs), leading to dysfunctionality of the neuronal cells and eventually their death. Drug delivery for the treatment of effected nervous system is notoriously complicated because of the presence of natural barriers, i.e., the blood-brain barrier and the blood cerebrospinal fluid barrier. Palliative care is currently the standard care for many diseases. Therefore, treatment programs that target the disease's origin rather than its symptoms are recommended. Nanotechnology-based drug delivery platforms offer an innovative way to circumvent these obstacles and deliver medications directly to the central nervous system, thereby enabling treatment of several common neurological problems, i.e., Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. Interestingly, the combination of nanomedicine and gene therapy enables targeting of selective mutant genes responsible for the progression of NDs, which may provide a much-needed boost in the struggle against these diseases. Herein, we discussed various central nervous system delivery obstacles, followed by a detailed insight into the recently developed techniques to restore neurological function via the differentiation of neural stem cells. Moreover, a comprehensive background on the role of nanomedicine in controlling neurogenesis via differentiation of neural stem cells is explained. Additionally, numerous phytoconstituents with their neuroprotective properties and molecular targets in the identification and management of NDs are also deliberated. Furthermore, a detailed insight of the ongoing clinical trials and currently marketed products for the treatment of NDs is provided in this manuscript.}, }
@article {pmid38086800, year = {2023}, author = {Wei, J and Li, M and Ye, Z and Hu, X and He, X and Wang, J and Chen, G and Zou, C and Xu, D and Zhang, H and Yuan, J and Zha, Y}, title = {Elevated peripheral levels of receptor-interacting protein kinase 1 (RIPK1) and IL-8 as biomarkers of human amyotrophic lateral sclerosis.}, journal = {Signal transduction and targeted therapy}, volume = {8}, number = {1}, pages = {451}, pmid = {38086800}, issn = {2059-3635}, support = {WJ2021M257//Health and Family Planning Commission of Hubei Province (Hubei Provincial Health Department)/ ; 2019SHZDZX02//Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission)/ ; 32070737//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82188101, 91849204, 21837004, 92049303 and 32170755//National Natural Science Foundation of China (National Science Foundation of China)/ ; 20JC1411600//Shanghai Science and Technology Development Foundation (Shanghai Science and Technology Development Fund)/ ; 20QA1411500//Shanghai Science and Technology Development Foundation (Shanghai Science and Technology Development Fund)/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Biomarkers ; Interleukin-8/genetics ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; *Neurodegenerative Diseases/metabolism ; Primidone/metabolism/pharmacology/therapeutic use ; Protein Kinases/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics/metabolism/pharmacology ; Superoxide Dismutase/metabolism/pharmacology/therapeutic use ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to mediate pathogenesis of ALS. Primidone has been identified as an old drug that can also inhibit RIPK1 kinase. We conducted a drug-repurposing biomarker study of primidone as a RIPK1 inhibitor using SOD1[G93A] mice and ALS patients. SOD1[G93A] mice treated with primidone showed significant delay of symptomatic onset and improved motor performance. One-hundred-sixty-two ALS participants dosed daily with primidone (62.5 mg) completed 24-week follow-up. A significant reduction was showed in serum levels of RIPK1 and IL-8, which were significantly higher in ALS patients than that of healthy controls (P < 0.0001). Serum RIPK1 levels were correlated positively with the severity of bulbar symptoms (P < 0.05). Our study suggests that serum levels of RIPK1 and IL-8 in peripheral can be used as clinical biomarkers for the activation of RIPK1 in central nervous system in human ALS patients. Repurposing primidone may provide a promising therapeutic strategy for ALS. The effect of primidone for the treatment of other inflammatory diseases may also be considered, since the activation of RIPK1 has been implicated in mediating a variety of inflammatory diseases including COVID-19-associated cytokine release syndrome (CRS). (ChiCTR2200060149).}, }
@article {pmid38082598, year = {2023}, author = {Zhang, C and Deng, F and Li, Y and Hall, T and Goldys, E}, title = {Paper-based lateral flow assay for the point-of-care detection of neurofilament light chain.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2023}, number = {}, pages = {1-4}, doi = {10.1109/EMBC40787.2023.10340109}, pmid = {38082598}, issn = {2694-0604}, mesh = {Humans ; *Point-of-Care Systems ; Intermediate Filaments/metabolism ; Reproducibility of Results ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Biomarkers ; }, abstract = {Neurofilament light chain (NF-L) is a protein found in neurons of the nervous system and is widely used as a biomarker for neurological disorders. However, the current methods for detecting NF-L levels are complicated, expensive, and require specialized equipment, making it challenging to implement in a point-of-care (POC) setting. In this study, we developed a gold nanoshell (AuNS)-assisted lateral flow assay (LFA) based test strip for the POC detection of NF-L at a low ng/mL level (8 ng/mL = 117.65 pM). The test strip is a simple, rapid, and cost-effective method for detecting NF-L, making it suitable for use in a POC setting for the diagnosis and treatment of various neurological disorders. With its ease of use and reliability, the paper-based LFA is a valuable tool for the diagnosis and management of neurological conditions.Clinical Relevance- The AuNS-assisted LFA test strip developed in this study offers a rapid, cost-effective, and simple method for detecting NF-L levels, making it of great interest to practicing clinicians for the diagnosis of various neurological diseases such as HIV-associated dementia (HID), Amyotrophic Lateral Sclerosis (ALS), and Creutzfeldt-Jakob disease (CJD).}, }
@article {pmid38069154, year = {2023}, author = {Belosludtseva, NV and Matveeva, LA and Belosludtsev, KN}, title = {Mitochondrial Dyshomeostasis as an Early Hallmark and a Therapeutic Target in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {23}, pages = {}, pmid = {38069154}, issn = {1422-0067}, support = {23-25-00286//Russian Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Mitochondria/metabolism ; Motor Neurons/metabolism ; Energy Metabolism ; Disease Progression ; Superoxide Dismutase-1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal multisystem disease characterized by progressive death of motor neurons, loss of muscle mass, and impaired energy metabolism. More than 40 genes are now known to be associated with ALS, which together account for the majority of familial forms of ALS and only 10% of sporadic ALS cases. To date, there is no consensus on the pathogenesis of ALS, which makes it difficult to develop effective therapy. Accumulating evidence indicates that mitochondria, which play an important role in cellular homeostasis, are the earliest targets in ALS, and abnormalities in their structure and functions contribute to the development of bioenergetic stress and disease progression. Mitochondria are known to be highly dynamic organelles, and their stability is maintained through a number of key regulatory pathways. Mitochondrial homeostasis is dynamically regulated via mitochondrial biogenesis, clearance, fission/fusion, and trafficking; however, the processes providing "quality control" and distribution of the organelles are prone to dysregulation in ALS. Here, we systematically summarized changes in mitochondrial turnover, dynamics, calcium homeostasis, and alterations in mitochondrial transport and functions to provide in-depth insights into disease progression pathways, which may have a significant impact on current symptomatic therapies and personalized treatment programs for patients with ALS.}, }
@article {pmid38068696, year = {2023}, author = {Sun, J and Yu, X and Xu, H and Yang, Y and Liu, M and Zhang, Y and Lu, Y and Tang, W}, title = {Post-Emergence Water-Dispersal Application Provides Equal Herbicidal Activity against Echinochloa crus-galli and Rice Safety as Foliar Spraying of Penoxsulam.}, journal = {Plants (Basel, Switzerland)}, volume = {12}, number = {23}, pages = {}, pmid = {38068696}, issn = {2223-7747}, support = {LGN21C140003//Zhejiang Provincial Natural Science Foundation/ ; 32071508//National Natural Science Foundation of China/ ; CARS-01//the China Agriculture Research System/ ; }, abstract = {Penoxsulam is an acetolactate synthase (ALS)-inhibiting herbicide usually applied by post-emergence foliar spraying (PFS) for the control of Echinochloa crus-galli and numerous annual weeds in paddy fields. Herbicides applied by foliar spraying can have negative impacts on the environment, ecosystems, and human health. In this study, the response of E. crus-galli and rice to the PFS and post-emergence water-dispersal (PWD) applications of penoxsulam, and the differences in the detoxification displayed by them between the two treatment methods were compared. The results showed that the PWD application of penoxsulam provides a similar control efficacy against E. crus-galli as PFS at the 1-, 3-, and 5-leaf stages. Meanwhile, the PWD application had a higher safety for the rice. After being treated with 30 g a.i. ha[-1] penoxsulam, residues were not detected in the rice treated by the PWD application method, whereas, with the PFS treatment, there was 59.0 µg/kg penoxsulam remaining. With the PFS application, there were many more residues of penoxsulam in the E. crus-galli than with the PWD method; the amount of residues was 32-fold higher 12 h after treatment. The in vitro enzyme activity assays revealed that the activities of ALS, glutathione-S-transferase (GST), and cytochrome P450 monooxygenases (P450) were increased in the PWD treatments, and were 1.5-, 1.3-, and 2.3-fold higher than with PFS 72 h after treatment. The real-time quantitative PCR (qRT-PCR) revealed that the GST1 and P450 genes, CYP81A14, CYP81A12, CYP81A18, and CYP81A21 were upregulated with the PWD application versus PFS in the E. crus-galli. In summary, these results demonstrate that the herbicidal activity was not affected by the upregulation of target and metabolic enzyme activities with the PWD application of penoxsulam. This research could contribute to application strategies reducing the risk of rice injury and environmental impacts by using water-dispersal formulations of penoxsulam.}, }
@article {pmid38053196, year = {2023}, author = {Lombardo, FL and Spila Alegiani, S and Mayer, F and Cipriani, M and Lo Giudice, M and Ludolph, AC and McDermott, CJ and Corcia, P and Van Damme, P and Van den Berg, LH and Hardiman, O and Nicolini, G and Vanacore, N and Dickie, B and Albanese, A and Puopolo, M and , }, title = {A randomized double-blind clinical trial on safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS): the statistical analysis plan of TUDCA-ALS trial.}, journal = {Trials}, volume = {24}, number = {1}, pages = {792}, pmid = {38053196}, issn = {1745-6215}, support = {755094//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Riluzole ; *Neuroprotective Agents/adverse effects ; Reproducibility of Results ; Double-Blind Method ; Treatment Outcome ; Disease Progression ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately 3 months. Recently, tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities.<br><br>METHODS: The ongoing TUDCA-ALS study is a double-blinded, parallel arms, placebo-controlled, randomized multicenter phase III trial with the aim to assess the efficacy and safety of TUDCA as add-on therapy to riluzole in patients with ALS. The primary outcome measure is the treatment response defined as a minimum of 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomized treatment period (18&#xa0;months) compared to the lead-in period (3&#xa0;months). Randomization will be stratified by country. Primary analysis will be conducted based on the intention-to-treat principle through an unadjusted logistic regression model. Patient recruitment commenced on February 22, 2019, and was closed on December 23, 2021. The database will be locked in September 2023.<br><br>DISCUSSION: This paper provides a comprehensive description of the statistical analysis plan in order to ensure the reproducibility of the analysis and avoid selective reporting of outcomes and data-driven analysis. Sensitivity analyses have been included in the protocol to assess the impact of intercurrent events related to the coronavirus disease 2019. By focusing on clinically meaningful and robust outcomes, this trial aims to determine whether TUDCA can be effective in slowing the disease progression in patients with ALS.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT03800524 . Registered on January 11, 2019.}, }
@article {pmid38052188, year = {2024}, author = {Crowe, AL and Kerr, K and McAneney, H and McMullan, J and Duffy, G and McKnight, AJ}, title = {Stakeholder Perceptions of Complementary and Integrative Medicines from People Living with Rare Diseases in Northern Ireland: A Mixed Methods Study.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {107-115}, pmid = {38052188}, issn = {2504-2106}, abstract = {INTRODUCTION: Only 5% of rare diseases have an approved treatment available, therefore patients often utilise complementary and integrative medicines (CIMs) to help manage their condition. Limited high-quality evidence-based studies are available which support the effectiveness of CIM, as it is difficult to show that an outcome is a direct result of the CIM intervention and not due to bias. Patients and healthcare professionals must weigh up the evidence quality, safety, efficacy, practical logistics, and financial implications of utilising CIM for rare diseases. This study aimed to elucidate perspectives of stakeholders (individuals with rare diseases, carers, family members, CIM practitioners and healthcare professionals), on the usage of CIM for rare diseases across Northern Ireland.<br><br>METHODS: This was a mixed methods study. An online survey was open from January to February 2019 (n = 29 responses). Themes identified from the survey were then discussed with stakeholders in a semi-structured discussion workshop in March 2019.<br><br>RESULTS: A limited number of participants responded to the survey (n = 29). Some individuals with rare diseases reported CIM as effective in the management of their condition, in particular acupuncture, dietary supplements, herbal medicines, homoeopathy, hydrotherapy, kinesiology, mindfulness, pilates, reflexology, tai chi, and yoga. However, a number of respondents (n = 7) experienced a negative side effect from CIM. Workshop participants raised concerns over the lack of information available about CIM and rare disease. Both the survey and workshop identified inequality of access with participants reporting CIM to be expensive.<br><br>CONCLUSIONS: More information, high-quality research, and education about CIM are required for patients and healthcare professionals to help make informed decisions about the usage of CIM for rare diseases. Improved communication, information, and health and social care in general would help individuals be more confident and knowledgeable about therapeutic options in relation to their rare disease(s).<br><br>UNLABELLED: <title>Einleitung</title>Nur f&#xfc;r f&#xfc;nf Prozent der seltenen Erkrankungen existiert eine zugelassene Behandlung, weshalb Patienten h&#xe4;ufig komplement&#xe4;re und integrative Medizin (CIM) nutzen, um ihre Krankheit zu behandeln. Es liegen nur wenige qualitativ hochwertige evidenzbasierte Studien vor, die die Wirksamkeit von CIM st&#xfc;tzen, da sich schwer nachweisen l&#xe4;sst, dass ein Behandlungsergebnis direkt durch die CIM-Intervention bedingt und nicht Folge einer Verzerrung ist. Patienten und Angeh&#xf6;rige der Gesundheitsberufe m&#xfc;ssen die Qualit&#xe4;t der Evidenz, die Sicherheit und Wirksamkeit sowie praktische logistische Aspekte und die finanziellen Folgen der Anwendung von CIM bei seltenen Erkrankungen abw&#xe4;gen. Mit der vorliegenden Studie sollte die Perspektive der Betroffenen (Menschen mit seltenen Erkrankungen, Betreuungspersonen, Familienangeh&#xf6;rige, CIM-Praktiker und Angeh&#xf6;rige der Gesundheitsberufe) in Bezug auf die Anwendung von CIM bei seltenen Erkrankungen in Nordirland untersucht werden.<title>Methoden</title>Es handelte sich um eine Studie mit gemischten Methoden. Eine Online-Umfrage war von Januar bis Februar 2019 ge&#xf6;ffnet (<italic>n</italic> = 29 Antworten). Die in der Umfrage ermittelten Themen wurden anschlie&#xdf;end im M&#xe4;rz 2019 im Rahmen eines halbstrukturierten Diskussionsworkshops mit den Betroffenen er&#xf6;rtert.<title>Ergebnisse</title>Eine begrenzte Anzahl von Teilnehmern antwortete auf die Umfrage (<italic>n</italic> = 29). Einige Personen mit seltenen Erkrankungen gaben an, dass CIM bei der Behandlung ihrer Erkrankung wirksam war, insbesondere Akupunktur, Nahrungserg&#xe4;nzungsmittel, pflanzliche Arzneimittel, Hom&#xf6;opathie, Hydrotherapie, Kinesiologie, Achtsamkeit, Pilates, Reflexologie, Tai Chi und Yoga. Einige Befragte (<italic>n</italic> = 7) berichteten jedoch &#xfc;ber negative Nebenwirkungen der CIM. Die Workshop-Teilnehmer &#xe4;u&#xdf;erten Bedenken in Bezug auf den Mangel an Informationen &#xfc;ber CIM und seltene Erkrankungen. Sowohl in der Umfrage als auch im Workshop zeigte sich eine Ungleichheit beim Zugang zu CIM und die Teilnehmer berichteten, dass CIM teuer sei.<title>Schlussfolgerungen</title>Patienten und Angeh&#xf6;rige der Gesundheitsberufe ben&#xf6;tigen mehr Informationen, qualitativ hochwertige Forschung und Aufkl&#xe4;rung &#xfc;ber CIM, um fundierte Entscheidungen &#xfc;ber die Anwendung von CIM bei seltenen Erkrankungen treffen zu k&#xf6;nnen. Eine bessere Kommunikation, Information sowie gesundheitliche und soziale Versorgung im Allgemeinen w&#xfc;rden zu mehr Selbstvertrauen und Wissen der Betroffenen &#xfc;ber die therapeutischen M&#xf6;glichkeiten im Zusammenhang mit ihrer seltenen Erkrankung beitragen.}, }
@article {pmid38050066, year = {2024}, author = {Bowser, R and An, J and Mehta, L and Chen, J and Timmons, J and Cudkowicz, M and Paganoni, S}, title = {Effect of sodium phenylbutyrate and taurursodiol on plasma concentrations of neuroinflammatory biomarkers in amyotrophic lateral sclerosis: results from the CENTAUR trial.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {7}, pages = {605-608}, pmid = {38050066}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/drug therapy ; *Biomarkers/blood ; *Chitinase-3-Like Protein 1/blood ; *C-Reactive Protein/analysis ; *Phenylbutyrates/therapeutic use ; Female ; Male ; Middle Aged ; Hexosaminidases/blood ; Aged ; Double-Blind Method ; Chitinases/blood ; }, abstract = {BACKGROUND: An oral sodium phenylbutyrate and taurursodiol combination (PB and TURSO) significantly reduced functional decline in people living with amyotrophic lateral sclerosis (ALS) in the CENTAUR trial. Biomarkers linking clinical therapeutic effect with biological changes are of high interest in ALS. We performed analyses of neuroinflammatory biomarkers associated with ALS in the literature, including YKL-40 (also known as chitinase-3-like protein 1), chitinase 1 (CHIT1) and C reactive protein (CRP), in plasma samples collected in CENTAUR.<br><br>METHODS: Log10-transformed plasma biomarker measurements were analysed using a linear mixed-effects model. Correlation between paired biomarker concentrations and ALS Functional Rating Scale-Revised (ALSFRS-R) total scores was assessed via Pearson correlation coefficients.<br><br>RESULTS: By week 24, geometric least squares mean YKL-40 plasma concentration decreased by approximately 20% (p=0.008) and CRP by 30% (p=0.048) in the PB and TURSO versus placebo group. YKL-40 (r of -0.21; p<0.0001) and CRP (r of -0.19; p=0.0002) concentration correlated with ALSFRS-R total score. CHIT1 levels were not significantly different between groups.<br><br>CONCLUSIONS: YKL-40 and CRP plasma levels were significantly reduced in participants with ALS receiving PB and TURSO in CENTAUR and correlated with disease progression. These findings suggest YKL-40 and CRP could be treatment-sensitive biomarkers in ALS, pending further confirmatory studies.<br><br>TRIAL REGISTRATION NUMBER: https://clinicaltrials.gov/study/NCT03127514.}, }
@article {pmid38049068, year = {2024}, author = {Wang, B and Huang, Y and Li, J}, title = {Response to John et al's comments of "paroxetine is an effective treatment for refractory erythema of rosacea: Primary results from the prospective rosacea refractory erythema randomized clinical trial".}, journal = {Journal of the American Academy of Dermatology}, volume = {90}, number = {4}, pages = {e143-e144}, doi = {10.1016/j.jaad.2023.11.050}, pmid = {38049068}, issn = {1097-6787}, mesh = {Humans ; *Paroxetine/therapeutic use ; Prospective Studies ; *Rosacea/drug therapy ; Erythema/drug therapy/etiology ; Treatment Outcome ; }, }
@article {pmid38046608, year = {2023}, author = {Wang, R and Sun, Y and Lan, Y and Wei, S and Huang, H and Li, X and Huang, Z}, title = {ALS gene overexpression and enhanced metabolism conferring Digitaria sanguinalis resistance to nicosulfuron in China.}, journal = {Frontiers in plant science}, volume = {14}, number = {}, pages = {1290600}, pmid = {38046608}, issn = {1664-462X}, abstract = {Crabgrass (Digitaria sanguinalis) is a common malignant weed in corn fields in China. Recently, the acetolactate synthase (ALS) inhibitor, nicosulfuron, has shown decreasing efficacy against crabgrass. In order to elucidate the molecular basis of resistance to nicosulfuron in crabgrass, we conducted bioassays, combined with gene sequence analysis, relative expression and relative copy number analysis, to characterize resistance in crabgrass populations collected from Beijing, Heilongjiang, Jilin and Anhui provinces. Whole-plant dose-response results indicated that only population collected in Heilongjiang province (HLJ) had developed low level of resistance to nicosulfuron compared with the sensitive population (SD22). No known resistant mutation of ALS gene was found in HLJ population. The real-time fluorescence quantitative PCR results showed that the ALS gene copy number did not differ significantly between the HLJ and SD22 populations. However, the ALS gene expression in the HLJ was 2.07-fold higher than that of the SD22 population at 24 h after treatment with nicosulfuron. Pretreatment with the cytochrome P450 (CYP450) inhibitor malathion, piperonyl butoxide (PBO), and the glutathione S-transferase (GST) inhibitor 4-Chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) all partially reversed HLJ resistance. Among them, the synergistic effect of PBO and nicosulfuron is the most significant. This is the first report of resistance to nicosulfuron in crabgrass through ALS gene overexpression and possible metabolic resistance.}, }
@article {pmid38037913, year = {2024}, author = {Zhong, G and Wang, X and Li, J and Xie, Z and Wu, Q and Chen, J and Wang, Y and Chen, Z and Cao, X and Li, T and Liu, J and Wang, Q}, title = {Insights Into the Role of Copper in Neurodegenerative Diseases and the Therapeutic Potential of Natural Compounds.}, journal = {Current neuropharmacology}, volume = {22}, number = {10}, pages = {1650-1671}, pmid = {38037913}, issn = {1875-6190}, support = {81973918, 82274616//National Natural Science Foundation of China/ ; 2019KSYS005//Key laboratory project of colleges and universities in Guangdong Province/ ; 2020A0505100052//Guangdong province science and technology plan international cooperation project/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Copper/metabolism ; Animals ; Biological Products/therapeutic use/pharmacology ; Homeostasis/drug effects ; Chelating Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases encompass a collection of neurological disorders originating from the progressive degeneration of neurons, resulting in the dysfunction of neurons. Unfortunately, effective therapeutic interventions for these diseases are presently lacking. Copper (Cu), a crucial trace element within the human body, assumes a pivotal role in various biological metabolic processes, including energy metabolism, antioxidant defense, and neurotransmission. These processes are vital for the sustenance, growth, and development of organisms. Mounting evidence suggests that disrupted copper homeostasis contributes to numerous age-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), Menkes disease (MD), prion diseases, and multiple sclerosis (MS). This comprehensive review investigates the connection between the imbalance of copper homeostasis and neurodegenerative diseases, summarizing pertinent drugs and therapies that ameliorate neuropathological changes, motor deficits, and cognitive impairments in these conditions through the modulation of copper metabolism. These interventions include Metal-Protein Attenuating Compounds (MPACs), copper chelators, copper supplements, and zinc salts. Moreover, this review highlights the potential of active compounds derived from natural plant medicines to enhance neurodegenerative disease outcomes by regulating copper homeostasis. Among these compounds, polyphenols are particularly abundant. Consequently, this review holds significant implications for the future development of innovative drugs targeting the treatment of neurodegenerative diseases.}, }
@article {pmid38036035, year = {2024}, author = {Wang, X and Zhu, Z and Sun, J and Jia, L and Cai, L and Chen, Q and Yang, W and Wang, Y and Zhang, Y and Guo, S and Liu, W and Yang, Z and Zhao, P and Wang, Z and Lv, H}, title = {Changes in iron load in specific brain areas lead to neurodegenerative diseases of the central nervous system.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {129}, number = {}, pages = {110903}, doi = {10.1016/j.pnpbp.2023.110903}, pmid = {38036035}, issn = {1878-4216}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/pathology ; Iron ; Genome-Wide Association Study ; Magnetic Resonance Imaging/methods ; Brain/diagnostic imaging/pathology ; *Alzheimer Disease/pathology ; *Parkinson Disease ; *Multiple Sclerosis ; }, abstract = {The causes of neurodegenerative diseases remain largely elusive, increasing their personal and societal impacts. To reveal the causal effects of iron load on Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis and multiple sclerosis, we used Mendelian randomisation and brain imaging data from a UK Biobank genome-wide association study of 39,691 brain imaging samples (predominantly of European origin). Using susceptibility-weighted images, which reflect iron load, we analysed genetically significant brain regions. Inverse variance weighting was used as the main estimate, while MR Egger and weighted median were used to detect heterogeneity and pleiotropy. Nine clear associations were obtained. For AD and PD, an increased iron load was causative: the right pallidum for AD and the right caudate, left caudate and right accumbens for PD. However, a reduced iron load was identified in the right and left caudate for multiple sclerosis, the bilateral hippocampus for mixed vascular dementia and the left thalamus and bilateral accumbens for subcortical vascular dementia. Thus, changes in iron load in different brain regions have causal effects on neurodegenerative diseases. Our results are crucial for understanding the pathogenesis and investigating the treatment of these diseases.}, }
@article {pmid38033869, year = {2023}, author = {Vukolova, MN and Yen, LY and Khmyz, MI and Sobolevsky, AI and Yelshanskaya, MV}, title = {Parkinson's disease, epilepsy, and amyotrophic lateral sclerosis-emerging role of AMPA and kainate subtypes of ionotropic glutamate receptors.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1252953}, pmid = {38033869}, issn = {2296-634X}, support = {R37 NS083660/NS/NINDS NIH HHS/United States ; R01 NS107253/NS/NINDS NIH HHS/United States ; R01 NS083660/NS/NINDS NIH HHS/United States ; R01 AR078814/AR/NIAMS NIH HHS/United States ; R01 CA206573/CA/NCI NIH HHS/United States ; }, abstract = {Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission and are implicated in various neurological disorders. In this review, we discuss the role of the two fastest iGluRs subtypes, namely, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, in the pathogenesis and treatment of Parkinson's disease, epilepsy, and amyotrophic lateral sclerosis. Although both AMPA and kainate receptors represent promising therapeutic targets for the treatment of these diseases, many of their antagonists show adverse side effects. Further studies of factors affecting the selective subunit expression and trafficking of AMPA and kainate receptors, and a reasonable approach to their regulation by the recently identified novel compounds remain promising directions for pharmacological research.}, }
@article {pmid38031465, year = {2024}, author = {Ghasemi, A and Sadedel, M and Moghaddam, MM}, title = {A wearable system to assist impaired-neck patients: Design and evaluation.}, journal = {Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine}, volume = {238}, number = {1}, pages = {63-77}, doi = {10.1177/09544119231211362}, pmid = {38031465}, issn = {2041-3033}, mesh = {Humans ; *Robotics ; Electromyography/methods ; *Stroke ; Movement ; *Wearable Electronic Devices ; }, abstract = {Patients with neurological disorders, such as amyotrophic lateral sclerosis, Parkinson's disease, and cerebral palsy, often face challenges due to head-neck immobility. The conventional treatment approach involves using a neck collar to maintain an upright head position, but this can be cumbersome and restricts head-neck movements over prolonged periods. This study introduces a wearable robot capable of providing three anatomical head motions for training and assistance. The primary contributions of this research include the design of an optimized structure and the incorporation of human-robot interaction. Based on human head motion data, our primary focus centered on developing a robot capable of accommodating a significant range of neutral head movements. To ensure safety, impedance control was employed to facilitate human-robot interaction. A human study was conducted involving 10 healthy subjects who participated in an experiment to assess the robot's assistance capabilities. Passive and active modes were used to evaluate the robot's effectiveness, taking into account head-neck movement error and muscle activity levels. Surface electromyography signals (sEMG) were collected from the splenius capitis muscles during the experiment. The results demonstrated that the robot covered nearly 85% of the overall range of head rotations. Importantly, using the robot during rehabilitation led to reduced muscle activation, highlighting its potential for assisting individuals with post-stroke movement impairments.}, }
@article {pmid38022117, year = {2023}, author = {Jain, A and Madkan, S and Patil, P}, title = {The Role of Gut Microbiota in Neurodegenerative Diseases: Current Insights and Therapeutic Implications.}, journal = {Cureus}, volume = {15}, number = {10}, pages = {e47861}, pmid = {38022117}, issn = {2168-8184}, abstract = {Small microscopic entities known as microbes, having a population of hundreds of billions or perhaps even in trillions, reside in our gastrointestinal tract. A healthy immune system, digestion, and creation of vitamins and enzymes are all thanks to these microbes. However, new research has shown a hitherto unrecognized connection between the microbiota of the intestines and the genesis of neurodegenerative diseases. Neurons in the CNS gradually deteriorate in neurodegenerative illnesses like multiple sclerosis and Parkinson's disease (PD). This deterioration impairs cognitive and physical function. Amyotrophic lateral sclerosis (ALS), PD, and Alzheimer's disease (AD) are just a few examples of neurodegenerative illnesses that pose a serious threat to world health and have few effective treatments. Recent research suggests that the gut microbiota, a diverse microbial population found in the gastrointestinal system, may substantially impact the cause and development of various diseases. The discovery of altered gut microbiota composition in people with these illnesses is one of the most critical lines of evidence connecting gut microbiota dysbiosis to neurodegenerative diseases. AD patients have a distinct characteristic of having a particular microbiota profile. In addition, an excess population of a specific microbe data profile is seen as compared to a healthy individual. Similar changes in the gut microbiota composition have been noted in people with multiple sclerosis and PD. The latest study indicates the potential that dysbiosis, a condition characterized by alteration in the intestinal microbiota's makeup and functioning, may have an effect on the onset and progression of neurodegenerative diseases, including PD and multiple sclerosis. In order to emphasize any potential underlying mechanisms and examine potential treatment repercussions, the review article's goal is to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders. The review article aims to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders, highlighting potential underlying mechanisms and examining potential treatment repercussions.}, }
@article {pmid38018119, year = {2024}, author = {Brown, A and Armon, C and Barkhaus, P and Beauchamp, M and Bertorini, T and Bromberg, M and Cadavid, JM and Carter, GT and Crayle, J and Feldman, EL and Heiman-Patterson, T and Jhooty, S and Linares, A and Li, X and Mallon, E and Mcdermott, C and Mushannen, T and Nathaniel, G and Pattee, G and Pierce, K and Ratner, D and Slactova, L and Wicks, P and Bedlack, R}, title = {ALSUntangled #72: Insulin.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {416-419}, doi = {10.1080/21678421.2023.2288110}, pmid = {38018119}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Insulin/adverse effects ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review insulin, which has at least one plausible mechanism for slowing ALS progression. However, pre-clinical studies are limited and there have been no trials in PALS yet. Insulin use in patients without a metabolic need may cause very serious and potentially lethal side effects. While further studies to evaluate potential benefits may be warranted, at this time we cannot endorse insulin treatment to slow ALS progression.}, }
@article {pmid38014622, year = {2023}, author = {Yamashita, T and Nakano, Y and Sasaki, R and Tadokoro, K and Omote, Y and Yunoki, T and Kawahara, Y and Matsumoto, N and Taira, Y and Matsuoka, C and Morihara, R and Abe, K}, title = {Safety and Clinical Effects of a Muse Cell-Based Product in Patients With Amyotrophic Lateral Sclerosis: Results of a Phase 2 Clinical Trial.}, journal = {Cell transplantation}, volume = {32}, number = {}, pages = {9636897231214370}, pmid = {38014622}, issn = {1555-3892}, mesh = {Animals ; Mice ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Alprostadil/therapeutic use ; Interleukin-6 ; Tumor Necrosis Factor-alpha ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons. Multilineage-differentiating stress-enduring (Muse) cells are unique endogenous stem cells that show therapeutic effects on motor function in ALS mouse models. We conducted a single-center open phase II clinical trial to evaluate the safety and clinical effects of repeated intravenous injections of an allogenic Muse cell-based product, CL2020, in patients with ALS. Five patients with ALS received CL2020 intravenously once a month for a total of six doses. The primary endpoints were safety and tolerability, and the secondary endpoint was the rate of change in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score. In addition, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), sphingosine-1-phosphate (S1P), cerebrospinal fluid chitotriosidase-1 (CHIT-1), and neurofilament light chain (NfL) levels were evaluated. The CL2020 treatment was highly tolerated without serious side effects. The ALSFRS-R score change trended upward at 12 months post-CL2020 treatment compared with that at 3 months pre-administration, but the difference was not statistically significant. Among five patients diagnosed with ALS, three exhibited a decrease in the rate of ALSFRS-R score change, one demonstrated an increase, and another showed no change. In addition, the patients' serum IL-6 and TNF-α levels and cerebrospinal fluid CHIT-1 and NfL levels increased for up to 6 months post-treatment; however, their serum S1P levels continuously decreased over 12 months. These findings indicate a favorable safety profile of CL2020 therapy. In the near future, a double-blind study of a larger number of ALS patients should be conducted to confirm the efficacy of ALS treatment with CL2020.}, }
@article {pmid38014203, year = {2023}, author = {Wilkins, OG and Chien, MZYJ and Wlaschin, JJ and Pisliakova, M and Thompson, D and Digby, H and Simkin, RL and Diaz, JA and Mehta, PR and Keuss, MJ and Zanovello, M and Brown, AL and Harley, P and Darbey, A and Karda, R and Fisher, EMC and Cunningham, TJ and Le Pichon, CE and Ule, J and Fratta, P}, title = {Creation of de novo cryptic splicing for ALS/FTD precision medicine.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38014203}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; ZIA HD008966/ImNIH/Intramural NIH HHS/United States ; }, abstract = {A system enabling the expression of therapeutic proteins specifically in diseased cells would be transformative, providing greatly increased safety and the possibility of pre-emptive treatment. Here we describe "TDP-REG", a precision medicine approach primarily for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which exploits the cryptic splicing events that occur in cells with TDP-43 loss-of-function (TDP-LOF) in order to drive expression specifically in diseased cells. In addition to modifying existing cryptic exons for this purpose, we develop a deep-learning-powered algorithm for generating customisable cryptic splicing events, which can be embedded within virtually any coding sequence. By placing part of a coding sequence within a novel cryptic exon, we tightly couple protein expression to TDP-LOF. Protein expression is activated by TDP-LOF in vitro and in vivo, including TDP-LOF induced by cytoplasmic TDP-43 aggregation. In addition to generating a variety of fluorescent and luminescent reporters, we use this system to perform TDP-LOF-dependent genomic prime editing to ablate the UNC13A cryptic donor splice site. Furthermore, we design a panel of tightly gated, autoregulating vectors encoding a TDP-43/Raver1 fusion protein, which rescue key pathological cryptic splicing events. In summary, we combine deep-learning and rational design to create sophisticated splicing sensors, resulting in a platform that provides far safer therapeutics for neurodegeneration, potentially even enabling preemptive treatment of at-risk individuals.}, }
@article {pmid38013317, year = {2023}, author = {Wang, Z and Yang, H and Han, Y and Teng, J and Kong, X and Qi, X}, title = {Screening and identification of key biomarkers associated with amyotrophic lateral sclerosis and depression using bioinformatics.}, journal = {Medicine}, volume = {102}, number = {47}, pages = {e36265}, pmid = {38013317}, issn = {1536-5964}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Depression/diagnosis/genetics ; Gene Expression Profiling ; *MicroRNAs/genetics ; Biomarkers ; Gene Regulatory Networks ; Computational Biology/methods ; }, abstract = {This study aims to identify common molecular biomarkers between amyotrophic lateral sclerosis (ALS) and depression using bioinformatics methods, in order to provide potential targets and new ideas and methods for the diagnosis and treatment of these diseases. Microarray datasets GSE139384, GSE35978 and GSE87610 were obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) between ALS and depression were identified. After screening for overlapping DEGs, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Furthermore, a protein-protein interaction (PPI) network was constructed using the STRING database and Cytoscape software, and hub genes were identified. Finally, a network between miRNAs and hub genes was constructed using the NetworkAnalyst tool, and possible key miRNAs were predicted. A total of 357 genes have been identified as common DEGs between ALS and depression. GO and KEGG enrichment analyses of the 357 DEGs showed that they were mainly involved in cytoplasmic translation. Further analysis of the PPI network using Cytoscape and MCODE plugins identified 6 hub genes, including mitochondrial ribosomal protein S12 (MRPS12), poly(rC) binding protein 1 (PARP1), SNRNP200, PCBP1, small G protein signaling modulator 1 (SGSM1), and DNA methyltransferase 1 (DNMT1). Five possible target miRNAs, including miR-221-5p, miR-21-5p, miR-100-5p, miR-30b-5p, and miR-615-3p, were predicted by constructing a miRNA-gene network. This study used bioinformatics techniques to explore the potential association between ALS and depression, and identified potential biomarkers. These biomarkers may provide new ideas and methods for the early diagnosis, treatment, and monitoring of ALS and depression.}, }
@article {pmid38011840, year = {2024}, author = {Asawadethmetakul, P and Xie, F and Xie, C and Ma, J and You, Y and Yao, F}, title = {Effect of Tuina Combined with Chinese Herbal Compress on Primary Dysmenorrhea with Cold Coagulation and Blood Stasis Syndrome: A Study Protocol for a Randomized Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {20-29}, doi = {10.1159/000534335}, pmid = {38011840}, issn = {2504-2106}, mesh = {Female ; Humans ; *Dysmenorrhea/drug therapy ; China ; *Pain Threshold ; Randomized Controlled Trials as Topic ; Observational Studies as Topic ; }, abstract = {INDRODUCTION: Primary dysmenorrhea (PD) is a very common issue in young women that reduces the quality of women's lives. Both Western medicine and traditional Chinese medicine (TCM) provide several ways to treat PD; however, TCM treatment exhibits fewer side effects for the patient. Tuina massage and Chinese herbal compresses are considered forms of external TCM therapy that have been widely used to treat PD, especially in China. Therefore, to provide the most effective and safe treatment for PD, we combined Tuina and Chinese herbal compresses together in this observational study.<br><br>METHODS: A randomized controlled trial (RCT) consisting of 114 participants from the Shanghai University of Traditional Chinese Medicine who meet inclusion criteria will be divided into two groups in a 1:1 allocation ratio. The intervention group will receive Tuina combined with Chinese herbal compress therapy, while the control group will only receive Chinese herbal compress therapy. The treatment will be given 3 days before menstruation (once per day, 3 times per menstrual cycle). The primary outcome will be measured with the Visual Analog Scale (VAS). The secondary outcomes will be measured by the Dysmenorrhea Symptom Score, the Chinese Medical Dysmenorrhea Symptom Score, the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), and the pain threshold at Guanyuan (CV4).<br><br>CONCLUSION: This study will be the first RCT that will entail the combination of Tuina and Chinese herbal compresses to treat PD in the category of cold coagulation and blood stasis syndrome. If the results demonstrate that Tuina combined with a Chinese herbal compress is effective, we posit that this study will provide evidence-based references for a potential alternative treatment to treat PD in the future.<br><br>UNLABELLED: <title>Einleitung</title>Die prim&#xe4;re Dysmenorrhoe (PD) ist ein Problem, das bei jungen Frauen sehr h&#xe4;ufig auftritt und ihre Lebensqualit&#xe4;t beeintr&#xe4;chtigt. Sowohl die westliche Medizin als auch die traditionelle chinesische Medizin (TCM) bieten verschiedene Therapiem&#xf6;glichkeiten zur Behandlung der PD, allerdings ist die TCM mit weniger Nebenwirkungen f&#xfc;r die Patientin verbunden. Tuina-Massage und chinesische Kr&#xe4;uterkompressen gelten als Formen der &#xe4;u&#xdf;erlichen TCM-Therapie, die besonders in China zur Behandlung der PD weit verbreitet sind. Daher haben wir in dieser Beobachtungsstudie Tuina und chinesische Kr&#xe4;uterkompressen kombiniert, um eine m&#xf6;glichst wirksame und sichere Behandlung der PD bereitzustellen.<title>Methoden</title>Es handelt sich um eine randomisierte kontrollierte Studie (randomized controlled trial, RCT), bei der 114 Teilnehmerinnen der Shanghai University of Traditional Chinese Medicine, die die Einschlusskriterien erf&#xfc;llen, im Verh&#xe4;ltnis 1:1 in zwei Gruppen aufgeteilt werden. Die Interventionsgruppe erh&#xe4;lt Tuina in Kombination mit chinesischen Kr&#xe4;uterkompressen, w&#xe4;hrend die Kontrollgruppe nur eine Behandlung mit chinesischen Kr&#xe4;uterkompressen erh&#xe4;lt. Die Behandlung erfolgt drei Tage vor der Menstruation (einmal t&#xe4;glich, dreimal pro Menstruationszyklus). Das prim&#xe4;re Zielkriterium wird anhand der visuellen Analogskala (VAS) gemessen. Die sekund&#xe4;ren Zielkriterien werden mithilfe des Dysmenorrhoe-Symptom-Scores, des chinesischen medizinischen Dysmenorrhoe-Symptom-Scores, der Self-rating Anxiety Scale (SAS), der Self-rating Depression Scale (SDS) und der Schmerzschwelle am Guanyuan-Akupunkturpunkt (<italic>CV4</italic>) ermittelt.<title>Schlussfolgerung</title>Diese Studie ist die erste randomisierte kontrollierte Studie, die die Kombination von Tuina und chinesischen Kr&#xe4;uterkompressen zur Behandlung von PD in der Kategorie K&#xe4;ltekoagulation und Blutstauungssyndrom untersucht. Sollten die Ergebnisse zeigen, dass Tuina in Kombination mit chinesischen Kr&#xe4;uterkompressen wirksam ist, erwarten wir, dass diese Studie evidenzbasierte Belege f&#xfc;r eine m&#xf6;gliche alternative Behandlung von PD in der Zukunft liefern wird.}, }
@article {pmid38010626, year = {2024}, author = {Zhong, R and Rua, MT and Wei-LaPierre, L}, title = {Targeting mitochondrial Ca[2+] uptake for the treatment of amyotrophic lateral sclerosis.}, journal = {The Journal of physiology}, volume = {602}, number = {8}, pages = {1519-1549}, pmid = {38010626}, issn = {1469-7793}, support = {R01 NS127858/NS/NINDS NIH HHS/United States ; R21 NS099545/NS/NINDS NIH HHS/United States ; R56 NS117429/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Calcium/metabolism ; *Neurodegenerative Diseases ; Motor Neurons/physiology ; Mitochondria/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare adult-onset neurodegenerative disease characterized by progressive motor neuron (MN) loss, muscle denervation and paralysis. Over the past several decades, researchers have made tremendous efforts to understand the pathogenic mechanisms underpinning ALS, with much yet to be resolved. ALS is described as a non-cell autonomous condition with pathology detected in both MNs and non-neuronal cells, such as glial cells and skeletal muscle. Studies in ALS patient and animal models reveal ubiquitous abnormalities in mitochondrial structure and function, and disturbance of intracellular calcium homeostasis in various tissue types, suggesting a pivotal role of aberrant mitochondrial calcium uptake and dysfunctional calcium signalling cascades in ALS pathogenesis. Calcium signalling and mitochondrial dysfunction are intricately related to the manifestation of cell death contributing to MN loss and skeletal muscle dysfunction. In this review, we discuss the potential contribution of intracellular calcium signalling, particularly mitochondrial calcium uptake, in ALS pathogenesis. Functional consequences of excessive mitochondrial calcium uptake and possible therapeutic strategies targeting mitochondrial calcium uptake or the mitochondrial calcium uniporter, the main channel mediating mitochondrial calcium influx, are also discussed.}, }
@article {pmid38010108, year = {2024}, author = {Hincelin-Mery, A and Nicolas, X and Cantalloube, C and Pomponio, R and Lewanczyk, P and Benamor, M and Ofengeim, D and Krupka, E and Hsiao-Nakamoto, J and Eastenson, A and Atassi, N}, title = {Safety, pharmacokinetics, and target engagement of a brain penetrant RIPK1 inhibitor, SAR443820 (DNL788), in healthy adult participants.}, journal = {Clinical and translational science}, volume = {17}, number = {1}, pages = {e13690}, pmid = {38010108}, issn = {1752-8062}, mesh = {Adult ; Humans ; Healthy Volunteers ; Dose-Response Relationship, Drug ; Area Under Curve ; Half-Life ; Double-Blind Method ; *Brain ; *Receptor-Interacting Protein Serine-Threonine Kinases ; }, abstract = {SAR443820 (DNL788) is a selective, orally bioavailable, brain penetrant inhibitor of receptor-interacting serine/threonine protein kinase 1 (RIPK1). This phase I first-in-human healthy participant study (NCT05795907) was comprised of three parts: randomized, double-blind, placebo-controlled single ascending dose (SAD; part 1a); 14-day multiple ascending dose (MAD; part 2) parts that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of SAR443820; and a separate open-label, single-dose part 1b (PK-cerebrospinal fluid [CSF]) to assess SAR443820 levels in CSF. SAR443820 was well-tolerated in healthy participants, and no treatment discontinuation related to an adverse event (AE) occurred. Most common AEs were dizziness and headache. No clinically meaningful changes were noted in laboratory values, vital signs, or electrocardiogram parameters. SAR443820 had a favorable PK profile, with plasma half-lives (geometric mean) ranged between 5.7-8.0 h and 7.2-8.9 h after single and repeated doses, respectively. There were no major deviations from dose proportionality for maximum concentration and area under the curve across SAR443820 doses. Mean CSF-to-unbound plasma concentration ratio ranged from 0.8 to 1.3 over time (assessed up to 10 h postdose), indicating high brain penetrance. High levels of inhibition of activated RIPK1, as measured by decrease in pS166-RIPK1, were achieved in both SAD and MAD parts, with a maximum median inhibition from baseline close to 90% at predose (Ctrough) after multiple dosing in MAD, reflecting a marked RIPK1 target engagement at the peripheral level. These results support further development of SAR443820 in phase II trials in amyotrophic lateral sclerosis (NCT05237284) and multiple sclerosis (NCT05630547).}, }
@article {pmid38008627, year = {2024}, author = {Zhang, J and Wang, C and Zhou, M and Wang, Z}, title = {Comprehensive treatment of amyotrophic lateral sclerosis combined with colon cancer: A case report.}, journal = {Asian journal of surgery}, volume = {47}, number = {2}, pages = {1274-1275}, doi = {10.1016/j.asjsur.2023.11.063}, pmid = {38008627}, issn = {0219-3108}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Colonic Neoplasms ; }, }
@article {pmid38008074, year = {2024}, author = {Saha, S and Singh, R and Mani, I and Chakraborty, K and Sarkar, P and Saha, S and Rana, A and Chattopadhyay, R}, title = {Individualized Homeopathic Medicines in the Treatment of Post-COVID-19 Fatigue in Adults: Single-Blind, Randomized, Placebo-Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {1-9}, doi = {10.1159/000535279}, pmid = {38008074}, issn = {2504-2106}, mesh = {Adult ; Humans ; *COVID-19/therapy ; India ; *Materia Medica ; Quality of Life ; Single-Blind Method ; Sulfur ; }, abstract = {INTRODUCTION: The coronavirus disease 2019 (COVID-19) is leading to unknown and unusual health conditions that are challenging to manage. Post-COVID-19 fatigue is one of those challenges, becoming increasingly common as the pandemic evolves, as it impairs the quality of life of an individual. This trial attempts to identify the preliminary evidence of the efficacy of individualized homeopathic medicines (IHMs) against placebos in the treatment of post-COVID-19 fatigue in adults.<br><br>METHODS: A 3-month, single-blind, randomized, placebo-controlled, parallel-arm trial was conducted at the outpatient department of The Calcutta Homoeopathic Medical College and Hospital, India. Sixty participants were randomized in a 1:1 ratio to receive either IHMs (n = 30) or identical-looking placebos (n = 30). The primary and secondary outcome measures were the Fatigue Assessment Scale (FAS) and Outcome in Relation to Impact on Daily Living (ORIDL), respectively, measured every month, for up to 3 months. Comparative analysis was carried out on the intention-to-treat sample to detect group differences.<br><br>RESULTS: Group differences in both the primary (FAS total: F1, 58 = 14.356, p < 0.001) and secondary outcomes (ORIDL: F1, 58 = 210.986, p < 0.001) after 3 months favored IHMs against placebos. Lycopodium clavatum (11.7%), sulfur (11.7%), Arsenicum album (10%), and Thuja occidentalis (10%) were the most frequently indicated medicines. No harm, unintended effects, homeopathic aggravations, or any serious adverse events were reported from either of the groups.<br><br>CONCLUSION: IHMs produced significantly better effects than placebos in the treatment of post-COVID-19 fatigue in adults. Definitive robust trials may be undertaken to confirm the findings.<br><br>UNLABELLED: <title>Einleitung</title>Die Coronainfektion (COVID-19) zieht unbekannte und ungew&#xf6;hnliche gesundheitliche Probleme nach sich, deren Management oft eine Herausforderung darstellt. Das gilt unter anderem f&#xfc;r Erm&#xfc;dung nach einer COVID-19-Erkrankung, die mit zunehmender Dauer der Pandemie immer h&#xe4;ufiger auftritt und die Lebensqualit&#xe4;t der Betroffenen beeintr&#xe4;chtigt. In dieser Studie wird versucht, vorl&#xe4;ufige Belege f&#xfc;r die Wirksamkeit individualisierter hom&#xf6;opathischer Mittel (IHM) im Vergleich zu Placebo zur Behandlung von Erm&#xfc;dung nach COVID-19 bei Erwachsenen zu identifizieren.<title>Methoden</title>Eine einfach verblindete, randomisierte, placebokontrollierte Parallelgruppenstudie von 3 Monaten Dauer wurde im ambulanten Bereich des Calcutta Homoeopathic Medical College and Hospital in Indien durchgef&#xfc;hrt. 60 Teilnehmer erhielten nach Randomisierung im Verh&#xe4;ltnis 1:1 entweder IHM (<italic>n</italic> = 30) oder identisch aussehendes Placebo (<italic>n</italic> = 30). Die prim&#xe4;re und die sekund&#xe4;re Zielgr&#xf6;&#xdf;e waren die Fatigue Assessment Scale (FAS) und das Outcome in Relation to Impact on Daily Living (ORIDL) f&#xfc;r bis zu 3 Monate, jeweils monatlich gemessen. Vergleichende Analysen wurden an der Intent-to-treat-Population durchgef&#xfc;hrt, um Unterschiede zwischen den Gruppen zu erkennen.<title>Ergebnisse</title>Gruppenunterschiede bei der prim&#xe4;ren (FAS gesamt: <italic>F</italic>1, 58 = 14,356; <italic>p</italic> < 0.001) sowie der sekund&#xe4;ren Zielgr&#xf6;&#xdf;e (ORIDL: <italic>F</italic>1, 58 = 210,986; <italic>p</italic> < 0.001) nach 3 Monaten sprachen f&#xfc;r die IHM gegen&#xfc;ber Placebo. <italic>Lycopodium clavatum</italic> (11.7%), <italic>sulfur</italic> (11.7%), <italic>Arsenicum album</italic> (10%) und <italic>Thuja occidentalis</italic> (10%) waren die am h&#xe4;ufigsten indizierten Mittel. In beiden Gruppen wurden keine Sch&#xe4;digungen, unbeabsichtigten Wirkungen, hom&#xf6;opathischen Verschlechterungen oder jegliche schwerwiegenden unerw&#xfc;nschten Ereignisse beobachtet.<title>Schlussfolgerung</title>Die IHM erzielten signifikant bessere Effekte als Placebo in der Behandlung von Post-COVID-Erm&#xfc;dung bei Erwachsenen. Definitive, belastbare Studien k&#xf6;nnen eingeleitet werden, um diese Befunde zu best&#xe4;tigen.}, }
@article {pmid38008065, year = {2024}, author = {Maier, GS and Rosar, G and Dietz, G and Hemken, N and Kafchitsas, K and Seeger, JB and Horas, K}, title = {Effectiveness of Mud-Pack Therapy and Mud-Bath Therapy in Osteoarthritis: A Systematic Review.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {30-39}, doi = {10.1159/000535437}, pmid = {38008065}, issn = {2504-2106}, mesh = {Humans ; *Mud Therapy ; *Osteoarthritis, Knee ; *Osteoarthritis, Hip ; Quality of Life ; *Low Back Pain ; }, abstract = {OBJECTIVES: Osteoarthritis has a tremendous socioeconomic impact in terms of drug spending, hospital admissions, work productivity, and temporary or permanent incapacity. Mud therapy has been discussed as potential conservative treatment options for osteoarthritis. However, findings from several trials still remain controversial. For this reason, we aimed to systematically review the highest evidence provided by published trials to estimate the clinical effect of mud-pack and mud-bath therapy for the treatment of osteoarthritis.<br><br>METHODS: We searched PubMed, PEDro, and the Cochrane CENTRAL Register for Controlled Trials for articles published between 2000 and 2020 using the terms "orthopedics," "orthopaedics," "musculoskeletal," "osteoarthritis," and "mud bath," "mud pack."<br><br>RESULTS: Of the 19 studies included, 15 examined the effects of mud-bath therapy in knee osteoarthritis treatment. One study focused on the treatment effect of mud bath on hand osteoarthritis, another study examined treatment effects in hip and knee osteoarthritis, and two studies enrolled patients with chronic low back pain caused by lumbar spine osteoarthritis. We systematically reviewed the data obtained from the literature and summarized the results on the basis of the main outcomes. The results show significant improvements in function, quality of life, and perceived pain for patients with osteoarthritis.<br><br>CONCLUSION: Results of randomized controlled trials suggest that mud therapy is part of a promising integrated and synergistic multidisciplinary approach in combination with other treatment forms like pharmacotherapy or physiotherapy.<br><br>UNLABELLED: <title>Ziele</title>Die sozio-&#xf6;konomischen Auswirkungen der Arthrose sind immens. Heiltorfbehandlungen sind seit einiger Zeit als m&#xf6;gliche Erg&#xe4;nzung der konservativen Therapieoptionen dieser Erkrankung Gegenstand wissenschaftlicher Untersuchungen. Ziel dieser Studie war es, die aktuellen Erkenntnisse zur Heiltorftherapie bei Arthrose zusammenzufassen.<title>Methoden</title>Wir f&#xfc;hrten eine systematische Literaturrecherche der Datenbanken Pubmed, PEDro und Cochrane CENTRAL Register of Controlled Trials durch. Hierbei wurden Artikel, die zwischen 2000 und 2020 publiziert wurden und mit den Schlagw&#xf6;rtern &#x201c;orthopedics&#x201d;, &#x201c;orthopaedics&#x201d;, &#x201c;musculoskeletal&#x201d;, &#x201c;osteoarthritis&#x201d; und &#x201c;mud-bath&#x201d;, &#x201c;mud-pack&#x201d; assoziiert waren, erfasst.<title>Ergebnisse</title>Von den 19 n&#xe4;her untersuchten Studien besch&#xe4;ftigten sich 15 mit den Effekten der Heiltorftherapie bei Patienten mit Kniearthrose, eine Studie untersuchte Patienten mit Arthrose der Hand, eine weitere Studie untersuchte die Auswirkung der Therapie bei Arthrose der H&#xfc;fte. 2 Studien untersuchten den Effekt der Moorb&#xe4;der bei Patienten mit chronischen R&#xfc;ckenschmerzen. Insgesamt zeigten sich signifikante Verbesserungen der Funktion, Lebensqualit&#xe4;t und Schmerzlinderung bei den Patienten unter Heiltorftherapie.<title>Zusammenfassung</title>Die Ergebnisse der randomisierten, kontrollierten Studien zeigen, dass die Heiltorftherapie eine vielversprechende Erg&#xe4;nzung in einem multidisziplin&#xe4;ren Ansatz der Arthrosetherapie ist.}, }
@article {pmid38007795, year = {2023}, author = {Feng, T}, title = {Applications of Artificial Intelligence to Diagnosis of Neurodegenerative Diseases.}, journal = {Studies in health technology and informatics}, volume = {308}, number = {}, pages = {648-655}, doi = {10.3233/SHTI230896}, pmid = {38007795}, issn = {1879-8365}, mesh = {Humans ; Artificial Intelligence ; *Neurodegenerative Diseases/diagnostic imaging ; *Alzheimer Disease/diagnostic imaging ; Machine Learning ; Natural Language Processing ; }, abstract = {Artificial Intelligence (AI) is an umbrella term that represents a new technology for simulating and expanding human intelligence by using machines and computer systems. It consists of methods such as machine learning (ML), deep learning (DL), and natural language processing (NLP). In the era of big data, AI has emerged as an essential tool for improving the detection of neurodegenerative diseases, such as Alzheimer's diseases (AD), Parkinson's diseases, amyotrophic lateral sclerosis, etc. AI with its ability to extract critical information from the mass of data has enabled scientists to deal with various types of large-volume data, including genetic data, imaging data, and clinical data, rapidly generated in the course of neurodegenerative disease research. This review provides a comprehensive overview of the literature on current AI applications in the diagnosis of neurodegenerative diseases. Firstly, bioinformatics and AI approaches to identify potential biomarkers for neurodegenerative diseases such as AD are reviewed. Secondly, the use of ML and DL methods to analyze Magnetic Resonance Imaging (MRI) data for a better understanding of disease progression and predicting patient outcomes is discussed. Finally, the use of AI methods including NLP for Electronic Health Record (EHR) data analysis to extract meaningful information and identify patterns that may contribute to early diagnosis and treatment planning are reviewed. The potential benefits of AI-based approaches in improving patient outcomes and the challenges associated with their implementations are also discussed. Overall, this paper highlights the promise of AI in transforming the diagnosis and management of neurodegenerative diseases.}, }
@article {pmid38005288, year = {2023}, author = {Lapshina, MA and Shevtsova, EF and Grigoriev, VV and Aksinenko, AY and Ustyugov, AA and Steinberg, DA and Maleev, GV and Dubrovskaya, ES and Goreva, TV and Epishina, TA and Zamoyski, VL and Makhaeva, GF and Fisenko, VP and Veselov, IM and Vinogradova, DV and Bachurin, SO}, title = {New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {22}, pages = {}, pmid = {38005288}, issn = {1420-3049}, support = {19-13-00378-P//Russian Science Foundation/ ; }, mesh = {Humans ; Edaravone/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Adamantane ; Riluzole ; Amantadine/therapeutic use ; }, abstract = {Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have very limited efficacy. The aim of this work was to modify the structural core of the Edaravone-phenylpyrazolone moiety and combine it with aminoadamantane pharmacophore in order to expand the spectrum of its action to a number of processes involved in the pathogenesis of ALS. New conjugates of edaravone derivatives with 1-aminoadamantanes combined with alkylene or hydroxypropylene spacers were synthesized, and their biological activity was investigated. Compounds were found that could inhibit lipid peroxidation and calcium-related mitochondrial permeability, block fast sodium currents of CNS neurons, and reduce aggregation of the mutated form of the FUS-protein typical to ALS. So, the proposed modification of the edaravone molecule has allowed the obtaining of new original structures that combine some prospective therapeutic mechanisms against key chains of the pathogenesis of ALS. The identified lead compounds can be used for further optimization and development of new promising drugs on this basis for the treatment of ALS.}, }
@article {pmid38003309, year = {2023}, author = {Toader, C and Dobrin, N and Brehar, FM and Popa, C and Covache-Busuioc, RA and Glavan, LA and Costin, HP and Bratu, BG and Corlatescu, AD and Popa, AA and Ciurea, AV}, title = {From Recognition to Remedy: The Significance of Biomarkers in Neurodegenerative Disease Pathology.}, journal = {International journal of molecular sciences}, volume = {24}, number = {22}, pages = {}, pmid = {38003309}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Amyotrophic Lateral Sclerosis ; *Parkinson Disease/diagnosis/metabolism ; *Alzheimer Disease/diagnosis ; Biomarkers/metabolism ; }, abstract = {With the inexorable aging of the global populace, neurodegenerative diseases (NDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose escalating challenges, which are underscored by their socioeconomic repercussions. A pivotal aspect in addressing these challenges lies in the elucidation and application of biomarkers for timely diagnosis, vigilant monitoring, and effective treatment modalities. This review delineates the quintessence of biomarkers in the realm of NDs, elucidating various classifications and their indispensable roles. Particularly, the quest for novel biomarkers in AD, transcending traditional markers in PD, and the frontier of biomarker research in ALS are scrutinized. Emergent susceptibility and trait markers herald a new era of personalized medicine, promising enhanced treatment initiation especially in cases of SOD1-ALS. The discourse extends to diagnostic and state markers, revolutionizing early detection and monitoring, alongside progression markers that unveil the trajectory of NDs, propelling forward the potential for tailored interventions. The synergy between burgeoning technologies and innovative techniques like -omics, histologic assessments, and imaging is spotlighted, underscoring their pivotal roles in biomarker discovery. Reflecting on the progress hitherto, the review underscores the exigent need for multidisciplinary collaborations to surmount the challenges ahead, accelerate biomarker discovery, and herald a new epoch of understanding and managing NDs. Through a panoramic lens, this article endeavors to provide a comprehensive insight into the burgeoning field of biomarkers in NDs, spotlighting the promise they hold in transforming the diagnostic landscape, enhancing disease management, and illuminating the pathway toward efficacious therapeutic interventions.}, }
@article {pmid38002490, year = {2023}, author = {Yang, J and Xin, C and Huo, J and Li, X and Dong, H and Liu, Q and Li, R and Liu, Y}, title = {Rab Geranylgeranyltransferase Subunit Beta as a Potential Indicator to Assess the Progression of Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {13}, number = {11}, pages = {}, pmid = {38002490}, issn = {2076-3425}, support = {H2021206310//Natural Science Foundation of Hebei Province/ ; }, abstract = {BACKGROUND: Currently, there is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder. Many biomarkers have been proposed, but because ALS is a clinically heterogeneous disease with an unclear etiology, biomarker discovery for ALS has been challenging due to the lack of specificity of these biomarkers. In recent years, the role of autophagy in the development and treatment of ALS has become a research hotspot. In our previous studies, we found that the expression of RabGGTase (low RABGGTB expression and no change in RABGGTA) is lower in the lumbar and thoracic regions of spinal cord motoneurons in SOD1G93A mice compared with WT (wild-type) mice groups, and upregulation of RABGGTB promoted prenylation modification of Rab7, which promoted autophagy to protect neurons by degrading SOD1. Given that RabGGTase is associated with autophagy and autophagy is associated with inflammation, and based on the above findings, since peripheral blood mononuclear cells are readily available from patients with ALS, we proposed to investigate the expression of RabGGTase in peripheral inflammatory cells.<br><br>METHODS: Information and venous blood were collected from 86 patients diagnosed with ALS between January 2021 and August 2023. Flow cytometry was used to detect the expression of RABGGTB in monocytes from peripheral blood samples collected from patients with ALS and healthy controls. Extracted peripheral blood mononuclear cells (PBMCs) were differentiated in vitro into macrophages, and then the expression of RABGGTB was detected by immunofluorescence. RABGGTB levels in patients with ALS were analyzed to determine their impact on disease progression.<br><br>RESULTS: Using flow cytometry in monocytes and immunofluorescence in macrophages, we found that RABGGTB expression in the ALS group was significantly higher than in the control group. Age, sex, original location, disease course, C-reactive protein (CRP), and interleukin-6 (IL-6) did not correlate with the ALS functional rating scale-revised (ALSFRS-R), whereas the RABGGTB level was significantly correlated with the ALSFRS-R. In addition, multivariate analysis revealed a significant correlation between RABGGTB and ALSFRS-R score. Further analysis revealed a significant correlation between RABGGTB expression levels and disease progression levels (&#x394;FS).<br><br>CONCLUSIONS: The RABGGTB level was significantly increased in patients with ALS compared with healthy controls. An elevated RABGGTB level in patients with ALS is associated with the rate of progression in ALS, suggesting that elevated RABGGTB levels in patients with ALS may serve as an indicator for tracking ALS progression.}, }
@article {pmid38001967, year = {2023}, author = {Seki, S and Kitaoka, Y and Kawata, S and Nishiura, A and Uchihashi, T and Hiraoka, SI and Yokota, Y and Isomura, ET and Kogo, M and Tanaka, S}, title = {Characteristics of Sensory Neuron Dysfunction in Amyotrophic Lateral Sclerosis (ALS): Potential for ALS Therapy.}, journal = {Biomedicines}, volume = {11}, number = {11}, pages = {}, pmid = {38001967}, issn = {2227-9059}, support = {21K17088//JSPS KAKENHI/ ; 20H03887//JSPS KAKENHI/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by the progressive degeneration of motor neurons, resulting in muscle weakness, paralysis, and, ultimately, death. Presently, no effective treatment for ALS has been established. Although motor neuron dysfunction is a hallmark of ALS, emerging evidence suggests that sensory neurons are also involved in the disease. In clinical research, 30% of patients with ALS had sensory symptoms and abnormal sensory nerve conduction studies in the lower extremities. Peroneal nerve biopsies show histological abnormalities in 90% of the patients. Preclinical research has reported several genetic abnormalities in the sensory neurons of animal models of ALS, as well as in motor neurons. Furthermore, the aggregation of misfolded proteins like TAR DNA-binding protein 43 has been reported in sensory neurons. This review aims to provide a comprehensive description of ALS-related sensory neuron dysfunction, focusing on its clinical changes and underlying mechanisms. Sensory neuron abnormalities in ALS are not limited to somatosensory issues; proprioceptive sensory neurons, such as MesV and DRG neurons, have been reported to form networks with motor neurons and may be involved in motor control. Despite receiving limited attention, sensory neuron abnormalities in ALS hold potential for new therapies targeting proprioceptive sensory neurons.}, }
@article {pmid38001861, year = {2023}, author = {Fu, RH}, title = {Pectolinarigenin Improves Oxidative Stress and Apoptosis in Mouse NSC-34 Motor Neuron Cell Lines Induced by C9-ALS-Associated Proline-Arginine Dipeptide Repeat Proteins by Enhancing Mitochondrial Fusion Mediated via the SIRT3/OPA1 Axis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {11}, pages = {}, pmid = {38001861}, issn = {2076-3921}, support = {MOST 105-2314-B-039-017-MY3//The Ministry of Science and Technology (Taiwan)/ ; DMR112-122//China Medical University Hospital (Taiwan)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is considered a fatal progressive degeneration of motor neurons (MN) caused by oxidative stress and mitochondrial dysfunction. There are currently no treatments available. The most common inherited form of ALS is the C9orf72 mutation (C9-ALS). The proline-arginine dipeptide repeat protein (PR-DPR) produced by C9-ALS has been confirmed to be a functionally acquired pathogenic factor that can cause increased ROS, mitochondrial defects, and apoptosis in motor neurons. Pectolinarigenin (PLG) from the traditional medicinal herb Linaria vulgaris has antioxidant and anti-apoptotic properties. I established a mouse NSC-34 motor neuron cell line model expressing PR-DPR and confirmed the neuroprotective effect of PLG. The results showed that ROS production and apoptosis caused by PR-DPR could be improved by PLG treatment. In terms of mechanism research, PR-DPR inhibited the activity of the mitochondrial fusion proteins OPA1 and mitofusin 2. Conversely, the expression of fission protein fission 1 and dynamin-related protein 1 (DRP1) increased. However, PLG treatment reversed these effects. Furthermore, I found that PLG increased the expression and deacetylation of OPA1. Deacetylation of OPA1 enhances mitochondrial fusion and resistance to apoptosis. Finally, transfection with Sirt3 small interfering RNA abolished the neuroprotective effects of PLG. In summary, the mechanism by which PLG alleviates PR-DPR toxicity is mainly achieved by activating the SIRT3/OPA1 axis to regulate the balance of mitochondrial dynamics. Taken together, the potential of PLG in preclinical studies for C9-ALS drug development deserves further evaluation.}, }
@article {pmid38001557, year = {2024}, author = {Genge, A and Wainwright, S and Vande Velde, C}, title = {Amyotrophic lateral sclerosis: exploring pathophysiology in the context of treatment.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {225-236}, doi = {10.1080/21678421.2023.2278503}, pmid = {38001557}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex, neurodegenerative disorder in which alterations in structural, physiological, and metabolic parameters act synergistically. Over the last decade there has been a considerable focus on developing drugs to slow the progression of the disease. Despite this, only four disease-modifying therapies are approved in North America. Although additional research is required for a thorough understanding of ALS, we have accumulated a large amount of knowledge that could be better integrated into future clinical trials to accelerate drug development and provide patients with improved treatment options. It is likely that future, successful ALS treatments will take a multi-pronged therapeutic approach, targeting different pathways, akin to personalized medicine in oncology. In this review, we discuss the link between ALS pathophysiology and treatments, looking at the therapeutic failures as learning opportunities that can help us refine and optimize drug development.}, }
@article {pmid38001260, year = {2023}, author = {Kuan, LH and Parnianpour, P and Kushol, R and Kumar, N and Anand, T and Kalra, S and Greiner, R}, title = {Accurate personalized survival prediction for amyotrophic lateral sclerosis patients.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {20713}, pmid = {38001260}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Neurodegenerative Diseases ; Probability ; Brain ; Learning ; Disease Progression ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease. Accurately predicting the survival time for ALS patients can help patients and clinicians to plan for future treatment and care. We describe the application of a machine-learned tool that incorporates clinical features and cortical thickness from brain magnetic resonance (MR) images to estimate the time until a composite respiratory failure event for ALS patients, and presents the prediction as individual survival distributions (ISDs). These ISDs provide the probability of survival (none of the respiratory failures) at multiple future time points, for each individual patient. Our learner considers several survival prediction models, and selects the best model to provide predictions. We evaluate our learned model using the mean absolute error margin (MAE-margin), a modified version of mean absolute error that handles data with censored outcomes. We show that our tool can provide helpful information for patients and clinicians in planning future treatment.}, }
@article {pmid37992921, year = {2024}, author = {Li, L and Lei, T and Xing, C and Du, H}, title = {Advances in microfluidic chips targeting toxic aggregation proteins for neurodegenerative diseases.}, journal = {International journal of biological macromolecules}, volume = {256}, number = {Pt 2}, pages = {128308}, doi = {10.1016/j.ijbiomac.2023.128308}, pmid = {37992921}, issn = {1879-0003}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Microfluidics ; *Alzheimer Disease ; Amyloid beta-Peptides ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by nervous system damage, often influenced by genetic and aging factors. Pathological analysis frequently reveals the presence of aggregated toxic proteins. The intricate and poorly understood origins of these diseases have hindered progress in early diagnosis and drug development. The development of novel in-vitro and in-vivo models could enhance our comprehension of ND mechanisms and facilitate clinical treatment advancements. Microfluidic chips are employed to establish three-dimensional culture conditions, replicating the human ecological niche and creating a microenvironment conducive to neuronal cell survival. The incorporation of mechatronic controls unifies the chip, cells, and culture medium optimizing living conditions for the cells. This study provides a comprehensive overview of microfluidic chip applications in drug and biomarker screening for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Our Lab-on-a-Chip system releases toxic proteins to simulate the pathological characteristics of neurodegenerative diseases, encompassing β-amyloid, α-synuclein, huntingtin, TAR DNA-binding protein 43, and Myelin Basic Protein. Investigating molecular and cellular interactions in vitro can enhance our understanding of disease mechanisms while minimizing harmful protein levels and can aid in screening potential therapeutic agents. We anticipate that our research will promote the utilization of microfluidic chips in both fundamental research and clinical applications for neurodegenerative diseases.}, }
@article {pmid37992159, year = {2023}, author = {Shimizu, M and Shiraishi, N and Tada, S and Sasaki, T and Beck, G and Nagano, S and Kinoshita, M and Sumi, H and Sugimoto, T and Ishida, Y and Koda, T and Ishikura, T and Sugiyama, Y and Kihara, K and Kanakura, M and Nakajima, T and Takeda, S and Takahashi, MP and Yamashita, T and Okuno, T and Mochizuki, H}, title = {RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS.}, journal = {Science advances}, volume = {9}, number = {47}, pages = {eadg3193}, pmid = {37992159}, issn = {2375-2548}, mesh = {Animals ; Humans ; Mice ; Actins ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Antibodies ; Mice, Transgenic ; Motor Neurons/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone-collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we demonstrated that RGMa concentration was elevated in the cerebrospinal fluid of both patients with ALS and transgenic mice overexpressing the mutant human superoxide dismutase1 (mSOD1 mice). Treatment with humanized anti-RGMa monoclonal antibody ameliorated the clinical symptoms in mSOD1 mice. Histochemical analysis revealed that the anti-RGMa antibody significantly decreased mutant SOD1 protein accumulation in the motor neurons of mSOD1 mice via inhibition of actin depolymerization. In vitro analysis revealed that the anti-RGMa antibody inhibited the cellular uptake of the mutant SOD1 protein, presumably by reinforcing the neuronal actin barrier. Collectively, these data suggest that RGMa leads to the collapse of the neuronal actin barrier and promotes aberrant protein deposition, resulting in exacerbation of the ALS pathology.}, }
@article {pmid37986827, year = {2023}, author = {Simmonds, E and Levine, KS and Han, J and Iwaki, H and Koretsky, MJ and Kuznetsov, N and Faghri, F and Solsberg, CW and Schuh, A and Jones, L and Bandres-Ciga, S and Blauwendraat, C and Singleton, A and Escott-Price, V and Leonard, HL and Nalls, MA}, title = {Sleep disturbances as risk factors for neurodegeneration later in life.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {37986827}, abstract = {The relationship between sleep disorders and neurodegeneration is complex and multi-faceted. Using over one million electronic health records (EHRs) from Wales, UK, and Finland, we mined biobank data to identify the relationships between sleep disorders and the subsequent manifestation of neurodegenerative diseases (NDDs) later in life. We then examined how these sleep disorders' severity impacts neurodegeneration risk. Additionally, we investigated how sleep attributed risk may compensate for the lack of genetic risk factors (i.e. a lower polygenic risk score) in NDD manifestation. We found that sleep disorders such as sleep apnea were associated with the risk of Alzheimer's disease (AD), amyotrophic lateral sclerosis, dementia, Parkinson's disease (PD), and vascular dementia in three national scale biobanks, with hazard ratios (HRs) ranging from 1.31 for PD to 5.11 for dementia. These sleep disorders imparted significant risk up to 15 years before the onset of an NDD. Cumulative number of sleep disorders in the EHRs were associated with a higher risk of neurodegeneration for dementia and vascular dementia. Sleep related risk factors were independent of genetic risk for Alzheimer's and Parkinson's, potentially compensating for low genetic risk in overall disease etiology. There is a significant multiplicative interaction regarding the combined risk of sleep disorders and Parkinson's disease. Poor sleep hygiene and sleep apnea are relatively modifiable risk factors with several treatment options, including CPAP and surgery, that could potentially reduce the risk of neurodegeneration. This is particularly interesting in how sleep related risk factors are significantly and independently enriched in manifesting NDD patients with low levels of genetic risk factors for these diseases.}, }
@article {pmid37984338, year = {2023}, author = {Topaloğlu Ören, ED and Dorukoğlu, S and Ertem, G}, title = {The Use of Complementary and Alternative Medicine and Coping with Stress by Patients with Gynecological Cancer: A Cross-Sectional Study in Türkiye.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {502-516}, doi = {10.1159/000534707}, pmid = {37984338}, issn = {2504-2106}, mesh = {Humans ; Female ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Cross-Sectional Studies ; Turkey ; *Neoplasms ; *Complementary Therapies ; Adaptation, Psychological ; }, abstract = {INTRODUCTION: Gynecological cancers are long-term, challenging, and stressful diseases. In Türkiye, the majority of patients with gynecological cancer use complementary and alternative medicine (CAM). Considering the stress that gynecological cancer patients are exposed to, patients need to know how to cope with stress.<br><br>OBJECTIVE: This study aimed to determine the use of CAM and coping with stress by patients with gynecological cancer and the relationships between them and the factors that predict the approaches to coping with stress in women with gynecological cancer in T&#xfc;rkiye.<br><br>METHODS: This is a descriptive and cross-sectional study. The study was conducted with 204 patients between April and August 2022. The data of the study were collected by face-to-face interview and filled out by the patients using the Descriptive Information Form and the Stress Coping Styles Scale (SCSS). Number, percentage, mean, &#x3c7;2, one-way ANOVA, t test, and the Spearman correlation analysis were used in the data analysis. To analyze the multivariate independent associations between variables, a multivariate ordinal logistic regression model was used, with the SCSS domains as dependent variables. A 95% confidence interval was calculated, and all statistical tests had an alpha level of 0.05.<br><br>RESULTS: The mean age of the patients was 58.38 &#xb1; 12.64 years (32-80). The prevalence of CAM use by patients was 39.2%, and the most common types of CAM were herbal products (43.8%) and supplication (42.5%). The reasons for using CAM were relaxation (symptomatic)-feeling healthy (63.8%) and treating cancer (36.2%). No statistically significant difference was found between the use of CAM and their approaches to coping with stress (p > 0.05). As a result of multivariate ordinal logistic regression analysis, education level under high school, having ovary, cervix, and endometrium cancer, being in the first stage of cancer, receiving chemotherapy, receiving surgical treatment, having another cancer patient in the social environment and increased interest in a partner after the diagnosis of cancer was associated with an effective coping with stress (p < 0.05, adjusted R2 = 0.27, 0.79, and 0.32, respectively). Not working, experiencing an abortion, having another cancer patient in their social environment, being in the third stage of cancer, having an extended family, and living in a rural area of residence were associated with ineffective coping with stress (p < 0.05, adjusted R2 = 0.20 and 0.24, respectively).<br><br>CONCLUSIONS: The prevalence of CAM use by patients was low. While determining the approaches of the patients to cope with stress, their education level, place of residence, family type, diagnosis of cancer, stage of cancer, treatment, partner support, and stressful life events should be considered. As nurses, we need to be more knowledgeable about the use of CAM to provide correct guidance to our patients for access to accurate and effective information. We need to determine our patients' stressors and how our patients cope with stress.<br><br>UNLABELLED: <title>Einleitung</title>Gyn&#xe4;kologische Krebserkrankungen sind langfristige, herausfordernde und belastende Krankheiten. In der T&#xfc;rkei nehmen die meisten Patientinnen mit gyn&#xe4;kologischen Krebserkrankungen Komplement&#xe4;r- und Alternativmedizin in Anspruch. Angesichts der gro&#xdf;en Belastungen, denen Patientinnen mit gyn&#xe4;kologischen Krebserkrankungen ausgesetzt sind, m&#xfc;ssen sie wissen, wie sie mit Stress umgehen k&#xf6;nnen.<title>Ziel</title>Mit dieser Studie sollen die Inanspruchnahme von Komplement&#xe4;r- und Alternativmedizin und die Stressbew&#xe4;ltigung von Patientinnen mit gyn&#xe4;kologischer Krebserkrankung ermittelt werden und es sollen die Zusammenh&#xe4;nge zwischen diesen beiden Aspekten und den pr&#xe4;diktiven Faktoren f&#xfc;r die Ans&#xe4;tze zur Stressbew&#xe4;ltigung bei Frauen mit gyn&#xe4;kologischer Krebserkrankung untersucht werden.<title>Methoden</title>Es handelt sich um eine deskriptive Querschnittsstudie. Die Studie wurde mit 204 Patientinnen zwischen April und August 2022 durchgef&#xfc;hrt. Die Erhebung der Studiendaten erfolgte durch pers&#xf6;nliche Befragung und mithilfe des deskriptiven Informationsformulars sowie der Stress Coping Styles-Skala, die die Patientinnen ausf&#xfc;llten. F&#xfc;r die Datenanalyse wurden Anzahl, Prozentanteil, Mittelwert, Chi-Quadrat-Test, einfaktorielle ANOVA, <italic>t</italic> Test und die Spearman-Korrelationsanalyse verwendet. Zur Analyse der multivariaten unabh&#xe4;ngigen Zusammenh&#xe4;nge zwischen den Variablen wurde ein multivariates ordinales logistisches Regressionsmodell verwendet mit den SCSS (Stress Coping Styles-Skala)-Dom&#xe4;nen als abh&#xe4;ngigen Variablen. Es wurde ein 95%-Konfidenzintervall berechnet, und das Signifikanzniveau betrug f&#xfc;r alle statistischen Tests &#x3b1; = 0.05.<title>Ergebnisse</title>Das Durchschnittsalter der Patientinnen betrug 58.38 &#xb1; 12.64 Jahre (32&#x2013;80 Jahre). Die Pr&#xe4;valenz der Inanspruchnahme von Komplement&#xe4;r- und Alternativmedizin (CAM) durch die Patientinnen lag bei 39.2%, und die h&#xe4;ufigsten CAM-Arten waren pflanzliche Produkte (43.8%) und Bittgebete (42.5%). Die Gr&#xfc;nde f&#xfc;r die Inanspruchnahme von Komplement&#xe4;r- und Alternativmedizin waren Entspannung (symptomatisch), das Gef&#xfc;hl von Gesundheit (63.8%) und die Behandlung der Krebserkrankung (36.2%). Es fand sich kein statistisch signifikanter Unterschied zwischen der Inanspruchnahme von Komplement&#xe4;r- und Alternativmedizin und ihren Ans&#xe4;tzen zur Stressbew&#xe4;ltigung (<italic>p</italic> > 0.05). Die multivariate ordinale logistische Regressionsanalyse zeigte, dass ein Bildungsniveau unterhalb der Oberstufe sowie Ovarial-, Zervix- und Endometriumkarzinom, Krebs im Anfangsstadium, Chemotherapie, operative Behandlung, eine andere Krebspatientin im sozialen Umfeld und ein gesteigertes Interesse an einem Partner nach der Krebsdiagnose mit effektiver Stressbew&#xe4;ltigung assoziiert waren (<italic>p</italic> < 0.05, adjustiertes <italic>R</italic>2 = 0.27, 0.79 bzw. 0.32). Fehlende Berufst&#xe4;tigkeit, Fehlgeburt/Schwangerschaftsabbruch, eine andere Krebspatientin im sozialen Umfeld, eine Krebserkrankung im dritten Stadium, eine Gro&#xdf;familie zu haben und in einer l&#xe4;ndlichen Gegend zu leben waren mit ineffektiver Stressbew&#xe4;ltigung verbunden (<italic>p</italic> < 0.05, adjustiertes <italic>R</italic>2 = 0.20 bzw. 0.24).<title>Schlussfolgerungen</title>Die Pr&#xe4;valenz der Inanspruchnahme von Komplement&#xe4;r- und Alternativmedizin durch die Patientinnen war gering. Bei der Ermittlung der Ans&#xe4;tze der Patientinnen zur Stressbew&#xe4;ltigung sollten ihr Bildungsniveau, ihr Wohnort, ihr Familientyp, die Krebsdiagnose, das Krebsstadium, die Behandlung, die Unterst&#xfc;tzung durch den Partner und belastende Lebensereignisse ber&#xfc;cksichtigt werden. Als Pflegekr&#xe4;fte m&#xfc;ssen wir mehr &#xfc;ber die Inanspruchnahme von Komplement&#xe4;r- und Alternativmedizin wissen, um unsere Patientinnen in Hinblick auf den Zugang zu genauen und wirksamen Informationen die richtige Orientierungshilfe zu geben. Wir m&#xfc;ssen die Stressfaktoren unserer Patientinnen ermitteln und herausfinden, wie unsere Patientinnen mit Stress umgehen.}, }
@article {pmid37983563, year = {2024}, author = {Wen, D and Ji, Y and Li, Y and Duan, W and Wang, Y and Li, Z and Tao, M and Liu, Y}, title = {OPTN gene therapy increases autophagy and protects mitochondria in SOD1-G93A-expressing transgenic mice and cells.}, journal = {The FEBS journal}, volume = {291}, number = {4}, pages = {795-813}, doi = {10.1111/febs.17009}, pmid = {37983563}, issn = {1742-4658}, support = {H2021206048//Hebei Natural Science Foundation/ ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; Superoxide Dismutase/genetics/metabolism ; Autophagy/genetics ; Mitochondria/genetics/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron (MN) death. Mutation of the superoxide dismutase 1 (SOD1) gene, which results in abnormal protein aggregation, is one of the causes of familial ALS. Autophagic dysfunction occurs in SOD1-G93A mutant mice as the disease progresses, but the etiology of this disease is still unclear. Optineurin (OPTN) is an adaptor that is involved in autophagy and participates in aggrephagy and mitophagy. Previous studies have established that OPTN mutations contribute to diseases such as glaucoma and ALS. However, the function of OPTN in autophagy and mitophagy has not been intensively investigated in models of ALS. In this study, we assessed the beneficial effect of OPTN on autophagy and mitochondrial function by intrathecally injecting adeno-associated virus 9 (AAV9)-OPTN into SOD1-G93A transgenic mice and by administering lentivirus (LV)-OPTN to cells expressing the SOD1-G93A mutant protein. The expression of voltage-dependent anion channel 1 (VDAC1) was increased and autophagy was elevated after OPTN gene therapy, as shown by a lower level of p62 and a higher level of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II. Moreover, using electron microscopy, we observed a hyperpolarized mitochondrial transmembrane potential and reversal of mitochondrial morphological abnormalities. Furthermore, the protein level of TANK-binding kinase 1 (TBK1) was increased, suggesting that mitophagy was increased. Our findings from both animal and cell line studies strongly suggest that OPTN gene therapy is a powerful strategy to increase autophagy and protect mitochondria to prevent the progression of ALS and could be effective in the treatment of ALS.}, }
@article {pmid37982993, year = {2023}, author = {Tsui, A and Kouznetsova, VL and Kesari, S and Fiala, M and Tsigelny, IF}, title = {Role of Senataxin in Amyotrophic Lateral Sclerosis.}, journal = {Journal of molecular neuroscience : MN}, volume = {73}, number = {11-12}, pages = {996-1009}, pmid = {37982993}, issn = {1559-1166}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Motor Neurons/metabolism ; Gene Expression Regulation ; Mutation ; DNA Helicases/genetics ; RNA Helicases/genetics/metabolism ; Multifunctional Enzymes/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, uncurable neurodegenerative disorder characterized by the degradation of motor neurons leading to muscle impairment, failure, and death. Senataxin, encoded by the SETX gene, is a human helicase protein whose mutations have been linked with ALS onset, particularly in its juvenile ALS4 form. Using senataxin's yeast homolog Sen1 as a model for study, it is suggested that senataxin's N-terminus interacts with RNA polymerase II, whilst its C-terminus engages in helicase activity. Senataxin is heavily involved in transcription regulation, termination, and R-loop resolution, enabled by recruitment and interactions with enzymes such as ubiquitin protein ligase SAN1 and ribonuclease H (RNase H). Senataxin also engages in DNA damage response (DDR), primarily interacting with the exosome subunit Rrp45. The Sen1 mutation E1597K, alongside the L389S and R2136H gain-of-function mutations to senataxin, is shown to cause negative structural and thus functional effects to the protein, thus contributing to a disruption in WT functions, motor neuron (MN) degeneration, and the manifestation of ALS clinical symptoms. This review corroborates and summarizes published papers concerning the structure and function of senataxin as well as the effects of their mutations in ALS pathology in order to compile current knowledge and provide a reference for future research. The findings compiled in this review are indicative of the experimental and therapeutic potential of senataxin and its mutations as a target in future ALS treatment/cure discovery, with some potential therapeutic routes also being discussed in the review.}, }
@article {pmid37981210, year = {2024}, author = {Kim, Y and Lee, Y and Choo, M and Yun, N and Cho, JW and Oh, YJ}, title = {A surge of cytosolic calcium dysregulates lysosomal function and impairs autophagy flux during cupric chloride-induced neuronal death.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {1}, pages = {105479}, pmid = {37981210}, issn = {1083-351X}, mesh = {*Autophagy/drug effects/genetics ; *Calcium/metabolism ; *Copper/pharmacology ; *Dopaminergic Neurons/cytology/drug effects/metabolism/ultrastructure ; *Lysosomes/metabolism ; Animals ; Mice ; Cell Line ; Cell Survival/drug effects ; Cytosol/metabolism ; }, abstract = {Autophagy is a degradative pathway that plays an important role in maintaining cellular homeostasis. Dysfunction of autophagy is associated with the progression of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although one of the typical features of brain aging is an accumulation of redox-active metals that eventually lead to neurodegeneration, a plausible link between trace metal-induced neurodegeneration and dysregulated autophagy has not been clearly determined. Here, we used a cupric chloride-induced neurodegeneration model in MN9D dopaminergic neuronal cells along with ultrastructural and biochemical analyses to demonstrate impaired autophagic flux with accompanying lysosomal dysfunction. We found that a surge of cytosolic calcium was involved in cupric chloride-induced dysregulated autophagy. Consequently, buffering of cytosolic calcium by calbindin-D28K overexpression or co-treatment with the calcium chelator BAPTA attenuated the cupric chloride-induced impairment in autophagic flux by ameliorating dysregulation of lysosomal function. Thus, these events allowed the rescue of cells from cupric chloride-induced neuronal death. These phenomena were largely confirmed in cupric chloride-treated primary cultures of cortical neurons. Taken together, these results suggest that abnormal accumulation of trace metal elements and a resultant surge of cytosolic calcium leads to neuronal death by impairing autophagic flux at the lysosomal level.}, }
@article {pmid37977335, year = {2023}, author = {Benussi, A and Cantoni, V and Grassi, M and Libri, I and Cotelli, MS and Tarantino, B and Datta, A and Thomas, C and Huber, N and Kärkkäinen, S and Herukka, SK and Haapasalo, A and Filosto, M and Padovani, A and Borroni, B}, title = {Cortico-spinal tDCS in amyotrophic lateral sclerosis: A randomized, double-blind, sham-controlled trial followed by an open-label phase.}, journal = {Brain stimulation}, volume = {16}, number = {6}, pages = {1666-1676}, doi = {10.1016/j.brs.2023.11.008}, pmid = {37977335}, issn = {1876-4754}, mesh = {Humans ; *Transcranial Direct Current Stimulation ; *Amyotrophic Lateral Sclerosis/therapy ; Quality of Life ; Transcranial Magnetic Stimulation ; Double-Blind Method ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive disease for which no curative treatment is currently available.<br><br>OBJECTIVE: This study aimed to investigate whether cortico-spinal transcranial direct current stimulation (tDCS) could mitigate symptoms in ALS patients via a randomized, double-blind, sham-controlled trial, followed by an open-label phase.<br><br>METHODS: Thirty-one participants were randomized into two groups for the initial controlled phase. At baseline (T0), Group 1 received placebo stimulation (sham tDCS), while Group 2 received cortico-spinal stimulation (real tDCS) for five days/week for two weeks (T1), with an 8-week (T2) follow-up (randomized, double-blind, sham-controlled phase). At the 24-week follow-up (T3), all participants (Groups 1 and 2) received a second treatment of anodal bilateral motor cortex and cathodal spinal stimulation (real tDCS) for five days/week for two weeks (T4). Follow-up evaluations were performed at 32-weeks (T5) and 48-weeks (T6) (open-label phase). At each time point, clinical assessment, blood sampling, and intracortical connectivity measures using transcranial magnetic stimulation (TMS) were evaluated. Additionally, we evaluated survival rates.<br><br>RESULTS: Compared to sham stimulation, cortico-spinal tDCS significantly improved global strength, caregiver burden, and quality of life scores, which correlated with the restoration of intracortical connectivity measures. Serum neurofilament light levels decreased among patients who underwent real tDCS but not in those receiving sham tDCS. The number of completed 2-week tDCS treatments significantly influenced patient survival.<br><br>CONCLUSIONS: Cortico-spinal tDCS may represent a promising therapeutic and rehabilitative approach for patients with ALS. Further larger-scale studies are necessary to evaluate whether tDCS could potentially impact patient survival.<br><br>CLINICAL TRIAL REGISTRATION: NCT04293484.}, }
@article {pmid37975798, year = {2024}, author = {Saini, A and Chawla, PA}, title = {Breaking barriers with tofersen: Enhancing therapeutic opportunities in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {2}, pages = {e16140}, pmid = {37975798}, issn = {1468-1331}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases ; Oligonucleotides/therapeutic use ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects adults, characterized by muscle weakness resulting from the specific death of motor neurons in the spinal cord and brain. The pathogenesis of ALS is associated with the accumulation of mutant superoxide dismutase 1 (SOD1) proteins and neurofilaments in motor neurons, highlighting the critical need for disease-modifying treatments. Current therapies, such as riluzole and edaravone, provide only symptomatic relief. Recently, tofersen gained approval from the US FDA under the brand name Qalsody as the first and only gene therapy for ALS, addressing a significant pathological aspect of the disease.<br><br>METHODS: We carried out a literature survey using PubMed, Scopus, National Institutes of Health, and Biogen for articles published in the English language concerned with "amyotrophic lateral sclerosis", pathophysiology, current treatment, treatment under clinical trial, and the newly approved drug "tofersen" and its detailed summary.<br><br>RESULTS: A comprehensive review of the literature on the pathophysiology, available treatment, and newly approved drug for this condition revealed convincing evidence that we are now able to better monitor and treat ALS.<br><br>CONCLUSIONS: Although treatment of ALS is difficult, the newly approved drug tofersen has emerged as a potential therapy to slow down the progression of ALS by targeting SOD1 mRNA, representing a significant advancement in the treatment of ALS.}, }
@article {pmid37975796, year = {2024}, author = {Witzel, S and Statland, JM and Steinacker, P and Otto, M and Dorst, J and Schuster, J and Barohn, RJ and Ludolph, AC}, title = {Longitudinal course of neurofilament light chain levels in amyotrophic lateral sclerosis-insights from a completed randomized controlled trial with rasagiline.}, journal = {European journal of neurology}, volume = {31}, number = {3}, pages = {e16154}, pmid = {37975796}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Intermediate Filaments ; Biomarkers ; Neurofilament Proteins ; Disease Progression ; *Indans ; }, abstract = {BACKGROUND AND PURPOSE: Rasagiline might be disease modifying in patients with amyotrophic lateral sclerosis (ALS). The aim was to evaluate the effect of rasagiline 2 mg/day on neurofilament light chain (NfL), a prognostic biomarker in ALS.<br><br>METHODS: In 65 patients with ALS randomized in a 3:1 ratio to rasagiline 2&#x2009;mg/day (n&#x2009;=&#x2009;48) or placebo (n&#x2009;=&#x2009;17) in a completed randomized controlled multicentre trial, NfL levels in plasma were measured at baseline, month 6 and month 12. Longitudinal changes in NfL levels were evaluated regarding treatment and clinical parameters.<br><br>RESULTS: Baseline NfL levels did not differ between the study arms and correlated with disease progression rates both pre-baseline (r&#x2009;=&#x2009;0.64, p&#x2009;<&#x2009;0.001) and during the study (r&#x2009;= 0.61, p&#x2009;<&#x2009;0.001). NfL measured at months 6 and 12 did not change significantly from baseline in both arms, with a median individual NfL change of +1.4&#x2009;pg/mL (interquartile range [IQR] -5.6, 14.2) across all follow-up time points. However, a significant difference in NfL change at month 12 was observed between patients with high and low NfL baseline levels treated with rasagiline (high [n&#x2009;=&#x2009;13], -6.9&#x2009;pg/mL, IQR -20.4, 6.0; low [n&#x2009;=&#x2009;18], +5.9&#x2009;pg/mL, IQR -1.4, 19.7; p&#x2009;=&#x2009;0.025). Additionally, generally higher longitudinal NfL variability was observed in patients with high baseline levels, whereas disease progression rates and disease duration at baseline had no impact on the longitudinal NfL course.<br><br>CONCLUSION: Post hoc NfL measurements in completed clinical trials are helpful in interpreting NfL data from ongoing and future interventional trials and could provide hypothesis-generating complementary insights. Further studies are warranted to ultimately differentiate NfL response to treatment from other factors.}, }
@article {pmid37975632, year = {2024}, author = {Fornage, LB and O'Neil, C and Dowker, SR and Wanta, ER and Lewis, RS and Brown, LH}, title = {Prehospital Intervention Improves Outcomes for Patients Presenting in Atrial Fibrillation with Rapid Ventricular Response.}, journal = {Prehospital emergency care}, volume = {28}, number = {7}, pages = {910-919}, doi = {10.1080/10903127.2023.2283885}, pmid = {37975632}, issn = {1545-0066}, mesh = {Humans ; Retrospective Studies ; Male ; Female ; *Atrial Fibrillation/therapy/drug therapy ; Aged ; *Emergency Medical Services/methods ; Middle Aged ; Adult ; Aged, 80 and over ; Adolescent ; Cohort Studies ; Advanced Cardiac Life Support/methods ; Propensity Score ; Out-of-Hospital Cardiac Arrest/therapy/mortality ; Young Adult ; }, abstract = {OBJECTIVE: To compare outcomes of patients presenting to emergency medical services (EMS) with atrial fibrillation with rapid ventricular response (AF-RVR) who did and did not receive prehospital advanced life support (ALS) rate or rhythm control intervention(s).<br><br>METHODS: This retrospective cohort study used the 2021 ESO Data Collaborative (Austin, TX) dataset. We identified 9-1-1 scene responses for patients aged 16 to 100&#x2009;years old presenting with AF and an initial heart rate &#x2265; 110 beats per minute (bpm). Prehospital ALS interventions for AF-RVR included medications (e.g., calcium channel blockers, beta blockers, etc.) or electrical cardioversion. Outcome measures included prehospital rate control (i.e., final prehospital heart rate < 110 bpm), emergency department (ED) discharge to home, ED and hospital length of stay, and mortality. We also evaluated prehospital adverse events-specifically bradycardia, hypotension, and cardiac arrest. We used propensity score matching to compare outcomes among treated and untreated patients with similar demographic and clinical characteristics. We determined the average treatment effect on the treated (ATET) with 95% confidence intervals (CI) and the number needed to treat (NNT).<br><br>RESULTS: After propensity score matching, prehospital outcomes were available for 4,859 treated patients matched with 4,859 similar untreated patients. Prehospital rate control was more frequent for treated than for untreated patients (41.0% vs. 18.2%, ATET +22.8%, CI: +21.1%; +24.6%, NNT = 5). Hospital outcomes were available for 1,347 treated patients matched with 1,347 similar untreated patients. Treated patients were more likely to be discharged from the ED (37.9% vs. 34.0%, ATET +3.9%, CI: +0.2%; +7.5%, NNT = 26) and less likely to die (4.3% vs. 6.7%, ATET -2.5%, CI: -4.2%; -0.8%, NNT = 40) compared to untreated patients. Hypotension occurred more often in treated patients (ATET +2.6%, CI: +1.5%; +3.7%), but resolved before ED arrival in 73% of affected patients. Otherwise, adverse event rates did not significantly differ for the two groups.<br><br>CONCLUSIONS: In this propensity score matched study of patients presenting to EMS with AF-RVR, prehospital ALS interventions were associated with more frequent prehospital rate control, more frequent discharge to home from the ED, and lower mortality.}, }
@article {pmid37974279, year = {2023}, author = {Pelaez, MC and Desmeules, A and Gelon, PA and Glasson, B and Marcadet, L and Rodgers, A and Phaneuf, D and Pozzi, S and Dutchak, PA and Julien, JP and Sephton, CF}, title = {Neuronal dysfunction caused by FUSR521G promotes ALS-associated phenotypes that are attenuated by NF-κB inhibition.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {182}, pmid = {37974279}, issn = {2051-5960}, support = {RGPIN-2020-06376//Natural Sciences and Engineering Research Council of Canada/ ; DGECR-2020-00060//Natural Sciences and Engineering Research Council of Canada/ ; RGPIN-2018-06227//Natural Sciences and Engineering Research Council of Canada/ ; DGECR-2018-00093//Natural Sciences and Engineering Research Council of Canada/ ; Junior 1//Fonds de Recherche du Qu&#xe9;bec - Sant&#xe9;/ ; }, mesh = {Aged ; Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; Disease Progression ; *Frontotemporal Dementia/pathology ; Mice, Transgenic ; Motor Neurons/metabolism ; Mutation ; NF-kappa B/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative diseases that belong to a common disease spectrum based on overlapping clinical, pathological and genetic evidence. Early pathological changes to the morphology and synapses of affected neuron populations in ALS/FTD suggest a common underlying mechanism of disease that requires further investigation. Fused in sarcoma (FUS) is a DNA/RNA-binding protein with known genetic and pathological links to ALS/FTD. Expression of ALS-linked FUS mutants in mice causes cognitive and motor defects, which correlate with loss of motor neuron dendritic branching and synapses, in addition to other pathological features of ALS/FTD. The role of ALS-linked FUS mutants in causing ALS/FTD-associated disease phenotypes is well established, but there are significant gaps in our understanding of the cell-autonomous role of FUS in promoting structural changes to motor neurons, and how these changes relate to disease progression. Here we generated a neuron-specific FUS-transgenic mouse model expressing the ALS-linked human FUSR521G variant, hFUS[R521G/Syn1], to investigate the cell-autonomous role of FUSR521G in causing loss of dendritic branching and synapses of motor neurons, and to understand how these changes relate to ALS-associated phenotypes. Longitudinal analysis of mice revealed that cognitive impairments in juvenile hFUS[R521G/Syn1] mice coincide with reduced dendritic branching of cortical motor neurons in the absence of motor impairments or changes in the neuromorphology of spinal motor neurons. Motor impairments and dendritic attrition of spinal motor neurons developed later in aged hFUS[R521G/Syn1] mice, along with FUS cytoplasmic mislocalisation, mitochondrial abnormalities and glial activation. Neuroinflammation promotes neuronal dysfunction and drives disease progression in ALS/FTD. The therapeutic effects of inhibiting the pro-inflammatory nuclear factor kappa B (NF-κB) pathway with an analog of Withaferin A, IMS-088, were assessed in symptomatic hFUS[R521G/Syn1] mice and were found to improve cognitive and motor function, increase dendritic branches and synapses of motor neurons, and attenuate other ALS/FTD-associated pathological features. Treatment of primary cortical neurons expressing FUSR521G with IMS-088 promoted the restoration of dendritic mitochondrial numbers and mitochondrial activity to wild-type levels, suggesting that inhibition of NF-κB permits the restoration of mitochondrial stasis in our models. Collectively, this work demonstrates that FUSR521G has a cell-autonomous role in causing early pathological changes to dendritic and synaptic structures of motor neurons, and that these changes precede motor defects and other well-known pathological features of ALS/FTD. Finally, these findings provide further support that modulation of the NF-κB pathway in ALS/FTD is an important therapeutic approach to attenuate disease.}, }
@article {pmid37974227, year = {2023}, author = {Awuah, WA and Ahluwalia, A and Ghosh, S and Roy, S and Tan, JK and Adebusoye, FT and Ferreira, T and Bharadwaj, HR and Shet, V and Kundu, M and Yee, ALW and Abdul-Rahman, T and Atallah, O}, title = {The molecular landscape of neurological disorders: insights from single-cell RNA sequencing in neurology and neurosurgery.}, journal = {European journal of medical research}, volume = {28}, number = {1}, pages = {529}, pmid = {37974227}, issn = {2047-783X}, mesh = {Humans ; *Neurosurgery ; Neurosurgical Procedures ; *Neurology ; *Brain Neoplasms/genetics ; Sequence Analysis, RNA ; Tumor Microenvironment ; }, abstract = {Single-cell ribonucleic acid sequencing (scRNA-seq) has emerged as a transformative technology in neurological and neurosurgical research, revolutionising our comprehension of complex neurological disorders. In brain tumours, scRNA-seq has provided valuable insights into cancer heterogeneity, the tumour microenvironment, treatment resistance, and invasion patterns. It has also elucidated the brain tri-lineage cancer hierarchy and addressed limitations of current models. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis have been molecularly subtyped, dysregulated pathways have been identified, and potential therapeutic targets have been revealed using scRNA-seq. In epilepsy, scRNA-seq has explored the cellular and molecular heterogeneity underlying the condition, uncovering unique glial subpopulations and dysregulation of the immune system. ScRNA-seq has characterised distinct cellular constituents and responses to spinal cord injury in spinal cord diseases, as well as provided molecular signatures of various cell types and identified interactions involved in vascular remodelling. Furthermore, scRNA-seq has shed light on the molecular complexities of cerebrovascular diseases, such as stroke, providing insights into specific genes, cell-specific expression patterns, and potential therapeutic interventions. This review highlights the potential of scRNA-seq in guiding precision medicine approaches, identifying clinical biomarkers, and facilitating therapeutic discovery. However, challenges related to data analysis, standardisation, sample acquisition, scalability, and cost-effectiveness need to be addressed. Despite these challenges, scRNA-seq has the potential to transform clinical practice in neurological and neurosurgical research by providing personalised insights and improving patient outcomes.}, }
@article {pmid37973064, year = {2024}, author = {Lisi, E and Abellan, JJ}, title = {Statistical analysis of actigraphy data with generalised additive models.}, journal = {Pharmaceutical statistics}, volume = {23}, number = {3}, pages = {308-324}, doi = {10.1002/pst.2350}, pmid = {37973064}, issn = {1539-1612}, support = {//GlaxoSmithKline/ ; }, mesh = {Humans ; *Actigraphy/statistics &amp; numerical data/methods ; *Models, Statistical ; Exercise/physiology ; Data Interpretation, Statistical ; Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Pulmonary Disease, Chronic Obstructive/physiopathology/diagnosis ; Time Factors ; }, abstract = {There is a growing interest in the use of physical activity data in clinical studies, particularly in diseases that limit mobility in patients. High-frequency data collected with digital sensors are typically summarised into actigraphy features aggregated at epoch level (e.g., by minute). The statistical analysis of such volume of data is not straightforward. The general trend is to derive metrics, capturing specific aspects of physical activity, that condense (say) a week worth of data into a single numerical value. Here we propose to analyse the entire time-series data using Generalised Additive Models (GAMs). GAMs are semi-parametric models that allow inclusion of both parametric and non-parametric terms in the linear predictor. The latter are smooth terms (e.g., splines) and, in the context of actigraphy minute-by-minute data analysis, they can be used to assess daily patterns of physical activity. This in turn can be used to better understand changes over time in longitudinal studies as well as to compare treatment groups. We illustrate the application of GAMs in two clinical studies where actigraphy data was collected: a non-drug, single-arm study in patients with amyotrophic lateral sclerosis, and a physical-activity sub-study included in a phase 2b clinical trial in patients with chronic obstructive pulmonary disease.}, }
@article {pmid37972860, year = {2023}, author = {Rizzuti, M and Sali, L and Melzi, V and Scarcella, S and Costamagna, G and Ottoboni, L and Quetti, L and Brambilla, L and Papadimitriou, D and Verde, F and Ratti, A and Ticozzi, N and Comi, GP and Corti, S and Gagliardi, D}, title = {Genomic and transcriptomic advances in amyotrophic lateral sclerosis.}, journal = {Ageing research reviews}, volume = {92}, number = {}, pages = {102126}, doi = {10.1016/j.arr.2023.102126}, pmid = {37972860}, issn = {1872-9649}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Transcriptome/genetics ; Gene Expression Profiling/methods ; *MicroRNAs/genetics/metabolism ; Biomarkers ; Epigenomics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. ALS shows substantial clinical and molecular heterogeneity. In vitro and in vivo models coupled with multiomic techniques have provided important contributions to unraveling the pathomechanisms underlying ALS. To date, despite promising results and accumulating knowledge, an effective treatment is still lacking. Here, we provide an overview of the literature on the use of genomics, epigenomics, transcriptomics and microRNAs to deeply investigate the molecular mechanisms developing and sustaining ALS. We report the most relevant genes implicated in ALS pathogenesis, discussing the use of different high-throughput sequencing techniques and the role of epigenomic modifications. Furthermore, we present transcriptomic studies discussing the most recent advances, from microarrays to bulk and single-cell RNA sequencing. Finally, we discuss the use of microRNAs as potential biomarkers and promising tools for molecular intervention. The integration of data from multiple omic approaches may provide new insights into pathogenic pathways in ALS by shedding light on diagnostic and prognostic biomarkers, helping to stratify patients into clinically relevant subgroups, revealing novel therapeutic targets and supporting the development of new effective therapies.}, }
@article {pmid37968433, year = {2024}, author = {Quattrocchi, S and Bonan, L and Cirillo, L and Avoni, P and Di Stasi, V and Rizzo, G and Liguori, R and Vacchiano, V}, title = {Bibrachial amyotrophy as a rare manifestation of intraspinal fluid collection: a case report and systematic review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {2279-2288}, pmid = {37968433}, issn = {1590-3478}, mesh = {Humans ; Male ; Middle Aged ; *Magnetic Resonance Imaging ; Electromyography ; Motor Neuron Disease/diagnosis/complications ; }, abstract = {INTRODUCTION: Intraspinal cerebrospinal fluid (CSF) collection has been reported as a rare cause of lower motor neuron (LMN) disorder. We report a case of bibrachial diplegia associated with intraspinal CSF collection and perform a systematic literature review.<br><br>PATIENT AND METHODS: A 52-year-old man developed a bibrachial amyotrophy over 6&#xa0;years, confirmed by the presence of cervical subacute neurogenic changes at electromyography (EMG). Brain magnetic resonance imaging (MRI) revealed cerebral siderosis, while spine MRI showed a ventral longitudinal intraspinal fluid collection (VLISFC) from C2 to L2. No CSF leakage was localized at myelography; a conservative treatment was chosen. We searched for all published cases until 30th April 2023 and extrapolated data of 44 patients reported in 27 publications.<br><br>RESULTS: We observed a male predominance, a younger disease onset compared to amyotrophic lateral sclerosis, and a quite long disease duration, highlighting a slow disease progression. LMN signs were more frequently bilateral, mostly involving C5-C6 myotomes. Around 61% of patients presented additional symptoms, but only three referred to a history of headache. Accordingly, CSF opening pressure was mostly normal. Spinal MRI revealed the presence of VLISFC and in some cases myelomalacia. EMG patterns displayed both chronic and subacute neurogenic change in the cervical region. The disease course mainly depended on the treatment choice, which was mostly represented by a surgical approach when a specific dural defect was detected by imaging.<br><br>CONCLUSION: Bibrachial diplegia due to VLISFC can be a treatable cause of focal amyotrophy and presents some clinical and radiological "red flags" which cannot be missed by a clinical neurologist.}, }
@article {pmid37966683, year = {2024}, author = {Ansari, MA and Tripathi, T and Venkidasamy, B and Monziani, A and Rajakumar, G and Alomary, MN and Alyahya, SA and Onimus, O and D'souza, N and Barkat, MA and Al-Suhaimi, EA and Samynathan, R and Thiruvengadam, M}, title = {Multifunctional Nanocarriers for Alzheimer's Disease: Befriending the Barriers.}, journal = {Molecular neurobiology}, volume = {61}, number = {5}, pages = {3042-3089}, pmid = {37966683}, issn = {1559-1182}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Animals ; *Drug Carriers/chemistry ; Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism/drug effects ; Nanoparticles/chemistry ; Multifunctional Nanoparticles/chemistry ; }, abstract = {Neurodegenerative diseases (NDDs) have been increasing in incidence in recent years and are now widespread worldwide. Neuronal death is defined as the progressive loss of neuronal structure or function which is closely associated with NDDs and represents the intrinsic features of such disorders. Amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's, Parkinson's, and Huntington's diseases (AD, PD, and HD, respectively) are considered neurodegenerative diseases that affect a large number of people worldwide. Despite the testing of various drugs, there is currently no available therapy that can remedy or effectively slow the progression of these diseases. Nanomedicine has the potential to revolutionize drug delivery for the management of NDDs. The use of nanoparticles (NPs) has recently been developed to improve drug delivery efficiency and is currently subjected to extensive studies. Nanoengineered particles, known as nanodrugs, can cross the blood-brain barrier while also being less invasive compared to the most treatment strategies in use. Polymeric, magnetic, carbonic, and inorganic NPs are examples of NPs that have been developed to improve drug delivery efficiency. Primary research studies using NPs to cure AD are promising, but thorough research is needed to introduce these approaches to clinical use. In the present review, we discussed the role of metal-based NPs, polymeric nanogels, nanocarrier systems such as liposomes, solid lipid NPs, polymeric NPs, exosomes, quantum dots, dendrimers, polymersomes, carbon nanotubes, and nanofibers and surfactant-based systems for the therapy of neurodegenerative diseases. In addition, we highlighted nanoformulations such as N-butyl cyanoacrylate, poly(butyl cyanoacrylate), D-penicillamine, citrate-coated peptide, magnetic iron oxide, chitosan (CS), lipoprotein, ceria, silica, metallic nanoparticles, cholinesterase inhibitors, an acetylcholinesterase inhibitors, metal chelators, anti-amyloid, protein, and peptide-loaded NPs for the treatment of AD.}, }
@article {pmid37958929, year = {2023}, author = {Boylan, MA and Pincetic, A and Romano, G and Tatton, N and Kenkare-Mitra, S and Rosenthal, A}, title = {Targeting Progranulin as an Immuno-Neurology Therapeutic Approach.}, journal = {International journal of molecular sciences}, volume = {24}, number = {21}, pages = {}, pmid = {37958929}, issn = {1422-0067}, mesh = {Humans ; Progranulins/genetics ; Intercellular Signaling Peptides and Proteins/genetics ; *Frontotemporal Dementia/genetics ; Neurons/pathology ; *Amyotrophic Lateral Sclerosis ; }, abstract = {Immuno-neurology is an emerging therapeutic strategy for dementia and neurodegeneration designed to address immune surveillance failure in the brain. Microglia, as central nervous system (CNS)-resident myeloid cells, routinely perform surveillance of the brain and support neuronal function. Loss-of-function (LOF) mutations causing decreased levels of progranulin (PGRN), an immune regulatory protein, lead to dysfunctional microglia and are associated with multiple neurodegenerative diseases, including frontotemporal dementia caused by the progranulin gene (GRN) mutation (FTD-GRN), Alzheimer's disease (AD), Parkinson's disease (PD), limbic-predominant age-related transactivation response deoxyribonucleic acid binding protein 43 (TDP-43) encephalopathy (LATE), and amyotrophic lateral sclerosis (ALS). Immuno-neurology targets immune checkpoint-like proteins, offering the potential to convert aging and dysfunctional microglia into disease-fighting cells that counteract multiple disease pathologies, clear misfolded proteins and debris, promote myelin and synapse repair, optimize neuronal function, support astrocytes and oligodendrocytes, and maintain brain vasculature. Several clinical trials are underway to elevate PGRN levels as one strategy to modulate the function of microglia and counteract neurodegenerative changes associated with various disease states. If successful, these and other immuno-neurology drugs have the potential to revolutionize the treatment of neurodegenerative disorders by harnessing the brain's immune system and shifting it from an inflammatory/pathological state to an enhanced physiological/homeostatic state.}, }
@article {pmid37958767, year = {2023}, author = {Gonzalo-Gobernado, R and Moreno-Martínez, L and González, P and Dopazo, XM and Calvo, AC and Pidal-Ladrón de Guevara, I and Seisdedos, E and Díaz-Muñoz, R and Mellström, B and Osta, R and Naranjo, JR}, title = {Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice.}, journal = {International journal of molecular sciences}, volume = {24}, number = {21}, pages = {}, pmid = {37958767}, issn = {1422-0067}, support = {PI21/00372//Instituto de Salud Carlos III/ ; 307//Biomedical Research Networking Center on Neurodegenerative Diseases/ ; }, mesh = {Mice ; Animals ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Activating Transcription Factor 6/genetics/metabolism ; Neuroprotection ; Motor Neurons/metabolism ; Kv Channel-Interacting Proteins/metabolism ; Superoxide Dismutase/genetics/metabolism ; Disease Models, Animal ; }, abstract = {The interaction of the activating transcription factor 6 (ATF6), a key effector of the unfolded protein response (UPR) in the endoplasmic reticulum, with the neuronal calcium sensor Downstream Regulatory Element Antagonist Modulator (DREAM) is a potential therapeutic target in neurodegeneration. Modulation of the ATF6-DREAM interaction with repaglinide (RP) induced neuroprotection in a model of Huntington's disease. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no cure, characterized by the progressive loss of motoneurons resulting in muscle denervation, atrophy, paralysis, and death. The aim of this work was to investigate the potential therapeutic significance of DREAM as a target for intervention in ALS. We found that the expression of the DREAM protein was reduced in the spinal cord of SOD1G93A mice compared to wild-type littermates. RP treatment improved motor strength and reduced the expression of the ALS progression marker collagen type XIXα1 (Col19α1 mRNA) in the quadriceps muscle in SOD1G93A mice. Moreover, treated SOD1G93A mice showed reduced motoneuron loss and glial activation and increased ATF6 processing in the spinal cord. These results indicate that the modulation of the DREAM-ATF6 interaction ameliorates ALS symptoms in SOD1G93A mice.}, }
@article {pmid37955056, year = {2024}, author = {Spörndly-Nees, S and Jakobsson Larsson, B and Zetterberg, L and Åkerblom, Y and Nyholm, D and Åsenlöf, P}, title = {Pain in patients with motor neuron disease: Variation of pain and association with disease severity, health-related quality of life and depression - A longitudinal study.}, journal = {Palliative &amp; supportive care}, volume = {22}, number = {5}, pages = {1150-1157}, doi = {10.1017/S1478951523001347}, pmid = {37955056}, issn = {1478-9523}, mesh = {Humans ; Female ; Male ; *Quality of Life/psychology ; Middle Aged ; Longitudinal Studies ; *Depression/psychology/etiology/complications ; Aged ; *Motor Neuron Disease/complications/psychology ; Prospective Studies ; *Pain/psychology/etiology/complications ; Severity of Illness Index ; Surveys and Questionnaires ; Pain Measurement/methods ; Adult ; Cohort Studies ; Disease Progression ; Psychometrics/methods/instrumentation ; }, abstract = {OBJECTIVES: To describe levels of pain over time during disease progression in individual patients and for a total sample of patients with motor neuron disease (MND), respectively, and to examine associations between pain, disease severity, health-related quality of life (HRQOL), and depression.<br><br>METHODS: A prospective cohort study was conducted on 68 patients with MND, including data collected on five occasions over a period of 2 years. Pain was assessed using the Brief Pain Inventory - Short Form. Depression was assessed using the Amyotrophic Lateral Sclerosis (ALS)-Depression-Inventory (ADI-12). Disability progression was measured using the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Version (ALSFRS-R). HRQOL was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5).<br><br>RESULTS: Participants reported great individual variation over time. The median level of pain was 4 (min 0 and max 10). Higher levels of pain during the last 24&#xa0;h were associated with higher depression scores (ADI-12), poorer quality of life (ALSAQ-5), and lower reporting of fine and gross motor skills (ALSFRS-R). Baseline pain levels did not predict future values of depression and function. Individuals reporting average pain >3 experienced more hopelessness toward the future and reported higher depression scores compared with participants reporting average pain <3.<br><br>SIGNIFICANCE OF RESULTS: Great within-individual variation of pain intensity was reported. Pain intensity was associated with depression, function and HRQOL cross-sectionally, but it did not have a strong prognostic value for future depression, function, or HRQOL. Patients with MND should be offered frequent assessment of pain and depressive symptoms in person-centered care, allowing for individualization of treatment.}, }
@article {pmid37954904, year = {2023}, author = {Zhao, K and Chen, P and Alexander-Bloch, A and Wei, Y and Dyrba, M and Yang, F and Kang, X and Wang, D and Fan, D and Ye, S and Tang, Y and Yao, H and Zhou, B and Lu, J and Yu, C and Wang, P and Liao, Z and Chen, Y and Huang, L and Zhang, X and Han, Y and Li, S and Liu, Y}, title = {A neuroimaging biomarker for Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN): a cross-sectional study.}, journal = {EClinicalMedicine}, volume = {65}, number = {}, pages = {102276}, pmid = {37954904}, issn = {2589-5370}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that poses a worldwide public health challenge. A neuroimaging biomarker would significantly improve early diagnosis and intervention, ultimately enhancing the quality of life for affected individuals and reducing the burden on healthcare systems.<br><br>METHODS: Cross-sectional and longitudinal data (10,099 participants with 13,380 scans) from 12 independent datasets were used in the present study (this study was performed between September 1, 2021 and February 15, 2023). The Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN) score was developed via integrated regional- and network-based measures under an ensemble machine learning model based on structural MRI data. We systematically assessed whether IBRAIN could be a neuroimaging biomarker for AD.<br><br>FINDINGS: IBRAIN accurately differentiated individuals with AD from NCs (AUC&#xa0;=&#xa0;0.92) and other neurodegenerative diseases, including Frontotemporal dementia (FTD), Parkinson's disease (PD), Vascular dementia (VaD) and Amyotrophic Lateral Sclerosis (ALS) (AUC&#xa0;=&#xa0;0.92). IBRAIN was significantly correlated to clinical measures and gene expression, enriched in immune process and protein metabolism. The IBRAIN score exhibited a significant ability to reveal the distinct progression of prodromal AD (i.e., Mild cognitive impairment, MCI) (Hazard Ratio (HR)&#xa0;=&#xa0;6.52 [95% CI: 4.42&#x223c;9.62], p&#xa0;<&#xa0;1&#xa0;&#xd7;&#xa0;10[-16]), which offers similar powerful performance with Cerebrospinal Fluid (CSF) A&#x3b2; (HR&#xa0;=&#xa0;3.78 [95% CI: 2.63&#x223c;5.43], p&#xa0;=&#xa0;2.13&#xa0;&#xd7;&#xa0;10[-14]) and CSF Tau (HR&#xa0;=&#xa0;3.77 [95% CI: 2.64&#x223c;5.39], p&#xa0;=&#xa0;9.53&#xa0;&#xd7;&#xa0;10[-15]) based on the COX and Log-rank test. Notably, the IBRAIN shows comparable sensitivity (beta&#xa0;=&#xa0;-0.70, p&#xa0;<&#xa0;1&#xa0;&#xd7;&#xa0;10[-16]) in capturing longitudinal changes in individuals with conversion to AD than CSF A&#x3b2; (beta&#xa0;=&#xa0;-0.26, p&#xa0;=&#xa0;4.40&#xa0;&#xd7;&#xa0;10[-9]) and CSF Tau (beta&#xa0;=&#xa0;0.12, p&#xa0;=&#xa0;1.02&#xa0;&#xd7;&#xa0;10[-5]).<br><br>INTERPRETATION: Our findings suggested that IBRAIN is a biologically relevant, specific, and sensitive neuroimaging biomarker that can serve as a clinical measure to uncover prodromal AD progression. It has strong potential for application in future clinical practice and treatment trials.<br><br>FUNDING: Science and Technology Innovation 2030 Major Projects, the National Natural Science Foundation of China, Beijing Natural Science Funds, the Fundamental Research Funds for the CentralUniversity, and the Startup Funds for Talents at Beijing Normal University.}, }
@article {pmid37953075, year = {2023}, author = {Shimizu, H and Nishimura, Y and Shiide, Y and Akimoto, M and Yashiro, M and Ueda, M and Hirai, M and Yoshino, H and Mizutani, T and Kanai, K and Kano, O and Kimura, H and Sekino, H and Ito, K}, title = {Pharmacokinetics of Edaravone Oral Suspension in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Clinical therapeutics}, volume = {45}, number = {12}, pages = {1251-1258}, doi = {10.1016/j.clinthera.2023.09.025}, pmid = {37953075}, issn = {1879-114X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/pharmacokinetics ; Glucuronides/therapeutic use ; *Neuroprotective Agents/pharmacokinetics ; Sulfates/therapeutic use ; }, abstract = {PURPOSE: Edaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a burden on patients and there is a clinical need for oral agents for the treatment of ALS. This report aimed to assess the pharmacokinetics and safety of an edaravone oral suspension in patients with ALS after oral and percutaneous endoscopic gastrostomy (PEG) tube administration.<br><br>METHODS: Two single-dose, open-label phase 1 clinical studies were conducted. Edaravone oral suspension (105 mg of edaravone in 5 mL aqueous suspension) was administered orally and via PEG tube to 9 and 6 Japanese patients with ALS, respectively. Plasma and urinary pharmacokinetics of unchanged edaravone and its metabolites (sulfate and glucuronide conjugates) were determined. Safety was also evaluated.<br><br>FINDINGS: After reaching maximum plasma concentration, the mean plasma concentration-time of unchanged edaravone showed a triphasic elimination. Mean plasma concentration-time profiles of the metabolites were higher than those of unchanged edaravone. The mean urinary excretion ratios were higher for the glucuronide conjugate than for either unchanged edaravone or the sulfate conjugate. In patients administered edaravone orally, a single adverse event occurred (blood urine present), which was mild and improved without medical intervention. No adverse drug reactions or serious adverse events were reported. In patients administered edaravone via PEG tube, 5 treatment-emergent adverse events were reported in 3 patients; none were related to the study drug. No adverse drug reactions were reported.<br><br>IMPLICATIONS: In patients with ALS, a single dose of edaravone oral suspension was well absorbed and mainly eliminated in urine as the glucuronide conjugate. No safety concerns emerged. Pharmacokinetics were similar to those previously reported in healthy participants following oral administration. This indicates that effective drug concentrations were achieved and edaravone can be successfully administered both orally and via a PEG tube in patients with ALS.<br><br>CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04176224 (oral administration) and NCT04254913 (PEG tube administration), www.<br><br>CLINICALTRIALS: gov.}, }
@article {pmid37952981, year = {2023}, author = {Okano, H and Morimoto, S and Kato, C and Nakahara, J and Takahashi, S}, title = {Induced pluripotent stem cells-based disease modeling, drug screening, clinical trials, and reverse translational research for amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {167}, number = {5}, pages = {603-614}, doi = {10.1111/jnc.16005}, pmid = {37952981}, issn = {1471-4159}, support = {JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Drug Evaluation, Preclinical ; *Neurodegenerative Diseases/metabolism ; Translational Research, Biomedical ; Randomized Controlled Trials as Topic ; }, abstract = {It has been more than 10 years since the hopes for disease modeling and drug discovery using induced pluripotent stem cell (iPSC) technology boomed. Recently, clinical trials have been conducted with drugs identified using this technology, and some promising results have been reported. For amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, several groups have identified candidate drugs, ezogabine (retigabine), bosutinib, and ropinirole, using iPSCs-based drug discovery, and clinical trials using these drugs have been conducted, yielding interesting results. In our previous study, an iPSCs-based drug repurposing approach was utilized to show the potential of ropinirole hydrochloride (ROPI) in reducing ALS-specific pathological phenotypes. Recently, a phase 1/2a trial was conducted to investigate the effects of ropinirole on ALS further. This double-blind, randomized, placebo-controlled study confirmed the safety and tolerability of and provided evidence of its ability to delay disease progression and prolong the time to respiratory failure in ALS patients. Furthermore, in the reverse translational research, in vitro characterization of patient-derived iPSCs-motor neurons (MNs) mimicked the therapeutic effects of ROPI in vivo, suggesting the potential application of this technology to the precision medicine of ALS. Interestingly, RNA-seq data showed that ROPI treatment suppressed the sterol regulatory element-binding protein 2-dependent cholesterol biosynthesis pathway. Therefore, this pathway may be involved in the therapeutic effect of ROPI on ALS. The possibility that this pathway may be involved in the therapeutic effect of ALS was demonstrated. Finally, new future strategies for ALS using iPSCs technology will be discussed in this paper.}, }
@article {pmid37952517, year = {2024}, author = {Zürcher, BF}, title = {The Tibetan Formula Cong zhi 6 in the ORL (ENT) Practice: Experiences with Laryngopharyngeal Reflux.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {84-88}, doi = {10.1159/000534212}, pmid = {37952517}, issn = {2504-2106}, mesh = {Humans ; *Laryngopharyngeal Reflux/drug therapy ; Retrospective Studies ; Pepsin A ; Tibet ; Europe ; }, abstract = {BACKGROUND: Laryngopharyngeal reflux (LPR) is a frequent condition; in European countries, the prevalence can be estimated as 10-30% of the general population. Treatment includes lifestyle measures and highly dosed proton pump inhibitors (PPIs) over at least 4 weeks. However, PPIs are not unproblematic due to their potential side effects and the known phenomenon of rebound acid hypersecretion. Cong zhi 6 is a multi-herbal Tibetan formula additionally containing calcium carbonate and is available in several European countries as a food supplement Padma Aciben/Padma AciTib.<br><br>CASE REPORT: Ten patients with LPR took Cong zhi 6. The course of the complaints was documented, and the data were retrospectively analysed. Clinical symptoms as assessed with the Reflux Symptom Index (RSI) questionnaire and the findings in laryngoscopy with the Reflux Finding Score (RFS) both showed marked improvement of several symptoms. The number of patients with pathological LPR sum score was significantly reduced from 8 to 2 patients and from 10 to 1 patient in RSI and RFS, respectively. The mean sum scores were reduced from 18.1 to 8.4 (RSI) and from 12.9 to 4.4 (RFS), respectively. Also, other gastrointestinal symptoms, such as abdominal pain, bloating, feeling of fullness, and nausea, which are usually associated with functional dyspepsia and irritable bowel syndrome, were markedly improved (reduction of mean score of the 3 most frequent symptoms by 77-87%).<br><br>CONCLUSION: Standard medical treatment for LPR consists in high dosed PPI for at least 4 weeks, which is known for several side effects and does not treat reliable the nonacid component of LPR of pepsin or other gastric enzymes. Therefore, other medical treatment options are urgently needed. The promising data of this case series suggest that the Tibetan herbal formula Cong zhi 6 may be a treatment option in LPR and related gastrointestinal symptoms and warrant further research.<br><br>UNLABELLED: <title>Hintergrund</title>Der laryngopharyngeale Reflux (LPR) ist eine h&#xe4;ufige Erkrankung. In europ&#xe4;ischen L&#xe4;ndern wird die Pr&#xe4;valenz in der Gesamtbev&#xf6;lkerung auf 10&#x2013;30% gesch&#xe4;tzt. Die Behandlung beinhaltet Ern&#xe4;hrungs- und Verhaltens&#xe4;nderung sowie die Gabe hochdosierter Protonen-Pumpen-Hemmer (PPI) &#xfc;ber mindestens 4 Wochen. PPI sind jedoch aufgrund ihrer hohen potenziellen Nebenwirkungen und des bekannten Rebound-Ph&#xe4;nomens der sauren Magensafthypersekretion nicht unproblematisch. Cong zhi 6 ist eine tibetische Rezeptur aus einem Vielpflanzengemisch sowie zus&#xe4;tzlich Calciumcarbonat und ist in einigen europ&#xe4;ischen L&#xe4;ndern als Nahrungserg&#xe4;nzungsmittel Padma Aciben/Padma AciTib erh&#xe4;ltlich.<title>Case Report</title>Zehn Patienten mit laryngo-pharyngealem Reflux (LPR) nahmen Cong zhi 6 ein. Der Beschwerdeverlauf wurde dokumentiert und die Daten retrospektiv analysiert. Die klinischen Symptome, die mithilfe des Reflux Symptom Index (RSI) Fragebogens erfasst wurden und die mittels des Reflux Finding Score (RFS) beurteilten laryngoskopischen Befunde zeigten beide eine deutliche Verbesserung verschiedener Symptome. Die Zahl der Patienten mit pathologischen LPR-Summenscore reduzierte sich signifikant, im RSI von 8 auf 2 und im RFS von 10 auf 1 Patienten. Der mittlere Summenwert sank von 18.1 auf 8.4 (RSI) und von 12.9 auf 4.4 (RFS). Des Weiteren zeigte sich auch bei anderen gastrointestinalen Beschwerden, wie Bauchschmerzen, Bl&#xe4;hungen, V&#xf6;llegef&#xfc;hl und &#xdc;belkeit, die normalerweise mit funktioneller Dyspepsie oder Reizdarm zusammenh&#xe4;ngen, eine deutliche Verbesserung (durchschnittliche Verringerung des Scores der drei h&#xe4;ufigsten Symptome um 77&#x2013;87%).<title>Zusammenfassung</title>Die medikament&#xf6;se Standardbehandlung bei LPR besteht aus der hochdosierten PPI-Gabe &#xfc;ber mindestens 4 Wochen, die jedoch f&#xfc;r verschiedene Nebenwirkungen bekannt ist und die nicht-saure Komponente von LPR, wie Pepsin oder andere digestive Enzyme, nicht mitbehandelt. Daher sind andere medikament&#xf6;se Behandlungsm&#xf6;glichkeiten dringend erforderlich. Die vielversprechenden Daten dieser Fallserie deuten darauf hin, dass die tibetische Pflanzenrezeptur Cong zhi 6 eine Behandlungsoption bei LPR sowie deren gastrointestinalen Symptome darstellt und rechtfertigen weitere Studien.}, }
@article {pmid37951279, year = {2024}, author = {Vu Trung, K and Heise, C and Abou-Ali, E and Auriemma, F and Karam, E and van der Wiel, SE and Bruno, MJ and Caillol, F and Giovannini, M and Masaryk, V and Will, U and Anderloni, A and Pérez-Cuadrado-Robles, E and Dugic, A and Meier, B and Paik, WH and Petrone, MC and Wichmann, D and Dinis-Ribeiro, M and Gonçalves, TC and Wedi, E and Schmidt, A and Gulla, A and Hoffmeister, A and Rosendahl, J and Ratone, JP and Saadeh, R and Repici, A and Deprez, P and Sauvanet, A and Souche, FR and Fabre, JM and Muehldorfer, S and Caca, K and Löhr, M and Michl, P and Krug, S and Regner, S and Gaujoux, S and Hollenbach, M}, title = {Endoscopic papillectomy for ampullary lesions of minor papilla.}, journal = {Gastrointestinal endoscopy}, volume = {99}, number = {4}, pages = {587-595.e1}, doi = {10.1016/j.gie.2023.10.040}, pmid = {37951279}, issn = {1097-6779}, mesh = {Humans ; Treatment Outcome ; *Ampulla of Vater/surgery/pathology ; Endoscopy, Gastrointestinal ; Pancreatic Ducts/pathology ; *Pancreatic Neoplasms/pathology ; *Duodenal Neoplasms/pathology ; *Common Bile Duct Neoplasms/surgery/pathology ; Retrospective Studies ; }, abstract = {BACKGROUND AND AIMS: Ampullary lesions (ALs) of the minor duodenal papilla are extremely rare. Endoscopic papillectomy (EP) is a routinely used treatment for AL of the major duodenal papilla, but the role of EP for minor AL has not been accurately studied.<br><br>METHODS: We identified 20 patients with ALs of minor duodenal papilla in the multicentric database from the Endoscopic Papillectomy vs Surgical Ampullectomy vs Pancreatitcoduodenectomy for Ampullary Neoplasm study, which included 1422 EPs. We used propensity score matching (nearest-neighbor method) to match these cases with ALs of the major duodenal papilla based on age, sex, histologic subtype, and size of the lesion in a 1:2 ratio. Cohorts were compared by means of chi-square or Fisher exact test as well as Mann-Whitney U test.<br><br>RESULTS: Propensity score-based matching identified a cohort of 60 (minor papilla 20, major papilla 40) patients with similar baseline characteristics. The most common histologic subtype of lesions of minor papilla was an ampullary adenoma in 12 patients (3 low-grade dysplasia and 9 high-grade dysplasia). Five patients revealed nonneoplastic lesions. Invasive cancer (T1a), adenomyoma, and neuroendocrine neoplasia were each found in 1 case. The rate of complete resection, en-bloc resection, and recurrences were similar between the groups. There were no severe adverse events after EP of lesions of minor papilla. One patient had delayed bleeding that could be treated by endoscopic hemostasis, and 2 patients showed a recurrence in surveillance endoscopy after a median follow-up of 21 months (interquartile range, 12-50 months).<br><br>CONCLUSIONS: EP is safe and effective in ALs of the minor duodenal papilla. Such lesions could be managed according to guidelines for EP of major duodenal papilla.}, }
@article {pmid37950760, year = {2024}, author = {Beloribi-Djefaflia, S and Morales, RJ and Fatehi, F and Isapof, A and Servais, L and Leonard-Louis, S and Michaud, M and Verdure, P and Gidaro, T and Pouget, J and Poinsignon, V and Bonello-Palot, N and Attarian, S}, title = {Clinical and genetic features of patients suffering from CMT4J.}, journal = {Journal of neurology}, volume = {271}, number = {3}, pages = {1355-1365}, pmid = {37950760}, issn = {1432-1459}, mesh = {Adolescent ; Humans ; *Amyotrophic Lateral Sclerosis ; *Charcot-Marie-Tooth Disease/diagnosis/genetics ; *Flavoproteins/genetics ; Heterozygote ; Mutation/genetics ; Phenotype ; *Phosphoric Monoester Hydrolases/genetics ; }, abstract = {Mutations in the FIG4 gene have been identified in various diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Charcot-Marie-Tooth 4 J (CMT4J), with a wide range of phenotypic manifestations. We present eight cases of CMT4J patients carrying the p.Ile41Thr mutation of FIG4. The patients were categorized according to their phenotype. Six patients had a pure CMT; whereas, two patients had a CMT associated with parkinsonism. Three patients had an early onset and exhibited more severe forms of the disease. Three others experienced symptoms in their teenage years and had milder forms. Two patients had a late onset in adulthood. Four patients showed electrophysiological evidence of conduction blocks, typically associated with acquired neuropathies. Consequently, two of them received intravenous immunoglobulin treatment without a significant objective response. Interestingly, two heterozygous patients with the same mutations exhibited contrasting phenotypes, one having a severe early-onset form and the other experiencing a slow disease progression starting at the age of 49. Notably, although 7 out of 8 patients in this study were compound heterozygous for the p.Ile41Thr mutation, only one individual was found to be homozygous for this genetic variant and exhibited an early-onset, severe form of the disease. Additionally, one patient who developed the disease in his youth was also diagnosed with hereditary neuropathy with pressure palsies. Our findings provide insights into the CMT4J subtype by reporting on eight heterogeneous patient cases and highlight the potential for misdiagnosis when conduction blocks or asymmetrical nerve conduction study results are observed in patients with FIG4 mutations.}, }
@article {pmid37946793, year = {2023}, author = {Rogers, ML and Schultz, DW and Karnaros, V and Shepheard, SR}, title = {Urinary biomarkers for amyotrophic lateral sclerosis: candidates, opportunities and considerations.}, journal = {Brain communications}, volume = {5}, number = {6}, pages = {fcad287}, pmid = {37946793}, issn = {2632-1297}, support = {U01 NS107027/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis is a relentless neurodegenerative disease that is mostly fatal within 3-5 years and is diagnosed on evidence of progressive upper and lower motor neuron degeneration. Around 15% of those with amyotrophic lateral sclerosis also have frontotemporal degeneration, and gene mutations account for ∼10%. Amyotrophic lateral sclerosis is a variable heterogeneous disease, and it is becoming increasingly clear that numerous different disease processes culminate in the final degeneration of motor neurons. There is a profound need to clearly articulate and measure pathological process that occurs. Such information is needed to tailor treatments to individuals with amyotrophic lateral sclerosis according to an individual's pathological fingerprint. For new candidate therapies, there is also a need for methods to select patients according to expected treatment outcomes and measure the success, or not, of treatments. Biomarkers are essential tools to fulfil these needs, and urine is a rich source for candidate biofluid biomarkers. This review will describe promising candidate urinary biomarkers of amyotrophic lateral sclerosis and other possible urinary candidates in future areas of investigation as well as the limitations of urinary biomarkers.}, }
@article {pmid37945695, year = {2023}, author = {Faria Assoni, A and Giove Mitsugi, T and Wardenaar, R and Oliveira Ferreira, R and Farias Jandrey, EH and Machado Novaes, G and Fonseca de Oliveira Granha, I and Bakker, P and Kaid, C and Zatz, M and Foijer, F and Keith Okamoto, O}, title = {Neurodegeneration-associated protein VAPB regulates proliferation in medulloblastoma.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19481}, pmid = {37945695}, issn = {2045-2322}, mesh = {Child ; Humans ; *Medulloblastoma/genetics ; *Cerebellar Neoplasms/genetics ; Cell Proliferation/genetics ; Vesicular Transport Proteins ; }, abstract = {VAMP (Vesicle-associated membrane protein)-associated protein B and C (VAPB) has been widely studied in neurodegenerative diseases such as ALS, but little is known about its role in cancer. Medulloblastoma is a common brain malignancy in children and arises from undifferentiated cells during neuronal development. Therefore, medulloblastoma is an interesting model to investigate the possible relationship between VAPB and tumorigenesis. Here we demonstrate that high VAPB expression in medulloblastoma correlates with decreased overall patient survival. Consistent with this clinical correlation, we find that VAPB is required for normal proliferation rates of medulloblastoma cells in vitro and in vivo. Knockout of VAPB (VAPB[KO]) delayed cell cycle progression. Furthermore, transcript levels of WNT-related proteins were decreased in the VAPB[KO]. We conclude that VAPB is required for proliferation of medulloblastoma cells, thus revealing VAPB as a potential therapeutic target for medulloblastoma treatment.}, }
@article {pmid37944503, year = {2023}, author = {Sun, HJ and Zhang, J and Lu, JP and Wu, MT}, title = {The Improvement in Function of Poststroke Spasticity by Vibrational and Heated Stone-Needle Therapy and Meridian Dredging Exercise: A Randomized, Controlled, Preliminary Trial.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {492-501}, doi = {10.1159/000534993}, pmid = {37944503}, issn = {2504-2106}, mesh = {Humans ; Animals ; Mice ; *Quality of Life ; *Meridians ; Physical Therapy Modalities ; }, abstract = {BACKGROUND: Poststroke spasticity (PSS) is a common complication of stroke. Current PSS treatments have been linked to high costs, lack of long-term effectiveness, and undesirable side effects. Vibrational and heated stone-needle therapy (VHS) has not been utilized to treat PSS, and its safety and effectiveness have yet to be proven by high-quality clinical research.<br><br>OBJECTIVE: The aim of this study was to determine the effectiveness of VHS combined with meridian dredging exercise (MDE) in patients with PSS.<br><br>METHODS: One hundred participants with stroke were included and randomly assigned to a treatment group (VHS plus MDEs) and a control group (MDEs alone). Patients in both groups were treated for 4 weeks. The primary outcome measures were the Modified Ashworth Scale (MAS) and Fugl-Meyer Assessment (FMA), while the secondary outcome measures were the Activity of Daily Living (ADL) Scale and Stroke-Specific Quality of Life Scale (SS-QOL). The evaluations were at baseline (T0) at 4 weeks of treatment (T1) and at 12 weeks of follow-up without treatment (T2).<br><br>RESULTS: At T1 and T2, there were significant differences in MAS between the two groups (p = 0.001). From the perspective of distribution, the VHS plus MDE group had significant changes, and the group-time interactions of upper and lower extremities in FMA, ADL, and SS-QOL were statistically significant (p < 0.001), indicating that patients' symptoms improved after treatment. But the overall effect size is small, especially the effect size of improvement in SS-QOL at T1.<br><br>CONCLUSION: VHS in combination with MDE can consistently alleviate PSS, enhance limb function, and improve the quality of life of patients with PSS. But we need to optimize the device further and observe the improvement of patients for a more extended period.<br><br>UNLABELLED: <title>Hintergrund</title>Spastik nach Schlaganfall (PSS; <italic>post-stroke spasticity</italic>) ist eine h&#xe4;ufige Komplikation des Schlaganfalls. Gegenw&#xe4;rtige PSS-Behandlungen sind mit hohen Kosten, mangelnder langfristiger Wirksamkeit und unerw&#xfc;nschten Nebenwirkungen in Verbindung gebracht worden. Vibrierende und erhitzte Steinnadeln (VHS) sind bisher nicht zur Behandlung des PSS eingesetzt worden, und der Nachweis ihrer Sicherheit und Wirksamkeit durch hochwertige klinische Forschung steht noch aus.<title>Ziel</title>Beurteilung der Wirksamkeit von vibrierenden und erhitzten Steinnadeln (VHS) in Kombination mit Meridian-Ausbagger-&#xdc;bungen (MDE) bei Patienten mit PSS.<title>Methoden</title>100 Patienten mit Schlaganfall wurden eingeschlossen und per Randomisierung auf eine Behandlungsgruppe (VHS plus MDEs) und eine Kontrollgruppe (nur MDE) aufgeteilt. In beiden Gruppen wurden die Patienten 4 Wochen lang behandelt. Die prim&#xe4;ren Messinstrumente waren die Modified Ashworth Scale (MAS) und das Fugl-Meyer Assessment (FMA), als sekund&#xe4;re Messinstrumente wurden die Activity of Daily Living Scale (ADL) und die Stroke-Specific Quality of Life Scale (SS-QOL) erhoben. Die Beurteilungszeitpunkte waren bei Baseline (T0) nach 4 Wochen Behandlung (T1) und nach 12 Wochen Nachbeobachtung ohne Behandlung (T2).<title>Ergebnisse</title>Bei T1 und T2 bestanden signifikante Unterschiede bei der MAS zwischen den Gruppen (<italic>p</italic> = 0.001). Aus der Perspektive der Distribution zeigte die &#x201c;VHS plus MDE&#x201d;-Gruppe signifikante Ver&#xe4;nderungen, und die Gruppe*Zeit-Interaktionen der oberen and unteren Extremit&#xe4;ten bei FMA, ADL und SS-QOL waren statistisch signifikant (<italic>p</italic> < 0.001), was darauf hindeutet, dass die Beschwerden der Patienten sich nach der Behandlung besserten. Die Effektst&#xe4;rke ist allerdings gering, insbesondere die der SS-QOL-Verbesserung bei T1.<title>Schlussfolgerung</title>Die Anwendung von vibrierenden und erhitzten Steinnadeln in Kombination mit Meridian-Ausbagger-&#xdc;bungen kann PSS durchg&#xe4;ngig lindern, die Funktion der Extremit&#xe4;ten verbessern und die Lebensqualit&#xe4;t der Patienten mit PSS erh&#xf6;hen. Jedoch muss das Produkt weiter optimiert werden, und die Verbesserungen bei den Patienten m&#xfc;ssen &#xfc;ber einen l&#xe4;ngeren Zeitraum beobachtet werden.}, }
@article {pmid37942135, year = {2023}, author = {Shi, Y and Zhu, R}, title = {Analysis of damage-associated molecular patterns in amyotrophic lateral sclerosis based on ScRNA-seq and bulk RNA-seq data.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1259742}, pmid = {37942135}, issn = {1662-4548}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons. Despite extensive research, the exact etiology of ALS remains elusive. Emerging evidence highlights the critical role of the immune system in ALS pathogenesis and progression. Damage-Associated Molecular Patterns (DAMPs) are endogenous molecules released by stressed or damaged cells, acting as danger signals and activating immune responses. However, their specific involvement in ALS remains unclear.<br><br>METHODS: We obtained single-cell RNA sequencing (scRNA-seq) data of ALS from the primary motor cortex in the Gene Expression Omnibus (GEO) database. To better understand genes associated with DAMPs, we performed analyses on cell-cell communication and trajectory. The abundance of immune-infiltrating cells was assessed using the single-sample Gene Set Enrichment Analysis (ssGSEA) method. We performed univariate Cox analysis to construct the risk model and utilized the least absolute shrinkage and selection operator (LASSO) analysis. Finally, we identified potential small molecule drugs targeting ALS by screening the Connectivity Map database (CMap) and confirmed their potential through molecular docking analysis.<br><br>RESULTS: Our study annotated 10 cell types, with the expression of genes related to DAMPs predominantly observed in microglia. Analysis of intercellular communication revealed 12 ligand-receptor pairs in the pathways associated with DAMPs, where microglial cells acted as ligands. Among these pairs, the SPP1-CD44 pair demonstrated the greatest contribution. Furthermore, trajectory analysis demonstrated distinct differentiation fates of different microglial states. Additionally, we constructed a risk model incorporating four genes (TRPM2, ROCK1, HSP90AA1, and HSPA4). The validity of the risk model was supported by multivariate analysis. Moreover, external validation from dataset GSE112681 confirmed the predictive power of the model, which yielded consistent results with datasets GSE112676 and GSE112680. Lastly, the molecular docking analysis suggested that five compounds, namely mead-acid, nifedipine, nifekalant, androstenol, and hydrastine, hold promise as potential candidates for the treatment of ALS.<br><br>CONCLUSION: Taken together, our study demonstrated that DAMP entities were predominantly observed in microglial cells within the context of ALS. The utilization of a prognostic risk model can accurately predict ALS patient survival. Additionally, genes related to DAMPs may present viable drug targets for ALS therapy.}, }
@article {pmid37938192, year = {2023}, author = {Maharaj, D and Kaur, K and Saltese, A and Gouvea, J}, title = {Personalized Precision Immunotherapy for Amyotrophic Lateral Sclerosis (ALS).}, journal = {Critical reviews in immunology}, volume = {43}, number = {2}, pages = {1-11}, doi = {10.1615/CritRevImmunol.2023048372}, pmid = {37938192}, issn = {1040-8401}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Immunotherapy ; Brain ; Cytokines ; Inflammation ; }, abstract = {Neurological syndrome amyotrophic lateral sclerosis (ALS) affects motor neurons and is characterized by progressive motor neuron loss in the brain and spinal cord. ALS starts with mainly focal onset but when the disease progresses, it spreads to different parts of the body, with survival limits of 2-5 years after disease initiation. To date, only supportive care is provided for ALS patients, and no effective treatment or cure has been discovered. This review is focused on clinical and immunological aspects of ALS patients, based on our case studies, and we discuss the treatment we have provided to those patients based on a detailed evaluation of their peripheral blood immune cells and blood-derived serum secreted factors, cytokines, chemokines and growth factors. We show that using a personalized approach of low dose immunotherapy there is an improvement in the effects on inflammation and immunological dysfunction.}, }
@article {pmid37934576, year = {2023}, author = {Gao, H and Yu, J and Chen, J and Wang, H and Liang, S and Feng, Z and Gu, Y and Dong, L}, title = {Target-Site and Metabolic Resistance Mechanisms to Penoxsulam in Late Watergrass (Echinochloa phyllopogon) in China.}, journal = {Journal of agricultural and food chemistry}, volume = {71}, number = {46}, pages = {17742-17751}, doi = {10.1021/acs.jafc.3c05921}, pmid = {37934576}, issn = {1520-5118}, mesh = {*Echinochloa/genetics/metabolism ; Herbicide Resistance/genetics ; Tandem Mass Spectrometry ; *Herbicides/pharmacology/metabolism ; *Acetolactate Synthase/genetics/metabolism ; }, abstract = {Echinochloa phyllopogon, a malignant weed in Northeast China's paddy fields, is currently presenting escalating resistance concerns. Our study centered on the HJHL-715 E. phyllopogon population, which showed heightened resistance to penoxsulam, through a whole-plant bioassay. Pretreatment with a P450 inhibitor malathion significantly increased penoxsulam sensitivity in resistant plants. In order to determine the resistance mechanism of the resistant population, we purified the resistant population from individual plants and isolated target-site resistance (TSR) and nontarget-site resistance (NTSR) materials. Pro-197-Thr and Trp-574-Leu mutations in acetolactate synthase (ALS) 1 and ALS2 of the resistant population drove reduced sensitivity of penoxsulam to the target-site ALS, the primary resistance mechanisms. To fully understand the NTSR mechanism, NTSR materials were investigated by using RNA-sequencing (RNA-seq) combined with a reference genome. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis further supported the enhanced penoxsulam metabolism in NTSR materials. Gene expression data and quantitative reverse transcription polymerase chain reaction (qRT-PCR) validation confirmed 29 overexpressed genes under penoxsulam treatment, with 16 genes concurrently upregulated with quinclorac and metamifop treatment. Overall, our study confirmed coexisting TSR and NTSR mechanisms in E. phyllopogon's resistance to ALS inhibitors.}, }
@article {pmid37930481, year = {2024}, author = {Domi, T and Schito, P and Sferruzza, G and Russo, T and Pozzi, L and Agosta, F and Carrera, P and Riva, N and Filippi, M and Quattrini, A and Falzone, YM}, title = {Unveiling the SOD1-mediated ALS phenotype: insights from a comprehensive meta-analysis.}, journal = {Journal of neurology}, volume = {271}, number = {3}, pages = {1342-1354}, pmid = {37930481}, issn = {1432-1459}, mesh = {Humans ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Phenotype ; Genetic Testing ; Mutation ; C9orf72 Protein/genetics ; RNA-Binding Protein FUS/genetics ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis associated with mutations in SOD1 (SOD1-ALS) might be susceptible to specific treatment. The aim of the study is to outline the clinical features of SOD1-ALS patients by comparing them to patients without ALS major gene variants and patients with variants in other major ALS genes. Defining SOD1-ALS phenotype may assist clinicians in identifying patients who should be prioritized for genetic testing.<br><br>METHODS: We performed an extensive literature research including original studies which reported the clinical features of SOD1-ALS and at least one of the following patient groups: C9ORF72 hexanucleotide repeat expansion (C9-ALS), TARDBP (TARDBP-ALS), FUS (FUS-ALS) or patients without a positive test for a major-ALS gene (N-ALS). A random effects meta-analytic model was applied to clinical data extracted encompassing sex, site and age of onset. To reconstruct individual patient survival data, the published Kaplan-Meier curves were digitized. Data were measured as odds ratio (OR) or standardized mean difference (SMD) as appropriate. Median survival was compared between groups.<br><br>RESULTS: Twenty studies met the inclusion criteria. We identified 721 SOD1-ALS, 470 C9-ALS, 183 TARDBP-ALS, 113 FUS-ALS and 2824 N-ALS. SOD1-ALS showed a higher rate of spinal onset compared with N-ALS and C9-ALS (OR&#x2009;=&#x2009;4.85, 95% CI&#x2009;=&#x2009;3.04-7.76; OR&#x2009;=&#x2009;10.47, 95% CI&#x2009;=&#x2009;4.32-27.87) and an earlier onset compared with N-ALS (SMD&#x2009;=&#x2009;-&#xa0;0.45, 95% CI&#x2009;=&#x2009;-&#xa0;0.72 to -&#xa0;0.18). SOD1-ALS had a similar survival compared with N-ALS (p&#x2009;=&#x2009;0.14), a longer survival compared with C9-ALS (p&#x2009;<&#x2009;0.01) and FUS-ALS (p&#x2009;=&#x2009;0.019) and a shorter survival compared with TARDBP-ALS (p&#x2009;<&#x2009;0.01).<br><br>DISCUSSION: This study indicates the presence of a specific SOD1-ALS phenotype. Insights in SOD1-ALS clinical features are important in genetic counseling, disease prognosis and support patients' stratification in clinical trials.}, }
@article {pmid37928442, year = {2023}, author = {Chen, SK and Hawley, ZCE and Zavodszky, MI and Hana, S and Ferretti, D and Grubor, B and Hawes, M and Xu, S and Hamann, S and Marsh, G and Cullen, P and Challa, R and Carlile, TM and Zhang, H and Lee, WH and Peralta, A and Clarner, P and Wei, C and Koszka, K and Gao, F and Lo, SC}, title = {Efficacy and safety of a SOD1-targeting artificial miRNA delivered by AAV9 in mice are impacted by miRNA scaffold selection.}, journal = {Molecular therapy. Nucleic acids}, volume = {34}, number = {}, pages = {102057}, pmid = {37928442}, issn = {2162-2531}, abstract = {Toxic gain-of-function mutations in superoxide dismutase 1 (SOD1) contribute to approximately 2%-3% of all amyotrophic lateral sclerosis (ALS) cases. Artificial microRNAs (amiRs) delivered by adeno-associated virus (AAV) have been proposed as a potential treatment option to silence SOD1 expression and mitigate disease progression. Primary microRNA (pri-miRNA) scaffolds are used in amiRs to shuttle a hairpin RNA into the endogenous miRNA pathway, but it is unclear whether different primary miRNA (pri-miRNA) scaffolds impact the potency and safety profile of the expressed amiR in vivo. In our process to develop an AAV amiR targeting SOD1, we performed a preclinical characterization of two pri-miRNA scaffolds, miR155 and miR30a, sharing the same guide strand sequence. We report that, while the miR155-based vector, compared with the miR30a-based vector, leads to a higher level of the amiR and more robust suppression of SOD1 in vitro and in vivo, it also presents significantly greater risks for CNS-related toxicities in vivo. Despite miR30a-based vector showing relatively lower potency, it can significantly delay the development of ALS-like phenotypes in SOD1-G93A mice and increase survival in a dose-dependent manner. These data highlight the importance of scaffold selection in the pursuit of highly efficacious and safe amiRs for RNA interference gene therapy.}, }
@article {pmid37924056, year = {2023}, author = {Sun, J and Chen, J and Xie, Q and Sun, M and Zhang, W and Wang, H and Liu, N and Wang, Q and Wang, M}, title = {Sodium butyrate alleviates R97-116 peptide-induced myasthenia gravis in mice by improving the gut microbiota and modulating immune response.}, journal = {Journal of inflammation (London, England)}, volume = {20}, number = {1}, pages = {37}, pmid = {37924056}, issn = {1476-9255}, abstract = {Fermented butyrate exhibits an anti-inflammatory response to maintain immune homeostasis within the gut. However, the effect and underlying mechanism of butyrate on myasthenia gravis (MG) remain unclear. The changes in the gut microbiota and fecal contents of SCFAs in MG patients were examined. R97-116 peptide was used to induce the experimental autoimmune myasthenia gravis (EAMG) mice and sodium butyrate (NaB) was gavaged to the EAMG mice. Gut microbiota, the frequency of Th1, Th17, Treg, Tfh, and B cells, the levels of IFN-γ, IL-17 A, IL-10, IL-21, and anti-R97-116 IgG, RNA-seq of total B cells in the spleen were explored by metagenomics, flow cytometry, ELISA, and transcriptomics. A significant reduction in SCFA-producing bacteria including Butyricimonas synergistica and functional modules including butyrate synthesis/production II was observed in MG patients and fecal SCFAs detection confirmed the increase. The EAMG mice were successfully constructed and NaB supplementation has changed the composition and function of the gut microbiota. The numbers of Th1, Th17, Tfh, and B cells were significantly increased while that of Treg cells was obviously decreased in EAMG mice compared with controls. Interestingly, NaB treatment has reduced the amounts of Th17, Tfh, and B cells but increased that of Treg cells. Accordingly, the levels of IL-17 A, IL-21, and IgG were increased while IL-10 was decreased in EAMG mice. However, NaB treatment reduced IL-17 A and IL-21 but increased that of IL-10. RNA-seq of B cells has revealed 4577 deferentially expressed genes (DEGs), in which 1218 DEGs were up-regulated while 3359 DEGs were down-regulated in NaB-treated EAMG mice. GO enrichment and KEGG pathway analysis unveiled that the function of these DEGs was mainly focused on immunoglobulin production, mitochondrial respiratory chain complex, ribosome, oxidative phosphorylation, and CNS diseases including amyotrophic lateral sclerosis. We have found that butyrate was significantly reduced in MG patients and NaB gavage could evidently improve MG symptoms in EAMG mice by changing the gut microbiota, regulating the immune response, and altering the gene expression and function of B cells, suggesting NaB might be a potential immunomodulatory supplement for MG drugs.}, }
@article {pmid37922093, year = {2024}, author = {Jellinger, KA}, title = {Understanding depression with amyotrophic lateral sclerosis: a short assessment of facts and perceptions.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {131}, number = {2}, pages = {107-115}, pmid = {37922093}, issn = {1435-1463}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/diagnosis ; Depression/complications ; Quality of Life ; Affect ; *Neurodegenerative Diseases/complications ; }, abstract = {Depression with an average prevalence of 25-40% is a serious condition in amyotrophic lateral sclerosis (ALS) that can impact quality of life and survival of patients and caregiver burden, yet the underlying neurobiology is poorly understood. Preexisting depression has been associated with a higher risk of developing ALS, while people with ALS have a significantly higher risk of developing depression that can cause multiple complications. Depression may be a prodromal or subclinical symptom prior to motor involvement, although its relations with disease progression and impairment of quality of life are under discussion. Unfortunately, there are no studies existing that explore the pathogenic mechanisms of depression associated with the basic neurodegenerative process, and no specific neuroimaging data or postmortem findings for the combination of ALS and depression are currently available. Experience from other neurodegenerative processes suggests that depressive symptoms in ALS may be the consequence of cortical thinning in prefrontal regions and other cortex areas, disruption of mood-related brain networks, dysfunction of neurotransmitter systems, changing cortisol levels and other, hitherto unknown mechanisms. Treatment of both ALS and depression is a multidisciplinary task, depression generally being treated with a combination of antidepressant medication, physiotherapy, psychological and other interventions, while electroconvulsive therapy and deep brain stimulation might not be indicated in the majority of patients in view of their poor prognosis. Since compared to depression in other neurodegenerative diseases, our knowledge of its molecular basis in ALS is missing, multidisciplinary clinicopathological studies to elucidate the pathomechanism of depression in motor system disorders including ALS are urgently warranted.}, }
@article {pmid37920145, year = {2024}, author = {Stamatelatou, A and Bertinetto, CG and Jansen, JJ and Postma, G and Selnaes, KM and Bathen, TF and Heerschap, A and Scheenen, TWJ and , }, title = {A multivariate curve resolution analysis of multicenter proton spectroscopic imaging of the prostate for cancer localization and assessment of aggressiveness.}, journal = {NMR in biomedicine}, volume = {37}, number = {3}, pages = {e5062}, doi = {10.1002/nbm.5062}, pmid = {37920145}, issn = {1099-1492}, support = {813120//European Union's Horizon 2020 research and innovation program/ ; }, mesh = {Male ; Humans ; *Prostate/diagnostic imaging/pathology ; Protons ; *Prostatic Neoplasms/diagnostic imaging ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy/methods ; Least-Squares Analysis ; }, abstract = {In this study, we investigated the potential of the multivariate curve resolution alternating least squares (MCR-ALS) algorithm for analyzing three-dimensional (3D) [1] H-MRSI data of the prostate in prostate cancer (PCa) patients. MCR-ALS generates relative intensities of components representing spectral profiles derived from a large training set of patients, providing an interpretable model. Our objectives were to classify magnetic resonance (MR) spectra, differentiating tumor lesions from benign tissue, and to assess PCa aggressiveness. We included multicenter 3D [1] H-MRSI data from 106 PCa patients across eight centers. The patient cohort was divided into a training set (N = 63) and an independent test set (N = 43). Singular value decomposition determined that MR spectra were optimally represented by five components. The profiles of these components were extracted from the training set by MCR-ALS and assigned to specific tissue types. Using these components, MCR-ALS was applied to the test set for a quantitative analysis to discriminate tumor lesions from benign tissue and to assess tumor aggressiveness. Relative intensity maps of the components were reconstructed and compared with histopathology reports. The quantitative analysis demonstrated a significant separation between tumor and benign voxels (t-test, p < 0.001). This result was achieved including voxels with low-quality MR spectra. A receiver operating characteristic analysis of the relative intensity of the tumor component revealed that low- and high-risk tumor lesions could be distinguished with an area under the curve of 0.88. Maps of this component properly identified the extent of tumor lesions. Our study demonstrated that MCR-ALS analysis of [1] H-MRSI of the prostate can reliably identify tumor lesions and assess their aggressiveness. It handled multicenter data with minimal preprocessing and without using prior knowledge or quality control. These findings indicate that MCR-ALS can serve as an automated tool to assess the presence, extent, and aggressiveness of tumor lesions in the prostate, enhancing diagnostic capabilities and treatment planning of PCa patients.}, }
@article {pmid37915644, year = {2023}, author = {Kassahun Bekele, B and Kwizera, L and Abdul Razzak, R and Alfadul, ESA and Anand, A and Wojtara, M and Nazir, A and Uwishema, O}, title = {ALS in Africa: current knowledge and exciting opportunities for future study - short communication.}, journal = {Annals of medicine and surgery (2012)}, volume = {85}, number = {11}, pages = {5827-5830}, pmid = {37915644}, issn = {2049-0801}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that can present with motor and extra-motor manifestations. Its global prevalence is 4.42 per 1 000 000, and it has a high mortality rate. In sub-Saharan Africa alone, 15 per 100 000 develop ALS mainly between their 40s and 60s and only one-fourth of them have access to treatment. ALS was found to be not only affected by genetic variation but also by the patient's mood and lifestyle. In Africa, males and younger people tend to be affected with ALS and rarely present with bulbar onset. ALS diagnosis is very challenging due to the lack of ALS-specific biomarkers and the sharing of some clinical features with other syndromes. ALS treatment is mainly riluzole and supportive treatment via nasogastric tube and ventilatory support. The access to treatment in Africa is very limited, thus a very bad prognosis with a median survival time of 14 months post-diagnosis. Further research is needed to assess the real situation in Africa and to try to closely monitor patients suffering from ALS.}, }
@article {pmid37913752, year = {2023}, author = {Chou, PY and Chen, CM and Wang, CC and Tai, CJ and Lin, YK and Tang, YJ}, title = {Characteristics and Effects of Chinese Herbal Medicine in the Management of Female Infertility: A Hospital-Based Study.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {481-491}, doi = {10.1159/000534590}, pmid = {37913752}, issn = {2504-2106}, mesh = {Humans ; Female ; Retrospective Studies ; *Drugs, Chinese Herbal/therapeutic use ; *Infertility, Female/therapy ; Treatment Outcome ; Hospitals ; }, abstract = {BACKGROUND: In Taiwan, Chinese herbal medicine (CHM) is used to treat female infertility. Evidence indicates that the absence of monotherapy efficacy assessment and comparison with mainstream interventions may lead to the improper use of CHM for female infertility.<br><br>METHODS: A retrospective cohort study enrolled female patients at a hospital undergoing CHM intervention to treat infertility from 2012 to 2020 in order to determine the outcomes of CHM monotherapy for female infertility. Kaplan-Meier analysis under strict assumptions was used to estimate the cumulative probability of pregnancy and live births after CHM. Cox hazard regression analysis was used to estimate the hazard ratios of prognostic variables, namely, the woman's age and diagnostic category.<br><br>RESULTS: 694 women met the inclusion criteria and accounted for 2,145 cycles. A total of 190 pregnancies resulted in 125 live births, all of which were singleton births of babies with 16 perinatal complications requiring hospitalization. The real cumulative pregnancy rate and cumulative live birth rate (CLBR) for the total population after 10 cycles were between 27.4% and 35.2% and between 18% and 22.1%, respectively. Compared with the live birth rate corresponding to patients aged under 35 years, that of older patients, particularly those aged 38-39 years, was significantly lower (hazard ratio: 0.19, 95% confidence interval: 0.11-0.33). Women with other diagnoses, namely, uterine problems or endometriosis, had a greater probability of a live birth than did women with tubal pathology (hazard ratio: 6.31, 95% confidence interval: 1.99-20.07).<br><br>CONCLUSION: To the best of our knowledge, this is the first retrospective study to employ life table analysis to determine the CHM treatment outcomes in terms of female infertility. The study established a basis to compare in vitro fertilization (IVF) with CHM and identified the advantages and disadvantages of CHM for treating female infertility. Although the CLBR of present study is lower than those reported in IVF studies, CHM in treating female infertility can still be beneficial to women aged younger than 38 years or with diagnoses other than tubal pathology and worth recommendation by reproductive specialists according to the promising results gained from the strict criteria. However, in order to determine the optimal timing, possible mechanism, corresponding side effects, and the efficacy of CHM combined with IVF for treating female infertility, rigorous research is required.<br><br>UNLABELLED: <title>Hintergrund</title>In Taiwan wird die chinesische Heilpflanzenmedizin (CHM) zur Behandlung weiblicher Infertilit&#xe4;t angewendet. Es liegen Hinweise vor, nach denen fehlende Wirksamkeitsbeurteilungen der Monotherapien und Vergleiche mit herk&#xf6;mmlichen Interventionen zu einer unsachgem&#xe4;&#xdf;en Anwendung von CHM bei weiblicher Infertilit&#xe4;t f&#xfc;hren k&#xf6;nnen.<title>Methoden</title>Eine retrospektive Kohortenstudie schloss Patientinnen eines Krankenhauses ein, die von 2012 bis 2020 wegen Infertilit&#xe4;t mit CHM behandelt wurden, um die Behandlungsergebnisse der CHM-Monotherapie bei weiblicher Infertilit&#xe4;t zu ermitteln. Zur Sch&#xe4;tzung der kumulativen Wahrscheinlichkeit von Schwangerschaften und Lebendgeburten nach einer CHM-Behandlung wurde die Kaplan-Meier-Analyse unter strengen Annahmen verwendet. Mit Hilfe der Cox-Hazard-Regressionsanalyse wurden die Risikoverh&#xe4;ltnisse der prognostischen Variablen Alter der Frau und Diagnosekategorie gesch&#xe4;tzt.<title>Ergebnisse</title>694 Frauen erf&#xfc;llten die Einschlusskriterien und die Zahl der Zyklen betrug 2,145. Insgesamt 190 Schwangerschaften f&#xfc;hrten zu 125 Lebendgeburten, allesamt Einlingsgeburten, mit 16 perinatalen Komplikationen, die eine Hospitalisierung erforderten. Die reale kumulative Schwangerschaftsrate und die kumulative Lebendgeburtenrate (cumulative live birth rate, CLBR) f&#xfc;r die Gesamtpopulation nach 10 Zyklen lagen zwischen 27.4% und 35.2% bzw. zwischen 18% und 22.1%. Die Lebendgeburtenrate bei &#xe4;lteren Patientinnen, insbesondere im Alter von 38 bis 39 Jahren, war deutlich niedriger als bei Patientinnen unter 35 Jahren (Hazard Ratio: 0.19, 95%-Konfidenzintervall: 0.11&#x2013;0.33). Bei Frauen mit anderen Diagnosen wie Geb&#xe4;rmutterproblemen oder Endometriose war die Wahrscheinlichkeit einer Lebendgeburt h&#xf6;her als bei Frauen mit Eileitererkrankungen (Hazard Ratio: 6.31, 95%-Konfidenzintervall: 1.99&#x2013;20.07).<title>Schlussfolgerung</title>Unseres Wissens ist dies die erste retrospektive Studie, in der die Ergebnisse der CHM-Behandlung bei weiblicher Infertilit&#xe4;t mittels Sterbetafelanalyse ermittelt wurden. Die Studie bildet eine Grundlage f&#xfc;r den Vergleich von In-vitro-Fertilisation (IVF) mit CHM und zeigt die Vor- und Nachteile der CHM zur Behandlung weiblicher Infertilit&#xe4;t auf. Zwar f&#xe4;llt die kumulative Lebendgeburtenrate in der vorliegenden Studie niedriger aus als in IVF-Studien, doch kann die CHM bei der Behandlung weiblicher Infertilit&#xe4;t f&#xfc;r Frauen unter 38 Jahren oder Frauen, die eine andere Diagnose als eine Eileitererkrankung haben, von Nutzen sein und angesichts der vielversprechenden Ergebnisse, die aus den strengen Kriterien gewonnen wurden, ist sie eine Empfehlung durch Reproduktionsspezialisten wert. Allerdings sind rigorose Forschungsarbeiten erforderlich, um die optimale Zeitplanung, den m&#xf6;glichen Mechanismus, die entsprechenden Nebenwirkungen und die Wirksamkeit der CHM in Kombination mit IVF zur Behandlung der weiblichen Infertilit&#xe4;t zu ermitteln.}, }
@article {pmid37910649, year = {2025}, author = {Franklin, JE}, title = {Palliative hypnosis approaches in the symptomatic treatment of amyotrophic lateral sclerosis (ALS).}, journal = {The American journal of clinical hypnosis}, volume = {67}, number = {1}, pages = {54-68}, doi = {10.1080/00029157.2023.2252875}, pmid = {37910649}, issn = {2160-0562}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Hypnosis/methods ; *Palliative Care/methods ; Male ; Middle Aged ; Aged ; Female ; Veterans/psychology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, incurable, and ultimately fatal, devastating, progressive degenerative neurologic disease. It causes upheaval in the lives of patients and family caregivers alike. Palliative care can play an important supportive role in the care of patients and families dealing with the devastation of this illness. Clinical hypnosis has demonstrated benefits in treating the symptoms associated with severe chronic illness. There are, however, few studies looking at the benefits of clinical hypnosis in treating the symptom burden of ALS. This article describes palliative care and how it can provide an additional layer of support to seriously ill patients. A brief review of previous studies of hypnosis in the supportive, symptomatic treatment of ALS is provided, followed by a description of a case series of 30 Veterans who received clinical hypnosis and self-hypnosis training as a complementary treatment for the symptoms of ALS. Details of three case histories are included to highlight and discuss specific strategies and emblematic clinical responses. There is evidence that clinical hypnosis can benefit ALS patients and family caregivers struggling with this devastating illness.}, }
@article {pmid37907717, year = {2024}, author = {Yamamoto, K and Itoi, T and Matsunami, Y and Sofuni, A and Tsuchiya, T and Mukai, S and Kojima, H and Minami, H and Nakatsubo, R and Tonozuka, R}, title = {Early and late effects of endoscopic interventions in patients with malignant afferent loop syndrome: A single-center experience and literature review.}, journal = {Journal of hepato-biliary-pancreatic sciences}, volume = {31}, number = {2}, pages = {120-132}, doi = {10.1002/jhbp.1380}, pmid = {37907717}, issn = {1868-6982}, mesh = {Humans ; *Afferent Loop Syndrome/diagnostic imaging/etiology/surgery ; *Cholestasis/etiology ; Drainage ; Endoscopy ; Endosonography ; Liver/pathology ; Retrospective Studies ; Stents/adverse effects ; Treatment Outcome ; }, abstract = {BACKGROUND/PURPOSE: Afferent loop syndrome (ALS) is a rare adverse event after gastrointestinal surgery requiring appropriate early decompression treatment. Several endoscopic interventions have been attempted for treatment, including endoscopic enteral metal stent placement (EMSP), endoscopic ultrasound (EUS)-guided entero-enterostomy (EUS-EE), and EUS-guided hepaticogastrostomy (EUS-HGS). However, there are limited data on outcomes, including duration of stent patency. In this study, we evaluated the usefulness of each endoscopic intervention for malignant ALS.<br><br>METHODS: We retrospectively investigated nine patients with malignant ALS who underwent EMSP, EUS-EE, or EUS-HGS. Information on technical success, clinical efficacy, adverse events, stent dysfunction, and overall survival was collected and analyzed.<br><br>RESULTS: The most common symptoms were abdominal pain and cholangitis. ALS was treated by EMSP in three patients, EUS-EE in three patients, and EUS-HGS in three patients. Stent placement was successful and clinically effective in all patients with no adverse events. During follow-up, stent dysfunction occurred in two patients treated by EUS-HGS. Eight patients died of primary disease during a median follow-up of 157&#x2009;days.<br><br>CONCLUSIONS: Each of the available endoscopic interventions for malignant ALS can be expected to produce similar outcomes, including duration of stent patency. The choice of endoscopic intervention should be made based on the characteristics of each treatment.}, }
@article {pmid37907134, year = {2023}, author = {Birajdar, SV and Mazahir, F and Alam, MI and Kumar, A and Yadav, AK}, title = {Repurposing and clinical attributes of antidiabetic drugs for the treatment of neurodegenerative disorders.}, journal = {European journal of pharmacology}, volume = {961}, number = {}, pages = {176117}, doi = {10.1016/j.ejphar.2023.176117}, pmid = {37907134}, issn = {1879-0712}, mesh = {Humans ; Mice ; Animals ; Hypoglycemic Agents/pharmacology/therapeutic use ; Amyloid beta-Peptides/metabolism ; *Diabetes Mellitus, Type 2/drug therapy ; Drug Repositioning ; Neuroinflammatory Diseases ; *Alzheimer Disease/drug therapy ; Insulin/metabolism ; *Metformin/pharmacology ; }, abstract = {The risk of neurodegeneration was found to be increased among people with type 2 diabetes mellitus (T2DM). Brain disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and others are considered neurodegenerative diseases and can be characterized by progressive loss of neurons. The deficiency of insulin, impaired signaling, and its resistance lead to alteration in the neuronal functioning of the brain. Insulin degrading enzyme (IDE) plays a significant role in the amyloid β metabolism, aggregation, and deposition of misfolded proteins in the brain's hippocampal and cortical neuronal regions. The insulin signaling via IP3 activation upregulates the IDE and could be a promising approach to regulate neurodegeneration. The repurposing of existing antidiabetic drugs such as Metformin, DPP-4 inhibitors, thiazolidinediones, glucagon-like peptides (GLP-1), sodium-glucose co-transport-2 (SGCT-2) inhibitors, and insulin could be an alternative and effective strategy to treat neurodegeneration via modulating insulin signaling, insulin resistance, IDE activity, oxidative stress, mitochondrial dysfunction, serum lipid profile and neuroinflammation in the brain. Antidiabetic medications reduce the risk of neuroinflammation, oxidative stress, and Aβ deposition by enhancing their clearance rate. The downregulation of IDE alters the degradation of Aβ monomers in the Tg2576 APP mice. Also, the treatment with metformin activated the AMPK pathway and suppressed mTOR and BACE-1 protein expression in the APP/PS1-induced mice model. Thus, the primary intention of this review is to explore the link between T2DM and neurodegenerative disorders, and the possible role of various antidiabetic drugs in the management of neurodegenerative disorders.}, }
@article {pmid37906991, year = {2023}, author = {Prohaska, S and Matthias, K}, title = {Effectiveness of Mindfulness-Based Stress Reduction as a Nondrug Preventive Intervention in Patients with Migraine: A Systematic Review with Meta-Analyses.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {525-534}, doi = {10.1159/000534653}, pmid = {37906991}, issn = {2504-2106}, mesh = {Adult ; Humans ; *Mindfulness ; Treatment Outcome ; *Migraine Disorders/prevention &amp; control ; Headache ; Stress, Psychological ; }, abstract = {INTRODUCTION: Migraine is a neurological disorder characterized by recurrent, severe headaches that are often accompanied by other symptoms. There are various factors that can trigger a migraine in sufferers. Stress can be such a trigger. Drug and nondrug treatments are available for the preventive treatment of migraine. According to a German guideline, mindfulness can be recommended for the prophylaxis of migraine. Therefore, the aim was to investigate the effectiveness of mindfulness-based stress reduction (MBSR) in relation to patient-relevant outcomes in adult patients with migraine. Patient-relevant outcomes in this context are migraine frequency, headache intensity during a migraine attack, depressive symptoms, and quality of life.<br><br>MATERIAL AND METHODS: The conduct of this study was guided by the PRISMA 2020 statement. A systematic literature search for randomized controlled trials (RCTs) of the effectiveness of MBSR in adult migraine patients was conducted in December 2021 in three databases: MEDLINE via PubMed, the Cochrane Library, and Web of Science. In addition, a review of reference lists and a search of study registries were performed. The last search was conducted on October 7, 2022. In a two-step process, studies were selected based on predefined inclusion and exclusion criteria. The potential for bias was assessed using the Cochrane Risk of Bias Tool 2. The results were summarized descriptively and by means of quantitative synthesis.<br><br>RESULTS: Four RCTs with a total of 275 patients and the follow-up publication of one of these studies were included. The risk of bias in one study each was judged to be low or of some concern and high in two studies. Four studies were included in the quantitative analysis. For the endpoint migraine frequency, the meta-analytic summary of three studies failed to show a statistically significant benefit for MBSR (SMD: -0.23; 95% CI: -0.79 to 0.32). For the endpoint depressive symptoms, a meta-analytic summary of three studies showed a statistically significant benefit for MBSR (SMD: -0.59; 95% CI: -0.93 to -0.25). No study had examined the severity of headaches during a migraine episode.<br><br>CONCLUSION: Some results suggest that migraine patients may benefit from MBSR. However, the evidence base is currently insufficient for recommendations on the use of MBSR as a nondrug treatment option. Further adequately powered, high-quality RCTs are needed.<br><br>UNLABELLED: <title>Einleitung</title>Migr&#xe4;ne ist eine neurologische Erkrankung, die durch wiederkehrende, starke Kopfschmerzen gekennzeichnet ist, die h&#xe4;ufig von anderen Symptomen einhergehen. Es gibt verschiedene Faktoren, die bei den Betroffenen eine Migr&#xe4;ne ausl&#xf6;sen k&#xf6;nnen. Ein solcher Ausl&#xf6;ser kann Stress sein. F&#xfc;r die pr&#xe4;ventive Behandlung der Migr&#xe4;ne stehen medikament&#xf6;se und nichtmedikament&#xf6;se Verfahren zur Verf&#xfc;gung. Laut einer deutschen Leitlinie kann Achtsamkeit zur Prophylaxe von Migr&#xe4;ne empfohlen werden. Ziel der Studie war es daher, die Wirksamkeit von achtsamkeitsbasierter Stressreduktion (MBSR) in Bezug auf patientenrelevante Outcomes bei erwachsenen Migr&#xe4;nepatienten zu untersuchen. Patientenrelevante Outcomes in diesem Zusammenhang sind Migr&#xe4;neh&#xe4;ufigkeit, Kopfschmerzintensit&#xe4;t w&#xe4;hrend einer Migr&#xe4;neattacke, depressive Symptome und Lebensqualit&#xe4;t.<title>Methoden</title>Die Durchf&#xfc;hrung dieser Studie orientierte sich am PRISMA-Statement. Eine systematische Literatursuche nach randomisierten kontrollierten Studien zur Wirksamkeit von MBSR bei erwachsenen Migr&#xe4;nepatienten wurde im Dezember 2021 in drei Datenbanken durchgef&#xfc;hrt: MEDLINE &#xfc;ber PubMed, die Cochrane Library und Web of Science. Dar&#xfc;ber hinaus wurden Referenzlisten und Studienregister durchsucht. Die letzte Suche erfolgte am 7. Oktober 2022. In einem zweistufigen Verfahren wurden die Studien anhand von vordefinierten Ein- und Ausschlusskriterien ausgew&#xe4;hlt. Das Verzerrungspotential der Studien wurde mit dem Cochrane Risk of Bias Tool 2 bewertet. Die Ergebnisse wurden deskriptiv und mit Hilfe einer quantitativen Synthese zusammengefasst.<title>Ergebnisse</title>Es wurden vier randomisiert-kontrollierte Studien mit insgesamt 275 Patienten und die Nachfolgepublikation einer dieser Studien eingeschlossen. Das Verzerrungspotential wurde bei je einer Studie als gering oder bedenklich und bei zwei Studien als hoch eingestuft. Vier Studien wurden in die quantitative Analyse einbezogen. F&#xfc;r den Endpunkt Migr&#xe4;neh&#xe4;ufigkeit ergab die metaanalytische Zusammenfassung von drei Studien keinen statistisch signifikanten Vorteil f&#xfc;r MBSR (SMD &#x2212;0.23; 95% CI &#x2212;0.79 bis 0.32). F&#xfc;r den Endpunkt depressive Symptome zeigte eine metaanalytische Zusammenfassung von drei Studien einen statistisch signifikanten Vorteil f&#xfc;r MBSR (SMD &#x2212;0.59; 95% CI &#x2212;0.93 bis &#x2212;0.25). Keine Studie hatte die Schwere der Kopfschmerzen w&#xe4;hrend einer Migr&#xe4;neepisode untersucht.<title>Schlussfolgerung</title>Einige Ergebnisse deuten darauf hin, dass Migr&#xe4;nepatienten von MBSR profitieren k&#xf6;nnen. Allerdings ist die Evidenzbasis derzeit nicht ausreichend, um Empfehlungen f&#xfc;r den Einsatz von MBSR als nichtmedikament&#xf6;se Behandlungsoption abzuleiten. Es werden daher weitere qualitativ hochwertige randomisiert-kontrollierte Studien mit ausreichender statistischer Power ben&#xf6;tigt.}, }
@article {pmid37906785, year = {2022}, author = {Matamala, JM and Moreno-Roco, J and Acosta, I and Hughes, R and Lillo, P and Casar, JC and Earle, N}, title = {[Multidisciplinary care and therapeutic advances in amyotrophic lateral sclerosis].}, journal = {Revista medica de Chile}, volume = {150}, number = {12}, pages = {1633-1646}, doi = {10.4067/s0034-98872022001201633}, pmid = {37906785}, issn = {0717-6163}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/psychology ; *Neurodegenerative Diseases ; Quality of Life ; Palliative Care ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that mainly affects the motor system, resulting in progressive weakness and muscle wasting. Despite the tremendous advances in physiopathological and clinical characterization, we do not have a curative treatment yet. The progressive and fatal course of ALS makes its management particularly complex and challenging given the diversity of symptoms presenting during the disease progression. The main goal in the treatment of ALS patients is to minimize morbidity and maximize the quality of life. Currently, a series of therapeutic interventions improve the quality of life and prolong survival, including multidisciplinary care, respiratory management, and disease-modifying therapy. Within the supportive interventions, weight maintenance through nutritional and metabolic support is critical. In addition, the management of neuropsychiatric manifestations and preservation of communicative capacity before speech loss are also crucial. Lastly, early palliative care intervention is essential to optimize symptomatic management. Anticipatory guidelines to face the inevitable patient deterioration should be devised. This article updates the main therapeutic strategies used in these patients, including evolving clinical trials with promising novel therapies.}, }
@article {pmid37904013, year = {2024}, author = {Chen, X and Luo, J and Zheng, W and Huang, Q and Du, C and Yuan, H and Xiao, F}, title = {Hyperhidrosis as the initial symptom in FUS mutation-associated amyotrophic lateral sclerosis: a case report and comprehensive literature review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {4}, pages = {1523-1527}, pmid = {37904013}, issn = {1590-3478}, mesh = {Female ; Humans ; Young Adult ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/genetics ; *Hyperhidrosis/genetics ; Mutation ; *Neurodegenerative Diseases ; Quality of Life ; RNA-Binding Protein FUS/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is now recognized to involve autonomic dysfunction. The burden of autonomic dysfunction is an important factor in the quality of life and prognosis of ALS patients. This article presents the clinical characteristics of a young female ALS patient with a fused in sarcoma (FUS) gene mutation and notable hyperhidrosis.<br><br>METHOD: Detailed clinical characteristics of the patients were collected, and comprehensive examinations such as electrophysiological assessment, neuro-ultrasound, genetic testing, and relevant blood tests were conducted.<br><br>RESULT: A 24-year-old female experienced progressive weakness in both lower limbs for over 5 months, along with excessive sweating on both palms and feet. A positive skin iodine-starch test was observed. Electromyography revealed extensive neurogenic damage and prolonged sympathetic skin response (SSR) latency in both lower limbs. Full exon gene sequencing showed a heterozygous mutation c.1574C>T (p.Pro525Leu) in the FUS gene.<br><br>CONCLUSION: The pathogenesis of ALS remains unclear at present. This case underscores the presence of autonomic nervous symptoms in ALS associated with FUS mutation and highlights the importance of early diagnosis and timely treatment intervention to enhance patient prognosis.}, }
@article {pmid37901127, year = {2023}, author = {Aslam, A and Sarmad, E and Nawaz, A and Numan, A and Ahmad, A and Hassan, MA}, title = {Brait-Fahn-Schwartz Disease: A Unique Co-Occurrence of Parkinson's Disease and Amyotrophic Lateral Sclerosis.}, journal = {Case reports in neurology}, volume = {15}, number = {1}, pages = {207-214}, pmid = {37901127}, issn = {1662-680X}, abstract = {The Parkinson's disease-amyotrophic lateral sclerosis (ALS) complex typically manifests as levodopa-responsive parkinsonism, followed by ALS. It is extremely rare for Parkinson's disease and ALS to coexist without other neurological disorders. Named after the scientists who first described this overlap of two neurodegenerative conditions, it is referred to as Brait-Fahn-Schwartz disease. Given its variable presentation, increasing rarity, and lack of any diagnostic test, it poses a diagnostic challenge for physicians. We present a case of a 55-year-old Pakistani male experiencing progressive quadriparesis with spastic lower limbs and flaccid upper limbs, in addition to the cardinal features of idiopathic Parkinson's disease. Since there is currently no cure available for either Parkinson's disease or ALS, all available treatment focuses on improving quality of life, which we achieved in our patient. This case is unique in being the first incidence of Parkinson's disease-ALS complex in a novel geographic region such as Pakistan, where genetic testing and cost constraints limit the diagnosis of rare disorders. The coexistence of extrapyramidal symptoms and pyramidal symptoms is uncommon. In such situations, physicians may overlook one group of symptoms, potentially leading to a misdiagnosis. This case highlights the value of a thorough physical examination and electrodiagnostic studies and suggests the association between Parkinson's disease and ALS. This case demonstrates the significance of understanding when Parkinson's disease symptoms start to appear in patients with ALS and the need to start dopaminergic therapy in those who had Parkinson's disease features before ALS to alleviate the suffering of an individual and enhance quality of life.}, }
@article {pmid37894774, year = {2023}, author = {Moțățăianu, A and Șerban, G and Andone, S}, title = {The Role of Short-Chain Fatty Acids in Microbiota-Gut-Brain Cross-Talk with a Focus on Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {24}, number = {20}, pages = {}, pmid = {37894774}, issn = {1422-0067}, support = {PN-III-P1-1.1-TE-2021-0960//Ministry of Research, Innovation and Digitization, CNCS - UEFISCDI/ ; }, mesh = {Humans ; Aged ; *Gastrointestinal Microbiome/physiology ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Brain/metabolism ; Fatty Acids, Volatile/metabolism ; Fatty Acids/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by the gradual loss of motor neurons in the brain and spinal cord, leading to progressive motor function decline. Unfortunately, there is no effective treatment, and its increasing prevalence is linked to an aging population, improved diagnostics, heightened awareness, and changing lifestyles. In the gastrointestinal system, the gut microbiota plays a vital role in producing metabolites, neurotransmitters, and immune molecules. Short-chain fatty acids, of interest for their potential health benefits, are influenced by a fiber- and plant-based diet, promoting a diverse and balanced gut microbiome. These fatty acids impact the body by binding to receptors on enteroendocrine cells, influencing hormones like glucagon-like peptide-1 and peptide YY, which regulate appetite and insulin sensitivity. Furthermore, these fatty acids impact the blood-brain barrier, neurotransmitter levels, and neurotrophic factors, and directly stimulate vagal afferent nerves, affecting gut-brain communication. The vagus nerve is a crucial link between the gut and the brain, transmitting signals related to appetite, inflammation, and various processes. Dysregulation of this pathway can contribute to conditions like obesity and irritable bowel syndrome. Emerging evidence suggests the complex interplay among these fatty acids, the gut microbiota, and environmental factors influences neurodegenerative processes via interconnected pathways, including immune function, anti-inflammation, gut barrier, and energy metabolism. Embracing a balanced, fiber-rich diet may foster a diverse gut microbiome, potentially impacting neurodegenerative disease risk. Comprehensive understanding requires further research into interventions targeting the gut microbiome and fatty acid production and their potential therapeutic role in neurodegeneration.}, }
@article {pmid37893165, year = {2023}, author = {De Marchi, F and Munitic, I and Vidatic, L and Papić, E and Rački, V and Nimac, J and Jurak, I and Novotni, G and Rogelj, B and Vuletic, V and Liscic, RM and Cannon, JR and Buratti, E and Mazzini, L and Hecimovic, S}, title = {Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders.}, journal = {Biomedicines}, volume = {11}, number = {10}, pages = {}, pmid = {37893165}, issn = {2227-9059}, abstract = {Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann-Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation.}, }
@article {pmid37893003, year = {2023}, author = {Wu, YS and Taniar, D and Adhinugraha, K and Tsai, LK and Pai, TW}, title = {Detection of Amyotrophic Lateral Sclerosis (ALS) Comorbidity Trajectories Based on Principal Tree Model Analytics.}, journal = {Biomedicines}, volume = {11}, number = {10}, pages = {}, pmid = {37893003}, issn = {2227-9059}, support = {MOST 111-2221-E-027 -113 -MY2//National Science and Technology Council/ ; }, abstract = {The multifaceted nature and swift progression of Amyotrophic Lateral Sclerosis (ALS) pose considerable challenges to our understanding of its evolution and interplay with comorbid conditions. This study seeks to elucidate the temporal dynamics of ALS progression and its interaction with associated diseases. We employed a principal tree-based model to decipher patterns within clinical data derived from a population-based database in Taiwan. The disease progression was portrayed as branched trajectories, each path representing a series of distinct stages. Each stage embodied the cumulative occurrence of co-existing diseases, depicted as nodes on the tree, with edges symbolizing potential transitions between these linked nodes. Our model identified eight distinct ALS patient trajectories, unveiling unique patterns of disease associations at various stages of progression. These patterns may suggest underlying disease mechanisms or risk factors. This research re-conceptualizes ALS progression as a migration through diverse stages, instead of the perspective of a sequence of isolated events. This new approach illuminates patterns of disease association across different progression phases. The insights obtained from this study hold the potential to inform doctors regarding the development of personalized treatment strategies, ultimately enhancing patient prognosis and quality of life.}, }
@article {pmid37891975, year = {2023}, author = {Fu, RH and Chen, HJ and Hong, SY}, title = {Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {10}, pages = {}, pmid = {37891975}, issn = {2076-3921}, support = {MOST 105-2314-B-039-017-MY3//the Ministry of Science and Technology (Taiwan)/ ; DMR-111-140//China Medical University Hospital (Taiwan)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal rare disease of progressive degeneration of motor neurons. The most common genetic mutation in ALS is the hexanucleotide repeat expansion (HRE) located in the first intron of the C9orf72 gene (C9-ALS). HRE can produce dipeptide repeat proteins (DPRs) such as poly glycine-alanine (GA) in a repeat-associated non-ATG (RAN) translation. GA-DPR has been shown to be toxic to motor neurons in various biological models. However, its effects on microglia involved in C9-ALS have not been reported. Here, we show that GA-DPR (GA50) activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome in a human HMC3 microglia model. MCC950 (specific inhibitor of the NLRP3) treatment can abrogate this activity. Next, using yeast two-hybrid screening, we identified sulfide quinone oxidoreductase (SQOR) as a GA50 interacting protein. SQOR knockdown in HMC3 cells can significantly induce the activity of the NLRP3 inflammasome by upregulating the level of intracellular reactive oxygen species and the cytoplasmic escape of mitochondrial DNA. Furthermore, we obtained irisflorentin as an effective blocker of the interaction between SQOR and GA50, thus inhibiting NLRP3 inflammasome activity in GA50-expressing HMC3 cells. These results imply the association of GA-DPR, SQOR, and NLRP3 inflammasomes in microglia and establish a treatment strategy for C9-ALS with irisflorentin.}, }
@article {pmid37891966, year = {2023}, author = {Grossini, E and De Marchi, F and Venkatesan, S and Mele, A and Ferrante, D and Mazzini, L}, title = {Effects of Acetyl-L-Carnitine on Oxidative Stress in Amyotrophic Lateral Sclerosis Patients: Evaluation on Plasma Markers and Members of the Neurovascular Unit.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {10}, pages = {}, pmid = {37891966}, issn = {2076-3921}, abstract = {Oxidative stress, the alteration of mitochondrial function, and the neurovascular unit (NVU), play a role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. We aimed to demonstrate the changes in the plasma redox system and nitric oxide (NO) in 32 new ALS-diagnosed patients in treatment with Acetyl-L-Carnitine (ALCAR) compared to healthy controls. We also evaluated the effects of plasma on human umbilical cord-derived endothelial vascular cells (HUVEC) and astrocytes. The analyses were performed at the baseline (T0), after three months (T1), and after six months (T2). In ALS patients at T0/T1, the plasma markers of lipid peroxidation, thiobarbituric acid reactive substances (TBARS) and 4-hydroxy nonenal (4-HNE) were higher, whereas the antioxidants, glutathione (GSH) and the glutathione peroxidase (GPx) activity were lower than in healthy controls. At T2, plasma TBARS and 4-HNE decreased, whereas plasma GSH and the GPx activity increased in ALS patients. As regards NO, the plasma levels were firmly lower at T0-T2 than those of healthy controls. Cell viability, and mitochondrial membrane potential in HUVEC/astrocytes treated with the plasma of ALS patients at T0-T2 were reduced, while the oxidant release increased. Those results, which confirmed the fundamental role of oxidative stress, mitochondrial function, and of the NVU in ALS pathogenesis, can have a double meaning, acting as disease markers at baseline and potential markers of drug effects in clinical practice and during clinical trials.}, }
@article {pmid37890889, year = {2023}, author = {Ilieva, H and Vullaganti, M and Kwan, J}, title = {Advances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis.}, journal = {BMJ (Clinical research ed.)}, volume = {383}, number = {}, pages = {e075037}, pmid = {37890889}, issn = {1756-1833}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Pathology, Molecular ; Disease Progression ; }, abstract = {Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an effective therapy remains slow. This review summarizes the critical discoveries and outlines the advances in disease characterization, diagnosis, imaging, and biomarkers, along with the current status of approaches to ALS care and treatment. Additional knowledge of the factors driving disease progression and heterogeneity will hopefully soon transform the care for patients with ALS into an individualized, multi-prong approach able to prevent disease progression sufficiently to allow for a dignified life with limited disability.}, }
@article {pmid37887320, year = {2023}, author = {Fu, RH and Chen, HJ and Hong, SY}, title = {Interaction of the C9orf72-Amyotrophic Lateral Sclerosis-Related Proline-Arginine Dipeptide Repeat Protein with the RNA-Binding Protein NOVA1 Causes Decreased Expression of UNC13A Due to Enhanced Inclusion of Cryptic Exons, Which Is Reversed by Betulin Treatment.}, journal = {Cells}, volume = {12}, number = {20}, pages = {}, pmid = {37887320}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Arginine/metabolism ; C9orf72 Protein/genetics/metabolism ; Dipeptides/metabolism ; Motor Neurons/pathology ; Neuro-Oncological Ventral Antigen ; Proline/metabolism ; RNA, Messenger/genetics/metabolism ; RNA-Binding Proteins/genetics/metabolism ; }, abstract = {C9orf72 mutations are the most common form of familial amyotrophic lateral sclerosis (C9-ALS). It causes the production of proline-arginine dipeptide repeat proteins (PR-DPRs) in motor neurons (MNs), leading to the molecular pathology characteristic of ALS. UNC13A is critical for maintaining the synaptic function of MNs. Most ALS patients have nuclear deletion of the splicing repressor TDP-43 in MNs, which causes inclusion of the cryptic exon (CE) of UNC13A mRNA, resulting in nonsense-mediated mRNA decay and reduced protein expression. Therefore, in this study, we explored the role of PR-DPR in CE inclusion of UNC13A mRNA. Our results showed that PR-DPR (PR50) induced CE inclusion and decreased the protein expression of UNC13A in human neuronal cell lines. We also identified an interaction between the RNA-binding protein NOVA1 and PR50 by yeast two-hybrid screening. NOVA1 expression is known to be reduced in patients with ALS. We found that knockdown of NOVA1 enhanced CE inclusion of UNC13A mRNA. Furthermore, the naturally occurring triterpene betulin can inhibit the interaction between NOVA1 and PR50, thus preventing CE inclusion of UNC13A mRNA and protein reduction in human neuronal cell lines. This study linked PR-DPR with CE inclusion of UNC13A mRNA and developed candidate therapeutic strategies for C9-ALS using betulin.}, }
@article {pmid37887305, year = {2023}, author = {Provasek, VE and Kodavati, M and Guo, W and Wang, H and Boldogh, I and Van Den Bosch, L and Britz, G and Hegde, ML}, title = {lncRNA Sequencing Reveals Neurodegeneration-Associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists in Motor Neurons.}, journal = {Cells}, volume = {12}, number = {20}, pages = {}, pmid = {37887305}, issn = {2073-4409}, support = {RF1NS112719/NS/NINDS NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; R03AG064266/NH/NIH HHS/United States ; R01NS094535/NH/NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; R01NS088645/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; Motor Neurons/metabolism ; Mutation/genetics ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Fused-in sarcoma (FUS) gene mutations have been implicated in amyotrophic lateral sclerosis (ALS). This study aimed to investigate the impact of FUS mutations (R521H and P525L) on the transcriptome of induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs). Using RNA sequencing (RNA Seq), we characterized differentially expressed genes (DEGs) and differentially expressed lncRNAs (DELs) and subsequently predicted lncRNA-mRNA target pairs (TAR pairs). Our results show that FUS mutations significantly altered the expression profiles of mRNAs and lncRNAs in iPSCs. Using this large dataset, we identified and verified six key differentially regulated TAR pairs in iPSCs that were also altered in iMNs. These target transcripts included: GPR149, NR4A, LMO3, SLC15A4, ZNF404, and CRACD. These findings indicated that selected mutant FUS-induced transcriptional alterations persist from iPSCs into differentiated iMNs. Functional enrichment analyses of DEGs indicated pathways associated with neuronal development and carcinogenesis as likely altered by these FUS mutations. Furthermore, ingenuity pathway analysis (IPA) and GO network analysis of lncRNA-targeted mRNAs indicated associations between RNA metabolism, lncRNA regulation, and DNA damage repair. Our findings provide insights into potential molecular mechanisms underlying the pathophysiology of ALS-associated FUS mutations and suggest potential therapeutic targets for the treatment of ALS.}, }
@article {pmid37885757, year = {2023}, author = {Krannich, T and Sarrias, MH and Ben Aribi, H and Shokrof, M and Iacoangeli, A and Al-Chalabi, A and Sedlazeck, FJ and Busby, B and Al Khleifat, A}, title = {VariantSurvival: a tool to identify genotype-treatment response.}, journal = {Frontiers in bioinformatics}, volume = {3}, number = {}, pages = {1277923}, pmid = {37885757}, issn = {2673-7647}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Motivation: For a number of neurological diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, and many others, certain genes are known to be involved in the disease mechanism. A common question is whether a structural variant in any such gene may be related to drug response in clinical trials and how this relationship can contribute to the lifecycle of drug development. Results: To this end, we introduce VariantSurvival, a tool that identifies changes in survival relative to structural variants within target genes. VariantSurvival matches annotated structural variants with genes that are clinically relevant to neurological diseases. A Cox regression model determines the change in survival between the placebo and clinical trial groups with respect to the number of structural variants in the drug target genes. We demonstrate the functionality of our approach with the exemplary case of the SETX gene. VariantSurvival has a user-friendly and lightweight graphical user interface built on the shiny web application package.}, }
@article {pmid37882882, year = {2023}, author = {Wang, Y and Sun, S and Zhai, J and Liu, Y and Song, C and Sun, C and Li, Q and Liu, J and Jiang, H and Liu, Y}, title = {scAAV9-VEGF alleviates symptoms of amyotrophic lateral sclerosis (ALS) mice through regulating aromatase.}, journal = {Experimental brain research}, volume = {241}, number = {11-12}, pages = {2817-2827}, pmid = {37882882}, issn = {1432-1106}, support = {ZR2020QH126//Natural Science Foundation of Shandong Province Youth Fund/ ; ZR2020QH124//Natural Science Foundation of Shandong Province Youth Fund/ ; 2019ZC010137//Zibo city key research and development plan/ ; 2021Q048//TCM science and technology Project of Shandong Province/ ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Motor Neurons/physiology ; Vascular Endothelial Growth Factor A/metabolism/pharmacology ; *Neurodegenerative Diseases/metabolism ; Aromatase/genetics/metabolism/pharmacology ; Superoxide Dismutase/genetics/metabolism/pharmacology ; Mice, Transgenic ; Disease Models, Animal ; Estrogens/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset, chronic, progressive, and fatal neurodegenerative disease that leads to progressive atrophy and weakness of the muscles throughout the body. Herein, we found that the intrathecal injection of adeno-associated virus (AAV)-delivered VEGF in SOD1-G93A transgenic mice, as well as ALS mice, could significantly delay disease onset and preserve motor functions and neurological functions, thus prolonging the survival of mice models. Moreover, we found that VEGF treatment could induce the elevated expression of aromatase, which is a key enzyme in estrogen synthesis, in neurons but not in astrocytes. On the other hand, the changes in the expression of oxidative stress-related factors HO-1 and GCLM and autophagy-related proteins p62 and LC3II upon the administration of VEGF revealed the involvement of oxidative stress and autophagy underlying the downstream of the VEGF-induced mitigation of ALS. In conclusion, this study proved the protective effects of VEGF in the onset and development of ALS and revealed the involvement of estrogen, oxidative stress and autophagy in the VEGF-induced alleviation of ALS. Our results highlighted the potential of VEGF as a promising therapeutic agent in the treatment of ALS.}, }
@article {pmid37882288, year = {2023}, author = {Barco-Antoñanzas, M and Font-Farre, M and Eceiza, MV and Gil-Monreal, M and van der Hoorn, RAL and Royuela, M and Zabalza, A}, title = {Cysteine proteases are activated in sensitive Amaranthus palmeri populations upon treatment with herbicides inhibiting amino acid biosynthesis.}, journal = {Physiologia plantarum}, volume = {175}, number = {5}, pages = {e13993}, doi = {10.1111/ppl.13993}, pmid = {37882288}, issn = {1399-3054}, support = {//Eusko Jaurlaritza/ ; 2020 117723-RB-100//Ministerio de Ciencia e Innovaci&#xf3;n/ ; AGL2016-77531-R//Ministerio de Econom&#xed;a y Competitividad/ ; }, mesh = {Herbicide Resistance ; *Amaranthus/metabolism ; *Herbicides/pharmacology/metabolism ; *Cysteine Proteases/metabolism/pharmacology ; }, abstract = {The herbicides glyphosate and pyrithiobac inhibit the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) in the aromatic amino acid biosynthetic pathway and acetolactate synthase (ALS) in the branched-chain amino acid biosynthetic pathway, respectively. Here we characterise the protease activity profiles of a sensitive (S), a glyphosate-resistant (GR) and a multiple-resistant (MR) population of Amaranthus palmeri in response to glyphosate and pyrithiobac. Amino acid accumulation and cysteine protease activities were induced with both herbicides in the S population and with pyrithiobac in the GR population, suggesting that the increase in cysteine proteases is responsible for the increased degradation of the available proteins and the observed increase in free amino acids. Herbicides did not induce any changes in the proteolytic activities in the populations with target-site resistance, indicating that this effect was only induced in sensitive plants.}, }
@article {pmid37879951, year = {2023}, author = {Liu, JY and Lu, YR and Guo, J and Li, H and Wang, Y and Zhao, YQ and Li, J and Wang, Q}, title = {Effect of electroacupuncture intervention on the spinal cord PPIA/NF-κB signaling pathway in mice with amyotrophic lateral sclerosis.}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {48}, number = {10}, pages = {1009-1016}, doi = {10.13702/j.1000-0607.20230251}, pmid = {37879951}, issn = {1000-0607}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; DNA-Binding Proteins/metabolism ; *Electroacupuncture ; Motor Neurons/metabolism ; NF-kappa B/genetics/metabolism ; Riluzole ; Signal Transduction ; Spinal Cord ; Superoxide Dismutase-1/genetics/metabolism ; Peptidylprolyl Isomerase/metabolism ; }, abstract = {OBJECTIVES: To observe the effects of electroacupuncture (EA) on motor function, expression of extracellular cyclophile A(PPIA) and PPIA/nuclear factor-κB (NF-κB) signaling pathway in spinal cord of amyotrophic la-teral sclerosis (ALS) mice, so as to explore the mechanism of EA intervention in regulating extracellular PPIA on neuroinflammation in ALS mice.<br><br>METHODS: Thirty ALS-SOD1[G93A] mice with hSOD1-G93A gene were randomly divided into model, EA and Riluzole groups , with 10 mice in each group, and other 10 ALS-SOD1[G93A] negative mice were used as the blank group. EA was applied to bilateral "Yanglingquan"(GB34) and "Zusanli"(ST36) for 20 min once daily, 5 days a week for 2 weeks. In the Riluzole group, riluzole solution (30 mg&#xb7;kg[-1]&#xb7;d[-1]) was administrated intragastrically, and the treatment time was the same as that in the EA group.Rotating rod experiment and open field experiment were used to evaluate the changes in motor function of mice .The morphology of motor neurons in the anterior horn of spinal cord was observed by HE staining.The relative protein expression levels of PPIA, TDP-43 and NF-&#x3ba;B in the spinal cord were detected by Western blot.The positive expression level of TDP-43 in the spinal cord was detected by immunohistochemistry. The positive expression level of PPIA in spinal cord was marked by immunofluorescence. Serum PPIA content was determined by ELISA.<br><br>RESULTS: Compared with the blank group, the time of rod dropping and the total distance of open field movement in the model group were shortened (P<0.01), the number of motor neurons in the anterior horn of the spinal cord was reduced, the cell morphology was incomplete, the cell body was atrophied, the protein expression and positive expression of TDP-43 were increased (P<0.01), the protein expressions of PPIA and NF-&#x3ba;B in the spinal cord were increased(P<0.01), the serum content of PPIA and immunofluorescence expression of PPIA in spinal cord were increased (P<0.01). Compared with the model group, the time of rod dropping and the total distance of open field movement of mice in the EA group and the Riluzole group were prolonged (P<0.05, P<0.01), and the injury of motor neuron in the anterior horn of the spinal cord was decreased, the protein expression and positive expression of TDP-43 in the spinal cord were decreased (P<0.05, P<0.01)&#xff1b;the relative expression levels of PPIA and NF-&#x3ba;B proteins were decreased (P<0.05, P<0.01), and the content of PPIA in serum and the immunofluorescence expression of PPIA in the spinal cord were decreased (P<0.05, P<0.01) in the EA group&#xff1b;the relative protein expression of NF-&#x3ba;B and fluorescence expression of PPIA in spinal cord of mice in the Riluzole group were decreased (P<0.05).<br><br>CONCLUSIONS: EA intervention can improve motor function in ALS mice, and its mechanism may be related to the inhibition of PPIA/NF-&#x3ba;B signaling pathway by EA to alleviating neuroinflammatory response.}, }
@article {pmid37877583, year = {2024}, author = {Haldar, S and Khan, AH and De, A and Reichmayr, F and Morag, A and Yu, M and Schneemann, A and Kaskel, S}, title = {Fluorinated Benzimidazole-Linked Highly Conjugated Polymer Enabling Covalent Polysulfide Anchoring for Stable Sulfur Batteries.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {30}, number = {2}, pages = {e202302779}, doi = {10.1002/chem.202302779}, pmid = {37877583}, issn = {1521-3765}, support = {SPP2248//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Sulfur is one of the most abundant and economical elements in the p-block family and highly redox active, potentially utilizable as a charge-storing electrode with high theoretical capacities. However, its inherent good solubility in many electrolytes inhibits its accessibility as an electrode material in typical metal-sulfur batteries. In this work, the synthetically designed fluorinated porous polymer, when treated with elemental sulfur through a well-known nucleophilic aromatic substitution mechanism (SN Ar), allows for the covalent integration of polysulfides into a highly conjugated benzimidazole polymer by replacing the fluorine atoms. Chemically robust benzimidazole linkages allow such harsh post-synthetic treatment and facilitate the electronic activation of the anchored polysulfides for redox reactions under applied potential. The electrode amalgamated with sulfurized polymer mitigates the so-called polysulfide shuttle effect in the lithium-sulfur (Li-S) battery and also enables a reversible, more environmentally friendly, and more economical aluminum-sulfur (Al-S) battery that is configured with mostly p-block elements as cathode, anode, and electrolytes. The improved cycling stabilities and reduction of the overpotential in both cases pave the way for future sustainable energy storage solutions.}, }
@article {pmid37875807, year = {2023}, author = {Loubet, I and Meyer, L and Michel, S and Pernin, F and Carrère, S and Barrès, B and Le Corre, V and Délye, C}, title = {A high diversity of non-target site resistance mechanisms to acetolactate-synthase (ALS) inhibiting herbicides has evolved within and among field populations of common ragweed (Ambrosia artemisiifolia L.).}, journal = {BMC plant biology}, volume = {23}, number = {1}, pages = {510}, pmid = {37875807}, issn = {1471-2229}, support = {DRAGON 29001099-1944//Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement/ ; DRAGON 29001099-1944//ACTA - Les instituts techniques agricoles/ ; 2018-CRD-02 PPV18//Agence Nationale de S&#xe9;curit&#xe9; Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de S&#xe9;curit&#xe9; Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de S&#xe9;curit&#xe9; Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de S&#xe9;curit&#xe9; Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de S&#xe9;curit&#xe9; Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de S&#xe9;curit&#xe9; Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; }, mesh = {Humans ; Ambrosia/genetics ; *Herbicides/pharmacology ; *Acetolactate Synthase ; Transcriptome ; Herbicide Resistance/genetics ; }, abstract = {BACKGROUND: Non-target site resistance (NTSR) to herbicides is a polygenic trait that threatens the chemical control of agricultural weeds. NTSR involves differential regulation of plant secondary metabolism pathways, but its precise genetic determinisms remain fairly unclear. Full-transcriptome sequencing had previously been implemented to identify NTSR genes. However, this approach had generally been applied to a single weed population, limiting our insight into the diversity of NTSR mechanisms. Here, we sought to explore the diversity of NTSR mechanisms in common ragweed (Ambrosia artemisiifolia L.) by investigating six field populations from different French regions where NTSR to acetolactate-synthase-inhibiting herbicides had evolved.<br><br>RESULTS: A de novo transcriptome assembly (51,242 contigs, 80.2% completeness) was generated as a reference to seek genes differentially expressed between sensitive and resistant plants from the six populations. Overall, 4,609 constitutively differentially expressed genes were identified, of which none were common to all populations, and only 197 were shared by several populations. Similarly, population-specific transcriptomic response was observed when investigating early herbicide response. Gene ontology enrichment analysis highlighted the involvement of stress response and regulatory pathways, before and after treatment. The expression of 121 candidate constitutive NTSR genes including CYP71, CYP72, CYP94, oxidoreductase, ABC transporters, gluco and glycosyltransferases was measured in 220 phenotyped plants. Differential expression was validated in at least one ragweed population for 28 candidate genes. We investigated whether expression patterns at some combinations of candidate genes could predict phenotype. Within populations, prediction accuracy decreased when applied to an additional, independent plant sampling. Overall, a wide variety of genes linked to NTSR was identified within and among ragweed populations, of which only a subset was captured in our experiments.<br><br>CONCLUSION: Our results highlight the complexity and the diversity of NTSR mechanisms that can evolve in a weed species in response to herbicide selective pressure. They strongly point to a non-redundant, population-specific evolution of NTSR to ALS inhibitors in ragweed. It also alerts on the potential of common ragweed for rapid adaptation to drastic environmental or human-driven selective pressures.}, }
@article {pmid37875101, year = {2024}, author = {Karacaoglu, C and Ersoy, S and Pala, E and Engin, VS}, title = {Evaluation of the Effectiveness of Wet Cupping Therapy in Fibromyalgia Patients: A Randomized Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {10-19}, doi = {10.1159/000534637}, pmid = {37875101}, issn = {2504-2106}, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *Cupping Therapy ; *Fibromyalgia/therapy ; Quality of Life ; Treatment Outcome ; Adolescent ; Young Adult ; Aged ; }, abstract = {INTRODUCTION: The aim of this study was to investigate the efficacy of wet cupping therapy (WCT) in patients diagnosed with fibromyalgia syndrome (FMS) as a complementary method in fibromyalgia treatment.<br><br>MATERIALS AND METHODS: A total of 120 participants between 18 and 65 years who were diagnosed with FMS were included in the study. They were randomized into two groups: 60 patients as the intervention and 60 patients as the control group. Each participant in the intervention group received 3 sessions of WCT once a month in addition to their ongoing treatment whereas the control group received only routine medical treatment. The evaluation was conducted in both groups based on the fibromyalgia impact questionnaire (FIQ), visual analog scale (VAS), and quality of life scale (QoL) parameters initially (at 0th week) and 1 week after the WCT sessions (at the 10th week). For the comparison of quantitative variables showing a normal distribution between the two groups, the Student's t test was used, while the Mann-Whitney U test was employed for variables not showing a normal distribution. The &#x3c7;2 test and Continuity (Yates) Correction were used for the comparison of qualitative data. The significance level was set at p < 0.05.<br><br>RESULTS: The study included 107 female and 13 male participants, with a mean age of 45.79 &#xb1; 8.49 years. When comparing the pretreatment FIQ, VAS, and QoL scores with the scores obtained after three sessions of WCT, it was observed that in the WCT group, the FIQ and VAS values significantly decreased compared to the control group while the QoL significantly increased compared to the control group (p < 0.001 in all).<br><br>CONCLUSION: The findings obtained from this study indicate that WCT can be an effective treatment option for patients with FMS.<br><br>UNLABELLED: <title>Einleitung</title>Mit dieser Studie soll die Wirksamkeit der blutigen Schr&#xf6;pftherapie (wet cupping therapy, WCT) bei Patienten mit diagnostiziertem Fibromyalgie-Syndrom (FMS) als komplement&#xe4;re Methode in der Fibromyalgie-Behandlung untersucht werden.<title>Material und Methoden</title>Insgesamt wurden 120 Teilnehmer mit diagnostiziertem FMS zwischen 18 und 65 Jahren in die Studie aufgenommen. Diese wurden randomisiert zwei Gruppen zugeordnet: 60 Patienten wurden der Interventionsgruppe zugewiesen und 60 Patienten der Kontrollgruppe. Alle Teilnehmer der Interventionsgruppe erhielten einmal im Monat drei Sitzungen WCT zus&#xe4;tzlich zu ihrer laufenden Therapie, w&#xe4;hrend die Kontrollgruppe lediglich die Standardbehandlung erhielt. Die Bewertung erfolgte in beiden Gruppen anhand des Fibromyalgia Impact Questionnaire (FIQ), der Visuellen Analogskala (VAS) und der Parameter der Quality of Life (QoL) Scale zu Beginn (in Woche 0) und eine Woche nach den WCT-Sitzungen (in Woche 10). F&#xfc;r den Vergleich von quantitativen Variablen, die eine Normalverteilung zwischen den beiden Gruppen aufwiesen, wurde der Student&#x2019;s <italic>t</italic>-Test verwendet, w&#xe4;hrend bei Variablen ohne Normalverteilung der Mann-Whitney-U-Test zur Anwendung kam. Qualitative Daten wurden mit dem Chi-Quadrat-Test und der Kontinuit&#xe4;tskorrektur (Yates) verglichen. Das Signifikanzniveau wurde auf <italic>p</italic> < 0,05 festgelegt.<title>Ergebnisse</title>In die Studie wurden 107 Frauen und 13 M&#xe4;nner mit einem Durchschnittsalter von 45,79 &#xb1; 8,49 Jahren aufgenommen. Beim Vergleich der FIQ-, VAS- und QoL-Werte vor der Behandlung mit den nach drei WCT-Sitzungen erhobenen Werten zeigte sich in der WCT-Gruppe ein signifikanter R&#xfc;ckgang der FIQ- und VAS-Werte im Vergleich zur Kontrollgruppe, wohingegen bei der QoL ein signifikanter Anstieg gegen&#xfc;ber der Kontrollgruppe zu beobachten war (<italic>p</italic> < 0,001 in allen F&#xe4;llen).<title>Schlussfolgerung</title>Die Ergebnisse dieser Studie deuten darauf hin, dass die WCT eine wirksame therapeutische Option f&#xfc;r Patienten mit FMS sein kann.}, }
@article {pmid37874905, year = {2023}, author = {Harrison, D and Billinton, A and Bock, MG and Doedens, JR and Gabel, CA and Holloway, MK and Porter, RA and Reader, V and Scanlon, J and Schooley, K and Watt, AP}, title = {Discovery of Clinical Candidate NT-0796, a Brain-Penetrant and Highly Potent NLRP3 Inflammasome Inhibitor for Neuroinflammatory Disorders.}, journal = {Journal of medicinal chemistry}, volume = {66}, number = {21}, pages = {14897-14911}, doi = {10.1021/acs.jmedchem.3c01398}, pmid = {37874905}, issn = {1520-4804}, mesh = {Humans ; *Inflammasomes/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/physiology ; Neuroinflammatory Diseases ; Brain/metabolism ; Esters ; }, abstract = {The NLRP3 inflammasome is a component of the innate immune system involved in the production of proinflammatory cytokines. Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, have been shown to have a component driven by NLRP3 inflammasome activation. Diseases such as these with large unmet medical needs have resulted in an interest in inhibiting the NLRP3 inflammasome as a potential pharmacological treatment, but to date, no marketed drugs specifically targeting NLRP3 have been approved. Furthermore, the requirement for CNS-penetrant molecules adds additional complexity to the search for NLRP3 inflammasome inhibitors suitable for clinical investigation of neuroinflammatory disorders. We designed a series of ester-substituted carbamate compounds as selective NLRP3 inflammasome inhibitors, leading to NT-0796, an isopropyl ester that undergoes intracellular conversion to NDT-19795, the carboxylic acid active species. NT-0796 was shown to be a potent and selective NLRP3 inflammasome inhibitor with demonstrated in vivo brain penetration.}, }
@article {pmid37873269, year = {2023}, author = {Pottinger, TD and Motelow, JE and Povysil, G and Moreno, CAM and Ren, Z and Phatnani, H and ,  and Aitman, TJ and Santoyo-Lopez, J and ,  and Mitsumoto, H and ,  and ,  and ,  and Goldstein, DB and Harms, MB}, title = {Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {37873269}, support = {K01 MH098126/MH/NIMH NIH HHS/United States ; RC2 MH089915/MH/NIMH NIH HHS/United States ; P01 HD080642/HD/NICHD NIH HHS/United States ; R01 MH097971/MH/NIMH NIH HHS/United States ; RC2 NS070344/NS/NINDS NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UM1 AI100645/AI/NIAID NIH HHS/United States ; P30 AG028377/AG/NIA NIH HHS/United States ; U54 NS078059/NS/NINDS NIH HHS/United States ; P01 AG007232/AG/NIA NIH HHS/United States ; RF1 AG054023/AG/NIA NIH HHS/United States ; R01 HD048805/HD/NICHD NIH HHS/United States ; U01 HG007672/HG/NHGRI NIH HHS/United States ; U01 NS053998/NS/NINDS NIH HHS/United States ; U01 NS077303/NS/NINDS NIH HHS/United States ; U19 AI067854/AI/NIAID NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; R01 ES016348/ES/NIEHS NIH HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 30,000 people in the United States. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms, such as antisense oligonucleotides, continue to develop, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.<br><br>METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger cohort of 6,970 ALS patients from a large multi-ethnic cohort as well as 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.<br><br>RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR=19.18, p = 3.67 &#xd7; 10[-39]; OR=4.73, p = 2 &#xd7; 10[-10]; OR=2.3, p = 7.49 &#xd7; 10[-9], respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 &#xd7; 10[-7]), was protective for ALS in this model. An intolerant domain based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR=10.08, p = 3.62 &#xd7; 10[-16]). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p=8.38 &#xd7; 10[-6]).<br><br>CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, rare variant burden testing validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.}, }
@article {pmid37872794, year = {2023}, author = {You, FL and Xia, GF and Cai, J}, title = {Behavioural Variant Frontotemporal Dementia due to CCNF Gene Mutation: A Case Report.}, journal = {Current Alzheimer research}, volume = {20}, number = {5}, pages = {371-378}, doi = {10.2174/1567205020666230811092906}, pmid = {37872794}, issn = {1875-5828}, mesh = {Male ; Humans ; Aged ; *Frontotemporal Dementia/diagnosis/genetics ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Neurodegenerative Diseases ; Memantine/therapeutic use ; Mutation/genetics ; Neuropsychological Tests ; Sodium ; Cyclins/genetics ; }, abstract = {BACKGROUND: Frontal, temporal lobe dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative diseases. Studies have found that CCNF mutations have been found in patients with familial and sporadic ALS and FTD. Behavioural variant frontotemporal dementia (bvFTD) is a clinical syndrome characterized by progressive deterioration of personality, social behaviour, and cognitive function, which is most closely related to genetic factors. As the early symptoms of bvFTD are highly heterogeneous, the condition is often misdiagnosed as Alzheimer's disease or psychiatric disorders. In this study, a bvFTD patient had a CCNF gene mutation, which led to ubiquitinated protein accumulation and ultimately caused neurodegenerative disease. Genetic detection should be improved urgently for bvFTD patients and family members to provide a clinical reference for early diagnosis of frontotemporal dementia.<br><br>CASE PRESENTATION: In this case, the patient was 65 years old with an insidious onset, early-onset memory loss, a significant decline in the episodic memory, an early AD diagnosis, and oral treatment with donepezil hydrochloride for 3 years with poor efficacy, followed by a change to oral memantine hydrochloride tablets, which controlled the condition for several months. His medication was switched to sodium oligomannate capsules, and his condition was gradually controlled, but no significant improvement was observed. After spontaneous drug withdrawal, the patient's condition progressed rapidly; therefore, he visited our hospital and underwent neuropsychological tests for moderate to severe cognitive impairment. AD cerebrospinal fluid markers showed no significant abnormalities, and cranial MRI revealed frontotemporal lobe atrophy and decreased hippocampal volume. Genetic testing for the presence of the CCNF gene revealed a c.1532C > A (p. T511N) heterozygous variant, which might be a diagnostic criterion for bvFTD. Therefore, the patient's symptoms recurred after transient improvement with the combination of donepezil, oral memantine hydrochloride tablets, and sodium oligomannate, but his overall condition was improved compared to that before, and this treatment regimen was continued to observe changes during the follow-up.<br><br>CONCLUSION: The early clinical manifestations of bvFTD are complex and variable, and the condition is easily misdiagnosed, thus delaying treatment. Therefore, for patients with a high clinical suspicion of FTD, in addition to a detailed understanding of their medical history and family history and improvement of relevant examinations, genetic testing should be performed as early as possible to help confirm the diagnosis. For diseases closely related to genes, genetic testing of other family members should be optimised as much as possible to allow early diagnosis and intervention and guide fertility in the next generation.}, }
@article {pmid37868386, year = {2023}, author = {Hoxhaj, P and Hastings, N and Kachhadia, MP and Gupta, R and Sindhu, U and Durve, SA and Azam, A and Auz Vinueza, MJ and Bhuvan,  and Win, SH and Rathod, DC and Afsar, AP}, title = {Exploring Advancements in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review of Current Modalities and Future Prospects.}, journal = {Cureus}, volume = {15}, number = {9}, pages = {e45489}, pmid = {37868386}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable disease requiring a multidisciplinary treatment approach and a collaborative therapeutic effort. A combination of both upper and lower motor neuron degeneration ultimately leads to respiratory failure, similar to other dementia-type neurodegenerative diseases. The aim of this paper is to pioneer current ALS research by carrying out a narrative literature review of the current treatment modalities of the disease. Through these efforts, we hope to condense the most pertinent information regarding current treatments and enhance the management of ALS patients as a whole, giving these patients a better quality of life as the search for a cure continues. We used a Pubmed search strategy and specific MeSH terms for the selection of the literature articles using the keywords "ALS," "new treatment," "treatment," and "symptomatic treatment." A combination of pharmaceutical interventions, psychological support, and physical rehabilitation has been most effective in enhancing the quality of life of patients with ALS (PALS). Among potential pharmacological therapies, only a few have been approved by the US Food and Drug Administration(FDA) to be used to treat ALS and its symptoms. Other treatment modalities being considered include gene therapy, cellular therapy, psychological therapy, physical therapy, and speech therapy, alongside robotics, alternative feeding methods, and communication devices.}, }
@article {pmid37864389, year = {2024}, author = {Xiao, F and He, Z and Wang, S and Li, J and Fan, X and Yan, T and Yang, M and Yang, D}, title = {Regulatory mechanism of circular RNAs in neurodegenerative diseases.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {30}, number = {4}, pages = {e14499}, pmid = {37864389}, issn = {1755-5949}, support = {//China Scholarship Council/ ; //National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/genetics ; RNA, Circular/metabolism ; *MicroRNAs/genetics ; *Alzheimer Disease/genetics ; *Parkinson Disease ; Biomarkers ; }, abstract = {BACKGROUND: Neurodegenerative disease is a collective term for a category of diseases that are caused by neuronal dysfunction, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Circular RNAs (circRNAs) are a class of non-coding RNAs without the 3' cap and 5' poly(A) and are linked by covalent bonds. CircRNAs are highly expressed in brain neurons and can regulate the pathological process of neurodegenerative diseases by affecting the levels of various deposition proteins.<br><br>AIMS: This review is aiming to suggest that the majority of circRNAs influence neurodegenerative pathologies mainly by affecting the abnormal deposition of proteins in neurodegenerative diseases.<br><br>METHODS: We systematically summarized the pathological features of neurodegenerative diseases and the regulatory mechanisms of circRNAs in various types of neurodegenerative diseases.<br><br>RESULTS: Neurodegenerative disease main features include intercellular ubiquitin-proteasome system abnormalities, changes in cytoskeletal proteins, and the continuous deposition of insoluble protein fragments and inclusion bodies in the cytoplasm or nucleus, resulting in impairment of the normal physiological processes of the neuronal system. CircRNAs have multiple mechanisms, such as acting as microRNA sponges, binding to proteins, and regulating transcription. CircRNAs, which are highly stable molecules, are expected to be potential biomarkers for the pathological detection of neurodegenerative diseases such as AD and PD.<br><br>CONCLUSIONS: In this review, we describe the regulatory roles and mechanisms of circRNAs in neurodegenerative diseases and aim to employ circRNAs as biomarkers for the diagnosis and treatment of neurodegenerative diseases.}, }
@article {pmid37862967, year = {2023}, author = {Rabeh, N and Hajjar, B and Maraka, JO and Sammanasunathan, AF and Khan, M and Alkhaaldi, SMI and Mansour, S and Almheiri, RT and Hamdan, H and Abd-Elrahman, KS}, title = {Targeting mGluR group III for the treatment of neurodegenerative diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {168}, number = {}, pages = {115733}, doi = {10.1016/j.biopha.2023.115733}, pmid = {37862967}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Signal Transduction/physiology ; Glutamic Acid ; Neurotransmitter Agents ; Neurons ; *Receptors, Metabotropic Glutamate/physiology ; }, abstract = {Glutamate, an excitatory neurotransmitter, is essential for neuronal function, and it acts on ionotropic or metabotropic glutamate receptors (mGluRs). A disturbance in glutamatergic signaling is a hallmark of many neurodegenerative diseases. Developing disease-modifying treatments for neurodegenerative diseases targeting glutamate receptors is a promising avenue. The understudied group III mGluR 4, 6-8 are commonly found in the presynaptic membrane, and their activation inhibits glutamate release. Thus, targeted mGluRs therapies could aid in treating neurodegenerative diseases. This review describes group III mGluRs and their pharmacological ligands in the context of amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's diseases. Attempts to evaluate the efficacy of these drugs in clinical trials are also discussed. Despite a growing list of group III mGluR-specific pharmacological ligands, research on the use of these drugs in neurodegenerative diseases is limited, except for Parkinson's disease. Future efforts should focus on delineating the contribution of group III mGluR to neurodegeneration and developing novel ligands with superior efficacy and a favorable side effect profile for the treatment of neurodegenerative diseases.}, }
@article {pmid37862206, year = {2024}, author = {Hu, Y and Chen, W and Wei, C and Jiang, S and Li, S and Wang, X and Xu, R}, title = {Pathological mechanisms of amyotrophic lateral Sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {5}, pages = {1036-1044}, pmid = {37862206}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system, the cause of which remains unexplained despite several years of research. Thus, the journey to understanding or treating amyotrophic lateral sclerosis is still a long one. According to current research, amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways. The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis. Here, we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis, as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis. In addition, we discuss current emerging strategies for the treatment of amyotrophic lateral sclerosis. Studying the emergence of these new therapies may help to further our understanding of the pathogenic mechanisms of the disease.}, }
@article {pmid37862205, year = {2024}, author = {Romano, R and Bucci, C}, title = {Antisense therapy: a potential breakthrough in the treatment of neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {19}, number = {5}, pages = {1027-1035}, pmid = {37862205}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system. Currently, there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide. Therefore, it is necessary to find new therapeutic approaches, and antisense therapies offer this possibility, having the great advantage of not modifying cellular genome and potentially being safer. Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases. The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases, with a focus on those antisense therapies that have already received the approval of the U.S. Food and Drug Administration.}, }
@article {pmid37862202, year = {2024}, author = {Tarot, P and Lasbleiz, C and Liévens, JC}, title = {NRF2 signaling cascade in amyotrophic lateral sclerosis: bridging the gap between promise and reality.}, journal = {Neural regeneration research}, volume = {19}, number = {5}, pages = {1006-1012}, pmid = {37862202}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons. Symptoms include muscle weakness and atrophy, spasticity, and progressive paralysis. Currently, there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis. The only two treatments actually approved, riluzole and edaravone, have shown mitigated beneficial effects. The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis. Among mechanisms, abnormal RNA metabolism, nucleocytoplasmic transport defects, accumulation of unfolded protein, and mitochondrial dysfunction would in fine induce oxidative damage and vice versa. A potent therapeutic strategy will be to find molecules that break this vicious circle. Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense, mitochondrial functioning, and inflammation. We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.}, }
@article {pmid37855859, year = {2024}, author = {Vieira, TCRG and Barros, CA and Domingues, R and Outeiro, TF}, title = {PrP meets alpha-synuclein: Molecular mechanisms and implications for disease.}, journal = {Journal of neurochemistry}, volume = {168}, number = {8}, pages = {1625-1639}, doi = {10.1111/jnc.15992}, pmid = {37855859}, issn = {1471-4159}, support = {SFB1286 (B8)//Deutsche Forschungsgemeinschaft/ ; EXC 2067/1-390729940//Deutsche Forschungsgemeinschaft/ ; //Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro (FAPERJ)/ ; //Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico (CNPq)/ ; }, mesh = {Humans ; *alpha-Synuclein/metabolism ; Animals ; Synucleinopathies/metabolism/pathology ; Prion Proteins/metabolism ; }, abstract = {The discovery of prions has challenged dogmas and has revolutionized our understanding of protein-misfolding diseases. The concept of self-propagation via protein conformational changes, originally discovered for the prion protein (PrP), also applies to other proteins that exhibit similar behavior, such as alpha-synuclein (aSyn), a central player in Parkinson's disease and in other synucleinopathies. aSyn pathology appears to spread from one cell to another during disease progression, and involves the misfolding and aggregation of aSyn. How the transfer of aSyn between cells occurs is still being studied, but one important hypothesis involves receptor-mediated transport. Interestingly, recent studies indicate that the cellular prion protein (PrP[C]) may play a crucial role in this process. PrP[C] has been shown to act as a receptor/sensor for protein aggregates in different neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. Here, we provide a comprehensive overview of the current state of knowledge regarding the interaction between aSyn and PrP[C] and discuss its role in synucleinopathies. We examine the properties of PrP and aSyn, including their structure, function, and aggregation. Additionally, we discuss the current understanding of PrP[C]'s role as a receptor/sensor for aSyn aggregates and identify remaining unanswered questions in this area of research. Ultimately, we posit that exploring the interaction between aSyn and PrP[C] may offer potential treatment options for synucleinopathies.}, }
@article {pmid37851042, year = {2023}, author = {Izenberg, A}, title = {Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {29}, number = {5}, pages = {1538-1563}, pmid = {37851042}, issn = {1538-6899}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; *Motor Neuron Disease/diagnosis/genetics/therapy ; Biomarkers ; }, abstract = {OBJECTIVE: This article reviews the clinical spectrum of amyotrophic lateral sclerosis (ALS), its variant presentations, and the approach to diagnosis and management. This review includes a detailed discussion of current and emerging disease-modifying therapies and the management of respiratory and bulbar manifestations of disease. An updated review of ALS genetics and pathophysiology is also provided. This article also touches on several other important motor neuron diseases.<br><br>LATEST DEVELOPMENTS: A new set of simplified diagnostic criteria may help identify patients at earlier stages of the disease. A coformulation of sodium phenylbutyrate and tauroursodeoxycholic acid has been shown to have a significant benefit on disease progression and survival, leading to approval by regulatory authorities in the United States and Canada. An oral formulation of edaravone and an antisense oligonucleotide to a SOD1 gene variation (tofersen) have also recently been approved by the US Food and Drug Administration (FDA). Phase 3 trials of intrathecal mesenchymal stem cells failed to meet primary end points for efficacy. Updated American Academy of Neurology quality measures for the care of patients with ALS were published in 2023.<br><br>ESSENTIAL POINTS: There has been continued progress in ALS genetics, diagnosis, and disease-modifying therapies. However, we still lack a definitive biomarker or a treatment that can halt the progression or reverse the course of disease. The evolving understanding of the genetic and pathophysiologic underpinnings of disease offers promise for more effective and clinically meaningful treatments in the future.}, }
@article {pmid37849894, year = {2023}, author = {Fang, M and Deibler, SK and Nana, AL and Vatsavayai, SC and Banday, S and Zhou, Y and Almeida, S and Weiss, A and Brown, RH and Seeley, WW and Gao, FB and Green, MR}, title = {Loss of TDP-43 function contributes to genomic instability in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1251228}, pmid = {37849894}, issn = {1662-4548}, support = {R01 NS104437/NS/NINDS NIH HHS/United States ; RF1 NS101986/NS/NINDS NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; R01 GM035490/GM/NIGMS NIH HHS/United States ; R21 NS119952/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; R21 NS112766/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; }, abstract = {A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the cytoplasmic mislocalization and aggregation of the DNA/RNA-binding protein TDP-43, but how loss of nuclear TDP-43 function contributes to ALS and FTD pathogenesis remains largely unknown. Here, using large-scale RNAi screening, we identify TARDBP, which encodes TDP-43, as a gene whose loss-of-function results in elevated DNA mutation rate and genomic instability. Consistent with this finding, we observe increased DNA damage in induced pluripotent stem cells (iPSCs) and iPSC-derived post-mitotic neurons generated from ALS patients harboring TARDBP mutations. We find that the increase in DNA damage in ALS iPSC-derived neurons is due to defects in two major pathways for DNA double-strand break repair: non-homologous end joining and homologous recombination. Cells with defects in DNA repair are sensitive to DNA damaging agents and, accordingly, we find that ALS iPSC-derived neurons show a marked reduction in survival following treatment with a DNA damaging agent. Importantly, we find that increased DNA damage is also observed in neurons with nuclear TDP-43 depletion from ALS/FTD patient brain tissues. Collectively, our results demonstrate that ALS neurons with loss of nuclear TDP-43 function have elevated levels of DNA damage and contribute to the idea that genomic instability is a defining pathological feature of ALS/FTD patients with TDP-43 pathology.}, }
@article {pmid37847372, year = {2023}, author = {Sattler, R and Traynor, BJ and Robertson, J and Van Den Bosch, L and Barmada, SJ and Svendsen, CN and Disney, MD and Gendron, TF and Wong, PC and Turner, MR and Boxer, A and Babu, S and Benatar, M and Kurnellas, M and Rohrer, JD and Donnelly, CJ and Bustos, LM and Van Keuren-Jensen, K and Dacks, PA and Sabbagh, MN and , }, title = {Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit.}, journal = {Neurology and therapy}, volume = {12}, number = {6}, pages = {1821-1843}, pmid = {37847372}, issn = {2193-8253}, support = {RF1 NS114128/NS/NINDS NIH HHS/United States ; ZIAAG000933-15/AG/NIA NIH HHS/United States ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; MR/T046015/1/MRC_/Medical Research Council/United Kingdom ; ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; R35 NS116846/NS/NINDS NIH HHS/United States ; }, abstract = {A summit held March 2023 in Scottsdale, Arizona (USA) focused on the intronic hexanucleotide expansion in the C9ORF72 gene and its relevance in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS; C9ORF72-FTD/ALS). The goal of this summit was to connect basic scientists, clinical researchers, drug developers, and individuals affected by C9ORF72-FTD/ALS to evaluate how collaborative efforts across the FTD-ALS disease spectrum might break down existing disease silos. Presentations and discussions covered recent discoveries in C9ORF72-FTD/ALS disease mechanisms, availability of disease biomarkers and recent advances in therapeutic development, and clinical trial design for prevention and treatment for individuals affected by C9ORF72-FTD/ALS and asymptomatic pathological expansion carriers. The C9ORF72-associated hexanucleotide repeat expansion is an important locus for both ALS and FTD. C9ORF72-FTD/ALS may be characterized by loss of function of the C9ORF72 protein and toxic gain of functions caused by both dipeptide repeat (DPR) proteins and hexanucleotide repeat RNA. C9ORF72-FTD/ALS therapeutic strategies discussed at the summit included the use of antisense oligonucleotides, adeno-associated virus (AAV)-mediated gene silencing and gene delivery, and engineered small molecules targeting RNA structures associated with the C9ORF72 expansion. Neurofilament light chain, DPR proteins, and transactive response (TAR) DNA-binding protein 43 (TDP-43)-associated molecular changes were presented as biomarker candidates. Similarly, brain imaging modalities (i.e., magnetic resonance imaging [MRI] and positron emission tomography [PET]) measuring structural, functional, and metabolic changes were discussed as important tools to monitor individuals affected with C9ORF72-FTD/ALS, at both pre-symptomatic and symptomatic disease stages. Finally, summit attendees evaluated current clinical trial designs available for FTD or ALS patients and concluded that therapeutics relevant to FTD/ALS patients, such as those specifically targeting C9ORF72, may need to be tested with composite endpoints covering clinical symptoms of both FTD and ALS. The latter will require novel clinical trial designs to be inclusive of all patient subgroups spanning the FTD/ALS spectrum.}, }
@article {pmid37845449, year = {2023}, author = {Shin, J and Kang, H and Kim, S}, title = {Primo Vessels Inside Lymphatic Vessels Are Absent in an ALS Mouse Model.}, journal = {Advances in experimental medicine and biology}, volume = {1438}, number = {}, pages = {113-117}, pmid = {37845449}, issn = {0065-2598}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; *Lymphatic Vessels ; Lymph Nodes ; Oxygen/analysis ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the central nervous system. It is also a representative rare disease among degenerative diseases of the nervous system. Although many drugs for the treatment of degenerative brain diseases are being developed, they are not delivered correctly to the target due to the blood-brain barrier. The present study aimed to analyze changes in the primo vascular system (PVS) in ALS mice with symptoms and the partial oxygen pressure (pO2) in normal mice. In normal mice, we consistently observed primo vessels in lymphatic vessels (L-PVS). However, in ALS mice with symptoms, L-PVS were mostly lost, rendering them difficult to observe. The pO2 of the L-PVS in normal mice was significantly higher than that of normal dermis and lymph nodes.In conclusion, the relatively higher oxygen levels measured in the L-PVS than in normal dermis and lymph nodes suggest a role for the PVS in oxygen transport and enable a hypothesis that the L-PVS can function as a drug delivery pathway.}, }
@article {pmid37842553, year = {2023}, author = {Zucchi, E and Musazzi, UM and Fedele, G and Martinelli, I and Gianferrari, G and Simonini, C and Fini, N and Ghezzi, A and Caputo, M and Sette, E and Vacchiano, V and Zinno, L and Anceschi, P and Canali, E and Vinceti, M and Ferro, S and Mandrioli, J and , }, title = {Effect of tauroursodeoxycholic acid on survival and safety in amyotrophic lateral sclerosis: a retrospective population-based cohort study.}, journal = {EClinicalMedicine}, volume = {65}, number = {}, pages = {102256}, pmid = {37842553}, issn = {2589-5370}, abstract = {BACKGROUND: Oral tauroursodeoxycholic acid (TUDCA) is a commercial drug currently tested in patients with amyotrophic lateral sclerosis (ALS) both singly and combined with sodium phenylbutyrate. This retrospective study aimed to investigate, in a real-world setting, whether TUDCA had an impact on the overall survival of patients with ALS who were treated with this drug compared to those patients who received standard care only.<br><br>METHODS: This propensity score-matched study was conducted in the Emilia Romagna Region (Italy), which has had an ALS regional registry since 2009. Out of 627 patients with ALS diagnosed from January 1st, 2015 to June 30th, 2021 and recorded in the registry with available information on death/tracheostomy, 86 patients took TUDCA and were matched in a 1:2 ratio with patients who received only usual care according to age at onset, sex, phenotype, diagnostic latency, ALS Functional Rating Scale-Revised (ALSFRS-R) at first visit, disease progression rate at first visit, and BMI at diagnosis. The primary outcome was survival difference (time from onset of symptoms to tracheostomy/death) between TUDCA exposed and unexposed patients.<br><br>FINDINGS: A total of 86 patients treated with TUDCA were matched to 172 patients who did not receive treatment. TUDCA-exposed patients were stratified based on dosage (less than or equal to 1000&#xa0;mg/day or greater) and duration (less than or equal to 12 months or longer) of treatment. The median overall survival was 49.6 months (95% CI 41.7-93.5) among those treated with TUDCA and 36.2 months (95% CI 32.7-41.6) in the control group, with a reduced risk of death observed in patients exposed to a higher dosage (defined as&#xa0;&#x2265;&#xa0;1000&#xa0;mg/day) of TUDCA (HR 0.56; 95% CI 0.38-0.83; p&#xa0;=&#xa0;0.0042) compared to both the control group and those with lower TUDCA dosages (defined as&#xa0;<&#xa0;1000&#xa0;mg/day). TUDCA was generally well-tolerated, except for a minority of patients (n&#xa0;=&#xa0;7, 8.1%) who discontinued treatment due to side effects, primarily gastrointestinal and mild in severity; only 2 adverse events required hospital access but resolved without sequelae.<br><br>INTERPRETATION: In this population-based exploratory study, patients with ALS who were treated with TUDCA may have prolonged survival compared to patients receiving standard care only. Additional prospective randomized studies are needed to confirm the efficacy and safety of this drug.<br><br>FUNDING: Emilia-Romagna Region.}, }
@article {pmid37838979, year = {2024}, author = {Jagadish, A and Shankaranarayana, AM and Natarajan, M and Solomon, JM}, title = {Transcranial direct current stimulation for fatigue in neurological conditions: A systematic scoping review.}, journal = {Physiotherapy research international : the journal for researchers and clinicians in physical therapy}, volume = {29}, number = {1}, pages = {e2054}, doi = {10.1002/pri.2054}, pmid = {37838979}, issn = {1471-2865}, mesh = {Humans ; *Brain Injuries, Traumatic ; Fatigue/therapy/etiology ; *Multiple Sclerosis/complications/therapy ; *Parkinson Disease ; Quality of Life ; *Stroke ; *Transcranial Direct Current Stimulation/adverse effects ; }, abstract = {BACKGROUND AND PURPOSE: Fatigue following neurological conditions negatively impacts daily activities, reducing overall quality of life. Transcranial direct current stimulation (tDCS) for fatigue management is still underexplored. This scoping review explores its use in managing fatigue among various neurological conditions.<br><br>METHODS: A thorough literature search was carried out using PubMed, Scopus, CINAHL, Web of Science, Embase, ProQuest, and the Cochrane Library. Google Scholar and clinicaltrials.gov were manually searched for gray literature and ongoing trials, respectively. Regardless of the study design, all studies utilizing tDCS for the management of fatigue in various neurological conditions were considered. Two reviewers independently screened all the studies, following which the data were retrieved.<br><br>RESULTS: Studies employing tDCS for fatigue management across neurological conditions is as follows: Multiple sclerosis (MS) (n&#xa0;=&#xa0;28, 66%), stroke (n&#xa0;=&#xa0;5, 12%), Parkinson's disease (PD) (n&#xa0;=&#xa0;4, 10%), post-polio syndrome (PPS) (n&#xa0;=&#xa0;2, 5%), traumatic brain injury (TBI) (n&#xa0;=&#xa0;2, 5%), and amyotrophic lateral sclerosis (n&#xa0;=&#xa0;1, 2%). All the studies used anodal stimulation, with the common stimulation site being the left dorsolateral prefrontal cortex for MS, stroke, and PD. A stimulation intensity of 1.0-4.0&#xa0;mA with a duration ranging from 15 to 30&#xa0;min in 1 to 24 sessions were commonly reported. The Fatigue Severity Scale (n&#xa0;=&#xa0;21) and Modified Fatigue Impact Scale (n&#xa0;=&#xa0;17) were frequently implemented outcome measures. Regardless of the study design, 36/42 (85.7%) studies reported an improvement in fatigue scores in the tDCS group. The common adverse events noted were tingling (n&#xa0;=&#xa0;8, 35%), headache (n&#xa0;=&#xa0;6, 26%), and itching (n&#xa0;=&#xa0;6, 26%).<br><br>DISCUSSION: Application of tDCS for fatigue was explored in individuals with stroke, PD, PPS, and TBI after MS. Even though a wide range of treatment parameters and outcome measures were adopted to assess and target fatigue, tDCS proves to have a promising role in alleviating this symptom.}, }
@article {pmid37836771, year = {2023}, author = {Colombo, E and Olla, S and Minnelli, C and Formato, A and Veroni, C and Corbisiero, S and Pericolo, M and Siguri, C and Mobbili, G and Agresti, C and Seneci, P}, title = {Synthesis and Characterization of Edaravone Analogues as Remyelinating Agents and Putative Mechanistic Probes.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {19}, pages = {}, pmid = {37836771}, issn = {1420-3049}, support = {2017/R/2//Fondazione Italiana Sclerosi Multipla/ ; }, mesh = {Humans ; Edaravone/pharmacology/therapeutic use ; *Antioxidants/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Oxidative Stress ; Esters/pharmacology ; }, abstract = {Edaravone (EDA), an antioxidant drug approved for the treatment of ischemic stroke and amyotrophic lateral sclerosis, was recently proposed as a remyelinating candidate for the treatment of multiple sclerosis. Here, we synthesized twelve EDA analogues 2b-4c showing three substitution patterns A-C, searching for improved remyelinating agents and putative molecular targets responsible for their regenerative activity. We profiled them in three primary assays to determine their stimulation of oligodendrocyte progenitor cell metabolism (tetrazolium MTT assay), their antioxidant potential (2,2-diphenyl-1-picrylhydrazyl-DPPH assay) and to predict their bioavailability (virtual ADME profile). Active 4'-carboxylate 2b, 4'-ester 2c and N[1]-carbamate-4'-ester 4a were further characterized, justifying their in vitro effects and selecting 4a as a putative EDA 1 prodrug suitable for in vivo testing.}, }
@article {pmid37833013, year = {2023}, author = {Bryukhovetskiy, AS and Grivtsova, LY and Bogachev, SS and Ustyugov, AA and Nebogatikov, VO and Shurdov, MA}, title = {Technology of genomic balancing of chromatin of autologous hematopoietic stem cells for gene therapy of fatal immune-mediated diseases of civilization, extended life expectancy and sudden human death prevention.}, journal = {International review of neurobiology}, volume = {172}, number = {}, pages = {237-284}, doi = {10.1016/bs.irn.2023.07.005}, pmid = {37833013}, issn = {2162-5514}, mesh = {Rats ; Humans ; Animals ; Mice ; *Chromatin/metabolism ; *Quality of Life ; Rats, Wistar ; Hematopoietic Stem Cells/metabolism ; Genetic Therapy ; Life Expectancy ; Genomics ; DNA/metabolism ; Technology ; Death, Sudden ; Civilization ; }, abstract = {A biotechnology for personalized ex vivo gene therapy based on molecular genomic balancing of hematopoietic stem cell (HSC) chromatin with nucleosome monomers of human genomic DNA (hDNA[nmr]) has been developed and implemented in the clinic to change (to "correct") mutant chromosome loci genomes of dominant HSC clones that form mono- and oligoclonal hematopoiesis during aging and major (oncological, cardiovascular, neurodegenerative and autoimmune) fatal immune-mediated diseases of civilization. A fundamentally new biotechnological approach has been applied to the delivery of genetic material into eukaryotic stem and progenitor cells by establishing an artificial "recombinogenic situation" in them to induce homologous recombination (equivalent replacement) of mutant DNA regions with healthy hDNA[nmr]. In experimental preclinical trials, the effectiveness of genomic balancing technology has been proven to reduce the risk of sudden death in old animals and to increase the lifespan of outbred mice by 30% and Wistar rats by 57%. The improvement in their quality of life, compared with the control, is explained by an increase in the telomeric regions of the HSCs and HPCs chromosomes by 1.5-2 times. The potential of the technology to slow down the hereditary neurodegenerative diseases on the model of amyotrophic lateral sclerosis is shown. The effectiveness of this technology in clinical practice is presented on the example of a terminal patient with stage 4 neuroendocrine cancer. This technology used in the treatment of a number of oncological, neurodegenerative, autoimmune and hereditary diseases with clonal hematopoiesis is able to arrest the progression of the disease, prevent its recurrence, prolong the active life of a person, increase the average life expectancy and prevent sudden death.}, }
@article {pmid37831200, year = {2023}, author = {Latorre-Rodríguez, AR and Huang, J and Schaheen, L and Smith, MA and Hashimi, S and Bremner, RM and Mittal, SK}, title = {Diagnosis and management of anastomotic leaks after Ivor Lewis esophagectomy: a single-center experience.}, journal = {Langenbeck's archives of surgery}, volume = {408}, number = {1}, pages = {397}, pmid = {37831200}, issn = {1435-2451}, mesh = {Humans ; *Anastomotic Leak/diagnosis/etiology/therapy ; Esophagectomy/adverse effects ; *Esophageal Neoplasms/surgery ; Endoscopy, Gastrointestinal/adverse effects ; Retrospective Studies ; Postoperative Complications/diagnosis/epidemiology/etiology ; Anastomosis, Surgical/adverse effects ; Treatment Outcome ; }, abstract = {PURPOSE: Esophageal anastomotic leaks (ALs) after esophagectomy are a common and serious complication. The incidence, diagnostic approach, and management have changed over time. We described the diagnosis and management of patients who developed an esophageal AL after an Ivor Lewis esophagectomy at our center.<br><br>METHODS: After IRB approval, we queried our prospectively maintained database for patients who developed an esophageal AL after esophagectomy from August 2016 through July 2022. Data pertaining to demographics, comorbidities, surgical and oncological characteristics, and clinical course were extracted and analyzed.<br><br>RESULTS: During the study period, 145 patients underwent an Ivor Lewis esophagectomy; 10 (6.9%) developed an AL, diagnosed a median of 7.5&#xa0;days after surgery, and detected by enteric contents in wound drains (n&#x2009;=&#x2009;3), endoscopy (n&#x2009;=&#x2009;3), CT (n&#x2009;=&#x2009;2), and contrast esophagogram (n&#x2009;=&#x2009;2). Nine patients (90%) had an increasing white blood cell count and additional signs of sepsis. One asymptomatic patient was identified by contrast esophagography. All patients received enteral nutritional support, intravenous antibiotics, and antifungals. Primary treatment of ALs included endoscopic placement of a self-expanding metal stent (SEMS; n&#x2009;=&#x2009;6), surgery (n&#x2009;=&#x2009;2), and SEMS with endoluminal vacuum therapy (n&#x2009;=&#x2009;2). One patient required surgery after SEMS placement. The median length of&#xa0;ICU and total hospital stays were 11.5 and 22.5&#xa0;days, respectively. There was no 30-day mortality.<br><br>CONCLUSION: The incidence of esophageal ALs at our center is similar to that of&#xa0;other high-volume centers. Most ALs can be managed without surgery; however, ALs remain a significant source of postoperative morbidity despite clinical advancements that have improved mortality.}, }
@article {pmid37827930, year = {2023}, author = {Cassereau, J and Bernard, E and Genestet, S and Chebbah, M and Le Clanche, S and Verschueren, A and Couratier, P}, title = {Management of amyotrophic lateral sclerosis in clinical practice: Results of the expert consensus using the Delphi methodology.}, journal = {Revue neurologique}, volume = {179}, number = {10}, pages = {1134-1144}, doi = {10.1016/j.neurol.2023.07.011}, pmid = {37827930}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Riluzole/therapeutic use ; Motor Neurons ; Diagnosis, Differential ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare disease characterized by a progressive and irreversible degeneration of upper and lower motor neurons leading to death. In France, limited data exist describing the criteria used in clinical practice for diagnosis and follow-up, and how novel therapies may fit in. The objective of this Delphi panel was to obtain an overview of current French practices in ALS diagnosis, management, and follow-up by determining the scales and criteria used in clinical practice outside of clinical trials, as well as the place of a future treatment like AMX0035, acting on endoplasmic reticulum (ER) stress and mitochondrial dysfunction, in the current therapeutic strategies. A questionnaire was administered to 24 ALS healthcare providers practicing in ALS centers in France. Two rounds of remote voting were organized, before proposition of final consensus statements. Consensus was considered reached when at least 66% of the voters agreed. Consensus were obtained to define the new Gold Coast criteria as the ones used in clinical practice to establish the diagnosis of ALS, thus replacing the revised El Escorial criteria, considered too complex and now mainly used to characterize the patient populations to be included in clinical trials. The clinical factors considered to establish ALS diagnosis are mainly the demonstration of progression of the motor deficit and elimination of differential diagnoses. The ALSFRS-R scale is used in daily clinical practice to assess patient's functional impairment in terms of number of points lost, with the bulbar, respiratory, and fine motor subscores being the most important to evaluate independently. A critical medical need was identified regarding the provision of new therapeutic alternatives in ALS. The panel members would support the earliest management of patients. In this landscape, based on data from a very encouraging phase II (Centaur trial), AMX0035 represents a new tool of choice in current treatment strategies for all patients for whom experts are confident in the diagnosis of ALS, in combination with riluzole. These results will need to be confirmed by the ongoing phase III trial (Phoenix trial).}, }
@article {pmid37827137, year = {2024}, author = {Heckmann, JG and Kiem, M and Immich, G}, title = {Forest Therapy as a Nature-Based Intervention: An Option for Neurological Rehabilitation?.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {56-63}, doi = {10.1159/000534533}, pmid = {37827137}, issn = {2504-2106}, mesh = {Humans ; *Medicine ; *Neurological Rehabilitation ; *Sleep Wake Disorders ; *Stroke/therapy ; *Dementia ; Observational Studies as Topic ; }, abstract = {BACKGROUND: Forest therapy demonstrates positive effects on mood, immune system, stress levels, and general well-being. Studies on depression, stress-related illnesses, sleep disorders, and arterial hypertension have provided evidence-based proof of this.<br><br>SUMMARY: The aim of this review was to examine the possible effects of forest therapy with regard to its evidence in the treatment of chronic neurological diseases such as stroke in the rehabilitation phase, Parkinson's disease, dementia, and multiple sclerosis. Therefore, the electronic databases Medline, Scopus, and Cochrane were searched for such clinical trials for the years 1970 to mid-2023 without language restriction. The literature search revealed only few studies with positive indications but too few cases to be able to make generalizable evidence-based statements. In terms of improvement in the Hamilton Depression Scale analysis of two studies in stroke patients showed slight benefits in the forest therapy group (standard mean difference -0.43; 95% CI: -0.76 to -0.10; p < 0.01). One observational study revealed a higher rate of stroke survival in patients living in marked greenness. Few nature-based interventions in dementia patients showed certain benefits in particular details.<br><br>KEY MESSAGES: There are no evidence-based results on the benefit of forest therapy for chronic neurological diseases. However, there are hints that forest therapy could have a positive benefit. Therefore, a proposal for forest therapy as a component of multimodal neurological rehabilitation is presented.<br><br>UNLABELLED: <title>Hintergrund</title>Die Waldtherapie zeigt positive Auswirkungen auf die Stimmung, das Immunsystem, das Stressniveau und das allgemeine Wohlbefinden. Studien zu Depressionen, stressbedingten Erkrankungen, Schlafst&#xf6;rungen und arteriellem Bluthochdruck haben dies evidenzbasiert belegt.<title>Zusammenfassung</title>Ziel dieser &#xdc;bersichtsarbeit war es, die m&#xf6;glichen Wirkungen der Waldtherapie im Hinblick auf ihre Evidenz bei der Behandlung chronischer neurologischer Erkrankungen wie Schlaganfall in der Rehabilitationsphase, Morbus Parkinson, Demenz und Multiple Sklerose zu untersuchen. Dazu wurden die elektronischen Datenbanken Medline, Scopus und Cochrane f&#xfc;r die Jahre 1970 bis Mitte 2023 ohne sprachliche Einschr&#xe4;nkung nach solchen klinischen Studien durchsucht. Die Literaturrecherche ergab nur wenige Studien mit positiven Indikationen, aber zu wenigen F&#xe4;llen, um verallgemeinerbare evidenzbasierte Aussagen machen zu k&#xf6;nnen. Im Hinblick auf Verbesserung in der Hamilton Depressionsskala zeigte die Analyse von 2 Studien bei Schlaganfallpatienten leichte Vorteile der Waldtherapiegruppen (Standard Mean Difference &#x2212;0.43; 95% CI: -0.76- -0,10; <italic>p</italic> < 0.01). Eine Beobachtungsstudie ergab eine h&#xf6;here Schlaganfall-&#xdc;berlebensrate bei Patienten, die in ausgepr&#xe4;gtem Gr&#xfc;n leben. Einige naturbasierte Interventionen bei Demenzpatienten zeigten in einzelnen Parametern gewisse Vorteile.<title>Fazit</title>Es gibt bis dato keine verallgemeinerbaren evidenzbasierten Ergebnisse zum Nutzen der Waldtherapie bei chronischen neurologischen Erkrankungen. Es gibt jedoch Hinweise, dass die Waldtherapie einen positiven Nutzen haben k&#xf6;nnte. Es wird daher ein Vorschlag f&#xfc;r eine Waldtherapie als Bestandteil einer multimodalen neurologischen Rehabilitation vorgestellt.}, }
@article {pmid37816542, year = {2024}, author = {McHenry, KL}, title = {Airway Clearance Strategies and Secretion Management in Amyotrophic Lateral Sclerosis.}, journal = {Respiratory care}, volume = {69}, number = {2}, pages = {227-237}, pmid = {37816542}, issn = {1943-3654}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Respiratory Therapy/methods ; *Chest Wall Oscillation ; Bodily Secretions ; *Insufflation/methods ; Cough/etiology ; *Respiratory Insufficiency/therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative motor neuron disease that affects voluntary muscle movement. Often, difficulty in coughing, breathing, and swallowing are sequela associated with the condition, and the presence of bulbar muscle predominant weakness results in deleterious effects on airway clearance and secretion management. This narrative review will provide practical guidance for clinicians treating this population. Cough insufficiency in this population typically manifests as a prolonged, slow, weak cough effort that impedes the clearability of secretions and airway protection. Dystussia and dysphagia frequently occur simultaneously in bulbar dysfunction, subsequently impacting respiratory health. Measures of respiratory strength should be obtained and monitored every 3-6 months, preferably in a multidisciplinary clinic setting. Cough augmentation, whether manual or mechanical techniques, should be sought as early in the disease progression as possible to adequately control secretions in the proximal airways. This airway clearance strategy can aid in the prevention and treatment of respiratory tract infections (RTIs), which can pose a significant clinical hurdle to those with ALS. The use of mechanical insufflation-exsufflation may be complicated by severe bulbar dysfunction rendering this technique ineffective. Though peripheral airway clearance strategies, such as high-frequency chest-wall compression, have the advantage of being less impacted by bulbar dysfunction, it is only recommended this modality be used in conjunction with, versus in lieu of, proximal strategies. Salivary secretion management includes the use of anticholinergics, botulinum toxin, and radiation therapy depending on severity and desire for relief.}, }
@article {pmid37815307, year = {2024}, author = {Liu, KF and Ramachandran, S and Chang, CW and Chen, RF and Huang, CH and Huang, HT and Lee, CC and Li, YT and Kuo, YR}, title = {The Synergistic Effect of Full-Spectrum Light Therapy and Transient Immunosuppressants Prolonged Allotransplant Survival.}, journal = {Plastic and reconstructive surgery}, volume = {154}, number = {4}, pages = {775-783}, doi = {10.1097/PRS.0000000000011135}, pmid = {37815307}, issn = {1529-4242}, support = {SH11003//Kaohsiung Medical University Hospital, Taiwan./ ; }, mesh = {Animals ; *Immunosuppressive Agents/therapeutic use ; *Graft Survival/drug effects/immunology ; *Rats, Inbred Lew ; Rats ; *Vascularized Composite Allotransplantation/methods ; *Hindlimb/transplantation ; Male ; Combined Modality Therapy ; Cyclosporine ; Graft Rejection/prevention &amp; control/immunology ; Phototherapy/methods ; Rats, Inbred BN ; Antilymphocyte Serum ; }, abstract = {BACKGROUND: The lifelong administration of immunosuppressants remains the largest drawback in vascularized composite allotransplantation (VCA). Therefore, developing alternative strategies to minimize the long-term use of immunosuppressive agents is crucial. This study investigated whether full-spectrum bright light therapy (FBLT) combined with short-term immunosuppressant therapy could prolong VCA survival in a rodent hindlimb model.<br><br>METHODS: Hindlimb allotransplantation was conducted from Brown-Norway to Lewis rats, and the rats were divided into 4 groups. Group 1 did not receive treatment as a rejection control. Group 2 received FBLT alone. Group 3 was treated with short-term antilymphocyte serum (ALS) and cyclosporine A (CsA). Group 4 was administered short-term ALS/CsA combined with FBLT for 8 weeks. Peripheral blood and transplanted tissues were collected for analysis.<br><br>RESULTS: The results revealed median survival time of FBLT alone (group 2) did not increase allograft survival compared with the control (group 1). However, in group 4, FBLT combined with short-term ALS/CsA, median composite tissue allograft survival time (266 days) was significantly prolonged compared with groups 1 (11 days), 2 (10 days), and 3 (41 days) (P < 0.01). Group 4 also showed a significant increase in regulatory T cells (P = 0.04) and transforming growth factor-&#x3b2;1 levels (P = 0.02), and a trend toward a decrease in interleukin-1&#x3b2; levels (P = 0.03) at 16 weeks after transplantation as compared with control (group 1).<br><br>CONCLUSIONS: FBLT combined with short-term immunosuppressants prolonged allotransplant survival by modulating T-cell regulatory functions and antiinflammatory cytokine expression. This approach could be a potential strategy to increase VCA survival.<br><br>CLINICAL RELEVANCE STATEMENT: Full-spectrum light therapy could be a potential strategy to increase vascularized composite allotransplant survival.}, }
@article {pmid37814618, year = {2023}, author = {Li, B and Zhang, W and Zhong, S and Pan, J and Wang, X and Zou, H and Dou, X}, title = {Short-term outcome of plasma adsorption therapy in amyotrophic lateral sclerosis.}, journal = {Journal of medical biochemistry}, volume = {42}, number = {3}, pages = {401-406}, pmid = {37814618}, issn = {1452-8258}, abstract = {BACKGROUND: To observe the short-term outcome of plasma adsorption PA therapy in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: 28 cases of als patients were recruited in this study, of which 20 were male and 8 were female with a mean age of 53.21&#xb1;9.07 years and the average course of 33&#xb1;23.35 months. The clinical manifestations were limb weakness (N=27), muscular atrophy (N=27), muscular tremor (N=5), dysphagia (N=12) and dysarthria (N=12). The clinical data of the patients recruited were graded by Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRSR) : <10 (N=1), 11-20 (N=4), 21-30 (N=6), 31-40 (N=12), >40 (N=5). All patients received PA therapy once a week for three successive times after examining the conditions of blood coagulation and virus infection. PA therapy was supplemented with neurotrophic therapy meanwhile. All patients' clinical manifestations and scores of ALSFRSR before treatment and one week after treatment were evaluated and compared. The levels of serum superoxide dismutase (SOD), interleukin-10 (IL-10), serum creatine kinase (CK) and lactate dehydrogenase (LDH) before and after treatment were compared.<br><br>RESULTS: After PA therapy, 14 patients have improved obviously in muscle strength, 4 patients in hypermyotonia partially, 3 patients in muscular tremor, 5 patients in dysarthria, 3 patients in salivation to some extent and 2 patients in swallowing function. The score of ALSFRSR after PA treatment (31.89&#xb1;10.36) was remarkably higher than that before PA treatment (30.68&#xb1;10.52) (P<0.01). The levels of SOD (155.10&#xb1;21.87 IU/L) and IL-10 (138.06&#xb1;185.88 pg/mL) after PA treatment were significantly higher than the levels before PA treatment (143.08.3&#xb1;19.16 IU/L and 46.34&#xb1;75.31 pg/mL, respectively) (P<0.05). The levels of CK (168.86&#xb1;113.50 IU/L) and LDH (152.07&#xb1;32.65 IU/L) after PA treatment were significantly lower than the levels before PA treatment (356.68&#xb1;250.30 IU/L and 181.36&#xb1;33.74 IU/L respectively) (P<0.01). At the end of follow-up period (November, 2019), five patients died of respiratory failure 16-21 months after PA treatment and two patents died of respiratory infection 15-20 months after PA treatment. 7 patients were still alive. The score of ALSFRS-R of these patients who survived at the end of follow-up (13.00&#xb1;13.37) were significantly lower than before PA treatment (36.71&#xb1;8.56) (P<0.05) and after PA treatment (38.14&#xb1;8.82) (P<0.05).<br><br>CONCLUSIONS: Plasma adsorption (PA) therapy has shortterm therapeutic effects on als. The effects might be attributed to the anti-oxygen free radical effect by increasing SOD level and the anti-inflammation effect by increasing IL-10 level. As the efficacy of PA therapy was obtained in a small sample size and short follow-up period, the longterm observation of PA efficacy in treating als should be further investigated.}, }
@article {pmid37807839, year = {2023}, author = {Paganoni, S and Quintana, M and Sherman, AV and Vestrucci, M and Wu, Y and Timmons, J and Cudkowicz, M and , }, title = {Analysis of sodium phenylbutyrate and taurursodiol survival effect in ALS using external controls.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {12}, pages = {2297-2304}, pmid = {37807839}, issn = {2328-9503}, support = {//ALS Association/ ; //ALS Finding a Cure&#xae;/ ; //Amylyx Pharmaceuticals, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Phenylbutyrates/pharmacology/therapeutic use ; Survival Analysis ; Proportional Hazards Models ; }, abstract = {OBJECTIVE: Sodium phenylbutyrate and taurursodiol (PB and TURSO) was evaluated in amyotrophic lateral sclerosis (ALS) in the CENTAUR trial encompassing randomized placebo-controlled and open-label extension phases. On intent-to-treat (ITT) survival analysis, median overall survival (OS) was 4.8 months longer and risk of death 36% lower in those originally randomized to an initial 6-month double-blind period of PB and TURSO versus placebo. To estimate PB and TURSO treatment effect without placebo-to-active crossover, we performed a post hoc survival analysis comparing PB and TURSO-randomized participants from CENTAUR and a propensity score-matched, PB and TURSO-naïve external control cohort from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.<br><br>METHODS: Clinical trial control participants from the PRO-ACT database who met prespecified eligibility criteria were propensity score matched 1:1 with PB and TURSO-randomized CENTAUR participants using prognostically significant covariates in ALS.<br><br>RESULTS: Baseline characteristics including propensity score-matched covariates were generally well balanced between CENTAUR PB and TURSO (n&#x2009;=&#x2009;89) and PRO-ACT external control (n&#x2009;=&#x2009;85) groups. Estimated median (IQR) OS was 23.54 (14.56-39.32) months in the CENTAUR PB and TURSO group and 13.15 (9.83-19.20) months in the PRO-ACT external control group; hazard of death was 52% lower in the former group (hazard ratio, 0.48; 95% CI, 0.31-0.72; p&#x2009;=&#x2009;0.00048).<br><br>INTERPRETATION: This analysis suggests potentially greater survival benefit with PB and TURSO in ALS without placebo-to-active crossover than seen on ITT analysis in CENTAUR. Analyses using well-matched external controls may provide additional context for evaluating survival effects in future ALS trials.}, }
@article {pmid37807406, year = {2023}, author = {Anderson, G}, title = {Gut Microbiome and Circadian Interactions with Platelets Across Human Diseases, including Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Cancer.}, journal = {Current topics in medicinal chemistry}, volume = {23}, number = {28}, pages = {2699-2719}, doi = {10.2174/0115680266253465230920114223}, pmid = {37807406}, issn = {1873-4294}, mesh = {Humans ; *Melatonin/metabolism ; *Alzheimer Disease ; *Gastrointestinal Microbiome ; *Amyotrophic Lateral Sclerosis ; *Neoplasms ; Tumor Microenvironment ; }, abstract = {Platelets have traditionally been investigated for their role in clot formation in the course of cardiovascular diseases and strokes. However, recent work indicates platelets to be an integral aspect of wider systemic processes, with relevance to the pathophysiology of a host of diverse medical conditions, including neurodegenerative disorders and cancer. This article reviews platelet function and interactions with the gut microbiome and circadian systems, highlighting the role of the platelet mitochondrial melatonergic pathway in determining platelet activation, fluxes and plasticity. This provides a number of novel conceptualizations of platelet function and mode of interaction with other cell types, including in the pathoetiology and pathophysiology of diverse medical conditions, such as cancer, Alzheimer's disease, and amyotrophic lateral sclerosis. It is proposed that a platelet-gut axis allows platelets to contribute to many of the pathophysiological processes linked to gut dysbiosis and gut permeability. This is at least partly via platelet sphingosine- 1-phosphate release, which regulates enteric glial cells and lymphocyte chemotaxis, indicating an etiological role for platelets in a wide array of medical conditions linked to alterations in the gut microbiome. Platelets are also an important regulator of the various microenvironments that underpin most human medical conditions, including the tumor microenvironment, neurodegenerative diseases, and autoimmune disorders. Platelet serotonin release regulates the availability of the mitochondrial melatonergic pathway systemically, thereby being an important determinant of the dynamic metabolic interactions occurring across cell types that underpin the pathoetiology of many medical conditions. In addition, a number of novel and diverse future research directions and treatment implications are proposed.}, }
@article {pmid37804412, year = {2024}, author = {Kusama-Eguchi, K and Tokui, Y and Minoura, A and Yanai, Y and Hirose, D and Furukawa, M and Kosuge, Y and Miura, M and Ohkoshi, E and Makino, M and Minagawa, K and Matsuzaki, K and Ogawa, Y and Watanabe, K and Ohsaki, A}, title = {2(3H)-Dihydrofranolactone metabolites from Pleosporales sp. NUH322 as anti-amyotrophic lateral sclerosis drugs.}, journal = {Journal of natural medicines}, volume = {78}, number = {1}, pages = {146-159}, pmid = {37804412}, issn = {1861-0293}, support = {12-021//A Grant from the Ministry of Education, Culture, Sports, Science, and Technology to promote 2001-multidisciplinary research projects/ ; 13-023//A Grant from the Ministry of Education, Culture, Sports, Science, and Technology to promote 2001-multidisciplinary research projects/ ; 22590088//Grant-in-Aid for Scientific Research/ ; }, mesh = {Mice ; Male ; Female ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Motor Neurons/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; Spinal Cord/metabolism ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor disease with limited treatment options. A domestic fungal extract library was screened using three assays related to the pathophysiology of ALS with the aim of developing a novel ALS drug. 2(3H)-dihydrofuranolactones 1 and 2, and five known compounds 3-7 were isolated from Pleosporales sp. NUH322 culture media, and their protective activity against the excitotoxicity of β-N-oxalyl-L-α,β-diaminopropionic acid (ODAP), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamatergic agonist, was evaluated under low mitochondrial glutathione levels induced by ethacrynic acid (EA) and low sulfur amino acids using our developed ODAP-EA assay. Additional assays evaluated the recovery from cytotoxicity caused by transfected SOD1-G93A, an ALS-causal gene, and the inhibitory effect against reactive oxygen species (ROS) elevation. The structures of 1 and 2 were elucidated using various spectroscopic methods. We synthesized 1 from D-ribose, and confirmed the absolute structure. Isolated and synthesized 1 displayed higher ODAP-EA activities than the extract and represented its activity. Furthermore, 1 exhibited protective activity against SOD1-G93A-induced toxicity. An ALS mouse model, SOD1-G93A, of both sexes, was treated orally with 1 at pre- and post-symptomatic stages. The latter treatment significantly extended their lifespan (p = 0.03) and delayed motor deterioration (p = 0.001-0.01). Our result suggests that 1 is a promising lead compound for the development of ALS drugs with a new spectrum of action targeting both SOD1-G93A proteopathy and excitotoxicity through its action on the AMPA-type glutamatergic receptor.}, }
@article {pmid37800457, year = {2023}, author = {Billings, JL and Hilton, JBW and Liddell, JR and Hare, DJ and Crouch, PJ}, title = {Fundamental Neurochemistry Review: Copper availability as a potential therapeutic target in progressive supranuclear palsy: Insight from other neurodegenerative diseases.}, journal = {Journal of neurochemistry}, volume = {167}, number = {3}, pages = {337-346}, doi = {10.1111/jnc.15978}, pmid = {37800457}, issn = {1471-4159}, mesh = {Humans ; *Supranuclear Palsy, Progressive/diagnosis/pathology ; Copper ; *Neurodegenerative Diseases/therapy ; Superoxide Dismutase-1 ; *Neurochemistry ; *Parkinson Disease/pathology ; }, abstract = {Since the first description of Parkinson's disease (PD) over two centuries ago, the recognition of rare types of atypical parkinsonism has introduced a spectrum of related PD-like diseases. Among these is progressive supranuclear palsy (PSP), a neurodegenerative condition that clinically differentiates through the presence of additional symptoms uncommon in PD. As with PD, the initial symptoms of PSP generally present in the sixth decade of life when the underpinning neurodegeneration is already significantly advanced. The causal trigger of neuronal cell loss in PSP is unknown and treatment options are consequently limited. However, converging lines of evidence from the distinct neurodegenerative conditions of PD and amyotrophic lateral sclerosis (ALS) are beginning to provide insights into potential commonalities in PSP pathology and opportunity for novel therapeutic intervention. These include accumulation of the high abundance cuproenzyme superoxide dismutase 1 (SOD1) in an aberrant copper-deficient state, associated evidence for altered availability of the essential micronutrient copper, and evidence for neuroprotection using compounds that can deliver available copper to the central nervous system. Herein, we discuss the existing evidence for SOD1 pathology and copper imbalance in PSP and speculate that treatments able to provide neuroprotection through manipulation of copper availability could be applicable to the treatment of PSP.}, }
@article {pmid37795580, year = {2024}, author = {Rodriguez, P and Blakely, RD}, title = {Sink or swim: Does a worm paralysis phenotype hold clues to neurodegenerative disease?.}, journal = {Journal of cellular physiology}, volume = {239}, number = {6}, pages = {e31125}, doi = {10.1002/jcp.31125}, pmid = {37795580}, issn = {1097-4652}, support = {22A01//Florida Department of Health Ed/ ; }, mesh = {Animals ; *Caenorhabditis elegans/genetics ; *Neurodegenerative Diseases/genetics ; *Phenotype ; Humans ; *Disease Models, Animal ; Caenorhabditis elegans Proteins/genetics/metabolism ; Paralysis/genetics ; Swimming ; Signal Transduction/genetics ; Dopamine/metabolism ; }, abstract = {Receiving a neurodegenerative disease (NDD) diagnosis, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis, is devastating, particularly given the limited options for treatment. Advances in genetic technologies have allowed for efficient modeling of NDDs in animals and brought hope for new disease-modifying medications. The complexity of the mammalian brain and the costs and time needed to identify and develop therapeutic leads limits progress. Modeling NDDs in invertebrates, such as the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, offers orders of magnitude increases in speed of genetic analysis and manipulation, and can be pursued at substantially reduced cost, providing an important, platform complement and inform research with mammalian NDD models. In this review, we describe how our efforts to exploit C. elegans for the study of neural signaling and health led to the discovery of a paralytic phenotype (swimming-induced paralysis) associated with altered dopamine signaling and, surprisingly, to the discovery of a novel gene and pathway whose dysfunction in glial cells triggers neurodegeneration. Research to date on swip-10 and its putative mammalian ortholog MBLAC1, suggests that a tandem analysis will offer insights into NDD mechanisms and insights into novel, disease-modifying therapeutics.}, }
@article {pmid37791873, year = {2023}, author = {Kour, S and Fortuna, T and Anderson, EN and Mawrie, D and Bilstein, J and Sivasubramanian, R and Ward, C and Roy, R and Rajasundaram, D and Sterneckert, J and Pandey, UB}, title = {Drosha-dependent microRNAs modulate FUS-mediated neurodegeneration in vivo.}, journal = {Nucleic acids research}, volume = {51}, number = {20}, pages = {11258-11276}, pmid = {37791873}, issn = {1362-4962}, support = {R01 NS081303/NS/NINDS NIH HHS/United States ; S10 OD028483/OD/NIH HHS/United States ; }, mesh = {Animals ; Amyotrophic Lateral Sclerosis/metabolism ; Drosophila/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; Mutation ; Neurons/metabolism ; RNA-Binding Proteins/genetics/metabolism ; Neurodegenerative Diseases/metabolism ; *Heterogeneous-Nuclear Ribonucleoprotein Group F-H/metabolism ; Humans ; *Ribonuclease III/metabolism ; *Drosophila Proteins/metabolism ; }, abstract = {Mutations in the Fused in Sarcoma (FUS) gene cause the familial and progressive form of amyotrophic lateral sclerosis (ALS). FUS is a nuclear RNA-binding protein involved in RNA processing and the biogenesis of a specific set of microRNAs. Here we report that Drosha and two previously uncharacterized Drosha-dependent miRNAs are strong modulators of FUS expression and prevent the cytoplasmic segregation of insoluble mutant FUS in vivo. We demonstrate that depletion of Drosha mitigates FUS-mediated degeneration, survival and motor defects in Drosophila. Mutant FUS strongly interacts with Drosha and causes its cytoplasmic mis-localization into the insoluble FUS inclusions. Reduction in Drosha levels increases the solubility of mutant FUS. Interestingly, we found two Drosha dependent microRNAs, miR-378i and miR-6832-5p, which differentially regulate the expression, solubility and cytoplasmic aggregation of mutant FUS in iPSC neurons and mammalian cells. More importantly, we report different modes of action of these miRNAs against mutant FUS. Whereas miR-378i may regulate mutant FUS inclusions by preventing G3BP-mediated stress granule formation, miR-6832-5p may affect FUS expression via other proteins or pathways. Overall, our research reveals a possible association between ALS-linked FUS mutations and the Drosha-dependent miRNA regulatory circuit, as well as a useful perspective on potential ALS treatment via microRNAs.}, }
@article {pmid37787835, year = {2024}, author = {Li, S and Zhao, L and Xiao, J and Guo, Y and Fu, R and Zhang, Y and Xu, S}, title = {The gut microbiome: an important role in neurodegenerative diseases and their therapeutic advances.}, journal = {Molecular and cellular biochemistry}, volume = {479}, number = {9}, pages = {2217-2243}, pmid = {37787835}, issn = {1573-4919}, support = {No. 81973626, No. 81774059//National Natural Science Foundation of China/ ; No. 21JCYBJC01620//Tianjin Municipal Science and Technology Commission of China/ ; No. 2021099//Tianjin Health Committee/ ; No. 2021KJ146//Tianjin Education Committee/ ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; *Neurodegenerative Diseases/therapy/microbiology ; *Fecal Microbiota Transplantation ; *Probiotics/therapeutic use ; Animals ; Parkinson Disease/therapy/microbiology ; Alzheimer Disease/therapy/microbiology ; }, abstract = {There are complex interactions between the gut and the brain. With increasing research on the relationship between gut microbiota and brain function, accumulated clinical and preclinical evidence suggests that gut microbiota is intimately involved in the pathogenesis of neurodegenerative diseases (NDs). Increasingly studies are beginning to focus on the association between gut microbiota and central nervous system (CNS) degenerative pathologies to find potential therapies for these refractory diseases. In this review, we summarize the changes in the gut microbiota in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis and contribute to our understanding of the function of the gut microbiota in NDs and its possible involvement in the pathogenesis. We subsequently discuss therapeutic approaches targeting gut microbial abnormalities in these diseases, including antibiotics, diet, probiotics, and fecal microbiota transplantation (FMT). Furthermore, we summarize some completed and ongoing clinical trials of interventions with gut microbes for NDs, which may provide new ideas for studying NDs.}, }
@article {pmid37787812, year = {2024}, author = {Beswick, E and Johnson, M and Newton, J and Dakin, R and Stenson, A and Abrahams, S and Carson, A and Chandran, S and Pal, S}, title = {Factors impacting trial participation in people with motor neuron disease.}, journal = {Journal of neurology}, volume = {271}, number = {1}, pages = {543-552}, pmid = {37787812}, issn = {1432-1459}, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/therapy ; *Motor Neuron Disease/therapy ; Probability ; Prospective Studies ; Randomized Controlled Trials as Topic ; Adaptive Clinical Trials as Topic ; }, abstract = {Motor neuron disease (MND) is a rapidly progressive neurodegenerative disorder with limited treatment options. Historically, neurological trials have been plagued by suboptimal recruitment and high rates of attrition. The Motor Neuron Disease-Systematic Multi-Arm Randomised Adaptive Trial (MND-SMART) seeks to identify effective disease modifying drugs. This study investigates person-specific factors affecting recruitment and retention. Improved understanding of these factors may improve trial protocol design, optimise recruitment and retention. Participants with MND completed questionnaires and this was supplemented with clinical data. 12 months after completing the questionnaires we used MND-SMART recruitment data to establish if members of our cohort engaged with the trial. 120 people with MND completed questionnaires for this study. Mean age at participation was 66 (SD = 9), 14% (n = 17) were categorised as long survivors, with 68% (n = 81) of participants male and 60% (n = 73) had the ALS sub-type. Of the 120 study participants, 50% (n = 60) were randomised into MND-SMART and 78% (n = 94) expressed interest an in participating. After the 1-year follow-up period 65% (n = 39) of the 60 randomised participants remained in MND-SMART. Older age was significantly associated with reduced likelihood of participation (OR = 0.92, 95% CI = 0.88-0.96, p = 0.000488). The findings show that people with MND are highly motivated to engage in research, but older individuals remain significantly less likely to participate. We recommend the inclusion of studies to explore characteristics of prospective and current participants alongside trials.}, }
@article {pmid37783557, year = {2023}, author = {Chen, D and Huang, H and Saberi, H and Sharma, HS}, title = {Positive and negative cell therapy in randomized control trials for central nervous system diseases.}, journal = {International review of neurobiology}, volume = {171}, number = {}, pages = {241-254}, doi = {10.1016/bs.irn.2023.05.017}, pmid = {37783557}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Quality of Life ; *Central Nervous System Diseases/therapy ; Cell- and Tissue-Based Therapy ; *Parkinson Disease/therapy ; Brain Damage, Chronic ; }, abstract = {Neurorestorative cell therapies have been tested to treat patients with nervous system diseases for over 20 years. Now it is still hard to answer which kinds of cells can really play a role on improving these patients' quality of life. Non-randomized clinical trials or studies could not provide strong evidences in answering this critical question. In this review, we summarized randomized clinical trials of cell therapies for central nervous diseases, such as stroke, spinal cord injury, cerebral palsy (CP), Parkinson's disease (PD), multiple sclerosis (MS), brain trauma, amyotrophic lateral sclerosis (ALS), etc. Most kinds of cell therapies demonstrated negative results for stoke, brain trauma and amyotrophic lateral sclerosis. A few kinds of cell therapies showed neurorestorative effects in this level of evidence-based medicine, such as olfactory ensheating cells for chronic ischemic stroke. Some kinds of cells showed positive or negative effects from different teams in the same or different diseases. We analyzed the possible failed reasons of negative results and the cellular bio-propriety basis of positive results. Based on therapeutic results of randomized control trials and reasonable analysis, we recommend: (1) to further conduct trials for successful cell therapies with positive results to increase neurorestorative effects; (2) to avoid in repeating failed cell therapies with negative results in same diseases because it is nonsense for them to be done with similar treatment methods, such as cell dosage, transplanting way, time of window, etc. Furthermore, we strongly suggest not to do non-randomized clinical trials for cells that had shown negative results in randomized clinical trials.}, }
@article {pmid37781884, year = {2023}, author = {Erdag, E and Haskologlu, IC and Mercan, M and Abacioglu, N and Sehirli, AO}, title = {An in silico investigation: Can melatonin serve as an adjuvant in NR1D1-linked chronotherapy for amyotrophic lateral sclerosis?.}, journal = {Chronobiology international}, volume = {40}, number = {10}, pages = {1395-1403}, doi = {10.1080/07420528.2023.2265476}, pmid = {37781884}, issn = {1525-6073}, mesh = {Animals ; Humans ; *Melatonin/pharmacology ; Circadian Rhythm/physiology ; *Amyotrophic Lateral Sclerosis/drug therapy ; Molecular Docking Simulation ; Chronotherapy/methods ; Nuclear Receptor Subfamily 1, Group D, Member 1/genetics ; }, abstract = {Chronobiology, which studies biological rhythms and their impacts on health, presents a potential avenue for treating amyotrophic lateral sclerosis. Clock gene-related therapies, focusing on genes responsible for regulating biological rhythms, may hold promise in the treatment. Among these clock genes, nuclear receptor subfamily 1 Group D member 1 (NR1D1) plays a vital role in neurodegenerative diseases. In this particular study, it was aimed to investigate the potential of FDA-approved drugs commonly used in amyotrophic lateral sclerosis treatment and melatonin, a hormone known for its role in regulating sleep-wake cycles, as ligands for clock gene-related therapy. The ligands were subjected to molecular docking and molecular dynamics simulation methods against the NR1D1 clock gene. These results suggested that combining melatonin with FDA-approved medications commonly used in the treatment might yield positive outcomes. This study provides preliminary data and lays the groundwork for future investigations involving in vitro (laboratory-based) and in vivo (animal or human-based) research on chronotherapy. In summary, this research highlights the potential of clock gene-related therapy utilizing melatonin in conjunction with FDA-approved drugs for amyotrophic lateral sclerosis treatment, offering insights into novel treatment strategies. The findings underscore the need for further studies to explore the effectiveness of this hypothetical approach in experimental and clinical settings.}, }
@article {pmid37774774, year = {2023}, author = {Gschwendtberger, T and Thau-Habermann, N and von der Ohe, J and Luo, T and Hass, R and Petri, S}, title = {Protective effects of EVs/exosomes derived from permanently growing human MSC on primary murine ALS motor neurons.}, journal = {Neuroscience letters}, volume = {816}, number = {}, pages = {137493}, doi = {10.1016/j.neulet.2023.137493}, pmid = {37774774}, issn = {1872-7972}, mesh = {Mice ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Exosomes/metabolism ; Antioxidants/pharmacology ; Motor Neurons/metabolism ; *Mesenchymal Stem Cells/metabolism ; }, abstract = {In recent years, the neuroprotective potential of mesenchymal stroma-/stem-like cells (MSC) as well as of MSC-derived extracellular vesicles (EVs) like exosomes has been intensively explored. This included preclinical evaluation regarding treatment of neurodegenerative disorders such as the fatal motor neuron disease amyotrophic Lateral Sclerosis (ALS). Several studies have reported that MSC-derived exosomes can stimulate tissue regeneration and reduce inflammation. MSC release EVs and trophic factors and thereby modify cell-to-cell communication. These cell-free products may protect degenerating motor neurons (MNs) and represent a potential therapeutic approach for ALS. In the present study we investigated the effects of exosomes derived from a permanently growing MSC line on both, wild type and ALS (SOD1[G93A] transgenic) primary motor neurons. Following application in a normal and stressed environment we could demonstrate beneficial effects of MSC exosomes on neurite growth and morphology indicating the potential for further preclinical evaluation and clinical therapeutic development. Investigation of gene expression profiles detected transcripts of several antioxidant and anti-inflammatory genes in MSC exosomes. Characterization of their microRNA (miRNA) content revealed miRNAs capable of regulating antioxidant and anti-apoptotic pathways.}, }
@article {pmid37773166, year = {2023}, author = {Aguilar-Vázquez, CA and Gallardo-González, LI and Raymundo-Carrillo, AD and Reyes-Sosa, LC and Martínez-Romo, ES}, title = {[Parkinson-dementia and amyotrophic lateral sclerosis association (complex of Guam). Diagnostic challenge, Mexican patient].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {61}, number = {5}, pages = {677-684}, pmid = {37773166}, issn = {2448-5667}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; *Parkinson Disease/complications/pathology ; *Dementia/complications/epidemiology/pathology ; *Neurodegenerative Diseases ; Guam/epidemiology ; *Parkinsonian Disorders/etiology/complications ; }, abstract = {BACKGROUND: The Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Complex (ALS-PDC) was first described in the islands of Guam. This pathology presented its peak incidence in the 1950s. Due to the rarity of the association, we report a clinical case with this complex. The objective was to describe the nosological and pathogenic implications of these neurodegenerative disorder, since they are not frequent to find in our population.<br><br>CLINICAL CASE: We present a case of Latinoamerican origin who initially manifested systemic symptoms of more than 6 years of evolution, with subsequent cognitive alterations. Later, patient began with gait disturbances and motor symptoms suggestive of parkinsonism with atypical data and data of motor neurone disease (MND). More studies were carried out and confirmed findings compatible with upper and lower motor neuron involvement. A mutation in the POLG gene was observed, related to mitochondrial depletion syndrome.<br><br>CONCLUSION: Despite the knowledge of this association, it is an entity whose clinical diagnosis could be very difficult to achieve. In addition, molecular mechanisms have not been fully identified, the most common genes related to Parkinsonism and ALS have been excluded, and even attempts to locate the locus were made, without achieving accurate results. Unfortunately, being a neurodegenerative disease, the prognosis is fatal, with no disease-modifying treatment.}, }
@article {pmid37770137, year = {2023}, author = {Bivehed, E and Hellman, B and Fan, Y and Haglöf, J and Buratovic, S}, title = {DNA integrity under alkaline conditions: An investigation of factors affecting the comet assay.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {891}, number = {}, pages = {503680}, doi = {10.1016/j.mrgentox.2023.503680}, pmid = {37770137}, issn = {1879-3592}, mesh = {Humans ; *Comet Assay/methods ; DNA ; DNA Damage ; DNA Repair ; Hydrogen-Ion Concentration ; }, abstract = {The effect of pH on DNA integrity was assessed using a three-step approach. The comet assay was used on a whole genome level, with three different protocols: neutral (no alkaline unwinding), flash (pH 12.5 with 2.5 min unwinding), and the conventional alkaline protocol (pH>13 with 40 min unwinding). Real-time quantitative PCR (RT-qPCR) was then used to study the isolated DNA, revealing that gene amplification decreased with increasing pH, indicating DNA degradation. Specially designed molecular beacons were used to examine DNA at the molecular level, with or without alkali-labile site (ALS) insertions. At pH 12.5, fluorescence in the hairpins with ALS started to increase after 30 min, while at pH> 13, this increase was already observed after 5 min, indicating a significant increase in DNA strand breaks. Liquid chromatography analysis was also used, demonstrating that the hairpins remained intact up to pH 10, even after 1 h exposure, whereas, at pH 12.5, partial conversion into strand breaks occurred after 30 min. At pH> 13, the hairpins were almost completely degraded after 30 min. The flash protocol effectively detects DNA single- and double-strand breaks and identified these damages after 2.5 min of alkaline treatment at pH 12.5. When the hairpins were exposed to pH 12.5 for 60 min, ALS were converted to strand breaks, demonstrating the sensitivity of this approach to detect changes in DNA structure. These findings indicate that pH poses a substantial risk to DNA integrity, leading to significantly higher background levels of DNA damage compared to conditions closer to neutrality. Our study demonstrates the importance of understanding the influence of pH on DNA stability and provides insights into risks associated with alkaline environments, especially at pH> 13.}, }
@article {pmid37766843, year = {2023}, author = {Olukoya, AO and Stires, H and Bahnassy, S and Persaud, S and Guerra, Y and Ranjit, S and Ma, S and Cruz, MI and Benitez, C and Rozeboom, AM and Ceuleers, H and Berry, DL and Jacobsen, BM and Raj, GV and Riggins, RB}, title = {Riluzole Suppresses Growth and Enhances Response to Endocrine Therapy in ER+ Breast Cancer.}, journal = {Journal of the Endocrine Society}, volume = {7}, number = {10}, pages = {bvad117}, pmid = {37766843}, issn = {2472-1972}, support = {T32 CA009686/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a significant clinical problem. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis. A benzothiazole-based glutamate release inhibitor with several context-dependent mechanism(s) of action, riluzole has shown antitumor activity in multiple malignancies, including melanoma, glioblastoma, and breast cancer. We previously reported that the acquisition of tamoxifen resistance in a cellular model of invasive lobular breast cancer is accompanied by the upregulation of GRM mRNA expression and growth inhibition by riluzole.<br><br>METHODS: We tested the ability of riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent, ESR1-mutated invasive lobular breast cancer patient-derived xenograft model HCI-013EI.<br><br>RESULTS: Single-agent riluzole suppressed the growth of ER+ invasive ductal and lobular breast cancer cell lines in vitro, inducing a histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). Riluzole induced apoptosis and ferroptosis and reduced phosphorylation of multiple prosurvival signaling molecules, including Akt/mTOR, CREB, and Fak/Src family kinases. Riluzole, in combination with either fulvestrant or 4-hydroxytamoxifen, additively suppressed ER+ breast cancer cell growth in vitro. Single-agent riluzole significantly inhibited HCI-013EI patient-derived xenograft growth in vivo, and the combination of riluzole plus fulvestrant significantly reduced proliferation in ex vivo primary breast tumor explant cultures.<br><br>CONCLUSION: Riluzole may offer therapeutic benefits in diverse ER+ breast cancers, including lobular breast cancer.}, }
@article {pmid37766430, year = {2023}, author = {Cheng, W and Huang, J and Fu, XQ and Tian, WY and Zeng, PM and Li, Y and Luo, ZG}, title = {Intrathecal delivery of AAV-NDNF ameliorates disease progression of ALS mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {31}, number = {11}, pages = {3277-3289}, pmid = {37766430}, issn = {1525-0024}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Dependovirus/genetics ; Disease Models, Animal ; Disease Progression ; Mice, Transgenic ; Motor Neurons/metabolism ; Nerve Growth Factors/metabolism ; *Neurodegenerative Diseases/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a uniformly lethal neurodegenerative disease characterized by progressive deterioration of motor neurons and neuromuscular denervation. Adeno-associated virus (AAV)-mediated delivery of trophic factors is being considered as a potential disease-modifying therapeutic avenue. Here we show a marked effect of AAV-mediated over-expression of neuron-derived neurotrophic factor (NDNF) on SOD1[G93A] ALS model mice. First, we adopt AAV-PHP.eB capsid to enable widespread expression of target proteins in the brain and spinal cord when delivered intrathecally. Then we tested the effects of AAV-NDNF on SOD1[G93A] mice at different stages of disease. Interestingly, AAV-NDNF markedly improved motor performance and alleviated weight loss when delivered at early post-symptomatic stage. Injection in the middle post-symptomatic stages still improved the locomotion ability, although it did not alleviate the loss of body weight. Injection in the late stage also extended the life span of SOD1[G93A] mice. Furthermore, NDNF expression promoted the survival of spinal motoneurons, reduced abnormal protein aggregation, and preserved the innervated neuromuscular functions. We further analyzed the signaling pathways of NDNF expression and found that it activates cell survival and growth-associated mammalian target of rapamycin signaling pathway and downregulates apoptosis-related pathways. Thus, intrathecally AAV-NDNF delivery has provided a potential strategy for the treatment of ALS.}, }
@article {pmid37762599, year = {2023}, author = {Taneva, SG and Todinova, S and Andreeva, T}, title = {Morphometric and Nanomechanical Screening of Peripheral Blood Cells with Atomic Force Microscopy for Label-Free Assessment of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {18}, pages = {}, pmid = {37762599}, issn = {1422-0067}, support = {KP-06-H31/8//Bulgarian Science Fund/ ; funding programme Open Access Publishing//Baden-W&#xfc;rttemberg Ministry of Science, Research and Culture/ ; }, mesh = {Humans ; *Parkinson Disease/diagnosis ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Alzheimer Disease/diagnosis ; Microscopy, Atomic Force ; Blood Cells ; }, abstract = {Neurodegenerative disorders (NDDs) are complex, multifactorial disorders with significant social and economic impact in today's society. NDDs are predicted to become the second-most common cause of death in the next few decades due to an increase in life expectancy but also to a lack of early diagnosis and mainly symptomatic treatment. Despite recent advances in diagnostic and therapeutic methods, there are yet no reliable biomarkers identifying the complex pathways contributing to these pathologies. The development of new approaches for early diagnosis and new therapies, together with the identification of non-invasive and more cost-effective diagnostic biomarkers, is one of the main trends in NDD biomedical research. Here we summarize data on peripheral biomarkers, biofluids (cerebrospinal fluid and blood plasma), and peripheral blood cells (platelets (PLTs) and red blood cells (RBCs)), reported so far for the three most common NDDs-Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). PLTs and RBCs, beyond their primary physiological functions, are increasingly recognized as valuable sources of biomarkers for NDDs. Special attention is given to the morphological and nanomechanical signatures of PLTs and RBCs as biophysical markers for the three pathologies. Modifications of the surface nanostructure and morphometric and nanomechanical signatures of PLTs and RBCs from patients with AD, PD, and ALS have been revealed by atomic force microscopy (AFM). AFM is currently experiencing rapid and widespread adoption in biomedicine and clinical medicine, in particular for early diagnostics of various medical conditions. AFM is a unique instrument without an analog, allowing the generation of three-dimensional cell images with extremely high spatial resolution at near-atomic scale, which are complemented by insights into the mechanical properties of cells and subcellular structures. Data demonstrate that AFM can distinguish between the three pathologies and the normal, healthy state. The specific PLT and RBC signatures can serve as biomarkers in combination with the currently used diagnostic tools. We highlight the strong correlation of the morphological and nanomechanical signatures between RBCs and PLTs in PD, ALS, and AD.}, }
@article {pmid37759773, year = {2023}, author = {Goto, S and Zhang, Y and Vyas, SA and Zhu, Q and Wildsoet, CF}, title = {Changes in Expression in BMP2 and Two Closely Related Genes in Guinea Pig Retinal Pigment Epithelium during Induction and Recovery from Myopia.}, journal = {Biomolecules}, volume = {13}, number = {9}, pages = {}, pmid = {37759773}, issn = {2218-273X}, support = {R01 EY012392/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Guinea Pigs ; Bone Morphogenetic Protein 2/genetics ; Choroid ; *Myopia/genetics ; *Retinal Pigment Epithelium ; }, abstract = {PURPOSE: We previously reported differential gene expression of the bone morphogenetic protein 2 (Bmp2) in guinea pig retinal pigment epithelium (RPE) after 1 day of hyperopic defocus, imposed with a negative contact lens (CLs). The study reported here sought to obtain insights into the temporal profiles of gene expression changes in Bmp2, as well as those of two closely related genes, the inhibitor of DNA binding 3 (Id3) and Noggin (Nog), both during myopia induction and when the CL treatment was terminated to allow recovery from induced myopia.<br><br>METHODS: To induce myopia, 2-week-old pigmented guinea pigs (New Zealand strain, n = 8) wore monocular -10 diopter (D) rigid gas-permeable (RGP) CLs for one week, while the other eye served as a control. Ocular measurements were made at baseline, 3 days, and 7 days after the initiation of CL wear, with treatment then being terminated and additional measurements being made after a further 3 days, 1 week, and 2 weeks. Spherical equivalent refractive errors (SERs), axial length (AL), choroidal thickness (ChT), and scleral thickness (ScT) data were collected using retinoscopy, optical biometry (Lenstar), and spectral domain optical coherence tomography (SD-OCT), respectively. RPE samples were collected from both eyes of the guinea pigs after either 1 day or 1 week of CL wear or 1 day or 2 weeks after its termination, and RNA was subsequently isolated and subjected to quantitative real-time PCR (qRT-PCR) analyses, targeting the Bmp2, Id3, and Nog genes.<br><br>RESULTS: Mean interocular differences (treated-control) in AL and SER were significantly different from baseline after 3 and 7 days of CL wear, consistent with induced myopia (p < 0.001 for all cases). Termination of CL wear resulted in the normalization (i.e., recovery) of the ALs and SERs of the treated eyes within 7 days, and the earlier significant ChT thinning with CL wear (p = 0004, day 7) was replaced by rapid thickening, which remained significant on day 7 (p = 0.009) but had normalized by day 14. The ChT changes were much smaller in magnitude than the AL changes in both phases. Interocular differences in the ScT showed no significant changes. The Bmp2 and Id3 genes were both significantly downregulated with CL wear, after 1 day (p = 0.012 and 0.016) and 7 days (p = 0.002 and 0.005), while Bmp2 gene expression increased and Nog gene expression decreased after the termination of CL wear, albeit transiently, which was significant on 1 day (p = 0.004 and 0.04) but not 2 weeks later. No change in Id3 gene expression was observed over the latter period. Conclusions: The above patterns of myopia induction and recovery validate this negative RGP-CL model as an alternative to traditional spectacle lens models for guinea pigs. The defocus-driven, sign-dependent changes in the expression of the Bmp2 gene in guinea pig RPE are consistent with observations in chicks and demonstrate the important role of BMP2 in eye growth regulation.}, }
@article {pmid37756598, year = {2023}, author = {Prior-González, M and Lazo-Gómez, R and Tapia, R}, title = {Sodium butyrate does not protect spinal motor neurons from AMPA-induced excitotoxic degeneration in vivo.}, journal = {Disease models &amp; mechanisms}, volume = {16}, number = {10}, pages = {}, pmid = {37756598}, issn = {1754-8411}, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis/pathology ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism ; Butyric Acid/pharmacology/metabolism ; Motor Neurons/pathology ; Spinal Cord/pathology ; }, abstract = {Motor neuron (MN) loss is the primary pathological hallmark of amyotrophic lateral sclerosis (ALS). Histone deacetylase 4 (HDAC4) is one of several factors involved in nerve-muscle communication during MN loss, hindering muscle reinnervation, as shown in humans and in animal models of ALS, and may explain the differential progression observed in patients with ALS - rapid versus slow progression. In this work, we inhibited HDAC4 activity through the administration of a pan-histone deacetylase inhibitor, sodium butyrate, in an in vivo model of chronic spinal MN death induced by AMPA-mediated excitotoxicity. We infused AMPA into the spinal cord at low and high doses, which mimic the rapid and slow progression observed in humans, respectively. We found that muscle HDAC4 expression was increased by high-dose infusion of AMPA. Treatment of animals with sodium butyrate further decreased expression of muscle HDAC4, although non-significantly, and did not prevent the paralysis or the MN loss induced by AMPA infusion. These results inform on the role of muscle HDAC4 in MN degeneration in vivo and provide insights for the search for more suitable therapeutic strategies.}, }
@article {pmid37752364, year = {2023}, author = {Guan, T and Zhou, T and Zhang, X and Guo, Y and Yang, C and Lin, J and Zhang, JV and Cheng, Y and Marzban, H and Wang, YT and Kong, J}, title = {Selective removal of misfolded SOD1 delays disease onset in a mouse model of amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {80}, number = {10}, pages = {304}, pmid = {37752364}, issn = {1420-9071}, mesh = {Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases ; Disease Models, Animal ; Motor Neurons ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. There is no cure currently. The discovery that mutations in the gene SOD1 are a cause of ALS marks a breakthrough in the search for effective treatments for ALS. SOD1 is an antioxidant that is highly expressed in motor neurons. Human SOD1 is prone to aberrant modifications. Familial ALS-linked SOD1 variants are particularly susceptible to aberrant modifications. Once modified, SOD1 undergoes conformational changes and becomes misfolded. This study aims to determine the effect of selective removal of misfolded SOD1 on the pathogenesis of ALS.<br><br>METHODS: Based on the chaperone-mediated protein degradation pathway, we designed a fusion peptide named CT4 and tested its efficiency in knocking down intracellularly misfolded SOD1 and its efficacy in modifying the pathogenesis of ALS.<br><br>RESULTS: Expression of the plasmid carrying the CT4 sequence in human HEK cells resulted in robust removal of misfolded SOD1 induced by serum deprivation. Co-transfection of the CT4 and the G93A-hSOD1 plasmids at various ratios demonstrated a dose-dependent knockdown efficiency on G93A-hSOD1, which could be further increased when misfolding of SOD1 was enhanced by serum deprivation. Application of the full-length CT4 peptide to primary cultures of neurons expressing the G93A variant of human SOD1 revealed a time course of the degradation of misfolded SOD1; misfolded SOD1 started to decrease by 2 h after the application of CT4 and disappeared by 7 h. Intravenous administration of the CT4 peptide at 10&#xa0;mg/kg to the G93A-hSOD1 reduced human SOD1 in spinal cord tissue by 68% in 24 h and 54% in 48 h in presymptomatic ALS mice. Intraperitoneal administration of the CT4 peptide starting from 60&#xa0;days of age significantly delayed the onset of ALS and prolonged the lifespan of the G93A-hSOD1 mice.<br><br>CONCLUSIONS: The CT4 peptide directs the degradation of misfolded SOD1 in high efficiency and specificity. Selective removal of misfolded SOD1 significantly delays the onset of ALS, demonstrating that misfolded SOD1 is the toxic form of SOD1 that causes motor neuron death. The study proves that selective removal of misfolded SOD1 is a promising treatment for ALS.}, }
@article {pmid37746513, year = {2023}, author = {Singh, A and Arora, S and Chavan, M and Shahbaz, S and Jabeen, H}, title = {An Overview of the Neurotrophic and Neuroprotective Properties of the Psychoactive Drug Lithium as an Autophagy Modulator in Neurodegenerative Conditions.}, journal = {Cureus}, volume = {15}, number = {8}, pages = {e44051}, pmid = {37746513}, issn = {2168-8184}, abstract = {For both short-term and long-term treatment of bipolar disorder, lithium is a prototypical mood stabilizer. Lithium's neuroprotective properties were revealed by cumulative translational research, which opened the door to reforming the chemical as a treatment for neurodegenerative illnesses. The control of homeostatic systems such as oxidative stress, autophagy, apoptosis, mitochondrial function, and inflammation underlies lithium's neuroprotective characteristics. The fact that lithium inhibits the enzymes inositol monophosphatase (IMPase) and glycogen synthase kinase (GSK)-3 may be the cause of the various intracellular reactions. In this article, we review lithium's neurobiological properties, as demonstrated by its neurotrophic and neuroprotective capabilities, as well as translational studies in cells in culture and in animal models of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Prion disease, amyotrophic lateral sclerosis (ALS), ischemic stroke, and neuronal ceroid lipofuscinosis (NCL), discussing the justification for the drug's use in the treatment of these neurodegenerative disorders.}, }
@article {pmid37745304, year = {2023}, author = {Yokota, M and Yoshino, Y and Hosoi, M and Hashimoto, R and Kakuta, S and Shiga, T and Ishikawa, KI and Okano, H and Hattori, N and Akamatsu, W and Koike, M}, title = {Reduced ER-mitochondrial contact sites and mitochondrial Ca[2+] flux in PRKN-mutant patient tyrosine hydroxylase reporter iPSC lines.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1171440}, pmid = {37745304}, issn = {2296-634X}, abstract = {Endoplasmic reticulum-mitochondrial contact sites (ERMCS) play an important role in mitochondrial dynamics, calcium signaling, and autophagy. Disruption of the ERMCS has been linked to several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, the etiological role of ERMCS in these diseases remains unclear. We previously established tyrosine hydroxylase reporter (TH-GFP) iPSC lines from a PD patient with a PRKN mutation to perform correlative light-electron microscopy (CLEM) analysis and live cell imaging in GFP-expressing dopaminergic neurons. Here, we analyzed ERMCS in GFP-expressing PRKN-mutant dopaminergic neurons from patients using CLEM and a proximity ligation assay (PLA). The PLA showed that the ERMCS were significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control under normal conditions. The reduction of the ERMCS in PRKN-mutant patient dopaminergic neurons was further enhanced by treatment with a mitochondrial uncoupler. In addition, mitochondrial calcium imaging showed that mitochondrial Ca[2+] flux was significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control. These results suggest a defect in calcium flux from ER to mitochondria is due to the decreased ERMCS in PRKN-mutant patient dopaminergic neurons. Our study of ERMCS using TH-GFP iPSC lines would contribute to further understanding of the mechanisms of dopaminergic neuron degeneration in patients with PRKN mutations.}, }
@article {pmid37740686, year = {2023}, author = {Vucic, S and Kiernan, MC}, title = {Nanocrystalline gold (CNM-Au8): a novel bioenergetic treatment for ALS.}, journal = {Expert opinion on investigational drugs}, volume = {32}, number = {9}, pages = {783-785}, doi = {10.1080/13543784.2023.2263368}, pmid = {37740686}, issn = {1744-7658}, }
@article {pmid37739033, year = {2023}, author = {Tanaka, Y and Ito, SI and Honma, Y and Hasegawa, M and Kametani, F and Suzuki, G and Kozuma, L and Takeya, K and Eto, M}, title = {Dysregulation of the progranulin-driven autophagy-lysosomal pathway mediates secretion of the nuclear protein TDP-43.}, journal = {The Journal of biological chemistry}, volume = {299}, number = {11}, pages = {105272}, pmid = {37739033}, issn = {1083-351X}, mesh = {Humans ; *Autophagy/drug effects/genetics ; *DNA-Binding Proteins/genetics/metabolism ; HeLa Cells ; Intercellular Signaling Peptides and Proteins/genetics/metabolism ; *Lysosomes/metabolism ; *Progranulins/genetics/metabolism ; Microtubule-Associated Proteins/genetics/metabolism ; Gene Expression Regulation/drug effects ; Extracellular Vesicles/metabolism ; Enzyme Inhibitors/pharmacology ; Autophagosomes/drug effects/metabolism ; Autophagy-Related Proteins/genetics/metabolism ; }, abstract = {The cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 kDa (TDP-43) has been linked to the progression of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 secreted into the extracellular space has been suggested to contribute to the cell-to-cell spread of the cytoplasmic accumulation of TDP-43 throughout the brain; however, the underlying mechanisms remain unknown. We herein demonstrated that the secretion of TDP-43 was stimulated by the inhibition of the autophagy-lysosomal pathway driven by progranulin (PGRN), a causal protein of frontotemporal lobar degeneration. Among modulators of autophagy, only vacuolar-ATPase inhibitors, such as bafilomycin A1 (Baf), increased the levels of the full-length and cleaved forms of TDP-43 and the autophagosome marker LC3-II (microtubule-associated proteins 1A/1B light chain 3B) in extracellular vesicle fractions prepared from the culture media of HeLa, SH-SY5Y, or NSC-34 cells, whereas vacuolin-1, MG132, chloroquine, rapamycin, and serum starvation did not. The C-terminal fragment of TDP-43 was required for Baf-induced TDP-43 secretion. The Baf treatment induced the translocation of the aggregate-prone GFP-tagged C-terminal fragment of TDP-43 and mCherry-tagged LC3 to the plasma membrane. The Baf-induced secretion of TDP-43 was attenuated in autophagy-deficient ATG16L1 knockout HeLa cells. The knockdown of PGRN induced the secretion of cleaved TDP-43 in an autophagy-dependent manner in HeLa cells. The KO of PGRN in mouse embryonic fibroblasts increased the secretion of the cleaved forms of TDP-43 and LC3-II. The treatment inducing TDP-43 secretion increased the nuclear translocation of GFP-tagged transcription factor EB, a master regulator of the autophagy-lysosomal pathway in SH-SY5Y cells. These results suggest that the secretion of TDP-43 is promoted by dysregulation of the PGRN-driven autophagy-lysosomal pathway.}, }
@article {pmid37735683, year = {2023}, author = {Sołek, P and Czechowska, E and Sowa-Kućma, M and Stachowicz, K and Kaczka, P and Tabęcka-Łonczyńska, A}, title = {Elucidating the molecular mechanisms underlying the induction of autophagy by antidepressant-like substances in C57BL/6J mouse testis model upon LPS challenge.}, journal = {Cell communication and signaling : CCS}, volume = {21}, number = {1}, pages = {251}, pmid = {37735683}, issn = {1478-811X}, mesh = {Animals ; Male ; Mice ; Antidepressive Agents/pharmacology ; Autophagy ; *Lipopolysaccharides/pharmacology ; Mice, Inbred C57BL ; Testis ; }, abstract = {The treatment of depression with pharmaceuticals is associated with many adverse side effects, including male fertility problems. The precise mechanisms by which these agents affect testicular cells remain largely unknown, but they are believed to induce cellular stress, which is sensed by the endoplasmic reticulum (ER) and the Golgi apparatus. These organelles are responsible for maintaining cellular homeostasis and regulating signal pathways that lead to autophagy or apoptosis. Therefore, in this study, we aimed to investigate the autophagy, ER, and Golgi stress-related pathways in mouse testis following treatment with antidepressant-like substances (ALS) and ALS combined with lipopolysaccharide (LPS). We found that most ALS and activated proteins are associated with the induction of apoptosis. However, when imipramine (IMI) was combined with NS-398 (a cyclooxygenase-2 inhibitor) after LPS administration, we observed a marked increase in the BECLIN1, Bcl-2, ATG16L, and LC3 expression, which are marker proteins of autophagosome formation. The expression of the BECN1 and ATG16L genes was also high compared to the control, indicating the induction of autophagy processes that may potentially protect mouse testicular cells from death and regulate metabolism in the testis. Our findings may provide a better understanding of the stress-related effects of specific ALS on the testis. Video Abstract.}, }
@article {pmid37720931, year = {2023}, author = {Martínez-Camarena, &#xc1; and Sour, A and Faller, P}, title = {Impact of human serum albumin on Cu[II] and Zn[II] complexation by ATSM (diacetyl-bis(N4-methylthiosemicarbazone)) and a water soluble analogue.}, journal = {Dalton transactions (Cambridge, England : 2003)}, volume = {52}, number = {38}, pages = {13758-13768}, doi = {10.1039/d3dt02380j}, pmid = {37720931}, issn = {1477-9234}, mesh = {Humans ; *Coordination Complexes ; *Organometallic Compounds/chemistry ; Diacetyl ; Serum Albumin, Human ; Ligands ; Zinc ; *Thiosemicarbazones/chemistry ; Copper Radioisotopes ; Radiopharmaceuticals ; }, abstract = {The chelator diacetyl-bis(N4-methylthiosemicarbazone) (ATSM) and its complexes with Cu[II] and Zn[II] are becoming increasingly investigated for medical applications such as PET imaging for anti-tumour therapy and the treatment of amyotrophic lateral sclerosis. However, the solubility in water of both the ligand and the complexes presents certain limitations for in vitro studies. Moreover, the stability of the Cu[II] and Zn[II] complexes and their metal exchange reaction against the potential biological competitor human serum albumin (HSA) has not been studied in depth. In this work it was observed that the ATSM with an added carboxylic group into the structure increases its solubility in aqueous solutions without altering the coordination mode and the conjugated system of the ligand. The poorly water-soluble Cu[II]- and Zn[II]-ATSM complexes were prevented from precipitating due to the binding to HSA. Both HSA and ATSM show a similar thermodynamic affinity for Zn[II]. Finally, the Cu[II]-competition experiments with EDTA and the water-soluble ATSM ligands yielded an apparent log Kd at pH 7.4 of about -19. When ATSM was added to Cu[II]- and Zn[II]-loaded HSA, withdrawing of Zn[II] was kinetically favoured, but this metal is slowly substituted by the Cu[II] afterwards taken from HSA so that this protein could be considered as a source of Cu[II] for ATSM.}, }
@article {pmid37711512, year = {2023}, author = {Tomiyama, ALMR and Cartarozzi, LP and de Oliveira Coser, L and Chiarotto, GB and Oliveira, ALR}, title = {Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1[G93A] mice.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1211486}, pmid = {37711512}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that progressively affects motoneurons, causing muscle atrophy and evolving to death. Astrocytes inhibit the expression of MHC-I by neurons, contributing to a degenerative outcome. The present study verified the influence of interferon β (IFN β) treatment, a proinflammatory cytokine that upregulates MHC-I expression, in SOD1[G93A] transgenic mice. For that, 17 days old presymptomatic female mice were subjected to subcutaneous application of IFN β (250, 1,000, and 10,000 IU) every other day for 20 days. Rotarod motor test, clinical score, and body weight assessment were conducted every third day throughout the treatment period. No significant intergroup variations were observed in such parameters during the pre-symptomatic phase. All mice were then euthanized, and the spinal cords collected for comparative analysis of motoneuron survival, reactive gliosis, synapse coverage, microglia morphology classification, cytokine analysis by flow cytometry, and RT-qPCR quantification of gene transcripts. Additionally, mice underwent Rotarod motor assessment, weight monitoring, and neurological scoring. The results show that IFN β treatment led to an increase in the expression of MHC-I, which, even at the lowest dose (250 IU), resulted in a significant increase in neuronal survival in the ALS presymptomatic period which lasted until the onset of the disease. The treatment also influenced synaptic preservation by decreasing excitatory inputs and upregulating the expression of AMPA receptors by astrocytes. Microglial reactivity quantified by the integrated density of pixels did not decrease with treatment but showed a less activated morphology, coupled with polarization to an M1 profile. Disease progression upregulated gene transcripts for pro- and anti-inflammatory cytokines, and IFN β treatment significantly decreased mRNA expression for IL4. Overall, the present results demonstrate that a low dosage of IFN β shows therapeutic potential by increasing MHC-I expression, resulting in neuroprotection and immunomodulation.}, }
@article {pmid37711011, year = {2023}, author = {Rodrigues, RB and Orsini, M and Neves, SV and de Rezende Pinto, WBV and da Silva Catarino, AM and Pereira, DA and Oliveira, ASB}, title = {Differential Diagnosis or Etiology: A Case Report on Amyotrophic Lateral Sclerosis-like Neuropathy Associated with HIV Infection.}, journal = {Current HIV research}, volume = {21}, number = {5}, pages = {323-329}, doi = {10.2174/1570162X21666230914104220}, pmid = {37711011}, issn = {1873-4251}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/drug therapy ; *HIV Infections/complications/drug therapy ; Diagnosis, Differential ; }, abstract = {BACKGROUND: Retroviruses are described as a risk factor for chronic neuropathy. However, it is still unknown if they can work as amyotrophic lateral sclerosis triggers. Over the years, some cases of this association have been described with heterogenous disclosures.<br><br>CASE REPRESENTATION: This study aimed to report a case of HIV and ALS-like neuropathy and briefly discuss peculiarities of clinical aspects, such as physiopathology and treatment options. The patient underwent neurological examination associated with blood tests, electromyography, analysis of cerebrospinal fluid, and imaging studies.<br><br>DISCUSSION: A non-systematic review was performed in major databases regarding the topic. The case presented mixed upper and lower motor neuron signs and was framed as a probable case of ALS following the present criteria.<br><br>CONCLUSION: After a short follow-up and viral load cleansing, neurological stabilization was achieved.}, }
@article {pmid37709589, year = {2023}, author = {Jin, J and Zhong, XB}, title = {ASO drug Qalsody (tofersen) targets amyotrophic lateral sclerosis.}, journal = {Trends in pharmacological sciences}, volume = {44}, number = {12}, pages = {1043-1044}, pmid = {37709589}, issn = {1873-3735}, support = {R35 GM140862/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Oligonucleotides ; }, }
@article {pmid37704056, year = {2023}, author = {Tang, J and Kang, Y and Zhou, Y and Chen, Q and Lan, J and Liu, X and Peng, Y}, title = {Umbilical cord mesenchymal stem cell-conditioned medium inhibits microglial activation to ameliorate neuroinflammation in amyotrophic lateral sclerosis mice and cell models.}, journal = {Brain research bulletin}, volume = {202}, number = {}, pages = {110760}, doi = {10.1016/j.brainresbull.2023.110760}, pmid = {37704056}, issn = {1873-2747}, mesh = {Mice ; Animals ; Microglia ; Neuroinflammatory Diseases ; *Amyotrophic Lateral Sclerosis ; Culture Media, Conditioned/pharmacology ; *Neurodegenerative Diseases ; Superoxide Dismutase-1 ; *Mesenchymal Stem Cells ; Mice, Transgenic ; Cytokines ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease for which few effective therapeutic strategies are available. Increasing evidence indicates that neuroinflammation plays a significant role in ALS pathogenesis. Mesenchymal stem cell (MSC)-based therapy has been proposed for the treatment of neurodegenerative diseases, including ALS. In this study, we first demonstrated that systemic administration of conditioned medium derived from umbilical cord MSCs (UCMSC-CM) extends the lifespan of transgenic SOD1-G93A mice, a well-characterized model of familial ALS. Moreover, UCMSC-CM inhibits microglial activation and astrogliosis and alleviates the inflammatory milieu by reducing the release of proinflammatory cytokines and the expression of iNOS in the spinal cord. Using BV-2 cells overexpressing the SOD1-G93A mutant as an ALS cellular model, we uncovered that UCMSC-CM also suppresses the lipopolysaccharide (LPS)-induced inflammatory response, including reduced expression of proinflammatory cytokines and iNOS. Importantly, by culturing astrocytes alone in microglia-conditioned medium (MCM) or together with microglia in a transwell coculture system, we found that UCMSC-CM modulates the secretome of microglia exposed to inflammatory stimuli, thereby preventing the conversion of astrocytes to the A1 neurotoxic phenotype. This study revealed the anti-inflammatory properties of UCMSC-CM and its regulatory effect on glial activation in the treatment of neuroinflammation in ALS, providing strong evidence for the clinical application of UCMSC-CM.}, }
@article {pmid37703175, year = {2023}, author = {Runfola, V and Giambruno, R and Caronni, C and Pannese, M and Andolfo, A and Gabellini, D}, title = {MATR3 is an endogenous inhibitor of DUX4 in FSHD muscular dystrophy.}, journal = {Cell reports}, volume = {42}, number = {9}, pages = {113120}, pmid = {37703175}, issn = {2211-1247}, support = {R21 CA249378/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Amyotrophic Lateral Sclerosis/genetics ; Gene Expression Regulation ; Genes, Homeobox ; *Homeodomain Proteins/genetics/metabolism ; Muscle, Skeletal/metabolism ; *Muscular Dystrophy, Facioscapulohumeral/genetics/metabolism ; Neurodegenerative Diseases/genetics ; Nuclear Matrix-Associated Proteins/metabolism ; RNA-Binding Proteins/metabolism ; }, abstract = {Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders and has no cure. Due to an unknown molecular mechanism, FSHD displays overlapping manifestations with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). FSHD is caused by aberrant gain of expression of the transcription factor double homeobox 4 (DUX4), which triggers a pro-apoptotic transcriptional program resulting in inhibition of myogenic differentiation and muscle wasting. Regulation of DUX4 activity is poorly known. We identify Matrin 3 (MATR3), whose mutation causes ALS and dominant distal myopathy, as a cellular factor controlling DUX4 expression and activity. MATR3 binds to the DUX4 DNA-binding domain and blocks DUX4-mediated gene expression, rescuing cell viability and myogenic differentiation of FSHD muscle cells, without affecting healthy muscle cells. Finally, we characterize a shorter MATR3 fragment that is necessary and sufficient to directly block DUX4-induced toxicity to the same extent as the full-length protein. Collectively, our data suggest MATR3 as a candidate for developing a treatment for FSHD.}, }
@article {pmid37695947, year = {2024}, author = {Sanson, G and Antonaglia, V and Buttignon, G and Caggegi, GD and Pegani, C and Peratoner, A}, title = {Dynamic Course of Clinical State Transitions in Patients Undergoing Advanced Life Support after Out-of-Hospital Cardiac Arrest.}, journal = {Prehospital emergency care}, volume = {28}, number = {3}, pages = {461-469}, doi = {10.1080/10903127.2023.2258192}, pmid = {37695947}, issn = {1545-0066}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/complications ; *Cardiopulmonary Resuscitation ; Retrospective Studies ; *Emergency Medical Services ; Ventricular Fibrillation/therapy/complications ; *Tachycardia, Ventricular/complications ; Arrhythmias, Cardiac ; }, abstract = {OBJECTIVES: Studies of out-of-hospital cardiac arrest generally document the presenting (pulseless electrical activity [PEA], ventricular fibrillation/tachycardia (VF/VT), asystole), and the final states (resuming stable spontaneous circulation [s-ROSC], being declared dead). Only a few studies described the transitions between clinical states during advanced life support (ALS). The aim of this study was to describe and analyze the dynamics of state transitions during ALS.<br><br>METHODS: A retrospective analysis of 464 OHCA events was conducted. Any observed state and its corresponding changing time were documented through continuous electrocardiographic and trans-thoracic impedance recording.<br><br>RESULTS: When achieved, most s-ROSCs were obtained by 30&#x2009;min, regardless of the presenting state. After this time point, the persistence of any transient state was associated with a great probability of being declared dead. The most probable change for VF/VT or PEA at any time was the transition to asystole (36.4% and 34.4%, respectively); patients in asystole at any time had a 70% probability of death. Patients achieving s-ROSC mostly came from a VF/VT state.In most cases, the presenting rhythm tended to persist over time during ALS. Asystole was the most stable state; a higher degree of instability was observed when the presenting rhythms were VF/VT or PEA. Transient ROSC episodes occurred mainly as the first transition after the presenting state, especially for initial PEA.<br><br>CONCLUSIONS: An understanding of the dynamic course of clinical state transitions during ALS may allow treatment strategies to be tailored in patients affected by OHCA.}, }
@article {pmid37695623, year = {2023}, author = {Genge, A and van den Berg, LH and Frick, G and Han, S and Abikoff, C and Simmons, A and Lin, Q and Patra, K and Kupperman, E and Berry, JD}, title = {Efficacy and Safety of Ravulizumab, a Complement C5 Inhibitor, in Adults With Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {80}, number = {10}, pages = {1089-1097}, pmid = {37695623}, issn = {2168-6157}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects/administration &amp; dosage ; Middle Aged ; Double-Blind Method ; Aged ; Adult ; Complement Inactivating Agents/therapeutic use/adverse effects/administration &amp; dosage ; Treatment Outcome ; Complement C5/antagonists &amp; inhibitors ; }, abstract = {IMPORTANCE: Additional therapies for amyotrophic lateral sclerosis (ALS) are urgently needed. Immune-mediated complement activation may be involved in ALS pathogenesis as evidenced by the upregulation of terminal components; thus, complement inhibition could potentially slow progression.<br><br>OBJECTIVE: To evaluate the safety and efficacy of the terminal complement C5 inhibitor ravulizumab in adults with ALS.<br><br>This double-blind, placebo-controlled, parallel-group, multinational, randomized, phase 3 clinical trial was conducted from March 30, 2020, to October 17, 2021, in 81 ALS specialty centers across 17 countries. A preplanned, unmasked, nonbinding interim futility analysis was conducted when 33% of participants had completed week 26, wherein a conditional power of less than 10% would halt the trial. A total of 478 individuals were screened, and 96 were excluded. Inclusion criteria were weight of 40 kg or more, fulfillment of the El Escorial diagnostic criteria, and a minimal prestudy Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) progression score of -0.3 points per month.<br><br>INTERVENTIONS: Study treatment consisted of placebo or a weight-based dose of intravenous ravulizumab every 8 weeks until week 42. Participants could continue standard-of-care treatment.<br><br>MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline in ALSFRS-R score at week 50 based on the Combined Assessment of Function and Survival (CAFS).<br><br>RESULTS: A total of 382 participants were randomly assigned 2:1 to receive ravulizumab (n&#x2009;=&#x2009;255; mean [SD] age, 58.6 [10.6] years; 94 female [36.9%] and 161 male [63.1%]) or placebo (n&#x2009;=&#x2009;127; mean [SD] age, 58.0 [11.0] years; 58 female [45.7%] and 69 male [54.3%]). The interim analysis showed that the observed mean change from baseline in ALSFRS-R at week 50 was -14.67 points (SE, 0.89 points; 95% CI, -16.42 to -12.91 points) for ravulizumab and -13.33 points (SE, 1.22 points; 95% CI, -15.72 to -10.93 points) for placebo, with no significant difference between the groups (mean [SE] difference, -1.34 [1.46] points; 95% CI, -4.21 to 1.53 points). Based on these data, the trial was terminated for futility. The primary analysis at week 50 showed no significant difference in CAFS between groups (mean [SE], 5.5 [10.8] points; 95% CI, -15.7 to 26.6 points; P&#x2009;=&#x2009;.61). Overall incidence rates for treatment-emergent adverse events were similar for ravulizumab (204 participants [80.0%]) and placebo (108 participants [85.0%]).<br><br>CONCLUSIONS AND RELEVANCE: This trial rapidly showed that terminal complement C5 inhibition with ravulizumab did not slow functional decline in participants with ALS and that the safety profiles of ravulizumab and placebo were similar. Highly effective, novel treatments are critically needed to slow functional decline and extend survival in patients with ALS.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04248465.}, }
@article {pmid37695446, year = {2024}, author = {Yang, EJ}, title = {Combined Treatment with Bojungikgi-tang (Buzhong Yiqi Decoction) and Riluzole Attenuates Cell Death in TDP-43-Expressing Cells.}, journal = {Chinese journal of integrative medicine}, volume = {30}, number = {7}, pages = {616-622}, pmid = {37695446}, issn = {1993-0402}, mesh = {*Drugs, Chinese Herbal/pharmacology ; *DNA-Binding Proteins/metabolism ; *Cell Death/drug effects ; *Riluzole/pharmacology ; Cell Line ; Autophagy/drug effects ; Animals ; Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; Cell Survival/drug effects ; Drug Therapy, Combination ; Humans ; }, abstract = {OBJECTIVE: To examine the effect of combined treatment with Bojungikgi-tang (BJIGT, Buzhong Yiqi Decoction) and riluzole (RZ) in transactive response DNA-binding protein 43 (TDP-43) stress granule (SG) cells, a amyotrophic lateral sclerosis (ALS) cell line using transcriptomic and molecular techniques.<br><br>METHODS: TDP-43 SG cells were pretreated with BJIGT (100 &#xb5;g/mL), RZ (50 &#xb5;mol/L), and combined BJIGT (100 &#xb5;g/mL)/RZ (50 &#xb5;mol/L) for 6 h before treatment with lipopolysaccharide (LPS, 200 &#xb5;mol/L). Cell viability assay was performed to elucidate cell toxicity in TDP-43 SC cells using a cell-counting kit-8 (CCK8) assay kit. The expression levels of cell death-related proteins, including Bax, caspase 1, cleaved caspase 3 and DJ1 in TDP-43 SG cells were examined by Western blot analysis. The autophagy-related proteins, including pmTOR/mTOR, LC3b, P62, ATG7 and Bcl-2-associated athanogene 3 (Bag3) were investigated using immunofluorescence and immunoblotting assays.<br><br>RESULTS: Cell viability assay and Western blot analysis showed that combined treatment with BJIGT and RZ suppressed LPS-induced cell death and expression of cell death-related proteins, including Bax, caspase 1, and DJ1 (P<0.05 or P<0.01). Immunofluorescence and immunoblotting assays showed that combined treatment with BJIGT and RZ reduced LPS-induced formation of TDP-43 aggregates and regulated autophagy-related protein levels, including p62, light chain 3b, Bag3, and ATG7, in TDP-43-expressing cells (P<0.05 or P<0.01).<br><br>CONCLUSION: The combined treatment of BJIGT and RZ might reduce inflammation and regulate autophagy dysfunction in TDP-43-induced ALS.}, }
@article {pmid37692101, year = {2023}, author = {Stansberry, WM and Pierchala, BA}, title = {Neurotrophic factors in the physiology of motor neurons and their role in the pathobiology and therapeutic approach to amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1238453}, pmid = {37692101}, issn = {1662-5099}, support = {R01 NS089585/NS/NINDS NIH HHS/United States ; }, abstract = {The discovery of the neurotrophins and their potent survival and trophic effects led to great enthusiasm about their therapeutic potential to rescue dying neurons in neurodegenerative diseases. The further discovery that brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF) had potent survival-promoting activity on motor neurons led to the proposal for their use in motor neuron diseases such as amyotrophic lateral sclerosis (ALS). In this review we synthesize the literature pertaining to the role of NGF, BDNF, CNTF and GDNF on the development and physiology of spinal motor neurons, as well as the preclinical studies that evaluated their potential for the treatment of ALS. Results from the clinical trials of these molecules will also be described and, with the aid of decades of hindsight, we will discuss what can reasonably be concluded and how this information can inform future clinical development of neurotrophic factors for ALS.}, }
@article {pmid37689321, year = {2023}, author = {Donini, L and Tanel, R and Zuccarino, R and Basso, M}, title = {Protein biomarkers for the diagnosis and prognosis of Amyotrophic Lateral Sclerosis.}, journal = {Neuroscience research}, volume = {197}, number = {}, pages = {31-41}, doi = {10.1016/j.neures.2023.09.002}, pmid = {37689321}, issn = {1872-8111}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Prognosis ; Biomarkers ; Disease Progression ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease, still incurable. The disease is highly heterogenous both genetically and phenotypically. Therefore, developing efficacious treatments is challenging in many aspects because it is difficult to predict the rate of disease progression and stratify the patients to minimize statistical variability in clinical studies. Moreover, there is a lack of sensitive measures of therapeutic effect to assess whether a pharmacological intervention ameliorates the disease. There is also urgency of markers that reflect a molecular mechanism dysregulated by ALS pathology and can be rescued when a treatment relieves the condition. Here, we summarize and discuss biomarkers tested in multicentered studies and across different laboratories like neurofilaments, the most used marker in ALS clinical studies, neuroinflammatory-related proteins, p75[ECD], p-Tau/t-Tau, and UCHL1. We also explore the applicability of muscle proteins and extracellular vesicles as potential biomarkers.}, }
@article {pmid37686737, year = {2023}, author = {Zhou, J and Zhang, W and Cao, Z and Lian, S and Li, J and Nie, J and Huang, Y and Zhao, K and He, J and Liu, C}, title = {Association of Selenium Levels with Neurodegenerative Disease: A Systemic Review and Meta-Analysis.}, journal = {Nutrients}, volume = {15}, number = {17}, pages = {}, pmid = {37686737}, issn = {2072-6643}, support = {81903294//National Natural Science Foundation of China/ ; 202102020120//Guangzhou Basic and Applied Basic Research Foundation/ ; A2022080//Medical Scientific Research Foundation of Guangdong Province of China/ ; }, mesh = {Humans ; *Selenium ; *Neurodegenerative Diseases ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; Databases, Factual ; }, abstract = {BACKGROUND: Neurodegenerative diseases (NDs) have posed significant challenges to public health, and it is crucial to understand their mechanisms in order to develop effective therapeutic strategies. Recent studies have highlighted the potential role of selenium in ND pathogenesis, as it plays a vital role in maintaining cellular homeostasis and preventing oxidative damage. However, a comprehensive analysis of the association between selenium and NDs is still lacking.<br><br>METHOD: Five public databases, namely PubMed, Web of Science, EMBASE, Cochrane and Clinical Trials, were searched in our research. Random model effects were chosen, and Higgins inconsistency analyses (I[2]), Cochrane's Q test and Tau2 were calculated to evaluate the heterogeneity.<br><br>RESULT: The association of selenium in ND patients with Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) was studied. A statistically significant relationship was only found for AD patients (SMD = -0.41, 95% CI (-0.64, -0.17), p < 0.001), especially for erythrocytes. However, no significant relationship was observed in the analysis of the other four diseases.<br><br>CONCLUSION: Generally, this meta-analysis indicated that AD patients are strongly associated with lower selenium concentrations compared with healthy people, which may provide a clinical reference in the future. However, more studies are urgently needed for further study and treatment of neurodegenerative diseases.}, }
@article {pmid37686322, year = {2023}, author = {Badu-Mensah, A and Guo, X and Mendez, R and Parsaud, H and Hickman, JJ}, title = {The Effect of Skeletal Muscle-Specific Creatine Treatment on ALS NMJ Integrity and Function.}, journal = {International journal of molecular sciences}, volume = {24}, number = {17}, pages = {}, pmid = {37686322}, issn = {1422-0067}, support = {R01 NS050452/NS/NINDS NIH HHS/United States ; R01NS050452/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Creatine/pharmacology/therapeutic use ; Muscle Fatigue ; Muscle, Skeletal ; Neuromuscular Junction ; }, abstract = {Although skeletal muscle (hSKM) has been proven to be actively involved in Amyotrophic Lateral Sclerosis (ALS) neuromuscular junction (NMJ) dysfunction, it is rarely considered as a pharmacological target in preclinical drug discovery. This project investigated how improving ALS hSKM viability and function effects NMJ integrity. Phenotypic ALS NMJ human-on-a-chip models developed from patient-derived induced pluripotent stem cells (iPSCs) were used to study the effect of hSKM-specific creatine treatment on clinically relevant functional ALS NMJ parameters, such as NMJ numbers, fidelity, stability, and fatigue index. Results indicated comparatively enhanced NMJ numbers, fidelity, and stability, as well as reduced fatigue index, across all hSKM-specific creatine-treated systems. Immunocytochemical analysis of the NMJs also revealed improved post-synaptic nicotinic Acetylcholine receptor (AChR) clustering and cluster size in systems supplemented with creatine relative to the un-dosed control. This work strongly suggests hSKM as a therapeutic target in ALS drug discovery. It also demonstrates the need to consider all tissues involved in multi-systemic diseases, such as ALS, in drug discovery efforts. Finally, this work further establishes the BioMEMs NMJ platform as an effective means of performing mutation-specific drug screening, which is a step towards personalized medicine for rare diseases.}, }
@article {pmid37682161, year = {2023}, author = {Tang, X and Zhan, Y and Yang, B and Du, B and Huang, J}, title = {Exploring the mechanism of Semen Strychni in treating amyotrophic lateral sclerosis based on network pharmacology.}, journal = {Medicine}, volume = {102}, number = {36}, pages = {e35101}, pmid = {37682161}, issn = {1536-5964}, mesh = {Humans ; *Semen ; *Amyotrophic Lateral Sclerosis/drug therapy ; Network Pharmacology ; Molecular Docking Simulation ; Phosphatidylinositol 3-Kinases ; }, abstract = {Semen Strychni (SS), known as an agonist of central nervous system, is a traditional herb widely used in treating amyotrophic lateral sclerosis (ALS) in small doses to relieve muscle weakness and improve muscle strength. However, the potential mechanisms and the main components of SS in treating ALS remain unclear. To explore the underlying mechanism of SS in treating ALS based on network pharmacology and molecular docking. The active components of SS were obtained using TCMSP, Herb, ETCM, and BATMAN-TCM. The targets of SS were gained from PharmMapper. The targets of ALS were searched on Genecards, Drugbank, DisGeNET, OMIM, TTD and GEO database. After obtaining the coincidence targets, we submitted them to the STRING database to build a protein-protein interaction network. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed subsequently. The active components and targets were further investigated using molecular docking technology. 395 targets of SS and 1925 targets of ALS were obtained with 125 common targets. The protein-protein interaction analysis indicated that SRC, AKT1, MAPK1, EGFR, and HSP90AA1 received the higher degree value and were considered the central genes. The Ras, PI3K-Akt, and MAPK signaling pathway could be involved in the treatment of ALS. Brucine-N-oxide obtained the lowest binding energy in molecular docking. This study explored the mechanism of SS in the treatment of ALS and provides a new perspective for future study. However, further experimental studies are needed to validate the therapeutic effect.}, }
@article {pmid37680538, year = {2023}, author = {Dunn, E and Zhang, B and Sahota, VK and Augustin, H}, title = {Potential benefits of medium chain fatty acids in aging and neurodegenerative disease.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1230467}, pmid = {37680538}, issn = {1663-4365}, abstract = {Neurodegenerative diseases are a large class of neurological disorders characterized by progressive dysfunction and death of neurones. Examples include Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Aging is the primary risk factor for neurodegeneration; individuals over 65 are more likely to suffer from a neurodegenerative disease, with prevalence increasing with age. As the population ages, the social and economic burden caused by these diseases will increase. Therefore, new therapies that address both aging and neurodegeneration are imperative. Ketogenic diets (KDs) are low carbohydrate, high-fat diets developed initially as an alternative treatment for epilepsy. The classic ketogenic diet provides energy via long-chain fatty acids (LCFAs); naturally occurring medium chain fatty acids (MCFAs), on the other hand, are the main components of the medium-chain triglyceride (MCT) ketogenic diet. MCT-based diets are more efficient at generating the ketone bodies that are used as a secondary energy source for neurones and astrocytes. However, ketone levels alone do not closely correlate with improved clinical symptoms. Recent findings suggest an alternative mode of action for the MCFAs, e.g., via improving mitochondrial biogenesis and glutamate receptor inhibition. MCFAs have been linked to the treatment of both aging and neurodegenerative disease via their effects on metabolism. Through action on multiple disease-related pathways, MCFAs are emerging as compounds with notable potential to promote healthy aging and ameliorate neurodegeneration. MCFAs have been shown to stimulate autophagy and restore mitochondrial function, which are found to be disrupted in aging and neurodegeneration. This review aims to provide insight into the metabolic benefits of MCFAs in neurodegenerative disease and healthy aging. We will discuss the use of MCFAs to combat dysregulation of autophagy and mitochondrial function in the context of "normal" aging, Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease.}, }
@article {pmid37674720, year = {2023}, author = {Chen, S and Puri, A and Bell, B and Fritsche, J and Palacios, H and Balch, M and Sprunger, M and Howard, M and Patterson, J and Patti, G and Davis, A and Jackrel, M}, title = {HtrA1 prevents and reverses α-synuclein aggregation, rendering it non-toxic and seeding incompetent.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37674720}, issn = {2693-5015}, support = {K08 NS101118/NS/NINDS NIH HHS/United States ; R35 GM128772/GM/NIGMS NIH HHS/United States ; }, abstract = {Parkinson disease (PD) is closely linked to the misfolding and accumulation of α-synuclein (α-syn) into Lewy bodies. HtrA1 is a PDZ serine protease that degrades fibrillar tau, which is associated with Alzheimer disease (AD). Further, inactivating mutations to mitochondrial HtrA2 have been implicated in PD. Here, we establish that HtrA1 inhibits the aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We demonstrate that the protease domain of HtrA1 is necessary and sufficient for inhibition of aggregation, yet this activity is independent of HtrA1 proteolytic activity. Further, we find that HtrA1 also disaggregates preformed α-syn fibrils, which may promote their clearance. Treatment of α-syn fibrils with HtrA1 renders α-syn incapable of seeding the aggregation of endogenous α-syn in mammalian biosensor cells. We find that HtrA1 remodels α-syn by specifically targeting the NAC domain, which is the key domain that catalyzes α-syn oligomerization and fibrillization. Finally, in a primary neuron model of α-syn aggregation, we show that HtrA1 and its proteolytically inactive form both detoxify α-syn and prevent the formation of hyperphosphorylated α-syn accumulations. Our findings suggest that HtrA1 prevents aggregation and promotes disaggregation of multiple disease-associated proteins, and may be a therapeutic target for treating a range of neurodegenerative disorders.}, }
@article {pmid37672770, year = {2023}, author = {Naveed, M and Aqib Shabbir, M and Aziz, T and Hurraira, HM and Fatima Zaidi, S and Athar, R and Chattha, HA and Alharbi, M and Alshammari, A and Alasmari, AF}, title = {CRISPR-Cas9 guided rna based model for the treatment of Amyotrophic Lateral Sclerosis: A progressive neurodegenerative disorder.}, journal = {Acta biochimica Polonica}, volume = {70}, number = {3}, pages = {643-653}, doi = {10.18388/abp.2020_6789}, pmid = {37672770}, issn = {1734-154X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; CRISPR-Cas Systems/genetics ; Gene Editing ; Muscles ; RNA, Guide, CRISPR-Cas Systems ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that leads to the degeneration of motor neurons and the weakening of muscles. Despite extensive research efforts, there is currently no cure for ALS and existing treatments only address its symptoms. To address this unmet medical need, genome editing technologies, such as CRISPR-Cas9, have emerged as a promising solution for the development of new treatments for ALS. Studies have shown that CRISPR-Cas9-guided RNAs have the potential to provide accurate and effective silencing in the genetic disease of ALS. Results have demonstrated a 67% on-target score and a 98% off-target score with GC content within the range of 40-60%. This is further validated by the correlation between the gRNA's structural accuracy and the minimum free energy. The use of CRISPR-Cas9 provides a unique opportunity to target this disease at the molecular level, offering hope for the development of a more effective treatment. In silico and computational therapeutic approaches for ALS suggest that the CRISPR-Cas9 protein holds promise as a future treatment candidate. The CRISPR mechanism and the specificity of gRNA provide a novel therapeutic approach for this genetic disease, offering new hope to those affected by ALS. This study highlights the potential of CRISPR-Cas9 as a promising solution for the development of new treatments for ALS. Further research is required to validate these findings in preclinical and clinical trials and to establish the safety and efficacy of this approach in the treatment of ALS.}, }
@article {pmid37670160, year = {2023}, author = {Devalckeneer, A and Bourgeois, P and Caudron, Y and Estrade, L and Obled, L and Leclerc, X and Assaker, R and Lejeune, JP and Aboukais, R}, title = {Surgical evolution in spinal dural arteriovenous fistula treatment-a 7 years monocentric experience.}, journal = {Neurosurgical review}, volume = {46}, number = {1}, pages = {225}, pmid = {37670160}, issn = {1437-2320}, mesh = {Adult ; Humans ; *Central Nervous System Vascular Malformations ; Cerebrospinal Fluid Leak ; Laminectomy ; Retrospective Studies ; *Spinal Cord Diseases ; }, abstract = {Accounting for 70% of all spinal vascular malformations, spinal dural arteriovenous fistulas (SDAVF) are the most common type of malformation. Interruption of the fistulous arterialized vein point is the goal of surgical treatment. The aim of the study was to compare open surgery (laminectomy) versus minimal invasive surgery (MIS) in SDAVF treatment. Between March 2013 and March 2020, we retrospectively collected 21 consecutive adult patients with SDAVF. Since March 2017, MIS has been routinely used for surgical treatment. Pre- and post-operative clinical evaluations used Aminoff-Logue score (ALS). Complication rate was noted. Post-operative occlusion of the malformation was confirmed by digital subtraction angiography (DSA) in all patients. MIS was compared to open surgery in terms of efficacy and complications with statistical evaluation. Standard laminectomy was performed in 12 patients and MIS technique in 9 patients. No difference was noted on pre-operative parameters. ALS and MRI signs of myelopathy were improved in all cases except for 1 patient in each group. All SDAVFs were excluded based on post-operative DSA. Significant differences were noted between the 2 groups in terms of perioperative blood loss (p<0.001), post-operative pain visual analog scale values (p<0.001), and first time out of bed (p<0.001). Wrong level surgery occurred in one patient in each group; patients were re-operated using the same technique. No infection or cerebrospinal fluid (CSF) leak was noted. In our experience, MIS is a safe alternative to open laminectomy for SDAVF treatment. MIS contributes to patient comfort and minimizes blood loss without increasing complication rate.}, }
@article {pmid37669876, year = {2023}, author = {Quinn, L and Bird, P and Remsing, S and Reeves, K and Lilford, R}, title = {Unintended consequences of the 18-week referral to treatment standard in NHS England: a threshold analysis.}, journal = {BMJ quality &amp; safety}, volume = {32}, number = {12}, pages = {712-720}, pmid = {37669876}, issn = {2044-5423}, mesh = {Humans ; *State Medicine ; *Hospitals ; Patients ; England ; Referral and Consultation ; }, abstract = {OBJECTIVE: In 2012, an '18-week referral to treatment standard' was introduced in England. Among people on the list of those waiting for hospital treatment at a point in time, the standard states that at least '92% of patients should have been waiting for less than 18 weeks'. Targets can have unintended consequences, where patients are prioritised based on the target rather than clinical need. Such an effect will be evident as a spike in the number of hospital trusts at the target threshold, referred to as a threshold effect. This study examines for threshold effects across all non-specialist acute NHS England hospital trusts by financial year.<br><br>METHODS: A retrospective observational study of publicly available data examined waiting times for patients on the waiting list. We examined trust performance against the 92% target by financial year, from 2015/16 to 2021/22, using Cattaneo et al's manipulation density test (test for discontinuity/spike in data around target threshold) for all patients and by type of treatment.<br><br>RESULTS: The proportion of NHS hospital trusts meeting the 92% target deteriorated over time. From 2015/16 to 2019/20, there was strong evidence of a threshold effect at the 92% target (p<0.001). There was no evidence of a threshold effect in 2020/21 (p=0.063) or 2021/22 (p=0.090). Threshold effects were present across most types of treatment in 2016/17 and fewer types from 2017/18 onwards.<br><br>CONCLUSION: We observed striking evidence of a threshold effect suggesting that while targets change behaviour, they do so in a selective way, focusing on the threshold rather than a pervasive improvement in practice. However, at the height of the pandemic, as almost no trusts could reach the target, the threshold effect disappeared.}, }
@article {pmid37666395, year = {2023}, author = {Atiya, A and Muhsinah, AB and Alrouji, M and Alhumaydhi, FA and Al Abdulmonem, W and Aljasir, MA and Sharaf, SE and Furkan, M and Khan, RH and Shahwan, M and Shamsi, A}, title = {Unveiling promising inhibitors of superoxide dismutase 1 (SOD1) for therapeutic interventions.}, journal = {International journal of biological macromolecules}, volume = {253}, number = {Pt 2}, pages = {126684}, doi = {10.1016/j.ijbiomac.2023.126684}, pmid = {37666395}, issn = {1879-0003}, mesh = {Humans ; Superoxide Dismutase-1/genetics ; Molecular Docking Simulation ; *Amyotrophic Lateral Sclerosis/metabolism ; Oxidation-Reduction ; *Neoplasms ; Superoxide Dismutase/metabolism ; Mutation ; }, abstract = {Superoxide dismutase 1 (SOD1) is a vital enzyme responsible for controlling cellular oxidative stress. Any dysregulation of SOD1 activity is linked with cancer pathogenesis and neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). Among the inhibitors known to be effective against SOD1, LCS-1 stands out; however, its efficacy, specificity, and safety profiles are somewhat restricted. In this study, we used PubChem library to retrieve compounds that exhibited a structural similarity of at least 90 % with LCS-1. These compounds underwent molecular docking analyses to examine their interaction patterns and binding affinities with SOD1. Further, we applied filters based on physicochemical and ADMET properties, refining the selection process. Our analysis revealed that selected compounds interact with crucial residues of SOD1 active site. To gain further insights into conformational stability and dynamics of the SOD1-ligand complexes, we conducted all-atom molecular dynamics (MD) simulations for 100 ns. We identified two compounds, CID:133306073 and CID:133446715, as potential scaffolds with promising inhibitory properties against SOD1. Both compounds hold significant potential for further exploration as therapeutic SOD1 inhibitors. Further studies are warranted to fully harness their therapeutic potential in targeting SOD1 for cancer and ALS treatment, offering new avenues for improved patient outcomes and disease management.}, }
@article {pmid37664456, year = {2023}, author = {Garodia, P and Hegde, M and Kunnumakkara, AB and Aggarwal, BB}, title = {Curcumin, inflammation, and neurological disorders: How are they linked?.}, journal = {Integrative medicine research}, volume = {12}, number = {3}, pages = {100968}, pmid = {37664456}, issn = {2213-4220}, abstract = {BACKGROUND: Despite the extensive research in recent years, the current treatment modalities for neurological disorders are suboptimal. Curcumin, a polyphenol found in Curcuma genus, has been shown to mitigate the pathophysiology and clinical sequalae involved in neuroinflammation and neurodegenerative diseases.<br><br>METHODS: We searched PubMed database for relevant publications on curcumin and its uses in treating neurological diseases. We also reviewed relevant clinical trials which appeared on searching PubMed database using 'Curcumin and clinical trials'.<br><br>RESULTS: This review details the pleiotropic immunomodulatory functions and neuroprotective properties of curcumin, its derivatives and formulations in various preclinical and clinical investigations. The effects of curcumin on neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), brain tumors, epilepsy, Huntington's disorder (HD), ischemia, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI) with a major focus on associated signalling pathways have been thoroughly discussed.<br><br>CONCLUSION: This review demonstrates curcumin can suppress spinal neuroinflammation by modulating diverse astroglia mediated cascades, ensuring the treatment of neurological disorders.}, }
@article {pmid37660686, year = {2023}, author = {Bhakta, P and Dutta, A}, title = {Homeopathic Treatment of Ramsay Hunt Syndrome: A Case Report.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {544-552}, doi = {10.1159/000533849}, pmid = {37660686}, issn = {2504-2106}, mesh = {Female ; Humans ; Young Adult ; Adult ; *Facial Paralysis ; *Homeopathy ; *Herpes Zoster Oticus/therapy ; *Deglutition Disorders ; Quality of Life ; Ulcer ; }, abstract = {INTRODUCTION: Ramsay Hunt syndrome (RHS) is an uncommon neurological complication resulting from the reactivation of latent herpes zoster virus. The condition often presents with facial paralysis, palatal ulcers, dysphagia, and altered taste sensation, leading to reduced quality of life. Standard therapeutic options for RHS have limitations, prompting the exploration of alternative treatments with improved prognostic outcomes. This case report aims to present a noteworthy clinical observation of RHS managed with individualized homeopathic treatment, emphasizing its potential therapeutic effect.<br><br>CASE DESCRIPTION: A 24-year-old female patient exhibited left-sided facial weakness, along with palatal ulcers, dysphagia, and ageusia, prompting the diagnosis of RHS. Following the principles of homeopathy, a personalized therapeutic regimen was formulated, consisting tailored administration of Rhus toxicodendron, Spigelia anthelmia, and Sulfur. The House-Brackmann scale was employed to objectively assess the severity of facial palsy, while photographic documentation tracked the progression of palatal ulcers and facial paralysis. Over a carefully monitored observation period of 14 days, the patient demonstrated notable therapeutic response. There was a significant reduction in the extent of palatal ulceration and left-sided facial palsy exhibited marked improvement. Subsequent days of follow-up witnessed a consistent amelioration of the patient's condition, substantiating the effect of the individualized homeopathic treatment.<br><br>CONCLUSION: This case report highlights an exceptional instance of RHS recovery within a relatively short timeframe, achieved through the administration of individualized homeopathic therapy. The favorable outcomes observed in this case underscore the potential of homeopathy as a promising intervention for RHS management. Nevertheless, further systematic investigations are imperative to comprehensively evaluate the scope and applicability of homeopathy in the treatment of RHS.<br><br>UNLABELLED: <title>Einleitung</title>Das Ramsay&#x2010;Hunt&#x2010;Syndrom (RHS) ist eine seltene neurologische Komplikation, die durch die Reaktivierung einer latenten Herpes&#x2010;Zoster&#x2010;Virusinfektion verursacht wird. Die Krankheit manifestiert sich h&#xe4;ufig mit Gesichtsl&#xe4;hmung, Ulcerationen am Gaumen, Dysphagie und ver&#xe4;ndertem Geschmacksempfinden und ist mit einer Einschr&#xe4;nkung der Lebensqualit&#xe4;t verbunden. Die Standardtherapieoptionen f&#xfc;r RHS sind begrenzt, weshalb nach alternativen Behandlungsm&#xf6;glichkeiten mit besseren prognostischen Ergebnissen gesucht wird. Im vorliegenden Fallbericht wird eine interessante klinische Beobachtung bei RHS vorgestellt, das mit individualisierter Hom&#xf6;opathie behandelt wurde, und deren potenzielle therapeutische Wirksamkeit wird hervorgehoben.<title>Der Fall</title>Eine 24-j&#xe4;hrige Patientin zeigte eine linksseitige Gesichtsschw&#xe4;che in Verbindung mit Ulcerationen am Gaumen, Dysphagie und Ageusie, so dass die Diagnose RHS gestellt wurde. Gem&#xe4;&#xdf; den Prinzipien der Hom&#xf6;opathie wurde ein personalisiertes Therapieschema formuliert, das die individuell zugeschnittene Gabe von <italic>Rhus toxicodendron, Spigelia anthelmia</italic>, und <italic>Sulphur</italic> umfasste. Die objektive Bewertung des Schweregrads der Gesichtsl&#xe4;hmung erfolgte mithilfe der House-Brackmann-Skala, wohingegen das Fortschreiten der Gaumenulcerationen und der Gesichtsl&#xe4;hmung fotografisch dokumentiert wurde. W&#xe4;hrend eines sorgf&#xe4;ltig &#xfc;berwachten Beobachtungszeitraums von 14 Tagen zeigte die Patientin ein deutliches therapeutisches Ansprechen. Das Ausma&#xdf; der Gaumenulcerationen ging signifikant zur&#xfc;ck, und die linksseitige Gesichtsl&#xe4;hmung besserte sich deutlich. In den folgenden Tagen besserte sich der Zustand der Patientin kontinuierlich, was die Wirkung der individualisierten hom&#xf6;opathischen Behandlung untermauert.<title>Schlussfolgerung</title>Dieser Fallbericht beleuchtet einen ungew&#xf6;hnlichen Fall von Genesung nach einem RHS innerhalb relativ kurzer Zeit, die durch Verabreichung einer individualisierten hom&#xf6;opathischen Therapie erreicht wurde. Die im vorliegenden Fall beobachteten g&#xfc;nstigen Ergebnisse unterstreichen das Potenzial der Hom&#xf6;opathie als vielversprechende Intervention zur Behandlung von RHS. Allerdings sind weitere systematische Untersuchungen unabdingbar, um den Umfang und die Anwendbarkeit der Hom&#xf6;opathie bei der Behandlung von RHS umfassend zu beurteilen.}, }
@article {pmid37658972, year = {2023}, author = {Singh, S and Shukla, R}, title = {Nanovesicular-Mediated Intranasal Drug Therapy for Neurodegenerative Disease.}, journal = {AAPS PharmSciTech}, volume = {24}, number = {7}, pages = {179}, pmid = {37658972}, issn = {1530-9932}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Nose ; Drug Delivery Systems ; Brain ; *Glioblastoma ; }, abstract = {Numerous neurodegenerative conditions, such as Alzheimer's, Huntington's, Parkinson's, amyotrophic lateral sclerosis, and glioblastoma multiform are now becoming significant concerns of global health. Formulation-related issues, physiological and anatomical barriers, post-administration obstacles, physical challenges, regulatory limitations, environmental hurdles, and health and safety issues have all hindered successful delivery and effective outcomes despite a variety of treatment options. In the current review, we covered the intranasal route, an alternative strategic route targeting brain for improved delivery across the BBB. The trans-nasal pathway is non-invasive, directing therapeutics directly towards brain, circumventing the barrier and reducing peripheral exposure. The delivery of nanosized vesicles loaded with drugs was also covered in the review. Nanovesicle systems are organised in concentric bilayered lipid membranes separated with aqueous layers. These carriers surmount the disadvantages posed by intranasal delivery of rapid mucociliary clearance and enzymatic degradation, and enhance retention of drug to reach the site of target. In conclusion, the review covers in-depth conclusions on numerous aspects of formulation of drug-loaded vesicular system delivery across BBB, current marketed nasal devices, significant jeopardies, potential therapeutic aids, and current advancements followed by future perspectives.}, }
@article {pmid37657967, year = {2023}, author = {Ryan, SK and Ugalde, CL and Rolland, AS and Skidmore, J and Devos, D and Hammond, TR}, title = {Therapeutic inhibition of ferroptosis in neurodegenerative disease.}, journal = {Trends in pharmacological sciences}, volume = {44}, number = {10}, pages = {674-688}, doi = {10.1016/j.tips.2023.07.007}, pmid = {37657967}, issn = {1873-3735}, support = {MC_PC_19032/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Ferroptosis ; *Neurodegenerative Diseases/drug therapy ; Iron ; }, abstract = {Iron accumulation has been associated with the etiology and progression of multiple neurodegenerative diseases (NDDs). The exact role of iron in these diseases is not fully understood, but an iron-dependent form of regulated cell death called ferroptosis could be key. Although there is substantial preclinical and clinical evidence that ferroptosis plays a role in NDD, there are still questions regarding how to target ferroptosis therapeutically, including which proteins to target, identification of clinically relevant biomarkers, and which patients might benefit most. Clinical trials of iron- and ferroptosis-targeted therapies are beginning to provide some answers, but there is growing interest in developing new ferroptosis inhibitors. We describe newly identified ferroptosis targets, opportunities, and challenges in NDD, as well as key considerations for progressing new therapeutics to the clinic.}, }
@article {pmid37657764, year = {2023}, author = {Zhou, S and Zhou, Y and Zhong, W and Su, Z and Qin, Z}, title = {Involvement of protein L-isoaspartyl methyltransferase in the physiopathology of neurodegenerative diseases: Possible substrates associated with synaptic function.}, journal = {Neurochemistry international}, volume = {170}, number = {}, pages = {105606}, doi = {10.1016/j.neuint.2023.105606}, pmid = {37657764}, issn = {1872-9754}, mesh = {Humans ; *Protein D-Aspartate-L-Isoaspartate Methyltransferase/metabolism ; *Neurodegenerative Diseases/metabolism ; Proteins/metabolism ; Isoaspartic Acid/metabolism ; Aspartic Acid/metabolism ; }, abstract = {Synaptic dysfunction is a typical pathophysiologic change in neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Hintington's disease (HD) and amyotrophic lateral sclerosis (ALS), which involves protein post-translational modifications (PTMs) including L-isoaspartate (L-isoAsp) formed by isomerization of aspartate or deamidation of asparagine. The formation of L-isoAsp could be repaired by protein L-isoaspartyl methyltransferase (PIMT). Some synaptic proteins have been identified as PIMT potential substrates and play an essential role in ensuring synaptic function. In this review, we discuss the role of certain synaptic proteins as PIMT substrates in neurodegenerative disease, thus providing therapeutic synapse-centered targets for the treatment of NDs.}, }
@article {pmid37651612, year = {2023}, author = {Sadžak, A and Eraković, M and Šegota, S}, title = {Kinetics of Flavonoid Degradation and Controlled Release from Functionalized Magnetic Nanoparticles.}, journal = {Molecular pharmaceutics}, volume = {20}, number = {10}, pages = {5148-5159}, doi = {10.1021/acs.molpharmaceut.3c00478}, pmid = {37651612}, issn = {1543-8392}, abstract = {Flavonoids are naturally occurring antioxidants that have been shown to protect cell membranes from oxidative stress and have a potential use in photodynamic cancer treatment. However, they degrade at physiological pH values, which is often neglected in drug release studies. Kinetic study of flavonoid oxidation can help to understand the mechanism of degradation and to correctly analyze flavonoid release data. Additionally, the incorporation of flavonoids into magnetic nanocarriers can be utilized to mitigate degradation and overcome their low solubility, while the release can be controlled using magnetic fields (MFs). An approach that combines alternating least squares (ALS) and multilinear regression to consider flavonoid autoxidation in release studies is presented. This approach can be used in general cases to account for the degradation of unstable drugs released from nanoparticles. The oxidation of quercetin, myricetin (MCE), and myricitrin (MCI) was studied in PBS buffer (pH = 7.4) using UV-vis spectrophotometry. ALS was used to determine the kinetic profiles and characteristic spectra, which were used to analyze UV-vis data of release from functionalized magnetic nanoparticles (MNPs). MNPs were selected for their unique magnetic properties, which can be exploited for both targeted drug delivery and control over the drug release. MNPs were prepared and characterized by X-ray diffraction, infrared spectroscopy, scanning electron microscopy, superconducting quantum interference device magnetometer, and electrophoretic mobility measurements. Autoxidation of all three flavonoids follows a two-step first-order kinetic model. MCE showed the fastest degradation, while the oxidation of MCI was the slowest. The flavonoids were successfully loaded into the prepared MNPs, and the drug release was described by the first-order and Korsmeyer-Peppas models. External MFs were utilized to control the release mechanism and the cumulative mass of the flavonoids released.}, }
@article {pmid37650499, year = {2023}, author = {Morichon, L and Hirtz, C and Tiers, L and Mezghrani, A and Raoul, C and Esselin, F and La Cruz, E and Julien, JP and Camu, W and Lehmann, S}, title = {Ultrasensitive digital immunoassays for SOD1 conformation in amyotrophic lateral sclerosis.}, journal = {Bioanalysis}, volume = {15}, number = {15}, pages = {927-936}, doi = {10.4155/bio-2023-0103}, pmid = {37650499}, issn = {1757-6199}, support = {misSOD1//ARSLA: Association pour la recherche sur la SLA/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Superoxide Dismutase-1 ; Biological Assay ; Immunoassay ; Molecular Conformation ; }, abstract = {Aim: The aim of this study was to detect misfolded Cu/Zn SOD1 as a potential biomarker for amyotrophic lateral sclerosis (ALS). Materials &amp; methods: Two ultrasensitive immunodetection assays were developed for the quantification of total and misfolded SOD1. Results: The detection of total and misfolded SOD1 was possible in human serum and cerebrospinal fluid. Total SOD1 was increased in cerebrospinal fluid from ALS patients. Misfolded SOD1 had low and variable expression in both control and ALS patient samples. Conclusion: These assays hold promise for improving our understanding of ALS and its detection, and could lead to more effective treatment options in the future. Further studies in larger cohorts are now required.}, }
@article {pmid37646130, year = {2023}, author = {Pattee, GL and Genge, A and Couratier, P and Lunetta, C and Sobue, G and Aoki, M and Yoshino, H and Jackson, CE and Wymer, J and Salah, A and Nelson, S}, title = {Oral Edaravone - Introducing a Flexible Treatment Option for Amyotrophic Lateral Sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {23}, number = {10}, pages = {859-866}, doi = {10.1080/14737175.2023.2251687}, pmid = {37646130}, issn = {1744-8360}, mesh = {Humans ; Edaravone/pharmacokinetics ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neurodegenerative Diseases/drug therapy ; Free Radical Scavengers/pharmacology ; Administration, Intravenous ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease. While pharmacotherapy options remain limited, the Food and Drug Administration (FDA) approved intravenous (IV) and oral edaravone for the treatment of ALS in 2017 and 2022, respectively. With the addition of oral edaravone, patients with ALS may exclusively use oral medications.<br><br>AREAS COVERED: The authors performed a review of the published literature using the United States (US) National Library of Medicine's PubMed.gov resource to describe the pharmacokinetics, pharmacodynamics, safety, and efficacy of oral edaravone, as well as pertinent completed and ongoing clinical trials, including the oral edaravone clinical trial development program. The clinical profile of oral edaravone is also discussed.<br><br>EXPERT OPINION: Edaravone has been shown to slow the rate of motor function deterioration experienced by patients with ALS. As the oral formulation has been approved, patients with ALS may use it alone or in combination with other approved therapeutics. Additional clinical trials and real-world evidence are ongoing to gain further understanding of the clinical profile of oral edaravone.}, }
@article {pmid37645251, year = {2023}, author = {Rojas, F and Aguilar, R and Almeida, S and Fritz, E and Corvalán, D and Ampuero, E and Abarzúa, S and Garcés, P and Amaro, A and Diaz, I and Arredondo, C and Cortes, N and Sanchez, M and Mercado, C and Varela-Nallar, L and Gao, FB and Montecino, M and van Zundert, B}, title = {Mature iPSC-derived astrocytes of an ALS/FTD patient carrying the TDP43[A90V] mutation display a mild reactive state and release polyP toxic to motoneurons.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1226604}, pmid = {37645251}, issn = {2296-634X}, support = {R01 NS101986/NS/NINDS NIH HHS/United States ; R21 NS119952/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; RF1 NS101986/NS/NINDS NIH HHS/United States ; }, abstract = {Astrocytes play a critical role in the maintenance of a healthy central nervous system and astrocyte dysfunction has been implicated in various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). There is compelling evidence that mouse and human ALS and ALS/FTD astrocytes can reduce the number of healthy wild-type motoneurons (MNs) in co-cultures or after treatment with astrocyte conditioned media (ACM), independently of their genotype. A growing number of studies have shown that soluble toxic factor(s) in the ACM cause non-cell autonomous MN death, including our recent identification of inorganic polyphosphate (polyP) that is excessively released from mouse primary astrocytes (SOD1, TARDBP, and C9ORF72) and human induced pluripotent stem cells (iPSC)-derived astrocytes (TARDBP) to kill MNs. However, others have reported that astrocytes carrying mutant TDP43 do not produce detectable MN toxicity. This controversy is likely to arise from the findings that human iPSC-derived astrocytes exhibit a rather immature and/or reactive phenotype in a number of studies. Here, we have succeeded in generating a highly homogenous population of functional quiescent mature astrocytes from control subject iPSCs. Using identical conditions, we also generated mature astrocytes from an ALS/FTD patient carrying the TDP43[A90V] mutation. These mutant TDP43 patient-derived astrocytes exhibit key pathological hallmarks, including enhanced cytoplasmic TDP-43 and polyP levels. Additionally, mutant TDP43 astrocytes displayed a mild reactive signature and an aberrant function as they were unable to promote synaptogenesis of hippocampal neurons. The polyP-dependent neurotoxic nature of the TDP43[A90V] mutation was further confirmed as neutralization of polyP in ACM derived from mutant TDP43 astrocytes prevented MN death. Our results establish that human astrocytes carrying the TDP43[A90V] mutation exhibit a cell-autonomous pathological signature, hence providing an experimental model to decipher the molecular mechanisms underlying the generation of the neurotoxic phenotype.}, }
@article {pmid37642362, year = {2023}, author = {Bireley, JD and Morren, JA}, title = {CNM-Au8: an experimental agent for the treatment of amyotrophic lateral sclerosis (ALS).}, journal = {Expert opinion on investigational drugs}, volume = {32}, number = {8}, pages = {677-683}, doi = {10.1080/13543784.2023.2252738}, pmid = {37642362}, issn = {1744-7658}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/pharmacokinetics/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Quality of Life ; Drugs, Investigational/therapeutic use ; }, abstract = {INTRODUCTION: Two established disease-specific therapies for the treatment of amyotrophic lateral sclerosis (ALS) are riluzole and edaravone. Limitations of these medications include minimal progression slowing or survival benefit, and effectiveness only in selected populations, particularly for edaravone. AMX0035 and tofersen received US FDA approval in September 2022 and April 2023, respectively. However, phase 3 trials, further examining both medications' efficacy, are ongoing. CNM-Au8 is an efficient catalyst of energy metabolism and is therefore a potential disease-modifying treatment for ALS, a neurodegenerative condition in which there is bioenergetics impairment.<br><br>AREAS COVERED: In this review, we provide an overview of the current ALS treatment market, followed by a description of the pharmacodynamics and pharmacokinetics of CNM-Au8. The main preclinical and available early clinical evidence of CNM-Au8 is then described, as well as its potential as an ALS treatment.<br><br>EXPERT OPINION: Oral treatment with CNM-Au8 failed to meet primary clinical and electrodiagnostic endpoints in phase 2/3 clinical trials. Despite this failure, a number of exploratory endpoints included in phase 2/3 trials suggest CNM-Au8 has the potential to significantly slow clinical worsening, improve quality of life, and prolong survival in ALS. Further study of CNM-Au8 in a phase 3 clinical trial is currently underway.}, }
@article {pmid37641579, year = {2024}, author = {Shefner, JM and Jacobsen, B and Kupfer, S and Malik, FI and Meng, L and Wei, J and Wolff, AA and Rudnicki, SA}, title = {Relationship between quantitative strength and functional outcomes in the phase 2 FORTITUDE-ALS trial.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {162-169}, doi = {10.1080/21678421.2023.2252468}, pmid = {37641579}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Hand Strength ; Quality of Life ; Surveys and Questionnaires ; Muscle Strength ; Disease Progression ; }, abstract = {OBJECTIVE: To assess the relationship among measurements of strength, function, and quality of life in an amyotrophic lateral sclerosis (ALS) clinical trial.<br><br>METHODS: In the FORTITUDE-ALS clinical trial (NCT03160898), 456 participants in the full-analysis set were treated with either reldesemtiv or placebo for 12 weeks; this post hoc analysis included all participants regardless of treatment assignments. Assessments included slow vital capacity (SVC), the ALS Functional Rating Scale-Revised (ALSFRS-R), and the 5-item ALS Assessment Questionnaire (ALSAQ-5). Muscle strength was measured quantitatively with hand-held dynamometry, and grip strength with a dedicated dynamometer. The relationship between strength and ALSFRS-R fine and gross motor domain scores, or responses to ALSAQ-5 questions on hand function and walking, was assessed with Spearman's rank correlation. The relationship between mean upper- or lower-extremity muscle strength and specific ALSFRS-R domains was modeled using principal-components analysis.<br><br>RESULTS: Upper-extremity muscle strength and hand grip were highly correlated with ALSFRS-R fine motor scores and the ALSAQ-5 hand function question. Similarly, lower-extremity strength correlated well with ALSFRS-R gross motor domain and the ALSAQ-5 walking question. For SVC, correlation was poor with the ALSFRS-R respiratory domain, but stronger with the total score, potentially reflecting the insensitivity of the respiratory questions in the scale. Upper- and lower-extremity strength were both strong predictors of ALSFRS-R domain scores.<br><br>CONCLUSIONS: In this analysis of data from an ALS clinical trial, muscle strength quantified by dynamometry was strongly correlated with functional capacity. These results suggest that muscle strength directly relates to specific functions of importance to people with ALS.}, }
@article {pmid37636024, year = {2023}, author = {Nouri Nojadeh, J and Bildiren Eryilmaz, NS and Ergüder, BI}, title = {CRISPR/Cas9 genome editing for neurodegenerative diseases.}, journal = {EXCLI journal}, volume = {22}, number = {}, pages = {567-582}, pmid = {37636024}, issn = {1611-2156}, abstract = {Gene therapy has emerged as a promising therapeutic strategy for various conditions, including blood disorders, ocular disease, cancer, and nervous system disorders. The advent of gene editing techniques has facilitated the ability of researchers to specifically target and modify the eukaryotic cell genome, making it a valuable tool for gene therapy. This can be performed through either in vivo or ex vivo approaches. Gene editing tools, such as zinc finger nucleases, transcription activator-like effector nucleases, and CRISPR-Cas-associated nucleases, can be employed for gene therapy purposes. Among these tools, CRISPR-Cas-based gene editing stands out because of its ability to introduce heritable genome changes by designing short guide RNAs. This review aims to provide an overview of CRISPR-Cas technology and summarizes the latest research on the application of CRISPR/Cas9 genome editing technology for the treatment of the most prevalent neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Spinocerebellar ataxia.}, }
@article {pmid37632964, year = {2023}, author = {Wang, T and Yang, X and Du, R and Zheng, S and Cui, H}, title = {Acupuncture in the Treatment of Amyotrophic Lateral Sclerosis: A Research Progress in Clinical Trials.}, journal = {Alternative therapies in health and medicine}, volume = {29}, number = {7}, pages = {114-118}, pmid = {37632964}, issn = {1078-6791}, abstract = {BACKGROUND: Acupuncture, a complementary and alternative medicine (CAM) modality, shows promise as an integrative therapy for Amyotrophic Lateral Sclerosis (ALS) due to the chronic nature of the disease and its persistent symptoms. Many patients turn to CAM for ALS treatment.<br><br>OBJECTIVE: This review assesses acupuncture's efficacy in treating Amyotrophic Lateral Sclerosis.<br><br>METHODS: We searched China National Knowledge Network (CNKI) and PubMed databases for Chinese and English articles, including clinical trials, case studies, cohorts, and randomized controlled trials. The search, performed on March 31, 2023, encompassed literature published up to that date. Keywords used in titles and abstracts were (acupuncture) OR (electro-acupuncture)) AND (Amyotrophic Lateral Sclerosis).<br><br>RESULTS: Among the 45 articles studied, 34 were included in this research. Acupuncture's benefits primarily lie in neuro-immune system regulation, enhanced quality of life, reduced fatigue, disease progression delay, and fewer relapses.<br><br>CONCLUSIONS: Recent clinical trials highlight the potential of traditional Chinese acupuncture in improving Amyotrophic Lateral Sclerosis symptoms (e.g., fatigue, neural functional deficits) and curtailing relapses. Consequently, acupuncture holds promise as an integrative therapy for ALS patients.}, }
@article {pmid37627315, year = {2023}, author = {Kandeel, M and Morsy, MA and Alkhodair, KM and Alhojaily, S}, title = {Mesenchymal Stem Cell-Derived Extracellular Vesicles: An Emerging Diagnostic and Therapeutic Biomolecules for Neurodegenerative Disabilities.}, journal = {Biomolecules}, volume = {13}, number = {8}, pages = {}, pmid = {37627315}, issn = {2218-273X}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis ; *Mesenchymal Stem Cells ; *Adult Stem Cells ; *Alzheimer Disease ; *Extracellular Vesicles ; *Huntington Disease ; *Multiple Sclerosis ; *Parkinson Disease/diagnosis/therapy ; }, abstract = {Mesenchymal stem cells (MSCs) are a type of versatile adult stem cells present in various organs. These cells give rise to extracellular vesicles (EVs) containing a diverse array of biologically active elements, making them a promising approach for therapeutics and diagnostics. This article examines the potential therapeutic applications of MSC-derived EVs in addressing neurodegenerative disorders such as Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Furthermore, the present state-of-the-art for MSC-EV-based therapy in AD, HD, PD, ALS, and MS is discussed. Significant progress has been made in understanding the etiology and potential treatments for a range of neurodegenerative diseases (NDs) over the last few decades. The contents of EVs are carried across cells for intercellular contact, which often results in the control of the recipient cell's homeostasis. Since EVs represent the therapeutically beneficial cargo of parent cells and are devoid of many ethical problems connected with cell-based treatments, they offer a viable cell-free therapy alternative for tissue regeneration and repair. Developing innovative EV-dependent medicines has proven difficult due to the lack of standardized procedures in EV extraction processes as well as their pharmacological characteristics and mechanisms of action. However, recent biotechnology and engineering research has greatly enhanced the content and applicability of MSC-EVs.}, }
@article {pmid37620092, year = {2023}, author = {Fink, JK}, title = {The hereditary spastic paraplegias.}, journal = {Handbook of clinical neurology}, volume = {196}, number = {}, pages = {59-88}, doi = {10.1016/B978-0-323-98817-9.00022-3}, pmid = {37620092}, issn = {0072-9752}, mesh = {Child, Preschool ; Humans ; *Spastic Paraplegia, Hereditary/genetics ; Biological Transport ; *Cerebral Palsy ; Exercise ; Family ; }, abstract = {The hereditary spastic paraplegias (HSPs) are a group of more than 90 genetic disorders in which lower extremity spasticity and weakness are either the primary neurologic impairments ("uncomplicated HSP") or when accompanied by other neurologic deficits ("complicated HSP"), important features of the clinical syndrome. Various genetic types of HSP are inherited such as autosomal dominant, autosomal recessive, X-linked, and maternal (mitochondrial) traits. Symptoms that begin in early childhood may be nonprogressive and resemble spastic diplegic cerebral palsy. Symptoms that begin later, typically progress insidiously over a number of years. Genetic testing is able to confirm the diagnosis for many subjects. Insights from gene discovery indicate that abnormalities in diverse molecular processes underlie various forms of HSP, including disturbance in axon transport, endoplasmic reticulum morphogenesis, vesicle transport, lipid metabolism, and mitochondrial function. Pathologic studies in "uncomplicated" HSP have shown axon degeneration particularly involving the distal ends of corticospinal tracts and dorsal column fibers. Treatment is limited to symptom reduction including amelioration of spasticity, reducing urinary urgency, proactive physical therapy including strengthening, stretching, balance, and agility exercise.}, }
@article {pmid37620070, year = {2023}, author = {Younger, DS and Brown, RH}, title = {Amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {196}, number = {}, pages = {203-229}, doi = {10.1016/B978-0-323-98817-9.00031-4}, pmid = {37620070}, issn = {0072-9752}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Motor Neurons ; Syndrome ; }, abstract = {The scientific landscape surrounding amyotrophic lateral sclerosis has shifted immensely with a number of well-defined ALS disease-causing genes, each with related phenotypical and cellular motor neuron processes that have come to light. Yet in spite of decades of research and clinical investigation, there is still no etiology for sporadic amyotrophic lateral sclerosis, and treatment options even for those with well-defined familial syndromes are still limited. This chapter provides a comprehensive review of the genetic basis of amyotrophic lateral sclerosis, highlighting factors that contribute to its heritability and phenotypic manifestations, and an overview of past, present, and upcoming therapeutic strategies.}, }
@article {pmid37619619, year = {2023}, author = {Wang, Y and Lv, MN and Zhao, WJ}, title = {Research on ferroptosis as a therapeutic target for the treatment of neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {91}, number = {}, pages = {102035}, doi = {10.1016/j.arr.2023.102035}, pmid = {37619619}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Ferroptosis ; *Alzheimer Disease/drug therapy ; *Parkinson Disease/drug therapy ; *Huntington Disease ; }, abstract = {Ferroptosis is an iron- and lipid peroxidation (LPO)-mediated programmed cell death type. Recently, mounting evidence has indicated the involvement of ferroptosis in neurodegenerative diseases, especially in Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and so on. Treating ferroptosis presents opportunities as well as challenges for neurodegenerative diseases. This review provides a comprehensive overview of typical features of ferroptosis and the underlying mechanisms that contribute to its occurrence, as well as their implications in the pathogenesis and advancement of major neurodegenerative disorders. Meanwhile, we summarize the utilization of ferroptosis inhibition in both experimental and clinical approaches for the treatment of major neurodegenerative disorders. In addition, we specifically summarize recent advances in developing therapeutic means targeting ferroptosis in these diseases, which may guide future approaches for the effective management of these devastating medical conditions.}, }
@article {pmid37619554, year = {2023}, author = {Cheesbrough, A and Harley, P and Riccio, F and Wu, L and Song, W and Lieberam, I}, title = {A scalable human iPSC-based neuromuscular disease model on suspended biobased elastomer nanofiber scaffolds.}, journal = {Biofabrication}, volume = {15}, number = {4}, pages = {}, pmid = {37619554}, issn = {1758-5090}, support = {/DH_/Department of Health/United Kingdom ; MR/W006251/1/MRC_/Medical Research Council/United Kingdom ; MR/N026063/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; BB/M009513/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MR/N025865/1/MRC_/Medical Research Council/United Kingdom ; 108874/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; WT098503/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Induced Pluripotent Stem Cells ; *Nanofibers ; Elastomers ; *Neuromuscular Diseases ; }, abstract = {Many devastating neuromuscular diseases currently lack effective treatments. This is in part due to a lack of drug discovery platforms capable of assessing complex human neuromuscular disease phenotypes in a scalable manner. A major obstacle has been generating scaffolds to stabilise mature contractile myofibers in a multi-well assay format amenable to high content image (HCI) analysis. This study describes the development of a scalable human induced pluripotent stem cell (iPSC)-neuromuscular disease model, whereby suspended elastomer nanofibers support long-term stability, alignment, maturation, and repeated contractions of iPSC-myofibers, innervated by iPSC-motor neurons in 96-well assay plates. In this platform, optogenetic stimulation of the motor neurons elicits robust myofiber-contractions, providing a functional readout of neuromuscular transmission. Additionally, HCI analysis provides rapid and automated quantification of axonal outgrowth, myofiber morphology, and neuromuscular synapse number and morphology. By incorporating amyotrophic lateral sclerosis (ALS)-related TDP-43[G298S]mutant motor neurons and CRISPR-corrected controls, key neuromuscular disease phenotypes are recapitulated, including weaker myofiber contractions, reduced axonal outgrowth, and reduced number of neuromuscular synapses. Treatment with a candidate ALS drug, the receptor-interacting protein kinase-1 (RIPK1)-inhibitor necrostatin-1, rescues these phenotypes in a dose-dependent manner, highlighting the potential of this platform to screen novel treatments for neuromuscular diseases.}, }
@article {pmid37610866, year = {2023}, author = {Kołodziej, D and Sobczak, &#x141; and Łączkowski, KZ}, title = {New opportunities for treatment and prevention of neurodegenerative diseases with PTP1B inhibitors.}, journal = {Future medicinal chemistry}, volume = {15}, number = {16}, pages = {1443-1447}, doi = {10.4155/fmc-2023-0187}, pmid = {37610866}, issn = {1756-8927}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/prevention &amp; control ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis ; }, }
@article {pmid37610446, year = {2023}, author = {Bombaci, A and Lupica, A and Pozzi, FE and Remoli, G and Manera, U and Di Stefano, V}, title = {Sensory neuropathy in amyotrophic lateral sclerosis: a systematic review.}, journal = {Journal of neurology}, volume = {270}, number = {12}, pages = {5677-5691}, pmid = {37610446}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; *Neurodegenerative Diseases ; Quality of Life ; Motor Neurons/physiology ; Electromyography ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of both upper and lower motoneurons, leading to motor and non-motor symptoms. Recent evidence suggests that ALS is indeed a multisystem disorder, associated with cognitive impairment, dysautonomia, pain and fatigue, excess of secretions, and sensory symptoms. To evaluate whether sensory neuropathy could broaden its spectrum, we systematically reviewed its presence and characteristics in ALS, extracting data on epidemiological, clinical, neurophysiological, neuropathological, and genetic features. Sensory neuropathy can be found in up to 20% of ALS patients, affecting both large and small fibers, although there is a great heterogeneity related to different techniques used for its detection (electromyography vs skin biopsy vs nerve biopsy). Moreover, the association between CIDP-like neuropathy and ALS needs to be better explored, although it could be interpreted as part of the neuroinflammatory process in the latter disease. Sensory neuropathy in ALS may be associated with a spinal onset and might be more frequent in SOD1 patients. Moreover, it seems mutually exclusive with cognitive impairment. No associations with sex and other genetic mutation were observed. All these data in the literature reveal the importance of actively looking for sensory neuropathy in ALS patients, and suggest including sensory neuropathy among ALS non-motor features, as it may explain sensory symptoms frequently reported throughout the course of the disease. Its early identification could help avoid diagnostic delays and improve patients' treatment and quality of life.}, }
@article {pmid37607205, year = {2023}, author = {Keifer, OP and Gutierrez, J and Butt, MT and Cramer, SD and Bartus, R and Tansey, M and Deaver, D and Betourne, A and Boulis, NM}, title = {Spinal cord and brain concentrations of riluzole after oral and intrathecal administration: A potential new treatment route for amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {18}, number = {8}, pages = {e0277718}, pmid = {37607205}, issn = {1932-6203}, mesh = {Humans ; Animals ; Dogs ; *Amyotrophic Lateral Sclerosis/drug therapy ; Riluzole/therapeutic use ; Brain ; Administration, Oral ; *Drug-Related Side Effects and Adverse Reactions ; }, abstract = {Riluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and clearance, is formulated as an oral drug in a patient population plagued with dysphagia, and has known systemic side-effects like asthenia (limiting patient compliance) and elevated liver enzymes. In this context, we postulated that continuous intrathecal (IT) infusion of low doses of riluzole could provide consistent elevations of the drug spinal cord (SC) concentrations at or above those achieved with oral dosing, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects in the brain. We developed a formulation of riluzole for IT delivery and conducted our studies in purpose-bred hound dogs. Our non-GLP studies revealed that IT infusion alone was able to increase SC concentrations above those provided by oral administration, without increasing plasma concentrations. We then conducted two GLP studies that combined IT infusion with oral administration at human equivalent dose, to evaluate SC and brain concentrations of riluzole along with assessments of safety and tolerability. In the 6-week study, the highest IT dose (0.2 mg/hr) was well tolerated by the animals and increased SC concentrations above those achieved with oral riluzole alone, without increasing brain concentrations. In the 6-month study, the highest dose tested (0.4 mg/hr) was not tolerated and yielded SC significantly above those achieved in all previous studies. Our data show the feasibility and safety profile of continuous IT riluzole delivery to the spinal cord, without concurrent elevated liver enzymes, and minimal brain concentrations creating another potential therapeutic route of delivery to be used in isolation or in combination with other therapeutics."}, }
@article {pmid37605404, year = {2024}, author = {De, SK}, title = {New Pyrrolopyrimidines as LRRK2 Inhibitors for Treating Parkinson's Disease.}, journal = {Current medicinal chemistry}, volume = {31}, number = {33}, pages = {5477-5480}, pmid = {37605404}, issn = {1875-533X}, mesh = {Humans ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists &amp; inhibitors/metabolism ; *Parkinson Disease/drug therapy/metabolism ; *Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use ; *Pyrimidines/chemistry/pharmacology/therapeutic use ; *Pyrroles/chemistry/pharmacology/therapeutic use ; Patents as Topic ; }, abstract = {This patent describes the novel pyrroloppyrimidine compounds as LRRK2 kinase inhibitors. The patent includes the synthesis of compounds, compositions containing them and their use in the treatment of or prevention of diseases associated with LRRK2 kinase activity, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).}, }
@article {pmid37604125, year = {2023}, author = {Lee, SW and Lyu, YR and Yang, WK and Kim, SH and Kim, SY and Kang, W and Jung, IC and Lee, BJ and Choi, JY and Lee, MY and Park, YC}, title = {Efficacy and Safety of Yukmijihwang-Tang in the Treatment of Cough-Variant Asthma: Study Protocol for a Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.}, journal = {Complementary medicine research}, volume = {30}, number = {5}, pages = {424-430}, doi = {10.1159/000533252}, pmid = {37604125}, issn = {2504-2106}, mesh = {Humans ; *Cough/drug therapy ; *Asthma/drug therapy ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; Clinical Trials, Phase II as Topic ; }, abstract = {BACKGROUND: Cough-variant asthma (CVA), a precursor of typical asthma, is the main cause of chronic cough. We hypothesize that yukmijihwang-tang (YJT), which has been used for chronic cough in traditional medicine and has been reported to have an anti-inflammatory effect, could be an adjuvant to asthma treatment.<br><br>METHODS: We plan a randomized, double-blind, placebo-controlled, multicenter, phase 2 trial to investigate the efficacy and safety of YJT in CVA patients. A total of 60 patients with CVA will be recruited and randomly assigned to either a high-dose YJT group, standard-dose YJT group, or control group (placebo) in a 1:1:1 allocation ratio after a 2-week run-in period. For the run-in period, only inhaled corticosteroids (ICSs) will be used, and the investigational drug will be administered once a day with concomitant ICS for 6 weeks. Data will be collected at baseline, week 3, and week 6, and the primary outcome measure will be the mean cough symptom score (CSS) change before and after medication. The secondary outcome measures will include the Leicester cough questionnaire-Korean version (LCQ-K) score, eosinophil count and eosinophil cationic protein level, pulmonary function test, and the number of uses of rescue medication, and so on.<br><br>CONCLUSION: This study aimed to evaluate the efficacy and safety of YJT in concomitant treatment with ICS in patients with CVA and to determine the optimal dosage of YJT. The results are expected to provide evidence for the use of YJT as an adjuvant treatment for CVA.<br><br>UNLABELLED: <title>Hintergrund</title>Cough-Variant-Asthma (CVA), eine Fr&#xfc;hform von typischem Asthma, ist die Hauptursache von chronischem Husten. Unserer Vermutung nach k&#xf6;nnte Yukmijihwang-Tang (YJT), das in der traditionellen Medizin zur Behandlung von chronischem Husten eingesetzt wird und das Berichten zufolge einen entz&#xfc;ndungshemmenden Effekt hat, unterst&#xfc;tzend in der Asthma-Therapie wirken.<title>Method</title>en: Wir planen eine randomisierte, doppelblinde, placebokontrollierte, multizentrische Phase-2-Studie, um die Wirksamkeit und Sicherheit von YJT bei Patienten mit CVA zu untersuchen. Insgesamt werden 60 CVA-Patienten f&#xfc;r die Studie rekrutiert und nach einer zweiw&#xf6;chigen Run-in-Phase randomisiert im Verh&#xe4;ltnis 1:1:1 einer Gruppe mit hochdosiertem YJT, einer Gruppe, die YJT in der Standarddosierung erh&#xe4;lt oder einer Kontrollgruppe (Placebo) zugewiesen. W&#xe4;hrend der Run-in-Phase werden nur inhalative Corticosteroide (ICS) verwendet, und das Pr&#xfc;fpr&#xe4;parat wird &#xfc;ber 6 Wochen einmal t&#xe4;glich gleichzeitig mit den ICS angewendet. Die Datenerhebung erfolgt bei Studienbeginn, in Woche 3 sowie in Woche 6, und das prim&#xe4;re Zielkriterium ist die &#xc4;nderung des mittleren Hustenscores (cough symptom score, CSS) vor und nach der Anwendung der Medikamente. Zu den sekund&#xe4;ren Zielkriterien geh&#xf6;ren der Score des Leicester Hustenfragebogens - koreanische Version (LCQ-K), die Eosinophilenzahl und der Spiegel an eosinophilem kationischen Protein, Lungenfunktionstests sowie die Anzahl der Anwendungen von Bedarfsmedikation usw.<title>Schlussfolgerung</title>Ziel dieser Studie ist es, die Wirksamkeit und Sicherheit von YJT bei gleichzeitiger Behandlung mit ICS bei Patienten mit CVA zu bewerten und die optimale YJT-Dosis zu ermitteln. Es wird erwartet, dass die Ergebnisse Belege f&#xfc;r die Anwendung von YJT als adjuvante Therapie bei CVA liefern werden.<title>Registrierung der Studie</title>WHO International Clinical Trials Registry Platform, Clinical Research Information Service (CRIS), KCT0006994, registriert am 10. Februar 2022, <ext-link ext-link-type="uri" xlink:href="https://cris.nih.go.kr/cris/search/detailSearch.do/217431" xmlns:xlink="http://www.w3.org/1999/xlink">https://cris.nih.go.kr/cris/search/detailSearch.do/21743</ext-link>.}, }
@article {pmid37600635, year = {2023}, author = {Fathi, M and Sedaghat, M and Ahadi, H}, title = {Quality of Life of Amyotrophic Lateral Sclerosis Patients in Iran.}, journal = {Medical journal of the Islamic Republic of Iran}, volume = {37}, number = {}, pages = {76}, pmid = {37600635}, issn = {1016-1430}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rare disease that can bring different emotional, physical, and psychological burdens. This study aimed to investigate the quality of life in patients with ALS.<br><br>METHODS: This is a cross-sectional study. Fifty-two patients contributed in this study. The setting was an ALS clinic in Iran. A mixed method was used in this study. We applied a short form of the WHO Quality of Life questionnaire (WHOQOL) to measure the quality of life of patients. Also, all participants were interviewed through the semi-structured interview guide. To measure physical strength and functioning the Appel ALS Rating Scale (AALS) was employed in this study. To analyze the data, a two-tailed t-test and x2 test were used.<br><br>RESULTS: 42.3% of the participants were female. The age of the participants ranged between 28 to 81 (mean=57.6). The disease duration ranged from 0.07 to 14 years (mean=1.8). The overall mean QOL was 58.7 (&#xb1;8.1). The overall mean of the AALS score was 74.4 (&#xb1;24.2). The results of the qualitative part of the study showed four psychosocial themes: (1) internal personality traits, communicating with friends and family; (2) religion and spirituality; (3) stress, mood changes, and difficult relationship; and (4) changes in lifestyle, work, leisure time and financial situation.<br><br>CONCLUSION: Despite recent advances, ALS is still one of the diseases for which there is no effective treatment. Paying attention to psychosocial issues in patients with ALS can play a very important role in increasing the quality of life of patients.}, }
@article {pmid37591957, year = {2023}, author = {Mandrioli, J and D'Amico, R and Zucchi, E and De Biasi, S and Banchelli, F and Martinelli, I and Simonini, C and Lo Tartaro, D and Vicini, R and Fini, N and Gianferrari, G and Pinti, M and Lunetta, C and Gerardi, F and Tarlarini, C and Mazzini, L and De Marchi, F and Scognamiglio, A and Sorarù, G and Fortuna, A and Lauria, G and Bella, ED and Caponnetto, C and Meo, G and Chio, A and Calvo, A and Cossarizza, A}, title = {Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {4970}, pmid = {37591957}, issn = {2041-1723}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Interleukin-18 ; Quality of Life ; Ribosomal Proteins ; Autophagy ; }, abstract = {In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells, and affecting autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/m[2]/day,1 mg/m[2]/day or placebo (EUDRACT 2016-002399-28; NCT03359538). The primary outcome, the number of patients exhibiting an increase >30% in regulatory T cells from baseline to treatment end, was not attained. Secondary outcomes were changes from baseline of T, B, NK cell subpopulations, inflammasome mRNA expression and activation status, S6-ribosomal protein phosphorylation, neurofilaments; clinical outcome measures of disease progression; survival; safety and quality of life. Of the secondary outcomes, rapamycin decreased mRNA relative expression of the pro-inflammatory cytokine IL-18, reduced plasmatic IL-18 protein, and increased the percentage of classical monocytes and memory switched B cells, although no corrections were applied for multiple tests. In conclusion, we show that rapamycin treatment is well tolerated and provides reassuring safety findings in ALS patients, but further trials are necessary to understand the biological and clinical effects of this drug in ALS.}, }
@article {pmid37590829, year = {2023}, author = {Lee-Iannotti, JK}, title = {Sleep Disorders in Patients with Neurologic Disease.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {29}, number = {4}, pages = {1188-1204}, pmid = {37590829}, issn = {1538-6899}, mesh = {Humans ; *Neurodegenerative Diseases ; *Sleep Wake Disorders/complications/diagnosis ; *Parkinson Disease ; *Multiple Sclerosis ; *Stroke ; }, abstract = {OBJECTIVE: This article provides an overview of the growing body of evidence showing bidirectional relationships between sleep and various neurologic disorders.<br><br>LATEST DEVELOPMENTS: Mounting evidence demonstrates that disrupted sleep can negatively impact various neurologic disease processes, including stroke, multiple sclerosis, epilepsy, neuromuscular disorders including amyotrophic lateral sclerosis, and headache syndromes. Abnormal sleep can also be a precursor to Alzheimer disease and neurodegenerative disease states such as Parkinson disease and dementia with Lewy bodies. Interventions to improve sleep and treat obstructive sleep apnea may play a vital role in preventing neurologic disease development and progression.<br><br>ESSENTIAL POINTS: Sleep disorders are common among patients with neurologic disorders. To provide comprehensive care to patients with neurologic conditions, neurologists must ask patients about sleep issues that may warrant further diagnostic testing, treatment, and sleep medicine referral when indicated.}, }
@article {pmid37582053, year = {2024}, author = {Assoni, AF and Guerrero, EN and Wardenaar, R and Oliveira, D and Bakker, PL and Alves, LM and Carvalho, VM and Okamoto, OK and Zatz, M and Foijer, F}, title = {IFNγ protects motor neurons from oxidative stress via enhanced global protein synthesis in FUS-associated amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {1}, pages = {e13206}, pmid = {37582053}, issn = {1750-3639}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Motor Neurons/metabolism ; Mutation ; Oxidative Stress ; RNA-Binding Protein FUS/genetics ; }, abstract = {Amyotrophic lateral sclerosis type 6 (ALS6) is a familial subtype of ALS linked to Fused in Sarcoma (FUS) gene mutation. FUS mutations lead to decreased global protein synthesis, but the mechanism that drives this has not been established. Here, we used ALS6 patient-derived induced pluripotent stem cells (hIPSCs) to study the effect of the ALS6 FUS[R521H] mutation on the translation machinery in motor neurons (MNs). We find, in agreement with findings of others, that protein synthesis is decreased in FUS[R521H] MNs. Furthermore, FUS[R521H] MNs are more sensitive to oxidative stress and display reduced expression of TGF-β and mTORC gene pathways when stressed. Finally, we show that IFNγ treatment reduces apoptosis of FUS[R521H] MNs exposed to oxidative stress and partially restores the translation rates in FUS[R521H] MNs. Overall, these findings suggest that a functional IFNγ response is important for FUS-mediated protein synthesis, possibly by FUS nuclear translocation in ALS6.}, }
@article {pmid37581487, year = {2023}, author = {van Roon-Mom, W and Ferguson, C and Aartsma-Rus, A}, title = {From Failure to Meet the Clinical Endpoint to U.S. Food and Drug Administration Approval: 15th Antisense Oligonucleotide Therapy Approved Qalsody (Tofersen) for Treatment of SOD1 Mutated Amyotrophic Lateral Sclerosis.}, journal = {Nucleic acid therapeutics}, volume = {33}, number = {4}, pages = {234-237}, doi = {10.1089/nat.2023.0027}, pmid = {37581487}, issn = {2159-3345}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Mutation ; *Oligonucleotides, Antisense/therapeutic use ; Superoxide Dismutase-1/genetics ; United States ; United States Food and Drug Administration ; Drug Approval ; Endpoint Determination ; }, }
@article {pmid37576491, year = {2023}, author = {Seidel, M and Rajkumar, S and Steffke, C and Noeth, V and Agarwal, S and Roger, K and Lipecka, J and Ludolph, A and Guerrera, CI and Boeckers, T and Catanese, A}, title = {Propranolol reduces the accumulation of cytotoxic aggregates in C9orf72-ALS/FTD in vitro models.}, journal = {Current research in neurobiology}, volume = {5}, number = {}, pages = {100105}, pmid = {37576491}, issn = {2665-945X}, abstract = {Mutations in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The pathogenetic mechanisms linked to this gene are a direct consequence of an aberrant intronic expansion of a GGGGCC hexanucleotide located between the 1a and 1b non-coding exons, which can be transcribed to form cytotoxic RNA foci or even translated into aggregation-prone dipeptide repeat proteins. Importantly, the abnormal length of these repeats affects also the expression levels of C9orf72 itself, which suggests haploinsufficiency as additional pathomechanism. Thus, it appears that both toxic gain of function and loss of function are distinct but still coexistent features contributing to the insurgence of the disease in case of C9orf72 mutations. In this study, we aimed at identifying a strategy to address both aspects of the C9orf72-related pathobiochemistry and provide proof-of-principle information for a better understanding of the mechanisms leading to neuronal loss. By using primary neurons overexpressing toxic poly(GA), the most abundant protein product of the GGGGCC repeats, we found that the antiarrhythmic drug propranolol could efficiently reduce the accumulation of aberrant aggregates and increase the survival of C9orf72-related cultures. Interestingly, the improved catabolism appeared to not depend on major degradative pathways such as autophagy and the proteasome. By analyzing the proteome of poly(GA)-expressing neurons after exposure to propranolol, we found that the drug increased lysosomal degradation through a mechanism directly involving C9orf72 protein, whose levels were increased after treatment. Further confirmation of the beneficial effect of the beta blocker on aggregates' accumulation and survival of hiPSC-derived C9orf72-mutant motoneurons strengthened the finding that addressing both facets of C9orf72 pathology might represent a valid strategy for the treatment of these ALS/FTD cases.}, }
@article {pmid37573779, year = {2023}, author = {Zhang, Z and Zhu, Y and Zhu, C and Li, S and Zhao, Y and Yang, J and Qin, Y and Hou, J and Zhang, J and Han, C}, title = {Effects of Dihuang Yinzi Decoction on Alzheimer's Disease: A Systematic Review and Meta-Analysis.}, journal = {Complementary medicine research}, volume = {30}, number = {5}, pages = {440-452}, doi = {10.1159/000531931}, pmid = {37573779}, issn = {2504-2106}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Treatment Outcome ; *Medicine ; Medicine, Chinese Traditional ; China ; }, abstract = {OBJECTIVE: The aim of this study was to systematically evaluate the therapeutic effects of Dihuang Yinzi decoction on Alzheimer's disease (AD) and provide a medical evidence-based clinical application of traditional Chinese medicine (TCM).<br><br>METHODS: A comprehensive search was conducted across multiple databases, including PubMed, Embase, Cochrane Library, China National Journals Full-text Database, VIP Database for Chinese Technical Periodicals, Wan Fang database, and SinoMed database, to collect clinical randomized controlled trials of Dihuang Yinzi decoction in the treatment of AD. Strict literature screening was performed based on predefined inclusion and exclusion criteria. The Cochrane Collaboration risk of bias assessment tool and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system recommendation-level method was used to assess the quality of the included studies. Review Manager 5.4 and Stata 17 software were used for data synthesis and processing, while GRADE Profiler 3.6 software was used to evaluate the quality of evidence for outcome indicators (risk ratio, standardized mean difference, and weighted mean difference).<br><br>RESULTS: A total of 11 studies involving 798 patients met the inclusion criteria. Dihuang Yinzi decoction, whether used alone or in combination with conventional Western medicine, demonstrated superior efficacy compared to conventional Western medicine alone in improving the clinical effective rate, TCM syndrome score, activity of daily living score, Mini-Mental State Examination score, and Hasegawa Dementia Scale score in AD treatment. Furthermore, it exhibited a favorable safety profile. However, the GRADE evidence quality rating for the included studies was low.<br><br>CONCLUSIONS: Dihuang Yinzi decoction, either used alone or in combination with conventional Western medicine, shows promising results in enhancing cognitive and memory functions as well as the self-care ability of patients with AD. However, the low GRADE evidence quality rating highlights the need for focused advancements in the planning and execution of clinical randomized controlled trials during future research attempts.<br><br>UNLABELLED: <title>ZIEL</title>Ziel dieser Studie ist es, die therapeutischen Effekte von Dihuang Yinzi-Dekokt auf die Alzheimer-Krankheit systematisch zu bewerten und eine evidenzbasierte klinische Anwendung der traditionellen chinesischen Medizin (TCM) bereitzustellen.<title>Methoden</title>Es wurde eine umfassende Suche in mehreren Datenbanken, darunter PubMed, Embase, Cochrane Library, China National Journals Volltext-Datenbank, VIP Database for Chinese Technical Periodicals, Wan Fang Datenbank und SinoMed-Datenbank durchgef&#xfc;hrt, um randomisierte, kontrollierte klinische Studien zu Dihuang Yinzi-Dekokt in der Behandlung der Alzheimer-Krankheit zu erfassen. Die strenge Literatursuche erfolgte auf Grundlage von vordefinierten Ein-und Ausschlusskriterien. Zur Bewertung der Qualit&#xe4;t der eingeschlossenen Studien wurden das Risk-of-Bias-Tool von Cochrane und das GRADE (Grading of Recommendations Assessment, Development, and Evaluation)-System zur Beurteilung der Empfehlungsgrade herangezogen. Die Datensynthese und -verarbeitung erfolgten mithilfe der Review Manager 5.4- und der Stata 17-Software, w&#xe4;hrend f&#xfc;r die Bewertung der Evidenzqualit&#xe4;t der Outcome-Indikatoren (Risikoverh&#xe4;ltnis, standardisierte Mittelwertdifferenz und gewichtete Mittelwertdifferenz) die Software GRADE Profiler 3.6 verwendet wurde.<title>Ergebnisse</title>Insgesamt erf&#xfc;llten 11 Studien, an denen 798 Patienten teilnahmen, die Einschlusskriterien. Dihuang Yinzi-Dekokt zeigte allein oder in Kombination mit konventioneller westlicher Medizin eine &#xfc;berlegene Wirksamkeit gegen&#xfc;ber der alleinigen Verwendung von konventioneller westlicher Medizin in Bezug auf die klinische Gesamtwirksamkeitsrate, den TCM-Syndrom-Score, den Score f&#xfc;r die Alltagsaktivit&#xe4;ten, den Mini-Mental State Examination-Score und den Score der Hasegawa-Demenz-Skala in der Behandlung der Alzheimer-Krankheit. Dar&#xfc;ber hinaus wies es ein g&#xfc;nstiges Sicherheitsprofil auf. Die Evidenzqualit&#xe4;t der eingeschlossenen Studien gem&#xe4;&#xdf; GRADE wurde jedoch als gering eingestuft.<title>Schlussfolgerungen</title>Dihuang Yinzi-Dekokt zeigt allein oder in Kombination mit konventioneller westlicher Medizin vielversprechende Ergebnisse in Bezug auf die Verbesserung der kognitiven und Ged&#xe4;chtnisfunktionen sowie die Selbstversorgungsf&#xe4;higkeit von Alzheimer-Patienten. Die niedrige Bewertung der Evidenzqualit&#xe4;t gem&#xe4;&#xdf; GRADE unterstreicht jedoch die Notwendigkeit von zielgerichteten Weiterentwicklungen bei der Planung und Durchf&#xfc;hrung von randomisierten, kontrollierten klinischen Studien in zuk&#xfc;nftigen Forschungsunternehmungen.}, }
@article {pmid39291146, year = {2023}, author = {Mathew, AM and Bhuvanendran, S and Nair, RS and K Radhakrishnan, A}, title = {Exploring the anti-inflammatory activities, mechanism of action and prospective drug delivery systems of tocotrienol to target neurodegenerative diseases.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {338}, pmid = {39291146}, issn = {2046-1402}, abstract = {A major cause of death in the elderly worldwide is attributed to neurodegenerative diseases, such as AD (Alzheimer's disease), PD (Parkinson's disease), ALS (Amyotrophic lateral sclerosis), FRDA (Friedreich's ataxia), VaD (Vascular dementia) etc. These can be caused due to multiple factors such as genetic, physiological problems like stroke or tumor, or even external causes like viruses, toxins, or chemicals. T3s (tocotrienols) exhibit various bioactive properties where it acts as an antioxidant, anti-inflammatory, anti-tumorigenic, and cholesterol lowering agent. Since T3 interferes with and influences several anti-inflammatory mechanisms, it aids in combating inflammatory responses that lead to disease progression. T3s are found to have a profound neuroprotective ability, however, due to their poor oral bioavailability, their full potential could not be exploited. Hence there is a need to explore other drug delivery techniques, especially focusing on aspects of nanotechnology. In this review paper we explore the anti-inflammatory mechanisms of T3 to apply it in the treatment of neurodegenerative diseases and also discusses the possibilities of nano methods of administering tocotrienols to target neurodegenerative diseases.}, }
@article {pmid38011426, year = {2022}, author = {Fateh, HR and Askary-Kachoosangy, R and Shirzad, N and Akbarzadeh-Baghban, A and Fatehi, F}, title = {The effect of energy conservation strategies on fatigue, function, and quality of life in adults with motor neuron disease: Randomized controlled trial.}, journal = {Current journal of neurology}, volume = {21}, number = {2}, pages = {83-90}, pmid = {38011426}, issn = {2717-011X}, abstract = {Background: Fatigue is one of the most frequent complaints in patients with motor neuron diseases (MNDs), with a significant impact on the quality of life (QOL). There is lack of enough evidence for current pharmacological or non-pharmacological treatments of fatigue in this population to be applied in clinical setting. Energy conservation strategies are one of the key interventions for fatigue management in chronic diseases. We aimed to investigate the effect of applying these techniques in the fatigue management of patients with MND. Methods: This randomized controlled trial (RCT) study was carried out on 28 patients with MND. Participants were randomly assigned to either the intervention or control group. In addition to routine treatment, patients in the intervention group participated in 3 weekly 1-hour energy conservation programs provided by an experienced occupational therapist. The Fatigue Severity Scale (FSS) score, 36-Item Short Form Survey (SF-36), and Canadian Occupational Performance Measure (COPM) were measured at baseline, immediately after the last intervention session, and one month later. Results: FSS and COPM significantly changed after the course in the intervention group (P < 0.001 and P = 0.001, respectively). Both FSS and COPM improved significantly toward the final assessment only in the intervention group. The SF-36 changes were not significant in each of the groups. Conclusion: According to the findings of the present study, using energy conservation strategies could lead to better mid-term fatigue management and occupational performance improvement, but it did not improve QOL in patients with MND.}, }
@article {pmid38283317, year = {2022}, author = {Cheung, K and Mitsumoto, H}, title = {Evaluating Personalized (N-of-1) Trials in Rare Diseases: How Much Experimentation Is Enough?.}, journal = {Harvard data science review}, volume = {2022}, number = {Spec Iss 3}, pages = {}, pmid = {38283317}, issn = {2644-2353}, support = {P30 AG063786/AG/NIA NIH HHS/United States ; R01 LM012836/LM/NLM NIH HHS/United States ; R01 MH109496/MH/NIMH NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; }, abstract = {For rare diseases, conducting large, randomized trials of new treatments can be infeasible due to limited sample size, and it may answer the wrong scientific questions due to heterogeneity of treatment effects. Personalized (N-of-1) trials are multi-period crossover studies that aim to estimate individual treatment effects, thereby identifying the optimal treatments for individuals. This article examines the statistical design issues of evaluating a personalized (N-of-1) treatment program in people with amyotrophic lateral sclerosis (ALS). We propose an evaluation framework based on an analytical model for longitudinal data observed in a personalized trial. Under this framework, we address two design parameters: length of experimentation in each trial and number of trials needed. For the former, we consider patient-centric design criteria that aim to maximize the benefits of enrolled patients. Using theoretical investigation and numerical studies, we demonstrate that, from a patient's perspective, the duration of an experimentation period should be no longer than one-third of the entire follow-up period of the trial. For the latter, we provide analytical formulae to calculate the power for testing quality improvement due to personalized trials in a randomized evaluation program and hence determine the required number of trials needed for the program. We apply our theoretical results to design an evaluation program for ALS treatments informed by pilot data and show that the length of experimentation has a small impact on power relative to other factors such as the degree of heterogeneity of treatment effects.}, }
@article {pmid37786905, year = {2021}, author = {Huang, ZQ and Ba, ZS and Huang, NQ and Li, YY and Luo, Y}, title = {Aberrant TDP-43 phosphorylation: a key wind gap from TDP-43 to TDP-43 proteinopathy.}, journal = {Ibrain}, volume = {7}, number = {2}, pages = {119-131}, pmid = {37786905}, issn = {2769-2795}, abstract = {TDP-43 proteinopathy is a kind of neurodegenerative diseases related to the TAR DNA-binding protein of 43-kDa molecular weight (TDP-43). The typical neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), Parkinson's disease (PD) and so on. As the disease process cannot be blocked or slowed down, these patients have poor quality of life and poor prognosis, and bring a huge burden to the family and society. So far, the specific pathogenesis of TDP-43 proteinopathy is not clear, and there is no effective preventive measure and treatment program for this kind of disease. TDP-43 plays an important role in triggering or promoting the occurrence and progression of TDP-43 proteinopathy. The hyperphosphorylation of TDP-43 is undoubtedly an important factor in triggering or promoting the process of TDP-43 proteinopathy. Hyperphosphorylation of TDP-43 can inhibit the degradation of TDP-43, aggravate the aggregation of TDP-43 protein, increase the wrong localization of TDP-43 in cells, and enhance the cytotoxicity of TDP-43. More and more evidences show that the hyperphosphorylation of TDP-43 plays an important role in the pathogenesis of TDP-43 proteinopathy. Inhibition of TDP-43 hyperphosphorylation may be one of the important strategies for the treatment of TDP-43 proteinopathy. Therefore, this article reviews the role of TDP-43 phosphorylation in TDP-43 proteinopathy and the related mechanisms.}, }
@article {pmid38011420, year = {2021}, author = {Eishi-Oskouei, A and Basiri, K}, title = {Safety and efficacy of edaravone in well-defined Iranian patients with amyotrophic lateral sclerosis: A parallel-group single-blind trial.}, journal = {Current journal of neurology}, volume = {20}, number = {1}, pages = {1-7}, pmid = {38011420}, issn = {2717-011X}, abstract = {Background: This parallel-group single-blind trial evaluates the safety and efficacy of Edaravone, as a free radical scavenger, in a highly selective subgroup of Iranian patients with amyotrophic lateral sclerosis (ALS). Methods: The study was registered in ClinicalTrials.gov (registration number: NCT03272802) and Iranian Registry of Clinical Trials (registration number: IRCT20190324043105N). Patients were included into the study, who were diagnosed as probable or definite ALS (according to revised El Escorial criteria), mildly to moderately affected by the disease [according to Amyotrophic Lateral Sclerosis Health State Scale (ALS/HSS)], scored ≥ 2 points on all items of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and had forced vital capacity (FVC) of at least 80%. 20 patients (10 cases, 10 controls) were observed for 12 cycles (each cycle lasted four weeks). Cases received Edaravone for the first 14 days in the first cycle and for the first 10 days in the next cycles. In addition, all patients received Riluzole. The 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40), ALSFRS-R, and Manual Muscle Testing (MMT) scores were measured every 3 cycles to evaluate the physical and functional status of the patients. Besides, injection reactions, adverse events (AEs), and serious adverse events (SAEs) were measured during the study. Results: ALSAQ-40, ALSFRS-R, and MMT scores were not significantly different between cases and controls in 5 different time points. During the study, no injection reactions were observed. AEs and SAEs were not significantly different between cases and controls. Conclusion: Our data did not demonstrate efficacy of Edaravone in ALS treatment, but showed its safety for use in patients with ALS. Further studies are necessary to investigate Edaravone efficacy in patients with ALS before prescribing this new drug outside Japan.}, }
@article {pmid37573101, year = {2023}, author = {Queral-Beltran, A and Marín-García, M and Lacorte, S and Tauler, R}, title = {UV-Vis absorption spectrophotometry and LC-DAD-MS-ESI(+)-ESI(-) coupled to chemometrics analysis of the monitoring of sulfamethoxazole degradation by chlorination, photodegradation, and chlorination/photodegradation.}, journal = {Analytica chimica acta}, volume = {1276}, number = {}, pages = {341563}, doi = {10.1016/j.aca.2023.341563}, pmid = {37573101}, issn = {1873-4324}, mesh = {*Sulfamethoxazole ; *Chemometrics ; Halogenation ; Photolysis ; Chlorine ; Spectrophotometry/methods ; Mass Spectrometry/methods ; Chromatography, Liquid ; }, abstract = {Sulfamethoxazole (SMX) is one of the most widely used antibiotics worldwide and has been detected at high concentrations in wastewater treatment plant effluents and river waters. In this study, the SMX degradation process combining the simultaneous chlorine oxidation and UV photodegradation is assessed and compared with both photodegradation and chlorine oxidation processes individually. Photodegradation and Chlorine/UV tests were performed using Suntest CPS equipment. Different experimental techniques, including UV-Visible spectrophotometry and liquid chromatography coupled to a diode array detector and positive and negative ionization mass spectrometry (LC-DAD-MS-ESI(+)-ESI(-)), were used to evaluate the degradation reaction of SMX. All the analytical data generated have been processed with the Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) method to monitor, resolve, and identify the several transformation products generated during the studied degradation processes. A new data fusion analysis strategy is proposed to examine the three processes simultaneously (with only photodegradation, only chlorination, and simultaneous chlorination+photodegradation). Combined with the analysis of different analytical techniques individually (spectrophotometry, LC-DAD, and LC-MS), the fusion of all generated data improved the description of the degradation processes. Detection using DAD allowed a better correspondence among the species monitored spectrophotometrically (UV-Vis) with those analyzed chromatographically. On the other side, detection using MS in both positive and negative acquisition modes allowed resolving a larger number of chemical compounds (specially SMX degradation subproducts) that could not be detected by UV-Vis spectrometry. The results obtained permitted the comparison of the effects produced by the three different degradation processes.}, }
@article {pmid37570771, year = {2023}, author = {Liu, X and Zhao, X and He, J and Wang, S and Shen, X and Liu, Q and Wang, S}, title = {Advances in the Structure of GGGGCC Repeat RNA Sequence and Its Interaction with Small Molecules and Protein Partners.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {15}, pages = {}, pmid = {37570771}, issn = {1420-3049}, support = {22274050//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia/genetics ; Base Sequence ; DNA Repeat Expansion ; RNA/genetics/chemistry ; RNA-Binding Proteins/genetics/metabolism ; }, abstract = {The aberrant expansion of GGGGCC hexanucleotide repeats within the first intron of the C9orf72 gene represent the predominant genetic etiology underlying amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The transcribed r(GGGGCC)n RNA repeats form RNA foci, which recruit RNA binding proteins and impede their normal cellular functions, ultimately resulting in fatal neurodegenerative disorders. Furthermore, the non-canonical translation of the r(GGGGCC)n sequence can generate dipeptide repeats, which have been postulated as pathological causes. Comprehensive structural analyses of r(GGGGCC)n have unveiled its polymorphic nature, exhibiting the propensity to adopt dimeric, hairpin, or G-quadruplex conformations, all of which possess the capacity to interact with RNA binding proteins. Small molecules capable of binding to r(GGGGCC)n have been discovered and proposed as potential lead compounds for the treatment of ALS and FTD. Some of these molecules function in preventing RNA-protein interactions or impeding the phase transition of r(GGGGCC)n. In this review, we present a comprehensive summary of the recent advancements in the structural characterization of r(GGGGCC)n, its propensity to form RNA foci, and its interactions with small molecules and proteins. Specifically, we emphasize the structural diversity of r(GGGGCC)n and its influence on partner binding. Given the crucial role of r(GGGGCC)n in the pathogenesis of ALS and FTD, the primary objective of this review is to facilitate the development of therapeutic interventions targeting r(GGGGCC)n RNA.}, }
@article {pmid37566177, year = {2024}, author = {Meyer, M and Meijer, O and Hunt, H and Belanoff, J and Lima, A and de Kloet, ER and Gonzalez Deniselle, MC and De Nicola, AF}, title = {Stress-induced Neuroinflammation of the Spinal Cord is Restrained by Cort113176 (Dazucorilant), A Specific Glucocorticoid Receptor Modulator.}, journal = {Molecular neurobiology}, volume = {61}, number = {1}, pages = {1-14}, pmid = {37566177}, issn = {1559-1182}, support = {PIP 11220170100002CO//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; PIP 11220210100091CO//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; PICT 2021 00389//Ministerio de Ciencia, Tecnolog&#xed;a e Innovaci&#xf3;n Productiva/ ; Ubacyt 20020170100224BA//Secretaria de Ciencia y Tecnica, Universidad de Buenos Aires/ ; }, mesh = {Male ; Mice ; Humans ; Animals ; Receptors, Glucocorticoid/metabolism ; Corticosterone ; *HMGB1 Protein/metabolism ; Neuroinflammatory Diseases ; Gliosis/metabolism ; Toll-Like Receptor 4/metabolism ; Glucocorticoids/pharmacology ; Spinal Cord/metabolism ; *Neurodegenerative Diseases/metabolism ; *Isoquinolines ; *Pyrazoles ; }, abstract = {Glucocorticoids exert antiinflammatory, antiproliferative and immunosupressive effects. Paradoxically they may also enhance inflammation particularly in the nervous system, as shown in Cushing´ syndrome and neurodegenerative disorders of humans and models of human diseases. ."The Wobbler mouse model of amyotrophic lateral sclerosis shows hypercorticoidism and neuroinflammation which subsided by treatment with the glucocorticoid receptor (GR) modulator Dazucorilant (CORT113176). This effect suggests that GR mediates the chronic glucocorticoid unwanted effects. We now tested this hypothesis using a chronic stress model resembling the condition of the Wobbler mouse Male NFR/NFR mice remained as controls or were subjected to a restraining / rotation stress protocol for 3 weeks, with a group of stressed mice receiving CORT113176 also for 3 weeks. We determined the mRNAS or reactive protein for the proinflamatory factors HMGB1, TLR4, NFkB, TNFα, markers of astrogliosis (GFAP, SOX9 and acquaporin 4), of microgliosis (Iba, CD11b, P2RY12 purinergic receptor) as well as serum IL1β and corticosterone. We showed that chronic stress produced high levels of serum corticosterone and IL1β, decreased body and spleen weight, produced microgliosis and astrogliosis and increased proinflammatory mediators. In stressed mice, modulation of the GR with CORT113176 reduced Iba + microgliosis, CD11b and P2RY12 mRNAs, immunoreactive HMGB1 + cells, GFAP + astrogliosis, SOX9 and acquaporin expression and TLR4 and NFkB mRNAs vs. stress-only mice. The effects of CORT113176 indicate that glucocorticoids are probably involved in neuroinflammation. Thus, modulation of the GR would become useful to dampen the inflammatory component of neurodegenerative disorders.}, }
@article {pmid37566027, year = {2023}, author = {Bagyinszky, E and Hulme, J and An, SSA}, title = {Studies of Genetic and Proteomic Risk Factors of Amyotrophic Lateral Sclerosis Inspire Biomarker Development and Gene Therapy.}, journal = {Cells}, volume = {12}, number = {15}, pages = {}, pmid = {37566027}, issn = {2073-4409}, mesh = {Humans ; Child ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; *Neurodegenerative Diseases ; Proteomics ; DNA-Binding Proteins/metabolism ; Superoxide Dismutase-1 ; Biomarkers ; Risk Factors ; DNA Helicases ; RNA Helicases ; Multifunctional Enzymes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease affecting the upper and lower motor neurons, leading to muscle weakness, motor impairments, disabilities and death. Approximately 5-10% of ALS cases are associated with positive family history (familial ALS or fALS), whilst the remainder are sporadic (sporadic ALS, sALS). At least 50 genes have been identified as causative or risk factors for ALS. Established pathogenic variants include superoxide dismutase type 1 (SOD1), chromosome 9 open reading frame 72 (c9orf72), TAR DNA Binding Protein (TARDBP), and Fused In Sarcoma (FUS); additional ALS-related genes including Charged Multivesicular Body Protein 2B (CHMP2B), Senataxin (SETX), Sequestosome 1 (SQSTM1), TANK Binding Kinase 1 (TBK1) and NIMA Related Kinase 1 (NEK1), have been identified. Mutations in these genes could impair different mechanisms, including vesicle transport, autophagy, and cytoskeletal or mitochondrial functions. So far, there is no effective therapy against ALS. Thus, early diagnosis and disease risk predictions remain one of the best options against ALS symptomologies. Proteomic biomarkers, microRNAs, and extracellular vehicles (EVs) serve as promising tools for disease diagnosis or progression assessment. These markers are relatively easy to obtain from blood or cerebrospinal fluids and can be used to identify potential genetic causative and risk factors even in the preclinical stage before symptoms appear. In addition, antisense oligonucleotides and RNA gene therapies have successfully been employed against other diseases, such as childhood-onset spinal muscular atrophy (SMA), which could also give hope to ALS patients. Therefore, an effective gene and biomarker panel should be generated for potentially "at risk" individuals to provide timely interventions and better treatment outcomes for ALS patients as soon as possible.}, }
@article {pmid37565183, year = {2023}, author = {Sheers, NL and O'Sullivan, R and Howard, ME and Berlowitz, DJ}, title = {The role of lung volume recruitment therapy in neuromuscular disease: a narrative review.}, journal = {Frontiers in rehabilitation sciences}, volume = {4}, number = {}, pages = {1164628}, pmid = {37565183}, issn = {2673-6861}, abstract = {Respiratory muscle weakness results in substantial discomfort, disability, and ultimately death in many neuromuscular diseases. Respiratory system impairment manifests as shallow breathing, poor cough and associated difficulty clearing mucus, respiratory tract infections, hypoventilation, sleep-disordered breathing, and chronic ventilatory failure. Ventilatory support (i.e., non-invasive ventilation) is an established and key treatment for the latter. As survival outcomes improve for people living with many neuromuscular diseases, there is a shift towards more proactive and preventative chronic disease multidisciplinary care models that aim to manage symptoms, improve morbidity, and reduce mortality. Clinical care guidelines typically recommend therapies to improve cough effectiveness and mobilise mucus, with the aim of averting acute respiratory compromise or respiratory tract infections. Moreover, preventing recurrent infective episodes may prevent secondary parenchymal pathology and further lung function decline. Regular use of techniques that augment lung volume has similarly been recommended (volume recruitment). It has been speculated that enhancing lung inflation in people with respiratory muscle weakness when well may improve respiratory system "flexibility", mitigate restrictive chest wall disease, and slow lung volume decline. Unfortunately, clinical care guidelines are based largely on clinical rationale and consensus opinion rather than level A evidence. This narrative review outlines the physiological changes that occur in people with neuromuscular disease and how these changes impact on breathing, cough, and respiratory tract infections. The biological rationale for lung volume recruitment is provided, and the clinical trials that examine the immediate, short-term, and longer-term outcomes of lung volume recruitment in paediatric and adult neuromuscular diseases are presented and the results synthesised.}, }
@article {pmid37564731, year = {2023}, author = {Kudritzki, V and Howard, IM}, title = {Telehealth-based exercise in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1238916}, pmid = {37564731}, issn = {1664-2295}, abstract = {The Veterans Health Administration (VHA) has served as a leader in the implementation of telerehabilitation technologies and continues to expand utilization of non-traditional patient encounters to better serve a geographically and demographically diverse population. Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease impacting Veterans at a higher rate than the civilian population and associated with high levels of disability and limited access to subspecialized care. There is growing evidence supporting exercise-based interventions as an independent or adjunctive treatment to maintain or restore function for this patient population; many of these interventions can be delivered remotely by telehealth. The recent advancements in disease-modifying therapies for neuromuscular disorders will likely increase the importance of rehabilitation interventions to maximize functional outcomes. Here, we review the evidence for specific exercise interventions in ALS and the evidence for telehealth-based exercise in neuromuscular disorders. We then use this existing literature to propose a framework for telehealth delivery of these treatments, including feasible exercise interventions and remote outcome measures, recommended peripheral devices, and an example of a current remote group exercise program offered through VHA.}, }
@article {pmid37559423, year = {2023}, author = {Kim, S and An, S and Lee, J and Jeong, Y and You, CL and Kim, H and Bae, JH and Yun, CE and Ryu, D and Bae, GU and Kang, JS}, title = {Cdon ablation in motor neurons causes age-related motor neuron degeneration and impaired sciatic nerve repair.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {14}, number = {5}, pages = {2239-2252}, pmid = {37559423}, issn = {2190-6009}, support = {NRF-2016R1A5A2945889//National Research Foundation Grant funded by the Korean Government (MSIP)/ ; NRF-2022R1A2B5B02001482//National Research Foundation Grant funded by the Korean Government (MSIP)/ ; }, abstract = {BACKGROUND: The functional deterioration and loss of motor neurons are tightly associated with degenerative motor neuron diseases and aging-related muscle wasting. Motor neuron diseases or aging-related muscle wasting in turn contribute to increased risk of adverse health outcomes in the elderly. Cdon (cell adhesion molecule-downregulated oncogene) belongs to the immunoglobulin superfamily of cell adhesion molecule and plays essential roles in multiple signalling pathways, including sonic hedgehog (Shh), netrin, and cadherin-mediated signalling. Cdon as a Shh coreceptor plays a critical role in motor neuron specification during embryonic development. However, its role in adult motor neuron function is unknown.<br><br>METHODS: Hb9-Cre recombinase-driven motor neuron-specific Cdon deficient mice (mnKO) and a compound mutant mice (mnKO::SOD1[G93A]) were generated to investigate the role of Cdon in motor neuron degeneration. Motor neuron regeneration was examined by using a sciatic nerve crush injury model. To investigate the phenotype, physical activity, compound muscle action potential, immunostaining, and transmission electron microscopy were carried out. In the mechanism study, RNA sequencing and RNA/protein analyses were employed.<br><br>RESULTS: Mice lacking Cdon in motor neurons exhibited middle age onset lethality and aging-related decline in motor function. In the sciatic nerve crush injury model, mnKO mice exhibited an impairment in motor function recovery evident by prolonged compound muscle action potential duration (4.63&#xa0;&#xb1;&#xa0;0.35 vs. 3.93&#xa0;&#xb1;&#xa0;0.22&#xa0;s for f/f, P&#xa0;<&#xa0;0.01) and physical activity. Consistently, neuromuscular junctions of mnKO muscles were incompletely occupied (49.79&#xa0;&#xb1;&#xa0;5.74 vs. 79.39&#xa0;&#xb1;&#xa0;3.77% fully occupied neuromuscular junctions for f/f, P&#xa0;<&#xa0;0.0001), suggesting an impaired reinnervation. The transmission electron microscopy analysis revealed that mnKO sciatic nerves had smaller axon diameter (0.88&#xa0;&#xb1;&#xa0;0.13 vs. 1.43&#xa0;&#xb1;&#xa0;0.48&#xa0;&#x3bc;m for f/f, P&#xa0;<&#xa0;0.0001) and myelination defects. RNA sequencing of mnKO lumbar spinal cords showed alteration in genes related to neurogenesis, inflammation and cell death. Among the altered genes, ErbB4 and FgfR expressions were significantly altered in mnKO as well as in Cdon-depleted NSC34 motor neuron cells. Consistently, Cdon-depleted NSC34 cells exhibited elevated levels of cleaved Caspase3 and &#x3b3;H2AX proteins, as well as Bax transcription. Cdon-depleted NSC34 cells also exhibited impaired activation of Akt in response to neuregulin-1 (NRG1) treatment.<br><br>CONCLUSIONS: Our current data demonstrate the functional importance of Cdon in motor neuron function and nerve repair. Cdon ablation causes alterations in neurotrophin signalling that leads to motor neuron degeneration.}, }
@article {pmid37558009, year = {2023}, author = {Monteiro Neto, JR and Ribeiro, GD and Magalhães, RSS and Follmer, C and Outeiro, TF and Eleutherio, ECA}, title = {Glycation modulates superoxide dismutase 1 aggregation and toxicity in models of sporadic amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1869}, number = {8}, pages = {166835}, doi = {10.1016/j.bbadis.2023.166835}, pmid = {37558009}, issn = {1879-260X}, mesh = {Humans ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/pathology ; Superoxide Dismutase/metabolism ; Maillard Reaction ; Magnesium Oxide ; Motor Neurons/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {Different SOD1 proteoforms are implicated## in both familial and sporadic cases of Amyotrophic Lateral Sclerosis (ALS), an aging-associated disease that affects motor neurons. SOD1 is crucial to neuronal metabolism and health, regulating the oxidative stress response and the shift between oxidative-fermentative metabolism, which is important for astrocyte-neuron metabolic cooperation. Neurons have a limited capacity to metabolize methylglyoxal (MGO), a potentially toxic side product of glycolysis. MGO is highly reactive and can readily posttranslationally modify proteins, in a reaction known as glycation, impacting their normal biology. Here, we aimed to investigate the effect of glycation on the aggregation and toxicity of human SOD1WT (hSOD1WT). Cells with deficiency in MGO metabolism showed increased levels of hSOD1WT inclusions, displaying also reduced hSOD1WT activity and viability. Strikingly, we also found that the presence of hSOD1WT in stress granules increased upon MGO treatment. The treatment of recombinant hSOD1WT with MGO resulted in the formation of SDS-stable oligomers, specially trimers, and thioflavin-T positive aggregates, which can promote cell toxicity and TDP-43 pathology. Together, our results suggest that glycation may play a still underappreciated role on hSOD1WT and TDP-43 pathologies in sporadic ALS, which could open novel perspectives for therapeutic intervention.}, }
@article {pmid37555646, year = {2023}, author = {Ribeiro, SS and Gnutt, D and Azoulay-Ginsburg, S and Fetahaj, Z and Spurlock, E and Lindner, F and Kuz, D and Cohen-Erez, Y and Rapaport, H and Israelson, A and Gruzman, AL and Ebbinghaus, S}, title = {Intracellular spatially-targeted chemical chaperones increase native state stability of mutant SOD1 barrel.}, journal = {Biological chemistry}, volume = {404}, number = {10}, pages = {909-930}, pmid = {37555646}, issn = {1437-4315}, mesh = {Humans ; Superoxide Dismutase-1/genetics/chemistry/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy ; Protein Folding ; Mutation ; Molecular Chaperones ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder with currently no cure. Central to the cellular dysfunction associated with this fatal proteinopathy is the accumulation of unfolded/misfolded superoxide dismutase 1 (SOD1) in various subcellular locations. The molecular mechanism driving the formation of SOD1 aggregates is not fully understood but numerous studies suggest that aberrant aggregation escalates with folding instability of mutant apoSOD1. Recent advances on combining organelle-targeting therapies with the anti-aggregation capacity of chemical chaperones have successfully reduce the subcellular load of misfolded/aggregated SOD1 as well as their downstream anomalous cellular processes at low concentrations (micromolar range). Nevertheless, if such local aggregate reduction directly correlates with increased folding stability remains to be explored. To fill this gap, we synthesized and tested here the effect of 9 ER-, mitochondria- and lysosome-targeted chemical chaperones on the folding stability of truncated monomeric SOD1 (SOD1bar) mutants directed to those organelles. We found that compound ER-15 specifically increased the native state stability of ER-SOD1bar-A4V, while scaffold compound FDA-approved 4-phenylbutyric acid (PBA) decreased it. Furthermore, our results suggested that ER15 mechanism of action is distinct from that of PBA, opening new therapeutic perspectives of this novel chemical chaperone on ALS treatment.}, }
@article {pmid37553906, year = {2023}, author = {Runacres, F and Mathers, S and Lee, SC and Hearn, R and Gregory, S and Bear, N and Aoun, S}, title = {Motor neurone disease: A point-prevalence study of patient reported symptom prevalence, severity and palliative care needs.}, journal = {Palliative medicine}, volume = {37}, number = {9}, pages = {1402-1412}, doi = {10.1177/02692163231191545}, pmid = {37553906}, issn = {1477-030X}, mesh = {Humans ; *Palliative Care ; Prevalence ; Cross-Sectional Studies ; Syndrome ; *Motor Neuron Disease/epidemiology/therapy ; Patient Reported Outcome Measures ; }, abstract = {BACKGROUND: Motor neurone disease is a rare but debilitating illness with incomplete evidence regarding patients' symptom burden. Palliative care and generalist clinicians are often in-experienced in caring for these patients and assessing their needs.<br><br>AIM: To identify the symptom prevalence and severity experienced by patients with motor neurone disease. Secondary objectives were to examine differences in symptom burden and clusters according to phenotype, functional status, palliative care provision and those in their last months of life.<br><br>DESIGN: A point prevalence study assessing patient-reported symptoms using a modified IPOS-Neuro assessment tool, incorporating 41 symptom items.<br><br>SETTING/PARTICIPANTS: Patients with motor neurone disease attending the State-wide Progressive Neurological Disease Service or inpatient unit at Calvary Health Care Bethlehem, Melbourne Australia, from March to December 2021.<br><br>RESULTS: A total of 102 patients participated, the majority diagnosed with lumber-onset (30.4%), bulbar-onset (28.4%) and cervical-onset (25.5%) phenotypes. Patients experienced a median of 17 symptoms (range 2-32) with a median of 3 symptoms rated as severe/overwhelming (range 0-13). Motor and functional symptoms predominated, with differences in symptom clusters present according to phenotype. Patients had a higher number of severe/overwhelming symptoms if they were accessing palliative care services (p&#x2009;=&#x2009;0.005), in their last 6&#x2009;months of life (p&#x2009;=&#x2009;0.003) and experiencing moderate or severe functional impairment (p&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: Patients with motor neurone disease report high symptom burden. A validated motor neurone disease-specific symptom assessment tool is needed to accurately assess patients, including important variations in symptom clusters according to phenotype. Further research must focus on evidence-based treatment guidelines for symptoms experienced commonly and severely.}, }
@article {pmid37550954, year = {2023}, author = {Weemering, DN and Midei, M and Milner, P and Gopalakrishnan, V and Kumar, A and Dannenberg, AJ and Bunte, TM and Foucher, J and Ingre, C and Ķēniņa, V and Rallmann, K and van den Berg, LH and van Eijk, RPA}, title = {A randomized, double-blind, placebo-controlled phase 2 study to assess safety, tolerability, and efficacy of RT001 in patients with amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {30}, number = {12}, pages = {3722-3731}, doi = {10.1111/ene.16020}, pmid = {37550954}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Linoleic Acids/therapeutic use ; Double-Blind Method ; Treatment Outcome ; }, abstract = {BACKGROUND AND PURPOSE: RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: We conducted a randomized, multicenter, placebo-controlled clinical trial. Patients with ALS were randomly allocated to receive either RT001 or placebo for 24&#x2009;weeks. After the double-blind period, all patients received RT001 during an open-label phase for 24&#x2009;weeks. The primary outcome measures were safety and tolerability. Key efficacy outcomes included the ALS Functional Rating Scale (ALSFRS-R), percent predicted slow vital capacity, and plasma neurofilament light chain concentration.<br><br>RESULTS: In total, 43 patients (RT001&#x2009;=&#x2009;21; placebo&#x2009;=&#x2009;22) were randomized. RT001 was well tolerated; one patient required dose reduction due to adverse events (AEs). Numerically, there were more AEs in the RT001 group compared to the placebo group (71% versus 55%, p&#x2009;=&#x2009;0.35), with gastrointestinal symptoms being the most common (43% in RT001, 27% in placebo, p&#x2009;=&#x2009;0.35). Two patients in the RT001 group experienced a serious AE, though unrelated to treatment. The least-squares mean difference in ALSFRS-R total score at week 24 of treatment was 1.90 (95% confidence interval = -1.39 to 5.19) in favor of RT001 (p&#x2009;=&#x2009;0.25). The directions of other efficacy outcomes favored RT001 compared to placebo, although no inferential statistics were performed.<br><br>CONCLUSIONS: Initial data indicate that RT001 is safe and well tolerated. Given the exploratory nature of the study, a larger clinical trial is required to evaluate its efficacy.}, }
@article {pmid37550578, year = {2024}, author = {Maksymowicz, S and Siwek, T}, title = {Diagnostic odyssey in amyotrophic lateral sclerosis: diagnostic criteria and reality.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {1}, pages = {191-196}, pmid = {37550578}, issn = {1590-3478}, mesh = {Male ; Female ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Quality of Life ; *Physicians ; Rare Diseases ; }, abstract = {BACKGROUND: Diagnosing a rare disease, such as amyotrophic lateral sclerosis, is a major challenge for physicians and patients. Despite detailed diagnostic criteria, this process often does not proceed as it should, exacerbating the problems of patients. In the following study, we show how the process, which in medical sciences has been called the "diagnostic odyssey", proceeds and how it affects patients.<br><br>MATERIALS AND METHODS: Participants were recruited via a neurology clinic. Twenty-four patients with the diagnosed disease were interviewed using in-depth interviews and an author questionnaire: 9 females and 15 males ages ranging from 30-39 to 60-69.<br><br>RESULTS: The median time from 1st symptoms to diagnosis was almost 12&#xa0;months and mean almost 20&#xa0;months (min. 3, max 106). Only 5 patients waited less than 6&#xa0;months for being diagnosed. Over 80% of patients received an alternative diagnosis on the first attempt.<br><br>CONCLUSION: ALS is a fast-paced fatal disease, which requires immediate action to slow down the course of the disease and improve patients' quality of life. However, in many cases, the disease is diagnosed too late. It also happens that a wrong diagnosis causes inaccurate treatment, which accelerates the development of ALS. For this reason, it is necessary to expand the clinical and communication competences of medical personnel already at the stage of medical studies. In addition, the diagnostic criteria should highlight the common problem with diagnosing ALS.}, }
@article {pmid37548234, year = {2023}, author = {Notarstefano, V and Belloni, A and Mariani, P and Orilisi, G and Orsini, G and Giorgini, E and Byrne, HJ}, title = {Multivariate curve Resolution-Alternating least squares coupled with Raman microspectroscopy: new insights into the kinetic response of primary oral squamous carcinoma cells to cisplatin.}, journal = {The Analyst}, volume = {148}, number = {18}, pages = {4365-4372}, doi = {10.1039/d3an01182h}, pmid = {37548234}, issn = {1364-5528}, mesh = {Humans ; *Cisplatin/pharmacology ; Least-Squares Analysis ; Spectrum Analysis, Raman/methods ; *Carcinoma, Squamous Cell/drug therapy ; Multivariate Analysis ; }, abstract = {Raman MicroSpectroscopy (RMS) is a powerful label-free tool to probe the effects of drugs at a cellular/subcellular level. It is important, however, to be able to extract relevant biochemical and kinetic spectroscopic signatures of the specific cellular responses. In the present study, a combination of Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and Principal Component Analysis (PCA) is used to analyse the RMS data for the example of exposure of primary Oral Squamous Carcinoma Cells (OSCC) to the chemotherapeutic agent cisplatin. Dosing regimens were established by cytotoxicity assays, and the effects of the drug on cellular spectral profiles were monitored from 16 to 72 hours post-exposure using an apoptosis assay, to establish the relative populations of viable (V), early (EA) and late apoptotic/dead (LA/D) cells after the drug treatment. Based on a kinetic model of the progression from V > EA > D, MCR-ALS regression analysis of the RMS responses was able to extract spectral profiles associated with each stage of the cellular responses, enabling a quantitative comparison of the response rates for the respective drug treatments. Moreover, PCA was used to compare the spectral profiles of the viable cells exposed to the drug. Spectral differences were highlighted in the early stages (16 hours exposure), indicative of the initial cellular response to the drug treatment, and also in the late stages (48-72 hours exposure), representing the cell death pathway. The study demonstrates that RMS coupled with multivariate analysis can be used to quantitatively monitor the progression of cellular responses to different drugs, towards future applications for label-free, in vitro, pre-clinical screening.}, }
@article {pmid37545536, year = {2023}, author = {Ramachandran, S and Grozdanov, V and Leins, B and Kandler, K and Witzel, S and Mulaw, M and Ludolph, AC and Weishaupt, JH and Danzer, KM}, title = {Low T-cell reactivity to TDP-43 peptides in ALS.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1193507}, pmid = {37545536}, issn = {1664-3224}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; CD8-Positive T-Lymphocytes/metabolism ; DNA-Binding Proteins/metabolism ; Interleukin-2 ; }, abstract = {BACKGROUND: Dysregulation of the immune system in amyotrophic lateral sclerosis (ALS) includes changes in T-cells composition and infiltration of T cells in the brain and spinal cord. Recent studies have shown that cytotoxic T cells can directly induce motor neuron death in a mouse model of ALS and that T cells from ALS patients are cytotoxic to iPSC-derived motor neurons from ALS patients. Furthermore, a clonal expansion to unknown epitope(s) was recently found in familial ALS and increased peripheral and intrathecal activation of cytotoxic CD8[+] T cells in sporadic ALS.<br><br>RESULTS: Here, we show an increased activation of peripheral T cells from patients with sporadic ALS by IL-2 treatment, suggesting an increase of antigen-experienced T cells in ALS blood. However, a putative antigen for T-cell activation in ALS has not yet been identified. Therefore, we investigated if peptides derived from TDP-43, a key protein in ALS pathogenesis, can act as epitopes for antigen-mediated activation of human T cells by ELISPOT and flow cytometry. We found that TDP-43 peptides induced only a weak MHCI or MHCII-restricted activation of both na&#xef;ve and antigen-experienced T cells from healthy controls and ALS patients. Interestingly, we found less activation in T cells from ALS patients to TDP-43 and control stimuli. Furthermore, we found no change in the levels of naturally occurring auto-antibodies against full-length TDP-43 in ALS.<br><br>CONCLUSION: Our data suggests a general increase in antigen-experienced T cells in ALS blood, measured by in-vitro culture with IL-2 for 14 days. Furthermore, it suggests that TDP-43 is a weak autoantigen.}, }
@article {pmid37540049, year = {2023}, author = {Ko, JI and Choi, SJ and Yoo, SH and Cho, B and Kim, MS and Kim, KH and Lee, SY}, title = {Epidemiology and characteristics of emergency department utilization by patients with amyotrophic lateral sclerosis in Korea from 2016 to 2020: A nationwide study.}, journal = {Muscle &amp; nerve}, volume = {68}, number = {4}, pages = {451-459}, doi = {10.1002/mus.27952}, pmid = {37540049}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy ; Cross-Sectional Studies ; Emergency Service, Hospital ; *Respiratory Insufficiency/epidemiology/etiology/therapy ; Dyspnea ; Republic of Korea/epidemiology ; Retrospective Studies ; }, abstract = {INTRODUCTION/AIMS: Patients with amyotrophic lateral sclerosis (ALS) inevitably visit the emergency department (ED) due to their increased risk of respiratory failure and mobility limitations. However, nationwide data on ED visits by patients with ALS are limited. This study investigated the characteristics of patients with ALS-related ED visits.<br><br>METHODS: We conducted a cross-sectional study from 2016 to 2020, utilizing a nationwide ED database. The total number of patients with ALS who visited the ED and their primary reasons for visiting/diagnoses were analyzed.<br><br>RESULTS: In total, 6036 visits to the ED were made by patients with ALS. Of these, 41.8% arrived by ambulance and 27.7% spent >9&#x2009;h in the ED. Following ED treatment, 57.4% were hospitalized, including 19.3% admitted to the intensive care unit (ICU) and 5.4% who died in the hospital. The primary reasons for ALS-related ED visits were dyspnea (35.2%), feeding tube problems (10.1%), fever (7.8%), and mental status changes (3.6%). The most common diagnoses were pneumonia (14.5%), respiratory failure (5.7%), dyspnea (5.5%), aspiration pneumonia (4.3%), and tracheostomy complications (3.4%).<br><br>DISCUSSION: Reasons for ED visits for patients with ALS include acute respiratory distress, as well as concerns related to tube feeding and tracheostomy. To reduce the risk of patients with ALS requiring ED visits, it is essential to ensure the provision of timely respiratory support and high-quality home-based medical care teams that can support and address patients before their condition deteriorates.}, }
@article {pmid37535076, year = {2023}, author = {Yang, X and Zhang, Y and Luo, JX and Zhu, T and Ran, Z and Mu, BR and Lu, MH}, title = {Targeting mitophagy for neurological disorders treatment: advances in drugs and non-drug approaches.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {396}, number = {12}, pages = {3503-3528}, pmid = {37535076}, issn = {1432-1912}, mesh = {Animals ; Humans ; Mitophagy/physiology ; Mitochondria/metabolism ; *Parkinson Disease/metabolism ; *Alzheimer Disease/metabolism ; }, abstract = {Mitochondria serve as a vital energy source for nerve cells. The mitochondrial network also acts as a defense mechanism against external stressors that can threaten the stability of the nervous system. However, excessive accumulation of damaged mitochondria can lead to neuronal death. Mitophagy is an essential pathway in the mitochondrial quality control system and can protect neurons by selectively removing damaged mitochondria. In most neurological disorders, dysfunctional mitochondria are a common feature, and drugs that target mitophagy can improve symptoms. Here, we reviewed the role of mitophagy in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, stroke, and traumatic brain injuries. We also summarized drug and non-drug approaches to promote mitophagy and described their therapeutic role in neurological disorders in order to provide valuable insight into the potential therapeutic agents available for neurological disease treatment. However, most studies on mitophagy regulation are based on preclinical research using cell and animal models, which may not accurately reflect the effects in humans. This poses a challenge to the clinical application of drugs targeting mitophagy. Additionally, these drugs may carry the risk of intolerable side effects and toxicity. Future research should focus on the development of safer and more targeted drugs for mitophagy.}, }
@article {pmid37532350, year = {2023}, author = {Zhao, B and Xu, X and Li, B and Qi, Z and Huang, J and Hu, A and Wang, G and Liu, X}, title = {Target-site mutation and enhanced metabolism endow resistance to nicosulfuron in a Digitaria sanguinalis population.}, journal = {Pesticide biochemistry and physiology}, volume = {194}, number = {}, pages = {105488}, doi = {10.1016/j.pestbp.2023.105488}, pmid = {37532350}, issn = {1095-9939}, mesh = {Digitaria/genetics ; Sulfonylurea Compounds/pharmacology ; Pyridines ; Mutation ; *Acetolactate Synthase/metabolism ; Enzyme Inhibitors/pharmacology ; *Herbicides/pharmacology ; Herbicide Resistance/genetics ; }, abstract = {Digitaria sanguinalis is a competitive and annual grass weed that commonly infests crops across the world. In recent years, the control of D. sanguinalis by nicosulfuron has declined in Hebei Province, China. To determine the resistance mechanisms of D. sanguinalis to nicosulfuron, a population of D. sanguinalis where nicosulfuron had failed was collected from a maize field of Hebei Province, China. Whole-plant dose-response experiments demonstrated that the resistant population (HBMT-15) displayed 6.9-fold resistance to nicosulfuron compared with the susceptible population (HBMT-5). Addition of the glutathione S-transferase (GSTs) inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) significantly reduced the resistance level of the HBMT-15 population to nicosulfuron, and the GSTs activity of the HBMT-15 population was higher than the HBMT-5 population after nicosulfuron treatment. In vitro acetolactate synthase (ALS) enzyme experiments revealed that the nicosulfuron I50 value for the HBMT-15 population was 41 times higher than that of the HBMT-5 population. An Asp376 to Glu substitution in the ALS gene was identified in the HBMT-15 population. The HBMT-15 population had a moderate (2- to 4-fold) level of cross-resistance to three other ALS inhibitors (imazethapyr, pyroxsulam, and flucarbazone‑sodium), but was susceptible to pyrithiobac‑sodium. This study demonstrated that both an Asp376 to Glu substitution in the ALS gene and GSTs-involved metabolic resistance to ALS inhibitors coexisted in a D. sanguinalis population.}, }
@article {pmid37527390, year = {2023}, author = {Firnberg, MT and Lerner, EB and Nan, N and Ma, CX and Shah, MI and Mann, NC and Dayan, PS}, title = {National Variation in EMS Response and Antiepileptic Medication Administration for Children with Seizures in the Prehospital Setting.}, journal = {The western journal of emergency medicine}, volume = {24}, number = {4}, pages = {805-813}, pmid = {37527390}, issn = {1936-9018}, mesh = {Male ; Female ; Humans ; Child ; United States/epidemiology ; Anticonvulsants/therapeutic use ; Midazolam/therapeutic use ; *Emergency Medical Services ; *Emergency Medical Technicians ; Seizures/drug therapy ; Retrospective Studies ; }, abstract = {BACKGROUND AND OBJECTIVES: Prehospital Advanced Life Support (ALS) is important to improve patient outcomes in children with seizures, yet data is limited regarding national prehospital variation in ALS response for these children. We aimed to determine the variation in ALS response and prehospital administration of antiepileptic medication for children with seizures across the United States.<br><br>METHODS: We analyzed children <19 years with 9-1-1 dispatch codes for seizure in the 2019 National Emergency Medical Services Information System dataset. We defined ALS response as ALS-paramedic, ALS-Advanced Emergency Medical Technician, or ALS-intermediate responses. We conducted regression analyses to identify associations between ALS response (primary outcome), antiepileptic administration (secondary outcome) and age, gender, location, and US census regions.<br><br>RESULTS: Of 147,821 pediatric calls for seizures, 88% received ALS responses. Receipt of ALS response was associated with urbanicity, with wilderness (adjusted odds ratio [aOR] 0.44, 0.39-0.49) and rural (aOR 0.80, 0.75-0.84) locations less likely to have ALS responses than urban areas. Of 129,733 emergency medical service (EMS) activations with an ALS responder's impression of seizure, antiepileptic medications were administered in 9%. Medication administration was independently associated with age (aOR 1.008, 95% confidence interval [CI] 1.005-1.010) and gender (aOR 1.22, 95% CI 1.18-1.27), with females receiving medications more than males. Of the 11,698 children who received antiepileptic medications, midazolam was the most commonly used (83%).<br><br>CONCLUSION: The majority of children in the US receive ALS responses for seizures. Although medications are infrequently administered, the majority who received medications had midazolam given, which is the current standard of care. Further research should determine the proportion of children who are continuing to seize upon EMS arrival and would most benefit from immediate treatment.}, }
@article {pmid37525592, year = {2023}, author = {Brooks, BR and Pioro, EP and Sakata, T and Takahashi, F and Hagan, M and Apple, S}, title = {The effects of intervention with intravenous edaravone in Study 19 on hospitalization, tracheostomy, ventilation, and death in patients with amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {68}, number = {4}, pages = {397-403}, doi = {10.1002/mus.27946}, pmid = {37525592}, issn = {1097-4598}, mesh = {Humans ; Edaravone/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Tracheostomy ; Proportional Hazards Models ; Survival Analysis ; }, abstract = {INTRODUCTION/AIMS: Intravenous (IV) edaravone is a US Food and Drug Administration-approved treatment for amyotrophic lateral sclerosis (ALS), shown in clinical trials to slow physical functional decline. In this study we compared the effect of IV edaravone (edaravone-first group) versus placebo followed by IV edaravone (placebo-first group) on survival and additional milestone events.<br><br>METHODS: This work is a post hoc analysis of Study 19/MCI186-19, which was a randomized, placebo-controlled, phase 3 study investigating IV edaravone versus placebo. Study 19 and its 24-week extension have been described previously (NCT01492686). Edaravone-first versus placebo-first group time to events for specific milestone(s) were analyzed post hoc. Time-to-event composite endpoints were time to death; time to death, tracheostomy, or permanent assisted ventilation (PAV); and time to death, tracheostomy, PAV, or hospitalization.<br><br>RESULTS: The risk for death, tracheostomy, PAV, or hospitalization was 53% lower among patients in the edaravone-first vs placebo-first groups (hazard ratio&#x2009;=&#x2009;0.47 [95% confidence interval 0.25 to 0.88], P&#x2009;=&#x2009;.02). The overall effect of IV edaravone on ALS progression could be seen in the significant separation of time-to-event curves for time to death, tracheostomy, PAV, or hospitalization. ALS survival composite endpoint analyses (ALS/SURV) suggested a treatment benefit (least-squares mean difference) for the edaravone-first versus the placebo-first group at week 24 (0.15&#x2009;&#xb1;&#x2009;0.05 [95% confidence interval 0.06 to 0.25], P&#x2009;<&#x2009;.01) and week 48 (0.11&#x2009;&#xb1;&#x2009;0.05 [95% confidence interval 0.02 to 0.21], P&#x2009;=&#x2009;.02).<br><br>DISCUSSION: These analyses illustrate the value of timely and continued IV edaravone treatment, as earlier initiation was associated with a lower risk of death, tracheostomy, PAV, or hospitalization in patients with ALS.}, }
@article {pmid37522558, year = {2023}, author = {Chen, PC and Kaur, K and Ko, MW and Huerta-Yepez, S and Jain, Y and Jewett, A}, title = {Regulation of Cytotoxic Immune Effector Function by AJ3 Probiotic Bacteria in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Critical reviews in immunology}, volume = {43}, number = {1}, pages = {13-26}, doi = {10.1615/CritRevImmunol.2023047231}, pmid = {37522558}, issn = {1040-8401}, mesh = {Humans ; Interleukin-10/pharmacology ; *Amyotrophic Lateral Sclerosis/therapy ; Leukocytes, Mononuclear ; Interleukin-2 ; Cytokines ; Interferon-gamma ; *Antineoplastic Agents/pharmacology ; Antibodies, Monoclonal ; }, abstract = {Our recent studies indicated that amyotrophic lateral sclerosis (ALS) patients suffer from significantly elevated levels of interferon-gamma (IFN-γ) secretion by natural killer (NK) and CD8+ T cells, which may be responsible for the immune-pathologies seen in central nervous system and in peripheral organs of the patients. In order to counter such elevated induction of IFN-γ in patients we designed a treatment strategy to increase anti-inflammatory cytokine interleukin-10 (IL-10) by the use of probiotic strains which significantly increase the levels of IL-10. Therefore, in this paper we demonstrate disease specific functions of Al-Pro (AJ3) formulated for the adjunct treatment of auto-immune diseases including ALS, and compared the function with CA/I-Pro (AJ4) for the treatment of cancer and viral diseases, and NK-CLK (AJ2) for maintenance of immune balance and promotion of disease prevention. The three different formulations of probiotic bacteria have distinct profiles of activation of peripheral blood mononuclear cells (PBMCs), NK, and CD8+ T cells, and their induced activation is different from those mediated by either IL-2 or IL-2 + anti-CD16 monoclonal antibodies (mAbs) or IL-2 + anti-CD3/CD28 mAbs. IL-2 + anti-CD16 mAb activation of PBMCs and NK cells had the highest IFN-γ/IL-10 ratio, whereas IL-2 combination with sAJ4 had the next highest followed by IL-2 + sAJ2 and the lowest was seen with IL-2 + sAJ3. Accordingly, the highest secretion of IFN-γ was seen when the PBMCs and NK cells were treated with IL-2 + sAJ4, intermediate for IL-2 + sAJ2 and the lowest with IL-2 + sAJ3. The levels of IFN-γ induction and the ratio of IFN-γ to IL-10 induced by different probiotic bacteria formulation in the absence of IL-2 treatment remained much lower when compared to those treated in the presence of IL-2. Of note is the difference between NK cells and CD8+ T cells in which synergistic induction of IFN-y by IL-2 + sAJ4 was significantly higher in NK cells than those seen by CD8+ T cells. Based on these results, sAJ3 should be effective in alleviating auto-immunity seen in ALS since it will greatly regulate the levels and function of IFN-γ negatively, decreasing overactivation of cytotoxic immune effectors and prevention of death in motor neurons.}, }
@article {pmid37522557, year = {2023}, author = {Kaur, K and Chen, PC and Ko, MW and Mei, A and Huerta-Yepez, S and Maharaj, D and Malarkannan, S and Jewett, A}, title = {Successes and Challenges in Taming the Beast: Cytotoxic Immune Effectors in Amyotrophic Lateral Sclerosis.}, journal = {Critical reviews in immunology}, volume = {43}, number = {1}, pages = {1-11}, doi = {10.1615/CritRevImmunol.2023047235}, pmid = {37522557}, issn = {1040-8401}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Motor Neurons/metabolism/pathology ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; Cytokines/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of motor neurons in the brain and spinal cord. No effective therapeutic strategies have been established thus far, and therefore there is a significant unmet need for effective therapeutics to arrest the disease and reverse the pathologies induced by it. Although the cause of ALS is not well-defined, it appears to be heterogenous. Currently over 20 genes have been found to be associated with ALS. Family history can only be found in 10% of ALS patients, but in the remaining 90% no association with family history is found. The most common genetic causes are expansion in the C9orf72 gene and mutations in superoxide dismutase 1, TDP-43, and FUS. In our recent study, we also found mutations in TDP43 and FUS in ALS patients. To understand the pathogenesis of the disease, we set ourselves the task of analyzing the phenotype and function of all key immune effectors in ALS patients, comparing them with either a genetically healthy twin or healthy individuals. Our study demonstrated a significant increase in functional activation of NK and CD8+ T cytotoxic immune effectors and release of significant IFN-γ not only by the effector cells but also in the serum of ALS patients. Longitudinal analysis of CD8+ T cell-mediated IFN-γ secretion from ALS patients demonstrated continued and sustained increase in IFN-γ secretion with periods of decrease which coincided with certain treatments; however, the effects were largely short-lived. N-acetyl cysteine (NAC), one of the treatments used, is known to block cell death; however, even though such treatment was able to block most of the proinflammatory cytokines, chemokines, and growth factor release, it was not able to block IFN-γ and TNF-α, the two cytokines we had demonstrated previously to induce differentiation of the cells. In this review, we discuss the contribution of cytotoxic effector cells, especially primary NK cells, supercharged NK cells (sNK), and the contribution of sNK cells in expansion and functional activation of CD8+ T cells to memory/effector T cells in the pathogenesis of ALS. Potential new targeted therapeutic strategies are also discussed.}, }
@article {pmid37520009, year = {2023}, author = {Gouveia, D and Correia, J and Cardoso, A and Carvalho, C and Oliveira, AC and Almeida, A and Gamboa, &#xd3; and Ribeiro, L and Branquinho, M and Sousa, A and Lopes, B and Sousa, P and Moreira, A and Coelho, A and Rêma, A and Alvites, R and Ferreira, A and Maurício, AC and Martins, &#xc2;}, title = {Intensive neurorehabilitation and allogeneic stem cells transplantation in canine degenerative myelopathy.}, journal = {Frontiers in veterinary science}, volume = {10}, number = {}, pages = {1192744}, pmid = {37520009}, issn = {2297-1769}, abstract = {INTRODUCTION: Degenerative myelopathy (DM) is a neurodegenerative spinal cord disease with upper motor neurons, with progressive and chronic clinical signs, similar to amyotrophic lateral sclerosis (ALS). DM has a complex etiology mainly associated with SOD1 gene mutation and its toxic role, with no specific treatment. Daily intensive rehabilitation showed survival time near 8 months but most animals are euthanized 6-12 months after clinical signs onset.<br><br>METHODS: This prospective controlled blinded cohort clinical study aims to evaluate the neural regeneration response ability of DM dogs subjected to an intensive neurorehabilitation protocol with mesenchymal stem cells (MSCs) transplantation. In total, 13 non-ambulatory (OFS 6 or 8) dogs with homozygous genotype DM/DM and diagnosed by exclusion were included. All were allocated to the intensive neurorehabilitation with MSCs protocol (INSCP) group (n = 8) or to the ambulatory rehabilitation protocol (ARP) group (n = 5), which differ in regard to training intensity, modalities frequency, and MSCs transplantation. The INSCP group was hospitalized for 1 month (T0 to T1), followed by MSCs transplantation (T1) and a second month (T2), whereas the ARP group was under ambulatory treatment for the same 2 months.<br><br>RESULTS: Survival mean time of total population was 375 days, with 438 days for the INSCP group and 274 for the ARP group, with a marked difference on the Kaplan-Meier survival analysis. When comparing the literature's results, there was also a clear difference in the one-sample t-test (p = 0.013) with an increase in time of approximately 70%. OFS classifications between groups at each time point were significantly different (p = 0.008) by the one-way ANOVA and the independent sample t-test.<br><br>DISCUSSION: This INSCP showed to be safe, feasible, and a possibility for a long progression of DM dogs with quality of life and functional improvement. This study should be continued.}, }
@article {pmid37517821, year = {2023}, author = {Huang, Y and Yang, H and Yang, B and Zheng, Y and Hou, X and Chen, G and Zhang, W and Zeng, X and DU, B}, title = {Ginsenoside-Rg1 combined with a conditioned medium from induced neuron-like hUCMSCs alleviated the apoptosis in a cell model of ALS through regulating the NF-κB/Bcl-2 pathway.}, journal = {Chinese journal of natural medicines}, volume = {21}, number = {7}, pages = {540-550}, doi = {10.1016/S1875-5364(23)60445-5}, pmid = {37517821}, issn = {1875-5364}, mesh = {Humans ; NF-kappa B/genetics/metabolism ; *Ginsenosides/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Culture Media, Conditioned/pharmacology ; Superoxide Dismutase-1 ; *Neurodegenerative Diseases ; Neurons/metabolism ; Apoptosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons in the brain and spinal cord. One important aspect of ALS pathogenesis is superoxide dismutase 1 (SOD1) mutant-mediated mitochondrial toxicity, leading to apoptosis in neurons. This study aimed to evaluate the neural protective synergistic effects of ginsenosides Rg1 (G-Rg1) and conditioned medium (CM) on a mutational SOD1 cell model, and to explore the underlying mechanisms. We found that the contents of nerve growth factor, glial cell line-derived neurotrophic factor, and brain-derived neurotrophic factor significantly increased in CM after human umbilical cord mesenchymal stem cells (hUCMSCs) were exposed to neuron differentiation reagents for seven days. CM or G-Rg1 decreased the apoptotic rate of SOD1[G93A]-NSC34 cells to a certain extent, but their combination brought about the least apoptosis, compared with CM or G-Rg1 alone. Further research showed that the anti-apoptotic protein Bcl-2 was upregulated in all the treatment groups. Proteins associated with mitochondrial apoptotic pathways, such as Bax, caspase 9 (Cas-9), and cytochrome c (Cyt c), were downregulated. Furthermore, CM or G-Rg1 also inhibited the activation of the nuclear factor-kappa B (NF-κB) signaling pathway by reducing the phosphorylation of p65 and IκBα. CM/G-Rg1 or their combination also reduced the apoptotic rate induced by betulinic acid (BetA), an agonist of the NF-κB signaling pathway. In summary, the combination of CM and G-Rg1 effectively reduced the apoptosis of SOD1[G93A]-NSC34 cells through suppressing the NF-κB/Bcl-2 signaling pathway (Fig. 1 is a graphical representation of the abstract).}, }
@article {pmid37516990, year = {2023}, author = {Tröger, J and Baltes, J and Baykara, E and Kasper, E and Kring, M and Linz, N and Robin, J and Schäfer, S and Schneider, A and Hermann, A}, title = {PROSA-a multicenter prospective observational study to develop low-burden digital speech biomarkers in ALS and FTD.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2023.2239312}, pmid = {37516990}, issn = {2167-9223}, abstract = {Objective: There is a need for novel biomarkers that can indicate disease state, project disease progression, or assess response to treatment for amyotrophic lateral sclerosis (ALS) and associated neurodegenerative diseases such as frontotemporal dementia (FTD). Digital biomarkers are especially promising as they can be collected non-invasively and at low burden for patients. Speech biomarkers have the potential to objectively measure cognitive, motor as well as respiratory symptoms at low-cost and in a remote fashion using widely available technology such as telephone calls. Methods: The PROSA study aims to develop and evaluate low-burden frequent prognostic digital speech biomarkers. The main goal is to create a single, easy-to-perform battery that serves as a valid and reliable proxy for cognitive, respiratory, and motor domains in ALS and FTD. The study will be a multicenter 12-months observational study aiming to include 75 ALS and 75 FTD patients as well as 50 healthy controls and build on three established longitudinal cohorts: DANCER, DESCRIBE-ALS and DESCRIBE-FTD. In addition to the extensive clinical phenotyping in DESCRIBE, PROSA collects a comprehensive speech protocol in fully remote and automated fashion over the telephone at four time points. This longitudinal speech data, together with gold standard measures, will allow advanced speech analysis using artificial intelligence for the development of speech-based phenotypes of ALS and FTD patients measuring cognitive, motor and respiratory symptoms. Conclusion: Speech-based phenotypes can be used to develop diagnostic and prognostic models predicting clinical change. Results are expected to have implications for future clinical trial stratification as well as supporting innovative trial designs in ALS and FTD.}, }
@article {pmid37516663, year = {2023}, author = {Ahmed, M and Spicer, C and Harley, J and Taylor, JP and Hanna, M and Patani, R and Greensmith, L}, title = {Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models.}, journal = {Molecular neurobiology}, volume = {60}, number = {12}, pages = {6896-6915}, pmid = {37516663}, issn = {1559-1182}, support = {MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Frontotemporal Dementia/drug therapy/genetics/pathology ; Hydroxylamines/therapeutic use ; Heat-Shock Response ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are now known as parts of a disease spectrum with common pathological features and genetic causes. However, as both conditions are clinically heterogeneous, patient groups may be phenotypically similar but pathogenically and genetically variable. Despite numerous clinical trials, there remains no effective therapy for these conditions, which, in part, may be due to challenges of therapy development in a heterogeneous patient population. Disruption to protein homeostasis is a key feature of different forms of ALS and FTD. Targeting the endogenous protein chaperone system, the heat shock response (HSR) may, therefore, be a potential therapeutic approach. We conducted a preclinical study of a known pharmacological amplifier of the HSR, called arimoclomol, in mice with a mutation in valosin-containing protein (VCP) which causes both ALS and FTD in patients. We demonstrate that amplification of the HSR ameliorates the ALS/FTD-like phenotype in the spinal cord and brain of mutant VCP mice and prevents neuronal loss, replicating our earlier findings in the SOD1 mouse model of ALS. Moreover, in human cell models, we demonstrate improvements in pathology upon arimoclomol treatment in mutant VCP patient fibroblasts and iPSC-derived motor neurons. Our findings suggest that targeting of the HSR may have therapeutic potential, not only in non-SOD1 ALS, but also for the treatment of FTD.}, }
@article {pmid37511037, year = {2023}, author = {Xiang, L and Wang, Y and Liu, S and Liu, B and Jin, X and Cao, X}, title = {Targeting Protein Aggregates with Natural Products: An Optional Strategy for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37511037}, issn = {1422-0067}, support = {32000387//National Natural Science Foundation of China/ ; LY23C060001//Zhejiang Provincial Natural Science Foundation/ ; 2021LFR053//Scientific Research Foundation of Zhejiang A&amp;F University/ ; 19 0069//Swedish Cancer Society/ ; VR 2019-03604//Swedish Research Council/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Protein Aggregates ; *Biological Products/pharmacology/therapeutic use ; *Parkinson Disease ; *Alzheimer Disease ; }, abstract = {Protein aggregation is one of the hallmarks of aging and aging-related diseases, especially for the neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and others. In these diseases, many pathogenic proteins, such as amyloid-β, tau, α-Syn, Htt, and FUS, form aggregates that disrupt the normal physiological function of cells and lead to associated neuronal lesions. Protein aggregates in NDs are widely recognized as one of the important targets for the treatment of these diseases. Natural products, with their diverse biological activities and rich medical history, represent a great treasure trove for the development of therapeutic strategies to combat disease. A number of in vitro and in vivo studies have shown that natural products, by virtue of their complex molecular scaffolds that specifically bind to pathogenic proteins and their aggregates, can inhibit the formation of aggregates, disrupt the structure of aggregates and destabilize them, thereby alleviating conditions associated with NDs. Here, we systematically reviewed studies using natural products to improve disease-related symptoms by reducing or inhibiting the formation of five pathogenic protein aggregates associated with NDs. This information should provide valuable insights into new directions and ideas for the treatment of neurodegenerative diseases.}, }
@article {pmid37510999, year = {2023}, author = {Halder, SK and Milner, R}, title = {Spinal Cord Blood Vessels in Aged Mice Show Greater Levels of Hypoxia-Induced Vascular Disruption and Microglial Activation.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37510999}, issn = {1422-0067}, support = {RF1 NS119477/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; Hypoxia ; Microglia/pathology ; *Spinal Cord/pathology ; *White Matter/pathology ; *Aging/pathology ; }, abstract = {In response to chronic mild hypoxia (CMH, 8% O2), spinal cord blood vessels launch a robust angiogenic response that is associated with transient disruption of the blood-spinal cord barrier (BSCB) which, in turn, triggers a microglial vasculo-protective response. Because hypoxia occurs in many age-related conditions, the goal of this study was to define how aging influences these responses by comparing events in young (8-10 weeks) and aged (20 months) mice. This revealed that aged mice had much greater (3-4-fold) levels of hypoxic-induced BSCB disruption than young mice and that, while the early stage of the angiogenic response in aged mice was no different to young mice, the maturation of newly formed vessels was significantly delayed. Interestingly, microglia in the spinal cords of aged mice were much more activated than young mice, even under normoxic conditions, and this was further enhanced by CMH, though, surprisingly, this resulted in reduced microglial clustering around leaky blood vessels and diminished vasculo-protection. Vascular disruption was associated with loss of myelin in spinal cord white matter (WM) in both young and aged mice. Furthermore, it was notable that the spinal cord of aged mice contained a lower density of Olig2+ oligodendroglial cells even under normoxic conditions and that CMH significantly reduced the density of Olig2+ cells in spinal cord WM of the aged, but not the young, mice. These results demonstrate that spinal cord blood vessels of aged mice are much more vulnerable to the damaging effects of hypoxia than young mice, in part due to the reduced vasculo-protection conferred by chronically activated microglial cells. These observations may have implications for the pathogenesis and/or treatment of spinal cord diseases such as amyotrophic lateral sclerosis (ALS) and suggest that an improvement in microglial function could offer therapeutic potential for treating these age-related conditions.}, }
@article {pmid37508574, year = {2023}, author = {Malhotra, S and Miras, MCM and Pappolla, A and Montalban, X and Comabella, M}, title = {Liquid Biopsy in Neurological Diseases.}, journal = {Cells}, volume = {12}, number = {14}, pages = {}, pmid = {37508574}, issn = {2073-4409}, mesh = {Humans ; Liquid Biopsy/methods ; *Cell-Free Nucleic Acids ; *MicroRNAs ; *Central Nervous System Neoplasms ; Biomarkers ; }, abstract = {The most recent and non-invasive approach for studying early-stage biomarkers is liquid biopsy. This implies the extraction and analysis of non-solid biological tissues (serum, plasma, saliva, urine, and cerebrospinal fluid) without undergoing invasive procedures to determine disease prognosis. Liquid biopsy can be used for the screening of several components, such as extracellular vesicles, microRNAs, cell-free DNA, cell-free mitochondrial and nuclear DNA, circulating tumour cells, circulating tumour DNA, transfer RNA, and circular DNA or RNA derived from body fluids. Its application includes early disease diagnosis, the surveillance of disease activity, and treatment response monitoring, with growing evidence for validating this methodology in cancer, liver disease, and central nervous system (CNS) disorders. This review will provide an overview of mentioned liquid biopsy components, which could serve as valuable biomarkers for the evaluation of complex neurological conditions, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, stroke, traumatic brain injury, CNS tumours, and neuroinfectious diseases. Furthermore, this review highlights the future directions and potential limitations associated with liquid biopsy.}, }
@article {pmid37508548, year = {2023}, author = {Morello, G and La Cognata, V and Guarnaccia, M and La Bella, V and Conforti, FL and Cavallaro, S}, title = {A Diagnostic Gene-Expression Signature in Fibroblasts of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {14}, pages = {}, pmid = {37508548}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism ; Transcriptome/genetics ; *Neurodegenerative Diseases/metabolism ; Gene Expression Profiling/methods ; Fibroblasts/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease with limited treatment options. Diagnosis can be difficult due to the heterogeneity and non-specific nature of the initial symptoms, resulting in delays that compromise prompt access to effective therapeutic strategies. Transcriptome profiling of patient-derived peripheral cells represents a valuable benchmark in overcoming such challenges, providing the opportunity to identify molecular diagnostic signatures. In this study, we characterized transcriptome changes in skin fibroblasts of sporadic ALS patients (sALS) and controls and evaluated their utility as a molecular classifier for ALS diagnosis. Our analysis identified 277 differentially expressed transcripts predominantly involved in transcriptional regulation, synaptic transmission, and the inflammatory response. A support vector machine classifier based on this 277-gene signature was developed to discriminate patients with sALS from controls, showing significant predictive power in both the discovery dataset and in six independent publicly available gene expression datasets obtained from different sALS tissue/cell samples. Taken together, our findings support the utility of transcriptional signatures in peripheral cells as valuable biomarkers for the diagnosis of ALS.}, }
@article {pmid37508478, year = {2023}, author = {La Cognata, V and D'Amico, AG and Maugeri, G and Morello, G and Guarnaccia, M and Magrì, B and Aronica, E and D'Agata, V and Cavallaro, S}, title = {CXCR2 Is Deregulated in ALS Spinal Cord and Its Activation Triggers Apoptosis in Motor Neuron-Like Cells Overexpressing hSOD1-G93A.}, journal = {Cells}, volume = {12}, number = {14}, pages = {}, pmid = {37508478}, issn = {2073-4409}, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Apoptosis ; Chemokine CXCL2/metabolism ; Ligands ; Mice, Transgenic ; Motor Neurons/pathology ; *Neurodegenerative Diseases/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by progressive depletion of motor neurons (MNs). Recent evidence suggests a role in ALS pathology for the C-X-C motif chemokine receptor 2 (CXCR2), whose expression was found increased at both mRNA and protein level in cortical neurons of sporadic ALS patients. Previous findings also showed that the receptor inhibition is able to prevent iPSC-derived MNs degeneration in vitro and improve neuromuscular function in SOD1-G93A mice. Here, by performing transcriptional analysis and immunofluorescence studies, we detailed the increased expression and localization of CXCR2 and its main ligand CXCL8 in the human lumbar spinal cord of sporadic ALS patients. We further investigated the functional role of CXCR2/ligands axis in NSC-34 motor neuron-like cells expressing human wild-type (WT) or mutant (G93A) SOD1. A significant expression of CXCR2 was found in doxycycline-induced G93A-SOD1-expressing cells, but not in WT cells. In vitro assays showed CXCR2 activation by GROα and MIP2α, two murine endogenous ligands and functional homologs of CXCL8, reduces cellular viability and triggers apoptosis in a dose dependent manner, while treatment with reparixin, a non-competitive allosteric CXCR2 inhibitor, effectively counteracts GROα and MIP2α toxicity, significantly inhibiting the chemokine-induced cell death. Altogether, data further support a role of CXCR2 axis in ALS etiopathogenesis and confirm its pharmacological modulation as a candidate therapeutic strategy.}, }
@article {pmid37500993, year = {2023}, author = {Ludolph, A and Dupuis, L and Kasarskis, E and Steyn, F and Ngo, S and McDermott, C}, title = {Nutritional and metabolic factors in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {9}, pages = {511-524}, pmid = {37500993}, issn = {1759-4766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases ; Energy Metabolism ; Prognosis ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease that is classically thought to impact the motor system. Over the past 20 years, research has started to consider the contribution of non-motor symptoms and features of the disease, and how they might affect ALS prognosis. Of the non-motor features of the disease, nutritional status (for example, malnutrition) and metabolic balance (for example, weight loss and hypermetabolism) have been consistently shown to contribute to more rapid disease progression and/or earlier death. Several complex cellular changes observed in ALS, including mitochondrial dysfunction, are also starting to be shown to contribute to bioenergetic failure. The resulting energy depletion in high energy demanding neurons makes them sensitive to apoptosis. Given that nutritional and metabolic stressors at the whole-body and cellular level can impact the capacity to maintain optimal function, these factors present avenues through which we can identify novel targets for treatment in ALS. Several clinical trials are now underway evaluating the effectiveness of modifying energy balance in ALS, making this article timely in reviewing the evidence base for metabolic and nutritional interventions.}, }
@article {pmid37494786, year = {2023}, author = {Jin, S and Zhang, L and Wang, L}, title = {Kaempferol, a potential neuroprotective agent in neurodegenerative diseases: From chemistry to medicine.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {165}, number = {}, pages = {115215}, doi = {10.1016/j.biopha.2023.115215}, pmid = {37494786}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/pathology ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; *Amyotrophic Lateral Sclerosis/drug therapy ; Kaempferols/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy ; *Parkinson Disease/drug therapy ; *Huntington Disease/drug therapy ; }, abstract = {Neurodegenerative diseases (NDDs) encompass a range of conditions that involve progressive deterioration and dysfunction of the nervous system. Some of the common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Although significant progress has been made in understanding the pathological mechanisms of NDDs in recent years, the development of targeted and effective drugs for their treatment remains challenging. Kaempferol is a flavonoid whose derivatives include kaempferol-O-rhamnoside, 3-O-β-rutinoside/6-hydroxykaempferol 3,6-di-O-β-d-glucoside, and kaempferide. Emerging studies have suggested that kaempferol and its derivatives possess neuroprotective properties and may have potential therapeutic benefits in NDDs. Here, we aimed to provide a theoretical basis for the use of kaempferol and its derivatives in the clinical treatment of NDDs. We systematically reviewed the literature in the PubMed, Web of Science, and Science Direct databases until June 2022 using the search terms "kaempferol," "kaempferol derivatives," "NDDs," "pharmacokinetics," and "biosynthesis" according to the reporting items for systematic review (PRISMA) standard. Based on combined results of in vivo and in vitro studies, we summarize the basic mechanisms and targets of kaempferol and its derivatives in the management of AD, PD, HD, and ALS. Kaempferol and its derivatives exert a neuroprotective role mainly by preventing the deposition of amyloid fibrils (such as Aβ, tau, and α-synuclein), inhibiting microglia activation, reducing the release of inflammatory factors, restoring the mitochondrial membrane to prevent oxidative stress, protecting the blood-brain barrier, and inhibiting specific enzyme activities (such as cholinesterase). Kaempferol and its derivatives are promising natural neuroprotective agents. By determining their pharmacological mechanism, kaempferol and its derivatives may be new candidate drugs for the treatment of NDDs.}, }
@article {pmid37493197, year = {2024}, author = {Sun, Y and Benatar, M and Mascías Cadavid, J and Ennist, D and Wicks, P and Staats, K and Beauchamp, M and Jhooty, S and Pattee, G and Brown, A and Bertorini, T and Barkhaus, P and Bromberg, M and Carter, G and Bedlack, R and Li, X}, title = {ALSUntangled #71: Nuedexta.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {218-222}, doi = {10.1080/21678421.2023.2239292}, pmid = {37493197}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Dextromethorphan/therapeutic use ; Drug Combinations ; *Quinidine/therapeutic use ; }, abstract = {Nuedexta is a combination of dextromethorphan hydrobromide and quinidine sulfate and was approved by the Food and Drug Administration (FDA) in 2010 to treat pseudobulbar affect (PBA). There have since been anecdotal case reports of bulbar function improvements after Nuedexta treatment. Here, we review the off-label use of Nuedexta for improving bulbar function in people with ALS. Nuedexta has plausible mechanisms for protecting brain stem motor neurons via its effects on S1R and glutamate excitotoxicity. Recent clinical trials support that Nuedexta can improve bulbar function in PALS, with or without PBA. Nuedexta causes mild to moderate side effects. Based on this information, we support considering Nuedexta treatment for bulbar dysfunction in ALS patients with or without PBA.}, }
@article {pmid37490673, year = {2023}, author = {Kovrazhkina, EA and Serdyuk, AV and Razinskaya, OD and Shurdumova, MH and Vyatkina, NV and Baranova, EA}, title = {[Myasthenic syndrome in a patient with end-stage amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {123}, number = {7}, pages = {102-107}, doi = {10.17116/jnevro2023123071102}, pmid = {37490673}, issn = {1997-7298}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/therapy ; *Myasthenia Gravis/complications/diagnosis ; *Lambert-Eaton Myasthenic Syndrome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and myasthenia gravis are diseases with similar clinical features but different prognosis and approach to treatment. It is possible as an extremely rare combination of these diseases, as well as myasthenia gravis with signs of ALS (MuSK-positive), as well as ALS, accompanied by myasthenic syndrome. Latter option is the most common. Myasthenic syndrome accompanying the ALS characterized by pathological muscle fatigue signs, symptoms variability during the day, partial sensitivity to neostigmine, M-wave decrements detection during electromyographyc study. We present a case of a patient with terminal ALS and myasthenic syndrome. The main pathogenesis theories of this condition and the differential diagnosis of ALS and myasthenia gravis are discussed.}, }
@article {pmid37489926, year = {2023}, author = {Greensmith, L and Bryson, JB}, title = {The cholesterol depleting agent, (2-Hydroxypropyl)-ß-cyclodextrin, does not affect disease progression in SOD1[G93A] mice.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2023.2239867}, pmid = {37489926}, issn = {2167-9223}, abstract = {Objective: Previously, we demonstrated that Amyloid Precursor Protein (APP) contributes to pathology in the SOD1[G93A] mouse model of ALS and that genetic ablation of APP in SOD1[G93A] mice significantly improved multiple disease parameters, including muscle innervation and motor neuron survival. We also observed elevated levels of potentially neurotoxic Aß peptides that have been implicated in Alzheimer's Disease (AD) pathogenesis, within motor neurons and astrocytes in SOD1[G93A] mice. More recently, it has been shown that blocking Aß production improves outcome measures in SOD1[G93A] mice. The cyclodextrin, (2-Hydroxypropyl)-ß-cyclodextrin (HP-β-CD), has previously been shown to deplete intraneuronal unesterified cholesterol, resulting in effective reduction of Aß production and amelioration of disease progression in mouse models of AD and Niemann Pick Type C (NPC) disease. Here, we tested whether HP-β-CD could also improve phenotypic progression in SOD1[G93A] mice. Methods: Pre-symptomatic male SOD1[G93A] mice were randomly assigned to the following treatment groups: HP-β-CD (4000mg/kg, n = 9) or vehicle (saline; n = 10), delivered by weekly subcutaneous injection, commencing at 67 days of age. Longitudinal grip-strength and body mass analysis was performed until late-stage disease (120 days of age), followed by in vivo bilateral isometric muscle tension analysis of tibialis anterior (TA) and extensor digitorum longus (EDL) muscles. Results: HP-β-CD administration had no effect on body mass or grip-strength compared to vehicle treated SOD1[G93A] mice. Similarly, HP-β-CD treatment had no effect on muscle force, contractile properties or motor unit number estimates (MUNE) at late-stage disease in SOD1[G93A] mice. Conclusion: This study shows that HP-β-CD does not confer any therapeutic benefit in SOD1[G93A] mice. However, the absence of detrimental effects is informative, given the common use of cyclodextrins as complexing agents for other pharmaceutical products, their standalone therapeutic potential and the emerging association between dyslipidaemia and ALS progression.}, }
@article {pmid37489441, year = {2023}, author = {Ramakrishna, K and Nalla, LV and Naresh, D and Venkateswarlu, K and Viswanadh, MK and Nalluri, BN and Chakravarthy, G and Duguluri, S and Singh, P and Rai, SN and Kumar, A and Singh, V and Singh, SK}, title = {WNT-β Catenin Signaling as a Potential Therapeutic Target for Neurodegenerative Diseases: Current Status and Future Perspective.}, journal = {Diseases (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {37489441}, issn = {2079-9721}, abstract = {Wnt/β-catenin (WβC) signaling pathway is an important signaling pathway for the maintenance of cellular homeostasis from the embryonic developmental stages to adulthood. The canonical pathway of WβC signaling is essential for neurogenesis, cell proliferation, and neurogenesis, whereas the noncanonical pathway (WNT/Ca[2+] and WNT/PCP) is responsible for cell polarity, calcium maintenance, and cell migration. Abnormal regulation of WβC signaling is involved in the pathogenesis of several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and spinal muscular atrophy (SMA). Hence, the alteration of WβC signaling is considered a potential therapeutic target for the treatment of neurodegenerative disease. In the present review, we have used the bibliographical information from PubMed, Google Scholar, and Scopus to address the current prospects of WβC signaling role in the abovementioned neurodegenerative diseases.}, }
@article {pmid37488208, year = {2023}, author = {Aly, A and Laszlo, ZI and Rajkumar, S and Demir, T and Hindley, N and Lamont, DJ and Lehmann, J and Seidel, M and Sommer, D and Franz-Wachtel, M and Barletta, F and Heumos, S and Czemmel, S and Kabashi, E and Ludolph, A and Boeckers, TM and Henstridge, CM and Catanese, A}, title = {Integrative proteomics highlight presynaptic alterations and c-Jun misactivation as convergent pathomechanisms in ALS.}, journal = {Acta neuropathologica}, volume = {146}, number = {3}, pages = {451-475}, pmid = {37488208}, issn = {1432-0533}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Neurodegenerative Diseases/pathology ; Proteomics ; Superoxide Dismutase-1/genetics ; Motor Neurons/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease mainly affecting upper and lower motoneurons. Several functionally heterogeneous genes have been associated with the familial form of this disorder (fALS), depicting an extremely complex pathogenic landscape. This heterogeneity has limited the identification of an effective therapy, and this bleak prognosis will only improve with a greater understanding of convergent disease mechanisms. Recent evidence from human post-mortem material and diverse model systems has highlighted the synapse as a crucial structure actively involved in disease progression, suggesting that synaptic aberrations might represent a shared pathological feature across the ALS spectrum. To test this hypothesis, we performed the first comprehensive analysis of the synaptic proteome from post-mortem spinal cord and human iPSC-derived motoneurons carrying mutations in the major ALS genes. This integrated approach highlighted perturbations in the molecular machinery controlling vesicle release as a shared pathomechanism in ALS. Mechanistically, phosphoproteomic analysis linked the presynaptic vesicular phenotype to an accumulation of cytotoxic protein aggregates and to the pro-apoptotic activation of the transcription factor c-Jun, providing detailed insights into the shared pathobiochemistry in ALS. Notably, sub-chronic treatment of our iPSC-derived motoneurons with the fatty acid docosahexaenoic acid exerted a neuroprotective effect by efficiently rescuing the alterations revealed by our multidisciplinary approach. Together, this study provides strong evidence for the central and convergent role played by the synaptic microenvironment within the ALS spinal cord and highlights a potential therapeutic target that counteracts degeneration in a heterogeneous cohort of human motoneuron cultures.}, }
@article {pmid37484758, year = {2023}, author = {Chen, TY and Hsu, CW and Chang, YP and Wang, MT and Wu, YJ and Wang, CH and Wang, KY and Chu, TH and Lee, YK}, title = {Percutaneous transhepatic duodenal drainage is good option for afferent loop syndrome for obstructive colorectal cancer patient with history of Billroth's operation II: A case report of a rare postoperative complication.}, journal = {Clinical case reports}, volume = {11}, number = {7}, pages = {e7725}, pmid = {37484758}, issn = {2050-0904}, abstract = {KEY CLINICAL MESSAGE: Temporal percutaneous transhepatic duodenum drainage (PTDD) seems to be effective in the treatment of postoperative afferent loop syndrome (ALS) following transverse loop colostomy for obstructive colorectal cancer.<br><br>ABSTRACT: Management of obstructive colorectal cancer still remains a challenge. There are various options with different risks of mortality and mobility for obstructive colorectal cancer. A rare unexpected postoperative ALS following a low anterior resection and transverse loop colostomy for obstructive colorectal cancer is presented in this report. A 64-year-old man had the acute ALS had been noted 10&#x2009;days after transverse loop colostomy. An option was temporal PTDD treatment in the patient with history of Billroth's operation II for upper gastrointestinal bleeding 30&#x2009;years ago. Acute ALS was treated by temporal PTDD. The drainage tube for PTDD was not removed until closure of the transverse colostomy 2&#x2009;months later. The patient recovered uneventfully. Acute ALS after transverse loop colostomy for obstructive colorectal cancer is rare and has never been reported in the literature. The mechanism of acute ALS after construction of a loop colostomy and the treatment strategy of PTDD for acute ALS is presented.}, }
@article {pmid37483353, year = {2023}, author = {Shi, Y and Zhao, Y and Lu, L and Gao, Q and Yu, D and Sun, M}, title = {CRISPR/Cas9: implication for modeling and therapy of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1223777}, pmid = {37483353}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a deadly neurological disease with a complicated and variable pathophysiology yet to be fully understood. There is currently no effective treatment available to either slow or terminate it. However, recent advances in ALS genomics have linked genes to phenotypes, encouraging the creation of novel therapeutic approaches and giving researchers more tools to create efficient animal models. Genetically engineered rodent models replicating ALS disease pathology have a high predictive value for translational research. This review addresses the history of the evolution of gene editing tools, the most recent ALS disease models, and the application of CRISPR/Cas9 against ALS disease.}, }
@article {pmid37480846, year = {2023}, author = {Ziff, OJ and Harley, J and Wang, Y and Neeves, J and Tyzack, G and Ibrahim, F and Skehel, M and Chakrabarti, AM and Kelly, G and Patani, R}, title = {Nucleocytoplasmic mRNA redistribution accompanies RNA binding protein mislocalization in ALS motor neurons and is restored by VCP ATPase inhibition.}, journal = {Neuron}, volume = {111}, number = {19}, pages = {3011-3027.e7}, doi = {10.1016/j.neuron.2023.06.019}, pmid = {37480846}, issn = {1097-4199}, support = {FC010110/WT_/Wellcome Trust/United Kingdom ; FC010110/CRUK_/Cancer Research UK/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; FC010110/MRC_/Medical Research Council/United Kingdom ; MC_PC_19038/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Adenosine Triphosphatases/genetics/metabolism ; RNA, Messenger/metabolism ; Motor Neurons/metabolism ; RNA-Binding Proteins/metabolism ; Valosin Containing Protein/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by nucleocytoplasmic mislocalization of the RNA-binding protein (RBP) TDP-43. However, emerging evidence suggests more widespread mRNA and protein mislocalization. Here, we employed nucleocytoplasmic fractionation, RNA sequencing, and mass spectrometry to investigate the localization of mRNA and protein in induced pluripotent stem cell-derived motor neurons (iPSMNs) from ALS patients with TARDBP and VCP mutations. ALS mutant iPSMNs exhibited extensive nucleocytoplasmic mRNA redistribution, RBP mislocalization, and splicing alterations. Mislocalized proteins exhibited a greater affinity for redistributed transcripts, suggesting a link between RBP mislocalization and mRNA redistribution. Notably, treatment with ML240, a VCP ATPase inhibitor, partially restored mRNA and protein localization in ALS mutant iPSMNs. ML240 induced changes in the VCP interactome and lysosomal localization and reduced oxidative stress and DNA damage. These findings emphasize the link between RBP mislocalization and mRNA redistribution in ALS motor neurons and highlight the therapeutic potential of VCP inhibition.}, }
@article {pmid37474587, year = {2023}, author = {Zilio, F and Gomez-Pilar, J and Chaudhary, U and Fogel, S and Fomina, T and Synofzik, M and Schöls, L and Cao, S and Zhang, J and Huang, Z and Birbaumer, N and Northoff, G}, title = {Altered brain dynamics index levels of arousal in complete locked-in syndrome.}, journal = {Communications biology}, volume = {6}, number = {1}, pages = {757}, pmid = {37474587}, issn = {2399-3642}, support = {//CIHR/Canada ; }, mesh = {Humans ; *Locked-In Syndrome ; Electroencephalography/methods ; Brain/physiology ; Wakefulness ; Biomarkers ; }, abstract = {Complete locked-in syndrome (CLIS) resulting from late-stage amyotrophic lateral sclerosis (ALS) is characterised by loss of motor function and eye movements. The absence of behavioural indicators of consciousness makes the search for neuronal correlates as possible biomarkers clinically and ethically urgent. EEG-based measures of brain dynamics such as power-law exponent (PLE) and Lempel-Ziv complexity (LZC) have been shown to have explanatory power for consciousness and may provide such neuronal indices for patients with CLIS. Here, we validated PLE and LZC (calculated in a dynamic way) as benchmarks of a wide range of arousal states across different reference states of consciousness (e.g., awake, sleep stages, ketamine, sevoflurane). We show a tendency toward high PLE and low LZC, with high intra-subject fluctuations and inter-subject variability in a cohort of CLIS patients with values graded along different arousal states as in our reference data sets. In conclusion, changes in brain dynamics indicate altered arousal in CLIS. Specifically, PLE and LZC are potentially relevant biomarkers to identify or diagnose the arousal level in CLIS and to determine the optimal time point for treatment, including communication attempts.}, }
@article {pmid37470509, year = {2023}, author = {Strnad, P and San Martin, J}, title = {RNAi therapeutics for diseases involving protein aggregation: fazirsiran for alpha-1 antitrypsin deficiency-associated liver disease.}, journal = {Expert opinion on investigational drugs}, volume = {32}, number = {7}, pages = {571-581}, doi = {10.1080/13543784.2023.2239707}, pmid = {37470509}, issn = {1744-7658}, mesh = {Humans ; *Protein Aggregates ; RNA Interference ; RNAi Therapeutics ; *alpha 1-Antitrypsin Deficiency/complications/genetics/therapy ; RNA, Small Interfering ; }, abstract = {INTRODUCTION: Therapeutic agents that prevent protein misfolding or promote protein clearance are being studied to treat proteotoxic diseases. Among them, alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the alpha-1 antitrypsin (SERPINA1) gene. Fazirsiran is a small interfering RNA (siRNA) that is intended to address the underlying cause of liver disease associated with AATD through the RNA interference (RNAi) mechanism.<br><br>AREAS COVERED: This article describes the role of misfolded proteins and protein aggregates in disease and options for therapeutic approaches. The RNAi mechanism is discussed, along with how the siRNA therapeutic fazirsiran for the treatment of AATD was developed. We also describe the implications of siRNA therapeutics in extrahepatic diseases.<br><br>EXPERT OPINION: Using RNAi as a therapeutic approach is well suited to treat disease in conditions where an excess of a protein or the effect of an abnormal mutated protein causes disease. The results observed for the first few siRNA therapeutics that were approved or are in development provide an important promise for the development of future drugs that can address such conditions in a specific and targeted way. Current developments should enable the use of RNAi therapeutics outside the liver, where there are many more possible diseases to address.}, }
@article {pmid37467213, year = {2023}, author = {Oey, A and McClure, M and Symons, JA and Chanda, S and Fry, J and Smith, PF and Luciani, K and Fayon, M and Chokephaibulkit, K and Uppala, R and Bernatoniene, J and Furuno, K and Stanley, T and Huntjens, D and Witek, J and , }, title = {Lumicitabine, an orally administered nucleoside analog, in infants hospitalized with respiratory syncytial virus (RSV) infection: Safety, efficacy, and pharmacokinetic results.}, journal = {PloS one}, volume = {18}, number = {7}, pages = {e0288271}, pmid = {37467213}, issn = {1932-6203}, mesh = {Adult ; Child ; Humans ; Infant ; Infant, Newborn ; Antiviral Agents/adverse effects ; *Neutropenia/complications ; Nucleosides/therapeutic use ; *Respiratory Syncytial Virus Infections ; *Respiratory Syncytial Virus, Human ; }, abstract = {Respiratory syncytial virus (RSV) infection is the leading cause of infant hospitalizations and mortality. Lumicitabine, an oral nucleoside analog was studied for the treatment of RSV. The phase 1b and phase 2b studies reported here assessed the safety, pharmacokinetics, and pharmacodynamics of lumicitabine in infants/neonates hospitalized with RSV. In the phase 1b study, infants (≥1 to ≤12 months) and neonates (<28 days) received a single-ascending or multiple-ascending doses (single loading dose [LD] then 9 maintenance doses [MD] of lumicitabine, or placebo [3:1]). In the phase 2b study, infants/children (28 days to ≤36 months old) received lumicitabine 40/20 mg/kg, 60/40 mg/kg LD/MD twice-daily or placebo (1:1:1) for 5 days. Safety, pharmacokinetics, and efficacy parameters were assessed over 28 days. Lumicitabine was associated with a dose-related increase in the incidence and severity of reversible neutropenia. Plasma levels of ALS-008112, the active nucleoside analog, were dose-proportional with comparable mean exposure levels at the highest doses in both studies. There were no significant differences between the lumicitabine groups and placebo in reducing viral load, time to viral non-detectability, and symptom resolution. No emergent resistance-associated substitutions were observed at the RSV L-gene positions of interest. In summary, lumicitabine was associated with a dose-related increase in the incidence and severity of reversible neutropenia and failed to demonstrate antiviral activity in RSV-infected hospitalized infants. This contrasts with the findings of the previous RSV-A adult challenge study where significant antiviral activity was noted, without incidence of neutropenia. Trial registration ClinicalTrials.gov Identifier: NCT02202356 (phase 1b); NCT03333317 (phase 2b).}, }
@article {pmid37466825, year = {2024}, author = {Poppe, C and Elger, BS}, title = {Brain-Computer Interfaces, Completely Locked-In State in Neurodegenerative Diseases, and End-of-Life Decisions.}, journal = {Journal of bioethical inquiry}, volume = {21}, number = {1}, pages = {19-27}, pmid = {37466825}, issn = {1872-4353}, mesh = {Humans ; *Brain-Computer Interfaces/ethics ; *Terminal Care/ethics ; *Neurodegenerative Diseases ; *Quality of Life ; *Decision Making/ethics ; Suicide, Assisted/ethics ; Locked-In Syndrome ; Mental Competency ; }, abstract = {In the future, policies surrounding end-of-life decisions will be faced with the question of whether competent people in a completely locked-in state should be enabled to make end-of-life decisions via brain-computer interfaces (BCI). This article raises ethical issues with acting through BCIs in the context of these decisions, specifically self-administration requirements within assisted suicide policies. We argue that enabling patients to end their life even once they have entered completely locked-in state might, paradoxically, prolong and uphold their quality of life.}, }
@article {pmid37465304, year = {2023}, author = {Kargbo, RB}, title = {Microbiome-Gut-Brain Axis Modulation: New Approaches in Treatment of Parkinson's Disease and Amyotrophic Lateral Sclerosis.}, journal = {ACS medicinal chemistry letters}, volume = {14}, number = {7}, pages = {886-888}, pmid = {37465304}, issn = {1948-5875}, abstract = {Parkinson's Disease (PD) is a neurodegenerative movement disorder characterized by symptoms like resting tremor, rigidity, bradykinesia, and postural instability, mainly due to dopamine depletion and degeneration of dopaminergic neurons. Mitochondrial dysfunction plays a critical role in the disease's progression, while amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig's disease, is a fatal progressive neurodegenerative disease characterized by significant motor neuron loss in the primary motor cortex, brainstem, and spinal cord. This loss results in impaired movements such as breathing, leading to death within 2-5 years of diagnosis. Patients experience muscle weakness in the hands, arms, legs, and swallowing muscles and may require breathing aids. This Patent Highlight describes blends, such as microbiome compositions, that can be used to treat various diseases or conditions, particularly those affecting the nervous system, like neurodegenerative diseases (PD and ALS).}, }
@article {pmid37461717, year = {2023}, author = {Provasek, VE and Kodavati, M and Guo, W and Wang, H and Boldogh, I and Van Den Bosch, L and Britz, G and Hegde, M}, title = {lncRNA Sequencing Reveals Neurodegeneration-associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists In Motor Neurons.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37461717}, issn = {2693-5015}, support = {R01 NS088645/NS/NINDS NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {Fused-in Sarcoma (FUS) gene mutations have been implicated in amyotrophic lateral sclerosis (ALS). This study aimed to investigate the impact of FUS mutations (R521H and P525L) on the transcriptome of induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs). Using RNA sequencing (RNA Seq), we characterized differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs), and subsequently predicted lncRNA-mRNA target pairs (TAR pairs). Our results show that FUS mutations significantly altered expression profiles of mRNAs and lncRNAs in iPSCs. We identified key differentially regulated TAR pairs, including LMO3, TMEM132D, ERMN, GPR149, CRACD, and ZNF404 in mutant FUS iPSCs. We performed reverse transcription PCR (RT-PCR) validation in iPSCs and iMNs. Validation confirmed RNA-Seq findings and suggested that mutant FUS-induced transcriptional alterations persisted from iPSCs into differentiated iMNs. Functional enrichment analyses of DEGs indicated pathways associated with neuronal development and carcinogenesis that were likely altered by FUS mutations. Ingenuity Pathway Analysis (IPA) and GO network analysis of lncRNA-targeted mRNAs indicated associations related to RNA metabolism, lncRNA regulation, and DNA damage repair. Our findings provide insights into the molecular mechanisms underlying the pathophysiology of ALS-associated FUS mutations and suggest potential therapeutic targets for the treatment of ALS.}, }
@article {pmid37461167, year = {2023}, author = {Berger, A and Locatelli, M and Arcila-Londono, X and Hayat, G and Olney, N and Wymer, J and Gwathmey, K and Lunetta, C and Heiman-Patterson, T and Ajroud-Driss, S and Macklin, EA and Bind, MA and Goslin, K and Stuchiner, T and Brown, L and Bazan, T and Regan, T and Adamo, A and Ferment, V and Schroeder, C and Somers, M and Manousakis, G and Faulconer, K and Sinani, E and Mirochnick, J and Yu, H and Sherman, AV and Walk, D and , }, title = {The natural history of ALS: Baseline characteristics from a multicenter clinical cohort.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2023.2232812}, pmid = {37461167}, issn = {2167-9223}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare disease with urgent need for improved treatment. Despite the acceleration of research in recent years, there is a need to understand the full natural history of the disease. As only 40% of people living with ALS are eligible for typical clinical trials, clinical trial datasets may not generalize to the full ALS population. While biomarker and cohort studies have more generous inclusion criteria, these too may not represent the full range of phenotypes, particularly if the burden for participation is high. To permit a complete understanding of the heterogeneity of ALS, comprehensive data on the full range of people with ALS is needed.<br><br>METHODS: The ALS Natural History Consortium (ALS NHC) consists of nine ALS clinics and was created to build a comprehensive dataset reflective of the ALS population. At each clinic, most patients are asked to participate and about 95% do. After obtaining consent, a minimum dataset is abstracted from each participant's electronic health record. Participant burden is therefore minimal.<br><br>RESULTS: Data on 1925 ALS patients were submitted as of 9 December 2022. ALS NHC participants were more heterogeneous relative to anonymized clinical trial data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The ALS NHC includes ALS patients of older age of onset and a broader distribution of El Escorial categories, than the PRO-ACT database.<br><br>CONCLUSIONS: ALS NHC participants had a higher diversity of diagnostic and demographic data compared to ALS clinical trial participants.Key MessagesWhat is already known on this topic: Current knowledge of the natural history of ALS derives largely from regional and national registries that have broad representation of the population of people living with ALS but do not always collect covariates and clinical outcomes. Clinical studies with rich datasets of participant characteristics and validated clinical outcomes have stricter inclusion and exclusion criteria that may not be generalizable to the full ALS population.What this study adds: To bridge this gap, we collected baseline characteristics for a sample of the population of people living with ALS seen at a consortium of ALS clinics that collect extensive, pre-specified participant-level data, including validated outcome measures.How this study might affect research, practice, or policy: A clinic-based longitudinal dataset can improve our understanding of the natural history of ALS and can be used to inform the design and analysis of clinical trials and health economics studies, to help the prediction of clinical course, to find matched controls for open label extension trials and expanded access protocols, and to document real-world evidence of the impact of novel treatments and changes in care practice.}, }
@article {pmid37460793, year = {2023}, author = {Gawlik-Dziki, U and Wrzesińska-Krupa, B and Nowak, R and Pietrzak, W and Zyprych-Walczak, J and Obrępalska-Stęplowska, A}, title = {Herbicide resistance status impacts the profile of non-anthocyanin polyphenolics and some phytomedical properties of edible cornflower (Centaurea cyanus L.) flowers.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {11538}, pmid = {37460793}, issn = {2045-2322}, mesh = {*Herbicide Resistance ; *Herbicides/pharmacology ; Flowers ; Centaurea ; Plant Weeds ; }, abstract = {To ensure sufficient food supply worldwide, plants are treated with pesticides to provide protection against pathogens and pests. Herbicides are the most commonly utilised pesticides, used to reduce the growth of weeds. However, their long-term use has resulted in the emergence of herbicide-resistant biotypes in many weed species. Cornflower (Centaurea cyanus L., Asteraceae) is one of these plants, whose biotypes resistant to herbicides from the group of acetolactate synthase (ALS) inhibitors have begun to emerge in recent years. Some plants, although undesirable in crops and considered as weeds, are of great importance in phytomedicine and food production, and characterised by a high content of health-promoting substances, including antioxidants. Our study aimed to investigate how the acquisition of herbicide resistance affects the health-promoting properties of plants on the example of cornflower, as well as how they are affected by herbicide treatment. To this end, we analysed non-anthocyanin polyphenols and antioxidant capacity in flowers of C. cyanus from herbicide-resistant and susceptible biotypes. Our results indicated significant compositional changes associated with an increase in the content of substances and activities that have health-promoting properties. High antioxidant activity and higher total phenolic and flavonoid compounds as well as reducing power were observed in resistant biotypes. The latter one increased additionally after herbicide treatment which might also suggest their role in the resistance acquisition mechanism. Overall, these results show that the herbicide resistance development, although unfavourable to crop production, may paradoxically have very positive effects for medicinal plants such as cornflower.}, }
@article {pmid37460332, year = {2023}, author = {Lacroix, C and Guilhaumou, R and Micallef, J and Bruneteau, G and Desnuelle, C and Blin, O}, title = {Cannabis for the treatment of amyotrophic lateral sclerosis: What is the patients' view?.}, journal = {Revue neurologique}, volume = {179}, number = {9}, pages = {967-974}, doi = {10.1016/j.neurol.2023.03.018}, pmid = {37460332}, issn = {0035-3787}, mesh = {Humans ; *Cannabis/adverse effects ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; Quality of Life ; *Cannabinoids/adverse effects ; Pain ; }, abstract = {Cannabis may have therapeutic benefits to relieve symptoms of amyotrophic lateral sclerosis (ALS) thanks to its pleiotropic pharmacological activity. This study is the first to present a large questionnaire-based survey about the "real-life" situation regarding cannabis use in the medical context in ALS patients in France. There were 129 respondents and 28 reported the use of cannabis (21.7%) to relieve symptoms of ALS. Participants mostly reported the use of cannabidiol (CBD) oil and cannabis weed and declared benefits both on motor (rigidity, cramps, fasciculations) and non-motor (sleep quality, pain, emotional state, quality of life, depression) symptoms and only eight reported minor adverse reactions (drowsiness, euphoria and dry mouth). Even if cannabis is mostly used outside medical pathways and could expose patients to complications (street and uncontrolled drugs, drug-drug interactions, adverse effects…), most of the participants reported "rational" consumption (legal cannabinoids, with only few combustion and adverse reactions). Despite some limitations, this study highlights the need for further research on the potential benefits of cannabis use for the management of ALS motor and non-motor symptoms. Indeed, there is an urgent need and call for and from patients to know more about cannabis and secure its use in a medical context.}, }
@article {pmid37451615, year = {2023}, author = {Yen, H and Yen, H and Huang, CH and Huang, IH and Hung, WK and Su, HJ and Tai, CC and Haw, WWY and Flohr, C and Yiu, ZZN and Chi, CC}, title = {Systematic Review and Critical Appraisal of Urticaria Clinical Practice Guidelines: A Global Guidelines in Dermatology Mapping Project (GUIDEMAP).}, journal = {The journal of allergy and clinical immunology. In practice}, volume = {11}, number = {10}, pages = {3213-3220.e11}, doi = {10.1016/j.jaip.2023.07.002}, pmid = {37451615}, issn = {2213-2201}, mesh = {Humans ; Australia ; Databases, Factual ; *Dermatology ; Stakeholder Participation ; *Urticaria/diagnosis/therapy ; Practice Guidelines as Topic ; }, abstract = {BACKGROUND: Management of urticaria can be optimized with clinical practice guidelines (CPGs). However, the quality of recent urticaria CPGs remains unclear.<br><br>OBJECTIVE: To identify and appraise urticaria CPGs worldwide published in the last 5 years.<br><br>METHODS: A search for relevant urticaria CPGs was conducted between January 1, 2017, and May 31, 2022, using the following databases: MEDLINE, Embase, National Institute for Health and Care Excellence (NICE) Evidence Search, Guidelines International Network, ECRI Guidelines Trust, Australian Clinical Practice Guidelines, Trip Medical Database, and DynaMed. The included CPGs were critically appraised using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, Lenzer et&#xa0;al's red flags, and the Institute of Medicine (IOM) criteria of trustworthiness.<br><br>RESULTS: We included 21 urticaria CPGs. Most guidelines reviewed treatment recommendations of chronic spontaneous urticaria. The majority of guidelines were from European and Asian countries with high and high-middle sociodemographic index, written in English, and openly accessible. Seventeen guidelines (81%) had at least 1 AGREE II domain rated poor quality. Applicability, rigor of development, and stakeholder involvement were the 3 AGREE II domains that scored the lowest across guidelines. Appraisal with Lenzer et&#xa0;al's red flags showed that 18 guidelines (86%) raised at least 1 red flag indicating potential bias. The top 3 domains raising red flags were: no inclusion of nonphysician experts/patient representative/community stakeholders, no or limited involvement of a methodologist in the evaluation of evidence, and lack of external review. Based on IOM's criteria of trustworthiness, 20 guidelines (95%) had 1 or more criteria that did not meet best practice standards. The 3 domains with the highest number of best practice standards not met were updating procedures, rating strength of recommendations, and external review. Guidelines scored highest for the AGREE II domains of defining scope and purpose and clarity of presentation, and had the most fully met IOM's best practice standard for articulation of recommendations. However, only 1 urticaria CPG by NICE was identified as rigorously developed across all 3 appraisal tools.<br><br>CONCLUSIONS: The quality of urticaria CPGs in the last 5 years varied widely. Only the NICE urticaria guideline consistently demonstrated excellent quality, high trustworthiness, and low risk of bias. Use of a rigorous framework to rate certainty of evidence and grade strength of recommendation, involvement of methodologists, stakeholder engagement with external review, and clear guidance for updating can help improve the quality of future CPGs.}, }
@article {pmid37450244, year = {2023}, author = {Dubowsky, M and Theunissen, F and Carr, JM and Rogers, ML}, title = {The Molecular Link Between TDP-43, Endogenous Retroviruses and Inflammatory Neurodegeneration in Amyotrophic Lateral Sclerosis: a Potential Target for Triumeq, an Antiretroviral Therapy.}, journal = {Molecular neurobiology}, volume = {60}, number = {11}, pages = {6330-6345}, pmid = {37450244}, issn = {1559-1182}, support = {1950//Motor Neurone Disease Australia/ ; 1950//Andrew Butcher Grant/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Endogenous Retroviruses ; *Motor Neuron Disease/pathology ; Motor Neurons/metabolism ; DNA-Binding Proteins/metabolism ; *HIV Infections/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurological disorder, characterised by the death of upper and lower motor neurons. The aetiology of ALS remains unknown, and treatment options are limited. Endogenous retroviruses (ERVs), specifically human endogenous retrovirus type K (HERV-K), have been proposed to be involved in the propagation of neurodegeneration in ALS. ERVs are genomic remnants of ancient viral infection events, with most being inactive and not retaining the capacity to encode a fully infectious virus. However, some ERVs retain the ability to be activated and transcribed, and ERV transcripts have been found to be elevated within the brain tissue of MND patients. A hallmark of ALS pathology is altered localisation of the transactive response (TAR) DNA binding protein 43 kDa (TDP-43), which is normally found within the nucleus of neuronal and glial cells and is involved in RNA regulation. In ALS, TDP-43 aggregates within the cytoplasm and facilitates neurodegeneration. The involvement of ERVs in ALS pathology is thought to occur through TDP-43 and neuroinflammatory mediators. In this review, the proposed involvement of TDP-43, HERV-K and immune regulators on the onset and progression of ALS will be discussed. Furthermore, the evidence supporting a therapy based on targeting ERVs in ALS will be reviewed.}, }
@article {pmid37446372, year = {2023}, author = {Alarcan, H and Vourc'h, P and Berton, L and Benz-De Bretagne, I and Piver, E and Andres, CR and Corcia, P and Veyrat-Durebex, C and Blasco, H}, title = {Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients.}, journal = {International journal of molecular sciences}, volume = {24}, number = {13}, pages = {}, pmid = {37446372}, issn = {1422-0067}, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics ; Retrospective Studies ; Sex Factors ; Delayed Diagnosis ; Central Nervous System ; }, abstract = {Central nervous system (CNS) barrier impairment has been reported in amyotrophic lateral sclerosis (ALS), highlighting its potential significance in the disease. In this context, we aim to shed light on its involvement in the disease, by determining albumin quotient (QAlb) at the time of diagnosis of ALS in a large cohort of patients. Patients from the university hospital of Tours (n = 307) were included in this monocentric, retrospective study. In total, 92 patients (30%) had elevated QAlb levels. This percentage was higher in males (43%) than in females (15%). Interestingly, QAlb was not associated with age of onset, age at sampling or diagnostic delay. However, we found an association with ALS functional rating scale-revised (ALSFRS-r) at diagnosis but this was significant only in males. The QAlb levels were not linked to the presence of a pathogenic mutation. Finally, we performed a multivariate survival analysis and found that QAlb was significantly associated with survival in male patients (HR = 2.3, 95% CI = 1.2-4.3, p = 0.009). A longitudinal evaluation of markers of barrier impairment, in combination with inflammatory biomarkers, could give insight into the involvement of CNS barrier impairment in the pathogenesis of the disease. The gender difference might guide the development of new drugs and help personalise the treatment of ALS.}, }
@article {pmid37445986, year = {2023}, author = {Ciurea, AV and Mohan, AG and Covache-Busuioc, RA and Costin, HP and Glavan, LA and Corlatescu, AD and Saceleanu, VM}, title = {Unraveling Molecular and Genetic Insights into Neurodegenerative Diseases: Advances in Understanding Alzheimer's, Parkinson's, and Huntington's Diseases and Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {13}, pages = {}, pmid = {37445986}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Huntington Disease/genetics ; *Alzheimer Disease/genetics ; *Parkinson Disease/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Neurodegenerative diseases are, according to recent studies, one of the main causes of disability and death worldwide. Interest in molecular genetics has started to experience exponential growth thanks to numerous advancements in technology, shifts in the understanding of the disease as a phenomenon, and the change in the perspective regarding gene editing and the advantages of this action. The aim of this paper is to analyze the newest approaches in genetics and molecular sciences regarding four of the most important neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We intend through this review to focus on the newest treatment, diagnosis, and predictions regarding this large group of diseases, in order to obtain a more accurate analysis and to identify the emerging signs that could lead to a better outcome in order to increase both the quality and the life span of the patient. Moreover, this review could provide evidence of future possible novel therapies that target the specific genes and that could be useful to be taken into consideration when the classical approaches fail to shed light.}, }
@article {pmid37442650, year = {2024}, author = {Lopez-Garcia, YK and Valdez-Carrizales, M and Nuñez-Zuno, JA and Apodaca-Chávez, E and Rangel-Patiño, J and Demichelis-Gómez, R}, title = {Are delays in diagnosis and treatment of acute leukemia in a middle-income country associated with poor outcomes? A retrospective cohort study.}, journal = {Hematology, transfusion and cell therapy}, volume = {46}, number = {4}, pages = {366-373}, pmid = {37442650}, issn = {2531-1387}, abstract = {INTRODUCTION: Acute leukemias (ALs) are aggressive diseases that lead to death without medical attention. We evaluated the association between delays in diagnosis and poor outcomes in AL by evaluating the symptom onset to treatment intervals in adults with newly diagnosed AL and their effect on an early death (ED).<br><br>METHODS: We assessed adults diagnosed with AL between 2015 and 2020 and evaluated baseline characteristics, the patient interval (PI), diagnostic interval (DI), treatment interval (TI) and the total time interval (TTI) to determine ED-associated factors.<br><br>MAIN RESULTS: We assessed 102 patients with acute lymphoblastic leukemia (ALL), 57 with acute myeloblastic leukemia (AML) and 29 with acute promyelocytic leukemia (APL). Median interval days were PI 14, DI 10, TI 4 and TTI 31.5. The TI and TTI intervals were lower in APL than in ALL and AML; TI 1 vs. 4 and 3 (p = 0.001) and TTI 21 vs. 31 and 35 (p = 0.016). The 30-day and 60-day EDs were 13.8% and 20.7%, mainly infections. ECOG > 2 (OR = 15.0) and PI < 7 days (OR = 4.06) were associated with 30-day ED; AML (OR = 2.69), high-risk (OR = 3.34), albumin < 3.5 g/dl (OR = 5) and platelets < 20 &#xd7; 10[3]/uL (OR = 2.71) with a 60-day ED.<br><br>CONCLUSION: None of the interval-delays were associated with an ED. Intervals seemed to be longer in patients without an ED, except for the TI, probably because of "the waiting time paradox." Aggressive manifestations of disease may lead to shorter diagnostic intervals, but increased mortality.}, }
@article {pmid37440197, year = {2023}, author = {Yang, J and Li, H and Zhao, Y}, title = {Dessert or Poison? The Roles of Glycosylation in Alzheimer's, Parkinson's, Huntington's Disease, and Amyotrophic Lateral Sclerosis.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {24}, number = {16}, pages = {e202300017}, doi = {10.1002/cbic.202300017}, pmid = {37440197}, issn = {1439-7633}, mesh = {Humans ; Aged ; *Huntington Disease ; *Neurodegenerative Diseases ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; *Parkinson Disease ; Glycosylation ; *Poisons ; Quality of Life ; }, abstract = {Ministry of Education and Key Laboratory of Neurons and glial cells of the central nervous system (CNS) are modified by glycosylation and rely on glycosylation to achieve normal neural function. Neurodegenerative disease is a common disease of the elderly, affecting their healthy life span and quality of life, and no effective treatment is currently available. Recent research implies that various glycosylation traits are altered during neurodegenerative diseases, suggesting a potential implication of glycosylation in disease pathology. Herein, we summarized the current knowledge about glycosylation associated with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS) pathogenesis, focusing on their promising functional avenues. Moreover, we collected research aimed at highlighting the need for such studies to provide a wealth of disease-related glycosylation information that will help us better understand the pathophysiological mechanisms and hopefully specific glycosylation information to provide further diagnostic and therapeutic directions for neurodegenerative diseases.}, }
@article {pmid37433768, year = {2023}, author = {Zhang, W and Xiao, D and Mao, Q and Xia, H}, title = {Role of neuroinflammation in neurodegeneration development.}, journal = {Signal transduction and targeted therapy}, volume = {8}, number = {1}, pages = {267}, pmid = {37433768}, issn = {2059-3635}, support = {UL1 TR002538/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Inflammation/genetics ; Neuroinflammatory Diseases ; *Parkinson Disease/genetics ; Protein Aggregates ; Humans ; Clinical Trials as Topic ; Disease Models, Animal ; }, abstract = {Studies in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis, Huntington's disease, and so on, have suggested that inflammation is not only a result of neurodegeneration but also a crucial player in this process. Protein aggregates which are very common pathological phenomenon in neurodegeneration can induce neuroinflammation which further aggravates protein aggregation and neurodegeneration. Actually, inflammation even happens earlier than protein aggregation. Neuroinflammation induced by genetic variations in CNS cells or by peripheral immune cells may induce protein deposition in some susceptible population. Numerous signaling pathways and a range of CNS cells have been suggested to be involved in the pathogenesis of neurodegeneration, although they are still far from being completely understood. Due to the limited success of traditional treatment methods, blocking or enhancing inflammatory signaling pathways involved in neurodegeneration are considered to be promising strategies for the therapy of neurodegenerative diseases, and many of them have got exciting results in animal models or clinical trials. Some of them, although very few, have been approved by FDA for clinical usage. Here we comprehensively review the factors affecting neuroinflammation and the major inflammatory signaling pathways involved in the pathogenicity of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. We also summarize the current strategies, both in animal models and in the clinic, for the treatment of neurodegenerative diseases.}, }
@article {pmid37433093, year = {2023}, author = {Wong, W}, title = {Managed care considerations to improve health care utilization for patients with ALS.}, journal = {The American journal of managed care}, volume = {29}, number = {7 Suppl}, pages = {S120-S126}, doi = {10.37765/ajmc.2023.89388}, pmid = {37433093}, issn = {1936-2692}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Edaravone ; Activities of Daily Living ; Quality of Life ; Patient Acceptance of Health Care ; Managed Care Programs ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatally progressive degenerative disease, with many patients succumbing to the condition within 3 to 5 years after diagnosis. It is a rare, orphan disease with an estimated US prevalence of 25,000 patients. Patients with ALS and their caregivers are faced with a substantial financial burden as a result of the condition, as ALS has an estimated national financial burden of $1.03 billion. A significant driver of the patient financial burden includes the continued need for caregiver support as the weakening of muscles progresses to dysphagia and dyspnea, making it difficult to complete activities of daily living as the disease progresses. Caregivers also experience financial burdens, as well as feelings of anxiety, depression, and decreased quality of life. In addition to needed caregiver support, patients with ALS and their families also incur substantial nonmedical costs including travel expenses, home modifications such as ramps, and indirect costs such as productivity loss. Due to the wide range of clinical symptoms that patients may exhibit when first presenting with ALS symptoms, diagnosis is often delayed, which negatively affects patient outcomes and impacts missed opportunity for clinical trial recruitment aimed at developing new disease-modifying therapies. Additionally, delay in diagnosis and referral to ALS treatment centers results in increased overall health care costs. Telemedicine may be a tool used to promote timely care from an ALS treatment center in addition to clinical trial participation for those patients who cannot overcome mobility barriers for care. Currently, 4 therapies are approved for the treatment of ALS. Riluzole has demonstrated modest improvement in survival. Other recently approved therapies include oral edaravone, a combination therapy of sodium phenylbutyrate and taurursodiol (PB/TURSO), and tofersen, which is administered intrathecally and approved under an accelerated approval. Long-term studies have shown PB/TURSO to have a dual benefit on survival and function. The Institute for Clinical and Economic Review (ICER) 2022 Evidence Report for ALS does not value the high price points of edaravone and PB/TURSO as cost-effective based on the current evidence, despite valuing the need for new treatment options for this patient population.}, }
@article {pmid37433092, year = {2023}, author = {Lynch, K}, title = {Optimizing pharmacologic treatment for ALS to improve outcomes and quality of life.}, journal = {The American journal of managed care}, volume = {29}, number = {7 Suppl}, pages = {S112-S119}, doi = {10.37765/ajmc.2023.89389}, pmid = {37433092}, issn = {1936-2692}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Quality of Life ; Riluzole ; Edaravone ; }, abstract = {Just 3 disease-modifying treatments-edaravone, riluzole, and sodium phenylbutyrate and taurursodiol (PB/TURSO)-are currently FDA approved to slow progression of amyotrophic lateral sclerosis (ALS). A fourth therapy has been recently approved under accelerated approval and is contingent upon verification of clinical benefit in confirmatory trials(s). Therapy selection is based largely upon patient characteristics, as guidelines have not been updated since the recent approval of PB/TURSO or accelerated approval of tofersen. Managing ALS symptomatically is important to improve patients' quality of life. Although evidence is lacking for many pharmacologic therapies, providers use symptomatic treatments to address common symptoms including anxiety, depression, emotional lability (pseudobulbar affect), fasciculations, fatigue, insomnia, muscle cramps or spasms, musculoskeletal pain due to immobility, neuropathic type pain, excessive salivation (sialorrhea), spasticity, constipation, and urinary urgency. Emerging agents offer some hope for patients with ALS. Among the drugs, biologics, and interventions under investigation for ALS are an oral tyrosine kinase inhibitor, RIPK1 inhibition, the use of mesenchymal stem cells, antisense oligonucleotides, sequential administration of all experimental treatments in a new study design, and modification of the patient's own mesenchymal stem cells.}, }
@article {pmid37433091, year = {2023}, author = {Lynch, K}, title = {Pathogenesis and presentation of ALS: examining reasons for delayed diagnosis and identifying opportunities for improvement.}, journal = {The American journal of managed care}, volume = {29}, number = {7 Suppl}, pages = {S104-S111}, doi = {10.37765/ajmc.2023.89390}, pmid = {37433091}, issn = {1936-2692}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Delayed Diagnosis ; Quality of Life ; Brain ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS), or Lou Gehrig disease, is a progressive, always-fatal neuromuscular disease characterized by motor neuron degeneration in the brain and spinal cord. As upper and lower motor neurons fail, inability to transmit messages to the muscles causes muscle stiffness, atrophy, and wasting. The incidence of this incurable disease is increasing in the United States, and its prognosis is grim. On average, patients survive about 3 to 5 years from symptom onset. Until recently, few risk factors were known, but some are newly emerging. About 10% of cases are related to genetic variants. Patients who develop ALS often experience diagnostic delays (10-16 months on average), and its heterogeneity contributes to that delay. Diagnosis is based primarily on clinical signs and symptoms and exclusion of other causes of motor neuron dysfunction. Reliable, accessible biomarkers are needed to aid early ALS diagnosis, differentiate from ALS-mimicking diseases, predict survival, and monitor disease progression and treatment response. Misdiagnosing ALS can have devastating consequences, including unnecessary emotional burden, delayed and/or inappropriate treatment, and undue financial burden. The grim prognosis and sure progression to death creates considerable burden and reduces quality of life for patients and caregivers.}, }
@article {pmid37432640, year = {2024}, author = {Maurya, S and Gaur, M and Yadav, AB}, title = {Staphylococcus aureus Biofilm Destabilization by Tween-80 and Lung Surfactants to Overcome Biofilm-Imposed Drug Resistance.}, journal = {Applied biochemistry and biotechnology}, volume = {196}, number = {3}, pages = {1558-1569}, pmid = {37432640}, issn = {1559-0291}, mesh = {Animals ; *Staphylococcus aureus ; Anti-Bacterial Agents/pharmacology ; Polysorbates/pharmacology ; Biofilms ; *Staphylococcal Infections/microbiology ; Surface-Active Agents/pharmacology ; Drug Resistance ; Lung ; }, abstract = {This study is aimed to evaluating the potential of tween-80 and artificial lung surfactant (ALS) to destabilize S. aureus biofilm. The biofilm destabilization was studied by crystal violet staining, bright field microscopy, and scanning electron microscopy (SEM). During the study, S. aureus biofilm was exposed with tween-80 along various concentrations (1%, 0.1%, and 0.05%) or LS (lung surfactant) at (2.5%, 5%, and 15%) for 2 hrs. It was observed that 0.1% of tween-80 destabilized 63.83 ± 4.35% and 15% ALS 77 ± 1.7% biofilm in comparison to without treatment. The combination of tween-80 and ALS was used and showed a synergistic effect to destabilize 83.4 ± 1.46% biofilm. These results showed the potential of tween-80 and ALS as biofilm disruptors, which further needs to explore in an in-vivo animal model to access the actual potential of biofilm disruption in natural conditions. This study could play a pivotal role to overcome the problem of antibiotic resistance imposed due to biofilm formation to combat antibiotic resistance imposed by bacteria.}, }
@article {pmid37431079, year = {2023}, author = {Kurashige, T}, title = {[Histopathological Diagnostic Marker for ALS: Phosphorylated Transacting Response DNA-Binding Protein of 43kDa in Intramuscular Nerve Bundles].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {75}, number = {7}, pages = {877-887}, doi = {10.11477/mf.1416202436}, pmid = {37431079}, issn = {1881-6096}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Retrospective Studies ; Autopsy ; DNA-Binding Proteins ; }, abstract = {The discovery of transacting response DNA-binding protein of 43 kDa (TDP-43) led to a deeper understanding of the pathogenesis of amyotrophic lateral sclerosis (ALS). Since this discovery, blood and cerebrospinal fluid biomarkers of ALS have been reported. However, these biomarkers do not exhibit sufficient specificity for ALS. Our case-control postmortem and retrospective muscle biopsy cohort studies revealed phosphorylated TDP-43 in intramuscular nerve bundles, which precedes the clinical fulfillment of the Gold Coast criteria. We attempted to establish a histopathological biomarker for ALS and identify molecular targets for the treatment of lower motor dysfunction in patients with ALS.}, }
@article {pmid37430314, year = {2023}, author = {Mitsumoto, H and Cheung, K and Oskarsson, B and Andrews, HF and Jang, GE and Andrews, JA and Shah, JS and Fernandes, JA and McElhiney, M and Santella, RM}, title = {Randomized double-blind personalized N-of-1 clinical trial to test the safety and potential efficacy of TJ-68 for treating muscle cramps in amyotrophic lateral sclerosis (ALS): study protocol for a TJ-68 trial.}, journal = {Trials}, volume = {24}, number = {1}, pages = {449}, pmid = {37430314}, issn = {1745-6215}, support = {no number//Tsumura and Company/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/drug therapy ; Drug Combinations ; *Drugs, Chinese Herbal ; Muscle Cramp/diagnosis/drug therapy/etiology ; Quality of Life ; Randomized Controlled Trials as Topic ; }, abstract = {INTRODUCTION/AIMS: Muscle cramps are a common and often disabling symptom in amyotrophic lateral sclerosis (ALS), a devastating and incurable neurodegenerative disorder. To date, there are no medications specifically approved for the treatment of muscle cramps. Ameliorating muscle cramps in ALS may improve and sustain quality of life. A widely prescribed traditional Japanese (Kampo) medicine against muscle cramps, shakuyakukanzoto (TJ-68), has been studied in advanced liver disease, spinal stenosis, kidney failure, and diabetic neuropathy. The Japanese ALS Management Guideline mentions TJ-68 for difficult muscle cramps in ALS. Therefore, the rationale of our trial is to investigate the safety and effectiveness of TJ-68 in treating painful and disabling muscle cramps in people with ALS outside of Japan. Accordingly, we are conducting a randomized clinical trial to test the safety and efficacy of TJ-68 in participants with ALS reporting frequent muscle cramps using an innovative, personalized N-of-1 design. If successful, TJ-68 may be used for muscle cramps in a broader population of people with ALS.<br><br>METHODS: This is a two-site, double-blind, randomized personalized N-of-1 early clinical trial with TJ-68. At least 22 participants with ALS and daily muscle cramps will receive drug or placebo for 2&#xa0;weeks (one treatment period) followed by a 1-week washout in a four-period cross-over design. While the primary objective is to evaluate the safety of TJ-68, the study has 85% power to detect a one-point shift on the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity of the Columbia Muscle Cramp Scale (MCS). Secondary outcomes include the full MCS score, a Cramp Diary, Clinical Global Impression of Changes, Goal Attainment Scale, quality of life scale and ALS functional rating scale-revised (ALSFRS-R).<br><br>DISCUSSION: The study is underway. A personalized N-of-1 trial design is an efficient approach to testing medications that alleviate muscle cramps in rare disorders. If TJ-68 proves safe and efficacious then it may be used to treat cramps in ALS, and help to improve and sustain quality of life.<br><br>TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov (NCT04998305), 8/9/2021.}, }
@article {pmid37427325, year = {2023}, author = {Najafi, S and Najafi, P and Kaffash Farkhad, N and Hosseini Torshizi, G and Assaran Darban, R and Boroumand, AR and Sahab-Negah, S and Khodadoust, MA and Tavakol-Afshari, J}, title = {Mesenchymal stem cell therapy in amyotrophic lateral sclerosis (ALS) patients: A comprehensive review of disease information and future perspectives.}, journal = {Iranian journal of basic medical sciences}, volume = {26}, number = {8}, pages = {872-881}, pmid = {37427325}, issn = {2008-3866}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare deadly progressive neurological disease that primarily affects the upper and lower motor neurons with an annual incidence rate of 0.6 to 3.8 per 100,000 people. Weakening and gradual atrophy of the voluntary muscles are the first signs of the disease onset affecting all aspects of patients' lives, including eating, speaking, moving, and even breathing. Only 5-10% of patients have a familial type of the disease and show an autosomal dominant pattern, but the cause of the disease is unknown in the remaining 90% of patients (Sporadic ALS). However, in both types of disease, the patient's survival is 2 to 5 years from the disease onset. Some clinical and molecular biomarkers, magnetic resonance imaging (MRI), blood or urine test, muscle biopsy, and genetic testing are complementary methods for disease diagnosis. Unfortunately, with the exception of Riluzole, the only medically approved drug for the management of this disease, there is still no definitive cure for it. In this regard, the use of mesenchymal stem cells (MSCs) for the treatment or management of the disease has been common in preclinical and clinical studies for many years. MSCs are multipotent cells having immunoregulatory, anti-inflammatory, and differentiation ability that makes them a good candidate for this purpose. This review article aims to discuss multiple aspects of ALS disease and focus on MSCs' role in disease management based on performed clinical trials.}, }
@article {pmid37427180, year = {2023}, author = {Chapagain, S and Khati, N and Lama, R and Karki, R and Aryal, R and Pangyani, B and Koirala, A}, title = {Amyotrophic lateral sclerosis with respiratory failure and dysautonomia: a case report.}, journal = {Annals of medicine and surgery (2012)}, volume = {85}, number = {7}, pages = {3623-3625}, pmid = {37427180}, issn = {2049-0801}, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a disease that affects both upper and lower motor neurons, causing a range of symptoms beyond the motor system. Recent research has shown that the autonomic nervous system can also be affected, with symptoms such as orthostatic hypotension, fluctuations in blood pressure, and dizziness being reported.<br><br>CASE PRESENTATION: A 58-year-old male presented with left lower limb limping, difficulty climbing stairs, and left foot weakness, followed by right upper limb weakness and was diagnosed with ALS and received edaravone and riluzole treatment. He presented again with right lower limb weakness, shortness of breath, and wide fluctuations in blood pressure, leading to ICU admission with new diagnosis of ALS with dysautonomia with respiratory failure and was managed with non-invasive ventilation, physiotherapy, and gait training exercises.<br><br>CLINICAL DISCUSSION: ALS is a progressive neurodegenerative disease affecting motor neurons but non-motor symptoms can also occur, including dysautonomia, which can result in blood pressure fluctuations. Dysautonomia in ALS is caused by several mechanisms such as severe muscle atrophy, prolonged ventilatory support, and upper and lower motor neuron lesions. Management of ALS involves giving a definitive diagnosis, providing nutritional support, using disease-modifying drugs such as riluzole and non-invasive ventilation to improve survival and quality of life. Early diagnosis is essential for effective management of the disease.<br><br>CONCLUSION: Early diagnosis, use of disease-modifying drugs, non-invasive ventilation, and maintaining the patient's nutritional status are crucial for managing ALS which can have non-motor symptoms as well.}, }
@article {pmid37422655, year = {2023}, author = {van Eijk, RPA and van den Berg, LH and Roes, KCB and Tian, L and Lai, TL and Nelson, LM and Li, C and Scowcroft, A and Garcia-Segovia, J and Lu, Y}, title = {Hybrid Controlled Clinical Trials Using Concurrent Registries in Amyotrophic Lateral Sclerosis: A Feasibility Study.}, journal = {Clinical pharmacology and therapeutics}, volume = {114}, number = {4}, pages = {883-892}, doi = {10.1002/cpt.2994}, pmid = {37422655}, issn = {1532-6535}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Feasibility Studies ; Research Design ; }, abstract = {Hybrid designs with both randomized arms and an external control cohort preserve key features of randomization and utilize external information to augment clinical trials. In this study, we propose to leverage high-quality, patient-level concurrent registries to enhance clinical trials and illustrate the impact on trial design for amyotrophic lateral sclerosis. The proposed methodology was evaluated in a randomized, placebo-controlled clinical trial. We used patient-level information from a well-defined, population-based registry, that was running parallel to the randomized clinical trial, to identify concurrently nonparticipating, eligible patients who could be matched with trial participants, and integrate them into the statistical analysis. We assessed the impact of the addition of the external controls on the treatment effect estimate, precision, and time to reach a conclusion. During the runtime of the trial, a total of 1,141 registry patients were alive; 473 (41.5%) of them fulfilled the eligibility criteria and 133 (11.7%) were enrolled in the study. A matched control population could be identified among the nonparticipating patients. Augmenting the randomized controls with matched external controls could have avoided unnecessary randomization of 17 patients (-12.8%) as well as reducing the study duration from 30.1 months to 22.6 months (-25.0%). Matching eligible external controls from a different calendar period led to bias in the treatment effect estimate. Hybrid trial designs utilizing a concurrent registry with rigorous matching can minimize bias due to a mismatch in calendar time and differences in standard of care, and may accelerate the development of new treatments.}, }
@article {pmid37408276, year = {2023}, author = {Hosaka, T and Tsuji, H and Kwak, S}, title = {Roles of Aging, Circular RNAs, and RNA Editing in the Pathogenesis of Amyotrophic Lateral Sclerosis: Potential Biomarkers and Therapeutic Targets.}, journal = {Cells}, volume = {12}, number = {10}, pages = {}, pmid = {37408276}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; RNA, Circular/genetics/metabolism ; RNA Editing/genetics ; RNA/genetics/metabolism ; Aging/genetics ; Biomarkers/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease caused by upper and lower motor neuron death. Despite advances in our understanding of ALS pathogenesis, effective treatment for this fatal disease remains elusive. As aging is a major risk factor for ALS, age-related molecular changes may provide clues for the development of new therapeutic strategies. Dysregulation of age-dependent RNA metabolism plays a pivotal role in the pathogenesis of ALS. In addition, failure of RNA editing at the glutamine/arginine (Q/R) site of GluA2 mRNA causes excitotoxicity due to excessive Ca[2+] influx through Ca[2+]-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, which is recognized as an underlying mechanism of motor neuron death in ALS. Circular RNAs (circRNAs), a circular form of cognate RNA generated by back-splicing, are abundant in the brain and accumulate with age. Hence, they are assumed to play a role in neurodegeneration. Emerging evidence has demonstrated that age-related dysregulation of RNA editing and changes in circRNA expression are involved in ALS pathogenesis. Herein, we review the potential associations between age-dependent changes in circRNAs and RNA editing, and discuss the possibility of developing new therapies and biomarkers for ALS based on age-related changes in circRNAs and dysregulation of RNA editing.}, }
@article {pmid37399802, year = {2023}, author = {Pannek, J and Mahler, J and Wöllner, J and Krebs, J}, title = {Satisfaction with Homeopathic Service and Care for Persons with Spinal Cord Injury.}, journal = {Complementary medicine research}, volume = {30}, number = {5}, pages = {408-414}, doi = {10.1159/000531658}, pmid = {37399802}, issn = {2504-2106}, mesh = {Humans ; Cross-Sectional Studies ; *Homeopathy ; Surveys and Questionnaires ; Switzerland ; }, abstract = {BACKGROUND: The aim of the study was to investigate the satisfaction of individuals with spinal cord injury (SCI) with a homeopathic service at an SCI rehabilitation center.<br><br>PATIENTS AND METHODS: A cross-sectional questionnaire study was performed at an SCI rehabilitation center in Switzerland. It included patients with chronic SCI who presented themselves to a homeopathic service offered by the hospital in a 12-months period. The participants filled in standardized questionnaires in German: "Measure Yourself Medical Outcome Profile" (MYMOP), Treatment Satisfaction Questionnaire for Medication (TSQM-9), the European Project on Patient Evaluation of General Practice Care (EUROPEP) questionnaire, and a self-administered questionnaire.<br><br>RESULTS: The data of 14 patients were analyzed. Symptom severity as well as bother by the symptoms that led to homeopathic treatment decreased under homeopathic treatment (severity: from 4.3 to 3.3; bother: from 4.2 to 2.9) and remained lower over time (severity: 2.6; bother: 2.7), suggesting a sustained effect. Irrespective of the test instrument used, satisfaction rates were higher for homeopathic service than for homeopathic medication, which was rated as successful by 50% of the participants.<br><br>CONCLUSION: Persons with SCI suffering from secondary complications of SCI who accessed homeopathic care reported high satisfaction rates with the service. Therefore, homeopathic service can be considered as an additive measure in persons with SCI suffering from recurrent symptoms.<br><br>UNLABELLED: <title>Hintergrund</title>Evaluierung der Zufriedenheit von Personen mit Querschnittl&#xe4;hmung (QSL) mit einer hom&#xf6;opathischen Betreuung an einem Rehabilitationszentrum f&#xfc;r QSL.<title>Patient*innen und Methodik</title>An einem Rehabilitationszentrum f&#xfc;r QSL in der Schweiz wurde eine Querschnittserhebung mittels Frageb&#xf6;gen durchgef&#xfc;hrt. Eingeschlossen wurden Personen mit chronischer QSL, die sich in einer von der Klinik angebotenen hom&#xf6;opathischen Sprechstunde in einem 12-Monats-Intervall vorstellten. Die Teilnehmenden f&#xfc;llten standardisierte Fragebogen in deutscher Sprache aus: "Measure Yourself Medical Outcome Profile" (MYMOP), Treatment Satisfaction Questionnaire for Medication (TSQM-9), den "European Project on Patient Evaluation of General Practice Care (EUROPEP)" Fragebogen sowie einen selbst-erstellten Fragebogen.<title>Ergebnisse</title>Die Daten von 14 Teilnehmenden wurden ausgewertet. Der Schweregrad der Symptome sowie die Belastung durch die Symptome die zur hom&#xf6;opathischen Behandlung gef&#xfc;hrt haben, wurden unter der hom&#xf6;opathischen Therapie geringer (Schweregrad: von 4.3 auf 3.3; Belastung: von 4.2 auf 2.9) und blieben &#xfc;ber den Untersuchungszeitraum geringer (Schweregrad: 2.6; Belastung 2.7), was einen anhaltenden Effekt nahelegt. Unabh&#xe4;ngig von dem verwendeten Testinstrument waren die Zufriedenheitsraten f&#xfc;r die hom&#xf6;opathische Betreuung h&#xf6;her als diejenigen f&#xfc;r die hom&#xf6;opathische Medikation, die von 50% der Teilnehmenden als erfolgreich bewertet wurde.<title>Schlussfolgerung</title>Personen mit QSL, die wegen Sekund&#xe4;rkomplikationen eine hom&#xf6;opathische Sprechstunde aufsuchten, berichteten eine hohe Zufriedenheit mit dieser Betreuung. Daher kann eine hom&#xf6;opathische Betreuung als zus&#xe4;tzliche Massnahme bei Personen mit QSL mit persistierender Symptomatik in Betracht gezogen werden.}, }
@article {pmid37396808, year = {2023}, author = {Vucic, S and Menon, P and Huynh, W and Mahoney, C and Ho, KS and Hartford, A and Rynders, A and Evan, J and Evan, J and Ligozio, S and Glanzman, R and Hotchkin, MT and Kiernan, MC}, title = {Efficacy and safety of CNM-Au8 in amyotrophic lateral sclerosis (RESCUE-ALS study): a phase 2, randomised, double-blind, placebo-controlled trial and open label extension.}, journal = {EClinicalMedicine}, volume = {60}, number = {}, pages = {102036}, pmid = {37396808}, issn = {2589-5370}, abstract = {BACKGROUND: CNM-Au8® is a catalytically-active gold nanocrystal neuroprotective agent that enhances intracellular energy metabolism and reduces oxidative stress. The phase 2, randomised, double-blind, placebo-controlled trial and open label extension RESCUE-ALS trial evaluated the efficacy and safety of CNM-Au8 for treatment of amyotrophic lateral sclerosis (ALS).<br><br>METHODS: RESCUE-ALS and its long-term open label extension (OLE) were conducted at two multidisciplinary ALS clinics located in Sydney, Australia: (i) the Brain and Mind Centre and (ii) Westmead Hospital. The double-blind portion of RESCUE-ALS was conducted from January 16, 2020 (baseline visit, first-patient first-visit (FPFV)) through July 13, 2021 (double-blind period, last-patient last-visit (LPLV)). Participants (N&#xa0;=&#xa0;45) were randomised 1:1 to receive 30&#xa0;mg of CNM-Au8 or matching placebo daily over 36 weeks in addition to background standard of care, riluzole. The primary outcome was mean percent change in summed motor unit number index (MUNIX), a sensitive neurophysiological biomarker of lower motor neuron function. Change in total (or summated) MUNIX score and change in forced vital capacity (FVC) were secondary outcome measures. ALS disease progression events, ALS Functional Rating Scale (ALSFRS-R) change, change in quality of life (ALSSQOL-SF) were assessed as exploratory outcome measures. Long-term survival evaluated vital status of original active versus placebo randomisation for all participants through at least 12 months following last-patient last-visit (LPLV) of the double-blind period. RESCUE-ALS and the open label study are registered in clinicaltrials.gov with registration numbers NCT04098406 and NCT05299658, respectively.<br><br>FINDINGS: In the intention-to-treat (ITT) population, there was no significant difference in the summated MUNIX score percent change (LS mean difference: 7.7%, 95% CI:&#xa0;-11.9 to 27.3%, p&#xa0;=&#xa0;0.43), total MUNIX score change (18.8, 95% CI:&#xa0;-56.4 to 94.0), or FVC change (LS mean difference: 3.6, 95% CI:&#xa0;-12.4 to 19.7) between the active and placebo treated groups at week 36. In contrast, survival analyses through 12-month LPLV demonstrated a 60% reduction in all-cause mortality with CNM-Au8 treatment [hazard ratio&#xa0;=&#xa0;0.408 (95% Wald CI: 0.166 to 1.001, log-rank p&#xa0;=&#xa0;0.0429). 36 participants entered the open label extension (OLE), and those initially randomised to CNM-Au8 exhibited a slower rate of disease progression, as measured by time to the occurrence of death, tracheostomy, initiation of non-invasive ventilatory support, or gastrostomy tube placement. CNM-Au8 was well-tolerated, and no safety signals were observed.<br><br>INTERPRETATION: CNM-Au8, in combination with riluzole, was well-tolerated in ALS with no identified safety signals. While the primary and secondary outcomes of this trial were not significant, the clinically meaningful exploratory results support further investigation of CNM-Au8 in ALS.<br><br>FUNDING: The RESCUE-ALS was substantially funded by a grant from FightMND. Additional funding was provided by Clene Australia Pty Ltd.}, }
@article {pmid37391647, year = {2023}, author = {Karati, D and Mukherjee, S and Roy, S}, title = {Molecular and Structural Insight into Adenosine A2A Receptor in Neurodegenerative Disorders: A Significant Target for Efficient Treatment Approach.}, journal = {Molecular neurobiology}, volume = {60}, number = {10}, pages = {5987-6000}, pmid = {37391647}, issn = {1559-1182}, mesh = {Humans ; *Adenosine/pharmacology ; Receptor, Adenosine A2A/metabolism ; Ligands ; *Neurodegenerative Diseases/drug therapy ; Purinergic P1 Receptor Antagonists/therapeutic use ; Receptors, Purinergic P1 ; }, abstract = {All biological tissues and bodily fluids include the autacoid adenosine. The P1 class of purinergic receptors includes adenosine receptors. Four distinct G-protein-coupled receptors on the cellular membrane mediate the effects of adenosine, whose cytoplasmic content is regulated by producing/degrading enzymes and nucleoside transporters. A2A receptor has received a great deal of attention in recent years because it has a wide range of potential therapeutic uses. A2B and, more significantly, A2A receptors regulate numerous physiological mechanisms in the central nervous system (CNS). The inferior targetability of A2B receptors towards adenosine points that they might portray a promising medicinal target since they are triggered only under pharmacological circumstances (when adenosine levels rise up to micromolar concentrations). The accessibility of specific ligands for A2B receptors would permit the exploration of such a theory. A2A receptors mediate both potentially neurotoxic and neuroprotective actions. Hence, it is debatable to what extent they play a role in neurodegenerative illnesses. However, A2A receptor blockers have demonstrated clear antiparkinsonian consequences, and a significant attraction exists in the role of A2A receptors in other neurodegenerative disorders. Amyloid peptide extracellular accumulation and tau hyperphosphorylation are the pathogenic components of AD that lead to neuronal cell death, cognitive impairment, and memory loss. Interestingly, in vitro and in vivo research has shown that A2A adenosine receptor antagonists may block each of these clinical symptoms, offering a crucial new approach to combat a condition for which, regrettably, only symptomatic medications are currently available. At least two requirements must be met to determine whether such receptors are a target for diseases of the CNS: a complete understanding of the mechanisms governing A2A-dependent processes and the availability of ligands that can distinguish between the various receptor populations. This review concisely summarises the biological effects mediated by A2A adenosine receptors in neurodegenerative disorders and discusses the chemical characteristics of A2A adenosine receptor antagonists undergoing clinical trials. Selective A2A receptor blocker against neurodegenerative disorders.}, }
@article {pmid37390744, year = {2023}, author = {Eskandari, S and Rezayof, A and Asghari, SM and Hashemizadeh, S}, title = {Neurobiochemical characteristics of arginine-rich peptides explain their potential therapeutic efficacy in neurodegenerative diseases.}, journal = {Neuropeptides}, volume = {101}, number = {}, pages = {102356}, doi = {10.1016/j.npep.2023.102356}, pmid = {37390744}, issn = {1532-2785}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Arginine ; Oxidative Stress ; Peptides/metabolism ; *Nucleic Acids/metabolism/therapeutic use ; *Alzheimer Disease/metabolism ; }, abstract = {Neurodegenerative diseases, including Alzheimer̕ s disease (AD), Parkinson̕ s disease (PD), Huntington̕ s disease (HD), and Amyotrophic Lateral Sclerosis (ALS) require special attention to find new potential treatment methods. This review aims to summarize the current knowledge of the relationship between the biochemical properties of arginine-rich peptides (ARPs) and their neuroprotective effects to deal with the harmful effects of risk factors. It seems that ARPs have portrayed a promising and fantastic landscape for treating neurodegeneration-associated disorders. With multimodal mechanisms of action, ARPs play various unprecedented roles, including as the novel delivery platforms for entering the central nervous system (CNS), the potent antagonists for calcium influx, the invader molecules for targeting mitochondria, and the protein stabilizers. Interestingly, these peptides inhibit the proteolytic enzymes and block protein aggregation to induce pro-survival signaling pathways. ARPs also serve as the scavengers of toxic molecules and the reducers of oxidative stress agents. They also have anti-inflammatory, antimicrobial, and anti-cancer properties. Moreover, by providing an efficient nucleic acid delivery system, ARPs can play an essential role in developing various fields, including gene vaccines, gene therapy, gene editing, and imaging. ARP agents and ARP/cargo therapeutics can be raised as an emergent class of neurotherapeutics for neurodegeneration. Part of the aim of this review is to present recent advances in treating neurodegenerative diseases using ARPs as an emerging and powerful therapeutic tool. The applications and progress of ARPs-based nucleic acid delivery systems have also been discussed to highlight their usefulness as a broad-acting class of drugs.}, }
@article {pmid37390359, year = {2023}, author = {Sheers, NL and Howard, ME and Rochford, PD and Rautela, L and Chao, C and McKim, DA and Berlowitz, DJ}, title = {A Randomized Controlled Clinical Trial of Lung Volume Recruitment in Adults with Neuromuscular Disease.}, journal = {Annals of the American Thoracic Society}, volume = {20}, number = {10}, pages = {1445-1455}, pmid = {37390359}, issn = {2325-6621}, mesh = {Female ; Humans ; Adult ; Middle Aged ; Adolescent ; *Quality of Life ; Prospective Studies ; Lung Volume Measurements ; Lung ; *Neuromuscular Diseases/complications ; }, abstract = {Rationale: Clinical care guidelines advise that lung volume recruitment (LVR) be performed routinely by people with neuromuscular disease (NMD) to maintain lung and chest wall flexibility and slow lung function decline. However, the evidence base is limited, and no randomized controlled trials of regular LVR in adults have been published. Objectives: To evaluate the effect of regular LVR on respiratory function and quality of life in adults with NMD. Methods: A randomized controlled trial with assessor blinding was conducted between September 2015 and May 2019. People (>14 years old) with NMD and vital capacity <80% predicted were eligible, stratified by disease subgroup (amyotrophic lateral sclerosis/motor neuron disease or other NMDs), and randomized to 3 months of twice-daily LVR or breathing exercises. The primary outcome was change in maximum insufflation capacity (MIC) from baseline to 3 months, analyzed using a linear mixed model approach. Results: Seventy-six participants (47% woman; median age, 57 [31-68] years; mean baseline vital capacity, 40 ± 18% predicted) were randomized (LVR, n = 37). Seventy-three participants completed the study. There was a statistically significant difference in MIC between groups (linear model interaction effect P = 0.002, observed mean difference, 0.19 [0.00-0.39] L). MIC increased by 0.13 (0.01-0.25) L in the LVR group, predominantly within the first month. No interaction or treatment effects were observed in secondary outcomes of lung volumes, respiratory system compliance, and quality of life. No adverse events were reported. Conclusions: Regular LVR increased MIC in a sample of LVR-naive participants with NMD. We found no direct evidence that regular LVR modifies respiratory mechanics or slows the rate of lung volume decline. The implications of increasing MIC are unclear, and the change in MIC may represent practice. Prospective long-term clinical cohorts with comprehensive follow-up, objective LVR use, and clinically meaningful outcome data are needed. Clinical trial registered with anzctr.org.au (ACTRN12615000565549).}, }
@article {pmid37388502, year = {2023}, author = {Mohamed, W and Kumar, J and Alghamdi, BS and Soliman, AH and Toshihide, Y}, title = {Neurodegeneration and inflammation crosstalk: Therapeutic targets and perspectives.}, journal = {IBRO neuroscience reports}, volume = {14}, number = {}, pages = {95-110}, pmid = {37388502}, issn = {2667-2421}, abstract = {Glia, which was formerly considered to exist just to connect neurons, now plays a key function in a wide range of physiological events, including formation of memory, learning, neuroplasticity, synaptic plasticity, energy consumption, and homeostasis of ions. Glial cells regulate the brain's immune responses and confers nutritional and structural aid to neurons, making them an important player in a broad range of neurological disorders. Alzheimer's, ALS, Parkinson's, frontotemporal dementia (FTD), and epilepsy are a few of the neurodegenerative diseases that have been linked to microglia and astroglia cells, in particular. Synapse growth is aided by glial cell activity, and this activity has an effect on neuronal signalling. Each glial malfunction in diverse neurodegenerative diseases is distinct, and we will discuss its significance in the progression of the illness, as well as its potential for future treatment.}, }
@article {pmid37385457, year = {2023}, author = {DuMont, M and Agostinis, A and Singh, K and Swan, E and Buttle, Y and Tropea, D}, title = {Sex representation in neurodegenerative and psychiatric disorders' preclinical and clinical studies.}, journal = {Neurobiology of disease}, volume = {184}, number = {}, pages = {106214}, doi = {10.1016/j.nbd.2023.106214}, pmid = {37385457}, issn = {1095-953X}, mesh = {Humans ; Male ; Female ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy ; *Attention Deficit Disorder with Hyperactivity ; }, abstract = {Many studies show the importance of biological sex for the onset, progression, and response to treatment in brain disorders. In line with these reports, health agencies have requested that all trials, both at the clinical and preclinical level, use a similar number of male and female subjects to correctly interpret the results. Despite these guidelines, many studies still tend to be unbalanced in the use of male and female subjects. In this review we consider three neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and three psychiatric disorders: Depression, Attention Deficit Hyperactivity Disorder, and Schizophrenia. These disorders were chosen because of their prevalence and their recognized sex-specific differences in onset, progression, and response to treatment. Alzheimer's disease and Depression demonstrate higher prevalence in females, whereas Parkinson's Disease, Amyotrophic lateral sclerosis, Attention Deficit Hyperactivity Disorder, and schizophrenia show higher prevalence in males. Results from preclinical and clinical studies examining each of these disorders revealed sex-specific differences in risk factors, diagnostic biomarkers, and treatment response and efficacy, suggesting a role for sex-specific therapies in neurodegenerative and neuropsychiatric disorders. However, the qualitative analysis of the percentage of males and females enrolled in clinical trials in the last two decades shows that for most of the disorders, there is still a sex bias in the patients' enrolment.}, }
@article {pmid37383106, year = {2023}, author = {Wu, C and Feng, Y}, title = {Exploring the potential of mindfulness-based therapy in the prevention and treatment of neurodegenerative diseases based on molecular mechanism studies.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1097067}, pmid = {37383106}, issn = {1662-4548}, abstract = {Neurodegenerative diseases (ND) have received increasing attention due to their irreversibility, but there is still no means to completely cure ND in clinical practice. Mindfulness therapy (MT), including Qigong, Tai Chi, meditation, and yoga, etc., has become an effective complementary treatment modality in solving clinical and subclinical problems due to its advantages of low side effects, less pain, and easy acceptance by patients. MT is primarily used to treat mental and emotional disorders. In recent years, evidence has shown that MT has a certain therapeutic effect on ND with a potential molecular basis. In this review, we summarize the pathogenesis and risk factors of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), relating to telomerase activity, epigenetics, stress, and the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB) mediated inflammatory response, and analyze the molecular mechanism basis of MT to prevent and treat ND, to provide possible explanations for the potential of MT treatments for ND.}, }
@article {pmid37382103, year = {2023}, author = {Benatar, M and Turner, MR and Wuu, J}, title = {Presymptomatic amyotrophic lateral sclerosis: from characterization to prevention.}, journal = {Current opinion in neurology}, volume = {36}, number = {4}, pages = {360-364}, pmid = {37382103}, issn = {1473-6551}, support = {R01 NS105479/NS/NINDS NIH HHS/United States ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/prevention &amp; control ; *Frontotemporal Dementia/genetics ; Longitudinal Studies ; Biomarkers ; Asymptomatic Diseases ; }, abstract = {PURPOSE OF REVIEW: Significant progress in characterizing presymptomatic amyotrophic lateral sclerosis (ALS) is ushering in an era of potential disease prevention. Although these advances have largely been based on cohorts of deep-phenotyped mutation carriers at an elevated risk for ALS, there are increasing opportunities to apply principles and insights gleaned, to the broader population at risk for ALS [and frontotemporal dementia (FTD)].<br><br>RECENT FINDINGS: The discovery that blood neurofilament light chain (NfL) level increases presymptomatically and may serve as a susceptibility biomarker, predicting timing of phenoconversion in some mutation carriers, has empowered the first-ever prevention trial in SOD1 -ALS. Moreover, there is emerging evidence that presymptomatic disease is not uniformly clinically silent, with mild motor impairment (MMI), mild cognitive impairment (MCI), and/or mild behavioral impairment (MBI) representing a prodromal stage of disease. Structural and functional brain abnormalities, as well as systemic markers of metabolic dysfunction, have emerged as potentially even earlier markers of presymptomatic disease. Ongoing longitudinal studies will determine the extent to which these reflect an endophenotype of genetic risk.<br><br>SUMMARY: The discovery of presymptomatic biomarkers and the delineation of prodromal states is yielding unprecedented opportunities for earlier diagnosis, treatment, and perhaps even prevention of genetic and apparently sporadic forms of disease.}, }
@article {pmid37380145, year = {2023}, author = {Mercadante, S and Al-Husinat, L}, title = {Palliative Care in Amyotrophic Lateral Sclerosis.}, journal = {Journal of pain and symptom management}, volume = {66}, number = {4}, pages = {e485-e499}, doi = {10.1016/j.jpainsymman.2023.06.029}, pmid = {37380145}, issn = {1873-6513}, mesh = {Humans ; Palliative Care ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis ; Quality of Life ; *Neurodegenerative Diseases ; *Hospice and Palliative Care Nursing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease of the motor neurons. Given the evolutive characteristics of this disease, palliative care principles should be a foundation of ALS care. A multidisciplinary medical intervention is of paramount importance in the different phases of disease. The involvement of the palliative care team improves quality of life and symptoms, and prognosis. Early initiation is of paramount importance to ensuring patient-centered care, when the patient has still the capability to communicate effectively and participate in his medical care. Advance care planning supports patients and family members in understanding and sharing their preferences according to their personal values and life goals regarding future medical treatment. The principal problems which require intensive supportive care include cognitive disturbances, psychological distress, pain, sialorrhrea, nutrition, and ventilatory support. Communication skills of health-care professionals are mandatory to manage the inevitability of death. Palliative sedation has peculiar aspects in this population, particularly with the decision of withdrawing ventilatory support.}, }
@article {pmid37379726, year = {2023}, author = {Floudiotis, N and Modi, G and Mochan, A}, title = {Motor neuron disease in black African patients at a tertiary care hospital in Soweto, South Africa.}, journal = {Journal of the neurological sciences}, volume = {451}, number = {}, pages = {120710}, doi = {10.1016/j.jns.2023.120710}, pmid = {37379726}, issn = {1878-5883}, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis ; Cross-Sectional Studies ; Delayed Diagnosis ; *Motor Neuron Disease ; South Africa/epidemiology ; Tertiary Care Centers ; Adult ; Middle Aged ; }, abstract = {INTRODUCTION: In this brief report, we describe the nature of ALS in a South African cohort of patients of Black African ancestry - a population which has been historically understudied.<br><br>METHODS: We performed a chart review of all patients attending the ALS/MND clinic at the Chris Hani Baragwanath Academic Hospital in Soweto, Johannesburg, South Africa, during the period 1 January 2015 to 30 June 2020. Cross-sectional demographic and clinical data captured at the time of diagnosis was collected.<br><br>RESULTS: Seventy-one patients were included in the study. Males constituted 66% (n&#xa0;=&#xa0;47), with a male to female sex ratio of 2:1. The median age at onset of symptoms was 46&#xa0;years (IQR 40-57) with a median disease duration at diagnosis (diagnostic delay) of 2&#xa0;years (IQR 1-3). The onset was spinal in 76% and bulbar in 23%. The median ALSFRS-R score at time of presentation was 29 (IQR 23-38.5). The median ALSFRS-R slope (unit/month) was 0.80 (IQR 0.43-1.39). Sixty five patients (92%) were diagnosed with the classic ALS phenotype. Fourteen patients were known to be HIV positive, and of those, 12 were on antiretroviral treatment (ART). None of the patients had familial ALS.<br><br>CONCLUSION: Our findings of an earlier age at symptom onset and seemingly advanced disease at presentation in patients with Black African ancestry support the existing literature on the African population.}, }
@article {pmid37378756, year = {2023}, author = {Sassi, S and Bianchi, E and Diamanti, L and Tornabene, D and Sette, E and Medici, D and Matà, S and Leccese, D and Sperti, M and Martinelli, I and Ghezzi, A and Mandrioli, J and Iuzzolino, VV and Dubbioso, R and Trojsi, F and Passaniti, C and D'Alvano, G and Filosto, M and Padovani, A and Mazzini, L and De Marchi, F and Zinno, L and Nuredini, A and Bongioanni, P and Dolciotti, C and Canali, E and Toschi, G and Petrucci, A and Perna, A and Riso, V and Inghilleri, M and Libonati, L and Cambieri, C and Pupillo, E}, title = {Retrospective observational study on the use of acetyl-L-carnitine in ALS.}, journal = {Journal of neurology}, volume = {270}, number = {11}, pages = {5344-5357}, pmid = {37378756}, issn = {1432-1459}, mesh = {Humans ; *Acetylcarnitine/therapeutic use ; *Amyotrophic Lateral Sclerosis/diagnosis ; Retrospective Studies ; Case-Control Studies ; Double-Blind Method ; }, abstract = {ALCAR (Acetyl-L-carnitine) is a donor of acetyl groups and increases the intracellular levels of carnitine, the primary transporter of fatty acids across the mitochondrial membranes. In vivo studies showed that ALCAR decrease oxidative stress markers and pro-inflammatory cytokines. In a previous double-blind placebo-controlled phase II trial showed positive effects on self-sufficiency (defined as a score of 3+ on the ALSFRS-R items for swallowing, cutting food and handling utensils, and walking) ALSFRS-R total score and FVC. We conducted an observational, retrospective, multicentre, case-control study to provide additional data on the effects of ALCAR in subjects with ALS in Italy. Subjects treated with ALCAR 1.5 g/day or 3 g/day were included and matched with not treated subjects by sex, age at diagnosis, site of onset, and time from diagnosis to baseline, (45 subjects per group). ALCAR 3 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 23 (51.1%) treated subjects (adj. OR 1.18, 95% CI 0.46-3.02). No statistically significant differences were detected in ALSFRS nor FVC nor self-sufficiency. ALCAR 1.5 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 32 (71.1%) treated subjects (adj. OR 0.27, 95% CI 0.10-0.71). For ALSFRS-R, a mean slope of - 1.0 was observed in treated subjects compared to - 1.4 in those not treated (p = 0.0575). No statistically significant difference was detected in the FVC nor self-sufficiency. Additional evidence should be provided to confirm the efficacy of the drug and provide a rationale for the dosage.}, }
@article {pmid37375224, year = {2023}, author = {Zhang, Y and Huang, J and Yu, K and Cui, X}, title = {G-Quadruplexes Formation by the C9orf72 Nucleotide Repeat Expansion d(GGGGCC)n and Conformation Regulation by Fangchinoline.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {12}, pages = {}, pmid = {37375224}, issn = {1420-3049}, support = {KLEEMA202201//Key Laboratory of Ecology and Environment in 458 Minority Areas (Minzu University of China), National Ethnic Affairs Commission/ ; }, mesh = {Humans ; *Frontotemporal Dementia ; *G-Quadruplexes ; C9orf72 Protein/genetics ; Nucleotides ; *Amyotrophic Lateral Sclerosis/genetics ; RNA/chemistry ; DNA/genetics ; }, abstract = {The G-quadruplex (GQ)-forming hexanucleotide repeat expansion (HRE) in the C9orf72 (C9) gene has been found to be the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (collectively, C9ALS/FTD), implying the great significance of modulating C9-HRE GQ structures in C9ALS/FTD therapeutic treatment strategies. In this study, we investigated the GQ structures formed by varied lengths of C9-HRE DNA sequences d(GGGGCC)4 (C9-24mer) and d(GGGGCC)8 (C9-48mer), and found that the C9-24mer forms anti-parallel GQ (AP-GQ) in the presence of potassium ions, while the long C9-48mer bearing eight guanine tracts forms unstacked tandem GQ consisting of two C9-24mer unimolecular AP-GQs. Moreover, the natural small molecule Fangchinoline was screened out in order to be able to stabilize and alter the C9-HRE DNA to parallel GQ topology. Further study of the interaction of Fangchinoline with the C9-HRE RNA GQ unit r(GGGGCC)4 (C9-RNA) revealed that it can also recognize and improve the thermal stability of C9-HRE RNA GQ. Finally, use of AutoDock simulation results indicated that Fangchinoline binds to the groove regions of the parallel C9-HRE GQs. These findings pave the way for further studies of GQ structures formed by pathologically related long C9-HRE sequences, and also provide a natural small-molecule ligand that modulates the structure and stability of C9-HRE GQ, both in DNA and RNA levels. Altogether, this work may contribute to therapeutic approaches of C9ALS/FTD which take the upstream C9-HRE DNA region, as well as the toxic C9-HRE RNA, as targets.}, }
@article {pmid37375216, year = {2023}, author = {De Luca, M and Ioele, G and Grande, F and Occhiuzzi, MA and Chieffallo, M and Garofalo, A and Ragno, G}, title = {Multivariate Curve Resolution Methodology Applied to the ATR-FTIR Data for Adulteration Assessment of Virgin Coconut Oil.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {12}, pages = {}, pmid = {37375216}, issn = {1420-3049}, support = {PON R&amp;I 2014-2020 - ARS01_00568//PON R&amp;I 2014-2020 - ARS01_00568 - SI.F.I.PA.CRO.DE. - Sviluppo e industrializzazione farmaci innovativi per terapia molecolare personalizzata PA.CRO.DE/ ; }, mesh = {Coconut Oil ; Spectroscopy, Fourier Transform Infrared/methods ; Fourier Analysis ; *Food Contamination/analysis ; *Plant Oils/analysis ; Least-Squares Analysis ; Olive Oil/analysis ; }, abstract = {Virgin coconut oil (VCO) is a functional food with important health benefits. Its economic interest encourages fraudsters to deliberately adulterate VCO with cheap and low-quality vegetable oils for financial gain, causing health and safety problems for consumers. In this context, there is an urgent need for rapid, accurate, and precise analytical techniques to detect VCO adulteration. In this study, the use of Fourier transform infrared (FTIR) spectroscopy combined with multivariate curve resolution-alternating least squares (MCR-ALS) methodology was evaluated to verify the purity or adulteration of VCO with reference to low-cost commercial oils such as sunflower (SO), maize (MO) and peanut (PO) oils. A two-step analytical procedure was developed, where an initial control chart approach was designed to assess the purity of oil samples using the MCR-ALS score values calculated on a data set of pure and adulterated oils. The pre-treatment of the spectral data by derivatization with the Savitzky-Golay algorithm allowed to obtain the classification limits able to distinguish the pure samples with 100% of correct classifications in the external validation. In the next step, three calibration models were developed using MCR-ALS with correlation constraints for analysis of adulterated coconut oil samples in order to assess the blend composition. Different data pre-treatment strategies were tested to best extract the information contained in the sample fingerprints. The best results were achieved by derivative and standard normal variate procedures obtaining RMSEP and RE% values in the ranges of 1.79-2.66 and 6.48-8.35%, respectively. The models were optimized using a genetic algorithm (GA) to select the most important variables and the final models in the external validations gave satisfactory results in quantifying adulterants, with absolute errors and RMSEP of less than 4.6% and 1.470, respectively.}, }
@article {pmid37369861, year = {2023}, author = {Zhu, Q and Xu, D and Huang, H and Li, D and Yang, D and Zhou, J and Zhao, Y}, title = {The safety and effectiveness of high-calorie therapy for treating amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurology}, volume = {270}, number = {10}, pages = {4729-4743}, pmid = {37369861}, issn = {1432-1459}, support = {2022BCA055//Department of Science and Technology, Hubei Provincial People's Government/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Lipids/therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting the upper and lower motor neurons, which can lead to death from respiratory failure within 3-5 years after the onset of this disease. Nowadays, no drug can effectively slow down the progression of this disease. High-calorie therapy, an emerging complementary alternative treatment, has been reported in studies to prolong the survival time of patients, prevent muscle atrophy and provide a better prognosis. However, no systematic review and meta-analysis were performed to summarize the evidence of this therapy. This meta-analysis comprehensively evaluates the effectiveness and safety of high-calorie therapy for treating ALS.<br><br>METHODS: We searched the electronic databases from inception to 1 April 2023: PubMed, Embase, Web of Science, Cochrane Library, Scopus, Ovid/Medline, and ProQuest. Randomized controlled trials (RCTs) that met the inclusion criteria were performed by meta-analysis. All statistical analyses were performed in STATA software.<br><br>RESULTS: A total of six eligible RCTs were included in this meta-analysis, involving 370 ALS patients. The meta-analyses showed that high-calorie therapy had superiority in improving body weight (SMD&#x2009;=&#x2009;1, 95% CI 0.36, 1.65) and BMI (SMD&#x2009;=&#x2009;0.83, 95% CI 0.02, 1.63). With respect to safety, there was no difference between the high-calorie therapy and the control group regarding the number of adverse events (RR&#x2009;=&#x2009;3.61, 95% CI 0.08, 162.49). However, ALSFRS-R scores (SMD&#x2009;=&#x2009;0.34, 95% CI -&#x2009;0.4, 1.08), survival rate (RR&#x2009;=&#x2009;1.23, 95% CI 0.98, 1.55), and lipid profile (LDL: SMD&#x2009;=&#x2009;0.21, 95% CI -&#x2009;0.33, 0.75; HDL: SMD&#x2009;=&#x2009;0.17, 95% CI -&#x2009;0.37, 0.71; TC: SMD&#x2009;=&#x2009;0.21, 95% CI -&#x2009;0.33, 0.75), CRP (SMD&#x2009;=&#x2009;0.85, 95% CI -&#x2009;1.37, 3.06) showed no significant difference compared to the control groups.<br><br>CONCLUSIONS: High-calorie therapy is effective in gaining weight and BMI with few side effects. However, no significant superiority was detected in ALSFRS-R scores, survival time, lipid profile, and CRP indicator. The overall quality of the included studies is high, and the results have some credibility, but future corroboration by high-quality RCTs is also expected.}, }
@article {pmid37363428, year = {2022}, author = {Sienes Bailo, P and Llorente Martín, E and Calmarza, P and Montolio Breva, S and Bravo Gómez, A and Pozo Giráldez, A and Sánchez-Pascuala Callau, JJ and Vaquer Santamaría, JM and Dayaldasani Khialani, A and Cerdá Micó, C and Camps Andreu, J and Sáez Tormo, G and Fort Gallifa, I}, title = {The role of oxidative stress in neurodegenerative diseases and potential antioxidant therapies.}, journal = {Advances in laboratory medicine}, volume = {3}, number = {4}, pages = {342-360}, pmid = {37363428}, issn = {2628-491X}, abstract = {OBJECTIVES: The central nervous system (CNS) is essential for homeostasis and controls the physiological functions of the body. However, the biochemical characteristics of the CNS make it especially vulnerable to oxidative damage (OS). This phenomenon compromises correct CNS functioning, leading to neurodegeneration and neuronal death.<br><br>CONTENTS: OS plays a crucial role in the physiopathology of neurodegenerative diseases. It is involved in multiple mechanisms of nucleic acid, protein, and lipid oxidation, thereby contributing to progressive brain damage. These mechanisms include mitochondrial dysfunction; excessive production of reactive oxygen and nitrogen species; deficiency of antioxidant defenses; protein oligomerization; cytokine production and inflammatory response; blood-brain barrier abnormalities; and proteasome dysfunction. All these dysfunctions are involved in the pathogenesis of&#xa0;neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, or amyotrophic lateral sclerosis.<br><br>SUMMARY AND OUTLOOK: A curative treatment is currently not available. Research is focused on the search for therapies that reduce oxidative damage and delay disease progression. In the recent years, researchers have focused their attention on the effects of antioxidant therapies.}, }
@article {pmid37360345, year = {2023}, author = {Iijima, K and Watanabe, H and Nakashiro, Y and Iida, Y and Nonaka, M and Moriwaka, F and Hamada, S}, title = {Long-term effects of the gait treatment using a wearable cyborg hybrid assistive limb in a patient with spinal and bulbar muscular atrophy: a case report with 5 years of follow-up.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1143820}, pmid = {37360345}, issn = {1664-2295}, abstract = {BACKGROUND: Spinal and bulbar muscular atrophy (SBMA) is a progressive neuromuscular degenerative disease characterized by the degeneration of lower motor neurons in the spinal cord and brainstem and neurogenic atrophy of the skeletal muscle. Although the short-term effectiveness of gait treatment using a wearable cyborg hybrid assistive limb (HAL) has been demonstrated for the rehabilitation of patients with SBMA, the long-term effects of this treatment are unclear. Thus, this study aimed to investigate the long-term effects of the continued gait treatment with HAL in a patient with SBMA.<br><br>RESULTS: A 68-year-old man with SBMA had lower limb muscle weakness and atrophy, gait asymmetry, and decreased walking endurance. The patient performed nine courses of HAL gait treatment (as one course three times per week for 3 weeks, totaling nine times) for ~5 years. The patient performed HAL gait treatment to improve gait symmetry and endurance. A physical therapist adjusted HAL based on the gait analysis and physical function of the patient. Outcome measurements, such as 2-min walking distance (2MWD), 10-meter walking test (maximal walking speed, step length, cadence, and gait symmetry), muscle strength, Revised Amyotrophic Lateral Sclerosis Functional Assessment Scale (ALSFRS-R), and patient-reported outcomes, were evaluated immediately before and after gait treatment with HAL for each course. 2MWD improved from 94 m to 101.8 m, and the ALSFRS-R gait items remained unchanged (score 3) for approximately 5 years. The patient could maintain walking ability in terms of gait symmetry, walking endurance, and independence walking despite disease progression during HAL treatment.<br><br>CONCLUSION: The long-term gait treatment with HAL in a patient with SBMA may contribute to the maintenance and improvement of the gait endurance and ability to perform activities of daily living. The cybernics treatment using HAL may enable patients to relearn correct gait movements. The gait analysis and physical function assessment by a physical therapist might be important to maximize the benefits of HAL treatment.}, }
@article {pmid37356043, year = {2023}, author = {Nguyen, QT and Thanh, LN and Hoang, VT and Phan, TTK and Heke, M and Hoang, DM}, title = {Bone Marrow-Derived Mononuclear Cells in the Treatment of Neurological Diseases: Knowns and Unknowns.}, journal = {Cellular and molecular neurobiology}, volume = {43}, number = {7}, pages = {3211-3250}, pmid = {37356043}, issn = {1573-6830}, mesh = {Humans ; *Autism Spectrum Disorder ; Bone Marrow ; *Stroke/therapy ; Bone Marrow Cells ; }, abstract = {Bone marrow-derived mononuclear cells (BMMNCs) have been used for decades in preclinical and clinical studies to treat various neurological diseases. However, there is still a knowledge gap in the understanding of the underlying mechanisms of BMMNCs in the treatment of neurological diseases. In addition, prerequisite factors for the efficacy of BMMNC administration, such as the optimal route, dose, and number of administrations, remain unclear. In this review, we discuss known and unknown aspects of BMMNCs, including the cell harvesting, administration route and dose; mechanisms of action; and their applications in neurological diseases, including stroke, cerebral palsy, spinal cord injury, traumatic brain injury, amyotrophic lateral sclerosis, autism spectrum disorder, and epilepsy. Furthermore, recommendations on indications for BMMNC administration and the advantages and limitations of BMMNC applications for neurological diseases are discussed. BMMNCs in the treatment of neurological diseases. BMMNCs have been applied in several neurological diseases. Proposed mechanisms for the action of BMMNCs include homing, differentiation and paracrine effects (angiogenesis, neuroprotection, and anti-inflammation). Further studies should be performed to determine the optimal cell dose and administration route, the roles of BMMNC subtypes, and the indications for the use of BMMNCs in neurological conditions with and without genetic abnormalities.}, }
@article {pmid37353279, year = {2023}, author = {van Eenennaam, RM and Kruithof, W and Beelen, A and Bakker, LA and van Eijk, RPA and Maessen, M and Baardman, JF and Visser-Meily, JMA and Veldink, JH and van den Berg, LH}, title = {Frequency of euthanasia, factors associated with end-of-life practices, and quality of end-of-life care in patients with amyotrophic lateral sclerosis in the Netherlands: a population-based cohort study.}, journal = {The Lancet. Neurology}, volume = {22}, number = {7}, pages = {591-601}, doi = {10.1016/S1474-4422(23)00155-2}, pmid = {37353279}, issn = {1474-4465}, mesh = {Male ; Female ; Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Netherlands/epidemiology ; Cohort Studies ; Quality of Life ; *Neurodegenerative Diseases/complications ; *Terminal Care ; *Suicide, Assisted ; Death ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis is a progressive and lethal neurodegenerative disease that is at the forefront of debates on regulation of assisted dying. Since 2002, when euthanasia was legally regulated in the Netherlands, the frequency of this end-of-life practice has increased substantially from 1·7% of all deaths in 1990 and 2005 to 4·5% in 2015. We aimed to investigate whether the frequency of euthanasia in patients with amyotrophic lateral sclerosis had similarly increased since 2002, and to assess the factors associated with end-of-life practices and the quality of end-of-life care in patients with this disease.<br><br>METHODS: Using data from the Netherlands ALS registry, we did a population-based cohort study of clinicians and informal caregivers of patients with amyotrophic lateral sclerosis to assess factors associated with end-of-life decision making and the quality of end-of-life care. We included individuals who were diagnosed with amyotrophic lateral sclerosis according to the revised El-Escorial criteria, and who died between Jan 1, 2014, and Dec 31, 2016. We calculated the frequency of euthanasia in patients with amyotrophic lateral sclerosis from reports made to euthanasia review committees (ERCs) between 2012 and 2020. Results were compared with clinic-based survey studies conducted in 1994-2005. End-of-life practices were end-of-life decisions by a clinician when hastening of death was considered as the potential, probable, or definite effect comprising euthanasia, physician-assisted suicide, ending of life without explicit request, forgoing life-prolonging treatment, and intensified alleviation of symptoms.<br><br>FINDINGS: Between Jan 1, 2012, and Dec 31, 2020, 4130 reports of death from amyotrophic lateral sclerosis were made to ERCs, of which 1014 were from euthanasia or physician-assisted suicide (mean frequency 25% [SD 3] per year). Sex and gender data were unavailable from the ERC registry. Of 884 patients with amyotrophic lateral sclerosis who died between Jan 1, 2014, and Dec 31, 2016, their treating clinician was identified for 731 and a caregiver was identified for 741, of whom 356 (49%) and 450 (61%), respectively, agreed to participate in the population-based survey study. According to clinicians, end-of-life practices were chosen by 280 (79%) of 356 patients with amyotrophic lateral sclerosis who died. The frequency of euthanasia in patients with amyotrophic lateral sclerosis in 2014-16 (141 [40%] of 356 deaths in patients with amyotrophic lateral sclerosis) was higher than in 1994-98 (35 [17%] of 203) and 2000-05 (33 [16%] of 209). Median survival of patients with amyotrophic lateral sclerosis from diagnosis was 15&#xb7;9 months (95% CI 12&#xb7;6-17&#xb7;6) for those who chose euthanasia and 16&#xb7;1 months (13&#xb7;4-19&#xb7;1) for those who did not choose euthanasia (hazard ratio 1&#xb7;07, 95% CI 0&#xb7;85-1&#xb7;34; p=0&#xb7;58). According to caregivers, compared with other end-of-life practices, patients with amyotrophic lateral sclerosis choosing euthanasia commonly reported reasons to hasten death as no chance of improvement (53 [56%] of 94 patients who chose euthanasia vs 28 [39%] of 72 patients who chose other end-of-life practices), loss of dignity (47 [50%] vs 15 [21%]), dependency (34 [36%] vs five [7%]), and fatigue or extreme weakness (41 [44%] vs 14 [20%]). According to caregivers, people with amyotrophic lateral sclerosis-whether they chose euthanasia or did not-were satisfied with the general quality (83 [93%] of 89 patients who chose euthanasia vs 73 [86%] of 85 patients who did not) and availability (85 [97%] of 88 vs 81 [91%] of 90) of end-of-life care.<br><br>INTERPRETATION: The proportion of patients with amyotrophic lateral sclerosis who chose euthanasia in the Netherlands has increased since 2002. The choice of euthanasia was not associated with disease or patient characteristics, depression or hopelessness, or the availability or quality of end-of-life care. The choice of euthanasia had no effect on overall survival. Future studies could focus on the effect of discussing end-of-life options on quality of life as part of multidisciplinary care throughout the course of the disease, to reduce feelings of loss of autonomy and dignity in patients living with amyotrophic lateral sclerosis.<br><br>FUNDING: Netherlands ALS Foundation.}, }
@article {pmid37345246, year = {2023}, author = {Li, X and Tian, Y and Wu, H and Wang, T}, title = {Network Pharmacology and Molecular Docking to Unveil the Mechanism of Shudihuang against Amyotrophic Lateral Sclerosis.}, journal = {Current pharmaceutical design}, volume = {29}, number = {19}, pages = {1535-1545}, doi = {10.2174/1381612829666230621105552}, pmid = {37345246}, issn = {1873-4286}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Molecular Docking Simulation ; Network Pharmacology ; Sitosterols ; Cyclooxygenase 2 ; PPAR gamma ; Stigmasterol ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Medicine, Chinese Traditional ; }, abstract = {BACKGROUND: Shudihuang has been clinically proven to be an effective Chinese medicine compatible with the treatment of amyotrophic lateral sclerosis. However, the underlying mechanism of Shudihuang against amyotrophic lateral sclerosis remains unclear.<br><br>OBJECTIVES: The present study aims to elucidate the possible mechanism of Shudihuang in treating ALS using network pharmacology and molecular docking.<br><br>METHODS: The primary active components of Shudihuang and their relevant targets were identified by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the Swiss Target Prediction database, respectively. The ALS-related targets were obtained from the Disgenet and OMIM databases. The shared targets were derived by the intersection of disease-associated and component-associated targets and then introduced into the Cytoscape software to construct a network of drug-component-target. In addition, protein interaction relationships among the shared targets were analyzed by the STRING and Cytoscape software. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) functional enrichment analysis were conducted by the Metascape platform. The binding activities between the hub targets and the active components were assessed with molecular docking.<br><br>RESULTS: Stigmasterol and sitosterol were identified as the core components of Shudihuang, and the hub targets of ALS are PTGS2, PPARG, ESR1, IGF-1R, and MAPK3, with the highest degrees in the PPI network. The finding that stigmasterol and sitosterol had a good affinity with PTGS2, PPARG, ESR1, IGF-1R, and MAPK3 also supported this. Finally, it was revealed that Shudihuang treatment of ALS predominantly involves estrogen- related pathways such as nuclear receptor activity and steroid binding.<br><br>CONCLUSION: In summary, this study suggested that the main active components of Shudihuang (stigmasterol and sitosterol) may exert a critical effect in ALS treatment by binding to hub targets (PTGS2, PPARG, ESR1, IGF-1R, and MAPK3) and then modulating estrogen receptor-related pathways to attenuate glutamate excitotoxicity, inhibit oxidative stress and antagonize inflammation.}, }
@article {pmid37344230, year = {2023}, author = {Bjornevik, K and Cortese, M and Furtado, JD and Paganoni, S and Schwarzschild, MA and Cudkowicz, ME and Ascherio, A}, title = {Association of Polyunsaturated Fatty Acids and Clinical Progression in Patients With ALS: Post Hoc Analysis of the EMPOWER Trial.}, journal = {Neurology}, volume = {101}, number = {7}, pages = {e690-e698}, pmid = {37344230}, issn = {1526-632X}, mesh = {Male ; Humans ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; Fatty Acids, Unsaturated ; *Fatty Acids, Omega-3 ; Fatty Acids, Omega-6 ; Disease Progression ; Fatty Acids ; }, abstract = {BACKGROUND AND OBJECTIVES: Polyunsaturated fatty acids (PUFAs) have neuroprotective and anti-inflammatory effects and could be beneficial in amyotrophic lateral sclerosis (ALS). Higher dietary intake and plasma levels of PUFAs, in particular alpha-linolenic acid (ALA), have been associated with a lower risk of ALS in large epidemiologic cohort studies, but data on disease progression in patients with ALS are sparse. We examined whether plasma levels of ALA and other PUFAs contributed to predicting survival time and functional decline in patients with ALS.<br><br>METHODS: We conducted a study among participants in the EMPOWER clinical trial who had plasma samples collected at the time of randomization that were available for fatty acid analyses. Plasma fatty acids were measured using gas chromatography. We used Cox proportional hazards models and linear regression to evaluate the association of individual fatty acids with risk of death and joint rank test score of functional decline and survival.<br><br>RESULTS: Fatty acid analyses were conducted in 449 participants. The mean (SD) age of these participants at baseline was 57.5 (10.7) years, and 293 (65.3%) were men; 126 (28.1%) died during follow-up. Higher ALA levels were associated with lower risk of death (age-adjusted and sex-adjusted hazard ratio comparing highest vs lowest quartile 0.50, 95% CI 0.29-0.86, p-trend = 0.041) and higher joint rank test score (difference in score according to 1 SD increase 10.7, 95% CI 0.2-21.1, p = 0.045), consistent with a slower functional decline. The estimates remained similar in analyses adjusted for body mass index, race/ethnicity, symptom duration, site of onset, riluzole use, family history of ALS, predicted upright slow vital capacity, and treatment group. Higher levels of the n-3 fatty acid eicosapentaenoic acid and the n-6 fatty acid linoleic acid were associated with a lower risk of death during follow-up.<br><br>DISCUSSION: Higher levels of ALA were associated with longer survival and slower functional decline in patients with ALS. These results suggest that ALA may have a favorable effect on disease progression in patients with ALS.}, }
@article {pmid37342380, year = {2023}, author = {Shamsaei, G and Houshmand, F and Ahmadzadeh Deylami, A and Valizadeh, A and Rafie, S and Moradi, M}, title = {The Efficacy and Safety of Intrathecal Autologous Bone Marrow-Derived Mesenchymal Stromal Cells in Amyotrophic Lateral Sclerosis: A Pilot Study.}, journal = {Advanced pharmaceutical bulletin}, volume = {13}, number = {2}, pages = {361-367}, pmid = {37342380}, issn = {2228-5881}, abstract = {Purpose: Amyotrophic lateral sclerosis (ALS) is an uncommon and aggressive neurodegenerative disorder that influences the lower and upper motor neurons. There are low eligible drugs for ALS treatment; in this regard, supplemental and replacement treatments are essential. There are relative studies in the field of mesenchymal stromal cells (MSCs) therapy in ALS, but the different methods, differently used medium, and difference in follow-up periods affect the outcome treatment. Methods: The current survey is a single-center, phase I clinical trial to evaluating the efficacy and safety of autologous bone marrow (BM)-derived MSCs through intrathecal administration in ALS patients. MNCs were isolated from BM specimens and cultured. The clinical outcome was evaluated based Revised Amyotrophic Lateral Sclerosis Functional Rating (ALSFRS-R) Scale. Results: Each patient received 15±3×10[6] cells through subarachnoid space. No adverse events (AEs) were detected. Just one patient experienced a mild headache after injection. Following injection, no new intradural cerebrospinal pathology transplant-related was observed. None of the patients' pathologic disruptions following transplantation were detected by magnetic resonance imaging (MRI). The additional analyses have shown the average rate of ALSFRS-R score and forced vital capacity (FVC) reduction have decreased during 10 months following MSCs transplantation versus the pretreatment period, from -5.4±2.3 to -2±3.08 ALSFRS-R points/period (P=0.014) and -12.6±5.22% to -4.8±14.72%/period (P<0.001), respectively. Conclusion: These results have shown that autologous MSCs transplantation reduces the disease's progression and has favorable safety. Trial Registration: This study performed as a phase I clinical trial (code IRCT20200828048551N1).}, }
@article {pmid37338820, year = {2023}, author = {Willemse, SW and van Es, MA}, title = {Susceptibility and disease modifier genes in amyotrophic lateral sclerosis: from genetic associations to therapeutic implications.}, journal = {Current opinion in neurology}, volume = {36}, number = {4}, pages = {365-370}, pmid = {37338820}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; Genes, Modifier ; Superoxide Dismutase-1/genetics/therapeutic use ; Motor Neurons ; Mutation ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a severe disease characterized by the degeneration of motor neurons. Large-scale genetic studies have now identified over 60 genes that are associated with ALS, which in large part have also been functionally characterized. The purpose of this review is to outline how these advances are being translated into novel therapeutic strategies.<br><br>RECENT FINDINGS: The emergence of techniques that allow the specific therapeutic targeting of a (mutant) gene, in particular antisense oligonucleotide therapy (ASOs), have led to the first successful gene therapy for SOD1-ALS and multiple other gene-targeted trials are underway. This includes genetic variants that modify the disease phenotype as well as causal mutations.<br><br>SUMMARY: Technological and methodological advances are enabling researchers to unravel the genetics of ALS. Both causal mutations and genetic modifiers are viable therapeutic targets. By performing natural history studies, the phenotype-genotype correlations can be characterized. In conjunction with biomarkers for target engagement and international collaboration, this makes performing gene-targeted trials ALS feasible. The first effective treatment has now been developed for SOD1-ALS and, with multiple studies underway, it seems realistic that more therapies will follow.}, }
@article {pmid37334341, year = {2023}, author = {Galeazzi, L and Holzman, J and Mondoloni, M and Rochefort, J}, title = {Lingual fasciculation: A point of call for the diagnosis of amyotrophic lateral sclerosis.}, journal = {Clinical case reports}, volume = {11}, number = {6}, pages = {e7560}, pmid = {37334341}, issn = {2050-0904}, abstract = {A 60-year-old female patient, with no notable medical history, was referred by the internal medicine department for a dry mouth workup. The clinical examination revealed an absence of dryness, and the presence of lingual fasciculations, associated with difficulties in mastication and phonation. These symptoms appeared spontaneously 9 months before the consultation, after leaving confinement. Given the presence of lingual fasciculations, the diagnostic hypothesis of a neurological pathology, in particular amyotrophic lateral sclerosis (ALS), was suspected. After performing an electromyogram (EMG), the diagnosis of ALS was retained. Riluzole treatment was then started, and physical therapy sessions were scheduled. Riluzole allows an average gain of 4 to 6 months of life expectancy. Speech therapy and physical therapy allow to maintain the functions as long as possible and to improve the end-of-life conditions. The interest of early detection of ALS allows delaying the progression of the disease.}, }
@article {pmid37333039, year = {2023}, author = {Mann, RH}, title = {Impaired Thiamine Metabolism in Amyotrophic Lateral Sclerosis and Its Potential Treatment With Benfotiamine: A Case Report and a Review of the Literature.}, journal = {Cureus}, volume = {15}, number = {6}, pages = {e40511}, pmid = {37333039}, issn = {2168-8184}, abstract = {Homogenates of brain tissue from the frontal cortex at autopsy in patients with amyotrophic lateral sclerosis (ALS) showed dramatically reduced levels of the enzyme thiamine pyrophosphatase (TPPase), the enzyme responsible for the conversion of thiamine pyrophosphate (TPP) to thiamine monophosphate (TMP). Additionally, free thiamine (vitamin B1) and TMP levels have been shown to be significantly reduced in the plasma and cerebral spinal fluid (CSF) of patients with ALS. These findings suggest that there is impaired thiamine metabolism in patients with ALS. Impaired thiamine metabolism decreases adenosine triphosphate (ATP) production and is a well-established cause of neurodegeneration. Decreased levels of TPPase, resulting in decreased levels of TMP in the cells of the frontal cortex, might account for the focal neurodegenerative changes observed in motor neurons in ALS. Benfotiamine, a safe, lipid-soluble, highly absorbable thiamine analogue, significantly raises free thiamine, TMP, and TPP levels in the blood. A case in which benfotiamine may have positively impacted the symptoms of a patient with ALS is presented. The use of benfotiamine in patients with ALS appears to be a promising therapeutic option. Considering the severity and the lack of satisfactory treatment options associated with this disease, more research on the effects of benfotiamine on the course of ALS is urgently needed.}, }
@article {pmid37331636, year = {2023}, author = {Zhang, H and Qi, G and Wang, K and Yang, J and Shen, Y and Yang, X and Chen, X and Yao, X and Gu, X and Qi, L and Zhou, C and Sun, H}, title = {Oxidative stress: Roles in skeletal muscle atrophy.}, journal = {Biochemical pharmacology}, volume = {214}, number = {}, pages = {115664}, doi = {10.1016/j.bcp.2023.115664}, pmid = {37331636}, issn = {1873-2968}, mesh = {Humans ; *Muscular Atrophy/metabolism ; Oxidative Stress ; Muscle, Skeletal/metabolism ; *Sarcopenia/drug therapy/metabolism/pathology ; Antioxidants/metabolism ; Chronic Disease ; }, abstract = {Oxidative stress, inflammation, mitochondrial dysfunction, reduced protein synthesis, and increased proteolysis are all critical factors in the process of muscle atrophy. In particular, oxidative stress is the key factor that triggers skeletal muscle atrophy. It is activated in the early stages of muscle atrophy and can be regulated by various factors. The mechanisms of oxidative stress in the development of muscle atrophy have not been completely elucidated. This review provides an overview of the sources of oxidative stress in skeletal muscle and the correlation of oxidative stress with inflammation, mitochondrial dysfunction, autophagy, protein synthesis, proteolysis, and muscle regeneration in muscle atrophy. Additionally, the role of oxidative stress in skeletal muscle atrophy caused by several pathological conditions, including denervation, unloading, chronic inflammatory diseases (diabetes mellitus, chronic kidney disease, chronic heart failure, and chronic obstructive pulmonary disease), sarcopenia, hereditary neuromuscular diseases (spinal muscular atrophy, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy), and cancer cachexia, have been discussed. Finally, this review proposes the alleviation oxidative stress using antioxidants, Chinese herbal extracts, stem cell and extracellular vesicles as a promising therapeutic strategy for muscle atrophy. This review will aid in the development of novel therapeutic strategies and drugs for muscle atrophy.}, }
@article {pmid37327376, year = {2023}, author = {Shefner, JM and Musaro, A and Ngo, ST and Lunetta, C and Steyn, FJ and Robitaille, R and De Carvalho, M and Rutkove, S and Ludolph, AC and Dupuis, L}, title = {Skeletal muscle in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {146}, number = {11}, pages = {4425-4436}, pmid = {37327376}, issn = {1460-2156}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Motor Neurons/pathology ; Muscle, Skeletal/pathology ; Neuromuscular Junction/pathology ; Muscle Weakness ; }, abstract = {Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS. Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other motor neuron diseases and draw perspectives for future research and treatment.}, }
@article {pmid37326935, year = {2023}, author = {Cantisani, TA}, title = {Is there a treatment effective and safe for sialorrhea in people with amyotrophic lateral sclerosis (ALS)? Summary of a Cochrane Systematic Review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {9}, pages = {3083-3085}, pmid = {37326935}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; *Botulinum Toxins/therapeutic use ; *Sialorrhea/therapy/drug therapy ; Treatment Outcome ; Systematic Reviews as Topic ; }, }
@article {pmid37326908, year = {2023}, author = {Zheng, C and Li, W and Ali, T and Peng, Z and Liu, J and Pan, Z and Feng, J and Li, S}, title = {Ibrutinib Delays ALS Installation and Increases Survival of SOD1[G93A] Mice by Modulating PI3K/mTOR/Akt Signaling.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {18}, number = {3}, pages = {383-396}, pmid = {37326908}, issn = {1557-1904}, support = {NCT03721302//International Cooperation Project&#xff08;NCT03721302&#xff09;of Shenzhen Children's Hospital/ ; 2019SHIBS0004//Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions/ ; JCYJ20220530155611026//Basic research of Shenzhen Science and Technology Plan Project&#xff08;General Program/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal multisystem degenerative disorder with minimal available therapeutic. However, some recent studies showed promising results of immunological-based treatment. Here, we aimed to evaluate the efficacy of ibrutinib against ALS-associated abnormalities by targeting inflammation and muscular atrophy. Ibrutinib was administrated orally to SOD1 [G93A] mice from 6 to 19 weeks for prophylactic administration and 13 to 19 weeks for therapeutic administration. Our results demonstrated that ibrutinib treatment significantly delayed ALS-like symptom onset in the SOD1 [G93A] mice, as shown by improved survival time and reduced behavioral impairments. Ibrutinib treatment significantly reduced muscular atrophy by increasing muscle/body weight and decreasing muscular necrosis. The ibrutinib treatment also considerably reduced pro-inflammatory cytokine production, IBA-1, and GFAP expression, possibly mediated by mTOR/Akt/Pi3k signaling in the medulla, motor cortex and spinal cord of the ALS mice. In conclusion, our study demonstrated that ibrutinib could delay ALS onset, increase survival time, and reduce ALS progression by targeting inflammation and muscular atrophy via mTOR/Akt/PI3K modulation.}, }
@article {pmid37323141, year = {2023}, author = {Khatoon, S and Kalam, N and Rashid, S and Bano, G}, title = {Effects of gut microbiota on neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1145241}, pmid = {37323141}, issn = {1663-4365}, abstract = {A progressive degradation of the brain's structure and function, which results in a reduction in cognitive and motor skills, characterizes neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The morbidity linked to NDs is growing, which poses a severe threat to human being's mental and physical ability to live well. The gut-brain axis (GBA) is now known to have a crucial role in the emergence of NDs. The gut microbiota is a conduit for the GBA, a two-way communication system between the gut and the brain. The myriad microorganisms that make up the gut microbiota can affect brain physiology by transmitting numerous microbial chemicals from the gut to the brain via the GBA or neurological system. The synthesis of neurotransmitters, the immunological response, and the metabolism of lipids and glucose have all been demonstrated to be impacted by alterations in the gut microbiota, such as an imbalance of helpful and harmful bacteria. In order to develop innovative interventions and clinical therapies for NDs, it is crucial to comprehend the participation of the gut microbiota in these conditions. In addition to using antibiotics and other drugs to target particular bacterial species that may be a factor in NDs, this also includes using probiotics and other fecal microbiota transplantation to maintain a healthy gut microbiota. In conclusion, the examination of the GBA can aid in understanding the etiology and development of NDs, which may benefit the improvement of clinical treatments for these disorders and ND interventions. This review indicates existing knowledge about the involvement of microbiota present in the gut in NDs and potential treatment options.}, }
@article {pmid37319115, year = {2023}, author = {Yang, F and Mahaman, YAR and Zhang, B and Wang, JZ and Liu, R and Liu, F and Wang, X}, title = {C9orf72 poly-PR helps p53 escape from the ubiquitin-proteasome system and promotes its stability.}, journal = {Journal of neurochemistry}, volume = {166}, number = {2}, pages = {389-402}, doi = {10.1111/jnc.15872}, pmid = {37319115}, issn = {1471-4159}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Proteasome Endopeptidase Complex/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Ubiquitin/metabolism ; C9orf72 Protein/genetics/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; Cytoplasm/metabolism ; Dipeptides/genetics ; DNA Repeat Expansion ; }, abstract = {C9orf72-derived dipeptide repeats (DPRs) proteins have been regarded as the pathogenic cause of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). As the most toxic DPRs in C9-ALS/FTD, poly-proline-arginine (poly-PR) is associated with the stability and accumulation of p53, which consequently induces neurodegeneration. However, the exact molecular mechanism via which C9orf72 poly-PR stabilizes p53 remains unclear. In this study, we showed that C9orf72 poly-PR induces not only neuronal damage but also p53 accumulation and p53 downstream gene activation in primary neurons. C9orf72 (PR)50 also slows down p53 protein turnover without affecting the p53 transcription level and thus promotes its stability in N2a cells. Interestingly, the ubiquitin-proteasome system but not the autophagy function was impaired in (PR)50 transfected N2a cells, resulting in defective p53 degradation. Moreover, we found that (PR)50 induces mdm2 mistranslocation from the nucleus to the cytoplasm and competitively binds to p53, reducing mdm2-p53 interactions in the nucleus in two different (PR)50 transfected cells. Our data strongly indicate that (PR)50 reduces mdm2-p53 interactions and causes p53 to escape from the ubiquitin-proteasome system, promoting its stability and accumulation. Inhibiting or at least downregulating (PR)50 binding with p53 may be therapeutically exploited for the treatment of C9-ALS/FTD.}, }
@article {pmid37317638, year = {2023}, author = {Yang, Y and Rowe, D and McCann, H and Shepherd, CE and Kril, JJ and Kiernan, MC and Halliday, GM and Tan, RH}, title = {Treatment with the copper compound CuATSM has no significant effect on motor neuronal pathology in patients with ALS.}, journal = {Neuropathology and applied neurobiology}, volume = {49}, number = {4}, pages = {e12919}, pmid = {37317638}, issn = {1365-2990}, support = {R28 AA012725/AA/NIAAA NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology ; Copper ; Superoxide Dismutase-1 ; Riluzole ; Superoxide Dismutase ; Motor Neurons/pathology ; Spinal Cord/pathology ; DNA-Binding Proteins ; Mice, Transgenic ; }, abstract = {AIMS: Although the orally available brain-penetrant copper compound CuATSM has demonstrated promising effects in SOD1-linked mouse models, the impact of CuATSM on disease pathology in patients with amyotrophic lateral sclerosis (ALS) remains unknown.<br><br>METHODS: The present study set out to address this deficit by performing the first pilot comparative analysis of ALS pathology in patients that had been administered CuATSM and riluzole [N&#x2009;=&#x2009;6 cases composed of ALS-TDP (n&#x2009;=&#x2009;5) and ALS-SOD1 (n&#x2009;=&#x2009;1)] versus riluzole only [N&#x2009;=&#x2009;6 cases composed of ALS-TDP (n&#x2009;=&#x2009;4) and ALS-SOD1 (n&#x2009;=&#x2009;2)].<br><br>RESULTS: Our results revealed no significant difference in neuron density or TDP-43 burden in the motor cortex and spinal cord of patients that had received CuATSM compared with patients that had not. In patients that had received CuATSM, p62-immunoreactive astrocytes were observed in the motor cortex and reduced Iba1 density was found in the spinal cord. However, no significant difference in measures of astrocytic activity and SOD1 immunoreactivity was found with CuATSM treatment.<br><br>DISCUSSION: These findings, in this first postmortem investigation of patients with ALS in CuATSM trials, demonstrate that in contrast to that seen in preclinical models of disease, CuATSM does not significantly alleviate neuronal pathology or astrogliosis in patients with ALS.}, }
@article {pmid37316950, year = {2023}, author = {Petri, S and Grehl, T and Grosskreutz, J and Hecht, M and Hermann, A and Jesse, S and Lingor, P and Löscher, W and Maier, A and Schoser, B and Weber, M and Ludolph, AC}, title = {Guideline "Motor neuron diseases" of the German Society of Neurology (Deutsche Gesellschaft für Neurologie).}, journal = {Neurological research and practice}, volume = {5}, number = {1}, pages = {25}, pmid = {37316950}, issn = {2524-3489}, abstract = {INTRODUCTION: In 2021, the Deutsche Gesellschaft für Neurology published a new guideline on diagnosis and therapy of motor neuron disorders. Motor neuron disorders affect upper motor neurons in the primary motor cortex and/or lower motor neurons in the brain stem and spinal cord. The most frequent motor neuron disease amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease with an average life expectancy of 2-4 years with a yearly incidence of 3.1/100,000 in Central Europe (Rosenbohm et al. in J Neurol 264(4):749-757, 2017. https://doi.org/10.1007/s00415-017-8413-3). It is considered a rare disease mainly due to its low prevalence as a consequence of short disease duration.<br><br>RECOMMENDATIONS: These guidelines comprise recommendations regarding differential diagnosis, neuroprotective therapies and multidisciplinary palliative care including management of respiration and nutrition as well as provision of assistive devices and end-of-life situations.<br><br>CONCLUSION: Diagnostic and therapeutic guidelines are necessary due the comparatively high number of cases and the aggressive disease course. Given the low prevalence and the severe impairment of patients, it is often impossible to generate evidence-based data so that ALS guidelines are partially dependent on expert opinion.}, }
@article {pmid37316681, year = {2023}, author = {Blair, HA}, title = {Tofersen: First Approval.}, journal = {Drugs}, volume = {83}, number = {11}, pages = {1039-1043}, pmid = {37316681}, issn = {1179-1950}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase/genetics ; Oligonucleotides/pharmacology/therapeutic use ; Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Tofersen (Qalsody[™]) is an antisense oligonucleotide being developed by Biogen for the treatment of amyotrophic lateral sclerosis (ALS). On 25 April 2023, tofersen was approved in the USA for the treatment of ALS in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This article summarizes the milestones in the development of tofersen leading to this first approval for ALS.}, }
@article {pmid37316165, year = {2023}, author = {Ziegler, A and Öner, A and Quadflieg, G and Betschart, RO and Thiéry, A and Babel, H and Mwambi, HG and Neumeyer, H and Mackschin, S and Hintz, S and Mann, M and Dittrich, H and Schmidt, C}, title = {Cost-effectiveness of a telemonitoring programme in patients with cardiovascular diseases compared with standard of care.}, journal = {Heart (British Cardiac Society)}, volume = {109}, number = {21}, pages = {1617-1623}, pmid = {37316165}, issn = {1468-201X}, mesh = {Humans ; *Cardiovascular Diseases/therapy ; Cost-Benefit Analysis ; Quality of Life ; Standard of Care ; *Hypertension/diagnosis/therapy ; Quality-Adjusted Life Years ; }, abstract = {OBJECTIVES: The main aim of this work was to analyse the cost-effectiveness of an integrated care concept (NICC) that combines telemonitoring with the support of a care centre in addition to guideline therapy for patients. Secondary aims were to compare health utility and health-related quality of life (QoL) between NICC and standard of care (SoC).<br><br>METHODS: The randomised controlled CardioCare MV Trial compared NICC and SoC in patients from Mecklenburg-West Pomerania (Germany) with atrial fibrillation, heart failure or treatment-resistant hypertension. QoL was measured using the EQ-5D-5L at baseline, 6 months and 1 year follow-up. Quality-adjusted life years (QALYs), EQ5D utility scores, Visual Analogue Scale (VAS) Scores and VAS adjusted life years (VAS-AL) were calculated. Cost data were obtained from health insurance companies, and the payer perspective was taken in health economic analyses. Quantile regression was used with adjustments for stratification variables.<br><br>RESULTS: The net benefit of NICC (QALY) was 0.031 (95% CI 0.012 to 0.050; p=0.001) in this trial involving 957 patients. EQ5D Index values, VAS-ALs and VAS were larger for NICC compared with SoC at 1 year follow-up (all p&#x2264;0.004). Direct cost per patient and year were &#x20ac;323 (CI &#x20ac;157 to &#x20ac;489) lower in the NICC group. When 2000 patients are served by the care centre, NICC is cost-effective if one is willing to pay &#x20ac;10 652 per QALY per year.<br><br>CONCLUSION: NICC was associated with higher QoL and health utility. The programme is cost-effective if one is willing to pay approximately &#x20ac;11 000 per QALY per year.}, }
@article {pmid37314311, year = {2023}, author = {Sharma, S and Tomar, VR and Deep, S}, title = {Myricetin: A Potent Anti-Amyloidogenic Polyphenol against Superoxide Dismutase 1 Aggregation.}, journal = {ACS chemical neuroscience}, volume = {14}, number = {13}, pages = {2461-2475}, doi = {10.1021/acschemneuro.3c00276}, pmid = {37314311}, issn = {1948-7193}, mesh = {Humans ; Superoxide Dismutase-1/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Polyphenols/pharmacology ; Flavonoids/pharmacology ; Superoxide Dismutase/metabolism ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is believed to be caused by the aggregation of misfolded or mutated superoxide dismutase 1 (SOD1). As there is currently no treatment, research into aggregation inhibitors continues. Based on docking, molecular dynamics (MD) simulations, and experimental observations, we propose that myricetin, a plant flavonoid, can act as a potent anti-amyloidogenic polyphenol against SOD1 aggregation. Our MD simulation results showed that myricetin stabilizes the protein interface, destabilizes the preformed fibril, and decreases the rate of fibril elongation. Myricetin inhibits the aggregation of SOD1 in a dose-dependent manner as shown by the ThT aggregation kinetics curves. Our transmission electron microscopy, dynamic light scattering, and circular dichroism experiments indicate that fewer shorter fibrils have formed. Fluorescence spectroscopy results predict the involvement of a static quenching mechanism characterized by a strong binding between protein and myricetin. Importantly, size exclusion chromatography revealed the potential of myricetin for fibril destabilization and depolymerization. These experimental observations complement the MD results. Thus, myricetin is a potent SOD1 aggregation inhibitor that can reduce the fibril load. Using the structure of myricetin as a reference, it is possible to design more effective therapeutic inhibitors against ALS that prevent the disease and reverse its effects.}, }
@article {pmid37310359, year = {2023}, author = {Fang, J and Huang, Y and Wu, J and Shen, B and Yang, Y and Ju, M}, title = {Fluorogenic methodology for visualization of phase separation in chemical biology.}, journal = {Organic &amp; biomolecular chemistry}, volume = {21}, number = {25}, pages = {5140-5149}, doi = {10.1039/d3ob00660c}, pmid = {37310359}, issn = {1477-0539}, mesh = {Humans ; *Alzheimer Disease ; Biology ; }, abstract = {Phase separation is a common biological phenomenon in the liquid environment of organisms. Phase separation has been shown to be a key cause of many existing incurable diseases, such as the protein aggregates formed by phase separation of Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, etc. Tracking the occurrence of phase separation in vivo is critical to many disease detection methods and solving many treatment problems. Its physicochemical properties and visual detection methods have flourished in the last few years in chemical biology, among which the fluorogenic toolbox has great application potential compared to the traditional detection methods that cannot visualize the phase separation process intuitively, but just show some parameters indirectly. This paper reviews the mechanism and disease correlation proven in recent years for phase separation and analyzes the detection methods for phase separation, including functional microscope imaging techniques, turbidity monitoring, macromolecule congestion sensing, in silico analysis, etc. It is worth mentioning that the qualitative and quantitative analysis of aggregates formed by phase separation using in vitro parameters has successfully provided basic physical and chemical properties for phase separation aggregates, and is an important cornerstone for researchers to carry forward the past and break through the existing technical shackles to create new in vivo monitoring methods such as fluorescence methodology. Crucially, fluorescence methods for cell microenvironment imaging based on different mechanisms are discussed, such as AIE-based probes, TICT-based probes and FRET-based probes, etc.}, }
@article {pmid37307822, year = {2024}, author = {Chen, S and Cai, X and Lao, L and Wang, Y and Su, H and Sun, H}, title = {Brain-Gut-Microbiota Axis in Amyotrophic Lateral Sclerosis: A Historical Overview and Future Directions.}, journal = {Aging and disease}, volume = {15}, number = {1}, pages = {74-95}, pmid = {37307822}, issn = {2152-5250}, mesh = {Humans ; Aged ; Child, Preschool ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Neurodegenerative Diseases/complications ; *Gastrointestinal Microbiome/physiology ; Brain-Gut Axis ; Brain ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease which is strongly associated with age. The incidence of ALS increases from the age of 40 and peaks between the ages of 65 and 70. Most patients die of respiratory muscle paralysis or lung infections within three to five years of the appearance of symptoms, dealing a huge blow to patients and their families. With aging populations, improved diagnostic methods and changes in reporting criteria, the incidence of ALS is likely to show an upward trend in the coming decades. Despite extensive researches have been done, the cause and pathogenesis of ALS remains unclear. In recent decades, large quantities of studies focusing on gut microbiota have shown that gut microbiota and its metabolites seem to change the evolvement of ALS through the brain-gut-microbiota axis, and in turn, the progression of ALS will exacerbate the imbalance of gut microbiota, thereby forming a vicious cycle. This suggests that further exploration and identification of the function of gut microbiota in ALS may be crucial to break the bottleneck in the diagnosis and treatment of this disease. Hence, the current review summarizes and discusses the latest research advancement and future directions of ALS and brain-gut-microbiota axis, so as to help relevant researchers gain correlative information instantly.}, }
@article {pmid37304072, year = {2023}, author = {Santiago, JA and Potashkin, JA}, title = {Physical activity and lifestyle modifications in the treatment of neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1185671}, pmid = {37304072}, issn = {1663-4365}, support = {R01 AG062176/AG/NIA NIH HHS/United States ; }, abstract = {Neurodegenerative diseases have reached alarming numbers in the past decade. Unfortunately, clinical trials testing potential therapeutics have proven futile. In the absence of disease-modifying therapies, physical activity has emerged as the single most accessible lifestyle modification with the potential to fight off cognitive decline and neurodegeneration. In this review, we discuss findings from epidemiological, clinical, and molecular studies investigating the potential of lifestyle modifications in promoting brain health. We propose an evidence-based multidomain approach that includes physical activity, diet, cognitive training, and sleep hygiene to treat and prevent neurodegenerative diseases.}, }
@article {pmid37302030, year = {2023}, author = {Rudge, JD}, title = {The Lipid Invasion Model: Growing Evidence for This New Explanation of Alzheimer's Disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {94}, number = {2}, pages = {457-470}, pmid = {37302030}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Brain/pathology ; Blood-Brain Barrier/metabolism ; Cholesterol ; }, abstract = {The Lipid Invasion Model (LIM) is a new hypothesis for Alzheimer's disease (AD) which argues that AD is a result of external lipid invasion to the brain, following damage to the blood-brain barrier (BBB). The LIM provides a comprehensive explanation of the observed neuropathologies associated with the disease, including the lipid irregularities first described by Alois Alzheimer himself, and accounts for the wide range of risk factors now identified with AD, all of which are also associated with damage to the BBB. This article summarizes the main arguments of the LIM, and new evidence and arguments in support of it. The LIM incorporates and extends the amyloid hypothesis, the current main explanation of the disease, but argues that the greatest cause of late-onset AD is not amyloid-β (Aβ) but bad cholesterol and free fatty acids, let into the brain by a damaged BBB. It suggests that the focus on Aβ is the reason why we have made so little progress in treating the disease in the last 30 years. As well as offering new perspectives for further research into the diagnosis, prevention, and treatment of AD, based on protecting and repairing the BBB, the LIM provides potential new insights into other neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis/motor neuron disease.}, }
@article {pmid37296644, year = {2023}, author = {Tzeplaeff, L and Wilfling, S and Requardt, MV and Herdick, M}, title = {Current State and Future Directions in the Therapy of ALS.}, journal = {Cells}, volume = {12}, number = {11}, pages = {}, pmid = {37296644}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Riluzole/therapeutic use ; Motor Neurons/pathology ; Biomarkers ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying causative pathological pathway is unclear and potentially diverse, finding a suitable therapy to slow down or possibly stop disease progression remains challenging. Varying by country Riluzole, Edaravone, and Sodium phenylbutyrate/Taurursodiol are the only drugs currently approved in ALS treatment for their moderate effect on disease progression. Even though curative treatment options, able to prevent or stop disease progression, are still unknown, recent breakthroughs, especially in the field of targeting genetic disease forms, raise hope for improved care and therapy for ALS patients. In this review, we aim to summarize the current state of ALS therapy, including medication as well as supportive therapy, and discuss the ongoing developments and prospects in the field. Furthermore, we highlight the rationale behind the intense research on biomarkers and genetic testing as a feasible way to improve the classification of ALS patients towards personalized medicine.}, }
@article {pmid37290723, year = {2023}, author = {Lu, Y and Wang, JT and Li, N and Zhu, X and Li, Y and Bansal, S and Wang, Y and Al-Jamal, KT}, title = {Intranasal administration of edaravone nanoparticles improves its stability and brain bioavailability.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {359}, number = {}, pages = {257-267}, doi = {10.1016/j.jconrel.2023.06.001}, pmid = {37290723}, issn = {1873-4995}, mesh = {Animals ; Mice ; Administration, Intranasal ; *Amyotrophic Lateral Sclerosis/drug therapy ; Biological Availability ; Brain/metabolism ; Chromatography, Liquid ; Drug Carriers/chemistry ; Drug Delivery Systems ; *Edaravone/administration &amp; dosage/pharmacokinetics ; Hydrogen Peroxide/metabolism ; *Nanoparticles/administration &amp; dosage ; Particle Size ; Polylactic Acid-Polyglycolic Acid Copolymer/metabolism ; Tandem Mass Spectrometry ; Tissue Distribution ; Cell Line ; }, abstract = {The clinical application of EDV, a potent antioxidant drug approved for amyotrophic lateral sclerosis (ALS), is limited by its short biological half-life and poor water solubility necessitating hospitalization during intravenous infusion. Nanotechnology-based drug delivery constitutes a powerful tool through inferring drug stability and targeted drug delivery improving drug bioavailability at the diseased site. Nose-to-brain drug delivery offers direct access to the brain bypassing the blood brain barrier and reducing systemic biodistribution. In this study, we designed EDV-loaded poly(lactic-co-glycolic acid) (PLGA)-based polymeric nanoparticles (NP-EDV) for intranasal administration. NPs were formulated by the nanoprecipitation method. Morphology, EDV loading, physicochemical properties, shelf-life stability, in vitro release and pharmacokinetic assessment in mice were conducted. EDV was efficiently loaded into ∼90 nm NPs, stable up to 30 days of storage, at ∼3% drug loading. NP-EDV reduced H2O2-induced oxidative stress toxicity in mouse microglial cell line BV-2. Optical imaging and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) showed that intranasal delivery of NP-EDV offered higher and more sustained brain uptake of EDV compared to intravenous administration. This study is the first of its kind to develop an ALS drug in a nanoparticulate formulation for nose-to-brain delivery raising hope to ALS patients where currently treatment options are limited to two clinically approved drugs only.}, }
@article {pmid37288776, year = {2023}, author = {Hatch, J and Barkhaus, P and Barnes, B and Beauchamp, M and Benatar, M and Bertorini, T and Bowser, R and Bromberg, M and Brown, A and Mascias Cadavid, J and Carter, GT and Cole, N and Crayle, J and Dimachkie, M and Ennist, D and Feldman, E and Fullam, T and Heiman-Patterson, T and Jhooty, S and Levine, T and Li, X and Lund, I and Mallon, E and Maragakis, N and McDermott, C and Pattee, G and Pierce, K and Ratner, D and Staats, K and Wicks, P and Wiedau, M and Bedlack, R}, title = {ALSUntangled #70: caffeine.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/21678421.2023.2220742}, pmid = {37288776}, issn = {2167-9223}, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here, we review caffeine which has plausible mechanisms for slowing ALS progression. However, pre-clinical studies are contradictory, and a large case series showed no relationship between caffeine intake and ALS progression rate. While low doses of caffeine are safe and inexpensive, higher doses can cause serious side effects. At this time, we cannot endorse caffeine as a treatment to slow ALS progression.}, }
@article {pmid37280513, year = {2023}, author = {Vidovic, M and Freigang, M and Aust, E and Linse, K and Petzold, D and Günther, R}, title = {Cognitive performance of adult patients with SMA before and after treatment initiation with nusinersen.}, journal = {BMC neurology}, volume = {23}, number = {1}, pages = {216}, pmid = {37280513}, issn = {1471-2377}, mesh = {Humans ; Adult ; Longitudinal Studies ; *Muscular Atrophy, Spinal/drug therapy ; *Spinal Muscular Atrophies of Childhood ; Cognition ; }, abstract = {BACKGROUND: Spinal muscular atrophy (SMA) is a genetic neuromuscular disease caused by mutations of the SMN1 gene. Deficient SMN protein causes irreversible degeneration of alpha motor neurons characterized by progressive muscle weakness and atrophy. Considering that SMA is a multi-systemic disorder and SMN protein was found to be expressed in cortical structures, the cognitive profile of adult patients with SMA has recently been of particular interest. With nusinersen, a novel, disease-modifying drug has been established, but its effects on neuropsychological functions have not been validated yet. Aim of this study was to investigate the cognitive profile of adult patients with SMA during treatment initiation with nusinersen and to reveal improvement or deterioration in cognitive performance.<br><br>METHODS: This monocentric longitudinal study included 23 patients with SMA type 2 and 3. All patients were assessed with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) before and after 14 months of treatment initiation with nusinersen. Additionally, motor function was evaluated by Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM) and Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R).<br><br>RESULTS: Of the treatment-naive patients, only three were below the age- and education-matched cut-off for cognitive impairment in the ECAS total score. Significant differences between SMA type 2 and 3 were only detected in the domain of Language. After 14 months of treatment, patients showed significant improvement of absolute scores in all three ALS-specific domains, in the non-ALS-specific domain of Memory, in both subscores and in the ECAS total score. No associations were detected between cognitive and functional outcome measures.<br><br>CONCLUSIONS: In some adult patients with SMA abnormal cognitive performance in ALS-specific functions of the ECAS was evident. However, the presented results suggest no clinically significant cognitive changes during the observed treatment period with nusinersen.}, }
@article {pmid37279301, year = {2023}, author = {Fehlings, MG and Moghaddamjou, A and Harrop, JS and Stanford, R and Ball, J and Aarabi, B and Freeman, BJC and Arnold, PM and Guest, JD and Kurpad, SN and Schuster, JM and Nassr, A and Schmitt, KM and Wilson, JR and Brodke, DS and Ahmad, FU and Yee, A and Ray, WZ and Brooks, NP and Wilson, J and Chow, DS and Toups, EG and Kopjar, B}, title = {Safety and Efficacy of Riluzole in Acute Spinal Cord Injury Study (RISCIS): A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial.}, journal = {Journal of neurotrauma}, volume = {40}, number = {17-18}, pages = {1878-1888}, pmid = {37279301}, issn = {1557-9042}, mesh = {Humans ; Riluzole/adverse effects ; *Neuroprotective Agents/adverse effects ; Pandemics ; Prospective Studies ; Treatment Outcome ; Double-Blind Method ; *COVID-19 ; *Spinal Cord Injuries/drug therapy/chemically induced ; }, abstract = {Riluzole is a sodium-glutamate antagonist that attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favorable results in promoting recovery in pre-clinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. Patients with American Spinal Injury Association Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 h from injury were randomized to receive either riluzole, at an oral dose of 100 mg twice per day (BID) for the first 24 h followed by 50 mg BID for the following 13 days, or placebo. The primary efficacy end-point was change in Upper Extremity Motor (UEM) scores at 180 days. The primary efficacy analyses were conducted on an intention to treat (ITT) and completed cases (CC) basis. The study was powered at a planned enrolment of 351 patients. The trial began in October 2013 and was halted by the sponsor on May 2020 (and terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the pre-planned enrolment) were randomized with a follow-up rate of 82.7% at 180 days. At 180 days, in the CC population the riluzole-treated patients compared with placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor scores (CI: -6.79-12.52). No drug-related serious adverse events were associated with the use of riluzole. Additional pre-planned sensitivity analyses revealed that in the AIS C population, riluzole was associated with significant improvement in total motor scores (estimate: standard error [SE] 8.0; CI 1.5-14.4) and upper extremity motor scores (SE 13.8; CI 3.1-24.5) at 6 months. AIS B patients had higher reported independence, measured by the Spinal Cord Independence Measure score (45.3 vs. 27.3; d: 18.0 CI: -1.7-38.0) and change in mental health scores, measured by the Short Form 36 mental health domain (2.01 vs. -11.58; d: 13.2 CI: 1.2-24.8) at 180 days. AIS A patients who received riluzole had a higher average gain in neurological levels at 6 months compared with placebo (mean 0.50 levels gained vs. 0.12 in placebo; d: 0.38, CI: -0.2-0.9). The primary analysis did not achieve the predetermined end-point of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.}, }
@article {pmid37269231, year = {2024}, author = {Alqallaf, A and Cates, DW and Render, KP and Patel, KA}, title = {Sodium Phenylbutyrate and Taurursodiol: A New Therapeutic Option for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {The Annals of pharmacotherapy}, volume = {58}, number = {2}, pages = {165-173}, doi = {10.1177/10600280231172802}, pmid = {37269231}, issn = {1542-6270}, mesh = {United States ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Phenylbutyrates/adverse effects ; }, abstract = {OBJECTIVE: To review the safety and efficacy of sodium phenylbutyrate and taurursodiol (SP + T) in slowing progression of amyotrophic lateral sclerosis (ALS) compared with pre-existing therapies.<br><br>DATA SOURCES: A PubMed (from January 1, 2009, to April 13, 2023) and ClinicalTrials.gov search conducted using sodium phenylbutyrate, taurursodiol, AMX0035, riluzole, and edaravone. Additional articles were identified by hand from references.<br><br>This included English-language articles evaluating SP + T efficacy or safety in humans for decreasing neuronal death and slowing the progression of ALS.<br><br>DATA SYNTHESIS: In one phase II clinical trial that encompassed an open-label extension phase, disease severity, assessed by the rate of decline in overall score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised with higher scores indicating more functional ability, was -1.24 points per month with active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03-0.81; P = 0.03). Post hoc analysis found survival benefit of median 4.8 months with active medication compared with placebo.<br><br>SP + T is a new US Food and Drug Administration-approved oral suspension for the treatment of ALS. Patients who received active medication through the phase II trial showed decreased rates of disease progression. Overall, SP + T could be considered a potential agent for the treatment of ALS which has a high unmet need.<br><br>CONCLUSION: SP + T is an option for the treatment of ALS; however, additional data regarding efficacy in phase III trials with long-term safety profile considerations, as well as trials to compare current therapy with SP + T, are needed.}, }
@article {pmid37267911, year = {2023}, author = {Mazzini, L and De Marchi, F}, title = {iPSC-based research in ALS precision medicine.}, journal = {Cell stem cell}, volume = {30}, number = {6}, pages = {748-749}, doi = {10.1016/j.stem.2023.05.008}, pmid = {37267911}, issn = {1875-9777}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Induced Pluripotent Stem Cells/physiology ; Precision Medicine ; Motor Neurons ; }, abstract = {Clinical trials in amyotrophic lateral sclerosis (ALS) are challenged by the lack of pre-clinical models and biomarkers of disease onset and progression. In this issue, Morimoto et al. use induced pluripotent stem cell (iPSC)-derived motor neurons from patients with ALS to study therapeutic mechanisms of ropinirole in a clinical trial and identify treatment responders.}, }
@article {pmid37265174, year = {2023}, author = {Tabor Gray, L and Locatelli, E and Vasilopoulos, T and Wymer, J and Plowman, EK}, title = {Dextromethorphan/quinidine for the treatment of bulbar impairment in amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {8}, pages = {1296-1304}, pmid = {37265174}, issn = {2328-9503}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/drug therapy ; Dextromethorphan/pharmacology/therapeutic use ; Quinidine/pharmacology/therapeutic use ; Deglutition ; Speech ; }, abstract = {OBJECTIVE: No efficacious treatments exist to improve or prolong bulbar functions of speech and swallowing in persons with amyotrophic lateral sclerosis (pALS). This study evaluated the short-term impact of dextromethorphan/quinidine (DMQ) treatment on speech and swallowing function in pALS.<br><br>METHODS: This was a cohort trial conducted between August 2019 to August 2021 in pALS with a confirmed diagnosis of probable-definite ALS (El-Escorial Criteria-revisited) and bulbar impairment (ALS Functional Rating Scale score&#x2009;&#x2264;&#x2009;10 and speaking rate&#x2009;&#x2264;&#x2009;140 words per minute) who were DMQ na&#xef;ve. Efficacy of DMQ was assessed via pre-post change in the ALS Functional Rating Scale-Revised bulbar subscale and validated speech and swallowing outcomes. Paired t-tests, Fisher's exact, and &#x3c7;[2] tests were conducted with alpha at 0.05.<br><br>RESULTS: Twenty-eight pALS enrolled, and 24 participants completed the 28-day trial of DMQ. A significant increase in ALSFRS-R bulbar subscale score pre- (7.47&#x2009;&#xb1;&#x2009;1.98) to post- (8.39&#x2009;&#xb1;&#x2009;1.79) treatment was observed (mean difference: 0.92, 95% CI: 0.46-1.36, p&#x2009;<&#x2009;0.001). Functional swallowing outcomes improved, with a reduction in unsafe (75% vs. 44%, p&#x2009;=&#x2009;0.003) and inefficient swallowing (67% vs. 58%, p&#x2009;=&#x2009;0.002); the relative speech event duration in a standard reading passage increased, indicating a greater duration of uninterrupted speech (mean difference: 0.33&#x2009;s, 95% CI: 0.02-0.65, p&#x2009;=&#x2009;0.035). No differences in diadochokinetic rate or speech intelligibility were observed (p&#x2009;>&#x2009;0.05).<br><br>INTERPRETATION: Results of this study provide preliminary evidence that DMQ pharmacologic intervention may have the potential to improve or maintain bulbar function in pALS.}, }
@article {pmid37263249, year = {2023}, author = {Balamurugan, D and Nayak, C and Chattopadhyay, A and Karuppusamy, A and Ambrose, MM and Kumar, A and Singh, NK and Koley, M and Saha, S}, title = {Individualized Homeopathic Medicines in the Treatment of Psoriasis Vulgaris: Double-Blind, Randomized, Placebo-Controlled Trial.}, journal = {Complementary medicine research}, volume = {30}, number = {4}, pages = {317-331}, doi = {10.1159/000530180}, pmid = {37263249}, issn = {2504-2106}, mesh = {Humans ; *Psoriasis/drug therapy ; Double-Blind Method ; *Homeopathy ; India ; }, abstract = {INTRODUCTION: Psoriasis is a chronic inflammatory skin disorder, affecting the trunk and extensor surfaces of the limbs and scalp predominantly. Worldwide prevalence ranges between 0.1 and 11.4%, and in India between 0.4 and 2.8%; this creates a serious health burden. Psoriasis remains a frequently encountered condition in homeopathy practice, but there is a dearth of conclusive efficacy data supporting its use.<br><br>METHODS: This 6-month, double-blind, randomized trial was conducted on 51 patients suffering from psoriasis at the National Institute of Homoeopathy, India. Patients were randomized to receive either individualized homeopathic medicines (IHMs; n = 25) in LM potencies or identical-looking placebos (n = 26). Psoriasis area and severity index (PASI; primary), psoriasis disability index (PDI), and dermatological life quality index (DLQI; secondary) were measured at baseline and every 2 months, up to 6 months. The intention-to-treat sample was analyzed using a two-way repeated measure analysis of variance.<br><br>RESULTS: Although intragroup changes were significant in both groups in the outcome measures, improvements were significantly higher in the IHMs group than in placebos in PASI scores after 6 months of intervention (F1, 49 = 10.448, p = 0.002). DLQI daily activity subscale scores also yielded similar significant results favoring IHMs against placebos after 6 months (F1, 49 = 5.480, p = 0.023). Improvement in PDI total (F1, 49 = 0.063, p = 0.803), DLQI total (F1, 49 = 1.371, p = 0.247), and all remaining subscales were higher in the IHMs group than placebos after 6 months, but nonsignificant statistically. Calcarea carbonica, Mercurius solubilis, Arsenicum album, and Petroleum were the most frequently prescribed medicines.<br><br>CONCLUSIONS: IHMs exhibited better results than placebos in the treatment of psoriasis. Further research is warranted.<br><br>UNLABELLED: <title>Einleitung</title>Psoriasis ist eine chronisch entz&#xfc;ndliche Hauterkrankung, die vor allem den K&#xf6;rperstamm und die Streckseiten der Extremit&#xe4;ten sowie die Kopfhaut betrifft. Die weltweite Pr&#xe4;valenz liegt zwischen 0,1 und 11,4% und in Indien zwischen 0,4 und 2,8%, was sie zu einer erheblichen Belastung f&#xfc;r das Gesundheitssystem macht. In der hom&#xf6;opathischen Praxis ist die Psoriasis nach wie vor h&#xe4;ufig anzutreffen, doch mangelt es an schl&#xfc;ssigen Wirksamkeitsdaten, die deren Anwendung st&#xfc;tzen.<title>Methoden</title>Diese sechsmonatige, doppelblinde, randomisierte Studie wurde mit 51 Psoriasis-Patienten am National Institute of Homoeopathy in Indien durchgef&#xfc;hrt. Die Patienten erhielten randomisiert entweder individualisierte hom&#xf6;opathische Arzneimittel (individualized homeopathic medicines, IHMs; <italic>n</italic> = 25) in LM-Potenzen oder identisch aussehende Placebos (<italic>n</italic> = 26). Der Psoriasis Area and Severity Index (PASI; prim&#xe4;r), der Psoriasis Disability Index (PDI) und der Dermatological Life Quality Index (DLQI; sekund&#xe4;r) wurden bei Baseline und anschlie&#xdf;end alle zwei Monate f&#xfc;r bis zu sechs Monate gemessen. Die Analyse der Intention-to-Treat-Stichprobe erfolgte mittels zweifaktorieller Varianzanalyse mit wiederholten Messungen.<title>Ergebnisse</title>Zwar waren in beiden Gruppen die gruppeninternen Ver&#xe4;nderungen bei den Zielkriterien signifikant, doch fielen die Verbesserungen der PASI-Werte nach der sechsmonatigen Intervention in der IHM-Gruppe signifikant h&#xf6;her aus als in der Placebogruppe (<italic>F</italic>1, 49 = 10,448, <italic>p</italic> = 0,002), und die Werte der DLQI-Subskala f&#xfc;r die t&#xe4;gliche Aktivit&#xe4;t zeigten nach 6 Monaten &#xe4;hnliche signifikante Ergebnisse zugunsten der IHMs gegen&#xfc;ber Placebo (<italic>F</italic>1, 49 = 5,480, <italic>p</italic> = 0,023). Die Verbesserungen beim PDI-Gesamt-Score (<italic>F</italic>1, 49 = 0,063, <italic>p</italic> = 0,803), beim DLQI-Gesamt-Score (<italic>F</italic>1, 49 = 1,371, <italic>p</italic> = 0,247) und bei den anderen Subskalen waren nach 6 Monaten in der IHM-Gruppe h&#xf6;her als in der Placebo-Gruppe, erreichten jedoch keine statistische Signifikanz. <italic>Calcarea carbonica</italic>, <italic>Mercurius solubilis</italic>, <italic>Arsenicum album</italic> und <italic>Petroleum</italic> waren die am h&#xe4;ufigsten verordneten Arzneimittel.<title>Schlussfolgerungen</title>Die IHMs zeigten in der Behandlung der Psoriasis bessere Ergebnisse als Placebo. Weitere Untersuchungen sind erforderlich.}, }
@article {pmid37257710, year = {2023}, author = {Kim, S and Yang, M and Ku, B and Cha, E and Seo, W and Son, I and Kang, H and Kim, D and Song, B and Yang, CS and Kim, S}, title = {Efficacy of mecasin for treatment of amyotrophic lateral sclerosis: A phase IIa multicenter randomized double-blinded placebo-controlled trial.}, journal = {Journal of ethnopharmacology}, volume = {315}, number = {}, pages = {116670}, doi = {10.1016/j.jep.2023.116670}, pmid = {37257710}, issn = {1872-7573}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Vital Capacity ; Disease Progression ; Pain ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder characterized by progressive paralysis of voluntary muscles. Mecasin, the extract of modified jakyakgamchobuja-tang-a herbal preparation comprising of Radix Paeoniae Alba, Radix Glycyrrhizae, Radix Aconiti Lateralis Preparata, Radix Salviae Miltiorrhizae, Rhizoma Gastrodiae, Radix Polygalae, Curcuma Root, Fructus Chaenomelis, and Rhizoma Atractylodis Japonicae-shows neuroprotective and anti-neuroinflammatory effects and alleviates the symptoms in patients with ALS.<br><br>AIM OF THE STUDY: This trial aimed to evaluate the efficacy and safety of mecasin in these patients.<br><br>MATERIAL AND METHODS: Patients were randomized to receive mecasin 1.6&#xa0;g daily, mecasin 2.4&#xa0;g daily, or placebo for 12 weeks. The primary endpoint was the Korean version of ALS Functional Rating Scale-Revised (K-ALSFRS-R) score. The secondary endpoints were muscular atrophy measurements, pulmonary function test results, creatine kinase levels, body weight, safety, and scores of the Medical Research Council (MRC) scale for muscle strength; Visual Analog Scale for pain (VAS pain); Hamilton Rating Scale for Depression; and Fatigue Severity Scale.<br><br>RESULTS: Among the 30 patients randomized, 24 completed the follow-up. Significant between-group differences were detected in the primary endpoint using the omnibus F-test. The changes in the K-ALSFRS-R score between 12 weeks and baseline were -0&#xb7;25, -1&#xb7;32, and -2&#xb7;78 in the mecasin 1.6&#xa0;g, mecasin 2.4&#xa0;g, and placebo groups, respectively. The difference in the K-ALSFRS-R score between the mecasin 1.6&#xa0;g and placebo groups was 2&#xb7;53 points (95% confidence interval [CI]: 0&#xb7;61-4&#xb7;45), and that between the 2.4&#xa0;g and placebo groups was 1&#xb7;46 points (95% CI: 0&#xb7;48-3&#xb7;40). However, no significant differences were detected in the secondary endpoints (MRC: dyspnea, p&#xa0;=&#xa0;0&#xb7;139; VAS pain, p&#xa0;=&#xa0;0&#xb7;916; forced vital capacity, p&#xa0;=&#xa0;0&#xb7;373). The incidence of adverse events was similar and low in all groups.<br><br>CONCLUSIONS: Mecasin may retard symptomatic progression without major adverse effects. A phase IIb study to evaluate its long-term effects in ALS is ongoing.}, }
@article {pmid37257467, year = {2023}, author = {Fidelix, EC and Santana, GC and Barros, DMDS and Dourado Junior, MET}, title = {Telehealth for amyotrophic lateral sclerosis in a multidisciplinary service in a Brazilian reference center.}, journal = {Arquivos de neuro-psiquiatria}, volume = {81}, number = {5}, pages = {469-474}, pmid = {37257467}, issn = {1678-4227}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/therapy ; Brazil ; Retrospective Studies ; *COVID-19 ; *Telemedicine ; }, abstract = {BACKGROUND: Telehealth has been used in the treatment of different diseases, and it has been shown to provide benefits for patients with amyotrophic lateral sclerosis (ALS). Due to the social distancing measures put into effect during the coronavirus disease 2019 (COVID-19) pandemic, there was an urgent need for telehealth to ensure the provision of healthcare.<br><br>OBJECTIVE: To evaluate the feasibility of telehealth for the provision of multidisciplinary ALS care, and to assess its acceptability among patients and caregivers.<br><br>METHODS: We conducted a retrospective cohort study in which multidisciplinary evaluations were performed using the Teleconsulta platform. The patients included had ALS and at least one in-person clinical evaluation. The patients and the caregivers answered satisfaction questionnaires.<br><br>RESULTS: The sample was composed of 46 patients, 32 male and 14 female subjects. The average distance from their residences to the reference services was of 115&#x2009;km. Respiratory adjustment was the most addressed topic.<br><br>CONCLUSION: The strategy is viable and well accepted in terms of satisfaction. It was even more positive for patients in advanced stages of the disease or for those living far from the referral center.}, }
@article {pmid37255643, year = {2023}, author = {Saucedo, S and Katsuura, Y}, title = {Preventing Unnecessary Surgery in Patients Presenting for Orthopedic Spine Surgery: Literature Review and Case Series.}, journal = {Journal of orthopaedic case reports}, volume = {13}, number = {5}, pages = {76-81}, pmid = {37255643}, issn = {2250-0685}, abstract = {INTRODUCTION: Almost 40% of patients who have been diagnosed with amyotrophic lateral sclerosis (ALS) may have been misdiagnosed. Some of these patients may have undergone surgical procedures to address symptoms that could have actually be early indications of ALS.Up to 40% of patients diagnosed with amyotrophic lateral sclerosis (ALS) have received an incorrect diagnosis, a number undergo surgical treatment for signs and symptoms that can be attributed to early manifestations of ALS. Initial presentation of ALS is elusive and is often mistaken for other disorders originating from the cervical spine such as cervical radiculopathy or myelopathy. Such incorrect diagnoses often display symptoms that fall within the scope of an orthopedic spine surgeon, who can remedy said diagnoses. Given that a diagnosis of ALS is grave, it is crucial to establish a definitive diagnosis quickly, without unnecessary surgery. The objective of this series is to highlight patients who were referred by other physicians for spine surgery to remedy potential side effects of cervical myelopathy but were ultimately diagnosed with ALS.<br><br>CASE REPORT: Case 1: A 46-year-old Caucasian woman with carpal tunnel syndrome and cervical intervertebral disc degeneration. Case 2: A 77-year-old African American man with a history of arthritis, GERD, a herniated disc, claw hand, hypertension, prostate disease, and general weakness. Case 3: A 74-year-old Caucasian woman with a background history of hypertension, dyslipidemia, hypothyroidism, osteopenia, and foot drop.<br><br>CONCLUSION: In orthopedic spine surgery, ALS could be an easily misdiagnosed disease, which can be mistaken for cervical spondylosis, cervical radiculopathy, cervical myelopathy, lumbar radiculopathy, and lumbar myelopathy; it is of note to be aware of how ALS may initially present. It is imperative for the orthopedic spine surgeon to consider ALS with patients presenting with progressive unilateral/bilateral upper extremity weakness.}, }
@article {pmid37254449, year = {2023}, author = {Shefner, JM and Al-Chalabi, A and Andrews, JA and Chio, A and De Carvalho, M and Cockroft, BM and Corcia, P and Couratier, P and Cudkowicz, ME and Genge, A and Hardiman, O and Heiman-Patterson, T and Henderson, RD and Ingre, C and Jackson, CE and Johnston, W and Lechtzin, N and Ludolph, A and Maragakis, NJ and Miller, TM and Mora Pardina, JS and Petri, S and Simmons, Z and Van Den Berg, LH and Zinman, L and Kupfer, S and Malik, FI and Meng, L and Simkins, TJ and Wei, J and Wolff, AA and Rudnicki, SA}, title = {COURAGE-ALS: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {523-534}, doi = {10.1080/21678421.2023.2216223}, pmid = {37254449}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; *Courage ; Double-Blind Method ; Probability ; Disease Progression ; }, abstract = {Objective: To determine the target population and optimize the study design of the phase 3 clinical trial evaluating reldesemtiv in participants with amyotrophic lateral sclerosis (ALS).Methods: We evaluated the phase 2 study of reldesemtiv, FORTITUDE-ALS, to inform eligibility criteria and design features that would increase trial efficiency and reduce participant burden of the phase 3 trial.Results: In FORTITUDE-ALS, the effect of reldesemtiv was particularly evident among participants in the intermediate- and fast-progressing tertiles for pre-study disease progression. These participants most often had symptom onset ≤24 months and an ALS Functional Rating Scale-Revised (ALSFRS-R) total score ≤44 at baseline. Compared with the overall FORTITUDE-ALS population, the subgroup meeting these criteria declined by fewer ALSFRS-R points at 12 weeks (difference of least-squares mean [SE] versus placebo 1.84 [0.49] and 0.87 [0.35] for the overall population). These inclusion criteria will be used for the phase 3 clinical trial, COURAGE-ALS, in which the primary outcome is the change in ALSFRS-R total score at week 24. We also measure durable medical equipment use and evaluate strength in muscles expected to change rapidly. To reduce participant burden, study visits are often remote, and strength evaluation is simplified to reduce time and effort.Conclusions: In COURAGE-ALS, the phase 3 clinical trial to evaluate reldesemtiv, the sensitivity of detecting a potential treatment effect may be increased by defining eligibility criteria that limit the proportion of participants who have slower disease progression. Implementing remote visits and simplifying strength measurements will reduce both site and participant burden.ClinicalTrials.gov identifiers: NCT03160898 (FORTITUDE-ALS) and NCT04944784 (COURAGE-ALS).}, }
@article {pmid37253318, year = {2023}, author = {Liu, W and Ma, R and Sun, C and Xu, Y and Liu, Y and Hu, J and Ma, Y and Wang, D and Wen, D and Yu, Y}, title = {Implications from proteomic studies investigating circadian rhythm disorder-regulated neurodegenerative disease pathology.}, journal = {Sleep medicine reviews}, volume = {70}, number = {}, pages = {101789}, doi = {10.1016/j.smrv.2023.101789}, pmid = {37253318}, issn = {1532-2955}, mesh = {Humans ; *Neurodegenerative Diseases ; Proteomics ; *Parkinson Disease/metabolism ; *Alzheimer Disease ; *Chronobiology Disorders ; Circadian Rhythm/genetics ; }, abstract = {Neurodegenerative diseases (NDs) affect 15% of the world's population and are becoming an increasingly common cause of morbidity and mortality worldwide. Circadian rhythm disorders (CRDs) have been reported to be involved in the pathogenic regulation of various neurologic diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis. Proteomic technology is helpful to explore treatment targets for CRDs in patients with NDs. Here, we review the key differentially expressed (DE) proteins identified in previous proteomic studies investigating NDs, CRDs and associated models and the related pathways identified by enrichment analysis. Furthermore, we summarize the advantages and disadvantages of the above studies and propose new proteomic technologies for the precise study of circadian disorder-mediated regulation of ND pathology. This review provides a theoretical and technical reference for the precise study of circadian disorder-mediated regulation of ND pathology.}, }
@article {pmid37250330, year = {2023}, author = {Pang, W and Hu, F}, title = {C9ORF72 suppresses JAK-STAT mediated inflammation.}, journal = {iScience}, volume = {26}, number = {5}, pages = {106579}, pmid = {37250330}, issn = {2589-0042}, abstract = {Hexanucleotide repeat expansion in the gene C9ORF72 is a leading cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). C9ORF72 deficiency leads to severe inflammatory phenotypes in mice, but exactly how C9ORF72 regulates inflammation remains to be fully elucidated. Here, we report that loss of C9ORF72 leads to the hyperactivation of the JAK-STAT pathway and an increase in the protein levels of STING, a transmembrane adaptor protein involved in immune signaling in response to cytosolic DNA. Treatment with a JAK inhibitor rescues the enhanced inflammatory phenotypes caused by C9ORF72 deficiency in cell culture and mice. Furthermore, we showed that the ablation of C9ORF72 results in compromised lysosome integrity, which could contribute to the activation of the JAK/STAT-dependent inflammatory responses. In summary, our study identifies a mechanism by which C9ORF72 regulates inflammation, which might facilitate therapeutic development for ALS/FTLD with C9ORF72 mutations.}, }
@article {pmid37249795, year = {2023}, author = {Patel, RB and Bajpai, AK and Thirumurugan, K}, title = {Differential Expression of MicroRNAs and Predicted Drug Target in Amyotrophic Lateral Sclerosis.}, journal = {Journal of molecular neuroscience : MN}, volume = {73}, number = {6}, pages = {375-390}, pmid = {37249795}, issn = {1559-1166}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/diagnosis ; *Neurodegenerative Diseases ; *Curcumin ; Molecular Docking Simulation ; *MicroRNAs/genetics/metabolism ; Gene Expression Profiling ; }, abstract = {ALS (Amyotrophic Lateral Sclerosis) is a rare type of neurodegenerative disease. It shows progressive degradation of motor neurons in the brain and spinal cord. At present, there is no treatment available that can completely cure ALS. The available treatments can only increase a patient's life span by a few months. Recently, microRNAs (miRNAs), a sub-class of small non-coding RNAs have been shown to play an essential role in the diagnosis, prognosis, and therapy of ALS. Our study focuses on analyzing differential miRNA profiles and predicting drug targets in ALS using bioinformatics and computational approach. The study identifies eight highly differentially expressed miRNAs in ALS patients, four of which are novel. We identified 42 hub genes for these eight highly expressed miRNAs with Amyloid Precursor Protein (APP) as a candidate gene among them for highly expressed down-regulated miRNA, hsa-miR-455-3p using protein-protein interaction network and Cytoscape analysis. A novel association has been found between hsa-miR-455-3p/APP/serotonergic pathway using KEGG pathway analysis. Also, molecular docking studies have revealed curcumin as a potential drug target that may be used for the treatment of ALS. Thus, the present study has identified four novel miRNA biomarkers: hsa-miR-3613-5p, hsa-miR-24, hsa-miR-3064-5p, and hsa-miR-4455. There is a formation of a novel axis, hsa-miR-455-3p/APP/serotonergic pathway, and curcumin is predicted as a potential drug target for ALS.}, }
@article {pmid37249667, year = {2023}, author = {Nourelden, AZ and Kamal, I and Hagrass, AI and Tawfik, AG and Elhady, MM and Fathallah, AH and Eshag, MME and Zaazouee, MS}, title = {Safety and efficacy of edaravone in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {10}, pages = {3429-3442}, pmid = {37249667}, issn = {1590-3478}, mesh = {United States ; Humans ; Edaravone/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/chemically induced ; Prospective Studies ; Quality of Life ; Severity of Illness Index ; }, abstract = {AIM: The study aims to increase understanding of edaravone's efficacy and safety as an amyotrophic lateral sclerosis (ALS) treatment and provide significant insights regarding this field's future research.<br><br>METHODS: We conducted a comprehensive search of the Embase, PubMed, Cochrane Library, Web of Science, and Scopus databases for randomized controlled trials and observational studies up until September 2022. We evaluated the studies' quality using the Cochrane risk of bias tool and the National Institutes of Health tool.<br><br>RESULTS: We included 11 studies with 2845 ALS patients. We found that edaravone improved the survival rate at 18, 24, and 30&#xa0;months (risk ratio (RR)&#x2009;=&#x2009;1.03, 95% confidence interval (CI) [1.02 to 1.24], P&#x2009;=&#x2009;0.02), (RR&#x2009;=&#x2009;1.22, 95% CI [1.06 to 1.41], P&#x2009;=&#x2009;0.007), and (RR&#x2009;=&#x2009;1.17, 95% CI [1.01 to 1.34], P&#x2009;=&#x2009;0.03), respectively. However, the administration of edaravone did not result in any significant difference in adverse effects or efficacy outcomes between the two groups, as indicated by a P value greater than 0.05.<br><br>CONCLUSION: Edaravone improves survival rates of ALS patients at 18, 24, and 30&#xa0;months with no adverse effects. However, edaravone does not affect functional outcomes. In order to ensure the validity of our findings and assess the results in accordance with the disease stage, it is essential to carry out additional prospective, rigorous, and high-quality clinical trials. The current study offers preliminary indications regarding the effectiveness and safety of edaravone. However, further comprehensive research is required to establish the generalizability and sustainability of the findings.}, }
@article {pmid37247505, year = {2023}, author = {Moreno, R and Recio, J and Barber, S and Gil, C and Martinez, A}, title = {The emerging role of mixed lineage kinase 3 (MLK3) and its potential as a target for neurodegenerative diseases therapies.}, journal = {European journal of medicinal chemistry}, volume = {257}, number = {}, pages = {115511}, doi = {10.1016/j.ejmech.2023.115511}, pmid = {37247505}, issn = {1768-3254}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Parkinson Disease/drug therapy ; MAP Kinase Kinase Kinases ; Cell Death ; Mitogen-Activated Protein Kinase Kinase Kinase 11 ; }, abstract = {Selective and brain-permeable protein kinase inhibitors are in preclinical development for treating neurodegenerative diseases. Among them, MLK3 inhibitors, with a potent neuroprotective biological action have emerged as valuable agents for the treatment of pathologies such as Alzheimer's, Parkinson's disease and amyotrophic lateral sclerosis. In fact, one MLK3 inhibitor, CEP-1347, reached clinical trials for Parkinson's disease. Additionally, another compound called prostetin/12k, a potent and rather selective MLK3 inhibitor has started clinical development for ALS based on its motor neuron protection in both in vitro and in vivo models. In this review, we will focus on the role of MLK3 in neuron-related cell death processes, neurodegenerative diseases, and the potential advantages of targeting this kinase through pharmacological modulation for neuroprotective treatment.}, }
@article {pmid37245191, year = {2023}, author = {Louapre, C and Rosenzwajg, M and Golse, M and Roux, A and Pitoiset, F and Adda, L and Tchitchek, N and Papeix, C and Maillart, E and Ungureanu, A and Charbonnier-Beaupel, F and Galanaud, D and Corvol, JC and Vicaut, E and Lubetzki, C and Klatzmann, D}, title = {A randomized double-blind placebo-controlled trial of low-dose interleukin-2 in relapsing-remitting multiple sclerosis.}, journal = {Journal of neurology}, volume = {270}, number = {9}, pages = {4403-4414}, pmid = {37245191}, issn = {1432-1459}, support = {ANR-16-RHUS-0001//ANR/ ; }, mesh = {Female ; Humans ; Double-Blind Method ; Interleukin-2/therapeutic use ; *Multiple Sclerosis ; *Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging/drug therapy ; Treatment Outcome ; Male ; Adult ; }, abstract = {BACKGROUND: Multiple sclerosis (MS) is associated with regulatory T cells (Tregs) insufficiency while low-dose interleukin-2 (IL2LD) activates Tregs and reduces disease activity in autoimmune diseases.<br><br>METHODS: We aimed at addressing whether IL2LD improved Tregs from MS patients. MS-IL2 was a single-center double-blind phase-2 study. Thirty patients (mean [SD] age 36.8&#xa0;years [8.3], 16 female) with relapsing-remitting MS with new MRI lesions within 6&#xa0;months before inclusion were randomly assigned in a 1:1 ratio to placebo or IL-2 at 1 million IU, daily for 5&#xa0;days and then fortnightly for 6&#xa0;months. The primary endpoint was change in Tregs at day-5.<br><br>RESULTS: Unlike previous trials of IL2LD in more than 20 different autoimmune diseases, Tregs were not expanded at day-5 in IL2LD group, but only at day-15 (median [IQR] fold change from baseline: 1.26 [1.21-1.33] in IL2LD group; 1.01 [0.95-1.05] in placebo group, p&#x2009;<&#x2009;0.001). At day-5, however, Tregs had acquired an activated phenotype (fold change of CD25 expression in Tregs: 2.17 [1.70-3.55] in IL2LD versus 0.97 [0.86-1.28] in placebo group, p&#x2009;<&#x2009;0.0001). Regulator/effector T cells ratio remained elevated throughout treatment period in the IL2LD group (p&#x2009;<&#x2009;0.001). Number of new active brain lesions and of relapses tended to be reduced in IL2LD treated patients, but the difference did not reach significance in this trial not powered to detect clinical efficacy.<br><br>CONCLUSION: The effect of IL2LD on Tregs in MS patients was modest and delayed, compared to other auto-immune diseases. This, together with findings that Tregs improve remyelination in MS models and recent reports of IL2LD efficacy in amyotrophic lateral sclerosis, warrants larger studies of IL2LD in MS, notably with increased dosages and/or modified modalities of administration.<br><br>ClinicalTrials.gov: NCT02424396; EU Clinical trials Register: 2014-000088-42.}, }
@article {pmid37245090, year = {2023}, author = {Quintana, M and Saville, BR and Vestrucci, M and Detry, MA and Chibnik, L and Shefner, J and Berry, JD and Chase, M and Andrews, J and Sherman, AV and Yu, H and Drake, K and Cudkowicz, M and Paganoni, S and Macklin, EA and , }, title = {Design and Statistical Innovations in a Platform Trial for Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {94}, number = {3}, pages = {547-560}, doi = {10.1002/ana.26714}, pmid = {37245090}, issn = {1531-8249}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Bayes Theorem ; Disease Progression ; Time Factors ; Clinical Trials as Topic ; Adaptive Clinical Trials as Topic ; }, abstract = {Platform trials allow efficient evaluation of multiple interventions for a specific disease. The HEALEY ALS Platform Trial is testing multiple investigational products in parallel and sequentially in persons with amyotrophic lateral sclerosis (ALS) with the goal of rapidly identifying novel treatments to slow disease progression. Platform trials have considerable operational and statistical efficiencies compared with typical randomized controlled trials due to their use of shared infrastructure and shared control data. We describe the statistical approaches required to achieve the objectives of a platform trial in the context of ALS. This includes following regulatory guidance for the disease area of interest and accounting for potential differences in outcomes of participants within the shared control (potentially due to differences in time of randomization, mode of administration, and eligibility criteria). Within the HEALEY ALS Platform Trial, the complex statistical objectives are met using a Bayesian shared parameter analysis of function and survival. This analysis serves to provide a common integrated estimate of treatment benefit, overall slowing in disease progression, as measured by function and survival while accounting for potential differences in the shared control group using Bayesian hierarchical modeling. Clinical trial simulation is used to provide a better understanding of this novel analysis method and complex design. ANN NEUROL 2023;94:547-560.}, }
@article {pmid37243319, year = {2023}, author = {Elmansy, MF and Reidl, CT and Rahaman, M and Özdinler, PH and Silverman, RB}, title = {Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis.}, journal = {Medicinal research reviews}, volume = {43}, number = {6}, pages = {2260-2302}, pmid = {37243319}, issn = {1098-1128}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Neurodegenerative Diseases/metabolism ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease in which the motor neuron circuitry displays progressive degeneration, affecting mostly the motor neurons in the brain and in the spinal cord. There are no effective cures, albeit three drugs, riluzole, edaravone, and AMX0035 (a combination of sodium phenylbutyrate and taurursodiol), have been approved by the Food and Drug Administration, with limited improvement in patients. There is an urgent need to build better and more effective treatment strategies for ALS. Since the disease is very heterogenous, numerous approaches have been explored, such as targeting genetic mutations, decreasing oxidative stress and excitotoxicity, enhancing mitochondrial function and protein degradation mechanisms, and inhibiting neuroinflammation. In addition, various chemical libraries or previously identified drugs have been screened for potential repurposing in the treatment of ALS. Here, we review previous drug discovery efforts targeting a variety of cellular pathologies that occur from genetic mutations that cause ALS, such as mutations in SOD1, C9orf72, FUS, and TARDP-43 genes. These mutations result in protein aggregation, which causes neuronal degeneration. Compounds used to target cellular pathologies that stem from these mutations are discussed and comparisons among different preclinical models are presented. Because the drug discovery landscape for ALS and other motor neuron diseases is changing rapidly, we also offer recommendations for a novel, more effective, direction in ALS drug discovery that could accelerate translation of effective compounds from animals to patients.}, }
@article {pmid37240459, year = {2023}, author = {Carlucci, A and Fusar Poli, B}, title = {Getting It Right in Restrictive Lung Disease.}, journal = {Journal of clinical medicine}, volume = {12}, number = {10}, pages = {}, pmid = {37240459}, issn = {2077-0383}, abstract = {Restrictive lung disease (predominantly in patients with neuromuscular disease (NMD) and ribcage deformity) may induce chronic hypercapnic respiratory failure, which represents an absolute indication to start home NIV (HNIV). However, in the early phases of NMD, patients may present only diurnal symptoms or orthopnoea and sleep disturbances with normal diurnal gas exchange. The evaluation of respiratory function decline may predict the presence of sleep disturbances (SD) and nocturnal hypoventilation that can be respectively diagnosed with polygraphy and PCO2 transcutaneous monitoring. If nocturnal hypoventilation and/or apnoea/hypopnea syndrome are detected, HNIV should be introduced. Once HNIV has been started, adequate follow-up is mandatory. The ventilator's built-in software provides important information about patient adherence and eventual leaks to correct. Detailed data about pressure and flow curves may suggest the presence of upper airway obstruction (UAO) during NIV that may occur with or without decrease in respiratory drive. Etiology and treatment of these two different forms of UAO are different. For this reason, in some circumstances, it might be useful to perform a polygraph. PtCO2 monitoring, together with pulse-oximetry, seem to be very important tools to optimize HNIV. The role of HNIV in neuromuscular disease is to correct diurnal and nocturnal hypoventilation with the consequence of improving quality of life, symptoms, and survival.}, }
@article {pmid37239468, year = {2023}, author = {Hedges, EC and Cocks, G and Shaw, CE and Nishimura, AL}, title = {Generation of an Open-Access Patient-Derived iPSC Biobank for Amyotrophic Lateral Sclerosis Disease Modelling.}, journal = {Genes}, volume = {14}, number = {5}, pages = {}, pmid = {37239468}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Neurodegenerative Diseases/metabolism ; Biological Specimen Banks ; Motor Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting the upper and lower motor neurons, causing patients to lose control over voluntary movement, and leading to gradual paralysis and death. There is no cure for ALS, and the development of viable therapeutics has proved challenging, demonstrated by a lack of positive results from clinical trials. One strategy to address this is to improve the tool kit available for pre-clinical research. Here, we describe the creation of an open-access ALS iPSC biobank generated from patients carrying mutations in the TARDBP, FUS, ANXA11, ARPP21, and C9ORF72 genes, alongside healthy controls. To demonstrate the utilisation of these lines for ALS disease modelling, a subset of FUS-ALS iPSCs were differentiated into functionally active motor neurons. Further characterisation revealed an increase in cytoplasmic FUS protein and reduced neurite outgrowth in FUS-ALS motor neurons compared to the control. This proof-of-principle study demonstrates that these novel patient-derived iPSC lines can recapitulate specific and early disease-related ALS phenotypes. This biobank provides a disease-relevant platform for discovery of ALS-associated cellular phenotypes to aid the development of novel treatment strategies.}, }
@article {pmid37238732, year = {2023}, author = {Maksimovic, K and Youssef, M and You, J and Sung, HK and Park, J}, title = {Evidence of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis (ALS) Patients and Animal Models.}, journal = {Biomolecules}, volume = {13}, number = {5}, pages = {}, pmid = {37238732}, issn = {2218-273X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Models, Animal ; Glucose/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventual death. Research from the past few decades has appreciated that ALS is not only a disease of the motor neurons but also a disease that involves systemic metabolic dysfunction. This review will examine the foundational research of understanding metabolic dysfunction in ALS and provide an overview of past and current studies in ALS patients and animal models, spanning from full systems to various metabolic organs. While ALS-affected muscle tissue exhibits elevated energy demand and a fuel preference switch from glycolysis to fatty acid oxidation, adipose tissue in ALS undergoes increased lipolysis. Dysfunctions in the liver and pancreas contribute to impaired glucose homeostasis and insulin secretion. The central nervous system (CNS) displays abnormal glucose regulation, mitochondrial dysfunction, and increased oxidative stress. Importantly, the hypothalamus, a brain region that controls whole-body metabolism, undergoes atrophy associated with pathological aggregates of TDP-43. This review will also cover past and present treatment options that target metabolic dysfunction in ALS and provide insights into the future of metabolism research in ALS.}, }
@article {pmid37219985, year = {2023}, author = {Lavender, V and Duarte, J and Lusted, C}, title = {Comprehensive evaluation of a cutaneous T-cell lymphoma education webinar.}, journal = {British journal of nursing (Mark Allen Publishing)}, volume = {32}, number = {10}, pages = {S10-S16}, doi = {10.12968/bjon.2023.32.10.S10}, pmid = {37219985}, issn = {2052-2819}, mesh = {Humans ; Learning ; Knowledge ; *Lymphoma, T-Cell, Cutaneous ; Referral and Consultation ; *Skin Neoplasms ; }, abstract = {BACKGROUND: Effective and timely referral, treatment and care of people with cutaneous T-cell lymphoma (CTCL) depend on clinical staff possessing highly specialised knowledge and skills. Because of the fragmented nature of the CTCL workforce, specialist education was delivered via a webinar.<br><br>AIM: The study aimed to comprehensively evaluate the webinar and test the validity of using an evaluation model for a one-off education event.<br><br>METHODS: The webinar was evaluated using Moore et al's conceptual model for evaluation of education. Data were collected using polling questions and post-webinar questionnaires and analysed using descriptive summaries and content analysis.<br><br>FINDINGS: Respondents agreed or strongly agreed that the webinar was an effective way to learn, enjoyable, relevant to their role and interesting. Learners also reported improvements in awareness, knowledge and understanding of CTCL, its referral and treatment.<br><br>CONCLUSION: Evaluating one-off education events using a conceptual model of evaluation for continuous medical education is recommended, with some adaptations to overcome limitations.}, }
@article {pmid37219865, year = {2023}, author = {Li, X and Koeberl, DD and Lutz, MW and Bedlack, R}, title = {Clenbuterol Treatment Is Safe and Associated With Slowed Disease Progression in a Small Open-Label Trial in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Journal of clinical neuromuscular disease}, volume = {24}, number = {4}, pages = {214-221}, doi = {10.1097/CND.0000000000000438}, pmid = {37219865}, issn = {1537-1611}, mesh = {Humans ; Female ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis ; *Clenbuterol ; Hand Strength ; Riluzole ; Disease Progression ; }, abstract = {OBJECTIVE: Clenbuterol, a beta-agonist, has plausible mechanisms for treating amyotrophic lateral sclerosis (ALS). In this highly inclusive open-label trial (NCT04245709), we aimed to study the safety and efficacy of clenbuterol in patients with ALS.<br><br>METHODS: All participants received clenbuterol starting at 40 &#x3bc;g daily and increased to 80 &#x3bc;g twice daily. Outcomes included safety, tolerability, ALS Functional Rating Score (ALSFRS-R) progression, forced vital capacity (FVC) progression, and myometry. ALSFRS-R and FVC slopes measured during treatment were compared with slopes before treatment (calculated by assuming ALSFRS-R was 48 and FVC was 100% at ALS onset).<br><br>RESULTS: The 25 participants had a mean age of 59, mean disease duration of 43 months, ALSFRS-R score at enrollment 34, and FVC at enrollment 77%. Forty-eight percent were female, 68% were taking riluzole, and none were taking edaravone. Two participants experienced severe adverse events, neither related to the study. Twenty-four participants experienced adverse events, most commonly tremors/jitters, cramps/spasms, insomnia, and stiffness/spasticity. Fourteen participants withdrew early from the trial, 13 due to adverse events. Patients who withdrew early were significantly older and more likely to be male. Per-protocol and intention-to-treat analyses showed meaningfully slower ALSFRS-R and FVC progression during treatment. Hand grip dynamometry and myometry changes were highly variable between participants; most declined slowly, but some showed improvements.<br><br>CONCLUSIONS: Clenbuterol was safe but less tolerable at the doses we selected compared with an earlier Italian case series. Consistent with that series, our study suggested benefits on ALS progression. However, the latter result should be interpreted with caution as our study is limited by small sample size, large drop out, lack of randomization, and blinding and placebo controls. A larger, more traditional trial now seems warranted.}, }
@article {pmid37217723, year = {2023}, author = {Nguyen, TT and Nguyen-Thi, PT and Nguyen, THA and Ho, TT and Tran, NM and Van Vo, T and Van Vo, G}, title = {Recent Advancements in Nanomaterials: A Promising Way to Manage Neurodegenerative Disorders.}, journal = {Molecular diagnosis &amp; therapy}, volume = {27}, number = {4}, pages = {457-473}, pmid = {37217723}, issn = {1179-2000}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/drug therapy ; *Alzheimer Disease/diagnosis/drug therapy ; Brain/metabolism ; Blood-Brain Barrier/metabolism ; *Nanoparticles/therapeutic use/chemistry ; }, abstract = {Neurodegenerative diseases (NDs) such as dementia, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis are some of the most prevalent disorders currently afflicting healthcare systems. Many of these diseases share similar pathological hallmarks, including elevated oxidative stress, mitochondrial dysfunction, protein misfolding, excitotoxicity, and neuroinflammation, all of which contribute to the deterioration of the nervous system's structure and function. The development of diagnostic and therapeutic materials in the monitoring and treatment of these diseases remains challenging. One of the biggest challenges facing therapeutic and diagnostic materials is the blood-brain barrier (BBB). The BBB is a multifunctional membrane possessing a plethora of biochemical, cellular, and immunological features that ensure brain homeostasis by preventing the entry and accumulation of unwanted compounds. With regards to neurodegenerative diseases, the recent application of tailored nanomaterials (nanocarriers and nanoparticles) has led to advances in diagnostics and therapeutics. In this review, we provide an overview of commonly used nanoparticles and their applications in NDs, which may offer new therapeutic strategies for the prevention and treatment of neurodegenerative diseases.}, }
@article {pmid37210918, year = {2023}, author = {Perumal, AB and Nambiar, RB and Luo, X and Su, Z and Li, X and He, Y}, title = {Exploring dynamic changes of fungal cellular components during nanoemulsion treatment by multivariate microRaman imaging.}, journal = {Talanta}, volume = {261}, number = {}, pages = {124666}, doi = {10.1016/j.talanta.2023.124666}, pmid = {37210918}, issn = {1873-3573}, mesh = {*Antifungal Agents/pharmacology/chemistry ; *Oils, Volatile/chemistry ; Diagnostic Imaging ; Tea ; Least-Squares Analysis ; }, abstract = {Recently, essential oils (EO) have gained a lot of interest for use as antifungal agent in food and agricultural industry and extensive research is ongoing to understand their mode of action. However, the exact mechanism is not yet elucidated. Here, we integrated spectral unmixing and Raman microspectroscopy imaging to unveil the antifungal mechanism of green tea EO based nanoemulsion (NE) against Magnaporthe oryzae. The dramatic change in protein, lipid, adenine, and guanine bands indicate that NE has a significant impact on the protein, lipid and metabolic processes of purine. The results also demonstrated that the NE treatment caused damage to fungal hyphae by inducing a physical injury leading to cell wall damage and loss of integrity. Our study shows that MCR-ALS (Multivariate Curve Resolution-Alternating Least Squares) and N-FINDR (N-finder algorithm) Raman imaging could serve as a suitable complementary package to the traditional methods, for revealing the antifungal mechanism of action of EO/NE.}, }
@article {pmid37210484, year = {2023}, author = {Jandhyala, R}, title = {Neutral theory: applicability and neutrality of clinical study endpoints where a disease-specific instrument is available.}, journal = {BMC medical research methodology}, volume = {23}, number = {1}, pages = {121}, pmid = {37210484}, issn = {1471-2288}, mesh = {Humans ; *Rare Diseases/diagnosis/epidemiology ; *Endpoint Determination ; Clinical Studies as Topic ; }, abstract = {BACKGROUND: There is a pressing need to improve the accuracy of rare disease clinical study endpoints. Neutral theory, first described here, can be used to assess the accuracy of endpoints and improve their selection in rare disease clinical studies, reducing the risk of patient misclassification.<br><br>METHODS: Neutral theory was used to assess the accuracy of rare disease clinical study endpoints and the resulting probability of false positive and false negative classifications at different disease prevalence rates. Search strings were extracted from the Orphanet Register of Rare Diseases using a proprietary algorithm to conduct a systematic review of studies published until January 2021. Overall, 11 rare diseases with one disease-specific disease severity scale (133 studies) and 12 rare diseases with more than one disease-specific disease severity scale (483 studies) were included. All indicators from clinical studies were extracted, and Neutral theory was used to calculate their match to disease-specific disease severity scales, which were used as surrogates for the disease phenotype. For those with more than one disease-severity scale, endpoints were compared with the first disease-specific disease severity scale and a composite of all later scales. A Neutrality score of&#x2009;>&#x2009;1.50 was considered acceptable.<br><br>RESULTS: Around half the clinical studies for half the rare diseases with one disease-specific disease severity score (palmoplantar psoriasis, achalasia, systemic lupus erythematosus, systemic sclerosis and Fournier's gangrene) met the threshold for an acceptable match to the disease phenotype, one rare disease (Guillain-Barr&#xe9; syndrome) had one study with an acceptable match, and four diseases (Behcet's syndrome, Creutzfeldt-Jakob disease, atypical hemolytic uremic syndrome and Prader-Willi syndrome) had no studies. Clinical study endpoints in almost half the rare diseases with more than one disease-specific DSS (acromegaly, amyotrophic lateral sclerosis, cystic fibrosis, Fabry disease and juvenile rheumatoid arthritis) were a better match to the composite, while endpoints in the remaining rare diseases (Charcot Marie Tooth disease, Gaucher disease Type I, Huntington's disease, Sjogren's syndrome and Tourette syndrome) were a worse match. Misclassifications varied with increasing disease prevalence.<br><br>CONCLUSIONS: Neutral theory confirmed that disease-severity measurement needs improvement in rare disease clinical studies, especially for some diseases, and suggested that the potential for accuracy increases as the body of knowledge on a disease increases. Using Neutral theory to benchmark disease-severity measurement in rare disease clinical studies may reduce the risk of misclassification, ensuring that recruitment and treatment effect assessment optimise medicine adoption and benefit patients.}, }
@article {pmid37207075, year = {2023}, author = {Sato, K and Takayama, KI and Inoue, S}, title = {Role of piRNA biogenesis and its neuronal function in the development of neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1157818}, pmid = {37207075}, issn = {1663-4365}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are caused by neuronal loss and dysfunction. Despite remarkable improvements in our understanding of these pathogeneses, serious worldwide problems with significant public health burdens are remained. Therefore, new efficient diagnostic and therapeutic strategies are urgently required. PIWI-interacting RNAs (piRNAs) are a major class of small non-coding RNAs that silence gene expression through transcriptional and post-transcriptional processes. Recent studies have demonstrated that piRNAs, originally found in the germ line, are also produced in non-gonadal somatic cells, including neurons, and further revealed the emerging roles of piRNAs, including their roles in neurodevelopment, aging, and neurodegenerative diseases. In this review, we aimed to summarize the current knowledge regarding the piRNA roles in the pathophysiology of neurodegenerative diseases. In this context, we first reviewed on recent updates on neuronal piRNA functions, including biogenesis, axon regeneration, behavior, and memory formation, in humans and mice. We also discuss the aberrant expression and dysregulation of neuronal piRNAs in neurodegenerative diseases, such as AD, PD, and ALS. Moreover, we review pioneering preclinical studies on piRNAs as biomarkers and therapeutic targets. Elucidation of the mechanisms underlying piRNA biogenesis and their functions in the brain would provide new perspectives for the clinical diagnosis and treatment of AD and various neurodegenerative diseases.}, }
@article {pmid37204819, year = {2023}, author = {Aouti, S and Padavattan, S and Padmanabhan, B}, title = {Structure-based discovery of an antipsychotic drug, paliperidone, as a modulator of human superoxide dismutase 1: a potential therapeutic target in amyotrophic lateral sclerosis.}, journal = {Acta crystallographica. Section D, Structural biology}, volume = {79}, number = {Pt 6}, pages = {531-544}, doi = {10.1107/S2059798323003649}, pmid = {37204819}, issn = {2059-7983}, support = {ICMR/001/101/2015/00787//Indian Council of Medical Research/ ; SR/FST/LS-I/2017(C)//Department of Science and Technology, Ministry of Science and Technology, India/ ; }, mesh = {Humans ; Superoxide Dismutase-1/chemistry/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Paliperidone Palmitate/therapeutic use ; *Antipsychotic Agents/therapeutic use ; Ligands ; Mutation ; }, abstract = {Aggregates of the antioxidant superoxide dismutase 1 (SOD1) are one of the major contributors to the pathogenesis of amyotrophic lateral sclerosis (ALS). Mutations in SOD1 lead to an unstable structure and aggregation that perturbs the balance of reactive oxygen species in cells. Oxidation damage to the solvent-exposed Trp32 also causes aggregation of SOD1. Here, the FDA-approved antipsychotic drug paliperidone is identified to interact with Trp32 of SOD1 by structure-based pharmacophore mapping and crystallographic studies. Paliperidone is used for the treatment of schizophrenia. The crystal structure of the complex with SOD1, refined to 2.1 Å resolution, revealed that the ligand binds to the SOD1 β-barrel in the β-strand 2 and 3 regions, which are known to scaffold SOD1 fibrillation. The drug also makes substantial π-π interaction with Trp32. Microscale thermophoresis studies confirm significant binding affinity of the compound, suggesting that the ligand can inhibit or prevent tryptophan oxidation. Thus, the antipsychotic drug paliperidone or a derivative may avert SOD1 aggregation and can be used as a lead for ALS drug development.}, }
@article {pmid37203321, year = {2023}, author = {Martin, M and Wongwattanakul, M and Khemtonglang, N and Kiatchoosakun, P and Heraud, P and Jearanaikoon, P and Wood, BR}, title = {Identification of Glucose-6 Phosphate Dehydrogenase Deficient Patients Using Attenuated Total Reflection Fourier Transform Infrared Spectroscopy Using Partial Least Squares Discriminant Analysis in Aqueous Blood Samples.}, journal = {Applied spectroscopy}, volume = {77}, number = {5}, pages = {513-520}, doi = {10.1177/00037028231170851}, pmid = {37203321}, issn = {1943-3530}, mesh = {Humans ; Discriminant Analysis ; *Glucosephosphate Dehydrogenase Deficiency/diagnosis ; Least-Squares Analysis ; *Malaria/diagnosis ; Phosphates ; Spectroscopy, Fourier Transform Infrared/methods ; Thailand ; }, abstract = {Glucose-6 phosphate dehydrogenase (G6PD) deficiency is an X-linked blood disease that affects 400 million people globally and is especially prevalent in malaria-endemic regions. A significant portion of carriers are asymptomatic and undiagnosed posing complications in the eradication of malaria as it restricts the types of drugs used for malaria treatment. A simple and accurate diagnosis of the deficiency is vital in the eradication of malaria. In this study, we investigate the potential of attenuated total reflection Fourier transform infrared spectroscopy (ATR FT-IR) as a diagnostic technique for G6PD deficiency. Venous blood samples were collected in lithium heparin anticoagulant tubes from G6PD partial and fully deficient volunteers, n = 17, and normal volunteers, n = 59, in Khon Kaen, Thailand. Spectra of aqueous and dry samples were acquired of whole blood, plasma, and red blood cells, and modeled using partial least squares discriminant analysis (PLS-DA). PLS-DA modeling resulted in a sensitivity of 0.800 and specificity of 0.800 correctly classifying fully deficient participants as well as a majority of partially deficient females who are often misdiagnosed as normal by current screening methods. The viability of utilizing aqueous samples has always been hindered by the variability of hydration in the sample, but by employing multicurve curve resolution-alternating least squares to subtract water from each sample we are able to produce high-quality spectra with minimized water contributions. The approach shows proof of principle that ATR FT-IR combined with multivariate data analysis could become a frontline screening tool for G6PD deficiency by improving tailored drug treatments and ultimately saving lives.}, }
@article {pmid37196683, year = {2023}, author = {Prasad Panda, S and Kesharwani, A and Prasanna Mallick, S and Prasanth, D and Kumar Pasala, P and Bharadwaj Tatipamula, V}, title = {Viral-induced neuronal necroptosis: Detrimental to brain function and regulation by necroptosis inhibitors.}, journal = {Biochemical pharmacology}, volume = {213}, number = {}, pages = {115591}, doi = {10.1016/j.bcp.2023.115591}, pmid = {37196683}, issn = {1873-2968}, mesh = {Humans ; *Protein Kinases/metabolism ; Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Necroptosis ; Neuroinflammatory Diseases ; Apoptosis ; Necrosis ; Caspase 1/metabolism ; Receptors, Death Domain/metabolism ; Interleukin-1/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics/metabolism ; *MicroRNAs ; }, abstract = {Neuronal necroptosis (programmed necrosis) in the CNS naturally occurs through a caspase-independent way and, especially in neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parknson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and viral infections. Understanding necroptosis pathways (death receptor-dependent and independent), and its connections with other cell death pathways could lead to new insights into treatment. Receptor-interacting protein kinase (RIPK) mediates necroptosis via mixed-lineage kinase-like (MLKL) proteins. RIPK/MLKL necrosome contains FADD, procaspase-8-cellular FLICE-inhibitory proteins (cFLIPs), RIPK1/RIPK3, and MLKL. The necrotic stimuli cause phosphorylation of MLKL and translocate to the plasma membrane, causing an influx of Ca[2+] and Na[+] ions and, the immediate opening of mitochondrial permeability transition pore (mPTP) with the release of inflammatory cell damage-associated molecular patterns (DAMPs) like mitochondrial DNA (mtDNA), high-mobility group box1 (HMGB1), and interleukin1 (IL-1). The MLKL translocates to the nucleus to induce transcription of the NLRP3 inflammasome complex elements. MLKL-induced NLRP3 activity causes caspase-1 cleavage and, IL-1 activation which promotes neuroinflammation. RIPK1-dependent transcription increases illness-associated microglial and lysosomal abnormalities to facilitate amyloid plaque (Aβ) aggregation in AD. Recent research has linked neuroinflammation and mitochondrial fission with necroptosis. MicroRNAs (miRs) such as miR512-3p, miR874, miR499, miR155, and miR128a regulate neuronal necroptosis by targeting key components of necroptotic pathways. Necroptosis inhibitors act by inhibiting the membrane translocation of MLKL and RIPK1 activity. This review insights into the RIPK/MLKL necrosome-NLRP3 inflammasome interactions during death receptor-dependent and independent neuronal necroptosis, and clinical intervention by miRs to protect the brain from NDDs.}, }
@article {pmid37194520, year = {2023}, author = {Ogino, M}, title = {[Drugs for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {75}, number = {5}, pages = {503-506}, doi = {10.11477/mf.1416202367}, pmid = {37194520}, issn = {1881-6096}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/therapeutic use ; *Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Japan ; }, abstract = {Riluzole and edaravone for the treatment of amyotrophic lateral sclerosis (ALS) are currently covered by insurance in Japan. Both have been shown to prolong survival and/or inhibit progression, but neither is a cure-all treatment, and the effects are difficult to realize. The data presented in clinical trials are not applicable to all patients with ALS; the risks and benefits should be explained carefully before use. So far, edaravone has been administered intravenously, but an oral form became available in Japan on April 17, 2023. For symptomatic treatment, morphine hydrochloride and morphine sulfate are insurance-covered alternatives.}, }
@article {pmid37191604, year = {2023}, author = {Thomson, CG and Hutchinson, PR and Stern, PJ}, title = {Misdiagnosis in Amyotrophic Lateral Sclerosis.}, journal = {The Journal of hand surgery}, volume = {48}, number = {8}, pages = {822-826}, doi = {10.1016/j.jhsa.2023.03.023}, pmid = {37191604}, issn = {1531-6564}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/surgery ; Referral and Consultation ; *Cubital Tunnel Syndrome ; Diagnostic Errors ; Neurosurgical Procedures ; }, abstract = {The symptoms of amyotrophic lateral sclerosis (ALS) can mimic those of compressive neuropathies, such as carpal and cubital tunnel syndromes, especially early in a patient's clinical course. We surveyed members of the American Society for Surgery of the Hand and found that 11% of active and retired members have performed nerve decompression surgeries on patients later diagnosed with ALS. Hand surgeons are commonly the first providers to evaluate patients with undiagnosed ALS. As such, it is important to be aware of the history, signs, and symptoms of ALS to provide an accurate diagnosis and prevent unnecessary morbidities, such as nerve decompression surgery, which invariably results in poor outcomes. The major "red flag" symptoms warranting further work-up include weakness without sensory symptoms, profound weakness and atrophy in multiple nerve distributions, progressively bilateral and global symptoms, presence of bulbar symptoms (such as tongue fasciculations and speech/swallowing difficulties), and, if surgery is performed, failure to improve. If any of these red flags are present, we recommend neurodiagnostic testing and prompt referral to a neurologist for further work-up and treatment.}, }
@article {pmid37190795, year = {2023}, author = {Varma, A and Weinstein, J and Seabury, J and Rosero, S and Zizzi, C and Alexandrou, D and Wagner, E and Dilek, N and Heatwole, J and Wuu, J and Caress, J and Bedlack, R and Granit, V and Statland, J and Mehta, P and Benatar, M and Kaat, A and Heatwole, C}, title = {The amyotrophic lateral sclerosis-health index (ALS-HI): development and evaluation of a novel outcome measure.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {514-522}, doi = {10.1080/21678421.2023.2204871}, pmid = {37190795}, issn = {2167-9223}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/therapy ; Reproducibility of Results ; Cross-Sectional Studies ; Disease Progression ; Outcome Assessment, Health Care ; }, abstract = {Objective: The identification of effective therapeutics for ALS necessitates valid and responsive outcome measures to track disease progression and therapeutic gain in clinical trial settings. The Amyotrophic Lateral Sclerosis-Health Index (ALS-HI) is a multifaceted, disease-specific patient-reported outcome measure (PRO) designed to measure ALS symptomatic disease burden in adults with ALS. Methods: Through a national cross-sectional study of individuals with ALS, we identified the most important symptoms in ALS. These symptoms were incorporated into the ALS-HI, a measure that quantifies the multifaceted disease burden in ALS. We performed factor analysis, qualitative patient interviews, test-retest reliability assessment, and known groups analysis to evaluate and validate the ALS-HI. Results: The cross-sectional study included 497 participants with ALS who identified the most important symptoms to include in the ALS-HI. Fifteen participants beta tested the ALS-HI and found it to be clear, easy to use, and relevant. Twenty-one participants engaged in a test-retest reliability study, which indicated the reliability of the instrument (intraclass correlation coefficient = 0.952 for full instrument). The final ALS-HI and its subscales demonstrated a high internal consistency (Cronbach's α = 0.981 for full instrument) and an ability to differentiate between groups with dissimilar disease severity. Conclusions: This research supports use of the ALS-HI as a valid, sensitive, reliable, and relevant PRO to assess the multifactorial disease burden faced by adults with ALS. The ALS-HI has potential as a mechanism to track disease progression and treatment efficacy during therapeutic trials.}, }
@article {pmid37190538, year = {2023}, author = {Liu, P and Xue, X and Zhang, C and Zhou, H and Ding, Z and Wang, L and Jiang, Y and Shen, W and Yang, S and Wang, F}, title = {Transcriptional Profile Changes after Noise-Induced Tinnitus in Rats.}, journal = {Brain sciences}, volume = {13}, number = {4}, pages = {}, pmid = {37190538}, issn = {2076-3425}, abstract = {Tinnitus is an unpleasant symptom characterized by detective hearing without the actual sound input. Despite numerous studies elucidating a variety of pathomechanisms inducing tinnitus, the pathophysiology of tinnitus is not fully understood. The genes that are closely associated with this subtype of the auditory hallucination that could be utilized as potential treatment targets are still unknown. In this study, we explored the transcriptional profile changes of the auditory cortex after noise-induced tinnitus in rats using high throughput sequencing and verification of the detected genes using quantitative PCR (qPCR). Tinnitus models were established by analyzing startle behaviors through gap pre-pulse inhibition (PPI) of the acoustic startle. Two hundred and fifty-nine differential genes were identified, of which 162 genes were up-regulated and 97 genes were down-regulated. Analysis of the pathway enrichment indicated that the tinnitus group exhibited increased gene expression related to neurodegenerative disorders such as Huntington's disease and Amyotrophic lateral sclerosis. Based on the identified genes, networks of protein-protein interaction were established and five hub genes were identified through degree rank, including Fos, Nr4a1, Nr4a3, Egr2, and Egr3. Therein, the Fos gene ranked first with the highest degree after noise exposure, and may be a potential target for the modulation of noise-induced tinnitus.}, }
@article {pmid37189613, year = {2023}, author = {Wintz, K and Post, J and Langen, KJ and Willbold, D and Willuweit, A and Kutzsche, J}, title = {Oral Treatment with d-RD2RD2 Impedes Early Disease Mechanisms in SOD1*G93A Transgenic Mice but Does Not Prolong Survival.}, journal = {Biomedicines}, volume = {11}, number = {4}, pages = {}, pmid = {37189613}, issn = {2227-9059}, support = {HVF0079//Helmholtz Association/ ; INST 208 /616-1 FUGG, INST 208/794-1 FUGG//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, thus, progressing to complete muscle loss until the patient dies from respiratory arrest. The disease is not curable, and patients die approximately 2-5 years after diagnosis. Studying the underlying disease mechanisms to get access to new treatment options is, therefore, essential for patients' benefit. However, so far, only three drugs that alleviate the symptoms have been approved by the U.S. Food and Drug Administration (FDA). A new drug candidate for the treatment of ALS is the all-d-enantiomeric peptide RD2RD2. In this study, we investigated the therapeutic effect of RD2RD2 in two setups. First, we analyzed disease progression and survival in 7 week-old B6.Cg-Tg(SOD1*G93A)1Gur/J mice. Second, we confirmed the result of the survival analysis in the B6SJL-Tg(SOD1*G93A)1Gur/J mouse line. Shortly before disease onset, the mice were treated daily with an oral dose of 50 mg/kg body weight. Treatment with RD2RD2 led to a delayed disease onset and reduced motor phenotype as shown using the SHIRPA test, the splay reflex test, and the pole test, but did not affect survival. In conclusion, RD2RD2 has the ability to delay the onset of symptoms.}, }
@article {pmid37184603, year = {2023}, author = {Lefebvre-Omar, C and Liu, E and Dalle, C and d'Incamps, BL and Bigou, S and Daube, C and Karpf, L and Davenne, M and Robil, N and Jost Mousseau, C and Blanchard, S and Tournaire, G and Nicaise, C and Salachas, F and Lacomblez, L and Seilhean, D and Lobsiger, CS and Millecamps, S and Boillée, S and Bohl, D}, title = {Neurofilament accumulations in amyotrophic lateral sclerosis patients' motor neurons impair axonal initial segment integrity.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {80}, number = {6}, pages = {150}, pmid = {37184603}, issn = {1420-9071}, support = {16465//AFM-T&#xe9;l&#xe9;thon/ ; EQU202103012581//FRM/ ; ANR-10-LABX-73//Labex Revive/ ; ALS-iPSC/AAP10//Fondation Thierry Latran/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Intermediate Filaments ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; Motor Neurons/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease in adults with no curative treatment. Neurofilament (NF) level in patient' fluids have recently emerged as the prime biomarker of ALS disease progression, while NF accumulation in MNs of patients is the oldest and one of the best pathological hallmarks. However, the way NF accumulations could lead to MN degeneration remains unknown. To assess NF accumulations and study the impact on MNs, we compared MNs derived from induced pluripotent stem cells (iPSC) of patients carrying mutations in C9orf72, SOD1 and TARDBP genes, the three main ALS genetic causes. We show that in all mutant MNs, light NF (NF-L) chains rapidly accumulate in MN soma, while the phosphorylated heavy/medium NF (pNF-M/H) chains pile up in axonal proximal regions of only C9orf72 and SOD1 MNs. Excitability abnormalities were also only observed in these latter MNs. We demonstrate that the integrity of the MN axonal initial segment (AIS), the region of action potential initiation and responsible for maintaining axonal integrity, is impaired in the presence of pNF-M/H accumulations in C9orf72 and SOD1 MNs. We establish a strong correlation between these pNF-M/H accumulations, an AIS distal shift, increased axonal calibers and modified repartition of sodium channels. The results expand our understanding of how NF accumulation could dysregulate components of the axonal cytoskeleton and disrupt MN homeostasis. With recent cumulative evidence that AIS alterations are implicated in different brain diseases, preserving AIS integrity could have important therapeutic implications for ALS.}, }
@article {pmid37175765, year = {2023}, author = {Llorente, X and Esteruelas, G and Bonilla, L and Agudelo, MG and Filgaira, I and Lopez-Ramajo, D and Gong, RC and Soler, C and Espina, M and García, ML and Manils, J and Pujol, M and Sánchez-López, E}, title = {Riluzole-Loaded Nanostructured Lipid Carriers for Hyperproliferative Skin Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {9}, pages = {}, pmid = {37175765}, issn = {1422-0067}, support = {PID2021-122187NB-C32//Spanish Ministry of Science and Innovation/ ; PID2020-114477RB-I00//Spanish Ministry of Science and Innovation/ ; PID2021-126249OA-I00//Spanish Ministry of Science and Innovation/ ; }, mesh = {Humans ; Riluzole/pharmacology ; Drug Carriers ; *Nanostructures ; *Skin Diseases/metabolism ; Drug Liberation ; Lipids/pharmacology ; Particle Size ; *Nanoparticles ; Skin/metabolism ; }, abstract = {Nanocarriers, and especially nanostructured lipid carriers (NLC), represent one of the most effective systems for topical drug administration. NLCs are biodegradable, biocompatible and provide a prolonged drug release. The glutamate release inhibitor Riluzole (RLZ) is a drug currently used for amyotrophic lateral sclerosis (ALS), with anti-proliferative effects potentially beneficial for diseases with excessive cell turnover. However, RLZ possesses low water solubility and high light-sensibility. We present here optimized NLCs loaded with RLZ (RLZ-NLCs) as a potential topical treatment. RLZ-NLCs were prepared by the hot-pressure homogenization method using active essential oils as liquid lipids, and optimized using the design of experiments approach. RLZ-NLCs were developed obtaining optimal properties for dermal application (mean size below 200 nm, negative surface charge and high RLZ entrapment efficacy). In vitro release study demonstrates that RLZ-NLCs allow the successful delivery of RLZ in a sustained manner. Moreover, RLZ-NLCs are not angiogenic and are able to inhibit keratinocyte cell proliferation. Hence, a NLCs delivery system loading RLZ in combination with natural essential oils constitutes a promising strategy against keratinocyte hyperproliferative conditions.}, }
@article {pmid37174703, year = {2023}, author = {Kinger, S and Dubey, AR and Kumar, P and Jagtap, YA and Choudhary, A and Kumar, A and Prajapati, VK and Dhiman, R and Mishra, A}, title = {Molecular Chaperones' Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {9}, pages = {}, pmid = {37174703}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Proteostasis ; Molecular Chaperones/metabolism ; HSP40 Heat-Shock Proteins ; Mutant Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuronal degenerative condition identified via a build-up of mutant aberrantly folded proteins. The native folding of polypeptides is mediated by molecular chaperones, preventing their pathogenic aggregation. The mutant protein expression in ALS is linked with the entrapment and depletion of chaperone capacity. The lack of a thorough understanding of chaperones' involvement in ALS pathogenesis presents a significant challenge in its treatment. Here, we review how the accumulation of the ALS-linked mutant FUS, TDP-43, SOD1, and C9orf72 proteins damage cellular homeostasis mechanisms leading to neuronal loss. Further, we discuss how the HSP70 and DNAJ family co-chaperones can act as potential targets for reducing misfolded protein accumulation in ALS. Moreover, small HSPB1 and HSPB8 chaperones can facilitate neuroprotection and prevent stress-associated misfolded protein apoptosis. Designing therapeutic strategies by pharmacologically enhancing cellular chaperone capacity to reduce mutant protein proteotoxic effects on ALS pathomechanisms can be a considerable advancement. Chaperones, apart from directly interacting with misfolded proteins for protein quality control, can also filter their toxicity by initiating strong stress-response pathways, modulating transcriptional expression profiles, and promoting anti-apoptotic functions. Overall, these properties of chaperones make them an attractive target for gaining fundamental insights into misfolded protein disorders and designing more effective therapies against ALS.}, }
@article {pmid37170865, year = {2023}, author = {Baugh, SD and Morrice, JR and Reitz, AB and Shaw, CA and Gregory-Evans, CY}, title = {Levamisole derivatives as immune modulators for the treatment of amyotrophic lateral sclerosis (ALS).}, journal = {Future medicinal chemistry}, volume = {15}, number = {8}, pages = {651-659}, doi = {10.4155/fmc-2023-0028}, pmid = {37170865}, issn = {1756-8927}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Levamisole/pharmacology/therapeutic use ; Cytokines/metabolism ; Tetramisole/therapeutic use ; }, abstract = {Aim: To discover derivatives of the anthelmintic drug levamisole, which has been reported to possess immune-modulatory properties, as treatments for amyotrophic lateral sclerosis (ALS), which has been suggested to be in part an autoimmune disease. Results: We have synthesized ten analogs of the racemic version of levamisole, tetramisole, as well as eleven analogs on a related system. All of the analogs have been tested for their ability to affect the response of five ALS-relevant cytokines. Conclusion: We have discovered a number of interesting derivatives that have encouraging cytokine response data and good metabolic stability, with the potential to have a positive impact on ALS either as single agents, or in combination.}, }
@article {pmid37167080, year = {2023}, author = {Gold, ND and Mallard, AJ and Hermann, JC and Zeifman, RJ and Pagni, BA and Bogenschutz, MP and Ross, S}, title = {Exploring the Potential Utility of Psychedelic Therapy for Patients With Amyotrophic Lateral Sclerosis.}, journal = {Journal of palliative medicine}, volume = {26}, number = {10}, pages = {1408-1418}, doi = {10.1089/jpm.2022.0604}, pmid = {37167080}, issn = {1557-7740}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Hallucinogens/therapeutic use ; *Neurodegenerative Diseases ; *Motor Neuron Disease ; *Ketamine ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is an aggressive, terminal neurodegenerative disease that causes death of motor neurons and has an average survival time of 3-4 years. ALS is the most common motor neuron degenerative disease and is increasing in prevalence. There is a pressing need for more effective ALS treatments as available pharmacotherapies do not reverse disease progression or provide substantial clinical benefit. Furthermore, despite psychological distress being highly prevalent in ALS patients, psychological treatments remain understudied. Psychedelics (i.e., serotonergic psychedelics and related compounds like ketamine) have seen a resurgence of research into therapeutic applications for treating a multitude of neuropsychiatric conditions, including psychiatric and existential distress in life-threatening illnesses. Methods: We conducted a narrative review to examine the potential of psychedelic assisted-psychotherapy (PAP) to alleviate psychiatric and psychospiritual distress in ALS. We also discussed the safety of using psychedelics in this population and proposed putative neurobiological mechanisms that may therapeutically intervene on ALS neuropathology. Results: PAP has the potential to treat psychological dimensions and may also intervene on neuropathological dimensions of ALS. Robust improvements in psychiatric and psychospiritual distress from PAP in other populations provide a strong rationale for utilizing this therapy to treat ALS-related psychiatric and existential distress. Furthermore, relevant neuroprotective properties of psychedelics warrant future preclinical trials to investigate this area in ALS models. Conclusion: PAP has the potential to serve as an effective treatment in ALS. Given the lack of effective treatment options, researchers should rigorously explore this therapy for ALS in future trials.}, }
@article {pmid37166702, year = {2023}, author = {Malar, DS and Thitilertdecha, P and Ruckvongacheep, KS and Brimson, S and Tencomnao, T and Brimson, JM}, title = {Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders.}, journal = {CNS drugs}, volume = {37}, number = {5}, pages = {399-440}, pmid = {37166702}, issn = {1179-1934}, mesh = {Humans ; *Receptors, sigma/metabolism/therapeutic use ; *Amyotrophic Lateral Sclerosis ; Neurons/metabolism ; *Huntington Disease ; *Neurodevelopmental Disorders/drug therapy/metabolism ; }, abstract = {The sigma-1 receptor is a 223 amino acid-long protein with a recently identified structure. The sigma-2 receptor is a genetically unrelated protein with a similarly shaped binding pocket and acts to influence cellular activities similar to the sigma-1 receptor. Both proteins are highly expressed in neuronal tissues. As such, they have become targets for treating neurological diseases, including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), multiple sclerosis (MS), Rett syndrome (RS), developmental and epileptic encephalopathies (DEE), and motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). In recent years, there have been many pre-clinical and clinical studies of sigma receptor (1 and 2) ligands for treating neurological disease. Drugs such as blarcamesine, dextromethorphan and pridopidine, which have sigma-1 receptor activity as part of their pharmacological profile, are effective in treating multiple aspects of several neurological diseases. Furthermore, several sigma-2 receptor ligands are under investigation, including CT1812, rivastigmine and SAS0132. This review aims to provide a current and up-to-date analysis of the current clinical and pre-clinical data of drugs with sigma receptor activities for treating neurological disease.}, }
@article {pmid37162686, year = {2023}, author = {Mangrulkar, SV and Wankhede, NL and Kale, MB and Upaganlawar, AB and Taksande, BG and Umekar, MJ and Anwer, MK and Dailah, HG and Mohan, S and Behl, T}, title = {Mitochondrial Dysfunction as a Signaling Target for Therapeutic Intervention in Major Neurodegenerative Disease.}, journal = {Neurotoxicity research}, volume = {41}, number = {6}, pages = {708-729}, pmid = {37162686}, issn = {1476-3524}, mesh = {Humans ; Aged ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; DNA, Mitochondrial/genetics/metabolism/therapeutic use ; Oxidative Stress ; Aging ; }, abstract = {Neurodegenerative diseases (NDD) are incurable and the most prevalent cognitive and motor disorders of elderly. Mitochondria are essential for a wide range of cellular processes playing a pivotal role in a number of cellular functions like metabolism, intracellular signaling, apoptosis, and immunity. A plethora of evidence indicates the central role of mitochondrial functions in pathogenesis of many aging related NDD. Considering how mitochondria function in neurodegenerative diseases, oxidative stress, and mutations in mtDNA both contribute to aging. Many substantial reports suggested the involvement of numerous contributing factors including, mitochondrial dysfunction, oxidative stress, mitophagy, accumulation of somatic mtDNA mutations, compromised mitochondrial dynamics, and transport within axons in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. Therapies therefore target fundamental mitochondrial processes such as energy metabolism, free-radical generation, mitochondrial biogenesis, mitochondrial redox state, mitochondrial dynamics, mitochondrial protein synthesis, mitochondrial quality control, and metabolism hold great promise to develop pharmacological based therapies in NDD. By emphasizing the most efficient pharmacological strategies to target dysfunction of mitochondria in the treatment of neurodegenerative diseases, this review serves the scientific community engaged in translational medical science by focusing on the establishment of novel, mitochondria-targeted treatment strategies.}, }
@article {pmid37155370, year = {2023}, author = {Fukuta, T and Ikeda-Imafuku, M and Iwao, Y}, title = {Development of Edaravone Ionic Liquids and Their Application for the Treatment of Cerebral Ischemia/Reperfusion Injury.}, journal = {Molecular pharmaceutics}, volume = {20}, number = {6}, pages = {3115-3126}, pmid = {37155370}, issn = {1543-8392}, mesh = {Rats ; Animals ; Edaravone ; *Ionic Liquids ; Antipyrine/pharmacology/therapeutic use ; Free Radical Scavengers/therapeutic use ; Tissue Distribution ; *Reperfusion Injury/drug therapy ; *Brain Ischemia/drug therapy ; *Ischemic Stroke/complications/drug therapy ; }, abstract = {Preparation of the ionic liquid (IL) form of active pharmaceutical ingredients (APIs), termed API-IL, has attracted attention because it can improve upon certain disadvantages of APIs, such as poor water solubility and low stability. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a clinically approved cerebroprotective agent against ischemic stroke and amyotrophic lateral sclerosis, while new formulations that enable improvement of its physicochemical properties and biodistribution are desired. Herein, we report a newly developed API-IL of edaravone (edaravone-IL), in which edaravone is used as an anionic molecule. We investigated the physicochemical properties of edaravone-IL and its therapeutic effect against cerebral ischemia/reperfusion (I/R) injury, a secondary injury after an ischemic stroke. Among the cationic molecules used for edaravone-IL preparation, the IL prepared with tetrabutylphosphonium cation existed as a liquid at room temperature, and significantly increased the water solubility of edaravone without decreasing its antioxidative activity. Importantly, edaravone-IL formed negatively charged nanoparticles upon suspension in water. Intravenous administration of edaravone-IL showed significantly higher blood circulation time and lower distribution in the kidney compared with edaravone solution. Moreover, edaravone-IL significantly suppressed brain cell damage and motor functional deficits in model rats of cerebral I/R injury and showed comparable cerebroprotective effect to edaravone. Taken together, these results suggest that edaravone-IL could be a new form of edaravone with superior physicochemical properties and could be useful for the treatment of cerebral I/R injury.}, }
@article {pmid37153900, year = {2023}, author = {Ren, B and Geng, Y and Chen, S and Gao, Z and Zheng, K and Yang, Y and Luo, Q and Feng, J and Luo, Z and Ju, Y and Huang, Z}, title = {Alisertib exerts KRAS allele‑specific anticancer effects on colorectal cancer cell lines.}, journal = {Experimental and therapeutic medicine}, volume = {25}, number = {6}, pages = {243}, pmid = {37153900}, issn = {1792-1015}, abstract = {The aim of the present study was to examine the effects of alisertib (ALS) on RAS signaling pathways against a panel of colorectal cancer (CRC) cell lines and engineered Flp-In stable cell lines expressing different Kirsten rat sarcoma virus (KRAS) mutants. The viability of Caco-2KRAS wild-type, Colo-678KRAS G12D, SK-CO-1KRAS G12V, HCT116KRAS G13D, CCCL-18KRAS A146T and HT29BRAF V600E cells was examined by Cell Titer-Glo assay, and that of stable cell lines was monitored by IncuCyte. The expression levels of phosphorylated (p-)Akt and p-Erk as RAS signal outputs were measured by western blotting. The results suggested that ALS exhibited different inhibitory effects on cell viability and different regulatory effects on guanosine triphosphate (GTP)-bound RAS in CRC cell lines. ALS also exhibited various regulatory effects on the PI3K/Akt and mitogen-activated protein kinase (MAPK) pathways, the two dominant RAS signaling pathways, and induced apoptosis and autophagy in a RAS allele-specific manner. Combined treatment with ALS and selumetinib enhanced the regulatory effects of ALS on apoptosis and autophagy in CRC cell lines in a RAS allele-specific manner. Notably, combined treatment exhibited a synergistic inhibitory effect on cell proliferation in Flp-In stable cell lines. The results of the present study suggested that ALS differentially regulates RAS signaling pathways. The combined approach of ALS and a MEK inhibitor may represent a new therapeutic strategy for precision therapy for CRC in a KRAS allele-specific manner; however, this effect requires further study in vivo.}, }
@article {pmid37153676, year = {2023}, author = {Reggiardo, G and Lo Giudice, M and Lalli, S and Rinaldi, G and Albanese, A}, title = {Cox regression and survival analysis from the tauro-urso-deoxycholic trial in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1163855}, pmid = {37153676}, issn = {1664-2295}, abstract = {Recent phase II pilot clinical trials suggested that tauro-urso-deoxycholic acid (TUDCA) might slow functional decline and increase survival in patients with amyotrophic lateral sclerosis (ALS). We performed a multivariate analysis of the original TUDCA cohort to better define the treatment effect and allow comparability with other trials. Linear regression slope analysis showed statistical differences in the decline rate, favoring the active treatment arm (p-value < 0.01; -0.262 for the TUDCA group and -0.388 for the placebo group). Mean survival time, estimated by the Kaplan-Meier analysis, showed a 1-month difference, favoring active treatment (log-rank test p-value = 0.092). Cox regression analysis demonstrated that placebo treatment was associated with a higher risk of death (p-value = 0.055). These data further support the disease-modifying effect of TUDCA monotherapy and raise the question of what could be the additional effect of combining TUDCA with sodium phenylbutyrate.}, }
@article {pmid37153665, year = {2023}, author = {Hong, D and Zhang, C and Wu, W and Lu, X and Zhang, L}, title = {Modulation of the gut-brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1133546}, pmid = {37153665}, issn = {1664-2295}, abstract = {There are trillions of different microorganisms in the human digestive system. These gut microbes are involved in the digestion of food and its conversion into the nutrients required by the body. In addition, the gut microbiota communicates with other parts of the body to maintain overall health. The connection between the gut microbiota and the brain is known as the gut-brain axis (GBA), and involves connections via the central nervous system (CNS), the enteric nervous system (ENS), and endocrine and immune pathways. The gut microbiota regulates the central nervous system bottom-up through the GBA, which has prompted researchers to pay considerable attention to the potential pathways by which the gut microbiota might play a role in the prevention and treatment of amyotrophic lateral sclerosis (ALS). Studies with animal models of ALS have shown that dysregulation of the gut ecology leads to dysregulation of brain-gut signaling. This, in turn, induces changes in the intestinal barrier, endotoxemia, and systemic inflammation, which contribute to the development of ALS. Through the use of antibiotics, probiotic supplementation, phage therapy, and other methods of inducing changes in the intestinal microbiota that can inhibit inflammation and delay neuronal degeneration, the clinical symptoms of ALS can be alleviated, and the progression of the disease can be delayed. Therefore, the gut microbiota may be a key target for effective management and treatment of ALS.}, }
@article {pmid37137507, year = {2023}, author = {D'Cruz, RF and Kaltsakas, G and Suh, ES and Hart, N}, title = {Quality of life in patients with chronic respiratory failure on home mechanical ventilation.}, journal = {European respiratory review : an official journal of the European Respiratory Society}, volume = {32}, number = {168}, pages = {}, pmid = {37137507}, issn = {1600-0617}, mesh = {Humans ; Respiration, Artificial/adverse effects ; Quality of Life ; *Respiratory Insufficiency/diagnosis/etiology/therapy ; *Neuromuscular Diseases/complications/diagnosis/therapy ; *Pulmonary Disease, Chronic Obstructive/diagnosis/therapy ; *Home Care Services ; }, abstract = {Home mechanical ventilation (HMV) is a treatment for chronic respiratory failure that has shown clinical and cost effectiveness in patients with underlying COPD, obesity-related respiratory failure and neuromuscular disease (NMD). By treating chronic respiratory failure with adequate adherence to HMV, improvement in patient-reported outcomes including health-related quality of life (HRQoL) have been evaluated using general and disease-specific quantitative, semi-qualitative and qualitative methods. However, the treatment response in terms of trajectory of change in HRQoL is not uniform across the restrictive and obstructive disease groups. In this review, the effect of HMV on HRQoL across the domains of symptom perception, physical wellbeing, mental wellbeing, anxiety, depression, self-efficacy and sleep quality in stable and post-acute COPD, rapidly progressive NMD (such as amyotrophic lateral sclerosis), inherited NMD (including Duchenne muscular dystrophy) and obesity-related respiratory failure will be discussed.}, }
@article {pmid37130044, year = {2023}, author = {Chow, DS and Nguyen, A and Park, J and Wu, L and Toups, EG and Harrop, JS and Guest, JD and Schmitt, KM and Aarabi, B and Fehlings, MG and Boakye, M and Grossman, RG}, title = {Riluzole in Spinal Cord Injury Study (RISCIS)-Pharmacokinetic (PK) Sub-Study: An Analysis of Pharmacokinetics, Pharmacodynamics, and Impact on Axonal Degradation of Riluzole in Patients With Traumatic Cervical Spinal Cord Injury Enrolled in the RISCIS Phase III Randomized Controlled Trial.}, journal = {Journal of neurotrauma}, volume = {40}, number = {17-18}, pages = {1889-1906}, doi = {10.1089/neu.2022.0499}, pmid = {37130044}, issn = {1557-9042}, mesh = {Male ; Middle Aged ; Humans ; Riluzole/adverse effects ; *Neuroprotective Agents/adverse effects/pharmacokinetics ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Cervical Cord ; *Spinal Cord Injuries/drug therapy ; *Neck Injuries/drug therapy ; }, abstract = {To date, no drug therapy has shown significant efficacy in improving functional outcomes in patients with acute spinal cord injury (SCI). Riluzole is an approved benzothiazole sodium channel blocker to attenuate neurodegeneration in amyotrophic lateral sclerosis (ALS) and is of interest for neuroprotection in SCI. In a Phase I clinical trial (ClinicalTrials.gov Identifier: NCT00876889), riluzole was well tolerated with a 2-week treatment at the dose level approved for ALS and exhibited potential efficacy in patients with SCI. The acute and progressive nature of traumatic SCI and the complexity of secondary injury processes alter the pharmacokinetics (PK) of therapeutics. In the PK sub-study of the multi-center, randomized, placebo-controlled, double-blinded Riluzole in Spinal Cord Injury Study (RISCIS) Phase II/III trial (ClinicalTrials.gov Identifier: NCT01597518), a total of 32 SCI patients were enrolled, and most of our patients were middle-age Caucasian males with head and neck injuries. We studied the PK and pharmacodynamics (PD) of riluzole on motor recovery, measured by International Standards for Neurological Classification of SCI (ISNCSCI) Motor Score at injury and at 3-month and 6-month follow-ups, along with levels of the axonal injury biomarker phosphorylated neurofilament heavy chain (pNF-H), during the 2-week treatment. PK modeling, PK/PD correlations were developed to identify the potential effective exposure of riluzole for intended PD outcomes. The longitudinal impacts of SCI on the PK of riluzole are characterized. A time-varying population PK model of riluzole is established, incorporating time-varying clearance and volume of distribution from combined data of Phase I and Phase II/III trials. With the developed model, a rational, optimal dosing scheme can be designed with time-dependent modification to preserve the required therapeutic exposure of riluzole. The PD of riluzole and the relationship between PK and neurological outcomes of the treatment were established. The time course of efficacy in total motor score improvement (ΔTMS) and pNF-H were monitored. A three-dimensional (3D) PK/PD correlation was established for ΔTMS at 6 months with overall riluzole exposure area under the curve for Day 0-Day14 (AUCD0-D14) and baseline TMS for individual patients. Patients with baseline TMS between 1 and 36 benefited from the optimal exposure range of 16-48 mg*h/mL. The PD models of pNF-H revealed the riluzole efficacy, as treated subjects exhibited a diminished increase in progression of pNF-H, indicative of reduced axonal breakdown. The independent parameter of area between effective curves (ABEC) between the time profiles of pNF-H in placebo and treatment groups was statistically identified as a significant predictor for the treatment effect on the biomarker. A mechanistic clinical outcomes (CO)/PD (pNF-H) model was established, and the proposed structure demonstrated the feasibility of PK/PD/CO correlation model. No appreciable hepatic toxicity was observed with the current riluzole treatment regimen. The development of effective treatment for SCI is challenging. However, the future model-informed and PK-guided drug development and regimen modification can be rationally executed with the optimal dosing regimen design based on the developed 3D PK/PD model. The PK/PD/CO model can serve as a rational guide for future drug development, PKPD model refinement, and extension to other studies in SCI settings.}, }
@article {pmid37127082, year = {2023}, author = {Nicoletti, A and Baschi, R and Cicero, CE and Iacono, S and Re, VL and Luca, A and Schirò, G and Monastero, R and , }, title = {Sex and gender differences in Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis: A narrative review.}, journal = {Mechanisms of ageing and development}, volume = {212}, number = {}, pages = {111821}, doi = {10.1016/j.mad.2023.111821}, pmid = {37127082}, issn = {1872-6216}, mesh = {Male ; Female ; Humans ; *Alzheimer Disease/diagnosis/epidemiology ; *Parkinson Disease/diagnosis/epidemiology/genetics ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; Sex Factors ; Biomarkers ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), exhibit high phenotypic variability and they are very common in the general population. These diseases are associated with poor prognosis and a significant burden on patients and their caregivers. Although increasing evidence suggests that biological sex is an important factor for the development and phenotypical expression of some NDs, the role of sex and gender in the diagnosis and prognosis of NDs has been poorly explored. Current knowledge relating to sex- and gender-related differences in the epidemiology, clinical features, biomarkers, and treatment of AD, PD, and ALS will be summarized in this narrative review. The cumulative evidence hitherto collected suggests that sex and gender are factors to be considered in explaining the heterogeneity of these NDs. Clarifying the role of sex and gender in AD, PD, and ALS is a key topic in precision medicine, which will facilitate sex-specific prevention and treatment strategies to be implemented in the near future.}, }
@article {pmid37123224, year = {2023}, author = {Djaja, NA and Chang, MT and Beinart, FR and Morris, VM and Ganser, LR and Myong, S}, title = {Nucleation and dissolution mechanism underlying amyotrophic lateral sclerosis/frontotemporal lobar dementia-linked fused in sarcoma condensates.}, journal = {iScience}, volume = {26}, number = {4}, pages = {106537}, pmid = {37123224}, issn = {2589-0042}, support = {F31 NS124267/NS/NINDS NIH HHS/United States ; RF1 NS113636/NS/NINDS NIH HHS/United States ; T32 GM007231/GM/NIGMS NIH HHS/United States ; }, abstract = {Fused in sarcoma (FUS) is a nuclear RNA-binding protein. Mutations in FUS lead to the mislocalization of FUS from the nucleus to the cytosol and formation of pathogenic aggregates in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD), yet with unknown molecular mechanisms. Using mutant and stress conditions, we visualized FUS localization and aggregate formation in cells. We used single-molecule pull-down (SiMPull) to quantify the native oligomerization states of wildtype (WT) and mutant FUS in cells. We demonstrate that the NLS mutants exhibited the highest oligomerization (>3) followed by other FUS mutants (>2) and WT FUS which is primarily monomeric. Strikingly, the mutant FUS oligomers are extremely stable and resistant to treatment by high salt, hexanediol, RNase, and Karyopherin-β2 and only soluble in GdnHCl and SDS. We propose that the increased oligomerization units of mutant FUS and their high stability may contribute to ALS/FTLD pathogenesis.}, }
@article {pmid37122380, year = {2023}, author = {Nam, JY and Chun, S and Lee, TY and Seo, Y and Kim, K and Park, J and Sung, W and Oh, KW and Lee, S and Park, JS and Oh, J and Chung, KC and An, H and Chu, HS and Son, B and Kim, SH}, title = {Long-term survival benefits of intrathecal autologous bone marrow-derived mesenchymal stem cells (Neuronata-R®: lenzumestrocel) treatment in ALS: Propensity-score-matched control, surveillance study.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1148444}, pmid = {37122380}, issn = {1663-4365}, abstract = {OBJECTIVE: Neuronata-R® (lenzumestrocel) is an autologous bone marrow-derived mesenchymal stem cell (BM-MSC) product, which was conditionally approved by the Korean Ministry of Food and Drug Safety (KMFDS, Republic of Korea) in 2013 for the treatment of amyotrophic lateral sclerosis (ALS). In the present study, we aimed to investigate the long-term survival benefits of treatment with intrathecal lenzumestrocel.<br><br>METHODS: A total of 157 participants who received lenzumestrocel and whose symptom duration was less than 2 years were included in the analysis (BM-MSC group). The survival data of placebo participants from the Pooled-Resource Open-Access ALS Clinical Trials (PROACT) database were used as the external control, and propensity score matching (PSM) was used to reduce confounding biases in baseline characteristics. Adverse events were recorded during the entire follow-up period after the first treatment.<br><br>RESULTS: Survival probability was significantly higher in the BM-MSC group compared to the external control group from the PROACT database (log-rank, p&#x2009;<&#x2009;0.001). Multivariate Cox proportional hazard analysis showed a significantly lower hazard ratio for death in the BM-MSC group and indicated that multiple injections were more effective. Additionally, there were no serious adverse drug reactions found during the safety assessment, lasting a year after the first administration.<br><br>CONCLUSION: The results of the present study showed that lenzumestrocel treatment had a long-term survival benefit in real-world ALS patients.}, }
@article {pmid37122073, year = {2024}, author = {Rowe, HP and Stipancic, KL and Campbell, TF and Yunusova, Y and Green, JR}, title = {The association between longitudinal declines in speech sound accuracy and speech intelligibility in speakers with amyotrophic lateral sclerosis.}, journal = {Clinical linguistics &amp; phonetics}, volume = {38}, number = {3}, pages = {227-248}, pmid = {37122073}, issn = {1464-5076}, support = {R01 DC013547/DC/NIDCD NIH HHS/United States ; R42 DC019877/DC/NIDCD NIH HHS/United States ; F31 DC019556/DC/NIDCD NIH HHS/United States ; K24 DC016312/DC/NIDCD NIH HHS/United States ; R01 DC017291/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; Speech Intelligibility/physiology ; Phonetics ; *Amyotrophic Lateral Sclerosis/complications ; Movement ; *Voice ; Speech Production Measurement ; }, abstract = {The purpose of this study was to examine how neurodegeneration secondary to amyotrophic lateral sclerosis (ALS) impacts speech sound accuracy over time and how speech sound accuracy, in turn, is related to speech intelligibility. Twenty-one participants with ALS read the Bamboo Passage over multiple data collection sessions across several months. Phonemic and orthographic transcriptions were completed for all speech samples. The percentage of phonemes accurately produced was calculated across each phoneme, sound class (i.e. consonants versus vowels), and distinctive feature (i.e. features involved in Manner of Articulation, Place of Articulation, Laryngeal Voicing, Tongue Height, and Tongue Advancement). Intelligibility was determined by calculating the percentage of words correctly transcribed orthographically by naive listeners. Linear mixed effects models were conducted to assess the decline of each distinctive feature over time and its impact on intelligibility. The results demonstrated that overall phonemic production accuracy had a nonlinear relationship with speech intelligibility and that a subset of features (i.e. those dependent on precise lingual and labial constriction and/or extensive lingual and labial movement) were more important for intelligibility and were more impacted over time than other features. Furthermore, findings revealed that consonants were more strongly associated with intelligibility than vowels, but consonants did not significantly differ from vowels in their decline over time. These findings have the potential to (1) strengthen mechanistic understanding of the physiological constraints imposed by neuronal degeneration on speech production and (2) inform the timing and selection of treatment and assessment targets for individuals with ALS.}, }
@article {pmid37121991, year = {2023}, author = {Gangfuß, A and Kohl, Z}, title = {[Amyotrophic lateral sclerosis-Motor neuron disease with a wide clinical and genetic spectrum].}, journal = {Der Nervenarzt}, volume = {94}, number = {6}, pages = {494-500}, pmid = {37121991}, issn = {1433-0407}, mesh = {Young Adult ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; *Motor Neuron Disease/diagnosis/genetics/therapy ; Diagnosis, Differential ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Besides a timely diagnosis, precise knowledge of the clinical manifestations and differential diagnoses is essential. While most patients develop the disease at an older age, hereditary causes play a more frequent role in the juvenile forms.<br><br>OBJECTIVE: What is the current state of ALS diagnostics, which new treatment options exist?<br><br>MATERIAL AND METHOD: Literature search using Pubmed.gov.<br><br>RESULTS: The main focus is on an individualized symptomatic treatment as no curative treatment approaches exist. However, new insights into the genetic and pathophysiological principles of the different forms of ALS open the way for future disease-modifying treatment options.<br><br>CONCLUSION: In cases of a clinical suspicion of ALS molecular genetic diagnostics should be considered, particularly in juvenile and young adult patients, to exclude differential diagnoses and to enable patients access to new treatment approaches.}, }
@article {pmid37121113, year = {2023}, author = {Peng, SJ and Feng, Y and Li, X and Wang, XX and Wang, Y and Zhou, BT and Liu, Y and Liu, T and Wu, YC}, title = {Thymopentin (TP-5) prevents lipopolysaccharide-induced neuroinflammation and dopaminergic neuron injury by inhibiting the NF-κB/NLRP3 signaling pathway.}, journal = {International immunopharmacology}, volume = {119}, number = {}, pages = {110109}, doi = {10.1016/j.intimp.2023.110109}, pmid = {37121113}, issn = {1878-1705}, mesh = {Animals ; Mice ; Cell Line ; Dopaminergic Neurons/metabolism ; Inflammation/chemically induced/drug therapy/metabolism ; Lipopolysaccharides ; Microglia ; Neuroinflammatory Diseases ; *NF-kappa B/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Signal Transduction ; *Thymopentin/therapeutic use ; }, abstract = {Neuroinflammation plays a pivotal role in neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and stroke, and is accompanied by excessive release of inflammatory cytokines and mediators by activated microglia. Microglial inflammatory response inhibition may be an effective strategy for preventing inflammatory disorders. However, the reciprocal connections between the central nervous system (CNS) and immune system have not been elucidated. Thus far, these links have been proven to mainly involve immuno- and neuropeptides. The pentapeptide thymopentin (TP-5) exerts a significant immunomodulatory effect; however, its antineuroinflammatory effects and underlying mechanism are still unclear. In this study, lipopolysaccharide (LPS) was used to establish an inflammation model, and the therapeutic effect of TP-5 was evaluated. Behavioral tests showed that TP-5 treatment could improve the performance of LPS-treated mice in the open field and pole test, but not hanging wire test. TP-5 also attenuated neuronal lesions in the brains of LPS-treated mice. TP-5 reduced cytotoxicity and morphological changes in activated microglia. Label-free quantitative analysis indicated that the expression of multiple proteins and the activation of associated signaling pathways were altered by TP-5. Moreover, TP-5 could inhibit LPS-induced neuroinflammation in the brain and BV2 microglia and the expression of major genes in the NF-κB/NLRP3 signaling pathway. Additionally, tyrosine hydroxylase (TH) expression downregulation was rescued in the LPS + TP-5 group compared with the LPS group. We conclude that TP-5 exerts neuroprotection by alleviating LPS-induced inflammatory damage and dopaminergic neurodegeneration. The protective effect of TP-5 may involve the NF-κB/NLRP3 signaling pathway.}, }
@article {pmid37111580, year = {2023}, author = {Pereira, GRC and Abrahim-Vieira, BA and de Mesquita, JF}, title = {In Silico Analyses of a Promising Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis Targeting Superoxide Dismutase I Protein.}, journal = {Pharmaceutics}, volume = {15}, number = {4}, pages = {}, pmid = {37111580}, issn = {1999-4923}, support = {NA//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; NA//Coordena&#xe7;&#xe3;o de Aperfeicoamento de Pessoal de N&#xed;vel Superior/ ; NA//National Council for Scientific and Technological Development/ ; NA//Federal University of the State of Rio de Janeiro/ ; NA//Federal University of Rio de Janeiro/ ; NA//Financiadora de Estudos e Projetos/ ; NA//Nvidia (United States)/ ; NA//Oracle (United States)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disorder in adults, which is associated with a highly disabling condition. To date, ALS remains incurable, and the only drugs approved by the FDA for its treatment confer a limited survival benefit. Recently, SOD1 binding ligand 1 (SBL-1) was shown to inhibit in vitro the oxidation of a critical residue for SOD1 aggregation, which is a central event in ALS-related neurodegeneration. In this work, we investigated the interactions between SOD1 wild-type and its most frequent variants, i.e., A4V (NP_000445.1:p.Ala5Val) and D90A (NP_000445.1:p.Asp91Val), with SBL-1 using molecular dynamics (MD) simulations. The pharmacokinetics and toxicological profile of SBL-1 were also characterized in silico. The MD results suggest that the complex SOD1-SBL-1 remains relatively stable and interacts within a close distance during the simulations. This analysis also suggests that the mechanism of action proposed by SBL-1 and its binding affinity to SOD1 may be preserved upon mutations A4V and D90A. The pharmacokinetics and toxicological assessments suggest that SBL-1 has drug-likeness characteristics with low toxicity. Our findings, therefore, suggested that SBL-1 may be a promising strategy to treat ALS based on an unprecedented mechanism, including for patients with these frequent mutations.}, }
@article {pmid37111380, year = {2023}, author = {Kim, GA and Cho, HC and Jeong, SW and Kang, BK and Kim, M and Jung, S and Hwang, J and Yoon, EL and Jun, DW}, title = {A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of ALS-L1023 in Non-Alcoholic Fatty Liver Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {16}, number = {4}, pages = {}, pmid = {37111380}, issn = {1424-8247}, support = {NA//AngioLab, Inc./ ; }, abstract = {Preclinical data have shown that the herbal extract, ALS-L1023, from Melissa officinalis reduces visceral fat and hepatic steatosis. We aimed to assess the safety and efficacy of ALS-L1023 as the treatment of non-alcoholic fatty liver disease (NAFLD). We conducted a 24-week randomized, double-blind, placebo-controlled 2a study in patients with NAFLD (MRI-proton density fat fraction [MRI-PDFF] ≥ 8% and liver fibrosis ≥ 2.5 kPa on MR elastography [MRE]) in Korea. Patients were randomly assigned to 1800 mg ALS-L1023 (n = 19), 1200 mg ALS-L1023 (n = 21), or placebo (n = 17) groups. Efficacy endpoints included changes in liver fat on MRI-PDFF, liver stiffness on MRE, and liver enzymes. For the full analysis set, a relative hepatic fat reduction from baseline was significant in the 1800 mg ALS-L1023 group (-15.0%, p = 0.03). There was a significant reduction in liver stiffness from baseline in the 1200 mg ALS-L1023 group (-10.7%, p = 0.03). Serum alanine aminotransferase decreased by -12.4% in the 1800 mg ALS-L1023 group, -29.8% in the 1200 mg ALS-L1023 group, and -4.9% in the placebo group. ALS-L1023 was well tolerated and there were no differences in the incidence of adverse events among the study groups. ALS-L1023 could reduce hepatic fat content in patients with NAFLD.}, }
@article {pmid37111040, year = {2023}, author = {Rogers, CQ and Ramirez, M and Landon, CS and DeBlasi, JM and Koutnik, AP and Ari, C and D'Agostino, DP}, title = {A Glutamate Scavenging Protocol Combined with Deanna Protocol in SOD1-G93A Mouse Model of ALS.}, journal = {Nutrients}, volume = {15}, number = {8}, pages = {}, pmid = {37111040}, issn = {2072-6643}, support = {111990//Winning the Fight Foundation/ ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/metabolism ; Glutamic Acid/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease of neuronal degeneration in the motor cortex, brainstem, and spinal cord, resulting in impaired motor function and premature demise as a result of insufficient respiratory drive. ALS is associated with dysfunctions in neurons, neuroglia, muscle cells, energy metabolism, and glutamate balance. Currently, there is not a widely accepted, effective treatment for this condition. Prior work from our lab has demonstrated the efficacy of supplemental nutrition with the Deanna Protocol (DP). In the present study, we tested the effects of three different treatments in a mouse model of ALS. These treatments were the DP alone, a glutamate scavenging protocol (GSP) alone, and a combination of the two treatments. Outcome measures included body weight, food intake, behavioral assessments, neurological score, and lifespan. Compared to the control group, DP had a significantly slower decline in neurological score, strength, endurance, and coordination, with a trend toward increased lifespan despite a greater loss of weight. GSP had a significantly slower decline in neurological score, strength, endurance, and coordination, with a trend toward increased lifespan. DP+GSP had a significantly slower decline in neurological score with a trend toward increased lifespan, despite a greater loss of weight. While each of the treatment groups fared better than the control group, the combination of the DP+GSP was not better than either of the individual treatments. We conclude that the beneficial effects of the DP and the GSP in this ALS mouse model are distinct, and appear to offer no additional benefit when combined.}, }
@article {pmid37109269, year = {2023}, author = {Al-Zamil, M and Shnayder, NA and Davydova, TK and Nasyrova, RF and Trefilova, VV and Narodova, EA and Petrova, MM and Romanova, IV and Chumakova, GA}, title = {Amyotrophic Lateral Sclerosis Mimic Syndrome in a 24-Year-Old Man with Chiari 1 Malformation and Syringomyelia: A Clinical Case.}, journal = {Journal of clinical medicine}, volume = {12}, number = {8}, pages = {}, pmid = {37109269}, issn = {2077-0383}, abstract = {Chiari 1 Malformation (CM1) is classically defined as a caudal displacement of the cerebellar tonsils through the foramen magnum into the spinal cord. Modern imaging techniques and experimental studies disclose a different etiology for the development of CM1, but the main etiology factor is a structural defect in the skull as a deformity or partial reduction, which push down the lower part of the brain and cause the cerebellum to compress into the spinal canal. CM1 is classified as a rare disease. CM1 can present with a wide variety of symptoms, also non-specific, with consequent controversies on diagnosis and surgical decision-making, particularly in asymptomatic or minimally symptomatic. Other disorders, such as syringomyelia (Syr), hydrocephalus, and craniocervical instability can be associated at the time of the diagnosis or appear secondarily. Therefore, CM1-related Syr is defined as a single or multiple fluid-filled cavities within the spinal cord and/or the bulb. A rare CM1-related disorder is syndrome of lateral amyotrophic sclerosis (ALS mimic syndrome). We present a unique clinical case of ALS mimic syndrome in a young man with CM1 and a huge singular syringomyelic cyst with a length from segment C2 to Th12. At the same time, the clinical picture showed upper hypotonic-atrophic paraparesis in the absence of motor disorders in the lower extremities. Interestingly, this patient did not have a disorder of superficial and deep types of sensitivity. This made it difficult to diagnose CM1. For a long time, the patient's symptoms were regarded as a manifestation of ALS, as an independent neurological disease, and not as a related disorder of CM1. Surgical treatment for CM1 was not effective, but it allowed to stabilize the course of CM1-related ALS mimic syndrome over the next two years.}, }
@article {pmid37109262, year = {2023}, author = {Russo, E and Montt Guevara, MM and Sacinti, KG and Misasi, G and Falcone, M and Morganti, R and Mereu, L and Dalprà, F and Tateo, S and Simoncini, T}, title = {Minimal Invasive Abdominal Sacral Colpopexy and Abdominal Lateral Suspension: A Prospective, Open-Label, Multicenter, Non-Inferiority Trial.}, journal = {Journal of clinical medicine}, volume = {12}, number = {8}, pages = {}, pmid = {37109262}, issn = {2077-0383}, abstract = {BACKGROUND: Abdominal minimally invasive surgery has become increasingly prominent for the treatment of prolapse. Abdominal sacral colpopexy (ASC) is the gold standard for the treatment of advanced apical prolapse; however, alternative surgical approaches such as the abdominal lateral suspension (ALS) have been developed to improve patient outcomes. This study aims to determine whether ALS improves outcomes compared to ASC in multicompartmental prolapse patients.<br><br>METHODS: A prospective, open-label, multicenter, non-inferiority trial was conducted in 360 patients who underwent ASC or ALS for the treatment of apical prolapse. The primary outcome was anatomical and symptomatic cure of the apical compartment at 1-year follow-up; secondary outcomes included prolapse recurrence, re-operation rate, and post-operative complications. A 300-patient cohort was subdivided into 200-patients who underwent ALS and 100-patients who underwent ASC. The confidence interval method was used to calculate the p-value of non-inferiority.<br><br>RESULTS: At the 12-months follow-up, the objective cure rate of the apical defect was 92% for ALS and 94% for ASC (recurrence rates were 8% and 6%, respectively, and the p-value for non-inferiority was <0.01). The mMesh complication rates were 1% and 2% for ALS and ASC, respectively.<br><br>CONCLUSIONS: This study demonstrated that the ALS technique is not inferior to the gold standard ASC for the surgical treatment of apical prolapse.}, }
@article {pmid37108267, year = {2023}, author = {Cao, Y and Lan, Y and Huang, H and Wei, S and Li, X and Sun, Y and Wang, R and Huang, Z}, title = {Molecular Characterization of Resistance to Nicosulfuron in Setaria viridis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {8}, pages = {}, pmid = {37108267}, issn = {1422-0067}, support = {CARS-25//Agriculture Research System of China/ ; 2019ZX08013011-001//Major Projects for Cultivation of New Varieties of National Genetically Modified Organisms/ ; }, mesh = {*Setaria Plant/genetics ; Sulfonylurea Compounds/pharmacology ; Pyridines ; Sequence Analysis, RNA ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; }, abstract = {The green foxtail, Setaria viridis (L.) P. Beauv. (Poales: Poaceae), is a troublesome and widespread grass weed in China. The acetolactate synthase (ALS)-inhibiting herbicide nicosulfuron has been intensively used to manage S. viridis, and this has substantially increased the selection pressure. Here we confirmed a 35.8-fold resistance to nicosulfuron in an S. viridis population (R376 population) from China and characterized the resistance mechanism. Molecular analyses revealed an Asp-376-Glu mutation of the ALS gene in the R376 population. The participation of metabolic resistance in the R376 population was proved by cytochrome P450 monooxygenases (P450) inhibitor pre-treatment and metabolism experiments. To further elucidate the mechanism of metabolic resistance, eighteen genes that could be related to the metabolism of nicosulfuron were obtained bythe RNA sequencing. The results of quantitative real-time PCR validation indicated that three ATP-binding cassette (ABC) transporters (ABE2, ABC15, and ABC15-2), four P450 (C76C2, CYOS, C78A5, and C81Q32), and two UDP-glucosyltransferase (UGT) (UGT13248 and UGT73C3), and one glutathione S-transferases (GST) (GST3) were the major candidates that contributed to metabolic nicosulfuron resistance in S. viridis. However, the specific role of these ten genes in metabolic resistance requires more research. Collectively, ALS gene mutations and enhanced metabolism may be responsible for the resistance of R376 to nicosulfuron.}, }
@article {pmid37108151, year = {2023}, author = {Kondo, T and Ebinuma, I and Tanaka, H and Nishikawa, Y and Komiya, T and Ishikawa, M and Okano, H}, title = {Rapid and Robust Multi-Phenotypic Assay System for ALS Using Human iPS Cells with Mutations in Causative Genes.}, journal = {International journal of molecular sciences}, volume = {24}, number = {8}, pages = {}, pmid = {37108151}, issn = {1422-0067}, support = {JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22bm0804023//Japan Agency for Medical Research and Development/ ; JP17K10083//Japan Society for the Promotion of Science/ ; JP20H03567//Japan Society for the Promotion of Science/ ; JP22K18388//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Induced Pluripotent Stem Cells ; Motor Neurons/metabolism ; Superoxide Dismutase-1/metabolism ; Mutation ; Phenotype ; Superoxide Dismutase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a major life-threatening disease caused by motor neuron degeneration. More effective treatments through drug discovery are urgently needed. Here, we established an effective high-throughput screening system using induced pluripotent stem cells (iPSCs). Using a Tet-On-dependent transcription factor expression system carried on the PiggyBac vector, motor neurons were efficiently and rapidly generated from iPSCs by a single-step induction method. Induced iPSC transcripts displayed characteristics similar to those of spinal cord neurons. iPSC-generated motor neurons carried a mutation in fused in sarcoma (FUS) and superoxide dismutase 1 (SOD1) genes and had abnormal protein accumulation corresponding to each mutation. Calcium imaging and multiple electrode array (MEA) recordings demonstrated that ALS neurons were abnormally hyperexcitable. Noticeably, protein accumulation and hyperexcitability were ameliorated by treatment with rapamycin (mTOR inhibitor) and retigabine (Kv7 channel activator), respectively. Furthermore, rapamycin suppressed ALS neuronal death and hyperexcitability, suggesting that protein aggregate clearance through the activation of autophagy effectively normalized activity and improved neuronal survival. Our culture system reproduced several ALS phenotypes, including protein accumulation, hyperexcitability, and neuronal death. This rapid and robust phenotypic screening system will likely facilitate the discovery of novel ALS therapeutics and stratified and personalized medicine for sporadic motor neuron diseases.}, }
@article {pmid37106792, year = {2023}, author = {Yang, C and Wang, H and Duan, Y and Bei, F and Jia, S and Wang, J and Wang, H and Liu, W}, title = {Enhanced Herbicide Metabolism and Target-Site Mutations Confer Multiple Resistance to Fomesafen and Nicosulfuron in Amaranthus retroflexus L.}, journal = {Biology}, volume = {12}, number = {4}, pages = {}, pmid = {37106792}, issn = {2079-7737}, support = {2021CXGC010811//Key R&amp;D Program of Shandong Province, China/ ; ZR2021MC030//Shandong Provincial Natural Science Foundation/ ; 32202353//National Natural Science Foundation of China/ ; J18KA134//Project of Shandong Province Higher Educational Science and Technology Program/ ; }, abstract = {Amaranthus retroflexus L. is a highly competitive broadleaf weed of corn-soybean rotation in northeastern China. In recent years, the herbicide(s) resistance evolution has been threatening its effective management in crop fields. One resistant A. retroflexus (HW-01) population that survived the protoporphyrinogen oxidase (PPO) inhibitor fomesafen and acetolactate synthase (ALS) inhibitor nicosulfuron applied at their field-recommended rate was collected from a soybean field in Wudalianchi City, Heilongjiang Province. This study aimed to investigate the resistance mechanisms of fomesafen and nicosulfuron and determine the resistance profile of HW-01 to other herbicides. Whole plant dose-response bioassays revealed that HW-01 had evolved resistance to fomesafen (50.7-fold) and nicosulfuron (5.2-fold). Gene sequencing showed that the HW-01 population has a mutation in PPX2 (Arg-128-Gly) and a rare mutation in ALS (Ala-205-Val, eight/twenty mutations/total plants). In vitro enzyme activity assays showed that ALS extracted from the HW-01 plants was less sensitive to nicosulfuron (3.2-fold) than ST-1 plants. Pre-treatment with the cytochrome P450 inhibitors malathion, piperonyl butoxide (PBO), 3-amino-1,2,4-triazole (amitrole), and the GSTs inhibitor 4-chloro-7-nitrobenzofurazan (NBD-Cl) significantly increased fomesafen and nicosulfuron sensitivity in the HW-01 population compared with that of the sensitive (S) population ST-1. Moreover, the rapid fomesafen and nicosulfuron metabolism in the HW-01 plants was also confirmed via HPLC-MS/MS analysis. Furthermore, the HW-01 population showed multiple resistance (MR) to PPO, ALS, and PSII inhibitors, with resistance index (RI) values ranging from 3.8 to 9.6. This study confirmed MR to PPO-, ALS-, and PSII-inhibiting herbicides in the A. retroflexus population HW-01, as well as confirming that the cytochrome P450- and GST-based herbicide metabolic along with TSR mechanisms contribute to their multiple resistance to fomesafen and nicosulfuron.}, }
@article {pmid37100932, year = {2023}, author = {Guo, C and Chen, L and Wang, Y}, title = {Substance abuse and neurodegenerative diseases: focus on ferroptosis.}, journal = {Archives of toxicology}, volume = {97}, number = {6}, pages = {1519-1528}, pmid = {37100932}, issn = {1432-0738}, support = {81973404//National Natural Science Foundation of China/ ; 2022-MS-224//Natural Science Foundation of Liaoning Province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/chemically induced ; *Ferroptosis ; Oxidative Stress/physiology ; *Parkinson Disease ; *Alzheimer Disease/drug therapy ; Lipid Peroxidation ; }, abstract = {Psychostimulants and alcohol are widely abused substances with the adverse effects on global public health. Substance abuse seriously harms people's health and causes various diseases, especially neurodegenerative diseases. Neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). The pathogenesis of neurodegenerative diseases is complex and diverse, usually involving oxidative stress, mitochondrial dysfunction, metal homeostasis disorder, and neuro-inflammation. The precise molecular mechanisms underlying neurodegeneration remain unclear, which is a major obstacle to therapeutic approaches. Therefore, it is urgent to improve the understanding of the molecular mechanisms of neurodegenerative processes and to identify the therapeutic targets for treatment and prevention. Ferroptosis is a regulatory cell necrosis caused by iron ion catalysis and lipid peroxidation induced by reactive oxygen species (ROS), which is thought to be associated with nervous system diseases, particularly neurodegenerative diseases. This review overviewed the ferroptosis process and explored the relationship of ferroptosis with substance abuse and neurodegenerative diseases, which provides a new way to study the molecular mechanisms of neurodegenerative diseases induced by alcohol, cocaine, and methamphetamine (MA), and also provides the potential therapeutic targets for substance abuse-induced neurodegenerative diseases.}, }
@article {pmid37096898, year = {2023}, author = {Verbić, T&#x17d; and Tam, KY and Veljković, D&#x17d; and Serajuddin, ATM and Avdeef, A}, title = {Clofazimine pKa Determination by Potentiometry and Spectrophotometry: Reverse Cosolvent Dependence as an Indicator of the Presence of Dimers in Aqueous Solutions.}, journal = {Molecular pharmaceutics}, volume = {20}, number = {6}, pages = {3160-3169}, doi = {10.1021/acs.molpharmaceut.3c00172}, pmid = {37096898}, issn = {1543-8392}, mesh = {*Methanol ; *Clofazimine ; Potentiometry/methods ; Hydrogen-Ion Concentration ; Water/chemistry ; Spectrophotometry/methods ; }, abstract = {The weakly basic antibiotic and anti-inflammatory drug, clofazimine (CFZ), was first described in 1957. It has been used therapeutically, most notably in the treatment of leprosy. However, the compound is extremely insoluble in aqueous media, and, indeed, there is poor consensus about what its intrinsic solubility is since the reported values range from 0.04 to 11 ng/mL. To understand the speciation and solubilization of CFZ as a function of pH, it is of paramount importance to know the true aqueous pKa. However, there is also poor consensus about the value of the pKa (reported measured values range from 6.08 to 9.11). In the present study, we report the determination of the CFZ ionization constant using two independent techniques. A state-of-the-art potentiometric analysis was performed, drawing on titration data in methanol-water solutions (46-75 wt % MeOH) of CFZ, using the bias-reducing consensus of two different procedures of extrapolating the apparent psKa values to zero cosolvent to approximate the true aqueous pKa as 9.43 ± 0.12 (25 °C, I = 0.15 M reference ionic strength). In parallel, spectrophotometric UV/vis titration data were acquired (250-600 nm at different pH) in 10 mM HEPES buffer solutions containing up to 54 wt % MeOH. The alternating least squares (ALS) method was used in the analysis of the absorbance-pH spectra. Uncharacteristically, the cosolvent UV/vis data in our study showed reverse cosolvent dependence (apparent pKa values increased with increasing cosolvent) which could be explained by a dimerization of the free base. The analysis of UV/vis data obtained from 54 wt % MeOH-water solution containing 20 μM CFZ yielded the apparent pKa 9.51 ± 0.17 (I ≈ 0.005 M). To assess whether self-assembly of CFZ was energetically feasible, density functional theory (DFT) calculations were used to study the putative CFZ dimers in aqueous and methanol media. The DFT-optimized geometries and infrared spectra of CFZ dimers using water and methanol as solvents were calculated and analyzed. Based on the lack of negative frequencies in calculated infrared spectra, it was confirmed that optimized geometries correspond to the true energetic minima. Visual analysis of optimized structures indicates the presence of stacking interactions between two CFZ molecules. The protonation site (the imine nitrogen atom) was determined by [1]H NMR spectroscopy.}, }
@article {pmid37095852, year = {2023}, author = {Schlotterose, L and Beldjilali-Labro, M and Schneider, G and Vardi, O and Hattermann, K and Even, U and Shohami, E and Haustein, HD and Leichtmann-Bardoogo, Y and Maoz, BM}, title = {Traumatic Brain Injury in a Well: A Modular Three-Dimensional Printed Tool for Inducing Traumatic Brain Injury In vitro.}, journal = {Neurotrauma reports}, volume = {4}, number = {1}, pages = {255-266}, pmid = {37095852}, issn = {2689-288X}, abstract = {Traumatic brain injury (TBI) is a major health problem that affects millions of persons worldwide every year among all age groups, mainly young children, and elderly persons. It is the leading cause of death for children under the age of 16 and is highly correlated with a variety of neuronal disorders, such as epilepsy, and neurodegenerative disease, such as Alzheimer's disease or amyotrophic lateral sclerosis. Over the past few decades, our comprehension of the molecular pathway of TBI has improved, yet despite being a major public health issue, there is currently no U.S. Food and Drug Administration-approved treatment for TBI, and a gap remains between these advances and their application to the clinical treatment of TBI. One of the major hurdles for pushing TBI research forward is the accessibility of TBI models and tools. Most of the TBI models require costume-made, complex, and expensive equipment, which often requires special knowledge to operate. In this study, we present a modular, three-dimensional printed TBI induction device, which induces, by the pulse of a pressure shock, a TBI-like injury on any standard cell-culture tool. Moreover, we demonstrate that our device can be used on multiple systems and cell types and can induce repetitive TBIs, which is very common in clinical TBI. Further, we demonstrate that our platform can recapitulate the hallmarks of TBI, which include cell death, decrease in neuronal functionality, axonal swelling (for neurons), and increase permeability (for endothelium). In addition, in view of the continued discussion on the need, benefits, and ethics of the use of animals in scientific research, this in vitro, high-throughput platform will make TBI research more accessible to other labs that prefer to avoid the use of animals yet are interested in this field. We believe that this will enable us to push the field forward and facilitate/accelerate the availability of novel treatments.}, }
@article {pmid37090492, year = {2023}, author = {Pingle, SC and Lin, F and Anekoji, MS and Patro, CPK and Datta, S and Jones, LD and Kesari, S and Ashili, S}, title = {Exploring the role of cerebrospinal fluid as analyte in neurologic disorders.}, journal = {Future science OA}, volume = {9}, number = {4}, pages = {FSO851}, pmid = {37090492}, issn = {2056-5623}, abstract = {The cerebrospinal fluid (CSF) is a clear ultrafiltrate of blood that envelopes and protects the central nervous system while regulating neuronal function through the maintenance of interstitial fluid homeostasis in the brain. Due to its anatomic location and physiological functions, the CSF can provide a reliable source of biomarkers for the diagnosis and treatment monitoring of different neurological diseases, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and primary and secondary brain malignancies. The incorporation of CSF biomarkers into the drug discovery and development can improve the efficiency of drug development and increase the chances of success. This review aims to consolidate the current use of CSF biomarkers in clinical practice and explore future perspectives for the field.}, }
@article {pmid37089709, year = {2023}, author = {Wijeweera, G and Wijekoon, N and Gonawala, L and Imran, Y and Mohan, C and De Silva, KRD}, title = {Therapeutic Implications of Some Natural Products for Neuroimmune Diseases: A Narrative of Clinical Studies Review.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2023}, number = {}, pages = {5583996}, pmid = {37089709}, issn = {1741-427X}, abstract = {Neuroimmune diseases are a group of disorders that occur due to the dysregulation of both the nervous and immune systems, and these illnesses impact tens of millions of people worldwide. However, patients who suffer from these debilitating conditions have very few FDA-approved treatment options. Neuroimmune crosstalk is important for controlling the immune system both centrally and peripherally to maintain tissue homeostasis. This review aims to provide readers with information on how natural products modulate neuroimmune crosstalk and the therapeutic implications of natural products, including curcumin, epigallocatechin-3-gallate (EGCG), ginkgo special extract, ashwagandha, Centella asiatica, Bacopa monnieri, ginseng, and cannabis to mitigate the progression of neuroimmune diseases, such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, depression, and anxiety disorders. The majority of the natural products based clinical studies mentioned in this study have yielded positive results. To achieve the expected results from natural products based clinical studies, researchers should focus on enhancing bioavailability and determining the synergistic mechanisms of herbal compounds and extracts, which will lead to the discovery of more effective phytomedicines while averting the probable negative effects of natural product extracts. Therefore, future studies developing nutraceuticals to mitigate neuroimmune diseases that incorporate phytochemicals to produce synergistic effects must analyse efficacy, bioavailability, gut-brain axis function safety, chemical modifications, and encapsulation with nanoparticles.}, }
@article {pmid37085329, year = {2023}, author = {van Unnik, JWJ and Nikolakopoulos, S and Eijkemans, MJC and Gonzalez-Bermejo, J and Bruneteau, G and Morelot-Panzini, C and van den Berg, LH and Cudkowicz, ME and McDermott, CJ and Similowski, T and van Eijk, RPA and , }, title = {Development and Evaluation of a Simulation-Based Algorithm to Optimize the Planning of Interim Analyses for Clinical Trials in ALS.}, journal = {Neurology}, volume = {100}, number = {23}, pages = {e2398-e2408}, pmid = {37085329}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Retrospective Studies ; Computer Simulation ; Medical Futility ; Uncertainty ; Research Design ; }, abstract = {BACKGROUND AND OBJECTIVES: Late-phase clinical trials for neurodegenerative diseases have a low probability of success. In this study, we introduce an algorithm that optimizes the planning of interim analyses for clinical trials in amyotrophic lateral sclerosis (ALS) to better use the time and resources available and minimize the exposure of patients to ineffective or harmful drugs.<br><br>METHODS: A simulation-based algorithm was developed to determine the optimal interim analysis scheme by integrating prior knowledge about the success rate of ALS clinical trials with drug-specific information obtained in early-phase studies. Interim analysis schemes were optimized by varying the number and timing of interim analyses, together with their decision rules about when to stop a trial. The algorithm was applied retrospectively to 3 clinical trials that investigated the efficacy of diaphragm pacing or ceftriaxone on survival in patients with ALS. Outcomes were additionally compared with conventional interim designs.<br><br>RESULTS: We evaluated 183-1,351 unique interim analysis schemes for each trial. Application of the optimal designs correctly established lack of efficacy, would have concluded all studies 1.2-19.4 months earlier (reduction of 4.6%-57.7% in trial duration), and could have reduced the number of randomized patients by 1.7%-58.1%. By means of simulation, we illustrate the efficiency for other treatment scenarios. The optimized interim analysis schemes outperformed conventional interim designs in most scenarios.<br><br>DISCUSSION: Our algorithm uses prior knowledge to determine the uncertainty of the expected treatment effect in ALS clinical trials and optimizes the planning of interim analyses. Improving futility monitoring in ALS could minimize the exposure of patients to ineffective or harmful treatments and result in significant ethical and efficiency gains.}, }
@article {pmid37084148, year = {2023}, author = {Wuerch, E and Urgoiti, GR and Yong, VW}, title = {The Promise of Niacin in Neurology.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {20}, number = {4}, pages = {1037-1054}, pmid = {37084148}, issn = {1878-7479}, mesh = {Humans ; *Niacin/therapeutic use/metabolism ; Amyloid beta-Peptides ; *Pellagra/metabolism ; *Nervous System Diseases ; *Alzheimer Disease ; *Neurology ; }, abstract = {Niacin (vitamin B3) is an essential nutrient that treats pellagra, and prior to the advent of statins, niacin was commonly used to counter dyslipidemia. Recent evidence has posited niacin as a promising therapeutic for several neurological disorders. In this review, we discuss the biochemistry of niacin, including its homeostatic roles in NAD[+] supplementation and metabolism. Niacin also has roles outside of metabolism, largely through engaging hydroxycarboxylic acid receptor 2 (Hcar2). These receptor-mediated activities of niacin include regulation of immune responses, phagocytosis of myelin debris after demyelination or of amyloid beta in models of Alzheimer's disease, and cholesterol efflux from cells. We describe the neurological disorders in which niacin has been investigated or has been proposed as a candidate medication. These are multiple sclerosis, Alzheimer's disease, Parkinson's disease, glioblastoma and amyotrophic lateral sclerosis. Finally, we explore the proposed mechanisms through which niacin may ameliorate neuropathology. While several questions remain, the prospect of niacin as a therapeutic to alleviate neurological impairment is promising.}, }
@article {pmid37083797, year = {2023}, author = {Li, B and Liu, H and Li, C and Yang, M and Zhang, T}, title = {Combined Tui na and Western medicine treatment improves pulmonary function and quality of life in patients with amyotrophic lateral sclerosis: A case report.}, journal = {Medicine}, volume = {102}, number = {16}, pages = {e33612}, pmid = {37083797}, issn = {1536-5964}, mesh = {Male ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/therapy ; Quality of Life ; *Motor Neuron Disease ; Combined Modality Therapy ; Lung ; }, abstract = {RATIONALE: Amyotrophic lateral sclerosis is a rare disease that cannot be cured. We report a case of a patient with amyotrophic lateral sclerosis whose pulmonary function and quality of life were improved by a combined tui na treatment and Western medicine.<br><br>PATIENT CONCERNS: A 48-year-old male was diagnosed with ALS 1 year ago and was treated with western medicine and herbal medicine with no significant effect. This time, he was admitted to our department because of slurred speech, coughing and choking, and weakness of the left upper limb for more than 1 year.<br><br>INTERVENTION AND OUTCOME: After 1 month of treatment with tui na and traditional western medicine, the patient's lung function and quality of life improved and he was discharged from the hospital.<br><br>DIAGNOSES: Motor neuron disease. Amyotrophic lateral sclerosis.<br><br>LESSONS: The physiological function of ALS patients can be improved through the intervention of tui na.}, }
@article {pmid37074774, year = {2023}, author = {Belisle Haley, C and Agrawal, M and Newton, K and Yeung, B and Dayal, R}, title = {Management of high-dose intrathecal baclofen pump explant: A case report.}, journal = {Pain practice : the official journal of World Institute of Pain}, volume = {23}, number = {7}, pages = {847-850}, doi = {10.1111/papr.13229}, pmid = {37074774}, issn = {1533-2500}, mesh = {Male ; Humans ; Middle Aged ; Baclofen/therapeutic use ; *Muscle Relaxants, Central/therapeutic use ; *Amyotrophic Lateral Sclerosis/complications/drug therapy ; Infusion Pumps, Implantable/adverse effects ; Muscle Spasticity/drug therapy/etiology ; Diazepam/therapeutic use ; *Substance Withdrawal Syndrome ; *Chronic Pain/drug therapy ; Injections, Spinal ; }, abstract = {BACKGROUND: Intrathecal baclofen (ITB) is a proven, effective treatment for refractory spasticity and chronic pain, with applications ranging from spinal cord injury to amyotrophic lateralsclerosis (ALS). Despite its effectiveness, the withdrawal syndrome of intrathecal baclofen can be life-threatening.<br><br>CASE REPORT: This case describes the treatment of a patient with chronic spasticity related to ALS with an ITB pump infection requiring explant and a prolonged period of antibiotics before reimplantation. A 62-year-old man with ALS-related spasticity maintained on high-dose ITB for 20&#x2009;years presented to the emergency department with one week of fever, confusion, and localized erythema to the R-side of his abdomen. Laboratories indicated a mild leukocytosis 12.9&#x2009;K/uL and imaging showed a 2.9-cm fluid collection with fat stranding surrounding the ITB pump. The pack was explanted, and the patient started on intravenous antibiotics. Due to the high baclofen dosage, our pain service recommended PO (per os) baclofen 30&#x2009;mg every 6&#x2009;h via gastrostomy and PO diazepam 10&#x2009;mg every 6&#x2009;h via gastrostomy. These doses were titrated carefully to avoid oversedation while preventing withdrawal symptoms. On Day 23 postexplant, the patient had the baclofen pump reimplanted and baclofen titrated over three days to his previous dose of ITB.<br><br>CONCLUSION: This case demonstrates a successful approach to avoiding severe baclofen withdrawal using PO baclofen combined with PO diazepam. The high dose of maintenance ITB (1188.8 mcg/day), the inability to reinsert the patient's intrathecal pump, and the high risk of intubation in a patient with severe neuromuscular dysfunction all made this a challenging case.}, }
@article {pmid37071691, year = {2023}, author = {Thorborg, T and Finderup, J and Winther, DS and Lorenzen, CK and Dreyer, P}, title = {The experiences of patients with amyotrophic lateral sclerosis of their decision-making processes to invasive home mechanical ventilation-A qualitative study.}, journal = {Nursing open}, volume = {10}, number = {8}, pages = {5139-5148}, pmid = {37071691}, issn = {2054-1058}, mesh = {Humans ; *Respiration, Artificial ; *Amyotrophic Lateral Sclerosis/therapy ; Qualitative Research ; Uncertainty ; Decision Making, Shared ; }, abstract = {AIM: To explore and gain knowledge of the experiences and needs among patients with amyotrophic lateral sclerosis (ALS) of their decision-making processes whether to choose invasive home mechanical ventilation or not.<br><br>DESIGN: A qualitative study.<br><br>METHODS: A phenomenological-hermeneutic approach influenced by Ricoeur's interpretation theory was used. Seven patients with ALS were interviewed. The Consolidated Criteria for Reporting Qualitative Research checklist was used for reporting.<br><br>RESULTS: Three themes were evident in patients' accounts of the decision-making process: (1) being taken care of directly after receiving the diagnosis, (2) living in uncertainty about what the future would bring and (3) doubt causing patients with ALS to change their minds. Patients with ALS were burdened with everyday life challenging decision-making processes about future treatment and doubt caused patients to change their minds about their future treatment. It is necessary to support patients in their decision-making processes using shared decision-making.<br><br>No Patient or Public Contribution.}, }
@article {pmid37065386, year = {2023}, author = {Valaparla, VL and Lobaina, M and Patel, C and Patel, AV}, title = {Motor Band Sign in Primary Lateral Sclerosis: A Case Report Proposing the Need for an Imaging Biomarker.}, journal = {Cureus}, volume = {15}, number = {3}, pages = {e36121}, pmid = {37065386}, issn = {2168-8184}, abstract = {Motor neuron disease is a degenerative condition involving both upper motor neurons (UMN) and lower motor neurons (LMN). While amyotrophic lateral sclerosis (ALS) is an overlap of upper and lower motor neuron involvement, primary lateral sclerosis (PLS) is predominantly an upper motor neuron involvement with lower motor involvement seen in the later stages of illness. Diagnostic criteria rely on clinical features and electrodiagnostic tests such as electromyography (EMG). EMG predominantly helps in determining lower motor neuron involvement. No definitive objective measures are currently available to determine upper motor neuron involvement. We describe a patient diagnosed with PLS based on consensus diagnostic criteria. The patient had absent LMN features both clinically and on EMG. Magnetic resonance imaging (MRI) was significant for hypointense signals in the bilateral motor strip area on susceptibility weighted sequence, suggesting a surrogate marker of degeneration involving motor neurons in the brain. Early recognition of this MRI pattern called motor band sign (MBS) can help determine the earlier diagnosis of this neurodegenerative condition, potentially translating to better treatment and outcome measures.}, }
@article {pmid37065090, year = {2023}, author = {Patzwaldt, K and Berezhnoy, G and Ionescu, T and Schramm, L and Wang, Y and Owczorz, M and Calderón, E and Poli, S and Serna Higuita, LM and Gonzalez-Menendez, I and Quintanilla-Martinez, L and Herfert, K and Pichler, B and Trautwein, C and Castaneda-Vega, S}, title = {Repurposing the mucolytic agent ambroxol for treatment of sub-acute and chronic ischaemic stroke.}, journal = {Brain communications}, volume = {5}, number = {2}, pages = {fcad099}, pmid = {37065090}, issn = {2632-1297}, abstract = {Ambroxol is a well-known mucolytic expectorant, which has gained much attention in amyotrophic lateral sclerosis, Parkinson's and Gaucher's disease. A specific focus has been placed on ambroxol's glucocerebrosidase-stimulating activity, on grounds that the point mutation of the gba1 gene, which codes for this enzyme, is a risk factor for developing Parkinson's disease. However, ambroxol has been attributed other characteristics, such as the potent inhibition of sodium channels, modification of calcium homeostasis, anti-inflammatory effects and modifications of oxygen radical scavengers. We hypothesized that ambroxol could have a direct impact on neuronal rescue if administered directly after ischaemic stroke induction. We longitudinally evaluated 53 rats using magnetic resonance imaging to examine stroke volume, oedema, white matter integrity, resting state functional MRI and behaviour for 1 month after ischemic stroke onset. For closer mechanistic insights, we evaluated tissue metabolomics of different brain regions in a subgroup of animals using ex vivo nuclear magnetic resonance spectroscopy. Ambroxol-treated animals presented reduced stroke volumes, reduced cytotoxic oedema, reduced white matter degeneration, reduced necrosis, improved behavioural outcomes and complex changes in functional brain connectivity. Nuclear magnetic resonance spectroscopy tissue metabolomic data at 24 h post-stroke proposes several metabolites that are capable of minimizing post-ischaemic damage and that presented prominent shifts during ambroxol treatment in comparison to controls. Taking everything together, we propose that ambroxol catalyzes recovery in energy metabolism, cellular homeostasis, membrane repair mechanisms and redox balance. One week of ambroxol administration following stroke onset reduced ischaemic stroke severity and improved functional outcome in the subacute phase followed by reduced necrosis in the chronic stroke phase.}, }
@article {pmid37060838, year = {2023}, author = {Fujiwara, Y and Kusakabe, KT and Baba, K and Sasaki, N}, title = {Effect of platelet lysate on Schwann-like cell differentiation of equine bone marrow-derived mesenchymal stem cells.}, journal = {Research in veterinary science}, volume = {159}, number = {}, pages = {11-18}, doi = {10.1016/j.rvsc.2023.03.023}, pmid = {37060838}, issn = {1532-2661}, mesh = {Humans ; Animals ; Horses ; Nestin/metabolism/pharmacology ; *Amyotrophic Lateral Sclerosis/metabolism/veterinary ; Bone Marrow ; Cell Differentiation/physiology ; *Mesenchymal Stem Cells ; Cells, Cultured ; *Horse Diseases/therapy/metabolism ; }, abstract = {Currently, treatment for peripheral nerve injuries in horses primarily relies upon physical therapy and anti-inflammatory drugs. In humans, various treatments using mesenchymal stem cells (MSCs) are being attempted. Therefore, in this study, Schwann-like cell differentiation cultures of equine MSCs were prepared using fetal bovine serum (FBS) and equine platelet lysate (ePL). ePL increased the platelet count to 1 × 10[6]/μl, the optimal concentration for culture. In both groups, an elongated morphology at both ends, characteristic of Schwann cells, was observed under the microscope. Real-time PCR analysis of the expression levels of neuronal markers showed that the ePL group tended to express higher levels of Nestin, Musashi1, and Pax3 than the FBS group. p75 was expressed at low levels in both groups. Immunostaining results showed localization of Nestin in both groups of differentiated cells, but the positive cell rate was significantly higher in the ePL group than in the FBS group. Overall, the ePL gro showed good results for Schwann-like cell differentiation, which may be useful for future use in the treatment of equine motor neuron disease. This knowledge could be applied translationaly in the treatment of amyotrophic lateral sclerosis in humans.Overall, the ePL group showed good results for Schwann-like cell differentiation, which may be useful for future use in the treatment of equine motor neuron disease and in the treatment of amyotrophic lateral sclerosis in humans.}, }
@article {pmid37056816, year = {2023}, author = {Guo, Q and Qian, J and Zeng, Q and Zhang, L and Zhu, X and Zheng, J and Chen, K and Liu, E}, title = {Characterization of an orally available respiratory syncytial virus L protein polymerase inhibitor DZ7487.}, journal = {American journal of translational research}, volume = {15}, number = {3}, pages = {1680-1692}, pmid = {37056816}, issn = {1943-8141}, abstract = {OBJECTIVES: Respiratory Syncytial Virus (RSV) is a leading cause of death and hospitalization among infants and young children. People with an immunocompromised status are also at risk for severe RSV infection. There is no specific treatment for RSV infection available. Ribavirin, an antiviral drug approved for severe lung infection by RSV, has shown limited clinical efficacies with severe side effects. Additionally, given the genetic variability of RSV genomes and seasonal change of different strains, a broad-spectrum antiviral drug is highly desirable. The RNA-dependent RNA polymerase (RdRp) domain is relatively conserved and indispensable for the replication of the virus genome and therefore serves as a potential therapeutic target. Previous attempts to identify an RdRp inhibitor have not been successful due to lack of potency or high enough blood exposure. DZ7487 is a novel orally available small molecule inhibitor specifically designed to target the RSV RdRp. Here we present our data showing that DZ7487 can potently inhibited all clinical viral isolates tested, with large safety margin predicted for human.<br><br>METHODS: HEp-2 cells were infected by RSV A and B. Antiviral activities were assessed by in vitro cytopathic effect assay (CPE) and Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). DZ7487 antiviral effects in lower airway cells were evaluated in A549 and human small airway epithelial cells (SAEC) cells. DZ7487 induced RSV A2 escape mutations were selected through continuous culture with increasing DZ7487 concentrations in the culture medium. Resistant mutations were identified by next generation sequencing and confirmed by recombinant RSV CPE assays. RSV infection models in both BALB/c mice and cotton rats were used to evaluate DZ7487 in vivo antiviral effects.<br><br>RESULTS: DZ7487 potently inhibited viral replication of all clinical isolates of both RSVA and B subtypes. In lower airway cells, DZ7487 showed superior efficacy than the nucleoside analog ALS-8112. Acquired resistant mutation was predominantly restricted at the RdRp domain resulting asparagine to threonine mutation (N363T) of the L protein. This finding is consistent with DZ7487's presumed binding mode. DZ7487 was well tolerated in animal models. Unlike fusion inhibitors, which can only prevent viral infection, DZ7487 potently inhibited RSV replication before and after RSV infection in vitro and in vivo.<br><br>CONCLUSIONS: DZ7487 demonstrated potent anti-RSV replication effect both in vitro and in vivo assays. It has the desired drug-like physical properties to be an effective orally available anti-RSV replication drug with broad spectrum.}, }
@article {pmid37049492, year = {2023}, author = {Kitaoka, Y and Seki, S and Kawata, S and Nishiura, A and Kawamura, K and Hiraoka, SI and Kogo, M and Tanaka, S}, title = {Analysis of Feeding Behavior Characteristics in the Cu/Zn Superoxide Dismutase 1 (SOD1) SOD1G93A Mice Model for Amyotrophic Lateral Sclerosis (ALS).}, journal = {Nutrients}, volume = {15}, number = {7}, pages = {}, pmid = {37049492}, issn = {2072-6643}, support = {19K24117//KAKENHI/ ; 21K17088//KAKENHI/ ; 20H03887//KAKENHI/ ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy ; Superoxide Dismutase-1 ; Superoxide Dismutase ; Artificial Intelligence ; Mice, Transgenic ; Motor Neurons/physiology ; Disease Models, Animal ; Feeding Behavior ; Zinc/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease affecting upper and lower motor neurons. Feeding disorders are observed in patients with ALS. The mastication movements and their systemic effects in patients with ALS with feeding disorders remain unclear. Currently, there is no effective treatment for ALS. However, it has been suggested that treating feeding disorders and improving nutritional status may prolong the lives of patients with ALS. Therefore, this study elucidates feeding disorders observed in patients with ALS and future therapeutic agents. We conducted a temporal observation of feeding behavior and mastication movements using an open-closed mouth evaluation artificial intelligence (AI) model in an ALS mouse model. Furthermore, to determine the cause of masticatory rhythm modulation, we conducted electrophysiological analyses of mesencephalic trigeminal neurons (MesV). Here, we observed the modulation of masticatory rhythm with a prolonged open phase in the ALS mouse model from the age of 12 weeks. A decreased body weight was observed simultaneously, indicating a correlation between the prolongation of the open phase and the decrease observed. We found that the percentage of firing MesV was markedly decreased. This study partially clarifies the role of feeding disorders in ALS.}, }
@article {pmid37048088, year = {2023}, author = {Fabbrizio, P and Margotta, C and D'Agostino, J and Suanno, G and Quetti, L and Bendotti, C and Nardo, G}, title = {Intramuscular IL-10 Administration Enhances the Activity of Myogenic Precursor Cells and Improves Motor Function in ALS Mouse Model.}, journal = {Cells}, volume = {12}, number = {7}, pages = {}, pmid = {37048088}, issn = {2073-4409}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/pathology ; Interleukin-10 ; Superoxide Dismutase ; Motor Neurons/pathology ; Disease Models, Animal ; Muscular Atrophy/drug therapy/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common adult motor neuron disease, with a poor prognosis, a highly unmet therapeutic need, and a burden on health care costs. Hitherto, strategies aimed at protecting motor neurons have missed or modestly delayed ALS due to a failure in countering the irreversible muscular atrophy. We recently provided direct evidence underlying the pivotal role of macrophages in preserving skeletal muscle mass. Based on these results, we explored whether the modulation of macrophage muscle response and the enhancement of satellite cell differentiation could effectively promote the generation of new myofibers and counteract muscle dysfunction in ALS mice. For this purpose, disease progression and the survival of SOD1G93A mice were evaluated following IL-10 injections in the hindlimb skeletal muscles. Thereafter, we used ex vivo methodologies and in vitro approaches on primary cells to assess the effect of the treatment on the main pathological signatures. We found that IL-10 improved the motor performance of ALS mice by enhancing satellite cells and the muscle pro-regenerative activity of macrophages. This resulted in delayed muscle atrophy and motor neuron loss. Our findings provide the basis for a suitable adjunct multisystem therapeutic approach that pinpoints a primary role of muscle pathology in ALS.}, }
@article {pmid37047320, year = {2023}, author = {Bianco, A and Antonacci, Y and Liguori, M}, title = {Sex and Gender Differences in Neurodegenerative Diseases: Challenges for Therapeutic Opportunities.}, journal = {International journal of molecular sciences}, volume = {24}, number = {7}, pages = {}, pmid = {37047320}, issn = {1422-0067}, mesh = {Male ; Female ; Humans ; *Neurodegenerative Diseases/therapy/pathology ; Sex Factors ; Sex Characteristics ; *Parkinson Disease/pathology ; Neurons/pathology ; }, abstract = {The term "neurodegenerative diseases" (NDs) identifies a group of heterogeneous diseases characterized by progressive loss of selectively vulnerable populations of neurons, which progressively deteriorates over time, leading to neuronal dysfunction. Protein aggregation and neuronal loss have been considered the most characteristic hallmarks of NDs, but growing evidence confirms that significant dysregulation of innate immune pathways plays a crucial role as well. NDs vary from multiple sclerosis, in which the autoimmune inflammatory component is predominant, to more "classical" NDs, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. Of interest, many of the clinical differences reported in NDs seem to be closely linked to sex, which may be justified by the significant changes in immune mechanisms between affected females and males. In this review, we examined some of the most studied NDs by looking at their pathogenic and phenotypical features to highlight sex-related discrepancies, if any, with particular interest in the individuals' responses to treatment. We believe that pointing out these differences in clinical practice may help achieve more successful precision and personalized care.}, }
@article {pmid37047273, year = {2023}, author = {Russo, C and Valle, MS and Casabona, A and Malaguarnera, L}, title = {Chitinase Signature in the Plasticity of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {7}, pages = {}, pmid = {37047273}, issn = {1422-0067}, support = {E63C22002080006//This research was founded by PNRR: "Health Extended ALliance for Innovative Therapies, Advanced Lab-research, and Integrated Approaches of Precision"/ ; }, mesh = {Humans ; *Neurodegenerative Diseases ; *Chitinases/genetics ; Neuroinflammatory Diseases ; Biomarkers ; *Multiple Sclerosis ; }, abstract = {Several reports have pointed out that Chitinases are expressed and secreted by various cell types of central nervous system (CNS), including activated microglia and astrocytes. These cells play a key role in neuroinflammation and in the pathogenesis of many neurodegenerative disorders. Increased levels of Chitinases, in particular Chitotriosidase (CHIT-1) and chitinase-3-like protein 1 (CHI3L1), have been found increased in several neurodegenerative disorders. Although having important biological roles in inflammation, to date, the molecular mechanisms of Chitinase involvement in the pathogenesis of neurodegenerative disorders is not well-elucidated. Several studies showed that some Chitinases could be assumed as markers for diagnosis, prognosis, activity, and severity of a disease and therefore can be helpful in the choice of treatment. However, some studies showed controversial results. This review will discuss the potential of Chitinases in the pathogenesis of some neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, to understand their role as distinctive biomarkers of neuronal cell activity during neuroinflammatory processes. Knowledge of the role of Chitinases in neuronal cell activation could allow for the development of new methodologies for downregulating neuroinflammation and consequently for diminishing negative neurological disease outcomes.}, }
@article {pmid37028542, year = {2023}, author = {Yeo, KFH and Dong, Y and Xue, T and Chen, Z and Zhang, N and Yang, Y and Han, L and Liu, M and Nsilani Kouediatouka, A and Mouguegue, HPPL and Wang, W}, title = {Characterisation of kapok fibre's biochar for arsenate adsorption removal from aqueous solution.}, journal = {Environmental research}, volume = {228}, number = {}, pages = {115822}, doi = {10.1016/j.envres.2023.115822}, pmid = {37028542}, issn = {1096-0953}, mesh = {*Arsenates ; Adsorption ; Spectroscopy, Fourier Transform Infrared ; *Water Pollutants, Chemical/chemistry ; Kinetics ; Water ; Hydrogen-Ion Concentration ; }, abstract = {Al-KBC was produced through the simple pyrolysis of Al-modified kapok fibres at high temperatures. Using the N2 adsorption Brunauer Emmett Teller (BET) process, Fourier transforms infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), the energy-dispersive X-ray spectroscopy (EDS) spectroscopy, and X-ray photoelectron spectroscopy (XPS), the sorbent changes and characteristics were analysed. As a result of Al's addition to the fibre's surface, Al-KBC exhibited superior As(V) adsorption performance compared to KBC due to better pore structures. Experiments on the kinetics of As(V) adsorption revealed that the adsorption followed the pseudo-second-order model and that intradiffusion was not the only factor governing the adsorption. Experiments with isotherms indicated that the adsorption mechanism corresponded to the Langmuir model, and the adsorption capacity Qm of Al-KBC at 25 °C was 483 μg/g. The thermodynamic experiments suggested that the adsorption reactions were spontaneous endothermic with a random approach at the adsorption interface. 25 mg/L of coexisting ions such as sulphate and phosphate reduced the sorbent As(V) removal ability to 65% and 39%. After seven cycles of adsorption/desorption, Al-KBC demonstrated satisfactory performance in terms of reusability, adsorbing 53% of 100 μg/L As(V) from the water. This novel BC can probably be used as a filter to purify groundwater with high As(V) concentration in the rural zone.}, }
@article {pmid37028456, year = {2023}, author = {Zou, Y and Zhao, B and Cao, S and Guan, Y and Liu, L and Ji, M}, title = {Mutation at the 197 site and P450-mediated metabolic resistance are involved in bensulfuron-methyl resistance in Sagittaria trifolia.}, journal = {Plant science : an international journal of experimental plant biology}, volume = {331}, number = {}, pages = {111700}, doi = {10.1016/j.plantsci.2023.111700}, pmid = {37028456}, issn = {1873-2259}, mesh = {Malathion/pharmacology ; *Sagittaria/genetics ; Molecular Docking Simulation ; Mutation ; *Arabidopsis/genetics ; *Herbicides/pharmacology ; Herbicide Resistance/genetics ; *Acetolactate Synthase/genetics ; }, abstract = {Sagittaria trifolia control is threatened by the emergence of resistance to acetolactate synthase (ALS)-inhibiting herbicides. Hence, we systematically uncovered the molecular mechanism of resistance to the main herbicide (bensulfuron-methyl) in Liaoning Province from target-site and non-target-site resistance perspectives. The suspected resistant population (TR-1) exhibited high-level resistance. A new amino acid substitution (Pro-197-Ala) in resistant Sagittaria trifolia for ALS was detected, and the molecular docking results showed that the spatial structure of ALS changed significantly after the substitution, manifested by an increase in the number of contacted amino acid residues and the disappearance of hydrogen bonds. Dose-response test of transgenic Arabidopsis thaliana further demonstrated that the Pro-197-Ala substitution conferred bensulfuron-methyl resistance. The assays found that the sensitivity of the ALS enzyme in TR-1 to this herbicide was decreased in vitro; and this population had developed resistance to other types of ALS-inhibiting herbicides. Furthermore, the resistance of TR-1 to bensulfuron-methyl was significantly alleviated after co-treatment with a P450-inhibitor (malathion). TR-1 metabolized bensulfuron-methyl significantly faster than sensitive population (TS-1) did, but this gap was narrowed after malathion treatment. Overall, the resistance of Sagittaria trifolia to bensulfuron-methyl was derived from the mutation of the target-site gene and the enhancement of the P450s-mediated detoxification metabolism.}, }
@article {pmid37027074, year = {2023}, author = {Cecerska-Heryć, E and Pękała, M and Serwin, N and Gliźniewicz, M and Grygorcewicz, B and Michalczyk, A and Heryć, R and Budkowska, M and Dołęgowska, B}, title = {The Use of Stem Cells as a Potential Treatment Method for Selected Neurodegenerative Diseases: Review.}, journal = {Cellular and molecular neurobiology}, volume = {43}, number = {6}, pages = {2643-2673}, pmid = {37027074}, issn = {1573-6830}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/therapy ; *Amyotrophic Lateral Sclerosis/therapy ; Stem Cells ; *Huntington Disease/pathology/therapy ; *Alzheimer Disease ; *Parkinson Disease/therapy ; }, abstract = {Stem cells have been the subject of research for years due to their enormous therapeutic potential. Most neurological diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are incurable or very difficult to treat. Therefore new therapies are sought in which autologous stem cells are used. They are often the patient's only hope for recovery or slowing down the progress of the disease symptoms. The most important conclusions arise after analyzing the literature on the use of stem cells in neurodegenerative diseases. The effectiveness of MSC cell therapy has been confirmed in ALS and HD therapy. MSC cells slow down ALS progression and show early promising signs of efficacy. In HD, they reduced huntingtin (Htt) aggregation and stimulation of endogenous neurogenesis. MS therapy with hematopoietic stem cells (HSCs) inducted significant recalibration of pro-inflammatory and immunoregulatory components of the immune system. iPSC cells allow for accurate PD modeling. They are patient-specific and therefore minimize the risk of immune rejection and, in long-term observation, did not form any tumors in the brain. Extracellular vesicles derived from bone marrow mesenchymal stromal cells (BM-MSC-EVs) and Human adipose-derived stromal/stem cells (hASCs) cells are widely used to treat AD. Due to the reduction of Aβ42 deposits and increasing the survival of neurons, they improve memory and learning abilities. Despite many animal models and clinical trial studies, cell therapy still needs to be refined to increase its effectiveness in the human body.}, }
@article {pmid37026513, year = {2023}, author = {Li, F and Liu, A and Zhao, M and Luo, L}, title = {Astrocytic Chitinase-3-like protein 1 in neurological diseases: Potential roles and future perspectives.}, journal = {Journal of neurochemistry}, volume = {165}, number = {6}, pages = {772-790}, doi = {10.1111/jnc.15824}, pmid = {37026513}, issn = {1471-4159}, support = {2021-ZZ-JC030//Project of Shaanxi Provincial Administration of Traditional Chinese Medicine/ ; 82204425//National Natural Science Foundation of China/ ; 32241007//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Chitinase-3-Like Protein 1/metabolism ; Astrocytes/metabolism ; *Chitinases/metabolism ; *Neurodegenerative Diseases/metabolism ; Synapsins/metabolism ; *Brain Neoplasms/metabolism ; }, abstract = {Chitinase-3-like protein 1 (CHI3L1) is a secreted glycoprotein characterized by its ability to regulate multiple biological processes, such as the inflammatory response and gene transcriptional signaling activation. Abnormal CHI3L1 expression has been associated with multiple neurological disorders and serves as a biomarker for the early detection of several neurodegenerative diseases. Aberrant CHI3L1 expression is also reportedly associated with brain tumor migration and metastasis, as well as contributions to immune escape, playing important roles in brain tumor progression. CHI3L1 is synthesized and secreted mainly by reactive astrocytes in the central nervous system. Thus, targeting astrocytic CHI3L1 could be a promising approach for the treatment of neurological diseases, such as traumatic brain injury, ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and glioma. Based on current knowledge of CHI3L1, we assume that it acts as a molecule mediating several signaling pathways driving the initiation and progression of neurological disorders. This narrative review is the first to introduce the potential roles of astrocytic CHI3L1 in neurological disorders. We also equally explore astrocytic CHI3L1 mRNA expression under physiological and pathological conditions. Inhibiting CHI3L1 and disrupting its interaction with its receptors through multiple mechanisms of action are briefly discussed. These endeavors highlight the pivotal roles of astrocytic CHI3L1 in neurological disorders and could contribute to the development of effective inhibitors based on the strategy of structure-based drug discovery, which could be an attractive therapeutic approach for neurological disease treatment.}, }
@article {pmid37023778, year = {2025}, author = {Trenti, E and Palermo, S and D'Elia, C and Comploj, E and Ladurner, C and Gamper, C and Pycha, S and Palermo, M and Pycha, A}, title = {Treatment of long ureteric strictures with a free peritoneal graft: long-term results.}, journal = {Aktuelle Urologie}, volume = {56}, number = {1}, pages = {65-70}, doi = {10.1055/a-2058-7983}, pmid = {37023778}, issn = {1438-8820}, mesh = {Humans ; Male ; *Ureteral Obstruction/surgery/etiology ; Female ; Middle Aged ; Adult ; Constriction, Pathologic/surgery ; Peritoneum/surgery ; Ureter/surgery ; Aged ; Treatment Outcome ; }, abstract = {ZIEL DER STUDIE: Beschreibung einer neuen Technik zur Rekonstruktion von komplexen Ureterstrikturen unter Verwendung eines freien Peritoneallappens.<br><br>MATERIAL UND METHODEN: Zwischen 2006 und 2021 behandelten wir 11 Patienten mit langen komplexen Harnleiterstrikturen, die in 9 F&#xe4;llen den mittleren- und in 2 F&#xe4;llen den proximalen Harnleiter betrafen. Die L&#xe4;nge der Strikturen variierte von 3 bis 12 cm (Mittelwert 7 cm). In drei F&#xe4;llen handelte es sich um eine retroperitoneale Fibrose nach einem gef&#xe4;&#xdf;chirurgischen Eingriff, in zwei F&#xe4;llen um einen Morbus Ormond, in vier F&#xe4;llen um eine ausgedehnte Resektion gro&#xdf;er Harnleitertumoren, in drei F&#xe4;llen um wiederholte endoskopische Eingriffe bei Harnsteinen und in einem Fall um eine viermal fehlgeschlagene Pyeloplastik. Der Harnleiter wurde l&#xe4;ngs gespalten, ein freier Peritoneallappen aus dem nahe gelegenen gesunden Bauchfell entnommen und nach Positionierung eines Harnleiterkatheters als Onlay-Patch mit einer fortlaufenden Naht an der verbleibenden Harnleiterplatte fixiert. Der Ureter wurde zuletzt mit Omentum gedeckt.<br><br>ERGEBNISSE: Die Nachbeobachtungszeit reichte von 12 bis 122 (Mittelwert 61,6) Monate. Sieben Patienten waren nach 12, 18, 60, 78, 98, 99 und 122 Monaten (Mittelwert 69,5 Monate) rezidivfrei, ohne Erweiterung des oberen Harntrakts und mit normaler Nierenfunktion. Bei vier Patienten kam es zu einem Rezidiv: Bei einem Patienten wurde das Rezidiv nach 60 Monaten ohne Symptome und mit leichter Hydronephrose festgestellt, ohne dass eine Operation erforderlich war. Bei einem Patienten mit Morbus Ormond trat das Rezidiv 6 Monate nach dem Eingriff symptomlos im distalen Teil des 10 cm langen Omlays auf. Es wurde eine Resektion des stenotischen Segments mit Psoas-Hitch durchgef&#xfc;hrt. Bei den beiden anderen Patienten trat 3 und 6 Monate nach dem Eingriff eine Obstruktion unterhalb des rekonstruierten Segments mit Hydronephrose auf, ohne dass die Nierenfunktion beeintr&#xe4;chtigt war. Bei diesen Patienten wurde keine weitere Operation durchgef&#xfc;hrt. Die Limitation dieser Studie besteht in der kleinen Studiengr&#xf6;&#xdf;e, die auf die strenge Indikationsstellung zur&#xfc;ckzuf&#xfc;hren ist.<br><br>SCHLUSSFOLGERUNGEN: Die beschriebene Technik erm&#xf6;glicht den Erhalt der verbleibenden Gef&#xe4;&#xdf;versorgung des Harnleiters und stellt eine praktikable und n&#xfc;tzliche Alternative zu Nephrektomie, Ileum-Ureter, Uretero-Uretero-Stomie und Autotransplantation in hochselektierten F&#xe4;llen dar.}, }
@article {pmid37014017, year = {2023}, author = {Huang, B and Geng, X and Yu, Z and Zhang, C and Chen, Z}, title = {Dynamic effects of prognostic factors and individual survival prediction for amyotrophic lateral sclerosis disease.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {6}, pages = {892-903}, pmid = {37014017}, issn = {2328-9503}, mesh = {Humans ; Prognosis ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; Disease Progression ; Proportional Hazards Models ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons, with broad heterogeneity in disease progression and survival in different patients. Therefore, an accurate prediction model will be crucial to implement timely interventions and prolong patient survival time.<br><br>METHODS: A total of 1260 ALS patients from the PRO-ACT database were included in the analysis. Their demographics, clinical variables, and death reports were included. We constructed an ALS dynamic Cox model through the landmarking approach. The predictive performance of the model at different landmark time points was evaluated by calculating the area under the curve (AUC) and Brier score.<br><br>RESULTS: Three baseline covariates and seven time-dependent covariates were selected to construct the ALS dynamic Cox model. For better prognostic analysis, this model identified dynamic effects of treatment, albumin, creatinine, calcium, hematocrit, and hemoglobin. Its prediction performance (at all landmark time points, AUC&#x2009;&#x2265;&#x2009;0.70 and Brier score&#x2009;&#x2264;&#x2009;0.12) was better than that of the traditional Cox model, and it predicted the dynamic 6-month survival probability according to the longitudinal information of individual patients.<br><br>INTERPRETATION: We developed an ALS dynamic Cox model with ALS longitudinal clinical trial datasets as the inputs. This model can not only capture the dynamic prognostic effect of both baseline and longitudinal covariates but also make individual survival predictions in real time, which are valuable for improving the prognosis of ALS patients and providing a reference for clinicians to make clinical decisions.}, }
@article {pmid37009997, year = {2023}, author = {Romero-Gangonells, E and Virgili-Casas, MN and Povedano, M and Barceló, MA}, title = {Clinical and demographical characteristics in a cohort of MND patients treated with riluzole. Differences between tablets and oral suspension.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {369-382}, doi = {10.1080/21678421.2023.2192247}, pmid = {37009997}, issn = {2167-9223}, mesh = {Male ; Female ; Humans ; Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Neuroprotective Agents/therapeutic use ; Retrospective Studies ; Prospective Studies ; *Deglutition Disorders/etiology ; }, abstract = {Objective: To describe the clinical and demographic characteristics of patients with MND treated with riluzole by comparing two dosage forms (oral suspension and tablets), as well as the impact on survival in patients with and without dysphagia according to the form of dosage.Methods: Retrospective and prospective cohort of patients diagnosed with MND at the multidisciplinary functional unit of Motor Neuron Disease in our center in the period between 1 of January 2011 and 31 of December 2020 (n = 742). A descriptive analysis (univariate and bivariate) was carried out and survival curves were estimated.Results: During the follow-up period, 402 males (54.18%) and 340 females (45.82%) were diagnosed with MND. Of these patients, 632 (97.23%) were being treated with 100mg riluzole: 282 (54.55%) patients took this in tablet form and 235 (45.45%) oral suspension. Riluzole in tablet form is taken more frequently by men than women, in younger age ranges, and mostly without dysphagia (78.31%). Also, it is the predominant dosage form for classic spinal ALS and respiratory phenotypes. Dosages via oral suspension are taken by patients in the older age ranges (over 64.8 years), mostly with dysphagia (53.67%) and more frequently with bulbar phenotypes such as classic bulbar ALS and PBP. Because of this, patients using oral suspension (most of them with dysphagia) had a poorer survival rate (at 90% CI) than patients using tablets (most of them without dysphagia).Conclusions: The most appropriate dosage form should be given according to the patient's needs at each stage of the disease and, furthermore, oral suspension could improve adherence to treatment because it avoids having to change from one form (tablet) to the other (suspension) when swallowing disorders appear.}, }
@article {pmid37005761, year = {2023}, author = {Dahlmanns, M and Dahlmanns, JK and Savaskan, N and Steiner, HH and Yakubov, E}, title = {Glial Glutamate Transporter-Mediated Plasticity: System xc[-]/xCT/SLC7A11 and EAAT1/2 in Brain Diseases.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {28}, number = {3}, pages = {57}, doi = {10.31083/j.fbl2803057}, pmid = {37005761}, issn = {2768-6698}, mesh = {Humans ; Amino Acid Transport System X-AG ; *Amyotrophic Lateral Sclerosis ; Cystine/metabolism ; *Parkinson Disease ; *Alzheimer Disease ; Antioxidants ; Glutamic Acid/metabolism ; Microglia/metabolism ; *Multiple Sclerosis ; *Glioma ; Amino Acid Transport System y+/genetics/metabolism ; }, abstract = {Glial cells play an essential role in the complex function of the nervous system. In particular, astrocytes provide nutritive support for neuronal cells and are involved in regulating synaptic transmission. Oligodendrocytes ensheath axons and support information transfer over long distances. Microglial cells constitute part of the innate immune system in the brain. Glial cells are equipped with the glutamate-cystine-exchanger xCT (SLC7A11), the catalytic subunit of system xc-, and the excitatory amino acid transporter 1 (EAAT1, GLAST) and EAAT2 (GLT-1). Thereby, glial cells maintain balanced extracellular glutamate levels that enable synaptic transmission and prevent excitotoxic states. Expression levels of these transporters, however, are not fixed. Instead, expression of glial glutamate transporters are highly regulated in reaction to the external situations. Interestingly, such regulation and homeostasis is lost in diseases such as glioma, (tumor-associated) epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis or multiple sclerosis. Upregulation of system xc- (xCT or SLC7A11) increases glutamate export from the cell, while a downregulation of EAATs decreases intracellular glutamate import. Occurring simultaneously, these reactions entail excitotoxicity and thus harm neuronal function. The release of glutamate via the antiporter system xc- is accompanied by the import of cystine-an amino acid essential in the antioxidant glutathione. This homeostasis between excitotoxicity and intracellular antioxidant response is plastic and off-balance in central nervous system (CNS) diseases. System xc- is highly expressed on glioma cells and sensitizes them to ferroptotic cell death. Hence, system xc- is a potential target for chemotherapeutic add-on therapy. Recent research reveals a pivotal role of system xc- and EAAT1/2 in tumor-associated and other types of epilepsy. Numerous studies show that in Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease, these glutamate transporters are dysregulated-and disease mechanisms could be interposed by targeting system xc- and EAAT1/2. Interestingly, in neuroinflammatory diseases such as multiple sclerosis, there is growing evidence for glutamate transporter involvement. Here, we propose that the current knowledge strongly suggest a benefit from rebalancing glial transporters during treatment.}, }
@article {pmid37004595, year = {2023}, author = {Liu, Y}, title = {Zebrafish as a Model Organism for Studying Pathologic Mechanisms of Neurodegenerative Diseases and other Neural Disorders.}, journal = {Cellular and molecular neurobiology}, volume = {43}, number = {6}, pages = {2603-2620}, pmid = {37004595}, issn = {1573-6830}, support = {ZR2022MC192//Shandong Provincial Natural Science Foundation/ ; 2021boshi01//the Doctoral Research Startup Funding from Qingdao Huanghai University , China/ ; hhxyjg2021//the School Teaching Reform Project of Qingdao Huanghai University, China/ ; }, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/genetics/pathology ; Zebrafish/genetics ; }, abstract = {Zebrafish are widely considered an excellent vertebrate model for studying the pathogenesis of human diseases because of their transparency of embryonic development, easy breeding, high similarity with human genes, and easy gene manipulation. Previous studies have shown that zebrafish as a model organism provides an ideal operating platform for clarifying the pathological and molecular mechanisms of neurodegenerative diseases and related human diseases. This review mainly summarizes the achievements and prospects of zebrafish used as model organisms in the research of neurodegenerative diseases and other human diseases related to the nervous system in recent years. In the future study of human disease mechanisms, the application of the zebrafish model will continue to provide a valuable operating platform and technical support for investigating and finding better prevention and treatment of these diseases, which has broad application prospects and practical significance. Zebrafish models used in neurodegenerative diseases and other diseases related to the nervous system.}, }
@article {pmid37004330, year = {2023}, author = {Wei, X and Huang, G and Liu, J and Ge, J and Zhang, W and Mei, Z}, title = {An update on the role of Hippo signaling pathway in ischemia-associated central nervous system diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {162}, number = {}, pages = {114619}, doi = {10.1016/j.biopha.2023.114619}, pmid = {37004330}, issn = {1950-6007}, mesh = {Humans ; Hippo Signaling Pathway ; *Brain Ischemia/metabolism ; Blood-Brain Barrier/metabolism ; *Parkinson Disease ; *Alzheimer Disease ; Ischemia ; *Ischemic Stroke ; }, abstract = {The most frequent reason of morbidity and mortality in the world, cerebral ischemia sets off a chain of molecular and cellular pathologies that associated with some central nervous system (CNS) disorders mainly including ischemic stroke, Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy and other CNS diseases. In recent times, despite significant advancements in the treatment of the pathological processes underlying various neurological illnesses, effective therapeutic approaches that are specifically targeted to minimizing the damage of such diseases remain absent. Hippo signaling pathway, characterized by enzyme linked reactions between MSTI/2, LAST1/2, and YAP or TAZ proteins, controls cell division, survival, and differentiation, as well as being engaged in a variety of biological activities, such as the development and transformation of the nervous system. Recently, accumulating studies demonstrated that Hippo pathway takes part in the processes of ischemic stroke, AD, PD, etc., including but not limited to oxidative stress, inflammatory response, blood-brain barrier damage, mitochondrial disorders, and neural cells death. Thus, it's crucial to understand the molecular basis of the Hippo signaling pathway for determining potential new therapeutic targets against ischemia-associated CNS diseases. Here, we discuss latest advances in the deciphering of the Hippo signaling pathway and highlight the therapeutic potential of targeting the pathway in treating ischemia-associated CNS diseases.}, }
@article {pmid36998129, year = {2023}, author = {Khaafi, F and Javadi, B}, title = {Molecular Targets Underlying the Neuroprotective Effects of Boswellic Acid: A Systematic Review.}, journal = {Mini reviews in medicinal chemistry}, volume = {23}, number = {19}, pages = {1912-1925}, doi = {10.2174/1389557523666230330113611}, pmid = {36998129}, issn = {1875-5607}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Alzheimer Disease/drug therapy ; *Parkinson Disease/drug therapy ; }, abstract = {BACKGROUND: Neurodegenerative procedures include a large spectrum of disorders with diverse pathological features and clinical manifestations, such as Alzheimer's Disease (AD), Parkinson's disease (PD), Multiple sclerosis, and Amyotrophic lateral sclerosis (ALS). Neurodegenerative diseases (NDs) are indicated by progressive loss of neurons and cognitive function, which is associated with free radical formation, extra and intercellular accumulation of misfolded proteins, oxidative stress, mitochondrial and neurotrophins dysfunction, bioenergetic impairment, inflammation, and apoptotic cell death. Boswellic acid is a pentacyclic triterpene molecule of plant origin that has been applied for treating several inflammatory disorders. Numerous studies have also investigated its' therapeutic potential against multiple NDs.<br><br>OBJECTIVE: In this article, we aim to review the neuroprotective effects of boswellic acid on NDs and the related mechanisms of action.<br><br>METHODS: The databases of PubMed, Google Scholar, Web of Sciences, and Scopus were searched to find studies that reported the effects of boswellic acid on NDs without time limits. Review articles, letters, editorials, unpublished data, and articles not published in the English language were not included in the study.<br><br>RESULTS: Overall, 17 studies were included in the present study (8 NDs in general, 5 AD, 3 PD, and 1 ALS). According to the reports, boswellic acid exerts anti-inflammatory, antioxidant, antiapoptotic, and neuromodulatory effects against NDs. Boswellic acid decreases Tau phosphorylation and amyloid-&#x3b2; (A&#x3b2;) generation in AD. This substance also protects nigrostriatal dopaminergic neurons and improves motor impairments in PD and modulates neurotransmitters, decreases the demyelination region, and improves behavioral functions in ALS.<br><br>CONCLUSION: Due to the significant effects of boswellic acid in NDs, more clinical studies are necessary to evaluate the pharmacokinetics of this substance because it seems that boswellic acid can be used as a complementary or alternative treatment in patients with NDs.}, }
@article {pmid36994103, year = {2023}, author = {Walter, S and Jung, T and Herpich, C and Norman, K and Pivovarova-Ramich, O and Ott, C}, title = {Determination of the autophagic flux in murine and human peripheral blood mononuclear cells.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1122998}, pmid = {36994103}, issn = {2296-634X}, abstract = {The autophagy lysosomal system (ALS) is crucial for cellular homeostasis, contributing to maintain whole body health and alterations are associated with diseases like cancer or cardiovascular diseases. For determining the autophagic flux, inhibition of lysosomal degradation is mandatory, highly complicating autophagy measurement in vivo. To overcome this, herein blood cells were used as they are easy and routinely to isolate. Within this study we provide detailed protocols for determination of the autophagic flux in peripheral blood mononuclear cells (PBMCs) isolated from human and, to our knowledge the first time, also from murine whole blood, extensively discussing advantages and disadvantages of both methods. Isolation of PBMCs was performed using density gradient centrifugation. To minimize changes on the autophagic flux through experimental conditions, cells were directly treated with concanamycin A (ConA) for 2 h at 37°C in their serum or for murine cells in serum filled up with NaCl. ConA treatment decreased lysosomal cathepsins activity and increased Sequestosome 1 (SQSTM1) protein and LC3A/B-II:LC3A/B-I ratio in murine PBMCs, while transcription factor EB was not altered yet. Aging further enhanced ConA-associated increase in SQSTM1 protein in murine PBMCs but not in cardiomyocytes, indicating tissue-specific differences in autophagic flux. In human PBMCs, ConA treatment also decreased lysosomal activity and increased LC3A/B-II protein levels, demonstrating successful autophagic flux detection in human subjects. In summary, both protocols are suitable to determine the autophagic flux in murine and human samples and may facilitate a better mechanistic understanding of altered autophagy in aging and disease models and to further develop novel treatment strategies.}, }
@article {pmid36991279, year = {2023}, author = {Mueller, S and Decker, L and Menge, S and Ludolph, AC and Freischmidt, A}, title = {The Fragile X Protein Family in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {60}, number = {7}, pages = {3898-3910}, pmid = {36991279}, issn = {1559-1182}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Neurodegenerative Diseases/genetics ; RNA-Binding Proteins/genetics ; Motor Neurons/metabolism ; DNA Damage ; RNA-Binding Protein FUS/genetics ; Fragile X Mental Retardation Protein/genetics ; }, abstract = {The fragile X protein (FXP) family comprises the multifunctional RNA-binding proteins FMR1, FXR1, and FXR2 that play an important role in RNA metabolism and regulation of translation, but also in DNA damage and cellular stress responses, mitochondrial organization, and more. FMR1 is well known for its implication in neurodevelopmental diseases. Recent evidence suggests substantial contribution of this protein family to amyotrophic lateral sclerosis (ALS) pathogenesis. ALS is a highly heterogeneous neurodegenerative disease with multiple genetic and unclear environmental causes and very limited treatment options. The loss of motoneurons in ALS is still poorly understood, especially because pathogenic mechanisms are often restricted to patients with mutations in specific causative genes. Identification of converging disease mechanisms evident in most patients and suitable for therapeutic intervention is therefore of high importance. Recently, deregulation of the FXPs has been linked to pathogenic processes in different types of ALS. Strikingly, in many cases, available data points towards loss of expression and/or function of the FXPs early in the disease, or even at the presymptomatic state. In this review, we briefly introduce the FXPs and summarize available data about these proteins in ALS. This includes their relation to TDP-43, FUS, and ALS-related miRNAs, as well as their possible contribution to pathogenic protein aggregation and defective RNA editing. Furthermore, open questions that need to be addressed before definitively judging suitability of these proteins as novel therapeutic targets are discussed.}, }
@article {pmid36989565, year = {2023}, author = {Körner, S and Maximilian Koch, M and Hendrik Müschen, L and Seeliger, T and Schreiber-Katz, O and Gingele, S and Stangel, M and Dengler, R and Petri, S and Skripuletz, T and Osmanovic, A}, title = {Cranial nerve involvement in patients with immune-mediated neuropathy: An observational blink reflex study.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {149}, number = {}, pages = {168-175}, doi = {10.1016/j.clinph.2023.02.178}, pmid = {36989565}, issn = {1872-8952}, mesh = {Adult ; Humans ; *Blinking ; *Peripheral Nervous System Diseases ; Trigeminal Nerve ; Reflex/physiology ; }, abstract = {OBJECTIVE: This study aimed to assess cranial nerve involvement in a large adult cohort of patients with immune-mediated neuropathy undergoing immunoglobulin treatment by measuring blink reflex R1 latency prolongation in correlation with clinical findings and nerve conduction studies.<br><br>METHODS: 104 patients underwent blink reflex examination and ulnar nerve conduction studies and were assessed by the Inflammatory Neuropathy Cause and Treatment disability score, the revised Amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and focused clinical examination.<br><br>RESULTS: Prolonged R1 latencies were identified in 23 of 104 patients (22.1 %). These patients had more severe functional impairments according to the ALSFRS-R, yet only five clinically presented with bulbar dysfunction, facial- or trigeminal nerve impairment. Overall R1 latency was inversely correlated to ulnar motor conduction velocity. In preliminary follow-up assessments under continuous immunoglobulin treatment, prolonged R1 latencies partially improved.<br><br>CONCLUSIONS: Cranial nerve involvement is a common feature in immune-mediated neuropathies and is associated with a more severe disease stage. Here, R1 prolongation was detected less frequently compared to previously reported untreated cohorts.<br><br>SIGNIFICANCE: Blink reflex studies can detect subclinical cranial nerve involvement in immune-mediated neuropathies. Further studies are needed to evaluate the clinical utility of measuring R1 latency.}, }
@article {pmid36985530, year = {2023}, author = {Abramowicz, M and Osial, M and Urbańska, W and Walicki, M and Wilczewski, S and Pregowska, A and Skórczewska, K and Jenczyk, P and Warczak, M and Pisarek, M and Giersig, M}, title = {Upcycling of Acid-Leaching Solutions from Li-Ion Battery Waste Treatment through the Facile Synthesis of Magnetorheological Fluid.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {6}, pages = {}, pmid = {36985530}, issn = {1420-3049}, abstract = {The rapidly growing production and usage of lithium-ion batteries (LIBs) dramatically raises the number of harmful wastes. Consequently, the LIBs waste management processes, taking into account reliability, efficiency, and sustainability criteria, became a hot issue in the context of environmental protection as well as the scarcity of metal resources. In this paper, we propose for the first time a functional material-a magnetorheological fluid (MRF) from the LIBs-based liquid waste containing heavy metal ions. At first, the spent battery waste powder was treated with acid-leaching, where the post-treatment acid-leaching solution (ALS) contained heavy metal ions including cobalt. Then, ALS was used during wet co-precipitation to obtain cobalt-doped superparamagnetic iron oxide nanoparticles (SPIONs) and as an effect, the harmful liquid waste was purified from cobalt. The obtained nanoparticles were characterized with SEM, TEM, XPS, and magnetometry. Subsequently, superparamagnetic nanoparticles sized 15 nm average in diameter and magnetization saturation of about 91 emu g[-1] doped with Co were used to prepare the MRF that increases the viscosity by about 300% in the presence of the 100 mT magnetic fields. We propose a facile and cost-effective way to utilize harmful ALS waste and use them in the preparation of superparamagnetic particles to be used in the magnetorheological fluid. This work describes for the first time the second life of the battery waste in the MRF and a facile way to remove the harmful ingredients from the solutions obtained after the acid leaching of LIBs as an effective end-of-life option for hydrometallurgical waste utilization.}, }
@article {pmid36982324, year = {2023}, author = {Panizzutti, B and Skvarc, D and Lin, S and Croce, S and Meehan, A and Bortolasci, CC and Marx, W and Walker, AJ and Hasebe, K and Kavanagh, BE and Morris, MJ and Mohebbi, M and Turner, A and Gray, L and Berk, L and Walder, K and Berk, M and Dean, OM}, title = {Minocycline as Treatment for Psychiatric and Neurological Conditions: A Systematic Review and Meta-Analysis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {6}, pages = {}, pmid = {36982324}, issn = {1422-0067}, mesh = {Humans ; Minocycline/therapeutic use ; *Schizophrenia/drug therapy ; *Bipolar Disorder/drug therapy ; *Obsessive-Compulsive Disorder ; Anti-Inflammatory Agents/therapeutic use ; }, abstract = {Minocycline has anti-inflammatory, antioxidant, and anti-apoptotic properties that explain the renewed interest in its use as an adjunctive treatment for psychiatric and neurological conditions. Following the completion of several new clinical trials using minocycline, we proposed an up-to-date systematic review and meta-analysis of the data available. The PICO (patient/population, intervention, comparison and outcomes) framework was used to search 5 databases aiming to identify randomized controlled trials that used minocycline as an adjunctive treatment for psychiatric and neurological conditions. Search results, data extraction, and risk of bias were performed by two independent authors for each publication. Quantitative meta-analysis was performed using RevMan software. Literature search and review resulted in 32 studies being included in this review: 10 in schizophrenia, 3 studies in depression, and 7 in stroke, with the benefit of minocycline being used in some of the core symptoms evaluated; 2 in bipolar disorder and 2 in substance use, without demonstrating a benefit for using minocycline; 1 in obsessive-compulsive disorder, 2 in brain and spinal injuries, 2 in amyotrophic lateral sclerosis, 1 in Alzheimer's disease, 1 in multiple systems atrophy, and 1 in pain, with mixes results. For most of the conditions included in this review the data is still limited and difficult to interpret, warranting more well-designed and powered studies. On the other hand, the studies available for schizophrenia seem to suggest an overall benefit favoring the use of minocycline as an adjunctive treatment.}, }
@article {pmid36982140, year = {2023}, author = {Picher-Martel, V and Boutej, H and Vézina, A and Cordeau, P and Kaneb, H and Julien, JP and Genge, A and Dupré, N and Kriz, J}, title = {Distinct Plasma Immune Profile in ALS Implicates sTNFR-II in pAMPK/Leptin Homeostasis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {6}, pages = {}, pmid = {36982140}, issn = {1422-0067}, support = {2020/21//ALS Society of Canada/ ; }, mesh = {Animals ; Humans ; Male ; *Leptin ; *Amyotrophic Lateral Sclerosis ; AMP-Activated Protein Kinases ; Receptors, Tumor Necrosis Factor ; Homeostasis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a clinically highly heterogeneous disease with a survival rate ranging from months to decades. Evidence suggests that a systemic deregulation of immune response may play a role and affect disease progression. Here, we measured 62 different immune/metabolic mediators in plasma of sporadic ALS (sALS) patients. We show that, at the protein level, the majority of immune mediators including a metabolic sensor, leptin, were significantly decreased in the plasma of sALS patients and in two animal models of the disease. Next, we found that a subset of patients with rapidly progressing ALS develop a distinct plasma assess immune-metabolic molecular signature characterized by a differential increase in soluble tumor necrosis factor receptor II (sTNF-RII) and chemokine (C-C motif) ligand 16 (CCL16) and further decrease in the levels of leptin, mostly dysregulated in male patients. Consistent with in vivo findings, exposure of human adipocytes to sALS plasma and/or sTNF-RII alone, induced a significant deregulation in leptin production/homeostasis and was associated with a robust increase in AMP-activated protein kinase (AMPK) phosphorylation. Conversely, treatment with an AMPK inhibitor restored leptin production in human adipocytes. Together, this study provides evidence of a distinct plasma immune profile in sALS which affects adipocyte function and leptin signaling. Furthermore, our results suggest that targeting the sTNF-RII/AMPK/leptin pathway in adipocytes may help restore assess immune-metabolic homeostasis in ALS.}, }
@article {pmid36980310, year = {2023}, author = {Du, H and Huo, Z and Chen, Y and Zhao, Z and Meng, F and Wang, X and Liu, S and Zhang, H and Zhou, F and Liu, J and Zhang, L and Zhou, S and Guan, Y and Wang, X}, title = {Induced Pluripotent Stem Cells and Their Applications in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {6}, pages = {}, pmid = {36980310}, issn = {2073-4409}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Neurodegenerative Diseases/metabolism ; Neurons/metabolism ; Cell- and Tissue-Based Therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in the loss of motor function in the central nervous system (CNS) and ultimately death. The mechanisms underlying ALS pathogenesis have not yet been fully elucidated, and ALS cannot be treated effectively. Most studies have applied animal or single-gene intervention cell lines as ALS disease models, but they cannot accurately reflect the pathological characteristics of ALS. Induced pluripotent stem cells (iPSCs) can be reprogrammed from somatic cells, possessing the ability to self-renew and differentiate into a variety of cells. iPSCs can be obtained from ALS patients with different genotypes and phenotypes, and the genetic background of the donor cells remains unchanged during reprogramming. iPSCs can differentiate into neurons and glial cells related to ALS. Therefore, iPSCs provide an excellent method to evaluate the impact of diseases on ALS patients. Moreover, patient-derived iPSCs are obtained from their own somatic cells, avoiding ethical concerns and posing only a low risk of immune rejection. The iPSC technology creates new hope for ALS treatment. Here, we review recent studies on iPSCs and their applications in disease modeling, drug screening and cell therapy in ALS, with a particular focus on the potential for ALS treatment.}, }
@article {pmid36979267, year = {2023}, author = {Gandla, K and Babu, AK and Unnisa, A and Sharma, I and Singh, LP and Haque, MA and Dashputre, NL and Baig, S and Siddiqui, FA and Khandaker, MU and Almujally, A and Tamam, N and Sulieman, A and Khan, SL and Emran, TB}, title = {Carotenoids: Role in Neurodegenerative Diseases Remediation.}, journal = {Brain sciences}, volume = {13}, number = {3}, pages = {}, pmid = {36979267}, issn = {2076-3425}, abstract = {Numerous factors can contribute to the development of neurodegenerative disorders (NDs), such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Oxidative stress (OS), a fairly common ND symptom, can be caused by more reactive oxygen species being made. In addition, the pathological state of NDs, which includes a high number of protein aggregates, could make chronic inflammation worse by activating microglia. Carotenoids, often known as "CTs", are pigments that exist naturally and play a vital role in the prevention of several brain illnesses. CTs are organic pigments with major significance in ND prevention. More than 600 CTs have been discovered in nature, and they may be found in a wide variety of creatures. Different forms of CTs are responsible for the red, yellow, and orange pigments seen in many animals and plants. Because of their unique structure, CTs exhibit a wide range of bioactive effects, such as anti-inflammatory and antioxidant effects. The preventive effects of CTs have led researchers to find a strong correlation between CT levels in the body and the avoidance and treatment of several ailments, including NDs. To further understand the connection between OS, neuroinflammation, and NDs, a literature review has been compiled. In addition, we have focused on the anti-inflammatory and antioxidant properties of CTs for the treatment and management of NDs.}, }
@article {pmid36978829, year = {2023}, author = {Rodríguez-Periñán, G and de la Encarnación, A and Moreno, F and López de Munain, A and Martínez, A and Martín-Requero, &#xc1; and Alquézar, C and Bartolomé, F}, title = {Progranulin Deficiency Induces Mitochondrial Dysfunction in Frontotemporal Lobar Degeneration with TDP-43 Inclusions.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {3}, pages = {}, pmid = {36978829}, issn = {2076-3921}, support = {CP21/00049//Instituto de Salud Carlos III/ ; CP20/0007//Instituto de Salud Carlos III/ ; PI21/00183//Instituto de Salud Carlos III/ ; CB18/05/00040//Biomedical Research Networking Center on Neurodegenerative Diseases/ ; RTI2018-096100-B-I00//Agencia Estatal de Investigacion/ ; PID2019-105600RB-I00//Agencia Estatal de Investigaci&#xf3;n/ ; B2017/BMD-3813//Comunidad de Madrid/ ; HR21-00931//Fundaci&#xf3;n La Caixa-Fundaci&#xf3;n Luz&#xf3;n/ ; PI2/00345//Instituto de Salud Carlos III/ ; FERP-2022-5//Fundaci&#xf3;n Eugenio Rodrigez Pascual/ ; }, abstract = {Loss-of-function (LOF) mutations in GRN gene, which encodes progranulin (PGRN), cause frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). FTLD-TDP is one of the most common forms of early onset dementia, but its pathogenesis is not fully understood. Mitochondrial dysfunction has been associated with several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Here, we have investigated whether mitochondrial alterations could also contribute to the pathogenesis of PGRN deficiency-associated FTLD-TDP. Our results showed that PGRN deficiency induced mitochondrial depolarization, increased ROS production and lowered ATP levels in GRN KD SH-SY5Y neuroblastoma cells. Interestingly, lymphoblasts from FTLD-TDP patients carrying a LOF mutation in the GRN gene (c.709-1G > A) also demonstrated mitochondrial depolarization and lower ATP levels. Such mitochondrial damage increased mitochondrial fission to remove dysfunctional mitochondria by mitophagy. Interestingly, PGRN-deficient cells showed elevated mitochondrial mass together with autophagy dysfunction, implying that PGRN deficiency induced the accumulation of damaged mitochondria by blocking its degradation in the lysosomes. Importantly, the treatment with two brain-penetrant CK-1δ inhibitors (IGS-2.7 and IGS-3.27), known for preventing the phosphorylation and cytosolic accumulation of TDP-43, rescued mitochondrial function in PGRN-deficient cells. Taken together, these results suggest that mitochondrial function is impaired in FTLD-TDP associated with LOF GRN mutations and that the TDP-43 pathology linked to PGRN deficiency might be a key mechanism contributing to such mitochondrial dysfunction. Furthermore, our results point to the use of drugs targeting TDP-43 pathology as a promising therapeutic strategy for restoring mitochondrial function in FTLD-TDP and other TDP-43-related diseases.}, }
@article {pmid36973580, year = {2023}, author = {Marra, JM and de Castro Vieira, PV and de Senna Migueletto, AM and de Oliveira, LFA and de Souza, ECF and Marquini, GV}, title = {Neurogenic Disorders and the Lower Urinary Tract Dysfunction: Proposed Approach for the Gynecologist.}, journal = {Reproductive sciences (Thousand Oaks, Calif.)}, volume = {30}, number = {7}, pages = {2087-2091}, pmid = {36973580}, issn = {1933-7205}, mesh = {Humans ; *Urinary Bladder ; *Urinary Bladder, Neurogenic/diagnosis/therapy/etiology ; Quality of Life ; Activities of Daily Living ; Gynecologists ; }, abstract = {BACKGROUND: The scenario of the patient with neuropathies, which are related to urinary disorders, impacts the quality of life. Symptoms can lead to social isolation, impair activities of daily living, and shorten life expectancy. This study aims to make a practical and integrative review of current recommendations for the urogynecological approach of patients with neuropathy and urinary dysfunction.<br><br>METHODS: The authors searched for data on combinations of the terms "lower urinary tract symptoms" AND "neurogenic voiding dysfunction" from January 2012 to January 2022 in the following scientific databases: PUBMED, MEDLINE, EMBASE, and The Cochrane Library.<br><br>INCLUSION CRITERIA: randomized clinical trials, protocols from specialized societies and articles before that period, and according to clinical relevance.<br><br>EXCLUSION CRITERIA: case series or reports, expert opinions not endorsed by medical societies in the area.<br><br>RESULTS: From the 25 studies mentioned, 09 studies were selected according to pre-established criteria and qualitative analysis of relevance. The authors add 2 references for relevance in the area of &#x200b;&#x200b;urogynecology and neurological diseases. According to the selected scientific references, the main neuropathies that can cause urinary dysfunction are CNS injuries such as stroke, spinal cord injury, meningomyelocele, and amyotrophic lateral sclerosis. Ten steps below were compiled to facilitate the gynecological approach, according to the researched literature.<br><br>CONCLUSION: It is important for the medical assistant to pay close attention to careful anamnesis and post-emptying urinary residual volume. The treatment in general addresses greater fluid intake, maneuvers to favor bladder emptying, medications, and/or intermittent self-catheterization. The approach of a multidisciplinary team can make a difference in the patient's prognosis and quality of life.}, }
@article {pmid36967828, year = {2023}, author = {Gao, T and Huo, J and Xin, C and Yang, J and Liu, Q and Dong, H and Li, R and Liu, Y}, title = {Protective effects of intrathecal injection of AAV9-RabGGTB-GFP[+] in SOD1[G93A] mice.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1092607}, pmid = {36967828}, issn = {1663-4365}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that widely affects motor neurons of the CNS. About 20% of patients with ALS have familial ALS (fALS). One of the classic models of ALS are SOD1[G93A] mice. Misfolded SOD1 protein can be overexpressed in motor neurons, which results in progressive paralysis of the limbs of mice. There is still no effective treatment for ALS. In recent years, the treatment of ALS by regulating autophagy has become a research hotspot. Autophagy obstacles have been confirmed to be one of the early pathological events of ALS. Rab7 is a member of the Ras superfamily and plays a key role in the late stage of autophagy. In our previous studies, we found that prenoylation of Rab7 was inhibited in the ALS model. Prenylation is a post-translational modification in which farnesyl or geranylgeranyl groups are covalently linked to target proteins. Based on these findings, we proposed the novel idea that the regulation of RabGGTB (the β-subunit of RabGGTase) mediated prenylation modification of Rab7, and that this can be used as a prevention and treatment of ALS associated with abnormal protein accumulation.<br><br>METHODS: In the present study, RabGGTB was overexpressed in mouse spinal cord motoneurons by using adeno-associated virus as vector. Then immunofluorescence quantitative analysis was used for pathological study. The body weight, footprint analysis, the accelerating rotarod test, and neurological deficits score were used to evaluate animal behavior.<br><br>RESULTS: Our results show that the protein level of RabGGTB was significantly increased in the lumbar and thoracic regions of spinal cord motoneurons of injected mice. Furthermore, the onset time and survival time of SOD1[G93A] mice injected with AAV9-RabGGTB-GFP[+] were delayed compared with those of mice without overexpression. At the same time, we also observed a decrease in SOD1 misfolded and glial overactivation in the lumbar spinal cord of these SOD1[G93A] mice.<br><br>CONCLUSION: The findings reported here show that RabGGTB plays a significant role in the pathogenesis of SOD1[G93A] mice and with great therapeutic potential for reducing abnormal aggregation of SOD1 in ALS.}, }
@article {pmid36964253, year = {2023}, author = {Kim, J and Kim, HS and Chung, JH}, title = {Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathway.}, journal = {Experimental &amp; molecular medicine}, volume = {55}, number = {3}, pages = {510-519}, pmid = {36964253}, issn = {2092-6413}, mesh = {Humans ; *DNA, Mitochondrial/genetics/metabolism ; Immunity, Innate ; *Inflammasomes/metabolism ; Inflammation/metabolism ; Mitochondria/metabolism ; Nucleotidyltransferases/genetics ; Signal Transduction ; Membrane Proteins/metabolism ; }, abstract = {In addition to constituting the genetic material of an organism, DNA is a tracer for the recognition of foreign pathogens and a trigger of the innate immune system. cGAS functions as a sensor of double-stranded DNA fragments and initiates an immune response via the adaptor protein STING. The cGAS-STING pathway not only defends cells against various DNA-containing pathogens but also modulates many pathological processes caused by the immune response to the ectopic localization of self-DNA, such as cytosolic mitochondrial DNA (mtDNA) and extranuclear chromatin. In addition, macrophages can cause inflammation by forming a class of protein complexes called inflammasomes, and the activation of the NLRP3 inflammasome requires the release of oxidized mtDNA. In innate immunity related to inflammasomes, mtDNA release is mediated by macropores that are formed on the outer membrane of mitochondria via VDAC oligomerization. These macropores are specifically formed in response to mitochondrial stress and tissue damage, and the inhibition of VDAC oligomerization mitigates this inflammatory response. The rapidly expanding area of research on the mechanisms by which mtDNA is released and triggers inflammation has revealed new treatment strategies not only for inflammation but also, surprisingly, for neurodegenerative diseases such as amyotrophic lateral sclerosis.}, }
@article {pmid36963939, year = {2023}, author = {Casey, A and Köcher, T and Caygill, S and Champion, C and Bonnot, C and Dolan, L}, title = {Transcriptome changes in chlorsulfuron-treated plants are caused by acetolactate synthase inhibition and not induction of a herbicide detoxification system in Marchantia polymorpha.}, journal = {Pesticide biochemistry and physiology}, volume = {191}, number = {}, pages = {105370}, doi = {10.1016/j.pestbp.2023.105370}, pmid = {36963939}, issn = {1095-9939}, mesh = {*Herbicides/toxicity ; *Acetolactate Synthase/metabolism ; *Marchantia/genetics/metabolism ; Transcriptome ; Herbicide Resistance/genetics ; }, abstract = {A sensing mechanism in mammals perceives xenobiotics and induces the transcription of genes encoding proteins that detoxify these molecules. However, it is unclear if plants sense xenobiotics, and activate an analogous signalling system leading to their detoxification. Using the liverwort Marchantia polymorpha, we tested the hypothesis that there is a sensing system in plants that perceives herbicides resulting in the increased transcription of genes encoding proteins that detoxify these herbicides. Consistent with the hypothesis, we show that chlorsulfuron-treatment induces changes in the M. polymorpha transcriptome. However, these transcriptome changes do not occur in chlorsulfuron (CS)-treated target site resistant mutants, where the gene encoding the target carries a mutation that confers resistance to chlorsulfuron. Instead, we show that inactivation of the chlorsulfuron target, acetolactate synthase (ALS) (also known as acetohydroxyacid synthase (AHAS)), is required for the transcriptome response. These data demonstrate that the transcriptome changes in chlorsulfuron-treated plants are caused by disrupted amino acid synthesis and metabolism resulting from acetolactate synthase inhibition, and indicate that the transcriptome changes are not caused by a herbicide sensing mechanism.}, }
@article {pmid36959428, year = {2023}, author = {Issahaku, AR and Ibrahim, MAA and Mukelabai, N and Soliman, MES}, title = {Intermolecular And Dynamic Investigation of The Mechanism of Action of Reldesemtiv on Fast Skeletal Muscle Troponin Complex Toward the Treatment of Impaired Muscle Function.}, journal = {The protein journal}, volume = {42}, number = {4}, pages = {263-275}, pmid = {36959428}, issn = {1875-8355}, mesh = {Humans ; *Calcium/metabolism ; *Muscle, Skeletal/metabolism ; Pyrimidines/pharmacology ; Troponin C/metabolism/pharmacology ; }, abstract = {Muscle weakness as a secondary feature of attenuated neuronal input often leads to disability and sometimes death in patients with neurogenic neuromuscular diseases. These impaired muscle function has been observed in several diseases including amyotrophic lateral sclerosis, Charcot-Marie-Tooth, spinal muscular atrophy and Myasthenia gravis. This has spurred the search for small molecules which could activate fast skeletal muscle troponin complex as a means to increase muscle strength. Discovered small molecules have however been punctuated by off-target and side effects leading to the development of the second-generation small molecule, Reldesemtiv. In this study, we investigated the impact of Reldesemtiv binding to the fast skeletal troponin complex and the molecular determinants that condition the therapeutic prowess of Redesemtiv through computational techniques. It was revealed that Reldesemtiv binding possibly potentiates troponin C compacting characterized by reduced exposure to solvent molecules which could favor the slow release of calcium ions and the resultant sensitization of the subunit to calcium. These conformational changes were underscored by conventional and carbon hydrogen bonds, pi-alkyl, pi-sulfur and halogen interactions between Reldesemtiv the binding site residues. Arg113 (-3.96 kcal/mol), Met116 (-2.23 kcal/mol), Val114 (-1.28 kcal/mol) and Met121 (-0.63 kcal/mol) of the switch region of the inhibitory subunit were among the residues that contributed the most to the total free binding energy of Reldesemtiv highlighting their importance. These findings present useful insights which could lay the foundation for the development of fast skeletal muscle small molecule activators with high specificity and potency.}, }
@article {pmid36951082, year = {2023}, author = {Wang, SL and Sun, YZ and Yu, TY and Zhao, GR and Sun, Y}, title = {[Early electroacupuncture intervention delays progression of disease in mice with amyotrophic lateral sclerosis by down-regulating TLR4/NF-κB signaling].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {48}, number = {3}, pages = {287-293}, doi = {10.13702/j.1000-0607.20211379}, pmid = {36951082}, issn = {1000-0607}, mesh = {Mice ; Animals ; NF-kappa B/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology ; Toll-Like Receptor 4/genetics ; Tumor Necrosis Factor-alpha/genetics/metabolism ; Superoxide Dismutase-1/metabolism ; *Electroacupuncture ; Signal Transduction ; Spinal Cord ; }, abstract = {OBJECTIVE: To observe the effect of early electroacupuncture (EA) intervention on Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway in mice with amyotrophic lateral sclerosis (ALS), so as to explore its mechanisms underlying alleviation of ALS.<br><br>METHODS: Fifty-four ALS (ALS-SOD1[G93A]) mice with SOD1[G93A] gene mutation identified by PCR were randomly divided into model group, 60 day(d) EA group and 90 d EA group(n=18 mice in each group), and other 18 ALS-SOD1[G93A] negative mice were used as the control group. At the age of 60 and 90 days, mice of the two EA groups received EA (2 Hz, 1 mA) stimulation of bilateral "Jiaji" (EX-B2) of L1-L2 and L5-L6 for 20 min, twice a week for 4 weeks,respectively. When being 60 days old, the mice in the model and control groups were subjected to the same binding as that in the two EA groups but without EA intervention. The tail suspension test was used to judge the onset time of disease and the survival period, and rotary rod fatigue test was used to evaluate the hind limb motor function. Nissl staining method was used to observe the content of Nissl bodies in the anterior horn of the lumbar spinal cord. Immunohistochemical staining was used to observe the expression of ionized calcium binding adaptor molecule-1 (Iba-1) in the anterior horn of the lumbar spinal cord, and Western blot was used to detect the relative expression of TLR4, NF-&#x3ba;B and tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) in the lumbar spinal cord.<br><br>RESULTS: The disease onset time apparently delayed in the 60 d EA group than in the model group (P<0.01). The survival time was apparently shorter in the model group than in the control group (P<0.01), and obviously prolonged in the 60 d EA and 90 d EA groups than in the model group (P<0.01). The rotatory rod time was obviously shorter in the model group than in the control group (P<0.05), and apparently longer in the 60 d EA group than in the model group and 90 d EA group (P<0.05). Compared with the control group, the model group had a decrease in the number of Nissl bodies in the anterior horn of the lumbar spinal cord (P<0.01), and an increase in the expression levels of Iba-1, TLR4, NF-&#x3ba;B and TNF-&#x3b1; in the lumbar spinal cord (P<0.01). In contrast to the model group, both 60 d EA and 90 d EA groups had an apparent increase in the number of Nissl bodies and a marked decrease in the expression levels of Iba-1, TLR4, NF-&#x3ba;B and TNF-&#x3b1; in the lumbar spinal cord (P<0.05, P<0.01). The therapeutic effects of 60 d EA group were evidently superior to those of 90 d EA group in delaying the onset time of disease, prolonging the survival time and rotatory rod time, increasing the number of Nissl bodies, and in down-regulating the expression of Iba-1, TLR4, NF-&#x3ba;B and TNF-&#x3b1; (P<0.05, P<0.01).<br><br>CONCLUSION: The early intervention of EX-B2 EA is more effective in delaying the progression of ALS than post-onset intervention in ALS-SOD1[G93A] mice, which may be related to its functions in inhibiting the excessive activation of microglia, and down-regulating TLR4/NF-&#x3ba;B signaling.}, }
@article {pmid36950516, year = {2023}, author = {Karvandi, MS and Sheikhzadeh Hesari, F and Aref, AR and Mahdavi, M}, title = {The neuroprotective effects of targeting key factors of neuronal cell death in neurodegenerative diseases: The role of ER stress, oxidative stress, and neuroinflammation.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1105247}, pmid = {36950516}, issn = {1662-5102}, abstract = {Neuronal loss is one of the striking causes of various central nervous system (CNS) disorders, including major neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). Although these diseases have different features and clinical manifestations, they share some common mechanisms of disease pathology. Progressive regional loss of neurons in patients is responsible for motor, memory, and cognitive dysfunctions, leading to disabilities and death. Neuronal cell death in neurodegenerative diseases is linked to various pathways and conditions. Protein misfolding and aggregation, mitochondrial dysfunction, generation of reactive oxygen species (ROS), and activation of the innate immune response are the most critical hallmarks of most common neurodegenerative diseases. Thus, endoplasmic reticulum (ER) stress, oxidative stress, and neuroinflammation are the major pathological factors of neuronal cell death. Even though the exact mechanisms are not fully discovered, the notable role of mentioned factors in neuronal loss is well known. On this basis, researchers have been prompted to investigate the neuroprotective effects of targeting underlying pathways to determine a promising therapeutic approach to disease treatment. This review provides an overview of the role of ER stress, oxidative stress, and neuroinflammation in neuronal cell death, mainly discussing the neuroprotective effects of targeting pathways or molecules involved in these pathological factors.}, }
@article {pmid36949352, year = {2023}, author = {Xu, HJ and Yao, Y and Yao, F and Chen, J and Li, M and Yang, X and Li, S and Lu, F and Hu, P and He, S and Peng, G and Jing, N}, title = {Generation of functional posterior spinal motor neurons from hPSCs-derived human spinal cord neural progenitor cells.}, journal = {Cell regeneration (London, England)}, volume = {12}, number = {1}, pages = {15}, pmid = {36949352}, issn = {2045-9769}, support = {2019YFA0801402//National Key Basic Research and Development Program of China/ ; }, abstract = {Spinal motor neurons deficiency results in a series of devastating disorders such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and spinal cord injury (SCI). These disorders are currently incurable, while human pluripotent stem cells (hPSCs)-derived spinal motor neurons are promising but suffered from inappropriate regional identity and functional immaturity for the study and treatment of posterior spinal cord related injuries. In this study, we have established human spinal cord neural progenitor cells (hSCNPCs) via hPSCs differentiated neuromesodermal progenitors (NMPs) and demonstrated the hSCNPCs can be continuously expanded up to 40 passages. hSCNPCs can be rapidly differentiated into posterior spinal motor neurons with high efficiency. The functional maturity has been examined in detail. Moreover, a co-culture scheme which is compatible for both neural and muscular differentiation is developed to mimic the neuromuscular junction (NMJ) formation in vitro. Together, these studies highlight the potential avenues for generating clinically relevant spinal motor neurons and modeling neuromuscular diseases through our defined hSCNPCs.}, }
@article {pmid36944314, year = {2023}, author = {Liu, Y and Wang, S and Chen, W and Tan, Y and Dun, W and Zhang, Y and Lu, T and Hou, X and Liu, J}, title = {The Consistency between Registered Acupuncture-Moxibustion Clinical Studies and Their Published Studies and Update Status of Registered Information.}, journal = {Complementary medicine research}, volume = {30}, number = {4}, pages = {307-316}, doi = {10.1159/000530245}, pmid = {36944314}, issn = {2504-2106}, mesh = {*Moxibustion/methods ; *Acupuncture Therapy/methods ; *Acupuncture ; Publications ; }, abstract = {BACKGROUND: Few studies have analyzed the consistency between registered acupuncture-moxibustion clinical studies and their published research results as well as their update status of registered information.<br><br>METHODS: We searched for acupuncture-moxibustion clinical studies that were registered at the World Health Organization International Clinical Trials Registry Platform between 2013 and 2015 and collected data regarding their characteristics and update status. Published results of these registered studies were identified and compared with registered information.<br><br>RESULTS: A total of 425 registered acupuncture-moxibustion clinical studies were included; 379 (89.2%) of them were interventional studies, and the remaining 46 (10.8%) were observational studies. Forty-six studies (10.8%) were found to have published results, and 51 published articles were identified. Overall, 73.2% (311) of registered studies did not update the research status in time; 46.6% (198) stopped updating before recruiting; 21.6% (92) stopped updating after recruiting; and 4.9% (21) stopped updating after completion. Regarding the 46 studies with published results, 29 (63.0%) were considered to be affected by reporting bias. These reporting biases predominantly involved the omission of some predefined outcomes or endpoints (16 studies), contradictions regarding descriptions of sample sizes (9 studies), discrepancies in treatment measurements or group distribution (7 studies), and inconsistent treatment durations (4 studies). When compared with other studies, significant and various reporting biases could also be commonly found in fields other than acupuncture-moxibustion.<br><br>CONCLUSIONS: There were many discrepancies between registered information and published reports on acupuncture-moxibustion, which could also be commonly observed in other fields. Moreover, a large proportion of registered studies did not update their research status in time. Efforts should be made to improve the reporting quality and timely updates.<br><br>UNLABELLED: <title>Hintergrund</title>Es gibt nur wenige Studien, in denen die &#xdc;bereinstimmung zwischen den registrierten klinischen Studien zur Akupunktur und Moxibustion mit den ver&#xf6;ffentlichten Studienergebnissen und dem Aktualisierungsstand der Informationen im Register untersucht wurde.<title>Methoden</title>Wir suchten nach klinischen Studien zur Akupunktur und Moxibustion, die zwischen 2013 und 2015 auf der International Clinical Trials Registry Platform der Weltgesundheitsorganisation registriert wurden, und erhoben Daten zu ihren Merkmalen und ihrem Aktualisierungsstand. Die ver&#xf6;ffentlichten Ergebnisse der registrierten Studien wurden identifiziert und mit den Informationen im Register verglichen.<title>Ergebnisse</title>Insgesamt wurden 425 registrierte klinische Studien zur Akupunktur und Moxibustion eingeschlossen, davon waren 379 (89,2&#xa0;%) Interventionsstudien und die restlichen 46 (10,8&#xa0;%) waren Beobachtungsstudien. Es wurden 46 Studien (10,8&#xa0;%) mit ver&#xf6;ffentlichten Ergebnissen gefunden und 51 ver&#xf6;ffentlichte Artikel identifiziert. Insgesamt wurde bei 73,2&#xa0;% (311) der registrierten Studien der Forschungsstand nicht zeitnah aktualisiert; bei 46,6&#xa0;% (198) wurde die Aktualisierung vor der Rekrutierung eingestellt; bei 21,6&#xa0;% (92) wurde die Aktualisierung nach der Rekrutierung eingestellt und bei 4,9&#xa0;% (21) wurde die Aktualisierung nach Abschluss der Studie eingestellt. Von den 46 Studien mit ver&#xf6;ffentlichten Ergebnissen wurden 29 (63,0&#xa0;%) als von Publikationsverzerrung betroffen angesehen. Diese Publikationsverzerrung betraf vor allem die Auslassung einiger vordefinierter Zielkriterien oder Endpunkte (16&#xa0;Studien), Widerspr&#xfc;che bei der Beschreibung des Stichprobenumfangs (9&#xa0;Studien), Diskrepanzen bei den Behandlungsmessungen oder der Gruppenverteilung (7&#xa0;Studien) und Inkonsistenzen bei der Behandlungsdauer (4&#xa0;Studien). Beim Vergleich mit anderen Studien wurden auch in anderen Bereichen als Akupunktur und Moxibustion h&#xe4;ufig signifikante und unterschiedliche Publikationsverzerrungen festgestellt.<title>Schlussfolgerungen</title>Es bestanden zahlreiche Diskrepanzen zwischen den Informationen im Register und den ver&#xf6;ffentlichten Berichten &#xfc;ber Akupunktur und Moxibustion, die auch in anderen Bereichen h&#xe4;ufig zu beobachten waren. Dar&#xfc;ber hinaus wurde bei einem Gro&#xdf;teil der registrierten Studien der Forschungsstand nicht zeitnah aktualisiert. Es sollten Anstrengungen unternommen werden, um die Qualit&#xe4;t der Berichterstattung und die zeitnahe Aktualisierung zu verbessern.}, }
@article {pmid36939382, year = {2023}, author = {Koyama, M and Ueha, R and Sato, T and Goto, T and Yamauchi, A and Kaneoka, A and Suzuki, S and Nito, T and Yamasoba, T}, title = {Aspiration Prevention Surgery: Clinical Factors Associated With Improvements in Oral Status Intake and Suction Frequency.}, journal = {Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery}, volume = {168}, number = {5}, pages = {1146-1155}, doi = {10.1002/ohn.183}, pmid = {36939382}, issn = {1097-6817}, mesh = {Male ; Humans ; Aged ; Suction/adverse effects ; Retrospective Studies ; *Deglutition Disorders/etiology ; Postoperative Complications/prevention &amp; control/etiology ; Risk Factors ; }, abstract = {OBJECTIVE: In recent years, the use of aspiration prevention surgery (APS) for the treatment of severe dysphagia has been on the rise. However, relevant clinical studies have included small samples, and the frequency of, and risk factors for postoperative complications have not been clarified. We investigated the clinical features of patients undergoing APS and whether oral-intake status and suction frequency could be reduced.<br><br>STUDY DESIGN: A case series.<br><br>SETTING: Single-institution academic center.<br><br>METHODS: We retrospectively evaluated medical charts generated from 2010 to 2021. The clinical characteristics of patients undergoing APS, changes in the oral-intake status (Functional Oral Intake Scale, FOIS), suction frequency before and after surgery, risk factors for postoperative complications, and factors contributing to improvements in postoperative oral-intake status were retrieved.<br><br>RESULTS: We included the data of 100 patients (median age: 65 years, 72 men). Amyotrophic lateral sclerosis was the most common primary disease (28%), and glottis closure was the most common APS (69%). Postoperatively, 78% of patients showed improvements in the FOIS score, and suction frequency decreased in 85% of cases. Postoperative complications were observed in 10 patients (10%), wound infection in 6, and bleeding in 4; all improved. Higher preoperative FOIS scores were significantly associated with postoperative complications (p&#x2009;=&#x2009;0.02).<br><br>CONCLUSION: APS contributed to improving the FOIS score and helped reduce the suction frequency in most cases. APS can be performed safely with proper perioperative management, even in patients with poor preoperative general conditions and nutritional status.}, }
@article {pmid36930524, year = {2023}, author = {Ma, Z and Jeong, H and Yang, Y and Jiang, X and Ikeda, SI and Negishi, K and Kurihara, T and Tsubota, K}, title = {Contralateral effect in progression and recovery of lens-induced myopia in mice.}, journal = {Ophthalmic &amp; physiological optics : the journal of the British College of Ophthalmic Opticians (Optometrists)}, volume = {43}, number = {3}, pages = {558-565}, doi = {10.1111/opo.13125}, pmid = {36930524}, issn = {1475-1313}, mesh = {Animals ; Male ; Mice ; Mice, Inbred C57BL ; Eye ; *Myopia/etiology/genetics ; Refraction, Ocular ; Choroid ; *Contact Lenses ; Disease Models, Animal ; }, abstract = {PURPOSE: Apart from genetic factors, recent animal studies on myopia have focused on localised mechanisms. In this study, we aimed to examine the contralateral effects of monocular experimental myopia and recovery, which cannot be explained by a mere local mechanism.<br><br>METHODS: One eye of 3-week-old C57BL/6 male mice was fitted with a&#x2009;-30 dioptre (D) lens. The mice were distributed into two groups based on different conditions in the contralateral eye: either no lens (NLC) (n&#xa0;=&#xa0;10) or a Plano lens on the contralateral eye (PLC) group (n&#xa0;=&#xa0;6). Mice receiving no treatment on either eye were set as a control group (n&#xa0;=&#xa0;6). Lenses were removed after 3&#x2009;weeks of myopia induction. All mice were allowed to recover for 1&#xa0;week in the same environment. Refractive status, axial length (AL) and choroidal thickness were measured before myopia induction, after 1 and 3&#x2009;weeks of lens wear and after 1&#xa0;week of recovery.<br><br>RESULTS: One week after removing the lenses, complete recovery was observed in the eyes that wore the -30 D lenses. In both the PLC and NLC groups, the refractive status showed a myopic shift after lens removal. Additionally, the choroid was significantly thinned in these eyes. The -30 D wearing eye showed a significant increase in AL after 3&#x2009;weeks of lens wear. While the AL of the -30 D wearing eye ceased to grow after the lens was removed, the AL in the PLC and NLC contralateral eyes increased, and the binocular ALs gradually converged.<br><br>CONCLUSIONS: Recovery of lens-induced myopia was observed in mouse models. In the fellow eyes, the effects, including thinning of the choroid and changes in refractive status, were triggered by contralateral visual cues.}, }
@article {pmid36928619, year = {2023}, author = {Meyer, T and Schumann, P and Weydt, P and Petri, S and Koc, Y and Spittel, S and Bernsen, S and Günther, R and Weishaupt, JH and Dreger, M and Kolzarek, F and Kettemann, D and Norden, J and Boentert, M and Vidovic, M and Meisel, C and Münch, C and Maier, A and Körtvélyessy, P}, title = {Neurofilament light-chain response during therapy with antisense oligonucleotide tofersen in SOD1-related ALS: Treatment experience in clinical practice.}, journal = {Muscle &amp; nerve}, volume = {67}, number = {6}, pages = {515-521}, doi = {10.1002/mus.27818}, pmid = {36928619}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Oligonucleotides, Antisense/therapeutic use ; Superoxide Dismutase-1/genetics ; Intermediate Filaments ; Biomarkers ; Neurofilament Proteins ; }, abstract = {INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1-ALS), the antisense oligonucleotide tofersen had been investigated in a phase III study (VALOR) and subsequently introduced in an expanded access program. In this study we assess neurofilament light chain (NfL) before and during tofersen treatment.<br><br>METHODS: In six SOD1-ALS patients treated with tofersen at three specialized ALS centers in Germany, NfL in cerebrospinal fluid (CSF-NfL) and/or serum (sNfL) were investigated using the ALS Functional Rating Scale Revised (ALSFRS-R) and ALS progression rate (ALS-PR), defined by monthly decline of ALSFRS-R.<br><br>RESULTS: Three of the six SOD1-ALS patients reported a negative family history. Three patients harbored a homozygous c.272A > C, p.(Asp91Ala) mutation. These and two other patients showed slower progressing ALS (defined by ALS-PR <0.9), whereas one patient demonstrated rapidly progressing ALS (ALS-PR&#x2009;=&#x2009;2.66). Mean treatment duration was 6.5 (range 5 to 8) months. In all patients, NfL decreased (mean CSF-NfL: -66%, range -52% to -86%; mean sNfL: -62%, range -36% to -84%). sNfL after 5&#x2009;months of tofersen treatment was significantly reduced compared with the nearest pretreatment measurement (P&#x2009;=&#x2009;.017). ALS-PR decreased in two patients, whereas no changes in ALSFRS-R were observed in four participants who had very low ALS-PR or ALSFRS-R values before treatment.<br><br>DISCUSSION: In this case series, the significant NfL decline after tofersen treatment confirmed its value as response biomarker in an expanded clinical spectrum of SOD1-ALS. Given the previously reported strong correlation between sNfL and ALS progression, the NfL treatment response supports the notion of tofersen having disease-modifying activity.}, }
@article {pmid36927428, year = {2023}, author = {Rahman, MM and Tumpa, MAA and Rahaman, MS and Islam, F and Sutradhar, PR and Ahmed, M and Alghamdi, BS and Hafeez, A and Alexiou, A and Perveen, A and Ashraf, GM}, title = {Emerging Promise of Therapeutic Approaches Targeting Mitochondria in Neurodegenerative Disorders.}, journal = {Current neuropharmacology}, volume = {21}, number = {5}, pages = {1081-1099}, pmid = {36927428}, issn = {1875-6190}, mesh = {Humans ; Oxidative Stress/physiology ; *Mitochondrial Diseases/drug therapy/metabolism ; Mitochondria/metabolism ; *Neurodegenerative Diseases/drug therapy/genetics ; DNA, Mitochondrial/metabolism/therapeutic use ; }, abstract = {Mitochondria are critical for homeostasis and metabolism in all cellular eukaryotes. Brain mitochondria are the primary source of fuel that supports many brain functions, including intracellular energy supply, cellular calcium regulation, regulation of limited cellular oxidative capacity, and control of cell death. Much evidence suggests that mitochondria play a central role in neurodegenerative disorders (NDDs) such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Ongoing studies of NDDs have revealed that mitochondrial pathology is mainly found in inherited or irregular NDDs and is thought to be associated with the pathophysiological cycle of these disorders. Typical mitochondrial disturbances in NDDs include increased free radical production, decreased ATP synthesis, alterations in mitochondrial permeability, and mitochondrial DNA damage. The main objective of this review is to highlight the basic mitochondrial problems that occur in NDDs and discuss the use mitochondrial drugs, especially mitochondrial antioxidants, mitochondrial permeability transition blockade, and mitochondrial gene therapy, for the treatment and control of NDDs.}, }
@article {pmid36925418, year = {2023}, author = {Prajjwal, P and Shashank, S and Al-Ezzi, SMS and Sharma, B and Aubourg, O and Kaushish, A and Marsool, MDM and Nagre, A and Asharaf, S}, title = {Frontotemporal dementia: Addressing the scattered harbingers of genetics and its relationship with glucose metabolism, bipolar disorder, and amyotrophic lateral sclerosis.}, journal = {Disease-a-month : DM}, volume = {69}, number = {5}, pages = {101545}, doi = {10.1016/j.disamonth.2023.101545}, pmid = {36925418}, issn = {1557-8194}, mesh = {Humans ; *Pick Disease of the Brain ; *Frontotemporal Dementia/diagnosis/genetics ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Bipolar Disorder/diagnosis/genetics ; Brain/diagnostic imaging ; Glucose ; }, abstract = {Frontotemporal Dementia, also known by the name Pick's disease, is a rare form of dementia that can run for several generations. The two key characteristics are argyrophilic, spherical intraneuronal inclusions, which most frequently impact the frontal and temporal poles, and localized cortical atrophy (Pick bodies). Although personality decline and memory loss are frequently more severe than the visuospatial and apraxia disorders that are common in Alzheimer's disease, clinical overlap with other non-Alzheimer degenerative disorders is being increasingly recognized. The limbic system, which includes the hippocampus, entorhinal cortex, and amygdala, typically experiences the greatest levels of neuronal loss and degeneration. In the hippocampus's dentate fascia, several Pick bodies are frequently seen. Leukoencephalopathy and inflated cortical neurons are less specific symptoms (Pick cells). In this paper, we review the factors leading to Picks disease along with its pathophysiology, clinical manifestations, diagnosis, imaging, treatment, prognosis, and a comprehensive discussion on the same. We have also discussed the relationship of frontotemporal dementia with glucose metabolism, bipolar disorder, and amyotrophic lateral sclerosis, all of which are emerging fields of interest and need more studies.}, }
@article {pmid36921894, year = {2023}, author = {Khan, A and Frazer-Green, L and Amin, R and Wolfe, L and Faulkner, G and Casey, K and Sharma, G and Selim, B and Zielinski, D and Aboussouan, LS and McKim, D and Gay, P}, title = {Respiratory Management of Patients With Neuromuscular Weakness: An American College of Chest Physicians Clinical Practice Guideline and Expert Panel Report.}, journal = {Chest}, volume = {164}, number = {2}, pages = {394-413}, doi = {10.1016/j.chest.2023.03.011}, pmid = {36921894}, issn = {1931-3543}, mesh = {Humans ; Quality of Life ; Respiration, Artificial ; *Noninvasive Ventilation ; *Respiratory Insufficiency/etiology/therapy ; *Physicians ; }, abstract = {BACKGROUND: Respiratory failure is a significant concern in neuromuscular diseases (NMDs). This CHEST guideline examines the literature on the respiratory management of patients with NMD to provide evidence-based recommendations.<br><br>STUDY DESIGN AND METHODS: An expert panel conducted a systematic review addressing the respiratory management of NMD and applied the Grading of Recommendations, Assessment, Development, and Evaluations approach for assessing the certainty of the evidence and formulating and grading recommendations. A modified Delphi technique was used to reach a consensus on the recommendations.<br><br>RESULTS: Based on 128 studies, the panel generated 15 graded recommendations, one good practice statement, and one consensus-based statement.<br><br>INTERPRETATION: Evidence of best practices for respiratory management in NMD is limited and is based primarily on observational data in amyotrophic lateral sclerosis. The panel found that pulmonary function testing every 6&#xa0;months may be beneficial and may be used to initiate noninvasive ventilation (NIV) when clinically indicated. An individualized approach to NIV settings may benefit patients with chronic respiratory failure and sleep-disordered breathing related to NMD. When resources allow, polysomnography or overnight oximetry can help to guide the initiation of NIV. The panel provided guidelines for mouthpiece ventilation, transition to home mechanical ventilation, salivary secretion management, and airway clearance therapies. The guideline panel emphasizes that NMD pathologic characteristics represent a diverse group of disorders with differing rates of decline in lung function. The clinician's role is to add evaluation at the bedside to shared decision-making with patients and families, including respect for patient preferences and treatment goals, considerations of quality of life, and appropriate use of available resources in decision-making.}, }
@article {pmid36917918, year = {2023}, author = {Dorst, J and Weydt, P and Brenner, D and Witzel, S and Kandler, K and Huss, A and Herrmann, C and Wiesenfarth, M and Knehr, A and Günther, K and Müller, K and Weishaupt, JH and Prudlo, J and Forsberg, K and Andersen, PM and Rosenbohm, A and Schuster, J and Roselli, F and Dupuis, L and Mayer, B and Tumani, H and Kassubek, J and Ludolph, AC}, title = {Metabolic alterations precede neurofilament changes in presymptomatic ALS gene carriers.}, journal = {EBioMedicine}, volume = {90}, number = {}, pages = {104521}, pmid = {36917918}, issn = {2352-3964}, mesh = {Humans ; Male ; Adult ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Intermediate Filaments ; C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; Biomarkers ; }, abstract = {BACKGROUND: The emergence of potentially effective new therapies for genetic forms of amyotrophic lateral sclerosis (ALS) necessitates the identification of biomarkers to facilitate early treatment, prior to the onset of motor symptoms. Here, we sought to investigate whether metabolic alterations are detectable in presymptomatic ALS gene mutation carriers, and whether such alterations precede neurofilament light chain (NfL) changes in serum.<br><br>METHODS: Between 02/2014 and 11/2021, we prospectively studied 60 presymptomatic ALS gene mutation carriers (40% male, age 48.7&#xa0;&#xb1;&#xa0;14.9; 28 C9orf72, 22 SOD1, 10 other) compared to 73 individuals from the same families (47%&#xa0;male, age 47.4&#xa0;&#xb1;&#xa0;12.9) without pathogenic mutations as controls. Bioimpedance analysis (BIA) and indirect calorimetry were performed, and Body Mass Index (BMI), Fat Mass (FM), Body Fat Percentage, Body Water (BW), Lean Body Mass (LBM), Extracellular Mass (ECM), Body Cell Mass (BCM), ECM/BCM ratio, Cells Percentage, Phase Angle, Resting Metabolic Rate (RMR), Metabolic Ratio (MR), and NfL were measured. Participants and evaluators were blinded regarding gene carrier status.<br><br>FINDINGS: Presymptomatic ALS gene carriers showed reduced LBM (p&#xa0;=&#xa0;0.02), BCM (p&#xa0;=&#xa0;0.004), Cells Percentage (p&#xa0;=&#xa0;0.04), BW (p&#xa0;=&#xa0;0.02), Phase Angle (p&#xa0;=&#xa0;0.04), and increased ECM/BCM ratio (p&#xa0;=&#xa0;0.04), consistently indicating a loss of metabolically active body cells. While in C9orf72 mutation carriers all tissue masses were reduced, only metabolically active tissue was affected in SOD1 mutation carriers. Unexpectedly, RMR (p&#xa0;=&#xa0;0.009) and MR (p&#xa0;=&#xa0;0.01) were lower in presymptomatic ALS gene carriers compared to non-carriers. NfL serum levels were similar in mutation carriers and non-carriers (p&#xa0;=&#xa0;0.60).<br><br>INTERPRETATION: The observed metabolic phenomena might reflect reduced physical activity and/or preemptive, insufficient compensatory mechanisms to prepare for the later hypermetabolic state. As pre-symptomatic biomarkers we propose ECM/BCM ratio and Phase Angle for SOD1, and a 4-compartment affection in BIA for C9orf72 mutation carriers.<br><br>FUNDING: This work was an investigator-initiated trial. On the German side, there was no institutional or industrial funding. On the Swedish side, this work was supported by grants from the Swedish Brain Foundation (grants nr. 2013-0279, 2016-0303, 2018-0310, 2020-0353), the Swedish Research Council (grants nr. 2012-3167, 2017-03100), the Knut and Alice Wallenberg Foundation (grants nr. 2012.0091, 2014.0305, 2020.0232), the Ulla-Carin Lindquist Foundation, Ume&#xe5; University (223-2808-12, 223-1881-13, 2.1.12-1605-14) and the V&#xe4;sterbotten County Council (grants nr 56103-7002829), King Gustaf V:s and Queen Victoria's Freemason's Foundation.}, }
@article {pmid36913894, year = {2023}, author = {Jin, T and Zhang, Y and Botchway, BOA and Huang, M and Lu, Q and Liu, X}, title = {Quercetin activates the Sestrin2/AMPK/SIRT1 axis to improve amyotrophic lateral sclerosis.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {161}, number = {}, pages = {114515}, doi = {10.1016/j.biopha.2023.114515}, pmid = {36913894}, issn = {1950-6007}, mesh = {Humans ; AMP-Activated Protein Kinases/metabolism ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; Quercetin/pharmacology/therapeutic use ; Sirtuin 1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease with poor prognosis. The intricacies surrounding its pathophysiology could partly account for the lack of effective treatment for ALS. Sestrin2 has been reported to improve metabolic, cardiovascular and neurodegenerative diseases, and is involved in the direct and indirect activation of the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/silent information regulator 1 (SIRT1) axis. Quercetin, as a phytochemical, has considerable biological activities, such as anti-oxidation, anti-inflammation, anti-tumorigenicity, and neuroprotection. Interestingly, quercetin can activate the AMPK/SIRT1 signaling pathway to reduce endoplasmic reticulum stress, and alleviate apoptosis and inflammation. This report examines the molecular relationship between Sestrin2 and AMPK/SIRT1 axis, as well as the main biological functions and research progress of quercetin, together with the correlation between quercetin and Sestrin2/AMPK/SIRT1 axis in neurodegenerative diseases.}, }
@article {pmid36902233, year = {2023}, author = {Potes, Y and Cachán-Vega, C and Antuña, E and García-González, C and Menéndez-Coto, N and Boga, JA and Gutiérrez-Rodríguez, J and Bermúdez, M and Sierra, V and Vega-Naredo, I and Coto-Montes, A and Caballero, B}, title = {Benefits of the Neurogenic Potential of Melatonin for Treating Neurological and Neuropsychiatric Disorders.}, journal = {International journal of molecular sciences}, volume = {24}, number = {5}, pages = {}, pmid = {36902233}, issn = {1422-0067}, support = {PI21/01596//Instituto de Salud Carlos III/ ; IDI/2021/000033//Foundation for the Promotion of Applied Scientific Research and Technology in Asturias/ ; 2021-030-INTRAMURALES-POOCY//Instituto de Investigaci&#xf3;n Sanitaria del Principado de Asturias/ ; }, mesh = {*Melatonin/pharmacology ; *Neural Stem Cells ; Hippocampus ; Neurogenesis ; Neurons ; }, abstract = {There are several neurological diseases under which processes related to adult brain neurogenesis, such cell proliferation, neural differentiation and neuronal maturation, are affected. Melatonin can exert a relevant benefit for treating neurological disorders, given its well-known antioxidant and anti-inflammatory properties as well as its pro-survival effects. In addition, melatonin is able to modulate cell proliferation and neural differentiation processes in neural stem/progenitor cells while improving neuronal maturation of neural precursor cells and newly created postmitotic neurons. Thus, melatonin shows relevant pro-neurogenic properties that may have benefits for neurological conditions associated with impairments in adult brain neurogenesis. For instance, the anti-aging properties of melatonin seem to be linked to its neurogenic properties. Modulation of neurogenesis by melatonin is beneficial under conditions of stress, anxiety and depression as well as for the ischemic brain or after a brain stroke. Pro-neurogenic actions of melatonin may also be beneficial for treating dementias, after a traumatic brain injury, and under conditions of epilepsy, schizophrenia and amyotrophic lateral sclerosis. Melatonin may represent a pro-neurogenic treatment effective for retarding the progression of neuropathology associated with Down syndrome. Finally, more studies are necessary to elucidate the benefits of melatonin treatments under brain disorders related to impairments in glucose and insulin homeostasis.}, }
@article {pmid36899872, year = {2023}, author = {Vidovic, M and Müschen, LH and Brakemeier, S and Machetanz, G and Naumann, M and Castro-Gomez, S}, title = {Current State and Future Directions in the Diagnosis of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {5}, pages = {}, pmid = {36899872}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Neurodegenerative Diseases ; Delayed Diagnosis ; Motor Neurons/pathology ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all voluntary muscles and eventual respiratory failure. Non-motor symptoms, such as cognitive and behavioral changes, frequently occur over the course of the disease. Considering its poor prognosis with a median survival time of 2 to 4 years and limited causal treatment options, an early diagnosis of ALS plays an essential role. In the past, diagnosis has primarily been determined by clinical findings supported by electrophysiological and laboratory measurements. To increase diagnostic accuracy, reduce diagnostic delay, optimize stratification in clinical trials and provide quantitative monitoring of disease progression and treatment responsivity, research on disease-specific and feasible fluid biomarkers, such as neurofilaments, has been intensely pursued. Advances in imaging techniques have additionally yielded diagnostic benefits. Growing perception and greater availability of genetic testing facilitate early identification of pathogenic ALS-related gene mutations, predictive testing and access to novel therapeutic agents in clinical trials addressing disease-modified therapies before the advent of the first clinical symptoms. Lately, personalized survival prediction models have been proposed to offer a more detailed disclosure of the prognosis for the patient. In this review, the established procedures and future directions in the diagnostics of ALS are summarized to serve as a practical guideline and to improve the diagnostic pathway of this burdensome disease.}, }
@article {pmid36894028, year = {2023}, author = {Costa, I and Barbosa, DJ and Benfeito, S and Silva, V and Chavarria, D and Borges, F and Remião, F and Silva, R}, title = {Molecular mechanisms of ferroptosis and their involvement in brain diseases.}, journal = {Pharmacology &amp; therapeutics}, volume = {244}, number = {}, pages = {108373}, doi = {10.1016/j.pharmthera.2023.108373}, pmid = {36894028}, issn = {1879-016X}, mesh = {Humans ; Cell Death/physiology ; *Ferroptosis ; Reactive Oxygen Species/metabolism ; Lipid Peroxidation ; *Brain Diseases/drug therapy ; }, abstract = {Ferroptosis is a type of regulated cell death characterized by intracellular accumulation of iron and reactive oxygen species, inhibition of system Xc-, glutathione depletion, nicotinamide adenine dinucleotide phosphate oxidation and lipid peroxidation. Since its discovery and characterization in 2012, many efforts have been made to reveal the underlying mechanisms, modulating compounds, and its involvement in disease pathways. Ferroptosis inducers include erastin, sorafenib, sulfasalazine and glutamate, which, by inhibiting system Xc-, prevent the import of cysteine into the cells. RSL3, statins, Ml162 and Ml210 induce ferroptosis by inhibiting glutathione peroxidase 4 (GPX4), which is responsible for preventing the formation of lipid peroxides, and FIN56 and withaferin trigger GPX4 degradation. On the other side, ferroptosis inhibitors include ferrostatin-1, liproxstatin-1, α-tocopherol, zileuton, FSP1, CoQ10 and BH4, which interrupt the lipid peroxidation cascade. Additionally, deferoxamine, deferiprone and N-acetylcysteine, by targeting other cellular pathways, have also been classified as ferroptosis inhibitors. Increased evidence has established the involvement of ferroptosis in distinct brain diseases, including Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, multiple sclerosis, and Friedreich's ataxia. Thus, a deep understanding of how ferroptosis contributes to these diseases, and how it can be modulated, can open a new window of opportunities for novel therapeutic strategies and targets. Other studies have shown a sensitivity of cancer cells with mutated RAS to ferroptosis induction and that chemotherapeutic agents and ferroptosis inducers synergize in tumor treatment. Thus, it is tempting to consider that ferroptosis may arise as a target mechanistic pathway for the treatment of brain tumors. Therefore, this work provides an up-to-date review on the molecular and cellular mechanisms of ferroptosis and their involvement in brain diseases. In addition, information on the main ferroptosis inducers and inhibitors and their molecular targets is also provided.}, }
@article {pmid36883762, year = {2023}, author = {Marciante, AB and Mitchell, GS}, title = {Mild inflammation impairs acute intermittent hypoxia-induced phrenic long-term facilitation by a spinal adenosine-dependent mechanism.}, journal = {Journal of neurophysiology}, volume = {129}, number = {4}, pages = {799-806}, pmid = {36883762}, issn = {1522-1598}, support = {R01HL149800/HL/NHLBI NIH HHS/United States ; T32 HL134621/HL/NHLBI NIH HHS/United States ; R01 HL149800/HL/NHLBI NIH HHS/United States ; R01 HL148030/HL/NHLBI NIH HHS/United States ; T32HL134621/HL/NHLBI NIH HHS/United States ; R01HL148030/HL/NHLBI NIH HHS/United States ; }, mesh = {Rats ; Male ; Animals ; Rats, Sprague-Dawley ; *Long-Term Potentiation ; *Lipopolysaccharides/pharmacology ; Adenosine/pharmacology ; Neuroinflammatory Diseases ; Hypoxia ; Inflammation ; Phrenic Nerve/physiology ; Spinal Cord ; }, abstract = {Inflammation undermines neuroplasticity, including serotonin-dependent phrenic long-term facilitation (pLTF) following moderate acute intermittent hypoxia (mAIH: 3, 5-min episodes, arterial Po2: 40-50 mmHg; 5-min intervals). Mild inflammation elicited by a low dose of the TLR-4 receptor agonist, lipopolysaccharide (LPS; 100 µg/kg, ip), abolishes mAIH-induced pLTF by unknown mechanisms. In the central nervous system, neuroinflammation primes glia, triggering ATP release and extracellular adenosine accumulation. As spinal adenosine 2 A (A2A) receptor activation impairs mAIH-induced pLTF, we hypothesized that spinal adenosine accumulation and A2A receptor activation are necessary in the mechanism whereby LPS impairs pLTF. We report that 24 h after LPS injection in adult male Sprague Dawley rats: 1) adenosine levels increase in ventral spinal segments containing the phrenic motor nucleus (C3-C5; P = 0.010; n = 7/group) and 2) cervical spinal A2A receptor inhibition (MSX-3, 10 µM, 12 µL intrathecal) rescues mAIH-induced pLTF. In LPS vehicle-treated rats (saline, ip), MSX-3 enhanced pLTF versus controls (LPS: 110 ± 16% baseline; controls: 53 ± 6%; P = 0.002; n = 6/group). In LPS-treated rats, pLTF was abolished as expected (4 ± 6% baseline; n = 6), but intrathecal MSX-3 restored pLTF to levels equivalent to MSX-3-treated control rats (120 ± 14% baseline; P < 0.001; n = 6; vs. LPS controls with MSX-3: P = 0.539). Thus, inflammation abolishes mAIH-induced pLTF by a mechanism that requires increased spinal adenosine levels and A2A receptor activation. As repetitive mAIH is emerging as a treatment to improve breathing and nonrespiratory movements in people with spinal cord injury or ALS, A2A inhibition may offset undermining effects of neuroinflammation associated with these neuromuscular disorders.NEW &amp; NOTEWORTHY Mild inflammation undermines motor plasticity elicited by mAIH. In a model of mAIH-induced respiratory motor plasticity (phrenic long-term facilitation; pLTF), we report that inflammation induced by low-dose lipopolysaccharide undermines mAIH-induced pLTF by a mechanism requiring increased cervical spinal adenosine and adenosine 2 A receptor activation. This finding advances the understanding of mechanisms impairing neuroplasticity, potentially undermining the ability to compensate for the onset of lung/neural injury or to harness mAIH as a therapeutic modality.}, }
@article {pmid36881098, year = {2023}, author = {Lehrer, S and Rheinstein, PH}, title = {Insulin Docking Within the Open Hemichannel of Connexin 43 May Reduce Risk of Amyotrophic Lateral Sclerosis.}, journal = {In vivo (Athens, Greece)}, volume = {37}, number = {2}, pages = {539-547}, pmid = {36881098}, issn = {1791-7549}, mesh = {Humans ; Insulin ; *Amyotrophic Lateral Sclerosis/drug therapy ; Connexin 43 ; *Diabetes Mellitus, Type 2 ; Molecular Docking Simulation ; }, abstract = {BACKGROUND/AIM: Type 2 diabetes (T2D), characterized by hyperinsulinemia, protects motor neurons against amyotrophic lateral sclerosis (ALS). Type 1 diabetes and a total lack of insulin are associated with increased risk of ALS. Connexin 43 (Cx43), an astrocyte protein, operates as an open pore via which toxic substances from the astrocytes reach motor neurons.<br><br>MATERIALS AND METHODS: In the current study, we performed molecular docking of insulin with monomeric Cx31, monomeric Cx43, and hexameric Cx31 to assess whether insulin might affect the pore. Hexameric Cx31 and hexameric Cx43 are transmembrane hemichannels composed of 6 subunits; they bind together to form gap junction intercellular channels. We used the program AutoDock Vina Extended for the molecular docking study.<br><br>RESULTS: Cx31 shares amino acid and structural similarity to Cx43, and insulin docks to the same position at the N-terminal domain of monomeric Cx31 and monomeric Cx43. Insulin docks within the open hemichannel of hexameric Cx31, potentially blocking it. Molecular dynamics simulation shows that the block is highly stable and may be responsible for the protective effect of T2D on ALS.<br><br>CONCLUSION: Insulin, especially intranasal insulin, might be a treatment for ALS. An insulin secretogogue such as oral sulfonylurea or meglitinide might also be of value.}, }
@article {pmid36880940, year = {2023}, author = {Arslan, B and Zetterberg, H}, title = {Neurofilament light chain as neuronal injury marker - what is needed to facilitate implementation in clinical laboratory practice?.}, journal = {Clinical chemistry and laboratory medicine}, volume = {61}, number = {7}, pages = {1140-1149}, pmid = {36880940}, issn = {1437-4331}, mesh = {Humans ; Laboratories, Clinical ; Intermediate Filaments ; Neurofilament Proteins ; *Alzheimer Disease ; Biomarkers ; *Nervous System Diseases/diagnosis ; }, abstract = {Neurobiomarkers have attracted significant attention over the last ten years. One promising biomarker is the neurofilament light chain protein (NfL). Since the introduction of ultrasensitive assays, NfL has been developed into a widely used axonal damage marker of relevance to the diagnosis, prognostication, follow-up, and treatment monitoring of a range of neurological disorders, including multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. The marker is increasingly used clinically, as well as in clinical trials. Even if we have validated precise, sensitive, and specific assays for NfL quantification in both cerebrospinal fluid and blood, there are analytical, as well as pre- and post-analytical aspects of the total NfL testing process, including biomarker interpretation, to consider. Although the biomarker is already in use in specialised clinical laboratory settings, a more general use requires some further work. In this review, we provide brief basic information and opinions on NfL as a biomarker of axonal injury in neurological diseases and pinpoint additional work needed to facilitate biomarker implementation in clinical practice.}, }
@article {pmid36879025, year = {2023}, author = {Johnson, SA and Karas, M and Burke, KM and Straczkiewicz, M and Scheier, ZA and Clark, AP and Iwasaki, S and Lahav, A and Iyer, AS and Onnela, JP and Berry, JD}, title = {Wearable device and smartphone data quantify ALS progression and may provide novel outcome measures.}, journal = {NPJ digital medicine}, volume = {6}, number = {1}, pages = {34}, pmid = {36879025}, issn = {2398-6352}, support = {22-PDF-604//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) therapeutic development has largely relied on staff-administered functional rating scales to determine treatment efficacy. We sought to determine if mobile applications (apps) and wearable devices can be used to quantify ALS disease progression through active (surveys) and passive (sensors) data collection. Forty ambulatory adults with ALS were followed for 6-months. The Beiwe app was used to administer the self-entry ALS functional rating scale-revised (ALSFRS-RSE) and the Rasch Overall ALS Disability Scale (ROADS) surveys every 2-4 weeks. Each participant used a wrist-worn activity monitor (ActiGraph Insight Watch) or an ankle-worn activity monitor (Modus StepWatch) continuously. Wearable device wear and app survey compliance were adequate. ALSFRS-R highly correlated with ALSFRS-RSE. Several wearable data daily physical activity measures demonstrated statistically significant change over time and associations with ALSFRS-RSE and ROADS. Active and passive digital data collection hold promise for novel ALS trial outcome measure development.}, }
@article {pmid36875937, year = {2023}, author = {Donohue, C and Carnaby, G and Reilly, MC and Colquhoun, RJ and Lacomis, D and Garand, KLF}, title = {A meta-analysis of post-exercise outcomes in people with amyotrophic lateral sclerosis.}, journal = {eNeurologicalSci}, volume = {31}, number = {}, pages = {100452}, pmid = {36875937}, issn = {2405-6502}, abstract = {OBJECTIVE: To systematically evaluate post-exercise outcomes related to function and quality of life in people with ALS.<br><br>METHODS: PRISMA guidelines were used for identifying and extracting articles. Levels of evidence and quality of articles were judged based on The Oxford Centre for Evidence-based Medicine Levels of Evidence and the QualSyst. Outcomes were analyzed with Comprehensive Meta-Analysis V2 software, random effects models, and Hedge's G. Effects were examined at 0-4&#xa0;months, up to 6&#xa0;months, and&#xa0;>&#xa0;6&#xa0;months. Pre-specified sensitivity analyses were performed for 1) controlled trials vs. all studies and 2) ALSFRS-R bulbar, respiratory, and motor subscales. Heterogeneity of pooled outcomes was computed with the I[2] statistic.<br><br>RESULTS: 16 studies and seven functional outcomes met inclusion for the meta-analysis. Of the outcomes explored, the ALSFRS-R demonstrated a favorable summary effect size and had acceptable heterogeneity and dispersion. While FIM scores demonstrated a favorable summary effect size, heterogeneity limited interpretations. Other outcomes did not demonstrate a favorable summary effect size and/or could not be reported due to few studies reporting outcomes.<br><br>CONCLUSIONS: This study provides inconclusive guidance regarding exercise regimens to maintain function and quality of life in people with ALS due to study limitations (e.g., small sample size, high attrition rate, heterogeneity in methods and participants, etc.). Future research is warranted to determine optimal treatment regimens and dosage parameters in this patient population.}, }
@article {pmid36873166, year = {2023}, author = {Zhou, Y and Tang, J and Lan, J and Zhang, Y and Wang, H and Chen, Q and Kang, Y and Sun, Y and Feng, X and Wu, L and Jin, H and Chen, S and Peng, Y}, title = {Honokiol alleviated neurodegeneration by reducing oxidative stress and improving mitochondrial function in mutant SOD1 cellular and mouse models of amyotrophic lateral sclerosis.}, journal = {Acta pharmaceutica Sinica. B}, volume = {13}, number = {2}, pages = {577-597}, pmid = {36873166}, issn = {2211-3835}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both upper and lower motor neurons (MNs) with large unmet medical needs. Multiple pathological mechanisms are considered to contribute to the progression of ALS, including neuronal oxidative stress and mitochondrial dysfunction. Honokiol (HNK) has been reported to exert therapeutic effects in several neurologic disease models including ischemia stroke, Alzheimer's disease and Parkinson's disease. Here we found that honokiol also exhibited protective effects in ALS disease models both in vitro and in vivo. Honokiol improved the viability of NSC-34 motor neuron-like cells that expressed the mutant G93A SOD1 proteins (SOD1-G93A cells for short). Mechanistical studies revealed that honokiol alleviated cellular oxidative stress by enhancing glutathione (GSH) synthesis and activating the nuclear factor erythroid 2-related factor 2 (NRF2)-antioxidant response element (ARE) pathway. Also, honokiol improved both mitochondrial function and morphology via fine-tuning mitochondrial dynamics in SOD1-G93A cells. Importantly, honokiol extended the lifespan of the SOD1-G93A transgenic mice and improved the motor function. The improvement of antioxidant capacity and mitochondrial function was further confirmed in the spinal cord and gastrocnemius muscle in mice. Overall, honokiol showed promising preclinical potential as a multiple target drug for ALS treatment.}, }
@article {pmid36860617, year = {2023}, author = {Spencer, PS and Palmer, VS and Kisby, GE and Lagrange, E and Horowitz, BZ and Valdes Angues, R and Reis, J and Vernoux, JP and Raoul, C and Camu, W}, title = {Early-onset, conjugal, twin-discordant, and clusters of sporadic ALS: Pathway to discovery of etiology via lifetime exposome research.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1005096}, pmid = {36860617}, issn = {1662-4548}, abstract = {The identity and role of environmental factors in the etiology of sporadic amyotrophic lateral sclerosis (sALS) is poorly understood outside of three former high-incidence foci of Western Pacific ALS and a hotspot of sALS in the French Alps. In both instances, there is a strong association with exposure to DNA-damaging (genotoxic) chemicals years or decades prior to clinical onset of motor neuron disease. In light of this recent understanding, we discuss published geographic clusters of ALS, conjugal cases, single-affected twins, and young-onset cases in relation to their demographic, geographic and environmental associations but also whether, in theory, there was the possibility of exposure to genotoxic chemicals of natural or synthetic origin. Special opportunities to test for such exposures in sALS exist in southeast France, northwest Italy, Finland, the U.S. East North Central States, and in the U.S. Air Force and Space Force. Given the degree and timing of exposure to an environmental trigger of ALS may be related to the age at which the disease is expressed, research should focus on the lifetime exposome (from conception to clinical onset) of young sALS cases. Multidisciplinary research of this type may lead to the identification of ALS causation, mechanism, and primary prevention, as well as to early detection of impending ALS and pre-clinical treatment to slow development of this fatal neurological disease.}, }
@article {pmid36856022, year = {2023}, author = {Matthews, PJ and Ader, DR and Harrison, CK and Ostahowski, PJ and Nomura, JT}, title = {The Safety, Efficacy, and Expediency of Albuterol Nebulizer Administration by BLS Providers.}, journal = {Prehospital and disaster medicine}, volume = {38}, number = {2}, pages = {149-152}, doi = {10.1017/S1049023X23000249}, pmid = {36856022}, issn = {1945-1938}, mesh = {Humans ; United States ; *Emergency Medical Services ; *Cardiopulmonary Resuscitation ; Retrospective Studies ; Albuterol ; Nebulizers and Vaporizers ; *Respiratory Distress Syndrome ; }, abstract = {INTRODUCTION: Many Emergency Medical Service (EMS) systems in the United States restrict albuterol therapy by scope of practice to Advanced Life Support (ALS). The State of Delaware has a two-tiered EMS system in which Basic Life Support (BLS) arrives on scene prior to ALS in the majority of respiratory distress calls.<br><br>STUDY OBJECTIVE: This study sought to evaluate the safety, efficacy, and expedience of albuterol administration by BLS compared to ALS.<br><br>METHODS: This retrospective observational study used data collected from July 2015 through January 2017 throughout a State BLS albuterol pilot program. Pilot BLS agencies participated in a training session on the indications and administration of albuterol, and were then authorized to carry and administer nebulized albuterol. Heart rate (HR), respiratory rate (RR), and pulse oximetry (spO2) were obtained before and after albuterol administration by BLS and ALS. The times from BLS arrival to the administration of albuterol by pilot BLS agencies versus ALS were compared. Study encounters required both BLS and ALS response. Data were analyzed using chi-square and t-test as appropriate.<br><br>RESULTS: Three hundred eighty-eight (388) incidents were reviewed. One hundred eighty-five (185) patients received albuterol by BLS pilot agencies and 203 patients received albuterol by ALS. Of note, the population treated by ALS was significantly older than the population treated by BLS (61.9 versus 51.6 years; P <.001). A comparison of BLS arrival time to albuterol administration time showed significantly shorter times in the BLS pilot group compared to the ALS group (3.50 minutes versus 8.00 minutes, respectively; P <.001). After albuterol administration, BLS pilot patients showed improvements in HR (P <.01), RR (P <.01), and spO2 (P <.01). Alternately, ALS treatment patients showed improvement in spO2 (P <.01) but not RR (P = .17) or HR (P = 1.00). Review by ALS or hospital staff showed albuterol was indicated in 179 of 185 BLS patients and administered correctly in 100% of these patients.<br><br>CONCLUSION: Patients both received albuterol significantly sooner and showed superior improvements in vital signs when treated by BLS agencies carrying albuterol rather than by BLS agencies who required ALS arrival for albuterol. Two-tiered EMS systems should consider allowing BLS to carry and administer albuterol for safe, effective, and expedient treatment of respiratory distress patients amenable to albuterol therapy.}, }
@article {pmid36854931, year = {2023}, author = {Arslan, D and Inan, B and Kilinc, M and Bekircan-Kurt, CE and Erdem-Ozdamar, S and Tan, E}, title = {Nusinersen for adults with spinal muscular atrophy.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {7}, pages = {2393-2400}, pmid = {36854931}, issn = {1590-3478}, mesh = {Humans ; Male ; Adult ; Child ; Female ; *Muscular Atrophy, Spinal/drug therapy ; Oligonucleotides/therapeutic use ; *Spinal Muscular Atrophies of Childhood/drug therapy ; *Amyotrophic Lateral Sclerosis/drug therapy ; }, abstract = {INTRODUCTION: Nusinersen was effective in improving motor function and survival in infantile and childhood-onset spinal muscular atrophy (SMA), and the value of real-world experiences in adult SMA patients increase gradually. Here, we present our clinical experience in adult SMA patients treated with nusinersen according to CHERISH study.<br><br>MATERIAL AND METHODS: Thirty-two SMA patients treated with nusinersen were included in the study.<br><br>RESULTS: Median age at nusinersen initiation was 33.5 (20.0-60.0) years and 23 of SMA patients were male. Six (18.8%) patients had SMA type 2, and 26 (81.2%) had SMA type 3. Median follow-up period of patients under nusinersen treatment was 17 months (9-21). Twenty-three patients improved by at least 3 Hammersmith Functional Motor Scale Expanded (HFMSE) points after loading doses. There was significant HFMSE score increase in type 3 patients at each time point, whereas type 2 patients seem to benefit from nusinersen loading doses, subsequently stayed stable. Motor improvement was positively correlated with baseline HFMSE scores in patients whose baseline HFMSE scores were &#x2264;47. There was a correlation between the changes in Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) score and HFMSE scores. Ambulatory patients who could not show clinically meaningful increase in HFMSE scores improved at least 30 m by 6-min walk test (6MWT).<br><br>CONCLUSION: Overall, 78% of patients have responded to treatment according to HFMSE or 6MWT. ALSFRS-R and 6MWT may be alternative tools to monitor nusinersen effect.}, }
@article {pmid36842068, year = {2024}, author = {Dobbs, D and Yauk, J and Vogel, CE and Fanfan, D and Buck, H and Haley, WE and Meng, H}, title = {Feasibility of the Palliative Care Education in Assisted Living Intervention for Dementia Care Providers: A Cluster Randomized Trial.}, journal = {The Gerontologist}, volume = {64}, number = {1}, pages = {}, doi = {10.1093/geront/gnad018}, pmid = {36842068}, issn = {1758-5341}, support = {9AZ26//Florida Department of Health/ ; }, mesh = {Humans ; *Palliative Care ; Nursing Homes ; Pilot Projects ; Feasibility Studies ; *Dementia/therapy ; Pain ; }, abstract = {BACKGROUND AND OBJECTIVES: Alzheimer's disease and related dementia (ADRD) is a major cause of death in the United States. While effective interventions have been developed to deliver palliative care to nursing home residents with ADRD, little work has identified effective interventions to reach assisted living (AL) residents with dementia.<br><br>RESEARCH DESIGN AND METHODS: One hundred and eighteen AL residents with dementia from 10 different ALs in Florida participated. A pilot study using a cluster randomized trial was conducted, with 6 sites randomized to receive a palliative care educational intervention for staff (N = 23) to deliver care to residents; 4 sites were usual care. The feasibility of the intervention was assessed by examining recruitment, retention, and treatment fidelity at 6 months. Cohen's d statistic was used to calculate facility-level treatment effect sizes on key outcomes (documentation of advance care planning [ACP] discussions, hospice admission, and documentation of pain screening).<br><br>RESULTS: The intervention proved feasible with high ratings of treatment fidelity. The intervention also demonstrated preliminary evidence for efficacy of the intervention, with effect sizes for the treatment group over 0.80 for increases in documentation of ACP discussions compared to the control group. Hospice admissions had a smaller effect size (0.16) and documentation of pain screenings had no effect.<br><br>DISCUSSION AND IMPLICATIONS: The pilot results suggest that the intervention shows promise as a resource for educating and empowering AL staff on implementing person-centered palliative care delivery to persons with dementia in AL. A larger, fully powered randomized trial is needed to test for its efficacy.}, }
@article {pmid36840949, year = {2023}, author = {Walk, D and Nicholson, K and Locatelli, E and Chan, J and Macklin, EA and Ferment, V and Manousakis, G and Chase, M and Connolly, M and Dagostino, D and Hall, M and Ostrow, J and Pothier, L and Lieberman, C and Gelevski, D and Randall, R and Sherman, AV and Steinhart, E and Walker, DG and Walker, J and Yu, H and Wills, AM and Schwarzschild, MA and Beukenhorst, AL and Onnela, JP and Berry, JD and Cudkowicz, ME and Paganoni, S}, title = {Randomized trial of inosine for urate elevation in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {67}, number = {5}, pages = {378-386}, doi = {10.1002/mus.27807}, pmid = {36840949}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Uric Acid ; Retrospective Studies ; Inosine/therapeutic use ; Double-Blind Method ; }, abstract = {INTRODUCTION/AIMS: Higher urate levels are associated with improved ALS survival in retrospective studies, however whether raising urate levels confers a survival advantage is unknown. In the Safety of Urate Elevation in Amyotrophic Lateral Sclerosis (SURE-ALS) trial, inosine raised serum urate and was safe and well-tolerated. The SURE-ALS2 trial was designed to assess longer term safety. Functional outcomes and a smartphone application were also explored.<br><br>METHODS: Participants were randomized 2:1 to inosine (n&#xa0;=&#xa0;14) or placebo (n&#xa0;=&#xa0;9) for 20&#x2009;weeks, titrated to serum urate of 7-8&#xa0;mg/dL. Primary outcomes were safety and tolerability. Functional outcomes were measured with the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). Mobility and ALSFRS-R were also assessed by a smartphone application.<br><br>RESULTS: During inosine treatment, mean urate ranged 5.68-6.82&#x2009;mg/dL. Treatment-emergent adverse event (TEAE) incidence was similar between groups (p&#x2009;>&#x2009;.10). Renal TEAEs occurred in three (21%) and hypertension in one (7%) of participants randomized to inosine. Inosine was tolerated in 71% of participants versus placebo 67%. Two participants (14%) in the inosine group experienced TEAEs deemed related to treatment (nephrolithiasis); one was a severe adverse event. Mean ALSFRS-R decline did not differ between groups (p&#xa0;=&#xa0;.69). Change in measured home time was similar between groups. Digital and in-clinic ALSFRS-R correlated well.<br><br>DISCUSSION: Inosine met pre-specified criteria for safety and tolerability. A functional benefit was not demonstrated in this trial designed for safety and tolerability. Findings suggested potential utility for a smartphone application in ALS clinical and research settings.}, }
@article {pmid36835433, year = {2023}, author = {Vasilopoulou, C and McDaid-McCloskey, SL and McCluskey, G and Duguez, S and Morris, AP and Duddy, W}, title = {Genome-Wide Gene-Set Analysis Identifies Molecular Mechanisms Associated with ALS.}, journal = {International journal of molecular sciences}, volume = {24}, number = {4}, pages = {}, pmid = {36835433}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Genome-Wide Association Study ; Genotype ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal late-onset motor neuron disease characterized by the loss of the upper and lower motor neurons. Our understanding of the molecular basis of ALS pathology remains elusive, complicating the development of efficient treatment. Gene-set analyses of genome-wide data have offered insight into the biological processes and pathways of complex diseases and can suggest new hypotheses regarding causal mechanisms. Our aim in this study was to identify and explore biological pathways and other gene sets having genomic association to ALS. Two cohorts of genomic data from the dbGaP repository were combined: (a) the largest available ALS individual-level genotype dataset (N = 12,319), and (b) a similarly sized control cohort (N = 13,210). Following comprehensive quality control pipelines, imputation and meta-analysis, we assembled a large European descent ALS-control cohort of 9244 ALS cases and 12,795 healthy controls represented by genetic variants of 19,242 genes. Multi-marker analysis of genomic annotation (MAGMA) gene-set analysis was applied to an extensive collection of 31,454 gene sets from the molecular signatures database (MSigDB). Statistically significant associations were observed for gene sets related to immune response, apoptosis, lipid metabolism, neuron differentiation, muscle cell function, synaptic plasticity and development. We also report novel interactions between gene sets, suggestive of mechanistic overlaps. A manual meta-categorization and enrichment mapping approach is used to explore the overlap of gene membership between significant gene sets, revealing a number of shared mechanisms.}, }
@article {pmid36835277, year = {2023}, author = {El Ouaamari, Y and Van den Bos, J and Willekens, B and Cools, N and Wens, I}, title = {Neurotrophic Factors as Regenerative Therapy for Neurodegenerative Diseases: Current Status, Challenges and Future Perspectives.}, journal = {International journal of molecular sciences}, volume = {24}, number = {4}, pages = {}, pmid = {36835277}, issn = {1422-0067}, support = {DOCPRO42551//Intern funding of the University of Antwerp: DOCPRO4 BOF PhD fellowship at the University of Antwerp/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Nerve Growth Factors/metabolism ; *Parkinson Disease/metabolism ; Central Nervous System/metabolism ; *Alzheimer Disease ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), spinal cord injury (SCI), and amyotrophic lateral sclerosis (ALS), are characterized by acute or chronic progressive loss of one or several neuronal subtypes. However, despite their increasing prevalence, little progress has been made in successfully treating these diseases. Research has recently focused on neurotrophic factors (NTFs) as potential regenerative therapy for neurodegenerative diseases. Here, we discuss the current state of knowledge, challenges, and future perspectives of NTFs with a direct regenerative effect in chronic inflammatory and degenerative disorders. Various systems for delivery of NTFs, such as stem and immune cells, viral vectors, and biomaterials, have been applied to deliver exogenous NTFs to the central nervous system, with promising results. The challenges that currently need to be overcome include the amount of NTFs delivered, the invasiveness of the delivery route, the blood-brain barrier permeability, and the occurrence of side effects. Nevertheless, it is important to continue research and develop standards for clinical applications. In addition to the use of single NTFs, the complexity of chronic inflammatory and degenerative diseases may require combination therapies targeting multiple pathways or other possibilities using smaller molecules, such as NTF mimetics, for effective treatment.}, }
@article {pmid36834611, year = {2023}, author = {Pizcueta, P and Vergara, C and Emanuele, M and Vilalta, A and Rodríguez-Pascau, L and Martinell, M}, title = {Development of PPARγ Agonists for the Treatment of Neuroinflammatory and Neurodegenerative Diseases: Leriglitazone as a Promising Candidate.}, journal = {International journal of molecular sciences}, volume = {24}, number = {4}, pages = {}, pmid = {36834611}, issn = {1422-0067}, support = {SPW-EER/DRDT/DPjR/DEMO/ML/D&#xe9;f-8296//Region Wallonne/ ; }, mesh = {Humans ; *Central Nervous System Diseases/metabolism ; *Neurodegenerative Diseases/metabolism ; Neuroinflammatory Diseases ; PPAR gamma/metabolism ; }, abstract = {Increasing evidence suggests that the peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, plays an important role in physiological processes in the central nervous system (CNS) and is involved in cellular metabolism and repair. Cellular damage caused by acute brain injury and long-term neurodegenerative disorders is associated with alterations of these metabolic processes leading to mitochondrial dysfunction, oxidative stress, and neuroinflammation. PPARγ agonists have demonstrated the potential to be effective treatments for CNS diseases in preclinical models, but to date, most drugs have failed to show efficacy in clinical trials of neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. The most likely explanation for this lack of efficacy is the insufficient brain exposure of these PPARγ agonists. Leriglitazone is a novel, blood-brain barrier (BBB)-penetrant PPARγ agonist that is being developed to treat CNS diseases. Here, we review the main roles of PPARγ in physiology and pathophysiology in the CNS, describe the mechanism of action of PPARγ agonists, and discuss the evidence supporting the use of leriglitazone to treat CNS diseases.}, }
@article {pmid36831041, year = {2023}, author = {Marsili, L and Sharma, J and Outeiro, TF and Colosimo, C}, title = {Stem Cell Therapies in Movement Disorders: Lessons from Clinical Trials.}, journal = {Biomedicines}, volume = {11}, number = {2}, pages = {}, pmid = {36831041}, issn = {2227-9059}, abstract = {Stem cell-based therapies (SCT) to treat neurodegenerative disorders have promise but clinical trials have only recently begun, and results are not expected for several years. While most SCTs largely lead to a symptomatic therapeutic effect by replacing lost cell types, there may also be disease-modifying therapeutic effects. In fact, SCT may complement a multi-drug, subtype-specific therapeutic approach, consistent with the idea of precision medicine, which matches molecular therapies to biological subtypes of disease. In this narrative review, we examine published and ongoing trials in SCT in Parkinson's Disease, atypical parkinsonian disorders, Huntington's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia in humans. We discuss the benefits and pitfalls of using this treatment approach within the spectrum of disease-modification efforts in neurodegenerative diseases. SCT may hold greater promise in the treatment of neurodegenerative disorders, but much research is required to determine the feasibility, safety, and efficacy of these complementary aims of therapeutic efforts.}, }
@article {pmid36829250, year = {2023}, author = {Hosaka, T and Furuno, S and Terada, M and Hamano, Y and Komatsu, K and Okubo, K and Koyama, Y and Suzuki, T and Tsuji, H and Tamaoka, A and Mizutani, T}, title = {Tracheoarterial fistula in a patient with amyotrophic lateral sclerosis successfully managed by overinflation of the tracheostomy tube cuff alone: a case report.}, journal = {Journal of medical case reports}, volume = {17}, number = {1}, pages = {65}, pmid = {36829250}, issn = {1752-1947}, support = {21K15178//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; Adult ; Tracheostomy ; *Amyotrophic Lateral Sclerosis/complications ; *Tracheal Diseases/etiology ; *Respiratory Tract Fistula/complications/surgery ; Hemorrhage/etiology ; }, abstract = {BACKGROUND: Tracheoarterial fistula is the most devastating complication after tracheostomy, and its mortality, without definitive treatment, approaches 100%. In general, the combination of bedside emergency management, that is, overinflation of the tracheostomy tube cuff, and definitive treatment such as surgical or endovascular intervention is necessary to prevent the poor outcome. Patients with neuromuscular diseases such as amyotrophic lateral sclerosis are susceptible to tracheoarterial fistula because of long-term mechanical ventilation and muscle weakness.<br><br>CASE PRESENTATION: We describe a case of tracheoarterial fistula in a Japanese 39-year-old patient with amyotrophic lateral sclerosis with long-term ventilator management. The patient was clinically diagnosed with a tracheoarterial fistula because of massive bleeding following sentinel hemorrhage. The massive hemorrhage was controlled by overinflation of the tracheostomy tube cuff alone, without definitive treatment.<br><br>CONCLUSIONS: This case suggests overinflation of the tracheostomy tube cuff alone plays an important role, semi-permanently, in the management of tracheoarterial fistula, especially in cases where surgical or endovascular intervention is not indicated. Clinicians taking care of patients with tracheostomy undergoing long-term mechanical ventilation should be aware that tracheoarterial fistula might occur following tracheostomy.}, }
@article {pmid36824725, year = {2024}, author = {Li, A and Yi, J and Li, X and Dong, L and Ostrow, LW and Ma, J and Zhou, J}, title = {Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.02.12.528218}, pmid = {36824725}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder characterized by progressive weakness of almost all skeletal muscles, whereas extraocular muscles (EOMs) are comparatively spared. While hindlimb and diaphragm muscles of end-stage SOD1G93A (G93A) mice (a familial ALS mouse model) exhibit severe denervation and depletion of Pax7 [+] satellite cells (SCs), we found that the pool of SCs and the integrity of neuromuscular junctions (NMJs) are maintained in EOMs. In cell sorting profiles, SCs derived from hindlimb and diaphragm muscles of G93A mice exhibit denervation-related activation, whereas SCs from EOMs of G93A mice display spontaneous (non-denervation-related) activation, similar to SCs from wild-type mice. Specifically, cultured EOM SCs contain more abundant transcripts of axon guidance molecules, including Cxcl12 , along with more sustainable renewability than the diaphragm and hindlimb counterparts under differentiation pressure. In neuromuscular co-culture assays, AAV-delivery of Cxcl12 to G93A-hindlimb SC-derived myotubes enhances motor neuron axon extension and innervation, recapitulating the innervation capacity of EOM SC-derived myotubes. G93A mice fed with sodium butyrate (NaBu) supplementation exhibited less NMJ loss in hindlimb and diaphragm muscles. Additionally, SCs derived from G93A hindlimb and diaphragm muscles displayed elevated expression of Cxcl12 and improved renewability following NaBu treatment in vitro . Thus, the NaBu-induced transcriptomic changes resembling the patterns of EOM SCs may contribute to the beneficial effects observed in G93A mice. More broadly, the distinct transcriptomic profile of EOM SCs may offer novel therapeutic targets to slow progressive neuromuscular functional decay in ALS and provide possible "response biomarkers" in pre-clinical and clinical studies.}, }
@article {pmid36823441, year = {2023}, author = {Genç, B and Nho, B and Seung, H and Helmold, B and Park, H and Gözütok, &#xd6; and Kim, S and Park, J and Ye, S and Lee, H and Lee, N and Yu, SS and Kim, S and Lee, J and Özdinler, H}, title = {Novel rAAV vector mediated intrathecal HGF delivery has an impact on neuroimmune modulation in the ALS motor cortex with TDP-43 pathology.}, journal = {Gene therapy}, volume = {30}, number = {7-8}, pages = {560-574}, pmid = {36823441}, issn = {1476-5462}, support = {P30 CA060553/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Cattle ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; DNA-Binding Proteins/genetics ; Gliosis ; Hepatocyte Growth Factor/genetics ; *Motor Cortex/pathology ; }, abstract = {Recombinant adeno-associated virus (rAAV)-based gene therapies offer an immense opportunity for rare diseases, such as amyotrophic lateral sclerosis (ALS), which is defined by the loss of the upper and the lower motor neurons. Here, we describe generation, characterization, and utilization of a novel vector system, which enables expression of the active form of hepatocyte growth factor (HGF) under EF-1α promoter with bovine growth hormone (bGH) poly(A) sequence and is effective with intrathecal injections. HGF's role in promoting motor neuron survival had been vastly reported. Therefore, we investigated whether intrathecal delivery of HGF would have an impact on one of the most common pathologies of ALS: the TDP-43 pathology. Increased astrogliosis, microgliosis and progressive upper motor neuron loss are important consequences of ALS in the motor cortex with TDP-43 pathology. We find that cortex can be modulated via intrathecal injection, and that expression of HGF reduces astrogliosis, microgliosis in the motor cortex, and help restore ongoing UMN degeneration. Our findings not only introduce a novel viral vector for the treatment of ALS, but also demonstrate modulation of motor cortex by intrathecal viral delivery, and that HGF treatment is effective in reducing astrogliosis and microgliosis in the motor cortex of ALS with TDP-43 pathology.}, }
@article {pmid36817728, year = {2023}, author = {Takeuchi, T and Maeta, K and Ding, X and Oe, Y and Takeda, A and Inoue, M and Nagano, S and Fujihara, T and Matsuda, S and Ishigaki, S and Sahashi, K and Minakawa, EN and Mochizuki, H and Neya, M and Sobue, G and Nagai, Y}, title = {Sustained therapeutic benefits by transient reduction of TDP-43 using ENA-modified antisense oligonucleotides in ALS/FTD mice.}, journal = {Molecular therapy. Nucleic acids}, volume = {31}, number = {}, pages = {353-366}, pmid = {36817728}, issn = {2162-2531}, abstract = {The abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although how TDP-43 forms cytoplasmic aggregates and causes neurodegeneration in patients with ALS/FTD remains unclear, reducing cellular TDP-43 levels is likely to prevent aggregation and to rescue neurons from TDP-43 toxicity. To address this issue, here we developed gapmer-type antisense oligonucleotides (ASOs) against human TDP-43 using 2'-O,4'-C-ethylene nucleic acids (ENAs), which are modified nucleic acids with high stability, and tested the therapeutic potential of lowering TDP-43 levels using ENA-modified ASOs. We demonstrated that intracerebroventricular administration of ENA-modified ASOs into a mouse model of ALS/FTD expressing human TDP-43 results in the efficient reduction of TDP-43 levels in the brain and spinal cord. Surprisingly, a single injection of ENA-modified ASOs into TDP-43 mice led to long-lasting improvement of behavioral abnormalities and the suppression of cytoplasmic TDP-43 aggregation, even after TDP-43 levels had returned to the initial levels. Our results demonstrate that transient reduction of TDP-43 using ENA-modified ASOs leads to sustained therapeutic benefits in vivo, indicating the possibility of a disease-modifying therapy by lowering TDP-43 levels for the treatment of the TDP-43 proteinopathies, including ALS/FTD.}, }
@article {pmid36812393, year = {2023}, author = {Bongioanni, P and Borasio, GD and Oliver, DJ and Romagnoli, A and Kapitza, KP and Sidle, K and Tramonti, F}, title = {Methods for informing people with amyotrophic lateral sclerosis/motor neuron disease of their diagnosis.}, journal = {The Cochrane database of systematic reviews}, volume = {2}, number = {2}, pages = {CD007593}, pmid = {36812393}, issn = {1469-493X}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis ; *Motor Neuron Disease/psychology/therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), causes increasing physical impairment and disability. People with ALS/MND face huge physical challenges, and the diagnosis can be a source of great psychological distress for both people with ALS/MND and their carers. In such a context, how news of the diagnosis is broken is important. At present, there are no systematic reviews of methods for informing people with ALS/MND of their diagnosis.<br><br>OBJECTIVES: To examine the effects and effectiveness of different methods for informing people of a diagnosis of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), including effects on the person's knowledge and understanding of their disease, its treatment, and care; and on coping and adjustment to the effects of ALS/MND, its treatment, and care.<br><br>SEARCH METHODS: We searched the Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and two trials registers (February 2022). We contacted individuals or organisations to locate studies. We contacted study authors to obtain additional unpublished data.<br><br>SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) and quasi-RCTs of techniques for informing people with ALS/MND of their diagnosis. We planned to include adults (aged 17 years or over) with ALS/MND, according to the El Escorial criteria.<br><br>DATA COLLECTION AND ANALYSIS: Three review authors independently reviewed the results of the search to identify RCTs, and three review authors identified non-randomised studies to include in the discussion section. We planned that two review authors would independently extract data, and three would assess the risk of bias in any included trials.<br><br>MAIN RESULTS: We did not identify any RCTs that met our inclusion criteria.<br><br>AUTHORS' CONCLUSIONS: There are no RCTs that evaluate different communication strategies for breaking the bad news for people diagnosed with ALS/MND. Focused research studies are needed to assess the effectiveness and efficacy of different communication methods.}, }
@article {pmid36811812, year = {2023}, author = {Darpo, B and Geva, M and Ferber, G and Goldberg, YP and Cruz-Herranz, A and Mehra, M and Kovacs, R and Hayden, MR}, title = {Pridopidine Does Not Significantly Prolong the QTc Interval at the Clinically Relevant Therapeutic Dose.}, journal = {Neurology and therapy}, volume = {12}, number = {2}, pages = {597-617}, pmid = {36811812}, issn = {2193-8253}, abstract = {INTRODUCTION: Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in development for the treatment of Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Pridopidine's activation of S1R enhances cellular processes that are crucial for neuronal function and survival but are impaired in neurodegenerative diseases. Human brain positron emission tomography (PET) imaging studies show that at the therapeutic dose of 45 mg twice daily (bid), pridopidine selectively and robustly occupies the S1R. We conducted concentration-QTc (C-QTc) analyses to assess pridopidine's effect on the QT interval and investigated its cardiac safety profile.<br><br>METHODS: C-QTc analysis was conducted using data from PRIDE-HD, a phase 2, placebo-controlled trial evaluating four pridopidine doses (45, 67.5, 90, 112.5&#xa0;mg bid) or placebo over 52&#xa0;weeks in HD patients. Triplicate electrocardiograms (ECGs) with simultaneous plasma drug concentrations were determined in 402 patients with HD. The effect of pridopidine on the Fridericia-corrected QT interval (QTcF) was evaluated. Cardiac-related adverse events (AEs) were analyzed from PRIDE-HD alone and from pooled safety data of three double-blind, placebo-controlled trials with pridopidine in HD (HART, MermaiHD, and PRIDE-HD).<br><br>RESULTS: A concentration-dependent effect of pridopidine on the change from baseline in the Fridericia-corrected QT interval (&#x394;QTcF) was observed, with a slope of 0.012&#xa0;ms (ms) per ng/mL (90% confidence interval (CI), 0.0109-0.0127). At the therapeutic dose of 45&#xa0;mg bid, the predicted placebo-corrected &#x394;QTcF (&#x394;&#x394;QTcF) was 6.6&#xa0;ms (upper bound 90% CI, 8.0&#xa0;ms), which is below the level of concern and not clinically relevant. Analysis of pooled safety data from three HD trials demonstrates that at 45&#xa0;mg bid, pridopidine cardiac-related AE frequencies are similar to those with placebo. No patients reached a QTcF of 500&#xa0;ms and no patients experienced torsade de pointes (TdP) at any pridopidine dose.<br><br>CONCLUSIONS: At the 45&#xa0;mg bid therapeutic dose, pridopidine demonstrates a favorable cardiac safety profile, with an effect on the QTc interval that is below the level of concern and not clinically relevant.<br><br>TRIAL REGISTRATION: PRIDE-HD (TV7820-CNS-20002) trial registration: ClinicalTrials.gov identifier, NCT02006472, EudraCT 2013-001888-23; HART (ACR16C009) trial registration: ClinicalTrials.gov identifier, NCT00724048; MermaiHD (ACR16C008) trial registration: ClinicalTrials.gov identifier, NCT00665223, EudraCT No. 2007-004988-22.}, }
@article {pmid36810369, year = {2023}, author = {Guo, H and Li, X and Zhang, X and Wang, H and Li, J}, title = {Comparing the effects of highly aspherical lenslets versus defocus incorporated multiple segment spectacle lenses on myopia control.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {3048}, pmid = {36810369}, issn = {2045-2322}, mesh = {Child ; Humans ; *Eyeglasses ; Retrospective Studies ; *Myopia/therapy ; Refraction, Ocular ; Data Collection ; }, abstract = {To compare spectacle lenses with highly aspherical lenslets (HAL) versus defocus incorporated multiple segments (DIMS) on myopia progression control in 1 year. This retrospective cohort study involved data from children prescribed HAL or DIMS spectacle lenses in Guangzhou Aier Eye Hospital, China. To address the discrepancy that some children followed up at less than or more than 1 year, the standardized 1-year spherical equivalent refraction (SER) and axial length (AL) changes from baseline were calculated. The mean differences in the changes between the two groups were compared with linear multivariate regression models. Age, sex, baseline SER/AL, and treatment were included in the models. A total of 257 children who qualified for the inclusion criteria were included for the analyses (193 in the HAL group and 64 in the DIMS group). After controlling baseline variates, the adjusted mean (standard error, SE) of the standardized 1-year changes in SER for HAL and DIMS spectacle lens users were - 0.34 (0.04) D and - 0.63 (0.07) D, respectively. HAL spectacle lenses reduced myopia progression by 0.29 D (95% confidence interval [CI] 0.13 to 0.44 D) at 1 year compared to DIMS lenses. Accordingly, the adjusted mean (SE) ALs increased by 0.17 (0.02) and 0.28 (0.04) mm for children wearing HAL lenses and DIMS lenses, respectively. HAL users had 0.11 mm less AL elongation (95% CI - 0.20 to - 0.02 mm) than DIMS users. Age at baseline was significantly associated with AL elongation. Chinese children wearing spectacle lenses designed with HAL had less myopia progression and axial elongation than those wearing spectacle lenses designed with DIMS.}, }
@article {pmid36809847, year = {2023}, author = {Afroz, T and Chevalier, E and Audrain, M and Dumayne, C and Ziehm, T and Moser, R and Egesipe, AL and Mottier, L and Ratnam, M and Neumann, M and Havas, D and Ollier, R and Piorkowska, K and Chauhan, M and Silva, AB and Thapa, S and Stöhr, J and Bavdek, A and Eligert, V and Adolfsson, O and Nelson, PT and Porta, S and Lee, VM and Pfeifer, A and Kosco-Vilbois, M and Seredenina, T}, title = {Immunotherapy targeting the C-terminal domain of TDP-43 decreases neuropathology and confers neuroprotection in mouse models of ALS/FTD.}, journal = {Neurobiology of disease}, volume = {179}, number = {}, pages = {106050}, doi = {10.1016/j.nbd.2023.106050}, pmid = {36809847}, issn = {1095-953X}, support = {P01 AG019724/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; *Alzheimer Disease/genetics ; Neuroprotection ; DNA-Binding Proteins/metabolism ; *Pick Disease of the Brain ; Immunotherapy ; }, abstract = {Effective therapies are urgently needed to safely target TDP-43 pathology as it is closely associated with the onset and development of devastating diseases such as frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). In addition, TDP-43 pathology is present as a co-pathology in other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Our approach is to develop a TDP-43-specific immunotherapy that exploits Fc gamma-mediated removal mechanisms to limit neuronal damage while maintaining physiological TDP-43 function. Thus, using both in vitro mechanistic studies in conjunction with the rNLS8 and CamKIIa inoculation mouse models of TDP-43 proteinopathy, we identified the key targeting domain in TDP-43 to accomplish these therapeutic objectives. Targeting the C-terminal domain of TDP-43 but not the RNA recognition motifs (RRM) reduces TDP-43 pathology and avoids neuronal loss in vivo. We demonstrate that this rescue is dependent on Fc receptor-mediated immune complex uptake by microglia. Furthermore, monoclonal antibody (mAb) treatment enhances phagocytic capacity of ALS patient-derived microglia, providing a mechanism to restore the compromised phagocytic function in ALS and FTD patients. Importantly, these beneficial effects are achieved while preserving physiological TDP-43 activity. Our findings demonstrate that a mAb targeting the C-terminal domain of TDP-43 limits pathology and neurotoxicity, enabling clearance of misfolded TDP-43 through microglia engagement, and supporting the clinical strategy to target TDP-43 by immunotherapy. SIGNIFICANCE STATEMENT: TDP-43 pathology is associated with various devastating neurodegenerative disorders with high unmet medical needs such as frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Thus, safely and effectively targeting pathological TDP-43 represents a key paradigm for biotechnical research as currently there is little in clinical development. After years of research, we have determined that targeting the C-terminal domain of TDP-43 rescues multiple patho-mechanisms involved in disease progression in two animal models of FTD/ALS. In parallel, importantly, our studies establish that this approach does not alter the physiological functions of this ubiquitously expressed and indispensable protein. Together, our findings substantially contribute to the understanding of TDP-43 pathobiology and support the prioritization for clinical testing of immunotherapy approaches targeting TDP-43.}, }
@article {pmid36805843, year = {2023}, author = {Rajanala, K and Wedegaertner, PB}, title = {Gβγ signaling regulates microtubule-dependent control of Golgi integrity.}, journal = {Cellular signalling}, volume = {106}, number = {}, pages = {110630}, pmid = {36805843}, issn = {1873-3913}, support = {R01 GM132426/GM/NIGMS NIH HHS/United States ; R01 GM138943/GM/NIGMS NIH HHS/United States ; }, mesh = {Nocodazole/pharmacology ; Pertussis Toxin ; *GTP-Binding Protein beta Subunits/metabolism ; *GTP-Binding Protein gamma Subunits/metabolism ; Microtubules/metabolism ; }, abstract = {Gβγ subunits regulate several non-canonical functions at distinct intracellular organelles. Previous studies have shown that Gβγ signaling at the Golgi is necessary to mediate vesicular protein transport function and to regulate mitotic Golgi fragmentation. Disruption of Golgi structure also occurs in response to microtubule depolymerizing agents, such as nocodazole. In this study, we use siRNA against Gβ1/2 or specific Gγ subunits to deplete their expression, and show that their knockdown causes a significant reduction in nocodazole-induced Golgi fragmentation. We establish that knockdown of Gβγ or inhibition of Gβγ with gallein resulted in decreased activation of protein kinase D (PKD) in response to nocodazole treatment. We demonstrate that restricting the amount of free Gβγ available for signaling by either inhibiting Gαi activation using pertussis toxin or by knockdown of the non-GPCR GEF, Girdin/GIV protein, results in a substantial decrease in nocodazole-induced Golgi fragmentation and PKD phosphorylation. Our results also indicate that depletion of Gβγ or inhibition with gallein or pertussis toxin significantly reduces the microtubule disruption-dependent Golgi fragmentation phenotype observed in cells transfected with mutant SOD1, a major causative protein in familial amyotrophic lateral sclerosis (ALS). These results provide compelling evidence that Gβγ signaling is critical for the regulation of Golgi integrity.}, }
@article {pmid36805548, year = {2023}, author = {Liu, M and Yao, X and Huang, X and Shang, H and Fan, D and He, J and Cui, L and , }, title = {A multicenter, randomized, double blind, placebo-controlled clinical trial of DL-3-n-butylphthalide in treatment of amyotrophic lateral sclerosis.}, journal = {Chinese medical journal}, volume = {136}, number = {3}, pages = {354-356}, pmid = {36805548}, issn = {2542-5641}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Benzofurans/therapeutic use ; Double-Blind Method ; Treatment Outcome ; }, }
@article {pmid36805435, year = {2023}, author = {Plowman, EK and Gray, LT and Chapin, J and Anderson, A and Vasilopoulos, T and Gooch, C and Vu, T and Wymer, JP}, title = {Respiratory Strength Training in Amyotrophic Lateral Sclerosis: A Double-Blind, Randomized, Multicenter, Sham-Controlled Trial.}, journal = {Neurology}, volume = {100}, number = {15}, pages = {e1634-e1642}, pmid = {36805435}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Cough/therapy ; *Resistance Training ; Respiration ; Lung ; }, abstract = {BACKGROUND AND OBJECTIVE: The objective of this study was to evaluate the short-term physiologic effect and one-year functional effect of a 12-week inspiratory and expiratory respiratory strength training (RST) program in individuals with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: A double-blinded, randomized, sham-controlled trial was conducted in 45 individuals with early-stage ALS. Participants were randomized into 12 weeks of active RST (30% load, n = 23) or sham RST (0% load, n = 22). An intent-to-treat analysis was conducted. Linear regression of pre-post change with group status and pretest scores as predictors was conducted. Primary outcomes included maximum expiratory and inspiratory pressure (MEP, MIP), and secondary outcomes were cough spirometry and forced vital capacity. Exploratory follow-up outcomes included one-year global and bulbar decline (ALS Functional Rating Scale-Revised [ALSFRS-R] total and bulbar subscale slope), oral intake status, and time to noninvasive ventilation (NIV).<br><br>RESULTS: TheRST completion rate was 91% with no RST-related adverse events. A 12-week RST program led to increases in MEP (p = 0.004), but not MIP (p = 0.33). On average, MEP increased by 20.8 cm H2O after active RST (95% CI +7.6 to +33.9) and decreased by 1.0 cm H2O (95% CI -9.1 to +7.2) after sham RST. Mean MIP increased by 8.9 cm H2O (95% CI +1.5 to +16.3) and 4.8 cm H2O (95% CI -0.6 to +10.2) for the active and sham groups, respectively. Regarding secondary outcomes, RST led to significant increases in cough peak inspiratory flow (p = 0.02); however, it did not affect cough expiratory flow (p = 0.06) or FVC (p = 0.60). Regarding 12-month outcomes, a significant difference in the ALSFRS-R bulbar subscale slope was observed across treatment groups, with a more than two-fold faster rate of bulbar decline in the sham vs active RST groups observed (-0.29 vs -0.12 points/month, p = 0.02). Total ALSFRS-R slope, feeding status, and time to NIV did not differ across treatment groups (p > 0.05).<br><br>DISCUSSION: RST was well tolerated and led to improvements in some, but not all, short and long-term outcomes. RST represents a proactive rehabilitative intervention that could increase physiologic capacity of specific breathing and airway clearance functions during the early stages of ALS. Further work is needed to determine optimal training intensity, resistance load specifications, and potential long-term functional outcomes.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that a mild-intensity respiratory strength training program improves maximum expiratory pressure, but not maximum inspiratory pressure, in patients with early-stage ALS.}, }
@article {pmid36804827, year = {2023}, author = {Rotter, G and Binting, S and Teut, M and Ortiz, M and Willich, SN and Brinkhaus, B}, title = {Characteristics of Patients Presenting at a University Outpatient Department for Complementary and Integrative Medicine.}, journal = {Complementary medicine research}, volume = {30}, number = {4}, pages = {279-288}, doi = {10.1159/000529798}, pmid = {36804827}, issn = {2504-2106}, mesh = {Humans ; Female ; Adult ; Middle Aged ; Aged ; Male ; Outpatients ; *Integrative Medicine/methods ; Etorphine ; Universities ; *Musculoskeletal Diseases/therapy ; }, abstract = {BACKGROUND: Complementary and integrative medicine (CIM) is increasingly provided at university outpatient departments (OPDs) in Germany, but its scientific evaluation is sparse. Therefore, we aimed to investigate and evaluate feasibility, patients' characteristics and complaints at a university's CIM-OPD.<br><br>METHODS: A prospective evaluation included new patients without age restriction. At baseline, and after 6 and 12 months, patients filled out paper questionnaires. Patients rated their mean subjectively perceived severity of the main complaint within the last 7 days on a numerical rating scale (NRS) from 0 = no complaints to 10 = maximum complaints, their perceived resilience capacity in everyday life within the last 7 days (0 = not resilient to 10 = very resilient), and their contentment with the treatment (0 = not content to 10 = very content). Diagnoses were provided by physicians and coded according to the International Statistical Classification of Diseases and Related Health Problems, 10th revision. All data were analyzed descriptively.<br><br>RESULTS: During two years, 536 new patients {72.6% response, age (mean &#xb1; standard deviation [SD] and range) 49.6 &#xb1; 15.8 and 1-86 years, 75.7% female} chose to participate. The most frequent diagnosis groups were neoplasms (C00-C97, n = 143, 18.6%) and musculoskeletal diseases (M00-M99, n = 137, 17.9%). In n = 165 patients (30.8%), more than one diagnosis was provided. In a subgroup of 187 patients, who returned the questionnaire after 6 months, we compared baseline to 6-month values: severity of main complaint (mean &#xb1; SD) 5.2 &#xb1; 2.6 changed to 3.9 &#xb1; 2.6; resilience capacity 5.1 &#xb1; 2.6 to 5.6 &#xb1; 2.4. After 6 months, respondents rated their contentment with the treatment with (mean &#xb1; SD) 7.7 &#xb1; 2.6. Data after 12 months (n = 113) are comparable to data after 6 months.<br><br>CONCLUSION: Patients of our CIM-OPD had a broad age range, were predominantly female, and suffered mostly from oncologic-related complaints and musculoskeletal diseases. In the responding subgroup after 6 months, patients were content with the treatment. These results should be verified by further prospective evaluations.<br><br>UNLABELLED: <title>Hintergrund</title>Komplement&#xe4;re und integrative Medizin (CIM) wird in Deutschland zunehmend in Hochschulambulanzen (OPDs) angeboten, deren wissenschaftliche Evaluation ist jedoch unzureichend. Deshalb war es unser Ziel, die Durchf&#xfc;hrbarkeit einer Evaluation, die Charakteristika und die Beschwerden der Patienten und Patientinnen an einer CIM-ODP zu untersuchen.<title>Methoden</title>Eine prospektive Evaluation schloss neue Patienten und Patientinnen ohne Altersbeschr&#xe4;nkung ein. Zu Baseline sowie nach sechs und 12 Monaten f&#xfc;llten die Patienten und Patientinnen Papierfrageb&#xf6;gen aus. Die Patienten und Patientinnen bewerteten ihre mittlere subjektiv empfundene Schwere der Hauptbeschwerden in den letzten sieben Tagen auf einer numerischen Ratingskala (NRS) von 0 = keine Beschwerden bis 10 = maximale Beschwerden, ihre mittlere subjektiv empfundene Belastbarkeit im Alltag in den letzten sieben Tagen (0 = nicht belastbar bis 10 = sehr belastbar) und ihre Zufriedenheit mit der Behandlung (0 = nicht zufrieden bis 10 = sehr zufrieden). Die Diagnosen wurden von den &#xc4;rzten und &#xc4;rztinnen gestellt und nach der International Statistical Classification of Diseases and Related Health Problems, 10. Revision, kodiert. Die Daten wurden deskriptiv ausgewertet.<title>Ergebnisse</title>Im Laufe von zwei Jahren nahmen 536 neue Patienten und Patientinnen (72.6% R&#xfc;cklauf, Alter (Mittelwert &#xb1; SD und Range) 49.6 &#xb1; 15.8 und 1&#x2013;86 Jahre, 75.7% weiblich) teil. Die h&#xe4;ufigsten Diagnosen waren Neoplasmen (C00-C97, <italic>n</italic> = 143, 18.6%) und Erkrankungen des Bewegungsapparates (M00-M99, <italic>n</italic> = 137, 17.9%). Bei <italic>n</italic> = 165 (30.8%) Patienten und Patientinnen wurde mehr als eine Diagnose vergeben. In einer Subgruppe von 187 Patienten und Patientinnen, die den Fragebogen nach 6 Monaten zur&#xfc;cksendeten, verglichen wir die Ausgangs-und 6-Monats-Werte: Schweregrad der Hauptbeschwerden (Mittelwert&#xb1;SD) 5.2 &#xb1; 2.6 ver&#xe4;nderte sich zu 3.9 &#xb1; 2.6; Belastbarkeit 5.1 &#xb1; 2.6 zu 5.6 &#xb1; 2.4. Nach sechs Monaten bewerteten die Befragten ihre Zufriedenheit mit der Behandlung mit (Mittelwert&#xb1;SD) 7.7 &#xb1; 2.6. Die Daten nach 12 Monaten (<italic>n</italic> = 113) sind mit den Daten nach 6 Monaten vergleichbar.<title>Schlussfolgerung</title>Die Patienten und Patientinnen unserer CIM-OPD hatten eine breite Altersspanne, &#xfc;berwiegend weiblich und litten zumeist unter onkologisch bedingten Beschwerden und Erkrankungen des Bewegungsapparates. Patienten und Patientinnen der nach sechs Monaten antwortenden Subgruppe waren mit der Behandlung zufrieden. Die Ergebnisse sollten durch weitere prospektive Evaluationen verifiziert werden.}, }
@article {pmid36800114, year = {2023}, author = {de Oliveira, LMG and Carreira, RB and de Oliveira, JVR and do Nascimento, RP and Dos Santos Souza, C and Trias, E and da Silva, VDA and Costa, SL}, title = {Impact of Plant-Derived Compounds on Amyotrophic Lateral Sclerosis.}, journal = {Neurotoxicity research}, volume = {41}, number = {3}, pages = {288-309}, pmid = {36800114}, issn = {1476-3524}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; Riluzole ; Edaravone/therapeutic use ; Glutamic Acid ; Phytochemicals/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal illness characterized by progressive motor neuron degeneration. Conventional therapies for ALS are based on treatment of symptoms, and the disease remains incurable. Molecular mechanisms are unclear, but studies have been pointing to involvement of glia, neuroinflammation, oxidative stress, and glutamate excitotoxicity as a key factor. Nowadays, we have few treatments for this disease that only delays death, but also does not stop the neurodegenerative process. These treatments are based on glutamate blockage (riluzole), tyrosine kinase inhibition (masitinib), and antioxidant activity (edaravone). In the past few years, plant-derived compounds have been studied for neurodegenerative disorder therapies based on neuroprotection and glial cell response. In this review, we describe mechanisms of action of natural compounds associated with neuroprotective effects, and the possibilities for new therapeutic strategies in ALS.}, }
@article {pmid36795184, year = {2023}, author = {Sharma, VK and Singh, TG and Mehta, V and Mannan, A}, title = {Biomarkers: Role and Scope in Neurological Disorders.}, journal = {Neurochemical research}, volume = {48}, number = {7}, pages = {2029-2058}, pmid = {36795184}, issn = {1573-6903}, mesh = {Humans ; *Nervous System Diseases/diagnosis ; Biomarkers ; Brain ; }, abstract = {Neurological disorders pose a great threat to social health and are a major cause for mortality and morbidity. Effective drug development complemented with the improved drug therapy has made considerable progress towards easing symptoms associated with neurological illnesses, yet poor diagnosis and imprecise understanding of these disorders has led to imperfect treatment options. The scenario is complicated by the inability to extrapolate results of cell culture studies and transgenic models to clinical applications which has stagnated the process of improving drug therapy. In this context, the development of biomarkers has been viewed as beneficial to easing various pathological complications. A biomarker is measured and evaluated in order to gauge the physiological process or a pathological progression of a disease and such a marker can also indicate the clinical or pharmacological response to a therapeutic intervention. The development and identification of biomarkers for neurological disorders involves several issues including the complexity of the brain, unresolved discrepant data from experimental and clinical studies, poor clinical diagnostics, lack of functional endpoints, and high cost and complexity of techniques yet research in the area of biomarkers is highly desired. The present work describes existing biomarkers for various neurological disorders, provides support for the idea that biomarker development may ease our understanding underlying pathophysiology of these disorders and help to design and explore therapeutic targets for effective intervention.}, }
@article {pmid36788871, year = {2023}, author = {Neupane, P and Thada, PK and Singh, P and Faisal, AR and Rai, N and Poudel, P and Waleed, MS and Quinonez, J and Ruxmohan, S and Jain, E}, title = {Investigating Edaravone Use for Management of Amyotrophic Lateral Sclerosis (ALS): A Narrative Review.}, journal = {Cureus}, volume = {15}, number = {1}, pages = {e33746}, pmid = {36788871}, issn = {2168-8184}, abstract = {The use of Edaravone, given orally, for the treatment of amyotrophic lateral sclerosis (ALS) was officially approved by the Federal Drug Association (FDA) in 2017. ALS is a rare and progressive degenerative disease that worsens over time. It attacks and destroys the nerve cells that control voluntary muscles, thus leading to weakness, eventual paralysis, and, ultimately death. Edaravone was given initially intravenously, but recent evidence shows better results with oral suspension. This narrative review is aimed to investigate the benefit of Edaravone for the management of ALS, compare it to Riluzole, discuss its mechanism of action, route of use, and side effects, and ultimately discuss future implications of this pharmacotherapy.}, }
@article {pmid36788520, year = {2023}, author = {Gotkine, M and Caraco, Y and Lerner, Y and Blotnick, S and Wanounou, M and Slutsky, SG and Chebath, J and Kuperstein, G and Estrin, E and Ben-Hur, T and Hasson, A and Molakandov, K and Sonnenfeld, T and Stark, Y and Revel, A and Revel, M and Izrael, M}, title = {Safety and efficacy of first-in-man intrathecal injection of human astrocytes (AstroRx®) in ALS patients: phase I/IIa clinical trial results.}, journal = {Journal of translational medicine}, volume = {21}, number = {1}, pages = {122}, pmid = {36788520}, issn = {1479-5876}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Astrocytes ; Injections, Spinal ; *Mesenchymal Stem Cell Transplantation/methods ; }, abstract = {BACKGROUND: Malfunction of astrocytes is implicated as one of the pathological factors of ALS. Thus, intrathecal injection of healthy astrocytes in ALS can potentially compensate for the diseased astrocytes. AstroRx® is an allogeneic cell-based product, composed of healthy and functional human astrocytes derived from embryonic stem cells. AstroRx® was shown to clear excessive glutamate, reduce oxidative stress, secrete various neuroprotective factors, and act as an immunomodulator. Intrathecal injection of AstroRx® to animal models of ALS slowed disease progression and extended survival. Here we report the result of a first-in-human clinical study evaluating intrathecal injection of AstroRx® in ALS patients.<br><br>METHODS: We conducted a phase I/IIa, open-label, dose-escalating clinical trial to evaluate the safety, tolerability, and therapeutic effects of intrathecal injection of AstroRx&#xae; in patients with ALS. Five patients were injected intrathecally with a single dose of 100&#x2009;&#xd7;&#x2009;10[6] AstroRx&#xae; cells and 5 patients with 250&#x2009;&#xd7;&#x2009;10[6] cells (low and high dose, respectively). Safety and efficacy assessments were recorded for 3&#xa0;months pre-treatment (run-in period) and 12&#xa0;months post-treatment (follow-up period).<br><br>RESULTS: A single administration of AstroRx&#xae; at either low or high doses was safe and well tolerated. No adverse events (AEs) related to AstroRx&#xae; itself were reported. Transient AEs related to the Intrathecal (IT) procedure were all mild to moderate. The study demonstrated a clinically meaningful effect that was maintained over the first 3&#xa0;months after treatment, as measured by the pre-post slope change in ALSFRS-R. In the 100&#x2009;&#xd7;&#x2009;10[6] AstroRx&#xae; arm, the ALSFRS-R rate of deterioration was attenuated from -&#xa0;0.88/month pre-treatment to -&#xa0;0.30/month in the first 3&#xa0;months post-treatment (p&#x2009;=&#x2009;0.039). In the 250&#x2009;&#xd7;&#x2009;10[6] AstroRx&#xae; arm, the ALSFRS-R slope decreased from -&#xa0;1.43/month to -&#xa0;0.78/month (p&#x2009;=&#x2009;0.0023). The effect was even more profound in a rapid progressor subgroup of 5 patients. No statistically significant change was measured in muscle strength using hand-held dynamometry and slow vital capacity continued to deteriorate during the study.<br><br>CONCLUSIONS: Overall, these findings suggest that a single IT administration of AstroRx&#xae; to ALS patients at a dose of 100&#x2009;&#xd7;&#x2009;10[6] or 250&#x2009;&#xd7;&#x2009;10[6] cells is safe. A signal of beneficial clinical effect was observed for the first 3&#xa0;months following cell injection. These results support further investigation of repeated intrathecal administrations of AstroRx&#xae;, e.g., every 3&#xa0;months.<br><br>TRIAL REGISTRATION: NCT03482050.}, }
@article {pmid36788405, year = {2023}, author = {Khalid, MU and Masroor, T}, title = {The promise of stem cells in amyotrophic lateral sclerosis: a review of clinical trials.}, journal = {JPMA. The Journal of the Pakistan Medical Association}, volume = {73(Suppl 1)}, number = {2}, pages = {S138-S142}, doi = {10.47391/JPMA.AKUS-22}, pmid = {36788405}, issn = {0030-9982}, mesh = {Humans ; Child ; *Amyotrophic Lateral Sclerosis/drug therapy ; Quality of Life ; Stem Cells ; Treatment Outcome ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative condition with high cost of care, poor treatment outcomes, and a significant decrease in quality of life, eventually culminating in high mortality rates. Stem cells present an attractive alternative to conventional therapies as they can regenerate tissue and introduce growth factors to slow down the progression of disease. We conducted a comprehensive review of literature available in the MEDLINE (PUBMED), Scopus, and Cochrane Library databases, of current usage of stem cells and stem cell-based biomaterials for ALS treatment. Clinical trials, less than 10 years old, on human subjects were included in the study. Overall, stem cells, whether mesenchymal, non-lineage, or neural stem cells all seem safe for use in therapy for ALS. However, due to the chronic nature of the disease the efficacy of the treatment is not proven and warrants further investigation.}, }
@article {pmid36776068, year = {2023}, author = {Hui, BSM and Zhi, LR and Retinasamy, T and Arulsamy, A and Law, CSW and Shaikh, MF and Yeong, KY}, title = {The Role of Interferon-α in Neurodegenerative Diseases: A Systematic Review.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {94}, number = {s1}, pages = {S45-S66}, pmid = {36776068}, issn = {1875-8908}, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; Interferon-alpha/therapeutic use ; Cytokines ; Databases, Factual ; }, abstract = {BACKGROUND: Neurodegenerative diseases (NDs) impose significant financial and healthcare burden on populations all over the world. The prevalence and incidence of NDs have been observed to increase dramatically with age. Hence, the number of reported cases is projected to increase in the future, as life spans continues to rise. Despite this, there is limited effective treatment against most NDs. Interferons (IFNs), a family of cytokines, have been suggested as a promising therapeutic target for NDs, particularly IFN-α, which governs various pathological pathways in different NDs.<br><br>OBJECTIVE: This systematic review aimed to critically appraise the currently available literature on the pathological role of IFN-&#x3b1; in neurodegeneration/NDs.<br><br>METHODS: Three databases, Scopus, PubMed, and Ovid Medline, were utilized for the literature search.<br><br>RESULTS: A total of 77 journal articles were selected for critical evaluation, based on the inclusion and exclusion criteria. The studies selected and elucidated in this current systematic review have showed that IFN-&#x3b1; may play a deleterious role in neurodegenerative diseases through its strong association with the inflammatory processes resulting in mainly neurocognitive impairments. IFN-&#x3b1; may be displaying its neurotoxic function via various mechanisms such as abnormal calcium mineralization, activation of STAT1-dependent mechanisms, and increased quinolinic acid production.<br><br>CONCLUSION: The exact role IFN-&#x3b1; in these neurodegenerative diseases have yet to be determine due to a lack in more recent evidence, thereby creating a variability in the role of IFN-&#x3b1;. Future investigations should thus be conducted, so that the role played by IFN-&#x3b1; in neurodegenerative diseases could be delineated.}, }
@article {pmid36774721, year = {2023}, author = {Ketabforoush, AHME and Chegini, R and Barati, S and Tahmasebi, F and Moghisseh, B and Joghataei, MT and Faghihi, F and Azedi, F}, title = {Masitinib: The promising actor in the next season of the Amyotrophic Lateral Sclerosis treatment series.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {160}, number = {}, pages = {114378}, doi = {10.1016/j.biopha.2023.114378}, pmid = {36774721}, issn = {1950-6007}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neurodegenerative Diseases ; Quality of Life ; Seasons ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with high mortality and morbidity rate affecting both upper and lower motor neurons (MN). Muscle force reduction, behavioral change, pseudobulbar affect, and cognitive impairments are the most common clinical manifestations of ALS. The main physiopathology of ALS is still unclear, though several studies have identified that oxidative stress, proteinopathies, glutamate-related excitotoxicity, microglial activation, and neuroinflammation may be involved in the pathogenesis of ALS. From 1995 until October 2022, only Riluzole, Dextromethorphan Hydrobromide (DH) with Quinidine sulfate (Q), Edaravone, and Sodium phenylbutyrate with Taurursodiol (PB/TUDCO) have achieved FDA approval for ALS treatment. Despite the use of these four approved agents, the survival rate and quality of life of ALS patients are still low. Thus, finding novel treatments for ALS patients is an urgent requirement. Masitinib, a tyrosine kinase inhibitor, emphasizes the neuro-inflammatory activity of ALS by targeting macrophages, mast cells, and microglia cells. Masitinib downregulates the proinflammatory cytokines, indirectly reduces inflammation, and induces neuroprotection. Also, it was effective in phase 2/3 and 3 clinical trials (CTs) by increasing overall survival and delaying motor, bulbar, and respiratory function deterioration. This review describes the pathophysiology of ALS, focusing on Masitinib's mechanism of action and explaining why Masitinib could be a promising actor in the treatment of ALS patients. In addition, Masitinib CTs and other competitor drugs in phase 3 CTs have been discussed.}, }
@article {pmid36773012, year = {2023}, author = {Corcia, P and Lunetta, C and Vourc'h, P and Pradat, PF and Blasco, H}, title = {Time for optimism in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {30}, number = {5}, pages = {1459-1464}, doi = {10.1111/ene.15738}, pmid = {36773012}, issn = {1468-1331}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; *Motor Neuron Disease ; Biomarkers ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is among the most common motor neuron diseases in adults. Nevertheless, ALS remains fatal, despite decades of research and clinical trials, which has led to negative conclusions until recently in regard to four specific treatments. It is well known that we can learn from failures, and we consider that the time has come to present positive insight on this disease.<br><br>METHODS: We did a literature search using PubMed and Scopus for articles published in English from 1 January 2016, to 30 June 2022 dealing with "amyotrophic lateral sclerosis", diagnosis, treatment, and biomarkers.<br><br>RESULTS: A comprehensive review of the literature on diagnosis, monitoring, and treatment of this condition showed convincing evidence that we are now able to diagnose earlier as well as to better monitor and treat ALS.<br><br>CONCLUSIONS: Although ALS is often difficult to diagnose and remains incurable, there are many indications that an optimistic view of ALS management in the coming years is now realistic.}, }
@article {pmid36762798, year = {2023}, author = {Martinez-Gonzalez, L and Martinez, A}, title = {Emerging clinical investigational drugs for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert opinion on investigational drugs}, volume = {32}, number = {2}, pages = {141-160}, doi = {10.1080/13543784.2023.2178416}, pmid = {36762798}, issn = {1744-7658}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Drugs, Investigational/pharmacology/therapeutic use ; Drug Discovery ; Motor Neurons ; Treatment Outcome ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by motoneuron death with a median survival time of 3-5 years since disease onset. There are no effective treatments to date. However, a variety of innovative investigational drugs and biological-based therapies are under clinical development.<br><br>AREAS COVERED: This review provides an overview of the clinical investigational small molecules as well as a brief summary of the biological-based therapies that are currently undergoing clinical trials for the treatment of ALS. All the data were obtained from ClinicalTrials.gov (registered through November 1).<br><br>EXPERT OPINION: Drug discovery for ALS is an active and evolving field, where many investigational clinical drugs are in different trials. There are several mechanisms of action supporting all these new therapies, although proteostasis is gaining stage. Probably, small orally bioavailable molecules able to recover functional TDP-43 homeostasis may have solid chances to modify ALS progression.}, }
@article {pmid36759259, year = {2023}, author = {Ge, YJ and Ou, YN and Deng, YT and Wu, BS and Yang, L and Zhang, YR and Chen, SD and Huang, YY and Dong, Q and Tan, L and Yu, JT and , }, title = {Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood.}, journal = {Biological psychiatry}, volume = {93}, number = {9}, pages = {770-779}, doi = {10.1016/j.biopsych.2022.11.002}, pmid = {36759259}, issn = {1873-2402}, support = {MC_UU_00005/12/MRC_/Medical Research Council/United Kingdom ; MR/M008983/1/MRC_/Medical Research Council/United Kingdom ; MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; MC_UU_00030/14/MRC_/Medical Research Council/United Kingdom ; R01 MH120794/MH/NIMH NIH HHS/United States ; MR/T046015/1/MRC_/Medical Research Council/United Kingdom ; R01 AG062268/AG/NIA NIH HHS/United States ; MC_U105597119/MRC_/Medical Research Council/United Kingdom ; MR/L023784/2/MRC_/Medical Research Council/United Kingdom ; MR/T033371/1/MRC_/Medical Research Council/United Kingdom ; U01 AG079850/AG/NIA NIH HHS/United States ; MR/M023664/1/MRC_/Medical Research Council/United Kingdom ; G0301152/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/genetics/metabolism ; *Alzheimer Disease/drug therapy/genetics/metabolism ; *Parkinson Disease/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Genome-Wide Association Study ; Proteomics ; Brain/metabolism ; *Multiple Sclerosis/metabolism ; Sodium-Phosphate Cotransporter Proteins, Type III/genetics/metabolism ; Membrane Glycoproteins/metabolism ; 17-Hydroxysteroid Dehydrogenases/metabolism ; }, abstract = {BACKGROUND: Neurodegenerative diseases are among the most prevalent and devastating neurological disorders, with few effective prevention and treatment strategies. We aimed to integrate genetic and proteomic data to prioritize drug targets for neurodegenerative diseases.<br><br>METHODS: We screened human proteomes through Mendelian randomization to identify causal mediators of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, and Lewy body dementia. For instruments, we used brain and blood protein quantitative trait loci identified from one genome-wide association study with 376 participants and another with 3301 participants, respectively. Causal associations were subsequently validated by sensitivity analyses and colocalization. The safety and druggability of identified targets were also evaluated.<br><br>RESULTS: Our analyses showed targeting BIN1, GRN, and RET levels in blood as well as ACE, ICA1L, MAP1S, SLC20A2, and TOM1L2 levels in brain might reduce Alzheimer's disease risk, while ICA1L, SLC20A2, and TOM1L2 were not recommended as prioritized drugs due to the identified potential side effects. Brain CD38, DGKQ, GPNMB, and SEC23IP were candidate targets for Parkinson's disease. Among them, GPNMB was the most promising target for Parkinson's disease with their causal relationship evidenced by studies on both brain and blood tissues. Interventions targeting FCRL3, LMAN2, and MAPK3 in blood and DHRS11, FAM120B, SHMT1, and TSFM in brain might affect multiple sclerosis risk. The risk of amyotrophic lateral sclerosis might be reduced by medications targeting DHRS11, PSMB3, SARM1, and SCFD1 in brain.<br><br>CONCLUSIONS: Our study prioritized 22 proteins as targets for neurodegenerative diseases and provided preliminary evidence for drug development. Further studies are warranted to validate these targets.}, }
@article {pmid36751779, year = {2023}, author = {Imbimbo, BP and Triaca, V and Imbimbo, C and Nisticò, R}, title = {Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations: lessons from recent clinical trials.}, journal = {Neural regeneration research}, volume = {18}, number = {8}, pages = {1679-1683}, pmid = {36751779}, issn = {1673-5374}, abstract = {We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors. Specifically, we discussed randomized clinical trials in subjects with Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations, and glucocerebrosidase-associated Parkinson's disease. Learning potential lessons to improve future therapeutic approaches is the aim of this review. Two long-term, controlled trials on three anti-β-amyloid monoclonal antibodies (solanezumab, gantenerumab and crenezumab) in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits. A major trial on tominersen, an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease, was prematurely interrupted because the drug failed to show higher efficacy than placebo and, at highest doses, led to worsened outcomes. A 28-week trial of tofersen, an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy. A trial of venglustat, a potent and brain-penetrant glucosylceramide synthase inhibitor, in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo. We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies, antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.}, }
@article {pmid36751500, year = {2022}, author = {Romano, R and De Luca, M and Del Fiore, VS and Pecoraro, M and Lattante, S and Sabatelli, M and La Bella, V and Bucci, C}, title = {Allele-specific silencing as therapy for familial amyotrophic lateral sclerosis caused by the p.G376D TARDBP mutation.}, journal = {Brain communications}, volume = {4}, number = {6}, pages = {fcac315}, pmid = {36751500}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons. There is no treatment for this disease that affects the ability to move, eat, speak and finally breathe, causing death. In an Italian family, a heterozygous pathogenic missense variant has been previously discovered in Exon 6 of the gene TARDBP encoding the TAR DNA-binding protein 43 protein. Here, we developed a potential therapeutic tool based on allele-specific small interfering RNAs for familial amyotrophic lateral sclerosis with the heterozygous missense mutation c.1127G>A. We designed a small interfering RNA that was able to diminish specifically the expression of the exogenous Green Fluorescent Protein (TAR DNA-binding protein 43[G376D] mutant protein) in HEK-293T cells but not that of the Green Fluorescent Protein (TAR DNA-binding protein 43 wild-type). Similarly, this small interfering RNA silenced the mutated allele in fibroblasts derived from patients with amyotrophic lateral sclerosis but did not silence the wild-type gene in control fibroblasts. In addition, we established that silencing the mutated allele was able to strongly reduce the pathological cellular phenotypes induced by TAR DNA-binding protein 43[G376D] expression, such as the presence of cytoplasmic aggregates. Thus, we have identified a small interfering RNA that could be used to silence specifically the mutated allele to try a targeted therapy for patients carrying the p.G376D TAR DNA-binding protein 43 mutation.}, }
@article {pmid36747854, year = {2023}, author = {Pain, O and Jones, A and Al Khleifat, A and Agarwal, D and Hramyka, D and Karoui, H and Kubica, J and Llewellyn, DJ and Ranson, JM and Yao, Z and Iacoangeli, A and Al-Chalabi, A}, title = {Harnessing Transcriptomic Signals for Amyotrophic Lateral Sclerosis to Identify Novel Drugs and Enhance Risk Prediction.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {36747854}, support = {/WT_/Wellcome Trust/United Kingdom ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; RF1 AG055654/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. This study integrates the latest ALS genome-wide association study (GWAS) summary statistics with functional genomic annotations with the aim of providing mechanistic insights into ALS risk loci, inferring drug repurposing opportunities, and enhancing prediction of ALS risk and clinical characteristics.<br><br>METHODS: Genes associated with ALS were identified using GWAS summary statistic methodology including SuSiE SNP-based fine-mapping, and transcriptome- and proteome-wide association study (TWAS/PWAS) analyses. Using several approaches, gene associations were integrated with the DrugTargetor drug-gene interaction database to identify drugs that could be repurposed for the treatment of ALS. Furthermore, ALS gene associations from TWAS were combined with observed blood expression in two external ALS case-control datasets to calculate polytranscriptomic scores and evaluate their utility for prediction of ALS risk and clinical characteristics, including site of onset, age at onset, and survival.<br><br>RESULTS: SNP-based fine-mapping, TWAS and PWAS identified 117 genes associated with ALS, with TWAS and PWAS providing novel mechanistic insights. Drug repurposing analyses identified five drugs significantly enriched for interactions with ALS associated genes, with directional analyses highlighting &#x3b1;-glucosidase inhibitors may exacerbate ALS pathology. Additionally, drug class enrichment analysis showed calcium channel blockers may reduce ALS risk. Across the two observed expression target samples, ALS polytranscriptomic scores significantly predicted ALS risk (R[2] = 4%; p-value = 2.1&#xd7;10[-21]).<br><br>CONCLUSIONS: Functionally-informed analyses of ALS GWAS summary statistics identified novel mechanistic insights into ALS aetiology, highlighted several therapeutic research avenues, and enabled statistically significant prediction of ALS risk.}, }
@article {pmid36741054, year = {2022}, author = {Lee, AJB and Kittel, TE and Kim, RB and Bach, TN and Zhang, T and Mitchell, CS}, title = {Comparing therapeutic modulators of the SOD1 G93A Amyotrophic Lateral Sclerosis mouse pathophysiology.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1111763}, pmid = {36741054}, issn = {1662-4548}, support = {K01 NS069616/NS/NINDS NIH HHS/United States ; R21 NS081426/NS/NINDS NIH HHS/United States ; T32 EB025816/EB/NIBIB NIH HHS/United States ; U19 AG065169/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a paralyzing, multifactorial neurodegenerative disease with limited therapeutics and no known cure. The study goal was to determine which pathophysiological treatment targets appear most beneficial.<br><br>METHODS: A big data approach was used to analyze high copy SOD1 G93A experimental data. The secondary data set comprised 227 published studies and 4,296 data points. Treatments were classified by pathophysiological target: apoptosis, axonal transport, cellular chemistry, energetics, neuron excitability, inflammation, oxidative stress, proteomics, or systemic function. Outcome assessment modalities included onset delay, health status (rotarod performance, body weight, grip strength), and survival duration. Pairwise statistical analysis (two-tailed t-test with Bonferroni correction) of normalized fold change (treatment/control) assessed significant differences in treatment efficacy. Cohen's d quantified pathophysiological treatment category effect size compared to "all" (e.g., all pathophysiological treatment categories combined).<br><br>RESULTS: Inflammation treatments were best at delaying onset (d = 0.42, p > 0.05). Oxidative stress treatments were significantly better for prolonging survival duration (d = 0.18, p < 0.05). Excitability treatments were significantly better for prolonging overall health status (d = 0.22, p < 0.05). However, the absolute best pathophysiological treatment category for prolonging health status varied with disease progression: oxidative stress was best for pre-onset health (d = 0.18, p > 0.05); excitability was best for prolonging function near onset (d = 0.34, p < 0.05); inflammation was best for prolonging post-onset function (d = 0.24, p > 0.05); and apoptosis was best for prolonging end-stage function (d = 0.49, p > 0.05). Finally, combination treatments simultaneously targeting multiple pathophysiological categories (e.g., polytherapy) performed significantly (p < 0.05) better than monotherapies at end-stage.<br><br>DISCUSSION: In summary, the most effective pathophysiological treatments change as function of assessment modality and disease progression. Shifting pathophysiological treatment category efficacy with disease progression supports the homeostatic instability theory of ALS disease progression.}, }
@article {pmid36737245, year = {2023}, author = {Willemse, SW and Harley, P and van Eijk, RPA and Demaegd, KC and Zelina, P and Pasterkamp, RJ and van Damme, P and Ingre, C and van Rheenen, W and Veldink, JH and Kiernan, MC and Al-Chalabi, A and van den Berg, LH and Fratta, P and van Es, MA}, title = {UNC13A in amyotrophic lateral sclerosis: from genetic association to therapeutic target.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {94}, number = {8}, pages = {649-656}, pmid = {36737245}, issn = {1468-330X}, support = {MR/M008606/1/MRC_/Medical Research Council/United Kingdom ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/W005190/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/complications ; *Frontotemporal Dementia/pathology ; *Neurodegenerative Diseases/complications ; Nerve Tissue Proteins/genetics ; Polymorphism, Genetic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although genomewide association studies (GWAS) have advanced our understanding of the disease, the precise manner in which risk polymorphisms contribute to disease pathogenesis remains unclear. Of relevance, GWAS have shown that a polymorphism (rs12608932) in the UNC13A gene is associated with risk for both ALS and frontotemporal dementia (FTD). Homozygosity for the C-allele at rs12608932 modifies the ALS phenotype, as these patients are more likely to have bulbar-onset disease, cognitive impairment and FTD at baseline as well as shorter survival. UNC13A is expressed in neuronal tissue and is involved in maintaining synaptic active zones, by enabling the priming and docking of synaptic vesicles. In the absence of functional TDP-43, risk variants in UNC13A lead to the inclusion of a cryptic exon in UNC13A messenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion of UNC13A leads to impaired neurotransmission. Recent discoveries have identified UNC13A as a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate in UNC13A cases now underway and future approaches with antisense oligonucleotides currently under consideration. Considering UNC13A is a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery of UNC13A as a risk gene in ALS to the current therapeutic options being explored and how knowledge of its distinct phenotype needs to be taken into account in future trials.}, }
@article {pmid36728125, year = {2023}, author = {Clements, TW and Van Gent, JM and Hatton, GE and Estrada, M and Agarwal, AK and Cotton, BA}, title = {Is the use of nonsteroidal anti-inflammatories after bowel anastomosis in trauma safe?.}, journal = {The journal of trauma and acute care surgery}, volume = {94}, number = {5}, pages = {678-683}, doi = {10.1097/TA.0000000000003872}, pmid = {36728125}, issn = {2163-0763}, mesh = {Humans ; *Anti-Inflammatory Agents, Non-Steroidal/adverse effects ; Anastomosis, Surgical ; Anastomotic Leak/epidemiology/etiology ; Intestines ; *Digestive System Surgical Procedures/adverse effects ; Retrospective Studies ; }, abstract = {BACKGROUND: With an increasing interest in multimodal and opioid-reducing pain strategies, nonsteroidal anti-inflammatory drugs (NSAIDs) have become common place in the care of injured patients. Long-standing concerns of increased anastomotic leak (AL) rate with the use of NSAIDs, however, have persisted. We hypothesized that there would be no significant risk associated with NSAID use after bowel anastomosis in trauma patients.<br><br>METHODS: All patients presenting to a level 1 trauma center who required intestinal resection and anastomosis from 2011 to 2017 were reviewed. Patients receiving NSAIDs were compared with those managed without NSAIDs. Primary outcome of interest was anastomosis-related complications (AL, intra-abdominal abscess, anastomotic bleed, fascial dehiscence, fascial dehiscence, and enterocutaneous fistula). Multivariable logistic regression analyses were performed with propensity adjustment for inverse probability of NSAID treatment weights.<br><br>RESULTS: A total of 295 patients met the inclusion criteria with 192 receiving NSAIDs. Patients receiving NSAIDs had lower abdominal Abbreviated Injury Scale and Injury Severity Score (p < 0.046). Arrival systolic blood pressure, diastolic blood pressure, and Glasgow Coma Scale were higher in the NSAID group (p < 0.013). After propensity weighting, NSAID use was not a major predictor of anastomotic complication (p = 0.39). There was an increased risk of AL with perioperative vasopressor exposure (odds ratio [OR], 3.33; 95% confidence interval [CI], 1.17-9.05; p < 0.001). Increasing red blood cell transfusions in the first 24 hours were associated with intra-abdominal complications (OR, 1.02; 95% CI, 1.00-1.04; p = 0.05). Nonsteroidal anti-inflammatory drug exposure demonstrated a weak association with AL (OR, 1.92; 95% CI, 0.97-3.90; p = 0.06).<br><br>CONCLUSION: Consistent with previous studies, perioperative vasopressor exposure and increased number of red blood cell transfusions are risk factors for ALs and intra-abdominal complications, respectively. Nonsteroidal anti-inflammatory drug use in trauma patients with multiple risk factors may be associated with an increased risk of AL and should be used with caution in the setting of other established risk factors.<br><br>LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.}, }
@article {pmid36726750, year = {2022}, author = {Schröder, S and Litscher, G and Pan, W}, title = {Editorial: Translational study for amyotrophic lateral sclerosis treatment.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {1105360}, pmid = {36726750}, issn = {1664-2295}, }
@article {pmid36725099, year = {2023}, author = {Wong, C and Gregory, JM and Liao, J and Egan, K and Vesterinen, HM and Ahmad Khan, A and Anwar, M and Beagan, C and Brown, FS and Cafferkey, J and Cardinali, A and Chiam, JY and Chiang, C and Collins, V and Dormido, J and Elliott, E and Foley, P and Foo, YC and Fulton-Humble, L and Gane, AB and Glasmacher, SA and Heffernan, &#xc1; and Jayaprakash, K and Jayasuriya, N and Kaddouri, A and Kiernan, J and Langlands, G and Leighton, D and Liu, J and Lyon, J and Mehta, AR and Meng, A and Nguyen, V and Park, NH and Quigley, S and Rashid, Y and Salzinger, A and Shiell, B and Singh, A and Soane, T and Thompson, A and Tomala, O and Waldron, FM and Selvaraj, BT and Chataway, J and Swingler, R and Connick, P and Pal, S and Chandran, S and Macleod, M}, title = {Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus.}, journal = {BMJ open}, volume = {13}, number = {2}, pages = {e064169}, pmid = {36725099}, issn = {2044-6055}, support = {MC_EX_MR/N50192X/1/MRC_/Medical Research Council/United Kingdom ; MR/R001162/1/MRC_/Medical Research Council/United Kingdom ; MRF_MRF-024-0001-RG-PARM-C0860/MRF/MRF/United Kingdom ; }, mesh = {Humans ; Consensus ; Induced Pluripotent Stem Cells ; *Motor Neuron Disease/drug therapy ; Randomized Controlled Trials as Topic ; Adaptive Clinical Trials as Topic ; }, abstract = {OBJECTIVES: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol.<br><br>METHODS: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART.<br><br>RESULTS: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART.<br><br>DISCUSSION: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.}, }
@article {pmid36720792, year = {2023}, author = {Usmani, MT and Krattli, RP and El-Khatib, SM and Le, ACD and Smith, SM and Baulch, JE and Ng, DQ and Acharya, MM and Chan, A}, title = {BDNF Augmentation Using Riluzole Reverses Doxorubicin-Induced Decline in Cognitive Function and Neurogenesis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {20}, number = {3}, pages = {838-852}, pmid = {36720792}, issn = {1878-7479}, support = {P30 CA062203/CA/NCI NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; }, mesh = {Female ; Mice ; Animals ; *Brain-Derived Neurotrophic Factor/metabolism ; Riluzole/pharmacology/therapeutic use ; Neuroinflammatory Diseases ; Extinction, Psychological ; Quality of Life ; Fear ; Doxorubicin/toxicity ; Cognition ; *Antineoplastic Agents/adverse effects ; Neurogenesis ; Hippocampus ; }, abstract = {Cancer-related cognitive impairment (CRCI) considerably affects the quality of life of millions of cancer survivors. Brain-derived neurotrophic factor (BDNF) has been shown to promote survival, differentiation, and maintenance of in vivo dentate neurogenesis, and chemotherapy induces a plethora of physiological and cellular alterations, including a decline in neurogenesis and increased neuroinflammation linked with cognitive impairments. In our clinical studies, breast cancer patients treated with doxorubicin (Adriamycin[®], ADR) experienced a significant reduction in the blood levels of BDNF that was associated with a higher risk of CRCI. Our past rodent studies in CRCI have also shown a significant reduction in dentate neurogenesis accompanied by cognitive impairment. In this study, using a female mouse model of ADR-induced cognitive decline, we tested the impact of riluzole (RZ), an orally active BDNF-enhancing medication that is FDA-approved for amyotrophic lateral sclerosis. ADR-treated mice receiving RZ in the drinking water for 1 month showed significant improvements in hippocampal-dependent learning and memory function (spatial recognition), fear extinction memory consolidation, and reduced anxiety-like behavior. RZ prevented chemotherapy-induced reductions of BDNF levels in the hippocampus. Importantly, RZ mitigated chemotherapy-induced loss of newly born, immature neurons, dentate neurogenesis, and neuroinflammation. In conclusion, this data provides pre-clinical evidence for a translationally feasible approach to enhance the neuroprotective effects of RZ treatment to prevent CRCI.}, }
@article {pmid36716828, year = {2023}, author = {Gautam, M and Genç, B and Helmold, B and Ahrens, A and Kuka, J and Makrecka-Kuka, M and Günay, A and Koçak, N and Aguilar-Wickings, IR and Keefe, D and Zheng, G and Swaminathan, S and Redmon, M and Zariwala, HA and Özdinler, PH}, title = {SBT-272 improves TDP-43 pathology in ALS upper motor neurons by modulating mitochondrial integrity, motility, and function.}, journal = {Neurobiology of disease}, volume = {178}, number = {}, pages = {106022}, doi = {10.1016/j.nbd.2023.106022}, pmid = {36716828}, issn = {1095-953X}, support = {R21 NS085750/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Motor Neurons/pathology ; Mitochondria/pathology ; DNA-Binding Proteins/metabolism ; }, abstract = {Mitochondrial defects are one of the common underlying causes of neuronal vulnerability in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is the most commonly observed proteinopathy. Disrupted inner mitochondrial membrane (IMM) reported in the upper motor neurons (UMNs) of ALS patients with TDP-43 pathology is recapitulated in the UMNs of well-characterized hTDP-43 mouse model of ALS. The construct validity, such as shared and common cellular pathology in mice and human, offers a unique opportunity to test treatment strategies that may translate to patients. SBT-272 is a well-tolerated brain-penetrant small molecule that stabilizes cardiolipin, a phospholipid found in IMM, thereby restoring mitochondrial structure and respiratory function. We investigated whether SBT-272 can improve IMM structure and health in UMNs diseased with TDP-43 pathology in our well-characterized UMN reporter line for ALS. We found that SBT-272 significantly improved mitochondrial structural integrity and restored mitochondrial motility and function. This led to improved health of diseased UMNs in vitro. In comparison to edaravone and AMX0035, SBT-272 appeared more effective in restoring health of diseased UMNs. Chronic treatment of SBT-272 for sixty days starting at an early symptomatic stage of the disease in vivo led to a significant reduction in astrogliosis, microgliosis, and TDP-43 pathology in the ALS motor cortex. Our results underscore the therapeutic potential of SBT-272, especially within the context of TDP-43 pathology and mitochondrial dysfunction.}, }
@article {pmid36716091, year = {2023}, author = {Haji, S and Fujita, K and Oki, R and Osaki, Y and Miyamoto, R and Morino, H and Nagano, S and Atsuta, N and Kanazawa, Y and Matsumoto, Y and Arisawa, A and Kawai, H and Sato, Y and Sakaguchi, S and Yagi, K and Hamatani, T and Kagimura, T and Yanagawa, H and Mochizuki, H and Doyu, M and Sobue, G and Harada, M and Izumi, Y}, title = {An Exploratory Trial of EPI-589 in Amyotrophic Lateral Sclerosis (EPIC-ALS): Protocol for a Multicenter, Open-Labeled, 24-Week, Single-Group Study.}, journal = {JMIR research protocols}, volume = {12}, number = {}, pages = {e42032}, pmid = {36716091}, issn = {1929-0748}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, with its currently approved drugs, including riluzole and edaravone, showing limited therapeutic effects. Therefore, safe and effective drugs are urgently necessary. EPI-589 is an orally available, small-molecule, novel redox-active agent characterized by highly potent protective effects against oxidative stress with high blood-brain barrier permeability. Given the apparent oxidative stress and mitochondrial dysfunction involvement in the pathogenesis of ALS, EPI-589 may hold promise as a therapeutic agent.<br><br>OBJECTIVE: This protocol aims to describe the design and rationale for the EPI-589 Early Phase 2 Investigator-Initiated Clinical Trial for ALS (EPIC-ALS).<br><br>METHODS: EPIC-ALS is an explorative, open-labeled, single-arm trial that evaluates the safety and tolerability of EPI-589 in patients with ALS. This trial consists of 12-week run-in, 24-week treatment, and 4-week follow-up periods. Patients will receive 500 mg of EPI-589 3 times daily over the 24-week treatment period. Clinical assessments include the mean monthly change of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised total score. The biomarkers are selected to analyze the effect on oxidative stress and neuronal damage. The plasma biomarkers are 8-hydroxy-2'-deoxyguanosine (8-OHdG), 3-nitrotyrosine (3-NT), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), homocysteine, and creatinine. The cerebrospinal fluid biomarkers are 8-OHdG, 3-NT, NfL, pNfH, and ornithine. The magnetic resonance biomarkers are fractional anisotropy in the corticospinal tract and N-acetylaspartate in the primary motor area.<br><br>RESULTS: This trial began data collection in September 2021 and is expected to be completed in October 2023.<br><br>CONCLUSIONS: This study can provide useful data to understand the characteristics of EPI-589.<br><br>TRIAL REGISTRATION: Japan Primary Registries Network jRCT2061210031; tinyurl.com/2p84emu6.<br><br>DERR1-10.2196/42032.}, }
@article {pmid36714840, year = {2022}, author = {Zhang, Y and Jeong, H and Mori, K and Ikeda, SI and Shoda, C and Miwa, Y and Nakai, A and Chen, J and Ma, Z and Jiang, X and Torii, H and Kubota, Y and Negishi, K and Kurihara, T and Tsubota, K}, title = {Vascular endothelial growth factor from retinal pigment epithelium is essential in choriocapillaris and axial length maintenance.}, journal = {PNAS nexus}, volume = {1}, number = {4}, pages = {pgac166}, pmid = {36714840}, issn = {2752-6542}, abstract = {Myopia, which prevalence is rapidly increasing, causes visual impairment; however, the onset mechanism of pathological axial length (AL) elongation remains unclear. A highly vascularized choroid between the retinal pigment epithelium (RPE) and sclera not only maintains physiological activities, but also contributes to ocular development and growth regulation. Vascular endothelial growth factor (VEGF) secreted from the RPE to the choroid is essential for retinal function and maintenance of the choriocapillaris. Herein, we demonstrated that the loss of VEGF secreted from the RPE caused abnormal choriocapillaris development and AL elongation, with features similar to those of the lens-induced myopia (LIM) mouse model, whereas VEGF overexpression by knocking-out von Hippel-Lindau (VHL) specific to the RPE expands the choriocapillaris and shortens the AL. Additionally, LDL Receptor Related Protein 2 (LRP2) deletion in the RPE downregulated VEGF expression and leads to pathological AL elongation. Furthermore, high-myopia patients without choriocapillaris demonstrated longer ALs than did those with preserved choriocapillaris. These results suggest that physiological secretion of VEGF from the RPE is required for proper AL development by maintaining the choriocapillaris. The pinpoint application of VEGF to the choriocapillaris may become a potential intervention for the prevention and treatment of axial myopia progression.}, }
@article {pmid36705941, year = {2023}, author = {Sun, Y and Li, X and Bedlack, R}, title = {An evaluation of the combination of sodium phenylbutyrate and taurursodiol for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {23}, number = {1}, pages = {1-7}, doi = {10.1080/14737175.2023.2174018}, pmid = {36705941}, issn = {1744-8360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/therapeutic use ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative motor neuron disease. Despite the overwhelming need for effective therapeutics for ALS, riluzole and edaravone were the only two FDA-approved disease-modifying therapies prior to 2022. The randomized, double-blind, multicenter, placebo-controlled CENTAUR trial demonstrated the safety and efficacy of sodium phenylbutyrate-taurursodiol (PB-TURSO) in persons with ALS (PALS), leading to its conditional approval in Canada in June 2022 and full approval in the USA in September 2022.<br><br>AREAS COVERED: Herein, the authors provide a review of the pharmacology and clinical trials evaluating sodium phenylbutyrate and/or taurursodiol in PALS.<br><br>EXPERT OPINION: The safety and tolerability of both PB and TURSO were previously demonstrated in small PALS trials. The phase 2 CENTAUR study and its open-label extension demonstrated the safety and efficacy of AMX0035 (a sachet containing a fixed co-formulation of 3&#xa0;g of PB and 1&#xa0;g of TURSO given twice daily) in PALS. A phase 3 PHOENIX trial (NCT05021536) will offer more insight into safety and efficacy of AMX0035. AMX0035 currently costs $ 158,000 annually in the US, which may become a financial barrier for PALS to receive the medication.}, }
@article {pmid36703583, year = {2023}, author = {Lustoza Rodrigues, TCM and de Sousa, NF and Dos Santos, AMF and Aires Guimarães, RD and Scotti, MT and Scotti, L}, title = {Challenges and Discoveries in Polypharmacology of Neurodegenerative Diseases.}, journal = {Current topics in medicinal chemistry}, volume = {23}, number = {5}, pages = {349-370}, doi = {10.2174/1568026623666230126112628}, pmid = {36703583}, issn = {1873-4294}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Molecular Docking Simulation ; Polypharmacology ; Acetylcholinesterase ; *Alzheimer Disease/drug therapy ; }, abstract = {BACKGROUND: Neurological disorders are composed of several diseases that affect the central and peripheral nervous system; among these are neurodegenerative diseases, which lead to neuronal death. Many of these diseases have treatment for the disease and symptoms, leading patients to use several drugs that cause side effects.<br><br>INTRODUCTION: The search for new treatments has led to the investigation of multi-target drugs.<br><br>METHODS: This review aimed to investigate in the literature the multi-target effect in neurological disorders through an in silico approach. Studies were reviewed on the diseases such as epilepsy, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, cerebral ischemia, and Parkinson's disease.<br><br>RESULTS: As a result, the study emphasize the relevance of research by computational techniques such as quantitative structure-activity relationship (QSAR) prediction models, pharmacokinetic prediction models, molecular docking, and molecular dynamics, besides presenting possible drug candidates with multi-target activity.<br><br>CONCLUSION: It was possible to identify several targets with pharmacological activities. Some of these targets had diseases in common such as carbonic anhydrase, acetylcholinesterase, NMDA, and MAO being relevant for possible multi-target approaches.}, }
@article {pmid36687305, year = {2023}, author = {Edriss, MT and Parker, JJ and Pritchett, EN}, title = {Response to Gu et al's "Treatment-resistant dermatophytosis: A representative case highlighting an emerging public health threat".}, journal = {JAAD case reports}, volume = {32}, number = {}, pages = {88-89}, pmid = {36687305}, issn = {2352-5126}, }
@article {pmid36686537, year = {2022}, author = {Benkirane, A and Warlop, T and Ivanoiu, A and Baret, P and Wiame, E and Haufroid, V and Duprez, T and Hantson, P}, title = {Case report: Motor neuron disease phenotype associated with symptomatic copper deficiency: Challenging diagnosis and treatment.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {1063803}, pmid = {36686537}, issn = {1664-2295}, abstract = {Copper deficiency is an acquired condition that can lead to neurologic dysfunctions, such as myelopathy, motor neuron impairment, polyneuropathy, cognitive impairment, and optic nerve neuropathy. Associated biological findings are low serum copper and ceruloplasmin levels with low copper urinary excretion. We report the case of a previously healthy 59-year-old man who presented a complex neurological picture starting with symptoms and radiological signs consistent with degenerative myelopathy in the presence of persisting low serum copper and ceruloplasmin despite oral and intravenous copper supplementation. Over time, his symptoms evolved into a motor neuron disease evocating an amyotrophic lateral sclerosis (ALS) phenotype. The potential role of copper deficiency is discussed, together with the difficulties in biomonitoring copper supplementation.}, }
@article {pmid36678841, year = {2023}, author = {Andrade, S and Nunes, D and Dabur, M and Ramalho, MJ and Pereira, MC and Loureiro, JA}, title = {Therapeutic Potential of Natural Compounds in Neurodegenerative Diseases: Insights from Clinical Trials.}, journal = {Pharmaceutics}, volume = {15}, number = {1}, pages = {}, pmid = {36678841}, issn = {1999-4923}, support = {LA/P/0045/2020 (ALiCE)//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; UIDB/00511/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; UIDP/00511/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; NORTE-01-0145-FEDER-000054//European Regional Development Fund/ ; EXPL/NAN-MAT/0209/2021//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; UI/BD/150946/2021//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; SFRH/BD/040932/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; CEEC-IND/01741/2021//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; CEEC-INST/00049/2018//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; }, abstract = {Neurodegenerative diseases are caused by the gradual loss of neurons' function. These neurological illnesses remain incurable, and current medicines only alleviate the symptoms. Given the social and economic burden caused by the rising frequency of neurodegenerative diseases, there is an urgent need for the development of appropriate therapeutics. Natural compounds are gaining popularity as alternatives to synthetic drugs due to their neuroprotective properties and higher biocompatibility. While natural compounds' therapeutic effects for neurodegenerative disease treatment have been investigated in numerous in vitro and in vivo studies, only few have moved to clinical trials. This article provides the first systematic review of the clinical trials evaluating natural compounds' safety and efficacy for the treatment of the five most prevalent neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease.}, }
@article {pmid36676070, year = {2022}, author = {McCluskey, G and Morrison, KE and Donaghy, C and Rene, F and Duddy, W and Duguez, S}, title = {Extracellular Vesicles in Amyotrophic Lateral Sclerosis.}, journal = {Life (Basel, Switzerland)}, volume = {13}, number = {1}, pages = {}, pmid = {36676070}, issn = {2075-1729}, abstract = {Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disease and is the most common adult motor neuron disease. The disease pathogenesis is complex with the perturbation of multiple pathways proposed, including mitochondrial dysfunction, RNA processing, glutamate excitotoxicity, endoplasmic reticulum stress, protein homeostasis and endosomal transport/extracellular vesicle (EV) secretion. EVs are nanoscopic membrane-bound particles that are released from cells, involved in the intercellular communication of proteins, lipids and genetic material, and there is increasing evidence of their role in ALS. After discussing the biogenesis of EVs, we review their roles in the propagation of pathological proteins in ALS, such as TDP-43, SOD1 and FUS, and their contribution to disease pathology. We also discuss the ALS related genes which are involved in EV formation and vesicular trafficking, before considering the EV protein and RNA dysregulation found in ALS and how these have been investigated as potential biomarkers. Finally, we highlight the potential use of EVs as therapeutic agents in ALS, in particular EVs derived from mesenchymal stem cells and EVs as drug delivery vectors for potential treatment strategies.}, }
@article {pmid36676050, year = {2022}, author = {Lee, EJ and Kim, Y and Kim, JE and Yoon, EL and Lee, SR and Jun, DW}, title = {ALS-L1023 from Melissa officinalis Alleviates Liver Fibrosis in a Non-Alcoholic Fatty Liver Disease Model.}, journal = {Life (Basel, Switzerland)}, volume = {13}, number = {1}, pages = {}, pmid = {36676050}, issn = {2075-1729}, support = {2020R1A2C2009227//National Research Foundation of Korea/ ; }, abstract = {ALS-L1023 is an ingredient extracted from Melissa officinalis L. (Labiatae; lemon balm), which is known as a natural medicine that suppresses angiogenesis. Herein, we aimed to determine whether ALS-L1023 could alleviate liver fibrosis in the non-alcoholic fatty liver disease (NAFLD) model. C57BL/6 wild-type male mice (age, 6 weeks old) were fed a choline-deficient high-fat diet (CDHFD) for 10 weeks to induce NAFLD. For the next 10 weeks, two groups of mice received the test drug along with CDHFD. Two doses (a low dose, 800 mg/kg/day; and a high dose, 1200 mg/kg/day) of ALS-L1023 were selected and mixed with feed for administration. Obeticholic acid (OCA; 10 mg/kg/day) was used as the positive control. Biochemical analysis revealed that the ALS-L1023 low-dose group had significantly decreased alanine transaminase and aspartate transaminase. The area of fibrosis significantly decreased due to the administration of ALS-L1023, and the anti-fibrotic effect of ALS-L1023 was greater than that of OCA. RNA sequencing revealed that the responder group had lower expression of genes related to the hedgehog-signaling pathway than the non-responder group. ALS-L1023 may exert anti-fibrotic effects in the NAFLD model, suggesting that it may provide potential benefits for the treatment of liver fibrosis.}, }
@article {pmid36674643, year = {2023}, author = {Lejman, J and Panuciak, K and Nowicka, E and Mastalerczyk, A and Wojciechowska, K and Lejman, M}, title = {Gene Therapy in ALS and SMA: Advances, Challenges and Perspectives.}, journal = {International journal of molecular sciences}, volume = {24}, number = {2}, pages = {}, pmid = {36674643}, issn = {1422-0067}, mesh = {Infant ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Quality of Life ; *Muscular Atrophy, Spinal/genetics/therapy ; *Motor Neuron Disease ; Genetic Therapy ; }, abstract = {Gene therapy is defined as the administration of genetic material to modify, manipulate gene expression or alter the properties of living cells for therapeutic purposes. Recent advances and improvements in this field have led to many breakthroughs in the treatment of various diseases. As a result, there has been an increasing interest in the use of these therapies to treat motor neuron diseases (MNDs), for which many potential molecular targets have been discovered. MNDs are neurodegenerative disorders that, in their most severe forms, can lead to respiratory failure and death, for instance, spinal muscular atrophy (SMA) or amyotrophic lateral sclerosis (ALS). Despite the fact that SMA has been known for many years, it is still one of the most common genetic diseases causing infant mortality. The introduction of drugs based on ASOs-nusinersen; small molecules-risdiplam; and replacement therapy (GRT)-Zolgensma has shown a significant improvement in both event-free survival and the quality of life of patients after using these therapies in the available trial results. Although there is still no drug that would effectively alleviate the course of the disease in ALS, the experience gained from SMA gene therapy gives hope for a positive outcome of the efforts to produce an effective and safe drug. The aim of this review is to present current progress and prospects for the use of gene therapy in the treatment of both SMA and ALS.}, }
@article {pmid36674517, year = {2023}, author = {Matheson, JT and Holsinger, RMD}, title = {The Role of Fecal Microbiota Transplantation in the Treatment of Neurodegenerative Diseases: A Review.}, journal = {International journal of molecular sciences}, volume = {24}, number = {2}, pages = {}, pmid = {36674517}, issn = {1422-0067}, mesh = {Humans ; Fecal Microbiota Transplantation ; *Neurodegenerative Diseases/therapy ; *Gastrointestinal Microbiome ; *Microbiota ; *Clostridium Infections/therapy ; Dysbiosis/therapy ; }, abstract = {Neurodegenerative diseases are highly prevalent but poorly understood, and with few treatment options despite decades of intense research, attention has recently shifted toward other mediators of neurological disease that may present future targets for therapeutic research. One such mediator is the gut microbiome, which communicates with the brain through the gut-brain axis and has been implicated in various neurological disorders. Alterations in the gut microbiome have been associated with numerous neurological and other diseases, and restoration of the dysbiotic gut has been shown to improve disease conditions. One method of restoring a dysbiotic gut is via fecal microbiota transplantation (FMT), recolonizing the "diseased" gut with normal microbiome. Fecal microbiota transplantation is a treatment method traditionally used for Clostridium difficile infections, but it has recently been used in neurodegenerative disease research as a potential treatment method. This review aims to present a summary of neurodegenerative research that has used FMT, whether as a treatment or to investigate how the microbiome influences pathogenesis.}, }
@article {pmid36674509, year = {2023}, author = {Meanti, R and Licata, M and Rizzi, L and Bresciani, E and Molteni, L and Coco, S and Locatelli, V and Omeljaniuk, RJ and Torsello, A}, title = {Protective Effects of Hexarelin and JMV2894 in a Human Neuroblastoma Cell Line Expressing the SOD1-G93A Mutated Protein.}, journal = {International journal of molecular sciences}, volume = {24}, number = {2}, pages = {}, pmid = {36674509}, issn = {1422-0067}, mesh = {Humans ; Animals ; Mice ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase/genetics/metabolism ; Hydrogen Peroxide/pharmacology ; *Neuroblastoma/drug therapy/genetics ; Cell Line ; Disease Models, Animal ; Mice, Transgenic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease whose etiology remains unresolved; nonetheless, mutations of superoxide dismutase 1 (SOD1) have been associated with several variants of ALS. Currently available pharmacologic interventions are only symptomatic and palliative in effect; therefore, there is a pressing demand for more effective drugs. This study examined potential therapeutic effects of growth hormone secretagogues (GHSs), a large family of synthetic compounds, as possible candidates for the treatment of ALS. Human neuroblastoma cells expressing the SOD1-G93A mutated protein (SH-SY5Y SOD1[G93A] cells) were incubated for 24 h with H2O2 (150 µM) in the absence, or presence, of GHS (1 µM), in order to study the protective effect of GHS against increased oxidative stress. The two GHSs examined in this study, hexarelin and JMV2894, protected cells from H2O2-induced cytotoxicity by activating molecules that regulate apoptosis and promote cell survival processes. These findings suggest the possibility of developing new GHS-based anti-oxidant and neuroprotective drugs with improved therapeutic potential. Further investigations are required for the following: (i) to clarify GHS molecular mechanisms of action, and (ii) to envisage the development of new GHSs that may be useful in ALS therapy.}, }
@article {pmid36661322, year = {2023}, author = {Li, H and Yuan, L and Yang, H and Guo, Y and Zheng, W and Fan, K and Deng, S and Gong, L and Xu, H and Yang, Z and Cheng, J and Kang, M and Deng, H}, title = {Analysis of SOD1 variants in Chinese patients with familial amyotrophic lateral sclerosis.}, journal = {QJM : monthly journal of the Association of Physicians}, volume = {116}, number = {5}, pages = {365-374}, doi = {10.1093/qjmed/hcad010}, pmid = {36661322}, issn = {1460-2393}, support = {81873686//National Natural Science Foundation of China/ ; 2020JJ3057//Natural Science Foundation of Hunan Province/ ; B202303078399//Scientific Research Project of Health Commission of Hunan Province/ ; 2021zzts0407//Fundamental Research Funds for the Central Universities of Central South University/ ; S2022105330685//Province-level College Students' Innovative Training Plan Program/ ; XCX2022118//Undergraduate Innovative Training Plan Program of Central South University/ ; //Wisdom Accumulation and Talent Cultivation Project/ ; YX202109//Third Xiangya Hospital of Central South University/ ; //Distinguished Professor of the Lotus Scholars Award Program of Hunan Province/ ; }, mesh = {Humans ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Acetylcysteine/therapeutic use ; Reactive Oxygen Species ; *Neurodegenerative Diseases ; East Asian People ; Mutation ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, and genetic contributors exert a significant role in the complicated pathogenesis. Identification of the genetic causes in ALS families could be valuable for early diagnosis and management. The development of potential drugs for patients with genetic defects will shed new light on ALS therapy.<br><br>AIM: To identify causative variants in three Chinese families with familial ALS (FALS), reveal the pathogenic mechanism and look for the targeted drug for ALS.<br><br>DESIGN AND METHODS: Whole-exome sequencing and bioinformatics were used to perform genetic analysis of the ALS families. Functional analysis was performed to study the variants' function and search for potential drug targets.<br><br>RESULTS: Three heterozygous missense variants of the superoxide dismutase 1 gene (SOD1) were identified in families with FALS. The clinical manifestations of these patients include spinal onset, predominant lower motor neurons presentation and absence of cognitive involvement. Functional analysis showed that all three SOD1 variants led to increased reactive oxygen species (ROS) levels, reduced cell viability and formation of cytoplasmic aggregates. Remarkably, the decreased cell viability induced by variants was rescued after treatment with the ROS inhibitor N-acetylcysteine.<br><br>CONCLUSIONS: This study identified three SOD1 variants in three families with FALS. The variant SOD1 toxicity was associated with oxidative damage and aggregation, and N-acetylcysteine could rescue the decreased cell viability induced by these variants. Our findings support a pathogenic role for ROS in SOD1 deficiencies and provide a potential drug N-acetylcysteine for ALS therapy, especially in SOD1 patients with limb onset.}, }
@article {pmid36660079, year = {2022}, author = {Chakraborty, A and Diwan, A}, title = {Biomarkers and molecular mechanisms of Amyotrophic Lateral Sclerosis.}, journal = {AIMS neuroscience}, volume = {9}, number = {4}, pages = {423-443}, pmid = {36660079}, issn = {2373-7972}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in adults involving non-demyelinating motor disorders. About 90% of ALS cases are sporadic, while 10-12% of cases are due to some genetic reasons. Mutations in superoxide dismutase 1 (SOD1), TAR, c9orf72 (chromosome 9 open reading frame 72) and VAPB genes are commonly found in ALS patients. Therefore, the mechanism of ALS development involves oxidative stress, endoplasmic reticulum stress, glutamate excitotoxicity and aggregation of proteins, neuro-inflammation and defective RNA function. Cholesterol and LDL/HDL levels are also associated with ALS development. As a result, sterols could be a suitable biomarker for this ailment. The main mechanisms of ALS development are reticulum stress, neuroinflammation and RNA metabolism. The multi-nature development of ALS makes it more challenging to pinpoint a treatment.}, }
@article {pmid36652954, year = {2024}, author = {Bertossi, D and Sacchetto, L and Chirumbolo, S and Panozzo, G and Kapoor, KM}, title = {Single-Step Full-Face Surgical Treatment of the Facial Profile.}, journal = {Facial plastic surgery : FPS}, volume = {40}, number = {1}, pages = {9-18}, doi = {10.1055/a-2015-0853}, pmid = {36652954}, issn = {1098-8793}, mesh = {Male ; Female ; Humans ; *Face/surgery ; *Rhinoplasty/adverse effects/methods ; Treatment Outcome ; Forehead/surgery ; Genioplasty ; }, abstract = {The present study was performed to describe how much affordable, feasible, and straightforward is the approach the authors called "single-stage full-face surgical profileplasty," tailored to greatly improve the surgery of the facial profiling setting and achieve complete profile correction at the same time. From January 2010 to May 2019, 113 patients (95 females and 18 males; aged 19 - 63 years) were surgically treated for full-face profile amelioration. Profile correction was performed by using a combination of five procedures out of other various previously experienced: forehead fat grafting, rhinoplasty, lip fat grafting, genioplasty, and submental liposuction. All patients were assessed at 1, 3, 6, and 12 months following surgery for assessing the surgical profile treatment (SPT) outcome and any possible side effects of the combined treatment. Facial profile stability at 1 year was taken as the completion point of this treatment. Arnett et al's "Soft Tissue Cephalometric Analysis" (1999) was used to clinically evaluate the soft tissues before and after the SPT. Patients' satisfaction was measured with the Client Satisfaction Questionnaire-8" at 3 and 12 months after surgery. Statistics were used for Arnett et al's evaluation. Almost all the values were consistent and reached the normal ranges indicated by Arnett et al (p < 0.001), confirming that the desired results of the surgical profileplasty have been achieved. Single-stage full-face surgical profile treatment helps in correcting faults of the global facial deformity, in every single treated area, providing an overall improvement in facial aesthetics and harmony. Obtaining the simultaneous correction in the whole face has also the advantage of avoiding multiple surgical procedures, reducing postoperative discomfort, and the overall risks for the patient due to multiple surgical and anesthetic procedures.}, }
@article {pmid36652469, year = {2023}, author = {Pulst, SM and Scoles, DR and Paul, S}, title = {Effects of STAU1/staufen1 on autophagy in neurodegenerative diseases.}, journal = {Autophagy}, volume = {19}, number = {9}, pages = {2607-2608}, pmid = {36652469}, issn = {1554-8635}, support = {R35 NS127253/NS/NINDS NIH HHS/United States ; R37 NS033123/NS/NINDS NIH HHS/United States ; R61 NS124965/NS/NINDS NIH HHS/United States ; R01 NS097903/NS/NINDS NIH HHS/United States ; R21 NS103009/NS/NINDS NIH HHS/United States ; R21 NS081182/NS/NINDS NIH HHS/United States ; R56 NS033123/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; HEK293 Cells ; Autophagy/genetics ; RNA-Binding Proteins/metabolism ; *Frontotemporal Dementia/genetics ; *Spinocerebellar Ataxias ; TOR Serine-Threonine Kinases/metabolism ; Cytoskeletal Proteins/metabolism ; }, abstract = {The double-stranded RNA-binding protein, STAU1 (staufen double-stranded RNA binding protein 1) is a multifunctional protein that localizes to stress granules (SGs). We had previously found that STAU1 is overabundant in fibroblast cell lines from patients with spinocerebellar ataxia type 2 (SCA2) or amyotrophic lateral sclerosis (ALS)-frontotemporal dementia (FTD) as well as in animal models of these diseases. STAU1 overabundance is post-transcriptional and associated with MTOR hyperactivation and links SG formation with macroautophagy/autophagy. Reducing STAU1 levels in mice with ALS mutations normalizes MTOR activity and autophagy-related marker proteins. We also see increased STAU1 levels in HEK293 cells expressing C9orf72-relevant dipeptide repeats (DPRs), and DPRs are not observed in cells where STAU1 is targeted by RNAi. Overexpression of STAU1 in HEK293 cells increases MTOR translation by directly interacting with the MTOR mRNA 5'UTR, activating downstream targets and impairing autophagic flux. STAU1 may constitute a novel target to modulate MTOR activity and autophagy and for the treatment of neurodegenerative diseases.}, }
@article {pmid36649137, year = {2022}, author = {Sadowska, A and Grzesiak, M}, title = {[The role of steroid hormones in the neurodegenerative diseases].}, journal = {Postepy biochemii}, volume = {68}, number = {4}, pages = {387-398}, doi = {10.18388/pb.2021_468}, pmid = {36649137}, issn = {0032-5422}, mesh = {Male ; Humans ; Female ; Aged ; *Neurodegenerative Diseases/drug therapy ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Alzheimer Disease/drug therapy ; *Parkinson Disease/drug therapy ; Steroids ; Hormones ; }, abstract = {An increasing number of elders in a general population and longer life expectancy have a negative outcome in the growth of dissemination of neurodegenerative diseases (NDs). The NDs like Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) show sex-dependent prevalence. It is considered that sex steroids could influence on the NDs occurrence. Epidemiological studies indicate that women suffer more frequently from AD, whereas men from PD and ALS. Research suggest neuroprotective effects of estrogens and confirm that factors reducing their level may have a contribution to a higher morbidity rate to NDs. Adverse effects of androgens on NDs have been noticed, however some data suggest their beneficial actions. Therefore, the understanding of the potential role of sex steroids and their receptors in the pathogenesis and course of NDs would contribute to broadening the knowledge of molecular mechanisms leading to NDs. Moreover effective prevention and treatment could be assessed in the future.}, }
@article {pmid36648959, year = {2023}, author = {Vignaroli, F and Mele, A and Tondo, G and De Giorgis, V and Manfredi, M and Comi, C and Mazzini, L and De Marchi, F}, title = {The Need for Biomarkers in the ALS-FTD Spectrum: A Clinical Point of View on the Role of Proteomics.}, journal = {Proteomes}, volume = {11}, number = {1}, pages = {}, pmid = {36648959}, issn = {2227-7382}, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are severely debilitating and progressive neurodegenerative disorders. A distinctive pathological feature of several neurodegenerative diseases, including ALS and FTD, is the deposition of aberrant protein inclusions in neuronal cells, which leads to cellular dysfunction and neuronal damage and loss. Despite this, to date, the biological process behind developing these protein inclusions must be better clarified, making the development of disease-modifying treatment impossible until this is done. Proteomics is a powerful tool to characterize the expression, structure, functions, interactions, and modifications of proteins of tissue and biological fluid, including plasma, serum, and cerebrospinal fluid. This protein-profiling characterization aims to identify disease-specific protein alteration or specific pathology-based mechanisms which may be used as markers of these conditions. Our narrative review aims to highlight the need for biomarkers and the potential use of proteomics in clinical practice for ALS-FTD spectrum disorders, considering the emerging rationale in proteomics for new drug development. Certainly, new data will emerge in the near future in this regard and support clinicians in the development of personalized medicine.}, }
@article {pmid36647114, year = {2023}, author = {Parker, RA and Weir, CJ and Pham, TM and White, IR and Stallard, N and Parmar, MKB and Swingler, RJ and Dakin, RS and Pal, S and Chandran, S}, title = {Statistical analysis plan for the motor neuron disease systematic multi-arm adaptive randomised trial (MND-SMART).}, journal = {Trials}, volume = {24}, number = {1}, pages = {29}, pmid = {36647114}, issn = {1745-6215}, support = {MC_EX_MR/N50192X/1/MRC_/Medical Research Council/United Kingdom ; MRF_MRF-024-0001-RG-PARM-C0860/MRF/MRF/United Kingdom ; MC_UU_00004/07/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; *Motor Neuron Disease/diagnosis/drug therapy ; Therapies, Investigational ; Transcranial Magnetic Stimulation ; Treatment Outcome ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; Adaptive Clinical Trials as Topic ; }, abstract = {BACKGROUND: MND-SMART is a platform, multi-arm, multi-stage, multi-centre, randomised controlled trial recruiting people with motor neuron disease. Initially, the treatments memantine and trazodone will each be compared against placebo, but other investigational treatments will be introduced into the trial later. The co-primary outcomes are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALS-FRS-R) functional outcome, which is assessed longitudinally, and overall survival.<br><br>METHODS: Initially in MND-SMART, participants are randomised 1:1:1 via a minimisation algorithm to receive placebo or one of the two investigational treatments with up to 531 to be randomised in total. The comparisons between each research arm and placebo will be conducted in four stages, with the opportunity to cease further randomisations to poorly performing research arms at the end of stages 1 or 2. The final ALS-FRS-R analysis will be at the end of stage 3 and final survival analysis at the end of stage 4. The estimands for the co-primary outcomes are described in detail. The primary analysis of ALS-FRS-R at the end of stages 1 to 3 will involve fitting a normal linear mixed model to the data to calculate a mean difference in rate of ALS-FRS-R change between each research treatment and placebo. The pairwise type 1 error rate will be controlled, because each treatment comparison will generate its own distinct and separate interpretation. This publication is based on a formal statistical analysis plan document that was finalised and signed on 18 May 2022.<br><br>DISCUSSION: In developing the statistical analysis plan, we had to carefully consider several issues such as multiple testing, estimand specification, interim analyses, and statistical analysis of the repeated measurements of ALS-FRS-R. This analysis plan attempts to balance multiple factors, including minimisation of bias, maximising power and precision, and deriving clinically interpretable summaries of treatment effects.<br><br>TRIAL REGISTRATION: EudraCT Number, 2019-000099-41. Registered 2 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=mnd-smart ClinicalTrials.gov, NCT04302870 . Registered 10 March 2020.}, }
@article {pmid36646255, year = {2023}, author = {Ashique, S and Afzal, O and Yasmin, S and Hussain, A and Altamimi, MA and Webster, TJ and Altamimi, ASA}, title = {Strategic nanocarriers to control neurodegenerative disorders: Concept, challenges, and future perspective.}, journal = {International journal of pharmaceutics}, volume = {633}, number = {}, pages = {122614}, doi = {10.1016/j.ijpharm.2023.122614}, pmid = {36646255}, issn = {1873-3476}, mesh = {Humans ; *Nanoparticles ; Blood-Brain Barrier ; Brain ; Drug Delivery Systems ; Nanomedicine ; *Neurodegenerative Diseases/drug therapy ; }, abstract = {Various neurodegenerative diseases (parkinson, huntington, alzheimer, and amyotrophic lateral sclerosis) are becoming serious global health challenges. Despite various treatment options, successful delivery and effective outcomes have been challenged with several physiological-anatomical barriers, formulation related issues, post-administration hurdles, regulatory constraints, physical hurdles, environmental issues, and safety concern. In the present review, we addressed a brief understanding of pathological and normal condition of blood brain barrier (BBB), rational for brain delivery using nanocarriers, major challenges, advantages of nanomedicine, critical aspects of nanomedicine to translate from bed to clinics, and strategic approaches for improved delivery across BBB. The review addressed various mechanistic perspective for delivery of drug loaded nanocarriers across BBB. Moreover, several reports have been published wherein phytomedicine, exosomes, magnetic nanopartilces, functionalized nanocarriers, cationic nanopartilces, and nano-phytomedicine were investigated for remarkable improvement in neurological disorders. These findings are informative for healthcare professionals, researchers, and scientists working in the domains. The successful application and convincing outcomes of nanomedicines were envisaged with clinical trials conducted on various drugs intended to control neurological disorders (NDs). Conclusively, the review addressed comprehensive findings on various aspects of drug loaded nanocarrier delivery across BBB, considerable risks, potential therapeutic benefits, clinical trial based outcomes, and recent advances followed by future perspectives.}, }
@article {pmid36641254, year = {2023}, author = {Nishijima, DK and Tancredi, DJ and Adelgais, KM and Chadha, K and Chang, TP and Harris, MI and Leonard, JC and Lerner, EB and Linakis, SW and Lowe, GS and Magill, CF and Schwartz, HP and Shah, MI and Browne, LR}, title = {Impact of Race and Ethnicity on Emergency Medical Services Administration of Opioid Pain Medications for Injured Children.}, journal = {The Journal of emergency medicine}, volume = {64}, number = {1}, pages = {55-61}, doi = {10.1016/j.jemermed.2022.10.011}, pmid = {36641254}, issn = {0736-4679}, mesh = {Humans ; Child ; Ethnicity ; Analgesics, Opioid/therapeutic use ; Prospective Studies ; *Emergency Medical Services ; Pain/drug therapy ; Emergency Service, Hospital ; *Fractures, Bone/drug therapy ; }, abstract = {BACKGROUND: Treatment with analgesics for injured children is often not provided or delayed during prehospital transport.<br><br>OBJECTIVE: Our aim was to evaluate racial and ethnic disparities with the use of opioids during transport of injured children.<br><br>METHODS: We conducted a prospective study of injured children transported to 1 of 10 emergency departments from July 2019 to April 2020. Emergency medical services (EMS) providers were surveyed about prehospital pain interventions during transport. Our primary outcome was the use of opioids. We performed multivariate regression analyses to evaluate the association of patient demographic characteristics (race, ethnicity, age, and gender), presence of a fracture, EMS provider type (Advanced Life Support [ALS] or non-ALS) and experience (years), and study site with the use of opioids.<br><br>RESULTS: We enrolled 465 patients; 19% received opioids during transport. The adjusted odds ratios (AORs) for Black race and Hispanic ethnicity were 0.5 (95% CI 0.2-1.2) and 0.4 (95% CI 0.2-1.3), respectively. The presence of a fracture (AOR 17.0), ALS provider (AOR 5.6), older patient age (AOR 1.1 for each year), EMS provider experience (AOR 1.1 for each year), and site were associated with receiving opioids.<br><br>CONCLUSIONS: There were no statistically significant associations between race or ethnicity and use of opioids for injured children. The presence of a fracture, ALS provider, older patient age, EMS provider experience, and site were associated with receiving opioids.}, }
@article {pmid36641216, year = {2023}, author = {Murray, DT and Shin, DS and Classen, S and Brosey, CA and Hura, GL}, title = {Visualizing and accessing correlated SAXS data sets with Similarity Maps and Simple Scattering web resources.}, journal = {Methods in enzymology}, volume = {678}, number = {}, pages = {411-440}, pmid = {36641216}, issn = {1557-7988}, support = {P01 CA092584/CA/NCI NIH HHS/United States ; P30 GM124169/GM/NIGMS NIH HHS/United States ; R35 CA220430/CA/NCI NIH HHS/United States ; }, mesh = {X-Ray Diffraction ; Scattering, Small Angle ; *Proteins ; Molecular Conformation ; Macromolecular Substances ; }, abstract = {Constructing a comprehensive understanding of macromolecular behavior from a set of correlated small angle scattering (SAS) data is aided by tools that analyze all scattering curves together. SAS experiments on biological systems can be performed on specimens that are more easily prepared, modified, and formatted relative to those of most other techniques. An X-ray SAS measurement (SAXS) can be performed in less than a milli-second in-line with treatment steps such as purification or exposure to modifiers. These capabilities are valuable since biological macromolecules (proteins, polynucleotides, lipids, and carbohydrates) change conformation or assembly under specific conditions that often define their biological role. Furthermore, mutation or post-translational modification change their behavior and provides an avenue to tailor their mechanics. Here, we describe tools to combine multiple correlated SAS measurements for analysis and review their application to biological systems. The SAXS Similarity Map (SSM) compares a set of scattering curves and quantifies the similarity between them for display as a color on a grid. Visualizing an entire correlated data set with SSMs helps identify patterns that reveal biological functions. The SSM analysis is available as a web-based tool at https://sibyls.als.lbl.gov/saxs-similarity/. To make data available and promote tool development, we have also deployed a repository of correlated SAS data sets called Simple Scattering (available at https://simplescattering.com). The correlated data sets used to demonstrate the SSM are available on the Simple Scattering website. We expect increased utilization of correlated SAS measurements to characterize the tightly controlled mechanistic properties of biological systems and fine-tune engineered macromolecules for nanotechnology-based applications.}, }
@article {pmid36639403, year = {2023}, author = {Segura, T and Medrano, IH and Collazo, S and Maté, C and Sguera, C and Del Rio-Bermudez, C and Casero, H and Salcedo, I and García-García, J and Alcahut-Rodríguez, C and ,  and Taberna, M}, title = {Symptoms timeline and outcomes in amyotrophic lateral sclerosis using artificial intelligence.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {702}, pmid = {36639403}, issn = {2045-2322}, mesh = {Humans ; Male ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; Retrospective Studies ; Artificial Intelligence ; Delayed Diagnosis ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative motor neuron disease. Although an early diagnosis is crucial to provide adequate care and improve survival, patients with ALS experience a significant diagnostic delay. This study aimed to use real-world data to describe the clinical profile and timing between symptom onset, diagnosis, and relevant outcomes in ALS. Retrospective and multicenter study in 5 representative hospitals and Primary Care services in the SESCAM Healthcare Network (Castilla-La Mancha, Spain). Using Natural Language Processing (NLP), the clinical information in electronic health records of all patients with ALS was extracted between January 2014 and December 2018. From a source population of all individuals attended in the participating hospitals, 250 ALS patients were identified (61.6% male, mean age 64.7 years). Of these, 64% had spinal and 36% bulbar ALS. For most defining symptoms, including dyspnea, dysarthria, dysphagia and fasciculations, the overall diagnostic delay from symptom onset was 11 (6-18) months. Prior to diagnosis, only 38.8% of patients had visited the neurologist. In a median post-diagnosis follow-up of 25 months, 52% underwent gastrostomy, 64% non-invasive ventilation, 16.4% tracheostomy, and 87.6% riluzole treatment; these were more commonly reported (all Ps < 0.05) and showed greater probability of occurrence (all Ps < 0.03) in bulbar ALS. Our results highlight the diagnostic delay in ALS and revealed differences in the clinical characteristics and occurrence of major disease-specific events across ALS subtypes. NLP holds great promise for its application in the wider context of rare neurological diseases.}, }
@article {pmid36638994, year = {2023}, author = {Chen, A and Lv, L and Hu, R and Wei, X and Guan, J and Meng, X}, title = {Achieving win-win outcomes with cerium-loaded porous aluminum sludge hydrogel microspheres for enhanced phosphate removal.}, journal = {The Science of the total environment}, volume = {867}, number = {}, pages = {161530}, doi = {10.1016/j.scitotenv.2023.161530}, pmid = {36638994}, issn = {1879-1026}, abstract = {Breaking the technical bottleneck of traditional powdered adsorbent in phosphate adsorption application treatment, a macroscopic high adsorption performance aluminum sludge-based composite hydrogel material was constructed to synergistically solve the problems of water eutrophication and aluminum sludge resourcization. In this study, porous Ce-modified aluminum sludge hydrogel microspheres (Ce-AlS-SA) were prepared to improve the surface chemical structure and microscopic morphology of the macroscopic adsorbent material to enhance the adsorption capacity and achieve effective solid-liquid separation. The best adsorption performance of the material (Ce-AlS12-SA1) was obtained when the Ce-AlS: SA: Na2CO3 was 12:1:1, and obtained the optimal adsorption conditions by Response Surface Method (RSM) with 1.5 mg/L of the dosage, 4 of pH and 50 mg/L of Cphosphate. The maximum adsorption of 20.36 mg P/g was obtained by the Langmuir model at 303 K, which was 2.92 times more than raw sludge. According to the Freundlich and pseudo-second-order kinetic model, the adsorption process is chemisorption; the multi-stage adsorption process is reflected in the intraparticle diffusion and film diffusion models. The main mechanisms combined with the characterization analysis are electrostatic gravity, ligand exchange, and inner-sphere complexation. Meanwhile, Ce-AlS12-SA1 shows good resistance to interference in the coexistence of multiple ions. Therefore, this material can be recognized as a new material with in-depth, diversified and practical needs for resourceful utilization, which is expected to achieve extensive engineering applications in the future.}, }
@article {pmid36627836, year = {2023}, author = {Kreple, CJ and Searles Nielsen, S and Schoch, KM and Shen, T and Shabsovich, M and Song, Y and Racette, BA and Miller, TM}, title = {Protective Effects of Lovastatin in a Population-Based ALS Study and Mouse Model.}, journal = {Annals of neurology}, volume = {93}, number = {5}, pages = {881-892}, pmid = {36627836}, issn = {1531-8249}, support = {K01 ES028295/ES/NIEHS NIH HHS/United States ; K24 ES017765/ES/NIEHS NIH HHS/United States ; R01 NS078398/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; United States ; Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Superoxide Dismutase-1 ; Sulfasalazine/therapeutic use ; Case-Control Studies ; Telmisartan/therapeutic use ; Spinal Cord/pathology ; Mice, Transgenic ; Superoxide Dismutase/therapeutic use ; Medicare ; *Motor Neuron Disease ; Disease Models, Animal ; }, abstract = {OBJECTIVE: The objective of this study was to use a novel combined pharmacoepidemiologic and amyotrophic lateral sclerosis (ALS) mouse model approach to identify potential motor neuron protective medications.<br><br>METHODS: We constructed a large, population-based case-control study to investigate motor neuron disease (MND) among US Medicare beneficiaries aged 66 to 90 in 2009. We included 1,128 incident MND cases and 56,400 age, sex, race, and ethnicity matched controls. We calculated MND relative risk for >1,000 active ingredients represented in Part D (pharmacy) claims in 2006 to 2007 (>1&#x2009;year before diagnosis/reference). We then applied a comprehensive screening approach to select medications for testing in SOD1[G93A] mice: sulfasalazine, telmisartan, and lovastatin. We treated mice with the human dose equivalent of the medication or vehicle via subcutaneous osmotic pump before onset of weakness. We then assessed weight, gait, and survival. In additional mice, we conducted histological studies.<br><br>RESULTS: We observed previously established medical associations for MND and an inverse dose-response association between lovastatin and MND, with 28% reduced risk at 40&#x2009;mg/day. In SOD1[G93A] mouse studies, sulfasalazine and telmisartan conferred no benefit, whereas lovastatin treatment delayed onset and prolonged survival. Lovastatin treated mice also had less microgliosis, misfolded SOD1, and spinal motor neuron loss in the ventral horn.<br><br>INTERPRETATION: Lovastatin reduced the risk of ALS in humans, which was confirmed in an ALS mouse model by delayed symptom onset, prolonged survival, and preservation of motor neurons. Although further studies to understand the mechanism are required, lovastatin may represent a potential neuroprotective therapy for patients with ALS. These data demonstrate the utility of a combined pharmacoepidemiologic and mouse model approach. ANN NEUROL 2023;93:881-892.}, }
@article {pmid36619755, year = {2022}, author = {Zhan, Y and Liu, H and Cao, Z and Chen, W and Li, Z and Bai, L and Pan, L}, title = {Comparative analysis of fungal communities between herbicide-resistant and -susceptible Alopecurus aequalis.}, journal = {Frontiers in cellular and infection microbiology}, volume = {12}, number = {}, pages = {1094853}, pmid = {36619755}, issn = {2235-2988}, mesh = {*Mycobiome ; *Herbicides/pharmacology ; Acetyl-CoA Carboxylase/genetics ; Poaceae ; *Acetolactate Synthase/genetics ; }, abstract = {INTRODUCTION: Alopecurus aequalis is a grass species invading Chinese canola and wheat fields. An A. aequalis KMN-R population surviving mesosulfuron-methyl treatment with recommended rates was acquired from wheatland. Here, we aimed to confirm the resistance profiles of KMN-R to acetolactate synthetase (ALS) inhibiting herbicides and explore the possible resistance mechanisms to mesosulfuron-methyl in this weed population.<br><br>METHODS: The dose-response tests performed in our study were used to test the toxicity of A. aequalis to ALS-inhibiting herbicides. Sanger sequencing was used to analyze the ALS gene of mesosulfuron-methyl -resistant and -susceptible A. aequalis. RNA sequencing analysis was used to find candidate genes that may confer metabolic resistance to the mesosulfuron-methyl in resistant A. aequalis population. Mesosulfuron-methyl -resistant and -susceptible A. aequalis populations fungal composition was measured via Illumina MiSeq Sequencing.<br><br>RESULTS: Dose-response results indicated that KMN-R population evolved resistance to mesosulfuron-methyl and other tested ALS-inhibiting herbicides. Known resistance-conferring Trp-574-Leu gene mutation in A. aequalis ALS was detected in the KMN-R population. Pretreatment with 4-chloro-7-nitrobenzoxadiazole reversed mesosulfuron-methyl resistance in KMN-R. Glutathione S-transferases (GST) gene GSTZ2 and GSTT3 were highly expressed in KMN-R population. In addition, we evaluated the alpha diversity in A. aequalis, centering on OTU abundance, equality, and multiplicity, and found that the fungal community composition had more unexplained variance between KMN-R and KMN-S A. aequalis. We also observed higher abundances of specific fungi in KMN-R A. aequalis.<br><br>DISCUSSION: The results proved that resistance to mesosulfuron-methyl in A. aequalis KMN-R population is probably caused by target site- and non-target site-based relating GST and provided the basis for further research between fungal interaction and herbicide resistance.}, }
@article {pmid36614963, year = {2022}, author = {Dong, X and Wang, L and Xu, H and Ye, Y and Zhou, Z and Zhang, L}, title = {Effect of a Targeted Ambulance Treatment Quality Improvement Programme on Outcomes from Out-of-Hospital Cardiac Arrest: A Metropolitan Citywide Intervention Study.}, journal = {Journal of clinical medicine}, volume = {12}, number = {1}, pages = {}, pmid = {36614963}, issn = {2077-0383}, support = {72074144//National Natural Science Foundation of China/ ; KJXW2019055//Program of &quot;science, education and health promotion&quot; for youth in Suzhou/ ; SHSMU-ZDCX20212801//Innovative Research Team of High-level Local Universities in Shanghai/ ; }, abstract = {The performance of ambulance crew affects the quality of pre-hospital treatment, which is vital to the survival for out-of-hospital cardiac arrest (OHCA) patients, yet remains suboptimal in China. In this retrospective analysis study, we aimed to examine the effect of a citywide quality improvement programme on provision of prehospital advanced life support (ALS) by emergency medical service (EMS) system. EMS-treated adult OHCA patients after the implementation of the programme (1 January 2021 to 30 June 2022) were compared with historical controls (1 June 2019 to 31 August 2020) in Suzhou. Multivariable logistic regression analysis and propensity score matching procedures were applied to compare the outcomes between two periods for total OHCA cases and subgroup of cases treated by fixed or non-fixed ambulance crews. A total of 1465 patients (pre-period/post-period: 610/855) were included. In the 1:1 matched analysis of 591 cases for each period, significant improvement (p < 0.05) was observed for the proportion of intravenous (IV) access (23.4% vs. 68.2%), advanced airway management (49.2% vs. 57.0%), and return of spontaneous circulation (ROSC) at handover (5.4% vs. 9.0%). The fixed ambulance crews performed better than non-fixed group in IV access and advanced airway management for both periods. There were significant increases in IV access (AOR 12.66, 95%CI 9.02−18.10, p < 0.001), advanced airway management (AOR 1.67, 95% CI 1.30−2.16, p < 0.001) and ROSC at handover (AOR 2.37, 95%CI 1.38−4.23, p = 0.002) after intervention in unfixed group, while no significant improvement was observed in fixed group except for IV access (AOR 7.65, 95%CI 9.02−18.10, p < 0.001). In conclusion, the quality improvement program was positively associated with the provision of prehospital ALS interventions and prehospital ROSC following OHCA. The fixed ambulance crews performed better in critical care provision and prehospital outcome, yet increased protocol adherence and targeted training could fill the underperformance of non-fixed crews efficaciously.}, }
@article {pmid36614029, year = {2022}, author = {Anderson, G}, title = {Amyotrophic Lateral Sclerosis Pathoetiology and Pathophysiology: Roles of Astrocytes, Gut Microbiome, and Muscle Interactions via the Mitochondrial Melatonergic Pathway, with Disruption by Glyphosate-Based Herbicides.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36614029}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/etiology/physiopathology ; Astrocytes/metabolism ; *Gastrointestinal Microbiome ; *Melatonin/metabolism ; Muscles/metabolism ; Reactive Oxygen Species ; *Herbicides/toxicity ; Glyphosate ; }, abstract = {The pathoetiology and pathophysiology of motor neuron loss in amyotrophic lateral sclerosis (ALS) are still to be determined, with only a small percentage of ALS patients having a known genetic risk factor. The article looks to integrate wider bodies of data on the biological underpinnings of ALS, highlighting the integrative role of alterations in the mitochondrial melatonergic pathways and systemic factors regulating this pathway across a number of crucial hubs in ALS pathophysiology, namely glia, gut, and the muscle/neuromuscular junction. It is proposed that suppression of the mitochondrial melatonergic pathway underpins changes in muscle brain-derived neurotrophic factor, and its melatonergic pathway mimic, N-acetylserotonin, leading to a lack of metabolic trophic support at the neuromuscular junction. The attenuation of the melatonergic pathway in astrocytes prevents activation of toll-like receptor agonists-induced pro-inflammatory transcription factors, NF-kB, and yin yang 1, from having a built-in limitation on inflammatory induction that arises from their synchronized induction of melatonin release. Such maintained astrocyte activation, coupled with heightened microglia reactivity, is an important driver of motor neuron susceptibility in ALS. Two important systemic factors, gut dysbiosis/permeability and pineal melatonin mediate many of their beneficial effects via their capacity to upregulate the mitochondrial melatonergic pathway in central and systemic cells. The mitochondrial melatonergic pathway may be seen as a core aspect of cellular function, with its suppression increasing reactive oxygen species (ROS), leading to ROS-induced microRNAs, thereby altering the patterning of genes induced. It is proposed that the increased occupational risk of ALS in farmers, gardeners, and sportsmen and women is intimately linked to exposure, whilst being physically active, to the widely used glyphosate-based herbicides. This has numerous research and treatment implications.}, }
@article {pmid36613534, year = {2022}, author = {Renzini, A and Pigna, E and Rocchi, M and Cedola, A and Gigli, G and Moresi, V and Coletti, D}, title = {Sex and HDAC4 Differently Affect the Pathophysiology of Amyotrophic Lateral Sclerosis in SOD1-G93A Mice.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613534}, issn = {1422-0067}, support = {RBFR12BUMH//Governo Italiano/ ; AR120172839F7670//Sapienza University of Rome/ ; }, mesh = {Animals ; Female ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Disease Models, Animal ; *Histone Deacetylases/genetics ; Mice, Transgenic ; *Neurodegenerative Diseases ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; *Sex Factors ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating adult-onset neurodegenerative disease, with ineffective therapeutic options. ALS incidence and prevalence depend on the sex of the patient. Histone deacetylase 4 (HDAC4) expression in skeletal muscle directly correlates with the progression of ALS, pointing to the use of HDAC4 inhibitors for its treatment. Contrarily, we have found that deletion of HDAC4 in skeletal muscle worsened the pathological features of ALS, accelerating and exacerbating skeletal muscle loss and negatively affecting muscle innervations in male SOD1-G93A (SOD1) mice. In the present work, we compared SOD1 mice of both sexes with the aim to characterize ALS onset and progression as a function of sex differences. We found a global sex-dependent effects on disease onset and mouse lifespan. We further investigated the role of HDAC4 in SOD1 females with a genetic approach, and discovered morpho-functional effects on skeletal muscle, even in the early phase of the diseases. The deletion of HDAC4 decreased muscle function and exacerbated muscle atrophy in SOD1 females, and had an even more dramatic effect in males. Therefore, the two sexes must be considered separately when studying ALS.}, }
@article {pmid36611007, year = {2023}, author = {Taminato, T and Takeuchi, T and Ueyama, M and Mori, K and Ikeda, M and Mochizuki, H and Nagai, Y}, title = {Therapeutic reduction of GGGGCC repeat RNA levels by hnRNPA3 suppresses neurodegeneration in Drosophila models of C9orf72-linked ALS/FTD.}, journal = {Human molecular genetics}, volume = {32}, number = {10}, pages = {1673-1682}, doi = {10.1093/hmg/ddac298}, pmid = {36611007}, issn = {1460-2083}, mesh = {Animals ; Humans ; *Frontotemporal Dementia/pathology ; *Amyotrophic Lateral Sclerosis/metabolism ; RNA/genetics/metabolism ; C9orf72 Protein/genetics ; Drosophila/genetics/metabolism ; *Pick Disease of the Brain/genetics ; Proteins/genetics ; Dipeptides/genetics ; DNA Repeat Expansion/genetics ; }, abstract = {The abnormal expansion of GGGGCC hexanucleotide repeats within the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The accumulation of GGGGCC repeat-containing RNAs as RNA foci, and the deposition of dipeptide repeat proteins (DPR) produced from these repeat RNAs by unconventional translation are major pathological hallmarks of C9orf72-linked ALS/FTD (C9-ALS/FTD), and are both thought to play a crucial role in the pathogenesis of these diseases. Because GGGGCC repeat RNA is likely to be the most upstream therapeutic target in the pathogenic cascade of C9-ALS/FTD, lowering the cellular level of GGGGCC repeat RNA is expected to mitigate repeat RNA toxicity, and will therefore be a disease-modifying therapeutic strategy for the treatment of C9-ALS/FTD. In this study, we demonstrated using a Drosophila model of C9-ALS/FTD that elevated expression of a subset of human RNA-binding proteins that bind to GGGGCC repeat RNA, including hnRNPA3, IGF2BP1, hnRNPA2B1, hnRNPR and SF3B3, reduces the level of GGGGCC repeat RNA, resulting in the suppression of neurodegeneration. We further showed that hnRNPA3-mediated reduction of GGGGCC repeat RNA suppresses disease pathology, such as RNA foci and DPR accumulation. These results demonstrate that hnRNPA3 and other RNA-binding proteins negatively regulate the level of GGGGCC repeat RNA, and mitigate repeat RNA toxicity in vivo, indicating the therapeutic potential of the repeat RNA-lowering approach mediated by endogenous RNA-binding proteins for the treatment of C9-ALS/FTD.}, }
@article {pmid36610130, year = {2023}, author = {Bai, X and Bian, Z and Zhang, M}, title = {Targeting the Nrf2 signaling pathway using phytochemical ingredients: A novel therapeutic road map to combat neurodegenerative diseases.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {109}, number = {}, pages = {154582}, doi = {10.1016/j.phymed.2022.154582}, pmid = {36610130}, issn = {1618-095X}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; NF-E2-Related Factor 2/metabolism ; *Alzheimer Disease/drug therapy ; *Parkinson Disease ; Signal Transduction ; Antioxidants/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a classical nuclear transcription factor that regulates the system's anti-oxidative stress response. The activation of Nrf2 induces the expression of antioxidant proteins and improves the system's anti-oxidative stress ability. Accumulating evidence suggests that Nrf2-centered signaling pathways may be a key pharmacological target for the treatment of neurodegenerative diseases (NDDs). However, phytochemicals as new therapeutic agents against NDDs have not been clearly delineated.<br><br>PURPOSE: To review the therapeutic effects of phytochemical ingredients on NDDs by activating Nrf2 and reducing oxidative stress injury.<br><br>METHODS: A comprehensive search of published articles was performed using various literature databases including PubMed, Google Scholar, and China National Knowledge Infrastructure. The search terms included "Nrf2", "phytochemical ingredients", "natural bioactive agents", "neurodegenerative diseases", "Antioxidant", "Alzheimer's disease", "Parkinson's disease", "Huntington's disease", "amyotrophic lateral sclerosis" "multiple sclerosis", "toxicity", and combinations of these keywords. A total of 769 preclinical studies were retrieved until August 2022, and we included 39 of these articless on phytochemistry, pharmacology, toxicology and other fields.<br><br>RESULTS: Numerous in vivo and in vitro studies showed that phytochemical ingredients could act as an Nrf2 activator in the treatment of NDDs through the antioxidant defense mechanism. These phytochemical ingredients, such as salidroside, naringenin, resveratrol, sesaminol, ellagic acid, ginsenoside Re, tanshinone I, sulforaphane, curcumin, naringin, tetramethylpyrazine, withametelin, magnolol, piperine, and myricetin, had the potential to improve Nrf2 signaling, thereby combatting NDDs.<br><br>CONCLUSION: As Nrf2 activators, phytochemical ingredients may provide a novel potential strategy for the treatment of NDDs. Here, we reviewed the interaction between phytochemical ingredients, Nrf2, and its antioxidant damaging pathway in NDDs and explored the advantages of phytochemical ingredients in anti-oxidative stress, which provides a reliable basis for improving the treatment of NDDs. However, further clinical trials are needed to determine the safety and efficacy of Nrf2 activators for NDDs.}, }
@article {pmid36599670, year = {2023}, author = {Aghaizu, ND and Jolly, S and Samra, SK and Kalmar, B and Craessaerts, K and Greensmith, L and Salinas, PC and De Strooper, B and Whiting, PJ}, title = {Microglial Expression of the Wnt Signaling Modulator DKK2 Differs between Human Alzheimer's Disease Brains and Mouse Neurodegeneration Models.}, journal = {eNeuro}, volume = {10}, number = {1}, pages = {}, pmid = {36599670}, issn = {2373-2822}, support = {/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Mice ; Humans ; Rats ; Animals ; *Alzheimer Disease/pathology ; Microglia/metabolism ; Wnt Signaling Pathway ; *Neurodegenerative Diseases/metabolism ; Brain/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Intercellular Signaling Peptides and Proteins/genetics/metabolism ; Proteins ; }, abstract = {Wnt signaling is crucial for synapse and cognitive function. Indeed, deficient Wnt signaling is causally related to increased expression of DKK1, an endogenous negative Wnt regulator, and synapse loss, both of which likely contribute to cognitive decline in Alzheimer's disease (AD). Increasingly, AD research efforts have probed the neuroinflammatory role of microglia, the resident immune cells of the CNS, which have furthermore been shown to be modulated by Wnt signaling. The DKK1 homolog DKK2 has been previously identified as an activated response and/or disease-associated microglia (DAM/ARM) gene in a mouse model of AD. Here, we performed a detailed analysis of DKK2 in mouse models of neurodegeneration, and in human AD brain. In APP/PS1 and APP[NL-G-F] AD mouse model brains as well as in SOD1[G93A] ALS mouse model spinal cords, but not in control littermates, we demonstrated significant microgliosis and microglial Dkk2 mRNA upregulation in a disease-stage-dependent manner. In the AD models, these DAM/ARM Dkk2[+] microglia preferentially accumulated close to βAmyloid plaques. Furthermore, recombinant DKK2 treatment of rat hippocampal primary neurons blocked WNT7a-induced dendritic spine and synapse formation, indicative of an anti-synaptic effect similar to that of DKK1. In stark contrast, no such microglial DKK2 upregulation was detected in the postmortem human frontal cortex from individuals diagnosed with AD or pathologic aging. In summary, the difference in microglial expression of the DAM/ARM gene DKK2 between mouse models and human AD brain highlights the increasingly recognized limitations of using mouse models to recapitulate facets of human neurodegenerative disease.}, }
@article {pmid36599511, year = {2023}, author = {Mazzola, MA and Russell, JA}, title = {Neurology ethics at the end of life.}, journal = {Handbook of clinical neurology}, volume = {191}, number = {}, pages = {235-257}, doi = {10.1016/B978-0-12-824535-4.00012-4}, pmid = {36599511}, issn = {0072-9752}, mesh = {Humans ; *Terminal Care ; Palliative Care ; Death ; *Neurology ; *Suicide, Assisted ; Ethics, Medical ; }, abstract = {Ethical challenges in medical decision making are commonly encountered by clinicians caring for patients afflicted by neurological injury or disease at the end of life (EOL). In many of these cases, there are conflicting opinions as to what is right and wrong originating from multiple sources. There is a particularly high prevalence of impaired patient judgment and decision-making capacity in this population that may result in a misrepresentation of their premorbid values and goals. Conflict may originate from a discordance between what is legal or from stakeholders who view and value life and existence differently from the patient, at times due to religious or cultural influences. Promotion of life, rather than preservation of existence, is the goal of many patients and the foundation on which palliative care is built. Those who provide EOL care, while being respectful of potential cultural, religious, and legal stakeholder perspectives, must at the same time recognize that these perspectives may conflict with the optimal ethical course to follow. In this chapter, we will attempt to review some of the more notable ethical challenges that may arise in the neurologically afflicted at the EOL. We will identify what we believe to be the most compelling ethical arguments both in support of and opposition to specific EOL issues. At the same time, we will consider how ethical analysis may be influenced by these legal, cultural, and religious considerations that commonly arise.}, }
@article {pmid36589282, year = {2022}, author = {Wei, C and Zhu, Y and Li, S and Chen, W and Li, C and Jiang, S and Xu, R}, title = {Identification of an immune-related gene prognostic index for predicting prognosis, immunotherapeutic efficacy, and candidate drugs in amyotrophic lateral sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {993424}, pmid = {36589282}, issn = {1662-5102}, abstract = {RATIONALE AND OBJECTIVES: Considering the great insufficiency in the survival prediction and therapy of amyotrophic lateral sclerosis (ALS), it is fundamental to determine an accurate survival prediction for both the clinical practices and the design of treatment trials. Therefore, there is a need for more accurate biomarkers that can be used to identify the subtype of ALS which carries a high risk of progression to guide further treatment.<br><br>METHODS: The transcriptome profiles and clinical parameters of a total of 561 ALS patients in this study were analyzed retrospectively by analysis of four public microarray datasets. Based on the results from a series of analyses using bioinformatics and machine learning, immune signatures are able to be used to predict overall survival (OS) and immunotherapeutic response in ALS patients. Apart from other comprehensive analyses, the decision tree and the nomogram, based on the immune signatures, were applied to guide individual risk stratification. In addition, molecular docking methodology was employed to screen potential small molecular to which the immune signatures might response.<br><br>RESULTS: Immune was determined as a major risk factor contributing to OS among various biomarkers of ALS patients. As compared with traditional clinical features, the immune-related gene prognostic index (IRGPI) had a significantly higher capacity for survival prediction. The determination of risk stratification and assessment was optimized by integrating the decision tree and the nomogram. Moreover, the IRGPI may be used to guide preventative immunotherapy for patients at high risks for mortality. The administration of 2MIU IL2 injection in the short-term was likely to be beneficial for the prolongment of survival time, whose dosage should be reduced to 1MIU if the long-term therapy was required. Besides, a useful clinical application for the IRGPI was to screen potential compounds by the structure-based molecular docking methodology.<br><br>CONCLUSION: Ultimately, the immune-derived signatures in ALS patients were favorable biomarkers for the prediction of survival probabilities and immunotherapeutic responses, and the promotion of drug development.}, }
@article {pmid36588399, year = {2023}, author = {Abdulaal, WH and Hosny, KM and Alhakamy, NA and Bakhaidar, RB and Almuhanna, Y and Sabei, FY and Alissa, M and Majrashi, M and Alamoudi, JA and Hazzazi, MS and Jafer, A and Khallaf, RA}, title = {Fabrication, assessment, and optimization of alendronate sodium nanoemulsion-based injectable in-situ gel formulation for management of osteoporosis.}, journal = {Drug delivery}, volume = {30}, number = {1}, pages = {2164094}, pmid = {36588399}, issn = {1521-0464}, mesh = {Animals ; Rats ; Alendronate ; Emulsions ; *Osteoporosis/drug therapy ; Water ; }, abstract = {Low bone mass, degeneration of bone tissue, and disruption of bone microarchitecture are all symptoms of the disease osteoporosis, which can decrease bone strength and increase the risk of fractures. The main objective of the current study was to use a phospholipid-based phase separation in-situ gel (PPSG) in combination with an alendronate sodium nanoemulsion (ALS-NE) to help prevent bone resorption in rats. The effect of factors such as concentrations of the ALS aqueous solution, surfactant Plurol Oleique CC 497, and Maisine CC oil on nanoemulsion characteristics such as stability index and globular size was investigated using an l-optimal coordinate exchange statistical design. Injectable PPSG with the best nanoemulsion formulation was tested for viscosity, gel strength, water absorption, and in-vitro ALS release. ALS retention in the rats' muscles was measured after 30 days. The droplet size and stability index of the optimal nanoemulsion were 90 ± 2.0 nm and 85 ± 1.9%, respectively. When mixed with water, the optimal ALS-NE-loaded PPSG became viscous and achieved 36 seconds of gel strength, which was adequate for an injectable in-situ formulation. In comparison with the ALS solution-loaded in-situ gel, the newly created optimal ALS-NE-loaded PPSG produced the sustained and regulated release of ALS; hence, a higher percentage of ALS remained in rats' muscles after 30 days. PPSG that has been loaded with an ALS-NE may therefore be a more auspicious, productive, and effective platform for osteoporosis treatment than conventional oral forms.}, }
@article {pmid36585109, year = {2023}, author = {Tu, LF and Zhang, TZ and Zhou, YF and Zhou, QQ and Gong, HB and Liang, L and Hai, LN and You, NX and Su, Y and Chen, YJ and Mo, XK and Shi, CZ and Luo, LP and Sun, WY and Duan, WJ and Kurihara, H and Li, YF and He, RR}, title = {GPX4 deficiency-dependent phospholipid peroxidation drives motor deficits of ALS.}, journal = {Journal of advanced research}, volume = {43}, number = {}, pages = {205-218}, pmid = {36585109}, issn = {2090-1224}, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Glutathione Peroxidase/genetics/metabolism ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; *Neurodegenerative Diseases/genetics/pathology ; Peroxides ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; *Phospholipids/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by oxidative stress that triggers motor neurons loss in the brain and spinal cord. However, the mechanisms underlying the exact role of oxidative stress in ALS-associated neural degeneration are not definitively established. Oxidative stress-generated phospholipid peroxides are known to have extensive physiological and pathological consequences to tissues. Here, we discovered that the deficiency of glutathione peroxidase 4 (GPX4), an essential antioxidant peroxidase, led to the accumulation of phospholipid peroxides and resulted in a loss of motor neurons in spinal cords of ALS mice. Mutant human SOD1[G93A] transgenic mice were intrathecally injected with neuron-targeted adeno-associated virus (AAV) expressing GPX4 (GPX4-AAV) or phospholipid peroxidation inhibitor, ferrostatin-1. The results showed that impaired motor performance and neural loss induced by SOD1[G93A] toxicity in the lumbar spine were substantially alleviated by ferrostatin-1 treatment and AAV-mediated GPX4 delivery. In addition, the denervation of neuron-muscle junction and spinal atrophy in ALS mice were rescued by neural GPX4 overexpression, suggesting that GPX4 is essential for the motor neural maintenance and function. In comparison, conditional knockdown of Gpx4 in the spinal cords of Gpx4[fl/fl] mice triggered an obvious increase of phospholipid peroxides and the occurrence of ALS-like motor phenotype. Altogether, our findings underscore the importance of GPX4 in maintaining phospholipid redox homeostasis in the spinal cord and presents GPX4 as an attractive therapeutic target for ALS treatment.}, }
@article {pmid36584643, year = {2023}, author = {Caixeta, DC and Lima, C and Xu, Y and Guevara-Vega, M and Espindola, FS and Goodacre, R and Zezell, DM and Sabino-Silva, R}, title = {Monitoring glucose levels in urine using FTIR spectroscopy combined with univariate and multivariate statistical methods.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {290}, number = {}, pages = {122259}, doi = {10.1016/j.saa.2022.122259}, pmid = {36584643}, issn = {1873-3557}, mesh = {Rats ; Animals ; Spectroscopy, Fourier Transform Infrared/methods ; Creatinine ; *Blood Glucose Self-Monitoring ; Blood Glucose ; Glucose/analysis ; Urea ; *Insulins ; }, abstract = {The development of novel platforms for non-invasive continuous glucose monitoring applied in the screening and monitoring of diabetes is crucial to improve diabetes surveillance systems. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy of urine can be an alternative as a sustainable, label-free, fast, non-invasive, and highly sensitive analysis to detect changes in urine promoted by diabetes and insulin treatment. In this study, we used ATR-FTIR to evaluate the urinary components of non-diabetic (ND), diabetic (D), and diabetic insulin-treated (D + I) rats. As expected, insulin treatment was capable to revert changes in glycemia, 24-h urine collection volume, urine creatinine, urea, and glucose excretion promoted by diabetes. Several differences in the urine spectra of ND, D, and D + I were observed, with urea, creatinine, and glucose analytes being related to these changes. Principal components analysis (PCA) scores plots allowed for the discrimination of ND and D + I from D with an accuracy of ∼ 99 %. The PCA loadings associated with PC1 confirmed the importance of urea and glucose vibrational modes for this discrimination. Univariate analysis of second derivative spectra showed a high correlation (r: 0.865, p < 0.0001) between the height of 1074 cm-1 vibrational mode with urinary glucose concentration. In order to estimate the amount of glucose present in the infrared spectra from urine, multivariate curve resolution-alternating least square (MCR-ALS) was applied and a higher predicted concentration of glucose in the urine was observed with a correlation of 78.9 % compared to urinary glucose concentration assessed using enzyme assays. In summary, ATR-FTIR combined with univariate and multivariate chemometric analyses provides an innovative, non-invasive, and sustainable approach to diabetes surveillance.}, }
@article {pmid36582871, year = {2022}, author = {Pudasaini, P and Neupane, S and Dhakal, B and Rana, A and Pathak, BD and Dawadi, S}, title = {Bulbar onset amyotrophic lateral sclerosis: A case report.}, journal = {Annals of medicine and surgery (2012)}, volume = {84}, number = {}, pages = {104889}, pmid = {36582871}, issn = {2049-0801}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis is a rare progressive neurodegenerative disease that affects the brain and spinal cord nerve cells. The study highlights the role of early diagnosis and prognosis of bulbar onset ALS.<br><br>CASE PRESENTATION: We present a case of 60 years old female who presented with slurring of speech with a deviation of tongue and progressive dysphagia. With the role of Magnetic Resonance Imaging (MRI), Electromyography (EMG) and Nerve Conduction Study (NCS), a diagnosis of ALS was made.<br><br>CLINICAL DISCUSSION: ALS is a progressive neurodegenerative disorder, and the presence of genioglossus muscle involvement at diagnosis implies a shorter survival. It mandates multidisciplinary aspects requiring a professional opinion from neurologists, speech therapists, otolaryngologists, and electrophysiologists for effective treatment. Edaravone has antioxidant properties which counteract oxidative stress leading to neuronal injury in patients with ALS.<br><br>CONCLUSION: ALS with bulbar onset can have a grave prognosis and hence requires a multidisciplinary approach toward effective treatment.}, }
@article {pmid36581807, year = {2022}, author = {Pegani, C and Buttignon, G and Tullio, A and Naccarato, M and Manganotti, P and Rakar, S and Fabris, E and Nadalin, F and Mione, V and Gigli, GL and Lorenzut, S and Spedicato, L and Passadore, P and Pavan, D and Lutman, C and Andrian, M and Borelli, M and Novello, S and Belfiore, R and Daneluzzi, C and Sinagra, G and Peratoner, A}, title = {The impact of COVID-19 on myocardial infarctions, strokes and out-of-hospital cardiopulmonary arrests: an observational retrospective study on time-sensitive disorders in the Friuli Venezia Giulia region (Italy).}, journal = {International journal of emergency medicine}, volume = {15}, number = {1}, pages = {68}, pmid = {36581807}, issn = {1865-1372}, abstract = {The COVID-19 global pandemic has changed considerably the way time-sensitive disorders are treated. Home isolation, people's fear of contracting the virus and hospital reorganisation have led to a significant decrease in contacts between citizens and the healthcare system, with an expected decrease in calls to the Emergency Medical Services (EMS) of the Friuli-Venezia Giulia (FVG) region. However, mortality in clinical emergencies like acute ST-elevation myocardial infarction (STEMI), stroke and out-of-hospital cardiopulmonary arrest (OHCA) remained high. An observational retrospective cross-sectional study was carried out in FVG, taking into account the period between March 1, 2020, and May 31, 2020, the first wave of the COVID-19 pandemic, and comparing it with the same period in 2019. The flow of calls to the EMS was analysed and COVID-19 impact on time-sensitive disorders (STEMIs, ischemic strokes and OHCPAs) was measured in terms of hospitalisation, treatment and mortality. Despite a -8.01% decrease (p value ˂0.001) in emergency response, a 10.89% increase in calls to the EMS was observed. A lower number of advanced cardiopulmonary resuscitations (CPR) (75.8 vs 45.2%, p=0.000021 in April) and ROSC (39.1 vs 11.6%, p=0.0001 in April) was remarked, and survival rate dropped from 8.5 to 5%. There were less strokes (-27.5%, p value=0.002) despite a more severe onset of symptoms at hospitalisation with NHISS˃10 in 38.47% of cases. Acute myocardial infarctions decreased as well (-20%, p value=0.05), but statistical significances were not determined in the variables considered and in mortality. Despite a lower number of emergency responses, the number of calls to the EMS was considerably higher. The number of cardiac arrests treated with advanced CPR (ALS) was lower, but mortality was higher. The number of strokes decreased as well, but at the time of hospitalisation the clinical picture of the patient was more severe, thus affecting the outcome when the patient was discharged. Finally, STEMI patients decreased; however, no critical issues were observed in the variables taken into account, neither in terms of response times nor in terms of treatment times.}, }
@article {pmid36579116, year = {2022}, author = {Li, X and Pan, XH and Fang, Q and Liang, Y}, title = {Pomolidomide for relapsed/refractory light chain amyloidosis after resistance to both bortezomib and daratumumab: A case report.}, journal = {World journal of clinical cases}, volume = {10}, number = {34}, pages = {12703-12710}, pmid = {36579116}, issn = {2307-8960}, abstract = {BACKGROUND: Immunoglobulin light chain (AL) amyloidosis is a rare disease characterized by deposition of ALs essentially in any organ or tissue, with cardiac involvement being very frequent (61%). Early diagnosis is of high importance because early initiation of treatment in AL amyloidosis may improve outcomes. Despite the administration of immunotherapeutic agents, in particular bortezomib and daratumumab, which have improved the outcomes of AL amyloidosis, anti-plasma cell therapy remains suboptimal for some patients.<br><br>CASE SUMMARY: We report the case of a 55-year-old man presenting with heart failure who was diagnosed with cardiac AL amyloidosis by an endomyocardial biopsy. He experienced a short-term hematological remission with no organ response after being administered a bortezomib-daratumumab containing regimen. The treatment was switched to pomolidomide due to pulmonary involvement and progressive pleural effusion, in which flow cytometry analysis showed abnormal plasma cells. After two cycles of this regimen, the pleural effusion was controlled effectively with no recurrence.<br><br>CONCLUSION: This case emphasizes the crucial role of endomyocardial biopsy in early diagnosis of cardiac amyloidosis and suggests that pomolidomide may be an effective treatment for patients with AL amyloidosis that is relapsed/refractory to both bortezomib and daratumumab.}, }
@article {pmid36578193, year = {2023}, author = {Wu, CCH and Brindise, E and Abiad, RE and Khashab, MA}, title = {The Role of Endoscopic Management in Afferent Loop Syndrome.}, journal = {Gut and liver}, volume = {17}, number = {3}, pages = {351-359}, pmid = {36578193}, issn = {2005-1212}, mesh = {Humans ; *Afferent Loop Syndrome/diagnostic imaging/etiology/surgery ; Endoscopy ; Endosonography/methods ; Stents ; Ultrasonography, Interventional ; }, abstract = {Afferent loop syndrome (ALS) is a morbid complication that may occur after gastrectomy and gastrojejunostomy reconstruction. The aim of this article is to review the different endoscopic treatment options of ALS. We describe the evolution of the endoscopic treatment of ALS and its limitations despite the overall propitious profile. We analyze the advantages of endoscopic ultrasound-guided entero-enterostomy (EUS EE) over enteroscopy-guided intervention, and the clinical outcomes of EUS EE. We expound on pre-procedural considerations, intra-procedural techniques and post-procedural care following EUS EE. We conclude that given the simplification of the technique and the ability to place a stent away from the tumor, EUS EE is a promising technique that will likely be established as the treatment of choice for ALS.}, }
@article {pmid36575589, year = {2023}, author = {Hu, WB and Wang, X and Pang, ZL and Duan, R and Hong, CG and Liu, ZZ}, title = {Neutralizing peripheral circulating IL1β slows the progression of ALS in a lentivirus-infected OPTN[E478G] mouse model.}, journal = {Animal models and experimental medicine}, volume = {6}, number = {1}, pages = {18-25}, pmid = {36575589}, issn = {2576-2095}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Interleukin-1beta/metabolism ; Neuroinflammatory Diseases ; Lentivirus/metabolism ; Quality of Life ; Cell Cycle Proteins/metabolism ; Membrane Transport Proteins ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is irreversible and fatal within 3-5 years, with limited options for treatment. It is imperative to develop a symptom-based treatment that may increase the survival of ALS patients and improve their quality of life. Inflammation status, especially elevated interleukin 1β (IL1β), has been reported to play a critical role in ALS progression. Our study determined that neutralizing circulating IL1β slows down the progression of ALS in an ALS mouse model.<br><br>METHODS: The ALS mouse model was developed by microinjection of lentivirus-carrying OPTN[E478G] (optineurin, a mutation from ALS patients) into the intra-motor cortex of mice. Peripheral circulating IL1&#x3b2; was neutralized by injecting anti-IL1&#x3b2; antibody into the tail vein. Enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (RT-PCR) were carried out to determine the protein and gene expression levels of IL1&#x3b2;. TUNEL assay was used to assess the neural cell death. Immunofluorescent staining of MAP2 and CASP3 was accomplished to evaluate neuronal cell apoptosis. Glial fibrillary acidic protein staining was performed to analyze the number of astrocytes. Rotarod test, grip strength test, balance beam test, and footprint test were conducted to assess the locomotive function after anti-IL1&#x3b2; treatment.<br><br>RESULTS: The model revealed that neuroinflammation contributes to ALS progression. ALS mice exhibited elevated neuroinflammation and IL1&#x3b2; secretion. After anti-IL1&#x3b2; treatment, ALS mice revealed decreased neural cell death and astrogliosis and gained improved muscle strength and motor ability.<br><br>CONCLUSIONS: Blocking IL1&#x3b2; is a promising strategy to slow down the progression of ALS.}, }
@article {pmid36573972, year = {2022}, author = {Marcus, R}, title = {What Is Amyotrophic Lateral Sclerosis?.}, journal = {JAMA}, volume = {328}, number = {24}, pages = {2466}, doi = {10.1001/jama.2022.19305}, pmid = {36573972}, issn = {1538-3598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; }, }
@article {pmid36569317, year = {2022}, author = {Wei, L and Wang, R and Lin, K and Jin, X and Li, L and Wazir, J and Pu, W and Lian, P and Lu, R and Song, S and Zhao, Q and Li, J and Wang, H}, title = {Creatine modulates cellular energy metabolism and protects against cancer cachexia-associated muscle wasting.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1086662}, pmid = {36569317}, issn = {1663-9812}, abstract = {Cancer cachexia is a multifactorial syndrome defined by progressive loss of body weight with specific depletion of skeletal muscle and adipose tissue. Since there are no FDA-approved drugs that are available, nutritional intervention is recommended as a supporting therapy. Creatine supplementation has an ergogenic effect in various types of sports training, but the regulatory effects of creatine supplementation in cancer cachexia remain unknown. In this study, we investigated the impact of creatine supplementation on cachectic weight loss and muscle loss protection in a tumor-bearing cachectic mouse model, and the underlying molecular mechanism of body weight protection was further assessed. We observed decreased serum creatine levels in patients with cancer cachexia, and the creatine content in skeletal muscle was also significantly decreased in cachectic skeletal muscle in the C26 tumor-bearing mouse model. Creatine supplementation protected against cancer cachexia-associated body weight loss and muscle wasting and induced greater improvements in grip strength. Mechanistically, creatine treatment altered the dysfunction and morphological abnormalities of mitochondria, thus protecting against cachectic muscle wasting by inhibiting the abnormal overactivation of the ubiquitin proteasome system (UPS) and autophagic lysosomal system (ALS). In addition, electron microscopy revealed that creatine supplementation alleviated the observed increase in the percentage of damaged mitochondria in C26 mice, indicating that nutritional intervention with creatine supplementation effectively counteracts mitochondrial dysfunction to mitigate muscle loss in cancer cachexia. These results uncover a previously uncharacterized role for creatine in cachectic muscle wasting by modulating cellular energy metabolism to reduce the level of muscle cell atrophy.}, }
@article {pmid36563944, year = {2023}, author = {Lan, J and Zhou, Y and Wang, H and Tang, J and Kang, Y and Wang, P and Liu, X and Peng, Y}, title = {Protective effect of human umbilical cord mesenchymal stem cell derived conditioned medium in a mutant TDP-43 induced motoneuron-like cellular model of ALS.}, journal = {Brain research bulletin}, volume = {193}, number = {}, pages = {106-116}, doi = {10.1016/j.brainresbull.2022.12.008}, pmid = {36563944}, issn = {1873-2747}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Culture Media, Conditioned/pharmacology/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Mesenchymal Stem Cells/metabolism ; Motor Neurons/metabolism ; *Neurodegenerative Diseases/metabolism ; NF-E2-Related Factor 2/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multi-factor neurodegenerative disease, characterized by the loss of motor neurons. TAR DNA-binding protein 43 (TDP-43) mutation, accumulation and aggregation, as well as oxidative stress are recognized as major pathological denominators and biochemical markers for ALS. Recently, human umbilical cord mesenchymal stem cell-derived conditioned medium (UC-CM) has been introduced to treat ALS patients. However, there is no research for the protective effect of UC-CM on the TDP-43 model of ALS. In this study, we evaluated the potential neuroprotective effect of UC-CM on a cellular ALS model expressing TDP-43mutant M337V, as well as its underlying mechanism. We found that 24 h UC-CM treatment could protect M337V expressing motor neurons by increasing cell viability and reducing LDH leakage. Furthermore, the aggregation of M337V, generation of ROS, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), protein carbonyl and 8-OHdG were also reduced by UC-CM, indicating that UC-CM protected cells by reducing oxidative damage. Moreover, UC-CM significantly increased the expression of nuclear Nrf2 and its downstream enzyme HO1. The Nrf2 translocation inhibitor ML385 could inhibit the effect of UC-CM on the cell viability and aggregate of M337V. Our results suggest that UC-CM protect cells against M337V expression by its strong antioxidative effect via Nrf-2/HO-1 axis activation.}, }
@article {pmid36559085, year = {2022}, author = {Kurano, T and Kanazawa, T and Iioka, S and Kondo, H and Kosuge, Y and Suzuki, T}, title = {Intranasal Administration of N-acetyl-L-cysteine Combined with Cell-Penetrating Peptide-Modified Polymer Nanomicelles as a Potential Therapeutic Approach for Amyotrophic Lateral Sclerosis.}, journal = {Pharmaceutics}, volume = {14}, number = {12}, pages = {}, pmid = {36559085}, issn = {1999-4923}, support = {JP21J10187, JP20H04537, 22J23853, 22K19921//Japan Society for the Promotion of Science/ ; }, abstract = {Intranasal administration is a promising route for direct drug delivery to the brain; its combination with nanocarriers enhances delivery. We have previously shown that intranasal administration combined with PEG-PCL-Tat (a nanocarrier) efficiently delivers drugs to the brain and exhibits excellent therapeutic efficacy against brain diseases. We aimed to clarify whether intranasal administration combined with PEG-PCL-Tat represents a useful drug delivery system (DDS) for amyotrophic lateral sclerosis (ALS) pharmacotherapy. We used N-acetyl-L-cysteine (NAC) as a model drug with low transferability to the spinal cord and determined the physicochemical properties of NAC/PEG-PCL-Tat. After intranasal administration of NAC/PEG-PCL-Tat, we measured the survival duration of superoxide dismutase-1 G93A mutant transgenic mice (G93A mice), widely used in ALS studies, and quantitatively analyzed the tissue distribution of NAC/PEG-PCL-Tat in ddY mice. The mean particle size and zeta potential of NAC/PEG-PCL-Tat were 294 nm and + 9.29 mV, respectively. Treatment with repeated intranasal administration of NAC/PEG-PCL-Tat considerably prolonged the median survival of G93A mice by 11.5 days compared with that of untreated G93A mice. Moreover, the highest distribution after a single administration of NAC/PEG-PCL-Tat was measured in the spinal cord. These results suggest that intranasal administration combined with PEG-PCL-Tat might represent a useful DDS for ALS therapeutics.}, }
@article {pmid36557291, year = {2022}, author = {Ogbu, D and Zhang, Y and Claud, K and Xia, Y and Sun, J}, title = {Target Metabolites to Slow Down Progression of Amyotrophic Lateral Sclerosis in Mice.}, journal = {Metabolites}, volume = {12}, number = {12}, pages = {}, pmid = {36557291}, issn = {2218-1989}, support = {BC191198//Department of Defence/ ; I01 BX004824/BX/BLRD VA/United States ; DK105118, and R01DK114126//National Institute of Health/ ; VA 1 I01BX004824-01//Veterans for America/ ; R01 DK114126/DK/NIDDK NIH HHS/United States ; R01 DK105118/DK/NIDDK NIH HHS/United States ; DOD CDMRP W81XWH-20-1-0623 (BC191198), DOD BC160450P1//NIDDK/National Institutes of Health/ ; }, abstract = {Microbial metabolites affect the neuron system and muscle cell functions. Amyotrophic lateral sclerosis (ALS) is a multifactorial neuromuscular disease. Our previous study has demonstrated elevated intestinal inflammation and dysfunction of the microbiome in patients with ALS and an ALS mouse model (human-SOD1[G93A] transgenic mice). However, the metabolites in ALS progression are unknown. Using an unbiased global metabolomic measurement and targeted measurement, we investigated the longitudinal changes of fecal metabolites in SOD1[G93A] mice over the course of 13 weeks. We further compared the changes of metabolites and inflammatory response in age-matched wild-type (WT) and SOD1[G93A] mice treated with the bacterial product butyrate. We found changes in carbohydrate levels, amino acid metabolism, and the formation of gamma-glutamyl amino acids. Shifts in several microbially contributed catabolites of aromatic amino acids agree with butyrate-induced changes in the composition of the gut microbiome. Declines in gamma-glutamyl amino acids in feces may stem from differential expression of gamma-glutamyltransferase (GGT) in response to butyrate administration. Due to the signaling nature of amino acid-derived metabolites, these changes indicate changes in inflammation, e.g., histamine, and contribute to differences in systemic levels of neurotransmitters, e.g., γ-Aminobutyric acid (GABA) and glutamate. Butyrate treatment was able to restore some of the healthy metabolites in ALS mice. Moreover, microglia in the spinal cord were measured by IBA1 staining. Butyrate treatment significantly suppressed the IBA1 level in the SOD1[G93A] mice. Serum IL-17 and LPS were significantly reduced in the butyrate-treated SOD1[G93A] mice. We have demonstrated an inter-organ communications link among microbial metabolites, neuroactive metabolites from the gut, and inflammation in ALS progression. The study supports the potential to use metabolites as ALS hallmarks and for treatment.}, }
@article {pmid36556343, year = {2022}, author = {Alarcón-Jimenez, J and de la Rubia Ortí, JE and Martín Ruiz, J and de Bernardo, N and Proaño, B and Villarón-Casales, C}, title = {Muscular Response in ALS Patients during Maximal Bilateral Isometric Work of the Biceps Brachii until Fatigue.}, journal = {Life (Basel, Switzerland)}, volume = {12}, number = {12}, pages = {}, pmid = {36556343}, issn = {2075-1729}, support = {H1479983999044//Valencia Catholic University Saint Vincent Martyr/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative and fatal disease, characterized by the loss of motor neurons and progressive musculoskeletal deterioration. The clinical onset is mainly bulbar or spinal. Considering that there is no effective medical treatment, there is a need to understand the muscle activation patterns to design better physical exercise routines. The objective of this study was to determine muscle strength and fatigue in patients with ALS performing a unilateral exercise, and according to sex and type of ALS. A cross-sectional, analytical study was conducted with 23 patients. Five maximal unilateral isometric contractions were performed with the right and left biceps brachii. Muscle activation was calculated by surface electromyography bilaterally in the biceps brachii, triceps brachii, rectus femoris anterior, and tibialis anterior. The results showed more accentuated fatigue in men than in women, between the first and last contractions performed and especially on the dominant side (p = 0.016). In addition, there was evidence of a coactivation effect on the muscles around the work joint, which reflects a growing activation of synergists, regardless of sex or type of ALS. These findings support the use of systematic and extensive resistance exercise as a non-invasive option for maintaining the functional capacity of patients with ALS.}, }
@article {pmid36552253, year = {2022}, author = {Sato, T and Sato, K}, title = {Adverse Effect of Blue Light on DNA Integrity Is Accelerated by 5-Aminolevulinic Acid in HaCaT Human Keratinocyte Cells and B16F1 Murine Melanoma Cells.}, journal = {Biology}, volume = {11}, number = {12}, pages = {}, pmid = {36552253}, issn = {2079-7737}, abstract = {Several studies have suggested the potential benefits of 5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT). 5-ALA is a precursor of heme, which generates reactive oxygen species (ROS) following photoirradiation. Some reports indicate that blue light induces intracellular ROS production. In the present study, we elucidated the effects of blue light and 5-ALA on DNA integrity in B16F1 murine melanoma and human keratinocyte HaCaT cells using a variety of comet assay techniques. Co-treatment with blue light and 5-ALA significantly decreased cell viability in both cell lines. A neutral comet assay was performed to assess DNA double-strand break (DSB) formation and blue light and 5-ALA caused DSBs. We also performed an alkali comet assay to detect single-strand breaks (SSB) and alkali labile sites (ALS). The results indicated that 5-ALA accelerated blue light-induced SSB formation. In addition, modified comet assays were done using two types of enzymes to evaluate oxidative DNA damages. The results indicated that blue light and 5-ALA generated oxidized purine and pyrimidines in both cell lines. In summary, co-treatment with 5-ALA and photoirradiation may cause unexpected DNA damage in cells and tissues.}, }
@article {pmid36551799, year = {2022}, author = {Silva, D and Rocha, R and Correia, AS and Mota, B and Madeira, MD and Vale, N and Cardoso, A}, title = {Repurposed Edaravone, Metformin, and Perampanel as a Potential Treatment for Hypoxia-Ischemia Encephalopathy: An In Vitro Study.}, journal = {Biomedicines}, volume = {10}, number = {12}, pages = {}, pmid = {36551799}, issn = {2227-9059}, abstract = {Hypoxia-ischemia encephalopathy results from the interruption of oxygen delivery and blood flow to the brain. In the developing brain, it can lead to a brain injury, which is associated with high mortality rates and comorbidities. The hippocampus is one of the brain regions that may be affected by hypoxia-ischemia with consequences on cognition. Unfortunately, clinically approved therapeutics are still scarce and limited. Therefore, in this study, we aimed to test three repurposed drugs with good pharmacological properties to evaluate if they can revert, or at least attenuate, the deleterious effects of hypoxia-ischemia in an in vitro model. Edaravone, perampanel, and metformin are used for the treatment of stroke and amyotrophic lateral sclerosis, some forms of epileptic status, and diabetes type 2, respectively. Through cell viability assays, morphology analysis, and detection of reactive oxygen species (ROS) production, in two different cell lines (HT-22 and SH-SY5Y), we found that edaravone and low concentrations of perampanel are able to attenuate cell damage induced by hypoxia and oxygen-glucose deprivation. Metformin did not attenuate hypoxic-induced events, at least in the initial phase. Among these repurposed drugs, edaravone emerged as the most efficient in the attenuation of events induced by hypoxia-ischemia, and the safest, since it did not exhibit significant cytotoxicity, even in high concentrations, and induced a decrease in ROS. Our results also reinforce the view that ROS and overexcitation play an important role in the pathophysiology of hypoxia-ischemia brain injury.}, }
@article {pmid36547203, year = {2022}, author = {Yoshikawa, S and Taniguchi, K and Sawamura, H and Ikeda, Y and Tsuji, A and Matsuda, S}, title = {Potential Diets to Improve Mitochondrial Activity in Amyotrophic Lateral Sclerosis.}, journal = {Diseases (Basel, Switzerland)}, volume = {10}, number = {4}, pages = {}, pmid = {36547203}, issn = {2079-9721}, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease, the pathogenesis of which is based on alternations in the mitochondria of motor neurons, causing their progressive death. A growing body of evidence shows that more efficient mitophagy could prevent and/or treat this disorder by suppressing mitochondrial dysfunction-induced oxidative stress and inflammation. Mitophagy has been considered one of the main mechanisms responsible for mitochondrial quality control. Since ALS is characterized by enormous oxidative stress, several edible phytochemicals that can activate mitophagy to remove damaged mitochondria could be considered a promising option to treat ALS by providing neuroprotection. Therefore, it is of great significance to explore the mechanisms of mitophagy in ALS and to understand the effects and/or molecular mechanisms of phytochemical action, which could translate into a treatment for neurodegenerative diseases, including ALS.}, }
@article {pmid36546400, year = {2023}, author = {Kaselas, C and Florou, M and Demiri, C and Tsopozidi, M and Anastasiadis, K and Spyridakis, I}, title = {Classification systems of acute appendicitis as an indicator for paediatric surgical consultation of children with acute abdominal pain.}, journal = {Journal of paediatrics and child health}, volume = {59}, number = {2}, pages = {360-364}, doi = {10.1111/jpc.16308}, pmid = {36546400}, issn = {1440-1754}, mesh = {Child ; Humans ; Abdominal Pain/diagnosis/etiology ; Acute Disease ; Appendectomy ; *Appendicitis/diagnosis/surgery ; Sensitivity and Specificity ; }, abstract = {AIM: This study examined if the classification systems for acute appendicitis could be applied in the emergency department as an indicator for surgical consultation, in order to reduce unnecessary paediatric surgery admission.<br><br>METHODS: The Alvarado Score (ALS) and the Pediatric Appendicitis Score (PAS) were applied. The decisions for hospitalisation and treatment were made independent of the scores.<br><br>RESULTS: In total, 307 children with abdominal pain suggestive of acute appendicitis were included. We used a cut-off point of 7 and divided the patients into groups; the group with score&#x2009;&#x2265;&#x2009;7 points was considered the positive ALS and/or PAS group, and the group with score&#x2009;<&#x2009;7 points was the negative ALS and/or PAS group. The same process for cut-values set at 6 points was followed. The joint probabilities for the 7-point-thresholds were: ALS-sensitivity 84%, PAS-sensitivity 85%, ALS-specificity 92%, PAS-specificity 92%, ALS-positive predictive value (PPV) 83%, PAS-PPV 84% and 93% negative predictive value (NPV) for both scores. Considering the 6-point-thresholds, we estimated: 94% sensitivity for both scores, 74% ALS-specificity, 84% PAS-specificity, 66% ALS-PPV, 73% PAS-PPV, 91% ALS-NPV and 97% PAS-NPV.<br><br>CONCLUSION: The scoring systems provided acceptable prediction of patients with and without appendicitis. They may be of use in the emergency department, as assistive diagnostic-tools, in order to reduce paediatric surgery consultations, admissions and treatment costs.}, }
@article {pmid36545529, year = {2022}, author = {Sippel, JL and Daly, JE and Poggensee, L and Ristau, KD and Eberhart, AC and Tam, K and Evans, CT and Lancaster, B and Wickremasinghe, IM and Burns, SP and Goldstein, B and Smith, BM}, title = {Modernization of a Large Spinal Cord Injuries and Disorders Registry: The Veterans Administration Experience.}, journal = {Archives of rehabilitation research and clinical translation}, volume = {4}, number = {4}, pages = {100237}, pmid = {36545529}, issn = {2590-1095}, support = {IK6 HX003156/HX/HSRD VA/United States ; }, abstract = {Since the 1990s, Veterans Health Administration (VHA) has maintained a registry of Veterans with Spinal Cord Injuries and Disorders (SCI/Ds) to guide clinical care, policy, and research. Historically, methods for collecting and recording data for the VHA SCI/D Registry (VSR) have required significant time, cost, and staffing to maintain, were susceptible to missing data, and caused delays in aggregation and reporting. Each subsequent data collection method was aimed at improving these issues over the last several decades. This paper describes the development and validation of a case-finding and data-capture algorithm that uses primary clinical data, including diagnoses and utilization across 9 million VHA electronic medical records, to create a comprehensive registry of living and deceased Veterans seen for SCI/D services since 2012. A multi-step process was used to develop and validate a computer algorithm to create a comprehensive registry of Veterans with SCI/D whose records are maintained in the enterprise wide VHA Corporate Data Warehouse. Chart reviews and validity checks were used to validate the accuracy of cases that were identified using the new algorithm. An initial cohort of 28,202 living and deceased Veterans with SCI/D who were enrolled in VHA care from 10/1/2012 through 9/30/2017 was validated. Tables, reports, and charts using VSR data were developed to provide operational tools to study, predict, and improve targeted management and care for Veterans with SCI/Ds. The modernized VSR includes data on diagnoses, qualifying fiscal year, recent utilization, demographics, injury, and impairment for 38,022 Veterans as of 11/2/2022. This establishes the VSR as one of the largest ongoing longitudinal SCI/D datasets in North America and provides operational reports for VHA population health management and evidence-based rehabilitation. The VSR also comprises one of the only registries for individuals with non-traumatic SCI/Ds and holds potential to advance research and treatment for multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other motor neuron disorders with spinal cord involvement. Selected trends in VSR data indicate possible differences in the future lifelong care needs of Veterans with SCI/Ds. Future collaborative research using the VSR offers opportunities to contribute to knowledge and improve health care for people living with SCI/Ds.}, }
@article {pmid36543326, year = {2022}, author = {Ashhurst, JF and Tu, S and Timmins, HC and Kiernan, MC}, title = {Progress, development, and challenges in amyotrophic lateral sclerosis clinical trials.}, journal = {Expert review of neurotherapeutics}, volume = {22}, number = {11-12}, pages = {905-913}, doi = {10.1080/14737175.2022.2161893}, pmid = {36543326}, issn = {1744-8360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Biomarkers ; Phenotype ; Disease Progression ; Precision Medicine ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) brings unique challenges to a clinical trial setting, due in part to relatively low disease prevalence coupled with a poor prognosis, in addition to the complexities linked to disease heterogeneity. As critical understanding of the disease develops, particularly in relation to clinical phenotype and the mechanisms of disease progression, so too new concepts evolve in relation to clinical trials, including the advent of precision therapy, targeted to subgroups of ALS patients.<br><br>AREAS COVERED: Individualized, or precision medicine in ALS recognizes the heterogeneous nature of the disease and utilizes information such as the clinical phenotype of the disease, clinical biomarkers, and genotyping to promote a tailored approach to treatment. Separate to these considerations, the present review will discuss clinical trial design and how this can be improved to better match patient and investigator needs in ALS clinical trials.<br><br>EXPERT OPINION: Precision therapy will promote a more focused treatment approach, with the goal of improving clinical outcomes for ALS patients. An increased community awareness of ALS, coupled with significant industry and philanthropic funding for ALS research, is accelerating this process.}, }
@article {pmid36535289, year = {2022}, author = {Alencar, MA and Soares, BL and Rangel, MFA and Abdo, JS and Almeida, RAP and Araújo, CM and Souza, LC and Gomes, GC}, title = {Fatigue in amyotrophic lateral sclerosis and correlated factors.}, journal = {Arquivos de neuro-psiquiatria}, volume = {80}, number = {10}, pages = {1045-1051}, pmid = {36535289}, issn = {1678-4227}, mesh = {Female ; Humans ; *Amyotrophic Lateral Sclerosis/complications ; Fatigue/complications ; Muscle Weakness ; *Neurodegenerative Diseases ; Quality of Life ; Male ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to muscle weakness and paralysis. Fatigue is a disabling symptom, frequently reported in ALS, but remains under-investigated in this population. Thus, an accurate investigation of this symptom and possible associated factors in this clinical condition is needed to assist in the establishment of an adequate treatment approach.<br><br>OBJECTIVE: To investigate the presence of fatigue in individuals with ALS and possible factors correlated with this symptom.<br><br>METHODS: Sixty-five individuals with sporadic ALS participated in the present study. Demographic, clinical, and functional aspects were investigated. Evaluations involved the Fatigue Severity Scale (FSS), ALS Functional Scale (ALSRFS-R), and Quality of Life (QoL) questionnaire (ALSAQ-40). Descriptive and correlation analyses were performed with SPSS statistical program for Windows version 19.0 (IBM Corp., Armonk, NY, USA).<br><br>RESULTS: Among the 65 individuals evaluated, 44.6% (n&#x2009;=&#x2009;29) presented fatigue based on the FSS. The mean fatigue intensity was 5.4&#x2009;&#xb1;&#x2009;1.2 and only 10.4% used a specific medication for fatigue. Differences between the groups with and without fatigue were found regarding sex (p&#x2009;=&#x2009;0.049), pain intensity (p&#x2009;=&#x2009;0.026), functioning (p&#x2009;=&#x2009;0.004), disease severity (p&#x2009;=&#x2009;0.029), and QoL (p&#x2009;=&#x2009;0.000). Fatigue was correlated with pain intensity (r&#x2009;=&#x2009;0.425; p&#x2009;=&#x2009;0.001), muscle strength (r&#x2009;=&#x2009;- 0.356; p&#x2009;=&#x2009;0.004), functioning (r&#x2009;=&#x2009;- 0.363; p&#x2009;=&#x2009;0.003), and QoL (r&#x2009;=&#x2009;0.481; p&#x2009;=&#x2009;0.000). No correlations were found with age, time since diagnosis, cramps, or other mobility parameters.<br><br>CONCLUSIONS: Fatigue is a common symptom among individuals with ALS and may be present in all stages of the disease. This symptom was correlated with worse functioning, poorer QoL, greater pain intensity, disease severity, muscle weakness, and the female sex in individuals with ALS.}, }
@article {pmid36533976, year = {2023}, author = {Gelevski, D and Addy, G and Rohrer, M and Cohen, C and Roderick, A and Winter, A and Carey, J and Scalia, J and Yerton, M and Weber, H and Doyle, M and Parikh, N and Kane, G and Ellrodt, A and Burke, K and D'Agostino, D and Sinani, E and Yu, H and Sherman, A and Agosti, J and Redlich, G and Charmley, P and Crowe, D and Appleby, M and Ziegelaar, B and Hanus, K and Li, Z and Babu, S and Nicholson, K and Luppino, S and Berry, J and Baecher-Allan, C and Paganoni, S and Cudkowicz, M}, title = {Safety and activity of anti-CD14 antibody IC14 (atibuclimab) in ALS: Experience with expanded access protocol.}, journal = {Muscle &amp; nerve}, volume = {67}, number = {5}, pages = {354-362}, doi = {10.1002/mus.27775}, pmid = {36533976}, issn = {1097-4598}, support = {1UL1TR002541-01/NH/NIH HHS/United States ; }, mesh = {United States ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Antibodies, Monoclonal/adverse effects ; Disease Progression ; }, abstract = {INTRODUCTION/AIMS: IC14 (atibuclimab) is a monoclonal anti-CD14 antibody. A previous phase 1 trial of 10 participants with amyotrophic lateral sclerosis (ALS) demonstrated initial safety of IC14 in an acute treatment setting. We provided long-term treatment with IC14 to individuals with ALS via an expanded access protocol (EAP) and documented target engagement, biomarker, safety, and disease endpoints.<br><br>METHODS: Participants received intravenous IC14 every 2&#x2009;weeks. Consistent with United States Food and Drug Administration guidelines, participants were not eligible for clinical trials and the EAP was inclusive of a broad population. Whole blood and serum were collected to determine monocyte CD14 receptor occupancy (RO), IC14 levels, and antidrug antibodies. Ex vivo T-regulatory functional assays were performed in a subset of participants.<br><br>RESULTS: Seventeen participants received IC14 for up to 103&#x2009;weeks (average, 30.1&#x2009;weeks; range, 1 to 103&#x2009;weeks). Treatment-emergent adverse events (TEAEs) were uncommon, mild, and self-limiting. There were 18 serious adverse events (SAEs), which were related to disease progression and unrelated or likely unrelated to IC14. Three participants died due to disease progression. Monocyte CD14 RO increased for all participants after IC14 infusion. One individual required more frequent dosing (every 10&#x2009;days) to achieve over 80% RO. Antidrug antibodies were detected in only one participant and were transient, low titer, and non-neutralizing.<br><br>DISCUSSION: Administration of IC14 in ALS was safe and well-tolerated in this intermediate-size EAP. Measuring RO guided dosing frequency. Additional placebo-controlled trials are required to determine the efficacy of IC14 in ALS.}, }
@article {pmid36531135, year = {2022}, author = {Zhang, Y and Chen, L and Li, Z and Li, D and Wu, Y and Guo, Y}, title = {Endothelin-1, over-expressed in SOD1[G93A] mice, aggravates injury of NSC34-hSOD1G93A cells through complicated molecular mechanism revealed by quantitative proteomics analysis.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {1069617}, pmid = {36531135}, issn = {1662-5102}, abstract = {Endothelin-1 (ET-1), a secreted signaling peptide, is suggested to be involved in multiple actions in various tissues including the brain, but its role in amyotrophic lateral sclerosis (ALS) remains unknown. In this study, we detected the expression changes as well as the cellular localization of ET-1, endothelin A (ET-A) and endothelin B (ET-B) receptors in spinal cord of transgenic SOD1-G93A (TgSOD1-G93A) mice, which showed that the two ET receptors (ET-Rs) expressed mainly on neurons and decreased as the disease progressed especially ET-B, while ET-1 expression was up-regulated and primarily localized on astrocytes. We then explored the possible mechanisms underlying the effect of ET-1 on cultured NSC34-hSOD1G93A cell model. ET-1 showed toxic effect on motor neurons (MNs), which can be rescued by the selective ET-A receptor antagonist BQ-123 or ET-B receptor antagonist BQ-788, suggesting that clinically used ET-Rs pan-antagonist could be a potential strategy for ALS. Using proteomic analysis, we revealed that 110 proteins were differentially expressed in NSC34-hSOD1G93A cells after ET-1 treatment, of which 54 were up-regulated and 56 were down-regulated. Bioinformatic analysis showed that the differentially expressed proteins (DEPs) were primarily enriched in hippo signaling pathway-multiple species, ABC transporters, ErbB signaling pathway and so on. These results provide further insights on the potential roles of ET-1 in ALS and present a new promising therapeutic target to protect MNs of ALS.}, }
@article {pmid36527565, year = {2023}, author = {Ashraf, SS and Hosseinpour Sarmadi, V and Larijani, G and Naderi Garahgheshlagh, S and Ramezani, S and Moghadamifar, S and Mohebi, SL and Brouki Milan, P and Haramshahi, SMA and Ahmadirad, N and Amini, N}, title = {Regenerative medicine improve neurodegenerative diseases.}, journal = {Cell and tissue banking}, volume = {24}, number = {3}, pages = {639-650}, pmid = {36527565}, issn = {1573-6814}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Parkinson Disease ; *Alzheimer Disease/therapy ; Regenerative Medicine ; *Amyotrophic Lateral Sclerosis/drug therapy ; }, abstract = {Regenerative medicine is a subdivision of medicine that improves methods to regrow, repair or replace unhealthy cells and tissues to return to normal function. Cell therapy, gene therapy, nanomedicine as choices used to cure neurodegenerative disease. Recently, studies related to the treatment of neurodegenerative disorders have been focused on stem cell therapy and Nano-drugs beyond other than regenerative medicine. Hence, by data from experimental models and clinical trials, we review the impact of stem cell therapy, gene therapy, and nanomedicine on the treatment of Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). Indeed, improved knowledge and continued research on gene therapy and nanomedicine in treating Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis lead to advancements in effective and practical treatments for neurodegenerative diseases.}, }
@article {pmid36522273, year = {2023}, author = {Dufrayer, MC and Monteiro, YMC and Carlesse, FAMC and Motta, F and Daudt, LE and Michalowski, MB}, title = {Antibiotic prophylaxis in acute childhood leukemia: What is known so far?.}, journal = {Hematology, transfusion and cell therapy}, volume = {45}, number = {4}, pages = {473-482}, pmid = {36522273}, issn = {2531-1387}, abstract = {INTRODUCTION: The treatment of acute lymphoblastic leukemia (ALL) has evolved in recent decades, reaching an overall survival rate close to 90%. Currently, approximately 4% of patients with ALL die from secondary complications of chemotherapy. Among these complications, the most frequent is febrile neutropenia (FN). The treatment of acute myeloid leukemias (AMLs) is even more aggressive, being consequently related to a considerable amount of treatment-related toxicity with a high risk of severe infection and death.<br><br>METHOD: In order to reduce the infection-related risks in these groups of patients, systemic antibacterial prophylaxis has emerged as a possible approach.<br><br>RESULTS: Antibiotic prophylaxis during neutropenia periods in those undergoing chemotherapy have .already been proven in adults with acute leukemias (ALs). Among the possible available therapeutic options for bacterial prophylaxis in children with cancer, fluoroquinolones emerged with the most amount of evidence. Within this class, levofloxacin became the best choice.<br><br>CONCLUSION: Therefore, the use of levofloxacin seems to be indicated in very specific situations: in children who are known to be neutropenic for a long time, secondary to intensive chemotherapy; in children with AL undergoing chemotherapy to induce remission; or in children undergoing hematopoietic stem cell transplantation (HSCT). This article aims to describe recent evidence focusing on antibiotic prophylaxis in children with ALs.}, }
@article {pmid36518658, year = {2022}, author = {Jiang, J and Wang, Y and Deng, M}, title = {New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1054006}, pmid = {36518658}, issn = {1663-9812}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily affects motor neurons in the brain and spinal cord. In the recent past, there have been just two drugs approved for treatment, riluzole and edaravone, which only prolong survival by a few months. However, there are many novel experimental drugs in development. In this review, we summarize 53 new drugs that have been evaluated in clinical trials from 2020 to 2022, which we have classified into eight mechanistic groups (anti-apoptotic, anti-inflammatory, anti-excitotoxicity, regulated integrated stress response, neurotrophic factors and neuroprotection, anti-aggregation, gene therapy and other). Six were tested in phase 1 studies, 31 were in phase 2 studies, three failed in phase 3 studies and stopped further development, and the remaining 13 drugs were being tested in phase 3 studies, including methylcobalamin, masitinib, MN-166, verdiperstat, memantine, AMX0035, trazodone, CNM-Au8, pridopidine, SLS-005, IONN363, tofersen, and reldesemtiv. Among them, five drugs, including methylcobalamin, masitinib, AMX0035, CNM-Au8, and tofersen, have shown potent therapeutic effects in clinical trials. Recently, AMX0035 has been the third medicine approved by the FDA for the treatment of ALS after riluzole and edaravone.}, }
@article {pmid36516126, year = {2022}, author = {Rei, N and Valente, CA and Vaz, SH and Farinha-Ferreira, M and Ribeiro, JA and Sebastião, AM}, title = {Changes in adenosine receptors and neurotrophic factors in the SOD1G93A mouse model of amyotrophic lateral sclerosis: Modulation by chronic caffeine.}, journal = {PloS one}, volume = {17}, number = {12}, pages = {e0272104}, pmid = {36516126}, issn = {1932-6203}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; Caffeine/pharmacology/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Vascular Endothelial Growth Factor Receptor-2/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Spinal Cord/metabolism ; Receptors, Purinergic P1/genetics/metabolism ; Adenosine/metabolism ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of corticospinal tract motor neurons. Previous studies showed that adenosine-mediated neuromodulation is disturbed in ALS and that vascular endothelial growth factor (VEGF) has a neuroprotective function in ALS mouse models. We evaluated how adenosine (A1R and A2AR) and VEGF (VEGFA, VEGFB, VEGFR-1 and VEGFR-2) system markers are altered in the cortex and spinal cord of pre-symptomatic and symptomatic SOD1G93A mice. We then assessed if/how chronic treatment of SOD1G93A mice with a widely consumed adenosine receptor antagonist, caffeine, modulates VEGF system and/or the levels of Brain-derived Neurotrophic Factor (BDNF), known to be under control of A2AR. We found out decreases in A1R and increases in A2AR levels even before disease onset. Concerning the VEGF system, we detected increases of VEGFB and VEGFR-2 levels in the spinal cord at pre-symptomatic stage, which reverses at the symptomatic stage, and decreases of VEGFA levels in the cortex, in very late disease states. Chronic treatment with caffeine rescued cortical A1R levels in SOD1G93A mice, bringing them to control levels, while rendering VEGF signaling nearly unaffected. In contrast, BDNF levels were significantly affected in SOD1G93A mice treated with caffeine, being decreased in the cortex and increased in spinal the cord. Altogether, these findings suggest an early dysfunction of the adenosinergic system in ALS and highlights the possibility that the negative influence of caffeine previously reported in ALS animal models results from interference with BDNF rather than with the VEGF signaling molecules.}, }
@article {pmid36516010, year = {2023}, author = {Gao, L and Giannousis, P and Thoolen, M and Kaushik, D and Latham, J and Tansy, A and Ma, J and Johnston, M and Dali, M and Golden, L and Klein, M and Kong, R and Trimmer, J}, title = {First-in-Human Studies of Pharmacokinetics and Safety of Utreloxastat (PTC857), a Novel 15-Lipooxygenase Inhibitor for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Clinical pharmacology in drug development}, volume = {12}, number = {2}, pages = {141-151}, pmid = {36516010}, issn = {2160-7648}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Area Under Curve ; Half-Life ; Double-Blind Method ; Kinetics ; }, abstract = {Utreloxastat (PTC857) is a 15-lipoxygenase inhibitor being developed to treat amyotrophic lateral sclerosis. This first-in-human study investigated the safety and pharmacokinetics of utreloxastat in healthy volunteers (N = 82) in a double-blind, placebo-controlled trial. The effects of a single ascending dose (100-1000 mg), multiple ascending doses (150-500 mg), and food (500 mg) on the pharmacokinetics and safety of utreloxastat were evaluated. Following single doses, the time to maximum plasma concentration (Cmax) was observed ≈4 hours after dosing and the terminal half-life ranged from 20 to 25.3 hours. The Cmax and area under the concentration-time curve (AUC) increased slightly over dose proportionally. Following multiple doses (once daily/twice daily), the apparent clearance reduced and terminal half-life was ≥33 hours. There was no apparent difference of exposure following morning or evening doses. Varying diets increased the Cmax and AUCs of utreloxastat but did not alter time to Cmax . There were no gender-based differences in exposure. Utreloxastat showed no marked safety signal following single doses up to 1000 mg and multiple doses over 14 days of 500 mg once daily or 250 mg twice daily. The results support further development of utreloxastat for the treatment of patients with amyotrophic lateral sclerosis at a 250-mg twice-daily dose administered with food.}, }
@article {pmid36513873, year = {2024}, author = {Ahmad, F and Sachdeva, P and Sachdeva, B and Singh, G and Soni, H and Tandon, S and Rafeeq, MM and Alam, MZ and Baeissa, HM and Khalid, M}, title = {Dioxinodehydroeckol: A Potential Neuroprotective Marine Compound Identified by In Silico Screening for the Treatment and Management of Multiple Brain Disorders.}, journal = {Molecular biotechnology}, volume = {66}, number = {4}, pages = {663-686}, pmid = {36513873}, issn = {1559-0305}, mesh = {*Molecular Docking Simulation ; Humans ; *Neuroprotective Agents/pharmacology/chemistry ; *Molecular Dynamics Simulation ; Dioxins/pharmacology/chemistry ; Computer Simulation ; Brain Diseases/drug therapy/metabolism ; Aquatic Organisms/chemistry ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Glioblastoma multiforme (GBM), Amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD) are some of the most prevalent neurodegenerative disorders in humans. Even after a variety of advanced therapies, prognosis of all these disorders is not favorable, with survival rates of 14-20 months only. To further improve the prognosis of these disorders, it is imperative to discover new compounds which will target effector proteins involved in these disorders. In this study, we have focused on in silico screening of marine compounds against multiple target proteins involved in AD, GBM, ALS, and PD. Fifty marine-origin compounds were selected from literature, out of which, thirty compounds passed ADMET parameters. Ligand docking was performed after ADMET analysis for AD, GBM, ALS, and PD-associated proteins in which four protein targets Keap1, Ephrin A2, JAK3 Kinase domain, and METTL3-METTL14 N6-methyladenosine methyltransferase (MTA70) were found to be binding strongly with the screened compound Dioxinodehydroeckol (DHE). Molecular dynamics simulations were performed at 100 ns with triplicate runs to validate the docking score and assess the dynamics of DHE interactions with each target protein. The results indicated Dioxinodehydroeckol, a novel marine compound, to be a putative inhibitor among all the screened molecules, which might be effective against multiple target proteins involved in neurological disorders, requiring further in vitro and in vivo validations.}, }
@article {pmid36510311, year = {2022}, author = {Xia, X and Wang, Y and Zheng, JC}, title = {Extracellular vesicles, from the pathogenesis to the therapy of neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {11}, number = {1}, pages = {53}, pmid = {36510311}, issn = {2047-9158}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/therapy/pathology ; *Extracellular Vesicles/pathology ; *Alzheimer Disease/pathology ; Brain/pathology ; Central Nervous System/pathology ; Biomarkers ; }, abstract = {Extracellular vesicles (EVs) are small bilipid layer-enclosed vesicles that can be secreted by all tested types of brain cells. Being a key intercellular communicator, EVs have emerged as a key contributor to the pathogenesis of various neurodegenerative diseases (NDs) including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease through delivery of bioactive cargos within the central nervous system (CNS). Importantly, CNS cell-derived EVs can be purified via immunoprecipitation, and EV cargos with altered levels have been identified as potential biomarkers for the diagnosis and prognosis of NDs. Given the essential impact of EVs on the pathogenesis of NDs, pathological EVs have been considered as therapeutic targets and EVs with therapeutic effects have been utilized as potential therapeutic agents or drug delivery platforms for the treatment of NDs. In this review, we focus on recent research progress on the pathological roles of EVs released from CNS cells in the pathogenesis of NDs, summarize findings that identify CNS-derived EV cargos as potential biomarkers to diagnose NDs, and comprehensively discuss promising potential of EVs as therapeutic targets, agents, and drug delivery systems in treating NDs, together with current concerns and challenges for basic research and clinical applications of EVs regarding NDs.}, }
@article {pmid36504406, year = {2023}, author = {Genge, A and Pattee, GL and Sobue, G and Aoki, M and Yoshino, H and Couratier, P and Lunetta, C and Petri, S and Selness, D and Bidani, S and Hirai, M and Sakata, T and Salah, A and Apple, S and Wamil, A and Kalin, A and Jackson, CE}, title = {Oral edaravone demonstrated a favorable safety profile in patients with amyotrophic lateral sclerosis after 48 weeks of treatment.}, journal = {Muscle &amp; nerve}, volume = {67}, number = {2}, pages = {124-129}, pmid = {36504406}, issn = {1097-4598}, mesh = {Female ; Humans ; Male ; Middle Aged ; Administration, Oral ; *Amyotrophic Lateral Sclerosis/drug therapy ; Constipation ; *Edaravone/administration &amp; dosage/adverse effects ; }, abstract = {INTRODUCTION/AIMS: An intravenous (IV) formulation of edaravone has been shown to slow the rate of physical functional decline in amyotrophic lateral sclerosis (ALS). An oral suspension formulation of edaravone was recently approved by the United States Food and Drug Administration for use in patients with ALS. This study assessed the safety and tolerability of oral edaravone.<br><br>METHODS: This global, open-label, phase 3 study evaluated the long-term safety and tolerability of oral edaravone in adults with ALS who had a baseline forced vital capacity &#x2265;70% of predicted and disease duration &#x2264;3&#xa0;y. The primary safety analysis was assessed at weeks 24 and 48. Patients received a 105-mg dose of oral edaravone in treatment cycles replicating the dosing of IV edaravone.<br><br>RESULTS: The study enrolled 185 patients (64.3% male; mean age, 59.9&#xa0;y; mean disease duration, 1.56&#x2009;y). The most common treatment-emergent adverse events (TEAEs) at week 48 were fall (22.2%), muscular weakness (21.1%) and constipation (17.8%). Serious TEAEs were reported by 25.9% of patients; the most common were worsening ALS symptoms, dysphagia, dyspnea, and respiratory failure. Twelve TEAEs leading to death were reported. Forty-six (24.9%) patients reported TEAEs that were considered related to study drug; the most common were fatigue, dizziness, headache, and constipation. Sixteen (8.6%) patients discontinued study drug due to TEAEs. No serious TEAEs were related to study drug.<br><br>DISCUSSION: This study indicated that oral edaravone was well tolerated during 48&#x2009;wk of treatment, with no new safety concerns identified.}, }
@article {pmid36504281, year = {2023}, author = {Hansson, O and Kumar, A and Janelidze, S and Stomrud, E and Insel, PS and Blennow, K and Zetterberg, H and Fauman, E and Hedman, &#xc5;K and Nagle, MW and Whelan, CD and Baird, D and Mälarstig, A and Mattsson-Carlgren, N}, title = {The genetic regulation of protein expression in cerebrospinal fluid.}, journal = {EMBO molecular medicine}, volume = {15}, number = {1}, pages = {e16359}, pmid = {36504281}, issn = {1757-4684}, support = {U01 AG046152/AG/NIA NIH HHS/United States ; R01 MH109897/MH/NIMH NIH HHS/United States ; R37 MH057881/MH/NIMH NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; 681712/ERC_/European Research Council/International ; R01 AG017917/AG/NIA NIH HHS/United States ; U01 MH103392/MH/NIMH NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; HHSN271201300031C/DA/NIDA NIH HHS/United States ; P50 MH066392/MH/NIMH NIH HHS/United States ; R01 AG018023/AG/NIA NIH HHS/United States ; R01 AG068398/AG/NIA NIH HHS/United States ; R01 MH109677/MH/NIMH NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; P50 MH084053/MH/NIMH NIH HHS/United States ; R01 MH097276/MH/NIMH NIH HHS/United States ; P01 AG002219/AG/NIA NIH HHS/United States ; R01 MH093725/MH/NIMH NIH HHS/United States ; P50 AG005138/AG/NIA NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; R01 AG048015/AG/NIA NIH HHS/United States ; P50 AG025711/AG/NIA NIH HHS/United States ; R01 MH110921/MH/NIMH NIH HHS/United States ; P01 AG017216/AG/NIA NIH HHS/United States ; R01 MH080405/MH/NIMH NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; R01 AG036836/AG/NIA NIH HHS/United States ; R01 MH085542/MH/NIMH NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics/cerebrospinal fluid ; Matrix Metalloproteinase 10/genetics ; *Parkinson Disease/genetics ; Proteomics ; Quantitative Trait Loci ; Biomarkers/cerebrospinal fluid ; Antigens, CD ; Sialic Acid Binding Immunoglobulin-like Lectins/genetics ; Membrane Proteins/genetics ; ADAM Proteins/genetics ; Membrane Glycoproteins/genetics ; }, abstract = {Studies of the genetic regulation of cerebrospinal fluid (CSF) proteins may reveal pathways for treatment of neurological diseases. 398 proteins in CSF were measured in 1,591 participants from the BioFINDER study. Protein quantitative trait loci (pQTL) were identified as associations between genetic variants and proteins, with 176 pQTLs for 145 CSF proteins (P < 1.25 × 10[-10] , 117 cis-pQTLs and 59 trans-pQTLs). Ventricular volume (measured with brain magnetic resonance imaging) was a confounder for several pQTLs. pQTLs for CSF and plasma proteins were overall correlated, but CSF-specific pQTLs were also observed. Mendelian randomization analyses suggested causal roles for several proteins, for example, ApoE, CD33, and GRN in Alzheimer's disease, MMP-10 in preclinical Alzheimer's disease, SIGLEC9 in amyotrophic lateral sclerosis, and CD38, GPNMB, and ADAM15 in Parkinson's disease. CSF levels of GRN, MMP-10, and GPNMB were altered in Alzheimer's disease, preclinical Alzheimer's disease, and Parkinson's disease, respectively. These findings point to pathways to be explored for novel therapies. The novel finding that ventricular volume confounded pQTLs has implications for design of future studies of the genetic regulation of the CSF proteome.}, }
@article {pmid36503675, year = {2023}, author = {Camu, W and De La Cruz, E and Esselin, F}, title = {Therapeutic tools for familial ALS.}, journal = {Revue neurologique}, volume = {179}, number = {1-2}, pages = {49-53}, doi = {10.1016/j.neurol.2022.10.001}, pmid = {36503675}, issn = {0035-3787}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Superoxide Dismutase-1/genetics ; Mutation ; Oligonucleotides, Antisense/therapeutic use ; Genetic Therapy/methods ; }, abstract = {Familial ALS (FALS) accounts for 10 to 15% of ALS cases. In more than 70% of FALS patients, a causal gene is identified and animal models have been developed for a subset of them, mainly for the most frequently mutated genes. Therapeutic tools to treat those patients are dominated by gene-specific therapy and the most advanced approaches target the SOD1 gene mutations. Either by direct delivery of antisense oligonucleotides (ASO) or using viral vectors such as adenoviruses (AAV) to deliver ASOs, gene specific therapies have shown promising results in animal models. The recent use of subpial injections of AAV9+anti SOD1 ASO now shows that the disease is completely prevented or stopped in the animal, depending on the moment of injection, e.g., before or after disease onset. However, the use of viral vectors in humans seems to be limited at least by their immunogenicity. Antibody-based therapies are also efficient to treat animal models, but to a lesser extent. Most of the experiments targeted the SOD1 protein in its misfolded conformation. This approach seems better tolerated than the AAV one, an important limit being the choice of the epitope. Unexpectedly, some advances in treating the C9ORF72 animal model have been obtained using a modulation of microbiota, and this strategy has the great advantage to have an easy route of administration and a good safety profile. The landscape of experimental FALS treatment is rapidly evolving and results are promising. This is an important unmet need for ALS patients and several human phase I, II and III trials are ongoing.}, }
@article {pmid36503310, year = {2023}, author = {Gebrehiwet, P and Meng, L and Rudnicki, SA and Sarocco, P and Wei, J and Wolff, AA and Chiò, A and Andrews, JA and Genge, A and Jackson, CE and Lechtzin, N and Miller, TM and Shefner, JM}, title = {MiToS and King's staging as clinical outcome measures in ALS: a retrospective analysis of the FORTITUDE-ALS trial.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {3-4}, pages = {304-310}, doi = {10.1080/21678421.2022.2154678}, pmid = {36503310}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Retrospective Studies ; Disease Progression ; Outcome Assessment, Health Care ; }, abstract = {OBJECTIVE: To evaluate the Milano-Torino staging (MiToS) and King's staging systems as potential outcome measures for clinical trials in amyotrophic lateral sclerosis (ALS) by assessing these outcomes in FORTITUDE-ALS.<br><br>METHODS: This was a post hoc analysis of the phase 2b FORTITUDE-ALS trial (NCT03160898), a double-blind, randomized, dose-ranging, placebo-controlled, parallel-group study of reldesemtiv in patients with ALS. The treatment period was 12 weeks, with a follow-up assessment at week 16. Patients were retrospectively classified into MiToS and King's stages. Outcomes were the mean time maintaining baseline stage and risk of progression from the baseline stage to a later stage.<br><br>RESULTS: The full analysis set consisted of 456 patients randomized 3:1 (reldesemtiv n&#x2009;=&#x2009;342, placebo n&#x2009;=&#x2009;114) who received at least one dose of double-blind study drug and had at least one post-baseline assessment. At baseline, MiToS and King's stages were balanced between the reldesemtiv and placebo groups: >99% of patients were in MiToS stage 0 or 1 and King's stage 1, 2 or 3. Time of maintaining the baseline stage was similar in both groups, for each staging system. The two staging systems exhibited considerably disparate results for risk of progression from baseline to a later stage: hazard ratio (HR) = 0.62 (95% confidence interval [CI] 0.38, 0.99) for MiToS and HR = 0.96 (95% CI 0.63, 1.44) for King's.<br><br>CONCLUSION: This exploratory analysis showed the feasibility of MiToS and King's staging as potential outcome measures in ALS. Additional studies of these staging systems are needed to further explore their utility in ALS clinical trials.}, }
@article {pmid36501398, year = {2022}, author = {Cusaro, CM and Grazioli, C and Capelli, E and Picco, AM and Guarise, M and Gozio, E and Zarpellon, P and Brusoni, M}, title = {Involvement of miRNAs in Metabolic Herbicide Resistance to Bispyribac-Sodium in Echinochloa crus-galli (L.) P. Beauv.}, journal = {Plants (Basel, Switzerland)}, volume = {11}, number = {23}, pages = {}, pmid = {36501398}, issn = {2223-7747}, support = {41 - EPIRESISTENZE//Lombardy Region/ ; liberal research grant//Dow AgroSciences/ ; }, abstract = {Several mechanisms involved in weed herbicide resistance are unknown, particularly those acting at the epigenetic level, such as the capacity of small-non-coding RNAs (sncRNAs) to target messenger RNAs of genes involved in herbicide detoxification. The transcription of these sncRNAs is stimulated by epigenetic factors, thereby affecting gene expression. This study was carried out in order to evaluate, for the first time in Echinochloa crus-galli (L.) P. Beauv. (barnyardgrass), the capacity of miRNAs to regulate the expression of genes associated with bispyribac-sodium detoxification. The expression profiles of eight miRNAs with a high degree of complementarity (≥80%) with mRNAs of genes involved in herbicide detoxification (CYP450, GST and eIF4B) were determined by qRT-PCR before and after herbicide spraying. Five of the miRNAs studied (gra-miR7487c, gma-miR396f, gra-miR8759, osa-miR395f, ath-miR847) showed an increased expression after herbicide application in both susceptible and resistant biotypes. All the miRNAs, except gra-miR8759, were more highly expressed in the herbicide-resistant biotypes. In specimens with increased expression of miRNAs, we observed reduced expression of the target genes. The remaining three miRNAs (ata-miR166c-5p, ath-miR396b-5p and osa-miR5538) showed no over-expression after herbicide treatment, and no difference in expression was recorded between susceptible and resistant biotypes. Our results represent a first overview of the capacity of miRNAs to regulate the expression of genes involved in bispyribac-sodium detoxification in the genus Echinochloa. Further research is required to identify novel miRNAs and target genes to develop more focused and sustainable strategies of weed control.}, }
@article {pmid36500540, year = {2022}, author = {Angelopoulou, E and Pyrgelis, ES and Piperi, C}, title = {Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {23}, pages = {}, pmid = {36500540}, issn = {1420-3049}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/pathology ; Phosphoric Diester Hydrolases ; Proteasome Endopeptidase Complex ; Pyridines/pharmacology ; Ubiquitin ; }, abstract = {Neurodegenerative diseases constitute a broad range of central nervous system disorders, characterized by neuronal degeneration. Alzheimer's disease, Parkinson's disease, amyolotrophic lateral sclerosis (ALS), and progressive forms of multiple sclerosis (MS) are some of the most frequent neurodegenerative diseases. Despite their diversity, these diseases share some common pathophysiological mechanisms: the abnormal aggregation of disease-related misfolded proteins, autophagosome-lysosome pathway dysregulation, impaired ubiquitin-proteasome system, oxidative damage, mitochondrial dysfunction and excessive neuroinflammation. There is still no effective drug that could halt the progression of neurodegenerative diseases, and the current treatments are mainly symptomatic. In this regard, the development of novel multi-target pharmaceutical approaches presents an attractive therapeutic strategy. Ibudilast, an anti-inflammatory drug firstly developed as an asthma treatment, is a cyclic nucleotide phosphodiesterases (PDEs) inhibitor, which mainly acts by increasing the amount of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), while downregulating the pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α), macrophage migration inhibitory factor (MIF) and Toll-like receptor 4 (TLR-4). The preclinical evidence shows that ibudilast may act neuroprotectively in neurodegenerative diseases, by suppressing neuroinflammation, inhibiting apoptosis, regulating the mitochondrial function and by affecting the ubiquitin-proteasome and autophagosome-lysosome pathways, as well as by attenuating oxidative stress. The clinical trials in ALS and progressive MS also show some promising results. Herein, we aim to provide an update on the emerging preclinical and clinical evidence on the therapeutic potential of ibudilast in these disorders, discuss the potential challenges and suggest the future directions.}, }
@article {pmid36499544, year = {2022}, author = {Giallongo, S and Longhitano, L and Denaro, S and D'Aprile, S and Torrisi, F and La Spina, E and Giallongo, C and Mannino, G and Lo Furno, D and Zappalà, A and Giuffrida, R and Parenti, R and Li Volti, G and Tibullo, D and Vicario, N}, title = {The Role of Epigenetics in Neuroinflammatory-Driven Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {23}, pages = {}, pmid = {36499544}, issn = {1422-0067}, support = {(FUV)//F.T. was supported by the Fondazione Umberto Veronesi./ ; R&amp;I 2014-2020-E68D19001340001//C.G. was supported by the PON AIM/ ; R&amp;I 2014-2020-E66C18001240007//N.V. was supported by the PON AIM/ ; }, mesh = {Humans ; *Histones/metabolism ; Neuroinflammatory Diseases ; Epigenesis, Genetic ; Epigenomics ; *Neurodegenerative Diseases/genetics ; }, abstract = {Neurodegenerative disorders are characterized by the progressive loss of central and/or peripheral nervous system neurons. Within this context, neuroinflammation comes up as one of the main factors linked to neurodegeneration progression. In fact, neuroinflammation has been recognized as an outstanding factor for Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS). Interestingly, neuroinflammatory diseases are characterized by dramatic changes in the epigenetic profile, which might provide novel prognostic and therapeutic factors towards neuroinflammatory treatment. Deep changes in DNA and histone methylation, along with histone acetylation and altered non-coding RNA expression, have been reported at the onset of inflammatory diseases. The aim of this work is to review the current knowledge on this field.}, }
@article {pmid36495857, year = {2023}, author = {Tse, NY and Bocchetta, M and Todd, EG and Devenney, EM and Tu, S and Caga, J and Hodges, JR and Halliday, GM and Irish, M and Kiernan, MC and Piguet, O and Rohrer, JD and Ahmed, RM}, title = {Distinct hypothalamic involvement in the amyotrophic lateral sclerosis-frontotemporal dementia spectrum.}, journal = {NeuroImage. Clinical}, volume = {37}, number = {}, pages = {103281}, pmid = {36495857}, issn = {2213-1582}, support = {MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; MR/M023664/1/MRC_/Medical Research Council/United Kingdom ; MR/T046015/1/MRC_/Medical Research Council/United Kingdom ; BRC149/NS/MH/DH_/Department of Health/United Kingdom ; }, mesh = {Humans ; *Frontotemporal Dementia/pathology ; *Amyotrophic Lateral Sclerosis/pathology ; *Apathy ; Feeding Behavior ; Hypothalamus/pathology ; }, abstract = {BACKGROUND: Hypothalamic dysregulation plays an established role in eating abnormalities in behavioural variant frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis (ALS). Its contribution to cognitive and behavioural impairments, however, remains unexplored.<br><br>METHODS: Correlation between hypothalamic subregion atrophy and cognitive and behavioural impairments was examined in a large sample of 211 participants (52 pure ALS, 42 mixed ALS-FTD, 59 bvFTD, and 58 age- and education- matched healthy controls).<br><br>RESULTS: Graded variation in hypothalamic involvement but relative sparing of the inferior tuberal region was evident across all patient groups. Bilateral anterior inferior, anterior superior, and posterior hypothalamic subregions were selectively implicated in memory, fluency and processing speed impairments in addition to apathy and abnormal eating habits, taking into account disease duration, age, sex, total intracranial volume, and acquisition parameters (all p&#xa0;&#x2264;&#xa0;.001).<br><br>CONCLUSIONS: These findings revealed that subdivisions of the hypothalamus are differentially affected in the ALS-FTD spectrum and contribute to canonical cognitive and behavioural disturbances beyond eating abnormalities. The anterior superior and superior tuberal subregions containing the paraventricular nucleus (housing oxytocin-producing neurons) displayed the greatest volume loss in bvFTD and ALS-FTD, and ALS, respectively. Importantly, the inferior tuberal subregion housing the arcuate nucleus (containing different groups of neuroendocrine neurons) was selectively preserved across the ALS-FTD spectrum, supporting pathophysiological findings of discrete neuropeptide expression abnormalities that may underlie the pathogenesis of autonomic and metabolic abnormalities and potentially certain cognitive and behavioural symptom manifestations, representing avenues for more refined symptomatic treatment targets.}, }
@article {pmid36495645, year = {2023}, author = {Ramachandran, D and R, A and Panicker, P and S, J and Sathyabhama, MC and Nair, A and Chandran, RS and George, S and S, C and Iype, T}, title = {The mucormycosis and stroke: The learning curve during the second COVID-19 pandemic.}, journal = {Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association}, volume = {32}, number = {2}, pages = {106819}, doi = {10.1016/j.jstrokecerebrovasdis.2022.106819}, pmid = {36495645}, issn = {1532-8511}, mesh = {Humans ; Antifungal Agents/therapeutic use ; *COVID-19/complications ; Learning Curve ; *Mucormycosis/diagnosis/epidemiology/therapy ; *Pandemics ; *Stroke/diagnostic imaging/epidemiology ; }, abstract = {BACKGROUND: The Angio-invasive Rhino-orbito-cerebral mucormycosis (ROCM) producing strokes is a less explored entity. Our hospital, a stroke-ready one, had an opportunity to manage mucormycosis when it was identified as the nodal center for mucormycosis management. We are sharing our experiences and mistakes in managing the cerebrovascular manifestations of ROCM.<br><br>METHODS: We conducted a prospective observational study during the second wave of the COVID-19 pandemic from 1st May 2021 to 30th September 2021, where consecutive patients aged more than 18 years with microbiologically confirmed cases of ROCM were included. Clinical details (timing of stroke onset after ROCM symptoms, GCS, NIHSS), imaging findings (ASPECTS, the territory of stroke, the pattern of infarct, hemorrhagic transformation, cavernous sinus thrombosis), angiogram findings, management details (IV thrombolysis), and outcomes (mRS at discharge and duration of hospital stay) were documented. We also compared the demographics, clinical features (NIHSS), radiological findings, treatment details, duration of hospital stay, and functional outcome at the discharge of the ROCM stroke patients with stroke patients without ROCM.<br><br>RESULTS: Stroke developed in 42% of patients with ROCM, predominantly anterior circulation border zone ischemic infarcts. Strokes occurred after a median of five days from the onset of ROCM symptoms. The most common vessel involved was the ophthalmic artery, followed by the cavernous ICA. We could not thrombolyse ROCM stroke patients. ROCM patients who developed stroke compared with patients without stroke had a more infiltrative fungal infection and higher inflammatory markers. Mucormycosis associated stroke patients had higher in-hospital mortality and poor functional outcomes.<br><br>T CONCLUSION: Due to delayed recognition of stroke symptoms, none received reperfusion strategies, leading to poor functional outcomes. For early stroke detection, ROCM cases need frequent monitoring and education of patients and their relatives about the ALS acronym (loss of ambulation, limb weakness, and loss of speech).}, }
@article {pmid36481799, year = {2023}, author = {Giovannelli, I and Higginbottom, A and Kirby, J and Azzouz, M and Shaw, PJ}, title = {Prospects for gene replacement therapies in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {1}, pages = {39-52}, pmid = {36481799}, issn = {1759-4766}, support = {MR/V000470/1/MRC_/Medical Research Council/United Kingdom ; MR/V030140/1/MRC_/Medical Research Council/United Kingdom ; NECTAR/OCT15/974-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Neurodegenerative Diseases/therapy ; Motor Neurons ; *Motor Neuron Disease ; Genetic Therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons. ALS causes death, usually within 2-5 years of diagnosis. Riluzole, the only drug currently approved in Europe for the treatment of this condition, offers only a modest benefit, increasing survival by 3 months on average. Recent advances in our understanding of causative or disease-modifying genetic variants and in the development of genetic therapy strategies present exciting new therapeutic opportunities for ALS. In addition, the approval of adeno-associated virus-mediated delivery of functional copies of the SMN1 gene to treat spinal muscular atrophy represents an important therapeutic milestone and demonstrates the potential of gene replacement therapies for motor neuron disorders. In this Review, we describe the current landscape of genetic therapies in ALS, highlighting achievements and critical challenges. In particular, we discuss opportunities for gene replacement therapy in subgroups of people with ALS, and we describe loss-of-function mutations that are known to contribute to the pathophysiology of ALS and could represent novel targets for gene replacement therapies.}, }
@article {pmid36477882, year = {2023}, author = {Sparasci, D and Castelli, C and Staedler, C and Gobbi, C and Ripellino, P}, title = {Inclusions in macrophages of the cerebrospinal fluid during treatment with Tofersen.}, journal = {Muscle &amp; nerve}, volume = {67}, number = {2}, pages = {E3-E5}, doi = {10.1002/mus.27763}, pmid = {36477882}, issn = {1097-4598}, mesh = {Humans ; *Oligonucleotides ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid ; Macrophages ; Superoxide Dismutase-1/genetics ; Superoxide Dismutase/genetics ; Mutation ; Spinal Cord ; }, }
@article {pmid36477638, year = {2022}, author = {Tian, Y and Hu, D and Li, Y and Yang, L}, title = {Development of therapeutic vaccines for the treatment of diseases.}, journal = {Molecular biomedicine}, volume = {3}, number = {1}, pages = {40}, pmid = {36477638}, issn = {2662-8651}, abstract = {Vaccines are one of the most effective medical interventions to combat newly emerging and re-emerging diseases. Prophylactic vaccines against rabies, measles, etc., have excellent effectiveness in preventing viral infection and associated diseases. However, the host immune response is unable to inhibit virus replication or eradicate established diseases in most infected people. Therapeutic vaccines, expressing specific endogenous or exogenous antigens, mainly induce or boost cell-mediated immunity via provoking cytotoxic T cells or elicit humoral immunity via activating B cells to produce specific antibodies. The ultimate aim of a therapeutic vaccine is to reshape the host immunity for eradicating a disease and establishing lasting memory. Therefore, therapeutic vaccines have been developed for the treatment of some infectious diseases and chronic noncommunicable diseases. Various technological strategies have been implemented for the development of therapeutic vaccines, including molecular-based vaccines (peptide/protein, DNA and mRNA vaccines), vector-based vaccines (bacterial vector vaccines, viral vector vaccines and yeast-based vaccines) and cell-based vaccines (dendritic cell vaccines and genetically modified cell vaccines) as well as combinatorial approaches. This review mainly summarizes therapeutic vaccine-induced immunity and describes the development and status of multiple types of therapeutic vaccines against infectious diseases, such as those caused by HPV, HBV, HIV, HCV, and SARS-CoV-2, and chronic noncommunicable diseases, including cancer, hypertension, Alzheimer's disease, amyotrophic lateral sclerosis, diabetes, and dyslipidemia, that have been evaluated in recent preclinical and clinical studies.}, }
@article {pmid36473592, year = {2023}, author = {De Lazzari, F and Agostini, F and Plotegher, N and Sandre, M and Greggio, E and Megighian, A and Bubacco, L and Sandrelli, F and Whitworth, AJ and Bisaglia, M}, title = {DJ-1 promotes energy balance by regulating both mitochondrial and autophagic homeostasis.}, journal = {Neurobiology of disease}, volume = {176}, number = {}, pages = {105941}, doi = {10.1016/j.nbd.2022.105941}, pmid = {36473592}, issn = {1095-953X}, support = {MC_UU_00015/6/MRC_/Medical Research Council/United Kingdom ; MC_UU_00028/6/MRC_/Medical Research Council/United Kingdom ; P40 OD018537/OD/NIH HHS/United States ; }, mesh = {Animals ; Mitochondria/metabolism ; Antioxidants ; *Parkinson Disease/metabolism ; *Parkinsonian Disorders/metabolism ; Drosophila/metabolism ; Protein Deglycase DJ-1/genetics/metabolism ; Oxidative Stress ; Nerve Tissue Proteins/metabolism ; *Drosophila Proteins/genetics/metabolism ; }, abstract = {The protein DJ-1 is mutated in rare familial forms of recessive Parkinson's disease and in parkinsonism accompanied by amyotrophic lateral sclerosis symptoms and dementia. DJ-1 is considered a multitasking protein able to confer protection under various conditions of stress. However, the precise cellular function still remains elusive. In the present work, we evaluated fruit flies lacking the expression of the DJ-1 homolog dj-1β as compared to control aged-matched individuals. Behavioral evaluations included lifespan, locomotion in an open field arena, sensitivity to oxidative insults, and resistance to starvation. Molecular analyses were carried out by analyzing the mitochondrial morphology and functionality, and the autophagic response. We demonstrated that dj-1β null mutant flies are hypoactive and display higher sensitivity to oxidative insults and food deprivation. Analysis of mitochondrial homeostasis revealed that loss of dj-1β leads to larger and more circular mitochondria, characterized by impaired complex-I-linked respiration while preserving ATP production capacity. Additionally, dj-1β null mutant flies present an impaired autophagic response, which is suppressed by treatment with the antioxidant molecule N-Acetyl-L-Cysteine. Overall, our data point to a mechanism whereby DJ-1 plays a critical role in the maintenance of energy homeostasis, by sustaining mitochondrial homeostasis and affecting the autophagic flux through the maintenance of the cellular redox state. In light of the involvement of DJ-1 in neurodegenerative diseases and considering that neurons are highly energy-demanding cells, particularly sensitive to redox stress, our study sheds light on a key role of DJ-1 in the maintenance of cellular homeostasis.}, }
@article {pmid36471413, year = {2022}, author = {Willemse, SW and Roes, KCB and Van Damme, P and Hardiman, O and Ingre, C and Povedano, M and Wray, NR and Gijzen, M and de Pagter, MS and Demaegd, KC and Janse, AFC and Vink, RG and Sleutjes, BTHM and Chiò, A and Corcia, P and Reviers, E and Al-Chalabi, A and Kiernan, MC and van den Berg, LH and van Es, MA and van Eijk, RPA}, title = {Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial.}, journal = {Trials}, volume = {23}, number = {1}, pages = {978}, pmid = {36471413}, issn = {1745-6215}, support = {ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; T003519N//Fonds Wetenschappelijk Onderzoek/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/genetics ; Lithium Carbonate/adverse effects ; Polymorphism, Single Nucleotide ; Alleles ; Quality of Life ; *Respiratory Insufficiency/drug therapy ; Randomized Controlled Trials as Topic ; Meta-Analysis as Topic ; }, abstract = {BACKGROUND: Given the large genetic heterogeneity in amyotrophic lateral sclerosis (ALS), it seems likely that genetic subgroups may benefit differently from treatment. An exploratory meta-analysis identified that patients homozygous for the C-allele at SNP rs12608932, a single nucleotide polymorphism in the gene UNC13A, had a statistically significant survival benefit when treated with lithium carbonate. We aim to confirm the efficacy of lithium carbonate on the time to death or respiratory insufficiency in patients with ALS homozygous for the C-allele at SNP rs12608932 in UNC13A.<br><br>METHODS: A randomized, group-sequential, event-driven, double-blind, placebo-controlled trial will be conducted in 15 sites across Europe and Australia. Patients will be genotyped for UNC13A; those homozygous for the C-allele at SNP rs12608932 will be eligible. Patients must have a diagnosis of ALS according to the revised El Escorial criteria, and a TRICALS risk-profile score between -6.0 and -2.0. An expected number of 1200 patients will be screened in order to enroll a target sample size of 171 patients. Patients will be randomly allocated in a 2:1 ratio to lithium carbonate or matching placebo, and treated for a maximum duration of 24 months. The primary endpoint is the time to death or respiratory insufficiency, whichever occurs first. Key secondary endpoints include functional decline, respiratory function, quality of life, tolerability, and safety. An interim analysis for futility and efficacy will be conducted after the occurrence of 41 events.<br><br>DISCUSSION: Lithium carbonate has been proven to be safe and well-tolerated in patients with ALS. Given the favorable safety profile, the potential benefits are considered to outweigh the burden and risks associated with study participation. This study may provide conclusive evidence about the life-prolonging potential of lithium carbonate in a genetic ALS subgroup.<br><br>TRIAL REGISTRATION: EudraCT number 2020-000579-19 . Registered on 29 March 2021.}, }
@article {pmid36467452, year = {2022}, author = {Imamura, K and Izumi, Y and Nagai, M and Nishiyama, K and Watanabe, Y and Hanajima, R and Egawa, N and Ayaki, T and Oki, R and Fujita, K and Uozumi, R and Morinaga, A and Hirohashi, T and Fujii, Y and Yamamoto, T and Tatebe, H and Tokuda, T and Takahashi, N and Morita, S and Takahashi, R and Inoue, H}, title = {Safety and tolerability of bosutinib in patients with amyotrophic lateral sclerosis (iDReAM study): A multicentre, open-label, dose-escalation phase 1 trial.}, journal = {EClinicalMedicine}, volume = {53}, number = {}, pages = {101707}, pmid = {36467452}, issn = {2589-5370}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the loss of motor neurons, and development of effective medicines is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified the Src/c-Abl inhibitor bosutinib, which is approved for the treatment of chronic myelogenous leukemia (CML), as a candidate for the molecular targeted therapy of ALS.<br><br>METHODS: An open-label, multicentre, dose-escalation phase 1 study using a 3&#xa0;+&#xa0;3 design was conducted in 4 hospitals in Japan to evaluate the safety and tolerability of bosutinib in patients with ALS. Furthermore, the exploratory efficacy was evaluated using Revised ALS Functional Rating Scale (ALSFRS-R), predictive biomarkers including plasma neurofilament light chain (NFL) were explored, and single-cell RNA sequencing of iPSC-derived motor neurons was conducted. Patients, whose total ALSFRS-R scores decreased by 1-3 points during the 12-week, received escalating doses starting from 100&#xa0;mg quaque die (QD) up to 400&#xa0;mg QD based on dose-limiting toxicity (DLT) occurrence, and all participants who received one dose of the study drug were included in the primary analysis. This trial is registered with ClinicalTrials.gov, NCT04744532, as Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic Lateral Sclerosis Medicine (iDReAM) study.<br><br>FINDINGS: Between March 29, 2019 and May 7, 2021, 20 patients were enrolled, 13 of whom received bosutinib treatment and 12 were included in the safety and efficacy analyses. No DLTs were observed up to 300&#xa0;mg QD, but DLTs were observed in 3/3 patients of the 400&#xa0;mg QD cohort. In all patients receiving 100&#xa0;mg-400&#xa0;mg, the prevalent adverse events (AEs) were gastrointestinal AEs in 12 patients (92.3%), liver function related AEs in 7 patients (53.8%), and rash in 3 patients (23.1%). The safety profile was consistent with that known for CML treatment, and ALS-specific AEs were not observed. A subset of patients (5/9 patients) was found to respond well to bosutinib treatment over the 12-week treatment period. It was found that the treatment-responsive patients could be distinguished by their lower levels of plasma NFL. Furthermore, single-cell RNA sequencing of iPSC-derived motor neurons revealed the pathogenesis related molecular signature in patients with ALS showing responsiveness to bosutinib.<br><br>INTERPRETATION: This is the first trial of a Src/c-Abl inhibitor, bosutinib, for patients with ALS. The safety and tolerability of bosutinib up to 300&#xa0;mg, not 400&#xa0;mg, in ALS were described, and responsiveness of patients on motor function was observed. Since this was an open-label trial within a short period with a limited number of patients, further clinical trials will be required.<br><br>FUNDING: AMED and iPS Cell Research Fund.}, }
@article {pmid36464456, year = {2023}, author = {Gao, F and Sun, J and Yao, M and Song, Y and Yi, H and Yang, M and Ni, Q and Kong, J and Yuan, H and Sun, B and Wang, Y}, title = {SERS "hot spot" enhance-array assay for misfolded SOD1 correlated with white matter lesions and aging.}, journal = {Analytica chimica acta}, volume = {1238}, number = {}, pages = {340163}, doi = {10.1016/j.aca.2022.340163}, pmid = {36464456}, issn = {1873-4324}, mesh = {Humans ; Antibodies ; Gold ; *Neurodegenerative Diseases/diagnosis/genetics/metabolism ; Reproducibility of Results ; Superoxide Dismutase ; *Superoxide Dismutase-1/analysis/genetics/metabolism ; *White Matter/metabolism/physiopathology ; *Proteostasis Deficiencies/diagnosis/genetics/metabolism ; }, abstract = {Misfolding of superoxide dismutase-1 (SOD1) has been correlated with many neurodegenerative diseases, such as Amyotrophic lateral sclerosis's and Alzheimer's among others. However, it is unclear whether misfolded SOD1 plays a role in another neurodegenerative disease of white matter lesions (WMLs). In this study, a sensitive and specific method based on SERS technique was proposed for quantitative detection of misfolded SOD1 content in WMLs. To fabricate the double antibodysandwich substrates for SERS detection, gold nanostars modified with capture antibody were immobilized on glass substrates to prepare active SERS substrates, and then SERS probes conjugated with a Raman reporter and a specific target antibody were coupled with active SERS substrates. This SERS substrates had been employed for quantitative detection of misfolded SOD1 levels in WMLs and exhibited excellent stability, reliability, and accuracy. Moreover, experimental results indicated that the level of misfolded SOD1 increased with the increase in age and the degree of WMLs. Hence, misfolded SOD1 may be a potential blood marker for WMLs and aging. Meanwhile, SERS-based gold nanostars have great clinical application potential in the screening, diagnosis and treatment of WMLs.}, }
@article {pmid36462105, year = {2023}, author = {Gao, M and Zhu, L and Chang, J and Cao, T and Song, L and Wen, C and Chen, Y and Zhuo, Y and Chen, F}, title = {Safety and Efficacy of Edaravone in Patients with Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-analysis.}, journal = {Clinical drug investigation}, volume = {43}, number = {1}, pages = {1-11}, pmid = {36462105}, issn = {1179-1918}, support = {No. 2019-JYB-TD-003//Special Funds for Basic Scientific Research in Central Universities of China/ ; }, mesh = {Humans ; Edaravone/adverse effects ; *Amyotrophic Lateral Sclerosis/drug therapy ; Surveys and Questionnaires ; }, abstract = {BACKGROUND AND OBJECTIVE: The efficacy and safety of edaravone for the treatment of amyotrophic lateral sclerosis (ALS) remain unclear. The aim of this meta-analysis was to provide evidence-based medical guidance and advice for the clinical application of edaravone in the treatment of ALS.<br><br>METHODS: PubMed, Embase, Chinese Biomedical Literature Database (CBM), Cochrane Library and Web of Science were searched through 09 March 2022 for randomized controlled trials (RCTs) on the safety and efficacy of edaravone versus placebo during follow-up of patients with ALS. A summary of the outcome measures with GRADE was performed. This study was registered on PROSPERO (ID: CRD 42022319997).<br><br>RESULTS: Five RCTs with a total of 566 participants were included, and there was a significant difference (mean difference [MD] 1.33, 95% confidence interval [CI] 0.33-2.34; p&#xa0;=&#xa0;0.009) in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score between the treatment and placebo groups. The edaravone group had an increased grip strength (MD 0.26, 95% CI 0.03-0.49; p&#xa0;=&#xa0;0.03) and modified Norris Scale score (MD 2.81, 95% CI 1.18-4.43; p&#xa0;=&#xa0;0.0007). However, there were no significant differences between groups for the change in forced vital capacity (FVC)% (MD 0.55, 95% CI -&#xa0;3.15 to 4.24; p&#xa0;=&#xa0;0.77), pinch strength (MD 0.05, 95% CI -&#xa0;0.05 to 0.16; p&#xa0;=&#xa0;0.33) or Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) score (MD -&#xa0;4.76, 95% CI -&#xa0;9.56 to 0.03; p&#xa0;=&#xa0;0.05). The incidence of adverse events (AEs) (risk ratio [RR] 0.09, 95% CI 0.93-1.05; p&#xa0;=&#xa0;0.65), serious adverse events (SAEs) (RR 0.72, 95% CI 0.52-1.00; p&#xa0;=&#xa0;0.05) and the number of deaths (risk difference [RD] 0.00, 95% CI -&#xa0;0.02 to 0.03; p&#xa0;=&#xa0;0.83) were not statistically different from the placebo group. The quality of evidence was low only for SAEs, and the remaining outcome measures were of moderate quality.<br><br>CONCLUSIONS: Compared with placebo, edaravone may provide potential clinical benefits in the treatment of ALS and may not increase the number of AEs and deaths. However, due to the low-quality evidence of the included studies and the small sample size, more high-quality and high-standard research evidence is needed to confirm these results.<br><br>PROTOCOL REGISTRATION: This study was registered on PROSPERO (ID: CRD 42022319997).}, }
@article {pmid36460700, year = {2022}, author = {Rodríguez-Sánchez, S and Valiente, N and Seseña, S and Cabrera-Pinto, M and Rodríguez, A and Aranda, A and Palop, L and Fernández-Martos, CM}, title = {Ozone modified hypothalamic signaling enhancing thermogenesis in the TDP-43[A315T] transgenic model of Amyotrophic Lateral Sclerosis.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {20814}, pmid = {36460700}, issn = {2045-2322}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/genetics ; *Ozone ; *Neurodegenerative Diseases ; Thermogenesis ; Hypothalamus ; DNA-Binding Proteins/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a devastating progressive neurodegenerative disease, has no effective treatment. Recent evidence supports a strong metabolic component in ALS pathogenesis. Indeed, metabolic abnormalities in ALS correlate to disease susceptibility and progression, raising additional therapeutic targets against ALS. Ozone (O3), a natural bioactive molecule, has been shown to elicit beneficial effects to reduce metabolic disturbances and improved motor behavior in TDP-43[A315T] mice. However, it is fundamental to determine the mechanism through which O3 acts in ALS. To characterize the association between O3 exposure and disease-associated weight loss in ALS, we assessed the mRNA and protein expression profile of molecular pathways with a main role in the regulation of the metabolic homeostasis on the hypothalamus and the brown adipose tissue (BAT) at the disease end-stage, in TDP-43[A315T] mice compared to age-matched WT littermates. In addition, the impact of O3 exposure on the faecal bacterial community diversity, by Illumina sequencing, and on the neuromuscular junctions (NMJs), by confocal imaging, were analysed. Our findings suggest the effectiveness of O3 exposure to induce metabolic effects in the hypothalamus and BAT of TDP-43[A315T] mice and could be a new complementary non-pharmacological approach for ALS therapy.}, }
@article {pmid36454749, year = {2022}, author = {Jambeau, M and Meyer, KD and Hruska-Plochan, M and Tabet, R and Lee, CZ and Ray-Soni, A and Aguilar, C and Savage, K and Mishra, N and Cavegn, N and Borter, P and Lin, CC and Jansen-West, KR and Jiang, J and Freyermuth, F and Li, N and De Rossi, P and Pérez-Berlanga, M and Jiang, X and Daughrity, LM and Pereira, J and Narayanan, S and Gu, Y and Dhokai, S and Dalkilic-Liddle, I and Maniecka, Z and Weber, J and Workman, M and McAlonis-Downes, M and Berezovski, E and Zhang, YJ and Berry, J and Wainger, BJ and Kankel, MW and Rushe, M and Hock, C and Nitsch, RM and Cleveland, DW and Petrucelli, L and Gendron, TF and Montrasio, F and Grimm, J and Polymenidou, M and Lagier-Tourenne, C}, title = {Comprehensive evaluation of human-derived anti-poly-GA antibodies in cellular and animal models of C9orf72 disease.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {119}, number = {49}, pages = {e2123487119}, pmid = {36454749}, issn = {1091-6490}, support = {P50 AG005134/AG/NIA NIH HHS/United States ; R01 NS087227/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; Antigen-Antibody Complex ; C9orf72 Protein/genetics ; Dipeptides ; Disease Models, Animal ; *Genes, Regulator ; *Poly A ; }, abstract = {Hexanucleotide G4C2 repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Dipeptide repeat proteins (DPRs) generated by translation of repeat-containing RNAs show toxic effects in vivo as well as in vitro and are key targets for therapeutic intervention. We generated human antibodies that bind DPRs with high affinity and specificity. Anti-GA antibodies engaged extra- and intra-cellular poly-GA and reduced aggregate formation in a poly-GA overexpressing human cell line. However, antibody treatment in human neuronal cultures synthesizing exogenous poly-GA resulted in the formation of large extracellular immune complexes and did not affect accumulation of intracellular poly-GA aggregates. Treatment with antibodies was also shown to directly alter the morphological and biochemical properties of poly-GA and to shift poly-GA/antibody complexes to more rapidly sedimenting ones. These alterations were not observed with poly-GP and have important implications for accurate measurement of poly-GA levels including the need to evaluate all centrifugation fractions and disrupt the interaction between treatment antibodies and poly-GA by denaturation. Targeting poly-GA and poly-GP in two mouse models expressing G4C2 repeats by systemic antibody delivery for up to 16 mo was well-tolerated and led to measurable brain penetration of antibodies. Long-term treatment with anti-GA antibodies produced improvement in an open-field movement test in aged C9orf72[450] mice. However, chronic administration of anti-GA antibodies in AAV-(G4C2)149 mice was associated with increased levels of poly-GA detected by immunoassay and did not significantly reduce poly-GA aggregates or alleviate disease progression in this model.}, }
@article {pmid36453391, year = {2023}, author = {Yap, KH and Azmin, S and Makpol, S and Damanhuri, HA and Mustapha, M and Hamzah, JC and Ibrahim, NM}, title = {Profiling neuroprotective potential of trehalose in animal models of neurodegenerative diseases: a systematic review.}, journal = {Neural regeneration research}, volume = {18}, number = {6}, pages = {1179-1185}, pmid = {36453391}, issn = {1673-5374}, abstract = {Trehalose, a unique nonreducing crystalline disaccharide, is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging, intrinsic mutations, or autophagy dysregulation. This systematic review summarizes the effects of trehalose on its underlying mechanisms in animal models of selected neurodegenerative disorders (tau pathology, synucleinopathy, polyglutamine tract, and motor neuron diseases). All animal studies on neurodegenerative diseases treated with trehalose published in Medline (accessed via EBSCOhost) and Scopus were considered. Of the 2259 studies screened, 29 met the eligibility criteria. According to the SYstematic Review Center for Laboratory Animal Experiment (SYRCLE) risk of bias tool, we reported 22 out of 29 studies with a high risk of bias. The present findings support the purported role of trehalose in autophagic flux and protein refolding. This review identified several other lesser-known pathways, including modifying amyloid precursor protein processing, inhibition of reactive gliosis, the integrity of the blood-brain barrier, activation of growth factors, upregulation of the downstream antioxidant signaling pathway, and protection against mitochondrial defects. The absence of adverse events and improvements in the outcome parameters were observed in some studies, which supports the transition to human clinical trials. It is possible to conclude that trehalose exerts its neuroprotective effects through both direct and indirect pathways. However, heterogeneous methodologies and outcome measures across the studies rendered it impossible to derive a definitive conclusion. Translational studies on trehalose would need to clarify three important questions: 1) bioavailability with oral administration, 2) optimal time window to confer neuroprotective benefits, and 3) optimal dosage to confer neuroprotection.}, }
@article {pmid36450833, year = {2023}, author = {Chen, YA and Kankel, MW and Hana, S and Lau, SK and Zavodszky, MI and McKissick, O and Mastrangelo, N and Dion, J and Wang, B and Ferretti, D and Koske, D and Lehman, S and Koszka, K and McLaughlin, H and Liu, M and Marshall, E and Fabian, AJ and Cullen, P and Marsh, G and Hamann, S and Craft, M and Sebalusky, J and Arnold, HM and Driscoll, R and Sheehy, A and Luo, Y and Manca, S and Carlile, T and Sun, C and Sigrist, K and McCampbell, A and Henderson, CE and Lo, SC}, title = {In vivo genome editing using novel AAV-PHP variants rescues motor function deficits and extends survival in a SOD1-ALS mouse model.}, journal = {Gene therapy}, volume = {30}, number = {5}, pages = {443-454}, pmid = {36450833}, issn = {1476-5462}, mesh = {Mice ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Superoxide Dismutase-1/genetics ; Gene Editing ; Superoxide Dismutase/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; }, abstract = {CRISPR-based gene editing technology represents a promising approach to deliver therapies for inherited disorders, including amyotrophic lateral sclerosis (ALS). Toxic gain-of-function superoxide dismutase 1 (SOD1) mutations are responsible for ~20% of familial ALS cases. Thus, current clinical strategies to treat SOD1-ALS are designed to lower SOD1 levels. Here, we utilized AAV-PHP.B variants to deliver CRISPR-Cas9 guide RNAs designed to disrupt the human SOD1 (huSOD1) transgene in SOD1[G93A] mice. A one-time intracerebroventricular injection of AAV.PHP.B-huSOD1-sgRNA into neonatal H11[Cas9] SOD1[G93A] mice caused robust and sustained mutant huSOD1 protein reduction in the cortex and spinal cord, and restored motor function. Neonatal treatment also reduced spinal motor neuron loss, denervation at neuromuscular junction (NMJ) and muscle atrophy, diminished axonal damage and preserved compound muscle action potential throughout the lifespan of treated mice. SOD1[G93A] treated mice achieved significant disease-free survival, extending lifespan by more than 110 days. Importantly, a one-time intrathecal or intravenous injection of AAV.PHP.eB-huSOD1-sgRNA in adult H11[Cas9] SOD1[G93A] mice, immediately before symptom onset, also extended lifespan by at least 170 days. We observed substantial protection against disease progression, demonstrating the utility of our CRISPR editing preclinical approach for target evaluation. Our approach uncovered key parameters (e.g., AAV capsid, Cas9 expression) that resulted in improved efficacy compared to similar approaches and can also serve to accelerate drug target validation.}, }
@article {pmid36448513, year = {2024}, author = {Peters, B and O'Brien, K and Fried-Oken, M}, title = {A recent survey of augmentative and alternative communication use and service delivery experiences of people with amyotrophic lateral sclerosis in the United States.}, journal = {Disability and rehabilitation. Assistive technology}, volume = {19}, number = {4}, pages = {1121-1134}, doi = {10.1080/17483107.2022.2149866}, pmid = {36448513}, issn = {1748-3115}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation ; *Communication Devices for People with Disabilities ; Male ; Middle Aged ; Female ; United States ; Cross-Sectional Studies ; Aged ; Adult ; Surveys and Questionnaires ; Speech Disorders/rehabilitation ; Communication ; }, abstract = {PURPOSE: The objective of this study was to explore and describe current trends in the augmentative and alternative communication (AAC) use and service delivery experiences of people with amyotrophic lateral sclerosis (PALS) in the U.S.<br><br>METHODS: Cross-sectional data were collected from 216 PALS via an anonymous online questionnaire in 2021.<br><br>RESULTS: Over 70% of participants reported at least some detectable speech disturbance, and approximately half used aided communication during face-to-face interactions. Among respondents with severe speech impairment, over 90% reported using speech-generating devices, and just over half reported using low-tech AAC. Most participants had met with an SLP to discuss speech and communication, but varied in both timing of the initial intervention and frequency of ongoing intervention. Fewer than half reported that their family members or other important people had received education or support related to communication for PALS. Participants also shared their use of and experiences with telephone and video calls, access methods, mounting systems, word prediction and stored phrases, and message and voice banking.<br><br>CONCLUSIONS: Results highlight the importance of early referral for AAC intervention, ongoing re-evaluation and treatment, involvement of communication partners and support for multimodal communication and adaptation to changing needs.}, }
@article {pmid36442393, year = {2022}, author = {Lasbleiz, C and Peyrel, A and Tarot, P and Sarniguet, J and Crouzier, L and Cubedo, N and Delprat, B and Rossel, M and Maurice, T and Liévens, JC}, title = {Sigma-1 receptor agonist PRE-084 confers protection against TAR DNA-binding protein-43 toxicity through NRF2 signalling.}, journal = {Redox biology}, volume = {58}, number = {}, pages = {102542}, pmid = {36442393}, issn = {2213-2317}, mesh = {Animals ; Zebrafish/metabolism ; NF-E2-Related Factor 2/genetics/metabolism ; *Neurodegenerative Diseases ; Antioxidants/therapeutic use ; *Amyotrophic Lateral Sclerosis/genetics ; DNA-Binding Proteins/genetics ; Endoplasmic Reticulum Stress ; Sigma-1 Receptor ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons. As a consequence, ALS patients display a locomotor disorder related to muscle weakness and progressive paralysis. Pathological mechanisms that participate in ALS involve deficient unfolded protein response, mitochondrial dysfunction and oxidative stress, among others. Finding a therapeutic target to break the vicious circle is particularly challenging. Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone that may be one of those targets. We here address and decipher the efficiency of S1R activation on a key ALS gene, TDP43, in zebrafish vertebrate model. While expression of mutant TDP43 (TDP43[G348C]) led to locomotor defects, treatment with the reference S1R agonist PRE-084 rescued motor performances in a zebrafish model. Treatment with the agonist ameliorated maximal mitochondrial respiration in the TDP43 context. We observed that TDP43[G348C] exacerbated ER stress induced by tunicamycin, resulting in increased levels of ER stress chaperone BiP and pro-apoptotic factor CHOP. Importantly, PRE-084 treatment in the same condition further heightened BiP levels but also EIF2α/ATF4 and NRF2 signalling cascades, both known to promote antioxidant protection during ER stress. Moreover, we showed that increasing NRF2 levels directly or by sulforaphane treatment rescued locomotor defects of TDP43[G348C] zebrafish. For the first time, we here provide the proof of concept that PRE-084 prevents mutant TDP43 toxicity by boosting ER stress response and antioxidant cascade through NRF2 signalling.}, }
@article {pmid36432051, year = {2022}, author = {Alharbi, M and Alshammari, A and Kaur, G and Kalra, S and Mehan, S and Suri, M and Chhabra, S and Kumar, N and Alanazi, WA and Alshanwani, AR and Al-Ghamdi, AH and Narula, AS and Kalfin, R}, title = {Effect of Natural Adenylcyclase/cAMP/CREB Signalling Activator Forskolin against Intra-Striatal 6-OHDA-Lesioned Parkinson's Rats: Preventing Mitochondrial, Motor and Histopathological Defects.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {22}, pages = {}, pmid = {36432051}, issn = {1420-3049}, support = {RITS/IAEC/2014/03/06//Rajendra Institute of Technology and Sciences, Hisar Road, 4thMile stone, Sirsa, Haryana, India/ ; }, mesh = {Animals ; Rats ; Oxidopamine/adverse effects ; Colforsin/pharmacology ; *Adenylyl Cyclases/metabolism ; *Parkinson Disease/drug therapy/etiology/metabolism ; Mitochondria/metabolism ; }, abstract = {Parkinson's disease (PD) is characterised by dopaminergic neuronal loss in the brain area. PD is a complex disease that deteriorates patients' motor and non-motor functions. In experimental animals, the neurotoxin 6-OHDA induces neuropathological, behavioural, neurochemical and mitochondrial abnormalities and the formation of free radicals, which is related to Parkinson-like symptoms after inter-striatal 6-OHDA injection. Pathological manifestations of PD disrupt the cAMP/ATP-mediated activity of the transcription factor CREB, resulting in Parkinson's-like symptoms. Forskolin (FSK) is a direct AC/cAMP/CREB activator isolated from Coleus forskohlii with various neuroprotective properties. FSK has already been proven in our laboratory to directly activate the enzyme adenylcyclase (AC) and reverse the neurodegeneration associated with the progression of Autism, Multiple Sclerosis, ALS, and Huntington's disease. Several behavioural paradigms were used to confirm the post-lesion effects, including the rotarod, open field, grip strength, narrow beam walk (NBW) and Morris water maze (MWM) tasks. Our results were supported by examining brain cellular, molecular, mitochondrial and histopathological alterations. The FSK treatment (15, 30 and 45 mg/kg, orally) was found to be effective in restoring behavioural and neurochemical defects in a 6-OHDA-induced experimental rat model of PD. As a result, the current study successfully contributes to the investigation of FSK's neuroprotective role in PD prevention via the activation of the AC/cAMP/PKA-driven CREB pathway and the restoration of mitochondrial ETC-complex enzymes.}, }
@article {pmid36430421, year = {2022}, author = {Lee, DG and Kim, YK and Baek, KH}, title = {The bHLH Transcription Factors in Neural Development and Therapeutic Applications for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {22}, pages = {}, pmid = {36430421}, issn = {1422-0067}, support = {NRF-2019R1A6A1A03032888//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Neurogenesis ; *Neural Stem Cells ; Neurons/physiology ; }, abstract = {The development of functional neural circuits in the central nervous system (CNS) requires the production of sufficient numbers of various types of neurons and glial cells, such as astrocytes and oligodendrocytes, at the appropriate periods and regions. Hence, severe neuronal loss of the circuits can cause neurodegenerative diseases such as Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Treatment of such neurodegenerative diseases caused by neuronal loss includes some strategies of cell therapy employing stem cells (such as neural progenitor cells (NPCs)) and gene therapy through cell fate conversion. In this report, we review how bHLH acts as a regulator in neuronal differentiation, reprogramming, and cell fate determination. Moreover, several different researchers are conducting studies to determine the importance of bHLH factors to direct neuronal and glial cell fate specification and differentiation. Therefore, we also investigated the limitations and future directions of conversion or transdifferentiation using bHLH factors.}, }
@article {pmid36428474, year = {2022}, author = {Zhang, R and Bracci, PM and Azhir, A and Forrest, BD and McGrath, MS}, title = {Macrophage-Targeted Sodium Chlorite (NP001) Slows Progression of Amyotrophic Lateral Sclerosis (ALS) through Regulation of Microbial Translocation.}, journal = {Biomedicines}, volume = {10}, number = {11}, pages = {}, pmid = {36428474}, issn = {2227-9059}, support = {//Neuvivo Inc, Palo Alto, CA/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous, progressive, and universally fatal neurodegenerative disease. A subset of ALS patients has measurable plasma levels of lipopolysaccharide (LPS) and C-reactive protein (CRP) consistent with low-grade microbial translocation (MT). Unless interrupted, MT sets up a self-perpetuating loop of inflammation associated with systemic macrophage activation. To test whether MT contributed to ALS progression, blood specimens from a phase 2 study of NP001 in ALS patients were evaluated for changes in activity in treated patients as compared to controls over the 6-month study. In this post hoc analysis, plasma specimens from baseline and six-month timepoints were analyzed. Compared with baseline values, biomarkers related to MT were significantly decreased (LPS, LPS binding protein (LBP), IL-18, Hepatocyte growth factor (HGF), soluble CD163 (sCD163)) in NP001-treated patients as compared to controls, whereas wound healing and immunoregulatory factors were increased (IL-10, Epidermal growth factor (EGF), neopterin) by the end of study. These biomarker results linked to the positive clinical trial outcome confirm that regulation of macrophage activation may be an effective approach for the treatment of ALS and, potentially, other neuroinflammatory diseases related to MT.}, }
@article {pmid36421882, year = {2022}, author = {Castro-Gomez, S and Binder, J and Schievelkamp, AH and Heneka, MT}, title = {CNS Superficial Siderosis Mimicking a Motor Neuron Disease.}, journal = {Brain sciences}, volume = {12}, number = {11}, pages = {}, pmid = {36421882}, issn = {2076-3425}, abstract = {Superficial siderosis of the central nervous system (SS-CNS) is a rare condition characterized by a hemosiderin accumulation along the subpial surfaces and arises from an intermittent chronic bleeding in the subarachnoid space usually as a result of a chronic subarachnoid hemorrhage by trauma, vascular malformations, CNS tumors, or cerebral amyloid angiopathy (CAA). We present a 61-year-old male with a 12-year history of limb weakness, muscle wasting, cramps, clumsiness, progressive unsteady gait, and fine motor impairments. His medical history included the resection of a left parietal meningioma and a myxopapillary ependymoma near the conus terminalis (L3/4) at the age of 51 years. The clinical examination revealed a motor neuron syndrome with a clear bilateral wasting of the hand muscles, a diffuse atrophy of the shoulder and calf muscles, and a weakness of the arms, fingers, hips, and feet. Deep tendon reflexes were symmetrically briskly hyperactive. Standing and walking were only possible with a support. Magnetic resonance imaging of the entire neuroaxis showed progressive severe cerebral, brainstem, and spinal superficial siderosis in form of extensive hypointensities on T2-weighted gradient-echo images and susceptibility-weighted sequences. Despite a successful neurosurgical removal of the tumors and delaed medical treatment with an iron chelator for one year, we observed no clinical recovery or stability in our patient, making this case unique, and suggesting an irreversible neurodegenerative process. This case reinforces the need of including SS-CNS in the list of amyotrophic lateral sclerosis (ALS)-mimics and demonstrates the fundamental use of a complete neuraxial MRI investigation on evaluating possible ALS cases.}, }
@article {pmid36420480, year = {2023}, author = {Ati, S and Chhetri, D and Wiedau, M and Soltanzadeh, P and Bordelon, Y and Chin, RK and Savjani, RR}, title = {Using Intensity Modulated Radiation Therapy for the Treatment of Sialorrhea in Amyotrophic Lateral Sclerosis.}, journal = {Advances in radiation oncology}, volume = {8}, number = {1}, pages = {101116}, pmid = {36420480}, issn = {2452-1094}, }
@article {pmid36418457, year = {2022}, author = {Daneshafrooz, N and Bagherzadeh Cham, M and Majidi, M and Panahi, B}, title = {Identification of potentially functional modules and diagnostic genes related to amyotrophic lateral sclerosis based on the WGCNA and LASSO algorithms.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {20144}, pmid = {36418457}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism ; Gene Regulatory Networks ; Motor Neurons/metabolism ; Algorithms ; Genetic Markers ; Intracellular Signaling Peptides and Proteins/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a genetically and phenotypically heterogeneous disease results in the loss of motor neurons. Mounting information points to involvement of other systems including cognitive impairment. However, neither the valid biomarker for diagnosis nor effective therapeutic intervention is available for ALS. The present study is aimed at identifying potentially genetic biomarker that improves the diagnosis and treatment of ALS patients based on the data of the Gene Expression Omnibus. We retrieved datasets and conducted a weighted gene co-expression network analysis (WGCNA) to identify ALS-related co-expression genes. Functional enrichment analysis was performed to determine the features and pathways of the main modules. We then constructed an ALS-related model using the least absolute shrinkage and selection operator (LASSO) regression analysis and verified the model by the receiver operating characteristic (ROC) curve. Besides we screened the non-preserved gene modules in FTD and ALS-mimic disorders to distinct ALS-related genes from disorders with overlapping genes and features. Altogether, 4198 common genes between datasets with the most variation were analyzed and 16 distinct modules were identified through WGCNA. Blue module had the most correlation with ALS and functionally enriched in pathways of neurodegeneration-multiple diseases', 'amyotrophic lateral sclerosis', and 'endocytosis' KEGG terms. Further, some of other modules related to ALS were enriched in 'autophagy' and 'amyotrophic lateral sclerosis'. The 30 top of hub genes were recruited to a LASSO regression model and 5 genes (BCLAF1, GNA13, ARL6IP5, ARGLU1, and YPEL5) were identified as potentially diagnostic ALS biomarkers with validating of the ROC curve and AUC value.}, }
@article {pmid36417289, year = {2022}, author = {Mazhari, F and Heidari, S and Iranmanesh, S and Sabzevari, S}, title = {Examining the mother's supportive role caring for a child with cancer.}, journal = {International journal of palliative nursing}, volume = {28}, number = {11}, pages = {531-539}, doi = {10.12968/ijpn.2022.28.11.531}, pmid = {36417289}, issn = {2052-286X}, mesh = {Female ; Child ; Humans ; *Mothers/psychology ; *Neoplasms ; Palliative Care ; Qualitative Research ; Power, Psychological ; }, abstract = {Background: Childhood cancer is a stressful experience for patients and their families; it has a profound effect on families emotionally, psychologically and financially. The mother's supportive role affects the child's treatment outcomes and the health of all family members. Aims: This study was conducted to describe the experiences of mothers of children with cancer. Methods: A total of 14 mothers of children with cancer were recruited using purposive sampling. In-depth semi-structured interviews were conducted using a qualitative inductive content analysis. Data were analysed using Graneheim et al's (2004) approach. Findings: According to data analysis, the mother's supportive role can be depicted across four subthemes: 'being genuinely present with a sick child'; 'keeping the family together and strengthening its cohesion'; 'providing compassionate collaborative care for peers'; and 'empowering the self and taking charge of one's own life'. The main overarching theme extracted from this study was 'sacrifice'. Conclusion: This study results suggest that the mothers' supportive role is relying on their own personal power, in which they not only give the care to the child, family and counterparts, but also drive personal growth and empowerment of mothers. A deeper understanding of mothers' experiences of their supportive role may enhance the quality of care and promote further paediatric approaches to palliative care.}, }
@article {pmid36414305, year = {2022}, author = {Silva, ST and Souza, AA and Pondofe, K and Melo, LP and Resqueti, VR and Valentim, RAM and Ribeiro, TS}, title = {Physical therapy for the management of motor symptoms in amyotrophic lateral sclerosis: protocol for a systematic review.}, journal = {BMJ open}, volume = {12}, number = {11}, pages = {e063689}, pmid = {36414305}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Exercise Therapy ; *Physical Therapy Modalities ; Quality of Life ; Systematic Reviews as Topic ; }, abstract = {INTRODUCTION: The prescription of an intervention plan can be challenging for the physical therapist, considering clinical phenotypes, individual prognosis and the rapid, progressive and deteriorating nature of amyotrophic lateral sclerosis (ALS). In this context, therapeutic exercises (eg, resistance and aerobic exercises) for patients with ALS remain controversial and may influence the treatment plan. Therefore, this review aims to critically assess whether physical therapy interventions are effective for improving functional capacity, quality of life and fatigue of individuals with ALS.<br><br>METHODS AND ANALYSIS: Studies will be selected according to eligibility criteria, and language, geographical area or publication date will not be restricted. Four databases will be used: MEDLINE, EMBASE, Cochrane Library (CENTRAL) and Physiotherapy Evidence Database (PEDro). Searches will also be conducted on ClinicalTrials.gov and references from included studies. We plan to conduct the searches between October and December 2022. Two independent authors will examine titles and abstracts and exclude irrelevant studies and duplicates. We will assess the quality of studies and quality of evidence, and disagreements will be resolved with a third researcher. The findings will be presented in the text and tables; if possible, we will perform meta-analyses.<br><br>ETHICS AND DISSEMINATION: No ethical approval is required because this study does not involve human beings. We will publish our findings in peer-reviewed journals.<br><br>PROSPERO REGISTRATION NUMBER: CRD42021251350.}, }
@article {pmid36411673, year = {2022}, author = {Das, T and Kaur, H and Gour, P and Prasad, K and Lynn, AM and Prakash, A and Kumar, V}, title = {Intersection of network medicine and machine learning towards investigating the key biomarkers and pathways underlying amyotrophic lateral sclerosis: a systematic review.}, journal = {Briefings in bioinformatics}, volume = {23}, number = {6}, pages = {}, doi = {10.1093/bib/bbac442}, pmid = {36411673}, issn = {1477-4054}, support = {BMI/11(63)/2020//Indian Council of Medical Research/ ; YSS/2015/000228/LS//Science and Engineering Research Board/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Biomarkers/metabolism ; Machine Learning ; }, abstract = {BACKGROUND: Network medicine is an emerging area of research that focuses on delving into the molecular complexity of the disease, leading to the discovery of network biomarkers and therapeutic target discovery. Amyotrophic lateral sclerosis (ALS) is a complicated rare disease with unknown pathogenesis and no available treatment. In ALS, network properties appear to be potential biomarkers that can be beneficial in disease-related applications when explored independently or in tandem with machine learning (ML) techniques.<br><br>OBJECTIVE: This systematic literature review explores recent trends in network medicine and implementations of network-based ML algorithms in ALS. We aim to provide an overview of the identified primary studies and gather details on identifying the potential biomarkers and delineated pathways.<br><br>METHODS: The current study consists of searching for and investigating primary studies from PubMed and Dimensions.ai, published between 2018 and 2022 that reported network medicine perspectives and the coupling of ML techniques. Each abstract and full-text study was individually evaluated, and the relevant studies were finally included in the review for discussion once they met the inclusion and exclusion criteria.<br><br>RESULTS: We identified 109 eligible publications from primary studies representing this systematic review. The data coalesced into two themes: application of network science to identify disease modules and promising biomarkers in ALS, along with network-based ML approaches. Conclusion This systematic review gives an overview of the network medicine approaches and implementations of network-based ML algorithms in ALS to determine new disease genes, and identify critical pathways and therapeutic target discovery for personalized treatment.}, }
@article {pmid36411653, year = {2022}, author = {Probert, F and Gorlova, A and Deikin, A and Bettendorff, L and Veniaminova, E and Nedorubov, A and Chaprov, KD and Ivanova, TA and Anthony, DC and Strekalova, T}, title = {In FUS[1-359]-tg mice O,S-dibenzoyl thiamine reduces muscle atrophy, decreases glycogen synthase kinase 3 beta, and normalizes the metabolome.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {156}, number = {}, pages = {113986}, doi = {10.1016/j.biopha.2022.113986}, pmid = {36411653}, issn = {1950-6007}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy ; RNA-Binding Protein FUS/genetics ; Glycogen Synthase Kinase 3 beta/metabolism ; Muscular Atrophy ; Mice, Transgenic ; Thiamine/pharmacology/therapeutic use ; Metabolome ; RNA, Messenger/metabolism ; }, abstract = {Mutations in the gene encoding the RNA/DNA-binding protein Fused in Sarcoma (FUS) have been detected in familial amyotrophic lateral sclerosis (ALS) patients. FUS has been found to be a critical component of the oxidative damage repair complex that might explain its role in neurodegeneration. Here, we examined what impact antioxidant treatment with thiamine (vitamine B1), or its more bioavailable derivative O,S-dibenzoylthiamine (DBT), would have on the hallmarks of pathology in the FUS[1-359]-transgenic mouse model of ALS. From 8-weeks old, in the pre-symptomatic phase of disease, animals received either thiamine, DBT (200 mg/kg/day), or vehicle for 6 weeks. We examined physiological, behavioral, molecular and histological outcomes, as well as the serum metabolome using nuclear magnetic resonance (NMR). The DBT-treated mice displayed improvements in physiological outcomes, motor function and muscle atrophy compared to vehicle, and the treatment normalized levels of brain glycogen synthase kinase-3β (GSK-3β), GSK-3β mRNA and IL-1β mRNA in the spinal cord. Analysis of the metabolome revealed an increase in the levels of choline and lactate in the vehicle-treated FUS mutants alone, which is also elevated in the cerebrospinal fluid of ALS patients, and reduced glucose and lipoprotein concentrations in the FUS[1-359]-tg mice, which were not the case in the DBT-treated mutants. The administration of thiamine had little impact on the outcome measures, but it did normalize circulating HDL levels. Thus, our study shows that DBT therapy in FUS mutants is more effective than thiamine and highlights how metabolomics may be used to evaluate therapy in this model.}, }
@article {pmid36408510, year = {2022}, author = {Peng, S and Tian, Y and Chang, W and Yang, Y and Li, S and Ni, J and Zhu, W}, title = {Current state of research on acupuncture for the treatment of amyotrophic lateral sclerosis: A scoping review.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {1019156}, pmid = {36408510}, issn = {1664-2295}, abstract = {OBJECTIVE: To provide an overview of the range and characteristics of existing evidence, research gaps, and future research priorities in treating amyotrophic lateral sclerosis (ALS) with acupuncture.<br><br>METHOD: Clinical studies on acupuncture treatment for ALS were searched in 9 databases and two websites. Two independent researchers screened the literature according to the inclusion and exclusion criteria; extracted the demographic data, interventions, and significant findings of the studies; and comprehensively analyzed the characteristics and limitations of the included articles.<br><br>RESULTS: A total of 2,326 studies were retrieved, of which 92 were included. Most of the studies were conducted in China, with the number increasing over time. Study designs included case reports, case series, randomized controlled trials (RCTs), and before-and-after studies, among which case reports were the most frequently used. A total of 1,388 patients were enrolled, of whom 1,031 had ALS, 274 had progressive bulbar palsy (PBP), 60 had progressive muscle atrophy (PMA), and 23 had primary lateral sclerosis (PLS). Acupuncture interventions included body acupuncture, electroacupuncture, acupoint injection, scalp acupuncture, acupoint massage, Sa-am acupuncture, needle-embedding therapy, auricular acupuncture, venom pharmacopuncture therapy, plum blossom needling, acupoint paste, electroacupuncture, and needle warming through moxibustion. The most frequently used acupoints were ST36, LI4, SP6, and LI11. Acupuncture is often applied in combination with other treatments, such as herbal or Western medicine. The frequency of treatment ranged from once a month to three times a day, and the duration of treatment ranged from 5 days to 3 years. Clinical symptoms, muscle strength, and effective rates were the most frequently used outcomes. Most studies reported significant efficacy, and only a few studies reported adverse events explicitly.<br><br>CONCLUSION: Evidence gaps include poor study design, complex interventions, limited significance of the selected outcomes, and limited study reporting. The promotion of acupuncture treatment for ALS still faces several obstacles. Rigorous study design and conduct, standardized intervention and outcome measurements, and normative reporting are needed to investigate the efficacy and safety of acupuncture treatment for ALS.}, }
@article {pmid36402404, year = {2023}, author = {Soares, P and Silva, C and Chavarria, D and Silva, FSG and Oliveira, PJ and Borges, F}, title = {Drug discovery and amyotrophic lateral sclerosis: Emerging challenges and therapeutic opportunities.}, journal = {Ageing research reviews}, volume = {83}, number = {}, pages = {101790}, doi = {10.1016/j.arr.2022.101790}, pmid = {36402404}, issn = {1872-9649}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Edaravone/therapeutic use ; Riluzole/therapeutic use ; Oxidative Stress ; Drug Discovery ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons (MNs) leading to paralysis and, ultimately, death by respiratory failure 3-5 years after diagnosis. Edaravone and Riluzole, the only drugs currently approved for ALS treatment, only provide mild symptomatic relief to patients. Extraordinary progress in understanding the biology of ALS provided new grounds for drug discovery. Over the last two decades, mitochondria and oxidative stress (OS), iron metabolism and ferroptosis, and the major regulators of hypoxia and inflammation - HIF and NF-κB - emerged as promising targets for ALS therapeutic intervention. In this review, we focused our attention on these targets to outline and discuss current advances in ALS drug development. Based on the challenges and the roadblocks, we believe that the rational design of multi-target ligands able to modulate the complex network of events behind the disease can provide effective therapies in a foreseeable future.}, }
@article {pmid36398749, year = {2023}, author = {Sun, Y and Barkhaus, P and Barnes, B and Beauchamp, M and Benatar, M and Bertorini, T and Bromberg, M and Carter, GT and Crayle, J and Cudkowicz, M and Dimachkie, M and Feldman, EL and Fullam, T and Heiman-Patterson, T and Jhooty, S and Lund, I and Mcdermott, C and Pattee, G and Pierce, K and Ratner, D and Wicks, P and Bedlack, R}, title = {ALSUntangled #68: ozone therapy.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {548-552}, doi = {10.1080/21678421.2022.2145904}, pmid = {36398749}, issn = {2167-9223}, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Disease Models, Animal ; Mitochondria ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review ozone therapy. Ozone therapy has possible mechanisms for slowing ALS progression based on its antioxidant, anti-inflammatory, and mitochondrial effects. A non-peer-reviewed report suggests that ozone treatment may slow progression in a mTDP-43 mouse model of ALS. One verified "ALS reversal" occurred on a cocktail of alternative treatments including ozone. There are no ALS trials using ozone to treat PALS. There can be potentially serious side effects associated with ozone therapy, depending on the dose. Based on the above information, we support an investigation of ozone therapy in ALS cell or animal models but cannot yet recommend it as a treatment in PALS.}, }
@article {pmid36398461, year = {2022}, author = {Rufino, RA and Pereira-Rufino, LDS and Vissoto, TCS and Kerkis, I and Neves, ADC and da Silva, MCP}, title = {The Immunomodulatory Potential Role of Mesenchymal Stem Cells in Diseases of the Central Nervous System.}, journal = {Neuro-degenerative diseases}, volume = {22}, number = {2}, pages = {68-82}, doi = {10.1159/000528036}, pmid = {36398461}, issn = {1660-2862}, mesh = {Humans ; *Mesenchymal Stem Cells/metabolism ; *Neurodegenerative Diseases/therapy ; Central Nervous System ; *Multiple Sclerosis ; *Parkinson Disease/metabolism ; }, abstract = {INTRODUCTION: Several studies indicate the role of mesenchymal stem cells (MSCs) as an important tool in regenerative medicine associated with injuries that affect the central nervous system (CNS). The MSCs have the capacity to differentiate into cells of the embryonic tissue, such as the mesoderm. So, these cells can be found in a variety of tissues. Also, the MSCs can release immunomodulatory and neurotrophic factors performance as inflammation mediators operating in injured tissue regeneration. Furthermore, they can differentiate into neural-like cells in vitro. Thereby, because of the high immunomodulatory role of MSCs, this review sought to describe the main immunomodulatory mechanisms performed by MSCs in CNS recovery after tissue injury or neurodegenerative diseases.<br><br>METHODS: PubMed and ScienceDirect were searched between January 2011 to March 2021, and 43 articles met the criteria of the review.<br><br>RESULTS: This systematic review indicates that MSCs were used in vivo experimental multiple sclerosis, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ischemic stroke, and traumatic brain injury. The treatment MSCs were usually from human origin, derived from bone marrow, and administered intravenously.<br><br>CONCLUSION: It was shown that MSCs, independent from origin or administration pathway, can reduce inflammation and help in the recovery and preservation of injured neural tissue. Thus, the use of MSCs represents a potential therapeutic option in the treatment of neurological disorders mediated by inflammatory processes.}, }
@article {pmid36398199, year = {2022}, author = {Dinsmoor, DA and Usoro, JO and Barka, ND and Billstrom, TM and Litvak, LM and Poree, LR}, title = {Using evoked compound action potentials to quantify differential neural activation with burst and conventional, 40 Hz spinal cord stimulation in ovines.}, journal = {Pain reports}, volume = {7}, number = {6}, pages = {e1047}, pmid = {36398199}, issn = {2471-2531}, abstract = {UNLABELLED: Unlike conventional dorsal spinal cord stimulation (SCS)-which uses single pulses at a fixed rate-burst SCS uses a fixed-rate, five-pulse stimuli cluster as a treatment for chronic pain; mechanistic explanations suggest burst SCS differentially modulate the medial and lateral pain pathways vs conventional SCS. Neural activation differences between burst and conventional SCS are quantifiable with the spinal-evoked compound action potential (ECAP), an electrical measure of synchronous neural activation.<br><br>METHODS: We implanted 7 sheep with a dorsal stimulation lead at T9/T10, a dorsal ECAP sensing lead at T6/T7, and a lead also at T9/T10 but adjacent to the anterolateral system (ALS). Both burst and conventional SCS with stimulation amplitudes up to the visual motor threshold (vMT) were delivered to 3 different dorsal spinal locations, and ECAP thresholds (ECAPTs) were calculated for all combinations. Then, changes in ALS activation were assessed with both types of SCS.<br><br>RESULTS: Evoked compound action potential thresholds and vMTs were significantly higher (P < 0.05) with conventional vs burst SCS, with no statistical difference (P > 0.05) among stimulation sites. However, the vMT-ECAPT window (a proxy for the useable therapeutic dosing range) was significantly wider (P < 0.05) with conventional vs burst SCS. No significant difference (P > 0.05) in ALS activation was noted between conventional and burst SCS.<br><br>CONCLUSION: When dosed equivalently, no differentially unique change in ALS activation results with burst SCS vs conventional SCS; in addition, sub-ECAPT burst SCS results in no discernable excitability changes in the neural pathways feeding pain relevant supraspinal sites.}, }
@article {pmid36389059, year = {2022}, author = {Guo, Y and Wang, S and Chao, X and Li, D and Wang, Y and Guo, Q and Chen, T}, title = {Multi-omics studies reveal ameliorating effects of physical exercise on neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1026688}, pmid = {36389059}, issn = {1663-4365}, abstract = {INTRODUCTION: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, are heavy burdens to global health and economic development worldwide. Mounting evidence suggests that exercise, a type of non-invasive intervention, has a positive impact on the life quality of elderly with neurodegenerative diseases. X-omics are powerful tools for mapping global biochemical changes in disease and treatment.<br><br>METHOD: Three major databases were searched related to current studies in exercise intervention on neurodegenerative diseases using omics tools, including metabolomics, metagenomics, genomics, transcriptomics, and proteomics.<br><br>RESULT: We summarized the omics features and potential mechanisms associated with exercise and neurodegenerative diseases in the current studies. Three main mechanisms by which exercise affects neurodegenerative diseases were summed up, including adult neurogenesis, brain-derived neurotrophic factor (BDNF) signaling, and short-chain fatty acids (SCFAs) metabolism.<br><br>CONCLUSION: Overall, there is compelling evidence that exercise intervention is a feasible way of preventing the onset and alleviating the severity of neurodegenerative diseases. These studies highlight the importance of exercise as a complementary approach to the treatment and intervention of neurodegenerative diseases in addition to traditional treatments. More mechanisms on exercise interventions for neurodegenerative diseases, the specification of exercise prescriptions, and differentiated exercise programs should be explored so that they can actually be applied to the clinic.}, }
@article {pmid36388611, year = {2023}, author = {Sotoudeh, H and Alizadeh, M and Shahidi, R and Shobeiri, P and Love, N and Singhal, A}, title = {Subcortical signal alteration of corticospinal tracts. A radiologic manifestation of ARIA: A case report.}, journal = {Radiology case reports}, volume = {18}, number = {1}, pages = {275-279}, pmid = {36388611}, issn = {1930-0433}, abstract = {Patients with Alzheimer's disease who have been given monoclonal antibodies targeting amyloid-β (Aβ) (eg, gantenerumab, donanemab, lecanemab, and aducanumab) for scientific purposes may have a spectrum of imaging findings known as amyloid-related imaging abnormalities (ARIA), shown on brain magnetic resonance imaging (MRI) scans. These neuroimaging abnormalities are caused by antibody-mediated destruction of accumulated Aβ aggregates in cerebral blood vessels and brain parenchyma. ARIA may demonstrate as brain edema or sulcal effusion (ARIA-E) or as hemosiderin deposits caused by brain parenchymal or pial hemorrhage (ARIA-H). The current study explores 2 cases with interval development of FLAIR hyper signal intensity along the bilateral corticospinal tracts in the motor cortex/precentral gyri after treatment by aducanumab. We believe this manifestation is a subtype of ARIA-A that has not been explored earlier. Our first case was a 72-year-old woman with a history of HTN and kidney transplant (polycystic kidney) who presented with mild cognitive impairment with clinical findings consistent with early Alzheimer's disease. After receiving 3 doses of aducunumab and experiencing cognition improvement, she underwent a brain MRI because of dizziness and vertigo. The brain MRI demonstrated new FLAIR hyper signal intensity in subcortical regions of precentral gyri (motor cortex) symmetrically as well as trace subarachnoid hemorrhage at the vertex compatible with ARIA-E and ARIA-H. Our second case was an 85-year-old woman with a history of small lymphocytic leukemia which was treated 20 years earlier. After orthopedic surgery 2 years ago, she developed dementia with anterograde amnesia. Since then, Aricept and Namenda have been started, but there have been no improvements in her subjective condition. The initial Amyloid PET/MR imaging showed diffuse cerebral Amyloid deposition. After tolerating 6 doses of aducanumab a safety MRI revealed new bilateral symmetric FLAIR hyper signal intensity in the subcortical motor cortex. Results of our study suggest that the subcortical corticospinal tract is another hotspot for ARIA findings. Hence, these regions might be an unknown site for both the action and adverse effects of aducanumab on amyloid plaques with secondary inflammation. In addition, radiologists must take this phenomenon into the account, and be cognizant that the FLAIR hyper signal intensities should not be misinterpreted as motor neuron disease (eg, amyotrophic lateral sclerosis).}, }
@article {pmid36388178, year = {2022}, author = {Mao, D and Zheng, Y and Xu, F and Han, X and Zhao, H}, title = {HMGB1 in nervous system diseases: A common biomarker and potential therapeutic target.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {1029891}, pmid = {36388178}, issn = {1664-2295}, abstract = {High-mobility group box-1 (HMGB1) is a nuclear protein associated with early inflammatory changes upon extracellular secretion expressed in various cells, including neurons and microglia. With the progress of research, neuroinflammation is believed to be involved in the pathogenesis of neurological diseases such as Parkinson's, epilepsy, and autism. As a key promoter of neuroinflammation, HMGB1 is thought to be involved in the pathogenesis of Parkinson's disease, stroke, traumatic brain injury, epilepsy, autism, depression, multiple sclerosis, and amyotrophic lateral sclerosis. However, in the clinic, HMGB1 has not been described as a biomarker for the above-mentioned diseases. However, the current preclinical research results show that HMGB1 antagonists have positive significance in the treatment of Parkinson's disease, stroke, traumatic brain injury, epilepsy, and other diseases. This review discusses the possible mechanisms by which HMGB1 mediates Parkinson's disease, stroke, traumatic brain injury, epilepsy, autism, depression, multiple sclerosis, amyotrophic lateral sclerosis, and the potential of HMGB1 as a biomarker for these diseases. Future research needs to further explore the underlying molecular mechanisms and clinical translation.}, }
@article {pmid36387978, year = {2022}, author = {Shivani,  and Grewal, SK and Gill, RK and Kaur Virk, H and Bhardwaj, RD}, title = {Impact of post-emergent imazethapyr on morpho-physiological and biochemical responses in lentil (Lens culinaris Medik.).}, journal = {Physiology and molecular biology of plants : an international journal of functional plant biology}, volume = {28}, number = {9}, pages = {1681-1693}, pmid = {36387978}, issn = {0971-5894}, abstract = {UNLABELLED: Yield reduction in lentil crop due to weed infestation is a key hindrance to its growth due to poor weed-crop competition. Imazethapyr (IM), a selective herbicide, target acetolactate synthase (ALS) which catalyzes the first reaction in biosynthesis of branched chain amino acids, required for plant growth and development. The objective of the present study was to investigate the impact of IM treatment on weeds, ALS enzyme activity, antioxidant capacity, osmolyte accumulation, growth and yield related parameters in lentil genotypes. Two IM tolerant (LL1397 and LL1612) and two susceptible (FLIP2004-7L and PL07) lentil genotypes were cultivated under weed free, weedy check and IM treatments. Weed control efficiency reached its peak at 21 days after spray (DAS). Imazethapyr treatment decreased chlorophyll and carotenoid content up to 28 DAS with higher reduction in susceptible genotypes. FLIP2004-7L and PL07 had reduced plant height and lower number of pods under IM treatment which resulted in decreased seed yield. Higher ALS activity in LL1397 and LL1612 at 21 DAS, higher antioxidant capacity and glycine betaine content both at 21 and 28 DAS and lower decrease in relative leaf water content might be mediating herbicide tolerance in these genotypes that led to higher seed yield. The identified IM tolerance mechanism can be used to impart herbicide resistance in lentil.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-022-01244-x.}, }
@article {pmid36385663, year = {2023}, author = {Xu, Y and Zhao, J and Zhao, Y and Zhou, L and Qiao, H and Xu, Q and Liu, Y}, title = {The role of ferroptosis in neurodegenerative diseases.}, journal = {Molecular biology reports}, volume = {50}, number = {2}, pages = {1655-1661}, pmid = {36385663}, issn = {1573-4978}, support = {82172147//National Natural Science Foundation of China/ ; 81571880//National Natural Science Foundation of China/ ; 81373147//National Natural Science Foundation of China/ ; 30901555//National Natural Science Foundation of China/ ; 30972870//National Natural Science Foundation of China/ ; 81360080//National Natural Science Foundation of China/ ; 2021JJ30900//Natural Science Foundation of&#xa0;Hunan Province/ ; 2016JJ2157//Natural Science Foundation of&#xa0;Hunan Province/ ; 2020zzts222//Fundamental Research Funds for Central Universities of the Central South University/ ; }, mesh = {Humans ; *Neurodegenerative Diseases ; *Ferroptosis/genetics ; Apoptosis ; Cell Death ; Oxidative Stress/physiology ; }, abstract = {Ferroptosis is newly identified as a non-apoptotic form of programmed cell death. It is characterized by iron-dependent intracellular accumulation of lipid peroxides which ultimately leads to oxidative stress and cell death. Ferroptosis has been identified in several diseases, such as cancer, renal failure, liver injury, and ischemia-reperfusion injury. Besides, it has been reported to be involved in the pathological mechanism of neurodegenerative diseases (NDD). In addition, interventions targeting ferroptosis can influence the course of NDD, making it a potential therapeutic target for NDD. By summarizing the current research on ferroptosis and its impact on many neurological diseases, we hope to provide valuable strategies for the underlying mechanisms and treatment of these neurological diseases.}, }
@article {pmid36384165, year = {2022}, author = {Spiesshoefer, J and Storre, JH and Dreher, M}, title = {[Non-invasive Home-Ventilation: Pathophysiology, Initiation and Follow-up].}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {76}, number = {11}, pages = {820-831}, doi = {10.1055/a-1947-3162}, pmid = {36384165}, issn = {1438-8790}, mesh = {Humans ; Hypercapnia/diagnosis/therapy ; Carbon Dioxide ; Follow-Up Studies ; *Noninvasive Ventilation/methods ; Respiration, Artificial ; *Respiratory Insufficiency/diagnosis/etiology/therapy ; }, abstract = {COPD is the most common reason for hypercapnia. However, it is - by far - not the only reason. In fact, numerous neuromuscular disorders (not only ALS) as well as restrictive thoracic disorders do also lead to clinically highly relevant hypercapnia. Early diagnosis of hypercapnic ventilatory failure usually takes place at nighttime. NIV devices work with a periodic interplay of alternating IPAP and EPAP which results in a ventilation of the lungs, thereby elimination CO2 to treat hypercapnic respiratory failure. Firstline settings for a NIV therapy to treat "stable hypercapnia" are as follows: Pressure Support Ventilation Modus, EPAP 5 cm H2O, IPAP 15 cm H2O, Back Up rate 15/Minute. The overall goal of NIV treatment is a successful reduction in CO2. This can be achieved by changing the following variables of the ventilator settings: increase in IPAP ± increase in back up respiratory rate ± use of assisted pressure controlled ventilation mode (APCV)-.}, }
@article {pmid36381809, year = {2022}, author = {Bazzi, T and Kropman, K and Benjamin, M and Al-Rammahi, A}, title = {Light Chain Amyloidosis Presenting as a Septic Shock: A Case Report and Review of Literature.}, journal = {Cureus}, volume = {14}, number = {10}, pages = {e30263}, pmid = {36381809}, issn = {2168-8184}, abstract = {Light chain (AL) amyloidosis is a plasma cell dyscrasia that results in an overproduction of immunoglobulins of the lambda or kappa light chains. These monoclonal ALs begin to form fibrils with each other and exert their toxic effect by depositing in different organs around the body. Disease presentation is indistinct, but it is ideal to diagnose this disorder before end-organ damage is caused. Once the diagnosis of AL amyloidosis is confirmed, the best treatment is autologous stem cell transplantation once a candidate is deemed fit for it; however, there are other chemotherapy agents whose patients can be administered until they undergo stem cell transplantation. In this case presentation and systematic review of AL amyloidosis, we discuss a patient who presented with septic shock and further workup leading to a diagnosis of advanced-stage amyloidosis. We also take a deeper look at AL amyloidosis providing a comprehensive review of the disease process and its treatment options.}, }
@article {pmid36381721, year = {2022}, author = {Perez, JA and Lopez, JJ and Torres Badillo, CC and Gill, J and Kesari, S and Novak, P and Temnikov, M and Byshovets, R and Bychkov, O}, title = {Phase 1 First-in-Human Dose Escalation and Dose Expansion Study of KLS-1 (64Zinc Aspartate) in Patients With Cancer and Neurodegenerative Diseases.}, journal = {Cureus}, volume = {14}, number = {10}, pages = {e29921}, pmid = {36381721}, issn = {2168-8184}, abstract = {Background KLS-1 is zinc (Zn) aspartate enriched with isotope [64]Zn to 99.2% mass fraction of total zinc. KLS-1 is intended as a novel therapeutic approach for patients with a variety of diseases including but not limited to different forms of cancer and neurodegenerative diseases. The purpose of this first-in-human study was to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics (PK) in patients with medical disorders. Methods The study was designed as consisting of two consecutive parts: the dose escalation part and the dose expansion part. Adult patients with refractory glioblastoma, primary progressive aphasia/dementia, amyotrophic lateral sclerosis, Parkinson's disease (PD), and type 1 diabetes were included. KLS-1 formulated as a 10 mL water solution containing 26.42 mg/mL of [64]zinc aspartate (that is equivalent to 5.184 mg/mL of [64]Zn) was administered twice weekly in two-week cycles via two-hour intravenous (IV) infusion at various dose levels during the dose escalation part and twice weekly during five subsequent weeks in the dose expansion part. The study was conducted at Pan American Cancer Treatment Center (Tijuana, Mexico) in 2020 and had a duration of 10 months. Results A total of eight patients (all white/Caucasian) were enrolled in both parts of the study. A total of four patients who participated in the dose escalation part were dosed twice weekly at 1, 2, and 4 mg/kg in two-week cycles for each dose level with the dose increased to the next higher level in the subsequent cycle. Dose-limiting toxicities (DLTs) were defined at dose level 4 mg/kg due to treatment-emergent reversible adverse events that required medications for symptomatic relief. The most common drug-related toxicities that occurred in two or more patients (≥25%) were weakness (five patients), fatigue (four patients), dizziness (three patients), nausea (two patients), poor sleep (two patients), and abdominal discomfort (two patients). In the dose expansion part, a dose of 2 mg/kg administered twice weekly was investigated for five continuous weeks in four patients and was established as recommended phase 1b/2 dose. Systemic exposure to KLS-1 (area under the curve (AUC) and maximum serum concentration (Cmax)) increased from 1 to 4 mg/kg and showed a linear relationship. Conclusions Multiple doses of KLS-1 ranging from 1 to 2 mg/kg administered twice a week via intravenous infusion for up to five continuous weeks were safe and well tolerated in patients with different types of therapeutic conditions including but not limited to a few forms of cancer and Parkinson's disease, and the evaluated pharmacokinetic parameters exhibited favorable profile.}, }
@article {pmid36376130, year = {2022}, author = {Shimizu, H and Nishimura, Y and Shiide, Y and Akimoto, M and Matsuda, H and Kato, Y and Hirai, M}, title = {Food Effect Study to Assess the Impact on Edaravone Pharmacokinetic Profiles in Healthy Participants.}, journal = {Clinical therapeutics}, volume = {44}, number = {12}, pages = {1552-1565}, doi = {10.1016/j.clinthera.2022.10.001}, pmid = {36376130}, issn = {1879-114X}, mesh = {Adult ; Female ; Humans ; Male ; Administration, Oral ; Area Under Curve ; Biological Availability ; Cross-Over Studies ; Edaravone ; *Fasting ; *Food-Drug Interactions ; Healthy Volunteers ; }, abstract = {PURPOSE: The safety and efficacy of intravenous edaravone, a neuroprotectant used for the treatment of amyotrophic lateral sclerosis (ALS), have been shown in clinical trials. An oral suspension of edaravone has been developed, but the food effect on its pharmacokinetic profile has not been evaluated. This study aimed to assess the food effect on the pharmacokinetic profile of edaravone after oral administration and to investigate dosing regimens and administration instructions with different meal intake and timing.<br><br>METHODS: Data from 3 Phase I clinical studies were used to evaluate the effect of food on the pharmacokinetic profiles of a single dose of edaravone oral suspension. In all 3 studies, participants received a single dose of edaravone with various meal conditions. Healthy Japanese adult male participants (Studies 1, 2, and 3) or female participants (Study 3) aged 20 to 45 years at the time of informed consent were included.<br><br>FINDINGS: In Study 1, 6 participants were enrolled and 5 completed the study. Nine and 16 participants were treated in Studies 2 and 3, respectively, and all completed the study. The Cmax and AUC0-&#x221e; of edaravone were lower when administered 30 minutes after a high-fat meal compared with those in a fasted condition (Study 1). Lower plasma edaravone concentrations (approximately within the first hour) and subsequent lower Cmax and AUC0-&#x221e; were observed after administration of edaravone 4 hours after a high-fat meal (Study 2) or 2 hours after a low-fat meal (Study 3). The Cmax and AUC0-&#x221e; of oral edaravone were generally similar and not affected when administered 8 hours after a high-fat meal, 4 hours after a low-fat meal, or 2 hours after a light meal relative to the fasted condition. Administration of edaravone 1 hour before a high-fat meal resulted in no effect on Cmax or AUC0-&#x221e; relative to the fasted condition. Administration of edaravone in the fed or fasted conditions resulted in a similar urine pharmacokinetic profile.<br><br>IMPLICATIONS: Oral administration of edaravone with a meal decreased the plasma concentration of edaravone. Oral administration of edaravone 8 hours after a high-fat meal, 4 hours after a low-fat meal, 2 hours after a light meal, and 1 hour before a high-fat meal showed no effect of food on the PK profile of unchanged edaravone compared with that observed under a fasted condition.<br><br>CLINICALTRIALS: gov identifiers: NCT04481750, NCT04481789, and NCT05342597.}, }
@article {pmid36364033, year = {2022}, author = {Dailah, HG}, title = {Potential of Therapeutic Small Molecules in Apoptosis Regulation in the Treatment of Neurodegenerative Diseases: An Updated Review.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {21}, pages = {}, pmid = {36364033}, issn = {1420-3049}, support = {RUP-5//Deputyship for Research &amp; Innovation, Ministry of Education in Saudi Arabia/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Amyotrophic Lateral Sclerosis ; Apoptosis/physiology ; Caspases ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Neurodegenerative disorders (NDs) include Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) and the common feature of NDs is the progressive death of specific neurons in the brain. Apoptosis is very important in developing the nervous system, nonetheless an elevated level of cell death has been observed in the case of NDs. NDs are different in terms of their neuronal vulnerability and clinical manifestations, however they have some overlapping neurodegenerative pathways. It has been demonstrated by several studies with cell lines and animal models that apoptosis has a significant contribution to make in advancing AD, ALS, HD, and PD. Numerous dying neurons were also identified in the brains of individuals with NDs and these conditions were found to be linked with substantial cell loss along with common characteristics of apoptosis including activation of caspases and cysteine-proteases, DNA fragmentation, and chromatin condensation. It has been demonstrated that several therapeutic agents including antioxidants, minocycline, GAPDH ligands, p53 inhibitors, JNK (c-Jun N-Terminal Kinase) inhibitors, glycogen synthase kinase-3 inhibitor, non-steroidal anti-inflammatory drugs, D2 dopamine receptor agonists, FK506, cell cycle inhibitors, statins, drugs targeting peroxisome proliferator-activated receptors, and gene therapy have the potential to provide protection to neurons against apoptosis. Therefore, the use of these potential therapeutic agents might be beneficial in the treatment of NDs. In this review, we have summarized the pathways that are linked with apoptotic neuronal death in the case of various NDs. We have particularly focused on the therapeutic agents that have neuroprotective properties and the potential to regulate apoptosis in NDs.}, }
@article {pmid36359871, year = {2022}, author = {Zayed, MA and Sultan, S and Alsaab, HO and Yousof, SM and Alrefaei, GI and Alsubhi, NH and Alkarim, S and Al Ghamdi, KS and Bagabir, SA and Jana, A and Alghamdi, BS and Atta, HM and Ashraf, GM}, title = {Stem-Cell-Based Therapy: The Celestial Weapon against Neurological Disorders.}, journal = {Cells}, volume = {11}, number = {21}, pages = {}, pmid = {36359871}, issn = {2073-4409}, mesh = {Animals ; *Nervous System Diseases/therapy ; Stem Cell Transplantation ; *Huntington Disease/metabolism ; *Parkinson Disease/metabolism ; Motor Neurons/pathology ; }, abstract = {Stem cells are a versatile source for cell therapy. Their use is particularly significant for the treatment of neurological disorders for which no definitive conventional medical treatment is available. Neurological disorders are of diverse etiology and pathogenesis. Alzheimer's disease (AD) is caused by abnormal protein deposits, leading to progressive dementia. Parkinson's disease (PD) is due to the specific degeneration of the dopaminergic neurons causing motor and sensory impairment. Huntington's disease (HD) includes a transmittable gene mutation, and any treatment should involve gene modulation of the transplanted cells. Multiple sclerosis (MS) is an autoimmune disorder affecting multiple neurons sporadically but induces progressive neuronal dysfunction. Amyotrophic lateral sclerosis (ALS) impacts upper and lower motor neurons, leading to progressive muscle degeneration. This shows the need to try to tailor different types of cells to repair the specific defect characteristic of each disease. In recent years, several types of stem cells were used in different animal models, including transgenic animals of various neurologic disorders. Based on some of the successful animal studies, some clinical trials were designed and approved. Some studies were successful, others were terminated and, still, a few are ongoing. In this manuscript, we aim to review the current information on both the experimental and clinical trials of stem cell therapy in neurological disorders of various disease mechanisms. The different types of cells used, their mode of transplantation and the molecular and physiologic effects are discussed. Recommendations for future use and hopes are highlighted.}, }
@article {pmid36359844, year = {2022}, author = {Martin, LJ and Adams, DA and Niedzwiecki, MV and Wong, M}, title = {Aberrant DNA and RNA Methylation Occur in Spinal Cord and Skeletal Muscle of Human SOD1 Mouse Models of ALS and in Human ALS: Targeting DNA Methylation Is Therapeutic.}, journal = {Cells}, volume = {11}, number = {21}, pages = {}, pmid = {36359844}, issn = {2073-4409}, support = {R01 NS034100/NS/NINDS NIH HHS/United States ; R01 NS052098/NS/NINDS NIH HHS/United States ; R01 NS065895/NS/NINDS NIH HHS/United States ; NS34100/NH/NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Disease Models, Animal ; DNA/chemistry/metabolism ; *DNA Methylation/genetics ; Methylation ; *Methyltransferases/metabolism ; Mice, Transgenic ; Muscle, Skeletal/metabolism ; RNA/chemistry/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; *RNA Processing, Post-Transcriptional ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease. Skeletal muscles and motor neurons (MNs) degenerate. ALS is a complex disease involving many genes in multiple tissues, the environment, cellular metabolism, and lifestyles. We hypothesized that epigenetic anomalies in DNA and RNA occur in ALS and examined this idea in: (1) mouse models of ALS, (2) human ALS, and (3) mouse ALS with therapeutic targeting of DNA methylation. Human superoxide dismutase-1 (hSOD1) transgenic (tg) mice were used. They expressed nonconditionally wildtype (WT) and the G93A and G37R mutant variants or skeletal muscle-restricted WT and G93A and G37R mutated forms. Age-matched non-tg mice were controls. hSOD1 mutant mice had increased DNA methyltransferase enzyme activity in spinal cord and skeletal muscle and increased 5-methylcytosine (5mC) levels. Genome-wide promoter CpG DNA methylation profiling in skeletal muscle of ALS mice identified hypermethylation notably in cytoskeletal genes. 5mC accumulated in spinal cord MNs and skeletal muscle satellite cells in mice. Significant increases in DNA methyltransferase-1 (DNMT1) and DNA methyltransferase-3A (DNMT3A) levels occurred in spinal cord nuclear and chromatin bound extracts of the different hSOD1 mouse lines. Mutant hSOD1 interacted with DNMT3A in skeletal muscle. 6-methyladenosine (6mA) RNA methylation was markedly increased or decreased in mouse spinal cord depending on hSOD1-G93A model, while fat mass and obesity associated protein was depleted and methyltransferase-like protein 3 was increased in spinal cord and skeletal muscle. Human ALS spinal cord had increased numbers of MNs and interneurons with nuclear 5mC, motor cortex had increased 5mC-positive neurons, while 6mA was severely depleted. Treatment of hSOD1-G93A mice with DNMT inhibitor improved motor function and extended lifespan by 25%. We conclude that DNA and RNA epigenetic anomalies are prominent in mouse and human ALS and are potentially targetable for disease-modifying therapeutics.}, }
@article {pmid36359827, year = {2022}, author = {Kaur, K and Chen, PC and Ko, MW and Mei, A and Chovatiya, N and Huerta-Yepez, S and Ni, W and Mackay, S and Zhou, J and Maharaj, D and Malarkannan, S and Jewett, A}, title = {The Potential Role of Cytotoxic Immune Effectors in Induction, Progression and Pathogenesis of Amyotrophic Lateral Sclerosis (ALS).}, journal = {Cells}, volume = {11}, number = {21}, pages = {}, pmid = {36359827}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/metabolism/pathology ; *CD8-Positive T-Lymphocytes/metabolism ; Cytokines/metabolism ; Granzymes/metabolism ; Leukocytes, Mononuclear/metabolism ; *T-Lymphocytes, Cytotoxic/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an auto-immune neurodegenerative disorder affecting the motor-neuron system. The causes of ALS are heterogeneous, and are only partially understood. We studied different aspects of immune pathogenesis in ALS and found several basic mechanisms which are potentially involved in the disease. Our findings demonstrated that ALS patients' peripheral blood contains higher proportions of NK and B cells in comparison to healthy individuals. Significantly increased IFN-γ secretion by anti-CD3/28 mAbs-treated peripheral blood mononuclear cells (PBMCs) were observed in ALS patients, suggesting that hyper-responsiveness of T cell compartment could be a potential mechanism for ALS progression. In addition, elevated granzyme B and perforin secretion at a single cell level, and increased cytotoxicity and secretion of IFN-γ by patients' NK cells under specific treatment conditions were also observed. Increased IFN-γ secretion by ALS patients' CD8+ T cells in the absence of IFN-γ receptor expression, and increased CD8+ T cell effector/memory phenotype as well as increased granzyme B at the single cell level points to the CD8+ T cells as potential cells in targeting motor neurons. Along with the hyper-responsiveness of cytotoxic immune cells, significantly higher levels of inflammatory cytokines including IFN-γ was observed in peripheral blood-derived serum of ALS patients. Supernatants obtained from ALS patients' CD8+ T cells induced augmented cell death and differentiation of the epithelial cells. Weekly N-acetyl cysteine (NAC) infusion in patients decreased the levels of many inflammatory cytokines in peripheral blood of ALS patient except IFN-γ, TNF-α, IL-17a and GMCSF which remained elevated. Findings of this study indicated that CD8+ T cells and NK cells are likely culprits in targeting motor neurons and therefore, strategies should be designed to decrease their function, and eliminate the aggressive nature of these cells. Analysis of genetic mutations in ALS patient in comparison to identical twin revealed a number of differences and similarities which may be important in the pathogenesis of the disease.}, }
@article {pmid36358942, year = {2022}, author = {Huseby, CJ and Delvaux, E and Brokaw, DL and Coleman, PD}, title = {Blood Transcript Biomarkers Selected by Machine Learning Algorithm Classify Neurodegenerative Diseases including Alzheimer's Disease.}, journal = {Biomolecules}, volume = {12}, number = {11}, pages = {}, pmid = {36358942}, issn = {2218-273X}, support = {T32 AG044402/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/genetics/drug therapy ; *Alzheimer Disease/diagnosis/genetics ; *Huntington Disease ; Machine Learning ; Biomarkers ; }, abstract = {The clinical diagnosis of neurodegenerative diseases is notoriously inaccurate and current methods are often expensive, time-consuming, or invasive. Simple inexpensive and noninvasive methods of diagnosis could provide valuable support for clinicians when combined with cognitive assessment scores. Biological processes leading to neuropathology progress silently for years and are reflected in both the central nervous system and vascular peripheral system. A blood-based screen to distinguish and classify neurodegenerative diseases is especially interesting having low cost, minimal invasiveness, and accessibility to almost any world clinic. In this study, we set out to discover a small set of blood transcripts that can be used to distinguish healthy individuals from those with Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, or frontotemporal dementia. Using existing public datasets, we developed a machine learning algorithm for application on transcripts present in blood and discovered small sets of transcripts that distinguish a number of neurodegenerative diseases with high sensitivity and specificity. We validated the usefulness of blood RNA transcriptomics for the classification of neurodegenerative diseases. Information about features selected for the classification can direct the development of possible treatment strategies.}, }
@article {pmid36355135, year = {2022}, author = {Yoshikawa, S and Taniguchi, K and Sawamura, H and Ikeda, Y and Tsuji, A and Matsuda, S}, title = {A New Concept of Associations between Gut Microbiota, Immunity and Central Nervous System for the Innovative Treatment of Neurodegenerative Disorders.}, journal = {Metabolites}, volume = {12}, number = {11}, pages = {}, pmid = {36355135}, issn = {2218-1989}, abstract = {Nerve cell death accounts for various neurodegenerative disorders, in which altered immunity to the integrated central nervous system (CNS) might have destructive consequences. This undesirable immune response often affects the progressive neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, schizophrenia and/or amyotrophic lateral sclerosis (ALS). It has been shown that commensal gut microbiota could influence the brain and/or several machineries of immune function. In other words, neurodegenerative disorders may be connected to the gut-brain-immune correlational system. The engrams in the brain could retain the information of a certain inflammation in the body which might be involved in the pathogenesis of neurodegenerative disorders. Tactics involving the use of probiotics and/or fecal microbiota transplantation (FMT) are now evolving as the most promising and/or valuable for the modification of the gut-brain-immune axis. More deliberation of this concept and the roles of gut microbiota would lead to the development of stupendous treatments for the prevention of, and/or therapeutics for, various intractable diseases including several neurodegenerative disorders.}, }
@article {pmid36354563, year = {2022}, author = {Li, Q and Liu, X and Liu, W and Zhang, Y and Liu, W and Wu, M and Chen, Z and Zhao, Y and Zou, L}, title = {Placenta-Targeted Nanoparticles Loaded with PFKFB3 Overexpression Plasmids Enhance Angiogenesis and Placental Function.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {9}, number = {11}, pages = {}, pmid = {36354563}, issn = {2306-5354}, support = {81873844//National Natural Science Foundation of China/ ; }, abstract = {Placental angiogenesis disorder and placental dysplasia are important causes of many pregnancy complications. Due to safety and economic benefits, effective treatment strategies are currently limited. PFKFB3 is a key regulator of glycolysis that controls angiogenesis through a metabolic pathway independent of genetic signals. In this study, we constructed the nanodrug T-NPPFKFB3 and explored its feasibility to promote angiogenesis and enhance placental function. First, liposomes containing PFKFB3 overexpression plasmids modified by the placental homing peptide CGKRK were synthesized by the thin film method. In vivo experiments revealed that T-NPPFKFB3 injected intravenously specifically accumulated in the mouse placenta and therein upregulated the expression of PFKFB3 without affecting its expression in other important organs. In addition, T-NPPFKFB3 promoted placental angiogenesis and increased the fetal and placental weights of the mice. Finally, we evaluated the safety of T-NPPFKFB3. The expression levels of ALS/AST/BUN in the sera of pregnant mice were not significantly different from those in the sera of control group mice. However, T-NPPFKFB3 did not cause obvious fetal abnormalities or alter the average litter size. In conclusion, T-NPPFKFB3 can specifically target the placenta, promote angiogenesis, and enhance placental function without obvious side effects. Therefore, it has potential as a new strategy for the treatment of pregnancy complications.}, }
@article {pmid36354298, year = {2022}, author = {Castro-Rodríguez, E and Azagra-Ledesma, R and Gómez-Batiste Alertón, X and Aguyé-Batista, A and Zwart-Salmerón, M and Cabanas-Valdés, R and Caballero-Gómez, FM and Clemente-Azagra, C}, title = {[Analysis of accidental falls and the integration in the chronicity programs of patients with amyotrophic lateral sclerosis].}, journal = {Revista de neurologia}, volume = {75}, number = {10}, pages = {297-303}, pmid = {36354298}, issn = {1576-6578}, mesh = {Humans ; Male ; Aged ; Female ; *Amyotrophic Lateral Sclerosis/therapy ; Accidental Falls ; Quality of Life ; *Noninvasive Ventilation ; *Motor Neuron Disease ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is the most common degenerative motor neuron disease. There is no curative treatment available, and these patients require multidisciplinary support to promote their comfort and quality of life.<br><br>PATIENTS AND METHODS: Longitudinal descriptive study in patients registered in primary care (PC), Costa de Ponent-Barcelona Institut Catala de la Salut to analyse emergency hospital visits, use of support devices and their integration into the primary care chronicity program. Variables were sex, age and evolution time, emergency visits, patients with percutaneous gastrostomy (PEG), non-invasive or invasive ventilation (NIV/VI), integration in the primary care chronicity program.<br><br>RESULTS: 81 patients, 49.4% male, mean age 65.6 years (&#xb1;11.7), evolution time less than 2 years or equal to or greater than 2 years (42 and 58%, respectively). Of them, 47 (58.5%) made 107 consultations. The most frequent reasons for consultation were falls (26.8%), respiratory difficulties (23.3%), comorbidity (16.7%), eating problems (11%) and pain (10.2%) without differences by age or sex. Greater frequency (p < 0.001) was observed in patients with less than two years of evolution and significant increases in the use of NIV and PEG up to 51.9 and 35.8% respectively, as well as integration in primary care chronicity program of 61.7%.<br><br>CONCLUSIONS: Accidental falls were the most frequent and potentially avoidable reason for hospital emergency visits in patients with ALS, especially in the first two years of the disease. Significant increases are detected in the use of support devices and in primary care chronicity program integration. It is necessary to increase home resources, especially in physiotherapy and occupational therapy.}, }
@article {pmid36353522, year = {2022}, author = {Pognan, F and Buono, C and Couttet, P and Galarneau, JR and Timsit, Y and Wolf, A}, title = {Liver enzyme delayed clearance in rat treated by CSF1 receptor specific antagonist Sotuletinib.}, journal = {Current research in toxicology}, volume = {3}, number = {}, pages = {100091}, pmid = {36353522}, issn = {2666-027X}, abstract = {Sotuletinib (BLZ945), a CSF1-R specific kinase inhibitor developed for the treatment of Amyotrophic Lateral Sclerosis, induced liver enzyme elevation in absence of hepatocellular lesions in preclinical rat and monkey studies. The monocytic cell family, including Kupffer cells, e.g., the liver-resident macrophages, are dependent upon CSF1 pathway activation for their survival, proliferation, and differentiation. Kupffer cells act as the main body compartment responsible for elimination of some blood-borne proteins, like ALT, AST, and few others. The depletion of Kupffer cells through CSF1 pathway inhibition has already been hypothesized as responsible for apparent liver enzyme elevation without detectable corresponding liver damage. However, a release of these biomarkers from unseen hepatic lesions or from other organs cannot be excluded. In order to eliminate a potential contribution of ALT elevation from an internal organ source, we injected recombinant his-Tagged ALT1 into rats pretreated with Sotuletinib. The elimination rate of the exogenous ALT1 was significantly lower in treated animals, demonstrating a delayed clearance independently of any potential organ lesions.}, }
@article {pmid36342754, year = {2023}, author = {Wlaschin, JJ and Donahue, C and Gluski, J and Osborne, JF and Ramos, LM and Silberberg, H and Le Pichon, CE}, title = {Promoting regeneration while blocking cell death preserves motor neuron function in a model of ALS.}, journal = {Brain : a journal of neurology}, volume = {146}, number = {5}, pages = {2016-2028}, pmid = {36342754}, issn = {1460-2156}, support = {ZIA HD008966/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Axons/pathology ; *Neurodegenerative Diseases/pathology ; Superoxide Dismutase/metabolism ; Nerve Regeneration ; Motor Neurons/metabolism ; Cell Death ; Disease Models, Animal ; Mice, Transgenic ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease of motor neurons with very few treatment options. We had previously found that motor neuron degeneration in a mouse model of ALS can be delayed by deleting the axon damage sensor MAP3K12 or dual leucine zipper kinase (DLK). However, DLK is also involved in axon regeneration, prompting us to ask whether combining DLK deletion with a way to promote axon regeneration would result in greater motor neuron protection. To achieve this, we used a mouse line that constitutively expresses ATF3, a master regulator of regeneration in neurons. Although there is precedence for each individual strategy in the SOD1G93A mouse model of ALS, these have not previously been combined. By several lines of evidence including motor neuron electrophysiology, histology and behaviour, we observed a powerful synergy when combining DLK deletion with ATF3 expression. The combinatorial strategy resulted in significant protection of motor neurons with fewer undergoing cell death, reduced axon degeneration and preservation of motor function and connectivity to muscle. This study provides a demonstration of the power of combinatorial therapy to treat neurodegenerative disease.}, }
@article {pmid36339574, year = {2022}, author = {Parrella, E and Porrini, V and Scambi, I and Gennari, MM and Gussago, C and Bankole, O and Benarese, M and Mariotti, R and Pizzi, M}, title = {Synergistic association of resveratrol and histone deacetylase inhibitors as treatment in amyotrophic lateral sclerosis.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1017364}, pmid = {36339574}, issn = {1663-9812}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, progressive paralysis and finally death. Despite the research efforts, currently there is no cure for ALS. In recent years, multiple epigenetic mechanisms have been associated with neurodegenerative diseases. A pathological role for histone hypoacetylation and the abnormal NF-κB/RelA activation involving deacetylation of lysines, with the exclusion of lysine 310, has been established in ALS. Recent findings indicate that the pathological acetylation state of NF-κB/RelA and histone 3 (H3) occurring in the SOD1(G93A) murine model of ALS can be corrected by the synergistic combination of low doses of the AMP-activated kinase (AMPK)-sirtuin 1 pathway activator resveratrol and the histone deacetylase (HDAC) inhibitors MS-275 (entinostat) or valproate. The combination of the epigenetic drugs, by rescuing RelA and the H3 acetylation state, promotes a beneficial and sexually dimorphic effect on disease onset, survival and motor neurons degeneration. In this mini review, we discuss the potential of the epigenetic combination of resveratrol with HDAC inhibitors in the ALS treatment.}, }
@article {pmid36339573, year = {2022}, author = {Kuroda, Y and Oguma, Y and Hall, K and Dezawa, M}, title = {Endogenous reparative pluripotent Muse cells with a unique immune privilege system: Hint at a new strategy for controlling acute and chronic inflammation.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1027961}, pmid = {36339573}, issn = {1663-9812}, abstract = {Multilineage-differentiating stress enduring (Muse) cells, non-tumorigenic endogenous pluripotent stem cells, reside in the bone marrow (BM), peripheral blood, and connective tissue as pluripotent surface marker SSEA-3(+) cells. They express other pluripotent markers, including Nanog, Oct3/4, and Sox2 at moderate levels, differentiate into triploblastic lineages, self-renew at a single cell level, and exhibit anti-inflammatory effects. Cultured mesenchymal stromal cells (MSCs) and fibroblasts contain several percent of SSEA-3(+)-Muse cells. Circulating Muse cells, either endogenous or administered exogenously, selectively accumulate at the damaged site by sensing sphingosine-1-phosphate (S1P), a key mediator of inflammation, produced by damaged cells and replace apoptotic and damaged cells by spontaneously differentiating into multiple cells types that comprise the tissue and repair the tissue. Thus, intravenous injection is the main route for Muse cell treatment, and surgical operation is not necessary. Furthermore, gene introduction or cytokine induction are not required for generating pluripotent or differentiated states prior to treatment. Notably, allogenic and xenogenic Muse cells escape host immune rejection after intravenous injection and survive in the tissue as functioning cells over 6 and ∼2 months, respectively, without immunosuppressant treatment. Since Muse cells survive in the host tissue for extended periods of time, therefore their anti-inflammatory, anti-fibrotic, and trophic effects are long-lasting. These unique characteristics have led to the administration of Muse cells via intravenous drip in clinical trials for stroke, acute myocardial infarction, epidermolysis bullosa, spinal cord injury, neonatal hypoxic ischemic encephalopathy, amyotrophic lateral sclerosis, and COVID-19 acute respiratory distress syndrome without HLA-matching or immunosuppressive treatment.}, }
@article {pmid36336493, year = {2023}, author = {Corcia, P and Blasco, H and Beltran, S and Piegay, AS and Vourc'h, P}, title = {Treatment of hereditary amyotrophic lateral sclerosis.}, journal = {Revue neurologique}, volume = {179}, number = {1-2}, pages = {54-60}, doi = {10.1016/j.neurol.2022.09.001}, pmid = {36336493}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Mutation ; Riluzole ; }, abstract = {Currently, only four molecules can be prescribed for amyotrophic lateral sclerosis (ALS), of which only one is approved worldwide for this indication, riluzole. Although progress in the therapeutic field remains unsatisfactory, we have to notice that genetics have undergone impressive improvements over the last three decades and, by extension, our knowledge of ALS cases linked to a pathogenic mutation that accounts for 10% of all cases (either sporadic or familiar) and is currently called hereditary ALS (hALS). In many neurological diseases treatment targeting pathogenic genes have significatively improved the natural profile of the disease: this is perfectly illustrated for familial amyloid neuropathy and spinal muscular atrophy. Because of these findings and the urgent need to find a cure for ALS, many trials have focused on familial ALS targeting the four most important genes linked to the disease: C9orf72, SOD1, TARDBP and FUS. We propose in this review an update on the perspectives of treatment that may be available in mid-term in hALS and will discuss in the last part the potential consequences for asymptomatic relatives of patients with a hALS and for ALS patients.}, }
@article {pmid36325941, year = {2023}, author = {Borges, LI and Forcato, S and do Nascimento Olanda, LC and Frigoli, GF and Vidigal, CB and Moura, KF and Fernandes, GSA and Franco, MDCP and Ceravolo, GS and Gerardin, DCC}, title = {Treatment with topiramate in rats during childhood causes testicular structural impairment at adulthood.}, journal = {Journal of developmental origins of health and disease}, volume = {14}, number = {2}, pages = {279-285}, doi = {10.1017/S2040174422000587}, pmid = {36325941}, issn = {2040-1752}, mesh = {Male ; Animals ; Rats ; *Testis ; Topiramate ; *Semen ; Spermatozoa ; Testosterone ; Disease Progression ; }, abstract = {Topiramate (TOP) is a psychotropic drug prescribed for the treatment of epilepsy in children older than 2 years of age and for migraine prophylaxis in adolescents. There is evidence that TOP promotes negative effects on the reproductive system of male rats. This study aimed to evaluate the immediate and late treatment effects of TOP during childhood and adolescence on the male rat reproductive system. Two experimental groups received 41 mg/kg of TOP daily, by gavage, from postnatal day (PND) 16 to 28 (TOPc group) or from PND 28 to 50 (TOPa group). Control groups (CTRc group or CTRa group) received water daily. Half of the anim-als were evaluated 24 h after the end of treatment (PND 29 and PND 51, respectively) and the remainder were evaluated in adulthood (PND120). The following parameters were determined: anogenital distance, sperm evaluation, testis' histomorphometry and plasma testosterone concentration. At PND 120, the volume (CTRc:62.58 ± 2.13; TOPc: 54.54 ± 2.10*%, p = 0.018) and total length (CTRc: 25.48 ± 1.61; TOPc: 18.94 ± 2.41*, p = 0.035) of seminiferous tubules were decreased and the volume of interstitial tissue (CTRc:37.41 ± 2.13; TOPc: 45.45 ± 2.09*%, p = 0.018) and number of Leydig cells/testis (CTRc: 277.00 ± 36.70; TOPc: 400.20 ± 13.23*, p = 0.013) were increased in the TOPc group. The other parameters remained similar between the groups. Therefore, the present study contributes to our understanding that childhood treatment with TOP has an impact on the rat reproductive system in adulthood, suggesting that this period is more sensitive to TOP exposure than adolescence.}, }
@article {pmid36324375, year = {2022}, author = {Schröder, S and Wang, M and Sima, D and Schröder, J and Zhu, X and Zheng, X and Liu, L and Li, T and Wang, Q and Friedemann, T and Liu, T and Pan, W}, title = {Slower progression of amyotrophic lateral sclerosis with external application of a Chinese herbal plaster-The randomized, placebo-controlled triple-blinded ALS-CHEPLA trial.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {990802}, pmid = {36324375}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by gradually increasing damage to the upper and lower motor neurons. However, definitive and efficacious treatment for ALS is not available, and oral intake in ALS patients with bulbar involvement is complicated due to swallowing difficulties.<br><br>HYPOTHESIS/PURPOSE: This study investigated whether the external plaster application of the herbal composition Ji-Wu-Li efficiently slows ALS progression because prior studies obtained promising evidence with oral herbal applications.<br><br>STUDY DESIGN: The randomized, triple-blinded study compared the efficacy, safety, and tolerability of the application of Ji-Wu-Li plaster (JWLP) with placebo plaster (PLAP).<br><br>METHODS: In total, 120 patients with definite ALS, clinically probable ALS, or clinically probable laboratory-supported ALS were randomized in a 1:1 ratio to receive JWLP or PLAP. Patients were treated and observed for 20 weeks. The primary outcome was the ALSFRS-R score, while the secondary outcomes were the ALS-SSIT score and weight loss.<br><br>RESULTS: The mean&#xb1;SD decrease in the ALSFRS-R over 20 weeks differed by 0.84 points in a group comparison (JWLP, -4.44 &#xb1; 1.15; PLAP, -5.28 &#xb1; 1.98; p = 0.005). The mean increase in the ALS-SSIT over 20 weeks differed by 2.7 points in a group comparison (JWLP, 5.361.15; PLAP, 8.06 &#xb1; 1.72; p < 0.001). The mean weight loss over 20 weeks differed by 1.65 kg in a group comparison (JWLP, -3.98 &#xb1; 2.61; PLAP, -5.63 &#xb1; 3.17; p = 0.002). Local allergic dermatitis suspected as causal to the intervention occurred in 10 of 60 participants in the JWLP group and 9 of 60 participants in the PLAP group. Systemic adverse events were mild, temporary, and considered unrelated to the intervention.<br><br>CONCLUSION: The JWLP showed clinical efficacy in the progression of ALS, as measured by the ALSFRS-R, ALS-SSIT, and weight loss in a randomized, placebo-controlled trial. Because skin reactions occurred in both groups, the covering material needs improvement. All of the Ji Wu Li herbal ingredients regulate multiple mechanisms of neurodegeneration in ALS. Hence, JWLP may offer a promising and safe add-on therapy for ALS, particularly in patients with bulbar involvement, but a confirmative long-term multicentre study is required.}, }
@article {pmid36311026, year = {2022}, author = {Chia, K and Klingseisen, A and Sieger, D and Priller, J}, title = {Zebrafish as a model organism for neurodegenerative disease.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {940484}, pmid = {36311026}, issn = {1662-5099}, abstract = {The zebrafish is increasingly recognized as a model organism for translational research into human neuropathology. The zebrafish brain exhibits fundamental resemblance with human neuroanatomical and neurochemical pathways, and hallmarks of human brain pathology such as protein aggregation, neuronal degeneration and activation of glial cells, for example, can be modeled and recapitulated in the fish central nervous system. Genetic manipulation, imaging, and drug screening are areas where zebrafish excel with the ease of introducing mutations and transgenes, the expression of fluorescent markers that can be detected in vivo in the transparent larval stages overtime, and simple treatment of large numbers of fish larvae at once followed by automated screening and imaging. In this review, we summarize how zebrafish have successfully been employed to model human neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. We discuss advantages and disadvantages of choosing zebrafish as a model for these neurodegenerative conditions.}, }
@article {pmid36310382, year = {2023}, author = {Iachettini, S and Ciccarone, F and Maresca, C and D' Angelo, C and Petti, E and Di Vito, S and Ciriolo, MR and Zizza, P and Biroccio, A}, title = {The telomeric protein TERF2/TRF2 impairs HMGB1-driven autophagy.}, journal = {Autophagy}, volume = {19}, number = {5}, pages = {1479-1490}, pmid = {36310382}, issn = {1554-8635}, mesh = {*HMGB1 Protein/genetics ; DNA Damage ; Autophagy/genetics ; Telomere/metabolism ; Nuclear Proteins/metabolism ; }, abstract = {TERF2/TRF2 is a pleiotropic telomeric protein that plays a crucial role in tumor formation and progression through several telomere-dependent and -independent mechanisms. Here, we uncovered a novel function for this protein in regulating the macroautophagic/autophagic process upon different stimuli. By using both biochemical and cell biology approaches, we found that TERF2 binds to the non-histone chromatin-associated protein HMGB1, and this interaction is functional to the nuclear/cytoplasmic protein localization. Specifically, silencing of TERF2 alters the redox status of the cells, further exacerbated upon EBSS nutrient starvation, promoting the cytosolic translocation and the autophagic activity of HMGB1. Conversely, overexpression of wild-type TERF2, but not the mutant unable to bind HMGB1, negatively affects the cytosolic translocation of HMGB1, counteracting the stimulatory effect of EBSS starvation. Moreover, genetic depletion of HMGB1 or treatment with inflachromene, a specific inhibitor of its cytosolic translocation, completely abolished the pro-autophagic activity of TERF2 silencing. In conclusion, our data highlighted a novel mechanism through which TERF2 modulates the autophagic process, thus demonstrating the key role of the telomeric protein in regulating a process that is fundamental, under both physiological and pathological conditions, in defining the fate of the cells.Abbreviations: ALs: autolysosomes; ALT: alternative lengthening of telomeres; ATG: autophagy related; ATM: ATM serine/threonine kinase; CQ: Chloroquine; DCFDA: 2',7'-dichlorofluorescein diacetate; DDR: DNA damage response; DHE: dihydroethidium; EBSS: Earle's balanced salt solution; FACS: fluorescence-activated cell sorting; GFP: green fluorescent protein; EGFP: enhanced green fluorescent protein; GSH: reduced glutathione; GSSG: oxidized glutathione; HMGB1: high mobility group box 1; ICM: inflachromene; IF: immunofluorescence; IP: immunoprecipitation; NAC: N-acetyl-L-cysteine; NHEJ: non-homologous end joining; PLA: proximity ligation assay; RFP: red fluorescent protein; ROS: reactive oxygen species; TIF: telomere-induced foci; TERF2/TRF2: telomeric repeat binding factor 2.}, }
@article {pmid36309345, year = {2022}, author = {Wang, MJ and Kang, L and Wang, YZ and Yang, BR and Zhang, C and Lu, YF and Kang, L}, title = {Microglia in motor neuron disease: Signaling evidence from last 10 years.}, journal = {Developmental neurobiology}, volume = {82}, number = {7-8}, pages = {625-638}, pmid = {36309345}, issn = {1932-846X}, mesh = {Humans ; Microglia/metabolism ; Superoxide Dismutase/metabolism ; *Motor Neuron Disease/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Motor Neurons/metabolism ; }, abstract = {Motor neuron disease (MND), including amyotrophic lateral sclerosis, spinal muscular atrophy and others, involved the upper or lower motor neurons selective loss, is characterized by neurodegeneration and neuroinflammation, in conjunction with microglia. We summarized that pathways and key mediators are associated with microglia, such as fractalkine signaling, purinergic signaling, NF-κB signaling, p38 MAPK signaling, TREM2-APOE signaling, ROCK signaling, C1q signaling, and Ion channel, which are involved in the activation, proliferation, and inflammation of microglia. This review aims to identify the microglia-related molecular target and explore potential treatment strategies for MND based on that target.}, }
@article {pmid36305960, year = {2022}, author = {Rowe, HP and Gochyyev, P and Lammert, AC and Lowit, A and Spencer, KA and Dickerson, BC and Berry, JD and Green, JR}, title = {The efficacy of acoustic-based articulatory phenotyping for characterizing and classifying four divergent neurodegenerative diseases using sequential motion rates.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {129}, number = {12}, pages = {1487-1511}, pmid = {36305960}, issn = {1435-1463}, support = {R01 DC014296/DC/NIDCD NIH HHS/United States ; R01 DC013547/DC/NIDCD NIH HHS/United States ; R01DC014296/DC/NIDCD NIH HHS/United States ; F31 DC019556/DC/NIDCD NIH HHS/United States ; K24 DC016312/DC/NIDCD NIH HHS/United States ; F31DC019556/DC/NIDCD NIH HHS/United States ; R01DC013547/DC/NIDCD NIH HHS/United States ; R21 DC019567/DC/NIDCD NIH HHS/United States ; 24DC016312/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Neurodegenerative Diseases/diagnosis/complications ; Speech Disorders/etiology ; *Parkinson Disease/complications ; Disease Progression ; Acoustics ; Speech ; }, abstract = {Despite the impacts of neurodegeneration on speech function, little is known about how to comprehensively characterize the resulting speech abnormalities using a set of objective measures. Quantitative phenotyping of speech motor impairments may have important implications for identifying clinical syndromes and their underlying etiologies, monitoring disease progression over time, and improving treatment efficacy. The goal of this research was to investigate the validity and classification accuracy of comprehensive acoustic-based articulatory phenotypes in speakers with distinct neurodegenerative diseases. Articulatory phenotypes were characterized based on acoustic features that were selected to represent five components of motor performance: Coordination, Consistency, Speed, Precision, and Rate. The phenotypes were first used to characterize the articulatory abnormalities across four progressive neurologic diseases known to have divergent speech motor deficits: amyotrophic lateral sclerosis (ALS), progressive ataxia (PA), Parkinson's disease (PD), and the nonfluent variant of primary progressive aphasia and progressive apraxia of speech (nfPPA + PAOS). We then examined the efficacy of articulatory phenotyping for disease classification. Acoustic analyses were conducted on audio recordings of 217 participants (i.e., 46 ALS, 52 PA, 60 PD, 20 nfPPA + PAOS, and 39 controls) during a sequential speech task. Results revealed evidence of distinct articulatory phenotypes for the four clinical groups and that the phenotypes demonstrated strong classification accuracy for all groups except ALS. Our results highlight the phenotypic variability present across neurodegenerative diseases, which, in turn, may inform (1) the differential diagnosis of neurological diseases and (2) the development of sensitive outcome measures for monitoring disease progression or assessing treatment efficacy.}, }
@article {pmid36294741, year = {2022}, author = {Khamaysa, M and Pradat, PF}, title = {Status of ALS Treatment, Insights into Therapeutic Challenges and Dilemmas.}, journal = {Journal of personalized medicine}, volume = {12}, number = {10}, pages = {}, pmid = {36294741}, issn = {2075-4426}, abstract = {Amyotrophic lateral sclerosis (ALS) is an extremely heterogeneous disease of motor neurons that eventually leads to death. Despite impressive advances in understanding the genetic, molecular, and pathological mechanisms of the disease, the only drug approved to date by both the FDA and EMA is riluzole, with a modest effect on survival. In this opinion view paper, we will discuss how to address some challenges for drug development in ALS at the conceptual, technological, and methodological levels. In addition, socioeconomic and ethical issues related to the legitimate need of patients to benefit quickly from new treatments will also be addressed. In conclusion, this brief review takes a more optimistic view, given the recent approval of two new drugs in some countries and the development of targeted gene therapies.}, }
@article {pmid36293534, year = {2022}, author = {Maestro, I and de la Ballina, LR and Porras, G and Corrochano, S and De Lago, E and Simonsen, A and Boya, P and Martinez, A}, title = {Discovery of Mitophagy Inhibitors with Therapeutic Potential in Different Familial Amyotrophic Lateral Sclerosis Mutations.}, journal = {International journal of molecular sciences}, volume = {23}, number = {20}, pages = {}, pmid = {36293534}, issn = {1422-0067}, support = {H2020-MSCA-ITN-2017 (grant no. 765912, DRIVE project)//European Commission/ ; B2017/BMD-3813//Comunidad de Madrid/ ; CB18/05/00040//Instituto de Salud Carlos III/ ; Interdisciplinary Thematic Platform (PTI+) NEURO-AGINGl+//Spanish National Research Council/ ; Fondos de recuperaci&#xf3;n//European Council/ ; }, mesh = {Humans ; *Mitophagy ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Mitophagy is the selective degradation of mitochondria by autophagy. It promotes the turnover of mitochondria and prevents the accumulation of dysfunctional mitochondria, which can lead to cellular degeneration. Mitophagy is known to be altered in several pathological conditions, especially in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We recently demonstrated an increase in autophagy flux in lymphoblasts from ALS patients bearing a mutation in SOD1. Thus, the identification of mitophagy inhibitors may be a therapeutic option to recover mitochondrial homeostasis. Here, using a phenotypic mitophagy assay, we identified a new mitophagy inhibitor, the small molecule named IGS2.7 from the MBC library. Interestingly, the treatment of different cellular and in vivo models of ALS with mutations on SOD1 and TARDBP with this inhibitor restores autophagy to control levels. These results point mitophagy inhibitors, especially IGS2.7, to a new therapeutic approach for familial ALS patients.}, }
@article {pmid36293457, year = {2022}, author = {Mantle, D and Hargreaves, IP}, title = {Mitochondrial Dysfunction and Neurodegenerative Disorders: Role of Nutritional Supplementation.}, journal = {International journal of molecular sciences}, volume = {23}, number = {20}, pages = {}, pmid = {36293457}, issn = {1422-0067}, mesh = {Humans ; NAD/metabolism ; *Thioctic Acid/therapeutic use/metabolism ; Mitochondria/metabolism ; Dietary Supplements ; *Multiple System Atrophy/metabolism ; Vitamins/therapeutic use/metabolism ; Carnitine/metabolism ; Vitamin D/metabolism ; Adenosine Triphosphate/metabolism ; }, abstract = {Mitochondrial dysfunction has been implicated in the pathogenesis of a number of neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multisystem atrophy, and progressive supranuclear palsy. This article is concerned specifically with mitochondrial dysfunction as defined by reduced capacity for ATP production, the role of depleted levels of key nutritionally related metabolites, and the potential benefit of supplementation with specific nutrients of relevance to normal mitochondrial function in the above neurodegenerative disorders. The article provides a rationale for a combination of CoQ10, B-vitamins/NADH, L-carnitine, vitamin D, and alpha-lipoic acid for the treatment of the above neurodegenerative disorders.}, }
@article {pmid36293018, year = {2022}, author = {Quiroz-Iturra, LF and Simpson, K and Arias, D and Silva, C and González-Calquin, C and Amaza, L and Handford, M and Stange, C}, title = {Carrot DcALFIN4 and DcALFIN7 Transcription Factors Boost Carotenoid Levels and Participate Differentially in Salt Stress Tolerance When Expressed in Arabidopsis thaliana and Actinidia deliciosa.}, journal = {International journal of molecular sciences}, volume = {23}, number = {20}, pages = {}, pmid = {36293018}, issn = {1422-0067}, support = {ACT192073//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; PhD Fellowship CONICYT 21160890//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; Scholarship (LFQ-I)//Fundaci&#xf3;n Maria Ghilardi Venegas/ ; }, mesh = {*Arabidopsis/metabolism ; Abscisic Acid/pharmacology/metabolism ; *Daucus carota/genetics/metabolism ; *Actinidia/genetics ; Transcription Factors/genetics/metabolism ; Gene Expression Regulation, Plant ; Plants, Genetically Modified/metabolism ; Salt Stress/genetics ; Stress, Physiological/genetics ; Carotenoids/metabolism ; Chlorophyll/metabolism ; Nuclear Proteins/genetics ; Plant Proteins/genetics/metabolism ; }, abstract = {ALFIN-like transcription factors (ALs) are involved in several physiological processes such as seed germination, root development and abiotic stress responses in plants. In carrot (Daucus carota), the expression of DcPSY2, a gene encoding phytoene synthase required for carotenoid biosynthesis, is induced after salt and abscisic acid (ABA) treatment. Interestingly, the DcPSY2 promoter contains multiple ALFIN response elements. By in silico analysis, we identified two putative genes with the molecular characteristics of ALs, DcAL4 and DcAL7, in the carrot transcriptome. These genes encode nuclear proteins that transactivate reporter genes and bind to the carrot DcPSY2 promoter in yeast. The expression of both genes is induced in carrot under salt stress, especially DcAL4 which also responds to ABA treatment. Transgenic homozygous T3 Arabidopsis thaliana lines that stably express DcAL4 and DcAL7 show a higher survival rate with respect to control plants after chronic salt stress. Of note is that DcAL4 lines present a better performance in salt treatments, correlating with the expression level of DcAL4, AtPSY and AtDXR and an increase in carotenoid and chlorophyll contents. Likewise, DcAL4 transgenic kiwi (Actinidia deliciosa) lines show increased carotenoid and chlorophyll content and higher survival rate compared to control plants after chronic salt treatment. Therefore, DcAL4 and DcAL7 encode functional transcription factors, while ectopic expression of DcAL4 provides increased tolerance to salinity in Arabidopsis and Kiwi plants.}, }
@article {pmid36292944, year = {2022}, author = {Agnello, L and Ciaccio, M}, title = {Molecular Research on Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {23}, number = {20}, pages = {}, pmid = {36292944}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Motor Neurons ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, lethal, and degenerative disease of motor neurons for which there is no treatment currently available [...].}, }
@article {pmid36289738, year = {2022}, author = {Ferrero, ME}, title = {Neuron Protection by EDTA May Explain the Successful Outcomes of Toxic Metal Chelation Therapy in Neurodegenerative Diseases.}, journal = {Biomedicines}, volume = {10}, number = {10}, pages = {}, pmid = {36289738}, issn = {2227-9059}, abstract = {Many mechanisms have been related to the etiopathogenesis of neurodegenerative diseases (NDs) such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. In this context, the detrimental role of environmental agents has also been highlighted. Studies focused on the role of toxic metals in the pathogenesis of ND demonstrate the efficacy of treatment with the chelating agent calcium disodium ethylenediaminetetraacetic acid (EDTA) in eliminating toxic metal burden in all ND patients, improving their symptoms. Lead, cadmium, aluminum, nickel, and mercury were the most important toxic metals detected in these patients. Here, I provide an updated review on the damage to neurons promoted by toxic metals and on the impact of EDTA chelation therapy in ND patients, along with the clinical description of a representative case.}, }
@article {pmid36288715, year = {2022}, author = {Rodriguez, CM and Bechek, SC and Jones, GL and Nakayama, L and Akiyama, T and Kim, G and Solow-Cordero, DE and Strittmatter, SM and Gitler, AD}, title = {Targeting RTN4/NoGo-Receptor reduces levels of ALS protein ataxin-2.}, journal = {Cell reports}, volume = {41}, number = {4}, pages = {111505}, pmid = {36288715}, issn = {2211-1247}, support = {UL1 TR001863/TR/NCATS NIH HHS/United States ; F31 NS125681/NS/NINDS NIH HHS/United States ; T32 NS007280/NS/NINDS NIH HHS/United States ; F32 NS116208/NS/NINDS NIH HHS/United States ; RF1 AG064690/AG/NIA NIH HHS/United States ; R35 NS097283/NS/NINDS NIH HHS/United States ; T32 AG047126/AG/NIA NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; R35 NS097263/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; Humans ; Ataxin-2/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; RNA, Small Interfering ; Nogo Receptors/metabolism ; *Spinocerebellar Ataxias/genetics ; Mice, Knockout ; Peptides/metabolism ; Nogo Proteins/genetics/metabolism ; }, abstract = {Gene-based therapeutic strategies to lower ataxin-2 levels are emerging for the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). Additional strategies to lower levels of ataxin-2 could be beneficial. Here, we perform a genome-wide arrayed small interfering RNA (siRNA) screen in human cells and identify RTN4R, the gene encoding the RTN4/NoGo-Receptor, as a potent modifier of ataxin-2 levels. RTN4R knockdown, or treatment with a peptide inhibitor, is sufficient to lower ataxin-2 protein levels in mouse and human neurons in vitro, and Rtn4r knockout mice have reduced ataxin-2 levels in vivo. We provide evidence that ataxin-2 shares a role with the RTN4/NoGo-Receptor in limiting axonal regeneration. Reduction of either protein increases axonal regrowth following axotomy. These data define the RTN4/NoGo-Receptor as a novel therapeutic target for ALS and SCA2 and implicate the targeting of ataxin-2 as a potential treatment following nerve injury.}, }
@article {pmid36287176, year = {2023}, author = {Xu, Q and Cho, J and Ben Chaouch, Z and Lo, AW}, title = {Incorporating patient preferences and burden-of-disease in evaluating ALS drug candidate AMX0035: a Bayesian decision analysis perspective.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {3-4}, pages = {281-288}, doi = {10.1080/21678421.2022.2136994}, pmid = {36287176}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Bayes Theorem ; Patient Preference ; Disease Progression ; Decision Support Techniques ; }, abstract = {OBJECTIVE: Provide US FDA and amyotrophic lateral sclerosis (ALS) society with a systematic, transparent, and quantitative framework to evaluate the efficacy of the ALS therapeutic candidate AMX0035 in its phase 2 trial, which showed statistically significant effects (p-value 3%) in slowing the rate of ALS progression on a relatively small sample size of 137 patients.<br><br>METHODS: We apply Bayesian decision analysis (BDA) to determine the optimal type I error rate (p-value) under which the clinical evidence of AMX0035 supports FDA approval. Using rigorous estimates of ALS disease burden, our BDA framework strikes the optimal balance between FDA's need to limit adverse effects (type I error) and patients' need for expedited access to a potentially effective therapy (type II error). We apply BDA to evaluate long-term patient survival based on clinical evidence from AMX0035 and Riluzole.<br><br>RESULTS: The BDA-optimal type I error for approving AMX0035 is higher than the 3% p-value reported in the phase 2 trial if the probability of the therapy being effective is at least 30%. Assuming a 50% probability of efficacy and a signal-to-noise ratio of treatment effect between 25% and 50% (benchmark: 33%), the optimal type I error rate ranges from 2.6% to 26.3% (benchmark: 15.4%). The BDA-optimal type I error rate is robust to perturbations in most assumptions except for a probability of efficacy below 5%.<br><br>CONCLUSION: BDA provides a useful framework to incorporate subjective perspectives of ALS patients and objective burden-of-disease metrics to evaluate the therapeutic effects of AMX0035 in its phase 2 trial.}, }
@article {pmid36281667, year = {2022}, author = {Silverman, MH and Duggan, S and Bardelli, G and Sadler, B and Key, C and Medlock, M and Reynolds, L and Wallner, B}, title = {Safety, Tolerability and Pharmacokinetics of Icapamespib, a Selective Epichaperome Inhibitor, in Healthy Adults.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {9}, number = {4}, pages = {635-645}, pmid = {36281667}, issn = {2426-0266}, mesh = {Adult ; Male ; Humans ; Female ; Middle Aged ; Aged ; Dose-Response Relationship, Drug ; *Alzheimer Disease/drug therapy ; Double-Blind Method ; Cross-Over Studies ; Purines ; }, abstract = {BACKGROUND: Neurodegenerative diseases are devastating conditions that most commonly affect individuals 65 years and older. Currently there are no effective treatments or cures for neurodegenerative diseases, and therapeutics that selectively target the underlying causes of these diseases are needed. Epichaperomes play a major role in the maintenance and progression of neuronal pathology. Inhibiting epichaperomes induces degradation of disease associated proteins and is a promising therapeutic approach to treat neurodegenerative diseases, in particular Alzheimer's Disease and amyotrophic lateral sclerosis.<br><br>OBJECTIVES: This Phase 1 clinical study evaluated the safety, tolerability, pharmacokinetics, and bioavailability of icapamespib, a purine scaffold inhibitor of epichaperomes that is specific to epichaperomes, in healthy subjects.<br><br>DESIGN: Double-blind, placebo-controlled dose escalating single ascending dose and multiple ascending doses and an unblinded two-period cross-over bioavailability study design.<br><br>SETTING: Single site in the United States.<br><br>PARTICIPANTS: Healthy men or women of 18 to 60 years of age, inclusive, for Part 1 (single ascending dose), &#x2265; 60 years of age for Part 2 (multiple ascending dose), or 18 to 49 years of age for Part 3 (bioavailability).<br><br>TREATMENT: In the single ascending dose group, oral single doses (10, 20, and 30 mg icapamespib or placebo) were administered to healthy non-elderly subjects. In the multiple ascending dose group, multiple doses (20 and 30 mg icapamespib once daily for 7 days or placebo) were administered to healthy elderly subjects. In the bioavailability group, the bioavailability of once daily oral icapamespib solution and tablet was assessed in healthy non elderly subjects.<br><br>MEASUREMENTS: Safety was evaluated based on assessments of treatment-emergent adverse events, physical examinations, clinical laboratory tests (hematology, clinical chemistry, and urinalysis), vital signs, and 12-lead electrocardiograms. Icapamespib concentration was evaluated in plasma and cerebrospinal fluid, the latter in Part 2 (multiple ascending dose) only.<br><br>RESULTS: Forty-eight subjects in total were randomized and assessed for tolerability, pharmacokinetics, and bioavailability parameters as follows: 24 subjects in Part 1 (single ascending dose) with PU-AD 10 mg (n = 6), 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 6); 16 subjects in Part 2 (multiple ascending dose) with icapamespib 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 4); and 8 subjects in Part 3 (bioavailability) crossed-over between icapamespib 30 mg (tablet) and icapamespib 30 mg (oral solution). Single doses of icapamespib up to 30 mg and multiple doses of icapamespib up to 30 mg for 7 days were generally safe and well tolerated in healthy non-elderly and elderly subjects. Treatment-emergent adverse events were mild, with headache being the most common treatment-emergent adverse event. Mean icapamespib exposure (area under the curve) was dose-proportional over the dose range tested. The median time to maximum observed plasma concentration ranged from 1.00 to 2.00 h across single ascending dose, multiple ascending dose, and bioavailability groups; icapamespib exposure was 50% higher in elderly subjects compared with non-elderly subjects but was well tolerated.<br><br>CONCLUSIONS: The study provides clinical evidence of the safety of icapamespib in healthy non elderly and elderly subjects and supports the advancement of icapamespib to Phase 2 evaluation in Alzheimer's Disease and other neurodegenerative diseases.}, }
@article {pmid36277914, year = {2022}, author = {Liao, Y and He, S and Liu, D and Gu, L and Chen, Q and Yang, S and Li, D}, title = {The efficacy and safety of Chinese herbal medicine as an add-on therapy for amyotrophic lateral sclerosis: An updated systematic review and meta-analysis of randomized controlled trials.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {988034}, pmid = {36277914}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) has attracted widespread attention because of its unknown pathogenesis, rapid progression, and life-threatening and incurable characteristics. A series of complementary therapies, including Chinese herbal medicine (CHM), is available for use in the clinic and has been the focus of much research. However, it is unclear as to whether supplementary CHM relieves disease symptoms or extends life span; thus, we conducted this updated meta-analysis to validate the efficacy and safety of this practice.<br><br>METHODS: We searched six electronic databases for randomized controlled trials involving CHM and patients with ALS that were published up to April 2022. Two researchers independently screened the literature, assessed the risk of bias for each trial, and then extracted data. The methodological quality of the included trials was assessed using the Cochrane risk of bias tool, and a pooled data analysis was performed using RevMan 5.3.<br><br>RESULTS: A total of 14 trials led to the publication of 15 articles featuring 1,141 participants during the study period; the articles were included in the systematic review. In terms of increasing ALS functional rating scale (ALSFRS) scores, CHM was superior to the placebo after 3 months of treatment [mean difference (MD):0.7; 95% CI:0.43 to 0.98; P < 0.01] and to riluzole after 4 weeks of treatment (MD: 2.87; 95% CI: 0.81 to 4.93; P < 0.05), and it was superior to conventional medicine (CM) alone when used as an add-on therapy after 8 weeks of treatment (MD: 3.5; 95% CI: 0.51 to 6.49; P < 0.05). The change in the modified Norris score (m-Norris) from baseline to the end of more than 3 months of treatment was significantly different when compared between the CHM plus CM group and the CM alone group (MD: 2.09; 95% CI: 0.62 to 3.55; P < 0.01). In addition, CHM had a significantly better effect on increase in clinical effective rate (RR: 1.54; 95% CI: 1.23 to 1.92; P < 0.01) and improvement in forced vital capacity (MD: 7.26; 95% CI: 2.92 to 11.6; P < 0.01). However, there was no significant difference between the CHM therapy and CM in terms of improving life quality (MD: 5.13; 95% CI: -7.04 to 17.31; P = 0.41) and decreasing mortality (RR: 0.41; 95% CI: 0.04 to 4.21; P = 0.46).<br><br>CONCLUSION: The analysis suggested that the short-term adjunct use of CHM could improve the ALSFRS score and clinical effect with a good safety profile when compared with the placebo or riluzole alone. However, future research should be centered on the long-term efficacy of patient-oriented outcomes.<br><br>https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=323047, identifier: CRD42022323047.}, }
@article {pmid36275622, year = {2022}, author = {Baier, A and Szyszka, R}, title = {CK2 and protein kinases of the CK1 superfamily as targets for neurodegenerative disorders.}, journal = {Frontiers in molecular biosciences}, volume = {9}, number = {}, pages = {916063}, pmid = {36275622}, issn = {2296-889X}, abstract = {Casein kinases are involved in a variety of signaling pathways, and also in inflammation, cancer, and neurological diseases. Therefore, they are regarded as potential therapeutic targets for drug design. Recent studies have highlighted the importance of the casein kinase 1 superfamily as well as protein kinase CK2 in the development of several neurodegenerative pathologies, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. CK1 kinases and their closely related tau tubulin kinases as well as CK2 are found to be overexpressed in the mammalian brain. Numerous substrates have been detected which play crucial roles in neuronal and synaptic network functions and activities. The development of new substances for the treatment of these pathologies is in high demand. The impact of these kinases in the progress of neurodegenerative disorders, their bona fide substrates, and numerous natural and synthetic compounds which are able to inhibit CK1, TTBK, and CK2 are discussed in this review.}, }
@article {pmid36241230, year = {2022}, author = {Liu, XX and Duan, XH and Zhang, S and Sun, AP and Zhang, YS and Fan, DS}, title = {[Genetic distribution in Chinese patients with hereditary peripheral neuropathy].}, journal = {Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences}, volume = {54}, number = {5}, pages = {874-883}, pmid = {36241230}, issn = {1671-167X}, mesh = {*Amyotrophic Lateral Sclerosis ; *Charcot-Marie-Tooth Disease/genetics ; DNA Helicases/genetics ; DNA-Binding Proteins/genetics ; Flavoproteins ; HSP40 Heat-Shock Proteins ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Kinesins ; Ligases/genetics ; Molecular Chaperones ; Multifunctional Enzymes ; *Muscular Atrophy, Spinal/genetics ; Mutation ; Phosphoric Monoester Hydrolases ; Protein Serine-Threonine Kinases ; RNA Helicases/genetics ; RNA, Transfer ; Transcription Factors/genetics ; }, abstract = {OBJECTIVE: To analyze the distribution characteristics of hereditary peripheral neuropathy (HPN) pathogenic genes in Chinese Han population, and to explore the potential pathogenesis and treatment prospects of HPN and related diseases.<br><br>METHODS: Six hundred and fifty-six index patients with HPN were enrolled in Peking University Third Hospital and China-Japan Friendship Hospital from January 2007 to May 2022. The PMP22 duplication and deletion mutations were screened and validated by multiplex ligation probe amplification technique. The next-generation sequencing gene panel or whole exome sequencing was used, and the suspected genes were validated by Sanger sequencing.<br><br>RESULTS: Charcot-Marie-Tooth (CMT) accounted for 74.3% (495/666) of the patients with HPN, of whom 69.1% (342/495) were genetically confirmed. The most common genes of CMT were PMP22 duplication, MFN2 and GJB1 mutations, which accounted for 71.3% (244/342) of the patients with genetically confirmed CMT. Hereditary motor neuropathy (HMN) accounted for 16.1% (107/666) of HPN, and 43% (46/107) of HPN was genetically confirmed. The most common genes of HMN were HSPB1, aminoacyl tRNA synthetases and SORD mutations, which accounted for 56.5% (26/46) of the patients with genetically confirmed HMN. Most genes associated with HMN could cause different phenotypes. HMN and CMT shared many genes (e.g. HSPB1, GARS, IGHMBP2). Some genes associated with dHMN-plus shared genes associated with amyotrophic lateral sclerosis (KIF5A, FIG4, DCTN1, SETX, VRK1), hereditary spastic paraplegia (KIF5A, ZFYVE26, BSCL2) and spinal muscular atrophy (MORC2, IGHMBP, DNAJB2), suggesting that HMN was a continuum rather than a distinct entity. Hereditary sensor and autosomal neuropathy (HSAN) accounted for a small proportion of 2.6% (17/666) in HPN. The most common pathogenic gene was SPTLC1 mutation. TTR was the main gene causing hereditary amyloid peripheral neuropathy. The most common types of gene mutations were p.A117S and p.V50M. The symptoms were characterized by late-onset and prominent autonomic nerve involvement.<br><br>CONCLUSION: CMT and HMN are the most common diseases of HPN. There is a large overlap between HMN and motor-CMT2 pathogenic genes, and some HMN pathogenic genes overlap with amyotrophic lateral sclerosis, hereditary spastic hemiplegia and spinal muscular atrophy, suggesting that there may be a potential common pathogenic pathway between different diseases.}, }
@article {pmid36241096, year = {2022}, author = {Zhang, L and Liu, Y and Lu, Y and Wang, G}, title = {Targeting epigenetics as a promising therapeutic strategy for treatment of neurodegenerative diseases.}, journal = {Biochemical pharmacology}, volume = {206}, number = {}, pages = {115295}, doi = {10.1016/j.bcp.2022.115295}, pmid = {36241096}, issn = {1873-2968}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/genetics ; Epigenesis, Genetic ; DNA Methylation ; Histones/metabolism ; Chromatin Assembly and Disassembly ; }, abstract = {Nowadays, epigenetics is of great research value as a new gateway that can solve the sophisticated mysteries behind neurodegenerative diseases. Epigenetic mechanisms, including DNA methylation, various post-translational modifications of histones, chromatin remodeling enzymes, and long non-coding RNAs, are robust modulators of gene expression levels. Over the past years, epigenetic processes have emerged as important factors in many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's disease. Here, we review the diverse types of epigenetic modifications and how these mechanisms become dysregulated across the lifespan. We then discuss the various promising strategies for the treatment of neurodegenerative diseases targeting epigenetics, paving the way for the development of novel treatment strategies in neurodegenerative diseases.}, }
@article {pmid36240025, year = {2022}, author = {Díaz-García, D and Ferrer-Donato, &#xc1; and Méndez-Arriaga, JM and Cabrera-Pinto, M and Díaz-Sánchez, M and Prashar, S and Fernandez-Martos, CM and Gómez-Ruiz, S}, title = {Design of Mesoporous Silica Nanoparticles for the Treatment of Amyotrophic Lateral Sclerosis (ALS) with a Therapeutic Cocktail Based on Leptin and Pioglitazone.}, journal = {ACS biomaterials science &amp; engineering}, volume = {8}, number = {11}, pages = {4838-4849}, pmid = {36240025}, issn = {2373-9878}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Pioglitazone/pharmacology ; Leptin ; Mice, Transgenic ; Silicon Dioxide ; *Neurodegenerative Diseases ; DNA-Binding Proteins/metabolism ; *Nanoparticles ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disease with no cure to date. Therapeutic agents used to treat ALS are very limited, although combined therapies may offer a more effective treatment strategy. Herein, we have studied the potential of nanomedicine to prepare a single platform based on mesoporous silica nanoparticles (MSNs) for the treatment of an ALS animal model with a cocktail of agents such as leptin (neuroprotective) and pioglitazone (anti-inflammatory), which have already demonstrated promising therapeutic ability in other neurodegenerative diseases. Our goal is to study the potential of functionalized mesoporous materials as therapeutic agents against ALS using MSNs as nanocarriers for the proposed drug cocktail leptin/pioglitazone (MSN-LEP-PIO). The nanostructured materials have been characterized by different techniques, which confirmed the incorporation of both agents in the nanosystem. Subsequently, the effect, in vivo, of the proposed drug cocktail, MSN-LEP-PIO, was used in the murine model of TDP-43 proteinopathy (TDP-43[A315T] mice). Body weight loss was studied, and using the rotarod test, motor performance was assessed, observing a continuous reduction in body weight and motor coordination in TDP-43[A315T] mice and wild-type (WT) mice. Nevertheless, the disease progression was slower and showed significant improvements in motor performance, indicating that TDP-43[A315T] mice treated with MSN-LEP-PIO seem to have less energy demand in the late stage of the symptoms of ALS. Collectively, these results seem to indicate the efficiency of the systems in vivo and the usefulness of their use in neurodegenerative models, including ALS.}, }
@article {pmid36237618, year = {2022}, author = {Albanese, A and Ludolph, AC and McDermott, CJ and Corcia, P and Van Damme, P and Van den Berg, LH and Hardiman, O and Rinaldi, G and Vanacore, N and Dickie, B and , }, title = {Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: The TUDCA-ALS trial protocol.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {1009113}, pmid = {36237618}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative rare disease that affects motor neurons in the brain, brainstem, and spinal cord, resulting in progressive weakness and atrophy of voluntary skeletal muscles. Although much has been achieved in understanding the disease pathogenesis, treatment options are limited, and in Europe, riluzole is the only approved drug. Recently, some other drugs showed minor effects.<br><br>METHODS: The TUDCA-ALS trial is a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The study aims to enroll 320 patients in 25 centers across seven countries in Europe. Enrolled patients are randomized to one of two treatment arms: TUDCA or identical placebo by oral route. The study measures disease progression during the treatment period and compares it to natural progression during a no-treatment run-in phase. Clinical data and specific biomarkers are measured during the trial. The study is coordinated by a consortium composed of leading European ALS centers.<br><br>CONCLUSION: This trial is aimed to determine whether TUDCA has a disease-modifying activity in ALS. Demonstration of TUDCA efficacy, combined with the validation of new biomarkers, could advance ALS patient care.<br><br>CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT03800524.}, }
@article {pmid36235295, year = {2022}, author = {Villareal, MO and Chaochaiphat, T and Makbal, R and Gadhi, C and Isoda, H}, title = {Molecular Analysis of the Melanogenesis Inhibitory Effect of Saponins-Rich Fraction of Argania spinosa Leaves Extract.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {19}, pages = {}, pmid = {36235295}, issn = {1420-3049}, support = {Not applicable//Japan Science and Technology Agency/ ; }, mesh = {Animals ; Humans ; Mice ; *Cosmeceuticals/chemistry/pharmacology ; DNA/metabolism ; *Melanins/antagonists &amp; inhibitors/metabolism ; Melanocytes/metabolism ; Microphthalmia-Associated Transcription Factor/genetics/metabolism ; Monophenol Monooxygenase/metabolism ; *Plant Extracts/chemistry/pharmacology ; Plant Leaves/chemistry ; RNA, Messenger/metabolism ; *Saponins/metabolism/pharmacology ; *Sapotaceae/chemistry ; Hyperpigmentation/drug therapy ; }, abstract = {Plant saponins are abundant and diverse natural products with a great potential for use in drug-discovery research. Here, we evaluated extracts of saponins-rich fractions of argan leaves and argan oil extraction byproducts (shell, pulp, press cake) for their effect on melanogenesis. Results show that from among the samples tested, only the saponins-rich fraction from leaves (ALS) inhibited melanin production in B16 murine melanoma (B16) cells. The mechanism of the melanogenesis inhibition was elucidated by determining the protein and mRNA expression of melanogenesis-associated enzymes tyrosinase (TYR), tyrosinase-related protein 1 (TRP1), and dopachrome tautomerase (DCT), and microphthalmia-associated transcription factor (MITF), and performing DNA microarray analysis. Results showed that 10 µg/mL ALS significantly inhibited melanogenesis in B16 cells and human epidermal melanocytes by 59% and 48%, respectively, without cytotoxicity. The effect of ALS on melanogenesis can be attributed to the decrease in TYR, TRP1, and MITF expression at the protein and mRNA levels. MITF inhibition naturally led to the downregulation of the expression of Tyr and Trp1 genes. Results of the DNA microarray analysis revealed the effect on melanogenesis-associated cAMP and Wnt signaling pathways' genes. The results of this study suggest that ALS may be used in cosmeceuticals preparations for hyperpigmentation treatment.}, }
@article {pmid36233034, year = {2022}, author = {Reddy, DS and Abeygunaratne, HN}, title = {Experimental and Clinical Biomarkers for Progressive Evaluation of Neuropathology and Therapeutic Interventions for Acute and Chronic Neurological Disorders.}, journal = {International journal of molecular sciences}, volume = {23}, number = {19}, pages = {}, pmid = {36233034}, issn = {1422-0067}, support = {U01 NS117209/NS/NINDS NIH HHS/United States ; U01 NS117278/NS/NINDS NIH HHS/United States ; }, mesh = {*Alzheimer Disease ; Biomarkers/metabolism ; Chronic Disease ; Humans ; *Nervous System Diseases/diagnosis/metabolism/therapy ; Neuropathology ; }, abstract = {This article describes commonly used experimental and clinical biomarkers of neuronal injury and neurodegeneration for the evaluation of neuropathology and monitoring of therapeutic interventions. Biomarkers are vital for diagnostics of brain disease and therapeutic monitoring. A biomarker can be objectively measured and evaluated as a proxy indicator for the pathophysiological process or response to therapeutic interventions. There are complex hurdles in understanding the molecular pathophysiology of neurological disorders and the ability to diagnose them at initial stages. Novel biomarkers for neurological diseases may surpass these issues, especially for early identification of disease risk. Validated biomarkers can measure the severity and progression of both acute neuronal injury and chronic neurological diseases such as epilepsy, migraine, Alzheimer's disease, Parkinson's disease, Huntington's disease, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and other brain diseases. Biomarkers are deployed to study progression and response to treatment, including noninvasive imaging tools for both acute and chronic brain conditions. Neuronal biomarkers are classified into four core subtypes: blood-based, immunohistochemical-based, neuroimaging-based, and electrophysiological biomarkers. Neuronal conditions have progressive stages, such as acute injury, inflammation, neurodegeneration, and neurogenesis, which can serve as indices of pathological status. Biomarkers are critical for the targeted identification of specific molecules, cells, tissues, or proteins that dramatically alter throughout the progression of brain conditions. There has been tremendous progress with biomarkers in acute conditions and chronic diseases affecting the central nervous system.}, }
@article {pmid36232630, year = {2022}, author = {Zhang, Y and Zeng, B and Gu, A and Kang, Q and Zhao, M and Peng, G and Zhou, M and Liu, W and Liu, M and Ding, L and Liang, D and Liu, X and Liu, M}, title = {Damaged DNA Is an Early Event of Neurodegeneration in Induced Pluripotent Stem Cell-Derived Motoneurons with UBQLN2[P497H] Mutation.}, journal = {International journal of molecular sciences}, volume = {23}, number = {19}, pages = {}, pmid = {36232630}, issn = {1422-0067}, support = {2016YFC0905100//the National Key Research and Development Program of China/ ; 2021zzts0565//the Postgraduate Freedom Exploration Project of Central South University/ ; kq2202077//the Natural Science Foundation of Changsha/ ; }, mesh = {Adaptor Proteins, Signal Transducing/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Autophagy-Related Proteins/genetics/metabolism ; DNA/metabolism ; DNA Damage ; DNA-Binding Proteins/genetics/metabolism ; Humans ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; Mutation ; Transcription Factors/metabolism ; }, abstract = {Ubiquilin-2 (UBQLN2) mutations lead to familial amyotrophic lateral sclerosis (FALS)/and frontotemporal dementia (FTLD) through unknown mechanisms. The combination of iPSC technology and CRISPR-mediated genome editing technology can generate an iPSC-derived motor neuron (iPSC-MN) model with disease-relevant mutations, which results in increased opportunities for disease mechanism research and drug screening. In this study, we introduced a UBQLN2-P497H mutation into a healthy control iPSC line using CRISPR/Cas9, and differentiated into MNs to study the pathology of UBQLN2-related ALS. Our in vitro MN model faithfully recapitulated specific aspects of the disease, including MN apoptosis. Under sodium arsenite (SA) treatment, we found differences in the number and the size of UBQLN2[+] inclusions in UBQLN2[P497H] MNs and wild-type (WT) MNs. We also observed cytoplasmic TAR DNA-binding protein (TARDBP, also known as TDP-43) aggregates in UBQLN2[P497H] MNs, but not in WT MNs, as well as the recruitment of TDP-43 into stress granules (SGs) upon SA treatment. We noted that UBQLN2-P497H mutation induced MNs DNA damage, which is an early event in UBQLN2-ALS. Additionally, DNA damage led to an increase in compensation for FUS, whereas UBQLN2-P497H mutation impaired this function. Therefore, FUS may be involved in DNA damage repair signaling.}, }
@article {pmid36224351, year = {2022}, author = {Baek, Y and Woo, TG and Ahn, J and Lee, D and Kwon, Y and Park, BJ and Ha, NC}, title = {Structural analysis of the overoxidized Cu/Zn-superoxide dismutase in ROS-induced ALS filament formation.}, journal = {Communications biology}, volume = {5}, number = {1}, pages = {1085}, pmid = {36224351}, issn = {2399-3642}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Cysteine ; Disulfides/chemistry ; Humans ; Mutation ; Reactive Oxygen Species ; Superoxide Dismutase/chemistry/genetics/metabolism ; Superoxide Dismutase-1/chemistry ; Zinc/metabolism ; }, abstract = {Eukaryotic Cu, Zn-superoxide dismutase (SOD1) is primarily responsible for cytotoxic filament formation in amyotrophic lateral sclerosis (ALS) neurons. Two cysteine residues in SOD1 form an intramolecular disulfide bond. This study aims to explore the molecular mechanism of SOD1 filament formation by cysteine overoxidation in sporadic ALS (sALS). In this study, we determined the crystal structure of the double mutant (C57D/C146D) SOD1 that mimics the overoxidation of the disulfide-forming cysteine residues. The structure revealed the open and relaxed conformation of loop IV containing the mutated Asp57. The double mutant SOD1 produced more contagious filaments than wild-type protein, promoting filament formation of the wild-type SOD1 proteins. Importantly, we further found that HOCl treatment to the wild-type SOD1 proteins facilitated their filament formation. We propose a feasible mechanism for SOD1 filament formation in ALS from the wild-type SOD1, suggesting that overoxidized SOD1 is a triggering factor of sALS. Our findings extend our understanding of other neurodegenerative disorders associated with ROS stresses at the molecular level.}, }
@article {pmid36220871, year = {2022}, author = {Khademullah, CS and De Koninck, Y}, title = {A novel assessment of fine-motor function reveals early hindlimb and detectable forelimb deficits in an experimental model of ALS.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {17010}, pmid = {36220871}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Animals ; Disease Models, Animal ; Forelimb ; Hindlimb/pathology ; Mice ; Mice, Transgenic ; Superoxide Dismutase/physiology ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with the loss of cortical and spinal motor neurons (MNs) and muscle degeneration (Kiernan et al. in Lancet 377:942-955, 2011). In the preclinical setting, functional tests that can detect early changes in motor function in rodent models of ALS are critical to understanding the etiology of the disease and treatment development. Here, we established a string-pulling paradigm that can detect forelimb and hindlimb motor deficits in the SOD1 mouse model of ALS earlier than traditional motor performance tasks. Additionally, our findings indicate that early loss of forelimb and hindlimb function is correlated with cortical and spinal MN loss, respectively. This task is not only ecological, low-cost, efficient, and non-onerous, it also requires little animal handling and reduces the stress placed on the animal. It has long been a concern in the field that the SOD1 mouse does not display forelimb motor deficits and does not give researchers a complete picture of the disease. Here, we provide evidence that the SOD1 model does in fact develop early forelimb motor deficits due to the task's ability to assess fine-motor function, reconciling this model with the various clinical presentation of ALS. Taken together, the string-pulling paradigm may provide novel insights into the pathogenesis of ALS, offer nuanced evaluation of prospective treatments, and has high translational potential to the clinic.}, }
@article {pmid36213964, year = {2023}, author = {Dennys, CN and Roussel, F and Rodrigo, R and Zhang, X and Sierra Delgado, A and Hartlaub, A and Saelim-Ector, A and Ray, W and Heintzman, S and Fox, A and Kolb, SJ and Beckman, J and Franco, MC and Meyer, K}, title = {CuATSM effectively ameliorates ALS patient astrocyte-mediated motor neuron toxicity in human in vitro models of amyotrophic lateral sclerosis.}, journal = {Glia}, volume = {71}, number = {2}, pages = {350-365}, pmid = {36213964}, issn = {1098-1136}, support = {R01 NS107479/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Astrocytes/metabolism ; Motor Neurons ; Coculture Techniques ; Superoxide Dismutase-1/metabolism ; }, abstract = {Patient diversity and unknown disease cause are major challenges for drug development and clinical trial design for amyotrophic lateral sclerosis (ALS). Transgenic animal models do not adequately reflect the heterogeneity of ALS. Direct reprogramming of patient fibroblasts to neuronal progenitor cells and subsequent differentiation into patient astrocytes allows rapid generation of disease relevant cell types. Thus, this methodology can facilitate compound testing in a diverse genetic background resulting in a more representative population for therapeutic evaluation. Here, we used established co-culture assays with motor neurons and reprogrammed patient skin-derived astrocytes (iAs) to evaluate the effects of (SP-4-2)-[[2,2'-(1,2-dimethyl-1,2-ethanediylidene)bis[N-methylhydrazinecarbothioamidato-κN[2] ,κS]](2-)]-copper (CuATSM), currently in clinical trial for ALS in Australia. Pretreatment of iAs with CuATSM had a differential effect on neuronal survival following co-culture with healthy motor neurons. Using this assay, we identified responding and non-responding cell lines for both sporadic and familial ALS (mutant SOD1 and C9ORF72). Importantly, elevated mitochondrial respiration was the common denominator in all CuATSM-responders, a metabolic phenotype not observed in non-responders. Pre-treatment of iAs with CuATSM restored mitochondrial activity to levels comparable to healthy controls. Hence, this metabolic parameter might allow selection of patient subpopulations best suited for CuATSM treatment. Moreover, CuATSM might have additional therapeutic value for mitochondrial disorders. Enhanced understanding of patient-specific cellular and molecular profiles could help improve clinical trial design in the future.}, }
@article {pmid36213785, year = {2022}, author = {Furukawa, Y}, title = {A pathological link between dysregulated copper binding in Cu/Zn-superoxide dismutase and amyotrophic lateral sclerosis.}, journal = {Journal of clinical biochemistry and nutrition}, volume = {71}, number = {2}, pages = {73-77}, pmid = {36213785}, issn = {0912-0009}, abstract = {Mutations in the gene coding Cu/Zn-superoxide dismutase (SOD1) are linked to a familial form of amyotrophic lateral sclerosis (ALS), and its pathological hallmark includes abnormal accumulation of mutant SOD1 proteins in spinal motorneurons. Mutant SOD1 proteins are considered to be susceptible to misfolding, resulting in the accumulation as oligomers/aggregates. While it remains obscure how and why SOD1 becomes misfolded under pathological conditions in vivo, the failure to bind a copper and zinc ion in SOD1 in vitro leads to the significant destabilization of its natively folded structure. Therefore, genetic and pharmacological attempts to promote the metal binding in mutant SOD1 could serve as an effective treatment of ALS. Here, I briefly review the copper and zinc binding process of SOD1 in vivo and discuss a copper chaperone for SOD1 as a potential target for developing ALS therapeutics.}, }
@article {pmid36211189, year = {2022}, author = {Samadhiya, S and Sardana, V and Bhushan, B and Maheshwari, D and Goyal, R and Pankaj, }, title = {Assessment of Therapeutic Response of Edaravone and Riluzole Combination Therapy in Amyotrophic Lateral Sclerosis Patients.}, journal = {Annals of Indian Academy of Neurology}, volume = {25}, number = {4}, pages = {692-697}, pmid = {36211189}, issn = {0972-2327}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive disease characterized by chronic degeneration of upper and lower motor neurons and finally death within 3-5 years usually because of respiratory failure. Riluzole and edaravone are presently available treatments. It may be better to try combination therapy rather than taking individual medications.<br><br>OBJECTIVES: To compare the effectiveness of (edaravone + riluzole) combination therapy versus riluzole therapy alone in slowing down the progression of ALS and to evaluate the role of serum creatinine as a marker of disease progression.<br><br>MATERIALS AND METHODS: Observational, randomized, parallel assignment, open label study. Thirty patients with definite and probable ALS were randomly assigned to two treatment groups. The case group received (riluzole + edaravone) for the initial 6 months, followed by riluzole for the next 6 months. The control group received riluzole for 12 months. After 6 and 12 months, changes in ALS functional rating scale (ALSFRS-R), mRS, and Japanese ALS scores were determined. P value <.05 was considered significant.<br><br>RESULTS: An increase in mRS at 6 months in the case group versus control group was 0.07 versus 0.20, respectively (p =0.02). At 12 months, it was 0.47 versus 0.53, respectively (p =0.17). A decrease in serum creatinine at 6 months in case group versus control group was 0.08 versus 0.09, respectively (p =.82). There was no change in ALS FRS for bulbar symptoms (salivation), 3.46 versus 3.46 in the case group (p =.018) for the first 6 months.<br><br>CONCLUSIONS: Combined with riluzole, edaravone slows disease progression and is safe, but the effect is short-term. Bulbar symptoms respond better to combination therapy. The serum creatinine is helpful in monitoring disease progression.}, }
@article {pmid36211158, year = {2022}, author = {Koh, JS and Fam, SR and Ng, PS and Umapathi, T}, title = {ALS Treatment- We Still Await the "Magic Cocktail".}, journal = {Annals of Indian Academy of Neurology}, volume = {25}, number = {4}, pages = {577-578}, pmid = {36211158}, issn = {0972-2327}, }
@article {pmid36210213, year = {2023}, author = {Methaneethorn, J}, title = {Effects of missed dose and delayed dose quetiapine on its pharmacokinetics and pharmacodynamics.}, journal = {Therapie}, volume = {78}, number = {4}, pages = {367-374}, doi = {10.1016/j.therap.2022.08.001}, pmid = {36210213}, issn = {1958-5578}, abstract = {AIM OF THE STUDY: Nonadherence to the prescribed medication can result in a poor treatment outcome. This study determined the impacts of multiple missed dose or delayed dose scenarios on quetiapine (QTP) pharmacokinetics and pharmacodynamics.<br><br>METHODS: QTP concentration-time profiles and Brief Psychiatric Rating Scale (BPRS) scores under multiple missed doses and delayed dose scenarios were simulated using Monte Carlo simulations and compared with those of the full adherence scenario using the Mann-Whitney U test. The simulations were performed using the model structure and parameter estimates obtained from Kimko et al's study.<br><br>RESULTS: Missing one, two and three consecutive QTP doses significantly decreased trough concentration (Ctrough) by 71.4, 103, and 128ng/mL. However, Ctrough rapidly increased to values close to those of the full adherence scenario when the regular dose was resumed. Further, all missed dose scenarios did not significantly impact the maximum percent reduction of BPRS score from baseline, but significant impacts on the minimum percent reduction of BPRS score from baseline were observed. However, the change in BPRS score from the full adherence scenario rapidly resumed when the regular dose was taken. Moreover, this study identified that a delayed dose as late as 6 hours did not significantly impact the maximum concentrations when the regular dose was resumed.<br><br>CONCLUSION: Based on the simulations, a missed dose can be taken as late as 6 hours before the next scheduled dose, otherwise it should be skipped. For multiple missed doses scenarios, QTP pharmacokinetics and pharmacodynamics rapidly returned to the stage close to the full adherence scenario when a single regular dose was resumed.}, }
@article {pmid36206551, year = {2022}, author = {Mundkar, M and Bijalwan, A and Soni, D and Kumar, P}, title = {Neuroprotective potential of Moringa oleifera mediated by NF-kB/Nrf2/HO-1 signaling pathway: A review.}, journal = {Journal of food biochemistry}, volume = {46}, number = {12}, pages = {e14451}, doi = {10.1111/jfbc.14451}, pmid = {36206551}, issn = {1745-4514}, mesh = {Humans ; Animals ; Antioxidants/pharmacology/therapeutic use ; *Moringa oleifera ; NF-kappa B ; NF-E2-Related Factor 2/genetics ; *Moringa ; Signal Transduction ; }, abstract = {Moringa oleifera is a traditional Indian herb belonging to the Moringaceae family, it is commonly known as the horse-radish tree, drumstick, or sahajna. In developing countries, Moringa is used as feed for both humans and animals due to its well-known antioxidant, anti-inflammatory, and anti-apoptotic properties owing to its several phytoconstituents including β-carotene, quercetin, kaempferol, ascorbic acid, flavonoids, phenolic acid, rhamnose, glycosylates, glucomoringin, and isothiocyanates. These constituents help to maintain the brain antioxidant enzyme levels, mitochondrial functions, and neurogenesis, showing neuroprotective effects in several neurodegenerative disorders including Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, and Amyotrophic lateral sclerosis. This review discusses various phytoconstituent of moringa and their therapeutic potential in various neurological disorders. Additionally, we also concise the safety and toxicity profile, of different molecular pathways involved in the neuroprotective effect of M. oleifera including M. oleifera nanoparticles for better therapeutic value. PRACTICAL APPLICATIONS: Several clinical and preclinical studies on Moringa oleifera have been conducted, and the outcomes indicate moringa could be used in the treatment of brain disorders. As a result, we conclude that moringa and its nanoformulations could be employed to treat neurological problems. In the future, M. oleifera phytoconstituents could be evaluated against specific signaling pathways, which could aid researchers in discovering their mechanism of action. Furthermore, the use of moringa as a nutraceutical owing to its myriad pharmacological potential will go a long way in boosting the economy of countries that grow moringa on a large scale.}, }
@article {pmid36200031, year = {2022}, author = {Lu, Y and Gao, Q and Ren, X and Li, J and Yang, D and Zhang, Z and Han, J}, title = {Incidence and prevalence of 121 rare diseases in China: Current status and challenges: 2022 revision.}, journal = {Intractable &amp; rare diseases research}, volume = {11}, number = {3}, pages = {96-104}, pmid = {36200031}, issn = {2186-3644}, abstract = {The current study updated data on the incidence and prevalence of 121 rare diseases listed in China's First List of Rare Diseases to provide rationales and references for the development and promotion of rare-disease-related policies. The National Health Commission of the People's Republic of China issued the Rare Disease Diagnosis and Treatment Guide (2019) (denoted here as China's Rare Disease Diagnosis and Treatment Guide). Then 121 diseases were registered with the national rare disease diagnosis and treatment network. The incidence/prevalence of 121 rare diseases varied from country to country. Data are available for a total of 76 rare diseases (76 of 121 rare diseases, 62.81%) in China, including data on the incidence of 23 rare diseases (19.01%) and data on the prevalence of 66 (54.55%). There are data on the incidence/prevalence of 112 rare diseases (112 of 121 rare diseases, 92.56%) at the global level, including data on the incidence of 86 rare diseases (71.07%) and data on the prevalence of 91 (75.21%). On average, the incidence of progressive muscular dystrophies, hyperphenylalaninemia, citrullinemia, and methylmalonic acidemia is over 1/10,000 in China. The prevalence of coronary artery ectasia, congenital scoliosis, retinitis pigmentosa, severe congenital neutropenia, congenital hyperinsulinemic hypoglycemia, and osteogenesis imperfecta is over 1/10,000 in China. All of these figures are beyond the cut-off of 1/10,000 according to the 2021 definition of rare diseases in China. As registration and investigation of rare diseases continues, the spectrum of rare diseases in some provinces is expanding. Diseases such as idiopathic pulmonary arterial hypertension, hepatolenticular degeneration, hemophilia, amyotrophic lateral sclerosis, idiopathic pulmonary fibrosis, and multiple sclerosis are relatively prevalent in some regions and cities of China. Registration efforts promote the correction of incidence/prevalence data, development of orphan drugs, coverage by medical insurance, and development of clinical and diagnostic pathways.}, }
@article {pmid36188541, year = {2022}, author = {Yadav, E and Yadav, P and Khan, MMU and Singh, H and Verma, A}, title = {Resveratrol: A potential therapeutic natural polyphenol for neurodegenerative diseases associated with mitochondrial dysfunction.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {922232}, pmid = {36188541}, issn = {1663-9812}, abstract = {Most polyphenols can cross blood-brain barrier, therefore, they are widely utilized in the treatment of various neurodegenerative diseases (ND). Resveratrol, a natural polyphenol contained in blueberry, grapes, mulberry, etc., is well documented to exhibit potent neuroprotective activity against different ND by mitochondria modulation approach. Mitochondrial function impairment is the most common etiology and pathological process in various neurodegenerative disorders, viz. Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Nowadays these ND associated with mitochondrial dysfunction have become a major threat to public health as well as health care systems in terms of financial burden. Currently available therapies for ND are limited to symptomatic cures and have inevitable toxic effects. Therefore, there is a strict requirement for a safe and highly effective drug treatment developed from natural compounds. The current review provides updated information about the potential of resveratrol to target mitochondria in the treatment of ND.}, }
@article {pmid36187357, year = {2022}, author = {Bergh, S and Cheong, RY and Petersén, &#xc5; and Gabery, S}, title = {Oxytocin in Huntington's disease and the spectrum of amyotrophic lateral sclerosis-frontotemporal dementia.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {984317}, pmid = {36187357}, issn = {1662-5099}, abstract = {Neurodegenerative disorders (NDDs) such as Huntington's disease (HD) and the spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by progressive loss of selectively vulnerable populations of neurons. Although often associated with motor impairments, these NDDs share several commonalities in early symptoms and signs that extend beyond motor dysfunction. These include impairments in social cognition and psychiatric symptoms. Oxytocin (OXT) is a neuropeptide known to play a pivotal role in the regulation of social cognition as well as in emotional behaviors such as anxiety and depression. Here, we present an overview of key results implicating OXT in the pathology of HD, ALS and FTD and seek to identify commonalities across these NDDs. OXT is produced in the hypothalamus, a region in the brain that during the past decade has been shown to be affected in HD, ALS, and FTD. Several studies using human post-mortem neuropathological analyses, measurements of cerebrospinal fluid, experimental treatments with OXT as well as genetic animal models have collectively implicated an important role of central OXT in the development of altered social cognition and psychiatric features across these diseases. Understanding central OXT signaling may unveil the underlying mechanisms of early signs of the social cognitive impairment and the psychiatric features in NDDs. It is therefore possible that OXT might have potential therapeutic value for early disease intervention and better symptomatic treatment in NDDs.}, }
@article {pmid36184826, year = {2023}, author = {Jiao, F and Zhou, B and Meng, L}, title = {The regulatory mechanism and therapeutic potential of transcription factor EB in neurodegenerative diseases.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {29}, number = {1}, pages = {37-59}, pmid = {36184826}, issn = {1755-5949}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Autophagy ; *Alzheimer Disease/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Lysosomes ; }, abstract = {The autophagy-lysosomal pathway (ALP) is involved in the degradation of protein aggregates and damaged organelles. Transcription factor EB (TFEB), a major regulator of ALP, has emerged as a leading factor in addressing neurodegenerative disease pathology, including Alzheimer's disease (AD), Parkinson's disease (PD), PolyQ diseases, and Amyotrophic lateral sclerosis (ALS). In this review, we delineate the regulation of TFEB expression and its functions in ALP. Dysfunctions of TFEB and its role in the pathogenesis of several neurodegenerative diseases are reviewed. We summarize the protective effects and molecular mechanisms of some TFEB-targeted agonists in neurodegenerative diseases. We also offer our perspective on analyzing the pros and cons of these agonists in the treatment of neurodegenerative diseases from the perspective of drug development. More studies on the regulatory mechanisms of TFEB in other biological processes will aid our understanding of the application of TFEB-targeted therapy in neurodegeneration.}, }
@article {pmid36184105, year = {2023}, author = {Sataer, X and Qifeng, Z and Yingying, Z and Chunhua, H and Bingzhenga, F and Zhiran, X and Wanli, L and Yuwei, Y and Shuangfeng, C and Lingling, W and Hongri, H and Jibing, C and Xiaoping, R and Hongjun, G}, title = {Exosomal microRNAs as diagnostic biomarkers and therapeutic applications in neurodegenerative diseases.}, journal = {Neurological research}, volume = {45}, number = {3}, pages = {191-199}, doi = {10.1080/01616412.2022.2129768}, pmid = {36184105}, issn = {1743-1328}, mesh = {Humans ; *MicroRNAs/genetics/therapeutic use/metabolism ; *Neurodegenerative Diseases/diagnosis/genetics/therapy ; *Alzheimer Disease/metabolism ; *Huntington Disease ; Biomarkers/metabolism ; }, abstract = {Originating from slow irreversible and progressive loss and dysfunction of neurons and synapses in the nervous system, neurodegenerative diseases (NDDs) affect millions of people worldwide. Common NDDs include Parkinson's disease, Alzheimer's disease multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis. Currently, no sensitive biomarkers are available to monitor the progression and treatment response of NDDs or to predict their prognosis. Exosomes (EXOs) are small bilipid layer-enclosed extracellular vesicles containing numerous biomolecules, including proteins, nucleic acids, and lipids. Recent evidence indicates that EXOs are pathogenic participants in the spread of neurodegenerative diseases, contributing to disease progression and spread. EXOs are also important tools for diagnosis and treatment. Recently, studies have proposed exosomal microRNAs (miRNAs) as the targets for therapies or biomarkers of NDDs. In this review, we outline the latest research on the roles of exosomal miRNAs in NDDs and their applications as potential diagnostic and therapeutic biomarkers, targets, and drugs for NDDs.}, }
@article {pmid36181767, year = {2022}, author = {Monsour, M and Garbuzova-Davis, S and Borlongan, CV}, title = {Patching Up the Permeability: The Role of Stem Cells in Lessening Neurovascular Damage in Amyotrophic Lateral Sclerosis.}, journal = {Stem cells translational medicine}, volume = {11}, number = {12}, pages = {1196-1209}, pmid = {36181767}, issn = {2157-6580}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Spinal Cord/metabolism ; Central Nervous System ; Stem Cells/pathology ; Permeability ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating disease with poor prognosis. The pathophysiology of ALS is commonly debated, with theories involving inflammation, glutamate excitotoxity, oxidative stress, mitochondria malfunction, neurofilament accumulation, inadequate nutrients or growth factors, and changes in glial support predominating. These underlying pathological mechanisms, however, act together to weaken the blood brain barrier and blood spinal cord barrier, collectively considered as the blood central nervous system barrier (BCNSB). Altering the impermeability of the BCNSB impairs the neurovascular unit, or interdependent relationship between the brain and advances the concept that ALS is has a significant neurovascular component contributing to its degenerative presentation. This unique categorization of ALS opens a variety of treatment options targeting the reestablishment of BCNSB integrity. This review will critically assess the evidence implicating the significant neurovascular components of ALS pathophysiology, while also offering an in-depth discussion regarding the use of stem cells to repair these pathological changes within the neurovascular unit.}, }
@article {pmid36180986, year = {2022}, author = {Gureev, AP and Sadovnikova, IS and Popov, VN}, title = {Molecular Mechanisms of the Neuroprotective Effect of Methylene Blue.}, journal = {Biochemistry. Biokhimiia}, volume = {87}, number = {9}, pages = {940-956}, doi = {10.1134/S0006297922090073}, pmid = {36180986}, issn = {1608-3040}, mesh = {Methylene Blue/metabolism/pharmacology/therapeutic use ; Mitochondria/metabolism ; Monoamine Oxidase/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Nitric Oxide Synthase/metabolism ; }, abstract = {Methylene blue (MB) is the first fully synthetic compound that had found its way into medicine over 120 years ago as a treatment against malaria. MB has been approved for the treatment of methemoglobinemia, but there are premises for its repurposing as a neuroprotective agent based on the efficacy of this compound demonstrated in the models of Alzheimer's, Parkinson's, and Huntington's diseases, traumatic brain injury, amyotrophic lateral sclerosis, depressive disorders, etc. However, the goal of this review was not so much to focus on the therapeutic effects of MB in the treatment of various neurodegeneration diseases, but to delve into the mechanisms of direct or indirect effect of this drug on the signaling pathways. MB can act as an alternative electron carrier in the mitochondrial respiratory chain in the case of dysfunctional electron transport chain. It also displays the anti-inflammatory and anti-apoptotic effects, inhibits monoamine oxidase (MAO) and nitric oxide synthase (NOS), activates signaling pathways involved in the mitochondrial pool renewal (mitochondrial biogenesis and autophagy), and prevents aggregation of misfolded proteins. Comprehensive understanding of all aspects of direct and indirect influence of MB, and not just some of its effects, can help in further research of this compound, including its clinical applications.}, }
@article {pmid36180205, year = {2023}, author = {Portelli, S and Albanaz, A and Pires, DEV and Ascher, DB}, title = {Identifying the molecular drivers of ALS-implicated missense mutations.}, journal = {Journal of medical genetics}, volume = {60}, number = {5}, pages = {484-490}, doi = {10.1136/jmg-2022-108798}, pmid = {36180205}, issn = {1468-6244}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mutation, Missense/genetics ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases ; Mutation ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressively fatal, neurodegenerative disease associated with both motor and non-motor symptoms, including frontotemporal dementia. Approximately 10% of cases are genetically inherited (familial ALS), while the majority are sporadic. Mutations across a wide range of genes have been associated; however, the underlying molecular effects of these mutations and their relation to phenotypes remain poorly explored.<br><br>METHODS: We initially curated an extensive list (n=1343) of missense mutations identified in the clinical literature, which spanned across 111 unique genes. Of these, mutations in genes SOD1, FUS and TDP43 were analysed using in silico biophysical tools, which characterised changes in protein stability, interactions, localisation and function. The effects of pathogenic and non-pathogenic mutations within these genes were statistically compared to highlight underlying molecular drivers.<br><br>RESULTS: Compared with previous ALS-dedicated databases, we have curated the most extensive missense mutation database to date and observed a twofold increase in unique implicated genes, and almost a threefold increase in the number of mutations. Our gene-specific analysis identified distinct molecular drivers across the different proteins, where SOD1 mutations primarily reduced protein stability and dimer formation, and those in FUS and TDP-43 were present within disordered regions, suggesting different mechanisms of aggregate formation.<br><br>CONCLUSION: Using our three genes as case studies, we identified distinct insights which can drive further research to better understand ALS. The information curated in our database can serve as a resource for similar gene-specific analyses, further improving the current understanding of disease, crucial for the development of treatment strategies.}, }
@article {pmid36176229, year = {2022}, author = {Shibahashi, K and Konishi, T and Ohbe, H and Yasunaga, H}, title = {Cost-effectiveness analysis of termination-of-resuscitation rules for patients with out-of-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {180}, number = {}, pages = {45-51}, doi = {10.1016/j.resuscitation.2022.09.006}, pmid = {36176229}, issn = {1873-1570}, abstract = {AIM: To evaluate the cost-effectiveness of practices with and without termination-of-resuscitation (TOR) rules for out-of-hospital cardiac arrest (OHCA), using an analytic model based on a nationwide population-based registry in Japan.<br><br>METHODS: A combined model using a decision tree and Markov model was developed to compare costs and treatment effectiveness of three scenarios: basic life support (BLS) TOR rules (BLS-rule scenario), advanced life support (ALS) TOR rules (ALS-rule scenario), and no TOR rules (No-rule scenario). A nationwide population-based OHCA registry from January 1 to December 31, 2019 and published data were used. Analyses were performed from healthcare payers' perspectives. Life-time incremental cost-effectiveness ratio (ICER) was determined by the difference in cost between two scenarios, divided by the difference in quality adjusted life year (QALY).<br><br>RESULTS: The OHCA registry included 126,271 patients (57.3% men; median age, 80&#xa0;years). The BLS-rule scenario yielded lower cost and less QALY than the ALS-rule scenario and No-rule scenario. With reference to the BLS-rule scenario, the ICERs for the ALS-rule scenario and No-rule scenario were 81,000 and 98,762 USD per QALY, respectively. The BLS-rule scenario was cost-effective in 100% of simulations at the willingness-to-pay threshold in Japan (5 million JPY&#xa0;=&#xa0;45,455 USD). The willingness-to-pay threshold higher than 80,000 and 204,000 USD were required for the ALS-rule scenario and No-rule scenarios, respectively, to be cost-effective.<br><br>CONCLUSION: No-rule scenario was not cost-effective compared with BLS-rule scenario within acceptable willingness-to-pay thresholds. Further research on health economics of TOR rules is warranted to support constructive discussion on implementing TOR rules.}, }
@article {pmid36170200, year = {2022}, author = {Wang, X and Rimal, S and Tantray, I and Geng, J and Bhurtel, S and Khaket, TP and Li, W and Han, Z and Lu, B}, title = {Prevention of ribosome collision-induced neuromuscular degeneration by SARS CoV-2-encoded Nsp1.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {119}, number = {42}, pages = {e2202322119}, pmid = {36170200}, issn = {1091-6490}, support = {R01 HL134940/HL/NHLBI NIH HHS/United States ; }, mesh = {Alzheimer Disease ; Amyotrophic Lateral Sclerosis ; Animals ; *COVID-19/genetics ; Drosophila ; Humans ; *Neurodegenerative Diseases/genetics ; Pandemics ; Parkinson Disease ; Proto-Oncogene Proteins c-akt ; RNA, Messenger/metabolism ; *RNA-Dependent RNA Polymerase ; *Ribosomes/genetics/metabolism ; SARS-CoV-2/genetics ; *Viral Nonstructural Proteins/metabolism ; }, abstract = {An overarching goal of aging and age-related neurodegenerative disease research is to discover effective therapeutic strategies applicable to a broad spectrum of neurodegenerative diseases. Little is known about the extent to which targetable pathogenic mechanisms are shared among these seemingly diverse diseases. Translational control is critical for maintaining proteostasis during aging. Gaining control of the translation machinery is also crucial in the battle between viruses and their hosts. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing COVID-19 pandemic. Here, we show that overexpression of SARS-CoV-2-encoded nonstructural protein 1 (Nsp1) robustly rescued neuromuscular degeneration and behavioral phenotypes in Drosophila models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. These diseases share a common mechanism: the accumulation of aberrant protein species due to the stalling and collision of translating ribosomes, leading to proteostasis failure. Our genetic and biochemical analyses revealed that Nsp1 acted in a multipronged manner to resolve collided ribosomes, abort stalled translation, and remove faulty translation products causative of disease in these models, at least in part through the ribosome recycling factor ABCE1, ribosome-associated quality-control factors, autophagy, and AKT signaling. Nsp1 exhibited exquisite specificity in its action, as it did not modify other neurodegenerative conditions not known to be associated with ribosome stalling. These findings uncover a previously unrecognized mechanism of Nsp1 in manipulating host translation, which can be leveraged for combating age-related neurodegenerative diseases that are affecting millions of people worldwide and currently without effective treatment.}, }
@article {pmid36168148, year = {2023}, author = {Wymer, J and Apple, S and Harrison, A and Hill, BA}, title = {Pharmacokinetics, Bioavailability, and Swallowing Safety With Riluzole Oral Film.}, journal = {Clinical pharmacology in drug development}, volume = {12}, number = {1}, pages = {57-64}, pmid = {36168148}, issn = {2160-7648}, mesh = {United States ; Humans ; *Riluzole/adverse effects ; *Amyotrophic Lateral Sclerosis/drug therapy/chemically induced ; Biological Availability ; Deglutition ; Cross-Over Studies ; }, abstract = {Dysphagia is highly prevalent in patients with amyotrophic lateral sclerosis (ALS). Riluzole is a US Food and Drug Administration-approved treatment for ALS. Riluzole oral film (ROF; Exservan™) contains riluzole in a polymer-based film matrix. The ROF is administered by placing on the tongue, where it dissolves and the drug is ingested with the saliva. Two clinical trials assessed the safety and tolerability of the ROF. Bioavailability and pharmacokinetics (PK) were evaluated in an open-label, randomized, single-dose, replicate crossover study of 50 mg of ROF and riluzole 50-mg tablets in 32 healthy volunteers. The second study was a videofluoroscopic swallowing examination conducted with nine patients with ALS before and after receiving a single dose of 50 mg of ROF. The primary outcome was change on penetration-aspiration scale (PAS) scores from pre- to post-dose. Overall, the PK parameters for ROF and riluzole tablets were comparable between treatments and administrations when administered under fasting conditions. Administration of ROF with food resulted in a 15% reduction in area under the curve and a 45% reduction in maximum serum concentration. A total of 44 treatment-emergent adverse events (AEs) were reported in the study; all were mild in severity. No serious AEs were observed and no subjects discontinued due to AEs. In the swallowing study, very little numerical or categorical change was observed following the dose of ROF. No evidence of deterioration of swallowing function was observed post-dose. The ROF was bioequivalent to riluzole tablets, was well tolerated, and had no detrimental effect on swallowing.}, }
@article {pmid36161717, year = {2022}, author = {Yang, C and Zhang, X}, title = {Research progress on vesicular trafficking in amyotrophic lateral sclerosis.}, journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences}, volume = {51}, number = {3}, pages = {380-387}, pmid = {36161717}, issn = {1008-9292}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; C9orf72 Protein/genetics/metabolism ; Humans ; Motor Neurons/metabolism/pathology ; *Neurodegenerative Diseases ; Proteostasis Deficiencies ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Vesicular trafficking is a basic physiological process by which vesicles transport materials between cells and environment (intercellular transport) and between different cellular compartments (intracellular trafficking). In recent years, more and more evidences have suggested that vesicular trafficking dysfunction plays a key role in pathogenesis of neurodegenerative diseases. Abnormal vesicular trafficking promotes the propagation of misfolded proteins by mechanisms involving endocytosis, endosomal-lysosomal pathway, endosomal escape and exosome release, leading to further acceleration of disease progression. Amyotrophic lateral sclerosis (ALS), as a neurodegenerative disease, is characterized by the selective death of upper and lower motor neurons. A variety of causative genes for ALS have been implicated in vesicle trafficking dysfunction, such as C9ORF72, TARDBP and SOD1. Therefore, the aggregation and propagation of misfolded proteins may be prevented through regulation of vesicle trafficking-related proteins, thus delay the progression of ALS. A more in-depth understanding of vesicular trafficking in ALS will be helpful in revealing the mechanism and clinical treatment of ALS. This review focuses on molecular mechanisms of vesicular trafficking in ALS, to provide reference for exploring new therapeutic strategies.}, }
@article {pmid36158555, year = {2022}, author = {Li, Y and Li, F and Qin, D and Chen, H and Wang, J and Wang, J and Song, S and Wang, C and Wang, Y and Liu, S and Gao, D and Wang, ZH}, title = {The role of brain derived neurotrophic factor in central nervous system.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {986443}, pmid = {36158555}, issn = {1663-4365}, abstract = {Brain derived neurotrophic factor (BDNF) has multiple biological functions which are mediated by the activation of two receptors, tropomyosin receptor kinase B (TrkB) receptor and the p75 neurotrophin receptor, involving in physiological and pathological processes throughout life. The diverse presence and activity of BDNF indicate its potential role in the pathogenesis, progression and treatment of both neurological and psychiatric disorders. This review is to provide a comprehensive assessment of the current knowledge and future directions in BDNF-associated research in the central nervous system (CNS), with an emphasis on the physiological and pathological functions of BDNF as well as its potential treatment effects in CNS diseases, including depression, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and cerebral ischemic stroke.}, }
@article {pmid36158411, year = {2022}, author = {Carotenuto, A and Menke, B and Jolton, J and Dowdall, JR}, title = {Recurrent Lingual Abscess in an Elderly Female With Bulbar Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {14}, number = {8}, pages = {e28280}, pmid = {36158411}, issn = {2168-8184}, abstract = {A lingual abscess is a rare condition that was scarcely described in clinical textbooks. A lingual abscess recurrence is rare and has only been described twice in the literature. Typically, the tongue and oral cavity have multiple intrinsic properties which stave off intralingual infection; however, there may be situations in which these properties are compromised, as demonstrated in oro-motor disability. Lingual abscesses have the potential to develop into catastrophic obstructive airway issues; therefore, early detection and management are paramount. The following is a presentation of an elderly female with Bulbar Amyotrophic Lateral Sclerosis (ALS) treated conservatively for a lingual abscess with recurrence at eleven months post-treatment. Due to her baseline neuromuscular disorder and elevated anesthesia risk, she was treated in the interventional radiology suite with drain placement and Povidone-Iodine sclerotherapy under conscious sedation with excellent results.}, }
@article {pmid36157626, year = {2022}, author = {Fahrner-Scott, K and Zapata, C and O'Riordan, DL and Cohen, E and Rosow, L and Pantilat, SZ and Lomen-Hoerth, C and Bischoff, KE}, title = {Embedded Palliative Care for Amyotrophic Lateral Sclerosis: A Pilot Program and Lessons Learned.}, journal = {Neurology. Clinical practice}, volume = {12}, number = {1}, pages = {68-75}, pmid = {36157626}, issn = {2163-0402}, abstract = {BACKGROUND AND OBJECTIVES: Palliative care (PC) is recommended for people with amyotrophic lateral sclerosis (ALS), but there is scant literature about how to best provide this care. We describe the structure and impact of a pilot program that integrates longitudinal, interdisciplinary PC into the care of patients with ALS.<br><br>METHODS: Observational cohort study of patients with ALS referred to outpatient PC and seen for at least 3 PC visits October 2017-July 2020.<br><br>RESULTS: Fifty-five patients met the inclusion criteria. Three-quarters (74.5%) were Caucasian, and 78.2% spoke English. Patients were referred for advance care planning (58.2%), support for patient/family (52.7%), and symptoms other than pain (50.9%). Patients had a mean of 5 scheduled PC visits, the majority occurred by video. A PC physician, nurse, social worker, and chaplain addressed pain (for 43.6% of patients), nonpain symptoms (94.5%), psychosocial distress (78.2%), spiritual concerns (29.1%), care planning (96.4%), and supported family caregivers (96.4%). With PC, the rate of completion of advance directives increased from 16.4% to 36.4% (p = 0.001) and Physician Orders for Life-Sustaining Treatment forms from 10.9% to 63.6% (p < 0.001). Of the 27 patients who died, 77.8% used hospice, typically for more than 30 days. Eleven patients obtained aid-in-dying prescriptions, and 8 took these medications, accounting for 29.6% of the deaths.<br><br>DISCUSSION: Integrating longitudinal, interdisciplinary PC into the care of patients with ALS is feasible, addresses needs in multiple domains, and is associated with increased rates of advance care planning. Controlled studies are needed to further elucidate the impact of PC on patients with ALS, their families, and clinicians.}, }
@article {pmid36156207, year = {2022}, author = {Sturmey, E and Malaspina, A}, title = {Blood biomarkers in ALS: challenges, applications and novel frontiers.}, journal = {Acta neurologica Scandinavica}, volume = {146}, number = {4}, pages = {375-388}, pmid = {36156207}, issn = {1600-0404}, support = {TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid ; Biomarkers ; DNA-Binding Proteins ; Humans ; *Motor Neuron Disease ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease among adults. With diagnosis reached relatively late into the disease process, extensive motor cell loss narrows the window for therapeutic opportunities. Clinical heterogeneity in ALS and the lack of disease-specific biomarkers have so far led to large-sized clinical trials with long follow-up needed to define clinical outcomes. In advanced ALS patients, there is presently limited scope to use imaging or invasive cerebrospinal fluid (CSF) collection as a source of disease biomarkers. The development of more patient-friendly and accessible blood biomarker assays is hampered by analytical hurdles like the matrix effect of blood components. However, blood also provides the opportunity to identify disease-specific adaptive changes of the stoichiometry and conformation of target proteins and the endogenous immunological response to low-abundance brain peptides, such as neurofilaments (Nf). Among those biomarkers under investigation in ALS, the change in concentration before or after diagnosis of Nf has been shown to aid prognostication and to allow the a priori stratification of ALS patients into smaller sized and clinically more homogeneous cohorts, supporting more affordable clinical trials. Here, we discuss the technical hurdles affecting reproducible and sensitive biomarker measurement in blood. We also summarize the state of the art of non-CSF biomarkers in the study of prognosis, disease progression, and treatment response. We will then address the potential as disease-specific biomarkers of the newly discovered cryptic peptides which are formed down-stream of TDP-43 loss of function, the hallmark of ALS pathobiology.}, }
@article {pmid36154605, year = {2023}, author = {Koerich, S and Parreira, GM and de Almeida, DL and Vieira, RP and de Oliveira, ACP}, title = {Receptors for Advanced Glycation End Products (RAGE): Promising Targets Aiming at the Treatment of Neurodegenerative Conditions.}, journal = {Current neuropharmacology}, volume = {21}, number = {2}, pages = {219-234}, pmid = {36154605}, issn = {1875-6190}, support = {APQ-01532-18, APQ-02559-17//FAPEMIG, Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de Minas Gerais/ ; 140585/2019-2, 310347/2018-1//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico- CNPq/ ; 001//Coordena&#xe7;&#xe3;o de Aperfeicoamento de Pessoal de Nivel Superior, Brazil (CAPES)/ ; }, mesh = {Humans ; *Alzheimer Disease ; Amyloid beta-Peptides ; Glycation End Products, Advanced/metabolism ; *Neurodegenerative Diseases ; Receptor for Advanced Glycation End Products/metabolism ; }, abstract = {Advanced glycation end products (AGEs) are compounds formed after the non-enzymatic addition of reducing sugars to lipids, proteins, and nucleic acids. They are associated with the development of various clinical complications observed in diabetes and cardiovascular diseases, such as retinopathy, nephropathy, diabetic neuropathy, and others. In addition, compelling evidence indicates that these molecules participate in the progression of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Multiple cellular and molecular alterations triggered by AGEs that could alter homeostasis have been identified. One of the main targets for AGE signaling is the receptor for advanced glycation end-products (RAGE). Importantly, this receptor is the target of not only AGEs, but also amyloid β peptides, HMGB1 (high-mobility group box-1), members of the S100 protein family, and glycosaminoglycans. The activation of this receptor induces intracellular signaling cascades that are involved in pathological processes and cell death. Therefore, RAGE represents a key target for pharmacological interventions in neurodegenerative diseases. This review will discuss the various effects of AGEs and RAGE activation in the pathophysiology of neurodegenerative diseases, as well as the currently available pharmacological tools and promising drug candidates.}, }
@article {pmid36151701, year = {2023}, author = {Paul, S and Dansithong, W and Gandelman, M and Figueroa, KP and Zu, T and Ranum, LPW and Scoles, DR and Pulst, SM}, title = {Staufen Impairs Autophagy in Neurodegeneration.}, journal = {Annals of neurology}, volume = {93}, number = {2}, pages = {398-416}, pmid = {36151701}, issn = {1531-8249}, support = {R35 NS127253/NS/NINDS NIH HHS/United States ; R37 NS033123/NS/NINDS NIH HHS/United States ; R61 NS124965/NS/NINDS NIH HHS/United States ; R01 NS097903/NS/NINDS NIH HHS/United States ; R21 NS103009/NS/NINDS NIH HHS/United States ; R21 NS081182/NS/NINDS NIH HHS/United States ; R56 NS033123/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Mice ; Animals ; C9orf72 Protein ; HEK293 Cells ; *TOR Serine-Threonine Kinases/metabolism ; *Spinocerebellar Ataxias ; Mice, Transgenic ; Autophagy ; RNA, Messenger ; Sirolimus ; Cytoskeletal Proteins/genetics ; RNA-Binding Proteins/metabolism ; }, abstract = {OBJECTIVE: The mechanistic target of rapamycin (mTOR) kinase is one of the master coordinators of cellular stress responses, regulating metabolism, autophagy, and apoptosis. We recently reported that staufen1 (STAU1), a stress granule (SG) protein, was overabundant in fibroblast cell lines from patients with spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis, frontotemporal degeneration, Huntington's, Alzheimer's, and Parkinson's diseases as well as animal models, and patient tissues. STAU1 overabundance is associated with mTOR hyperactivation and links SG formation with autophagy. Our objective was to determine the mechanism of mTOR regulation by STAU1.<br><br>METHODS: We determined STAU1 abundance with disease- and chemical-induced cellular stressors in patient cells and animal models. We also used RNA-binding assays to contextualize STAU1 interaction with MTOR mRNA.<br><br>RESULTS: STAU1 and mTOR were overabundant in bacterial artificial chromosome (BAC)-C9ORF72, ATXN2[Q127] , and Thy1-TDP-43 transgenic mouse models. Reducing STAU1 levels in these mice normalized mTOR levels and activity and autophagy-related marker proteins. We also saw increased STAU1 levels in HEK293 cells transfected to express C9ORF72-relevant dipeptide repeats (DPRs). Conversely, DPR accumulations were not observed in cells treated by STAU1 RNA interference (RNAi). Overexpression of STAU1 in HEK293 cells increased mTOR levels through direct MTOR mRNA interaction, activating downstream targets and impairing autophagic flux. Targeting mTOR by rapamycin or RNAi normalized STAU1 abundance in an SCA2 cellular model.<br><br>INTERPRETATION: STAU1 interaction with mTOR drives its hyperactivation and inhibits autophagic flux in multiple models of neurodegeneration. Staufen, therefore, constitutes a novel target to modulate mTOR activity and autophagy, and for the treatment of neurodegenerative diseases. ANN NEUROL 2023;93:398-416.}, }
@article {pmid36150722, year = {2022}, author = {Mahase, E}, title = {Motor neurone disease treatment misses primary endpoint but reports benefits within a year.}, journal = {BMJ (Clinical research ed.)}, volume = {378}, number = {}, pages = {o2301}, doi = {10.1136/bmj.o2301}, pmid = {36150722}, issn = {1756-1833}, mesh = {Humans ; *Motor Neuron Disease/therapy ; Palliative Care ; }, }
@article {pmid36148821, year = {2023}, author = {Beghi, E and Pupillo, E and Bianchi, E and Bonetto, V and Luotti, S and Pasetto, L and Bendotti, C and Tortarolo, M and Sironi, F and Camporeale, L and Sherman, AV and Paganoni, S and Scognamiglio, A and De Marchi, F and Bongioanni, P and Del Carratore, R and Caponnetto, C and Diamanti, L and Martinelli, D and Calvo, A and Filosto, M and Padovani, A and Piccinelli, SC and Ricci, C and Dalla Giacoma, S and De Angelis, N and Inghilleri, M and Spataro, R and La Bella, V and Logroscino, G and Lunetta, C and Tarlarini, C and Mandrioli, J and Martinelli, I and Simonini, C and Zucchi, E and Monsurrò, MR and Ricciardi, D and Trojsi, F and Riva, N and Filippi, M and Simone, IL and Sorarù, G and Spera, C and Florio, L and Messina, S and Russo, M and Siciliano, G and Conte, A and Saddi, MV and Carboni, N and Mazzini, L and , }, title = {Effect of RNS60 in amyotrophic lateral sclerosis: a phase II multicentre, randomized, double-blind, placebo-controlled trial.}, journal = {European journal of neurology}, volume = {30}, number = {1}, pages = {69-86}, pmid = {36148821}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Quality of Life ; *Neurodegenerative Diseases ; Double-Blind Method ; Biomarkers ; Treatment Outcome ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. RNS60 is an immunomodulatory and neuroprotective investigational product that has shown efficacy in animal models of ALS and other neurodegenerative diseases. Its administration has been safe and well tolerated in ALS subjects in previous early phase trials.<br><br>METHODS: This was a phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial. Participants diagnosed with definite, probable or probable laboratory-supported ALS were assigned to receive RNS60 or placebo administered for 24&#x2009;weeks intravenously (375&#x2009;ml) once a week and via nebulization (4 ml/day) on non-infusion days, followed by an additional 24&#x2009;weeks off-treatment. The primary objective was to measure the effects of RNS60 treatment on selected biomarkers of inflammation and neurodegeneration in peripheral blood. Secondary objectives were to measure the effect of RNS60 on functional impairment (ALS Functional Rating Scale-Revised), a measure of self-sufficiency, respiratory function (forced vital capacity, FVC), quality of life (ALS Assessment Questionnaire-40, ALSAQ-40) and survival. Tolerability and safety were assessed.<br><br>RESULTS: Seventy-four participants were assigned to RNS60 and 73 to placebo. Assessed biomarkers did not differ between arms. The mean rate of decline in FVC and the eating and drinking domain of ALSAQ-40 was slower in the RNS60 arm (FVC, difference 0.41 per week, standard error 0.16, p =&#x2009;0.0101; ALSAQ-40, difference -0.19 per week, standard error 0.10, p =&#x2009;0.0319). Adverse events were similar in the two arms. In a post hoc analysis, neurofilament light chain increased over time in bulbar onset placebo participants whilst remaining stable in those treated with RNS60.<br><br>CONCLUSIONS: The positive effects of RNS60 on selected measures of respiratory and bulbar function warrant further investigation.}, }
@article {pmid36145083, year = {2022}, author = {Folope, V and Meret, C and Castres, I and Tourny, C and Houivet, E and Grigioni, S and Lelandais, H and Petit, A and Coquard, A and Guérin, C and Quillard, M and Bôle-Feysot, C and Déchelotte, P and Achamrah, N and Coëffier, M}, title = {Evaluation of a Supervised Adapted Physical Activity Program Associated or Not with Oral Supplementation with Arginine and Leucine in Subjects with Obesity and Metabolic Syndrome: A Randomized Controlled Trial.}, journal = {Nutrients}, volume = {14}, number = {18}, pages = {}, pmid = {36145083}, issn = {2072-6643}, support = {PHRC-N 2008//Centre Hospitalier Universitaire de Rouen/ ; }, mesh = {Arginine ; Dietary Supplements ; Exercise ; Glucose ; Humans ; Leucine ; Lipids ; *Metabolic Syndrome/therapy ; Obesity/complications/therapy ; Quality of Life ; }, abstract = {Background: In patients with obesity and metabolic syndrome (MetS), lifestyle interventions combining diet, in particular, and physical exercise are recommended as the first line treatment. Previous studies have suggested that leucine or arginine supplementation may have beneficial effects on the body composition or insulin sensitivity and endothelial function, respectively. We thus conducted a randomized controlled study to evaluate the effects of a supervised adapted physical activity program associated or not with oral supplementation with leucine and arginine in MetS-complicated patients with obesity. Methods: Seventy-nine patients with obesity and MetS were randomized in four groups: patients receiving arginine and leucine supplementation (ALs group, n = 20), patients on a supervised adapted physical activity program (APA group, n = 20), patients combining ALs and APA (ALs+APA group, n = 20), and a control group (n = 19). After the baseline evaluation (m0), patients received ALs and/or followed the APA program for 6 months (m6). Body composition, MetS parameters, lipid and glucose metabolism markers, inflammatory markers, and a cardiopulmonary exercise test (CPET) were assessed at m0, m6, and after a 3-month wash-out period (m9). Results: After 6 months of intervention, we did not observe variable changes in body weight, body composition, lipid and glucose metabolism markers, inflammatory parameters, or quality of life scores between the four groups. However, during the CPET, the maximal power (Pmax and Ppeak), power, and O2 consumption at the ventilatory threshold (P(VT) and O2(VT)) were improved in the APA and ALs+APA groups (p < 0.05), as well as the forced vital capacity (FVC). Between m6 and m9, a gain in fat mass was only observed in patients in the APA and ALs+APA groups. Conclusion: In our randomized controlled trial, arginine and leucine supplementation failed to improve MetS in patients with obesity, as did the supervised adapted physical activity program and the combination of both. Only the cardiorespiratory parameters were improved by exercise training.}, }
@article {pmid36144268, year = {2022}, author = {Lanznaster, D and Dingeo, G and Samey, RA and Emond, P and Blasco, H}, title = {Metabolomics as a Crucial Tool to Develop New Therapeutic Strategies for Neurodegenerative Diseases.}, journal = {Metabolites}, volume = {12}, number = {9}, pages = {}, pmid = {36144268}, issn = {2218-1989}, support = {SLAMAIT//ARD CVL/ ; }, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's (AD), Parkinson's (PD), and amyotrophic lateral sclerosis (ALS), share common pathological mechanisms, including metabolism alterations. However, their specific neuronal cell types affected and molecular biomarkers suggest that there are both common and specific alterations regarding metabolite levels. In this review, we were interested in identifying metabolite alterations that have been reported in preclinical models of NDs and that have also been documented as altered in NDs patients. Such alterations could represent interesting targets for the development of targeted therapy. Importantly, the translation of such findings from preclinical to clinical studies is primordial for the study of possible therapeutic agents. We found that N-acetyl-aspartate (NAA), myo-inositol, and glutamate are commonly altered in the three NDs investigated here. We also found other metabolites commonly altered in both AD and PD. In this review, we discuss the studies reporting such alterations and the possible pathological mechanism underlying them. Finally, we discuss clinical trials that have attempted to develop treatments targeting such alterations. We conclude that the treatment combination of both common and differential alterations would increase the chances of patients having access to efficient treatments for each ND.}, }
@article {pmid36142514, year = {2022}, author = {Jeon, H and Kim, YJ and Hwang, SK and Seo, J and Mun, JY}, title = {Restoration of Cathepsin D Level via L-Serine Attenuates PPA-Induced Lysosomal Dysfunction in Neuronal Cells.}, journal = {International journal of molecular sciences}, volume = {23}, number = {18}, pages = {}, pmid = {36142514}, issn = {1422-0067}, support = {2022R1A2C1009376//National Research Foundation of Korea/ ; 2017R1A5A1015366//National Research Foundation of Korea/ ; 21-BR-01-03//Korea Brain Research Institute/ ; }, mesh = {*Cathepsin D/metabolism ; Humans ; Lysosomes/metabolism ; Neurons/metabolism ; *Neuroprotective Agents/metabolism/pharmacology ; Propionates/pharmacology ; Serine/metabolism/pharmacology ; }, abstract = {L-serine is a non-essential amino acid endogenously produced by astrocytes and is abundant in human diets. Beneficial roles of the metabolic products from L-serine in various conditions in the brain including neuronal development have been reported. Through several preclinical studies, L-serine treatment was also shown to offer beneficial therapeutic effects for brain damage such as ischemic stroke, amyotrophic lateral sclerosis, and Parkinson's disease. Despite evidence for the value of L-serine in the clinic, however, its beneficial effects on the propionic acid (PPA)-induced neuronal toxicity and underlying mechanisms of L-serine-mediated neuroprotection are unknown. In this study, we observed that PPA-induced acidic stress induces abnormal lipid accumulation and functional defects in lysosomes of hippocampal neurons. L-serine treatment was able to rescue the structure and function of lysosomes in PPA-treated hippocampal neuronal cells. We further identified that L-serine suppressed the formation of lipid droplets and abnormal lipid membrane accumulations inside the lysosomes in PPA-treated hippocampal neuronal cells. Taken together, these findings indicate that L-serine can be utilized as a neuroprotective agent for the functionality of lysosomes through restoration of cathepsin D in disease conditions.}, }
@article {pmid36140184, year = {2022}, author = {Proaño, B and Casani-Cubel, J and Benlloch, M and Rodriguez-Mateos, A and Navarro-Illana, E and Lajara-Romance, JM and de la Rubia Ortí, JE}, title = {Is Dutasteride a Therapeutic Alternative for Amyotrophic Lateral Sclerosis?.}, journal = {Biomedicines}, volume = {10}, number = {9}, pages = {}, pmid = {36140184}, issn = {2227-9059}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by the loss of upper and lower motor neurons (MNs) in the cerebral cortex, brainstem and spinal cord, with consequent weakness, atrophy and the progressive paralysis of all muscles. There is currently no medical cure, and riluzole and edaravone are the only two known approved drugs for treating this condition. However, they have limited efficacy, and hence there is a need to find new molecules. Dutasteride, a dual inhibitor of type 1 and type 2 5α-reductase (5AR) enzymes, the therapeutic purposes of which, to date, are the treatment of benign prostatic hyperplasia and androgenic alopecia, shows great anti-ALS properties by the molecular-topology methodology. Based on this evidence, this review aims to assess the effects of dutasteride on testosterone (T), progesterone (PROG) and 17β-estradiol (17BE) as a therapeutic alternative for the clinical improvement of ALS, based on the hormonal, metabolic and molecular pathways related to the pathogenesis of the disease. According to the evidence found, dutasteride shows great neuroprotective, antioxidant and anti-inflammatory effects. It also appears effective against glutamate toxicity, and it is capable of restoring altered dopamine activity (DA). These effects are achieved both directly and through steroid hormones. Therefore, dutasteride seems to be a promising molecule for the treatment of ALS, although clinical studies are required for confirmation.}, }
@article {pmid36139039, year = {2022}, author = {Lastres-Becker, I and de Lago, E and Martínez, A and Fernández-Ruiz, J}, title = {New Statement about NRF2 in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Biomolecules}, volume = {12}, number = {9}, pages = {}, pmid = {36139039}, issn = {2218-273X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Antioxidants ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics ; Humans ; Mice ; Mice, Transgenic ; NF-E2-Related Factor 2/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative disorders displaying substantial overlay, although there are substantial differences at the molecular level. Currently, there is no effective treatment for these diseases. The transcription factor NRF2 has been postulated as a promising therapeutic target as it is capable of modulating key pathogenic events affecting cellular homeostasis. However, there is little experimental evidence on the status of this pathway in both ALS and FTD. Therefore, in this work, we wanted to carry out an exhaustive analysis of this signaling pathway in both transgenic mouse models (ALS and FTD) and human samples from patients with sporadic ALS (sALS) versus controls. In samples from patients with sALS and in the transgenic model with overexpression of TDP-43[A315T], we observed a significant increase in the NRF2/ARE pathway in the motor cortex and the spinal cord, indicating that NRF2 antioxidant signaling was being induced, but it was not enough to reach cellular homeostasis. On the other hand, in the transgenic FTD model with overexpression of the TDP-43[WT] protein in forebrain neurons, a significantly decreased expression of NQO1 in the prefrontal cortex was seen, which cannot be attributed to alterations in the NRF2 pathway. Our results show that NRF2 signature is differently affected for ALS and FTD.}, }
@article {pmid36138349, year = {2022}, author = {Liu, G and Hrabe, J and Sanchez, R}, title = {Colostomy as a definitive treatment in an ALS patient with acute colonic Pseudo-obstruction refractory to medical management, a case report.}, journal = {BMC neurology}, volume = {22}, number = {1}, pages = {366}, pmid = {36138349}, issn = {1471-2377}, mesh = {Acute Disease ; Adult ; *Amyotrophic Lateral Sclerosis/complications/drug therapy ; *Colonic Pseudo-Obstruction/complications/drug therapy/surgery ; Colostomy/adverse effects ; Dioctyl Sulfosuccinic Acid/therapeutic use ; Erythromycin/therapeutic use ; Humans ; Male ; Metoclopramide/therapeutic use ; Neostigmine/adverse effects ; Polyethylene Glycols/therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease, and ALS patients may experience disturbed gastrointestinal motility often resulting in acute colonic pseudo-obstruction (ACPO). There is currently a paucity in the literature to guide the treatment of patients with both ALS and ACPO.<br><br>CASE PRESENTATION: Here we describe a 39-year-old male patient with advanced ALS who developed ACPO. His condition was refractory to both medical and procedural managements including polyethylene glycol, senna, and docusate suppository, metoclopramide, linaclotide, erythromycin, prucalopride, neostigmine, and repeated colonoscopies. He ultimately underwent successful colostomy for palliation. Here we report the peri-operative multidisciplinary approach taken with this case, the surgical procedures, the potential risks, and the outcome.<br><br>CONCLUSION: The patient is delighted with the result and requested publication of this case to raise awareness of constipation in ALS patients and promote the consideration of colostomy as a treatment option for patients with ileus resistant to conservative management. Ultimately, a multidisciplinary team approach is required to properly assess the risks and benefits to achieve good clinical outcomes.}, }
@article {pmid36135988, year = {2022}, author = {Tang, Q and Li, X and Wang, J}, title = {Tubulin deacetylase NDST3 modulates lysosomal acidification: Implications in neurological diseases.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {44}, number = {11}, pages = {e2200110}, pmid = {36135988}, issn = {1521-1878}, support = {R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS128494/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Disaccharides/metabolism ; *Frontotemporal Dementia/metabolism/pathology ; Hydrogen-Ion Concentration ; Lysosomes/metabolism ; Microtubules/metabolism ; Sirtuin 2/metabolism ; Sulfotransferases/metabolism ; Tubulin/metabolism ; }, abstract = {Neurological diseases (NDs), featured by progressive dysfunctions of the nervous system, have become a growing burden for the aging populations. N-Deacetylase and N-sulfotransferase 3 (NDST3) is known to catalyze deacetylation and N-sulfation on disaccharide substrates. Recently, NDST3 is identified as a novel deacetylase for tubulin, and its newly recognized role in modulating microtubule acetylation and lysosomal acidification provides fresh insights into ND therapeutic approaches using NDST3 as a target. Microtubule acetylation and lysosomal acidification have been reported to be critical for activities in neurons, implying that the regulators of these two biological processes, such as the previously known microtubule deacetylases, histone deacetylase 6 (HDAC6) and sirtuin 2 (SIRT2), could play important roles in various NDs. Aberrant NDST3 expression or tubulin acetylation has been observed in an increasing number of NDs, including amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), schizophrenia and bipolar disorder, Alzheimer's disease (AD), and Parkinson's disease (PD), suggesting that NDST3 is a key player in the pathogenesis of NDs and may serve as a target for development of new treatment of NDs.}, }
@article {pmid36134987, year = {2022}, author = {Highlander, MM and Elbasiouny, SM}, title = {Non-Invasive Transcutaneous Spinal DC Stimulation as a Neurorehabilitation ALS Therapy in Awake G93A Mice: The First Step to Clinical Translation.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {9}, number = {9}, pages = {}, pmid = {36134987}, issn = {2306-5354}, support = {AG067758/AG/NIA NIH HHS/United States ; 2000009148//National Academy of Sciences/ ; R01 AG067758/AG/NIA NIH HHS/United States ; R01 NS091836/NS/NINDS NIH HHS/United States ; NS 091836/NS/NINDS NIH HHS/United States ; }, abstract = {Spinal direct current stimulation (sDCS) modulates motoneuron (MN) excitability beyond the stimulation period, making it a potential neurorehabilitation therapy for amyotrophic lateral sclerosis (ALS), a MN degenerative disease in which MN excitability dysfunction plays a critical and complex role. Recent evidence confirms induced changes in MN excitability via measured MN electrophysiological properties in the SOD1 ALS mouse during and following invasive subcutaneous sDCS (ssDCS). The first aim of our pilot study was to determine the clinical potential of these excitability changes at symptom onset (P90-P105) in ALS via a novel non-invasive transcutaneous sDCS (tsDCS) treatment paradigm on un-anesthetized SOD1-G93A mice. The primary outcomes were motor function and survival. Unfortunately, skin damage avoidance limited the strength of applied stimulation intensity, likewise limiting measurable primary effects. The second aim of this study was to determine which orientation of stimulation (anodal vs cathodal, which are expected to have opposing effects) is beneficial vs harmful in ALS. Despite the lack of measured primary effects, strong trends in survival of the anodal stimulation group, combined with an analysis of survival variance and correlations among symptoms, suggest anodal stimulation is harmful at symptom onset. Therefore, cathodal stimulation may be beneficial at symptom onset if a higher stimulation intensity can be safely achieved via subcutaneously implanted electrodes or alternative methods. Importantly, the many logistical, physical, and stimulation parameters explored in developing this novel non-invasive treatment paradigm on unanesthetized mice provide insight into an appropriate and feasible methodology for future tsDCS study designs and potential clinical translation.}, }
@article {pmid36129856, year = {2022}, author = {Kmetzsch, V and Becker, E and Saracino, D and Rinaldi, D and Camuzat, A and Le Ber, I and Colliot, O}, title = {Disease Progression Score Estimation From Multimodal Imaging and MicroRNA Data Using Supervised Variational Autoencoders.}, journal = {IEEE journal of biomedical and health informatics}, volume = {26}, number = {12}, pages = {6024-6035}, doi = {10.1109/JBHI.2022.3208517}, pmid = {36129856}, issn = {2168-2208}, mesh = {Humans ; *MicroRNAs/genetics ; Cross-Sectional Studies ; Multimodal Imaging ; Biomarkers ; Disease Progression ; }, abstract = {Frontotemporal dementia and amyotrophic lateral sclerosis are rare neurodegenerative diseases with no effective treatment. The development of biomarkers allowing an accurate assessment of disease progression is crucial for evaluating new therapies. Concretely, neuroimaging and transcriptomic (microRNA) data have been shown useful in tracking their progression. However, no single biomarker can accurately measure progression in these complex diseases. Additionally, large samples are not available for such rare disorders. It is thus essential to develop methods that can model disease progression by combining multiple biomarkers from small samples. In this paper, we propose a new framework for computing a disease progression score (DPS) from cross-sectional multimodal data. Specifically, we introduce a supervised multimodal variational autoencoder that can infer a meaningful latent space, where latent representations are placed along a disease trajectory. A score is computed by orthogonal projections onto this path. We evaluate our framework with multiple synthetic datasets and with a real dataset containing 14 patients, 40 presymptomatic genetic mutation carriers and 37 controls from the PREV-DEMALS study. There is no ground truth for the DPS in real-world scenarios, therefore we use the area under the ROC curve (AUC) as a proxy metric. Results with the synthetic datasets support this choice, since the higher the AUC, the more accurate the predicted simulated DPS. Experiments with the real dataset demonstrate better performance in comparison with state-of-the-art approaches. The proposed framework thus leverages cross-sectional multimodal datasets with small sample sizes to objectively measure disease progression, with potential application in clinical trials.}, }
@article {pmid36123867, year = {2022}, author = {Alobaid, MA and Alshahrani, EM and Alshehri, EM and Shaiban, AS and Haralur, SB and Chaturvedi, S and Khaled Addas, M}, title = {Radiographic assessment of root canal morphology of mandibular central incisors using new classification system: A cross-sectional study.}, journal = {Medicine}, volume = {101}, number = {37}, pages = {e30751}, pmid = {36123867}, issn = {1536-5964}, mesh = {Cross-Sectional Studies ; Dental Pulp Cavity/diagnostic imaging ; Female ; Humans ; *Incisor/anatomy &amp; histology/diagnostic imaging ; Male ; Mandible/anatomy &amp; histology/diagnostic imaging ; Retrospective Studies ; Saudi Arabia ; *Tooth Root ; }, abstract = {Lack of basic knowledge about the external and internal anatomies of the root canal system and common variations in teeth may lead to various procedural errors or treatment failure. In this study, the root canal configurations of mandibular incisors and the symmetry of the contralateral incisors of Saudi Arabian subpopulations were analyzed and determined using cone beam computed tomography (CBCT). A retrospective evaluation of 700 patients was conducted, and 1260 fully developed permanent mandibular central incisors were assessed. The number of root canals was determined, and the internal root canal anatomies were categorized based on Ahmed et al.'s criteria. The CBCT images were independently evaluated by 2 trained dentists and an endodontist. The data were assessed using the chi-square and one-way analysis of variance tests. All the mandibular central incisors included in the study were single-rooted. According to Ahmed et al's classification system, the most common classification (82.6%) was 1ManA1 (Vertucci type I), followed by 1ManA1-2-1 (Vertucci type III; 13%). Second canals were more frequently recorded in the male participants than in the female participants. The root canal configuration between contralateral incisors was largely symmetrical. Most of the mandibular incisors in the examined Saudi Arabian population had a single canal. Nevertheless, a substantial number of patients had a complex root morphology. Hence, CBCT can be utilized as a potential supplementary tool during root canal treatment.}, }
@article {pmid36123619, year = {2022}, author = {McDonald, N and Kriellaars, D and Pryce, RT}, title = {Paramedic attitudes towards prehospital spinal care: a cross-sectional survey.}, journal = {BMC emergency medicine}, volume = {22}, number = {1}, pages = {162}, pmid = {36123619}, issn = {1471-227X}, mesh = {Allied Health Personnel ; Cross-Sectional Studies ; *Emergency Medical Services ; *Emergency Medical Technicians ; Humans ; Reproducibility of Results ; *Spinal Injuries ; }, abstract = {BACKGROUND: The optimal application of spinal motion restriction (SMR) in the prehospital setting continues to be debated. Few studies have examined how changing guidelines have been received and interpreted by emergency medical services (EMS) personnel. This study surveys paramedics' attitudes, observations, and self-reported practices around the treatment of potential spine injuries in the prehospital setting.<br><br>METHODS: This was a cross-sectional survey of a North American EMS agency. After development and piloting, the final version of the survey contained four sections covering attitudes towards 1) general practice, 2) specific techniques, 3) assessment protocols, and 4) mechanisms of injury (MOI). Questions used Likert-scale, multiple-choice, yes/no, and free-text responses. Exploratory factor analysis (EFA) was used to identify latent constructs within responses, and factor scores were analyzed by ordinal logistic regression for associations with demographic characteristics (including qualification level, gender, and years of experience). MOI evaluations were assessed for inter-rater reliability (Fleiss' kappa). Inductive qualitative content analysis, following Elo &amp; Kyng&#xe4;s (2008), was used to examine free-text responses.<br><br>RESULTS: Two hundred twenty responses were received (36% of staff). Raw results indicated that respondents felt that SMR was seen as less important than in the past, that they were treating fewer patients than previously, and that they follow protocol in most situations. The EFA identified two factors: one (Judging MOIs) captured paramedics' estimation that the presented MOI could potentially cause a spine injury, and another (Treatment Value) reflected respondents' composite view of the effectiveness, importance, and applicability of SMR. Respondents with advanced life support (ALS) qualification were more likely to be skeptical of the value of SMR compared to those at the basic life support (BLS) level (OR: 2.40, 95%CI: 1.21-4.76, p&#x2009;=&#x2009;0.01). Overall, respondents showed fair agreement in the evaluation of MOIs (k&#x2009;=&#x2009;0.31, 95%CI: 0.09-0.49). Content analysis identified tension expressed by respondents between SMR-as-directed and SMR-as-applied.<br><br>CONCLUSION: Results of this survey show that EMS personnel are skeptical of many elements of SMR but use various strategies to balance protocol adherence with optimizing patient care. While identifying several areas for future research, these findings argue for incorporating provider feedback and judgement into future guideline revision.}, }
@article {pmid36121037, year = {2024}, author = {Calvo, PM and Hernández, RG and Pastor, AM and de la Cruz, RR}, title = {VEGF and Neuronal Survival.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {30}, number = {1}, pages = {71-86}, doi = {10.1177/10738584221120803}, pmid = {36121037}, issn = {1089-4098}, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Motor Neurons/metabolism ; Vascular Endothelial Growth Factors/metabolism ; Disease Models, Animal ; }, abstract = {Vascular endothelial growth factor (VEGF) is well known for its angiogenic activity, but recent evidence has revealed a neuroprotective action of this factor on injured or diseased neurons. In the present review, we summarize the most relevant findings that have contributed to establish a link between VEGF deficiency and neuronal degeneration. At issue, 1) mutant mice with reduced levels of VEGF show adult-onset muscle weakness and motoneuron degeneration resembling amyotrophic lateral sclerosis (ALS), 2) administration of VEGF to different animal models of motoneuron degeneration improves motor performance and ameliorates motoneuronal degeneration, and 3) there is an association between low plasmatic levels of VEGF and human ALS. Altogether, the results presented in this review highlight VEGF as an essential motoneuron neurotrophic factor endowed with promising therapeutic potential for the treatment of motoneuron disorders.}, }
@article {pmid36120351, year = {2022}, author = {Song, Y and Jia, Q and Guan, X and Kazuo, S and Liu, J and Duan, W and Feng, L and Zhang, C and Gao, Y}, title = {Herbal medicine for amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {946548}, pmid = {36120351}, issn = {1663-9812}, abstract = {Background: The effect of herbal medicine (HM) on amyotrophic lateral sclerosis (ALS) is controversial. Clinical trials investigating HMs continue; however, the use of HM is still questioned. We aimed to systematically review the literature pertaining to the effects and safety of HM in ALS. Methods: Randomised controlled trials (RCTs) that investigated the efficacy of HMs in ALS patients compared to any types of controls were identified. Nine databases and six registers were searched from their inception dates to 25 March 2022. Per the PRISMA guidelines, trials were identified and extracted. The risk of bias was evaluated using the Cochrane's tool. Certainty of evidence was assessed as per the GRADE criteria. Forest plots were constructed to assess the effect size and corresponding 95% CIs using fixed-effect models, and random-effect models were employed when required. The primary outcome was the activity limitation measured by validated tools, such as the revised ALS Functional Rating Scale. Results: Twenty studies (N = 1,218) were eligible. Of these, only five studies were double-blinded, and two were placebo-controlled. Fourteen HMs (fifty-one single botanicals) were involved; Astragalus mongholicus Bunge, Atractylodes macrocephala Koidz., and Glycyrrhiza glabra L. were commonly used in nine, eight, and six trials, respectively. For delaying activity limitation, Jiweiling injection (MD, 2.84; 95% CI, 1.21 to 4.46; p = 0.0006) and Shenmai injection (SMD, 1.07; 0.69 to 1.45; p < 0.00001) were significantly more efficacious than Riluzole, but the evidence was low quality. For ameliorating motor neuron loss, Jiweiling injection [right abductor pollicis brevis (APB): MD, 32.42; 7.91 to 56.93; p = 0.01 and left APB: MD, 34.44; 12.85 to 56.03; p = 0.002] was favoured, but the evidence was very low quality. Nine studies reported one hundred and twenty-three adverse events, twenty-six of which occurred in the treatment groups and ninety-seven in the control groups. Conclusion: Very low to low quality of evidence suggests that HMs seem to produce superior treatment responses for ALS without increased risk of adverse events. Additional studies with homogeneous participants, reduced methodological issues, and more efficient outcome measures are required to provide confirmatory evidence. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021277443.}, }
@article {pmid36119129, year = {2022}, author = {Junghans, M and John, F and Cihankaya, H and Schliebs, D and Winklhofer, KF and Bader, V and Matschke, J and Theiss, C and Matschke, V}, title = {ROS scavengers decrease γH2ax spots in motor neuronal nuclei of ALS model mice in vitro.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {963169}, pmid = {36119129}, issn = {1662-5102}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the loss of motor neurons in cerebral cortex, brainstem and spinal cord. Numerous studies have demonstrated signs of oxidative stress in postmortem neuronal tissue, cerebrospinal fluid, plasma and urine of ALS patients, without focusing on the specific processes within motor neurons. Thus, we aimed to investigate the relevance of reactive oxygen species (ROS) detoxification mechanisms and its consequences on the formation of toxic/lethal DNA double strand breaks (DSBs) in the ALS model of the Wobbler mouse. Methods: Live cell imaging in dissociated motor neuronal cultures was used to investigate the production of ROS using Dihydroethidium (DHE). The expression levels of ROS detoxifying molecules were investigated by qPCR as well as Western blots. Furthermore, the expression levels of DNA damage response proteins p53bp1 and H2ax were investigated using qPCR and immunofluorescence staining. Proof-of-principle experiments using ROS scavengers were performed in vitro to decipher the influence of ROS on the formation of DNA double strand breaks quantifying the γH2ax spots formation. Results: Here, we verified an elevated ROS-level in spinal motor neurons of symptomatic Wobbler mice in vitro. As a result, an increased number of DNA damage response proteins p53bp1 and γH2ax in dissociated motor neurons of the spinal cord of Wobbler mice was observed. Furthermore, we found a significantly altered expression of several antioxidant molecules in the spinal cord of Wobbler mice, suggesting a deficit in ROS detoxification mechanisms. This hypothesis could be verified by using ROS scavenger molecules in vitro to reduce the number of γH2ax foci in dissociated motor neurons and thus counteract the harmful effects of ROS. Conclusion: Our data indicate that maintenance of redox homeostasis may play a key role in the therapy of the neurodegenerative disease ALS. Our results underline a necessity for multimodal treatment approaches to prolong the average lifespan of motor neurons and thus slow down the progression of the disease, since a focused intervention in one pathomechanism seems to be insufficient in ALS therapy.}, }
@article {pmid36117390, year = {2022}, author = {Thakore, NJ and Lapin, BR and Mitsumoto, H and Pooled Resource Open-Access Als Clinical Trials Consortium, }, title = {Early initiation of riluzole may improve absolute survival in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {66}, number = {6}, pages = {702-708}, pmid = {36117390}, issn = {1097-4598}, mesh = {Humans ; Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis ; *Neuroprotective Agents/therapeutic use ; Proportional Hazards Models ; Early Diagnosis ; }, abstract = {INTRODUCTION/AIMS: Riluzole improves survival in amyotrophic lateral sclerosis (ALS), but optimal time and duration of treatment are unknown. The aim of this study was to examine if timing of riluzole initiation and duration of treatment modified its effect on survival.<br><br>METHODS: Patients from the PRO-ACT dataset with information on ALS Functional Rating Scale, time from onset to enrollment (TFOE), and riluzole use were selected for analysis. Survival from enrollment was the outcome. Multivariable Cox proportional hazard models were examined for interactions between riluzole and TFOE. Inverse probability of treatment weighting (IPTW) was used to assess average treatment effect.<br><br>RESULTS: Of 4778 patients, 3446 (72.1%) had received riluzole. In unadjusted analyses, riluzole improved median survival significantly (22.6 vs. 20.2&#xa0;months, log-rank p&#x2009;<&#x2009;0.001). In multivariable analyses, no significant interaction between TFOE and riluzole was found. Riluzole effect was uniform during follow-up. By IPTW, estimated riluzole hazard ratio was 0.798 (95% confidence interval 0.686-0.927). Delaying riluzole initiation by 1&#xa0;y (6 to 18&#x2009;months from onset) may translate to reducing median survival from onset by 1.9&#xa0;months (40.1 to 38.2&#xa0;months).<br><br>DISCUSSION: Riluzole appears to reduce risk of death uniformly, regardless of time from onset to treatment, and duration of treatment. Earlier treatment with riluzole may be associated with greater absolute survival gain from onset. Early diagnosis of ALS will facilitate early treatment and is expected to improve survival.}, }
@article {pmid36113300, year = {2022}, author = {Fu, Q and Qi, T and Wu, Z and He, Y and Guan, S and Luo, S and Zhang, Q and Luo, W and Xiao, W and Situ, B and Zheng, L}, title = {A portable smartphone-based hemoglobin point-of-care testing platform for accurate anemia diagnostics.}, journal = {Biosensors &amp; bioelectronics}, volume = {217}, number = {}, pages = {114711}, doi = {10.1016/j.bios.2022.114711}, pmid = {36113300}, issn = {1873-4235}, mesh = {*Anemia/diagnosis ; *Biosensing Techniques ; Child ; Female ; Hemoglobins/analysis ; Humans ; Point-of-Care Systems ; Point-of-Care Testing ; Pregnancy ; Smartphone ; }, abstract = {Anemia affects over 2 billion people worldwide, with the heaviest burden borne by women and children. At present, anemia is diagnosed by measuring hemoglobin (Hb) levels, which must be done in hospitals or commercial laboratories by skilled operators. In this work, we report a portable, affordable ($3), easy-to-operate (1 min) and accurate smartphone-based Hb analyzer (SHbA) that uses a drop of finger-pricked blood for anemia point-of-care test (POCT) applications. POCT of Hb was achieved using a smartphone ambient light sensor (ALS) to accurately measure the absorbance of colorimetric Hb biochemical analysis reagents in a microcuvette, as well as an Android-based application for results analysis. SHbA validation results agreed well with those reported by a hematology analyzer, and the SHbA has an anemia diagnosis sensitivity of 95.4% and specificity of 96.3% for venous blood (n = 360) and a sensitivity of 96.39% and specificity of 95.58% for fingertip blood (n = 475). In addition, SHbA exhibits excellent performance in the diagnosis and treatment guidance of anemia high-risk populations, including tumor chemotherapy patients (n = 424), pregnant women (n = 214) and thalassemia patients (n = 208). Importantly, volunteer self-testing results (n = 20) indicate that SHbA can be used for home-based anemia diagnosis and monitoring. SHbA has the advantages of high sensitivity and specificity while being cheap and easy to operate, making it widely applicable for the diagnosis and treatment of anemia, especially for high-risk patients in areas with poor medical resources.}, }
@article {pmid36111771, year = {2023}, author = {Meanti, R and Bresciani, E and Rizzi, L and Coco, S and Zambelli, V and Dimitroulas, A and Molteni, L and Omeljaniuk, RJ and Locatelli, V and Torsello, A}, title = {Potential Applications for Growth Hormone Secretagogues Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Current neuropharmacology}, volume = {21}, number = {12}, pages = {2376-2394}, pmid = {36111771}, issn = {1875-6190}, mesh = {Humans ; *Ghrelin/therapeutic use/metabolism ; Receptors, Ghrelin/physiology ; *Amyotrophic Lateral Sclerosis/drug therapy ; Secretagogues ; Growth Hormone/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) arises from neuronal death due to complex interactions of genetic, molecular, and environmental factors. Currently, only two drugs, riluzole and edaravone, have been approved to slow the progression of this disease. However, ghrelin and other ligands of the GHS-R1a receptor have demonstrated interesting neuroprotective activities that could be exploited in this pathology. Ghrelin, a 28-amino acid hormone, primarily synthesized and secreted by oxyntic cells in the stomach wall, binds to the pituitary GHS-R1a and stimulates GH secretion; in addition, ghrelin is endowed with multiple extra endocrine bioactivities. Native ghrelin requires esterification with octanoic acid for binding to the GHS-R1a receptor; however, this esterified form is very labile and represents less than 10% of circulating ghrelin. A large number of synthetic compounds, the growth hormone secretagogues (GHS) encompassing short peptides, peptoids, and non-peptidic moieties, are capable of mimicking several biological activities of ghrelin, including stimulation of GH release, appetite, and elevation of blood IGF-I levels. GHS have demonstrated neuroprotective and anticonvulsant effects in experimental models of pathologies both in vitro and in vivo. To illustrate, some GHS, currently under evaluation by regulatory agencies for the treatment of human cachexia, have a good safety profile and are safe for human use. Collectively, evidence suggests that ghrelin and cognate GHS may constitute potential therapies for ALS.}, }
@article {pmid36106861, year = {2023}, author = {Li, X and Armon, C and Barkhaus, P and Barnes, B and Benatar, M and Bertorini, T and Bromberg, M and Carter, GT and Crayle, J and Cudkowicz, M and Dimachkie, M and Feldman, EL and Glass, J and Goslinga, J and Heiman-Patterson, T and Jhooty, S and Lichtenstein, R and Lund, I and Mcdermott, C and Pattee, G and Pierce, K and Ratner, D and Salmon, K and Wicks, P and Bedlack, R}, title = {ALSUntangled #67: rituximab.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {544-547}, doi = {10.1080/21678421.2022.2122845}, pmid = {36106861}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Off-Label Use ; *Rituximab/therapeutic use ; }, abstract = {ALSUntangled reviews alternative and off-label treatments on behalf of people with ALS who ask about them. Here we review rituximab, a drug which specifically depletes B lymphocytes. We show a current lack of evidence for a role of these cells in ALS progression. The one patient we found who described using Rituximab for their ALS found no benefit. Given all this, and the known serious risks of rituximab, we advise against its use as an ALS treatment.}, }
@article {pmid36106817, year = {2023}, author = {Salomon-Zimri, S and Pushett, A and Russek-Blum, N and Van Eijk, RPA and Birman, N and Abramovich, B and Eitan, E and Elgrart, K and Beaulieu, D and Ennist, DL and Berry, JD and Paganoni, S and Shefner, JM and Drory, VE}, title = {Combination of ciprofloxacin/celecoxib as a novel therapeutic strategy for ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {3-4}, pages = {263-271}, doi = {10.1080/21678421.2022.2119868}, pmid = {36106817}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Biomarkers ; Celecoxib/therapeutic use ; *COVID-19 ; Disease Progression ; DNA-Binding Proteins ; Double-Blind Method ; *Neurodegenerative Diseases ; Ciprofloxacin/therapeutic use ; }, abstract = {OBJECTIVE: This study aimed to evaluate the safety and tolerability of a fixed-dose co-formulation of ciprofloxacin and celecoxib (PrimeC) in patients with amyotrophic lateral sclerosis (ALS), and to examine its effects on disease progression and ALS-related biomarkers.<br><br>METHODS: In this proof of concept, open-label, phase IIa study of PrimeC in 15 patients with ALS, participants were administered PrimeC thrice daily for 12 months. The primary endpoints were safety and tolerability. Exploratory endpoints included disease progression outcomes such as forced vital capacity, revised ALS functional rating scale, and effect on algorithm-predicted survival. In addition, indications of a biological effect were assessed by selected biomarker analyses, including TDP-43 and LC3 levels in neuron-derived exosomes (NDEs), and serum neurofilaments.<br><br>RESULTS: Four participants experienced adverse events (AEs) related to the study drug. None of these AEs were unexpected, and most were mild or moderate (69%). Additionally, no serious AEs were related to the study drug. One participant tested positive for COVID-19 and recovered without complications, and no other abnormal laboratory investigations were found. Participants' survival compared to their predictions showed no safety concerns. Biomarker analyses demonstrated significant changes associated with PrimeC in neural-derived exosomal TDP-43 levels and levels of LC3, a key autophagy marker.<br><br>INTERPRETATION: This study supports the safety and tolerability of PrimeC in ALS. Biomarker analyses suggest early evidence of a biological effect. A placebo-controlled trial is required to disentangle the biomarker results from natural progression and to evaluate the efficacy of PrimeC for the treatment of ALS. Summary for social media if publishedTwitter handles: @NeurosenseT, @ShiranZimri&#x2022;What is the current knowledge on the topic? ALS is a severe neurodegenerative disease, causing death within 2-5 years from diagnosis. To date there is no effective treatment to halt or significantly delay disease progression.&#x2022;What question did this study address? This study assessed the safety, tolerability and exploratory efficacy of PrimeC, a fixed dose co-formulation of ciprofloxacin and celecoxib in the ALS population.&#x2022;What does this study add to our knowledge? This study supports the safety and tolerability of PrimeC in ALS, and exploratory biomarker analyses suggest early insight for disease related-alteration.&#x2022;How might this potentially impact the practice of neurology? These results set the stage for a larger, placebo-controlled study to examine the efficacy of PrimeC, with the potential to become a new drug candidate for ALS.}, }
@article {pmid36105357, year = {2022}, author = {Amorós, MA and Choi, ES and Cofré, AR and Dokholyan, NV and Duzzioni, M}, title = {Motor neuron-derived induced pluripotent stem cells as a drug screening platform for amyotrophic lateral sclerosis.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {962881}, pmid = {36105357}, issn = {2296-634X}, support = {R35 GM134864/GM/NIGMS NIH HHS/United States ; }, abstract = {The development of cell culture models that recapitulate the etiology and features of nervous system diseases is central to the discovery of new drugs and their translation onto therapies. Neuronal tissues are inaccessible due to skeletal constraints and the invasiveness of the procedure to obtain them. Thus, the emergence of induced pluripotent stem cell (iPSC) technology offers the opportunity to model different neuronal pathologies. Our focus centers on iPSCs derived from amyotrophic lateral sclerosis (ALS) patients, whose pathology remains in urgent need of new drugs and treatment. In this sense, we aim to revise the process to obtain motor neurons derived iPSCs (iPSC-MNs) from patients with ALS as a drug screening model, review current 3D-models and offer a perspective on bioinformatics as a powerful tool that can aid in the progress of finding new pharmacological treatments.}, }
@article {pmid36105066, year = {2022}, author = {Liu, J and Zhou, F and Chen, Y and Guan, Y and Meng, F and Zhao, Z and Wang, X and Gao, X and Jiang, X and Zhang, H and Wang, Q and Zhou, S and Wang, X}, title = {Wnt5a protects motor neurons in amyotrophic lateral sclerosis by regulating the Wnt/Ca[2+] signaling pathway.}, journal = {American journal of translational research}, volume = {14}, number = {8}, pages = {5343-5362}, pmid = {36105066}, issn = {1943-8141}, abstract = {OBJECTIVES: We aimed to detect the expression profile of downstream signaling molecules of non-canonical Wnt pathway in SOD1[G93A] transgenic mice (ALS mice) and SOD1[G93A] mutant motor neuron-like hybrid (NSC-34) cells. Characterizing the molecular mechanism of the Wnt5a-mediated non-canonical Wnt/Ca[2+] signaling pathway in motor neuron (MN) degeneration may provide a feasible approach to effective treatment of amyotrophic lateral sclerosis (ALS).<br><br>METHODS: The expressions of CaMKII-&#x3b1;, CaMKII-&#x3b2; and TAK1 in the spinal cord of SOD1[G93A] ALS transgenic mice at different ages were determined using western blotting and immunofluorescence. The level of Ca[2+] and cell apoptosis were assessed with flow cytometry and cell viability was evaluated using MTS assay. Cell proliferation was analyzed by the EdU cell proliferation assay. Neurite length was measured after treatment with retinoic acid.<br><br>RESULTS: CaMKII-&#x3b1;, CaMKII-&#x3b2;, and TAK1 were down-regulated in the spinal cord of ALS mice. Ca[2+] level and CaMKII-&#x3b1;, CaMKII-&#x3b2;, and TAK1 were down-regulated in SOD1[G93A] mutant NSC-34 cells. Expression of Ca[2+], CaMKII-&#x3b1;, CaMKII-&#x3b2;, and TAK1 were up-regulated in SOD1[G93A] mutant NSC-34 cells after Wnt5a overexpression and down-regulated after Wnt5a knockdown. Overexpression of Wnt5a promoted cell viability and proliferation but inhibited cell apoptosis. Contrastingly, Wnt5a knockdown inhibited cell viability and proliferation but promoted cell apoptosis. CaMKII inhibitor KN-93 and CaMKII activator oleic acid reversed changes in cell viability, proliferation, apoptosis, and neurite outgrowth induced by Wnt5a overexpression and knockdown.<br><br>CONCLUSIONS: This study demonstrates that Wnt5a protects MNs in ALS by regulating cell viability, proliferation, apoptosis, and neurite growth through the Wnt/Ca[2+] signaling pathway. Our data indicate that the non-canonical Wnt/Ca[2+] signaling pathway regulated by Wnt5a is involved in MN degeneration in ALS.}, }
@article {pmid36100788, year = {2022}, author = {Singh, S and Hema,  and Sharma, N and Sachdeva, M and Behl, T and Zahoor, I and Fuloria, NK and Sekar, M and Fuloria, S and Subramaniyan, V and Alsubayiel, AM and Dailah, HG and Naved, T and Bhatia, S and Al-Harrasi, A and Aleya, L}, title = {Focusing the pivotal role of nanotechnology in Huntington's disease: an insight into the recent advancements.}, journal = {Environmental science and pollution research international}, volume = {29}, number = {49}, pages = {73809-73827}, pmid = {36100788}, issn = {1614-7499}, mesh = {Glutamine ; Humans ; *Huntington Disease/genetics/metabolism/pathology ; Liposomes ; Nanoparticles ; Nanotechnology ; }, abstract = {Neurodegeneration is the loss of neuronal capacity and structure over time which causes neurodegenerative disorders like Alzheimer, amyotrophic lateral sclerosis, Parkinson, and Huntington's disease (HD). This review is primarily concerned with HD, which was fully described by George Huntington in 1872. In developed countries, HD has become another common single-gene neurological disorder. Because of its autosomal dominant inheritance, the sickness affects both individuals and their families. Huntington disease has been recognized as a disorder that affects the complete body and brain in which the mutant huntingtin polyglutamine (polyQ) sequence is extensively increased and gets correlated to CAG trinucleotide which codes for glutamine (Q). These proteins have characteristics that produce apoptosis and dysfunction. HD is a lethal condition which needs an immediate diagnosis and treatment, and therefore, nanoparticle has come into sight out as opportunistic strategies for treatment of HD. Nanostructures have great potential to cross the blood brain barrier and also prevent breakdown of active molecule and reduces the drug toxicity. This review explains the distinguishing symptoms, genetics, and stages during the development of Huntington's disease, and also provides an overview of HD with an emphasis on its epidemiology, pathogenesis, and management. This review focuses on the latest studies on nanotechnology-related technologies, i.e., magnetic nanoparticle, solid lipid nanoparticle, and polymeric nanoparticle for Huntington's disease treatment. The pioneering patents and in-progress clinical trials related to Huntington's disease has also been summarized in this review.}, }
@article {pmid36100191, year = {2022}, author = {Pallier, PN and Ferrara, M and Romagnolo, F and Ferretti, MT and Soreq, H and Cerase, A}, title = {Chromosomal and environmental contributions to sex differences in the vulnerability to neurological and neuropsychiatric disorders: Implications for therapeutic interventions.}, journal = {Progress in neurobiology}, volume = {219}, number = {}, pages = {102353}, doi = {10.1016/j.pneurobio.2022.102353}, pmid = {36100191}, issn = {1873-5118}, mesh = {Animals ; Female ; Male ; Sex Factors ; Sex Characteristics ; *Schizophrenia ; *Brain Diseases ; *Autism Spectrum Disorder ; }, abstract = {Neurological and neuropsychiatric disorders affect men and women differently. Multiple sclerosis, Alzheimer's disease, anxiety disorders, depression, meningiomas and late-onset schizophrenia affect women more frequently than men. By contrast, Parkinson's disease, autism spectrum condition, attention-deficit hyperactivity disorder, Tourette's syndrome, amyotrophic lateral sclerosis and early-onset schizophrenia are more prevalent in men. Women have been historically under-recruited or excluded from clinical trials, and most basic research uses male rodent cells or animals as disease models, rarely studying both sexes and factoring sex as a potential source of variation, resulting in a poor understanding of the underlying biological reasons for sex and gender differences in the development of such diseases. Putative pathophysiological contributors include hormones and epigenetics regulators but additional biological and non-biological influences may be at play. We review here the evidence for the underpinning role of the sex chromosome complement, X chromosome inactivation, and environmental and epigenetic regulators in sex differences in the vulnerability to brain disease. We conclude that there is a pressing need for a better understanding of the genetic, epigenetic and environmental mechanisms sustaining sex differences in such diseases, which is critical for developing a precision medicine approach based on sex-tailored prevention and treatment.}, }
@article {pmid36096745, year = {2023}, author = {Krawczyk, P and Huras, H and Jaworowski, A and Tyszecki, P and Kołak, M}, title = {Cesarean section complicated with presumed massive pulmonary embolism and cardiac arrest treated with rescue thrombolytic therapy-two case reports.}, journal = {Annals of palliative medicine}, volume = {12}, number = {1}, pages = {219-226}, doi = {10.21037/apm-22-435}, pmid = {36096745}, issn = {2224-5839}, abstract = {BACKGROUND: Massive pulmonary embolus (PE), resulting in cardiac arrest during pregnancy and postpartum, is a rare but potentially catastrophic event. The most severe manifestation of massive PE is cardiovascular instability, including cardiogenic shock and cardiac arrest requiring intensive care unit (ICU) admissions. Up to 23% of high-risk PE pregnant and postpartum patients experience cardiac arrest.<br><br>CASE DESCRIPTION: Case 1, a 34-year-old obese patient, with a twin pregnancy, had cesarean sections in the 24th week of pregnancy due to premature abruption of the placenta. Immediately after the birth, she experienced a sudden cardiac arrest. Treatment was initiated in line with antimicrobial lock solutions (ALS), heparine and alteplase was administered due to suspected massive pulmonary embolism. After 20 minutes from return of spontaneous circulation (ROSC), the uterine atony and severe hemorrhage occurred, and a postpartum hysterectomy was performed. The mother and two daughters are alive in 2021. Case 2, a 24-year-old obese patient had a cesarean section due to abruption of the placenta in the 28th week of pregnancy. Twelve hours after cesarean delivery, the patient's condition suddenly deteriorated. The patient reported dyspnea, chest pain, and presented cyanosis. The blood pressure was 66/30 mmHg, heart rate 130/min, tachypnea with a respiratory rate of 30/min, saturation 80% on air. High flow oxygen via face mask with reservoir (FiO2 0.85) and ephedrine 2&#xd7;10 mg i.v. were administered. Due to suspected pulmonary embolism, a bolus of 5,000 IU of heparin was administered iv. Despite the implemented measures, cardiac arrest was confirmed with the initial rhythm of pulseless electrical activity (PEA) (sinus tachycardia 120/min). Treatment consistent with ALS was initiated. Due to the high probability of pulmonary embolism, a bolus of alteplase was administrated. ROSC was obtained 7 minutes later. Because of obstetric hemorrhage hysterectomy was performed. The mother and the baby are alive in 2022.<br><br>CONCLUSIONS: In light of current evidence, presented data suggest that early and aggressive recombinant thrombolytic use in case of cardiac arrest and suspected PE in obstetric patients may be life-saving, effective treatment with a good neurological outcome. Major bleeding complications should be anticipated when administering this therapy.}, }
@article {pmid36089786, year = {2022}, author = {Tsagkaris, C and Bilal, M and Aktar, I and Aboufandi, Y and Tas, A and Aborode, AT and Suvvari, TK and Ahmad, S and Shkodina, A and Phadke, R and Emhamed, MS and Baig, AA and Alexiou, A and Ashraf, GM and Kamal, MA}, title = {Cytokine Storm and Neuropathological Alterations in Patients with Neurological Manifestations of COVID-19.}, journal = {Current Alzheimer research}, volume = {19}, number = {9}, pages = {641-657}, pmid = {36089786}, issn = {1875-5828}, abstract = {The COVID-19 pandemic is caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), a respiratory pathogen with neuroinvasive potential. Neurological COVID-19 manifestations include loss of smell and taste, headache, dizziness, stroke, and potentially fatal encephalitis. Several studies found elevated proinflammatory cytokines, such as TNF-α, IFN-γ, IL-6 IL-8, IL- 10 IL-16, IL-17A, and IL-18 in severely and critically ill COVID-19 patients may persist even after apparent recovery from infection. Biomarker studies on CSF and plasma and serum from COVID-19 patients have also shown a high level of IL-6, intrathecal IgG, neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and tau protein. Emerging evidence on the matter has established the concept of COVID-19-associated neuroinflammation, in the context of COVID-19-associated cytokine storm. While the short-term implications of this condition are extensively documented, its longterm implications are yet to be understood. The association of the aforementioned cytokines with the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, may increase COVID-19 patients' risk of developing neurodegenerative diseases. Analysis of proinflammatory cytokines and CSF biomarkers in patients with COVID-19 can contribute to the early detection of the disease's exacerbation, monitoring the neurological implications of the disease and devising risk scales, and identifying treatment targets.}, }
@article {pmid36089326, year = {2022}, author = {Omidikia, N}, title = {The effect of multilinear data fusion on the accuracy of multivariate curve resolution outputs.}, journal = {Analytica chimica acta}, volume = {1227}, number = {}, pages = {340325}, doi = {10.1016/j.aca.2022.340325}, pmid = {36089326}, issn = {1873-4324}, abstract = {Vast evolution in the analytical instruments (e.g. Chemical imaging) makes higher-order data recording more facile. Such sophisticated data acquisition schemes, definitely call for updated data treatment tools. In this way, chemometrics has a decisive role in the analytical chemistry area not only to analyze, but also to expect such data generation possibilities, e.g. combining data coming from instruments with different orders. "Partial trilinearity constraint" is specially planned to cope with differences in bi-and-trilinear models. In this research, we tried to shed light on the accuracy of the mixed multilinear multimodal analysis under partial trilinearity constraint and its conjugation with force-to-zero constraint. For this, several numerical and real experiments are designed by changing the number of components in each block. Finally, some practical guidelines are provided for the analytical chemists.}, }
@article {pmid36083004, year = {2022}, author = {Fels, JA and Dash, J and Leslie, K and Manfredi, G and Kawamata, H}, title = {Effects of PB-TURSO on the transcriptional and metabolic landscape of sporadic ALS fibroblasts.}, journal = {Annals of clinical and translational neurology}, volume = {9}, number = {10}, pages = {1551-1564}, pmid = {36083004}, issn = {2328-9503}, support = {R21 NS104520/NS/NINDS NIH HHS/United States ; R35 NS122209/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Drugs, Investigational ; Fibroblasts/metabolism ; Humans ; RNA ; Taurochenodeoxycholic Acid ; }, abstract = {OBJECTIVE: ALS is a rapidly progressive, fatal disorder caused by motor neuron degeneration, for which there is a great unmet therapeutic need. AMX0035, a combination of sodium phenylbutyrate (PB) and taurursodiol (TUDCA, TURSO), has shown promising results in early ALS clinical trials, but its mechanisms of action remain to be elucidated. Therefore, our goal was to obtain an unbiased landscape of the molecular effects of AMX0035 in ALS patient-derived cells.<br><br>METHODS: We investigated the transcriptomic and metabolomic profiles of primary skin fibroblasts from sporadic ALS patients and healthy controls (n&#x2009;=&#x2009;12/group) treated with PB, TUDCA, or PB-TUDCA combination (Combo). Data were evaluated with multiple approaches including differential gene expression and metabolite abundance, Gene Ontology and metabolic pathway analysis, weighted gene co-expression correlation analysis (WGCNA), and combined multiomics integrated analysis.<br><br>RESULTS: Combo changed many more genes and metabolites than either PB or TUDCA individually. Most changes were unique to Combo and affected the expression of genes involved in nucleocytoplasmic transport, unfolded protein response, mitochondrial function, RNA metabolism, and innate immunity. WGCNA showed significant correlations between ALS gene expression modules and clinical parameters that were abolished by Combo treatment.<br><br>INTERPRETATION: This study is the first to explore the molecular effects of Combo in ALS patient-derived cells. It shows that Combo has a greater and distinct impact compared with the individual compounds and provides clues to drug targets and mechanisms of action, which may underlie the benefits of this investigational drug combination.}, }
@article {pmid36068922, year = {2022}, author = {Xu, Y and Cen, P and Ma, L and Tian, M and Zhang, X and Zhang, Q and Yu, K and Zhang, H and Gu, W and He, Q}, title = {Highly Efficient Radiosynthesis and Biological Evaluation of [[18] F]Safinamide, a Radiolabelled Anti-Parkinsonian Drug for Positron Emission Tomography Imaging.}, journal = {ChemMedChem}, volume = {17}, number = {20}, pages = {e202200472}, doi = {10.1002/cmdc.202200472}, pmid = {36068922}, issn = {1860-7187}, mesh = {Animals ; Rats ; Tissue Distribution ; Fluorides ; Fluorine ; Tetraethylammonium ; *Brain Ischemia ; Rats, Sprague-Dawley ; *Stroke ; Positron-Emission Tomography/methods ; Fluorine Radioisotopes ; Monoamine Oxidase ; Glutamates ; Sodium ; Potassium Channels ; }, abstract = {As an add-on drug approved for Parkinson's disease treatment, safinamide has multiple functions, such as selective and reversible monoamine oxidase-B inhibition, voltage-sensitive sodium/potassium channel blockage, and glutamate release inhibition. Meanwhile, safinamide shows tremendous therapeutic potential in the context of other central nervous system diseases (e. g. ischaemic stroke, amyotrophic lateral sclerosis, depression, etc.). In this work, [[18] F]safinamide, which is safinamide labelled by the positron-emitting radionuclide [[18] F]fluorine, was synthesized automatically based on iodonium ylide precursors with high radiochemical yield and high molar activity. Density functional theory was applied to calculate the Gibbs free energy change during iodonium ylide-mediated fluorination and to interpret the effect of tetraethylammonium (TEA[+]) as the counter cation in these reactions to improve the nucleophilicity of [[18] F/[19] F]fluoride. In addition, positron emission tomography studies on Sprague Dawley rats were carried out to determine the imaging characteristics, pharmacokinetics, and metabolism of the [[18] F]safinamide radiotracer. The results displayed the complete biodistribution of the radiotracer, especially in rat brains, and revealed that [[18] F]safinamide has moderate brain uptake, rapid and reversible binding kinetics, and good stability.}, }
@article {pmid36057844, year = {2022}, author = {Li, J and Li, J and Wang, H and Chen, Y and Qin, J and Zeng, H and Wang, K and Wang, S}, title = {Microscopic Raman illustrating antitumor enhancement effects by the combination drugs of γ-secretase inhibitor and cisplatin on osteosarcoma cells.}, journal = {Journal of biophotonics}, volume = {15}, number = {12}, pages = {e202200189}, doi = {10.1002/jbio.202200189}, pmid = {36057844}, issn = {1864-0648}, mesh = {Humans ; Amyloid Precursor Protein Secretases ; *Bone Neoplasms/drug therapy/pathology ; Cisplatin/pharmacology/therapeutic use ; *Osteosarcoma/drug therapy/pathology ; Platelet Aggregation Inhibitors/therapeutic use ; Antinematodal Agents/therapeutic use ; }, abstract = {By using Raman microspectroscopy, it aims to elucidate the cellular variations caused by the combination drug of γ-secretase inhibitor (DAPT) and cisplatin in osteosarcoma (OS) cells. Illustrated by the obtained results of spectral analysis, the intracellular composition significantly changed after combined drug actions compared to the solo DAPT treatment, indicating the synergistic effect of DAPT combined with cisplatin on OS cells. Meanwhile, multivariate curve resolution-alternating least squares (MCR-ALS) algorithm was utilized to address the biochemical constitution changes in all investigated groups including the untreated (UT), DAPT (40D) and combined drug (40D + 20C) treated cells. K-means cluster and univariate imaging were both utilized to visualize the changes in subcellular morphology and biochemical distribution. The presented study provides a unique understanding on the cellular responses to DAPT combined with cisplatin from the natural biochemical perspectives, and laids an experimental foundation for exploring the therapeutic strategies of other combined anticancer drugs in cancer cell model.}, }
@article {pmid36054038, year = {2022}, author = {Takahashi, F and Kano, O and Nagano, Y and Yoneoka, T and Nelson, S and Ushirogawa, Y}, title = {Associations between urate levels and amyotrophic lateral sclerosis functional score with edaravone treatment: Post hoc analysis of studies MCI186-16, MCI186-17, and MCI186-19.}, journal = {Muscle &amp; nerve}, volume = {66}, number = {5}, pages = {583-592}, doi = {10.1002/mus.27699}, pmid = {36054038}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Disease Progression ; *Edaravone/therapeutic use ; Free Radical Scavengers/therapeutic use ; *Uric Acid/blood ; Double-Blind Method ; Clinical Trials, Phase III as Topic ; }, abstract = {INTRODUCTION/AIMS: Edaravone in amyotrophic lateral sclerosis (ALS) was analyzed in two phase 3 studies (MCI186-16 and MCI186-19). Those trials enrolled patients with Japanese ALS severity grades 1 and 2 (less severe ALS), but many patients progressed to grades 3 and 4 during the double-blind treatment period. The placebo patients who initiated edaravone treatment in the open-label periods provided an opportunity to assess the effects of edaravone in more severe ALS. This study also assessed the association between ALS Functional Rating Scale-Revised (ALSFRS-R) slope and biomarker changes after open-label edaravone initiation.<br><br>METHODS: Change in ALSFRS-R slope in placebo patients before and after initiating edaravone treatment was assessed using the random coefficient model. The association of ALSFRS-R change and blood marker changes was explored by the least absolute shrinkage and selection operator (LASSO) method of machine learning.<br><br>RESULTS: Twenty-four percent of patients (35/146) in the placebo-edaravone group showed &#x2265;25% slowing of decline in the ALSFRS-R slope. Within the 25% slower-decline group, 60% (21/35) had Japanese ALS severity grades 3 or 4 at the start of edaravone treatment. The LASSO model identified serum urate as associated with the percentage change in ALSFRS-R slope. The rate of decrease in urate was smaller in the 25% slower-decline group than in the non-25% slower-decline group during edaravone treatment.<br><br>DISCUSSION: This post hoc analysis indicated that ALS patients, including those with advanced ALS severity grades, may receive benefit in the group of patients whose urate levels are stable during the course of the edaravone treatment.}, }
@article {pmid36053970, year = {2022}, author = {Takahashi, F and Kano, O and Nagano, Y and Yoneoka, T and Nelson, S and Ushirogawa, Y}, title = {Associations between the ALSFRS-R score and urate levels during 12 months of edaravone treatment for amyotrophic lateral sclerosis: Post hoc analysis of ALSFRS-R scores in clinical studies MCI186-16, MCI186-17, and MCI186-19.}, journal = {Muscle &amp; nerve}, volume = {66}, number = {5}, pages = {593-602}, doi = {10.1002/mus.27700}, pmid = {36053970}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Disease Progression ; Edaravone/therapeutic use ; Free Radical Scavengers/therapeutic use ; Uric Acid ; Clinical Trials as Topic ; }, abstract = {INTRODUCTION/AIMS: In this study we examined the relationship between urate levels at baseline and functional change measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score after edaravone treatment.<br><br>METHODS: Data from the edaravone trials MCI186-16, MCI186-17, and MCI186-19 were analyzed, including the following treatment sequence groups: edaravone-edaravone (EE, n&#xa0;=&#xa0;113); edaravone-placebo (EP, n&#xa0;=&#xa0;45); and placebo-edaravone (PE, n&#xa0;=&#xa0;146). Subgroups were defined as low baseline urate (below the median value of 4.8&#xa0;mg/dL) and high baseline urate (&#x2265;4.8&#xa0;mg/dL). The differences in ALSFRS-R total score change and urate change were evaluated using the mixed model for repeated measurement for overall population, by urate-level subgroup, and by trial.<br><br>RESULTS: Compared with the PE group, the EE group showed a slower decline in ALSFRS-R score, regardless of the urate baseline level, and a slower decline in urate level in the higher baseline urate subgroup. Smaller changes in ALSFRS-R score and urate were observed in patients diagnosed with "probable, laboratory-supported ALS." There was a positive correlation between changes from baseline to cycle 12 in urate levels and ALSFRS-R score.<br><br>DISCUSSION: Edaravone treatment in ALS patients diagnosed with "definite ALS" or "probable ALS" showed slowing of disease progression, regardless of baseline urate level. In addition, because edaravone treatment was associated with a slower decline in urate level in the higher baseline urate subgroup and urate-level changes were associated with changes in ALSFRS-R score, urate level, and/or change may be one indicator in predicting disease progression after edaravone administration.}, }
@article {pmid36049647, year = {2025}, author = {Boll, MC and Alcaraz-Zubeldia, M and Rios, C and González-Esquivel, D and Montes, S}, title = {A phase 2, double-blind, placebo-controlled trial of a valproate/lithium combination in ALS patients.}, journal = {Neurologia}, volume = {40}, number = {1}, pages = {32-40}, doi = {10.1016/j.nrleng.2022.07.003}, pmid = {36049647}, issn = {2173-5808}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Valproic Acid/therapeutic use ; Double-Blind Method ; Male ; Female ; Middle Aged ; Aged ; Lithium Carbonate/therapeutic use ; Drug Therapy, Combination ; Treatment Outcome ; Quality of Life ; Adult ; Disease Progression ; }, abstract = {BACKGROUND: Few treatments are currently available for amyotrophic lateral sclerosis (ALS). A combination of lithium carbonate and valproic acid (VPA-Li) was shown to inhibit motor neuron death and delay disease progression.<br><br>METHODS: Outpatients with a typical ALS presentation were enrolled in a randomized, placebo-controlled trial to assess the efficacy of orally administered VPA-Li. Changes in a functional scale score (ALSFRS-R) and survival rate were chosen as primary outcome variables. Secondary outcome variables included BMI, respiratory monitoring, quality of life, and a global impression of the treatment.<br><br>RESULTS: Out of 42 patients enrolled, 20 individuals receiving VPA-Li and 18 on placebo treatment were included in the final analysis. Forty-five percent of patients receiving VPA-Li completed the trial, whereas only 22.22% of patients in the placebo group attended the final visit 18 months later (P = 0.09). Major changes in the ALSFRS-R score were observed, including a decrease of 1.195 points/month in the placebo group (95% CI: 0.7869-1.6031) and of 0.5085 under VPA-Li treatment (95% CI: 0.2288-0.7882) between months 6 and 14. Adverse events included bad mouth taste, constipation, and anorexia. Survival rate, body weight, and quality of life were positive outcomes by the end of the trial despite a high sample reduction, especially in the placebo group. The inclusion of 212 subjects in each group would confirm these differences.<br><br>CONCLUSIONS: Combined VPA-Li treatment associated with slower ALS progression and better secondary outcomes. This dual treatment overcame the futility threshold and merits further investigation in ALS.}, }
@article {pmid36048877, year = {2022}, author = {Latham, BD and Oskin, DS and Crouch, RD and Vergne, MJ and Jackson, KD}, title = {Cytochromes P450 2C8 and 3A Catalyze the Metabolic Activation of the Tyrosine Kinase Inhibitor Masitinib.}, journal = {Chemical research in toxicology}, volume = {35}, number = {9}, pages = {1467-1481}, pmid = {36048877}, issn = {1520-5010}, support = {R35 GM143044/GM/NIGMS NIH HHS/United States ; }, mesh = {Activation, Metabolic ; Benzamides ; *COVID-19 ; Catalysis ; Cytochrome P-450 Enzyme System/metabolism ; Humans ; Microsomes, Liver/metabolism ; NADP/metabolism ; Piperidines ; Potassium Cyanide ; Protein Kinase Inhibitors/metabolism/pharmacology ; Pyridines ; Thiazoles ; }, abstract = {Masitinib is a small molecule tyrosine kinase inhibitor under investigation for the treatment of amyotrophic lateral sclerosis, mastocytosis, and COVID-19. Hepatotoxicity has been reported in some patients while taking masitinib. The liver injury is thought to involve hepatic metabolism of masitinib by cytochrome P450 (P450) enzymes to form chemically reactive, potentially toxic metabolites. The goal of the current investigation was to determine the P450 enzymes involved in the metabolic activation of masitinib in vitro. In initial studies, masitinib (30 μM) was incubated with pooled human liver microsomes in the presence of NADPH and potassium cyanide to trap reactive iminium ion metabolites as cyano adducts. Masitinib metabolites and cyano adducts were analyzed using reversed-phase liquid chromatography-tandem mass spectrometry. The primary active metabolite, N-desmethyl masitinib (M485), and several oxygenated metabolites were detected along with four reactive metabolite cyano adducts (MCN510, MCN524, MCN526, and MCN538). To determine which P450 enzymes were involved in metabolite formation, reaction phenotyping experiments were conducted by incubation of masitinib (2 μM) with a panel of recombinant human P450 enzymes and by incubation of masitinib with human liver microsomes in the presence of P450-selective chemical inhibitors. In addition, enzyme kinetic assays were conducted to determine the relative kinetic parameters (apparent Km and Vmax) of masitinib metabolism and cyano adduct formation. Integrated analysis of the results from these experiments indicates that masitinib metabolic activation is catalyzed primarily by P450 3A4 and 2C8, with minor contributions from P450 3A5 and 2D6. These findings provide further insight into the pathways involved in the generation of reactive, potentially toxic metabolites of masitinib. Future studies are needed to evaluate the impact of masitinib metabolism on the toxicity of the drug in vivo.}, }
@article {pmid36047967, year = {2022}, author = {Vázquez-Costa, JF and Povedano, M and Nascimiento-Osorio, AE and Moreno Escribano, A and Kapetanovic Garcia, S and Dominguez, R and Exposito, JM and González, L and Marco, C and Medina Castillo, J and Muelas, N and Natera de Benito, D and Ñungo Garzón, NC and Pitarch Castellano, I and Sevilla, T and Hervás, D}, title = {Validation of motor and functional scales for the evaluation of adult patients with 5q spinal muscular atrophy.}, journal = {European journal of neurology}, volume = {29}, number = {12}, pages = {3666-3675}, pmid = {36047967}, issn = {1468-1331}, mesh = {Child ; Adult ; Humans ; *Spinal Muscular Atrophies of Childhood ; *Muscular Atrophy, Spinal ; Outcome Assessment, Health Care ; Upper Extremity ; }, abstract = {BACKGROUND AND PURPOSE: Mos scales currently used to evaluate spinal muscular atrophy (SMA) patients have only been validated in children. The aim of this study was to assess the construct validity and responsiveness of several outcome measures in adult SMA patients.<br><br>METHODS: Patients older than 15&#x2009;years and followed up in five referral centres for at least 6&#xa0;months, between October 2015 and August 2020, with a motor function scale score (Hammersmith Functional Motor Scale Expanded [HFMSE], Revised Upper Limb module [RULM]) were included. Bedside functional scales (Egen Klassification [EK2], Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) were also collected when available. Spearman's rho correlations (rs) and Bangdiwala's concordance test (B) were used to evaluate the scales' construct validity. Monthly slopes of change were used to calculate their responsiveness of the scales.<br><br>RESULTS: The study included 79 SMA patients, followed up for a mean of 16&#x2009;months. All scales showed strong correlations with each other (rs&#x2009;>&#x2009;0.70). A floor effect in motor function scales was found in the weakest patients (HFMSE&#x2009;<&#x2009;5 and RULM&#x2009;<&#x2009;10), and a ceiling effect was found in stronger patients (HFMSE&#x2009;>&#x2009;60 and RULM&#x2009;>&#x2009;35). The ALSFRS-R (B&#xa0;=&#xa0;0.72) showed a strong ability to discriminate between walkers, sitters and non-sitters, and the HFMSE (B&#xa0;=&#xa0;0.86) between walkers and sitters. The responsiveness was low overall, although in treated patients a moderate responsiveness was found for the ALSFRS-R and HFMSE in walkers (0.69 and 0.61, respectively) and for EK2 in sitters (0.65) and non-sitters (0.60).<br><br>CONCLUSIONS: This study shows the validity and limitations of the scales most frequently used to assess adult SMA patients. Overall, bedside functional scales showed some advantages over motor scales, although all showed limited responsiveness.}, }
@article {pmid36047007, year = {2023}, author = {Bekteshi, S and Konings, M and Karlsson, P and Criekinge, TV and Dan, B and Monbaliu, E}, title = {Teleintervention for users of augmentative and alternative communication devices: A systematic review.}, journal = {Developmental medicine and child neurology}, volume = {65}, number = {2}, pages = {171-184}, doi = {10.1111/dmcn.15387}, pmid = {36047007}, issn = {1469-8749}, mesh = {Humans ; Cohort Studies ; *Communication Disorders/etiology/therapy ; *Autistic Disorder ; Language Therapy/methods ; Communication ; }, abstract = {AIM: To synthesize existing evidence on the effectiveness of speech-language teleinterventions delivered via videoconferencing to users of augmentative and alternative communication (AAC) devices.<br><br>METHOD: A systematic literature search was conducted in 10 electronic databases, from inception until August 2021. Included were speech-language teleinterventions delivered by researchers and/or clinicians via videoconferencing to users of AAC devices, without restrictions on chronological age and clinical diagnosis. The quality of the studies included in the review was appraised using the Downs and Black checklist and the Single-Case Experimental Design Scale; risk of bias was assessed using the Risk Of Bias In Non-Randomized Studies - of Interventions and the single-case design risk of bias tools.<br><br>RESULTS: Six teleinterventions including 25 participants with a variety of conditions, such as Down syndrome, autism, Rett syndrome, and amyotrophic lateral sclerosis met the inclusion criteria. Five studies used a single-case experimental design and one was a cohort study. Teleinterventions included active consultation (n&#xa0;=&#xa0;2), functional communication training (n&#xa0;=&#xa0;2), brain-computer interface (n&#xa0;=&#xa0;1), and both teleintervention and in-person intervention (n&#xa0;=&#xa0;1). All teleinterventions reported an increase in participants' independent use of AAC devices during the training sessions compared to baseline, as well as an overall high satisfaction and treatment acceptability.<br><br>INTERPRETATION: Speech-language teleinterventions for users of AAC devices show great potential for a successful method of service delivery. Future telehealth studies with larger sample sizes and more robust methodology are strongly encouraged to allow the generalization of results across different populations.<br><br>WHAT THIS PAPER ADDS: Individuals can learn to use augmentative and alternative communication (AAC) devices independently during tele-AAC interventions. Service providers and recipients reported an overall high satisfaction and acceptability for AAC services delivered via teleinterventions. Speech-language teleinterventions may be an effective method of providing AAC intervention services.}, }
@article {pmid36043794, year = {2022}, author = {Tao, Y and Leng, SX and Zhang, H}, title = {Ketogenic Diet: An Effective Treatment Approach for Neurodegenerative Diseases.}, journal = {Current neuropharmacology}, volume = {20}, number = {12}, pages = {2303-2319}, pmid = {36043794}, issn = {1875-6190}, mesh = {Humans ; *Diet, Ketogenic ; *Neurodegenerative Diseases/therapy ; *Alzheimer Disease/metabolism ; *Parkinson Disease ; Treatment Outcome ; }, abstract = {This review discusses the effects and mechanisms of a ketogenic diet on neurodegenerative diseases on the basis of available evidence. A ketogenic diet refers to a high-fat, mediumprotein, and low-carbohydrate diet that leads to a metabolic shift to ketosis. This review systematically summarizes the scientific literature supporting this effective treatment approach for neurodegenerative diseases, including effects on mitochondrial function, oxidative stress, neuronal apoptosis, neuroinflammation, and the microbiota-gut-brain axis. It also highlights the clinical evidence for the effects of the ketogenic diet in the treatment of Alzheimer's disease, Parkinson's disease, and motor neuron disease. Finally, it discusses the common adverse effects of ketogenic therapy. Although the complete mechanism of the ketogenic diet in the treatment of neurodegenerative diseases remains to be elucidated, its clinical efficacy has attracted many new followers. The ketogenic diet is a good candidate for adjuvant therapy, but its specific applicability depends on the type and the degree of the disease.}, }
@article {pmid36042292, year = {2023}, author = {Liu, W and Zhu, SO and Guo, YL and Tu, LF and Zhen, YQ and Zhao, RY and Ou-Yang, L and Kurihara, H and He, RR and Liu, B}, title = {BL-918, a small-molecule activator of ULK1, induces cytoprotective autophagy for amyotrophic lateral sclerosis therapy.}, journal = {Acta pharmacologica Sinica}, volume = {44}, number = {3}, pages = {524-537}, pmid = {36042292}, issn = {1745-7254}, mesh = {Animals ; Mice ; Rats ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Autophagy ; Autophagy-Related Protein-1 Homolog/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Spinal Cord/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most common fatal neurodegenerative diseases in adults. ALS pathogenesis is associated with toxic SOD1 aggregates generated by mutant SOD1. Since autophagy is responsible for the clearance of toxic protein aggregates including SOD1 aggregates, autophagy induction has been considered as a potential strategy for treating ALS. Autophagic signaling is initiated by unc-51 like autophagy activating kinase 1 (ULK1) complex. We previously identified that BL-918 as a specific ULK1 activator, which exerted cytoprotective effect against Parkinson's disease in vitro and in vivo. In this study we investigated whether BL-918 exerted a therapeutic effect against ALS, and characterized its pharmacokinetic profile in rats. In hSOD[G93A]-NSC34 cells, treatment with BL-918 (5, 10 μM) dose-dependently induced ULK1-dependent autophagy, and eliminated toxic SOD1 aggregates. In SOD[G93A] mice, administration of BL-918 (40, 80 mg/kg, b.i.d., i.g.) dose-dependently prolonged lifespan and improved the motor function, and enhanced the clearance of SOD1 aggregates in spinal cord and cerebral cortex through inducing autophagy. In the pharmacokinetic study conducted in rats, we found BL-918 and its 2 metabolites (M8 and M10) present in spinal cord and brain; after intragastric and intravenous administration, BL-918 reached the highest blood concentration compared to M8 and M10. Collectively, ULK1 activator BL-918 displays a therapeutic potential on ALS through inducing cytoprotective autophagy. This study provides a further clue for autophagic dysfunction in ALS pathogenesis.}, }
@article {pmid36041329, year = {2022}, author = {Kobayakawa, Y and Todaka, K and Hashimoto, Y and Ko, S and Shiraishi, W and Kishimoto, J and Kira, JI and Yamasaki, R and Isobe, N and , }, title = {A novel quantitative indicator for disease progression rate in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {442}, number = {}, pages = {120389}, doi = {10.1016/j.jns.2022.120389}, pmid = {36041329}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Disease Progression ; Vital Capacity ; Cohort Studies ; Prognosis ; }, abstract = {OBJECTIVE: The current study sought to develop a new indicator for disease progression rate in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: We used a nonparametric method to score diverse patterns of decline in the percentage of predicted forced vital capacity (%FVC) in patients with ALS. This involved 6317 longitudinal %FVC data sets from 920 patients in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database volunteered by PRO-ACT Consortium members. To assess the utility of the derived scores as a disease indicator, we examined changes over time, the association with prognosis, and correlation with the Risk Profile of the Treatment Research Initiative to Cure ALS (TRICALS). Our local cohort (n&#xa0;=&#xa0;92) was used for external validation.<br><br>RESULTS: We derived scores ranging from 35 to 106 points to construct the FVC Decline Pattern scale (FVC-DiP). Individuals' FVC-DiP scores were determined from a single measurement of %FVC and disease duration at assessment. Although the %FVC declined over the disease course (p&#xa0;<&#xa0;0.0001), the FVC-DiP remained relatively stable. Low FVC-DiP scores were associated with rapid disease progression. Using our cohort, we demonstrated an association between FVC-DiP and the survival prognosis, the stability of the FVC-DiP per individual, and a correlation between FVC-DiP scores and the TRICALS Risk Profile (r[2]&#xa0;=&#xa0;0.904, p&#xa0;<&#xa0;0.0001).<br><br>CONCLUSIONS: FVC-DiP scores reflected patterns of declining %FVC over the natural course of ALS and indicated the disease progression rate. The FVC-DiP may enable easy assessment of disease progression patterns and could be used for assessing treatment efficacy.}, }
@article {pmid36038262, year = {2022}, author = {Thonhoff, JR and Berry, JD and Macklin, EA and Beers, DR and Mendoza, PA and Zhao, W and Thome, AD and Triolo, F and Moon, JJ and Paganoni, S and Cudkowicz, M and Appel, SH}, title = {Combined Regulatory T-Lymphocyte and IL-2 Treatment Is Safe, Tolerable, and Biologically Active for 1 Year in Persons With Amyotrophic Lateral Sclerosis.}, journal = {Neurology(R) neuroimmunology &amp; neuroinflammation}, volume = {9}, number = {6}, pages = {}, pmid = {36038262}, issn = {2332-7812}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Biomarkers ; Disease Progression ; Humans ; Inflammation ; Interleukin-2/adverse effects ; T-Lymphocytes, Regulatory ; *COVID-19 Drug Treatment ; }, abstract = {BACKGROUND AND OBJECTIVES: In a phase 1 amyotrophic lateral sclerosis (ALS) study, autologous infusions of expanded regulatory T-lymphocytes (Tregs) combined with subcutaneous interleukin (IL)-2 were safe and well tolerated. Treg suppressive function increased and disease progression stabilized during the study. The present study was conducted to confirm the reliability of these results.<br><br>METHODS: Participants with ALS underwent leukapheresis, and their Tregs were isolated and expanded in a current Good Manufacturing Practice facility. Seven participants were randomly assigned in a 1:1 ratio to receive Treg infusions (1 &#xd7; 10[6] cells/kg) IV every 4 weeks and IL-2 (2 &#xd7; 10[5] IU/m[2]) injections 3 times/wk or matching placebo in a 24-week randomized controlled trial (RCT). Six participants proceeded into a 24-week dose-escalation open-label extension (OLE). Two additional participants entered directly into the OLE. The OLE included dose escalation of Treg infusions to 2 &#xd7; 10[6] cells/kg and 3 &#xd7; 10[6] cells/kg at 4-week intervals.<br><br>RESULTS: The Treg/IL-2 treatments were safe and well tolerated, and Treg suppressive function was higher in the active group of the RCT. A meaningful evaluation of progression rates in the RCT between the placebo and active groups was not possible due to the limited number of enrolled participants aggravated by the COVID-19 pandemic. In the 24-week OLE, the Treg/IL-2 treatments were also safe and well tolerated in 8 participants who completed the escalating doses. Treg suppressive function and numbers were increased compared with baseline. Six of 8 participants changed by an average of -2.7 points per the ALS Functional Rating Scale-Revised, whereas the other 2 changed by an average of -10.5 points. Elevated levels of 2 markers of peripheral inflammation (IL-17C and IL-17F) and 2 markers of oxidative stress (oxidized low-density lipoprotein receptor 1 and oxidized LDL) were present in the 2 rapidly progressing participants but not in the slower progressing group.<br><br>DISCUSSION: Treg/IL-2 treatments were safe and well tolerated in the RCT and OLE with higher Treg suppressive function. During the OLE, 6 of 8 participants showed slow to no progression. The 2 of 8 rapid progressors had elevated markers of oxidative stress and inflammation, which may help delineate responsiveness to therapy. Whether Treg/IL-2 treatments can slow disease progression requires a larger clinical study (ClinicalTrials.gov number, NCT04055623).<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that Treg infusions and IL-2 injections are safe and effective for patients with ALS.}, }
@article {pmid36038019, year = {2022}, author = {Li, SH and Abd-Elrahman, KS and Ferguson, SSG}, title = {Targeting mGluR2/3 for treatment of neurodegenerative and neuropsychiatric diseases.}, journal = {Pharmacology &amp; therapeutics}, volume = {239}, number = {}, pages = {108275}, doi = {10.1016/j.pharmthera.2022.108275}, pmid = {36038019}, issn = {1879-016X}, support = {PJT-148656//CIHR/Canada ; PJT-153317//CIHR/Canada ; PJT-165967//CIHR/Canada ; }, mesh = {Humans ; *Receptors, Metabotropic Glutamate/metabolism ; Presynaptic Terminals/metabolism ; Glutamic Acid/metabolism ; Neurons/metabolism ; }, abstract = {Glutamate is the primary excitatory neurotransmitter in the brain and plays critical roles in all aspects of neuronal function. Disruption of normal glutamate transmission has been implicated in a variety of neurodegenerative and neuropsychiatric diseases. Glutamate exerts its effect through ionotropic and metabotropic glutamate receptors (mGluRs). mGluR2 and mGluR3 are members of the Group II mGluR family and their activation leads to the inhibition of glutamate release from presynaptic nerve terminals and is also poised upstream of a myriad of signaling pathways in postsynaptic nerve terminals and neuroglia. Therefore, mGluR2 and mGluR3 have been considered as potential drug targets for the treatment of many neurological conditions and several compounds targeting these receptors have been developed. In this review, we discuss what is currently known regarding the contribution of mGluR2 and mGluR3 to the pathophysiology of some neurodegenerative and neuropsychiatric diseases including Amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's diseases, schizophrenia and depression as well as drug addiction. We then highlight the evidence supporting the use of various drugs including orthosteric and allosteric ligands acting on either mGluR2, mGluR3 or both for the management of these brain disorders.}, }
@article {pmid36037815, year = {2022}, author = {Nakamura, T and Takagi, T}, title = {Differentiated Approaches to Treat Lesions of the TFCC Based on new arthroscopic Classification.}, journal = {Handchirurgie, Mikrochirurgie, plastische Chirurgie : Organ der Deutschsprachigen Arbeitsgemeinschaft fur Handchirurgie : Organ der Deutschsprachigen Arbeitsgemeinschaft fur Mikrochirurgie der Peripheren Nerven und Gefasse : Organ der V...}, volume = {54}, number = {5}, pages = {389-398}, doi = {10.1055/a-1872-0109}, pmid = {36037815}, issn = {1439-3980}, abstract = {In this article, pathology of the TFCC lesions, image diagnosis and arthroscopic examination were described. According to the radiocarpal arthroscopic findings, TFCC lesions are classified into intra-disc lesions (Class 1), radial lesion (Class 2), peripheral disc lesions which indicate slight to moderate DRUJ instability (Class 3) and degenerative lesion (Class 4). The radioulnar ligament (RUL) lesions that indicate moderate to severe DRUJ instability were classified with staging system with DRUJ arthroscopic findings (Stage 1 to 5). Author's treatment algorism with wrist arthroscopic findings including DRUJ arthroscopy was demonstrated and along with this algorism, various arthroscopic and open techniques to treat TFCC injuries were selected and resulted in success. Precise diagnosis of the TFCC lesions helped to select an adequate treatment for each lesion.Dieser Artikel beschreibt die pathologischen Veränderungen des TFCC sowie deren Befunde in der Bildgebung und Arthroskopie. Am TFCC lassen sich mittels Arthroskopie bei Sicht von radiokarpal zentrale (Typ 1), radiale (Typ 2) sowie periphere Läsionen (Typ 3), die mit einer moderaten Instabilität des distalen Radioulnargelenkes (DRUG) einhergehen, und degenerative Läsionen (Typ 4) unterscheiden. Läsionen der radioulnaren Bänder, die mit einer moderaten bis ausgeprägten Instabilität des DRUG vergesellschaftet sind, werden anhand der Befunde bei der DRUG-Arthroskopie in fünf Stadien eingeteilt. Diesen unterschiedlichen Befunden angepasst wurde ein Behandlungsalgorithmus mit verschiedenen arthroskopischen und offenen Verfahren entwickelt, der sich als erfolgreich erwies. Eine exakte Klassifizierung von TFCC-Läsionen ermöglicht die Wahl des für die jeweilige Läsion adäquaten Therapieverfahrens.}, }
@article {pmid36036324, year = {2022}, author = {Pu, M and Tai, Y and Yuan, L and Zhang, Y and Guo, H and Hao, Z and Chen, J and Qi, X and Wang, G and Tao, Z and Ren, J}, title = {The contribution of proteasomal impairment to autophagy activation by C9orf72 poly-GA aggregates.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {79}, number = {9}, pages = {501}, pmid = {36036324}, issn = {1420-9071}, support = {21DZ2291100//Science and Technology Innovation Plan Of Shanghai Science and Technology Commission/ ; 21ZR1475100//Science and Technology Innovation Plan Of Shanghai Science and Technology Commission/ ; SIMM2103ZZ-01//State Key Laboratory of Drug Research/ ; ZYYCXTD-D-202210//Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis ; Autophagy ; C9orf72 Protein ; *Frontotemporal Dementia ; Proteasome Endopeptidase Complex ; Sirolimus ; Disease Models, Animal ; }, abstract = {BACKGROUND: Poly-GA, a dipeptide repeat protein unconventionally translated from GGGGCC (G4C2) repeat expansions in C9orf72, is abundant in C9orf72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9orf72-ALS/FTD). Although the poly-GA aggregates have been identified in C9orf72-ALS/FTD neurons, the effects on UPS (ubiquitin-proteasome system) and autophagy and their exact molecular mechanisms have not been fully elucidated.<br><br>RESULTS: Herein, our in vivo experiments indicate that the mice expressing ploy-GA with 150 repeats instead of 30 repeats exhibit significant aggregates in cells. Mice expressing 150 repeats ploy-GA shows behavioral deficits and activates autophagy in the brain. In vitro findings suggest that the poly-GA aggregates influence proteasomal by directly binding proteasome subunit PSMD2. Subsequently, the poly-GA aggregates activate phosphorylation and ubiquitination of p62 to recruit autophagosomes. Ultimately, the poly-GA aggregates lead to compensatory activation of autophagy. In vivo studies further reveal that rapamycin (autophagy activator) treatment significantly improves the degenerative symptoms and alleviates neuronal injury in mice expressing 150 repeats poly-GA. Meanwhile, rapamycin administration to mice expressing 150 repeats poly-GA reduces neuroinflammation and aggregates in the brain.<br><br>CONCLUSION: In summary, we elucidate the relationship between poly-GA in the proteasome and autophagy: when poly-GA forms complexes with the proteasome, it recruits autophagosomes and affects proteasome function. Our study provides support for further promoting the comprehension of the pathogenesis of C9orf72, which may bring a hint for the exploration of rapamycin for the treatment of ALS/FTD.}, }
@article {pmid36034988, year = {2022}, author = {Zhang, HB and Zhai, XL and Li, L and Wu, DS and Zhuang, GL and Xu, QW and Guo, H and Wang, J}, title = {Imaging characteristics, misdiagnosis and microsurgical outcomes of patients with spinal dural arteriovenous fistula: a retrospective study of 32 patients.}, journal = {Annals of translational medicine}, volume = {10}, number = {15}, pages = {832}, pmid = {36034988}, issn = {2305-5839}, abstract = {BACKGROUND: Spinal dural arteriovenous fistula (SDAVF) is an extremely rare spinal vascular malformation. As SDAVF exhibits no specific clinical manifestations nor diverse imaging results, it is easily misdiagnosed, resulting in delayed treatment and irreversible neurological damage. Most patients were initially misdiagnosed, but there were few reports on reducing misdiagnosis.<br><br>METHODS: A total of 32 consecutive patients, who presented to our institution (Shanghai Deji Hospital) with SDAVF between June 2013 and January 2016 were retrospectively analyzed. Data were collected on demographics, clinical presentation, imaging findings, follow-up, and clinical outcomes. The Aminoff-Logue scale (ALS) was used to assess clinical outcomes.<br><br>RESULTS: Of the 32 enrolled patients (3 females, mean age 59.1&#xb1;3.8 years), 23 patients (71.9%) were misdiagnosed as acute myelitis (11 patients), intramedullary tumors (6 patients), lumbar disc herniation (4 patients), and other conditions (2 patients). All patients underwent surgical procedures under electrophysiological monitoring. Fistulas were found in all 32 patients and were successfully occluded. The mean follow-up period was 19.22&#xb1;8.21 months (ranging from 2 weeks to 30 months). One year later, 20 patients underwent magnetic resonance imaging (MRI), and 14 showed no T2 edema, and the edema was relieved in 6 patients. A total of 10 patients underwent enhancement MRI and no enhancement signs were detected. Among the 27 patients with long-time follow-up, the fistula had no residual or recurrence, 21 patients showed decreased ALS scores (P<0.05). Six patients exhibited nonsignificant improvement. No aggravating patient was found. Prognosis differed significantly between patients with ALS <6 and those with ALS &#x2265;6 (P<0.05).<br><br>CONCLUSIONS: Spinal angiography should be performed with full intubation, and microcatheter angiography can reduce misdiagnosis. SDAVF must be differentiated from acute myelitis, intramedullary tumor, and other spinal vascular malformations. Microsurgical treatment is effective with a low recurrence rate.}, }
@article {pmid36033924, year = {2022}, author = {Poda, A and Klevor, R and Salym, A and Sarih, I and Salhi, S and Nissrine, L and Kissani, N}, title = {Etiological profile of peripheral neuropathies in an academic hospital in southern Morocco.}, journal = {The Egyptian journal of neurology, psychiatry and neurosurgery}, volume = {58}, number = {1}, pages = {97}, pmid = {36033924}, issn = {1110-1083}, abstract = {BACKGROUND: Peripheral neuropathies constitute a common complaint in general and neurology practice, and are a source of handicap to patients. Epidemiological data in the Middle East and North Africa region as well as in the African continent are sparse. Nevertheless, regional etiological profiles are crucial in navigating the diagnostic maze of neuropathies. This study outlines the etiological profile of peripheral neuropathies in an academic hospital in southern Morocco.<br><br>RESULTS: A total of 180 cases were recorded in a span of 8&#xa0;years (22.5 cases per year). The mean age of patients was 42.35&#xa0;years. Male gender was predominant (68.88%), with a sex ratio of 2.2. Motor symptoms were the most frequently reported (86.6%). The axonal form (40.56%) was the most frequently encountered electrophysiologic form. The most frequent etiologies in the study were diabetes (26.7%), acute polyradiculoneuropathy (26.1%) and amyotrophic lateral sclerosis (16.1%). Alcohol neuropathy was found in 2.2% of the cohort. No cause was found in 5% of cases. Outcome was mostly favorable under treatment, although 10 deaths due to acute polyradiculoneuropathy were recorded (mortality&#x2009;=&#x2009;21.3%).<br><br>CONCLUSIONS: Knowledge of the etiological profile of peripheral neuropathies should guide clinicians to an early diagnosis and aid in an adapted management of patients.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41983-022-00531-4.}, }
@article {pmid36017737, year = {2022}, author = {Xiong, LL and Chen, L and Deng, IB and Zhou, XF and Wang, TH}, title = {P75 neurotrophin receptor as a therapeutic target for drug development to treat neurological diseases.}, journal = {The European journal of neuroscience}, volume = {56}, number = {8}, pages = {5299-5318}, doi = {10.1111/ejn.15810}, pmid = {36017737}, issn = {1460-9568}, mesh = {Biomarkers ; Drug Development ; Humans ; Nerve Growth Factors ; *Nervous System Diseases/drug therapy ; *Receptor, Nerve Growth Factor/metabolism ; Receptors, Nerve Growth Factor/metabolism ; }, abstract = {The interaction of neurotrophins with their receptors is involved in the pathogenesis and progression of various neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury and acute and chronic cerebral damage. The p75 neurotrophin receptor (p75NTR) plays a pivotal role in the development of neurological dysfunctions as a result of its high expression, abnormal processing and signalling. Therefore, p75NTR represents as a vital therapeutic target for the treatment of neurodegeneration, neuropsychiatric disorders and cerebrovascular insufficiency. This review summarizes the current research progress on the p75NTR signalling in neurological deficits. We also summarize the present therapeutic approaches by genetically and pharmacologically targeting p75NTR for the attenuation of pathological changes. Based on the evolving knowledge, the role of p75NTR in the regulation of tau hyperphosphorylation, Aβ metabolism, the degeneration of motor neurons and dopaminergic neurons has been discussed. Its position as a biomarker to evaluate the severity of diseases and as a druggable target for drug development has also been elucidated. Several prototype small molecule compounds were introduced to be crucial in neuronal survival and functional recovery via targeting p75NTR. These small molecule compounds represent desirable agents in attenuating neurodegeneration and cell death as they abolish activation-induced neurotoxicity of neurotrophins via modulating p75NTR signalling. More comprehensive and in-depth investigations on p75NTR-based drug development are required to shed light on effective treatment of numerous neurological disorders.}, }
@article {pmid36016682, year = {2022}, author = {Shakeri, R and Savari, B and Sheikholeslami, MN and Radjabian, T and Khorshidi, J and Safavi, M}, title = {Untargeted Metabolomics Analysis of Crocus cancellatus subsp. damascenus (Herb.) B. Mathew Stigmas and Their Anticarcinogenic Effect on Breast Cancer Cells.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2022}, number = {}, pages = {3861783}, pmid = {36016682}, issn = {1741-427X}, abstract = {Safranal, crocin, crocetin, and picrocrocin are major known compounds in the stigma extract of Crocus sativus with various medicinal properties. Crocus cancellatus is another Crocus species that grows extensively in Iran's various regions, such as the Kurdistan province. The predominant metabolites and biological properties of C. cancellatus have not yet been investigated. The ingredients of the stigma ethanol extract of C. cancellatus were investigated using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography with tandem mass spectrometry (LC-MS). The ROIMCR approach was performed to analyze the LC-MS full scan data sets. This method searches the MS regions of interest (ROI) data in the m/z domain and analyses the results using the multivariate curve-resolution alternating least squares (MCR-ALS) chemometrics technique for simultaneous resolution of two extracts. Also, the antiproliferative properties of C. cancellatus against MDA-MB-231 and MCF-7 cancer cells were examined by MTT, dual acridine orange/ethidium bromide test, Annexin V-FITC/PI, and zymography. The GC-MS and LC-MS untargeted metabolomics data analysis of the extract indicated the presence of cytotoxic agents including safranal, crocin, picrocrocin, and crocetin in the stigma ethanol extract of C. cancellatus. Biological tests showed that the viability of MDA-MB-231 and MCF-7 cancer cells is decreased following C. cancellatus treatment in a time- and dose-dependent way in both monolayer and 3D cell cultures. The MCF-7 cell spheroids had greater resistance to the cytotoxic activity of the extract in 3D cell culture than the MDA-MB-231 cell spheroids. The morphological changes of the cells treated with C. cancellatus stigmas extract were indicative of apoptosis. Zymography analysis revealed a similar trend of matrix metallopeptidase-2 (MMP-2) and matrix metallopeptidase-9 (MMP-9) activity in the treated cells with C. cancellatus extract in comparison with doxorubicin treatment as a positive control. The findings of this research indicate that the ethanolic extract of C. cancellatus stigmas was a good source of bioactive metabolites with anticancer activity.}, }
@article {pmid36012622, year = {2022}, author = {Roberts, B and Theunissen, F and Mastaglia, FL and Akkari, PA and Flynn, LL}, title = {Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?.}, journal = {International journal of molecular sciences}, volume = {23}, number = {16}, pages = {}, pmid = {36012622}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Humans ; Lewy Bodies/metabolism ; *Lewy Body Disease/pathology ; *Multiple System Atrophy/pathology ; *Synucleinopathies ; alpha-Synuclein/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease classified as both a neurodegenerative and neuromuscular disorder. With a complex aetiology and no current cure for ALS, broadening the understanding of disease pathology and therapeutic avenues is required to progress with patient care. Alpha-synuclein (αSyn) is a hallmark for disease in neurodegenerative disorders, such as Parkinson's disease, Lewy body dementia, and multiple system atrophy. A growing body of evidence now suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43. This review endeavours to capture the scope of literature regarding the aetiology and development of ALS and its commonalities with "synucleinopathy disorders". We will discuss the involvement of αSyn in ALS and motor neuron disease pathology, and the current theories and strategies for therapeutics in ALS treatment, as well as those targeting αSyn for synucleinopathies, with a core focus on small molecule RNA technologies.}, }
@article {pmid36012599, year = {2022}, author = {Morén, C and deSouza, RM and Giraldo, DM and Uff, C}, title = {Antioxidant Therapeutic Strategies in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {16}, pages = {}, pmid = {36012599}, issn = {1422-0067}, mesh = {Antioxidants/metabolism/therapeutic use ; Humans ; *Melatonin/metabolism/therapeutic use ; Mitochondria/metabolism ; *Neurodegenerative Diseases/pathology ; Oxidative Stress ; }, abstract = {The distinguishing pathogenic features of neurodegenerative diseases include mitochondrial dysfunction and derived reactive oxygen species generation. The neural tissue is highly sensitive to oxidative stress and this is a prominent factor in both chronic and acute neurodegeneration. Based on this, therapeutic strategies using antioxidant molecules towards redox equilibrium have been widely used for the treatment of several brain pathologies. Globally, polyphenols, carotenes and vitamins are among the most typical exogenous antioxidant agents that have been tested in neurodegeneration as adjunctive therapies. However, other types of antioxidants, including hormones, such as the widely used melatonin, are also considered neuroprotective agents and have been used in different neurodegenerative contexts. This review highlights the most relevant mitochondrial antioxidant targets in the main neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and Huntington's disease and also in the less represented amyotrophic lateral sclerosis, as well as traumatic brain injury, while summarizing the latest randomized placebo-controlled trials.}, }
@article {pmid36012563, year = {2022}, author = {Raghunathan, R and Turajane, K and Wong, LC}, title = {Biomarkers in Neurodegenerative Diseases: Proteomics Spotlight on ALS and Parkinson's Disease.}, journal = {International journal of molecular sciences}, volume = {23}, number = {16}, pages = {}, pmid = {36012563}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Biomarkers ; Humans ; *Neurodegenerative Diseases/diagnosis ; *Parkinson Disease ; Proteomics ; }, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) are both characterized by pathogenic protein aggregates that correlate with the progressive degeneration of neurons and the loss of behavioral functions. Both diseases lack biomarkers for diagnosis and treatment efficacy. Proteomics is an unbiased quantitative tool capable of the high throughput quantitation of thousands of proteins from minimal sample volumes. We review recent proteomic studies in human tissues, plasma, cerebrospinal fluid (CSF), and exosomes in ALS and PD that identify proteins with potential utility as biomarkers. Further, we review disease-related post-translational modifications in key proteins TDP43 in ALS and α-synuclein in PD studies, which may serve as biomarkers. We compare relative and absolute quantitative proteomic approaches in key biomarker studies in ALS and PD and discuss recent technological advancements which may identify suitable biomarkers for the early-diagnosis treatment efficacy of these diseases.}, }
@article {pmid36009245, year = {2022}, author = {De Lazzari, F and Agostini, F and Doni, D and Malacrida, S and Zordan, MA and Costantini, P and Bubacco, L and Sandrelli, F and Bisaglia, M}, title = {DJ-1 and SOD1 Act Independently in the Protection against Anoxia in Drosophila melanogaster.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {8}, pages = {}, pmid = {36009245}, issn = {2076-3921}, support = {ALSoDJ1//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, abstract = {Redox homeostasis is a vital process the maintenance of which is assured by the presence of numerous antioxidant small molecules and enzymes and the alteration of which is involved in many pathologies, including several neurodegenerative disorders. Among the different enzymes involved in the antioxidant response, SOD1 and DJ-1 have both been associated with the pathogenesis of amyotrophic lateral sclerosis and Parkinson's disease, suggesting a possible interplay in their mechanism of action. Copper deficiency in the SOD1-active site has been proposed as a central determinant in SOD1-related neurodegeneration. SOD1 maturation mainly relies on the presence of the protein copper chaperone for SOD1 (CCS), but a CCS-independent alternative pathway also exists and functions under anaerobic conditions. To explore the possible involvement of DJ-1 in such a pathway in vivo, we exposed Drosophila melanogaster to anoxia and evaluated the effect of DJ-1 on fly survival and SOD1 levels, in the presence or absence of CCS. Loss of DJ-1 negatively affects the fly response to the anoxic treatment, but our data indicate that the protective activity of DJ-1 is independent of SOD1 in Drosophila, indicating that the two proteins may act in different pathways.}, }
@article {pmid36009116, year = {2022}, author = {Yang, Z and He, L and Ren, M and Lu, Y and Meng, H and Yin, D and Chen, S and Zhou, Q}, title = {Paraneoplastic Amyotrophic Lateral Sclerosis: Case Series and Literature Review.}, journal = {Brain sciences}, volume = {12}, number = {8}, pages = {}, pmid = {36009116}, issn = {2076-3425}, support = {18SG15//Shanghai Shuguang Plan Project/ ; 2019044//Shanghai outstanding young scholars Project, Shanghai talent development project/ ; SHDC 2020CR2027B//Clinical Research Plan of SHDC/ ; 82101476//National Natural Science Foundation of China/ ; }, abstract = {Paraneoplastic amyotrophic lateral sclerosis (ALS) is a rare and special type of ALS. The pathogenesis, clinical presentation, treatment and prognosis remain poorly understood. We herein presented three cases of paraneoplastic ALS. In case 1, we first reported an ALS patient with the positive serum antibodies against both Sry-like high mobility group box 1 (SOX1) and glutamic acid decarboxylase 65 (GAD65). However, immunotherapy did not improve his neurological symptoms. We also reported two ALS patients with renal clear cell carcinoma and chronic myelogenous leukemia. No positive paraneoplastic antibodies were detected in either the serum or the cerebrospinal fluid of the two patients, and their clinical symptoms progressed slowly after tumor treatment. The three cases enriched the existing case pool of this rare disorder. In addition, we have comprehensively reviewed the literature of paraneoplastic ALS. The clinical features, treatment effect and prognosis were summarized to broaden our understanding of paraneoplastic ALS.}, }
@article {pmid36008057, year = {2022}, author = {Vilar, MDC and Coutinho, KMD and Vale, SHL and Medeiros, GCBS and Piuvezam, G and Leite-Lais, L and Brandao-Neto, J}, title = {Nutritional therapy in amyotrophic lateral sclerosis: protocol for a systematic review and meta-analysis.}, journal = {BMJ open}, volume = {12}, number = {8}, pages = {e064086}, pmid = {36008057}, issn = {2044-6055}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Meta-Analysis as Topic ; *Nutrition Therapy ; Systematic Reviews as Topic ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease characterised by the degeneration of motor neurons. Nutritional interventions in ALS are essential and must be based on scientific evidence to provide quality of healthcare, improve the quality of life and increase survival time. Therefore, this protocol of systematic reviews and meta-analyses aims to present a synthesis of evidence-based recommendations to support adequate nutrition therapy for patients with ALS.<br><br>METHODS AND ANALYSIS: The search will be performed using the following databases: PubMed, Excerpta Medica Database (Embase), Scopus, SciELO, Web of Science, LILACS, Cochrane Central Register of Controlled Trials (CENTRAL), ScienceDirect, ProQuest and Google Scholar. We will include clinical practice guidelines, treatment protocols, systematic reviews and clinical trials according to the three research questions to be answered related to nutrition therapy and interventions in patients with ALS. This protocol will be developed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols. To evaluate the methodological quality of the studies, Appraisal of Guidelines, Research and Evaluation II, Cochrane Risk of Bias 2.0 and Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tools will be used. In addition, the Grading of Recommendations Assessment, Development and Evaluation will be used to assess the quality of evidence and the strength of the recommendations. The findings will be summarised and presented descriptively according to the Cochrane Collaboration Handbook and the standard statistical meta-analysis techniques.<br><br>ETHICS AND DISSEMINATION: Ethical approval and human consent are not required because this is a protocol for systematic review and only secondary data will be used. Findings will be published in a peer-reviewed journal and presented at conferences. In case of any changes in this protocol, amendments will be updated in International Prospective Register of Systematic Reviews (PROSPERO) and the modifications will be explained in the final report of this review.<br><br>PROSPERO REGISTRATION NUMBER: CRD42021233088.}, }
@article {pmid36005791, year = {2022}, author = {Aschenbrenner, DS}, title = {New Oral Form for ALS Drug.}, journal = {The American journal of nursing}, volume = {122}, number = {9}, pages = {24-25}, doi = {10.1097/01.NAJ.0000874104.26408.02}, pmid = {36005791}, issn = {1538-7488}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/therapeutic use ; Free Radical Scavengers/therapeutic use ; Humans ; Suspensions ; }, abstract = {The Food and Drug Administration has approved an oral suspension form of edaravone (Radicava ORS) for the treatment of amyotrophic lateral sclerosis.Edaravone should be taken on an empty stomach in the morning either by mouth or through a feeding tube. Feeding tubes should be flushed before and after drug administration.}, }
@article {pmid36005581, year = {2022}, author = {Jiang, L and Ngo, ST}, title = {Altered TDP-43 Structure and Function: Key Insights into Aberrant RNA, Mitochondrial, and Cellular and Systemic Metabolism in Amyotrophic Lateral Sclerosis.}, journal = {Metabolites}, volume = {12}, number = {8}, pages = {}, pmid = {36005581}, issn = {2218-1989}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disorder with no cure available and limited treatment options. ALS is a highly heterogeneous disease, whereby patients present with vastly different phenotypes. Despite this heterogeneity, over 97% of patients will exhibit pathological TAR-DNA binding protein-43 (TDP-43) cytoplasmic inclusions. TDP-43 is a ubiquitously expressed RNA binding protein with the capacity to bind over 6000 RNA and DNA targets-particularly those involved in RNA, mitochondrial, and lipid metabolism. Here, we review the unique structure and function of TDP-43 and its role in affecting the aforementioned metabolic processes in ALS. Considering evidence published specifically in TDP-43-relevant in vitro, in vivo, and ex vivo models we posit that TDP-43 acts in a positive feedback loop with mRNA transcription/translation, stress granules, cytoplasmic aggregates, and mitochondrial proteins causing a relentless cycle of disease-like pathology eventuating in neuronal toxicity. Given its undeniable presence in ALS pathology, TDP-43 presents as a promising target for mechanistic disease modelling and future therapeutic investigations.}, }
@article {pmid36004509, year = {2023}, author = {Ito, D and Morimoto, S and Takahashi, S and Okada, K and Nakahara, J and Okano, H}, title = {Maiden voyage: induced pluripotent stem cell-based drug screening for amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {146}, number = {1}, pages = {13-19}, doi = {10.1093/brain/awac306}, pmid = {36004509}, issn = {1460-2156}, support = {21H02812//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; //Foundation of Japan Amyotrophic Lateral Sclerosis Association, the Ice Bucket Challenge Grant/ ; //Japan Agency for Medical Research and Development/ ; JP 19bm0804003//AMED/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Drug Evaluation, Preclinical ; *Induced Pluripotent Stem Cells/pathology ; *Neurodegenerative Diseases/pathology ; Reproducibility of Results ; Humans ; }, abstract = {Using patient-derived induced pluripotent stem cells, neurodegenerative disease phenotypes have been recapitulated and their pathogenesis analysed leading to significant progress in drug screening. In amyotrophic lateral sclerosis, high-throughput screening using induced pluripotent stem cells-derived motor neurons has identified candidate drugs. Owing to induced pluripotent stem cell-based drug evaluation/screening, three compounds, retigabine, ropinirole and bosutinib, have progressed to clinical trials. Retigabine blocks hyperexcitability and improves survival in amyotrophic lateral sclerosis patient-derived motor neurons. In a randomized clinical trial (n = 65), treatment with retigabine reduced neuronal excitability after 8 weeks. Ropinirole, identified in a high-throughput screening, attenuates pathological phenotypes in patient-derived motor neurons. In a trial limited by a small sample size (n = 20), ropinirole was tolerable and had clinical benefits on function and survival. A phase 1 study of bosutinib has reported safety and tolerability for 12 weeks. Thus, these clinical trials show safety and positive effects and confirm the reliability of stem cell-based drug discovery. This novel strategy leads to reduced costs and time when compared to animal testing and opens new avenues for therapy in intractable diseases.}, }
@article {pmid36000050, year = {2022}, author = {Rautiola, J and Laaksovirta, H and Geneid, A and Ilmarinen, T and Pietarinen, P and Kinnari, TJ}, title = {ALS patients in otorhinolaryngology: A retrospective study.}, journal = {Laryngoscope investigative otolaryngology}, volume = {7}, number = {4}, pages = {1071-1077}, pmid = {36000050}, issn = {2378-8038}, abstract = {OBJECTIVES: Given its rarity and the lack of clear clinical markers, amyotrophic lateral sclerosis (ALS) remains a diagnostic challenge. Because bulbar-onset ALS (buALS) presents with impaired speech or swallowing, patients are often primarily referred to an otolaryngologist (ORL) or phoniatrician. The objectives of this retrospective cohort study were to analyze the role of ORLs and phoniatricians in ALS diagnostics and treatment and the potential diagnostic delay related to initial visit to aforementioned specialists.<br><br>METHODS: We reviewed data for all 327 patients treated for ALS through the Hospital District of Helsinki and Uusimaa (HUS) between 2010 and 2014, focusing specifically on 110 (34%) patients presenting with bulbar nerve onset (buALS). Their presenting symptoms, referral to specialized care, and delay in referral to a neurology clinic were assessed. Indications and findings from swallowing studies were reviewed as well as the incidence of percutaneous endoscopic gastrostomy (PEG) and tracheostomy.<br><br>RESULTS: Among the 110 patients with buALS, 64 (58%) were primarily referred to a neurologist, 28 (25%) to an ORL, and five (5%) to a phoniatrician. The most common presenting symptom was dysarthria in 89 patients, (81%), followed by dysphagia in 26 (24%). In most cases, an ORL or phoniatrician suspected a neuromuscular disease; however, in eight (24%) cases, the neurological etiology of symptoms was missed. Overall, 49 (45%) patients underwent a swallowing study and 86 (78%) patients underwent PEG placement.<br><br>CONCLUSIONS: Among buALS patients, 30% initially consulted an ORL or phoniatrician and 45% underwent a swallowing study. Based on our results, swallowing studies rarely lead to immediate PEG placement. An initial visit to other specialists had no impact on diagnostic delays or survival.}, }
@article {pmid35999998, year = {2022}, author = {Rinaldi, S and Rinaldi, C and Rinaldi, A and Fontani, V}, title = {Radio Electric Asymmetric Conveyer (REAC) Neurobiological Stimulation Treatments in Dysfunctional Motor Behavior in Flail Arm Syndrome: A Case Report.}, journal = {Cureus}, volume = {14}, number = {8}, pages = {e28159}, pmid = {35999998}, issn = {2168-8184}, abstract = {Flail arm syndrome (FAS) is a variant of amyotrophic lateral sclerosis (ALS) that manifests itself with the progressive loss of motor control of the upper limbs starting from the proximal part. Both electrophysiological and magnetic resonance studies have shown that functional alterations in the subcortical structures, cerebellum, and cortex are present in this pathology. These alterations appear to play a significant component in determining cognitive, motor, and behavioral effects. To try to modulate these alterations, in this case report, we used three noninvasive and specific neuromodulation treatments of the Radio Electric Asymmetric Conveyer (REAC) technology. The Neuro Postural Optimization (NPO), the Neuro Psycho Physical Optimization (NPPO), and the Neuro Psycho Physical Optimization Cervico-Brachial (NPPO-CB) with the aim of improving motor control, depression, anxiety, and stress. At the end of the treatment cycle that lasted five consecutive days, the patient regained the ability to raise his arms, a capacity he had lost for several months. This case demonstrates that REAC neurobiological modulation treatments aimed at improving dysfunctional neuropsychomotor behavior (DNPMB) can be useful in highlighting and reducing these components, allowing for better evaluation of the real neurodegenerative damage and determination of a better quality of life for these patients.}, }
@article {pmid35997522, year = {2023}, author = {Goslinga, JA and Terrelonge, M and Bedlack, R and Barkhaus, P and Barnes, B and Bertorini, T and Bromberg, M and Carter, G and Chen, A and Crayle, J and Dimachkie, M and Jiang, L and Levitsky, G and Lund, I and Martin, S and Mcdermott, C and Pattee, G and Pierce, K and Ratner, D and Slachtova, L and Sun, Y and Wicks, P}, title = {ALSUntangled #65: glucocorticoid corticosteroids.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {3-4}, pages = {351-357}, doi = {10.1080/21678421.2022.2099746}, pmid = {35997522}, issn = {2167-9223}, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Glucocorticoids/therapeutic use ; Disease Models, Animal ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people with amyotrophic lateral sclerosis (PALS). Here we review glucocorticoids. Neuroinflammation plays a prominent role in amyotrophic lateral sclerosis (ALS) pathogenesis, so some hypothesize that glucocorticoids might be an effective ALS therapy through their immunosuppressive effects. In this paper, we review the available evidence for glucocorticoids in ALS, including one pre-clinical study with a genetic mouse model of ALS, nine case reports (ranging from 1 to 26 patients each), and four clinical trials. We also review the possible side effects (including steroid myopathy) and the costs of therapy. We graded the level of evidence as follows: Mechanism, D; Pre-Clinical, F; Cases, B; Trials, F; Risks, C. Our review of the current evidence concludes that glucocorticoids do not offer clinical benefit in ALS and confer serious risks. Thus, ALSUntangled does not recommend glucocorticoids as a treatment for ALS.}, }
@article {pmid35982439, year = {2022}, author = {Bilbao, A and Spanagel, R}, title = {Medical cannabinoids: a pharmacology-based systematic review and meta-analysis for all relevant medical indications.}, journal = {BMC medicine}, volume = {20}, number = {1}, pages = {259}, pmid = {35982439}, issn = {1741-7015}, mesh = {*Cannabinoids/adverse effects ; *Chronic Pain/drug therapy ; Dronabinol/adverse effects ; Humans ; Nausea ; Vomiting ; }, abstract = {BACKGROUND: Medical cannabinoids differ in their pharmacology and may have different treatment effects. We aimed to conduct a pharmacology-based systematic review (SR) and meta-analyses of medical cannabinoids for efficacy, retention and adverse events.<br><br>METHODS: We systematically reviewed (registered at PROSPERO: CRD42021229932) eight databases for randomized controlled trials (RCTs) of dronabinol, nabilone, cannabidiol and nabiximols for chronic pain, spasticity, nausea /vomiting, appetite, ALS, irritable bowel syndrome, MS, Chorea Huntington, epilepsy, dystonia, Parkinsonism, glaucoma, ADHD, anorexia nervosa, anxiety, dementia, depression, schizophrenia, PTSD, sleeping disorders, SUD and Tourette. Main outcomes and measures included patient-relevant/disease-specific outcomes, retention and adverse events. Data were calculated as standardized mean difference (SMD) and ORs with confidence intervals (CI) via random effects. Evidence quality was assessed by the Cochrane Risk of Bias and GRADE tools.<br><br>RESULTS: In total, 152 RCTs (12,123 participants) were analysed according to the type of the cannabinoid, outcome and comparator used, resulting in 84 comparisons. Significant therapeutic effects of medical cannabinoids show a large variability in the grade of evidence that depends on the type of cannabinoid. CBD has a significant therapeutic effect for epilepsy (SMD&#x2009;-&#x2009;0.5[CI&#x2009;-&#x2009;0.62,&#x2009;-&#x2009;0.38] high grade) and Parkinsonism (-&#x2009;0.41[CI&#x2009;-&#x2009;0.75,&#x2009;-&#x2009;0.08] moderate grade). There is moderate evidence for dronabinol for chronic pain (-&#x2009;0.31[CI&#x2009;-&#x2009;0.46,&#x2009;-&#x2009;0.15]), appetite (-&#x2009;0.51[CI&#x2009;-&#x2009;0.87,&#x2009;-&#x2009;0.15]) and Tourette (-&#x2009;1.01[CI&#x2009;-&#x2009;1.58,&#x2009;-&#x2009;0.44]) and moderate evidence for nabiximols on chronic pain (-&#x2009;0.25[-&#x2009;0.37,&#x2009;-&#x2009;0.14]), spasticity (-&#x2009;0.36[CI&#x2009;-&#x2009;0.54,&#x2009;-&#x2009;0.19]), sleep (-&#x2009;0.24[CI&#x2009;-&#x2009;0.35,&#x2009;-&#x2009;0.14]) and SUDs (-&#x2009;0.48[CI&#x2009;-&#x2009;0.92,&#x2009;-&#x2009;0.04]). All other significant therapeutic effects have either low, very low, or even no grade of evidence. Cannabinoids produce different adverse events, and there is low to moderate grade of evidence for this conclusion depending on the type of cannabinoid.<br><br>CONCLUSIONS: Cannabinoids are effective therapeutics for several medical indications if their specific pharmacological properties are considered. We suggest that future systematic studies in the cannabinoid field should be based upon their specific pharmacology.}, }
@article {pmid35981308, year = {2023}, author = {Altinkaynak, M and Gok, GK and Ozmen, B and Buyukdemir, S and Akpinar, TS and Erten, SN and Saka, B}, title = {Prognostic Value of Regular Nutritional Treatment in Patients With Amyotrophic Lateral Sclerosis.}, journal = {The neurologist}, volume = {28}, number = {3}, pages = {166-172}, doi = {10.1097/NRL.0000000000000460}, pmid = {35981308}, issn = {2331-2637}, mesh = {Humans ; Prognosis ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Nutritional Status ; Body Mass Index ; *Malnutrition/etiology ; Serum Albumin/analysis ; }, abstract = {BACKGROUND: Malnutrition adversely affects the prognosis of amyotrophic lateral sclerosis (ALS). The aim of this study was to evaluate the effect of regular nutrition treatment and follow-up in clinical nutrition outpatient clinic (CNOC) on survival in ALS patients.<br><br>MATERIALS AND METHODS: The study included 55 ALS patients who were admitted and followed up in CNOC. Malnutrition was diagnosed using ESPEN criteria and nutrition treatment was planned according to needs of each patient. Nutritional status was followed up by body mass index (BMI), bioelectrical impedence analysis, and serum albumin. During the follow-up, survivors and nonsurvivors were compared according to their nutrition treatment success and changes in the anthropometric and laboratory measurements.<br><br>RESULTS: Body weight, BMI, and fat free mass were decreased during the follow-up in both survivors and nonsurvivors (P <0.01). The decrease in the serum albumin and BMI were significantly higher in nonsurvivors (P <0.01). Mortality rate was lower in those with higher adherence to nutrition treatment (P <0.01) and patients with lower adherence to nutrition treatment showed more significant decrease in serum albumin levels (P <0.01).<br><br>CONCLUSION: A personalized nutrition treatment combined with increased nutritional adherence in CNOC can decrease mortality in ALS patients.}, }
@article {pmid35980063, year = {2023}, author = {Jaberi, KR and Alamdari-Palangi, V and Jaberi, AR and Esmaeli, Z and Shakeri, A and Gheibi Hayat, SM and Tajbakhsh, A and Savardashtaki, A}, title = {The Regulation, Functions, and Signaling of miR-153 in Neurological Disorders, and Its Potential as a Biomarker and Therapeutic Target.}, journal = {Current molecular medicine}, volume = {23}, number = {9}, pages = {863-875}, doi = {10.2174/1566524023666220817145638}, pmid = {35980063}, issn = {1875-5666}, mesh = {Humans ; Animals ; Mice ; *MicroRNAs/genetics/metabolism ; *Alzheimer Disease ; Neurogenesis ; Biomarkers ; *Biological Phenomena ; }, abstract = {Treatment of neurological disorders has always been one of the challenges facing scientists due to poor prognosis and symptom overlap, as well as the progress of the disease process. Neurological disorders such as Huntington's, Parkinson's, Alzheimer's diseases, and Amyotrophic Lateral Sclerosis are very debilitating. Therefore, finding a biomarker is essential for early diagnosis and treatment goals. Recent studies have focused more on molecular factors and gene manipulation to find effective diagnostic and therapeutic biomarkers. Among these factors, microRNAs (miRNAs/ miRs) have attracted much attention. On the other hand, a growing correlation between miRNAs and neurological disorders has caused scientists to consider it as a diagnostic and therapeutic target. In this line, the miR-153 is one of the most important and highly conserved miRNAs in mice and humans, whose expression level is not only altered in neurological disorders but also improves neurogenesis. MiR-153 can regulate multiple biological processes by targeting various factors. Furthermore, the miR-153 expression also can be regulated by important regulators, such as long non-coding RNAs (e.g., KCNQ1OT1) and some compounds (e.g., Tanshinone IIA) altering the expression of miR-153. Given the growing interest in miR-153 as a biomarker and therapeutic target for neurological diseases as well as the lack of comprehensive investigation of miR-153 function in these disorders, it is necessary to identify the downstream and upstream targets and also it's potential as a therapeutic biomarker target. In this review, we will discuss the critical role of miR-153 in neurological disorders for novel diagnostic and prognostic purposes and its role in multi-drug resistance.}, }
@article {pmid35974950, year = {2022}, author = {Hakiminia, S and Esmaeeli, Z and Moghadamnia, AA and Jorsaraei, SGA and Feizi, F and Khafri, S and Memariani, Z and Shirafkan, H and Mozaffarpur, SA}, title = {Effect of Cassia fistula L. aqueous extract in maternal reproductive outcome, some serum indices and fetal anomaly frequency in rat.}, journal = {Caspian journal of internal medicine}, volume = {13}, number = {3}, pages = {475-483}, pmid = {35974950}, issn = {2008-6164}, abstract = {BACKGROUND: Cassia fistula was used traditionally as laxative in pregnant women. Nevertheless, its fetal and maternal effects in pregnancy have not been studied yet.<br><br>METHODS: Oral (Lethal Dose, 50%) LD50 was determined in mice. In addition, a control group, pregnant rats in other 5 experimental groups (n=12) received orally C. fistula aqueous extract (500, 1000 and 2000 mg/kg), tween80 (10%) and distilled water during pregnancy up to the delivery (21-23 days). Some serum indices were evaluated in maternal blood samples after delivery. Histopathologic and histomorphometric evaluations were performed on the selected slices of newborn rats.<br><br>RESULTS: Anthraquinone&#x200e; content of the aqueous extract was 0.34% w/w. Oral LD50 was obtained more than 5000mg/kg. No abortions and newborn anomalies were observed in groups. The height and weight of the offspring were significantly reduced by the administration of 500, and 2000 mg/kg of extract compared to control. There was no significant change in maternal blood urea and creatinine. Higher concentration (2000mg/kg) led to ALT elevation. ALS levels decreased dose-dependency in treatment groups comparing to control. Histopathological findings showed significant lung vascular congestion, and hypertrophy of heart in group tween80, and significant hepatic parenchymal inflammation in tween80 and 2000mg/kg and 1000mg/kg groups. In all tissues of all groups, malpighian body area and bowman's capsule space significantly increased compared to the control group.<br><br>CONCLUSION: It seems C. fistula extract is safe in pregnancy. Because of confounding role of tween80 in histopathological finding, more research is necessary.}, }
@article {pmid35973771, year = {2022}, author = {Li, W and Cao, Y and Liu, Z and Wei, S and Huang, H and Lan, Y and Sun, Y and Huang, Z}, title = {Investigation of resistance mechanisms to bentazone in multiple resistant Amaranthus retroflexus populations.}, journal = {Pesticide biochemistry and physiology}, volume = {186}, number = {}, pages = {105164}, doi = {10.1016/j.pestbp.2022.105164}, pmid = {35973771}, issn = {1095-9939}, mesh = {*Amaranthus/genetics ; Benzothiadiazines ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; }, abstract = {Redroot amaranth (Amaranthus retroflexus L.) is a noxious weed that affects soybean production in China. Experiments were conducted to determine the molecular basis of resistance to bentazone. Whole-plant dose-response experiments showed that two populations (R1 and R2) exhibited resistance to bentazone with resistance indices of 9.01 and 6.85, respectively. Sequencing of the psbA gene revealed no amino acid substitution in the two populations. qRT-PCR analysis verified that psbA gene expression in R1 and R2 populations was increased significantly after treatment with bentazone, which was 3-fold and 5-fold higher than that in S1 and S2 populations, respectively. The P450 inhibitor malathion significantly reduced the level of resistance in the R1 and R2 populations when used prior to bentazone treatment. The R1 population exhibited multiple resistance to thifensulfuron-methyl and lactofen, caused by target site mutations (Asp-376-Glu in ALS, Arg-128-Gly in PPO2). In conclusion, increased gene expression of the psbA gene and enhanced herbicide metabolism seem to be the basis of resistance to bentazone in these A. retroflexus populations.}, }
@article {pmid35973760, year = {2022}, author = {Cao, Y and Zhou, X and Wei, S and Huang, H and Lan, Y and Li, W and Sun, Y and Huang, Z}, title = {Multiple resistance to ALS-inhibiting and PPO-inhibiting herbicides in Chenopodium album L. from China.}, journal = {Pesticide biochemistry and physiology}, volume = {186}, number = {}, pages = {105155}, doi = {10.1016/j.pestbp.2022.105155}, pmid = {35973760}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Chenopodium album/genetics/metabolism ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Protoporphyrinogen Oxidase ; }, abstract = {Common lambsquarters (Chenopodium album L.) is a broadleaf weed that can severely damage soybean fields. Two C. album populations (1744 and 1731) suspected resistant to imazethapyr were investigated for resistance levels to imazethapyr, thifensulfuron-methyl, and fomesafen and their resistance mechanisms were investigated. Whole-plant dose-response assays revealed that, compared to the susceptible (S) population, the 1744 population was 16.5-fold resistant to imazethapyr, slightly resistant to thifensulfuron-methyl (resistance index [R/S], <3). The 1731 population was 18.8-fold resistant to imazethapyr, 2.9-fold resistant to thifensulfuron-methyl, and 5.1-fold resistant to fomesafen. In vitro acetolactate synthase (ALS) assays showed 17.1-fold and 19.3-fold resistance levels of 1744 and 1731 populations to imazethapyr respectively. ALS gene sequence analysis identified Ala122Thr amino acid substitution in the 1744 population and Ser653Thr amino acid substitution in the 1731 population. No mutations of the protoporphyrinogen oxidase (PPO) gene were detected. However, pre-treatment with malathion reversed fomesafen resistance, suggesting nontarget-site resistance mechanisms likely play a role in the 1731 population.}, }
@article {pmid35972130, year = {2022}, author = {Al-Madboly, LA and Abd El-Salam, MA and Bastos, JK and El-Shorbagy, SH and El-Morsi, RM}, title = {Novel Preclinical Study of Galloylquinic Acid Compounds from Copaifera lucens with Potent Antifungal Activity against Vaginal Candidiasis Induced in a Murine Model via Multitarget Modes of Action.}, journal = {Microbiology spectrum}, volume = {10}, number = {5}, pages = {e0272421}, pmid = {35972130}, issn = {2165-0497}, mesh = {Female ; Mice ; Humans ; Animals ; Antifungal Agents/pharmacology/therapeutic use ; *Fabaceae ; Disease Models, Animal ; Cytochromes c/pharmacology/therapeutic use ; Agar/pharmacology/therapeutic use ; Catalase/pharmacology/therapeutic use ; *Candidiasis, Vulvovaginal/drug therapy/microbiology ; Candida albicans ; *Candidiasis/drug therapy ; Biofilms ; Microbial Sensitivity Tests ; Virulence Factors ; Ergosterol ; Phospholipases/pharmacology/therapeutic use ; Peptide Hydrolases/pharmacology/therapeutic use ; }, abstract = {Vaginal candidiasis is a medical condition characterized by the overgrowth of Candida spp. in the vaginal cavity with complex recurrent pathogenicity as well as tolerance to antifungal therapy and hence is awaiting more safe and effective treatments. This work aimed to assess the potential antifungal activity of galloylquinic acid compounds (GQAs) from Copaifera lucens leaves against vaginal Candida albicans. The antifungal susceptibility test was performed against 20 isolates of multidrug-resistant (MDR) C. albicans using agar diffusion and broth microdilution assays. The results showed that GQAs exhibited strong antagonistic activity against the test isolates, with inhibition zone diameters ranging from 26 to 38 mm and low MICs (1 to 16 μg/mL) as well as minimum fungicidal concentrations (2 to 32 μg/mL). The MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] assay confirmed the safety of GQAs against the Vero cell line, showing a 50% inhibitory concentration (IC50) of 168.17 mg/mL. A marked difference in the growth pattern of the treated and untreated pathogens was also observed, where a concentration-dependent reduction in the growth rate occurred. Moreover, a pronounced fungicidal effect was demonstrated 6 h after treatment with 1× the minimum fungicidal concentration (MFC), as evidenced by time-kill assays, where the number of survivors was decreased a 6-fold. GQAs effectively inhibited and eradicated about 80% of C. albicans biofilm at 6 μg/mL and 32 μg/mL, respectively. Interestingly, GQAs disturbed the fungal membrane integrity, induced cell lysis, and reduced the virulence factors (proteinase and phospholipase) as well as the catalase activity. Moreover, the ergosterol content in the plasma membrane decreased in a concentration-dependent manner. Additionally, the altered mitochondrial membrane potential was associated with an increased release of cytochrome c from mitochondria to the cytosol, suggesting the initiation of early apoptosis in GQA-treated cells. Transcriptional analysis revealed that all test genes encoding virulence traits, including SAP1, PLB1, LIP1, HWP1, and ALS1, were markedly downregulated in GQA-treated cells compared to the control. The in vivo murine model of vaginal candidiasis further confirmed the therapeutic activity of GQAs (4 mg/kg of body weight) against C. albicans. This work comprehensively evaluated the antifungal, antivirulence, and antibiofilm activities of GQAs against C. albicans isolates using in vitro and in vivo models, providing molecular-level insights into the antifungal mechanism of action and experimental evidence that supports the potential use of GQAs for the treatment of vaginal candidiasis. IMPORTANCE Our work presents a new perspective on the potential use of GQAs as safe and highly effective phytochemicals against MDR C. albicans. This microorganism colonizes the human vaginal epithelium, causing vaginal candidiasis, a condition characterized by recurrent pathogenicity and tolerance to traditional antifungal therapy. Based on the results of in vitro tests, our study reports GQAs antifungal modes of action. These compounds exhibited an anticandidal effect by deactivating the fungal hydrolytic enzymes, reducing ergosterol content in the plasma membrane, altering the potential of the mitochondrial membrane, and inducing apoptosis. Additionally, GQAs showed high activity in eradicating the biofilm formed by the fungus via the downregulation of HWP1, ALS, SAP, PLB, and LIP genes, which are constitutively expressed in the biofilm. In an in vivo murine model of vaginal candidiasis, GQAs further demonstrated strong evidence of their effectiveness as an antifungal therapy. In this regard, our findings provide novel insights into the potential therapeutic use of these phytoactive molecules for vaginal candidiasis treatment.}, }
@article {pmid35963713, year = {2022}, author = {Chaytow, H and Carroll, E and Gordon, D and Huang, YT and van der Hoorn, D and Smith, HL and Becker, T and Becker, CG and Faller, KME and Talbot, K and Gillingwater, TH}, title = {Targeting phosphoglycerate kinase 1 with terazosin improves motor neuron phenotypes in multiple models of amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {83}, number = {}, pages = {104202}, pmid = {35963713}, issn = {2352-3964}, support = {TALBOT-GORDON/APR15/831-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Animals ; DNA-Binding Proteins/genetics ; Humans ; Mice ; Motor Neurons/metabolism ; Phenotype ; Phosphoglycerate Kinase/genetics/*metabolism ; Prazosin/analogs &amp; derivatives ; Zebrafish/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with heterogeneous aetiology and a complex genetic background. Effective therapies are therefore likely to act on convergent pathways such as dysregulated energy metabolism, linked to multiple neurodegenerative diseases including ALS.<br><br>METHODS: Activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) was increased genetically or pharmacologically using terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS. Multiple disease phenotypes were assessed to determine the therapeutic potential of this approach, including axon growth and motor behaviour, survival and cell death following oxidative stress.<br><br>FINDINGS: We have found that targeting a single bioenergetic protein, PGK1, modulates motor neuron vulnerability in vivo. In zebrafish models of ALS, overexpression of PGK1 rescued motor axon phenotypes and improved motor behaviour. Treatment with terazosin, an FDA-approved compound with a known non-canonical action of increasing PGK1 activity, also improved these phenotypes. Terazosin treatment extended survival, improved motor phenotypes and increased motor neuron number in Thy1-hTDP-43 mice. In ESC-derived motor neurons expressing TDP-43[M337V], terazosin protected against oxidative stress-induced cell death and increased basal glycolysis rates, while rescuing stress granule assembly.<br><br>INTERPRETATION: Our data demonstrate that terazosin protects motor neurons via multiple pathways, including upregulating glycolysis and rescuing stress granule formation. Repurposing terazosin therefore has the potential to increase the limited therapeutic options across all forms of ALS, irrespective of disease cause.<br><br>FUNDING: This work was supported by project grant funding from MND Scotland, the My Name'5 Doddie Foundation, Medical Research Council Doctoral Student Training Fellowship [Ref: BST0010Z] and Academy of Medical Sciences grant [SGL023\1100].}, }
@article {pmid35962027, year = {2022}, author = {Pancotti, C and Birolo, G and Rollo, C and Sanavia, T and Di Camillo, B and Manera, U and Chiò, A and Fariselli, P}, title = {Deep learning methods to predict amyotrophic lateral sclerosis disease progression.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {13738}, pmid = {35962027}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; *Deep Learning ; Disease Progression ; Humans ; Machine Learning ; *Neurodegenerative Diseases ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a highly complex and heterogeneous neurodegenerative disease that affects motor neurons. Since life expectancy is relatively low, it is essential to promptly understand the course of the disease to better target the patient's treatment. Predictive models for disease progression are thus of great interest. One of the most extensive and well-studied open-access data resources for ALS is the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) repository. In 2015, the DREAM-Phil Bowen ALS Prediction Prize4Life Challenge was held on PRO-ACT data, where competitors were asked to develop machine learning algorithms to predict disease progression measured through the slope of the ALSFRS score between 3 and 12 months. However, although it has already been successfully applied in several studies on ALS patients, to the best of our knowledge deep learning approaches still remain unexplored on the ALSFRS slope prediction in PRO-ACT cohort. Here, we investigate how deep learning models perform in predicting ALS progression using the PRO-ACT data. We developed three models based on different architectures that showed comparable or better performance with respect to the state-of-the-art models, thus representing a valid alternative to predict ALS disease progression.}, }
@article {pmid35959400, year = {2022}, author = {Lee, S and Plavina, T and Singh, CM and Xiong, K and Qiu, X and Rudick, RA and Calabresi, PA and Stevenson, L and Graham, D and Raitcheva, D and Green, C and Matias, M and Uzgiris, AJ}, title = {Development of a Highly Sensitive Neurofilament Light Chain Assay on an Automated Immunoassay Platform.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {935382}, pmid = {35959400}, issn = {1664-2295}, support = {U01 NS111678/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Neurofilament light chain (NfL) is an axonal cytoskeletal protein that is released into the extracellular space following neuronal or axonal injury associated with neurological conditions such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other diseases. NfL is detectable in the cerebrospinal fluid (CSF) and blood. Numerous studies on MS have demonstrated that NfL is correlated with disease activity, predicts disease progression, and is reduced by treatment with MS disease-modifying drugs, making NfL an attractive candidate to supplement existing clinical and imaging measures in MS. However, for NfL to achieve its potential as a clinically useful biomarker for clinical decision-making or drug development, a standardized, practical, and widely accessible assay is needed. Our objective was to develop a novel NfL assay on an automated, globally available immunoassay platform and validate its performance.<br><br>METHODS: A prototype NfL assay was first developed and evaluated on the ADVIA Centaur[&#xae;] XP immunoassay system from Siemens Healthineers. The lower limit of quantitation (LLoQ), within-lab precision, assay range, cross-reactivity with neurofilament medium and heavy chains, and effect of interfering substances were determined. NfL assay values in serum and CSF were compared with radiological and clinical disease activity measures in patients with MS and ALS, respectively. This assay was further optimized to utilize serum, plasma, and CSF sample types on the Atellica[&#xae;] IM system and transferred to Siemens' CLIA laboratory where it was analytically validated as a laboratory-developed test (LDT).<br><br>RESULTS: In this study, an LLoQ of 1.85 pg/mL, within-lab precision <6%, and an assay range of up to 646 pg/mL were demonstrated with the serum prototype assay. Cross-reactivity of <0.7% with the neurofilament medium and heavy chains was observed. Serum and CSF NfL assay values were associated with radiological and clinical disease activity measures in patients with MS and ALS, respectively. The optimized version of the NfL assay demonstrated specimen equivalence with additional plasma tube types and was analytically validated as an LDT.<br><br>CONCLUSION: The analytical performance of the NfL assay fulfilled all acceptance criteria; therefore, we suggest that the assay is acceptable for use in both research and clinical practice settings to determine elevated NfL levels in patients.}, }
@article {pmid35959105, year = {2022}, author = {Dissanayake, KN and Redman, RR and Mackenzie, H and Eddleston, M and Ribchester, RR}, title = {"Calcium bombs" as harbingers of synaptic pathology and their mitigation by magnesium at murine neuromuscular junctions.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {937974}, pmid = {35959105}, issn = {1662-5099}, support = {MR/M024075/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Excitotoxicity is thought to be an important factor in the onset and progression of amyotrophic lateral sclerosis (ALS). Evidence from human and animal studies also indicates that early signs of ALS include degeneration of motor nerve terminals at neuromuscular junctions (NMJs), before degeneration of motor neuron cell bodies. Here we used a model of excitotoxicity at NMJs in isolated mouse muscle, utilizing the organophosphorus (OP) compound omethoate, which inhibits acetylcholinesterase activity. Acute exposure to omethoate (100 μM) induced prolonged motor endplate contractures in response to brief tetanic nerve stimulation at 20-50 Hz. In some muscle fibers, Fluo-4 fluorescence showed association of these contractures with explosive increases in Ca[2+] ("calcium bombs") localized to motor endplates. Calcium bombs were strongly and selectively mitigated by increasing Mg[2+] concentration in the bathing medium from 1 to 5 mM. Overnight culture of nerve-muscle preparations from Wld[S] mice in omethoate or other OP insecticide components and their metabolites (dimethoate, cyclohexanone, and cyclohexanol) induced degeneration of NMJs. This degeneration was also strongly mitigated by increasing [Mg[2+]] from 1 to 5 mM. Thus, equivalent increases in extracellular [Mg[2+]] mitigated both post-synaptic calcium bombs and degeneration of NMJs. The data support a link between Ca[2+] and excitotoxicity at NMJs and suggest that elevating extracellular [Mg[2+]] could be an effective intervention in treatment of synaptic pathology induced by excitotoxic triggers.}, }
@article {pmid35958519, year = {2022}, author = {Brooks, BR and Berry, JD and Ciepielewska, M and Liu, Y and Zambrano, GS and Zhang, J and Hagan, M}, title = {Intravenous edaravone treatment in ALS and survival: An exploratory, retrospective, administrative claims analysis.}, journal = {EClinicalMedicine}, volume = {52}, number = {}, pages = {101590}, pmid = {35958519}, issn = {2589-5370}, abstract = {BACKGROUND: We aimed to evaluate overall survival in US patients with amyotrophic lateral sclerosis (ALS) treated with intravenous (IV) edaravone compared with those not treated with IV edaravone in a real-world setting.<br><br>METHODS: This exploratory retrospective comparative effectiveness observational analysis included patients with ALS who were enrolled in an administrative claims database from 8 August 2017 to 31 March 2020. Propensity score matching identified IV edaravone-treated patients (cases) and non-edaravone-treated patients (controls) matched for covariates: age, race, geographic region, sex, pre-index disease duration, insurance, history of cardiovascular disease, riluzole prescription, gastrostomy tube placement, artificial nutrition, noninvasive ventilation, and all-cause hospitalisation. For cases, the index date was the date of the first claim for IV edaravone. For controls, it was the date IV edaravone was available (8 August 2017). The effect of IV edaravone on all-cause mortality was estimated with shared frailty Cox regression analysis.<br><br>FINDINGS: 318 cases were matched to 318 controls. In both groups, 208 patients (65.4%) had a history of riluzole prescription. As of 31 March 2021, there were 155 deaths (48.7%) among the cases and 196 among the controls (61.6%). Median overall survival time was 29.5 months with edaravone and 23.5 months without, respectively, and the risk of death was 27% lower in cases than in controls (HR, 0.73; 95% CI, 0.59-0.91; p=0.005).<br><br>INTERPRETATION: In this real-world analysis, IV edaravone treatment in a large predominantly riluzole-treated US cohort was associated with prolonged overall survival compared with not using IV edaravone. Data from adequately powered RCTs are needed to support this finding.<br><br>FUNDING: Funded by Mitsubishi Tanabe Pharma America.}, }
@article {pmid35954242, year = {2022}, author = {Zhang, Q and Terawaki, S and Oikawa, D and Okina, Y and Usuki, Y and Ito, H and Tokunaga, F}, title = {Suppression of Linear Ubiquitination Ameliorates Cytoplasmic Aggregation of Truncated TDP-43.}, journal = {Cells}, volume = {11}, number = {15}, pages = {}, pmid = {35954242}, issn = {2073-4409}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Humans ; Hydrocarbons, Aromatic ; NF-kappa B/metabolism ; Ubiquitin/metabolism ; Ubiquitination ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a predominant component of inclusions in the brains and spines of patients with amyotrophic lateral sclerosis (ALS). The progressive accumulation of inclusions leads to proteinopathy in neurons. We have previously shown that Met1(M1)-linked linear ubiquitin, which is specifically generated by the linear ubiquitin chain assembly complex (LUBAC), is colocalized with TDP-43 inclusions in neurons from optineurin-associated familial and sporadic ALS patients, and affects NF-κB activation and apoptosis. To examine the effects of LUBAC-mediated linear ubiquitination on TDP-43 proteinopathies, we performed cell biological analyses using full-length and truncated forms of the ALS-associated Ala315→Thr (A315T) mutant of TDP-43 in Neuro2a cells. The truncated A315T mutants of TDP-43, which lack a nuclear localization signal, efficiently generated cytoplasmic aggregates that were colocalized with multiple ubiquitin chains such as M1-, Lys(K)48-, and K63-chains. Genetic ablation of HOIP or treatment with a LUBAC inhibitor, HOIPIN-8, suppressed the cytoplasmic aggregation of A315T mutants of TDP-43. Moreover, the enhanced TNF-α-mediated NF-κB activity by truncated TDP-43 mutants was eliminated in the presence of HOIPIN-8. These results suggest that multiple ubiquitinations of TDP-43 including M1-ubiquitin affect protein aggregation and inflammatory responses in vitro, and therefore, LUBAC inhibition ameliorates TDP-43 proteinopathy.}, }
@article {pmid35950263, year = {2022}, author = {Petzold, A}, title = {The 2022 Lady Estelle Wolfson lectureship on neurofilaments.}, journal = {Journal of neurochemistry}, volume = {163}, number = {3}, pages = {179-219}, pmid = {35950263}, issn = {1471-4159}, mesh = {Humans ; *Intermediate Filaments/metabolism ; Neurofilament Proteins/metabolism ; *Charcot-Marie-Tooth Disease/genetics ; Biomarkers ; Protein Isoforms ; }, abstract = {Neurofilament proteins (Nf) have been validated and established as a reliable body fluid biomarker for neurodegenerative pathology. This review covers seven Nf isoforms, Nf light (NfL), two splicing variants of Nf medium (NfM), two splicing variants of Nf heavy (NfH), α -internexin (INA) and peripherin (PRPH). The genetic and epigenetic aspects of Nf are discussed as relevant for neurodegenerative diseases and oncology. The comprehensive list of mutations for all Nf isoforms covers Amyotrophic Lateral Sclerosis, Charcot-Marie Tooth disease, Spinal muscular atrophy, Parkinson Disease and Lewy Body Dementia. Next, emphasis is given to the expanding field of post-translational modifications (PTM) of the Nf amino acid residues. Protein structural aspects are reviewed alongside PTMs causing neurodegenerative pathology and human autoimmunity. Molecular visualisations of NF PTMs, assembly and stoichiometry make use of Alphafold2 modelling. The implications for Nf function on the cellular level and axonal transport are discussed. Neurofilament aggregate formation and proteolytic breakdown are reviewed as relevant for biomarker tests and disease. Likewise, Nf stoichiometry is reviewed with regard to in vitro experiments and as a compensatory mechanism in neurodegeneration. The review of Nf across a spectrum of 87 diseases from all parts of medicine is followed by a critical appraisal of 33 meta-analyses on Nf body fluid levels. The review concludes with considerations for clinical trial design and an outlook for future research.}, }
@article {pmid35943279, year = {2025}, author = {Rushanan, SG and Nilsen, DM and Grajo, L and Caroll, K}, title = {Assessing and Building Clinical Competence in Occupational Therapists Treating Patients with Neurodegenerative Disease: A Community of Practice Study.}, journal = {Occupational therapy in health care}, volume = {39}, number = {1}, pages = {1-21}, doi = {10.1080/07380577.2022.2105470}, pmid = {35943279}, issn = {1541-3098}, mesh = {Humans ; *Clinical Competence ; *Neurodegenerative Diseases/therapy ; *Occupational Therapy ; Female ; Male ; *Occupational Therapists ; Middle Aged ; Adult ; Health Knowledge, Attitudes, Practice ; Community of Practice ; }, abstract = {Communities of practice (CoPs) can be an effective means by which to efficiently build skills, knowledge, and competence for occupational therapists. The objective of this study was to assess changes in clinical competence for occupational therapists treating patients with neurodegenerative diseases (NDD) after participating in a CoP. A cohort of home health occupational therapists was recruited to participate in a seven-week CoP focused on treating patients with NDD. A single group pretest posttest mixed methods design was used to measure changes in clinical competence of the participants through a validated self-report assessment tool and a qualitative analysis of treatment summaries. Thirteen occupational therapists participated in the study. There were significant changes in pretest and post-test knowledge, beliefs, and action scores, indicating a positive change in the participants' competence to treat patients with NDD. Qualitative findings support positive changes in clinical competence through increased knowledge, confidence, and use of interventions aimed at optimizing occupational performance for this population. In summary, the CoP was an effective method for building clinical competence for treating patients with NDD with this cohort of occupational therapists.}, }
@article {pmid35942674, year = {2022}, author = {Witzel, S and Mayer, K and Oeckl, P}, title = {Biomarkers for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {35}, number = {5}, pages = {699-704}, doi = {10.1097/WCO.0000000000001094}, pmid = {35942674}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Biomarkers ; Humans ; *Neurodegenerative Diseases ; Prognosis ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is an incurable, devastating neurodegenerative disease. Still, the diagnosis is mainly based on clinical symptoms, and the treatment options are strongly limited. However, the pipeline of potential treatments currently tested in clinical trials is promising. This review will discuss developments in ALS biomarker research and applications within the last 2 years and suggest future directions and needs.<br><br>RECENT FINDINGS: The diagnostic and prognostic utility of neurofilaments, a general marker for axoneuronal degeneration, has been confirmed by further studies in patients with ALS, and neurofilaments are finding their way into routine diagnostic and clinical trials. Additionally, there have been advancements in developing and implementing disease-specific biomarkers, especially in patients with a genetic variant, such as SOD1 or C9orf72 . Here, biomarkers have already been used as target markers and outcome parameters for novel treatment approaches. In addition, several novel biomarkers have shown encouraging results but should be discussed in the context of their early stage of assay and clinical establishment.<br><br>SUMMARY: The first biomarkers have found their way into clinical routine in ALS. In light of an increasing pipeline of potential treatments, further progress in discovering and implementing novel and existing biomarkers is crucial.}, }
@article {pmid35942672, year = {2022}, author = {Dorst, J and Genge, A}, title = {Clinical studies in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {35}, number = {5}, pages = {686-692}, doi = {10.1097/WCO.0000000000001099}, pmid = {35942672}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/therapeutic use ; Follow-Up Studies ; Humans ; Longitudinal Studies ; }, abstract = {PURPOSE OF REVIEW: The purpose of this review is to discuss the most important recent clinical studies in amyotrophic lateral sclerosis (ALS), including their impact on clinical practice, their methodology, and open questions to be addressed in the future.<br><br>RECENT FINDINGS: This article focuses on studies, which provided either a positive primary endpoint or positive post hoc analysis, including edaravone, sodium phenylbutyrate-taurursodiol, rasagiline, tofersen, and high-caloric, fat-rich nutrition. It also covers recent developments in the design of clinical ALS studies with regard to inclusion criteria, stratification factors, and outcome parameters.<br><br>SUMMARY: Recent clinical studies have indicated various substances to be considered for treatment of ALS. Edaravone has been approved by the US Food and Drug Association (FDA) but not by the European Medicines Agency (EMA), and further studies testing oral formulations are currently conducted. A follow-up study with sodium phenylbutyrate-taurursodiol is ongoing, while follow-up studies for rasagiline and high-caloric, fat-rich nutrition are planned. A phase III study with tofersen was negative but nevertheless yielded promising results. Important developments regarding the design of clinical ALS studies include the implementation of neurofilament light chain (NfL) levels as a standard outcome parameter and the consideration of progression rate for therapeutic response and stratification.}, }
@article {pmid35936442, year = {2022}, author = {Marino, A and Battaglini, M and Moles, N and Ciofani, G}, title = {Natural Antioxidant Compounds as Potential Pharmaceutical Tools against Neurodegenerative Diseases.}, journal = {ACS omega}, volume = {7}, number = {30}, pages = {25974-25990}, pmid = {35936442}, issn = {2470-1343}, abstract = {Natural antioxidants are a very large diversified family of molecules classified by activity (enzymatic or nonenzymatic), chemical-physical properties (e.g., hydrophilic or lipophilic), and chemical structure (e.g., vitamins, polyphenols, etc.). Research on natural antioxidants in various fields, such as pharmaceutics, nutraceutics, and cosmetics, is among the biggest challenges for industry and science. From a biomedical point of view, the scavenging activity of reactive oxygen species (ROS) makes them a potential tool for the treatment of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, and amyotrophic lateral sclerosis (ALS). In addition to the purified phytochemical compounds, a variety of natural extracts characterized by a complex mixture of antioxidants and anti-inflammatory molecules have been successfully exploited to rescue preclinical models of these diseases. Extracts derived from Ginkgo biloba, grape, oregano, curcumin, tea, and ginseng show multitherapeutic effects by synergically acting on different biochemical pathways. Furthermore, the reduced toxicity associated with many of these compounds limits the occurrence of side effects. The support of nanotechnology for improving brain delivery, controlling release, and preventing rapid degradation and excretion of these compounds is of fundamental importance. This review reports on the most promising results obtained on in vitro systems, in vivo models, and in clinical trials, by exploiting natural-derived antioxidant compounds and extracts, in their free form or encapsulated in nanocarriers.}, }
@article {pmid35933467, year = {2022}, author = {Cunha-Oliveira, T and Carvalho, M and Sardão, V and Ferreiro, E and Mena, D and Pereira, FB and Borges, F and Oliveira, PJ and Silva, FSG}, title = {Integrative Profiling of Amyotrophic Lateral Sclerosis Lymphoblasts Identifies Unique Metabolic and Mitochondrial Disease Fingerprints.}, journal = {Molecular neurobiology}, volume = {59}, number = {10}, pages = {6373-6396}, pmid = {35933467}, issn = {1559-1182}, mesh = {Adenosine Triphosphate ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Bayes Theorem ; Humans ; *Mitochondrial Diseases ; Mutation/genetics ; *Neurodegenerative Diseases ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with a rapid progression and no effective treatment. Metabolic and mitochondrial alterations in peripheral tissues of ALS patients may present diagnostic and therapeutic interest. We aimed to identify mitochondrial fingerprints in lymphoblast from ALS patients harboring SOD1 mutations (mutSOD1) or with unidentified mutations (undSOD1), compared with age-/sex-matched controls. Three groups of lymphoblasts, from mutSOD1 or undSOD1 ALS patients and age-/sex-matched controls, were obtained from Coriell Biobank and divided into 3 age-/sex-matched cohorts. Mitochondria-associated metabolic pathways were analyzed using Seahorse MitoStress and ATP Rate assays, complemented with metabolic phenotype microarrays, metabolite levels, gene expression, and protein expression and activity. Pooled (all cohorts) and paired (intra-cohort) analyses were performed by using bioinformatic tools, and the features with higher information gain values were selected and used for principal component analysis and Naïve Bayes classification. Considering the group as a target, the features that contributed to better segregation of control, undSOD1, and mutSOD1 were found to be the protein levels of Tfam and glycolytic ATP production rate. Metabolic phenotypic profiles in lymphoblasts from ALS patients with mutSOD1 and undSOD1 revealed unique age-dependent different substrate oxidation profiles. For most parameters, different patterns of variation in experimental endpoints in lymphoblasts were found between cohorts, which may be due to the age or sex of the donor. In the present work, we investigated several metabolic and mitochondrial hallmarks in lymphoblasts from each donor, and although a high heterogeneity of results was found, we identified specific metabolic and mitochondrial fingerprints, especially protein levels of Tfam and glycolytic ATP production rate, that may have a diagnostic and therapeutic interest.}, }
@article {pmid35923520, year = {2022}, author = {Ronquest, NA and Paret, K and Lucas, A and Ciepielewska, M and Hagan, M}, title = {Quantifying the Value of Introducing an Oral Drug Delivery Option for Edaravone: A Review of Analyses Evaluating the Economic Impact of Oral versus Intravenous Formulations.}, journal = {ClinicoEconomics and outcomes research : CEOR}, volume = {14}, number = {}, pages = {499-511}, pmid = {35923520}, issn = {1178-6981}, abstract = {BACKGROUND: Drug formulation and route of administration can have an impact on not only patients' quality of life and disease outcomes but also costs of care. It is essential for decision makers to use appropriate economic modeling methods to guide drug coverage policies and to support patients' decision-making.<br><br>PURPOSE: To illustrate key cost considerations for decision makers in economic evaluation of innovative oral formulations as alternatives to intravenous medication.<br><br>MATERIALS AND METHODS: A structured literature review was conducted using the PubMed database to examine methods used for quantifying the economic impact of introducing a new oral pharmaceutical formulation as an alternative to intravenous medication. To illustrate the methods described in this review, a cost-minimization analysis was conducted to quantify the impact of introducing an oral formulation of a medication originally developed as an intravenous treatment for amyotrophic lateral sclerosis.<br><br>RESULTS: We identified 14 published evaluations of oral and intravenous formulations from 10 countries across a variety of disease areas. The identified studies used cost-effectiveness (n=10), cost-minimization (n=2), and cost-calculation (n=2) modeling approaches. All but one (13/14) reported outcomes from payers' perspective, while societal perspectives were also incorporated in 3 of the reviewed evaluations. One study estimated costs from a public hospital's perspective. Only a subset of the identified studies accounted for the effects of safety (n=6) or efficacy (n=8) differences on treatment costs when estimating the costs of a formulation choice. Many studies that omitted these aspects did not include rationales for their decisions.<br><br>CONCLUSION: We found significant design variations in published models that estimated the impact of an additional formulation option on the treatment costs to payers and the society. Models need to be accompanied with clear descriptions on rationales for their time horizons and assumptions on how different formulations may affect healthcare costs from the selected perspectives.}, }
@article {pmid35915574, year = {2023}, author = {Glennie, N and Harris, FM and France, EF}, title = {Perceptions and experiences of control among people living with motor neurone disease: a systematic review and thematic synthesis.}, journal = {Disability and rehabilitation}, volume = {45}, number = {16}, pages = {2554-2566}, doi = {10.1080/09638288.2022.2104942}, pmid = {35915574}, issn = {1464-5165}, mesh = {Humans ; Qualitative Research ; *Health Personnel ; }, abstract = {PURPOSE: Current research suggests that feeling a lack of control is common among people living with Motor Neurone Disease (plwMND). This systematic review explores and synthesises evidence about: (1) What factors contribute towards perceptions of control in plwMND (2) How do plwMND attempt to maintain control in their daily lives?<br><br>METHODS: A systematic search from inception to January 2022 for peer-reviewed journal articles in English reporting qualitative and mixed-method primary studies or reviews of plwMND's perceptions or experiences of control was conducted on CINAHL, MEDLINE, PsycINFO, ASSIA, Embase and AMED. Eligible articles underwent quality appraisal, data extraction and a thematic synthesis was carried out.<br><br>RESULTS: Twenty publications, 19 primary studies and one review, from nine countries, reporting the views of 578 participants aged from 20 to 90&#x2009;years were included. Two key analytical themes were identified (1) diagnosis can lead to a disruption of previously held control beliefs (2) plwMND use a range of control strategies to attempt to retain control in their lives.<br><br>CONCLUSION: This is the first systematic review and qualitative evidence synthesis to reveal the strategies plwMND use to regain control and that control beliefs about health, fate, identity and bodily control are significantly altered by the diagnosis. Implications for rehabilitationOutcome measures for plwMND should consider personal values and preferences as well as objective clinical measurements.plwMND use a range of control strategies which may alter and change over time therefore healthcare professionals may also need to review and adapt treatment decisions over time.The differing viewpoints of healthcare professionals and plwMND should be considered in clinical situations to reduce the potential for conflict.}, }
@article {pmid35913017, year = {2023}, author = {Pierce, ES and Barkhaus, P and Beauchamp, M and Bromberg, M and Carter, GT and Goslinga, J and Greeley, D and Kihuwa-Mani, S and Levitsky, G and Lund, I and McDermott, C and Pattee, G and Pierce, K and Polak, M and Ratner, D and Wicks, P and Bedlack, R}, title = {ALSUntangled #66: antimycobacterial antibiotics.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {539-543}, doi = {10.1080/21678421.2022.2104650}, pmid = {35913017}, issn = {2167-9223}, mesh = {Animals ; Humans ; Anti-Bacterial Agents/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; *Crohn Disease/etiology/microbiology ; *Mycobacterium avium subsp. paratuberculosis ; *Motor Neuron Disease/complications ; }, abstract = {Several infections have been associated with motor neuron diseases resembling ALS, including species of viruses, bacteria, and parasites. Mycobacterium avium subspecies paratuberculosis (MAP), most known for its probable etiologic association with Crohn's disease, has been suggested as another possible infectious cause of motor neuron disease. Two published case reports describe the successful treatment of ALS-like symptoms with antimycobacterial antibiotics. Both cases had atypical features. Based on these, we believe it would be reasonable to begin performing chest imaging in PALS who have features of their history or exam that are atypical for ALS such as pain, fevers, or eye movement abnormalities. If the chest imaging is abnormal, more specific testing for mycobacteria may be indicated. Until there is more clear evidence of an association between mycobacteria and ALS, we cannot endorse the widespread use of potentially toxic antimycobacterial antibiotics for PALS.}, }
@article {pmid35912377, year = {2022}, author = {Boegle, K and Bassi, M and Comanducci, A and Kuehlmeyer, K and Oehl, P and Raiser, T and Rosenfelder, M and Sitt, JD and Valota, C and Willacker, L and Bender, A and Grill, E}, title = {Informal Caregivers of Patients with Disorders of Consciousness: a Qualitative Study of Communication Experiences and Information Needs with Physicians.}, journal = {Neuroethics}, volume = {15}, number = {3}, pages = {24}, pmid = {35912377}, issn = {1874-5490}, abstract = {UNLABELLED: Due to improvements in medicine, the figures of patients with disorders of consciousness (DoC) are increasing. Diagnostics of DoC and prognostication of rehabilitation outcome is challenging but necessary to evaluate recovery potential and to decide on treatment options. Such decisions should be made by doctors and patients' surrogates based on medico-ethical principles. Meeting information needs and communicating effectively with caregivers as the patients´ most common surrogate-decision makers is crucial, and challenging when novel tech-nologies are introduced. This qualitative study aims to explore information needs of informal DoC caregivers, how they manage the obtained information and their perceptions and experiences with caregiver-physician communication in facilities that implemented innovative neurodiagnostics studies. In 2021, we conducted semi-structured interviews with nine caregivers of clinically stable DoC patients in two rehabilitation centers in Italy and Germany. Participants were selected based on consecutive purposeful sampling. Caregivers were recruited at the facilities after written informed consent. All interviews were recorded, transcribed verbatim and translated. For analysis, we used reflexive thematic analysis according to Braun &amp; Clarke (2006). Caregivers experienced the conversations emotionally, generally based on the value of the information provided. They reported to seek positive information, comfort and empathy with-in the communication of results of examinations. They needed detailed information to gain a deep understanding and a clear picture of their loved-one's condition. The results suggest a mismatch between the perspectives of caregivers and the perspectives of medical profession-als, and stress the need for more elaborate approaches to the communication of results of neu-rodiagnostics studies.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12152-022-09503-0.}, }
@article {pmid35907635, year = {2022}, author = {Husbands, E and Talbot, K}, title = {Pathological laughter and crying in neurological disorders: recognition and treatment.}, journal = {Practical neurology}, volume = {22}, number = {6}, pages = {486-490}, doi = {10.1136/pn-2021-003301}, pmid = {35907635}, issn = {1474-7766}, mesh = {Humans ; *Laughter/psychology ; Crying/psychology ; Quinidine/therapeutic use ; *Nervous System Diseases/therapy/drug therapy ; }, abstract = {Pathological laughter and crying is a disabling symptom complex associated with damage to various central nervous system pathways that control the reflex motor component of emotional expression. Many underlying conditions-including neurodegenerative diseases, CNS inflammation, vascular lesions and traumatic brain injury-can be associated with disinhibition of emotional reflex control. This suggests a disruption of anatomical and functional networks, rather than any specific unifying pathological process. There is a wide differential diagnosis, including depression, dementia and other forms of behavioural disturbance. Diagnostic criteria and rating scales can help with clinical assessments and facilitate clinical trials. There is now good-quality evidence for a combination of dextromethorphan and quinidine, with weaker evidence for tricyclic and selective serotonin reuptake inhibitor antidepressants. Pathological laughter and crying is disabling and underdiagnosed but potentially treatable, and its wider recognition is important.}, }
@article {pmid35907317, year = {2022}, author = {Sanz, I and Altomare, A and Mondanelli, G and Protti, M and Valsecchi, V and Mercolini, L and Volpi, C and Regazzoni, L}, title = {Chromatographic measurement of 3-hydroxyanthranilate 3,4-dioxygenase activity reveals that edaravone can mitigate the formation of quinolinic acid through a direct enzyme inhibition.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {219}, number = {}, pages = {114948}, doi = {10.1016/j.jpba.2022.114948}, pmid = {35907317}, issn = {1873-264X}, mesh = {3-Hydroxyanthranilate 3,4-Dioxygenase/chemistry/metabolism ; 3-Hydroxyanthranilic Acid/metabolism/pharmacology ; *Amyotrophic Lateral Sclerosis ; Edaravone/pharmacology ; Humans ; *Neurodegenerative Diseases ; Quinolinic Acid/metabolism ; }, abstract = {Herein it is reported the development and application of two chromatographic assays for the measurement of the activity of 3-Hydroxyanthranilate-3,4-dioxygenase (3HAO). Such an enzyme converts 3-Hydroxyanthranilic acid (3HAA) to 2-amino-3-carboxymuconic semialdehyde (ACMS), which undergo a spontaneous, non-enzymatic cyclization to produce quinolinic acid (QUIN). The enzyme activity was measured by quantitation of the substrate consumption over time either with spectrophotometric (UV) or mass spectrometric (MS) detection upon reversed-phase chromatographic separation. MS detection resulted more selective and sensitive, but less accurate and precise. However, both methods have sufficient sensitivity to allow the measurement of enzyme activity with consistent results compared to literature data. Since MS detection allowed less sample consumption it was used to calculate the kinetics parameters (i.e., Vmax and Kd) of recombinant 3HAO. Another MS-based method was then developed to measure the amount of QUIN produced, revealing an incomplete conversion of 3HAA to QUIN. As suggested by previous studies, the enzyme activity was apparently sensitive to the redox state of the enzyme thiols. In fact, thiol reducing agents such as dithiothreitol (DTT) and glutathione (GSH), can alter the enzyme activity although the investigation on the exact mechanism involved in such effect was beyond the scope of the research. Interestingly, edaravone (EDA) induced an in vitro suppression of QUIN production through direct, competitive 3HAO inhibition. EDA is a molecule approved for the treatment of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease associated with an increase of QUIN concentrations in both serum and cerebrospinal fluid. Although EDA was reported to mitigate ALS progression its mode of action is still largely unknown. Some studies reported antioxidant and radical scavenger properties of EDA, but none confirm a direct activity as 3HAO enzyme inhibitor. Since QUIN is reported to be a neurotoxic metabolite, 3HAO inhibition can contribute to the beneficial effect of EDA in ALS, although such a mechanism must be then confirmed in vivo. However, EDA might be a convenient scaffold for the design of selective 3HAO inhibitors with potential applications in ALS treatment.}, }
@article {pmid35907175, year = {2022}, author = {Heo, YA}, title = {Sodium Phenylbutyrate and Ursodoxicoltaurine: First Approval.}, journal = {CNS drugs}, volume = {36}, number = {9}, pages = {1007-1013}, pmid = {35907175}, issn = {1179-1934}, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Pharmaceutical Preparations ; Phenylbutyrates/pharmacology/therapeutic use ; Taurochenodeoxycholic Acid ; }, abstract = {An oral, fixed-dose coformulation of sodium phenylbutyrate and ursodoxicoltaurine (ALBRIOZA[™]; hereafter denoted sodium phenylbutyrate/ursodoxicoltaurine) is being developed by Amylyx Pharmaceuticals for the treatment of neurodegenerative diseases. In June 2022, the coformulation received its first approval with conditions in Canada for the treatment of amyotrophic lateral sclerosis (ALS) in adults. The approval was based on results from the multicentre, phase II CENTAUR trial, in which slowing of ALS progression was demonstrated with sodium phenylbutyrate/ursodoxicoltaurine relative to placebo. This article summarizes the milestones in the development of sodium phenylbutyrate/ursodoxicoltaurine leading to this first approval.}, }
@article {pmid35899270, year = {2022}, author = {Wendebourg, MJ and Kuhle, J and Hardmeier, M}, title = {Case Report: A 72-Year-Old Woman With Progressive Motor Weakness, Dry Eyes and High Levels of Serum Neurofilament Light Chain.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {889894}, pmid = {35899270}, issn = {1664-2295}, abstract = {BACKGROUND: Diagnosis of Amyotrophic Lateral Sclerosis (ALS) is challenging as initial presentations are various and diagnostic biomarkers are lacking. The diagnosis relies on the presence of both upper and lower motor neuron signs and thorough exclusion of differential diagnoses, particularly as receiving an ALS diagnosis has major implications for the patient. Sjögren's syndrome may mimic peripheral ALS phenotypes and should be considered in the work-up.<br><br>CASE: A 72-year-old female presented with a mono-neuropathy of the right leg and a complaint of dry eyes and mouth. Initial diagnostic work-up confirmed a regional sensorimotor neuropathy and a Sj&#xf6;gren's syndrome; a causal relationship was assumed. However, motor symptoms spread progressively despite immunosuppressive treatment, eventually including both legs, both arms and the diaphragm. Clinically, unequivocal central signs were lacking, but further along in the disease course, the atrophy pattern followed a split phenotype and deep tendon reflexes were preserved. Nerve biopsy did not show vasculitic infiltration; however, serum neurofilament light chain (sNfL) concentrations were and remained persistently highly elevated despite immunosuppressive treatment. Electrodiagnostic re-evaluation confirmed denervation in 3 regions. A diagnosis of familial ALS was finally confirmed by a C9orf 72 repeat expansion. Stationary sensory symptoms were best explained by a neuropathy associated with concomitant Sj&#xf6;gren's syndrome.<br><br>DISCUSSION: Our instructive case shows the difficulties of diagnosing ALS in the setting of a peripheral symptom onset and a concurrent but unrelated condition also causing neuropathy. Such cases require high clinical vigilance and readiness to reappraise diagnostic findings if the disease course deviates from expectation. Recently proposed simplified diagnostic criteria, genetic testing and body fluid biomarkers such as sNfL may facilitate the diagnostic process and lead to an earlier diagnosis of ALS.}, }
@article {pmid35897192, year = {2022}, author = {Cai, W and Li, Z and Pan, Y and Feng, X and Han, L and Cui, T and Hu, Y and Hu, W}, title = {A novel approach simultaneously imparting well-hydrophobicity and photothermal conversion effect to polymer materials: solar-promoted absorption of organic solvents and oils.}, journal = {Journal of hazardous materials}, volume = {437}, number = {}, pages = {129446}, doi = {10.1016/j.jhazmat.2022.129446}, pmid = {35897192}, issn = {1873-3336}, abstract = {In this work, a series of polymer materials including pomelo peel, cotton fabric, polyurethane foam, and so on, are treated by heated CH3SiCl3, presenting desirable photo-thermal conversion function and hydrophobicity. As a representative material, the surface element and skeleton morphology of pomelo peel foam treated by CH3SiCl3 are analyzed detailedly. It is found that well-hydrophobicity (water contact angle of ~147°) and photo-thermal conversion performance (~91.2 °C under one sun) are attributed to the surface carbonization reaction and formation of CH3-SiO2 nanoparticles. Meanwhile, the treatment of CH3SiCl3 significantly increases the BET surface area to 3.0635 m[2]/g from 0.0973 m[2]/g. Therefore, pomelo peel-derived carbon foam presents a desirable adsorption capacity of organic solvents and oils (up to 43.2 times its original weight) and excellent removal efficiency (>99.0%). In addition, the rapid photo-thermal response (achieve ~73 °C at 40 s) and high equilibrium temperature (~91.2 °C) are als° demonstrated in pomelo peel-derived carbon foam. As a result, the absorption rate of highly-viscous oils is effectively promoted by the higher fluidity and capillary action caused by the solar-promoted mechanism. This study offers a scalable, easily operated, and environmentally friendly approach to prepare hydrophobic and photo-thermal materials, thus demonstrating a huge potential in oil/water separation application.}, }
@article {pmid35890313, year = {2022}, author = {Thinard, R and Farkas, AE and Halasa, M and Chevalier, M and Brodaczewska, K and Majewska, A and Zdanowski, R and Paprocka, M and Rossowska, J and Duc, LT and Greferath, R and Krizbai, I and Van Leuven, F and Kieda, C and Nicolau, C}, title = {"Endothelial Antibody Factory" at the Blood Brain Barrier: Novel Approach to Therapy of Neurodegenerative Diseases.}, journal = {Pharmaceutics}, volume = {14}, number = {7}, pages = {}, pmid = {35890313}, issn = {1999-4923}, abstract = {The failures of anti-β-amyloid immunotherapies suggested that the very low fraction of injected antibodies reaching the brain parenchyma due to the filtering effect of the BBB may be a reason for the lack of therapeutic effect. However, there is no treatment, as yet, for the amyotrophic lateral sclerosis (ALS) despite substantial evidence existing of the involvement of TDP-43 protein in the evolution of ALS. To circumvent this filtering effect, we have developed a novel approach to facilitate the penetration of antibody fragments (Fabs) into the brain parenchyma. Leveraging the homing properties of endothelial progenitor cells (EPCs), we transfected, ex vivo, such cells with vectors encoding anti-β-amyloid and anti-TDP43 Fabs turning them into an "antibody fragment factory". When injected these cells integrate into the BBB, where they secrete anti-TDP43 Fabs. The results showed the formation of tight junctions between the injected engineered EPCs and the unlabeled resident endothelial cells. When the EPCs were further modified to express the anti-TDP43 Fab, we could observe integration of these cells into the vasculature and the secretion of Fabs. Results confirm that production and secretion of Fabs at the BBB level leads to their migration to the brain parenchyma where they might exert a therapeutic effect.}, }
@article {pmid35890141, year = {2022}, author = {Soejima-Kusunoki, A and Okada, K and Saito, R and Watabe, K}, title = {The Protective Effect of Edaravone on TDP-43 Plus Oxidative Stress-Induced Neurotoxicity in Neuronal Cells: Analysis of Its Neuroprotective Mechanisms Using RNA Sequencing.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {15}, number = {7}, pages = {}, pmid = {35890141}, issn = {1424-8247}, abstract = {Edaravone is a free-radical scavenger drug that was recently approved for the treatment of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. A pathological hallmark of ALS is the accumulation of ubiquitinated or phosphorylated aggregates of the 43-kDa transactive response DNA binding protein (TDP-43) within the cytoplasm of motor neurons. This study revealed the efficacy of edaravone in preventing neuronal cell death in a TDP-43 proteinopathy model and analyzed the molecular changes associated with the neuroprotection. The viability of the neuronal cells expressing TDP-43 was reduced by oxidative stress, and edaravone (≥10 μmol/L) protected in a concentration-dependent manner against the neurotoxic insult. Differential gene expression analysis revealed changes among pathways related to nuclear erythroid 2-related-factor (Nrf2)-mediated oxidative stress response in cells expressing TDP-43. In edaravone-treated cells expressing TDP-43, significant changes in gene expression were also identified among Nrf2-oxidative response, unfolded protein response, and autophagy pathways. In addition, the expression of genes belonging to phosphatidylinositol metabolism pathways was modified. These findings suggest that the neuroprotective effect of edaravone involves the prevention of TDP-43 misfolding and enhanced clearance of pathological TDP-43 in TDP-43 proteinopathy.}, }
@article {pmid35889517, year = {2022}, author = {Basile, MS and Bramanti, P and Mazzon, E}, title = {Inosine in Neurodegenerative Diseases: From the Bench to the Bedside.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {14}, pages = {}, pmid = {35889517}, issn = {1420-3049}, support = {Current Research Funds 2022//Ministry of Health, Italy/ ; }, mesh = {*Alzheimer Disease/drug therapy ; *Amyotrophic Lateral Sclerosis/drug therapy ; Antioxidants/metabolism/therapeutic use ; Humans ; Inosine/therapeutic use ; *Multiple Sclerosis/drug therapy ; *Neurodegenerative Diseases/metabolism ; *Parkinson Disease/drug therapy ; Quality of Life ; Uric Acid/metabolism ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), currently represent major unmet medical needs. Therefore, novel therapeutic strategies are needed in order to improve patients' quality of life and prognosis. Since oxidative stress can be strongly involved in neurodegenerative diseases, the potential use of inosine, known for its antioxidant properties, in this context deserves particular attention. The protective action of inosine treatment could be mediated by its metabolite urate. Here, we review the current preclinical and clinical studies investigating the use of inosine in AD, PD, ALS, and MS. The most important properties of inosine seem to be its antioxidant action and its ability to raise urate levels and to increase energetic resources by improving ATP availability. Inosine appears to be generally safe and well tolerated; however, the possible formation of kidney stones should be monitored, and data on its effectiveness should be further explored since, so far, they have been controversial. Overall, inosine could be a promising potential strategy in the management of neurodegenerative diseases, and additional studies are needed in order to further investigate its safety and efficacy and its use as a complementary therapy along with other approved drugs.}, }
@article {pmid35881020, year = {2022}, author = {Sleutjes, BTHM and Stikvoort García, DJL and Kovalchuk, MO and Heuberger, JAAC and Groeneveld, GJ and Franssen, H and van den Berg, LH}, title = {Acute retigabine-induced effects on myelinated motor axons in amyotrophic lateral sclerosis.}, journal = {Pharmacology research &amp; perspectives}, volume = {10}, number = {4}, pages = {e00983}, pmid = {35881020}, issn = {2052-1707}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Axons/physiology ; Carbamates ; Humans ; Motor Neurons ; Phenylenediamines/pharmacology/therapeutic use ; }, abstract = {Altered motor neuron excitability in patients with amyotrophic lateral sclerosis (ALS) has been suggested to be an early pathophysiological mechanism associated with motor neuron death. Compounds that affect membrane excitability may therefore have disease-modifying effects. Through which mechanism(s), these compounds modulate membrane excitability is mostly provided by preclinical studies, yet remains challenging to verify in clinical studies. Here, we investigated how retigabine affects human myelinated motor axons by applying computational modeling to interpret the complex excitability changes in a recent trial involving 18 ALS patients. Compared to baseline, the post-dose excitability differences were modeled well by a hyperpolarizing shift of the half-activation potential of slow potassium (K[+])-channels (till 2 mV). These findings verify that retigabine targets slow K[+] -channel gating and highlight the usefulness of computational models. Further developments of this approach may facilitate the identification of early target engagement and ultimately aid selecting responders leading to more personalized treatment strategies.}, }
@article {pmid35874609, year = {2022}, author = {Pavan, M and Menin, S and Bassani, D and Sturlese, M and Moro, S}, title = {Implementing a Scoring Function Based on Interaction Fingerprint for Autogrow4: Protein Kinase CK1δ as a Case Study.}, journal = {Frontiers in molecular biosciences}, volume = {9}, number = {}, pages = {909499}, pmid = {35874609}, issn = {2296-889X}, abstract = {In the last 20 years, fragment-based drug discovery (FBDD) has become a popular and consolidated approach within the drug discovery pipeline, due to its ability to bring several drug candidates to clinical trials, some of them even being approved and introduced to the market. A class of targets that have proven to be particularly suitable for this method is represented by kinases, as demonstrated by the approval of BRAF inhibitor vemurafenib. Within this wide and diverse set of proteins, protein kinase CK1δ is a particularly interesting target for the treatment of several widespread neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Computational methodologies, such as molecular docking, are already routinely and successfully applied in FBDD campaigns alongside experimental techniques, both in the hit-discovery and in the hit-optimization stage. Concerning this, the open-source software Autogrow, developed by the Durrant lab, is a semi-automated computational protocol that exploits a combination between a genetic algorithm and a molecular docking software for de novo drug design and lead optimization. In the current work, we present and discuss a modified version of the Autogrow code that implements a custom scoring function based on the similarity between the interaction fingerprint of investigated compounds and a crystal reference. To validate its performance, we performed both a de novo and a lead-optimization run (as described in the original publication), evaluating the ability of our fingerprint-based protocol to generate compounds similar to known CK1δ inhibitors based on both the predicted binding mode and the electrostatic and shape similarity in comparison with the standard Autogrow protocol.}, }
@article {pmid35872571, year = {2022}, author = {Vázquez-Costa, JF and Povedano, M and Nascimiento-Osorio, AE and Moreno Escribano, A and Kapetanovic Garcia, S and Dominguez, R and Exposito, JM and González, L and Marco, C and Medina Castillo, J and Muelas, N and Natera de Benito, D and Ñungo Garzón, NC and Pitarch Castellano, I and Sevilla, T and Hervás, D}, title = {Nusinersen in adult patients with 5q spinal muscular atrophy: A multicenter observational cohorts' study.}, journal = {European journal of neurology}, volume = {29}, number = {11}, pages = {3337-3346}, pmid = {35872571}, issn = {1468-1331}, mesh = {Adult ; Humans ; Injections, Spinal ; *Muscular Atrophy, Spinal/drug therapy ; Oligonucleotides/adverse effects ; *Spinal Muscular Atrophies of Childhood/drug therapy ; }, abstract = {BACKGROUND AND PURPOSE: The aim was to assess the safety and efficacy of nusinersen in adult 5q spinal muscular atrophy (SMA) patients.<br><br>METHODS: Patients older than 15&#x2009;years and followed for at least 6&#xa0;months with one motor scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb Module, RULM) in five referral centers were included. The clinical and patients' global impression of change (CGI-C and PGI-C) were recorded in treated patients at the last visit. Functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) and the percentage predicted forced vital capacity were collected when available.<br><br>RESULTS: Seventy-nine SMA patients (39 treated with nusinersen) were included. Compared with untreated patients, treated patients showed a significant improvement of 2 points (&#xb1;0.46) in RULM (p&#x2009;<&#x2009;0.001) after 6 months. After a mean follow-up of 16&#x2009;months, nusinersen treatment was associated with a significant improvement in HFMSE (odds ratio [OR]&#xa0;1.15, p&#xa0;=&#xa0;0.006), the 6-min walk test (OR&#xa0;=&#xa0;1.07, p&#x2009;<&#x2009;0.001) and the EK2 (OR&#xa0;=&#xa0;0.81, p&#xa0;=&#xa0;0.001). Compared with untreated patients, more treated patients experienced clinically meaningful improvements in all scales, but these differences were statistically significant only for RULM (p&#xa0;=&#xa0;0.033), ALSFRS-R (p&#xa0;=&#xa0;0.005) and EK2 (p&#x2009;<&#x2009;0.001). According to the CGI-C and PGI-C, 64.1% and 61.5% of treated patients improved with treatment. Being a non-sitter was associated with less response to treatment, whilst a longer time of treatment was associated with better response. Most treated patients (77%) presented at least one adverse event, mostly mild.<br><br>CONCLUSIONS: Nusinersen treatment is associated with some improvements in adult SMA patients. Most severely affected patients with complex spines are probably those with the most unfavorable risk-benefit ratio.}, }
@article {pmid35872012, year = {2022}, author = {Cai, Z and Yin, K and Liu, Q and Liu, M and Yang, X and Cui, L}, title = {Association between abnormal expression and methylation of LGALS1 in amyotrophic lateral sclerosis.}, journal = {Brain research}, volume = {1792}, number = {}, pages = {148022}, doi = {10.1016/j.brainres.2022.148022}, pmid = {35872012}, issn = {1872-6240}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; CpG Islands ; *DNA Methylation ; Galectin 1/*genetics/metabolism ; Humans ; RNA, Messenger/metabolism ; }, abstract = {OBJECTIVE: DNA methylation has been identified to play an important role in amyotrophic lateral sclerosis (ALS). Galectin-1, encoded by LGALS1 gene, has been proved to be associated with ALS. We aimed to investigate the association between the expression and methylation of LGALS1 in blood samples from ALS patients.<br><br>METHODS: Forty-five patients diagnosed with ALS were enrolled. Thirty-two healthy relatives consisted the control group. Among them, samples from 12 patients and 12 controls consisted the exploration samples. In the exploration samples, mRNA expression levels were detected by quantitative real-time PCR. In all the samples, DNA methylation levels of one CpG island containing 12 CpG sites in the gene promoter were detected by bisulfite sequencing PCR, and galectin-1 levels were examined by enzyme linked immunosorbent assay. Associations between the gene expression and methylation level, as well as between the region-specific methylation level and clinical variables were calculated.<br><br>RESULTS: The mRNA expression level of LGALS1 was significantly increased and the promoter of LGALS1 was hypomethylated in ALS patients. Serum galectin-1 levels were significantly elevated in the ALS patients. The ALS group had significantly lower methylation level at certain CpG sites than the control group. There were significant negative associations between abnormal expression and methylation of LGALS1, as well as between region-specific methylation levels and the age of onset.<br><br>CONCLUSIONS: The aberrant expression and DNA methylation of LGALS1 and their association reveals epigenetic changes in ALS patients, which are helpful for early intervention and treatment for the disease.}, }
@article {pmid35864981, year = {2022}, author = {Abulseoud, OA and Alasmari, F and Hussein, AM and Sari, Y}, title = {Ceftriaxone as a Novel Therapeutic Agent for Hyperglutamatergic States: Bridging the Gap Between Preclinical Results and Clinical Translation.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {841036}, pmid = {35864981}, issn = {1662-4548}, abstract = {Dysregulation of glutamate homeostasis is a well-established core feature of neuropsychiatric disorders. Extracellular glutamate concentration is regulated by glutamate transporter 1 (GLT-1). The discovery of a beta-lactam antibiotic, ceftriaxone (CEF), as a safe compound with unique ability to upregulate GLT-1 sparked the interest in testing its efficacy as a novel therapeutic agent in animal models of neuropsychiatric disorders with hyperglutamatergic states. Indeed, more than 100 preclinical studies have shown the efficacy of CEF in attenuating the behavioral manifestations of various hyperglutamatergic brain disorders such as ischemic stroke, amyotrophic lateral sclerosis (ALS), seizure, Huntington's disease, and various aspects of drug use disorders. However, despite rich and promising preclinical data, only one large-scale clinical trial testing the efficacy of CEF in patients with ALS is reported. Unfortunately, in that study, there was no significant difference in survival between placebo- and CEF-treated patients. In this review, we discussed the translational potential of preclinical efficacy of CEF based on four different parameters: (1) initiation of CEF treatment in relation to induction of the hyperglutamatergic state, (2) onset of response in preclinical models in relation to onset of GLT-1 upregulation, (3) mechanisms of action of CEF on GLT-1 expression and function, and (4) non-GLT-1-mediated mechanisms for CEF. Our detailed review of the literature brings new insights into underlying molecular mechanisms correlating the preclinical efficacy of CEF. We concluded here that CEF may be clinically effective in selected cases in acute and transient hyperglutamatergic states such as early drug withdrawal conditions.}, }
@article {pmid35858632, year = {2022}, author = {Mishra, A and Pandey, S}, title = {Functional Neurological Disorders: Clinical Spectrum, Diagnosis, and Treatment.}, journal = {The neurologist}, volume = {27}, number = {5}, pages = {276-289}, pmid = {35858632}, issn = {2331-2637}, mesh = {*Conversion Disorder/diagnosis/epidemiology/therapy ; Humans ; }, abstract = {BACKGROUND: Functional neurological disorders (FNDs) are common but often misdiagnosed.<br><br>REVIEW SUMMARY: The incidence of FNDs is between 4 and 12 per 100,000, comparable to multiple sclerosis and amyotrophic lateral sclerosis, and it is the second most common diagnosis in neurology clinics. Some clues in the history are sudden onset, intermittent time course, variability of manifestation over time, childhood trauma, and history of other somatic symptoms. Anxiety and depression are common, but not necessarily more than in the general population. Although there are no tests currently capable of demonstrating whether symptoms are willfully produced, there may not be a clear categorical difference between voluntary and involuntary symptoms. The prognosis of an FND is linked to early diagnosis and symptom duration, but unfortunately, the majority of the patients are diagnosed after considerable delays.<br><br>CONCLUSIONS: A positive diagnosis of FNDs can be made on the basis of history and neurological signs without reliance on psychological stressors. Past sensitizing events and neurobiological abnormalities contribute to the pathogenesis of FNDs. Physical rehabilitation and psychological interventions alone or in combination are helpful in the treatment.}, }
@article {pmid35858577, year = {2022}, author = {Duan, L and Zaepfel, BL and Aksenova, V and Dasso, M and Rothstein, JD and Kalab, P and Hayes, LR}, title = {Nuclear RNA binding regulates TDP-43 nuclear localization and passive nuclear export.}, journal = {Cell reports}, volume = {40}, number = {3}, pages = {111106}, pmid = {35858577}, issn = {2211-1247}, support = {R03 NS127011/NS/NINDS NIH HHS/United States ; ZIA HD008954/ImNIH/Intramural NIH HHS/United States ; K08 NS104273/NS/NINDS NIH HHS/United States ; R01 NS123538/NS/NINDS NIH HHS/United States ; T32 GM007445/GM/NIGMS NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus ; *Amyotrophic Lateral Sclerosis/metabolism ; Cell Nucleus/metabolism ; DNA-Binding Proteins/metabolism ; Humans ; *RNA, Nuclear/metabolism ; }, abstract = {Nuclear clearance of the RNA-binding protein TDP-43 is a hallmark of neurodegeneration and an important therapeutic target. Our current understanding of TDP-43 nucleocytoplasmic transport does not fully explain its predominantly nuclear localization or mislocalization in disease. Here, we show that TDP-43 exits nuclei by passive diffusion, independent of facilitated mRNA export. RNA polymerase II blockade and RNase treatment induce TDP-43 nuclear efflux, suggesting that nuclear RNAs sequester TDP-43 in nuclei and limit its availability for passive export. Induction of TDP-43 nuclear efflux by short, GU-rich oligomers (presumably by outcompeting TDP-43 binding to endogenous nuclear RNAs), and nuclear retention conferred by splicing inhibition, demonstrate that nuclear TDP-43 localization depends on binding to GU-rich nuclear RNAs. Indeed, RNA-binding domain mutations markedly reduce TDP-43 nuclear localization and abolish transcription blockade-induced nuclear efflux. Thus, the nuclear abundance of GU-RNAs, dictated by the balance of transcription, pre-mRNA processing, and RNA export, regulates TDP-43 nuclear localization.}, }
@article {pmid35857139, year = {2022}, author = {Sista, SR and Crum, B and Aboseif, A and Devine, MF and Zekeridou, A and Hammami, MB and Rezk, MM and Truffert, A and Lalive, PH and Kunchok, A and McKeon, A and Dubey, D}, title = {Motor-neuron-disease-like phenotype associated with IgLON5 disease.}, journal = {Journal of neurology}, volume = {269}, number = {11}, pages = {6139-6144}, pmid = {35857139}, issn = {1432-1459}, support = {R01 NS126227/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/complications ; Autoantibodies ; Cell Adhesion Molecules, Neuronal ; Humans ; Immunoglobulin G ; Immunosuppressive Agents ; *Motor Neuron Disease/complications ; Motor Neurons ; Phenotype ; }, abstract = {A growing spectrum of neurological manifestations are being recognized in association with IgLON5 autoimmunity, including recent reports of motor-neuron-disease-like phenotype. Here we describe four cases of IgLON5 autoimmunity with motor neuron involvement and evaluate an additional 109 probable or definite amyotrophic lateral sclerosis cases seen in our neuromuscular clinic for IgLON5-IgG seropositivity. The presence of parasomnias, vocal cord dysfunction or hyperkinetic movements in a patient with motor-neuron-disease-like phenotype should prompt evaluation for IgLON5-IgG autoantibodies. Recognition and treatment of this autoimmune disease with immunosuppressive agents may bring about significant neurological improvement in a minority of cases.}, }
@article {pmid35856508, year = {2022}, author = {Maurya, SK and Gupta, S and Bakshi, A and Kaur, H and Jain, A and Senapati, S and Baghel, MS}, title = {Targeting mitochondria in the regulation of neurodegenerative diseases: A comprehensive review.}, journal = {Journal of neuroscience research}, volume = {100}, number = {10}, pages = {1845-1861}, doi = {10.1002/jnr.25110}, pmid = {35856508}, issn = {1097-4547}, mesh = {Homeostasis ; Humans ; Inflammation/metabolism ; Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Mitochondria are one of the essential cellular organelles. Apart from being considered as the powerhouse of the cell, mitochondria have been widely known to regulate redox reaction, inflammation, cell survival, cell death, metabolism, etc., and are implicated in the progression of numerous disease conditions including neurodegenerative diseases. Since brain is an energy-demanding organ, mitochondria and their functions are important for maintaining normal brain homeostasis. Alterations in mitochondrial gene expression, mutations, and epigenetic modification contribute to inflammation and neurodegeneration. Dysregulation of reactive oxygen species production by mitochondria and aggregation of proteins in neurons leads to alteration in mitochondria functions which further causes neuronal death and progression of neurodegeneration. Pharmacological studies have prioritized mitochondria as a possible drug target in the regulation of neurodegenerative diseases. Therefore, the present review article has been intended to provide a comprehensive understanding of mitochondrial role in the development and progression of neurodegenerative diseases mainly Alzheimer's, Parkinson's, multiple sclerosis, and amyotrophic lateral sclerosis followed by possible intervention and future treatment strategies to combat mitochondrial-mediated neurodegeneration.}, }
@article {pmid35855338, year = {2022}, author = {Jiang, Z and Yin, X and Wang, M and Chen, T and Wang, Y and Gao, Z and Wang, Z}, title = {Effects of Ketogenic Diet on Neuroinflammation in Neurodegenerative Diseases.}, journal = {Aging and disease}, volume = {13}, number = {4}, pages = {1146-1165}, pmid = {35855338}, issn = {2152-5250}, abstract = {The ketogenic diet (KD) is a low-carbohydrate, high-fat and adequate-protein diet. As a diet mimicking fasting, it triggers the production of ketone bodies (KBs) and brings the body into a state of ketosis. Recent and accumulating studies on humans and animal models have shown that KD is beneficial to neurodegenerative diseases through modulating central and peripheral metabolism, mitochondrial function, inflammation, oxidative stress, autophagy, and the gut microbiome. Complicated interplay of metabolism, gut microbiome, and other mechanisms can regulate neuroinflammation in neurodegenerative diseases by activating multiple molecular and cellular pathways. In this review, we detail the physiological basis of the KD, its functions in regulating neuroinflammation, and its protective role in normal brain aging and neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). We aimed to elucidate the underlying neuroinflammatory mechanisms of KD therapies in neurodegenerative diseases and provide novel insights into their application for neurodegenerative disease prevention and treatment.}, }
@article {pmid35855239, year = {2022}, author = {Jayasinghe, M and Jena, R and Singhal, M and Jain, S and Karnakoti, S and Silva, MS and Kayani, AMA}, title = {Ethnical Disparities in Response to Edaravone in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {14}, number = {6}, pages = {e25960}, pmid = {35855239}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurodegenerative disease characterized by the weakness of voluntary muscles due to the loss of motor neurons. Symptoms ultimately culminate in the form of respiratory failure due to the involvement of the diaphragm. Unfortunately, there is no known cure for this disease. Hence, supportive therapy is the only available option in most terminal cases. However, Riluzole and Edaravone (EDA) are the only two known drugs approved by the U.S. Food and Drug Administration (FDA) for treating this condition. In 2017, EDA was approved for the treatment of ALS. It is hypothesized that Riluzole and EDA work via a mechanism involving antioxidants, which nullifies the oxidative stress believed to be involved in ALS. However, most studies in several countries have found a wide range of disparities in the efficacy of this drug. In this review, we aim to summarize the differences in results from epidemiological studies across 10 different countries and hypothesize the potential causes of these differences.}, }
@article {pmid35853395, year = {2022}, author = {Mominur Rahman, M and Afsana Mim, S and Afroza Alam Tumpa, M and Taslim Sarker, M and Ahmed, M and Alghamdi, BS and Hafeez, A and Alexiou, A and Perveen, A and Md Ashraf, G}, title = {Exploring the management approaches of cytokines including viral infection and neuroinflammation for neurological disorders.}, journal = {Cytokine}, volume = {157}, number = {}, pages = {155962}, doi = {10.1016/j.cyto.2022.155962}, pmid = {35853395}, issn = {1096-0023}, mesh = {*Alzheimer Disease ; Cytokines/physiology ; Humans ; *Nervous System Diseases/therapy ; Neuroinflammatory Diseases ; *Virus Diseases ; }, abstract = {Considerable evidence supports that cytokines are important mediators of pathophysiologic processes within the central nervous system (CNS). Numerous studies have documented the increased production of various cytokines in the human CNS in various neurological and neuropsychiatric disorders. Deciphering cytokine actions in the intact CNS has important implications for our understanding of the pathogenesis and treatment of these disorders. The purpose of this study is to discuss the recent research on treating cytokine storm and amyloids, including stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's condition, Multi-sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS). Neuroinflammation observed in neurological disorders has a pivotal role in exacerbating Aβ burden and tau hyperphosphorylation, suggesting that stimulating cytokines in response to an undesirable external response could be a checkpoint for treating neurological disorders. Furthermore, the pro-inflammatory cytokines help our immune system through a neuroprotective mechanism in clearing viral infection by recruiting mononuclear cells. This study reveals that cytokine applications may play a vital role in providing novel regulation and methods for the therapeutic approach to neurological disorders and the causes of the deregulation, which is responsible for neuroinflammation and viral infection. However, it needs to be further investigated to clarify better the mechanisms of cytokine release in response to various stimuli, which could be the central point for treating neurological disorders.}, }
@article {pmid35852606, year = {2022}, author = {Bertin, E and Martinez, A and Fayoux, A and Carvalho, K and Carracedo, S and Fernagut, PO and Koch-Nolte, F and Blum, D and Bertrand, SS and Boué-Grabot, E}, title = {Increased surface P2X4 receptors by mutant SOD1 proteins contribute to ALS pathogenesis in SOD1-G93A mice.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {79}, number = {8}, pages = {431}, pmid = {35852606}, issn = {1420-9071}, support = {ANR-20-CE17-001//ANR/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; Disease Models, Animal ; Disease Progression ; Mice ; Mice, Transgenic ; *Motor Neuron Disease/genetics/metabolism/pathology ; Motor Neurons/metabolism/pathology ; *Receptors, Purinergic P2X4/genetics/metabolism ; Spinal Cord/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron (MN) disease characterized by protein misfolding and aggregation leading to cellular degeneration. So far neither biomarker, nor effective treatment has been found. ATP signaling and P2X4 receptors (P2X4) are upregulated in various neurodegenerative diseases. Here we show that several ALS-related misfolded proteins including mutants of SOD1 or TDP-43 lead to a significant increase in surface P2X4 receptor density and function in vitro. In addition, we demonstrate in the spinal the cord of SOD1-G93A (SOD1) mice that misfolded SOD1-G93A proteins directly interact with endocytic adaptor protein-2 (AP2); thus, acting as negative competitors for the interaction between AP2 and P2X4, impairing constitutive P2X4 endocytosis. The higher P2X4 surface density was particularly observed in peripheral macrophages of SOD1 mice before the onset and during the progression of ALS symptoms positioning P2X4 as a potential early biomarker for ALS. P2X4 expression was also upregulated in spinal microglia of SOD1 mice during ALS and affect microglial inflammatory responses. Importantly, we report using double transgenic SOD1 mice expressing internalization-defective P2X4mCherryIN knock-in gene or invalidated for the P2X4 gene that P2X4 is instrumental for motor symptoms, ALS progression and survival. This study highlights the role of P2X4 in the pathophysiology of ALS and thus its potential for the development of biomarkers and treatments. We also decipher the molecular mechanism by which misfolded proteins related to ALS impact P2X4 trafficking at early pathological stage in cells expressing-P2X4.}, }
@article {pmid35850103, year = {2022}, author = {Tatu, L and Bogousslavsky, J}, title = {Treatments in Neurology: The Winding Road from 1897 to 2022.}, journal = {European neurology}, volume = {85}, number = {5}, pages = {367-370}, doi = {10.1159/000525689}, pmid = {35850103}, issn = {1421-9913}, mesh = {*Amyotrophic Lateral Sclerosis ; *Brain Neoplasms ; Humans ; *Multiple Sclerosis/therapy ; *Neurology ; *Parkinson Disease/therapy ; }, abstract = {BACKGROUND: For many years, neurology was seen as a purely observational discipline, focused on pathology and with little interest in treatments.<br><br>SUMMARY: From the creation in 1897 of Monatsschrift f&#xfc;r Psychiatrie und Neurologie, the forebear of European Neurology, to nowadays, there have been great changes in the paradigms and concepts of treatments in neurology. We present an overview of the evolution of neurological treatments from 1897 to 2022.<br><br>KEY MESSAGES: However, the last 125 years have not consisted of constant progress. The exceptional advances made in some diseases (multiple sclerosis or surgical treatment of Parkinson's disease) cannot hide the stagnation in others (certain brain tumors or amyotrophic lateral sclerosis).}, }
@article {pmid35845697, year = {2022}, author = {Shah, S and Lonhienne, T and Murray, CE and Chen, Y and Dougan, KE and Low, YS and Williams, CM and Schenk, G and Walter, GH and Guddat, LW and Chan, CX}, title = {Genome-Guided Analysis of Seven Weed Species Reveals Conserved Sequence and Structural Features of Key Gene Targets for Herbicide Development.}, journal = {Frontiers in plant science}, volume = {13}, number = {}, pages = {909073}, pmid = {35845697}, issn = {1664-462X}, abstract = {Herbicides are commonly deployed as the front-line treatment to control infestations of weeds in native ecosystems and among crop plants in agriculture. However, the prevalence of herbicide resistance in many species is a major global challenge. The specificity and effectiveness of herbicides acting on diverse weed species are tightly linked to targeted proteins. The conservation and variance at these sites among different weed species remain largely unexplored. Using novel genome data in a genome-guided approach, 12 common herbicide-target genes and their coded proteins were identified from seven species of Weeds of National Significance in Australia: Alternanthera philoxeroides (alligator weed), Lycium ferocissimum (African boxthorn), Senecio madagascariensis (fireweed), Lantana camara (lantana), Parthenium hysterophorus (parthenium), Cryptostegia grandiflora (rubber vine), and Eichhornia crassipes (water hyacinth). Gene and protein sequences targeted by the acetolactate synthase (ALS) inhibitors and glyphosate were recovered. Compared to structurally resolved homologous proteins as reference, high sequence conservation was observed at the herbicide-target sites in the ALS (target for ALS inhibitors), and in 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase (target for glyphosate). Although the sequences are largely conserved in the seven phylogenetically diverse species, mutations observed in the ALS proteins of fireweed and parthenium suggest resistance of these weeds to ALS-inhibiting and other herbicides. These protein sites remain as attractive targets for the development of novel inhibitors and herbicides. This notion is reinforced by the results from the phylogenetic analysis of the 12 proteins, which reveal a largely consistent vertical inheritance in their evolutionary histories. These results demonstrate the utility of high-throughput genome sequencing to rapidly identify and characterize gene targets by computational methods, bypassing the experimental characterization of individual genes. Data generated from this study provide a useful reference for future investigations in herbicide discovery and development.}, }
@article {pmid35844238, year = {2022}, author = {Murphy, ER and Thompson, R and Osman, KL and Haxton, C and Brothers, M and Lee, L and Warncke, K and Smith, CL and Keilholz, AN and Hamad, A and Golzy, M and Bunyak, F and Ma, L and Nichols, NL and Lever, TE}, title = {A Strength Endurance Exercise Paradigm Mitigates Deficits in Hypoglossal-Tongue Axis Function, Strength, and Structure in a Rodent Model of Hypoglossal Motor Neuron Degeneration.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {869592}, pmid = {35844238}, issn = {1662-4548}, support = {R01 HL153612/HL/NHLBI NIH HHS/United States ; }, abstract = {The tongue plays a crucial role in the swallowing process, and impairment can lead to dysphagia, particularly in motor neuron diseases (MNDs) resulting in hypoglossal-tongue axis degeneration (e.g., amyotrophic lateral sclerosis and progressive bulbar palsy). This study utilized our previously established inducible rodent model of dysphagia due to targeted degeneration of the hypoglossal-tongue axis. This model was created by injecting cholera toxin B conjugated to saporin (CTB-SAP) into the genioglossus muscle of the tongue base for retrograde transport to the hypoglossal (XII) nucleus via the hypoglossal nerve, which provides the sole motor control of the tongue. Our goal was to investigate the effect of high-repetition/low-resistance tongue exercise on tongue function, strength, and structure in four groups of male rats: (1) control + sham exercise (n = 13); (2) control + exercise (n = 10); (3) CTB-SAP + sham exercise (n = 13); and (4) CTB-SAP + exercise (n = 12). For each group, a custom spout with adjustable lick force requirement for fluid access was placed in the home cage overnight on days 4 and 6 post-tongue injection. For the two sham exercise groups, the lick force requirement was negligible. For the two exercise groups, the lick force requirement was set to ∼40% greater than the maximum voluntary lick force for individual rats. Following exercise exposure, we evaluated the effect on hypoglossal-tongue axis function (via videofluoroscopy), strength (via force-lickometer), and structure [via Magnetic Resonance Imaging (MRI) of the brainstem and tongue in a subset of rats]. Results showed that sham-exercised CTB-SAP rats had significant deficits in lick rate, swallow timing, and lick force. In exercised CTB-SAP rats, lick rate and lick force were preserved; however, swallow timing deficits persisted. MRI revealed corresponding degenerative changes in the hypoglossal-tongue axis that were mitigated by tongue exercise. These collective findings suggest that high-repetition/low-resistance tongue exercise in our model is a safe and effective treatment to prevent/diminish signs of hypoglossal-tongue axis degeneration. The next step is to leverage our rat model to optimize exercise dosing parameters and investigate corresponding treatment mechanisms of action for future translation to MND clinical trials.}, }
@article {pmid35843530, year = {2022}, author = {Liu, Y and Xing, H and Ernst, AF and Liu, C and Maugee, C and Yokoi, F and Lakshmana, M and Li, Y}, title = {Hyperactivity of Purkinje cell and motor deficits in C9orf72 knockout mice.}, journal = {Molecular and cellular neurosciences}, volume = {121}, number = {}, pages = {103756}, pmid = {35843530}, issn = {1095-9327}, support = {R01 NS082244/NS/NINDS NIH HHS/United States ; R21 NS111498/NS/NINDS NIH HHS/United States ; R21 NS118397/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; C9orf72 Protein/genetics ; DNA Repeat Expansion/genetics ; *Frontotemporal Dementia/genetics ; Mice, Knockout ; Purkinje Cells/metabolism ; Disease Models, Animal ; }, abstract = {A hexanucleotide (GGGGCC) repeat expansion in the first intron of the C9ORF72 gene is the most frequently reported genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The cerebellum has not traditionally been thought to be involved in the pathogenesis of C9ORF72-associated ALS/FTD, but recent evidence suggested a potential role. C9ORF72 is highly expressed in the cerebellum. Decreased C9ORF72 transcript and protein levels were detected in the postmortem cerebellum, suggesting a loss-of-function effect of C9ORF72 mutation. This study investigated the role of loss of C9ORF72 function using a C9orf72 knockout mouse line. C9orf72 deficiency led to motor impairment in rotarod, beam-walking, paw-print, open-field, and grip-strength tests. Purkinje cells are the sole output neurons in the cerebellum, and we next determined their involvement in the motor phenotypes. We found hyperactivity of Purkinje cells in the C9orf72 knockout mouse accompanied by a significant increase of the large-conductance calcium-activated potassium channel (BK) protein in the cerebellum. The link between BK and Purkinje cell firing was demonstrated by the acute application of the BK activator that increased the firing frequency of the Purkinje cells ex vivo. In vivo chemogenetic activation of Purkinje cells in wild-type mice led to similar motor deficits in rotarod and beam-walking tests. Our results highlight that C9ORF72 loss alters the activity of the Purkinje cell and potentially the pathogenesis of the disease. Manipulating the Purkinje cell firing or cerebellar output may contribute to C9ORF72-associated ALS/FTD treatment.}, }
@article {pmid35836136, year = {2022}, author = {Park, JM and Park, D and Kim, HJ and Park, JS}, title = {Long-term outcomes of edaravone in amyotrophic lateral sclerosis in South Korea: 72-week observational study.}, journal = {BMC neurology}, volume = {22}, number = {1}, pages = {260}, pmid = {35836136}, issn = {1471-2377}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Antipyrine/adverse effects ; Double-Blind Method ; Edaravone/therapeutic use ; Humans ; *Neurodegenerative Diseases ; Republic of Korea/epidemiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease characterized by the gradual loss of upper and lower motor neurons that leads to progressive muscle atrophy and weakness. Edaravone, a free-radical scavenger, was approved as an ALS treatment in 2015 in South Korea.<br><br>METHODS: This study investigated the long-term effects and safety of edaravone by reviewing the medical records of 16 Korean patients with ALS who received extended edaravone between 2015 and 2021 in a single tertiary ALS center.<br><br>RESULTS: Among sixteen patients, eleven patients underwent extended edaravone therapy for more than 18&#x2009;cycles (72&#x2009;weeks). The mean monthly changes in the revised ALS Functional Rating Scale (ALSFRS-R) were&#x2009;-&#x2009;0.96&#x2009;&#xb1;&#x2009;0.83 (0-24&#x2009;weeks), -&#x2009;0.70&#x2009;&#xb1;&#x2009;0.76 (24-48&#x2009;weeks), -&#x2009;1.18&#x2009;&#xb1;&#x2009;1.67 (48-72&#x2009;weeks), and&#x2009;-&#x2009;0.81&#x2009;&#xb1;&#x2009;0.60 (0-72&#x2009;weeks). The mean decline in forced vital capacity (FVC) was 17.4&#x2009;&#xb1;&#x2009;24.1. The changes were significant in both ALSFRS-R (p&#x2009;<&#x2009;0.001) and FVC (p&#x2009;=&#x2009;0.048); however, the mean change in compound muscle action potential of phrenic nerves was not. Patients experienced only minor adverse events, which were well tolerated.<br><br>CONCLUSIONS: This study verifies previous reported outcomes of edaravone in 16 Korean ALS patients, indicating a modest effect with a favorable safety profile.}, }
@article {pmid35832305, year = {2022}, author = {Yang, EJ and Lee, SH and Cai, M}, title = {Treatment with Herbal Formula Extract in the hSOD1[G93A] Mouse Model Attenuates Muscle and Spinal Cord Dysfunction via Anti-Inflammation.}, journal = {Mediators of inflammation}, volume = {2022}, number = {}, pages = {4754732}, pmid = {35832305}, issn = {1466-1861}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Disease Models, Animal ; Female ; Male ; Mice ; Mice, Transgenic ; Muscles/metabolism ; *Neurodegenerative Diseases/metabolism ; Spinal Cord/pathology ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a multicomplex neurodegenerative disease, has multiple underlying pathological factors and can induce other neuromuscular diseases, leading to muscle atrophy and respiratory failure. Currently, there is no effective drug for treating patients with ALS. Herbal medicine, used to treat various diseases, has multitarget effects and does not usually induce side effects. Each bioactive component in such herbal combinations can exert a mechanism of action to increase therapeutic efficacy. Herein, we investigated the efficacy of an herbal formula, comprising Achyranthes bidentata Blume, Eucommia ulmoides Oliver, and Paeonia lactiflora Pallas, in suppressing the pathological mechanism of ALS in male hSOD1[G93A] mice. Herbal formula extract (HFE) (1 mg/g) were orally administered once daily for six weeks, starting at eight weeks of age, in hSOD1[G93A] transgenic mice. To evaluate the effects of HFE, we performed footprint behavioral tests, western blotting, and immunohistochemistry to detect protein expression and quantitative PCR to detect mRNA levels in the muscles and spinal cord of hSOD1[G93A] mice. HFE-treated hSOD1[G93A] mice showed increased anti-inflammation, antioxidation, and regulation of autophagy in the muscles and spinal cord. Thus, HEF can be therapeutic candidates for inhibiting disease progression in patients with ALS. This study has some limitations. Although this experiment was performed only in male hSOD1[G93A] mice, studies that investigate the efficacy of HEF in various ALS models including female mice, such as mice modeling TAR DNA-binding protein 43 (TDP43) and ORF 72 on chromosome 9 (C9orf72) ALS, are required before it can be established that HEF are therapeutic candidates for patients with ALS.}, }
@article {pmid35821195, year = {2022}, author = {Lu, G and Wen, Q and Cui, B and Li, Q and Zhang, F}, title = {Washed microbiota transplantation stopped the deterioration of amyotrophic lateral sclerosis: The first case report and narrative review.}, journal = {Journal of biomedical research}, volume = {37}, number = {1}, pages = {69-76}, pmid = {35821195}, issn = {1674-8301}, abstract = {Amyotrophic lateral sclerosis (ALS) is known as a progressive paralysis disorder characterized by degeneration of upper and lower motor neurons, and has an average survival time of three to five years. Growing evidence has suggested a bidirectional link between gut microbiota and neurodegeneration. Here we aimed to report one female case with ALS, who benefited from washed microbiota transplantation (WMT), an improved fecal microbiota transplantation (FMT), through a transendoscopic enteral tube during a 12-month follow-up. Notedly, the accidental scalp trauma the patient suffered later was treated with prescribed antibiotics that caused ALS deterioration. The subsequent rescue WMTs successfully stopped the progression of the disease with a quick improvement. The plateaus and reversals occurred during the whole course of WMT. The stool and blood samples from the first WMT to the last were collected for dynamic microbial and metabolomic analysis. We observed the microbial and metabolomic changing trend consistent with the disease status. This case report for the first time shows the direct clinical evidence on using WMT for treating ALS, indicating that WMT may be the novel treatment strategy for controlling this so-called incurable disease.}, }
@article {pmid35819713, year = {2022}, author = {Fournier, CN}, title = {Considerations for Amyotrophic Lateral Sclerosis (ALS) Clinical Trial Design.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {19}, number = {4}, pages = {1180-1192}, pmid = {35819713}, issn = {1878-7479}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Reproducibility of Results ; Clinical Trials as Topic ; Biomarkers ; Disease Progression ; }, abstract = {Thoughtful clinical trial design is critical for efficient therapeutic development, particularly in the field of amyotrophic lateral sclerosis (ALS), where trials often aim to detect modest treatment effects among a population with heterogeneous disease progression. Appropriate outcome measure selection is necessary for trials to provide decisive and informative results. Investigators must consider the outcome measure's reliability, responsiveness to detect change when change has actually occurred, clinical relevance, and psychometric performance. ALS clinical trials can also be performed more efficiently by utilizing statistical enrichment techniques. Innovations in ALS prediction models allow for selection of participants with less heterogeneity in disease progression rates without requiring a lead-in period, or participants can be stratified according to predicted progression. Statistical enrichment can reduce the needed sample size and improve study power, but investigators must find a balance between optimizing statistical efficiency and retaining generalizability of study findings to the broader ALS population. Additional progress is still needed for biomarker development and validation to confirm target engagement in ALS treatment trials. Selection of an appropriate biofluid biomarker depends on the treatment mechanism of interest, and biomarker studies should be incorporated into early phase trials. Inclusion of patients with ALS as advisors and advocates can strengthen clinical trial design and study retention, but more engagement efforts are needed to improve diversity and equity in ALS research studies. Another challenge for ALS therapeutic development is identifying ways to respect patient autonomy and improve access to experimental treatment, something that is strongly desired by many patients with ALS and ALS advocacy organizations. Expanded access programs that run concurrently to well-designed and adequately powered randomized controlled trials may provide an opportunity to broaden access to promising therapeutics without compromising scientific integrity or rushing regulatory approval of therapies without adequate proof of efficacy.}, }
@article {pmid35812619, year = {2022}, author = {Funo, K and Negishi, Y and Akamine, C and Takeuchi, R and Uzawa, Y}, title = {Setting Mechanical Insufflation-Exsufflation (MI-E) Pressures for Amyotrophic Lateral Sclerosis (ALS) Patients to Improve Atelectasis and Reduce Risk of Pneumothorax: A Case Report.}, journal = {Cureus}, volume = {14}, number = {6}, pages = {e25786}, pmid = {35812619}, issn = {2168-8184}, abstract = {Mechanical insufflation-exsufflation (MI-E) has been used to supplement the ability to cough and expel pulmonary secretions in patients with neuromuscular disease who have a reduced ability to cough. The manufacturer's guidelines for MI-E recommend a setting of inspiratory pressure of +40 cmH2O and expiratory pressure of -40 cmH2O. However, patients with small stature and restricted ventilatory impairment are prone to pneumothorax, so the manufacturer's recommendations are not used as is, and should be adjusted for the physical and pulmonary characteristics of each patient. Here, we report a case in which MI-E was used for an amyotrophic lateral sclerosis (ALS) patient with short height, low BMI, and restricted lung capacity at inspiratory and expiratory pressures lower than the manufacturer's recommendations. In adjusting MI-E pressure, physical observations such as chest auscultation, visual chest dilation, and observation of secretion movement toward the tracheal tube were performed to avoid unnecessary pressure. As a result, the pressure level set was lower than the manufacturer's recommendation (25 cmH2O) but sufficient to improve atelectasis and no pneumothorax occurred. The method we practiced in this study is feasible in any clinical setting. We also believe that MI-E, when performed in conjunction with treatment response observation, can be expected to improve at lower pressures than generally recommended, thereby reducing the risk of lung injury and providing safer treatment.}, }
@article {pmid35807977, year = {2022}, author = {Waris, A and Ali, A and Khan, AU and Asim, M and Zamel, D and Fatima, K and Raziq, A and Khan, MA and Akbar, N and Baset, A and Abourehab, MAS}, title = {Applications of Various Types of Nanomaterials for the Treatment of Neurological Disorders.}, journal = {Nanomaterials (Basel, Switzerland)}, volume = {12}, number = {13}, pages = {}, pmid = {35807977}, issn = {2079-4991}, support = {22UQU4290565DSR22//Umm Al-Qura University Saudi Arabia/ ; }, abstract = {Neurological disorders (NDs) are recognized as one of the major health concerns globally. According to the World Health Organization (WHO), neurological disorders are one of the main causes of mortality worldwide. Neurological disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Prion disease, Brain tumor, Spinal cord injury, and Stroke. These diseases are considered incurable diseases because no specific therapies are available to cross the blood-brain barrier (BBB) and reach the brain in a significant amount for the pharmacological effect in the brain. There is a need for the development of strategies that can improve the efficacy of drugs and circumvent BBB. One of the promising approaches is the use of different types of nano-scale materials. These nano-based drugs have the ability to increase the therapeutic effect, reduce toxicity, exhibit good stability, targeted delivery, and drug loading capacity. Different types and shapes of nanomaterials have been widely used for the treatment of neurological disorders, including quantum dots, dendrimers, metallic nanoparticles, polymeric nanoparticles, carbon nanotubes, liposomes, and micelles. These nanoparticles have unique characteristics, including sensitivity, selectivity, and the ability to cross the BBB when used in nano-sized particles, and are widely used for imaging studies and treatment of NDs. In this review, we briefly summarized the recent literature on the use of various nanomaterials and their mechanism of action for the treatment of various types of neurological disorders.}, }
@article {pmid35801347, year = {2022}, author = {Steiner, JP and Bachani, M and Malik, N and DeMarino, C and Li, W and Sampson, K and Lee, MH and Kowalak, J and Bhaskar, M and Doucet-O'Hare, T and Garcia-Montojo, M and Cowen, M and Smith, B and Reoma, LB and Medina, J and Brunel, J and Pierquin, J and Charvet, B and Perron, H and Nath, A}, title = {Human Endogenous Retrovirus K Envelope in Spinal Fluid of Amyotrophic Lateral Sclerosis Is Toxic.}, journal = {Annals of neurology}, volume = {92}, number = {4}, pages = {545-561}, pmid = {35801347}, issn = {1531-8249}, support = {ZIA NS003130/ImNIH/Intramural NIH HHS/United States ; ZIA NS003149/ImNIH/Intramural NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Animals ; *Endogenous Retroviruses ; Gene Products, env ; Humans ; Integrin beta1 ; Mice ; Mice, Transgenic ; }, abstract = {OBJECTIVE: Human endogenous retroviruses have been implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Expression of human endogenous retrovirus K (HERV-K) subtype HML-2 envelope (Env) in human neuronal cultures and in transgenic mice results in neurotoxicity and neurodegeneration, and mice expressing HML-2 Env display behavioral and neuromuscular characteristics resembling ALS. This study aims to characterize the neurotoxic properties of HML-2 Env.<br><br>METHODS: Env neurotoxicity was detected in ALS cerebrospinal fluid and confirmed using recombinant Env protein in a cell-based assay and a mouse model. The mechanism of neurotoxicity was assessed with immunoprecipitation followed by mass spectrometry and Western blot, and by screening a panel of inhibitors.<br><br>RESULTS: We observed that recombinant HML-2 Env protein caused neurotoxicity resulting in neuronal cell death, retraction of neurites, and decreased neuronal electrical activity. Injection of the Env protein into the brains of mice also resulted in neuronal cell death. HML-2 Env protein was also found in the cerebrospinal fluid of patients with sporadic ALS. The neurotoxic properties of the Env and the cerebrospinal fluid could be rescued with the anti-Env antibody. The Env was found to bind to CD98HC complexed to &#x3b2;1 integrin on the neuronal cell surface. Using a panel of compounds to screen for their ability to block Env-induced neurotoxicity, we found that several compounds were protective and are linked to the &#x3b2;1 integrin pathway.<br><br>INTERPRETATION: HERV-K Env is released extracellularly in ALS and causes neurotoxicity via a novel mechanism. Present results pave the way for new treatment strategies in sporadic ALS. ANN NEUROL 2022;92:545-561.}, }
@article {pmid35798698, year = {2022}, author = {Rhymes, ER and Tosolini, AP and Fellows, AD and Mahy, W and McDonald, NQ and Schiavo, G}, title = {Bimodal regulation of axonal transport by the GDNF-RET signalling axis in healthy and diseased motor neurons.}, journal = {Cell death &amp; disease}, volume = {13}, number = {7}, pages = {584}, pmid = {35798698}, issn = {2041-4889}, support = {(FC001115)//Wellcome Trust (Wellcome)/ ; FC001115/ARC_/Arthritis Research UK/United Kingdom ; 543129//RCUK | Medical Research Council (MRC)/ ; /WT_/Wellcome Trust/United Kingdom ; 520909//Alzheimer's Research UK (ARUK)/ ; (FC001115)//Cancer Research UK (CRUK)/ ; (FC001115)//RCUK | Medical Research Council (MRC)/ ; 107116/Z/15/Z//Wellcome Trust (Wellcome)/ ; 223022/Z/21/Z//Wellcome Trust (Wellcome)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Animals ; *Axonal Transport/physiology ; Disease Models, Animal ; *Glial Cell Line-Derived Neurotrophic Factor/metabolism ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism ; *Proto-Oncogene Proteins c-ret/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Deficits in axonal transport are one of the earliest pathological outcomes in several models of amyotrophic lateral sclerosis (ALS), including SOD1[G93A] mice. Evidence suggests that rescuing these deficits prevents disease progression, stops denervation, and extends survival. Kinase inhibitors have been previously identified as transport enhancers, and are being investigated as potential therapies for ALS. For example, inhibitors of p38 mitogen-activated protein kinase and insulin growth factor receptor 1 have been shown to rescue axonal transport deficits in vivo in symptomatic SOD1[G93A] mice. In this work, we investigated the impact of RET, the tyrosine kinase receptor for glial cell line-derived neurotrophic factor (GDNF), as a modifier of axonal transport. We identified the fundamental interplay between RET signalling and axonal transport in both wild-type and SOD1[G93A] motor neurons in vitro. We demonstrated that blockade of RET signalling using pharmacological inhibitors and genetic knockdown enhances signalling endosome transport in wild-type motor neurons and uncovered a divergence in the response of primary motor neurons to GDNF compared with cell lines. Finally, we showed that inhibition of the GDNF-RET signalling axis rescues in vivo transport deficits in early symptomatic SOD1[G93A] mice, promoting RET as a potential therapeutic target in the treatment of ALS.}, }
@article {pmid35798516, year = {2022}, author = {Wong, C and Dakin, RS and Williamson, J and Newton, J and Steven, M and Colville, S and Stavrou, M and Gregory, JM and Elliott, E and Mehta, AR and Chataway, J and Swingler, RJ and Parker, RA and Weir, CJ and Stallard, N and Parmar, MKB and Macleod, MR and Pal, S and Chandran, S}, title = {Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease.}, journal = {BMJ open}, volume = {12}, number = {7}, pages = {e064173}, pmid = {35798516}, issn = {2044-6055}, support = {MC_EX_MR/N50192X/1/MRC_/Medical Research Council/United Kingdom ; MEHTA/JUL17/948-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R001162/1/MRC_/Medical Research Council/United Kingdom ; MRF_MRF-024-0001-RG-PARM-C0860/MRF/MRF/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Humans ; Memantine/therapeutic use ; *Motor Neuron Disease/drug therapy ; *Neurodegenerative Diseases ; Riluzole/therapeutic use ; *Trazodone/therapeutic use ; Treatment Outcome ; }, abstract = {INTRODUCTION: Motor neuron disease (MND) is a rapidly fatal neurodegenerative disease. Despite decades of research and clinical trials there remains no cure and only one globally approved drug, riluzole, which prolongs survival by 2-3 months. Recent improved mechanistic understanding of MND heralds a new translational era with many potential targets being identified that are ripe for clinical trials. Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART) aims to evaluate the efficacy of drugs efficiently and definitively in a multi-arm, multi-stage, adaptive trial. The first two drugs selected for evaluation in MND-SMART are trazodone and memantine.<br><br>METHODS AND ANALYSIS: Initially, up to 531 participants (177/arm) will be randomised 1:1:1 to oral liquid trazodone, memantine and placebo. The coprimary outcome measures are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) and survival. Comparisons will be conducted in four stages. The decision to continue randomising to arms after each stage will be made by the Trial Steering Committee who receive recommendations from the Independent Data Monitoring Committee. The primary analysis of ALSFRS-R will be conducted when 150 participants/arm, excluding long survivors, have completed 18 months of treatment; if positive the survival effect will be inferentially analysed when 113 deaths have been observed in the placebo group. The trial design ensures that other promising drugs can be added for evaluation in planned trial adaptations. Using this novel trial design reduces time, cost and number of participants required to definitively (phase III) evaluate drugs and reduces exposure of participants to potentially ineffective treatments.<br><br>ETHICS AND DISSEMINATION: MND-SMART was approved by the West of Scotland Research Ethics Committee on 2 October 2019. (REC reference: 19/WS/0123) Results of the study will be submitted for publication in a peer-reviewed journal and a summary provided to participants.<br><br>TRIAL REGISTRATION NUMBERS: European Clinical Trials Registry (2019-000099-41); NCT04302870.}, }
@article {pmid35796900, year = {2022}, author = {Plewka, P and Raczynska, KD}, title = {Long Intergenic Noncoding RNAs Affect Biological Pathways Underlying Autoimmune and Neurodegenerative Disorders.}, journal = {Molecular neurobiology}, volume = {59}, number = {9}, pages = {5785-5808}, pmid = {35796900}, issn = {1559-1182}, support = {UMO-2018/30/E/NZ2/00295//Narodowe Centrum Nauki/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics/pathology ; *RNA, Long Noncoding/genetics ; }, abstract = {Long intergenic noncoding RNAs (lincRNAs) are a class of independently transcribed molecules longer than 200 nucleotides that do not overlap known protein-coding genes. LincRNAs have diverse roles in gene expression and participate in a spectrum of biological processes. Dysregulation of lincRNA expression can abrogate cellular homeostasis, cell differentiation, and development and can also deregulate the immune and nervous systems. A growing body of literature indicates their important and multifaceted roles in the pathogenesis of several different diseases. Furthermore, certain lincRNAs can be considered potential therapeutic targets and valuable diagnostic or prognostic biomarkers capable of predicting the onset of a disease, its degree of activity, or the progression phase. In this review, we discuss possible mechanisms and molecular functions of lincRNAs in the pathogenesis of selected autoimmune and neurodegenerative disorders: multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. This summary can provide new ideas for future research, diagnosis, and treatment of these highly prevalent and devastating diseases.}, }
@article {pmid35792195, year = {2022}, author = {Jankowiak, T and Cholewiński, M and Bączyk, M}, title = {Differential Effects of Invasive Anodal Trans-spinal Direct Current Stimulation on Monosynaptic Excitatory Postsynaptic Potentials, Ia Afferents Excitability, and Motoneuron Intrinsic Properties Between Superoxide Dismutase Type-1 Glycine to Alanine Substitution at Position 93 and Wildtype Mice.}, journal = {Neuroscience}, volume = {498}, number = {}, pages = {125-143}, doi = {10.1016/j.neuroscience.2022.06.035}, pmid = {35792195}, issn = {1873-7544}, mesh = {Alanine ; Amyotrophic Lateral Sclerosis ; Animals ; *Electric Stimulation Therapy/methods ; *Excitatory Postsynaptic Potentials/physiology ; Glycine ; Mice ; Motor Neurons/physiology ; Spinal Cord ; Superoxide Dismutase ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {In presymptomatic amyotrophic lateral sclerosis (ALS), spinal motoneurons (MNs) have reduced firing patterns and synaptic excitation levels. Preliminary data indicated that in the SOD1 G93A mouse model of ALS, monosynaptic excitatory postsynaptic potentials (EPSPs) evoked in spinal MN by Ia proprioceptive afferent stimulation could be facilitated by trans-spinal direct current stimulation (tsDCS). However, which element of the Ia afferent-MN circuit is affected by tsDCS, and whether tsDCS-induced EPSP facilitation is a general phenomenon or specific to the superoxide dismutase type-1 (SOD1) Glycine to Alanine substitution at position 93 (G93A) mutation, remain to be determined. In this study, we have applied 15-minute tsDCS to the lumbar segments of presymptomatic SOD1 and wildtype (WT) mice and explored its impact on MN passive membrane properties, EPSP amplitude, and Ia afferent activity. While anodal tsDCS induced short-lasting EPSP facilitation in both SOD1 and WT mice, Ia afferent activity and passive membrane properties were altered only in SOD1 mice. Interestingly, EPSP amplitudes of SOD1 mice remained facilitated for at least 1 h after current application, but no long-lasting effect was observed in WT mice. Moreover, anodal tsDCS failed to induce any long-lasting changes in MN passive membrane properties in both SOD1 and WT mice. Conversely, cathodal tsDCS decreased Ia afferent induced EPSP amplitudes only during current application in SOD1 MNs, and no significant effects on Ia afferents excitability were observed. Our findings indicate the high susceptibility of SOD1 MNs to tsDCS and highlight the potential of this neuromodulation technique for the treatment of ALS.}, }
@article {pmid35791387, year = {2022}, author = {Coskuner-Weber, O and Mirzanli, O and Uversky, VN}, title = {Intrinsically disordered proteins and proteins with intrinsically disordered regions in neurodegenerative diseases.}, journal = {Biophysical reviews}, volume = {14}, number = {3}, pages = {679-707}, pmid = {35791387}, issn = {1867-2450}, abstract = {Many different intrinsically disordered proteins and proteins with intrinsically disordered regions are associated with neurodegenerative diseases. These types of proteins including amyloid-β, tau, α-synuclein, CHCHD2, CHCHD10, and G-protein coupled receptors are increasingly becoming evaluated as potential drug targets in the pharmaceutical-based treatment approaches. Here, we focus on the neurobiology of this class of proteins, which lie at the center of numerous neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, Huntington's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Charcot-Marie-Tooth diseases, spinal muscular atrophy, and mitochondrial myopathy. Furthermore, we discuss the current treatment design strategies involving intrinsically disordered proteins and proteins with intrinsically disordered regions in neurodegenerative diseases. In addition, we emphasize that although the G-protein coupled receptors are traditionally investigated using structural biology-based models and approaches, current studies show that these receptors are proteins with intrinsically disordered regions and therefore they require new ways for their analysis.}, }
@article {pmid35790562, year = {2022}, author = {Aust, E and Linse, K and Graupner, ST and Joos, M and Liebscher, D and Grosskreutz, J and Prudlo, J and Meyer, T and Günther, R and Pannasch, S and Hermann, A}, title = {Quality of life and mental health in the locked-in-state-differences between patients with amyotrophic lateral sclerosis and their next of kin.}, journal = {Journal of neurology}, volume = {269}, number = {11}, pages = {5910-5925}, pmid = {35790562}, issn = {1432-1459}, support = {13GW0482//Bundesministerium f&#xfc;r Bildung und Forschung/ ; 01VSF16026//Innovationsausschuss beim Gemeinsamen Bundesausschuss/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/complications/psychology ; Anxiety Disorders/psychology ; Caregivers/psychology ; Depression/etiology ; Humans ; Mental Health ; *Quality of Life/psychology ; Surveys and Questionnaires ; }, abstract = {For both patients with amyotrophic lateral sclerosis (ALS) and their next of kin (NOK), the maintenance of quality of life (QoL) and mental health is particularly important. First studies suggest significant discrepancies between QoL reports by patients and NOK, but little is known for advanced ALS stages. To address this issue, we screened 52 ALS patients in incomplete locked-in state (iLIS). Final results were obtained for 15 couples of iLIS patients and NOK. We assessed patients' and NOK's subjective QoL, depression and anxiety and NOK's caregiver burden. Gaze controlled questionnaires allowed direct assessment of patients. Patients and NOK self-reported comparable, mostly moderate to high levels of QoL. Of note, NOK indicated stronger anxiety symptoms. Higher anxiety levels in NOK were associated with stronger caregiver burden and reduced QoL. No significant misjudgment of patient's QoL by the NOK was evident, while patients overestimated NOK's global QoL. However, NOK with severe caregiver burden and depression symptoms gave poorer estimations of patients' QoL. This relationship is relevant, considering NOK's impact on life critical treatment decisions. While the daily time NOK and patient spend together was positively correlated with NOK's QoL and mental health, this was not reversely found for the patients. Our results suggest that NOK adapt less successfully to the disease and concomitant experience of loss and point to an urgent need for specialized psychosocial support. The findings emphasize the importance of direct psychological wellbeing assessment of both patients and NOK in clinical practice, enabled by eye-tracking technology for patients in iLIS.}, }
@article {pmid35790423, year = {2022}, author = {Tipton, PW and Deutschlaender, AB and Savica, R and Heckman, MG and Brushaber, DE and Dickerson, BC and Gavrilova, RH and Geschwind, DH and Ghoshal, N and Graff-Radford, J and Graff-Radford, NR and Grossman, M and Hsiung, GR and Huey, ED and Irwin, DJ and Jones, DT and Knopman, DS and McGinnis, SM and Rademakers, R and Ramos, EM and Forsberg, LK and Heuer, HW and Onyike, C and Tartaglia, C and Domoto-Reilly, K and Roberson, ED and Mendez, MF and Litvan, I and Appleby, BS and Grant, I and Kaufer, D and Boxer, AL and Rosen, HJ and Boeve, BF and Wszolek, ZK and , }, title = {Differences in Motor Features of C9orf72, MAPT, or GRN Variant Carriers With Familial Frontotemporal Lobar Degeneration.}, journal = {Neurology}, volume = {99}, number = {11}, pages = {e1154-e1167}, pmid = {35790423}, issn = {1526-632X}, support = {K24 AG045333/AG/NIA NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; U54 NS092089/NS/NINDS NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; U01 AG045390/AG/NIA NIH HHS/United States ; }, mesh = {C9orf72 Protein/genetics ; *Frontotemporal Dementia/diagnosis/genetics ; *Frontotemporal Lobar Degeneration/genetics ; Granulins/genetics ; Humans ; Mutation/genetics ; Progranulins/genetics ; Quality of Life ; *Supranuclear Palsy, Progressive ; tau Proteins/genetics ; }, abstract = {BACKGROUND AND OBJECTIVES: Familial frontotemporal lobar degeneration (f-FTLD) is a phenotypically heterogeneous spectrum of neurodegenerative disorders most often caused by variants within chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), or granulin (GRN). The phenotypic association with each of these genes is incompletely understood. We hypothesized that the frequency of specific clinical features would correspond with different genes.<br><br>METHODS: We screened the Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)/ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium for symptomatic carriers of pathogenic variants in C9orf72, MAPT, or GRN. We assessed for clinical differences among these 3 groups based on data recorded as part of a detailed neurologic examination, the Progressive Supranuclear Palsy Rating Scale, Progressive Supranuclear Palsy-Quality of Life Rating Scale, Unified Parkinson's Disease Rating Scale Part III (motor items), and the Amyotrophic Lateral Sclerosis Functional Rating Scale, revised version. Data were analyzed using Kruskal-Wallis and Wilcoxon rank-sum tests and Fisher exact test.<br><br>RESULTS: We identified 184 symptomatic participants who had a single pathogenic variant in C9orf72 (n = 88), MAPT (n = 53), or GRN (n = 43). Motor symptom age at onset was earliest in the MAPT participants followed by C9orf72, whereas the GRN pathogenic variant carriers developed symptoms later. C9orf72 participants more often had fasciculations, muscle atrophy, and weakness, whereas parkinsonism was less frequent. Vertical oculomotor abnormalities were more common in the MAPT cohort, whereas apraxia and focal limb dystonia occurred more often in participants with GRN variants.<br><br>DISCUSSION: We present a large comparative study of motor features in C9orf72, MAPT, and GRN pathogenic variant carriers with symptomatic f-FTLD. Our findings demonstrate characteristic phenotypic differences corresponding with specific gene variants that increase our understanding of the genotype-phenotype relationship in this complex spectrum of neurodegenerative disorders.<br><br>NCT02365922, NCT02372773, and NCT04363684.}, }
@article {pmid35787407, year = {2022}, author = {Pathoulas, JT and Flanagan, KE and Walker, CJ and Wiss, IP and Azimi, E and Senna, MM}, title = {Reply to "Response to Pathoulas et al's 'Evaluation of standardized scalp photography on patient perception of hair loss severity, anxiety, and treatment'".}, journal = {Journal of the American Academy of Dermatology}, volume = {87}, number = {5}, pages = {e169}, doi = {10.1016/j.jaad.2022.06.033}, pmid = {35787407}, issn = {1097-6787}, mesh = {Alopecia/diagnosis ; *Anxiety/etiology ; Humans ; Perception ; Photography ; *Scalp ; }, }
@article {pmid35785436, year = {2022}, author = {Frater, JL and Shirai, CL and Brestoff, JR}, title = {Technological features of blast identification in the cerebrospinal fluid: A systematic review of flow cytometry and laboratory haematology methods.}, journal = {International journal of laboratory hematology}, volume = {44 Suppl 1}, number = {Suppl 1}, pages = {45-53}, pmid = {35785436}, issn = {1751-553X}, support = {DP5 OD028125/OD/NIH HHS/United States ; R01 AI168044/AI/NIAID NIH HHS/United States ; DP5 OD028125/CD/ODCDC CDC HHS/United States ; #1019648//Burroughs Wellcome Fund Career Award for Medical Scientists/ ; }, mesh = {Adult ; Cerebrospinal Fluid ; Child ; Flow Cytometry/methods ; *Hematology/methods ; Humans ; *Leukemia ; Leukocyte Count ; Technology ; }, abstract = {BACKGROUND: Involvement of the central nervous system (CNS) by acute leukemias (ALs) has important implications for risk stratification and disease outcome. The clinical laboratory plays an essential role in assessment of cerebrospinal fluid (CSF) specimens from patients with ALs at initial diagnosis, at the end of treatment, and when CNS involvement is clinically suspected. The two challenges for the laboratory are 1) to accurately provide a cell count of the CSF and 2) to successfully distinguish blasts from other cell types. These tasks are classically performed using manual techniques, which suffer from suboptimal turnaround time, imprecision, and inconsistent inter-operator performance. Technological innovations in flow cytometry and hematology analyzer technology have provided useful complements and/or alternatives to conventional manual techniques.<br><br>AIMS: We performed a PRISMA-compliant systematic review to address the medical literature regarding the development and current state of the art of CSF blast identification using flow cytometry and laboratory hematology technologies.<br><br>MATERIALS AND METHODS: We searched the peer reviewed medical literature using MEDLINE (PubMed interface), Web of Science, and Embase using the keywords "CSF or cerebrospinal" AND "blasts(s)".<br><br>RESULTS: 108 articles were suitable for inclusion in our systematic review. These articles covered 1) clinical rationale for CSF blast identification; 2) morphology-based CSF blast identification; 3) the role of flow cytometry; 4) use of hematology analyzers for CSF blast identification; and 5) quality issues. [9] /L, which is much lower than the original machine count and platelet transfusion was warranted.<br><br>DISCUSSION: 1) Clinical laboratory testing plays a central role in risk stratification and clinical management of patients with acute leukemias, most clearly in pediatric ALs; 2) studies focused on other patient populations, including adults and patients with AML are less prevalent in the literature; 3) improvements in instrumentation may provide better performance for the classification of CSF specimens.<br><br>CONCLUSION: Current challenges include: 1) more precisely characterizing the natural history of AL involvement of the CNS, 2) improvements in automated cell count technology of low cellularity specimens, 3) defining the role of flow MRD testing of CSF specimens and 4) improved recognition of specimen quality by clinicians and laboratory personnel.}, }
@article {pmid35782440, year = {2022}, author = {Sharbafshaaer, M and Buonanno, D and Passaniti, C and De Stefano, M and Esposito, S and Canale, F and D'Alvano, G and Silvestro, M and Russo, A and Tedeschi, G and Siciliano, M and Trojsi, F}, title = {Psychological Support for Family Caregivers of Patients With Amyotrophic Lateral Sclerosis at the Time of the Coronavirus Disease 2019 Pandemic: A Pilot Study Using a Telemedicine Approach.}, journal = {Frontiers in psychiatry}, volume = {13}, number = {}, pages = {904841}, pmid = {35782440}, issn = {1664-0640}, abstract = {The coronavirus disease 2019 (COVID-19) pandemic confined most of the population to homes worldwide, and then, a lot of amyotrophic lateral sclerosis (ALS) centers moved to telemedicine services to continue to assist both patients with ALS and their caregivers. This pilot, randomized, controlled study aimed to explore the potential role of psychological support interventions for family caregivers of patients with ALS through resilience-oriented sessions of group therapy during the COVID-19 pandemic. In total, 12 caregivers agreed to be remotely monitored by our center since March 2020 and underwent scales for global burden (i.e., Caregiver Burden Inventory, CBI), resilience (i.e., Connor Davidson Resilience Scale, CD-RISC), and perceived stress (i.e., Perceived Stress Scale, PSS) at two-time points (i.e., at pre-treatment assessment and after 9 months or at post-treatment assessment). They were randomized into two groups: the former group underwent resilience-oriented sessions of group therapy two times a month for 3 months, while the latter one was only remotely monitored. No significant differences were found in CBI, CD-RISC, and PSS during the 9-month observation period in the treated group compared with the control group, suggesting a trend toward stability of caregiver burden together with resilience and perceived stress scores in all the subjects monitored. The lack of differences in caregivers' burden, resilience, and perceived stress scores by comparing the two groups monitored during 9 months could be due to the co-occurrence of the COVID-19 pandemic with the stressful events related to caring for patients with ALS that might have hindered the detection of significant benefits from short-lasting psychological support.}, }
@article {pmid35779869, year = {2022}, author = {Castillo-Álvarez, F and Marzo-Sola, ME}, title = {Role of the gut microbiota in the development of various neurological diseases.}, journal = {Neurologia}, volume = {37}, number = {6}, pages = {492-498}, doi = {10.1016/j.nrleng.2019.03.026}, pmid = {35779869}, issn = {2173-5808}, mesh = {*Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; *Gastrointestinal Microbiome ; Humans ; *Multiple Sclerosis ; *Nervous System Diseases ; *Neuromyelitis Optica ; *Parkinson Disease ; }, abstract = {INTRODUCTION: In recent years, the scientific evidence supporting a relationship between the microbiota and various diseases has increased significantly; this trend has also been observed for neurological diseases. This has given rise to the concept of the gut-brain axis and the idea of a relationship between the gut microbiota and several neurological diseases whose aetiopathogenesis is yet to be clearly defined.<br><br>DEVELOPMENT: We review the role of the gut microbiota in the gut-brain axis and analyse those neurological diseases in which alterations in the gut microbiota have been described as a result of human studies: specifically, Parkinson's disease, Alzheimer disease, amyotrophic lateral sclerosis, neuromyelitis optica, and multiple sclerosis.<br><br>CONCLUSIONS: The body of evidence linking the gut microbiota to various neurological diseases has grown considerably. Several interesting studies show a relationship between the gut microbiota and Parkinson's disease, Alzheimer disease, neuromyelitis optica, and multiple sclerosis, whereas other controversial studies implicate it in amyotrophic lateral sclerosis. Many of these studies place considerable emphasis on modulation of inflammation, particularly by bacteria capable of producing short-chain fatty acids. Despite these encouraging results, many questions remain, and there is a need to demonstrate causality, determine the role of fungi or viruses, and research possible treatment through diet, probiotics, or faecal microbiota transplantation.}, }
@article {pmid35774867, year = {2022}, author = {Sommer, D and Rajkumar, S and Seidel, M and Aly, A and Ludolph, A and Ho, R and Boeckers, TM and Catanese, A}, title = {Aging-Dependent Altered Transcriptional Programs Underlie Activity Impairments in Human C9orf72-Mutant Motor Neurons.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {894230}, pmid = {35774867}, issn = {1662-5099}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease characterized by dysfunction and loss of upper and lower motor neurons (MN). Despite several studies identifying drastic alterations affecting synaptic composition and functionality in different experimental models, the specific contribution of impaired activity to the neurodegenerative processes observed in ALS-related MN remains controversial. In particular, contrasting lines of evidence have shown both hyper- as well as hypoexcitability as driving pathomechanisms characterizing this specific neuronal population. In this study, we combined high definition multielectrode array (HD-MEA) techniques with transcriptomic analysis to longitudinally monitor and untangle the activity-dependent alterations arising in human C9orf72-mutant MN. We found a time-dependent reduction of neuronal activity in ALS[C9orf72] cultures occurring as synaptic contacts undergo maturation and matched by a significant loss of mutant MN upon aging. Notably, ALS-related neurons displayed reduced network synchronicity most pronounced at later stages of culture, suggesting synaptic imbalance. In concordance with the HD-MEA data, transcriptomic analysis revealed an early up-regulation of synaptic terms in ALS[C9orf72] MN, whose expression was decreased in aged cultures. In addition, treatment of older mutant cells with Apamin, a K[+] channel blocker previously shown to be neuroprotective in ALS, rescued the time-dependent loss of firing properties observed in ALS[C9orf72] MN as well as the expression of maturity-related synaptic genes. All in all, this study broadens the understanding of how impaired synaptic activity contributes to MN degeneration in ALS by correlating electrophysiological alterations to aging-dependent transcriptional programs.}, }
@article {pmid35772643, year = {2022}, author = {Liu, X and Zhang, J and Li, J and Song, C and Shi, Y}, title = {Pharmacological inhibition of ALCAT1 mitigates amyotrophic lateral sclerosis by attenuating SOD1 protein aggregation.}, journal = {Molecular metabolism}, volume = {63}, number = {}, pages = {101536}, pmid = {35772643}, issn = {2212-8778}, support = {P30 AG013319/AG/NIA NIH HHS/United States ; R01 AG055747/AG/NIA NIH HHS/United States ; }, mesh = {*Acyltransferases/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Animals ; Cardiolipins/therapeutic use ; Disease Models, Animal ; Mice ; Mice, Transgenic ; *Protein Aggregates/genetics ; Superoxide Dismutase/genetics/metabolism/therapeutic use ; *Superoxide Dismutase-1/genetics/metabolism/therapeutic use ; }, abstract = {OBJECTIVE: Mutations in the copper-zinc superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS), a progressive fatal neuromuscular disease characterized by motor neurons death and severe skeletal muscle degeneration. However, there is no effective treatment for this debilitating disease, since the underlying cause for the pathogenesis remains poorly understood. Here, we investigated a role of acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1), an acyltransferase that promotes mitochondrial dysfunction in age-related diseases by catalyzing pathological remodeling of cardiolipin, in promoting the development of ALS in the SOD1[G93A] transgenic mice.<br><br>METHODS: Using SOD1[G93A] transgenic mice with targeted deletion of the ALCAT1 gene and treated with Dafaglitapin (Dafa), a very potent and highly selective ALCAT1 inhibitor, we determined whether ablation or pharmaceutical inhibition of ALCAT1 by Dafa would mitigate ALS and the underlying pathogenesis by preventing pathological remodeling of cardiolipin, oxidative stress, and mitochondrial dysfunction by multiple approaches, including lifespan analysis, behavioral tests, morphological and functional analysis of skeletal muscle, electron microscopic and Seahorse analysis of mitochondrial morphology and respiration, western blot analysis of the SOD1[G93A] protein aggregation, and lipidomic analysis of cardiolipin content and acyl composition in mice spinal cord.<br><br>RESULTS: ALCAT1 protein expression is potently upregulated in the skeletal muscle of the SOD1[G93A] mice. Consequently, ablation or pharmacological inhibition of ALCAT1 by Dafa attenuates motor neuron dysfunction, neuronal inflammation, and skeletal muscle atrophy in SOD1[G93A] mice by preventing SOD1[G93A] protein aggregation, mitochondrial dysfunction, and pathological CL remodeling, leading to moderate extension of lifespan in the SOD1[G93A] transgenic mice.<br><br>CONCLUSIONS: ALCAT1 promotes the development of ALS by linking SOD1[G93A] protein aggregation to mitochondrial dysfunction, implicating Dafa as a potential treatment for this debilitating disorder.}, }
@article {pmid35770772, year = {2022}, author = {Hastings, N and Kuan, WL and Osborne, A and Kotter, MRN}, title = {Therapeutic Potential of Astrocyte Transplantation.}, journal = {Cell transplantation}, volume = {31}, number = {}, pages = {9636897221105499}, pmid = {35770772}, issn = {1555-3892}, support = {MR/S005528/1/MRC_/Medical Research Council/United Kingdom ; CS-2015-15-023/DH_/Department of Health/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Astrocytes/metabolism ; Humans ; *Huntington Disease ; *Neurodegenerative Diseases/metabolism ; *Stroke/metabolism ; }, abstract = {Cell transplantation is an attractive treatment strategy for a variety of brain disorders, as it promises to replenish lost functions and rejuvenate the brain. In particular, transplantation of astrocytes has come into light recently as a therapy for amyotrophic lateral sclerosis (ALS); moreover, grafting of astrocytes also showed positive results in models of other conditions ranging from neurodegenerative diseases of older age to traumatic injury and stroke. Despite clear differences in etiology, disorders such as ALS, Parkinson's, Alzheimer's, and Huntington's diseases, as well as traumatic injury and stroke, converge on a number of underlying astrocytic abnormalities, which include inflammatory changes, mitochondrial damage, calcium signaling disturbance, hemichannel opening, and loss of glutamate transporters. In this review, we examine these convergent pathways leading to astrocyte dysfunction, and explore the existing evidence for a therapeutic potential of transplantation of healthy astrocytes in various models. Existing literature presents a wide variety of methods to generate astrocytes, or relevant precursor cells, for subsequent transplantation, while described outcomes of this type of treatment also differ between studies. We take technical differences between methodologies into account to understand the variability of therapeutic benefits, or lack thereof, at a deeper level. We conclude by discussing some key requirements of an astrocyte graft that would be most suitable for clinical applications.}, }
@article {pmid35765222, year = {2022}, author = {Yerton, M and Winter, A and Kostov, A and Lieberman, C and Gelevski, D and Weber, H and Doyle, M and Kane, G and Parikh, N and Burke, KM and Rohrer, M and Stirrat, T and Bruno, M and Hochman, A and Luppino, S and Scalia, J and Skoniecki, D and D'Agostino, D and Sinani, E and Yu, H and Sherman, AV and Babu, S and Berry, JD and Midei, MG and Milner, PG and Cudkowicz, ME and Paganoni, S}, title = {An expanded access protocol of RT001 in amyotrophic lateral sclerosis-Initial experience with a lipid peroxidation inhibitor.}, journal = {Muscle &amp; nerve}, volume = {66}, number = {4}, pages = {421-425}, pmid = {35765222}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; Esters/therapeutic use ; Fatty Acids ; Humans ; Linoleic Acids/therapeutic use ; Randomized Controlled Trials as Topic ; }, abstract = {INTRODUCTION/AIMS: Lipid peroxidation is thought to play a biologically important role in motor neuron death in amyotrophic lateral sclerosis (ALS). 11,11 Di-deuterated linoleic ethyl ester (RT001) prevents lipid peroxidation in cellular and mitochondrial membranes. Herein we report on the use of RT001 under expanded access (EA).<br><br>METHODS: We provided RT001 to patients with ALS via EA at a single site. The starting dose was 2.88&#x2009;g/day, which was increased to to 8.64&#x2009;g/day as tolerated. Participants were not eligible for alternative clinical trials. Participants were followed for adverse events and pharmacokinetic (PK) parameters were measured approximately 3&#xa0;months after RT001 initiation.<br><br>RESULTS: Sixteen participants received RT001 (5.6&#x2009;&#xb1;&#x2009;1.6 g/day; dose range, 1.92 to 8.64&#x2009;g/day) for a mean period of 10.8&#x2009;&#xb1;&#x2009;7.1&#xa0;months. After 3&#xa0;months of treatment, PK studies showed that RT001 was absorbed, metabolized, and incorporated into red blood cell membranes at concentrations expected to be therapeutic based on in vitro models. The most common adverse events were gastrointestinal, including diarrhea, which occurred in 25% of the participants, and were considered possibly related to RT001. One participant (6%) discontinued due to an adverse event. Ten serious adverse events occurred: these events were recognized complications of ALS and none were attributed to treatment with RT001.<br><br>DISCUSSION: RT001 was administered safely to a small group of people living with ALS in the context of an EA protocol. Currently, there is an ongoing randomized, double-blind, controlled study of RT001 in ALS.}, }
@article {pmid35760227, year = {2022}, author = {Gamberini, L and Mazzoli, CA and Allegri, D and Scquizzato, T and Baroncini, S and Guarnera, M and Tartaglione, M and Chiarini, V and Picoco, C and Semeraro, F and Gordini, G and Coniglio, C}, title = {Factors influencing prehospital physicians' decisions to initiate advanced resuscitation for asystolic out-of-hospital cardiac arrest patients.}, journal = {Resuscitation}, volume = {177}, number = {}, pages = {19-27}, doi = {10.1016/j.resuscitation.2022.06.015}, pmid = {35760227}, issn = {1873-1570}, mesh = {*Cardiopulmonary Resuscitation ; Clinical Decision-Making ; *Emergency Medical Services ; Humans ; *Out-of-Hospital Cardiac Arrest/therapy ; *Physicians ; }, abstract = {BACKGROUND: The decision to initiate or continue advanced life support (ALS) in out-of-hospital cardiac arrest (OHCA) could be difficult due to the lack of information and contextual elements, especially in non-shockable rhythms. This study aims to explore factors associated with clinicians' decision to initiate or continue ALS and the conditions associated with higher variability in asystolic patients.<br><br>METHODS: This retrospective observational study enrolled 2653 asystolic patients on whom either ALS was attempted or not by the emergency medical services (EMS) physician. A multivariable logistic regression analysis was performed to find the factors associated with the decision to access ALS. A subgroup analysis was performed on patients with a predicted probability of ALS between 35% and 65%. The single physician's behaviour was compared to that predicted by the model taking into account the entire agency.<br><br>RESULTS: Age, location of event, bystander cardiopulmonary resuscitation and EMS-witnessed event were independent factors influencing physicians' choices about ALS. Non-medical OHCA, younger patients, less experienced physicians, presence of breath activity at the emergency call and a longer time for ALS arrival were more frequent among cases with an expected higher variability in behaviours with ALS. Significant variability was detected between physicians.<br><br>CONCLUSIONS: Significant inter-physician variability in access to ALS could be present within the same EMS, especially among less experienced physicians, non-medical OHCA and in presence of signs of life during emergency call. This arbitrariness has been observed and should be properly addressed by EMS team members as it raises ethical issues regarding the disparity in treatment.}, }
@article {pmid35754709, year = {2022}, author = {Guo, W and Zou, ZY and Leng, Y and Shen, DD and Chen, S}, title = {Editorial: Current Concept and Translational Study in ALS-FTD Spectrum: From Genetics, Neuroinflammation to Neurodegeneration.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {935115}, pmid = {35754709}, issn = {1662-5099}, }
@article {pmid35751632, year = {2022}, author = {Esselin, F and De la Cruz, E and Hirtz, C and Tiers, L and Alphandery, S and Baudesson, L and Taieb, G and Camu, W and Lehmann, S}, title = {Repeated neurofilament light chain measurements did not capture Riluzole therapeutic effect in amyotrophic lateral sclerosis patients.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {28}, number = {10}, pages = {1532-1538}, pmid = {35751632}, issn = {1755-5949}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Biomarkers ; Female ; Humans ; Intermediate Filaments ; Neurofilament Proteins ; Prognosis ; *Riluzole/therapeutic use ; }, abstract = {BACKGROUND: Little is known about the influence of Riluzole on serum neurofilament light chain (sNfL) levels, a biomarker of prognosis in amyotrophic lateral sclerosis (ALS), and variations with time of sNfL concentrations are controversial.<br><br>METHODS: Sera from ALS patients (n&#xa0;=&#x2009;141) and controls (n&#xa0;=&#x2009;33) were collected at inclusion (sNfL1) and second visit (sNfL2, mean delay 10.4&#x2009;&#xb1;&#x2009;8.7&#xa0;months). sNfL levels, determined by single-molecule array, were compared between ALS and controls at both time points. sNfL concentration changes were compared between patients with Riluzole (w/Ril) at inclusion in the study and those who were treated by Riluzole following inclusion (w/o Ril). The factors influencing sNfL concentrations and changes were studied using linear regression and multivariate analysis.<br><br>RESULTS: sNfL levels were higher in ALS patients than in controls at the two time points (p&#x2009;<&#x2009;0.00001). In ALS patients, sNfL concentrations were higher in females for both sNfL1 (p&#xa0;=&#xa0;0.014) and sNfL2 (p&#x2009;<&#x2009;0.001). In the whole ALS group, sNfL levels were higher at sNfL2 than at sNfL1 (p&#x2009;<&#x2009;0.001). sNfL1 and sNfL2 concentrations were similar between the two ALS subgroups (w/ and w/o Ril). ALS functional rating scale-revised rate of decline and gender were the two main factors significantly influencing both sNfL1 and sNfL2 levels (p&#x2009;<&#x2009;0.01). However, only gender was shown to significantly influence sNfL changes with time (p&#xa0;=&#xa0;0.003).<br><br>CONCLUSIONS: In this study, sNfL levels increased with time in ALS patients and there was no difference between subjects already treated by Riluzole and those treated after sNfL1. Further studies with larger population samples and different sampling intervals are warranted to better determine the real potential of sNfL measurement as a tool to monitor treatment response in ALS.}, }
@article {pmid35743976, year = {2022}, author = {Oda, S and Hisatome, T and Cho, E and Fujimaki, H and Nakanishi, K}, title = {MRI Findings of Muscle Damage after Total Hip Arthroplasty Using the Complete Muscle Preserving Anterolateral Supine Approach.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {58}, number = {6}, pages = {}, pmid = {35743976}, issn = {1648-9144}, mesh = {*Arthroplasty, Replacement, Hip/adverse effects ; Buttocks/pathology ; Humans ; *Magnetic Resonance Imaging/methods ; Muscle, Skeletal/diagnostic imaging/pathology ; Muscular Atrophy/diagnostic imaging/etiology/pathology ; }, abstract = {Background and Objectives: We performed anterolateral total hip arthroplasty (ALS THA) with the purpose of complete muscle-tendon preservation without muscle-tendon dissection. This study aimed to evaluate muscle damage in the periprosthetic hip joint muscles of patients undergoing ALS THA at 1-year post-operative hip magnetic resonance imaging (MRI). Materials and Methods: We evaluated changes in the muscle cross-sectional area (M-CSA) and fatty atrophy of the periprosthetic muscles. We also assessed the Harris hip score on pre-operative and 12-month post-operative MRI in 66 patients who underwent ALS THA. The grade of M-CSA atrophy was classified into no atrophy, slight atrophy, moderate atrophy, and severe atrophy. Fatty atrophy was classified as improved, no change, and worsened using the Goutallier classification. Results: More than 90% of patients' M-CSA had no atrophy in the obturator internus (Oi), obturator externus (Oe), gluteus medius (Gmed), and gluteus minimus (Gmin), and some improvement was observed in terms of fatty atrophy. In contrast, M-CSA of the tensor fascia latae (TFL) muscle was clearly decreased, and there was no improvement in the TFL fatty atrophy. However, the presence or absence of TFL atrophy did not affect clinical outcome. Conclusions: We performed the complete muscle preserving procedure, ALS THA, with attention to preserving the Oi and Oe by direct visual confirmation and gentle treatment of the Gmed and Gmin with effective retraction. Post-operative M-CSA atrophy evaluation on MRI showed that the Oi, Oe, Gmed, and Gmin were satisfactorily preserved; however, the TFL was clearly atrophic. In the ALS approach, where entry is made between Gmed and TFL, atrophy of the TFL due to superior gluteal nerve injury must be tolerated to some extent.}, }
@article {pmid35743272, year = {2022}, author = {Prtenjaca, N and Rob, M and Alam, MS and Markovinovic, A and Stuani, C and Buratti, E and Munitic, I}, title = {Optineurin Deficiency and Insufficiency Lead to Higher Microglial TDP-43 Protein Levels.}, journal = {International journal of molecular sciences}, volume = {23}, number = {12}, pages = {}, pmid = {35743272}, issn = {1422-0067}, support = {IP-2018-01-8563//Croatian Science Foundation/ ; 18-211-1369//University of Rijeka/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Cell Cycle Proteins/genetics ; DNA-Binding Proteins/genetics/metabolism ; Humans ; Inflammation ; Lipopolysaccharides/pharmacology ; Mice ; Microglia/metabolism ; Mutation ; *Neurodegenerative Diseases ; Transcription Factor TFIIIA/genetics/metabolism ; Ubiquitins/genetics ; }, abstract = {Mutations in optineurin, a ubiquitin-binding adaptor protein, cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease of motor neurons linked to chronic inflammation and protein aggregation. The majority of ALS patients, including those carrying the optineurin mutations, exhibit cytoplasmic mislocalization, ubiquitination, and aggregation of nuclear TAR DNA-binding protein 43 kDa (TDP-43). To address the crosstalk between optineurin and TDP-43, we generated optineurin knockout (KO) neuronal and microglial cell lines using the CRISPR/Cas9 approach. Interestingly, we observed that loss of optineurin resulted in elevated TDP-43 protein expression in microglial BV2 but not neuronal Neuro 2a and NSC-34 cell lines. No changes were observed at the mRNA level, suggesting that this increase was post-translationally regulated. To confirm this observation in primary cells, we then used microglia and macrophages from an optineurin loss-of-function mouse model that lacks the C-terminal ubiquitin-binding region (Optn[470T]), mimicking optineurin truncations in ALS patients. As observed in the BV2 cells, we also found elevated basal levels of TDP-43 protein in Optn[470T] microglia and bone marrow-derived macrophages. To test if inflammation could further enhance TDP-43 accumulation in cells lacking functional optineurin, we stimulated them with lipopolysaccharide (LPS), and we observed a significant increase in TDP-43 expression following LPS treatment of WT cells. However, this was absent in both BV2 Optn KO and primary Optn[470T] microglia, which exhibited the same elevated TDP-43 levels as in basal conditions. Furthermore, we did not observe nuclear TDP-43 depletion or cytoplasmic aggregate formation in either Optn[470T] microglia or LPS-treated WT or Optn[470T] microglia. Taken together, our results show that optineurin deficiency and insufficiency post-translationally upregulate microglial TDP-43 protein levels and that elevated TDP-43 levels in cells lacking functional optineurin could not be further increased by an inflammatory stimulus, suggesting the presence of a plateau.}, }
@article {pmid35743271, year = {2022}, author = {Azman, KF and Zakaria, R}, title = {Recent Advances on the Role of Brain-Derived Neurotrophic Factor (BDNF) in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {12}, pages = {}, pmid = {35743271}, issn = {1422-0067}, support = {None//Universiti Sains Malaysia/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuronal Plasticity/physiology ; *Parkinson Disease/metabolism ; }, abstract = {Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are essential for neuronal survival and growth. The signaling cascades initiated by BDNF and its receptor are the key regulators of synaptic plasticity, which plays important role in learning and memory formation. Changes in BDNF levels and signaling pathways have been identified in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, and have been linked with the symptoms and course of these diseases. This review summarizes the current understanding of the role of BDNF in several neurodegenerative diseases, as well as the underlying molecular mechanism. The therapeutic potential of BDNF treatment is also discussed, in the hope of discovering new avenues for the treatment of neurodegenerative diseases.}, }
@article {pmid35737276, year = {2023}, author = {Vafaei Mastanabad, M and Nooraei, A and Hassan Zadeh Tabatabaei, MS and Akbari Fakhrabadi, A and Jafarzadeh, F}, title = {Granulocyte-colony stimulating factor (G-CSF): an emerging therapeutic approach for amyotrophic lateral sclerosis (ALS).}, journal = {Acta neurologica Belgica}, volume = {123}, number = {3}, pages = {763-771}, pmid = {35737276}, issn = {2240-2993}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy ; Granulocyte Colony-Stimulating Factor/pharmacology/therapeutic use/metabolism ; Cytokines/metabolism ; Hematopoietic Stem Cells/metabolism ; Granulocytes/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by neuronal degeneration and inflammation in the nerves. G-CSF is a 19.6-kDa hematopoietic growth factor which is essential for the proliferation and differentiation of granulocyte hematopoietic progenitors. G-CSF exerts neuroprotective activities by induction of neuronal regeneration, inhibition of neuronal apoptosis, mobilization of Hematopoietic stem cells (HSCs), regulation of pro and anti-inflammatory cytokines, and activation of angiogenesis. Pre-clinical studies have shown significant efficacy of G-CSF therapy in mSOD1[G93A] mice models. G-CSF treatments were able to increase the survival of mice. However, clinical studies on ALS patients failed to clone pre-clinical results. Considering the potential role of G-CSF in nervous system regeneration, this study aimed to comprehensively review the clinical and pre-clinical studies addressing G-CSF in ALS treatment.}, }
@article {pmid35736877, year = {2022}, author = {Bøgh, N and Laustsen, C and Hansen, ESS and Tankisi, H and Bertelsen, LB and Blicher, JU}, title = {Imaging Neurodegenerative Metabolism in Amyotrophic Lateral Sclerosis with Hyperpolarized [1-[13]C]pyruvate MRI.}, journal = {Tomography (Ann Arbor, Mich.)}, volume = {8}, number = {3}, pages = {1570-1577}, pmid = {35736877}, issn = {2379-139X}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging ; Bicarbonates ; Humans ; Lactic Acid/metabolism ; Magnetic Resonance Imaging/methods ; *Neurodegenerative Diseases ; Pyruvic Acid/metabolism ; }, abstract = {The cause of amyotrophic lateral sclerosis (ALS) is still unknown, and consequently, early diagnosis of the disease can be difficult and effective treatment is lacking. The pathology of ALS seems to involve specific disturbances in carbohydrate metabolism, which may be diagnostic and therapeutic targets. Magnetic resonance imaging (MRI) with hyperpolarized [1-[13]C]pyruvate is emerging as a technology for the evaluation of pathway-specific changes in the brain's metabolism. By imaging pyruvate and the lactate and bicarbonate it is metabolized into, the technology is sensitive to the metabolic changes of inflammation and mitochondrial dysfunction. In this study, we performed hyperpolarized MRI of a patient with newly diagnosed ALS. We found a lateralized difference in [1-[13]C]pyruvate-to-[1-[13]C]lactate exchange with no changes in exchange from [1-[13]C]pyruvate to [13]C-bicarbonate. The 40% increase in [1-[13]C]pyruvate-to-[1-[13]C]lactate exchange corresponded with the patient's symptoms and presentation with upper-motor neuron affection and cortical hyperexcitability. The data presented here demonstrate the feasibility of performing hyperpolarized MRI in ALS. They indicate potential in pathway-specific imaging of dysfunctional carbohydrate metabolism in ALS, an enigmatic neurodegenerative disease.}, }
@article {pmid35727341, year = {2022}, author = {Abati, E and Manini, A and Comi, GP and Corti, S}, title = {Inhibition of myostatin and related signaling pathways for the treatment of muscle atrophy in motor neuron diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {79}, number = {7}, pages = {374}, pmid = {35727341}, issn = {1420-9071}, support = {Ricerca corrente//Ministero della Salute/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Animals ; Disease Models, Animal ; Humans ; Muscle, Skeletal/metabolism ; Muscular Atrophy/metabolism ; *Muscular Atrophy, Spinal/drug therapy/genetics ; Myostatin/genetics/metabolism/therapeutic use ; Signal Transduction ; }, abstract = {Myostatin is a negative regulator of skeletal muscle growth secreted by skeletal myocytes. In the past years, myostatin inhibition sparked interest among the scientific community for its potential to enhance muscle growth and to reduce, or even prevent, muscle atrophy. These characteristics make it a promising target for the treatment of muscle atrophy in motor neuron diseases, namely, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), which are rare neurological diseases, whereby the degeneration of motor neurons leads to progressive muscle loss and paralysis. These diseases carry a huge burden of morbidity and mortality but, despite this unfavorable scenario, several therapeutic advancements have been made in the past years. Indeed, a number of different curative therapies for SMA have been approved, leading to a revolution in the life expectancy and outcomes of SMA patients. Similarly, tofersen, an antisense oligonucleotide, is now undergoing clinical trial phase for use in ALS patients carrying the SOD1 mutation. However, these therapies are not able to completely halt or reverse progression of muscle damage. Recently, a trial evaluating apitegromab, a myostatin inhibitor, in SMA patients was started, following positive results from preclinical studies. In this context, myostatin inhibition could represent a useful strategy to tackle motor symptoms in these patients. The aim of this review is to describe the myostatin pathway and its role in motor neuron diseases, and to summarize and critically discuss preclinical and clinical studies of myostatin inhibitors in SMA and ALS. Then, we will highlight promises and pitfalls related to the use of myostatin inhibitors in the human setting, to aid the scientific community in the development of future clinical trials.}, }
@article {pmid35722139, year = {2022}, author = {Xu, J and Lu, Z and Zhang, H and Shen, Y and Zhao, H}, title = {Analysis on Acupoint Selection and Combination for Amyotrophic Lateral Sclerosis Treated with Acupuncture Based on Data Mining.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2022}, number = {}, pages = {6541600}, pmid = {35722139}, issn = {1741-427X}, abstract = {OBJECTIVE: The aim of the study was to explore the regularity of acupoints in the treatment of amyotrophic lateral sclerosis (ALS) by means of data mining technology.<br><br>METHODS: Nine databases, including SinoMed, Chongqing VIP (CQVIP), China National Knowledge Infrastructure (CNKI), Wanfang Data, Cochrane Library, PubMed, MEDLINE, Web of Science, and Embase, were comprehensively searched till December 2021. The published clinical literature testing acupuncture in the treatment of ALS was eligible for inclusion. Studies were organized to establish the prescription database. Modular data mining analysis, including acupoint frequency, complex network analysis, association rule analysis, and cluster analysis were used to conduct statistical analysis.<br><br>RESULTS: Forty-two literature studies on 141 acupoints were included, involving 626 times the total application frequency. The top 5 acupoints in application frequency were Hegu (LI 4, 67%), Zusanli (ST 36, 67%), Quchi (LI 11, 52%), Sanyinjiao (SP 6, 48%), and Yanglingquan (GB 34, 45%). The most involved meridian was the large intestine meridian of hand Yangming (90 times). The generally used acupoints were mainly distributed in the lower limbs. The top 5 combinations in application frequency were Hegu-Quchi (75 times), Quchi-Zusanli (66 times), Zusanli-Sanyinjiao (54 times), Hegu-Sanyinjiao (54 times), and Quchi-Sanyinjiao (49 times). The acupoint combinations with the strongest association were Quchi, Hegu, Zusanli, Sanyinjiao, and Shousanli (LI 10). There were 7 acupoint groups according to the cluster analysis. The core prescriptions were Hegu, Zusanli, Quchi, and Jiaji (EX-B 2).<br><br>CONCLUSIONS: Hegu, Zusanli, Quchi, and Jiaji could be used as the main prescriptions in treating ALS. The combination of Quchi, Hegu, Zusanli, and Sanyinjiao should be selected with priority in acupuncture therapy.}, }
@article {pmid35718222, year = {2022}, author = {Chiarotto, GB and Cartarozzi, LP and Perez, M and Tomiyama, ALMR and de Castro, MV and Duarte, ASS and Luzo, &#xc2;CM and Oliveira, ALR}, title = {Delayed onset, immunomodulation, and lifespan improvement of SOD1[G93A] mice after intravenous injection of human mesenchymal stem cells derived from adipose tissue.}, journal = {Brain research bulletin}, volume = {186}, number = {}, pages = {153-164}, doi = {10.1016/j.brainresbull.2022.06.008}, pmid = {35718222}, issn = {1873-2747}, mesh = {Adipose Tissue/metabolism ; Animals ; Disease Models, Animal ; Gliosis/metabolism ; Humans ; Immunomodulation ; Injections, Intravenous ; Longevity ; *Mesenchymal Stem Cells/metabolism ; Mice ; Mice, Transgenic ; *Neurodegenerative Diseases/drug therapy ; Quality of Life ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective and progressive loss of motor neurons from the spinal cord, brain stem, and motor cortex. Although the hallmark of ALS is motor neuron degeneration, astrocytes, microglia, and T cells actively participate. Pharmacological treatment with riluzole has little effect on the lifespan of the patient. Thus, the development of new therapeutic strategies is of utmost importance. The objective of this study was to verify whether human mesenchymal stem cells (hMSCs) from adipose tissue have therapeutic potential in SOD1[G93A] transgenic mice. The treatment was carried out in the asymptomatic phase of the disease (10th week) by a single systemic application of ad-hMSCs (1 ×10[5] cells). The animals were sacrificed at the 14th week (the initial stage of symptoms) or the end-stage (ES) of the disease. The lumbar spinal cords were dissected and processed for Nissl staining (neuronal survival), immunohistochemistry (gliosis and synaptic preservation), and gene transcript expression (qRT-PCR). Behavioral analyses considering the onset of disease and its progression, neurological score, body weight, and motor control (rotarod test) started on the 10th week and were performed every three days until the ES of the disease. The results revealed that treatment with ad-hMSCs promoted greater neuronal survival (44%) than vehicle treatment. However, no effect was seen at the ES of the disease. Better structural preservation of the ventral horn in animals treated with ad-hMSCs was observed, together with decreased gliosis and greater synapse protection. In line with this, we found that the transcript levels of Hgf1 were upregulated in ad-hMSCs-treated mice. These results corroborate the behavioral data showing that ad-hMSCs had delayed motor deficits and reduced weight loss compared to vehicle animals. Additionally, cell therapy delayed the course of the disease and significantly improved survival by 20 days. Overall, our results indicate that treatment with ad-hMSCs has beneficial effects, enhancing neuronal survival and promoting a less degenerative neuronal microenvironment. Thus, this may be a potential therapy to improve the quality of life and to extend the lifespan of ALS patients.}, }
@article {pmid35718207, year = {2022}, author = {Wu, S and Yin, Y and Du, L}, title = {FUS aggregation following ischemic stroke favors brain astrocyte activation through inducing excessive autophagy.}, journal = {Experimental neurology}, volume = {355}, number = {}, pages = {114144}, doi = {10.1016/j.expneurol.2022.114144}, pmid = {35718207}, issn = {1090-2430}, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Astrocytes/metabolism ; Autophagy ; Brain/pathology ; *Brain Ischemia ; Cerebral Infarction ; Humans ; *Ischemic Stroke ; Mutation ; *Neurodegenerative Diseases ; RNA-Binding Protein FUS/genetics ; *Stroke ; }, abstract = {As is the case with neurodegenerative diseases, abnormal accumulation of aggregated proteins in neurons and glial are also known to implicate in the pathogenesis of ischemic stroke. However, the potential role of protein aggregates in brain ischemia remains largely unknown. Fused in Sarcoma (FUS) protein has a vital role in RNA metabolism and regulating cellular homeostasis. FUS pathology has been demonstrated in the formation of toxic aggregates and critically affecting cell viability in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but whether this also applies to neurological injury following cerebral ischemia is unclear. Herein, we demonstrated a critical role of aggregated FUS in astrocyte activation caused by cerebral ischemia and a possible underlying molecular mechanism. Cerebral ischemic injury significantly induced the formation of cytoplasmic FUS aggregates in reactive astrocytes and injured neurons, thereby aggravating neurofunctional damages and worsening stroke outcomes. Further analysis revealed that extranuclear aggregation of FUS in astrocytes was involved in the induction of excessive autophagy, which contributes to autophagic cell injury or death. In conclusion, our results reveal the important contribution of FUS aggregates in promoting astrocyte activation in stroke pathology independent of its transcriptional regulation activity. We thus propose that aggregation of FUS is an important pathological process in ischemic stroke and targeting FUS aggregates might be of unique therapeutic value in the development of future treatment strategies for ischemic stroke.}, }
@article {pmid35716729, year = {2022}, author = {Lambert-Smith, IA and Saunders, DN and Yerbury, JJ}, title = {Proteostasis impairment and ALS.}, journal = {Progress in biophysics and molecular biology}, volume = {174}, number = {}, pages = {3-27}, doi = {10.1016/j.pbiomolbio.2022.06.001}, pmid = {35716729}, issn = {1873-1732}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Motor Neurons/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Proteome ; Proteostasis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disease that results from the loss of both upper and lower motor neurons. It is the most common motor neuron disease and currently has no effective treatment. There is mounting evidence to suggest that disturbances in proteostasis play a significant role in ALS pathogenesis. Proteostasis is the maintenance of the proteome at the right level, conformation and location to allow a cell to perform its intended function. In this review, we present a thorough synthesis of the literature that provides evidence that genetic mutations associated with ALS cause imbalance to a proteome that is vulnerable to such pressure due to its metastable nature. We propose that the mechanism underlying motor neuron death caused by defects in mRNA metabolism and protein degradation pathways converges on proteostasis dysfunction. We propose that the proteostasis network may provide an effective target for therapeutic development in ALS.}, }
@article {pmid35714755, year = {2022}, author = {Liu, X and Henty-Ridilla, JL}, title = {Multiple roles for the cytoskeleton in ALS.}, journal = {Experimental neurology}, volume = {355}, number = {}, pages = {114143}, pmid = {35714755}, issn = {1090-2430}, support = {R35 GM133485/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Cytoskeleton/metabolism ; Humans ; Kinesins ; Microtubules/metabolism ; Motor Neurons/metabolism ; *Neurodegenerative Diseases/metabolism ; Profilins/genetics/metabolism ; Spastin/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by more than sixty genes identified through classic linkage analysis and new sequencing methods. Yet no clear mechanism of onset, cure, or effective treatment is known. Popular discourse classifies the proteins encoded from ALS-related genes into four disrupted processes: proteostasis, mitochondrial function and ROS, nucleic acid regulation, and cytoskeletal dynamics. Surprisingly, the mechanisms detailing the contribution of the neuronal cytoskeletal in ALS are the least explored, despite involvement in these cell processes. Eight genes directly regulate properties of cytoskeleton function and are essential for the health and survival of motor neurons, including: TUBA4A, SPAST, KIF5A, DCTN1, NF, PRPH, ALS2, and PFN1. Here we review the properties and studies exploring the contribution of each of these genes to ALS.}, }
@article {pmid35710076, year = {2022}, author = {Rahmani, M and Negro Álvarez, SE and Hernández, EB}, title = {The potential use of tetracyclines in neurodegenerative diseases and the role of nano-based drug delivery systems.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {175}, number = {}, pages = {106237}, doi = {10.1016/j.ejps.2022.106237}, pmid = {35710076}, issn = {1879-0720}, mesh = {*Alzheimer Disease/drug therapy ; *Amyotrophic Lateral Sclerosis/drug therapy ; Anti-Bacterial Agents/therapeutic use ; Doxycycline/pharmacology/therapeutic use ; Drug Delivery Systems/methods ; Humans ; Minocycline/pharmacology/therapeutic use ; Nanoparticle Drug Delivery System ; *Neurodegenerative Diseases/drug therapy ; *Parkinson Disease/drug therapy ; }, abstract = {Neurodegenerative diseases are still a challenge for effective treatments. The high cost of approved drugs, severity of side effects, injection site pain, and restrictions on drug delivery to the Central Nervous System (CNS) can overshadow the management of these diseases. Due to the chronic and progressive evolution of neurodegenerative disorders and since there is still no cure for them, new therapeutic strategies such as the combination of several drugs or the use of existing drugs with new therapeutic applications are valuable strategies. Tetracyclines are traditionally classified as antibiotics. However, in this class of drugs, doxycycline and minocycline exhibit also anti-inflammatory effects by inhibiting microglia/macrophages. Hence, they have been studied as potential agents for the treatment of neurodegenerative diseases. The results of in vitro and in vivo studies confirm the effective role of these two drugs as anti-inflammatory agents in experimentally induced models of neurodegenerative diseases. In clinical studies, satisfactory results have been obtained in Multiple sclerosis (MS) but not yet in other disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), or Amyotrophic lateral sclerosis (ALS). In recent years, researchers have developed and evaluated nanoparticulate drug delivery systems to improve the clinical efficacy of these two tetracyclines for their potential application in neurodegenerative diseases. This study reviews the neuroprotective roles of minocycline and doxycycline in four of the main neurodegenerative disorders: AD, PD, ALS and MS. Moreover, the potential applications of nanoparticulate delivery systems developed for both tetracyclines are also reviewed.}, }
@article {pmid35708081, year = {2023}, author = {Birmann, PT and Casaril, AM and Abenante, L and Penteado, F and Brüning, CA and Savegnago, L and Lenardão, EJ}, title = {Neuropharmacology of Organoselenium Compounds in Mental Disorders and Degenerative Diseases.}, journal = {Current medicinal chemistry}, volume = {30}, number = {21}, pages = {2357-2395}, doi = {10.2174/0929867329666220615124412}, pmid = {35708081}, issn = {1875-533X}, mesh = {Humans ; Neuropharmacology ; Antioxidants/pharmacology/therapeutic use/chemistry ; *Mental Disorders/drug therapy ; *Organoselenium Compounds/pharmacology/therapeutic use/chemistry ; }, abstract = {Neurodegenerative and mental disorders are a public health burden with pharmacological treatments of limited efficacy. Organoselenium compounds are receiving great attention in medicinal chemistry mainly because of their antioxidant and immunomodulatory activities, with a multi-target profile that can favor the treatment of multifactorial diseases. Therefore, the purpose of this review is to discuss recent preclinical studies about organoselenium compounds as therapeutic agents for the management of mental (e.g., depression, anxiety, bipolar disorder, and schizophrenia) and neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis). We have summarized around 70 peer-reviewed articles from 2016 to the present that used in silico, in vitro, and/or in vivo approaches to assess the neuropharmacology of selenium- containing compounds. Among the diversity of organoselenium molecules investigated in the last five years, diaryl diselenides, Ebselen-derivatives, and Se-containing heterocycles are the most representative. Ultimately, this review is expected to provide disease-oriented information regarding the neuropharmacology of organoselenium compounds that can be useful for the design, synthesis, and pharmacological characterization of novel bioactive molecules that can potentially be clinically viable candidates.}, }
@article {pmid35708049, year = {2023}, author = {Alugoju, P and Krishna Swamy, VKD and Anthikapalli, NVA and Tencomnao, T}, title = {Health benefits of astaxanthin against age-related diseases of multiple organs: A comprehensive review.}, journal = {Critical reviews in food science and nutrition}, volume = {63}, number = {31}, pages = {10709-10774}, doi = {10.1080/10408398.2022.2084600}, pmid = {35708049}, issn = {1549-7852}, mesh = {Male ; Humans ; *Quality of Life ; *Antioxidants/pharmacology/therapeutic use ; Aging ; Carotenoids ; Ischemia/drug therapy ; }, abstract = {Age-related diseases are associated with increased morbidity in the past few decades and the cost associated with the treatment of these age-related diseases exerts a substantial impact on social and health care expenditure. Anti-aging strategies aim to mitigate, delay and reverse aging-associated diseases, thereby improving quality of life and reducing the burden of age-related pathologies. The natural dietary antioxidant supplementation offers substantial pharmacological and therapeutic effects against various disease conditions. Astaxanthin is one such natural carotenoid with superior antioxidant activity than other carotenoids, as well as well as vitamins C and E, and additionally, it is known to exhibit a plethora of pharmacological effects. The present review summarizes the protective molecular mechanisms of actions of astaxanthin on age-related diseases of multiple organs such as Neurodegenerative diseases [Alzheimer's disease (AD), Parkinson's disease (PD), Stroke, Multiple Sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Status Epilepticus (SE)], Bone Related Diseases [Osteoarthritis (OA) and Osteoporosis], Cancers [Colon cancer, Prostate cancer, Breast cancer, and Lung Cancer], Cardiovascular disorders [Hypertension, Atherosclerosis and Myocardial infarction (MI)], Diabetes associated complications [Diabetic nephropathy (DN), Diabetic neuropathy, and Diabetic retinopathy (DR)], Eye disorders [Age related macular degeneration (AMD), Dry eye disease (DED), Cataract and Uveitis], Gastric Disorders [Gastritis, Colitis, and Functional dyspepsia], Kidney Disorders [Nephrolithiasis, Renal fibrosis, Renal Ischemia reperfusion (RIR), Acute kidney injury (AKI), and hyperuricemia], Liver Diseases [Nonalcoholic fatty liver disease (NAFLD), Alcoholic Liver Disease (AFLD), Liver fibrosis, and Hepatic Ischemia-Reperfusion (IR) Injury], Pulmonary Disorders [Pulmonary Fibrosis, Acute Lung injury (ALI), and Chronic obstructive pulmonary disease (COPD)], Muscle disorders (skeletal muscle atrophy), Skin diseases [Atopic dermatitis (ATD), Skin Photoaging, and Wound healing]. We have also briefly discussed astaxanthin's protective effects on reproductive health.}, }
@article {pmid35700157, year = {2022}, author = {Brooks, BR and Heiman-Patterson, T and Wiedau-Pazos, M and Liu, S and Zhang, J and Apple, S}, title = {Edaravone efficacy in amyotrophic lateral sclerosis with reduced forced vital capacity: Post-hoc analysis of Study 19 (MCI186-19) [clinical trial NCT01492686].}, journal = {PloS one}, volume = {17}, number = {6}, pages = {e0258614}, pmid = {35700157}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Antipyrine/pharmacology/therapeutic use ; Double-Blind Method ; Edaravone/therapeutic use ; Free Radical Scavengers/pharmacology ; Humans ; Vital Capacity ; }, abstract = {BACKGROUND: Edaravone slowed the rate of functional decline in subjects with amyotrophic lateral sclerosis (ALS) in phase 3 study MCI186-19 (Study 19). One of the Study 19 inclusion criteria was forced vital capacity (FVC) ≥80% of predicted (≥80%p). Therefore, the study provided no information on edaravone efficacy in subjects with FVC <80%p. In Study 19, 24-week, double-blind treatment was followed by open-label treatment where all subjects received edaravone. At 24 weeks, some subjects had FVC <80%p (FVC24 <80%p). This allowed for post-hoc assessment of the effects of edaravone in subgroups of subjects with FVC24 ≥80%p vs <80%p.<br><br>OBJECTIVE: To address the question of the efficacy of edaravone in ALS patients with FVC <80%p.<br><br>METHODS: Post-hoc analysis of Study 19 comparing edaravone efficacy at week 48 in subjects with FVC24 &#x2265;80%p vs <80%p.<br><br>RESULTS: With edaravone treatment, subjects in both the FVC24 &#x2265;80%p and the FVC24 <80%p subgroups experienced a reduction in ALS Functional Rating Scale-Revised (ALSFRS-R) score loss vs placebo subjects through week 48. For the FVC24 &#x2265;80%p subgroup, the changes in ALSFRS-R scores from baseline to week 48 were -7.63 for edaravone-edaravone vs -9.69 for placebo-edaravone, a difference of 2.05 (P = .034; 95% CI: 0.16, 3.94). For the FVC24 <80%p subgroup, the changes in ALSFRS-R scores from baseline to week 48 were -10.26 for edaravone-edaravone vs -15.20 for placebo-edaravone, a difference of 4.94 (P = .0038; 95% CI: 1.64, 8.25). Linear regression analysis indicated that, in the FVC24 <80%p subgroup, there was a notable change in the slope of the ALSFRS-R score-vs-time graph after the start of edaravone treatment.<br><br>CONCLUSION: ALS subjects in the Study 19 placebo arm had a slowing in disease progression, even when edaravone was added with an FVC of <80%p prior to starting edaravone. A randomized, placebo-controlled study is needed to validate these post-hoc findings.}, }
@article {pmid35692681, year = {2022}, author = {Amekura, S and Shiozawa, K and Kiryu, C and Yamamoto, Y and Fujisawa, A}, title = {Edaravone, a scavenger for multiple reactive oxygen species, reacts with singlet oxygen to yield 2-oxo-3-(phenylhydrazono)-butanoic acid.}, journal = {Journal of clinical biochemistry and nutrition}, volume = {70}, number = {3}, pages = {240-247}, pmid = {35692681}, issn = {0912-0009}, abstract = {Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a synthetic antioxidant used as a drug to treat acute ischemic stroke in Japan and amyotrophic lateral sclerosis in Japan and the USA. Its pharmacological mechanism is thought to be scavenging of reactive oxygen species, which are intimately related with these diseases. Recently, the singlet oxygen (‍[1]O2) has attracted attention among reactive oxygen species. In this study, we investigated the reactivity of edaravone toward [1]O2 and identified its reaction products. Edaravone showed a reactivity toward [1]O2 greater than those of uric acid, histidine, and tryptophan, which are believed to be ‍[1]O2 scavengers in vivo. And we confirmed that 2-oxo-3-(phenylhydrazono)-butanoic acid was formed as an oxidation product. We propose a plausible mechanism for 2-oxo-3-(phenylhydrazono)-butanoic acid production by ‍[1]O2-induced edaravone oxidation. Since 2-oxo-3-(phenylhydrazono)-butanoic acid has already been identified as a radical-initiated oxidation product, free radical-induced oxidation should be seriously reconsidered. We also found that edaravone can react with not only hypochlorous anions but also ‍[1]O2 that are formed from myeloperoxidase. This result suggests that edaravone treatment can be beneficial against myeloperoxidase-related injuries such as inflammation.}, }
@article {pmid35691696, year = {2022}, author = {Campos, ST and Bruno, MJ}, title = {Endoscopic Papillectomy.}, journal = {Gastrointestinal endoscopy clinics of North America}, volume = {32}, number = {3}, pages = {545-562}, doi = {10.1016/j.giec.2022.01.005}, pmid = {35691696}, issn = {1558-1950}, mesh = {*Adenoma/diagnosis ; *Ampulla of Vater/diagnostic imaging/pathology/surgery ; *Common Bile Duct Neoplasms/diagnostic imaging/surgery ; Endoscopy, Gastrointestinal ; Humans ; Treatment Outcome ; }, abstract = {Most ampullary lesions (ALs) are sporadic, involve the major papilla, and are premalignant (adenomas). They are often diagnosed as an incidental finding during endoscopy or imaging procedures. Diagnosis and staging of ALs include endoscopic, histologic, and radiological evaluations. Currently, endoscopic papillectomy is the preferred treatment for ALs in most situations. In this article, we will describe the diagnostic work-up and focus on the endoscopic treatment, including indications, technique, outcomes, complications, and follow-up.}, }
@article {pmid35690735, year = {2022}, author = {Cao, MC and Cawston, EE and Chen, G and Brooks, C and Douwes, J and McLean, D and Graham, ES and Dragunow, M and Scotter, EL}, title = {Serum biomarkers of neuroinflammation and blood-brain barrier leakage in amyotrophic lateral sclerosis.}, journal = {BMC neurology}, volume = {22}, number = {1}, pages = {216}, pmid = {35690735}, issn = {1471-2377}, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Biomarkers ; Blood-Brain Barrier/metabolism ; Cytokines ; Humans ; Intercellular Signaling Peptides and Proteins ; Neuroinflammatory Diseases ; Proteome/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable and rapidly progressive neurological disorder. Biomarkers are critical to understanding disease causation, monitoring disease progression and assessing the efficacy of treatments. However, robust peripheral biomarkers are yet to be identified. Neuroinflammation and breakdown of the blood-brain barrier (BBB) are common to familial and sporadic ALS and may produce a unique biomarker signature in peripheral blood. Using cytometric bead array (n = 15 participants per group (ALS or control)) and proteome profiling (n = 6 participants per group (ALS or control)), we assessed a total of 106 serum cytokines, growth factors, and BBB breakdown markers in the serum of control and ALS participants. Further, primary human brain pericytes, which maintain the BBB, were used as a biosensor of inflammation following pre-treatment with ALS serum. Principal components analysis of all proteome profile data showed no clustering of control or ALS sera, and no individual serum proteins met the threshold for statistical difference between ALS and controls (adjusted P values). However, the 20 most changed proteins between control and ALS sera showed a medium effect size (Cohen's d = 0.67) and cluster analysis of their levels together identified three sample subsets; control-only, mixed control-ALS, and ALS-only. These 20 proteins were predominantly pro-angiogenic and growth factors, including fractalkine, BDNF, EGF, PDGF, Dkk-1, MIF and angiopoietin-2. S100β, a protein highly concentrated in glial cells and therefore a marker of BBB leakage when found in blood, was unchanged in ALS serum, suggesting that serum protein profiles were reflective of peripheral rather than CNS biofluids. Finally, primary human brain pericytes remained proliferative and their secretome was unchanged by chronic exposure to ALS serum. Our exploratory study suggests that individual serum cytokine levels may not be robust biomarkers in small studies of ALS, but that larger studies using multiplexed analysis of pro-angiogenic and growth factors may identify a peripheral signature of ALS pathogenesis.}, }
@article {pmid35690179, year = {2022}, author = {Wang, C and Zhang, Y and Chen, D and Weng, H and Li, H and Lu, Y}, title = {Oral subacute nephrotoxicity of aristololactam I in rats.}, journal = {Toxicology}, volume = {475}, number = {}, pages = {153228}, doi = {10.1016/j.tox.2022.153228}, pmid = {35690179}, issn = {1879-3185}, mesh = {Animals ; *Aristolochic Acids/toxicity ; Fibrosis ; Kidney/metabolism ; Rats ; }, abstract = {Aristolactams (ALs) have been recognized as one kind of metabolites of aristolochic acids (AAs), the nephrotoxic components of Aristolochiaceae plants, and are more widely distributed than AAs in herbal medicines. This study evaluated the oral subacute nephrotoxicity of aristolactam I (AL I), a representative compound of ALs. AL I was intragastrically administered to rats at 20 mg·kg[-1]·d[-1] for 10 or 20 days, with aristolochic acid I (AA I) used as positive control at the same dose. After 10-day treatment, AL I led to a significant increase in early renal injury-related indices in urine and obvious histopathological lesions in kidneys, including degeneration of tubular epithelial cells, inflammatory cell infiltration and fibrosis. The lesions induced by AL I were significantly aggravated after 20-day exposure. However, AL I induced less histopathological damage in kidneys than AA I in both 10- and 20-day groups. Our results indicated that oral AL I caused nephrotoxicity by inducing oxidative stress, inflammation, and overactivation of the complement system as AA I did. Three detected apoptosis-associated indicators were not affected by AL I but remarkably increased by AA I. In summary, oral AL I induced evident renal damage in rats after only 10 days of treatment, and the damage was aggravated after 20 days. However, AL I was obviously less nephrotoxic than AA I via oral gavage.}, }
@article {pmid35688956, year = {2022}, author = {Maier, A and Gaudlitz, M and Grehl, T and Weyen, U and Steinbach, R and Grosskreutz, J and Rödiger, A and Koch, JC and Lengenfeld, T and Weydt, P and Günther, R and Wolf, J and Baum, P and Metelmann, M and Dorst, J and Ludolph, AC and Kettemann, D and Norden, J and Koc, RY and Walter, B and Hildebrandt, B and Münch, C and Meyer, T and Spittel, S}, title = {Use and subjective experience of the impact of motor-assisted movement exercisers in people with amyotrophic lateral sclerosis: a multicenter observational study.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {9657}, pmid = {35688956}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Cross-Sectional Studies ; Humans ; Muscle Weakness ; Self Report ; }, abstract = {Motor-assisted movement exercisers (MME) are devices that assist with physical therapy in domestic settings for people living with ALS. This observational cross-sectional study assesses the subjective experience of the therapy and analyzes users' likelihood of recommending treatment with MME. The study was implemented in ten ALS centers between February 2019 and October 2020, and was coordinated by the research platform Ambulanzpartner. Participants assessed symptom severity, documented frequency of MME use and rated the subjective benefits of therapy on a numerical scale (NRS, 0 to 10 points, with 10 being the highest). The Net Promotor Score (NPS) determined the likelihood of a participant recommending MME. Data for 144 participants were analyzed. Weekly MME use ranged from 1 to 4 times for 41% of participants, 5 to 7 times for 42%, and over 7 times for 17%. Particularly positive results were recorded in the following domains: amplification of a sense of achievement (67%), diminution of the feeling of having rigid limbs (63%), diminution of the feeling of being immobile (61%), improvement of general wellbeing (55%) and reduction of muscle stiffness (52%). Participants with more pronounced self-reported muscle weakness were more likely to note a beneficial effect on the preservation and improvement of muscle strength during MME treatment (p < 0.05). Overall, the NPS for MME was high (+ 61). High-frequency MME-assisted treatment (defined as a minimum of five sessions a week) was administered in the majority of participants (59%) in addition to physical therapy. Most patients reported having achieved their individual therapeutic objectives, as evidenced by a high level of satisfaction with MME therapy. The results bolster the justification for extended MME treatment as part of a holistic approach to ALS care.}, }
@article {pmid35678836, year = {2022}, author = {Batur, AF and Batur, EB}, title = {Regarding the readability of online resources for third-line treatment of overactive bladder in the US population based on Werner et al's study.}, journal = {International urogynecology journal}, volume = {33}, number = {7}, pages = {2071-2072}, pmid = {35678836}, issn = {1433-3023}, mesh = {Comprehension ; Humans ; *Urinary Bladder, Overactive/therapy ; }, }
@article {pmid35675776, year = {2022}, author = {Czuppa, M and Dhingra, A and Zhou, Q and Schludi, C and König, L and Scharf, E and Farny, D and Dalmia, A and Täger, J and Castillo-Lizardo, M and Katona, E and Mori, K and Aumer, T and Schelter, F and Müller, M and Carell, T and Kalliokoski, T and Messinger, J and Rizzu, P and Heutink, P and Edbauer, D}, title = {Drug screen in iPSC-Neurons identifies nucleoside analogs as inhibitors of (G4C2)n expression in C9orf72 ALS/FTD.}, journal = {Cell reports}, volume = {39}, number = {10}, pages = {110913}, doi = {10.1016/j.celrep.2022.110913}, pmid = {35675776}, issn = {2211-1247}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Animals ; C9orf72 Protein/genetics/metabolism ; DNA Repeat Expansion ; Decitabine/metabolism ; Dipeptides/metabolism ; *Frontotemporal Dementia/genetics ; Humans ; *Induced Pluripotent Stem Cells/metabolism ; Mice ; Neurons/metabolism ; Nucleosides/metabolism ; RNA, Antisense/metabolism ; }, abstract = {An intronic (G4C2)n expansion in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal dementia primarily through gain-of-function mechanisms: the accumulation of sense and antisense repeat RNA foci and dipeptide repeat (DPR) proteins (poly-GA/GP/GR/PA/PR) translated from repeat RNA. To therapeutically block this pathway, we screen a library of 1,430 approved drugs and known bioactive compounds in patient-derived induced pluripotent stem cell-derived neurons (iPSC-Neurons) for inhibitors of DPR expression. The clinically used guanosine/cytidine analogs decitabine, entecavir, and nelarabine reduce poly-GA/GP expression, with decitabine being the most potent. Hit compounds nearly abolish sense and antisense RNA foci and reduce expression of the repeat-containing nascent C9orf72 RNA transcript and its mature mRNA with minimal effects on global gene expression, suggesting that they specifically act on repeat transcription. Importantly, decitabine treatment reduces (G4C2)n foci and DPRs in C9orf72 BAC transgenic mice. Our findings suggest that nucleoside analogs are a promising compound class for therapeutic development in C9orf72 repeat-expansion-associated disorders.}, }
@article {pmid35673830, year = {2022}, author = {Kwak, S}, title = {Pain in amyotrophic lateral sclerosis: a narrative review.}, journal = {Journal of Yeungnam medical science}, volume = {39}, number = {3}, pages = {181-189}, pmid = {35673830}, issn = {2799-8010}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition characterized by loss of motor neurons, resulting in motor weakness of the limbs and/or bulbar muscles. Pain is a prevalent but neglected symptom of ALS, and it has a significant negative impact on the quality of life of patients and their caregivers. This review outlines the epidemiology, clinical characteristics, underlying mechanisms, and management strategies of pain in ALS to improve clinical practice and patient outcomes related to pain. Pain is a prevalent symptom among patients with ALS, with a variable reported prevalence. It may occur at any stage of the disease and can involve any part of the body without a specific pattern. Primary pain includes neuropathic pain and pain from spasticity or cramps, while secondary pain is mainly nociceptive, occurring with the progression of muscle weakness and atrophy, prolonged immobility causing degenerative changes in joints and connective tissue, and long-term home mechanical ventilation. Prior to treatment, the exact patterns and causes of pain must first be identified, and the treatment should be tailored to each patient. Treatment options can be classified into pharmacological treatments, including nonsteroidal anti-inflammatory drugs, antiepileptic drugs, drugs for cramps or spasticity, and opioid; and nonpharmacological treatments, including positioning, splints, joint injections, and physical therapy. The development of standardized and specific assessment tools for pain-specific to ALS is required, as are further studies on treatments to reduce pain, diminish suffering, and improve the quality of life of patients with ALS.}, }
@article {pmid35663577, year = {2022}, author = {Wang, X and Zhang, Y and Jin, T and Botchway, BOA and Fan, R and Wang, L and Liu, X}, title = {Adipose-Derived Mesenchymal Stem Cells Combined With Extracellular Vesicles May Improve Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {830346}, pmid = {35663577}, issn = {1663-4365}, abstract = {The complexity of central nervous system diseases together with their intricate pathogenesis complicate the establishment of effective treatment strategies. Presently, the superiority of adipose-derived mesenchymal stem cells (ADSCs) on neuronal injuries has attracted significant attention. Similarly, extracellular vesicles (EVs) are potential interventional agents that could identify and treat nerve injuries. Herein, we reviewed the potential effects of ADSCs and EVs on amyotrophic lateral sclerosis (ALS) injured nerves, and expound on their practical application in the clinic setting. This article predominantly focused on the therapeutic role of ADSCs concerning the pathogenesis of ALS, the protective and reparative effects of EVs on nerve injury, as well as the impact following the combined usage of ADSCs and EVs in ALS.}, }
@article {pmid35659112, year = {2022}, author = {Khalaf, K and Tornese, P and Cocco, A and Albanese, A}, title = {Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {11}, number = {1}, pages = {33}, pmid = {35659112}, issn = {2047-9158}, support = {755094/ERC_/European Research Council/International ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Bile Acids and Salts/therapeutic use ; *Neurodegenerative Diseases/drug therapy ; Taurochenodeoxycholic Acid/metabolism/pharmacology/therapeutic use ; }, abstract = {Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. In recent years, hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases. Experimental evidence on the mechanisms underlying TUDCA's neuroprotective action derives from animal models of Alzheimer's disease, Parkinson's disease, Huntington's diseases, amyotrophic lateral sclerosis (ALS) and cerebral ischemia. Preclinical studies indicate that TUDCA exerts its effects not only by regulating and inhibiting the apoptotic cascade, but also by reducing oxidative stress, protecting the mitochondria, producing an anti-neuroinflammatory action, and acting as a chemical chaperone to maintain the stability and correct folding of proteins. Furthermore, data from phase II clinical trials have shown TUDCA to be safe and a potential disease-modifier in ALS. ALS is the first neurodegenerative disease being treated with hydrophilic bile acids. While further clinical evidence is being accumulated for the other diseases, TUDCA stands as a promising treatment for neurodegenerative diseases.}, }
@article {pmid35653060, year = {2022}, author = {Boros, BD and Schoch, KM and Kreple, CJ and Miller, TM}, title = {Antisense Oligonucleotides for the Study and Treatment of ALS.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {19}, number = {4}, pages = {1145-1158}, pmid = {35653060}, issn = {1878-7479}, support = {RF1 MH126723/MH/NIMH NIH HHS/United States ; R01 NS078398/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Oligonucleotides, Antisense/therapeutic use/genetics ; C9orf72 Protein ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases/drug therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss. ALS is now associated with mutations in numerous genes, many of which cause disease in part through toxic gain-of-function mechanisms. Antisense oligonucleotides (ASOs) are small sequences of DNA that can reduce expression of a target gene at the post-transcriptional level, making them attractive for neutralizing mutant or toxic gene products. Advancements in the medicinal chemistries of ASOs have improved their pharmacodynamic profile to allow safe and effective delivery to the central nervous system. ASO therapies for ALS have rapidly developed over the last two decades, and ASOs that target SOD1, C9orf72, FUS, and ATXN2 are now in clinical trials for familial or sporadic forms of ALS. This review discusses the current state of ASO therapies for ALS, outlining their successes from preclinical development to early clinical trials.}, }
@article {pmid35652455, year = {2022}, author = {Fels, JA and Casalena, G and Konrad, C and Holmes, HE and Dellinger, RW and Manfredi, G}, title = {Gene expression profiles in sporadic ALS fibroblasts define disease subtypes and the metabolic effects of the investigational drug EH301.}, journal = {Human molecular genetics}, volume = {31}, number = {20}, pages = {3458-3477}, pmid = {35652455}, issn = {1460-2083}, support = {R35 NS122209/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Antioxidants/metabolism ; Drugs, Investigational/metabolism/therapeutic use ; Fibroblasts/metabolism ; Humans ; Transcriptome/genetics ; }, abstract = {Metabolic alterations shared between the nervous system and skin fibroblasts have emerged in amyotrophic lateral sclerosis (ALS). Recently, we found that a subgroup of sporadic ALS (sALS) fibroblasts (sALS1) is characterized by metabolic profiles distinct from other sALS cases (sALS2) and controls, suggesting that metabolic therapies could be effective in sALS. The metabolic modulators nicotinamide riboside and pterostilbene (EH301) are under clinical development for the treatment of ALS. Here, we studied the transcriptome and metabolome of sALS cells to understand the molecular bases of sALS metabotypes and the impact of EH301. Metabolomics and transcriptomics were investigated at baseline and after EH301 treatment. Moreover, weighted gene coexpression network analysis (WGCNA) was used to investigate the association of the metabolic and clinical features. We found that the sALS1 transcriptome is distinct from sALS2 and that EH301 modifies gene expression differently in sALS1, sALS2 and the controls. Furthermore, EH301 had strong protective effects against metabolic stress, an effect linked to the antiinflammatory and antioxidant pathways. WGCNA revealed that the ALS functional rating scale and metabotypes are associated with gene modules enriched for the cell cycle, immunity, autophagy and metabolic genes, which are modified by EH301. The meta-analysis of publicly available transcriptomic data from induced motor neurons by Answer ALS confirmed the functional associations of genes correlated with disease traits. A subset of genes differentially expressed in sALS fibroblasts was used in a machine learning model to predict disease progression. In conclusion, multiomic analyses highlighted the differential metabolic and transcriptomic profiles in patient-derived fibroblast sALS, which translate into differential responses to the investigational drug EH301.}, }
@article {pmid35652285, year = {2022}, author = {Ojaimi, YA and Dangoumau, A and Alarcan, H and Hergesheimer, R and Vourc'h, P and Corcia, P and Lanznaster, D and Blasco, H}, title = {TAR DNA-binding protein of 43 kDa (TDP-43) and amyotrophic lateral sclerosis (ALS): a promising therapeutic target.}, journal = {Expert opinion on therapeutic targets}, volume = {26}, number = {6}, pages = {575-592}, doi = {10.1080/14728222.2022.2083958}, pmid = {35652285}, issn = {1744-7631}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; DNA-Binding Proteins/metabolism ; *Neurodegenerative Diseases/drug therapy ; *TDP-43 Proteinopathies/metabolism ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that lacks an effective treatment. Aggregates of the TAR DNA-binding protein-43 (TDP-43) are observed in 97% of all ALS cases, thus making this protein a major therapeutic target in ALS. .<br><br>AREAS COVERED: The authors describe the major cellular functions of TDP-43 and the features and consequences of TDP-43 proteinopathy. Drawing from fundamental and preclinical studies on cellular and animal TDP-43 models of ALS and selected clinical trials, the major pathways that have been targeted for the mitigation of TDP-43 pathology in ALS are discussed. The authors provide insights on the approaches targeting the tendency of TDP-43 for aggregation, defective nucleocytoplasmic transport, dysfunctional proteostasis, abnormal stress granule dynamics, and pathological post-translational modifications of TDP-43.<br><br>EXPERT OPINION: The complexity of ALS and TDP-43 proteinopathy generates challenges for the development of novel therapeutic approaches. However, the critical involvement of TDP-43 in the initiation and progression of ALS, makes it a promising therapeutic target. Further research should be centered on the development of precision strategies, consideration of patient subgroups, the prevention of the mislocalization of TDP-43 and restoration of the lost functions of TPD-43.&#x202f;.}, }
@article {pmid35650294, year = {2022}, author = {Nakazato, T and Kanai, K and Kataura, T and Nojiri, S and Hattori, N and Saiki, S}, title = {Plasma taurine is an axonal excitability-translatable biomarker for amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {9155}, pmid = {35650294}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis ; Axons/physiology ; Biomarkers ; Humans ; Motor Neurons/physiology ; Taurine ; }, abstract = {Although various body fluid biomarkers for amyotrophic lateral sclerosis (ALS) have been reported, no biomarkers specifically reflecting abnormalities in axonal excitability indices have currently been established. Capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry were used to perform a comprehensive metabolome analysis of plasma from seven ALS patients and 20 controls, and correlation analysis with disease phenotypes was then performed in 22 other ALS patients. Additionally, electrophysiological studies of motor nerve axonal excitability were performed in all ALS patients. In the ALS and control groups, levels of various metabolites directly associated with skeletal muscle metabolism, such as those involved in fatty acid β-oxidation and the creatine pathway, were detected. Receiver operating characteristic curve analysis of the top four metabolites (ribose-5-phosphate, N6-acetyllysine, dyphylline, 3-methoxytyrosine) showed high diagnostic accuracy (area under the curve = 0.971) in the ALS group compared with the control group. Furthermore, hierarchical cluster analysis revealed that taurine levels were correlated with the strength-duration time constant, an axonal excitability indicator established to predict survival. No significant effects of diabetes mellitus and treatment (Riluzole and Edaravone) on this relationship were detected in the study. Therefore, plasma taurine is a potential novel axonal excitability-translatable biomarker for ALS.}, }
@article {pmid35645791, year = {2022}, author = {Budgett, RF and Bakker, G and Sergeev, E and Bennett, KA and Bradley, SJ}, title = {Targeting the Type 5 Metabotropic Glutamate Receptor: A Potential Therapeutic Strategy for Neurodegenerative Diseases?.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {893422}, pmid = {35645791}, issn = {1663-9812}, abstract = {The type 5 metabotropic glutamate receptor, mGlu5, has been proposed as a potential therapeutic target for the treatment of several neurodegenerative diseases. In preclinical neurodegenerative disease models, novel allosteric modulators have been shown to improve cognitive performance and reduce disease-related pathology. A common pathological hallmark of neurodegenerative diseases is a chronic neuroinflammatory response, involving glial cells such as astrocytes and microglia. Since mGlu5 is expressed in astrocytes, targeting this receptor could provide a potential mechanism by which neuroinflammatory processes in neurodegenerative disease may be modulated. This review will discuss current evidence that highlights the potential of mGlu5 allosteric modulators to treat neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, this review will explore the role of mGlu5 in neuroinflammatory responses, and the potential for this G protein-coupled receptor to modulate neuroinflammation.}, }
@article {pmid35643264, year = {2022}, author = {Ziukelis, ET and Mak, E and Dounavi, ME and Su, L and T O'Brien, J}, title = {Fractal dimension of the brain in neurodegenerative disease and dementia: A systematic review.}, journal = {Ageing research reviews}, volume = {79}, number = {}, pages = {101651}, doi = {10.1016/j.arr.2022.101651}, pmid = {35643264}, issn = {1872-9649}, support = {/DH_/Department of Health/United Kingdom ; }, mesh = {*Alzheimer Disease/pathology ; Atrophy/pathology ; Brain/diagnostic imaging/pathology ; Fractals ; Humans ; Magnetic Resonance Imaging/methods ; *Neurodegenerative Diseases/diagnostic imaging/pathology ; }, abstract = {Sensitive and specific antemortem biomarkers of neurodegenerative disease and dementia are crucial to the pursuit of effective treatments, required both to reliably identify disease and to track its progression. Atrophy is the structural magnetic resonance imaging (MRI) hallmark of neurodegeneration. However in most cases it likely indicates a relatively advanced stage of disease less susceptible to treatment as some disease processes begin decades prior to clinical onset. Among emerging metrics that characterise brain shape rather than volume, fractal dimension (FD) quantifies shape complexity. FD has been applied in diverse fields of science to measure subtle changes in elaborate structures. We review its application thus far to structural MRI of the brain in neurodegenerative disease and dementia. We identified studies involving subjects who met criteria for mild cognitive impairment, Alzheimer's Disease, Vascular Dementia, Lewy Body Dementia, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Parkinson's Disease, Huntington's Disease, Multiple Systems Atrophy, Spinocerebellar Ataxia and Multiple Sclerosis. The early literature suggests that neurodegenerative disease processes are usually associated with a decline in FD of the brain. The literature includes examples of disease-related change in FD occurring independently of atrophy, which if substantiated would represent a valuable advantage over other structural imaging metrics. However, it is likely to be non-specific and to exhibit complex spatial and temporal patterns. A more harmonious methodological approach across a larger number of studies as well as careful attention to technical factors associated with image processing and FD measurement will help to better elucidate the metric's utility.}, }
@article {pmid35640762, year = {2022}, author = {Mitsui, S and Otomo, A and Sato, K and Ishiyama, M and Shimakura, K and Okada-Yamaguchi, C and Warabi, E and Yanagawa, T and Aoki, M and Shang, HF and Hadano, S}, title = {SQSTM1, a protective factor of SOD1-linked motor neuron disease, regulates the accumulation and distribution of ubiquitinated protein aggregates in neuron.}, journal = {Neurochemistry international}, volume = {158}, number = {}, pages = {105364}, doi = {10.1016/j.neuint.2022.105364}, pmid = {35640762}, issn = {1872-9754}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Mutation ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Proteasome Endopeptidase Complex/metabolism ; Protein Aggregates ; Sequestosome-1 Protein/genetics ; Spinal Cord/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Ubiquitin/metabolism ; *Ubiquitinated Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective loss of motor neurons in the brain and spinal cord. Recent studies have shown that mutations in SQSTM1 are linked to ALS. It has also been demonstrated that a systemic loss of SQSTM1 exacerbates disease phenotypes in an ALS mouse model. However, it is still unclear whether and how SQSTM1 in the central nervous system (CNS) specifically regulates ALS-associated disease phenotypes. To address this issue, we generated CNS-specific Sqstm1 deficient SOD1[H46R] transgenic mice, and conducted gross phenotype analyses as well as the immunohistochemical and biochemical examinations of spinal cord tissues using these mice. CNS-specific SQSTM1 deficiency accelerated the disease onset and shortened the lifespan of SOD1[H46R] mice. The CNS-specific SQSTM1 ablation also resulted in increased number of ubiquitin-positive aggregates, while their size rather became much smaller. Remarkably, ubiquitin-positive aggregates, which were usually present in extracellular space and/or neuropil in SOD1[H46R] mice, were preferentially localized to soma and neurites of spinal neurons in CNS-specific SQSTM1 deficient SOD1[H46R] mice. Next, to further clarify the function of SQSTM1 in neurons, we investigated the contribution of SQSTM1 to the accumulation of polyubiquitinated proteins in relation to the ubiquitin proteasome system (UPS) and the autophagy-endolysosomal system (APELS) in primary cultured motor neurons (PMNs). Loss of SQSTM1 in PMNs resulted in decreased accumulation of insoluble polyubiquitinated proteins, which was induced by simultaneous treatment with proteasome and lysosome inhibitors, suggesting a pivotal role of SQSTM1 in the formation of insoluble protein aggregates. However, SQSTM1 silencing had a limited impact on the susceptibility to proteasome and/or lysosome inhibitor-induced apoptosis in PMNs. Taken together, neuronal SQSTM1, whose functions are associated with both the UPS and APELS, might primarily regulate the distribution and accumulation of misfolded protein aggregates in the CNS, thereby protecting neurons from degeneration in mice.}, }
@article {pmid35638376, year = {2022}, author = {Kmezic, I and Samuelsson, K and Finn, A and Upate, Z and Blennow, K and Zetterberg, H and Press, R}, title = {Neurofilament light chain and total tau in the differential diagnosis and prognostic evaluation of acute and chronic inflammatory polyneuropathies.}, journal = {European journal of neurology}, volume = {29}, number = {9}, pages = {2810-2822}, pmid = {35638376}, issn = {1468-1331}, mesh = {*Amyotrophic Lateral Sclerosis ; Biomarkers/cerebrospinal fluid ; Diagnosis, Differential ; *Guillain-Barre Syndrome/diagnosis ; Humans ; Intermediate Filaments ; Neurofilament Proteins/cerebrospinal fluid ; *Polyneuropathies/diagnosis ; *Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis ; Prognosis ; }, abstract = {BACKGROUND AND PURPOSE: To investigate the diagnostic and prognostic value of axonal injury biomarkers in patients with inflammatory polyneuropathies.<br><br>METHODS: Neurofilament light chain (NfL) and total tau (T-tau) were measured in the cerebrospinal fluid (CSF) and plasma in 41 patients with Guillain-Barr&#xe9; syndrome (GBS), 32 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 10 with paraproteinemia-related demyelinating polyneuropathy (PDN), and 8 with multifocal motor neuropathy (MMN), in comparison with 39 disease-free controls and 59 other controls. Outcome was measured with the GBS-disability score (GBS-ds) or Inflammatory Neuropathy Cause and Treatment (INCAT) disability score.<br><br>RESULTS: Neurofilament light chain levels in CSF and plasma were higher in GBS, CIDP, and PDN vs. disease-free controls. Patients with MMN had higher NfL levels in plasma vs. disease-free controls, but lower levels in CSF and plasma vs. patients with amyotrophic lateral sclerosis (ALS). T-tau levels in plasma were higher in GBS, CIDP, PDN, and MMN vs. all control groups. Neurofilament light chain levels in CSF and plasma in patients with GBS correlated with GBS-ds, as higher levels were associated with inability to run after 6 and 12&#x2009;months. NfL levels in CSF and plasma in CIDP did not correlate significantly with outcome.<br><br>CONCLUSIONS: Acute and chronic inflammatory neuropathies are associated with an increase in levels of NfL in CSF and plasma, but NfL is validated as a prognostic biomarker only in GBS. NfL could be used in differentiating patients with MMN from ALS. T-tau in plasma is a novel biomarker that could be used in a diagnostic assessment of patients with acute and chronic inflammatory polyneuropathies.}, }
@article {pmid35630064, year = {2022}, author = {Rugaitienė, M and Damulevičienė, G and Lesauskaitė, V and Ulozienė, I}, title = {Oropharyngeal Dysphagia as the Main Expression of Amyotrophic Lateral Sclerosis.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {58}, number = {5}, pages = {}, pmid = {35630064}, issn = {1648-9144}, mesh = {Aged ; *Amyotrophic Lateral Sclerosis/complications ; *Deglutition Disorders/complications/diagnosis ; Dyspnea/etiology ; Female ; Humans ; Muscle Weakness/complications ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease. Only about 10% of ALS patients survive more than 10 years. Clinical studies show that multidisciplinary care statistically significantly improves survival compared to neurological care. ALS tends to manifest as limb weakness, but some patients present with bulbar symptoms, such as dysphagia and dysarthria. In rarer cases, the main symptom of ALS is oropharyngeal dysphagia. Respiratory muscle weakness is a relatively rare symptom at the onset of this disease and may lead to a fatal outcome due to aspiration pneumonia within about 1.4 years. These reasons led to a particularly complicated diagnosis of ALS in a 66-year-old Caucasian female patient complaining of dyspnoea and coughing while drinking water. Notably, dyspnoea is only present in one out of four treatment-seeking patients, and the course of ALS is non-specific. For these reasons, the diagnosis took an entire year while the patient underwent many tests and visited many specialists. However, the diagnosis was only made at a late stage of the disease. At present, the patient is almost unable to swallow food, water, or saliva, and is at a very high risk of aspiration, but refuses to have a percutaneous endoscopic gastrostomy performed. The objective of this case report is to highlight the fact that a symptom as simple as difficulty swallowing may be the result of severe disease, a frequent outcome of which is death.}, }
@article {pmid35625816, year = {2022}, author = {Hatanaka, Y and Umeda, T and Shigemori, K and Takeuchi, T and Nagai, Y and Tomiyama, T}, title = {C9orf72 Hexanucleotide Repeat Expansion-Related Neuropathology Is Attenuated by Nasal Rifampicin in Mice.}, journal = {Biomedicines}, volume = {10}, number = {5}, pages = {}, pmid = {35625816}, issn = {2227-9059}, support = {Not applicable//the Research Foundation for Dementia of Osaka/ ; }, abstract = {The non-coding GGGGCC hexanucleotide repeat expansion (HRE) in C9orf72 gene is a dominant cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This intronic mutation elicits the formation of nuclear and cytoplasmic inclusions containing RNA, RNA-binding proteins, and HRE-derived dipeptide repeat proteins (DPRs), leading to neurodegeneration via the gain-of-toxic function or loss-of-function of relevant proteins. Using C9-500 mice harboring ~500 repeats of the GGGGCC sequence in human C9orf72 gene, we investigated the effects of rifampicin against HRE-related pathological phenotypes. Rifampicin was administered intranasally to 4.5- to 5-month-old mice for 1 month, and their cognitive function and neuropathology were assessed by the Morris water maze test and immunohistochemical staining. Rifampicin treatment reduced the formation of RNA foci and cytoplasmic inclusions containing DPRs or phosphorylated TDP-43, and furthermore, the levels of phosphorylated double-strand RNA-dependent protein kinase (PKR) that regulates repeat-associated non-ATG (RAN) translation. Synapse loss in the hippocampus and neuronal loss and microglial activation in the prefrontal and motor cortices were also attenuated, and mouse memory was significantly improved. Our findings suggest a therapeutic potential of nasal rifampicin in the prevention of C9orf72-linked neurodegenerative disorders.}, }
@article {pmid35625595, year = {2022}, author = {Landolfo, E and Cutuli, D and Petrosini, L and Caltagirone, C}, title = {Effects of Palmitoylethanolamide on Neurodegenerative Diseases: A Review from Rodents to Humans.}, journal = {Biomolecules}, volume = {12}, number = {5}, pages = {}, pmid = {35625595}, issn = {2218-273X}, mesh = {Amides ; Animals ; Ethanolamines/pharmacology/therapeutic use ; Humans ; *Neurodegenerative Diseases/drug therapy ; Palmitic Acids/pharmacology/therapeutic use ; *Rodentia ; }, abstract = {Palmitoylethanolamide (PEA) stands out among endogenous lipid mediators for its neuroprotective, anti-inflammatory, and analgesic functions. PEA belonging to the N-acetylanolamine class of phospholipids was first isolated from soy lecithin, egg yolk, and peanut flour. It is currently used for the treatment of different types of neuropathic pain, such as fibromyalgia, osteoarthritis, carpal tunnel syndrome, and many other conditions. The properties of PEA, especially of its micronized or ultra-micronized forms maximizing bioavailability and efficacy, have sparked a series of innovative research to evaluate its possible application as therapeutic agent for neurodegenerative diseases. Neurodegenerative diseases are widespread throughout the world, and although they are numerous and different, they share common patterns of conditions that result from progressive damage to the brain areas involved in mobility, muscle coordination and strength, mood, and cognition. The present review is aimed at illustrating in vitro and in vivo research, as well as human studies, using PEA treatment, alone or in combination with other compounds, in the presence of neurodegeneration. Namely, attention has been paid to the effects of PEA in counteracting neuroinflammatory conditions and in slowing down the progression of diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Frontotemporal dementia, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. Literature research demonstrated the efficacy of PEA in addressing the damage typical of major neurodegenerative diseases.}, }
@article {pmid35618326, year = {2022}, author = {Souza, AA and Silva, STD and Pondofe, KM and Resqueti, VR and Melo, LP and Valentim, RAM and Ribeiro, TS}, title = {Remote versus face-to-face home-based exercise programme in people with amyotrophic lateral sclerosis: protocol for a randomised clinical trial.}, journal = {BMJ open}, volume = {12}, number = {5}, pages = {e056323}, pmid = {35618326}, issn = {2044-6055}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Amyotrophic Lateral Sclerosis/drug therapy ; Exercise Therapy/methods ; Fatigue ; Humans ; Middle Aged ; *Neurodegenerative Diseases ; Pain ; Randomized Controlled Trials as Topic ; Single-Blind Method ; Young Adult ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease with variable and complex clinical manifestations that requires a multidisciplinary approach. However, face-to-face treatment in this population may experience barriers, such as difficulty accessing physical therapists or other professionals. As a result, strategies (eg, telerehabilitation) emerged to facilitate treatment and physical therapy monitoring. This study aims to evaluate the effects of remote versus face-to-face home-based exercise programmes on clinical outcomes and treatment adherence of people with ALS.<br><br>METHODS AND ANALYSIS: This is a single-blind randomised clinical trial protocol that will include 44 people with clinical diagnosis of ALS at any clinical stage and aged between 18 and 80 years. Participants will be randomised into two groups after face-to-face evaluation and perform a home-based exercise programme three times a week for 6&#x2009;months. A physical therapist will monitor the exercise programme once a week remotely (phone calls-experimental group) or face-to-face (home visits-control group). The primary outcome measure will be functional capacity (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised). Secondary outcomes will include disease severity (Amyotrophic Lateral Sclerosis Severity Scale), fatigue (Fatigue Severity Scale), pain (Visual Analogue Scale and body pain diagram), adverse events and adherence rate. Outcomes will be initially evaluated face-to-face and revaluated remotely every 2&#x2009;months and 1&#x2009;month after interventions. Linear mixed models will compare outcome measures between groups and evaluations (&#x3b1;=5%).<br><br>ETHICS AND DISSEMINATION: This study was approved by the research ethics committee of Hospital Universit&#xe1;rio Onofre Lopes/Universidade Federal do Rio Grande do Norte (no. 3735479). We expect to identify the effects of an exercise programme developed according to ALS stages and associated with remote or face-to-face monitoring on clinical outcomes using revaluations and follow-up after interventions.<br><br>TRIAL REGISTRATION NUMBER: Brazilian Registry Clinical Trials (RBR-10z9pgfv).}, }
@article {pmid35614479, year = {2022}, author = {Cummings, J and Montes, A and Kamboj, S and Cacho, JF}, title = {The role of basket trials in drug development for neurodegenerative disorders.}, journal = {Alzheimer's research &amp; therapy}, volume = {14}, number = {1}, pages = {73}, pmid = {35614479}, issn = {1758-9193}, support = {P20 AG068053/AG/NIA NIH HHS/United States ; R35 AG071476/AG/NIA NIH HHS/United States ; U01 NS093334/NS/NINDS NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; P20 GM109025/GM/NIGMS NIH HHS/United States ; R01 AG053798/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease ; Biomarkers ; Drug Development ; Humans ; *Neurodegenerative Diseases/diagnosis/drug therapy ; *Parkinson Disease ; }, abstract = {BACKGROUND: Drug development for neurodegenerative disorders (NDDs) is a long, complex, and expensive enterprise. Methods to optimize drug development for NDDs are needed. Basket trials have been widely used in oncology and have been promoted by the Food and Drug Administration as a means of enhancing the efficiency of drug development.<br><br>DISCUSSION: We reviewed clinical trials for NDDs registered on clinicaltrials.gov in the past 10 years. We identified 59 basket trials assessing the impact of treatment on more than one NDD in the trial. Forty-one of the trials were for 25 agents addressing symptoms of NDD such as motor impairment, hypotension, or psychosis. Eighteen of the trials assessed 14 disease-modifying therapies; the principal targets were mitochondrial function, tau biology, or alpha-synuclein aggregation. Basket trials are most common in phase 2 but have been conducted in phase 1, phase 3, and phase 4. The duration and size of the basket trials are highly variable depending on their developmental phase and the intent of the trial. Parkinson's disease was the most common disorder included in basket trials of symptomatic agents, and Alzheimer's disease was the most common disorder included in basket trials of disease-modifying therapies. Most of the basket trials of symptomatic agents were sponsored by pharmaceutical companies (29 of 41 trials); similarly, most of the basket trials investigating DMTs in basket trials were sponsored by the biopharmaceutical industry (11/17 trials).<br><br>CONCLUSIONS: Basket trials may increase drug development efficiency by reducing redundancy in trial implementation, enhancing recruitment, sharing placebo groups, and using biomarkers relevant to the mechanism of action of the treatment across NDDs. There have been relatively few basket trials including multiple NDDs in the same trial conducted over the past 10 years. The use of the basket trial strategy may represent an opportunity to increase the efficiency of development programs for agents to treat NDDs.}, }
@article {pmid35613082, year = {2022}, author = {Logan, A and Nagy, Z and Barnes, NM and Belli, A and Di Pietro, V and Tavazzi, B and Lazzarino, G and Lazzarino, G and Bruce, L and Persson, LI}, title = {A phase II open label clinical study of the safety, tolerability and efficacy of ILB® for Amyotrophic Lateral Sclerosis.}, journal = {PloS one}, volume = {17}, number = {5}, pages = {e0267183}, pmid = {35613082}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis ; Biomarkers ; Cohort Studies ; Humans ; Outcome Assessment, Health Care ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an invariably lethal progressive disease, causing degeneration of neurons and muscle. No current treatment halts or reverses disease advance. This single arm, open label, clinical trial in patients with ALS investigated the safety and tolerability of a novel modified low molecular weight dextran sulphate (LMW-DS, named ILB®) previously proven safe for use in healthy volunteers and shown to exert potent neurotrophic effects in pre-clinical studies. Secondary endpoints relate to efficacy and exploratory biomarkers.<br><br>METHODS: Thirteen patients with ALS were treated with 5 weekly subcutaneous injections of ILB&#xae;. Safety and efficacy outcome measures were recorded weekly during treatment and at regular intervals for a further 70 days. Functional and laboratory biomarkers were assessed before, during and after treatment.<br><br>RESULTS: No deaths, serious adverse events or participant withdrawals occurred during or after ILB&#xae; treatment and no significant drug-related changes in blood safety markers were evident, demonstrating safety and tolerability of the drug in this cohort of patients with ALS. The PK of ILB&#xae; in patients with ALS was similar to that seen in healthy controls. The ILB&#xae; injection elicited a transient elevation of plasma Hepatocyte Growth Factor, a neurotrophic and myogenic growth factor. Following the ILB&#xae; injections patients reported increased vitality, decreased spasticity and increased mobility. The ALSFRS-R rating improved from 36.31 &#xb1; 6.66 to 38.77 &#xb1; 6.44 and the Norris rating also improved from 70.61 &#xb1; 13.91 to 77.85 &#xb1; 14.24 by Day 36. The improvement of functions was associated with a decrease in muscle atrophy biomarkers. These therapeutic benefits decreased 3-4 weeks after the last dosage.<br><br>CONCLUSIONS: This pilot clinical study demonstrates safety and tolerability of ILB&#xae; in patients with ALS. The exploratory biomarker and functional measures must be cautiously interpreted but suggest clinical benefit and have a bearing on the mechanism of action of ILB&#xae;. The results support the drug's potential as the first disease modifying treatment for patients with ALS.<br><br>TRIAL REGISTRATION: EudraCT 2017-005065-47.}, }
@article {pmid35611897, year = {2022}, author = {Khabibrakhmanov, AN and Mukhamedyarov, MA and Bogdanov, EI}, title = {[Biomarkers of amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {122}, number = {5}, pages = {30-35}, doi = {10.17116/jnevro202212205130}, pmid = {35611897}, issn = {1997-7298}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Biomarkers/metabolism ; Humans ; Motor Neurons ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that has no effective treatment. To date, ALS is considered as a multifactorial heterogeneous disease, in which the death of motor neurons is a final result of the different pathological pathways. Modern diagnostic criteria and classification of ALS do not take into account all heterogeneity of the disease. Despite the development of molecular neurobiology and neurophysiology, genetics, and technology, significant progress in understanding the pathogenesis of ALS, the disease is diagnosed primarily on the basis of clinical manifestations. In recent years, a number of clinical trials of promising drugs have failed to show positive results. Among the reasons for these failures are variability of ALS forms, patients enrollment already at a late stage of the disease, the lack of use of biomarkers for patients selection and drugs' pharmacodynamics assessment. The study of biomarkers and their implementation in clinical practice can help to solve these problems. Here we will discuss the fluid-based biomarkers for ALS.}, }
@article {pmid35607838, year = {2022}, author = {Kwan, J and Vullaganti, M}, title = {Amyotrophic lateral sclerosis mimics.}, journal = {Muscle &amp; nerve}, volume = {66}, number = {3}, pages = {240-252}, doi = {10.1002/mus.27567}, pmid = {35607838}, issn = {1097-4598}, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; *Motor Neuron Disease/diagnosis ; Motor Neurons ; Prognosis ; Syndrome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disorder characterized by progressive degeneration of cortical, bulbar, and spinal motor neurons. When a patient presents with a progressive upper and/or lower motor syndrome, clinicians must pay particular attention to any atypical features in the history and/or clinical examination suggesting an alternate diagnosis, as up to 10% percent of patients initially diagnosed with ALS have a mimic of ALS. ALS is a clinical diagnosis and requires the exclusion of other disorders that may have similar presentations but a more favorable prognosis or an effective therapy. Because there is currently no specific diagnostic biomarker that is sensitive or specific for ALS, understanding the spectrum of clinical presentations of ALS and its mimics is paramount. While true mimics of ALS are rare, the clinician must correctly identify these disorders to avoid the misdiagnosis of ALS and to initiate effective treatment where available.}, }
@article {pmid35606613, year = {2022}, author = {Shen, X and Tang, C and Wei, C and Zhu, Y and Xu, R}, title = {Melatonin Induces Autophagy in Amyotrophic Lateral Sclerosis Mice via Upregulation of SIRT1.}, journal = {Molecular neurobiology}, volume = {59}, number = {8}, pages = {4747-4760}, pmid = {35606613}, issn = {1559-1182}, support = {30560042//National Natural Science Foundation of China/ ; 81160161//National Natural Science Foundation of China/ ; 81360198//National Natural Science Foundation of China/ ; 82160255//National Natural Science Foundation of China/ ; GJJ13198//Education Department of Jiangxi Province/ ; GJJ170021//Education Department of Jiangxi Province/ ; [2014]-47//Jiangxi Provincial Department of Science and Technology/ ; 20142BBG70062//Jiangxi Provincial Department of Science and Technology/ ; 20171BAB215022//Jiangxi Provincial Department of Science and Technology/ ; 20192BAB205043//Jiangxi Provincial Department of Science and Technology/ ; 20181019//Health and Family Planning Commission of Jiangxi province/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Autophagy ; Beclin-1/metabolism ; *Melatonin/pharmacology/therapeutic use ; Mice ; *Neurodegenerative Diseases ; Sirtuin 1/metabolism ; Up-Regulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the neurodegenerative disease that leads to the motor dysfunction damaged by both upper and lower motor neurons. The etiology and pathogenesis of ALS hasn't completely been understood yet up to now, the current study suggests that autophagy plays an important role in the development of ALS. Meanwhile, melatonin is found to inhibit the progression of ALS. To this end, this study aimed to investigate the potential relation between melatonin and autophagy in ALS. The in vivo model of ALS was established to investigate the effects of melatonin in ALS. The mRNA expressions were performed to detect by RT-qPCR, and the protein levels were tested by western blot and immunofluorescence histochemistry staining. The inflammatory cytokine was applied to detect by ELISA. The results showed that melatonin dose-dependently reversed the ALS-induced survival time shortened, weight loss and rotating rod latency decrease. The expressions of both SIRT1 and Beclin-1 as well as the ratio of LC3II/LC3I were significantly upregulated in the ALS mice, while melatonin reversed the upregulation of both SIRT1 and Beclin-1 expression and LC3II/LC3I ratio in a dose-dependent manner. In contrast, melatonin dose-dependently significantly restored the ALS-induced downregulation of p62. Furthermore, SIRT1 silencing notably reduced the effect of melatonin on Beclin-1, LC3II/LC3I, and p62. Melatonin induced autophagy in the ALS mice via the upregulation of SIRT1. Thus, melatonin might act as a new agent for the treatment of ALS.}, }
@article {pmid35596795, year = {2022}, author = {Lunetta, C and Lizio, A and Cabona, C and Gerardi, F and Sansone, VA and Corbo, M and Scialò, C and Angelucci, E and Gualandi, F and Marenco, P and Grillo, G and Cairoli, R and Cesana, C and Saccardi, R and Melazzini, MG and Mancardi, G and Caponnetto, C}, title = {A phase I/IIa clinical trial of autologous hematopoietic stem cell transplantation in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {269}, number = {10}, pages = {5337-5346}, pmid = {35596795}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/surgery ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Male ; Quality of Life ; Transplantation Conditioning/methods ; Transplantation, Autologous ; }, abstract = {OBJECTIVE: To verify the safety and potential effect on ALS progression of a low-intensity immunosuppressive regimen followed by autologous hematopoietic stem cell transplantation (aHSCT) in amyotrophic lateral sclerosis (ALS) patients.<br><br>METHODS: ALS eligible patients underwent a set of clinical and laboratory evaluations at T-4 (screening), T-1 (pre-treatment visit), and for the 12 consecutive months after treatment (T3, T6, T9, T12). We evaluated the tolerability of the procedure, its efficacy on clinical course and quality of life (QoL).<br><br>RESULTS: Eight of the 11 ALS patients enrolled received the established immunoablative protocol. The procedure was well tolerated and side effects were those expected. One patient died 4&#xa0;months after the conditioning regimen and another patient underwent tracheotomy just before T3 for a sudden respiratory failure, but he is still alive 4&#xa0;years after the procedure without being ventilated any more. A third patient died 10&#xa0;months after conditioning. In the other cases, there was no statistical difference in all functional measures and QoL pre- and post-treatment; however, a transitory slopes' reduction of ALSFRS-R and seated SVC% after the conditioning procedures was reported. Moreover, although not statistically significant, trends of reduction of CD4&#x2009;+&#x2009;and increment of CD8&#x2009;+&#x2009;were found.<br><br>CONCLUSIONS: aHSCT was overall well tolerated, but it was not followed by any significant modification in disease progression. Considering the negative results of this small trial, further studies aimed to evaluate the possible efficacy of the aHSCT using a higher-intensity regimen should be carefully and with caution evaluated.}, }
@article {pmid35593746, year = {2022}, author = {James, E and Ellis, C and Brassington, R and Sathasivam, S and Young, CA}, title = {Treatment for sialorrhea (excessive saliva) in people with motor neuron disease/amyotrophic lateral sclerosis.}, journal = {The Cochrane database of systematic reviews}, volume = {5}, number = {5}, pages = {CD006981}, pmid = {35593746}, issn = {1469-493X}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; *Botulinum Toxins, Type A/therapeutic use ; Clinical Trials, Phase II as Topic ; *Deglutition Disorders/complications/etiology ; Diarrhea/complications ; Humans ; *Motor Neuron Disease/complications ; Nausea ; Randomized Controlled Trials as Topic ; Saliva ; Scopolamine Derivatives ; *Sialorrhea/drug therapy/etiology ; }, abstract = {BACKGROUND: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative condition that may cause dysphagia, as well as limb weakness, dysarthria, emotional lability, and respiratory failure. Since normal salivary production is 0.5 L to 1.5 L daily, loss of salivary clearance due to dysphagia leads to salivary pooling and sialorrhea, often resulting in distress and inconvenience to people with MND. This is an update of a review first published in 2011.<br><br>OBJECTIVES: To assess the effects of treatments for sialorrhea in MND, including medications, radiotherapy and surgery.<br><br>SEARCH METHODS: On 27 August 2021, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, AMED, CINAHL, ClinicalTrials.gov and the WHO ICTRP. We checked the bibliographies of the identified randomized trials and contacted trial authors as needed. We contacted known experts in the field to identify further published and unpublished papers.<br><br>SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs, including cross-over trials, on any intervention for sialorrhea and related symptoms, compared with each other, placebo or no intervention, in people with ALS/MND.<br><br>DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane.<br><br>MAIN RESULTS: We identified four RCTs involving 110 participants with MND who were described as having intractable sialorrhea or bulbar dysfunction. A well-designed study of botulinum toxin B compared to placebo injected into the parotid and submandibular glands of 20 participants showed that botulinum toxin B may produce participant-reported improvement in sialorrhea, but the confidence interval (CI) was also consistent with no effect.&#xa0;Six of nine participants in the botulinum group and two of nine participants in the placebo group reported improvement (risk ratio (RR) 3.00, 95% CI 0.81 to 11.08; 1 RCT; 18 participants; low-certainty evidence). An objective measure indicated that botulinum toxin B probably reduced saliva production (in mL/5 min) at eight weeks compared to placebo (MD -0.50, 95% CI -1.07 to 0.07; 18 participants, moderate-certainty evidence). Botulinum toxin B may have little to no effect on quality of life, measured on the Schedule for Evaluation of Individual Quality of Life direct weighting scale (SEIQoL-DW; 0-100, higher values indicate better quality of life) (MD -2.50, 95% CI -17.34 to 12.34; 1 RCT; 17 participants; low-certainty evidence). The rate of adverse events may be similar with botulinum toxin B and placebo (20 participants; low-certainty evidence). Trialists did not consider any serious events to be related to treatment. A randomized pilot study of botulinum toxin A or radiotherapy in 20 participants, which was at high risk of bias, provided very low-certainty evidence on the primary outcome of the Drool Rating Scale (DRS; range 8 to 39 points, higher scores indicate worse drooling) at 12 weeks (effect size -4.8, 95% CI -10.59 to 0.92; P = 0.09; 1 RCT; 16 participants). Quality of life was not measured. Evidence for adverse events, measured immediately after treatment (RR 7.00, 95% CI 1.04 to 46.95; 20 participants), and after four weeks (when two people in each group had viscous saliva) was also very uncertain. A phase 2, randomized, placebo-controlled cross-over study of 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate (DMQ) found that DMQ may produce a participant-reported improvement in sialorrhea, indicated by a slight improvement (decrease) in mean scores for the primary outcome, the Center for Neurologic Study Bulbar Function Scale (CNS-BFS). Mean total CNS-BFS (range 21 (no symptoms) to 112 (maximum symptoms)) was 53.45 (standard error (SE) 1.07) for the DMQ treatment period and 59.31 (SE 1.10) for the placebo period (mean difference) MD -5.85, 95% CI -8.77 to -2.93) with a slight decrease in the CNS-BFS sialorrhea subscale score (range 7 (no symptoms) to 35 (maximum symptoms)) compared to placebo (MD -1.52, 95% CI -2.52 to -0.52) (1 RCT; 60 participants; moderate-certainty evidence). The trial did not report an objective measure of saliva production or measure quality of life. The study was at an unclear risk of bias. Adverse events were similar to other trials of DMQ, and may occur at a similar rate as placebo (moderate-certainty evidence, 60 participants), with the most common side effects being constipation, diarrhea, nausea, and dizziness. Nausea and diarrhea on DMQ treatment resulted in one withdrawal. A randomized, double-blind, placebo-controlled cross-over study of scopolamine (hyoscine), administered using a skin patch, involved 10 randomized participants, of whom eight provided efficacy data. The participants were unrepresentative of clinic cohorts under routine clinical care as they had feeding tubes and tracheostomy ventilation, and the study was at high risk of bias. The trial provided very low-certainty evidence on sialorrhea in the short term (7 days' treatment, measured on the Amyotrophic Lateral Scelerosis Functional Rating Scale-Revised (ALSFRS-R) saliva item (P = 0.572)), and the amount of saliva production in the short term, as indicated by the weight of a cotton roll (P = 0.674), or daily oral suction volume (P = 0.69). Quality of life was not measured. Adverse events evidence was also very uncertain. One person treated with scopolamine had a dry mouth and one died of aspiration pneumonia considered unrelated to treatment.<br><br>AUTHORS' CONCLUSIONS: There is some low-certainty or moderate-certainty evidence for the use of botulinum toxin B injections to salivary glands and moderate-certainty evidence for the use of oral dextromethorphan with quinidine (DMQ) for the treatment of sialorrhea in MND. Evidence on radiotherapy versus botulinum toxin A injections, and scopolamine patches is too uncertain for any conclusions to be drawn. Further research is required on treatments for sialorrhea. Data are needed on the problem of sialorrhea in MND and its measurement, both by participant self-report measures and objective tests. These will allow the development of better RCTs.}, }
@article {pmid35592494, year = {2022}, author = {Liu, Y and Andreucci, A and Iwamoto, N and Yin, Y and Yang, H and Liu, F and Bulychev, A and Hu, XS and Lin, X and Lamore, S and Patil, S and Mohapatra, S and Purcell-Estabrook, E and Taborn, K and Dale, E and Vargeese, C}, title = {Preclinical evaluation of WVE-004, aninvestigational stereopure oligonucleotide forthe treatment of C9orf72-associated ALS or FTD.}, journal = {Molecular therapy. Nucleic acids}, volume = {28}, number = {}, pages = {558-570}, pmid = {35592494}, issn = {2162-2531}, abstract = {A large hexanucleotide (G4C2) repeat expansion in the first intronic region of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Several mechanisms have been proposed to explain how the repeat expansion drives disease, and we hypothesize that a variant-selective approach, in which transcripts affected by the repeat expansion are preferentially decreased, has the potential to address most of them. We report a stereopure antisense oligonucleotide, WVE-004, that executes this variant-selective mechanism of action. WVE-004 dose-dependently and selectively reduces repeat-containing transcripts in patient-derived motor neurons carrying a C9orf72-repeat expansion, as well as in the spinal cord and cortex of C9 BAC transgenic mice. In mice, selective transcript knockdown was accompanied by substantial decreases in dipeptide-repeat proteins, which are pathological biomarkers associated with the repeat expansion, and by preservation of healthy C9orf72 protein expression. These in vivo effects were durable, persisting for at least 6 months. These data support the advancement of WVE-004 as an investigational stereopure antisense oligonucleotide targeting C9orf72 for the treatment of C9orf72-associated ALS or FTD.}, }
@article {pmid35586308, year = {2022}, author = {West, RL and Otto, Q and Drennan, IR and Rudd, S and Böttiger, BW and Parnia, S and Soar, J}, title = {CPR-related cognitive activity, consciousness, awareness and recall, and its management: A scoping review.}, journal = {Resuscitation plus}, volume = {10}, number = {}, pages = {100241}, pmid = {35586308}, issn = {2666-5204}, abstract = {BACKGROUND: There are increasing numbers of reports of cognitive activity, consciousness, awareness and recall related to cardiopulmonary resuscitation (CPR) and interventions such as the use of sedative and analgesic drugs during CPR.<br><br>OBJECTIVES: This scoping review aims to describe the available evidence concerning CPR-related cognitive activity, consciousness, awareness and recall and interventions such as the use of sedative and analgesic drugs during CPR.<br><br>METHODS: A literature search was conducted of Medline, Embase and CINAHL from inception to 21 October 2021. We included case studies, observational studies, review studies and grey literature.<br><br>RESULTS: We identified 8 observational studies including 40,317 patients and 464 rescuers, and 26 case reports including 33 patients. The reported prevalence of CPR-induced consciousness was between 0.23% to 0.9% of resuscitation attempts, with 48-59% of experienced professional rescuers surveyed estimated to have observed CPR-induced consciousness. CPR-induced consciousness is associated with professional rescuer CPR, witnessed arrest, a shockable rhythm, increased return of spontaneous circulation (ROSC), and survival to hospital discharge when compared to patients without CPR-induced consciousness. Few studies of sedation for CPR-induced consciousness were identified. Although local protocols for treating CPR-induced consciousness exist, there is no widely accepted guidance.<br><br>CONCLUSIONS: CPR-related cognitive activity, consciousness, awareness and recall is uncommon but increasingly reported by professional rescuers. The data available was heterogeneous in nature and not suitable for progression to a systematic review process. Although local treatment protocols exist for management of CPR-induced consciousness, there are no widely accepted treatment guidelines. More studies are required to investigate the management of CPR-induced consciousness.}, }
@article {pmid35585556, year = {2022}, author = {Nam, JY and Lee, TY and Kim, K and Chun, S and Kim, MS and Shin, JH and Sung, JJ and Kim, BJ and Kim, BJ and Oh, KW and Kim, KS and Kim, SH}, title = {Efficacy and safety of Lenzumestrocel (Neuronata-R® inj.) in patients with amyotrophic lateral sclerosis (ALSUMMIT study): study protocol for a multicentre, randomized, double-blind, parallel-group, sham procedure-controlled, phase III trial.}, journal = {Trials}, volume = {23}, number = {1}, pages = {415}, pmid = {35585556}, issn = {1745-6215}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Cell- and Tissue-Based Therapy ; Clinical Trials, Phase III as Topic ; Disease Progression ; Double-Blind Method ; Humans ; *Mesenchymal Stem Cells ; Multicenter Studies as Topic ; Observational Studies as Topic ; Randomized Controlled Trials as Topic ; Treatment Outcome ; }, abstract = {BACKGROUND: A single cycle (two repeated treatments) with intrathecal autologous bone marrow-derived mesenchymal stem cells (BM-MSCs, 26-day interval) showed safety and provided therapeutic benefit lasting 6 months in patients with ALS but did not demonstrate long-term efficacy. This phase III clinical trial (ALSUMMIT) protocol was developed to evaluate the long-term efficacy and safety of the combined protocol of single-cycle intrathecal therapy and three additional booster injections of BM-MSC (Lenzumestrocel) treatment in patients with ALS.<br><br>METHODS: ALSUMMIT is a multicentre, randomized, double-blind, parallel-group, sham procedure-controlled, phase III trial for ALS. The 115 subjects will be randomized (1:2:2) into three groups: (1) study Group 1 (single-cycle, two repeated injections with 26-day interval), (2) study Group 2 (single-cycle + three additional booster injections at 4, 7, and 10 months), and (3) the control group. Participants who have an intermediate rate of disease progression will be included in this trial to reduce clinical heterogeneity. The primary endpoint will be evaluated by combined assessment of function and survival (CAFS), also known as joint rank scores (JRS), at 6 months (study Group 1 vs. control) and 12 months (study Group 2 vs. control) after the first Lenzumestrocel or placebo administration. Safety assessment will be performed throughout the study period. Additionally, after the 56-week main study, a long-term follow-up observational study will be conducted to evaluate the long-term efficacy and safety up to 36 months.<br><br>DISCUSSION: Lenzumestrocel is the orphan cell therapy product for ALS conditionally approved by the South Korea Ministry of Food and Drug Safety (MFDS). This ALSUMMIT protocol was developed for the adoption of enrichment enrolment, add-on design, and consideration of ethical issues for the placebo group.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT04745299 . Registered on Feb 9, 2021. Clinical Research Information Service (CRIS) KCT0005954 . Registered on Mar 4, 2021.}, }
@article {pmid35585374, year = {2022}, author = {Benatar, M and Wuu, J and Andersen, PM and Bucelli, RC and Andrews, JA and Otto, M and Farahany, NA and Harrington, EA and Chen, W and Mitchell, AA and Ferguson, T and Chew, S and Gedney, L and Oakley, S and Heo, J and Chary, S and Fanning, L and Graham, D and Sun, P and Liu, Y and Wong, J and Fradette, S}, title = {Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {19}, number = {4}, pages = {1248-1258}, pmid = {35585374}, issn = {1878-7479}, support = {R01 NS105479/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase/genetics ; *Neurodegenerative Diseases ; Oligonucleotides, Antisense/therapeutic use ; Biomarkers ; RNA, Messenger ; Mutation ; }, abstract = {Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antisense oligonucleotide designed to reduce synthesis of superoxide dismutase 1 (SOD1) protein through degradation of SOD1 mRNA. Informed by Pre-fALS and the tofersen clinical development program, the ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease activity (elevated plasma NfL). The ATLAS study will investigate whether tofersen can delay the emergence of clinically manifest ALS. To our knowledge, ATLAS is the first interventional trial in presymptomatic ALS and has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS.}, }
@article {pmid35583482, year = {2023}, author = {Ehlers, J and Fisher, B and Peterson, S and Dai, M and Larkin, A and Bradt, L and Mann, NC}, title = {Description of the 2020 NEMSIS Public-Release Research Dataset.}, journal = {Prehospital emergency care}, volume = {27}, number = {4}, pages = {473-481}, doi = {10.1080/10903127.2022.2079779}, pmid = {35583482}, issn = {1545-0066}, mesh = {Humans ; United States ; *Emergency Medical Services/methods ; Patient Care ; Information Systems ; *Emergency Medical Technicians ; *Emergency Medical Dispatch ; }, abstract = {BACKGROUND: The National Emergency Medical Services Information System (NEMSIS) is a federally funded program designed to standardize Emergency Medical Services (EMS) patient care reporting and facilitate state and national data repositories for the assessment and improvement of EMS systems of care. This manuscript characterizes the 2020 submissions to the National EMS Database, detailing the strengths and limitations associated with use of these data for public health surveillance, improving prehospital patient care, critical resource allocation, clinician safety, system quality assurance and research purposes.<br><br>METHODOLOGY: Using the 2020 NEMSIS Public-Release Research Dataset (NEMSIS dataset), we evaluated the dataset completeness (i.e., presence of missing/null values), dataset content and assessed data generalizability. The analysis focused on 9-1-1 EMS activations resulting in the treatment and transport of a patient, except for out-of-hospital cardiac arrests for which all patients were included regardless of transport status.<br><br>RESULTS: In 2020, 43,488,767 EMS activations were reported to the National EMS Database by 12,319 agencies serving 50 states and territories. Of the 19,533,036 9-1-1 EMS activations reportedly treating and transporting a patient, the majority were attended by "non-volunteer" clinicians (77%) working in a fire-based EMS agency (35%) certified to offer Advanced Life Support (ALS) Paramedic service (80%) and located in an urban area (82%). 9-1-1 call centers most often dispatched EMS for "sick person" (20%), while EMS clinicians most likely reported asthenia (7%) as the patient's primary symptom as well as the clinician's primary impression (6%), and documented "fall on same level, slip, or trip" as the most common cause of injury (37%). The NEMSIS dataset demonstrates some "missingness" and element inconsistencies, but methods may be employed to mitigate these data limitations.<br><br>CONCLUSIONS: The National EMS Database is a free and publicly available resource for evaluating EMS system utilization, response, and prehospital patient care. Understanding the characteristics of the underlying dataset and known data limitations will help ensure proper analysis and reporting of research and quality metrics based on nationally standardized NEMSIS data.}, }
@article {pmid35581326, year = {2022}, author = {François-Moutal, L and Scott, DD and Ambrose, AJ and Zerio, CJ and Rodriguez-Sanchez, M and Dissanayake, K and May, DG and Carlson, JM and Barbieri, E and Moutal, A and Roux, KJ and Shorter, J and Khanna, R and Barmada, SJ and McGurk, L and Khanna, M}, title = {Heat shock protein Grp78/BiP/HspA5 binds directly to TDP-43 and mitigates toxicity associated with disease pathology.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {8140}, pmid = {35581326}, issn = {2045-2322}, support = {P30 AG053760/AG/NIA NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R35GM126949/NH/NIH HHS/United States ; P20 GM103620/GM/NIGMS NIH HHS/United States ; R35 GM126949/GM/NIGMS NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; R21 AG065854/AG/NIA NIH HHS/United States ; R01NS097542/NH/NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Animals ; DNA-Binding Proteins/metabolism ; Drosophila/metabolism ; Endoplasmic Reticulum Chaperone BiP ; HSP70 Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; Humans ; Molecular Chaperones ; *Neurodegenerative Diseases ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure or effective treatment in which TAR DNA Binding Protein of 43 kDa (TDP-43) abnormally accumulates into misfolded protein aggregates in affected neurons. It is widely accepted that protein misfolding and aggregation promotes proteotoxic stress. The molecular chaperones are a primary line of defense against proteotoxic stress, and there has been long-standing interest in understanding the relationship between chaperones and aggregated protein in ALS. Of particular interest are the heat shock protein of 70 kDa (Hsp70) family of chaperones. However, defining which of the 13 human Hsp70 isoforms is critical for ALS has presented many challenges. To gain insight into the specific Hsp70 that modulates TDP-43, we investigated the relationship between TDP-43 and the Hsp70s using proximity-dependent biotin identification (BioID) and discovered several Hsp70 isoforms associated with TDP-43 in the nucleus, raising the possibility of an interaction with native TDP-43. We further found that HspA5 bound specifically to the RNA-binding domain of TDP-43 using recombinantly expressed proteins. Moreover, in a Drosophila strain that mimics ALS upon TDP-43 expression, the mRNA levels of the HspA5 homologue (Hsc70.3) were significantly increased. Similarly we observed upregulation of HspA5 in prefrontal cortex neurons from human ALS patients. Finally, overexpression of HspA5 in Drosophila rescued TDP-43-induced toxicity, suggesting that upregulation of HspA5 may have a compensatory role in ALS pathobiology.}, }
@article {pmid35577578, year = {2022}, author = {Mitsumoto, H and Kasarskis, EJ and Simmons, Z}, title = {Hastening the Diagnosis of Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {99}, number = {2}, pages = {60-68}, doi = {10.1212/WNL.0000000000200799}, pmid = {35577578}, issn = {1526-632X}, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/drug therapy ; *Neurodegenerative Diseases/pathology ; Reproducibility of Results ; Motor Neurons/pathology ; Mice, Transgenic ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic progressive neurodegenerative disease. Neurologists generally see patients as requested and as schedules allow. This practice is part of the reason it takes approximately 12 months from onset of new progressive weakness to receive a definitive diagnosis of ALS. It is well recognized that the disease of ALS starts long before symptom onset. In mutant SOD1 transgenic mice, early loss of motor neurons and compensatory morphological changes precede a rapid loss of motor neurons that coincides with symptom onset. In a human autopsy study, anterior roots in the "presymptomatic" stage indicate that ∼20% loss of motor neurons had already occurred. Sera collected from individuals who later developed ALS and sera from presymptomatic members of families with ALS harboring pathogenic gene variants demonstrated high neurofilament (Nf) levels, again suggesting that the neurodegenerative process is already active at a clinically presymptomatic stage. Potential benefits of hastening the diagnosis of ALS include earlier initiation of therapy to slow the fundamental neurodegenerative process. Such effects are observed in treatment with riluzole, edaravone, methylcobalamin, and sodium phenylbutyrate-taurursodiol in patient care and clinical trial settings. Early initiation of multidisciplinary care results in cost savings and prolonged survival. Early diagnosis after symptom onset also seems to reduce psychological distress. Hence, how can we facilitate an earlier diagnosis of ALS? We already have the necessary tools. New and simple ALS diagnostic criteria (Gold Coast Criteria) have been introduced along with genetic testing. At least 2 studies provide Class II evidence that establishes the reliability and sensitivity of CSF and/or serum Nf levels in supporting a diagnosis of ALS. Challenges, however, still exist as to how to facilitate earlier recognition of possible ALS by primary care physicians and other nonneurologist providers and how to foster a sense of urgency among neurologists to accelerate the diagnostic process. In this article, we provide a number of recommendations that we hope will help achieve these ends.}, }
@article {pmid35577511, year = {2022}, author = {Paganoni, S and Hendrix, S and Dickson, SP and Knowlton, N and Berry, JD and Elliott, MA and Maiser, S and Karam, C and Caress, JB and Owegi, MA and Quick, A and Wymer, J and Goutman, SA and Heitzman, D and Heiman-Patterson, TD and Jackson, C and Quinn, C and Rothstein, JD and Kasarskis, EJ and Katz, J and Jenkins, L and Ladha, SS and Miller, TM and Scelsa, SN and Vu, TH and Fournier, C and Johnson, KM and Swenson, A and Goyal, N and Pattee, GL and Babu, S and Chase, M and Dagostino, D and Hall, M and Kittle, G and Eydinov, M and Ostrow, J and Pothier, L and Randall, R and Shefner, JM and Sherman, AV and Tustison, E and Vigneswaran, P and Yu, H and Cohen, J and Klee, J and Tanzi, R and Gilbert, W and Yeramian, P and Cudkowicz, M}, title = {Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {93}, number = {8}, pages = {871-875}, pmid = {35577511}, issn = {1468-330X}, support = {UL1 TR001414/TR/NCATS NIH HHS/United States ; }, abstract = {BACKGROUND: Coformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS).<br><br>OBJECTIVE: Determine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial.<br><br>METHODS: Adults with El Escorial Definite ALS &#x2264;18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for &#x2264;30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation.<br><br>RESULTS: Risk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95%&#x2009;CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95%&#x2009;CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95%&#x2009;CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO.<br><br>CONCLUSIONS: Early PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS.<br><br>TRIAL REGISTRATION NUMBER: NCT03127514; NCT03488524.}, }
@article {pmid35573709, year = {2022}, author = {Katsomboon, K and Sindhu, S and Utriyaprasit, K and Viwatwongkasem, C}, title = {Factors Associated with 24-Hour Clinical Outcome of Emergency Patients; a Cohort Study.}, journal = {Archives of academic emergency medicine}, volume = {10}, number = {1}, pages = {e30}, pmid = {35573709}, issn = {2645-4904}, abstract = {INTRODUCTION: Pre-hospital and in-hospital emergency management play an important role in quality of care for emergency patients. This prospective cohort study aimed to determine factors associated with the 24-hour clinical outcome of emergency patients.<br><br>METHODS: The sample included 1,630 patients, randomly selected through multi-stage stratified sampling from 13 hospitals in 13 provinces of Thailand. Data were collected during January-November 2018. Clinical outcome was determined using pre-arrest sign score. Data were analyzed via ordinal multivariate regression analysis.<br><br>RESULTS: Factors influencing 24-hour clinical outcome of emergency patients were age (OR: 0.965; 95% CI: 0.96-0.97), having coronary vascular disease (CAD) (OR: 1.41; 95% CI: 1.05-1.88), and severity of illness based on Rapid Emergency Medical Score (REMS) (OR:1.09; 95% CI: 1.05-1.15). Self-transportation and being transported by emergency medical service ambulance with non-advanced life support (EMS-Non-ALS) did not influence clinical outcome when compared to EMS-ALS transport. Being transported from a community hospital increased pre-arrest sign score 1.78 times when compared to EMS-ALS (OR: 1.78; 95% CI: 1.17-2.72). Increased transportation distance increased the risk of poor clinical outcome (OR: 1.01; 95% CI: 1.002-1.011). Length of stay in emergency department (ED-LOS) more than 4 hours (OR: 0.21; 95% CI: 0.15-0.29) and between 2-4 hours (OR: 0.60; 95% CI: 0.47-0.75) decreased the risk of poor clinical outcome when compared to ED-LOS less than 2 hours.<br><br>CONCLUSION: Having CAD, severity of illness, increased transport distance, and ED-LOS less than 2 hours were found to negatively influence 24-hour clinical outcome of emergency patients.}, }
@article {pmid35571129, year = {2022}, author = {Lacroix, C and Alleman-Brimault, I and Zalta, A and Rouby, F and Cassé-Perrot, C and Jouve, E and Attolini, L and Guilhaumou, R and Micallef, J and Blin, O}, title = {What Do We Know About Medical Cannabis in Neurological Disorders and What Are the Next Steps?.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {883987}, pmid = {35571129}, issn = {1663-9812}, abstract = {Medical use of cannabis has been receiving growing attention over the last few decades in modern medicine. As we know that the endocannabinoid system is largely involved in neurological disorders, we focused on the scientific rationale of medical cannabis in three neurological disorders: amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease through pharmacological plausibility, clinical studies, and patients' view. Clinical studies (randomized controlled trials, open-label studies, cohorts, and case reports) exploring medical cannabis in these disorders show different results depending on the methods and outcomes. Some show benefits on motor symptoms and others on non-motor symptoms and quality of life. Concerning patients' view, several web surveys were collected, highlighting the real use of cannabis to relieve symptoms of neurological disorders, mostly outside a medical pathway. This anarchic use keeps questioning particularly in terms of risks: consumption of street cannabis, drug-drug interactions with usual medical treatment, consideration of medical history, and adverse reactions (psychiatric, respiratory, cardiovascular disorders, etc.), underlining the importance of a medical supervision. To date, most scientific data support the therapeutic potential of cannabis in neurological disorders. As far as patients and patients' associations are calling for it, there is an urgent need to manage clinical studies to provide stronger evidence and secure medical cannabis use.}, }
@article {pmid35569927, year = {2022}, author = {Morioka, H and Murata, K and Sugisawa, T and Shibukawa, M and Ebina, J and Sawada, M and Hanashiro, S and Nagasawa, J and Yanagihashi, M and Hirayama, T and Uchi, M and Kawabe, K and Ebihara, S and Murakami, Y and Nakajima, T and Kano, O}, title = {Effects of Long-term Hybrid Assistive Limb Use on Gait in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {61}, number = {10}, pages = {1479-1484}, pmid = {35569927}, issn = {1349-7235}, mesh = {*Amyotrophic Lateral Sclerosis/complications/drug therapy ; Exercise Therapy/methods ; Female ; Gait ; Humans ; Walk Test ; Walking ; }, abstract = {Objective To assess the long-term effects of hybrid assistive limb (HAL) treatment on gait in patients with amyotrophic lateral sclerosis (ALS). Methods Three courses of treatment with HAL were administered to three women with ALS. Each course had a four- to five-week duration, during which the treatment was performed nine times, with a rest period of at least two months between each course. Gait ability (2-minutes-walk and 10-m-walk tests), ALS Functional Rating Scale-Revised, and respiratory function tests were performed before and after each treatment course. Patients Patients diagnosed with ALS, according to the updated Awaji criteria, by board-certified neurologists in the Department of Neurology and Department of Rehabilitation Medicine, Toho University Omori Faculty of Medicine between January and December 2019 were recruited. Results The average time from the start to the end of the 3 courses was 319.7±33.7 days. A multiple regression analysis was performed for the 2-minutes-walk and 10-m-walk tests, using the baseline value, each participant's ID, and time point as covariates. Changes after each course were considered outcomes. Following the 3 treatment courses, the 2-minutes walk distance improved by 16.61 m (95% confidence interval, -9.33-42.54) compared with the baseline value, but this improvement was not statistically significant (p=0.21). However, cadence significantly improved by 1.30 steps (95% confidence interval, 0.17-2.42; p=0.02). Conclusion Long-term, repetitive HAL treatments may help patients with ALS maintain their gait.}, }
@article {pmid35569547, year = {2022}, author = {Majkutewicz, I}, title = {Dimethyl fumarate: A review of preclinical efficacy in models of neurodegenerative diseases.}, journal = {European journal of pharmacology}, volume = {926}, number = {}, pages = {175025}, doi = {10.1016/j.ejphar.2022.175025}, pmid = {35569547}, issn = {1879-0712}, mesh = {Animals ; Dimethyl Fumarate/pharmacology/therapeutic use ; Fumarates/pharmacology ; Humans ; Mice ; *Multiple Sclerosis/drug therapy/metabolism ; NF-E2-Related Factor 2/metabolism ; *Neurodegenerative Diseases/drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction ; }, abstract = {Dimethyl fumarate (DMF) is an antioxidative and anti-inflammatory drug approved for treatment of multiple sclerosis and psoriasis; however, beneficial effects of DMF have also been found in other inflammatory diseases and cancers. DMF is a prodrug that is immediately hydrolysed to monomethyl fumarate (MMF) in vivo. Both fumarates activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, and Nrf2 is a key transcription factor of the antioxidant response. The immunosuppressive and anti-inflammatory actions of DMF occur through several mechanisms: via inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and by downregulation of aerobic glycolysis and pyroptosis in activated myeloid and lymphoid cells. MMF is also an agonist of hydroxycarboxylic acid receptor 2 (HCAR2). Differences in the strength of effects and mechanisms of action of both fumarates are discussed. The aim of this review was to analyse and compare the neuroprotective, antioxidative and anti-inflammatory effects of DMF and its active metabolite, MMF, in cellular (in vitro) and animal models of neurodegenerative diseases (NDs), other than multiple sclerosis. There are more than twenty studies that currently represent this field. Most of the studies are concerned with cellular or animal models of Alzheimer's disease (AD) and Parkinson's disease (PD), one utilized a mouse model of Huntington's disease (HD) and one clinical trial was carried out with amyotrophic lateral sclerosis (ALS) patients. The discrepancies in the results of the various studies are discussed, and issues requiring further research have been identified.}, }
@article {pmid35569295, year = {2022}, author = {Schooling, CN and Healey, TJ and McDonough, HE and French, SJ and McDermott, CJ and Shaw, PJ and Kadirkamanathan, V and Alix, JJP}, title = {Tensor electrical impedance myography identifies bulbar disease progression in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {139}, number = {}, pages = {69-75}, doi = {10.1016/j.clinph.2022.04.015}, pmid = {35569295}, issn = {1872-8952}, support = {IS-BRC-1215-20017/DH_/Department of Health/United Kingdom ; NF-SI-0617-10077/DH_/Department of Health/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Biomarkers ; Disease Progression ; Electric Impedance ; Humans ; Muscle, Skeletal ; Myography/methods ; }, abstract = {OBJECTIVE: Electrical impedance myography (EIM) is a promising biomarker for amyotrophic lateral sclerosis (ALS). A key issue is how best to utilise the complex high dimensional, multi-frequency data output by EIM to fully characterise the progression of disease.<br><br>METHODS: Muscle volume conduction properties were obtained from EIM recordings of the tongue across three electrode configurations and 14 input frequencies (76&#xa0;Hz-625&#xa0;kHz). Analyses of individual frequencies, averaged EIM spectra and non-negative tensor factorisation were undertaken. Longitudinal data were collected from 28 patients and 17 healthy volunteers at 3-monthly intervals for a maximum of 9&#xa0;months. EIM was evaluated against the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) bulbar sub-score, tongue strength and an overall bulbar disease burden score.<br><br>RESULTS: Longitudinal changes to individual patient EIM spectra demonstrated complex shifts in the spectral shape. At a group level, a clear pattern emerged over time, characterised by an increase in centre frequency and general shift to the right of the spectral shape. Tensor factorisation reduced the spectral data from a total of 168 data points per participant per recording to a single value which captured the complexity of the longitudinal data and which we call tensor EIM (T-EIM). The absolute change in tensor EIM significantly increased within 3&#xa0;months and continued to do so over the 9-month study duration. In a hypothetical clinical trial scenario tensor EIM required fewer participants (n&#xa0;=&#xa0;64 at 50% treatment effect), than single frequency measures (n range 87-802) or ALSFRS-R bulbar subscore (n&#xa0;=&#xa0;298).<br><br>CONCLUSIONS: Changes to tongue EIM spectra over time in ALS are complex. Tensor EIM captured and quantified disease progression and was more sensitive to changes than single frequency EIM measures and other biomarkers of bulbar disease.<br><br>SIGNIFICANCE: Objective biomarkers for the assessment of bulbar disease in ALS are lacking. Tensor EIM enhances the biomarker potential of EIM data and can improve bulbar symptom monitoring in clinical trials.}, }
@article {pmid35567903, year = {2022}, author = {Sjoqvist, S and Otake, K}, title = {A pilot study using proximity extension assay of cerebrospinal fluid and its extracellular vesicles identifies novel amyotrophic lateral sclerosis biomarker candidates.}, journal = {Biochemical and biophysical research communications}, volume = {613}, number = {}, pages = {166-173}, doi = {10.1016/j.bbrc.2022.04.127}, pmid = {35567903}, issn = {1090-2104}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/pathology ; Biomarkers/cerebrospinal fluid ; Extracellular Matrix Proteins ; *Extracellular Vesicles/pathology ; Humans ; Pilot Projects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder which is characterized by progressive degeneration of the motor system. Typically, the disease starts with focal weakness which spreads to involve most muscles and leads to death from respiratory failure within five years of diagnosis. Due to the heterogenic nature of the disease, diagnostics is complex, and it generally takes twelve months from symptom-onset to diagnosis. The discovery of novel biomarkers could lead to accelerated diagnosis, earlier start of treatment, improved patient-segmentation, and treatment follow-up as well as an increased insight into the pathology. Here, we analyzed cerebrospinal fluid (CSF) and CSF-derived extracellular vesicles (CSF-EVs) from ALS-patients and matched controls (n = 9 each) using the ultra-sensitive proximity extension assay (PEA), cardiovascular III-panel. On average, 84 and 61 proteins could be detected in CSF and CSF-EVs respectively. In CSF, three proteins were significantly upregulated in ALS-patients (Junctional Adhesion Molecule A Protein, Tumor necrosis factor receptor 2 and Chitinase 1) while myoglobin was down-regulated. In CSF-EVs, no significantly differentially expressed proteins were identified, but there was a trend for downregulation of Perlecan. To our knowledge, only CHIT1 has been previously described as a CSF-based biomarker candidate for ALS. By combining the four differentially expressed markers in CSF and support vector machine algorithm, all ALS patients and 8 of 9 controls were correctly classified. In conclusion, we here demonstrate the feasibility of using PEA of CSF and CSF-EVs for biomarker discovery and propose three de novo biomarker candidates for ALS, however, further studies are necessary to demonstrate clinical usability.}, }
@article {pmid35567447, year = {2022}, author = {Akiyama, T and Koike, Y and Petrucelli, L and Gitler, AD}, title = {Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers.}, journal = {Clinical and translational medicine}, volume = {12}, number = {5}, pages = {e818}, pmid = {35567447}, issn = {2001-1326}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R35 NS097263/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; T32 AG047126/AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism ; Biomarkers ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/diagnosis/genetics/metabolism ; Humans ; *Pick Disease of the Brain ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating human neurodegenerative diseases. A hallmark pathological feature of both diseases is the depletion of the RNA-binding protein TDP-43 from the nucleus in the brain and spinal cord of patients. A major function of TDP-43 is to repress the inclusion of cryptic exons during RNA splicing. When it becomes depleted from the nucleus in disease, this function is lost, and recently, several key cryptic splicing targets of TDP-43 have emerged, including STMN2, UNC13A, and others. UNC13A is a major ALS/FTD risk gene, and the genetic variations that increase the risk for disease seem to do so by making the gene more susceptible to cryptic exon inclusion when TDP-43 function is impaired. Here, we discuss the prospects and challenges of harnessing these cryptic splicing events as novel therapeutic targets and biomarkers. Deciphering this new cryptic code may be a touchstone for ALS and FTD diagnosis and treatment.}, }
@article {pmid35565972, year = {2022}, author = {Das, BC and Nandwana, NK and Das, S and Nandwana, V and Shareef, MA and Das, Y and Saito, M and Weiss, LM and Almaguel, F and Hosmane, NS and Evans, T}, title = {Boron Chemicals in Drug Discovery and Development: Synthesis and Medicinal Perspective.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {9}, pages = {}, pmid = {35565972}, issn = {1420-3049}, support = {R01 AI132614/AI/NIAID NIH HHS/United States ; R01 NS109423/NS/NINDS NIH HHS/United States ; R21 AA027374/AA/NIAAA NIH HHS/United States ; R01AI132614-01A1, R21 AA027374-01, 1R01NS109423-01A1/NH/NIH HHS/United States ; }, mesh = {*Boranes ; *Boron/chemistry ; Boron Compounds/chemistry ; Bortezomib ; Drug Discovery ; Enzyme Inhibitors/pharmacology ; Humans ; }, abstract = {A standard goal of medicinal chemists has been to discover efficient and potent drug candidates with specific enzyme-inhibitor abilities. In this regard, boron-based bioactive compounds have provided amphiphilic properties to facilitate interaction with protein targets. Indeed, the spectrum of boron-based entities as drug candidates against many diseases has grown tremendously since the first clinically tested boron-based drug, Velcade. In this review, we collectively represent the current boron-containing drug candidates, boron-containing retinoids, benzoxaboroles, aminoboronic acid, carboranes, and BODIPY, for the treatment of different human diseases.In addition, we also describe the synthesis, key structure-activity relationship, and associated biological activities, such as antimicrobial, antituberculosis, antitumor, antiparasitic, antiprotozoal, anti-inflammatory, antifolate, antidepressant, antiallergic, anesthetic, and anti-Alzheimer's agents, as well as proteasome and lipogenic inhibitors. This compilation could be very useful in the exploration of novel boron-derived compounds against different diseases, with promising efficacy and lesser side effects.}, }
@article {pmid35563884, year = {2022}, author = {Kasindi, A and Fuchs, DT and Koronyo, Y and Rentsendorj, A and Black, KL and Koronyo-Hamaoui, M}, title = {Glatiramer Acetate Immunomodulation: Evidence of Neuroprotection and Cognitive Preservation.}, journal = {Cells}, volume = {11}, number = {9}, pages = {}, pmid = {35563884}, issn = {2073-4409}, support = {R01 AG055865/AG/NIA NIH HHS/United States ; R01 AG056478/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Cognition ; *Encephalomyelitis, Autoimmune, Experimental ; Glatiramer Acetate/pharmacology/therapeutic use ; Humans ; Immunomodulation ; *Neuroprotection ; Randomized Controlled Trials as Topic ; }, abstract = {Novel, neuroprotective uses of Copaxone (generic name: glatiramer acetate-GA) are being examined, primarily in neurological conditions involving cognitive decline. GA is a well-studied synthetic copolymer that is FDA-approved for immune-based treatment of relapsing remitting multiple sclerosis (RRMS). Clinical studies have explored the potential mechanism of action (MOA) and outcomes of GA immunization in patients. Furthermore, results from these and animal studies suggest that GA has a direct immunomodulatory effect on adaptive and innate immune cell phenotypes and responses. These MOAs have been postulated to have a common neuroprotective impact in several neuroinflammatory and neurodegenerative diseases. Notably, several clinical studies report that the use of GA mitigated MS-associated cognitive decline. Its propensity to ameliorate neuro-proinflammatory and degenerative processes ignites increased interest in potential alternate uses such as in age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD). Preclinical studies are exploring less frequent subcutaneous administration of GA, such as once weekly or monthly or a single dosing regimen. Indeed, cognitive functions were found to be either preserved, reversed, or improved after the less frequent treatment regimens with GA in animal models of AD. In this systematic review, we examine the potential novel uses of GA across clinical and pre-clinical studies, with evidence for its beneficial impact on cognition. Future investigation in large-size, double-blind clinical trials is warranted to establish the impact of GA immunomodulation on neuroprotection and cognitive preservation in various neurological conditions.}, }
@article {pmid35563001, year = {2022}, author = {Doroszkiewicz, J and Groblewska, M and Mroczko, B}, title = {Molecular Biomarkers and Their Implications for the Early Diagnosis of Selected Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {9}, pages = {}, pmid = {35563001}, issn = {1422-0067}, support = {SUB/1/DN/22/005/1198, SUB/1/DN/22/003/1198//Medical University of Bia&#x142;ystok/ ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis ; Biomarkers ; Disease Progression ; Early Diagnosis ; *Exosomes/genetics ; Humans ; *MicroRNAs/genetics ; *Neurodegenerative Diseases/diagnosis/genetics ; }, abstract = {The degeneration and dysfunction of neurons are key features of neurodegenerative diseases (NDs). Currently, one of the main challenges facing researchers and clinicians is the ability to obtain reliable diagnostic tools that will allow for the diagnosis of NDs as early as possible and the detection of neuronal dysfunction, preferably in the presymptomatic stage. Additionally, better tools for assessing disease progression in this group of disorders are also being sought. The ideal biomarker must have high sensitivity and specificity, be easy to measure, give reproducible results, and reflect the disease progression. Molecular biomarkers include miRNAs and extracellular microvesicles known as exosomes. They may be measured in two extracellular fluids of the highest importance in NDs, i.e., cerebrospinal fluid (CSF) and blood. The aim of the current review is to summarize the pathophysiology of the four most frequent NDs-i.e., Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)-as well as current progress in the research into miRNAs as biomarkers in these major neurodegenerative diseases. In addition, we discuss the possibility of using miRNA-based therapies in the treatment of neurodegenerative diseases, and present the limitations of this type of therapy.}, }
@article {pmid35551085, year = {2022}, author = {Vandenbogaerde, I and Miranda, R and De Bleecker, JL and Carduff, E and van der Heide, A and Van den Block, L and Deliens, L and De Vleminck, A}, title = {Advance care planning in amyotrophic lateral sclerosis (ALS): study protocol for a qualitative longitudinal study with persons with ALS and their family carers.}, journal = {BMJ open}, volume = {12}, number = {5}, pages = {e060451}, pmid = {35551085}, issn = {2044-6055}, mesh = {*Advance Care Planning ; *Amyotrophic Lateral Sclerosis/therapy ; Caregivers/psychology ; Humans ; Longitudinal Studies ; Qualitative Research ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron degenerative disease that has rapid progression and is associated with cognitive impairment. For people with ALS (pALS) and their family carers, advance care planning (ACP) is beneficial, as it can lead to feelings of control/relief and refusal of unwanted treatments. However, evidence concerning the experiences and preferences regarding ACP of pALS and their family carers, especially when their symptoms progress, is scarce. This article describes the protocol for a qualitative longitudinal study that aims to explore: (1) the experiences with ACP and the preferences for future care and treatment of pALS and their family carers and (2) how these experiences and preferences change over time.<br><br>METHODS AND ANALYSIS: A qualitative, longitudinal, multiperspective design. A total of eight to nine dyads (pALS and their family carers) will be recruited, and semistructured interviews administered every 3 months over a 9-month period. Qualitative longitudinal analysis involves content analysis via in-depth reading, followed by a two-step timeline method to describe changes in experiences and preferences within and across participants.<br><br>ETHICS AND DISSEMINATION: This protocol has been approved by the central ethical committee of the University Hospital of Brussels, and local ethical committees of the other participating hospitals (B.U.N. B1432020000128). The results will be disseminated via the research group's (endoflifecare.be) website, social media and newsletter and via presentations at national and international scientific conferences.}, }
@article {pmid35550203, year = {2022}, author = {Westerhaus, A and Joseph, T and Meyers, AJ and Jang, Y and Na, CH and Cave, C and Sockanathan, S}, title = {The distribution and function of GDE2, a regulator of spinal motor neuron survival, are disrupted in Amyotrophic Lateral Sclerosis.}, journal = {Acta neuropathologica communications}, volume = {10}, number = {1}, pages = {73}, pmid = {35550203}, issn = {2051-5960}, support = {F31 AG072745/AG/NIA NIH HHS/United States ; R01 AG068043/AG/NIA NIH HHS/United States ; T32 GM007445/GM/NIGMS NIH HHS/United States ; S10 OD021844/OD/NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Animals ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism ; *Neurodegenerative Diseases/pathology ; Spinal Cord/pathology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the viability of upper and lower motor neurons. Current options for treatment are limited, necessitating deeper understanding of the mechanisms underlying ALS pathogenesis. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a six-transmembrane protein that acts on the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers some proteins to the membrane. GDE2 is required for the survival of spinal motor neurons but whether GDE2 neuroprotective activity is disrupted in ALS is not known. We utilized a combination of mouse models and patient post-mortem samples to evaluate GDE2 functionality in ALS. Haplogenetic reduction of GDE2 exacerbated motor neuron degeneration and loss in SOD1[G93A] mice but not in control SOD1[WT] transgenic animals, indicating that GDE2 neuroprotective function is diminished in the context of SOD1[G93A]. In tissue samples from patients with ALS, total levels of GDE2 protein were equivalent to healthy controls; however, membrane levels of GDE2 were substantially reduced. Indeed, GDE2 was found to aberrantly accumulate in intracellular compartments of ALS motor cortex, consistent with a disruption of GDE2 function at the cell surface. Supporting the impairment of GDE2 activity in ALS, tandem-mass-tag mass spectrometry revealed a pronounced reduction of GPI-anchored proteins released into the CSF of patients with ALS compared with control patients. Taken together, this study provides cellular and biochemical evidence that GDE2 distribution and activity is disrupted in ALS, supporting the notion that the failure of GDE2-dependent neuroprotective pathways contributes to neurodegeneration and motor neuron loss in disease. These observations highlight the dysregulation of GPI-anchored protein pathways as candidate mediators of disease onset and progression and accordingly, provide new insight into the mechanisms underlying ALS pathogenesis.}, }
@article {pmid35543124, year = {2023}, author = {Oudman, E and Baert, JCM}, title = {Eye movement desensitization and reprocessing (EMDR) and mediative behavioral therapy for the treatment of suffocation related post-traumatic stress disorder (PTSD) in amyotrophic lateral sclerosis (ALS): A case report.}, journal = {Palliative &amp; supportive care}, volume = {21}, number = {1}, pages = {181-183}, doi = {10.1017/S1478951522000542}, pmid = {35543124}, issn = {1478-9523}, mesh = {Female ; Humans ; Middle Aged ; *Stress Disorders, Post-Traumatic ; *Eye Movement Desensitization Reprocessing/methods ; *Amyotrophic Lateral Sclerosis ; Asphyxia ; Eye Movements ; Treatment Outcome ; }, abstract = {OBJECTIVE: Eye movement desensitization and reprocessing (EMDR) is an established treatment for post-traumatic stress disorders (PTSD). Some patients diagnosed with amyotrophic lateral sclerosis (ALS) experience PTSD following choking or suffocation in the course of progressive loss of the ability to breathe. Although a loss of breathing functions in ALS is relatively common, there are currently no studies available on treatment for the fear of choking following advanced ALS.<br><br>METHODS: In this case study, we describe the positive effects of EMDR, an evidence-based form of trauma therapy, in a 48-year-old female, suffering from advanced ALS. As the consequence of ALS, she was not able to speak or breath independently, but could communicate through a speech-generating device. She experienced panic attacks, flashbacks, nightmares, and severe anxiety after her tracheostomy jammed, and she almost suffocated.<br><br>RESULTS: Mediative treatment was started by instructing the care staff to respond neutrally with step-by-step instructions following tracheostomy jam, resulting in significantly less panic attacks and flashbacks. EMDR was initiated two weeks later, and resulted in full remittance of the trauma symptomatology.<br><br>SIGNIFICANCE OF THE RESULTS: The present case study suggests that symptoms of PTSD, namely the strong fear of suffocation, can be successfully treated by means of mediative behavioral therapy combined with EMDR.}, }
@article {pmid35538301, year = {2022}, author = {Iida, T and Yanai, K and Yoshikawa, T}, title = {Histamine and Microglia.}, journal = {Current topics in behavioral neurosciences}, volume = {59}, number = {}, pages = {241-259}, pmid = {35538301}, issn = {1866-3370}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Brain/metabolism ; Cytokines/metabolism ; *Histamine/metabolism/pharmacology/therapeutic use ; Humans ; *Microglia ; }, abstract = {Microglia, a category of glial cells in the central nervous system (CNS), have attracted much attention because of their important role in neuroinflammation. Many translational studies are currently ongoing to discover novel drugs targeting microglia for the treatment of various CNS disorders, such as Alzheimer's disease, Parkinson's disease (PD), and depression. Recent studies have shown that brain histamine, a neurotransmitter essential for the regulation of diverse brain functions, controls glial cells and neurons. In vitro studies using primary microglia and microglial cell lines have reported that histamine receptors are expressed in microglia and control microglial functions, including chemotaxis, migration, cytokine secretion, and autophagy. In vivo studies have demonstrated that histamine-related reagents could ameliorate abnormal symptoms in animal models of human diseases, such as amyotrophic lateral sclerosis (ALS), PD, and brain ischemia. Several human studies have revealed alterations in histamine receptor levels in ALS and PD, emphasizing the importance of the CNS histamine system, including histamine-dependent microglial modulation, as a therapeutic target for these disorders. In this review article, we summarize histamine-related research focusing on microglial functions.}, }
@article {pmid35532908, year = {2022}, author = {Oki, R and Izumi, Y and Fujita, K and Miyamoto, R and Nodera, H and Sato, Y and Sakaguchi, S and Nokihara, H and Kanai, K and Tsunemi, T and Hattori, N and Hatanaka, Y and Sonoo, M and Atsuta, N and Sobue, G and Shimizu, T and Shibuya, K and Ikeda, K and Kano, O and Nishinaka, K and Kojima, Y and Oda, M and Komai, K and Kikuchi, H and Kohara, N and Urushitani, M and Nakayama, Y and Ito, H and Nagai, M and Nishiyama, K and Kuzume, D and Shimohama, S and Shimohata, T and Abe, K and Ishihara, T and Onodera, O and Isose, S and Araki, N and Morita, M and Noda, K and Toda, T and Maruyama, H and Furuya, H and Teramukai, S and Kagimura, T and Noma, K and Yanagawa, H and Kuwabara, S and Kaji, R and , }, title = {Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {79}, number = {6}, pages = {575-583}, pmid = {35532908}, issn = {2168-6157}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Double-Blind Method ; Humans ; Male ; Middle Aged ; Treatment Outcome ; Vital Capacity ; Vitamin B 12/analogs &amp; derivatives/therapeutic use ; }, abstract = {IMPORTANCE: The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent.<br><br>OBJECTIVE: To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset.<br><br>This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo.<br><br>INTERVENTIONS: Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks.<br><br>MAIN OUTCOMES AND MEASURES: The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set.<br><br>RESULTS: A total of 130 patients (mean [SD] age, 61.0&#x2009;[11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P&#x2009;=&#x2009;.01). The incidence of adverse events was similar between the 2 groups.<br><br>CONCLUSIONS AND RELEVANCE: Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03548311.}, }
@article {pmid35524757, year = {2022}, author = {Neel, DV and Basu, H and Gunner, G and Chiu, IM}, title = {Catching a killer: Mechanisms of programmed cell death and immune activation in Amyotrophic Lateral Sclerosis.}, journal = {Immunological reviews}, volume = {311}, number = {1}, pages = {130-150}, pmid = {35524757}, issn = {1600-065X}, support = {R01 AI130019/AI/NIAID NIH HHS/United States ; R01 DK127257/DK/NIDDK NIH HHS/United States ; T32 GM007753/GM/NIGMS NIH HHS/United States ; T32 GM144273/GM/NIGMS NIH HHS/United States ; }, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/metabolism/therapy ; Apoptosis ; Humans ; Inflammation/metabolism ; Motor Neurons/metabolism ; Necrosis/metabolism ; }, abstract = {In the central nervous system (CNS), execution of programmed cell death (PCD) is crucial for proper neurodevelopment. However, aberrant activation of these pathways in adult CNS leads to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). How a cell dies is critical, as it can drive local immune activation and tissue damage. Classical apoptosis engages several mechanisms to evoke "immunologically silent" responses, whereas other forms of programmed death such as pyroptosis, necroptosis, and ferroptosis release molecules that can potentiate immune responses and inflammation. In ALS, a fatal neuromuscular disorder marked by progressive death of lower and upper motor neurons, several cell types in the CNS express machinery for multiple PCD pathways. The specific cell types engaging PCD, and ultimate mechanisms by which neuronal death occurs in ALS are not well defined. Here, we provide an overview of different PCD pathways implicated in ALS. We also examine immune activation in ALS and differentiate apoptosis from necrotic mechanisms based on downstream immunological consequences. Lastly, we highlight therapeutic strategies that target cell death pathways in the treatment of neurodegeneration and inflammation in ALS.}, }
@article {pmid35523814, year = {2022}, author = {Nouri Barkestani, M and Naserian, S and Khoddam, F and Shamdani, S and Bambai, B}, title = {Optimization of IL-1RA structure to achieve a smaller protein with a higher affinity to its receptor.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {7483}, pmid = {35523814}, issn = {2045-2322}, mesh = {*Arthritis, Rheumatoid ; Humans ; Inflammation/metabolism ; *Interleukin 1 Receptor Antagonist Protein/pharmacology ; Ligands ; Signal Transduction ; }, abstract = {Interleukine-1 family cytokines are key orchestrators of innate and adaptive immunity. In particular, up-regulation of IL-1R1 via its agonistic ligands consisting of IL-1β and IL-1α is implicated in a variety of human diseases, such as rheumatoid arthritis, psoriasis, type I diabetes, amyotrophic lateral sclerosis, and dry-eye disease. Until now, there are no small-molecule inhibitors of the IL-1R1 with increased antagonistic potency to be used for the treatment of peripheral inflammation. The objective of this study was to engineer a low-molecular-weight version of IL-1RA with increased affinity and enhanced antagonistic activity for potential therapeutic use. To develop a smaller protein-ligand with a better affinity to IL-1R, we used bioinformatics studies and in silico simulations to anticipate non-binding areas on IL-1RA. In this study, we have identified a 41aa (F57-F98) non-binding site of IL-1RA. Overall RMSF of the Truncated complex (1.5 nm) was lower than the Native complex (2 nm), which could prove higher stability of the Truncated complex. The free binding energy of the T-IL-1RA (- 1087.037 kJ/mol) was significantly lower than the IL-1RA (- 836.819 kJ/mol) which could demonstrate a higher binding affinity of the truncated ligand with its receptor as a result of new important interactions. These findings have demonstrated a higher binding affinity of the T-IL-1RA with its receptor than the native protein. These results should: have an impact on the development of new treatments that block IL-1 signaling, although more research is needed in vitro and in vivo.}, }
@article {pmid35510537, year = {2023}, author = {Pinto, S and Gromicho, M and Oliveira Santos, MO and Swash, M and De Carvalho, M}, title = {Respiratory onset in amyotrophic lateral sclerosis: clinical features and spreading pattern.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {1-2}, pages = {40-44}, doi = {10.1080/21678421.2022.2067777}, pmid = {35510537}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Noninvasive Ventilation ; Respiration, Artificial ; Respiratory Function Tests ; *Respiratory Insufficiency/therapy ; Disease Progression ; }, abstract = {Objective To describe the clinical features and progression of patients with respiratory onset amyotrophic lateral sclerosis (ALS). Methods: We analyzed the clinical features, including respiratory tests, functional score, noninvasive ventilation (NIV) time and survival of ALS patients with respiratory-onset in our database consisting of 1688 patients. In a subset of 625 ALS patients we analyzed the spreading pattern to other bodily regions. Results: We included 1579 patients with ALS. Sixty-three patients (4%) presented respiratory-onset (79.4% men, mean onset-age 67.7 ± 8.9yrs). All had predominant LMN involvement, and significant weight loss (>10%) was identified in 38.9%. The respiratory tests were abnormal in these respiratory-onset patients (p < 0.001). ALSFRS-R respiratory subscore was lower in this population (p < 0.001). NIV was adapted in 84.1%, sooner than in the larger group of ALS patients (p < 0.001), and survival from disease onset was shorter (p < 0.001). Respiratory-onset was a predictor of time to NIV (X[2]=42.0, p < 0.001) and of survival (X[2]=7.1, p = 0.008). The spreading pattern was studied in 18 patients with isolated respiratory-onset. The progression interval to the 2nd region was 4.7 ± 5.7mo and to a 3rd region 6.1 ± 8.7mo. Different patterns of spread had no impact on survival. Conclusions: This phenotype is typically seen in emaciated older men with predominant lower motor neuron involvement, and is associated with diaphragm paresis and central respiratory involvement. NIV adaptation is rapid but total survival is shorter than in the other patients. Spreading pattern did not affect time to NIV adaptation or total survival, as NIV support is a modifying treatment in the course of ALS.}, }
@article {pmid35508892, year = {2022}, author = {Paganoni, S and Watkins, C and Cawson, M and Hendrix, S and Dickson, SP and Knowlton, N and Timmons, J and Manuel, M and Cudkowicz, M}, title = {Survival analyses from the CENTAUR trial in amyotrophic lateral sclerosis: Evaluating the impact of treatment crossover on outcomes.}, journal = {Muscle &amp; nerve}, volume = {66}, number = {2}, pages = {136-141}, pmid = {35508892}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Cross-Over Studies ; Double-Blind Method ; Humans ; Survival Analysis ; }, abstract = {INTRODUCTION/AIMS: Trials incorporating placebo-to-active treatment crossover are encouraged in fatal conditions like amyotrophic lateral sclerosis (ALS) but may underestimate active treatment survival benefit. Here, we apply methods for modeling survival without crossover, including the rank-preserving structural failure time model (RPSFTM), to data from the CENTAUR trial of sodium phenylbutyrate and taurursodiol (PB and TURSO) in ALS incorporating both randomized placebo-controlled and open-label extension (OLE) phases.<br><br>METHODS: Intent-to-treat (ITT) and RPSFTM survival analyses were performed with final data at a July 2020 cutoff date. Analyses of subgroups based on randomized treatment and OLE phase participation were also performed.<br><br>RESULTS: Hazard ratios (95% confidence intervals) of death for PB and TURSO versus participants initially on placebo were 0.57 (0.35-0.92) on ITT analysis and 0.39 (0.17-0.88) in the primary on-treatment RPSFTM analysis (p&#xa0;=&#xa0;.023). Median ITT survival duration for PB and TURSO (25.8&#xa0;mo) was 6.9&#xa0;mo longer than placebo (18.9&#xa0;mo) on ITT analysis and 10.6&#xa0;mo longer than the median RPSFTM-adjusted survival duration for placebo (15.2&#xa0;mo). Median survival duration was 18.8&#xa0;mo longer in the PB and TURSO-randomized subgroup who continued into the OLE phase versus the placebo-randomized subgroup who did not continue into the OLE phase (p&#x2009;<&#x2009;.0001), although OLE phase selection bias may have potentially confounded these results.<br><br>DISCUSSION: Similar to the prespecified ITT analysis, post hoc analyses adjusting for treatment crossover in CENTAUR showed a significant survival benefit for PB and TURSO. Such methods may provide clinical context for observed survival outcomes in future ALS crossover trials.}, }
@article {pmid35507432, year = {2023}, author = {Wang, SM and Wu, HE and Yasui, Y and Geva, M and Hayden, M and Maurice, T and Cozzolino, M and Su, TP}, title = {Nucleoporin POM121 signals TFEB-mediated autophagy via activation of SIGMAR1/sigma-1 receptor chaperone by pridopidine.}, journal = {Autophagy}, volume = {19}, number = {1}, pages = {126-151}, pmid = {35507432}, issn = {1554-8635}, support = {K02 DA000206/DA/NIDA NIH HHS/United States ; Z01 DA000206/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; *Autophagy/genetics ; C9orf72 Protein/genetics ; *Frontotemporal Dementia/genetics ; Heat-Shock Proteins/metabolism ; *Membrane Proteins/genetics ; Nuclear Pore Complex Proteins ; *Receptors, sigma/metabolism ; Sigma-1 Receptor ; Transcription Factors/metabolism ; Cell Line ; }, abstract = {Macroautophagy/autophagy is an essential process for cellular survival and is implicated in many diseases. A critical step in autophagy is the transport of the transcription factor TFEB from the cytosol into the nucleus, through the nuclear pore (NP) by KPNB1/importinβ1. In the C9orf72 subtype of amyotrophic lateral sclerosis-frontotemporal lobar degeneration (ALS-FTD), the hexanucleotide (G4C2)RNA expansion (HRE) disrupts the nucleocytoplasmic transport of TFEB, compromising autophagy. Here we show that a molecular chaperone, the SIGMAR1/Sigma-1 receptor (sigma non-opioid intracellular receptor 1), facilitates TFEB transport into the nucleus by chaperoning the NP protein (i.e., nucleoporin) POM121 which recruits KPNB1. In NSC34 cells, HRE reduces TFEB transport by interfering with the association between SIGMAR1 and POM121, resulting in reduced nuclear levels of TFEB, KPNB1, and the autophagy marker LC3-II. Overexpression of SIGMAR1 or POM121, or treatment with the highly selective and potent SIGMAR1 agonist pridopidine, currently in phase 2/3 clinical trials for ALS and Huntington disease, rescues all of these deficits. Our results implicate nucleoporin POM121 not merely as a structural nucleoporin, but also as a chaperone-operated signaling molecule enabling TFEB-mediated autophagy. Our data suggest the use of SIGMAR1 agonists, such as pridopidine, for therapeutic development of diseases in which autophagy is impaired.Abbreviations: ALS-FTD, amyotrophic lateral sclerosis-frontotemporal dementiaC9ALS-FTD, C9orf72 subtype of amyotrophic lateral sclerosis-frontotemporal dementiaCS, citrate synthaseER, endoplasmic reticulumGSS, glutathione synthetaseHRE, hexanucleotide repeat expansionHSPA5/BiP, heat shock protein 5LAMP1, lysosomal-associated membrane protein 1MAM, mitochondria-associated endoplasmic reticulum membraneMAP1LC3/LC3, microtubule-associated protein 1 light chain 3NP, nuclear poreNSC34, mouse motor neuron-like hybrid cell lineNUPs, nucleoporinsPOM121, nuclear pore membrane protein 121SIGMAR1/Sigma-1R, sigma non-opioid intracellular receptor 1TFEB, transcription factor EBTMEM97/Sigma-2R, transmembrane protein 97.}, }
@article {pmid35501630, year = {2022}, author = {Bai, Y and Treins, C and Volpi, VG and Scapin, C and Ferri, C and Mastrangelo, R and Touvier, T and Florio, F and Bianchi, F and Del Carro, U and Baas, FF and Wang, D and Miniou, P and Guedat, P and Shy, ME and D'Antonio, M}, title = {Treatment with IFB-088 Improves Neuropathy in CMT1A and CMT1B Mice.}, journal = {Molecular neurobiology}, volume = {59}, number = {7}, pages = {4159-4178}, pmid = {35501630}, issn = {1559-1182}, mesh = {Animals ; *Charcot-Marie-Tooth Disease/drug therapy/genetics/metabolism ; Disease Models, Animal ; Eukaryotic Initiation Factor-2/metabolism ; Humans ; Mice ; Myelin Sheath/metabolism ; Schwann Cells/metabolism ; Unfolded Protein Response ; }, abstract = {Charcot-Marie-Tooth disease type 1A (CMT1A), caused by duplication of the peripheral myelin protein 22 (PMP22) gene, and CMT1B, caused by mutations in myelin protein zero (MPZ) gene, are the two most common forms of demyelinating CMT (CMT1), and no treatments are available for either. Prior studies of the MpzSer63del mouse model of CMT1B have demonstrated that protein misfolding, endoplasmic reticulum (ER) retention and activation of the unfolded protein response (UPR) contributed to the neuropathy. Heterozygous patients with an arginine to cysteine mutation in MPZ (MPZR98C) develop a severe infantile form of CMT1B which is modelled by MpzR98C/ + mice that also show ER stress and an activated UPR. C3-PMP22 mice are considered to effectively model CMT1A. Altered proteostasis, ER stress and activation of the UPR have been demonstrated in mice carrying Pmp22 mutations. To determine whether enabling the ER stress/UPR and readjusting protein homeostasis would effectively treat these models of CMT1B and CMT1A, we administered Sephin1/IFB-088/icerguestat, a UPR modulator which showed efficacy in the MpzS63del model of CMT1B, to heterozygous MpzR98C and C3-PMP22 mice. Mice were analysed by behavioural, neurophysiological, morphological and biochemical measures. Both MpzR98C/ + and C3-PMP22 mice improved in motor function and neurophysiology. Myelination, as demonstrated by g-ratios and myelin thickness, improved in CMT1B and CMT1A mice and markers of UPR activation returned towards wild-type values. Taken together, our results demonstrate the capability of IFB-088 to treat a second mouse model of CMT1B and a mouse model of CMT1A, the most common form of CMT. Given the recent benefits of IFB-088 treatment in amyotrophic lateral sclerosis and multiple sclerosis animal models, these data demonstrate its potential in managing UPR and ER stress for multiple mutations in CMT1 as well as in other neurodegenerative diseases. (Left panel) the accumulation of overexpressed PMP22 or misfolded mutant P0 in the Schwann cell endoplasmic reticulum (ER) leads to overwhelming of the degradative capacity, activation of ER-stress mechanisms, and myelination impairment. (Right panel) by prolonging eIF2α phosphorylation, IFB-088 reduces the amount of newly synthesized proteins entering the ER, allowing the protein quality control systems to better cope with the unfolded/misfolded protein and allowing myelination to progress.}, }
@article {pmid35496270, year = {2022}, author = {Barbato, G and Nisticò, R and Triaca, V}, title = {Exploiting Focused Ultrasound to Aid Intranasal Drug Delivery for Brain Therapy.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {786475}, pmid = {35496270}, issn = {1663-9812}, abstract = {Novel effective therapeutic strategies are needed to treat brain neurodegenerative diseases and to improve the quality of life of patients affected by Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral sclerosis (ALS) as well as other brain conditions. At present no effective treatment options are available; current therapeutics for neurodegenerative diseases (NDs) improve cognitive symptoms only transiently and in a minor number of patients. Further, most of the amyloid-based phase III clinical trials recently failed in AD, in spite of promising preclinical and phase I-II clinical trials, further pinpointing the need for a better knowledge of the early mechanisms of disease as well as of more effective routes of drug administration. In fact, beyond common pathological events and molecular substrates, each of these diseases preferentially affect defined subpopulations of neurons in specific neuronal circuits (selective neuronal vulnerability), leading to the typical age-related clinical profile. In this perspective, key to successful drug discovery is a robust and reproducible biological validation of potential new molecular targets together with a concomitant set up of protocols/tools for efficient and targeted brain delivery to a specific area of interest. Here we propose and discuss Focused UltraSound aided drug administration as a specific and novel technical approach to achieve optimal concentration of the drug at the target area of interest. We will focus on drug delivery to the brain through the nasal route coupled to FUS as a promising approach to achieve neuroprotection and rescue of cognitive decline in several NDs.}, }
@article {pmid35490234, year = {2022}, author = {Salzmann, L and Alt-Epping, B and Simon, A}, title = {Palliative sedation in amyotrophic lateral sclerosis: results of a nationwide survey among neurologists and palliative care practitioners in Germany.}, journal = {BMC neurology}, volume = {22}, number = {1}, pages = {161}, pmid = {35490234}, issn = {1471-2377}, mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis/therapy ; Germany/epidemiology ; Humans ; Neurologists ; *Palliative Care/methods/psychology ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Palliative sedation has become widely accepted as a method to alleviate refractory symptoms in terminally ill patients. Controversies regarding this topic especially concern the use of palliative sedation for psychological symptoms, the use in patients who are not imminently dying and the simultaneous withdrawal of life-sustaining measures. Amyotrophic lateral sclerosis (ALS) is characterized by symptoms including muscle weakness, dysphagia, dysarthria, muscle spasms and progressive respiratory insufficiency. Due to these characteristic symptoms, palliative sedation might be considered to be necessary to alleviate refractory suffering in ALS patients. However, palliative sedation in ALS is only rarely discussed in current medical literature and guidelines.<br><br>METHODS: A questionnaire survey was conducted among neurologists and palliative care practitioners in Germany. The participants were asked to evaluate the use of palliative sedation in different situations.<br><br>RESULTS: Two hundred and ninety-six completed questionnaires were analyzed. The results suggest high levels of support for the use of palliative sedation in ALS patients. 42% of the participants stated that they had already used palliative sedation in the treatment of ALS patients. Acceptance of palliative sedation was higher in case of physical symptoms than in case of psychological symptoms. Refusal of artificial nutrition did not lead to a lower acceptance of palliative sedation. Doctors with specialist training in palliative care had already used palliative sedation in ALS patients more often and they were more likely to accept palliative sedation in different situations than the participants without a background in palliative care.<br><br>CONCLUSION: Our survey showed that palliative sedation in ALS is widely accepted by the attending doctors. In case of psychological symptoms, palliative sedation is looked at with more concern than in case of physical symptoms. The refusal of artificial nutrition does not result in a decreased acceptance of palliative sedation. Doctors with specialist training in palliative care are more likely to approve of palliative sedation in ALS.}, }
@article {pmid35485374, year = {2022}, author = {Vázquez Polo, A and López Briz, E and Poveda Andrés, JL and Vázquez Costa, JF}, title = {[Handling of drugs for administration by percutaneous endoscopic gastrostomy in patients with amyotrophic lateral sclerosis and enteral nutrition].}, journal = {Nutricion hospitalaria}, volume = {39}, number = {4}, pages = {716-722}, doi = {10.20960/nh.03946}, pmid = {35485374}, issn = {1699-5198}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Enteral Nutrition ; Gastrostomy ; Humans ; *Neurodegenerative Diseases ; Pharmaceutical Preparations ; }, abstract = {Introduction: amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. Its symptoms include dysphagia that may make it necessary to place a percutaneous endoscopic gastrostomy (PEG) for feeding. The administration of drugs by PEG can obstruct it, decrease the effectiveness of treatment, and increase the risk of toxicity by altering the original pharmaceutical form. Objective: to describe and analyze the degree of adequacy of the prescription of drugs administered by PEG in patients with ALS and with enteral nutrition (EN). Material and methods: the prescription of pharmacological treatment for patients with ALS who were admitted for placement of a PEG was reviewed. The degree of adequacy of the prescribed drugs was analyzed according to criteria of loss of efficacy, toxicity, risk for handler, and compatibility with EN by consulting the available scientific evidence. Results: the medical prescriptions of the treatments of 34 patients were reviewed, with a total of 307 medications (median of 9 drugs per patient, range 2-17). Via PEG 267 oral medications (median 8 per patient, range 2-15) were prescribed; 81.65 % were solid forms, and the pharmaceutical form was modified in 43 %, due to the risk of catheter occlusion, toxicity or loss of efficacy, affecting 97 % of the patients. Conclusions: patients with ALS and PEG are at risk of presenting safety problems and loss of treatment efficacy related to alteration of the original pharmaceutical form and the interaction with EN.}, }
@article {pmid35482908, year = {2022}, author = {Holm, A and Hansen, SN and Klitgaard, H and Kauppinen, S}, title = {Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases.}, journal = {RNA biology}, volume = {19}, number = {1}, pages = {594-608}, pmid = {35482908}, issn = {1555-8584}, mesh = {Animals ; Amyloid Neuropathies, Familial ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Neuromuscular Diseases/genetics/therapy ; Oligonucleotides, Antisense/genetics/therapeutic use ; Quality of Life ; RNA, Messenger/genetics/therapeutic use ; RNA, Small Interfering/genetics/therapeutic use ; United States ; *Genetic Therapy/methods/trends ; Humans ; Disease Models, Animal ; }, abstract = {RNA therapeutics comprise a diverse group of oligonucleotide-based drugs such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs) that can be designed to selectively interact with drug targets currently undruggable with small molecule-based drugs or monoclonal antibodies. Furthermore, RNA-based therapeutics have the potential to modulate entire disease pathways, and thereby represent a new modality with unprecedented potential for generating disease-modifying drugs for a wide variety of human diseases, including central nervous system (CNS) disorders. Here, we describe different strategies for delivering RNA drugs to the CNS and review recent advances in clinical development of ASO drugs and siRNA-based therapeutics for the treatment of neurological diseases and neuromuscular disorders.Abbreviations 2'-MOE: 2'-O-(2-methoxyethyl); 2'-O-Me: 2'-O-methyl; 2'-F: 2'-fluoro; AD: Alzheimer's disease; ALS: Amyotrophic lateral sclerosis; ALSFRS-R: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale; ARC: Antibody siRNA Conjugate; AS: Angelman Syndrome; ASGRP: Asialoglycoprotein receptor; ASO: Antisense oligonucleotide; AxD: Alexander Disease; BBB: Blood brain barrier; Bp: Basepair; CNM: Centronuclear myopathies; CNS: Central Nervous System; CPP: Cell-penetrating Peptide; CSF: Cerebrospinal fluid; DMD: Duchenne muscular dystrophy; DNA: Deoxyribonucleic acid; FAP: Familial amyloid polyneuropathy; FALS: Familial amyotrophic lateral sclerosis; FDA: The United States Food and Drug Administration; GalNAc: N-acetylgalactosamine; GoF: Gain of function; hATTR: Hereditary transthyretin amyloidosis; HD: Huntington's disease; HRQOL: health-related quality of life; ICV: Intracerebroventricular; IT: Intrathecal; LNA: Locked nucleic acid; LoF: Loss of function; mRNA: Messenger RNA; MS: Multiple Sclerosis; MSA: Multiple System Atrophy; NBE: New Biological Entity; NCE: New Chemical Entity; NHP: Nonhuman primate; nt: Nucleotide; PD: Parkinson's disease; PNP: Polyneuropathy; PNS: Peripheral nervous system; PS: Phosphorothioate; RISC: RNA-Induced Silencing Complex; RNA: Ribonucleic acid; RNAi: RNA interference; s.c.: Subcutaneous; siRNA: Small interfering RNA; SMA: Spinal muscular atrophy; SMN: Survival motor neuron; TTR: Transthyretin.}, }
@article {pmid35481502, year = {2022}, author = {Hübers, A and Fayolle, D and Ochsner, F and Echaniz-Laguna, A and Magy, L and Vicino, A and Théaudin, M}, title = {[Cramps and fasciculations: is it amyotrophic lateral sclerosis?].}, journal = {Revue medicale suisse}, volume = {18}, number = {779}, pages = {790-793}, doi = {10.53738/REVMED.2022.18.779.790}, pmid = {35481502}, issn = {1660-9379}, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Fasciculation/diagnosis/etiology/therapy ; Humans ; Muscle Cramp ; *Respiratory Insufficiency/etiology/therapy ; Switzerland ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease of the adult age. It is an aggressive condition with a mean disease duration of only 3 to 5 years, characterized by progressive weakness and atrophy of limb, bulbar, and respiratory muscles. In general, death is caused by chronic hypoventilation due to respiratory insufficiency. No causal treatment is known today, but the two therapeutic agents authorized in Switzerland for the treatment of ALS can slow disease progression significantly. Other important therapeutic strategies include invasive/non-invasive ventilation, pain therapy, as well as physio-, ergo- and speech therapy on a regular basis.}, }
@article {pmid35480384, year = {2022}, author = {Andersen, T and Fondenes, O and Røksund, OD and Clemm, H and Halvorsen, T and Vollsæter, M}, title = {From bedside to bench - In vivo and in vitro evaluation of mechanically assisted cough treatment in a patient with bulbar Amyotrophic Lateral Sclerosis.}, journal = {Respiratory medicine case reports}, volume = {37}, number = {}, pages = {101649}, pmid = {35480384}, issn = {2213-0071}, abstract = {When the ability to cough is impaired, secretion clearance may be assisted and augmented by Mechanical Insufflation-Exsufflation (MI-E) treatment. In patients with Amyotrophic Lateral Sclerosis, the efficacy of MI-E may be hampered by counterproductive upper airway responses. Careful adjustment of MI-E settings can be beneficial. During the disease progression, a 41-year-old woman with bulbar Amyotrophic Lateral Sclerosis experienced that treatment with MI-E was exhausting and inefficient. Despite adjustments of settings, all treatment led to retching. A change of MI-E device led to more effective treatment. A bench test revealed variations in flow and pressure waveforms in the two devices. When MI-E treatment fails, differences in equipment delivery need to be considered in addition to the adjustment of MI-E settings.}, }
@article {pmid35472653, year = {2022}, author = {Gerges, ANH and Hordacre, B and Pietro, FD and Moseley, GL and Berryman, C}, title = {Do Adults with Stroke have Altered Interhemispheric Inhibition? A Systematic Review with Meta-Analysis.}, journal = {Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association}, volume = {31}, number = {7}, pages = {106494}, doi = {10.1016/j.jstrokecerebrovasdis.2022.106494}, pmid = {35472653}, issn = {1532-8511}, mesh = {Adult ; *Cerebral Palsy ; Evoked Potentials, Motor/physiology ; Functional Laterality/physiology ; Humans ; *Motor Cortex ; *Stroke/diagnosis/therapy ; *Stroke Rehabilitation/methods ; Transcranial Magnetic Stimulation ; }, abstract = {OBJECTIVE: Interhemispheric inhibition is an important cortical mechanism to support motor control. Altered interhemispheric inhibition has been the target of neuromodulation interventions. This systematic review investigated the evidence for altered interhemispheric inhibition in adults with unilateral neurological conditions: stroke, amyotrophic lateral sclerosis, cerebral palsy, complex regional pain syndrome, traumatic brain injury, and cerebral palsy METHODS: We pre-registered the protocol and followed PRISMA guidelines. Five databases were systematically searched to identify studies reporting interhemispheric inhibition measures in unilateral neurological conditions and healthy controls. Data were grouped according to the measure (ipsilateral silent period and dual-coil), stimulated hemisphere, and stage of the condition (subacute and chronic).<br><br>RESULTS: 1372 studies were identified, of which 14 were included (n&#xa0;=&#xa0;226 adults with stroke and 161 age-matched controls). Ipsilateral silent period-duration was longer in people with stroke than in controls (stimulation of dominant hemisphere) regardless of stroke stage. Motor evoked potential was less suppressed in people with sub-acute stroke (stimulation of the unaffected hemisphere) than controls (stimulation of dominant hemisphere) and this reversed in chronic stroke.<br><br>CONCLUSION: Detection of altered interhemispheric inhibition appears to be dependent on the measure of interhemispheric inhibition and the stage of recovery.<br><br>SIGNIFICANCE: Rebalancing interhemispheric inhibition using neuromodulation is considered a promising line of treatment for stroke rehabilitation. Our results did not find compelling evidence to support consistent alterations in interhemispheric inhibition in adults with stroke.}, }
@article {pmid35469217, year = {2022}, author = {Zheng, X and Schröder, J and Sima, D and Wang, M and Wang, Q and Pan, W}, title = {Amyotrophic Lateral Sclerosis Symptom Score in Integrative Treatments (ALS-SSIT) for Evaluating Therapeutic Effect of Traditional Chinese Medicine: A Prospective Study.}, journal = {Computational and mathematical methods in medicine}, volume = {2022}, number = {}, pages = {7594481}, pmid = {35469217}, issn = {1748-6718}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Medicine, Chinese Traditional ; Prospective Studies ; Reproducibility of Results ; Severity of Illness Index ; }, abstract = {OBJECTIVE: To evaluate the reliability, validity, sensitivity, and clinical applicability of a new scale-the amyotrophic lateral sclerosis symptom score in integrative treatments (ALS-SSIT)-for measuring the effect of traditional Chinese medicine (TCM) in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: A total of 160 patients with ALS were enrolled and followed up for 6 months. All patients received TCM. Patients were evaluated at enrollment and at the end of 6 months with a new scale, the ALS-SSIT, developed after extensive consultations with TCM experts with several years of experience in the treatment of ALS. The 36-item Medical Outcomes Study Short Form (SF-36) scale and the amyotrophic lateral sclerosis functional rating scale (ALSFRS) were used as the reference standards.<br><br>RESULTS: The acceptance rate and completion rate of the ALS-SSIT scale were high, and the content validity was confirmed by experts. Test-retest performed at enrollment and at 6 months showed good reliability of the ALS-SSIT scale (Cronbach &#x3b1;, 0.9172 and 0.9181, respectively). The ALS-SSIT scale score showed significant change at 6 months, indicating the ability to reflect the change in disease severity.<br><br>CONCLUSION: The ALS-SSIT appears to be a feasible, reliable, and sensitive tool for the evaluation of the effect of TCM in patients with ALS.}, }
@article {pmid35464630, year = {2022}, author = {Skulstad Johanson, GA and Tysnes, OB and Bjerknes, TL}, title = {Use of Off-Label Drugs and Nutrition Supplements among Patients with Amyotrophic Lateral Sclerosis in Norway.}, journal = {Neurology research international}, volume = {2022}, number = {}, pages = {1789946}, pmid = {35464630}, issn = {2090-1852}, abstract = {MATERIALS AND METHODS: A cross-sectional questionnaire study was performed, where 41 ALS patients reported their use of off-label treatments, as well as self-perceived HRQOL using the RAND-12 questionnaire.<br><br>RESULTS: A majority of respondents used riluzole. Of the 41 respondents, 18 (43.9%) reported use of off-label medications and 18 (43.9%) used nutritional supplements. Low-dose naltrexone was the most commonly used off-label medication, whereas vitamins accounted for most of the nutritional supplements. The respondents' RAND-12 component scores were significantly lower than those of the general population. Low-dose naltrexone and vitamin B were associated with a better physical component score.<br><br>CONCLUSIONS: Most of the respondents in our study adhere to the recommended treatment protocols, as less than half of them reported using off-label medications or nutritional supplements against ALS. Positive correlations between physical HRQOL and use of low-dose naltrexone or vitamin B were demonstrated. These results warrant further investigations.}, }
@article {pmid35462696, year = {2022}, author = {Gong, F and Zhu, W and Liao, W and Wang, M and Zheng, X and Wang, C and Liu, T and Pan, W}, title = {Mechanism of the Curative Effect of Wen-Shen-Jian-Pi Prescription in the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {873224}, pmid = {35462696}, issn = {1663-4365}, abstract = {OBJECTIVE: To study the mechanism of the effect of Wen-Shen-Jian-Pi (WSJP) prescription on an ALS model comprising mice knocked out for an encoding RNA editing, mice (AR2).<br><br>METHODS: Twenty-four transgenic AR2 mice were randomly divided into a vehicle group, a low dose WSJP group (15 mg), a medium-dose WSJP group (30 mg), and a high-dose WSJP group (45 mg) (all n = 6 per group). In the treatment groups, the WSJP prescription was given once a day while the vehicle group was fed the same volume of water. The weekly changes in body weight, rotarod test, and grip strength were used to detect the changes in the AR2 and changes of the number of normal mitochondria, abnormal mitochondria, and autophagosomes in injured spinal cord cells were used to evaluate the pathogenetic effects of WSJP treatment.<br><br>RESULTS: The WSJP-treated AR2 mice gained weight more quickly from 8 weeks, and showed active behavior and displayed significantly better constant rotarod scores and grip strengths during the experiment compared with those of the vehicle AR2 mice. The number of normal mitochondria in the WSJP-treated AR2 mice had significantly more normal mitochondria than the vehicle group, while the numbers of abnormal mitochondria and autophagosomes were greatly decreased compared with those in the vehicle group.<br><br>CONCLUSION: The WSJP prescription could delay the decline in motor function of ALS model mice by reducing the degeneration of neurons. The potential of WSJP to treat ALS should be assessed in a clinical trial.}, }
@article {pmid35455952, year = {2022}, author = {Bordoni, M and Pansarasa, O and Scarian, E and Cristofani, R and Leone, R and Fantini, V and Garofalo, M and Diamanti, L and Bernuzzi, S and Gagliardi, S and Carelli, S and Poletti, A and Cereda, C}, title = {Lysosomes Dysfunction Causes Mitophagy Impairment in PBMCs of Sporadic ALS Patients.}, journal = {Cells}, volume = {11}, number = {8}, pages = {}, pmid = {35455952}, issn = {2073-4409}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Humans ; Leukocytes, Mononuclear/metabolism ; Lysosomes/metabolism ; *Mitophagy ; TOR Serine-Threonine Kinases/metabolism ; Trehalose/metabolism ; }, abstract = {Mitochondria alterations are present in tissues derived from patients and animal models, but no data are available for peripheral blood mononuclear cells (PBMCs) of ALS patients. This work aims to investigate mitophagy in PBMCs of sporadic (sALS) patients and how this pathway can be tuned by using small molecules. We found the presence of morphologically atypical mitochondria by TEM and morphological abnormalities by MitoTracker™. We found a decreased number of healthy mitochondria in sALS PBMCs and an impairment of mitophagy with western blot and immunofluorescence. After rapamycin treatment, we found a higher increase in the LC3 marker in sALS PBMCs, while after NH4Cl treatment, we found a lower increase in the LC3 marker. Finally, mTOR-independent autophagy induction with trehalose resulted in a significant decrease in the lysosomes level sALS PBMCs. Our data suggest that the presence of morphologically altered mitochondria and an inefficient turnover of damaged mitochondria in PBMCs of sALS patients rely on the impairment of the mitophagy pathway. We also found that the induction of the mTOR-independent autophagy pathway leads to a decrease in lysosomes level, suggesting a more sensitivity of sALS PBMCs to trehalose. Such evidence suggests that trehalose could represent an effective treatment for ALS patients.}, }
@article {pmid35453510, year = {2022}, author = {Virgilio, E and De Marchi, F and Contaldi, E and Dianzani, U and Cantello, R and Mazzini, L and Comi, C}, title = {The Role of Tau beyond Alzheimer's Disease: A Narrative Review.}, journal = {Biomedicines}, volume = {10}, number = {4}, pages = {}, pmid = {35453510}, issn = {2227-9059}, abstract = {Nowadays, there is a need for reliable fluid biomarkers to improve differential diagnosis, prognosis, and the prediction of treatment response, particularly in the management of neurogenerative diseases that display an extreme variability in clinical phenotypes. In recent years, Tau protein has been progressively recognized as a valuable neuronal biomarker in several neurological conditions, not only Alzheimer's disease (AD). Cerebrospinal fluid and serum Tau have been extensively investigated in several neurodegenerative disorders, from classically defined proteinopathy, e.g., amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson's disease (PD), but also in inflammatory conditions such as multiple sclerosis (MS), as a marker of axonal damage. In MS, total Tau (t-Tau) may represent, along with other proteins, a marker with diagnostic and prognostic value. In ALS, t-Tau and, mainly, the phosphorylated-Tau/t-Tau ratio alone or integrated with transactive DNA binding protein of ~43 kDa (TDP-43), may represent a tool for both diagnosis and differential diagnosis of other motoneuron diseases or tauopathies. Evidence indicated the crucial role of the Tau protein in the pathogenesis of PD and other parkinsonian disorders. This narrative review summarizes current knowledge regarding non-AD neurodegenerative diseases and the Tau protein.}, }
@article {pmid35450377, year = {2022}, author = {May-Dracka, TL and Gao, F and Hopkins, BT and Hronowski, X and Chen, T and Chodaparambil, JV and Metrick, CM and Cullivan, M and Enyedy, I and Kaliszczak, M and Kankel, MW and Marx, I and Michell-Robinson, MA and Murugan, P and Kumar, PR and Rooney, M and Schuman, E and Sen, A and Wang, T and Ye, T and Peterson, EA}, title = {Discovery of Phospholipase D Inhibitors with Improved Drug-like Properties and Central Nervous System Penetrance.}, journal = {ACS medicinal chemistry letters}, volume = {13}, number = {4}, pages = {665-673}, pmid = {35450377}, issn = {1948-5875}, abstract = {Phospholipase D (PLD) is a phospholipase enzyme responsible for hydrolyzing phosphatidylcholine into the lipid signaling molecule, phosphatidic acid, and choline. From a therapeutic perspective, PLD has been implicated in human cancer progression as well as a target for neurodegenerative diseases, including Alzheimer's. Moreover, knockdown of PLD rescues the ALS phenotype in multiple Drosophila models of ALS (amyotrophic lateral sclerosis) and displays modest motor benefits in an SOD1 ALS mouse model. To further validate whether inhibiting PLD is beneficial for the treatment of ALS, a brain penetrant small molecule inhibitor with suitable PK properties to test in an ALS animal model is needed. Using a combination of ligand-based drug discovery and structure-based design, a dual PLD1/PLD2 inhibitor was discovered that is single digit nanomolar in the Calu-1 cell assay and has suitable PK properties for in vivo studies. To capture the in vivo measurement of PLD inhibition, a transphosphatidylation pharmacodynamic LC-MS assay was developed, in which a dual PLD1/PLD2 inhibitor was found to reduce PLD activity by 15-20-fold.}, }
@article {pmid35450015, year = {2022}, author = {Zhang, S and Zhao, J and Quan, Z and Li, H and Qing, H}, title = {Mitochondria and Other Organelles in Neural Development and Their Potential as Therapeutic Targets in Neurodegenerative Diseases.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {853911}, pmid = {35450015}, issn = {1662-4548}, abstract = {The contribution of organelles to neural development has received increasing attention. Studies have shown that organelles such as mitochondria, endoplasmic reticulum (ER), lysosomes, and endosomes play important roles in neurogenesis. Specifically, metabolic switching, reactive oxygen species production, mitochondrial dynamics, mitophagy, mitochondria-mediated apoptosis, and the interaction between mitochondria and the ER all have roles in neurogenesis. Lysosomes and endosomes can regulate neurite growth and extension. Moreover, metabolic reprogramming represents a novel strategy for generating functional neurons. Accordingly, the exploration and application of mechanisms underlying metabolic reprogramming will be beneficial for neural conversion and regenerative medicine. There is adequate evidence implicating the dysfunction of cellular organelles-especially mitochondria-in neurodegenerative disorders, and that improvement of mitochondrial function may reverse the progression of these diseases through the reinforcement of adult neurogenesis. Therefore, these organelles have potential as therapeutic targets for the treatment of neurodegenerative diseases. In this review, we discuss the function of these organelles, especially mitochondria, in neural development, focusing on their potential as therapeutic targets in neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid35448025, year = {2022}, author = {Apreleva Kolomeytseva, AT and Brylev, L and Eshghi, M and Bottaeva, Z and Zhang, J and Fachner, JC and Street, AJ}, title = {Home-Based Music Therapy to Support Bulbar and Respiratory Functions of Persons with Early and Mid-Stage Amyotrophic Lateral Sclerosis-Protocol and Results from a Feasibility Study.}, journal = {Brain sciences}, volume = {12}, number = {4}, pages = {}, pmid = {35448025}, issn = {2076-3425}, support = {K23 DC019179/DC/NIDCD NIH HHS/United States ; }, abstract = {Respiratory failure, malnutrition, aspiration pneumonia, and dehydration are the precursors to mortality in ALS. Loss of natural communication is considered one of the worst aspects of ALS. This first study to test the feasibility of a music therapy protocol for bulbar and respiratory rehabilitation in ALS employs a mixed-methods case study series design with repeated measures. Newly diagnosed patients meeting the inclusion criteria were invited to participate, until the desired sample size (n = 8) was achieved. The protocol was delivered to participants in their homes twice weekly for six weeks. Individualised exercise sets for independent practice were provided. Feasibility data (recruitment, retention, adherence, tolerability, self-motivation and personal impressions) were collected. Bulbar and respiratory changes were objectively measured. Results. A high recruitment rate (100%), a high retention rate (87.5%) and high mean adherence to treatment (95.4%) provide evidence for the feasibility of the study protocol. The treatment was well tolerated. Mean adherence to the suggested independent exercise routine was 53%. The outcome measurements to evaluate the therapy-induced change in bulbar and respiratory functions were defined. Findings suggest that the protocol is safe to use in early- and mid-stage ALS and that music therapy was beneficial for the participants' bulbar and respiratory functions. Mean trends suggesting that these functions were sustained or improved during the treatment period were observed for most outcome parameters: Maximal Inspiratory Pressure, Maximal Expiratory Pressure, Peak Expiratory Flow, the Center for Neurologic Study-Bulbar Function Scale speech and swallowing subscales, Maximum Phonation Time, Maximum Repetition Rate-Alternating, Maximum Repetition Rate-Sequential, Jitter, Shimmer, NHR, Speaking rate, Speech-pause ratio, Pause frequency, hypernasality level, Time-to-Laryngeal Vestibule Closure, Maximum Pharyngeal Constriction Area, Peak Position of the Hyoid Bone, Total Pharyngeal Residue C24area. Conclusion. The suggested design and protocol are feasible for a larger study, with some modifications, including aerodynamic measure of nasalance, abbreviated voice sampling and psychological screening.}, }
@article {pmid35448021, year = {2022}, author = {Zhang, G and Liu, R and Sheng, Z and Zhang, Y and Fan, D}, title = {SIRT1 Interacts with Prepro-Orexin in the Hypothalamus in SOD1G93A Mice.}, journal = {Brain sciences}, volume = {12}, number = {4}, pages = {}, pmid = {35448021}, issn = {2076-3425}, support = {81030019//National Natural Science Foundation of China/ ; 81873784//National Natural Science Foundation of China/ ; }, abstract = {The participation of silent mating type information regulation 2 homolog 1 (SIRT1) in amyotrophic lateral sclerosis (ALS) has been reported in many studies. However, the role of the expression and function of SIRT1 in the hypothalamus in ALS remains unknown. In the current study, we performed western blot, co-immunoprecipitation and immunofluorescence analyses to determine the expression and in-depth mechanism of SIRT1 in the hypothalamus in SOD1G93A transgenic mice. We found that SIRT1 was overexpressed in the hypothalamus after motor symptom onset. In addition, SIRT1 interacted with prepro-orexin, a molecule involved in energy balance and the sleep/wake cycle, in both preclinical and clinical ALS regardless of whether SIRT1 levels were elevated. These findings indicate that SIRT1 might participate in sleep and metabolic changes in ALS, suggesting that SIRT1 is a new target for ALS treatment.}, }
@article {pmid35445431, year = {2022}, author = {Beers, DR and Thonhoff, JR and Faridar, A and Thome, AD and Zhao, W and Wen, S and Appel, SH}, title = {Tregs Attenuate Peripheral Oxidative Stress and Acute Phase Proteins in ALS.}, journal = {Annals of neurology}, volume = {92}, number = {2}, pages = {195-200}, pmid = {35445431}, issn = {1531-8249}, mesh = {Acute-Phase Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/therapy ; Clinical Trials, Phase I as Topic ; Humans ; Inflammation/metabolism ; Oxidative Stress ; T-Lymphocytes, Regulatory/metabolism ; }, abstract = {Oxidative stress (OS) induces inflammation, which in turn exacerbates OS and the expression of acute phase proteins (APPs). Regulatory T lymphocyte (Treg) therapy was assessed for suppression of OS and APP responses in longitudinal serum samples from subjects with amyotrophic lateral sclerosis (ALS) enrolled in a phase I clinical trial. The first round of Treg therapy suppressed levels of oxidized low-density lipoprotein (ox-LDL). During a 6-month washout period, ox-LDL levels increased. A second round of therapy again suppressed ox-LDL levels and then rose following the cessation of treatment. Serum levels of APPs, soluble CD14, lipopolysaccharide binding protein, and C-reactive protein, were stabilized during Treg administrations, but rose during the washout period and again after therapy was discontinued. Treg therapy potentially suppresses peripheral OS and the accompanying circulating pro-inflammatory induced APPs, both of which may serve as peripheral candidates for monitoring efficacies of immunomodulating therapies. ANN NEUROL 2022;92:195-200.}, }
@article {pmid35443425, year = {2022}, author = {Tomar, S and Gupta, S and Singal, A and Soni, R}, title = {Efficacy and Safety of Edaravone in Amyotrophic Lateral Sclerosis Patients in Indian Population.}, journal = {The Journal of the Association of Physicians of India}, volume = {70}, number = {4}, pages = {11-12}, pmid = {35443425}, issn = {0004-5772}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Animals ; Antipyrine/pharmacology/therapeutic use ; Double-Blind Method ; Edaravone/therapeutic use ; Humans ; *Neurodegenerative Diseases ; }, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS), is a progressive fatal neurodegenerative disease. It leads to scarring or hardening of Motor neurons. The cause of ALS remains unknown. Oxidative stress caused by free radicals might be an essential factor in the progression of the disease. Edaravone, is a free-radical scavenger, it has been shown to inhibit motor neuron death in animal models by reducing oxidative stress &amp; it has shown efficacy in a small subset of people with ALS. This study was planned to see the efficacy and safety of Edaravone in Indian population.<br><br>MATERIAL: This study was a single centric observational study, on use of Edaravone in ALS patients. Who were more than 18 years of age and diagnosed to have possible, probable or definite ALS as per the El Escorial Criteria 2014. Total 30 patients were included. All patients had their Revised ALSFRS-R recorded &amp; SFEMG was done at the time of diagnosis then after 6 months of completion of treatment protocol. They were given Edaravone as per as per defined treatment protocol. The treatment protocol consists of 24 weeks (6 cycles). In cycle 1, the study drug was administered for 14 consecutive days followed by a 2 week drug-free period. In cycle 2 and thereafter, the study drug was administered for first 10 days, followed by 18 days drug-free period. The primary efficacy endpoint was a difference in ALSFRS-R score of at least 20% from base line. Secondary endpoints were change in increase in jitter by 10%. Safety endpoints was include the incidence of adverse drug reactions.<br><br>OBSERVATION: Total of 30 patients were included in the study and 23 patients completed the treatment protocol. 93.3% of patients reported with weakness of limbs while 80% suffered from atrophy of limbs. 96.7% of patients was having fasciculation.2 patients (6.6%) of subjects receiving Edaravone therapy reported with adverse side-effects.After completing the treatment protocol in the study group. On comparing the mean values of ALSFRS-R score at different end-points, no statistical significance was obtained.<br><br>CONCLUSION: This study failed to demonstrate efficacy of Edaravone to delay the progression of ALS. While the primary desired endpoint was not achieved but there was small improvement in SF-EMG jitter difference of the patients that was not significant statistically. We consider that the study with large sample size results can be helpful to identify the patient population in which Edaravone could be expected to show efficacy.}, }
@article {pmid35440308, year = {2022}, author = {Benmelouka, AY and Ouerdane, Y and Outani, O and Alnasser, YT and Alghamdi, BS and Perveen, A and Ashraf, GM and Ebada, MA}, title = {Alzheimer's Disease-Related Psychosis: An Overview of Clinical Manifestations, Pathogenesis, and Current Treatment.}, journal = {Current Alzheimer research}, volume = {19}, number = {4}, pages = {285-301}, doi = {10.2174/1567205019666220418151914}, pmid = {35440308}, issn = {1875-5828}, mesh = {*Alzheimer Disease/complications/diagnosis ; Comorbidity ; Delusions/genetics ; Hallucinations/genetics ; Humans ; *Psychotic Disorders/diagnosis/etiology/therapy ; Risk Factors ; }, abstract = {Behavioral and psychotic manifestations, including aggression, delusions, and hallucinations, are frequent comorbidities in patients with debilitating nervous illnesses such as Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Parkinson's disease. ADrelated psychosis may be linked to a poor disease prognosis, highlighting that early detection and management are mandatory. The manifestations are variable and may be very heterogeneous, imposing a real diagnostic issue. Some assessment tools such as BEHAVE-AD, CERAD-BRSD, and the Psycho-Sensory Hallucinations Scale have been designed to facilitate the diagnosis. The mechanisms behind neurodegeneration-related psychosis are complex and are not fully understood, imposing a burden on researchers to find appropriate management modalities. Familial history and some genetic disturbances may have a determinant role in these delusions and hallucinations in cases with AD. The loss of neuronal cells, atrophy in some regions of the central nervous, and synaptic dysfunction may also contribute to these comorbidities. Furthermore, inflammatory disturbances triggered by pro-inflammatory agents such as interleukins and tumor necrosis factors are stratified among the potential risk factors for the onset of numerous psychotic symptoms in Alzheimer's patients. Little is known about the possible management tools; therefore, it is urgent to conduct well-designed trials to investigate pharmacological and non-pharmacological interventions that can improve the care process of these patients. This review summarizes the current findings regarding the AD-related psychosis symptoms, pathological features, assessment, and management.}, }
@article {pmid35439439, year = {2022}, author = {Yoshikawa, M and Aizawa, S and Oppenheim, RW and Milligan, C}, title = {Neurovascular unit pathology is observed very early in disease progression in the mutant SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {353}, number = {}, pages = {114084}, doi = {10.1016/j.expneurol.2022.114084}, pmid = {35439439}, issn = {1090-2430}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; Disease Models, Animal ; Disease Progression ; Mice ; Mice, Transgenic ; *Neurodegenerative Diseases/pathology ; Spinal Cord/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by motor neuron degeneration that causes neuromuscular denervation, resulting in muscle weakness and atrophy. Work over the decades using ALS mouse models has revealed that while initial pathology may occur within motor neurons, disease pathology is cell non-autologous. Impairment of the blood-spinal cord barrier (BSCB) occurs before motor neuron frank degeneration; however, precisely when the early pathogenesis of the neurovascular units occurs is not fully understood. Here we examine changes in morphology of neurovascular units, associated gene and protein expression in the lumbar spinal cord of SOD1[G93A], and wild-type mice and correlate results with previous reports of early pathological events. Using RNA-sequencing and immunolabeling, we also show that both the neurovascular units and the vasculature of the SOD1[G93A] lumbar spinal cord present important modifications throughout the disease. Genes relevant for the neurovascular unit and immune cells were differentially expressed in the SOD1[G93A] ventral lumbar spinal cord compared to wild-type. A reduction in capillary density and tight junction (TJ) with overt BSCB breakdown was observed in the SOD1[G93A] lumbar spinal cord and ultrastructural observation revealed intact TJ. Additionally, thickened basement membrane, increased pericytes, and string vessels were observed. These alterations in neurovascular units and the vasculature are observed prior to reports of initial neuromuscular junction denervation. The identification of early pathogenesis may be critical to develop diagnostic tests and development of novel treatment strategies that target these early events.}, }
@article {pmid35437168, year = {2022}, author = {Dalton, MK and Semco, RS and Ordoobadi, AJ and Goralnick, E and Chovanes, J and Salim, A and Jarman, MP}, title = {Opioid administration in the prehospital setting for patients sustaining traumatic injuries: An evaluation of national emergency medical services data.}, journal = {Injury}, volume = {53}, number = {9}, pages = {2923-2929}, pmid = {35437168}, issn = {1879-0267}, support = {K01 AG065414/AG/NIA NIH HHS/United States ; L60 AG074600/AG/NIA NIH HHS/United States ; L60 MD014600/MD/NIMHD NIH HHS/United States ; }, mesh = {*Acute Pain/drug therapy ; Analgesics, Opioid/adverse effects ; *Emergency Medical Services ; Humans ; Pain Management ; Pain Measurement ; }, abstract = {INTRODUCTION: Despite concerns about long-term dependence, opioids remain the mainstay of treatment for acute pain from traumatic injuries. Additionally, early pain management has been associated with improved long-term outcomes in injured patients. We sought to identify the patterns of prehospital pain management across the United States.<br><br>METHODS: We used 2019 national emergency medical services (EMS) data to identify the use of pain management for acutely injured patients. Opioid specific dosing was calculated in morphine milligram equivalents (MME). The effects of opioids as well as adverse events were identified through objective patient data and structured provider documentation.<br><br>RESULTS: We identified a total of 3,831,768 injured patients, 85% of whom were treated by an advanced life support (ALS) unit. There were 269,281 (7.0%) patients treated with opioids, including a small number of patients intubated by EMS (n&#xa0;=&#xa0;1537; 0.6%). The median opioid dose was 10 MME [IQR 5-10] and fentanyl was the most commonly used opioid (88.2%). Patients treated with opioids had higher initial pain scores documented by EMS than those not receiving opioids (median: 9&#xa0;vs 4, p<0.001), and had a median reduction in pain score of 3 points (IQR 1-5) based on the final prehospital pain score. Adverse events associated with opioid administration, including episodes of altered mental status (n&#xa0;=&#xa0;453; 0.2%) and respiratory compromise (n&#xa0;=&#xa0;252; 0.1%), were rare. For patients with severe pain (&#x2265;8/10), 27.3% of patients with major injuries (ISS &#x2265;15) were treated with opioids, compared with 24.8% of those with moderate injuries (ISS 9-14), and 21.4% of those with minor (ISS 1-8) injuries (p<0.001).<br><br>CONCLUSION: The use of opioids in the prehospital setting significantly reduced pain among injured patients with few adverse events. Despite its efficacy and safety, the majority of patients with major injuries and severe pain do not receive opioid analgesia in the prehospital setting.}, }
@article {pmid35436682, year = {2022}, author = {Nabizadeh, F and Nikfarjam, M and Azami, M and Sharifkazemi, H and Sodeifian, F}, title = {Pseudobulbar affect in neurodegenerative diseases: A systematic review and meta-analysis.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {100}, number = {}, pages = {100-107}, doi = {10.1016/j.jocn.2022.04.009}, pmid = {35436682}, issn = {1532-2653}, mesh = {*Alzheimer Disease/complications ; *Amyotrophic Lateral Sclerosis/complications/epidemiology ; Crying ; Humans ; *Laughter ; *Multiple Sclerosis/complications/epidemiology ; *Neurodegenerative Diseases/complications/epidemiology ; *Parkinson Disease/complications ; Quality of Life ; }, abstract = {BACKGROUND: Pseudobulbar affect (PBA) is characterized by uncontrolled episodes of crying and laughing which is associated with a variety of neurological diseases including traumatic brain injury, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), brain tumors, stroke, Parkinson's disease (PD), Alzheimer's disease (AD) and other dementias. However, there is a lack of exact estimated prevalence of PBA among neurological disorders.<br><br>AIM: In this systematic review and meta-analysis study we aimed to assess the prevalence of PBA in four neurodegenerative diseases including ALS, MS, AD, and PD.<br><br>METHODS: PubMed, Scopus, and Web of Science were searched in July 2021 for studies that reported the prevalence of PBA in ALS, MS, AD, and PD patients. The mean point of PBA prevalence and odds ratios were calculated as effect size (ES) using the random-effect model with a 95% confidence interval (CI).<br><br>RESULTS: The summarized prevalence of PBA was of PBA in PD patients were ranged between 1% and 31% with an overall meta-analysis prevalence of 16.5% and high heterogeneity (I[2]: 98.7%, p: 0.000). Patients with ALS showed a PBA prevalence of 38.5%, which is higher than other neurodegenerative diseases (CI 95%: 31%-45%, I[2]: 61.4%, p: 0.034). Moreover, the prevalence of PBA in MS patients in the analysis was 23.3% ranging between 11% and 35% with high-level heterogeneity according to the I[2] value (I[2]: 98.9%, p: 0.000). Also, our meta-analysis showed that the PBA prevalence in AD was 16.4% (CI 95%: 7%-25%) with high heterogeneity (I[2]: 97.8%, p: 0.000).<br><br>CONCLUSION: This review showed that PBA is common in patients with neurodegenerative diseases including PD, AD, MS, and especially ALS. Due to the lack of proper recognition, medication and treatment would not be effective and sufficient. Therefore, it can dramatically lower the quality of life in PBA patients and decrease their social interactions.}, }
@article {pmid35429360, year = {2022}, author = {Pérez-Cuadrado-Robles, E and Bronswijk, M and Prat, F and Barthet, M and Palazzo, M and Arcidiacono, P and Schaefer, M and Devière, J and van Wanrooij, RLJ and Tarantino, I and Donatelli, G and Camus, M and Sanchez-Yague, A and Pham, KD and Gonzalez, JM and Anderloni, A and Vila, JJ and Jezequel, J and Larghi, A and Jaïs, B and Vazquez-Sequeiros, E and Deprez, PH and Van der Merwe, S and Cellier, C and Rahmi, G}, title = {Endoscopic ultrasound-guided drainage using lumen-apposing metal stent of malignant afferent limb syndrome in patients with previous Whipple surgery: Multicenter study (with video).}, journal = {Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society}, volume = {34}, number = {7}, pages = {1433-1439}, doi = {10.1111/den.14330}, pmid = {35429360}, issn = {1443-1661}, mesh = {Adolescent ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Cholangitis/etiology/surgery ; Drainage/methods ; Endosonography/methods ; Stents/adverse effects ; Treatment Outcome ; Ultrasonography, Interventional/methods ; }, abstract = {OBJECTIVES: Endoscopic ultrasound-guided digestive anastomosis (EUS-A) is a new alternative under evaluation in patients presenting with afferent limb syndrome (ALS) after Whipple surgery. The aim of the present study is to analyze the safety and effectiveness of EUS-A in ALS.<br><br>METHODS: This is an observational multicenter study. All patients &#x2265;18&#x2009;years old with previous Whipple surgery presenting with ALS who underwent an EUS-A using a lumen-apposing metal stent (LAMS) between 2015 and 2021 were included. The primary outcome was clinical success, defined as resolution of the ALS or ALS-related cholangitis. Furthermore, technical success, adverse event rate, and mortality were evaluated.<br><br>RESULTS: Forty-five patients (mean age: 65.5&#x2009;&#xb1;&#x2009;10.2&#x2009;years; 44.4% male) were included. The most common underlying disease was pancreatic cancer (68.9%). EUS-A was performed at a median of 6&#x2009;weeks after local tumor recurrence. The most common approach used was the direct/freehand technique (66.7%). Technical success was achieved in 95.6%, with no differences between large (&#x2265;15&#x2009;mm) and small LAMS (97.4% vs. 100%, P&#x2009;=&#x2009;0.664). Clinical success was retained in 91.1% of patients. A complementary treatment by dilation of the stent followed by endoscopic retrograde cholangiopancreatography through the LAMS was performed in three cases (6.7%). There were six recurrent episodes of cholangitis (14.6%) and two procedure-related adverse events (4.4%) after a median follow-up of 4&#x2009;months. Twenty-six patients (57.8%) died during the follow-up due to disease progression.<br><br>CONCLUSION: EUS-A is a safe and effective technique in the treatment of malignant ALS, achieving high clinical success with an acceptable recurrence rate.}, }
@article {pmid35426522, year = {2022}, author = {Mueller, M and Thompson, R and Osman, KL and Andel, E and DeJonge, CA and Kington, S and Stephenson, Z and Hamad, A and Bunyak, F and Nichols, NL and Lever, TE}, title = {Impact of Limb Phenotype on Tongue Denervation Atrophy, Dysphagia Penetrance, and Survival Time in a Mouse Model of ALS.}, journal = {Dysphagia}, volume = {37}, number = {6}, pages = {1777-1795}, pmid = {35426522}, issn = {1432-0460}, support = {R01 HL153612/HL/NHLBI NIH HHS/United States ; R21 DC016071/DC/NIDCD NIH HHS/United States ; }, mesh = {Female ; Mice ; Male ; Humans ; Animals ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/complications/genetics ; Superoxide Dismutase/genetics ; *Deglutition Disorders/genetics/pathology ; Penetrance ; Tongue ; Disease Models, Animal ; Atrophy/pathology ; Phenotype ; Denervation ; }, abstract = {Current treatments for dysphagia in ALS do not target the underlying tongue weakness and denervation atrophy that is prevalent in spinal and bulbar ALS cases. To address this clinical gap, we studied the low copy number SOD1-G93A (LCN-SOD1) mouse model of ALS to quantify the impact of limb phenotype on tongue denervation atrophy, dysphagia penetrance, and survival time in preparation for future treatment-based studies. Two male LCN-SOD1 breeders and 125 offspring were followed for limb phenotype inheritance, of which 52 (30 LCN-SOD1 and 22 wild-type/WT, both sexes) underwent characterization of dysphagia penetrance (via videofluoroscopic swallow study; VFSS) and survival time at disease end-stage (15-20% body weight loss). From these, 16 mice (8/genotype) underwent postmortem histological analysis of the genioglossus for evidence of denervation atrophy. Results revealed that both breeders displayed a mixed (hindlimb and forelimb) ALS phenotype and sired equal proportions of hindlimb vs. mixed phenotype offspring. Dysphagia penetrance was complete for mixed (100%) versus incomplete for hindlimb (64%) phenotype mice; yet survival times were similar. Regardless of limb phenotype, LCN-SOD1 mice had significantly smaller genioglossus myofibers and more centralized myonuclei compared to WT mice (p < 0.05). These biomarkers of denervation atrophy were significantly correlated with VFSS metrics (lick and swallow rates, p < 0.05) but not survival time. In conclusion, both LCN-SOD1 phenotypes had significant tongue denervation atrophy, even hindlimb phenotype mice without dysphagia. This finding recapitulates human ALS, providing robust rationale for using this preclinical model to explore targeted treatments for tongue denervation atrophy and ensuing dysphagia.}, }
@article {pmid35415080, year = {2022}, author = {Solek, P and Mytych, J and Sujkowska, E and Grzegorczyk, M and Jasiewicz, P and Sowa-Kucma, M and Stachowicz, K and Koziorowski, M and Tabecka-Lonczynska, A}, title = {Trade-offs between male fertility reduction and selected growth factors or the klotho response in a lipopolysaccharide-dependent mouse model.}, journal = {Toxicological research}, volume = {38}, number = {2}, pages = {175-186}, pmid = {35415080}, issn = {1976-8257}, abstract = {The increasing number of depression cases leads to a greater need for new antidepressant treatment development. It is postulated that antidepressants may harm male fertility, but the cellular mechanism is still poorly understood. The role of growth factors and klotho protein in maintaining normal male reproductive function is well documented. Hence, the study aimed to investigate the effect of the antidepressant drug - imipramine (tricyclic AD), and other substances with antidepressant potential (ALS), administered in combination or in combination with LPS (an animal model of depression) on gene expression and protein synthesis of IGF-2 (insulin-like growth factor 2), TGF-β1 (transforming growth factor β1), NGF (nerve growth factor), KGF (keratinocyte growth factor) and protein synthesis of VEGF-A (vascular endothelial growth factor A), IGF-IR (insulin-like growth factor receptor 1), EGFR (epidermal growth factor receptor) and klotho in the testis of mice. Mice were injected intraperitoneally with selected ALS and LPS or 10% DMSO (controls) (n = 7/group) once a day for 14 days. Animals were decapitated and testes collected for RNA and protein purification. PCR and western blot methods were employed for the evaluation of growth factors and klotho expression. The results obtained indicated a decreased level of most of the analyzed genes and proteins, except KGF; its expression increased after treatment with MTEP and IMI administrated individually and after NS-398, and IMI in combination with LPS. Our results may suggest that the tested ALS and LPS can contribute to a reduction of male fertility, but NS-398, IMI, and IMI+NS-398 may also act as stimulants after LPS.}, }
@article {pmid35413536, year = {2022}, author = {Jiang, X and Liu, J and Guan, Y and Zhao, Z and Meng, F and Wang, X and Gao, X and Zhou, F and Chen, Y and Wang, X}, title = {The mechanism of the WNT5A and FZD4 receptor mediated WNT/β-catenin pathway in the degeneration of ALS spinal cord motor neurons.}, journal = {Biochemical and biophysical research communications}, volume = {609}, number = {}, pages = {23-30}, doi = {10.1016/j.bbrc.2022.03.126}, pmid = {35413536}, issn = {1090-2104}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Disease Models, Animal ; Frizzled Receptors/*metabolism ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism ; *Neurodegenerative Diseases/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/metabolism ; Wnt Signaling Pathway ; Wnt-5a Protein/*metabolism ; beta Catenin/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with unknown etiology, characterized by motor neuron degeneration, and there is no highly effective treatment. The canonical WNT/β-catenin signaling pathway has a critical role in the physiological and pathophysiological processes of the central nervous system. In this study, we investigated the regulatory mechanism of the WNT/β-catenin signaling pathway from the perspective of ligand-receptor binding and its relationship with the degeneration of ALS motor neurons. We used hSOD1-G93A mutant ALS transgenic mice and hSOD1-G93A mutant NSC34 cells combined with morphological and molecular biology techniques to determine the role of the WNT/β-catenin pathway in ALS. Our findings demonstrated that WNT5A regulates the WNT/β-catenin signaling pathway by binding to the FZD4 receptor in the pathogenesis of ALS and affects the proliferation and apoptosis of ALS motor neurons. Therefore, these findings may lead to the development of novel therapies to support the survival of ALS motor neurons.}, }
@article {pmid35410943, year = {2022}, author = {Maurier, F and Michaud, M and Reviron, R and Lipsker, D}, title = {Neuromyotonia: a skin-deep problem.}, journal = {BMJ case reports}, volume = {15}, number = {4}, pages = {}, pmid = {35410943}, issn = {1757-790X}, mesh = {Antibodies ; Female ; Humans ; *Isaacs Syndrome/complications/diagnosis ; Leucine ; Middle Aged ; Muscle Cramp ; *Scleroderma, Localized/complications ; }, abstract = {A 45-year-old woman was evaluated for right-sided hemicorporal scar-like skin lesions on her arm and thoracic and inguinal areas that appeared shortly after reduction mammoplasty. Five years later, she developed spontaneous cramps and involuntary abnormal, painful, twitching movements in the same areas. With time, the cramps worsened and disabled the patient. The use of her right arm triggered contractures of muscles and abnormal movements. A diagnosis of neuromyotonia (NMT) was established on the basis of clinical findings and on electromyographic findings of a burst of high-frequency motor unit potentials recorded in the right triceps in the area of skin lesions. The results of medullary, encephalic MRI as well as a comprehensive metabolic panel were normal. She was positive for antinuclear antibodies without specificity. Neither antineural antibodies nor antivoltage-gated potassium channel complex antibodies (specifically, leucine-rich glioma inactivated protein 1 and contactin-associated protein-like-2) were detected. Her skin lesions were diagnosed as morphea. Two combined strategies of treatment were initiated: antiepileptic drugs for NMT and corticosteroids and methotrexate for morphea. NMT is a rare, debilitating neurological complication of morphea.}, }
@article {pmid35410603, year = {2022}, author = {Bojja, SL and Singh, N and Kolathur, KK and Rao, CM}, title = {What is the Role of Lithium in Epilepsy?.}, journal = {Current neuropharmacology}, volume = {20}, number = {10}, pages = {1850-1864}, pmid = {35410603}, issn = {1875-6190}, mesh = {*Epilepsy/drug therapy ; Humans ; *Lithium/pharmacology/therapeutic use ; Lithium Compounds/pharmacology/therapeutic use ; Mood Disorders/drug therapy ; Neuroprotection ; }, abstract = {Lithium is a well-known FDA-approved treatment for bipolar and mood disorders. Lithium has been an enigmatic drug with multifaceted actions involving various neurotransmitters and intricate cell signalling cascades. Recent studies highlight the neuroprotective and neurotrophic actions of lithium in amyotrophic lateral sclerosis, Alzheimer's disease, intracerebral hemorrhage, and epilepsy. Of note, lithium holds a significant interest in epilepsy, where the past reports expose its non-specific proconvulsant action, followed lately by numerous studies for anti-convulsant action. However, the exact mechanism of action of lithium for any of its effects is still largely unknown. The present review integrates findings from several reports and provides detailed possible mechanisms of how a single molecule exhibits marked pro-epileptogenic as well as anti-convulsant action. This review also provides clarity regarding the safety of lithium therapy in epileptic patients.}, }
@article {pmid35400321, year = {2022}, author = {Rahman, MM and Mim, SA and Islam, MR and Parvez, A and Islam, F and Uddin, MB and Rahaman, MS and Shuvo, PA and Ahmed, M and Greig, NH and Kamal, MA}, title = {Exploring the Recent Trends in Management of Dementia and Frailty: Focus on Diagnosis and Treatment.}, journal = {Current medicinal chemistry}, volume = {29}, number = {32}, pages = {5289-5314}, pmid = {35400321}, issn = {1875-533X}, support = {Z99 AG999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Aged ; *Alzheimer Disease/diagnosis ; *Frailty/diagnosis/therapy ; *Frontotemporal Dementia ; Humans ; *Malnutrition ; Weight Loss ; }, abstract = {Dementia and frailty increase health adversities in older adults, which are topics of growing research interest. Frailty is considered to correspond to a biological syndrome associated with age. Frail patients may ultimately develop multiple dysfunctions across several systems, including stroke, transient ischemic attack, vascular dementia, Parkinson's disease, Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, cortico-basal degeneration, multiple system atrophy, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease. Patients with dementia and frailty often develop malnutrition and weight loss. Rigorous nutritional, pharmacological, and non-pharmacological interventions generally are required for these patients, which is a challenging issue for healthcare providers. A healthy diet and lifestyle instigated at an early age can reduce the risk of frailty and dementia. For optimal treatment, accurate diagnosis involving clinical evaluation, cognitive screening, essential laboratory evaluation, structural imaging, functional neuroimaging, and neuropsychological testing is necessary. Diagnosis procedures best apply the clinical diagnosis, identifying the cause(s) and the condition(s) appropriate for treatment. The patient's history, caregiver's interview, physical examination, cognitive evaluation, laboratory tests, and structural imaging should best be involved in the diagnostic process. Varying types of physical exercise can aid the treatment of these disorders. Nutrition maintenance is a particularly significant factor, such as exceptionally high-calorie dietary supplements and a Mediterranean diet to support weight gain. The core purpose of this article is to investigate trends in the management of dementia and frailty, focusing on improving diagnosis and treatment. Substantial evidence builds the consensus that a combination of balanced nutrition and good physical activity is an integral part of treatment. Notably, more evidence-based medicine knowledge is required.}, }
@article {pmid35397353, year = {2022}, author = {Jouffroy, R and Brami, E and Scannavino, M and Daniel, Y and Bertho, K and Abriat, A and Salomé, M and Lemoine, S and Jost, D and Prunet, B and Travers, S}, title = {Association between prehospital shock index and mortality among patients with COVID-19 disease.}, journal = {The American journal of emergency medicine}, volume = {56}, number = {}, pages = {133-136}, pmid = {35397353}, issn = {1532-8171}, mesh = {Aged ; Aged, 80 and over ; *COVID-19/therapy ; *Emergency Medical Services/methods ; Female ; Humans ; Intensive Care Units ; Male ; Middle Aged ; Retrospective Studies ; *Shock ; }, abstract = {BACKGROUND: There exists a need for prognostic tools for the early identification of COVID-19 patients requiring intensive care unit (ICU) admission and mortality. Here we investigated the association between a clinical (initial prehospital shock index (SI)) and biological (initial prehospital lactatemia) tool and the ICU admission and 30-day mortality among COVID-19 patients cared for in the prehospital setting.<br><br>METHODS: We retrospectively analysed COVID-19 patients initially cared for by a Paris Fire Brigade advanced (ALS) or basic life support (BLS) team in the prehospital setting between 2020, March 08th and 2020, May 30th. We assessed the association between prehospital SI and prehospital lactatemia and ICU admission and mortality using logistic regression model analysis after propensity score matching with Inverse Probability Treatment Weighting (IPTW) method. Covariates included in the IPTW propensity analysis were: age, sex, body mass index (BMI), initial respiratory rate (iRR), initial pulse oximetry without (SpO2i) and with oxygen supplementation (SpO2i.O2), initial Glasgow coma scale (GCSi) value, initial prehospital SI and initial prehospital lactatemia.<br><br>RESULTS: We analysed 410 consecutive COVID-19 patients [254 males (62%); mean age, 64 &#xb1; 18 years]. Fifty-seven patients (14%) deceased on the scene, of whom 41 (72%) were male and were significantly older (71 &#xb1; 12 years vs. 64 &#xb1; 19 years; P &#x3008;10[-3]). Fifty-three patients (15%) were admitted in ICU and 39 patients (11%) were deceased on day-30. The mean prehospital SI value was 1.5 &#xb1; 0.4 and the mean prehospital lactatemia was 2.0 &#xb1; 1.7 mmol.l[-1]. Multivariate logistic regression analysis on matched population after IPTW propensity analysis reported a significant association between ICU admission and age (adjusted Odd-Ratio (aOR), 0.90; 95% confidence interval (95%CI): 0.93-0.98;p = 10[-3]), SpO2i.O2 (aOR, 1.10; 95%CI: 1.02-1.20;p = 0.002) and BMI (aOR, 1.09; 95% CI: 1.03-1.16;p = 0.02). 30-day mortality was significantly associated with SpO2i.O2 (aOR, 0.92; 95% CI: 0.87-0.98;p = 0.01 P < 10[-3]) and GCSi (aOR, 0.90; 95% CI: 0.82-0.99;p = 0.04). Neither prehospital SI nor prehospital lactatemia were associated with ICU admission and 30-day mortality.<br><br>CONCLUSION: Neither prehospital initial SI nor lactatemia were associated with ICU admission and 30-day mortality among COVID-19 patients initially cared for by a Paris Fire Brigade BLS or ALS team. Further prospective studies are needed to confirm these preliminary results.}, }
@article {pmid35395400, year = {2022}, author = {Liu, W and Wang, G and Wang, Z and Wang, G and Huang, J and Liu, B}, title = {Repurposing small-molecule drugs for modulating toxic protein aggregates in neurodegenerative diseases.}, journal = {Drug discovery today}, volume = {27}, number = {7}, pages = {1994-2007}, doi = {10.1016/j.drudis.2022.04.003}, pmid = {35395400}, issn = {1878-5832}, mesh = {Aged ; *Alzheimer Disease/drug therapy ; Drug Repositioning ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Parkinson Disease ; Protein Aggregates ; Proteins/therapeutic use ; }, abstract = {Neurodegenerative diseases (NDs) are often age-related disorders that can cause dementia in people, usually over 65 years old, are still lacking effective therapies. Some NDs have recently been linked to toxic protein aggregates, for example Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and Huntington disease; therefore, mulating toxic protein aggregates would be a promising therapeutic strategy. Moreover, drug repurposing, in other words exploiting drugs that are already in use for another indication, has been attracting mounting attention for potential therapeutic purposes in NDs. Thus, in this review, we focus on summarizing a series of repurposed small-molecule drugs for eliminating or inhibiting toxic protein aggregates and further discuss their intricate molecular mechanisms to improve the current ND treatment. Taken together, these findings will shed new light on exploiting more repurposed small-molecule drugs targeting different types of toxic proteins to fight NDs in the future.}, }
@article {pmid35393241, year = {2022}, author = {Kobashi, S and Terashima, T and Katagi, M and Urushitani, M and Kojima, H}, title = {Bone marrow-derived inducible microglia-like cells ameliorate motor function and survival in a mouse model of amyotrophic lateral sclerosis.}, journal = {Cytotherapy}, volume = {24}, number = {8}, pages = {789-801}, doi = {10.1016/j.jcyt.2022.02.001}, pmid = {35393241}, issn = {1477-2566}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Animals ; Bone Marrow/metabolism ; Disease Models, Animal ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology ; Interleukin-4/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; *Microglia/metabolism ; *Neurodegenerative Diseases/therapy ; Spinal Cord/metabolism ; }, abstract = {BACKGROUND AIMS: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. Neuroinflammation in the spinal cord plays a pivotal role in the pathogenesis of ALS, and microglia are involved in neuroinflammation. Microglia mainly have two opposite phenotypes involving cytotoxic and neuroprotective properties, and neuroprotective microglia are expected to be a novel application for the treatment of ALS. Therefore, to establish a clinically applicable therapeutic method using neuroprotective microglia, the authors investigated the effect of inducing neuroprotective microglia-like cells from bone marrow for transplantation into ALS model mice.<br><br>METHODS: Bone marrow-derived mononuclear cells were isolated from green fluorescent protein mice and cultured using different protocols of cytokine treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. Cells with a high potency of proliferation and differentiation into microglia were evaluated by gene analysis, flow cytometry and direct neuroprotective effects in vitro. These cells were named bone marrow-derived inducible microglia-like (BM-iMG) cells and transplanted into the spinal cords of ALS model mice, and behavioral tests, immunohistochemistry and gene expression profiling were performed.<br><br>RESULTS: Three-day GM-CSF and 4-day GM-CSF&#xa0;+&#xa0;IL-4 stimulations were most effective in inducing BM-iMG cells from the bone marrow. Transplantation of BM-iMG cells improved motor function, prolonged survival and suppressed neuronal cell death, astrogliosis and microgliosis in the spinal cords of ALS mice. Moreover, neuroprotective genes such as Arg1 and Mrc1 were upregulated, whereas pro-inflammatory genes such as Nos2 and Il6 were downregulated.<br><br>CONCLUSIONS: Intraspinal transplantation of BM-iMG cells demonstrated therapeutic effects in a mouse model of ALS. Further studies and clinical applications in patients with ALS are expected in the future.}, }
@article {pmid35384723, year = {2022}, author = {Moll, L and Baró, A and Montesinos, L and Badosa, E and Bonaterra, A and Montesinos, E}, title = {Induction of Defense Responses and Protection of Almond Plants Against Xylella fastidiosa by Endotherapy with a Bifunctional Peptide.}, journal = {Phytopathology}, volume = {112}, number = {9}, pages = {1907-1916}, doi = {10.1094/PHYTO-12-21-0525-R}, pmid = {35384723}, issn = {0031-949X}, mesh = {Peptides/pharmacology ; *Plant Diseases/microbiology/prevention &amp; control ; *Prunus dulcis/microbiology ; *Xylella/genetics ; }, abstract = {Xylella fastidiosa is a plant pathogenic bacterium that has been introduced in the European Union (EU), causing significant yield losses in economically important Mediterranean crops. Almond leaf scorch (ALS) is currently one of the most relevant diseases observed in Spain, and no cure has been found to be effective for this disease. In previous reports, the peptide BP178 has shown a strong bactericidal activity in vitro against X. fastidiosa and to other plant pathogens, and to trigger defense responses in tomato plants. In the present work, BP178 was applied by endotherapy to almond plants of cultivar Avijor using preventive and curative strategies. The capacity of BP178 to reduce the population levels of X. fastidiosa and to decrease disease symptoms and its persistence over time were demonstrated under greenhouse conditions. The most effective treatment consisted of a combination of preventive and curative applications, and the peptide was detected in the stem up to 60 days posttreatment. Priming plants with BP178 induced defense responses mainly through the salicylic acid pathway, but also overexpressed some genes of the jasmonic acid and ethylene pathways. It is concluded that the bifunctional peptide is a promising candidate to be further developed to manage ALS caused by X. fastidiosa.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.}, }
@article {pmid35383205, year = {2022}, author = {Piao, X and Meng, D and Zhang, X and Song, Q and Lv, H and Jia, Y}, title = {Dual-gRNA approach with limited off-target effect corrects C9ORF72 repeat expansion in vivo.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {5672}, pmid = {35383205}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; DNA Repeat Expansion ; *Frontotemporal Dementia/genetics ; Humans ; RNA, Guide, CRISPR-Cas Systems ; }, abstract = {C9ORF72 GGGGCC repeat expansion is the most common genetic cause for amyotrophic lateral sclerosis and frontotemporal dementia, which generates abnormal DNA and RNA structures and produces toxic proteins. Recently, efficacy of CRISPR/Cas9-mediated editing has been proven in treatment of disease. However, DNA low complexity surrounding C9ORF72 expansion increases the off-target risks. Here we provide a dual-gRNA design outside of the low complexity region which enables us to remove the repeat DNA in a 'cutting-deletion-fusion' manner with a high fusion efficiency (50%). Our dual-gRNA design limits off-target effect and does not significantly affect C9ORF72 expression. In neurons carrying patient C9ORF72 expansion, our approach removes the repeat DNA and corrects the RNA foci in vitro and in vivo. Therefore, we conclude that our proof-of-concept design correct C9ORF72 repeat expansion, which may have potential therapeutic value for the patients.}, }
@article {pmid35380400, year = {2022}, author = {Zahra, W and Birla, H and Singh, SS and Rathore, AS and Dilnashin, H and Singh, R and Keshri, PK and Gautam, P and Singh, SP}, title = {Neuroprotection by Mucuna pruriens in Neurodegenerative Diseases.}, journal = {Neurochemical research}, volume = {47}, number = {7}, pages = {1816-1829}, pmid = {35380400}, issn = {1573-6903}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Male ; *Mucuna ; *Neurodegenerative Diseases/drug therapy ; Neuroprotection ; *Parkinson Disease/drug therapy ; Plant Extracts/pharmacology/therapeutic use ; Seeds ; *Stroke/drug therapy ; }, abstract = {The medicinal plant Mucuna pruriens (Fabaceae) is widely known for its anti-oxidative and anti-inflammatory properties. It is a well-established drug in Ayurveda and has been widely used for the treatment of neurological disorders and male infertility for ages. The seeds of the plant have potent medicinal value and its extract has been tested in different models of neurodegenerative diseases, especially Parkinson's disease (PD). Apart from PD, Mucuna pruriens is now being studied in models of other nervous systems disorders such as Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS) and stroke because of its neuroprotective importance. This review briefly discusses the pathogenesis of PD, AD, ALS and stroke. It aims to summarize the medicinal importance of Mucuna pruriens in treatment of these diseases, and put forward the potential targets where Mucuna pruriens can act for therapeutic interventions. In this review, the effect of Mucuna pruriens on ameliorating the neurodegeneration evident in PD, AD, ALS and stroke is briefly discussed. The potential targets for neuroprotection by the plant are delineated, which can be studied further to validate the hypothesis regarding the use of Mucuna pruriens for the treatment of these diseases.}, }
@article {pmid35378353, year = {2022}, author = {Georges, M and Perez, T and Rabec, C and Jacquin, L and Finet-Monnier, A and Ramos, C and Patout, M and Attali, V and Amador, M and Gonzalez-Bermejo, J and Salachas, F and Morelot-Panzini, C}, title = {Proposals from a French expert panel for respiratory care in ALS patients.}, journal = {Respiratory medicine and research}, volume = {81}, number = {}, pages = {100901}, doi = {10.1016/j.resmer.2022.100901}, pmid = {35378353}, issn = {2590-0412}, mesh = {*Amyotrophic Lateral Sclerosis/complications/epidemiology/therapy ; Cough ; Humans ; *Neurodegenerative Diseases/complications ; Quality of Life ; *Respiratory Insufficiency/etiology/therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive diaphragm weakness and deteriorating lung function. Bulbar involvement and cough weakness contribute to respiratory morbidity and mortality. ALS-related respiratory failure significantly affects quality of life and is the leading cause of death. Non-invasive ventilation (NIV), which is the main recognized treatment for alleviating the symptoms of respiratory failure, prolongs survival and improves quality of life. However, the optimal timing for the initiation of NIV is still a matter of debate. NIV is a complex intervention. Multiple factors influence the efficacy of NIV and patient adherence. The aim of this work was to develop practical evidence-based advices to standardize the respiratory care of ALS patients in French tertiary care centres.<br><br>METHODS: For each proposal, a French expert panel systematically searched an indexed bibliography and prepared a written literature review that was then shared and discussed. A combined draft was prepared by the chairman for further discussion. All of the proposals were unanimously approved by the expert panel.<br><br>RESULTS: The French expert panel updated the criteria for initiating NIV in ALS patients. The most recent criteria were established in 2005. Practical advice for NIV initiation were included and the value of each tool available for NIV monitoring was reviewed. A strategy to optimize NIV parameters was suggested. Revisions were also suggested for the use of mechanically assisted cough devices in ALS patients.<br><br>CONCLUSION: Our French expert panel proposes an evidence-based review to update the respiratory care recommendations for ALS patients in daily practice.}, }
@article {pmid35370875, year = {2022}, author = {Yang, X and Qiang, Q and Li, N and Feng, P and Wei, W and Hölscher, C}, title = {Neuroprotective Mechanisms of Glucagon-Like Peptide-1-Based Therapies in Ischemic Stroke: An Update Based on Preclinical Research.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {844697}, pmid = {35370875}, issn = {1664-2295}, abstract = {The public and social health burdens of ischemic stroke have been increasing worldwide. Hyperglycemia leads to a greater risk of stroke. This increased risk is commonly seen among patients with diabetes and is in connection with worsened clinical conditions and higher mortality in patients with acute ischemic stroke (AIS). Therapy for stroke focuses mainly on restoring cerebral blood flow (CBF) and ameliorating neurological impairment caused by stroke. Although choices of stroke treatment remain limited, much advance have been achieved in assisting patients in recovering from ischemic stroke, along with progress of recanalization therapy through pharmacological and mechanical thrombolysis. However, it is still necessary to develop neuroprotective therapies for AIS to protect the brain against injury before and during reperfusion, prolong the time window for intervention, and consequently improve neurological prognosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are broadly regarded as effective drugs in the treatment of type 2 diabetes mellitus (T2DM). Preclinical data on GLP-1 and GLP-1 RAs have displayed an impressive neuroprotective efficacy in stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and other neurodegenerative diseases. Based on the preclinical studies in the past decade, we review recent progress in the biological roles of GLP-1 and GLP-1 RAs in ischemic stroke. Emphasis will be placed on their neuroprotective effects in experimental models of cerebral ischemia stroke at cellular and molecular levels.}, }
@article {pmid35367809, year = {2022}, author = {Truong, TT and Chiu, WT and Lai, YS and Huang, H and Jiang, X and Huang, CC}, title = {Ca[2+] signaling-mediated low-intensity pulsed ultrasound-induced proliferation and activation of motor neuron cells.}, journal = {Ultrasonics}, volume = {124}, number = {}, pages = {106739}, doi = {10.1016/j.ultras.2022.106739}, pmid = {35367809}, issn = {1874-9968}, mesh = {Animals ; *Calcium Signaling ; Cell Proliferation ; Mice ; *Motor Neurons/physiology ; NF-kappa B ; *Ultrasonic Waves ; }, abstract = {Motor neuron diseases (MND) including amyotrophic lateral sclerosis and Parkinson disease are commonly neurodegenerative, causing a gradual loss of nerve cells and affecting the mechanisms underlying changes in calcium (Ca[2+])-regulated dendritic growth. In this study, the NSC-34 cell line, a population of hybridomas generated using mouse spinal cord cells with neuroblastoma, was used to investigate the effect of low-intensity pulsed ultrasound (LIPUS) as part of an MND treatment model. After NSC-34 cells were seeded for 24 h, LIPUS stimulation was performed on the cells at days 1 and 3 using a non-focused transducer at 1.15 MHz for 8 min. NSC-34 cell proliferation and morphological changes were observed at various LIPUS intensities and different combinations of Ca[2+] channel blockers. The nuclear translocation of Ca[2+]-dependent transcription factors was also examined. We observed that the neurite outgrowth and cell number of NSC-34 significantly increased with LIPUS stimulation at days 2 and 4, which may be associated with the treatment's positive effect on the activation of Ca[2+]-dependent transcription factors, such as nuclear factor of activated T cells and nuclear factor-kappa B. Our findings suggest that the LIPUS-induced Ca[2+] signaling and transcription factor activation facilitate the morphological maturation and proliferation of NSC-34 cells, presenting a promising noninvasive method to improve stimulation therapy for MNDs in the future.}, }
@article {pmid35364656, year = {2022}, author = {Rybakowski, JK}, title = {Antiviral, immunomodulatory, and neuroprotective effect of lithium.}, journal = {Journal of integrative neuroscience}, volume = {21}, number = {2}, pages = {68}, doi = {10.31083/j.jin2102068}, pmid = {35364656}, issn = {0219-6352}, mesh = {Animals ; Antiviral Agents/pharmacology/therapeutic use ; *Bipolar Disorder/drug therapy ; Lithium/pharmacology/therapeutic use ; Lithium Compounds/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {Currently, in psychiatry, lithium is a drug of choice as a mood stabilizer in the maintenance treatment of bipolar disorder for the prevention of manic and depressive recurrences. The second most important psychiatric use of lithium is probably increasing the efficacy of antidepressants in treatment-resistant depression. In addition to its mood-stabilizing properties, lithium exerts antisuicidal, antiviral, immunomodulatory, and neuroprotective effects. The goal of the review is to describe the experimental and clinical studies on the last three properties of lithium. Antiviral effects of lithium pertain mostly to DNA viruses, especially herpes viruses. The therapeutic effects of lithium in systemic and topical administration on labial and genital herpes were demonstrated in clinical studies. There is also some evidence, mostly in experimental studies, that lithium possesses antiviral activity against RNA viruses, including coronaviruses. The immunomodulatory effect of lithium can mitigate "low-grade inflammatory" conditions in bipolar illness. The neuroprotective properties of lithium make this ion a plausible candidate for the prevention and treatment of neurodegenerative disorders. A favorable effect of lithium was shown in experimental models of neurodegenerative disorders. On the clinical level, some preventive action against dementia and moderately therapeutic activity in Alzheimer's disease, and mild cognitive impairment were observed. Despite promising results of lithium obtained in animal models of Huntington's disease and amyotrophic lateral sclerosis, they have not been confirmed in clinical studies. A suggestion for common mechanisms of antiviral, immunomodulatory, and neuroprotective effects of lithium is advanced.}, }
@article {pmid35360111, year = {2022}, author = {Martin, S and Battistini, C and Sun, J}, title = {A Gut Feeling in Amyotrophic Lateral Sclerosis: Microbiome of Mice and Men.}, journal = {Frontiers in cellular and infection microbiology}, volume = {12}, number = {}, pages = {839526}, pmid = {35360111}, issn = {2235-2988}, support = {I01 BX004824/BX/BLRD VA/United States ; R01 DK105118/DK/NIDDK NIH HHS/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; *Gastrointestinal Microbiome/physiology ; Humans ; Immunity, Innate ; *Microbiota ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severely debilitating disease characterized by progressive degeneration of motor neurons. ALS etiology and pathophysiology are not well understood. It could be the consequences of complex interactions among host factors, microbiome, and the environmental factors. Recent data suggest the novel roles of intestinal dysfunction and microbiota in ALS etiology and progression. Although microbiome may indeed play a critical role in ALS pathogenesis, studies implicating innate immunity and intestinal changes in early disease pathology are limited. The gastrointestinal symptoms in the ALS patients before their diagnosis are largely ignored in the current medical practice. This review aims to explore existing evidence of gastrointestinal symptoms and progress of microbiome in ALS pathogenesis from human and animal studies. We discuss dietary, metabolites, and possible therapeutic approaches by targeting intestinal function and microbiome. Finally, we evaluate existing evidence and identify gaps in the knowledge for future directions in ALS. It is essential to understanding the microbiome and intestinal pathogenesis that determine when, where, and whether microbiome and metabolites critical to ALS progression. These studies will help us to develop more accurate diagnosis and better treatment not only for this challenging disease, but also for other neurodegenerative diseases.}, }
@article {pmid35356196, year = {2022}, author = {Wei, L and Baeken, C and Liu, D and Zhang, J and Wu, GR}, title = {Functional connectivity-based prediction of global cognition and motor function in riluzole-naive amyotrophic lateral sclerosis patients.}, journal = {Network neuroscience (Cambridge, Mass.)}, volume = {6}, number = {1}, pages = {161-174}, pmid = {35356196}, issn = {2472-1751}, abstract = {Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a multisystem disorder accompanied by cognitive changes. To date, no effective therapy is available for ALS patients, partly due to disease heterogeneity and an imperfect understanding of the underlying pathophysiological processes. Reliable models that can predict cognitive and motor deficits are needed to improve symptomatic treatment and slow down disease progression. This study aimed to identify individualized functional connectivity-based predictors of cognitive and motor function in ALS by using multiple kernel learning (MKL) regression. Resting-state fMRI scanning was performed on 34 riluzole-naive ALS patients. Motor severity and global cognition were separately measured with the revised ALS functional rating scale (ALSFRS-R) and the Montreal Cognitive Assessment (MoCA). Our results showed that functional connectivity within the default mode network (DMN) as well as between the DMN and the sensorimotor network (SMN), fronto-parietal network (FPN), and salience network (SN) were predictive for MoCA scores. Additionally, the observed connectivity patterns were also predictive for the individual ALSFRS-R scores. Our findings demonstrate that cognitive and motor impairments may share common connectivity fingerprints in ALS patients. Furthermore, the identified brain connectivity signatures may serve as novel targets for effective disease-modifying therapies.}, }
@article {pmid35354901, year = {2022}, author = {Genç, B and Gautam, M and Helmold, BR and Koçak, N and Günay, A and Goshu, GM and Silverman, RB and Hande Ozdinler, P}, title = {NU-9 improves health of hSOD1[G93A] mouse upper motor neurons in vitro, especially in combination with riluzole or edaravone.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {5383}, pmid = {35354901}, issn = {2045-2322}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; AG061708/NH/NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Edaravone/pharmacology ; Humans ; Mice ; Motor Neurons ; *Riluzole/pharmacology/therapeutic use ; Superoxide Dismutase ; }, abstract = {Even though amyotrophic lateral sclerosis (ALS) is a disease of the upper and lower motor neurons, to date none of the compounds in clinical trials have been tested for improving the health of diseased upper motor neurons (UMNs). There is an urgent need to develop preclinical assays that include UMN health as a readout. Since ALS is a complex disease, combinatorial treatment strategies will be required to address the mechanisms perturbed in patients. Here, we describe a novel in vitro platform that takes advantage of an UMN reporter line in which UMNs are genetically labeled with fluorescence and have misfolded SOD1 toxicity. We report that NU-9, an analog of the cyclohexane-1,3-dione family of compounds, improves the health of UMNs with misfolded SOD1 toxicity more effectively than riluzole or edaravone, -the only two FDA-approved ALS drugs to date-. Interestingly, when NU-9 is applied in combination with riluzole or edaravone, there is an additive effect on UMN health, as they extend longer axons and display enhanced branching and arborization, two important characteristics of healthy UMNs in vitro.}, }
@article {pmid35353910, year = {2022}, author = {Geronimo, A and Albertson, RM and Noto, J and Simmons, Z}, title = {Ten years of riluzole use in a tertiary ALS clinic.}, journal = {Muscle &amp; nerve}, volume = {65}, number = {6}, pages = {659-666}, pmid = {35353910}, issn = {1097-4598}, support = {UL1 TR000127/TR/NCATS NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Female ; Humans ; Male ; *Neuroprotective Agents/therapeutic use ; Retrospective Studies ; Riluzole/therapeutic use ; Tracheostomy ; }, abstract = {INTRODUCTION/AIMS: Riluzole is a glutamate inhibitor approved for the treatment of amyotrophic lateral sclerosis (ALS). There are scant data on factors associated with riluzole initiation and adherence. The goal of this study was to describe the use of riluzole at the Penn State Hershey Medical Center (PSHMC) ALS clinic.<br><br>METHODS: A retrospective medical record review of ALS patients seen at the PSHMC from January 2007 to December 2016. A timeline of riluzole use was established for each patient. Factors contributing to dose changes or discontinuations were recorded. Riluzole adherence was assessed using the proportion of days covered (PDC) calculated by the patient-reported length of riluzole use divided by total time from prescription to death/censor. Multivariable analysis was performed to evaluate the association of demography and clinical course with adherence.<br><br>RESULTS: Seven hundred twenty-three records were screened, with 508 (307 men, 201 women) meeting the criteria for inclusion. The median duration of riluzole use was 435 (range, 0-3773) days. The median PDC for the group was 64%. Those with higher initial overall function and slower rate of decline were more likely to have a larger PDC. No trends in patients' demographics, riluzole use, and tracheostomy-free survival were found over time.<br><br>DISCUSSION: A high rate of riluzole initiation and adherence was found in this sample. The most common reasons for dose modification were related to adverse effects, yet social-, economic-, and patient-related factors were also common. The characteristics of riluzole prescription and use have remained relatively unchanged in a single tertiary ALS center over the past 10&#x2009;years.}, }
@article {pmid35351301, year = {2022}, author = {Barco-Antoñanzas, M and Gil-Monreal, M and Eceiza, MV and Royuela, M and Zabalza, A}, title = {Primary metabolism in an Amaranthus palmeri population with multiple resistance to glyphosate and pyrithiobac herbicides.}, journal = {Plant science : an international journal of experimental plant biology}, volume = {318}, number = {}, pages = {111212}, doi = {10.1016/j.plantsci.2022.111212}, pmid = {35351301}, issn = {1873-2259}, mesh = {*Amaranthus/genetics ; Glycine/analogs &amp; derivatives/pharmacology ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Glyphosate ; }, abstract = {The objective of this work was to characterize the resistance mechanisms and the primary metabolism of a multiple resistant (MR) population of Amaranthus palmeri to glyphosate and to the acetolactate synthase (ALS) inhibitor pyrithiobac. All MR plants analysed were glyphosate-resistant due to 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene amplification. Resistance to pyrithiobac was more variable among individuals and was related to point mutations at five positions in the ALS gene sequence: A122, A205, W574, S653 and G654. All MR plants were heterozygous for W574, the most abundant mutation. In nontreated plants, the presence of mutations did not affect ALS functionality, and plants with the W574L mutation showed the highest ALS resistance level to pyrithiobac. The accumulation of the transcripts corresponding to several genes of the aromatic amino acid (AAA) and branched-chain amino acid (BCAA) pathways detected in nontreated MR plants indicated additional effects of EPSPS gene amplification and ALS mutations. The physiological performance of the MR population after treatment with glyphosate and/or pyrithiobac was compared with that of a sensitive (S) population. The increase induced in total soluble sugars, AAA or BCAA content by both herbicides was higher in the S population than in the MR population. Physiological effects were not exacerbated after the mixture of both herbicides in S or in MR populations. This study provides new insights into the physiology of a multiple resistant A. palmeri, which could be very useful for achieving effective management of this weed.}, }
@article {pmid35350017, year = {2022}, author = {Büssing, A}, title = {[Welche Behandlungsoptionen wurden von COVID-19-infizierten Yogaübenden als hilfreich empfunden? Ergebnisse einer Querschnittsanalyse].}, journal = {Complementary medicine research}, volume = {29}, number = {4}, pages = {309-319}, pmid = {35350017}, issn = {2504-2106}, mesh = {Adult ; *COVID-19/therapy ; *Cough ; Cross-Sectional Studies ; Dyspnea ; Female ; Humans ; Male ; Middle Aged ; Pain ; }, abstract = {UNLABELLED: Einführung: Die meisten COVID-19 Infizierten machen die Infektion im häuslichen Umfeld durch und werden vermutliche Maßnahmen zur Symptomlinderung anwenden, die aus dem Bereich der Selbstverordnung kommen. Von Interesse ist daher, welche Maßnahmen von COVID-19-Infizierten genutzt werden. Methoden: Anonyme Querschnittsanalyse, bei der die eigenen Behandlungsoptionen in Bezug zu acht Haupt-symptomen mit Hilfe von Freitextfeldern erfasst und kategorisiert werden. Einbezogen wurden Datensätze von Yoga-übenden als spezifische Zielgruppe, die sich in den Zeiträumen der drei dominanten Virus-Varianten infiziert hatten (n = 208: 89% Frauen; Altersmittel 49 ± 11). Die Aussagen wurden deskriptiv dargestellt und die Inhalte der Freitextfelder nach inhaltsanalytischen Gesichtspunkten kategorisiert und den jeweiligen Hauptsymptomen einer COVID-19-Infektion zugeordnet. Ergebnisse: In Bezug auf die acht Symptomgruppen ergab sich ein differenziertes Bild der als hilfreich empfundenen Behandlungsoptionen. Die meisten Nennungen hatte die Kategorie Zeit/Ruhe/Schlaf, insbesondere bei Schwäche/Erschöpfung und Rumpf-/Gliederschmerzen, gefolgt von Atemübungen (Pranayama), die insbesondere bei Atemnot/Kurzatmigkeit und Husten zur Anwendung kamen. Yogaübungen wurden insbesondere bei Rumpf-/Gliederschmerzen sowie Schwäche/Erschöpfung genutzt. Die konventionelle Schmerzmedikation stand bei Kopfschmerzen sowie Rumpf-/Gliederschmerzen im Vordergrund. Bewegung an der frischen Luft und Spaziergänge zur Regeneration waren relevant bei Schwäche/Erschöpfung, Atemnot/Kurzatmigkeit sowie Husten. Phytotherapeutische Anwendungen waren insbesondere bei Husten bedeutsam. Ätherische Öle und Riechtraining hatten ihren Schwerpunkt bei Geruchs-/Geschmacksstörungen und Husten. Schlussfolgerungen: In Bezug auf das angewendete Spektrum der unterstützenden Therapieoptionen im Sinne des Selbstmanagements wurden einige sehr häufig und differenziert angewendet. Hier könnte man eine subjektiv empfundene "Nützlichkeit" annehmen. In der Literatur lassen sich für einige dieser Optionen auch Hinweise für eine mögliche Wirksamkeit finden, für andere nicht ohne weiteres. Diese unterstützenden Therapieoptionen könnten außerdem eine Möglichkeit sein, um einer abwar-tenden Hilflosigkeit proaktiv entgegenzuwirken.<br><br>INTRODUCTION: Most COVID-19-infected people deal with the infection in their home setting and will thus presumably use symptom-relieving measures chosen from the self-prescribing realm. It is therefore of interest which treatment options are used by COVID-19-infected people.<br><br>METHODS: Anonymous cross-sectional analysis, in which individual treatment options are recorded with free text fields. These were subsequently categorized in relation to eight main symptom groups. Data sets from yoga practitioners were included as a specific target group, who had been infected during the periods of the three dominant virus variants (n = 208: 89% women; mean age 49 &#xb1; 11). Data were presented descriptively and the content of the free text fields was categorized according to content analysis aspects and assigned to the respective main symptoms of a COVID-19 infection.<br><br>RESULTS: With regard to the eight symptom groups, a differentiated picture of the treatment options found to be helpful emerged. The category time/rest/sleep had the most mentions, especially in the case of weakness/exhaustion and pain in the trunk/limbs, followed by breathing exercises (pranayama), which were used in particular for shortness of breath and cough. Yoga exercises were used in particular for trunk/limb pain and weakness/exhaustion. Conventional pain medication was in the forefront for headaches and trunk/limb pain. Exercise in the fresh air and walks for regeneration were relevant for weakness/exhaustion, shortness of breath and cough. Phytotherapeutic applications were particularly important for coughs. Essential oils and olfactory training were used on affected smell/taste and coughs.<br><br>CONCLUSIONS: With regard to the spectrum of supportive therapy options used in the sense of self-management, some were used very frequently and in a differentiated manner. Here one may assume a subjectively perceived &#x201c;usefulness.&#x201d; Indications of a possible effectiveness can be found in the literature for some of these options, but not so easily for others. These supportive therapy options could also be a way to proactively counteract wait-and-see helplessness.}, }
@article {pmid35349255, year = {2022}, author = {Alici, H and Uversky, VN and Kang, DE and Woo, JA and Coskuner-Weber, O}, title = {Structures of the Wild-Type and S59L Mutant CHCHD10 Proteins Important in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia.}, journal = {ACS chemical neuroscience}, volume = {13}, number = {8}, pages = {1273-1280}, doi = {10.1021/acschemneuro.2c00011}, pmid = {35349255}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Humans ; Mitochondria/metabolism ; Mitochondrial Proteins/chemistry ; Mutant Proteins/genetics ; Mutation/genetics ; }, abstract = {The S59L genetic mutation of the mitochondrial coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10) is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The wild-type and mutant forms of this protein contain intrinsically disordered regions, and their structural characterization has been facing challenges. Here, for the first time in the literature, we present the structural ensemble properties of the wild-type and S59L mutant form of CHCHD10 in an aqueous solution environment at the atomic level with dynamics. Even though available experiments suggested that the S59L mutation may not change the structure of the CHCHD10 protein, our structural analysis clearly shows that the structure of this protein is significantly affected by the S59L mutation. We present here the secondary structure components with their abundances per residue, the tertiary structure properties, the free energy surfaces based on the radius of gyration and end-to-end distance values, the Ramachandran plots, the quantity of intramolecular hydrogen bonds, and the principal component analysis results. These results may be crucial in designing more efficient treatment for ALS and FTD diseases.}, }
@article {pmid35341051, year = {2022}, author = {Ababneh, NA and Al-Kurdi, B and Jamali, F and Awidi, A}, title = {A comparative study of the capability of MSCs isolated from different human tissue sources to differentiate into neuronal stem cells and dopaminergic-like cells.}, journal = {PeerJ}, volume = {10}, number = {}, pages = {e13003}, pmid = {35341051}, issn = {2167-8359}, mesh = {Humans ; Nestin/metabolism ; Neurons ; *Mesenchymal Stem Cells ; Cell Differentiation ; *Wharton Jelly ; }, abstract = {BACKGROUND: Neurodegenerative diseases are characterized by progressive neuronal loss and degeneration. The regeneration of neurons is minimal and neurogenesis is limited only to specific parts of the brain. Several clinical trials have been conducted using Mesenchymal Stem Cells (MSCs) from different sources to establish their safety and efficacy for the treatment of several neurological disorders such as Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis.<br><br>AIM: The aim of this study was to provide a comparative view of the capabilities of MSCs, isolated from different human tissue sources to differentiate into neuronal stem cell-like cells (NSCs) and possibly into dopaminergic neural- like cells.<br><br>METHODS: Mesenchymal stem cells were isolated from human bone marrow, adipose, and Wharton's jelly (WJ) tissue samples. Cells were characterized by flow cytometry for their ability to express the most common MSC markers. The differentiation potential was also assessed by differentiating them into osteogenic and adipogenic cell lineages. To evaluate the capacity of these cells to differentiate towards the neural stem cell-like lineage, cells were cultured in media containing small molecules. Cells were utilized for gene expression and immunofluorescence analysis at different time points.<br><br>RESULTS: Our results indicate that we have successfully isolated MSCs from bone marrow, adipose tissue, and Wharton's jelly. WJ-MSCs showed a slightly higher proliferation rate after 72 hours compared to BM and AT derived MSCs. Gene expression of early neural stem cell markers revealed that WJ-MSCs had higher expression of Nestin and PAX6 compared to BM and AT-MSCs, in addition to LMX expression as an early dopaminergic neural marker. Immunofluorescence analysis also revealed that these cells successfully expressed SOX1, SOX2, Nestin, TUJ1, FOXA2 and TH.<br><br>CONCLUSION: These results indicate that the protocol utilized has successfully differentiated BM, AT and WJ-MSCs into NSC-like cells. WJ-MSCs possess a higher potential to transdifferentiate into NSC and dopaminergic-like cells. Thus, it might indicate that this protocol can be used to induce MSC into neuronal lineage, which provides an additional or alternative source of cells to be used in the neurological cell-based therapies.}, }
@article {pmid35334628, year = {2022}, author = {Urata, R and Igawa, T and Suzuki, A and Sasao, Y and Isogai, N and Funao, H and Ishii, K}, title = {The Short and Intensive Rehabilitation (SHAiR) Program Improves Dropped Head Syndrome Caused by Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {58}, number = {3}, pages = {}, pmid = {35334628}, issn = {1648-9144}, mesh = {Aged ; *Amyotrophic Lateral Sclerosis/complications ; Humans ; Male ; Muscle Weakness ; *Muscular Diseases ; Neck ; Walking ; }, abstract = {Background and Objectives: Dropped head syndrome (DHS) is a syndrome that presents with correctable cervical kyphotic deformity as a result of weakening cervical paraspinal muscles. DHS with amyotrophic lateral sclerosis (ALS) is a relatively rare condition, and there is no established treatment. This is the first case report describing the improvement of both dropped head (DH) and cervical pain after the short and intensive rehabilitation (SHAiR) program in an ALS patient with DHS. Case Report: After being diagnosed with ALS in June 2020, a 75-year-old man visited our hospital in October 2020 to receive treatment for DHS. At the initial visit, the patient's DH was prominent during standing and walking. The pain intensity of the neck was 9 out of 10 on the numerical rating scale (NRS), which was indicative of severe pain. The patient was hospitalized for 2 weeks and admitted into the SHAiR program. DH began to decrease one week after undergoing the SHAiR program and improved two weeks later. Neck pain decreased from 9 to 6 on the NRS. Results: The SHAiR program is a rehabilitation program aimed at improving DH in patients with idiopathic DHS. The program was designed to improve neck extensor and flexor function and global spinal alignment, and the program may have contributed to the improvement of DH and neck pain. Currently, reports of conservative therapies for this disease are limited to the use of cervical orthosis. Although further research is needed on the safety and indications of treatment, the SHAiR program may be a viable treatment option.}, }
@article {pmid35334073, year = {2022}, author = {Yin, P and Li, S and Li, XJ and Yang, W}, title = {New pathogenic insights from large animal models of neurodegenerative diseases.}, journal = {Protein &amp; cell}, volume = {13}, number = {10}, pages = {707-720}, pmid = {35334073}, issn = {1674-8018}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Animals ; Brain/pathology ; Disease Models, Animal ; Gene Editing ; *Neurodegenerative Diseases/genetics/pathology ; Swine ; }, abstract = {Animal models are essential for investigating the pathogenesis and developing the treatment of human diseases. Identification of genetic mutations responsible for neurodegenerative diseases has enabled the creation of a large number of small animal models that mimic genetic defects found in the affected individuals. Of the current animal models, rodents with genetic modifications are the most commonly used animal models and provided important insights into pathogenesis. However, most of genetically modified rodent models lack overt neurodegeneration, imposing challenges and obstacles in utilizing them to rigorously test the therapeutic effects on neurodegeneration. Recent studies that used CRISPR/Cas9-targeted large animal (pigs and monkeys) have uncovered important pathological events that resemble neurodegeneration in the patient's brain but could not be produced in small animal models. Here we highlight the unique nature of large animals to model neurodegenerative diseases as well as the limitations and challenges in establishing large animal models of neurodegenerative diseases, with focus on Huntington disease, Amyotrophic lateral sclerosis, and Parkinson diseases. We also discuss how to use the important pathogenic insights from large animal models to make rodent models more capable of recapitulating important pathological features of neurodegenerative diseases.}, }
@article {pmid35330435, year = {2022}, author = {Antoniadi, AM and Galvin, M and Heverin, M and Wei, L and Hardiman, O and Mooney, C}, title = {A Clinical Decision Support System for the Prediction of Quality of Life in ALS.}, journal = {Journal of personalized medicine}, volume = {12}, number = {3}, pages = {}, pmid = {35330435}, issn = {2075-4426}, support = {16/RC/3948/SFI_/Science Foundation Ireland/Ireland ; ICE/2012/6 JPND/2013/1//Irish Health Research Board/ ; 17 CM-324//American ALS Association/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS), also known as Motor Neuron Disease (MND), is a rare and fatal neurodegenerative disease. As ALS is currently incurable, the aim of the treatment is mainly to alleviate symptoms and improve quality of life (QoL). We designed a prototype Clinical Decision Support System (CDSS) to alert clinicians when a person with ALS is experiencing low QoL in order to inform and personalise the support they receive. Explainability is important for the success of a CDSS and its acceptance by healthcare professionals. The aim of this work isto announce our prototype (C-ALS), supported by a first short evaluation of its explainability. Given the lack of similar studies and systems, this work is a valid proof-of-concept that will lead to future work. We developed a CDSS that was evaluated by members of the team of healthcare professionals that provide care to people with ALS in the ALS/MND Multidisciplinary Clinic in Dublin, Ireland. We conducted a user study where participants were asked to review the CDSS and complete a short survey with a focus on explainability. Healthcare professionals demonstrated some uncertainty in understanding the system's output. Based on their feedback, we altered the explanation provided in the updated version of our CDSS. C-ALS provides local explanations of its predictions in a post-hoc manner, using SHAP (SHapley Additive exPlanations). The CDSS predicts the risk of low QoL in the form of a probability, a bar plot shows the feature importance for the specific prediction, along with some verbal guidelines on how to interpret the results. Additionally, we provide the option of a global explanation of the system's function in the form of a bar plot showing the average importance of each feature. C-ALS is available online for academic use.}, }
@article {pmid35328829, year = {2022}, author = {Bette, M and Cors, E and Kresse, C and Schütz, B}, title = {Therapeutic Treatment of Superoxide Dismutase 1 (G93A) Amyotrophic Lateral Sclerosis Model Mice with Medical Ozone Decelerates Trigeminal Motor Neuron Degeneration, Attenuates Microglial Proliferation, and Preserves Monocyte Levels in Mesenteric Lymph Nodes.}, journal = {International journal of molecular sciences}, volume = {23}, number = {6}, pages = {}, pmid = {35328829}, issn = {1422-0067}, support = {Sc10/6//Deutsche Gesellschaft f&#xfc;r Muskelkranke/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/pathology ; Animals ; Cell Proliferation ; Disease Models, Animal ; Disease Progression ; Inflammation/pathology ; Lymph Nodes/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia ; Monocytes/pathology ; Nerve Degeneration/pathology ; *Neurodegenerative Diseases/pathology ; *Ozone/pharmacology/therapeutic use ; Superoxide Dismutase/genetics/pharmacology ; Superoxide Dismutase-1/genetics/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable and lethal neurodegenerative disease in which progressive motor neuron loss and associated inflammation represent major pathology hallmarks. Both the prevention of neuronal loss and neuro-destructive inflammation are still unmet challenges. Medical ozone, an ozonized oxygen mixture (O3/O2), has been shown to elicit profound immunomodulatory effects in peripheral organs, and beneficial effects in the aging brain. We investigated, in a preclinical drug testing approach, the therapeutic potential of a five-day O3/O2i.p. treatment regime at the beginning of the symptomatic disease phase in the superoxide dismutase (SOD1[G93A]) ALS mouse model. Clinical assessment of SOD1[G93A] mice revealed no benefit of medical ozone treatment over sham with respect to gross body weight, motor performance, disease duration, or survival. In the brainstem of end stage SOD1[G93A] mice, however, neurodegeneration was found decelerated, and SOD1-related vacuolization was reduced in the motor trigeminal nucleus in the O3/O2 treatment group when compared to sham-treated mice. In addition, microglia proliferation was less pronounced in the brainstem, while the hypertrophy of astroglia remained largely unaffected. Finally, monocyte numbers were reduced in the blood, spleen, and mesenteric lymph nodes at postnatal day 60 in SOD1[G93A] mice. A further decrease in monocyte numbers seen in mesenteric lymph nodes from sham-treated SOD1[G93A] mice at an advanced disease stage, however, was prevented by medical ozone treatment. Collectively, our study revealed a select neuroprotective and possibly anti-inflammatory capacity for medical ozone when applied as a therapeutic agent in SOD1[G93A] ALS mice.}, }
@article {pmid35328666, year = {2022}, author = {Ribarič, S}, title = {Physical Exercise, a Potential Non-Pharmacological Intervention for Attenuating Neuroinflammation and Cognitive Decline in Alzheimer's Disease Patients.}, journal = {International journal of molecular sciences}, volume = {23}, number = {6}, pages = {}, pmid = {35328666}, issn = {1422-0067}, support = {P3-0171//Slovenian Research Agency/ ; }, mesh = {*Alzheimer Disease/drug therapy ; *Amyotrophic Lateral Sclerosis ; Animals ; *Cognitive Dysfunction/metabolism ; Exercise ; Humans ; Inflammation/drug therapy ; Neuroinflammatory Diseases ; *Parkinson Disease ; }, abstract = {This narrative review summarises the evidence for considering physical exercise (PE) as a non-pharmacological intervention for delaying cognitive decline in patients with Alzheimer's disease (AD) not only by improving cardiovascular fitness but also by attenuating neuroinflammation. Ageing is the most important risk factor for AD. A hallmark of the ageing process is a systemic low-grade chronic inflammation that also contributes to neuroinflammation. Neuroinflammation is associated with AD, Parkinson's disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders. Pharmacological treatment of AD is currently limited to mitigating the symptoms and attenuating progression of the disease. AD animal model studies and human studies on patients with a clinical diagnosis of different stages of AD have concluded that PE attenuates cognitive decline not only by improving cardiovascular fitness but possibly also by attenuating neuroinflammation. Therefore, low-grade chronic inflammation and neuroinflammation should be considered potential modifiable risk factors for AD that can be attenuated by PE. This opens the possibility for personalised attenuation of neuroinflammation that could also have important health benefits for patients with other inflammation associated brain disorders (i.e., Parkinson's disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders). In summary, life-long, regular, structured PE should be considered as a supplemental intervention for attenuating the progression of AD in human. Further studies in human are necessary to develop optimal, personalised protocols, adapted to the progression of AD and the individual's mental and physical limitations, to take full advantage of the beneficial effects of PE that include improved cardiovascular fitness, attenuated systemic inflammation and neuroinflammation, stimulated brain Aβ peptides brain catabolism and brain clearance.}, }
@article {pmid35326301, year = {2022}, author = {Jopowicz, A and Wiśniowska, J and Tarnacka, B}, title = {Cognitive and Physical Intervention in Metals' Dysfunction and Neurodegeneration.}, journal = {Brain sciences}, volume = {12}, number = {3}, pages = {}, pmid = {35326301}, issn = {2076-3425}, abstract = {Metals-especially iron, copper and manganese-are important elements of brain functions and development. Metal-dysregulation homeostasis is associated with brain-structure damage to the motor, cognitive and emotional systems, and leads to neurodegenerative processes. There is more and more evidence that specialized cognitive and motor exercises can enhance brain function and attenuate neurodegeneration in mechanisms, such as improving neuroplasticity by altering the synaptic structure and function in many brain regions. Psychological and physical methods of rehabilitation are now becoming increasingly important, as pharmacological treatments for movement, cognitive and emotional symptoms are limited. The present study describes physical and cognitive rehabilitation methods of patients associated with metal-induced neurotoxicity such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and Wilson's disease. In our review, we describe physical (e.g., virtual-reality environments, robotic-assists training) and psychological (cognitive training, cognitive stimulation, neuropsychological rehabilitation and cognitive-behavioral and mindfulness-based therapies) methods, significantly improving the quality of life and independence of patients associated with storage diseases. Storage diseases are a diverse group of hereditary metabolic defects characterized by the abnormal cumulation of storage material in cells. This topic is being addressed due to the fact that rehabilitation plays a vital role in the treatment of neurodegenerative diseases. Unfortunately so far there are no specific guidelines concerning physiotherapy in neurodegenerative disorders, especially in regards to duration of exercise, type of exercise and intensity, as well as frequency of exercise. This is in part due to the variety of symptoms of these diseases and the various levels of disease progression. This further proves the need for more research to be carried out on the role of exercise in neurodegenerative disorder treatment.}, }
@article {pmid35326229, year = {2022}, author = {Cai, M and Yang, EJ}, title = {Combined Treatment with Bojungikgi-Tang and Riluzole Regulates Muscle Metabolism and Dysfunction in the hSOD1[G93A] Mouse Model.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {35326229}, issn = {2076-3921}, support = {NRF-2020R1A2C2006703//National Research Foundation of Korea/ ; }, abstract = {The progressive neurodegenerative disease, amyotrophic lateral sclerosis (ALS), is characterized by muscle weakness and atrophy owing to selective motoneuron degeneration. The anti-glutamatergic drug, riluzole (RZ), is the standard-of-care treatment for ALS. Bojungikgi-tang (BJIGT), a traditional herbal formula, improves motor function and prolongs the survival of mice with ALS. As ALS is a multicomplex disease, effective therapies must target multiple mechanisms. Here, we evaluated the efficacy of a BJIGT/RZ combination (5-week treatment) in 2-month-old hSOD1[G93A] mice with ALS. We performed quantitative polymerase chain reaction, Western blotting, immunohistochemistry, and enzyme activity assays. BJIGT/RZ significantly attenuated inflammation, autophagy, and metabolic and mitochondrial dysfunctions in the gastrocnemius (GC) compared with the control. It reduced the mRNA and protein levels of muscle denervation-related proteins and creatine kinase levels. The total creatine level was significantly higher in the BJIGT/RZ-treated GC. Moreover, after BJIGT/RZ treatment, the number of Nissl-stained motoneurons and choline acetyl transferase-positive neurons in the spinal cord significantly increased via the regulation of proinflammatory cytokines. Collectively, the BJIGT/RZ treatment was superior to single-drug treatments in alleviating multiple ALS-related pathological mechanisms in the ALS mouse model. Overall, BJIGT can serve as a dietary supplement and be combined with RZ to achieve superior therapeutic effects against ALS.}, }
@article {pmid35319354, year = {2022}, author = {Im, H and Lim, J}, title = {Antioxidant Responses are Crucial for Defense against Misfolded Human Z-Type α1-Antitrypsin.}, journal = {Protein and peptide letters}, volume = {29}, number = {5}, pages = {384-391}, doi = {10.2174/0929866529666220321151913}, pmid = {35319354}, issn = {1875-5305}, support = {NRF-2015R1D1A1A01058206//Korea Research Foundation, by the Korean Government/ ; }, mesh = {*Antioxidants ; Humans ; Phenotype ; Saccharomyces cerevisiae ; *alpha 1-Antitrypsin Deficiency/genetics ; }, abstract = {BACKGROUND: The Z-type variant of human α1-antitrypsin is involved in liver cirrhosis and pulmonary emphysema. Due to its slow folding characteristics, this variant accumulates folding intermediates and forms protein aggregates within hepatocytes. Misfolded proteins may induce oxidative stress and subsequent cell death.<br><br>OBJECTIVE: The potential application of antioxidant response signaling pathway and antioxidants to cope with Z-type &#x3b1;1-antitrypsin-induced oxidative stress was evaluated.<br><br>METHODS: Overexpression of Z-type &#x3b1;1-antitrypsin in Saccharomyces cerevisiae provoked oxidative stress and increased susceptibility to oxidative challenges such as hydrogen peroxide treatment. Deletion of antioxidant-response genes, including yap1, skn7, sod2, tsa1, and pst2, exacerbated the slow growth phenotype of Z-type &#x3b1;1-antitrypsin-expressing cells. Antioxidant treatment alleviated oxidative stress and cytotoxicity induced by Z-type &#x3b1;1-antitrypsin.<br><br>RESULTS: Our results show that cellular antioxidant capacity is crucial to protection against misfolded Z-type &#x3b1;1-antitrypsin.<br><br>CONCLUSION: The information obtained here may be used to prevent oxidative stress caused by misfolded proteins, which are associated with several degenerative diseases, including amyotrophic lateral sclerosis and Parkinson's disease.}, }
@article {pmid35315050, year = {2022}, author = {Zhao, H and Niu, Q}, title = {[Advance in research on pathogenetic genes for amyotrophic lateral sclerosis].}, journal = {Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics}, volume = {39}, number = {3}, pages = {343-349}, doi = {10.3760/cma.j.cn511374-20200903-00649}, pmid = {35315050}, issn = {1003-9406}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Genetic Testing ; Genotype ; Humans ; *Neurodegenerative Diseases/genetics ; Phenotype ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which is associated with genetic and environmental factors, though the pathogenesis is still unclear and there is also a lack of effective treatment. With the rapid advance of genetic testing techniques, over 30 genes have been associated with the disease. Some ALS patients harboring genetic variants may present unique clinical characteristics and particular mode of inheritance, but the correlation between genotype and phenotype is still not very clear. Studies have shown that research on the pathogenic genes of ALS is important for the diagnosis and selection of potential drug targets. Here the pathogenic genes of ALS, in particular the newly discovered genes, and their underlying mechanisms are reviewed. The necessity of genetic testing for ALS patients is also stressed.}, }
@article {pmid35304623, year = {2022}, author = {Park, YC and Lee, JY and Lee, JS and Park, JS and Oh, KW and Kim, SH and Kim, MJ}, title = {Characteristics of Dysphagia Based on the Type of ALS in Korean Patients Evaluated Using Videofluoroscopic Study: A Retrospective Analysis.}, journal = {Dysphagia}, volume = {37}, number = {6}, pages = {1748-1756}, pmid = {35304623}, issn = {1432-0460}, mesh = {Humans ; *Deglutition Disorders/diagnostic imaging/etiology ; *Amyotrophic Lateral Sclerosis/complications ; Retrospective Studies ; Severity of Illness Index ; Republic of Korea ; }, abstract = {Dysphagia is one of the main serious issues for amyotrophic lateral sclerosis (ALS) patients because of causing malnutrition and aspiration pneumonia. Early detection and management of dysphagia are essential for the long-term survival. In this study, videofluoroscopic swallowing study (VFSS) results of bulbar and spinal onset ALS patients were compared. VFSS results and revised ALS Functional Rating Scale (ALSFRS-R) score were also analyzed to assess the correlation between dysphagia and functional status of patients. ALS patients with swallowing difficulties who underwent VFSS were recruited retrospectively. Two oral, seven pharyngeal, and two esophageal components of VFSS were evaluated. An ALSRFRS-R bulbar subtype score < 9 was used to divide the groups with severe bulbar symptoms. Total 109 Korean ALS patients (39 bulbar vs 70 spinal) were included. Bulbar ALS patients exhibited a significantly longer oral transit time (OTT) then spinal ALS patients, especially in severe bulbar patients with low ALSRFRS-R bulbar subscale. In bulbar ALS patients, penetration (thick liquid), aspiration, OTT, and Penetration-Aspiration Scale (PAS) were significantly correlated with ALSFRS-R bulbar subscale score. However, in spinal ALS patients, only OTT (thin liquid) and aspiration (thick liquid) were significantly correlated with ALSFRS-R bulbar subscale score. Bulbar ALS patients demonstrated significantly longer OTT than spinal ALS patients, and ALSFRS-R bulbar subscale score also correlated well with bulbar ALS patients. Therefore, high vigilance and aggressive treatment for dysphagia especially in bulbar ALS patients rather than spinal ALS patients are mandatory.}, }
@article {pmid35298717, year = {2022}, author = {Aghanoori, MR and Agarwal, P and Gauvin, E and Nagalingam, RS and Bonomo, R and Yathindranath, V and Smith, DR and Hai, Y and Lee, S and Jolivalt, CG and Calcutt, NA and Jones, MJ and Czubryt, MP and Miller, DW and Dolinsky, VW and Mansuy-Aubert, V and Fernyhough, P}, title = {CEBPβ regulation of endogenous IGF-1 in adult sensory neurons can be mobilized to overcome diabetes-induced deficits in bioenergetics and axonal outgrowth.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {79}, number = {4}, pages = {193}, pmid = {35298717}, issn = {1420-9071}, support = {MOP-130282//Canadian Institute of Health Research/ ; }, mesh = {Aging/*metabolism ; Animals ; Antibodies, Neutralizing/pharmacology ; Axons/drug effects/metabolism/*pathology ; Base Sequence ; CCAAT-Enhancer-Binding Protein-beta/genetics/*metabolism ; Cell Respiration/drug effects ; Cells, Cultured ; Diabetes Mellitus, Experimental/genetics/*metabolism/*pathology ; Diabetes Mellitus, Type 1/genetics/pathology ; Diabetes Mellitus, Type 2/genetics/pathology ; *Energy Metabolism/drug effects ; Ganglia, Spinal/drug effects/metabolism ; Gene Expression Regulation/drug effects ; Glycolysis/drug effects ; HEK293 Cells ; Humans ; Insulin-Like Growth Factor I/genetics/*metabolism ; Liver/metabolism ; Male ; Mitochondria/drug effects/metabolism ; NFATC Transcription Factors/metabolism ; Neuronal Outgrowth/drug effects ; Polymers/metabolism ; Promoter Regions, Genetic/genetics ; Protein Transport/drug effects ; Rats, Sprague-Dawley ; Sensory Receptor Cells/*metabolism/pathology ; Signal Transduction/drug effects ; Rats ; }, abstract = {Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer's disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P < 0.05) reduced in liver and DRG from streptozotocin (STZ)-induced type 1 diabetic rats, Zucker diabetic fatty (ZDF) rats, mice on a high-fat/ high-sugar diet and db/db type 2 diabetic mice. Hyperglycemia suppressed IGF-1 gene expression in cultured DRG neurons and this was reversed by exogenous IGF-1 or the aldose reductase inhibitor sorbinil. Transcription factors, such as NFAT1 and CEBPβ, were also less enriched at the IGF-1 promoter in DRG from diabetic rats vs control rats. CEBPβ overexpression promoted neurite outgrowth and mitochondrial respiration, both of which were blunted by knocking down or blocking IGF-1. Suppression of endogenous IGF-1 in diabetes may contribute to neuropathy and its upregulation at the transcriptional level by CEBPβ can be a promising therapeutic approach.}, }
@article {pmid35296219, year = {2022}, author = {Han, HJ and Shin, HY and Choi, YC and Kim, SM and Kim, SW}, title = {Serum uric acid level predicts the progression of amyotrophic lateral sclerosis following treatment with edaravone.}, journal = {Redox report : communications in free radical research}, volume = {27}, number = {1}, pages = {79-84}, pmid = {35296219}, issn = {1743-2928}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/therapeutic use ; Humans ; Oxidative Stress ; *Uric Acid ; }, abstract = {INTRODUCTION: Uric acid and edaravone might exert a neuroprotective effect in amyotrophic lateral sclerosis (ALS) by reducing oxidative stress. We analyzed whether the treatment effect of edaravone is pronounced in patients whose uric acid level increased after the treatment with edaravone.<br><br>MATERIALS AND METHODS: Forty patients with ALS who underwent treatment with edaravone were included. Baseline uric acid level and the rate of decline in uric acid after edaravone treatment were recorded. The rate of change of ALS functional rating scale-revised (&#x394;ALSFRS-R/month) was calculated based on baseline ALSFRS-R score and ALSFRS-R score 6-24 weeks after the treatment.<br><br>RESULTS: The serum uric acid levels decreased after treatment in 26 (65%) patients and increased in 12 (30%) patients. The &#x394;ALSFRS-R/month was significantly faster in patients whose uric acid decreased (median 1.5 [Q1-Q3, 0.7-3.1]) than in patients whose uric acid increased (0.2 [0-1.0], p&#x2009;=&#x2009;0.021). A high baseline uric acid level and low rate of decline in uric acid was associated with slower disease progression after adjusting for age, initial symptoms, and riluzole administration (p&#x2009;=&#x2009;0.030 and p&#x2009;=&#x2009;0.041, respectively).<br><br>DISCUSSION: High baseline values and low rate of decline in uric acid may predict slow disease progression in ALS patients treated with edaravone.}, }
@article {pmid35294549, year = {2022}, author = {Kon, T and Mori, F and Tanji, K and Miki, Y and Nishijima, H and Nakamura, T and Kinoshita, I and Suzuki, C and Kurotaki, H and Tomiyama, M and Wakabayashi, K}, title = {Accumulation of Nonfibrillar TDP-43 in the Rough Endoplasmic Reticulum Is the Early-Stage Pathology in Amyotrophic Lateral Sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {81}, number = {4}, pages = {271-281}, doi = {10.1093/jnen/nlac015}, pmid = {35294549}, issn = {1554-6578}, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; *DNA-Binding Proteins/metabolism ; *Endoplasmic Reticulum, Rough/metabolism ; Humans ; Inclusion Bodies/pathology ; Motor Neurons/pathology ; }, abstract = {Transactivation response DNA-binding protein 43 (TDP-43)-immunoreactive neuronal cytoplasmic inclusions (NCIs) are the histopathological hallmarks of amyotrophic lateral sclerosis (ALS). They are classified as skein-like inclusions, round inclusions, dot-like inclusions, linear wisps, and diffuse punctate cytoplasmic staining (DPCS). We hypothesized that TDP-43-immunoreactive DPCS may form the early-stage pathology of ALS. Hence, we investigated phosphorylated TDP-43 pathology in the upper and lower motor neurons of patients with ALS and control participants. We designated patients whose disease duration was ≤1 year as short-duration ALS (n = 7) and those whose duration equaled 3-5 years as standard-duration ALS (n = 6). DPCS and skein-like inclusions were the most common NCIs in short-duration and standard-duration ALS, respectively. The density of DPCS was significantly higher in short-duration ALS than that in standard-duration ALS and was inversely correlated with disease duration. DPCS was not ubiquitinated and disappeared after proteinase K treatment, suggesting that it was not aggregated. Immunoelectron microscopy revealed that DPCS corresponded to nonfibrillar TDP-43 localized to the ribosomes of the rough endoplasmic reticulum (ER). These findings suggest that nonfibrillar TDP-43 accumulation in the rough ER is the earliest TDP-43 pathology in ALS, which may be helpful in developing future TDP-43 breakdown strategies for ALS.}, }
@article {pmid35292673, year = {2022}, author = {Olivera-Bravo, S and Bolatto, C and Otero Damianovich, G and Stancov, M and Cerri, S and Rodríguez, P and Boragno, D and Hernández Mir, K and Cuitiño, MN and Larrambembere, F and Isasi, E and Alem, D and Canclini, L and Marco, M and Davyt, D and Díaz-Amarilla, P}, title = {Neuroprotective effects of violacein in a model of inherited amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {4439}, pmid = {35292673}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Animals ; Disease Models, Animal ; Indoles ; Matrix Metalloproteinase 2 ; Mice ; Mice, Transgenic ; Motor Neurons/pathology ; *Neurodegenerative Diseases/pathology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Rats ; Spinal Cord/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive death of motor neurons and muscle atrophy, with defective neuron-glia interplay and emergence of aberrant glial phenotypes having a role in disease pathology. Here, we have studied if the pigment violacein with several reported protective/antiproliferative properties may control highly neurotoxic astrocytes (AbAs) obtained from spinal cord cultures of symptomatic hSOD1G93A rats, and if it could be neuroprotective in this ALS experimental model. At concentrations lower than those reported as protective, violacein selectively killed aberrant astrocytes. Treatment of hSOD1G93A rats with doses equivalent to the concentrations that killed AbAs caused a marginally significant delay in survival, partially preserved the body weight and soleus muscle mass and improved the integrity of the neuromuscular junction. Reduced motor neuron death and glial reactivity was also found and likely related to decreased inflammation and matrix metalloproteinase-2 and -9. Thus, in spite that new experimental designs aimed at extending the lifespan of hSOD1G93A rats are needed, improvements observed upon violacein treatment suggest a significant therapeutic potential that deserves further studies.}, }
@article {pmid35287738, year = {2022}, author = {Zamani, A and Walker, AK and Rollo, B and Ayers, KL and Farah, R and O'Brien, TJ and Wright, DK}, title = {Impaired glymphatic function in the early stages of disease in a TDP-43 mouse model of amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {11}, number = {1}, pages = {17}, pmid = {35287738}, issn = {2047-9158}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics/metabolism ; Animals ; DNA-Binding Proteins/genetics/metabolism ; Disease Models, Animal ; Disease Progression ; Mice ; Mice, Transgenic ; Telomere/metabolism/pathology ; Telomere Shortening ; }, abstract = {BACKGROUND: Multiple lines of evidence suggest possible impairment of the glymphatic system in amyotrophic lateral sclerosis (ALS). To investigate this, we used in vivo magnetic resonance imaging (MRI) to assess glymphatic function early in the course of disease in a transgenic mouse with doxycycline (Dox)-controlled expression of cytoplasmic human TDP-43 (hTDP-43ΔNLS), mimicking the key pathology implicated in ALS.<br><br>METHODS: Adult TDP-43 transgenic and littermate monogenic control mice underwent longitudinal multimodal MRI one and three weeks after the cessation of Dox feed, together with weekly rotarod assessments of motor performance. Glymphatic function was assessed using dynamic contrast-enhanced MRI to track the clearance of an MR contrast agent injected into the cisterna magna.<br><br>RESULTS: Compared to their littermate controls, TDP-43 mice exhibited progressive neurodegeneration including that within the primary motor cortex, primary somatosensory cortex and corticospinal tract, significant weight loss including gastrocnemius atrophy, and shortened telomere length. Furthermore, in the presence of this ALS-like phenotype, these mice have significantly disrupted glymphatic function.<br><br>CONCLUSIONS: Although the relationship between glymphatic clearance and ALS disease progression remains to be elucidated, these changes occurred very early in the disease course. This provides initial evidence to suggest that the glymphatic system might be a potential therapeutic target in the treatment of ALS.}, }
@article {pmid35281495, year = {2022}, author = {Bigelow, LJ and Perry, MA and Ogilvie, SL and Tasker, RA}, title = {Longitudinal Assessment of Behaviour and Associated Bio-Markers Following Chronic Consumption of β-Sitosterol β-D-Glucoside in Rats: A Putative Model of Parkinson's Disease.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {810148}, pmid = {35281495}, issn = {1662-4548}, abstract = {The consumption of cycad (Cycas circinalis) seeds has been linked to the development of Amyotrophic Lateral Sclerosis-Parkinsonism Dementia Complex (ALS-PDC) in humans. ALS-PDC is a clinically variable disease presenting as a combination of symptoms typical of PD and/or ALS. Chronic consumption of β-sitosterol β-D-glucoside (BSSG), a component of the cycad seed, by rats (Rattus norvegicus) has been previously reported to initiate a progressive pathology that develops over several months and manifests as behavioural and histopathological changes that resemble characteristic features of Parkinson's disease. As part of an independent multi-site validation study, we have tried to replicate and further characterize the BSSG model with a focus on motor function, and associated immunohistochemical markers. Beginning at 3 months of age, male CD[®] (Sprague Dawley) rats (N = 80) were dosed orally with either a flour pellet or a flour pellet containing BSSG (3 mg) daily (5×/week) for 16 weeks consistent with previous reports of the model. Following BSSG intoxication, separate cohorts of animals (n = 10/treatment) were exposed to a behavioural test battery at 16, 24, 32, or 40 weeks post-initial BSSG feeding. The test battery consisted of the open field test, cylinder test, and ultrasonic vocalization (USV) assessment. No changes in behaviour were observed at any time point. Following behavioural testing, animals were processed for immunohistochemical markers of substantia nigra integrity. Immunohistochemistry of brain tissue revealed no differences in the microglial marker, Iba1, or the dopaminergic integrity marker, tyrosine hydroxylase (TH), in the substantia nigra at any assessment point. The absence of any group differences in behaviour and immunhistochemistry indicates an inability to replicate previous reports. Further investigation into the sources of variability in the model is necessary prior to further utilization of the BSSG model in preclinical studies.}, }
@article {pmid35281483, year = {2022}, author = {Qosja, K and Absar, NM and Yu, AT}, title = {Frontotemporal Dementia as a Possible Manifestation of Primary Lateral Sclerosis: A Case Report and Literature Review.}, journal = {Case reports in psychiatry}, volume = {2022}, number = {}, pages = {8936467}, pmid = {35281483}, issn = {2090-682X}, abstract = {Primary lateral sclerosis (PLS) is currently defined as a restricted phenotype of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with upper motor neuron (UMN) symptoms that causes slowly progressive spasticity. The diagnostic criteria of this disorder currently do not include any effects on frontal executive or other cortical functioning. We report an 84-year-old woman diagnosed with six years of PLS who also had concurrent symptoms of difficulties in language, anxiety, emotional lability, and executive function. This case, as well as previously reported cases in the literature, is an example that shows the importance of more widespread consideration for PLS in patients with UMN signs and indications of frontotemporal dementia (FTD). Increased consideration for PLS would be beneficial for many patients and positively affect treatment, especially since patients live with the disorder for longer periods than ALS.}, }
@article {pmid35280283, year = {2022}, author = {Petro, TM and Agarkova, IV and Esmael, A and Dunigan, DD and Van Etten, JL and Pattee, GL}, title = {Chlorovirus ATCV-1 Accelerates Motor Deterioration in SOD1-G93A Transgenic Mice and Its SOD1 Augments Induction of Inflammatory Factors From Murine Macrophages.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {821166}, pmid = {35280283}, issn = {1664-2295}, abstract = {BACKGROUND: Genetically polymorphic Superoxide Dismutase 1 G93A (SOD1-G93A) underlies one form of familial Amyotrophic Lateral Sclerosis (ALS). Exposures from viruses may also contribute to ALS, possibly by stimulating immune factors, such as IL-6, Interferon Stimulated Genes, and Nitric Oxide. Recently, chlorovirus ATCV-1, which encodes a SOD1, was shown to replicate in macrophages and induce inflammatory factors.<br><br>OBJECTIVE: This study aimed to determine if ATCV-1 influences development of motor degeneration in an ALS mouse model and to assess whether SOD1 of ATCV-1 influences production of inflammatory factors from macrophages.<br><br>METHODS: Sera from sporadic ALS patients were screened for antibody to ATCV-1. Active or inactivated ATCV-1, saline, or a viral mimetic, polyinosinic:polycytidylic acid (poly I:C) were injected intracranially into transgenic mice expressing human SOD1-G93A- or C57Bl/6 mice. RAW264.7 mouse macrophage cells were transfected with a plasmid vector expressing ATCV-1 SOD1 or an empty vector prior to stimulation with poly I:C with or without Interferon-gamma (IFN-&#x3b3;).<br><br>RESULTS: Serum from sporadic ALS patients had significantly more IgG1 antibody directed against ATCV-1 than healthy controls. Infection of SOD1-G93A mice with active ATCV-1 significantly accelerated onset of motor loss, as measured by tail paralysis, hind limb tucking, righting reflex, and latency to fall in a hanging cage-lid test, but did not significantly affect mortality when compared to saline-treated transgenics. By contrast, poly I:C treatment significantly lengthened survival time but only minimally slowed onset of motor loss, while heat-inactivated ATCV-1 did not affect motor loss or survival. ATCV-1 SOD1 significantly increased expression of IL-6, IL-10, ISG promoter activity, and production of Nitric Oxide from RAW264.7 cells.<br><br>CONCLUSION: ATCV-1 chlorovirus encoding an endogenous SOD1 accelerates pathogenesis but not mortality, while poly I:C that stimulates antiviral immune responses delays mortality in an ALS mouse model. ATCV-1 SOD1 enhances induction of inflammatory factors from macrophages.}, }
@article {pmid35280276, year = {2022}, author = {Zhang, L and Ji, T and Wu, C and Zhang, S and Tang, L and Zhang, N and Liu, X and Fan, D}, title = {Serum Neurofilament Light Chain Levels May Be a Marker of Lower Motor Neuron Damage in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {833507}, pmid = {35280276}, issn = {1664-2295}, abstract = {Objectives The aims of this study were to investigate whether serum neurofilament light chain (NfL) levels were correlated with the severity of the axonal degeneration of lower motor neurons (LMNs) in the early symptomatic phase of amyotrophic lateral sclerosis (ALS). Methods In this prospective study, the serum samples used for NfL measurement were obtained from 103 sporadic ALS outpatients within 2 years of disease duration. The severity of axonal degeneration was assessed by assessing the decrease in the compound muscle action potentials (CMAPs) within a 1-month interval from serum sampling. Results The NfL levels showed a significant positive correlation with the relative score as a proxy for the axonal damage of LMNs in patients with ALS (coefficient: 0.264, p = 0.009). Furthermore, this correlation became stronger (coefficient: 0.582, p = 0.037) when estimated only among patients with disease subtypes that involve only LMNs, that is, patients with flail arm or leg syndrome (FAS or FLS). The levels of NfL increased with the severity of axonal damage of LMNs (F = 6.694, P = 0.0001). Conclusions Serum NfL levels mirrored the severity of the axonal degeneration of LMNs, particularly in patients with signs of predominant LMN involvement. These results may have a profound effect on the selection of patients and the monitoring of treatment efficacy in future disease-modifying clinical trials.}, }
@article {pmid35279589, year = {2022}, author = {Morioka, H and Hirayama, T and Sugisawa, T and Murata, K and Shibukawa, M and Ebina, J and Sawada, M and Hanashiro, S and Nagasawa, J and Yanagihashi, M and Uchi, M and Kawabe, K and Washizawa, N and Ebihara, S and Nakajima, T and Kano, O}, title = {Robot-assisted training using hybrid assistive limb ameliorates gait ability in patients with amyotrophic lateral sclerosis.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {99}, number = {}, pages = {158-163}, doi = {10.1016/j.jocn.2022.02.032}, pmid = {35279589}, issn = {1532-2653}, mesh = {Activities of Daily Living ; *Amyotrophic Lateral Sclerosis/complications ; Exercise Therapy ; Gait ; Humans ; *Robotics ; }, abstract = {OBJECTIVE: The Hybrid Assistive Limb (HAL; CYBERDYNE, Inc., Japan) is a wearable robot device that provides effective gait assistance according to voluntary intention by detecting weak bioelectrical signals of neuromuscular activity on the surface of the skin. We used HAL for patients with amyotrophic lateral sclerosis (ALS) to determine whether HAL training had an effect on their gait ability.<br><br>METHODS: We conducted a single-center, single-arm, observational study. Patients with ALS underwent HAL training once per day (20-40&#xa0;min per session) for 9-10&#xa0;days for at least 4&#xa0;weeks. Gait ability was evaluated using the 2-minute walk test, the 10-meter walk test without the assistance of HAL, and activities of daily living (ADL) using the Barthel Index and Functional Independence Measures before and after a full course of HAL training.<br><br>RESULTS: There were no dropouts or adverse events during the observation period. Gait function improved after HAL training. The 2-minute walk test revealed a mean gait distance of 73.87&#xa0;m (36.65) at baseline and 89.9m (36.70) after HAL training (p = 0.004). The 10-meter walk test showed significantly improved cadence, although gait speed, step length on the 10-m walk, or ADL measurements did not change significantly.<br><br>CONCLUSIONS: Although HAL is not a curative treatment for ALS, our data suggest that HAL may be effective in ameliorating and preserving gait ability in patients with ALS.}, }
@article {pmid35278658, year = {2022}, author = {Ding, Y and Botchway, BOA and Zhang, Y and Jin, T and Liu, X}, title = {The combination of autologous mesenchymal stem cell-derived exosomes and neurotrophic factors as an intervention for amyotrophic lateral sclerosis.}, journal = {Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft}, volume = {242}, number = {}, pages = {151921}, doi = {10.1016/j.aanat.2022.151921}, pmid = {35278658}, issn = {1618-0402}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; *Exosomes ; Humans ; *Mesenchymal Stem Cells/physiology ; Motor Neurons ; Nerve Growth Factors ; }, abstract = {Amyotrophic lateral sclerosis is a chronic progressive degeneration of motor neurons and has a high mortality. Riluzole and edaravone are the only approved medications currently being used for amyotrophic lateral sclerosis in clinical settings. However, they can lead to serious complications, such as injuries to the liver and kidney. To date, there is no effective treatment for amyotrophic lateral sclerosis. In this regard, investigations concerning the employment of exosomes, mesenchymal stem cells, and neurotrophic factors to ameliorate amyotrophic lateral sclerosis are attracting considerable attention in the scientific community. Herein, we systematically analyze the relationship relevant to autologous mesenchymal stem cell derived-exosomes, neurotrophic factors and amyotrophic lateral sclerosis. Mesenchymal stem cells modulate immune response, mitigate oxidative stress, promote neuronal regeneration, and differentiate into neuronal and glial cells. Furthermore, exosomes from mesenchymal stem cells exert beneficial effects on their mother cells by preventing abnormal differentiation of mesenchymal stem cells. Similarly, neurotrophic factors regulate inflammatory response, stimulate the neuron repair, and the recovery of neuronal functioning. Therefore, autologous mesenchymal stem cells-derived exosomes combined with neurotrophic factors could potentially be an effective interventional medium for amyotrophic lateral sclerosis.}, }
@article {pmid35277554, year = {2022}, author = {Gautam, M and Gunay, A and Chandel, NS and Ozdinler, PH}, title = {Mitochondrial dysregulation occurs early in ALS motor cortex with TDP-43 pathology and suggests maintaining NAD[+] balance as a therapeutic strategy.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {4287}, pmid = {35277554}, issn = {2045-2322}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Animals ; DNA-Binding Proteins/genetics/metabolism ; Humans ; Mice ; Mice, Transgenic ; *Motor Cortex/metabolism ; NAD/metabolism ; Tandem Mass Spectrometry ; }, abstract = {Mitochondrial defects result in dysregulation of metabolomics and energy homeostasis that are detected in upper motor neurons (UMNs) with TDP-43 pathology, a pathology that is predominantly present in both familial and sporadic cases of amyotrophic lateral sclerosis (ALS). While same mitochondrial problems are present in the UMNs of ALS patients with TDP-43 pathology and UMNs of TDP-43 mouse models, and since pathologies are shared at a cellular level, regardless of species, we first analyzed the metabolite profile of both healthy and diseased motor cortex to investigate whether metabolomic changes occur with respect to TDP-43 pathology. High-performance liquid chromatography, high-resolution mass spectrometry and tandem mass spectrometry (HPLC-MS/MS) for metabolite profiling began to suggest that reduced levels of NAD+ is one of the underlying causes of metabolomic problems. Since nicotinamide mononucleotide (NMN) was reported to restore NAD[+] levels, we next investigated whether NMN treatment would improve the health of diseased corticospinal motor neurons (CSMN, a.k.a. UMN in mice). prpTDP-43[A315T]-UeGFP mice, the CSMN reporter line with TDP-43 pathology, allowed cell-type specific responses of CSMN to NMN treatment to be assessed in vitro. Our results show that metabolomic defects occur early in ALS motor cortex and establishing NAD[+] balance could offer therapeutic benefit to UMNs with TDP-43 pathology.}, }
@article {pmid35272713, year = {2022}, author = {Cox, LM and Calcagno, N and Gauthier, C and Madore, C and Butovsky, O and Weiner, HL}, title = {The microbiota restrains neurodegenerative microglia in a model of amyotrophic lateral sclerosis.}, journal = {Microbiome}, volume = {10}, number = {1}, pages = {47}, pmid = {35272713}, issn = {2049-2618}, support = {R01NS088137/NS/NINDS NIH HHS/United States ; R01AG054672/AG/NIA NIH HHS/United States ; R01 NS088137/NS/NINDS NIH HHS/United States ; R01NS115951/NS/NINDS NIH HHS/United States ; R01AG051812/AG/NIA NIH HHS/United States ; R01 AG054672/AG/NIA NIH HHS/United States ; R01 NS115951/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; Anti-Bacterial Agents/pharmacology ; Disease Models, Animal ; Disease Progression ; Mice ; Mice, Transgenic ; *Microbiota ; Microglia/pathology ; *Neurodegenerative Diseases/pathology ; Superoxide Dismutase/genetics/pharmacology/therapeutic use ; Superoxide Dismutase-1/genetics/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: The gut microbiota can affect neurologic disease by shaping microglia, the primary immune cell in the central nervous system (CNS). While antibiotics improve models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and the C9orf72 model of amyotrophic lateral sclerosis (ALS), antibiotics worsen disease progression the in SOD1[G93A] model of ALS. In ALS, microglia transition from a homeostatic to a neurodegenerative (MGnD) phenotype and contribute to disease pathogenesis, but whether this switch can be affected by the microbiota has not been investigated.<br><br>RESULTS: In this short report, we found that a low-dose antibiotic treatment worsened motor function and decreased survival in the SOD1 mice, which is consistent with studies using high-dose antibiotics. We also found that co-housing SOD1 mice with wildtype mice had no effect on disease progression. We investigated changes in the microbiome and found that antibiotics reduced Akkermansia and butyrate-producing bacteria, which may be beneficial in ALS, and cohousing had little effect on the microbiome. To investigate changes in CNS resident immune cells, we sorted spinal cord microglia and found that antibiotics downregulated homeostatic genes and increased neurodegenerative disease genes in SOD1 mice. Furthermore, antibiotic-induced changes in microglia preceded changes in motor function, suggesting that this may be contributing to disease progression.<br><br>CONCLUSIONS: Our findings suggest that the microbiota play a protective role in the SOD1 model of ALS by restraining MGnD microglia, which is opposite to other neurologic disease models, and sheds new light on the importance of disease-specific interactions between microbiota and microglia. Video abstract.}, }
@article {pmid35272709, year = {2022}, author = {Kim, D and Kim, S and Sung, A and Patel, N and Wong, N and Conboy, MJ and Conboy, IM}, title = {Autologous treatment for ALS with implication for broad neuroprotection.}, journal = {Translational neurodegeneration}, volume = {11}, number = {1}, pages = {16}, pmid = {35272709}, issn = {2047-9158}, support = {R01 AG071787/AG/NIA NIH HHS/United States ; R01 EB023776/EB/NIBIB NIH HHS/United States ; R01 HL139605/HL/NHLBI NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Animals ; Humans ; Hydrogen Peroxide ; Mice ; Mice, Transgenic ; Neuroprotection ; Paralysis ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by a progressive loss of motor neurons (MNs), leading to paralysis, respiratory failure and death within 2-5 years of diagnosis. The exact mechanisms of sporadic ALS, which comprises 90% of all cases, remain unknown. In familial ALS, mutations in superoxide dismutase (SOD1) cause 10% of cases.<br><br>METHODS: ALS patient-derived human-induced pluripotent stem cells (ALS hiPSCs, harboring the SOD1[AV4] mutation), were differentiated to MNs (ALS-MNs). The neuroprotective effects of conditioned medium (CM) of hESCs (H9), wt hiPSCs (WTC-11) and the ALS iPSCs, on MN apoptosis and viability, formation and maintenance of neurites, mitochondrial activity and expression of inflammatory genes, were examined. For in vivo studies, 200&#xa0;&#x3bc;l of CM from the ALS iPSCs (CS07 and CS053) was injected subcutaneously into the ALS model mice (transgenic for the human SOD1[G93A] mutation). Animal agility and strength, muscle innervation and mass, neurological score, onset of paralysis and lifespan of the ALS mice were assayed. After observing significant disease-modifying effects, the CM was characterized biochemically by fractionation, comparative proteomics, and epigenetic screens for the dependence on pluripotency. CM of fibroblasts that were differentiated from the wt hiPSCs lacked any neuroprotective activity and was used as a negative control throughout the studies.<br><br>RESULTS: The secretome of PSCs including the ALS patient iPSCs was neuroprotective in the H2O2 model. In the model with pathogenic SOD1 mutation, ALS iPSC-CM attenuated all examined hallmarks of ALS pathology, rescued human ALS-MNs from denervation and death, restored mitochondrial health, and reduced the expression of inflammatory genes. The ALS iPSC-CM also improved neuro-muscular health and function, and&#xa0;delayed paralysis and morbidity in ALS mice. Compared side by side, cyclosporine (CsA), a mitochondrial membrane blocker that prevents the leakage of mitochondrial DNA, failed to avert the death of ALS-MNs, although CsA and ALS iPSC-CM equally stabilized MN mitochondria and attenuated inflammatory genes. Biochemical characterization, comparative proteomics, and epigenetic screen all suggested that it was the interactome of several key proteins from different fractions of PSC-CM that delivered the multifaceted neuroprotection.<br><br>CONCLUSIONS: This work introduces and mechanistically characterizes a new biologic for treating ALS and other complex neurodegenerative diseases.}, }
@article {pmid35272595, year = {2022}, author = {Chavda, VP and Patel, C and Modh, D and Ertas, YN and Sonak, SS and Munshi, NK and Anand, K and Soni, A and Pande, S}, title = {Therapeutic Approaches to Amyotrophic Lateral Sclerosis from the Lab to the Clinic.}, journal = {Current drug metabolism}, volume = {23}, number = {3}, pages = {200-222}, doi = {10.2174/1389200223666220310113110}, pmid = {35272595}, issn = {1875-5453}, support = {118C346//T&#xdc;B&#x130;TAK/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/therapy ; Animals ; Genetic Therapy ; Humans ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a terminal neuro-degenerative disorder that is clinically recognized as a gradual degeneration of the upper and lower motor neurons, with an average duration of 3 to 5 years from initial of symptoms to death. The mechanisms underlying the pathogenesis and progression of the disease are multifactorial. Therefore, to find effective treatments, it is necessary to understand the heterogeneity underlying the progression of ALS. Recent developments in gene therapy have opened a new avenue to treat this condition, especially for the characterized genetic types. Gene therapy methods have been studied in various pre-clinical settings and clinical trials, and they may be a promising path for developing an effective and safe ALS cure. A growing body of evidence demonstrates abnormalities in metabolic energy at the cellular and whole-body level in animal models and people living with ALS. Using and incorporatig high-throughput "omics" methods have radically transformed our thoughts about ALS, strengthened our understanding of the disease's dynamic molecular architecture, differentiated distinct patient subtypes, and created a reasonable basis for identifying biomarkers and novel individualised treatments. Future clinical and laboratory trials would also focus on the diverse relationships between metabolism and ALS to address the issue of whether targeting poor metabolism in ALS is an effective way to change disease progression. In this review, we focus on the detailed pathogenesis of ALS and highlight principal genes, i.e., SOD1, TDP-43, C9orf72, and FUS, as well as targeted ALS therapies. An attempt is made to provide up-to-date clinical outcomes, including various biomarkers that are thought to be important players in early ALS detection.}, }
@article {pmid35269723, year = {2022}, author = {Pansarasa, O and Garofalo, M and Scarian, E and Dragoni, F and Garau, J and Di Gerlando, R and Diamanti, L and Bordoni, M and Gagliardi, S}, title = {Biomarkers in Human Peripheral Blood Mononuclear Cells: The State of the Art in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {23}, number = {5}, pages = {}, pmid = {35269723}, issn = {1422-0067}, support = {GR-2016-02361552//Ministero della Salute/ ; RC2020-2021//Ministero della Salute/ ; MLOpathy//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism ; Biomarkers/metabolism ; Humans ; Leukocytes, Mononuclear/metabolism ; Motor Neurons/metabolism ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the progressive loss of lower motor neurons, weakness and muscle atrophy. ALS lacks an effective cure and diagnosis is often made by exclusion. Thus, it is imperative to search for biomarkers. Biomarkers can help in understanding ALS pathomechanisms, identification of targets for treatment and development of effective therapies. Peripheral blood mononuclear cells (PBMCs) represent a valid source for biomarkers compared to cerebrospinal fluid, as they are simple to collect, and to plasma, because of the possibility of detecting lower expressed proteins. They are a reliable model for patients' stratification. This review provides an overview on PBMCs as a potential source of biomarkers in ALS. We focused on altered RNA metabolism (coding/non-coding RNA), including RNA processing, mRNA stabilization, transport and translation regulation. We addressed protein abnormalities (aggregation, misfolding and modifications); specifically, we highlighted that SOD1 appears to be the most characterizing protein in ALS. Finally, we emphasized the correlation between biological parameters and disease phenotypes, as regards prognosis, severity and clinical features. In conclusion, even though further studies are needed to standardize the use of PBMCs as a tool for biomarker investigation, they represent a promising approach in ALS research.}, }
@article {pmid35269543, year = {2022}, author = {Sever, B and Ciftci, H and DeMirci, H and Sever, H and Ocak, F and Yulug, B and Tateishi, H and Tateishi, T and Otsuka, M and Fujita, M and Başak, AN}, title = {Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {23}, number = {5}, pages = {}, pmid = {35269543}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Combined Modality Therapy/*methods ; Deep Brain Stimulation ; Drug Discovery ; Edaravone/therapeutic use ; Humans ; Induced Pluripotent Stem Cells/transplantation ; Riluzole/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.}, }
@article {pmid35268587, year = {2022}, author = {Wu, L and Gu, YC and Li, YH and Meng, FF and Zhou, S and Li, ZM}, title = {Degradation of 5-Dialkylamino-Substituted Chlorsulfuron Derivatives in Alkaline Soil.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {5}, pages = {}, pmid = {35268587}, issn = {1420-3049}, support = {Syngenta PhD Scholarship//Syngenta PhD Scholarship/ ; 2021YFD1700103//National Key Research and Development Program of China , Nankai University/ ; }, abstract = {Sulfonylurea herbicides are widely used as acetolactate synthase (ALS) inhibitors due to their super-efficient activity. However, some sulfonylurea herbicides show toxicity under crop rotation due to their long degradation time, for example, chlorsulfuron. Our research goal is to obtain chlorsulfuron-derived herbicides with controllable degradation time, good crop safety and high herbicidal activities. Based on our previously reported results in acidic soil, we studied the degradation behaviors of 5-dialkylamino-substituted chlorsulfuron derivatives (NL101-NL108) in alkaline soil (pH 8.39). The experimental data indicate that addition of the 5-dialkylamino groups on the benzene ring of chlorsulfuron greatly accelerated degradation in alkaline soil. These chlorsulfuron derivatives degrade 10.8 to 51.8 times faster than chlorsulfuron and exhibit excellent crop safety on wheat and corn (through pre-emergence treatment). With a comprehensive consideration of structures, bioassay activities, soil degradation and crop safety, it could be concluded that 5-dialkylamino-substituted chlorsulfuron derivatives are potential green sulfonylurea herbicides for pre-emergence treatment on both wheat and corn. The study also provides valuable information for the discovery of new sulfonylurea herbicides for crop rotation.}, }
@article {pmid35268572, year = {2022}, author = {Arslanbaeva, L and Bisaglia, M}, title = {Activation of the Nrf2 Pathway as a Therapeutic Strategy for ALS Treatment.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {5}, pages = {}, pmid = {35268572}, issn = {1420-3049}, support = {PG_25_2020//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {*NF-E2-Related Factor 2/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy ; Humans ; Animals ; *Signal Transduction/drug effects ; *Oxidative Stress/drug effects ; Antioxidants/pharmacology/therapeutic use ; Astrocytes/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis is a progressive and fatal disease that causes motoneurons degeneration and functional impairment of voluntary muscles, with limited and poorly efficient therapies. Alterations in the Nrf2-ARE pathway are associated with ALS pathology and result in aberrant oxidative stress, making the stimulation of the Nrf2-mediated antioxidant response a promising therapeutic strategy in ALS to reduce oxidative stress. In this review, we first introduce the involvement of the Nrf2 pathway in the pathogenesis of ALS and the role played by astrocytes in modulating such a protective pathway. We then describe the currently developed activators of Nrf2, used in both preclinical animal models and clinical studies, taking into consideration their potentialities as well as the possible limitations associated with their use.}, }
@article {pmid35266043, year = {2022}, author = {Tavazzi, E and Daberdaku, S and Zandonà, A and Vasta, R and Nefussy, B and Lunetta, C and Mora, G and Mandrioli, J and Grisan, E and Tarlarini, C and Calvo, A and Moglia, C and Drory, V and Gotkine, M and Chiò, A and Di Camillo, B and , }, title = {Predicting functional impairment trajectories in amyotrophic lateral sclerosis: a probabilistic, multifactorial model of disease progression.}, journal = {Journal of neurology}, volume = {269}, number = {7}, pages = {3858-3878}, pmid = {35266043}, issn = {1432-1459}, support = {ERRALS register grant//Regione Emilia-Romagna/ ; 259867//Seventh Framework Programme/ ; "Departments of Excellence" (Law 232/2016)//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; PRIN, grant 2017SNW5MB//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; CompALS project//Ministero degli Affari Esteri e della Cooperazione Internazionale/ ; Ricerca Sanitaria Finalizzata, grant RF-2016-02362//Ministero della Salute/ ; CompALS project//Ministry of Science, Technology and Space of the State of Israel/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Artificial Intelligence ; Bayes Theorem ; Disease Progression ; Humans ; Models, Statistical ; }, abstract = {OBJECTIVE: To employ Artificial Intelligence to model, predict and simulate the amyotrophic lateral sclerosis (ALS) progression over time in terms of variable interactions, functional impairments, and survival.<br><br>METHODS: We employed demographic and clinical variables, including functional scores and the utilisation of support interventions, of 3940 ALS patients from four Italian and two Israeli registers to develop a new approach based on Dynamic Bayesian Networks (DBNs) that models the ALS evolution over time, in two distinct scenarios of variable availability. The method allows to simulate patients' disease trajectories and predict the probability of functional impairment and survival at different time points.<br><br>RESULTS: DBNs explicitly represent the relationships between the variables and the pathways along which they influence the disease progression. Several notable inter-dependencies were identified and validated by comparison with literature. Moreover, the implemented tool allows the assessment of the effect of different markers on the disease course, reproducing the probabilistically expected clinical progressions. The tool shows high concordance in terms of predicted and real prognosis, assessed as time to functional impairments and survival (integral of the AU-ROC in the first 36&#xa0;months between 0.80-0.93 and 0.84-0.89 for the two scenarios, respectively).<br><br>CONCLUSIONS: Provided only with measurements commonly collected during the first visit, our models can predict time to the loss of independence in walking, breathing, swallowing, communicating, and survival and it can be used to generate in silico patient cohorts with specific characteristics. Our tool provides a comprehensive framework to support physicians in treatment planning and clinical decision-making.}, }
@article {pmid35262502, year = {2022}, author = {Gopal, A and Hsu, WY and Allen, DD and Bove, R}, title = {Remote Assessments of Hand Function in Neurological Disorders: Systematic Review.}, journal = {JMIR rehabilitation and assistive technologies}, volume = {9}, number = {1}, pages = {e33157}, pmid = {35262502}, issn = {2369-2529}, abstract = {BACKGROUND: Loss of fine motor skills is observed in many neurological diseases, and remote monitoring assessments can aid in early diagnosis and intervention. Hand function can be regularly assessed to monitor loss of fine motor skills in people with central nervous system disorders; however, there are challenges to in-clinic assessments. Remotely assessing hand function could facilitate monitoring and supporting of early diagnosis and intervention when warranted.<br><br>OBJECTIVE: Remote assessments can facilitate the tracking of limitations, aiding in early diagnosis and intervention. This study aims to systematically review existing evidence regarding the remote assessment of hand function in populations with chronic neurological dysfunction.<br><br>METHODS: PubMed and MEDLINE, CINAHL, Web of Science, and Embase were searched for studies that reported remote assessment of hand function (ie, outside of traditional in-person clinical settings) in adults with chronic central nervous system disorders. We excluded studies that included participants with orthopedic upper limb dysfunction or used tools for intervention and treatment. We extracted data on the evaluated hand function domains, validity and reliability, feasibility, and stage of development.<br><br>RESULTS: In total, 74 studies met the inclusion criteria for Parkinson disease (n=57, 77% studies), stroke (n=9, 12%), multiple sclerosis (n=6, 8%), spinal cord injury (n=1, 1%), and amyotrophic lateral sclerosis (n=1, 1%). Three assessment modalities were identified: external device (eg, wrist-worn accelerometer), smartphone or tablet, and telerehabilitation. The feasibility and overall participant acceptability were high. The most common hand function domains assessed included finger tapping speed (fine motor control and rigidity), hand tremor (pharmacological and rehabilitation efficacy), and finger dexterity (manipulation of small objects required for daily tasks) and handwriting (coordination). Although validity and reliability data were heterogeneous across studies, statistically significant correlations with traditional in-clinic metrics were most commonly reported for telerehabilitation and smartphone or tablet apps. The most readily implementable assessments were smartphone or tablet-based.<br><br>CONCLUSIONS: The findings show that remote assessment of hand function is feasible in neurological disorders. Although varied, the assessments allow clinicians to objectively record performance in multiple hand function domains, improving the reliability of traditional in-clinic assessments. Remote assessments, particularly via telerehabilitation and smartphone- or tablet-based apps that align with in-clinic metrics, facilitate clinic to home transitions, have few barriers to implementation, and prompt remote identification and treatment of hand function impairments.}, }
@article {pmid35250834, year = {2022}, author = {Li, JT and Dong, SQ and Qian, T and Yang, WB and Chen, XJ}, title = {Mouse Nerve Growth Factor Injection and Progression Rate in Patients With Amyotrophic Lateral Sclerosis: An Observational Study.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {829569}, pmid = {35250834}, issn = {1664-2295}, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease with no curative treatment up to now. This study aims to analyze ALS progression of patients treated with mouse nerve growth factor (mNGF), as well as the effects, side effects, and adverse events of the therapy.<br><br>MATERIALS AND METHODS: A retrospective, observational study was performed including 94 patients with ALS from July 2020 to July 2021. Thirty-two of them were treated with at least one course of mNGF on a regular riluzole use, and the rest 62 were treated with riluzole only. The declining rates of body mass index (BMI) and ALS Functional Rating Scale-Revised (ALSFRS-R) scores were compared between the two groups to indicate ALS progression.<br><br>RESULTS: No significant differences in ALS progression indicated by the declining rates of BMI and ALSFRS-R score were observed between the two cohorts. ALS progression before and after the first treatment course of mNGF also showed no discernible difference. However, we noticed a moderate 62.7 and 25.1% reduction in the declining rate of BMI and ALSFRS-R motor subscore when comparing mNGF + riluzole treatment to riluzole only. The mNGF treatment was overall safe and well-tolerated, and a rare case of diarrhea was reported after mNGF injection.<br><br>CONCLUSIONS: Our study revealed that mNGF treatment was overall safe and well-tolerated in patients of ALS. Application of mNGF combined with regular riluzole treatment had no significant clinical effects on delaying ALS progression. Prospective cohort studies and randomized clinical trials based on larger cohorts and longer follow-up times are needed to make a more convincing conclusion.}, }
@article {pmid35240461, year = {2022}, author = {Policepatil, BV}, title = {A case report: Ayurvedic intervention in motor neuron disease contemplating Kaphavrutavata.}, journal = {Journal of Ayurveda and integrative medicine}, volume = {13}, number = {2}, pages = {100548}, pmid = {35240461}, issn = {0975-9476}, abstract = {Motor neuron disease (MND) otherwise referred as Amyotrophic lateral sclerosis (ALS) affects human life in various ways. ALS with multifocal onset might exhibit muscle stiffness and muscle weakness of upper and lower limbs, muscle twitching, atrophy, falling/tripping, slurred speech, difficulty in swallowing and loss of dexterity. In Ayurvedic contexts Avarana vatavyadhis are found to have close resemblance to MND. The patient presented with features of multifocal onset of ALS which can be related to Kaphavruta Udanavata. The treatment principle of kaphavarana including Swedana (∼sudation), Niruhabasti (∼medicated enema), Vamana (∼therapeutic emesis) Virechana (∼purgation) and Sarpipana (∼oral intake of medicated ghee) along with other oral medications have been explained in Ayurvedic texts. In the present study, the same treatments were administered except for vamana due to patient's unwillingness. The Functional Rating Scale for ALS (ALSFRS-R) was used for assessment. The ALSFRS-R score before the treatment was 29 which was increased to 38 with remarkable improvement in Salivation and moderate improvement in Speech, Swallowing, Walking, Climbing stairs, Dyspnea and Orthopnea. The treatment was found to be highly effective in preventing the late stage complications which usually occur within 1-2 years of the disease onset and thereby helps the patient to be self-reliant.}, }
@article {pmid35227277, year = {2022}, author = {Quek, H and Cuní-López, C and Stewart, R and Colletti, T and Notaro, A and Nguyen, TH and Sun, Y and Guo, CC and Lupton, MK and Roberts, TL and Lim, YC and Oikari, LE and La Bella, V and White, AR}, title = {ALS monocyte-derived microglia-like cells reveal cytoplasmic TDP-43 accumulation, DNA damage, and cell-specific impairment of phagocytosis associated with disease progression.}, journal = {Journal of neuroinflammation}, volume = {19}, number = {1}, pages = {58}, pmid = {35227277}, issn = {1742-2094}, support = {APP1125796//National Health and Medical Research Council/ ; APP1095227//National Health and Medical Research Council/ ; APP1118452//National Health and Medical Research Council/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; DNA Damage ; *DNA-Binding Proteins/metabolism ; Disease Progression ; Humans ; Microglia/metabolism ; Monocytes/metabolism ; *Neurodegenerative Diseases/metabolism ; Phagocytosis ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterised by the loss of upper and lower motor neurons. Increasing evidence indicates that neuroinflammation mediated by microglia contributes to ALS pathogenesis. This microglial activation is evident in post-mortem brain tissues and neuroimaging data from patients with ALS. However, the role of microglia in the pathogenesis and progression of amyotrophic lateral sclerosis remains unclear, partly due to the lack of a model system that is able to faithfully recapitulate the clinical pathology of ALS. To address this shortcoming, we describe an approach that generates monocyte-derived microglia-like cells that are capable of expressing molecular markers, and functional characteristics similar to in vivo human brain microglia.<br><br>METHODS: In this study, we have established monocyte-derived microglia-like cells from 30 sporadic patients with ALS, including 15 patients with slow disease progression, 6 with intermediate progression, and 9 with rapid progression, together with 20 non-affected healthy controls.<br><br>RESULTS: We demonstrate that patient monocyte-derived microglia-like cells recapitulate canonical pathological features of ALS including non-phosphorylated and phosphorylated-TDP-43-positive inclusions. Moreover, ALS microglia-like cells showed significantly impaired phagocytosis, altered cytokine profiles, and abnormal morphologies consistent with a neuroinflammatory phenotype. Interestingly, all ALS microglia-like cells showed abnormal phagocytosis consistent with the progression of the disease. In-depth analysis of ALS microglia-like cells from the rapid disease progression cohort revealed significantly altered cell-specific variation in phagocytic function. In addition, DNA damage and NOD-leucine rich repeat and pyrin containing protein 3&#xa0;(NLRP3) inflammasome activity were also elevated in ALS patient monocyte-derived microglia-like cells, indicating a potential new pathway involved in driving disease progression.<br><br>CONCLUSIONS: Taken together,&#xa0;our work demonstrates that&#xa0;the&#xa0;monocyte-derived microglia-like cell model&#xa0;recapitulates disease-specific hallmarks and characteristics&#xa0;that substantiate patient heterogeneity associated with disease subgroups. Thus, monocyte-derived microglia-like cells are highly applicable to monitor disease progression and can be applied as a functional readout in clinical trials for anti-neuroinflammatory agents, providing a basis for personalised treatment for patients with ALS.}, }
@article {pmid35225121, year = {2022}, author = {Sun, Y and Bedlack, R and Armon, C and Beauchamp, M and Bertorini, T and Bowser, R and Bromberg, M and Caress, J and Carter, G and Crayle, J and Cudkowicz, ME and Glass, JD and Jackson, C and Lund, I and Martin, S and Paganoni, S and Pattee, G and Ratner, D and Salmon, K and Wicks, P}, title = {ALSUntangled #64: butyrates.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {7-8}, pages = {638-643}, doi = {10.1080/21678421.2022.2045323}, pmid = {35225121}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Butyrates/therapeutic use ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review butyrate and its different chemical forms (butyrates). Butyrates have plausible mechanisms for slowing ALS progression and positive pre-clinical studies. One trial suggests that sodium phenylbutyrate (NaPB) in combination with Tauroursodeoxycholic acid (TUDCA) can slow ALS progression and prolong survival, but the specific contribution of NaPB toward this effect is unclear. Butyrates appear reasonably safe for use in humans. Based on the above information, we support a trial of a butyrate in PALS, but we cannot yet recommend one as a treatment.}, }
@article {pmid35224258, year = {2022}, author = {Yamagishi, H and Shigematsu, K}, title = {Perspectives on Stem Cell-Based Regenerative Medicine with a Particular Emphasis on Mesenchymal Stem Cell Therapy.}, journal = {JMA journal}, volume = {5}, number = {1}, pages = {36-43}, pmid = {35224258}, issn = {2433-3298}, abstract = {Regenerative medicine is a medical treatment that aims to restore lost human body functions by regenerating missing or dysfunctional organs and tissues using stem cells, etc. There are three major types of stem cells used in regenerative medicine: induced pluripotent stem cells (iPS cells), embryonic stem cells (ES cells), and mesenchymal stem cells (MSCs). MSCs are expected to be widely applied to regenerative medicine because of their ability to differentiate into various types of cells, repair cells and tissues; anti-inflammatory effects; secretion of various growth factors; and resolution of abnormally accumulated protein amyloid. MSCs can be derived from bone marrow, dental pulp, and other sources, but adipose tissue-derived stem cells (ADSCs) may be superior in that they can be harvested with the least amount of invasion, and therefore, a sufficient amount of stem cells can be cultured relatively easily. When MSCs are administered systemically by intravenous infusion, they tend to accumulate at the site of disease, a property known as "homing," which is extremely advantageous for clinical applications. In Japan, stem cell therapy can be performed only after the research or treatment plan has been reviewed and approved by the "Committee for Specific Approval of Regenerative Medicine" and submitted to the Ministry of Health, Labor and Welfare for approval in accordance with the "Act on Securing the Safety of Regenerative Medicine" and after approval by the ethics committee of the facility where the therapy is performed. In this review, the characteristics of MSCs, the actual status of their clinical application, and their future prospects are presented.}, }
@article {pmid35221507, year = {2022}, author = {Tanaka, M and Homma, K and Soejima, A}, title = {Histopathological changes of the spinal cord and motor neuron dynamics in SOD1 Tg mice.}, journal = {Journal of toxicologic pathology}, volume = {35}, number = {1}, pages = {129-133}, pmid = {35221507}, issn = {0914-9198}, abstract = {We analyzed the histopathological changes and the number of motor neurons (MNs) in the lumbar spinal cord of Cu/Zn superoxide dismutase transgenic (SOD1[G93A]Tg) mice, which are frequently used as a disease model of amyotrophic lateral sclerosis (ALS). In SOD1[G93A]Tg mice, hyaline inclusions and foamy vacuoles in the neuronal cell body were observed at 7 weeks of age before neurologic symptoms, and large vacuoles, spheroid formation, and nerve cell aggregation became prominent after 13 weeks of age. The number of healthy MNs was 28.7 to 37.1 cells/animal in wild-type mice and 9.3 to 13.6 cells/animal in transgenic (Tg) mice. Furthermore, the number of MNs, including degenerative neurons, in Tg mice was 27.3-36.1 cells/animal at 18 weeks of age and 17.8-19.6 cells/animal at 21 weeks of age. The present results provide useful information for the development of drugs in ALS treatment.}, }
@article {pmid35208248, year = {2022}, author = {Gautam, M and Carratore, RD and Helmold, B and Tessa, A and Gozutok, O and Chandel, N and Idrisoglu, H and Bongioanni, P and Battini, R and Ozdinler, PH}, title = {2-Year-Old and 3-Year-Old Italian ALS Patients with Novel ALS2 Mutations: Identification of Key Metabolites in Their Serum and Plasma.}, journal = {Metabolites}, volume = {12}, number = {2}, pages = {}, pmid = {35208248}, issn = {2218-1989}, support = {no//A Long Swim/ ; }, abstract = {Pathogenic variants in ALS2 have been detected mostly in juvenile cases of amyotrophic lateral sclerosis (ALS), affecting mainly children and teenagers. Patients with ALS2 mutations demonstrate early onset cortical involvement in ALS. Currently, there are no effective treatment options. There is an immense need to reveal the underlying causes of the disease and to identify potential biomarkers. To shed light onto the metabolomic events that are perturbed with respect to ALS2 mutations, we investigated the metabolites present in the serum and plasma of a three-year-old female patient (AO) harboring pathogenic variants in ALS2, together with her relatives, healthy male and female controls, as well as another two-year-old patient DH, who had mutations at different locations and domains of ALS2. Serum and plasma samples were analyzed with a quantitative metabolomic approach to reveal the identity of metabolites present in serum and plasma. This study not only shed light onto the perturbed cellular pathways, but also began to reveal the presence of a distinct set of key metabolites that are selectively present or absent with respect to ALS2 mutations, laying the foundation for utilizing metabolites as potential biomarkers for a subset of ALS.}, }
@article {pmid35208176, year = {2022}, author = {Loganathan, S and Wilson, BA and Carey, SB and Manzo, E and Joardar, A and Ugur, B and Zarnescu, DC}, title = {TDP-43 Proteinopathy Causes Broad Metabolic Alterations including TCA Cycle Intermediates and Dopamine Levels in Drosophila Models of ALS.}, journal = {Metabolites}, volume = {12}, number = {2}, pages = {}, pmid = {35208176}, issn = {2218-1989}, support = {N/A//Sandra Harsha Estate/ ; R21 NS115514/NS/NINDS NIH HHS/United States ; B2I//Muscular Dystrophy Association/ ; R01 NS091299/NS/NINDS NIH HHS/United States ; R21NS115514//National Institute of Health/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, complex neurodegenerative disorder that causes selective degeneration of motor neurons. ALS patients exhibit symptoms consistent with altered cellular energetics such as hypermetabolism, weight loss, dyslipidemia, insulin resistance, and altered glucose tolerance. Although evidence supports metabolic changes in ALS patients, metabolic alterations at a cellular level remain poorly understood. Here, we used a Drosophila model of ALS based on TDP-43 expression in motor neurons that recapitulates hallmark features of motor neuron disease including TDP-43 aggregation, locomotor dysfunction, and reduced lifespan. To gain insights into metabolic changes caused by TDP-43, we performed global metabolomic profiling in larvae expressing TDP-43 (WT or ALS associated mutant variant, G298S) and identified significant alterations in several metabolic pathways. Here, we report alterations in multiple metabolic pathways and highlight upregulation of Tricarboxylic acid (TCA) cycle metabolites and defects in neurotransmitter levels. We also show that modulating TCA cycle flux either genetically or by dietary intervention mitigates TDP-43-dependent locomotor defects. In addition, dopamine levels are significantly reduced in the context of TDP-43[G298S], and we find that treatment with pramipexole, a dopamine agonist, improves locomotor function in vivo in Drosophila models of TDP-43 proteinopathy.}, }
@article {pmid35205670, year = {2022}, author = {Quinet, G and Xolalpa, W and Reyes-Garau, D and Profitós-Pelejà, N and Azkargorta, M and Ceccato, L and Gonzalez-Santamarta, M and Marsal, M and Andilla, J and Aillet, F and Bosch, F and Elortza, F and Loza-Alvarez, P and Sola, B and Coux, O and Matthiesen, R and Roué, G and Rodriguez, MS}, title = {Constitutive Activation of p62/Sequestosome-1-Mediated Proteaphagy Regulates Proteolysis and Impairs Cell Death in Bortezomib-Resistant Mantle Cell Lymphoma.}, journal = {Cancers}, volume = {14}, number = {4}, pages = {}, pmid = {35205670}, issn = {2072-6694}, support = {Grant agreement No 765445.//European Union/ ; PLBIO16-251//French National Cancer Institute/ ; CONACYT-SRE 0280365//Consejo Nacional de Ciencia y Tecnolog&#xed;a/ ; SEV-2015-0522//Ministry of Economy, Industry and Competitiveness/ ; 654148//LASERLAB Europe/ ; PI15/00102 and PI18/01383//Instituto de Salud Carlos III/ ; }, abstract = {Protein ubiquitylation coordinates crucial cellular events in physiological and pathological conditions. A comparative analysis of the ubiquitin proteome from bortezomib (BTZ)-sensitive and BTZ-resistant mantle cell lymphoma (MCL) revealed an enrichment of the autophagy-lysosome system (ALS) in BTZ-resistant cells. Pharmacological inhibition of autophagy at the level of lysosome-fusion revealed a constitutive activation of proteaphagy and accumulation of proteasome subunits within autophagosomes in different MCL cell lines with acquired or natural resistance to BTZ. Inhibition of the autophagy receptor p62/SQSTM1 upon verteporfin (VTP) treatment disrupted proteaphagosome assembly, reduced co-localization of proteasome subunits with autophagy markers and negatively impacted proteasome activity. Finally, the silencing or pharmacological inhibition of p62 restored the apoptosis threshold at physiological levels in BTZ-resistant cells both in vitro and in vivo. In total, these results demonstrate for the first time a proteolytic switch from the ubiquitin-proteasome system (UPS) to ALS in B-cell lymphoma refractory to proteasome inhibition, pointing out a crucial role for proteaphagy in this phenomenon and paving the way for the design of alternative therapeutic venues in treatment-resistant tumors.}, }
@article {pmid35205286, year = {2022}, author = {Allison, RL and Adelman, JW and Abrudan, J and Urrutia, RA and Zimmermann, MT and Mathison, AJ and Ebert, AD}, title = {Microglia Influence Neurofilament Deposition in ALS iPSC-Derived Motor Neurons.}, journal = {Genes}, volume = {13}, number = {2}, pages = {}, pmid = {35205286}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Culture Media, Conditioned ; Humans ; *Induced Pluripotent Stem Cells/metabolism ; Intermediate Filaments/metabolism ; Male ; Microglia/metabolism ; Motor Neurons/metabolism ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which upper and lower motor neuron loss is the primary phenotype, leading to muscle weakness and wasting, respiratory failure, and death. Although a portion of ALS cases are linked to one of over 50 unique genes, the vast majority of cases are sporadic in nature. However, the mechanisms underlying the motor neuron loss in either familial or sporadic ALS are not entirely clear. Here, we used induced pluripotent stem cells derived from a set of identical twin brothers discordant for ALS to assess the role of astrocytes and microglia on the expression and accumulation of neurofilament proteins in motor neurons. We found that motor neurons derived from the affected twin which exhibited increased transcript levels of all three neurofilament isoforms and increased expression of phosphorylated neurofilament puncta. We further found that treatment of the motor neurons with astrocyte-conditioned medium and microglial-conditioned medium significantly impacted neurofilament deposition. Together, these data suggest that glial-secreted factors can alter neurofilament pathology in ALS iPSC-derived motor neurons.}, }
@article {pmid35204833, year = {2022}, author = {Li, X and Dong, L and Li, A and Yi, J and Brotto, M and Zhou, J}, title = {Butyrate Ameliorates Mitochondrial Respiratory Capacity of The Motor-Neuron-like Cell Line NSC34-G93A, a Cellular Model for ALS.}, journal = {Biomolecules}, volume = {12}, number = {2}, pages = {}, pmid = {35204833}, issn = {2218-273X}, support = {R01 HL138570/HL/NHLBI NIH HHS/United States ; R01 NS105621/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Butyrates/metabolism/pharmacology ; Cell Line ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Mitochondria/metabolism ; Motor Neurons/metabolism/pathology ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; RNA, Messenger/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Mitochondrial defects in motor neurons are pathological hallmarks of ALS, a neuromuscular disease with no effective treatment. Studies have shown that butyrate, a natural gut-bacteria product, alleviates the disease progression of ALS mice overexpressing a human ALS-associated mutation, hSOD1[G93A]. In the current study, we examined the potential molecular mechanisms underlying the effect of butyrate on mitochondrial function in cultured motor-neuron-like NSC34 with overexpression of hSOD1[G93A] (NSC34-G93A). The live cell confocal imaging study demonstrated that 1mM butyrate in the culture medium improved the mitochondrial network with reduced fragmentation in NSC34-G93A cells. Seahorse analysis revealed that NSC34-G93A cells treated with butyrate showed an increase of ~5-fold in mitochondrial Spare Respiratory Capacity with elevated Maximal Respiration. The time-dependent changes in the mRNA level of PGC1α, a master regulator of mitochondrial biogenesis, revealed a burst induction with an early increase (~5-fold) at 4 h, a peak at 24 h (~19-fold), and maintenance at 48 h (8-fold) post-treatment. In line with the transcriptional induction of PGC1α, both the mRNA and protein levels of the key molecules (MTCO1, MTCO2, and COX4) related to the mitochondrial electron transport chain were increased following the butyrate treatment. Our data indicate that activation of the PGC1α signaling axis could be one of the molecular mechanisms underlying the beneficial effects of butyrate treatment in improving mitochondrial bioenergetics in NSC34-G93A cells.}, }
@article {pmid35204078, year = {2022}, author = {Cha, SJ and Kim, K}, title = {Effects of the Edaravone, a Drug Approved for the Treatment of Amyotrophic Lateral Sclerosis, on Mitochondrial Function and Neuroprotection.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {35204078}, issn = {2076-3921}, support = {2021//Soonchunhyang University/ ; 2019R1F1A1045639//Ministry of Science and ICT (Korea)/ ; }, abstract = {Edaravone, the first known free radical scavenger, has demonstrated cellular protective properties in animals and humans. Owing to its antioxidant activity, edaravone modulates oxidative damage in various diseases, especially neurodegenerative diseases. In 2015, edaravone was approved in Japan to treat amyotrophic lateral sclerosis. The distinguishing pathogenic features of neurodegenerative diseases include high reactive oxygen species levels and mitochondrial dysfunction. However, the correlation between mitochondria and edaravone has not been elucidated. This review highlights recent studies on novel therapeutic perspectives of edaravone in terms of its effect on oxidative stress and mitochondrial function.}, }
@article {pmid35202419, year = {2022}, author = {Alhakamy, NA and Okbazghi, SZ and A Alfaleh, M and H Abdulaal, W and Bakhaidar, RB and Alselami, MO and Zahrani, MA and Alqarni, HM and F Alghaith, A and Alshehri, S and Badr-Eldin, SM and Aldawsari, HM and Al-Hejaili, OD and Aldhabi, BM and Mahdi, WA}, title = {Wasp venom peptide improves the proapoptotic activity of alendronate sodium in A549 lung cancer cells.}, journal = {PloS one}, volume = {17}, number = {2}, pages = {e0264093}, pmid = {35202419}, issn = {1932-6203}, mesh = {A549 Cells ; Alendronate/*pharmacology ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Caspase 3/metabolism ; Cell Cycle/drug effects ; Drug Screening Assays, Antitumor ; Drug Synergism ; Humans ; Intercellular Signaling Peptides and Proteins/*pharmacology ; Lung Neoplasms/*drug therapy ; Nanoconjugates/*therapeutic use ; Particle Size ; Wasp Venoms/*pharmacology ; }, abstract = {BACKGROUND: Lung cancer in men and women is considered the leading cause for cancer-related mortality worldwide. Anti-cancer peptides represent a potential untapped reservoir of effective cancer therapy.<br><br>METHODOLOGY: Box-Behnken response surface design was applied for formulating Alendronate sodium (ALS)-mastoparan peptide (MP) nanoconjugates using Design-Expert software. The optimization process aimed at minimizing the size of the prepared ALS-MP nanoconjugates. ALS-MP nanoconjugates' particle size, encapsulation efficiency and the release profile were determined. Cytotoxicity, cell cycle, annexin V staining and caspase 3 analyses on A549 cells were carried out for the optimized formula.<br><br>RESULTS: The results revealed that the optimized formula was of 134.91&#xb1;5.1 nm particle size. The novel ALS-MP demonstrated the lowest IC50 (1.3 &#xb1; 0.34 &#x3bc;M) in comparison to ALS-Raw (37.6 &#xb1; 1.79 &#x3bc;M). Thus, the results indicated that when optimized ALS-MP nanoconjugate was used, the IC50 of ALS was also reduced by half. Cell cycle analysis demonstrated a significantly higher percentage of cells in the G2-M phase following the treatment with optimized ALS-MP nanoconjugates.<br><br>CONCLUSION: The optimized ALS-MP formula had significantly improved the parameters related to the cytotoxic activity towards A549 cells, compared to control, MP and ALS-Raw.}, }
@article {pmid35197877, year = {2022}, author = {Vaccarino, AL and Beaton, D and Black, SE and Blier, P and Farzan, F and Finger, E and Foster, JA and Freedman, M and Frey, BN and Gilbert Evans, S and Ho, K and Javadi, M and Kennedy, SH and Lam, RW and Lang, AE and Lasalandra, B and Latour, S and Masellis, M and Milev, RV and Müller, DJ and Munoz, DP and Parikh, SV and Placenza, F and Rotzinger, S and Soares, CN and Sparks, A and Strother, SC and Swartz, RH and Tan, B and Tartaglia, MC and Taylor, VH and Theriault, E and Turecki, G and Uher, R and Zinman, L and Evans, KR}, title = {Common Data Elements to Facilitate Sharing and Re-use of Participant-Level Data: Assessment of Psychiatric Comorbidity Across Brain Disorders.}, journal = {Frontiers in psychiatry}, volume = {13}, number = {}, pages = {816465}, pmid = {35197877}, issn = {1664-0640}, abstract = {The Ontario Brain Institute's "Brain-CODE" is a large-scale informatics platform designed to support the collection, storage and integration of diverse types of data across several brain disorders as a means to understand underlying causes of brain dysfunction and developing novel approaches to treatment. By providing access to aggregated datasets on participants with and without different brain disorders, Brain-CODE will facilitate analyses both within and across diseases and cover multiple brain disorders and a wide array of data, including clinical, neuroimaging, and molecular. To help achieve these goals, consensus methodology was used to identify a set of core demographic and clinical variables that should be routinely collected across all participating programs. Establishment of Common Data Elements within Brain-CODE is critical to enable a high degree of consistency in data collection across studies and thus optimize the ability of investigators to analyze pooled participant-level data within and across brain disorders. Results are also presented using selected common data elements pooled across three studies to better understand psychiatric comorbidity in neurological disease (Alzheimer's disease/amnesic mild cognitive impairment, amyotrophic lateral sclerosis, cerebrovascular disease, frontotemporal dementia, and Parkinson's disease).}, }
@article {pmid35196715, year = {2023}, author = {Praus, P and Biebinger, E and Bepler, R and Kubath-Heimann, S and Funk, B and Dreßing, H}, title = {[Shortened Treatment Concepts in Forensic Commitment According to Section 64 of the German Penal Code: A Tailored Treatment Pathway?].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {91}, number = {3}, pages = {88-94}, doi = {10.1055/a-1728-6708}, pmid = {35196715}, issn = {1439-3522}, mesh = {Humans ; Prognosis ; *Forensic Psychiatry ; }, abstract = {Die forensische Therapie gemäß §64 StGB zeichnet sich aktuell durch hohe Abbruch- bzw. Erledigungsquoten aus. Das hier vorgestellte verkürzte Therapiekonzept der Klinik für Forensische Psychiatrie des Pfalzklinikums für Patienten mit günstigen Prognosemerkmalen soll durch Förderung von Eigeninitiative, Verantwortung und Motivation sowie eine möglichst individualisierte, störungsorientierte, strafzeit- und tatangemessene Behandlung mit intensiver Erprobung unter Alltagsbedingungen zu einer Verkürzung der stationären Unterbringung führen. Empirische Belege hierfür fehlen jedoch bislang. Erstmals werden hier Pilotdaten aus dem Zeitraum April 2016 bis Mai 2021 vorgestellt. Zusammenfassend hat sich das o.g. Konzept als umsetzbar erwiesen. Die erhobenen Daten weisen darauf hin, dass die im verkürzten Therapieprogramm behandelten Patienten eine geringere Erledigungsquote als der Durchschnitt aller gemäß §64 StGB untergebrachter Patienten aufweist. Eine deutliche Verkürzung der durchschnittlichen Behandlungsdauer ließ sich demgegenüber jedoch nicht belegen. Die vorliegende Arbeit will einen ersten Beitrag zur Diskussion und Weiterentwicklung derartiger Behandlungsoptionen leisten. Mögliche Nachteile derartiger Therapieangebote bei für ungeeignet befundenen Patienten, z. B. eine Abnahme der Therapiemotivation, werden diskutiert.Forensic therapy according to section 64 of the German penal code is currently characterized by high drop-out rates. The shortened therapy concept of the Department of Forensic Psychiatry of the Pfalzklinikum focusing on patients with favorable prognostic characteristics presented here is intended to lead to a shortening of hospital stay by promoting initiative, responsibility and motivation. It is supposed to provide a treatment as individualized and disorder-oriented as possible and appropriate to the individual time of detention as well as the specific kind of offense with intensified testing under everyday conditions. However, so far empirical evidence for this concept is lacking. For the first time, pilot data for the period from April 2016 to May 2021 are presented here. The concept described herein has proven to be feasible. The collected data hint at a lower drop-out rate of patients treated according the shortened therapy concept compared to the average of all patients assigned to forensic treatment according to section 64 of the German penal code. Yet, there was no evidence for a significant shortening of hospital stay. The present work aims at making a first contribution to the discussion and further development of such treatment options. Possible disadvantages for patients who are found to be unsuitable, e. g. those with a decrease in therapeutic motivation, are discussed.}, }
@article {pmid35195049, year = {2023}, author = {Picher-Martel, V and Magnussen, C and Blais, M and Bubela, T and Das, S and Dionne, A and Evans, AC and Genge, A and Greiner, R and Iturria-Medina, Y and Johnston, W and Jones, K and Kaneb, H and Karamchandani, J and Moradipoor, S and Robertson, J and Rogaeva, E and Taylor, DM and Vande Velde, C and Yunusova, Y and Zinman, L and Kalra, S and Dupré, N}, title = {CAPTURE ALS: the comprehensive analysis platform to understand, remedy and eliminate ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {24}, number = {1-2}, pages = {33-39}, doi = {10.1080/21678421.2022.2041668}, pmid = {35195049}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Canada ; Biomarkers ; Disease Progression ; Neuroimaging ; }, abstract = {The absence of disease modifying treatments for amyotrophic lateral sclerosis (ALS) is in large part a consequence of its complexity and heterogeneity. Deep clinical and biological phenotyping of people living with ALS would assist in the development of effective treatments and target specific biomarkers to monitor disease progression and inform on treatment efficacy. The objective of this paper is to present the Comprehensive Analysis Platform To Understand Remedy and Eliminate ALS (CAPTURE ALS), an open and translational platform for the scientific community currently in development. CAPTURE ALS is a Canadian-based platform designed to include participants' voices in its development and through execution. Standardized methods will be used to longitudinally characterize ALS patients and healthy controls through deep clinical phenotyping, neuroimaging, neurocognitive and speech assessments, genotyping and multisource biospecimen collection. This effort plugs into complementary Canadian and international initiatives to share common resources. Here, we describe in detail the infrastructure, operating procedures, and long-term vision of CAPTURE ALS to facilitate and accelerate translational ALS research in Canada and beyond.}, }
@article {pmid35187164, year = {2022}, author = {Silveira, AC and Moraes, &#xcd;AP and Vidigal, GP and Simcsik, AO and Rosa, RM and Favero, FM and Fernandes, SMS and Garner, DM and Araújo, LV and Massa, M and Vanderlei, LCM and Silva, TD and Monteiro, CBM}, title = {Cardiac Autonomic Modulation in Subjects with Amyotrophic Lateral Sclerosis (ALS) during an Upper Limb Virtual Reality Task: A Prospective Control Trial.}, journal = {BioMed research international}, volume = {2022}, number = {}, pages = {4439681}, pmid = {35187164}, issn = {2314-6141}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*physiopathology ; Autonomic Nervous System/physiopathology ; Female ; Heart Conduction System/*physiopathology ; Humans ; Male ; Middle Aged ; Prospective Studies ; Severity of Illness Index ; Surveys and Questionnaires ; Upper Extremity/*physiopathology ; Virtual Reality ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. As a result of the rapid progression and severity of the disease, people with ALS experience loss of functionality and independence. Furthermore, it has already been described presence of autonomic dysfunction. Despite the increasing use of virtual reality (VR) in the treatment of different diseases, the use of virtual reality environment as an intervention program for ALS patients is innovative. The benefits and limitations have not yet been proven. Our objective was to evaluate the autonomic function of individuals with amyotrophic lateral sclerosis throughout the virtual reality task. The analysis of autonomic function was completed before, during, and after the virtual reality task using the upper limbs; also, all steps lasted ten minutes in a sitting position. Heart rate variability (HRV) was taken via the Polar® RS800CX cardiofrequencymeter. The following questionnaire was enforced: Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS) and Fatigue Severity Scale (FSS). Different types of HRV were revealed for the groups, indicating that the ALS group has reduced HRV, with most of the representative indices of the sympathetic nervous system. Besides, the physiological process of reducing parasympathetic activity from rest to VR activity (vagal withdrawal), with reduction in HF (ms[2]) and an increase in HR from rest to activity, and a further increase throughout recovery, with withdrawal of sympathetic nervous system, occurs just for the control group (CG), with no alterations between rest, activity, and recovery in individuals with ALS. We could conclude that patients with ALS have the reduction of HRV with the sympathetic predominance when equated to the healthy CG. Besides that, the ALS individuals have no capability to adapt the autonomic nervous system when likened to the CG during therapy based on VR and their recovery.}, }
@article {pmid35185590, year = {2022}, author = {Li, J and Yu, H and Yang, C and Ma, T and Dai, Y}, title = {Therapeutic Potential and Molecular Mechanisms of Echinacoside in Neurodegenerative Diseases.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {841110}, pmid = {35185590}, issn = {1663-9812}, abstract = {Echinacoside (ECH) is a natural phenylethanoid glycoside (PhG) in Cistanche tubulosa. A large number of studies have shown that ECH has very promising potential in the inhibition of neurodegenerative disease progression. Experimental studies strongly suggest that ECH exhibits a variety of beneficial effects associated with in neuronal function, including protecting mitochondrial function, anti-oxidative stress, anti-inflammatory, anti-endoplasmic reticulum stress (ERS), regulating autophagy and so on. The aim of this paper is to provide an extensive and actual summarization of ECH and its neuroprotective efficacy in prevention and treatment of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and so on, based on published data from both in vivo and in vitro studies. There is a growing evidence that ECH may serve as an efficacious and safe substance in the future to counteract neurodegenerative disease.}, }
@article {pmid35185565, year = {2022}, author = {Ueda, T and Ito, T and Inden, M and Kurita, H and Yamamoto, A and Hozumi, I}, title = {Stem Cells From Human Exfoliated Deciduous Teeth-Conditioned Medium (SHED-CM) is a Promising Treatment for Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {805379}, pmid = {35185565}, issn = {1663-9812}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, characterized by the loss of upper and lower motor neurons, for which an effective treatment has yet to be developed. Previous reports have shown that excessive oxidative stress, related to mitochondrial dysfunction and the accumulation of misfolding protein, contributes to ALS pathology. In terms of treatment, it remains necessary to identify effective medicines for multiple therapeutic targets and have additive effects against several disorders. In this study, we investigated stem cells from human exfoliated deciduous teeth (SHED), which release many factors, such as neurotrophic factors and cytokines, and are applied to treat neurological diseases. Specifically, we examined whether SHED-conditioned medium (CM), i.e., the serum-free culture supernatant of SHED, reduced mutant SOD1-induced intracellular aggregates and neurotoxicity. We found that SHED-CM significantly suppressed the mutant SOD1-induced intracellular aggregates and neurotoxicity. The neuroprotective effects of SHED-CM are partly related to heat shock protein and the activation of insulin-like growth factor-1 receptor. SHED-CM also had a protective effect on induced pluripotent stem cell-derived motor neurons. Moreover, SHED-CM was effective against not only familial ALS but also sporadic ALS. Overall, these results suggest that SHED-CM could be a promising treatment for slowing the progression of ALS.}, }
@article {pmid35178253, year = {2022}, author = {Renga, V}, title = {Brain Connectivity and Network Analysis in Amyotrophic Lateral Sclerosis.}, journal = {Neurology research international}, volume = {2022}, number = {}, pages = {1838682}, pmid = {35178253}, issn = {2090-1852}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment or cure. ALS is characterized by the death of lower motor neurons (LMNs) in the spinal cord and upper motor neurons (UMNs) in the brain and their networks. Since the lower motor neurons are under the control of UMN and the networks, cortical degeneration may play a vital role in the pathophysiology of ALS. These changes that are not apparent on routine imaging with CT scans or MRI brain can be identified using modalities such as diffusion tensor imaging, functional MRI, arterial spin labelling (ASL), electroencephalogram (EEG), magnetoencephalogram (MEG), functional near-infrared spectroscopy (fNIRS), and positron emission tomography (PET) scan. They can help us generate a representation of brain networks and connectivity that can be visualized and parsed out to characterize and quantify the underlying pathophysiology in ALS. In addition, network analysis using graph measures provides a novel way of understanding the complex network changes occurring in the brain. These have the potential to become biomarker for the diagnosis and treatment of ALS. This article is a systematic review and overview of the various connectivity and network-based studies in ALS.}, }
@article {pmid35173147, year = {2022}, author = {Ruan, Y and Hu, J and Che, Y and Liu, Y and Luo, Z and Cheng, J and Han, Q and He, H and Zhou, Q}, title = {CHCHD2 and CHCHD10 regulate mitochondrial dynamics and integrated stress response.}, journal = {Cell death &amp; disease}, volume = {13}, number = {2}, pages = {156}, pmid = {35173147}, issn = {2041-4889}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Carbonyl Cyanide m-Chlorophenyl Hydrazone ; DNA-Binding Proteins/genetics ; Mitochondrial Dynamics/genetics ; Mitochondrial Proteins/metabolism ; Mutation ; *Neurodegenerative Diseases/metabolism ; Transcription Factors/genetics/metabolism ; Gene Knockdown Techniques ; Cell Line ; Humans ; }, abstract = {Mitochondrial dysfunction is becoming one of the main pathology factors involved in the etiology of neurological disorders. Recently, mutations of the coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and 10 (CHCHD10) which encode two homologous proteins that belong to the mitochondrial CHCH domain protein family, are linked to Parkinson's disease and amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), respectively. However, the physiological and pathological roles of these twin proteins have not been well elaborated. Here, we show that, in physiological conditions, CHCHD2 and CHCHD10 interact with OMA1 and suppress its enzyme activity, which not only restrains the initiation of the mitochondrial integrated response stress (mtISR), but also suppresses the processing of OPA1 for mitochondrial fusion. Further, during mitochondria stress-induced by carbonyl cyanide m-chlorophenylhydrazone (CCCP) treatment, CHCHD2 and CHCHD10 translocate to the cytosol and interacte with eIF2a, which attenuates mtISR overactivation by suppressing eIF2a phosphorylation and its downstream response. As such, knockdown of CHCHD2 and CHCHD10 triggers mitochondrial ISR, and such cellular response is enhanced by CCCP treatment. Therefore, our findings demonstrate the first "mtISR suppressor" localized in mitochondria for regulating stress responses in mammalian cells, which has a profound pathological impact on the CHCH2/CHCH10-linked neurodegenerative disorder.}, }
@article {pmid35171694, year = {2022}, author = {Park, CS and Lee, JY and Choi, HY and Yune, TY}, title = {Suppression of Transient Receptor Potential Melastatin 7 by Carvacrol Protects against Injured Spinal Cord by Inhibiting Blood-Spinal Cord Barrier Disruption.}, journal = {Journal of neurotrauma}, volume = {39}, number = {9-10}, pages = {735-749}, doi = {10.1089/neu.2021.0338}, pmid = {35171694}, issn = {1557-9042}, mesh = {Animals ; Blood-Brain Barrier/pathology ; Cymenes ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/metabolism ; *Spinal Cord Injuries/pathology ; *TRPM Cation Channels/metabolism ; }, abstract = {When the blood-spinal cord barrier (BSCB) is disrupted after a spinal cord injury (SCI), several pathophysiological cascades occur, including inflammation and apoptotic cell death of neurons and oligodendrocytes, resulting in permanent neurological deficits. Transient receptor potential melastatin 7 (TRPM7) is involved in the pathological processes in many neuronal diseases, including traumatic brain injury, amyotrophic lateral sclerosis, parkinsonism dementia, and Alzheimer's disease. Further, carvacrol (CAR), a TRPM7 inhibitor, is known to protect against SCI by reducing oxidative stress and inhibiting the endothelial nitric oxide synthase pathway. However, the functions of TRPM7 in the regulation of BSCB homeostasis after SCI have not been examined. Here, we demonstrated that TRPM7, a calcium-mediated non-selective divalent cation channel, plays a critical role after SCI in rats. Rats were contused at T9 and given CAR (50 mg/kg) intraperitoneally immediately and 12 h after SCI, and then given the same dose once a day for 7 days. TRPM7 was found to be up-regulated after SCI in both in vitro and in vivo studies, and it was expressed in blood vessels alongside neurons and oligodendrocytes. Additionally, CAR treatment suppressed BSCB disruption by inhibiting the loss of tight junction (TJ) proteins and preserved TJ integrity. CAR also reduced apoptotic cell death and improved functional recovery after SCI by preventing BSCB disruption caused by blood infiltration and inflammatory responses. Based on these findings, we propose that blocking the TRPM7 channel can inhibit the destruction of the BSCB and it is a potential target in therapeutic drug development for use in SCI.}, }
@article {pmid35170944, year = {2022}, author = {Pernak, J and Niemczak, M and Rzemieniecki, T and Marcinkowska, K and Praczyk, T}, title = {Dicationic Herbicidal Ionic Liquids Comprising Two Active Ingredients Exhibiting Different Modes of Action.}, journal = {Journal of agricultural and food chemistry}, volume = {70}, number = {8}, pages = {2545-2553}, pmid = {35170944}, issn = {1520-5118}, mesh = {Anions ; Cations ; *Herbicides/pharmacology ; *Ionic Liquids ; }, abstract = {In the framework of this study, dicationic herbicidal ionic liquids (HILs) containing tetramethylene-1,4-bis(decyldimethylammonium) and dodecylmethylene-1,12-bis(decyldimethylammonium), including two different herbicidal anions exhibiting different modes of action, were synthesized and characterized. One herbicide incorporated into the HILs was a tribenuron-methyl belonging to ALS inhibitors, while the second herbicidal anion was a synthetic auxin that acts as a growth regulator, namely 2,4-dichlorophenoxyacetate (2,4-D), 2-(2,4-dichlorophenoxy)propionate, (2,4-DP), 2,4,5-trichlorophenoxyacetate (2,4,5-T), 4-chloro-2-methylphenoxyacetiate (MCPA), 2-(4-chloro-2-methylphenoxy)propionate (MCPP), and 4-chlorophenoxyacetate (4-CPA). The obtained products were found to be unstable and decomposed, which can be attributed to the presence of an additional methyl group within the sulfonylurea bridge of the tribenuron-methyl. The synthesized HILs exhibited good affinity with polar and semipolar solvents, with ethyl acetate and hexane as the only solvents that did not dissolve the HILs. Greenhouse tests demonstrated that most of the obtained HILs were more effective than the reference herbicide containing tribenuron-methyl. The length of the alkyl chain in the cation also influenced the effectiveness of the HILs. Better effects were observed for dodecylmethylene-1,12-bis(decyldimethylammonium) cations compared to tetramethylene-1,4-bis(decyldimethylammonium). Therefore, the novel dicatonic HILs showed to integrate the advent of the combination of the different herbicides into a single molecule, enhance herbicidal efficacy, and reduce the risk of weed resistance due to the various modes of action of the applied treatment.}, }
@article {pmid35163773, year = {2022}, author = {Lamptey, RNL and Chaulagain, B and Trivedi, R and Gothwal, A and Layek, B and Singh, J}, title = {A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Nanotherapeutics.}, journal = {International journal of molecular sciences}, volume = {23}, number = {3}, pages = {}, pmid = {35163773}, issn = {1422-0067}, support = {U54 GM128729/GM/NIGMS NIH HHS/United States ; RO1 AG051574, RF1 AG068034, 1P20 GM109024, U54GM128729//National Institute of Health/ ; }, mesh = {Blood-Brain Barrier/pathology ; Brain/pathology ; Drug Delivery Systems ; Early Diagnosis ; Humans ; Nanoparticles/*administration &amp; dosage ; Neurodegenerative Diseases/*diagnosis/*drug therapy ; Theranostic Nanomedicine ; }, abstract = {Neurodegenerative disorders are primarily characterized by neuron loss. The most common neurodegenerative disorders include Alzheimer's and Parkinson's disease. Although there are several medicines currently approved for managing neurodegenerative disorders, a large majority of them only help with associated symptoms. This lack of pathogenesis-targeting therapies is primarily due to the restrictive effects of the blood-brain barrier (BBB), which keeps close to 99% of all "foreign substances" out of the brain. Since their discovery, nanoparticles have been successfully used for targeted delivery into many organs, including the brain. This review briefly describes the pathophysiology of Alzheimer's, Parkinson's disease, and amyotrophic lateral sclerosis, and their current management approaches. We then highlight the major challenges of brain-drug delivery, followed by the role of nanotherapeutics for the diagnosis and treatment of various neurological disorders.}, }
@article {pmid35163103, year = {2022}, author = {Toledo, ARL and Monroy, GR and Salazar, FE and Lee, JY and Jain, S and Yadav, H and Borlongan, CV}, title = {Gut-Brain Axis as a Pathological and Therapeutic Target for Neurodegenerative Disorders.}, journal = {International journal of molecular sciences}, volume = {23}, number = {3}, pages = {}, pmid = {35163103}, issn = {1422-0067}, support = {R21 AG072379/AG/NIA NIH HHS/United States ; R56 AG064075/AG/NIA NIH HHS/United States ; R56 AG069676/AG/NIA NIH HHS/United States ; RF1 AG071762/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Brain-Gut Axis ; *Gastrointestinal Microbiome ; Humans ; Neurodegenerative Diseases/microbiology/*pathology/*therapy ; }, abstract = {Human lifestyle and dietary behaviors contribute to disease onset and progression. Neurodegenerative diseases (NDDs), considered multifactorial disorders, have been associated with changes in the gut microbiome. NDDs display pathologies that alter brain functions with a tendency to worsen over time. NDDs are a worldwide health problem; in the US alone, 12 million Americans will suffer from NDDs by 2030. While etiology may vary, the gut microbiome serves as a key element underlying NDD development and prognosis. In particular, an inflammation-associated microbiome plagues NDDs. Conversely, sequestration of this inflammatory microbiome by a correction in the dysbiotic state of the gut may render therapeutic effects on NDDs. To this end, treatment with short-chain fatty acid-producing bacteria, the main metabolites responsible for maintaining gut homeostasis, ameliorates the inflammatory microbiome. This intimate pathological link between the gut and NDDs suggests that the gut-brain axis (GBA) acts as an underexplored area for developing therapies for NDDs. Traditionally, the classification of NDDs depends on their clinical presentation, mostly manifesting as extrapyramidal and pyramidal movement disorders, with neuropathological evaluation at autopsy as the gold standard for diagnosis. In this review, we highlight the evolving notion that GBA stands as an equally sensitive pathological marker of NDDs, particularly in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and chronic stroke. Additionally, GBA represents a potent therapeutic target for treating NDDs.}, }
@article {pmid35162978, year = {2022}, author = {Bankole, O and Scambi, I and Parrella, E and Muccilli, M and Bonafede, R and Turano, E and Pizzi, M and Mariotti, R}, title = {Beneficial and Sexually Dimorphic Response to Combined HDAC Inhibitor Valproate and AMPK/SIRT1 Pathway Activator Resveratrol in the Treatment of ALS Mice.}, journal = {International journal of molecular sciences}, volume = {23}, number = {3}, pages = {}, pmid = {35162978}, issn = {1422-0067}, support = {B34I19002690003//Fondazione Cariverona/ ; 754345//European Union/ ; }, mesh = {AMP-Activated Protein Kinases/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology ; Animals ; Disease Models, Animal ; Female ; Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Histones/metabolism ; Male ; Mice ; Mice, Transgenic ; NF-kappa B/metabolism ; Resveratrol/pharmacology/therapeutic use ; Sirtuin 1/metabolism ; Superoxide Dismutase/metabolism ; Valproic Acid/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder. There is no cure and current treatments fail to slow the progression of the disease. Epigenetic modulation in the acetylation state of NF-kB RelA and the histone 3 (H3) protein, involved in the development of neurodegeneration, is a drugable target for the class-I histone deacetylases (HDAC) inhibitors, entinostat or valproate, and the AMP-activated kinase (AMPK)-sirtuin 1 pathway activator, resveratrol. In this study, we demonstrated that the combination of valproate and resveratrol can restore the normal acetylation state of RelA in the SOD1(G93A) murine model of ALS, in order to obtain the neuroprotective form of NF-kB. We also investigated the sexually dimorphic development of the disease, as well as the sex-sensibility to the treatment administered. We showed that the combined drugs, which rescued AMPK activation, RelA and the histone 3 acetylation state, reduced the motor deficit and the disease pathology associated with motor neuron loss and microglial reactivity, Brain-Derived Neurotrophic Factor (BDNF) and B-cell lymphoma-extra large (Bcl-xL) level decline. Specifically, vehicle-administered males showed earlier onset and slower progression of the disease when compared to females. The treatment, administered at 50 days of life, postponed the time of onset in the male by 22 days, but not in a significant way in females. Nevertheless, in females, the drugs significantly reduced symptom severity of the later phase of the disease and prolonged the mice's survival. Only minor beneficial effects were produced in the latter stage in males. Overall, this study shows a beneficial and sexually dimorphic response to valproate and resveratrol treatment in ALS mice.}, }
@article {pmid35159383, year = {2022}, author = {Liu, J and Zhou, F and Guan, Y and Meng, F and Zhao, Z and Su, Q and Bao, W and Wang, X and Zhao, J and Huo, Z and Zhang, L and Zhou, S and Chen, Y and Wang, X}, title = {The Biogenesis of miRNAs and Their Role in the Development of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {11}, number = {3}, pages = {}, pmid = {35159383}, issn = {2073-4409}, support = {81871006//National Natural Science Foundation of China/ ; ZR2020MH150 and ZR2020MH149//Shandong Province Natural Science Foundation of China/ ; Grant No. 2019KJK004//Support Program for Youth Innovation Technology in Colleges and Universities of Shandong Province of China/ ; J18KZ013//Key Project of Shandong Province Higher Educational Science and Technology Program of China/ ; N/A//The Brigham and Women's Hospital BRI Fund to Sustain Research Excellence (to X.W.)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Biomarkers/metabolism ; Humans ; *MicroRNAs/genetics/metabolism ; Motor Neurons/pathology ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects upper and lower motor neurons. As there is no effective treatment for ALS, it is particularly important to screen key gene therapy targets. The identifications of microRNAs (miRNAs) have completely changed the traditional view of gene regulation. miRNAs are small noncoding single-stranded RNA molecules involved in the regulation of post-transcriptional gene expression. Recent advances also indicate that miRNAs are biomarkers in many diseases, including neurodegenerative diseases. In this review, we summarize recent advances regarding the mechanisms underlying the role of miRNAs in ALS pathogenesis and its application to gene therapy for ALS. The potential of miRNAs to target diverse pathways opens a new avenue for ALS therapy.}, }
@article {pmid35159280, year = {2022}, author = {Papa, A and Pasquini, S and Contri, C and Gemma, S and Campiani, G and Butini, S and Varani, K and Vincenzi, F}, title = {Polypharmacological Approaches for CNS Diseases: Focus on Endocannabinoid Degradation Inhibition.}, journal = {Cells}, volume = {11}, number = {3}, pages = {}, pmid = {35159280}, issn = {2073-4409}, support = {20175SA5JJ//Italian Ministry for University and Research/ ; }, mesh = {*Central Nervous System Diseases/drug therapy ; Endocannabinoids/metabolism ; Humans ; Monoacylglycerol Lipases/metabolism ; *Neurodegenerative Diseases/drug therapy ; Polypharmacology ; }, abstract = {Polypharmacology breaks up the classical paradigm of "one-drug, one target, one disease" electing multitarget compounds as potential therapeutic tools suitable for the treatment of complex diseases, such as metabolic syndrome, psychiatric or degenerative central nervous system (CNS) disorders, and cancer. These diseases often require a combination therapy which may result in positive but also negative synergistic effects. The endocannabinoid system (ECS) is emerging as a particularly attractive therapeutic target in CNS disorders and neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury (TBI), pain, and epilepsy. ECS is an organized neuromodulatory network, composed by endogenous cannabinoids, cannabinoid receptors type 1 and type 2 (CB1 and CB2), and the main catabolic enzymes involved in the endocannabinoid inactivation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The multiple connections of the ECS with other signaling pathways in the CNS allows the consideration of the ECS as an optimal source of inspiration in the development of innovative polypharmacological compounds. In this review, we focused our attention on the reported polypharmacological examples in which FAAH and MAGL inhibitors are involved.}, }
@article {pmid35159225, year = {2022}, author = {Tarantino, N and Canfora, I and Camerino, GM and Pierno, S}, title = {Therapeutic Targets in Amyotrophic Lateral Sclerosis: Focus on Ion Channels and Skeletal Muscle.}, journal = {Cells}, volume = {11}, number = {3}, pages = {}, pmid = {35159225}, issn = {2073-4409}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; Ion Channels ; Muscle, Skeletal/metabolism ; *Neurodegenerative Diseases/pathology ; Riluzole/pharmacology/therapeutic use ; }, abstract = {Amyotrophic Lateral Sclerosis is a neurodegenerative disease caused by progressive loss of motor neurons, which severely compromises skeletal muscle function. Evidence shows that muscle may act as a molecular powerhouse, whose final signals generate in patients a progressive loss of voluntary muscle function and weakness leading to paralysis. This pathology is the result of a complex cascade of events that involves a crosstalk among motor neurons, glia, and muscles, and evolves through the action of converging toxic mechanisms. In fact, mitochondrial dysfunction, which leads to oxidative stress, is one of the mechanisms causing cell death. It is a common denominator for the two existing forms of the disease: sporadic and familial. Other factors include excitotoxicity, inflammation, and protein aggregation. Currently, there are limited cures. The only approved drug for therapy is riluzole, that modestly prolongs survival, with edaravone now waiting for new clinical trial aimed to clarify its efficacy. Thus, there is a need of effective treatments to reverse the damage in this devastating pathology. Many drugs have been already tested in clinical trials and are currently under investigation. This review summarizes the already tested drugs aimed at restoring muscle-nerve cross-talk and on new treatment options targeting this tissue.}, }
@article {pmid35159176, year = {2022}, author = {Lee, J and An, S and Lee, SJ and Kang, JS}, title = {Protein Arginine Methyltransferases in Neuromuscular Function and Diseases.}, journal = {Cells}, volume = {11}, number = {3}, pages = {}, pmid = {35159176}, issn = {2073-4409}, mesh = {*Antineoplastic Agents/pharmacology ; Humans ; Methylation ; *Neoplasms ; *Neuromuscular Diseases ; Protein-Arginine N-Methyltransferases/metabolism ; Quality of Life ; }, abstract = {Neuromuscular diseases (NMDs) are characterized by progressive loss of muscle mass and strength that leads to impaired body movement. It not only severely diminishes the quality of life of the patients, but also subjects them to increased risk of secondary medical conditions such as fall-induced injuries and various chronic diseases. However, no effective treatment is currently available to prevent or reverse the disease progression. Protein arginine methyltransferases (PRMTs) are emerging as a potential therapeutic target for diverse diseases, such as cancer and cardiovascular diseases. Their expression levels are altered in the patients and molecular mechanisms underlying the association between PRMTs and the diseases are being investigated. PRMTs have been shown to regulate development, homeostasis, and regeneration of both muscle and neurons, and their association to NMDs are emerging as well. Through inhibition of PRMT activities, a few studies have reported suppression of cytotoxic phenotypes observed in NMDs. Here, we review our current understanding of PRMTs' involvement in the pathophysiology of NMDs and potential therapeutic strategies targeting PRMTs to address the unmet medical need.}, }
@article {pmid35154390, year = {2022}, author = {Herrmann, C and Schradt, F and Lindner-Pfleghar, B and Schuster, J and Ludolph, AC and Dorst, J}, title = {Pharyngeal electrical stimulation in amyotrophic lateral sclerosis: a pilot study.}, journal = {Therapeutic advances in neurological disorders}, volume = {15}, number = {}, pages = {17562864211068394}, pmid = {35154390}, issn = {1756-2856}, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) suffer from dysphagia that increases the risk for aspiration, pneumonia and weight loss. Pharyngeal electrical stimulation (PES) is a therapeutic technique that applies electric stimuli to the patient's pharynx in order to improve swallowing based on the principle of cortical plasticity and reorganization. Previous studies have demonstrated positive effects in patients with various neurological diseases.<br><br>OBJECTIVE: This study was initiated to investigate the effect of PES on swallowing function in patients with ALS.<br><br>METHODS: In all, 20 ALS patients with severe dysphagia [characterized by a Penetration Aspiration Scale (PAS) of at least 4 in thin liquid] were randomized to receive either PES for 10&#x2009;min at 3 consecutive days in addition to Standard Logopaedic Therapy (SLT) or SLT alone. Swallowing function was evaluated by Fiberoptic Endoscopic Evaluation of Swallowing (FEES) at five timepoints: at baseline, 1&#x2009;day, 4&#x2009;days, 3&#x2009;weeks and 3&#x2009;months after treatment. Primary endpoint was the severity of penetrations or aspirations as classified by PAS. Secondary endpoints were adverse events, dysphagia-related quality of life, Swallowing Quality of Life (SWAL-QOL), Dysphagia Severity Rating Scale (DSRS), residues, leaking, ALS Functional Rating Scale Revised (ALSFRS-R), and the performance in Clinical Evaluation of Swallowing (CES). The trial is registered under the name of 'Pharyngeal Electrical Stimulation in Amyotrophic Lateral Sclerosis' with ClinialTrials.gov, number NCT03481348 (https://clinicaltrials.gov/ct2/show/NCT03481348).<br><br>RESULTS: Both groups combined showed a significant improvement (p&#x2009;=&#x2009;0.003) of median Total-PAS from 3.6 [interquartile range (IQR)&#x2009;=&#x2009;2.9-5.0] at baseline to 2.3 (IQR&#x2009;=&#x2009;1.8-4.0) 1&#x2009;day after treatment. During subsequent study visits, PAS increased again but remained below baseline. PES and control group did not differ significantly 1&#x2009;day after intervention (p&#x2009;=&#x2009;0.32). Similar effects were found in the majority of secondary endpoints.<br><br>INTERPRETATION: The findings suggest that PES may not provide an additional positive effect on swallowing function in ALS. SLT seems to yield at least short-term positive effects on swallowing function and swallowing-specific life quality in ALS.Registration: ClinialTrials.gov: NCT03481348.}, }
@article {pmid35151118, year = {2022}, author = {Zhang, C and Sajith, AM and Xu, X and Jiang, J and Phillip Bowen, J and Kulkarni, A and Hao, J}, title = {Targeting NLRP3 signaling by a novel-designed sulfonylurea compound for inhibition of microglial inflammation.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {58}, number = {}, pages = {116645}, pmid = {35151118}, issn = {1464-3391}, support = {U54 MD007597/MD/NIMHD NIH HHS/United States ; P30 AI117970/AI/NIAID NIH HHS/United States ; R01 NS105787/NS/NINDS NIH HHS/United States ; R01 NS100947/NS/NINDS NIH HHS/United States ; R21 NS109687/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; Dose-Response Relationship, Drug ; Inflammation/*drug therapy/metabolism ; Mice ; Microglia/*drug effects/metabolism ; Models, Molecular ; Molecular Structure ; NLR Family, Pyrin Domain-Containing 3 Protein/*antagonists &amp; inhibitors/metabolism ; Signal Transduction/drug effects ; Structure-Activity Relationship ; Sulfonylurea Compounds/chemical synthesis/chemistry/*pharmacology ; }, abstract = {The nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays an important role in microglia-mediated inflammation. Dysregulation of NLRP3 signaling results in microglial activation and triggers inflammatory responses contributing to the development of neurological disorders including ischemic stroke, schizophrenia, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Inhibition of the NLRP3-linked inflammatory pathways reduces microglia-induced inflammation and is considered as a promising therapeutic approach for neuro-inflammatory diseases. In the present study, we report the development of AMS-17, a rationally-designed tertiary sulfonylurea compound for inhibition of inflammation in microglia. AMS-17 inhibited expression of the NLRP3, and its downstream components and cytokines such as caspase-1, tumor necrosis factor-α (TNF-α), IL-1β and inducible nitric oxide synthase (iNOS). It also suppressed lipopolysaccharide (LPS)-induced N9 microglial cell phagocytosis in vitro and activation of the microglia in mouse brain in vivo. Together, these results provide promising evidences for the inhibitory effects of AMS-17 in inflammation. This proof-of-concept study provides a new chemical scaffold, designed with the aid of pharmacophore modeling, with NLRP3 inhibitory activity which can be further developed for the treatment of inflammation-associated neurological disorders.}, }
@article {pmid35149928, year = {2022}, author = {Maksymowicz, S and Libura, M and Malarkiewicz, P}, title = {Overcoming therapeutic nihilism. Breaking bad news of amyotrophic lateral sclerosis-a patient-centred perspective in rare diseases.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {43}, number = {7}, pages = {4257-4265}, pmid = {35149928}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/psychology/therapy ; Communication ; Female ; Humans ; Male ; *Neurodegenerative Diseases ; Physician-Patient Relations ; Rare Diseases ; Surveys and Questionnaires ; Truth Disclosure ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, incurable, and fatal neurodegenerative disease with median survival time from onset to death ranging from 20 to 48 months. Breaking bad news about ALS diagnosis is a challenging task for physicians and a life-changing experience for patients. Several protocols for delivering difficult information are available, including SPIKES and EMPATHY. Our goal was to assess to what extent these guidelines are followed in Polish ALS patients' experience as well as to identify any other patients' preferences not addressed by the guidelines. Participants of our study were recruited via a neurology clinic. Twenty-four patients with confirmed ALS diagnosis were interviewed using in-depth interview and a self-constructed questionnaire: 9 females, 15 males in age ranging from 30-39 to 60-69. The analysis showed a pattern of shortcomings and fundamental violations of available protocols reported by ALS patients. Patients also had to deal with therapeutic nihilism, as they were perceived as "hopeless cases"; unlike in oncological setting, their end-of-life needs were not accommodated by some standard schemes. As a conclusion, we recommend using extended breaking bad news protocols with special emphasis on preparing a treatment plan, giving the patient hope and sense of purpose, offering psychological support and counselling directed to patients and caregivers, and providing the patient with meaningful information about the disease, social support, treatment options, and referral to appropriate health care centres.}, }
@article {pmid35144097, year = {2022}, author = {Krogsaeter, E and Rosato, AS and Grimm, C}, title = {TRPMLs and TPCs: Targets for lysosomal storage and neurodegenerative disease therapy?.}, journal = {Cell calcium}, volume = {103}, number = {}, pages = {102553}, doi = {10.1016/j.ceca.2022.102553}, pmid = {35144097}, issn = {1532-1991}, mesh = {Biological Transport ; Endosomes/metabolism ; Humans ; Lysosomes/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; *Transient Receptor Potential Channels/metabolism ; }, abstract = {Neurodegenerative diseases (ND) pose a serious health burden to society and healthcare systems alike, with increasing incidence rates especially within aging populations. Alzheimer's disease (AD) is the most prevalent type of ND or dementia, followed by Parkinson's disease (PD), multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. Progressive neurological dysfunction and regional neuronal loss constitute the common characteristics of ND. Many ND are accompanied by accumulation of protein aggregates such as extracellular amyloid-β (in AD), intraneuronal hyper-phosphorylated tau (in AD), or α-synuclein (in PD). Two main systems are responsible for the clearance of damaged, dysfunctional or senescent proteins inside cells: the autophagy-lysosomal pathway and the ubiquitin-proteasome system. The importance of lysosomes in neurodegenerative processes is further highlighted by clinical phenotypes of lysosomal storage disorders (LSDs), comprising more than 70 inheritable diseases caused by mutations in lysosomal enzymes or lysosomal membrane proteins, often resulting in severe neurodegeneration. Dysfunctional lysosomal proteins and enzymes result in the lysosomal accumulation of undigested macromolecules, e.g. lipids, glycoproteins, glycosaminoglycans, or gangliosides. Defects in intracellular transport pathways involving endosomes and lysosomes are increasingly recognized as drivers of neurodegenerative disease pathology including AD and PD. Thus, accumulation of damaged proteins and organelles (e.g. mitochondria) in neurons and glial cells overwhelms the capacity of intracellular recycling and degradation mechanisms, exacerbating disease pathology. Endolysosomal ion channels have recently been established as important regulators of lysosomal exocytosis, ion homeostasis/pH, endolysosomal trafficking, fusion and fission, and autophagy. In particular two non-selective endolysosomal cation channel families, the mucolipin/TRPML/MCOLN channels and the two-pore channels/TPCs will be discussed here as potential pharmacological targets for LSD/ND treatment.}, }
@article {pmid35135462, year = {2022}, author = {Puranik, N and Arukha, AP and Yadav, SK and Yadav, D and Jin, JO}, title = {Exploring the Role of Stem Cell Therapy in Treating Neurodegenerative Diseases: Challenges and Current Perspectives.}, journal = {Current stem cell research &amp; therapy}, volume = {17}, number = {2}, pages = {113-125}, doi = {10.2174/1574888X16666210810103838}, pmid = {35135462}, issn = {2212-3946}, support = {NRF2019R1G1A1008566, NRF-2020R1A6A1A03044512//National Research Foundation of Korea (NRF) Ministry of Education/ ; }, mesh = {Cell- and Tissue-Based Therapy ; Humans ; *Neural Stem Cells ; *Neurodegenerative Diseases/therapy ; *Parkinson Disease/therapy ; Stem Cell Transplantation ; }, abstract = {Several human neurological disorders, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, spinal cord injury, multiple sclerosis, and brain stroke, are caused by the injury to neurons or glial cells. The recent years have witnessed the successful generation of neurons and glia cells driving efforts to develop stem-cell-based therapies for patients to combat a broad spectrum of human neurological diseases. The inadequacy of suitable cell types for cell replacement therapy in patients suffering from neurological disorders has hampered the development of this promising therapeutic approach. Attempts are thus being made to reconstruct viable neurons and glial cells from different stem cells, such as embryonic stem cells, mesenchymal stem cells, and neural stem cells. Dedicated research to cultivate stem cell-based brain transplantation therapies has been carried out. We aim at compiling the breakthroughs in the field of stem cell-based therapy for the treatment of neurodegenerative maladies, emphasizing the shortcomings faced, victories achieved, and the future prospects of the therapy in clinical settings.}, }
@article {pmid35134775, year = {2022}, author = {Kononets, O and Karaiev, T and Lichman, L and Kucher, O and Kononets, O}, title = {MONITORING OF RENAL, HEPATIC AND IMMUNE FUNCTION INDICES IN PATIENTS WITH NEUROMUSCULAR DISORDERS: AMYOTROPHIC LATERAL SCLEROSIS AND DUCHENNE MUSCULAR DYSTROPHY.}, journal = {Georgian medical news}, volume = {}, number = {322}, pages = {131-139}, pmid = {35134775}, issn = {1512-0112}, mesh = {Adolescent ; Adult ; Aged ; *Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; Immunity ; Kidney/physiology ; Longitudinal Studies ; Middle Aged ; *Muscular Dystrophy, Duchenne/complications ; Prospective Studies ; Young Adult ; }, abstract = {The purpose of the study is to examine in depth and analyze renal, hepatic and immune function indices in patients who suffered from neuromuscular disorders: аmyotrophic lateral sclerosis and Duchenne muscular dystrophy (one-year prospective follow-up). We analyzed the follow up clinical and laboratory data of 55 patients, aged 56±10, with amyotrophic lateral sclerosis and 53 patients, aged 18±5, with Duchenne muscular dystrophy at presentation and a year after the treatment. The patients underwent a standardized examination, involving studying the medical case history, general clinical data, the detailed neurological status examination, laboratory and instrumental examinations. Through the laboratory examination we determined the general blood test indicators, total serum protein levels, total cholesterol, the ALAT, ASAT, CPK levels, creatinine and serum urea levels, glomerular filtration rate (GFR), the lactic dehydrogenase level, the alkaline phosphatase level, the immunogram indices (dynamic data (B-lymphocytes (CD19/CD45),%; T-lymphocytes (CD3/CD 45),%; T-helpers (CD3/CD45/CD4),%; T-suppressors (CD3/CD45/ CD8),%; CD4:CD8 ratio; natural killer cells ratio. The instrumental examination included the ultrasound of the abdominal organs, muscles, as well as echo-cardiography, electroneuromyography. Having analyzed the renal, hepatic and immunological indices in patients with such neuromuscular disorders as аmyotrophic lateral sclerosis and Duchenne muscular dystrophy, we found that both the patients with аmyotrophic lateral sclerosis and those with Duchenne muscular dystrophy suffered from renal dysfunction. Thus, most patients with аmyotrophic lateral sclerosis (69%) were observed to have the below normal serum creatinine level and 5,5% of the patients had the above normal serum creatinine level. A similar situation was observed in patients with Duchenne muscular dystrophy: 58.5% of the patients were detected to have the below normal serum creatinine level and 3.8% of the patients had the above normal serum creatinine level. At the same time, 40% of 25 patients with Duchenne muscular dystrophy, who we followed up, had low serum creatinine at presentation, while a year later, the%age of the patients increased to 44%. The serum urea level was within normal limits in most patients (89,1%) with аmyotrophic lateral sclerosis and in all the patients with Duchenne muscular dystrophy. The glomerular filtration rate was observed to be within the reference value in most patients with аmyotrophic lateral sclerosis and in all the patients with Duchenne muscular dystrophy (at presentation and a year after the treatment), however, it was observed a mild renal filtration dysfunction in 21,8% of patients with аmyotrophic lateral sclerosis; it was found a moderate renal filtration dysfunction in 5,5% of patients with аmyotrophic lateral sclerosis. At that we detected a weak positive correlation between the glomerular filtration rate and the lifespan of patients with аmyotrophic lateral sclerosis (r=0.28, p<0.01). Concurrently, we found no correlation between the serum creatinine and myoparesis severity in patients with аmyotrophic lateral sclerosis that somewhat contradicts Inês Martins' findings obtained in 2020. The serum aspartate aminotransferase level was found to be above normal in 40% of patients with amyotrophic lateral sclerosis (at the same time the alanine aminotransferase level was observed to be above normal only in 18% of the patients). The lactic dehydrogenase level was below normal in most patients. We found the significant changes when evaluating the immune status in patients with amyotrophic lateral sclerosis: almost all the patients (94.5%) had decreased levels of B-lymphocytes; 41.8% of patients had a reduced level of a subpopulation of T-lymphocytes - T-suppressors. The conducted comprehensive longitudinal study has shown the presence of significant predictive renal function impairments in patients with amyotrophic lateral sclerosis and Duchenne muscular dystrophy. The patients with amyotrophic lateral sclerosis were detected to have significantly deviated B-cell and T-cell components of the immune status and enzyme systems, including lactate dehydrogenase and aspartate aminotransferase levels; their nature and prognostic value need further investigation.}, }
@article {pmid35133737, year = {2022}, author = {Makizodila, BAM and van de Wijdeven, JHE and de Soet, JJ and Selms, MKAV and Volgenant, CMC}, title = {[Oral hygiene in patients with motor neuron disease: a cross-sectional survey].}, journal = {Nederlands tijdschrift voor tandheelkunde}, volume = {129}, number = {2}, pages = {73-80}, doi = {10.5177/ntvt.2022.02.21061}, pmid = {35133737}, issn = {0028-2200}, mesh = {*Amyotrophic Lateral Sclerosis ; Cross-Sectional Studies ; Humans ; *Motor Neuron Disease/complications ; Oral Hygiene ; Quality of Life ; }, abstract = {Neuromuscular disorders cause damage to the motor nerves. Arm-hand function can severely be impaired. The needs of and limitations of patients with neuromuscular disorders and the role of their carers in providing oral hygiene were studied. To this end, an online survey was sent to 706 patients with a neuromuscular disorder (amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis and progressive bulbar palsy). The survey questions concerned, among other things, self-reliance, the oral situation and oral hygiene. Oral health-related quality of life and subjective well-being were also measured. A total of 259 patients (36.7%) responded, of whom 71.9% declared themselves not to have been informed about the importance of maintaining good oral health. Moreover, 40.4% wished to receive help from an oral care professional regarding their oral hygiene; 19.8% was not satisfied with the oral care they provided for themselves or as provided by their carers. It was concluded that attention to oral hygiene for patients with neuromuscular disorders by both multidisciplinary treatment teams and oral care professionals is required.}, }
@article {pmid35123543, year = {2022}, author = {Margaretos, NM and Bawa, K and Engmann, NJ and Chambers, JD}, title = {Patients' access to rare neuromuscular disease therapies varies across US private insurers.}, journal = {Orphanet journal of rare diseases}, volume = {17}, number = {1}, pages = {36}, pmid = {35123543}, issn = {1750-1172}, mesh = {Delivery of Health Care ; Humans ; *Insurance Carriers ; Insurance Coverage ; *Muscular Atrophy, Spinal ; Rare Diseases/drug therapy ; }, abstract = {BACKGROUND: The extent to which different US private insurers require their enrollees to meet the same coverage criteria before gaining access to treatment is unclear. Our objective was to scrutinize the patient access criteria imposed by US private insurers for a set of rare neuromuscular disease (NMD) disease-modifying therapies (DMTs).<br><br>METHODS: We examined coverage policies issued by 17 large US private insurers for the following NMD treatments: nusinersen and onasemnogene abeparvovec for spinal muscular atrophy, edaravone for amyotrophic lateral sclerosis, and eteplirsen for Duchenne muscular dystrophy. We reviewed the plans' coverage policies and identified the patient access criteria, including clinical prerequisites, step therapy protocols, and prescriber requirements. We compared the plans' patient access criteria with the therapies' US Food and Drug Administration (FDA)-labeled indications.<br><br>RESULTS: The included insurers issued 65 coverage policies for the included therapies. Plans imposed coverage restrictions beyond the FDA-approved indications in 60 coverage policies; plans did not cover eteplirsen in five policies. No therapy was covered the same way by all insurers. Plans applied clinical criteria beyond the FDA label indication in 56 policies and step therapy protocols in three policies. Plans required that a neurologist prescribe the therapy in 37 policies, 22 of which required the neurologist to have expertise in the particular disease. Plans often required patients to suffer from symptoms of particular severity; e.g. for eteplirsen, plans differed in their 6-min walk test requirements; for edaravone, some plans required that patients had normal respiratory function, while others required only that patients did not require ventilation; for nusinersen and onasemnogene abeparvovec, plans differed in the number of SMN2 gene copies they required patients to have (SMN2 copy number is correlated with disease severity).<br><br>CONCLUSIONS: The evaluated large US private insurers tended to impose coverage restrictions beyond the FDA label indication for the included set of rare NMD DMTs. Plans rarely applied the same patient access criteria in their coverage policies for the same products. Inconsistent coverage criteria mean that patients with different insurers have variable access to the same therapies across insurers.}, }
@article {pmid35118923, year = {2022}, author = {Gondim, FAA and Fernandes, JMA and Marques Júnior, W}, title = {ALS due to a novel TBK1 mutation in Brazil.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {7-8}, pages = {620-622}, doi = {10.1080/21678421.2022.2028169}, pmid = {35118923}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Brazil ; *Frontotemporal Dementia/genetics/diagnosis ; Heterozygote ; Mutation/genetics ; Protein Serine-Threonine Kinases/genetics ; }, abstract = {TANK-binding kinase 1 (TBK1) gene mutations cause ALS and frontotemporal dementia (FTD). We report a novel TBK1 mutation in a Brazilian patient with ALS. Symptoms started at age 44 (lower-limb onset). Despite treatment with riluzole, his condition progressed over 5 years to aphemia, dysphagia, gastrostomy and tracheostomy. A diagnostic test panel for neurodegenerative disorders disclosed a novel likely pathogenic heterozygous intronic mutation in the TBK1 gene: c.1189 + 1G > T (Splice donor), intron 9. This mutation is expected to disrupt RNA splicing and lead to loss of protein function. Disruption of this splice site has been observed in patients with TBK1-related disorders. Separate and additional C9ORFF72 testing was negative. To our knowledge, this is the second patient with a TBK1 mutation (novel splice donor intronic mutation) reported in Brazil, and the first to include a full description of the clinical course. Further studies are necessary to establish the frequency of TBK1 mutations in Brazilian ALS patients (and worldwide) and to evaluate the possible different clinical phenotypes and the disease course.}, }
@article {pmid35111334, year = {2022}, author = {Berke Erdaş, &#xc7; and Sümer, E and Kibaroğlu, S}, title = {CNN-based severity prediction of neurodegenerative diseases using gait data.}, journal = {Digital health}, volume = {8}, number = {}, pages = {20552076221075147}, pmid = {35111334}, issn = {2055-2076}, abstract = {Neurodegenerative diseases occur because of degeneration in brain cells but can manifest as impairment of motor functions. One of the side effects of this impairment is an abnormality in walking. With the development of sensor technologies and artificial intelligence applications in recent years, the disease severity of patients can be estimated using their gait data. In this way, decision support applications for grading the severity of the disease that the patient suffers in the clinic can be developed. Thus, patients can have treatment methods more suitable for the severity of the disease. The presented research proposes a deep learning-based approach using gait data represented by a Quick Response code to develop an effective and reliable disease severity grading system for neurodegenerative diseases such as amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. The two-dimensional Quick Response data set was created by converting each one-dimensional gait data of the subjects with a novel representation approach to a Quick Response code. This data set was regressed with the convolutional neural network deep learning method, and a solution was sought for the problem of grading disease severity. Further, to demonstrate the success of the results obtained with the novel approach, native machine learning approaches such as Multilayer Perceptron, Random Forest, Extremely Randomized Trees, and K-Nearest Neighbours, and ensemble machine learning methods, such as voting and stacking, were applied on one-dimensional data. Finally, the results obtained on the prediction of disease severity by testing one-dimensional gait data with a convolutional neural network architecture that operates on one-dimensional data were included. The results showed that, in most cases, the two-dimensional convolutional neural network approach performed the best among all methods.}, }
@article {pmid35111126, year = {2021}, author = {Arjmand, B and Kokabi Hamidpour, S and Rabbani, Z and Tayanloo-Beik, A and Rahim, F and Aghayan, HR and Larijani, B}, title = {Organ on a Chip: A Novel in vitro Biomimetic Strategy in Amyotrophic Lateral Sclerosis (ALS) Modeling.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {788462}, pmid = {35111126}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis is a pernicious neurodegenerative disorder that is associated with the progressive degeneration of motor neurons, the disruption of impulse transmission from motor neurons to muscle cells, and the development of mobility impairments. Clinically, muscle paralysis can spread to other parts of the body. Hence it may have adverse effects on swallowing, speaking, and even breathing, which serves as major problems facing these patients. According to the available evidence, no definite treatment has been found for amyotrophic lateral sclerosis (ALS) that results in a significant outcome, although some pharmacological and non-pharmacological treatments are currently applied that are accompanied by some positive effects. In other words, available therapies are only used to relieve symptoms without any significant treatment effects that highlight the importance of seeking more novel therapies. Unfortunately, the process of discovering new drugs with high therapeutic potential for ALS treatment is fraught with challenges. The lack of a broad view of the disease process from early to late-stage and insufficiency of preclinical studies for providing validated results prior to conducting clinical trials are other reasons for the ALS drug discovery failure. However, increasing the combined application of different fields of regenerative medicine, especially tissue engineering and stem cell therapy can be considered as a step forward to develop more novel technologies. For instance, organ on a chip is one of these technologies that can provide a platform to promote a comprehensive understanding of neuromuscular junction biology and screen candidate drugs for ALS in combination with pluripotent stem cells (PSCs). The structure of this technology is based on the use of essential components such as iPSC- derived motor neurons and iPSC-derived skeletal muscle cells on a single miniaturized chip for ALS modeling. Accordingly, an organ on a chip not only can mimic ALS complexities but also can be considered as a more cost-effective and time-saving disease modeling platform in comparison with others. Hence, it can be concluded that lab on a chip can make a major contribution as a biomimetic micro-physiological system in the treatment of neurodegenerative disorders such as ALS.}, }
@article {pmid35105948, year = {2022}, author = {Sia, KC and Gan, SU and Mohd Rodhi, SH and Fu, ZY and Kopchick, JJ and Waters, MJ and Lee, KO}, title = {First use of gene therapy to treat growth hormone resistant dwarfism in a mouse model.}, journal = {Gene therapy}, volume = {29}, number = {6}, pages = {346-356}, pmid = {35105948}, issn = {1476-5462}, mesh = {Animals ; Disease Models, Animal ; Genetic Therapy ; *Growth Hormone/genetics/therapeutic use ; Humans ; Insulin-Like Growth Factor I/genetics/metabolism/therapeutic use ; *Laron Syndrome/drug therapy/therapy ; Mice ; Receptors, Somatotropin/genetics/metabolism/therapeutic use ; }, abstract = {The only treatment tested for growth hormone receptor (GHR) defective Laron Syndrome (LS) is injections of recombinant insulin-like-growth factor 1 (rhIGF1). The response is suboptimal and associated with progressive obesity. In this study, we treated 4-5-week-old Laron dwarf mice (GHR-/-) with an adeno-associated virus expressing murine GHR (AAV-GHR) injection at a dose of 4 × 10[10] vector genome per mouse. Serum growth hormone (GH) levels decreased, and GH-responsive IGF1, IGF binding protein 3 (IGFBP3) and acid labile subunit (ALS) increased. There was a significant but limited increase in body weight and length, similar to the response to rhIGF1 treatment in LS patients. All the major organs increased in weight except the brain. Our study is the first to use gene therapy to treat GH-receptor deficiency. We propose that gene therapy with AAV-GHR may eventually be useful for the treatment of human LS.}, }
@article {pmid35100568, year = {2022}, author = {Italia, M and Dercole, F and Lucchetti, R}, title = {Optimal chemotherapy counteracts cancer adaptive resistance in a cell-based, spatially-extended, evolutionary model.}, journal = {Physical biology}, volume = {19}, number = {2}, pages = {}, doi = {10.1088/1478-3975/ac509c}, pmid = {35100568}, issn = {1478-3975}, mesh = {Biological Evolution ; Humans ; *Neoplasms/drug therapy ; }, abstract = {Most aggressive cancers are incurable due to their fast evolution of drug resistance. We model cancer growth and adaptive response in a simplified cell-based (CB) setting, assuming a genetic resistance to two chemotherapeutic drugs. We show that optimal administration protocols can steer cells resistance and turned it into a weakness for the disease. Our work extends the population-based model proposed by Orlandoet al(2012Phys. Biol.), in which a homogeneous population of cancer cells evolves according to a fitness landscape. The landscape models three types of trade-offs, differing on whether the cells are more, less, or equal effective when generalizing resistance to two drugs as opposed to specializing to a single one. The CB framework allows us to include genetic heterogeneity, spatial competition, and drugs diffusion, as well as realistic administration protocols. By calibrating our model on Orlandoet al's assumptions, we show that dynamical protocols that alternate the two drugs minimize the cancer size at the end of (or at mid-points during) treatment. These results significantly differ from those obtained with the homogeneous model-suggesting static protocols under the pro-generalizing and neutral allocation trade-offs-highlighting the important role of spatial and genetic heterogeneities. Our work is the first attempt to search for optimal treatments in a CB setting, a step forward toward realistic clinical applications.}, }
@article {pmid35098554, year = {2022}, author = {Miller, RG and Zhang, R and Bracci, PM and Azhir, A and Barohn, R and Bedlack, R and Benatar, M and Berry, JD and Cudkowicz, M and Kasarskis, EJ and Mitsumoto, H and Manousakis, G and Walk, D and Oskarsson, B and Shefner, J and McGrath, MS}, title = {Phase 2B randomized controlled trial of NP001 in amyotrophic lateral sclerosis: Pre-specified and post hoc analyses.}, journal = {Muscle &amp; nerve}, volume = {66}, number = {1}, pages = {39-49}, pmid = {35098554}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Biomarkers ; C-Reactive Protein ; Disease Progression ; Double-Blind Method ; Humans ; Vital Capacity/physiology ; }, abstract = {INTRODUCTION/AIMS: ALS is a heterogeneous disease that may be complicated or in part driven by inflammation. NP001, a regulator of macrophage activation, was associated with slowing disease progression in those with higher levels of the plasma inflammatory marker C-reactive protein (CRP) in phase 2A studies in ALS. Here, we evaluate the effects of NP001 in a phase 2B trial, and perform a post hoc analysis with combined data from the preceding phase 2A trial.<br><br>METHODS: The phase 2B trial enrolled 138 participants within 3&#x2009;y of symptom onset and with plasma hs-CRP values >1.13&#x2009;mg/L. They were randomized 1:1 to receive either placebo or NP001 for 6&#xa0;mo. Change from baseline ALSFRS-R scores was the primary efficacy endpoint. Secondary endpoints included vital capacity (VC) change from baseline and percentage of participants showing no decline of ALSFRS-R score over 6&#xa0;mo (non-progressor).<br><br>RESULTS: The phase 2B study did not show significant differences between placebo and active treatment with respect to change in ALSFRS-R scores, or VC. The drug was safe and well tolerated. A post hoc analysis identified a 40- to 65-y-old subset in which NP001-treated patients demonstrated slower declines in ALSFRS-R score by 36% and VC loss by 51% compared with placebo. A greater number of non-progressors were NP001-treated compared with placebo (p&#xa0;=&#xa0;.004).<br><br>DISCUSSION: Although the phase 2B trial failed to meet its primary endpoints, post hoc analyses identified a subgroup whose decline in ALSFRS-R and VC scores were significantly slower than placebo. Further studies will be required to validate these findings.}, }
@article {pmid35098502, year = {2024}, author = {Wong, KL and Siu, KL}, title = {Pulmonary Complications in Premature Infants Using a Beractant or Poractant for Respiratory Distress Syndrome: A Retrospective Cohort Study.}, journal = {American journal of perinatology}, volume = {41}, number = {5}, pages = {641-648}, doi = {10.1055/a-1754-0943}, pmid = {35098502}, issn = {1098-8785}, mesh = {Infant, Newborn ; Humans ; Prospective Studies ; Retrospective Studies ; Infant, Premature ; *Biological Products ; *Respiratory Distress Syndrome, Newborn/therapy ; *Pulmonary Surfactants/adverse effects ; Surface-Active Agents ; Hemorrhage/chemically induced/epidemiology ; Oxygen/therapeutic use ; *Phospholipids ; }, abstract = {OBJECTIVE: Premature infants are at the risk of developing respiratory distress syndrome (RDS). Beractants and poractants are two commonly used natural surfactants. This retrospective cohort study aims to compare the incidence of pulmonary complications between beractant and poractant treatment groups.<br><br>STUDY DESIGN: This study evaluated 29 patients treated with beractant and 49 patients treated with poractant. The primary outcome was the incidence of air leak syndrome (ALS) and pulmonary hemorrhage. Secondary outcomes included mortality and pulmonary outcomes, such as mechanical ventilation duration, oxygen dependence duration, fraction of inspired oxygen, and mean airway pressure (MAP) requirement. Logistic regression analyses were conducted to identify independent risk factors for significant primary outcomes.<br><br>RESULTS: No significant difference was found in the demographics between the two groups. A significantly higher incidence of pulmonary hemorrhage was observed in the poractant group (14.3 vs. 0.0%, p&#x2009;=&#x2009;0.038). The difference in the incidence of ALS between the groups was insignificant (p&#x2009;=&#x2009;0.536). Logistic regression for the incidence of pulmonary hemorrhage identified coagulopathy as the only significant independent risk factor (odds ratio 39.855, 95% confidence interval [2.912-545.537]; p&#x2009;=&#x2009;0.006). Secondary outcomes in both treatment groups were similar, except that patients in the poractant group had a higher MAP before surfactant therapy (9 vs. 8&#x2009;cmH2O, p&#x2009;<&#x2009;0.001).<br><br>CONCLUSION: This study showed a significantly higher incidence of pulmonary hemorrhage in the poractant group. Coagulopathy was identified as an independent risk factor for pulmonary hemorrhage. Future long-term prospective studies are essential to establish the temporal and causal relationships between coagulopathy and pulmonary hemorrhage in premature infants receiving surfactant therapy for RDS; hence, there is the need for a screening protocol before surfactant administration.<br><br>KEY POINTS: &#xb7; A higher incidence of pulmonary hemorrhage was found in the poractant group.. &#xb7; Coagulopathy was the only significant risk factor that was related to the incidence of pulmonary hemorrhage.. &#xb7; A screening protocol might be useful to avoid pulmonary hemorrhage in infants receiving surfactant..}, }
@article {pmid35095044, year = {2022}, author = {Taniguchi, M and Yorishima, Y and Shoji, H and Ide, M and Kumura, Y and Kunisaki, K}, title = {[Survey of patients with advanced-stage Okinawa-type neurogenic muscular atrophy (hereditary motor and sensory neuropathy with proximal dominant involvement: HMSN-P)].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {62}, number = {2}, pages = {152-156}, doi = {10.5692/clinicalneurol.cn-001576}, pmid = {35095044}, issn = {1882-0654}, mesh = {Aged ; *Amyotrophic Lateral Sclerosis/genetics ; Female ; *Hereditary Sensory and Motor Neuropathy/diagnosis/genetics ; Humans ; Male ; Middle Aged ; Muscle Weakness ; Muscular Atrophy ; Surveys and Questionnaires ; }, abstract = {We conducted a survey of 16 Japanese patients (9 males, 7 females) aged 48-70 years in the advanced-stage Okinawa-type neurogenic muscular atrophy (i.e. hereditary motor and sensory neuropathy with proximal dominant involvement: HMSN-P) by a questionnaire asking the patients' disease name notification, acceptance, and expectations for treatment. In amyotrophic lateral sclerosis (ALS), since symptoms such as four-limb motor weakness and respiratory disorder are serious, patients are notified of the disease name at each progression stage. Individuals with HMSN-P exhibit ALS-like severe motor paralysis, but HMSN-P shows autosomal dominant inheritance, and progresses slowly (over >30 years). Many of the present patients who had one parent with the disease were able to predict what their diagnosis would be. However, several patients stated that they could not sleep for several months due to the shock of the diagnosis and their concern about how to explain to their children that the disease is hereditary. All patients in the advanced stage of HMSN-P progress to severe proximal dominant quadriplegia and ultimately need auxiliary tools such as a wheelchair. New developments toward a specific HMSN-P treatment are expected, with methods such as nucleic acid medicine.}, }
@article {pmid35086120, year = {2022}, author = {Chamberlain, P and Bradley, A and Arumugam, B and Hammond, D and McNally, J and Logan, NS and Jones, D and Ngo, C and Peixoto-de-Matos, SC and Hunt, C and Young, G}, title = {Long-term Effect of Dual-focus Contact Lenses on Myopia Progression in Children: A 6-year Multicenter Clinical Trial.}, journal = {Optometry and vision science : official publication of the American Academy of Optometry}, volume = {99}, number = {3}, pages = {204-212}, doi = {10.1097/OPX.0000000000001873}, pmid = {35086120}, issn = {1538-9235}, mesh = {Axial Length, Eye ; Child ; *Contact Lenses, Hydrophilic ; Disease Progression ; Humans ; *Myopia/diagnosis/therapy ; Refraction, Ocular ; Vision, Ocular ; }, abstract = {SIGNIFICANCE: Treatment of myopic children with a dual-focus soft contact lens (DFCL; MiSight 1 day) produced sustained slowing of myopia progression over a 6-year period. Significant slowing was also observed in children switched from a single vision control to treatment lenses (3 years in each lens).<br><br>PURPOSE: This study aimed to evaluate the effectiveness of DFCLs in sustaining slowed progression of juvenile-onset myopia over a 6-year treatment period and assess myopia progression in children who were switched to a DFCL at the end of year 3.<br><br>METHODS: Part 1 was a 3-year clinical trial comparing DFCLs with a control contact lens (Proclear 1 day) at four investigational sites. In part 2, subjects completing part 1 were invited to continue for 3 additional years during which all children were treated with MiSight 1 day DFCLs (52 and 56 from the initially treated [T6] and control [T3] groups, respectively). Eighty-five subjects (45 [T3] and 40 [T6]) completed part 2. Cyclopleged spherical equivalent refractive errors (SEREs) and axial lengths (ALs) were monitored, and a linear mixed model was used to compare their adjusted change annually.<br><br>RESULTS: Average ages at part 2 baseline were 13.2 &#xb1; 1.3 and 13.0 &#xb1; 1.5 years for the T6 and T3 groups, respectively. Slowed myopia progression in the T6 group observed during part 1 was sustained throughout part 2 (mean &#xb1; standard error of the mean: change from baseline SERE [in diopters], -0.52 &#xb1; 0.076 vs. -0.51 &#xb1; 0.076; change in AL [in millimeters], 0.28 &#xb1; 0.033 vs. 0.23 &#xb1; 0.033; both P > .05). Comparing progression rates in part 2 for the T6 and T3 groups, respectively, indicates that prior treatment does not influence efficacy (SERE, -0.51 &#xb1; 0.076 vs. -0.34 &#xb1; 0.077; AL, 0.23 &#xb1; 0.03 vs. 0.18 &#xb1; 0.03; both P > .05). Within-eye comparisons of AL growth revealed a 71% slowing for the T3 group (3 years older than part 1) and further revealed a small subset of eyes (10%) that did not respond to treatment.<br><br>CONCLUSIONS: Dual-focus soft contact lenses continue to slow the progression of myopia in children over a 6-year period revealing an accumulation of treatment effect. Eye growth of the initial control cohort with DFCL was slowed by 71% over the subsequent 3-year treatment period.}, }
@article {pmid35081899, year = {2022}, author = {Sivagurunathan, N and Ambatt, ATS and Calivarathan, L}, title = {Role of Long Non-coding RNAs in the Pathogenesis of Alzheimer's and Parkinson's Diseases.}, journal = {Current aging science}, volume = {15}, number = {2}, pages = {84-96}, doi = {10.2174/1874609815666220126095847}, pmid = {35081899}, issn = {1874-6128}, mesh = {Aged ; *Alzheimer Disease/genetics ; Biomarkers/metabolism ; Humans ; *Neurodegenerative Diseases/genetics/therapy ; *Parkinson Disease/genetics ; *RNA, Long Noncoding/genetics ; }, abstract = {Neurodegenerative diseases are a diverse group of diseases that are now one of the leading causes of morbidity in the elderly population. These diseases include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), etc. Although these diseases have a common characteristic feature of progressive neuronal loss from various parts of the brain, they differ in the clinical symptoms and risk factors, leading to the development and progression of the diseases. AD is a neurological condition that leads to dementia and cognitive decline due to neuronal cell death in the brain, whereas PD is a movement disorder affecting neuro-motor function and develops due to the death of the dopaminergic neurons in the brain, resulting in decreased dopamine levels. Currently, the only treatment available for these neurodegenerative diseases involves reducing the rate of progression of neuronal loss. This necessitates the development of efficient early biomarkers and effective therapies for these diseases. Long non-coding RNAs (LncRNAs) belong to a large family of non-coding transcripts with a minimum length of 200 nucleotides. They are implied to be involved in the development of the brain, a variety of diseases, and epigenetic, transcriptional, and posttranscriptional levels of gene regulation. Aberrant expression of lncRNAs in the CNS is considered to play a major role in the development and progression of AD and PD, two of the most leading causes of morbidity among elderly populations. In this mini-review, we discuss the role of various long non-coding RNAs in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, which can further be studied for the development of potential biomarkers and therapeutic targets for various neurodegenerative diseases.}, }
@article {pmid35080077, year = {2022}, author = {Estévez-Silva, HM and Mediavilla, T and Giacobbo, BL and Liu, X and Sultan, FR and Marcellino, DJ}, title = {Pridopidine modifies disease phenotype in a SOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {The European journal of neuroscience}, volume = {55}, number = {5}, pages = {1356-1372}, pmid = {35080077}, issn = {1460-9568}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Animals ; Cachexia ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Muscle Weakness ; *Neurodegenerative Diseases ; Phenotype ; Piperidines ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal and incurable neurodegenerative disease due to the loss of upper and lower motor neurons, which leads to muscle weakness, atrophy, and paralysis. Sigma-1 receptor (σ-1R) is a ligand-operated protein that exhibits pro-survival and anti-apoptotic properties. In addition, mutations in its codifying gene are linked to development of juvenile ALS pointing to an important role in ALS. Here, we investigated the disease-modifying effects of pridopidine, a σ-1R agonist, using a delayed onset SOD1 G93A mouse model of ALS. Mice were administered a continuous release of pridopidine (3.0 mg/kg/day) for 4 weeks starting before the appearance of any sign of muscle weakness. Mice were monitored weekly and several behavioural tests were used to evaluate muscle strength, motor coordination and gait patterns. Pridopidine-treated SOD1 G93A mice showed genotype-specific effects with the prevention of cachexia. In addition, these effects exhibited significant improvement of motor behaviour 5 weeks after treatment ended. However, the survival of the animals was not extended. In summary, these results show that pridopidine can modify the disease phenotype of ALS-associated cachexia and motor deficits in a SOD1 G93A mouse model.}, }
@article {pmid35076930, year = {2022}, author = {van Eijk, RPA and Roes, KCB and de Greef-van der Sandt, I and van den Berg, LH and Lu, Y}, title = {Functional Loss and Mortality in Randomized Clinical Trials for Amyotrophic Lateral Sclerosis: To Combine, or Not to Combine-That is the Estimand.}, journal = {Clinical pharmacology and therapeutics}, volume = {111}, number = {4}, pages = {817-825}, pmid = {35076930}, issn = {1532-6535}, support = {R01 HL089778/HL/NHLBI NIH HHS/United States ; P30 CA124435/CA/NCI NIH HHS/United States ; UL1 TR003142/TR/NCATS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Quality of Life ; Randomized Controlled Trials as Topic ; }, abstract = {Amyotrophic lateral sclerosis is a rapidly progressive disease leading to death in, on average, 3-5 years after first symptom onset. Consequently, there are frequently a non-negligible number of patients who die during the course of a clinical trial. This introduces bias in end points such as daily functioning, muscle strength, and quality of life. In this paper, we outline how the choice of strategy to handle death affects the interpretation of the trial results. We provide a general overview of the considerations, positioned in the estimand framework, and discuss the possibility that not every strategy provides a clinically relevant answer in each setting. The relevance of a strategy changes as a function of the intended trial duration, hypothesized treatment effect, and population included. It is important to consider this trade-off at the design stage of a clinical trial, as this will clarify the exact research question that is being answered, and better guide the planning, design, and analysis of the study.}, }
@article {pmid35064780, year = {2022}, author = {Pampalakis, G and Angelis, G and Zingkou, E and Vekrellis, K and Sotiropoulou, G}, title = {A chemogenomic approach is required for effective treatment of amyotrophic lateral sclerosis.}, journal = {Clinical and translational medicine}, volume = {12}, number = {1}, pages = {e657}, pmid = {35064780}, issn = {2001-1326}, support = {1876//Hellenic Foundation for Research and Innovation (HFRI) and General Secretariat for Research and Innovation (GSRI)/ ; T1EDK-03884//BIOLUMINPD/ ; NSRF 2014-2020//Competitiveness, Entrepreneurship and Innovation/ ; //Greece and the European Union (European Regional Development Fund)/ ; //Research Committee of the University of Patras/ ; }, mesh = {Amino Acids, Diamino/adverse effects ; Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/metabolism ; Animals ; Cyanobacteria Toxins/adverse effects ; Cycas/adverse effects/metabolism ; Disease Models, Animal ; Mice ; }, abstract = {ALS is a fatal untreatable disease involving degeneration of motor neurons. Μultiple causative genes encoding proteins with versatile functions have been identified indicating that diverse biological pathways lead to ALS. Chemical entities still represent a promising choice to delay ALS progression, attenuate symptoms and/or increase life expectancy, but also gene-based and stem cell-based therapies are in the process of development, and some are tested in clinical trials. Various compounds proved effective in transgenic models overexpressing distinct ALS causative genes unfortunately though, they showed no efficacy in clinical trials. Notably, while animal models provide a uniform genetic background for preclinical testing, ALS patients are not stratified, and the distinct genetic forms of ALS are treated as one group, which could explain the observed discrepancies between treating genetically homogeneous mice and quite heterogeneous patient cohorts. We suggest that chemical entity-genotype correlation should be exploited to guide patient stratification for pharmacotherapy, that is administered drugs should be selected based on the ALS genetic background.}, }
@article {pmid35062074, year = {2022}, author = {Kabir, MT and Rahman, MH and Shah, M and Jamiruddin, MR and Basak, D and Al-Harrasi, A and Bhatia, S and Ashraf, GM and Najda, A and El-Kott, AF and Mohamed, HRH and Al-Malky, HS and Germoush, MO and Altyar, AE and Alwafai, EB and Ghaboura, N and Abdel-Daim, MM}, title = {Therapeutic promise of carotenoids as antioxidants and anti-inflammatory agents in neurodegenerative disorders.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {146}, number = {}, pages = {112610}, doi = {10.1016/j.biopha.2021.112610}, pmid = {35062074}, issn = {1950-6007}, mesh = {Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Antioxidants/pharmacology/*therapeutic use ; Carotenoids/classification/pharmacology/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy ; Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative disorders (NDs) including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis have various disease-specific causal factors and pathological features. A very common characteristic of NDs is oxidative stress (OS), which takes place due to the elevated generation of reactive oxygen species during the progression of NDs. Furthermore, the pathological condition of NDs including an increased level of protein aggregates can further lead to chronic inflammation because of the microglial activation. Carotenoids (CTs) are naturally occurring pigments that play a significant role in averting brain disorders. More than 750 CTs are present in nature, and they are widely available in plants, microorganisms, and animals. CTs are accountable for the red, yellow, and orange pigments in several animals and plants, and these colors usually indicate various types of CTs. CTs exert various bioactive properties because of its characteristic structure, including anti-inflammatory and antioxidant properties. Due to the protective properties of CTs, levels of CTs in the human body have been markedly linked with the prevention and treatment of multiple diseases including NDs. In this review, we have summarized the relationship between OS, neuroinflammation, and NDs. In addition, we have also particularly focused on the antioxidants and anti-inflammatory properties of CTs in the management of NDs.}, }
@article {pmid35057094, year = {2022}, author = {Peters, S and Wirkert, E and Kuespert, S and Heydn, R and Johannesen, S and Friedrich, A and Mailänder, S and Korte, S and Mecklenburg, L and Aigner, L and Bruun, TH and Bogdahn, U}, title = {Safe and Effective Cynomolgus Monkey GLP-Tox Study with Repetitive Intrathecal Application of a TGFBR2 Targeting LNA-Gapmer Antisense Oligonucleotide as Treatment Candidate for Neurodegenerative Disorders.}, journal = {Pharmaceutics}, volume = {14}, number = {1}, pages = {}, pmid = {35057094}, issn = {1999-4923}, support = {031A386//Federal Ministry of Education and Research/ ; KF2525608MD3//Federal Ministry for Economic Affairs and Energy/ ; BIO-1506-0002//Bavarian Ministry of Economic Affairs and Media, Energy and Technology/ ; }, abstract = {The capability of the adult central nervous system to self-repair/regenerate was demonstrated repeatedly throughout the last decades but remains in debate. Reduced neurogenic niche activity paralleled by a profound neuronal loss represents fundamental hallmarks in the disease course of neurodegenerative disorders. We and others have demonstrated the endogenous TGFβ system to represent a potential pathogenic participant in disease progression, of amyotrophic lateral sclerosis (ALS) in particular, by generating and promoting a disequilibrium of neurodegenerative and neuroregenerative processes. The novel human/primate specific LNA Gapmer Antisense Oligonucleotide "NVP-13", targeting TGFBR2, effectively reduced its expression and lowered TGFβ signal transduction in vitro and in vivo, paralleled by boosting neurogenic niche activity in human neuronal progenitor cells and nonhuman primate central nervous system. Here, we investigated NVP-13 in vivo pharmacology, safety, and tolerability following repeated intrathecal injections in nonhuman primate cynomolgus monkeys for 13 weeks in a GLP-toxicology study approach. NVP-13 was administered intrathecally with 1, 2, or 4 mg NVP-13/animal within 3 months on days 1, 15, 29, 43, 57, 71, and 85 in the initial 13 weeks. We were able to demonstrate an excellent local and systemic tolerability, and no adverse events in physiological, hematological, clinical chemistry, and microscopic findings in female and male Cynomolgus Monkeys. Under the conditions of this study, the no observed adverse effect level (NOAEL) is at least 4 mg/animal NVP-13.}, }
@article {pmid35057079, year = {2022}, author = {Teixeira, MI and Lopes, CM and Gonçalves, H and Catita, J and Silva, AM and Rodrigues, F and Amaral, MH and Costa, PC}, title = {Formulation, Characterization, and Cytotoxicity Evaluation of Lactoferrin Functionalized Lipid Nanoparticles for Riluzole Delivery to the Brain.}, journal = {Pharmaceutics}, volume = {14}, number = {1}, pages = {}, pmid = {35057079}, issn = {1999-4923}, support = {UIDP/04378/2020 and UIDB/04378/2020//Research Unit on Applied Molecular Biosciences (UCIBIO)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a very poor prognosis. Its treatment is hindered by a lack of new therapeutic alternatives and the existence of the blood-brain barrier (BBB), which restricts the access of drugs commonly used in ALS, such as riluzole, to the brain. To overcome these limitations and increase brain targeting, riluzole-loaded nanostructured lipid carriers (NLC) were prepared and functionalized with lactoferrin (Lf), facilitating transport across the BBB by interacting with Lf receptors expressed in the brain endothelium. NLC were characterized with respect to their physicochemical properties (size, zeta potential, polydispersity index) as well as their stability, encapsulation efficiency, morphology, in vitro release profile, and biocompatibility. Moreover, crystallinity and melting behavior were assessed by DSC and PXRD. Nanoparticles exhibited initial mean diameters between 180 and 220 nm and a polydispersity index below 0.3, indicating a narrow size distribution. NLC remained stable over at least 3 months. Riluzole encapsulation efficiency was very high, around 94-98%. FTIR and protein quantification studies confirmed the conjugation of Lf on the surface of the nanocarriers, with TEM images showing that the functionalized NLC presented a smooth surface and uniform spherical shape. An MTT assay revealed that the nanocarriers developed in this study did not cause a substantial reduction in the viability of NSC-34 and hCMEC/D3 cells at a riluzole concentration up to 10 μM, being therefore biocompatible. The results suggest that Lf-functionalized NLC are a suitable and promising delivery system to target riluzole to the brain.}, }
@article {pmid35056151, year = {2022}, author = {Galvez-Llompart, M and Zanni, R and Garcia-Domenech, R and Galvez, J}, title = {How Molecular Topology Can Help in Amyotrophic Lateral Sclerosis (ALS) Drug Development: A Revolutionary Paradigm for a Merciless Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, pmid = {35056151}, issn = {1424-8247}, abstract = {Even if amyotrophic lateral sclerosis is still considered an orphan disease to date, its prevalence among the population is growing fast. Despite the efforts made by researchers and pharmaceutical companies, the cryptic information related to the biological and physiological onset mechanisms, as well as the complexity in identifying specific pharmacological targets, make it almost impossible to find effective treatments. Furthermore, because of complex ethical and economic aspects, it is usually hard to find all the necessary resources when searching for drugs for new orphan diseases. In this context, computational methods, based either on receptors or ligands, share the capability to improve the success rate when searching and selecting potential candidates for further experimentation and, consequently, reduce the number of resources and time taken when delivering a new drug to the market. In the present work, a computational strategy based on Molecular Topology, a mathematical paradigm capable of relating the chemical structure of a molecule to a specific biological or pharmacological property by means of numbers, is presented. The result was the creation of a reliable and accessible tool to help during the early in silico stages in the identification and repositioning of potential hits for ALS treatment, which can also apply to other orphan diseases. Considering that further computational and experimental results will be required for the final identification of viable hits, three linear discriminant equations combined with molecular docking simulations on specific proteins involved in ALS are reported, along with virtual screening of the Drugbank database as a practical example. In this particular case, as reported, a clinical trial has been already started for one of the drugs proposed in the present study.}, }
@article {pmid35052677, year = {2022}, author = {Park, HR and Yang, EJ}, title = {Combined Treatment with Herbal Medicine and Drug Ameliorates Inflammation and Metabolic Abnormalities in the Liver of an Amyotrophic Lateral Sclerosis Mouse Model.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {1}, pages = {}, pmid = {35052677}, issn = {2076-3921}, support = {NRF-2020R1A2C2006703//National Research Foundation of Korea/ ; }, abstract = {To date, no effective drugs exist for amyotrophic lateral sclerosis (ALS), although riluzole (RZ) and edaravone have been approved for treatment. We previously reported that Bojungikgi-tang (BJIGT) improved motor activity through anti-inflammatory effects in the muscle and spinal cord of hSOD1[G93A] mice. Therefore, whether combined treatment with BJIGT and RZ synergistically affects liver function in hSOD1[G93A] mice was investigated. Two-month-old male hSOD1[G93A] mice were treated with BJIGT (1 mg/g) and RZ (8 μg/g) administered orally for 5 weeks. Drug metabolism and liver function tests of serum and liver homogenates were conducted. mRNA expression levels of cytochrome P450 (CYP) isozymes, inflammatory cytokines, metabolic factors, and mitochondrial oxidative phosphorylation (OXPHOS) subunits were examined using qPCR and Western blotting. Combined administration of BJIGT and RZ did not alter mRNA expression levels of drug-metabolism-related isozymes (CYP1A2 and CYP3A4) but significantly decreased the activity of liver-function-related enzymes (AST, ALT, ALP, and LDH). Increased expression of inflammatory cytokines (IL-1β, TNF-α, and IL-6) and of intracellular stress-related proteins (Bax, AMPKα, JNK, and p38) was reduced by the combined treatment in hSOD1[G93A] mice compared to that in control mice. Combined administration reduced the mRNA expression of metabolism-related factors and the expression of OXPHOS subunits. Elevated ATP levels and mitochondrial-fusion-associated protein were decreased after co-administration. Co-administration of BJIGT and RZ did not cause liver damage or toxicity but rather restored liver function in hSOD1[G93A] mice. This suggests that this combination can be considered a candidate therapeutic agent for ALS.}, }
@article {pmid35052586, year = {2021}, author = {Jeon, YM and Kwon, Y and Lee, S and Kim, S and Jo, M and Lee, S and Kim, SR and Kim, K and Kim, HJ}, title = {Vitamin B12 Reduces TDP-43 Toxicity by Alleviating Oxidative Stress and Mitochondrial Dysfunction.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {1}, pages = {}, pmid = {35052586}, issn = {2076-3921}, support = {2019R1F1A1045639, 2020R1A2C4002366//Ministry of Science ICT and Future Planning/ ; 21-BR-02-15//KBRI Research Program of the Ministry of Science, ICT and Future Planning/ ; Kiyoung Kim//the Soonchunhyang University Research Fund/ ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a member of an evolutionarily conserved family of heterogeneous nuclear ribonucleoproteins that modulate multiple steps in RNA metabolic processes. Cytoplasmic aggregation of TDP-43 in affected neurons is a pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Mislocalized and accumulated TDP-43 in the cytoplasm induces mitochondrial dysfunction and reactive oxidative species (ROS) production. Here, we show that TDP-43- and rotenone-induced neurotoxicity in the human neuronal cell line SH-SY5Y were attenuated by hydroxocobalamin (Hb, vitamin B12 analog) treatment. Although Hb did not affect the cytoplasmic accumulation of TDP-43, Hb attenuated TDP-43-induced toxicity by reducing oxidative stress and mitochondrial dysfunction. Moreover, a shortened lifespan and motility defects in TDP-43-expressing Drosophila were significantly mitigated by dietary treatment with hydroxocobalamin. Taken together, these findings suggest that oral intake of hydroxocobalamin may be a potential therapeutic intervention for TDP-43-associated proteinopathies.}, }
@article {pmid35052556, year = {2021}, author = {Sanghai, N and Tranmer, GK}, title = {Hydrogen Peroxide and Amyotrophic Lateral Sclerosis: From Biochemistry to Pathophysiology.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {1}, pages = {}, pmid = {35052556}, issn = {2076-3921}, support = {FOAP 320125-348000-2000//Research Manitoba New Investigator Operating Grant/ ; }, abstract = {Free radicals are unstable chemical reactive species produced during Redox dyshomeostasis (RDH) inside living cells and are implicated in the pathogenesis of various neurodegenerative diseases. One of the most complicated and life-threatening motor neurodegenerative diseases (MND) is amyotrophic lateral sclerosis (ALS) because of the poor understanding of its pathophysiology and absence of an effective treatment for its cure. During the last 25 years, researchers around the globe have focused their interest on copper/zinc superoxide dismutase (Cu/Zn SOD, SOD1) protein after the landmark discovery of mutant SOD1 (mSOD1) gene as a risk factor for ALS. Substantial evidence suggests that toxic gain of function due to redox disturbance caused by reactive oxygen species (ROS) changes the biophysical properties of native SOD1 protein thus, instigating its fibrillization and misfolding. These abnormal misfolding aggregates or inclusions of SOD1 play a role in the pathogenesis of both forms of ALS, i.e., Sporadic ALS (sALS) and familial ALS (fALS). However, what leads to a decrease in the stability and misfolding of SOD1 is still in question and our scientific knowledge is scarce. A large number of studies have been conducted in this area to explore the biochemical mechanistic pathway of SOD1 aggregation. Several studies, over the past two decades, have shown that the SOD1-catalyzed biochemical reaction product hydrogen peroxide (H2O2) at a pathological concentration act as a substrate to trigger the misfolding trajectories and toxicity of SOD1 in the pathogenesis of ALS. These toxic aggregates of SOD1 also cause aberrant localization of TAR-DNA binding protein 43 (TDP-43), which is characteristic of neuronal cytoplasmic inclusions (NCI) found in ALS. Here in this review, we present the evidence implicating the pivotal role of H2O2 in modulating the toxicity of SOD1 in the pathophysiology of the incurable and highly complex disease ALS. Also, highlighting the role of H2O2 in ALS, we believe will encourage scientists to target pathological concentrations of H2O2 thereby halting the misfolding of SOD1.}, }
@article {pmid35048857, year = {2021}, author = {Bhattacherjee, S and Young, A and Ahuja, N and Allen, S}, title = {Should intramuscular clozapine be adopted into mainstream clinical practice?.}, journal = {The British journal of psychiatry : the journal of mental science}, volume = {219}, number = {1}, pages = {357-358}, doi = {10.1192/bjp.2021.36}, pmid = {35048857}, issn = {1472-1465}, mesh = {*Antipsychotic Agents/adverse effects ; *Clozapine/adverse effects ; Humans ; *Psychotic Disorders/drug therapy ; *Schizophrenia/drug therapy ; }, abstract = {Clozapine is under-used in the UK, and Casetta et al's recent paper in the BJPsych adds to a growing number of small studies that support the use of intramuscular clozapine to initiate and maintain treatment with oral clozapine. However, intramuscular clozapine remains unlicensed and, because of the risks associated with its administration, it should be used only cautiously before it can be adopted more widely into mainstream clinical practice.}, }
@article {pmid35022247, year = {2022}, author = {Akamatsu, M and Yamashita, T and Teramoto, S and Huang, Z and Lynch, J and Toda, T and Niu, L and Kwak, S}, title = {Testing of the therapeutic efficacy and safety of AMPA receptor RNA aptamers in an ALS mouse model.}, journal = {Life science alliance}, volume = {5}, number = {4}, pages = {}, pmid = {35022247}, issn = {2575-1077}, support = {R21 NS106392/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Aptamers, Nucleotide/*genetics ; Disease Models, Animal ; Drug Delivery Systems ; Male ; Mice ; Motor Neurons/metabolism ; RNA Editing/genetics ; *Receptors, AMPA/antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {In motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients, the RNA editing at the glutamine/arginine site of the GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors is defective or incomplete. As a result, AMPA receptors containing the abnormally expressed, unedited isoform of GluA2 are highly Ca[2+]-permeable, and are responsible for mediating abnormal Ca[2+] influx, thereby triggering motor neuron degeneration and cell death. Thus, blocking the AMPA receptor-mediated, abnormal Ca[2+] influx is a potential therapeutic strategy for treatment of sporadic ALS. Here, we report a study of the efficacy and safety of two RNA aptamers targeting AMPA receptors on the ALS phenotype of AR2 mice. A 12-wk continuous, intracerebroventricular infusion of aptamers to AR2 mice reduced the progression of motor dysfunction, normalized TDP-43 mislocalization, and prevented death of motor neurons. Our results demonstrate that the use of AMPA receptor aptamers as a novel class of AMPA receptor antagonists is a promising strategy for developing an ALS treatment approach.}, }
@article {pmid35017408, year = {2022}, author = {Liu, B and Li, M and Zhang, L and Chen, Z and Lu, P}, title = {Motor neuron replacement therapy for amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {17}, number = {8}, pages = {1633-1639}, pmid = {35017408}, issn = {1673-5374}, support = {I01 RX002264/RX/RRD VA/United States ; }, abstract = {Amyotrophic lateral sclerosis is a motor neuron degenerative disease that is also known as Lou Gehrig's disease in the United States, Charcot's disease in France, and motor neuron disease in the UK. The loss of motor neurons causes muscle wasting, paralysis, and eventually death, which is commonly related to respiratory failure, within 3-5 years after onset of the disease. Although there are a limited number of drugs approved for amyotrophic lateral sclerosis, they have had little success at treating the associated symptoms, and they cannot reverse the course of motor neuron degeneration. Thus, there is still a lack of effective treatment for this debilitating neurodegenerative disorder. Stem cell therapy for amyotrophic lateral sclerosis is a very attractive strategy for both basic and clinical researchers, particularly as transplanted stem cells and stem cell-derived neural progenitor/precursor cells can protect endogenous motor neurons and directly replace the lost or dying motor neurons. Stem cell therapies may also be able to re-establish the motor control of voluntary muscles. Here, we review the recent progress in the use of neural stem cells and neural progenitor cells for the treatment of amyotrophic lateral sclerosis. We focus on MN progenitor cells derived from fetal central nervous system tissue, embryonic stem cells, and induced pluripotent stem cells. In our recent studies, we found that transplanted human induced pluripotent stem cell-derived motor neuron progenitors survive well, differentiate into motor neurons, and extend axons into the host white matter, not only in the rostrocaudal direction, but also along motor axon tracts towards the ventral roots in the immunodeficient rat spinal cord. Furthermore, the significant motor axonal extension after neural progenitor cell transplantation in amyotrophic lateral sclerosis models demonstrates that motor neuron replacement therapy could be a promising therapeutic strategy for amyotrophic lateral sclerosis, particularly as a variety of stem cell derivatives, including induced pluripotent stem cells, are being considered for clinical trials for various diseases.}, }
@article {pmid35016464, year = {2021}, author = {Cui, X and Gao, M and Huang, Y and Liu, X and Xu, Y}, title = {Familial amyotrophic lateral sclerosis induced by gene mutation of SOD1G142A: a case report.}, journal = {Annals of palliative medicine}, volume = {10}, number = {12}, pages = {12900-12905}, doi = {10.21037/apm-21-3254}, pmid = {35016464}, issn = {2224-5839}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Mutation ; *Neurodegenerative Diseases ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving both upper and lower motor neurons. The total prevalence of ALS is [2-9]/100,000, with an annual incidence rate of 3/100,000. The disease progresses rapidly and clinically is considered to be progressive degeneration of the upper and lower motor neurons. Although this is a kind of rare disease, the mortality is high once it occurs, which has a great impact on patients and their families. Currently there is no treatment for either the sporadic or familial form. Therefore, it is of great significance to explore the diagnosis and treatment of familial amyotrophic lateral sclerosis (FALS). We report the diagnosis and treatment of a patient with familial ALS caused by mutation of the Cu/Zn superoxide dismutase (SOD1) gene c.425g > C (p.g142a), which is considered rare. We got to know that genetic testing of the patient and his immediate family members assisted in diagnosis and palliative care. Edaravone and Riluzole were used in this case according to the guideline in this case. The progress of the disease was alleviated and the survival experience of patients improved because of this medication administration. The aim of this case report is to provide a reference for the diagnosis and treatment strategy in FALS. What's more, further exploration of treatment using integrated traditional Chinese and Western medicine to delay the disease process has great significance for improved patient outcomes.}, }
@article {pmid35012575, year = {2022}, author = {Li, Q and Feng, Y and Xue, Y and Zhan, X and Fu, Y and Gui, G and Zhou, W and Richard, JP and Taga, A and Li, P and Mao, X and Maragakis, NJ and Ying, M}, title = {Edaravone activates the GDNF/RET neurotrophic signaling pathway and protects mRNA-induced motor neurons from iPS cells.}, journal = {Molecular neurodegeneration}, volume = {17}, number = {1}, pages = {8}, pmid = {35012575}, issn = {1750-1326}, support = {R01 NS099460/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Edaravone/metabolism/pharmacology/therapeutic use ; Glial Cell Line-Derived Neurotrophic Factor/metabolism/pharmacology/therapeutic use ; Humans ; Hydrogen Peroxide/metabolism/pharmacology/therapeutic use ; *Induced Pluripotent Stem Cells ; Motor Neurons/metabolism ; Proto-Oncogene Proteins c-ret/metabolism/therapeutic use ; RNA, Messenger/metabolism ; Signal Transduction ; }, abstract = {BACKGROUND: Spinal cord motor neurons (MNs) from human iPS cells (iPSCs) have wide applications in disease modeling and therapeutic development for amyotrophic lateral sclerosis (ALS) and other MN-associated neurodegenerative diseases. We need highly efficient MN differentiation strategies for generating iPSC-derived disease models that closely recapitulate the genetic and phenotypic complexity of ALS. An important application of these models is to understand molecular mechanisms of action of FDA-approved ALS drugs that only show modest clinical efficacy. Novel mechanistic insights will help us design optimal therapeutic strategies together with predictive biomarkers to achieve better efficacy.<br><br>METHODS: We induce efficient MN differentiation from iPSCs in 4&#x2009;days using synthetic mRNAs coding two transcription factors (Ngn2 and Olig2) with phosphosite modification. These MNs after extensive characterization were applied in electrophysiological and neurotoxicity assays as well as transcriptomic analysis, to study the neuroprotective effect and molecular mechanisms of edaravone, an FDA-approved drug for ALS, for improving its clinical efficacy.<br><br>RESULTS: We generate highly pure and functional mRNA-induced MNs (miMNs) from control and ALS iPSCs, as well as embryonic stem cells. Edaravone alleviates H2O2-induced neurotoxicity and electrophysiological dysfunction in miMNs, demonstrating its neuroprotective effect that was also found in the glutamate-induced miMN neurotoxicity model. Guided by the transcriptomic analysis, we show a previously unrecognized effect of edaravone to induce the GDNF receptor RET and the GDNF/RET neurotrophic signaling in vitro and in vivo, suggesting a clinically translatable strategy to activate this key neuroprotective signaling. Notably, edaravone can replace required neurotrophic factors (BDNF and GDNF) to support long-term miMN survival and maturation, further supporting the neurotrophic function of edaravone-activated signaling. Furthermore, we show that edaravone and GDNF combined treatment more effectively protects miMNs from H2O2-induced neurotoxicity than single treatment, suggesting a potential combination strategy for ALS treatment.<br><br>CONCLUSIONS: This study provides methodology to facilitate iPSC differentiation and disease modeling. Our discoveries will facilitate the development of optimal edaravone-based therapies for ALS and potentially other neurodegenerative diseases.}, }
@article {pmid35009270, year = {2021}, author = {Niccolini, B and Palmieri, V and De Spirito, M and Papi, M}, title = {Opportunities Offered by Graphene Nanoparticles for MicroRNAs Delivery for Amyotrophic Lateral Sclerosis Treatment.}, journal = {Materials (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, pmid = {35009270}, issn = {1996-1944}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration and death of motor neurons. This neurodegenerative disease leads to muscle atrophy, paralysis, and death due to respiratory failure. MicroRNAs (miRNAs) are small non-coding ribonucleic acids (RNAs) with a length of 19 to 25 nucleotides, participating in the regulation of gene expression. Different studies have demonstrated that miRNAs deregulation is critical for the onset of a considerable number of neurodegenerative diseases, including ALS. Some studies have underlined how miRNAs are deregulated in ALS patients and for this reason, design therapies are used to correct the aberrant expression of miRNAs. With this rationale, delivery systems can be designed to target specific miRNAs. Specifically, these systems can be derived from viral vectors (viral systems) or synthetic or natural materials, including exosomes, lipids, and polymers. Between many materials used for non-viral vectors production, the two-dimensional graphene and its derivatives represent a good alternative for efficiently delivering nucleic acids. The large surface-to-volume ratio and ability to penetrate cell membranes are among the advantages of graphene. This review focuses on the specific pathogenesis of miRNAs in ALS and on graphene delivery systems designed for gene delivery to create a primer for future studies in the field.}, }
@article {pmid35008771, year = {2021}, author = {Liu, Y and Ding, R and Xu, Z and Xue, Y and Zhang, D and Zhang, Y and Li, W and Li, X}, title = {Roles and Mechanisms of the Protein Quality Control System in Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {23}, number = {1}, pages = {}, pmid = {35008771}, issn = {1422-0067}, support = {81872626//National Natural Science Foundation of China/ ; 82003454//National Natural Science Foundation of China/ ; CNS-BMSG2020A63//Bright Moon Seaweed Group Nutrition and Health Research Fund/ ; CNS-ZD2019066//Zhen Dong National Physical Fitness and Health Research Fund/ ; No. 212102310219//Key R&amp;D and promotion projects in Henan Province/ ; }, mesh = {Alzheimer Disease/*metabolism/pathology ; Animals ; Autophagy ; Clinical Trials as Topic ; Endoplasmic Reticulum Stress ; Humans ; Lysosomes/metabolism ; Proteins/*metabolism ; }, abstract = {Alzheimer's disease (AD) is characterized by the deposition of senile plaques (SPs) and the formation of neurofibrillary tangles (NTFs), as well as neuronal dysfunctions in the brain, but in fact, patients have shown a sustained disease progression for at least 10 to 15 years before these pathologic biomarkers can be detected. Consequently, as the most common chronic neurological disease in the elderly, the challenge of AD treatment is that it is short of effective biomarkers for early diagnosis. The protein quality control system is a collection of cellular pathways that can recognize damaged proteins and thereby modulate their turnover. Abundant evidence indicates that the accumulation of abnormal proteins in AD is closely related to the dysfunction of the protein quality control system. In particular, it is the synthesis, degradation, and removal of essential biological components that have already changed in the early stage of AD, which further encourages us to pay more attention to the protein quality control system. The review mainly focuses on the endoplasmic reticulum system (ERS), autophagy-lysosome system (ALS) and the ubiquitin-proteasome system (UPS), and deeply discusses the relationship between the protein quality control system and the abnormal proteins of AD, which can not only help us to understand how and why the complex regulatory system becomes malfunctional during AD progression, but also provide more novel therapeutic strategies to prevent the development of AD.}, }
@article {pmid35008513, year = {2021}, author = {Zingale, VD and Gugliandolo, A and Mazzon, E}, title = {MiR-155: An Important Regulator of Neuroinflammation.}, journal = {International journal of molecular sciences}, volume = {23}, number = {1}, pages = {}, pmid = {35008513}, issn = {1422-0067}, support = {Current Research Funds 2021//Ministero della Salute/ ; }, mesh = {Animals ; Central Nervous System/pathology ; Humans ; MicroRNAs/*genetics ; Neuroinflammatory Diseases/*genetics/pathology ; }, abstract = {MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at the post-transcriptional level and that play an important role in many cellular processes, including modulation of inflammation. MiRNAs are present in high concentrations in the central nervous system (CNS) and are spatially and temporally expressed in a specific way. Therefore, an imbalance in the expression pattern of these small molecules can be involved in the development of neurological diseases. Generally, CNS responds to damage or disease through the activation of an inflammatory response, but many neurological disorders are characterized by uncontrolled neuroinflammation. Many studies support the involvement of miRNAs in the activation or inhibition of inflammatory signaling and in the promotion of uncontrolled neuroinflammation with pathological consequences. MiR-155 is a pro-inflammatory mediator of the CNS and plays an important regulatory role. The purpose of this review is to summarize how miR-155 is regulated and the pathological consequences of its deregulation during neuroinflammatory disorders, including multiple sclerosis, Alzheimer's disease and other neuroinflammatory disorders. Modulation of miRNAs' expression could be used as a therapeutic strategy in the treatment of pathological neuroinflammation.}, }
@article {pmid35006266, year = {2022}, author = {Witzel, S and Maier, A and Steinbach, R and Grosskreutz, J and Koch, JC and Sarikidi, A and Petri, S and Günther, R and Wolf, J and Hermann, A and Prudlo, J and Cordts, I and Lingor, P and Löscher, WN and Kohl, Z and Hagenacker, T and Ruckes, C and Koch, B and Spittel, S and Günther, K and Michels, S and Dorst, J and Meyer, T and Ludolph, AC and , }, title = {Safety and Effectiveness of Long-term Intravenous Administration of Edaravone for Treatment of Patients With Amyotrophic Lateral Sclerosis.}, journal = {JAMA neurology}, volume = {79}, number = {2}, pages = {121-130}, pmid = {35006266}, issn = {2168-6157}, mesh = {Administration, Intravenous ; Amyotrophic Lateral Sclerosis/*drug therapy ; Cohort Studies ; Disease Progression ; Double-Blind Method ; Edaravone/*adverse effects/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Patient Compliance ; Patient Satisfaction ; Propensity Score ; Respiration, Artificial ; Risk Assessment ; Treatment Outcome ; }, abstract = {IMPORTANCE: Intravenous edaravone is approved as a disease-modifying drug for patients with amyotrophic lateral sclerosis (ALS), but evidence for efficacy is limited to short-term beneficial effects shown in the MCI186-ALS19 study in a subpopulation in which efficacy was expected.<br><br>OBJECTIVE: To evaluate the long-term safety and effectiveness of intravenous edaravone therapy for patients with ALS in a real-world clinical setting.<br><br>Multicenter, propensity score-matched cohort study conducted between June 2017 and March 2020 at 12 academic ALS referral centers associated with the German Motor Neuron Disease Network. Of 1440 patients screened, 738 were included in propensity score matching. Final analyses included 324 patients with ALS comprising 194 patients who started intravenous edaravone treatment (141 received &#x2265;4 consecutive treatment cycles; 130 matched) and 130 propensity score-matched patients with ALS receiving standard therapy. All patients had probable or definite ALS according to the El Escorial criteria, with disease onset between December 2012 and April 2019. Subgroups were defined by applying the MCI186-ALS19 study inclusion criteria to evaluate whether patients would have been considered eligible (EFAS) or ineligible (non-EFAS).<br><br>EXPOSURES: Intravenous edaravone plus riluzole vs riluzole only.<br><br>MAIN OUTCOMES AND MEASURES: Patient characteristics and systematic safety assessment for patients who received at least 1 dose of intravenous edaravone. Effectiveness assessment of edaravone was conducted among patients who received at least 4 treatment cycles compared with propensity score-matched patients with ALS who received only standard therapy. Primary outcome was disease progression measured by decrease in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. Secondary outcomes were survival probability, time to ventilation, and change in disease progression before vs during treatment. To account for the matched design, patients receiving edaravone and their corresponding matched controls were regarded as related samples in disease progression analyses; stratification for propensity score quintiles was used for survival probability and time to ventilation analyses.<br><br>RESULTS: A total of 194 patients started intravenous edaravone treatment; 125 (64%) were male, and the median age was 57.5 years (IQR, 50.7-63.8 years). Potential adverse effects were observed in 30 cases (16%), most notably infections at infusion sites and allergic reactions. Disease progression among 116 patients treated for a median of 13.9 months (IQR, 8.9-13.9 months) with edaravone did not differ from 116 patients treated for a median of 11.2 months (IQR, 6.4-20.0 months) with standard therapy (ALSFRS-R points/month, -0.91 [95% CI, -0.69 to -1.07] vs -0.85 [95% CI, -0.66 to -0.99]; P&#x2009;=&#x2009;.37). No significant differences were observed in the secondary end points of survival probability, time to ventilation, and change in disease progression. Similarly, outcomes between patients treated with edaravone and matched patients did not differ within the EFAS and non-EFAS subgroups.<br><br>CONCLUSIONS AND RELEVANCE: This cohort study using propensity score matching found that, although long-term intravenous edaravone therapy for patients with ALS was feasible and mainly well tolerated, it was not associated with any disease-modifying benefit. Intravenous edaravone may not provide a clinically relevant additional benefit compared with standard therapy alone.}, }
@article {pmid35000309, year = {2022}, author = {Zha, SS and He, ZF and Guan, LL and Niu, JY and Fu, W and Chen, RC}, title = {[Clinical research progress in non-invasive positive pressure ventilation from 2020 to 2021].}, journal = {Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases}, volume = {45}, number = {1}, pages = {72-77}, doi = {10.3760/cma.j.cn112147-20211116-00808}, pmid = {35000309}, issn = {1001-0939}, support = {2017YFC1310600, 2017YFC1310601//National Key Research and Development Project/ ; KCXFZ202002011008256//Shenzhen Science and Technology Project/ ; }, mesh = {*COVID-19 ; Humans ; *Noninvasive Ventilation ; Positive-Pressure Respiration ; *Pulmonary Disease, Chronic Obstructive/therapy ; *Respiratory Insufficiency/therapy ; Retrospective Studies ; SARS-CoV-2 ; }, abstract = {Non-invasive positive pressure ventilation (NPPV), an essential respiratory support method, is widely used in acute/chronic respiratory failure and assisting rehabilitation in patients with chronic obstructive pulmonary disease (COPD). We searched the relevant research articles about NPPV published from 1[st] October 2020 to 30[th] September 2021 through Medline. Researches focusing on the clinical application and viral transmission protection during high-flow nasal cannula oxygen and NPPV in COVID-19, were mainly retrospective and of small sample size. It demonstrated that high-flow nasal cannula oxygen and NPPV might reduce intubation rates when treating patients with mild-to-moderate respiratory failure, but the risk of delayed intubation should draw particular precaution. When using NPPV in non-COVID-19-related de novo acute respiratory failure, diaphragm thickening fraction and tidal change of esophageal pressure were validated to predict the treatment outcome. In addition, some studies explored the compliance and related influencing factors associated with the treatment effects of early NPPV initiation on amyotrophic lateral sclerosis patients and the effects of NPPV on dynamic hyperinflation during exercise in COPD patients. Furthermore, the effectiveness of neurally adjusted ventilatory assist ventilation and a novel communication device optimizing the use of NPPV were also investigated and outlined.}, }
@article {pmid34994876, year = {2022}, author = {Turalde, CWR and Moalong, KMC and Espiritu, AI and Prado, MB}, title = {Perampanel for amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {43}, number = {2}, pages = {889-897}, pmid = {34994876}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Neurodegenerative Diseases ; Nitriles ; Pyridones/therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease. There is still no established cost-effective treatment that can improve functional status and survival of ALS patients. Perampanel, by inhibiting neuronal calcium ion influx and preventing dyslocalization of nuclear proteins, has the potential to ameliorate ALS neurodegeneration.<br><br>OBJECTIVES: This study aims to determine the efficacy and safety of perampanel among ALS patients in terms of improvement in functional status using a review of relevant studies.<br><br>METHODS: MedLine, Cochrane Central Register for Controlled Trials, Scopus, Embase, Literatura Latino-Americana e do Caribe em Ci&#xea;ncias da Sa&#xfa;de, ClinicalTrials.gov website, and HERDIN databases were searched from inception to August 2021 for relevant studies.<br><br>RESULTS: The search yielded 132 articles; 3 studies were included in the analysis. Pooled evidence shows that perampanel compared to placebo significantly improves cortical motor hyperexcitability but not the ALS functional rating scale-revised score. Perampanel is associated with adverse events such as aggression, somnolence, anger, and dysarthria.<br><br>CONCLUSION: There is no sufficient evidence to support the role of perampanel in improving functional status of ALS patients. Although it can ameliorate motor cortical hyperexcitability, its clinical benefit has not yet been elucidated. Perampanel is not well tolerated among ALS patients as it is associated with adverse events such as aggression, somnolence, anger, and dysarthria. Further studies investigating the role of perampanel early in the ALS disease course, excluding ALS patients with frontotemporal lobe degeneration features and C9ORF72 repeat expansion, and using gradual drug titration schedule are needed to evaluate the potential benefit of perampanel in ALS.}, }
@article {pmid34992533, year = {2021}, author = {Shah, S and Dooms, MM and Amaral-Garcia, S and Igoillo-Esteve, M}, title = {Current Drug Repurposing Strategies for Rare Neurodegenerative Disorders.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {768023}, pmid = {34992533}, issn = {1663-9812}, abstract = {Rare diseases are life-threatening or chronically debilitating low-prevalent disorders caused by pathogenic mutations or particular environmental insults. Due to their high complexity and low frequency, important gaps still exist in their prevention, diagnosis, and treatment. Since new drug discovery is a very costly and time-consuming process, leading pharmaceutical companies show relatively low interest in orphan drug research and development due to the high cost of investments compared to the low market return of the product. Drug repurposing-based approaches appear then as cost- and time-saving strategies for the development of therapeutic opportunities for rare diseases. In this article, we discuss the scientific, regulatory, and economic aspects of the development of repurposed drugs for the treatment of rare neurodegenerative disorders with a particular focus on Huntington's disease, Friedreich's ataxia, Wolfram syndrome, and amyotrophic lateral sclerosis. The role of academia, pharmaceutical companies, patient associations, and foundations in the identification of candidate compounds and their preclinical and clinical evaluation will also be discussed.}, }
@article {pmid34986670, year = {2022}, author = {Liu, M and Liu, P and Zheng, B and Liu, Y and Li, L and Han, X and Liu, Y and Chu, L}, title = {Cardioprotective effects of alantolactone on isoproterenol-induced cardiac injury and cobalt chloride-induced cardiomyocyte injury.}, journal = {International journal of immunopathology and pharmacology}, volume = {36}, number = {}, pages = {20587384211051993}, pmid = {34986670}, issn = {2058-7384}, mesh = {Animals ; Apoptosis/drug effects ; Calcium/metabolism ; Cardiotonic Agents/pharmacology/*therapeutic use ; Cell Line ; Cobalt/toxicity ; Heart Rate/drug effects ; Interleukin-6/metabolism ; Isoproterenol ; Lactones/pharmacology/*therapeutic use ; Male ; Myocardial Ischemia/chemically induced/*drug therapy/pathology/physiopathology ; Myocardium/metabolism/pathology ; Myocytes, Cardiac/drug effects/physiology ; Oxidative Stress/drug effects ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Sesquiterpenes, Eudesmane/pharmacology/*therapeutic use ; Tumor Necrosis Factor-alpha/metabolism ; Rats ; }, abstract = {OBJECTIVES: Alantolactone (AL) is a compound extracted from the roots of Inula Racemosa that has shown beneficial effects in cardiovascular disease. However, the cardioprotective mechanism of AL against hypoxic/ischemic (H/I) injury is still unclear. This research aimed to determine AL's ability to protect the heart against isoproterenol (ISO)-induced MI injury in vivo and cobalt chloride (CoCl2) induced H/I injury in vitro.<br><br>METHODS: Electrocardiography (ECG), lactate dehydrogenase (LDH), creatine kinase (CK), and cardiac troponin I (cTnI) assays in addition to histological analysis of the myocardium were used to investigate the effects of AL in vivo. Influences of AL on L-type Ca[2+] current (ICa-L) in isolated rat myocytes were observed by the patch-clamp technique. Furthermore, cell viability, apoptosis, oxidative stress injury, mitochondrial membrane potential, and intracellular Ca[2+] concentration were examined in vitro.<br><br>RESULTS: The results indicated that AL treatment ameliorated the morphological and ECG changes associated with MI, and decreased levels of LDH, CK, and cTnI. Furthermore, pretreatment with AL elevated antioxidant enzyme activity and suppressed ROS production. AL prevented H/I-induced apoptosis, mitochondria damage, and calcium overload while reducing ICa-L in a concentration and time dependent fashion. The 50% inhibiting concentration (IC50) and maximal inhibitory effect (Emax) of AL were 17.29&#xa0;&#x3bc;mol/L and 57.73 &#xb1; 1.05%, respectively.<br><br>CONCLUSION: AL attenuated MI-related injury by reducing oxidative stress, apoptosis, calcium overload, and mitochondria damage. These cardioprotective effects may be related to the direct inhibition of ICa-L.}, }
@article {pmid34985276, year = {2022}, author = {Martín-Cámara, O and Arribas, M and Wells, G and Morales-Tenorio, M and Martín-Requero, &#xc1; and Porras, G and Martínez, A and Giorgi, G and López-Alvarado, P and Lastres-Becker, I and Menéndez, JC}, title = {Multitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Journal of medicinal chemistry}, volume = {65}, number = {3}, pages = {1867-1882}, pmid = {34985276}, issn = {1520-4804}, mesh = {1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/*analogs &amp; derivatives/chemical synthesis/therapeutic use/toxicity ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Cell Line, Tumor ; Cell Survival/drug effects ; Coumaric Acids/chemical synthesis/*therapeutic use/toxicity ; Female ; Free Radical Scavengers/chemical synthesis/*therapeutic use/toxicity ; HEK293 Cells ; Humans ; Kelch-Like ECH-Associated Protein 1/metabolism ; Lymphocytes/drug effects ; Male ; Middle Aged ; NF-E2-Related Factor 2/agonists ; Protein Kinase Inhibitors/chemical synthesis/*therapeutic use/toxicity ; rho-Associated Kinases/antagonists &amp; inhibitors ; }, abstract = {Hybrid compounds containing structural fragments of the Rho kinase inhibitor fasudil and the NRF2 inducers caffeic and ferulic acids were designed with the aid of docking and molecular mechanics studies. Following the synthesis of the compounds using a peptide-coupling methodology, they were characterized for their ROCK2 inhibition, radical scavenging, effects on cell viability (MTT assay), and NRF2 induction (luciferase assay). One of the compounds (1d) was selected in view of its good multitarget profile and good tolerability. It was able to induce the NRF2 signature, promoting the expression of the antioxidant response enzymes HO-1 and NQO1, via a KEAP1-dependent mechanism. Analysis of mRNA and protein levels of the NRF2 pathway showed that 1d induced the NRF2 signature in control and SOD1-ALS lymphoblasts but not in sALS, where it was already increased in the basal state. These results show the therapeutic potential of this compound, especially for ALS patients with a SOD1 mutation.}, }
@article {pmid34982644, year = {2022}, author = {Verma, S and Lim, J and Buscemi-Kimmins, T and Brose, SW}, title = {Isolated pulmonary recovery in a veteran with late stage bulbar ALS following edaravone treatment and cessation.}, journal = {The journal of spinal cord medicine}, volume = {45}, number = {4}, pages = {638-642}, pmid = {34982644}, issn = {2045-7723}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/therapeutic use ; Humans ; *Respiratory Insufficiency/drug therapy ; *Spinal Cord Injuries/drug therapy ; *Veterans ; }, abstract = {CONTEXT: Amyotrophic lateral sclerosis (ALS) is a group of rare neurological diseases which cause progressive loss of upper and lower motor neurons at the spinal or bulbar level. ALS affects voluntary muscles of the body which control eating, talking, and moving. Individuals with ALS manifest difficulty breathing on their own due to weakness of the respiratory system. The average life expectancy of individuals with ALS is 2-5 years from the time of diagnosis, with death resulting from respiratory failure. There is no cure for ALS. At present, riluzole and edaravone are the only FDA-approved treatments that impact survival. Adverse reactions to edaravone include hypoxia and respiratory failure. To date, there are no published reports describing isolated dramatic respiratory improvement in ALS with continued global clinical worsening including limb and face function, particularly following edaravone use.<br><br>FINDINGS: We present a case report of late stage bulbar ALS, in which a dramatic respiratory improvement is seen following edaravone use, and subsequent cessation.<br><br>CONCLUSION/CLINICAL RELEVANCE: Isolated pulmonary decline and subsequent recovery following cessation of edaravone in the setting of continued systemic neurologic decline has not yet been described and may suggest potential for reversibility of edaravone-related pulmonary decline. Research is needed to evaluate this possibility further, and this case report may lead to further investigation to evaluate this possibility. Alternatively, although less likely, it is possible the observed that pulmonary improvement may either be beneficially attributed to edaravone, or unrelated to edaravone entirely - representing an undescribed phenomenon of isolated pulmonary decline and improvement in the setting of systemic continued ALS progression, possibly related to the bulbar subtype. Further investigation is warranted to evaluate both the role of edaravone in causing in a potentially reversible pulmonary decline upon cessation of the medication, and the possibility of other undefined variables including various subtypes of ALS contributing to this phenomenon.}, }
@article {pmid34979067, year = {2021}, author = {Nabavi, SM and Karimi, SH and Arab, L and Sanjari, L and Mardpour, S and Azimian, V and Jarughi, N and Ghaheri, A and Hosseini, SE and Aghdami, N and Vosough, M}, title = {Safety and Efficacy of Allogeneic Adipose Tissue Mesenchymal Stromal Cells in Amyotrophic Lateral Sclerosis Patients, Single-Center, Prospective, Open-Label, Single-Arm Clinical Trial, Long-Term Follow-up.}, journal = {Cell journal}, volume = {23}, number = {7}, pages = {772-778}, pmid = {34979067}, issn = {2228-5806}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with very limited treatment options. Stem cells have been raised as a new treatment modality for these patients. We have designed a single-center, prospective, open-label, and single arm clinical trial to assess the safety, feasibility, and rather efficacy of administrating allogeneic adipose-derived mesenchymal stromal cells (Ad-MSCs) in ALS patients. We enrolled 17 patients with confirmed ALS diagnosis with ALS Functional Rating Scale-Revised (ALSFRS-R) ≥24 and predicted forced vital capacity (FVC) ≥40%. Allogeneic Ad-MSCs were transplanted intravenously for all patients. Follow-ups were done at 24 hours, 2, 4, 6, and 12 months after cell infusion by checking adverse events, laboratory tests, and clinically by ALSFRS-R and FVC. Patients were also followed five years later and ALSFRS-R score was recorded in the survived individuals. There was no report of severe adverse events related to cell infusion. Two patients experienced dyspnea and chest pain 36 and 65 days after cell infusion due to pulmonary emboli. The progressive decrease in ALSFRS-R and FVC levels was recorded and three patients died in the first year. During five years follow up, despite a notable decrease in functional scores, 5 patients survived. Intravenous (IV) infusion of allogeneic Ad-MSCs in ALS patients is safe and feasible. The survival rate of the patients is more than IV autologous MSCs (Registration number: IRCT20080728001031N26).}, }
@article {pmid34978799, year = {2022}, author = {Nozal, V and Martínez-González, L and Gomez-Almeria, M and Gonzalo-Consuegra, C and Santana, P and Chaikuad, A and Pérez-Cuevas, E and Knapp, S and Lietha, D and Ramírez, D and Petralla, S and Monti, B and Gil, C and Martín-Requero, A and Palomo, V and de Lago, E and Martinez, A}, title = {TDP-43 Modulation by Tau-Tubulin Kinase 1 Inhibitors: A New Avenue for Future Amyotrophic Lateral Sclerosis Therapy.}, journal = {Journal of medicinal chemistry}, volume = {65}, number = {2}, pages = {1585-1607}, doi = {10.1021/acs.jmedchem.1c01942}, pmid = {34978799}, issn = {1520-4804}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Brain/*drug effects/metabolism ; Case-Control Studies ; DNA-Binding Proteins/*metabolism ; Humans ; Inflammation/*drug therapy/metabolism/pathology ; Macrophages/*drug effects/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; Phosphorylation ; Protein Kinase Inhibitors/chemistry/pharmacokinetics/*pharmacology ; Protein Serine-Threonine Kinases/*antagonists &amp; inhibitors ; Rats ; Rats, Wistar ; Spinal Cord/drug effects/metabolism ; Tissue Distribution ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without any effective treatment. Protein TDP-43 is a pathological hallmark of ALS in both sporadic and familiar patients. Post-translational modifications of TDP-43 promote its aggregation in the cytoplasm. Tau-Tubulin kinase (TTBK1) phosphorylates TDP-43 in cellular and animal models; thus, TTBK1 inhibitors emerge as a promising therapeutic strategy for ALS. The design, synthesis, biological evaluation, kinase-ligand complex structure determination, and molecular modeling studies confirmed novel pyrrolopyrimidine derivatives as valuable inhibitors for further development. Moreover, compound 29 revealed good brain penetration in vivo and was able to reduce TDP-43 phosphorylation not only in cell cultures but also in the spinal cord of transgenic TDP-43 mice. A shift to M2 anti-inflammatory microglia was also demonstrated in vivo. Both these activities led to motor neuron preservation in mice, proposing pyrrolopyrimidine 29 as a valuable lead compound for future ALS therapy.}, }
@article {pmid34978340, year = {2022}, author = {Rochat, C and Bernard-Marissal, N and Källstig, E and Pradervand, S and Perrin, FE and Aebischer, P and Raoul, C and Schneider, BL}, title = {Astrocyte-targeting RNA interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast-fatigable motor units in a mouse model of amyotrophic lateral sclerosis.}, journal = {Glia}, volume = {70}, number = {5}, pages = {842-857}, pmid = {34978340}, issn = {1098-1136}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Animals ; Astrocytes/metabolism ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism ; RNA Interference ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics/*metabolism ; }, abstract = {In amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, both cell-autonomous and noncell-autonomous mechanisms lead to the selective degeneration of motoneurons (MN). Here, we evaluate the therapeutic potential of gene therapy targeting mutated SOD1 in mature astrocytes using mice expressing the mutated SOD1[G93A] protein. An AAV-gfaABC1 D vector encoding an artificial microRNA is used to deliver RNA interference against mutated SOD1 selectively in astrocytes. The treatment leads to the progressive rescue of neuromuscular junction occupancy, to the recovery of the compound muscle action potential in the gastrocnemius muscle, and significantly improves neuromuscular function. In the spinal cord, gene therapy targeting astrocytes protects a small pool of the most vulnerable fast-fatigable MN until disease end stage. In the gastrocnemius muscle of the treated SOD1[G93A] mice, the fast-twitch type IIB muscle fibers are preserved from atrophy. Axon collateral sprouting is observed together with muscle fiber type grouping indicative of denervation/reinnervation events. The transcriptome profiling of spinal cord MN shows changes in the expression levels of factors regulating the dynamics of microtubules. Gene therapy delivering RNA interference against mutated SOD1 in astrocytes protects fast-fatigable motor units and thereby improves neuromuscular function in ALS mice.}, }
@article {pmid34975460, year = {2021}, author = {Gao, P and Li, X and Du, X and Liu, S and Xu, Y}, title = {Diagnostic and Therapeutic Potential of Exosomes in Neurodegenerative Diseases.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {790863}, pmid = {34975460}, issn = {1663-4365}, abstract = {Neurodegenerative diseases are closely related to brain function and the progression of the diseases are irreversible. Due to brain tissue being not easy to acquire, the study of the pathophysiology of neurodegenerative disorders has many limitations-lack of reliable early biomarkers and personalized treatment. At the same time, the blood-brain barrier (BBB) limits most of the drug molecules into the damaged areas of the brain, which makes a big drop in the effect of drug treatment. Exosomes, a kind of endogenous nanoscale vesicles, play a key role in cell signaling through the transmission of genetic information and proteins between cells. Because of the ability to cross the BBB, exosomes are expected to link peripheral changes to central nervous system (CNS) events as potential biomarkers, and can even be used as a therapeutic carrier to deliver molecules specifically to CNS. Here we summarize the role of exosomes in pathophysiology, diagnosis, prognosis, and treatment of some neurodegenerative diseases (Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis).}, }
@article {pmid34974247, year = {2022}, author = {Xu, K and Ji, H and Hu, N}, title = {Cardiovascular comorbidities in amyotrophic lateral sclerosis: A systematic review.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {96}, number = {}, pages = {43-49}, doi = {10.1016/j.jocn.2021.12.021}, pmid = {34974247}, issn = {1532-2653}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology ; *Cardiovascular Diseases/epidemiology ; Comorbidity ; Humans ; *Hypertension/epidemiology ; Incidence ; }, abstract = {OBJECTIVE: To summarize the prevalence of the cardiovascular comorbidities in patients with amyotrophic lateral sclerosis (ALS) and explore the impacts of cardiovascular diseases on ALS.<br><br>METHODS: PubMed, EMBASE, OVID and Web of Science were searched systematically until July 2021 for studies on the prevalence of cardiovascular diseases among ALS patients or quantitatively investigating the effects of cardiovascular comorbidities on incidence, progression or survival of ALS. We conducted a fixed-effects or random-effects meta-analysis to calculate the summary rate or ORs (odds ratios) with 95 %CIs (confidence intervals).<br><br>RESULTS: The comorbidity of hypertension in France (56.9%) was the highest, followed by Portugal (48%). Only 15% of Chinese ALS patients suffered from hypertension. A quarter of ALS patients in America had coronary heart disease while only 4-5% of patients with ALS in Australia or the Netherlands suffered from coronary heart disease. There was significant relationship between hypertension and survival of ALS (OR: 1.04, 95%CI: 1.01, 1.07). Coronary heart disease was considerably related to ALS onset (OR: 1.19, 95%CI: 1.14, 1.24) and heart failure could noticeably accelerate the progression rate of ALS (OR: 6.33, 95%CI: 1.55, 24.84).<br><br>CONCLUSIONS: Cardiovascular comorbidities in ALS patients varied significantly with different regions. Hypertension could reduce the survival of ALS so the intensive treatment of chronic hypertension should be recommended to ALS patients in clinical practice. Coronary heart disease could increase the risk of ALS and heart failure was a negative prognostic factor for ALS, which deserved more attention of clinicians.}, }
@article {pmid34964422, year = {2022}, author = {Diamanti, L and Bianchi, E and Mucaj, K and Cereda, C and Garattini, S and Beghi, E and Pupillo, E}, title = {Drug treatments and interactions, disease progression and quality of life in ALS patients.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {5-6}, pages = {415-423}, doi = {10.1080/21678421.2021.2019279}, pmid = {34964422}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Disease Progression ; Humans ; *Neurodegenerative Diseases ; Quality of Life ; Surveys and Questionnaires ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that causes a wide range of symptoms demanding treatment, but the evidence base for their effectiveness is limited. Affected individuals may present several comorbidities. Polypharmacy exposes ALS patients to the adverse effects of drugs and to drug-drug interactions. At present, no data on drug-drug and drug-disease interactions are available in patients with ALS. Methods: Multicenter, case-series, observational study aimed to provide a picture of the therapeutic habits of patients with ALS, and identify drug-drug interactions (DDIs) and their effects on the outcome of the disease (measured by ALSFRS-R) and quality of life (ALSAQ-40). Results: 440 patients were included, 50 of them with follow-up data. The maximum number of DDIs at baseline was 2 for minor, 9 for moderate, 3 for major, and 3 for contraindicated interactions. At least one minor, moderate, major, or contraindicated DDI was present in 18 (4.1%), 127 (28.9%), 46 (10.5%) and 37 (8.4%) patients. Patients with DDIs were older. In those with major/contraindicated DDIs, the scores on the emotional domain of the ALSAQ-40 and the ALSFRS-R total score were worse than the scores of patients without DDIs or with minor/moderate DDIs. At the 48-week visit, patients with DDIs showed lower ALSFRS-R scores, and higher scores on all domains of ALSAQ-40, as compared to patients without DDIs. Conclusions: Symptomatic treatment aims to improve quality of life of patients. The higher the number of drugs, the higher the risk to incurring (relevant) interactions.}, }
@article {pmid34963564, year = {2022}, author = {Altinoz, MA and Guloksuz, S and Ozpinar, A}, title = {Immunomodifying and neuroprotective effects of noscapine: Implications for multiple sclerosis, neurodegenerative, and psychiatric disorders.}, journal = {Chemico-biological interactions}, volume = {352}, number = {}, pages = {109794}, doi = {10.1016/j.cbi.2021.109794}, pmid = {34963564}, issn = {1872-7786}, mesh = {Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Bradykinin/metabolism ; Histamine Antagonists/pharmacology ; Humans ; Immunomodulating Agents/*pharmacology ; Ion Channels/drug effects ; Mental Disorders/drug therapy ; Multiple Sclerosis/drug therapy ; Neurodegenerative Diseases/drug therapy ; Neuroprotective Agents/*pharmacology ; Noscapine/administration &amp; dosage/blood/*pharmacology ; Oligodendroglia/drug effects ; Parkinsonian Disorders/drug therapy ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction/drug effects ; Stroke/drug therapy ; Taste Receptors, Type 2 ; }, abstract = {Noscapine is a phthalide isoquinoline alkaloid with antitussive activity. Noscapine protects oligodendroglia from ischemic and chemical injury, binds to bitter taste receptors, antagonizes the bradykinin and histaminergic systems, which may be of benefit in treatment of multiple sclerosis. Noscapine normalizes axonal transport and exerts significant therapeutic efficacy in animal models of Parkinson's Disease and Amyotrophic Lateral Sclerosis. Noscapine exerts neuroprotective effects on oxygen- and glucose-deprived fetal cortical neuronal cells and reduces ischemic brain damage in neonatal rat pups. Pilot clinical studies indicated some beneficial effects of noscapine in stroke. Noscapine harbours anxiolytic activity and methyl-noscapine blocks small conductance SK channels, which is beneficial in alleviating anxiety and depression. Noscapine exerts anticholinesterase activity and acts inhibitory on the inflammatory transcription factor NF-κB, which may be harnessed in treatment of Alzheimer's Disease. With its blood-brain barrier traversing features and versatile actions, noscapine may be a promising agent in the armamentarium against neurodegenerative and psychiatric diseases.}, }
@article {pmid34962222, year = {2022}, author = {Ketola, J and Jahangiri, E and Hakko, H and Riipinen, P and Räsänen, S}, title = {Assisted living for mentally ill-a systematic literature review and its recommendations.}, journal = {Nordic journal of psychiatry}, volume = {76}, number = {6}, pages = {403-422}, doi = {10.1080/08039488.2021.2001568}, pmid = {34962222}, issn = {1502-4725}, mesh = {Adult ; Hospitals, Psychiatric ; Housing ; Humans ; Male ; *Mental Disorders/therapy ; *Persons with Psychiatric Disorders ; Quality of Life ; }, abstract = {BACKGROUND: The reduction in psychiatric hospital beds in the past decades has created a need for assisted living (AL). Even though AL is widely used, studies on it are scarce.<br><br>AIMS: To identify (1) study characteristics of the reviewed articles, (2) characteristics of inhabitants and characteristics of different types of AL, (3) financial costs in different types of AL, (4) the individual outcomes in AL inhabitants and quality of care.<br><br>METHODS: A systematic literature review on AL for the mentally ill focusing on inhabitant and AL features and their costs was conducted. Articles written in English from January 2000 to June of 2020, concerning adults were included. Simple Taxonomy of Supported Housing (STAX-SA) was applied and used for categorizing types of AL.<br><br>RESULTS: Twenty-five papers met our criteria. The majority of inhabitants were unemployed single male with psychotic disorders. The type of AL is mainly categorized according to staffing, provided support, and housing arrangement. In UK ALs with moderate support (STAX-SA 2-3) had the best quality of care while ALs with low support (STAX-SA 4) was the cheapest. Quality of care was better in small units with preset expected length of stay for inhabitants. Hospital treatment was significantly more expensive than any type of AL. Living in AL improved quality of life compared to hospital treatment, also psychiatric symptoms were reduced.<br><br>CONCLUSION: There is an evident need for evidence-based studies in a longitudinal comprehensive manner that evaluates different AL types, function of the inhabitants, and costs with respect to the quality of AL and care and outcome.}, }
@article {pmid34960353, year = {2021}, author = {Breasail, M&#xd3; and Biswas, B and Smith, MD and Mazhar, MKA and Tenison, E and Cullen, A and Lithander, FE and Roudaut, A and Henderson, EJ}, title = {Wearable GPS and Accelerometer Technologies for Monitoring Mobility and Physical Activity in Neurodegenerative Disorders: A Systematic Review.}, journal = {Sensors (Basel, Switzerland)}, volume = {21}, number = {24}, pages = {}, pmid = {34960353}, issn = {1424-8220}, support = {GAT3676//The Gatsby Foundation/ ; }, mesh = {Accelerometry ; Exercise ; Geographic Information Systems ; Humans ; *Neurodegenerative Diseases ; Technology ; *Wearable Electronic Devices ; }, abstract = {Neurodegenerative disorders (NDDs) constitute an increasing global burden and can significantly impair an individual's mobility, physical activity (PA), and independence. Remote monitoring has been difficult without relying on diaries/questionnaires which are more challenging for people with dementia to complete. Wearable global positioning system (GPS) sensors and accelerometers present a cost-effective and noninvasive way to passively monitor mobility and PA. In addition, changes in sensor-derived outcomes (such as walking behaviour, sedentary, and active activity) may serve as potential biomarkers of disease onset, progression, and response to treatment. We performed a systematic search across four databases to identify papers published within the past 5 years, in which wearable GPS or accelerometers were used to monitor mobility or PA in patients with common NDDs (Parkinson's disease, Alzheimer's disease, motor neuron diseases/amyotrophic lateral sclerosis, vascular parkinsonism, and vascular dementia). Disease and technology-specific vocabulary were searched singly, and then in combination, identifying 4985 papers. Following deduplication, we screened 3115 papers and retained 28 studies following a full text review. One study used wearable GPS and accelerometers, while 27 studies used solely accelerometers in NDDs. GPS-derived measures had been validated against current gold standard measures in one Parkinson's cohort, suggesting that the technology may be applicable to other NDDs. In contrast, accelerometers are widely utilised in NDDs and have been operationalised in well-designed clinical trials.}, }
@article {pmid34959661, year = {2021}, author = {Ozturk, M and Nilsen-Hamilton, M and Ilgu, M}, title = {Aptamer Applications in Neuroscience.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {12}, pages = {}, pmid = {34959661}, issn = {1424-8247}, abstract = {Being the predominant cause of disability, neurological diseases have received much attention from the global health community. Over a billion people suffer from one of the following neurological disorders: dementia, epilepsy, stroke, migraine, meningitis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, prion disease, or brain tumors. The diagnosis and treatment options are limited for many of these diseases. Aptamers, being small and non-immunogenic nucleic acid molecules that are easy to chemically modify, offer potential diagnostic and theragnostic applications to meet these needs. This review covers pioneering studies in applying aptamers, which shows promise for future diagnostics and treatments of neurological disorders that pose increasingly dire worldwide health challenges.}, }
@article {pmid34959337, year = {2021}, author = {González, LF and Bevilacqua, LE and Naves, R}, title = {Nanotechnology-Based Drug Delivery Strategies to Repair the Mitochondrial Function in Neuroinflammatory and Neurodegenerative Diseases.}, journal = {Pharmaceutics}, volume = {13}, number = {12}, pages = {}, pmid = {34959337}, issn = {1999-4923}, support = {1191874//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; }, abstract = {Mitochondria are vital organelles in eukaryotic cells that control diverse physiological processes related to energy production, calcium homeostasis, the generation of reactive oxygen species, and cell death. Several studies have demonstrated that structural and functional mitochondrial disturbances are involved in the development of different neuroinflammatory (NI) and neurodegenerative (ND) diseases (NI&amp;NDDs) such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Remarkably, counteracting mitochondrial impairment by genetic or pharmacologic treatment ameliorates neurodegeneration and clinical disability in animal models of these diseases. Therefore, the development of nanosystems enabling the sustained and selective delivery of mitochondria-targeted drugs is a novel and effective strategy to tackle NI&amp;NDDs. In this review, we outline the impact of mitochondrial dysfunction associated with unbalanced mitochondrial dynamics, altered mitophagy, oxidative stress, energy deficit, and proteinopathies in NI&amp;NDDs. In addition, we review different strategies for selective mitochondria-specific ligand targeting and discuss novel nanomaterials, nanozymes, and drug-loaded nanosystems developed to repair mitochondrial function and their therapeutic benefits protecting against oxidative stress, restoring cell energy production, preventing cell death, inhibiting protein aggregates, and improving motor and cognitive disability in cellular and animal models of different NI&amp;NDDs.}, }
@article {pmid37323688, year = {2021}, author = {Zhang, Y and Yang, H and Wei, D and Zhang, X and Wang, J and Wu, X and Chang, J}, title = {Mitochondria-targeted nanoparticles in treatment of neurodegenerative diseases.}, journal = {Exploration (Beijing, China)}, volume = {1}, number = {3}, pages = {20210115}, pmid = {37323688}, issn = {2766-2098}, abstract = {Neurodegenerative diseases (NDs) are a class of heterogeneous diseases that includes Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Mitochondria play an important role in oxidative balance and metabolic activity of neurons; therefore, mitochondrial dysfunction is associated with NDs and mitochondria are considered a potential treatment target for NDs. Several obstacles, including the blood-brain barrier (BBB) and cell/mitochondrial membranes, reduce the efficiency of drug entry into the target lesions. Therefore, a variety of neuron mitochondrial targeting strategies has been developed. Among them, nanotechnology-based treatments show especially promising results. Owing to their adjustable size, appropriate charge, and lipophilic surface, nanoparticles (NPs) are the ideal theranostic system for crossing the BBB and targeting the neuronal mitochondria. In this review, we discussed the role of dysfunctional mitochondria in ND pathogenesis as well as the physiological barriers to various treatment strategies. We also reviewed the use and advantages of various NPs (including organic, inorganic, and biological membrane-coated NPs) for the treatment and diagnosis of NDs. Finally, we summarized the evidence and possible use for the promising role of NP-based theranostic systems in the treatment of mitochondrial dysfunction-related NDs.}, }
@article {pmid34955848, year = {2021}, author = {Gaja-Capdevila, N and Hernández, N and Navarro, X and Herrando-Grabulosa, M}, title = {Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1[G93A] ALS Mice.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {780588}, pmid = {34955848}, issn = {1663-9812}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by the death of motoneurons (MNs) with a poor prognosis. There is no available cure, thus, novel therapeutic targets are urgently needed. Sigma-1 receptor (Sig-1R) has been reported as a target to treat experimental models of degenerative diseases and, importantly, mutations in the Sig-1R gene cause several types of motoneuron disease (MND). In this study we compared the potential therapeutic effect of three Sig-1R ligands, the agonists PRE-084 and SA4503 and the antagonist BD1063, in the SOD1[G93A] mouse model of ALS. Pharmacological administration was from 8 to 16 weeks of age, and the neuromuscular function and disease progression were evaluated using nerve conduction and rotarod tests. At the end of follow up (16 weeks), samples were harvested for histological and molecular analyses. The results showed that PRE-084, as well as BD1063 treatment was able to preserve neuromuscular function of the hindlimbs and increased the number of surviving MNs in the treated female SOD1[G93A] mice. SA4503 tended to improve motor function and preserved neuromuscular junctions (NMJ), but did not improve MN survival. Western blot analyses revealed that the autophagic flux and the endoplasmic reticulum stress, two pathways implicated in the physiopathology of ALS, were not modified with Sig-1R treatments in SOD1[G93A] mice. In conclusion, Sig-1R ligands are promising tools for ALS treatment, although more research is needed to ascertain their mechanisms of action.}, }
@article {pmid34954462, year = {2022}, author = {Marín-García, M and De Luca, M and Ragno, G and Tauler, R}, title = {Coupling of spectrometric, chromatographic, and chemometric analysis in the investigation of the photodegradation of sulfamethoxazole.}, journal = {Talanta}, volume = {239}, number = {}, pages = {122953}, doi = {10.1016/j.talanta.2021.122953}, pmid = {34954462}, issn = {1873-3573}, mesh = {*Chemometrics ; Chromatography, Liquid ; Least-Squares Analysis ; Multivariate Analysis ; Photolysis ; *Sulfamethoxazole ; }, abstract = {A workflow is proposed for the study of the photodegradation process of the sulfamethoxazole (SMX) based on the combination of different experimental techniques, including liquid chromatography, mass spectrometry, UV-Visible spectrophotometry, and the treatment of all the analytical data with advanced chemometric methods. SMX, which is one of the most widely used antibiotics worldwide and has been found at remarkable concentrations in various rivers and effluents over all Europe, was degraded in the laboratory under a controlled source of UV radiation, which simulates the environmental solar radiation (Suntest). Kinetic monitoring of the photodegradation process was performed using UV-Visible spectrophotometric measurements and by further Liquid Chromatography with Diode Array Detector and Mass Spectrometry analysis (LC-DAD-MS). Additionally, the acid-base properties were also investigated to see how the pH can affect the speciation of this substance during the photodegradation process. Based on the Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) application, the proposed chemometric method coped with the large amounts of data generated by the different analytical techniques used to monitor the evolution of the photodegradation process. Their simultaneous analysis involved applying a data fusion strategy and an advanced MCR-ALS constrained analysis, which allowed and improved the description of the complete degradation process, detecting the different species of the reaction, and identifying the possible transformation products formed. A total number of six species were resolved in the degradation process of SMX. In addition to the initial SMX, a second species corresponded to a conformational isomer, and the other four species represented different photoproducts, which have also been identified. Furthermore, three different acid-base species of SMX were obtained, and their pKa values were estimated.}, }
@article {pmid34953016, year = {2022}, author = {Fathi, A and Mathivanan, S and Kong, L and Petersen, AJ and Harder, CRK and Block, J and Miller, JM and Bhattacharyya, A and Wang, D and Zhang, SC}, title = {Chemically induced senescence in human stem cell-derived neurons promotes phenotypic presentation of neurodegeneration.}, journal = {Aging cell}, volume = {21}, number = {1}, pages = {e13541}, pmid = {34953016}, issn = {1474-9726}, support = {P01 HD076892/HD/NICHD NIH HHS/United States ; R24 NS086604/NS/NINDS NIH HHS/United States ; P50 MH100031/MH/NIMH NIH HHS/United States ; R01 NS096282/NS/NINDS NIH HHS/United States ; U54 HD090256/HD/NICHD NIH HHS/United States ; }, mesh = {Cell Differentiation ; Humans ; Motor Neurons/*metabolism ; Neurodegenerative Diseases/*genetics ; Phenotype ; }, abstract = {Modeling age-related neurodegenerative disorders with human stem cells are difficult due to the embryonic nature of stem cell-derived neurons. We developed a chemical cocktail to induce senescence of iPSC-derived neurons to address this challenge. We first screened small molecules that induce embryonic fibroblasts to exhibit features characteristic of aged fibroblasts. We then optimized a cocktail of small molecules that induced senescence in fibroblasts and cortical neurons without causing DNA damage. The utility of the "senescence cocktail" was validated in motor neurons derived from ALS patient iPSCs which exhibited protein aggregation and axonal degeneration substantially earlier than those without cocktail treatment. Our "senescence cocktail" will likely enhance the manifestation of disease-related phenotypes in neurons derived from iPSCs, enabling the generation of reliable drug discovery platforms.}, }
@article {pmid34952382, year = {2022}, author = {Gouel, F and Timmerman, K and Gosset, P and Raoul, C and Dutheil, M and Jonneaux, A and Garçon, G and Moreau, C and Danel-Brunaud, V and Duce, J and Burnouf, T and Devedjian, JC and Devos, D}, title = {Whole and fractionated human platelet lysate biomaterials-based biotherapy induces strong neuroprotection in experimental models of amyotrophic lateral sclerosis.}, journal = {Biomaterials}, volume = {280}, number = {}, pages = {121311}, doi = {10.1016/j.biomaterials.2021.121311}, pmid = {34952382}, issn = {1878-5905}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Biocompatible Materials/therapeutic use ; Biological Therapy ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism ; *Neurodegenerative Diseases/therapy ; Neuroprotection ; Superoxide Dismutase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease of motor neurons leading to death within 3 years and without a curative treatment. Neurotrophic growth factors (NTFs) are pivotal for cell survival. A reason for the lack of patient efficacy with single recombinant NTF brain infusion is likely to be due to the synergistic neuroprotective action of multiple NTFs on a diverse set of signaling pathways. Fractionated (protein size <50, <30, <10, <3 kDa) heat-treated human platelet lysate (HHPL) preparations were adapted for use in brain tissue with the aim of demonstrating therapeutic value in ALS models and further elucidation of the mechanisms of action. In neuronal culture all fractions induced Akt-dependent neuroprotection as well as a strong anti-apoptotic and anti-ferroptotic action. In the <3 kDa fraction anti-ferroptotic properties were shown to be GPX4 dependent highlighting a role for other platelet elements associated with NTFs. In the SOD1[G86R] mouse model, lifespan was strongly increased by intracerebroventricular delivery of HHPL or by intranasal administration of <3 kDa fraction. Our results suggest that the platelet lysate biomaterials are neuroprotective in ALS. Further studies would now validate theragnostic biomarker on its antiferroptotic action, for further clinical development.}, }
@article {pmid34951107, year = {2022}, author = {Xu, Y and Li, S and Hao, L and Li, X and Zheng, M}, title = {Tribenuron-methyl-resistant Descurainia sophia L. exhibits negative cross-resistance to imazethapyr conferred by a Pro197Ser mutation in acetolactate synthase and reduced metabolism.}, journal = {Pest management science}, volume = {78}, number = {4}, pages = {1467-1473}, doi = {10.1002/ps.6764}, pmid = {34951107}, issn = {1526-4998}, mesh = {*Acetolactate Synthase ; Arylsulfonates ; *Brassicaceae/genetics ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Magnoliopsida ; Mutation ; Nicotinic Acids ; }, abstract = {BACKGROUND: Descurainia sophia L. is one of the most notorious weeds infesting winter wheat in China. Mutations at Pro197 in acetolactate synthase (ALS) results in resistance of D. sophia to tribenuron-methyl and cross-resistance to many ALS inhibitors. Negative cross-resistance to imazethapyr was observed in tribenuron-methyl-resistant (TR) D. sophia with the Pro197Ser mutation in a previous study. In the present research, another TR D. sophia with the Pro197Ser mutation was obtained. To explore the mechanisms of negative cross-resistance, the ALS sensitivity, the absorption and metabolism of imazethapyr in tribenuron-methyl-susceptible (TS) and TR D. sophia were studied.<br><br>RESULTS: The TR D. sophia population with the Pro197Ser mutation (pHB23) displayed negative cross-resistance to imazethapyr and no cross-resistance to imazamox and imazapic. In contrast, TR D. sophia populations with other Pro197 mutations had no or low resistance to imazethapyr. The ALS in the pHB23 population was more susceptible to imazethapyr than that in the TS population. There was no difference in the absorption of imazethapyr, imazamox, and imazapic between TS and pHB23 plants. However, the metabolism of imazethapyr in TS D. sophia was faster than that in pHB23 plants up to 1&#x2009;week after treatment. There was no significant difference in the metabolism of imazamox and imazapic between TS and pHB23 plants.<br><br>CONCLUSION: The TR D. sophia population with the Pro197Ser mutation exhibited negative cross-resistance to imazethapyr, which was likely due to reduced metabolism and increased sensitivity of ALS to imazethapyr. &#xa9; 2021 Society of Chemical Industry.}, }
@article {pmid34948191, year = {2021}, author = {Obsilova, V and Honzejkova, K and Obsil, T}, title = {Structural Insights Support Targeting ASK1 Kinase for Therapeutic Interventions.}, journal = {International journal of molecular sciences}, volume = {22}, number = {24}, pages = {}, pmid = {34948191}, issn = {1422-0067}, support = {19-00121S and 20-00058S//Czech Science Foundation/ ; 1160120//Charles University/ ; RVO:67985823//Czech Academy of Sciences/ ; }, mesh = {14-3-3 Proteins/metabolism ; Animals ; Apoptosis/physiology ; Apoptosis Regulatory Proteins/metabolism ; Endoplasmic Reticulum Stress ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Kinase Kinase 5/genetics/*metabolism/*physiology/ultrastructure ; MAP Kinase Kinase Kinases/genetics/metabolism ; MAP Kinase Signaling System ; Oxidation-Reduction ; Oxidative Stress ; Phosphorylation ; Protein Interaction Maps/genetics/physiology ; Signal Transduction/drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Apoptosis signal-regulating kinase (ASK) 1, a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, modulates diverse responses to oxidative and endoplasmic reticulum (ER) stress and calcium influx. As a crucial cellular stress sensor, ASK1 activates c-Jun N-terminal kinases (JNKs) and p38 MAPKs. Their excessive and sustained activation leads to cell death, inflammation and fibrosis in various tissues and is implicated in the development of many neurological disorders, such as Alzheimer's, Parkinson's and Huntington disease and amyotrophic lateral sclerosis, in addition to cardiovascular diseases, diabetes and cancer. However, currently available inhibitors of JNK and p38 kinases either lack efficacy or have undesirable side effects. Therefore, targeted inhibition of their upstream activator, ASK1, stands out as a promising therapeutic strategy for treating such severe pathological conditions. This review summarizes recent structural findings on ASK1 regulation and its role in various diseases, highlighting prospects for ASK1 inhibition in the treatment of these pathologies.}, }
@article {pmid34948077, year = {2021}, author = {García-García, R and Martín-Herrero, L and Blanca-Pariente, L and Pérez-Cabello, J and Roodveldt, C}, title = {Immune Signaling Kinases in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).}, journal = {International journal of molecular sciences}, volume = {22}, number = {24}, pages = {}, pmid = {34948077}, issn = {1422-0067}, support = {RTI2018-098432-B-I00//Ministry of Economy, Industry and Competitiveness/ ; CIVP19A5938//Fundaci&#xf3;n Ram&#xf3;n Areces/ ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*enzymology/immunology/metabolism ; Frontotemporal Dementia/drug therapy/*enzymology/immunology/metabolism ; Humans ; Immune System/*enzymology/metabolism ; *Inflammation ; Phosphotransferases/antagonists &amp; inhibitors/*metabolism ; *Signal Transduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disorder of motor neurons in adults, with a median survival of 3-5 years after appearance of symptoms, and with no curative treatment currently available. Frontotemporal dementia (FTD) is also an adult-onset neurodegenerative disease, displaying not only clinical overlap with ALS, but also significant similarities at genetic and pathologic levels. Apart from the progressive loss of neurons and the accumulation of protein inclusions in certain cells and tissues, both disorders are characterized by chronic inflammation mediated by activated microglia and astrocytes, with an early and critical impact of neurodegeneration along the disease course. Despite the progress made in the last two decades in our knowledge around these disorders, the underlying molecular mechanisms of such non-cell autonomous neuronal loss still need to be clarified. In particular, immune signaling kinases are currently thought to have a key role in determining the neuroprotective or neurodegenerative nature of the central and peripheral immune states in health and disease. This review provides a comprehensive and updated view of the proposed mechanisms, therapeutic potential, and ongoing clinical trials of immune-related kinases that have been linked to ALS and/or FTD, by covering the more established TBK1, RIPK1/3, RACK I, and EPHA4 kinases, as well as other emerging players in ALS and FTD immune signaling.}, }
@article {pmid34947402, year = {2021}, author = {Ergun-Kunt, G and Sasany, R and Koca, MF and Özcan, M}, title = {Comparison of Silane Heat Treatment by Laser and Various Surface Treatments on Microtensile Bond Strength of Composite Resin/Lithium Disilicate.}, journal = {Materials (Basel, Switzerland)}, volume = {14}, number = {24}, pages = {}, pmid = {34947402}, issn = {1996-1944}, abstract = {In the current study, we evaluated the effects of heat treatment (by Er:YAG or furnace) and various surface treatments on the microtensile bond strength (μTBS) of silanized lithium disilicate ceramic. Seventy lithium disilicate (IPS e. max Press; Ivoclar Vivadent) and composite resin (Tetric N-Ceram; Ivoclar Vivadent) blocks were made and distributed into seven groups (n = 10) at random: S: silanization alone; ALS: airborne particle abrasion (APA) and silanization; SC: APA modified with silica and silanization; SHT1: silanization and heat treatment by Er:YAG; SHT2: silanization and heat treatment performed in the furnace (100 °C, 1 min); HF: etching with HF; and HFS: etching with HF and silanization. Every ceramic specimen was cemented to a composite resin block after surface treatment. Cemented specimens were embedded into acrylic resin and were tested with the μTBS test. Data were analyzed using one-way ANOVA and Tamhane T2 tests (α = 0.05). The SHT1 group had the highest bond of strength compared to the other groups (27.46 MPa). The ALS group had the lowest strength of the groups (15.56 MPa). Between SHT2 and HFS (p = 1), the comparison of the mean µTBS values showed no significant differences. It was concluded that silane heat treatment increased the resin composite-ceramic bond strength; however, within the terms of μTBS, the Er:YAG laser treatment was more successful than other surface treatment applications.}, }
@article {pmid34944061, year = {2021}, author = {Latif, S and Kang, YS}, title = {Differences of Transport Activity of Arginine and Regulation on Neuronal Nitric Oxide Synthase and Oxidative Stress in Amyotrophic Lateral Sclerosis Model Cell Lines.}, journal = {Cells}, volume = {10}, number = {12}, pages = {}, pmid = {34944061}, issn = {2073-4409}, support = {2019R1F1A1044048//National Research Foundation of Korea/ ; }, mesh = {Amino Acid Transport Systems, Basic ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Animals ; Arginine/*metabolism/pharmacology ; Cell Line ; Gene Expression Regulation/drug effects ; Humans ; Hydrogen Peroxide/pharmacology ; Lysine/genetics ; Mice ; Motor Neurons/drug effects/metabolism ; Nitric Oxide Synthase Type I/*genetics ; Oxidative Stress/genetics ; Spinal Cord/drug effects/metabolism/pathology ; Superoxide Dismutase-1/*genetics ; }, abstract = {L-Arginine, a semi-essential amino acid, was shown to delay dysfunction of motor neurons and to prolong the lifespan, upon analysis of transgenic mouse models of amyotrophic lateral sclerosis (ALS). We investigated the transport function of arginine and neuronal nitric oxide synthase (nNOS) expression after pretreatment with L-arginine in NSC-34 hSOD1[WT] (wild-type, WT) and hSOD1[G93A] (mutant-type, MT) cell lines. [[3]H]L-Arginine uptake was concentration-dependent, voltage-sensitive, and sodium-independent in both cell lines. Among the cationic amino acid transporters family, including system y+, b[0,+], B[0,+], and y[+]L, system y[+] is mainly involved in [[3]H]L-arginine transport in ALS cell lines. System b[0,+] accounted for 23% of the transport in both cell lines. System B[0,+] was found only in MT, and whereas, system y[+]L was found only in WT. Lysine competitively inhibited [[3]H]L-arginine uptake in both cell lines. The nNOS mRNA expression was significantly lower in MT than in WT. Pretreatment with arginine elevated nNOS mRNA levels in MT. Oxidizing stressor, H2O2, significantly decreased their uptake; however, pretreatment with arginine restored the transport activity in both cell lines. In conclusion, arginine transport is associated with system y[+], and neuroprotection by L-arginine may provide an edge as a possible therapeutic target in the treatment of ALS.}, }
@article {pmid34938264, year = {2021}, author = {Aljabri, A and Halawani, A and Bin Lajdam, G and Labban, S and Alshehri, S and Felemban, R}, title = {The Safety and Efficacy of Stem Cell Therapy as an Emerging Therapy for ALS: A Systematic Review of Controlled Clinical Trials.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {783122}, pmid = {34938264}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a heterogeneous course that ultimately leads to death. Currently, there is no cure, and new treatments that can slow the progression of the disease are needed. Stem cell (SC) transplantation is an emerging therapy that has shown a lot of potential in recent clinical trials. This review is aimed to examine the results of various clinical trials on this topic, thus assessing the safety and efficacy of SC transplantation as a potential treatment for ALS. We identified 748 studies in our search, of which 134 full-text studies were assessed for eligibility. Six studies met the inclusion criteria and were included in this review. Although some of the included studies showed the positive effect of SC transplantation, other studies found that there was no significant difference compared to the control group. We observed more positive effects with bone marrow mesenchymal stem cells (BM-MSC) treatments than Granulocyte colony-stimulating factor (G-CSF) ones. However, other factors, such as route of administration, number of doses, and number of cells per dose, could also play a role in this discrepancy. Based on this information, we conclude that more properly conducted clinical trials are needed to appreciate the benefit of this treatment.}, }
@article {pmid34937577, year = {2021}, author = {Zhang, L and Dai, L and Li, D}, title = {Mitophagy in neurological disorders.}, journal = {Journal of neuroinflammation}, volume = {18}, number = {1}, pages = {297}, pmid = {34937577}, issn = {1742-2094}, support = {2017SZ0055//science and technology bureau of sichuan province/ ; }, mesh = {Animals ; Humans ; Mitochondria/pathology ; *Mitophagy ; Nervous System Diseases/*pathology ; Neurodegenerative Diseases ; }, abstract = {Selective autophagy is an evolutionarily conserved mechanism that removes excess protein aggregates and damaged intracellular components. Most eukaryotic cells, including neurons, rely on proficient mitophagy responses to fine-tune the mitochondrial number and preserve energy metabolism. In some circumstances (such as the presence of pathogenic protein oligopolymers and protein mutations), dysfunctional mitophagy leads to nerve degeneration, with age-dependent intracellular accumulation of protein aggregates and dysfunctional organelles, leading to neurodegenerative disease. However, when pathogenic protein oligopolymers, protein mutations, stress, or injury are present, mitophagy prevents the accumulation of damaged mitochondria. Accordingly, mitophagy mediates neuroprotective effects in some forms of neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis) and acute brain damage (e.g., stroke, hypoxic-ischemic brain injury, epilepsy, and traumatic brain injury). The complex interplay between mitophagy and neurological disorders suggests that targeting mitophagy might be applicable for the treatment of neurodegenerative diseases and acute brain injury. However, due to the complexity of the mitophagy mechanism, mitophagy can be both harmful and beneficial, and future efforts should focus on maximizing its benefits. Here, we discuss the impact of mitophagy on neurological disorders, emphasizing the contrast between the positive and negative effects of mitophagy.}, }
@article {pmid34936028, year = {2021}, author = {Fabbrizio, P and D'Agostino, J and Margotta, C and Mella, G and Panini, N and Pasetto, L and Sammali, E and Raggi, F and Sorarù, G and Bonetto, V and Bendotti, C and Nardo, G}, title = {Contingent intramuscular boosting of P2XR7 axis improves motor function in transgenic ALS mice.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {79}, number = {1}, pages = {7}, pmid = {34936028}, issn = {1420-9071}, support = {SG-2018-12366226//Ministero della Salute/ ; PG_8/2020 Macrophals//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; 2015-0023//Regione Lombardia/ ; }, mesh = {Adenosine Triphosphate/administration &amp; dosage/analogs &amp; derivatives/pharmacology ; Amyotrophic Lateral Sclerosis/*metabolism/*physiopathology ; Animals ; Axons/pathology ; Biomarkers/metabolism ; Cell Differentiation/drug effects ; Cell Polarity/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Denervation ; Disease Models, Animal ; Disease Progression ; Female ; Hindlimb/pathology ; Humans ; Inflammation/pathology ; Injections, Intramuscular ; MAP Kinase Signaling System/drug effects ; Macrophages/drug effects/metabolism ; Male ; Mice, Transgenic ; Motor Activity/*physiology ; Motor Neurons/drug effects/pathology ; Muscle, Skeletal/drug effects/innervation/*metabolism/*physiopathology ; Muscular Atrophy/pathology ; Phenotype ; Receptors, Purinergic P2X7/*metabolism ; Satellite Cells, Skeletal Muscle/drug effects/pathology ; Schwann Cells/pathology ; Sciatic Nerve/drug effects/pathology ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons and severe muscle atrophy without effective treatment. Most research on the disease has been focused on studying motor neurons and supporting cells of the central nervous system. Strikingly, the recent observations have suggested that morpho-functional alterations in skeletal muscle precede motor neuron degeneration, bolstering the interest in studying muscle tissue as a potential target for the delivery of therapies. We previously showed that the systemic administration of the P2XR7 agonist, 2'(3')-O-(4-benzoylbenzoyl) adenosine 5-triphosphate (BzATP), enhanced the metabolism and promoted the myogenesis of new fibres in the skeletal muscles of SOD1G93A mice. Here we further corroborated this evidence showing that intramuscular administration of BzATP improved the motor performance of ALS mice by enhancing satellite cells and the muscle pro-regenerative activity of infiltrating macrophages. The preservation of the skeletal muscle retrogradely propagated along with the motor unit, suggesting that backward signalling from the muscle could impinge on motor neuron death. In addition to providing the basis for a suitable adjunct multisystem therapeutic approach in ALS, these data point out that the muscle should be at the centre of ALS research as a target tissue to address novel therapies in combination with those oriented to the CNS.}, }
@article {pmid34935299, year = {2022}, author = {Ferrer-Donato, A and Contreras, A and Fernandez, P and Fernandez-Martos, CM}, title = {The potential benefit of leptin therapy against amyotrophic lateral sclerosis (ALS).}, journal = {Brain and behavior}, volume = {12}, number = {1}, pages = {e2465}, pmid = {34935299}, issn = {2162-3279}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Animals ; Disease Models, Animal ; Disease Progression ; Leptin/pharmacology ; Mice ; Mice, Transgenic ; }, abstract = {BACKGROUND: Targeting leptin could represent a rational strategy to treat amyotrophic lateral sclerosis (ALS), as previously clinical studies have shown its levels to be associated with a lower risk of ALS disease. However, very little is known about the potential influence of leptin in altering disease progression in ALS, as it has thus far been correlated with the protection exerted by increased fat mass stores.<br><br>METHODS: We studied the impact of leptin treatment beginning at 42-days of age (asymptomatic stage of disease) in the TDP-43 (TDP43[A315T]) transgenic (Tg) ALS mouse model.<br><br>RESULTS: Our study shows that leptin treatment was associated with altered expression of adipokines and metabolic proteins in TDP43[A315T] mice. We also observed that weight loss decline was less prominent after leptin treatment in TDP43[A315T] mice relative to vehicle-treated animals. In TDP43[A315T] mice treated with leptin the disease duration lasted longer along with an improvement in motor performance relative to vehicle-treated animals.<br><br>CONCLUSIONS: Collectively, our results support leptin as a potential novel treatment approach for ALS.}, }
@article {pmid34933675, year = {2021}, author = {Yang, W and Chen, X and Li, S and Li, XJ}, title = {Genetically modified large animal models for investigating neurodegenerative diseases.}, journal = {Cell &amp; bioscience}, volume = {11}, number = {1}, pages = {218}, pmid = {34933675}, issn = {2045-3701}, support = {32070534//National Natural Science Foundation of China/ ; 81830032//National Natural Science Foundation of China/ ; 82071421//National Natural Science Foundation of China/ ; }, abstract = {Neurodegenerative diseases represent a large group of neurological disorders including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. Although this group of diseases show heterogeneous clinical and pathological phenotypes, they share important pathological features characterized by the age-dependent and progressive degeneration of nerve cells that is caused by the accumulation of misfolded proteins. The association of genetic mutations with neurodegeneration diseases has enabled the establishment of various types of animal models that mimic genetic defects and have provided important insights into the pathogenesis. However, most of genetically modified rodent models lack the overt and selective neurodegeneration seen in the patient brains, making it difficult to use the small animal models to validate the effective treatment on neurodegeneration. Recent studies of pig and monkey models suggest that large animals can more faithfully recapitulate pathological features of neurodegenerative diseases. In this review, we discuss the important differences in animal models for modeling pathological features of neurodegenerative diseases, aiming to assist the use of animal models to better understand the pathogenesis and to develop effective therapeutic strategies.}, }
@article {pmid34925009, year = {2021}, author = {Lee, S and Jo, M and Lee, HE and Jeon, YM and Kim, S and Kwon, Y and Woo, J and Han, S and Mun, JY and Kim, HJ}, title = {HEXA-018, a Novel Inducer of Autophagy, Rescues TDP-43 Toxicity in Neuronal Cells.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {747975}, pmid = {34925009}, issn = {1663-9812}, abstract = {The autophagy-lysosomal pathway is an essential cellular mechanism that degrades aggregated proteins and damaged cellular components to maintain cellular homeostasis. Here, we identified HEXA-018, a novel compound containing a catechol derivative structure, as a novel inducer of autophagy. HEXA-018 increased the LC3-I/II ratio, which indicates activation of autophagy. Consistent with this result, HEXA-018 effectively increased the numbers of autophagosomes and autolysosomes in neuronal cells. We also found that the activation of autophagy by HEXA-018 is mediated by the AMPK-ULK1 pathway in an mTOR-independent manner. We further showed that ubiquitin proteasome system impairment- or oxidative stress-induced neurotoxicity was significantly reduced by HEXA-018 treatment. Moreover, oxidative stress-induced mitochondrial dysfunction was strongly ameliorated by HEXA-018 treatment. In addition, we investigated the efficacy of HEXA-018 in models of TDP-43 proteinopathy. HEXA-018 treatment mitigated TDP-43 toxicity in cultured neuronal cell lines and Drosophila. Our data indicate that HEXA-018 could be a new drug candidate for TDP-43-associated neurodegenerative diseases.}, }
@article {pmid34924158, year = {2021}, author = {López-Gómez, JJ and Ballesteros-Pomar, MD and Gómez-Hoyos, E and Pintor de la Maza, B and Penacho-Lázaro, M&#xc1; and Palacio-Mures, JM and Abreu-Padín, C and Sanz Gallego, I and de Luis-Román, DA}, title = {Effect of the type of specialized nutrition support on the course of the patient with amyotrophic lateral sclerosis (ALS). Interhospital registry SCLEDyN.}, journal = {Endocrinologia, diabetes y nutricion}, volume = {68}, number = {10}, pages = {699-707}, doi = {10.1016/j.endien.2021.11.032}, pmid = {34924158}, issn = {2530-0180}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Gastrostomy ; Humans ; *Neurodegenerative Diseases ; Nutritional Support ; Registries ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which specialized nutritional support is essential. The objectives of our study were to describe nutritional support at the beginning of follow-up and its impact on anthropometry and survival.<br><br>METHODS: An interhospital registry was created for the hospitals of Castilla-Le&#xf3;n through a web platform designed for this purpose. An anamnesis was carried out on the evolution and nutritional history of the disease; and classical anthropometry was determined. The prescribed nutritional treatment was recorded. The parameters were measured at the beginning, at six and twelve months of nutritional follow-up.<br><br>RESULTS: A total of 93 patients [49 (52.7%) spinal; 44 (47.3%) bulbar)] were analyzed. The nutritional support route at the beginning was oral diet in 36 (38.7%) patients; oral nutritional supplementation (SON) in 46 (49.5%) patients; and in 11 (11.8%) patients percutaneous endoscopic gastrostomy (PEG). A decrease in the body mass index (BMI) was observed between the first and second visit [Start: 24.18 (3.29) kg/m[2]; 6 months: 23.69 (4.12) kg/m[2]; P&#x202f;<&#x202f;.05]. Less weight loss was observed at 6 months compared to the start of nutritional follow-up [Start: 8.09 (8.72)%; 6 months: 1.4 (6.29)%; P&#x202f;<&#x202f;.01]. 36 (38.7%) patients died but with no differences according to when nutritional support was started. Survival from the onset of symptoms was higher in the group of patients with artificial nutrition, although without reaching statistical significance [Oral: 28 (20.25) months; SON: 30 (16.75-48.25) months; PEG: 39 (27-52) months; P&#x202f;=&#x202f;.90].<br><br>CONCLUSIONS: Patients with ALS present a severe deterioration in nutritional status before the start of nutritional support. After the nutritional intervention, a slowdown in weight loss and nutritional deterioration was observed.}, }
@article {pmid34921343, year = {2022}, author = {Dragusin, A and Grecu, N and Ribigan, AC and Badea, RS and Terecoasa, EO and Ene, A and Tiu, C}, title = {Low Fluctuation of Symptoms May Delay Diagnosis of Myasthenia Gravis: A Case Series.}, journal = {Neurology and therapy}, volume = {11}, number = {1}, pages = {481-487}, pmid = {34921343}, issn = {2193-8253}, abstract = {INTRODUCTION: Myasthenia gravis is an autoimmune disorder affecting neuromuscular transmission, and its hallmark is fluctuating muscular weakness affecting the ocular, bulbar, respiratory, or limb muscles. Our objective is to highlight the difficulties encountered in diagnosing this disorder in patients lacking this characteristic phenomenon.<br><br>METHODS: Three cases of patients presenting with progressive weakness of bulbar and ocular muscles, in whom a lack of fluctuation delayed the diagnosis of myasthenia gravis, are described.<br><br>RESULTS: Amyotrophic lateral sclerosis was considered in two of the patients, while cavernous sinus thrombosis was initially diagnosed in the third. Electrodiagnostic, pharmacologic, and serologic testing ultimately established the diagnosis of myasthenia gravis.<br><br>CONCLUSION: While the typical clinical pattern of myasthenia gravis is well known and easily recognizable, there are cases when the diagnosis, and thus the treatment, is delayed because of low or absent fluctuation of symptoms. The acknowledgment of this probably underestimated presentation is important for expeditious management.}, }
@article {pmid34921121, year = {2022}, author = {van Eijk, RPA and van den Berg, LH and Lu, Y}, title = {Composite endpoint for ALS clinical trials based on patient preference: Patient-Ranked Order of Function (PROOF).}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {93}, number = {5}, pages = {539-546}, pmid = {34921121}, issn = {1468-330X}, support = {P30 CA124435/CA/NCI NIH HHS/United States ; R01 HL089778/HL/NHLBI NIH HHS/United States ; UL1 TR003142/TR/NCATS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Patient Preference ; }, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) show considerable variation in symptoms. Treatments targeting an overall improvement in symptomatology may not address what the majority of patients consider to be most important. Here, we propose a composite endpoint for ALS clinical trials that weighs the improvement in symptoms compared with what the patient population actually wants.<br><br>METHODS: An online questionnaire was sent out to a population-based registry in The Netherlands. Patients with ALS were asked to score functional domains with a validated self-reported questionnaire, and rank the order of importance of each domain. This information was used to estimate variability in patient preferences and to develop the Patient-Ranked Order of Function (PROOF) endpoint.<br><br>RESULTS: There was extensive variability in patient preferences among the 433 responders. The majority of the patients (62.1%) preferred to prioritise certain symptoms over others when evaluating treatments. The PROOF endpoint was established by comparing each patient in the treatment arm to each patient in the placebo arm, based on their preferred order of functional domains. PROOF averages all pairwise comparisons, and reflects the probability that a patient receiving treatment has a better outcome on domains that are most important to them, compared with a patient receiving placebo. By means of simulation we illustrate how incorporating patient preference may upgrade or downgrade trial results.<br><br>CONCLUSIONS: The PROOF endpoint provides a balanced patient-focused analysis of the improvement in function and may help to refine the risk-benefit assessment of new treatments for ALS.}, }
@article {pmid34917028, year = {2021}, author = {Sun, X and Qiao, H and Cheng, X and Tian, H and Shen, K and Jin, W and Liu, X and Wang, Q and Miao, Y and Xu, Y and Zhao, C and Zhao, J}, title = {Case Report: Identifying Andersson-Like Lesions in Diffuse Idiopathic Skeletal Hyperostosis.}, journal = {Frontiers in endocrinology}, volume = {12}, number = {}, pages = {766209}, pmid = {34917028}, issn = {1664-2392}, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Hyperostosis, Diffuse Idiopathic Skeletal/*pathology ; Male ; Spinal Fractures/metabolism ; Spine/pathology ; Spondylitis, Ankylosing/metabolism ; Treatment Outcome ; }, abstract = {Andersson lesions (ALs) in ankylosing spondylitis (AS) pose a severe risk to the stability of ankylosed spine, which might result in significant deterioration of spinal cord function after traumatic or inflammatory causes. Herein, erosive discovertebral lesions in diffuse idiopathic skeletal hyperostosis (DISH) presented important clinical similarities to AL in AS, but failed to completely recognize unstable spinal lesions. Therefore, we pioneered to identify spinal discovertebral lesions similar to Andersson-like lesions (ALLs) in DISH, followed by the characterization and summarization of the etiology, radiology, laboratory results, clinical symptoms, and treatment strategies for AL in AS with ALL in DISH. By characterizing the ALL in DISH cases, we showed that the ALL was mainly traumatic and established at the junction of focal stress between two adjacent ossified level arms. Erosive discovertebral ALLs were formed after trivial stress of direct impact and could be subdivided into transdiscal, transvertebral, and discovertebral types radiologically. Patients who presented with ALL frequently suffered from consistent back pain clinically and experienced a decrease in motion ability that could reflect skeletal stability, which received treatment effectiveness after conservative external spinal immobilization or further surgical internal fixation, indicating the significance of recognizing ALL in the ankylosed DISH spine to further maintain spinal stability in order to prevent catastrophic neurologic sequelae. Our work highlighted the clinical relevance of ALL in DISH in comparison with AL in AS, which provided broader insight to identify ALL in DISH, thus facilitating early intervention against DISH deterioration.}, }
@article {pmid34915153, year = {2022}, author = {Huber, N and Hoffmann, D and Giniatullina, R and Rostalski, H and Leskelä, S and Takalo, M and Natunen, T and Solje, E and Remes, AM and Giniatullin, R and Hiltunen, M and Haapasalo, A}, title = {C9orf72 hexanucleotide repeat expansion leads to altered neuronal and dendritic spine morphology and synaptic dysfunction.}, journal = {Neurobiology of disease}, volume = {162}, number = {}, pages = {105584}, doi = {10.1016/j.nbd.2021.105584}, pmid = {34915153}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Animals ; C9orf72 Protein/genetics/metabolism ; DNA Repeat Expansion ; Dendritic Spines/metabolism ; *Frontotemporal Lobar Degeneration/metabolism ; Humans ; Mice ; Neurons/metabolism ; }, abstract = {Frontotemporal lobar degeneration (FTLD) comprises a heterogenous group of progressive neurodegenerative syndromes. To date, no validated biomarkers or effective disease-modifying therapies exist for the different clinical or genetic subtypes of FTLD. The most common genetic cause underlying FTLD and amyotrophic lateral sclerosis (ALS) is a hexanucleotide repeat expansion in the C9orf72 gene (C9-HRE). FTLD is accompanied by changes in several neurotransmitter systems, including the glutamatergic, GABAergic, dopaminergic, and serotonergic systems and many clinical symptoms can be explained by disturbances in these systems. Here, we aimed to elucidate the effects of the C9-HRE on synaptic function, molecular composition of synapses, and dendritic spine morphology. We overexpressed the pathological C9-HRE in cultured E18 mouse primary hippocampal neurons and characterized the pathological, morphological, and functional changes by biochemical methods, confocal microscopy, and live cell calcium imaging. The C9-HRE-expressing neurons were confirmed to display the pathological RNA foci and DPR proteins. C9-HRE expression led to significant changes in dendritic spine morphologies, as indicated by decreased number of mushroom-type spines and increased number of stubby and thin spines, as well as diminished neuronal branching. These morphological changes were accompanied by concomitantly enhanced susceptibility of the neurons to glutamate-induced excitotoxicity as well as augmented and prolonged responses to excitatory stimuli by glutamate and depolarizing potassium chloride as compared to control neurons. Mechanistically, the hyperexcitation phenotype in the C9-HRE-expressing neurons was found to be underlain by increased activity of extrasynaptic GluN2B-containing N-methyl-d-aspartate (NMDA) receptors. Our results are in accordance with the idea suggesting that C9-HRE is associated with enhanced excitotoxicity and synaptic dysfunction. Thus, therapeutic interventions targeted to alleviate synaptic disturbances might offer efficient avenues for the treatment of patients with C9-HRE-associated FTLD.}, }
@article {pmid34912464, year = {2021}, author = {Suh, WJ and Seo, Y and Jin, C and Cho, SY and Park, SU and Jung, WS and Moon, SK and Park, JM and Ko, CN and Kwon, S and Cho, KH}, title = {Traditional East Asian Herbal Medicine for Amyotrophic Lateral Sclerosis: A Scoping Review.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2021}, number = {}, pages = {5674142}, pmid = {34912464}, issn = {1741-427X}, abstract = {This study aimed to analyze and summarize the existing evidence regarding herbal medicine treatments for amyotrophic lateral sclerosis (ALS). Studies on herbal medicine treatment in patients with ALS were searched within English, Chinese, Japanese, and Korean databases up to July 31, 2021. In the selected studies, we collected the following information: the first author, year of publication, country, language, study methodology, sample size, demographic characteristics of the study participants, disease duration, diagnostic criteria, treatment method, treatment periods, evaluation tools, results, and side effects. The organized data were classified and analyzed narratively. This study included 59 studies. The first clinical study on the effect of herbal medicine was published in 1995; moreover, most studies were conducted in China. Among the 59 selected studies, 47.5% were observational studies, including case reports and case series. Moreover, there was one meta-analysis. The El Escorial criteria were the most commonly used diagnostic criterion for ALS; moreover, the ALS functional rating scale was the most common evaluation tool. Buzhongyiqitang, Sijunzitangjiawei, and Jianpiyifeitang were the most commonly used herbal medicines, with anti-inflammatory, protein aggregation, and anti-oxidant effects. There remain evidence of gaps in the effectiveness of herbal medicine for ALS. To allow effective treatment of patients with ALS using herbal medicine, large-scale and rigorously designed high-quality clinical studies should be performed.}, }
@article {pmid34912191, year = {2021}, author = {Poulin-Brière, A and Rezaei, E and Pozzi, S}, title = {Antibody-Based Therapeutic Interventions for Amyotrophic Lateral Sclerosis: A Systematic Literature Review.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {790114}, pmid = {34912191}, issn = {1662-4548}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a mid-life onset neurodegenerative disease that manifests its symptomatology with motor impairments and cognitive deficits overlapping with Frontotemporal Lobar Degeneration (FTLD). The etiology of ALS remains elusive, with various mechanisms and cellular targets implicated, and no treatment can reverse or stop the progression of the pathology. Therapeutic interventions based on passive immunization are gaining attention for neurodegenerative diseases, and FDA recently approved the first antibody-based approach for Alzheimer's disease. The present systematic review of the literature aims to highlight the efforts made over the past years at developing antibody-based strategies to cure ALS. Thirty-one original research papers have been selected where the therapeutic efficacy of antibodies were investigated and described in patients and animal models of ALS. Antibody-based interventions analyzed, target both extracellular molecules implicated in the pathology and intracellular pathogenic proteins known to drive the disease, such as SOD1, TDP-43 or C9ORF72 repeats expansions. The potentials and limitations of these therapeutic interventions have been described and discussed in the present review.}, }
@article {pmid34906191, year = {2021}, author = {Xia, K and Zhang, L and Zhang, G and Wang, Y and Huang, T and Fan, D}, title = {Leukocyte telomere length and amyotrophic lateral sclerosis: a Mendelian randomization study.}, journal = {Orphanet journal of rare diseases}, volume = {16}, number = {1}, pages = {508}, pmid = {34906191}, issn = {1750-1172}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Genome-Wide Association Study ; Humans ; Leukocytes ; Mendelian Randomization Analysis/methods ; Polymorphism, Single Nucleotide/genetics ; Telomere/genetics ; }, abstract = {BACKGROUND: Observational studies have suggested that telomere length is associated with amyotrophic lateral sclerosis (ALS). However, whether this association is causal remains unclear. In this study, we aimed to explore the causal relationship between leukocyte telomere length (LTL) and ALS by a two-sample Mendelian randomization (MR) approach. Single-nucleotide polymorphisms (SNPs) for LTL were identified through high-quality genome-wide association studies (GWASs). The ALS GWAS summary data (20,806 cases; 59,804 controls) with largest sample size to date was obtained. We adopted the inverse variance weighted (IVW) method to examine the effect of LTL on ALS and used the weighted median method, simple median method, MR Egger method and MR-PRESSO method to perform sensitivity analyses.<br><br>RESULTS: We found that genetically determined increased LTL was inversely associated with the risk of ALS (odds ratio (OR)&#x2009;=&#x2009;0.846, 95% confidence interval (CI): 0.744-0.962, P&#x2009;=&#x2009;0.011), which was mainly driven by rs940209 in the OBFC1 gene, suggesting a potential effect of OBFC1 on ALS. The results were further confirmed by sensitivity analysis with the MR Egger method (OR&#x2009;=&#x2009;0.647, 95% CI&#x2009;=&#x2009;0.447-0.936, P&#x2009;=&#x2009;0.050). Analyses by the weighted median method (OR&#x2009;=&#x2009;0.893, P&#x2009;=&#x2009;0.201) and simple median method (OR&#x2009;=&#x2009;0.935, P&#x2009;=&#x2009;0.535) also showed a similar trend. The MR Egger analysis did not suggest directional pleiotropy, with an intercept of 0.025 (P&#x2009;=&#x2009;0.168). Neither the influence of instrumental outliers nor heterogeneity was found.<br><br>CONCLUSIONS: Our results suggest that genetically predicted increased LTL has a causal relationship with a lower risk of ALS. Protecting against telomere loss may be of great importance in the prevention and treatment of ALS.}, }
@article {pmid34899177, year = {2021}, author = {Gao, M and Liu, R and Mao, J}, title = {Noise Robustness Low-Rank Learning Algorithm for Electroencephalogram Signal Classification.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {797378}, pmid = {34899177}, issn = {1662-4548}, abstract = {Electroencephalogram (EEG) is often used in clinical epilepsy treatment to monitor electrical signal changes in the brain of patients with epilepsy. With the development of signal processing and artificial intelligence technology, artificial intelligence classification method plays an important role in the automatic recognition of epilepsy EEG signals. However, traditional classifiers are easily affected by impurities and noise in epileptic EEG signals. To solve this problem, this paper develops a noise robustness low-rank learning (NRLRL) algorithm for EEG signal classification. NRLRL establishes a low-rank subspace to connect the original data space and label space. Making full use of supervision information, it considers the local information preservation of samples to ensure the low-rank representation of within-class compactness and between-classes dispersion. The asymmetric least squares support vector machine (aLS-SVM) is embedded into the objective function of NRLRL. The aLS-SVM finds the maximum quantile distance between the two classes of samples based on the pinball loss function, which further improves the noise robustness of the model. Several classification experiments with different noise intensity are designed on the Bonn data set, and the experiment results verify the effectiveness of the NRLRL algorithm.}, }
@article {pmid34899171, year = {2021}, author = {Guida, N and Sanguigno, L and Mascolo, L and Calabrese, L and Serani, A and Molinaro, P and Lau, CG and Annunziato, L and Formisano, L}, title = {The Transcriptional Complex Sp1/KMT2A by Up-Regulating Restrictive Element 1 Silencing Transcription Factor Accelerates Methylmercury-Induced Cell Death in Motor Neuron-Like NSC34 Cells Overexpressing SOD1-G93A.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {771580}, pmid = {34899171}, issn = {1662-4548}, abstract = {Methylmercury (MeHg) exposure has been related to amyotrophic lateral sclerosis (ALS) pathogenesis and molecular mechanisms of its neurotoxicity has been associated to an overexpression of the Restrictive Element 1 Silencing Transcription factor (REST). Herein, we evaluated the possibility that MeHg could accelerate neuronal death of the motor neuron-like NSC34 cells transiently overexpressing the human Cu[2+]/Zn[2+]superoxide dismutase 1 (SOD1) gene mutated at glycine 93 (SOD1-G93A). Indeed, SOD1-G93A cells exposed to 100 nM MeHg for 24 h showed a reduction in cell viability, as compared to cells transfected with empty vector or with unmutated SOD1 construct. Interestingly, cell survival reduction in SOD1-G93A cells was associated with an increase of REST mRNA and protein levels. Furthermore, MeHg increased the expression of the transcriptional factor Sp1 and promoted its binding to REST gene promoter sequence. Notably, Sp1 knockdown reverted MeHg-induced REST increase. Co-immunoprecipitation experiments demonstrated that Sp1 physically interacted with the epigenetic writer Lysine-Methyltransferase-2A (KMT2A). Moreover, knocking-down of KMT2A reduced MeHg-induced REST mRNA and protein increase in SOD1-G93A cells. Finally, we found that MeHg-induced REST up-regulation triggered necropoptotic cell death, monitored by RIPK1 increased protein expression. Interestingly, REST knockdown or treatment with the necroptosis inhibitor Necrostatin-1 (Nec) decelerated MeH-induced cell death in SOD1-G93A cells. Collectively, this study demonstrated that MeHg hastens necroptotic cell death in SOD1-G93A cells via Sp1/KMT2A complex, that by epigenetic mechanisms increases REST gene expression.}, }
@article {pmid34894926, year = {2022}, author = {Kato, H and Sato, H and Okuda, M and Wu, J and Koyama, S and Izumi, Y and Waku, T and Iino, M and Aoki, M and Arawaka, S and Ohta, Y and Ishizawa, K and Kawasaki, K and Urano, Y and Miyasaka, T and Noguchi, N and Kume, T and Akaike, A and Sugimoto, H and Kato, T}, title = {Therapeutic effect of a novel curcumin derivative GT863 on a mouse model of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {7-8}, pages = {489-495}, doi = {10.1080/21678421.2021.2012699}, pmid = {34894926}, issn = {2167-9223}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; *Curcumin/pharmacology/therapeutic use ; Antioxidants/therapeutic use ; Hydrogen Peroxide/metabolism/therapeutic use ; Mice, Transgenic ; Superoxide Dismutase/genetics ; Disease Models, Animal ; Spinal Cord/metabolism ; }, abstract = {The present study investigated the therapeutic effects of the curcumin derivative 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]ethenyl]-1H-pyrazole (GT863) in amyotrophic lateral sclerosis (ALS). The inhibitory effect of GT863 on superoxide dismutase 1 (SOD1) aggregation was evaluated in cell-free assays. GT863 interfered with the conformational changes of the SOD1 protein and later, oligomeric aggregation. Furthermore, its antioxidant, anti-inflammatory, and neuroprotective effects were evaluated in cell-free and cultured cell assays. GT863 inhibited H2O2- and glutamate-induced cytotoxicity and activated an antioxidant responsive element pathway. Additionally, in vivo effects of GT863 in the ALS mice model were evaluated by its oral administration to H46R mutant SOD1 transgenic mice. Rotarod test showed that GT863 administration significantly slowed the progression of motor dysfunction in the mice. In addition, GT863 substantially reduced highly-aggregated SOD1, further preserving large neurons in the spinal cord of GT863-treated mice. Collectively, these results indicated that GT863 could be a viable therapeutic agent with multiple vital actions for the treatment of ALS.}, }
@article {pmid34890834, year = {2022}, author = {Pateraki, G and Anargyros, K and Aloizou, AM and Siokas, V and Bakirtzis, C and Liampas, I and Tsouris, Z and Ziogka, P and Sgantzos, M and Folia, V and Peristeri, E and Dardiotis, E}, title = {Therapeutic application of rTMS in neurodegenerative and movement disorders: A review.}, journal = {Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology}, volume = {62}, number = {}, pages = {102622}, doi = {10.1016/j.jelekin.2021.102622}, pmid = {34890834}, issn = {1873-5711}, mesh = {Humans ; *Motor Cortex ; Movement ; Muscle, Skeletal ; *Parkinson Disease ; Transcranial Magnetic Stimulation ; }, abstract = {Transcranial magnetic stimulation (TMS) is a non-invasive form of brain stimulation that makes use of the magnetic field generated when an electric current passes through a magnetic coil placed over the scalp. It can be applied as a single stimulus at a time, in pairs of stimuli, or repetitively in trains of stimuli (repetitive TMS, rTMS). RTMS can induce changes in brain activity, whose after-effects reflect the processes of long-term potentiation and long-term depression, as certain protocols, namely those using low frequencies (≤1 Hz) seem to suppress cortical excitability, while those using high frequencies (>1 Hz) seem to enhance it. It is a technique with very few and mostly mild side-effects, whose effects can persist for long time periods, and as such, it has been studied as a potential treatment option in a multitude of neurodegenerative diseases, including those affecting movement. Although rTMS has received approval as a treatment strategy of only a few aspects in movement disorders in the latest guidelines, its further use seems to also be promising in their context. In this review, we gathered the available literature on the therapeutic application of rTMS in movement disorders, namely Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Dystonia, Tic disorders and Essential Tremor.}, }
@article {pmid34890069, year = {2022}, author = {Cudkowicz, ME and Lindborg, SR and Goyal, NA and Miller, RG and Burford, MJ and Berry, JD and Nicholson, KA and Mozaffar, T and Katz, JS and Jenkins, LJ and Baloh, RH and Lewis, RA and Staff, NP and Owegi, MA and Berry, DA and Gothelf, Y and Levy, YS and Aricha, R and Kern, RZ and Windebank, AJ and Brown, RH}, title = {A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {65}, number = {3}, pages = {291-302}, pmid = {34890069}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Double-Blind Method ; Humans ; *Mesenchymal Stem Cells ; Nerve Growth Factors/metabolism ; Transplantation, Autologous ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression.<br><br>METHODS: This randomized, double-blind, placebo-controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS-R) &#x2265;25 (screening) and&#x2009;&#x2265;3 ALSFRS-R points decline prior to randomization. Participants received three treatments of MSC-NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC-NTF through a responder analysis and safety. A change in disease progression post-treatment of &#x2265;1.25&#x2009;points/mo defines a clinical response. A pre-specified analysis leveraged baseline ALSFRS-R of 35 as a subgroup threshold.<br><br>RESULTS: Overall, MSC-NTF treatment was well tolerated; there were no safety concerns. Thirty-three percent of MSC-NTF and 28% of placebo participants met clinical response criteria at 28&#x2009;wk (odds ratio [OR]&#xa0;=&#xa0;1.33, P&#xa0;=&#xa0;.45); thus, the primary endpoint was not met. A pre-specified analysis of participants with baseline ALSFRS-R&#x2009;&#x2265;&#x2009;35 (n&#xa0;=&#xa0;58) showed a clinical response rate at 28&#x2009;wk of 35% MSC-NTF and 16% placebo (OR&#xa0;=&#xa0;2.6, P&#xa0;=&#xa0;.29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC-NTF, with placebo unchanged.<br><br>DISCUSSION: The study did not reach statistical significance on the primary endpoint. However, a pre-specified subgroup suggests that MSC-NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation.}, }
@article {pmid34879411, year = {2021}, author = {Meyer, T}, title = {[Amyotrophic lateral sclerosis (ALS) - diagnosis, course of disease and treatment options].}, journal = {Deutsche medizinische Wochenschrift (1946)}, volume = {146}, number = {24-25}, pages = {1613-1618}, doi = {10.1055/a-1562-7882}, pmid = {34879411}, issn = {1439-4413}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Humans ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disorder which is characterized by progressive motor symptoms, such as muscle weakness, muscle atrophy and spasticity. In Germany, 6000-8000 people are affected by ALS. Between 1200 and 1600 newly diagnosed patients are expected each year. Protein deposits in the cytoplasm of motor neurons are a molecular feature of ALS. The most common protein aggregates result from excessive deposition of TDP-43. Familial ALS is present in 5 to 10 % of all ALS patients. Common causal genes include C9orf72, SOD1, FUS, and TARDBP. Genetic factors may be involved even without a family history of ALS and may be underestimated. The disease course and progression are highly variable. Symptom severity and rate of progression are determined by the ALS Functional Scale (ALSFRS-R). Beyond clinical symptoms and the patient's perception of disease burden, measurement of slow vital capacity (SVC), peak cough flow (PCF), and body mass index (BMI) are used to underscore the indications for ventilatory and nutritional interventions, as well as palliative care. The validity of the biomarker neurofilament light chain (NF-L) for estimating prognosis is currently being investigated. ALS is not curable - however, various individual treatment options have to be considered for improving survival, symptom control and social participation. The care in specialized ALS centers is recommended to ensure optimal treatment regarding symptomatic medication, assistive devices, nutrition support and ventilation therapy. Optimal care is achieved by interdisciplinary collaboration of general practitioners, specialized physicians, neurologists and ALS experts being integrated in multiprofessional care networks.}, }
@article {pmid34877036, year = {2021}, author = {Ishikawa, Y and Miyakoshi, N and Kobayashi, T and Kikuchi, T}, title = {Treatment of progressive paralysis associated with cervical myelopathy and suspected amyotrophic lateral sclerosis: A case report.}, journal = {Surgical neurology international}, volume = {12}, number = {}, pages = {550}, pmid = {34877036}, issn = {2229-5097}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an intractable progressive disease, with an incidence of 2.2- 2.3 per 100,000 individuals, which is not extremely low. ALS symptoms are accompanied by spinal myeloradicular motor deficit; its differential diagnosis is must because progressive paralysis needs emergency surgery.<br><br>CASE DESCRIPTION: A 64-year-old man with suspected ALS showing progressive paralysis with cervical myelopathy was diagnosed as normal after performing a nerve conduction study preoperatively. Postoperative diffuse fasciculation after posterior decompression allowed the diagnosis of ALS through needle electromyography (EMG). Thereafter, the patient's condition slowly deteriorated and he died after 16 months.<br><br>CONCLUSION: Surgery might aggravate ALS symptoms; however, surgery for progressive paralysis in patients with suspected ALS is required for distinguishing patients with non-ALS paralysis. Approximately 70% of cases have spinal-onset ALS lacking typical cranial nerve symptoms; thus, to prevent unnecessary surgery, surgeons should at least know the characteristic features of ALS and should be aware that early diagnosis requires needle EMG for definitive diagnosis of ALS.}, }
@article {pmid34874888, year = {2021}, author = {van Genugten, CR and Schuurmans, J and Hoogendoorn, AW and Araya, R and Andersson, G and Baños, R and Botella, C and Cerga Pashoja, A and Cieslak, R and Ebert, DD and García-Palacios, A and Hazo, JB and Herrero, R and Holtzmann, J and Kemmeren, L and Kleiboer, A and Krieger, T and Smoktunowicz, E and Titzler, I and Topooco, N and Urech, A and Smit, JH and Riper, H}, title = {Examining the Theoretical Framework of Behavioral Activation for Major Depressive Disorder: Smartphone-Based Ecological Momentary Assessment Study.}, journal = {JMIR mental health}, volume = {8}, number = {12}, pages = {e32007}, pmid = {34874888}, issn = {2368-7959}, abstract = {BACKGROUND: Behavioral activation (BA), either as a stand-alone treatment or as part of cognitive behavioral therapy, has been shown to be effective for treating depression. The theoretical underpinnings of BA derive from Lewinsohn et al's theory of depression. The central premise of BA is that having patients engage in more pleasant activities leads to them experiencing more pleasure and elevates their mood, which, in turn, leads to further (behavioral) activation. However, there is a dearth of empirical evidence about the theoretical framework of BA.<br><br>OBJECTIVE: This study aims to examine the assumed (temporal) associations of the 3 constructs in the theoretical framework of BA.<br><br>METHODS: Data were collected as part of the "European Comparative Effectiveness Research on Internet-based Depression Treatment versus treatment-as-usual" trial among patients who were randomly assigned to receive blended cognitive behavioral therapy (bCBT). As part of bCBT, patients completed weekly assessments of their level of engagement in pleasant activities, the pleasure they experienced as a result of these activities, and their mood over the course of the treatment using a smartphone-based ecological momentary assessment (EMA) application. Longitudinal cross-lagged and cross-sectional associations of 240 patients were examined using random intercept cross-lagged panel models.<br><br>RESULTS: The analyses did not reveal any statistically significant cross-lagged coefficients (all P>.05). Statistically significant cross-sectional positive associations between activities, pleasure, and mood levels were identified. Moreover, the levels of engagement in activities, pleasure, and mood slightly increased over the duration of the treatment. In addition, mood seemed to carry over, over time, while both levels of engagement in activities and pleasurable experiences did not.<br><br>CONCLUSIONS: The results were partially in accordance with the theoretical framework of BA, insofar as the analyses revealed cross-sectional relationships between levels of engagement in activities, pleasurable experiences deriving from these activities, and enhanced mood. However, given that no statistically significant temporal relationships were revealed, no conclusions could be drawn about potential causality. A shorter measurement interval (eg, daily rather than weekly EMA reports) might be more attuned to detecting potential underlying temporal pathways. Future research should use an EMA methodology to further investigate temporal associations, based on theory and how treatments are presented to patients.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov, NCT02542891, https://clinicaltrials.gov/ct2/show/NCT02542891; German Clinical Trials Register, DRKS00006866, https://tinyurl.com/ybja3xz7; Netherlands Trials Register, NTR4962, https://www.trialregister.nl/trial/4838; ClinicalTrials.Gov, NCT02389660, https://clinicaltrials.gov/ct2/show/NCT02389660; ClinicalTrials.gov, NCT02361684, https://clinicaltrials.gov/ct2/show/NCT02361684; ClinicalTrials.gov, NCT02449447, https://clinicaltrials.gov/ct2/show/NCT02449447; ClinicalTrials.gov, NCT02410616, https://clinicaltrials.gov/ct2/show/NCT02410616; ISRCTN registry, ISRCTN12388725, https://www.isrctn.com/ISRCTN12388725.}, }
@article {pmid34874625, year = {2022}, author = {Xie, M and Zhao, S and Bosco, DB and Nguyen, A and Wu, LJ}, title = {Microglial TREM2 in amyotrophic lateral sclerosis.}, journal = {Developmental neurobiology}, volume = {82}, number = {1}, pages = {125-137}, pmid = {34874625}, issn = {1932-846X}, support = {U19 AG069701/AG/NIA NIH HHS/United States ; R21 AG064159/AG/NIA NIH HHS/United States ; R01 NS088627/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Central Nervous System/metabolism ; Humans ; *Membrane Glycoproteins/genetics/metabolism ; *Microglia/metabolism ; Motor Neurons/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; *Receptors, Immunologic/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is an aggressive motor neuron degenerative disease characterized by selective loss of both upper and lower motor neurons. The mechanisms underlying disease initiation and progression are poorly understood. The involvement of nonmotor neuraxis emphasizes the contribution of glial cells in disease progress. Microglia comprise a unique subset of glial cells and are the principal immune cells in the central nervous system (CNS). Triggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, within the CNS, is exclusively expressed on microglia and plays crucial roles in microglial proliferation, migration, activation, metabolism, and phagocytosis. Genetic evidence has linked TREM2 to neurodegenerative diseases including ALS, but its function in ALS pathogenesis is largely unknown. In this review, we summarize how microglial activation, with a specific focus on TREM2 function, affects ALS progression clinically and experimentally. Understanding microglial TREM2 function will help pinpoint the molecular target for ALS treatment.}, }
@article {pmid34870476, year = {2022}, author = {Inoue, C and Hagiya, H}, title = {Anti-Glomerular Basement Membrane Nephritis Potentially Induced by Nebulized Tobramycin Inhalation.}, journal = {Journal of aerosol medicine and pulmonary drug delivery}, volume = {35}, number = {2}, pages = {104-106}, doi = {10.1089/jamp.2021.0053}, pmid = {34870476}, issn = {1941-2703}, mesh = {Administration, Inhalation ; Aged ; Anti-Bacterial Agents ; Female ; Humans ; *Nephritis/drug therapy ; *Pseudomonas Infections/drug therapy ; Pseudomonas aeruginosa ; Tobramycin/adverse effects ; }, abstract = {Objective: To describe a case of anti-glomerular basement membrane (GBM) nephritis that occurred shortly after initiation of nebulized tobramycin (TOB) therapy using intravenous solution, suggesting an association with the inhalation therapy and the disease onset. Background: With the emergence of antimicrobial resistance, clinical importance of aminoglycosides that usually remain susceptibility against gram-negative organisms is increasingly acknowledged. Despite the growing number of evidence supporting the effectiveness of aminoglycoside inhalation therapy for respiratory tract infections, its clinical application has yet to be widely approved by Japanese health insurance. Case Presentation: A 79-year-old Japanese woman had developed amyotrophic lateral sclerosis and experienced recurrent pneumonia mainly caused by Pseudomonas aeruginosa, which required monthly treatments with broad-spectrum antibiotics. Owing to the limited approval, we had no choice but to use intravenous TOB solution for inhalation therapy as an off-label use under an endorsement of the Institutional Review Board of the hospital. Although the repeated pneumonia subsided, the patient subsequently needed immunosuppressive therapy along with plasma exchanges for the treatment of anti-GBM nephritis. Conclusion: Although this off-label use of intravenous solutions is common in both clinical and research purposes, our case raised an issue that its safety needs to be re-evaluated.}, }
@article {pmid34864682, year = {2022}, author = {Oliveira Santos, M and Domingues, S and Gromicho, M and Pinto, S and de Carvalho, M}, title = {Impact of SARS-CoV-2 Infection Among Non-Invasive Ventilated ALS Patients.}, journal = {Journal of neuromuscular diseases}, volume = {9}, number = {2}, pages = {257-259}, doi = {10.3233/JND-210733}, pmid = {34864682}, issn = {2214-3602}, mesh = {*Amyotrophic Lateral Sclerosis/complications/epidemiology/therapy ; *COVID-19/epidemiology ; Humans ; Male ; Middle Aged ; Pandemics ; Retrospective Studies ; SARS-CoV-2 ; }, abstract = {BACKGROUND: The impact of SARS-CoV-2 infection among neuromuscular diseases with respiratory involvement, including amyotrophic lateral sclerosis (ALS), is still to be elucidated.<br><br>OBJECTIVES: We aim to characterize the clinical outcome of ALS patients non-invasive ventilated (NIV), following SARS-CoV-2 infection.<br><br>METHODS: We analyzed retrospectively our patients followed regularly at our ALS clinic, from the beginning of the COVID-19 pandemic (middle March 2020) to March 2021. We included patients on NIV with a documented SARS-CoV-2 infection. We recorded demographic and clinical data, including from the acute infectious illness.<br><br>RESULTS: Three men with spinal-onset ALS are described, mean age of onset was 55&#xb1;9.1 years (45-61), and mean disease duration was 17.5&#xb1;15.9 months (6.1-41). All of them were wheelchair-bounded, with a mean ALSFRS-R of 15.3&#xb1;0.6 (15-16). One patient used NIV 15 hours/day, 2 between 4 to 7 hours/day, and all used assisted coughing twice daily. None had coexistent comorbidities. They were managed for SARS-CoV-2 infection as outpatients with fluticasone, bronchodilators, azithromycin and increasing frequency of assisted coughing. Supplemental oxygen (mean of 2 liters per minute) was needed in two patients, and one required NIV also during the daytime. Total recovery from SARS-CoV-2 infection was observed in all, despite being in an advanced stage of their disease, with severe respiratory involvement.<br><br>CONCLUSIONS: Prompt medical treatment is recommended for ALS patients with severe disease infected by SARS-CoV-2.}, }
@article {pmid34864433, year = {2022}, author = {De Marchi, F and Collo, A and Scognamiglio, A and Cavaletto, M and Bozzi Cionci, N and Biroli, G and Di Gioia, D and Riso, S and Mazzini, L}, title = {Study protocol on the safety and feasibility of a normocaloric ketogenic diet in people with amyotrophic lateral sclerosis.}, journal = {Nutrition (Burbank, Los Angeles County, Calif.)}, volume = {94}, number = {}, pages = {111525}, doi = {10.1016/j.nut.2021.111525}, pmid = {34864433}, issn = {1873-1244}, mesh = {Adolescent ; Adult ; Aged ; *Amyotrophic Lateral Sclerosis ; *Diet, Ketogenic/adverse effects ; Feasibility Studies ; Female ; Humans ; Male ; Middle Aged ; Pilot Projects ; Prospective Studies ; Reproducibility of Results ; Young Adult ; }, abstract = {OBJECTIVES: This study evaluates the safety and feasibility of a normocaloric ketogenic diet (KD) in people with amyotrophic lateral sclerosis (ALS) for reducing hyperexcitability levels and modulating neuroinflammation.<br><br>METHODS: This is a prospective, open-label pilot study involving men and women diagnosed with ALS, ages 18 to 75 y. The primary outcome is the safety and reproducibility of the KD in people with ALS. We will monitor secondary clinical outcomes with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale score, forced vital capacity, the Amyotrophic Lateral Sclerosis Assessment Questionnaire, blood parameters, and gut microbiota analyses. All participants will follow the KD for 8 wk. During the diet, the clinical status of all participants will be monitored every 15 d through neurologic and nutritional visits and biochemical markers. The research ethics committee approved the study.<br><br>RESULTS: Safety will be assessed by measuring the number and severity of adverse events, including death, and any changes in blood chemistry, vital signs, and clinical exam results. Tolerability will be assessed to complete the proposed 8 wk of treatment while maintaining adequate nutritional status without inducing malnutrition.<br><br>CONCLUSIONS: Adequate caloric intake is essential in ALS, because insufficient intake induces loss of body mass. We hope that the proposed study will provide a positive result in terms of the safety and feasibility of a KD in people ALS, with the purpose of developing a patient-centered diet program to limit disease progression and possibly improve survival.}, }
@article {pmid34864363, year = {2021}, author = {Su, WM and Cheng, YF and Jiang, Z and Duan, QQ and Yang, TM and Shang, HF and Chen, YP}, title = {Predictors of survival in patients with amyotrophic lateral sclerosis: A large meta-analysis.}, journal = {EBioMedicine}, volume = {74}, number = {}, pages = {103732}, pmid = {34864363}, issn = {2352-3964}, mesh = {Amyotrophic Lateral Sclerosis/*mortality ; Female ; Humans ; Life Style ; Male ; Prognosis ; Risk Assessment ; Survival Analysis ; Young Adult ; }, abstract = {BACKGROUND: The survival time of amyotrophic lateral sclerosis (ALS) is greatly variable and protective or risk effects of the potential survival predictors are controversial. Thus, we aim to undertake a comprehensive meta-analysis of studies investigating non-genetic prognostic and survival factors in patients with ALS.<br><br>METHODS: A search of relevant literature from PubMed, Embase, Cochrane library and other citations from 1[st] January 1966 to 1[st] December 020 was conducted. Random-effects models were conducted to pool the multivariable or adjusted hazard ratios (HR) by Stata MP 16.0. PROSPERO registration number: CRD42021256923.<br><br>FINDINGS: A total of 5717 reports were identified, with 115 studies meeting pre-designed inclusion criteria involving 55,169 ALS patients. Five dimensions, including demographic, environmental or lifestyle, clinical manifestations, biochemical index, therapeutic factors or comorbidities were investigated. Twenty-five prediction factors, including twenty non-intervenable and five intervenable factors, were associated with ALS survival. Among them, NFL (HR:3.70, 6.80, in serum and CSF, respectively), FTD (HR:2.98), ALSFRS-R change (HR:2.37), respiratory subtype (HR:2.20), executive dysfunction (HR:2.10) and age of onset (HR:1.03) were superior predictors for poor prognosis, but pLMN or pUMN (HR:0.32), baseline ALSFRS-R score (HR:0.95), duration (HR:0.96), diagnostic delay (HR:0.97) were superior predictors for a good prognosis. Our results did not support the involvement of gender, education level, diabetes, hypertension, NIV, gastrostomy, and statins in ALS survival.<br><br>INTERPRETATION: Our study provided a comprehensive and quantitative index for assessing the prognosis for ALS patients, and the identified non-intervenable or intervenable factors will facilitate the development of treatment strategies for ALS.<br><br>FUNDING: This study was supported by the National Natural Science Fund of China (Grant No. 81971188), the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (Grant No. 2019HXFH046), and the Science and Technology Bureau Fund of Sichuan Province (No. 2019YFS0216).}, }
@article {pmid34861197, year = {2022}, author = {Kobayashi, T and Higgins, Y and Melia, MT and Auwaerter, PG}, title = {Mistaken Identity: Many Diagnoses are Frequently Misattributed to Lyme Disease.}, journal = {The American journal of medicine}, volume = {135}, number = {4}, pages = {503-511.e5}, doi = {10.1016/j.amjmed.2021.10.040}, pmid = {34861197}, issn = {1555-7162}, mesh = {*Borrelia burgdorferi ; Depression/epidemiology ; Humans ; *Lyme Disease/complications/diagnosis ; *Migraine Disorders/complications ; Retrospective Studies ; }, abstract = {BACKGROUND: Prior studies have demonstrated that Lyme disease is frequently over-diagnosed. However, few studies describe which conditions are misdiagnosed as Lyme disease.<br><br>METHODS: This retrospective observational cohort study evaluated patients who lacked evidence for Borrelia burgdorferi infection referred for Lyme disease to a Mid-Atlantic academic center from 2000-2013. The primary outcome is clinically described diagnoses contributing to symptoms. Secondary outcomes included symptom duration and determination whether diagnoses were new or attributed to existing medical conditions.<br><br>RESULTS: Of 1261 referred patients, 1061 (84%) had no findings of active Lyme disease, with 690 (65%) receiving other diagnoses; resulting in 405 (59%) having newly diagnosed medical conditions, 134 (19%) attributed to pre-existing medical issues, and 151 (22%) with both new and pre-existing conditions. Among the 690 patients, the median symptom duration was 796 days, and a total of 139 discrete diagnoses were made. Infectious disease diagnoses comprised only 3.2%. Leading diagnoses were anxiety/depression 222 (21%), fibromyalgia 120 (11%), chronic fatigue syndrome 77 (7%), migraine disorder 74 (7%), osteoarthritis 62 (6%), and sleep disorder/apnea 48 (5%). Examples of less frequent but non-syndromic diseases newly diagnosed included multiple sclerosis (n&#xa0;=&#xa0;11), malignancy (n&#xa0;=&#xa0;8), Parkinson's disease (n&#xa0;=&#xa0;8), sarcoidosis (n&#xa0;=&#xa0;4), or amyotrophic lateral sclerosis (n&#xa0;=&#xa0;4).<br><br>CONCLUSIONS: Most patients with long-term symptoms have either new or pre-existing disorders accounting for their symptoms other than Lyme disease, suggesting overdiagnosis in this population. Patients referred for consideration of Lyme disease for chronic symptoms deserve careful assessment for diagnoses other than Borrelia burgdorferi infection.}, }
@article {pmid34859160, year = {2021}, author = {Akçay, B and Çolak, TK and Apti, A and Çolak, &#x130; and Kızıltaş, &#xd6;}, title = {The reliability of the augmented Lehnert-Schroth and Rigo classification in scoliosis management.}, journal = {The South African journal of physiotherapy}, volume = {77}, number = {2}, pages = {1568}, pmid = {34859160}, issn = {2410-8219}, abstract = {BACKGROUND: In pattern-specific scoliosis exercises and bracing, the corrective treatment plan differs according to different curve patterns. There are a limited number of studies investigating the reliability of the commonly used classifications systems.<br><br>OBJECTIVE: To test the reliability of the augmented Lehnert-Schroth (ALS) classification and the Rigo classification.<br><br>METHODS: X-rays and posterior photographs of 45 patients with scoliosis were sent by the first author to three clinicians twice at 1-week intervals. The clinicians classified images according to the ALS and Rigo classifications, and the data were analysed using SPSS V-16. Intraclass correlation coefficients (ICCs) and standard error measurement (SEM) were calculated to evaluate the inter- and intra-observer reliability.<br><br>RESULTS: The inter-observer ICC values were 0.552 (ALS), 0.452 (Rigo) for X-ray images and 0.494 (ALS), 0.518 (Rigo) for the photographs. The average intra-observer ICC value was 0.720 (ALS), 0.581 (Rigo) for the X-ray images and 0.726 (ALS) and 0.467 (Rigo) for the photographs.<br><br>CONCLUSIONS: The results of our study indicate moderate inter-observer reliability for X-ray images using the ALS classification and clinical photographs using the Rigo classification. Intra-observer reliability was moderate to good for X-ray images and clinical photographs using the ALS classification and poor to moderate for X-ray and clinical photographs using the Rigo classification.<br><br>CLINICAL IMPLICATIONS: Pattern classifications assist in creating a plan and indication of correction in specific scoliosis physiotherapy and pattern-specific brace applications and surgical treatment. More sub-types are needed to address the individual patterns of curvature. The optimisation of curve classification will likely reduce failures in diagnosis and treatment.}, }
@article {pmid34858980, year = {2021}, author = {Wang, K and Li, Y and Ren, C and Wang, Y and He, W and Jiang, Y}, title = {Extracellular Vesicles as Innovative Treatment Strategy for Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {754630}, pmid = {34858980}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron degenerative disease, and it is hard to diagnose in the early stage, and treatment means are limited, and the treatment effect is unsatisfactory. Therefore, exploring a new effective treatment strategy is urgently needed for ALS patients. Extracellular vesicles (EVs) are a heterogeneous group of natural membrane vesicles containing many bioactive substances, and they play important roles in the paracrine pathway and exhibit neuroprotection effects. A growing body of evidence shows that EVs have great application potential in diagnosis, treatment, and drug delivery in ALS, and they represent an innovative treatment strategy for ALS. In this review, we will briefly introduce the biogenesis of EVs and focus on discussing the role of EVs in ALS treatment to further enrich and boost the development of EVs as an innovative treatment strategy for ALS.}, }
@article {pmid34858128, year = {2021}, author = {Lee, SH and Cai, M and Yang, EJ}, title = {Anti-inflammatory Effects of a Novel Herbal Extract in the Muscle and Spinal Cord of an Amyotrophic Lateral Sclerosis Animal Model.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {743705}, pmid = {34858128}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex disease characterized by motor neuron loss and muscle atrophy. There is no prominent treatment for ALS as the pathogenic process in the skeletal muscle and spinal cord is complex and multifactorial. Therefore, we investigated the effects of a herbal formula on the multi-target effects in the skeletal muscle and spinal cord in hSOD1[G93A] transgenic mice. We prepared a herbal extract (HE) from Glycyrrhiza uralensis, Atractylodes macrocephala Koidzumi, Panax ginseng, and Astragalus membranaceus. Control and HE-treated mice underwent rotarod and footprint tests. We also performed immunohistochemical and Western blotting analyses to assess expression of inflammation-related and oxidative stress-related proteins in the muscle and spinal cord tissues. We found that the HE increased motor activity and reduced motor neuron loss in hSOD1[G93A] mice. In addition, the HE significantly reduced the levels of inflammatory proteins and oxidative stress-related proteins in the skeletal muscles and spinal cord of hSOD1[G93A] mice. Furthermore, we demonstrated that the HE regulated autophagy function and augmented neuromuscular junction in the muscle of hSOD1[G93A] mice. Based on these results, we propose that the HE formula may be a potential therapeutic strategy for multi-target treatment in complex and multifactorial pathological diseases.}, }
@article {pmid34857917, year = {2022}, author = {Wang, T and Tomas, D and Perera, ND and Cuic, B and Luikinga, S and Viden, A and Barton, SK and McLean, CA and Samson, AL and Southon, A and Bush, AI and Murphy, JM and Turner, BJ}, title = {Ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis.}, journal = {Cell death and differentiation}, volume = {29}, number = {6}, pages = {1187-1198}, pmid = {34857917}, issn = {1476-5403}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Cell Death/physiology ; Disease Models, Animal ; *Ferroptosis ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is caused by selective degeneration of motor neurons in the brain and spinal cord; however, the primary cell death pathway(s) mediating motor neuron demise remain elusive. We recently established that necroptosis, an inflammatory form of regulated cell death, was dispensable for motor neuron death in a mouse model of ALS, implicating other forms of cell death. Here, we confirm these findings in ALS patients, showing a lack of expression of key necroptotic effector proteins in spinal cords. Rather, we uncover evidence for ferroptosis, a recently discovered iron-dependent form of regulated cell death, in ALS. Depletion of glutathione peroxidase 4 (GPX4), an anti-oxidant enzyme and central repressor of ferroptosis, occurred in post-mortem spinal cords of both sporadic and familial ALS patients. GPX4 depletion was also an early and universal feature of spinal cords and brains of transgenic mutant superoxide dismutase 1 (SOD1[G93A]), TDP-43 and C9orf72 mouse models of ALS. GPX4 depletion and ferroptosis were linked to impaired NRF2 signalling and dysregulation of glutathione synthesis and iron-binding proteins. Novel BAC transgenic mice overexpressing human GPX4 exhibited high GPX4 expression localised to spinal motor neurons. Human GPX4 overexpression in SOD1[G93A] mice significantly delayed disease onset, improved locomotor function and prolonged lifespan, which was attributed to attenuated lipid peroxidation and motor neuron preservation. Our study discovers a new role for ferroptosis in mediating motor neuron death in ALS, supporting the use of anti-ferroptotic therapeutic strategies, such as GPX4 pathway induction and upregulation, for ALS treatment.}, }
@article {pmid34856358, year = {2022}, author = {Tak, YJ and Kang, S}, title = {The E2 ubiquitin-conjugating enzyme HIP2 is a crucial regulator of quality control against mutant SOD1 proteotoxicity.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1868}, number = {2}, pages = {166316}, doi = {10.1016/j.bbadis.2021.166316}, pmid = {34856358}, issn = {1879-260X}, mesh = {Animals ; Female ; HEK293 Cells ; Humans ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism/*pathology ; Mutant Proteins/genetics/*metabolism ; *Mutation ; Quality Control ; Superoxide Dismutase-1/genetics/*metabolism ; Ubiquitin/*metabolism ; Ubiquitin-Conjugating Enzymes/genetics/*metabolism ; Ubiquitination ; }, abstract = {Mutations in superoxide dismutase 1 (SOD1) leading to the formation of intracellular protein aggregates cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by a selective degeneration of motor neurons. The ALS-linked mutant SOD1 emerged as a possible target for ubiquitin-proteasome system (UPS)-mediated degradation. We aimed to elucidate the role of huntingtin interaction protein 2 (HIP2), an E2 ubiquitin-conjugating enzyme, in the proteotoxicity of mutant SOD1 aggregates. We found that HIP2 interacts with mutant SOD1, but not wild-type SOD1, and is upregulated in response to mutant SOD1 expression. Upregulation of HIP2 protein was observed in the spinal cord of 16-week-old SOD1-G93A transgenic mice. HIP2 further modified mutant SOD1 proteins via K48-linked polyubiquitination and degraded mutant SOD1 proteins through the UPS. Upregulation of HIP2 protected cells from mutant SOD1-induced toxicity. Taken together, our findings demonstrate that HIP2 is a crucial regulator of quality control against the proteotoxicity of mutant SOD1. Our results suggest that modulating HIP2 may represent a novel therapeutic strategy for the treatment of ALS.}, }
@article {pmid34846519, year = {2021}, author = {Ravichandran, KA and Heneka, MT}, title = {Inflammasome activation in neurodegenerative diseases.}, journal = {Essays in biochemistry}, volume = {65}, number = {7}, pages = {885-904}, doi = {10.1042/EBC20210021}, pmid = {34846519}, issn = {1744-1358}, mesh = {Amyloid beta-Peptides/metabolism ; Animals ; Humans ; *Inflammasomes/metabolism ; Mice ; Microglia/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Approximately ten million people are diagnosed with dementia annually since they experience difficulties with memory and thinking skills. Since neurodegenerative diseases are diagnosed late, most of them are difficult to treat. This is due to the increased severity of the disease during the progression when neuroinflammation plays a critical role. The activation of immune cells, especially microglia, plays a crucial role in the development of neurodegenerative diseases. Molecular sensors within these microglia, such as the NLRP3 inflammasome, are activated by signals that represent the hallmarks of neurodegenerative diseases. Here, we first summarize the two activation steps of NLRP3 inflammasome activation. Furthermore, we discuss the key factors that contribute to NLRP3 inflammasome activation in the different neuroinflammatory diseases, like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). The prominent NLRP3 inflammasome triggers include amyloid β and tau oligomers in AD, α-synuclein in PD, and superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP43) in ALS. NLRP3 inhibitor treatment has shown promising results in several preclinical mouse models of AD, PD, and ALS. Finally, we postulate that current understandings underpin the potential for NLRP3 inhibitors as a therapeutic target in neurodegenerative diseases.}, }
@article {pmid34841782, year = {2021}, author = {Tang, Q and Cao, L}, title = {[Intestinal flora and neurological disorders].}, journal = {Sheng wu gong cheng xue bao = Chinese journal of biotechnology}, volume = {37}, number = {11}, pages = {3757-3780}, doi = {10.13345/j.cjb.210253}, pmid = {34841782}, issn = {1872-2075}, mesh = {*Autism Spectrum Disorder ; Brain ; *Gastrointestinal Microbiome ; Humans ; *Microbiota ; *Nervous System Diseases ; }, abstract = {The human intestinal flora is a highly diverse ecosystem composed of trillions of bacteria. The imbalance of the flora is related to a variety of diseases. The intestinal flora interacts with the nervous system bidirectionally in many ways through the gut-brain axis. It causes neuroimmune inflammatory response, dysfunction of gut mucosa and blood-brain barrier, direct stimulation of the vagus nerve, spinal nerve of the enteric nervous system, and the neuroendocrine hypothalamus-pituitary-adrenal axis, causing neurological disorders. The metabolites of the intestinal microbial community also play a role. This article summarizes the characteristics of the altered intestinal flora and intervention measures in autism spectrum disorder, multiple sclerosis, Parkinson's disease, epilepsy, Guillain-Barré syndrome, Alzheimer's disease, neuromyelitis optica, hepatic encephalopathy, amyotrophic lateral sclerosis, schizophrenia, depression, chronic fatigue syndrome, Huntington's disease and stroke. The current research on intestinal flora is still in its infancy, and very few studies were carried out on causality and the underlying mechanisms, which prevents the development of precise flora-based clinical intervention measures. It is expected the research on intestinal flora would lead to novel approaches for treatment of some neurological disorders.}, }
@article {pmid34837216, year = {2022}, author = {Park, H and Kim, MK and Malandraki, GA and Lee, CH}, title = {Fabrication of Skin-Mountable Flexible Sensor Patch for Monitoring of Swallowing Function.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2393}, number = {}, pages = {863-876}, pmid = {34837216}, issn = {1940-6029}, mesh = {*Deglutition ; *Deglutition Disorders/diagnosis ; Electromyography ; Humans ; Movement ; Parkinson Disease ; }, abstract = {Swallowing is a critical function that enables humans to sustain life. When swallowing is compromised, the consequences can be devastating and include malnutrition, dehydration, respiratory compromise, and even death. Swallowing disorders (i.e., dysphagia) are very common in many disorders and diseases, such as stroke, ALS, Parkinson disease, and more, and in fact millions of people across the world are diagnosed with oropharyngeal swallowing disorders every year. Current rehabilitative interventions for dysphagia can be effective, but require daily performance of swallowing exercises that primarily rely on expensive biofeedback devices (e.g., oral manometers, electromyographic (EMG) devices, and endoscopic devices). These types of devices are often only available in medical facilities. However, it is not feasible or economically viable for patients to make multiple visits per day or week to a clinic to receive intensive treatment, especially given mobility limitations that many affected patients often experience. This can reduce treatment adherence and result in decreased rehabilitation potential, re-hospitalizations, and increased healthcare costs. To address this gap, we designed a novel specialized portable skin-mounted flexible sensor system that allows remote signal acquisition of swallowing-related signals. Herein, we report technical details for the fabrication of the skin-mounted flexible sensor patch that is tailored for the human submental (under the chin) area, enabling the continuous, reliable monitoring of both muscles' activity (i.e., EMG signals) and laryngeal movements during swallowing events. The sensor patch is wired to a portable reusable wireless (Bluetooth) unit compatible with smart watches, phones, and tablets for post-data analysis and reporting through a cloud server, which would potentially enable telemonitoring of patients with dysphagia.}, }
@article {pmid34836184, year = {2021}, author = {Zhang, N and Liu, J and Guo, X and Li, S and Wang, F and Wang, M}, title = {Armillaria luteo-virens Sacc Ameliorates Dextran Sulfate Sodium Induced Colitis through Modulation of Gut Microbiota and Microbiota-Related Bile Acids.}, journal = {Nutrients}, volume = {13}, number = {11}, pages = {}, pmid = {34836184}, issn = {2072-6643}, support = {CARS-04//the Knowledge Innovation Program Funding of Institute of Food Science and Technology/ ; }, mesh = {Agaricales ; Animals ; *Armillaria ; Bile Acids and Salts/*metabolism ; Colitis/*drug therapy/metabolism ; Colon/metabolism/pathology ; Dextran Sulfate/adverse effects ; Disease Models, Animal ; Gastrointestinal Microbiome/*drug effects ; Inflammation/metabolism ; Male ; Mice ; NF-kappa B/metabolism ; Phytotherapy/*methods ; Plant Preparations/*pharmacology ; RNA, Ribosomal, 16S/metabolism ; }, abstract = {Armillaria luteo-virens Sacc (ALS) is a rare wild Chinese medicinal and edible basidiomycete. However, its protective effect on intestinal functions and the underlying mechanism is still unknown. This work explored the improvement of dextran sulfate sodium (DSS)-induced colitis by ALS. ALS supplementation markedly improved colitis symptoms, gut barrier integrity, and goblet loss in DSS-treated mice. In addition, ALS inhibited colonic inflammation through the inhibition/activation of the mitogen-activated protein kinases/NF-κB signaling pathway. The 16S rRNA gene-based microbiota analysis revealed that ALS altered the gut microbiota composition, decreasing the richness of Enterobacteriaceae and increasing the abundance of Lactobacillaceae. The bile-acid-targeted metabolomic analysis showed that ALS recovered the microbial bile acid metabolism in the gut, enabling the activation of the farnesoid X receptor signaling by these acids, thus maintaining the intestinal homeostasis. Importantly, broad-spectrum antibiotic treatment reduced the efficacy of ALS-induced protection from colitis. Overall, our findings suggest that ALS may represent a novel approach in the nutritional intervention to prevent colitis.}, }
@article {pmid34835493, year = {2021}, author = {Zhang, Q and Li, J and Lu, W and Zhao, J and Zhang, H and Chen, W}, title = {Multi-Omics Reveals the Inhibition of Lactiplantibacillus plantarum CCFM8724 in Streptococcus mutans-Candida albicans Mixed-Species Biofilms.}, journal = {Microorganisms}, volume = {9}, number = {11}, pages = {}, pmid = {34835493}, issn = {2076-2607}, support = {32072197&#xff0c;32021005//National Natural Science Foundation of China/ ; }, abstract = {Lactiplantibacillus plantarum CCFM8724 is a probiotic with the potential to prevent dental caries in vitro and in vivo. To explore the effects of this probiotic at inhibiting Streptococcus mutans-Candida albicans mixed-species biofilm and preventing dental caries, multi-omics, including metabolomics and transcriptomics, was used to investigate the regulation of small-molecule metabolism during biofilm formation and the gene expression in the mixed-species biofilm. Metabolomic analysis revealed that some carbohydrates related to biofilm formation, such as sucrose, was detected at lower levels due to the treatment with the L. plantarum supernatant. Some sugar alcohols, such as xylitol and sorbitol, were detected at higher levels, which may have inhibited the growth of S. mutans. In transcriptomic analysis, the expression of the virulence genes of C. albicans, such as those that code agglutinin-like sequence (Als) proteins, was affected. In addition, metabolomics coupled with a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and RNA-seq revealed that the L. plantarum supernatant had an active role in sugar metabolism during the formation of the S. mutans-C. albicans mixed-species biofilm, and the L. plantarum supernatant was also related to carbohydrate utilization, glucan biosynthesis, and mycelium formation. Hence, L. plantarum CCFM8724 decreased the mixed-species biofilm mass from the perspective of gene expression and metabolic reprogramming. Our results provide a rationale for evaluating L. plantarum CCFM8724 as a potential oral probiotic for inhibiting cariogenic pathogen biofilm formation and improving dental caries.}, }
@article {pmid34819914, year = {2021}, author = {Cook, SF and Rhodes, T and Schlusser, C and Han, S and Chen, C and Zach, N and Murthy, V and Davé, S}, title = {A Descriptive Review of Global Real World Evidence Efforts to Advance Drug Discovery and Clinical Development in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {770001}, pmid = {34819914}, issn = {1664-2295}, abstract = {Understanding patient clinical progression is a key gateway to planning effective clinical trials and ultimately enabling bringing treatments to patients in need. In a rare disease like amyotrophic lateral sclerosis (ALS), studies of disease natural history critically depend on collaboration between clinical centers, regions, and countries to enable creation of platforms to allow patients, caregivers, clinicians, and researchers to come together and more fully understand the condition. Rare disease registries and collaborative platforms such as those developed in ALS collect real-world data (RWD) in standardized formats, including clinical and biological specimen data used to evaluate risk factors and natural history of disease, treatment patterns and clinical (ClinROs) and patient- reported outcomes (PROs) and validate novel endpoints. Importantly, these data support the development of new therapeutics by supporting the evaluation of feasibility and design of clinical trials and offer valuable information on real-world disease trajectory and outcomes outside of the clinical trial setting for comparative purposes. RWD may help to accelerate therapy development by identifying and validating outcome measures and disease subpopulations. RWD can also make potential contributions to the evaluation of the safety and effectiveness of new indications for approved products and to satisfy post-approval regulatory and market access requirements. There is a lack of amalgamated information on available registries, databases, and other sources of real-world data on ALS; thus, a global review of all available resources was warranted. This targeted review identifies and describes ALS registries, biobanks and collaborative research networks that are collecting and synthesizing RWD for the purposes of increasing patient awareness and advancing scientific knowledge with the hope of expediting future development of new therapies.}, }
@article {pmid34817079, year = {2022}, author = {Gotesman, RD and Lalonde, E and McKim, DA and Bourque, PR and Warman-Chardon, J and Zwicker, J and Breiner, A}, title = {Laryngospasm in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {65}, number = {4}, pages = {400-404}, doi = {10.1002/mus.27466}, pmid = {34817079}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; Dyspnea ; Female ; Humans ; *Laryngismus/complications/epidemiology ; Male ; Middle Aged ; Respiration ; Vocal Cords ; }, abstract = {INTRODUCTION: Laryngospasm is an involuntary, sustained closure of sphincter musculature that leads to an unpleasant subjective experience of dyspnea and choking. It is an underreported symptom in amyotrophic lateral sclerosis (ALS). In this study we aimed to better characterize the prevalence and clinical characteristics of laryngospasm in ALS patients.<br><br>METHODS: The medical records of 571 patients with ALS followed between 2008 and 2018 were searched for evidence of laryngospasm. A total of 23 patients with laryngospasm were identified and the data related to patient and laryngospasm characteristics were extracted.<br><br>RESULTS: Laryngospasm was reported in 4% of ALS patients. Females comprised 57% of patients and their mean age was 63.4&#x2009;years. Laryngospasm frequently manifested in patients with moderate bulbar dysfunction and seemed independent of respiratory function. Among laryngospasm patients, 26% were cigarette smokers and 13% had a history of gastroesophageal reflux. The most common reported trigger was excessive saliva irritating the vocal cords (35%) followed by eating a meal (17%). There was significant variation in laryngospasm frequency (up to 5 per hour) and duration (seconds to minutes). Most patients could not identify an effective coping mechanism, although 13% reported that drinking water was effective.<br><br>DISCUSSION: Despite its low prevalence in ALS, laryngospasm should be included in the symptom inquiry. The present findings may improve patient care through increased recognition of the clinical features of laryngospasm in ALS patients, identifying a link between laryngospasm and moderate bulbar dysfunction, and highlighting trigger avoidance as a management strategy. Additional research is required to understand the pathophysiology and optimal treatment.}, }
@article {pmid34816454, year = {2022}, author = {Brooks, BR and Pioro, EP and Katz, J and Takahashi, F and Takei, K and Zhang, J and Apple, S}, title = {Slowing the loss of physical function in amyotrophic lateral sclerosis with edaravone: Post hoc analysis of ALSFRS-R item scores in pivotal study MCI186-19.}, journal = {Muscle &amp; nerve}, volume = {65}, number = {2}, pages = {180-186}, pmid = {34816454}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Edaravone/therapeutic use ; Humans ; Quality of Life ; Surveys and Questionnaires ; }, abstract = {INTRODUCTION: Phase 3 study MCI186-19 demonstrated less loss of physical function with edaravone versus placebo, as measured by the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score. A 1-point drop in an individual ALSFRS-R item may be clinically meaningful. We assessed ALSFRS-R item score changes to identify clinical features protected by edaravone treatment.<br><br>METHODS: Time-to-event analysis was used to assess the cumulative probabilities of reductions in ALSFRS-R item scores and Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) subdomain scores.<br><br>RESULTS: Edaravone use was accompanied by: (1) delayed drop of &#x2265;1 point in ALSFRS-R item score for four items: salivation, walking, climbing stairs, orthopnea (unadjusted), or for two items: walking, climbing stairs (after Bonferroni correction for multiple comparisons); (2) delayed score transition from 4 or 3 at baseline to &#x2264;2 for five items: swallowing, eating motion, walking, climbing stairs, orthopnea (unadjusted), or for one item: climbing stairs (after Bonferroni correction for multiple comparisons); and (3) delayed worsening of ALSAQ-40 domain scores representing daily living/independence, eating and drinking (unadjusted).<br><br>DISCUSSION: These post-hoc analyses identified the ALSFRS-R item scores and ALSAQ-40 domain scores that were associated with preserved gross motor function and health-related quality of life, respectively, after edaravone treatment. Limitations of post-hoc analyses should be considered when interpreting these results. We recommend that clinical trials employing the ALSFRS-R include this type of analysis as a pre-specified secondary outcome measure.}, }
@article {pmid34813019, year = {2022}, author = {Guan, L and Han, Y and Yang, C and Lu, S and Du, J and Li, H and Lin, J}, title = {CRISPR-Cas9-Mediated Gene Therapy in Neurological Disorders.}, journal = {Molecular neurobiology}, volume = {59}, number = {2}, pages = {968-982}, pmid = {34813019}, issn = {1559-1182}, support = {81801127//National Natural Science Foundation of China/ ; 81771226//National Natural Science Foundation of China/ ; 81800792//National Natural Science Foundation of China/ ; U1804186//National Natural Science Foundation of China/ ; 202300410307//Natural Science Foundation of Henan Province for Distinguished Young Scholars/ ; 19IRTSTHN003//Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province/ ; 212102310215//Henan Province Science and Technology Project/ ; 20172DCG-03//Major Cultivation Plan of Scientific and Technological Achievements from Natural Science class of Xinxiang Medical University/ ; 21A180023//Key Scientific Research Program of Higher Education in Henan Province/ ; GG2019009//Xinxiang Scientific and Technological Project/ ; XYBSKYZZ201523//Doctoral Scientific Research Program Foundation of Xinxiang Medical University/ ; ZDSYS2015004//Open Program of Henan Key Lab of Biological Psychiatry/ ; }, mesh = {*CRISPR-Cas Systems/genetics ; Gene Editing ; Genetic Therapy ; Humans ; *Muscular Dystrophy, Duchenne ; }, abstract = {Neurological disorders are primarily diseases with sophisticated etiology that are always refractory and recrudescent. The major obstruction to effective therapies for neurological disorders is the poor understanding of their pathogenic mechanisms. CRISPR-Cas9 technology, which allows precise and effective gene editing in almost any cell type and organism, is accelerating the pace of basic biological research. An increasing number of groups are focusing on uncovering the molecular mechanisms of neurological disorders and developing novel therapies using the CRISPR-Cas9 system. This review highlights the application of CRISPR-Cas9 technology in the treatment of neurological disorders, including Alzheimer's disease, amyotrophic lateral sclerosis and/or frontotemporal dementia, Duchenne muscular dystrophy, Dravet syndrome, epilepsy, Huntington's disease, and Parkinson's disease. Hopefully, it will improve our understanding of neurological disorders and give insights into future treatments for neurological disorders.}, }
@article {pmid34810096, year = {2022}, author = {Berge, M and Dowek, A and Prognon, P and Legrand, FX and Tfayli, A and Minh Mai Lê, L and Caudron, E}, title = {Optimization of experimental conditions by surface enhanced Raman Scattering (SERS) spectroscopy with gold nanoparticles suspensions.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {268}, number = {}, pages = {120628}, doi = {10.1016/j.saa.2021.120628}, pmid = {34810096}, issn = {1873-3557}, mesh = {*Gold ; *Metal Nanoparticles ; Spectrum Analysis, Raman ; Suspensions ; }, abstract = {Surface Enhanced Raman Scattering (SERS) spectroscopy is a rapid and innovative analysis technique involving metallic nanoparticles (NPs). The interaction between NPs and norepinephrine gives an exaltation of the Raman signal under certain experimental conditions. The control of the signal exaltation, crucial for sensitive analyses, remains one of the main limitations of this technique. The aim of this work is to optimize the exaltation conditions for an optimal SERS signal at two concentrations of norepinephrine (NOR) and spherical gold NPs in suspension. This first work will fix the optimal experimental conditions essential for the development of robust discriminant and quantitative analysis of catecholamine. Two complete 3-factors 3-levels experiment designs were performed at 20 µg.mL[-1] and 100 µg.mL[-1] norepinephrine concentrations, each experiment being repeated 3 times. The optimization factors were the process of synthesis (variation of the quantity of gold and citrate used for the three synthesis SA, SB and SC) and HCl (0.3 M, 0.5 M, 0.7 M) as well as the volume ratio of NPs and norepinephrine (0.5, 2, 3.5) for SERS acquisition. Spectral acquisitions were performed with a handheld Raman spectrometer with an excitation source at 785 nm. For each sample, 31 acquisitions were realized during 3 s every 8 s. The optimization parameter was the intensity of the characteristic band of norepinephrine at 1280 cm[-1]. A total of 5,042 spectra were acquired and the pre-treatment selected for all spectra was asymmetric least square combined to a smoothing of Savistsky Golay (ALS - SG). The optimal contact time between norepinephrine and NPs depends on the experimental conditions and was determined for each experiment according to the mean intensity between the three replicates. After interpretation of the experimental designs, the optimal conditions retained were the quantity of gold corresponding to SA and the HCl concentration 0.7 M for the two concentrations of norepinephrine. Indeed, the optimal volume ratio depend on the NOR concentration.}, }
@article {pmid34803894, year = {2021}, author = {Falcão de Campos, C and Gromicho, M and Uysal, H and Grosskreutz, J and Kuzma-Kozakiewicz, M and Oliveira Santos, M and Pinto, S and Petri, S and Swash, M and de Carvalho, M}, title = {Delayed Diagnosis and Diagnostic Pathway of ALS Patients in Portugal: Where Can We Improve?.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {761355}, pmid = {34803894}, issn = {1664-2295}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with unsatisfactory treatment options. Best management and recruitment into clinical trials requires early diagnosis. However, diagnosis is often delayed. Analysis of the diagnostic pathway and identification of the causes of diagnostic delay are imperative. Methods: We studied a cohort of 580 ALS patients followed up in our ALS clinic in Lisbon. Demographic, disease, and sociocultural factors were collected. Time from first symptom onset to diagnosis, the specialist's assessment, and investigations requested were analyzed. Predictors of diagnostic delay were evaluated by multivariate linear regression, adjusting for potential confounders. Results: The median diagnostic delay from first symptom onset was 10 months. Spinal-onset, slower disease progression, cognitive symptoms at onset, and lower income were associated with increased diagnostic delay. Most patients were first assessed by general practitioners. Patients who were first evaluated by a neurologist were more likely to be correctly diagnosed, decreasing time to diagnosis. Electromyography was decisive in establishing the diagnosis. Conclusions: Late referral from non-neurologists to a neurologist is a potentially modifiable factor contributing to significant diagnostic delay. Educational interventions targeted to non-neurologists physicians, in order to increase awareness of ALS and, consequently, promote early referral to a neurologist at a tertiary center, will be important in reducing diagnostic delay.}, }
@article {pmid34802899, year = {2021}, author = {Cougnoux, A and Yerger, JC and Fellmeth, M and Serra-Vinardell, J and Navid, F and Wassif, CA and Cawley, NX and Porter, FD}, title = {Reduction of glutamate neurotoxicity: A novel therapeutic approach for Niemann-Pick disease, type C1.}, journal = {Molecular genetics and metabolism}, volume = {134}, number = {4}, pages = {330-336}, pmid = {34802899}, issn = {1096-7206}, support = {ZIA HD008988/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Astrocytes/metabolism ; Ceftriaxone/*therapeutic use ; Cells, Cultured ; Disease Models, Animal ; Excitatory Amino Acid Transporter 1/physiology ; Female ; Glutamic Acid/metabolism/*toxicity ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Niemann-Pick C1 Protein/physiology ; Niemann-Pick Disease, Type C/*drug therapy ; Riluzole/*therapeutic use ; }, abstract = {Niemann-Pick disease, type C1 is a progressive, lethal, neurodegenerative disorder due to endolysosomal storage of unesterified cholesterol. Cerebellar ataxia, as a result of progressive loss of cerebellar Purkinje neurons, is a major symptom of Nieman-Pick disease, type C1. Comparing single cell RNAseq data from control (Npc1[+/+]) and mutant (Npc1[-/-]) mice, we observed significantly decreased expression of Slc1a3 in Npc1[-/-] astrocytes. Slc1a3 encodes a glutamate transporter (GLAST, EAAT1) which functions to decrease glutamate concentrations in the post synaptic space after neuronal firing. Glutamate is an excitatory neurotransmitter and elevated extracellular levels of glutamate can be neurotoxic. Impaired EAAT1 function underlies type-6 episodic ataxia, a rare disorder with progressive cerebellar dysfunction, thus suggesting that impaired glutamate uptake in Niemann-Pick disease, type C1 could contribute to disease progression. We now show that decreased expression of Slc1a3 in Npc1[-/-] mice has functional consequences that include decreased surface protein expression and decreased glutamate uptake by Npc1[-/-] astrocytes. To test whether glutamate neurotoxicity plays a role in Niemann-Pick disease, type C1 progression, we treated NPC1 deficient mice with ceftriaxone and riluzole. Ceftriaxone is a β-lactam antibiotic that is known to upregulate the expression of Slc1a2, an alternative glial glutamate transporter. Although ceftriaxone increased Slc1a2 expression, we did not observe a treatment effect in NPC1 mutant mice. Riluzole is a glutamate receptor antagonist that inhibits postsynaptic glutamate receptor signaling and reduces the release of glutamate. We found that treatment with riluzole increased median survival in Npc1[-/-] by 12%. Given that riluzole is an approved drug for the treatment of amyotrophic lateral sclerosis, repurposing of this drug may provide a novel therapeutic approach to decrease disease progression in Niemann-Pick disease type, C1 patients.}, }
@article {pmid34801512, year = {2022}, author = {Dhasmana, S and Dhasmana, A and Narula, AS and Jaggi, M and Yallapu, MM and Chauhan, SC}, title = {The panoramic view of amyotrophic lateral sclerosis: A fatal intricate neurological disorder.}, journal = {Life sciences}, volume = {288}, number = {}, pages = {120156}, doi = {10.1016/j.lfs.2021.120156}, pmid = {34801512}, issn = {1879-0631}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*therapy ; Animals ; Humans ; Nervous System Diseases/*pathology/*therapy ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disease affecting both upper and lower motor neurons. In the United States alone, there are 16,000-20,000 established cases of ALS. The early disease diagnosis is challenging due to many overlapping pathophysiologies with other neurological diseases. The etiology of ALS is unknown; however, it is divided into two categories: familial ALS (fALS) which occurs due to gene mutations &amp; contributes to 5-10% of ALS, and sporadic ALS (sALS) which is due to environmental factors &amp; contributes to 90-95% of ALS. There is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. In this review, we provide a panoramic view of ALS, which includes epidemiology, risk factors, pathophysiologies, biomarkers, diagnosis, therapeutics (natural, synthetic, gene-based, pharmacological, stem cell, extracellular vesicles, and physical therapy), controversies (in the clinical trials of ALS), the scope of nanomedicine in ALS, and future perspectives.}, }
@article {pmid34791571, year = {2022}, author = {Povedano, M and Paipa, A and Barceló, M and Woodward, MK and Ortega, S and Domínguez, R and Aragonés, ME and Horrillo, R and Costa, M and Páez, A}, title = {Plasma exchange with albumin replacement and disease progression in amyotrophic lateral sclerosis: a pilot study.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {43}, number = {5}, pages = {3211-3221}, pmid = {34791571}, issn = {1590-3478}, mesh = {Adult ; Albumins ; *Amyotrophic Lateral Sclerosis ; Disease Progression ; Humans ; Pilot Projects ; Plasma Exchange ; Prospective Studies ; }, abstract = {BACKGROUND: Plasma exchange (PE) is used to treat a range of neurological disorders. Based on results demonstrated in Alzheimer's disease, we theorized that PE with albumin replacement (PE-A) might alter the metabolic profile of plasma and cerebrospinal fluid in patients with amyotrophic lateral sclerosis (ALS) by removing disease-inducing molecules. The aim of this study was to evaluate the effect of PE-A on disease progression in ALS.<br><br>METHODS: In this open-label, non-controlled, single-arm, prospective pilot study, 13 adults with ALS had 6&#xa0;months' treatment with PE-A 5% and 6&#xa0;months' follow-up. Primary endpoints were changes from baseline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score and forced vital capacity (FVC) through 48&#xa0;weeks. A post hoc analysis compared individual patient data with the expected ALSFRS-R progression slope.<br><br>RESULTS: The median ALSFRS-R score declined throughout the study, although the rate of decline was slower than expected in seven patients at treatment end and in five patients at study end. Six patients remained in the same baseline slope progression category, and four patients improved their slope category at treatment end. Median FVC decreased significantly during the study. Treatment was well tolerated. Of 330 PE-A procedures, 0.9% were associated with potentially related adverse events.<br><br>CONCLUSION: Although functional impairment progressed, about two-thirds of patients showed a slower than expected rate of decline at treatment end. Most patients had unaltered (54.5%) or reduced (36.4%) ALSFRS-R slope progression at treatment end. Further evaluation of PE-A in controlled studies involving more patients is warranted.<br><br>EUDRACT NUMBER: 2013-004842-40.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02479802.}, }
@article {pmid34788013, year = {2021}, author = {Bennett, SA and Cobos, SN and Mirzakandova, M and Fallah, M and Son, E and Angelakakis, G and Rana, N and Hugais, M and Torrente, MP}, title = {Trichostatin A Relieves Growth Suppression and Restores Histone Acetylation at Specific Sites in a FUS ALS/FTD Yeast Model.}, journal = {Biochemistry}, volume = {60}, number = {48}, pages = {3671-3675}, pmid = {34788013}, issn = {1520-4995}, support = {K22 NS091314/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylation/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy/*genetics ; Epigenesis, Genetic ; Frontotemporal Dementia/drug therapy/*genetics ; Histone Code/genetics ; Histones/genetics/*metabolism ; Humans ; Hydroxamic Acids/*pharmacology ; Mutation/genetics ; Neurons/drug effects/pathology ; Protein Aggregates/genetics ; Protein Aggregation, Pathological/genetics ; RNA-Binding Protein FUS/*genetics ; Saccharomyces cerevisiae/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that often occurs concurrently with frontotemporal dementia (FTD), another disorder involving progressive neuronal loss. ALS and FTD form a neurodegenerative continuum and share pathological and genetic features. Mutations in a multitude of genes have been linked to ALS/FTD, including FUS. The FUS protein aggregates and forms inclusions within affected neurons. However, the precise mechanisms connecting protein aggregation to neurotoxicity remain under intense investigation. Recent evidence points to the contribution of epigenetics to ALS/FTD. A main epigenetic mechanism involves the post-translational modification (PTM) of histone proteins. We have previously characterized the histone PTM landscape in a FUS ALS/FTD yeast model, finding a decreased level of acetylation on lysine residues 14 and 56 of histone H3. Here, we describe the first report of amelioration of disease phenotypes by controlling histone acetylation on specific modification sites. We show that inhibiting histone deacetylases, via treatment with trichostatin A, suppresses the toxicity associated with FUS overexpression in yeast by preserving the levels of H3K56ac and H3K14ac without affecting the expression or aggregation of FUS. Our data raise the novel hypothesis that the toxic effect of protein aggregation in neurodegeneration is related to its association with altered histone marks. Altogether, we demonstrate the ability to counter the repercussions of protein aggregation on cell survival by preventing specific histone modification changes. Our findings launch a novel mechanistic framework that will enable alternative therapeutic approaches for ALS/FTD and other neurodegenerative diseases.}, }
@article {pmid34787317, year = {2022}, author = {Takacs, SM and Comer, AR}, title = {Documentation of advance care planning forms in patients with amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {65}, number = {2}, pages = {187-192}, doi = {10.1002/mus.27462}, pmid = {34787317}, issn = {1097-4598}, mesh = {*Advance Care Planning ; *Amyotrophic Lateral Sclerosis/therapy ; Documentation ; Humans ; Palliative Care ; Retrospective Studies ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive weakness. Survival is typically only a few years from symptom onset. The often-predictable disease course creates opportunities to complete advance care planning (ACP) forms. The Physician Orders for Life-Sustaining Treatment (POLST) is a broadly used ACP paradigm to communicate end-of-life wishes but has not been well-studied in the ALS population.<br><br>METHODS: In this retrospective chart review study, patients diagnosed with ALS seen between 2014 and 2018 at an academic ALS center were identified. Demographic information, clinical characteristics, and ACP data were collected.<br><br>RESULTS: Of 513 patients identified, 30% had an ACP document. POLST forms were competed in 16.6% of patients with 73.8% of forms signed by a neurologist. Only 5.1% of patients saw a palliative care physician. Palliative care consultation was associated with having an POLST on file (P&#xa0;<&#x2009;.001). Patients with completed POLST forms were significantly more likely to have been seen in clinic more frequently (P&#xa0;<&#x2009;.001) and have a lower ALS Functional Rating Scale-Revised score on last visit (P&#xa0;=&#x2009;.005).<br><br>DISCUSSION: Less than one third of patients with ALS completed an ACP document, and only a small percentage completed POLST forms. The data suggest a need for greater documentation of goals of care in the ALS population.}, }
@article {pmid34786257, year = {2021}, author = {Jaber, J and Magadle, N and Arda, L and Somoza-Cano, FJ}, title = {Massive Incidental Pneumoperitoneum in an Amyotrophic Lateral Sclerosis Patient.}, journal = {Cureus}, volume = {13}, number = {10}, pages = {e18678}, pmid = {34786257}, issn = {2168-8184}, abstract = {In this report, we present the case of a 61-year-old male patient diagnosed with amyotrophic lateral sclerosis (ALS), who presented to the ER with worsening shortness of breath, several hours following elective percutaneous endoscopic gastrostomy (PEG) tube placement. During his hospitalization, he was diagnosed with massive pneumoperitoneum, a potential complication of such procedures. We aim to provide a general overview of this condition and to discuss the special considerations in the treatment of ALS.}, }
@article {pmid34783031, year = {2022}, author = {Scaricamazza, S and Salvatori, I and Amadio, S and Nesci, V and Torcinaro, A and Giacovazzo, G and Primiano, A and Gloriani, M and Candelise, N and Pieroni, L and Loeffler, JP and Renè, F and Quessada, C and Tefera, TW and Wang, H and Steyn, FJ and Ngo, ST and Dobrowolny, G and Lepore, E and Urbani, A and Musarò, A and Volonté, C and Ferraro, E and Coccurello, R and Valle, C and Ferri, A}, title = {Repurposing of Trimetazidine for amyotrophic lateral sclerosis: A study in SOD1[G93A] mice.}, journal = {British journal of pharmacology}, volume = {179}, number = {8}, pages = {1732-1752}, pmid = {34783031}, issn = {1476-5381}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Disease Models, Animal ; Drug Repositioning ; Female ; Male ; Mice ; Mice, Transgenic ; *Neurodegenerative Diseases ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics ; *Trimetazidine/pharmacology/therapeutic use ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles and is currently incurable. Although considered to be a pure motor neuron disease, increasing evidence indicates that the sole protection of motor neurons by a single targeted drug is not sufficient to improve the pathological phenotype. We therefore evaluated the therapeutic potential of the multi-target drug used to treatment of coronary artery disease, trimetazidine, in SOD1[G93A] mice.<br><br>EXPERIMENTAL APPROACH: As a metabolic modulator, trimetazidine improves glucose metabolism. Furthermore, trimetazidine enhances mitochondrial metabolism and promotes nerve regeneration, exerting an anti-inflammatory and antioxidant effect. We orally treated SOD1[G93A] mice with trimetazidine, solubilized in drinking water at a dose of 20&#x2009;mg&#x2009;kg[-1] , from disease onset. We assessed the impact of trimetazidine on disease progression by studying metabolic parameters, grip strength and histological alterations in skeletal muscle, peripheral nerves and the spinal cord.<br><br>KEY RESULTS: Trimetazidine administration delays motor function decline, improves muscle performance and metabolism, and significantly extends overall survival of SOD1[G93A] mice (increased median survival of 16&#x2009;days and 12.5&#x2009;days for male and female respectively). Moreover, trimetazidine prevents the degeneration of neuromuscular junctions, attenuates motor neuron loss and reduces neuroinflammation in the spinal cord and in peripheral nerves.<br><br>CONCLUSION AND IMPLICATIONS: In SOD1[G93A] mice, therapeutic effect of trimetazidine is underpinned by its action on mitochondrial function in skeletal muscle and spinal cord.}, }
@article {pmid34781865, year = {2022}, author = {Goyal, S and Seth, B and Chaturvedi, RK}, title = {Polyphenols and Stem Cells for Neuroregeneration in Parkinson's Disease and Amyotrophic Lateral Sclerosis.}, journal = {Current pharmaceutical design}, volume = {28}, number = {10}, pages = {806-828}, doi = {10.2174/1381612827666211115154450}, pmid = {34781865}, issn = {1873-4286}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Nerve Regeneration ; *Neural Stem Cells ; *Parkinson Disease/pathology/therapy ; Polyphenols/pharmacology/therapeutic use ; }, abstract = {Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS) are neurological disorders pathologically characterized by chronic degeneration of dopaminergic neurons and motor neurons, respectively. There is still no cure or effective treatment against the disease progression and most of the treatments are symptomatic. The present review offers an overview of the different factors involved in the pathogenesis of these diseases. Subsequently, we focused on the recent advanced studies of dietary polyphenols and stem cell therapies, which have made it possible to slow down the progression of neurodegeneration. To date, stem cells and different polyphenols have been used for the directional induction of neural stem cells into dopaminergic neurons and motor neurons. We have also discussed their involvement in the modulation of different signal transduction pathways and growth factor levels in various in vivo and in vitro studies. Likewise stem cells, polyphenols also exhibit the potential of neuroprotection by their anti-apoptotic, anti-inflammatory, and anti-oxidant properties regulating the growth factors levels and molecular signaling events. Overall this review provides a detailed insight into recent strategies that promise the use of polyphenol with stem cell therapy for the possible treatment of PD and ALS.}, }
@article {pmid34778302, year = {2021}, author = {Izrael, M and Molakandov, K and Revel, A and Slutsky, SG and Sonnenfeld, T and Weiss, JM and Revel, M}, title = {Astrocytes Downregulate Inflammation in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome: Applicability to COVID-19.}, journal = {Frontiers in medicine}, volume = {8}, number = {}, pages = {740071}, pmid = {34778302}, issn = {2296-858X}, abstract = {Background: An acute respiratory distress syndrome (ARDS) is caused by the increased amounts of pro-inflammatory cytokines and neutrophil-mediated tissue injury. To date, there is no effective treatment for the ARDS available, while the need for one is growing due to the most severe complications of the current coronavirus disease-2019 (COVID-19) pandemic. The human astrocytes (AstroRx) have shown immunomodulatory properties in the central nervous system (CNS). This study aimed to evaluate the capacity of astrocytes to decrease lung inflammation and to be applied as a treatment therapy in ARDS. Methods: First, we assessed the ability of clinical-grade AstroRx to suppress T-cell proliferation in a mixed lymphocyte reaction test. Next, we tested the therapeutical potential of AstroRx cells in a lipopolysaccharide (LPS)-based ARDS mouse model by injecting AstroRx intravenously (i.v). We determined the degree of lung injury by using a severity scoring scale of 0-2, based on the American Thoracic Society. The scoring measured the presence of neutrophils, fibrin deposits, and the thickening of alveolar walls. The state of inflammation was further assessed by quantifying the immune-cell infiltration to the bronchoalveolar lavage fluid (BALF) and by the presence of proinflammatory cytokines and chemokines in the BALF and serum. Results: We detected that AstroRx cells were capable to suppress T-cell proliferation in vitro after exposure to the mitogen concanavalin A (ConA). In vivo, AstroRx cells were able to lower the degree of lung injury in LPS-treated animals compared with the sham injected animals (P = 0.039). In this study, 30% of AstroRx treated mice showed no lung lesions (responder mice), these mice presented a steady number of eosinophils, T cells, and neutrophils comparable with the level of naïve control mice. The inflammatory cytokines and chemokines, such as TNFα, IL1b, IL-6, and CXCL1, were also kept in check in responder AstroRx-treated mice and were not upregulated as in the sham-injected mice (P < 0.05). As a result, the LPS-treated ARDS mice had a higher survival rate when they were treated with AstroRx. Conclusions: Our results demonstrate that the immunosuppressive activity of AstroRx cells support the application of AstroRx cells as a cell therapy treatment for ARDS. The immunoregulatory activity may also be a part of the mechanism of action of AstroRx reported in the amyotrophic lateral sclerosis (ALS) neurodegenerative disease.}, }
@article {pmid34778276, year = {2021}, author = {Sykova, E and Cizkova, D and Kubinova, S}, title = {Corrigendum: Mesenchymal Stem Cells in Treatment of Spinal Cord Injury and Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {770243}, pmid = {34778276}, issn = {2296-634X}, abstract = {[This corrects the article DOI: 10.3389/fcell.2021.695900.].}, }
@article {pmid34777211, year = {2021}, author = {Huang, B and Li, X and Zhu, X}, title = {The Role of GM130 in Nervous System Diseases.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {743787}, pmid = {34777211}, issn = {1664-2295}, abstract = {Golgi matrix protein 130 (GM130) is a Golgi-shaping protein located on the cis surface of the Golgi apparatus (GA). It is one of the most studied Golgin proteins so far. Its biological functions are involved in many aspects of life processes, including mitosis, autophagy, apoptosis, cell polarity, and directed migration at the cellular level, as well as intracellular lipid and protein transport, microtubule formation and assembly, lysosome function maintenance, and glycosylation modification. Mutation inactivation or loss of expression of GM130 has been detected in patients with different diseases. GM130 plays an important role in the development of the nervous system, but the studies on it are limited. This article reviewed the current research progress of GM130 in nervous system diseases. It summarized the physiological functions of GM130 in the occurrence and development of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), microcephaly (MCPH), sepsis associated encephalopathy (SAE), and Ataxia, aiming to provide ideas for the further study of GM130 in nervous system disease detection and treatment.}, }
@article {pmid34776962, year = {2021}, author = {Zhou, D and Yan, H and Yang, S and Zhang, Y and Xu, X and Cen, X and Lei, K and Xia, H}, title = {SC75741, A Novel c-Abl Inhibitor, Promotes the Clearance of TDP25 Aggregates via ATG5-Dependent Autophagy Pathway.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {741219}, pmid = {34776962}, issn = {1663-9812}, abstract = {Abnormal accumulation of TDP43-related mutant proteins in the cytoplasm causes amyotrophic lateral sclerosis (ALS). Herein, unbiased drug screening approaches showed that SC75741, a multi-target inhibitor, inhibited inflammation-induced aggregation by inhibiting NF-κB and also degraded already aggregated proteins by inhibiting c-Abl mediated autophagy-lysosomal pathway. We delineate the mechanism that SC75741 could markedly enhance TFEB nuclear translocation by an mTORC1-independent TFEB regulatory pathway. In addition, SC75741 enhanced the interaction between p62 with TDP25 and LC3C, thus promoting TDP25 degradation. Taken together, these findings show that SC75741 has beneficial neuroprotective effects in ALS. Our study elucidates that dual-targeted inhibition of c-Abl and NF-κB may be a potential treatment for TDP43 proteinopathies and ALS.}, }
@article {pmid34775697, year = {2021}, author = {Shiomi, H and Sakai, A and Nakano, R and Ota, S and Kobayashi, T and Masuda, A and Iijima, H}, title = {Endoscopic Ultrasound-Guided Gastroenterostomy for Afferent Loop Syndrome.}, journal = {Clinical endoscopy}, volume = {54}, number = {6}, pages = {810-817}, pmid = {34775697}, issn = {2234-2400}, support = {21K07913//JSPS KAKENHI/ ; }, abstract = {Afferent loop syndrome (ALS) is a mechanical obstruction of the afferent limbs after gastrectomy with gastrojejunostomy reconstruction. Patients with cancer recurrence require immediate and less invasive treatment because of their poor condition. Percutaneous transhepatic/transluminal drainage (PTD) and endoscopic enteral stenting offer reasonable palliative treatment for malignant ALS but are not fully satisfactory in terms of patient quality of life (QoL) and stent patency. Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) using a lumen-apposing metal stent may address these shortcomings. Clinical data from 11 reports showed that all patients who had undergone EUS-GE had positive technical and clinical outcomes. The adverse event rate was 11.4%, including only mild or moderate abdominal pain, with no severe adverse events. Indirect comparative studies indicated that patients who had undergone EUS-GE had a significantly superior QoL, a higher clinical success rate, and a lower reintervention rate than those who had undergone PTD or endoscopic enteral stenting. Although the evidence is limited, EUS-GE may be considered as a first-line treatment for malignant ALS because it has better clinical outcomes than other less invasive treatments, such as PTD or endoscopic enteral stenting. Further prospective randomized control trials are necessary to establish EUS-GE as a standard treatment for ALS.}, }
@article {pmid34772993, year = {2021}, author = {Wrzesińska, B and Kościelniak, K and Frąckowiak, P and Praczyk, T and Obrępalska-Stęplowska, A}, title = {The analysis of reference genes expression stability in susceptible and resistant Apera spica-venti populations under herbicide treatment.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {22145}, pmid = {34772993}, issn = {2045-2322}, support = {BIOSTRATEG/3/347445/1/NCBR/2017//Polish National Centre of Research and Development/ ; }, mesh = {Genes, Essential ; Herbicide Resistance/*genetics ; Herbicides ; Plant Weeds/genetics ; Poaceae/*genetics ; Pyrimidines ; Sulfonamides ; }, abstract = {Weed resistance to herbicides constitutes a serious problem to world crop production. One of the weeds that are significantly threatening the crops' yield and quality is Apera spica-venti. The target-site resistance (TSR) mechanism of A. spica-venti has been widely studied, though, little is known about its non-target-site resistance (NTSR) mechanisms at the molecular level. Molecular examination of NTSR is, to a great extent, based on the expression profiles of selected genes, e.g. those participating in detoxification. However, to obtain reliable results of gene expression analysis, the use of a normalizer is required. The aim of this study was to select the best reference genes in A. spica-venti plants of both populations, susceptible and resistant to ALS inhibitor, under treatment with herbicide. Eleven housekeeping genes were chosen for their expression stability assessment. The efficiency correction of raw quantification cycles (Cq) was included in the gene expression stability analyses, which resulted in indicating the TATA-box binding protein (TBP), glyceraldehyde-3-phosphate dehydrogenase, cytosolic (GAPC), and peptidyl-prolyl cis-trans isomerase CYP28 (CYP28) genes as the most stably expressed reference genes. The obtained results are of vital importance for future studies on the expression of genes associated with the non-target-site resistance mechanisms in the A. spica-venti populations susceptible and resistant to herbicides.}, }
@article {pmid34769277, year = {2021}, author = {Jurcau, A}, title = {Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress.}, journal = {International journal of molecular sciences}, volume = {22}, number = {21}, pages = {}, pmid = {34769277}, issn = {1422-0067}, mesh = {Animals ; Humans ; Mitochondria/genetics/*metabolism/pathology ; Mitochondrial Diseases/genetics/*metabolism/pathology ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; *Oxidative Stress ; }, abstract = {As the population ages, the incidence of neurodegenerative diseases is increasing. Due to intensive research, important steps in the elucidation of pathogenetic cascades have been made and significantly implicated mitochondrial dysfunction and oxidative stress. However, the available treatment in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis is mainly symptomatic, providing minor benefits and, at most, slowing down the progression of the disease. Although in preclinical setting, drugs targeting mitochondrial dysfunction and oxidative stress yielded encouraging results, clinical trials failed or had inconclusive results. It is likely that by the time of clinical diagnosis, the pathogenetic cascades are full-blown and significant numbers of neurons have already degenerated, making it impossible for mitochondria-targeted or antioxidant molecules to stop or reverse the process. Until further research will provide more efficient molecules, a healthy lifestyle, with plenty of dietary antioxidants and avoidance of exogenous oxidants may postpone the onset of neurodegeneration, while familial cases may benefit from genetic testing and aggressive therapy started in the preclinical stage.}, }
@article {pmid34765688, year = {2021}, author = {Ojo, OO and Wahab, KW and Bello, AH and Abubakar, SA and Ekeh, BC and Otubogun, FM and Iwuozo, EU and Farombi, TH and Adeniji, O and Ojini, FI and Imarhiagbe, FA and Nyandaiti, Y and Komolafe, MA and Fawale, MB and Onwuegbuzie, GA and Zubair, Y and Williams, UE and Taiwo, FT and Oyakhire, SI and Oshinaike, OO and Osemwegie, N and Osaigbovo, GO and Odiase, FE and Odeniyi, OA and Obiabo, YO and Obehighe, EE and Nwazor, EO and Nwani, PO and Kehinde, AJ and Erameh, CO and Ekenze, OS and Dike, FO and Balarabe, SA and Arigbodi, O and Arabambi, B and Ani-Osheku, I and Ali, MW and Akpekpe, JE and Akinyemi, RO and Agulanna, U and Agu, CE and Agabi, OP and Ademiluyi, BA and Adebowale, AA and Achoru, CO and Abiodun, OV and Rizig, M and Okubadejo, NU}, title = {A Cross-Sectional Comprehensive Assessment of the Profile and Burden of Non-motor Symptoms in Relation to Motor Phenotype in the Nigeria Parkinson Disease Registry Cohort.}, journal = {Movement disorders clinical practice}, volume = {8}, number = {8}, pages = {1206-1215}, pmid = {34765688}, issn = {2330-1619}, abstract = {BACKGROUND: Data on non-motor symptoms (NMS) in black Africans with Parkinson's disease (PD) are sparse.<br><br>OBJECTIVE: To describe the profile of NMS in the Nigeria PD Registry (NPDR) cohort and explore the relationship between NMS and PD motor phenotype.<br><br>METHODS: We conducted a cross-sectional study of the frequency and burden of NMS, based on the non-motor symptoms scale (NMSS) and the Chaudhuri method respectively in our cohort. Baseline demographics, disease characteristics (Hoehn and Yahr stage, MDS-UPDRS total score and Part III motor score), motor phenotype (based on Stebbin et al's algorithm), and levodopa equivalent daily dose (LEDD) were documented.<br><br>RESULTS: Data are presented for 825 PD whose mean age at study was 63.7&#x2009;&#xb1;&#x2009;10.1&#x2009;years, female sex-221 [26.8%] while median PD duration was 36&#x2009;months. PD phenotypes included tremor-dominant 466 (56.5%), postural instability and gait disorder (PIGD) 259 (31.4%), and indeterminate 100 (12.1%). 82.6% were on treatment (median LEDD of 500&#x2009;mg/24&#x2009;hours). 804 (97.5%) endorsed at least 1 NMS. The median NMSS score was 26.0 while subscores for urinary and sexual function domains were significantly higher in males (P&#xa0;<&#x2009;0.05). PIGD-PD had more frequent NMS and higher frequency of severe/very severe NMSS burden (P&#xa0;=&#x2009;0.000 for both). Nocturia and fatigue were the most prevalent NMS overall and across motor subtypes. PIGD phenotype and total UPDRS scores were the independent determinants of NMSS scores (P&#xa0;=&#x2009;0.000).<br><br>CONCLUSION: The profile and burden of NMS, and association with motor subtype in our black African cohort is largely similar to descriptions from other populations.}, }
@article {pmid34763523, year = {2022}, author = {Hardy, M and Castle, C and Jackson, C}, title = {Embedded Psychiatric Services in a Multidisciplinary Amyotrophic Lateral Sclerosis Clinic: An Assessment of Patient Needs and Perceptions.}, journal = {The Journal of neuropsychiatry and clinical neurosciences}, volume = {34}, number = {1}, pages = {53-59}, doi = {10.1176/appi.neuropsych.21040092}, pmid = {34763523}, issn = {1545-7222}, mesh = {*Amyotrophic Lateral Sclerosis/complications/epidemiology/therapy ; *Cognitive Dysfunction ; *Frontotemporal Dementia ; Humans ; *Mental Health Services ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is often associated with a range of difficult neuropsychiatric symptoms and conditions, including depression, apathy, pseudobulbar affect, and frontotemporal dementia (FTD). Despite the potential role for psychiatrists in the treatment of ALS, they are not typically involved in the ALS clinical team. The investigators describe a quality improvement intervention providing embedded psychiatric services within a multidisciplinary clinic (MDC).<br><br>METHODS: A psychiatrist working within an ALS MDC evaluated patients (N=116) over a 1-year period. The clinic assessed the prevalence of neuropsychiatric symptoms and conditions in patients with ALS (depression, anxiety, pseudobulbar affect, and cognitive impairment, including FTD) using standardized screening methods. Fifty-five patients and 47 family members completed surveys about perceptions of their need for psychiatric care, their experience of meeting with a psychiatrist, and their desire for future access to psychiatric care.<br><br>RESULTS: Prevalence rates for neuropsychiatric symptoms were 14.9% for depression, 11.3% for anxiety, 19% for cognitive impairment (including FTD, 8.6%), and 36.2% for pseudobulbar affect; 62.0% of patients were being prescribed at least one psychotropic medication. Both patients and family members reported that meeting with a psychiatrist was helpful, that the treatment provided was helpful, and that they would prefer continued availability of psychiatric services in the future. The presence of cognitive impairment and use of antidepressants increased the likelihood of patients reporting a benefit from psychiatric care.<br><br>CONCLUSIONS: Patients with ALS report a benefit from increased access to psychiatric services. The inclusion of a psychiatrist within the ALS MDC model should be considered to improve quality of care for this patient population.}, }
@article {pmid34761401, year = {2022}, author = {Quigg, KH and Wilson, MW and Choi, PJ}, title = {Transcutaneous CO2 monitoring as indication for inpatient non-invasive ventilation initiation in patients with amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {65}, number = {4}, pages = {444-447}, doi = {10.1002/mus.27457}, pmid = {34761401}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis/therapy ; Carbon Dioxide ; Humans ; Inpatients ; *Noninvasive Ventilation/methods ; *Respiratory Insufficiency/diagnosis/etiology/therapy ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is characterized by profound muscle weakness, including diaphragmatic weakness resulting in hypercapnic respiratory failure. While non-invasive ventilation (NIV) is usually initiated in the home, patients presenting with hypercapnic respiratory failure may be at high risk of adverse outcomes with delays in treatment. We aim to describe the clinical utility of transcutaneous CO2 (TCO2) to assess the need for inpatient initiation of NIV.<br><br>METHODS: Eight patients from the University of Michigan Pranger ALS clinic were directly admitted to the hospital for urgent initiation of NIV between May 2020-May 2021. A retrospective review of electronic medical records, including pre-hospital pulmonary function assessments, hospitalization blood gases, and NIV use metrics was performed.<br><br>RESULTS: All eight patients had symptoms of respiratory insufficiency at time of admission, although not all patients had forced vital capacity (FVC) measurements that would identify need for NIV. All patients had measured TCO2 &#x2009;>&#x2009;45&#x2009;mmHg. Seven of eight patients had worsening hypercapnia after admission, indicating advanced respiratory failure. All patients were titrated to tolerance of continuous nocturnal NIV while in the hospital, with an average length of stay of 6.5&#x2009;days (range, 3-8). All patients demonstrated compliance with NIV, >4&#xa0;h, at post-hospital follow-up.<br><br>DISCUSSION: Many current ambulatory measurements underestimate, or incompletely evaluate, respiratory dysfunction, and arterial blood gases are not typically readily available. Outpatient TCO2 measurements can serve as a useful screening tool to identify ALS patients who would benefit from inpatient initiation and titration of NIV.}, }
@article {pmid34757590, year = {2022}, author = {Petrozziello, T and Bordt, EA and Mills, AN and Kim, SE and Sapp, E and Devlin, BA and Obeng-Marnu, AA and Farhan, SMK and Amaral, AC and Dujardin, S and Dooley, PM and Henstridge, C and Oakley, DH and Neueder, A and Hyman, BT and Spires-Jones, TL and Bilbo, SD and Vakili, K and Cudkowicz, ME and Berry, JD and DiFiglia, M and Silva, MC and Haggarty, SJ and Sadri-Vakili, G}, title = {Targeting Tau Mitigates Mitochondrial Fragmentation and Oxidative Stress in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {59}, number = {1}, pages = {683-702}, pmid = {34757590}, issn = {1559-1182}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*metabolism ; Cell Line, Tumor ; Female ; Humans ; Male ; Middle Aged ; Mitochondria/*metabolism ; Neurons/*metabolism ; Oxidative Stress/*physiology ; Phosphorylation ; Synapses/metabolism ; tau Proteins/*metabolism ; }, abstract = {Understanding the mechanisms underlying amyotrophic lateral sclerosis (ALS) is crucial for the development of new therapies. Previous studies have demonstrated that mitochondrial dysfunction is a key pathogenetic event in ALS. Interestingly, studies in Alzheimer's disease (AD) post-mortem brain and animal models link alterations in mitochondrial function to interactions between hyperphosphorylated tau and dynamin-related protein 1 (DRP1), the GTPase involved in mitochondrial fission. Recent evidence suggest that tau may be involved in ALS pathogenesis, therefore, we sought to determine whether hyperphosphorylated tau may lead to mitochondrial fragmentation and dysfunction in ALS and whether reducing tau may provide a novel therapeutic approach. Our findings demonstrated that pTau-S396 is mis-localized to synapses in post-mortem motor cortex (mCTX) across ALS subtypes. Additionally, the treatment with ALS synaptoneurosomes (SNs), enriched in pTau-S396, increased oxidative stress, induced mitochondrial fragmentation, and altered mitochondrial connectivity without affecting cell survival in vitro. Furthermore, pTau-S396 interacted with DRP1, and similar to pTau-S396, DRP1 accumulated in SNs across ALS subtypes, suggesting increases in mitochondrial fragmentation in ALS. As previously reported, electron microscopy revealed a significant decrease in mitochondria density and length in ALS mCTX. Lastly, reducing tau levels with QC-01-175, a selective tau degrader, prevented ALS SNs-induced mitochondrial fragmentation and oxidative stress in vitro. Collectively, our findings suggest that increases in pTau-S396 may lead to mitochondrial fragmentation and oxidative stress in ALS and decreasing tau may provide a novel strategy to mitigate mitochondrial dysfunction in ALS. pTau-S396 mis-localizes to synapses in ALS. ALS synaptoneurosomes (SNs), enriched in pTau-S396, increase oxidative stress and induce mitochondrial fragmentation in vitro. pTau-S396 interacts with the pro-fission GTPase DRP1 in ALS. Reducing tau with a selective degrader, QC-01-175, mitigates ALS SNs-induced mitochondrial fragmentation and increases in oxidative stress in vitro.}, }
@article {pmid34752923, year = {2021}, author = {Tian, Y and Wang, Y and Jablonski, AM and Hu, Y and Sugam, JA and Koglin, M and Stachel, SJ and Zhou, H and Uslaner, JM and Parmentier-Batteur, S}, title = {Tau-tubulin kinase 1 phosphorylates TDP-43 at disease-relevant sites and exacerbates TDP-43 pathology.}, journal = {Neurobiology of disease}, volume = {161}, number = {}, pages = {105548}, doi = {10.1016/j.nbd.2021.105548}, pmid = {34752923}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; Caenorhabditis elegans ; DNA-Binding Proteins/genetics ; *Frontotemporal Lobar Degeneration/genetics/pathology ; Humans ; Mammals ; Protein Serine-Threonine Kinases/genetics ; }, abstract = {TDP-43 pathology is a hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal lobar degeneration (FTLD). Namely, both diseases feature aggregated and phosphorylated TDP-43 containing inclusions in the cytoplasm and a loss of nuclear TDP-43 in affected neurons. It has been reported that tau tubulin kinase (TTBK)1/2 phosphorylate TDP-43 and TTBK1/2 overexpression induced neuronal loss and behavioral deficits in a C. elegans model of ALS. Here we aimed to elucidate the molecular mechanisms of TTBK1 in TDP-43 pathology. TTBK1 levels were observed to be elevated in ALS patients' post-mortem motor cortex. Also, TTBK1 was found to phosphorylate TDP-43 at disease-relevant sites in vitro directly, and this phosphorylation accelerated TDP-43 formation of high molecular species. Overexpression of TTBK1 in mammalian cells induced TDP-43 phosphorylation and the construction of high molecular species, concurrent with TDP-43 mis-localization and cytoplasmic inclusions. In addition, when TTBK1 was knocked down or pharmacologically inhibited, TDP-43 phosphorylation and aggregation were significantly alleviated. Functionally, TTBK1 knockdown could rescue TDP-43 overexpression-induced neurite and neuronal loss in iPSC-derived GABAergic neurons. These findings suggest that phosphorylation plays a critical role in the pathogenesis of TDP-43 pathology and that TTBK1 inhibition may have therapeutic potential for the treatment of ALS and FTLD.}, }
@article {pmid34750982, year = {2022}, author = {Peng, G and Gu, A and Niu, H and Chen, L and Chen, Y and Zhou, M and Zhang, Y and Liu, J and Cai, L and Liang, D and Liu, X and Liu, M}, title = {Amyotrophic lateral sclerosis (ALS) linked mutation in Ubiquilin 2 affects stress granule assembly via TIA-1.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {28}, number = {1}, pages = {105-115}, pmid = {34750982}, issn = {1755-5949}, mesh = {Adaptor Proteins, Signal Transducing/*genetics ; Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Autophagy-Related Proteins/*genetics ; DNA Helicases ; Frontotemporal Dementia/genetics/metabolism ; HEK293 Cells ; Humans ; Mutation/*genetics ; Poly-ADP-Ribose Binding Proteins ; RNA Helicases ; RNA Recognition Motif Proteins ; *Stress Granules ; T-Cell Intracellular Antigen-1 ; }, abstract = {AIMS: The ubiquilin-like protein ubiquilin 2 (UBQLN2) is associated with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD). The biological function of UBQLN2 has previously been shown to be related to stress granules (SGs). In this study, we aimed to clarify the regulatory relationship between UBQLN2 and SGs.<br><br>METHODS: In this study, we transfected UBQLN2-WT or UBQLN2-P497H plasmids into cell lines (HEK293T, HeLa), and observed the process of SG dynamics by immunofluorescence. Meanwhile, immunoblot analyses the protein changes of stress granules related components.<br><br>RESULTS: We observed that ubiquilin 2 colocalizes with the SG component proteins G3BP1, TIA-1, ATXN2, and PABPC1. In cells expressing WT UBQLN2 or P497H mutants, in the early stages of SG formation under oxidative stress, the percentage of cells with SGs and the number of SGs per cell decreased to varying degrees. Between WT and mutant, there was no significant difference in eIF2&#x3b1; activity after stress treatment. Interestingly, the UBQLN2 P497H mutant downregulates the level of TIA-1. In addition, the overexpression of the UBQLN2 P497H mutant inhibited the phosphorylation of 4E-BP1 and affected the nucleoplasmic distribution of TDP-43.<br><br>CONCLUSIONS: Ubiquilin 2 colocalizes with the SG component proteins G3BP1, TIA-1, ATXN2, and PABPC1. It participates in regulating SG dynamics. And UBQLN2&#xa0;mutation affects the assembly of stress granules by regulating TIA-1. In addition, the overexpression of the UBQLN2 P497H mutant inhibited the phosphorylation of 4E-BP1 and affected the nuclear and cytoplasmic distribution of TDP-43. These provide new insights into the role of UBQLN2 in oxidative stress and the pathogenesis of ALS.}, }
@article {pmid34744700, year = {2021}, author = {Li, T and Tan, X and Li, S and Al-Nusaif, M and Le, W}, title = {Role of Glia-Derived Extracellular Vesicles in Neurodegenerative Diseases.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {765395}, pmid = {34744700}, issn = {1663-4365}, abstract = {Extracellular vesicles (EVs), as nano-sized vesicles secreted by almost all cells, have been recognized as the essential transmitter for cell-to-cell communication and participating in multiple biological processes. Neurodegenerative diseases (ND), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, share common mechanisms of the aggregation and propagation of distinct pathologic proteins among cells in the nervous systems and neuroinflammatory reactions mediated by glia during the pathogenic process. This feature indicates the vital role of crosstalk between neurons and glia in the pathogenesis of ND. In recent years, glia-derived EVs have been investigated as potential mediators of signals between neurons and glia, which provides a new direction and strategy for understanding ND. By a comprehensive summary, it can be concluded that glia-derived EVs have both a beneficial and/or a detrimental effect in the process of ND. Therefore, this review article conveys the role of glia-derived EVs in the pathogenesis of ND and raises current limitations of their potential application in the diagnosis and treatment of ND.}, }
@article {pmid34742724, year = {2022}, author = {Gupta, R and Ambasta, RK and Kumar, P}, title = {Multifaced role of protein deacetylase sirtuins in neurodegenerative disease.}, journal = {Neuroscience and biobehavioral reviews}, volume = {132}, number = {}, pages = {976-997}, doi = {10.1016/j.neubiorev.2021.10.047}, pmid = {34742724}, issn = {1873-7528}, mesh = {*Alzheimer Disease/metabolism ; Humans ; *Neurodegenerative Diseases/metabolism ; Oxidative Stress/physiology ; *Parkinson Disease/metabolism ; *Sirtuins/metabolism/therapeutic use ; }, abstract = {Sirtuins, a class III histone/protein deacetylase, is a central regulator of metabolic function and cellular stress response. This plays a pivotal role in the pathogenesis and progression of diseases such as cancer, neurodegeneration, metabolic syndromes, and cardiovascular disease. Sirtuins regulate biological and cellular processes, for instance, mitochondrial biogenesis, lipid and fatty acid oxidation, oxidative stress, gene transcriptional activity, apoptosis, inflammatory response, DNA repair mechanism, and autophagic cell degradation, which are known components for the progression of the neurodegenerative diseases (NDDs). Emerging evidence suggests that sirtuins are the useful molecular targets against NDDs like, Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), and Amyotrophic Lateral Sclerosis (ALS). However, the exact mechanism of neuroprotection mediated through sirtuins remains unsettled. The manipulation of sirtuins activity with its modulators, calorie restriction (CR), and micro RNAs (miR) is a novel therapeutic approach for the treatment of NDDs. Herein, we reviewed the current putative therapeutic role of sirtuins in regulating synaptic plasticity and cognitive functions, which are mediated through the different molecular phenomenon to prevent neurodegeneration. We also explained the implications of sirtuin modulators, and miR based therapies for the treatment of life-threatening NDDs.}, }
@article {pmid34741295, year = {2021}, author = {Spiesshoefer, J and Storre, JH and Dreher, M}, title = {[Non-invasive Home-Ventilation: Pathophysiology, Initiation and Follow up].}, journal = {Deutsche medizinische Wochenschrift (1946)}, volume = {146}, number = {22}, pages = {1497-1508}, doi = {10.1055/a-1242-8710}, pmid = {34741295}, issn = {1439-4413}, mesh = {Aged ; *Home Care Services ; Humans ; *Hypercapnia/physiopathology/therapy ; Neuromuscular Diseases/therapy ; *Noninvasive Ventilation ; Pulmonary Disease, Chronic Obstructive/therapy ; }, abstract = {COPD is the most common reason for hypercapnia. However, it is -by far- not the only reason. In fact, numerous neuromuscular disorders (not only ALS) as well as restrictive thoracic disorders do also lead to clinically highly relevant hypercapnia. Early diagnosis of hypercapnic ventilatory failure usually takes place at nighttime. NIV devices work with a periodic interplay of alternating IPAP and EPAP which results in a ventilation of the lungs, thereby elimination CO2 to treat hypercapnic respiratory failure. Firstline settings for a NIV therapy to treat "stable hypercapnia" are as follows: Pressure Support Ventilation Modus, EPAP 5 cmH2O, IPAP 15 cmH2O, Back Up rate 15/Minute. The overall goal of NIV treatment is a successful reduction in CO2. This can be achieved by changing the following variables of the ventilator settings: increase in IPAP ± increase in back up respiratory rate ± use of assisted pressure controlled ventilation mode (APCV).}, }
@article {pmid34737697, year = {2021}, author = {Sugimoto, K and Liu, J and Li, M and Song, Y and Zhang, C and Zhai, Z and Gao, Y}, title = {Neuroprotective Effects of Shenqi Fuzheng Injection in a Transgenic SOD1-G93A Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {701886}, pmid = {34737697}, issn = {1663-9812}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, in the pathogenesis of which oxidative stress (OS) was believed to play a key role. Shenqi Fuzheng Injection (SFI) concocted from two kinds of Chinese medicinal herbs, Radix Codonopsis and Radix Astragali, was proven to be eligible to reduce the OS injury and increase the activity of the nuclear factor-erythroid-2-related factor 2 (Nrf2) pathway, an antioxidant enzymes inducer. Objective: We aim to investigate the effects and potential mechanisms underlying the action of SFI on a well-established transgenic mouse model of ALS. Methods: Transgenic SOD1-G93A mice were intraperitoneally injected with SFI (40 ml/kg) three times a week from 87 days of age. Motor function, survival, pathological manifestations in the brain, and Nrf2 pathway-related assessments of the mice were performed. Results: SFI treatment efficiently postponed the disease onset (p = 0.022) and extended the overall survival (p = 0.038) of the SOD1-G93A mice. Moreover, SFI significantly reduced motor neuron loss (p < 0.001) and astrocytic activation (p < 0.05) in the motor cortex of the brain of SOD1-G93A mice at 130 days of age. The protective effects of SFI in the SOD1-G93A mice were associated with decreasing the level of malondialdehyde (p < 0.05) and increasing the levels of superoxide dismutase (p < 0.05), Nrf2 (p < 0.05), heme oxygenase-1 (p < 0.05), and glutathione S-transferase (p < 0.05) in the SOD1-G93A mice. Conclusion: The SFI treatment efficiently extended the overall survival and improved the pathological manifestations of the brain via alleviating the OS injury and activating the Nrf2 pathway in the animal model of ALS, which made SFI a potentially promising candidate for ALS treatment.}, }
@article {pmid34735295, year = {2021}, author = {Rowe, HP and Stipancic, KL and Lammert, AC and Green, JR}, title = {Validation of an Acoustic-Based Framework of Speech Motor Control: Assessing Criterion and Construct Validity Using Kinematic and Perceptual Measures.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {64}, number = {12}, pages = {4736-4753}, pmid = {34735295}, issn = {1558-9102}, support = {F31 DC019556/DC/NIDCD NIH HHS/United States ; R01 DC013547/DC/NIDCD NIH HHS/United States ; R01 DC009890/DC/NIDCD NIH HHS/United States ; K24 DC016312/DC/NIDCD NIH HHS/United States ; R01 DC017291/DC/NIDCD NIH HHS/United States ; }, mesh = {Acoustics ; Biomechanical Phenomena ; Humans ; *Speech ; Speech Acoustics ; *Speech Intelligibility ; Speech Production Measurement ; }, abstract = {PURPOSE: This study investigated the criterion (analytical and clinical) and construct (divergent) validity of a novel, acoustic-based framework composed of five key components of motor control: Coordination, Consistency, Speed, Precision, and Rate.<br><br>METHOD: Acoustic and kinematic analyses were performed on audio recordings from 22 subjects with amyotrophic lateral sclerosis during a sequential motion rate task. Perceptual analyses were completed by two licensed speech-language pathologists, who rated each subject's speech on the five framework components and their overall severity. Analytical and clinical validity were assessed by comparing performance on the acoustic features to their kinematic correlates and to clinician ratings of the five components, respectively. Divergent validity of the acoustic-based framework was then assessed by comparing performance on each pair of acoustic features to determine whether the features represent distinct articulatory constructs. Bivariate correlations and partial correlations with severity as a covariate were conducted for each comparison.<br><br>RESULTS: Results revealed moderate-to-strong analytical validity for every acoustic feature, both with and without controlling for severity, and moderate-to-strong clinical validity for all acoustic features except Coordination, without controlling for severity. When severity was included as a covariate, the strong associations for Speed and Precision became weak. Divergent validity was supported by weak-to-moderate pairwise associations between all acoustic features except Speed (second-formant [F2] slope of consonant transition) and Precision (between-consonant variability in F2 slope).<br><br>CONCLUSIONS: This study demonstrated that the acoustic-based framework has potential as an objective, valid, and clinically useful tool for profiling articulatory deficits in individuals with speech motor disorders. The findings also suggest that compared to clinician ratings, instrumental measures are more sensitive to subtle differences in articulatory function. With further research, this framework could provide more accurate and reliable characterizations of articulatory impairment, which may eventually increase clinical confidence in the diagnosis and treatment of patients with different articulatory phenotypes.}, }
@article {pmid34734342, year = {2021}, author = {Høegh, MC and Melle, I and Aminoff, SR and Haatveit, B and Olsen, SH and Huflåtten, IB and Ueland, T and Lagerberg, TV}, title = {Characterization of affective lability across subgroups of psychosis spectrum disorders.}, journal = {International journal of bipolar disorders}, volume = {9}, number = {1}, pages = {34}, pmid = {34734342}, issn = {2194-7511}, support = {#181831//research council of norway/ ; 147787/320//research council of norway/ ; 342#67153/V50//research council of norway/ ; #288542//research council of norway/ ; }, abstract = {BACKGROUND: Affective lability is elevated and associated with increased clinical burden in psychosis spectrum disorders. The extent to which the level, structure and dispersion of affective lability varies between the specific disorders included in the psychosis spectrum is however unclear. To have potential value as a treatment target, further characterization of affective lability in these populations is necessary. The main aim of our study was to investigate differences in the architecture of affective lability in different psychosis spectrum disorders, and if putative differences remained when we controlled for current symptom status.<br><br>METHODS: Affective lability was measured with The Affective Lability Scale Short Form (ALS-SF) in participants with schizophrenia (SZ, n&#x2009;=&#x2009;76), bipolar I disorder (BD-I, n&#x2009;=&#x2009;105), bipolar II disorder (BD-II, n&#x2009;=&#x2009;68) and a mixed psychosis-affective group (MP,&#xa0;n&#x2009;=&#x2009;48). Multiple analyses of covariance were conducted to compare the ALS-SF total and subdimension scores of the diagnostic groups, correcting for current psychotic, affective and anxiety symptoms, substance use and sex. Double generalized linear models were performed to compare the dispersion of affective lability in the different groups.<br><br>RESULTS: Overall group differences in affective lability remained significant after adjusting for covariates (p&#x2009;=&#x2009;.001). BD-II had higher affective lability compared to SZ and BD-I (p&#x2009;=&#x2009;.004), with no significant differences between SZ and BD-I. There were no significant differences in the contributions of ALS-SF dimensions to the total affective lability or in dispersion of affective lability between the groups.<br><br>CONCLUSIONS: This study provides the construct of affective lability in psychosis spectrum disorders with more granular details that may have implications for research and clinical care. It demonstrates that despite overlap in core symptom profiles, BD-I is more similar to SZ than it is to BD-II concerning affective lability and the BD groups should consequently be studied apart. Further, affective lability appears to be characterized by fluctuations between depressive- and other affective states across different psychosis spectrum disorders, indicating that affective lability may be related to internalizing problems in these disorders. Finally, although the level varies between groups, affective lability is evenly spread and not driven by extremes across psychosis spectrum disorders and should be assessed irrespective of diagnosis.}, }
@article {pmid34730342, year = {2021}, author = {Zilka, O and Poon, JF and Pratt, DA}, title = {Radical-Trapping Antioxidant Activity of Copper and Nickel Bis(Thiosemicarbazone) Complexes Underlies Their Potency as Inhibitors of Ferroptotic Cell Death.}, journal = {Journal of the American Chemical Society}, volume = {143}, number = {45}, pages = {19043-19057}, doi = {10.1021/jacs.1c08254}, pmid = {34730342}, issn = {1520-5126}, mesh = {Animals ; Cell Line ; Coordination Complexes/chemistry/*pharmacology ; Copper/chemistry ; Ferroptosis/*drug effects ; Free Radical Scavengers/chemistry/*pharmacology ; Lipid Peroxidation/drug effects ; Mice ; Models, Chemical ; Nickel/chemistry ; Phospholipids/metabolism ; Thiosemicarbazones/chemistry/*pharmacology ; }, abstract = {Herein we demonstrate that copper(II)-diacetyl-bis(N[4]-methylthiosemicarbazone)(CuATSM), clinical candidate for the treatment of ALS and Parkinson's disease, is a highly potent radical-trapping antioxidant (RTA) and inhibitor of (phospho)lipid peroxidation. In THF autoxidations, CuATSM reacts with THF-derived peroxyl radicals with kinh = 2.2 × 10[6] M[-1] s[-1]─roughly 10-fold greater than α-tocopherol (α-TOH), Nature's best RTA. Mechanistic studies reveal no H/D kinetic isotope effects and a lack of rate-suppressing effects from H-bonding interactions, implying a different mechanism from α-TOH and other canonical RTAs, which react by H-atom transfer (HAT). Similar reactivity was observed for the corresponding Ni[2+] complex and complexes of both Cu[2+] and Ni[2+] with other bis(thiosemicarbazone) ligands. Computations corroborate the experimental finding that rate-limiting HAT cannot account for the observed RTA activity and instead suggest that the reversible addition of a peroxyl radical to the bis(thiosemicarbazone) ligand is responsible. Subsequent HAT or combination with another peroxyl radical drives the reaction forward, such that a maximum of four radicals are trapped per molecule of CuATSM. This sequence is supported by spectroscopic and mass spectrometric experiments on isolated intermediates. Importantly, the RTA activity of CuATSM (and its analogues) translates from organic solution to phospholipid bilayers, thereby accounting for its (their) ability to inhibit ferroptosis. Experiments in mouse embryonic fibroblasts and hippocampal cells reveal that lipophilicity as well as inherent RTA activity contribute to the potency of ferroptosis rescue, and that one compound (CuATSP) is almost 20-fold more potent than CuATSM and among the most potent ferroptosis inhibitors reported to date.}, }
@article {pmid34728328, year = {2022}, author = {Funada, C and Tanino, N and Fukaya, M and Mikajiri, Y and Nishiguchi, M and Otake, M and Nakasuji, H and Kawahito, R and Abe, F}, title = {SOD1 mutations cause hypersensitivity to high-pressure-induced oxidative stress in Saccharomyces cerevisiae.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {1866}, number = {2}, pages = {130049}, doi = {10.1016/j.bbagen.2021.130049}, pmid = {34728328}, issn = {1872-8006}, mesh = {*Saccharomyces cerevisiae/genetics/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Oxidative Stress/genetics ; *Mutation ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Molecular Chaperones/metabolism/genetics ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Hydrostatic Pressure ; }, abstract = {UNLABELLED: Living organisms are subject to various mechanical stressors, such as high hydrostatic pressure. Empirical evidence shows that under high pressure, the oxidative stress response is activated in Saccharomyces cerevisiae. However, the mechanisms involved in its antioxidant systems are unclear. Here, we demonstrate that superoxide dismutase 1 (Sod1) plays a role in resisting high pressure for cell growth. Mutants lacking Sod1 or Ccs1, the copper chaperone for Sod1, displayed growth defects under 25 MPa. Of the various SOD1 mutations associated with familial amyotrophic lateral sclerosis, H46Q and S134N substitutions diminished SOD activity to levels comparable to those of catalytically deficient H63A and null mutants. When these mutant cells were cultured under 25 MPa, their intracellular O2[•-] levels increased while sod1∆ mutant genome stability was unaffected. The high-pressure sensitive sod1 mutants were also susceptible to sublethal levels of the O2[•-] generator paraquat. The sod1∆ mutant is known to exhibit methionine and lysine auxotrophy. However, excess methionine addition or overexpression of the lysine permease gene LYP1 did not counteract high-pressure sensitivity in the sod1 mutants, suggesting that their amino acid availability might be intact under 25 MPa. Interestingly, an exclusive localization of Sco2-Sod1 to the intermembrane space (IMS) of mitochondria appeared to partially restore the high-pressure growth ability in the sod1 mutants. Taken these results together, we suggest that high pressure enhances O2[•-] production and Sod1 within the IMS plays a role in scavenging O2[•-] allowing the cells to grow under high pressure.<br><br>BACKGROUND: Empirical evidence shows that under high hydrostatic pressure, the oxidative stress response is activated in Saccharomyces cerevisiae. However, the mechanisms involved in its antioxidant systems are unclear. In the current study, we aimed to explore the role of superoxide dismutase 1 (Sod1) in yeast able to grow under high pressure.<br><br>METHODS: Wild type and sod1 mutant cells were cultured in high-pressure chambers under 25&#xa0;MPa (~250&#xa0;kg/cm[2]). The SOD activity in whole cell extracts and 6His-tagged Sod1 recombinant proteins was analyzed using an SOD assay kit. The O2[&#x2022;-] generation in cells was estimated by fluorescence staining.<br><br>RESULTS: Mutants lacking Sod1 or Ccs1, the copper chaperone for Sod1, displayed growth defects under 25&#xa0;MPa. Of the various SOD1 mutations associated with familial amyotrophic lateral sclerosis, H46Q and S134N substitutions diminished SOD activity to levels comparable to those of catalytically deficient H63A and null mutants. The high-pressure sensitive sod1 mutants were also susceptible to sublethal levels of the O2[&#x2022;-] generator paraquat. Exclusive localization of Sco2-Sod1 to the intermembrane space (IMS) of mitochondria partially restored the high-pressure growth ability in the sod1 mutants.<br><br>CONCLUSIONS: High pressure enhances O2[&#x2022;-] production and Sod1 within the IMS plays a role in scavenging O2[&#x2022;-] allowing the cells to grow under high pressure.<br><br>GENERAL SIGNIFICANCE: Unlike external free radical-generating compounds, high-pressure treatment appeared to increase endogenous O2[&#x2022;-] levels in yeast cells. Our experimental system offers a unique approach to investigating the physiological responses to mechanical and oxidative stresses in human body.}, }
@article {pmid34726266, year = {2021}, author = {Amor, S and Nutma, E and Owen, D}, title = {Imaging immune responses in neuroinflammatory diseases.}, journal = {Clinical and experimental immunology}, volume = {206}, number = {3}, pages = {248-250}, pmid = {34726266}, issn = {1365-2249}, support = {MR/N008219/1/MRC_/Medical Research Council/United Kingdom ; MR/T031891/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Adaptive Immunity/*immunology ; Biomarkers/analysis ; Central Nervous System/*diagnostic imaging ; Disease Progression ; Glioblastoma/*diagnostic imaging/pathology ; Humans ; Immunity, Innate/*immunology ; Magnetic Resonance Imaging ; Neurodegenerative Diseases/*diagnostic imaging/immunology/pathology ; Neuroinflammatory Diseases/*diagnostic imaging/immunology/pathology ; Positron-Emission Tomography ; Tomography, Optical Coherence ; }, abstract = {Innate and adaptive immune responses in the central nervous system (CNS) play critical roles in the pathogenesis of neurological diseases. In the first of a two-part special issue, leading researchers discuss how imaging modalities are used to monitor immune responses in several neurodegenerative diseases and glioblastoma and brain metastases. While comparative studies in humans between imaging and pathology are biased towards the end stage of disease, animal models can inform regarding how immune responses change with disease progression and as a result of treatment regimens. Magnetic resonance imaging (MRI) and positron emission tomography (PET) are frequently used to image disease progression, and the articles indicate how one or more of these modalities have been applied to specific neuroimmune diseases. In addition, advanced microscopical imaging using two-dimensional photon microscopy and in vitro live cell imaging have also been applied to animal models. In this special issue (Parts 1 and 2), as well as the imaging modalities mentioned, several articles discuss biomarkers of disease and microscopical studies that have enabled characterization of immune responses. Future developments of imaging modalities should enable tracking of specific subsets of immune cells during disease allowing longitudinal monitoring of immune responses. These new approaches will be critical to more effectively monitor and thus target specific cell subsets for therapeutic interventions which may be applicable to a range of neurological diseases.}, }
@article {pmid34719771, year = {2022}, author = {Pathak, N and Vimal, SK and Tandon, I and Agrawal, L and Hongyi, C and Bhattacharyya, S}, title = {Neurodegenerative Disorders of Alzheimer, Parkinsonism, Amyotrophic Lateral Sclerosis and Multiple Sclerosis: An Early Diagnostic Approach for Precision Treatment.}, journal = {Metabolic brain disease}, volume = {37}, number = {1}, pages = {67-104}, pmid = {34719771}, issn = {1573-7365}, mesh = {Aged ; *Alzheimer Disease/diagnosis ; *Amyotrophic Lateral Sclerosis/diagnosis/pathology ; Humans ; *Multiple Sclerosis ; *Neurodegenerative Diseases/diagnosis/drug therapy ; *Parkinson Disease ; }, abstract = {Neurodegenerative diseases (NDs) are characterised by progressive dysfunction of synapses, neurons, glial cells and their networks. Neurodegenerative diseases can be classified according to primary clinical features (e.g., dementia, parkinsonism, or motor neuron disease), anatomic distribution of neurodegeneration (e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations), or principal molecular abnormalities. The most common neurodegenerative disorders are amyloidosis, tauopathies, a-synucleinopathy, and TAR DNA-binding protein 43 (TDP-43) proteopathy. The protein abnormalities in these disorders have abnormal conformational properties along with altered cellular mechanisms, and they exhibit motor deficit, mitochondrial malfunction, dysfunctions in autophagic-lysosomal pathways, synaptic toxicity, and more emerging mechanisms such as the roles of stress granule pathways and liquid-phase transitions. Finally, for each ND, microglial cells have been reported to be implicated in neurodegeneration, in particular, because the microglial responses can shift from neuroprotective to a deleterious role. Growing experimental evidence suggests that abnormal protein conformers act as seed material for oligomerization, spreading from cell to cell through anatomically connected neuronal pathways, which may in part explain the specific anatomical patterns observed in brain autopsy sample. In this review, we mention the human pathology of select neurodegenerative disorders, focusing on how neurodegenerative disorders (i.e., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis) represent a great healthcare problem worldwide and are becoming prevalent because of the increasing aged population. Despite many studies have focused on their etiopathology, the exact cause of these diseases is still largely unknown and until now with the only available option of symptomatic treatments. In this review, we aim to report the systematic and clinically correlated potential biomarker candidates. Although future studies are necessary for their use in early detection and progression in humans affected by NDs, the promising results obtained by several groups leads us to this idea that biomarkers could be used to design a potential therapeutic approach and preclinical clinical trials for the treatments of NDs.}, }
@article {pmid34716673, year = {2021}, author = {Puopolo, M and Bacigalupo, I and Piscopo, P and Lacorte, E and Di Pucchio, A and Santarelli, M and Inghilleri, M and Petrucci, A and Sabatelli, M and ,  and Vanacore, N}, title = {Prevalence of amyotrophic lateral sclerosis in Latium region, Italy.}, journal = {Brain and behavior}, volume = {11}, number = {12}, pages = {e2378}, pmid = {34716673}, issn = {2162-3279}, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Female ; Humans ; Italy/epidemiology ; Male ; Middle Aged ; Prevalence ; Prospective Studies ; Retrospective Studies ; Young Adult ; }, abstract = {OBJECTIVE: Prevalence estimate of amyotrophic lateral sclerosis (ALS) ranged between 1.1/100,000 and 11.2/100,000 inhabitants with different design of the study (prospective or retrospective) and sample size. The aim of this study is to conduct for the first time an estimate of the ALS prevalence in the Latium region.<br><br>MATERIALS AND METHODS: The study was performed in Latium, a region located in the center of Italy, with a population, as of January 1, 2016, of 5888.472 inhabitants. In this region, a network of 15 clinical centers (of which 4 referral ALS centers are located in Rome) and 10 local health authorities involved in the diagnosis and treatment of ALS patients has been identified. Each patient was classified according to the El Escorial revised criteria.<br><br>RESULTS: The prevalence study in 2016 identified 353 ALS cases (200 males). By considering population aged >=20 years, the total crude prevalence rate resulted 7.33 (CI95% 6.59-8.14) &#xd7; 100,000 and 8.75 and 6.05 in males and females, respectively. Age-specific prevalence rates did not differ among males and females in the population aged less than 49 years. The difference emerged in population aged&#xa0;>&#xa0;50 years. This type of diagnosis was recorded for 343 patients (11 missing). 68% of these patients have a definite diagnosis, 14% likely, 11% possible, and 12% defined as suspect.<br><br>CONCLUSIONS: The estimate of prevalence rates observed in this study is probably in line with the values reported in the literature for prospective prevalence studies.}, }
@article {pmid34714853, year = {2021}, author = {Pandeya, SR and Nagy, JA and Riveros, D and Semple, C and Taylor, RS and Sanchez, B and Rutkove, SB}, title = {Relationships between in vivo surface and ex vivo electrical impedance myography measurements in three different neuromuscular disorder mouse models.}, journal = {PloS one}, volume = {16}, number = {10}, pages = {e0259071}, pmid = {34714853}, issn = {1932-6203}, support = {R01 NS055099/NS/NINDS NIH HHS/United States ; R01 NS091159/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Electric Impedance ; Electromyography/*methods ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred mdx ; Muscle, Skeletal/pathology ; Neuromuscular Diseases/*diagnosis ; }, abstract = {Electrical impedance myography (EIM) using surface techniques has shown promise as a means of diagnosing and tracking disorders affecting muscle and assessing treatment efficacy. However, the relationship between such surface-obtained impedance values and pure muscle impedance values has not been established. Here we studied three groups of diseased and wild-type (WT) animals, including a Duchenne muscular dystrophy model (the D2-mdx mouse), an amyotrophic lateral sclerosis (ALS) model (the SOD1 G93A mouse), and a model of fat-related atrophy (the db/db diabetic obese mouse), performing hind limb measurements using a standard surface array and ex vivo measurements on freshly excised gastrocnemius muscle. A total of 101 animals (23 D2-mdx, 43 ALS mice, 12 db/db mice, and corresponding 30 WT mice) were studied with EIM across a frequency range of 8 kHz to 1 MHz. For both D2-mdx and ALS models, moderate strength correlations (Spearman rho values generally ranging from 0.3-0.7, depending on the impedance parameter (i.e., resistance, reactance and phase) were obtained. In these groups of animals, there was an offset in frequency with impedance values obtained at higher surface frequencies correlating more strongly to impedance values obtained at lower ex vivo frequencies. For the db/db model, correlations were comparatively weaker and strongest at very high and very low frequencies. When combining impedance data from all three disease models together, moderate correlations persisted (with maximal Spearman rho values of 0.45). These data support that surface EIM data reflect ex vivo muscle tissue EIM values to a moderate degree across several different diseases, with the highest correlations occurring in the 10-200 kHz frequency range. Understanding these relationships will prove useful for future applications of the technique of EIM in the assessment of neuromuscular disorders.}, }
@article {pmid34713302, year = {2021}, author = {Blyufer, A and Lhamo, S and Tam, C and Tariq, I and Thavornwatanayong, T and Mahajan, SS}, title = {Riluzole: A neuroprotective drug with potential as a novel anti‑cancer agent (Review).}, journal = {International journal of oncology}, volume = {59}, number = {5}, pages = {}, pmid = {34713302}, issn = {1791-2423}, support = {SC1 GM131929/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Humans ; Mice ; Neoplasms/*drug therapy/pathology ; Riluzole/*pharmacology/therapeutic use ; Xenograft Model Antitumor Assays ; }, abstract = {Riluzole, a glutamate release inhibitor, has been in use for the treatment of amyotrophic lateral sclerosis for over two decades since its approval by the Food and Drug Administration. Recently, riluzole has been evaluated in cancer cells and indicated to block cell proliferation and/or induce cell death. Riluzole has been proven effective as an anti‑neoplastic drug in cancers of various tissue origins, including the skin, breast, pancreas, colon, liver, bone, brain, lung and nasopharynx. While cancer cells expressing glutamate receptors frequently respond to riluzole treatment, numerous types of cancer cell lacking glutamate receptors unexpectedly responded to riluzole treatment as well. Riluzole was demonstrated to interfere with glutamate secretion, growth signaling pathways, Ca[2+] homeostasis, glutathione synthesis, reactive oxygen species generation and integrity of DNA, as well as autophagic and apoptotic pathways. Of note, riluzole is highly effective in inducing cell death in cisplatin‑resistant lung cancer cells. Furthermore, riluzole pretreatment sensitizes glioma and melanoma to radiation therapy. In addition, in triple‑negative breast cancer, colorectal cancer, melanoma and glioblastoma, riluzole has synergistic effects in combination with select drugs. In an effort to highlight the therapeutic potential of riluzole, the current study reviewed the effect and outcome of riluzole treatment on numerous cancer types investigated thus far. The mechanism of action and the various molecular pathways affected by riluzole are discussed.}, }
@article {pmid34709092, year = {2022}, author = {Young, C and Ealing, J and McDermott, C and Williams, T and Al-Chalabi, A and Majeed, T and Roberts, R and Mills, R and Tennant, A and , }, title = {Fatigue and anxiety mediate the effect of dyspnea on quality of life in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {5-6}, pages = {390-398}, doi = {10.1080/21678421.2021.1990343}, pmid = {34709092}, issn = {2167-9223}, support = {ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; YOUNG/JAN15/929-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Anxiety/etiology ; Depression/etiology ; Dyspnea/complications/therapy ; Fatigue/etiology ; Humans ; Quality of Life ; *Respiratory Insufficiency ; }, abstract = {Introduction: Dyspnea (or breathlessness) due to progressive neuromuscular respiratory failure is common in amyotrophic lateral sclerosis (ALS). It is associated with anxiety, depression and reduced quality of life (QoL). For effective treatment, it is essential to understand the relationships between dyspnea, anxiety, depression and QoL.Methods: The UK Trajectories of Outcomes in Neurological Conditions-ALS study (TONiC-ALS) collected self-report measures from patients with ALS. Ordinal scales were transformed to interval-scaled estimates by the Rasch Measurement model. They were subsequently included in a series of path models where the focal relationships were dyspnea to QoL and dyspnea to depression.Results: Path analyses using 1022 participants showed that 60.5% of the variance of QoL was explained by fatigue, anxiety, dyspnea and disability. For depression, 54.1% of the variance was explained by a model of these factors. Dyspnea played an important but mostly indirect role in influencing QoL and depressive symptoms. Disability was dominated by all other factors in the model.Discussion: Dyspnea in ALS influences quality of life and depression largely through indirect effects, principally acting via anxiety and fatigue. Recognition of this is essential for clinicians to understand where to intervene for greatest benefit. Researchers must be aware that studies of the effect of dyspnea on QoL and depression require path models, measuring both direct and indirect effects, as the impact of dyspnea is likely to be significantly miscalculated if only direct effects are assessed.}, }
@article {pmid34704267, year = {2022}, author = {Ito, D}, title = {Promise of Nucleic Acid Therapeutics for Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {91}, number = {1}, pages = {13-20}, doi = {10.1002/ana.26259}, pmid = {34704267}, issn = {1531-8249}, support = {//Serika Fund/ ; //the Foundation of Japan Amyotrophic Lateral Sclerosis Association/ ; //the Ice Bucket Challenge Grant (Japan Amyotrophic Lateral Sclerosis Association)/ ; 21H02812//the Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Gene Expression Regulation/*drug effects ; Humans ; Nucleic Acids/*therapeutic use ; }, abstract = {Nucleic acid therapeutics have been attracting attention as novel drug discovery modalities for intractable diseases, including amyotrophic lateral sclerosis. This review provides an overview of the current status and prospects of antisense oligonucleotide treatment for amyotrophic lateral sclerosis. Recently, the results of a phase I/II study using the antisense oligonucleotides Tofersen to treat familial amyotrophic lateral sclerosis with superoxide dismutase 1 mutation have been reported. Intrathecal Tofersen administration resulted in a 36% reduction in superoxide dismutase 1 level in the cerebrospinal fluid. Another report described 2 patients with mutant superoxide dismutase 1 treated with an adeno-associated virus encoding a microRNA targeting superoxide dismutase 1. The first patient, who possessed the fast progressive mutant A5V, received a single intrathecal infusion. Although the patient died of respiratory arrest 16 months after treatment, autopsy findings showed a reduction of >90% in superoxide dismutase 1 level in the spinal cord. Clinical trials on antisense oligonucleotide therapies targeting other major amyotrophic lateral sclerosis-causative genes, fused in sarcoma and chromosome 9 open reading frame 72, are ongoing. To attenuate the pathology of TDP-43, strategies targeting regulators of TDP-43 (ataxin 2) and proteins downstream of TDP-43 (stathmin 2) by antisense oligonucleotides are being developed. The advent of nucleic acid therapeutics has enabled to specifically attack the molecules in the amyotrophic lateral sclerosis pathological cascade, expanding the options for therapeutic targets. ANN NEUROL 2022;91:13-20.}, }
@article {pmid34704111, year = {2021}, author = {Anderl-Straub, S and Schuster, J and Dorst, J and Ludolph, AC}, title = {[Amyotrophic lateral sclerosis and frontotemporal dementia-On the way to common gene-specific treatment approaches].}, journal = {Der Nervenarzt}, volume = {92}, number = {12}, pages = {1219-1226}, pmid = {34704111}, issn = {1433-0407}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; C9orf72 Protein/genetics ; *Frontotemporal Dementia/diagnosis/genetics/therapy ; Humans ; Mutation/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share common neuropathological features and in the case of a gene mutation, also a genetic cause. To date five ALS-FTD genes are described in the literature in addition to other rare variants.<br><br>OBJECTIVE: The current state of research on treatment options for ALS and FTD is presented and an outlook on possible gene-specific approaches for ALS-FTD is provided.<br><br>MATERIAL AND METHODS: Analysis of the progression of ALS and FTD research by considering the increasing state of knowledge on the underlying pathomechanisms of the diseases.<br><br>RESULTS: In addition to anti-inflammatory approaches and stabilization of protein folding, promising gene-specific treatment approaches are currently being developed, which target common causes of ALS and FTD and therefore have an effect on both diseases.<br><br>CONCLUSION: So far there are no causal treatment options for ALS and FTD. The increasing importance of genetic causes directs the focus to the development of gene-specific treatment.}, }
@article {pmid34699945, year = {2022}, author = {Song, Y and Li, M and Sugimoto, K and Han, Y and Liu, J and Ma, B and Song, H and Zhang, C and Gao, Y and , }, title = {China amyotrophic lateral sclerosis registry of patients with Traditional Chinese Medicine (CARE-TCM): Rationale and design.}, journal = {Journal of ethnopharmacology}, volume = {284}, number = {}, pages = {114774}, doi = {10.1016/j.jep.2021.114774}, pmid = {34699945}, issn = {1872-7573}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*therapy ; China/epidemiology ; Humans ; *Medicine, Chinese Traditional ; *Registries ; }, abstract = {Traditional Chinese medicine (TCM) has become popular interventional treatment for amyotrophic lateral sclerosis (ALS). However, lack of knowledge about the general characteristics and long-term clinical outcomes hampers the development of herbal drugs for ALS.<br><br>AIM OF THE STUDY: The China Amyotrophic Lateral Sclerosis Registry of Patients with Traditional Chinese Medicine (CARE-TCM) provides an opportunity to better understand which TCM interventions patients with ALS are receiving, what the characteristics of patients with ALS are, and how these interventions impact clinical measures.<br><br>MATERIALS AND METHODS: This study includes a voluntary nationwide registry, and data will be collected prospectively using an electronic data system. Detailed data collection will be performed every 3 months for 5 years. Baseline characteristics and 5-year survival will be collected. This registry was initiated in March 2021. The number of participating medical centers will be about 30 hospitals, and the target procedure number will be 2000. We will also compare the results with those of other registries in China and other countries.<br><br>DISCUSSION: The CARE-TCM registry will first provide real-world data regarding TCM and ALS in China, focusing on the clinical characteristics of ALS patients with TCM, disease phenotypes that respond best to TCM, and correlating clinical response with other parameters. The CARE-TCM can be very helpful to improve the efficiency and quality of TCM clinical trial design.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04885374 (registered on May 8, 2021).}, }
@article {pmid34694422, year = {2022}, author = {Gaisendrees, C and Walter, S and Sabashnikov, A and Adler, C and Wahlers, T}, title = {[Extracorporeal cardiopulmonary resuscitation for treatment of out-of-hospital cardiac arrest].}, journal = {Der Anaesthesist}, volume = {71}, number = {5}, pages = {392-399}, pmid = {34694422}, issn = {1432-055X}, mesh = {*Cardiopulmonary Resuscitation ; *Extracorporeal Membrane Oxygenation ; Humans ; *Out-of-Hospital Cardiac Arrest/therapy ; Retrospective Studies ; Treatment Outcome ; }, abstract = {BACKGROUND: Out-of-hospital cardiac arrest (OHCA) affects ca. 75,000 people each year in Germany and is associated with a limited prognosis and a high mortality. Extracorporeal cardiopulmonary resuscitation (eCPR) using arteriovenous extracorporeal membrane oxygenation (av-ECMO) systems is an additional option for treatment, which is increasingly more widespread and since 2020 anchored in the guideline algorithm.<br><br>METHODS: A selective search of the literature was carried out in PubMed and Embase focusing on studies that investigated eCPR for OHCA. Furthermore, clinical studies on this topic that are currently recruiting and running are summarized.<br><br>RESULTS: The available data on the benefits of eCPR for OHCA are mostly based on retrospective cohort studies. A survival advantage and an advantage in the neurological outcome could be derived from these data for selected patients treated with eCPR vs. conventionally resuscitated patients (CPR). This effect could be confirmed by two current randomized controlled studies. Studies which are currently running are investigating if out-of-hospital ECMO cannulation at the earliest time possible at the site of OHCA of patients could be associated with a better survival.<br><br>CONCLUSION: Despite a current scarcity of data, a survival advantage for eCPR treatment in selected OHCA patients must be assumed. If this can be substantiated by other high-quality studies, it seems to be indicated to evaluate if and to what extent resource-intensive eCPR programs can be comprehensively established.}, }
@article {pmid34691359, year = {2021}, author = {Stein, J and Walkenfort, B and Cihankaya, H and Hasenberg, M and Bader, V and Winklhofer, KF and Röderer, P and Matschke, J and Theiss, C and Matschke, V}, title = {Increased ROS-Dependent Fission of Mitochondria Causes Abnormal Morphology of the Cell Powerhouses in a Murine Model of Amyotrophic Lateral Sclerosis.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {6924251}, pmid = {34691359}, issn = {1942-0994}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Disease Models, Animal ; Humans ; Mice ; Mitochondria/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in humans and remains to have a fatal prognosis. Recent studies in animal models and human ALS patients indicate that increased reactive oxygen species (ROS) play an important role in the pathogenesis. Considering previous studies revealing the influence of ROS on mitochondrial physiology, our attention was focused on mitochondria in the murine ALS model, wobbler mouse. The aim of this study was to investigate morphological differences between wild-type and wobbler mitochondria with aid of superresolution structured illumination fluorescence microscopy, TEM, and TEM tomography. To get an insight into mitochondrial dynamics, expression studies of corresponding proteins were performed. Here, we found significantly smaller and degenerated mitochondria in wobbler motor neurons at a stable stage of the disease. Our data suggest a ROS-regulated, Ox-CaMKII-dependent Drp1 activation leading to disrupted fission-fusion balance, resulting in fragmented mitochondria. These changes are associated with numerous impairments, resulting in an overall self-reinforcing decline of motor neurons. In summary, our study provides common pathomechanisms with other ALS models and human ALS cases confirming mitochondria and related dysfunctions as a therapeutic target for the treatment of ALS.}, }
@article {pmid34690692, year = {2021}, author = {Jensen, TL and Gøtzsche, CR and Woldbye, DPD}, title = {Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {695937}, pmid = {34690692}, issn = {1662-5099}, abstract = {In recent years, gene therapy has been raising hopes toward viable treatment strategies for rare genetic diseases for which there has been almost exclusively supportive treatment. We here review this progress at the pre-clinical and clinical trial levels as well as market approvals within diseases that specifically affect the brain and spinal cord, including degenerative, developmental, lysosomal storage, and metabolic disorders. The field reached an unprecedented milestone when Zolgensma® (onasemnogene abeparvovec) was approved by the FDA and EMA for in vivo adeno-associated virus-mediated gene replacement therapy for spinal muscular atrophy. Shortly after EMA approved Libmeldy®, an ex vivo gene therapy with lentivirus vector-transduced autologous CD34-positive stem cells, for treatment of metachromatic leukodystrophy. These successes could be the first of many more new gene therapies in development that mostly target loss-of-function mutation diseases with gene replacement (e.g., Batten disease, mucopolysaccharidoses, gangliosidoses) or, less frequently, gain-of-toxic-function mutation diseases by gene therapeutic silencing of pathologic genes (e.g., amyotrophic lateral sclerosis, Huntington's disease). In addition, the use of genome editing as a gene therapy is being explored for some diseases, but this has so far only reached clinical testing in the treatment of mucopolysaccharidoses. Based on the large number of planned, ongoing, and completed clinical trials for rare genetic central nervous system diseases, it can be expected that several novel gene therapies will be approved and become available within the near future. Essential for this to happen is the in depth characterization of short- and long-term effects, safety aspects, and pharmacodynamics of the applied gene therapy platforms.}, }
@article {pmid34681219, year = {2021}, author = {Orlandi, P and Solini, A and Banchi, M and Brunetto, MR and Cioni, D and Ghiadoni, L and Bocci, G}, title = {Antiangiogenic Drugs in NASH: Evidence of a Possible New Therapeutic Approach.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {34681219}, issn = {1424-8247}, support = {PRA//University of Pisa/ ; }, abstract = {Non-alcoholic fatty liver disease is the most common liver disorder worldwide, and its progressive form non-alcoholic steatohepatitis (NASH) is a growing cause of liver cirrhosis and hepatocellular carcinoma (HCC). Lifestyle changes, which are capable of improving the prognosis, are hard to achieve, whereas a pharmacologic therapy able to combine efficacy and safety is still lacking. Looking at the pathophysiology of various liver diseases, such as NASH, fibrosis, cirrhosis, and HCC, the process of angiogenesis is a key mechanism influencing the disease progression. The relationship between the worsening of chronic liver disease and angiogenesis may suggest a possible use of drugs with antiangiogenic activity as a tool to stop or slow the progression of the disorder. In this review, we highlight the available preclinical data supporting a role of known antiangiogenic drugs (e.g., sorafenib), or phytotherapeutic compounds with multiple mechanism of actions, including also antiangiogenic activities (e.g., berberine), in the treatment of NASH.}, }
@article {pmid34678870, year = {2021}, author = {Henderson, RD and Agosti, JM and McCombe, PA and Thorpe, K and Heggie, S and Heshmat, S and Appleby, MW and Ziegelaar, BW and Crowe, DT and Redlich, GL}, title = {Phase 1b dose-escalation, safety, and pharmacokinetic study of IC14, a monoclonal antibody against CD14, for the treatment of amyotrophic lateral sclerosis.}, journal = {Medicine}, volume = {100}, number = {42}, pages = {e27421}, pmid = {34678870}, issn = {1536-5964}, support = {ID:03_TRG_2017_Henderson.//FightMND/ ; }, mesh = {Administration, Intravenous ; Amyotrophic Lateral Sclerosis/*drug therapy ; *Antibodies, Monoclonal/administration &amp; dosage/adverse effects/pharmacokinetics ; Area Under Curve ; Biomarkers ; Dose-Response Relationship, Drug ; Half-Life ; Humans ; Lipopolysaccharide Receptors ; Metabolic Clearance Rate ; Quality of Life ; }, abstract = {BACKGROUND: The primary objective was to demonstrate the safety and tolerability of monoclonal antibody against CD14 (IC14) (atibuclimab) in amyotrophic lateral sclerosis patients. The secondary objectives were pharmacokinetics, pharmacodynamics, and preliminary effects on disease status and biomarkers.<br><br>METHODS: In this open-label, dose-escalation trial, IC14 was administered at 2&#x200a;mg/kg intravenous (IV) followed by 1&#x200a;mg/kg/d IV &#xd7; 3 (n&#x200a;=&#x200a;3) and in subsequent patients at 4&#x200a;mg/kg IV followed by 2&#x200a;mg/kg/d IV &#xd7; 3 (n&#x200a;=&#x200a;7) (NCT03487263). Disease status was measured using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, Edinburgh Cognitive and Behavioural ALS Screen, and Revised ALS-Specific Quality-of-Life Score. Disease biomarkers included cerebrospinal fluid and serum levels of neurofilament light chain (NfL) and urinary p75 neurotrophin receptor.<br><br>RESULTS: IC14 was safe and well tolerated. No antidrug antibodies were detected. The drug target saturation of monocyte CD14 receptors was rapid and sustained through day 8. There was no significant change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, or Revised ALS-Specific Quality-of-Life Score following a single cycle of treatment. Cerebrospinal fluid NfL levels decreased in 6 of 9 patients sampled with declines of 15% to 40% between baseline (not significant [ns]) and day 8 in 3 patients. Serum NfL modestly decreased in 5 of 10 patients (ns) at day 8 and was sustained in 4 (4%-37%, ns) over 33&#x200a;days of follow up.<br><br>CONCLUSION: IC14 quickly and durably saturated its target in all patients. This study demonstrated safety and tolerability in patients with amyotrophic lateral sclerosis. Even though only a single cycle of treatment was given, there were promising beneficial trends in the neurofilament light chain, a disease biomarker. The emerging understanding of the role of systemic inflammation in neurodegenerative diseases, and the potential for IC14 to serve as a safe, potent, and broad-spectrum inhibitor of immune dysregulation merits further clinical study.<br><br>CLINICAL TRIAL REGISTRATION: NCT03487263.}, }
@article {pmid34676348, year = {2021}, author = {Jugl, S and Okpeku, A and Costales, B and Morris, EJ and Alipour-Haris, G and Hincapie-Castillo, JM and Stetten, NE and Sajdeya, R and Keshwani, S and Joseph, V and Zhang, Y and Shen, Y and Adkins, L and Winterstein, AG and Goodin, A}, title = {A Mapping Literature Review of Medical Cannabis Clinical Outcomes and Quality of Evidence in Approved Conditions in the USA from 2016 to 2019.}, journal = {Medical cannabis and cannabinoids}, volume = {4}, number = {1}, pages = {21-42}, pmid = {34676348}, issn = {2504-3889}, abstract = {In 2017, a National Academies of Sciences, Engineering, and Medicine (NASEM) report comprehensively evaluated the body of evidence regarding cannabis health effects through the year 2016. The objectives of this study are to identify and map the most recently (2016-2019) published literature across approved conditions for medical cannabis and to evaluate the quality of identified recent systematic reviews, published following the NASEM report. Following the literature search from 5 databases and consultation with experts, 11 conditions were identified for evidence compilation and evaluation: amyotrophic lateral sclerosis, autism, cancer, chronic noncancer pain, Crohn's disease, epilepsy, glaucoma, human immunodeficiency virus/AIDS, multiple sclerosis (MS), Parkinson's disease, and posttraumatic stress disorder. A total of 198 studies were included after screening for condition-specific relevance and after imposing the following exclusion criteria: preclinical focus, non-English language, abstracts only, editorials/commentary, case studies/series, and non-U.S. study setting. Data extracted from studies included: study design type, outcome definition, intervention definition, sample size, study setting, and reported effect size. Few completed randomized controlled trials (RCTs) were identified. Studies classified as systematic reviews were graded using the Assessing the Methodological Quality of Systematic Reviews-2 tool to evaluate the quality of evidence. Few high-quality systematic reviews were available for most conditions, with the exceptions of MS (9 of 9 graded moderate/high quality; evidence for 2/9 indicating cannabis improved outcomes; evidence for 7/9 indicating cannabis inconclusive), epilepsy (3 of 4 graded moderate/high quality; 3 indicating cannabis improved outcomes; 1 indicating cannabis inconclusive), and chronic noncancer pain (12 of 13 graded moderate/high quality; evidence for 7/13 indicating cannabis improved outcomes; evidence from 6/7 indicating cannabis inconclusive). Among RCTs, we identified few studies of substantial rigor and quality to contribute to the evidence base. However, there are some conditions for which significant evidence suggests that select dosage forms and routes of administration likely have favorable risk-benefit ratios (i.e., epilepsy and chronic noncancer pain). The body of evidence for medical cannabis requires more rigorous evaluation before consideration as a treatment option for many conditions, and evidence necessary to inform policy and treatment guidelines is currently insufficient for many conditions.}, }
@article {pmid34666894, year = {2022}, author = {Nagore, E and Virós, A and Kumar, R}, title = {Positive Attributes of Anti-TERT CD4 T-Helper Type 1 Immune Responses in Melanoma.}, journal = {The Journal of investigative dermatology}, volume = {142}, number = {2}, pages = {279-281}, doi = {10.1016/j.jid.2021.09.005}, pmid = {34666894}, issn = {1523-1747}, support = {110078/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; Immunity ; Immunotherapy ; *Melanoma/drug therapy ; *Telomerase ; Th1 Cells ; }, abstract = {Nardin et al's (2021) study on melanoma reports anti-TERT CD4 T helper type (Th) 1 responses in more than half of patients. Besides indicating a trend for improved survival, increased anti-TERT CD4 Th1 responses predicted better outcomes for patients treated with immune checkpoint inhibitors. Thus, harnessing systemic anti-TERT CD4 Th1 responses together with tumor-specific elevation of telomerase can potentially open new avenues for biomarkers and treatment in melanoma.}, }
@article {pmid34660025, year = {2021}, author = {Garzon-Siatoya, WT and Carrillo-Martin, I and Rodenas, M and Gonzalez-Estrada, A}, title = {IgE-Mediated Reaction to Levamisole: Evaluation of a Patient With Severe Anaphylaxis.}, journal = {Cureus}, volume = {13}, number = {9}, pages = {e17815}, pmid = {34660025}, issn = {2168-8184}, abstract = {Levamisole has been used as adjuvant immunomodulatory therapy for certain conditions such as amyotrophic lateral sclerosis (ALS). We present a case of a 70-year-old man with ALS who was started on levamisole with adequate response. Within 10 days of treatment, he developed a maculopapular non-pruritic rash on his extremities, and the medication was discontinued. However, two days later, he developed angioedema of the face and hands, urticaria in the extremities and torso, and throat closing sensation that was successfully treated in the emergency department with epinephrine, systemic corticosteroids, and antihistamines. Eight hours later, he presented with recurrent facial angioedema. He was transferred to the ICU and received two more doses of epinephrine and intravenous methylprednisolone. The patient fully recovered within 72 hours and was discharged with the indication to avoid levamisole. One month after the reaction, skin tests (prick and intradermal) with 10-fold dilutions of 550 mg/mL levamisole were positive at a concentration of 55 mg/mL (1:10 dilution). Since the patient developed anaphylaxis and tested positive for levamisole on intradermal testing, and after discussing the options with him, we decided to advise against using this medication since the benefits did not outweigh the risks of administration. This case highlights that IgE-mediated reactions to levamisole, while rare, can occur and be life-threatening. Shared decision-making should be done between patients and physicians after open, evidence-based discussions.}, }
@article {pmid34649360, year = {2021}, author = {Rodríguez-Arce, E and Saldías, M}, title = {Antioxidant properties of flavonoid metal complexes and their potential inclusion in the development of novel strategies for the treatment against neurodegenerative diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {143}, number = {}, pages = {112236}, doi = {10.1016/j.biopha.2021.112236}, pmid = {34649360}, issn = {1950-6007}, mesh = {Animals ; Antioxidants/chemistry/*pharmacology ; Coordination Complexes/chemistry/*pharmacology ; Flavonoids/chemistry/*pharmacology ; Humans ; Molecular Structure ; *Nerve Degeneration ; Neurodegenerative Diseases/*drug therapy/metabolism/pathology ; *Oxidative Stress ; Quercetin/analogs &amp; derivatives/chemistry/pharmacology ; Rutin/analogs &amp; derivatives/chemistry/pharmacology ; Structure-Activity Relationship ; }, abstract = {The increased oxidative stress in the acceleration of the aging process and development of the neuronal disorder are the common feature detected in neurodegenerative illness, such as Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. Searching for new treatment against these diseases, the inclusion of exogenous antioxidant agents has shown good results. Flavonoids are polyphenols compounds present in plants, fruits and vegetables that exhibit potent antioxidant and biological properties, which are related to their chemical structure that to confer an excellent radical scavenging ability. The design of metal-flavonoid complexes allows to obtain compounds with improved biological and physicochemical properties, generating important increase of the flavonoid antioxidant properties. This evidence we motive to propose that antioxidant properties of the metal flavonoids compounds can play an important role in the design of potential novel therapeutic strategies. This review presents the structure-activity relationship on the antioxidant properties of three series of metal-flavonoid complexes: M-(quercetin), M-(morin), and M-(rutin). In general, we observed that the coordination sites, the metal ion type used, and the molar ratio metal:flavonoid present in the complexes, are important factors for to increase the antioxidant activity. On these evidences we motive to propose that the development of metal-flavonoid compounds is a potentially viable approach for combating neurodegenerative diseases.}, }
@article {pmid34645610, year = {2021}, author = {Paidi, SK and Rodriguez Troncoso, J and Raj, P and Monterroso Diaz, P and Ivers, JD and Lee, DE and Avaritt, NL and Gies, AJ and Quick, CM and Byrum, SD and Tackett, AJ and Rajaram, N and Barman, I}, title = {Raman Spectroscopy and Machine Learning Reveals Early Tumor Microenvironmental Changes Induced by Immunotherapy.}, journal = {Cancer research}, volume = {81}, number = {22}, pages = {5745-5755}, pmid = {34645610}, issn = {1538-7445}, support = {R15 CA238861/CA/NCI NIH HHS/United States ; P20 GM103429/GM/NIGMS NIH HHS/United States ; P20 GM121293/GM/NIGMS NIH HHS/United States ; R01 CA238025/CA/NCI NIH HHS/United States ; R01 CA236209/CA/NCI NIH HHS/United States ; DP2 GM128198/GM/NIGMS NIH HHS/United States ; R24 GM137786/GM/NIGMS NIH HHS/United States ; P41 EB015871/EB/NIBIB NIH HHS/United States ; }, mesh = {Animals ; B7-H1 Antigen/*antagonists &amp; inhibitors ; CTLA-4 Antigen/*antagonists &amp; inhibitors ; Colonic Neoplasms/drug therapy/*immunology/metabolism/pathology ; Immune Checkpoint Inhibitors/*pharmacology ; Immunotherapy/methods ; *Machine Learning ; Mice ; Mice, Inbred BALB C ; Spectrum Analysis, Raman/*methods ; Tumor Cells, Cultured ; *Tumor Microenvironment ; }, abstract = {Cancer immunotherapy provides durable clinical benefit in only a small fraction of patients, and identifying these patients is difficult due to a lack of reliable biomarkers for prediction and evaluation of treatment response. Here, we demonstrate the first application of label-free Raman spectroscopy for elucidating biomolecular changes induced by anti-CTLA4 and anti-PD-L1 immune checkpoint inhibitors (ICI) in the tumor microenvironment (TME) of colorectal tumor xenografts. Multivariate curve resolution-alternating least squares (MCR-ALS) decomposition of Raman spectral datasets revealed early changes in lipid, nucleic acid, and collagen content following therapy. Support vector machine classifiers and random forests analysis provided excellent prediction accuracies for response to both ICIs and delineated spectral markers specific to each therapy, consistent with their differential mechanisms of action. Corroborated by proteomics analysis, our observation of biomolecular changes in the TME should catalyze detailed investigations for translating such markers and label-free Raman spectroscopy for clinical monitoring of immunotherapy response in cancer patients. SIGNIFICANCE: This study provides first-in-class evidence that optical spectroscopy allows sensitive detection of early changes in the biomolecular composition of tumors that predict response to immunotherapy with immune checkpoint inhibitors.}, }
@article {pmid34640573, year = {2021}, author = {Vogt, S and Schlichte, I and Schreiber, S and Wigand, B and Debska-Vielhaber, G and Heitmann, J and Meyer, T and Dengler, R and Petri, S and Haghikia, A and Vielhaber, S}, title = {A Multi-Center Cohort Study on Characteristics of Pain, Its Impact and Pharmacotherapeutic Management in Patients with ALS.}, journal = {Journal of clinical medicine}, volume = {10}, number = {19}, pages = {}, pmid = {34640573}, issn = {2077-0383}, support = {none//Deutsche Gesellschaft f&#xfc;r Muskelkranke/ ; none//Stiftung f&#xfc;r Medizinische Wissenschaft Frankfurt am Main/ ; }, abstract = {BACKGROUND: Although pain is common in amyotrophic lateral sclerosis (ALS) and an effectively treatable symptom, it is widely under-recognized and undertreated. This study investigates epidemiological and clinical characteristics of pain, its impact and pharmacological treatment in ALS patients. In addition, opportunities for further optimization of pain therapy need to be identified.<br><br>METHODS: Patients from three German ALS outpatient clinics were asked to complete the Brief Pain Inventory and the ALS Functional Rating Scale-Extension and to participate in semi-structured telephone interviews.<br><br>RESULTS: Of the 150 study participants, 84 patients reported pain. Pain occurred across all disease stages, predominantly in the neck, back and lower extremities. It was described with a broad spectrum of pain descriptors and mostly interfered with activity-related functions. Of the 84 pain patients, 53.8% reported an average pain intensity &#x2265;4 on the numerical rating scale (NRS), indicating pain of at least moderate intensity, and 64.3% used pain medication. Irrespective of the medication type, 20.4% of them had no sufficient pain relief. Thirteen out of 30 patients without pain medication reported an average NRS value &#x2265;4. Eleven of them-mainly in the context of high pain interference with daily functions-were supposed to benefit from adequate pain therapy. However, many patients had relevant concerns and misconceptions about pain therapy.<br><br>CONCLUSION: Given the frequency, extent and multi-faceted impact of pain, it is necessary to systematically assess pain throughout the disease course. Potentials to optimize pain therapy were seen in the subset of patients with insufficient pain relief despite medication and in those patients without pain medication but high pain interference. However, there is a need to respond to patients' barriers to pain therapy.}, }
@article {pmid34637802, year = {2022}, author = {Vose, AK and Welch, JF and Nair, J and Dale, EA and Fox, EJ and Muir, GD and Trumbower, RD and Mitchell, GS}, title = {Therapeutic acute intermittent hypoxia: A translational roadmap for spinal cord injury and neuromuscular disease.}, journal = {Experimental neurology}, volume = {347}, number = {}, pages = {113891}, pmid = {34637802}, issn = {1090-2430}, support = {R01 HD081274/HD/NICHD NIH HHS/United States ; R01 HL147554/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Hypoxia ; Neuromuscular Diseases/*therapy ; Spinal Cord Injuries/*therapy ; *Translational Research, Biomedical ; }, abstract = {We review progress towards greater mechanistic understanding and clinical translation of a strategy to improve respiratory and non-respiratory motor function in people with neuromuscular disorders, therapeutic acute intermittent hypoxia (tAIH). In 2016 and 2020, workshops to create and update a "road map to clinical translation" were held to help guide future research and development of tAIH to restore movement in people living with chronic, incomplete spinal cord injuries. After briefly discussing the pioneering, non-targeted basic research inspiring this novel therapeutic approach, we then summarize workshop recommendations, emphasizing critical knowledge gaps, priorities for future research effort, and steps needed to accelerate progress as we evaluate the potential of tAIH for routine clinical use. Highlighted areas include: 1) greater mechanistic understanding, particularly in non-respiratory motor systems; 2) optimization of tAIH protocols to maximize benefits; 3) identification of combinatorial treatments that amplify plasticity or remove plasticity constraints, including task-specific training; 4) identification of biomarkers for individuals most/least likely to benefit from tAIH; 5) assessment of long-term tAIH safety; and 6) development of a simple, safe and effective device to administer tAIH in clinical and home settings. Finally, we update ongoing clinical trials and recent investigations of tAIH in SCI and other clinical disorders that compromise motor function, including ALS, multiple sclerosis, and stroke.}, }
@article {pmid34636234, year = {2021}, author = {Collibee, SE and Bergnes, G and Chuang, C and Ashcraft, L and Gardina, J and Garard, M and Jamison, CR and Lu, K and Lu, PP and Muci, A and Romero, A and Valkevich, E and Wang, W and Warrington, J and Yao, B and Durham, N and Hartman, J and Marquez, A and Hinken, A and Schaletzky, J and Xu, D and Hwee, DT and Morgans, D and Malik, FI and Morgan, BP}, title = {Discovery of Reldesemtiv, a Fast Skeletal Muscle Troponin Activator for the Treatment of Impaired Muscle Function.}, journal = {Journal of medicinal chemistry}, volume = {64}, number = {20}, pages = {14930-14941}, doi = {10.1021/acs.jmedchem.1c01067}, pmid = {34636234}, issn = {1520-4804}, mesh = {Dose-Response Relationship, Drug ; *Drug Discovery ; Humans ; Molecular Structure ; Muscle, Skeletal/*drug effects/metabolism/pathology ; Structure-Activity Relationship ; Troponin/*metabolism ; }, abstract = {The discovery of reldesemtiv, a second-generation fast skeletal muscle troponin activator (FSTA) that increases force production at submaximal stimulation frequencies, is reported. Property-based optimization of high throughput screening hit 1 led to compounds with improved free exposure and in vivo muscle activation potency compared to the first-generation FSTA, tirasemtiv. Reldesemtiv demonstrated increased muscle force generation in a phase 1 clinical trial and is currently being evaluated in clinical trials for the treatment of amyotrophic lateral sclerosis.}, }
@article {pmid34635126, year = {2021}, author = {Wang, J and Tierney, L and Mann, R and Lonsway, T and Walker, CL}, title = {Bisperoxovanadium promotes motor neuron survival and neuromuscular innervation in amyotrophic lateral sclerosis.}, journal = {Molecular brain}, volume = {14}, number = {1}, pages = {155}, pmid = {34635126}, issn = {1756-6606}, support = {IK2 RX002688/RX/RRD VA/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Anterior Horn Cells/drug effects ; Cells, Cultured ; Chromones/pharmacology ; Culture Media, Serum-Free/pharmacology ; Humans ; Mice, Transgenic ; Microglia/drug effects ; Models, Animal ; Morpholines/pharmacology ; Motor Neurons/*drug effects ; Muscular Atrophy/etiology/pathology ; Mutation, Missense ; Neuromuscular Junction/drug effects ; Neuroprotective Agents/pharmacology/*therapeutic use ; PTEN Phosphohydrolase/antagonists &amp; inhibitors ; Point Mutation ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors ; Superoxide Dismutase-1/deficiency/genetics ; Vanadium Compounds/pharmacology/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease, with no present cure. The progressive loss of MNs is the hallmark of ALS. We have previously shown the therapeutic effects of the phosphatase and tensin homolog (PTEN) inhibitor, potassium bisperoxo (picolinato) vanadium (bpV[pic]), in models of neurological injury and demonstrated significant neuroprotective effects on MN survival. However, accumulating evidence suggests PTEN is detrimental for MN survival in ALS. Therefore, we hypothesized that treating the mutant superoxide dismutase 1 G93A (mSOD1[G93A]) mouse model of ALS during motor neuron degeneration and an in vitro model of mSOD1[G93A] motor neuron injury with bpV(pic) would prevent motor neuron loss. To test our hypothesis, we treated mSOD1[G93A] mice intraperitoneally daily with 400 μg/kg bpV(pic) from 70 to 90 days of age. Immunolabeled MNs and microglial reactivity were analyzed in lumbar spinal cord tissue, and bpV(pic) treatment significantly ameliorated ventral horn motor neuron loss in mSOD1[G93A] mice (p = 0.003) while not significantly altering microglial reactivity (p = 0.701). Treatment with bpV(pic) also significantly increased neuromuscular innervation (p = 0.018) but did not affect muscle atrophy. We also cultured motor neuron-like NSC-34 cells transfected with a plasmid to overexpress mutant SOD1[G93A] and starved them in serum-free medium for 24 h with and without bpV(pic) and downstream inhibitor of Akt signaling, LY294002. In vitro, bpV(pic) improved neuronal viability, and Akt inhibition reversed this protective effect (p < 0.05). In conclusion, our study indicates systemic bpV(pic) treatment could be a valuable neuroprotective therapy for ALS.}, }
@article {pmid34635103, year = {2021}, author = {Chang, CP and Wu, KC and Lin, CY and Chern, Y}, title = {Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases.}, journal = {Journal of biomedical science}, volume = {28}, number = {1}, pages = {70}, pmid = {34635103}, issn = {1423-0127}, support = {AS-BRPT-110-11//academia sinica/ ; MOST 110-2321-B-001-011//ministry of science and technology, taiwan/ ; }, mesh = {Adenosine/*physiology ; Brain/*physiopathology ; *Homeostasis ; Humans ; Neurodegenerative Diseases/*physiopathology ; Proteins/*metabolism ; }, abstract = {In modern societies, with an increase in the older population, age-related neurodegenerative diseases have progressively become greater socioeconomic burdens. To date, despite the tremendous effort devoted to understanding neurodegenerative diseases in recent decades, treatment to delay disease progression is largely ineffective and is in urgent demand. The development of new strategies targeting these pathological features is a timely topic. It is important to note that most degenerative diseases are associated with the accumulation of specific misfolded proteins, which is facilitated by several common features of neurodegenerative diseases (including poor energy homeostasis and mitochondrial dysfunction). Adenosine is a purine nucleoside and neuromodulator in the brain. It is also an essential component of energy production pathways, cellular metabolism, and gene regulation in brain cells. The levels of intracellular and extracellular adenosine are thus tightly controlled by a handful of proteins (including adenosine metabolic enzymes and transporters) to maintain proper adenosine homeostasis. Notably, disruption of adenosine homeostasis in the brain under various pathophysiological conditions has been documented. In the past two decades, adenosine receptors (particularly A1 and A2A adenosine receptors) have been actively investigated as important drug targets in major degenerative diseases. Unfortunately, except for an A2A antagonist (istradefylline) administered as an adjuvant treatment with levodopa for Parkinson's disease, no effective drug based on adenosine receptors has been developed for neurodegenerative diseases. In this review, we summarize the emerging findings on proteins involved in the control of adenosine homeostasis in the brain and discuss the challenges and future prospects for the development of new therapeutic treatments for neurodegenerative diseases and their associated disorders based on the understanding of adenosine homeostasis.}, }
@article {pmid34624328, year = {2022}, author = {Sajjadi, E and Seven, YB and Ehrbar, JG and Wymer, JP and Mitchell, GS and Smith, BK}, title = {Acute intermittent hypoxia and respiratory muscle recruitment in people with amyotrophic lateral sclerosis: A preliminary study.}, journal = {Experimental neurology}, volume = {347}, number = {}, pages = {113890}, pmid = {34624328}, issn = {1090-2430}, support = {UL1 TR001427/TR/NCATS NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*therapy ; Female ; Humans ; *Hypoxia ; Male ; Middle Aged ; Respiratory Mechanics/physiology ; Respiratory Muscles/*physiology ; }, abstract = {Respiratory failure is the main cause of death in amyotrophic lateral sclerosis (ALS). Since no effective treatments to preserve independent breathing are available, there is a critical need for new therapies to preserve or restore breathing ability. Since acute intermittent hypoxia (AIH) elicits spinal respiratory motor plasticity in rodent ALS models, and may restore breathing ability in people with ALS, we performed a proof-of-principle study to investigate this possibility in ALS patients. Quiet breathing, sniff nasal inspiratory pressure (SNIP) and maximal inspiratory pressure (MIP) were tested in 13 persons with ALS and 10 age-matched controls, before and 60 min post-AIH (15, 1 min episodes of 10% O2, 2 min normoxic intervals) or sham AIH (continuous normoxia). The root mean square (RMS) of the right and left diaphragm, 2nd parasternal, scalene and sternocleidomastoid muscles were monitored. A vector analysis was used to calculate summated vector magnitude (Mag) and similarity index (SI) of collective EMG activity during quiet breathing, SNIP and MIP maneuvers. AIH facilitated tidal volume and minute ventilation (treatment main effects: p < 0.05), and Mag (ie. collective respiratory muscle activity; p < 0.001) during quiet breathing in ALS and control subjects, but there was no effect on SI during quiet breathing. SNIP SI decreased in both groups post-AIH (p < 0.005), whereas Mag was unchanged (p = 0.09). No differences were observed in SNIP or MIP post AIH in either group. Discomfort was not reported during AIH by any subject, nor were adverse events observed. Thus, AIH may be a safe way to increase collective inspiratory muscle activity during quiet breathing in ALS patients, although a single AIH presentation was not sufficient to significantly increase peak inspiratory pressure generation. These preliminary results provide evidence that AIH may improve breathing function in people with ALS, and that future studies of prolonged, repetitive AIH protocols are warranted.}, }
@article {pmid34616479, year = {2021}, author = {Yang, EJ}, title = {A Novel Supplement Attenuates Oxidative Stress-Induced TDP-43-Related Pathogenesis in TDP-43-Expressed Cells.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2021}, number = {}, pages = {6773260}, pmid = {34616479}, issn = {1741-427X}, abstract = {Amyotrophic lateral sclerosis (ALS) is caused by selective the loss of spinal motor neurons by multifactorial pathological mechanisms and results in muscle atrophy. Incidence rates of ALS are increasing over time, but there are no effective treatments at present due to limitations on approved therapies (riluzole and edaravone). Therefore, this study investigated whether combined treatment with Bojungikgi-tang and riluzole could act synergistically in transactive response DNA-binding protein 43 (TDP-43) stress granule cells. To examine the effect of combined treatment on oxidative stress-induced cell death, the CCK8 assay was performed for the detection of cell viability. The expression of oxidative stress-induced proteins was determined by Western blot. Quantification of sodium arsenite-induced reactive oxygen species (ROS) was measured in TDP-43 stress granular cells using 2,7-diacetyl dichlorofluorescein diacetate. To investigate the effect of combined treatment on TDP-43 aggregation, immunofluorescence and immunoblotting were performed in TDP-43 stress granular cells. This combined treatment alleviated oxidative stress-induced cell death by increasing the expression levels of antioxidation proteins, such as heme oxygenase-1 and B cell lymphoma-2-associated X protein. Furthermore, it reduced oxidative stress-induced TDP-43 aggregates and lowered the levels of autophagy-related proteins, including p62, light chain 3b, and ATG8, in TDP-43-expressing cells. Our results suggest that this combined treatment could be helpful for autophagy regulation in other neurodegenerative diseases.}, }
@article {pmid34606852, year = {2021}, author = {Gupta, R and Jha, A and Ambasta, RK and Kumar, P}, title = {Regulatory mechanism of cyclins and cyclin-dependent kinases in post-mitotic neuronal cell division.}, journal = {Life sciences}, volume = {285}, number = {}, pages = {120006}, doi = {10.1016/j.lfs.2021.120006}, pmid = {34606852}, issn = {1879-0631}, mesh = {Acetylation ; Animals ; Cyclin-Dependent Kinases/*metabolism ; Cyclins/*metabolism ; Histone Deacetylases/metabolism ; Humans ; *Mitosis ; Neurodegenerative Diseases/*metabolism/*pathology ; Neurons/*metabolism/*pathology ; Ubiquitin-Protein Ligases/metabolism ; }, abstract = {Neurodegenerative diseases (NDDs) are the most common life-threatening disease of the central nervous system and it cause the progressive loss of neuronal cells. The exact mechanism of the disease's progression is not clear and thus line of treatment for NDDs is a baffling issue. During the progression of NDDs, oxidative stress and DNA damage play an important regulatory function, and ultimately induces neurodegeneration. Recently, aberrant cell cycle events have been demonstrated in the progression of different NDDs. However, the pertinent role of signaling mechanism, for instance, post-translational modifications, oxidative stress, DNA damage response pathway, JNK/p38 MAPK, MEK/ERK cascade, actively participated in the aberrant cell cycle reentry induced neuronal cell death. Mounting evidence has demonstrated that aberrant cell cycle re-entry is a major contributing factor in the pathogenesis of NDDs rather than a secondary phenomenon. In the brain of AD patients with mild cognitive impairment, post miotic cell division can be seen in the early stage of the disease. However, in the brain of PD patients, response to various neurotoxic signals, the cell cycle re-entry has been observed that causes neuronal apoptosis. On contrary, the contributing factors that leads to the induction of cell cycle events in mature neurons in HD and ALS brain pathology is remain unclear. Various pharmacological drugs have been developed to reduce the pathogenesis of NDDs, but they are still not helpful in eliminating the cause of these NDDs.}, }
@article {pmid34590512, year = {2022}, author = {Vucic, S and Wray, N and Henders, A and Henderson, RD and Talman, P and Mathers, S and Bellgard, M and Aoun, S and Birks, C and Thomas, G and Hansen, C and Thomas, G and Hogden, A and Needham, M and Schultz, D and Soulis, T and Sheean, B and Milne, J and Rowe, D and Zoing, M and Kiernan, MC}, title = {MiNDAUS partnership: a roadmap for the cure and management of motor Neurone disease.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {5-6}, pages = {321-328}, doi = {10.1080/21678421.2021.1980889}, pmid = {34590512}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis ; Australia ; Caregivers ; Data Collection ; Humans ; *Motor Neuron Disease/therapy ; }, abstract = {An innovative approach to patient management, evidence-based policy development, and clinical drug trials is required to provide personalized care and to improve the likelihood of finding an effective treatment for Motor Neurone Disease (MND). The MiNDAus Partnership builds on and extends existing national collaborations in a targeted approach to improve the standard and coordination of care for people living with MND in Australia, and to enhance the prospects of discovering a cure or treatment. Relationships have been developed between leading clinical and research groups as well as patient-centered organizations, care providers, and philanthropy with a shared vision. MiNDAus has established a corporate structure and meets at least biannually to decide on how best to progress research, drug development, and patient management. The key themes are; (i) empowering patients and their family carers to engage in self-management and ensure personalized service provision, treatment, and policy development, (ii) integration of data collection so as to better inform policy development, (iii) unifying patients and carers with advocacy groups, funding bodies, clinicians and academic institutions so as to inform policy development and research, (iv) coordination of research efforts and development of standardized national infrastructure for conducting innovative clinical MND trials that can be harmonized within Australia and with international trials consortia. Such a collaborative approach is required across stakeholders in order to develop innovative management guidelines, underpinned by necessary and evidence-based policy change recommendations, which, will ensure the best patient care until a cure is discovered.}, }
@article {pmid34588483, year = {2021}, author = {Lum, JS and Brown, ML and Farrawell, NE and McAlary, L and Ly, D and Chisholm, CG and Snow, J and Vine, KL and Karl, T and Kreilaus, F and McInnes, LE and Nikseresht, S and Donnelly, PS and Crouch, PJ and Yerbury, JJ}, title = {CuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1[G93A] mice with a C57BL/6 background.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {19392}, pmid = {34588483}, issn = {2045-2322}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Disease Progression ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuroprotective Agents/*administration &amp; dosage ; *Organocopper Compounds/administration &amp; dosage/adverse effects/pharmacology ; Superoxide Dismutase-1/*metabolism ; }, abstract = {The synthetic copper-containing compound, CuATSM, has emerged as one of the most promising drug candidates developed for the treatment of amyotrophic lateral sclerosis (ALS). Multiple studies have reported CuATSM treatment provides therapeutic efficacy in various mouse models of ALS without any observable adverse effects. Moreover, recent results from an open label clinical study suggested that daily oral dosing with CuATSM slows disease progression in patients with both sporadic and familial ALS, providing encouraging support for CuATSM in the treatment of ALS. Here, we assessed CuATSM in high copy SOD1[G93A] mice on the congenic C57BL/6 background, treating at 100 mg/kg/day by gavage, starting at 70 days of age. This dose in this specific model has not been assessed previously. Unexpectedly, we report a subset of mice initially administered CuATSM exhibited signs of clinical toxicity, that necessitated euthanasia in extremis after 3-51 days of treatment. Following a 1-week washout period, the remaining mice resumed treatment at the reduced dose of 60 mg/kg/day. At this revised dose, treatment with CuATSM slowed disease progression and increased survival relative to vehicle-treated littermates. This work provides the first evidence that CuATSM produces positive disease-modifying outcomes in high copy SOD1[G93A] mice on a congenic C57BL/6 background. Furthermore, results from the 100 mg/kg/day phase of the study support dose escalation determination of tolerability as a prudent step when assessing treatments in previously unassessed models or genetic backgrounds.}, }
@article {pmid34585475, year = {2022}, author = {Gento-Caro, &#xc1; and Vilches-Herrando, E and Portillo, F and González-Forero, D and Moreno-López, B}, title = {Targeting autotaxin impacts disease advance in the SOD1-G93A mouse model of amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {32}, number = {3}, pages = {e13022}, pmid = {34585475}, issn = {1750-3639}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Animals ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism ; Nerve Degeneration/pathology ; RNA, Messenger/metabolism ; Spinal Cord/pathology ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/metabolism ; }, abstract = {A preclinical strategy to broaden the search of potentially effective treatments in amyotrophic lateral sclerosis (ALS) relies on identifying factors controlling motor neuron (MN) excitability. These partners might be part of still unknown pathogenic pathways and/or useful for the design of new interventions to affect disease progression. In this framework, the bioactive membrane-derived phospholipid lysophosphatidic acid (LPA) affects MN excitability through LPA receptor 1 (LPA1). Furthermore, LPA1 knockdown is neuroprotective in transgenic ALS SOD1-G93A mice. On this basis, we raised the hypothesis that the major LPA-synthesizing ectoenzyme, autotaxin (ATX), regulates MN excitability and is a potential target to modulate disease development in ALS mice. We show here that PF-8380, a specific ATX inhibitor, reduced intrinsic membrane excitability (IME) of hypoglossal MNs in brainstem slices, supporting that baseline ATX activity regulates MN IME. PF-8380-induced alterations were prevented by a small-interfering RNA directed against mRNA for lpa1 . These outcomes support that impact of ATX-originated lysophospholipids on MN IME engages, at least, the G-protein-coupled receptor LPA1 . Interestingly, mRNAatx levels increased in the spinal cord of pre-symptomatic (1-2 months old) SOD1-G93A mice, thus preceding MN loss. The rise in transcripts levels also occurred in cultured spinal cord MNs from SOD1-G93A embryos, suggesting that mRNAatx upregulation in MNs is an etiopathogenic event in the ALS cell model. Remarkably, chronic administration in the drinking water of the orally bioavailable ATX inhibitor PF-8380 delayed MN loss, motor deterioration and prolonged life span in ALS mice. Treatment also led to a reduction in LPA1 -immunoreactive patches in transgenic animals mostly in MNs. These outcomes support that neuroprotective effects of interfering with ATX in SOD1-G93A mice rely, at least in part, on LPA1 knockdown in MNs. Therefore, we propose ATX as a potential target and/or a biomarker in ALS and highlight ATX inhibitors as reasonable tools with therapeutic usefulness for this lethal pathology.}, }
@article {pmid34576165, year = {2021}, author = {Polgár, TF and Meszlényi, V and Nógrádi, B and Körmöczy, L and Spisák, K and Tripolszki, K and Széll, M and Obál, I and Engelhardt, JI and Siklós, L and Patai, R}, title = {Passive Transfer of Blood Sera from ALS Patients with Identified Mutations Results in Elevated Motoneuronal Calcium Level and Loss of Motor Neurons in the Spinal Cord of Mice.}, journal = {International journal of molecular sciences}, volume = {22}, number = {18}, pages = {}, pmid = {34576165}, issn = {1422-0067}, support = {GINOP-2.3.2-15-2016-00034//Nemzetgazdas&#xe1;gi Miniszt&#xe9;rium/ ; FEIF/433-4/2020-ITM_SZERZ//Innov&#xe1;ci&#xf3;s &#xe9;s Technol&#xf3;giai Miniszt&#xe9;rium/ ; NTP-NFT&#xd6;-21-B-0203//Emberi Eroforr&#xe1;sok Miniszt&#xe9;riuma/ ; EFOP 3.6.3-VEKOP-16-2017-00009//P&#xe9;nz&#xfc;gyminiszt&#xe9;rium/ ; }, mesh = {Amyotrophic Lateral Sclerosis/blood/*metabolism ; Animals ; Calcium/*metabolism ; Disease Models, Animal ; Immunoglobulins/genetics/metabolism ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred BALB C ; Motor Neurons/*metabolism ; Mutation/genetics ; }, abstract = {Introduction: Previously, we demonstrated the degeneration of axon terminals in mice after repeated injections of blood sera from amyotrophic lateral sclerosis (ALS) patients with identified mutations. However, whether a similar treatment affects the cell body of motor neurons (MNs) remained unresolved. Methods: Sera from healthy individuals or ALS patients with a mutation in different ALS-related genes were intraperitoneally injected into ten-week-old male Balb/c mice (n = 3/serum) for two days. Afterward, the perikaryal calcium level was measured using electron microscopy. Furthermore, the optical disector method was used to evaluate the number of lumbar MNs. Results: The cytoplasmic calcium level of the lumbar MNs of the ALS-serum-treated mice, compared to untreated and healthy-serum-treated controls, was significantly elevated. While injections of the healthy serum did not reduce the number of MNs compared to the untreated control group, ALS sera induced a remarkable loss of MNs. Discussion: Similarly to the distant motor axon terminals, the injection of blood sera of ALS patients has a rapid degenerative effect on MNs. Analogously, the magnitude of the evoked changes was specific to the type of mutation; furthermore, the degeneration was most pronounced in the group treated with sera from ALS patients with a mutation in the chromosome 9 open reading frame 72 gene.}, }
@article {pmid34575906, year = {2021}, author = {Bolcato, G and Cescon, E and Pavan, M and Bissaro, M and Bassani, D and Federico, S and Spalluto, G and Sturlese, M and Moro, S}, title = {A Computational Workflow for the Identification of Novel Fragments Acting as Inhibitors of the Activity of Protein Kinase CK1δ.}, journal = {International journal of molecular sciences}, volume = {22}, number = {18}, pages = {}, pmid = {34575906}, issn = {1422-0067}, support = {2017MT3993//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; }, mesh = {Binding Sites ; Casein Kinase Idelta/*antagonists &amp; inhibitors/*chemistry ; Drug Discovery/*methods ; Humans ; *Models, Molecular ; Molecular Conformation ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Binding ; Protein Kinase Inhibitors/*chemistry/*pharmacology ; Structure-Activity Relationship ; Workflow ; }, abstract = {Fragment-Based Drug Discovery (FBDD) has become, in recent years, a consolidated approach in the drug discovery process, leading to several drug candidates under investigation in clinical trials and some approved drugs. Among these successful applications of the FBDD approach, kinases represent a class of targets where this strategy has demonstrated its real potential with the approved kinase inhibitor Vemurafenib. In the Kinase family, protein kinase CK1 isoform δ (CK1δ) has become a promising target in the treatment of different neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In the present work, we set up and applied a computational workflow for the identification of putative fragment binders in large virtual databases. To validate the method, the selected compounds were tested in vitro to assess the CK1δ inhibition.}, }
@article {pmid34575481, year = {2021}, author = {Kang, DW and Kim, JH and Kim, KM and Cho, SJ and Jang, HW and Chang, JW and Dong, SM and Lim, JW and Kim, JS and Cho, HY}, title = {Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704.}, journal = {Pharmaceutics}, volume = {13}, number = {9}, pages = {}, pmid = {34575481}, issn = {1999-4923}, support = {202000380001//Theragen Etex Co. Ltd/ ; }, abstract = {Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger approved for the treatment of amyotrophic lateral sclerosis, a fatal neuromuscular disease. Edaravone is administered as an intravenous infusion over 60 min for several treatment cycles. To ease the burden of patients and caregivers, the oral formulation of edaravone has been developed. The purpose of this study was to evaluate pharmacokinetics and tissue distribution of TEJ-1704, an edaravone oral prodrug, in male Sprague Dawley rats and beagle dogs. Animal experiments were conducted using Sprague Dawley rats and beagle dogs to evaluate pharmacokinetics, tissue distribution, and excretion of TEJ-1704. Blood, tissues, cerebrospinal fluid, urine, and feces samples were collected at designated sampling time after intravenous (IV) or oral (PO) administration of edaravone or TEJ-1704. A modified bioanalysis method was developed to quantify edaravone in samples including plasma, tissues, cerebrospinal fluid, urine, and feces. The bioanalysis method was validated and successfully applied to pharmacokinetics, tissue distribution, and excretion studies of the novel edaravone prodrug. Although plasma Cmax of TEJ-1704 was low, groups administered with TEJ-1704 had high AUCinf, suggesting continuous metabolism of TEJ-1704 into edaravone. Groups treated with TEJ-1704 also showed lower CSF distribution than the control groups. After the administration of TEJ-1704, the majority of edaravone was distributed to the heart, lung, and kidney. It was excreted equally via urine and feces. The pharmacokinetics, tissue distribution, and excretion of TEJ-1704, a novel edaravone oral prodrug, were successfully characterized. Additional studies are needed to fully understand the difference between TEJ-1704 and edaravone and determine the potency of TEJ-1704.}, }
@article {pmid34573864, year = {2021}, author = {Krause, K and Wulf, M and Sommer, P and Barkovits, K and Vorgerd, M and Marcus, K and Eggers, B}, title = {CSF Diagnostics: A Potentially Valuable Tool in Neurodegenerative and Inflammatory Disorders Involving Motor Neurons: A Review.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {11}, number = {9}, pages = {}, pmid = {34573864}, issn = {2075-4418}, abstract = {Cerebrospinal fluid (CSF) diagnostics has emerged as a valid tool for a variety of neurological diseases. However, CSF diagnostics has been playing a subordinate role in the diagnosis of many neurological conditions. Thus, in the multitude of neuromuscular diseases in which motor neurons are affected, a CSF sample is rarely taken routinely. However, CSF diagnostics has the potential to specify the diagnosis and monitor the treatment of neuromuscular disorders. In this review, we therefore focused on a variety of neuromuscular diseases, among them amyotrophic lateral sclerosis (ALS), peripheral neuropathies, and spinal muscular atrophy (SMA), for which CSF diagnostics has emerged as a promising option for determining the disease itself and its progression. We focus on potentially valuable biomarkers among different disorders, such as neurofilaments, cytokines, other proteins, and lipids to determine their suitability, differentiating between different neurological disorders and their potential to determine early disease onset, disease progression, and treatment outcome. We further recommend novel approaches, e.g., the use of mass spectrometry as a promising alternative techniques to standard ELISA assays, potentially enhancing biomarker significance in clinical applications.}, }
@article {pmid34573264, year = {2021}, author = {Brakemeier, S and Stolte, B and Thimm, A and Kizina, K and Totzeck, A and Munoz-Rosales, J and Kleinschnitz, C and Hagenacker, T}, title = {Assessment of Bulbar Function in Adult Patients with 5q-SMA Type 2 and 3 under Treatment with Nusinersen.}, journal = {Brain sciences}, volume = {11}, number = {9}, pages = {}, pmid = {34573264}, issn = {2076-3425}, abstract = {The antisense oligonucleotide nusinersen has been shown to improve trunk and limb motor function in patients with spinal muscular atrophy (SMA). Bulbar dysfunction, which is regularly present in SMA, is not captured by standard motor scores, and validated measurement instruments to assess it have not yet been established. Data on whether and how bulbar function changes under gene-based therapies in adult SMA patients are also unavailable. Here, we present data on the course of bulbar dysfunction assessed prospectively before nusinersen treatment initiation and 6 and 14 months later in 23 adult SMA patients using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). While no improvement in bulbar scores was observed under treatment with nusinersen, the absence of a decline still implies a therapeutic effect of nusinersen on bulbar dysfunction. The results of this study aim to contribute to a standardized assessment of bulbar function in adult SMA patients, which may show therapeutic effects of gene-based therapies that are not evident from standard motor scores.}, }
@article {pmid34569363, year = {2022}, author = {Salmon, K and Anoja, N and Breiner, A and Chum, M and Dionne, A and Dupré, N and Fiander, A and Fok, D and Ghavanini, A and Gosselin, S and Izenberg, A and Johnston, W and Kalra, S and Matte, G and Melanson, M and O'Connell, C and Ritsma, B and Schellenberg, K and Shoesmith, C and Tremblay, S and Williams, H and Genge, A}, title = {Genetic testing for amyotrophic lateral sclerosis in Canada - an assessment of current practices.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {3-4}, pages = {305-312}, doi = {10.1080/21678421.2021.1980890}, pmid = {34569363}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; Canada/epidemiology ; Genetic Counseling ; Genetic Testing ; Humans ; Surveys and Questionnaires ; }, abstract = {Objective: To understand current genetic testing practices at Canadian ALS clinics. Methods: An online survey and phone interviews, with clinicians practicing in 27 ALS clinics in Canada, were employed to collect data. Quantitative and qualitative analyses were conducted. Results: Ninety-three percent (25/27) of ALS clinics in Canada are routinely ordering genetic testing for familial ALS, while 33% (9/27) of clinics are routinely ordering genetic testing for sporadic ALS. Barriers to genetic testing include a perceived lack of an impact on treatment plan, difficulty in obtaining approvals, primarily from provincial Ministries of Health, and limited access to genetic counseling. Predictive testing practices were found to be the most variable across the country. The average wait time for a symptomatic patient living with ALS to see a genetic counselor in Canada is 10 months (range 0-36 months). Conclusions: Access to genetic testing, and testing practices, vary greatly across Canadian ALS clinics. There may be patients with a monogenetic etiology to their ALS who are not being identified given that genetic testing for patients diagnosed with ALS is not routinely performed at all clinics. This study highlights potential inequities for patients with ALS that can arise from variability in health care delivery across jurisdictions, in a federally-funded, but provincially-regulated, health care system. Clinical trials for both symptomatic ALS patients and pre-symptomatic ALS gene carriers are ongoing, and ALS clinicians in Canada are motivated to improve access to genetic testing for ALS.}, }
@article {pmid34560799, year = {2023}, author = {Raspe, H and Lill, C}, title = {[Inflammatory Bowel Diseases: Regional Deprivation, Disease Characteristics and Relevant Health Care].}, journal = {Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany))}, volume = {85}, number = {3}, pages = {149-157}, doi = {10.1055/a-1530-5529}, pmid = {34560799}, issn = {1439-4421}, mesh = {Humans ; *Quality of Life ; Germany ; *Medicine ; Delivery of Health Care ; }, abstract = {HINTERGRUND: Regionale Deprivation ist als ökologischer Parameter eine Komponente der sozialen Determinanten von Gesundheit. Zu ihrer Messung stehen in Deutschland der "German Index of Multiple Deprivation" (GIMD) und der "German Index of Socioeconomic Deprivation" (GISD) zur Verfügung. Chronisch entzündliche Darmerkrankungen (CED) sind keine häufigen, aber ernste körperliche Erkrankungen unklarer Ätiologie, mit vergleichsweise frühem Auftreten im Erwachsenenalter, oft chronisch-behandlungsbedürftigem Verlauf und unsicherer Prognose. Daten einer kontrollierten Versorgungsstudie erlauben es, Assoziationen zwischen regio-naler Deprivation und Merkmalen der Krankheit und ihrer Versorgung zu untersuchen. Wir erwarteten ungünstigere Krankheitsverhältnisse bei höherer Deprivation.<br><br>METHODIK: Vorgestellt werden deskriptive Zusatzauswertungen (n=530) der 2016 bis 2019 durchgef&#xfc;hrten MERCED-Studie zu Wirksamkeit und Nutzen einer station&#xe4;ren medizinischen Rehabilitation bei Sozialversicherten mit einer CED. Analysiert wurden Daten aus der Basisbefragung zu selbstberichteten Krankheitsmerkmalen, Krankheitsfolgen und Versorgungsleistungen in ihrem Zusammenhang mit dem Ausma&#xdf; regionaler Deprivation der Wohnregion (Kreisebene).<br><br>ERGEBNISSE: Die Zuordnung der Wohnregion der Kranken zu den Quintilen von GIMD und GISD korrelieren unter rho=0,76 miteinander (gewichtetes kappa=0,74). Regionale Deprivation zeigt, gemessen mit dem GIMD, &#xfc;berzuf&#xe4;llige Unterschiede allein in den sozialen Teilhabeeinschr&#xe4;nkungen (IMET) und der Zahl der "Einschr&#xe4;nkungstage". Dabei schildern sich Personen aus dem niedrigsten Deprivationsquintil als am st&#xe4;rksten eingeschr&#xe4;nkt. F&#xfc;r die Einschr&#xe4;nkungstage findet sich ein irre-gul&#xe4;res Muster. Beim GISD wird eine unsystematische Variation der gesundheitsbezogenen Lebensqualit&#xe4;t (EQ-VAS) statistisch auff&#xe4;llig. Auch hier berichten Personen mit der geringsten regionalen Deprivation von einer besonders schlechten Lebensqualit&#xe4;t. In einem Extremgruppenvergleich weisen Personen, die in nach GIMD und GISD stark deprivierten Regionen leben, g&#xfc;nstigere Werte im Krankheitsverlauf beim IMET und EQ-VAS auf. Auch f&#xfc;r Parameter der medizinischen Versorgung lassen sich keine systematischen Zusammenh&#xe4;nge mit den Deprivationsindizes darstellen.<br><br>SCHLUSSFOLGERUNG: Krankheitsmerkmale, Krankheitsfolgen und die medizinische Versorgung von CED-Kranken zeigen sich weitgehend unabh&#xe4;ngig vom Ausma&#xdf; der mit zwei Indizes bestimmten regionalen Deprivation. Die wenigen auff&#xe4;lligen Unterschiede weisen in eine &#xfc;berraschende Richtung: Personen aus deprivierten Regionen berichten g&#xfc;nstigere Krankheitsverh&#xe4;ltnisse.<br><br>BACKGROUND: As an ecological parameter, area deprivation is one component of the social determinants of health. For Germany two indices to measure area deprivation are currently available: The German Index of Multiple Deprivation (GIMD) and the German Index of Socioeconomic Deprivation (GISD). Inflammatory bowel diseases (IBD) are not frequent but severe diseases of so far unknown etiology, comparatively early manifestation in adulthood, often chronic course requiring long-lasting medical attention, and uncertain prognosis. Data of a controlled health care trial enable us to study associations between area deprivation and disease and treatment variables. We expected more unfavourable conditions with increasing level of deprivation.<br><br>METHODS: We present secondary descriptive analyses of an RCT on effectiveness and benefit of medical inpatient rehab of 530 socially insured IBD patients. We used data from the initial assessment of numerous self-reported disease characteristics, consequences of disease, and health care items in relation to the extent of area deprivation at patients' county ("Kreis") level.<br><br>RESULTS: Grouped into quintiles, patients' results from GIMD and GISD are closely correlated (rho=0.76; weighted kappa=0.74). Regional deprivation, as assessed by GIMD, shows noticeable associations only with participation restriction (IMET scale) and number of disability days. However, subjects from least deprived areas report highest restrictions whereas the distribution of disability days exhibits an irregular pattern. GISD data are weakly and unsystematically related to quality of life measurements. Again, patients from least deprived areas show a considerably low quality of life. A comparison of two extreme groups (very low vs. very high deprivation in GIMD and GISD combined) corroborates the finding: Subjects from highly deprived areas report in general more favourable disease characteristics. We found no association between deprivation and any health care item.<br><br>CONCLUSION: Disease characteristics, psychosocial consequences, and health care of IBD seem to be mainly independent of the extent of area deprivation. The few statistically noticeable associations are unexpected: Patients from more deprived counties give more favourable reports.}, }
@article {pmid34560374, year = {2021}, author = {Sahu, R and Upadhayay, S and Mehan, S}, title = {Inhibition of extracellular regulated kinase (ERK)-1/2 signaling pathway in the prevention of ALS: Target inhibitors and influences on neurological dysfunctions.}, journal = {European journal of cell biology}, volume = {100}, number = {7-8}, pages = {151179}, doi = {10.1016/j.ejcb.2021.151179}, pmid = {34560374}, issn = {1618-1298}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Apoptosis ; Cell Proliferation ; Humans ; MAP Kinase Signaling System ; Neurons ; Signal Transduction ; }, abstract = {Cell signal transduction pathways are essential modulators of several physiological and pathological processes in the brain. During overactivation, these signaling processes may lead to disease progression. Abnormal protein kinase activation is associated with several biological dysfunctions that facilitate neurodegeneration under different biological conditions. As a result, these signaling pathways are essential in understanding brain disorders' development or progression. Recent research findings indicate the crucial role of extracellular signal-regulated kinase-1/2 (ERK-1/2) signaling during the neuronal development process. ERK-1/2 is a key component of its mitogen-activated protein kinase (MAPK) group, controlling certain neurological activities by regulating metabolic pathways, cell proliferation, differentiation, and apoptosis. ERK-1/2 also influences neuronal elastic properties, nerve growth, and neurological and cognitive processing during brain injuries. The primary goal of this review is to elucidate the activation of ERK1/2 signaling, which is involved in the development of several ALS-related neuropathological dysfunctions. ALS is a rare neurological disorder category that mainly affects the nerve cells responsible for regulating voluntary muscle activity. ALS is progressive, which means that the symptoms are getting worse over time, and there is no cure for ALS and no effective treatment to avoid or reverse. Genetic abnormalities, oligodendrocyte degradation, glial overactivation, and immune deregulation are associated with ALS progression. Furthermore, the current review also identifies ERK-1/2 signaling inhibitors that can promote neuroprotection and neurotrophic effects against the clinical-pathological presentation of ALS. As a result, in the future, the potential ERK-1/2 signaling inhibitors could be used in the treatment of ALS and related neurocomplications.}, }
@article {pmid34558138, year = {2022}, author = {Erekat, NS}, title = {Apoptosis and its therapeutic implications in neurodegenerative diseases.}, journal = {Clinical anatomy (New York, N.Y.)}, volume = {35}, number = {1}, pages = {65-78}, doi = {10.1002/ca.23792}, pmid = {34558138}, issn = {1098-2353}, mesh = {*Alzheimer Disease ; *Amyotrophic Lateral Sclerosis/drug therapy ; Apoptosis ; Humans ; *Huntington Disease ; *Neurodegenerative Diseases/drug therapy ; *Parkinson Disease/drug therapy ; }, abstract = {Neurodegenerative disorders are characterized by progressive loss of particular populations of neurons. Apoptosis has been implicated in the pathogenesis of neurodegenerative diseases, including Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. In this review, we focus on the existing notions relevant to comprehending the apoptotic death process, including the morphological features, mediators and regulators of cellular apoptosis. We also highlight the evidence of neuronal apoptotic death in Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. Additionally, we present evidence of potential therapeutic agents that could modify the apoptotic pathway in the aforementioned neurodegenerative diseases and delay disease progression. Finally, we review the clinical trials that were conducted to evaluate the use of anti-apoptotic drugs in the treatment of the aforementioned neurodegenerative diseases, in order to highlight the essential need for early detection and intervention of neurodegenerative diseases in humans.}, }
@article {pmid34554894, year = {2021}, author = {Chiò, A and Canosa, A and Calvo, A and Moglia, C and Cicolin, A and Mora, G}, title = {Developments in the assessment of non-motor disease progression in amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {21}, number = {12}, pages = {1419-1440}, doi = {10.1080/14737175.2021.1984883}, pmid = {34554894}, issn = {1744-8360}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; *Cognitive Dysfunction ; Disease Progression ; Humans ; Quality of Life ; Surveys and Questionnaires ; }, abstract = {INTRODUCTION: The burden of non-motor symptoms is a major determinant of quality of life and outcome in amyotrophic lateral sclerosis (ALS) and has profound negative effect also on caregivers.<br><br>AREAS COVERED: Non-motor symptoms in ALS include cognitive impairment, neurobehavioral symptoms, depression and anxiety, suicidal ideation, pain, disordered sleep, fatigue, weight loss and reduced appetite, and autonomic dysfunctions. This review summarizes the measures used for the assessment of non-motor symptoms and their properties and recaps the frequency and progression of these symptoms along the course of ALS.<br><br>EXPERT OPINION: Non-motor symptoms in ALS represent a major component of the disease and span over several domains. These symptoms require a high level of medical attention and should be checked at each visit using ad hoc questionnaires and proactively treated. Several instruments assessing non-motor symptoms have been used in ALS. Specific screening questionnaires for non-motor symptoms can be used for monitoring patients during telehealth visits and for remote surveillance through sensors and apps installed on smartphones. Novel trials for non-motor symptoms treatment specifically designed for ALS are necessary to increase and refine the therapeutic armamentarium. Finally, scales assessing the most frequent and burdensome non-motor symptoms should be included in clinical trials.}, }
@article {pmid34544176, year = {2021}, author = {Onder, ENA and Ertan, P}, title = {Fibrinogen-to-Albumin Ratio in Familial Mediterranean Fever: Association with Subclinical Inflammation.}, journal = {Klinische Padiatrie}, volume = {233}, number = {6}, pages = {292-298}, doi = {10.1055/a-1610-9745}, pmid = {34544176}, issn = {1439-3824}, mesh = {Albumins ; *Familial Mediterranean Fever/diagnosis/drug therapy/genetics ; *Fibrinogen ; Humans ; Inflammation ; Retrospective Studies ; }, abstract = {BACKGROUND: Familial Mediterranean fever (FMF) is the most seen monogenic periodic fever syndrome characterised by bouts of fever and serositis. It is known that subclinical inflammation (SI) can persist in the symptom-free period and lead to amyloidosis even under colchicine treatment. This study aimed to evaluate the role of the fibrinogen-to-albumin ratio (FAR) in FMF and its correlation with SI.<br><br>MATERIAL AND METHODS: A total of 112 patients with FMF and 78 controls were enrolled in this retrospective study. Demographic, laboratory and genetic data were obtained from the hospital records.<br><br>RESULTS: The FAR values of the FMF cases were significantly higher than the control group (p<0.001). In the FMF group, the patients with SI had higher FAR values than those without SI (p<0.001). FAR was positively correlated with SI (r=0.413, p<0.001). The receiver operating characteristic curve analysis showed that FAR had a higher area under the curve value than albumin and fibrinogen.<br><br>CONCLUSION: Detecting SI in patients with FMF is crucial in preventing amyloidosis, the most devastating complication of FMF. FAR is a simple, inexpensive, easily obtained indicator which can be used for reflecting SI in FMF.<br><br>HINTERGRUND: Famili&#xe4;res Mittelmeerfieber (FMF) ist das am h&#xe4;ufigsten auftretende monogene periodische Fiebersyndrom, das durch Fiebersch&#xfc;be und Serositis gekennzeichnet wird. Die subklinische Entz&#xfc;ndung (SI) kann bekanntlich auch in der symptomfreien Phase fortbestehen und zu Amyloidose f&#xfc;hren, selbst unter Behandlung mit Colchicin. Ziel dieser Studie ist es, die Beziehung zwischen Fibrinogen und Albumin (AFR) bei FMF und deren Korrelation mit SI zu untersuchen.<br><br>MATERIAL UND METHODEN: Insgesamt wurden f&#xfc;r diese retrospektive Studie 112 Patienten mit FMF und 78 Kontrollpatienten eingeschlossen. Die demographischen, labortechnischen und genetischen Daten wurden aus den Krankenhausunterlagen entnommen.<br><br>ERGEBNISSE: Die Werte von AFR bei Patienten mit FMF waren signifikant h&#xf6;her als die der Kontrollgruppe (<0,001). Patienten mit FMF mit SI zeigten h&#xf6;here AFR-Werte als FMF-Patienten ohne SI (<0,001). AFR korrelierte positiv mit SI (r=0,413, p<0,001). Die Analyse der ROC-Kurve (Receiver Operating Characteristic) zeigte, dass AFR einen h&#xf6;heren Wert der Fl&#xe4;che unter der Kurve (AUC) hatte als Albumin und Fibrinogen.<br><br>DISKUSSION: Die Erkennung von SI bei FMF-Patienten ist entscheidend f&#xfc;r die Vermeidung von Amyloidose, der schlimmsten Komplikation von FMF. AFR ist ein einfacher, kosteng&#xfc;nstiger, leicht durchzuf&#xfc;hrender Indikator, der in FMF zur Spiegelung von SI verwendet werden kann.}, }
@article {pmid34539339, year = {2021}, author = {Valori, CF and Neumann, M}, title = {Contribution of RNA/DNA Binding Protein Dysfunction in Oligodendrocytes in the Pathogenesis of the Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration Spectrum Diseases.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {724891}, pmid = {34539339}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders, often considered as the extreme manifestations of a disease spectrum, as they share similar pathomechanisms. In support of this, pathological aggregation of the RNA/DNA binding proteins trans-activation response element DNA-binding protein 43 (TDP-43) or fused in sarcoma (FUS) is the pathological hallmark found in neurons and glial cells of subsets of patients affected by either condition (i.e., ALS/FTLD-TDP-43 or ALS/FTLD-FUS, respectively). Among glia, oligodendrocytes are the most abundant population, designated to ensheath the axons with myelin and to provide them with metabolic and trophic support. In this minireview, we recapitulate the neuropathological evidence for oligodendroglia impairment in ALS/FTLD. We then debate how TDP-43 and FUS target oligodendrocyte transcripts, thereby controlling their homeostatic abilities toward the axons. Finally, we discuss cellular and animal models aimed at investigating the functional consequences of manipulating TDP-43 and FUS in oligodendrocytes in vivo. Taken together, current data provide increasing evidence for an important role of TDP-43 and FUS-mediated oligodendroglia dysfunction in the pathogenesis of ALS/FTLD. Thus, targeting disrupted oligodendroglial functions may represent a new treatment approach for these conditions.}, }
@article {pmid34536404, year = {2021}, author = {Cudkowicz, M and Genge, A and Maragakis, N and Petri, S and van den Berg, L and Aho, VV and Sarapohja, T and Kuoppamäki, M and Garratt, C and Al-Chalabi, A and , }, title = {Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial.}, journal = {The Lancet. Neurology}, volume = {20}, number = {10}, pages = {821-831}, doi = {10.1016/S1474-4422(21)00242-8}, pmid = {34536404}, issn = {1474-4465}, mesh = {Administration, Oral ; *Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Humans ; Simendan/therapeutic use ; Treatment Outcome ; }, abstract = {BACKGROUND: There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function.<br><br>METHODS: The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60-90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178) has also been completed, but will be reported separately.<br><br>FINDINGS: Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50&#xb7;1 (IQR 37&#xb7;5-51&#xb7;1) weeks. The median duration of treatment was 47&#xb7;9 (IQR 26&#xb7;4-48&#xb7;1) weeks. Change from baseline in supine SVC at 12 weeks was -6&#xb7;73% with levosimendan and -6&#xb7;99% with placebo, with no significant difference between the treatments (estimated treatment difference 0&#xb7;26%, 95% CI -2&#xb7;03 to 2&#xb7;55, p=0&#xb7;83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10&#xb7;69, 95% CI -15&#xb7;74 to 37&#xb7;12; nominal p value=0&#xb7;43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis.<br><br>INTERPRETATION: Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation.<br><br>FUNDING: Orion Corporation.}, }
@article {pmid34514988, year = {2021}, author = {Beltran-Beltran, V and Benetó, N and Lapeña-Luzón, T and Rodríguez, LR and Pallardó, FV and Gonzalez-Cabo, P}, title = {Role of Adenosine Receptors in Rare Neurodegenerative Diseases with Motor Symptoms.}, journal = {Current protein &amp; peptide science}, volume = {22}, number = {9}, pages = {675-694}, doi = {10.2174/1389203722666210910110126}, pmid = {34514988}, issn = {1875-5550}, support = {PI19/01084//Instituto de Salud Carlos III (ISCIII)-Subdirecci&#xf3;n General de Evaluaci&#xf3;n/ ; PROMETEO/2018/135, ACCI-2018-22, ACCI-2019- 22//Generalitat Valenciana/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics/drug therapy/pathology ; *Receptors, Purinergic P1/metabolism/genetics ; Adenosine/metabolism ; Animals ; Rare Diseases/metabolism/genetics/drug therapy/pathology ; Purines/metabolism/therapeutic use ; }, abstract = {The approval of istradefylline, an adenosine 2A receptor (A2AR) antagonist, as an addon treatment in adult patients with Parkinson's disease by the Food and Drug Administration (FDA) and European Medicines Agency (EMA), is the latest proof of the importance of the adenosinergic system in the nervous system. Adenosine is an endogenous purine nucleoside with a role as a modulator of both neurotransmission and the inflammatory response. As such, the expression pattern of the 4 adenosine receptors (A1R, A2AR, A2BR and A3R) and the extracellular adenosine levels have attracted great interest in the pathogenesis and possible treatment of rare neurodegenerative diseases with motor symptoms. These include Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Restless Legs Syndrome (RLS) and Machado-Joseph Disease (MJD, also known as spinocerebellar ataxia type 3, SCA3). In this review, we shall focus on the role of the different adenosine receptor subtypes in the development and possible treatment of the aforementioned rare neurodegenerative diseases with motor symptoms using the currently available data. The last section discusses the possibility of a role for the adenosine receptors in the treatment of other rare diseases based on the available molecular pathology knowledge.}, }
@article {pmid34513831, year = {2021}, author = {Xu, S and Zhang, X and Liu, C and Liu, Q and Chai, H and Luo, Y and Li, S}, title = {Role of Mitochondria in Neurodegenerative Diseases: From an Epigenetic Perspective.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {688789}, pmid = {34513831}, issn = {2296-634X}, abstract = {Mitochondria, the centers of energy metabolism, have been shown to participate in epigenetic regulation of neurodegenerative diseases. Epigenetic modification of nuclear genes encoding mitochondrial proteins has an impact on mitochondria homeostasis, including mitochondrial biogenesis, and quality, which plays role in the pathogenesis of neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. On the other hand, intermediate metabolites regulated by mitochondria such as acetyl-CoA and NAD[+], in turn, may regulate nuclear epigenome as the substrate for acetylation and a cofactor of deacetylation, respectively. Thus, mitochondria are involved in epigenetic regulation through bidirectional communication between mitochondria and nuclear, which may provide a new strategy for neurodegenerative diseases treatment. In addition, emerging evidence has suggested that the abnormal modification of mitochondria DNA contributes to disease development through mitochondria dysfunction. In this review, we provide an overview of how mitochondria are involved in epigenetic regulation and discuss the mechanisms of mitochondria in regulation of neurodegenerative diseases from epigenetic perspective.}, }
@article {pmid34512775, year = {2021}, author = {Pan, H and Wang, H and Tao, Y and Yuan, J and Xu, S and Ni, J and Huang, M and Wu, X and Liu, T}, title = {Evidence-Based Research Strategy of Traditional Chinese Medicine for Amyotrophic Lateral Sclerosis.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2021}, number = {}, pages = {3402753}, pmid = {34512775}, issn = {1741-427X}, abstract = {Among adult-onset motor neuron diseases, amyotrophic lateral sclerosis (ALS) is the most common. ALS involves the increasing loss of lower and upper motor neurons. Within a few years of onset, ALS causes patient death via progressive paralysis of respiratory muscles. However, the current drugs used to treat ALS, riluzole, edaravone, and dextromethorphan/quinidine, can only delay the progression of the disease and alleviate a small number of symptoms in some patients, and no completely effective treatment is available. Traditional Chinese medicine (TCM) has shown significant advantages in the treatment of ALS in China and Asia; however, the mechanism of its efficacy is unclear. This review discusses the pathogenetic hypothesis of ALS in detail from the level of neurons and glial cells and uses two current experimental animal models of ALS to design experimental strategies to study TCM treatment. We aim to provide a scientific explanation of the mechanism of the effect of TCM in the treatment of ALS, which will help clinicians and research scientists to accept the theory of TCM to treat ALS and promote the development of TCM modernization.}, }
@article {pmid34510973, year = {2022}, author = {Lou, K and Murphy, S and Talbot, C}, title = {Cannabinoids for the treatment of refractory neuropathic pruritus in amyotrophic lateral sclerosis: A case report.}, journal = {Palliative medicine}, volume = {36}, number = {1}, pages = {208-211}, pmid = {34510973}, issn = {1477-030X}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; *Cannabinoids/therapeutic use ; Dronabinol/therapeutic use ; Humans ; Middle Aged ; Pain/drug therapy ; Pruritus/drug therapy/etiology ; }, abstract = {BACKGROUND: Neuropathic symptoms have a wide variety of manifestations, ranging from pain to pruritus. Neuropathic pruritus is a type of chronic pruritus related to damaged small fibers. Cannabinoids have evidence to manage neuropathic symptoms. We present a case of refractory neuropathic pruritus that was successfully managed with the use of oral cannabinoids.<br><br>CASE PRESENTATION: A 60-year-old male with amyotrophic lateral sclerosis with ongoing pruritus despite the use of standard neuropathic therapies.<br><br>POSSIBLE COURSE OF ACTION: Sodium channel and N-methyl-D-aspartate receptor antagonists have evidence for neuropathic symptoms but can cause significant gastrointestinal side effects. Prescription cannabinoids such as nabiximol can be cost prohibitive to use in practice. Synthetic tetrahydrocannabinol products are dose limited by psychoactive side effects.<br><br>FORMULATION OF A PLAN: A balanced oral cannabinoid from a licensed producer was preferred as it has evidence for neuropathic symptoms and is generally well tolerated.<br><br>OUTCOME: The patient showed improvement to his pruritus score from 7/10 to 3/10. There was initial increased sedation but tolerance developed quickly.<br><br>LESSONS LEARNED FROM CASE: Cannabinoids are possibly safe and effective in management of neuropathic pruritus.<br><br>VIEW ON RESEARCH PROBLEMS: Additional research is needed to establish efficacy and safety.}, }
@article {pmid34505708, year = {2021}, author = {Cleary, S and Misiaszek, JE and Wheeler, S and Kalra, S and Genuis, SK and Johnston, WS}, title = {Lung volume recruitment improves volitional airway clearance in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {64}, number = {6}, pages = {676-682}, pmid = {34505708}, issn = {1097-4598}, mesh = {Activities of Daily Living ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Cough ; Cross-Over Studies ; Humans ; Lung Volume Measurements ; Respiratory Function Tests ; }, abstract = {INTRODUCTION/AIMS: In this study we evaluated the effects of lung volume recruitment treatment (LVR), a low-tech, low-cost, manual "breath-stacking" technique used to help people cough with enough force to clear their airways, thereby reducing the risk of aspiration and choking, on five volitional airway clearance and protection behaviors used by people living with amyotrophic lateral sclerosis (PwALS).<br><br>METHODS: Using a repeated-measures cross-over design, 29 PwALS performed five volitional airway clearance and protection behaviors in LVR treatment and in no-treatment, control conditions. Peak cough flow (PCF) was used to measure maximum expiratory rate during forced expiration, throat clearing, hawking, post-swallow coughing, and the supraglottic swallowing maneuver. Comparisons were made as a function of condition (treatment or control) and three time-points (pretreatment, and 15 and 30 minutes posttreatment).<br><br>RESULTS: LVR treatment had a significant positive effect on maximum expiratory rates during all tested airway clearance and protection behaviors. Increased PCF values lasted for up to 30&#x2009;minutes post-LVR for all tested behaviors in the treatment condition.<br><br>DISCUSSION: We found that LVR treatment could increase control over airway clearance in PwALS, as well as provide improved airway protection for up to 30&#x2009;minutes, the duration of a typical meal. This study has implications for patient care. These include offering patients control over some of the most feared symptoms of ALS, particularly choking during activities of daily living, and enhanced ALS respiratory care in low-resource settings. Findings may have implications for other neurodegenerative disorders in which dysphagia occurs with retained sensory function.}, }
@article {pmid34502460, year = {2021}, author = {Fernández-Beltrán, LC and Godoy-Corchuelo, JM and Losa-Fontangordo, M and Williams, D and Matias-Guiu, J and Corrochano, S}, title = {A Transcriptomic Meta-Analysis Shows Lipid Metabolism Dysregulation as an Early Pathological Mechanism in the Spinal Cord of SOD1 Mice.}, journal = {International journal of molecular sciences}, volume = {22}, number = {17}, pages = {}, pmid = {34502460}, issn = {1422-0067}, support = {2018-T1/BMD-10731//Consejer&#xed;a de Educaci&#xf3;n, Juventud y Deporte, Comunidad de Madrid/ ; }, mesh = {Amyotrophic Lateral Sclerosis/etiology/*metabolism ; Animals ; Disease Models, Animal ; Female ; *Lipid Metabolism ; Mice ; Spinal Cord/*metabolism ; Steroid Hydroxylases/genetics/metabolism ; *Transcriptome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial and complex fatal degenerative disorder. A number of pathological mechanisms that lead to motor neuron death have been identified, although there are many unknowns in the disease aetiology of ALS. Alterations in lipid metabolism are well documented in the progression of ALS, both at the systemic level and in the spinal cord of mouse models and ALS patients. The origin of these lipid alterations remains unclear. This study aims to identify early lipid metabolic pathways altered before systemic metabolic symptoms in the spinal cord of mouse models of ALS. To do this, we performed a transcriptomic analysis of the spinal cord of SOD1[G93A] mice at an early disease stage, followed by a robust transcriptomic meta-analysis using publicly available RNA-seq data from the spinal cord of SOD1 mice at early and late symptomatic disease stages. The meta-analyses identified few lipid metabolic pathways dysregulated early that were exacerbated at symptomatic stages; mainly cholesterol biosynthesis, ceramide catabolism, and eicosanoid synthesis pathways. We present an insight into the pathological mechanisms in ALS, confirming that lipid metabolic alterations are transcriptionally dysregulated and are central to ALS aetiology, opening new options for the treatment of these devastating conditions.}, }
@article {pmid34496365, year = {2022}, author = {Mohammadi, A and Hosseinzadeh Colagar, A and Khorshidian, A and Amini, SM}, title = {The Functional Roles of Curcumin on Astrocytes in Neurodegenerative Diseases.}, journal = {Neuroimmunomodulation}, volume = {29}, number = {1}, pages = {4-14}, doi = {10.1159/000517901}, pmid = {34496365}, issn = {1423-0216}, mesh = {Animals ; Astrocytes ; Brain ; *Curcumin/pharmacology/therapeutic use ; Humans ; *Neurodegenerative Diseases/drug therapy/pathology ; Neurons ; }, abstract = {Progressive abnormality and loss of axons and neurons in the central nervous system (CNS) cause neurodegenerative diseases (NDs). Protein misfolding and its collection are the most important pathological features of NDs. Astrocytes are the most plentiful cells in the mammalian CNS (about 20-40% of the human brain) and have several central functions in the maintenance of the health and correct function of the CNS. Astrocytes have an essential role in the preservation of brain homeostasis, and it is not surprising that these multifunctional cells have been implicated in the onset and progression of several NDs. Thus, they become an exciting target for the study of NDs. Over almost 15 years, it was revealed that curcumin has several therapeutic effects in a wide variety of diseases' treatment. Curcumin is a valuable ingredient present in turmeric spice and has several essential roles, including those which are anticarcinogenic, hepatoprotective, thrombosuppressive, cardioprotective, anti-arthritic, anti-inflammatory, antioxidant, chemopreventive, chemotherapeutic, and anti-infectious. Furthermore, curcumin can suppress inflammation; promote angiogenesis; and treat diabetes, pulmonary problems, and neurological dysfunction. Here, we review the effects of curcumin on astrocytes in NDs, with a focus on Alzheimer's disease, Parkinson's disease, multiple scleroses, Huntington's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid34492237, year = {2022}, author = {Subbarayan, MS and Joly-Amado, A and Bickford, PC and Nash, KR}, title = {CX3CL1/CX3CR1 signaling targets for the treatment of neurodegenerative diseases.}, journal = {Pharmacology &amp; therapeutics}, volume = {231}, number = {}, pages = {107989}, doi = {10.1016/j.pharmthera.2021.107989}, pmid = {34492237}, issn = {1879-016X}, support = {IK6 BX004214/BX/BLRD VA/United States ; }, mesh = {CX3C Chemokine Receptor 1/metabolism ; *Chemokine CX3CL1/metabolism ; Humans ; Microglia/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuroglia/metabolism ; }, abstract = {Neuroinflammation was initially thought of as a consequence of neurodegenerative disease pathology, but more recently it is becoming clear that it plays a significant role in the development and progression of disease. Thus, neuroinflammation is seen as a realistic and valuable therapeutic target for neurodegeneration. Neuroinflammation can be modulated by neuron-glial signaling through various soluble factors, and one such critical modulator is Fractalkine or C-X3-C Motif Chemokine Ligand 1 (CX3CL1). CX3CL1 is produced in neurons and is a unique chemokine that is initially translated as a transmembrane protein but can be proteolytically processed to generate a soluble chemokine. CX3CL1 has been shown to signal through its sole receptor CX3CR1, which is located on microglial cells within the central nervous system (CNS). Although both the membrane bound and soluble forms of CX3CL1 appear to interact with CX3CR1, they do seem to have different signaling capabilities. It is believed that the predominant function of CX3CL1 within the CNS is to reduce the proinflammatory response and many studies have shown neuroprotective effects. However, in some cases CX3CL1 appears to be promoting neurodegeneration. This review focusses on presenting a comprehensive overview of the complex nature of CX3CL1/CX3CR1 signaling in neurodegeneration and how it may present as a therapeutic in some neurodegenerative diseases but not others. The role of CX3CL1/CXCR1 is reviewed in the context of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), ischemia, retinopathies, spinal cord and neuropathic pain, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy.}, }
@article {pmid34491837, year = {2021}, author = {Bertozzi, M and Ruffoli, M and Vatta, F and Gazzaneo, M and Raffaele, A and Mencherini, S and Riccipetitoni, G}, title = {The Effectiveness of Abdominal Lymphangioma Laparoscopic Removal in Children: A Single Center Experience.}, journal = {Journal of laparoendoscopic &amp; advanced surgical techniques. Part A}, volume = {31}, number = {12}, pages = {1367-1371}, doi = {10.1089/lap.2021.0323}, pmid = {34491837}, issn = {1557-9034}, mesh = {Child ; *Digestive System Surgical Procedures ; Humans ; Infant ; *Laparoscopy ; *Lymphangioma/surgery ; Magnetic Resonance Imaging ; *Mesocolon ; }, abstract = {Background: Lymphangiomas represent 5% of all benign pediatric tumors. Abdominal lymphangiomas (ALs) are extremely rare. Therapy includes surgery, sclerotherapy, or pharmacological treatment. Laparoscopic resection (LR) has been already described, but mainly as case reports. The aim of this study is to present our series of ALs LR. Materials and Methods: From 2007 to 2020, 10 cases of ALs were electively treated by LR. Patients' age ranged from 4 months to 14 years. Preoperative diagnosis was achieved by ultrasonography and magnetic resonance images. In all cases LR was performed with four trocars: a 10 mm transumbilical trocar for camera and extraction and three 3-5 mm operative trocars. Results: Lymphangiomas arise from mesocolon in 5 giant cases, ileal mesentery in 3 and right adrenal gland in 2. LR was achieved without intraoperative complications and need of conversion in all cases. Two giant cases needed a percutaneous puncture under laparoscopic view to gain working space. A minimal ileal resection by video-assisted procedure was carried out in 2. Median hospital length was 4 days; no recurrence of disease at serial ultrasound examinations was seen at median follow-up of 5.9 years. Discussion: Several approaches have been proposed for AL treatment. The main challenges are the huge dimensions, the difficulty to achieve a complete resection, and the risk of recurrence. In this series, elective LR of ALs resulted as feasible and effective, and we consider it the standard surgical therapy.}, }
@article {pmid34481449, year = {2021}, author = {Alessenko, AV and Gutner, UA and Nebogatikov, VO and Shupik, MA and Ustyugov, AA}, title = {[The role of sphingolipids in pathogenesis of amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {121}, number = {8}, pages = {131-140}, doi = {10.17116/jnevro2021121081131}, pmid = {34481449}, issn = {1997-7298}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Motor Neurons ; *Neurodegenerative Diseases ; Sphingolipids ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by selective degeneration of motor neurons of the spinal cord and motor cortex and brain stem. The key features of the course of this disease are excitotoxicity, oxidative stress, mitochondrial dysfunction, neuro-inflammatory and immune reactions. Recently, the mechanisms of programmed cell death (apoptosis), which may be responsible for the degeneration of motor neurons in this disease, have been intensively studied. In this regard, sphingolipids, which are the most important sources of secondary messengers that transmit cell proliferation, differentiation and apoptosis signals, and are involved in the development of neuroinflammatory and immune responses, are of particular interest in the context of ALS pathogenesis. The review provides information from domestic and foreign authors on the involvement of various sphingolipids (sphingomyelins, ceramides, sphingosine, sphinganin, sphingosine-1-phosphate, galactosylceramides, glucosylceramides, gangliosides) in the development of pro-inflammatory reactions and apoptosis of motor neurons in ALS. The authors discuss the prospects of using new drugs that control the metabolism of sphingolipids for the treatment of ALS.}, }
@article {pmid34479980, year = {2021}, author = {Garbuzova-Davis, S and Boccio, KJ and Llauget, A and Shell, R and Hailu, S and Mustafa, H and Ehrhart, J and Sanberg, PR and Appel, SH and Borlongan, CV}, title = {Beneficial Effects of Transplanted Human Bone Marrow Endothelial Progenitors on Functional and Cellular Components of Blood-Spinal Cord Barrier in ALS Mice.}, journal = {eNeuro}, volume = {8}, number = {5}, pages = {}, pmid = {34479980}, issn = {2373-2822}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Animals ; Bone Marrow ; Disease Models, Animal ; Endothelial Cells ; Endothelium ; Humans ; Mice ; Mice, Transgenic ; Spinal Cord ; Superoxide Dismutase/genetics ; }, abstract = {Convincing evidence of blood-spinal cord barrier (BSCB) alterations has been demonstrated in amyotrophic lateral sclerosis (ALS) and barrier repair is imperative to prevent motor neuron dysfunction. We showed benefits of human bone marrow-derived CD34+ cells (hBM34+) and endothelial progenitor cells (hBM-EPCs) intravenous transplantation into symptomatic G93A SOD1 mutant mice on barrier reparative processes. These gains likely occurred by replacement of damaged endothelial cells, prolonging motor neuron survival. However, additional investigations are needed to confirm the effects of administered cells on integrity of the microvascular endothelium. The aim of this study was to determine tight junction protein levels, capillary pericyte coverage, microvascular basement membrane, and endothelial filamentous actin (F-actin) status in spinal cord capillaries of G93A SOD1 mutant mice treated with human bone marrow-derived stem cells. Tight junction proteins were detected in the spinal cords of cell-treated versus non-treated mice via Western blotting at four weeks after transplant. Capillary pericyte, basement membrane laminin, and endothelial F-actin magnitudes were determined in cervical/lumbar spinal cord tissues in ALS mice, including controls, by immunohistochemistry and fluorescent staining. Results showed that cell-treated versus media-treated ALS mice substantially increased tight junction protein levels, capillary pericyte coverage, basement membrane laminin immunoexpressions, and endothelial cytoskeletal F-actin fluorescent expressions. The greatest benefits were detected in mice receiving hBM-EPCs versus hBM34+ cells. These study results support treatment with a specific cell type derived from human bone marrow toward BSCB repair in ALS. Thus, hBM-EPCs may be advanced for clinical applications as a cell-specific approach for ALS therapy through restored barrier integrity.}, }
@article {pmid34479020, year = {2021}, author = {Nguyen, TT and Dung Nguyen, TT and Vo, TK and Tran, NM and Nguyen, MK and Van Vo, T and Van Vo, G}, title = {Nanotechnology-based drug delivery for central nervous system disorders.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {143}, number = {}, pages = {112117}, doi = {10.1016/j.biopha.2021.112117}, pmid = {34479020}, issn = {1950-6007}, mesh = {Animals ; Blood-Brain Barrier/metabolism ; Central Nervous System Agents/*administration &amp; dosage/chemistry/metabolism ; Central Nervous System Diseases/*drug therapy/metabolism ; *Drug Carriers ; Drug Compounding ; Drug Development ; Drug Discovery ; Humans ; *Nanomedicine ; *Nanoparticles ; Permeability ; Translational Research, Biomedical ; }, abstract = {Drug delivery to central nervous system (CNS) diseases is very challenging since the presence of the innate blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier that impede drug delivery. Among new strategies to overcome these limitations and successfully deliver drugs to the CNS, nanotechnology-based drug delivery platform, offers potential therapeutic approach for the treatment of some common neurological disorders like Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease. This review aimed to highlight advances in research on the development of nano-based therapeutics for their implications in therapy of CNS disorders. The challenges during clinical translation of nanomedicine from bench to bed side is also discussed.}, }
@article {pmid34476128, year = {2021}, author = {Berry, J and Brooks, B and Genge, A and Heiman-Patterson, T and Appel, S and Benatar, M and Bowser, R and Cudkowicz, M and Gooch, C and Shefner, J and Westra, J and Agnese, W and Merrill, C and Nelson, S and Apple, S}, title = {Radicava/Edaravone Findings in Biomarkers From Amyotrophic Lateral Sclerosis (REFINE-ALS): Protocol and Study Design.}, journal = {Neurology. Clinical practice}, volume = {11}, number = {4}, pages = {e472-e479}, pmid = {34476128}, issn = {2163-0402}, abstract = {OBJECTIVES: To identify putative biomarkers that may serve as quantifiable, biological, nonclinical measures of the pharmacodynamic effect of edaravone in amyotrophic lateral sclerosis (ALS) and to report real-world treatment outcomes.<br><br>METHODS: This is a prospective, observational, longitudinal, multicenter (up to 40 sites) US study (Clinicaltrials.gov; NCT04259255) with at least 200 patients with ALS who will receive edaravone for 24 weeks (6 cycles; Food and Drug Administration-approved regimen). All participants must either be treatment naive for edaravone or be more than 1 month without receiving any edaravone dose before screening. Biomarker quantification and other assessments will be performed at baseline (before cycle 1) and during cycles 1, 3, and 6. Selected biomarkers of oxidative stress, inflammation, neuronal injury and death, and muscle injury, as well as biomarker discovery panels (EpiSwitch and SOMAscan), will be evaluated and, when feasible, compared with biobanked samples. Clinical efficacy assessments will include the ALS Functional Rating Scale-Revised, King's clinical staging, ALS Assessment Questionnaire-40, Appel ALS Score (Rating Scale), slow vital capacity, hand-held dynamometry and grip strength, and time to specified states of disease progression or death. DNA samples will also be collected for potential genomic evaluation. The predicted rates of progression and survival, and their potential correlations with biomarkers, will be evaluated. Adverse events related to the study will be reported.<br><br>RESULTS: The study is estimated to be completed in 2022 with an interim analysis planned.<br><br>CONCLUSIONS: Findings may help to further the understanding of the pharmacodynamic effect of edaravone, including changes in biomarkers, in response to treatment.}, }
@article {pmid34472488, year = {2022}, author = {Wei, QQ and Hou, YB and Zhang, LY and Ou, RW and Cao, B and Chen, YP and Shang, HF}, title = {Neutrophil-to-lymphocyte ratio in sporadic amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {17}, number = {4}, pages = {875-880}, pmid = {34472488}, issn = {1673-5374}, abstract = {The neutrophil-to-lymphocyte ratio (NLR) is considered a robust prognostic biomarker for predicting patient survival outcomes in many diseases. However, it remains unclear whether it can be used as a biomarker for amyotrophic lateral sclerosis (ALS). To correlate NLR with disease progression and survival in sporadic ALS, 1030 patients with ALS between January 2012 and December 2018 were included in this study. These patients were assigned into three groups according to their NLR values: Group 1 (NLR < 2, n = 544 [52.8%]), Group 2 (NLR = 2-3, n = 314 [30.5%]), and Group 3 (NLR > 3, n = 172 [16.7%]). All patients were followed up until April 2020. Patients in Group 3 had a significantly older onset age, a lower score on the Revised ALS Functional Rating Scale, and rapidly progressing disease conditions. Furthermore, faster disease progression rates were associated with higher NLR values (odds ratio = 1.211, 95% confidence interval [CI]: 1.090-1.346, P < 0.001) after adjusting for other risk factors. Compared with Groups 1 and 2, the survival time in Group 3 was significantly shorter (log-rank P = 0.002). The NLR value was considered an independent parameter for the prediction of survival in ALS patients after normalizing for all other potential parameters (hazard ratio [HR] = 1.079, 95% CI: 1.016-1.146, P = 0.014). The effects on ALS survival remained significant when adjusted for treatment (HR = 1.074, 95% CI: 1.012-1.141, Ptrend = 0.019) or when considering the stratified NLR value (HR = 1.115, 95% CI: 1.009-1.232, Ptrend = 0.033). Thus, the NLR may help to predict the rate of disease progression and survival in patients with sporadic ALS. The study was approved by the Institutional Ethics Committee of West China Hospital of Sichuan University, China (approval No. 2015 (236)) on December 23, 2015.}, }
@article {pmid34472458, year = {2022}, author = {Martinez, B and Peplow, PV}, title = {MicroRNA expression in animal models of amyotrophic lateral sclerosis and potential therapeutic approaches.}, journal = {Neural regeneration research}, volume = {17}, number = {4}, pages = {728-740}, pmid = {34472458}, issn = {1673-5374}, abstract = {A review of recent animal models of amyotrophic lateral sclerosis showed a large number of miRNAs had altered levels of expression in the brain and spinal cord, motor neurons of spinal cord and brainstem, and hypoglossal, facial, and red motor nuclei and were mostly upregulated. Among the miRNAs found to be upregulated in two of the studies were miR-21, miR-155, miR-125b, miR-146a, miR-124, miR-9, and miR-19b, while those downregulated in two of the studies included miR-146a, miR-29, miR-9, and miR-125b. A change of direction in miRNA expression occurred in some tissues when compared (e.g., miR-29b-3p in cerebellum and spinal cord of wobbler mice at 40 days), or at different disease stages (e.g., miR-200a in spinal cord of SOD1(G93A) mice at 95 days vs. 108 and 112 days). In the animal models, suppression of miR-129-5p resulted in increased lifespan, improved muscle strength, reduced neuromuscular junction degeneration, and tended to improve motor neuron survival in the SOD1(G93A) mouse model. Suppression of miR-155 was also associated with increased lifespan, while lowering of miR-29a tended to improve lifespan in males and increase muscle strength in SOD1(G93A) mice. Overexpression of members of miR-17~92 cluster improved motor neuron survival in SOD1(G93A) mice. Treatment with an artificial miRNA designed to target hSOD1 increased lifespan and improved muscle strength in SOD1(G93A) animals. Further studies with animal models of amyotrophic lateral sclerosis are warranted to validate these findings and identify specific miRNAs whose suppression or directed against hSOD1 results in increased lifespan, improved muscle strength, reduced neuromuscular junction degeneration, and improved motor neuron survival in SOD1(G93A) animals.}, }
@article {pmid34466632, year = {2021}, author = {Tavakol-Afshari, J and Boroumand, AR and Farkhad, NK and Adhami Moghadam, A and Sahab-Negah, S and Gorji, A}, title = {Safety and efficacy of bone marrow derived-mesenchymal stem cells transplantation in patients with amyotrophic lateral sclerosis.}, journal = {Regenerative therapy}, volume = {18}, number = {}, pages = {268-274}, pmid = {34466632}, issn = {2352-3204}, abstract = {Stem cell-based treatments have emerged as potentially effective approaches to delay the progression of amyotrophic lateral sclerosis (ALS). This study was designed as a single-center, prospective, and open-label study without a placebo control group to assess the safety and efficacy of concurrent intrathecal (IT) and intravenous (IV) administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with ALS. Autologous BM-MSCs were isolated and expanded under standard conditions. Fifteen patients were neurologically examined before BM-MSCs transplantation (1 × 10 [6] cells/kg BW) to evaluate the rate of pre-treatment disease progression. To assess the safety and efficacy, patients were examined at 1, 3, and 6 months following the treatment with BM-MSCs. Adverse reactions were assessed, and the clinical outcome was determined by the evaluation of the ALS functional rating scale-revised (ALSFRS-R) and forced vital capacity (FVC). No serious adverse reaction was observed after combined IT and IV administration of BM-MSCs. The mean ALSFRS-R and FVC values remained stable during the first 3 months of the treatment. However, a significant reduction in ALSFRS-R and FVC levels was observed in these patients 6 months after BM-MSCs administration. Our study revealed that the concurrent IT and IV application of BM-MSCs in patients with ALS is a safe procedure. Furthermore, our data indicate a temporary delay in the progression of ALS after a single combined IT and IV administration of BM-MSCs. Further studies are required to explore if the repeated applications of BM-MSCs could prolong survival and delay the progression of ALS.}, }
@article {pmid34466357, year = {2021}, author = {Dhindsa, BS and Naga, Y and Saghir, SM and Daid, SGS and Chandan, S and Mashiana, H and Dhaliwal, A and Sidhu, A and Sayles, H and Ramai, D and Bhat, I and Singh, S and McDonough, S and Adler, DG}, title = {Endo-sponge in management of anastomotic colorectal leaks: a systematic review and meta-analysis.}, journal = {Endoscopy international open}, volume = {9}, number = {9}, pages = {E1342-E1349}, pmid = {34466357}, issn = {2364-3722}, abstract = {Background and study aims Following colorectal surgery, anastomotic dehiscence and leak formation has an incidence of 2 % to 7 %. Endo-SPONGE has been applied in the management of anastomatic leaks (ALs) after colorectal surgery. This is the first systematic review and meta analysis to evaluate the efficacy and safety of Endo-SPONGE in the management of colorectal ALs. Patients and methods The primary outcomes assessed were the technical and clinical success of Endo-SPONGE placement in colorectal ALs. The secondary outcomes assessed were the overall adverse events (AEs) and the AE subtypes. Pooled estimates were calculated using random-effects models with 95 % confidence interval (C. I.). The statistical analysis was done using STATA v16.1 software (StataCorp, LLC College Station, Texas, United States). Results The analysis included 17 independent cohort studies with a total of 384 patients. The rate of technical success was 99.86 % (95 % CI: 99.2 %, 100 %; P = 0.00; I [2] = 70.69 %) and the calculated pooled rate of clinical success was 84.99 % (95 % CI: 77.4 %, 91.41 %; P = 0.00; I [2] = 68.02 %). The calculated pooled rate of adverse events was 7.6 % (95 % CI: 3.99 %, 12.21 %; P = 0.03; I [2] = 42.5 %) with recurrent abscess formation and bleeding being the most common AEs. Moderate to substantial heterogeneity was noted in our meta-analysis. Conclusions Endoscopic vacuum therapy appears to be a minimally invasive, safe, and effective treatment modality for patients with a significant colorectal leak without any generalized peritonitis with high clinical and technical success rates and a low rate of adverse events. Further prospective or randomized controlled trials are needed to validate our findings.}, }
@article {pmid34462350, year = {2021}, author = {Krishna, S and Cheng, B and Sharma, DR and Yadav, S and Stempinski, ES and Mamtani, S and Shah, E and Deo, A and Acherjee, T and Thomas, T and Zhang, X and Zhang, J and Iacobas, DA and Ballabh, P}, title = {PPAR-γ activation enhances myelination and neurological recovery in premature rabbits with intraventricular hemorrhage.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {118}, number = {36}, pages = {}, pmid = {34462350}, issn = {1091-6490}, support = {P50 HD105352/HD/NICHD NIH HHS/United States ; R01 NS110760/NS/NINDS NIH HHS/United States ; R21 NS102897/NS/NINDS NIH HHS/United States ; }, mesh = {Amino Acid Transport Systems, Acidic/deficiency/metabolism ; Animals ; Animals, Newborn ; Antiporters/deficiency/metabolism ; Cerebral Intraventricular Hemorrhage/*metabolism/pathology ; Disease Models, Animal ; Hereditary Central Nervous System Demyelinating Diseases/metabolism ; Humans ; Infant, Premature ; Microglia/metabolism ; Mitochondrial Diseases/metabolism ; Myelin Proteins/*biosynthesis ; Oligodendroglia/pathology ; PPAR gamma/agonists/*metabolism ; Psychomotor Disorders/metabolism ; Rabbits ; Rosiglitazone/pharmacology ; Sequence Analysis, RNA/methods ; }, abstract = {Intraventricular hemorrhage (IVH) results in periventricular inflammation, hypomyelination of the white matter, and hydrocephalus in premature infants. No effective therapy exists to prevent these disorders. Peroxisome proliferator activated receptor-γ (PPAR-γ) agonists reduce inflammation, alleviate free radical generation, and enhance microglial phagocytosis, promoting clearance of debris and red blood cells. We hypothesized that activation of PPAR-γ would enhance myelination, reduce hydrocephalus, and promote neurological recovery in newborns with IVH. These hypotheses were tested in a preterm rabbit model of IVH; autopsy brain samples from premature infants with and without IVH were analyzed. We found that IVH augmented PPAR-γ expression in microglia of both preterm human infants and rabbit kits. The treatment with PPAR-γ agonist or PPAR-γ overexpression by adenovirus delivery further elevated PPAR-γ levels in microglia, reduced proinflammatory cytokines, increased microglial phagocytosis, and improved oligodendrocyte progenitor cell (OPC) maturation in kits with IVH. Transcriptomic analyses of OPCs identified previously unrecognized PPAR-γ-induced genes for purinergic signaling, cyclic adenosine monophosphate generation, and antioxidant production, which would reprogram these progenitors toward promoting myelination. RNA-sequencing analyses of microglia revealed PPAR-γ-triggered down-regulation of several proinflammatory genes and transcripts having roles in Parkinson's disease and amyotrophic lateral sclerosis, contributing to neurological recovery in kits with IVH. Accordingly, PPAR-γ activation enhanced myelination and neurological function in kits with IVH. This also enhanced microglial phagocytosis of red blood cells but did not reduce hydrocephalus. Treatment with PPAR-γ agonist might enhance myelination and neurological recovery in premature infants with IVH.}, }
@article {pmid34459327, year = {2022}, author = {Luna, J and Jost, J and Diagana, M and Ait Aissa, L and Tazir, M and Ali Pacha, L and Kacem, I and Gouider, R and Henning, F and Basse, A and Cisse, O and Balogou, AK and Kombate, D and Agbetou, M and Houinato, D and Gnonlonfoun, DD and Millogo, A and Agba, T and Belo, M and Sengxeu, N and Hamidou, B and Preux, PM and Benoit, M and Couratier, P and , }, title = {Clinical management and disease-modifying treatment for amyotrophic lateral sclerosis in African hospital centers: the TROPALS study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {3-4}, pages = {279-283}, doi = {10.1080/21678421.2021.1961806}, pmid = {34459327}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/epidemiology ; Hospitals ; Humans ; *Riluzole/therapeutic use ; }, abstract = {Objective: To assess the availability of health workers and medications for clinical management of amyotrophic lateral sclerosis (ALS) in African hospital centers. Availability and affordability analyses of disease-modifying treatments were performed. Methods: A multicenter observational study involving African hospitals was conducted. A standard questionnaire was developed based on the European Federation of the Neurological Societies (EFNS) guidelines. We collected data on multidisciplinary care and availability of medicines. The availability and affordability were evaluated according to the WHO guidelines. Results: Nine hospital centers from eight African countries participated. We observed a low degree of implementation of multidisciplinary care in ALS management. Riluzole was only available in centers from South Africa, Senegal, Tunisia, and Togo. This treatment was unaffordable and the adjusted price was highly variable among countries. The cost of riluzole was partly or fully covered by patients, which implies a substantial economic burden. Conclusion: Our findings strengthen the need to promote multidisciplinary care in the clinical management of ALS in Africa. Disease-modifying medication should be both available and affordable. Local and international collaboration is needed to improve ALS health care access in Africa.}, }
@article {pmid34457038, year = {2021}, author = {Mora, JS and Bradley, WG and Chaverri, D and Hernández-Barral, M and Mascias, J and Gamez, J and Gargiulo-Monachelli, GM and Moussy, A and Mansfield, CD and Hermine, O and Ludolph, AC}, title = {Long-term survival analysis of masitinib in amyotrophic lateral sclerosis.}, journal = {Therapeutic advances in neurological disorders}, volume = {14}, number = {}, pages = {17562864211030365}, pmid = {34457038}, issn = {1756-2856}, abstract = {BACKGROUND: A randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of <1.1 points/month. Here we assess long-term overall survival (OS) data of all participants from study AB10015 and test whether a signal in OS is evident in an enriched patient population similar to that prospectively defined for confirmatory study AB19001.<br><br>METHODS: Survival status of all patients originally randomized in AB10015 was collected from participating investigational sites. Survival analysis (using the multivariate log-rank test and Cox proportional hazards model, with stratification factors as covariates) was performed on the intention-to-treat population and enriched subgroups, which were defined according to initial randomization, baseline ALSFRS-R progression rate and baseline disease severity.<br><br>RESULTS: A significant survival benefit of 25&#x2009;months (p&#x2009;=&#x2009;0.037) and 47% reduced risk of death (p&#x2009;=&#x2009;0.025) was observed for patients receiving 4.5&#x2009;mg/kg/day masitinib (n&#x2009;=&#x2009;45) versus placebo (n&#x2009;=&#x2009;62) in an enriched cohort with &#x2a7e;2 on each baseline ALSFRS-R individual component score (i.e. prior to any complete loss or severe impairment of functionality) and post-onset ALSFRS-R progression rate <1.1 (i.e. exclusion of very fast progressors) [median OS of 69 versus 44&#x2009;months, respectively; hazard ratio, 0.53 [95% CI (0.31-0.92)]]. This corresponds to the population enrolled in confirmatory phase III study, AB19001.<br><br>CONCLUSIONS: Analysis of long-term OS (75&#x2009;months average follow-up from diagnosis) indicates that oral masitinib (4.5&#x2009;mg/kg/day) could prolong survival by over 2&#x2009;years as compared with placebo, provided that treatment starts prior to severe impairment of functionality.This trial was registered at www.ClinicalTrials.gov under identifier NCT02588677 (28 October 2015).}, }
@article {pmid34452489, year = {2021}, author = {Scialò, C and Celauro, L and Zattoni, M and Tran, TH and Bistaffa, E and Moda, F and Kammerer, R and Buratti, E and Legname, G}, title = {The Cellular Prion Protein Increases the Uptake and Toxicity of TDP-43 Fibrils.}, journal = {Viruses}, volume = {13}, number = {8}, pages = {}, pmid = {34452489}, issn = {1999-4915}, mesh = {Animals ; Biological Transport ; Cell Line ; Cell Survival ; DNA-Binding Proteins/genetics/*metabolism/pharmacology ; Humans ; Mice ; PrPC Proteins/classification/*genetics/*metabolism ; Prion Proteins/genetics/*metabolism ; }, abstract = {Cytoplasmic aggregation of the primarily nuclear TAR DNA-binding protein 43 (TDP-43) affects neurons in most amyotrophic lateral sclerosis (ALS) and approximately half of frontotemporal lobar degeneration (FTLD) cases. The cellular prion protein, PrP[C], has been recognized as a common receptor and downstream effector of circulating neurotoxic species of several proteins involved in neurodegeneration. Here, capitalizing on our recently adapted TDP-43 real time quaking induced reaction, we set reproducible protocols to obtain standardized preparations of recombinant TDP-43 fibrils. We then exploited two different cellular systems (human SH-SY5Y and mouse N2a neuroblastoma cells) engineered to express low or high PrP[C] levels to investigate the link between PrP[C] expression on the cell surface and the internalization of TDP-43 fibrils. Fibril uptake was increased in cells overexpressing either human or mouse prion protein. Increased internalization was associated with detrimental consequences in all PrP-overexpressing cell lines but was milder in cells expressing the human form of the prion protein. As described for other amyloids, treatment with TDP-43 fibrils induced a reduction in the accumulation of the misfolded form of PrP[C], PrP[Sc], in cells chronically infected with prions. Our results expand the list of misfolded proteins whose uptake and detrimental effects are mediated by PrP[C], which encompass almost all pathological amyloids involved in neurodegeneration.}, }
@article {pmid34451802, year = {2021}, author = {Houzen, H and Kano, T and Horiuchi, K and Wakita, M and Nagai, A and Yabe, I}, title = {Improved Long-Term Survival with Edaravone Therapy in Patients with Amyotrophic Lateral Sclerosis: A Retrospective Single-Center Study in Japan.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {8}, pages = {}, pmid = {34451802}, issn = {1424-8247}, abstract = {Reports on the long-term survival effect of edaravone, which was approved for the treatment of amyotrophic lateral sclerosis (ALS) in 2015 in Japan, are rare. Herein, we report our retrospective analysis of 45 consecutive patients with ALS who initially visited our hospital between 2013 and 2018. Of these, 22 patients were treated with edaravone for an average duration of 26.6 (range, 2-64) months, whereas the remaining patients were not treated with edaravone and comprised the control group. There were no differences in baseline demographics between the two groups. The primary endpoint was tracheostomy positive-pressure ventilation (TPPV) or death, and the follow-up period ended in December 2020. The survival rate was significantly better in the edaravone group than in the control group based on the Kaplan-Meier analysis, which revealed that the median survival durations were 49 (9-88) and 25 (8-41) months in the edaravone and control groups, respectively (p = 0.001, log-rank test). There were no serious edaravone-associated adverse effects during the study period. Overall, the findings of this single-center retrospective study suggest that edaravone might prolong survival in patients with ALS.}, }
@article {pmid34445680, year = {2021}, author = {Martínez-González, L and Gonzalo-Consuegra, C and Gómez-Almería, M and Porras, G and de Lago, E and Martín-Requero, &#xc1; and Martínez, A}, title = {Tideglusib, a Non-ATP Competitive Inhibitor of GSK-3β as a Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {22}, number = {16}, pages = {}, pmid = {34445680}, issn = {1422-0067}, support = {B2017/BMD3813 ELA-Madrid//Consejer&#xed;a de Educaci&#xf3;n, Juventud y Deporte, Comunidad de Madrid/ ; CIBERNED CB18/05/00040//Instituto de Salud Carlos III/ ; CIBERNED CB06/05/0089//Instituto de Salud Carlos III/ ; RTI2018-096100-B-I00//Agencia Estatal de Investigaci&#xf3;n/ ; PID2019-105600RB-I00//Agencia Estatal de Investigaci&#xf3;n/ ; RTI2018-0988885-B-I00//Agencia Estatal de Investigaci&#xf3;n/ ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; DNA-Binding Proteins/*metabolism/physiology ; Disease Models, Animal ; Drug Repositioning ; Glycogen Synthase Kinase 3 beta/*metabolism/physiology ; Humans ; Male ; Mice ; Mice, Transgenic ; Middle Aged ; Motor Neurons/metabolism ; Pharmaceutical Preparations/metabolism ; Phosphorylation ; Protein Kinases/metabolism ; Spinal Cord/metabolism ; Thiadiazoles/*pharmacology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common degenerative motor neuron disease in adults. About 97% of ALS patients present TDP-43 aggregates with post-translational modifications, such as hyperphosphorylation, in the cytoplasm of affected cells. GSK-3β is one of the protein kinases involved in TDP-43 phosphorylation. Up-regulation of its expression and activity is reported on spinal cord and cortex tissues of ALS patients. Here, we propose the repurposing of Tideglusib, an in-house non-ATP competitive GSK-3β inhibitor that is currently in clinical trials for autism and myotonic dystrophy, as a promising therapeutic strategy for ALS. With this aim we have evaluated the efficacy of Tideglusib in different experimental ALS models both in vitro and in vivo. Moreover, we observed that GSK-3β activity is increased in lymphoblasts from sporadic ALS patients, with a simultaneous increase in TDP-43 phosphorylation and cytosolic TDP-43 accumulation. Treatment with Tideglusib decreased not only phospho-TDP-43 levels but also recovered its nuclear localization in ALS lymphoblasts and in a human TDP-43 neuroblastoma model. Additionally, we found that chronic oral treatment with Tideglusib is able to reduce the increased TDP-43 phosphorylation in the spinal cord of Prp-hTDP-43[A315T] mouse model. Therefore, we consider Tideglusib as a promising drug candidate for ALS, being proposed to start a clinical trial phase II by the end of the year.}, }
@article {pmid34443678, year = {2021}, author = {Koike, H and Iguchi, Y and Sahashi, K and Katsuno, M}, title = {Significance of Oligomeric and Fibrillar Species in Amyloidosis: Insights into Pathophysiology and Treatment.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {16}, pages = {}, pmid = {34443678}, issn = {1420-3049}, support = {20FC1022//The Ministry of Health, Labor and Welfare of Japan/ ; }, mesh = {Amyloid/*metabolism ; Amyloidosis/*physiopathology/*therapy ; Animals ; Humans ; Organ Specificity ; Protein Aggregates ; Schwann Cells/pathology ; }, abstract = {Amyloidosis is a term referring to a group of various protein-misfolding diseases wherein normally soluble proteins form aggregates as insoluble amyloid fibrils. How, or whether, amyloid fibrils contribute to tissue damage in amyloidosis has been the topic of debate. In vitro studies have demonstrated the appearance of small globular oligomeric species during the incubation of amyloid beta peptide (Aβ). Nerve biopsy specimens from patients with systemic amyloidosis have suggested that globular structures similar to Aβ oligomers were generated from amorphous electron-dense materials and later developed into mature amyloid fibrils. Schwann cells adjacent to amyloid fibrils become atrophic and degenerative, suggesting that the direct tissue damage induced by amyloid fibrils plays an important role in systemic amyloidosis. In contrast, there is increasing evidence that oligomers, rather than amyloid fibrils, are responsible for cell death in neurodegenerative diseases, particularly Alzheimer's disease. Disease-modifying therapies based on the pathophysiology of amyloidosis have now become available. Aducanumab, a human monoclonal antibody against the aggregated form of Aβ, was recently approved for Alzheimer's disease, and other monoclonal antibodies, including gantenerumab, solanezumab, and lecanemab, could also be up for approval. As many other agents for amyloidosis will be developed in the future, studies to develop sensitive clinical scales for identifying improvement and markers that can act as surrogates for clinical scales should be conducted.}, }
@article {pmid34442438, year = {2021}, author = {Lazzarino, G and Mangione, R and Belli, A and Di Pietro, V and Nagy, Z and Barnes, NM and Bruce, L and Ropero, BM and Persson, LI and Manca, B and Saab, MW and Amorini, AM and Tavazzi, B and Lazzarino, G and Logan, A}, title = {ILB[®] Attenuates Clinical Symptoms and Serum Biomarkers of Oxidative/Nitrosative Stress and Mitochondrial Dysfunction in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Journal of personalized medicine}, volume = {11}, number = {8}, pages = {}, pmid = {34442438}, issn = {2075-4426}, abstract = {Oxidative/nitrosative stress and mitochondrial dysfunction is a hallmark of amyotrophic lateral sclerosis (ALS), an invariably fatal progressive neurodegenerative disease. Here, as an exploratory arm of a phase II clinical trial (EudraCT Number 2017-005065-47), we used high performance liquid chromatography(HPLC) to investigate changes in the metabolic profiles of serum from ALS patients treated weekly for 4 weeks with a repeated sub-cutaneous dose of 1 mg/kg of a proprietary low molecular weight dextran sulphate, called ILB[®]. A significant normalization of the serum levels of several key metabolites was observed over the treatment period, including N-acetylaspartate (NAA), oxypurines, biomarkers of oxidative/nitrosative stress and antioxidants. An improved serum metabolic profile was accompanied by significant amelioration of the patients' clinical conditions, indicating a response to ILB[®] treatment that appears to be mediated by improvement of tissue bioenergetics, decrease of oxidative/nitrosative stress and attenuation of (neuro)inflammatory processes.}, }
@article {pmid34440761, year = {2021}, author = {Bonaventura, G and Munafò, A and Bellanca, CM and La Cognata, V and Iemmolo, R and Attaguile, GA and Di Mauro, R and Di Benedetto, G and Cantarella, G and Barcellona, ML and Cavallaro, S and Bernardini, R}, title = {Stem Cells: Innovative Therapeutic Options for Neurodegenerative Diseases?.}, journal = {Cells}, volume = {10}, number = {8}, pages = {}, pmid = {34440761}, issn = {2073-4409}, mesh = {Alzheimer Disease/metabolism/pathology/physiopathology/surgery ; Amyotrophic Lateral Sclerosis/metabolism/pathology/physiopathology/surgery ; Animals ; Central Nervous System/immunology/metabolism/pathology/*physiopathology ; Humans ; *Nerve Degeneration ; *Nerve Regeneration ; Neural Stem Cells/immunology/metabolism/*transplantation ; Neurodegenerative Diseases/metabolism/pathology/physiopathology/*surgery ; Neuroimmunomodulation ; Parkinson Disease/metabolism/pathology/physiopathology/surgery ; Phenotype ; Recovery of Function ; *Stem Cell Transplantation/adverse effects ; }, abstract = {Neurodegenerative diseases are characterized by the progressive loss of structure and/or function of both neurons and glial cells, leading to different degrees of pathology and loss of cognition. The hypothesis of circuit reconstruction in the damaged brain via direct cell replacement has been pursued extensively so far. In this context, stem cells represent a useful option since they provide tissue restoration through the substitution of damaged neuronal cells with exogenous stem cells and create a neuro-protective environment through the release of bioactive molecules for healthy neurons, as well. These peculiar properties of stem cells are opening to potential therapeutic strategies for the treatment of severe neurodegenerative disorders, for which the absence of effective treatment options leads to an increasingly socio-economic burden. Currently, the introduction of new technologies in the field of stem cells and the implementation of alternative cell tissues sources are pointing to exciting frontiers in this area of research. Here, we provide an update of the current knowledge about source and administration routes of stem cells, and review light and shadows of cells replacement therapy for the treatment of the three main neurodegenerative disorders (Amyotrophic lateral sclerosis, Parkinson's, and Alzheimer's disease).}, }
@article {pmid34440645, year = {2021}, author = {Cen, X and Zhang, M and Zhou, M and Ye, L and Xia, H}, title = {Mitophagy Regulates Neurodegenerative Diseases.}, journal = {Cells}, volume = {10}, number = {8}, pages = {}, pmid = {34440645}, issn = {2073-4409}, mesh = {Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Humans ; Mitochondria/metabolism/*pathology ; *Mitophagy ; *Nerve Degeneration ; Neurodegenerative Diseases/metabolism/*pathology ; Neurons/metabolism/*pathology ; Parkinson Disease/metabolism/pathology ; Signal Transduction ; }, abstract = {Mitochondria play an essential role in supplying energy for the health and survival of neurons. Mitophagy is a metabolic process that removes dysfunctional or redundant mitochondria. This process preserves mitochondrial health. However, defective mitophagy triggers the accumulation of damaged mitochondria, causing major neurodegenerative disorders. This review introduces molecular mechanisms and signaling pathways behind mitophagy regulation. Furthermore, we focus on the recent advances in understanding the potential role of mitophagy in the pathogenesis of major neurodegenerative diseases (Parkinson's, Alzheimer's, Huntington's, etc.) and aging. The findings will help identify the potential interventions of mitophagy regulation and treatment strategies of neurodegenerative diseases.}, }
@article {pmid34440204, year = {2021}, author = {Obrador, E and Salvador-Palmer, R and López-Blanch, R and Dellinger, RW and Estrela, JM}, title = {NAD[+] Precursors and Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {9}, number = {8}, pages = {}, pmid = {34440204}, issn = {2227-9059}, support = {OTR2018-19337INVES//University of Valencia and Elysium Health Inc./ ; OTR2017-18255INVES//University of Valencia and Elysium Health Inc./ ; }, abstract = {Charcot first described amyotrophic lateral sclerosis (ALS) between 1865 and 1874 as a sporadic adult disease resulting from the idiopathic progressive degeneration of the motor neuronal system, resulting in rapid, progressive, and generalized muscle weakness and atrophy. There is no cure for ALS and no proven therapy to prevent it or reverse its course. There are two drugs specifically approved for the treatment of ALS, riluzol and edaravone, and many others have already been tested or are following clinical trials. However, at the present moment, we still cannot glimpse a true breakthrough in the treatment of this devastating disease. Nevertheless, our understanding of the pathophysiology of ALS is constantly growing. Based on this background, we know that oxidative stress, alterations in the NAD[+]-dependent metabolism and redox status, and abnormal mitochondrial dynamics and function in the motor neurons are at the core of the problem. Thus, different antioxidant molecules or NAD[+] generators have been proposed for the therapy of ALS. This review analyzes these options not only in light of their use as individual molecules, but with special emphasis on their potential association, and even as part of broader combined multi-therapies.}, }
@article {pmid34439911, year = {2021}, author = {Barp, A and Ferrero, A and Casagrande, S and Morini, R and Zuccarino, R}, title = {Circulating Biomarkers in Neuromuscular Disorders: What Is Known, What Is New.}, journal = {Biomolecules}, volume = {11}, number = {8}, pages = {}, pmid = {34439911}, issn = {2218-273X}, mesh = {Amyotrophic Lateral Sclerosis/*blood ; Animals ; Antibodies/chemistry ; Biomarkers/*blood ; Creatine Kinase/*metabolism ; Disease Progression ; Humans ; Intermediate Filaments/chemistry/metabolism ; Mice ; MicroRNAs/metabolism ; Models, Biological ; Motor Neuron Disease/metabolism ; Muscular Dystrophy, Duchenne/*blood ; Neuromuscular Diseases ; Reproducibility of Results ; }, abstract = {The urgent need for new therapies for some devastating neuromuscular diseases (NMDs), such as Duchenne muscular dystrophy or amyotrophic lateral sclerosis, has led to an intense search for new potential biomarkers. Biomarkers can be classified based on their clinical value into different categories: diagnostic biomarkers confirm the presence of a specific disease, prognostic biomarkers provide information about disease course, and therapeutic biomarkers are designed to predict or measure treatment response. Circulating biomarkers, as opposed to instrumental/invasive ones (e.g., muscle MRI or nerve ultrasound, muscle or nerve biopsy), are generally easier to access and less "time-consuming". In addition to well-known creatine kinase, other promising molecules seem to be candidate biomarkers to improve the diagnosis, prognosis and prediction of therapeutic response, such as antibodies, neurofilaments, and microRNAs. However, there are some criticalities that can complicate their application: variability during the day, stability, and reliable performance metrics (e.g., accuracy, precision and reproducibility) across laboratories. In the present review, we discuss the application of biochemical biomarkers (both validated and emerging) in the most common NMDs with a focus on their diagnostic, prognostic/predictive and therapeutic application, and finally, we address the critical issues in the introduction of new biomarkers.}, }
@article {pmid34439576, year = {2021}, author = {Novak, V and Rogelj, B and Župunski, V}, title = {Therapeutic Potential of Polyphenols in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {8}, pages = {}, pmid = {34439576}, issn = {2076-3921}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are severe neurodegenerative disorders that belong to a common disease spectrum. The molecular and cellular aetiology of the spectrum is a highly complex encompassing dysfunction in many processes, including mitochondrial dysfunction and oxidative stress. There is a paucity of treatment options aside from therapies with subtle effects on the post diagnostic lifespan and symptom management. This presents great interest and necessity for the discovery and development of new compounds and therapies with beneficial effects on the disease. Polyphenols are secondary metabolites found in plant-based foods and are well known for their antioxidant activity. Recent research suggests that they also have a diverse array of neuroprotective functions that could lead to better treatments for neurodegenerative diseases. We present an overview of the effects of various polyphenols in cell line and animal models of ALS/FTD. Furthermore, possible mechanisms behind actions of the most researched compounds (resveratrol, curcumin and green tea catechins) are discussed.}, }
@article {pmid34432256, year = {2022}, author = {Shan, L and Martens, GJM and Swaab, DF}, title = {Histamine-4 Receptor: Emerging Target for the Treatment of Neurological Diseases.}, journal = {Current topics in behavioral neurosciences}, volume = {59}, number = {}, pages = {131-145}, pmid = {34432256}, issn = {1866-3370}, mesh = {Animals ; Anti-Inflammatory Agents ; Genome-Wide Association Study ; *Histamine ; Histamine Antagonists/therapeutic use ; Humans ; *Neurodegenerative Diseases ; Receptors, Histamine/genetics ; }, abstract = {A major challenge in the field of the biogenic amine histamine is the search for new-generation histamine receptor specific drugs. Daniel Bovet and Sir James Black received their Nobel Prizes for Medicine for their work on histamine-1 receptor (H1R) and H2R antagonists to treat allergies and gastrointestinal disorders. The first H3R-targeting drug to reach the market was approved for the treatment of the neurological disorder narcolepsy in 2018. The antagonists for the most recently identified histamine receptor, H4R, are currently under clinical evaluation for their potential therapeutic effects on inflammatory diseases such as atopic dermatitis and pruritus. In this chapter, we propose that H4R antagonists are endowed with prominent anti-inflammatory and immune effects, including in the brain. To substantiate this proposition, we combine data from transcriptional analyses of postmortem human neurodegenerative disease brain samples, human genome-wide association studies (GWAS), and translational animal model studies. The results prompt us to suggest the potential involvement of the H4R in various neurodegenerative diseases and how manipulating the H4R may create new therapeutic opportunities in central nervous system diseases.}, }
@article {pmid34429248, year = {2021}, author = {Kato, Y and Sakamoto, K}, title = {Niclosamide affects intracellular TDP-43 distribution in motor neurons, activates mitophagy, and attenuates morphological changes under stress.}, journal = {Journal of bioscience and bioengineering}, volume = {132}, number = {6}, pages = {640-650}, doi = {10.1016/j.jbiosc.2021.06.015}, pmid = {34429248}, issn = {1347-4421}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; DNA-Binding Proteins/genetics ; Humans ; Mitophagy ; Motor Neurons ; *Niclosamide/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron loss in the brain and spinal cord; however, its etiology is unknown, and no curative treatment exists. TAR DNA-binding protein 43 (TDP-43), encoded by TARDBP, is a genetic mutation observed in 2-5% of familial ALS, and TDP is known to be mislocalized in the cytoplasm. This study aimed to identify compounds that inhibited the nuclear to cytoplasmic localization of TDP-43 in human induced pluripotent stem (iPS) cells-derived neurons. TDP-43 transgenic human iPS cells were constructed, differentiated into motor neurons, and then treated with MG-132 and sodium arsenite (stressors) to induce nuclear to cytoplasmic localization of TDP-43. STAT3 inhibitors, such as niclosamide, prevented TDP-43 mislocalization and degraded TDP-43 aggregates, and attenuated morphological changes under stress. Furthermore, niclosamide activated mitophagy via the PINK1-parkin-ubiquitin pathway. These findings suggest niclosamide may be a therapeutic candidate for ALS.}, }
@article {pmid34426623, year = {2021}, author = {Keerie, A and Brown-Wright, H and Kirkland, I and Grierson, A and Alix, JJP and Holscher, C and Mead, RJ}, title = {The GLP-1 receptor agonist, liraglutide, fails to slow disease progression in SOD1[G93A] and TDP-43[Q331K] transgenic mouse models of ALS.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {17027}, pmid = {34426623}, issn = {2045-2322}, support = {SITRAN/APR13/983-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; SITRAN/JUL16/987-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/blood/*pathology ; Animals ; Behavior, Animal/drug effects ; Biomarkers/metabolism ; Blood Glucose/metabolism ; Calcium-Binding Proteins/metabolism ; DNA-Binding Proteins/*genetics ; Disease Models, Animal ; *Disease Progression ; Glial Fibrillary Acidic Protein/metabolism ; Glucagon-Like Peptide-1 Receptor/metabolism ; Liraglutide/*pharmacology ; Lumbar Vertebrae/drug effects/pathology ; Mice, Inbred C57BL ; Mice, Transgenic ; Microfilament Proteins/metabolism ; Motor Neurons/drug effects/pathology ; Neuroglia/drug effects/metabolism ; Superoxide Dismutase-1/*genetics ; Mice ; *Glucagon-Like Peptide-1 Receptor Agonists ; }, abstract = {GLP-1 receptor agonists used for the treatment of diabetes, have shown some neuroprotective effects in cellular and animal models of Alzheimer's disease (AD) and Parkinson's disease (PD). There are currently few studies investigating GLP-1 receptor agonists in the treatment of ALS, where these neuroprotective effects may be beneficial. Here we investigate the effects of liraglutide, a GLP-1 receptor agonist, in two well characterised transgenic mouse models of ALS (SOD1[G93A] and TDP-43[Q331K]) to determine if liraglutide could be a potential treatment in ALS patients. Doses of liraglutide previously shown to have efficacy in AD and PD mouse models were used. Behavioural testing was carried out to ascertain the effect of liraglutide on disease progression. Immunohistochemical analysis of tissue was used to determine any neuroprotective effects on the CNS. We found that liraglutide dosed animals showed no significant differences in disease progression when compared to vehicle dosed animals in either the SOD1[G93A] or TDP-43[Q331K] mouse models of ALS. We also observed no changes in motor neuron counts or glial activation in lumbar spinal cords of liraglutide treated mice compared to vehicle dosed mice. Overall, we found no evidence to support clinical evaluation of liraglutide as a potential candidate for the treatment of ALS.}, }
@article {pmid34425427, year = {2022}, author = {Tian, M and Morais, CLM and Shen, H and Pang, W and Xu, L and Huang, Q and Martin, FL}, title = {Direct identification and visualisation of real-world contaminating microplastics using Raman spectral mapping with multivariate curve resolution-alternating least squares.}, journal = {Journal of hazardous materials}, volume = {422}, number = {}, pages = {126892}, doi = {10.1016/j.jhazmat.2021.126892}, pmid = {34425427}, issn = {1873-3336}, mesh = {Animals ; Least-Squares Analysis ; *Microplastics ; Multivariate Analysis ; Plastics ; Polyethylene ; *Water Pollutants, Chemical/analysis ; }, abstract = {Microplastics (MPs) contamination is ubiquitous in environmental matrices worldwide. Moreover these pollutants can be ingested by organisms and transported to organs via the circulatory system. Although efficient methods for the analysis of MPs derived from environment matrices and organisms' tissue samples have been developed after special sample pre-treatment, there remains a need for an optimised approach allowing direct identification and visualisation these MPs in real environmental matrices and organismal samples. Herein, we firstly used a multivariate curve resolution-alternating least squares (MCR-ALS) analysis of Raman hyperspectral imaging data to direct identification and visualisation of MPs in a complex serum background. Four common MPs types including polyethylene (PE), polystyrene (PS), polypropylene (PP) and polyethylene terephthalate (PET) were identified and visualised either individually or in mixtures within spiked samples at an 8-μm spatial resolution. Moreover, Raman imaging based on MCR-ALS was successfully applied in fish faeces biological samples and environmental sand samples for in situ MPs identification directly without washing or removal of organic matter. The current results demonstrate Raman imaging based on MCR-ALS as a novel imaging approach for direct identification and visualisation of MPs, through extraction of MPs' chemical spectra within a complicated biological or environmental background whilst eliminating overlapping Raman bands and fluorescence interference.}, }
@article {pmid34422879, year = {2021}, author = {Milošević, M and Arsić, A and Cvetković, Z and Vučić, V}, title = {Memorable Food: Fighting Age-Related Neurodegeneration by Precision Nutrition.}, journal = {Frontiers in nutrition}, volume = {8}, number = {}, pages = {688086}, pmid = {34422879}, issn = {2296-861X}, abstract = {Healthcare systems worldwide are seriously challenged by a rising prevalence of neurodegenerative diseases (NDDs), which mostly, but not exclusively, affect the ever-growing population of the elderly. The most known neurodegenerative diseases are Alzheimer's (AD) and Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, but some viral infections of the brain and traumatic brain injury may also cause NDD. Typical for NDD are the malfunctioning of neurons and their irreversible loss, which often progress irreversibly to dementia and ultimately to death. Numerous factors are involved in the pathogenesis of NDD: genetic variability, epigenetic changes, extent of oxidative/nitrosative stress, mitochondrial dysfunction, and DNA damage. The complex interplay of all the above-mentioned factors may be a fingerprint of neurodegeneration, with different diseases being affected to different extents by particular factors. There is a voluminous body of evidence showing the benefits of regular exercise to brain health and cognitive functions. Moreover, the importance of a healthy diet, balanced in macro- and micro-nutrients, in preventing neurodegeneration and slowing down a progression to full-blown disease is evident. Individuals affected by NDD almost inevitably have low-grade inflammation and anomalies in lipid metabolism. Metabolic and lipid profiles in NDD can be improved by the Mediterranean diet. Many studies have associated the Mediterranean diet with a decreased risk of dementia and AD, but a cause-and-effect relationship has not been deduced. Studies with caloric restriction showed neuroprotective effects in animal models, but the results in humans are inconsistent. The pathologies of NDD are complex and there is a great inter-individual (epi)genetic variance within any population. Furthermore, the gut microbiome, being deeply involved in nutrient uptake and lipid metabolism, also represents a pillar of the gut microbiome-brain axis and is linked with the pathogenesis of NDD. Numerous studies on the role of different micronutrients (omega-3 fatty acids, bioactive polyphenols from fruit and medicinal plants) in the prevention, prediction, and treatment of NDD have been conducted, but we are still far away from a personalized diet plan for individual NDD patients. For this to be realized, large-scale cohorts that would include the precise monitoring of food intake, mapping of genetic variants, epigenetic data, microbiome studies, and metabolome, lipidome, and transcriptome data are needed.}, }
@article {pmid34411705, year = {2021}, author = {Anzilotti, S and Valsecchi, V and Brancaccio, P and Guida, N and Laudati, G and Tedeschi, V and Petrozziello, T and Frecentese, F and Magli, E and Hassler, B and Cuomo, O and Formisano, L and Secondo, A and Annunziato, L and Pignataro, G}, title = {Prolonged NCX activation prevents SOD1 accumulation, reduces neuroinflammation, ameliorates motor behavior and prolongs survival in a ALS mouse model.}, journal = {Neurobiology of disease}, volume = {159}, number = {}, pages = {105480}, doi = {10.1016/j.nbd.2021.105480}, pmid = {34411705}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology/physiopathology ; Animals ; Astrocytes/drug effects/metabolism/pathology ; Benzodiazepinones/*pharmacology ; Humans ; Mice ; Mice, Transgenic ; Microglia/drug effects/metabolism/pathology ; Motor Neurons/*drug effects/metabolism/pathology ; Neuroinflammatory Diseases/*metabolism/pathology/physiopathology ; Neuroprotective Agents/*pharmacology ; Pyrrolidines/*pharmacology ; Sodium-Calcium Exchanger/*agonists ; Spinal Cord/*drug effects/metabolism/pathology ; Superoxide Dismutase/genetics ; Survival Rate ; }, abstract = {Imbalance in cellular ionic homeostasis is a hallmark of several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). Sodium-calcium exchanger (NCX) is a membrane antiporter that, operating in a bidirectional way, couples the exchange of Ca[2+] and Na [+] ions in neurons and glial cells, thus controlling the intracellular homeostasis of these ions. Among the three NCX genes, NCX1 and NCX2 are widely expressed within the CNS, while NCX3 is present only in skeletal muscles and at lower levels of expression in selected brain regions. ALS mice showed a reduction in the expression and activity of NCX1 and NCX2 consistent with disease progression, therefore we aimed to investigate their role in ALS pathophysiology. Notably, we demonstrated that the pharmacological activation of NCX1 and NCX2 by the prolonged treatment of SOD1[G93A] mice with the newly synthesized compound neurounina: (1) prevented the reduction in NCX activity observed in spinal cord; (2) preserved motor neurons survival in the ventral spinal horn of SOD1[G93A] mice; (3) prevented the spinal cord accumulation of misfolded SOD1; (4) reduced astroglia and microglia activation and spared the resident microglia cells in the spinal cord; (5) improved the lifespan and mitigated motor symptoms of ALS mice. The present study highlights the significant role of NCX1 and NCX2 in the pathophysiology of this neurodegenerative disorder and paves the way for the design of a new pharmacological approach for ALS.}, }
@article {pmid34411491, year = {2021}, author = {Roman, A and Baylor, C and Johnson, L and Barton, M}, title = {Expanding Availability of Speech-Generating Device Evaluation and Treatment to People With Amyotrophic Lateral Sclerosis (pALS) Through Telepractice: Perspectives of pALS and Communication Partners.}, journal = {American journal of speech-language pathology}, volume = {30}, number = {5}, pages = {2098-2114}, doi = {10.1044/2021_AJSLP-20-00334}, pmid = {34411491}, issn = {1558-9110}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Communication ; *Communication Devices for People with Disabilities ; Humans ; Speech ; *Speech-Language Pathology ; }, abstract = {Purpose To examine the experiences of people with ALS (pALS) and their communication partners (cALS) regarding receiving speech-generating device (SGD) evaluation and treatment via telepractice. Method Eight pALS along with a primary cALS participated in telepractice SGD evaluation and treatment with an augmentative and alternative communication (AAC) specialist and representatives from multiple SGD vendors. Participants were interviewed postevaluation and post-SGD training to examine their experiences. Mixed methods data were collected through Likert scale responses and qualitative interviews. Results Telepractice SGD evaluation and training were feasible and resulted in all pALS receiving SGDs they were able to use to communicate. In both Likert rating items and qualitative interviews, participants rated the telepractice experience very highly in terms of giving them access to AAC services via an AAC specialist that they would not have otherwise been able to access, and doing so in a format that was possible given their limitations in mobility, endurance, and caregiver availability. Suggestions for improving the telepractice experience were provided. Conclusions Telepractice should be considered as an option to provide vital SGD services to patients who are geographically remote, mobility impaired, unable to leave their home, experience fatigue with travel, or otherwise would not have access to these specialized services. Telepractice allows patients to preserve their time and energy for the assessment and treatment sessions, resulting in perhaps deeper and more frequent engagement in evaluation and training. Telepractice could serve as an alternative to outpatient, in-person evaluations, or be utilized in conjunction with in-person appointments. Supplemental Material https://doi.org/10.23641/asha.15094257.}, }
@article {pmid34411281, year = {2021}, author = {Cocozza, G and Garofalo, S and Morotti, M and Chece, G and Grimaldi, A and Lecce, M and Scavizzi, F and Menghini, R and Casagrande, V and Federici, M and Raspa, M and Wulff, H and Limatola, C}, title = {The feeding behaviour of Amyotrophic Lateral Sclerosis mouse models is modulated by the Ca[2+] -activated KCa 3.1 channels.}, journal = {British journal of pharmacology}, volume = {178}, number = {24}, pages = {4891-4906}, pmid = {34411281}, issn = {1476-5381}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Disease Models, Animal ; Energy Metabolism ; *Feeding Behavior ; Homeostasis ; Melanocortins ; Mice ; Mice, Transgenic ; Microglia/cytology ; Potassium Channels, Calcium-Activated/*metabolism ; Pyrazoles/pharmacology ; Receptors, Cannabinoid ; Spinal Cord/metabolism ; Superoxide Dismutase-1/metabolism ; Weight Gain ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) patients exhibit dysfunctional energy metabolism and weight loss, which is negatively correlated with survival, together with neuroinflammation. However, the possible contribution of neuroinflammation to deregulations of feeding behaviour in ALS has not been studied in detail. We here investigated if microglial KCa 3.1 is linked to hypothalamic neuroinflammation and affects feeding behaviours in ALS mouse models.<br><br>EXPERIMENTAL APPROACH: hSOD1[G93A] and TDP43[A315T] mice were treated daily with 120&#x2009;mg&#xb7;kg[-1] of TRAM-34 or vehicle by intraperitoneal injection from the presymptomatic until the disease onset phase. Body weight and food intake were measured weekly. The later by weighing food provided minus that left in the cage. RT-PCR and immunofluorescence analysis were used to characterize microglia phenotype and the main populations of melanocortin neurons in the hypothalamus of hSOD1[G93A] and age-matched non-tg mice. The cannabinoid-opioid interactions in feeding behaviour of hSOD1[G93A] mice were studied using an inverse agonist and an antagonist of the cannabinoid receptor CB1 (rimonabant) and &#x3bc;-opioid receptors (naloxone), respectively.<br><br>KEY RESULTS: We found that treatment of hSOD1[G93A] mice with the KCa 3.1 inhibitor TRAM-34 (i), attenuates the pro-inflammatory phenotype of hypothalamic microglia, (ii) increases food intake and promotes weight gain, (iii) increases the number of healthy pro-opiomelanocortin (POMC) neurons and (iv), changes the expression of cannabinoid receptors involved in energy homeostasis.<br><br>CONCLUSION AND IMPLICATIONS: Using ALS mouse models, we describe defects in the hypothalamic melanocortin system that affect appetite control. These results reveal a new regulatory role for KCa 3.1 to counteract weight loss in ALS.}, }
@article {pmid34409288, year = {2021}, author = {Giovannelli, I and Bayatti, N and Brown, A and Wang, D and Mickunas, M and Camu, W and Veyrune, JL and Payan, C and Garlanda, C and Locati, M and Juntas-Morales, R and Pageot, N and Malaspina, A and Andreasson, U and Suehs, C and Saker, S and Masseguin, C and de Vos, J and Zetterberg, H and Al-Chalabi, A and Leigh, PN and Tree, T and Bensimon, G and Heath, PR and Shaw, PJ and Kirby, J}, title = {Amyotrophic lateral sclerosis transcriptomics reveals immunological effects of low-dose interleukin-2.}, journal = {Brain communications}, volume = {3}, number = {3}, pages = {fcab141}, pmid = {34409288}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease causing upper and lower motor neuron loss and currently no effective disease-modifying treatment is available. A pathological feature of this disease is neuroinflammation, a mechanism which involves both CNS-resident and peripheral immune system cells. Regulatory T-cells are immune-suppressive agents known to be dramatically and progressively decreased in patients with amyotrophic lateral sclerosis. Low-dose interleukin-2 promotes regulatory T-cell expansion and was proposed as an immune-modulatory strategy for this disease. A randomized placebo-controlled pilot phase-II clinical trial called Immuno-Modulation in Amyotrophic Lateral Sclerosis was carried out to test safety and activity of low-dose interleukin-2 in 36 amyotrophic lateral sclerosis patients (NCT02059759). Participants were randomized to 1MIU, 2MIU-low-dose interleukin-2 or placebo and underwent one injection daily for 5 days every 28 days for three cycles. In this report, we describe the results of microarray gene expression profiling of trial participants' leukocyte population. We identified a dose-dependent increase in regulatory T-cell markers at the end of the treatment period. Longitudinal analysis revealed an alteration and inhibition of inflammatory pathways occurring promptly at the end of the first treatment cycle. These responses are less pronounced following the end of the third treatment cycle, although an activation of immune-regulatory pathways, involving regulatory T-cells and T helper 2 cells, was evident only after the last cycle. This indicates a cumulative effect of repeated low-dose interleukin-2 administration on regulatory T-cells. Our analysis suggested the existence of inter-individual variation amongst trial participants and we therefore classified patients into low, moderate and high-regulatory T-cell-responders. NanoString profiling revealed substantial baseline differences between participant immunological transcript expression profiles with the least responsive patients showing a more inflammatory-prone phenotype at the beginning of the trial. Finally, we identified two genes in which pre-treatment expression levels correlated with the magnitude of drug responsiveness. Therefore, we proposed a two-biomarker based regression model able to predict patient regulatory T-cell-response to low-dose interleukin-2. These findings and the application of this methodology could be particularly relevant for future precision medicine approaches to treat amyotrophic lateral sclerosis.}, }
@article {pmid34400291, year = {2021}, author = {Oli, V and Gupta, R and Kumar, P}, title = {FOXO and related transcription factors binding elements in the regulation of neurodegenerative disorders.}, journal = {Journal of chemical neuroanatomy}, volume = {116}, number = {}, pages = {102012}, doi = {10.1016/j.jchemneu.2021.102012}, pmid = {34400291}, issn = {1873-6300}, mesh = {Animals ; Forkhead Box Protein O1/*metabolism ; Forkhead Transcription Factors/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Neurons/*metabolism/pathology ; Oxidative Stress/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and others, are characterized by progressive loss of neuronal cells, which causes memory impairment and cognitive decline. Mounting evidence demonstrated the possible implications of diverse biological processes, namely oxidative stress, mitochondrial dysfunction, aberrant cell cycle re-entry, post-translational modifications, protein aggregation, impaired proteasome dysfunction, autophagy, and many others that cause neuronal cell death. The condition worsens as there is no effective treatment for such diseases due to their complex pathogenesis and mechanism. Mounting evidence demonstrated the role of regulatory transcription factors, such as NFκβ, FoxO, Myc, CREB, and others that regulate the biological processes and diminish the disease progression and pathogenesis. Studies demonstrated that forkhead box O (FoxO) transcription factors had been implicated in the regulation of aging and longevity. Further, the functions of FoxO proteins are regulated by different post-translational modifications (PTMs), namely acetylation, and ubiquitination. Various studies concluded that FoxO proteins exert both neuroprotective and neurotoxic properties depending on their regulation mechanism and activity in the brain. Thus, understanding the nature of FoxO expression and activity in the brain will help develop effective therapeutic strategies. Herein, firstly, we discuss the role of FoxO protein in cell cycle regulation and cell proliferation, followed by the regulation of FoxO proteins through acetylation and ubiquitination. We also briefly explain the activity and expression pattern of FoxO proteins in the neuronal cells and explain the mechanism through which FoxO proteins are rescued from oxidative stress-induced neurotoxicity. Later on, we present a detailed view of the implication of FoxO proteins in neurodegenerative disease and FoxO proteins as an effective therapeutic target.}, }
@article {pmid34396115, year = {2021}, author = {Harley, J and Hagemann, C and Serio, A and Patani, R}, title = {TDP-43 and FUS mislocalization in VCP mutant motor neurons is reversed by pharmacological inhibition of the VCP D2 ATPase domain.}, journal = {Brain communications}, volume = {3}, number = {3}, pages = {fcab166}, pmid = {34396115}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/M02492X/1/MRC_/Medical Research Council/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {RNA binding proteins have been shown to play a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Mutations in valosin-containing protein (VCP/p97) cause ALS and exhibit the hallmark nuclear-to-cytoplasmic mislocalization of RNA binding proteins (RBPs). However, the mechanism by which mutations in VCP lead to this mislocalization of RBPs remains incompletely resolved. To address this, we used human-induced pluripotent stem cell-derived motor neurons carrying VCP mutations. We first demonstrate reduced nuclear-to-cytoplasmic ratios of transactive response DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS) and splicing factor proline and glutamine rich (SFPQ) in VCP mutant motor neurons. Upon closer analysis, we also find these RBPs are mislocalized to motor neuron neurites themselves. To address the hypothesis that altered function of the D2 ATPase domain of VCP causes RBP mislocalization, we used pharmacological inhibition of this domain in control motor neurons and found this does not recapitulate RBP mislocalization phenotypes. However, D2 domain inhibition in VCP mutant motor neurons was able to robustly reverse mislocalization of both TDP-43 and FUS, in addition to partially relocalizing SFPQ from the neurites. Together these results argue for a gain-of-function of D2 ATPase in VCP mutant human motor neurons driving the mislocalization of TDP-43 and FUS. Our data raise the intriguing possibility of harnessing VCP D2 ATPase inhibitors in the treatment of VCP-related ALS.}, }
@article {pmid34396011, year = {2021}, author = {Grauffel, C and Weng, WH and Dudev, T and Lim, C}, title = {Trinuclear Calcium Site in the C2 Domain of PKCα/γ Is Prone to Lithium Attack.}, journal = {ACS omega}, volume = {6}, number = {31}, pages = {20657-20666}, pmid = {34396011}, issn = {2470-1343}, abstract = {Lithium (Li[+]) is the first-line therapy for bipolar disorder and a candidate drug for various diseases such as amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Despite being the captivating subject of many studies, the mechanism of lithium's therapeutic action remains unclear. To date, it has been shown that Li[+] competes with Mg[2+] and Na[+] to normalize the activity of inositol and neurotransmitter-related signaling proteins, respectively. Furthermore, Li[+] may co-bind with Mg[2+]-loaded adenosine or guanosine triphosphate to alter the complex's susceptibility to hydrolysis and mediate cellular signaling. Bipolar disorder patients exhibit abnormally high cytosolic Ca[2+] levels and protein kinase C (PKC) hyperactivity that can be downregulated by long-term Li[+] treatment. However, the possibility that monovalent Li[+] could displace the bulkier divalent Ca[2+] and inhibit PKC activity has not been considered. Here, using density functional theory calculations combined with continuum dielectric methods, we show that Li[+] may displace the native dication from the positively charged trinuclear site in the C2 domain of cytosolic PKCα/γ. This would affect the membrane-docking ability of cytosolic PKCα/γ and reduce the abnormally high membrane-associated active PKCα/γ levels, thus downregulating the PKC hyperactivity found in bipolar patients.}, }
@article {pmid34392765, year = {2022}, author = {Young, C and Pinto, S and Grosskreutz, J and Hardiman, O and Clawson, LL and Cudkowicz, ME and Andrews, JA}, title = {Medical therapies for amyotrophic lateral sclerosis-related respiratory decline: an appraisal of needs, opportunities and obstacles.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {1-2}, pages = {66-75}, doi = {10.1080/21678421.2021.1920981}, pmid = {34392765}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/complications/therapy ; *COVID-19 ; Humans ; *Noninvasive Ventilation ; Pandemics ; Quality of Life ; *Respiratory Insufficiency/etiology/therapy ; SARS-CoV-2 ; }, abstract = {A roundtable convened in July 2020 examined issues concerning respiratory support in amyotrophic lateral sclerosis (ALS), with reference to the potential for an early-phase orally administered medication that might either postpone the introduction of noninvasive ventilation (NIV) and/or enhance the benefits to be gained from it. Attention was also given to the impact of the COVID-19 pandemic on usual practice in the assessment and management of ALS-related respiratory difficulties. Implementation of NIV marks a step-change in clinical status for patients and a major increase in burden for caregivers. All means to ease this transition should be explored: an oral therapy that supported respiratory function and patients' independence and sense of well-being would aid discussions to facilitate the eventual successful introduction of NIV. Assessment of a candidate oral therapy that might support respiratory function in ALS patients would be aided by the development of improved patient-reported outcome measures for robust quantification of treatment effect and quality of life. Such instruments could also be used to monitor patients' status during the COVID-19 pandemic, averting some of the risks of face-to-face assessment plus the patient burden and costs of traditional methods. Several oral candidate therapies have recently failed to meet their primary endpoints in clinical trials. However, understanding of the underlying physiology and appropriate trial design have grown and will inform future developments in this field.}, }
@article {pmid34390468, year = {2021}, author = {Maraschi, A and Gumina, V and Dragotto, J and Colombrita, C and Mompeán, M and Buratti, E and Silani, V and Feligioni, M and Ratti, A}, title = {SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution.}, journal = {Molecular neurobiology}, volume = {58}, number = {11}, pages = {5682-5702}, pmid = {34390468}, issn = {1559-1182}, support = {SUMALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {Cell Line, Tumor ; Cell Nucleus/*chemistry ; Cytoplasm/*chemistry ; DNA-Binding Proteins/analysis/*metabolism ; HEK293 Cells ; Humans ; Models, Molecular ; Molecular Dynamics Simulation ; Nerve Tissue Proteins/analysis/*metabolism ; Neuroblastoma ; Peptide Fragments/pharmacology ; Potassium Chloride/pharmacology ; Protein Conformation ; *Protein Processing, Post-Translational ; Protein Transport ; RNA Interference ; RNA Splicing ; RNA, Small Interfering/pharmacology ; Sequence Alignment ; Sequence Homology, Amino Acid ; Stress Granules ; Sumoylation ; }, abstract = {The nuclear RNA-binding protein TDP-43 forms abnormal cytoplasmic aggregates in the brains of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients and several molecular mechanisms promoting TDP-43 cytoplasmic mislocalization and aggregation have been proposed, including defects in nucleocytoplasmic transport, stress granules (SG) disassembly and post-translational modifications (PTM). SUMOylation is a PTM which regulates a variety of cellular processes and, similarly to ubiquitination, targets lysine residues. To investigate the possible regulatory effects of SUMOylation on TDP-43 activity and trafficking, we first assessed that TDP-43 is SUMO-conjugated in the nuclear compartment both covalently and non-covalently in the RRM1 domain at the predicted lysine 136 and SUMO-interacting motif (SIM, 106-110 residues), respectively. By using the SUMO-mutant TDP-43 K136R protein, we demonstrated that SUMOylation modifies TDP-43 splicing activity, specifically exon skipping, and influences its sub-cellular localization and recruitment to SG after oxidative stress. When promoting deSUMOylation by SENP1 enzyme over-expression or by treatment with the cell-permeable SENP1 peptide TS-1, the cytoplasmic localization of TDP-43 increased, depending on its SUMOylation. Moreover, deSUMOylation by TS-1 peptide favoured the formation of small cytoplasmic aggregates of the C-terminal TDP-43 fragment p35, still containing the SUMO lysine target 136, but had no effect on the already formed p25 aggregates. Our data suggest that TDP-43 can be post-translationally modified by SUMOylation which may regulate its splicing function and trafficking, indicating a novel and druggable mechanism to explore as its dysregulation may lead to TDP-43 pathological aggregation in ALS and FTD.}, }
@article {pmid34390052, year = {2021}, author = {Wright, AL and Della Gatta, PA and Le, S and Berning, BA and Mehta, P and Jacobs, KR and Gul, H and San Gil, R and Hedl, TJ and Riddell, WR and Watson, O and Keating, SS and Venturato, J and Chung, RS and Atkin, JD and Lee, A and Shi, B and Blizzard, CA and Morsch, M and Walker, AK}, title = {Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis.}, journal = {The European journal of neuroscience}, volume = {54}, number = {6}, pages = {6237-6255}, doi = {10.1111/ejn.15422}, pmid = {34390052}, issn = {1460-9568}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; DNA-Binding Proteins/genetics ; Disease Models, Animal ; Female ; Mice ; Mice, Transgenic ; *Neurodegenerative Diseases ; Riluzole/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonly treated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespan for people living with ALS, and its precise mechanisms of action remain unclear. Most ALS cases are characterised by accumulation of cytoplasmic TAR DNA binding protein of 43 kDa (TDP-43), and understanding the effects of riluzole in models that closely recapitulate TDP-43 pathology may provide insights for development of improved therapeutics. We therefore investigated the effects of riluzole in female transgenic mice that inducibly express nuclear localisation sequence (NLS)-deficient human TDP-43 in neurons (NEFH-tTA/tetO-hTDP-43ΔNLS, 'rNLS8', mice). Riluzole treatment from the first day of hTDP-43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did not alter TDP-43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS8 mice, riluzole did not ameliorate this disease-associated molecular phenotype. Likewise, riluzole did not alter the disease-associated atrophy of hindlimb muscle in rNLS8 mice. Finally, riluzole treatment beginning after disease onset in rNLS8 mice similarly had no effect on progression of late-stage disease or animal survival. Together, we demonstrate specific glutamatergic receptor alterations and muscle fibre-type changes reminiscent of ALS in female rNLS8 mice, but riluzole had no effect on these or any other disease phenotypes. Future targeting of pathways related to accumulation of TDP-43 pathology may be needed to develop better treatments for ALS.}, }
@article {pmid34386317, year = {2021}, author = {Ahsan, A and Liu, M and Zheng, Y and Yan, W and Pan, L and Li, Y and Ma, S and Zhang, X and Cao, M and Wu, Z and Hu, W and Chen, Z and Zhang, X}, title = {Natural compounds modulate the autophagy with potential implication of stroke.}, journal = {Acta pharmaceutica Sinica. B}, volume = {11}, number = {7}, pages = {1708-1720}, pmid = {34386317}, issn = {2211-3835}, abstract = {Stroke is considered a leading cause of mortality and neurological disability, which puts a huge burden on individuals and the community. To date, effective therapy for stroke has been limited by its complex pathological mechanisms. Autophagy refers to an intracellular degrading process with the involvement of lysosomes. Autophagy plays a critical role in maintaining the homeostasis and survival of cells by eliminating damaged or non-essential cellular constituents. Increasing evidence support that autophagy protects neuronal cells from ischemic injury. However, under certain circumstances, autophagy activation induces cell death and aggravates ischemic brain injury. Diverse naturally derived compounds have been found to modulate autophagy and exert neuroprotection against stroke. In the present work, we have reviewed recent advances in naturally derived compounds that regulate autophagy and discussed their potential application in stroke treatment.}, }
@article {pmid35790096, year = {2021}, author = {Lay-Ekuakille, A and Chiffi, C and Celesti, A and Rahman, MZU and Singh, SP}, title = {Infrared Monitoring of Oxygenation Process Generated by Robotic Verticalization in Bedridden People.}, journal = {IEEE sensors journal}, volume = {21}, number = {13}, pages = {14426-14433}, pmid = {35790096}, issn = {1530-437X}, abstract = {Bedridden people, especially at home, suffer from diverse pathologies beyond the main one that brings them to a specific position. Long-term cares are suitable at home to avoid congestions within hospital facilities. There are different technologies available to improve such people's conditions in their daily life. The standing posture is the key solution to enhance people's wellness amid the psychological burden due to the almost impossibility to be completely healed. The paper proposes the use of a polyfunctional and robotic bed capable of displaying many positions namely vertical, tilting, anti-trendelenburg with necessary graduation. A three-year monitoring of a patient, using a polyfunctional and robotic bed, suffering from amyotrophic lateral sclerosis (ALS), has been investigated. Different physiological parameters have been measured and, particularly, the variation of temperature has been measured in presence of body position connected to the robotic bed rotation that provokes biomechanical effort. It is demonstrated that certain body positions correspond to major and minor physical effort, hence major and minor oxygenation. An infrared camera has been used. As a positive result, the variation of posture has been delaying the increase of the pathological signs, because of better conditions.}, }
@article {pmid37387779, year = {2021}, author = {Huang, H and Chen, L and Chopp, M and Young, W and Robert Bach, J and He, X and Sarnowaska, A and Xue, M and Chunhua Zhao, R and Shetty, A and Siniscalco, D and Guo, X and Khoshnevisan, A and Hawamdeh, Z}, title = {The 2020 Yearbook of Neurorestoratology.}, journal = {Journal of neurorestoratology}, volume = {9}, number = {1}, pages = {1-12}, pmid = {37387779}, issn = {2324-2426}, abstract = {COVID-19 has been an emerging and rapidly evolving risk to people of the world in 2020. Facing this dangerous situation, many colleagues in Neurorestoratology did their best to avoid infection if themselves and their patients, and continued their work in the research areas described in the 2020 Yearbook of Neurorestoratology. Neurorestorative achievements and progress during 2020 includes recent findings on the pathogenesis of neurological diseases, neurorestorative mechanisms and clinical therapeutic achievements. Therapeutic progress during this year included advances in cell therapies, neurostimulation/neuromodulation, brain-computer interface (BCI), and pharmaceutical neurorestorative therapies, which improved neurological functions and quality of life for patients. Four clinical guidelines or standards of Neurorestoratology were published in 2020. Milestone examples include: 1) a multicenter randomized, double-blind, placebo-controlled study of olfactory ensheathing cell treatment of chronic stroke showed functional improvements; 2) patients after transhumeral amputation experienced increased sensory acuity and had improved effectiveness in work and other activities of daily life using a prosthesis; 3) a patient with amyotrophic lateral sclerosis used a steady-state visual evoked potential (SSVEP)-based BCI to achieve accurate and speedy computer input; 4) a patient with complete chronic spinal cord injury recovered both motor function and touch sensation with a BCI and restored ability to detect objects by touch and several sensorimotor functions. We hope these achievements motivate and encourage other scientists and physicians to increase neurorestorative research and its therapeutic applications.}, }
@article {pmid35706763, year = {2022}, author = {Hamdeni, T and Gasmi, S}, title = {A proportional-hazards model for survival analysis and long-term survivors modeling: application to amyotrophic lateral sclerosis data.}, journal = {Journal of applied statistics}, volume = {49}, number = {3}, pages = {694-708}, pmid = {35706763}, issn = {0266-4763}, abstract = {The majority of survival data are affected by explanatory variables. We develop a new regression model for survival data analysis. As an alternative to standard mixture models, another model is proposed to describe the eventual presence of a surviving fraction. The proposed models are based on the Marshall-Olkin extended generalized Gompertz distribution. A maximum-likelihood inference is presented in the presence of covariates and a censorship phenomenon. Explanatory variables are incorporated into the model through proportional-hazards to evaluate the effect of risk factors on overall survival under different assumptions. Parametric, semi-parametric, and non-parametric methods are applied to survival analysis of patients treated for amyotrophic lateral sclerosis. Interesting results about riluzole use and other treatment effects on patients' survival have been obtained.}, }
@article {pmid35021426, year = {2019}, author = {Kim, K and Subramaniyam, S and Galaleldeen, A and Nakazawa, H and Umetsu, M and Teizer, W and Bhattacharyya, S}, title = {Nanoparticle Assisted Remodeling of Proteotoxic SOD1 Mutants Alters the Biointerface of the Functional Interaction of Microtubules and Kinesin Motors.}, journal = {ACS applied bio materials}, volume = {2}, number = {10}, pages = {4121-4128}, doi = {10.1021/acsabm.9b00501}, pmid = {35021426}, issn = {2576-6422}, abstract = {Transport deficits with motor neuron degeneration have been implicated in amyotrophic lateral sclerosis (ALS). We report a biomimetic system composed of microtubules/kinesin motor that mimics the dysregulated motor dynamics of ALS. Pathogenic ALS mutants A4V SOD1 completely shut off motility. Treatment with 5 nm citrate coated gold nanoparticles recovers the impaired motor stepping by remodeling the A4V SOD1 rather than stabilizing microtubules or protein folding. Instead, gold nanoparticles alter the protein by a mechanism that reforms protein elements of A4V SOD1, in turn fixing the aberrant interaction of kinesin with microtubules. Reinstating kinesin motility holds potential for managing debilitating ALS.}, }
@article {pmid34645020, year = {1997}, author = {Noble, WC and Lloyd, DH}, title = {Pathogenesis and management of wound infections in domestic animals.}, journal = {Veterinary dermatology}, volume = {8}, number = {4}, pages = {243-248}, doi = {10.1111/j.1365-3164.1997.tb00270.x}, pmid = {34645020}, issn = {1365-3164}, abstract = {Abstract The pathogenesis of wound infections is largely dependent on adherence mechanisms and toxins. Studies of Staphylococcus intermedins indicate that pyoderma isolates can bind to extracellular matrix proteins exposed in wounds but interpretation of adherence studies is complicated as some organisms possess multiple mechanisms. Studies of blocking and promotion of adherence by antibiotics also show variability. Epidermolytic toxins are recognized in S. aureus and S. hyicus but not in S. intermedins, although a synergohymenotropic toxin has been described and canine syndromes occur where epidermal splitting and S. intermedins infection co-exist. Staphylococcal enterotoxins and toxic shock toxin-1 are recognized as superantigens which cause cytokine release non-specifically, promoting inflammation in wounds. Treatment of infected skin depends largely on antibiotics but drug resistance will limit this; a move towards vaccines and re-examination of the value of antisepsis is occurring. Use of dressings which reduce microbial growth must also be a factor in wound management. Resumen La patogenesis de las infecciones de heridas depende en gran medida de los mecanismos de adherencia y de las toxinas. Algunos estudios en Staphylococcus intermedius indican que los aislamientos a partir de áreas de pioderma pueden adherirse a proteinas de la matriz extracelular expuesta en las heridas aunque la interpretación de estudios de adherencia es complicado ya que algunos organismos poseen múltiples mecanismos. Los estudios con antibióticos sobre su capacidad de bloqueo y promoción de la adherencia también muestran variabilidad. Se reconocen toxinas epidermolíticas en S. aureus y S. hyicus pero no en S. intermedius, aunque se ha descrito una toxina sinergohimenotrópica y se producen sindromes caninos en áreas de coexistencia de rotura epidérmica y S. intermedius. Las enterotoxinas estafilocócicas y la Toxina-1 de Shock Tóxico son reconocidas como superantígenos que causan liberación inespecífica de citoquinas, promoviendo la inflamación a nivel de las heridas. El tratamiento de la piel infectada depende en gran medida de los antibióticos, aunque esto se encuentra limitado por las resistencias; se está tendiendo a las vacunaciones y a una re-evaluación del valor de la antisepsia. El uso de vendas que reduzcan el crecimiento bacteriano deberia también ser un factor en el manejo de heridas. [Noble, W.C., Lloyd, D.H. Pathogenesis and management of wound infections in domestic animals (Patogenesis y manejo de heridas infectadas en animales domesticos). Veterinary Dermatology 1997; 8: 243-248] Zusammenfassung Die Pathogenese von Wundinfektionen hängt hauptsächlich von Haftungsmechanismen und Toxinen ab. Studien von Staphylokokkus intermedius weisen nach, dass Isolate von Pyodermien sich an in Wunden exponierte extrazelluläre Matrixproteine binden; die Interpretation dieser Haftungsstudien wird durch multiple Mechanismen einiger Organismen kompliziert. Studien, diese Haftung durch Antibiotika zu blockieren oder zu fördern, zeigen variable Ergebnisse. Epidermolytische Toxine sind für S. aureus und S. hyicus, aber nicht für S. intermedius beschrieben, obwohl von einem synergohymenotropischen Toxin berichtet wird und beim Hund Syndrome auftreten, in denen epidermale Spaltung und S. intermedius Infektion koexistieren. Enterotoxine und Toxischer Schock Toxin 1 von Staphylokokkus werden als Superantigene anerkannt, die nicht spezifische Zytokinfreisetzung verursachen und so die Entzündung in Wunden fördern. Die Behandlung infizierter Haut erfolgt weitgehend durch Antibiotika, aber Resistenzbildung wird deren Verwendung einschränken; im Moment geht die Tendenz mehr in Richtung Impfungen und die Neubewertung von Antisepsis. Die Verwendung von Verbandsmaterialien, die das Wachstum von Mikroorganismen einschränken, muss in der Wundversorgung berücksichtigt werden. [Noble, W.C., Lloyd, D.H. Pathogenesis and management of wound infections in domestic animals (Pathogenese und Versorgung von Wundinfektionen bei Haustieren). Veterinary Dermatology 1997; 8: 243-248] Résumé La pathogénie des plaies infectées dépend largement de mécanismes d'adhérence et de toxines. L'étude de Staphylococcus intermedius montre que des germes de pyodermite peuvent adhérer aux protéines des matrices extracellulaires mises à nu par des blessures mais l'interprétation des études d'adhérence est compliquée par le fait que certains germes possèdent de multiples mécanismes. Des études d'inhibition ou d'activation d'adhérence par des antibiotiques démontrent également une variabilité. On connait l'existence de toxines épidermolytiques chez S. aureus et S. hyicus mais pas chez S. intermedius, bien qu'une toxine synergohymenotropique ait été décrite, et que des syndrômes où clivage épidermique et infection àStaphylococcus intermedius coexistent aient été décrit chez le chien. II est admis que des entérotoxines staphylococciques et la toxine 1 du choc toxique agissent comme des superantigènes qui provoquent une libération non spécifique de cytokines, provoquant l'inflammation des plaies. Le traitement des plaies infectées dépend largement des antibiotiques mais est limité par le phénomène d'antibiorésistance; actuellement, une tendance à reconsidérer la valeur des vaccins et de l'antisepsie se dessine. L'utilisation de pansements qui réduisent la prolifération bactérienne peut également être un facteur du traitement des plaies. [Noble, W.C., Lloyd, D.H. Pathogenesis and management of wound infections in domestic animals (Pathogénie et traitement des plaies infectées chez les animaux domestiques). Veterinary Dermatology 1997; 8: 243-248].}, }
@article {pmid34644878, year = {1996}, author = {Medleau, L and Ristic, Z and McElveen, DR}, title = {Daily ivermectin for treatment of generalized demodicosis in dogs.}, journal = {Veterinary dermatology}, volume = {7}, number = {4}, pages = {209-212}, doi = {10.1111/j.1365-3164.1996.tb00248.x}, pmid = {34644878}, issn = {1365-3164}, abstract = {Abstract Twelve dogs with generalized demodicosis were treated with oral administration of ivermectin, 0.4 mg kg[-1] of body weight given once every 24 h. Results of skin scrapings were used to determine whether administration of ivermectin should be continued or stopped. Dogs that were free of clinical signs of demodicosis 12 months after administration of ivermectin was discontinued were considered cured. Five dogs were cured. The medían duration of treatment was 15 weeks (range 5-21 weeks). Seven dogs were failures, with five relapsing 3-11. 5 months after treatment was stopped, and two having persistent demodicosis in spite of treatment. Mild ivermectin toxicosis developed in one dog after 5 weeks of treatment; side-effects resolved shortly after the treatment was stopped. Resumen Se trataron doce perros con demodicosis generalizada con ivermectina oral, 0.4 mg/Kg de peso corporal una vez cada 24 h. Se realizaron raspados cutáneos para déterminar si debia retirarse o continuar con la administración de ivermectina. Se consideraron curados aquellos perros sin sintomatologia de demodicosis 12 meses después de retirar la terapia con ivermectina. La duración medía del tratamiento con ivermectina fue de 15 semanas (rango de 5-21). Se fracasó en siete perros, con cinco recidivas a los 3-11, 5 meses después de parar la terapia y dos con demodicosis persistente a pesar del tratamiento. Un perro desarrolló una toxicosis leve a la ivermectina a las 5 semanas del tratamiento; los efectos secundarios desaparecieron al poco de retirar el tratamiento. [Medleau, L., Ristic, Z., McElveen, D.R. Daily ivermectin for treatment of generalized demodicosis in dogs (Administración díaria de ivermectina para el tratamiento de le demodicosis generalizada en el perro). Veterinary Dermatology 1996; 7: 209-212.] Résumé Douze chiens présentant une démodécie généralisée fürent traités par administration orale d'ivermectine à la dose de 0.4 mg/kg de poids une fois par jour. Les résultats des raclages cutanés servirent à déterminar la nécessité de continuer ou d'arrêter l'administration d'ivermectine. Les chiens ne présentant aucun symptôme de démodécie 12 mois après l'arrêt de l'ivermectine fürent considérés guéris. Cinq chiens fürent guéris. La durée moyenne du traitement fut de 15 semaines (intervalles de 5 à 21 semaines. Sept cas fürent des échecs, avec 5 chiens récidivant 3 à 11, 5 mois après l'arrêt du traitement, et 2 présentant une démodécie persistante malgré le traitement. Un chien a développé une intoxication modéree après 5 semaines de traitement; les effets secondaires disparaissant rapidement après l'arrêt du traitement. [Medleau, L., Ristic, Z., McElveen, D.R. Daily ivermectin for treatment of generalized demodicosis in dogs (Administration quotidienne d'ivermectine dans le traitement de la démodécie généralisée chez le chien). Veterinary Dermatology 1996; 7: 209-212.] Zusammenfassung Zwölf Hunde mit generalisierter Demodikose wurden mit einer oralen Verabreichung von Ivermectin in der Dosierung von 0, 4 mg/kg Körpergewicht einmal alle 24 Stunden behandelt. Die Ergebnisse der Hautgeschabsel dienten zur Bestimmung, ob die Verabreichung weiterhin erfolgen sollte oder abzubrechen sei. Hunde, die 12 Monate nach Ende der Ivermectin-Verabreichung frei von klinischen Symptomen der Demodikose waren, wurden als geheilt betrachtet. Fünf Hunde waren geheilt. Die mittlere Therapiedauer betrug 15 Wochen (Spannweite 5 bis 21 Wochen). Bei sieben Hunden versagte die Therapie, wobei fünf nach 3 bis 11, 5 Monaten nach Behandlungsende ein Rezidiv bekamen und zwei Tiere trotz der Therapie einer persistierende Demodikose zeigten. Bel einem Hund entwickelte sich 5 Wochen nach der Behandlung eine milde Ivermectin-Intoxikation; die Nebenwirkungen verschwanden kurz nach Abbruch der Therapie. [Medleau, L., Ristic, Z., McElveen, D.R. Daily ivermectin for treatment of generalized demodicosis in dogs (Tägliche Ivermectinverabreichung als Behandlung für Hunde mit generalisierter Demodikose). Veterinary Dermatology 1996; 7: 209-212.].}, }
@article {pmid34644985, year = {1996}, author = {Schroeder, H and Swan, GE and Berry, WL and Pearson, J}, title = {Efficacy of a topical antimicrobial-anti-inflammatory combination in the treatment of pyotraumatic dermatitis in dogs.}, journal = {Veterinary dermatology}, volume = {7}, number = {3}, pages = {163-170}, doi = {10.1111/j.1365-3164.1996.tb00241.x}, pmid = {34644985}, issn = {1365-3164}, abstract = {Abstract The efficacy of a topical antimicrobial-corticosteroid combination for the treatment of pyotraumatic dermatitis in dogs, was investigated. An open-ended, double-blind, randomized trial design was used. Forty dogs were divided into two vehicle-treated control groups and three treatment groups. The dogs in the respective treatment groups were treated with emulsions of either neomycin, prednisolone or a neomycin-prednisolone combination. Lesions were shaved and cleaned before treatment commenced, whereafter the allocated emulsion was applied twice daily for 7 days. Lesions were evaluated for surface area and degree of pruritus and inflammation. Skin biopsy specimens for bacterial culture and histopathological examination were taken. Staphylococcus aureus was the predominant organism isolated. The antimicrobial-corticosteroid combination emulsion resulted in the quickest recovery, followed by the antimicrobial drug alone. Prednisolone alone gave significantly poorer results. Dogs in all groups, including the control groups, recovered completely within 7 days. Résumé L'efficacité d'un topique associant antimicrobien et corticoide dans le traitement de la dematite pyotraumatique du chien a étéétudiée. Une étude randomisée, ouverte, en double aveugle, a été réalisée. Quarante chiens ont été divisés en deux groupes controles traités seulement à l'aide du véhicule et trois groupes traités respectivement soit par l'émulsion de néomycine seule, de prednisolone seule ou par l'association néomycine-prednisolone. Les lésions ont été tondues et nettoyées avant la mise en place du traitement, après quoi l'émulsion a été appliquée deux fois par jour pour sept jours. Les lésions ont étéévaluées quant à leur extension et le degré de prurit et d'inflammation. Des biopsies cutanées ont été réalisées pour culture bactériologique et examen histopathologique. Le principal agent isolé est le staphyloccoque doré. L'émulsion associant antimicrobien et corticoide a entrainé la guérison la plus rapide, suivi par l'antimicrobien utilisé seul. La prednisolone utilisée seule a donné les plus mauvais résultats. Les chiens de tous les groupes, y compris les groupes controles, ont été complètement guéris en sept jours. [Schroeder, H., Swan, G. E., Berry, W. L., Pearson, J. Efficacy of a topical antimicrobial-anti-inflammatory combination in the treatment of pyotraumatic dermatitis in dogs (Efficatité d'un topique associant antimicrobien et antiinflammatoire dans le traitement de la dermatite pyotraumatique du chien). Veterinary Dermatology 1966; 7: 163-170.] Résumén Se investigó la eficacia de un preparado tópico combinado antimicrobiano-corticoesteroideo en el tratamiento de la dermatitis piotraumática canina. Se utilizó un ensayo de final abierto, doble-ciego y al azar. Cuarenta perros se dividieron en dos grupos control tratados con un vehiculador y tres grupos a los que se aplicó el tratamiento. Los perros en los respectivos grupos de tratamiento fueron tratados con emulsiónes de en neomicina o prednisolona o con una combinación de neomicina-prednisolona. Se afeitaron y lavaron las lesiones antes del inicio del tratamiento, y después se aplicó la emulsión asignada dos veces al día durante 7 días. Se evaluaron las lesiones según el área afectada y el grado de prurito e inflamación. Se tomaron biopsias cutáneas para cultivo bacteriano y examen histopatológico. Staphylococcus aureus fue el organismo que predominó en los aislamiento. La emulsión con combinación de antibiótico-corticoesteroide fue la que cursó con una recuperación más rápida, seguido del antimicrobiano solo. El tratamiento unicamente con prednisolona dio resultados significativamente peores. Los perros de todos los grupos, incluyendo los de los grupos control, se recuperaron dentro de los 7 días de tratamiento. [Schroeder, H., Swan, G. E., Berry, W. L., Pearson, J. Efficacy of a topical antimicrobial-anti-inflammatory combination in the treatment of pyotraumatic dermatitis in dogs (Eficacia de un tratamiento antimicrobiano-antiinflamatorio topico combinado en la dermatitis piotraumatica canina). Veterinary Dermatology 1966; 7: 163-170.] Zusammenfassung Die Wirksamkeit einer lokalen Antibiotikum-Kortikoid-Kombination für die Behandlung der pyotraumatischen Dermatitis des Hundes wurde untersucht. Es wurde das Modell einer offenen, randomisierten Doppelblindstudie verwendet. 40 Hunde wurden in zwei Vehikel-behandelte Kontroll-und drei Behandlungsgruppen eingeteilt. Die Hunde der drei Behandlungsgruppen wurden mit Emulsionen von Neomycin, Prednisolon oder einer Neomycin-Prednisolon-Kombination behandelt. Die Hautveränderungen wurden geschoren und gereinigt bevor die Behandlung begann. Dann wurde die entsprechende Emulsion zweimal täglich sieben Tage lang aufgetragen. Die Hautveränderungen wurden nach Größe der Oberfläche und Grad des Juckreizes und der Entzündung beurteilt. Es wurden Hautbioptate für bakteriologische Kulturen und histopathologische Untersuchungen entnommen. Als vorherrschender Keim wurde Staphylococcus aureus isoliert. Die Antibiotikum-Kortikoid-Kombination brachte die schnellste Abheilung, gefolgt von der ausschließlich antibiotischen Therapie. Prednisolon als Monotherapie ergab signifikant schlechtere Resultate. Die Hunde in alien Gruppen, einschließlich der Kontrollgruppen, gesundeten innerhalb von 7 Tagen vollständig. [Schroeder, H., Swan, G.E., Berry, W.L., Pearson, J. Efficacy of a topical antimicrobial-antiinflammatory combination in the treatment of pyotraumatic dermatitis in dogs (Wirksamkeit einer lokalen antimikrobiellen-entzündungshemmenden Kombination bei der Behandlung der pyotraumatischen Dermatitis des Hundes). Veterinary Dermatology 1996; 7: 163-170.].}, }
@article {pmid34645044, year = {1996}, author = {Fondati, A}, title = {Efficacy of daily oral ivermectin in the treatment of 10 cases of generalized demodicosis in adult dogs.}, journal = {Veterinary dermatology}, volume = {7}, number = {2}, pages = {99-104}, doi = {10.1111/j.1365-3164.1996.tb00233.x}, pmid = {34645044}, issn = {1365-3164}, abstract = {Abstract The purpose of this study was to evaluate the efficacy of oral ivermectin at the dosage of 0.35 mg kg[-1] day[-1] for the treatment of generalized demodicosis in 10 adult dogs. Five of these 10 dogs had failed to respond to previous topical amitraz therapy. The mean time to obtain negative skin scrapings was 2.7 months and the mean duration of treatment was 4 months (range 2.5-8.5 months). Three patients (30%) were cured and they remained free of mites within 1 year follow-up. Two dogs (20%) were in remission for less than 6 months and five dogs (50%) relapsed. These five cases that relapsed were retreated with the above dosage of ivermectin and topical amitraz solution (1 mL Taktic/30 mL mineral oil) applied to site(s) of recurrence. One of these five cases that relapsed was in remission for more than 6 months, two dogs were in remission for less than 6 months and two dogs are still receiving treatment. Résumé- Le propos de cette étude est d'évaluer l'efficacieté de l'ivermectine par voie orale à un dosage de 0,35 mg/kg/jour dans le traitement de la démodécie généralisée chez 10 chiens adultes. Cinq de ces chiens n'avaient pas répondu à une thérapeutique topique préalable à l'amitraz. Le délai moyen pour obtenir la négativation des raclages cutanés est de 2,7 mois, et la durée moyenne de traitement est de 4 mois (extrême 2,5-8,5 mois). Trois patients (30%) ont été guéris et n'ont pas rechuté dans l'année qui a suivi le traitement. Deux des chiens (20%) ont été en rémission pendant moins de 6 mois et 5 chiens (50%) ont rechuté. Ces 5 chiens qui ont rechuté ont été retraités avec l'ivermectine à la même posologie associée à une thérapeutique topique à l'amitraz (1 ml de Taktic dans 30 ml d'huile minérale), appliquée aux sites de rechute. Un de ces 5 chiens fut en rémission pendant plus de 6 mois, 2 chiens pendant moins de 6 mois, enfin, les deux derniers reçoivent encore le traitement. [Fondati, A. Efficacy of daily oral ivermectin in the treatment of 10 cases of generalized demodicosis in adult dogs (Efficacité de l'ivermectine administrée oralement tous les jours dans le traitement de 10 cas de démodécie généralisée du chien adulte). Veterinary Dermatology 1996; 7: 99-104.] Resumen El objetivo de este estudio fue evaluar la eficacia de la ivermectina oral con una dosis de 0.35 mg/Kg-dia para el tratamiento de la demodicosis generalizada en 10 perros adultos. Cinco de los 10 perros no habian respondido previamente a la terapia tópica con amitraz. El tiempo medio de obtención de raspados cutáneos negativos fue de 2.7 meses y la duratión media del tratamiento, de 4 meses (de 2.5 a 8.5 meses). Tres pacientes (30%) se curaron y permanecieron sin ácaros en un año de seguimiento. Dos perros (20%) estuvieron en remisión durante menos de 6 meses y en cinco (50%) se produjeron recaidas. Los animales que recayeron fueron tratados con la dosis de Ivermectina especificada arriba y solutión tópica de amitraz (1 mL Taktic/30 mL aceite mineral) aplicado a la(s) zona(s) de recidiva. Uno de los casos que recayó había estado en remisión durante 6 meses, dos perros estuvieron en remisión durante menos de 6 meses y dos estan aún bajo tratamiento. [Fondati, A. Efficacy of daily oral ivermectin in the treatment of 10 cases of generalized demodicosis in adult dogs (Eficacia de la Ivermectina oral en dosis diarias en el tratamiento de 10 casos de demodicosis generalizada en perros adultos). Veterinary Dermatology 1996; 7: 99-104.] Zusammenfassung- Zweck dieser Studie war, die Wirksamkeit von oralem Ivermectin mit einer Dosierung von 0,35 mg/kg und Tag bei der Behandlung von generalisierter Demodikose bei 10 erwachsenen Hunden auszuwerten. 5 dieser 10 Hunden hatten auf eine vorausgegangene topische Amitraz-Therapie nicht angesprochen. Die Durchschnittszeit, um negative Hautgeschabsel zu erhalten, lag bei 2,7 Monaten, die Durchschnittsdauer der Behandlung bei 4 Monaten (mit einer Spannweite von 2,5 bis 8,5 Monaten). 3 Patienten (30%) wurden geheilt und blieben innerhalb des überwachungszeitraumes von 1 Jahr milbenfrei. Zwei Hunde (20%) waren in Remission für weniger als 6 Monate und 5 Hunde (50%) hatten ein Rezidiv. Diese fünf Rezidivfälle wurden mit der oben genannten Dosis Ivermectin und topischer Amitraz-Lösung (1 ml Taktic/30 ml Mineralöl) an den Stellen erneuter Veränderungen behandelt. Einer dieser fünf Rezidivfälle war in Remission für mehr als 6 Monate, zwei Hunde waren in Remission für weniger als 6 Monate und zwei Hunde sind immer noch unter Therapie. [Fondati, A. Efficacy of daily oral ivermectin in the treatment of 10 cases of generalized demodicosis in adult dogs (Wirksamkeit einer täglichen oralen Ivermectingabe bei der Behandlung von 10 Fällen von generalisierter Demodikose bei erwachsenen Hunden). Veterinary Dermatology 1996; 7: 99-104.].}, }
@article {pmid34645070, year = {1994}, author = {Logas, D and Kunkle, GA}, title = {Double-blinded Crossover Study with Marine Oil Supplementation Containing High-dose icosapentaenoic Acid for the Treatment of Canine Pruritic Skin Disease.}, journal = {Veterinary dermatology}, volume = {5}, number = {3}, pages = {99-104}, doi = {10.1111/j.1365-3164.1994.tb00020.x}, pmid = {34645070}, issn = {1365-3164}, abstract = {Abstract- The objective of this double-blinded crossover study was to examine the effects of marine oil supplementation with high-dose eicosapentaenoic acid (EPA) on canine pruritic skin disease. Sixteen dogs that completed this study had clinical signs related to idiopathic pruritus, confirmed atopy and/or flea allergy. Each dog was randomly placed on one omega-3 fatty acid capsule (MVP: Meridian Veterinary Products, St. Augustine, FL, U.S.A.) which contained 1 ml of marine oil (180mg EPA and 120mg DHA) or one capsule containing 1 ml of corn oil (570 mg linoleic acid and 50 mg gamma linolenic acid) per 4.55 kg of body weight q 24 h for 6 weeks. After a 3-week washout period in which no supplement was given, each subject was crossed over to the other supplement for an additional 6 weeks. Dogs receiving marine oil showed a significant improvement in pruritus (P < 0.001), self-trauma (P <0.05) and coat character (P<0.01) over time. When compared to the corn oil control over time, marine oil supplementation significantly improved pruritus (P < 0.02), alopecia (P < 0.05) and coat character (P < 0.001). This study demonstrates the effectiveness of high doses of marine oil as an alternative anti-inflammatory for canine pruritic skin disease. Zusammenfassung- Ziel dieser Doppelblindkreuzstudie war die Untersuchung von Wirkungen der Substitution mit marinem Öl mit hohem Gehalt an Eicosapentensäure (EPA) auf juckende Hautkrankheiten beim hund. Sechzehn Hunde, die die Studie vollständig durchliefen, litten unter klinischen Symptomen, die mit idiopathischem Pruritus, nachgewiesener Atopie und/oder Flohallergie verbunden waren. Jeder Hund erhielt nach dem Zufallsprinzip eine omega-3-Fettsäurekapsel (MVP: Meridian Veterinary Product; St. Augustine, FL, U.S.A.), die 1 ml von marinem Öl enthielt (180 mg EPA und 120 mg DHA) oder eine Kapsel, die 1 ml Pflanzenöl enthielt (570 mg Linolensäure und 50 mg gamma-Linolensäure) bei einer Dosierung von 1 Kapsel pro 4,55 kg Körpergewicht alle 24 Stunden über 6 Wochen. Nach einer dreiwöchigen Ausschwemmphase, in der keine Substitution verabreicht wurde, wurde jedes Tier für weitere 6 Wochen auf die andere Supplementation gesetzt. Hunde, die marines Öl erhielten, zeigten eine signifikante Besserung des Juckreizes (P < 0,001), der Selbsttraumatisierung (P <0,05) und der Fellbeschaffenheit (P < 0,01) während des Unter-suchungszeitraumes. Im Verglich zur Pflanzenölkontrolle über den Zeitraum besserte die Substitution mit marinem Öl signifikant den Juckreiz (P < 0,02), die Alopezie (P < 0,05) und die Fellbeschaffenheit (P < 0,001). Diese Studie zeigt die Wirksamkeit von hohen Dosen von marinem Öl als alternativen Entzündungshemmer bei juckenden Hauterkrankungen des Hundes. [Double-blinded crossover study with marine oil supplementation containing high-dose eicosapentaenoic acid for the treatment of canine pruritic skin disease (Doppelblindkreuzstudie über die Substitution mit marinem Öl mit hohem Gehalt an Eicosapentensäure für die Behandlung von juckenden Hauterkrankungen bei Hunden.) Resumen- El objetivo de este estudio reciproco tipo doble-ciego era examinar los efectos del suplemento de aceite marino con dosis alta de ácido eucosapentanoico (EPA) en al enfermedad canina pruritica de la piel. Dieciséis perros fue completaron este estudio presentaban signos clinicos asociados con prurito idiopático, atopia confirmada y/o alergia a pulgas. Cada perro fue puesto al azar en una cápsula de ácido graso omega-3 (MVP: Meridian Veterinary Product; St. Augustine, FL, U.S.A.) fue contenia 1 ml de aceite marino (180mg EPA y 120 mg DMA) o una cápsula que contenia 1 ml de aceite de maiz (570 mg ácido linoleico y 50 mg ácido gamma linolénico) por 4,55 kg de peso corporal, 24 horas durante 6 semanas. Después de un periodo de 3 semanas durante el cual no se dió ningún suplemento, cada sujeto fue cambiado al otro suplemento por un periodo adicional de 6 semanas. Los perros que recibieron aceite marino mostraron una mejora significante en el prurito (P < 0,001), auto-trauma (P < 0,005) y carácter de la capa (P < 0,01) a lo largo del tiempo. Cuando se comparó al control del aceite de maiz a lo largo del tiempo, el suplemento de aceite marino mejoró significantemente el prurito (P < 0,02), alopecia (P < 0,005) y carácter de la capa (P < 0,001). Este estudio demuestra la efectividad de dosis altas de aceite marino como una alternativa antiinflamatoria para la enfermedad canina pruritca de la piel. [Double-blinded crossover study with marine oil supplementation containing high-dose eicosapentaenoic acid for the treatment of canine pruritic skin disease. (Estudio reciproco tipo doble-ciego con suplemento de aceite marino que contiene una dosis alta de ácido eucosapentanoico para el tratamiento de la enfermedad canina pruritica de la piel.).}, }
@article {pmid34644838, year = {1990}, author = {Paradis, M and Lemay, S and Scott, DW and Miller, WH and Wellington, J and Panich, R}, title = {Efficacy of Enrofloxacin in the Treatment of Canine Bacterial Pyoderma.}, journal = {Veterinary dermatology}, volume = {1}, number = {3}, pages = {123-127}, doi = {10.1111/j.1365-3164.1990.tb00090.x}, pmid = {34644838}, issn = {1365-3164}, abstract = {Abstract- Bacterial pyoderma was diagnosed in 30 dogs which were subsequently treated with enrofloxacin administered orally at 2.5 mg.kg[-1] of body weight every 12 h, for 2 to 14 weeks. Dogs were re-examined at the conclusion of antibiotic treatment and 28 (93.3 per cent) were found to have an excellent response. Relapses were seen in 25 per cent of these dogs after follow up periods of 1 to 4 months. Minor side effects were seen in only 1 dog. On the basis of this study, enrofloxacin is an excellent antibiotic for the treatment of canine bacterial pyoderma but must be administered well beyond the manufacturer's maximum recommendation for duration of therapy. Résumé- Une pyodermite bactérienne a été diagnostiquée chez 30 chiens qui furent traités avec de l'enrofloxacine administrée par voie orale à la dose de 2.5 mg/Kg toutes les 12 heures, pour une durée allant de 2.5 à 14 semaines. Les chiens furent réexaminés à la fin de l'antibiothérapie et 28 d'entre eux (93.3%) présentaient une excellente réponse au traitement. Des rechutes furent observées chez 25% des chiens lors de suivis portant sur des périodes de 1 à 4 mois. Des effets secondaires mineurs furent observés chez l'un des chiens. Cette étude montre que l'enrofloxacine est un excellent antibiotique pour le traitement des pyodermites canines mais, qu'il doit être administré pendant des délais beaucoup plus longs que ceux qui sont indiqués par le fabricant. Zusammenfassung- 30 Hunde mit bakteríellen Pyodermien wurden zweieinhalb bis vierzehn Wochen lang oral mit Enrofloxacin behandelt (2 täglich 2.5 mg/kg KGW). Nach Abschluß der Behandlung wurden die Tiere erneut untersucht. Bei 28 Patienten (93.3%) wurden hervorragende Ergebnisse erzielt. Bei 25% kam as nach 1 bis 4 Monaten zu Rezidiven. Geringe Nebenwirkungen wurden nur in einem Fall beobachtet. Die vorliegende Untersuchung zeigt, daß Enrofloxacin ein hervorragendes Antibiotikum für die Behandlung von Pyodermien ist, aber wesentlich länger als vom Hersteller angegeben verabreicht werden muß. Resumen Treinta perros, a los cuales se había diagnosticado una epiderma bacteriana, fueron tratado con Enrofloxacina via oral a una dosis de 2,5 mg/kg de peso corporal cada 12 horas durante un período de tiempo que oscíló entre las 2,5 semanas y las 14 semanas. Los perros se examinaron clínicamente de nuevo cuando acabó el tratamiento antibiótico y se observó en 28 (93,3%) una respuesta excelente. En un 25% de estos perros se observaron recidivas en un período comprendido entre uno y cuatro meses. Efectos colaterales de poca importancia se observaron úicamente en un animal. Según estos resultados puede concluirse que la Enrofloxacina es un antibiótico excelente para el tratamiento de las piodermas bacterianas del perro, aunque debe administrarse durante un período de tiempo superior al que recomiendan los productores.}, }
@article {pmid34382759, year = {2021}, author = {Barrington, CJ and Burruano, M and Carney, C and Choi, J and Januska, J and Lachuk, L and Oskarsson, B and Rodriguez, C and Speicher, L and Tereso, G}, title = {Addressing the role of edaravone in the management of amyotrophic lateral sclerosis and gaps in care and access: expert panel recommendations.}, journal = {The American journal of managed care}, volume = {27}, number = {12 Suppl}, pages = {S231-S237}, doi = {10.37765/ajmc.2021.88732}, pmid = {34382759}, issn = {1936-2692}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone ; Free Radical Scavengers ; Humans ; Managed Care Programs ; Specialization ; United States ; }, abstract = {A virtual key opinion leader (KOL) and payer discussion was held on December 5, 2020. In attendance were 2 KOLs, both specialists in amyotrophic lateral sclerosis (ALS) at leading clinics in the United States, and 6 managed care executives from US regional health plans. The objective of this panel was to share opinions, ideas, and information around the treatment of ALS with edaravone, gaps in management and guidelines, and potential solutions. The panel concluded that coverage criteria for edaravone may need to be reassessed and treatment guidelines could be revisited to include a determination of place in therapy for edaravone.}, }
@article {pmid34381654, year = {2021}, author = {Murray, NM and Reimer, RJ and Cao, M}, title = {Acute on Chronic Neuromuscular Respiratory Failure in the Intensive Care Unit: Optimization of Triage, Ventilation Modes, and Extubation.}, journal = {Cureus}, volume = {13}, number = {7}, pages = {e16297}, pmid = {34381654}, issn = {2168-8184}, abstract = {Critical care management of acute respiratory failure in patients with neuromuscular disease (NMD) such as amyotrophic lateral sclerosis (ALS) is not standardized and is challenging for many critical care specialists. Progressive hypercapnic respiratory failure and ineffective airway clearance are key issues in this patient population. Often at the time of hospital presentation, patients are already supported by home mechanical ventilatory support with noninvasive ventilation (NIV) and an airway clearance regimen. Prognosis is poor once a patient develops acute respiratory failure requiring intubation and invasive mechanical ventilatory support, commonly leading to tracheostomy or palliative-focused care. We focus on this understudied group of patients with ALS without tracheostomy and incorporate existing data to propose a technical approach to the triage and management of acute respiratory failure, primarily for those who require intubation and mechanical ventilatory support for reversible causes, and also for progression of end-stage disease. Optimizing management in this setting improves both quality and quantity of life. Neuromuscular patients with acute respiratory failure require protocolized and personalized triage and treatment. Here, we describe the technical methods used at our single institution. The triage phase incorporates comprehensive evaluation for new etiologies of hypoxia and hypercapnia, which are not initially presumed to be secondary to progression or end-stage neuromuscular respiratory failure. In select patients, this may involve intubation or advanced adjustments of NIV machines. Next, once the acute etiology(s) is identified and treated, the focus shifts: training and use of mechanical airway clearance to optimize pulmonary function, facilitation of NIV wean or successful extubation to NIV, and transition to a stable regimen for home ventilation. The comprehensive protocol described here incorporates multi-institutional approaches and effectively optimizes acute respiratory failure in patients with neuromuscular pulmonary disease.}, }
@article {pmid34376973, year = {2021}, author = {Conti, N and Gatti, M and Raschi, E and Diemberger, I and Potena, L}, title = {Evidence and Current Use of Levosimendan in the Treatment of Heart Failure: Filling the Gap.}, journal = {Drug design, development and therapy}, volume = {15}, number = {}, pages = {3391-3409}, pmid = {34376973}, issn = {1177-8881}, mesh = {Adenosine Triphosphate/metabolism ; Cardiotonic Agents/adverse effects/*pharmacology ; Heart Failure/*drug therapy/physiopathology ; Humans ; Phosphodiesterase 3 Inhibitors/adverse effects/pharmacology ; Simendan/*pharmacology ; Vasodilator Agents/adverse effects/pharmacology ; }, abstract = {Levosimendan is a distinctive inodilator combing calcium sensitization, phosphodiesterase inhibition and vasodilating properties through the opening of adenosine triphosphate-dependent potassium channels. It was first approved in Sweden in 2000 for the short-term treatment of acutely decompensated severe chronic heart failure when conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate. After more than 20 years, clinical applications have considerably expanded across critical care and emergency medicine, and levosimendan is now under investigation in different cardiac settings (eg, septic shock, pulmonary hypertension) and for non-cardiac applications (eg, amyotrophic lateral sclerosis). This narrative review outlines key milestones in levosimendan history, by addressing regulatory issues, pharmacological peculiarities and clinical aspects (efficacy and safety) of a drug that did not receive great attention in the heart failure guidelines. A brief outlook to the ongoing clinical trials is also offered.}, }
@article {pmid34376243, year = {2021}, author = {Pasetto, L and Callegaro, S and Corbelli, A and Fiordaliso, F and Ferrara, D and Brunelli, L and Sestito, G and Pastorelli, R and Bianchi, E and Cretich, M and Chiari, M and Potrich, C and Moglia, C and Corbo, M and Sorarù, G and Lunetta, C and Calvo, A and Chiò, A and Mora, G and Pennuto, M and Quattrone, A and Rinaldi, F and D'Agostino, VG and Basso, M and Bonetto, V}, title = {Decoding distinctive features of plasma extracellular vesicles in amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {16}, number = {1}, pages = {52}, pmid = {34376243}, issn = {1750-1326}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*blood/*diagnosis ; Animals ; Biomarkers/*blood ; Extracellular Vesicles/*metabolism/*ultrastructure ; Female ; Humans ; Machine Learning ; Male ; Mice ; Microscopy, Electron, Transmission ; Middle Aged ; Proteomics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multifactorial, multisystem motor neuron disease for which currently there is no effective treatment. There is an urgent need to identify biomarkers to tackle the disease's complexity and help in early diagnosis, prognosis, and therapy. Extracellular vesicles (EVs) are nanostructures released by any cell type into body fluids. Their biophysical and biochemical characteristics vary with the parent cell's physiological and pathological state and make them an attractive source of multidimensional data for patient classification and stratification.<br><br>METHODS: We analyzed plasma-derived EVs of ALS patients (n&#x2009;=&#x2009;106) and controls (n&#x2009;=&#x2009;96), and SOD1[G93A] and TDP-43[Q331K] mouse models of ALS. We purified plasma EVs by nickel-based isolation, characterized their EV size distribution and morphology respectively by nanotracking analysis and transmission electron microscopy, and analyzed EV markers and protein cargos by Western blot and proteomics. We used machine learning techniques to predict diagnosis and prognosis.<br><br>RESULTS: Our procedure resulted in high-yield isolation of intact and polydisperse plasma EVs, with minimal lipoprotein contamination. EVs in the plasma of ALS patients and the two mouse models of ALS had a distinctive size distribution and lower HSP90 levels compared to the controls. In terms of disease progression, the levels of cyclophilin A with the EV size distribution distinguished fast and slow disease progressors, a possibly new means for patient stratification. Immuno-electron microscopy also suggested that phosphorylated TDP-43 is not an intravesicular cargo of plasma-derived EVs.<br><br>CONCLUSIONS: Our analysis unmasked features in plasma EVs of ALS patients with potential straightforward clinical application. We conceived an innovative mathematical model based on machine learning which, by integrating EV size distribution data with protein cargoes, gave very high prediction rates for disease diagnosis and prognosis.}, }
@article {pmid34372914, year = {2021}, author = {Xu, X and Shen, D and Gao, Y and Zhou, Q and Ni, Y and Meng, H and Shi, H and Le, W and Chen, S and Chen, S}, title = {A perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed?.}, journal = {Translational neurodegeneration}, volume = {10}, number = {1}, pages = {29}, pmid = {34372914}, issn = {2047-9158}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Clinical Trials as Topic/*methods ; *Disease Management ; *Disease Progression ; Edaravone/therapeutic use ; Free Radical Scavengers/therapeutic use ; Humans ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Stem Cell Transplantation/methods/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper and lower motor neurons, leading to paralysis and eventually death. Symptomatic treatments such as inhibition of salivation, alleviation of muscle cramps, and relief of spasticity and pain still play an important role in enhancing the quality of life. To date, riluzole and edaravone are the only two drugs approved by the Food and Drug Administration for the treatment of ALS in a few countries. While there is adequate consensus on the modest efficacy of riluzole, there are still open questions concerning the efficacy of edaravone in slowing the disease progression. Therefore, identification of novel therapeutic strategies is urgently needed. Impaired autophagic process plays a critical role in ALS pathogenesis. In this review, we focus on therapies modulating autophagy in the context of ALS. Furthermore, stem cell therapies, gene therapies, and newly-developed biomaterials have great potentials in alleviating neurodegeneration, which might halt the disease progression. In this review, we will summarize the current and prospective therapies for ALS.}, }
@article {pmid34363869, year = {2021}, author = {Orienti, I and Armida, M and Dobrowolny, G and Pepponi, R and Sollazzini, G and Pezzola, A and Casola, I and Musarò, A and Popoli, P and Potenza, RL}, title = {Fenretinide Beneficial Effects on Amyotrophic Lateral Sclerosis-associated SOD1[G93A] Mutant Protein Toxicity: In Vitro and In Vivo Evidences.}, journal = {Neuroscience}, volume = {473}, number = {}, pages = {1-12}, doi = {10.1016/j.neuroscience.2021.07.033}, pmid = {34363869}, issn = {1873-7544}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Animals ; Disease Models, Animal ; Female ; *Fenretinide/pharmacology ; Mice ; Mice, Transgenic ; Mutant Proteins ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease for which effective treatment options are still lacking. ALS occurs in sporadic and familial forms which are clinically indistinguishable; about 20% of familial ALS cases are linked to mutations of the superoxide dismutase 1 (SOD1) gene. Fenretinide (FEN), a cancer chemopreventive and antiproliferative agent currently used in several clinical trials, is a multi-target drug which also exhibits redox regulation activities. We analyzed the effects of FEN on mutant SOD1 (mSOD1) toxicity in motoneuronal (NSC34) and a muscle (C2C12) cell lines and evaluated the impacts of chronic administration of a new nanomicellar fenretinide formulation (NanoMFen) on ALS disease progression in the SOD1[G93A] mouse model. The results showed that FEN significantly prevents the toxicity of mSOD1 expression in NSC34 motor neuron; furthermore, FEN is able to partially overcome the toxic effect of mSOD1 on the myogenic program of C2C12 muscle cells. Administration of NanoMFen ameliorates the disease progression and increases median survival of mSOD1[G93A] ALS mice, even when given after disease onset; beneficial effects in ALS mice, however, is restricted to female sex. Our data support the therapeutic potential of FEN against ALS-associated SOD1[G93A] mutant protein toxicity and promote further studies to elucidate specific cellular targets of the drug in ALS. Furthermore, the sex-related efficacy of NanoMFen in mSOD1[G93A] ALS mice strengthens the importance, in the perspective of a precision medicine approach, of gender pharmacology in ALS research.}, }
@article {pmid34360808, year = {2021}, author = {Jin, M and Akgün, K and Ziemssen, T and Kipp, M and Günther, R and Hermann, A}, title = {Interleukin-17 and Th17 Lymphocytes Directly Impair Motoneuron Survival of Wildtype and FUS-ALS Mutant Human iPSCs.}, journal = {International journal of molecular sciences}, volume = {22}, number = {15}, pages = {}, pmid = {34360808}, issn = {1422-0067}, support = {not applicable//Hermann und Lilly Schilling-Stiftung f&#xfc;r Medizinische Forschung/ ; n.a.//NOMIS Stiftung/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*immunology/pathology ; Cell Survival/immunology ; Humans ; Induced Pluripotent Stem Cells/*immunology/pathology ; Interleukin-17/*immunology ; Motor Neurons/*immunology/pathology ; RNA-Binding Protein FUS/*immunology ; Th17 Cells/*immunology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.}, }
@article {pmid34360586, year = {2021}, author = {Tarnacka, B and Jopowicz, A and Maślińska, M}, title = {Copper, Iron, and Manganese Toxicity in Neuropsychiatric Conditions.}, journal = {International journal of molecular sciences}, volume = {22}, number = {15}, pages = {}, pmid = {34360586}, issn = {1422-0067}, mesh = {Ceruloplasmin/*deficiency ; Copper/*adverse effects ; Humans ; Iron/*adverse effects ; Iron Metabolism Disorders/chemically induced/etiology/*pathology ; Manganese/*adverse effects ; Manganese Poisoning/complications ; Metabolic Diseases/chemically induced/*pathology ; Metalloproteins/metabolism ; Neuroaxonal Dystrophies/chemically induced/*pathology ; Neurodegenerative Diseases/etiology/*pathology ; Oxidative Stress ; }, abstract = {Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and "prion-like disease", amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, and depression.}, }
@article {pmid34359358, year = {2021}, author = {Youn, BY and Ko, Y and Moon, S and Lee, J and Ko, SG and Kim, JY}, title = {Digital Biomarkers for Neuromuscular Disorders: A Systematic Scoping Review.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {11}, number = {7}, pages = {}, pmid = {34359358}, issn = {2075-4418}, abstract = {Biomarkers play a vital role in clinical care. They enable early diagnosis and treatment by identifying a patient's condition and disease course and act as an outcome measure that accurately evaluates the efficacy of a new treatment or drug. Due to the rapid development of digital technologies, digital biomarkers are expected to grow tremendously. In the era of change, this scoping review was conducted to see which digital biomarkers are progressing in neuromuscular disorders, a diverse and broad-range disease group among the neurological diseases, to discover available evidence for their feasibility and reliability. Thus, a total of 10 studies were examined: 9 observational studies and 1 animal study. Of the observational studies, studies were conducted with amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), and spinal muscular atrophy (SMA) patients. Non-peer reviewed poster presentations were not considered, as the articles may lead to erroneous results. The only animal study included in the present review investigated the mice model of ALS for detecting rest disturbances using a non-invasive digital biomarker.}, }
@article {pmid34358737, year = {2021}, author = {Martín-Rivada, &#xc1; and Barrios, V and Martínez Díaz-Guerra, G and Pozo, J and Martos-Moreno, G&#xc1; and Argente, J}, title = {Adult height and long-term outcomes after rhIGF-1 therapy in two patients with PAPP-A2 deficiency.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {60-61}, number = {}, pages = {101419}, doi = {10.1016/j.ghir.2021.101419}, pmid = {34358737}, issn = {1532-2238}, mesh = {*Body Height ; Child ; Female ; Follow-Up Studies ; Growth Disorders/*drug therapy/genetics/metabolism/pathology ; Human Growth Hormone/*administration &amp; dosage ; Humans ; Insulin-Like Growth Factor Binding Protein 3/*metabolism ; Insulin-Like Growth Factor I/*metabolism ; Male ; Pregnancy-Associated Plasma Protein-A/*deficiency/genetics ; Prognosis ; Recombinant Proteins/*administration &amp; dosage ; }, abstract = {PAPP-A2 deficiency is a novel syndrome characterized by short stature due to low IGF bioactivity, skeletal abnormalities and decreased bone mineral density (BMD). Treatment with recombinant human IGF-1 (rhIGF-1) for 1 year demonstrated to increase growth velocity and BMD, without reported adverse effects, but data regarding the long-term efficacy and safety of rhIGF-1 administration in this entity has not yet been reported. Two Spanish siblings with short stature due to a homozygous loss-of-function mutation in the PAPP-A2 gene (p.D643fs25*) were treated with rhIGF-1 twice daily for six years. Growth velocity continued to increase and both patients achieved their target height. Free IGF-1 concentrations increased notably after rhIGF-1 administration, with serum IGFBP-3, IGFBP-5 and ALS levels also being higher during treatment. BMD was progressively normalized and an increase in lean mass was also noted during treatment. No episodes of hypoglycemia or any other adverse effects were documented. An increase in the growth of kidney and spleen length was observed in one of the patients.}, }
@article {pmid34357138, year = {2021}, author = {Pikatza-Menoio, O and Elicegui, A and Bengoetxea, X and Naldaiz-Gastesi, N and López de Munain, A and Gerenu, G and Gil-Bea, FJ and Alonso-Martín, S}, title = {The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis.}, journal = {Journal of personalized medicine}, volume = {11}, number = {7}, pages = {}, pmid = {34357138}, issn = {2075-4426}, support = {PI19/00175//Instituto de Salud Carlos III/ ; 2020-CIEN-000057-01//Diputaci&#xf3;n Foral de Gipuzkoa/ ; 2020111032//Osasun Saila, Eusko Jaurlaritzako/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.}, }
@article {pmid34339943, year = {2021}, author = {Manochkumar, J and Doss, CGP and El-Seedi, HR and Efferth, T and Ramamoorthy, S}, title = {The neuroprotective potential of carotenoids in vitro and in vivo.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {91}, number = {}, pages = {153676}, doi = {10.1016/j.phymed.2021.153676}, pmid = {34339943}, issn = {1618-095X}, mesh = {Antioxidants ; *Carotenoids/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy ; Neuroprotection ; *Neuroprotective Agents/pharmacology ; Oxidative Stress ; }, abstract = {BACKGROUND: Despite advances in research on neurodegenerative diseases, the pathogenesis and treatment response of neurodegenerative diseases remain unclear. Recent studies revealed a significant role of carotenoids to treat neurodegenerative diseases. The aim of this study was to systematically review the neuroprotective potential of carotenoids in vivo and in vitro and the molecular mechanisms and pathological factors contributing to major neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and stroke).<br><br>HYPOTHESIS: Carotenoids as therapeutic molecules to target neurodegenerative diseases.<br><br>RESULTS: Aggregation of toxic proteins, mitochondrial dysfunction, oxidative stress, the excitotoxic pathway, and neuroinflammation were the major pathological factors contributing to the progression of neurodegenerative diseases. Furthermore, in vitro and in vivo studies supported the beneficiary role of carotenoids, namely lycopene, &#x3b2;-carotene, crocin, crocetin, lutein, fucoxanthin and astaxanthin in alleviating disease progression. These carotenoids provide neuroprotection by inhibition of neuro-inflammation, microglial activation, excitotoxic pathway, modulation of autophagy, attenuation of oxidative damage and activation of defensive antioxidant enzymes. Additionally, studies conducted on humans also demonstrated that dietary intake of carotenoids lowers the risk of neurodegenerative diseases.<br><br>CONCLUSION: Carotenoids may be used as drugs to prevent and treat neurodegenerative diseases. Although, the in vitro and in vivo results are encouraging, further well conducted clinical studies on humans are required to conclude about the full potential of neurodegenerative diseases.}, }
@article {pmid34335276, year = {2021}, author = {Wang, X and Zhang, JB and He, KJ and Wang, F and Liu, CF}, title = {Advances of Zebrafish in Neurodegenerative Disease: From Models to Drug Discovery.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {713963}, pmid = {34335276}, issn = {1663-9812}, abstract = {Neurodegenerative disease (NDD), including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by the progressive loss of neurons which leads to the decline of motor and/or cognitive function. Currently, the prevalence of NDD is rapidly increasing in the aging population. However, valid drugs or treatment for NDD are still lacking. The clinical heterogeneity and complex pathogenesis of NDD pose a great challenge for the development of disease-modifying therapies. Numerous animal models have been generated to mimic the pathological conditions of these diseases for drug discovery. Among them, zebrafish (Danio rerio) models are progressively emerging and becoming a powerful tool for in vivo study of NDD. Extensive use of zebrafish in pharmacology research or drug screening is due to the high conserved evolution and 87% homology to humans. In this review, we summarize the zebrafish models used in NDD studies, and highlight the recent findings on pharmacological targets for NDD treatment. As high-throughput platforms in zebrafish research have rapidly developed in recent years, we also discuss the application prospects of these new technologies in future NDD research.}, }
@article {pmid34322776, year = {2021}, author = {Fadel, IM and Ragab, MH and Eid, OM and Helmy, NA and El-Bassyouni, HT and Mazen, I}, title = {IGF1R, IGFALS, and IGFBP3 gene copy number variations in a group of non-syndromic Egyptian short children.}, journal = {Journal, genetic engineering &amp; biotechnology}, volume = {19}, number = {1}, pages = {109}, pmid = {34322776}, issn = {2090-5920}, abstract = {BACKGROUND: Insulin-like growth factor-1 (IGF-1) is required for normal intrauterine and postnatal growth, and this action is mediated through IGF1 receptor (IGF1R). IGF1R copy number variants (CNVs) can cause pre- and postnatal growth restriction, affecting an individual's height. In this study, we used multiplex ligation-dependent probe amplification (MLPA) to detect CNVs in IGF1R, IGFALS, and IGFBP3 genes in the diagnostic workup of short stature for 40 Egyptian children with short stature.<br><br>RESULTS: We detected a heterozygous deletion of IGF1R (exons 4 through 21) in 1 out of the 40 studied children (2.5%). Meanwhile, we did not detect any CNVs in either IGFALS or IGFBP3.<br><br>CONCLUSION: The diagnostic workup of short stature using MLPA for CNVs of IGF1R and other recognized height-related genes, such as SHOX and GH, in non-syndromic short stature children can be a fast and inexpensive diagnostic tool to recognize a subcategory of patients in which growth hormone treatment can be considered.}, }
@article {pmid34321067, year = {2021}, author = {Freigang, M and Steinacker, P and Wurster, CD and Schreiber-Katz, O and Osmanovic, A and Petri, S and Koch, JC and Rostásy, K and Falkenburger, B and Ludolph, AC and Otto, M and Hermann, A and Günther, R}, title = {Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy.}, journal = {Orphanet journal of rare diseases}, volume = {16}, number = {1}, pages = {330}, pmid = {34321067}, issn = {1750-1172}, mesh = {Adult ; Child ; Hexosaminidases ; Humans ; *Muscular Atrophy, Spinal/drug therapy ; *Oligonucleotides ; Prospective Studies ; }, abstract = {BACKGROUND: Studies regarding the impact of (neuro)inflammation and inflammatory response following repetitive, intrathecally administered antisense oligonucleotides (ASO) in 5q-associated spinal muscular atrophy (SMA) are sparse. Increased risk of hydrocephalus in untreated SMA patients and a marginal but significant increase of the serum/CSF albumin ratio (Qalb) with rare cases of communicating hydrocephalus during nusinersen treatment were reported, which confirms the unmet need of an inflammatory biomarker in SMA. The aim of this study was to investigate the (neuro)inflammatory marker chitotriosidase 1 (CHIT1) in SMA patients before and following the treatment with the ASO nusinersen.<br><br>METHODS: In this prospective, multicenter observational study, we studied CSF CHIT1 concentrations in 58 adult and 21 pediatric patients with SMA type 1, 2 or 3 before treatment initiation in comparison to age- and sex-matched controls and investigated its dynamics during nusinersen treatment. Concurrently, motor performance and disease severity were assessed.<br><br>RESULTS: CHIT1 concentrations were elevated in treatment-na&#xef;ve SMA patients as compared to controls, but less pronounced than described for other neurodegenerative diseases such as amyotrophic lateral sclerosis. CHIT1 concentration did not correlate with disease severity and did not distinguish between clinical subtypes. CHIT1 concentration did show a significant increase during nusinersen treatment that was unrelated to the clinical response to nusinersen therapy.<br><br>CONCLUSIONS: CHIT1 elevation in treatment-na&#xef;ve SMA patients indicates the involvement of (neuro)inflammation in SMA. The lacking correlation of CHIT1 concentration with disease severity argues against its use as a marker of disease progression. The observed CHIT1 increase during nusinersen treatment may indicate an immune response-like, off-target reaction. Since antisense oligonucleotides are an establishing approach in the treatment of neurodegenerative diseases, this observation needs to be further evaluated.}, }
@article {pmid34311486, year = {2022}, author = {Elliesen, R and Glaesmer, H and Koranyi, S and Mehnert-Theuerkauf, A}, title = {[Death Wishes in Patients with Advanced Cancer: An Explorative Analysis of Psychotherapeutic Treatment Transcripts].}, journal = {Psychotherapie, Psychosomatik, medizinische Psychologie}, volume = {72}, number = {1}, pages = {18-25}, doi = {10.1055/a-1499-8082}, pmid = {34311486}, issn = {1439-1058}, mesh = {Humans ; *Neoplasms/therapy ; Pain ; }, abstract = {Todeswünsche bei Patienten mit einer fortgeschrittenen Krebserkrankung sind bereits seit längerem Gegenstand der psychoonkologischen Forschung. Auch wenn es inzwischen einige Ansätze gibt, die sich mit der Konzeptualisierung und Beschreibung von Todeswünschen befassen, fehlt es bislang an einem in der klinischen Praxis gut anwendbaren Konzept und dazugehörigen Erhebungsinstrumenten. Ziel der Studie ist deshalb die phänomenologische Beschreibung von Todeswünschen bei Patienten mit fortgeschrittenem Krebs. Dafür wurden N=228 transkribierte Psychotherapiegespräche von 76 Patienten im Rahmen der randomisiert-kontrollierten Psychotherapiestudie Managing Cancer and Living Meaningfully (CALM) hinsichtlich des Themas Todeswunsch explorativ analysiert. Von den untersuchten 76 Patienten berichteten 16 (21%) explizit von Todeswünschen. Mithilfe ihrer Beschreibungen konnten zwei Dimensionen identifiziert werden: (1) Gründe für Todeswünsche mit sieben Unterkategorien (Vermeidung von Schmerz und Leid, Kontrolle und Selbstbestimmung erhalten, körperlicher Abbau und Begrenzungen im Alltag, Angst vor Siechtum, Leben nicht mehr lebenswert, Gefühl der Lebensvollendung und alles getan zu haben, fehlende Zukunftsperspektiven) sowie (2) der Grad des mit dem Todeswunsch verbundenen Handlungsdrucks. Die Ergebnisse stimmen mit existierenden Theorien zu Todeswünschen bei Patienten mit einer fortgeschrittenen Krebserkrankung größtenteils überein. Als zusammengehörige Dimensionen des Phänomens Todeswunsch wurden sie jedoch bisher noch nicht beschrieben. Vor allem für die klinische Praxis scheint dies sehr sinnvoll zu sein, da die Gründe in der Therapie größtenteils bearbeitbar sein dürften und der Grad des Handlungsdrucks Aufschluss über die Notwendigkeit einer Intervention geben kann.Death wishes in patients with advanced cancer is a research topic of high interest in psycho-oncologic research. Despite existing concepts describing death wishes, there is a lack of clinically applicable concepts and appropriate instruments. The objective of this study was the phenomenological description of death wishes in patients with advanced cancer. For this purpose, we qualitatively explored N=228 transcribed psychotherapeutic treatment sessions of 76 patients derived from an RCT evaluating the efficacy of Managing Cancer and Living Meaningfully (CALM) psychotherapeutic intervention. Sixteen out of the 76 patients explicitly reported death wishes (21%). Two dimensions were identified: (1) reasons for a death wish with seven subcategories (avoidance of pain and suffering, maintaining control and self-determination, physical deterioration and limitations in everyday life, fear of infirmity, life not longer worth living, feeling of life completion and having done everything, lack of future perspectives) and (2) the degree of pressure to act associated with the death wish. These results are consistent with existing theories regarding death wishes in patients with advanced cancer. However, they have not yet been described as interrelated dimensions of the phenomenon of the death wish.}, }
@article {pmid34310733, year = {2022}, author = {Makizodila, BAM and van de Wijdeven, JHE and de Soet, JJ and van Selms, MKA and Volgenant, CMC}, title = {Oral hygiene in patients with motor neuron disease requires attention: A cross-sectional survey study.}, journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry}, volume = {42}, number = {1}, pages = {9-14}, pmid = {34310733}, issn = {1754-4505}, mesh = {*Amyotrophic Lateral Sclerosis ; Cross-Sectional Studies ; Humans ; *Motor Neuron Disease ; Oral Hygiene ; Quality of Life ; }, abstract = {AIMS: Motor Neuron Disease (MND) is a progressive neurodegenerative neuromuscular disease, which can progressively impair arm-hand function. Needs and barriers of MND patients and their caregivers in performing oral hygiene were studied.<br><br>METHODS: An online survey was sent to 706 MND patients. The questions of the survey included self-reliance, self-reported oral health, and oral hygiene. The oral health-related quality of life (GOHAI-NL) and the subjective well-being (ALSAQ-5) were also measured.<br><br>RESULTS: A total of 259 patients responded (36.7%), of which 71.9% stated not to be informed about the importance of maintaining good oral health by their MND treatment team. Moreover, 40.4% would like to receive help concerning oral hygiene from a dental professional. 19.8% were not satisfied about oral care as conducted by themselves or their caregivers. Patients who do not ask for support with their daily oral care had a significantly worse oral health-related quality of life compared to patients who do ask for support.<br><br>CONCLUSIONS: The support for daily oral hygiene of MND patients and their barriers to requesting support needs more attention from both MND-treatment teams and general dental professionals.}, }
@article {pmid34307464, year = {2021}, author = {Yang, C and Qi, Y and Sun, Z}, title = {The Role of Sonic Hedgehog Pathway in the Development of the Central Nervous System and Aging-Related Neurodegenerative Diseases.}, journal = {Frontiers in molecular biosciences}, volume = {8}, number = {}, pages = {711710}, pmid = {34307464}, issn = {2296-889X}, abstract = {The Sonic hedgehog (SHH) pathway affects neurogenesis and neural patterning during the development of the central nervous system. Dysregulation of the SHH pathway in the brain contributes to aging-related neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. At present, the SHH signaling pathway can be divided into the canonical signaling pathway and non-canonical signaling pathway, which directly or indirectly mediates other related pathways involved in the development of neurodegenerative diseases. Hence, an in-depth knowledge of the SHH signaling pathway may open an avenue of possibilities for the treatment of neurodegenerative diseases. Here, we summarize the role and mechanism of the SHH signaling pathway in the development of the central nervous system and aging-related neurodegenerative diseases. In this review, we will also highlight the potential of the SHH pathway as a therapeutic target for treating neurodegenerative diseases.}, }
@article {pmid34295920, year = {2021}, author = {Paß, T and Wiesner, RJ and Pla-Martín, D}, title = {Selective Neuron Vulnerability in Common and Rare Diseases-Mitochondria in the Focus.}, journal = {Frontiers in molecular biosciences}, volume = {8}, number = {}, pages = {676187}, pmid = {34295920}, issn = {2296-889X}, abstract = {Mitochondrial dysfunction is a central feature of neurodegeneration within the central and peripheral nervous system, highlighting a strong dependence on proper mitochondrial function of neurons with especially high energy consumptions. The fitness of mitochondria critically depends on preservation of distinct processes, including the maintenance of their own genome, mitochondrial dynamics, quality control, and Ca[2+] handling. These processes appear to be differently affected in common neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, as well as in rare neurological disorders, including Huntington's disease, Amyotrophic Lateral Sclerosis and peripheral neuropathies. Strikingly, particular neuron populations of different morphology and function perish in these diseases, suggesting that cell-type specific factors contribute to the vulnerability to distinct mitochondrial defects. Here we review the disruption of mitochondrial processes in common as well as in rare neurological disorders and its impact on selective neurodegeneration. Understanding discrepancies and commonalities regarding mitochondrial dysfunction as well as individual neuronal demands will help to design new targets and to make use of already established treatments in order to improve treatment of these diseases.}, }
@article {pmid34295897, year = {2021}, author = {Sykova, E and Cizkova, D and Kubinova, S}, title = {Mesenchymal Stem Cells in Treatment of Spinal Cord Injury and Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {695900}, pmid = {34295897}, issn = {2296-634X}, abstract = {Preclinical and clinical studies with various stem cells, their secretomes, and extracellular vesicles (EVs) indicate their use as a promising strategy for the treatment of various diseases and tissue defects, including neurodegenerative diseases such as spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS). Autologous and allogenic mesenchymal stem cells (MSCs) are so far the best candidates for use in regenerative medicine. Here we review the effects of the implantation of MSCs (progenitors of mesodermal origin) in animal models of SCI and ALS and in clinical studies. MSCs possess multilineage differentiation potential and are easily expandable in vitro. These cells, obtained from bone marrow (BM), adipose tissue, Wharton jelly, or even other tissues, have immunomodulatory and paracrine potential, releasing a number of cytokines and factors which inhibit the proliferation of T cells, B cells, and natural killer cells and modify dendritic cell activity. They are hypoimmunogenic, migrate toward lesion sites, induce better regeneration, preserve perineuronal nets, and stimulate neural plasticity. There is a wide use of MSC systemic application or MSCs seeded on scaffolds and tissue bridges made from various synthetic and natural biomaterials, including human decellularized extracellular matrix (ECM) or nanofibers. The positive effects of MSC implantation have been recorded in animals with SCI lesions and ALS. Moreover, promising effects of autologous as well as allogenic MSCs for the treatment of SCI and ALS were demonstrated in recent clinical studies.}, }
@article {pmid34293864, year = {2021}, author = {Baggio, C and Kulinich, A and Dennys, CN and Rodrigo, R and Meyer, K and Ethell, I and Pellecchia, M}, title = {NMR-Guided Design of Potent and Selective EphA4 Agonistic Ligands.}, journal = {Journal of medicinal chemistry}, volume = {64}, number = {15}, pages = {11229-11246}, pmid = {34293864}, issn = {1520-4804}, support = {P20 CA242620/CA/NCI NIH HHS/United States ; P41 GM103311/GM/NIGMS NIH HHS/United States ; R01 CA168517/CA/NCI NIH HHS/United States ; R01 NS107479/NS/NINDS NIH HHS/United States ; }, mesh = {Amino Acids/chemistry/*pharmacology ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Crystallography, X-Ray ; Dose-Response Relationship, Drug ; *Drug Design ; Fluorenes/chemistry/*pharmacology ; High-Throughput Screening Assays ; Humans ; Ligands ; Magnetic Resonance Spectroscopy ; Mice ; Mice, Transgenic ; Models, Molecular ; Molecular Structure ; Receptor, EphA4/*agonists/metabolism ; Structure-Activity Relationship ; Thermodynamics ; }, abstract = {In this paper, we applied an innovative nuclear magnetic resonance (NMR)-guided screening and ligand design approach, named focused high-throughput screening by NMR (fHTS by NMR), to derive potent, low-molecular-weight ligands capable of mimicking interactions elicited by ephrin ligands on the receptor tyrosine kinase EphA4. The agents bind with nanomolar affinity, trigger receptor activation in cellular assays with motor neurons, and provide remarkable motor neuron protection from amyotrophic lateral sclerosis (ALS) patient-derived astrocytes. Structural studies on the complex between EphA4 ligand-binding domain and a most active agent provide insights into the mechanism of the agents at a molecular level. Together with preliminary in vivo pharmacology studies, the data form a strong foundation for the translation of these agents for the treatment of ALS and potentially other human diseases.}, }
@article {pmid34293378, year = {2021}, author = {Aslani, M and Mortazavi-Jahromi, SS and Mirshafiey, A}, title = {Efficient roles of miR-146a in cellular and molecular mechanisms of neuroinflammatory disorders: An effectual review in neuroimmunology.}, journal = {Immunology letters}, volume = {238}, number = {}, pages = {1-20}, doi = {10.1016/j.imlet.2021.07.004}, pmid = {34293378}, issn = {1879-0542}, mesh = {Animals ; *Biomarkers ; Diagnosis, Differential ; Disease Management ; Disease Susceptibility ; *Gene Expression Regulation ; Humans ; MicroRNAs/*genetics ; Neuroimmunomodulation/genetics/immunology ; Neuroinflammatory Diseases/diagnosis/*etiology/*metabolism/therapy ; *RNA Interference ; Signal Transduction ; }, abstract = {Known as one of the most sophisticated systems of the human body, the nervous system consists of neural cells and controls all parts of the body. It is closely related to the immune system. The effects of inflammation and immune reactions have been observed in the pathogenesis of some neurological disorders. Defined as the gene expression regulators, miRNAs participate in cellular processes. miR-146a is a mediator in the neuroimmune system, leaving substantial effects on the homeostasis of immune and brain cells, neuronal identities acquisition, and immune responses regulation in the nervous system. Its positive efficiency has been proven in modulating inflammatory reactions, hemorrhagic complications, and pain. Moreover, the miR-146a targets play a key role in the pathogenesis of these illnesses. Based on the performance of its targets, miR-146a can have various effects on the disease progress. The abnormal expression/function of miR-146a has been reported in neuroinflammatory disorders. There is research evidence that this molecule qualifies as a desirable biomarker for some disorders and can even be a therapeutic target. This study aims to provide a meticulous review regarding the roles of miR-146a in the pathogenesis and progression of several neuroinflammatory disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, temporal lobe epilepsy, ischemic stroke, etc. The study also considers its eligibility for use as an ideal biomarker and therapeutic target in these diseases. The awareness of these mechanisms can facilitate the disease management/treatment, lead to patients' amelioration, improve the quality of life, and mitigate the risk of death.}, }
@article {pmid34290621, year = {2021}, author = {Kiriaev, L and Perry, BD and Mahns, DA and Shortland, PJ and Redwan, A and Morley, JW and Head, SI}, title = {Minocycline Treatment Reduces Mass and Force Output From Fast-Twitch Mouse Muscles and Inhibits Myosin Production in C2C12 Myotubes.}, journal = {Frontiers in physiology}, volume = {12}, number = {}, pages = {696039}, pmid = {34290621}, issn = {1664-042X}, abstract = {Minocycline, a tetracycline-class of antibiotic, has been tested with mixed effectiveness on neuromuscular disorders such as amyotrophic lateral sclerosis, autoimmune neuritis and muscular dystrophy. The independent effect of minocycline on skeletal muscle force production and signalling remain poorly understood. Our aim here is to investigate the effects of minocycline on muscle mass, force production, myosin heavy chain abundance and protein synthesis. Mice were injected with minocycline (40 mg/kg i.p.) daily for 5 days and sacrificed at day six. Fast-twitch EDL, TA muscles and slow-twitch soleus muscles were dissected out, the TA muscle was snap-frozen and the remaining muscles were attached to force transducer whilst maintained in an organ bath. In C2C12 myotubes, minocycline was applied to the media at a final concentration of 10 μg/mL for 48 h. In minocycline treated mice absolute maximal force was lower in fast-twitch EDL while in slow-twitch soleus there was an increase in the time to peak and relaxation of the twitch. There was no effect of minocycline treatment on the other contractile parameters measured in isolated fast- and slow-twitch muscles. In C2C12 cultured cells, minocycline treatment significantly reduced both myosin heavy chain content and protein synthesis without visible changes to myotube morphology. In the TA muscle there was no significant changes in myosin heavy chain content. These results indicate that high dose minocycline treatment can cause a reduction in maximal isometric force production and mass in fast-twitch EDL and impair protein synthesis during myogenesis in C2C12 cultured cells. These findings have important implications for future studies investigating the efficacy of minocycline treatment in neuromuscular or other muscle-atrophy inducing conditions.}, }
@article {pmid34283400, year = {2021}, author = {Betancor, M and Moreno-Martínez, L and López-Pérez, &#xd3; and Otero, A and Hernaiz, A and Barrio, T and Badiola, JJ and Osta, R and Bolea, R and Martín-Burriel, I}, title = {Therapeutic Assay with the Non-toxic C-Terminal Fragment of Tetanus Toxin (TTC) in Transgenic Murine Models of Prion Disease.}, journal = {Molecular neurobiology}, volume = {58}, number = {10}, pages = {5312-5326}, pmid = {34283400}, issn = {1559-1182}, support = {POCTEFA 2014-2020//European Regional Development Fund/ ; }, mesh = {Animals ; Brain/*drug effects/pathology ; *Disease Models, Animal ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Pilot Projects ; Prion Diseases/*drug therapy/*genetics/pathology ; Sheep ; Tetanus Toxin/*administration &amp; dosage ; }, abstract = {The non-toxic C-terminal fragment of the tetanus toxin (TTC) has been described as a neuroprotective molecule since it binds to Trk receptors and activates Trk-dependent signaling, activating neuronal survival pathways and inhibiting apoptosis. Previous in vivo studies have demonstrated the ability of this molecule to increase mice survival, inhibit apoptosis and regulate autophagy in murine models of neurodegenerative diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. Prion diseases are fatal neurodegenerative disorders in which the main pathogenic event is the conversion of the cellular prion protein (PrP[C]) into an abnormal and misfolded isoform known as PrP[Sc]. These diseases share different pathological features with other neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease or Alzheimer's disease. Hitherto, there are no effective therapies to treat prion diseases. Here, we present a pilot study to test the therapeutic potential of TTC to treat prion diseases. C57BL6 wild-type mice and the transgenic mice Tg338, which overexpress PrP[C], were intracerebrally inoculated with scrapie prions and then subjected to a treatment consisting of repeated intramuscular injections of TTC. Our results indicate that TTC displays neuroprotective effects in the murine models of prion disease reducing apoptosis, regulating autophagy and therefore increasing neuronal survival, although TTC did not increase survival time in these models.}, }
@article {pmid34269182, year = {2022}, author = {Panes, JD and Wendt, A and Ramirez-Molina, O and Castro, PA and Fuentealba, J}, title = {Deciphering the role of PGC-1α in neurological disorders: from mitochondrial dysfunction to synaptic failure.}, journal = {Neural regeneration research}, volume = {17}, number = {2}, pages = {237-245}, pmid = {34269182}, issn = {1673-5374}, abstract = {The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Additionally, it has been observed that PGC-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, PGC-1α downregulation in different brain areas (hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that PGC-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that PGC-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific PGC-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-to-date overview of the PGC-1α role in the physiopathology of neurodegenerative diseases, as well as establish the importance of PGC-1α function in synaptic transmission and neuronal survival.}, }
@article {pmid34266598, year = {2021}, author = {Ahmed, RM and Halliday, G and Hodges, JR}, title = {Hypothalamic symptoms of frontotemporal dementia disorders.}, journal = {Handbook of clinical neurology}, volume = {182}, number = {}, pages = {269-280}, doi = {10.1016/B978-0-12-819973-2.00019-8}, pmid = {34266598}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis ; Cognition ; Disease Progression ; Feeding Behavior ; *Frontotemporal Dementia ; Humans ; Hypothalamus ; }, abstract = {Frontotemporal dementia (FTD) has traditionally been regarded as a disease of cognition and behavior, but emerging evidence suggests that the disease also affects body functions including changes in eating behavior and metabolism, autonomic function, sleep behavior, and sexual function. Central to these changes are potentially complex neural networks involving the hypothalamus, with hypothalamic atrophy shown in behavioral variant FTD. The physiological changes found in FTD are reviewed and the key neural networks and neuroendocrine changes mediating these changes in function discussed, including the ability to use these changes as biomarkers to aid in disease diagnosis, monitoring disease progression, and as potential treatment targets.}, }
@article {pmid34260979, year = {2021}, author = {Sancho, J and Ferrer, S and Burés, E and Luis Díaz, J and Torrecilla, T and Signes-Costa, J and Servera, E}, title = {Effect of one-year dextromethorphan/quinidine treatment on management of respiratory impairment in amyotrophic lateral sclerosis.}, journal = {Respiratory medicine}, volume = {186}, number = {}, pages = {106536}, doi = {10.1016/j.rmed.2021.106536}, pmid = {34260979}, issn = {1532-3064}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications ; Dextromethorphan/*administration &amp; dosage ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Prospective Studies ; Quinidine/*administration &amp; dosage ; Respiratory Insufficiency/*drug therapy/*etiology ; Time Factors ; Treatment Outcome ; }, abstract = {UNLABELLED: Treatment with Dextromethorphan/Quinidine (DM/Q) has demonstrated benefit on pseudobulbar affect and bulbar function in amyotrophic lateral sclerosis (ALS). The aim of this study was to assess whether DM/Q could provide long-term improvement in bulbar function and thereby prolong noninvasive respiratory management in ALS.<br><br>MATERIALS AND METHODS: This prospective, case-cohort study, recruited ALS patients with bulbar dysfunction. Subjects included were compared with cross-matched historical controls. Cases received DM/Q (20/10&#xa0;mg twice daily) during one-year follow-up; bulbar dysfunction was evaluated with the Norris scale bulbar subscore (NBS) and bulbar subscale of AlSFRS-R (ALSFRSb).<br><br>RESULTS: In total, 21 cases and 20 controls were enrolled, of whom noninvasive respiratory muscle assistance failed in 6 (28.5%) patients in the DM/Q group, compared with 4 patients (20.0%) in the control group (p&#xa0;=&#xa0;0.645). Time from study onset to failure of respiratory muscle aids was 5.50&#xa0;+&#xa0;1.31 months in the DM/Q group and 5.20&#xa0;+&#xa0;1.15 months in the control group (p&#xa0;=&#xa0;0.663). The adjusted OR for the effect of treatment on failure of noninvasive respiratory muscle aids was 2.12 (95%CI 0.23-33.79, p&#xa0;=&#xa0;0.592). In the DM/Q group an impairment in scores was found in NBS (F&#xa0;=&#xa0;19.26, p&#xa0;=&#xa0;0.000) and ALSFRS-Rb (F&#xa0;=&#xa0;12.71, p&#xa0;=&#xa0;0.001) across different months of the study.<br><br>CONCLUSION: Treatment with DM/Q in ALS is unable to prolong noninvasive respiratory management, and moreover, has no effect on long-term deterioration of bulbar function. Notwithstanding the results on bulbar function, DM/Q was found to improve pseudobulbar affect during one-year follow-up.}, }
@article {pmid34251911, year = {2022}, author = {Brooks, BR and Pioro, EP and Beaulieu, D and Taylor, AA and Schactman, M and Keymer, M and Agnese, W and Perdrizet, J and Apple, S and Ennist, DL}, title = {Evidence for generalizability of edaravone efficacy using a novel machine learning risk-based subgroup analysis tool.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {1-2}, pages = {49-57}, doi = {10.1080/21678421.2021.1927102}, pmid = {34251911}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Edaravone/therapeutic use ; Humans ; Machine Learning ; Vital Capacity ; }, abstract = {Introduction: The edaravone development program for amyotrophic lateral sclerosis (ALS) included trials MCI186-16 (Study 16) and MCI186-19 (Study 19). A cohort enrichment strategy was based on a Study 16 post hoc analysis and applied to Study 19 to elucidate a treatment effect in that study. To determine whether the Study 19 results could be generalized to a broader ALS population, we used a machine learning (ML) model to create a novel risk-based subgroup analysis tool. Methods: A validated ML model was used to rank order all Study 16 participants by predicted time to 50% expected vital capacity. Subjects were stratified into nearest-neighbor risk-based subgroups that were systematically expanded to include the entire Study 16 population. For each subgroup, a statistical analysis generated heat maps that revealed statistically significant effect sizes. Results: A broad region of the Study 16 heat map with significant effect sizes was identified, including up to 70% of the trial population. Incorporating participants identified in the cohort enrichment strategy yielded a broad group comprising 76% of the original participants with a statistically significant treatment effect. This broad group spanned the full range of the functional score progression observed in Study 16. Conclusions: This analysis, applying predictions derived using an ML model to a novel methodology for subgroup identification, ascertained a statistically significant edaravone treatment effect in a cohort of participants with broader disease characteristics than the Study 19 inclusion criteria. This novel methodology may assist clinical interpretation of study results and potentially inform efficient future clinical trial design strategies.}, }
@article {pmid34248597, year = {2021}, author = {Asadi, MR and Sadat Moslehian, M and Sabaie, H and Jalaiei, A and Ghafouri-Fard, S and Taheri, M and Rezazadeh, M}, title = {Stress Granules and Neurodegenerative Disorders: A Scoping Review.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {650740}, pmid = {34248597}, issn = {1663-4365}, abstract = {Cytoplasmic ribonucleoproteins called stress granules (SGs) are considered as one of the main cellular solutions against stress. Their temporary presence ends with stress relief. Any factor such as chronic stress or mutations in the structure of the components of SGs that lead to their permanent presence can affect their interactions with pathological aggregations and increase the degenerative effects. SGs involved in RNA mechanisms are important factors in the pathophysiology of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTD), and Alzheimer's diseases (AD). Although many studies have been performed in the field of SGs and neurodegenerative disorders, so far, no systematic studies have been executed in this field. The purpose of this study is to provide a comprehensive perspective of all studies about the role of SGs in the pathogenesis of neurodegenerative disorders with a focus on the protein ingredients of these granules. This scoping review is based on a six-stage methodology structure and the PRISMA guideline. A systematic search of seven databases for qualified articles was conducted until December 2020. Publications were screened independently by two reviewers and quantitative and qualitative analysis was performed on the extracted data. Bioinformatics analysis was used to plot the network and predict interprotein interactions. In addition, GO analysis was performed. A total of 48 articles were identified that comply the inclusion criteria. Most studies on neurodegenerative diseases have been conducted on ALS, AD, and FTD using human post mortem tissues. Human derived cell line studies have been used only in ALS. A total 29 genes of protein components of SGs have been studied, the most important of which are TDP-43, TIA-1, PABP-1. Bioinformatics studies have predicted 15 proteins to interact with the protein components of SGs, which may be the constituents of SGs. Understanding the interactions between SGs and pathological aggregations in neurodegenerative diseases can provide new targets for treatment of these disorders.}, }
@article {pmid34248499, year = {2021}, author = {Molnar-Kasza, A and Hinteregger, B and Neddens, J and Rabl, R and Flunkert, S and Hutter-Paier, B}, title = {Evaluation of Neuropathological Features in the SOD1-G93A Low Copy Number Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {681868}, pmid = {34248499}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) still depicts an incurable and devastating disease. Drug development efforts are mostly based on superoxide dismutase 1 gene (SOD1)-G93A mice that present a very strong and early phenotype, allowing only a short time window for intervention. An alternative mouse model is available, that is based on the same founder line but has a reduced SOD1-G93A copy number, resulting in a weaker and delayed phenotype. To be able to use these SOD1-G93A/low mice for drug testing, we performed a characterization of ALS-typical pathologies. All analyses were performed compared to non-transgenic (ntg) littermates of the same sex and age. In vivo analysis of SOD1-G93A/low mice was performed by weekly body weight measurements, analysis of the survival rate, and measurement of the muscle strength of 24-30 weeks old female and male SOD1-G93A/low mice. Immunofluorescent labeling of SOD1, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule 1 (Iba1) protein was performed in the cervical, thoracic, and lumbar ventral horn of the spinal cord of 24-30 weeks old male and female SOD1-G93A/low mice. The musculus gastrocnemius of male SOD1-G93A/low mice was labeled with fluorophore-conjugated α-bungarotoxin and antibodies against phosphorylated neurofilaments. Fluorescent labeling was detected and quantified by macro-based image analysis. Although SOD1 protein levels were highly increased in both sexes and all age groups, levels strongly peaked in 30 weeks old male SOD1-G93A/low mice. Astrocytosis and activated microglia in the spinal cord ventral horn and phosphorylated neurofilaments in the motor unit of the musculus gastrocnemius progressively increased, while muscle strength progressively decreased in male SOD1-G93A/low mice. In female SOD1-G93A/low mice, only activated microglia increased progressively, while muscle strength was constantly reduced starting at 26 weeks. These differences result in a shorter survival time of male SOD1-G93A/low mice of about 3 weeks compared to female animals. The results suggest that male SOD1-G93A/low mice present a stronger pathology and are, therefore, better suitable to evaluate the efficacy of new drugs against ALS as most pathological features are developing progressively paralleled by a survival time that allows treatment to start before symptom onset.}, }
@article {pmid34238153, year = {2022}, author = {Mannan, A and Singh, TG and Singh, V and Garg, N and Kaur, A and Singh, M}, title = {Insights into the Mechanism of the Therapeutic Potential of Herbal Monoamine Oxidase Inhibitors in Neurological Diseases.}, journal = {Current drug targets}, volume = {23}, number = {3}, pages = {286-310}, doi = {10.2174/1389450122666210707120256}, pmid = {34238153}, issn = {1873-5592}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; Monoamine Oxidase/metabolism ; Monoamine Oxidase Inhibitors/pharmacology/therapeutic use ; *Parkinson Disease/drug therapy ; }, abstract = {Monoamine oxidase (MAO) is an enzyme that catalyzes the deamination of monoamines and other proteins. MAO's hyperactivation results in the massive generation of reactive oxygen species, which leads to a variety of neurological diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and depression-like disorders. Although synthetic MAO inhibitors are clinically available, they are associated with side effects such as hepatotoxicity, cheese reaction, hypertensive crisis, and so on, necessitating the investigation of alternative MAO inhibitors from a natural source with a safe profile. Herbal medications have a significant impact on the prevention of many diseases; additionally, they have fewer side effects and serve as a precursor for drug development. This review discusses the potential of herbal MAO inhibitors as well as their associated mechanism of action, with an aim to foster future research on herbal MAO inhibitors as a potential treatment for neurological diseases.}, }
@article {pmid34237390, year = {2021}, author = {Tang, W and Li, Y and Li, Y and Wang, Q}, title = {Caveolin-1, a novel player in cognitive decline.}, journal = {Neuroscience and biobehavioral reviews}, volume = {129}, number = {}, pages = {95-106}, doi = {10.1016/j.neubiorev.2021.06.044}, pmid = {34237390}, issn = {1873-7528}, mesh = {Caveolae/metabolism ; *Caveolin 1/metabolism ; *Cognitive Dysfunction/metabolism ; Humans ; Oxidative Stress ; Quality of Life ; }, abstract = {Cognitive decline (CD), which related to vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and diabetes mellitus, is a growing health concern that has a great impact on the patients' quality of life. Although extensive efforts, the mechanisms of CD are still far from being clarified, not to mention the effective treatment and prevention strategies. Caveolin-1 (Cav-1), a trans-membrane protein, is a major component of the caveolae structure and scaffolding proteins. Recently, ample evidence depicts a strong correlation between Cav-1 and CD, however, the specific role of Cav-1 in CD has not been clearly examined and how they might be connected have yet to be identified. This review seeks to provide a comprehensive overview about how Cav-1 modulates pathogeneses of CD-associated diseases. In summary, Cav-1 can promote structural and functional plasticity of neurons, improve neurogenesis, relieve mitochondrial dysfunction, inhibit inflammation and suppress oxidative stress, which have shed light on the idea that Cav-1 may be an efficacious therapeutic target to treat CD.}, }
@article {pmid34233722, year = {2021}, author = {Nakajima, T and Sankai, Y and Takata, S and Kobayashi, Y and Ando, Y and Nakagawa, M and Saito, T and Saito, K and Ishida, C and Tamaoka, A and Saotome, T and Ikai, T and Endo, H and Ishii, K and Morita, M and Maeno, T and Komai, K and Ikeda, T and Ishikawa, Y and Maeshima, S and Aoki, M and Ito, M and Mima, T and Miura, T and Matsuda, J and Kawaguchi, Y and Hayashi, T and Shingu, M and Kawamoto, H}, title = {Cybernic treatment with wearable cyborg Hybrid Assistive Limb (HAL) improves ambulatory function in patients with slowly progressive rare neuromuscular diseases: a multicentre, randomised, controlled crossover trial for efficacy and safety (NCY-3001).}, journal = {Orphanet journal of rare diseases}, volume = {16}, number = {1}, pages = {304}, pmid = {34233722}, issn = {1750-1172}, mesh = {Cross-Over Studies ; Exercise Therapy ; Humans ; Lower Extremity ; *Neuromuscular Diseases ; *Wearable Electronic Devices ; }, abstract = {BACKGROUND: Rare neuromuscular diseases such as spinal muscular atrophy, spinal bulbar muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, distal myopathy, sporadic inclusion body myositis, congenital myopathy, and amyotrophic lateral sclerosis lead to incurable amyotrophy and consequent loss of ambulation. Thus far, no therapeutic approaches have been successful in recovering the ambulatory ability. Thus, the aim of this trial was to evaluate the efficacy and safety of cybernic treatment with a wearable cyborg Hybrid Assistive Limb (HAL, Lower Limb Type) in improving the ambulatory function in those patients.<br><br>RESULTS: We conducted an open-label, randomised, controlled crossover trial to test HAL at nine hospitals between March 6, 2013 and August 8, 2014. Eligible patients were older than 18&#xa0;years and had a diagnosis of neuromuscular disease as specified above. They were unable to walk for 10&#xa0;m independently and had neither respiratory failure nor rapid deterioration in gait. The primary endpoint was the distance passed during a two-minute walk test (2MWT). The secondary endpoints were walking speed, cadence, and step length during the 10-m walk test (10MWT), muscle strength by manual muscle testing (MMT), and a series of functional measures. Adverse events and failures/problems/errors with HAL were also evaluated. Thirty patients were randomly assigned to groups A or B, with each group of 15 receiving both treatments in a crossover design. The efficacy of a 40-min walking program performed nine times was compared between HAL plus a hoist and a hoist only. The final analysis included 13 and 11 patients in groups A and B, respectively. Cybernic treatment with HAL resulted in a 10.066% significantly improved distance in 2MWT (95% confidence interval, 0.667-19.464; p&#x2009;=&#x2009;0.0369) compared with the hoist only treatment. Among the secondary endpoints, the total scores of MMT and cadence at 10MWT were the only ones that showed significant improvement. The only adverse effects were slight to mild myalgia, back pain, and contact skin troubles, which were easily remedied.<br><br>CONCLUSIONS: HAL is a new treatment device for walking exercise, proven to be more effective than the conventional method in patients with incurable neuromuscular diseases.<br><br>TRIAL REGISTRATION: JMACTR, JMA-IIA00156.}, }
@article {pmid34225938, year = {2021}, author = {Ahmed, RM and Steyn, F and Dupuis, L}, title = {Hypothalamus and weight loss in amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {180}, number = {}, pages = {327-338}, doi = {10.1016/B978-0-12-820107-7.00020-3}, pmid = {34225938}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Hypothalamus ; Weight Loss ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder. While initially pathophysiology was thought to be restricted to motor deficits, it is increasingly recognized that patients develop prominent changes in weight and eating behavior that result from and mediate the underlying neurodegenerative process. These changes include alterations in metabolism, lipid levels, and insulin resistance. Emerging research suggests that these alterations may be mediated through changes in the hypothalamic function, with atrophy of the hypothalamus shown in both ALS patients and also presymptomatic genetic at-risk patients. This chapter reviews the evidence for hypothalamic involvement in ALS, including melanocortin pathways and potential treatment targets.}, }
@article {pmid34223387, year = {2021}, author = {Charlton, K and McClelland, G and Millican, K and Haworth, D and Aitken-Fell, P and Norton, M}, title = {The impact of introducing real time feedback on ventilation rate and tidal volume by ambulance clinicians in the North East in cardiac arrest simulations.}, journal = {Resuscitation plus}, volume = {6}, number = {}, pages = {100130}, pmid = {34223387}, issn = {2666-5204}, abstract = {BACKGROUND: Research suggests rescuers deliver ventilations outside of recommendations during out of hospital cardiac arrest (OHCA), which can be deleterious to survival. We aimed to determine if ambulance clinician compliance with ventilation recommendations could be improved using the Zoll Accuvent real time ventilation feedback device (VFD).<br><br>METHODS: Participants simulated a two-minute cardiac arrest scenario using a mannequin and defibrillator without ventilation feedback. Eligible for inclusion were all clinicians aged &#x2265;18 years who perform cardiopulmonary resuscitation (CPR) as part of their role, who had completed an internal advanced life support (ALS) refresher. Following familiarisation of a few minutes with the VFD, participants repeated the two-minute scenario with ventilation feedback. Ventilation rate and volume and CPR quality were recorded. Primary outcome was % difference in ventilation compliance with and without feedback. Secondary outcomes were differences between paramedic and non-paramedic clinicians and compliance with chest compression guidelines.<br><br>RESULTS: One hundred and six participants completed the study. Median ventilation rate without feedback was 10 (IQR 8-14, range 4-30) compared to 9 (IQR 9-9, range 6-17) with feedback; median tidal volume without feedback was 630&#xa0;mls (IQR 518-725, range 201-1114) compared to 546&#xa0;mls (IQR 531-560, range 490-750) with feedback. Proportion of clinicians &#x2265;50% compliant with European Resuscitation Council ventilation recommendations were significantly greater with ventilation feedback compared to without, 91% vs. 9%, (McNemars test p&#xa0;=&#xa0;<0.0001). Paramedics out performed non-paramedic clinicians with and without feedback and compression quality was not compromised by using the VFD.<br><br>CONCLUSIONS: Ambulance clinician baseline ventilation quality was frequently outside of recommendations, but a VFD can ensure treatment is within evidence-based recommendations. Further research is required to validate the use of the VFD in true clinical practice and to evaluate the relationship between improved ventilation quality during OHCA and patient outcomes.}, }
@article {pmid34220504, year = {2021}, author = {Islam, MS and Quispe, C and Hossain, R and Islam, MT and Al-Harrasi, A and Al-Rawahi, A and Martorell, M and Mamurova, A and Seilkhan, A and Altybaeva, N and Abdullayeva, B and Docea, AO and Calina, D and Sharifi-Rad, J}, title = {Neuropharmacological Effects of Quercetin: A Literature-Based Review.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {665031}, pmid = {34220504}, issn = {1663-9812}, abstract = {Quercetin (QUR) is a natural bioactive flavonoid that has been lately very studied for its beneficial properties in many pathologies. Its neuroprotective effects have been demonstrated in many in vitro studies, as well as in vivo animal experiments and human trials. QUR protects the organism against neurotoxic chemicals and also can prevent the evolution and development of neuronal injury and neurodegeneration. The present work aimed to summarize the literature about the neuroprotective effect of QUR using known database sources. Besides, this review focuses on the assessment of the potential utilization of QUR as a complementary or alternative medicine for preventing and treating neurodegenerative diseases. An up-to-date search was conducted in PubMed, Science Direct and Google Scholar for published work dealing with the neuroprotective effects of QUR against neurotoxic chemicals or in neuronal injury, and in the treatment of neurodegenerative diseases. Findings suggest that QUR possess neuropharmacological protective effects in neurodegenerative brain disorders such as Alzheimer's disease, Amyloid β peptide, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. In summary, this review emphasizes the neuroprotective effects of QUR and its advantages in being used in complementary medicine for the prevention and treatment o of different neurodegenerative diseases.}, }
@article {pmid34218510, year = {2021}, author = {Laforest, M and Soufiane, B and Patterson, EL and Vargas, JJ and Boggess, SL and Houston, LC and Trigiano, RN and Brosnan, JT}, title = {Differential expression of genes associated with non-target site resistance in Poa annua with target site resistance to acetolactate synthase inhibitors.}, journal = {Pest management science}, volume = {77}, number = {11}, pages = {4993-5000}, pmid = {34218510}, issn = {1526-4998}, support = {//University of Tennessee Office of AgResearch/ ; //USDA-NACA/ ; }, mesh = {*Acetolactate Synthase/genetics ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Mutation ; Plant Proteins/genetics ; *Poa ; }, abstract = {BACKGROUND: Poa annua is a pervasive grassy, self-pollinating, weed that has evolved resistance to 10 different herbicide modes-of-action, third most of all weed species. We investigated constitutive overexpression of genes associated with non-target site resistance (NTSR) in POAAN-R3 and the response of those genes when treated with trifloxysulfuron despite the biotype having a known target site mutation in acetolactate synthase (ALS).<br><br>RESULTS: Despite having an ALS target site mutation, POAAN-R3 still had a transcriptomic response to herbicide application that differed from a susceptible biotype. We observed differential expression of genes associated with transmembrane transport and oxidation-reduction activities, with differences being most pronounced prior to herbicide treatment.<br><br>CONCLUSIONS: In the P. annua biotype we studied with confirmed target site resistance to ALS inhibitors, we also observed constitutive expression of genes regulating transmembrane transport, as well as differential expression of genes associated with oxidative stress after treatment with trifloxysulfuron. This accumulation of mechanisms, in addition to the manifestation of target site resistance, could potentially increase the chance of survival when plants are challenged by different modes of action.}, }
@article {pmid34217018, year = {2021}, author = {Tolkovsky, A and Kipervasser, S and Fainmesser, Y and Alcalay, Y and Gadoth, A}, title = {A paraneoplastic syndrome misdiagnosed as ALS: What are the red flags? A case report and review of the literature.}, journal = {Journal of neuroimmunology}, volume = {358}, number = {}, pages = {577635}, doi = {10.1016/j.jneuroim.2021.577635}, pmid = {34217018}, issn = {1872-8421}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/blood/*cerebrospinal fluid/*diagnosis ; *Diagnostic Errors ; Humans ; Male ; Paraneoplastic Syndromes, Nervous System/blood/*cerebrospinal fluid/*diagnosis ; }, abstract = {Background Paraneoplastic motor neuron disease (PMND) is a rare, non-classical form of paraneoplastic neurological syndrome (PNS). Anti-Hu and anti-CV2/CRMP5 PNS are mostly associated with small-cell lung cancer (SCLC) and consist of highly variable clinical syndromes, including sensory neuronopathy, cerebellar ataxia and/or limbic encephalitis. However, substantial motor impairment is uncommon, particularly when no sensory dysfunction co-exists. Case A 72-year-old man with a recent diagnosis of amyotrophic lateral sclerosis (ALS) was referred to our department of neurology for evaluation. The patient sub-acutely developed progressive neurological dysfunction including erectile dysfunction, behavioral changes, limb weakness, dysphagia, anorexia, as well as worsening stridor that necessitated tracheostomy due to bilateral vocal cord paralysis (BVCP). Neurological examination revealed motor weakness of upper and lower motor neuron origin with autonomic and cognitive dysfunction. Cerebrospinal fluid (CSF) analysis demonstrated pleocytosis, elevated protein, presence of oligoclonal bands (OCB), and neuronal antibody testing was positive for anti-Hu and anti-CV2/CRMP5. Based on these findings a diagnosis of a PNS was made. Evaluation for malignancy was negative, and immunosuppressive/immunomodulatory treatment was initiated but had little effect during fifteen months of follow-up. Conclusions Although PMND is very rare, in an atypical presentation, especially with features that are not usually present in ALS such as autonomic dysfunction, sensory disturbance or cognitive decline, this etiology should be in the differential diagnosis.}, }
@article {pmid34216082, year = {2021}, author = {Schneider, C and Wassermann, MK and Grether, NB and Fink, GR and Wunderlich, G and Lehmann, HC}, title = {Motor unit number estimation in adult patients with spinal muscular atrophy treated with nusinersen.}, journal = {European journal of neurology}, volume = {28}, number = {9}, pages = {3022-3029}, doi = {10.1111/ene.15005}, pmid = {34216082}, issn = {1468-1331}, mesh = {Adult ; Cross-Sectional Studies ; Humans ; Longitudinal Studies ; *Muscular Atrophy, Spinal/drug therapy ; *Oligonucleotides ; }, abstract = {BACKGROUND AND PURPOSE: The aim was to assess the organization and short-term changes of motor units in adult patients with spinal muscular atrophy (SMA) treated with nusinersen.<br><br>METHODS: In this single-centre cross-sectional and longitudinal study 15 adult patients with SMA type 3 were assessed and compared to 15 age-matched healthy controls and nine patients with amyotrophic lateral sclerosis. Moreover, 10 patients with SMA were followed up after 4-8&#xa0;months. All patients were investigated clinically and by the motor unit number estimation method MScanFit of the abductor pollicis brevis muscle.<br><br>RESULTS: The number of motor units (p&#xa0;<&#xa0;0.001) was significantly lower in patients with SMA compared to healthy controls at study entry. Mean unit amplitude, median amplitude and largest unit (p&#xa0;<&#xa0;0.001) were significantly increased in patients with SMA. Patients with amyotrophic lateral sclerosis showed a significant reduction of compound muscle action potential (p&#xa0;=&#xa0;0.005) and number of motor units (p&#xa0;=&#xa0;0.03) compared to patients with SMA, accompanied by a larger median amplitude (p&#xa0;=&#xa0;0.03). A prospective analysis identified patients with the ability to walk to improve the number of motor units (p&#xa0;=&#xa0;0.046) accompanied by a decreased median amplitude (p&#xa0;=&#xa0;0.03). Electrophysiological measures showed a moderate to strong correlation with clinical scores.<br><br>CONCLUSION: Patients with SMA show loss of motor units in distal muscles. MScanFit variables indicate that compound muscle action potential amplitudes are maintained by collateral sprouting. Prospective analyses suggest that milder affected adult patients with SMA preferentially benefit from nusinersen treatment through recovery of smaller motor units. Correlations with clinical scores underline the potential of MScanFit as a surrogate marker.}, }
@article {pmid34211575, year = {2021}, author = {Lin, M and Hu, X and Chang, S and Chang, Y and Bian, W and Hu, R and Wang, J and Zhu, Q and Qiu, J}, title = {Advances of Antisense Oligonucleotide Technology in the Treatment of Hereditary Neurodegenerative Diseases.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2021}, number = {}, pages = {6678422}, pmid = {34211575}, issn = {1741-427X}, abstract = {Antisense nucleic acids are single-stranded oligonucleotides that have been specially chemically modified, which can bind to RNA expressed by target genes through base complementary pairing and affect protein synthesis at the level of posttranscriptional processing or protein translation. In recent years, the application of antisense nucleic acid technology in the treatment of neuromuscular diseases has made remarkable progress. In 2016, the US FDA approved two antisense nucleic acid drugs for the treatment of Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), and the development to treat other neurodegenerative diseases has also entered the clinical stage. Therefore, ASO represents a treatment with great potential. The article will summarize ASO therapies in terms of mechanism of action, chemical modification, and administration methods and analyze their role in several common neurodegenerative diseases, such as SMA, DMD, and amyotrophic lateral sclerosis (ALS). This article systematically summarizes the great potential of antisense nucleic acid technology in the treatment of hereditary neurodegenerative diseases.}, }
@article {pmid34209688, year = {2021}, author = {Niccolai, E and Di Pilato, V and Nannini, G and Baldi, S and Russo, E and Zucchi, E and Martinelli, I and Menicatti, M and Bartolucci, G and Mandrioli, J and Amedei, A}, title = {The Gut Microbiota-Immunity Axis in ALS: A Role in Deciphering Disease Heterogeneity?.}, journal = {Biomedicines}, volume = {9}, number = {7}, pages = {}, pmid = {34209688}, issn = {2227-9059}, support = {RF-2016-02361616//Ministero della Salute/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder with an unknown etiology and no effective treatment, and is characterized by large phenotypic heterogeneity, including variable sites, ages of symptom onset and rates of disease progression. Increasing data support the role of the microbiota-immunity axis in the pathogenesis of neurodegenerative diseases. In the present study, we compared the inflammatory and microbiota profile of ALS patients with different clinical characteristics, with healthy family caregivers. Measuring a panel of 30 inflammatory cytokines in serum and fecal samples, we observed a distinct cytokine profile both at the systemic and intestinal level in patients compared to controls and even in patients with different clinical phenotypes and progression rates. The 16S targeted metagenome analysis revealed slight differences in patients compared to controls as well as in patients with slow progression, marked by the reduction of butyrate-producing bacteria and a decrease of the Firmicutes/Bacteroidetes ratio in ALS. Finally, the short chain fatty acid analysis did not show a different distribution among the groups. If confirmed in a larger number of patients, the inflammatory cytokine profile and the microbial composition could be appropriate biomarker candidates for deciphering ALS heterogeneity.}, }
@article {pmid34209129, year = {2021}, author = {Post, J and Schaffrath, A and Gering, I and Hartwig, S and Lehr, S and Shah, NJ and Langen, KJ and Willbold, D and Kutzsche, J and Willuweit, A}, title = {Oral Treatment with RD2RD2 Impedes Development of Motoric Phenotype and Delays Symptom Onset in SOD1[G93A] Transgenic Mice.}, journal = {International journal of molecular sciences}, volume = {22}, number = {13}, pages = {}, pmid = {34209129}, issn = {1422-0067}, support = {20-64-46027//Russian Science Foundation/ ; Technology Transfer Fund//Forschungszentrum J&#xfc;lich/ ; Portfolio Drug Research//Impuls und Vernetzungs-Fonds der Helmholtzgemeinschaft/ ; }, mesh = {Administration, Oral ; Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/genetics/pathology ; Animals ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Motor Neurons/*enzymology/pathology ; Peptides ; Superoxide Dismutase/genetics/*metabolism ; }, abstract = {Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and plays a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS). It has been implicated as driver of disease progression and is observed in ALS patients, as well as in the transgenic SOD1[G93A] mouse model. Here, we explore and validate the therapeutic potential of the d-enantiomeric peptide RD2RD2 upon oral administration in SOD1[G93A] mice. Transgenic mice were treated daily with RD2RD2 or placebo for 10 weeks and phenotype progression was followed with several behavioural tests. At the end of the study, plasma cytokine levels and glia cell markers in brain and spinal cord were analysed. Treatment resulted in a significantly increased performance in behavioural and motor coordination tests and a decelerated neurodegenerative phenotype in RD2RD2-treated SOD1[G93A] mice. Additionally, we observed retardation of the average disease onset. Treatment of SOD1[G93A] mice led to significant reduction in glial cell activation and a rescue of neurons. Analysis of plasma revealed normalisation of several cytokines in samples of RD2RD2-treated SOD1[G93A] mice towards the levels of non-transgenic mice. In conclusion, these findings qualify RD2RD2 to be considered for further development and testing towards a disease modifying ALS treatment.}, }
@article {pmid34208136, year = {2021}, author = {Sindona, C and Schepici, G and Contestabile, V and Bramanti, P and Mazzon, E}, title = {NOX2 Activation in COVID-19: Possible Implications for Neurodegenerative Diseases.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {57}, number = {6}, pages = {}, pmid = {34208136}, issn = {1648-9144}, support = {//Ministero della Salute/ ; }, mesh = {*Coronavirus Infections ; Humans ; *Neurodegenerative Diseases ; SARS-CoV-2 ; *COVID-19 Drug Treatment ; }, abstract = {Coronavirus disease 2019 (COVID-19) is a rapidly spreading contagious infectious disease caused by the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that primarily affects the respiratory tract as well as the central nervous system (CNS). SARS-CoV-2 infection occurs through the interaction of the viral protein Spike with the angiotensin II receptor (ACE 2), leading to an increase of angiotensin II and activation of nicotinamide adenine dinucleotide phosphate oxidase2 (NOX2), resulting in the release of both reactive oxygen species (ROS) and inflammatory molecules. The purpose of the review is to explain that SARS-CoV-2 infection can determine neuroinflammation that induces NOX2 activation in microglia. To better understand the role of NOX2 in inflammation, an overview of its involvement in neurodegenerative diseases (NDs) such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) is provided. To write this manuscript, we performed a PubMed search to evaluate the possible relationship of SARS-CoV-2 infection in NOX2 activation in microglia, as well as the role of NOX2 in NDs. Several studies highlighted that NOX2 activation in microglia amplifies neuroinflammation. To date, there is no clinical treatment capable of counteracting its activation, however, NOX2 could be a promising pharmaceutical target useful for both the treatment and prevention of NDs and COVID-19 treatment.}, }
@article {pmid34207859, year = {2021}, author = {Quessada, C and Bouscary, A and René, F and Valle, C and Ferri, A and Ngo, ST and Loeffler, JP}, title = {Skeletal Muscle Metabolism: Origin or Prognostic Factor for Amyotrophic Lateral Sclerosis (ALS) Development?.}, journal = {Cells}, volume = {10}, number = {6}, pages = {}, pmid = {34207859}, issn = {2073-4409}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Humans ; Male ; Muscle, Skeletal/*metabolism/pathology ; Superoxide Dismutase-1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons, amyotrophy and skeletal muscle paralysis usually leading to death due to respiratory failure. While generally considered an intrinsic motor neuron disease, data obtained in recent years, including our own, suggest that motor neuron protection is not sufficient to counter the disease. The dismantling of the neuromuscular junction is closely linked to chronic energy deficit found throughout the body. Metabolic (hypermetabolism and dyslipidemia) and mitochondrial alterations described in patients and murine models of ALS are associated with the development and progression of disease pathology and they appear long before motor neurons die. It is clear that these metabolic changes participate in the pathology of the disease. In this review, we summarize these changes seen throughout the course of the disease, and the subsequent impact of glucose-fatty acid oxidation imbalance on disease progression. We also highlight studies that show that correcting this loss of metabolic flexibility should now be considered a major goal for the treatment of ALS.}, }
@article {pmid34202494, year = {2021}, author = {Yang, X and Ji, Y and Wang, W and Zhang, L and Chen, Z and Yu, M and Shen, Y and Ding, F and Gu, X and Sun, H}, title = {Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Biomarkers, and Therapeutic Strategies.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {7}, pages = {}, pmid = {34202494}, issn = {2076-3921}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with the progressive loss of motor neurons, leading to a fatal paralysis. According to whether there is a family history of ALS, ALS can be roughly divided into two types: familial and sporadic. Despite decades of research, the pathogenesis of ALS is still unelucidated. To this end, we review the recent progress of ALS pathogenesis, biomarkers, and treatment strategies, mainly discuss the roles of immune disorders, redox imbalance, autophagy dysfunction, and disordered iron homeostasis in the pathogenesis of ALS, and introduce the effects of RNA binding proteins, ALS-related genes, and non-coding RNA as biomarkers on ALS. In addition, we also mention other ALS biomarkers such as serum uric acid (UA), cardiolipin (CL), chitotriosidase (CHIT1), and neurofilament light chain (NFL). Finally, we discuss the drug therapy, gene therapy, immunotherapy, and stem cell-exosomal therapy for ALS, attempting to find new therapeutic targets and strategies. A challenge is to study the various mechanisms of ALS as a syndrome. Biomarkers that have been widely explored are indispensable for the diagnosis, treatment, and prevention of ALS. Moreover, the development of new genes and targets is an urgent task in this field.}, }
@article {pmid34194298, year = {2021}, author = {Zhu, X and Zhang, Y and Yang, X and Hao, C and Duan, H}, title = {Gene Therapy for Neurodegenerative Disease: Clinical Potential and Directions.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {618171}, pmid = {34194298}, issn = {1662-5099}, abstract = {The pathogenesis of neurodegenerative diseases (NDDs) is complex and diverse. Over the decades, our understanding of NDD has been limited to pathological features. However, recent advances in gene sequencing have facilitated elucidation of NDD at a deeper level. Gene editing techniques have uncovered new genetic links to phenotypes, promoted the development of novel treatment strategies and equipped researchers with further means to construct effective cell and animal models. The current review describes the history of evolution of gene editing tools, with the aim of improving overall understanding of this technology, and focuses on the four most common NDD disorders to demonstrate the potential future applications and research directions of gene editing.}, }
@article {pmid34193885, year = {2021}, author = {Area-Gomez, E and Larrea, D and Yun, T and Xu, Y and Hupf, J and Zandkarimi, F and Chan, RB and Mitsumoto, H}, title = {Lipidomics study of plasma from patients suggest that ALS and PLS are part of a continuum of motor neuron disorders.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {13562}, pmid = {34193885}, issn = {2045-2322}, support = {R01 AG056387/AG/NIA NIH HHS/United States ; K01 AG045335/AG/NIA NIH HHS/United States ; R01 ES016348/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*blood ; Biomarkers/blood ; Female ; Humans ; *Lipidomics ; Lipids/*blood ; Male ; Middle Aged ; Prospective Studies ; }, abstract = {Motor neuron disorders (MND) include a group of pathologies that affect upper and/or lower motor neurons. Among them, amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle weakness, with fatal outcomes only in a few years after diagnosis. On the other hand, primary lateral sclerosis (PLS), a more benign form of MND that only affects upper motor neurons, results in life-long progressive motor dysfunction. Although the outcomes are quite different, ALS and PLS present with similar symptoms at disease onset, to the degree that both disorders could be considered part of a continuum. These similarities and the lack of reliable biomarkers often result in delays in accurate diagnosis and/or treatment. In the nervous system, lipids exert a wide variety of functions, including roles in cell structure, synaptic transmission, and multiple metabolic processes. Thus, the study of the absolute and relative concentrations of a subset of lipids in human pathology can shed light into these cellular processes and unravel alterations in one or more pathways. In here, we report the lipid composition of longitudinal plasma samples from ALS and PLS patients initially, and after 2 years following enrollment in a clinical study. Our analysis revealed common aspects of these pathologies suggesting that, from the lipidomics point of view, PLS and ALS behave as part of a continuum of motor neuron disorders.}, }
@article {pmid34191081, year = {2022}, author = {Aizawa, H and Kato, H and Oba, K and Kawahara, T and Okubo, Y and Saito, T and Naito, M and Urushitani, M and Tamaoka, A and Nakamagoe, K and Ishii, K and Kanda, T and Katsuno, M and Atsuta, N and Maeda, Y and Nagai, M and Nishiyama, K and Ishiura, H and Toda, T and Kawata, A and Abe, K and Yabe, I and Takahashi-Iwata, I and Sasaki, H and Warita, H and Aoki, M and Sobue, G and Mizusawa, H and Matsuyama, Y and Haga, T and Kwak, S}, title = {Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {269}, number = {2}, pages = {885-896}, pmid = {34191081}, issn = {1432-1459}, support = {CCT-B-2804//Japan Agency for Medical Research and Development/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Humans ; Nitriles ; Pyridones/adverse effects ; Treatment Outcome ; }, abstract = {OBJECTIVE: To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS).<br><br>METHODS: This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4&#xa0;mg perampanel, or 8&#xa0;mg perampanel daily for 48&#xa0;weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48&#xa0;weeks of treatment.<br><br>RESULTS: One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4&#xa0;mg perampanel (64%), and 7 of 21 patients randomized to 8&#xa0;mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [-&#xa0;8.4 (95% CI -&#xa0;13.9 to&#x2009;-&#x2009;2.9); p&#x2009;=&#x2009;0.015] between the placebo and the perampanel 8&#xa0;mg group, primarily due to worsening of the bulbar subscore in the perampanel 8&#xa0;mg group. Serious AEs were more frequent in the perampanel 8&#xa0;mg group than in the placebo group (p&#x2009;=&#x2009;0.0483).<br><br>CONCLUSIONS: Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8&#xa0;mg group.}, }
@article {pmid34187257, year = {2022}, author = {Bedlack, R and Barkhaus, P and Carter, G and Crayle, J and Mcdermott, C and Pattee, G and Polak, M and Salmon, K and Wicks, P}, title = {ALSUntangled #62: vitamin C.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {5-6}, pages = {476-479}, doi = {10.1080/21678421.2021.1946088}, pmid = {34187257}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; *Ascorbic Acid/therapeutic use ; Clinical Trials as Topic ; Dietary Supplements ; Humans ; Treatment Outcome ; *Vitamins/therapeutic use ; }, abstract = {Vitamin C is one of the most common supplements taken by people with ALS. As an antioxidant, it has a plausible mechanism for slowing disease progression and there are some flawed pre-clinical studies and case reports suggesting benefit. However, a small human trial showed no benefit. Given this negative trial, we do not currently advise vitamin C as an ALS treatment.}, }
@article {pmid34183988, year = {2021}, author = {Pervin, Z and Stephen, JM}, title = {Effect of alcohol on the central nervous system to develop neurological disorder: pathophysiological and lifestyle modulation can be potential therapeutic options for alcohol-induced neurotoxication.}, journal = {AIMS neuroscience}, volume = {8}, number = {3}, pages = {390-413}, pmid = {34183988}, issn = {2373-7972}, abstract = {The central nervous system (CNS) is the major target for adverse effects of alcohol and extensively promotes the development of a significant number of neurological diseases such as stroke, brain tumor, multiple sclerosis (MS), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Excessive alcohol consumption causes severe neuro-immunological changes in the internal organs including irreversible brain injury and it also reacts with the defense mechanism of the blood-brain barrier (BBB) which in turn leads to changes in the configuration of the tight junction of endothelial cells and white matter thickness of the brain. Neuronal injury associated with malnutrition and oxidative stress-related BBB dysfunction may cause neuronal degeneration and demyelination in patients with alcohol use disorder (AUD); however, the underlying mechanism still remains unknown. To address this question, studies need to be performed on the contributing mechanisms of alcohol on pathological relationships of neurodegeneration that cause permanent neuronal damage. Moreover, alcohol-induced molecular changes of white matter with conduction disturbance in neurotransmission are a likely cause of myelin defect or axonal loss which correlates with cognitive dysfunctions in AUD. To extend our current knowledge in developing a neuroprotective environment, we need to explore the pathophysiology of ethanol (EtOH) metabolism and its effect on the CNS. Recent epidemiological studies and experimental animal research have revealed the association between excessive alcohol consumption and neurodegeneration. This review supports an interdisciplinary treatment protocol to protect the nervous system and to improve the cognitive outcomes of patients who suffer from alcohol-related neurodegeneration as well as clarify the pathological involvement of alcohol in causing other major neurological disorders.}, }
@article {pmid34182408, year = {2021}, author = {van den Boom, M and Miller, KJ and Gregg, NM and Ojeda Valencia, G and Lee, KH and Richner, TJ and Ramsey, NF and Worrell, GA and Hermes, D}, title = {Typical somatomotor physiology of the hand is preserved in a patient with an amputated arm: An ECoG case study.}, journal = {NeuroImage. Clinical}, volume = {31}, number = {}, pages = {102728}, pmid = {34182408}, issn = {2213-1582}, support = {KL2 TR002379/TR/NCATS NIH HHS/United States ; R01 MH122258/MH/NIMH NIH HHS/United States ; R01 NS112144/NS/NINDS NIH HHS/United States ; R01 MH111417/MH/NIMH NIH HHS/United States ; R01 NS092882/NS/NINDS NIH HHS/United States ; }, mesh = {*Arm ; Electrocorticography ; Electroencephalography ; Hand ; Humans ; *Motor Cortex ; Movement ; }, abstract = {Electrophysiological signals in the human motor system may change in different ways after deafferentation, with some studies emphasizing reorganization while others propose retained physiology. Understanding whether motor electrophysiology is retained over longer periods of time can be invaluable for patients with paralysis (e.g. ALS or brainstem stroke) when signals from sensorimotor areas may be used for communication or control over neural prosthetic devices. In addition, a maintained electrophysiology can potentially benefit the treatment of phantom limb pains through prolonged use of these signals in a brain-machine interface (BCI). Here, we were presented with the unique opportunity to investigate the physiology of the sensorimotor cortex in a patient with an amputated arm using electrocorticographic (ECoG) measurements. While implanted with an ECoG grid for clinical evaluation of electrical stimulation for phantom limb pain, the patient performed attempted finger movements with the contralateral (lost) hand and executed finger movements with the ipsilateral (healthy) hand. The electrophysiology of the sensorimotor cortex contralateral to the amputated hand remained very similar to that of hand movement in healthy people, with a spatially focused increase of high-frequency band (65-175 Hz; HFB) power over the hand region and a distributed decrease in low-frequency band (15-28 Hz; LFB) power. The representation of the three different fingers (thumb, index and little) remained intact and HFB patterns could be decoded using support vector learning at single-trial classification accuracies of >90%, based on the first 1-3 s of the HFB response. These results indicate that hand representations are largely retained in the motor cortex. The intact physiological response of the amputated hand, the high distinguishability of the fingers and fast temporal peak are encouraging for neural prosthetic devices that target the sensorimotor cortex.}, }
@article {pmid34182195, year = {2021}, author = {Samara, VC and Jerant, P and Gibson, S and Bromberg, M}, title = {Bowel, bladder, and sudomotor symptoms in ALS patients.}, journal = {Journal of the neurological sciences}, volume = {427}, number = {}, pages = {117543}, doi = {10.1016/j.jns.2021.117543}, pmid = {34182195}, issn = {1878-5883}, mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; Constipation/epidemiology/etiology ; Humans ; Quality of Life ; *Urinary Bladder, Overactive/diagnosis/epidemiology/etiology ; }, abstract = {OBJECTIVES: To describe prevalence rates of bowel, bladder, and sudomotor symptoms in patients with amyotrophic lateral sclerosis (ALS) in relation to disease onset and progression. Treatment strategies and efficacies were also assessed.<br><br>METHODS: A pilot patient cohort revealed increased incidences of bowel/bladder and sudomotor symptoms. Questionnaires derived from formal bowel and bladder survey instruments were administered to a second cohort of patients during multidisciplinary ALS clinic visits.<br><br>RESULTS: The pilot cohort of 30 patients reported an increase in bowel symptoms from 17% prior to 70% after the diagnosis of ALS, and an increase in urinary symptoms from 24% to 76%. In the second cohort of 66 patients an increase in constipation from 33% prior to 64.7% after the diagnosis of ALS was reported. 25.4% of patients reported bowel urgency initially, which increased to 33.3% over time. Constipation was most commonly treated with docusate, dietary fiber supplementation, fluid/exercise, and polyethylene glycol. In the second cohort the prevalence of overactive bladder symptoms increased from 3.1% prior to 25.0% after the diagnosis of ALS. Urinary symptoms are most commonly treated with catheters and oxybutynin. A sudomotor survey found stinging eyes in 17.2% of patients, oily/greasy skin in 14.1% of patients, and flaking of the skin in 29.7% of patients.<br><br>CONCLUSIONS: Bowel and bladder symptoms are common in the ALS population and respond to treatment. Sudomotor symptoms are also common. Inquiring about these symptoms at clinic visits and initiating treatment can significantly improve the patients' quality of life.}, }
@article {pmid34179845, year = {2021}, author = {Mencattini, A and Spalloni, A and Casti, P and Comes, MC and Di Giuseppe, D and Antonelli, G and D'Orazio, M and Filippi, J and Corsi, F and Isambert, H and Di Natale, C and Longone, P and Martinelli, E}, title = {NeuriTES. Monitoring neurite changes through transfer entropy and semantic segmentation in bright-field time-lapse microscopy.}, journal = {Patterns (New York, N.Y.)}, volume = {2}, number = {6}, pages = {100261}, pmid = {34179845}, issn = {2666-3899}, abstract = {One of the most challenging frontiers in biological systems understanding is fluorescent label-free imaging. We present here the NeuriTES platform that revisits the standard paradigms of video analysis to detect unlabeled objects and adapt to the dynamic evolution of the phenomenon under observation. Object segmentation is reformulated using robust algorithms to assure regular cell detection and transfer entropy measures are used to study the inter-relationship among the parameters related to the evolving system. We applied the NeuriTES platform to the automatic analysis of neurites degeneration in presence of amyotrophic lateral sclerosis (ALS) and to the study of the effects of a chemotherapy drug on living prostate cancer cells (PC3) cultures. Control cells have been considered in both the two cases study. Accuracy values of 93% and of 92% are achieved, respectively. NeuriTES not only represents a tool for investigation in fluorescent label-free images but demonstrates to be adaptable to individual needs.}, }
@article {pmid34179015, year = {2021}, author = {Desole, C and Gallo, S and Vitacolonna, A and Montarolo, F and Bertolotto, A and Vivien, D and Comoglio, P and Crepaldi, T}, title = {HGF and MET: From Brain Development to Neurological Disorders.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {683609}, pmid = {34179015}, issn = {2296-634X}, abstract = {Hepatocyte growth factor (HGF) and its tyrosine kinase receptor, encoded by the MET cellular proto-oncogene, are expressed in the nervous system from pre-natal development to adult life, where they are involved in neuronal growth and survival. In this review, we highlight, beyond the neurotrophic action, novel roles of HGF-MET in synaptogenesis during post-natal brain development and the connection between deregulation of MET expression and developmental disorders such as autism spectrum disorder (ASD). On the pharmacology side, HGF-induced MET activation exerts beneficial neuroprotective effects also in adulthood, specifically in neurodegenerative disease, and in preclinical models of cerebral ischemia, spinal cord injuries, and neurological pathologies, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). HGF is a key factor preventing neuronal death and promoting survival through pro-angiogenic, anti-inflammatory, and immune-modulatory mechanisms. Recent evidence suggests that HGF acts on neural stem cells to enhance neuroregeneration. The possible therapeutic application of HGF and HGF mimetics for the treatment of neurological disorders is discussed.}, }
@article {pmid34175843, year = {2021}, author = {Cassina, P and Miquel, E and Martínez-Palma, L and Cassina, A}, title = {Glial Metabolic Reprogramming in Amyotrophic Lateral Sclerosis.}, journal = {Neuroimmunomodulation}, volume = {28}, number = {4}, pages = {204-212}, doi = {10.1159/000516926}, pmid = {34175843}, issn = {1423-0216}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Humans ; Motor Neurons ; Neuroglia ; Spinal Cord ; Superoxide Dismutase ; }, abstract = {ALS is a human neurodegenerative disorder that induces a progressive paralysis of voluntary muscles due to motor neuron loss. The causes are unknown, and there is no curative treatment available. Mitochondrial dysfunction is a hallmark of ALS pathology; however, it is currently unknown whether it is a cause or a consequence of disease progression. Recent evidence indicates that glial mitochondrial function changes to cope with energy demands and critically influences neuronal death and disease progression. Aberrant glial cells detected in the spinal cord of diseased animals are characterized by increased proliferation rate and reduced mitochondrial bioenergetics. These features can be compared with cancer cell behavior of adapting to nutrient microenvironment by altering energy metabolism, a concept known as metabolic reprogramming. We focus on data that suggest that aberrant glial cells in ALS undergo metabolic reprogramming and profound changes in glial mitochondrial activity, which are associated with motor neuron death in ALS. This review article emphasizes on the association between metabolic reprogramming and glial reactivity, bringing new paradigms from the area of cancer research into neurodegenerative diseases. Targeting glial mitochondrial function and metabolic reprogramming may result in promising therapeutic strategies for ALS.}, }
@article {pmid34169068, year = {2021}, author = {Ding, Q and Chaplin, J and Morris, MJ and Hilliard, MA and Wolvetang, E and Ng, DCH and Noakes, PG}, title = {TDP-43 Mutation Affects Stress Granule Dynamics in Differentiated NSC-34 Motoneuron-Like Cells.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {611601}, pmid = {34169068}, issn = {2296-634X}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is characterized by degeneration of motor neurons in the brain and spinal cord. Cytoplasmic inclusions of TDP-43 are frequently reported in motor neurons of ALS patients. TDP-43 has also been shown to associate with stress granules (SGs), a complex of proteins and mRNAs formed in response to stress stimuli that temporarily sequester mRNA translation. The effect of pathogenic TDP-43 mutations within glycine-rich regions (where the majority of ALS-causing TDP-43 mutations occur) on SG dynamics in motor neurons is poorly understood. To address this issue, we generated murine NSC-34 cell lines that stably over-express wild type TDP-43 (TDP-43 [W T]) or mutant forms (ALS-causing TDP-43 mutations TDP-43 [A315T] or TDP-43 [M337V]). We then differentiated these NSC-34 lines into motoneuron-like cells and evaluated SG formation and disassembly kinetics in response to oxidative or osmotic stress treatment. Wild type and mutant TDP-43 appeared to be largely retained in the nucleus following exposure to arsenite-induced oxidative stress. Upon arsenite removal, mutant TDP-43 clearly accumulated within HuR positive SGs in the cytoplasm, whereas TDP-43 [W T] remained mostly within the nucleus. 24 h following arsenite removal, all SGs were disassembled in both wild type and mutant TDP-43 expressing cells. By contrast, we observed significant differences in the dynamics of mutant TDP-43 association with SGs in response to hyperosmotic stress. Specifically, in response to sorbitol treatment, TDP-43 [W T] remained in the nucleus, whereas mutant TDP-43 relocalized to HuR positive SGs in the cytoplasm following exposure to sorbitol stress, resulting in a significant increase in TDP-43 SG numbers. These SGs remained assembled for 24 h following removal of sorbitol. Our data reveal that under certain stress conditions the rates of SG formation and disassembly is modulated by TDP-43 mutations associated with ALS, and suggest that this may be an early event in the seeding of insoluble cytoplasmic inclusions observed in ALS.}, }
@article {pmid34160014, year = {2021}, author = {Wall, JM and Basu, A and Zunica, ERM and Dubuisson, OS and Pergola, K and Broussard, JP and Kirwan, JP and Axelrod, CL and Johnson, AE}, title = {CRISPR/Cas9-engineered Drosophila knock-in models to study VCP diseases.}, journal = {Disease models &amp; mechanisms}, volume = {14}, number = {7}, pages = {}, pmid = {34160014}, issn = {1754-8411}, support = {K99 NS100988/NS/NINDS NIH HHS/United States ; R00 NS100988/NS/NINDS NIH HHS/United States ; R35 GM138116/GM/NIGMS NIH HHS/United States ; U54 GM104940/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Animals ; CRISPR-Cas Systems/genetics ; Cell Cycle Proteins/genetics/metabolism ; Disease Models, Animal ; *Drosophila ; Female ; Humans ; Male ; Mutation/genetics ; Valosin Containing Protein/genetics/metabolism ; }, abstract = {Mutations in Valosin Containing Protein (VCP) are associated with several degenerative diseases, including multisystem proteinopathy (MSP-1) and amyotrophic lateral sclerosis. However, patients with VCP mutations vary widely in their pathology and clinical penetrance, making it difficult to devise effective treatment strategies. A deeper understanding of how each mutation affects VCP function could enhance the prediction of clinical outcomes and design of personalized treatment options. The power of a genetically tractable model organism coupled with well-established in vivo assays and a relatively short life cycle make Drosophila an attractive system to study VCP disease pathogenesis. Using CRISPR/Cas9, we have generated individual Drosophila knock-in mutants that include nine hereditary VCP disease mutations. Our models display many hallmarks of VCP-mediated degeneration, including progressive decline in mobility, protein aggregate accumulation and defects in lysosomal and mitochondrial function. We also made some novel and unexpected findings, including nuclear morphology defects and sex-specific phenotypic differences in several mutants. Taken together, the Drosophila VCP disease models generated in this study will be useful for studying the etiology of individual VCP patient mutations and testing potential genetic and/or pharmacological therapies.}, }
@article {pmid34158851, year = {2021}, author = {Li, X and Chen, C and Zhan, X and Li, B and Zhang, Z and Li, S and Xie, Y and Song, X and Shen, Y and Liu, J and Liu, P and Liu, GP and Yang, X}, title = {R13 preserves motor performance in SOD1[G93A] mice by improving mitochondrial function.}, journal = {Theranostics}, volume = {11}, number = {15}, pages = {7294-7307}, pmid = {34158851}, issn = {1838-7640}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/enzymology/genetics/physiopathology ; Animals ; Central Nervous System/*enzymology ; Flavones/*pharmacology ; Humans ; Mice ; Mice, Transgenic ; *Mitochondria/enzymology/genetics ; *Motor Activity/drug effects/genetics ; *Superoxide Dismutase/genetics/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by death of motor neurons in the brain and spinal cord. However, so far, there is no effective treatment for ALS. Methods: In this study, R13, a prodrug of 7,8-dihydroxyflavone, selectively activating tyrosine kinase receptor B (TrkB) signaling pathway, was administered prophylactically to 40-day old SOD1[G93A] mice for 90 days. The motor performance was investigated by rotarod test, climbing-pole test, grip strength test and hanging endurance test. Afterwards, the spinal cord and medulla oblongata of 130-day old mice were harvested, and the proteomics revealed the effect of R13 on mouse protein expression profile. Astrocytes and microglial proliferation were assessed by immunohistochemical analysis. The number of motor neurons in the spinal cord is determined by Nissl staining. The effect of R13 on gastrocnemius morphology was assessed by HE staining. The effect of R13 on the survival rate was accomplished with worms stably expressing G93A SOD1. Results: Behavioral tests showed that R13 significantly attenuated abnormal motor performance of SOD1[G93A] mice. R13 reduced the advance of spinal motor neuron pathology and gastrocnemius muscle atrophy. The proliferation of microglia and astrocytes was reduced by R13 treatment. Mitochondriomics analysis revealed that R13 modified the mitochondrial protein expression profiles in the medulla oblongata and spinal cord of SOD1[G93A] mice, particularly promoting the expression of proteins related to oxidative phosphorylation (OXPHOS). Further study found that R13 activated AMPK/PGC-1α/Nrf1/Tfam, promoted mitochondrial biogenesis and ameliorated mitochondrial dysfunction. Lastly, R13 prolonged the survival rate of worms stably expressing G93A SOD1. Conclusions: These findings suggest oral R13 treatment slowed the advance of motor system disease in a reliable animal model of ALS, supporting that R13 might be useful for treating ALS.}, }
@article {pmid34156104, year = {2021}, author = {Serruya, MD and Rosenwasser, RH}, title = {An artificial nervous system to treat chronic stroke.}, journal = {Artificial organs}, volume = {45}, number = {8}, pages = {804-812}, doi = {10.1111/aor.13998}, pmid = {34156104}, issn = {1525-1594}, mesh = {Animals ; Brain-Computer Interfaces ; Chronic Disease ; Humans ; Nerve Transfer ; Neurofeedback ; Neuronal Plasticity ; Prostheses and Implants ; Recovery of Function ; Stroke Rehabilitation/*methods ; Wearable Electronic Devices ; }, abstract = {Despite remarkable advances in the treatment of numerous medical conditions, neurological disease and injury remains an outstanding challenge and cause of disability worldwide. The decreased regenerative capacity and extreme complexity and heterogeneity of nervous tissue, in particular the brain, and the fact that the brain remains the least understood organ, have hampered our ability to provide definitive treatments for prevalent conditions such as stroke. Stroke is the second-leading cause of death worldwide, and the nervous system is intimately involved in other prevalent conditions including ischemic heart disease, diabetes mellitus, and hypertension. Advances in neuromodulation, electroceuticals, microsurgical techniques, optogenetics, brain-computer interfaces, and autologous constructs offer potential solutions to address the otherwise permanent neurological deficits of stroke and other conditions. Here we review these various approaches to build an "artificial nervous system" that could restore function and independence in people living with these conditions. We focus on stroke both because it is the leading cause of neurological disability worldwide and because we anticipate that advances in the reversal of stroke-related deficits will have ripple effects benefiting people with other neurological conditions including spinal cord injury, traumatic brain injury, ALS, and muscular dystrophy.}, }
@article {pmid34153344, year = {2021}, author = {De Marchi, F and Munitic, I and Amedei, A and Berry, JD and Feldman, EL and Aronica, E and Nardo, G and Van Weehaeghe, D and Niccolai, E and Prtenjaca, N and Sakowski, SA and Bendotti, C and Mazzini, L}, title = {Interplay between immunity and amyotrophic lateral sclerosis: Clinical impact.}, journal = {Neuroscience and biobehavioral reviews}, volume = {127}, number = {}, pages = {958-978}, pmid = {34153344}, issn = {1873-7528}, support = {R01 ES030049/ES/NIEHS NIH HHS/United States ; R01 TS000289/TS/ATSDR CDC HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Humans ; Immune System ; *Neurodegenerative Diseases ; Positron-Emission Tomography ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease. Despite decades of research and many new insights into disease biology over the 150 years since the disease was first described, causative pathogenic mechanisms in ALS remain poorly understood, especially in sporadic cases. Our understanding of the role of the immune system in ALS pathophysiology, however, is rapidly expanding. The aim of this manuscript is to summarize the recent advances regarding the immune system involvement in ALS, with particular attention to clinical translation. We focus on the potential pathophysiologic mechanism of the immune system in ALS, discussing local and systemic factors (blood, cerebrospinal fluid, and microbiota) that influence ALS onset and progression in animal models and people. We also explore the potential of Positron Emission Tomography to detect neuroinflammation in vivo, and discuss ongoing clinical trials of therapies targeting the immune system. With validation in human patients, new evidence in this emerging field will serve to identify novel therapeutic targets and provide realistic hope for personalized treatment strategies.}, }
@article {pmid34145880, year = {2021}, author = {Matthews, DC and Mao, X and Dowd, K and Tsakanikas, D and Jiang, CS and Meuser, C and Andrews, RD and Lukic, AS and Lee, J and Hampilos, N and Shafiian, N and Sano, M and David Mozley, P and Fillit, H and McEwen, BS and Shungu, DC and Pereira, AC}, title = {Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer's disease.}, journal = {Brain : a journal of neurology}, volume = {144}, number = {12}, pages = {3742-3755}, pmid = {34145880}, issn = {1460-2156}, support = {R01 AG063819/AG/NIA NIH HHS/United States ; K76 AG054772/AG/NIA NIH HHS/United States ; R01 MH075895/MH/NIMH NIH HHS/United States ; UL1 TR001866/TR/NCATS NIH HHS/United States ; P50 AG005138/AG/NIA NIH HHS/United States ; R01 AG064020/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*drug therapy/metabolism ; Brain/*drug effects/metabolism ; Double-Blind Method ; Female ; Glucose/*metabolism ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Riluzole/*therapeutic use ; }, abstract = {Dysregulation of glutamatergic neural circuits has been implicated in a cycle of toxicity, believed among the neurobiological underpinning of Alzheimer's disease. Previously, we reported preclinical evidence that the glutamate modulator riluzole, which is FDA approved for the treatment of amyotrophic lateral sclerosis, has potential benefits on cognition, structural and molecular markers of ageing and Alzheimer's disease. The objective of this study was to evaluate in a pilot clinical trial, using neuroimaging biomarkers, the potential efficacy and safety of riluzole in patients with Alzheimer's disease as compared to placebo. A 6-month phase 2 double-blind, randomized, placebo-controlled study was conducted at two sites. Participants consisted of males and females, 50 to 95 years of age, with a clinical diagnosis of probable Alzheimer's disease, and Mini-Mental State Examination between 19 and 27. Ninety-four participants were screened, 50 participants who met inclusion criteria were randomly assigned to receive 50 mg riluzole (n = 26) or placebo (n = 24) twice a day. Twenty-two riluzole-treated and 20 placebo participants completed the study. Primary end points were baseline to 6 months changes in (i) cerebral glucose metabolism as measured with fluorodeoxyglucose-PET in prespecified regions of interest (hippocampus, posterior cingulate, precuneus, lateral temporal, inferior parietal, frontal); and (ii) changes in posterior cingulate levels of the neuronal viability marker N-acetylaspartate as measured with in vivo proton magnetic resonance spectroscopy. Secondary outcome measures were neuropsychological testing for correlation with neuroimaging biomarkers and in vivo measures of glutamate in posterior cingulate measured with magnetic resonance spectroscopy as a potential marker of target engagement. Measures of cerebral glucose metabolism, a well-established Alzheimer's disease biomarker and predictor of disease progression, declined significantly less in several prespecified regions of interest with the most robust effect in posterior cingulate, and effects in precuneus, lateral temporal, right hippocampus and frontal cortex in riluzole-treated participants in comparison to the placebo group. No group effect was found in measures of N-acetylaspartate levels. A positive correlation was observed between cognitive measures and regional cerebral glucose metabolism. A group × visit interaction was observed in glutamate levels in posterior cingulate, potentially suggesting engagement of glutamatergic system by riluzole. In vivo glutamate levels positively correlated with cognitive performance. These findings support our main primary hypothesis that cerebral glucose metabolism would be better preserved in the riluzole-treated group than in the placebo group and provide a rationale for more powered, longer duration studies of riluzole as a potential intervention for Alzheimer's disease.}, }
@article {pmid34139704, year = {2021}, author = {Parra-Cantu, C and Zaldivar-Ruenes, A and Martinez-Vazquez, M and Martinez, HR}, title = {Prevalence of Gastrointestinal Symptoms, Severity of Dysphagia, and Their Correlation with Severity of Amyotrophic Lateral Sclerosis in a Mexican Cohort.}, journal = {Neuro-degenerative diseases}, volume = {21}, number = {1-2}, pages = {42-47}, doi = {10.1159/000517613}, pmid = {34139704}, issn = {1660-2862}, mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; *Deglutition Disorders/diagnosis/epidemiology/etiology ; Disease Progression ; Humans ; Prevalence ; Quality of Life ; Severity of Illness Index ; }, abstract = {OBJECTIVES: Our study aimed to identify the prevalence and severity of gastrointestinal (GI) symptoms and dysphagia in patients with amyotrophic lateral sclerosis (ALS) and to assess whether a correlation exists between these symptoms and the severity of ALS progression.<br><br>METHODS: The presence and severity of GI symptoms and dysphagia were identified by means of the Gastrointestinal Symptom Rating Scale (GSRS) and the Functional Outcome Swallowing Scale (FOSS). The Revised ALS Functional Rating Scale (ALSFRS-R) was utilized to determine the severity of ALS. Analysis of data was performed with Spearman correlations in semi-qualitative variables of clinical scales. ALSFRS-R scores were divided into 2 categories: those with mild to moderate ALS (&#x2265;40-30 points) and patients with moderate to advanced ALS (29-&#x2264;20 points).<br><br>RESULTS: We studied 43 patients with definite ALS. The most frequent GI symptoms were constipation (60.5%), rectal tenesmus (57.5%), hard stools (55.0%), and borborygmus (42.5%). The moderate to advanced ALS stage was correlated with constipation (r = 0.334; p = 0.028), acid regurgitation (r = 0.384; p = 0.013), eructation (r = 0.334; p = 0.032), rectal tenesmus (r = 0.498; p = 0.001), and functional dysphagia (r = 0.656; p = <0.001).<br><br>CONCLUSIONS: Early detection of these GI symptoms can guide timely therapeutic decisions to avoid weight loss, a predictor for worse prognosis. This study highlights the relevance of the detection of these symptoms in ALS patients who score &#x2264;29 points in the ALSFRS-R scale to establish an appropriate treatment, prevent systemic complications, provide more comfort, and improve quality of life.}, }
@article {pmid34138531, year = {2021}, author = {Santur, K and Reinartz, E and Lien, Y and Tusche, M and Altendorf, T and Sevenich, M and Tamgüney, G and Mohrlüder, J and Willbold, D}, title = {Ligand-Induced Stabilization of the Native Human Superoxide Dismutase 1.}, journal = {ACS chemical neuroscience}, volume = {12}, number = {13}, pages = {2520-2528}, doi = {10.1021/acschemneuro.1c00253}, pmid = {34138531}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Ligands ; Motor Neurons ; Mutation/genetics ; *Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {A common characteristic of familial (fALS) and sporadic amyotrophic lateral sclerosis (sALS) is the accumulation of aberrant proteinaceous species in the motor neurons and spinal cord of ALS patients-including aggregates of the human superoxide dismutase 1 (hSOD1). hSOD1 is an enzyme that occurs as a stable dimeric protein with several post-translational modifications such as the formation of an intramolecular disulfide bond and the acquisition of metal cofactors that are essential for enzyme activity and further contribute to protein stability. Some mutations and/or destabilizing factors promote hSOD1 misfolding, causing neuronal death. Aggregates containing misfolded wild-type hSOD1 have been found in the spinal cords of sALS as well as in non-hSOD1 fALS patients, leading to the hypothesis that hSOD1 misfolding is a common part of the ALS pathomechanism. Therefore, stabilizing the native conformation of SOD1 may be a promising approach to prevent the formation of toxic hSOD1 species and thus ALS pathogenesis. Here, we present the 16-mer peptide S1VL-21 that interferes with hSOD1 aggregation. S1VL-21 was identified by phage display selection with the native conformation of hSOD1 as a target. Several methods such as microscale thermophoresis (MST) measurements, aggregation assays, and cell viability assays revealed that S1VL-21 has a micromolar binding affinity to native hSOD1 and considerably reduces the formation of hSOD1 aggregates. This present work therefore provides the first important data on a potential lead compound for hSOD1-related drug development for ALS therapy.}, }
@article {pmid34138412, year = {2022}, author = {De Nicola, AF and Meyer, M and Garay, L and Kruse, MS and Schumacher, M and Guennoun, R and Gonzalez Deniselle, MC}, title = {Progesterone and Allopregnanolone Neuroprotective Effects in the Wobbler Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Cellular and molecular neurobiology}, volume = {42}, number = {1}, pages = {23-40}, pmid = {34138412}, issn = {1573-6830}, support = {PIP 112 20120100016//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; 20020100100062//Universidad de Buenos Aires/ ; 2002010010008//Universidad de Buenos Aires/ ; PICT2012-0009//Ministry of Science and Technology/ ; PICT 2019 3292//Ministry of Science and Technology/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Animals ; Disease Models, Animal ; Mice ; Motor Neurons ; *Neuroprotective Agents/metabolism/pharmacology/therapeutic use ; Pregnanolone/metabolism/pharmacology/therapeutic use ; Progesterone/metabolism/pharmacology/therapeutic use ; Spinal Cord/metabolism ; }, abstract = {Progesterone regulates a number of processes in neurons and glial cells not directly involved in reproduction or sex behavior. Several neuroprotective effects are better observed under pathological conditions, as shown in the Wobbler mouse model of amyotrophic laterals sclerosis (ALS). Wobbler mice are characterized by forelimb atrophy due to motoneuron degeneration in the spinal cord, and include microgliosis and astrogliosis. Here we summarized current evidence on progesterone reversal of Wobbler neuropathology. We demonstrated that progesterone decreased motoneuron vacuolization with preservation of mitochondrial respiratory complex I activity, decreased mitochondrial expression and activity of nitric oxide synthase, increased Mn-dependent superoxide dismutase, stimulated brain-derived neurotrophic factor, increased the cholinergic phenotype of motoneurons, and enhanced survival with a concomitant decrease of death-related pathways. Progesterone also showed differential effects on glial cells, including increased oligodendrocyte density and downregulation of astrogliosis and microgliosis. These changes associate with reduced anti-inflammatory markers. The enhanced neurochemical parameters were accompanied by longer survival and increased muscle strength in tests of motor behavior. Because progesterone is locally metabolized to allopregnanolone (ALLO) in nervous tissues, we also studied neuroprotection by this derivative. Treatment of Wobbler mice with ALLO decreased oxidative stress and glial pathology, increased motoneuron viability and clinical outcome in a progesterone-like manner, suggesting that ALLO could mediate some progesterone effects in the spinal cord. In conclusion, the beneficial effects observed in different parameters support the versatile properties of progesterone and ALLO in a mouse model of motoneuron degeneration. The studies foresee future therapeutic opportunities with neuroactive steroids for deadly diseases like ALS.}, }
@article {pmid34131680, year = {2021}, author = {Zubair, A and Waheed, S and Shuja, F}, title = {Psychological impact of cadaveric dissection on first-year medical students.}, journal = {The journal of the Royal College of Physicians of Edinburgh}, volume = {51}, number = {2}, pages = {173-176}, doi = {10.4997/JRCPE.2021.419}, pmid = {34131680}, issn = {2042-8189}, mesh = {Anxiety/etiology ; Cadaver ; Cross-Sectional Studies ; Dissection ; Humans ; Pakistan ; Stress, Psychological/etiology ; *Students, Medical ; }, abstract = {BACKGROUND: This cross-sectional study was carried out to ascertain if first-time cadaver dissections can cause acute stress disorder (ASD) in medical students, and if death anxiety and gender play a role in the development of these symptoms.<br><br>METHODS: A total of 135 first-year medical students at the Services Institute of Medical Sciences and King Edward Medical University, Lahore, Pakistan, who had recently conducted their first ever cadaver dissection filled out three scales: the Impact of Event Scale-Revised (IES-R), the Appraisal of Life Scale (Revised) (ALS-R) and Death Anxiety Inventory. The results were then calculated via SPSS v.23. Any students with a history of psychiatric treatment or disorder were not included in the study.<br><br>RESULTS: Scores on the IES-R showed that the sample suffered from symptoms of ASD (mean = 36.15, standard deviation = 15.99). Multilinear regression showed that death anxiety did not predict any variance on the scores for IES-R, whereas higher scores on the ALS-R threat domain scale predicted higher scores on the IES-R. Death anxiety had little to no impact on the scores for IES-R.<br><br>CONCLUSIONS: Results showed that students who perceived the dissection situation as threatening and anxiety inducing were more likely to test positively for ASD symptoms. A major limitation of the study was that it did not measure whether these symptoms reduced with repeated exposure to cadaver dissection or how symptoms changed over time.}, }
@article {pmid34130902, year = {2021}, author = {Cullell, N and Cárcel-Márquez, J and Gallego-Fábrega, C and Muiño, E and Llucià-Carol, L and Lledós, M and Amaut, KEU and Krupinski, J and Fernández-Cadenas, I}, title = {Sleep/wake cycle alterations as a cause of neurodegenerative diseases: A Mendelian randomization study.}, journal = {Neurobiology of aging}, volume = {106}, number = {}, pages = {320.e1-320.e12}, doi = {10.1016/j.neurobiolaging.2021.05.008}, pmid = {34130902}, issn = {1558-1497}, mesh = {Alzheimer Disease ; Amyotrophic Lateral Sclerosis ; Female ; *Genome-Wide Association Study ; Humans ; Male ; Mendelian Randomization Analysis/*methods ; Neurodegenerative Diseases/*etiology/*genetics/physiopathology/psychology ; Parkinson Disease ; Risk ; Sleep/*physiology ; Sleepiness/*physiology ; Wakefulness/*physiology ; }, abstract = {Sleep and/or wake cycle alterations are common in neurodegenerative diseases (ND). Our aim was to determine whether there is a causal relationship between sleep and/or wake cycle patterns and ND (Parkinson's disease (PD) age at onset (AAO), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS)) using two-sample Mendelian Randomization (MR). We selected 12 sleep traits with available Genome-Wide Association Study (GWAS) to evaluate their causal relationship with the ND risk through Inverse-Variance Weighted regression as main analysis. We used as outcome the latest ND GWAS with available summary-statistics: PD-AAO (N = 17,996), AD (N = 21,235) and ALS (N = 40,136). MR results pointed to a causal effect of subjective and objective-measured morning chronotype on later PD-AAO (95%CI:0.33-1.81, p = 8.47×10[-09] and 95%CI:-7.28 to -4.44, p = 5.87×10[-16], respectively). Sleep efficiency was causally associated with a decreased AD risk (95%CI:-20.408 to -0.66, p = 0.04) and daytime sleepiness with an increased ALS risk (95%CI:0.15 to 1.61, p = 0.01). Our study suggests that sleep and/or wake patterns have causal relationship with ND. Given that sleep and/or wake patterns are modifiable risk factors, sleep interventions should be investigated as a potential treatment in PD-AAO, AD and ALS.}, }
@article {pmid34127438, year = {2021}, author = {López-Gómez, JJ and Ballesteros-Pomar, MD and Gómez-Hoyos, E and Pintor de la Maza, B and Penacho-Lázaro, M&#xc1; and Palacio-Mures, JM and Abreu-Padín, C and Sanz Gallego, I and de Luis-Román, DA}, title = {Effect of the type of specialized nutrition support on the course of the patient with amyotrophic lateral sclerosis (ALS). Interhospital registry SCLEDyN.}, journal = {Endocrinologia, diabetes y nutricion}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.endinu.2021.01.010}, pmid = {34127438}, issn = {2530-0180}, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which specialized nutritional support is essential. The objectives of our study were to describe nutritional support at the beginning of follow-up and its impact on anthropometry and survival.<br><br>METHODS: An interhospital registry was created for the hospitals of Castilla-Le&#xf3;n through a web platform designed for this purpose. An anamnesis was carried out on the evolution and nutritional history of the disease; and classical anthropometry was determined. The prescribed nutritional treatment was recorded. The parameters were measured at the beginning, at six and twelve months of nutritional follow-up.<br><br>RESULTS: A total of 93 patients [49 (52.7%) spinal; 44 (47.3%) bulbar)] were analyzed. The nutritional support route at the beginning was oral diet in 36 (38.7%) patients; oral nutritional supplementation (SON) in 46 (49.5%) patients; and in 11 (11.8%) patients percutaneous endoscopic gastrostomy (PEG). A decrease in the body mass index (BMI) was observed between the first and second visit [Start: 24.18 (3.29) kg/m2; 6 months: 23.69 (4.12) kg/m2; P<.05]. Less weight loss was observed at 6 months compared to the start of nutritional follow-up [Start: 8.09 (8.72)%; 6 months: 1.4 (6.29)%; P<.01]. 36 (38.7%) patients died but with no differences according to when nutritional support was started. Survival from the onset of symptoms was higher in the group of patients with artificial nutrition, although without reaching statistical significance [Oral: 28 (20.25) months; SON: 30 (16.75-48.25) months; PEG: 39 (27-52) months; P=.90].<br><br>CONCLUSIONS: Patients with ALS present a severe deterioration in nutritional status before the start of nutritional support. After the nutritional intervention, a slowdown in weight loss and nutritional deterioration was observed.}, }
@article {pmid34125534, year = {2021}, author = {P, P and Justin, A and Ananda Kumar, TD and Chinaswamy, M and Kumar, BRP}, title = {Glitazones Activate PGC-1α Signaling via PPAR-γ: A Promising Strategy for Antiparkinsonism Therapeutics.}, journal = {ACS chemical neuroscience}, volume = {12}, number = {13}, pages = {2261-2272}, doi = {10.1021/acschemneuro.1c00085}, pmid = {34125534}, issn = {1948-7193}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; PPAR gamma ; *Parkinson Disease/drug therapy ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Quality of Life ; *Thiazolidinediones ; }, abstract = {Understanding various aspects of Parkinson's disease (PD) by researchers could lead to a better understanding of the disease and provide treatment alternatives that could significantly improve the quality of life of patients suffering from neurodegenerative disorders. Significant progress has been made in recent years toward this goal, but there is yet no available treatment with confirmed neuroprotective effects. Recent studies have shown the potential of PPARγ agonists, which are the ligand activated transcriptional factor of the nuclear hormone superfamily, as therapeutic targets for various neurodegenerative disorders. The activation of central PGC-1α mediates the potential role against neurogenerative diseases like PD, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Further understanding the mechanism of neurodegeneration and the role of glitazones in the activation of PGC-1α signaling could lead to a novel therapeutic interventions against PD. Keeping this aspect in focus, the present review highlights the pathogenic mechanism of PD and the role of glitazones in the activation of PGC-1α via PPARγ for the treatment of neurodegenerative disorders.}, }
@article {pmid34122112, year = {2021}, author = {Zhu, FD and Hu, YJ and Yu, L and Zhou, XG and Wu, JM and Tang, Y and Qin, DL and Fan, QZ and Wu, AG}, title = {Nanoparticles: A Hope for the Treatment of Inflammation in CNS.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {683935}, pmid = {34122112}, issn = {1663-9812}, abstract = {Neuroinflammation, an inflammatory response within the central nervous system (CNS), is a main hallmark of common neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), among others. The over-activated microglia release pro-inflammatory cytokines, which induces neuronal death and accelerates neurodegeneration. Therefore, inhibition of microglia over-activation and microglia-mediated neuroinflammation has been a promising strategy for the treatment of neurodegenerative diseases. Many drugs have shown promising therapeutic effects on microglia and inflammation. However, the blood-brain barrier (BBB)-a natural barrier preventing brain tissue from contact with harmful plasma components-seriously hinders drug delivery to the microglial cells in CNS. As an emerging useful therapeutic tool in CNS-related diseases, nanoparticles (NPs) have been widely applied in biomedical fields for use in diagnosis, biosensing and drug delivery. Recently, many NPs have been reported to be useful vehicles for anti-inflammatory drugs across the BBB to inhibit the over-activation of microglia and neuroinflammation. Therefore, NPs with good biodegradability and biocompatibility have the potential to be developed as an effective and minimally invasive carrier to help other drugs cross the BBB or as a therapeutic agent for the treatment of neuroinflammation-mediated neurodegenerative diseases. In this review, we summarized various nanoparticles applied in CNS, and their mechanisms and effects in the modulation of inflammation responses in neurodegenerative diseases, providing insights and suggestions for the use of NPs in the treatment of neuroinflammation-related neurodegenerative diseases.}, }
@article {pmid34121923, year = {2021}, author = {Soar, J and Böttiger, BW and Carli, P and Couper, K and Deakin, CD and Djärv, T and Lott, C and Olasveengen, T and Paal, P and Pellis, T and Perkins, GD and Sandroni, C and Nolan, JP}, title = {[Adult advanced life support].}, journal = {Notfall &amp; rettungsmedizin}, volume = {24}, number = {4}, pages = {406-446}, pmid = {34121923}, issn = {1434-6222}, abstract = {These European Resuscitation Council Advanced Life Support guidelines are based on the 2020 International Consensus on Cardiopulmonary Resuscitation Science with Treatment Recommendations. This section provides guidelines on the prevention of and ALS treatments for both in-hospital cardiac arrest and out-of-hospital cardiac arrest.}, }
@article {pmid34118929, year = {2021}, author = {Milani, M and Mammarella, E and Rossi, S and Miele, C and Lattante, S and Sabatelli, M and Cozzolino, M and D'Ambrosi, N and Apolloni, S}, title = {Targeting S100A4 with niclosamide attenuates inflammatory and profibrotic pathways in models of amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {18}, number = {1}, pages = {132}, pmid = {34118929}, issn = {1742-2094}, support = {SpliceALS//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism ; Animals ; Animals, Genetically Modified ; Disease Models, Animal ; Fibroblasts/drug effects/metabolism ; Fibrosis/drug therapy/prevention &amp; control ; Humans ; Inflammation/drug therapy/prevention &amp; control ; Mice ; Mutation ; NF-kappa B/metabolism ; Niclosamide/*pharmacology/*therapeutic use ; RNA-Binding Protein FUS/genetics ; S100 Calcium-Binding Protein A4/*antagonists &amp; inhibitors/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {BACKGROUND: An increasing number of studies evidences that amyotrophic lateral sclerosis (ALS) is characterized by extensive alterations in different cell types and in different regions besides the CNS. We previously reported the upregulation in ALS models of a gene called fibroblast-specific protein-1 or S100A4, recognized as a pro-inflammatory and profibrotic factor. Since inflammation and fibrosis are often mutual-sustaining events that contribute to establish a hostile environment for organ functions, the comprehension of the elements responsible for these interconnected pathways is crucial to disclose novel aspects involved in ALS pathology.<br><br>METHODS: Here, we employed fibroblasts derived from ALS patients harboring the C9orf72 hexanucleotide repeat expansion and ALS patients with no mutations in known ALS-associated genes and we downregulated S100A4 using siRNA or the S100A4 transcriptional inhibitor niclosamide. Mice overexpressing human FUS were adopted to assess the effects of niclosamide in vivo on ALS pathology.<br><br>RESULTS: We demonstrated that S100A4 underlies impaired autophagy and a profibrotic phenotype, which characterize ALS fibroblasts. Indeed, its inhibition reduces inflammatory, autophagic, and profibrotic pathways in ALS fibroblasts, and interferes with different markers known as pathogenic in the disease, such as mTOR, SQSTM1/p62, STAT3, &#x3b1;-SMA, and NF-&#x3ba;B. Importantly, niclosamide in vivo treatment of ALS-FUS mice reduces the expression of S100A4, &#x3b1;-SMA, and PDGFR&#x3b2; in the spinal cord, as well as gliosis in central and peripheral nervous tissues, together with axonal impairment and displays beneficial effects on muscle atrophy, by promoting muscle regeneration and reducing fibrosis.<br><br>CONCLUSION: Our findings show that S100A4 has a role in ALS-related mechanisms, and that drugs such as niclosamide which are able to target inflammatory and fibrotic pathways could represent promising pharmacological tools for ALS.}, }
@article {pmid34118305, year = {2021}, author = {Yang, S and Yang, H and Luo, Y and Deng, X and Zhou, Y and Hu, B}, title = {Long non-coding RNAs in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {148}, number = {}, pages = {105096}, doi = {10.1016/j.neuint.2021.105096}, pmid = {34118305}, issn = {1872-9754}, mesh = {Animals ; Biomarkers ; Humans ; Neurodegenerative Diseases/diagnosis/*genetics/therapy ; RNA, Long Noncoding/drug effects/*genetics ; }, abstract = {Neurodegenerative diseases are gradually becoming the main burden of society. The morbidity and mortality caused by neurodegenerative diseases remain significant health-care concerns. For most neurodegenerative diseases, there are no effective treatments. Over the past few decades, in a quest to exploit efficacious disease-modifying therapies for the treatment of neurodegenerative diseases, disease mechanisms, reliable biomarkers and therapeutic targets have become a research priority. At present, lncRNA is an area with potential research value. In this article, we first summarize some of the existing results of research into lncRNAs, including origin, molecular characteristics, location types, and functional types. We then introduce the possible functions of lncRNAs in different neurodegenerative diseases. Furthermore, some lncRNAs which show promise as biomarkers or potential therapeutic targets are systematically summarized.}, }
@article {pmid34115761, year = {2021}, author = {Sofela, S and Sahloul, S and Song, YA}, title = {Biophysical analysis of drug efficacy on C. elegans models for neurodegenerative and neuromuscular diseases.}, journal = {PloS one}, volume = {16}, number = {6}, pages = {e0246496}, pmid = {34115761}, issn = {1932-6203}, mesh = {*Caenorhabditis elegans/drug effects ; Animals ; *Disease Models, Animal ; *Neuromuscular Diseases/drug therapy/genetics ; Drug Evaluation, Preclinical/methods ; Neurodegenerative Diseases/drug therapy ; Muscular Dystrophy, Duchenne/drug therapy/genetics/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/pathology/genetics ; Humans ; Parkinson Disease/drug therapy ; }, abstract = {Caenorhabditis elegans has emerged as a powerful model organism for drug screening due to its cellular simplicity, genetic amenability and homology to humans combined with its small size and low cost. Currently, high-throughput drug screening assays are mostly based on image-based phenotyping with the focus on morphological-descriptive traits not exploiting key locomotory parameters of this multicellular model with muscles such as its thrashing force, a critical biophysical parameter when screening drugs for muscle-related diseases. In this study, we demonstrated the use of a micropillar-based force assay chip in combination with a fluorescence assay to evaluate the efficacy of various drugs currently used in treatment of neurodegenerative and neuromuscular diseases. Using this two-dimensional approach, we showed that the force assay was generally more sensitive in measuring efficacy of drug treatment in Duchenne Muscular Dystrophy and Parkinson's Disease mutant worms as well as partly in Amyotrophic Lateral Sclerosis model. These results underline the potential of our force assay chip in screening of potential drug candidates for the treatment of neurodegenerative and neuromuscular diseases when combined with a fluorescence assay in a two-dimensional analysis approach.}, }
@article {pmid34114267, year = {2021}, author = {Essendoubi, M and Alsamad, F and Noël, P and Meunier, M and Scandolera, A and Sandré, J and Manfait, M and Gobinet, C and Reynaud, R and Piot, O}, title = {Combining Raman imaging and MCR-ALS analysis for monitoring retinol permeation in human skin.}, journal = {Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)}, volume = {27}, number = {6}, pages = {1100-1109}, doi = {10.1111/srt.13069}, pmid = {34114267}, issn = {1600-0846}, mesh = {Humans ; Least-Squares Analysis ; Multivariate Analysis ; *Skin/diagnostic imaging ; Spectrum Analysis, Raman ; *Vitamin A ; }, abstract = {BACKGROUND: Monitoring the transcutaneous permeation of exogenous molecules using conventional techniques generally requires long pre-analytical preparation or labelling of samples. However, Raman spectroscopy is a label-free and non-destructive method which provides spatial distribution of tracked actives in skin. The aim of our study was to prove the interest of Raman imaging coupled with multivariate curve resolution alternating least square (MCR-ALS) analysis in monitoring retinol penetration into frozen and living human skin.<br><br>MATERIALS AND METHODS: After topical treatment of skin samples by free or encapsulated retinol, thin cross sections were analysed by Raman imaging (up to 100&#xa0;&#xb5;m depth). Mann-Whitney test was used to identify retinol spectroscopic markers in skin. MCR-ALS was used to estimate retinol contribution in Raman spectral images. Heat maps were constructed to compare the distribution of free and encapsulated retinol in skin models.<br><br>RESULTS: We identified the bands at 1158, 1196 and 1591&#xa0;cm[-1] as specific features for monitoring retinol in skin. Moreover, our MCR-ALS results showed an improvement of retinol penetration (up to 30&#xa0;&#xb5;m depth) with the encapsulated form as well as storage reservoir formation in stratum corneum, for each skin model. Finally, greater retinol penetration into living skin was observed.<br><br>CONCLUSION: This study shows a proof of concept for the evaluation of retinol penetration in skin using Raman imaging coupled with MCR-ALS. This concept needs to be validated on more subjects to include inter-individual variability but also other factors affecting skin permeation (age, sex, pH, etc). Our study can be extended to other actives.}, }
@article {pmid34112310, year = {2021}, author = {Wang, X and Huang, S and Xia, Z and Yao, S and Xia, H}, title = {[Application progress of ultrasound monitoring of diaphragm function in clinic].}, journal = {Zhonghua wei zhong bing ji jiu yi xue}, volume = {33}, number = {5}, pages = {638-640}, doi = {10.3760/cma.j.cn121430-20200824-00591}, pmid = {34112310}, issn = {2095-4352}, mesh = {Airway Extubation ; Critical Care ; *Diaphragm/diagnostic imaging ; Humans ; *Respiration, Artificial ; Ultrasonography ; }, abstract = {In recent years, point of care ultrasound (POCUS) has developed rapidly in the fields of anesthesia and critical care. POCUS is widely used in clinic to monitor the function of human tissues and organs such as the heart, lungs, and diaphragm due to its visual, non-invasive, portable, and repeatable characters at the bedside. Diaphragm is an important structure to maintain respiratory function. Diaphragm paralysis or dysfunction can cause a significant decrease in inspiratory function. The patient's diaphragm function can be assessed through monitoring diaphragm thickness and activity by POCUS, and combined with other clinical indicators, the patient's recovery of respiratory function can be comprehensively evaluated, and rapidly identify the pathological conditions, such as diaphragm paralysis, diaphragm atrophy, diaphragmatic hypoplasia and amyotrophic lateral sclerosis. Dynamic evaluation of the process from diaphragmatic dysfunction to recovery can provide guidance for weaning and extubation, and real-time feedback on the treatment effect. This article reviews the ultrasound evaluation methods and clinical applications to the diaphragm, in order to guide clinicians to use relevant indicators to comprehensively evaluate the structure and function of the diaphragm, and then diagnose and treat diaphragm dysfunction, which may help making clinical decision.}, }
@article {pmid34111668, year = {2021}, author = {Matsuo, T and Adachi-Tominari, K and Sano, O and Kamei, T and Nogami, M and Ogi, K and Okano, H and Yano, M}, title = {Involvement of ferroptosis in human motor neuron cell death.}, journal = {Biochemical and biophysical research communications}, volume = {566}, number = {}, pages = {24-29}, doi = {10.1016/j.bbrc.2021.05.095}, pmid = {34111668}, issn = {1090-2104}, mesh = {Antioxidants/pharmacology ; *Cell Death/drug effects ; Cell Line ; Enzyme Inhibitors/pharmacology ; *Ferroptosis/drug effects ; Humans ; Motor Neurons/*cytology/drug effects ; Phospholipid Hydroperoxide Glutathione Peroxidase/antagonists &amp; inhibitors ; }, abstract = {Ferroptosis was recently defined as a novel type of programmed cell death depending on iron and lipid peroxidation. It is biologically different from other types of cell death such as apoptosis. While the involvement of ferroptosis in cancer, patient and animal model have been intensely studied, ferroptosis in human motor neuron model is still clearly unknown. Here we carefully assessed ferroptosis using human iPS cell-derived motor neuron (hiMNs). We found that almost all hiMNs died by the treatment of glutathione peroxidase 4 (GPX4) inhibitors. Importantly, the cell death was rescued by one antioxidant, vitamin E acetate, iron chelators and lipid peroxidase inhibitors with high dynamic ranges. Finally, these data clearly indicated that ferroptosis constitutively occurs in hiMNs, suggesting the possibility that it might play a biologically and pathologically important roles in motor neuron death such as motor neuron disease (MND)/Amyotrophic lateral sclerosis (ALS).}, }
@article {pmid34102977, year = {2021}, author = {Kulkarni, NP and Vaidya, B and Narula, AS and Sharma, SS}, title = {Neuroprotective Potential of Caffeic Acid Phenethyl Ester (CAPE) in CNS Disorders: Mechanistic and Therapeutic Insights.}, journal = {Current neuropharmacology}, volume = {19}, number = {9}, pages = {1401-1415}, pmid = {34102977}, issn = {1875-6190}, support = {2019-2020-NPLC-SSSHARMA//Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, India/ ; }, mesh = {Aged ; Anti-Inflammatory Agents ; Antioxidants/pharmacology/therapeutic use ; *Caffeic Acids/pharmacology/therapeutic use ; Humans ; *Phenylethyl Alcohol/analogs &amp; derivatives/pharmacology/therapeutic use ; }, abstract = {Neurological disorders like Alzheimer's disease (AD), Parkinson's disease (PD), stroke, amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), epilepsy, traumatic brain injury (TBI), depression, and anxiety are responsible for thousands of deaths worldwide every year. With the increase in life expectancy, there has been a rise in the prevalence of these disorders. Age is one of the major risk factors for these neurological disorders, and with the aged population set to rise to 1.25 billion by 2050, there is a growing concern to look for new therapeutic molecules to treat age-related diseases. Caffeic acid phenethyl ester (CAPE) is a molecule obtained from a number of botanical sources, such as the bark of conifer trees as well as propolis which is extracted from beehives. Though CAPE remains relatively unexplored in human trials, it possesses antioxidant, anti-inflammatory, antimitogenic, and anti-cancer activities, as shown by preclinical studies. Apart from this, it also exhibits tremendous potential for the treatment of neurological disorders through the modulation of multiple molecular pathways and attenuation of behavioural deficits. In the present article, we have reviewed the therapeutic potential of CAPE and its mechanisms in the treatment of neurological disorders.}, }
@article {pmid34101918, year = {2022}, author = {Shaat, MA and Bakry, NS and Elshafie, AM and Talaat, DM}, title = {Intranasal versus sublingual route of dexmedetomidine sedation in paediatric dentistry: A randomized controlled clinical trial.}, journal = {International journal of paediatric dentistry}, volume = {32}, number = {2}, pages = {232-239}, doi = {10.1111/ipd.12848}, pmid = {34101918}, issn = {1365-263X}, mesh = {Administration, Intranasal ; Child ; Conscious Sedation ; *Dexmedetomidine ; Humans ; Hypnotics and Sedatives ; Pediatric Dentistry ; }, abstract = {BACKGROUND: Many children experience dental anxiety during dental treatment. Conscious sedation is used to alleviate anxiety and enhance a child's cooperation.<br><br>AIM: This study aimed to compare the efficacy of intranasal versus sublingual dexmedetomidine.<br><br>DESIGN: Forty-two healthy, uncooperative children participated in the study. They were divided randomly into two groups: In the first visit, Group I received intranasal dexmedetomidine and group II received sublingual dexmedetomidine, whereas at the second visit, the alternate route was implemented in a crossover design. The child's acceptance of drug administration method was assessed using a 4-point rating scale. Time until optimum sedation was measured. Anxiety during local anesthesia administration was scored using Venham's rating scale. Postoperative response was recorded through Vernon et al's questionnaire.<br><br>RESULTS: The sublingual dexmedetomidine route was better accepted than the intranasal route (P=0.01), while the latter acted faster (P>0.001). No significant difference in anxiety scores was found between groups at baseline (P=0.84) or during local anesthetic administration (P=0.44). No negative effect was recorded by the parents who answered the Modified Vernon et al questionnaire 24 hour after the dental visit compared to before the dental visit (P=1.00).<br><br>CONCLUSIONS: Both routes prevented the increase in anxiety scores equally during local anesthesia and do not have negative effect on postoperative behavior of children. However, the sublingual route showed better acceptance with longer onset time of action than the intranasal route.}, }
@article {pmid34099897, year = {2021}, author = {Moujalled, D and Strasser, A and Liddell, JR}, title = {Molecular mechanisms of cell death in neurological diseases.}, journal = {Cell death and differentiation}, volume = {28}, number = {7}, pages = {2029-2044}, pmid = {34099897}, issn = {1476-5403}, support = {101671/WT_/Wellcome Trust/United Kingdom ; 1020363//Department of Health | National Health and Medical Research Council (NHMRC)/ ; 101671/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; *Autophagy ; Brain/pathology/*physiopathology ; Humans ; Neurodegenerative Diseases/pathology/*physiopathology/therapy ; Neurons/*pathology ; *Regulated Cell Death ; Signal Transduction ; }, abstract = {Tightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, and Huntington's disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.}, }
@article {pmid34092572, year = {2021}, author = {Okita, Y and Narita, Y}, title = {[Significance of Quality of Life Evaluation for Glioma Patients].}, journal = {No shinkei geka. Neurological surgery}, volume = {49}, number = {3}, pages = {660-664}, doi = {10.11477/mf.1436204440}, pmid = {34092572}, issn = {0301-2603}, mesh = {*Glioma/therapy ; Humans ; *Quality of Life ; }, abstract = {Typically, overall and progression-free survival are used as endpoints in clinical tri-als investigating gliomas, while health-related quality of life(HRQOL)plays a key role in cancer research and may be useful for individual patient care. Previous studies have shown that HRQOL parameters can serve as independent prognostic factors for survival in patients with cancer, while recent studies have highlighted the usefulness of HRQOL in information management and decision-making in cancer treatment. However, a few studies have shown differences between patients' and physicians' perceptions of cancer treatment. In the future, physicians will be expected to recog-nize the importance of the QOL evaluation tool, not only in clinical trials, but also in general practice for gliomas, considering the characteristics of patients with brain tu-mors. In this study, we reviewed the methods of major HRQOL evaluation and sum-marized the first clinical trials incorporating QOL in glioma treatment.}, }
@article {pmid34084973, year = {2021}, author = {Sadanandan, N and Lee, JY and Garbuzova-Davis, S}, title = {Extracellular vesicle-based therapy for amyotrophic lateral sclerosis.}, journal = {Brain circulation}, volume = {7}, number = {1}, pages = {23-28}, pmid = {34084973}, issn = {2455-4626}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) stands as a neurodegenerative disorder characterized by the rapid progression of motor neuron loss in the brain and spinal cord. Unfortunately, treatment options for ALS are limited, and therefore, novel therapies that prevent further motor neuron degeneration are of dire need. In ALS, the infiltration of pathological elements from the blood to the central nervous system (CNS) compartment that spur motor neuron damage may be prevented via restoration of the impaired blood-CNS-barrier. Transplantation of human bone marrow endothelial progenitor cells (hBM-EPCs) demonstrated therapeutic promise in a mouse model of ALS due to their capacity to mitigate the altered blood-CNS-barrier by restoring endothelial cell (EC) integrity. Remarkably, the hBM-EPCs can release angiogenic factors that endogenously ameliorate impaired ECs. In addition, these cells may produce extracellular vesicles (EVs) that carry a wide range of vesicular factors, which aid in alleviating EC damage. In an in vitro study, hBM-EPC-derived EVs were effectively uptaken by the mouse brain endothelial cells (mBECs) and cell damage was significantly attenuated. Interestingly, the incorporation of EVs into mBECs was inhibited via β1 integrin hindrance. This review explores preclinical studies of the therapeutic potential of hBM-EPCs, specifically via hBM-EPC-derived EVs, for the repair of the damaged blood-CNS-barrier in ALS as a novel treatment approach.}, }
@article {pmid34075589, year = {2021}, author = {Milligan, C and Atassi, N and Babu, S and Barohn, RJ and Caress, JB and Cudkowicz, ME and Evora, A and Hawkins, GA and Wosiski-Kuhn, M and Macklin, EA and Shefner, JM and Simmons, Z and Bowser, RP and Ladha, SS}, title = {Tocilizumab is safe and tolerable and reduces C-reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients.}, journal = {Muscle &amp; nerve}, volume = {64}, number = {3}, pages = {309-320}, pmid = {34075589}, issn = {1097-4598}, support = {UL1 TR001420/TR/NCATS NIH HHS/United States ; UL1 TR002366/TR/NCATS NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/*drug therapy ; Anti-Inflammatory Agents/*adverse effects/therapeutic use ; Antibodies, Monoclonal, Humanized/*adverse effects/therapeutic use ; Biomarkers/blood/cerebrospinal fluid ; C-Reactive Protein/*metabolism ; Cytokines/blood/cerebrospinal fluid/*metabolism ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Treatment Outcome ; Young Adult ; }, abstract = {INTRODUCTION/AIMS: We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients.<br><br>METHODS: Twenty-two participants, whose peripheral blood mononuclear cell (PBMC) gene expression profile reflected high messenger ribonucleic acid (mRNA) expression of inflammatory markers, were randomized 2:1 to three tocilizumab or placebo treatments (weeks 0, 4, and 8; 8&#xa0;mg/kg intravenous). Participants were followed every 4&#xa0;wk in a double-blind fashion for 16&#x2009;wk and assessed for safety, tolerability, plasma inflammatory markers, and clinical measures. Cerebrospinal fluid (CSF) was collected at baseline and after the third treatment. Participants were genotyped for Asp[358] Ala polymorphism of the interleukin 6 receptor (IL-6R) gene.<br><br>RESULTS: Baseline characteristics, safety, and tolerability were similar between treatment groups. One serious adverse event was reported in the placebo group; no deaths occurred. Mean plasma C-reactive protein (CRP) level decreased by 88% in the tocilizumab group and increased by 4% in the placebo group (-3.0-fold relative change, P&#x2009;<&#x2009;.001). CSF CRP reduction (-1.8-fold relative change, P&#xa0;=&#xa0;.01) was associated with IL-6R C allele count. No differences in PBMC gene expression or clinical measures were observed between groups.<br><br>DISCUSSION: Tocilizumab treatment was safe and well tolerated. PBMC gene expression profile was inadequate as a predictive or pharmacodynamic biomarker. Treatment reduced CRP levels in plasma and CSF, with CSF effects potentially dependent on IL-6R Asp[358] Ala genotype. IL-6 trans-signaling may mediate a distinct central nervous system response in individuals inheriting the IL-6R C allele. These results warrant further study in ALS patients where IL-6R genotype and CRP levels may be useful enrichment biomarkers.}, }
@article {pmid34075522, year = {2021}, author = {Minj, E and Upadhayay, S and Mehan, S}, title = {Nrf2/HO-1 Signaling Activator Acetyl-11-keto-beta Boswellic Acid (AKBA)-Mediated Neuroprotection in Methyl Mercury-Induced Experimental Model of ALS.}, journal = {Neurochemical research}, volume = {46}, number = {11}, pages = {2867-2884}, pmid = {34075522}, issn = {1573-6903}, mesh = {Amyotrophic Lateral Sclerosis/chemically induced/*metabolism/prevention &amp; control ; Animals ; Female ; Heme Oxygenase (Decyclizing)/*metabolism ; Male ; Methylmercury Compounds/*toxicity ; NF-E2-Related Factor 2/*metabolism ; Neuroprotection/*drug effects/physiology ; Rats ; Rats, Wistar ; Signal Transduction/drug effects/physiology ; Triterpenes/pharmacology/*therapeutic use ; }, abstract = {Methylmercury (MeHg) is a potent neurotoxin that causes neurotoxicity and neuronal cell death. MeHg exposure also leads to oligodendrocyte destruction, glial cell overactivation, and demyelination of motor neurons in the motor cortex and spinal cord. As a result, MeHg plays an important role in the progression of amyotrophic lateral sclerosis (ALS)-like neurocomplications. ALS is a fatal neurodegenerative disorder in which neuroinflammation is the leading cause of further CNS demyelination. Nuclear factor erythroid-2-related factor-2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling pathway was thought to be a potential target for neuroprotection in ALS. Acetyl-11-keto-beta-boswellic acid (AKBA) is a multi-component pentacyclic triterpenoid mixture derived from Boswellia serrata with anti-inflammatory and antioxidant properties. The research aimed to investigate whether AKBA, as a Nrf2 / HO-1 activator, can provide protection against ALS. Thus, we explored the role of AKBA on the Nrf2/HO-1 signaling pathway in a MeHg-induced experimental ALS model. In this study, ALS was induced in Wistar rats by oral gavage of MeHg 5 mg/kg for 21 days. An open field test, force swim test, and grip strength were performed to observe experimental rats' motor coordination behaviors. In contrast, a morris water maze was performed for learning and memory. Administration of AKBA 50 mg/kg and AKBA 100 mg/kg continued from day 22 to 42. Neurochemical parameters were evaluated in the rat's brain homogenate. In the meantime, post-treatment with AKBA significantly improved behavioral, neurochemical, and gross pathological characteristics in the brain of rats by increasing the amount of Nrf2/HO-1 in brain tissue. Collectively, our findings indicated that AKBA could potentially avoid demyelination and encourage remyelination.}, }
@article {pmid34073630, year = {2021}, author = {Malacarne, C and Galbiati, M and Giagnorio, E and Cavalcante, P and Salerno, F and Andreetta, F and Cagnoli, C and Taiana, M and Nizzardo, M and Corti, S and Pensato, V and Venerando, A and Gellera, C and Fenu, S and Pareyson, D and Masson, R and Maggi, L and Dalla Bella, E and Lauria, G and Mantegazza, R and Bernasconi, P and Poletti, A and Bonanno, S and Marcuzzo, S}, title = {Dysregulation of Muscle-Specific MicroRNAs as Common Pathogenic Feature Associated with Muscle Atrophy in ALS, SMA and SBMA: Evidence from Animal Models and Human Patients.}, journal = {International journal of molecular sciences}, volume = {22}, number = {11}, pages = {}, pmid = {34073630}, issn = {1422-0067}, support = {2015-2020//Italian Ministry of Health/ ; 2015-0023//FRRB TRANS-ALS/ ; 2017-1886//CARIPLO/ ; GGP14039 AND GGP19128//FONDAZIONE TELETHON/ ; ALS-HSPB8, ALS-GRANULOPATHY, MLOPATHY, TARGET-RAN//FONDAZIONE ARISLA/ ; 2015LFPNMN, 2017 F2A2C5//PRIN-PROGETTI DI RICERCA DI INTARESSE NAZIONALE/ ; PROGETTO DIPARTIMENTI DI ECCELLENZA//ITALIAN MINISTRY OF UNIVERSITY AND RESEARCH/ ; }, mesh = {Amino Acid Substitution ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; *Bulbo-Spinal Atrophy, X-Linked/genetics/metabolism ; Humans ; Mice ; Mice, Transgenic ; *MicroRNAs/genetics/metabolism ; *Mutation, Missense ; *Superoxide Dismutase/genetics/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Motor neuron diseases (MNDs) are neurodegenerative disorders characterized by upper and/or lower MN loss. MNDs include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). Despite variability in onset, progression, and genetics, they share a common skeletal muscle involvement, suggesting that it could be a primary site for MND pathogenesis. Due to the key role of muscle-specific microRNAs (myomiRs) in skeletal muscle development, by real-time PCR we investigated the expression of miR-206, miR-133a, miR-133b, and miR-1, and their target genes, in G93A-SOD1 ALS, Δ7SMA, and KI-SBMA mouse muscle during disease progression. Further, we analyzed their expression in serum of SOD1-mutated ALS, SMA, and SBMA patients, to demonstrate myomiR role as noninvasive biomarkers. Our data showed a dysregulation of myomiRs and their targets, in ALS, SMA, and SBMA mice, revealing a common pathogenic feature associated with muscle impairment. A similar myomiR signature was observed in patients' sera. In particular, an up-regulation of miR-206 was identified in both mouse muscle and serum of human patients. Our overall findings highlight the role of myomiRs as promising biomarkers in ALS, SMA, and SBMA. Further investigations are needed to explore the potential of myomiRs as therapeutic targets for MND treatment.}, }
@article {pmid34071187, year = {2021}, author = {Dharmadasa, T}, title = {Cortical Excitability across the ALS Clinical Motor Phenotypes.}, journal = {Brain sciences}, volume = {11}, number = {6}, pages = {}, pmid = {34071187}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by its marked clinical heterogeneity. Although the coexistence of upper and lower motor neuron signs is a common clinical feature for most patients, there is a wide range of atypical motor presentations and clinical trajectories, implying a heterogeneity of underlying pathogenic mechanisms. Corticomotoneuronal dysfunction is increasingly postulated as the harbinger of clinical disease, and neurophysiological exploration of the motor cortex in vivo using transcranial magnetic stimulation (TMS) has suggested that motor cortical hyperexcitability may be a critical pathogenic factor linked to clinical features and survival. Region-specific selective vulnerability at the level of the motor cortex may drive the observed differences of clinical presentation across the ALS motor phenotypes, and thus, further understanding of phenotypic variability in relation to cortical dysfunction may serve as an important guide to underlying disease mechanisms. This review article analyses the cortical excitability profiles across the clinical motor phenotypes, as assessed using TMS, and explores this relationship to clinical patterns and survival. This understanding will remain essential to unravelling central disease pathophysiology and for the development of specific treatment targets across the ALS clinical motor phenotypes.}, }
@article {pmid34067277, year = {2021}, author = {Soll, M and Goldshtein, H and Rotkopf, R and Russek-Blum, N and Gross, Z}, title = {A Synthetic SOD/Catalase Mimic Compound for the Treatment of ALS.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {6}, pages = {}, pmid = {34067277}, issn = {2076-3921}, support = {2026143//Israel Science Foundation/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. To date, the etiology of the disease is still unclear, with evidence of reactive oxygen species, mitochondrial dysfunction, iron homeostasis perturbation, protein misfolding and protein aggregation as key players in the pathology of the disease. Twenty percent of familial ALS and two percent of sporadic ALS instances are due to a mutation in Cu/Zn superoxide dismutase (SOD1). Sporadic and familial ALS affects the same neurons with similar pathology; therefore, the underlying hypothesis is that therapies effective in mutant SOD1 models could be translated to sporadic ALS. Corrole metal complexes have lately been identified as strong and potent catalytic antioxidants with beneficial effects in oxidative stress-related diseases such as Parkinson's disease, Alzheimer's disease, atherosclerosis, diabetes and its complications. One of the most promising candidates is the iron complex of an amphiphilic corrole, 1-Fe. In this study we used the SOD1 G93R mutant zebrafish ALS model to assess whether 1-Fe, as a potent catalytic antioxidant, displays any therapeutic merits in vivo. Our results show that 1-Fe caused a substantial increase in mutant zebrafish locomotor activity (up to 30%), bringing the locomotive abilities of the mutant treated group close to that of the wild type untreated group (50% more than the mutated untreated group). Furthermore, 1-Fe did not affect WT larvae locomotor activity, suggesting that 1-Fe enhances locomotor ability by targeting mechanisms underlying SOD1 ALS specifically. These results may pave the way for future development of 1-Fe as a viable treatment for ALS.}, }
@article {pmid34065874, year = {2021}, author = {Stoccoro, A and Smith, AR and Baldacci, F and Del Gamba, C and Lo Gerfo, A and Ceravolo, R and Lunnon, K and Migliore, L and Coppedè, F}, title = {Mitochondrial D-Loop Region Methylation and Copy Number in Peripheral Blood DNA of Parkinson's Disease Patients.}, journal = {Genes}, volume = {12}, number = {5}, pages = {}, pmid = {34065874}, issn = {2073-4425}, mesh = {Aged ; Aged, 80 and over ; Biomarkers/blood ; *DNA Methylation ; DNA, Mitochondrial/*genetics ; Female ; Humans ; Male ; Middle Aged ; Parkinson Disease/blood/*genetics ; }, abstract = {Altered mitochondrial DNA (mtDNA) methylation has been detected in several human pathologies, although little attention has been given to neurodegenerative diseases. Recently, altered methylation levels of the mitochondrial displacement loop (D-loop) region, which regulates mtDNA replication, were observed in peripheral blood cells of Alzheimer's disease and amyotrophic lateral sclerosis patients. However, nothing is yet known about D-loop region methylation levels in peripheral blood of Parkinson's disease (PD) patients. In the current study, we investigated D-loop methylation levels and mtDNA copy number in peripheral blood of 30 PD patients and 30 age- and sex-matched control subjects. DNA methylation analyses have been performed by means of methylation-sensitive high-resolution melting (MS-HRM) and pyrosequencing techniques, while mtDNA copy number was analyzed by quantitative PCR. MS-HRM and pyrosequencing analyses provided very similar D-loop methylation levels in PD patients and control subjects, and no differences between the two groups have been observed. Treatment with L-dopa and duration of the disease had no effect on D-loop methylation levels in PD patients. Additionally, mtDNA copy number did not differ between PD patients and control subjects. Current results suggest that D-loop methylation levels are not altered in peripheral blood of PD patients nor influenced by dopaminergic treatment.}, }
@article {pmid34062930, year = {2021}, author = {La Cognata, V and Morello, G and Cavallaro, S}, title = {Omics Data and Their Integrative Analysis to Support Stratified Medicine in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {22}, number = {9}, pages = {}, pmid = {34062930}, issn = {1422-0067}, support = {CTN01_00177_817708//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; }, mesh = {Alzheimer Disease/genetics/pathology ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Biomarkers/metabolism ; Computational Biology ; *Genomics ; Humans ; *Metabolomics ; Neurodegenerative Diseases/*genetics/pathology ; Parkinson Disease/genetics/pathology ; Precision Medicine ; *Proteomics ; }, abstract = {Molecular and clinical heterogeneity is increasingly recognized as a common characteristic of neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. This heterogeneity makes difficult the development of early diagnosis and effective treatment approaches, as well as the design and testing of new drugs. As such, the stratification of patients into meaningful disease subgroups, with clinical and biological relevance, may improve disease management and the development of effective treatments. To this end, omics technologies-such as genomics, transcriptomics, proteomics and metabolomics-are contributing to offer a more comprehensive view of molecular pathways underlying the development of NDs, helping to differentiate subtypes of patients based on their specific molecular signatures. In this article, we discuss how omics technologies and their integration have provided new insights into the molecular heterogeneity underlying the most prevalent NDs, aiding to define early diagnosis and progression markers as well as therapeutic targets that can translate into stratified treatment approaches, bringing us closer to the goal of personalized medicine in neurology.}, }
@article {pmid34054547, year = {2021}, author = {Garcia-Gil, M and Camici, M and Allegrini, S and Pesi, R and Tozzi, MG}, title = {Metabolic Aspects of Adenosine Functions in the Brain.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {672182}, pmid = {34054547}, issn = {1663-9812}, abstract = {Adenosine, acting both through G-protein coupled adenosine receptors and intracellularly, plays a complex role in multiple physiological and pathophysiological processes by modulating neuronal plasticity, astrocytic activity, learning and memory, motor function, feeding, control of sleep and aging. Adenosine is involved in stroke, epilepsy and neurodegenerative pathologies. Extracellular concentration of adenosine in the brain is tightly regulated. Adenosine may be generated intracellularly in the central nervous system from degradation of AMP or from the hydrolysis of S-adenosyl homocysteine, and then exit via bi-directional nucleoside transporters, or extracellularly by the metabolism of released nucleotides. Inactivation of extracellular adenosine occurs by transport into neurons or neighboring cells, followed by either phosphorylation to AMP by adenosine kinase or deamination to inosine by adenosine deaminase. Modulation of the nucleoside transporters or of the enzymatic activities involved in the metabolism of adenosine, by affecting the levels of this nucleoside and the activity of adenosine receptors, could have a role in the onset or the development of central nervous system disorders, and can also be target of drugs for their treatment. In this review, we focus on the contribution of 5'-nucleotidases, adenosine kinase, adenosine deaminase, AMP deaminase, AMP-activated protein kinase and nucleoside transporters in epilepsy, cognition, and neurodegenerative diseases with a particular attention on amyotrophic lateral sclerosis and Huntington's disease. We include several examples of the involvement of components of the adenosine metabolism in learning and of the possible use of modulators of enzymes involved in adenosine metabolism or nucleoside transporters in the amelioration of cognition deficits.}, }
@article {pmid34053435, year = {2021}, author = {van der Smissen, D and Rietjens, JAC and van Gemert-Pijnen, L and van Dulmen, S and van der Heide, A and Korfage, IJ}, title = {Information needs of patients with chronic diseases and their relatives for web-based advance care planning: a qualitative interview study.}, journal = {BMC palliative care}, volume = {20}, number = {1}, pages = {77}, pmid = {34053435}, issn = {1472-684X}, mesh = {Adult ; Female ; Humans ; Male ; *Advance Care Planning ; Chronic Disease ; Internet ; Qualitative Research ; *Quality of Life ; Adult Children ; }, abstract = {BACKGROUND: Advance care planning (ACP) enables persons to identify preferences for future treatment and care, and to discuss, record and review these preferences. However, the uptake of ACP among patients with chronic diseases is relatively low. Web-based ACP programs can support patients and their relatives in ACP. However, information needs of patients and their relatives for ACP are unknown. The aim of this study is to explore information needs of patients with chronic disease and their relatives for web-based ACP.<br><br>METHODS: We conducted semi-structured interviews with patients with chronic diseases and relatives at their home or at the study center. In three cases, the patient and relative were paired since they preferred to be interviewed together. We asked about information they would search for when to start with ACP, where they would search for information, what search terms they would use on the Internet, and what content and information they would consider important on an ACP website. The interviewer asked participants to clarify their responses during the interview. We used thematic analysis to analyze the interviewees' responses.<br><br>RESULTS: We interviewed nine patients with different chronic diseases including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), chronic obstructive pulmonary disease (COPD) and kidney diseases, and seven relatives, namely partners or (adult) children. The interviewees were aged 24 to 80&#x2009;years, nine were female and seven were male. Both patients with a chronic disease and relatives mentioned comparable information needs. Many interviewees indicated they would use the Internet to search for information about ACP. Mentioned search terms were "advance care planning", "treatment plan", "disease trajectory" and names of patient associations. Information needs concerned their disease trajectory and quality of life, medical treatment decisions, practical support in arranging care, the concept of ACP and guidance in ACP, communication of treatment and care preferences, peer support of others with chronic diseases, and information for relatives. Many appreciated encouragement of their healthcare providers to take a pro-active role in ACP.<br><br>CONCLUSIONS: We conclude that information needs for ACP included guidance in ACP, support in making decisions about medical treatment, and practical support in arranging care. We recommend adapting web-based ACP information to the information needs of patients and their relatives to increase its findability, uptake and usefulness.}, }
@article {pmid34040085, year = {2021}, author = {Tungtur, SK and Wilkins, HM and Rogers, RS and Badawi, Y and Sage, JM and Agbas, A and Jawdat, O and Barohn, RJ and Swerdlow, RH and Nishimune, H}, title = {Oxaloacetate treatment preserves motor function in SOD1[G93A] mice and normalizes select neuroinflammation-related parameters in the spinal cord.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {11051}, pmid = {34040085}, issn = {2045-2322}, support = {P20 RR016475/RR/NCRR NIH HHS/United States ; R01 AG051470/AG/NIA NIH HHS/United States ; P20 GM103418/GM/NIGMS NIH HHS/United States ; P20 GM104936/GM/NIGMS NIH HHS/United States ; U54 HD090216/HD/NICHD NIH HHS/United States ; R01 NS078214/NS/NINDS NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Disease Models, Animal ; Inflammation/drug therapy/metabolism ; Longevity/drug effects ; Mice ; Motor Activity/*drug effects ; Motor Neurons/drug effects/metabolism ; Oxaloacetic Acid/*pharmacology/therapeutic use ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/*metabolism ; Spinal Cord/*drug effects/metabolism ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) remains a devastating motor neuron disease with limited treatment options. Oxaloacetate treatment has a neuroprotective effect in rodent models of seizure and neurodegeneration. Therefore, we treated the ALS model superoxide dismutase 1 (SOD1) [G93A] mice with oxaloacetate and evaluated their neuromuscular function and lifespan. Treatment with oxaloacetate beginning in the presymptomatic stage significantly improved neuromuscular strength measured during the symptomatic stage in the injected mice compared to the non-treated group. Oxaloacetate treatment starting in the symptomatic stage significantly delayed limb paralysis compared with the non-treated group. For lifespan analysis, oxaloacetate treatment did not show a statistically significant positive effect, but the treatment did not shorten the lifespan. Mechanistically, SOD1[G93A] mice showed increased levels of tumor necrosis factor-α (TNFα) and peroxisome proliferative activated receptor gamma coactivator 1α (PGC-1α) mRNAs in the spinal cord. However, oxaloacetate treatment reverted these abnormal levels to that of wild-type mice. Similarly, the altered expression level of total NF-κB protein returned to that of wild-type mice with oxaloacetate treatment. These results suggest that the beneficial effects of oxaloacetate treatment in SOD1[G93A] mice may reflect the effects on neuroinflammation or bioenergetic stress.}, }
@article {pmid34035826, year = {2021}, author = {Zhao, Q and Zheng, B and Feng, P and Li, X}, title = {A Study to Decipher the Potential Effects of Butylphthalide against Central Nervous System Diseases Based on Network Pharmacology and Molecular Docking Integration Strategy.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2021}, number = {}, pages = {6694698}, pmid = {34035826}, issn = {1741-427X}, abstract = {BACKGROUND: Butylphthalide (NBP), approved by the China National Medical Products Administration (NMPA) for the treatment of ischemic stroke (IS), showed pleiotropic potentials against central nervous system (CNS) diseases, including neuroprotection and cognitive deficits improvement. However, the effects and corresponding modes of action were not fully explored. This study was designed to investigate the potential of NBP against IS-associated CNS diseases based on network pharmacology (NP) and molecular docking (MD).<br><br>METHODS: IS was inputted as the index disease to retrieve the "associated diseases" in DisGeNET. Three-database-based IS genes were obtained and integrated (DisGeNET, Malacards, and OMIM). Then, IS-associated genes were identified by combining these genes. Meanwhile, PubMed references and online databases were applied to identify NBP target genes. The IS-related disease-disease association (DDA) network and NBP-disease regulation network were constructed and analyzed in Cytoscape. In silico MD and references were used to validate the binding affinity of NBP with critical targets and the potential of NBP against certain IS-related CNS disease regulation.<br><br>RESULTS: 175 NBP target genes were obtained, while 312 IS-related disease genes were identified. 36 NBP target genes were predicted to be associated with IS-related CNS diseases, including Alzheimer's disease (AD), epilepsy, major depressive disorder (MDD), amyotrophic lateral sclerosis (ALS), and dementia. Six target genes (i.e., GRIN1, PTGIS, PTGES, ADRA1A, CDK5, and SULT1E1) indicating disease specificity index (DSI) >0.5 showed certain to good degree binding affinity with NBP, ranging from -9.2 to -6.7&#x2009;kcal/mol. And the binding modes may be mainly related to hydrogen bonds and hydrophobic "bonds." Further literature validations inferred that these critical NBP targets had a tight association with AD, epilepsy, ALS, and depression.<br><br>CONCLUSIONS: Our study proposed a drug-target-disease integrated method to predict the drug repurposing potentials to associated diseases by application of NP and MD, which could be an attractive alternative to facilitate the development of CNS disease therapies. NBP may be promising and showed potentials to be repurposed for treatments for AD, epilepsy, ALS, and depression, and further investigations are warranted to be carefully designed and conducted.}, }
@article {pmid34032759, year = {2021}, author = {Kakimoto, A and Ishizaki, M and Ueyama, H and Maeda, Y and Ueda, M}, title = {Renal function in amyotrophic lateral sclerosis patients on long-term treatment with edaravone.}, journal = {Medicine}, volume = {100}, number = {21}, pages = {e26127}, pmid = {34032759}, issn = {1536-5964}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/blood/*drug therapy/*physiopathology ; Cystatin C/blood ; Drug Administration Schedule ; Edaravone/*administration &amp; dosage/adverse effects ; Female ; Free Radical Scavengers/*administration &amp; dosage/adverse effects ; Glomerular Filtration Rate/*drug effects ; Humans ; Kidney/*physiopathology ; Male ; Middle Aged ; Retrospective Studies ; }, abstract = {Edaravone, a free radical-scavenger, was approved in Japan for the treatment of amyotrophic lateral sclerosis (ALS). However, the effect of the drug on renal function in ALS patients remains unclear. This study aimed to investigate renal function in ALS patients on long-term treatment with edaravone by measuring the serum estimated glomerular filtration rate based on cystatin C (eGFR-CysC).In a retrospective study, the data of ALS patients who were treated with over 10 cycles of intravenous edaravone treatment and were evaluated by eGFR-CysC before and after 10 cycles of treatment between July 2015 and June 2018 were analyzed. Then, the results were compared with those of a control ALS group that had never been treated with edaravone.There were 11 patients with ALS who received over 10 cycles of intravenous edaravone treatment. The mean interval between the first and final eGFR-CysC measurements was 18.7 ± 7.9 months. Three patients (27.3%) had >20 mL/min/1.73 m2 decrease in serum eGFR-CysC. However, no patients discontinued edaravone treatment because of renal dysfunction. The average variation rate of eGFR-CysC was not different between the long-term edaravone group (0.29 ± 1.07) and the control group (-0.34 ± 0.40).This retrospective, single-center analysis showed no clinical exacerbation of renal function in ALS patients who received long-term treatment with edaravone.}, }
@article {pmid34027769, year = {2022}, author = {Pagnini, F and Phillips, D and Haulman, A and Bankert, M and Simmons, Z and Langer, E}, title = {An online non-meditative mindfulness intervention for people with ALS and their caregivers: a randomized controlled trial.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {1-2}, pages = {116-127}, doi = {10.1080/21678421.2021.1928707}, pmid = {34027769}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/psychology/therapy ; Caregivers/psychology ; Depression/etiology/psychology/therapy ; Humans ; *Mindfulness ; Quality of Life/psychology ; }, abstract = {Objectives: Mindfulness-based interventions seem to be effective in promoting QOL of ALS patients and caregivers, but most require substantial time. In the Langerian approach, mindfulness can be easily promoted with mental tasks and short lectures. This study aims to explore the impact of an ALS-specific online Langerian mindfulness training program on QOL of ALS patients. Methods: We developed and tested with an Randomized Controlled Trial (RCT) a 5-week active learning mindfulness program. Participants were recruited from the ALS clinic at Penn State Health and online and were randomly assigned to either the mindfulness group or a wait-list control group. The primary outcome was the patient's QOL after the treatment. 3 and 6-month follow-ups, together with anxiety, depression, care burden, and physical function, assessed at all times for both patients and caregivers, were explored as secondary outcomes. Results: 47 ALS patients and 27 caregivers were recruited. Among the ALS patients, the experimental group reported higher levels of QOL at the end of the treatment (d = 0.54). Moreover, they showed lower values of depression, anxiety, and negative emotions, compared to the controls, over time. The caregivers from the mindfulness group reported lower scores of care burden, depression, and anxiety, with higher values of energy and emotional well-being over time. Conclusions: This small RCT provides preliminary evidence that this intervention leads to an increase of QOL and a reduction in psychological comorbidities in ALS patients and caregivers. Given the relatively short time commitment, it may be easily implemented by the ALS community.}, }
@article {pmid34025132, year = {2021}, author = {Nam, SM and Choi, JH and Choi, SH and Cho, HJ and Cho, YJ and Rhim, H and Kim, HC and Cho, IH and Kim, DG and Nah, SY}, title = {Ginseng gintonin alleviates neurological symptoms in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis through lysophosphatidic acid 1 receptor.}, journal = {Journal of ginseng research}, volume = {45}, number = {3}, pages = {390-400}, pmid = {34025132}, issn = {1226-8453}, abstract = {BACKGROUND: We recently showed that gintonin, an active ginseng ingredient, exhibits antibrain neurodegenerative disease effects including multiple target mechanisms such as antioxidative stress and antiinflammation via the lysophosphatidic acid (LPA) receptors. Amyotrophic lateral sclerosis (ALS) is a spinal disease characterized by neurodegenerative changes in motor neurons with subsequent skeletal muscle paralysis and death. However, pathophysiological mechanisms of ALS are still elusive, and therapeutic drugs have not yet been developed. We investigate the putative alleviating effects of gintonin in ALS.<br><br>METHODS: The G93A-SOD1 transgenic mouse ALS model was used. Gintonin (50 or 100 mg/kg/day, p.o.) administration started from week seven. We performed histological analyses, immunoblot assays, and behavioral tests.<br><br>RESULTS: Gintonin extended mouse survival and relieved motor dysfunctions. Histological analyses of spinal cords revealed that gintonin increased the survival of motor neurons, expression of brain-derived neurotrophic factors, choline acetyltransferase, NeuN, and Nissl bodies compared with the vehicle control. Gintonin attenuated elevated spinal NAD(P) quinone oxidoreductase 1 expression and decreased oxidative stress-related ferritin, ionized calcium-binding adapter molecule 1-immunoreactive microglia, S100&#x3b2;-immunoreactive astrocyte, and Olig2-immunoreactive oligodendrocytes compared with the control vehicle. Interestingly, we found that the spinal LPA1 receptor level was decreased, whereas gintonin treatment restored decreased LPA1 receptor expression levels in the G93A-SOD1 transgenic mouse, thereby attenuating neurological symptoms and histological deficits.<br><br>CONCLUSION: Gintonin-mediated symptomatic improvements of ALS might be associated with the attenuations of neuronal loss and oxidative stress via the spinal LPA1 receptor regulations. The present results suggest that the spinal LPA1 receptor is engaged in ALS, and gintonin may be useful for relieving ALS symptoms.}, }
@article {pmid34024773, year = {2021}, author = {Nash, Y and Sitty, M}, title = {Non-Motor Symptoms of Amyotrophic Lateral Sclerosis: A Multi-Faceted Disorder.}, journal = {Journal of neuromuscular diseases}, volume = {8}, number = {4}, pages = {699-713}, doi = {10.3233/JND-210632}, pmid = {34024773}, issn = {2214-3602}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Biomarkers ; Disease Progression ; Humans ; Quality of Life ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor pathways. A growing body of evidence from recent years suggests that ALS results in a wide range of non-motor symptoms as well, which can have a significant impact on patients' quality of life. These symptoms could also, in turn, provide useful information as biomarkers for disease progression, and can shed insight on ALS mechanisms. Here we aim to review a wide range of non-motor symptoms of ALS, with emphasis on their importance to research and clinical treatment of patients.}, }
@article {pmid34020673, year = {2021}, author = {Zeman, M and Czarnecki, M and Chmielik, E and Idasiak, A and Skałba, W and Strączyński, M and Paul, PJ and Czarniecka, A}, title = {The assessment of risk factors for long-term survival outcome in ypN0 patients with rectal cancer after neoadjuvant therapy and radical anterior resection.}, journal = {World journal of surgical oncology}, volume = {19}, number = {1}, pages = {154}, pmid = {34020673}, issn = {1477-7819}, mesh = {Disease-Free Survival ; Humans ; *Neoadjuvant Therapy ; Neoplasm Recurrence, Local/epidemiology/therapy ; Neoplasm Staging ; Prognosis ; *Rectal Neoplasms/pathology/surgery ; Retrospective Studies ; Risk Factors ; }, abstract = {BACKGROUND: The main negative prognostic factors in patients with rectal cancer after radical treatment include regional lymph node involvement, lymphovascular invasion, and perineural invasion. However, some patients still develop cancer recurrence despite the absence of the above risk factors. The aim of the study was to assess clinicopathological factors influencing long-term oncologic outcomes in ypN0M0 rectal cancer patients after neoadjuvant therapy and radical anterior resection.<br><br>METHODS: A retrospective survival analysis was performed on a group of 195 patients. We assessed clinicopathological factors which included tumor regression grade, number of lymph nodes in the specimen, Charlson comorbidity index (CCI), and colorectal anastomotic leakage (AL).<br><br>RESULTS: In the univariate analysis, AL and CCI > 3 had a significant negative impact on disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). After the division of ALs into early and late ALs, it was found that only patients with late ALs had a significantly worse survival. The multivariate Cox regression analysis showed that CCI > 3 was a significant adverse risk factor for DFS (HR 5.78, 95% CI 2.15-15.51, p < 0.001), DSS (HR 7.25, 95% CI 2.25-23.39, p < 0.001), and OS (HR 3.9, 95% CI 1.72-8.85, p = 0.001). Similarly, late ALs had a significant negative impact on the risk of DFS (HR 5.05, 95% CI 1.97-12.93, p < 0.001), DSS (HR 10.84, 95% CI 3.44-34.18, p < 0.001), and OS (HR 4.3, 95% CI 1.94-9.53, p < 0.001).<br><br>CONCLUSIONS: Late AL and CCI > 3 are the factors that may have an impact on long-term oncologic outcomes. The impact of lymph node yield on understaging was not demonstrated.}, }
@article {pmid34016561, year = {2021}, author = {Babu, S and Hightower, BG and Chan, J and Zürcher, NR and Kivisäkk, P and Tseng, CJ and Sanders, DL and Robichaud, A and Banno, H and Evora, A and Ashokkumar, A and Pothier, L and Paganoni, S and Chew, S and Dojillo, J and Matsuda, K and Gudesblatt, M and Berry, JD and Cudkowicz, ME and Hooker, JM and Atassi, N}, title = {Ibudilast (MN-166) in amyotrophic lateral sclerosis- an open label, safety and pharmacodynamic trial.}, journal = {NeuroImage. Clinical}, volume = {30}, number = {}, pages = {102672}, pmid = {34016561}, issn = {2213-1582}, support = {S10 OD023517/OD/NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Biomarkers ; Cohort Studies ; Humans ; Pyridines ; }, abstract = {Ibudilast (MN-166) is an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterases 3,4,10 and 11 (Gibson et al., 2006; Cho et al., 2010). Ibudilast attenuates CNS microglial activation and secretion of pro-inflammatory cytokines (Fujimoto et al., 1999; Cho et al., 2010). In vitro evidence suggests that ibudilast is neuroprotective by suppressing neuronal cell death induced by microglial activation. People with ALS have increased microglial activation measured by [[11]C]PBR28-PET in the motor cortices. The primary objective is to determine the impact of ibudilast on reducing glial activation and neuroaxonal loss in ALS, measured by PBR28-PET and serum Neurofilament light (NfL). The secondary objectives included determining safety and tolerability of ibudilast high dosage (up to 100 mg/day) over 36 weeks. In this open label trial, 35 eligible ALS participants underwent ibudilast treatment up to 100 mg/day for 36 weeks. Of these, 30 participants were enrolled in the main study cohort and were included in biomarker, safety and tolerability analyses. Five additional participants were enrolled in the expanded access arm, who did not meet imaging eligibility criteria and were included in the safety and tolerability analyses. The primary endpoints were median change from baseline in (a) PBR28-PET uptake in primary motor cortices, measured by standard uptake value ratio (SUVR) over 12-24 weeks and (b) serum NfL over 36-40 weeks. The secondary safety and tolerability endpoints were collected through Week 40. The baseline median (range) of PBR28-PET SUVR was 1.033 (0.847, 1.170) and NfL was 60.3 (33.1, 219.3) pg/ml. Participants who completed both pre and post-treatment scans had PBR28-PET SUVR median(range) change from baseline of 0.002 (-0.184, 0.156) , P = 0.5 (n = 22). The median(range) NfL change from baseline was 0.4 pg/ml (-1.8, 17.5), P = 0.2 (n = 10 participants). 30(86%) participants experienced at least one, possibly study drug related adverse event. 13(37%) participants could not tolerate 100 mg/day and underwent dose reduction to 60-80 mg/day and 11(31%) participants discontinued study drug early due to drug related adverse events. The study concludes that following treatment with ibudilast up to 100 mg/day in ALS participants, there were no significant reductions in (a) motor cortical glial activation measured by PBR28-PET SUVR over 12-24 weeks or (b) CNS neuroaxonal loss, measured by serum NfL over 36-40 weeks. Dose reductions and discontinuations due to treatment emergent adverse events were common at this dosage in ALS participants. Future pharmacokinetic and dose-finding studies of ibudilast would help better understand tolerability and target engagement in ALS.}, }
@article {pmid34014000, year = {2022}, author = {Palese, F and Gigli, GL and Manganotti, P and Passadore, P and Rana, M and Verriello, L}, title = {The diagnostic, therapeutic and assistance pathway for amyotrophic lateral sclerosis in a north-eastern Italian region: satisfaction of patients and their caregivers.}, journal = {Health &amp; social care in the community}, volume = {30}, number = {1}, pages = {124-132}, doi = {10.1111/hsc.13379}, pmid = {34014000}, issn = {1365-2524}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; *Caregivers ; Humans ; Patient Satisfaction ; Personal Satisfaction ; Surveys and Questionnaires ; }, abstract = {In order to evaluate the users' satisfaction degree for the diagnostic, therapeutic and assistance services for amyotrophic lateral sclerosis (ALS) in the Italian region Friuli-Venezia Giulia (FVG), a self-compiled anonymous multiple-choice questionnaire was administered to ALS patients and their caregivers. The questionnaire explored 41 different issues covering the following areas: (a) access to diagnostic pathway and communication among patients, families and health professionals; (b) quality of disease monitoring and effectiveness of interventions aimed at mitigating ALS symptoms; (c) easiness of access to assistive devices (e.g. wheelchair, ankle-foot-orthosis) and home assistance; (d) patient' choices sharing and health professionals empathy. The same issues were proposed both to patients and carers, appropriately adapting the questions, during the period between June and December 2019. The answers were categorised according to criticality level. Median with interquartile range of the numeric variables and percentages of the categorical variables and of the answers to questions were calculated. The mean percentage of satisfied users was 72.8%, considering all the areas. Pain treatment and easiness of access to ambulance transport were the most positive aspects (95.7% and 92.5% of satisfied respondents, respectively), while information about possible enrolment in clinical trials and about possible registration to the regional ALS association were the most critical issues (30.9% and 43.4% of satisfied users). Although the satisfaction level of ALS patients and their caregivers for the services provided resulted generally good, there were some areas that have to be improved. For this purpose, enhancement of multidisciplinary collaboration, sharing of points of view from users and different practitioners and rising awareness among healthcare professionals through clinical audits could be useful. Further research is needed to identify a wider range of users' unexplored unmet needs.}, }
@article {pmid34012311, year = {2021}, author = {Soldatov, VO and Kukharsky, MS and Belykh, AE and Sobolev, AM and Deykin, AV}, title = {Retinal Damage in Amyotrophic Lateral Sclerosis: Underlying Mechanisms.}, journal = {Eye and brain}, volume = {13}, number = {}, pages = {131-146}, pmid = {34012311}, issn = {1179-2744}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in a gradual loss of motor neuron function. Although ophthalmic complaints are not presently considered a classic symptom of ALS, retinal changes such as thinning, axonal degeneration and inclusion bodies have been found in many patients. Retinal abnormalities observed in postmortem human tissues and animal models are similar to spinal cord changes in ALS. These findings are not dramatically unexpected because retina shares an ontogenetic relationship with the brain, and many genes are associated both with neurodegeneration and retinal diseases. Experimental studies have demonstrated that ALS affects many "vulnerable points" of the retina. Aggregate deposition, impaired nuclear protein import, endoplasmic reticulum stress, glutamate excitotoxicity, vascular regression, and mitochondrial dysfunction are factors suspected as being the main cause of motor neuron damage in ALS. Herein, we show that all of these pathways can affect retinal cells in the same way as motor neurons. Furthermore, we suppose that understanding the patterns of neuro-ophthalmic interaction in ALS can help in the diagnosis and treatment of this disease.}, }
@article {pmid34010004, year = {2021}, author = {Ediriweera, GR and Chen, L and Yerbury, JJ and Thurecht, KJ and Vine, KL}, title = {Non-Viral Vector-Mediated Gene Therapy for ALS: Challenges and Future Perspectives.}, journal = {Molecular pharmaceutics}, volume = {18}, number = {6}, pages = {2142-2160}, doi = {10.1021/acs.molpharmaceut.1c00297}, pmid = {34010004}, issn = {1543-8392}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; CRISPR-Cas Systems/genetics ; Cells, Cultured ; Clinical Trials, Phase III as Topic ; Disease Models, Animal ; Gene Transfer Techniques/*adverse effects/trends ; Genetic Therapy/adverse effects/*methods/trends ; Genetic Vectors/*administration &amp; dosage/adverse effects ; Humans ; Nanoparticles/administration &amp; dosage ; Primary Cell Culture ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, for which no effective treatment is yet available to either slow or terminate it. Recent advances in gene therapy renew hope for developing an effective approach to control this disease. Non-viral vectors, such as lipid- and polymer-based nanoparticles, cationic polymers, and exosomes, can effectively transfer genes into primary neurons. The resulting gene expression can be long-term, stable, and without immunological complications, which is essential for the effective management of neurological disorders. This Review will first describe the current research and clinical stage of novel therapies for ALS. It will then touch on the journey of non-viral vector use in ALS, subsequently highlighting the application of non-viral vector-mediated gene therapy. The bottlenecks in the translation of non-viral vectors for ALS treatment are also discussed, including the biological barriers of systemic administration and the issues of "when, where, and how much?" for effective gene delivery. The prospect of employing emerging techniques, such as CRISPR-Cas9 gene editing, stem cell methodology, and low-intensity focused ultrasound for fueling the transport of non-viral vectors to the central nervous system for personalized gene therapy, is briefly discussed in the context of ALS. Despite the challenging road that lies ahead, with the current expansion in interest and technological advancement in non-viral vector-delivered gene therapy for ALS, we hold hope that the field is headed toward a positive future.}, }
@article {pmid34008857, year = {2021}, author = {Oskarsson, B and Mauricio, EA and Shah, JS and Li, Z and Rogawski, MA}, title = {Cortical excitability threshold can be increased by the AMPA blocker Perampanel in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {64}, number = {2}, pages = {215-219}, doi = {10.1002/mus.27328}, pmid = {34008857}, issn = {1097-4598}, support = {FYC-IIS-M001-1015//Eisai/ ; 17-002396//Mayo Foundation for Medical Education and Research/ ; //University of California, Davis/ ; //Mayo Clinic/ ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/blood/diagnosis/*drug therapy ; Cortical Excitability/*drug effects/physiology ; Double-Blind Method ; Evoked Potentials, Motor/drug effects/physiology ; Female ; Humans ; Male ; Middle Aged ; Motor Neurons/*drug effects/physiology ; Nitriles ; Pilot Projects ; Pyridones/*administration &amp; dosage/blood ; Receptors, AMPA/*antagonists &amp; inhibitors/physiology ; Transcranial Magnetic Stimulation/methods ; }, abstract = {INTRODUCTION/AIMS: Cortical hyperexcitability is a feature of amyotrophic lateral sclerosis (ALS) and cortical excitability can be measured using transcranial magnetic stimulation (TMS). Resting motor threshold (MT) is a measure of cortical excitability, largely driven by glutamate. Perampanel, a glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker, is predicted to increase the cortical excitability threshold. This study aimed to evaluate TMS to functionally assess target engagement in a study of perampanel in ALS.<br><br>METHOD: We studied the MT of ALS patients randomized to a single dose of perampanel or placebo 5:1 hourly for 4&#xa0;h. Twelve patients participated at 4&#xa0;mg and 7 returned for dosing and retesting at 8&#xa0;mg. The study was terminated in April 2020 due to coronavirus disease 2019-related restrictions, after 7 out of 12 planned patients had received the 8&#xa0;mg dose. Serum concentrations were also measured.<br><br>RESULTS: Ten patients received the 4&#xa0;mg dose (2 received placebo) and 5 received the 8&#xa0;mg dose (2 received placebo). Motor Threshold increased at 2&#xa0;h after dosing in the combined treatment group +7% of maximal stimulator output (P&#xa0;<&#x2009;.01). Change could be detected in the larger 4&#xa0;mg group (P&#xa0;=&#x2009;.02), but not in the smaller 8&#xa0;mg dose group (P&#xa0;=&#x2009;.1). No side effects were reported after single dose exposure.<br><br>DISCUSSION: This study shows that perampanel effects the physiology of upper motor neurons. Studies aiming at gauging the effect of perampanel on ALS disease progression are already ongoing. Motor threshold may serve as a marker of biological target engagement.}, }
@article {pmid34004234, year = {2021}, author = {Wu, HT and Yu, Y and Li, XX and Lang, XY and Gu, RZ and Fan, SR and Fang, X and Bai, JP and Lan, R and Qin, XY}, title = {Edaravone attenuates H2O2 or glutamate-induced toxicity in hippocampal neurons and improves AlCl3/D-galactose induced cognitive impairment in mice.}, journal = {Neurotoxicology}, volume = {85}, number = {}, pages = {68-78}, doi = {10.1016/j.neuro.2021.05.005}, pmid = {34004234}, issn = {1872-9711}, mesh = {Aluminum Chloride/*toxicity ; Animals ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Cognitive Dysfunction/chemically induced/metabolism/*prevention &amp; control ; Dose-Response Relationship, Drug ; Edaravone/pharmacology/*therapeutic use ; Female ; Free Radical Scavengers/pharmacology/therapeutic use ; Galactose/*toxicity ; Glutamic Acid/*toxicity ; Hippocampus/drug effects/metabolism ; Hydrogen Peroxide/*toxicity ; Mice ; Mice, Inbred C57BL ; Neurons/drug effects/metabolism ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Edaravone (Eda) is a free radical scavenger used in clinical trials for the treatment of ischemic stroke and amyotrophic lateral sclerosis. However, how Eda exerts its neuroprotective effects remains to be elucidated. We investigated the neuroprotective effects of Eda in cultured hippocampal neurons and in a mouse model of AlCl3/D-galactose-induced cognitive impairment. Eda protected hippocampal neurons by eliminating H2O2 or glutamate-induced toxicity, leading to decreased cell viability and neurite shortening. Consistently, Eda restored impaired levels of BDNF, FGF2 and their associated signaling axes (including TrkB, p-Akt and Bcl-2) to attenuate neuronal death. In a mouse model of chemically-induced cognitive impairment, Eda restored the levels of BDNF, FGF2 and TrkB/Akt signaling axis to attenuate neuronal apoptosis, thereby ameliorating cognitive impairment. Meanwhile, the pro-inflammation was eliminated due to the restoration of pro-inflammatory factors such as TNF-α, IL-6, IL-1β, and NOS2. In summary, Eda is an effective drug for protecting neurons from neurotoxic injury. BDNF, FGF2, and their regulated pathways may be potential therapeutic targets for neuroprotection.}, }
@article {pmid34002641, year = {2022}, author = {, }, title = {ALSUntangled #61: melatonin.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {1-2}, pages = {157-160}, doi = {10.1080/21678421.2021.1927103}, pmid = {34002641}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/complications/drug therapy ; Humans ; *Melatonin/therapeutic use ; Retrospective Studies ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people with amyotrophic lateral sclerosis (ALS). Here we review melatonin. We show that it has plausible mechanisms, some positive (and some negative) pre-clinical studies, two cases in which cocktails of supplements including melatonin were associated with recovery of lost motor function, and a very small, flawed retrospective study suggesting that patients in the PRO-ACT database who reported taking melatonin progressed more slowly and lived longer compared to those who were not taking it. Melatonin appears safe, but an optimal dose and route of administration for ALS have not been determined. Based on all this, we support a pilot trial of melatonin in people with ALS but we cannot yet recommend it as a treatment.}, }
@article {pmid34000059, year = {2021}, author = {Horvath, CM and Brill, AK and Baty, F and Brutsche, MH}, title = {Efficacy of non-invasive intelligent volume assured pressure support (iVAPS) and pressure support ventilation (PSV) in clinical practice.}, journal = {Swiss medical weekly}, volume = {151}, number = {}, pages = {w20506}, doi = {10.4414/smw.2021.20506}, pmid = {34000059}, issn = {1424-3997}, mesh = {Humans ; Lung ; *Noninvasive Ventilation ; Positive-Pressure Respiration ; *Pulmonary Disease, Chronic Obstructive/therapy ; Respiration ; *Respiratory Insufficiency/therapy ; Retrospective Studies ; }, abstract = {AIMS OF THE STUDY: Noninvasive ventilation (NIV) is a well-established treatment option for hypercapnic respiratory failure; however, the best mode of ventilation remains unknown. The aim of this retrospective study was to compare patients’ adherence to NIV using either pressure support ventilation (PSV) or intelligent volume-assured pressure support (iVAPS).<br><br>PATIENTS AND METHODS: In this retrospective cohort study, we assessed in- and outpatients suffering from hypercapnic respiratory failure of various aetiologies (chronic obstructive pulmonary disease [COPD], obese COPD [body mass index >30 kg/m2], obesity hypoventilation syndrome and other diseases such as amyotrophic lateral sclerosis or interstitial lung disease) after NIV initiation with PSV or iVAPS. Adherence to treatment was compared between these modes using the Wilcoxon test. Within-group differences were tested using linear regression models. Mortality and emergency hospital readmission rates were modelled using Kaplan-Meier estimates and Cox proportional hazards models.<br><br>RESULTS: Adherence to treatment was similar in both groups throughout the observation period &amp;ndash; after 6 weeks: PSV 363 min/night (interquartile range [IQR] 200&amp;ndash;448), iVAPS 369 min/night (IQR 310&amp;ndash;468) (p = 0.619); after 1 year: PSV 423 (323&amp;ndash;500), iVAPS 429 (298&amp;ndash;475) (p = 0.901); at the last follow up: PSV 481 (395&amp;ndash;586), iVAPS 426 (391&amp;ndash;565) (p = 0.284). NIV reduced PaCO2 significantly compared with baseline at all follow-ups: PSV &amp;minus;1.29/&amp;minus;1.49/&amp;minus;1.49 kPa, iVAPS &amp;minus;1.47/&amp;minus;1.23/&amp;minus;1.24 kPa, p <0.001 each, PSV vs iVAPS: p = 0.250, 0.756 and 0.352, respectively. Median survival time (PSV 5.06 years, iVAPS median not reached; p = 0.800) and time to first readmission (PSV 3.6 years, iVAPS 7.33 years, p = 0.200) did not differ between groups. Obese COPD patients had a longer time to hospital readmission than lean COPD patients (3.8 vs 1.5 years, hazard ratio (HR) 0.39, 95% confidence interval [CI] 0.16&amp;ndash;0. 74; p = 0.007). Good adherence (>4 h/night and >80% nightly usage) was associated with a lower mortality rate (HR 0.34, 95% CI 0.15&amp;ndash;0.77; p = 0.010).<br><br>CONCLUSION: In a real-world setting of a mixed population with hypercapnic respiratory failure, iVAPS and PSV seem to be similarly effective in improving gas exchange and demonstrate excellent adherence to treatment. A longer survival was noted in NIV-adherent patients. Randomised controlled studies are necessary to identify patients who might benefit more from hybrid ventilation modes.}, }
@article {pmid33996012, year = {2021}, author = {Häfliger, J and Livingstone, K and Daniliuc, CG and Gilmour, R}, title = {Difluorination of α-(bromomethyl)styrenes via I(I)/I(III) catalysis: facile access to electrophilic linchpins for drug discovery.}, journal = {Chemical science}, volume = {12}, number = {17}, pages = {6148-6152}, pmid = {33996012}, issn = {2041-6520}, abstract = {Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis. This inexpensive main group catalysis strategy employs p-TolI as an effective organocatalyst when combined with Selectfluor® and simple amine·HF complexes. Modulating Brønsted acidity enables simultaneous geminal and vicinal difluorination to occur, thereby providing a platform to generate multiply fluorinated scaffolds for further downstream derivatization. The method facilitates access to a tetrafluorinated API candidate for the treatment of amyotrophic lateral sclerosis. Preliminary validation of an enantioselective process is disclosed to access α-phenyl-β-difluoro-γ-bromo/chloro esters.}, }
@article {pmid33994932, year = {2021}, author = {Xie, Y and Luo, X and He, H and Tang, M}, title = {Novel Insight Into the Role of Immune Dysregulation in Amyotrophic Lateral Sclerosis Based on Bioinformatic Analysis.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {657465}, pmid = {33994932}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. The causative pathogenic mechanisms in ALS remain unclear, limiting the development of treatment strategies. Neuroinflammation and immune dysregulation were involved in the disease onset and progression of several neurodegenerative disorders, including ALS. In this study, we carried out a bioinformatic analysis using publicly available datasets from Gene Expression Omnibus (GEO) to investigate the role of immune cells and genes alterations in ALS. Single-sample gene set enrichment analysis revealed that the infiltration of multiple types of immune cells, including macrophages, type-1/17 T helper cells, and activated CD4 + /CD8 + T cells, was higher in ALS patients than in controls. Weighted gene correlation network analysis identified immune genes associated with ALS. The Gene Ontology analysis revealed that receptor and cytokine activities were the most highly enriched terms. Pathway analysis showed that these genes were enriched not only in immune-related pathways, such as cytokine-cytokine receptor interaction, but also in PI3K-AKT and MAPK signaling pathways. Nineteen immune-related genes (C3AR1, CCR1, CCR5, CD86, CYBB, FCGR2B, FCGR3A, HCK, ITGB2, PTPRC, TLR1, TLR2, TLR7, TLR8, TYROBP, VCAM1, CD14, CTSS, and FCER1G) were identified as hub genes based on least absolute shrinkage and selection operator analysis. This gene signature could differentiate ALS patients from non-neurological controls (p < 0.001) and predict disease occurrence (AUC = 0.829 in training set; AUC = 0.862 in test set). In conclusion, our study provides potential biomarkers of ALS for disease diagnosis and therapeutic monitoring.}, }
@article {pmid33993457, year = {2021}, author = {Mahoney, CJ and Ahmed, RM and Huynh, W and Tu, S and Rohrer, JD and Bedlack, RS and Hardiman, O and Kiernan, MC}, title = {Pathophysiology and Treatment of Non-motor Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {CNS drugs}, volume = {35}, number = {5}, pages = {483-505}, pmid = {33993457}, issn = {1179-1934}, support = {MR/M023664/1/MRC_/Medical Research Council/United Kingdom ; MR/T046015/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Cognitive Dysfunction/etiology/physiopathology/*therapy ; Disease Progression ; Humans ; Outcome Assessment, Health Care ; Research Design ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease typically presenting with bulbar or limb weakness. There is increasing evidence that amyotrophic lateral sclerosis is a multisystem disease with early and frequent impacts on cognition, behaviour, sleep, pain and fatigue. Dysfunction of normal physiological and metabolic processes also appears common. Evidence from pre-symptomatic studies and large epidemiological cohorts examining risk factors for the future development of amyotrophic lateral sclerosis have reported a high prevalence of changes in behaviour and mental health before the emergence of motor weakness. This suggests that changes beyond the motor system are underway at an early stage with dysfunction across brain networks regulating a variety of cognitive, behavioural and other homeostatic processes. The full impact of non-motor dysfunction continues to be established but there is now sufficient evidence that the presence of non-motor symptoms impacts overall survival in amyotrophic lateral sclerosis, and with up to 80% reporting non-motor symptoms, there is an urgent need to develop more robust therapeutic approaches. This review provides a contemporary overview of the pathobiology of non-motor dysfunction, offering readers a practical approach with regard to assessment and management. We review the current evidence for pharmacological and non-pharmacological treatment of non-motor dysfunction in amyotrophic lateral sclerosis and highlight the need to further integrate non-motor dysfunction as an important outcome measure for future clinical trial design.}, }
@article {pmid33982658, year = {2022}, author = {Kursun, O and Karatas, H and Bariskaner, H and Ozturk, S}, title = {Arachidonic Acid Metabolites in Neurologic Disorders.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {21}, number = {2}, pages = {150-159}, doi = {10.2174/1871527320666210512013648}, pmid = {33982658}, issn = {1996-3181}, mesh = {Alzheimer Disease/metabolism ; Animals ; Arachidonic Acid/*metabolism ; Docosahexaenoic Acids/metabolism ; Humans ; Inflammation/metabolism ; Neurodegenerative Diseases/*metabolism ; Parkinson Disease/metabolism ; }, abstract = {BACKGROUND AND OBJECTIVE: Arachidonic acid (ARA) is essential for the fluidity, selective permeability, and flexibility of the cell membrane. It is an important factor for the function of all cells, particularly in the nervous system, immune system, and vascular endothelium. ARA is the second most common polyunsaturated fatty acid in the phospholipids of the nerve cell membrane after docosahexaenoic acid. ARA metabolites have many kinds of physiologic roles. The major action of ARA metabolites is the promotion of the acute inflammatory response, mediated by the production of pro-inflammatory mediators such as PGE2 and PGI2, followed by the formation of lipid mediators, which have pro-resolving effects. Another important action of ARA derivatives, especially COX, is the regulation of vascular reactivity through PGs and TXA2. There is significant involvement of ARA metabolites in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and neuropsychiatric disorders. ARA derivatives also make an important contribution to acute stroke, global ischemia, subarachnoid hemorrhage, and anticoagulation-related hemorrhagic transformation.<br><br>CONCLUSION: In this review, we have discussed experimental and human study results of neurologic disorders related to ARA and its metabolites in line with treatment options.}, }
@article {pmid33976351, year = {2021}, author = {Lee, HS and Kang, HS and Kim, SM and Kim, CH and Yang, SH and Han, MH and Chung, CK}, title = {Treatment strategy to maximize the treatment outcome of spinal dural arteriovenous fistula after initial endovascular embolization attempt at diagnostic angiography.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {10004}, pmid = {33976351}, issn = {2045-2322}, mesh = {Aged ; Angiography ; Central Nervous System Vascular Malformations/diagnostic imaging/*therapy ; Endovascular Procedures/*statistics &amp; numerical data ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; }, abstract = {Initial attempt of endovascular treatment (EVT) for spinal dural arteriovenous fistula (SDAVF) is preferred because of concurrent diagnosis and treatment. However, outcomes following further treatment with initial EVT are not well studied. We retrospectively reviewed 71 patients with SDAVF to evaluate treatment outcomes of SDAVF after an initial EVT attempt. Pretreatment and posttreatment functional states were assessed by the Aminoff-Logue scale (ALS). In the case of incomplete occlusion or recurrence, overall outcomes after further treatments were compared. Of the 71 patients, 56 underwent initial EVT. Complete occlusion was achieved by initial EVT in 37 of 56 patients (66.1%). Multiple feeders were more frequently observed in patients with incomplete occlusion than complete occlusion after initial EVT (73.7% vs. 27%, P < 0.001). Among 19 patients with incomplete occlusion upon initial EVT, 14 underwent additional surgery, 13 of whom (92.9%) obtained improved or stationary functional outcomes. Functional improvement was not observed in patients who had repeated EVT or follow-up without further treatment. Recurrence was observed in 8 of 37 patients with complete occlusion upon initial EVT. Additional surgery achieved improved functional outcomes in cases of incomplete occlusion of SDAVF after the initial EVT attempt or recurrence rather than repeated EVT or follow-up.}, }
@article {pmid33974963, year = {2021}, author = {Tadokoro, K and Yamashita, T and Shang, J and Ohta, Y and Nomura, E and Morihara, R and Omote, Y and Takemoto, M and Abe, K}, title = {Switching the Proteolytic System from the Ubiquitin-Proteasome System to Autophagy in the Spinal Cord of an Amyotrophic Lateral Sclerosis Mouse Model.}, journal = {Neuroscience}, volume = {466}, number = {}, pages = {47-57}, doi = {10.1016/j.neuroscience.2021.04.034}, pmid = {33974963}, issn = {1873-7544}, mesh = {Adaptor Proteins, Signal Transducing ; *Amyotrophic Lateral Sclerosis ; Animals ; Apoptosis Regulatory Proteins ; Autophagy ; Disease Models, Animal ; Female ; Humans ; Mice ; Mice, Transgenic ; Proteasome Endopeptidase Complex ; Spinal Cord/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; Ubiquitin/metabolism ; }, abstract = {The degradation of damaged proteins takes place via two major proteolytic pathways: the ubiquitin-proteasome system (UPS) and autophagy. However, since it is unclear how these two proteolytic pathways contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), we investigated the switching mechanism from UPS to autophagy by pharmacologically modifying these pathways by treating the spinal cords of female ALS mouse model bearing G93A human SOD1 (G93A mice) with MG132 or 3-methyladenine (3MA). G93A mice exhibited a progressive increase in the amount of ubiquitin and p62 aggregates, BAG3 expression, and LC3-II/LC3-I ratio in both astroglia and motor neurons. Treatment with MG132 or 3MA significantly increased the clinical hanging wire score and exacerbated α-motor neuron loss at 18 weeks in G93A mice, and increased the amount of ubiquitin, p62 aggregates, and BAG3 expression. This study's results demonstrate that the molecular switch from UPS to autophagy occurred not only in motor neurons but also in astroglia at the end stage (18 weeks) when the autophagic flux was impaired in G93A mice. This finding suggests that the defense system was disrupted against aggregate-prone protein production in ALS.}, }
@article {pmid33973643, year = {2021}, author = {Patel, GN and Gudur, R and Gudur, A and Oswal, RM and Kanethkar, S}, title = {Clinicopathological Evaluation of Acute Leukemias in a Tertiary Care Hospital: A Cross-Sectional Study.}, journal = {Turk patoloji dergisi}, volume = {37}, number = {2}, pages = {145-153}, pmid = {33973643}, issn = {1309-5730}, mesh = {Adolescent ; Adult ; Aged ; Biomarkers, Tumor/analysis/genetics ; Bone Marrow Examination ; Child ; Clinical Decision-Making ; Cross-Sectional Studies ; Cytogenetic Analysis ; Female ; Flow Cytometry ; Humans ; Leukemia, Myeloid, Acute/*diagnosis/genetics/pathology/therapy ; Male ; Middle Aged ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*diagnosis/genetics/pathology/therapy ; Predictive Value of Tests ; Prognosis ; Tertiary Care Centers ; Young Adult ; }, abstract = {OBJECTIVE: Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) are clinically and biologically diverse phenotypic diseases amongst hematological malignancies. The current study objectives were to diagnose and classify cases of AL as per revised 4th edition of WHO 2016 classification of AL's and study their clinicopathological profiles.<br><br>MATERIAL AND METHOD: This cross-sectional, observational study included 68 patients, diagnosed with AL were recruited. Diagnosis was based on peripheral blood smear examination, bone marrow aspiration, flowcytometry, and cytogenetic and molecular studies.<br><br>RESULTS: Sixty-eight cases of AL were diagnosed in a period of 2 years, where 25 cases were of ALL and 43 cases were of AML. In the subclassification of AML as per WHO 2016, 20 cases were of AML, RGA, 21 cases were of AML, NOS, and 2 cases were of AML, MRC. In AML, RGA, APL with PML-RARA positive cases were 10 out of 20 cases, AML with (8;21) RUNX1-RUNX1T1 were 7/20 cases; there were two cases of AML with mutated NPM1 gene and one case of AML with biallelic mutation of CEBPA. In AML, NOS subcategory AML with maturation was more common with 9/21cases. In subcategory of ALL, B-ALL was more common than T-ALL. B-ALL, NOS was more common than B-ALL, RGA and we had 1 case of NK cell Leukemia.<br><br>CONCLUSION: The application of revised 4th edition WHO 2016 classification confers uniformity in reporting acute leukemia cases that aids in the treatment by using targeted therapies and helps in the prediction of prognosis. The WHO classification for acute leukemias is very objective, therapy oriented and the need of the hour.}, }
@article {pmid33968923, year = {2021}, author = {Barbosa, M and Gomes, C and Sequeira, C and Gonçalves-Ribeiro, J and Pina, CC and Carvalho, LA and Moreira, R and Vaz, SH and Vaz, AR and Brites, D}, title = {Recovery of Depleted miR-146a in ALS Cortical Astrocytes Reverts Cell Aberrancies and Prevents Paracrine Pathogenicity on Microglia and Motor Neurons.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {634355}, pmid = {33968923}, issn = {2296-634X}, abstract = {Reactive astrocytes in Amyotrophic Lateral Sclerosis (ALS) change their molecular expression pattern and release toxic factors that contribute to neurodegeneration and microglial activation. We and others identified a dysregulated inflammatory miRNA profile in ALS patients and in mice models suggesting that they represent potential targets for therapeutic intervention. Such cellular miRNAs are known to be released into the secretome and to be carried by small extracellular vesicles (sEVs), which may be harmful to recipient cells. Thus, ALS astrocyte secretome may disrupt cell homeostasis and impact on ALS pathogenesis. Previously, we identified a specific aberrant signature in the cortical brain of symptomatic SOD1-G93A (mSOD1) mice, as well as in astrocytes isolated from the same region of 7-day-old mSOD1 mice, with upregulated S100B/HMGB1/Cx43/vimentin and downregulated GFAP. The presence of downregulated miR-146a on both cases suggests that it can be a promising target for modulation in ALS. Here, we upregulated miR-146a with pre-miR-146a, and tested glycoursodeoxycholic acid (GUDCA) and dipeptidyl vinyl sulfone (VS) for their immunoregulatory properties. VS was more effective in restoring astrocytic miR-146a, GFAP, S100B, HMGB1, Cx43, and vimentin levels than GUDCA, which only recovered Cx43 and vimentin mRNA. The miR-146a inhibitor generated typical ALS aberrancies in wild type astrocytes that were abolished by VS. Similarly, pre-miR-146a transfection into the mSOD1 astrocytes abrogated aberrant markers and intracellular Ca[2+] overload. Such treatment counteracted miR-146a depletion in sEVs and led to secretome-mediated miR-146a enhancement in NSC-34-motor neurons (MNs) and N9-microglia. Secretome from mSOD1 astrocytes increased early/late apoptosis and FGFR3 mRNA in MNs and microglia, but not when derived from pre-miR-146a or VS-treated cells. These last strategies prevented the impairment of axonal transport and synaptic dynamics by the pathological secretome, while also averted microglia activation through either secretome, or their isolated sEVs. Proteomic analysis of the target cells indicated that pre-miR-146a regulates mitochondria and inflammation via paracrine signaling. We demonstrate that replenishment of miR-146a in mSOD1 cortical astrocytes with pre-miR-146a or by VS abrogates their phenotypic aberrancies and paracrine deleterious consequences to MNs and microglia. These results propose miR-146a as a new causal and emerging therapeutic target for astrocyte pathogenic processes in ALS.}, }
@article {pmid33964142, year = {2021}, author = {Bosanac, T and Hughes, RO and Engber, T and Devraj, R and Brearley, A and Danker, K and Young, K and Kopatz, J and Hermann, M and Berthemy, A and Boyce, S and Bentley, J and Krauss, R}, title = {Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy.}, journal = {Brain : a journal of neurology}, volume = {144}, number = {10}, pages = {3226-3238}, pmid = {33964142}, issn = {1460-2156}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/toxicity ; Armadillo Domain Proteins/*antagonists &amp; inhibitors/deficiency/genetics ; Axons/*drug effects/metabolism ; Cells, Cultured ; Cytoskeletal Proteins/*antagonists &amp; inhibitors/deficiency/genetics ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Induced Pluripotent Stem Cells/drug effects/metabolism ; Mice ; Mice, Knockout ; Paclitaxel/*toxicity ; Peripheral Nervous System Diseases/*chemically induced/*drug therapy/genetics/metabolism ; Thiazoles/pharmacology/*therapeutic use ; }, abstract = {Axonal degeneration is an early and ongoing event that causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of morbidity and the main cause of dose reductions and discontinuations in cancer treatment. Preclinical evidence indicates that activation of the Wallerian-like degeneration pathway driven by sterile alpha and TIR motif containing 1 (SARM1) is responsible for axonopathy in CIPN. SARM1 is the central driver of an evolutionarily conserved programme of axonal degeneration downstream of chemical, inflammatory, mechanical or metabolic insults to the axon. SARM1 contains an intrinsic NADase enzymatic activity essential for its pro-degenerative functions, making it a compelling therapeutic target to treat neurodegeneration characterized by axonopathies of the peripheral and central nervous systems. Small molecule SARM1 inhibitors have the potential to prevent axonal degeneration in peripheral and central axonopathies and to provide a transformational disease-modifying treatment for these disorders. Using a biochemical assay for SARM1 NADase we identified a novel series of potent and selective irreversible isothiazole inhibitors of SARM1 enzymatic activity that protected rodent and human axons in vitro. In sciatic nerve axotomy, we observed that these irreversible SARM1 inhibitors decreased a rise in nerve cADPR and plasma neurofilament light chain released from injured sciatic nerves in vivo. In a mouse paclitaxel model of CIPN we determined that Sarm1 knockout mice prevented loss of axonal function, assessed by sensory nerve action potential amplitudes of the tail nerve, in a gene-dosage-dependent manner. In that CIPN model, the irreversible SARM1 inhibitors prevented loss of intraepidermal nerve fibres induced by paclitaxel and provided partial protection of axonal function assessed by sensory nerve action potential amplitude and mechanical allodynia.}, }
@article {pmid33961562, year = {2022}, author = {Martins, AS and Gromicho, M and Pinto, S and de Carvalho, M and Madeira, SC}, title = {Learning Prognostic Models Using Disease Progression Patterns: Predicting the Need for Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis.}, journal = {IEEE/ACM transactions on computational biology and bioinformatics}, volume = {19}, number = {5}, pages = {2572-2583}, doi = {10.1109/TCBB.2021.3078362}, pmid = {33961562}, issn = {1557-9964}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Disease Progression ; Humans ; *Neurodegenerative Diseases/complications ; *Noninvasive Ventilation/adverse effects ; Prognosis ; Quality of Life ; *Respiratory Insufficiency/etiology/therapy ; }, abstract = {Amyotrophic Lateral Sclerosis is a devastating neurodegenerative disease causing rapid degeneration of motor neurons and usually leading to death by respiratory failure. Since there is no cure, treatment's goal is to improve symptoms and prolong survival. Non-invasive Ventilation (NIV) is an effective treatment, leading to extended life expectancy and improved quality of life. In this scenario, it is paramount to predict its need in order to allow preventive or timely administration. In this work, we propose to use itemset mining together with sequential pattern mining to unravel disease presentation patterns together with disease progression patterns by analysing, respectively, static data collected at diagnosis and longitudinal data from patient follow-up. The goal is to use these static and temporal patterns as features in prognostic models, enabling to take disease progression into account in predictions and promoting model interpretability. As case study, we predict the need for NIV within 90, 180 and 365 days (short, mid and long-term predictions). The learnt prognostic models are promising. Pattern evaluation through growth rate suggests bulbar function and phrenic nerve response amplitude, additionally to respiratory function, are significant features towards determining patient evolution. This confirms clinical knowledge regarding relevant biomarkers of disease progression towards respiratory insufficiency.}, }
@article {pmid33960080, year = {2021}, author = {Meyer, T and Maier, A and Uzelac, Z and Hagenacker, T and Günther, R and Schreiber-Katz, O and Weiler, M and Steinbach, R and Weyen, U and Koch, JC and Kettemann, D and Norden, J and Dorst, J and Wurster, C and Ludolph, AC and Stolte, B and Freigang, M and Osmanovic, A and Petri, S and Grosskreutz, J and Rödiger, A and Griep, R and Gaudlitz, M and Walter, B and Münch, C and Spittel, S}, title = {Treatment expectations and perception of therapy in adult patients with spinal muscular atrophy receiving nusinersen.}, journal = {European journal of neurology}, volume = {28}, number = {8}, pages = {2582-2595}, doi = {10.1111/ene.14902}, pmid = {33960080}, issn = {1468-1331}, mesh = {Adolescent ; Adult ; Aged ; Humans ; Middle Aged ; *Motivation ; *Muscular Atrophy, Spinal/drug therapy ; Oligonucleotides ; Perception ; Prospective Studies ; Young Adult ; }, abstract = {BACKGROUND AND PURPOSE: This was an investigation of treatment expectations and of the perception of therapy in adult patients with 5q-associated spinal muscular atrophy (5q-SMA) receiving nusinersen.<br><br>METHODS: A prospective, non-interventional observational study of nusinersen treatment in adult 5q-SMA patients was conducted at nine SMA centers in Germany. The functional status, treatment expectations and perceived outcomes were assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale-extended (ALS-FRS-ex), the Measure Yourself Medical Outcome Profile (MYMOP2), the Treatment Satisfaction Questionnaire for Medication (TSQM-9) and the Net Promoter Score (NPS).<br><br>RESULTS: In all, 151 patients were included with a median age of 36&#xa0;years (15-69&#xa0;years). SMA type 3 (n&#xa0;=&#xa0;90, 59.6%) prevailed, followed by type 2 (33.8%) and type 1 (6.6%). In SMA types 1-3, median ALS-FRS-ex scores were 25, 33 and 46 (of 60 scale points), respectively. MYMOP2 identified distinct treatment expectations: head verticalization (n&#xa0;=&#xa0;13), bulbar function (n&#xa0;=&#xa0;16), arm function (n&#xa0;=&#xa0;65), respiration (n&#xa0;=&#xa0;15), trunk function (n&#xa0;=&#xa0;34), leg function (n&#xa0;=&#xa0;76) and generalized symptoms (n&#xa0;=&#xa0;77). Median symptom severity decreased during nusinersen treatment (median observational period 6.1&#xa0;months, 0.5-16&#xa0;months) from 3.7 to 3.3 MYMOP2 score points (p&#xa0;<&#xa0;0.001). The convenience of drug administration was critical (49.7 of 100 TSQM-9 points, SD 22); however, the overall treatment satisfaction was high (74.3, SD 18) and the recommendation rating very positive (NPS +66).<br><br>CONCLUSIONS: Nusinersen was administered across a broad range of ages, disease durations and motor function deficits. Treatment expectations were highly differentiated and related to SMA type and functional status. Patient-reported outcomes demonstrated a positive perception of nusinersen therapy in adult patients with 5q-SMA.}, }
@article {pmid33955162, year = {2021}, author = {Shimizu, H and Nishimura, Y and Shiide, Y and Yoshida, K and Hirai, M and Matsuda, M and Nakamaru, Y and Kato, Y and Kondo, K}, title = {Bioequivalence Study of Oral Suspension and Intravenous Formulation of Edaravone in Healthy Adult Subjects.}, journal = {Clinical pharmacology in drug development}, volume = {10}, number = {10}, pages = {1188-1197}, pmid = {33955162}, issn = {2160-7648}, mesh = {Administration, Oral ; Adolescent ; Adult ; Cross-Over Studies ; Drug Compounding/*methods ; Edaravone/*administration &amp; dosage/*metabolism ; Female ; Free Radical Scavengers/*administration &amp; dosage/*metabolism ; Healthy Volunteers ; Humans ; Infusions, Intravenous ; Male ; Suspensions ; Therapeutic Equivalency ; Young Adult ; }, abstract = {The neuroprotective agent edaravone is an intravenous treatment for amyotrophic lateral sclerosis. As intravenous administration burdens patients, orally administered treatments are needed. This phase 1, open-label, single-dose crossover study in 42 healthy adults evaluated bioequivalence of a 105-mg edaravone oral suspension and intravenous edaravone (60 mg/60 min). The evaluation was whether the 90% confidence intervals (CIs) for the ratio of the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to the last quantifiable time point and to infinity of unchanged edaravone were between the bioequivalence limit of 0.80 and 1.25. Metabolic profiles and elimination pathways were also compared between the 2 routes. Geometric mean ratios and 90%CIs of area under the plasma concentration-time curve from time 0 to the last quantifiable time point and to infinity for unchanged edaravone satisfied bioequivalence limits. The geometric mean ratio and its lower limit of 90%CI of Cmax of the 105-mg oral suspension compared with 60-mg intravenous formulations for unchanged edaravone fell within bioequivalence limits. Both formulations showed triphasic plasma concentration-time profiles of unchanged edaravone after reaching Cmax . Plasma concentrations of edaravone inactive metabolites after oral administration were higher than with intravenous administration. Edaravone in both routes underwent urinary excretion, mainly as the glucuronide conjugate and, to a lesser extent, as the sulfate conjugate. Urinary excretion of unchanged edaravone was low, and urinary relative composition ratios of unchanged edaravone and metabolites were similar for both formulations. These findings showed equivalent exposure of the 105-mg oral suspension of edaravone to the 60-mg intravenous formulation, supporting further investigation of the oral suspension for treating amyotrophic lateral sclerosis.}, }
@article {pmid33949928, year = {2021}, author = {Petrella, C and Di Certo, MG and Gabanella, F and Barbato, C and Ceci, FM and Greco, A and Ralli, M and Polimeni, A and Angeloni, A and Severini, C and Vitali, M and Ferraguti, G and Ceccanti, M and Lucarelli, M and Severi, C and Fiore, M}, title = {Mediterranean Diet, Brain and Muscle: Olive Polyphenols and Resveratrol Protection in Neurodegenerative and Neuromuscular Disorders.}, journal = {Current medicinal chemistry}, volume = {28}, number = {37}, pages = {7595-7613}, doi = {10.2174/0929867328666210504113445}, pmid = {33949928}, issn = {1875-533X}, mesh = {Brain ; *Diet, Mediterranean ; Humans ; Muscles ; *Olea ; Olive Oil ; Polyphenols/pharmacology/therapeutic use ; Resveratrol ; }, abstract = {The Mediterranean diet is worldwide recognized as a good prototype of nutrition due to the conspicuous intake of olive oil, nuts, red wine, legumes, fruit, and vegetables, all fundamental elements rich in antioxidant substances and polyphenols. Polyphenols are a wide range of phytochemicals and/or synthetic chemical compounds with proven beneficial properties for human health. In the present review, we critically summarize the wellcharacterized antioxidant and anti-inflammatory properties of polyphenols contained in the olives and extra virgin olive oil and of resveratrol, a non-flavonoid phenolic compound. We discuss the potential use of these polyphenols as pharmaceutical formulations for the treatment of human diseases. We also show the emerging importance of their consumption in the prevention and management of crucial neurodegenerative conditions (alcohol-related brain disorders and aging) and in neuromuscular disorders (Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis and Duchenne Muscular Dystrophy), where oxidative stress plays a predominant role.}, }
@article {pmid33948878, year = {2021}, author = {Athira, KV and Sadanandan, P and Chakravarty, S}, title = {Repurposing Vorinostat for the Treatment of Disorders Affecting Brain.}, journal = {Neuromolecular medicine}, volume = {23}, number = {4}, pages = {449-465}, pmid = {33948878}, issn = {1559-1174}, mesh = {Brain ; *Drug Repositioning ; Histone Deacetylase Inhibitors/therapeutic use ; Humans ; *Hydroxamic Acids/pharmacology ; Vorinostat/pharmacology/therapeutic use ; }, abstract = {Based on the findings in recent years, we summarize the therapeutic potential of vorinostat (VOR), the first approved histone deacetylase (HDAC) inhibitor, in disorders of brain, and strategies to improve drug efficacy and reduce side effects. Scientific evidences provide a strong case for the therapeutic utility of VOR in various disorders affecting brain, including stroke, Alzheimer's disease, frontotemporal dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, X-linked adrenoleukodystrophy, epilepsy, Niemann-Pick type C disease, and neuropsychiatric disorders. Further elucidation of the neuroprotective and neurorestorative properties of VOR using proper clinical study designs could provide momentum towards its clinical application. To improve the therapeutic prospect, concerns on systemic toxicity and off-target actions need to be addressed along with the improvement in formulation and delivery aspects, especially with respect to solubility, permeability, and pharmacokinetic properties. Newer approaches in this regard include poly(ethylene glycol)-b-poly(DL-lactic acid) micelles, VOR-pluronic F127 micelles, encapsulation of iron complexes of VOR into PEGylated liposomes, human serum albumin bound VOR nanomedicine, magnetically guided layer-by-layer assembled nanocarriers, as well as convection-enhanced delivery. Even though targeting specific class or isoform of HDAC is projected as advantageous over pan-HDAC inhibitor like VOR, in terms of adverse effects and efficacy, till clinical validation, the idea is debated. As the VOR treatment-related adverse changes are mostly found reversible, further optimization of the therapeutic strategies with respect to dose, dosage regimen, and formulations of VOR could propel its clinical prospects.}, }
@article {pmid33945797, year = {2021}, author = {Zhang, J and Li, D and Yang, G and Zhang, X and Chen, L and Zhang, Y and Qi, X and Li, Y and Guo, Y}, title = {Oxymatrine Extends Survival by Attenuating Neuroinflammation in a Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Neuroscience}, volume = {465}, number = {}, pages = {11-22}, doi = {10.1016/j.neuroscience.2021.04.019}, pmid = {33945797}, issn = {1873-7544}, mesh = {*Alkaloids/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Motor Neurons ; Quinolizines ; Spinal Cord ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the leading causes of death associated with neurodegenerative diseases worldwide, and the progression of the disease is characteristically accompanied by severe neuroinflammation. Neuroprotective effects of oxymatrine (OMT) were shown to be due to reduced neuroinflammation in the mouse models of Alzheimer's disease and Parkinson's disease. The present study investigated whether OMT has a therapeutic potential in transgenic SOD1-G93A (TgSOD1-G93A) mice. Daily OMT treatment started at the age of 55 days until the end stage of the disease. Body weight and rotarod motor performance were assessed every 3 days starting from 70 days of age. Footprints were recorded to measure the stride length 40 days and 60 days after the initiation of the treatment. Some animals were sacrificed at the age of 115 days, and the lumbar spinal cord was harvested for immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR) to evaluate the neuroinflammatory responses. The results indicated that treatment with OMT delayed body weight loss, improved motor performance, and prolonged the survival of SOD1-G93A mice. Mechanistically, OMT treatment enhanced motor neuronal survival and alleviated the activation of microglia and astrocytes compared with those in the vehicle-treated group. Furthermore, the expression of the proinflammatory mediators was downregulated, and the expression of the anti-inflammatory factors was upregulated in the OMT-treated group compared with those in the vehicle-treated group (P < 0.05). Thus, the treatment with OMT had neuroprotective effects, promoting neuronal survival and extending the lifetime of SOD1-G93A mice by suppressing neuroinflammation.}, }
@article {pmid33942709, year = {2022}, author = {Gonçalves, F and Magalhães, B}, title = {Effects of prolonged interruption of rehabilitation routines in amyotrophic lateral sclerosis patients.}, journal = {Palliative &amp; supportive care}, volume = {20}, number = {3}, pages = {369-374}, doi = {10.1017/S1478951521000584}, pmid = {33942709}, issn = {1478-9523}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; *COVID-19 ; Communicable Disease Control ; Disease Progression ; Fatigue ; Humans ; Middle Aged ; Pandemics ; Quality of Life/psychology ; }, abstract = {OBJECTIVE: Patients with amyotrophic lateral sclerosis (ALS) experienced prolonged interruption of their rehabilitation palliative care routines due to restrictive COVID-19 pandemic public health measures. This study assesses the effects of before and after the lockdown on functionality rates and quality of life (QoL) in patients with ALS.<br><br>METHODS: A longitudinal observational study was conducted. Participants were assessed three times - early January (T0), before mandatory lockdown (T1), and during lockdown (T2) - using the ALS Functional Rating Scale-revised (ALSFRS-R), Fatigue Severity Scale (FSS), and the ALS-Specific Quality of Life-Short Form (ALSSQOL-SF). The paired-sample t-test and Wilcoxon signed-rank test were used.<br><br>RESULTS: Thirty-two patients were included with a mean age of 56.9 (SD 14.2) years and mean symptoms onset of 27.1 (SD 14.3) months. ALSFRS-R mean scores decayed significantly over time when comparing T0-T1 (0.26 &#xb1; 0.38) and T1-T2 (1.36 &#xb1; 1.43) slopes (p < 0.001). Significant differences were observed between T1 and T2 for ALSSQOL-SF scores (115.31 &#xb1; 17.06 vs. 104.31 &#xb1; 20.65), especially in four specific domains, and FSS scores (34.06 &#xb1; 16.84 vs. 40.09 &#xb1; 17.63). Negative correlations between negative emotions and physical symptoms assessed by ALSSQOL-SF and FSS were found.<br><br>SIGNIFICANCE OF THE RESULTS: Rehabilitation treatment routines in palliative care, such as physiotherapy and speech therapy, appear to mitigate the ALSFRS-R slope. Prolonged interruption of rehabilitation during the lockdown may have accelerated the functional decline in ALS patients' motor skills with as measured after 2 months by the ALSFRS-R in the limb and bulbar subscores, but not respiratory subscore. Other short-term effects, increased fatigue and negative impact on QoL, were also verified.}, }
@article {pmid33931856, year = {2021}, author = {Milanese, M and Bonifacino, T and Torazza, C and Provenzano, F and Kumar, M and Ravera, S and Zerbo, AR and Frumento, G and Balbi, M and Nguyen, TPN and Bertola, N and Ferrando, S and Viale, M and Profumo, A and Bonanno, G}, title = {Blocking glutamate mGlu5 receptors with the negative allosteric modulator CTEP improves disease course in SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {British journal of pharmacology}, volume = {178}, number = {18}, pages = {3747-3764}, pmid = {33931856}, issn = {1476-5381}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Disease Models, Animal ; Disease Progression ; Female ; Glutamic Acid ; Male ; Mice ; Mice, Transgenic ; Receptor, Metabotropic Glutamate 5 ; Spinal Cord ; Superoxide Dismutase ; Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND AND PURPOSE: The pathogenesis of amyotrophic lateral sclerosis (ALS) is not fully clarified, although excessive glutamate (Glu) transmission and the downstream cytotoxic cascades are major mechanisms for motor neuron death. Two metabotropic glutamate receptors (mGlu1 and mGlu5) are overexpressed in ALS and regulate cellular disease processes. Expression and function of mGlu5 receptors are altered at early symptomatic stages in the SOD1[G93A] mouse model of ALS and knockdown of mGlu5 receptors in SOD1[G93A] mice improved disease progression.<br><br>EXPERIMENTAL APPROACH: We treated male and female SOD1[G93A] mice with 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP), an orally available mGlu5 receptor negative allosteric modulator (NAM), using doses of 2&#x2009;mg&#xb7;kg[-1] per 48&#x2009;h or 4&#x2009;mg&#xb7;kg[-1] per 24&#x2009;h from Day 90, an early symptomatic disease stage. Disease progression was studied by behavioural and histological approaches.<br><br>KEY RESULTS: CTEP dose-dependently ameliorated clinical features in SOD1[G93A] mice. The lower dose increased survival and improved motor skills in female mice, with barely positive effects in male mice. Higher doses significantly ameliorated disease symptoms and survival in both males and females, females being more responsive. CTEP also reduced motor neuron death, astrocyte and microglia activation, and abnormal glutamate release in the spinal cord, with equal effects in male and female mice. No differences were also observed in CTEP access to the brain.<br><br>CONCLUSION AND IMPLICATIONS: Our results suggest that mGlu5 receptors are promising targets for the treatment of ALS and highlight mGlu5 receptor NAMs as effective pharmacological tools with translational potential.}, }
@article {pmid33929499, year = {2021}, author = {Huang, C and Li, J and Zhang, G and Lin, Y and Li, C and Zheng, X and Song, X and Han, B and Guo, B and Tu, Z and Zhang, J and Sun, Y and Wang, Y and Zhang, Z and Yan, S}, title = {TBN improves motor function and prolongs survival in a TDP-43M337V mouse model of ALS.}, journal = {Human molecular genetics}, volume = {30}, number = {16}, pages = {1484-1496}, doi = {10.1093/hmg/ddab101}, pmid = {33929499}, issn = {1460-2083}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Animals ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia ; *Frontotemporal Lobar Degeneration/metabolism ; Glycogen Synthase Kinase 3 beta ; Humans ; Mice ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are serious neurodegenerative diseases. Although their pathogenesis is unclear, the abnormal accumulation of TAR DNA-binding protein of 43 kDa (TDP-43) is a pathological feature that exists in almost all patients. Thus far, there is no drug that can cure ALS/FTLD. Tetramethylpyrazine nitrone (TBN) is a derivative of tetramethylapyrazine, derived from the traditional Chinese medicine Ligusticum chuanxiong, which has been widely proven to have therapeutic effects on models of various neurodegenerative diseases. TBN is currently under clinical investigation for several indications including a Phase II trial of ALS. Here, we explored the therapeutic effect of TBN in an ALS/FTLD mouse model. We injected the TDP-43 M337V virus into the striatum of mice unilaterally and bilaterally, and then administered 30 mg/kg TBN intragastrically to observe changes in behavior and survival rate of mice. The results showed that in mice with unilateral injection of TDP-43M337V into the striatum, TBN improved motor deficits and cognitive impairment in the early stages of disease progression. In mice with bilateral injection of TDP-43M337V into the striatum, TBN not only improved motor function but also prolonged survival rate. Moreover, we show that its therapeutic effect may be through activation of the Akt/mTOR/GSK-3β and AMPK/PGC-1α/Nrf2 signaling pathways. In summary, TBN is a promising agent for the treatment of ALS/FTLD.}, }
@article {pmid33924890, year = {2021}, author = {Kulczyńska-Przybik, A and Mroczko, P and Dulewicz, M and Mroczko, B}, title = {The Implication of Reticulons (RTNs) in Neurodegenerative Diseases: From Molecular Mechanisms to Potential Diagnostic and Therapeutic Approaches.}, journal = {International journal of molecular sciences}, volume = {22}, number = {9}, pages = {}, pmid = {33924890}, issn = {1422-0067}, mesh = {Animals ; Carrier Proteins/*metabolism ; Humans ; Membrane Proteins/*metabolism ; Molecular Targeted Therapy ; Nerve Tissue Proteins/*metabolism ; Neurodegenerative Diseases/diagnosis/*metabolism/therapy ; Nogo Proteins/*metabolism ; }, abstract = {Reticulons (RTNs) are crucial regulatory factors in the central nervous system (CNS) as well as immune system and play pleiotropic functions. In CNS, RTNs are transmembrane proteins mediating neuroanatomical plasticity and functional recovery after central nervous system injury or diseases. Moreover, RTNs, particularly RTN4 and RTN3, are involved in neurodegeneration and neuroinflammation processes. The crucial role of RTNs in the development of several neurodegenerative diseases, including Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), or other neurological conditions such as brain injury or spinal cord injury, has attracted scientific interest. Reticulons, particularly RTN-4A (Nogo-A), could provide both an understanding of early pathogenesis of neurodegenerative disorders and be potential therapeutic targets which may offer effective treatment or inhibit disease progression. This review focuses on the molecular mechanisms and functions of RTNs and their potential usefulness in clinical practice as a diagnostic tool or therapeutic strategy.}, }
@article {pmid33924240, year = {2021}, author = {Yamashita, T and Kushida, Y and Abe, K and Dezawa, M}, title = {Non-Tumorigenic Pluripotent Reparative Muse Cells Provide a New Therapeutic Approach for Neurologic Diseases.}, journal = {Cells}, volume = {10}, number = {4}, pages = {}, pmid = {33924240}, issn = {2073-4409}, mesh = {Animals ; Apoptosis ; Clinical Trials as Topic ; Humans ; Mesenchymal Stem Cells/cytology ; Neoplasms/*pathology ; Nervous System Diseases/*therapy ; Pluripotent Stem Cells/*pathology ; }, abstract = {Muse cells are non-tumorigenic endogenous reparative pluripotent cells with high therapeutic potential. They are identified as cells positive for the pluripotent surface marker SSEA-3 in the bone marrow, peripheral blood, and connective tissue. Muse cells also express other pluripotent stem cell markers, are able to differentiate into cells representative of all three germ layers, self-renew from a single cell, and are stress tolerant. They express receptors for sphingosine-1-phosphate (S1P), which is actively produced by damaged cells, allowing circulating cells to selectively home to damaged tissue. Muse cells spontaneously differentiate on-site into multiple tissue-constituent cells with few errors and replace damaged/apoptotic cells with functional cells, thereby contributing to tissue repair. Intravenous injection of exogenous Muse cells to increase the number of circulating Muse cells enhances their reparative activity. Muse cells also have a specific immunomodulatory system, represented by HLA-G expression, allowing them to be directly administered without HLA-matching or immunosuppressant treatment. Owing to these unique characteristics, clinical trials using intravenously administered donor-Muse cells have been conducted for myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, perinatal hypoxic ischemic encephalopathy, and amyotrophic lateral sclerosis. Muse cells have the potential to break through the limitations of current cell therapies for neurologic diseases, including amyotrophic lateral sclerosis. Muse cells provide a new therapeutic strategy that requires no HLA-matching or immunosuppressant treatment for administering donor-derived cells, no gene introduction or differentiation induction for cell preparation, and no surgery for delivering the cells to patients.}, }
@article {pmid33923609, year = {2021}, author = {Jin, Y and Vadukul, DM and Gialama, D and Ge, Y and Thrush, R and White, JT and Aprile, FA}, title = {The Diagnostic Potential of Amyloidogenic Proteins.}, journal = {International journal of molecular sciences}, volume = {22}, number = {8}, pages = {}, pmid = {33923609}, issn = {1422-0067}, support = {MR/S033947/1/MRC_/Medical Research Council/United Kingdom ; ARUK-PG2019B-020//Alzheimer's Research UK/ ; 511/ALZS_/Alzheimer's Society/United Kingdom ; UKRI Future Leaders Fellowship MR/S033947/1//UK Research and Innovation/ ; }, mesh = {Amyloid/chemistry/genetics/*metabolism ; Animals ; Biomarkers/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Protein Aggregation, Pathological/*metabolism/pathology ; }, abstract = {Neurodegenerative disorders are a highly prevalent class of diseases, whose pathological mechanisms start before the appearance of any clear symptoms. This fact has prompted scientists to search for biomarkers that could aid early treatment. These currently incurable pathologies share the presence of aberrant aggregates called amyloids in the nervous system, which are composed of specific proteins. In this review, we discuss how these proteins, their conformations and modifications could be exploited as biomarkers for diagnostic purposes. We focus on proteins that are associated with the most prevalent neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and frontotemporal dementia. We also describe current challenges in detection, the most recent techniques with diagnostic potentials and possible future developments in diagnosis.}, }
@article {pmid33920090, year = {2021}, author = {Ioele, G and Muzzalupo, R and Gündüz, MG and De Luca, M and Mazzotta, E and Grande, F and Occhiuzzi, MA and Garofalo, A and Ragno, G}, title = {Use of Pluronic Surfactants in Gel Formulations of Photosensitive 1,4-Dihydropyridine Derivatives: A Potential Approach in the Treatment of Neuropathic Pain.}, journal = {Pharmaceutics}, volume = {13}, number = {4}, pages = {}, pmid = {33920090}, issn = {1999-4923}, abstract = {1,4-Dihydropyridines (DHPs) are the most important class of L-type calcium channel blockers that are employed for the treatment of cardiovascular diseases, particularly hypertension. Various modifications on this scaffold lead to the discovery of new DHPs blocking different types of calcium channels. Among them, the T-type calcium channel has recently attracted great interest due to its role in chronic pain conditions. In this study, we selected three newly synthesized DHPs (HM8, HM10 and MD20) with different selectivity profiles to the T-type calcium channel and formulated them in micellar solutions and micellar-in-gel matrices to be tested for potential topical use in the treatment of neuropathic pain. To prevent the well-known sensitivity to light of the DHPs, the studied compounds were entrapped in colloidal aggregates obtained by using edible Pluronic[®] surfactants and adding α-tocopherol as an antioxidant. All the prepared formulations were exposed to stressing light, according to international rules. Along with the degradation experiments, the concentrations of the parent compounds and by-products were calculated by multivariate curve resolution-alternating least squares (MCR-ALS) applied to the spectral data. The defined formulations proved suitable as light-stable matrices for the DHP compounds, showing an increase in stability for HM8 and MD20 and an almost complete photoprotection for HM10, compared to ethanol solutions and standard gel formulations.}, }
@article {pmid33917816, year = {2021}, author = {Jiang, X and Guan, Y and Zhao, Z and Meng, F and Wang, X and Gao, X and Liu, J and Chen, Y and Zhou, F and Zhou, S and Wang, X}, title = {Potential Roles of the WNT Signaling Pathway in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {10}, number = {4}, pages = {}, pmid = {33917816}, issn = {2073-4409}, support = {81871006//National Natural Science Foundation of China/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology ; Animals ; Axons/metabolism/pathology ; Humans ; Ligands ; Neuromuscular Junction/metabolism/pathology ; Wnt Proteins/metabolism ; *Wnt Signaling Pathway ; }, abstract = {The WNT signaling pathway plays an important role in the physiological and pathophysiological processes of the central nervous system and the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We reviewed the literature pertinent to WNT/β-catenin signaling in ALS from cellular studies, animal models, and human clinical trials. WNT, WNT receptors, and other components of the WNT signaling pathway are expressed in both ALS patients and transgenic mice, and are involved in the pathogenesis of ALS. Studies have shown that abnormal activation of the WNT/β-catenin signaling pathway is related to neuronal degeneration and glial cell proliferation. WNT/Ca[2+] signaling is associated with the pro-inflammatory phenotype of microglia; data on the muscle skeletal receptor Tyr kinase receptor in superoxide dismutase-1-G93A mice indicate that gene therapy is necessary for successful treatment of ALS. The varying profiles of lipoprotein receptor-related protein 4 antibodies in different ethnic groups suggest that individual treatment and multifactorial personalized approaches may be necessary for effective ALS therapy. In conclusion, the WNT signaling pathway is important to the ALS disease process, making it a likely therapeutic target.}, }
@article {pmid33913406, year = {2022}, author = {Mohi-Ud-Din, R and Mir, RH and Shah, AJ and Sabreen, S and Wani, TU and Masoodi, MH and Akkol, EK and Bhat, ZA and Khan, H}, title = {Plant-Derived Natural Compounds for the Treatment of Amyotrophic Lateral Sclerosis: An Update.}, journal = {Current neuropharmacology}, volume = {20}, number = {1}, pages = {179-193}, pmid = {33913406}, issn = {1875-6190}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Motor Neuron Disease ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease (MND) that typically causes death within 3-5 years after diagnosis. Regardless of the substantial scientific knowledge accrued more than a century ago, truly effective therapeutic strategies remain distant. Various conventional drugs are being used but are having several adverse effects.<br><br>OBJECTIVE/AIM: The current study aims to thoroughly review plant-derived compounds with welldefined ALS activities and their structure-activity relationships. Moreover, the review also focuses on complex genetics, clinical trials, and the use of natural products that might decrypt the future and novel therapeutics in ALS.<br><br>METHODS: The collection of data for the compilation of this review work was searched in PubMed Scopus, Google Scholar, and Science Direct.<br><br>RESULTS: Results showed that phytochemicals like-Ginkgolides, Protopanaxatriol, Genistein, epigallocatechingallate, resveratrol, cassoside, and others possess Amyotrophic lateral sclerosis (ALS) activity by various mechanisms Conclusion: These plant-derived compounds may be considered as supplements for conventional (ALS). Moreover, further preclinical and clinical studies are required to understand the structureactivity relationships, metabolism, absorption, and mechanisms of plant-derived natural agents.}, }
@article {pmid33905493, year = {2021}, author = {Dalla Bella, E and Bersano, E and Antonini, G and Borghero, G and Capasso, M and Caponnetto, C and Chiò, A and Corbo, M and Filosto, M and Giannini, F and Spataro, R and Lunetta, C and Mandrioli, J and Messina, S and Monsurrò, MR and Mora, G and Riva, N and Rizzi, R and Siciliano, G and Silani, V and Simone, I and Sorarù, G and Tugnoli, V and Verriello, L and Volanti, P and Furlan, R and Nolan, JM and Abgueguen, E and Tramacere, I and Lauria, G}, title = {The unfolded protein response in amyotrophic later sclerosis: results of a phase 2 trial.}, journal = {Brain : a journal of neurology}, volume = {144}, number = {9}, pages = {2635-2647}, pmid = {33905493}, issn = {1460-2156}, mesh = {Adrenergic alpha-2 Receptor Agonists/pharmacology/*therapeutic use ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/*metabolism ; Double-Blind Method ; Female ; Guanabenz/pharmacology/*therapeutic use ; Humans ; Male ; Middle Aged ; Unfolded Protein Response/drug effects/*physiology ; }, abstract = {Strong evidence suggests that endoplasmic reticulum stress plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through altered regulation of proteostasis. Robust preclinical findings demonstrated that guanabenz selectively inhibits endoplasmic reticulum stress-induced eIF2α-phosphatase, allowing misfolded protein clearance, reduces neuronal death and prolongs survival in in vitro and in vivo models. However, its safety and efficacy in patients with ALS are unknown. To address these issues, we conducted a multicentre, randomized, double-blind trial with a futility design. Patients with ALS who had displayed an onset of symptoms within the previous 18 months were randomly assigned in a 1:1:1:1 ratio to receive 64 mg, 32 mg or 16 mg of guanabenz or placebo daily for 6 months as an add-on therapy to riluzole. The purpose of the placebo group blinding was to determine safety but not efficacy. The primary outcome was the proportion of patients progressing to higher stages of disease within 6 months as measured using the ALS Milano-Torino staging system, compared with a historical cohort of 200 patients with ALS. The secondary outcomes were the rate of decline in the total revised ALS functional rating scale score, slow vital capacity change, time to death, tracheotomy or permanent ventilation and serum light neurofilament level at 6 months. The primary assessment of efficacy was performed using intention-to-treat analysis. The treatment arms using 64 mg and 32 mg guanabenz, both alone and combined, reached the primary hypothesis of non-futility, with the proportions of patients who progressed to higher stages of disease at 6 months being significantly lower than that expected under the hypothesis of non-futility and a significantly lower difference in the median rate of change in the total revised ALS functional rating scale score. This effect was driven by patients with bulbar onset, none of whom (0/18) progressed to a higher stage of disease at 6 months compared with those on 16 mg guanabenz (4/8; 50%), the historical cohort alone (21/49; 43%; P = 0.001) or plus placebo (25/60; 42%; P = 0.001). The proportion of patients who experienced at least one adverse event was higher in any guanabenz arm than in the placebo arm, with higher dosing arms having a significantly higher proportion of drug-related side effects and the 64 mg arm a significantly higher drop-out rate. The number of serious adverse events did not significantly differ between the guanabenz arms and the placebo. Our findings indicate that a larger trial with a molecule targeting the unfolded protein response pathway without the alpha-2 adrenergic related side-effect profile of guanabenz is warranted.}, }
@article {pmid33898431, year = {2021}, author = {Wang, TY and Chang, MM and Li, YJ and Huang, TC and Chien, S and Wu, CC}, title = {Maintenance of HDACs and H3K9me3 Prevents Arterial Flow-Induced Venous Endothelial Damage.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {642150}, pmid = {33898431}, issn = {2296-634X}, abstract = {The transition of flow microenvironments from veins to arteries in vein graft surgery induces "peel-off" of venous endothelial cells (vECs) and results in restenosis. Recently, arterial laminar shear stress (ALS) and oscillatory shear stress (OS) have been shown to affect the cell cycle and inflammation through epigenetic controls such as histone deacetylation by histone deacetylases (HDACs) and trimethylation on lysine 9 of histone 3 (H3K9me3) in arterial ECs. However, the roles of H3K9me3 and HDAC in vEC damage under ALS are not known. We hypothesized that the different responses of HDACs and H3K9me3 might cause vEC damage under the transition of venous flow to arterial flow. We found that arterial ECs showed high expression of H3K9me3 protein and were retained in the G0 phase of the cell cycle after being subjected to ALS. vECs became round under ALS with a decrease in the expression of H3K9me3, HDAC3, and HDAC5, and an increase in the expression of vascular cell adhesion molecule 1 (VCAM-1). Inhibition of HDACs activity by a specific inhibitor, phenylbutyrate, in arterial ECs caused similar ALS-induced inflammation and cell loss as observed in vECs. Activation of HDACs and H3K9me3 by ITSA-1, an HDAC activator, could prevent ALS-induced peel-off and reduced VCAM-1 expression in vECs. Moreover, shear stress modulates EC morphology by the regulation of focal adhesion kinase (FAK) expression. ITSA-1 or EGF could increase phosphorylated (p)-FAK expression in vECs under ALS. We found that perturbation of the activity of p-FAK and increase in p-FAK expression restored ALS-induced H3K9me3 expression in vECs. Hence, the abnormal mechanoresponses of H3K9me3 and HDAC in vECs after being subjected to ALS could be reversed by ITSA-1 or EGF treatment: this offers a strategy to prevent vein graft failure.}, }
@article {pmid33897409, year = {2021}, author = {Ou, GY and Lin, WW and Zhao, WJ}, title = {Neuregulins in Neurodegenerative Diseases.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {662474}, pmid = {33897409}, issn = {1663-4365}, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), are typically characterized by progressive neuronal loss and neurological dysfunctions in the nervous system, affecting both memory and motor functions. Neuregulins (NRGs) belong to the epidermal growth factor (EGF)-like family of extracellular ligands and they play an important role in the development, maintenance, and repair of both the central nervous system (CNS) and peripheral nervous system (PNS) through the ErbB signaling pathway. They also regulate multiple intercellular signal transduction and participate in a wide range of biological processes, such as differentiation, migration, and myelination. In this review article, we summarized research on the changes and roles of NRGs in neurodegenerative diseases, especially in AD. We elaborated on the structural features of each NRG subtype and roles of NRG/ErbB signaling networks in neurodegenerative diseases. We also discussed the therapeutic potential of NRGs in the symptom remission of neurodegenerative diseases, which may offer hope for advancing related treatment.}, }
@article {pmid33879715, year = {2021}, author = {Kim, JY and Oh, HJ and Kim, Y and Seok, JM}, title = {Sporadic amyotrophic lateral sclerosis with seropositive neuromyelitis optica spectrum disorder: A case report.}, journal = {Medicine}, volume = {100}, number = {16}, pages = {e25580}, pmid = {33879715}, issn = {1536-5964}, support = {no//Soonchunhyang University Research Fund/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Aquaporin 4/*immunology ; Autoantibodies/*blood ; Female ; Humans ; Middle Aged ; Neuromyelitis Optica/blood/*immunology ; }, abstract = {RATIONALE: Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory disorder of the central nervous system with an autoantibody against aquaporin-4 protein (AQP4), and amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. We report a female patient with ALS who had asymptomatic AQP4 antibody at the diagnosis of ALS, and NMOSD occurred 4 years later after the diagnosis of ALS.<br><br>PATIENT CONCERNS: She was already bedridden and had tracheostomy because of ALS which was diagnosed at her age of 55. At the time of her ALS diagnosis, she had no brain or spinal cord lesions, but was seropositive for AQP4 antibody. At her age of 59, new-onset complete paralysis of all extremities and severe pain on the posterior neck and both shoulders occurred and visited the hospital.<br><br>DIAGNOSIS: Longitudinally extensive transverse myelitis was diagnosed, which was the onset attack of seropositive NMOSD. The diagnosis was confirmed based on the international consensus diagnostic criteria for NMOSD with MR imaging, cerebrospinal fluid exam and laboratory work-ups with AQP4 antibody test.<br><br>INTERVENTIONS: High dose methylprednisolone was administered for 5&#x200a;days. Plasma exchange as a further treatment was recommended, but she and her family refused.<br><br>OUTCOMES: Her pain was relieved after steroid treatment, but there was no improvement of her leg weakness.<br><br>LESSONS: This case is a rare combination of neuroinflammatory and neurodegenerative diseases. Considering the alterations of blood-brain barrier along with the progression of ALS, it highlights that the consequence of ALS pathogenesis might affect the development of NMOSD. And the careful follow-up is recommended even in patients with profound weakness, especially if those who were at risk of developing certain neurological disorders.}, }
@article {pmid33877561, year = {2021}, author = {Khan, H and Tiwari, P and Kaur, A and Singh, TG}, title = {Sirtuin Acetylation and Deacetylation: a Complex Paradigm in Neurodegenerative Disease.}, journal = {Molecular neurobiology}, volume = {58}, number = {8}, pages = {3903-3917}, pmid = {33877561}, issn = {1559-1182}, mesh = {Acetylation/drug effects ; Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neuroprotective Agents/pharmacology/*therapeutic use ; Sirtuins/*metabolism ; }, abstract = {Sirtuins are the class III of histone deacetylases that depend on nicotinamide adenine dinucleotide for their activity. Sirtuins can influence the progression of neurodegenerative disorders by switching between deacetylation and acetylation processes. Histone acetylation occurs when acetyl groups are added to lysine residues on the N-terminal part of histone proteins. Deacetylation, on the other hand, results in the removal of acetyl groups. Pharmacological modulation of sirtuin activity has been shown to influence various neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and amyotrophic lateral sclerosis. In this review, mechanistic perspective of sirtuins has been discussed in anti-inflammatory, antiapoptotic, and neuroprotective effects in various disorders. We have discussed the structure, neurobiology, and physiology of sirtuins in neurodegenerative disease. Recent preclinical and clinical studies and their outcome have also been elucidated. The aim of this review is to fill in the gaps in our understanding of sirtuins' role in histone acetylation and deacetylation in all neurodegenerative diseases. Here, we emphasized on reviewing all the studies carried out in various labs depicting the role of sirtuin modulators in neuroprotection and highlighted the ideas that can be considered for future perspectives. Taken together, sirtuins may serve as a promising therapeutic target for the treatment of neurodegenerative disorders.}, }
@article {pmid33872379, year = {2021}, author = {Sukockienė, E and Iancu Ferfoglia, R and Boegli, M and Lefranc Barranco, C and Truffert, A and Héritier Barras, AC and Genton, L and Leuchter, I and Adler, D and Janssens, JP and Escher, M}, title = {Early advance care planning in amyotrophic lateral sclerosis patients: results of a systematic intervention by a palliative care team in a multidisciplinary management programme - a 4-year cohort study.}, journal = {Swiss medical weekly}, volume = {151}, number = {}, pages = {w20484}, doi = {10.4414/smw.2021.20484}, pmid = {33872379}, issn = {1424-3997}, mesh = {*Advance Care Planning ; Aged ; Aged, 80 and over ; *Amyotrophic Lateral Sclerosis/therapy ; Cohort Studies ; Female ; Humans ; Middle Aged ; Palliative Care ; Prospective Studies ; }, abstract = {INTRODUCTION: Although recommended, the implementation of early advance care planning is suboptimal in amyotrophic lateral sclerosis (ALS) patients. Barriers to advance care planning include healthcare professionals’ and patients’ reluctance, and uncertainty about the right time to initiate a discussion.<br><br>AIM OF THE STUDY: To determine how often advance care planning was initiated, and the content of the discussion in a first routine palliative care consultation integrated within a multidisciplinary management programme.<br><br>METHODS: Between June 2012 and September 2016, a prospective cohort study was conducted in Geneva University Hospitals. Sixty-eight patients were seen every 3 months for a 1-day clinical evaluation in a day care centre.<br><br>RESULTS: The patients&rsquo; mean &plusmn; standard deviation age was 68.6 &plusmn; 11.9 years, 50% were women. Four patients were excluded because of dementia. Advance care planning was initiated with 49 (77%) patients in the first palliative care consultation. Interventions most often addressed were cardiopulmonary resuscitation (49%), intubation and tracheostomy (47%) and palliative sedation (36.7%). Assisted suicide was discussed with 16 patients (36.6%). Functional disability was the only factor associated with initiation of advance care planning. Nearly half of the patients wrote advance directives (45%) or designated a healthcare surrogate (41%). Bulbar onset, functional disability and noninvasive ventilation were not associated with the completion of advance directives.<br><br>CONCLUSION: Early initiation of advance care planning is feasible in most ALS patients during a routine consultation, and relevant treatment issues can be discussed. All ALS patients should be offered the opportunity to write advance directives as completion was not associated with disease severity.&amp;nbsp.}, }
@article {pmid33865343, year = {2021}, author = {Kjældgaard, AL and Pilely, K and Olsen, KS and Jessen, AH and Lauritsen, A&#xd8; and Pedersen, SW and Svenstrup, K and Karlsborg, M and Thagesen, H and Blaabjerg, M and Theódórsdóttir, &#xc1; and Elmo, EG and Møller, AT and Bonefeld, L and Berg, M and Garred, P and Møller, K}, title = {Prediction of survival in amyotrophic lateral sclerosis: a nationwide, Danish cohort study.}, journal = {BMC neurology}, volume = {21}, number = {1}, pages = {164}, pmid = {33865343}, issn = {1471-2377}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*mortality ; Cohort Studies ; Denmark ; *Disease Progression ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Prognosis ; *Severity of Illness Index ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with great heterogeneity. Biological prognostic markers are needed for the patients to plan future supportive treatment, palliative treatment, and end-of-life decisions. In addition, prognostic markers are greatly needed for the randomization in clinical trials.<br><br>OBJECTIVE: This study aimed to test the ALS Functional Rating Scale-Revised (ALSFRS-R) progression rate (&#x394;FS) as a prognostic marker of survival in a Danish ALS cohort.<br><br>METHODS: The ALSFRS-R score at test date in association with duration of symptoms, from the onset of symptoms until test date, (defined as &#x394;FS') was calculated for 90 Danish patients diagnosed with either probable or definite sporadic ALS. Median survival time was then estimated from the onset of symptoms until primary endpoint (either death or tracheostomy). &#x394;FS' was subjected to survival analysis using Cox proportional hazards modelling, log-rank test, and Kaplan-Meier survival analysis.<br><br>RESULTS AND CONCLUSIONS: Both &#x394;FS' and age was found to be strong predictors of survival of the Danish ALS cohort. Both variables are easily obtained at the time of diagnosis and could be used by clinicians and ALS patients to plan future supportive and palliative treatment. Furthermore, &#x394;FS', is a simple, prognostic marker that predicts survival in the early phase of disease as well as at later stages of the disease.}, }
@article {pmid33865016, year = {2021}, author = {Bai, X and Fu, RJ and Zhang, S and Yue, SJ and Chen, YY and Xu, DQ and Tang, YP}, title = {Potential medicinal value of celastrol and its synthesized analogues for central nervous system diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {139}, number = {}, pages = {111551}, doi = {10.1016/j.biopha.2021.111551}, pmid = {33865016}, issn = {1950-6007}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/pharmacology/therapeutic use ; Central Nervous System Agents/pharmacology/*therapeutic use ; Central Nervous System Diseases/*drug therapy ; Central Nervous System Neoplasms/drug therapy ; Humans ; Pentacyclic Triterpenes/*therapeutic use ; Tripterygium/chemistry ; }, abstract = {The central nervous system (CNS) is a vital part of the human nervous system, and the incidence of CNS disease is increasing year by year, which has become a major public health problem and a prominent social problem. At present, the drugs most commonly used in the clinic are receptor regulators, and neurotransmitter inhibitors, but they are accompanied by serious side effects. Therefore, the identification of new drugs and treatment strategies for CNS disease has been a research hotspot in the medical field. Celastrol, a highly bio-active pentacyclic triterpenoid isolated from Tripterygium wilfordii Hook. F, has been proved to have a wide range of pharmacological effects, such as anti-inflammation, immunosuppression, anti-obesity and anti-tumor activity. However, due to its poor water solubility, low bioavailability and toxicity, the clinical development and trials of celastrol have been postponed. However, in recent years, the extensive medical value of celastrol in the treatment of CNS diseases such as nervous system tumors, Alzheimer's disease, Parkinson's disease, cerebral ischemia, multiple sclerosis, spinal cord injury, and amyotrophic lateral sclerosis has gradually attracted intensive attention worldwide. In particular, celastrol has non-negligible anti-tumor efficacy, and as there are no 100% effective anti-tumor drugs, the study of its structural modification to obtain better leading compounds with higher efficiency and lower toxicity has aroused strong interest in pharmaceutical chemists. In this review, research progress on celastrol in CNS diseases and the synthesis of celastrol-type triterpenoid analogues and their application evaluation in disease models, such as CNS diseases and autotoxicity-related target organ cancers in the past decade are summarized in detail, in order to provide reference for future better application in the treatment of CNS diseases.}, }
@article {pmid33861641, year = {2021}, author = {Atif, M and Alsrhani, A and Naz, F and Imran, M and Imran, M and Ullah, MI and Alameen, AAM and Gondal, TA and Raza, Q}, title = {Targeting Adenosine Receptors in Neurological Diseases.}, journal = {Cellular reprogramming}, volume = {23}, number = {2}, pages = {57-72}, doi = {10.1089/cell.2020.0087}, pmid = {33861641}, issn = {2152-4998}, mesh = {Animals ; Humans ; Nervous System Diseases/*drug therapy/metabolism ; Neuroprotective Agents/*pharmacology ; Receptors, Purinergic P1/*chemistry/metabolism ; Signal Transduction ; }, abstract = {Adenosine plays a significant role in neurotransmission process by controlling the blood pressure, while adenosine triphosphate (ATP) acts as a neuromodulator and neurotransmitter and by activation of P2 receptors, regulates the contractility of the heart. Adenosine signaling is essential in the process of regeneration by regulating proliferation, differentiation, and apoptosis of stem cells. In this review, we have selected neurological disorders (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy) with clinical trials using antagonists and epigenetic tools targeting adenosine receptor as a therapeutic approach in the treatment of these disorders. Promising results have been reported from many clinical trials. It has been found that higher expression levels of A2A and P2X7 receptors in neurological disorders further complicate the disease condition. Therefore, modulations of these receptors by using antagonists of these receptors or SAM (S-adenosylmethionine) therapy as an epigenetic tool could be useful in reversing the complications of these disorders. Finally, we suggest that modulation of adenosine receptors in neurological disorders can increase the regenerative phase by increasing the rate of proliferation and differentiation in the damaged tissues.}, }
@article {pmid33861265, year = {2021}, author = {Wang, Y and Wang, Q and Han, X and Ma, Y and Zhang, Z and Zhao, L and Guan, F and Ma, S}, title = {Fucoidan: a promising agent for brain injury and neurodegenerative disease intervention.}, journal = {Food &amp; function}, volume = {12}, number = {9}, pages = {3820-3830}, doi = {10.1039/d0fo03153d}, pmid = {33861265}, issn = {2042-650X}, mesh = {Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Antiviral Agents/pharmacology/therapeutic use ; Apoptosis/drug effects ; Brain Injuries/*drug therapy/physiopathology ; Cholinergic Agents/pharmacology/therapeutic use ; Drug Therapy, Combination ; Humans ; Mitochondria/drug effects/physiology ; Neurites/drug effects/physiology ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neuroprotective Agents/pharmacology/*therapeutic use ; Polysaccharides/pharmacokinetics/pharmacology/*therapeutic use ; }, abstract = {Brain injury and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are urgent medical problems, which severely threaten the life quality of patients and their carers. However, there are currently no effective therapies. Fucoidan is a natural compound found in brown algae and some animals, which has multiple biological and pharmacological activities, such as antioxidant, anti-tumor, anti-coagulant, anti-thrombotic, immunoregulatory, anti-viral, and anti-inflammatory effects. A growing number of studies have shown that fucoidan also exerts a neuroprotective function. Particularly, recent findings have indicated that fucoidan could slow down the neurodegenerative processes and show protective effects against brain injury, which might be of therapeutic value for intervening in brain injury and neurodegenerative diseases. In this review, we have discussed the pharmacokinetics of fucoidan as well as the molecular mechanisms by which fucoidan exerts its neuroprotective effect on some neurological disorders. Along with this, we have also summarized the potential benefits of fucoidan in combination with other drugs in the treatment of neurodegenerative diseases and brain injury. Although the extraction process of fucoidan has been improved well, more efforts should be devoted to the translational research and clinical trials of fucoidan in the near future.}, }
@article {pmid33860461, year = {2021}, author = {Peters, S and Kuespert, S and Wirkert, E and Heydn, R and Jurek, B and Johannesen, S and Hsam, O and Korte, S and Ludwig, FT and Mecklenburg, L and Mrowetz, H and Altendorfer, B and Poupardin, R and Petri, S and Thal, DR and Hermann, A and Weishaupt, JH and Weis, J and Aksoylu, IS and Lewandowski, SA and Aigner, L and Bruun, TH and Bogdahn, U}, title = {Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGFβ Signaling.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {18}, number = {3}, pages = {1963-1979}, pmid = {33860461}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Dose-Response Relationship, Drug ; Female ; Humans ; Macaca fascicularis ; Male ; Neural Stem Cells/*drug effects/metabolism ; Neurogenesis/*drug effects/physiology ; Oligonucleotides, Antisense/*pharmacology ; Primates ; Signal Transduction/*drug effects/physiology ; Transforming Growth Factor beta/*antagonists &amp; inhibitors/biosynthesis ; }, abstract = {Adult neurogenesis is a target for brain rejuvenation as well as regeneration in aging and disease. Numerous approaches showed efficacy to elevate neurogenesis in rodents, yet translation into therapies has not been achieved. Here, we introduce a novel human TGFβ-RII (Transforming Growth Factor-Receptor Type II) specific LNA-antisense oligonucleotide ("locked nucleotide acid"-"NVP-13"), which reduces TGFβ-RII expression and downstream receptor signaling in human neuronal precursor cells (ReNcell CX® cells) in vitro. After we injected cynomolgus non-human primates repeatedly i.th. with NVP-13 in a preclinical regulatory 13-week GLP-toxicity program, we could specifically downregulate TGFβ-RII mRNA and protein in vivo. Subsequently, we observed a dose-dependent upregulation of the neurogenic niche activity within the hippocampus and subventricular zone: human neural progenitor cells showed significantly (up to threefold over control) enhanced differentiation and cell numbers. NVP-13 treatment modulated canonical and non-canonical TGFβ pathways, such as MAPK and PI3K, as well as key transcription factors and epigenetic factors involved in stem cell maintenance, such as MEF2A and pFoxO3. The latter are also dysregulated in clinical neurodegeneration, such as amyotrophic lateral sclerosis. Here, we provide for the first time in vitro and in vivo evidence for a novel translatable approach to treat neurodegenerative disorders by modulating neurogenesis.}, }
@article {pmid33855783, year = {2021}, author = {Zhao, MJ and Yao, X and Wei, P and Zhao, C and Cheng, M and Zhang, D and Xue, W and He, WT and Xue, W and Zuo, X and Jiang, LL and Luo, Z and Song, J and Shu, WJ and Yuan, HY and Liang, Y and Sun, H and Zhou, Y and Zhou, Y and Zheng, L and Hu, HY and Wang, J and Du, HN}, title = {O-GlcNAcylation of TDP-43 suppresses proteinopathies and promotes TDP-43's mRNA splicing activity.}, journal = {EMBO reports}, volume = {22}, number = {6}, pages = {e51649}, pmid = {33855783}, issn = {1469-3178}, support = {2013CB910700//Major State Basic Research Development Program of China/ ; 31770843//National Natural Science Foundation of China/ ; 32071135//National Natural Science Foundation of China/ ; 31471010//National Natural Science Foundation of China/ ; 31770833//National Natural Science Foundation of China/ ; 2020020601012225//Application Fundamental Frontier Foundation of Wuhan/ ; 19ZR1446400//Natural Science Foundation of Shanghai/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia ; Humans ; RNA Splicing ; RNA, Messenger/genetics ; }, abstract = {Pathological TDP-43 aggregation is characteristic of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP); however, how TDP-43 aggregation and function are regulated remain poorly understood. Here, we show that O-GlcNAc transferase OGT-mediated O-GlcNAcylation of TDP-43 suppresses ALS-associated proteinopathies and promotes TDP-43's splicing function. Biochemical and cell-based assays indicate that OGT's catalytic activity suppresses TDP-43 aggregation and hyperphosphorylation, whereas abolishment of TDP-43 O-GlcNAcylation impairs its RNA splicing activity. We further show that TDP-43 mutations in the O-GlcNAcylation sites improve locomotion defects of larvae and adult flies and extend adult life spans, following TDP-43 overexpression in Drosophila motor neurons. We finally demonstrate that O-GlcNAcylation of TDP-43 promotes proper splicing of many mRNAs, including STMN2, which is required for normal axonal outgrowth and regeneration. Our findings suggest that O-GlcNAcylation might be a target for the treatment of TDP-43-linked pathogenesis.}, }
@article {pmid33854472, year = {2021}, author = {Mix, L and Winter, B and Wurster, CD and Platen, S and Witzel, S and Uzelac, Z and Graf, H and Ludolph, AC and Lulé, D}, title = {Quality of Life in SMA Patients Under Treatment With Nusinersen.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {626787}, pmid = {33854472}, issn = {1664-2295}, abstract = {Background: Spinal Muscular Atrophy (SMA) is a severe neurodegenerative disease, characterized by progressive muscle weakness and atrophy. The approval of the antisense oligonucleotide (ASO) nusinersen now provides an effective pharmacological approach with the potential to slow down or stop disease progression with a potentially major impact on patients' well-being. Objective: This study evaluates quality of life (QoL) in pediatric and adult patients over the course of therapy with nusinersen. Methods: Twenty-six SMA patients treated with nusinersen were evaluated regarding global QoL (gQoL), health-related QoL (HRQoL) and depressiveness. Assessments were conducted three times over the first 6 months of treatment. Applied were different questionnaires: the Anamnestic Comparative Self-Assessment (ACSA) for gQoL, the Short Form-36 Health Survey (SF-36) for HRQoL in adult patients and the ALS Depression Inventory 12 Items (ADI-12) for depressiveness. The sample was matched with 22 healthy controls. Results: Despite severe physical restrictions, patients reported high levels of QoL and low levels of depressiveness at study entry. Early disease onset and low levels of physical functioning were associated with better gQoL and lower levels of depressiveness. A significant decrease of gQoL in patients was evident over the course of the study. Still, adult patients reported a significant increase in perceived health. Conclusions: Our study provides first insight that SMA patients experience a gQoL superior to healthy controls at start of therapy. This might indicate patients' high hopes and expectations toward treatment. gQoL returns to a level similar to that of healthy controls over the course of therapy.}, }
@article {pmid33846297, year = {2021}, author = {Bai, L and Wang, Y and Huo, J and Li, S and Wen, Y and Liu, Q and Yang, J and Liu, Y and Li, R}, title = {Simvastatin accelerated motoneurons death in SOD1[G93A] mice through inhibiting Rab7-mediated maturation of late autophagic vacuoles.}, journal = {Cell death &amp; disease}, volume = {12}, number = {4}, pages = {392}, pmid = {33846297}, issn = {2041-4889}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism ; Animals ; Autophagy/drug effects ; Female ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/*metabolism ; Simvastatin/*pharmacology ; Superoxide Dismutase-1/*genetics/metabolism ; Vacuoles/metabolism ; rab GTP-Binding Proteins/*metabolism ; rab7 GTP-Binding Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by motoneuron loss, for which there is currently no effective treatment. Statins, as inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, are used as drugs for treatment for a variety of disease such as ischemic diseases, neurodegenerative diseases, cancer, and inflammation. However, our previous evidence has demonstrated that simvastatin leads to cytotoxicity in NSC34-hSOD1[G93A] cells by aggravating the impairment of autophagic flux, but the role of simvastatin in ALS model remains elusive. In present study, we reported that after simvastatin treatment, SOD1[G93A] mice showed early onset of the disease phenotype and shortened life span, with aggravated autophagic flux impairment and increased aggregation of SOD1 protein in spinal cord motoneurons (MNs) of SOD1[G93A] mice. In addition, simvastatin repressed the ability of Rab7 localization on the membrane by inhibiting isoprenoid synthesis, leading to impaired late stage of autophagic flux rather than initiation. This study suggested that simvastatin significantly worsened impairment of late autophagic flux, resulting in massive MNs death in spinal cord and accelerated disease progression of SOD1[G93A] mice. Together, these findings might imply a potential risk of clinic application of statins in ALS.}, }
@article {pmid33839324, year = {2021}, author = {Amado, DA and Davidson, BL}, title = {Gene therapy for ALS: A review.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {29}, number = {12}, pages = {3345-3358}, pmid = {33839324}, issn = {1525-0024}, support = {F32 NS009435/NS/NINDS NIH HHS/United States ; K08 NS114106/NS/NINDS NIH HHS/United States ; S10 OD012006/OD/NIH HHS/United States ; U01 NS111671/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; C9orf72 Protein/genetics ; Dependovirus/genetics ; Genetic Therapy/methods ; Humans ; Oligonucleotides, Antisense/genetics/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has historically posed unique challenges for gene-therapy-based approaches, due to a paucity of therapeutic targets as well as the difficulty of accessing both the brain and spinal cord. Recent advances in our understanding of disease mechanism and ALS genetics, however, have combined with tremendous strides in CNS targeting, gene delivery, and gene editing and knockdown techniques to open new horizons of therapeutic possibility. Gene therapy clinical trials are currently underway for ALS patients with SOD1 mutations, C9orf72 hexanucleotide repeat expansions, ATXN2 trinucleotide expansions, and FUS mutations, as well as sporadic disease without known genetic cause. In this review, we provide an in-depth exploration of the state of ALS-directed gene therapy, including antisense oligonucleotides, RNA interference, CRISPR, adeno-associated virus (AAV)-mediated trophic support, and antibody-based methods. We discuss how each of these approaches has been implemented across known genetic causes as well as sporadic ALS, reviewing preclinical studies as well as completed and ongoing human clinical trials. We highlight the transformative potential of these evolving technologies as the gene therapy field advances toward a true disease-modifying treatment for this devastating illness.}, }
@article {pmid33837098, year = {2021}, author = {Pondofe, K and Fregonezi, GAF and Brito, O and Dourado Júnior, ME and Torres-Castro, R and Resqueti, VR}, title = {Effects of an optimised approach to home-based respiratory care in individuals with amyotrophic lateral sclerosis: a study protocol for a randomised controlled trial.}, journal = {BMJ open}, volume = {11}, number = {4}, pages = {e042780}, pmid = {33837098}, issn = {2044-6055}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Amyotrophic Lateral Sclerosis/therapy ; Female ; Humans ; Male ; Middle Aged ; Randomized Controlled Trials as Topic ; Respiration ; Respiratory Function Tests ; Respiratory Therapy ; Vital Capacity ; Young Adult ; }, abstract = {INTRODUCTION: This study aims to investigate the effects of an optimal home-based respiratory care protocol in individuals with amyotrophic lateral sclerosis (ALS).<br><br>METHODS AND ANALYSIS: This is a randomised, blinded controlled trial involving patients diagnosed with ALS, both sexes, age between 18 and 80 years. Patients will be randomly allocated into the conventional respiratory care (CRC) group and the optimised respiratory care home-based (ORC) group. Primary outcomes will be peak cough flow, the number of exacerbations and ALS Functional Rating Scale Revised. Secondary outcomes will include chest wall volumes, maximal respiratory pressures, sniff nasal inspiratory pressure, nasal expiratory pressure and forced vital capacity (FVC), forced expiratory volume in the 1st second (FEV1) and FEV1/FVC. The CRC group will receive educational information about respiratory care at the clinic. The ORC group will receive conventional care and home-based care. The clinical status of all individuals will be monitored weekly through telephone calls. A 6-month intervention is planned, the outcomes will be assessed every 3&#x2009;months and 3 and 6 months follow-up after final evaluation. The primary and secondary results will be described as average or median for continuous variables and absolute and relative frequencies for qualitative variables. Treatment effects or differences between the outcomes (baseline, 3&#x2009;months and 6&#x2009;months) of the study groups will be analysed using an analysis of variance. The level of significance will be set as p&#x2264;0.05.<br><br>ETHICS AND DISSEMINATION: The research ethics committee approved the study. It is expected to evaluate respiratory function in patients with ALS in the short, medium and long terms with home-based care protocol applied. The disease's rapid progression is a limitation for performing a long-term clinical study.<br><br>TRIAL REGISTRATION NUMBER: RBR-3z23ts; Pre-results.}, }
@article {pmid33818491, year = {2021}, author = {Bhuiyan, P and Wang, YW and Sha, HH and Dong, HQ and Qian, YN}, title = {Neuroimmune connections between corticotropin-releasing hormone and mast cells: novel strategies for the treatment of neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {16}, number = {11}, pages = {2184-2197}, pmid = {33818491}, issn = {1673-5374}, abstract = {Corticotropin-releasing hormone is a critical component of the hypothalamic-pituitary-adrenal axis, which plays a major role in the body's immune response to stress. Mast cells are both sensors and effectors in the interaction between the nervous and immune systems. As first responders to stress, mast cells can initiate, amplify and prolong neuroimmune responses upon activation. Corticotropin-releasing hormone plays a pivotal role in triggering stress responses and related diseases by acting on its receptors in mast cells. Corticotropin-releasing hormone can stimulate mast cell activation, influence the activation of immune cells by peripheral nerves and modulate neuroimmune interactions. The latest evidence shows that the release of corticotropin-releasing hormone induces the degranulation of mast cells under stress conditions, leading to disruption of the blood-brain barrier, which plays an important role in neurological diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorder and amyotrophic lateral sclerosis. Recent studies suggest that stress increases intestinal permeability and disrupts the blood-brain barrier through corticotropin-releasing hormone-mediated activation of mast cells, providing new insight into the complex interplay between the brain and gastrointestinal tract. The neuroimmune target of mast cells is the site at which the corticotropin-releasing hormone directly participates in the inflammatory responses of nerve terminals. In this review, we focus on the neuroimmune connections between corticotropin-releasing hormone and mast cells, with the aim of providing novel potential therapeutic targets for inflammatory, autoimmune and nervous system diseases.}, }
@article {pmid33818222, year = {2022}, author = {Hertzberg, VS and Singh, H and Fournier, CN and Moustafa, A and Polak, M and Kuelbs, CA and Torralba, MG and Tansey, MG and Nelson, KE and Glass, JD}, title = {Gut microbiome differences between amyotrophic lateral sclerosis patients and spouse controls.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {23}, number = {1-2}, pages = {91-99}, pmid = {33818222}, issn = {2167-9223}, support = {IK2 CX001595/CX/CSRD VA/United States ; RF1 AG057247/AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; *Gastrointestinal Microbiome/genetics ; Humans ; *Neurodegenerative Diseases ; RNA, Ribosomal, 16S/genetics ; Spouses ; }, abstract = {Objective: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is incurable and ultimately fatal. Few therapeutic options are available to patients. In this study, we explored differences in microbiome composition associated with ALS. Methods: We compared the gut microbiome and inflammatory marker profiles of ALS patients (n = 10) to those of their spouses (n = 10). Gut microbiome profiles were determined by 16S rRNA gene sequencing. Results: The gut microbial communities of the ALS patients were more diverse and were deficient in Prevotella spp. compared with those of their spouses. In contrast, healthy couples (n = 10 couples of the opposite sex) recruited from the same geographic region as the patient population did not exhibit these differences. Stool and plasma inflammatory markers were similar between ALS patients and their spouses. Predictive analysis of microbial enzymes revealed that ALS patients had decreased activity in several metabolic pathways, including carbon metabolism, butyrate metabolism, and systems involving histidine kinase and response regulators. Conclusions: ALS patients exhibit differences in their gut microbial communities compared with spouse controls. Our findings suggest that modifying the gut microbiome, such as via amelioration of Prevotella spp. deficiency, and/or altering butyrate metabolism may have translational value for ALS treatment.}, }
@article {pmid33815246, year = {2021}, author = {Johannesen, S and Huie, JR and Budeus, B and Peters, S and Wirth, AM and Iberl, S and Kammermaier, T and Kobor, I and Wirkert, E and Küspert, S and Tahedl, M and Grassinger, J and Pukrop, T and Schneider, A and Aigner, L and Schulte-Mattler, W and Schuierer, G and Koch, W and Bruun, TH and Ferguson, AR and Bogdahn, U}, title = {Modeling and Bioinformatics Identify Responders to G-CSF in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {616289}, pmid = {33815246}, issn = {1664-2295}, abstract = {Objective: Developing an integrative approach to early treatment response classification using survival modeling and bioinformatics with various biomarkers for early assessment of filgrastim (granulocyte colony stimulating factor) treatment effects in amyotrophic lateral sclerosis (ALS) patients. Filgrastim, a hematopoietic growth factor with excellent safety, routinely applied in oncology and stem cell mobilization, had shown preliminary efficacy in ALS. Methods: We conducted individualized long-term filgrastim treatment in 36 ALS patients. The PRO-ACT database, with outcome data from 23 international clinical ALS trials, served as historical control and mathematical reference for survival modeling. Imaging data as well as cytokine and cellular data from stem cell analysis were processed as biomarkers in a non-linear principal component analysis (NLPCA) to identify individual response. Results: Cox proportional hazard and matched-pair analyses revealed a significant survival benefit for filgrastim-treated patients over PRO-ACT comparators. We generated a model for survival estimation based on patients in the PRO-ACT database and then applied the model to filgrastim-treated patients. Model-identified filgrastim responders displayed less functional decline and impressively longer survival than non-responders. Multimodal biomarkers were then analyzed by PCA in the context of model-defined treatment response, allowing identification of subsequent treatment response as early as within 3 months of therapy. Strong treatment response with a median survival of 3.8 years after start of therapy was associated with younger age, increased hematopoietic stem cell mobilization, less aggressive inflammatory cytokine plasma profiles, and preserved pattern of fractional anisotropy as determined by magnetic resonance diffusion tensor imaging (DTI-MRI). Conclusion: Long-term filgrastim is safe, is well-tolerated, and has significant positive effects on disease progression and survival in a small cohort of ALS patients. Developing and applying a model-based biomarker response classification allows use of multimodal biomarker patterns in full potential. This can identify strong individual treatment responders (here: filgrastim) at a very early stage of therapy and may pave the way to an effective individualized treatment option.}, }
@article {pmid33815055, year = {2021}, author = {Bai, Y and Su, X and Piao, L and Jin, Z and Jin, R}, title = {Involvement of Astrocytes and microRNA Dysregulation in Neurodegenerative Diseases: From Pathogenesis to Therapeutic Potential.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {556215}, pmid = {33815055}, issn = {1662-5099}, abstract = {Astrocytes are the most widely distributed and abundant glial cells in the central nervous system (CNS). Neurodegenerative diseases (NDDs) are a class of diseases with a slow onset, progressive progression, and poor prognosis. Common clinical NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Although these diseases have different etiologies, they are all associated with neuronal loss and pathological dysfunction. Accumulating evidence indicates that neurotransmitters, neurotrophic factors, and toxic metabolites that are produced and released by activated astrocytes affect and regulate the function of neurons at the receptor, ion channel, antigen transfer, and gene transcription levels in the pathogenesis of NDDs. MicroRNAs (miRNAs) are a group of small non-coding RNAs that play a wide range of biological roles by regulating the transcription and post-transcriptional translation of target mRNAs to induce target gene expression and silencing. Recent studies have shown that miRNAs participate in the pathogenesis of NDDs by regulating astrocyte function through different mechanisms and may be potential targets for the treatment of NDDs. Here, we review studies of the role of astrocytes in the pathogenesis of NDDs and discuss possible mechanisms of miRNAs in the regulation of astrocyte function, suggesting that miRNAs may be targeted as a novel approach for the treatment of NDDs.}, }
@article {pmid33814477, year = {2021}, author = {Su, CL and Tam, KW and Fang, TP and Chiang, LL and Chen, HC}, title = {Effects of pulmonary rehabilitation program on amyotrophic lateral sclerosis: A meta-analysis of randomized controlled trials.}, journal = {NeuroRehabilitation}, volume = {48}, number = {3}, pages = {255-265}, doi = {10.3233/NRE-210052}, pmid = {33814477}, issn = {1878-6448}, mesh = {Amyotrophic Lateral Sclerosis/*rehabilitation ; Humans ; Muscle Weakness ; Randomized Controlled Trials as Topic ; Resistance Training/*methods ; *Respiration ; }, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) develop respiratory failure and progressive muscle weakness. The effects of pulmonary rehabilitation on the lung function of patients with ALS are unclear.<br><br>OBJECTIVE: Through this meta-analysis of randomized controlled trials (RCTs), we evaluated the effects of pulmonary rehabilitation, such as type of treatment, on patients with ALS and compared the effectiveness of this treatment.<br><br>METHODS: PubMed, EMBASE, Web of Science, and Cochrane databases were searched until December 2020. The methodological quality of each study was assessed using the updated Cochrane Risk of Bias tool (RoB 2.0). Data were analyzed using Review Manager version 5.4 (Cochrane Collaboration, Oxford, England), and the meta-analysis was performed in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines.<br><br>RESULTS: Of 2168 articles, 10 trials were reviewed; among these trials, two focused on respiratory training and eight on physical exercise, three of which involved a combination of aerobic and resistance training. Our meta-analysis demonstrated no difference in the ALSFRS-R score and % FVC among patients with ALS.<br><br>CONCLUSIONS: Respiratory training or physical exercise did not significantly affect the ALSFRS-R score and % FVC of patients with ALS. At 12 months after intervention, the ALSFRS-R score in the physical exercise group was higher than that in the usual care group. Further clinical trials are warranted to develop approaches for improving the lung function of patients with ALS.}, }
@article {pmid33811958, year = {2021}, author = {Saviluoto, A and Jäntti, H and Holm, A and Nurmi, JO}, title = {Does experience in prehospital post-resuscitation critical care affect outcomes? A retrospective cohort study.}, journal = {Resuscitation}, volume = {163}, number = {}, pages = {155-161}, doi = {10.1016/j.resuscitation.2021.03.023}, pmid = {33811958}, issn = {1873-1570}, mesh = {Adolescent ; *Air Ambulances ; Aircraft ; Critical Care ; *Emergency Medical Services ; Humans ; Retrospective Studies ; }, abstract = {AIMS OF THE STUDY: Helicopter Emergency Medical Services (HEMS) often provide post-resuscitation care. Our aims were to investigate whether physicians' frequent exposure to prehospital post-resuscitation care is associated with differences in (1) medical management, (2) achieving treatment targets recommended by resuscitation guidelines, (3) survival.<br><br>METHODS: We conducted a retrospective cohort study using data from a national HEMS quality register. We included patients between January 1st, 2012 and September 9th, 2019 who received post-resuscitation care by a HEMS physician. We excluded patients <16 years old. For each patient we determined the number of post-resuscitation cases the physician had attended in the previous 12 months. Patients were divided in to three groups: low (0-5), intermediate (6-11) and high exposure (&#x2265;12 cases). Medical management and proportions within treatment targets were compared. Survival at 30-days and 1-year was analysed by multivariate logistic regression analysis, controlling for known prognostic factors.<br><br>RESULTS: 2272 patients were analysed. Patients in the high exposure group had mechanical ventilation and vasoactive medications initiated more often (P&#x202f;<&#x202f;0.001 and P&#x202f;=&#x202f;0.008, respectively) and on-scene times were longer (P&#x202f;<&#x202f;0.001). The target for blood pressure was achieved more often in this group (P&#x202f;=&#x202f;0.026), but targets for oxygenation and ventilation were not. We did not see an association between survival and physicians' exposure to post-resuscitation care (odds ratio 0.96, 95% confidence interval 0.70-1.33 for low and 0.78, 0.56-1.08 for intermediate, compared to high exposure).<br><br>CONCLUSIONS: Physicians with more, frequent exposure take a more active approach to post-resuscitation care, but this does not seem to improve survival.}, }
@article {pmid33806803, year = {2021}, author = {Pandya, VA and Crerar, H and Mitchell, JS and Patani, R}, title = {A Non-Toxic Concentration of Telomerase Inhibitor BIBR1532 Fails to Reduce TERT Expression in a Feeder-Free Induced Pluripotent Stem Cell Model of Human Motor Neurogenesis.}, journal = {International journal of molecular sciences}, volume = {22}, number = {6}, pages = {}, pmid = {33806803}, issn = {1422-0067}, support = {MR/M02492X/1/MRC_/Medical Research Council/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Aminobenzoates/*pharmacology ; Cell Differentiation/drug effects ; Cell Line ; Enzyme Inhibitors/*pharmacology ; Gene Expression Regulation/drug effects ; Humans ; Induced Pluripotent Stem Cells/*cytology/*drug effects/metabolism ; Motor Neurons/*cytology/metabolism ; Naphthalenes/*pharmacology ; Neurogenesis/*drug effects ; Telomerase/*antagonists &amp; inhibitors/*genetics ; }, abstract = {Several studies have shown that human induced pluripotent stem cell (iPSC)-derivatives are essentially fetal in terms of their maturational status. Inducing ageing in iPSC-motor neuron (MN) models of amyotrophic lateral sclerosis (ALS) has the potential to capture pathology with higher fidelity and consequently improve translational success. We show here that the telomerase inhibitor BIBR1532, hypothesised to recapitulate the telomere attrition hallmark of ageing in iPSC-MNs, was in fact cytotoxic to feeder-free iPSCs when used at doses previously shown to be effective in iPSCs grown on a layer of mouse embryonic fibroblasts. Toxicity in feeder-free cultures was not rescued by co-treatment with Rho Kinase (ROCK) inhibitor (Y-27632). Moreover, the highest concentration of BIBR1532 compatible with continued iPSC culture proved insufficient to induce detectable telomerase inhibition. Our data suggest that direct toxicity by BIBR1532 is the most likely cause of iPSC death observed, and that culture methods may influence enhanced toxicity. Therefore, recapitulation of ageing hallmarks in iPSC-MNs, which might reveal novel and relevant human disease targets in ALS, is not achievable in feeder-free culture through the use of this small molecule telomerase inhibitor.}, }
@article {pmid33805709, year = {2021}, author = {Post, J and Kogel, V and Schaffrath, A and Lohmann, P and Shah, NJ and Langen, KJ and Willbold, D and Willuweit, A and Kutzsche, J}, title = {A Novel Anti-Inflammatory d-Peptide Inhibits Disease Phenotype Progression in an ALS Mouse Model.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {6}, pages = {}, pmid = {33805709}, issn = {1420-3049}, support = {20-64-46027//Russian Sciene Foundation/ ; Technology Transfer Fund//Forschungszentrum J&#xfc;lich GmbH/ ; Portfolio Drug Research//Impuls und Vernetzungs-Fonds der Helmholtzgemeinschaft/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/physiopathology ; Animals ; Anti-Inflammatory Agents/chemistry/*therapeutic use ; Brain Stem/drug effects/pathology ; Disease Models, Animal ; Disease Progression ; Female ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/pathology ; Motor Skills/drug effects/physiology ; Mutant Proteins/genetics ; Neurodegenerative Diseases/drug therapy/genetics/physiopathology ; Oligopeptides/chemistry/*therapeutic use ; Phenotype ; Spinal Cord/drug effects/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by selective neuronal death in the brain stem and spinal cord. The cause is unknown, but an increasing amount of evidence has firmly certified that neuroinflammation plays a key role in ALS pathogenesis. Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and has been implicated as driver of disease progression. Here, we describe a treatment study demonstrating the therapeutic potential of a tandem version of the well-known all-d-peptide RD2 (RD2RD2) in a transgenic mouse model of ALS (SOD1*G93A). Mice were treated intraperitoneally for four weeks with RD2RD2 vs. placebo. SOD1*G93A mice were tested longitudinally during treatment in various behavioural and motor coordination tests. Brain and spinal cord samples were investigated immunohistochemically for gliosis and neurodegeneration. RD2RD2 treatment in SOD1*G93A mice resulted not only in a reduction of activated astrocytes and microglia in both the brain stem and lumbar spinal cord, but also in a rescue of neurons in the motor cortex. RD2RD2 treatment was able to slow progression of the disease phenotype, especially the motor deficits, to an extent that during the four weeks treatment duration, no significant progression was observed in any of the motor experiments. Based on the presented results, we conclude that RD2RD2 is a potential therapeutic candidate against ALS.}, }
@article {pmid33804658, year = {2021}, author = {Silvestro, S and Sindona, C and Bramanti, P and Mazzon, E}, title = {A State of the Art of Antioxidant Properties of Curcuminoids in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {22}, number = {6}, pages = {}, pmid = {33804658}, issn = {1422-0067}, support = {//Ministero della Salute/ ; }, mesh = {Animals ; Antioxidants/chemistry/*pharmacology/therapeutic use ; Clinical Studies as Topic ; Diarylheptanoids/chemistry/*pharmacology/therapeutic use ; Disease Management ; Disease Models, Animal ; Disease Susceptibility ; Drug Evaluation, Preclinical ; Humans ; Neurodegenerative Diseases/drug therapy/etiology/metabolism ; Structure-Activity Relationship ; Treatment Outcome ; }, abstract = {Neurodegenerative diseases represent a set of pathologies characterized by an irreversible and progressive, and a loss of neuronal cells in specific areas of the brain. Oxidative phosphorylation is a source of energy production by which many cells, such as the neuronal cells, meet their energy needs. Dysregulations of oxidative phosphorylation induce oxidative stress, which plays a key role in the onset of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). To date, for most neurodegenerative diseases, there are no resolute treatments, but only interventions capable of alleviating the symptoms or slowing the course of the disease. Therefore, effective neuroprotection strategies are needed. In recent years, natural products, such as curcuminoids, have been intensively explored and studied for their therapeutic potentials in several neurodegenerative diseases. Curcuminoids are, nutraceutical compouns, that owen several therapeutic properties such as anti-oxidant, anti-inflammatory and neuroprotective effects. In this context, the aim of this review was to provide an overview of preclinical and clinical evidence aimed to illustrate the antioxidant effects of curcuminoids in neurodegenerative diseases. Promising results from preclinical studies encourage the use of curcuminoids for neurodegeneration prevention and treatment.}, }
@article {pmid33801336, year = {2021}, author = {Scaricamazza, S and Salvatori, I and Ferri, A and Valle, C}, title = {Skeletal Muscle in ALS: An Unappreciated Therapeutic Opportunity?.}, journal = {Cells}, volume = {10}, number = {3}, pages = {}, pmid = {33801336}, issn = {2073-4409}, support = {HyperALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; 2018//AFM-T&#xe9;l&#xe9;thon/ ; 21021//AFM-T&#xe9;l&#xe9;thon/ ; PGR01040//Ministero della Salute/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Muscle, Skeletal/*physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective degeneration of upper and lower motor neurons and by the progressive weakness and paralysis of voluntary muscles. Despite intense research efforts and numerous clinical trials, it is still an incurable disease. ALS had long been considered a pure motor neuron disease; however, recent studies have shown that motor neuron protection is not sufficient to prevent the course of the disease since the dismantlement of neuromuscular junctions occurs before motor neuron degeneration. Skeletal muscle alterations have been described in the early stages of the disease, and they seem to be mainly involved in the "dying back" phenomenon of motor neurons and metabolic dysfunctions. In recent years, skeletal muscles have been considered crucial not only for the etiology of ALS but also for its treatment. Here, we review clinical and preclinical studies that targeted skeletal muscles and discuss the different approaches, including pharmacological interventions, supplements or diets, genetic modifications, and training programs.}, }
@article {pmid33800571, year = {2021}, author = {Lavorgna, L and Brigo, F and Esposito, S and Abbadessa, G and Sparaco, M and Lanzillo, R and Moccia, M and Inglese, M and Bonfanti, L and Trojsi, F and Spina, E and Russo, A and De Micco, P and Clerico, M and Tedeschi, G and Bonavita, S}, title = {Public Engagement and Neurology: An Update.}, journal = {Brain sciences}, volume = {11}, number = {4}, pages = {}, pmid = {33800571}, issn = {2076-3425}, abstract = {BACKGROUND: Public engagement (PE) is defined as the involvement of "specialists who listen, develop their understanding, and interact with non-specialists in non-profit activities of educational, cultural, and social nature to engage the public in science-related matters". The public health relevance of PE consists in building up a scientifically literate society, able to participate in and support scientific and technological developments and their implications for educational settings. Neurological disorders account for 35% of all diseases. PE could have a positive impact on the lives of people affected by neurological diseases.<br><br>METHOD: This review evaluates the role of PE in dementia, stroke, epilepsy, multiple sclerosis, Parkinson's disease, migraine, neurogenetics, and amyotrophic lateral sclerosis.<br><br>RESULTS AND CONCLUSIONS: PE can provide accessible information, support research activities and prevention through appropriate lifestyles, and increase knowledge and awareness of neurological disorders, improving their diagnosis and treatment.}, }
@article {pmid33799476, year = {2021}, author = {Peseschkian, T and Cordts, I and Günther, R and Stolte, B and Zeller, D and Schröter, C and Weyen, U and Regensburger, M and Wolf, J and Schneider, I and Hermann, A and Metelmann, M and Kohl, Z and Linker, RA and Koch, JC and Büchner, B and Weiland, U and Schönfelder, E and Heinrich, F and Osmanovic, A and Klopstock, T and Dorst, J and Ludolph, AC and Boentert, M and Hagenacker, T and Deschauer, M and Lingor, P and Petri, S and Schreiber-Katz, O}, title = {A Nation-Wide, Multi-Center Study on the Quality of Life of ALS Patients in Germany.}, journal = {Brain sciences}, volume = {11}, number = {3}, pages = {}, pmid = {33799476}, issn = {2076-3425}, support = {Sc23/1//German Neuromuscular Society "Deutsche Gesellschaft fuer Muskelkranke" e.V./ ; }, abstract = {Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = -1.96 per increase of one point in the ALSFRS-R score, p < 0.001). "Limb-onset" ALS (lALS) was associated with a better QoL than "bulbar-onset" ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = -7.60, p = 0.001), being tracheostomized (β = -14.80, p = 0.004) and using non-invasive ventilation (β = -5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, p = 0.007), and increasing age (β = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care.}, }
@article {pmid33798740, year = {2021}, author = {Perera, ND and Tomas, D and Wanniarachchillage, N and Cuic, B and Luikinga, SJ and Rytova, V and Turner, BJ}, title = {Stimulation of mTOR-independent autophagy and mitophagy by rilmenidine exacerbates the phenotype of transgenic TDP-43 mice.}, journal = {Neurobiology of disease}, volume = {154}, number = {}, pages = {105359}, doi = {10.1016/j.nbd.2021.105359}, pmid = {33798740}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/chemically induced/genetics/metabolism ; Animals ; Antihypertensive Agents/toxicity ; Autophagy/*physiology ; DNA-Binding Proteins/biosynthesis/*genetics ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitophagy/*physiology ; *Phenotype ; Rilmenidine/*toxicity ; TOR Serine-Threonine Kinases/biosynthesis/*genetics ; }, abstract = {Autophagy, which mediates the delivery of cytoplasmic substrates to the lysosome for degradation, is essential for maintaining proper cell homeostasis in physiology, ageing, and disease. There is increasing evidence that autophagy is defective in neurodegenerative disorders, including motor neurons affected in amyotrophic lateral sclerosis (ALS). Restoring impaired autophagy in motor neurons may therefore represent a rational approach for ALS. Here, we demonstrate autophagy impairment in spinal cords of mice expressing mutant TDP-43[Q331K] or co-expressing TDP-43[WTxQ331K] transgenes. The clinically approved anti-hypertensive drug rilmenidine was used to stimulate mTOR-independent autophagy in double transgenic TDP-43[WTxQ331K] mice to alleviate impaired autophagy. Although rilmenidine treatment induced robust autophagy in spinal cords, this exacerbated the phenotype of TDP-43[WTxQ331K] mice, shown by truncated lifespan, accelerated motor neuron loss, and pronounced nuclear TDP-43 clearance. Importantly, rilmenidine significantly promoted mitophagy in spinal cords TDP-43[WTxQ331K] mice, evidenced by reduced mitochondrial markers and load in spinal motor neurons. These results suggest that autophagy induction accelerates the phenotype of this TDP-43 mouse model of ALS, most likely through excessive mitochondrial clearance in motor neurons. These findings also emphasise the importance of balancing autophagy stimulation with the potential negative consequences of hyperactive mitophagy in ALS and other neurodegenerative diseases.}, }
@article {pmid33797036, year = {2021}, author = {Naia, L and Ly, P and Mota, SI and Lopes, C and Maranga, C and Coelho, P and Gershoni-Emek, N and Ankarcrona, M and Geva, M and Hayden, MR and Rego, AC}, title = {The Sigma-1 Receptor Mediates Pridopidine Rescue of Mitochondrial Function in Huntington Disease Models.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {18}, number = {2}, pages = {1017-1038}, pmid = {33797036}, issn = {1878-7479}, mesh = {Animals ; Coculture Techniques ; *Disease Models, Animal ; Female ; Humans ; Huntington Disease/drug therapy/*metabolism/pathology ; Hydrogen Peroxide/toxicity ; Male ; Mice ; Mice, Transgenic ; Mitochondria/drug effects/*metabolism ; Neural Stem Cells/drug effects/metabolism ; Piperidines/*pharmacology/therapeutic use ; Pregnancy ; Receptors, sigma/*agonists/*metabolism ; Sigma-1 Receptor ; }, abstract = {Pridopidine is a selective Sigma-1 receptor (S1R) agonist in clinical development for Huntington disease (HD) and amyotrophic lateral sclerosis. S1R is a chaperone protein localized in mitochondria-associated endoplasmic reticulum (ER) membranes, a signaling platform that regulates Ca[2+] signaling, reactive oxygen species (ROS) and mitochondrial fission. Here, we investigate the protective effects of pridopidine on various mitochondrial functions in human and mouse HD models. Pridopidine effects on mitochondrial dynamics were assessed in primary neurons from YAC128 HD mice expressing the mutant human HTT gene. We observe that pridopidine prevents the disruption of mitochondria-ER contact sites and improves the co-localization of inositol 1,4,5-trisphosphate receptor (IP3R) and its chaperone S1R with mitochondria in YAC128 neurons, leading to increased mitochondrial activity, elongation, and motility. Increased mitochondrial respiration is also observed in YAC128 neurons and in pridopidine-treated HD human neural stem cells (hNSCs). ROS levels were assessed after oxidative insult or S1R knockdown in pridopidine-treated YAC128 neurons, HD hNSCs, and human HD lymphoblasts. All HD models show increased ROS levels and deficient antioxidant response, which are efficiently rescued with pridopidine. Importantly, pridopidine treatment before H2O2-induced mitochondrial dysfunction and S1R presence are required for HD cytoprotection. YAC128 mice treated at early/pre-symptomatic age with pridopidine show significant improvement in motor coordination, indicating a delay in symptom onset. Additionally, in vivo pridopidine treatment reduces mitochondrial ROS levels by normalizing mitochondrial complex activity. In conclusion, S1R-mediated enhancement of mitochondrial function contributes to the neuroprotective effects of pridopidine, providing insight into its mechanism of action and therapeutic potential.}, }
@article {pmid33795700, year = {2021}, author = {Morata-Tarifa, C and Azkona, G and Glass, J and Mazzini, L and Sanchez-Pernaute, R}, title = {Looking backward to move forward: a meta-analysis of stem cell therapy in amyotrophic lateral sclerosis.}, journal = {NPJ Regenerative medicine}, volume = {6}, number = {1}, pages = {20}, pmid = {33795700}, issn = {2057-3995}, abstract = {Transplantation of several types of stem cells (SC) for the treatment of amyotrophic lateral sclerosis (ALS) has been evaluated in numerous Phase I/II clinical trials with inconclusive results. Here, we conducted a meta-analysis to systematically assess the outcome of SC therapy trials which report the evolution of each patient before and after cell administration. In this way, we aimed to determine the effect of the SC intervention despite individual heterogeneity in disease progression. We identified 670 references by electronic search and 90 full-text studies were evaluated according to the eligibility criteria. Eleven studies were included comprising 220 cell-treated patients who received mesenchymal (M) SC (n = 152), neural (N) SC (n = 57), or mononuclear cells (MNC: CD34, CD117, and CD133 positive cells) (n = 11). Our analyses indicate that whereas intrathecal injection of mesenchymal stromal cells appears to have a transient positive effect on clinical progression, as measured by the ALS functional rating score, there was a worsening of respiratory function measured by forced vital capacity after all interventions. Based on current evidence, we conclude that optimal cell product and route of administration need to be determined in properly controlled preclinical models before further advancing into ALS patients. In addition, in-depth understanding of disease mechanisms in subsets of patients will help tailoring SC therapy to specific targets and increase the likelihood of improving outcomes.}, }
@article {pmid33792208, year = {2021}, author = {Freigang, M and Wurster, CD and Hagenacker, T and Stolte, B and Weiler, M and Kamm, C and Schreiber-Katz, O and Osmanovic, A and Petri, S and Kowski, A and Meyer, T and Koch, JC and Cordts, I and Deschauer, M and Lingor, P and Aust, E and Petzold, D and Ludolph, AC and Falkenburger, B and Hermann, A and Günther, R}, title = {Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment.}, journal = {Annals of clinical and translational neurology}, volume = {8}, number = {5}, pages = {1049-1063}, pmid = {33792208}, issn = {2328-9503}, mesh = {Adolescent ; Adult ; Aged ; Biomarkers/blood ; Creatine Kinase/*blood ; Creatinine/*blood ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Muscular Atrophy, Spinal/*blood/diagnosis/*drug therapy/physiopathology ; Oligonucleotides/*pharmacology ; Patient Acuity ; Prognosis ; Retrospective Studies ; Young Adult ; }, abstract = {OBJECTIVE: To determine whether serum creatine kinase activity (CK) and serum creatinine concentration (Crn) are prognostic and predictive biomarkers for disease severity, disease progression, and nusinersen treatment effects in adult patients with 5q-associated spinal muscular atrophy (SMA).<br><br>METHODS: Within this retrospective, multicenter observational study in 206 adult patients with SMA, we determined clinical subtypes (SMA types, ambulatory ability) and repeatedly measured CK and Crn and examined disease severity scores (Hammersmith Functional Motor Scale Expanded, Revised Upper Limb Module, and revised Amyotrophic Lateral Sclerosis Functional Rating Scale). Patients were followed under nusinersen treatment for 18&#xa0;months.<br><br>RESULTS: CK and Crn differed between clinical subtypes and correlated strongly with disease severity scores (e.g., for Hammersmith Functional Motor Scale Expanded: (CK) &#x3c1;&#xa0;=&#xa0;0.786/ (Crn) &#x3c1;&#xa0;=&#xa0;0.558). During the 18&#xa0;months of nusinersen treatment, CK decreased (&#x2206;CK&#xa0;=&#xa0;-17.56%, p&#xa0;<&#xa0;0.0001), whereas Crn slightly increased (&#x2206;Crn&#xa0;=&#xa0;+4.75%, p&#xa0;<&#xa0;0.05).<br><br>INTERPRETATION: Serum creatine kinase activity and serum creatinine concentration reflect disease severity of spinal muscular atrophy and are promising biomarkers to assess patients with spinal muscular atrophy during disease course and to predict treatment response. The decrease of creatine kinase activity, combined with the tendency of creatinine concentration to increase during nusinersen treatment, suggests reduced muscle mass wasting with improved muscle energy metabolism.}, }
@article {pmid33781562, year = {2021}, author = {Corcia, P and Beltran, S and Bakkouche, SE and Couratier, P}, title = {Therapeutic news in ALS.}, journal = {Revue neurologique}, volume = {177}, number = {5}, pages = {544-549}, doi = {10.1016/j.neurol.2020.12.003}, pmid = {33781562}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Genetic Therapy ; Humans ; Motor Neurons ; Riluzole ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by death of motor neurons in the cortex and the spinal cord. This loss of motor neurons causes progressive weakness and amyotrophy. To date, the median duration of survival in patients with ALS, from first symptoms to death, is estimated to be 36 months. Currently the treatment is limited to two options: riluzole which prolongs survival for a few months and edaravone which is available in only a few countries and also has a small impact on disease progression. There is an urgent need for more effective drugs in this disease to significantly improve progression. Over the last 30 years, all trials have failed to find a curative drug for ALS. This is due, partially, to the heterogeneity of the clinical features and the pathophysiology of motor neuron death. We present in this review the various treatment options currently being developed for ALS, with an emphasis on the range of therapeutic approaches being explored, from old drugs tested in a new indication to innovative drugs obtained via biotechnology or gene therapy.}, }
@article {pmid33773825, year = {2021}, author = {Soar, J and Böttiger, BW and Carli, P and Couper, K and Deakin, CD and Djärv, T and Lott, C and Olasveengen, T and Paal, P and Pellis, T and Perkins, GD and Sandroni, C and Nolan, JP}, title = {European Resuscitation Council Guidelines 2021: Adult advanced life support.}, journal = {Resuscitation}, volume = {161}, number = {}, pages = {115-151}, doi = {10.1016/j.resuscitation.2021.02.010}, pmid = {33773825}, issn = {1873-1570}, mesh = {Adult ; *Cardiopulmonary Resuscitation ; Consensus ; Humans ; *Out-of-Hospital Cardiac Arrest/therapy ; }, abstract = {These European Resuscitation Council Advanced Life Support guidelines, are based on the 2020 International Consensus on Cardiopulmonary Resuscitation Science with Treatment Recommendations. This section provides guidelines on the prevention of and ALS treatments for both in-hospital cardiac arrest and out-of-hospital cardiac arrest.}, }
@article {pmid33771265, year = {2021}, author = {Trezzi, MM and Alcántara-de la Cruz, R and Rojano-Delgado, AM and Alcántara, E and Pagnoncelli, FB and Viecelli, M and Diesel, F and Pacheco, V and De Prado, R}, title = {Influence of temperature on the retention, absorption and translocation of fomesafen and imazamox in Euphorbia heterophylla.}, journal = {Pesticide biochemistry and physiology}, volume = {173}, number = {}, pages = {104794}, doi = {10.1016/j.pestbp.2021.104794}, pmid = {33771265}, issn = {1095-9939}, mesh = {*Acetolactate Synthase ; Benzamides ; *Euphorbia ; Herbicide Resistance ; *Herbicides/pharmacology ; Imidazoles ; Temperature ; }, abstract = {Climate change will be an additional issue to the challenge to manage herbicide resistant weeds. This work investigated the impact of three temperature regimes (10/5, 20/15 and 30/25 °C) on the efficacy, foliar retention, absorption and translocation of fomesafen, protoporphyrinogen oxidase (PPO) inhibitor, and imazamox, acetolactate synthase (ALS) inhibitor, between two Euphorbia heterophylla populations, one susceptible (S) and one multiple PPO and ALS resistant (R). The R population went from 5 (fomesafen) and 12 (imazamox) times more resistant than the S population at 10/5 °C to more than 100 times to both herbicides at 20/15 and 30/25 °C. Leaf retention of fomesafen was not affected by temperature; however, imazamox retention was less at 10/5 and 20/15 °C than at 30/25 °C, and the R population always retained less imazamox than the S population. [14]C-fomesafen absorption was similar between populations, but lower amounts were absorbed at 10/5 °C regardless of the evaluation time. Recovered [14]C-imazamox rates decreased in both populations as the evaluation time increased, ranging from 82 to 92% at 6 h after treatment (HAT), and from 47 to 76% at 48 HAT, depending on the temperature regime. The [14]C-imazamox losses were greater from 24 HAT in R plants grown at 30/25 °C and in all temperature regimes at 48 HAT. Although both populations translocated large amounts of imazamox, the S population distributed it in the rest of the plant (33%) and roots (15%), while the R population kept it mainly on the treated leaf (24%) or lost ~20% more herbicide than S population at 48 HAT, indicating the need for further studies on root exudation between these populations. Low temperatures reduced resistance levels to fomesafen and imazamox in E. heterophylla, suggesting that temperature influences the expression of the mechanisms that govern this multiple resistance.}, }
@article {pmid33757953, year = {2021}, author = {Beswick, E and Glasmacher, SA and Dakin, R and Newton, J and Carson, A and Abrahams, S and Chandran, S and Pal, S}, title = {Prospective observational cohort study of factors influencing trial participation in people with motor neuron disease (FIT-participation-MND): a protocol.}, journal = {BMJ open}, volume = {11}, number = {3}, pages = {e044996}, pmid = {33757953}, issn = {2044-6055}, support = {MR/L023784/2/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Motor Neuron Disease ; Observational Studies as Topic ; Prospective Studies ; Quality of Life ; Scotland ; Adaptive Clinical Trials as Topic ; }, abstract = {INTRODUCTION: Motor neuron disease (MND) is a rapidly progressive and fatal neurodegenerative disorder with limited treatment options. The Motor Neuron Disease Systematic Multi-Arm Randomised Adaptive Trial (MND-SMART) is a multisite UK trial seeking to address the paucity in effective disease-modifying drugs for people with MND (pwMND). Historically, neurological trials have been plagued by suboptimal recruitment and high rates of attrition. Failure to recruit and/or retain participants can cause insufficiently representative samples, terminated trials or invalid conclusions. This study investigates patient-specific factors affecting recruitment and retention of pwMND to MND-SMART. Improved understanding of these factors may improve trial protocol design, optimise recruitment and retention.<br><br>METHODS AND ANALYSIS: PwMND on the Scottish MND Register, Clinical Audit Research and Evaluation of MND (CARE-MND), will be invited to participate in a prospective observational cohort study that investigates factors affecting trial participation and attrition. We hypothesise that patient-specific factors will significantly affect trial recruitment and retention. Participants will complete the Hospital Anxiety and Depression Scale, 9-Item Patient Health Questionnaire and State-Trait Anxiety Inventory-Form Y to evaluate neuropsychiatric symptoms, the ALS-Specific Quality of Life Questionnaire-Brief Form and Centre for Disease Control and Prevention-Health-Related Quality of Life for quality of life and a novel study-specific questionnaire on Attitudes towards Clinical Trial Participation (ACT-Q). Clinical data on phenotype, cognition (Edinburgh Cognitive and Behavioural ALS Screen) and physical functioning (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised) will also be collated. Caregivers will complete the Brief Dimensional Apathy Scale. After 12 months, a data request to MND-SMART will evaluate recruitment and retention. Descriptive statistics will summarise and compare assessments and participants reaching impairment thresholds. Variable groupings: attitudes, quality of life, cognition, behaviour, physical functioning, neuropsychiatric and phenotype. Univariate and multivariable logistic regression will explore association with participation/withdrawal in MND-SMART; presented as ORs and 95% CIs.<br><br>ETHICS AND DISSEMINATION: Ethical approval was provided by the West of Scotland Research Ethics Committee 3 (20/WS/0067) on 12 May 2020. The results of this study will be published in a peer-reviewed journal, presented at academic conferences and disseminated to participants and the public.}, }
@article {pmid33757892, year = {2021}, author = {Gillespie, J and Przybylak-Brouillard, A and Watt, CL}, title = {The Palliative Care Information Needs of Patients with Amyotrophic Lateral Sclerosis and their Informal Caregivers: A Scoping Review.}, journal = {Journal of pain and symptom management}, volume = {62}, number = {4}, pages = {848-862}, doi = {10.1016/j.jpainsymman.2021.03.008}, pmid = {33757892}, issn = {1873-6513}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Caregivers ; Humans ; *Neurodegenerative Diseases ; Palliative Care ; Quality of Life ; }, abstract = {CONTEXT: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease, associated with impaired quality of life for patients and caregivers. As treatment is largely supportive, early involvement of palliative care (PC) is recommended as standard of care. Despite this, literature surrounding PC information needs is limited.<br><br>OBJECTIVES: To explore the PC information needs of patients with ALS and their caregivers and identify gaps in the literature.<br><br>METHODS: A scoping review using MEDLINE, EMBASE, CINAHL and PsycINFO databases (2000-2019) was conducted. Articles examining PC information needs as stated by ALS patients and/or current/bereaved caregivers were included. Studies examining other diagnoses and those focused on healthcare workers were excluded. Thematic synthesis was used to summarize and identify prevalent domains and themes in the literature.<br><br>RESULTS: 581 articles underwent primary screening, with thirty-two ultimately included (26 original articles, six reviews). Fourteen examined information needs of both patients and caregivers, 13 caregivers only, 5 patients only. The most common PC information needs were as follows: for patients, disease course/prognosis (n&#x202f;=&#x202f;10), general disease information (n&#x202f;=&#x202f;9), decision-making (n&#x202f;=&#x202f;7) and symptoms (n&#x202f;=&#x202f;6); for caregivers, services and resources (n&#x202f;=&#x202f;15), disease course/prognosis (n&#x202f;=&#x202f;14), general disease information (n&#x202f;=&#x202f;13) and skills (n&#x202f;=&#x202f;10). There was substantial variability in information needs, both between patients and caregivers and among members of the same group.<br><br>CONCLUSION: ALS patients and caregivers have unique and varying PC information needs. Future research should better characterize these needs to improve patient and caregiver quality of life. The delivery of information must be tailored to individual patient or caregiver preferences.}, }
@article {pmid33754495, year = {2021}, author = {Chaprov, K and Rezvykh, A and Funikov, S and Ivanova, TA and Lysikova, EA and Deykin, AV and Kukharsky, MS and Yu Aksinenko, A and Bachurin, SO and Ninkina, N and Buchman, VL}, title = {A bioisostere of Dimebon/Latrepirdine delays the onset and slows the progression of pathology in FUS transgenic mice.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {27}, number = {7}, pages = {765-775}, pmid = {33754495}, issn = {1755-5949}, support = {075-15-2019-1661//Ministry of Science and Higher Education of the Russian Federation/ ; &#x41c;&#x41a;-3316.2019.4//Russian President Foundation/ ; 20-34-90028//Russian Foundation for Basic Research/ ; 0090-2019-0005//State Assignment of IPAC RAS/ ; Buchman/Apr13/6096/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/physiopathology ; Animals ; *Disease Progression ; Gait/drug effects/physiology ; Humans ; Indoles/*administration &amp; dosage/chemistry ; Mice ; Mice, Transgenic ; RNA-Binding Protein FUS/*genetics ; }, abstract = {AIMS: To assess effects of DF402, a bioisostere of Dimebon/Latrepirdine, on the disease progression in the transgenic model of amyotrophic lateral sclerosis (ALS) caused by expression of pathogenic truncated form of human FUS protein.<br><br>METHODS: Mice received DF402 from the age of 42&#xa0;days and the onset of clinical signs, the disease duration and animal lifespan were monitored for experimental and control animals, and multiple parameters of their gait were assessed throughout the pre-symptomatic stage using CatWalk system followed by a bioinformatic analysis. RNA-seq was used to compare the spinal cord transcriptomes of wild-type, untreated, and DF402-treated FUS transgenic mice.<br><br>RESULTS: DF402 delays the onset and slows the progression of pathology. We developed a CatWalk analysis protocol that allows detection of gait changes in FUS transgenic mice and the effect of DF402 on their gait already at early pre-symptomatic stage. At this stage, a limited number of genes significantly change expression in transgenic mice and for 60% of these genes, DF402 treatment causes the reversion of the expression pattern.<br><br>CONCLUSION: DF402 slows down the disease progression in the mouse model of ALS, which is consistent with previously reported neuroprotective properties of Dimebon and its other bioisosteres. These results suggest that these structures can be considered as lead compounds for further optimization to obtain novel medicines that might be used as components of complex ALS therapy.}, }
@article {pmid33753789, year = {2021}, author = {Malysz-Cymborska, I and Golubczyk, D and Kalkowski, L and Kwiatkowska, J and Zawadzki, M and Głodek, J and Holak, P and Sanford, J and Milewska, K and Adamiak, Z and Walczak, P and Janowski, M}, title = {Intra-arterial transplantation of stem cells in large animals as a minimally-invasive strategy for the treatment of disseminated neurodegeneration.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {6581}, pmid = {33753789}, issn = {2045-2322}, mesh = {Animals ; Disease Management ; Disease Models, Animal ; Dogs ; Fluorescent Antibody Technique ; Immunohistochemistry ; Magnetic Resonance Imaging/methods ; Mesenchymal Stem Cell Transplantation/methods ; Mesenchymal Stem Cells/cytology/metabolism ; *Minimally Invasive Surgical Procedures ; Neurodegenerative Diseases/etiology/*therapy ; Stem Cell Transplantation/adverse effects/*methods ; Surgery, Computer-Assisted ; Swine ; }, abstract = {Stem cell transplantation proved promising in animal models of neurological diseases; however, in conditions with disseminated pathology such as ALS, delivery of cells and their broad distribution is challenging. To address this problem, we explored intra-arterial (IA) delivery route, of stem cells. The goal of this study was to investigate the feasibility and safety of MRI-guided transplantation of glial restricted precursors (GRPs) and mesenchymal stem cells (MSCs) in dogs suffering from ALS-like disease, degenerative myelopathy (DM). Canine GRP transplantation in dogs resulted in rather poor retention in the brain, so MSCs were used in subsequent experiments. To evaluate the safety of MSC intraarterial transplantation, naïve pigs (n = 3) were used as a pre-treatment control before transplantation in dogs. Cells were labeled with iron oxide nanoparticles. For IA transplantation a 1.2-French microcatheter was advanced into the middle cerebral artery under roadmap guidance. Then, the cells were transplanted under real-time MRI with the acquisition of dynamic T2*-weighted images. The procedure in pigs has proven to be safe and histopathology has demonstrated the successful and predictable placement of transplanted porcine MSCs. Transplantation of canine MSCs in DM dogs resulted in their accumulation in the brain. Interventional and follow-up MRI proved the procedure was feasible and safe. Analysis of gene expression after transplantation revealed a reduction of inflammatory factors, which may indicate a promising therapeutic strategy in the treatment of neurodegenerative diseases.}, }
@article {pmid33735604, year = {2021}, author = {Alves Almeida, P and Schmitz de Souza, LF and Franzoni Maioral, M and Otto Walter, L and Fischer Duarte, B and Mattos Santos-Pirath, &#xcd; and Bauer Speer, D and Sens, L and Tizziani, T and Sena de Oliveira, A and Nunes, RJ and Santos-Silva, MC}, title = {Cell Cycle Arrest and Apoptosis Induction by a New 2,4-Dinitrobenzenesulfonamide Derivative In Acute Leukemia Cells.}, journal = {Journal of pharmacy &amp; pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques}, volume = {24}, number = {}, pages = {23-36}, doi = {10.18433/jpps31349}, pmid = {33735604}, issn = {1482-1826}, mesh = {Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology ; Apoptosis/*drug effects ; Benzene Derivatives/chemical synthesis/chemistry/*pharmacology ; Cell Cycle Checkpoints/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drug Screening Assays, Antitumor ; Humans ; Jurkat Cells ; K562 Cells ; Leukemia, Myeloid, Acute/*drug therapy/metabolism/pathology ; Molecular Structure ; Sulfonamides/chemical synthesis/chemistry/*pharmacology ; }, abstract = {BACKGROUND: Current therapies for acute leukemias (ALs) are associated with severe adverse reactions and high relapse rates, which makes the search for new antileukemic agents a necessity. Therefore, the aim of this study was to evaluate the effects of a new sulfonamide, S1, in AL cells K562 and Jurkat.<br><br>METHODS: The cytotoxic activity of S1 was assessed using MTT method. The involvement of apoptosis in the mechanism of cell death was assessed by flow cytometry and fluorescence microscopy.<br><br>RESULTS: Our results demonstrated that S1 induced morphological changes suggestive of apoptosis in both K562 and Jurkat cells. Additionally, S1 was not cytotoxic to normal erythrocytes and mononuclear cells and had a highly selective cytotoxicity for AL lineages. The mechanisms of cell death induced by S1 in K562 cells involves cell cycle arrest at G2/M phase and the activation of both extrinsic and intrinsic apoptosis, with an increased FasR and AIF expression and the loss of mitochondrial potential. As for Jurkat, we observed cell cycle blockade at G0/G1 phase, phosphatidylserine exposure and the involvement of intrinsic apoptosis only, with mitochondrial potential loss and a reduced expression of Survivin.&#xa0; Although sulfonamide S1 did not altered Bcl-2 and Bax expression in AL cell lines, it was able to activate caspase-3 in K562 cells.<br><br>CONCLUSION: Our results suggest that sulfonamide S1 may be a promising candidate for the development of new drugs for the treatment of ALs.}, }
@article {pmid33732107, year = {2021}, author = {Broce, IJ and Castruita, PA and Yokoyama, JS}, title = {Moving Toward Patient-Tailored Treatment in ALS and FTD: The Potential of Genomic Assessment as a Tool for Biological Discovery and Trial Recruitment.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {639078}, pmid = {33732107}, issn = {1662-4548}, support = {K01 AG070376/AG/NIA NIH HHS/United States ; R01 AG062588/AG/NIA NIH HHS/United States ; R03 AG063260/AG/NIA NIH HHS/United States ; T32 AG058529/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating and intertwined neurodegenerative diseases. Historically, ALS and FTD were considered distinct disorders given differences in presenting clinical symptoms, disease duration, and predicted risk of developing each disease. However, research over recent years has highlighted the considerable clinical, pathological, and genetic overlap of ALS and FTD, and these two syndromes are now thought to represent different manifestations of the same neuropathological disease spectrum. In this review, we discuss the need to shift our focus from studying ALS and FTD in isolation to identifying the biological mechanisms that drive these diseases-both common and distinct-to improve treatment discovery and therapeutic development success. We also emphasize the importance of genomic data to facilitate a "precision medicine" approach for treating ALS and FTD.}, }
@article {pmid33728912, year = {2021}, author = {Zhang, X and Wang, H and Bei, F and Wu, C and Zhang, L and Jia, S and Wang, J and Liu, W}, title = {Investigating the Mechanism of Metabolic Resistance to Tribenuron-Methyl in Capsella bursa-pastoris (L.) Medik. by Full-Length Transcriptome Assembly Combined with RNA-Seq.}, journal = {Journal of agricultural and food chemistry}, volume = {69}, number = {12}, pages = {3692-3701}, doi = {10.1021/acs.jafc.0c07512}, pmid = {33728912}, issn = {1520-5118}, mesh = {*Acetolactate Synthase/metabolism ; Arylsulfonates ; *Capsella/genetics/metabolism ; Chromatography, Liquid ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; RNA-Seq ; Sequence Analysis, RNA ; Tandem Mass Spectrometry ; Transcriptome ; }, abstract = {Capsella bursa-pastoris (L.) Medik. has evolved resistance to ALS-inhibiting herbicides on a large scale. Previous studies primarily focused on the target-site resistance (TSR), and the non-TSR (NTSR) is not well characterized. In this study, pre-treatment with the cytochrome P450 monooxygenase (P450) inhibitor malathion clearly reduced the tribenuron-methyl resistance in the resistant (R) population. After tribenuron-methyl treatment, the glutathione S-transferase (GST) activity of R plants was significantly higher than that of susceptible (S) plants. The higher tribenuron-methyl metabolism in R plants was also confirmed by using LC-MS/MS analysis. Isoform sequencing (Iso-Seq) combined with RNA sequencing (RNA-Seq) was used to identify candidate genes involved in non-target metabolic resistance in this population. A total of 37 differentially expressed genes were identified, 11 of them constitutively upregulated in R plants, including three P450s, one GST, two glycosyltransferases, two ATP-binding cassette transporters, one oxidase, and two peroxidases. This study confirmed the metabolic tribenuron-methyl resistance in C. bursa-pastoris, and the transcriptome data obtained by Iso-Seq combined with RNA-Seq provide gene resources for understanding the molecular mechanism of NTSR in C. bursa-pastoris.}, }
@article {pmid33726839, year = {2021}, author = {Quezada, E and Cappelli, C and Diaz, I and Jury, N and Wightman, N and Brown, RH and Montecino, M and van Zundert, B}, title = {BET bromodomain inhibitors PFI-1 and JQ1 are identified in an epigenetic compound screen to enhance C9ORF72 gene expression and shown to ameliorate C9ORF72-associated pathological and behavioral abnormalities in a C9ALS/FTD model.}, journal = {Clinical epigenetics}, volume = {13}, number = {1}, pages = {56}, pmid = {33726839}, issn = {1868-7083}, support = {R01 NS104022/NH/NIH HHS/United States ; 15090007//FONDAP/ ; ATA-2014-F-034//ALS Therapy Alliance/ ; AFB 170005 CARE UC//CONICYT PIA/BASAL/ ; NS111990-01/NH/NIH HHS/United States ; 1181645//FONDECYT/ ; 1170878//FONDECYT/ ; 20-DDC-497//Amyotrophic Lateral Sclerosis Association/ ; 2013-0030//DRI-USA/ ; 201161486//CONICYT/ ; R01 NS104022/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; C9orf72 Protein/*genetics ; Cell Line ; Disease Models, Animal ; Enzyme Inhibitors/*metabolism ; *Epigenesis, Genetic ; Frontotemporal Dementia/*genetics/*physiopathology ; Gene Expression Regulation ; Histone Acetyltransferases/*genetics ; Humans ; Mice ; Transcription Factors/*genetics ; }, abstract = {BACKGROUND: An intronic GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), referred to as C9ALS/FTD. No cure or effective treatment exist for C9ALS/FTD. Three major molecular mechanisms have emerged to explain C9ALS/FTD disease mechanisms: (1) C9ORF72 loss-of-function through haploinsufficiency, (2) dipeptide repeat (DPR) proteins mediated toxicity by the translation of the repeat RNAs, and more controversial, (3) RNA-mediated toxicity by bidirectional transcription of the repeats that form intranuclear RNA foci. Recent studies indicate a double-hit pathogenic mechanism in C9ALS/FTD, where reduced C9ORF72 protein levels lead to impaired clearance of toxic DPRs. Here we explored whether pharmacological compounds can revert these pathological hallmarks in vitro and cognitive impairment in a C9ALS/FTD mouse model (C9BAC). We specifically focused our study on small molecule inhibitors targeting chromatin-regulating proteins (epidrugs) with the goal of increasing C9ORF72 gene expression and reduce toxic DPRs.<br><br>RESULTS: We generated luciferase reporter cell lines containing 10 (control) or&#x2009;&#x2265;&#x2009;90 (mutant) G4C2 HRE located between exon 1a and 1b of the human C9ORF72 gene. In a screen of 14 different epidrugs targeting bromodomains, chromodomains and histone-modifying enzymes, we found that several bromodomain and extra-terminal domain (BET) inhibitors (BETi), including PFI-1 and JQ1, increased luciferase reporter activity. Using primary cortical cultures from C9BAC mice, we further found that PFI-1 treatment increased the expression of V1-V3 transcripts of the human mutant C9ORF72 gene, reduced poly(GP)-DPR inclusions but enhanced intranuclear RNA foci. We also tested whether JQ1, an BETi previously shown to reach the mouse brain by intraperitoneal (i.p.) injection, can revert behavioral abnormalities in C9BAC mice. Interestingly, it was found that JQ1 administration (daily i.p. administration for 7&#xa0;days) rescued hippocampal-dependent cognitive deficits in C9BAC mice.<br><br>CONCLUSIONS: Our findings place BET bromodomain inhibitors as a potential therapy for C9ALS/FTD by ameliorating C9ORF72-associated pathological&#xa0;and behavioral abnormalities. Our finding that PFI-1 increases accumulation of intranuclear RNA foci is in agreement with recent data in flies suggesting that nuclear RNA foci can be neuroprotective by sequestering repeat transcripts that result in toxic DPRs.}, }
@article {pmid33725356, year = {2021}, author = {Cagin, U}, title = {Targeting Age-Related Neurodegenerative Diseases by AAV-Mediated Gene Therapy.}, journal = {Advances in experimental medicine and biology}, volume = {1286}, number = {}, pages = {213-223}, pmid = {33725356}, issn = {0065-2598}, mesh = {*Alzheimer Disease/genetics/therapy ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Genetic Therapy ; Humans ; *Neurodegenerative Diseases/genetics/therapy ; *Parkinson Disease/genetics/therapy ; }, abstract = {Age-related neurodegenerative diseases have detrimental consequences on health of many patients and result in mortality. The current treatment options are limited and usually fail to correct the underlying pathology. AAV-based gene therapies have proved to be safe based on the data available on clinical trials for several monogenic diseases. Therefore, such therapies can pave the way to treat neurodegenerative diseases likes Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Here, the advantages of AAV-based gene therapies are discussed with emphasis on efforts of developing novel capsids with superior therapeutic efficacy. Furthermore, the results of clinical trials on AD, PD, and ALS are summarized.}, }
@article {pmid33711277, year = {2021}, author = {Pellegrino, GM and Corbo, M and Di Marco, F and Pompilio, P and Dellacà, R and Banfi, P and Pellegrino, R and Sferrazza Papa, GF}, title = {Effects of Air Stacking on Dyspnea and Lung Function in Neuromuscular Diseases.}, journal = {Archives of physical medicine and rehabilitation}, volume = {102}, number = {8}, pages = {1562-1567}, doi = {10.1016/j.apmr.2021.01.092}, pmid = {33711277}, issn = {1532-821X}, mesh = {Aged ; Dyspnea/*physiopathology/*rehabilitation ; Female ; Humans ; Male ; Middle Aged ; Neuromuscular Diseases/*physiopathology/*rehabilitation ; Respiratory Function Tests ; Respiratory Muscles/*physiopathology ; Respiratory Therapy/*methods ; Spirometry ; }, abstract = {OBJECTIVE: To investigate whether the decrease in dyspnea in neuromuscular diseases after air stacking (AS) occurs mostly in patients with decreased inspiratory muscle force and ensuing chest wall restriction or heterogeneous ventilation across the lungs.<br><br>DESIGN: Interventional, before-after study.<br><br>SETTING: A neurorehabilitation inpatient and outpatient center.<br><br>PARTICIPANTS: Fifteen consecutive adult patients affected by neuromuscular diseases (N=15).<br><br>INTERVENTIONS: AS treatment.<br><br>MAIN OUTCOME MEASURES: Patients had vital capacity (VC) and sniff nasal inspiratory pressure (SNIP) measured. We measured Borg score, oxygen saturation, and ventilation heterogeneity across the lung as estimated from the difference between respiratory resistance at 5 and 19 Hz (R5-19) with the forced oscillation technique before and 5, 30, 60, and 120 minutes after applying AS.<br><br>RESULTS: Before AS, Borg score was significantly related to R5-19 (r[2] 0.46, P<.05) but not to VC % predicted, SNIP % predicted, and time since symptom onset. After AS, average Borg score gradually decreased (P=.005), whereas inspiratory flow resistance at 5 Hz, R5-19, and inspiratory reactance at 5 Hz tended to improve, despite not reaching statistical significance. The decrease in dyspnea at 60 and 120 minutes after AS significantly correlated with baseline R5-19 (r[2] 0.49, P<.01 and r[2] 0.29, P<.05, respectively), but not with VC % predicted, SNIP % predicted, time since symptom onset, and clinical severity score for patients affected by amyotrophic lateral sclerosis.<br><br>CONCLUSIONS: These findings suggest that dyspnea in neuromuscular diseases is related to heterogeneous ventilation rather than inspiratory muscle force and/or lung volumes decrease. Restoring ventilation distribution across the lungs with AS appears to improve dyspnea.}, }
@article {pmid33709015, year = {2020}, author = {Guo, X and Smith, V and Jackson, M and Tran, M and Thomas, M and Patel, A and Lorusso, E and Nimbalkar, S and Cai, Y and McAleer, CW and Wang, Y and Long, CJ and Hickman, JJ}, title = {A Human-Based Functional NMJ System for Personalized ALS Modeling and Drug Testing.}, journal = {Advanced therapeutics}, volume = {3}, number = {11}, pages = {}, pmid = {33709015}, issn = {2366-3987}, support = {R01 NS050452/NS/NINDS NIH HHS/United States ; }, abstract = {Loss of the neuromuscular junction (NMJ) is an early and critical hallmark in all forms of ALS. The study design was to develop a functional NMJ disease model by integrating motoneurons (MNs) differentiated from multiple ALS-patients' induced pluripotent stem cells (iPSCs) and primary human muscle into a chambered system. NMJ functionality was tested by recording myotube contractions while stimulating MNs by field electrodes and a set of clinically relevant parameters were defined to characterize the NMJ function. Three ALS lines were analyzed, 2 with SOD1 mutations and 1 with a FUS mutation. The ALS-MNs reproduced pathological phenotypes, including increased axonal varicosities, reduced axonal branching and elongation and increased excitability. These MNs formed functional NMJs with wild type muscle, but with significant deficits in NMJ quantity, fidelity and fatigue index. Furthermore, treatment with the Deana protocol was found to correct the NMJ deficits in all the ALS mutant lines tested. Quantitative analysis also revealed the variations inherent in each mutant lines. This functional NMJ system provides a platform for the study of both fALS and sALS and has the capability of being adapted into subtype-specific or patient-specific models for ALS etiological investigation and patient stratification for drug testing.}, }
@article {pmid33704925, year = {2021}, author = {Shimizu, H and Nishimura, Y and Shiide, Y and Matsuda, H and Akimoto, M and Matsuda, M and Nakamaru, Y and Kato, Y and Kondo, K}, title = {Evaluation of Pharmacokinetics, Safety, and Drug-Drug Interactions of an Oral Suspension of Edaravone in Healthy Adults.}, journal = {Clinical pharmacology in drug development}, volume = {10}, number = {10}, pages = {1174-1187}, pmid = {33704925}, issn = {2160-7648}, mesh = {Administration, Oral ; Adult ; *Asian People ; Dose-Response Relationship, Drug ; Drug Interactions/physiology ; Edaravone/*administration &amp; dosage/*pharmacokinetics ; Free Radical Scavengers/*administration &amp; dosage/*pharmacokinetics ; Healthy Volunteers ; Humans ; Male ; Middle Aged ; Single-Blind Method ; Suspensions ; *White People ; Young Adult ; }, abstract = {Intravenous (IV) edaravone is approved as an amyotrophic lateral sclerosis (ALS) treatment. Because IV administration places a burden on patients, development of orally administered ALS treatments is needed. Therefore, 2 phase 1 studies of oral formulations of edaravone in healthy subjects examined the pharmacokinetics (PK), safety, racial differences, and drug-drug interactions (DDIs) and investigated the dose of the oral formulation considered to be bioequivalent to the approved dose of the IV formulation. Study 1 was a placebo-controlled, randomized, single-blind study of single-ascending-dose oral edaravone with the dose range of 30 to 300 mg (n = 56). Study 2 was conducted in 2 cohorts (n = 84); the first assessed DDIs with multiple-dose edaravone 120 mg/day given over 5 or 8 days (coadministered with single-dose rosuvastatin, sildenafil, or furosemide), and the second evaluated PK and racial (Japanese/White) differences in PK parameters with doses of 100-mg edaravone. The oral formulation of edaravone was well absorbed, and plasma concentrations of unchanged edaravone increased more than dose proportionally within the dose range of 30 to 300 mg. No effect of race on oral edaravone PK and no notable DDI effects possibly caused by orally administered edaravone were observed. The oral edaravone formulations were safe and tolerable under the assessed conditions. Mathematical modeling determined that equivalent exposures in plasma with the approved dose of the IV edaravone formulation, as reported previously, could be achieved when the oral edaravone formulation was administered at a dose of ≈100 mg, with an absolute bioavailability of ≈60%.}, }
@article {pmid33687180, year = {2022}, author = {Nicolini, A and Prato, P and Beccarelli, L and Grecchi, B and Garuti, G and Banfi, P and D'Abrosca, F}, title = {Comparison of two mechanical insufflation-exsufflation devices in patients with amyotrophic lateral sclerosis: a preliminary study.}, journal = {Panminerva medica}, volume = {64}, number = {4}, pages = {525-531}, doi = {10.23736/S0031-0808.21.04104-5}, pmid = {33687180}, issn = {1827-1898}, mesh = {Humans ; *Insufflation/adverse effects/methods ; *Amyotrophic Lateral Sclerosis/therapy ; Cough/complications ; *Neurodegenerative Diseases/complications ; *Respiratory Insufficiency/therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease affecting upper and lower motor neurons and resulting in progressive skeletal muscle weakness. Weak cough and difficulty in clearing secretions are often the cause of pulmonary infections and acute respiratory failure. Cough assistance is commonly used to provide support in coughing for patients with ALS.<br><br>METHODS: This was a preliminary parallel randomized study comparing two cough-assist devices: one utilizing mechanical insufflation/exsufflation (MI/E) and expiratory flow accelerator (EFA) technology, the other utilizing only MI/E technology. The aim was to compare the effectiveness, safety and acceptability of the two devices. Thirty patients with ALS and similar severity and functional scale were enrolled. The primary outcome was the change in respiratory function, respiratory muscle function, gas exchange, and peak cough expiratory flow as an indicator of cough efficacy. Secondary outcomes were the number of exacerbations at 1, 6 and 12 months of treatment, and the patient-perceived comfort/distress related to the interventions together with the perceived efficacy of cough.<br><br>RESULTS: Thirty subjects were recruited and randomized into the two groups (1:1 ratio). Primary outcomes : respiratory function parameters decreased over time in both groups, but significantly less in the Kalos group, as did the respiratory muscle strength parameters and peak cough flows. Gas exchanges decreased over time in both groups with no clinically relevant differences between groups. Secondary outcomes : there were no significant differences between groups regarding the number of exacerbations over time. No adverse events were reported. All participants, in both groups, reported a similar increase in perceived cough efficacy and there was no significant difference in comfort and distress between the two treatments.<br><br>CONCLUSIONS: The cough-assist device with EFA technology performed better than a traditional MI/E device in ALS patients regarding respiratory function and cough efficacy, although number of exacerbations and acceptability of the two devices was similar. Following these promising preliminary results, further investigation is required in a larger cohort to confirm the superiority of EFA technology associated with a MI/E device.}, }
@article {pmid33683161, year = {2021}, author = {Pinto, S and De Carvalho, M}, title = {Phrenic nerve study as outcome in clinical trials for amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {22}, number = {sup1}, pages = {9-13}, doi = {10.1080/21678421.2021.1895842}, pmid = {33683161}, issn = {2167-9223}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Amyotrophic Lateral Sclerosis/drug therapy ; *COVID-19 ; Humans ; Male ; Middle Aged ; Phrenic Nerve ; SARS-CoV-2 ; Vital Capacity ; Young Adult ; }, abstract = {Introduction: Respiratory tests are fundamental for monitoring respiratory function in ALS, and essential in clinical trials. Slow vital capacity (SVC) was canceled in some countries to prevent COVID-19 transmission. We aimed to test phrenic nerve motor responses as an option to SVC in clinical trials. Methodology: Patients followed-up in our unit were selected respecting inclusion criteria used elsewhere: possible/probable/definite disease; onset-age 18-80years; disease duration from disease duration ≤24months; body mass index (BMI)>20kg/m[2]; respiratory subscore of the revised ALS functional rating scale (ALSFRS-R)≥11; upright SVC ≥ 70%. We added normal phrenic responses (meanPhrenAmpl, ≥0.4mV). All patients were on riluzole. SVC and meanPhrenAmpl were recorded at study entry (T0) and 24 weeks later (T1). Decays were determined. Sample size was calculated for a treatment effect of 30% on the decay rate. Results: We included 317 ALS patients (191 males, 225 spinal-onset), mean onset-age 59.9 ± 10.7 (31-80)years, mean onset BMI 25.48 ± 3.2 (20.1-35)kg/m[2], mean disease duration 10.5 ± 5.6 (1-24)months, mean ALSFRS-R 41.54 ± 4.3 (22-47) and respiratory subscore 11.83 ± 0.38 (11-12). MeanPhrenAmpl and SVC were weakly but significantly correlated at T0 and T1. At T1, MeanPhrenAmpl decayed 16.94 ± 16.45% and SVC 13.5 ± 16.86%. For the proposed drug effect, 174 and 272 patients would be needed to recruit using respectively meanPhrenAmpl and SVC decline as the primary outcome measurement (accepting no dropouts). Discussion: Contrary to SVC, meanPhrenAmpl is non-volitional and not associated with aerosolization risk. Lower recruitment number (98 patients less) would be needed, translating shorter inclusion period, trial length and costs, and probable lower missed data rate. MeanPhrenAmp is an alternative test in ALS clinical trials.}, }
@article {pmid33675422, year = {2021}, author = {Kang, MG and Gwak, DW and Cho, HJ and Min, YS and Park, JS}, title = {Effect of leuprorelin in bulbar function of spinal and bulbar muscular atrophy patients: observational study for 1 year.}, journal = {Journal of neurology}, volume = {268}, number = {9}, pages = {3344-3351}, pmid = {33675422}, issn = {1432-1459}, mesh = {*Bulbo-Spinal Atrophy, X-Linked/drug therapy/genetics ; Deglutition ; *Deglutition Disorders/etiology ; Humans ; Leuprolide/therapeutic use ; *Muscular Atrophy, Spinal ; Reproducibility of Results ; }, abstract = {BACKGROUND: This study aimed to investigate the effect of androgen suppression therapy using leuprorelin focused on the bulbar function of patients with spinal and bulbar muscular atrophy (SBMA).<br><br>METHODS: Genetically confirmed SBMA patients who consented to participate in this observational study were enrolled. Leuprorelin was subcutaneously injected every 12&#xa0;weeks. Videofluoroscopic swallowing study was performed at baseline and after androgen suppression therapy for 1 year. The primary outcome measures were the changes in the vallecular residue and pyriform sinus residue. The videofluoroscopic swallowing study data were analyzed and interpreted by two experienced physiatrists.<br><br>RESULTS: A total of 40 patients with SBMA were analyzed in this study. The inter-rater reliability testing showed good agreement for the pharyngeal residue (ICC&#x2009;=&#x2009;0.84) and videofluoroscopic dysphagia scale (ICC&#x2009;=&#x2009;0.75). The vallecular residue and pyriform sinus residue after swallowing 9&#xa0;mL yogurt were significantly reduced (26.8&#x2009;&#xb1;&#x2009;22.6 to 14.6&#x2009;&#xb1;&#x2009;14.5, p&#x2009;<&#x2009;0.001, 14.9&#x2009;&#xb1;&#x2009;16.9 to 7.6&#x2009;&#xb1;&#x2009;9.9, p&#x2009;<&#x2009;0.001, respectively). The swallowing subscore of amyotrophic lateral sclerosis functional rating scale-revised improved after androgen suppression therapy (3.3&#x2009;&#xb1;&#x2009;0.5 to 3.5&#x2009;&#xb1;&#x2009;0.6, p&#x2009;=&#x2009;0.041).<br><br>CONCLUSIONS: Leuprorelin significantly reduced the pharyngeal residue in patients with SBMA after 1 year of treatment without any serious adverse events and longitudinal studies are needed to confirm these results.}, }
@article {pmid33668206, year = {2021}, author = {Chung, SA and Lee, HS and Kim, SW and Hwang, JS}, title = {Myopic Progression in Girls with Gonadotrophin-Releasing Hormone Agonist Treatment for Central Precocious Puberty.}, journal = {Children (Basel, Switzerland)}, volume = {8}, number = {3}, pages = {}, pmid = {33668206}, issn = {2227-9067}, support = {2017R1C1B5017453//Ministry of Science and ICT, South Korea/ ; }, abstract = {We sought to determine whether the myopic progression of patients with central precocious puberty (CPP) who were undergoing treatment differed from that of their healthy peers with normal pubertal onset and progression. Eighteen girls with CPP and 14 age-matched controls who underwent regular ophthalmic examinations for at least 1 year were included. All the CPP patients received a 3.75 mg leuprolide acetate depot subcutaneously every 28 days. The spherical equivalent (SE) and axial length (AL) for myopia progression and the pubertal parameters (height, body weight, body mass index, Tanner stage, and bone age) were compared between the two groups. Of 32 subjects with a mean age of 8.6 ± 0.7 years, the SEs and ALs did not differ at baseline between the two groups, which had similar weight and similar body mass index. After 1 year, both the CPP patients and controls showed myopic progression, with an average myopic shift of -0.73 ± 0.48 diopters (D) and AL elongation with a mean change of 0.44 ± 0.61 mm. The SE and AL changes over 1 year were greater in the controls than those in the CPP patients, which was not statistically significant (-0.85 ± 0.55 D vs. -0.64 ± 0.41 D and 0.55 ± 0.89 mm vs. 0.35 ± 0.22 mm, respectively). The change in AL correlated significantly with the change in the height (β = 0.691, p = 0.039). In this 1-year study, the CPP patients with treatments trended to show less myopic progression than the controls.}, }
@article {pmid33667787, year = {2021}, author = {Feng, YS and Tan, ZX and Wu, LY and Dong, F and Zhang, F}, title = {The involvement of NLRP3 inflammasome in the treatment of neurodegenerative diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {138}, number = {}, pages = {111428}, doi = {10.1016/j.biopha.2021.111428}, pmid = {33667787}, issn = {1950-6007}, mesh = {Animals ; Drug Delivery Systems/*methods/trends ; Humans ; NLR Family, Pyrin Domain-Containing 3 Protein/*antagonists &amp; inhibitors/*metabolism ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neuroprotective Agents/*administration &amp; dosage/metabolism ; Treatment Outcome ; }, abstract = {In an ageing society, neurodegenerative diseases have attracted attention because of their high incidence worldwide. Despite extensive research, there is a lack of conclusive insights into the pathogenesis of neurodegenerative diseases, which limit the strategies for symptomatic treatment. Therefore, better elucidation of the molecular mechanisms involved in neurodegenerative diseases can provide an important theoretical basis for the discovery of new and effective prevention and treatment methods. The innate immune system is activated during the ageing process and in response to neurodegenerative diseases. Inflammasomes are multiprotein complexes that play an important role in the activation of the innate immune system. They mediate inflammatory reactions and pyroptosis, which are closely involved in neurodegeneration. There are different types of inflammasomes, although the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is the most common inflammasome; NLRP3 plays an important role in the pathogenesis of neurodegenerative diseases. In this review, we will discuss the mechanisms that are involved in the activation of the NLRP3 inflammasome and its crucial role in the pathology of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. We will also review various treatments that target the NLRP3 inflammasome pathway and alleviate neuroinflammation. Finally, we will summarize the novel treatment strategies for neurodegenerative disorders.}, }
@article {pmid33664161, year = {2021}, author = {Galea, MP}, title = {Does respiratory muscle training improve respiratory function compared to sham training, no training, standard treatment or breathing exercises in children and adults with neuromuscular disease? A Cochrane Review summary with commentary.}, journal = {NeuroRehabilitation}, volume = {48}, number = {2}, pages = {243-245}, doi = {10.3233/NRE-218000}, pmid = {33664161}, issn = {1878-6448}, mesh = {Adult ; Breathing Exercises/*methods ; Child ; Female ; Humans ; Male ; Muscle Strength/*physiology ; Muscle Weakness/physiopathology/therapy ; Neuromuscular Diseases/physiopathology/*therapy ; Quality of Life ; Respiratory Function Tests/methods ; Respiratory Muscles/*physiology ; }, abstract = {BACKGROUND: Progressive muscle weakness is a feature of neuromuscular diseases (NMDs), a heterogeneous group of conditions with variable onset, presentation and prognosis that affect both children and adults. Respiratory muscle weakness compromises respiratory function and may lead to respiratory failure.<br><br>OBJECTIVE: To assess the effects of respiratory muscle training (RMT) in adults and children with NMD.<br><br>METHODS: A Cochrane Review by Silva et al. was summarized with comments.<br><br>RESULTS: Eleven studies involving 250 randomized participants with NMD were included. While the studies showed that RMT may lead to improvements in lung function and respiratory muscle strength in people with ALS and DMD, this was not a consistent finding. The evidence from all the included trials was of low or very low certainty.<br><br>CONCLUSIONS: There may be some improvement in lung capacity and respiratory muscle strength following RMT in some NMD. There appears to be no clinically meaningful effect of RMT on physical functioning and quality of life in ALS. The low certainty of the evidence means that the results need to be interpreted with caution.}, }
@article {pmid33662433, year = {2021}, author = {Zakyrjanova, GF and Giniatullin, AR and Mukhutdinova, KA and Kuznetsova, EA and Petrov, AM}, title = {Early differences in membrane properties at the neuromuscular junctions of ALS model mice: Effects of 25-hydroxycholesterol.}, journal = {Life sciences}, volume = {273}, number = {}, pages = {119300}, doi = {10.1016/j.lfs.2021.119300}, pmid = {33662433}, issn = {1879-0631}, mesh = {Acetylcholine/metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Ceramides/metabolism ; Cholesterol/metabolism ; *Disease Models, Animal ; Female ; Hydroxycholesterols/*pharmacology ; Male ; Membrane Microdomains/*drug effects/metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Muscle, Skeletal/*drug effects/metabolism/pathology ; Neuromuscular Junction ; Superoxide Dismutase-1/*physiology ; Synaptic Transmission ; }, abstract = {AIMS: Plasma hyperlipidemia is a protective factor in amyotrophic lateral sclerosis (ALS) while cholesterol-lowering drugs aggravate the pathology. We hypothesize that this phenomenon can be linked with membrane lipid alterations in the neuromuscular junctions (NMJs) occurring before motor neuron loss.<br><br>METHODS: Neurotransmitter release in parallel with lipid membrane properties in diaphragm NMJs of SOD1G93A (mSOD) mice at nine weeks of age (pre-onset stage) were assessed.<br><br>KEY FINDINGS: Despite on slight changes in spontaneous and evoked quantum release of acetylcholine, extracellular levels of choline at resting conditions, an indicator of non-quantum release, were significantly increased in mSOD mice. The use of lipid-sensitive fluorescent probes points to lipid raft disruption in the NMJs of mSOD mice. However, content of cholesterol, a key raft component was unchanged implying another pathway responsible for the loss of raft integrity. In the mSOD mice we found marked increase in levels of raft-destabilizing lipid ceramide. This was accompanied by enhanced ability to uptake of exogenous ceramide in NMJs. Acute and chronic administration of 25-hydroxycholesterol, whose levels increase due to hypercholesterolemia, recovered early alterations in membrane properties. Furthermore, chronic treatment with 25-hydroxycholesterol prevented increase in ceramide and extracellular choline levels as well as suppressed lipid peroxidation of NMJ membranes and fragmentation of end plates.<br><br>SIGNIFICANCE: Thus, lipid raft disruption likely due to ceramide accumulation could be early event in ALS which may trigger neuromuscular abnormalities. Cholesterol derivative 25-hydroxycholesterol may serve as a molecule restoring the membrane and functional properties of NMJs at the early stage.}, }
@article {pmid33661518, year = {2021}, author = {Azoulay-Ginsburg, S and Di Salvio, M and Weitman, M and Afri, M and Ribeiro, S and Ebbinghaus, S and Cestra, G and Gruzman, A}, title = {Chemical chaperones targeted to the endoplasmic reticulum (ER) and lysosome prevented neurodegeneration in a C9orf72 repeat expansion drosophila amyotrophic lateral sclerosis (ALS) model.}, journal = {Pharmacological reports : PR}, volume = {73}, number = {2}, pages = {536-550}, pmid = {33661518}, issn = {2299-5684}, support = {3-13325//Ministry of Science and Technology, Israel/ ; 3-13325//the Directorate General for Country Promotion (Unit for Scientific and Technological Co-operation)/ ; I-1410-201.9/2017//The Germany Israel Foundation/ ; 4//NAAMAT, the Edelson Foundation prize/ ; 2//Navon fellowship for PhD students/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/physiopathology ; Animals ; C9orf72 Protein/*genetics ; DNA Repeat Expansion/genetics ; Disease Models, Animal ; Drosophila melanogaster ; Endoplasmic Reticulum/drug effects ; Lysosomes/metabolism ; Magnetic Resonance Imaging ; Molecular Chaperones/chemical synthesis/chemistry/*pharmacology ; Phenylbutyrates/chemical synthesis/chemistry/*pharmacology ; }, abstract = {BACKGROUND: ALS is an incurable neuromuscular degenerative disorder. A familiar form of the disease (fALS) is related to point mutations. The most common one is an expansion of a noncoding GGGGCC hexanucleotide repeat of the C9orf72 gene on chromosome 9p21. An abnormal translation of the C9orf72 gene generates dipeptide repeat proteins that aggregate in the brain. One of the classical approaches for developing treatment against protein aggregation-related diseases is to use chemical chaperones (CSs). In this work, we describe the development of novel 4-phenylbutyric acid (4-PBA) lysosome/ER-targeted derivatives. We assumed that 4-PBA targeting to specific organelles, where protein degradation takes place, might reduce the 4-PBA effective concentration.<br><br>METHODS: Organic chemistry synthetic methods and solid-phase peptide synthesis (SPPS) were used for preparing the 4-PBA derivatives. The obtained compounds were evaluated in an ALS Drosophila model that expressed C9orf72 repeat expansion, causing eye degeneration. Targeting to lysosome was validated by the [19]F-nuclear magnetic resonance (NMR) technique.<br><br>RESULTS: Several synthesized compounds exhibited a significant biological effect by ameliorating the eye degeneration. They blocked the neurodegeneration of fly retina at different efficacy levels. The most active CS was compound 9, which is a peptide derivative and was targeted to ER. Another active compound targeted to lysosome was compound 4.<br><br>CONCLUSIONS: Novel CSs were more effective than 4-PBA; therefore, they might be used as a new class of drug candidates to treat ALS and other protein misfolding disorders.}, }
@article {pmid33659944, year = {2020}, author = {Gittings, LM and Sattler, R}, title = {Recent advances in understanding amyotrophic lateral sclerosis and emerging therapies.}, journal = {Faculty reviews}, volume = {9}, number = {}, pages = {12}, pmid = {33659944}, issn = {2732-432X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by degeneration of both upper and lower motor neurons and subsequent progressive loss of muscle function. Within the last decade, significant progress has been made in the understanding of the etiology and pathobiology of the disease; however, treatment options remain limited and only two drugs, which exert a modest effect on survival, are approved for ALS treatment in the US. Therefore, the search for effective ALS therapies continues, and over 60 clinical trials are in progress for patients with ALS and other therapeutics are at the pre-clinical stage of development. Recent advances in understanding the genetics, pathology, and molecular mechanisms of ALS have led to the identification of novel targets and strategies that are being used in emerging ALS therapeutic interventions. Here, we review the current status and mechanisms of action of a selection of emerging ALS therapies in pre-clinical or early clinical development, including gene therapy, immunotherapy, and strategies that target neuroinflammation, phase separation, and protein clearance.}, }
@article {pmid33655733, year = {2021}, author = {Lin, JZ and Duan, MR and Lin, N and Zhao, WJ}, title = {The emerging role of the chondroitin sulfate proteoglycan family in neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {32}, number = {7}, pages = {737-750}, doi = {10.1515/revneuro-2020-0146}, pmid = {33655733}, issn = {2191-0200}, mesh = {Central Nervous System ; *Chondroitin Sulfate Proteoglycans ; Extracellular Matrix ; Humans ; *Neurodegenerative Diseases ; }, abstract = {Chondroitin sulfate (CS) is a kind of linear polysaccharide that is covalently linked to proteins to form proteoglycans. Chondroitin sulfate proteoglycans (CSPGs) consist of a core protein, with one or more CS chains covalently attached. CSPGs are precisely regulated and they exert a variety of physiological functions by binding to adhesion molecules and growth factors. Widely distributed in the nervous system in human body, CSPGs contribute to the major component of extracellular matrix (ECM), where they play an important role in the development and maturation of the nervous system, as well as in the pathophysiological response to damage to the central nervous system (CNS). While there are more than 30 types of CSPGs, this review covers the roles of the most important ones, including versican, aggrecan, neurocan and NG2 in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. The updated reports of the treatment of neurodegenerative diseases are involving CSPGs.}, }
@article {pmid33655342, year = {2021}, author = {Distaso, E and Milella, G and Mezzapesa, DM and Introna, A and D'Errico, E and Fraddosio, A and Zoccolella, S and Dicuonzo, F and Simone, IL}, title = {Magnetic resonance metrics to evaluate the effect of therapy in amyotrophic lateral sclerosis: the experience with edaravone.}, journal = {Journal of neurology}, volume = {268}, number = {9}, pages = {3307-3315}, pmid = {33655342}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/drug therapy ; Benchmarking ; Edaravone ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Pyramidal Tracts ; }, abstract = {BACKGROUND: Edaravone was approved as a new treatment for amyotrophic lateral sclerosis (ALS), although there are different opinions on its effectiveness. Magnetic resonance (MRI) measures appear promising as diagnostic and prognostic indicators of disease. However, published studies on MRI using to monitor treatment efficacy in ALS are lacking.<br><br>PURPOSE: The objective of this study was to investigate changes in brain MRI measures in patients treated with edaravone.<br><br>METHODS: Thirteen ALS patients assuming edaravone (ALS-EDA) underwent MRI at baseline (T0) and after 6&#xa0;months (T6) to measure cortical thickness (CT) and fractional anisotropy (FA) of white matter (WM) tracts. MRI data of ALS-EDA were compared at T0 with those of 12 control subjects (CS), and at T6 with those of 11 ALS patients assuming only riluzole (ALS-RIL), extracted from our ALS cohort using a propensity-score-matching. A longitudinal MRI analysis was performed in ALS-EDA between T6 and T0.<br><br>RESULTS: At T0, ALS-EDA showed a cortical widespread thinning in both hemispheres, particularly in the bilateral precentral gyrus, and a reduction of FA in bilateral corticospinal tracts, in comparison to CS. Thinning in bilateral precentral cortex and significant widespread reduction of FA in several WM tracts were observed in ALS-EDA at T6 compared to T0. At T6, no significant differences in MRI measures of ALS-EDA versus ALS-RIL were found.<br><br>CONCLUSIONS: Patients treated with edaravone showed progression of damage in the motor cortex and several WM tracts, at a six-month follow-up. Moreover, this study showed no evidence of a difference between edaravone and riluzole.}, }
@article {pmid33653604, year = {2021}, author = {Garcia-Montojo, M and Fathi, S and Norato, G and Smith, BR and Rowe, DB and Kiernan, MC and Vucic, S and Mathers, S and van Eijk, RPA and Santamaria, U and Rogers, ML and Malaspina, A and Lombardi, V and Mehta, PR and Westeneng, HJ and van den Berg, LH and Al-Chalabi, A and Gold, J and Nath, A}, title = {Inhibition of HERV-K (HML-2) in amyotrophic lateral sclerosis patients on antiretroviral therapy.}, journal = {Journal of the neurological sciences}, volume = {423}, number = {}, pages = {117358}, pmid = {33653604}, issn = {1878-5883}, support = {MALASPINA/APR13/817-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; ZIA NS003130/ImNIH/Intramural NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Endogenous Retroviruses ; *HIV Infections/drug therapy ; Humans ; }, abstract = {Reactivation of Human Endogenous Retrovirus K (HERV-K), subtype HML-2, has been associated with pathophysiology of amyotrophic lateral sclerosis (ALS). We aimed to assess the efficacy of antiretroviral therapy in inhibiting HML-2 in patients with ALS and a possible association between the change in HML-2 levels and clinical outcomes. We studied the effect of 24-weeks antiretroviral combination therapy with abacavir, lamivudine, and dolutegravir on HML-2 levels in 29 ALS patients. HML-2 levels decreased progressively over 24 weeks (P = 0.001) and rebounded within a week of stopping medications (P = 0.02). The majority of participants (82%), defined as "responders", experienced a decrease in HML-2 at week 24 of treatment compared to the pre-treatment levels. Differences in the evolution of some of the clinical outcomes could be seen between responders and non-responders: FVC decreased 23.69% (SE = 11.34) in non-responders and 12.71% (SE = 8.28) in responders. NPI score decreased 91.95% (SE = 6.32) in non-responders and 53.05% (SE = 10.06) in responders (P = 0.01). Thus, participants with a virological response to treatment showed a trend for slower progression of the illness. These findings further support the possible involvement of HML-2 in the clinical course of the disease.}, }
@article {pmid33642372, year = {2021}, author = {Falzone, YM and Russo, T and Domi, T and Pozzi, L and Quattrini, A and Filippi, M and Riva, N}, title = {Current application of neurofilaments in amyotrophic lateral sclerosis and future perspectives.}, journal = {Neural regeneration research}, volume = {16}, number = {10}, pages = {1985-1991}, pmid = {33642372}, issn = {1673-5374}, abstract = {Motor neuron disease includes a heterogeneous group of relentless progressive neurological disorders defined and characterized by the degeneration of motor neurons. Amyotrophic lateral sclerosis is the most common and aggressive form of motor neuron disease with no effective treatment so far. Unfortunately, diagnostic and prognostic biomarkers are lacking in clinical practice. Neurofilaments are fundamental structural components of the axons and neurofilament light chain and phosphorylated neurofilament heavy chain can be measured in both cerebrospinal fluid and serum. Neurofilament light chain and phosphorylated neurofilament heavy chain levels are elevated in amyotrophic lateral sclerosis, reflecting the extensive damage of motor neurons and axons. Hence, neurofilaments are now increasingly recognized as the most promising candidate biomarker in amyotrophic lateral sclerosis. The potential usefulness of neurofilaments regards various aspects, including diagnosis, prognosis, patient stratification in clinical trials and evaluation of treatment response. In this review paper, we review the body of literature about neurofilaments measurement in amyotrophic lateral sclerosis. We also discuss the open issues concerning the use of neurofilaments clinical practice, as no overall guideline exists to date; finally, we address the most recent evidence and future perspectives.}, }
@article {pmid33642365, year = {2021}, author = {Lu, JX and Wang, Y and Zhang, YJ and Shen, MF and Li, HY and Yu, ZQ and Chen, G}, title = {Axonal mRNA localization and local translation in neurodegenerative disease.}, journal = {Neural regeneration research}, volume = {16}, number = {10}, pages = {1950-1957}, pmid = {33642365}, issn = {1673-5374}, abstract = {The regulation of mRNA localization and local translation play vital roles in the maintenance of cellular structure and function. Many human neurodegenerative diseases, such as fragile X syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, and spinal muscular atrophy, have been characterized by pathological changes in neuronal axons, including abnormal mRNA translation, the loss of protein expression, or abnormal axon transport. Moreover, the same protein and mRNA molecules have been associated with variable functions in different diseases due to differences in their interaction networks. In this review, we briefly examine fragile X syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, and spinal muscular atrophy, with a focus on disease pathogenesis with regard to local mRNA translation and axon transport, suggesting possible treatment directions.}, }
@article {pmid33634973, year = {2021}, author = {Genç, B and Gautam, M and Gözütok, &#xd6; and Dervishi, I and Sanchez, S and Goshu, GM and Koçak, N and Xie, E and Silverman, RB and Özdinler, PH}, title = {Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP-43 pathology.}, journal = {Clinical and translational medicine}, volume = {11}, number = {2}, pages = {e336}, pmid = {33634973}, issn = {2001-1326}, support = {P30 AG013854/AG/NIA NIH HHS/United States ; R01 AG061708/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Endoplasmic Reticulum/metabolism/*pathology ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism/*pathology ; Motor Neuron Disease/metabolism/*pathology ; Proteostasis Deficiencies/metabolism/*pathology ; Rotarod Performance Test ; Superoxide Dismutase-1/*metabolism ; TDP-43 Proteinopathies/metabolism/*pathology ; }, abstract = {BACKGROUND: Upper motor neurons (UMNs) are a key component of motor neuron circuitry. Their degeneration is a hallmark for diseases, such as hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and amyotrophic lateral sclerosis (ALS). Currently there are no preclinical assays investigating cellular responses of UMNs to compound treatment, even for diseases of the UMNs. The basis of UMN vulnerability is not fully understood, and no compound has yet been identified to improve the health of diseased UMNs: two major roadblocks for building effective treatment strategies.<br><br>METHODS: Novel UMN reporter models, in which UMNs that are diseased because of misfolded superoxide dismutase protein (mSOD1) toxicity and TDP-43 pathology are labeled with eGFP expression, allow direct assessment of UMN response to compound treatment. Electron microscopy reveals very precise aspects of endoplasmic reticulum (ER) and mitochondrial damage. Administration of NU-9, a compound initially identified based on its ability to reduce mSOD1 toxicity, has profound impact on improving the health and stability of UMNs, as identified by detailed cellular and ultrastructural analyses.<br><br>RESULTS: Problems with mitochondria and ER are conserved in diseased UMNs among different species. NU-9 has drug-like pharmacokinetic properties. It lacks toxicity and crosses the blood brain barrier. NU-9 improves the structural integrity of mitochondria and ER, reduces levels of mSOD1, stabilizes degenerating UMN apical dendrites, improves motor behavior measured by the hanging wire test, and eliminates ongoing degeneration of UMNs that become diseased both because of mSOD1 toxicity and TDP-43 pathology, two distinct and important overarching causes of motor neuron degeneration.<br><br>CONCLUSIONS: Mechanism-focused and cell-based drug discovery approaches not only addressed key cellular defects responsible for UMN loss, but also identified NU-9, the first compound to improve the health of diseased UMNs, neurons that degenerate in ALS, HSP, PLS, and ALS/FTLD patients.}, }
@article {pmid33632340, year = {2021}, author = {Dontje, ML and Kruitwagen-van Reenen, E and Visser-Meily, JMA and Beelen, A and , }, title = {Implementation and evaluation of an e-health innovation for personalized care for patients with amyotrophic lateral sclerosis (ALS): protocol for a participatory action research study.}, journal = {Implementation science communications}, volume = {2}, number = {1}, pages = {25}, pmid = {33632340}, issn = {2662-2211}, support = {80-83935-98-025/ZONMW_/ZonMw/Netherlands ; 2016-51//Stichting ALS Nederland/ ; }, abstract = {BACKGROUND: In the absence of a cure for amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, treatment consists of symptomatic management by a multidisciplinary healthcare team and is mainly aimed at optimizing patients' quality of life. Because the course of the disease is often erratic and varies between patients, it is imperative for patients with ALS to be closely monitored. E-health innovations that can monitor disease progression remotely have great potential to tailor the care to the needs of individual patients with ALS. Therefore, the e-health innovation "ALS Home-monitoring and Coaching" was developed employing a user-centered design process and implemented at the University Medical Center Utrecht, the Netherlands in 2017. Because ALS Home-monitoring and Coaching was shown to be feasible and well received by patients and healthcare professionals at University Medical Centre Utrecht, we aim to implement this e-health innovation nationwide, starting with 10 ALS care teams in different rehabilitation settings spread across the Netherlands.<br><br>METHODS: This research focuses on the implementation process and the user experiences with ALS Home-monitoring and Coaching of both patients and healthcare professionals. We will use a participatory action research approach, with the stakeholders involved in all stages of the implementation process. The implementation process model of Grol and Wensing was used to structure and support planning, execution and evaluation of the implementation strategy. The expected barriers and facilitators will be explored and identified in focus group settings using the Theoretical Domains Framework. After that, each team will develop their own action plan with strategies for how to resolve each barrier. The teams will include 5-10 ALS patients with whom they will test their implementation plan and provide care with ALS Home-monitoring and Coaching for approximately 3 months. Afterwards, the implementation and the user experiences will be evaluated with digital surveys based on the evaluation framework of Proctor (e.g., acceptability, adoption, appropriateness).<br><br>DISCUSSION: Using implementation theories, this study will provide inside in factors influencing implementation outcomes and strategies that can be used to overcome barriers. This will enhance our understanding of how to successfully implement e-health innovations in multidisciplinary care in rehabilitation settings.<br><br>TRIAL REGISTRATION: Trial NL8542 registered at Netherlands Trial Register (trialregister.nl) on 15th April 2020.}, }
@article {pmid33632084, year = {2021}, author = {Je, G and Keyhanian, K and Ghasemi, M}, title = {Overview of stem cells therapy in amyotrophic lateral sclerosis.}, journal = {Neurological research}, volume = {43}, number = {8}, pages = {616-632}, doi = {10.1080/01616412.2021.1893564}, pmid = {33632084}, issn = {1743-1328}, mesh = {Amyotrophic Lateral Sclerosis/immunology/*physiopathology/*therapy ; Animals ; Cell Differentiation/physiology ; Clinical Trials as Topic/methods ; Humans ; Stem Cell Transplantation/*methods/trends ; Stem Cells/*physiology ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons with high burden on society. Despite tremendous efforts over the last several decades, there is still no definite cure for ALS. Up to now, only two disease-modifying agents, riluzole and edaravone, are approved by U.S. Food and Drug Administration (FDA) for ALS treatment, which only modestly improves survival and disease progression. Major challenging issues to find an effective therapy are heterogeneity in the pathogenesis and genetic variability of ALS. As such, stem cell therapy has been recently a focus of both preclinical and clinical investigations of ALS. This is because stem cells have multifaceted features that can potentially target multiple pathogenic mechanisms in ALS even though its underlying mechanisms are not completely elucidated. Methods &amp; Results: Here, we will have an overview of stem cell therapy in ALS, including their therapeutic mechanisms, the results of recent clinical trials as well as ongoing clinical trials. In addition, we will further discuss complications and limitations of stem cell therapy in ALS. Conclusion: The determination of whether stem cells offer a viable treatment strategy for ALS rests on well-designed and appropriately powered future clinical trials. Randomized, double-blinded, and sham-controlled studies would be valuable.}, }
@article {pmid33631494, year = {2021}, author = {Reid, WK}, title = {Mycotoxins causing amyotrophic lateral sclerosis.}, journal = {Medical hypotheses}, volume = {149}, number = {}, pages = {110541}, doi = {10.1016/j.mehy.2021.110541}, pmid = {33631494}, issn = {1532-2777}, mesh = {*Amyotrophic Lateral Sclerosis/chemically induced ; Humans ; *Mycotoxins ; *Neurotoxicity Syndromes ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) remains a terminal disease without an established etiology for the majority of patients. The dominant theory of ALS before the 1970's was the presence of a poison. One of the primary means of treating patients with a toxic exposure has been plasma exchange, but plasma exchange of ALS patients failed to alter the clinical course. The failure of plasma exchange assumes the patient is no longer exposed to the poison. If the exposure to poison continued, then plasma exchange alone would fail. I found laboratory evidence of a poisoning in every patient with ALS examined. A search for specific poisons found evidence of mycotoxins. Treatment with antifungal agents corrected the laboratory findings. All of the ALS patients had evidence of immune suppression. There is mounting evidence that many mycotoxins cause both neurotoxicity and immune suppression. These mycotoxins may be able to explain the full spectrum of pathology in ALS without a secondaryevent.}, }
@article {pmid33621978, year = {2021}, author = {Menke, K and Schwermer, M and Schramm, A and Zuzak, TJ}, title = {[Präklinische Untersuchungen von Wechselwirkungen zwischen Mistel und Radio- oder Chemotherapie auf pädiatrische Tumorzellen].}, journal = {Complementary medicine research}, volume = {28}, number = {4}, pages = {308-316}, doi = {10.1159/000512670}, pmid = {33621978}, issn = {2504-2106}, mesh = {Anti-Bacterial Agents ; Child ; Humans ; *Viscum album ; }, abstract = {UNLABELLED: Hintergrund: Mistelanwendungen werden als komplementäre Therapien häufig in der pädiatrischen Onkologie zusammen mit einer Radio- oder Chemotherapie verabreicht. Wechselwirkungen bei simultaner Applikation sind gerade in der Pädiatrie von großer Bedeutung, sie sind allerdings nach wie vor unzureichend untersucht. Material und Methoden: Zytotoxische Effekte des Mistelextraktes abnobaVISCUM Fraxini (aVF) auf LAN-1 Neuroblastomzellen und deren Etoposid- bzw. Cisplatin-resistente Subzelllinien wurden mittels Viabilitätstest untersucht, sowie mögliche Synergieeffekte zwischen aVF und den Chemotherapeutika durch die Softwareprodukte Combenefit und CompuSyn analysiert. Effekte einer Kombinationstherapie aus aVF und Bestrahlung auf SH-SY5Y Zellen wurden mittels Koloniebildungstest untersucht und Auswirkungen auf die Reparatureffizienz strahleninduzierter Doppelstrangbrüche mit Hilfe durchflusszytometrischer Quantifizierungen von γ-H2AX-Foci nach PI/FITC Doppelfärbung analysiert. Ergebnisse: Die Chemotherapie-resistenten LAN-1 Subzelllinien erwiesen sich als resistenter gegenüber der Mistelbehandlung als die Ursprungszelllinie. Auf Basis vier verschiedener Referenz-modelle konnten vor allem synergistisch/additive Effekte zwischen aVF und den Zytostatika Etoposid und Cisplatin berechnet werden. Die Kombination aus Mistelbehandlung und Bestrahlung führte zu einer Verringerung der Koloniebildung und zu einer Verzögerung der Reparaturgeschwindigkeit von strahleninduzierten Doppelstrangbrüchen. Schlussfolgerung: Die präklinischen Daten könnten darauf hinweisen, dass die Verwendung des Mistelextraktes, aVF, eine unterstützende Wirkung auf Radio- und Chemotherapien hat.<br><br>BACKGROUND: Mistletoe therapies belong to the field of complementary medicines and are often administered simultaneously or successive to conventional radio- or chemotherapy. Drug-herb interactions are of great significance, especially in pediatrics, but are still insufficiently investigated.<br><br>MATERIAL AND METHODS: Cytotoxic effects of the mistletoe extract, abnobaVISCUM Fraxini (aVF), on LAN-1 neuroblastoma cell line and their chemotherapy-resistant (cisplatin; etoposide) subclones were investigated by cell viability assays. Potential synergistic or antagonistic effects of the co-treatment of aVF and cisplatin or etoposide, respectively, were analyzed by Combenefit and CompuSyn software. Combinational effects of mistletoe and irradiation were assessed by colony formation assays and repair efficiency of irradiation-induced double strand breaks was investigated by flow cytometric analyses of &#x3b3;-H2AX foci after PI/FITC double staining.<br><br>RESULTS: Chemotherapy-resistant subclones were more resistant to mistletoe therapy than the parental cells. Based on four different reference models, primarily synergistic/additive effects between aVF and the cytostatic drugs could be calculated. Simultaneous application of mistletoe extract and irradiation led to a delay of irradiation-induced double strand break repair in neuroblastoma cells and a decreased colony formation compared to irradiation monotherapy.<br><br>CONCLUSION: The preclinical data may indicate that the use of aVF has a supportive effect on radio- and chemotherapies.}, }
@article {pmid33619181, year = {2021}, author = {Vancak, V and Goldberg, Y and Levine, SZ}, title = {Guidelines to understand and compute the number needed to treat.}, journal = {Evidence-based mental health}, volume = {24}, number = {4}, pages = {131-136}, pmid = {33619181}, issn = {1468-960X}, mesh = {Humans ; *Numbers Needed To Treat ; Randomized Controlled Trials as Topic ; *Schizophrenia/drug therapy ; }, abstract = {OBJECTIVE: We aim to explain the unadjusted, adjusted and marginal number needed to treat (NNT) and provide software for clinicians to compute them.<br><br>METHODS: The NNT is an efficacy index that is commonly used in randomised clinical trials. The NNT is the average number of patients needed to treat to obtain one successful outcome (ie, response) due to treatment. We developed the nntcalc R package for desktop use and extended it to a user-friendly web application. We provided users with a user-friendly step-by-step guide. The application calculates the NNT for various models with and without explanatory variables. The implemented models for the adjusted NNT are linear regression and analysis of variance (ANOVA), logistic regression, Kaplan-Meier and Cox regression. If no explanatory variables are available, one can compute the unadjusted Laupacis et al's NNT, Kraemer and Kupfer's NNT and the Furukawa and Leucht's NNT. All NNT estimators are computed with their associated appropriate 95% confidence intervals. All calculations are in R and are replicable.<br><br>RESULTS: The application provides the user with an easy-to-use web application to compute the NNT in different settings and models. We illustrate the use of the application from examples in schizophrenia research based on the Positive and Negative Syndrome Scale. The application is available from https://nntcalc.iem.technion.ac.il. The output is given in a journal compatible text format, which users can copy and paste or download in a comma-separated values format.<br><br>CONCLUSION: This application will help researchers and clinicians assess the efficacy of treatment and consequently improve the quality and accuracy of decisions.}, }
@article {pmid33617986, year = {2021}, author = {Juncker, M and Kim, C and Reed, R and Haas, A and Schwartzenburg, J and Desai, S}, title = {ISG15 attenuates post-translational modifications of mitofusins and congression of damaged mitochondria in Ataxia Telangiectasia cells.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1867}, number = {6}, pages = {166102}, doi = {10.1016/j.bbadis.2021.166102}, pmid = {33617986}, issn = {1879-260X}, support = {T32 AA007577/AA/NIAAA NIH HHS/United States ; R21 NS060960/NS/NINDS NIH HHS/United States ; }, mesh = {Ataxia Telangiectasia/genetics/metabolism/*pathology ; Cytokines/genetics/*metabolism ; GTP Phosphohydrolases/chemistry/genetics/*metabolism ; HEK293 Cells ; Humans ; Mitochondria/metabolism/*pathology ; Mitochondrial Membrane Transport Proteins/chemistry/genetics/*metabolism ; *Mitophagy ; *Protein Processing, Post-Translational ; Ubiquitin/*metabolism ; Ubiquitins/genetics/*metabolism ; }, abstract = {Mitophagy is defective in several neurodegenerative diseases, including Ataxia Telangiectasia (A-T). However, the molecular mechanism underlying defective mitophagy in A-T is unknown. Literature indicates that damaged mitochondria are transported to the perinuclear region prior to their removal via mitophagy. Our previous work has indicated that conjugation of SUMO2 (Small Ubiquitin-like Modifier 2) to mitofusins (Mfns) may be necessary for congression of mitochondria into SUMO2-/ubiquitin-/LC3-positive compact structures resembling mito-aggresomes at the perinuclear region in CCCP-treated HEK293 cells. Here, we demonstrate that Mfns are SUMOylated, and mitochondria are transported to the perinuclear region; however, mitochondria fail to congress into mito-aggresome-like structures in CCCP-treated A-T cells. Defect in mitochondrial congression is causally related to constitutively elevated ISG15 (Interferon-Stimulated Gene 15), an antagonist of the ubiquitin pathway, in A-T cells. Suppression of the ISG15 pathway restores mitochondrial congression, reduce oxidative stress, and level of unhealthy mitochondria, which is suggestive of restoration of mitophagy in A-T cells. ISG15 is also constitutively elevated and mitophagy is defective in Amytrophic Lateral Sclerosis (ALS). The constitutively elevated ISG15 pathway therefore appears to be a common unifying biochemical mechanism underlying defective mitophagy in neurodegenerative disorders thus, implying the broader significance of our findings, and suggest the potential role of ISG15 inhibitors in their treatment.}, }
@article {pmid33617919, year = {2021}, author = {Xiao, Y and Wang, SK and Zhang, Y and Rostami, A and Kenkare, A and Casella, G and Yuan, ZQ and Li, X}, title = {Role of extracellular vesicles in neurodegenerative diseases.}, journal = {Progress in neurobiology}, volume = {201}, number = {}, pages = {102022}, doi = {10.1016/j.pneurobio.2021.102022}, pmid = {33617919}, issn = {1873-5118}, mesh = {Alzheimer Disease ; Blood-Brain Barrier ; *Extracellular Vesicles ; Humans ; *Neurodegenerative Diseases/therapy ; Parkinson Disease ; }, abstract = {Extracellular vesicles (EVs) are heterogeneous cell-derived membranous structures that arise from the endosome system or directly detach from the plasma membrane. In recent years, many advances have been made in the understanding of the clinical definition and pathogenesis of neurodegenerative diseases, but translation into effective treatments is hampered by several factors. Current research indicates that EVs are involved in the pathology of diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Besides, EVs are also involved in the process of myelin formation, and can also cross the blood-brain barrier to reach the sites of CNS injury. It is suggested that EVs have great potential as a novel therapy for the treatment of neurodegenerative diseases. Here, we reviewed the advances in understanding the role of EVs in neurodegenerative diseases and addressed the critical function of EVs in the CNS. We have also outlined the physiological mechanisms of EVs in myelin regeneration and highlighted the therapeutic potential of EVs in neurodegenerative diseases.}, }
@article {pmid33617426, year = {2021}, author = {Palmieri, A and Kleinbub, JR and Pagnini, F and Sorarù, G and Cipolletta, S}, title = {Empathy-based supportive treatment in amyotrophic lateral sclerosis: A pragmatic study.}, journal = {The American journal of clinical hypnosis}, volume = {63}, number = {3}, pages = {202-216}, doi = {10.1080/00029157.2020.1797623}, pmid = {33617426}, issn = {2160-0562}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Anxiety/therapy ; Empathy ; Humans ; *Hypnosis ; Quality of Life ; }, abstract = {Scarce literature has been dedicated to the psychological treatment of amyotrophic lateral sclerosis (ALS). However, there have been some encouraging findings, such as in hypnosis-based studies, which revealed patient improvements in anxiety, depression and quality of life (QoL). We replicated such a design of a pragmatic study on empathy-based supportive counseling treatment in four weekly domiciliary sessions. Twenty-one people with ALS (pALS) consecutively attending the Motor Neuron Disease Center of Padova University were recruited to the study; in total, 21 pALS who did not undergo any kind of psychological treatment served as the control group. In the treatment group, depression, anxiety and QoL (measured respectively with the HADS-D, HADS-A and ALSSQOL-R) were assessed at pre- and post-treatment levels and at 3- and 6-month follow-ups. Statistical mixed-model regression analyses revealed that in the treated group, perceived conditions of anxiety, depression and QoL were significantly stable compared to worsening in the control patients. Interestingly, there were improvements in the QoL domains "Interaction", "Emotion" and "Physical" at the 6-month follow-up. Overall, even if not directly comparable, our current results on support-based counseling, though interesting, seem not to reach the efficacy of a hypnosis-based study in which the observed dimensions were significantly improved with respect to the baseline. The implications of our results from a psychodynamic perspective are highlighted.}, }
@article {pmid33613818, year = {2021}, author = {Koda, EK}, title = {Acupuncture for Managing Amyotrophic Lateral Sclerosis.}, journal = {Medical acupuncture}, volume = {33}, number = {1}, pages = {103-106}, pmid = {33613818}, issn = {1933-6586}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a progressive upper- and lower-motor-neuron degenerative disease. Despite extensive research, there is no curative Western treatment. Medications, such as riluzole and edaravone, are, at best, slightly life-prolonging. Most published accounts of acupuncture treatments for ALS have described Traditional Chinese Medicine points. Case: A 60-year-old man had moderately advanced ALS. He was wheelchair-bound, and had wasting muscles, a weak voice, and dysphagia. No Western medical treatment altered the progression of his disease. Treatment for this patient started with Chinese Scalp Acupuncture (CSA) and, eventually, auricular acupuncture was incorporated. Traditional Chinese acupuncture points and other acupuncture techniques were added later for specific purposes. Results: This treatment combination produced several days of robust clinical improvement after each treatment in terms of speaking, sensation, ambulation, and breathing. Conclusions: It is possible that the combination of CSA and auriculotherapy had a synergistic effect that was beneficial for this patient. Other traditional Chinese acupuncture points that were added to the treatment helped address specific issues but did not appear to have any substantial impact on his larger ALS symptoms. ALS is a progressive neurologic disease that is uniformly fatal. More clinical research is needed to evaluate the role of CSA and auricular acupuncture in treating this disease.}, }
@article {pmid33613607, year = {2021}, author = {Torra, J and Montull, JM and Taberner, A and Onkokesung, N and Boonham, N and Edwards, R}, title = {Target-Site and Non-target-Site Resistance Mechanisms Confer Multiple and Cross- Resistance to ALS and ACCase Inhibiting Herbicides in Lolium rigidum From Spain.}, journal = {Frontiers in plant science}, volume = {12}, number = {}, pages = {625138}, pmid = {33613607}, issn = {1664-462X}, support = {BB/L001489/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/R506618/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, abstract = {Lolium rigidum is one the worst herbicide resistant (HR) weeds worldwide due to its proneness to evolve multiple and cross resistance to several sites of action (SoA). In winter cereals crops in Spain, resistance to acetolactate synthase (ALS)- and acetyl-CoA carboxylase (ACCase)-inhibiting herbicides has become widespread, with farmers having to rely on pre-emergence herbicides over the last two decades to maintain weed control. Recently, lack of control with very long-chain fatty acid synthesis (VLCFAS)-inhibiting herbicides has been reported in HR populations that are difficult to manage by chemical means. In this study, three Spanish populations of L. rigidum from winter cereals were confirmed as being resistant to ALS- and ACCase-inhibiting herbicides, with broad-ranging resistance toward the different chemistries tested. In addition, reduced sensitivity to photosystem II-, VLCFAS-, and phytoene desaturase-inhibiting herbicides were confirmed across the three populations. Resistance to ACCase-inhibiting herbicides was associated with point mutations in positions Trp-2027 and Asp-2078 of the enzyme conferring target site resistance (TSR), while none were detected in the ALS enzyme. Additionally, HR populations contained enhanced amounts of an ortholog of the glutathione transferase phi (F) class 1 (GSTF1) protein, a functional biomarker of non-target-site resistance (NTSR), as confirmed by enzyme-linked immunosorbent assays. Further evidence of NTSR was obtained in dose-response experiments with prosulfocarb applied post-emergence, following pre-treatment with the cytochrome P450 monooxygenase inhibitor malathion, which partially reversed resistance. This study confirms the evolution of multiple and cross resistance to ALS- and ACCase inhibiting herbicides in L. rigidum from Spain by mechanisms consistent with the presence of both TSR and NTSR. Moreover, the results suggest that NTSR, probably by means of enhanced metabolism involving more than one detoxifying enzyme family, confers cross resistance to other SoA. The study further demonstrates the urgent need to monitor and prevent the further evolution of herbicide resistance in L. rigidum in Mediterranean areas.}, }
@article {pmid33613416, year = {2020}, author = {Ranieri, F and Mariotto, S and Dubbioso, R and Di Lazzaro, V}, title = {Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {605335}, pmid = {33613416}, issn = {1664-2295}, abstract = {In the last 20 years, several modalities of neuromodulation, mainly based on non-invasive brain stimulation (NIBS) techniques, have been tested as a non-pharmacological therapeutic approach to slow disease progression in amyotrophic lateral sclerosis (ALS). In both sporadic and familial ALS cases, neurophysiological studies point to motor cortical hyperexcitability as a possible priming factor in neurodegeneration, likely related to dysfunction of both excitatory and inhibitory mechanisms. A trans-synaptic anterograde mechanism of excitotoxicity is thus postulated, causing upper and lower motor neuron degeneration. Specifically, motor neuron hyperexcitability and hyperactivity are attributed to intrinsic cell abnormalities related to altered ion homeostasis and to impaired glutamate and gamma aminobutyric acid gamma-aminobutyric acid (GABA) signaling. Several neuropathological mechanisms support excitatory and synaptic dysfunction in ALS; additionally, hyperexcitability seems to drive DNA-binding protein 43-kDA (TDP-43) pathology, through the upregulation of unusual isoforms directly contributing to ASL pathophysiology. Corticospinal excitability can be suppressed or enhanced using NIBS techniques, namely, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), as well as invasive brain and spinal stimulation. Experimental evidence supports the hypothesis that the after-effects of NIBS are mediated by long-term potentiation (LTP)-/long-term depression (LTD)-like mechanisms of modulation of synaptic activity, with different biological and physiological mechanisms underlying the effects of tDCS and rTMS and, possibly, of different rTMS protocols. This potential has led to several small trials testing different stimulation interventions to antagonize excitotoxicity in ALS. Overall, these studies suggest a possible efficacy of neuromodulation in determining a slight reduction of disease progression, related to the type, duration, and frequency of treatment, but current evidence remains preliminary. Main limitations are the small number and heterogeneity of recruited patients, the limited "dosage" of brain stimulation that can be delivered in the hospital setting, the lack of a sufficient knowledge on the excitatory and inhibitory mechanisms targeted by specific stimulation interventions, and the persistent uncertainty on the key pathophysiological processes leading to motor neuron loss. The present review article provides an update on the state of the art of neuromodulation in ALS and a critical appraisal of the rationale for the application/optimization of brain stimulation interventions, in the light of their interaction with ALS pathophysiological mechanisms.}, }
@article {pmid33598572, year = {2021}, author = {Saitoh, Y and Miyazaki, M and Arai, N and Takahashi, Y}, title = {Pneumomediastinum while using mechanical insufflation-exsufflation after recovery from riluzole-induced interstitial lung disease.}, journal = {eNeurologicalSci}, volume = {22}, number = {}, pages = {100326}, pmid = {33598572}, issn = {2405-6502}, abstract = {We, herein, report a 61-year-old male patient with amyotrophic lateral sclerosis (ALS) complicated pneumomediastinum while using mechanical insufflation-exsufflation (MI-E) after recovery from riluzole (RZ)-induced interstitial lung disease (RZ-ILD). After the treatment of RZ-ILD, he required non-invasive mechanical ventilation (NIV) at minimal pressure settings and MI-E to manage ALS-related breathing and airway-clearance issues, respectively. After a while, he developed progressive worsening dyspnoea, and chest computed tomography revealed extensive pneumomediastinum that had spread to the area surrounding the oesophagus, the retrosternal space, and the pericardial space. He was treated with immediate discontinuation of MI-E; however, he had to keep using NIV to support his severe respiratory muscle involvement. Pneumomediastinum gradually reduced in size and no recurrence of pneumomediastinum occurred. The clinical course of our patient suggests that excessive coughing associated with MI-E combined with his previous RZ-ILD, which potentially renders his lungs vulnerable to airway pressure, may have been the aetiological factors for secondary pneumomediastinum, i.e. barotrauma. Clinicians should be aware of the risk of pneumomediastinum while using MI-E in patients with ALS, who have other pre-existing risk factors for pneumomediastinum, such as drug-induced ILD in our case.}, }
@article {pmid33596293, year = {2021}, author = {Persano, F and Batasheva, S and Fakhrullina, G and Gigli, G and Leporatti, S and Fakhrullin, R}, title = {Recent advances in the design of inorganic and nano-clay particles for the treatment of brain disorders.}, journal = {Journal of materials chemistry. B}, volume = {9}, number = {12}, pages = {2756-2784}, doi = {10.1039/d0tb02957b}, pmid = {33596293}, issn = {2050-7518}, mesh = {Animals ; Blood-Brain Barrier/drug effects ; Brain Diseases/*drug therapy ; Clay/*chemistry ; Drug Carriers/chemistry ; *Drug Design ; Humans ; Nanoparticles/*chemistry ; Particle Size ; Porosity ; Silicon Dioxide/chemistry/*pharmacology ; }, abstract = {Inorganic materials, in particular nanoclays and silica nanoparticles, have attracted enormous attention due to their versatile and tuneable properties, making them ideal candidates for a wide range of biomedical applications, such as drug delivery. This review aims at overviewing recent developments of inorganic nanoparticles (like porous or mesoporous silica particles) and different nano-clay materials (like montmorillonite, laponites or halloysite nanotubes) employed for overcoming the blood brain barrier (BBB) in the treatment and therapy of major brain diseases such as Alzheimer's, Parkinson's, glioma or amyotrophic lateral sclerosis. Recent strategies of crossing the BBB through invasive and not invasive administration routes by using different types of nanoparticles compared to nano-clays and inorganic particles are overviewed.}, }
@article {pmid33590603, year = {2021}, author = {Gadgil, A and Raczyńska, KD}, title = {U7 snRNA: A tool for gene therapy.}, journal = {The journal of gene medicine}, volume = {23}, number = {4}, pages = {e3321}, pmid = {33590603}, issn = {1521-2254}, mesh = {Binding Sites/genetics ; Cell Nucleus/*genetics ; *Genetic Therapy ; Histones/*genetics ; Humans ; Protein Binding/genetics ; RNA, Small Nuclear/*genetics ; Ribonucleoproteins, Small Nuclear/genetics/therapeutic use ; }, abstract = {Most U-rich small nuclear ribonucleoproteins (snRNPs) are complexes that mediate the splicing of pre-mRNAs. U7 snRNP is an exception in that it is not involved in splicing but is a key factor in the unique 3' end processing of replication-dependent histone mRNAs. However, by introducing controlled changes in the U7 snRNA histone binding sequence and in the Sm motif, it can be used as an effective tool for gene therapy. The modified U7 snRNP (U7 Sm OPT) is thus not involved in the processing of replication-dependent histone pre-mRNA but targets splicing by inducing efficient skipping or inclusion of selected exons. U7 Sm OPT is of therapeutic importance in diseases that are an outcome of splicing defects, such as myotonic dystrophy, Duchenne muscular dystrophy, amyotrophic lateral sclerosis, β-thalassemia, HIV-1 infection and spinal muscular atrophy. The benefits of using U7 Sm OPT for gene therapy are its compact size, ability to accumulate in the nucleus without causing any toxic effects in the cells, and no immunoreactivity. The risk of transgene misregulation by using U7 Sm OPT is also low because it is involved in correcting the expression of an endogenous gene controlled by its own regulatory elements. Altogether, using U7 Sm OPT as a tool in gene therapy can ensure lifelong treatment, whereas an oligonucleotide or other drug/compound would require repeated administration. It would thus be strategic to harness these unique properties of U7 snRNP and deploy it as a tool in gene therapy.}, }
@article {pmid33586684, year = {2021}, author = {Li, J and Fredericks, M and Cannell, M and Wang, K and Sako, D and Maguire, MC and Grenha, R and Liharska, K and Krishnan, L and Bloom, T and Belcheva, EP and Martinez, PA and Castonguay, R and Keates, S and Alexander, MJ and Choi, H and Grinberg, AV and Pearsall, RS and Oh, P and Kumar, R and Suragani, RN}, title = {ActRIIB:ALK4-Fc alleviates muscle dysfunction and comorbidities in murine models of neuromuscular disorders.}, journal = {The Journal of clinical investigation}, volume = {131}, number = {4}, pages = {}, pmid = {33586684}, issn = {1558-8238}, mesh = {Activin Receptors, Type I/genetics/*pharmacology ; Activin Receptors, Type II/genetics/*pharmacology ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism/pathology ; Animals ; CHO Cells ; Cricetulus ; Disease Models, Animal ; Humans ; Immunoglobulin Fc Fragments/genetics/*pharmacology ; Male ; Mice ; Mice, Transgenic ; Muscle, Skeletal/*metabolism/pathology ; Muscular Disorders, Atrophic/*drug therapy/genetics/metabolism/pathology ; Muscular Dystrophy, Duchenne/*drug therapy/genetics/metabolism/pathology ; Recombinant Fusion Proteins/genetics/*pharmacology ; }, abstract = {Patients with neuromuscular disorders suffer from a lack of treatment options for skeletal muscle weakness and disease comorbidities. Here, we introduce as a potential therapeutic agent a heterodimeric ligand-trapping fusion protein, ActRIIB:ALK4-Fc, which comprises extracellular domains of activin-like kinase 4 (ALK4) and activin receptor type IIB (ActRIIB), a naturally occurring pair of type I and II receptors belonging to the TGF-β superfamily. By surface plasmon resonance (SPR), ActRIIB:ALK4-Fc exhibited a ligand binding profile distinctly different from that of its homodimeric variant ActRIIB-Fc, sequestering ActRIIB ligands known to inhibit muscle growth but not trapping the vascular regulatory ligand bone morphogenetic protein 9 (BMP9). ActRIIB:ALK4-Fc and ActRIIB-Fc administered to mice exerted differential effects - concordant with SPR results - on vessel outgrowth in a retinal explant assay. ActRIIB:ALK4-Fc induced a systemic increase in muscle mass and function in wild-type mice and in murine models of Duchenne muscular dystrophy (DMD), amyotrophic lateral sclerosis (ALS), and disuse atrophy. Importantly, ActRIIB:ALK4-Fc improved neuromuscular junction abnormalities in murine models of DMD and presymptomatic ALS and alleviated acute muscle fibrosis in a DMD model. Furthermore, in combination therapy ActRIIB:ALK4-Fc increased the efficacy of antisense oligonucleotide M12-PMO on dystrophin expression and skeletal muscle endurance in an aged DMD model. ActRIIB:ALK4-Fc shows promise as a therapeutic agent, alone or in combination with dystrophin rescue therapy, to alleviate muscle weakness and comorbidities of neuromuscular disorders.}, }
@article {pmid33586591, year = {2022}, author = {Sarmet, M and Mangilli, LD and Costa, GP and Paes, JPRS and Codeço, VM and Million, JL and Maldaner, V}, title = {The relationship between pulmonary and swallowing functions in patients with neuromuscular diseases followed up by a tertiary referral center: a cross-sectional study.}, journal = {Logopedics, phoniatrics, vocology}, volume = {47}, number = {2}, pages = {117-124}, doi = {10.1080/14015439.2021.1879254}, pmid = {33586591}, issn = {1651-2022}, mesh = {Cross-Sectional Studies ; Deglutition ; *Deglutition Disorders/diagnosis/etiology ; Humans ; *Neuromuscular Diseases/complications/diagnosis ; Tertiary Care Centers ; Voice Quality ; }, abstract = {INTRODUCTION: Respiratory muscle weakness is common in patients with neuromuscular diseases (NMD). This puts them at risk for dysphagia and other pulmonary complications.<br><br>OBJECTIVES: To investigate the relationship between pulmonary function and swallowing in NMD.<br><br>MATERIALS AND METHODS: In this cross-sectional study, medical records of patients undergoing treatment at the Tertiary Referral Center for Neuromuscular Diseases of Hospital de Apoio de Bras&#xed;lia, Brazil, were reviewed. Respiratory function was assessed through spirometry (FVC and FEV1 measured) and swallowing assessed by the Dysphagia Risk Evaluation Protocol and the Functional Oral Intake Scale.<br><br>RESULTS: Two hundred and twenty-two patients were included. Dysphagia was present in 46.8% of patients and impairment of pulmonary function in 64.0%. The mean FVC observed was 66.9% and FEV1 was 66.0%, indicating restrictive lung disease. A correlation between the decline of pulmonary and swallowing functions was observed in patients with NMDs (FVC vs. DREP, R&#x2009;=&#x2009;0.46; FVC vs. FOIS, R&#x2009;=&#x2009;0.42; FEV1 vs. DREP, R&#x2009;=&#x2009;0.42; FEV1 vs. FOIS, R&#x2009;=&#x2009;0.40, p<.01). FVC and FEV1 values tend to be lower in patients with dysphagia in the context of NMD.<br><br>CONCLUSIONS: A positive correlation between pulmonary function and swallowing outcomes was observed in patients with NMD. Despite respiratory and swallowing impairment being widely present in the population with NMD, they require different treatments according to the disease's pathophysiology. Future studies should be conducted to explore the disease-specific relationship between pulmonary function and swallowing in patients with NMD.}, }
@article {pmid33586315, year = {2022}, author = {Bhattarai, A and Egan, GF and Talman, P and Chua, P and Chen, Z}, title = {Magnetic Resonance Iron Imaging in Amyotrophic Lateral Sclerosis.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {55}, number = {5}, pages = {1283-1300}, doi = {10.1002/jmri.27530}, pmid = {33586315}, issn = {1522-2586}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging ; Humans ; Iron ; Magnetic Resonance Imaging/methods ; Magnetic Resonance Spectroscopy ; Motor Neurons/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) results in progressive impairment of upper and lower motor neurons. Increasing evidence from both in vivo and ex vivo studies suggest that iron accumulation in the motor cortex is a neuropathological hallmark in ALS. An in vivo neuroimaging marker of iron dysregulation in ALS would be useful in disease diagnosis and prognosis. Magnetic resonance imaging (MRI), with its unique capability to generate a variety of soft tissue contrasts, provides opportunities to image iron distribution in the human brain with millimeter to sub-millimeter anatomical resolution. Conventionally, MRI T1-weighted, T2-weighted, and T2*-weighted images have been used to investigate iron dysregulation in the brain in vivo. Susceptibility weighted imaging has enhanced contrast for para-magnetic materials that provides superior sensitivity to iron in vivo. Recently, the development of quantitative susceptibility mapping (QSM) has realized the possibility of using quantitative assessments of magnetic susceptibility measures in brain tissues as a surrogate measurement of in vivo brain iron. In this review, we provide an overview of MRI techniques that have been used to investigate iron dysregulation in ALS in vivo. The potential uses, strengths, and limitations of these techniques in clinical trials, disease diagnosis, and prognosis are presented and discussed. We recommend further longitudinal studies with appropriate cohort characterization to validate the efficacy of these techniques. We conclude that quantitative iron assessment using recent advances in MRI including QSM holds great potential to be a sensitive diagnostic and prognostic marker in ALS. The use of multimodal neuroimaging markers in combination with iron imaging may also offer improved sensitivity in ALS diagnosis and prognosis that could make a major contribution to clinical care and treatment trials. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.}, }
@article {pmid33581222, year = {2021}, author = {Tucker-Bartley, A and Lemme, J and Gomez-Morad, A and Shah, N and Veliu, M and Birklein, F and Storz, C and Rutkove, S and Kronn, D and Boyce, AM and Kraft, E and Upadhyay, J}, title = {Pain Phenotypes in Rare Musculoskeletal and Neuromuscular Diseases.}, journal = {Neuroscience and biobehavioral reviews}, volume = {124}, number = {}, pages = {267-290}, pmid = {33581222}, issn = {1873-7528}, support = {R21 MH122967/MH/NIMH NIH HHS/United States ; Z99 DE999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Cross-Sectional Studies ; Humans ; *Neuromuscular Diseases/complications/genetics ; Pain ; Phenotype ; Retrospective Studies ; }, abstract = {For patients diagnosed with a rare musculoskeletal or neuromuscular disease, pain may transition from acute to chronic; the latter yielding additional challenges for both patients and care providers. We assessed the present understanding of pain across a set of ten rare, noninfectious, noncancerous disorders; Osteogenesis Imperfecta, Ehlers-Danlos Syndrome, Achondroplasia, Fibrodysplasia Ossificans Progressiva, Fibrous Dysplasia/McCune-Albright Syndrome, Complex Regional Pain Syndrome, Duchenne Muscular Dystrophy, Infantile- and Late-Onset Pompe disease, Charcot-Marie-Tooth Disease, and Amyotrophic Lateral Sclerosis. Through the integration of natural history, cross-sectional, retrospective, clinical trials, &amp; case studies we described pathologic and genetic factors, pain sources, phenotypes, and lastly, existing therapeutic approaches. We highlight that while rare diseases possess distinct core pathologic features, there are a number of shared pain phenotypes and mechanisms that may be prospectively examined and therapeutically targeted in a parallel manner. Finally, we describe clinical and research approaches that may facilitate more accurate diagnosis, monitoring, and treatment of pain as well as elucidation of the evolving nature of pain phenotypes in rare musculoskeletal or neuromuscular illnesses.}, }
@article {pmid33580524, year = {2021}, author = {Mehta, TR and Bayat, E and Govindarajan, R}, title = {Palliative care in amyotrophic lateral sclerosis clinics: A survey of NEALS consortium membership.}, journal = {Muscle &amp; nerve}, volume = {63}, number = {5}, pages = {769-774}, doi = {10.1002/mus.27203}, pmid = {33580524}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Health Care Surveys ; Humans ; *Palliative Care ; *Patient Care Team ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition managed with a multidisciplinary approach. Palliative care is important for this approach, but there is a lack of recommendations for the role and involvement of palliative medicine (PM) specialists in multidisciplinary ALS care.<br><br>METHODS: This questionnaire-based survey assessed the state of palliative care in selective sites that are a part of Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS).<br><br>RESULTS: Twenty-seven percent of the sites included palliative care specialists as a part of their ALS clinics and they were introduced to the patients and family by ALS specialists (75.94%) usually at an advanced stage of ALS.<br><br>DISCUSSION: Our study when compared with other study results having a similar aim showed that there is a variability in the practice of palliative care specialists in ALS clinics. Having evidence-based guidelines will help in the management of ALS patients more effectively.}, }
@article {pmid33572505, year = {2021}, author = {Ullah, HMA and Elfadl, AK and Park, S and Kim, YD and Chung, MJ and Son, JY and Yun, HH and Park, JM and Yim, JH and Jung, SJ and Choi, YC and Shin, JH and Kim, DS and Park, JK and Jeong, KS}, title = {Nogo-A Is Critical for Pro-Inflammatory Gene Regulation in Myocytes and Macrophages.}, journal = {Cells}, volume = {10}, number = {2}, pages = {}, pmid = {33572505}, issn = {2073-4409}, support = {NRF-2017R1E1A1A01072781//This work was financially supported by the government of Republic of Korea (Ministry of Science and ICT)/ ; }, mesh = {Animals ; Gene Regulatory Networks/*genetics ; Humans ; Macrophages/*metabolism ; Mice ; Muscle Cells/*metabolism ; Nogo Proteins/*metabolism ; }, abstract = {Nogo-A (Rtn 4A), a member of the reticulon 4 (Rtn4) protein family, is a neurite outgrowth inhibitor protein that is primarily expressed in the central nervous system (CNS). However, previous studies revealed that Nogo-A was upregulated in skeletal muscles of Amyotrophic lateral sclerosis (ALS) patients. Additionally, experiments showed that endoplasmic reticulum (ER) stress marker, C/EBP homologous protein (CHOP), was upregulated in gastrocnemius muscle of a murine model of ALS. We therefore hypothesized that Nogo-A might relate to skeletal muscle diseases. According to our knocking down and overexpression results in muscle cell line (C2C12), we have found that upregulation of Nogo-A resulted in upregulation of CHOP, pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α, while downregulation of Nogo-A led to downregulation of CHOP, IL-6 and TNF-α. Immunofluorescence results showed that Nogo-A and CHOP were expressed by myofibers as well as tissue macrophages. Since resident macrophages share similar functions as bone marrow-derived macrophages (BMDM), we therefore, isolated macrophages from bone marrow to study the role of Nogo-A in activation of these cells. Lipopolysaccharide (LPS)-stimulated BMDM in Nogo-KO mice showed low mRNA expression of CHOP, IL-6 and TNF-α compared to BMDM in wild type (WT) mice. Interestingly, Nogo knockout (KO) BMDM exhibited lower migratory activity and phagocytic ability compared with WT BMDM after LPS treatment. In addition, mice experiments data revealed that upregulation of Nogo-A in notexin- and tunicamycin-treated muscles was associated with upregulation of CHOP, IL-6 and TNF-α in WT group, while in Nogo-KO group resulted in low expression level of CHOP, IL-6 and TNF-α. Furthermore, upregulation of Nogo-A in dystrophin-deficient (mdx) murine model, myopathy and Duchenne muscle dystrophy (DMD) clinical biopsies was associated with upregulation of CHOP, IL-6 and TNF-α. To the best of our knowledge, this is the first study to demonstrate Nogo-A as a regulator of inflammation in diseased muscle and bone marrow macrophages and that deletion of Nogo-A alleviates muscle inflammation and it can be utilized as a therapeutic target for improving muscle diseases.}, }
@article {pmid33571705, year = {2021}, author = {Calabrese, EJ and Calabrese, V and Giordano, J}, title = {Demonstrated hormetic mechanisms putatively subserve riluzole-induced effects in neuroprotection against amyotrophic lateral sclerosis (ALS): Implications for research and clinical practice.}, journal = {Ageing research reviews}, volume = {67}, number = {}, pages = {101273}, doi = {10.1016/j.arr.2021.101273}, pmid = {33571705}, issn = {1872-9649}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Neuroprotection ; *Neuroprotective Agents/pharmacology ; Riluzole/pharmacology ; }, abstract = {This paper provides evidence to support that riluzole, an FDA-approved treatment for amyotrophic lateral sclerosis (ALS), like many neuroprotective agents, displays and exerts hormetic biphasic dose responses. These findings have important implications for the experimental study and clinical treatment of ALS.}, }
@article {pmid33565152, year = {2021}, author = {Imamura, K and Yada, Y and Izumi, Y and Morita, M and Kawata, A and Arisato, T and Nagahashi, A and Enami, T and Tsukita, K and Kawakami, H and Nakagawa, M and Takahashi, R and Inoue, H}, title = {Prediction Model of Amyotrophic Lateral Sclerosis by Deep Learning with Patient Induced Pluripotent Stem Cells.}, journal = {Annals of neurology}, volume = {89}, number = {6}, pages = {1226-1233}, pmid = {33565152}, issn = {1531-8249}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diagnosis ; *Deep Learning ; *Early Diagnosis ; Female ; Humans ; *Induced Pluripotent Stem Cells ; Male ; Middle Aged ; *Motor Neurons ; }, abstract = {In amyotrophic lateral sclerosis (ALS), early diagnosis is essential for both current and potential treatments. To find a supportive approach for the diagnosis, we constructed an artificial intelligence-based prediction model of ALS using induced pluripotent stem cells (iPSCs). Images of spinal motor neurons derived from healthy control subject and ALS patient iPSCs were analyzed by a convolutional neural network, and the algorithm achieved an area under the curve of 0.97 for classifying healthy control and ALS. This prediction model by deep learning algorithm with iPSC technology could support the diagnosis and may provide proactive treatment of ALS through future prospective research. ANN NEUROL 2021;89:1226-1233.}, }
@article {pmid33558503, year = {2021}, author = {Liu, Y and Dodart, JC and Tran, H and Berkovitch, S and Braun, M and Byrne, M and Durbin, AF and Hu, XS and Iwamoto, N and Jang, HG and Kandasamy, P and Liu, F and Longo, K and Ruschel, J and Shelke, J and Yang, H and Yin, Y and Donner, A and Zhong, Z and Vargeese, C and Brown, RH}, title = {Variant-selective stereopure oligonucleotides protect against pathologies associated with C9orf72-repeat expansion in preclinical models.}, journal = {Nature communications}, volume = {12}, number = {1}, pages = {847}, pmid = {33558503}, issn = {2041-1723}, support = {R01 NS111990/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; C9orf72 Protein/chemistry/*genetics ; DNA Repeat Expansion/*genetics ; Exons/genetics ; Glutamates/toxicity ; Introns/genetics ; Mice ; Motor Neurons/drug effects/pathology ; Mutation/*genetics ; Oligonucleotides/*chemistry/*genetics ; RNA Splicing/genetics ; RNA, Messenger/genetics/metabolism ; Stereoisomerism ; }, abstract = {A large G4C2-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal degeneration associated with this expansion arises from a loss of C9orf72 protein, the accumulation of RNA foci, the expression of dipeptide repeat (DPR) proteins, or all these factors. We report the discovery of a new targeting sequence that is common to all C9orf72 transcripts but enables preferential knockdown of repeat-containing transcripts in multiple cellular models and C9BAC transgenic mice. We optimize stereopure oligonucleotides that act through this site, and we demonstrate that their preferential activity depends on both backbone stereochemistry and asymmetric wing design. In mice, stereopure oligonucleotides produce durable depletion of pathogenic signatures without disrupting protein expression. These oligonucleotides selectively protect motor neurons harboring C9orf72-expansion mutation from glutamate-induced toxicity. We hypothesize that targeting C9orf72 with stereopure oligonucleotides may be a viable therapeutic approach for the treatment of C9orf72-associated neurodegenerative disorders.}, }
@article {pmid33557137, year = {2021}, author = {Bailes, J and Soloviev, M}, title = {Insulin-Like Growth Factor-1 (IGF-1) and Its Monitoring in Medical Diagnostic and in Sports.}, journal = {Biomolecules}, volume = {11}, number = {2}, pages = {}, pmid = {33557137}, issn = {2218-273X}, mesh = {Animals ; *Apoptosis ; Biomarkers/metabolism ; Cell Differentiation ; Cell Proliferation ; Doping in Sports ; Growth Hormone/*metabolism ; Humans ; Insulin/metabolism ; Insulin-Like Growth Factor I/*metabolism ; Intercellular Signaling Peptides and Proteins/metabolism ; Mice ; Neoplasms/metabolism ; Peptides/chemistry ; Performance-Enhancing Substances/pharmacology ; Protein Binding ; Receptor, IGF Type 1/metabolism ; Recombinant Proteins/chemistry ; Substance Abuse Detection/*methods ; }, abstract = {Insulin-like growth factor-1 (IGF-1) is the principal mediator of growth hormone (GH), plays a crucial role in promoting cell growth and differentiation in childhood and continues to have an anabolic effect in adults. IGF-1 is part of a wide network of growth factors, receptors and binding proteins involved in mediating cellular proliferation, differentiation and apoptosis. Bioavailability of IGF-1 is affected by insulin-like growth factor binding proteins (IGFBPs) which bind IGF-1 in circulation with an affinity equal to or greater than that of the IGF-1 receptor (IGF-1R). The six IGFBPs serve as carrier proteins and bind approximately 98% of all circulating IGF-1. Other proteins known to bind IGF-1 include ten IGFBP-related proteins (IGFBP-rPs), albeit with lower affinities than the IGFBPs. IGF-1 expression levels vary in a number of clinical conditions suggesting it has the potential to provide crucial information as to the state of an individual's health. IGF-1 is also a popular doping agent in sport and has featured in many high-profile doping cases in recent years. However, the existence of IGFBPs significantly reduces the levels of immunoreactive IGF-1 in samples, requiring multiple pre-treatment steps that reduce reproducibility and complicates interpretation of IGF-1 assay results. Here we provide an overview of the IGF network of growth factors, their receptors and the entirety of the extended family of IGFBPs, IGFBP-rPs, E peptides as well as recombinant IGF-1 and their derivatives. We also discuss issues related to the detection and quantification of bioavailable IGF-1.}, }
@article {pmid33549783, year = {2021}, author = {Pelletier, Y and Lareyre, F and Cointat, C and Raffort, J}, title = {Management of Vascular Complications during Anterior Lumbar Spinal Surgery Using Mini-Open Retroperitoneal Approach.}, journal = {Annals of vascular surgery}, volume = {74}, number = {}, pages = {475-488}, doi = {10.1016/j.avsg.2021.01.077}, pmid = {33549783}, issn = {1615-5947}, mesh = {Blood Loss, Surgical ; Humans ; Lumbar Vertebrae/diagnostic imaging/*surgery ; Planning Techniques ; Preoperative Care ; Retroperitoneal Space/surgery ; Risk Factors ; Spinal Fusion/*adverse effects ; Total Disc Replacement/*adverse effects ; Vascular System Injuries/*etiology ; Venous Thrombosis/etiology ; }, abstract = {BACKGROUND: Anterior retroperitoneal spine exposure has become increasingly performed for the surgical treatment of various spinal disorders. Despite its advantages, the procedure is not riskless and can expose to potentially life-threatening vascular lesions. The aim of this review is to report the vascular lesions that can happen during anterior lumbar spinal surgery using mini-open retroperitoneal approach and to describe their management.<br><br>METHODS: A systematic literature search was performed according to PRISMA to identify studies published in English between January 1980 and December 2019 reporting vascular complications during anterior lumbar spinal surgery with mini-open retroperitoneal approach. Three authors independently conducted the literature search on PubMed/Medline database using a combination of the following terms: "spinal surgery", "anterior lumbar surgery (ALS)", "anterior lumbar interbody fusion (ALIF)", "lumbar total disc replacement", "artificial disc replacement", "vascular complications", "vascular injuries". Vascular complications were defined as any peri-operative or post-operative lesions related to an arterial or venous vessel. The management of the vascular injury was extracted.<br><br>RESULTS: Fifteen studies fulfilled the inclusion criteria. Venous injuries were observed in 13 studies. Lacerations and deep venous thrombosis ranged from 0.8% to 4.3% of cases. Arterial lesions were observed in 4 studies and ranged from 0.4% to 4.3% of cases. It included arterial thrombosis, lacerations or vasospasms. The estimated blood loss was reported in 10 studies and ranged from 50 mL up to 3000 mL. Vascular complications were identified as a cause of abortion of the procedure in 2 studies, representing respectively 0.3% of patients who underwent ALS and 0.5% of patients who underwent ALIF.<br><br>CONCLUSION: Imaging pre-operative planning is of utmost importance to evaluate risk factors and the presence of anatomic variations in order to prevent and limit vascular complications. Cautions should be taken during the intervention when manipulating major vessels and routine monitoring of the limb oxygen saturation should be systematically performed for an early detection of arterial thrombosis. The training of the surgeon access remains a key-point to prevent and manage vascular complications during anterior lumbar spinal surgery with mini-open retroperitoneal.}, }
@article {pmid33548116, year = {2021}, author = {Medchalmi, S and Tare, P and Sayyad, Z and Swarup, G}, title = {A glaucoma- and ALS-associated mutant of OPTN induces neuronal cell death dependent on Tbk1 activity, autophagy and ER stress.}, journal = {The FEBS journal}, volume = {288}, number = {15}, pages = {4576-4595}, doi = {10.1111/febs.15752}, pmid = {33548116}, issn = {1742-4658}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; *Apoptosis ; Autophagy ; Autophagy-Related Protein 5/metabolism ; Cell Cycle Proteins/*genetics/metabolism ; Endoplasmic Reticulum Stress ; Glaucoma/*genetics ; HEK293 Cells ; Humans ; Membrane Transport Proteins/*genetics/metabolism ; Microtubule-Associated Proteins/metabolism ; *Mutation ; Neurons/*metabolism ; Protein Binding ; Protein Serine-Threonine Kinases/*metabolism ; Transcription Factor CHOP/metabolism ; }, abstract = {Mutations in OPTN are associated with glaucoma, an eye disease, and also with amyotrophic lateral sclerosis (ALS), a motor neuron disease. A 2-bp insertion in OPTN (691_692insAG or 2bpIns-OPTN) is associated with both glaucoma and ALS. This mutation results in frame shift after 127 amino acids, giving rise to a protein with C-terminal aberrant sequence. We have explored the mechanism of induction of cell death by this mutant in a motor neuron cell line, NSC-34, and also in a retinal cell line, 661W. Compared to wild-type OPTN, this mutant induced more cell death in NSC-34 and 661W cells. This mutant localizes predominantly in the nucleus whereas normal OPTN localizes in the cytoplasm. Deletion analysis of 2bpIns-OPTN showed that the aberrant sequence was not essential for cell death induction. This mutant interacts with TANK-binding kinase 1 (Tbk1) but not with OPTN and activates Tbk1. This mutant induced ER stress in NSC-34 cells as seen by induction of C/EBP homologous protein (CHOP) and some other genes. Induction of CHOP, autophagosomal protein LC3-II and cell death by this mutant were abrogated by Tbk1 knockdown and also by 4-phenylbutyric acid, that inhibits ER stress. Induction of CHOP and cell death by 2bpIns-OPTN was autophagy dependent as shown by the effect of Atg5 knockdown. This mutant caused increased formation of LC3-positive aggregates. Treatment of cells with autophagy inducer rapamycin reduced LC3-positive aggregates, CHOP and cell death induced by 2bpIns-OPTN. These results suggest that constitutive activation of Tbk1 by 2bpIns-OPTN leads to impaired autophagy that results in ER stress and cell death.}, }
@article {pmid33546386, year = {2021}, author = {Štětkářová, I and Ehler, E}, title = {Diagnostics of Amyotrophic Lateral Sclerosis: Up to Date.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {33546386}, issn = {2075-4418}, support = {Progres Q35//Univerzita Karlova v Praze/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by gradual loss of upper and lower motor neurons and their pathways, usually without affecting the extraocular and sphincter muscles. The cause of the disease is not yet known. It is a chain of subsequent events, ending in programmed cell death in selective neuronal subpopulations. The prognosis for survival is rather short with a median of 2 to 4 years. Survival may be prolonged based on prompt diagnosis, ALS subtype and proper management with supportive treatment (tracheostomy, gastrostomy, etc.). According to the clinical picture, the typical form of ALS with upper and lower motoneuron involvement and progressive bulbar paralysis with bulbar muscle involvement is observed. The ALS form with progressive muscle atrophy, where only the lower motoneuron is affected, and primary lateral sclerosis with only upper motoneuron damage are rare. Familiar forms of ALS (FALS) associated with specific genes (the most common is C9orf72) have been discovered. FALS is usually associated with dementia (frontotemporal lobar dementia, FTLD), behavioral disorders, cognitive dysfunction and impairment of executive functions. The diagnosis of ALS is determined by excluding other conditions and utilizing clinical examinations, laboratory and genetic tests and nerve conduction/needle electromyography studies (EMG). Needle EMG records abnormal activities at rest and looks for neurogenic patterns during muscle contraction. Motor evoked potentials after transcranial magnetic stimulation remain the test of choice to identify impairment of upper motor neurons. New biochemical, neurophysiological and morphological biomarkers are extensively studied as early diagnostic and prognostic factors and have implications for clinical trials, research and drug development.}, }
@article {pmid33545661, year = {2021}, author = {Tahir, MS and Almezgagi, M and Zhang, Y and Bashir, A and Abdullah, HM and Gamah, M and Wang, X and Zhu, Q and Shen, X and Ma, Q and Ali, M and Solangi, ZA and Malik, WS and Zhang, W}, title = {Mechanistic new insights of flavonols on neurodegenerative diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {137}, number = {}, pages = {111253}, doi = {10.1016/j.biopha.2021.111253}, pmid = {33545661}, issn = {1950-6007}, mesh = {Animals ; Brain/*drug effects/metabolism/pathology ; Cognition/drug effects ; Drug Compounding ; Flavonols/adverse effects/*therapeutic use ; Humans ; Nanoparticles ; *Nerve Degeneration ; Neurodegenerative Diseases/*drug therapy/metabolism/pathology/psychology ; Neurons/*drug effects/metabolism/pathology ; Neuroprotective Agents/adverse effects/*therapeutic use ; }, abstract = {With a large and increasing elderly population, neurodegenerative diseases such as Parkinson's disease (PD), Huntington disease (HD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS) and Multiple sclerosis (MS) have become a major and growing health problem. During the past few decades, the elderly population has grown 2.5 % every year. Unfortunately, there are no specific therapeutic remedies available to slow the onset or development of these diseases. An aging brain causes many pathophysiological changes and is the major risk factor for most of the neurodegenerative disorders. Polyphenolic compounds such as flavonols have shown therapeutic potential and can contribute to the treatment of these diseases. In this review, evidence for the beneficial neuroprotective effect of multiple flavonols is discussed and their multifactorial cellular pathways for the progressions of age-associated brain changes are identified. Moreover, the animal models of these diseases support the neuroprotective effect and target the potential of flavonols in the treatment of neurodegenerative diseases.}, }
@article {pmid33545308, year = {2021}, author = {Garbuzova-Davis, S and Boccio, KJ and Ehrhart, J and Sanberg, PR and Appel, SH and Borlongan, CV}, title = {Detection of endothelial cell-associated human DNA reveals transplanted human bone marrow stem cell engraftment into CNS capillaries of ALS mice.}, journal = {Brain research bulletin}, volume = {170}, number = {}, pages = {22-28}, pmid = {33545308}, issn = {1873-2747}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Disease Models, Animal ; Endothelial Cells/*metabolism ; Mesenchymal Stem Cells/*metabolism ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Repairing the altered blood-CNS-barrier in amyotrophic lateral sclerosis (ALS) is imperative to prevent entry of detrimental blood-borne substances into the CNS. Cell transplantation with the goal of replacing damaged endothelial cells (ECs) may be a new therapeutic approach for barrier restoration. We showed positive effects of human bone marrow-derived CD34+ cells (hBM34+) and endothelial progenitor cells (hBM-EPCs) intravenous transplantation into symptomatic G93A SOD1 mutant mice on barrier reparative processes. These benefits mainly occurred by administered cells engraftment into vascular walls in ALS mice; however, additional studies are needed to confirm cell engraftment within capillaries. The aim of this investigation was to determine the presence of human DNA within microvascular ECs isolated from the CNS tissues of G93A SOD1 mutant mice treated with human bone marrow-derived stem cells. The CNS tissues were obtained from previously cell-treated and media-treated G93A mice at 17 weeks of age. Real-time PCR (RT-PCR) assay for detection of human DNA was performed in ECs isolated from mouse CNS tissue. Viability of these ECs was determined using the LIVE/DEAD viability/cytotoxicity assay. Results showed appropriate EC isolation as verified by immunoexpression of endothelial cell marker. Human DNA was detected in isolated ECs from cell-treated mice with greater concentrations in mice receiving hBM-EPCs vs. hBM34[+] cells. Also, higher numbers of live ECs were determined in mice treated with hBM-EPCs vs. hBM34[+] cells or media-injection. Results revealed that transplanted human cells engrafted into mouse capillary walls and efficaciously maintained endothelium function. These study results support our previous findings showing that intravenous administration of hBM-EPCs into symptomatic ALS mice was more beneficial than hBM34[+] cell treatment in repair of barrier integrity, likely due to replacement of damaged ECs in mouse CNS vessels. Based on this evidence, hBM-EPCs may be advanced as a cell-specific approach for ALS therapy through restored CNS barrier integrity.}, }
@article {pmid33543942, year = {2021}, author = {Nguyen, PH and Ramamoorthy, A and Sahoo, BR and Zheng, J and Faller, P and Straub, JE and Dominguez, L and Shea, JE and Dokholyan, NV and De Simone, A and Ma, B and Nussinov, R and Najafi, S and Ngo, ST and Loquet, A and Chiricotto, M and Ganguly, P and McCarty, J and Li, MS and Hall, C and Wang, Y and Miller, Y and Melchionna, S and Habenstein, B and Timr, S and Chen, J and Hnath, B and Strodel, B and Kayed, R and Lesné, S and Wei, G and Sterpone, F and Doig, AJ and Derreumaux, P}, title = {Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer's Disease, Parkinson's Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis.}, journal = {Chemical reviews}, volume = {121}, number = {4}, pages = {2545-2647}, pmid = {33543942}, issn = {1520-6890}, support = {R01 AG054025/AG/NIA NIH HHS/United States ; R56 NS113549/NS/NINDS NIH HHS/United States ; RF1 AG062135/AG/NIA NIH HHS/United States ; R35 GM134864/GM/NIGMS NIH HHS/United States ; R01 AG020135/AG/NIA NIH HHS/United States ; RF1 AG044342/AG/NIA NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; R01 NS094557/NS/NINDS NIH HHS/United States ; R01 GM107703/GM/NIGMS NIH HHS/United States ; R01 AG048934/AG/NIA NIH HHS/United States ; R01 NS092918/NS/NINDS NIH HHS/United States ; R21 AG065693/AG/NIA NIH HHS/United States ; R01 GM118560/GM/NIGMS NIH HHS/United States ; }, mesh = {Alzheimer Disease/metabolism/pathology ; Amyloid/*chemistry/*metabolism ; Amyloid beta-Peptides/chemistry/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; Diabetes Mellitus, Type 2/metabolism/pathology ; Humans ; Islet Amyloid Polypeptide/chemistry/metabolism ; Models, Molecular ; Neurodegenerative Diseases/*metabolism/pathology ; Parkinson Disease/metabolism/pathology ; Protein Aggregation, Pathological ; Proteostasis Deficiencies/metabolism ; Superoxide Dismutase-1/chemistry/metabolism ; alpha-Synuclein/chemistry/metabolism ; tau Proteins/chemistry/metabolism ; }, abstract = {Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo, and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP, and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D), and amyotrophic lateral sclerosis (ALS) research, respectively, for many years.}, }
@article {pmid33541995, year = {2021}, author = {Pandurangan, V and Dronamraju, SP and Ramadurai, S and Arthur, P}, title = {Masquerading Guillain-Barré syndrome: uncommon, in-hospital presentation of Miller-Fisher syndrome shadowed by secondary diseases.}, journal = {BMJ case reports}, volume = {14}, number = {2}, pages = {}, pmid = {33541995}, issn = {1757-790X}, mesh = {Back Pain/etiology ; *Diagnosis, Differential ; Female ; Guillain-Barre Syndrome/diagnosis ; Hospitals ; Humans ; Hyponatremia/etiology ; Immunoglobulins, Intravenous/*therapeutic use ; Lower Extremity/physiopathology ; Middle Aged ; Miller Fisher Syndrome/complications/*diagnosis/*drug therapy ; Oculomotor Muscles/*physiopathology ; Radiculopathy/*diagnosis ; }, abstract = {Presentation of severe pain syndromes prior to onset of motor weakness is an uncommon but documented finding in patients with Guillain-Barré syndrome (GBS). Sciatica in GBS is a difficult diagnosis when patients present with acute radiculopathy caused by herniated disc or spondylolysis. A middle-aged woman was admitted for severe low back pain, symptomatic hyponatraemia, vomiting and constipation. On further investigation, she was diagnosed with radiculopathy, and appropriate treatment was initiated. Brief symptomatic improvement was followed by new-onset weakness in lower limbs, which progressed to involve upper limbs and right extraocular muscles. With progressive, ascending, new-onset motor and sensory deficits and laboratory evidence of demyelination by Nerve Conduction Study, a diagnosis of variant GBS was made. She was treated with intravenous immunoglobulin 2 g/kg over 5 days. The presentation of severe low back pain that was masking an existing aetiology and possible dysautonomia and the unilateral right extraocular muscles instead of bilateral make our case unique and rare.}, }
@article {pmid33530247, year = {2021}, author = {Yue, P and Zhong, J and Huang, J and Lan, Z and Zhong, S}, title = {The effectiveness of acupuncture at Yaotongdian (EX-UE 7) for acute lumbar sprain: A protocol for a systematic review and meta-analysis.}, journal = {Medicine}, volume = {100}, number = {4}, pages = {e24440}, pmid = {33530247}, issn = {1536-5964}, support = {Grant No. 2016Z010//Sichuan Provincial Administration of Traditional Chinese Medicine/ ; }, mesh = {*Acupuncture Points ; Acupuncture Therapy/*methods ; Humans ; Lumbar Vertebrae/*injuries ; Meta-Analysis as Topic ; Research Design ; Sprains and Strains/*therapy ; Systematic Reviews as Topic ; Treatment Outcome ; }, abstract = {BACKGROUND: Acupuncture at Yaotongdian (EX-UE 7) is increasingly used in acute lumbar sprain (ALS), and many studies have published that it is effective in the treatment of ALS. However, it is controversy if acupuncture at (EX-UE 7) can provide an evidence-based clinical benefit in the ALS population.<br><br>METHODS: We will go through 8 databases, and conduct a systematic review of acupuncture on (EX-UE 7) and health-related outcomes in ALS patients according to the Preferred Reporting Items for Systematic Reviews. The primary objective is to assess the impact of Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines on clinical outcomes relevant to ALS patients, such as effective rate, life-quality evaluation, and adverse events. Cochrane Risk Assessment Tool will be used to assess the quality of eligible studies according to the Cochrane handbook.<br><br>RESULTS: The results of this systematic review will provide a synthesis of current evidence of Acupuncture at Yaotongdian (EX-UE 7) and we have a specific opportunity to determine the efficacy and safety of it.<br><br>CONCLUSION: This study will explore whether or not acupuncture on (EX-UE 7) can be used as one of the non-drug therapies to prevent or treat ALS.<br><br>REGISTRATION NUMBER: 10.17605/OSF.IO/29QV7 (https://osf.io/29qv7/).}, }
@article {pmid33529450, year = {2021}, author = {Maiwall, R and Bajpai, M and Choudhury, AK and Kumar, A and Sharma, MK and Duan, Z and Yu, C and Hu, J and Ghazinian, H and Ning, Q and Ma, K and Lee, GH and Lim, SG and Shah, S and Kalal, C and Dokmeci, A and Kumar, G and Jain, P and Rao Pasupuleti, SS and Paulson, I and Kumar, V and Sarin, SK and , }, title = {Therapeutic plasma-exchange improves systemic inflammation and survival in acute-on-chronic liver failure: A propensity-score matched study from AARC.}, journal = {Liver international : official journal of the International Association for the Study of the Liver}, volume = {41}, number = {5}, pages = {1083-1096}, doi = {10.1111/liv.14806}, pmid = {33529450}, issn = {1478-3231}, mesh = {*Acute-On-Chronic Liver Failure/therapy ; Adult ; Female ; Humans ; Inflammation/therapy ; Male ; Middle Aged ; Plasma Exchange ; Propensity Score ; }, abstract = {BACKGROUND AND AIM: Plasma-exchange (PE) has improved survival in acute liver failure by ameliorating systemic inflammatory response syndrome (SIRS). We evaluated PE and compared it to Fractional Plasma Separation and Adsorption (FPSA) and standard medical treatment (SMT) in a large multinational cohort of ACLF patients.<br><br>METHODS: Data were prospectively collected from the AARC database and analysed. Matching by propensity risk score (PRS) was performed. Competing risk survival analysis was done to identify deaths because of multiorgan failure (MOF). In a subset of 10 patients, we also evaluated the mechanistic basis of response to PE.<br><br>RESULTS: ACLF patients (n&#xa0;=&#xa0;1866, mean age 44.3&#xa0;&#xb1;&#xa0;12.3 yrs, 93% males, 65% alcoholics) received either artificial liver support (ALS) (n&#xa0;=&#xa0;162); [PE (n&#xa0;=&#xa0;131), FPSA (n&#xa0;=&#xa0;31)] or were continued on standard medical therapy (SMT) (n&#xa0;=&#xa0;1704). In the PRS-matched cohort (n&#xa0;=&#xa0;208, [ALS-119; PE-94, FPSA-25)], SMT-89). ALS therapies were associated with a significantly higher resolution of SIRS (Odd's ratio 9.23,3.42-24.8), lower and delayed development of MOF (Hazard ratio 7.1, 4.5-11.1), and lower liver-failure-related deaths as compared to FPSA and SMT (P&#xa0;<&#xa0;.05). PE cleared inflammatory cytokines, damage-associated molecular patterns, and endotoxin in all patients. Responders improved monocyte phagocytic function and mitochondrial respiration and increased the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1RA) compared to non-responders. PE was associated with lesser adverse effects as compared to FPSA.<br><br>CONCLUSIONS: PE improves systemic inflammation and lowers the development of MOF in patients with ACLF. Plasma-exchange provides significant survival benefit over FPSA and could be a preferred modality of liver support for ACLF patients.}, }
@article {pmid33527843, year = {2021}, author = {van Eijk, RPA and de Jongh, AD and Nikolakopoulos, S and McDermott, CJ and Eijkemans, MJC and Roes, KCB and van den Berg, LH}, title = {An old friend who has overstayed their welcome: the ALSFRS-R total score as primary endpoint for ALS clinical trials.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {22}, number = {3-4}, pages = {300-307}, doi = {10.1080/21678421.2021.1879865}, pmid = {33527843}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Disease Progression ; Clinical Trials as Topic ; Treatment Outcome ; }, abstract = {Objective: The ALSFRS-R is limited by multidimensionality, which originates from the summation of various subscales. This prevents a direct comparison between patients with identical total scores. We aim to evaluate how multidimensionality affects the performance of the ALSFRS-R in clinical trials. Methods: We simulated clinical trial data with different treatment effects for the ALSFRS-R total score and its subscales (i.e. bulbar, fine motor, gross motor and respiratory). We considered scenarios where treatment reduced the rate of ALSFRS-R subscale decline either uniformly (i.e. all subscales respond identically to treatment) or non-uniformly (i.e. subscales respond differently to treatment). Two main analytical strategies were compared: (1) analyzing only the total score or (2) utilizing a subscale-based test (i.e. alternative strategy). For each analytical strategy, we calculated the empirical power and required sample size. Results: Both strategies are valid when there is no treatment benefit and provide adequate control of type 1 error. If all subscales respond identically to treatment, using the total score is the most powerful approach. As the differences in treatment responses between subscales increase, the more the total score becomes affected. For example, to detect a 40% reduction in the bulbar rate of decline with 80% power, the total score requires 1380 patients, whereas this is 336 when using the alternative strategy. Conclusions: Ignoring the multidimensional structure of the ALSFRS-R total score could have negative consequences for ALS clinical trials. We propose determining treatment benefit on a subscale level, prior to stating whether a treatment is generally effective.}, }
@article {pmid33525757, year = {2021}, author = {Rojas-Prats, E and Tosat-Bitrián, C and Martínez-González, L and Nozal, V and Pérez, DI and Martínez, A}, title = {Increasing Brain Permeability of PHA-767491, a Cell Division Cycle 7 Kinase Inhibitor, with Biodegradable Polymeric Nanoparticles.}, journal = {Pharmaceutics}, volume = {13}, number = {2}, pages = {}, pmid = {33525757}, issn = {1999-4923}, support = {B2017/BMD-3813//Comunidad de Madr/ ; CIBERNED (CB18/05/00040)//Instituto de Salud Carlos III/ ; SAF2016-76693-R//Ministerio de Econom&#xed;a, Industria y Competitividad, Gobierno de Espa&#xf1;a/ ; PID2019-105600RB-I00//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; FPU14-00204 to E.R.P., FPU16-04466 to V.N., and FPU18-06310 to C.T.B.//Ministerio Educacion, cultura y deporte/ ; }, abstract = {A potent cell division cycle 7 (CDC7) kinase inhibitor, known as PHA-767491, has been described to reduce the transactive response DNA binding protein of 43 KDa (TDP-43) phosphorylation in vitro and in vivo, which is one of the main proteins found to aggregate and accumulate in the cytoplasm of motoneurons in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. However, the main drawback of this compound is its low permeability to the central nervous system (CNS), limiting its use for the treatment of neurological conditions. In this context, the use of drug delivery systems like nanocarriers has become an interesting approach to improve drug release to the CNS. In this study, we prepared and characterized biodegradable nanoparticles in order to encapsulate PHA-767491 and improve its permeability to the CNS. Our results demonstrate that poly (lactic-co-glycolic acid) (PLGA) nanoparticles with an average radius between 145 and 155 nm could be used to entrap PHA-767491 and enhance the permeability of this compound through the blood-brain barrier (BBB), becoming a promising candidate for the treatment of TDP-43 proteinopathies such as ALS.}, }
@article {pmid33523039, year = {2021}, author = {Cabrita, B and Dias, S and Fernandes, AL and Correia, S and Ferreira, J and Simão, P}, title = {Inspiratory muscle training in neuromuscular patients: Assessing the benefits of a novel protocol.}, journal = {Journal of back and musculoskeletal rehabilitation}, volume = {34}, number = {4}, pages = {537-543}, doi = {10.3233/BMR-200141}, pmid = {33523039}, issn = {1878-6324}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/rehabilitation ; Breathing Exercises/*methods ; Clinical Protocols ; Female ; Humans ; Inhalation/*physiology ; Male ; Middle Aged ; Muscle Strength ; Muscular Dystrophies/*rehabilitation ; Physical Therapy Modalities ; Prospective Studies ; Quality of Life ; Respiratory Function Tests ; Respiratory Muscles/*physiology ; Respiratory Therapy/*methods ; }, abstract = {BACKGROUND: Neuromuscular diseases are characterized by the compromise of respiratory muscles, thoracic ventilation, muscle strength and coughing capacity. Patients have low quality of life and increased morbidity and mortality mostly due to respiratory impairment.<br><br>OBJECTIVE: To assess the benefits of adding inspiratory muscle training to neuromuscular patients' treatment and their compliance to the approach.<br><br>METHODS: We conducted a single-center prospective study with neuromuscular patients with decreased maximal inspiratory pressure. We developed an inspiratory muscle training protocol with three-month duration and once-daily training. The protocol had a progressive intensity that was individually tailored based on patients' baseline characteristics and tolerance. We used Powerbreathe Medic Classic devices to perform the training.<br><br>RESULTS: There were 21 patients who met the inclusion criteria and were enrolled in the study. Muscular dystrophy (n= 12, 57.3%) and amyotrophic lateral sclerosis (n= 4, 19%) were the most common diseases. After three months of training, patients increased their maximal inspiratory muscle pressure (p= 0.002) and peak cough flow (p= 0.011). Compliance to the protocol was 99 &#xb1; 5.5%.<br><br>CONCLUSIONS: This protocol showed significant improvements on pulmonary muscles function and might be considered as an adjunct treatment to neuromuscular treatment. However, these positive results require larger further studies to validate the clinical benefits long-term.}, }
@article {pmid33519873, year = {2020}, author = {Shyam, C and Borgato, EA and Peterson, DE and Dille, JA and Jugulam, M}, title = {Predominance of Metabolic Resistance in a Six-Way-Resistant Palmer Amaranth (Amaranthus palmeri) Population.}, journal = {Frontiers in plant science}, volume = {11}, number = {}, pages = {614618}, pmid = {33519873}, issn = {1664-462X}, abstract = {Evolution of multiple herbicide resistance in Palmer amaranth across the United States is a serious challenge for its management. Recently, a Palmer amaranth population (KCTR; Kansas Conservation Tillage Resistant) from a long-term conservation tillage research project in Kansas, United States, was found uncontrolled by several commonly used herbicides. Importantly, this field did not have a history of repeated use of some of the herbicides for which the KCTR Palmer amaranth population showed lack of control. The objectives of this study were to confirm the evolution of multiple resistances and determine possible mechanism(s) of resistance in KCTR Palmer amaranth plants. In response to post-emergence application, 28-100% of KCTR Palmer amaranth survived field recommended rates of 2,4-D, ALS-, PS II-, EPSPS-, PPO-, HPPD-inhibitor herbicides, or tank- or pre-mixture of PS II- and HPPD-inhibitor herbicides, confirming evolution of six-way resistance in this Palmer amaranth population. However, this population was found susceptible to the PS I- and glutamine synthetase inhibitor herbicides. Chlorsulfuron-, imazethapyr-, and atrazine-resistant plants did not show any previously reported mutation in ALS and psbA genes, the target sites of these herbicides, respectively. However, the survivors of glyphosate treatment showed amplification of EPSPS gene (up to 88 copies). The KCTR plants pretreated with cytochrome P450 or GST inhibitors along with atrazine, 2,4-D, lactofen, or mesotrione had significantly less biomass accumulation than those treated with herbicides alone. Plants treated with P450 inhibitor followed by imazethapyr showed moderate reduction of biomass in KCTR which was statistically similar to a susceptible Palmer amaranth population treated with imazethapyr. These results suggest predominance of metabolic resistance possibly mediated by cytochrome P450 and GST enzyme activity that may have predisposed the KCTR Palmer amaranth population to evolve resistance to multiple herbicides. This is the first report of evolution of six-way resistance in a single Palmer amaranth population. Appropriate management strategies, including integration of cultural, and mechanical, and herbicide mixtures, are warranted to control such Palmer amaranth populations.}, }
@article {pmid33512025, year = {2021}, author = {Ngo, ST and Wang, H and Henderson, RD and Bowers, C and Steyn, FJ}, title = {Ghrelin as a treatment for amyotrophic lateral sclerosis.}, journal = {Journal of neuroendocrinology}, volume = {33}, number = {7}, pages = {e12938}, doi = {10.1111/jne.12938}, pmid = {33512025}, issn = {1365-2826}, support = {//FightMND Mid-career Fellowship/ ; //Australian Institute for Bioengineering and Nanotechnology (AIBN) at the University of Queensland/ ; }, abstract = {Ghrelin is a gut hormone best known for its role in regulating appetite and stimulating the secretion of the anabolic hormone growth hormone (GH). However, there is considerable evidence to show wider-ranging biological actions of ghrelin that favour improvements in cellular and systemic metabolism, as well as neuroprotection. Activation of these ghrelin-mediated pathways may alleviate pathogenic processes that are assumed to contribute to accelerated progression of disease in patients with neurodegenerative disease. Here, we provide a brief overview on the history of discoveries that led to the identification of ghrelin. Focussing on the neurodegenerative disease amyotrophic lateral sclerosis (ALS), we also present an overview of emerging evidence that suggests that ghrelin and ghrelin mimetics may serve as potential therapies for the treatment of ALS. Given that ALS is a highly heterogeneous disease, where multiple disease mechanisms contribute to variability in disease onset and rate of disease progression, we speculate that the wide-ranging biological actions of ghrelin might offer therapeutic benefit through modulating multiple disease-relevant processes observed in ALS. Expanding on the well-known actions of ghrelin in regulating food intake and GH secretion, we consider the potential of ghrelin-mediated pathways in improving body weight regulation, metabolism and the anabolic and neuroprotective actions of GH and insulin-like growth factor-1 (IGF-1). This is of clinical significance because loss of body weight, impairments in systemic and cellular metabolism, and reductions in IGF-1 are associated with faster disease progression and worse disease outcome in patients with ALS.}, }
@article {pmid33510061, year = {2021}, author = {Xu, RS and Yuan, M}, title = {Considerations on the concept, definition, and diagnosis of amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {16}, number = {9}, pages = {1723-1729}, pmid = {33510061}, issn = {1673-5374}, abstract = {The concept, definition, and diagnosis of amyotrophic lateral sclerosis (ALS) currently present some problems. This article systematically reviews the literature on the history, current concepts, definition, and diagnosis of ALS, and discloses the present problems based on the retrieved literature and the authors' clinical experience. The current concepts and definitions of ALS have not yet been unified or standardized in clinical practice, and are sometimes vague or inaccurate, which can cause difficulties for neurologists in the clinical treatment of ALS. The concept and definition of ALS need to be further ascertained, and the current diagnostic criteria for ALS require further development. The identification of effective and objective biomarkers may be a feasible method for the early and accurate diagnosis of ALS. Therefore, future research should focus on the identification of reliable biomarkers-especially neuroimaging biomarkers-through autopsy. Standardizing the concept and definition of ALS and formulating clear diagnostic criteria will largely avoid many uncertainties in the future clinical research and treatment of ALS, which will greatly benefit patients.}, }
@article {pmid33504366, year = {2021}, author = {Jung, H and Lee, MJ and Cho, JW and Lee, SH and Lee, SH and Mun, YH and Chung, HS and Kim, YH and Kim, GM and Park, SY and Jeon, JC and Kim, C and , }, title = {External validation of multimodal termination of resuscitation rules for out-of-hospital cardiac arrest patients in the COVID-19 era.}, journal = {Scandinavian journal of trauma, resuscitation and emergency medicine}, volume = {29}, number = {1}, pages = {19}, pmid = {33504366}, issn = {1757-7241}, mesh = {Aged ; Aged, 80 and over ; COVID-19/*prevention &amp; control ; Cardiopulmonary Resuscitation/*standards ; *Decision Support Techniques ; Emergency Medical Services ; Female ; Humans ; Male ; *Medical Futility ; Middle Aged ; Out-of-Hospital Cardiac Arrest/*therapy ; Predictive Value of Tests ; Registries ; Republic of Korea ; Resuscitation Orders ; }, abstract = {BACKGROUND: Futile resuscitation for out-of-hospital cardiac arrest (OHCA) patients in the coronavirus disease (COVID)-19 era can lead to risk of disease transmission and unnecessary transport. Various existing basic or advanced life support (BLS or ALS, respectively) rules for the termination of resuscitation (TOR) have been derived and validated in North America and Asian countries. This study aimed to evaluate the external validation of these rules in predicting the survival outcomes of OHCA patients in the COVID-19 era.<br><br>METHODS: This was a multicenter observational study using the WinCOVID-19 Daegu registry data collected during February 18-March 31, 2020. The subjects were patients who showed cardiac arrest of presumed cardiac etiology. The outcomes of each rule were compared to the actual patient survival outcomes. The sensitivity, specificity, false positive value (FPV), and positive predictive value (PPV) of each TOR rule were evaluated.<br><br>RESULTS: In total, 170 of the 184 OHCA patients were eligible and evaluated. TOR was recommended for 122 patients based on the international basic life support termination of resuscitation (BLS-TOR) rule, which showed 85% specificity, 74% sensitivity, 0.8% FPV, and 99% PPV for predicting unfavorable survival outcomes. When the traditional BLS-TOR rules and KoCARC TOR rule II were applied to our registry, one patient met the TOR criteria but survived at hospital discharge. With regard to the FPV (upper limit of 95% confidence interval&#x2009;<&#x2009;5%), specificity (100%), and PPV (>&#x2009;99%) criteria, only the KoCARC TOR rule I, which included a combination of three factors including not being witnessed by emergency medical technicians, presenting with an asystole at the scene, and not experiencing prehospital shock delivery or return of spontaneous circulation, was found to be superior to all other TOR rules.<br><br>CONCLUSION: Among the previous nine BLS and ALS TOR rules, KoCARC TOR rule I was most suitable for predicting poor survival outcomes and showed improved diagnostic performance. Further research on variations in resources and treatment protocols among facilities, regions, and cultures will be useful in determining the feasibility of TOR rules for COVID-19 patients worldwide.}, }
@article {pmid33503311, year = {2021}, author = {Regier, PJ and Case, JB and Fox-Alvarez, WA}, title = {Ligation of the ligamentum arteriosum and aberrant left subclavian artery in five dogs in which persistent right aortic arch had been diagnosed.}, journal = {Veterinary surgery : VS}, volume = {50 Suppl 1}, number = {}, pages = {O26-O31}, doi = {10.1111/vsu.13575}, pmid = {33503311}, issn = {1532-950X}, mesh = {Animals ; Aorta, Thoracic/abnormalities/diagnostic imaging/surgery ; *Cardiovascular Abnormalities/surgery/veterinary ; *Dog Diseases/surgery ; Dogs ; Ligation ; Subclavian Artery/*abnormalities/surgery ; }, abstract = {OBJECTIVE: To determine and report the diagnosis, treatment, and outcome in dogs with persistent right aortic arch (PRAA) with an aberrant left subclavian artery (ALS) that underwent thoracoscopic surgery.<br><br>ANIMALS: Dogs with PRAA and an ALS (n&#xa0;=&#xa0;5).<br><br>STUDY DESIGN: Short case series.<br><br>METHODS: Medical records were reviewed from 2014 to 2019. Dogs that underwent thoracoscopy for PRAA with an ALS at an academic referral hospital were included. Signalment, clinical signs, diagnostic imaging, surgical approach, complications, and short- and long-term outcomes were recorded.<br><br>RESULTS: Persistent right aortic arch with an ALS was identified in five dogs. Dogs initially underwent a three-port intercostal thoracoscopic approach, and an intercostal thoracotomy was performed in converted cases. In all five dogs, the ligamentum arteriosum (LA) and ALS were divided; three were performed by a thoracoscopy alone. Two cases were converted because of poor exposure (1) and requirement to temporary occlude an ALS (1). The ALS was ligated and divided in all dogs without apparent negative effects. No intraoperative or postoperative complications occurred. Four dogs had resolution of regurgitation, three of which required diet modification. One dog had reported regurgitation when it was excited. Median follow-up was 188&#x2009;days (range, 150-1133).<br><br>CONCLUSION: Ligation and division of both the LA and the ALS in all dogs in this case series was safe and allowed for improvement in clinical signs and good to excellent long-term outcomes. In addition, both thoracoscopy and thoracotomy were used safely and successfully for ligation and transection of the LA and ALS in all dogs.}, }
@article {pmid33498503, year = {2021}, author = {Devi, S and Kumar, V and Singh, SK and Dubey, AK and Kim, JJ}, title = {Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders.}, journal = {Biomedicines}, volume = {9}, number = {2}, pages = {}, pmid = {33498503}, issn = {2227-9059}, abstract = {Neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are the most concerning disorders due to the lack of effective therapy and dramatic rise in affected cases. Although these disorders have diverse clinical manifestations, they all share a common cellular stress response. These cellular stress responses including neuroinflammation, oxidative stress, proteotoxicity, and endoplasmic reticulum (ER)-stress, which combats with stress conditions. Environmental stress/toxicity weakened the cellular stress response which results in cell damage. Small molecules, such as flavonoids, could reduce cellular stress and have gained much attention in recent years. Evidence has shown the potential use of flavonoids in several ways, such as antioxidants, anti-inflammatory, and anti-apoptotic, yet their mechanism is still elusive. This review provides an insight into the potential role of flavonoids against cellular stress response that prevent the pathogenesis of neurodegenerative disorders.}, }
@article {pmid33498150, year = {2021}, author = {Yean, RA and Dilipkumar, M and Rahman, S and Song, BK}, title = {A Two-in-One Strategy: Target and Nontarget Site Mechanisms Both Play Important Role in IMI-Resistant Weedy Rice.}, journal = {International journal of molecular sciences}, volume = {22}, number = {3}, pages = {}, pmid = {33498150}, issn = {1422-0067}, support = {ASEAN-2019-01-SCI//Monash University Malaysia/ ; }, mesh = {Acetolactate Synthase/genetics ; *Drug Resistance ; Herbicides/*toxicity ; Imidazolines/*toxicity ; Oryza/drug effects/*genetics ; Plant Proteins/genetics ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; }, abstract = {The introduction of Clearfield technology allows the use of imidazolinone (IMI) herbicides to control weedy rice. Imidazolinone herbicides stop the acetolactate synthase (ALS) enzyme from synthesizing branched-chain amino acids, resulting in the death of the plant. Since the launch of Clearfield technology in Malaysia in 2010, many farmers have replaced traditional cultivars with Clearfield (CL) rice lines (MR220-CL1 and MR220-CL2). This technology was initially effective; however, in recent years, local farmers have reported the reduced efficacy of IMI herbicides in controlling the spread of weedy rice. Under IMI herbicide treatment, in previous weedy rice studies, the target-site resistance (TSR) mechanism of the ALS gene has been suggested as a key factor conferring herbicide resistance. In our study, a combination of ALS gene sequencing, enzyme colorimetric assay, and a genome-wide association study (GWAS) highlighted that a non-target-site resistance (NTSR) can be an alternative molecular mechanism in IMI-resistant weedy rice. This is supported by a series of evidence, including a weak correlation between single nucleotide polymorphisms (SNPs) within the ALS exonic region and ALS enzyme activity. Our findings suggest that the adaptability of weedy rice in Clearfield rice fields can be more complicated than previously found in other rice strains.}, }
@article {pmid33497646, year = {2021}, author = {Debska-Vielhaber, G and Miller, I and Peeva, V and Zuschratter, W and Walczak, J and Schreiber, S and Petri, S and Machts, J and Vogt, S and Szczepanowska, J and Gellerich, FN and Hermann, A and Vielhaber, S and Kunz, WS}, title = {Impairment of mitochondrial oxidative phosphorylation in skin fibroblasts of SALS and FALS patients is rescued by in vitro treatment with ROS scavengers.}, journal = {Experimental neurology}, volume = {339}, number = {}, pages = {113620}, doi = {10.1016/j.expneurol.2021.113620}, pmid = {33497646}, issn = {1090-2430}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/drug therapy/*metabolism/pathology ; Cells, Cultured ; Female ; Fibroblasts/*metabolism ; Free Radical Scavengers/*pharmacology/therapeutic use ; Humans ; Male ; Middle Aged ; Mitochondria/*metabolism ; *Oxidative Phosphorylation ; Reactive Oxygen Species/*metabolism ; Skin/drug effects/metabolism ; Young Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressive, neurodegenerative disorder affecting upper and lower motor neurons. Approximately 10% of patients suffer from familial ALS (FALS) with mutations in different ubiquitously expressed genes including SOD1, C9ORF72, TARDBP, and FUS. There is compelling evidence for mitochondrial involvement in the pathogenic mechanisms of FALS and sporadic ALS (SALS), which is believed to be relevant for disease. Owing to the ubiquitous expression of relevant disease-associated genes, mitochondrial dysfunction is also detectable in peripheral patient tissue. We here report results of a detailed investigation of the functional impairment of mitochondrial oxidative phosphorylation (OXPHOS) in cultured skin fibroblasts from 23 SALS and 17 FALS patients, harboring pathogenic mutations in SOD1, C9ORF72, TARDBP and FUS. A considerable functional and structural mitochondrial impairment was detectable in fibroblasts from patients with SALS. Similarly, fibroblasts from patients with FALS, harboring pathogenic mutations in TARDBP, FUS and SOD1, showed mitochondrial defects, while fibroblasts from C9ORF72 associated FALS showed a very mild impairment detectable in mitochondrial ATP production rates only. While we could not detect alterations in the mtDNA copy number in the SALS or FALS fibroblast cultures, the impairment of OXPHOS in SALS fibroblasts and SOD1 or TARDBP FALS could be rescued by in vitro treatments with CoQ10 (5 μM for 3 weeks) or Trolox (300 μM for 5 days). This underlines the role of elevated oxidative stress as a potential cause for the observed functional effects on mitochondria, which might be relevant disease modifying factors.}, }
@article {pmid33497520, year = {2021}, author = {Squires, A and Hovet, S and Li, R and Oshinski, J and Ho Tse, ZT}, title = {A body-mounted device for MRI-guided spinal therapy.}, journal = {The international journal of medical robotics + computer assisted surgery : MRCAS}, volume = {17}, number = {2}, pages = {e2235}, doi = {10.1002/rcs.2235}, pmid = {33497520}, issn = {1478-596X}, support = {//Royal Society Wolfson Fellowship/ ; //NIH Bench-to-Bedside Award/ ; //AU-UGA Inter-Institutional Seed Funding/ ; //American Society for Quality Dr. Richard J. Schlesinger Grant/ ; 1617340//National Science Foundation (NSF) I-Corps Team Grant/ ; 1359095//NSF REU site program/ ; //NIH Center for Interventional Oncology Grant/ ; UL1TR000454//Clinical and Translational Science Award Program of the NIH National Center for Advancing Translational Sciences/ ; }, mesh = {Animals ; Magnetic Resonance Imaging ; Needles ; *Neurodegenerative Diseases ; Phantoms, Imaging ; *Robotic Surgical Procedures ; *Spinal Cord ; Swine ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no cure and limited treatment options. Recent studies have shown that delivering cellular therapeutics to the ventral horn of the spinal cord can effectively halt neurodegeneration associated with ALS in small animal models.<br><br>METHODS: We developed a robotic system that assists with MRI-guided percutaneous injections to the spinal cord. The needle positioning robot consists of two linear axes with motorised translational sleds for two-degree-of-freedom (2-DOF) needle translation and a radial template for 2-DOF discrete rotation.<br><br>RESULTS: The robot's targeting capability, evaluated using phantom models and swine cadavers, showed mean targeting errors of 0.48 and 2.84 mm, respectively. The duration of the targeting procedure is approximately 60 min, with an extra 10 min for each additional injection.<br><br>CONCLUSIONS: The presented robot does not affect imaging quality during MRI-guided procedures, and it enables a simplified workflow for MRI-guided spinal therapy.}, }
@article {pmid33488207, year = {2020}, author = {Aliasgharlou, N and Bahram, M and Zolfaghari, P and Mohseni, N}, title = {Modeling and optimization of simultaneous degradation of rhodamine B and acid red 14 binary solution by homogeneous Fenton reaction: a chemometrics approach.}, journal = {Turkish journal of chemistry}, volume = {44}, number = {4}, pages = {987-1001}, pmid = {33488207}, issn = {1300-0527}, abstract = {This study aimed to propose a mathematical method to investigate and optimize the simultaneous elimination process of multiple organic pollutants using the Fenton process. Hence, the treatment of rhodamine B (RB) and acid red 14 (AR14) dyes in their binary solution was studied. Multivariate curve resolution alternating least square (MCR-ALS), a novel chemometric method, was applied along with correlation constraints to resolute the UV-Vis spectrophotometric data, enabling quantification of investigated dyes despite a high spectral overlapping. Response surface methodology was adopted to assess the model and optimize individual and interactive effects of three independent factors (Fe[2+], H2O2 and initial pH) on the simultaneous elimination of RB and AR14. The values of the regression coefficient for RB and AR14 were determined as 98.48 and 98.67 percent, respectively, revealing the reliability of the obtained polynomial models to predict decolorization efficiencies. Desirability function was employed to optimize the independent variables to attain the highest possible degradation performance for both dyes in their binary solution. At the optimum point of operation ([Fe[2+]] = 143.88 mg/L, [H2O2] = 126.89 mg/L and pH = 3.71), degradation efficiencies of RB and AR14 were found as 81.58% and 80.22%, respectively, which were nearly identical to the experimental results.}, }
@article {pmid33480168, year = {2021}, author = {Sharp, G and Steffens, D and Koh, CE}, title = {Evidence of negative pressure therapy for anastomotic leak: a systematic review.}, journal = {ANZ journal of surgery}, volume = {91}, number = {4}, pages = {537-545}, doi = {10.1111/ans.16581}, pmid = {33480168}, issn = {1445-2197}, mesh = {Anastomosis, Surgical/adverse effects ; *Anastomotic Leak/therapy ; Endoscopy ; Humans ; *Negative-Pressure Wound Therapy ; Rectum/surgery ; Treatment Outcome ; }, abstract = {BACKGROUND: Anastomotic leak (AL) is a devastating complication. Several new treatment options are available, endoluminal negative pressure therapy is one. The aims of this systematic review are; to report success rates and stoma closure rates following endoluminal negative pressure therapy in colorectal AL patients.<br><br>METHODS: A systematic review of MEDLINE, PubMed, Cochrane and Embase databases from inception to June 2018. Search limits were; English language, humans, sample >5 and >18&#x2009;years. Search terms were Endospong* OR Endo-spong* OR Endo spong* OR Endoluminal negative pressure OR Endoluninal vac* OR Vacuum assisted OR negative pressure. Combined with colon OR rectum OR colorect* AND anastomotic leak OR leak*.<br><br>RESULTS: Twenty articles met inclusion criteria. There were 334 patients. Reported success rates ranged from 60% to 100%. However, success definition varied considerably. The most widely used definition was endoscopic assessment of residual cavity size, but this also varied from 0.5 cm to 3 cm. Stoma closure rates were only reported in 11 studies and ranged from 31% to 100%. Complication rates were reported in 13 studies (65%). The most common was on-going sepsis.<br><br>CONCLUSIONS: Included studies suggest that 60-100% of ALs heal with endoluminal negative pressure therapy. However, results from this review need to be interpreted with caution because of the variable definition of success. A more objective assessment of success may be stoma closure but this is only reported in 60% of studies. Further studies are needed to assess the benefit of negative pressure therapy in anastomotic leaks.}, }
@article {pmid33476770, year = {2021}, author = {Mani, S and Swargiary, G and Chadha, R}, title = {Mitophagy impairment in neurodegenerative diseases: Pathogenesis and therapeutic interventions.}, journal = {Mitochondrion}, volume = {57}, number = {}, pages = {270-293}, doi = {10.1016/j.mito.2021.01.001}, pmid = {33476770}, issn = {1872-8278}, mesh = {Biomarkers/*metabolism ; Gene Expression Regulation ; Humans ; Life Expectancy ; Mitochondria/*metabolism ; Mitophagy ; Neurodegenerative Diseases/metabolism/*pathology ; }, abstract = {Neurons are specialized cells, requiring a lot of energy for its proper functioning. Mitochondria are the key cellular organelles and produce most of the energy in the form of ATP, required for all the crucial functions of neurons. Hence, the regulation of mitochondrial biogenesis and quality control is important for maintaining neuronal health. As a part of mitochondrial quality control, the aged and damaged mitochondria are removed through a selective mode of autophagy called mitophagy. However, in different pathological conditions, this process is impaired in neuronal cells and lead to a variety of neurodegenerative disease (NDD). Various studies indicate that specific protein aggregates, the characteristics of different NDDs, affect this process of mitophagy, adding to the severity and progression of diseases. Though, the detailed process of this association is yet to be explored. In light of the significant role of impaired mitophagy in NDDs, further studies have also investigated a large number of therapeutic strategies to target mitophagy in these diseases. Our current review summarizes the abnormalities in different mitophagy pathways and their association with different NDDs. We have also elaborated upon various novel therapeutic strategies and their limitations to enhance mitophagy in NDDs that may help in the management of symptoms and increasing the life expectancy of NDD patients. Thus, our study provides an overview of mitophagy in NDDs and emphasizes the need to elucidate the mechanism of impaired mitophagy prevalent across different NDDs in future research. This will help designing better treatment options with high efficacy and specificity.}, }
@article {pmid33474997, year = {2021}, author = {Bedlack, R and Kihuwa-Mani, S and Barkhaus, PE and Bereman, M and Caress, JB and Crayle, J and Pattee, GL and Heiman Patterson, T and Wicks, P and Zach, N and Carter, GT and Salmon, K}, title = {ALSUntangled 59: Tamoxifen.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {22}, number = {7-8}, pages = {595-598}, doi = {10.1080/21678421.2021.1876731}, pmid = {33474997}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Tamoxifen/therapeutic use ; }, abstract = {Here we use the ALSUntangled methodology to review Tamoxifen as an ALS treatment. We show that it has plausible mechanisms, a positive preclinical study, a case report and 2 small trials suggesting benefits. We show that it appears reasonably safe, though there is a small risk of developing cancer with long term use. While we cannot yet endorse this as an ALS treatment, there is enough evidence to warrant another larger ALS trial.}, }
@article {pmid33473007, year = {2020}, author = {Wang, Y and Yi, H and Liao, Q and Bi, F}, title = {Advances in genetics research in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences}, volume = {45}, number = {12}, pages = {1483-1489}, doi = {10.11817/j.issn.1672-7347.2020.190506}, pmid = {33473007}, issn = {1672-7347}, support = {81571256 and 81760238//the National Natural Science Foundation, China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Motor Neurons ; Mutation ; *Neurodegenerative Diseases ; Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease affecting the upper and lower motor neurons. It is characterized by progressive muscle weakness, atrophy and ultimate death due to dysphagia and dyspnea. There are many causes of ALS, among which the genetic factors show great relevance. Imbalance of protein homeostasis in neurons, prion-like proliferation and propagation of abnormal proteins, mitochondrial dysfunction, glutamate mediated excitotoxicity, and intraneuronal substance transport disorders are recognized as the pathogenesis.The study on gene mutation related to pathogenesis will bridge the molecular and cellular research of ALS, which can deepen the understanding of the occurrence and development of ALS and the role of gene mutation in ALS, and provide new ideas and enlightenment for the treatment of ALS.}, }
@article {pmid33467098, year = {2021}, author = {Gröger, V and Emmer, A and Staege, MS and Cynis, H}, title = {Endogenous Retroviruses in Nervous System Disorders.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {1}, pages = {}, pmid = {33467098}, issn = {1424-8247}, support = {ZS/2018/12/96228//European Regional Development Fund/ ; ZS/2018/12/96169//European Regional Development Fund/ ; }, abstract = {Human endogenous retroviruses (HERV) have been implicated in the pathogenesis of several nervous system disorders including multiple sclerosis and amyotrophic lateral sclerosis. The toxicity of HERV-derived RNAs and proteins for neuronal cells has been demonstrated. The involvement of HERV in the pathogenesis of currently incurable diseases might offer new treatment strategies based on the inhibition of HERV activities by small molecules or therapeutic antibodies.}, }
@article {pmid33464924, year = {2021}, author = {Chen, J and Wang, C and Xu, C and Qiu, J and Xu, J and Tsai, TY and Zhao, J}, title = {Effects of Anterolateral Structure Augmentation on the In Vivo Kinematics of Anterior Cruciate Ligament-Reconstructed Knees.}, journal = {The American journal of sports medicine}, volume = {49}, number = {3}, pages = {656-666}, doi = {10.1177/0363546520981743}, pmid = {33464924}, issn = {1552-3365}, mesh = {Anterior Cruciate Ligament/surgery ; *Anterior Cruciate Ligament Injuries/surgery ; *Anterior Cruciate Ligament Reconstruction ; Biomechanical Phenomena ; Cadaver ; Humans ; *Joint Instability/surgery ; Knee Joint/surgery ; Range of Motion, Articular ; Rotation ; }, abstract = {BACKGROUND: Double-bundle anterior cruciate ligament (ACL) reconstruction (ACLR) is a well-known treatment that restores the stability of ACL-deficient knees. However, some isolated ACL-reconstructed knees ultimately show rotatory laxity and develop osteoarthritis. Whether combined ACLR with anterolateral structure (ALS) augmentation (ALSA) can provide better improvement in the in vivo knee rotational kinematics remains unknown.<br><br>HYPOTHESIS: When compared with isolated double-bundle ACLR, combined double-bundle ACLR with ALSA can improve knee in vivo rotational kinematics and provide better restoration of knee kinematics.<br><br>STUDY DESIGN: Controlled laboratory study.<br><br>METHODS: Sixteen patients with unilateral ACL injury were randomly divided into 2 groups to receive either combined double-bundle ACLR and ALSA (ALSA group) or isolated double-bundle ACLR (ACLR group). All patients performed a single-leg lunge using the operative and nonoperative/contralateral legs under dual-fluoroscopic imaging system surveillance during a hospital visit at a minimum 1 year (12-13 months) of follow-up to assess the 6 degrees of freedom knee kinematics. Functional evaluation using the Lysholm and Marx rating scales and clinical examinations were also performed.<br><br>RESULTS: From full extension to approximately 90&#xb0; of knee flexion at 5&#xb0; intervals, the mean &#xb1; SD internal rotation of the reconstructed knees in the ALSA group (1.5&#xb0;&#xb1; 0.9&#xb0;) was significantly smaller than that of the contralateral knees (8.2&#xb0;&#xb1; 1.9&#xb0;; P = .008). The ALSA group knees also showed significantly (P = .045) more medial translation than the contralateral knees. In the ACLR group, the mean internal rotation of the reconstructed knee (6.0&#xb0;&#xb1; 2.1&#xb0;) was significantly smaller than that of the contralateral knees (8.9&#xb0;&#xb1; 0.6&#xb0;; P < .001). At full extension, the tibia was significantly more externally rotated than that of the contralateral legs (0.5&#xb0;&#xb1; 7.4&#xb0; vs 7.6&#xb0;&#xb1; 3.4&#xb0;, P = .049).<br><br>CONCLUSION: When compared with isolated double-bundle ACLR, double-bundle ACLR augmented with ALS reconstruction resulted in anterolateral rotatory overconstraint during the lunge motion.<br><br>CLINICAL RELEVANCE: Additional ALSA of double-bundle ACL-reconstructed knees overconstrained rotatory stability. Therefore, the use of ALSA for ACL-reconstructed knees should be considered with caution for patients with ACL deficiency and anterolateral rotatory instability. Longer-term follow-up to evaluate long-term outcomes and altered kinematics over time is recommended.}, }
@article {pmid33461912, year = {2022}, author = {Borges, ALF and Velasco, LC and Ramos, HVL and Imamura, R and Roldão, PMAC and Petrillo, MVB and Costa, CC}, title = {Association between dysphagia and tongue strength in patients with amyotrophic lateral sclerosis.}, journal = {Brazilian journal of otorhinolaryngology}, volume = {88}, number = {5}, pages = {752-757}, pmid = {33461912}, issn = {1808-8686}, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/complications ; Cross-Sectional Studies ; Deglutition/physiology ; *Deglutition Disorders/diagnosis/etiology ; Humans ; *Neurodegenerative Diseases/complications ; Pressure ; Tongue ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis is the most common motor neuron disease in adults despite it being rare. It is a neurodegenerative disease in which dysphagia is a common and debilitating symptom. Dysphagia can be assessed by complementary exams, such as fiberoptic endoscopic evaluation of swallowing and the tongue strength test, as this is one of the main muscles involved in swallowing.<br><br>OBJECTIVE: To compare the results of tongue strength and endurance measured by the Iowa oral performance instrument with the findings of the fiberoptic endoscopic evaluation of swallowing examination in patients affected by amyotrophic lateral sclerosis.<br><br>METHODS: Cross-sectional study, carried out in a tertiary hospital specialized in treatment and rehabilitation. Twenty-five patients diagnosed with amyotrophic lateral sclerosis underwent dysphagia questionnaires, fiberoptic endoscopic evaluation of swallowing examination and tongue strength and resistance test with the Iowa oral performance instrument to assess the presence of dysphagia.<br><br>RESULTS: Forty-eight percent of the sample had dysphagia at the fiberoptic endoscopic evaluation of swallowing and 76% had an altered tongue strength test. Ninety percent of patients with dysphagia had an average tongue pressure lower than 34.2KPa. The tongue strength test showed sensitivity of 91.67% and specificity of 38.46% and accuracy of 64%. There was a statistically significant relationship between tongue strength and dysphagia and between tongue resistance and dysphagia.<br><br>CONCLUSION: Tongue strength tests, such as the Iowa oral performance instrument, proved to be effective in assessing dysphagia. This result should encourage further research to facilitate the early diagnosis of dysphagia.}, }
@article {pmid33454337, year = {2021}, author = {Wang, XL and Feng, ST and Wang, ZZ and Chen, NH and Zhang, Y}, title = {Role of mitophagy in mitochondrial quality control: Mechanisms and potential implications for neurodegenerative diseases.}, journal = {Pharmacological research}, volume = {165}, number = {}, pages = {105433}, doi = {10.1016/j.phrs.2021.105433}, pmid = {33454337}, issn = {1096-1186}, mesh = {Animals ; Autophagy/physiology ; Humans ; Mitochondria/*metabolism/pathology ; Mitochondrial Dynamics/*physiology ; Mitophagy/*physiology ; Neurodegenerative Diseases/*metabolism/pathology ; Signal Transduction/physiology ; }, abstract = {Neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis) commonly characterized by the gradual loss of neurons have a seriously bad impact on motor and cognitive abilities of affected humans and bring great inconvenience to their lives. Mitochondrial dysfunction has been considered the key and common factor for the pathologies of neurodegenerative diseases for that neurons are extremely energy-intensive due to their unique properties in structures and functions. Thus, mitophagy, as a central role of mitochondrial quality control and currently believed to be the most effective pathway to clear dysfunctional or unwanted mitochondria, is rather crucial in the preservation of neuronal health. In addition, mitophagy establishes an intimated link with several other pathways of mitochondrial quality control (e.g., mitochondrial biogenesis and mitochondrial dynamics), and they work together to preserve mitochondrial health. Therefore, in this review, we summarized the recent process on the mechanisms of mitophagy pathways in mammals, it's linking to mitochondrial quality control, its role in several major neurodegenerative diseases, and possible therapeutic interventions focusing on mitophagy pathways. And we expect that it can provide us with more understanding of the mitophagy pathways and more promising approaches for the treatment of neurodegenerative diseases.}, }
@article {pmid33453999, year = {2020}, author = {Shinoda, Y and Haga, Y and Akagawa, K and Fukunaga, K}, title = {Wildtype σ1 receptor and the receptor agonist improve ALS-associated mutation-induced insolubility and toxicity.}, journal = {The Journal of biological chemistry}, volume = {295}, number = {51}, pages = {17573-17587}, pmid = {33453999}, issn = {1083-351X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology ; Apoptosis/drug effects ; Cell Line ; Endoplasmic Reticulum Stress ; Fluorescence Recovery After Photobleaching ; Humans ; Luminescent Proteins/genetics/metabolism ; Mutagenesis, Site-Directed ; Piperazines/pharmacology ; Protein Aggregates/drug effects ; Protein Multimerization/drug effects ; Receptors, sigma/agonists/genetics/*metabolism ; Recombinant Fusion Proteins/biosynthesis/genetics ; Solubility ; Red Fluorescent Protein ; Sigma-1 Receptor ; }, abstract = {Genetic mutations related to ALS, a progressive neurological disease, have been discovered in the gene encoding σ-1 receptor (σ1R). We previously reported that σ1RE102Q elicits toxicity in cells. The σ1R forms oligomeric states that are regulated by ligands. Nevertheless, little is known about the effect of ALS-related mutations on oligomer formation. Here, we transfected NSC-34 cells, a motor neuronal cell line, and HEK293T cells with σ1R-mCherry (mCh), σ1RE102Q-mCh, or nontagged forms to investigate detergent solubility and subcellular distribution using immunocytochemistry and fluorescence recovery after photobleaching. The oligomeric state was determined using crosslinking procedure. σ1Rs were soluble to detergents, whereas the mutants accumulated in the insoluble fraction. Within the soluble fraction, peak distribution of mutants appeared in higher sucrose density fractions. Mutants formed intracellular aggregates that were co-stained with p62, ubiquitin, and phosphorylated pancreatic eukaryotic translation initiation factor-2-α kinase in NSC-34 cells but not in HEK293T cells. The aggregates had significantly lower recovery in fluorescence recovery after photobleaching. Acute treatment with σ1R agonist SA4503 failed to improve recovery, whereas prolonged treatment for 48 h significantly decreased σ1RE102Q-mCh insolubility and inhibited apoptosis. Whereas σ1R-mCh formed monomers and dimers, σ1RE102Q-mCh also formed trimers and tetramers. SA4503 reduced accumulation of the four types in the insoluble fraction and increased monomers in the soluble fraction. The σ1RE102Q insolubility was diminished by σ1R-mCh co-expression. These results suggest that the agonist and WT σ1R modify the detergent insolubility, toxicity, and oligomeric state of σ1RE102Q, which may lead to promising new treatments for σ1R-related ALS.}, }
@article {pmid33450997, year = {2021}, author = {Madruga, E and Maestro, I and Martínez, A}, title = {Mitophagy Modulation, a New Player in the Race against ALS.}, journal = {International journal of molecular sciences}, volume = {22}, number = {2}, pages = {}, pmid = {33450997}, issn = {1422-0067}, support = {H2020-MSCA-ITN-2017 (grant no. 765912)//H2020 Marie Sk&#x142;odowska-Curie Actions/ ; BMD-3813 ELA_Madrid//CAM/ ; PID2019-105600RB-I00//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; CIBERNED (CB18/05/00040).//Instituto de Salud Carlos III/ ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*etiology/*metabolism ; Animals ; Autophagy/drug effects/genetics/immunology ; Disease Management ; Disease Models, Animal ; Disease Susceptibility ; Homeostasis ; Humans ; Mitochondria/*drug effects/genetics/immunology/metabolism ; Mitophagy/*drug effects/genetics/immunology ; Molecular Targeted Therapy/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that usually results in respiratory paralysis in an interval of 2 to 4 years. ALS shows a multifactorial pathogenesis with an unknown etiology, and currently lacks an effective treatment. The vast majority of patients exhibit protein aggregation and a dysfunctional mitochondrial accumulation in their motoneurons. As a result, autophagy and mitophagy modulators may be interesting drug candidates that mitigate key pathological hallmarks of the disease. This work reviews the most relevant evidence that correlate mitophagy defects and ALS, and discusses the possibility of considering mitophagy as an interesting target in the search for an effective treatment for ALS.}, }
@article {pmid33447124, year = {2020}, author = {Jaffer, M and Chung, M and Sharda, E and Ramsakal, A and Peguero, E and Verma, N and Mokhtari, S}, title = {Immunotherapy Induced Myasthenic-Like Syndrome in a Metastatic Melanoma Patient With Amyotrophic Lateral Sclerosis.}, journal = {Clinical Medicine Insights. Oncology}, volume = {14}, number = {}, pages = {1179554920978024}, pmid = {33447124}, issn = {1179-5549}, abstract = {Immunotherapy agents such as ipilimumab and nivolumab are immensely effective in the treatment of various malignancies. Despite this, neurologic immune-related sequelae (NIRS) have been observed. Prompt diagnosis and treatment is critical to improve patient outcomes. We present a case of a 63-year-old man with stage IV metastatic melanoma beginning treatment with ipilimumab and nivolumab. Gathered history from the patient showed that he had a 3-year presentation of bradykinesia, shuffling gait, and muscle cramping. After one dose, the patient began to have progressively worsening generalized weakness; after receiving the immunotherapy, there was a rapid decline in his health. In addition to weakness, the patient developed diplopia, impaired single breath count, lingual and upper/lower extremity fasciculations, and brisk reflexes. While the lumbar puncture and myasthenia panel were non-diagnostic, the electromyography (EMG) revealed axonal neuropathy and diffuse denervation/reinnervation changes. Furthermore, a magnetic resonance imaging (MRI) displayed fatty replacement of the tongue with a bright tongue sign. These results pointed to the diagnosis of amyotrophic lateral sclerosis (ALS) superimposed onto myasthenic-like syndrome. The patient was started on various treatments; however, unfortunately he died due to acute hypoxic respiratory failure. This case highlights important considerations that must be taken when using immunotherapy, especially in patients with pre-existing neurological deficits. Furthermore, it shows the importance of early diagnosis as treatment can potentially cure adverse sequelae.}, }
@article {pmid33439410, year = {2021}, author = {Namusamba, M and Li, Z and Zhang, Q and Wang, C and Wang, T and Wang, B}, title = {Biological roles of the B cell receptor-associated protein 31: Functional Implication in Cancer.}, journal = {Molecular biology reports}, volume = {48}, number = {1}, pages = {773-786}, pmid = {33439410}, issn = {1573-4978}, support = {No. 31370784; No. 31972898; No. 31670770; Liaoning Revitalization Talents Program (XLYC1902063), Key Research and Development Plan of Liaoning Province (2020JH2/10300080).//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Humans ; Alzheimer Disease/genetics/metabolism/mortality/pathology ; Amyotrophic Lateral Sclerosis/genetics/metabolism/mortality/pathology ; Atlases as Topic ; B-Lymphocytes/metabolism/pathology ; Disease Progression ; Gene Expression Regulation ; Liver Diseases/genetics/metabolism/mortality/pathology ; *Membrane Proteins/genetics/metabolism ; Metabolic Networks and Pathways/genetics ; *Neoplasms/genetics/metabolism/mortality/pathology ; Protein Interaction Mapping ; Signal Transduction ; Survival Analysis ; }, abstract = {BAP31 is a ubiquitously expressed integral membrane protein of the endoplasmic reticulum. BAP31 is involved in various biological and molecular processes, including protein transport, viral processing, apoptosis signaling, MHC 1 antigen processing and presentation, mitochondria and ER calcium regulation, and proteasomal protein degradation. We employed a BAP31 interaction search using STRING and inBioMap™ protein-protein interaction networks, and the Metabolic Atlas, which revealed molecular and metabolic interactors involved in various pathways essential for cell growth, cell survival, and disease development. BAP31, as a chaperone and resident protein of the ER, was reported in the development of some central nervous system disorders and metabolic diseases about AD, ALS, and Liver disease. In addition, BAP31 is overexpressed in many cancers. Furthermore, research around BAP31 involvement in cancer has taken up a shape, focusing on its roles in cancer cell survival, disease prognosis, and targeted treatment. Here, we address published data on the Biological roles of BAP31 in both health and disease. We present an analytical description of BAP31 expression and functional implication in some human cancers and the impact of its expression and regulation while it models as a potential target in cancer therapy. Besides, a profound understanding of BAP31 is insightful of the gap between cancer development and neurodegeneration, thus generating novel ideas surrounding the link between the two different cell phenomena.}, }
@article {pmid33436868, year = {2021}, author = {Dodge, JC and Yu, J and Sardi, SP and Shihabuddin, LS}, title = {Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {803}, pmid = {33436868}, issn = {2045-2322}, support = {HHSN275200900011C/HD/NICHD NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Cell Death/physiology ; Cells, Cultured ; Disease Models, Animal ; Feces/chemistry ; Humans ; Induced Pluripotent Stem Cells/metabolism/pathology ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism/*pathology ; Nervous System Diseases/metabolism/*pathology ; Spinal Cord/metabolism/*pathology ; Sterols/*chemistry/metabolism ; Superoxide Dismutase-1/genetics/*metabolism ; }, abstract = {Aberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acids (BAs) to promote its removal. In contrast, the auto oxidation of excess cholesterol is often detrimental to cellular survival. Although oxidized metabolites of cholesterol are altered in the blood and CSF of ALS patients, it is unknown if increased cholesterol oxidation occurs in the SC during ALS, and if exposure to oxidized cholesterol metabolites affects human MN viability. Here, we show that in the SOD1[G93A] mouse model of ALS that several oxysterols, BAs and auto oxidized sterols are increased in the lumbar SC, plasma, and feces during disease. Similar changes in cholesterol oxidation were found in the cervical SC of sporadic ALS patients. Notably, auto-oxidized sterols, but not oxysterols and BAs, were toxic to iPSC derived human MNs. Thus, increased cholesterol oxidation is a manifestation of ALS and non-regulated sterol oxidation likely contributes to MN death. Developing therapeutic approaches to restore cholesterol homeostasis in the SC may lead to a treatment for ALS.}, }
@article {pmid33433755, year = {2021}, author = {Zhou, Q and Yuan, M and Qiu, W and Cao, W and Xu, R}, title = {Preclinical studies of mesenchymal stem cells transplantation in amyotrophic lateral sclerosis: a systemic review and metaanalysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {42}, number = {9}, pages = {3637-3646}, pmid = {33433755}, issn = {1590-3478}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy ; Disease Models, Animal ; Disease Progression ; *Mesenchymal Stem Cell Transplantation ; *Mesenchymal Stem Cells ; }, abstract = {OBJECTIVES: To assess the quality of preclinical evidence for mesenchymal stromal cell (MSCs) therapy of amyotrophic lateral sclerosis (ALS), decide the effect size of MSCs treatment, and identify clinical parameters that associate with differences in MSCs effects.<br><br>METHODS: A literature search identified studies of MSCs in animal models of ALS. Four main indicators (age of onset, disease progression deceleration, survival time, hazard ratio reduction) obtained through specific neurobehavioral assessment, and 14 relative clinical parameters were extracted for metaanalysis and systematic review. Subgroup analysis and metaregression were performed to explore sources of heterogeneity.<br><br>RESULTS: A total of 25 studies and 41 independent treated arms were used for systematic review and metaanalysis. After adjusted by sensitivity analysis, the mean effect sizes were significantly improved by 0.28 for the age of onset, 0.25 for the disease progression deceleration, 0.54 for the survival time, and 0.48 for hazard ratio reduction. With further analysis, we demonstrated that both the clinical parameter of animal gender and immunosuppressive drug of cyclosporin A (CSA) had a close correlation with disease progression deceleration effect size.<br><br>CONCLUSIONS: These results showed that MSCs transplantation was beneficial for neurobehavioral improvement in the treatment of ALS animal model and recommended that all potential reparative roles of MSCs postdelivery, should be carefully considered and fused to maximize the effectiveness of MSCs therapy in ALS.}, }
@article {pmid33433460, year = {2021}, author = {Onyango, IG and Bennett, JP and Stokin, GB}, title = {Regulation of neuronal bioenergetics as a therapeutic strategy in neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {16}, number = {8}, pages = {1467-1482}, pmid = {33433460}, issn = {1673-5374}, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a heterogeneous group of debilitating disorders with multifactorial etiologies and pathogeneses that manifest distinct molecular mechanisms and clinical manifestations with abnormal protein dynamics and impaired bioenergetics. Mitochondrial dysfunction is emerging as an important feature in the etiopathogenesis of these age-related neurodegenerative diseases. The prevalence and incidence of these diseases is on the rise with the increasing global population and average lifespan. Although many therapeutic approaches have been tested, there are currently no effective treatment routes for the prevention or cure of these diseases. We present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in these diseases and highlight recent advances in novel therapeutic strategies targeting neuronal bioenergetics as potential approach for treating these diseases.}, }
@article {pmid33431874, year = {2021}, author = {Jaramillo-Gonzalez, A and Wu, S and Tonin, A and Rana, A and Ardali, MK and Birbaumer, N and Chaudhary, U}, title = {A dataset of EEG and EOG from an auditory EOG-based communication system for patients in locked-in state.}, journal = {Scientific data}, volume = {8}, number = {1}, pages = {8}, pmid = {33431874}, issn = {2052-4463}, support = {16SV7701 CoMiCon//Bundesministerium f&#xfc;r Bildung und Forschung (Federal Ministry of Education and Research)/International ; 16SV7701 CoMiCon//Bundesministerium f&#xfc;r Bildung und Forschung (Federal Ministry of Education and Research)/International ; 16SV7701 CoMiCon//Bundesministerium f&#xfc;r Bildung und Forschung (Federal Ministry of Education and Research)/International ; 16SV7701 CoMiCon//Bundesministerium f&#xfc;r Bildung und Forschung (Federal Ministry of Education and Research)/International ; DFG BI 195/77-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/International ; DFG BI 195/77-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/International ; LUMINOUS-H2020-FETOPEN-2014-2015-RIA (686764)//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/International ; LUMINOUS-H2020-FETOPEN-2014-2015-RIA (686764)//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/International ; LUMINOUS-H2020-FETOPEN-2014-2015-RIA (686764)//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/International ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Electroencephalography ; *Electrooculography ; Eye Movements ; Humans ; }, abstract = {The dataset presented here contains recordings of electroencephalogram (EEG) and electrooculogram (EOG) from four advanced locked-in state (LIS) patients suffering from ALS (amyotrophic lateral sclerosis). These patients could no longer use commercial eye-trackers, but they could still move their eyes and used the remnant oculomotor activity to select letters to form words and sentences using a novel auditory communication system. Data were recorded from four patients during a variable range of visits (from 2 to 10), each visit comprised of 3.22 ± 1.21 days and consisted of 5.57 ± 2.61 sessions recorded per day. The patients performed a succession of different sessions, namely, Training, Feedback, Copy spelling, and Free spelling. The dataset provides an insight into the progression of ALS and presents a valuable opportunity to design and improve assistive and alternative communication technologies and brain-computer interfaces. It might also help redefine the course of progression in ALS, thereby improving clinical judgement and treatment.}, }
@article {pmid33431491, year = {2021}, author = {Vucic, S and Kiernan, MC and Menon, P and Huynh, W and Rynders, A and Ho, KS and Glanzman, R and Hotchkin, MT}, title = {Study protocol of RESCUE-ALS: A Phase 2, randomised, double-blind, placebo-controlled study in early symptomatic amyotrophic lateral sclerosis patients to assess bioenergetic catalysis with CNM-Au8 as a mechanism to slow disease progression.}, journal = {BMJ open}, volume = {11}, number = {1}, pages = {e041479}, pmid = {33431491}, issn = {2044-6055}, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/drug therapy ; Australia ; Canada ; Catalysis ; Clinical Trials, Phase II as Topic ; Disease Progression ; Double-Blind Method ; Energy Metabolism ; Europe ; Humans ; Multicenter Studies as Topic ; Quality of Life ; Randomized Controlled Trials as Topic ; Treatment Outcome ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an adult-onset, progressive and universally fatal neurodegenerative disorder. In Europe, Australia and Canada, riluzole is the only approved therapeutic agent for the treatment of ALS, while in the USA, riluzole and edaravone have been approved by the Food and Drug Administration (FDA) . Neither riluzole nor edaravone treatment has resulted in substantial disease-modifying effects. There is, therefore, an urgent need for drugs that result in safe and effective treatment. Here, we present the design and rationale for the phase 2 RESCUE-ALS study, investigating the novel nanocatalytic drug, CNM-Au8, as a therapeutic intervention that enhances the metabolic and energetic capacity of motor neurones. CNM-Au8 is an aqueous suspension of clean-surfaced, faceted gold nanocrystals that have extraordinary catalytic capabilities, that enhance efficiencies of key metabolic reactions, while simultaneously reducing levels of reactive oxygen species. This trial utilises a novel design by employing motor unit number index (MUNIX), measured by electromyography, as a quantitative measure of lower motor neurone loss and as an early marker of ALS disease progression.<br><br>METHODS AND ANALYSIS: This is a multicentre, randomised, double-blind, parallel group, placebo-controlled study of the efficacy, safety, pharmacokinetics and pharmacodynamics of CNM-Au8 in ALS patients. Patients will be randomised 1:1 to either receive 30 mg of CNM-Au8 once daily or matching placebo over a 36-week double-blind treatment period. Efficacy will be assessed as the change in motor neurone loss as measured by electromyography (eg, MUNIX, the primary endpoint; and secondary endpoints including MScanFit, motor unit size index, Split Hand Index, Neurophysiology Index). Exploratory endpoints include standard clinical and quality of life assessments.<br><br>ETHICS AND DISSEMINATION: RESCUE-ALS was approved by the Western Sydney Local Health District Human Research Ethics Committee (Ethics Ref: 2019/ETH12107). Results of the study will be submitted for publication in a peer-reviewed journal.<br><br>TRIAL REGISTRATION NUMBER: NCT04098406.}, }
@article {pmid33431483, year = {2021}, author = {Riemslagh, FW and van der Toorn, EC and Verhagen, RFM and Maas, A and Bosman, LWJ and Hukema, RK and Willemsen, R}, title = {Inducible expression of human C9ORF72 36x G4C2 hexanucleotide repeats is sufficient to cause RAN translation and rapid muscular atrophy in mice.}, journal = {Disease models &amp; mechanisms}, volume = {14}, number = {2}, pages = {}, pmid = {33431483}, issn = {1754-8411}, abstract = {The hexanucleotide G4C2 repeat expansion in the first intron of the C9ORF72 gene explains the majority of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) cases. Numerous studies have indicated the toxicity of dipeptide repeats (DPRs) which are produced via repeat-associated non-AUG (RAN) translation from the repeat expansion and accumulate in the brain of C9FTD/ALS patients. Mouse models expressing the human C9ORF72 repeat and/or DPRs show variable pathological, functional, and behavioral characteristics of FTD and ALS. Here, we report a new Tet-on inducible mouse model that expresses 36x pure G4C2 repeats with 100bp upstream and downstream human flanking regions. Brain specific expression causes the formation of sporadic sense DPRs aggregates upon 6 months dox induction but no apparent neurodegeneration. Expression in the rest of the body evokes abundant sense DPRs in multiple organs, leading to weight loss, neuromuscular junction disruption, myopathy, and a locomotor phenotype within the time frame of four weeks. We did not observe any RNA foci or pTDP-43 pathology. Accumulation of DPRs and the myopathy phenotype could be prevented when 36x G4C2 repeat expression was stopped after 1 week. After 2 weeks of expression, the phenotype could not be reversed, even though DPR levels were reduced. In conclusion, expression of 36x pure G4C2 repeats including 100bp human flanking regions is sufficient for RAN translation of sense DPRs and evokes a functional locomotor phenotype. Our inducible mouse model suggests early diagnosis and treatment are important for C9FTD/ALS patients.}, }
@article {pmid33427561, year = {2021}, author = {Matsukawa, K and Kukharsky, MS and Park, SK and Park, S and Watanabe, N and Iwatsubo, T and Hashimoto, T and Liebman, SW and Shelkovnikova, TA}, title = {Long non-coding RNA NEAT1_1 ameliorates TDP-43 toxicity in in vivo models of TDP-43 proteinopathy.}, journal = {RNA biology}, volume = {18}, number = {11}, pages = {1546-1554}, pmid = {33427561}, issn = {1555-8584}, support = {MRF_MRF-060-0001-RG-SHELK/MRF/MRF/United Kingdom ; R35 GM136229/GM/NIGMS NIH HHS/United States ; SHELKOVNIKOVA/OCT17/968-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/etiology/metabolism/pathology/*prevention &amp; control ; Animals ; Brain/*metabolism/pathology ; DNA-Binding Proteins/*toxicity ; Disease Models, Animal ; Drosophila melanogaster ; Frontotemporal Dementia/etiology/metabolism/pathology/*prevention &amp; control ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuroblastoma/etiology/metabolism/pathology/*prevention &amp; control ; RNA, Long Noncoding/administration &amp; dosage/*genetics ; Saccharomyces cerevisiae ; TDP-43 Proteinopathies/etiology/metabolism/pathology/*prevention &amp; control ; }, abstract = {Pathological changes involving TDP-43 protein ('TDP-43 proteinopathy') are typical for several neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD). FTLD-TDP cases are characterized by increased binding of TDP-43 to an abundant lncRNA, NEAT1, in the cortex. However it is unclear whether enhanced TDP-43-NEAT1 interaction represents a protective mechanism. We show that accumulation of human TDP-43 leads to upregulation of the constitutive NEAT1 isoform, NEAT1_1, in cultured cells and in the brains of transgenic mice. Further, we demonstrate that overexpression of NEAT1_1 ameliorates TDP-43 toxicity in Drosophila and yeast models of TDP-43 proteinopathy. Thus, NEAT1_1 upregulation may be protective in TDP-43 proteinopathies affecting the brain. Approaches to boost NEAT1_1 expression in the CNS may prove useful in the treatment of these conditions.}, }
@article {pmid33424838, year = {2020}, author = {Guo, J and Xia, H and Wang, S and Yu, L and Zhang, H and Chen, J and Shi, D and Chen, Y and Zhang, Y and Xu, K and Xu, X and Sheng, J and Qiu, Y and Li, L}, title = {The Artificial-Liver Blood-Purification System Can Effectively Improve Hypercytokinemia for COVID-19.}, journal = {Frontiers in immunology}, volume = {11}, number = {}, pages = {586073}, pmid = {33424838}, issn = {1664-3224}, mesh = {Adult ; Aged ; Aged, 80 and over ; COVID-19/complications/*therapy ; Cytokine Release Syndrome/etiology/*therapy ; Cytokines/*blood ; Female ; *Hemoperfusion ; Humans ; Liver/*metabolism ; Male ; Middle Aged ; *Plasma Exchange ; *SARS-CoV-2 ; }, abstract = {Since the December 2019 outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, the infection has spread locally and globally resulting in a pandemic. As the numbers of confirmed diagnoses and deaths continue to rise, COVID-19 has become the focus of international public health. COVID-19 is highly contagious, and there is no effective treatment yet. New treatment strategies are urgently needed to improve the treatment success rate of severe and critically ill patients. Increasing evidence has shown that a cytokine storm plays an important role in the progression of COVID-19. The artificial-liver blood-purification system (ALS) is expected to improve the outcome of the cytokine storm. In the present study, the levels of cytokines were detected in 12 COVID-19 patients pre- and post-ALS with promising results. The present study shows promising evidence that ALS can block the cytokine storm, rapidly remove the inflammatory mediators, and hopefully, suppress the progression of the disease, thereby providing a new strategy for the clinical treatment of COVID-19.}, }
@article {pmid33423565, year = {2021}, author = {Gu, D and Ou, S and Tang, M and Yin, Z and Wang, Z and Liu, G}, title = {Trauma and amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {22}, number = {3-4}, pages = {170-185}, doi = {10.1080/21678421.2020.1861024}, pmid = {33423565}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology ; *Craniocerebral Trauma/complications/epidemiology ; Humans ; Observational Studies as Topic ; Odds Ratio ; Risk Factors ; }, abstract = {Background: Trauma especially head trauma is considered a potential risk factor of amyotrophic lateral sclerosis (ALS), but their association has not been well established. We aimed to determine the association of prior trauma with ALS risk. Methods: This study was performed according to the Meta-Analysis of Observational Studies in Epidemiology guideline to assess related literatures, and a random-effects model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Twenty-nine eligible articles involving 18,390 cases and 6,519,391 controls were included in this meta-analysis. The results showed that trauma was associated with an increased risk of ALS (pooled OR = 1.51, 95% CI: 1.32-1.73). Besides, patients with trunk trauma, head trauma and lower limb trauma had an increased risk of ALS, whereas no evidence suggested that upper limb trauma and spine trauma could increase ALS risk. Considering the number of traumatic events, the association between trauma and ALS risk was significant for patients with repeated trauma events (pooled OR = 1.21, 95% CI: 1.07-1.38). The results showed that individuals with a history of trauma within 5 years were more likely to be diagnosed with ALS (pooled OR = 1.84, 95% CI: 1.56-2.17). Importantly, both old trauma and very old trauma were found to be associated with an increased risk of ALS (pooled OR = 1.24, 95% CI: 1.12-1.38; pooled OR = 1.28, 95% CI: 1.10-1.49; respectively). Conclusions: This meta-analysis indicated that trauma could increase ALS risk, which may be applied for the clinicians to tailor targeted treatment regimens and make prophylactic strategies for ALS in traumatic patients.}, }
@article {pmid33419214, year = {2021}, author = {Testoni, I and Palazzo, L and Calamarà, N and Rossi, G and Wieser, MA}, title = {"Imagine You Have ALS": Death Education to Prepare for Advance Treatment Directives.}, journal = {Behavioral sciences (Basel, Switzerland)}, volume = {11}, number = {1}, pages = {}, pmid = {33419214}, issn = {2076-328X}, abstract = {The study presents the results of qualitative research carried out within a death education project dedicated to advance treatment directives (ATDs) in which it was proposed to participants to empathize with people who had received a diagnosis of Amyotrophic Lateral Sclerosis (ALS). The study involved 104 people who discussed and reflected on issues related to the knowledge of having to die, palliative care and ATDs, investigating what choices they would have made if they had received such a diagnosis. Finally, they were asked to write a paper describing their impressions and hypothetical choices. Qualitative analysis has elucidated among fundamental themes. Four thematic areas emerged from the data analysis: (1) ATDs and the family; (2) the importance of reducing pain and suffering; (3) emotions and considerations regarding death, illness and spirituality; and (4) opinions on the DeEd course. It has emerged that some people are unfamiliar with palliative care or the right to self-determination and that addressing these issues helps manage the thought of the future with less terror. The experience of death education has therefore proven to be very positive in dealing with complex and often censored issues, allowing thinking about death in a less distressing way.}, }
@article {pmid33417763, year = {2021}, author = {Patnaik, D and Pao, PC and Zhao, WN and Silva, MC and Hylton, NK and Chindavong, PS and Pan, L and Tsai, LH and Haggarty, SJ}, title = {Exifone Is a Potent HDAC1 Activator with Neuroprotective Activity in Human Neuronal Models of Neurodegeneration.}, journal = {ACS chemical neuroscience}, volume = {12}, number = {2}, pages = {271-284}, doi = {10.1021/acschemneuro.0c00308}, pmid = {33417763}, issn = {1948-7193}, mesh = {Benzophenones ; Histone Deacetylase 1 ; *Histone Deacetylases ; Humans ; *Induced Pluripotent Stem Cells ; Neurons ; }, abstract = {Genomic instability caused by a deficiency in the DNA damage response and repair has been linked to age-related cognitive decline and neurodegenerative diseases. Preventing genomic instability that ultimately leads to neuronal death may provide a broadly effective strategy to protect against multiple potential genotoxic stressors. Recently, the zinc-dependent class I histone deacetylase (HDAC1) has been identified as a critical factor for protecting neurons from deleterious effects of DNA damage in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Translating these observations to a novel neuroprotective therapy for AD, ALS, and FTD may be advanced by the identification of small molecules capable of increasing the deacetylase activity of HDAC1 selectively over other structurally similar HDACs. Here, we demonstrate that exifone, a drug previously shown to be effective in treating cognitive deficits associated with AD and Parkinson's disease, the molecular mechanism of which has remained poorly understood, potently activates the deacetylase activity of HDAC1. We show that exifone acts as a mixed, nonessential activator of HDAC1 that is capable of binding to both free and substrate-bound enzyme, resulting in an increased relative maximal rate of HDAC1-catalyzed deacetylation. Exifone can directly bind to HDAC1 based upon biolayer interferometry assays with kinetic and selectivity profiling, suggesting that HDAC1 is preferentially targeted compared to other class I HDACs and the kinase CDK5, which have also been implicated in neurodegeneration. Consistent with a mechanism of deacetylase activation intracellularly, the treatment of human induced pluripotent stem cell (iPSC)-derived neuronal cells resulted in globally decreased histone acetylation. Moreover, exifone treatment was neuroprotective in a tauopathy patient iPSC-derived neuronal model subject to oxidative stress. Taken together, these findings reveal exifone as a potent activator of HDAC1-mediated deacetylation, thereby offering a lead for novel therapeutic development aiming to protect genomic integrity in the context of neurodegeneration and aging.}, }
@article {pmid33416892, year = {2021}, author = {Fontana, L and Ghezzi, L and Cross, AH and Piccio, L}, title = {Effects of dietary restriction on neuroinflammation in neurodegenerative diseases.}, journal = {The Journal of experimental medicine}, volume = {218}, number = {2}, pages = {}, pmid = {33416892}, issn = {1540-9538}, support = {R01 NS102633/NS/NINDS NIH HHS/United States ; }, mesh = {Aging/physiology ; Animals ; Brain/*pathology ; Diet/methods ; Diet Therapy/methods ; Humans ; Inflammation/*pathology ; Neurodegenerative Diseases/*pathology ; }, abstract = {Recent and accumulating work in experimental animal models and humans shows that diet has a much more pervasive and prominent role than previously thought in modulating neuroinflammatory and neurodegenerative mechanisms leading to some of the most common chronic central nervous system (CNS) diseases. Chronic or intermittent food restriction has profound effects in shaping brain and peripheral metabolism, immunity, and gut microbiome biology. Interactions among calorie intake, meal frequency, diet quality, and the gut microbiome modulate specific metabolic and molecular pathways that regulate cellular, tissue, and organ homeostasis as well as inflammation during normal brain aging and CNS neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, among others. This review discusses these findings and their potential application to the prevention and treatment of CNS neuroinflammatory diseases and the promotion of healthy brain aging.}, }
@article {pmid33414425, year = {2021}, author = {Park, S and Park, JH and Kang, UB and Choi, SK and Elfadl, A and Ullah, HMA and Chung, MJ and Son, JY and Yun, HH and Park, JM and Yim, JH and Jung, SJ and Kim, SH and Choi, YC and Kim, DS and Shin, JH and Park, JS and Hur, K and Lee, SH and Lee, EJ and Hwang, D and Jeong, KS}, title = {Nogo-A regulates myogenesis via interacting with Filamin-C.}, journal = {Cell death discovery}, volume = {7}, number = {1}, pages = {1}, pmid = {33414425}, issn = {2058-7716}, support = {NRF-2017R1E1A1A01072781//National Research Foundation of Korea (NRF)/ ; 312062-5//Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries (iPET)/ ; }, abstract = {Among the three isoforms encoded by Rtn4, Nogo-A has been intensely investigated as a central nervous system inhibitor. Although Nogo-A expression is increased in muscles of patients with amyotrophic lateral sclerosis, its role in muscle homeostasis and regeneration is not well elucidated. In this study, we discovered a significant increase in Nogo-A expression in various muscle-related pathological conditions. Nogo[-/-] mice displayed dystrophic muscle structure, dysregulated muscle regeneration following injury, and altered gene expression involving lipid storage and muscle cell differentiation. We hypothesized that increased Nogo-A levels might regulate muscle regeneration. Differentiating myoblasts exhibited Nogo-A upregulation and silencing Nogo-A abrogated myoblast differentiation. Nogo-A interacted with filamin-C, suggesting a role for Nogo-A in cytoskeletal arrangement during myogenesis. In conclusion, Nogo-A maintains muscle homeostasis and integrity, and pathologically altered Nogo-A expression mediates muscle regeneration, suggesting Nogo-A as a novel target for the treatment of myopathies in clinical settings.}, }
@article {pmid33413517, year = {2021}, author = {Kumar, S and Phaneuf, D and Cordeau, P and Boutej, H and Kriz, J and Julien, JP}, title = {Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD.}, journal = {Molecular neurodegeneration}, volume = {16}, number = {1}, pages = {1}, pmid = {33413517}, issn = {1750-1326}, support = {//CIHR/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Autophagy/*physiology ; Brain/metabolism ; Disease Models, Animal ; Frontotemporal Dementia/*metabolism/pathology ; Humans ; Intermediate Filaments/metabolism/pathology ; Mice ; Neurons/metabolism ; RNA, Messenger/*metabolism ; Spinal Cord/metabolism ; TDP-43 Proteinopathies/*metabolism ; }, abstract = {BACKGROUND: TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile also remains unknown.<br><br>METHODS: Biochemical, immunohistology and assay-based studies were done with cell cultures and transgenic mice models. We also used Ribotag with microarray and proteomic analysis to determine the neuronal translational profile in the mice model of ALS/FTD.<br><br>RESULTS: Here, we report that oral administration of a novel analog (IMS-088) of withaferin-A, an antagonist of nuclear factor kappa-B (NF-&#x138;B) essential modulator (NEMO), induced autophagy and reduced TDP-43 proteinopathy in the brain and spinal cord of transgenic mice expressing human TDP-43 mutants, models of ALS/FTD. Treatment with IMS-088 ameliorated cognitive impairment, reduced gliosis in the brain of ALS/FTD mouse models. With the Ribotrap method, we investigated the impact of TDP-43 proteinopathy and IMS-088 treatment on the translation profile of neurons of one-year old hTDP-43[A315T] mice. TDP-43 proteinopathy caused translational dysregulation of specific mRNAs including translational suppression of neurofilament mRNAs resulting in 3 to 4-fold decrease in levels type IV neurofilament proteins. Oral administration of IMS-088 rescued the translational defects associated with TDP-43 proteinopathy and restored the synthesis of neurofilament proteins, which are essential for axon integrity and synaptic function.<br><br>CONCLUSIONS: Our study revealed that induction of autophagy reduces TDP-43 pathology and ameliorates the translational defect seen in mice models of ALS/FTD. Based on these results, we suggest IMS-088 and perhaps other inducers of autophagy should be considered as potential therapeutics for neurodegenerative disorders with TDP-43 proteinopathies.}, }
@article {pmid33411236, year = {2021}, author = {Lara, A and Esperante, I and Meyer, M and Liere, P and Di Giorgio, N and Schumacher, M and Guennoun, R and Gargiulo-Monachelli, G and De Nicola, AF and Gonzalez Deniselle, MC}, title = {Neuroprotective Effects of Testosterone in Male Wobbler Mouse, a Model of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {58}, number = {5}, pages = {2088-2106}, pmid = {33411236}, issn = {1559-1182}, support = {11220170100002CO//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; 11220170100301CO//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; PICT 2017 N&#xba; 1150//Fondo para la Investigaci&#xf3;n Cient&#xed;fica y Tecnol&#xf3;gica/ ; 20020170100224BA//Secretaria de Ciencia y Tecnica, Universidad de Buenos Aires/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Aromatase/metabolism ; Astrocytes/drug effects/metabolism/pathology ; Disease Models, Animal ; Estrogen Receptor alpha/metabolism ; Male ; Mice ; Motor Neurons/*drug effects/metabolism/pathology ; Neuroprotective Agents/pharmacology/*therapeutic use ; Receptors, Androgen/metabolism ; Spinal Cord/drug effects/metabolism/pathology ; Testosterone/metabolism/pharmacology/*therapeutic use ; Treatment Outcome ; }, abstract = {Patients suffering of amyotrophic lateral sclerosis (ALS) present motoneuron degeneration leading to muscle atrophy, dysphagia, and dysarthria. The Wobbler mouse, an animal model of ALS, shows a selective loss of motoneurons, astrocytosis, and microgliosis in the spinal cord. The incidence of ALS is greater in men; however, it increases in women after menopause, suggesting a role of sex steroids in ALS. Testosterone is a complex steroid that exerts its effects directly via androgen (AR) or Sigma-1 receptors and indirectly via estrogen receptors (ER) after aromatization into estradiol. Its reduced-metabolite 5α-dihydrotestosterone acts via AR. This study analyzed the effects of testosterone in male symptomatic Wobblers. Controls or Wobblers received empty or testosterone-filled silastic tubes for 2 months. The cervical spinal cord from testosterone-treated Wobblers showed (1) similar androgen levels to untreated control and (2) increased levels of testosterone, and its 5α-reduced metabolites, 5α- dihydrotestosterone, and 3β-androstanediol, but (3) undetectable levels of estradiol compared to untreated Wobblers. Testosterone-treated controls showed comparable steroid concentrations to its untreated counterpart. In testosterone- treated Wobblers a reduction of AR, ERα, and aromatase and high levels of Sigma-1 receptor mRNAs was demonstrated. Testosterone treatment increased ChAT immunoreactivity and the antiinflammatory mediator TGFβ, while it lessened vacuolated motoneurons, GFAP+ astrogliosis, the density of IBA1+ microgliosis, proinflammatory mediators, and oxidative/nitrosative stress. Clinically, testosterone treatment in Wobblers slowed the progression of paw atrophy and improved rotarod performance. Collectively, our findings indicate an antiinflammatory and protective effect of testosterone in the degenerating spinal cord. These results coincided with a high concentration of androgen-reduced derivatives after testosterone treatment suggesting that the steroid profile may have a beneficial role on disease progression.}, }
@article {pmid33398826, year = {2021}, author = {Asano, T and Teh, DBL and Yawo, H}, title = {Application of Optogenetics for Muscle Cells and Stem Cells.}, journal = {Advances in experimental medicine and biology}, volume = {1293}, number = {}, pages = {359-375}, pmid = {33398826}, issn = {0065-2598}, mesh = {*Induced Pluripotent Stem Cells ; Muscle Cells ; *Neural Stem Cells ; Neurons ; Optogenetics ; }, abstract = {This chapter describes the current progress of basic research, and potential therapeutic applications primarily focused on the optical manipulation of muscle cells and neural stem cells using microbial rhodopsin as a light-sensitive molecule. Since the contractions of skeletal, cardiac, and smooth muscle cells are mainly regulated through their membrane potential, several studies have been demonstrated to up- or downregulate the muscle contraction directly or indirectly using optogenetic actuators or silencers with defined stimulation patterns and intensities. Light-dependent oscillation of membrane potential also facilitates the maturation of myocytes with the development of T tubules and sarcomere structures, tandem arrays of minimum contractile units consists of contractile proteins and cytoskeletal proteins. Optogenetics has been applied to various stem cells and multipotent/pluripotent cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to generate light-sensitive neurons and to facilitate neuroscience. The chronic optical stimulation of the channelrhodopsin-expressing neural stem cells facilitates their neural differentiation. There are potential therapeutic applications of optogenetics in cardiac pacemaking, muscle regeneration/maintenance, locomotion recovery for the treatment of muscle paralysis due to motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Optogenetics would also facilitate maturation, network integration of grafted neurons, and improve the microenvironment around them when applied to stem cells.}, }
@article {pmid33398802, year = {2021}, author = {Borchelt, DR}, title = {Building a Case for Withaferin A as a Treatment for FTD/ALS Syndromes.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {18}, number = {1}, pages = {284-285}, pmid = {33398802}, issn = {1878-7479}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Frontotemporal Dementia/drug therapy ; Syndrome ; *Withanolides/therapeutic use ; }, }
@article {pmid33396271, year = {2020}, author = {Cho, H and Shukla, S}, title = {Role of Edaravone as a Treatment Option for Patients with Amyotrophic Lateral Sclerosis.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {1}, pages = {}, pmid = {33396271}, issn = {1424-8247}, abstract = {Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a progressive and fatal neurodegenerative disease that leads to a loss of muscle control due to nerve cells being affected in the brain and spinal cord. Some of the common clinical presentations of ALS include weakness of muscles, changes in behavior, dysfunction in speech, and cognitive difficulties. The cause of ALS is uncertain, but through several studies, it is known that mutations in SOD1 or C9orf72 genes could play a role as a factor of ALS. In addition, studies indicate that an excessive amount of free radicals, the reactive oxygen species (ROS), leads to neuronal damage by the peroxidation of unsaturated fatty acids in the neuronal cells. Edaravone, the newly approved antioxidant drug for ALS, halts the progression of ALS in the early stages through its cytoprotective effect and protects the nerves by reducing ROS. In this review, different aspects of ALS will be discussed, including its pathology, genetic aspect, and diagnosis. This review also focuses on edaravone as a treatment option for ALS, its mechanism of action, and its pharmacological properties. Clinical trials and adverse effects of edaravone and care for ALS patient are also discussed.}, }
@article {pmid33390543, year = {2021}, author = {Terada, T and Kulkarni, JA and Huynh, A and Tam, YYC and Cullis, P}, title = {Protective Effect of Edaravone against Cationic Lipid-Mediated Oxidative Stress and Apoptosis.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {44}, number = {1}, pages = {144-149}, doi = {10.1248/bpb.b20-00679}, pmid = {33390543}, issn = {1347-5215}, mesh = {Animals ; Apoptosis/*drug effects/physiology ; Cations ; Cell Survival/drug effects/physiology ; Dose-Response Relationship, Drug ; Edaravone/*pharmacology ; Free Radical Scavengers/*pharmacology ; Liposomes/*toxicity ; Mice ; Oxidative Stress/*drug effects/physiology ; RAW 264.7 Cells ; }, abstract = {Liposomes containing ionizable cationic lipids have been widely used for the delivery of nucleic acids such as small-interfering RNA and mRNA. The utility of cationic lipids with a permanent positive charge, however, is limited to in vitro transfection of cultured cells due to its dose-limiting toxic side effects observed in animals. Several reports have suggested that the permanently charged cationic lipids induce reactive oxygen species (ROS) and ROS-mediated toxicity in cells. We therefore hypothesized that the concomitant use of ROS inhibitor could reduce toxicity and improve drug efficacy. In this study, suppression of the cationic toxicity was evaluated using an ROS scavenger, edaravone, which is a low-molecular-weight antioxidant drug clinically approved for acute-phase cerebral infarction and amyotrophic lateral sclerosis. Cell viability assay in the mouse macrophage-like cell line RAW264 indicated that the concomitant use of edaravone were not able to suppress the cytotoxicity induced by cationic liposomes comprised of monovalent cationic lipid N-(1-[2,3-dioleyloxy]propyl)-N,N,N-trimethylammonium chloride (DOTMA) over a short period of time. Cationic lipids-induced necrosis was assumed to be involved in the cytotoxicity upon short-term exposure to cationic liposomes. On the other hand, the significant improvement of cell viability was observed when the short treatment with cationic liposomes was followed by exposure to edaravone for 24 h. It was also confirmed that apoptosis inhibition by ROS elimination might have contributed to this effect. These results suggest the utility of continuous administration with edaravone as concomitant drug for suppression of adverse reactions in therapeutic treatment using cationic liposomes.}, }
@article {pmid33389754, year = {2021}, author = {Moisse, M and Zwamborn, RAJ and van Vugt, J and van der Spek, R and van Rheenen, W and Kenna, B and Van Eijk, K and Kenna, K and Corcia, P and Couratier, P and Vourc'h, P and Hardiman, O and McLaughin, R and Gotkine, M and Drory, V and Ticozzi, N and Silani, V and de Carvalho, M and Mora Pardina, JS and Povedano, M and Andersen, PM and Weber, M and Başak, NA and Chen, X and Eberle, MA and Al-Chalabi, A and Shaw, C and Shaw, PJ and Morrison, KE and Landers, JE and Glass, JD and Robberecht, W and van Es, M and van den Berg, L and Veldink, J and Van Damme, P and , }, title = {The Effect of SMN Gene Dosage on ALS Risk and Disease Severity.}, journal = {Annals of neurology}, volume = {89}, number = {4}, pages = {686-697}, pmid = {33389754}, issn = {1531-8249}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; R56 NS073873/NS/NINDS NIH HHS/United States ; R01 NS073873/NS/NINDS NIH HHS/United States ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*pathology ; Case-Control Studies ; Cohort Studies ; Female ; Gene Dosage ; Humans ; Male ; Reproducibility of Results ; Risk Factors ; Severity of Illness Index ; Survival of Motor Neuron 1 Protein/*genetics ; Survival of Motor Neuron 2 Protein/genetics ; Whole Genome Sequencing ; }, abstract = {OBJECTIVE: The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency.<br><br>METHODS: In this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data.<br><br>RESULTS: The copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63).<br><br>INTERPRETATION: In our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies. ANN NEUROL 2021;89:686-697.}, }
@article {pmid33387887, year = {2021}, author = {Tanji, K and Mori, F and Shirai, F and Fukami, T and Seimiya, H and Utsumi, J and Kakita, A and Wakabayashi, K}, title = {Novel tankyrase inhibitors suppress TDP-43 aggregate formation.}, journal = {Biochemical and biophysical research communications}, volume = {537}, number = {}, pages = {85-92}, doi = {10.1016/j.bbrc.2020.12.037}, pmid = {33387887}, issn = {1090-2104}, mesh = {Arsenites/toxicity ; Cell Line, Tumor ; Cell Nucleus/drug effects/metabolism ; DNA-Binding Proteins/*metabolism ; Enzyme Inhibitors/*pharmacology ; HEK293 Cells ; Humans ; Poly Adenosine Diphosphate Ribose/toxicity ; *Protein Aggregates/drug effects ; TDP-43 Proteinopathies/pathology ; Tankyrases/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Transactive response DNA-binding protein of 43 kDa (TDP-43) abnormally forms aggregates in certain subtypes of frontotemporal lobar degeneration (FTLD) and in amyotrophic lateral sclerosis (ALS). The pathological forms of TDP-43 have reported to be associated with poly(ADP-ribose) (PAR), which regulates the properties of these aggregates. A recent study has indicated that tankyrase, a member of the PAR polymerase (PARP) family, regulates pathological TDP-43 formation under conditions of stress, and tankyrase inhibitors suppress TDP-43 aggregate formation and cytotoxicity. Since we reported the development of tankyrase inhibitors that are more specific than conventional inhibitors, in this study, we examined their effects on the formation of TDP-43 aggregates in cultured cells. Time-lapse imaging showed that TDP-43 aggregates appeared in the nucleus within 30 min of treatment with sodium arsenite. Several tankyrase inhibitors suppressed the formation of aggregates and decreased the levels of the tankyrase protein. Immunohistochemical studies demonstrated that tankyrase was localized to neuronal cytoplasmic inclusions in the spinal cords of patients with ALS. Moreover, the tankyrase protein levels were significantly higher in the brains of patients with FTLD than in the brains of control subjects. These findings suggest that the inhibition of tankyrase activity protects against TDP-43 toxicity. Tankyrase inhibitors may be a potential treatment to suppress the progression of TDP-43 proteinopathies.}, }
@article {pmid33387580, year = {2021}, author = {Thapa, K and Khan, H and Sharma, U and Grewal, AK and Singh, TG}, title = {Poly (ADP-ribose) polymerase-1 as a promising drug target for neurodegenerative diseases.}, journal = {Life sciences}, volume = {267}, number = {}, pages = {118975}, doi = {10.1016/j.lfs.2020.118975}, pmid = {33387580}, issn = {1879-0631}, mesh = {Animals ; Central Nervous System Diseases/drug therapy/metabolism ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/*enzymology/metabolism ; Poly (ADP-Ribose) Polymerase-1/antagonists &amp; inhibitors/genetics/*metabolism ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; }, abstract = {AIMS: Poly (ADP-ribose) polymerase- (PARP)-1 is predominantly triggered by DNA damage. Overexpression of PARP-1 is known for its association with the pathogenesis of several CNS disorders, such as Stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington (HD) and Amyotrophic lateral sclerosis (ALS). NAD+ depletion resulted PARP related cell death only happened when the trial used extreme high oxidization treatment. Inhibition of PARP1/2 may induce replication related cell death due to un-repaired DNA damage. This review has discussed PARP-1 modulated downstream pathways in neurodegeneration and various FDA approved PARP-1 inhibitors.<br><br>MATERIALS AND METHODS: A systematic literature review of PubMed, Medline, Bentham, Scopus and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on mechanistic role of Poly (ADP-ribose) polymerase and its inhibition in Neurodegenerative diseases.<br><br>KEY FINDINGS: Several researchers have put forward number of potential treatments, of which PARP-1 enzyme has been regarded as a potent target intended for the handling of neurodegenerative ailments. Targeting PARP using its chemical inhibitors in various neurodegenerative may have therapeutic outcomes by reducing neuronal death mediated by PARPi. Numerous PARP-1 inhibitors have been studied in neurodegenerative diseases but they haven't been clinically evaluated.<br><br>SIGNIFICANCE: In this review, the pathological role of PARP-1 in various neurodegenerative diseases has been discussed along with the therapeutic role of PARP-1 inhibitors in various neurodegenerative diseases.}, }
@article {pmid33387168, year = {2021}, author = {Naldini, G and Fabiani, B and Sturiale, A and Russo, E and Simoncini, T}, title = {Advantages of robotic surgery in the treatment of complex pelvic organs prolapse.}, journal = {Updates in surgery}, volume = {73}, number = {3}, pages = {1115-1124}, pmid = {33387168}, issn = {2038-3312}, mesh = {Female ; Humans ; *Laparoscopy ; *Pelvic Organ Prolapse/surgery ; Retrospective Studies ; *Robotic Surgical Procedures ; Surgical Mesh ; Treatment Outcome ; }, abstract = {Robot-assisted surgery is safe and effective to treat the complex pelvic organs prolapse (C-POP). The present study analyzes all the robotic procedures and their advantages in the treatment of C-POP performed in a Proctologic and Pelvic Floor Clinical Centre. All the patients affected by C-POP who had robot-assisted surgery were retrospective analyzed. The anatomical and functional outcomes were respectively evaluated through POP-Q grading system and Wexner score about constipation and incontinence. The satisfaction rate was investigated using a five-point scale. From September 2014 to December 2018, 229 women underwent robotic surgery. The follow-up was 12 months. There were no robot-related complications. One hematoma (4.5%) of the recto-vaginal space occurred after Robotic Ventral Rectopexy with Folded Mesh (R-VRP-FM). In the robotic assisted lateral suspension (R-ALS) group there was one case of anterior vaginal wall mesh exposure (0.9%). After the robotic ventral rectopexy (R-VRP) the recurrence rate of external rectal prolapse, internal rectal prolapse, rectocele and enterocele was respectively 6.6, 9.5, 7.4 and 9.5%. After R-VRP-FM only one cystocele (14%) and one partial rectal prolapse (25%) recurred. Vaginal bulge symptoms resolution rate was 95.4%. The mean Wexner constipation score significantly decreased after R-VRP and R-VRP-FM. Vaginal bulge symptoms improved in 98.3% of cases with any apical prolapse recurrence after robotic abdominal colposacropexy. Success rate after R-ALS was 99.1% and 96.4% for apical and anterior prolapse respectively. Robotic assistance makes some surgical steps easier and more precise and this may result in less morbidity and better results.}, }
@article {pmid33379128, year = {2021}, author = {Carabajal, M and Teglia, CM and Maine, MA and Goicoechea, HC}, title = {Multivariate optimization of a dispersive liquid-liquid microextraction method for the determination of six antiparasite drugs in kennel effluent waters by using second-order chromatographic data.}, journal = {Talanta}, volume = {224}, number = {}, pages = {121929}, doi = {10.1016/j.talanta.2020.121929}, pmid = {33379128}, issn = {1873-3573}, mesh = {Animals ; Chromatography, High Pressure Liquid ; Dogs ; *Liquid Phase Microextraction ; *Pharmaceutical Preparations ; Research Design ; Solvents ; }, abstract = {Six veterinary active ingredients (imidacloprid, albendazole, fenbendazole, praziquantel, fipronil and permethrin) were extracted and quantified by liquid chromatography with diode array detection in water samples from a wetland system used for the treatment of waste from a dog breeding plant. Response surface methodology, based on least-squares and artificial neural networks modelling, was applied for the optimization of a dispersive liquid-liquid microextraction (DLLME) procedure. Firstly, two experimental designs were built for screening and optimization, respectively. Then, the desirability function was implemented for the simultaneous optimization of the six recoveries (chromatographic areas of the six compounds). The optimum conditions were: 600 μL of acetone (dispersive solvent), 670 μL of dichloromethane (extractant solvent) and 0.6 min of vortex mixing. The preconcentration factor was 37.5. Then, in order to identify and quantify the six drugs, second-order calibration with MCR-ALS modeling of HPLC-DAD data was implemented attaining successful results. The limits of quantification were 4 ng mL[-1] for imidaclopril, albendazole and fenbendazole; 8 ng mL[-1] for praziquantel and fipronil; and 26 ng mL[-1] for permethrin. The developed method allowed the quantitation of the target analytes, even in the presence of unexpected compounds from dirty water samples. The following maximum levels of veterinary drugs were found (in ng mL[-1]): imidaclopril, 7; albendazole, 46; fenbendazole, 21; praziquantel, 29; fipronil, 29 and permethrin, 217.}, }
@article {pmid33375993, year = {2021}, author = {Taras, JS and Tadley, M and McCabe, L}, title = {Dorsal Coaptation for the Treatment of Digital Neuroma.}, journal = {The Journal of hand surgery}, volume = {46}, number = {6}, pages = {514.e1-514.e5}, doi = {10.1016/j.jhsa.2020.10.027}, pmid = {33375993}, issn = {1531-6564}, mesh = {Activities of Daily Living ; Animals ; *Axons ; Humans ; Nerve Regeneration ; *Neuroma/surgery ; Retrospective Studies ; }, abstract = {PURPOSE: The formation of a symptomatic neuroma after digital tip amputation presents a vexing problem. There is currently no procedure that completely and consistently prevents hypersensitive neuroma formation. This report presents the results of a technique designed to limit axon regeneration and mechanical irritation by neuroma excision, dorsal transposition, and coaptation with the corresponding digital nerve.<br><br>METHODS: A retrospective chart review was conducted to assess the effectiveness of neuroma excision with dorsal transposition and epineurial coaptation for postamputation symptomatic digital neuromas. Neuromas were excised using a midlateral fish-mouth incision. Digital nerves were mobilized to the dorsum of the digital tip and coapted using 9-0 nylon epineurial suture. The procedure was modified to salvage viable fingernails or to avoid excessive tension. Mass et&#xa0;al's criteria system was used to evaluate effectiveness.<br><br>RESULTS: Twenty-four patients with painful neuromas of the radial and ulnar digital nerves after traumatic amputation were included. Thirty-two digits underwent dorsal coaptation. This procedure was associated with a result considered good or excellent in 28 of 32 digits. Twenty-seven of 32 digits registered no pain or stump anesthesia after dorsal coaptation. Twenty-five of 32 digits demonstrated no interference with activities of daily living. Twenty-one of 24 patients returned to work.<br><br>CONCLUSIONS: Neuroma excision with dorsal transposition and epineurial coaptation is an effective treatment for postamputation symptomatic digital neuroma.<br><br>Therapeutic IV.}, }
@article {pmid33374302, year = {2020}, author = {Gyawali, A and Kang, YS}, title = {Pretreatment Effect of Inflammatory Stimuli and Characteristics of Tryptophan Transport on Brain Capillary Endothelial (TR-BBB) and Motor Neuron Like (NSC-34) Cell Lines.}, journal = {Biomedicines}, volume = {9}, number = {1}, pages = {}, pmid = {33374302}, issn = {2227-9059}, support = {2019R1F1A1044048//Young-Sook Kang/ ; }, abstract = {Tryptophan plays a key role in several neurological and psychiatric disorders. In this study, we investigated the transport mechanisms of tryptophan in brain capillary endothelial (TR-BBB) cell lines and motor neuron-like (NSC-34) cell lines. The uptake of [[3]H]l-tryptophan was stereospecific, and concentration- and sodium-dependent in TR-BBB cell lines. Transporter inhibitors and several neuroprotective drugs inhibited [[3]H]l-tryptophan uptake by TR-BBB cell lines. Gabapentin and baclofen exerted a competitive inhibitory effect on [[3]H]l-tryptophan uptake. Additionally, l-tryptophan uptake was time- and concentration-dependent in both NSC-34 wild type (WT) and mutant type (MT) cell lines, with a lower transporter affinity and higher capacity in MT than in WT cell lines. Gene knockdown of LAT1 (l-type amino acid transporter 1) and CAT1 (cationic amino acid transporter 1) demonstrated that LAT1 is primarily involved in the transport of [[3]H]l-tryptophan in both TR-BBB and NSC-34 cell lines. In addition, tryptophan uptake was increased by TR-BBB cell lines but decreased by NSC-34 cell lines after pro-inflammatory cytokine pre-treatment. However, treatment with neuroprotective drugs ameliorated tryptophan uptake by NSC-34 cell lines after inflammatory cytokines pretreatment. The tryptophan transport system may provide a therapeutic target for treating or preventing neurodegenerative diseases.}, }
@article {pmid33363116, year = {2020}, author = {Berto, S and Alladio, E}, title = {Application of Chemometrics Tools to the Study of the Fe(III)-Tannic Acid Interaction.}, journal = {Frontiers in chemistry}, volume = {8}, number = {}, pages = {614171}, pmid = {33363116}, issn = {2296-2646}, abstract = {Chemometric techniques were applied to the study of the interaction of iron(III) and tannic acid (TA). Modeling the interaction of Fe(III)-TA is a challenge, as can be the modeling of the metal complexation upon natural macromolecules without a well-defined molecular structure. The chemical formula for commercial TA is often given as C76H52O46, but in fact, it is a mixture of polygalloyl glucoses or polygalloyl quinic acid esters with the number of galloyl moieties per molecule ranging from 2 up to 12. Therefore, the data treatment cannot be based on just the stoichiometric approach. In this work, the redox behavior and the coordination capability of the TA toward Fe(III) were studied by UV-vis spectrophotometry and fluorescence spectroscopy. Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and Parallel Factor Analysis (PARAFAC) were used for the data treatment, respectively. The pH range in which there is the redox stability of the system Fe(III)-TA was evaluated. The binding capability of TA toward Fe(III), the spectral features of coordination compounds, and the concentration profiles of the species in solution as a function of pH were defined. Moreover, the stability of the interaction between TA and Fe(III) was interpreted through the chemical models usually employed to depict the interaction of metal cations with humic substances and quantified using the concentration profiles estimated by MCR-ALS.}, }
@article {pmid33359391, year = {2021}, author = {Sitruk-Ware, R and Bonsack, B and Brinton, R and Schumacher, M and Kumar, N and Lee, JY and Castelli, V and Corey, S and Coats, A and Sadanandan, N and Gonzales-Portillo, B and Heyck, M and Shear, A and Blaise, C and Zhang, H and Sheyner, M and García-Sánchez, J and Navarro, L and El-Etr, M and De Nicola, AF and Borlongan, CV}, title = {Progress in progestin-based therapies for neurological disorders.}, journal = {Neuroscience and biobehavioral reviews}, volume = {122}, number = {}, pages = {38-65}, doi = {10.1016/j.neubiorev.2020.12.007}, pmid = {33359391}, issn = {1873-7528}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; R01 NS102395/NS/NINDS NIH HHS/United States ; R21 NS109575/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Nervous System Diseases/drug therapy ; *Neuroprotective Agents/therapeutic use ; Progesterone ; *Progestins/therapeutic use ; Receptors, Progesterone ; Spinal Cord Injuries ; }, abstract = {Hormone therapy, primarily progesterone and progestins, for central nervous system (CNS) disorders represents an emerging field of regenerative medicine. Following a failed clinical trial of progesterone for traumatic brain injury treatment, attention has shifted to the progestin Nestorone for its ability to potently and selectively transactivate progesterone receptors at relatively low doses, resulting in robust neurogenetic, remyelinating, and anti-inflammatory effects. That CNS disorders, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury (SCI), and stroke, develop via demyelinating, cell death, and/or inflammatory pathological pathways advances Nestorone as an auspicious candidate for these disorders. Here, we assess the scientific and clinical progress over decades of research into progesterone, progestins, and Nestorone as neuroprotective agents in MS, ALS, SCI, and stroke. We also offer recommendations for optimizing timing, dosage, and route of the drug regimen, and identifying candidate patient populations, in advancing Nestorone to the clinic.}, }
@article {pmid33357560, year = {2021}, author = {Wang, J and Chen, J and Li, X and Cui, H}, title = {RNA-Seq transcriptome analysis to identify candidate genes involved in non-target site-based mesosulfuron-methyl resistance in Beckmannia syzigachne.}, journal = {Pesticide biochemistry and physiology}, volume = {171}, number = {}, pages = {104738}, doi = {10.1016/j.pestbp.2020.104738}, pmid = {33357560}, issn = {1095-9939}, mesh = {Herbicide Resistance/genetics ; *Herbicides/toxicity ; *RNA-Seq ; Sulfonylurea Compounds ; }, abstract = {American sloughgrass (Beckmannia syzigachne Steud.) has become a dominant weed in fields with rice-wheat rotation. Moreover, herbicide resistance has rendered weed control difficult. We identified a biotype showing resistance to ALS inhibitor mesosulfuron-methyl with a resistant index 3.3, but without any ALS mutation. This study aims to identify and confirm the factors associated with non-target site resistance of this biotype to mesosulfuron-methyl using RNA-Seq. 118,111 unigenes were assembled, and 50.9% of these were annotated across seven databases. Eleven contigs related to metabolic resistance were identified based on differential expression via RNA-Seq which include a novel resistance-related transcription factor (MYC3) and two disease resistance proteins were also identified (At1g58602 and At1g15890). Fold changes in expression of these genes in comparison M-R vs. M-S ranged from 3.9 to 11.6, as confirmed by qPCR. The expression of a contig annotated as cytochrome P450 (CYP86B1) in resistant individuals was over 3 times higher than that in sensitive individuals at 0-72 h after mesosulfuron-methyl treatment. A similar trend was noted for three other genes annotated as glutathione S-transferase (GST), namely GST-T3, GST-U6, and GST-U14; the expression of GST-U6 in resistant individuals was up to 142.3 times higher than that in sensitive individuals at 24 h after mesosulfuron-methyl treatment. In addition, GST activity in resistant individuals was 2.1 to 5.3 times higher than that in sensitive individuals. The GR50 of resistant biotype decreased from 24.4 to 11.3 g a.i. ha[-1] after P450 inhibitor malathion treatment. This study identified a cytochrome P450 gene CYP86B1 and three GST genes GST-T3, GST-U6, and GST-U14 that have higher expression in mesosulfuron-methyl resistant B. syzigachne, suggesting that both P450- and GST-based activities could be involved in resistance.}, }
@article {pmid33355881, year = {2021}, author = {Loewenbrück, KF and Werner, R and Günther, R and Dittrich, M and Klingenberger, R and Reichmann, H and Storch, A and Hermann, A}, title = {One nerve suffices: A clinically guided nerve ultrasound protocol for the differentiation of multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis (ALS).}, journal = {Journal of neurology}, volume = {268}, number = {4}, pages = {1495-1507}, pmid = {33355881}, issn = {1432-1459}, support = {03WKBH2F//Bundesministerium f&#xfc;r Bildung, Wissenschaft, Forschung und Technologie/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging ; Humans ; Neural Conduction ; *Polyneuropathies ; Prospective Studies ; Ultrasonography ; }, abstract = {OBJECTIVE: To investigate diagnostic accuracy of a nerve ultrasound (US) protocol that is individualized to a patient's clinical deficits for the differentiation of amyotrophic lateral sclerosis with predominant lower motoneuron disease (ALS/LMND) and multifocal motor neuropathy (MMN).<br><br>METHODS: Single-center, prospective, examiner-blinded, diagnostic study in two cohorts. Cohort I (model development): Convenience sample of subjects with ALS/LMND or MMN according to revised El-Escorial or EFNS guidelines. Cohort II (model validation): Consecutively recruited treatment-na&#xef;ve subjects with suspected diagnosis of ALS/LMND or MMN. Cutoffs for 28 different US values were determined by Receiver Operating Curve (ROC) in cohort I. Area Under The Curve (AUC) of US was compared to nerve conduction studies (NCS). Diagnostic accuracy of US protocols, individualized according to clinical deficits, was compared to former rigid non-individualized protocols and to random examination site selection in cohort II.<br><br>RESULTS: 48 patients were recruited. In cohort I (28 patients), US had higher ROC AUCs than NCS, US 0.82 (0.12)&#xa0;(mean (standard deviation)), NCS (compound muscle action potential (CMAP) 0.60 (0.09), p&#x2009;<&#x2009;.001; two-sided t-test). US models based on the nerve innervating the clinically most affected muscles had higher correct classification rates (CCRs, 93%) in cohort II than former rigid protocols (85% and 80%), or models with random measurement site selection (66% and 80%).<br><br>CONCLUSIONS: Clinically guided US protocols for differentiation of ALS/LMND from MMN increase diagnostic accuracy when compared to clinically unguided protocols. They also require less measurements sites to achieve this accuracy.}, }
@article {pmid33354770, year = {2021}, author = {Arenas, A and Kuang, L and Zhang, J and Kingren, MS and Zhu, H}, title = {FUS regulates autophagy by mediating the transcription of genes critical to the autophagosome formation.}, journal = {Journal of neurochemistry}, volume = {157}, number = {3}, pages = {752-763}, pmid = {33354770}, issn = {1471-4159}, support = {T32ES007266/ES/NIEHS NIH HHS/United States ; R01 NS077284/NS/NINDS NIH HHS/United States ; T32 ES007266/ES/NIEHS NIH HHS/United States ; I01 BX002149/BX/BLRD VA/United States ; R01 NS115507/NS/NINDS NIH HHS/United States ; R01NS077284/NS/NINDS NIH HHS/United States ; MDA352743//Muscular Dystrophy Association/ ; R01NS115507/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Autophagosomes/drug effects/*genetics/*physiology ; Autophagy/drug effects/*genetics/*physiology ; Autophagy-Related Proteins/genetics/physiology ; Cell Line ; Gene Expression Regulation ; Gene Knockout Techniques ; Macrolides/pharmacology ; Mice ; Proteasome Endopeptidase Complex ; RNA, Messenger/biosynthesis/genetics ; RNA-Binding Protein FUS/*genetics/*physiology ; Signal Transduction/genetics ; Sirolimus/pharmacology ; }, abstract = {Fused in sarcoma (FUS) is a ubiquitously expressed RNA/DNA-binding protein that plays different roles in the cell. FUS pathology has been reported in neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in FUS have also been linked to a subset of familial ALS. FUS is mainly localized in the nucleus although it shuttles between the nucleus and the cytoplasm. ALS-linked mutations cause the accumulation of the FUS protein in cytoplasm where it forms stress granule-like inclusions. The protein- and RNA-containing inclusions are reported to be positive of autophagosome markers and degraded by the autophagy pathway. However, the role of FUS in the autophagy pathway remains to be better understood. Using immunoblot and confocal imaging techniques in this study, we found that FUS knockout (KO) cells showed a decreased basal autophagy level. Rapamycin and bafilomycin A1 treatment showed that FUS KO cells were not able to initiate autophagy as efficiently as wild-type cells, suggesting that the autophagosome formation is affected in the absence of FUS. Moreover, using immunoblot and quantitative PCR techniques, we found that the mRNA and protein levels of the genes critical in the initial steps of the autophagy pathway (FIP200, ATG16L1 and ATG12) were significantly lower in FUS KO cells. Re-expressing FUS in the KO cells restored the expression of FIP200 and ATG16L1. Our findings demonstrate a novel role of FUS in the autophagy pathway, that is, regulating the transcription of genes involved in early stages of autophagy such as the initiation and elongation of autophagosomes.}, }
@article {pmid33352810, year = {2020}, author = {Carrascal, L and Gorton, E and Pardillo-Díaz, R and Perez-García, P and Gómez-Oliva, R and Castro, C and Nunez-Abades, P}, title = {Age-Dependent Vulnerability to Oxidative Stress of Postnatal Rat Pyramidal Motor Cortex Neurons.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {12}, pages = {}, pmid = {33352810}, issn = {2076-3921}, support = {RTI2018-099908-B-C21//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; FEDER-UCA18-106647//Consejer&#xed;a de Econom&#xed;a, Innovaci&#xf3;n, Ciencia y Empleo, Junta de Andaluc&#xed;a/ ; }, abstract = {Oxidative stress is one of the main proposed mechanisms involved in neuronal degeneration. To evaluate the consequences of oxidative stress on motor cortex pyramidal neurons during postnatal development, rats were classified into three groups: Newborn (P2-P7); infantile (P11-P15); and young adult (P20-P40). Oxidative stress was induced by 10 µM of cumene hydroperoxide (CH) application. In newborn rats, using the whole cell patch-clamp technique in brain slices, no significant modifications in membrane excitability were found. In infantile rats, the input resistance increased and rheobase decreased due to the blockage of GABAergic tonic conductance. Lipid peroxidation induced by CH resulted in a noticeable increase in protein-bound 4-hidroxynonenal in homogenates in only infantile and young adult rat slices. Interestingly, homogenates of newborn rat brain slices showed the highest capacity to respond to oxidative stress by dramatically increasing their glutathione and free thiol content. This increase correlated with a time-dependent increase in the glutathione reductase activity, suggesting a greater buffering capacity of newborn rats to resist oxidative stress. Furthermore, pre-treatment of the slices with glutathione monoethyl ester acted as a neuroprotector in pyramidal neurons of infantile rats. We conclude that during maturation, the vulnerability to oxidative stress in rat motor neurons increases with age.}, }
@article {pmid33339362, year = {2020}, author = {Forostyak, S and Forostyak, O and Kwok, JCF and Romanyuk, N and Rehorova, M and Kriska, J and Dayanithi, G and Raha-Chowdhury, R and Jendelova, P and Anderova, M and Fawcett, JW and Sykova, E}, title = {Transplantation of Neural Precursors Derived from Induced Pluripotent Cells Preserve Perineuronal Nets and Stimulate Neural Plasticity in ALS Rats.}, journal = {International journal of molecular sciences}, volume = {21}, number = {24}, pages = {}, pmid = {33339362}, issn = {1422-0067}, support = {MR/R004463/1/MRC_/Medical Research Council/United Kingdom ; MR/R004544/1/MRC_/Medical Research Council/United Kingdom ; CZ.02.1.01/0.0/0.0/15_003/0000419//Ministry of Education, Youth and Sports of the Czech Republic/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Apoptosis Regulatory Proteins/genetics/metabolism ; Cells, Cultured ; Humans ; Induced Pluripotent Stem Cells/cytology ; Male ; Nerve Growth Factors/genetics/metabolism ; Nerve Regeneration ; Neural Stem Cells/cytology/metabolism/*transplantation ; *Neuronal Plasticity ; Peripheral Nerves/physiology ; Rats ; Rats, Sprague-Dawley ; Stem Cell Transplantation/*methods ; Tenascin/genetics/metabolism ; Versicans/genetics/metabolism ; }, abstract = {A promising therapeutic strategy for amyotrophic lateral sclerosis (ALS) treatment is stem cell therapy. Neural progenitors derived from induced pluripotent cells (NP-iPS) might rescue or replace dying motoneurons (MNs). However, the mechanisms responsible for the beneficial effect are not fully understood. The aim here was to investigate the mechanism by studying the effect of intraspinally injected NP-iPS into asymptomatic and early symptomatic superoxide dismutase (SOD)1[G93A] transgenic rats. Prior to transplantation, NP-iPS were characterized in vitro for their ability to differentiate into a neuronal phenotype. Motor functions were tested in all animals, and the tissue was analyzed by immunohistochemistry, qPCR, and Western blot. NP-iPS transplantation significantly preserved MNs, slowed disease progression, and extended the survival of all treated animals. The dysregulation of spinal chondroitin sulfate proteoglycans was observed in SOD1[G93A] rats at the terminal stage. NP-iPS application led to normalized host genes expression (versican, has-1, tenascin-R, ngf, igf-1, bdnf, bax, bcl-2, and casp-3) and the protection of perineuronal nets around the preserved MNs. In the host spinal cord, transplanted cells remained as progenitors, many in contact with MNs, but they did not differentiate. The findings suggest that NP-iPS demonstrate neuroprotective properties by regulating local gene expression and regulate plasticity by modulating the central nervous system (CNS) extracellular matrix such as perineuronal nets (PNNs).}, }
@article {pmid33335227, year = {2020}, author = {Ito, T and Inden, M and Ueda, T and Asaka, Y and Kurita, H and Hozumi, I}, title = {The neuroprotective effects of activated α7 nicotinic acetylcholine receptor against mutant copper-zinc superoxide dismutase 1-mediated toxicity.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {22157}, pmid = {33335227}, issn = {2045-2322}, mesh = {AMP-Activated Protein Kinases/metabolism ; Autophagy ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Calcium/metabolism ; Humans ; Intracellular Space ; Lysosomes/metabolism ; Mutation ; Neurodegenerative Diseases/etiology/metabolism/pathology ; Neurons/*metabolism ; Neuroprotective Agents ; Protein Aggregates ; Protein Binding ; Protein Transport ; Signal Transduction ; Superoxide Dismutase-1/genetics/*metabolism ; TOR Serine-Threonine Kinases/metabolism ; alpha7 Nicotinic Acetylcholine Receptor/agonists/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective and progressive loss of motor neurons. Although many drugs have entered clinical trials, few have shown effectiveness in the treatment of ALS. Other studies have shown that the stimulation of α7 nicotinic acetylcholine receptor (nAChR) can have neuroprotective effects in some models of neurodegenerative disease, as well as prevent glutamate-induced motor neuronal death. However, the effect of α7 nAChR agonists on ALS-associated mutant copper-zinc superoxide dismutase 1 (SOD1) aggregates in motor neurons remains unclear. In the present study, we examined whether α7 nAChR activation had a neuroprotective effect against SOD1[G85R]-induced toxicity in a cellular model for ALS. We found that α7 nAChR activation by PNU282987, a selective agonist of α7 nAChR, exhibited significant neuroprotective effects against SOD1[G85R]-induced toxicity via the reduction of intracellular protein aggregates. This reduction also correlated with the activation of autophagy through the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling pathway. Furthermore, the activation of α7 nAChRs was found to increase the biogenesis of lysosomes by inducing translocation of the transcription factor EB (TFEB) into the nucleus. These results support the therapeutic potential of α7 nAChR activation in diseases that are characterized by SOD1[G85R] aggregates, such as ALS.}, }
@article {pmid33332713, year = {2021}, author = {Sen, MK and Hamouzová, K and Mikulka, J and Bharati, R and Košnarová, P and Hamouz, P and Roy, A and Soukup, J}, title = {Enhanced metabolism and target gene overexpression confer resistance against acetolactate synthase-inhibiting herbicides in Bromus sterilis.}, journal = {Pest management science}, volume = {77}, number = {4}, pages = {2122-2128}, doi = {10.1002/ps.6241}, pmid = {33332713}, issn = {1526-4998}, support = {QK1820081//N&#xe1;rodn&#xed; Agentura pro Zem&#x11b;d&#x11b;lsk&#xfd; V&#xfd;zkum/ ; CZ.02.1.01/0.0/0.0/15_003/0000433//OP RDE/ ; //Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences Prague/ ; //Faculty of Forestry and Wood Sciences, Czech University of Life Sciences Prague/ ; //Colorado State University/ ; }, mesh = {*Acetolactate Synthase/genetics ; Bromus ; DNA Copy Number Variations ; Europe ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Plant Proteins/genetics ; }, abstract = {BACKGROUND: Intensive application of acetolactate synthase (ALS)-inhibiting herbicides has resulted in herbicide-resistance in many weeds, including Bromus sterilis. The present study was conducted to identify the mechanisms conferring resistance to ALS-inhibiting herbicides in a Bromus sterilis biotype.<br><br>RESULTS: Dose-response studies revealed the resistant biotype to be 288 times less sensitive to pyroxsulam than the susceptible biotype. Furthermore, experiment with a single-dose, proved this biotype was also cross-resistant to propoxycarbazone, iodosulfuron plus mesosulfuron and sulfosulfuron. Prior treatment with malathion, a known inhibitor of cytochrome P450s, reduced the level of resistance to pyroxsulam. No mutations were detected from the partial ALS gene sequencing. Flow cytometry and chromosome counting rejected ploidy level variation between the susceptible and resistant biotypes. Relative copy number variation ruled out gene amplification. Quantitative real-time polymerase chain reaction (PCR) detected a significant difference in ALS gene expression between the susceptible and resistant biotypes.<br><br>CONCLUSIONS: Target gene overexpression and enhanced metabolism by cytochrome P450s are likely mechanisms of resistance to pyroxsulam in Bromus sterilis. The current findings highlight the need to monitor additional brome populations for herbicide resistance in Europe and endorse the need for alternate herbicides in integrated weed management to delay the possible evolution of herbicide resistance in these species. &#xa9; 2020 Society of Chemical Industry.}, }
@article {pmid33329336, year = {2020}, author = {Bertran Recasens, B and Rubio, MA}, title = {Neuromuscular Diseases Care in the Era of COVID-19.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {588929}, pmid = {33329336}, issn = {1664-2295}, abstract = {The COVID-19 pandemic has pushed health systems to their limit and forced readjustment of standards of care for different pathologies. Management of neuromuscular diseases becomes a challenge since most of them are chronic, disabling, progressive, and/or require immunosuppressive drugs. There are three main aspects of COVID-19 that affect neuromuscular diseases care. The first one relates to how SARS-CoV2 directly affects different neuromuscular pathologies. Respiratory weakness, as seen in myasthenia gravis, amyotrophic lateral sclerosis, and myopathies, and the use of immunomodulatory drugs (Myasthenia Gravis and Chronic Inflammatory Demyelinating Polyneuropathy) make this group of patients potentially more vulnerable. Secondly, safety measures also affect proper care, limiting care continuity, and physical rehabilitation (one of the essential aspects of myopathies treatment). Telemedicine can partially solve the problem allowing for a continuum of close care, avoiding unnecessary visits, and even guaranteeing the attention of professionals from tertiary care centers. However, one of the crucial steps in neuromuscular diseases is diagnosis, and in most scenarios, more than one face-to-face visit is needed. Lastly, the global COVID-19 situation will also have an economic impact on patients and their families. This situation is of particular concern given that neuromuscular diseases already present difficulties due to the scarcity of resources in terms of public healthcare and research.}, }
@article {pmid33326235, year = {2021}, author = {Bakavayev, S and Argueti, S and Venkatachalam, N and Yehezkel, G and Stavsky, A and Barak, Z and Israelson, A and Engel, S}, title = {Exposure of β6/β7-Loop in Zn/Cu Superoxide Dismutase (SOD1) Is Coupled to Metal Loss and Is Transiently Reversible During Misfolding.}, journal = {ACS chemical neuroscience}, volume = {12}, number = {1}, pages = {49-62}, doi = {10.1021/acschemneuro.0c00524}, pmid = {33326235}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Mutation ; *Neurodegenerative Diseases ; Protein Folding ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Zinc ; }, abstract = {Upon losing its structural integrity (misfolding), SOD1 acquires neurotoxic properties to become a pathogenic protein in ALS, a neurodegenerative disease targeting motor neurons; understanding the mechanism of misfolding may enable new treatment strategies for ALS. Here, we reported a monoclonal antibody, SE21, targeting the β6/β7-loop region of SOD1. The exposure of this region is coupled to metal loss and is entirely reversible during the early stages of misfolding. By using SE21 mAb, we demonstrated that, in apo-SOD1 incubated under the misfolding-promoting conditions, the reversible phase, during which SOD1 is capable of restoring its nativelike conformation in the presence of metals, is followed by an irreversible structural transition, autocatalytic in nature, which takes place prior to the onset of SOD1 aggregation and results in the formation of atypical apo-SOD1 that is unable to bind metals. The reversible phase defines a window of opportunity for pharmacological intervention using metal mimetics that stabilize SOD1 structure in its nativelike conformation to attenuate the spreading of the misfolding signal and disease progression by preventing the exposure of pathogenic SOD1 epitopes. Phenotypically similar apo-SOD1 species with impaired metal binding properties may also be produced via oxidation of Cys[111], underscoring the diversity of SOD1 misfolding pathways.}, }
@article {pmid33324192, year = {2020}, author = {Belbin, O and Lehmann, S and Sabidó, E and Hirtz, C}, title = {Editorial: Proteomics as a Tool for Biomarker and Drug Target Discovery: Improving the Diagnosis and Treatment of Neurodegenerative Diseases.}, journal = {Frontiers in aging neuroscience}, volume = {12}, number = {}, pages = {232}, pmid = {33324192}, issn = {1663-4365}, }
@article {pmid33314663, year = {2021}, author = {Yue, D and Cai, X and Fan, M and Zhu, J and Tian, J and Wu, L and Jiang, Q and Gu, Z}, title = {An Alternating Irradiation Strategy-Driven Combination Therapy of PDT and RNAi for Highly Efficient Inhibition of Tumor Growth and Metastasis.}, journal = {Advanced healthcare materials}, volume = {10}, number = {8}, pages = {e2001850}, doi = {10.1002/adhm.202001850}, pmid = {33314663}, issn = {2192-2659}, mesh = {Animals ; Cell Line, Tumor ; HeLa Cells ; Humans ; Mice ; Mice, Nude ; *Photochemotherapy ; Photosensitizing Agents ; RNA Interference ; RNA, Small Interfering ; Vascular Endothelial Growth Factor A/genetics ; }, abstract = {Hypoxia and hypoxia induced overexpression of vascular endothelial growth factor (VEGF) not only seriously affects the treatment effects of photodynamic therapy (PDT) but also promotes tumor metastasis. Herein, an alternating irradiation strategy (referred to as alternate use of low/high dose of light [ALHDL] irradiation)-driven combination therapy of PDT and RNA interference (RNAi) is developed to synergistically inhibit tumor growth and metastasis. A cationic amphipathic peptide (ALS) served as a carrier in the co-delivery system of photochlor (HPPH) and siVEGF (ALSH/siVEGF). At the beginning of ALHDL-driven ALSH/siVEGF treatment, short-term LDL irradiation can facilitate the tumor penetration, cellular uptake, and endosome escape of ALSH/siVEGF. Moreover, accompanied by HDL-mediated rapid cell apoptosis and LDL-mediated efficient VEGF silencing, the joint use of PDT and RNAi achieved remarkable antitumor effects both in vitro and in vivo. Importantly, benefited from the excellent performance of ALHDL in slowing the rapid deterioration of the anoxic environment of tumors, and ALSH/siVEGF treatment-mediated highly improved VEGF silencing efficacy and inhibitory effect on angiogenesis, the liver and lung metastases of HeLa cells have been successfully suppressed. Together, this study clearly indicates that ALHDL-driven combination therapy of PDT and RNAi is a highly effective modality for inhibition of tumor growth and metastasis.}, }
@article {pmid33312375, year = {2020}, author = {Zhang, Y and Fan, D and Liu, X and Liu, X and He, J and Zhang, N and Tang, L}, title = {hTBK1-c.978T&gt;A mutation promotes the ferroptosis in NSC-34 cells via mediation of KEAP1/NRF2/p62 signaling.}, journal = {American journal of translational research}, volume = {12}, number = {11}, pages = {7386-7394}, pmid = {33312375}, issn = {1943-8141}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) can result in the dysfunction of upper and lower motor neurons. A previous study has indicated that TBK1 mutation (hTBK1-c.978T>A) is involved in progression of ALS. However, the mechanism by which TBK1 mutation mediates the progression of ALS remains unclear.<br><br>METHODS: NSC-34 cells with hTBK1-c.978T>A mutation (TBK1 mutation status) was used to mimic ALS in vitro. In addition, cell proliferation was detected by Ki67 staining. Gene and protein expressions in NSC-34 cells were detected by RT-qPCR and western blot, respectively. ROS and PGSK levels in NSC-34 cells were detected by flow cytometry.<br><br>RESULTS: hTBK1-c.978T>A mutation significantly inhibited the proliferation of NSC-34 cells via inducing cell ferroptosis, while the effect of TBK1 mutation was notably reversed by Ferrostatin-1 or p62 siRNA. Meanwhile, hTBK1-c.978T>A mutation significantly increased the expression of KEAP1 in NSC-34 cells, while this phenomenon was partially reversed by p62 knockdown.<br><br>CONCLUSION: hTBK1-c.978T>A mutation promoted promotes the ferroptosis in NSC-34 cells via regulation of KEAP1/NRF2/p62 signaling. Thus, hTBK1-c.978T>A mutation may serve as a possible target for the treatment of ALS.}, }
@article {pmid33305472, year = {2020}, author = {Kazama, M and Kato, Y and Kakita, A and Noguchi, N and Urano, Y and Masui, K and Niida-Kawaguchi, M and Yamamoto, T and Watabe, K and Kitagawa, K and Shibata, N}, title = {Astrocytes release glutamate via cystine/glutamate antiporter upregulated in response to increased oxidative stress related to sporadic amyotrophic lateral sclerosis.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {40}, number = {6}, pages = {587-598}, doi = {10.1111/neup.12716}, pmid = {33305472}, issn = {1440-1789}, mesh = {Amino Acid Transport System y+/*metabolism ; Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Astrocytes/*metabolism ; Glutamic Acid/*metabolism ; Humans ; Mice ; Oxidative Stress/*physiology ; Spinal Cord/metabolism/pathology ; Up-Regulation ; }, abstract = {A vast body of evidence implicates increased oxidative stress and extracellular glutamate accumulation in the pathomechanism of sporadic amyotrophic lateral sclerosis (ALS). Cystine/glutamate antiporter (xCT) carries extracellular cystine uptake and intracellular glutamate release (cystine/glutamate exchange) in the presence of oxidative stress. The aim of the present study was to determine the involvement of xCT in ALS. Immunohistochemical observations in the spinal cord sections demonstrated that xCT was mainly expressed in astrocytes, with staining more intense in 12 sporadic ALS patients as compared to 12 age-matched control individuals. Western blot and densitometric analyses of the spinal cord samples revealed that the relative value of xCT/β-actin optical density ratio was significantly higher in the ALS group as compared to the control group. Next, we conducted cell culture experiments using a human astrocytoma-derived cell line (1321N1) and a mouse motor neuron/neuroblastoma hybrid cell line (NSC34). In 1321N1 cells, the normalized xCT expression levels in cell lysates were significantly increased by H2 O2 treatment. Glutamate concentrations in 1321 N1 cell culture-conditioned media were significantly elevated by H2 O2 treatment, and the H2 O2 -driven elevations were completely canceled by the xCT inhibitor erastin pretreatment. In motor neuron-differentiated NSC34 cells (NSC34d cells), both the normalized xCT expression levels in the cell lysates and glutamate concentrations in the cell-conditioned media were constant with or without H2 O2 treatment. The present results provide in vivo and in vitro evidence that astrocytes upregulate xCT expression to release glutamate in response to increased oxidative stress associated with ALS, contributing to extracellular glutamate accumulation.}, }
@article {pmid33305361, year = {2021}, author = {Essén, B and Mosselmans, L}, title = {How to ensure policies and interventions rely on strong supporting facts to improve women's health: The case of female genital cutting, using Rosling's Factfulness approach.}, journal = {Acta obstetricia et gynecologica Scandinavica}, volume = {100}, number = {4}, pages = {579-586}, pmid = {33305361}, issn = {1600-0412}, mesh = {Circumcision, Female/*ethnology ; Developing Countries ; Female ; *Global Health ; *Health Policy ; Humans ; *Women's Health ; }, abstract = {Rosling et al's book Factfulness aims to inspire people to use strong supporting facts in their decision-making, with 10 rules of thumb to fight dramatic instincts. In this paper, the Factfulness framework is applied to female genital cutting (FGC), in order to identify possible biases and promote evidence-based thinking in studies on FGC, clinical guidelines on management of FGC, and interventions aimed at abolishing FGC. The Factfulness framework helps to acknowledge that FGC is not a uniform practice and helps address that variability. This framework also highlights the importance of multidisciplinarity to understand causalities of the FGC issue, which the authors argue is essential. This paper highlights the fact that FGC is a dynamic practice, with changes in the practice that are ongoing, and that those changes are different in different contexts. The "zero tolerance" discourses on FGC fail to acknowledge this. Factfulness encourages us to be more critical of methodologies used in the area of FGC, for example when estimating girls at risk of FGC in migration contexts. Factfulness provides the tools to calculate risks rather than judgments based on fear. This may help limit stigmatization of women with FGC and to allocate resources to health problems of migrant women based on real risks. The framework also calls for more research and production of less biased facts in the field of FGC, in order to improve interventions aimed at abolishing FGC, and clinical guidelines for the treatment of FGC. Factfulness is a useful and structured foundation for reflection over constructs, biases and disputes surrounding FGC, and can help improve the quality of future evidence-based interventions and education that address the actual needs of women with FGC and girls at risk of FGC.}, }
@article {pmid33302404, year = {2020}, author = {Török, N and Tanaka, M and Vécsei, L}, title = {Searching for Peripheral Biomarkers in Neurodegenerative Diseases: The Tryptophan-Kynurenine Metabolic Pathway.}, journal = {International journal of molecular sciences}, volume = {21}, number = {24}, pages = {}, pmid = {33302404}, issn = {1422-0067}, support = {2.3.2-15-2016-00034//GINOP/ ; 2.3.2-15-2016-00048 (Stay Alive)//GINOP/ ; 2020//T&#xe9;mater&#xfc;leti Kiv&#xe1;l&#xf3;s&#xe1;gi Program/ ; 2020//TKP2020 Thematic Excellence Programme/ ; Grant number 5070//University of Szeged Open Access Fund (FundRef)/ ; }, mesh = {Animals ; Biomarkers/metabolism ; Brain/metabolism ; Gastrointestinal Microbiome ; Humans ; Kynurenine/*metabolism ; Neurodegenerative Diseases/*metabolism/microbiology/pathology ; Tryptophan/*metabolism ; }, abstract = {Neurodegenerative diseases are multifactorial, initiated by a series of the causative complex which develops into a certain clinical picture. The pathogenesis and disease course vary from patient to patient. Thus, it should be likewise to the treatment. Peripheral biomarkers are to play a central role for tailoring a personalized therapeutic plan for patients who suffered from neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, among others. Nevertheless, the use of biomarkers in clinical practice is still underappreciated and data presented in biomarker research for clinical use is still uncompelling, compared to the abundant data available for drug research and development. So is the case with kynurenines (KYNs) and the kynurenine pathway (KP) enzymes, which have been associated with a wide range of diseases including cancer, autoimmune diseases, inflammatory diseases, neurologic diseases, and psychiatric disorders. This review article discusses current knowledge of KP alterations observed in the central nervous system as well as the periphery, its involvement in pathogenesis and disease progression, and emerging evidence of roles of microbiota in the gut-brain axis, searching for practical peripheral biomarkers which ensure personalized treatment plans for neurodegenerative diseases.}, }
@article {pmid33301428, year = {2020}, author = {Siwek, T and Jezierska-Woźniak, K and Maksymowicz, S and Barczewska, M and Sowa, M and Badowska, W and Maksymowicz, W}, title = {Repeat Administration of Bone Marrow-Derived Mesenchymal Stem Cells for Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {26}, number = {}, pages = {e927484}, pmid = {33301428}, issn = {1643-3750}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Disease Progression ; Female ; Humans ; Male ; *Mesenchymal Stem Cell Transplantation/adverse effects ; Mesenchymal Stem Cells/*cytology ; Middle Aged ; Treatment Outcome ; }, abstract = {BACKGROUND The aim of this study was to investigate repeated intrathecal injection of autologous bone marrow-derived mesenchymal stem cells (BM-D MSCs) to patients for treatment of sporadic amyotrophic lateral sclerosis (ALS). MATERIAL AND METHODS Autologous MSCs were isolated from the patients' bone marrow, plated, expanded, harvested, and passaged. Stem cells from a single bone marrow collection were used for 3 injections per patient, given over a 3-month period. Outcomes were measured with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Participants were observed for a minimum of 6 months before transplantation to assess the natural course of ALS and for the same amount of time after transplantation to compare the rate of disease progression, estimated based on average monthly changes in ALSFRS-R scores. Data from 8 of the 15 participants eligible for the study were analyzed. RESULTS The safety of the MSC injections was confirmed and various effects of the therapy were documented. In patients who had ALS with an inherently slow course, there were no significant changes in the rate of disease progression. In patients who had ALS with an inherently rapid course, slowing of the disease was noted following treatment with MSCs. However, because that subgroup was so small, it was not possible to assess whether the changes were statistically significant. CONCLUSIONS Identifying groups of patients who are not responding or potentially responding negatively to injection of MSCs may help prevent it from being offered to individuals who may not benefit from the therapy. One of the limitations of this treatment method is the amount of time required for long-lasting preparation of bone marrow-derived MSCs for a disease that is rapidly progressive. Therefore, it is worth looking for other allogeneic sources of stromal cells for these types of injections.}, }
@article {pmid33299526, year = {2020}, author = {Silva, JM and Nobre, MSC and Albino, SL and Lócio, LL and Nascimento, APS and Scotti, L and Scotti, MT and Oshiro-Junior, JA and Lima, MCA and Mendonça-Junior, FJB and Moura, RO}, title = {Secondary Metabolites with Antioxidant Activities for the Putative Treatment of Amyotrophic Lateral Sclerosis (ALS): "Experimental Evidences".}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {5642029}, pmid = {33299526}, issn = {1942-0994}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism ; Animals ; Antioxidants/*metabolism ; Disease Models, Animal ; Humans ; Motor Neurons/metabolism/*pathology ; Oxidative Stress/*physiology ; Secondary Metabolism/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder that is characterized by progressive loss of the upper and lower motor neurons at the spinal or bulbar level. Oxidative stress (OS) associated with mitochondrial dysfunction and the deterioration of the electron transport chain are factors that contribute to neurodegeneration and perform a potential role in the pathogenesis of ALS. Natural antioxidant molecules have been proposed as an alternative form of treatment for the prevention of age-related neurological diseases, in which ALS is included. Researches support that regulations in cellular reduction/oxidation (redox) processes are being increasingly implicated in this disease, and antioxidant drugs are aimed at a promising pathway to treatment. Among the strategies used for obtaining new drugs, we can highlight the isolation of secondary metabolite compounds from natural sources that, along with semisynthetic derivatives, correspond to approximately 40% of the drugs found on the market. Among these compounds, we emphasize oxygenated and nitrogenous compounds, such as flavonoids, coumarins, and alkaloids, in addition to the fatty acids, that already stand out in the literature for their antioxidant properties, consisting in a part of the diets of millions of people worldwide. Therefore, this review is aimed at presenting and summarizing the main articles published within the last years, which represent the therapeutic potential of antioxidant compounds of natural origin for the treatment of ALS.}, }
@article {pmid33285734, year = {2020}, author = {Liang, S and Zhang, G and Li, J and Zhong, L and Zhang, C}, title = {Wrist ankle acupuncture in the treatment of acute lumbar sprain: A protocol for systematic review and meta-analysis.}, journal = {Medicine}, volume = {99}, number = {49}, pages = {e23420}, pmid = {33285734}, issn = {1536-5964}, mesh = {Acupuncture Therapy/*methods ; *Ankle ; Humans ; Lumbosacral Region/*injuries ; Pain Measurement ; Quality of Life ; Randomized Controlled Trials as Topic ; Research Design ; Sprains and Strains/*therapy ; *Wrist ; Meta-Analysis as Topic ; Systematic Review as Topic ; }, abstract = {BACKGROUND: Acute lumbar sprain (ALS) frequently occurs in the young and middle-aged people, causing great harm to people's quality of life. The systematic review program was designed to describe a meta-analysis to evaluate the efficacy and safety of wrist-ankle acupuncture (WAA) in treating patients with ALS.<br><br>METHODS AND ANALYSIS: Our systematic review will search electronically and manually for WAA treatments for ALS by August, 2020, regardless of publication status and language. Databases include: MEDLINE, PubMed, EMBASE, Springer, Web of Science, Cochrane Library, WHO International Clinical Trial Registration Platform (ICTRP), Chinese Medicine Database (TCMD), China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), China Science Journal Database (VIP), and Wanfang Database. Other sources of information, including bibliographies and meeting minutes for identified publications, will also be searched. Manually search for grey literature, including unpublished conference articles. Any clinical randomized controlled trials related to WAA treatments for ALS, regardless of publication status and language limitations, will be included in the study. Study selection, data extraction, and research quality assessment will be done independently by 2 researchers. The primary outcome included the effective rate and visual analogue scale (VAS) or other validated scales used to relieve pain after the treatment. If possible, meta-analysis will be performed using RevMan V.5.3 statistical software. If it is not suitable for meta-analysis, a descriptive analysis or subgroup analysis is performed.<br><br>RESULTS: This study will provide a comprehensive review and evaluation of the available evidence for the treatment of ALS using WAA.<br><br>CONCLUSION: This study will provide new evidence to evaluate the effectiveness and side effects of WAA on ALS. Because the data is not personalized, no formal ethical approval is required.<br><br>REGISTRATION NUMBER: PROSPERO CRD42020162945.}, }
@article {pmid33282484, year = {2020}, author = {Zhang, W and Rhodes, JS and Moon, KR and Knudsen, BS and Nokolova, L and Zhou, A}, title = {Imaging of PD-L1 in single cancer cells by SERS-based hyperspectral analysis.}, journal = {Biomedical optics express}, volume = {11}, number = {11}, pages = {6197-6210}, pmid = {33282484}, issn = {2156-7085}, abstract = {We developed a hyperspectral imaging tool based on surface-enhanced Raman spectroscopy (SERS) probes to determine the expression level and visualize the distribution of PD-L1 in individual cells. Electron-microscopic analysis of PD-L1 antibody - gold nanorod conjugates demonstrated binding the cell surface and internalization into endosomal vesicles. Stimulation of cells with IFN-γ or metformin was used to confirm the ability of SERS probes to report treatment-induced changes. The multivariate curve resolution-alternating least squares (MCR-ALS) analysis of spectra provided a greater signal-noise ratio than single peak mapping. However, single peak mapping allowed a systematic subtraction of background and the removal of non-specific binding and endocytic SERS signals. The mean or maximum peak height in the cell or the mean peak height in the area of specific PD-L1 positive pixels was used to estimate the PD-L1 expression levels in single cells. The PD-L1 levels were significantly up-regulated by IFN-γ and inhibited by metformin in human lung cancer cells from the A549 cell line. In conclusion, the method of analyzing hyperspectral SERS imaging data together with systematic and comprehensive removal of non-specific signals allows SERS imaging to be a quantitative tool in the detection of the cancer biomarker, PD-L1.}, }
@article {pmid33280374, year = {2020}, author = {Yeong, KY and Berdigaliyev, N and Chang, Y}, title = {Sirtuins and Their Implications in Neurodegenerative Diseases from a Drug Discovery Perspective.}, journal = {ACS chemical neuroscience}, volume = {11}, number = {24}, pages = {4073-4091}, doi = {10.1021/acschemneuro.0c00696}, pmid = {33280374}, issn = {1948-7193}, mesh = {*Alzheimer Disease/drug therapy ; Drug Discovery ; Humans ; *Neurodegenerative Diseases/drug therapy ; *Parkinson Disease ; *Sirtuins ; }, abstract = {Sirtuins are class III histone deacetylase (HDAC) enzymes that target both histone and non-histone substrates. They are linked to different brain functions and the regulation of different isoforms of these enzymes is touted to be an emerging therapy for the treatment of neurodegenerative diseases (NDs), including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). The level of sirtuins affects brain health as many sirtuin-regulated pathways are responsible for the progression of NDs. Certain sirtuins are also implicated in aging, which is a risk factor for many NDs. In addition to SIRT1-3, it has been suggested that the less studied sirtuins (SIRT4-7) also play critical roles in brain health. This review delineates the role of each sirtuin isoform in NDs from a disease centric perspective and provides an up-to-date overview of sirtuin modulators and their potential use as therapeutics in these diseases. Furthermore, the future perspectives for sirtuin modulator development and their therapeutic application in neurodegeneration are outlined in detail, hence providing a research direction for future studies.}, }
@article {pmid33272325, year = {2020}, author = {Young, FG and Nguyen, D}, title = {Treatment of pseudobulbar affect (PBA) in a patient with a history of traumatic brain injury, partial brain resection, and brainstem stroke: a case report.}, journal = {Journal of medical case reports}, volume = {14}, number = {1}, pages = {235}, pmid = {33272325}, issn = {1752-1947}, mesh = {Brain ; *Brain Injuries, Traumatic ; *Brain Stem Infarctions ; Dextromethorphan/therapeutic use ; Humans ; Male ; Middle Aged ; Quinidine/therapeutic use ; }, abstract = {BACKGROUND: Pseudobulbar affect is a very distressing and underdiagnosed neuropsychiatric disorder that causes contextually inappropriate episodes of laughing and crying and general emotional incontinence. Although many proposed etiologies exist, the most widely accepted theory espouses the disruption of a corticopontine-cerebellar circuit that governs the modulation of emotional response. Pseudobulbar affect is commonly diagnosed secondary to primary neurological disorders such as amyotrophic lateral sclerosis, multiple sclerosis, and traumatic brain injury. Traditional pharmacological treatment of pseudobulbar affect is largely comprised of antidepressant therapy, including tricyclic antidepressants such as amitriptyline and selective serotonin reuptake inhibitors such as fluvoxamine. However, neither of these medication classes has been studied for the treatment of pseudobulbar affect in controlled trials, and their utility remains questionable.<br><br>CASE PRESENTATION: We describe a case of a 62-year-old Caucasian man with history of traumatic brain injury, ischemic brainstem stroke, and depression who developed intractable pseudobulbar affect. This patient's intensely distressing symptoms were not alleviated by amitriptyline. However, after being placed on fixed-dose 20&#x2009;mg/10&#x2009;mg dextromethorphan/quinidine (Nuedexta), our patient experienced complete resolution of his symptoms. He has experienced no deleterious side effects.<br><br>CONCLUSIONS: This case provides anecdotal evidence for the efficacy of dextromethorphan/quinidine in the treatment of pseudobulbar affect with remarkably swift and complete cessation of symptoms. As a secondary point, it is worth noting that our&#xa0;patient had experienced two devastating neurological traumas, both in anatomical areas that have been implicated in the corticopontine-cerebellar circuit thought to be responsible for pseudobulbar affect. However, only the second trauma, an acute left pontine infarction, produced symptoms of emotional disinhibition. The authors hope that reporting this case will provide both context for physicians managing this condition and hope for patients with this socially and psychiatrically damaging disease.}, }
@article {pmid33271327, year = {2021}, author = {Dell'Orco, M and Sardone, V and Gardiner, AS and Pansarasa, O and Bordoni, M and Perrone-Bizzozero, NI and Cereda, C}, title = {HuD regulates SOD1 expression during oxidative stress in differentiated neuroblastoma cells and sporadic ALS motor cortex.}, journal = {Neurobiology of disease}, volume = {148}, number = {}, pages = {105211}, doi = {10.1016/j.nbd.2020.105211}, pmid = {33271327}, issn = {1095-953X}, support = {R01 NS089633/NS/NINDS NIH HHS/United States ; P20 GM121176/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Cell Line, Tumor ; ELAV-Like Protein 4/*genetics/metabolism ; Gene Expression Regulation/*genetics ; Humans ; Motor Cortex/*metabolism ; Neuroblastoma/*metabolism ; Neurons/*metabolism ; Oxidative Stress/*genetics ; RNA, Messenger/metabolism ; Superoxide Dismutase-1/*genetics/metabolism ; }, abstract = {The neuronal RNA-binding protein (RBP) HuD plays an important role in brain development, synaptic plasticity and neurodegenerative diseases such as Parkinson's (PD) and Alzheimer's (AD). Bioinformatics analysis of the human SOD1 mRNA 3' untranslated region (3'UTR) demonstrated the presence of HuD binding adenine-uridine (AU)-rich instability-conferring elements (AREs). Using differentiated SH-SY5Y cells along with brain tissues from sporadic amyotrophic lateral sclerosis (sALS) patients, we assessed HuD-dependent regulation of SOD1 mRNA. In vitro binding and mRNA decay assays demonstrate that HuD specifically binds to SOD1 ARE motifs promoting mRNA stabilization. In SH-SY5Y cells, overexpression of full-length HuD increased SOD1 mRNA and protein levels while a dominant negative form of the RBP downregulated its expression. HuD regulation of SOD1 mRNA was also found to be oxidative stress (OS)-dependent, as shown by the increased HuD binding and upregulation of this mRNA after H2O2 exposure. This treatment also induced a shift in alternative polyadenylation (APA) site usage in SOD1 3'UTR, increasing the levels of a long variant bearing HuD binding sites. The requirement of HuD for SOD1 upregulation during oxidative damage was validated using a specific siRNA that downregulated HuD protein levels to 36% and prevented upregulation of SOD1 and 91 additional genes. In the motor cortex from sALS patients, we found increases in SOD1 and HuD mRNAs and proteins, accompanied by greater HuD binding to this mRNA as confirmed by RNA-immunoprecipitation (RIP) assays. Altogether, our results suggest a role of HuD in the post-transcriptional regulation of SOD1 expression during ALS pathogenesis.}, }
@article {pmid33269270, year = {2020}, author = {Hu, HT and Ma, FH and Wu, ZM and Qi, XH and Zhong, YX and Xie, YB and Tian, YT}, title = {Treatment of afferent loop syndrome using fluoroscopic-guided nasointestinal tube placement: Two case reports.}, journal = {World journal of clinical cases}, volume = {8}, number = {21}, pages = {5353-5360}, pmid = {33269270}, issn = {2307-8960}, abstract = {BACKGROUND: Afferent loop syndrome (ALS) is a rare mechanical complication that occurs after reconstruction of the stomach or esophagus to the jejunum, such as Billroth II gastrojejunostomy, Roux-en-Y gastrojejunostomy, or Roux-en-Y esophagoje-junostomy. Traditionally, an operation is the first choice for benign causes. However, for patients in poor physical condition who experience ALS soon after R0 resection, the type of treatment remains controversial. Here, we present an efficient conservative method to treat ALS.<br><br>CASE SUMMARY: Case 1 was a 69-year-old male patient who underwent total gastrectomy with Roux-en-Y jejunojejunostomy. On postoperative day (POD) 10 he developed symptoms of ALS that persisted and increased over 1 wk. Case 2 was a 59-year-old male patient who underwent distal gastrectomy with Billroth II gastrojejunostomy. On postoperative day POD 9 he developed symptoms of ALS that persisted for 2 wk. Both patients underwent fluoroscopic-guided nasointestinal tube placement with maintenance of continuous negative pressure suction. Approximately 20 d after the procedure, both patients had recovered well and were discharged from hospital after removal of the tube. At 3-mo follow-up, there were no signs of ALS in these two patients.<br><br>CONCLUSION: This is the first report of treating postoperative ALS by fluoroscopic-guided nasointestinal tube placement. Our cases demonstrate that this procedure is an effective and safe method to treat ALS that relieves patients' symptoms and avoids complications caused by other invasive procedures.}, }
@article {pmid33263031, year = {2020}, author = {Kotanen, P and Kreivi, HR and Vainionpää, A and Laaksovirta, H and Brander, P and Siirala, W}, title = {Home invasive mechanical ventilation in Finland in 2015-2019.}, journal = {ERJ open research}, volume = {6}, number = {4}, pages = {}, pmid = {33263031}, issn = {2312-0541}, abstract = {INTRODUCTION: The prevalence of long-term invasive mechanical ventilation via tracheostomy in chronic respiratory insufficiency is largely unknown. We aimed to clarify prevalence and aetiology of the use of home invasive mechanical ventilation (HIMV) in Finland in 2015-2019.<br><br>METHODS: Information on HIMV patients was collected yearly from all Finnish Hospital District patient registries between 1 January 2015 and 1 January 2019. Data included underlying diagnosis, time from diagnosis to HIMV initiation, treatment length, mortality and basic sociodemographic data.<br><br>RESULTS: In 2015, we had 107 HIMV patients. During the follow-up we received 34 new patients (24.1%) and 46 patients (32.6%) died. In 2019, we had 95 HIMV patients and the prevalence in Finland was 2.0 in 100&#x2005;000. The most common diagnoses were motor neurone disease (29.1%) and spinal cord injuries (19.9%). Mean duration of HIMV among all patients on 1 January 2019 was 12.3 years and among deceased patients, 11.2 years. Treatment durations ranged from 7.7 years for motor neurone disease patients to 47.3 years for post-polio syndrome patients. Most patients (81.6%) used HIMV 24&#x2005;h&#xb7;day[-1].<br><br>CONCLUSIONS: HIMV is a rare, long-lasting treatment, most often used in chronic hypoventilation caused by chronic neurological disease. Based on our 4&#x2005;year follow-up the prevalence of HIMV seems to be diminishing in Finland. Treatment duration and survival vary greatly depending on the underlying diagnosis. Most of the patients were totally dependent on HIMV, requiring 24-h care.}, }
@article {pmid33257786, year = {2020}, author = {Strickland, MR and Ibanez, KR and Yaroshenko, M and Diaz, CC and Borchelt, DR and Chakrabarty, P}, title = {IL-10 based immunomodulation initiated at birth extends lifespan in a familial mouse model of amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {20862}, pmid = {33257786}, issn = {2045-2322}, support = {R01 NS092788/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Animals ; Dependovirus/immunology ; Disease Models, Animal ; Female ; Immunity, Innate/immunology ; Immunomodulation/*immunology ; Inflammation/immunology ; Interleukin-10/*immunology ; Longevity/*immunology ; Male ; Mice ; Mice, Inbred C3H ; Mice, Transgenic ; Microglia/immunology ; Neurodegenerative Diseases/immunology ; Phagocytosis/immunology ; Signal Transduction/immunology ; Superoxide Dismutase-1/immunology ; }, abstract = {Inflammatory signaling is thought to modulate the neurodegenerative cascade in amyotrophic lateral sclerosis (ALS). We have previously shown that expression of Interleukin-10 (IL-10), a classical anti-inflammatory cytokine, extends lifespan in the SOD1-G93A mouse model of familial ALS. Here we test whether co-expression of the decoy chemokine receptor M3, that can scavenge inflammatory chemokines, augments the efficacy of IL-10. We found that recombinant adeno-associated virus (AAV)-mediated expression of IL-10, alone, or in combination with M3, resulted in modest extension of lifespan relative to control SOD1-G93A cohort. Interestingly neither AAV-M3 alone nor AAV-IL-10 + AAV-M3 extend survival beyond that of the AAV-IL-10 alone cohort. Focused transcriptomic analysis revealed induction of innate immunity and phagocytotic pathways in presymptomatic SOD1-G93A mice expressing IL-10 + M3 or IL-10 alone. Further, while IL-10 expression increased microglial burden, the IL-10 + M3 group showed lower microglial burden, suggesting that M3 can successfully lower microgliosis before disease onset. Our data demonstrates that over-expression of an anti-inflammatory cytokine and a decoy chemokine receptor can modulate inflammatory processes in SOD1-G93A mice, modestly delaying the age to paralysis. This suggests that multiple inflammatory pathways can be targeted simultaneously in neurodegenerative disease and supports consideration of adapting these approaches to treatment of ALS and related disorders.}, }
@article {pmid33251493, year = {2020}, author = {Terashima, T and Kobashi, S and Watanabe, Y and Nakanishi, M and Honda, N and Katagi, M and Ohashi, N and Kojima, H}, title = {Enhancing the Therapeutic Efficacy of Bone Marrow-Derived Mononuclear Cells with Growth Factor-Expressing Mesenchymal Stem Cells for ALS in Mice.}, journal = {iScience}, volume = {23}, number = {11}, pages = {101764}, pmid = {33251493}, issn = {2589-0042}, abstract = {Several treatments have been attempted in amyotrophic lateral sclerosis (ALS) animal models and patients. Recently, transplantation of bone marrow-derived mononuclear cells (MNCs) was investigated as a regenerative therapy for ALS, but satisfactory treatments remain to be established. To develop an effective treatment, we focused on mesenchymal stem cells (MSCs) expressing hepatocyte growth factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor using human artificial chromosome vector (HAC-MSCs). Here, we demonstrated the transplantation of MNCs with HAC-MSCs in ALS mice. As per our results, the progression of motor dysfunction was significantly delayed, and their survival was prolonged dramatically. Additional analysis revealed preservation of motor neurons, suppression of gliosis, engraftment of numerous MNCs, and elevated chemotaxis-related cytokines in the spinal cord of treated mice. Therefore, growth factor-expressing MSCs enhance the therapeutic effects of bone marrow-derived MNCs for ALS and have a high potential as a novel cell therapy for patients with ALS.}, }
@article {pmid33248509, year = {2020}, author = {Thakore, NJ and Pioro, EP and Udeh, BL and Lapin, BR and Katzan, IL}, title = {A Cost-Effectiveness Framework for Amyotrophic Lateral Sclerosis, Applied to Riluzole.}, journal = {Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research}, volume = {23}, number = {12}, pages = {1543-1551}, doi = {10.1016/j.jval.2020.06.012}, pmid = {33248509}, issn = {1524-4733}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/economics ; Cost-Benefit Analysis ; Disease Progression ; Drug Costs ; Health Care Costs ; Humans ; Models, Statistical ; Neuroprotective Agents/economics/*therapeutic use ; Quality-Adjusted Life Years ; Riluzole/economics/*therapeutic use ; Time Factors ; }, abstract = {OBJECTIVES: Reexamine cost-effectiveness of riluzole in the treatment of amyotrophic lateral sclerosis (ALS) in light of recent advances in disease staging and understanding of stage-specific drug effect.<br><br>METHODS: ALS was staged according to the "fine'til 9" (FT9) staging method. Stage-specific health utilities (EQ-5D, US valuation) were estimated from an institutional cohort, whereas literature informed costs and transition probabilities. Costs at 2018 prices were disaggregated into recurring costs (RCs) and "one-off" transition/"tollgate" costs (TCs). Five- and 10-year horizons starting in stage 1 disease were examined from healthcare sector and societal perspectives using Markov models to evaluate riluzole use, at a threshold of $100&#x2009;000/quality-adjusted life year (QALY). Probabilistic and deterministic sensitivity analyses were conducted.<br><br>RESULTS: Mean EQ-5D utilities for stages 0 to 4 were 0.79, 0.74, 0.63, 0.54, and 0.46, respectively. From the healthcare sector perspective at the 5-year horizon, riluzole use contributed to 0.182 QALY gained at the cost difference of $12&#x2009;348 ($5403 riluzole cost, $8870 RC and -$1925 TC differences), translating to an incremental cost-effectiveness ratio (ICER) of $67&#xa0;658/QALY. Transition probability variation contributed considerably to ICER uncertainty (-30.2% to&#xa0;+90.0%). ICER was sensitive to drug price and RCs, whereas higher TCs modestly reduced ICER due to delayed tollgates.<br><br>CONCLUSION: This study provides a framework for health economic studies of ALS treatments using FT9 staging. Prospective stage-specific and disaggregated cost measurement is warranted for accurate future cost-effectiveness analyses. Appropriate separation of TCs from RCs substantially mitigates the high burden of background cost of care on the ICER.}, }
@article {pmid33244158, year = {2020}, author = {Guissart, C and Mouzat, K and Kantar, J and Louveau, B and Vilquin, P and Polge, A and Raoul, C and Lumbroso, S}, title = {Premature termination codons in SOD1 causing Amyotrophic Lateral Sclerosis are predicted to escape the nonsense-mediated mRNA decay.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {20738}, pmid = {33244158}, issn = {2045-2322}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Codon, Nonsense/*genetics ; Codon, Terminator/*genetics ; Humans ; Mutation, Missense/genetics ; Nonsense Mediated mRNA Decay/*genetics ; RNA, Messenger/genetics ; Superoxide Dismutase-1/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common and severe adult-onset motoneuron disease and has currently no effective therapy. Approximately 20% of familial ALS cases are caused by dominantly-inherited mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1), which represents one of the most frequent genetic cause of ALS. Despite the overwhelming majority of ALS-causing missense mutations in SOD1, a minority of premature termination codons (PTCs) have been identified. mRNA harboring PTCs are known to be rapidly degraded by nonsense-mediated mRNA decay (NMD), which limits the production of truncated proteins. The rules of NMD surveillance varying with PTC location in mRNA, we analyzed the localization of PTCs in SOD1 mRNA to evaluate whether or not those PTCs can be triggered to degradation by the NMD pathway. Our study shows that all pathogenic PTCs described in SOD1 so far can theoretically escape the NMD, resulting in the production of truncated protein. This finding supports the hypothesis that haploinsufficiency is not an underlying mechanism of SOD1 mutant-associated ALS and suggests that PTCs found in the regions that trigger NMD are not pathogenic. Such a consideration is particularly important since the availability of SOD1 antisense strategies, in view of variant treatment assignment.}, }
@article {pmid33244084, year = {2020}, author = {Leyton-Jaimes, MF and Ivert, P and Hoeber, J and Han, Y and Feiler, A and Zhou, C and Pankratova, S and Shoshan-Barmatz, V and Israelson, A and Kozlova, EN}, title = {Empty mesoporous silica particles significantly delay disease progression and extend survival in a mouse model of ALS.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {20675}, pmid = {33244084}, issn = {2045-2322}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/*pathology ; Animals ; Cell Survival/*drug effects ; Cells, Cultured ; Cervical Cord/drug effects/metabolism/pathology ; Disease Models, Animal ; Disease Progression ; Embryonic Stem Cells/drug effects/metabolism/pathology ; Female ; Glial Cell Line-Derived Neurotrophic Factor/metabolism ; Mice ; Motor Neurons/drug effects/metabolism/pathology ; Neural Crest/drug effects/metabolism/pathology ; Neural Stem Cells/drug effects/metabolism/pathology ; Silicon Dioxide/*pharmacology ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating incurable neurological disorder characterized by motor neuron (MN) death and muscle dysfunction leading to mean survival time after diagnosis of only 2-5 years. A potential ALS treatment is to delay the loss of MNs and disease progression by the delivery of trophic factors. Previously, we demonstrated that implanted mesoporous silica nanoparticles (MSPs) loaded with trophic factor peptide mimetics support survival and induce differentiation of co-implanted embryonic stem cell (ESC)-derived MNs. Here, we investigate whether MSP loaded with peptide mimetics of ciliary neurotrophic factor (Cintrofin), glial-derived neurotrophic factor (Gliafin), and vascular endothelial growth factor (Vefin1) injected into the cervical spinal cord of mutant SOD1 mice affect disease progression and extend survival. We also transplanted boundary cap neural crest stem cells (bNCSCs) which have been shown previously to have a positive effect on MN survival in vitro and in vivo. We show that mimetic-loaded MSPs and bNCSCs significantly delay disease progression and increase survival of mutant SOD1 mice, and also that empty particles significantly improve the condition of ALS mice. Our results suggest that intraspinal delivery of MSPs is a potential therapeutic approach for the treatment of ALS.}, }
@article {pmid33236694, year = {2020}, author = {Brunner, C and Theiler, M and Weibel, L and Schlüer, AB}, title = {Storytelling als innovative Methode zur videobasierten Edukation für Eltern von Kindern mit atopischer Dermatitis.}, journal = {Pflege}, volume = {33}, number = {6}, pages = {397-403}, doi = {10.1024/1012-5302/a000771}, pmid = {33236694}, issn = {1012-5302}, mesh = {Child ; Child, Preschool ; Chronic Disease ; *Dermatitis, Atopic/complications/diagnosis/therapy ; Humans ; Infant ; Infant, Newborn ; Parents ; *Patient Education as Topic ; Quality of Life ; *Sleep Wake Disorders/etiology ; *Video Recording ; }, abstract = {Storytelling as an innovative method of video-based education for parents of children with atopic dermatitis Abstract. Background: Atopic Dermatitis (AD) is the most chronic skin disease in children and affects up to 20 % of children in developed countries. Chronic inflammation of the skin, itching, redness, and non-dermatologic symptoms like sleep disturbance are frequent and have a negative impact on the child's quality of life and their family. Education is one of the most important aspects of managing AD. Aim: Production and evaluation of educational videos with the method storytelling for parents of children aged 0 to 5 years with atopic dermatitis. Methods: We produced the videos with the method of storytelling. The aim of storytelling is to help to recall important information more easily. A multi-professional team and parents of affected children tested the videos to ensure the understandability, the helpfulness and importance of the educational videos. Results: We created six different videos in all. The content of the educational videos includes information on the causes of AD, symptoms, skin care, treatment instruction and living with AD. We implemented the method of storytelling by two families with affected children who reported about their experience with the disease and the treatment. Three different specialists gave expert information. The evaluation showed that the information in the videos is simple, understandable and relevant. Conclusions: Evidence-based videos are an innovative, creative and modern method to support education. Storytelling is a user-friendly method to give simple and understandable information.}, }
@article {pmid33233922, year = {2021}, author = {Krasnoff, CC and Grigorian, A and Smith, BR and Jutric, Z and Nguyen, NT and Daly, S and Lekawa, ME and Nahmias, J}, title = {Predictors of Anastomotic Leak After Esophagectomy for Cancer: Not All Leaks Increase Mortality.}, journal = {The American surgeon}, volume = {87}, number = {6}, pages = {864-871}, doi = {10.1177/0003134820956329}, pmid = {33233922}, issn = {1555-9823}, mesh = {Aged ; Anastomotic Leak/*epidemiology/mortality ; Chemoradiotherapy ; Databases, Factual ; Esophageal Neoplasms/*surgery ; *Esophagectomy ; Female ; Humans ; Male ; Middle Aged ; Reoperation/statistics &amp; numerical data ; Risk Factors ; United States/epidemiology ; }, abstract = {BACKGROUND: The impact of preoperative chemotherapy/radiation on esophageal anastomotic leaks (ALs) and the correlation between AL severity and mortality risk have not been fully elucidated. We hypothesized that lower severity ALs have a similar risk of mortality compared to those without ALs, and preoperative chemotherapy/radiation increases AL risk.<br><br>METHODS: The 2016-2017 American College of Surgeons National Surgical Quality Improvement Program's procedure-targeted esophagectomy database was queried for patients undergoing any esophagectomy for cancer. A multivariable logistic regression analysis was performed for risk of ALs.<br><br>RESULTS: From 2042 patients, 280 (13.7%) had ALs. AL patients requiring intervention had increased mortality risk including those requiring reoperation, interventional procedure, and medical therapy (P < .05). AL patients requiring no intervention had similar mortality risk compared to patients without ALs (P > .05). Preoperative chemotherapy/radiation was not predictive of ALs (P > .05).<br><br>CONCLUSION: Preoperative chemotherapy/radiation does not contribute to risk for ALs after esophagectomy. There is a stepwise increased risk of 30-day mortality for ALs requiring increased invasiveness of treatment.}, }
@article {pmid33226425, year = {2021}, author = {Wainger, BJ and Macklin, EA and Vucic, S and McIlduff, CE and Paganoni, S and Maragakis, NJ and Bedlack, R and Goyal, NA and Rutkove, SB and Lange, DJ and Rivner, MH and Goutman, SA and Ladha, SS and Mauricio, EA and Baloh, RH and Simmons, Z and Pothier, L and Kassis, SB and La, T and Hall, M and Evora, A and Klements, D and Hurtado, A and Pereira, JD and Koh, J and Celnik, PA and Chaudhry, V and Gable, K and Juel, VC and Phielipp, N and Marei, A and Rosenquist, P and Meehan, S and Oskarsson, B and Lewis, RA and Kaur, D and Kiskinis, E and Woolf, CJ and Eggan, K and Weiss, MD and Berry, JD and David, WS and Davila-Perez, P and Camprodon, JA and Pascual-Leone, A and Kiernan, MC and Shefner, JM and Atassi, N and Cudkowicz, ME}, title = {Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {78}, number = {2}, pages = {186-196}, pmid = {33226425}, issn = {2168-6157}, support = {DP2 NS106664/NS/NINDS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy/physiopathology ; Anticonvulsants/pharmacology/therapeutic use ; Carbamates/pharmacology/*therapeutic use ; Cerebral Cortex/*drug effects/physiology ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Motor Neurons/*drug effects/physiology ; Phenylenediamines/pharmacology/*therapeutic use ; Spinal Cord/*drug effects/physiology ; Treatment Outcome ; }, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials.<br><br>OBJECTIVE: To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS.<br><br>This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements.<br><br>INTERVENTIONS: Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was change in short-interval intracortical inhibition (SICI; SICI-1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies.<br><br>RESULTS: A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI-1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P&#x2009;=&#x2009;.009) in the 900-mg/d ezogabine group vs placebo group. The SICI-1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P&#x2009;=&#x2009;.31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P&#x2009;=&#x2009;.04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, -2.64 to 6.54; P&#x2009;=&#x2009;.40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P&#x2009;<&#x2009;.001).<br><br>CONCLUSIONS AND RELEVANCE: Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02450552.}, }
@article {pmid33225955, year = {2020}, author = {Galvin, M and Gavin, T and Mays, I and Heverin, M and Hardiman, O}, title = {Individual quality of life in spousal ALS patient-caregiver dyads.}, journal = {Health and quality of life outcomes}, volume = {18}, number = {1}, pages = {371}, pmid = {33225955}, issn = {1477-7525}, support = {ICE/2012/6/HRBI_/Health Research Board/Ireland ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*psychology ; Caregivers/*psychology ; Disease Progression ; Female ; Humans ; Ireland/epidemiology ; Longitudinal Studies ; Male ; Middle Aged ; Quality of Life/*psychology ; Spouses ; }, abstract = {BACKGROUND: Quality of life is a basic goal of health and social care. The majority of people with Amyotrophic Lateral Sclerosis (ALS) are cared for at home by family caregivers. It is important to recognize the factors that contribute to quality of life for individuals to better understand the lived experiences in a condition for which there is currently no curative treatment.<br><br>AIM: To explore individual quality of life of people with ALS and their informal caregivers over time.<br><br>METHODS: Over three semi-structured home interviews, 28 patient-caregiver dyads provided information on a range of demographic and clinical features, psychological distress, caregiver burden, and individual quality of life. Quality of life data were analysed using quantitative and qualitative methods with integration at the analysis and interpretation phases.<br><br>RESULTS: Individual Quality of Life was high for patients and caregivers across the interviews series, and higher among patients than their care partners at each time point. Family, hobbies and social activities were the main self-defined contributors to quality of life. The importance of health declined relative to other areas over time. Friends and finances became less important for patients, but were assigned greater importance by caregivers across the illness trajectory. Psychological distress was higher among caregivers. Caregiver burden consistently increased.<br><br>CONCLUSION: The findings from this study point to the importance of exploring and monitoring quality of life at an individual level. Self-defined contributory factors are relevant to the individual within his/her context. As an integrated outcome measure individual quality of life should be assessed and monitored as part of routine clinical care during the clinical encounter. This can facilitate conversations between health care providers, patients and families, and inform interventions and contribute to decision support mechanisms. The ascertainment of self-defined life quality, especially in progressive neurodegenerative conditions, mean health care professionals are in a better position to provide person-centred care.}, }
@article {pmid33223091, year = {2021}, author = {Roy, B and Griggs, R}, title = {Advances in Treatments in Muscular Dystrophies and Motor Neuron Disorders.}, journal = {Neurologic clinics}, volume = {39}, number = {1}, pages = {87-112}, doi = {10.1016/j.ncl.2020.09.005}, pmid = {33223091}, issn = {1557-9875}, mesh = {Genetic Therapy/methods ; Humans ; Motor Neuron Disease/*therapy ; Muscular Dystrophies/*therapy ; Neuroprotective Agents/therapeutic use ; }, abstract = {Increased understanding of disease pathophysiology and advances in gene therapies and drug technologies are revolutionizing treatment of muscular dystrophies and motor neuron disorders (MNDs). New drugs have been approved for Duchenne muscular dystrophy, spinal muscular atrophy, and amyotrophic lateral sclerosis. For other diseases, new targets have been identified, and new therapies are in clinical trials. The impact of such therapies will be fully understood only in the next decades. Cost burden and accessibility are major challenges in the wide application of new drugs. This article reviews advances in gene therapies, newly approved drugs, and therapeutic promises in muscular dystrophies and MNDs.}, }
@article {pmid33222146, year = {2021}, author = {Wang, Y and Bai, L and Li, S and Wen, Y and Liu, Q and Li, R and Liu, Y}, title = {Simvastatin Enhances Muscle Regeneration Through Autophagic Defect-Mediated Inflammation and mTOR Activation in G93ASOD1 Mice.}, journal = {Molecular neurobiology}, volume = {58}, number = {4}, pages = {1593-1606}, pmid = {33222146}, issn = {1559-1182}, support = {81871001//the National Natural Science Foundation of China (NSFC)/ ; zh2018004//the Key Project of Technical Health Research and Achievement Transformation of Hebei Provincial Department of Health/ ; }, mesh = {Animals ; *Autophagy/drug effects ; Denervation ; Female ; Fibrosis ; Inflammation/*pathology ; Mice, Transgenic ; Motor Activity/drug effects ; Muscle Development/drug effects ; Muscle, Skeletal/drug effects/*pathology/physiopathology ; Muscular Atrophy/pathology ; Mutation/*genetics ; Neuromuscular Junction/drug effects ; Phenotype ; Protein Aggregates/drug effects ; *Regeneration/drug effects ; Signal Transduction/drug effects ; Simvastatin/*pharmacology ; Superoxide Dismutase/*genetics ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterised by the selective loss of motor neurons, muscular atrophy, and degeneration. Statins, as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are the most widely prescribed drugs to lower cholesterol levels and used for the treatment of cardiovascular and cerebrovascular diseases. However, statins are seldom used in muscular diseases, primarily because of their rare statin-associated myopathy. Recently, statins have been shown to reduce muscular damage and improve its function. Here, we investigated the role of statins in myopathy using G93ASOD1 mice. Our results indicated that simvastatin significantly increased the autophagic flux defect and increased inflammation in the skeletal muscles of G93ASOD1 mice. We also found that increased inflammation correlated with aggravated muscle atrophy and fibrosis. Nevertheless, long-term simvastatin treatment promoted the regeneration of damaged muscle by activating the mammalian target of rapamycin pathway. However, administration of simvastatin did not impede vast muscle degeneration and movement dysfunction resulting from the enhanced progressive impairment of the neuromuscular junction. Together, our findings highlighted that simvastatin exacerbated skeletal muscle atrophy and denervation in spite of promoting myogenesis in damaged muscle, providing new insights into the selective use of statin-induced myopathy in ALS.}, }
@article {pmid33210770, year = {2021}, author = {Spittel, S and Maier, A and Kettemann, D and Walter, B and Koch, B and Krause, K and Norden, J and Münch, C and Meyer, T}, title = {Non-invasive and tracheostomy invasive ventilation in amyotrophic lateral sclerosis: Utilization and survival rates in a cohort study over 12 years in Germany.}, journal = {European journal of neurology}, volume = {28}, number = {4}, pages = {1160-1171}, doi = {10.1111/ene.14647}, pmid = {33210770}, issn = {1468-1331}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Cohort Studies ; Germany/epidemiology ; Humans ; *Noninvasive Ventilation ; Prospective Studies ; *Respiratory Insufficiency ; Survival Rate ; Tracheostomy ; }, abstract = {BACKGROUND AND PURPOSE: The aim of this study was to investigate utilization rates, treatment pathways and survival prognosis in patients with amyotrophic lateral sclerosis (ALS) undergoing non-invasive (NIV) and tracheostomy invasive ventilation (TIV) in a real-world setting.<br><br>METHODS: A prospective cohort study using a single-centre register of 2702 ALS patients (2007 to 2019) was conducted. Utilization of NIV/TIV and survival data were analysed in three cohorts: (i) non-NIV; (ii) NIV (NIV without subsequent TIV); and (iii) TIV (including TIV preceded by NIV).<br><br>RESULTS: A total of 1720 patients with available data were identified, 72.0% of whom (n&#xa0;=&#xa0;1238) did not receive ventilation therapy. NIV was performed in 20.8% of patients (n&#xa0;=&#xa0;358). TIV was performed in 9.5% of patients (n&#xa0;=&#xa0;164), encompassing both primary TIV (7.2%, n&#xa0;=&#xa0;124) and TIV with preceding NIV (2.3%, n&#xa0;=&#xa0;40). TIV was more often utilized without previous NIV (25.7% vs. 8.3% of all ventilated patients), demonstrating that primary TIV was the prevailing pathway for invasive ventilation. The median (range) survival was significantly longer in the NIV cohort (40.8&#xa0;[37.2-44.3] months) and the TIV cohort (82.1&#xa0;[68.7-95.6] months) as compared to the non-NIV cohort (33.6&#xa0;[31.6-35.7] months).<br><br>CONCLUSIONS: Although NIV represents the standard of care, its utilization rate was low. TIV was mainly started without preceding NIV, suggesting that TIV may not be confined to NIV treatment escalation. However, TIV was pursued in a minority of patients who had previously undergone NIV. The survival benefit observed in the patients with NIV was equal to that reported in a controlled pivotal trial, but the prognosis with TIV is highly variable. The determinants of utilization of NIV/TIV and of survival (bulbar syndrome, availability of ventilation-related home nursing, cultural factors) warrant further investigation.}, }
@article {pmid33209213, year = {2020}, author = {Rantala, HA and Leivo-Korpela, S and Kettunen, S and Lehto, JT and Lehtimäki, L}, title = {Survival and end-of-life aspects among subjects on long-term noninvasive ventilation.}, journal = {European clinical respiratory journal}, volume = {8}, number = {1}, pages = {1840494}, pmid = {33209213}, issn = {2001-8525}, abstract = {BACKGROUND: The need for noninvasive ventilation (NIV) is commonly considered a predictor of poor survival, but life expectancy may vary depending on the underlying disease. We studied the factors associated with decreased survival and end-of-life characteristics in an unselected population of subjects starting NIV.<br><br>METHODS: We conducted a retrospective study including 205 subjects initiating NIV from 1/1/2012-31/12/2015 who were followed up until 31/12/2017.<br><br>RESULTS: The median survival time was shorter in subjects needing help with activities of daily living than in independent subjects (hazard ratio (HR) for death 1.7, 95% CI 1.2-2.6, P =&#xa0;0.008) and was also shorter in subjects on long-term oxygen therapy (LTOT) than in those not on LTOT (HR for death 2.8, 95% CI 1.9-4.3, P <&#xa0;0.001). There was marked difference in survival according to the disease necessitating NIV, and subjects with amyotrophic lateral sclerosis or interstitial lung disease seemed to have the shortest survival. The two most common diseases resulting in the need for NIV were chronic obstructive pulmonary disease (COPD) and obesity hypoventilation syndrome (OHS). The median survival time was 4.4&#xa0;years in COPD subjects, but the median survival time was not reached in subjects with OHS (HR for death COPD vs. OHS: 3.2, 95% CI 1.9-5.5, P <&#xa0;0.001). Most of the deceased subjects (55.6%) died in the hospital, while only 20.0% died at home. The last hospitalization admission leading to death occurred through the emergency room in 44.4% of the subjects.<br><br>CONCLUSIONS: Survival among subjects starting NIV in this real-life study varied greatly depending on the disease and degree of functional impairment. Subjects frequently died in the hospital after admission through the emergency department. A comprehensive treatment approach with timely advance care planning is therefore needed, especially for those needing help with activities of daily living and those with both NIV and LTOT.}, }
@article {pmid33202609, year = {2020}, author = {Brabham, C and Norsworthy, JK and González-Torralva, F}, title = {Presence of the HPPD Inhibitor Sensitive 1 Gene and ALS[S653N] Mutation in Weedy Oryza sativa Sensitive to Benzobicyclon.}, journal = {Plants (Basel, Switzerland)}, volume = {9}, number = {11}, pages = {}, pmid = {33202609}, issn = {2223-7747}, support = {n/a//Arkansas Rice Promotion Board and by Gowan Company/ ; }, abstract = {Benzobicyclon has shown varying results in controlling weedy rice, including those with imidazolinone (IMI) resistance. Tolerance to benzobicyclon in cultivated japonica rice, but not indica or aus-like cultivars, is conferred by a fully functional HPPD Inhibitor Sensitive 1 (HIS1) gene. Herein, a diagnostic Kompetitive Allele Specific PCR (KASP) assay was developed to predict the HIS1 genotype of weedy rice plants from 37 accessions and correlated to their response to benzobicyclon in the field. Two-thirds of the 693 weedy rice plants screened were tolerant to benzobicyclon (371 g ai ha[-1], SC formulation) at 30 days after treatment (DAT). Thirty-four percent of plants were homozygous for the HIS1 allele and 98% of these plants exhibited field tolerance. However, the his1 genotype did not always correlate with field data. Only 52% of his1 plants were considered sensitive, indicating that the single nucleotide polymorphisms (SNPs) chosen in the KASP assay are not a reliable tool in predicting his1 homozygous plants. In an additional experiment, 86% of the 344 plants with at least one copy of the ALS[S653N] trait harbored a HIS1 allele, suggesting fields infested with IMI herbicide-resistant weedy rice are unlikely to be controlled with benzobicyclon.}, }
@article {pmid33200912, year = {2020}, author = {}, title = {SOD1 Targeted as Treatment for Amyotrophic Lateral Sclerosis.}, journal = {American journal of medical genetics. Part A}, volume = {182}, number = {11}, pages = {2475-2476}, doi = {10.1002/ajmg.a.61250}, pmid = {33200912}, issn = {1552-4833}, }
@article {pmid33200713, year = {2021}, author = {Mylvaganam, S and Earnshaw, R and Heymann, G and Kalia, SK and Kalia, LV}, title = {C-terminus of Hsp70 Interacting Protein (CHIP) and Neurodegeneration: Lessons from the Bench and Bedside.}, journal = {Current neuropharmacology}, volume = {19}, number = {7}, pages = {1038-1068}, pmid = {33200713}, issn = {1875-6190}, mesh = {*Cerebellar Ataxia ; Humans ; *Huntington Disease ; Mutation ; *Spinocerebellar Ataxias ; *Ubiquitin-Protein Ligases/genetics ; }, abstract = {Neurodegenerative diseases are characterized by the increasing dysfunction and death of neurons, resulting in progressive impairment of a person's mobility and/or cognition. Protein misfolding and aggregation are commonly hypothesized to cause neurotoxicity and, eventually, neuronal degeneration that are associated with these diseases. Emerging experimental evidence, as well as recent findings from human studies, reveal that the C-terminus of Hsp70 Interacting Protein (CHIP), or STIP1 Homology and U-box containing Protein 1 (STUB1), is a quality control protein involved in neurodegeneration. Here, we review evidence that CHIP interacts with and plays a role in regulating proteins implicated in the pathogenesis of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and polyglutamine diseases, including Huntington's disease and spinocerebellar ataxias. We also review clinical findings identifying mutations in STUB1 as a cause of both autosomal recessive and autosomal dominant forms of cerebellar ataxia. We propose that CHIP modulation may have therapeutic potential for the treatment of multiple neurodegenerative diseases.}, }
@article {pmid33198383, year = {2020}, author = {Vallarola, A and Tortarolo, M and De Gioia, R and Iamele, L and de Jonge, H and de Nola, G and Bovio, E and Pasetto, L and Bonetto, V and Freschi, M and Bendotti, C and Gherardi, E}, title = {A Novel HGF/SF Receptor (MET) Agonist Transiently Delays the Disease Progression in an Amyotrophic Lateral Sclerosis Mouse Model by Promoting Neuronal Survival and Dampening the Immune Dysregulation.}, journal = {International journal of molecular sciences}, volume = {21}, number = {22}, pages = {}, pmid = {33198383}, issn = {1422-0067}, support = {SFMET-ALS//AriSLA/ ; 2015-0023//Regione Lombardia/ ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/immunology/*metabolism ; Animals ; Astrocytes/cytology/metabolism ; Behavior, Animal ; Cell Survival ; Coculture Techniques ; Disease Models, Animal ; Disease Progression ; Dogs ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Gliosis/metabolism ; Hepatocyte Growth Factor/*agonists ; Humans ; *Immune System ; Interleukin-4/metabolism ; Kringles ; Ligands ; Madin Darby Canine Kidney Cells ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/metabolism ; Motor Neurons/metabolism ; Neurons/*cytology/metabolism ; Schwann Cells/metabolism ; Spinal Cord/metabolism ; T-Lymphocytes/cytology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment. The Hepatocyte Growth Factor/Scatter Factor (HGF/SF), through its receptor MET, is one of the most potent survival-promoting factors for motor neurons (MN) and is known as a modulator of immune cell function. We recently developed a novel recombinant MET agonist optimized for therapy, designated K1K1. K1K1 was ten times more potent than HGF/SF in preventing MN loss in an in vitro model of ALS. Treatments with K1K1 delayed the onset of muscular impairment and reduced MN loss and skeletal muscle denervation of superoxide dismutase 1 G93A (SOD1G93A) mice. This effect was associated with increased levels of phospho-extracellular signal-related kinase (pERK) in the spinal cord and sciatic nerves and the activation of non-myelinating Schwann cells. Moreover, reduced activated microglia and astroglia, lower T cells infiltration and increased interleukin 4 (IL4) levels were found in the lumbar spinal cord of K1K1 treated mice. K1K1 treatment also prevented the infiltration of T cells in skeletal muscle of SOD1G93A mice. All these protective effects were lost on long-term treatment suggesting a mechanism of drug tolerance. These data provide a rational justification for further exploring the long-term loss of K1K1 efficacy in the perspective of providing a potential treatment for ALS.}, }
@article {pmid33196835, year = {2021}, author = {Takeuchi, T}, title = {Pathogenic and protective roles of extracellular vesicles in neurodegenerative diseases.}, journal = {Journal of biochemistry}, volume = {169}, number = {2}, pages = {181-186}, doi = {10.1093/jb/mvaa131}, pmid = {33196835}, issn = {1756-2651}, mesh = {Animals ; Brain/metabolism/pathology ; Extracellular Vesicles/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/*pathology ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and polyglutamine diseases are caused by aggregation and abnormal accumulation of the disease-causative proteins in brain and spinal cord. Recent studies have suggested that proteins associated with neurodegenerative diseases are secreted and transmitted intercellularly via extracellular vesicles (EVs), which may be involved in propagation of abnormal protein accumulation and progressive degeneration in patient brains. On the other hand, it has been also reported that EVs have neuroprotective roles in these diseases, which potentially contribute to preventing aggregation formation and aberrant accumulation of the disease-associated proteins. In this review, I summarize the current understanding of the roles of EVs in neurodegenerative diseases, especially focussing on the pathogenic and neuroprotective aspects. Elucidation of these two aspects of EVs would provide insight into not only potential therapeutic targets for treatment of neurodegenerative diseases but also development of EV-based biomarkers for disease diagnostics.}, }
@article {pmid33194549, year = {2020}, author = {Quevedo-Ramirez, A and Montenegro-Idrogo, JJ and Resurrección-Delgado, C and Salazar-Mesones, B and Gallardo-Cartagena, J and Cornejo-Venegas, G and Méndez-Guerra, C and Vargas-Matos, I and Chiappe-Gonzalez, A}, title = {Lateral amyotrophic sclerosis-like onset after combined antiretroviral treatment initiation.}, journal = {IDCases}, volume = {22}, number = {}, pages = {e00994}, pmid = {33194549}, issn = {2214-2509}, abstract = {Motor neuron disease (MND) have an incidence of 2 in 100 000 persons, resulting in the death of 1 in every 500 people affected. The most common disease in MND spectrum is amyotrophic lateral sclerosis (ALS). We describe the case of an ALS-like syndrome in a HIV patient. This case report presents a 38 years old male from Peru with HIV who after 2 months of combined antiretroviral treatment (cART) initiation was admitted to the hospital for spastic paraplegia. On his first admission, rapid plasma reagent (RPR) was positive and he was treated for neurosyphilis and discharged. Nevertheless, one month after, he was admitted for the second time because paraplegia persisted. Laboratory tests, electromyography and imaging were performed, and ALS was diagnosed. Normally, HIV treated patient with ALS tend to have a better prognosis, however this was not the case. In this case report, we discuss possible association between ALS and immune reconstitution inflammatory syndrome in HIV patients.}, }
@article {pmid33191416, year = {2021}, author = {Guo, J and Shen, S and Zhang, X and Wang, G and Lu, Y and Liu, X and Wang, S and Li, Q and Cong, Y and Shi, B}, title = {Chemical compounds with a neuroprotective effect from the seeds of Celosia argentea L.}, journal = {Food &amp; function}, volume = {12}, number = {1}, pages = {83-96}, doi = {10.1039/d0fo02033h}, pmid = {33191416}, issn = {2042-650X}, mesh = {Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Cattle ; Cell Culture Techniques ; Cell Survival/drug effects ; Celosia/*chemistry ; Medicine, Chinese Traditional ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/*drug effects ; Plant Extracts/*pharmacology ; Reactive Oxygen Species/metabolism ; Seeds/*chemistry ; }, abstract = {Oxidative stress plays a central role in the common pathophysiology of neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. Antioxidant therapy has been suggested for the prevention and treatment of neurodegenerative diseases. Compounds derived from natural sources may offer the potential for new treatment options. Semen Celosiae is a traditional Chinese edible herbal medicine with a long history in China and exhibits wide-reaching biological activities such as hepatoprotective, anti-tumor, anti-diarrheal, anti-diabetic, anti-oxidant, etc. In this study, nine saponins and two phenylacetonitrile glycosides were isolated from Semen Celosiae and their structures were identified using ESI-MS and NMR techniques. Among them, compounds 1 and 2 have not been previously reported. The total concentrations of the five triterpenoid saponins and the two phenylacetonitrile glycosides were 3.348 mg g[-1] and 0.187 mg g[-1], respectively, suggesting that Semen Celosiae is a novel viable source of the two kinds of compounds. These compounds were observed to significantly attenuate t-BHP-induced neuronal damage by effectively enhancing cell viability and decreasing reactive oxygen species generation and cell apoptosis rate in NSC-34 cells. Furthermore, compounds 1 and 7 reduced the ratios of cleaved caspase-3: caspase-3 and cleaved caspase-7: caspase-7 and the level of cytochrome C, while they increased the levels of SOD1 and Beclin 1. These findings suggest that compounds 1-11 are potent inhibitors of neuron injury elicited by t-BHP, possibly via inhibition of oxidative stress and apoptosis, and activation of autophagy; therefore they may be valuable leads for future therapeutic development.}, }
@article {pmid33185886, year = {2021}, author = {De Marchi, F and Sarnelli, MF and Serioli, M and De Marchi, I and Zani, E and Bottone, N and Ambrosini, S and Garone, R and Cantello, R and Mazzini, L and , }, title = {Telehealth approach for amyotrophic lateral sclerosis patients: the experience during COVID-19 pandemic.}, journal = {Acta neurologica Scandinavica}, volume = {143}, number = {5}, pages = {489-496}, doi = {10.1111/ane.13373}, pmid = {33185886}, issn = {1600-0404}, support = {//Regione Piemonte - Piattaforma tecnologica Salute e Benessere POR FESR 2014-2020/ ; //AGING Project for Department of Excellence at the Department of Translational Medicine (DIMET), Universit&#xe0; del Piemonte Orientale, Novara, Italy/ ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*epidemiology/psychology/*therapy ; COVID-19/*epidemiology/psychology ; Female ; Follow-Up Studies ; Humans ; Italy/epidemiology ; Male ; Middle Aged ; *Pandemics ; Patient Care Team/standards ; *Patient Satisfaction ; Quality of Life/psychology ; Telemedicine/*methods/standards ; }, abstract = {BACKGROUND AND OBJECTIVE: Specialized multidisciplinary ALS care has been shown to extend survival and improve patient's and caregiver's quality of life. During the COVID-19 pandemic, the management of patients suddenly changed and telemedicine has been proven to be as effective as outpatient care. We elaborate the experience with Telemedicine of a Tertiary ALS Center from an Italian geographical area with high infectious risk during the COVID-19 pandemic.<br><br>METHODS: 19 patients were evaluated in telemedicine by a multidisciplinary team including a neurologist (clinical evaluation, intercurrent events, and drug prescriptions); a dietician (diet and weight monitoring); a psychologist (psychological assessment and support); and a physiotherapist (physiotherapy treatment and device prescription). Telemedicine was performed using the online platform "IoMT Connected Care Platform (Ticuro Reply)."<br><br>RESULTS: All patients reported a positive perception of talking face to face with healthcare professionals and were satisfied with how the team understood their problems. During video televisits, there was a change in the patient's medication regimen in 11/19; 2/19 required pneumological evaluation and started NIV; and 9/16 patients required prescription of devices. The mean monthly decline of ALSFRS-R before televisit was 0.88 (SD 1.17) and during televisit of 0.49 (SD 0.75). Bodyweight and daily caloric content remain stable. Reduction in HADS scores and stability in ALSAQ-40 were observed.<br><br>DISCUSSION: Our study positively reproduced the multidisciplinary approach currently used with ALS patients, trying to stabilize the functional and metabolic status and improving the psychological one. Future directions include a personalized telemedicine program according to the patient's needs.}, }
@article {pmid33184449, year = {2021}, author = {Wu, BM and Bargaineer, J and Zhang, L and Yang, T and Xiong, ZG and Leng, TD}, title = {Upregulation of acid sensing ion channel 1a (ASIC1a) by hydrogen peroxide through the JNK pathway.}, journal = {Acta pharmacologica Sinica}, volume = {42}, number = {8}, pages = {1248-1255}, pmid = {33184449}, issn = {1745-7254}, support = {R01 NS128018/NS/NINDS NIH HHS/United States ; SC3 GM122593/GM/NIGMS NIH HHS/United States ; U54 MD007602/MD/NIMHD NIH HHS/United States ; }, mesh = {Acid Sensing Ion Channels/*metabolism ; Animals ; Butadienes/pharmacology ; Cell Line, Tumor ; Hydrogen Peroxide/*pharmacology ; Imidazoles/pharmacology ; MAP Kinase Signaling System/*drug effects ; Mice ; Neurons/drug effects/metabolism ; Nitriles/pharmacology ; Oxidative Stress/drug effects ; Protein Kinase Inhibitors/pharmacology ; Pyridines/pharmacology ; Up-Regulation/drug effects ; }, abstract = {Oxidative stress is intimately tied to neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, and acute injuries, such as ischemic stroke and traumatic brain injury. Acid sensing ion channel 1a (ASIC1a), a proton-gated ion channel, has been shown to be involved in the pathogenesis of these diseases. However, whether oxidative stress affects the expression of ASIC1a remains elusive. In the current study, we examined the effect of hydrogen peroxide (H2O2), a major reactive oxygen species (ROS), on ASIC1a protein expression and channel function in NS20Y cells and primary cultured mouse cortical neurons. We found that treatment of the cells with H2O2 (20 µM) for 6 h or longer increased ASIC1a protein expression and ASIC currents without causing significant cell injury. H2O2 incubation activated mitogen-activated protein kinases (MAPKs) pathways, including the extracellular signal-regulated kinase1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 pathways. We found that neither inhibition of the MEK/ERK pathway by U0126 nor inhibition of the p38 pathway by SB203580 affected H2O2-induced ASIC1a expression, whereas inhibition of the JNK pathway by SP600125 potently decreased ASIC1a expression and abolished the H2O2-mediated increase in ASIC1a expression and ASIC currents. Furthermore, we found that H2O2 pretreatment increased the sensitivity of ASIC currents to the ASIC1a inhibitor PcTx1, providing additional evidence that H2O2 increases the expression of functional ASIC1a channels. Together, our data demonstrate that H2O2 increases ASIC1a expression/activation through the JNK signaling pathway, which may provide insight into the pathogenesis of neurological disorders that involve both ROS and activation of ASIC1a.}, }
@article {pmid33180261, year = {2022}, author = {Venkataraman, L and Fair, SR and McElroy, CA and Hester, ME and Fu, H}, title = {Modeling neurodegenerative diseases with cerebral organoids and other three-dimensional culture systems: focus on Alzheimer's disease.}, journal = {Stem cell reviews and reports}, volume = {18}, number = {2}, pages = {696-717}, pmid = {33180261}, issn = {2629-3277}, support = {K01 AG056673/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism/pathology ; Animals ; Brain/metabolism ; Humans ; *Induced Pluripotent Stem Cells ; *Neurodegenerative Diseases ; Organoids/pathology ; }, abstract = {Many neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis and Huntington's disease, are characterized by the progressive accumulation of abnormal proteinaceous assemblies in specific cell types and regions of the brain, leading to cellular dysfunction and brain damage. Although animal- and in vitro-based studies of NDs have provided the field with an extensive understanding of some of the mechanisms underlying these diseases, findings from these studies have not yielded substantial progress in identifying treatment options for patient populations. This necessitates the development of complementary model systems that are better suited to recapitulate human-specific features of ND pathogenesis. Three-dimensional (3D) culture systems, such as cerebral organoids generated from human induced pluripotent stem cells, hold significant potential to model NDs in a complex, tissue-like environment. In this review, we discuss the advantages of 3D culture systems and 3D modeling of NDs, especially AD and FTD. We also provide an overview of the challenges and limitations of the current 3D culture systems. Finally, we propose a few potential future directions in applying state-of-the-art technologies in 3D culture systems to understand the mechanisms of NDs and to accelerate drug discovery. Graphical abstract.}, }
@article {pmid33176866, year = {2020}, author = {Chen, CC and Chen, RF and Shao, JS and Li, YT and Wang, YC and Brandacher, G and Chuang, JH and Kuo, YR}, title = {Adipose-derived stromal cells modulating composite allotransplant survival is correlated with B cell regulation in a rodent hind-limb allotransplantation model.}, journal = {Stem cell research &amp; therapy}, volume = {11}, number = {1}, pages = {478}, pmid = {33176866}, issn = {1757-6512}, mesh = {Adipose Tissue ; Animals ; B-Lymphocytes ; Hindlimb ; *Mesenchymal Stem Cells ; Rats ; Rats, Inbred Lew ; *Rodentia ; }, abstract = {BACKGROUND: Our previous studies demonstrated that adipose-derived mesenchymal stromal cells (ASCs) have immunomodulatory effects that prolong allograft survival in a rodent hind-limb allotransplant model. In this study, we investigated whether the effects of immunomodulation by ASCs on allograft survival are correlated with B cell regulation.<br><br>METHODS: B cells isolated from splenocytes were cocultured with ASCs harvested from adipose tissue from rodent groin areas for in vitro experiments. In an in vivo study, hind-limb allotransplantation from Brown-Norway to Lewis rats was performed, and rats were treated with ASCs combined with short-term treatment with anti-lymphocyte serum (ALS)/cyclosporine (CsA) as immunosuppressants. Peripheral blood and transplanted tissue were collected for further analysis.<br><br>RESULT: An in vitro study revealed that ASCs significantly suppressed lipopolysaccharide-activated B cell proliferation and increased the percentage of Bregs. The levels of immunoregulatory cytokines, such as TGF-&#x3b2;1 and IL-10, were significantly increased in supernatants of stimulated B cells cocultured with ASCs. The in vivo study showed that treatment with ASCs combined with short-term ALS/CsA significantly reduced the B cell population in alloskin tissue, increased the proportion of circulating CD45Ra[+]/Foxp3[+] B cells, and decreased C4d expression in alloskin.<br><br>CONCLUSION: ASCs combined with short-term immunosuppressant treatment prolong allograft survival and are correlated with B cell regulation, C4d expression and the modulation of immunoregulatory cytokines.}, }
@article {pmid33174532, year = {2020}, author = {Ruiz-Ruiz, C and García-Magro, N and Negredo, P and Avendaño, C and Bhattacharya, A and Ceusters, M and García, AG}, title = {Chronic administration of P2X7 receptor antagonist JNJ-47965567 delays disease onset and progression, and improves motor performance in ALS SOD1[G93A] female mice.}, journal = {Disease models &amp; mechanisms}, volume = {13}, number = {10}, pages = {}, pmid = {33174532}, issn = {1754-8411}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Animals ; Cell Survival/drug effects ; *Disease Progression ; Endpoint Determination ; Female ; Humans ; Mice, Inbred C57BL ; Mice, Transgenic ; *Motor Activity/drug effects ; Motor Neurons/drug effects/pathology ; Niacinamide/administration &amp; dosage/*analogs &amp; derivatives/chemistry/pharmacology/therapeutic use ; Piperazines/*administration &amp; dosage/chemistry/pharmacology/*therapeutic use ; Purinergic P2X Receptor Antagonists/*administration &amp; dosage/chemistry/pharmacology/*therapeutic use ; Receptors, Purinergic P2X7/*metabolism ; Rotarod Performance Test ; Survival Analysis ; Weight Loss/drug effects ; }, abstract = {Neuroinflammation is one of the main physiopathological mechanisms of amyotrophic lateral sclerosis (ALS), produced by the chronic activation of microglia in the CNS. This process is triggered by the persistent activation of the ATP-gated P2X7 receptor (P2RX7, hereafter referred to as P2X7R). The present study aimed to evaluate the effects of the chronic treatment with the P2X7R antagonist JNJ-47965567 in the development and progression of ALS in the SOD1[G93A] murine model. SOD1[G93A] mice were intraperitoneally (i.p.) injected with either 30 mg/kg of JNJ-47965567 or vehicle 4 times per week, from pre-onset age (here, postnatal day 60; P60) until study endpoint. Body weight, motor coordination, phenotypic score, disease onset and survival were measured throughout the study, and compared between vehicle- and drug-injected groups. Treatment with the P2X7R antagonist JNJ-47965567 delayed disease onset, reduced body weight loss and improved motor coordination and phenotypic score in female SOD1[G93A] mice, although it did not increase lifespan. Interestingly, neither beneficial nor detrimental effects were observed in males in any of the analyzed parameters. Treatment did not affect motor neuron survival or ChAT, Iba-1 and P2X7R protein expression in endpoint individuals of mixed sexes. Overall, chronic administration of JNJ-47965567 for 4 times per week to SOD1[G93A] mice from pre-onset stage altered disease progression in female individuals while it did not have any effect in males. Our results suggest a partial, yet important, effect of P2X7R in the development and progression of ALS.}, }
@article {pmid33173626, year = {2020}, author = {Ortiz, JF and Khan, SA and Salem, A and Lin, Z and Iqbal, Z and Jahan, N}, title = {Post-Marketing Experience of Edaravone in Amyotrophic Lateral Sclerosis: A Clinical Perspective and Comparison With the Clinical Trials of the Drug.}, journal = {Cureus}, volume = {12}, number = {10}, pages = {e10818}, pmid = {33173626}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease that affects the upper and lower motor neurons. Currently, the only treatment for ALS is riluzole, which only has a limited effect on increasing survival from 3 to 6 months. New therapies are needed in the clinical setting for ALS. We aim to compare and contrast the clinical trials of edaravone and the post-marketing experience of the drug during this study. For the method, a search strategy was made using PubMed with the search terms "Amyotrophic lateral sclerosis" (MeSH) and "Edaravone" (MeSH). For inclusion criteria, we used full papers, studies involving humans, and studies published in the English language. We exclude meta-analyses, literature reviews, systematic reviews, studies involving animals, and studies not published in English. After close examination, 20 papers were used for the discussion in this review. The clinical trials showed efficacy in patients in reducing the revised ALS functional rating scale (ALSFRS-R) in patients with early ALS with selective criteria. We documented edaravone's post-marketing experience in six countries: Kuwait, South Korea, Argentina, United States, Israel, and Italy. During the study we analyzed, the forced vital capacity (FVC) and ALSFRS-R scored, together with edaravone's safety in the clinical trials and post-marketing experience. Edaravone seems to be more effective in Asia, where the ALSFRS-R scores and the FVC decline were similar to the clinical trial results in Japan. Studies in Europe did not find the drug clinically useful. At the same time, studies in United States and Argentina were mainly descriptive, so more information is needed to evaluate the drug's efficacy in that part of the world. The drug was well-tolerated in all studies. In conclusion, more studies need to be done worldwide to carry out and clarify the effectiveness of edaravone in the clinical setting.}, }
@article {pmid33172304, year = {2021}, author = {Schwartz, JL and Jones, KL and Yeo, GW}, title = {Repeat RNA expansion disorders of the nervous system: post-transcriptional mechanisms and therapeutic strategies.}, journal = {Critical reviews in biochemistry and molecular biology}, volume = {56}, number = {1}, pages = {31-53}, pmid = {33172304}, issn = {1549-7798}, support = {R01 EY029166/EY/NEI NIH HHS/United States ; R01 NS103172/NS/NINDS NIH HHS/United States ; R56 AG069098/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics ; Animals ; Ataxia/drug therapy/*genetics ; Fragile X Syndrome/drug therapy/*genetics ; Frontotemporal Dementia/drug therapy/*genetics ; Humans ; Huntington Disease/drug therapy/*genetics ; Molecular Targeted Therapy/methods ; Muscular Atrophy, Spinal/drug therapy/*genetics ; Myotonic Dystrophy/drug therapy/*genetics ; Neurons/metabolism ; Protein Biosynthesis/genetics ; RNA Processing, Post-Transcriptional/*genetics ; RNA, Messenger/genetics/metabolism ; Transcription, Genetic/genetics ; Tremor/drug therapy/*genetics ; Trinucleotide Repeat Expansion/*genetics ; }, abstract = {Dozens of incurable neurological disorders result from expansion of short repeat sequences in both coding and non-coding regions of the transcriptome. Short repeat expansions underlie microsatellite repeat expansion (MRE) disorders including myotonic dystrophy (DM1, CUG50-3,500 in DMPK; DM2, CCTG75-11,000 in ZNF9), fragile X tremor ataxia syndrome (FXTAS, CGG50-200 in FMR1), spinal bulbar muscular atrophy (SBMA, CAG40-55 in AR), Huntington's disease (HD, CAG36-121 in HTT), C9ORF72- amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD and C9-ALS/FTD, GGGGCC in C9ORF72), and many others, like ataxias. Recent research has highlighted several mechanisms that may contribute to pathology in this heterogeneous class of neurological MRE disorders - bidirectional transcription, intranuclear RNA foci, and repeat associated non-AUG (RAN) translation - which are the subject of this review. Additionally, many MRE disorders share similar underlying molecular pathologies that have been recently targeted in experimental and preclinical contexts. We discuss the therapeutic potential of versatile therapeutic strategies that may selectively target disrupted RNA-based processes and may be readily adaptable for the treatment of multiple MRE disorders. Collectively, the strategies under consideration for treatment of multiple MRE disorders include reducing levels of toxic RNA, preventing RNA foci formation, and eliminating the downstream cellular toxicity associated with peptide repeats produced by RAN translation. While treatments are still lacking for the majority of MRE disorders, several promising therapeutic strategies have emerged and will be evaluated within this review.}, }
@article {pmid33161234, year = {2021}, author = {Côrtes, LR and Souza-Fabjan, JMG and Dias, DS and Martins, BB and Maia, ALRS and Veiga, MO and Arashiro, EKN and Brandão, FZ and Oliveira, MEF and Bartlewski, PM and Fonseca, JF}, title = {Administration of a single dose of 300 IU of human chorionic gonadotropin seven days after the onset of estrus improves pregnancy rate in dairy goats by an unknown mechanism.}, journal = {Domestic animal endocrinology}, volume = {74}, number = {}, pages = {106579}, doi = {10.1016/j.domaniend.2020.106579}, pmid = {33161234}, issn = {1879-0054}, mesh = {Animals ; Female ; Pregnancy ; *Chorionic Gonadotropin/administration &amp; dosage ; Drug Administration Schedule ; *Goats/physiology ; *Pregnancy Rate ; *Reproductive Control Agents/administration &amp; dosage ; *Ovulation Induction/methods/veterinary ; }, abstract = {This study examined the effects of exogenous hCG administration on ovarian function and pregnancy rates in estrous-induced dairy goats during the transition into the breeding season. Eighty-six Toggenburg does received 60 mg of medroxyprogesterone acetate intravaginal sponge for 6 d plus 200 IU of equine chorionic gonadotropin and 30 μg of d-cloprostenol i.m. 24 h before sponge removal, and were then bred for 96 h. Seven days (D7) after first mating the does received either 1 mL of saline (the control group, n = 43) or 300 IU of hCG (the hCG-treated group, n = 43) i.m. Transrectal ovarian ultrasonography (B-mode and color Doppler) was performed on D7, D13, D17, and D21 and ultrasonographic pregnancy detection on D30. Pregnancy rate was higher (P < 0.05) in hCG-treated goats (90.7%; 39/43) than that in control animals (74.4%; 32/43). Accessory luteal structures (ALSs) were detected in 46.5% (20/43) of hCG-treated does. All hCG-treated does that had ALSs and 82.6% of goats without ALS post-treatment remained pregnant. The total luteal area increased (P < 0.05) from D7 to D13 in pregnant animals of both groups, whereas mean vascular area declined (P < 0.05) by D21 in all nonpregnant does. Serum progesterone concentrations increased (P < 0.05) on D21 in pregnant goats of both groups, but they were related to changes in luteal tissue content only in control does throughout the present study. Mean daily numbers of small- and medium-sized antral follicles decreased (P < 0.05) only in pregnant animals of both groups with a decline in medium follicle numbers occurring earlier in hCG-treated (D13) compared with control does (D17). To summarize, a single dose of hCG given on D7 after estrus was followed by a decrease in the number of medium-sized antral follicles in gestating hCG-treated does, induced the formation of ALSs in ~47% of all hCG-treated does, and significantly increased the pregnancy rate in estrous-induced Toggenburg goats in the transition to the breeding season.}, }
@article {pmid33158182, year = {2020}, author = {Nikseresht, S and Hilton, JBW and Kysenius, K and Liddell, JR and Crouch, PJ}, title = {Copper-ATSM as a Treatment for ALS: Support from Mutant SOD1 Models and Beyond.}, journal = {Life (Basel, Switzerland)}, volume = {10}, number = {11}, pages = {}, pmid = {33158182}, issn = {2075-1729}, support = {N/A//University of Melbourne/ ; 04_TRG_2017_Crouch//FightMND/ ; N/A//Motor Neurone Disease Australia/ ; }, abstract = {The blood-brain barrier permeant, copper-containing compound, Cu[II](atsm), has successfully progressed from fundamental research outcomes in the laboratory through to phase 2/3 clinical assessment in patients with the highly aggressive and fatal neurodegenerative condition of amyotrophic lateral sclerosis (ALS). The most compelling outcomes to date to indicate potential for disease-modification have come from pre-clinical studies utilising mouse models that involve transgenic expression of mutated superoxide dismutase 1 (SOD1). Mutant SOD1 mice provide a very robust mammalian model of ALS with high validity, but mutations in SOD1 account for only a small percentage of ALS cases in the clinic, with the preponderant amount of cases being sporadic and of unknown aetiology. As per other putative drugs for ALS developed and tested primarily in mutant SOD1 mice, this raises important questions about the pertinence of Cu[II](atsm) to broader clinical translation. This review highlights some of the challenges associated with the clinical translation of new treatment options for ALS. It then provides a brief account of pre-clinical outcomes for Cu[II](atsm) in SOD1 mouse models of ALS, followed by an outline of additional studies which report positive outcomes for Cu[II](atsm) when assessed in cell and mouse models of neurodegeneration which do not involve mutant SOD1. Clinical evidence for Cu[II](atsm) selectively targeting affected regions of the CNS in patients is also presented. Overall, this review summarises the existing evidence which indicates why clinical relevance of Cu[II](atsm) likely extends beyond the context of cases of ALS caused by mutant SOD1.}, }
@article {pmid33153477, year = {2020}, author = {Silva, DF and Candeias, E and Esteves, AR and Magalhães, JD and Ferreira, IL and Nunes-Costa, D and Rego, AC and Empadinhas, N and Cardoso, SM}, title = {Microbial BMAA elicits mitochondrial dysfunction, innate immunity activation, and Alzheimer's disease features in cortical neurons.}, journal = {Journal of neuroinflammation}, volume = {17}, number = {1}, pages = {332}, pmid = {33153477}, issn = {1742-2094}, support = {FMUC-PEPITA-2018//Faculdade de Medicina, Universidade de Coimbra/ ; MB-40-2016//Santa Casa da Miseric&#xf3;rdia de Lisboa/ ; POCI-01-0145-FEDER-030712//FCT-Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; }, mesh = {Alzheimer Disease/immunology/*pathology ; Amino Acids, Diamino/*pharmacology ; Animals ; Cerebral Cortex/*drug effects/immunology/pathology ; Cyanobacteria Toxins ; Immunity, Innate/*drug effects ; Mice ; Mitochondria/*drug effects/immunology/pathology ; Neurons/*drug effects/immunology/pathology ; }, abstract = {BACKGROUND: After decades of research recognizing it as a complex multifactorial disorder, sporadic Alzheimer's disease (sAD) still has no known etiology. Adding to the myriad of different pathways involved, bacterial neurotoxins are assuming greater importance in the etiology and/or progression of sAD. β-N-Methylamino-L-alanine (BMAA), a neurotoxin produced by some microorganisms namely cyanobacteria, was previously detected in the brains of AD patients. Indeed, the consumption of BMAA-enriched foods has been proposed to induce amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), which implicated this microbial metabolite in neurodegeneration mechanisms.<br><br>METHODS: Freshly isolated mitochondria from C57BL/6 mice were treated with BMAA and O2 consumption rates were determined. O2 consumption and glycolysis rates were also measured in mouse primary cortical neuronal cultures. Further, mitochondrial membrane potential and ROS production were evaluated by fluorimetry and the integrity of mitochondrial network was examined by immunofluorescence. Finally, the ability of BMAA to activate neuronal innate immunity was quantified by addressing TLRs (Toll-like receptors) expression, p65 NF-&#x3ba;B translocation into the nucleus, increased expression of NLRP3 (Nod-like receptor 3), and pro-IL-1&#x3b2;. Caspase-1 activity was evaluated using a colorimetric substrate and mature IL-1&#x3b2; levels were also determined by ELISA.<br><br>RESULTS: Treatment with BMAA reduced O2 consumption rates in both isolated mitochondria and in primary cortical cultures, with additional reduced glycolytic rates, decrease mitochondrial potential and increased ROS production. The mitochondrial network was found to be fragmented, which resulted in cardiolipin exposure that stimulated inflammasome NLRP3, reinforced by decreased mitochondrial turnover, as indicated by increased p62 levels. BMAA treatment also activated neuronal extracellular TLR4 and intracellular TLR3, inducing p65 NF-&#x3ba;B translocation into the nucleus and activating the transcription of NLRP3 and pro-IL-1&#x3b2;. Increased caspase-1 activity resulted in elevated levels of mature IL-1&#x3b2;. These alterations in mitochondrial metabolism and inflammation increased Tau phosphorylation and A&#x3b2; peptides production, two hallmarks of AD.<br><br>CONCLUSIONS: Here we propose a unifying mechanism for AD neurodegeneration in which a microbial toxin can induce mitochondrial dysfunction and activate neuronal innate immunity, which ultimately results in Tau and A&#x3b2; pathology. Our data show that neurons, alone, can mount inflammatory responses, a role previously attributed exclusively to glial cells.}, }
@article {pmid33153123, year = {2020}, author = {Reinoso-Sánchez, JF and Baroli, G and Duranti, G and Scaricamazza, S and Sabatini, S and Valle, C and Morlando, M and Casero, RA and Bozzoni, I and Mariottini, P and Ceci, R and Cervelli, M}, title = {Emerging Role for Linear and Circular Spermine Oxidase RNAs in Skeletal Muscle Physiopathology.}, journal = {International journal of molecular sciences}, volume = {21}, number = {21}, pages = {}, pmid = {33153123}, issn = {1422-0067}, support = {ARTICOLO 1, COMMI 314 337 LEGGE 232/2016//Grant to Department of Science, Roma Tre University (MIUR Italy Dipartimento di Eccellenza)/ ; MAE0067342//Research project of basic and technological research approved in the Protocols of Scientific and Technological Bilateral Cooperation funded by the Ministry of Health, Italy-United States of America. 2019 "Whole transcriptome analysis in models of extended/ ; MDBR-20-135-SRS (RAC)//Research grant from University of Pennsylvania Orphan Disease Center in partnership with the Snyder-Robinson Foundation/ ; CDR2.BANDO2017SS//Research grant from the University of Rome 'Foro Italico'/ ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; Cell Differentiation/genetics ; Cells, Cultured ; Disease Models, Animal ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Muscle Fibers, Skeletal/pathology/physiology ; Muscle, Skeletal/*metabolism/pathology ; Muscular Atrophy/*genetics/metabolism/pathology ; Oxidoreductases Acting on CH-NH Group Donors/*genetics/physiology ; RNA, Circular/*physiology ; RNA, Messenger/*physiology ; RNA, Untranslated/physiology ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; Polyamine Oxidase ; }, abstract = {Skeletal muscle atrophy is a pathological condition so far without effective treatment and poorly understood at a molecular level. Emerging evidence suggest a key role for circular RNAs (circRNA) during myogenesis and their deregulation has been reported to be associated with muscle diseases. Spermine oxidase (SMOX), a polyamine catabolic enzyme plays a critical role in muscle differentiation and the existence of a circRNA arising from SMOX gene has been recently identified. In this study, we evaluated the expression profile of circular and linear SMOX in both C2C12 differentiation and dexamethasone-induced myotubes atrophy. To validate our findings in vivo their expression levels were also tested in two murine models of amyotrophic lateral sclerosis: SOD1[G93A] and hFUS[+/+], characterized by progressive muscle atrophy. During C2C12 differentiation, linear and circular SMOX show the same trend of expression. Interestingly, in atrophy circSMOX levels significantly increased compared to the physiological state, in both in vitro and in vivo models. Our study demonstrates that SMOX represents a new player in muscle physiopathology and provides a scientific basis for further investigation on circSMOX RNA as a possible new therapeutic target for the treatment of muscle atrophy.}, }
@article {pmid33152451, year = {2021}, author = {Wen, J and Li, S and Zheng, C and Wang, F and Luo, Y and Wu, L and Cao, J and Guo, B and Yu, P and Zhang, G and Li, S and Sun, Y and Yang, X and Zhang, Z and Wang, Y}, title = {Tetramethylpyrazine nitrone improves motor dysfunction and pathological manifestations by activating the PGC-1α/Nrf2/HO-1 pathway in ALS mice.}, journal = {Neuropharmacology}, volume = {182}, number = {}, pages = {108380}, doi = {10.1016/j.neuropharm.2020.108380}, pmid = {33152451}, issn = {1873-7064}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism ; Animals ; Female ; Hand Strength/physiology ; Heme Oxygenase-1/*metabolism ; Humans ; Male ; Membrane Proteins/*metabolism ; Mice ; Mice, Transgenic ; Muscle, Skeletal/metabolism/pathology ; NF-E2-Related Factor 2/*metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/*metabolism ; Pyrazines/pharmacology/*therapeutic use ; Superoxide Dismutase-1/biosynthesis/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of upper and lower motor neurons that results in skeletal muscle atrophy, weakness and paralysis. Oxidative stress plays a key role in the pathogenesis of ALS, including familial forms of the disease arising from mutation of the gene coding for superoxide dismutase (SOD1). We have used the SOD1[G93A] ALS mouse model to investigate the efficacy of 2-[[(1,1-dimethylethyl)oxidoimino]-methyl]-3,5,6-trimethylpyrazine (TBN), a novel tetramethylpyrazine derivative armed with a powerful free-radical scavenging nitrone moiety. TBN was administered to mice by intraperitoneal or intragastric injection after the onset of motor deficits. TBN slowed the progression of motor neuron disease as evidenced by improved motor performance, reduced spinal motor neuron loss and the associated glial response, and decreased skeletal muscle fiber denervation and fibrosis. TBN treatment activated mitochondrial antioxidant activity through the PGC-1α/Nrf2/HO-1 pathway and decreased the expression of human SOD1. These findings suggest that TBN holds promise as a therapeutic agent for ALS.}, }
@article {pmid33146585, year = {2021}, author = {Singer, JM and Rocha, FM and Pedroso-de-Lima, AC and Silva, GL and Coatti, GC and Zatz, M}, title = {Random changepoint segmented regression with smooth transition.}, journal = {Statistical methods in medical research}, volume = {30}, number = {3}, pages = {643-654}, doi = {10.1177/0962280220964953}, pmid = {33146585}, issn = {1477-0334}, mesh = {*Algorithms ; Animals ; Linear Models ; Mice ; *Software ; }, abstract = {We consider random changepoint segmented regression models to analyse data from a study conducted to verify whether treatment with stem cells may delay the onset of a symptom of amyotrophic lateral sclerosis in genetically modified mice. The proposed models capture the biological aspects of the data, accommodating a smooth transition between the periods with and without symptoms. An additional changepoint is considered to avoid negative predicted responses. Given the nonlinear nature of the model, we propose an algorithm to estimate the fixed parameters and to predict the random effects by fitting linear mixed models iteratively via standard software. We compare the variances obtained in the final step with bootstrapped and robust ones.}, }
@article {pmid33144500, year = {2020}, author = {Lin, Y and Zhou, X and Kato, M and Liu, D and Ghaemmaghami, S and Tu, BP and McKnight, SL}, title = {Redox-mediated regulation of an evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {117}, number = {46}, pages = {28727-28734}, pmid = {33144500}, issn = {1091-6490}, support = {R35 GM136370/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; R35 GM119502/GM/NIGMS NIH HHS/United States ; R35 GM130358/GM/NIGMS NIH HHS/United States ; S10 OD025242/OD/NIH HHS/United States ; R01 NS115546/NS/NINDS NIH HHS/United States ; S10 OD021685/OD/NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Ataxin-2/*metabolism ; Conserved Sequence ; DNA-Binding Proteins/*metabolism ; HEK293 Cells ; Humans ; Polymerization ; Protein Domains ; Reactive Oxygen Species/metabolism ; }, abstract = {A methionine-rich low complexity (LC) domain is found within a C-terminal region of the TDP43 RNA-binding protein. Self-association of this domain leads to the formation of labile cross-β polymers and liquid-like droplets. Treatment with H2O2 caused phenomena of methionine oxidation and droplet melting that were reversed upon exposure of the oxidized protein to methionine sulfoxide reductase enzymes. Morphological features of the cross-β polymers were revealed by H2O2-mediated footprinting. Equivalent TDP43 LC domain footprints were observed in polymerized hydrogels, liquid-like droplets, and living cells. The ability of H2O2 to impede cross-β polymerization was abrogated by the prominent M337V amyotrophic lateral sclerosis-causing mutation. These observations may offer insight into the biological role of TDP43 in facilitating synapse-localized translation as well as aberrant aggregation of the protein in neurodegenerative diseases.}, }
@article {pmid33144094, year = {2021}, author = {Soto, T and Buzzi, ED and Rotstein, NP and German, OL and Politi, LE}, title = {Damaging effects of BMAA on retina neurons and Müller glial cells.}, journal = {Experimental eye research}, volume = {202}, number = {}, pages = {108342}, doi = {10.1016/j.exer.2020.108342}, pmid = {33144094}, issn = {1096-0007}, mesh = {Amino Acids, Diamino/*toxicity ; Animals ; Animals, Newborn ; Cell Survival/drug effects ; Cyanobacteria Toxins ; DNA Fragmentation/drug effects ; Dizocilpine Maleate/pharmacology ; Ependymoglial Cells/*drug effects/pathology ; Excitatory Amino Acid Agonists/*toxicity ; Excitatory Amino Acid Antagonists/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors ; Retinal Diseases/*chemically induced/metabolism/prevention &amp; control ; Retinal Neurons/*drug effects/pathology ; }, abstract = {B-N-methylamino-L-alanine (BMAA), a cyanotoxin produced by most cyanobacteria, has been proposed to cause long term damages leading to neurodegenerative diseases, including Amyotrophic Lateral Sclerosis/Parkinsonism Dementia complex (ALS/PDC) and retinal pathologies. Previous work has shown diverse mechanisms leading to BMAA-induced degeneration; however, the underlying mechanisms of toxicity affecting retina cells are not fully elucidated. We here show that BMAA treatment of rat retina neurons in vitro induced nuclear fragmentation and cell death in both photoreceptors (PHRs) and amacrine neurons, provoking mitochondrial membrane depolarization. Pretreatment with the N-Methyl-D-aspartate (NMDA) receptor antagonist MK-801 prevented BMAA-induced death of amacrine neurons, but not that of PHRs, implying activation of NMDA receptors participated only in amacrine cell death. Noteworthy, BMAA stimulated a selective axonal outgrowth in amacrine neurons, simultaneously promoting growth cone destabilization. BMAA partially decreased the viability of Müller glial cells (MGC), the main glial cell type in the retina, induced marked alterations in their actin cytoskeleton and impaired their capacity to protect retinal neurons. BMAA also induced cell death and promoted axonal outgrowth in differentiated rat pheochromocytoma (PC12) cells, implying these effects were not limited to amacrine neurons. These results suggest that BMAA is toxic for retina neurons and MGC and point to the involvement of NMDA receptors in amacrine cell death, providing new insight into the mechanisms involved in BMAA neurotoxic effects in the retina.}, }
@article {pmid33139114, year = {2021}, author = {Mathew, B and Ruiz, P and Dutta, S and Entrekin, JT and Zhang, S and Patel, KD and Simmons, MS and Augelli-Szafran, CE and Cowell, RM and Suto, MJ}, title = {Structure-activity relationship (SAR) studies of N-(3-methylpyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (SRI-22819) as NF-ҡB activators for the treatment of ALS.}, journal = {European journal of medicinal chemistry}, volume = {210}, number = {}, pages = {112952}, doi = {10.1016/j.ejmech.2020.112952}, pmid = {33139114}, issn = {1768-3254}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Cell Line ; Humans ; Mice ; Molecular Docking Simulation ; NF-kappa B/*agonists/metabolism ; Oxadiazoles/chemistry/pharmacokinetics/pharmacology ; Structure-Activity Relationship ; Superoxide Dismutase/metabolism ; }, abstract = {ALS is a rare type of progressive neurological disease with unknown etiology. It results in the gradual degeneration and death of motor neurons responsible for controlling the voluntary muscles. Identification of mutations in the superoxide dismutase (SOD) 1 gene has been the most significant finding in ALS research. SOD1 abnormalities have been associated with both familial as well as sporadic ALS cases. SOD2 is a highly inducible SOD that performs in concurrence with SOD1 to detoxify ROS. Induction of SOD2 can be obtained through activation of NF-ҡBs. We previously reported that SRI-22819 increases NF-ҡB expression and activation in vitro, but it has poor ADME properties in general and has no oral bioavailability. Our initial studies were focused on direct modifications of SRI-22819. There were active compounds identified but no improvement in microsomal stability was observed. In this context, we focused on making more significant structural changes in the core of the molecule. Ataluren, an oxadiazole compound that promotes read-through and expression of dystrophin in patients with Duchenne muscular dystrophy, bears some structural similarity to SRI-22819. Thus, we synthesized a series of SRI-22819 and Ataluren (PTC124) hybrid compounds. Several compounds from this series exhibited improved activity, microsomal stability and lower calculated polar surface area (PSA). This manuscript describes the synthesis and biological evaluation of SRI-22819 analogs and its hybrid combination with Ataluren.}, }
@article {pmid33138865, year = {2020}, author = {Hinkelbein, J and Kerkhoff, S and Adler, C and Ahlbäck, A and Braunecker, S and Burgard, D and Cirillo, F and De Robertis, E and Glaser, E and Haidl, TK and Hodkinson, P and Iovino, IZ and Jansen, S and Johnson, KVL and Jünger, S and Komorowski, M and Leary, M and Mackaill, C and Nagrebetsky, A and Neuhaus, C and Rehnberg, L and Romano, GM and Russomano, T and Schmitz, J and Spelten, O and Starck, C and Thierry, S and Velho, R and Warnecke, T}, title = {Cardiopulmonary resuscitation (CPR) during spaceflight - a guideline for CPR in microgravity from the German Society of Aerospace Medicine (DGLRM) and the European Society of Aerospace Medicine Space Medicine Group (ESAM-SMG).}, journal = {Scandinavian journal of trauma, resuscitation and emergency medicine}, volume = {28}, number = {1}, pages = {108}, pmid = {33138865}, issn = {1757-7241}, mesh = {Aerospace Medicine/*methods ; Cardiopulmonary Resuscitation/*methods ; *Consensus ; Critical Care/*methods ; Emergencies ; Europe ; Heart Arrest/*therapy ; Humans ; *Societies, Medical ; *Space Flight ; }, abstract = {BACKGROUND: With the "Artemis"-mission mankind will return to the Moon by 2024. Prolonged periods in space will not only present physical and psychological challenges to the astronauts, but also pose risks concerning the medical treatment capabilities of the crew. So far, no guideline exists for the treatment of severe medical emergencies in microgravity. We, as a international group of researchers related to the field of aerospace medicine and critical care, took on the challenge and developed a an evidence-based guideline for the arguably most severe medical emergency - cardiac arrest.<br><br>METHODS: After the creation of said international group, PICO questions regarding the topic cardiopulmonary resuscitation in microgravity were developed to guide the systematic literature research. Afterwards a precise search strategy was compiled which was then applied to "MEDLINE". Four thousand one hundred sixty-five findings were retrieved and consecutively screened by at least 2 reviewers. This led to 88 original publications that were acquired in full-text version and then critically appraised using the GRADE methodology. Those studies formed to basis for the guideline recommendations that were designed by at least 2 experts on the given field. Afterwards those recommendations were subject to a consensus finding process according to the DELPHI-methodology.<br><br>RESULTS: We recommend a differentiated approach to CPR in microgravity with a division into basic life support (BLS) and advanced life support (ALS) similar to the Earth-based guidelines. In immediate BLS, the chest compression method of choice is the Evetts-Russomano method (ER), whereas in an ALS scenario, with the patient being restrained on the Crew Medical Restraint System, the handstand method (HS) should be applied. Airway management should only be performed if at least two rescuers are present and the patient has been restrained. A supraglottic airway device should be used for airway management where crew members untrained in tracheal intubation (TI) are involved.<br><br>DISCUSSION: CPR in microgravity is feasible and should be applied according to the Earth-based guidelines of the AHA/ERC in relation to fundamental statements, like urgent recognition and action, focus on high-quality chest compressions, compression depth and compression-ventilation ratio. However, the special circumstances presented by microgravity and spaceflight must be considered concerning central points such as rescuer position and methods for the performance of chest compressions, airway management and defibrillation.}, }
@article {pmid33131662, year = {2020}, author = {Cooksey, JA and Sergew, A}, title = {Noninvasive Ventilation in Amyotrophic Lateral Sclerosis.}, journal = {Sleep medicine clinics}, volume = {15}, number = {4}, pages = {527-538}, doi = {10.1016/j.jsmc.2020.08.004}, pmid = {33131662}, issn = {1556-4088}, mesh = {Amyotrophic Lateral Sclerosis/complications/*therapy ; Humans ; *Noninvasive Ventilation/standards ; Respiratory Insufficiency/etiology/*therapy ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease involving upper and lower motor neurons and has limited treatment options. The weakness progresses to involve the diaphragms, resulting in respiratory failure and death. Home noninvasive ventilation has been shown to improve survival and quality of life, especially in those with intact bulbar function. Once initiated, close monitoring with nocturnal oximetry, remote downloads from the home noninvasive ventilation machine, and measurement of serum bicarbonate should be conducted. Additionally, transcutaneous CO2 monitoring can be considered if available. This article discusses the indications, timing, initiation, and management of noninvasive ventilation in amyotrophic lateral sclerosis.}, }
@article {pmid33127590, year = {2021}, author = {Panchal, K and Tiwari, AK}, title = {Miro (Mitochondrial Rho GTPase), a key player of mitochondrial axonal transport and mitochondrial dynamics in neurodegenerative diseases.}, journal = {Mitochondrion}, volume = {56}, number = {}, pages = {118-135}, doi = {10.1016/j.mito.2020.10.005}, pmid = {33127590}, issn = {1872-8278}, mesh = {Apoptosis ; Axonal Transport ; Calcium/metabolism ; DNA, Mitochondrial/*genetics ; Humans ; Mitochondria/genetics/metabolism/*pathology ; Mitochondrial Dynamics ; Neurodegenerative Diseases/*metabolism ; Oxidative Stress ; rho GTP-Binding Proteins/*metabolism ; }, abstract = {Miro (mitochondrial Rho GTPases) a mitochondrial outer membrane protein, plays a vital role in the microtubule-based mitochondrial axonal transport, mitochondrial dynamics (fusion and fission) and Mito-Ca[2+] homeostasis. It forms a major protein complex with Milton (an adaptor protein), kinesin and dynein (motor proteins), and facilitates bidirectional mitochondrial axonal transport such as anterograde and retrograde transport. By forming this protein complex, Miro facilitates the mitochondrial axonal transport and fulfills the neuronal energy demand, maintain the mitochondrial homeostasis and neuronal survival. It has been demonstrated that altered mitochondrial biogenesis, improper mitochondrial axonal transport, and mitochondrial dynamics are the early pathologies associated with most of the neurodegenerative diseases (NDs). Being the sole mitochondrial outer membrane protein associated with mitochondrial axonal transport-related processes, Miro proteins can be one of the key players in various NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Thus, in the current review, we have discussed the evolutionarily conserved Miro proteins and its role in the pathogenesis of the various NDs. From this, we indicated that Miro proteins may act as a potential target for a novel therapeutic intervention for the treatment of various NDs.}, }
@article {pmid33126923, year = {2020}, author = {Huang, C and Yan, S and Zhang, Z}, title = {Maintaining the balance of TDP-43, mitochondria, and autophagy: a promising therapeutic strategy for neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {9}, number = {1}, pages = {40}, pmid = {33126923}, issn = {2047-9158}, support = {81922026//National Natural Science Foundation of China/International ; 91649115//National Natural Science Foundation of China/International ; 81872842//National Natural Science Foundation of China/International ; 82073821//National Natural Science Foundation of China/International ; 2017YFA0105104//National Key Research and Development Program of China Stem Cell and Translational Research/International ; 2017A020211019//Guang Dong Province science and technology plan project/International ; 2020A1515011061//Guang Dong Province science and technology plan project/International ; 21619104//Fundamental Research Funds for the Central Universities/International ; 202007030008//Guangzhou Key Research Program on Brain Science/International ; }, mesh = {Animals ; Autophagy/*physiology ; DNA-Binding Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Humans ; Mitochondria/genetics/*metabolism ; Neurodegenerative Diseases/genetics/*metabolism/*therapy ; Neurons/metabolism ; Protein Binding/physiology ; }, abstract = {Mitochondria are the energy center of cell operations and are involved in physiological functions and maintenance of metabolic balance and homeostasis in the body. Alterations of mitochondrial function are associated with a variety of degenerative and acute diseases. As mitochondria age in cells, they gradually become inefficient and potentially toxic. Acute injury can trigger the permeability of mitochondrial membranes, which can lead to apoptosis or necrosis. Transactive response DNA-binding protein 43 kDa (TDP-43) is a protein widely present in cells. It can bind to RNA, regulate a variety of RNA processes, and play a role in the formation of multi-protein/RNA complexes. Thus, the normal physiological functions of TDP-43 are particularly important for cell survival. Normal TDP-43 is located in various subcellular structures including mitochondria, mitochondrial-associated membrane, RNA particles and stress granules to regulate the endoplasmic reticulum-mitochondrial binding, mitochondrial protein translation, and mRNA transport and translation. Importantly, TDP-43 is associated with a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia and Alzheimer's disease, which are characterized by abnormal phosphorylation, ubiquitination, lysis or nuclear depletion of TDP-43 in neurons and glial cells. Although the pathogenesis of TDP-43 proteinopathy remains unknown, the presence of pathological TDP-43 inside or outside of mitochondria and the functional involvement of TDP-43 in the regulation of mitochondrial morphology, transport, and function suggest that mitochondria are associated with TDP-43-related diseases. Autophagy is a basic physiological process that maintains the homeostasis of cells, including targeted clearance of abnormally aggregated proteins and damaged organelles in the cytoplasm; therefore, it is considered protective against neurodegenerative diseases. However, the combination of abnormal TDP-43 aggregation, mitochondrial dysfunction, and insufficient autophagy can lead to a variety of aging-related pathologies. In this review, we describe the current knowledge on the associations of mitochondria with TDP-43 and the role of autophagy in the clearance of abnormally aggregated TDP-43 and dysfunctional mitochondria. Finally, we discuss a novel approach for neurodegenerative treatment based on the knowledge.}, }
@article {pmid33123310, year = {2020}, author = {Pichla, M and Bartosz, G and Sadowska-Bartosz, I}, title = {The Antiaggregative and Antiamyloidogenic Properties of Nanoparticles: A Promising Tool for the Treatment and Diagnostics of Neurodegenerative Diseases.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {3534570}, pmid = {33123310}, issn = {1942-0994}, mesh = {Amyloidogenic Proteins/antagonists &amp; inhibitors/metabolism ; Antioxidants/chemistry ; Dendrimers/chemistry ; Humans ; Nanoparticles/*chemistry/therapeutic use/toxicity ; Neurodegenerative Diseases/*diagnosis/drug therapy/genetics ; Protein Aggregates/drug effects ; Quantum Dots/chemistry/therapeutic use/toxicity ; Reactive Oxygen Species/metabolism ; alpha-Synuclein/antagonists &amp; inhibitors/metabolism ; }, abstract = {Due to the progressive aging of the society, the prevalence and socioeconomic burden of neurodegenerative diseases are predicted to rise. The most common neurodegenerative disorders nowadays, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, can be classified as proteinopathies. They can be either synucleinopathies, amyloidopathies, tauopathies, or TDP-43-related proteinopathies; thus, nanoparticles with a potential ability to inhibit pathological protein aggregation and/or degrade already existing aggregates can be a promising approach in the treatment of neurodegenerative diseases. As it turns out, nanoparticles can be a double-edged sword; they can either promote or inhibit protein aggregation, depending on coating, shape, size, surface charge, and concentration. In this review, we aim to emphasize the need of a breakthrough in the treatment of neurodegenerative disorders and draw attention to nanomaterials, as they can also serve as a diagnostic tool for protein aggregates or can be used in a high-throughput screening for novel antiaggregative compounds.}, }
@article {pmid33120727, year = {2020}, author = {Sun, L and Zhao, W and Yan, M and Yang, B and Xiong, P and Zhao, S}, title = {The efficacy and safety of Chinese herbal compound combined with western medicine for amyotrophic lateral sclerosis: A protocol for systematic review and meta-analysis.}, journal = {Medicine}, volume = {99}, number = {43}, pages = {e21933}, pmid = {33120727}, issn = {1536-5964}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Combined Modality Therapy ; Drugs, Chinese Herbal/*therapeutic use ; Humans ; Medicine, Chinese Traditional ; *Meta-Analysis as Topic ; Research Design ; *Systematic Reviews as Topic ; }, abstract = {BACKGROUND: Traditional Chinese medicine (TCM) compound formulations are selected according to different populations, with strong targeting and less adverse reactions. As a complex disease, amyotrophic lateral sclerosis (ALS) has limited efficacy in the use of conventional treatment regiments, short life cycle, high cost, many side effects, and low quality of life. It is urgent to seek new alternative therapies. Clinical practice shows that Chinese herbal compound combined with western medicine has certain therapeutic advantages, but there is no evidence of evidence-based medicine. The purpose of this study was to evaluate the efficacy and safety of Chinese herbal compound combined with western medicine in the treatment of ALS.<br><br>METHODS: Use computer to retrieve English database (PubMed, Embase, Web of Science, the Cochrane Library) and Chinese database (CNKI, Wanfang Database, Weipu database, and China Biomedical Literature Service System), moreover manually retrieve Baidu academic and Google academic from the establishment of the database to 2020 July for randomized controlled clinical study on ALS treated with compound Chinese medicine with western medicine therapy, 2 researchers independently conducted data extraction and literature quality evaluation on the quality of the included studies, and meta-analysis of the included literature was carried out using RevMan5.3 software.<br><br>RESULTS: This study evaluated the efficacy and safety of TCM combined with western medicine in the treatment of ALS by means of effective rate, improved Norris scale, ALS Functional Rating Scale, TCM syndrome score, and adverse reaction incidence.<br><br>CONCLUSION: This study will provide reliable evidence for the clinical application of Chinese herbal compound combined with western medicine in the treatment of ALS.OSF registration number: DOI 10.17605/OSF.IO/R5XG4.}, }
@article {pmid33118185, year = {2021}, author = {Tran, TD and Lesaffre, E and Verbeke, G and Molenberghs, G}, title = {Serial correlation structures in latent linear mixed models for analysis of multivariate longitudinal ordinal responses.}, journal = {Statistics in medicine}, volume = {40}, number = {3}, pages = {578-592}, doi = {10.1002/sim.8790}, pmid = {33118185}, issn = {1097-0258}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Linear Models ; Longitudinal Studies ; Multivariate Analysis ; }, abstract = {We propose a latent linear mixed model to analyze multivariate longitudinal data of multiple ordinal variables, which are manifestations of fewer continuous latent variables. We focus on the latent level where the effects of observed covariates on the latent variables are of interest. We incorporate serial correlation into the variance component rather than assuming independent residuals. We show that misleading inference may be drawn when misspecifying the variance component. Furthermore, we provide a graphical tool depicting latent empirical semi-variograms to detect serial correlation for latent stationary linear mixed models. We apply our proposed model to examine the treatment effect on patients having the amyotrophic lateral sclerosis disease. The result shows that the treatment can slow down progression of latent cervical and lumbar functions.}, }
@article {pmid33117120, year = {2020}, author = {Sipione, S and Monyror, J and Galleguillos, D and Steinberg, N and Kadam, V}, title = {Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {572965}, pmid = {33117120}, issn = {1662-4548}, abstract = {Gangliosides are glycosphingolipids highly abundant in the nervous system, and carry most of the sialic acid residues in the brain. Gangliosides are enriched in cell membrane microdomains ("lipid rafts") and play important roles in the modulation of membrane proteins and ion channels, in cell signaling and in the communication among cells. The importance of gangliosides in the brain is highlighted by the fact that loss of function mutations in ganglioside biosynthetic enzymes result in severe neurodegenerative disorders, often characterized by very early or childhood onset. In addition, changes in the ganglioside profile (i.e., in the relative abundance of specific gangliosides) were reported in healthy aging and in common neurological conditions, including Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), stroke, multiple sclerosis and epilepsy. At least in HD, PD and in some forms of epilepsy, experimental evidence strongly suggests a potential role of gangliosides in disease pathogenesis and potential treatment. In this review, we will summarize ganglioside functions that are crucial to maintain brain health, we will review changes in ganglioside levels that occur in major neurological conditions and we will discuss their contribution to cellular dysfunctions and disease pathogenesis. Finally, we will review evidence of the beneficial roles exerted by gangliosides, GM1 in particular, in disease models and in clinical trials.}, }
@article {pmid33114553, year = {2020}, author = {Gavriilaki, M and Kimiskidis, VK and Gavriilaki, E}, title = {Precision Medicine in Neurology: The Inspirational Paradigm of Complement Therapeutics.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {33114553}, issn = {1424-8247}, abstract = {Precision medicine has emerged as a central element of healthcare science. Complement, a component of innate immunity known for centuries, has been implicated in the pathophysiology of numerous incurable neurological diseases, emerging as a potential therapeutic target and predictive biomarker. In parallel, the innovative application of the first complement inhibitor in clinical practice as an approved treatment of myasthenia gravis (MG) and neuromyelitis optica spectrum disorders (NMOSD) related with specific antibodies raised hope for the implementation of personalized therapies in detrimental neurological diseases. A thorough literature search was conducted through May 2020 at MEDLINE, EMBASE, Cochrane Library and ClinicalTrials.gov databases based on medical terms (MeSH)" complement system proteins" and "neurologic disease". Complement's role in pathophysiology, monitoring of disease activity and therapy has been investigated in MG, multiple sclerosis, NMOSD, spinal muscular atrophy, amyotrophic lateral sclerosis, Parkinson, Alzheimer, Huntington disease, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, stroke, and epilepsy. Given the complexity of complement diagnostics and therapeutics, this state-of-the-art review aims to provide a brief description of the complement system for the neurologist, an overview of novel complement inhibitors and updates of complement studies in a wide range of neurological disorders.}, }
@article {pmid33111546, year = {2021}, author = {Mehta, AK and Jackson, NJ and Wiedau-Pazos, M}, title = {Palliative Care Consults in an Inpatient Setting for Patients With Amyotrophic Lateral Sclerosis.}, journal = {The American journal of hospice &amp; palliative care}, volume = {38}, number = {9}, pages = {1091-1098}, doi = {10.1177/1049909120969959}, pmid = {33111546}, issn = {1938-2715}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Inpatients ; *Palliative Care ; Referral and Consultation ; Retrospective Studies ; }, abstract = {BACKGROUND: Limited data about the frequency and outcomes of palliative care (PC) specialty consultations for patients with amyotrophic lateral sclerosis (ALS) are available.<br><br>METHODS: This study was a retrospective chart review. Patients with ALS admitted to 2 academic hospitals from 2013-2018 were included. We compared patients who were seen by an inpatient specialty PC service (PC group) with those who were not (NonPC group).<br><br>RESULTS: Twenty-four patients met inclusion criteria (9 PC group, 15 NonPC group). Patients in both groups were similar in age and had been diagnosed for a similar amount of time before admission. In the PC group, 6 patients were seen by more than 1 PC multidisciplinary team member (physician, social worker, spiritual care provider, clinical nurse specialist). PC consultations were requested for goals of care (GOC) (n = 7), pain (n = 4), hospice information/referral (n = 2), dyspnea (n = 1), and excessive oral secretions (n = 1). GOC topics addressed for both groups were code status, treatment preferences (tracheostomy placement, percutaneous endoscopic gastrostomy placement, change to comfort care), prognostication, and hospice information/referral. Patients in the PC group were significantly more likely to be discharged with GOC (89%, p = 0.02) and completed advance care planning (ACP) documents (89%, p = 0.04) than patients in the NonPC group (32%; 47%). Despite reason for consultation, at least 1 symptom was addressed for every patient seen by PC specialists.<br><br>CONCLUSIONS: Inpatient specialty PC consultation for patients with ALS leads to greater documentation of GOC and ACP by discharge. PC consultants participate in symptom management in patients with ALS during hospitalization.}, }
@article {pmid33109706, year = {2021}, author = {Al-Chalabi, A and Chiò, A and Merrill, C and Oster, G and Bornheimer, R and Agnese, W and Apple, S}, title = {Clinical staging in amyotrophic lateral sclerosis: analysis of Edaravone Study 19.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {92}, number = {2}, pages = {165-171}, pmid = {33109706}, issn = {1468-330X}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/drug therapy/pathology ; Disease Progression ; Double-Blind Method ; Edaravone/therapeutic use ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Neuroprotective Agents/therapeutic use ; Time Factors ; }, abstract = {OBJECTIVE: This was a post hoc analysis of the Edaravone Phase III Study MCI186-19 ('Study 19') to examine the utility of clinical staging systems as end points in clinical trials in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised item scores from Study 19 were retrospectively mapped to King's stage and Milano-Torino staging (MiToS) stage. We assessed the percentage of patients who experienced progression in King's and MiToS stages during Study 19. We also assessed disease progression in subgroups of patients according to baseline King's stage.<br><br>RESULTS: During double-blind treatment, the percentage of patients who experienced a progression in King's stage was lower for edaravone (42.0%, 95% CI 30.4% to 53.6%) than placebo (55.9%, 95% CI 44.1% to 67.6%). The most pronounced effect was noted among patients who were in stage 1 and was maintained throughout open-label treatment. An analysis of a &#x2265;2-stage progression in MiToS stage showed no difference between treatment arms during double-blind treatment, but during the open-label period, more rapid progression was noted among patients in the placebo-edaravone arm than among those in the edaravone-edaravone arm (log-rank test, p<0.001).<br><br>CONCLUSIONS: The King's and MiToS staging systems provided utility in assessing clinical progression in Edaravone Study 19. These findings may support the use of staging systems as end points in ALS clinical trials and to understand the timing of benefit as measured by these scales.}, }
@article {pmid33105491, year = {2020}, author = {Han, F and Lu, P}, title = {Introduction for Stem Cell-Based Therapy for Neurodegenerative Diseases.}, journal = {Advances in experimental medicine and biology}, volume = {1266}, number = {}, pages = {1-8}, doi = {10.1007/978-981-15-4370-8_1}, pmid = {33105491}, issn = {0065-2598}, support = {I01 RX002264/RX/RRD VA/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/therapy ; Animals ; Humans ; *Induced Pluripotent Stem Cells ; Neural Stem Cells ; *Neurodegenerative Diseases/therapy ; Parkinson Disease/therapy ; *Pluripotent Stem Cells ; *Stem Cell Transplantation ; }, abstract = {Neurodegenerative diseases (NDs) are a group of neurological diseases caused by the progressive degeneration of neurons and glial cells in the brain and spinal cords. Usually there is a selective loss of specific neuronal cells in a restricted brain area from any neurodegenerative diseases, such as dopamine (DA) neuron death in Parkinson disease (PD) and motor neuron loss in amyotrophic lateral sclerosis (ALS), or a widespread degeneration affecting many types of neurons in Alzheimer's disease (AD). As there is no effective treatment to stop the progression of these neurodegenerative diseases, stem cell-based therapies have provided great potentials for these disorders. Currently transplantation of different stem cells or their derivatives has improved neural function in animal models of neurodegenerative diseases by replacing the lost neural cells, releasing cytokines, modulation of inflammation, and mediating remyelination. With the advance in somatic cell reprogramming to generate induced pluripotent stem cells (iPS cells) and directly induced neural stem cells or neurons, pluripotent stem cell can be induced to differentiate to any kind of neural cells and overcome the immune rejection of the allogeneic transplantation. Recent studies have proved the effectiveness of transplanted stem cells in animal studies and some clinical trials on patients with NDs. However, some significant hurdles need to be resolved before these preclinical results can be translated to clinic. In particular, we need to better understand the molecular mechanisms of stem cell transplantation and develop new approaches to increase the directed neural differentiation, migration, survival, and functional connections of transplanted stem cells in the pathological environment of the patient's central nerve system.}, }
@article {pmid33101340, year = {2020}, author = {Wang, J and Chen, J and Li, X and Li, D and Li, Z and Cui, H}, title = {Pro-197-Ser Mutation in ALS and High-Level GST Activities: Multiple Resistance to ALS and ACCase Inhibitors in Beckmannia syzigachne.}, journal = {Frontiers in plant science}, volume = {11}, number = {}, pages = {572610}, pmid = {33101340}, issn = {1664-462X}, abstract = {American sloughgrass (Beckmannia syzigachne Steud.) is one of the most troublesome weeds infesting wheat and canola fields in China. Some biotypes cannot be controlled, either by acetolactate synthase (ALS) or acetyl coenzyme A carboxylase (ACCase) inhibitors, which are the main herbicides for controlling this weed. However, very few studies have investigated multiple resistance mechanism in B. syzigachne. In this study, a B. syzigachne biotype with a high resistance to ALS inhibitors we have reported was also showed relatively lower resistance to ACCase inhibitors, with a resistance index around 7. RNA-seq analysis was used to investigate the factors responsible for multiple resistance, and 60,108 unigenes were assembled by de novo transcriptome assembly and then annotated across eight databases. A Pro-197-Ser mutation was identified in the ALS gene by SNPs analysis and validated by PCR, while no mutation was identified in the ACCase gene. Nineteen candidate metabolic genes were screened and their overexpression was confirmed by qPCR. The expression of GST-T3 and GST-U6 in resistant plants ranged from 7.5- to 109.4-folds than that in susceptible ones at different times after two kinds of herbicide treatment. In addition, GST activities in resistant plants were 3.0-5.0 times higher than that in susceptible plants. Other novel resistance factors also showed high correlation with multiple resistance which included four genes encoding disease resistance proteins, a transcription factor (MYC3), and one gene conferring blight resistance. In this research, a B. syzigachne biotype was confirmed to have evolved multiple resistance to ACCase and ALS inhibitors. The Pro-197-Ser mutation in ALS gene and high-level GST activities were confirmed responsible for the multiple resistance. Characterized disease-resistance proteins, transcription factor, and blight-resistance proteins may play an essential role in these multiple herbicide resistance.}, }
@article {pmid33095366, year = {2021}, author = {Salari, N and Rasoulpoor, S and Hosseinian-Far, A and Razazian, N and Mansouri, K and Mohammadi, M and Vaisi-Raygani, A and Jalali, R and Shabani, S}, title = {Association between serum paraoxonase 1 activity and its polymorphisms with multiple sclerosis: a systematic review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {42}, number = {2}, pages = {491-500}, pmid = {33095366}, issn = {1590-3478}, mesh = {Alleles ; *Aryldialkylphosphatase/genetics ; Genotype ; Humans ; Iran ; *Multiple Sclerosis/genetics ; Polymorphism, Genetic ; }, abstract = {BACKGROUND: Human serum paraoxonase (PON) is an enzyme that is synthesized by the liver and enters the bloodstream, and it is transmitted by high-density lipoproteins (HDL). Paraoxonase 1 (PON1) is a hydrolytic enzyme with a wide range of substrates and the ability to protect against lipid oxidation. In this study, due to the activity of PON1 in the brain and its antioxidant effects on the reduction of neurological disorders in the central nervous system, the role of PON1 and its polymorphisms related to multiple sclerosis has been examined to enhance treatment methods.<br><br>METHODS: This article is a systematic review. In this study, the role of PON1 and its polymorphisms in multiple sclerosis (MS) has been investigated. Articles published in Persian and international databases of SID, Google Scholar, ISI (WoS), Magiran, PubMed, Scopus, IranDoc, Science Direct, and Iran Medix were examined, using the search keywords of Paraoxonase 1, polymorphism, multiple sclerosis, and PON1.<br><br>RESULTS: PON1 is undoubtedly a potential factor in the pathogenesis of multiple sclerosis, and it plays an important role in protecting antioxidants in the blood. Oxidative stress and lipid peroxidation are factors in the pathogenesis of MS. Both inflammatory cytokines and oxidative stress have a detrimental effect on PON1. However, reducing the activity of PON1 may help to restore the pathogenesis of the disease.<br><br>CONCLUSION: Decreased PON1 activity and PON1 polymorphism are associated with several neurological diseases, including ischemic stroke, white matter lesions (WMLs), amyotrophic lateral sclerosis (ALS), dementia, and Parkinson's disease. PON1-55M alleles in Italians and PON1-192Q alleles in Poles were associated with a high risk of MS. Moreover, PON1-55 and PON1-192 polymorphisms were not associated with MS onset age, nor its evolutionary type.}, }
@article {pmid33094209, year = {2020}, author = {Bianchi, VE and Rizzi, L and Bresciani, E and Omeljaniuk, RJ and Torsello, A}, title = {Androgen Therapy in Neurodegenerative Diseases.}, journal = {Journal of the Endocrine Society}, volume = {4}, number = {11}, pages = {bvaa120}, pmid = {33094209}, issn = {2472-1972}, abstract = {Neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington disease, are characterized by the loss of neurons as well as neuronal function in multiple regions of the central and peripheral nervous systems. Several studies in animal models have shown that androgens have neuroprotective effects in the brain and stimulate axonal regeneration. The presence of neuronal androgen receptors in the peripheral and central nervous system suggests that androgen therapy might be useful in the treatment of neurodegenerative diseases. To illustrate, androgen therapy reduced inflammation, amyloid-β deposition, and cognitive impairment in patients with AD. As well, improvements in remyelination in MS have been reported; by comparison, only variable results are observed in androgen treatment of PD. In ALS, androgen administration stimulated motoneuron recovery from progressive damage and regenerated both axons and dendrites. Only a few clinical studies are available in human individuals despite the safety and low cost of androgen therapy. Clinical evaluations of the effects of androgen therapy on these devastating diseases using large populations of patients are strongly needed.}, }
@article {pmid33093822, year = {2020}, author = {Chen, L and Wang, Y and Xie, J}, title = {A Human iPSC Line Carrying a de novo Pathogenic FUS Mutation Identified in a Patient With Juvenile ALS Differentiated Into Motor Neurons With Pathological Characteristics.}, journal = {Frontiers in cellular neuroscience}, volume = {14}, number = {}, pages = {273}, pmid = {33093822}, issn = {1662-5102}, abstract = {Human-induced pluripotent stem cells (hiPSCs) are used to establish patient-specific cell lines and are ideal models to mirror the pathological features of diseases and investigate their underlying mechanisms in vitro, especially for rare genic diseases. Here, a de novo mutation c.1509dupA (p.R503fs) in fused in sarcoma (FUS) was detected in a patient with sporadic juvenile amyotrophic lateral sclerosis (JALS). JALS is a rare and severe form of ALS with unclear pathogenesis and no effective cure. An induced pluripotent stem cell (iPSC) line carrying the de novo mutation was established, and it represents a good tool to study JALS pathogenesis and gene therapy strategies for the treatment of this condition. The established human iPSC line carrying the de novo FUS mutation strongly expressed pluripotency markers and could be differentiated into three embryonic germ layers with no gross chromosomal aberrations. Furthermore, the iPSCs could be successfully differentiated into motor neurons exhibiting the pathological characteristics of ALS. Our results indicate that this line may be useful for uncovering the pathogenesis of sporadic JALS and screen for drugs to treat this disorder.}, }
@article {pmid33093401, year = {2021}, author = {Chen, CC and Chen, RF and Wang, YC and Li, YT and Chuang, JH and Kuo, YR}, title = {Combination of a CD26 Inhibitor, G-CSF, and Short-term Immunosuppressants Modulates Allotransplant Survival and Immunoregulation in a Rodent Hindlimb Allotransplant Model.}, journal = {Transplantation}, volume = {105}, number = {6}, pages = {1250-1260}, doi = {10.1097/TP.0000000000003504}, pmid = {33093401}, issn = {1534-6080}, mesh = {Animals ; Antilymphocyte Serum/administration &amp; dosage ; CD4-Positive T-Lymphocytes/drug effects/immunology/metabolism ; Chemokine CXCL12/metabolism ; Composite Tissue Allografts/immunology/metabolism/*transplantation ; Cyclosporine/administration &amp; dosage ; Dipeptidyl Peptidase 4/immunology/*metabolism ; Dipeptidyl-Peptidase IV Inhibitors/*administration &amp; dosage ; Drug Administration Schedule ; Graft Rejection/immunology/metabolism/*prevention &amp; control ; Graft Survival/*drug effects ; Granulocyte Colony-Stimulating Factor/*administration &amp; dosage ; Hindlimb/immunology/metabolism/*transplantation ; Immunosuppressive Agents/*administration &amp; dosage ; Interleukin-10/metabolism ; Male ; Rats, Inbred BN ; Rats, Inbred Lew ; Time Factors ; Transforming Growth Factor beta1/metabolism ; *Vascularized Composite Allotransplantation/adverse effects ; Rats ; }, abstract = {BACKGROUND: Recent studies have demonstrated that inhibition of CD26 potentiates stromal cell-derived factor-1α (SDF-1α), promotes tissue regeneration, and suppresses the rejection of organ transplants. This study investigated whether the combination of a CD26 inhibitor (CD26i) with granulocyte colony-stimulating factor (G-CSF) and short-term immunosuppressants modulates vascularized composite tissue allotransplant survival in a rodent orthotopic hindlimb allotransplant model.<br><br>METHODS: The hindlimb allotransplantation from Brown-Norway to Lewis rats was divided into 4 groups. Group 1 (controls) did not receive any treatment. Group 2 was treated with short-term antilymphocyte serum (ALS) and cyclosporine-A (CsA). Group 3 was administrated CD26i and G-CSF. Group 4 received a combination of CD26i/G-CSF/ALS/CsA. Each subgroup comprised 10 rats. Peripheral blood and sampling of transplanted tissues were collected for immunological and histological analysis.<br><br>RESULTS: The results revealed that allotransplant survival was found to be significantly prolonged in group 4 with CD26i/G-CSF/ALS/CsA treatment compared with those in the other groups. The interleukin-10 and transforming growth factor-&#x3b2;l levels, the percentage of CD4+/CD25+/FoxP3+ T cells, as well as the levels of SDF-1&#x3b1; expressions were significantly increased in group 4 compared with those in the other groups. Group 4 revealed a statistical increase in the percentage of donor cells (RT1n) expression in the recipient peripheral blood, and the mixed lymphocyte reaction showed hyporesponsiveness of the T cells to donor alloantigens.<br><br>CONCLUSION: The combination of CD26i/G-CSF and short-term immunosuppressants prolongs allotransplant survival by inducing immunoregulatory effects and enhancing the percentage of SDF-1&#x3b1; expression. This immunomodulatory approach has great potential as a strategy to increase vascularized composite allotransplantation survival.}, }
@article {pmid33091034, year = {2020}, author = {Baldi, E and Sechi, GM and Mare, C and Canevari, F and Brancaglione, A and Primi, R and Palo, A and Contri, E and Ronchi, V and Beretta, G and Reali, F and Parogni, PP and Facchin, F and Rizzi, U and Bussi, D and Ruggeri, S and Oltrona Visconti, L and Savastano, S and , }, title = {Treatment of out-of-hospital cardiac arrest in the COVID-19 era: A 100 days experience from the Lombardy region.}, journal = {PloS one}, volume = {15}, number = {10}, pages = {e0241028}, pmid = {33091034}, issn = {1932-6203}, mesh = {Aged ; Aged, 80 and over ; Amiodarone/administration &amp; dosage ; *Betacoronavirus ; COVID-19 ; Cardiopulmonary Resuscitation ; Coronavirus Infections/*epidemiology/virology ; Defibrillators ; *Emergency Medical Services ; Epinephrine/administration &amp; dosage ; Female ; Humans ; Incidence ; Italy ; Longitudinal Studies ; Male ; Out-of-Hospital Cardiac Arrest/*therapy ; Pandemics ; Pneumonia, Viral/*epidemiology/virology ; Prospective Studies ; Registries ; SARS-CoV-2 ; Time Factors ; Vasoconstrictor Agents/administration &amp; dosage ; Vasodilator Agents/administration &amp; dosage ; }, abstract = {INTRODUCTION: An increase in the incidence of OHCA during the COVID-19 pandemic has been recently demonstrated. However, there are no data about how the COVID-19 epidemic influenced the treatment of OHCA victims.<br><br>METHODS: We performed an analysis of the Lombardia Cardiac Arrest Registry comparing all the OHCAs occurred in the Provinces of Lodi, Cremona, Pavia and Mantua (northern Italy) in the first 100 days of the epidemic with those occurred in the same period in 2019.<br><br>RESULTS: The OHCAs occurred were 694 in 2020 and 520 in 2019. Bystander cardiopulmonary resuscitation (CPR) rate was lower in 2020 (20% vs 31%, p<0.001), whilst the rate of bystander automated external defibrillator (AED) use was similar (2% vs 4%, p = 0.11). Resuscitation was attempted by EMS in 64.5% of patients in 2020 and in 72% in 2019, whereof 45% in 2020 and 64% in 2019 received ALS. At univariable analysis, the presence of suspected/confirmed COVID-19 was not a predictor of resuscitation attempt. Age, unwitnessed status, non-shockable presenting rhythm, absence of bystander CPR and EMS arrival time were independent predictors of ALS attempt. No difference regarding resuscitation duration, epinephrine and amiodarone administration, and mechanical compression device use were highlighted. The return of spontaneous circulation (ROSC) rate at hospital admission was lower in the general population in 2020 [11% vs 20%, p = 0.001], but was similar in patients with ALS initiated [19% vs 26%, p = 0.15]. Suspected/confirmed COVID-19 was not a predictor of ROSC at hospital admission.<br><br>CONCLUSION: Compared to 2019, during the 2020 COVID-19 outbreak we observed a lower attitude of laypeople to start CPR, while resuscitation attempts by BLS and ALS staff were not influenced by suspected/confirmed infection, even at univariable analysis.}, }
@article {pmid33086093, year = {2020}, author = {Colín, E and Ramírez-Jarquín, UN and Tapia, R}, title = {Early motor deficits in the phalangeal fine movements induced by chronic AMPA infusion in the rat spinal cord assessed by a novel method: Phalangeal tension recording test.}, journal = {Neuroscience letters}, volume = {739}, number = {}, pages = {135411}, doi = {10.1016/j.neulet.2020.135411}, pmid = {33086093}, issn = {1872-7972}, mesh = {Animals ; Disease Models, Animal ; Hand Strength ; Male ; Motor Neurons/*pathology ; Movement/*drug effects ; Rats, Wistar ; Receptors, AMPA/agonists ; Rotarod Performance Test ; Spinal Cord/*drug effects/*pathology ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/*administration &amp; dosage ; }, abstract = {Motor behavior alterations are a shared hallmark of neurodegenerative diseases affecting motor circuits, such as amyotrophic lateral sclerosis (ALS), Parkinson's, and Huntington's diseases. In patients and transgenic animal models of amyotrophic lateral sclerosis fine movements controlled by distal muscles are the first to be affected, but its study and knowledge remain poorly understood, mainly because most of the tests used for describing the motor alterations are focused on the function of proximal muscles and gross movements. In this study we demonstrate that alterations of phalangeal fine movements can be quantitatively evaluated using a novel procedure designed by us, phalangeal tension recording test, which showed high sensitivity to detect such alterations. The evaluation was carried out during the motor neuron (MN) degenerative process induced by the acute and chronic overactivation of AMPA receptors in the lumbar rat spinal cord, using previously described models. The new method allowed the quantification of significant alterations of the fine movements of the hindpaws phalanges when AMPA was infused in the lumbar segment controlling the distal muscles, but not when a more rostral spinal segment was infused, and these alterations were not detected by the rotarod or the stride tests. These changes occurred before the paralysis of the hindlimbs. Studying the early distal motor alterations before the total paralysis at late stages is essential for understanding the initial consequences of MN degeneration and therefore for designing new strategies for the control, treatment and prevention of MN diseases.}, }
@article {pmid33082770, year = {2020}, author = {Idiculla, PS and Govindarajan, R}, title = {A Case of Cervical Spondylotic Amyotrophy Mimicking Amyotrophic Lateral Sclerosis.}, journal = {Case reports in neurology}, volume = {12}, number = {3}, pages = {314-320}, pmid = {33082770}, issn = {1662-680X}, abstract = {Cervical spondylotic amyotrophy (CSA) is a rare clinical condition characterized by weakness and atrophy of the upper limb with minimal to no associated sensory deficits. The detection of the disease is based on clinical features at presentation, neurological examination, electrophysiological studies, and imaging. The proposed pathophysiological mechanisms include selective damage to the ventral root or anterior horn cells of the spinal cord. Depending on the muscle groups that are involved, CSA is broadly classified into a proximal type and a distal type. The clinical profiles of patients with CSA and ALS have a very close resemblance to each other, especially at the early stages of the disease. Cervical spine magnetic resonance imaging (MRI) may show T2 hyperintensity in both proximal and distal types. Electromyogram demonstrates denervation potentials and reduced motor unit potentials in the affected muscles. The conservative management is often the first-line modality, and those who fail to respond to conservative treatment have severe muscular atrophy and weakness, and distal-type CSA are considered potential candidates for surgery. We present the case of a 57-year-old female who presented with a 1-year history of left-hand weakness and wasting with no sensory deficits. She denied any involvement of her other hand or bilateral lower limbs, and she was referred to our clinic with the potential diagnosis of amyotrophic lateral sclerosis (ALS). An elaborate history, physical examination, electrophysiological studies, and imaging assisted us in reaching the diagnosis of CSA, 1 year after the onset of symptoms.}, }
@article {pmid33082217, year = {2021}, author = {Sancho, J and Burés, E and Ferrer, S and Lahosa, C and Signes-Costa, J and Servera, E}, title = {Mechanical Insufflation-Exsufflation With Oscillations in Amyotrophic Lateral Sclerosis With Home Ventilation via Tracheostomy.}, journal = {Respiratory care}, volume = {66}, number = {3}, pages = {378-383}, doi = {10.4187/respcare.08145}, pmid = {33082217}, issn = {1943-3654}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; Cough ; Cross-Over Studies ; Humans ; *Insufflation ; Prospective Studies ; Respiration, Artificial ; *Respiratory Insufficiency ; Tracheostomy ; }, abstract = {BACKGROUND: Mechanical insufflation-exsufflation (MI-E) applied via tracheostomy tubes in patients with amyotrophic lateral sclerosis (ALS) who are on home mechanical ventilation via tracheostomy is an effective procedure for respiratory secretion management. Nonetheless, tenacious secretions may remain and increase the risk of respiratory infections. The aim of this study was to determine whether adding oscillations to MI-E could reduce the rate of respiratory infections and the need for bronchoscopy to remove secretions in patients with ALS on home mechanical ventilation via tracheostomy.<br><br>METHODS: This was a 2-y, prospective, crossover study. Subjects were treated with conventional MI-E and MI-E with oscillations for 2 alternate 6-month periods. Data were collected on episodes of respiratory infections, hospital admission, and number of bronchoscopy procedures.<br><br>RESULTS: In the 19 ALS subjects enrolled, the median (interquartile range [IQR]) number of acute respiratory infections per subject was 1.0 (0.5-2.0) in the MI-E period and 0.0 (0.0-2.0) in the MI-E plus oscillations period (P = .92). The median (IQR) number of hospital stays was 0.0 (0.0-1.0) in the MI-E period and 0.0 (0.0-1.0) in the MI-E plus oscillations period (P = .80). The median (IQR) number of bronchoscopies per subject was 0.0 (0.0-1.0) in MI-E period and 0.0 (0.0-0.5) in the MI-E plus oscillations period (P = .26). MI-E plus oscillations treatment had no impact on the risk of respiratory infections (odds ratio 3.71, 95% CI 0.81-16.84, P = .09) or the need for bronchoscopy (odds ratio 2.70, 95% CI 0.44-16.68, P = .29).<br><br>CONCLUSIONS: Adding oscillations to MI-E therapy in subjects with ALS on home mechanical ventilation via tracheostomy did not decrease the risk of respiratory infections, hospital admission, or need for bronchoscopy.}, }
@article {pmid33082180, year = {2020}, author = {Osei, E and Kuupiel, D and Mashamba-Thompson, TP}, title = {Availability and use of mHealth for disease diagnosis and treatment support by health workers in sub-Saharan Africa: a scoping review protocol.}, journal = {BMJ open}, volume = {10}, number = {10}, pages = {e036641}, pmid = {33082180}, issn = {2044-6055}, mesh = {Delivery of Health Care ; Ghana ; Health Personnel ; Health Workforce ; Humans ; *Telemedicine ; Scoping Reviews As Topic ; }, abstract = {INTRODUCTION: Improving healthcare for all is one of the global health priorities, particularly in disease burdened settings such as sub-Saharan Africa (SSA). Considering the high penetration rate of mobile phones in SSA, mobile health (mHealth) could be used to achieve universal health coverage. The proposed study will map evidence on the availability and use of mHealth for disease diagnosis and treatment support by health workers in SSA.<br><br>METHODS AND ANALYSIS: This review will be guided by Arksey and O'Malley's scoping review framework and Levac et al's recommendations and guidelines from the Joanna Briggs Institute. A scoping review will be conducted to explore what is known about mHealth for disease diagnosis and treatment support by health workers in SSA and to identify areas for future research. In addition to searching the grey literature, the following databases will be explored from PubMed, MEDLINE and CINAHL with full text via EBSCOhost and ScienceDirect databases. A search in Google Scholar will be considered as an additional information source. The literature search will involve published studies from 2000 to 2020 in any language. This review will cover mHealth for disease diagnosis and treatment support by health workers in SSA. The primary investigator will conduct the title screening, and subsequently, two reviewers will independently conduct abstract and full article screening and data extraction. The results of this proposed review will be presented using the Preferred Reporting Items for Systematic Reviews and Meta-analysis: Extension for Scoping Review guidelines.<br><br>ETHICS AND DISSEMINATION: Ethical approval is not required for the scoping review, which is the first stage in a PhD study in public health on accessing mHealth for disease diagnosis and treatment support by health workers in Ghana. The final review will be submitted for publications to a scientific journal, and our results will be presented at appropriate conferences.}, }
@article {pmid33082139, year = {2020}, author = {Sévigny, M and Bourdeau Julien, I and Venkatasubramani, JP and Hui, JB and Dutchak, PA and Sephton, CF}, title = {FUS contributes to mTOR-dependent inhibition of translation.}, journal = {The Journal of biological chemistry}, volume = {295}, number = {52}, pages = {18459-18473}, pmid = {33082139}, issn = {1083-351X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology ; Cytoplasm/metabolism ; HEK293 Cells ; Humans ; Inclusion Bodies ; *Mutation ; Polyribosomes/genetics/*metabolism ; Protein Biosynthesis ; RNA-Binding Protein FUS/genetics/*metabolism ; TOR Serine-Threonine Kinases/genetics/*metabolism ; }, abstract = {The amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)-linked RNA-binding protein called FUS (fused in sarcoma) has been implicated in several aspects of RNA regulation, including mRNA translation. The mechanism by which FUS affects the translation of polyribosomes has not been established. Here we show that FUS can associate with stalled polyribosomes and that this association is sensitive to mTOR (mammalian target of rapamycin) kinase activity. Specifically, we show that FUS association with polyribosomes is increased by Torin1 treatment or when cells are cultured in nutrient-deficient media, but not when cells are treated with rapamycin, the allosteric inhibitor of mTORC1. Moreover, we report that FUS is necessary for efficient stalling of translation because deficient cells are refractory to the inhibition of mTOR-dependent signaling by Torin1. We also show that ALS-linked FUS mutants R521G and P525L associate abundantly with polyribosomes and decrease global protein synthesis. Importantly, the inhibitory effect on translation by FUS is impaired by mutations that reduce its RNA-binding affinity. These findings demonstrate that FUS is an important RNA-binding protein that mediates translational repression through mTOR-dependent signaling and that ALS-linked FUS mutants can cause a toxic gain of function in the cytoplasm by repressing the translation of mRNA at polyribosomes.}, }
@article {pmid33081454, year = {2020}, author = {Shpilyukova, YA and Fedotova, EY and Berdnikovich, ES and Konovalov, RN and Zakharova, MN and Grishina, DA and Yakhno, NN and Illarioshkin, SN}, title = {[C9orf72-associated frontotemporal dementia in the Russian population].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {120}, number = {9}, pages = {98-106}, doi = {10.17116/jnevro202012009198}, pmid = {33081454}, issn = {1997-7298}, mesh = {Adult ; Aged ; Aged, 80 and over ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; C9orf72 Protein/genetics ; Female ; *Frontotemporal Dementia/diagnosis/epidemiology/genetics ; Humans ; Middle Aged ; Proteins/genetics ; Russia/epidemiology ; }, abstract = {OBJECTIVE: To evaluate the frequency of C9orf72-associated frontotemporal dementia (FTD) in the Russian population and to study clinical features of GGGGCC-repeat expansion carriers.<br><br>MATERIAL AND METHODS: Twenty-eight patients with FTD are included in the study: 15 with a behavioral variant of FTD (bvFTD) and 13 with a agrammatic/non-fluent variant of primary progressive aphasia (avPPA). The mean age was 62 years (34-80), the mean disease duration was 4 years (1-10). The positive family history was noted in 46% of cases. DNA diagnosis was performed using repeat-primed polymerase chain reaction.<br><br>RESULTS: The frequency of the C9orf72 repeat expansion in patients with FTD was 14%, in patients with bvFTD 20%, in patients with avPPA 8%. The mean age of disease onset in the expansion carriers was 63 (55-75) years. The frequency of the C9orf72 repeats expansion in familial FTD cases was 31%, in sporadic cases 7%. bvFTD with parkinsonian syndrome was noted in two out of four cases, bvFTD with amyotrophic lateral sclerosis (ALS) was shown in one case, avPPA with ALS was shown in one case. One female patient with bvFTD with parkinsonian syndrome presented with cognitive fluctuations that required a differential diagnosis with Lewy body disease.<br><br>CONCLUSION: This is the first study of the genetic structure of FTD in the Russian population. The prevalence and clinical characteristics of C9orf72-associated FTD were defined, in particular, the spectrum of motor symptoms was shown along with behavioral and aphasic disturbances. DNA diagnosis plays an important role in confirming the diagnosis and selection of patients for potential disease-modifying treatment.}, }
@article {pmid33078279, year = {2021}, author = {Kumar, S and Phaneuf, D and Julien, JP}, title = {Withaferin-A Treatment Alleviates TAR DNA-Binding Protein-43 Pathology and Improves Cognitive Function in a Mouse Model of FTLD.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {18}, number = {1}, pages = {286-296}, pmid = {33078279}, issn = {1878-7479}, support = {//CIHR/Canada ; }, mesh = {Animals ; Avoidance Learning/drug effects ; Blotting, Western ; Brain/drug effects/metabolism ; Cells, Cultured ; Cognition/*drug effects ; DNA-Binding Proteins/*antagonists &amp; inhibitors/genetics ; Disease Models, Animal ; Female ; Fluorescent Antibody Technique ; Frontotemporal Lobar Degeneration/*drug therapy ; Male ; Mice ; Mice, Transgenic ; NF-kappa B/metabolism ; Signal Transduction/drug effects ; Withanolides/*therapeutic use ; }, abstract = {Withaferin-A, an active withanolide derived from the medicinal herbal plant Withania somnifera induces autophagy, reduces TDP-43 proteinopathy, and improves cognitive function in transgenic mice expressing mutant TDP-43 modelling FTLD. TDP-43 is a nuclear DNA/RNA-binding protein with cellular functions in RNA transcription and splicing. Abnormal cytoplasmic aggregates of TDP-43 occur in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). To date, no effective treatment is available for TDP-43 proteinopathies. Here, we tested the effects of withaferin-A (WFA), an active withanolide extracted from the medicinal herbal plant Withania somnifera, in a transgenic mouse model of FTLD expressing a genomic fragment encoding mutant TDP-43[G348C]. WFA treatment ameliorated the cognitive performance of the TDP-43[G348C] mice, and it reduced NF-κB activity and neuroinflammation in the brain. WFA alleviated TDP-43 pathology while it boosted the levels of the autophagic marker LC3BII in the brain. These data suggest that WFA and perhaps other autophagy inducers should be considered as potential therapy for neurodegenerative diseases with TDP-43 pathology.}, }
@article {pmid33074186, year = {2021}, author = {Cappella, M and Pradat, PF and Querin, G and Biferi, MG}, title = {Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy.}, journal = {Journal of neuromuscular diseases}, volume = {8}, number = {1}, pages = {25-38}, pmid = {33074186}, issn = {2214-3602}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*therapy ; *Clinical Trials as Topic ; *Genetic Therapy ; Humans ; Oligonucleotides, Antisense/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and incurable motor neuron (MN) disorder affecting both upper and lower MNs. Despite impressive advances in the understanding of the disease's pathological mechanism, classical pharmacological clinical trials failed to provide an efficient cure for ALS over the past twenty years. Two different gene therapy approaches were recently approved for the monogenic disease Spinal muscular atrophy, characterized by degeneration of lower MNs. This milestone suggests that gene therapy-based therapeutic solutions could be effective for the treatment of ALS. This review summarizes the possible reasons for the failure of traditional clinical trials for ALS. It provides then a focus on the advent of gene therapy approaches for hereditary forms of ALS. Specifically, it describes clinical use of antisense oligonucleotides in three familial forms of ALS, caused by mutations in SOD1, C9orf72 and FUS genes, respectively.. Clinical and pre-clinical studies based on AAV-mediated gene therapy approaches for both familial and sporadic ALS cases are presented as well. Overall, this overview highlights the potential of gene therapy as a transforming technology that will have a huge impact on treatment perspective for ALS patients and on the design of future clinical trials.}, }
@article {pmid33072247, year = {2020}, author = {Sharma, A and Sane, H and Paranjape, A and Pradhan, R and Das, R and Biju, H and Gokulchandran, N and Badhe, P}, title = {Multiple doses of cell therapy and neurorehabilitation in amyotrophic lateral sclerosis: A case report.}, journal = {Clinics and practice}, volume = {10}, number = {3}, pages = {1242}, pmid = {33072247}, issn = {2039-7275}, abstract = {Cell therapy, along with intensive rehabilitation has been shown to significantly improve outcomes in amyotrophic lateral sclerosis (ALS), in addition to standard therapy. We present a 40-years-old male ALS patient, suffering for the past four years, who underwent multiple doses of cell therapy at our institution. Along with riluzole treatment and lithium co-administration, his treatment involved multiple intrathecal transplants of autologous bone marrow-derived mononuclear cells, followed by multidisciplinary neurorehabilitation. The outcome measures of ALSFunctional Rating Scale Revised score remained stable, and importantly, Six Minute Walk Test distance improved from 475.2 m to 580.8 m, over a span of 16 months. Improved outcomes are indicative of slowing down of disease progression. Multiple doses of intrathecal autologous cell therapy along with rehabilitation and lithium, in addition to standard riluzole treatment is a novel approach for decelerating disease progression and qualitatively improving living conditions for ALS patients and their caregivers.}, }
@article {pmid33071748, year = {2020}, author = {Martier, R and Konstantinova, P}, title = {Gene Therapy for Neurodegenerative Diseases: Slowing Down the Ticking Clock.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {580179}, pmid = {33071748}, issn = {1662-4548}, abstract = {Gene therapy is an emerging and powerful therapeutic tool to deliver functional genetic material to cells in order to correct a defective gene. During the past decades, several studies have demonstrated the potential of AAV-based gene therapies for the treatment of neurodegenerative diseases. While some clinical studies have failed to demonstrate therapeutic efficacy, the use of AAV as a delivery tool has demonstrated to be safe. Here, we discuss the past, current and future perspectives of gene therapies for neurodegenerative diseases. We also discuss the current advances on the newly emerging RNAi-based gene therapies which has been widely studied in preclinical model and recently also made it to the clinic.}, }
@article {pmid33070647, year = {2021}, author = {Maurice, T}, title = {Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders.}, journal = {Expert opinion on drug discovery}, volume = {16}, number = {4}, pages = {373-389}, doi = {10.1080/17460441.2021.1838483}, pmid = {33070647}, issn = {1746-045X}, mesh = {Animals ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Development ; Humans ; Ligands ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neuroprotective Agents/*administration &amp; dosage/pharmacology ; Piperidines/administration &amp; dosage/pharmacology ; Receptors, sigma/*agonists/metabolism ; Sigma-1 Receptor ; }, abstract = {Introduction: The sigma-1 receptor (S1R) is attracting much attention for disease-modifying therapies in neurodegenerative diseases. It is a conserved protein, present in plasma and endoplasmic reticulum (ER) membranes and enriched in mitochondria-associated ER membranes (MAMs). It modulates ER-mitochondria Ca2+ transfer and ER stress pathways. Mitochondrial and MAM dysfunctions contribute to neurodegenerative processes in diseases such as Alzheimer, Parkinson, Huntington or Amyotrophic Lateral Sclerosis. Interestingly, the S1R can be activated by small druggable molecules and accumulating preclinical data suggest that S1R agonists are effective protectants in these neurodegenerative diseases.Area covered: In this review, we will present the data showing the high therapeutic potential of S1R drugs for the treatment of neurodegenerative diseases, focusing on pridopidine as a potent and selective S1R agonist under clinical development. Of particular interest is the bi-phasic (bell-shaped) dose-response effect, representing a common feature of all S1R agonists and described in numerous preclinical models in vitro, in vivo and in clinical trials.Expert opinion: S1R agonists modulate inter-organelles communication altered in neurodegenerative diseases and activate intracellular survival pathways. Research will continue growing in the future. The particular cellular nature of this chaperone protein must be better understood to facilitate the clinical developement of promising molecules.}, }
@article {pmid33069760, year = {2020}, author = {Khan, H and Tundis, R and Ullah, H and Aschner, M and Belwal, T and Mirzaei, H and Akkol, EK}, title = {Flavonoids targeting NRF2 in neurodegenerative disorders.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {146}, number = {}, pages = {111817}, doi = {10.1016/j.fct.2020.111817}, pmid = {33069760}, issn = {1873-6351}, mesh = {Animals ; Flavonoids/*pharmacology ; Humans ; NF-E2-Related Factor 2/*drug effects ; Neurodegenerative Diseases/*metabolism ; Neuroprotective Agents/pharmacology ; }, abstract = {Neurodegenerative disorders are characterized by progressive loss of neurons. To date, no efficacious therapies exist for these disorders, and current therapies provide only symptomatic relief. The neuroprotective effects of natural compounds have been reported in several neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) amyotrophic lateral sclerosis (ALS), cerebral ischemia and brain tumors. Flavonoids are the most widely studied natural products for the prevention and treatment of neurodegenerative disorders. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) represents a complex gene regulated cytoprotective pathway. Several natural compounds have been identified as Nrf2 regulators in various chronic disorders, including carcinogenic, liver ailments, inflammatory conditions, neurodegeneration, diabetes and cardiotoxicities. The current review focuses on Nrf2 targeting by flavonoids in the prevention and treatment of neurodegenerative disorders, addressing the most contemporary information available on this timely subject.}, }
@article {pmid33066585, year = {2020}, author = {Veenman, L}, title = {Raloxifene as Treatment for Various Types of Brain Injuries and Neurodegenerative Diseases: A Good Start.}, journal = {International journal of molecular sciences}, volume = {21}, number = {20}, pages = {}, pmid = {33066585}, issn = {1422-0067}, mesh = {Animals ; Brain Injuries/*drug therapy/metabolism ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism ; Neuroprotective Agents/*therapeutic use ; Raloxifene Hydrochloride/*therapeutic use ; Selective Estrogen Receptor Modulators/*therapeutic use ; }, abstract = {Recent studies have shown that the selective estrogen receptor modulator (SERM) raloxifene had pronounced protective effects against progressing brain damage after traumatic brain injury (TBI) in mice. These studies, indicating beneficial effects of raloxifene for brain health, prompted the study of the history and present state of knowledge of this topic. It appears that, apart from raloxifene, to date, four nonrelated compounds have shown comparable beneficial effects-fucoidan, pifithrin, SMM-189 (5-dihydroxy-phenyl]-phenyl-methanone), and translocator protein (TSPO) ligands. Raloxifene, however, is ahead of the field, as for more than two decades it has been used in medical practice for various chronic ailments in humans. Thus, apart from different types of animal and cell culture studies, it has also been assessed in various human clinical trials, including assaying its effects on mild cognitive impairments. Regarding cell types, raloxifene protects neurons from cell death, prevents glial activation, ameliorates myelin damage, and maintains health of endothelial cells. At whole central nervous system (CNS) levels, raloxifene ameliorated mild cognitive impairments, as seen in clinical trials, and showed beneficial effects in animal models of Parkinson's disease. Moreover, with stroke and TBI in animal models, raloxifene showed curative effects. Furthermore, raloxifene showed healing effects regarding multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) in cell culture. The adverse biological signals typical of these conditions relate to neuronal activity, neurotransmitters and their receptors, plasticity, inflammation, oxidative stress, nitric oxide, calcium homeostasis, cell death, behavioral impairments, etc. Raloxifene favorably modulates these signals toward cell health-on the one hand, by modulating gene expression of the relevant proteins, for example by way of its binding to the cell nuclear estrogen receptors ERα and ERβ (genomic effects) and, on the other hand (nongenomic effects) by modulation of mitochondrial activity, reduction of oxidative stress and programmed cell death, maintaining metabolic balance, degradation of Abeta, and modulation of intracellular cholesterol levels. More specifically regarding Alzheimer's disease, raloxifene may not cure diagnosed Alzheimer's disease. However, the onset of Alzheimer's disease may be delayed or arrested by raloxifene's capability to attenuate mild cognitive impairment. Mild cognitive impairment is a condition that may precede diagnosis of Alzheimer's disease. In this review, relatively new insights are addressed regarding the notion that Alzheimer's disease can be caused by bacterial (as well as viral) infections, together with the most recent findings that raloxifene can counteract infections of at least some bacterial and viral strains. Thus, here, an overview of potential treatments of neurodegenerative disease by raloxifene is presented, and attention is paid to subcellular molecular biological pathways that may be involved.}, }
@article {pmid33065300, year = {2021}, author = {Salah, AB and Pradat, PF and Villain, M and Balcerac, A and Pradat-Diehl, P and Salachas, F and Lacomblez, L and Bayen, E}, title = {Anosognosia in amyotrophic lateral sclerosis: A cross-sectional study of 85 individuals and their relatives.}, journal = {Annals of physical and rehabilitation medicine}, volume = {64}, number = {5}, pages = {101440}, doi = {10.1016/j.rehab.2020.08.004}, pmid = {33065300}, issn = {1877-0665}, mesh = {*Agnosia/etiology ; *Amyotrophic Lateral Sclerosis/complications ; *Apathy ; Cross-Sectional Studies ; Humans ; Male ; Middle Aged ; *Neurodegenerative Diseases ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) has long been considered a pure motor neurodegenerative disease. However, now, extra-motor manifestations such as cognitive-behavioral disorders are considered not rare and are even a severity factor of the disease. Experiencing anosognosia (i.e., the inability to recognize neurological symptoms) might affect care and treatment compliance in ALS. Regardless, this pivotal feature has been little investigated.<br><br>OBJECTIVES: By comparing patients' and caregivers' reports, we analysed whether patients with ALS would experience a lack of awareness about their executive disorders and their apathy symptoms.<br><br>METHODS: From the ALS reference center in Paris, we included 85 patients (47 men, mean [SD] age 60.5 [12] years and ALS-Functional Rating Scale-revised score 8 to 46) and their primary family caregivers who all completed the Dysexecutive Questionnaire (DEX) and the Apathy Evaluation Scale (AES). Overall scores and answers were compared by agreement/disagreement statistical methods.<br><br>RESULTS: Caregivers reported higher levels of cognitive-behavioral disorders than did patients, but reports matched when cognitive-behavioral disorders were absent or mild. With published DEX and AES cutoffs, 32% and 51% of patients had executive disorders and apathy, respectively. In these patients with significant impairment, Bland-Altman plots (i.e., visual display agreement that represents the difference between the patient's and caregiver's scores as a function of their average) showed a strong discrepancy between joint reports: patients underestimated their symptoms by a mean bias of -6.81 DEX points (95% confidence interval -11.88, -1.75) and -8.85 AES points (95% confidence interval -11.72, -5.98). We found no clear relationship between bulbar or spinal ALS subtypes and anosognosia.<br><br>CONCLUSIONS: ALS patients with a cognitive-behavioral phenotype show anosognosia by a mismatch between self and proxy reports, which warrants further investigation in neuroimaging. Systematic longitudinal screening of anosognosia is needed to propose targeted psychoeducation in patient-caregiver dyads showing disagreement.}, }
@article {pmid33063909, year = {2021}, author = {Paganoni, S and Hendrix, S and Dickson, SP and Knowlton, N and Macklin, EA and Berry, JD and Elliott, MA and Maiser, S and Karam, C and Caress, JB and Owegi, MA and Quick, A and Wymer, J and Goutman, SA and Heitzman, D and Heiman-Patterson, TD and Jackson, CE and Quinn, C and Rothstein, JD and Kasarskis, EJ and Katz, J and Jenkins, L and Ladha, S and Miller, TM and Scelsa, SN and Vu, TH and Fournier, CN and Glass, JD and Johnson, KM and Swenson, A and Goyal, NA and Pattee, GL and Andres, PL and Babu, S and Chase, M and Dagostino, D and Hall, M and Kittle, G and Eydinov, M and McGovern, M and Ostrow, J and Pothier, L and Randall, R and Shefner, JM and Sherman, AV and St Pierre, ME and Tustison, E and Vigneswaran, P and Walker, J and Yu, H and Chan, J and Wittes, J and Yu, ZF and Cohen, J and Klee, J and Leslie, K and Tanzi, RE and Gilbert, W and Yeramian, PD and Schoenfeld, D and Cudkowicz, ME}, title = {Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {63}, number = {1}, pages = {31-39}, pmid = {33063909}, issn = {1097-4598}, support = {UL1 TR001414/TR/NCATS NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy/*mortality ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Phenylbutyrates/*therapeutic use ; Taurochenodeoxycholic Acid/*therapeutic use ; Time ; Young Adult ; }, abstract = {An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.}, }
@article {pmid33061334, year = {2020}, author = {Maresova, P and Hruska, J and Klimova, B and Barakovic, S and Krejcar, O}, title = {Activities of Daily Living and Associated Costs in the Most Widespread Neurodegenerative Diseases: A Systematic Review.}, journal = {Clinical interventions in aging}, volume = {15}, number = {}, pages = {1841-1862}, pmid = {33061334}, issn = {1178-1998}, mesh = {*Activities of Daily Living ; Aged ; Aged, 80 and over ; Female ; Health Care Costs ; Humans ; Male ; Middle Aged ; Neurodegenerative Diseases/*economics ; Quality of Life ; }, abstract = {Nowadays, the population is rapidly ageing because of increasing life expectancy and decreasing birth rates. Thus, the purpose of this systematic review is to prepare a comprehensive overview which identifies the activities of daily living (ADLs) that are gradually reduced among patients with dementia, as well as explore the therapies applied in relation to dementia and how they effectively improve the quality of life (QoL) of patients and caregivers. Furthermore, we aim to summarise the ADL activities influenced by therapies and examine the treatment costs and care for patients so that recommendations for research and development (R&amp;D) can be made to improve both the QoL of people with dementia and cost-saving measures. The research focuses on four selected neurodegenerative diseases: Alzheimer, Parkinson, vascular dementia, and amyotrophic lateral sclerosis. Therefore, the peer-reviewed English written articles from 2014 to 2019 were searched between September 1 and December 13, 2019. Twenty-seven papers were included in the analysis. The results show that essential assistance occurs in connection with activities: eating, drinking, dressing, bathing, personal hygiene, use of the toilet, and transport. By contrast, shopping or cleaning is not addressed as much. A lower ability to take care of oneself is connected with poor patient health and higher social care costs because the patient requires care from external sources, such as home aid or nurse visits. The challenge that remains is to shift new knowledge from scientific disciplines and connect it with the needs of patients to remove legitimate barriers and increase the acceptance of new solutions by popularisation. Additionally, regarding the burden on caregivers, it would be appropriate to promote this area of education and employment so that family members can use formal caregivers, ensuring them free time and much-needed rest.}, }
@article {pmid33054766, year = {2020}, author = {Lee, S and Kim, S and Kang, HY and Lim, HR and Kwon, Y and Jo, M and Jeon, YM and Kim, SR and Kim, K and Ha, CM and Lee, S and Kim, HJ}, title = {The overexpression of TDP-43 in astrocytes causes neurodegeneration via a PTP1B-mediated inflammatory response.}, journal = {Journal of neuroinflammation}, volume = {17}, number = {1}, pages = {299}, pmid = {33054766}, issn = {1742-2094}, support = {20-BR-02-08//Ministry of Science, ICT and Future Planning/ ; NRF-2020R1A2C4002366//National Research Foundation of Korea/ ; NRF-2019R1F1A1045639//National Research Foundation of Korea/ ; NRF-2020R1F1A1058459//National Research Foundation of Korea/ ; HI14C1135//Korea Health Industry Development Institute/Republic of Korea ; HI18C1241//Korea Health Industry Development Institute/Republic of Korea ; Kiyoung Kim//Soonchunhyang University/ ; }, mesh = {Animals ; Animals, Genetically Modified ; Astrocytes/*metabolism/pathology ; Cells, Cultured ; DNA-Binding Proteins/*biosynthesis/genetics ; Drosophila ; Gene Expression ; Inflammation Mediators/antagonists &amp; inhibitors/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Nerve Degeneration/genetics/*metabolism/pathology ; Protein Tyrosine Phosphatase, Non-Receptor Type 1/*antagonists &amp; inhibitors/*biosynthesis/genetics ; }, abstract = {BACKGROUND: Cytoplasmic inclusions of transactive response DNA binding protein of 43 kDa (TDP-43) in neurons and astrocytes are a feature of some neurodegenerative diseases, such as frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). However, the role of TDP-43 in astrocyte pathology remains largely unknown.<br><br>METHODS: To investigate whether TDP-43 overexpression in primary astrocytes could induce inflammation, we transfected primary astrocytes with plasmids encoding Gfp or TDP-43-Gfp. The inflammatory response and upregulation of PTP1B in transfected cells were examined using quantitative RT-PCR and immunoblot analysis. Neurotoxicity was analysed in a transwell coculture system of primary cortical neurons with astrocytes and cultured neurons treated with astrocyte-conditioned medium (ACM). We also examined the lifespan, performed climbing assays and analysed immunohistochemical data in pan-glial TDP-43-expressing flies in the presence or absence of a Ptp61f RNAi transgene.<br><br>RESULTS: PTP1B inhibition suppressed TDP-43-induced secretion of inflammatory cytokines (interleukin 1 beta (IL-1&#x3b2;), interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-&#x3b1;)) in primary astrocytes. Using a neuron-astrocyte coculture system and astrocyte-conditioned media treatment, we demonstrated that PTP1B inhibition attenuated neuronal death and mitochondrial dysfunction caused by overexpression of TDP-43 in astrocytes. In addition, neuromuscular junction (NMJ) defects, a shortened lifespan, inflammation and climbing defects caused by pan-glial overexpression of TDP-43 were significantly rescued by downregulation of ptp61f (the Drosophila homologue of PTP1B) in flies.<br><br>CONCLUSIONS: These results indicate that PTP1B inhibition mitigates the neuronal toxicity caused by TDP-43-induced inflammation in mammalian astrocytes and Drosophila glial cells.}, }
@article {pmid33051552, year = {2020}, author = {Yamashita, T and Kushida, Y and Wakao, S and Tadokoro, K and Nomura, E and Omote, Y and Takemoto, M and Hishikawa, N and Ohta, Y and Dezawa, M and Abe, K}, title = {Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {17102}, pmid = {33051552}, issn = {2045-2322}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Muscle Strength ; *Pluripotent Stem Cells ; Rotarod Performance Test ; *Stem Cell Transplantation/methods ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. Muse cells are endogenous reparative pluripotent-like stem cells distributed in various tissues. They can selectively home to damaged sites after intravenous injection by sensing sphingosine-1-phosphate produced by damaged cells, then exert pleiotropic effects, including tissue protection and spontaneous differentiation into tissue-constituent cells. In G93A-transgenic ALS mice, intravenous injection of 5.0 × 10[4] cells revealed successful homing of human-Muse cells to the lumbar spinal cords, mainly at the pia-mater and underneath white matter, and exhibited glia-like morphology and GFAP expression. In contrast, such homing or differentiation were not recognized in human mesenchymal stem cells but were instead distributed mainly in the lung. Relative to the vehicle groups, the Muse group significantly improved scores in the rotarod, hanging-wire and muscle strength of lower limbs, recovered the number of motor neurons, and alleviated denervation and myofiber atrophy in lower limb muscles. These results suggest that Muse cells homed in a lesion site-dependent manner and protected the spinal cord against motor neuron death. Muse cells might also be a promising cell source for the treatment of ALS patients.}, }
@article {pmid33051352, year = {2020}, author = {Dodge, JC and Jensen, EH and Yu, J and Sardi, SP and Bialas, AR and Taksir, TV and Bangari, DS and Shihabuddin, LS}, title = {Neutral Lipid Cacostasis Contributes to Disease Pathogenesis in Amyotrophic Lateral Sclerosis.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {40}, number = {47}, pages = {9137-9147}, pmid = {33051352}, issn = {1529-2401}, support = {HHSN275200900011C/HD/NICHD NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Cell Death ; Cholesterol Esters/metabolism ; Gray Matter/metabolism ; Humans ; *Lipid Metabolism ; Lysophosphatidylcholines/metabolism ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/pathology ; Receptors, G-Protein-Coupled/genetics ; Receptors, Phospholipase A2/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase-1/genetics ; Triglycerides/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by motor neuron (MN) death. Lipid dysregulation manifests during disease; however, it is unclear whether lipid homeostasis is adversely affected in the in the spinal cord gray matter (GM), and if so, whether it is because of an aberrant increase in lipid synthesis. Moreover, it is unknown whether lipid dysregulation contributes to MN death. Here, we show that cholesterol ester (CE) and triacylglycerol levels are elevated several-fold in the spinal cord GM of male sporadic ALS patients. Interestingly, HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, was reduced in the spinal cord GM of ALS patients. Increased cytosolic phospholipase A2 activity and lyso-phosphatidylcholine (Lyso-PC) levels in ALS patients suggest that CE accumulation was driven by acyl group transfer from PC to cholesterol. Notably, Lyso-PC, a byproduct of CE synthesis, was toxic to human MNs in vitro Elevations in CE, triacylglycerol, and Lyso-PC were also found in the spinal cord of SOD1[G93A] mice, a model of ALS. Similar to ALS patients, a compensatory downregulation of cholesterol synthesis occurred in the spinal cord of SOD1[G93A] mice; levels of sterol regulatory element binding protein 2, a transcriptional regulator of cholesterol synthesis, progressively declined. Remarkably, overexpressing sterol regulatory element binding protein 2 in the spinal cord of normal mice to model CE accumulation led to ALS-like lipid pathology, MN death, astrogliosis, paralysis, and reduced survival. Thus, spinal cord lipid dysregulation in ALS likely contributes to neurodegeneration and developing therapies to restore lipid homeostasis may lead to a treatment for ALS.SIGNIFICANCE STATEMENT Neurons that control muscular function progressively degenerate in patients with amyotrophic lateral sclerosis (ALS). Lipid dysregulation is a feature of ALS; however, it is unclear whether disrupted lipid homeostasis (i.e., lipid cacostasis) occurs proximal to degenerating neurons in the spinal cord, what causes it, and whether it contributes to neurodegeneration. Here we show that lipid cacostasis occurs in the spinal cord gray matter of ALS patients. Lipid accumulation was not associated with an aberrant increase in synthesis or reduced hydrolysis, as enzymatic and transcriptional regulators of lipid synthesis were downregulated during disease. Last, we demonstrated that genetic induction of lipid cacostasis in the CNS of normal mice was associated with ALS-like lipid pathology, astrogliosis, neurodegeneration, and clinical features of ALS.}, }
@article {pmid33047656, year = {2020}, author = {Fève, A and Geipel, J}, title = {Herausforderungen und Bedürfnisse von Familien mit Neugeborenen mit Zwerchfellhernie - Musiktherapie als unterstützende Maßnahme?.}, journal = {Pflege}, volume = {33}, number = {6}, pages = {365-373}, doi = {10.1024/1012-5302/a000763}, pmid = {33047656}, issn = {1012-5302}, mesh = {Child ; Family ; *Hernias, Diaphragmatic, Congenital/complications/therapy ; Humans ; Infant ; Infant, Newborn ; *Infant, Premature ; *Parents ; }, abstract = {Challenges and needs of families of newborns with congenital diaphragmatic hernia - Music therapy as a supportive intervention? Abstract. Background: Newborns with diaphragmatic hernia (CDH) spend the first weeks of their lives in intensive care, which is extremely stressful for them and their families. Music therapy is already used in neonatology for premature infants to stabilize the child, to support the parents and to strengthen attachment and bonding. However, the benefits for term infants receiving intensive care and their families has not yet been comprehensively investigated. Aim: The aim of this paper was to investigate the specific needs, challenges and experiences of children with CDH and their parents and to derive appropriate music therapy interventions. Methods: Using the CAQDAS software f4analyse 15 parents' reports were examined with a qualitative content structuring analysis. Music therapy aspects were illustrated using a hypothetical case example. Results: Parents suffer above all from organisational and emotional challenges. They want to take care of their child and seek to be close despite limited influence on health and treatment. They are supported by their social environment and the medical staff. Protective factors include successful self-care, detachment and trust in a positive outcome. Conclusion: Additional to medical aspects like the withdrawal, bonding and attachment and parental well-being are of great importance. Music therapy literature offers the description of interventions, which address these aspects.}, }
@article {pmid33041513, year = {2020}, author = {Amekura, S and Nakajima, M and Watanabe, M and Saitoh, M and Iida, S and Yamamoto, Y and Fujisawa, A}, title = {4-Cl-edaravone and (E)-2-chloro-3-[(E)-phenyldiazenyl]-2-butenoic acid are the specific reaction products of edaravone with hypochlorite.}, journal = {Journal of clinical biochemistry and nutrition}, volume = {67}, number = {2}, pages = {159-166}, pmid = {33041513}, issn = {0912-0009}, abstract = {3-Methyl-1-phenyl-2-pyrazolin-5-one (edaravone) is a synthetic one-electron antioxidant used as a drug for treatment against acute phase cerebral infarction in Japan. This drug also reacts with two-electron oxidants like peroxynitrite to give predominantly 4-nitrosoedaravone but no one-electron oxidation products. It is believed that this plays a significant role in amelioration of amyotrophic lateral sclerosis. The drug was approved for treatment of amyotrophic lateral sclerosis in Japan and USA in 2015 and 2017, respectively. In this study, we examined the reaction of edaravone with another two-electron oxidant, hypochlorite anion (ClO[-]). Edaravone reacted with ClO[-] in 50% methanolic phosphate buffer (pH 7.4) solution containing typical two-electron reductants, such as glutathione, cysteine, methionine, and uric acid, as internal references. The concentration of edaravone decreased at a similar rate as each co-existing reference, indicating that it showed comparable reactivity toward ClO[-] as those references. Furthermore, 4-Cl-edaravone and (E)-2-chloro-3-[(E)-phenyldiazenyl]-2-butenoic acid (CPB) were identified as primary and end products, respectively, and no one-electron oxidation products were detected. These results suggest that edaravone treatment can bring greater benefit against ClO[-]-related injury such as inflammation, and 4-Cl-edaravone and CPB can be good biomarkers for ClO[-]-induced oxidative stress.}, }
@article {pmid33038587, year = {2020}, author = {Naser Moghadasi, A}, title = {Neural implant for the treatment of multiple sclerosis.}, journal = {Medical hypotheses}, volume = {145}, number = {}, pages = {110324}, doi = {10.1016/j.mehy.2020.110324}, pmid = {33038587}, issn = {1532-2777}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; *Multiple Sclerosis/therapy ; Prostheses and Implants ; Transcranial Magnetic Stimulation ; }, abstract = {The methods used to treat various neurological diseases are evolving. The facilities provided by the technology have led to creation of new treatment opportunities. Neuromodulation is one of these important methods. By definition, the neuromodulation is a change in neural activity which occurs by stimulating a specific area of nervous system. The mentioned stimulation can be electrical, magnetic, or chemical. This method is used in various diseases, such as stroke, Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis (ALS). Multiple sclerosis (MS) is no exception in this regard and methods including the neurofeedback and transcranial magnetic stimulation (TMS) are used to treat various complications of the MS. One aspect of neuromodulation is the use of neural implant, which is applied nowadays, especially in the Parkinson's disease, and the use of microchips and prostheses to treat various symptoms in different neurological diseases has received significant attention. Although neural implant has been exploited to improve the symptoms of MS, they appear to have much greater potential to improve the condition of patients with MS. It seems that more attention to the symptoms of MS, on the one hand, and a new approach to the pathogenesis of this disease and considering it as a connectomopathy, on the other hand, can provide new opportunities for application of this method in the treatment of MS.}, }
@article {pmid33036763, year = {2021}, author = {Chen, L}, title = {FUS mutation is probably the most common pathogenic gene for JALS, especially sporadic JALS.}, journal = {Revue neurologique}, volume = {177}, number = {4}, pages = {333-340}, doi = {10.1016/j.neurol.2020.06.010}, pmid = {33036763}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Mutation ; RNA-Binding Protein FUS/*genetics ; }, abstract = {Juvenile amyotrophic lateral sclerosis (JALS) is a rare and severe form of ALS. The development of gene sequencing methods has resulted in increased reports of JALS cases in recent years, and additional gene mutations in FUS have been identified. Fused in sarcoma (FUS) mutations, appeared rarely in classical ALS but indeed were the most frequent pathogenic mutations in JALS, especially in sporadic JALS. After studied the reports in the last 10 years about JALS cases, the case characteristics caused by FUS mutations and the commonality of the mutation sites were summarized in this review. FUS mutation associated with more than half of JALS and the very majority of sporadic JALS. It's worth noting that almost all of the mutations occur in nuclear localization signal (NLS) of FUS in sporadic JALS. This discovery emphasized a new perspective focus on NLS for the diagnosis and etiology of sporadic JALS as well as for further study about new treatment.}, }
@article {pmid33025330, year = {2020}, author = {Lee, DY and Jeon, GS and Sung, JJ}, title = {ALS-Linked Mutant SOD1 Associates with TIA-1 and Alters Stress Granule Dynamics.}, journal = {Neurochemical research}, volume = {45}, number = {12}, pages = {2884-2893}, doi = {10.1007/s11064-020-03137-5}, pmid = {33025330}, issn = {1573-6903}, support = {2018R1D1A1B07047684//Ministry of Education/ ; 2019M3C7A103186712//Ministry of Science and ICT (MSIT)/ ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; Cytoplasmic Granules/*metabolism ; Female ; HEK293 Cells ; Humans ; Male ; Mice ; Middle Aged ; Mutation ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase-1/genetics/*metabolism ; T-Cell Intracellular Antigen-1/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative disorder caused by motor neuron loss. T-cell intracellular antigen-1 (TIA-1), a cytotoxic T lymphocyte granule-associated RNA binding protein, is a key component of stress granules. However, it remains uncertain whether ALS-causing superoxide dismutase-1 (SOD1) toxicity alters the dynamics of stress granules. Thus, through mouse and cell line models, and human cells and tissues, we showed the subcellular location of TIA-1 and its recruitment by stress granules following mutant SOD1-related stimuli. An overexpression of MTSOD1 resulted in increased TIA-1-positive cytoplasmic inclusions in the spinal cord tissue of SOD1G93A transgenic mouse and the SOD1G86S familial ALS patient. Moreover, we demonstrated the stages of ALS-like disease-dependent increase in TIA-1 in the spinal cord of transgenic mice. A similar increase of TIA-1 was found in the spinal cord of the SOD1G86S patient and induced pluripotent stem cell-derived neural stem cells from the SOD1G17S patient. By using immunoprecipitation assays in wild type (WT) human SOD1 (hSOD1) or mutant (MT) hSOD1-transfected motor neuronal cell lines and SOD1G93A transgenic mouse model, we observed that MTSOD1 interacts with TIA-1. In WT or MT hSOD1-transfected HEK293 and NSC-34 cells, the formation of TIA-1-positive stress granules was delayed in MTSOD1 by sodium arsenite treatment. These findings suggest that MTSOD1 could affect the dynamics of stress granules through the abnormal MTSOD1-TIA-1 interaction. Consequently, the resulting pathological TIA-1 may be involved in RNA metabolism found in ALS.}, }
@article {pmid33022226, year = {2020}, author = {Nguyen, L and Laboissonniere, LA and Guo, S and Pilotto, F and Scheidegger, O and Oestmann, A and Hammond, JW and Li, H and Hyysalo, A and Peltola, R and Pattamatta, A and Zu, T and Voutilainen, MH and Gelbard, HA and Saxena, S and Ranum, LPW}, title = {Survival and Motor Phenotypes in FVB C9-500 ALS/FTD BAC Transgenic Mice Reproduced by Multiple Labs.}, journal = {Neuron}, volume = {108}, number = {4}, pages = {784-796.e3}, pmid = {33022226}, issn = {1097-4199}, support = {R01 NS098819/NS/NINDS NIH HHS/United States ; R37 NS040389/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Animals ; C9orf72 Protein/genetics ; DNA Repeat Expansion ; Disease Models, Animal ; *Frontotemporal Dementia/genetics ; Mice ; Mice, Transgenic ; Phenotype ; }, abstract = {Mordes et al. (2020) did not detect the survival or motor phenotypes in C9orf72 BAC transgenic mice originally described by Liu et al. (2016). We discuss methodological differences between the Mordes and Liu studies, several additional studies in which survival and motor phenotypes were found, and possible environmental and genetic effects. First, Nguyen et al. (2020) showed robust ALS/FTD phenotypes in C9-BAC versus non-transgenic (NT) mice and that α-GA1 treatment improved survival, behavior, and neurodegeneration. The groups of Gelbard and Saxena also show decreased survival of C9-BAC versus NT mice and neuropathological and behavioral deficits similar to those shown by Liu et al. (2016). Although FVB/N mice can have seizures, increases in seizure severity and death of C9 and NT animals, which may mask C9 disease phenotypes, have been observed in recent C9-500 FVB/NJ-bred cohorts. In summary, we provide an update on phenotypes seen in FVB C9-BAC mice and additional details to successfully use this model. This Matters Arising Response paper addresses the Mordes et al. (2020) Matters Arising paper, published concurrently in Neuron.}, }
@article {pmid33021723, year = {2021}, author = {Delaye, JB and Lanznaster, D and Veyrat-Durebex, C and Fontaine, A and Bacle, G and Lefevre, A and Hergesheimer, R and Lecron, JC and Vourc'h, P and Andres, CR and Maillot, F and Corcia, P and Emond, P and Blasco, H}, title = {Behavioral, Hormonal, Inflammatory, and Metabolic Effects Associated with FGF21-Pathway Activation in an ALS Mouse Model.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {18}, number = {1}, pages = {297-308}, pmid = {33021723}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism ; Animals ; Antibodies, Monoclonal/therapeutic use ; Chemokine CCL2/blood ; Disease Models, Animal ; Fibroblast Growth Factors/immunology/*metabolism/physiology ; Interleukin-6/blood ; Leptin/blood ; Male ; Metabolomics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Resistin/blood ; Rotarod Performance Test ; Signal Transduction ; Transcriptome ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {In amyotrophic lateral sclerosis (ALS), motor neuron degeneration occurs simultaneously with systemic metabolic dysfunction and neuro-inflammation. The fibroblast growth factor 21 (FGF21) plays an important role in the regulation of both phenomena and is a major hormone of energetic homeostasis. In this study, we aimed to determine the relevance of FGF21 pathway stimulation in a male mouse model of ALS (mutated SOD1-G93A mice) by using a pharmacological agonist of FGF21, R1Mab1. Mice (SOD1-WT and mutant SOD1-G93A) were treated with R1Mab1 or vehicle. Longitudinal data about clinical status (motor function, body weight) and biological parameters (including hormonal, immunological, and metabolomics profiles) were collected from the first symptoms to euthanasia at week 20. Multivariate models were performed to identify the main parameters associated with R1Mab1 treatment and to link them with clinical status, and metabolic pathways involving the discriminant metabolites were also determined. A beneficial clinical effect of R1Mab1 was revealed on slow rotarod (p = 0.032), despite a significant decrease in body weight of ALS mice (p < 0.001). We observed a decrease in serum TNF-α, MCP-1, and insulin levels (p = 0.0059, p = 0.003, and p = 0.01, respectively). At 16 weeks, metabolomics analyses revealed a clear discrimination (CV-ANOVA = 0.0086) according to the treatment and the most discriminant pathways, including sphingolipid metabolism, butanoate metabolism, pantothenate and CoA biosynthesis, and the metabolism of amino acids like tyrosine, arginine, proline, glycine, serine, alanine, aspartate, and glutamate. Mice treated with R1Mab1 had mildly higher performance on slow rotarod despite a decrease on body weight and could be linked with the anti-inflammatory effect of R1Mab1. These results indicate that FGF21 pathway is an interesting target in ALS, with a slight improvement in motor function combined with metabolic and anti-inflammatory effects.}, }
@article {pmid33017028, year = {2020}, author = {Vu, M and Tortorice, K and Zacher, J and Dong, D and Hur, K and Zhang, R and Good, CB and Glassman, PA and Cunningham, FE}, title = {Assessment of Use and Safety of Edaravone for Amyotrophic Lateral Sclerosis in the Veterans Affairs Health Care System.}, journal = {JAMA network open}, volume = {3}, number = {10}, pages = {e2014645}, pmid = {33017028}, issn = {2574-3805}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy ; Cohort Studies ; Disease Progression ; Edaravone/*therapeutic use ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Treatment Outcome ; United States ; Veterans/*statistics &amp; numerical data ; Veterans Health Services/*statistics &amp; numerical data ; }, abstract = {IMPORTANCE: Using real-world data, the US Department of Veterans Affairs (VA) initiated a surveillance evaluation of edaravone after its approval for amyotrophic lateral sclerosis (ALS) in 2017. The use and safety of edaravone for patients with ALS in the VA health care system remain to be assessed.<br><br>OBJECTIVE: To describe a pharmacovigilance surveillance initiative with edaravone to monitor patient characteristics, utilization (edaravone cycles and riluzole use), and safety and to evaluate safety/effectiveness.<br><br>This propensity score-matched cohort study used data on 369 patients with documented definite or probable ALS in the Veterans Health Administration (VHA) with at least 1 prescription for edaravone between August 1, 2017, and September 30, 2019. The analysis compared edaravone (alone or with riluzole) with riluzole only. For chronic users (&#x2265;6 months of drug), a time-to-event model evaluated ALS-related outcomes, with censoring at outcome, death, or end of evaluation. Patients with Parkinson disease, dementia, schizophrenia, or significant respiratory insufficiency per diagnosis codes within 2 years before prescription initiation were excluded. In overall matched cohorts, 223 patients treated with edaravone were 1:3 propensity score matched based on predefined confounders. For the chronic user subgroup analysis, 96 patients receiving edaravone and 424 patients receiving riluzole only were included.<br><br>EXPOSURES: Edaravone (alone or with riluzole) vs riluzole only.<br><br>MAIN OUTCOMES AND MEASURES: Patient characteristics, ALS drug use, and mortality. Acute outcomes (within 6 months of index) included proportion and mean time to event for death, discontinuation, or all-cause hospitalization, and outcomes for chronic users (receiving >6 months of treatment) included hazard ratios of outcomes related to disease-state progression.<br><br>RESULTS: Of 369 patients who received edaravone, most were older (mean [SD] age, 64.6 [11.3] years), male (346 [93.8%]), and White (261 [70.7%]). As of September 2019, 59.9% of edaravone patients had discontinued treatment; of those, 49.5% (108 of 218) received only 1 to 3 treatment cycles. Approximately 30% (110 patients) died. In a matched evaluation, significantly more acute all-cause hospitalization events occurred with edaravone (35.4% vs 22.0% for riluzole only); 72.6% of the edaravone cohort received edaravone with riluzole. Among chronic users, edaravone patients (70.8% edaravone with riluzole) had an increased hazard ratio of ALS-associated hospitalization (2.51; 95% CI, 1.18-8.16). The death rate was lower with edaravone but the difference was not statistically significant.<br><br>CONCLUSIONS AND RELEVANCE: Early edaravone discontinuation was common in the VA. Although outcomes favored use of riluzole only in the matched analysis, results should be interpreted with caution, as unmeasured bias in observational data is likely.}, }
@article {pmid33006184, year = {2021}, author = {Andrew, AS and Bradley, WG and Peipert, D and Butt, T and Amoako, K and Pioro, EP and Tandan, R and Novak, J and Quick, A and Pugar, KD and Sawlani, K and Katirji, B and Hayes, TA and Cazzolli, P and Gui, J and Mehta, P and Horton, DK and Stommel, EW}, title = {Risk factors for amyotrophic lateral sclerosis: A regional United States case-control study.}, journal = {Muscle &amp; nerve}, volume = {63}, number = {1}, pages = {52-59}, pmid = {33006184}, issn = {1097-4598}, support = {P30 CA023108/CA/NCI NIH HHS/United States ; R01 TS000288/TS/ATSDR CDC HHS/United States ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*diagnosis/*epidemiology ; *Environmental Exposure/adverse effects ; Female ; Humans ; Life Style ; Logistic Models ; Male ; Middle Aged ; *Occupational Exposure/adverse effects ; Risk Factors ; United States ; }, abstract = {Most amyotrophic lateral sclerosis (ALS) cases are considered sporadic, without a known genetic basis, and environmental exposures are thought to play a causal role. To learn more about sporadic ALS etiology, we recruited n = 188 ALS patients from northern New England and Ohio and matched controls 2:1 from the general population of the same regions. Questionnaires evaluated the association between a variety of lifestyle, behavioral (ie, hobbies and activities), and occupational factors and the risk of ALS, including the duration of time between exposure and ALS onset, and exposure frequency. Head trauma was associated with increased ALS risk (adjusted odds ratio [OR] 1.60 95% confidence interval [CI] 1.04-2.45), with significantly greater effects for injuries occurring 10 or more years prior to symptom onset (P = .037). ALS risk was increased for those reporting severe electrical burns (adjusted OR 2.86, 95% CI 1.37-6.03), with odds ratios highest for burns after age 30 (OR 3.14), and for burns 10 or more years prior to symptom onset (OR 3.09). Hobbies involving lead were the most strongly associated with ALS risk (adjusted OR 2.92, 95% CI 1.45-5.91). Exposures to lead 20 or more years prior to diagnosis had larger effect sizes compared to those occurring more recently. Holding a job in mechanics, painting, or construction was associated with ALS. The identification of these specific environmental factors associated with ALS highlight the need for future prospective and laboratory studies to assess causality, biological mechanisms, and find prevention or treatment opportunities.}, }
@article {pmid33006054, year = {2020}, author = {Wang, L and Zhang, L}, title = {MicroRNAs in amyotrophic lateral sclerosis: from pathogenetic involvement to diagnostic biomarker and therapeutic agent development.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {41}, number = {12}, pages = {3569-3577}, pmid = {33006054}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Animals ; Biomarkers ; Humans ; *MicroRNAs/genetics ; Motor Neurons ; *Neurodegenerative Diseases ; }, abstract = {MicroRNAs (miRNAs) are a class of endogenous non-coding small single-stranded RNAs that are 21-25 nucleotides (NTs) in length and participate in post-transcriptional gene regulation. Studies have shown that miRNA dysfunction plays a critical role in the occurrence and development of a variety of nervous system diseases, including neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an unclear etiology and is characterized by the selective invasion of motor neurons in the brain and spinal cord. Symptoms can range from mild spasms in the limbs or medulla oblongata muscles to paralysis in almost all skeletal muscles. The role of miRNAs in the pathogenesis, diagnosis, and treatment of ALS has become of greater importance to those studying ALS. In this review, we reviewed experimentally confirmed miRNAs shown to be involved in the pathogenesis of ALS and that are used as diagnostic biomarkers or therapeutic ALS agents. At present, there are at least 20-30 genes clearly related to the pathogenesis of ALS. Multiple miRNAs have been reported in different pathogenic gene models. MiRNAs could be used as biomarkers for the diagnosis of ALS; the differential expression of some miRNAs could be related to ALS prognosis. As therapeutic agents, miRNAs are still in the exploratory stage. Although encouraging results have been achieved using animal models, much research is still needed before clinical trials can ensue. However, with additional miRNA studies in ALS patients and animal models, the pathogenesis, early diagnosis, and therapy of ALS should be elucidated.}, }
@article {pmid33005040, year = {2020}, author = {Dalakas, MC and Alexopoulos, H and Spaeth, PJ}, title = {Complement in neurological disorders and emerging complement-targeted therapeutics.}, journal = {Nature reviews. Neurology}, volume = {16}, number = {11}, pages = {601-617}, pmid = {33005040}, issn = {1759-4766}, mesh = {Animals ; Complement Inactivating Agents/*administration &amp; dosage ; Complement Inactivator Proteins/administration &amp; dosage/immunology ; Complement System Proteins/*immunology/metabolism ; Drug Delivery Systems/methods/*trends ; Humans ; Immunoglobulins, Intravenous/administration &amp; dosage/immunology ; Immunotherapy/methods/*trends ; Nervous System Diseases/*immunology/*therapy ; Signal Transduction/drug effects/immunology ; Synapses/drug effects/immunology ; }, abstract = {The complement system consists of a network of plasma and membrane proteins that modulate tissue homeostasis and contribute to immune surveillance by interacting with the innate and adaptive immune systems. Dysregulation, impairment or inadvertent activation of complement components contribute to the pathogenesis of some autoimmune neurological disorders and could even contribute to neurodegenerative diseases. In this Review, we summarize current knowledge about the main functions of the complement pathways and the involvement of complement in neurological disorders. We describe the complex network of complement proteins that target muscle, the neuromuscular junction, peripheral nerves, the spinal cord or the brain and discuss the autoimmune mechanisms of complement-mediated myopathies, myasthenia, peripheral neuropathies, neuromyelitis and other CNS disorders. We also consider the emerging role of complement in some neurodegenerative diseases, such as Alzheimer disease, amyotrophic lateral sclerosis and even schizophrenia. Finally, we provide an overview of the latest complement-targeted immunotherapies including monoclonal antibodies, fusion proteins and peptidomimetics that have been approved, that are undergoing phase I-III clinical trials or that show promise for the treatment of neurological conditions that respond poorly to existing immunotherapies.}, }
@article {pmid33003004, year = {2020}, author = {Quinn, C and Elman, L}, title = {Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {26}, number = {5}, pages = {1323-1347}, pmid = {33003004}, issn = {1538-6899}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/genetics/physiopathology ; Female ; Humans ; Male ; Middle Aged ; *Motor Neuron Disease/diagnosis/drug therapy/genetics/physiopathology ; Young Adult ; }, abstract = {PURPOSE OF REVIEW: This article reviews the clinical features, diagnostic approach, and treatments available for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases. The article also provides an update on the genetics and pathophysiology of ALS.<br><br>RECENT FINDINGS: ALS remains a clinical diagnosis without a unique biomarker. The areas of greatest progress include a large expansion in the number of genes associated with familial and sporadic ALS. The discovery of these genes, along with other work, has provided a deeper understanding of the mechanisms of motor neuron failure in ALS. Areas of particular interest include the role of transactive response DNA-binding protein 43 and other RNA-processing proteins in the development of disease.<br><br>SUMMARY: ALS remains a relentlessly progressive disorder with an elusive core pathophysiology. The current mainstay of treatment remains symptom management and palliation, particularly in the setting of a multidisciplinary clinic. The future holds potential for targeted therapies based on an ever-evolving understanding of the pathophysiology of both familial and sporadic ALS.}, }
@article {pmid33001363, year = {2020}, author = {Rothstock, S and Weiss, HR and Krueger, D and Paul, L}, title = {Clinical classification of scoliosis patients using machine learning and markerless 3D surface trunk data.}, journal = {Medical &amp; biological engineering &amp; computing}, volume = {58}, number = {12}, pages = {2953-2962}, pmid = {33001363}, issn = {1741-0444}, support = {49MF170001//INNO-KOM BMWi/ ; }, mesh = {Humans ; Imaging, Three-Dimensional ; Machine Learning ; Reproducibility of Results ; *Scoliosis/diagnostic imaging ; Torso ; }, abstract = {Markerless 3D surface topography for scoliosis diagnosis and brace treatment can avoid repeated radiation known from standard X-ray analysis and possible side effects. Combined with the method of torso asymmetry analysis, curve severity and progression can be evaluated with high reliability. In the current study, a machine learning approach was utilised to classify scoliosis patients based on their trunk surface asymmetry pattern. Frontal X-ray and 3D scanning analysis with a clinical classification based on Cobb angle and spinal curve pattern were performed with 50 patients. Similar as in a previous study, each patient's trunk 3D reconstruction was used for an elastic registration of a reference surface mesh with fixed number of vertices. Subsequently, an asymmetry distance map between original and reflected torso was calculated. A fully connected neural network was then utilised to classify patients regarding their Cobb angle (mild, moderate, severe) and an Augmented Lehnert-Schroth (ALS) classification based on their full torso asymmetry distance map. The results reveal a classification success rate of 90% (SE: 80%, SP: 100%) regarding the curve severity (mild vs moderate-severe) and 50-72% regarding the ALS group. Identifying patient curve severity and treatment group was reasonably possible allowing for a decision support during diagnosis and treatment planning. Graphical abstract.}, }
@article {pmid32995749, year = {2020}, author = {Floare, ML and Allen, SP}, title = {Why TDP-43? Why Not? Mechanisms of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Neuroscience insights}, volume = {15}, number = {}, pages = {2633105520957302}, pmid = {32995749}, issn = {2633-1055}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder for which there is no effective curative treatment available and minimal palliative care. Mutations in the gene encoding the TAR DNA-binding protein 43 (TDP-43) are a well-recognized genetic cause of ALS, and an imbalance in energy homeostasis correlates closely to disease susceptibility and progression. Considering previous research supporting a plethora of downstream cellular impairments originating in the histopathological signature of TDP-43, and the solid evidence around metabolic dysfunction in ALS, a causal association between TDP-43 pathology and metabolic dysfunction cannot be ruled out. Here we discuss how TDP-43 contributes on a molecular level to these impairments in energy homeostasis, and whether the protein's pathological effects on cellular metabolism differ from those of other genetic risk factors associated with ALS such as superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9orf72) and fused in sarcoma (FUS).}, }
@article {pmid32987654, year = {2020}, author = {Sukhanova, MV and Singatulina, AS and Pastré, D and Lavrik, OI}, title = {Fused in Sarcoma (FUS) in DNA Repair: Tango with Poly(ADP-ribose) Polymerase 1 and Compartmentalisation of Damaged DNA.}, journal = {International journal of molecular sciences}, volume = {21}, number = {19}, pages = {}, pmid = {32987654}, issn = {1422-0067}, support = {20-14-00086//Russian Science Foundation/ ; }, mesh = {Animals ; *DNA Repair ; Humans ; Poly (ADP-Ribose) Polymerase-1/*metabolism ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; RNA-Binding Protein FUS/*physiology ; }, abstract = {The fused in sarcoma (FUS) protein combines prion-like properties with a multifunctional DNA/RNA-binding domain and has functions spanning the regulation of RNA metabolism, including transcription, pre-mRNA splicing, mRNA transport and translation. In addition to its roles in RNA metabolism, FUS is implicated in the maintenance of DNA integrity. In this review, we examine the participation of FUS in major DNA repair pathways, focusing on DNA repair associated with poly(ADP-ribosyl)ation events and on how the interaction of FUS with poly(ADP-ribose) may orchestrate transient compartmentalisation of DNA strand breaks. Unravelling how prion-like RNA-binding proteins control DNA repair pathways will deepen our understanding of the pathogenesis of some neurological diseases and cancer as well as provide the basis for the development of relevant innovative therapeutic technologies. This knowledge may also extend the range of applications of poly(ADP-ribose) polymerase inhibitors to the treatment of neurodegenerative diseases related to RNA-binding proteins in the cell, e.g., amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, }
@article {pmid32985493, year = {2021}, author = {Chen, XP and Wei, QQ and Ou, RW and Hou, YB and Zhang, LY and Yuan, XQ and Yao, YQ and Jia, DS and Zhang, Q and Li, WX and Shang, HF}, title = {Creatine kinase in the diagnosis and prognostic prediction of amyotrophic lateral sclerosis: a retrospective case-control study.}, journal = {Neural regeneration research}, volume = {16}, number = {3}, pages = {591-595}, pmid = {32985493}, issn = {1673-5374}, abstract = {Creatine kinase is a muscle enzyme that has been reported at various levels in different studies involving patients with amyotrophic lateral sclerosis. In the present retrospective case-control study, we included 582 patients with amyotrophic lateral sclerosis and 582 age- and sex-matched healthy controls. All amyotrophic lateral sclerosis participants received treatment in the Department of Neurology, West China Hospital, China, between May 2008 and December 2018. Serum creatine kinase levels in patients with amyotrophic lateral sclerosis were significantly higher than those in healthy controls. Subgroup analysis revealed that serum creatine kinase levels in men were higher than those in women in both amyotrophic lateral sclerosis patients and healthy controls. Compared with patients with bulbar-onset amyotrophic lateral sclerosis, patients with limb-onset amyotrophic lateral sclerosis had higher creatine kinase levels. Spearman's correlation analysis revealed that serum creatine kinase levels were not correlated with body mass index, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, or progression rate. After adjusting for prognostic covariates, higher log creatine kinase values were correlated with higher overall survival in the amyotrophic lateral sclerosis patients. We also investigated the longitudinal changes in serum creatine kinase levels in 81 amyotrophic lateral sclerosis patients; serum creatine kinase levels were decreased at the second blood test, which was sampled at least 6 months after the first blood test. Together, our results suggest that serum creatine kinase levels can be used as an independent factor for predicting the prognosis of amyotrophic lateral sclerosis patients. This study received ethical approval from the Ethics Committee of West China Hospital, China (approval No. 2015(236)) on December 23, 2015.}, }
@article {pmid32983232, year = {2020}, author = {Yang, Q and Jiao, B and Shen, L}, title = {The Development of C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Disorders.}, journal = {Frontiers in genetics}, volume = {11}, number = {}, pages = {562758}, pmid = {32983232}, issn = {1664-8021}, abstract = {The expanded GGGGCC hexanucleotide repeat in the non-coding region of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). There are three main disease mechanisms: loss of function of C9ORF72 protein, gain of function from the accumulation of sense and antisense (GGGGCC)n in RNA, and from the production of toxic dipeptides repeat proteins (DPRs) by non-AUG initiated translation. While many of the downstream mechanisms have been identified, the specific pathogenic pathway is still unclear. In this article, we provide an overview on the currently available literature and propose several hypotheses: (1) The pathogenesis of C9orf72-associated ALS/FTD, which cannot be explained by a single mechanism, involves a dual mechanism of both loss and gain of function. (2) The loss of function and gain of function can cause TDP-43 aggregation and damage nucleocytoplasmic transport. (3) Neurodegeneration can be caused by an accumulation of toxic substances in neurons themselves. In addition, we suggest that microglia may cause neurodegeneration by releasing inflammatory factors to neurons. Finally, we summarize several of the most promising treatment strategies.}, }
@article {pmid32979923, year = {2020}, author = {Zamudio, F and Loon, AR and Smeltzer, S and Benyamine, K and Navalpur Shanmugam, NK and Stewart, NJF and Lee, DC and Nash, K and Selenica, MB}, title = {TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model.}, journal = {Journal of neuroinflammation}, volume = {17}, number = {1}, pages = {283}, pmid = {32979923}, issn = {1742-2094}, mesh = {Animals ; Blood-Brain Barrier/*metabolism/pathology ; Capillary Permeability/drug effects/*physiology ; DNA-Binding Proteins/*biosynthesis ; Disease Models, Animal ; Female ; Humans ; Leukocytes/*metabolism/pathology ; Lipopolysaccharides/toxicity ; Male ; Mice ; Neurodegenerative Diseases/chemically induced/*metabolism/pathology ; Systemic Inflammatory Response Syndrome/chemically induced/*metabolism/pathology ; }, abstract = {BACKGROUND: Neuronal cytoplasmic inclusions containing TAR DNA-binding protein 43 (TDP-43) are a neuropathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's Disease (AD). Emerging evidence also indicates that systemic inflammation may be a contributor to the pathology progression of these neurodegenerative diseases.<br><br>METHODS: To investigate the role of systemic inflammation in the progression of neuronal TDP-43 pathology, AAV9 particles driven by the UCHL1 promoter were delivered to the frontal cortex of wild-type aged mice via intracranial injections to overexpress TDP-43 or green fluorescent protein (GFP) in corticospinal motor neurons. Animals were then subjected to a low-dose (500&#x2009;&#x3bc;g/kg) intraperitoneal E. coli lipopolysaccharide (LPS) administration challenge for 2 weeks to mimic a chronically altered low-grade systemic inflammatory state. Mice were then subjected to neurobehavioral studies, followed by biochemical and immunohistochemical analyses of the brain tissue.<br><br>RESULTS: In the present study, we report that elevated neuronal TDP-43 levels induced microglial and astrocytic activation in the cortex of injected mice followed by increased RANTES signaling. Moreover, overexpression of TDP-43 exerted abundant mouse immunoglobulin G (IgG), CD3, and CD4+ T cell infiltration as well as endothelial and pericyte activation suggesting increased blood-brain barrier permeability. The BBB permeability in TDP-43 overexpressing brains yielded the frontal cortex vulnerable to the systemic inflammatory response following LPS treatment, leading to marked neutrophil infiltration, neuronal loss, reduced synaptosome-associated protein 25 (SNAP-25) levels, and behavioral impairments in the radial arm water maze (RAWM) task.<br><br>CONCLUSIONS: These results reveal a novel role for TDP-43 in BBB permeability and leukocyte recruitment, indicating complex intermolecular interactions between an altered systemic inflammatory state and pathologically prone TDP-43 protein to promote disease progression.}, }
@article {pmid32972341, year = {2020}, author = {Deeb, O and Nabulsi, M}, title = {Exploring Multiple Sclerosis (MS) and Amyotrophic Lateral Scler osis (ALS) as Neurodegenerative Diseases and their Treatments: A Review Study.}, journal = {Current topics in medicinal chemistry}, volume = {20}, number = {26}, pages = {2391-2403}, doi = {10.2174/1568026620666200924114827}, pmid = {32972341}, issn = {1873-4294}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*pathology ; Animals ; Blood-Brain Barrier/metabolism ; Disease Progression ; Dose-Response Relationship, Drug ; Drug Discovery ; Humans ; Immunosuppressive Agents/*chemistry/pharmacology ; Magnetic Resonance Imaging ; Molecular Structure ; Motor Neurons/pathology ; Multiple Sclerosis/drug therapy/*pathology ; Neurodegenerative Diseases/drug therapy/*pathology ; Phenotype ; Quality of Life ; Spinal Cord/metabolism ; }, abstract = {Growing concern about neurodegenerative diseases is becoming a global issue. It is estimated that not only will their prevalence increase but also morbidity and health burden will be concerning. Scientists, researchers and clinicians share the responsibility of raising the awareness and knowledge about the restricting and handicapping health restrains related to these diseases. Multiple Sclerosis (MS), as one of the prevalent autoimmune diseases, is characterized by abnormal regulation of the immune system that periodically attacks parts of the nervous system; brain and spinal cord. Symptoms and impairments include weakness, numbness, visual problems, tingling pain that are quietly variable among patients. Amyotrophic Lateral Sclerosis (ALS) is another neurodegenerative disease that is characterized by the degeneration of motor neurons in the brain and spinal cord. Unlike MS, symptoms begin with muscle weakness and progress to affect speech, swallowing and finally breathing. Despite the major differences between MS and ALS, misdiagnosis is still influencing disease prognosis and patient's quality of life. Diagnosis depends on obtaining a careful history and neurological examination as well as the use of Magnetic Resonance Imaging (MRI), which are considered challenging and depend on the current disease status in individuals. Fortunately, a myriad of treatments is available now for MS. Most of the cases are steroid responsive. Disease modifying therapy is amongst the most important set of treatments. In ALS, few medications that slow down disease progression are present. The aim of this paper is to summarize what has been globally known and practiced about MS and ALS, as they are currently classified as important growing key players among autoimmune diseases. In terms of treatments, it is concluded that special efforts and input should be directed towards repurposing of older drugs and on stem cells trials. As for ALS, it is highlighted that supportive measurements and supplementary treatments remain essentially needed for ALS patients and their families. On the other hand, it is noteworthy to clarify that the patient-doctor communication is relatively a cornerstone in selecting the best treatment for each MS patient.}, }
@article {pmid32971256, year = {2020}, author = {Gagliardi, D and Costamagna, G and Taiana, M and Andreoli, L and Biella, F and Bersani, M and Bresolin, N and Comi, GP and Corti, S}, title = {Insights into disease mechanisms and potential therapeutics for C9orf72-related amyotrophic lateral sclerosis/frontotemporal dementia.}, journal = {Ageing research reviews}, volume = {64}, number = {}, pages = {101172}, doi = {10.1016/j.arr.2020.101172}, pmid = {32971256}, issn = {1872-9649}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; C9orf72 Protein/genetics ; DNA Repeat Expansion/genetics ; *Frontotemporal Dementia/genetics/therapy ; Humans ; Proteins/genetics ; }, abstract = {In 2011, a hexanucleotide repeat expansion (HRE) in the noncoding region of C9orf72 was associated with the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The main pathogenic mechanisms in C9-ALS/FTD are haploinsufficiency of the C9orf72 protein and gain of function toxicity from bidirectionally-transcribed repeat-containing RNAs and dipeptide repeat proteins (DPRs) resulting from non-canonical RNA translation. Additionally, abnormalities in different downstream cellular mechanisms, such as nucleocytoplasmic transport and autophagy, play a role in pathogenesis. Substantial research efforts using in vitro and in vivo models have provided valuable insights into the contribution of each mechanism in disease pathogenesis. However, conflicting evidence exists, and a unifying theory still lacks. Here, we provide an overview of the recently published literature on clinical, neuropathological and molecular features of C9-ALS/FTD. We highlight the supposed neuronal role of C9orf72 and the HRE pathogenic cascade, mainly focusing on the contribution of RNA foci and DPRs to neurodegeneration and discussing the several downstream mechanisms. We summarize the emerging biochemical and neuroimaging biomarkers, as well as the potential therapeutic approaches. Despite promising results, a specific disease-modifying treatment is still not available to date and greater insights into disease mechanisms may help in this direction.}, }
@article {pmid32969758, year = {2021}, author = {Shefner, JM and Andrews, JA and Genge, A and Jackson, C and Lechtzin, N and Miller, TM and Cockroft, BM and Meng, L and Wei, J and Wolff, AA and Malik, FI and Bodkin, C and Brooks, BR and Caress, J and Dionne, A and Fee, D and Goutman, SA and Goyal, NA and Hardiman, O and Hayat, G and Heiman-Patterson, T and Heitzman, D and Henderson, RD and Johnston, W and Karam, C and Kiernan, MC and Kolb, SJ and Korngut, L and Ladha, S and Matte, G and Mora, JS and Needham, M and Oskarsson, B and Pattee, GL and Pioro, EP and Pulley, M and Quan, D and Rezania, K and Schellenberg, KL and Schultz, D and Shoesmith, C and Simmons, Z and Statland, J and Sultan, S and Swenson, A and Berg, LHVD and Vu, T and Vucic, S and Weiss, M and Whyte-Rayson, A and Wymer, J and Zinman, L and Rudnicki, SA}, title = {A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {22}, number = {3-4}, pages = {287-299}, pmid = {32969758}, issn = {2167-9223}, support = {UL1 TR001420/TR/NCATS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Humans ; Muscle Strength ; }, abstract = {To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).}, }
@article {pmid32968789, year = {2020}, author = {Tidball, AM and Lopez-Santiago, LF and Yuan, Y and Glenn, TW and Margolis, JL and Clayton Walker, J and Kilbane, EG and Miller, CA and Martina Bebin, E and Scott Perry, M and Isom, LL and Parent, JM}, title = {Variant-specific changes in persistent or resurgent sodium current in SCN8A-related epilepsy patient-derived neurons.}, journal = {Brain : a journal of neurology}, volume = {143}, number = {10}, pages = {3025-3040}, pmid = {32968789}, issn = {1460-2156}, support = {R01 NS088571/NS/NINDS NIH HHS/United States ; R37 NS076752/NS/NINDS NIH HHS/United States ; U01 NS090364/NS/NINDS NIH HHS/United States ; }, mesh = {Action Potentials/physiology ; Adolescent ; Adult ; Child ; Epilepsy/*genetics/*physiopathology ; Female ; Genetic Variation/*genetics ; Humans ; Induced Pluripotent Stem Cells/physiology ; Infant ; Infant, Newborn ; Male ; Middle Aged ; NAV1.6 Voltage-Gated Sodium Channel/*genetics ; Neurons/*physiology ; }, abstract = {Missense variants in the SCN8A voltage-gated sodium channel gene are linked to early-infantile epileptic encephalopathy type 13, also known as SCN8A-related epilepsy. These patients exhibit a wide spectrum of intractable seizure types, severe developmental delay, movement disorders, and elevated risk of sudden unexpected death in epilepsy. The mechanisms by which SCN8A variants lead to epilepsy are poorly understood, although heterologous expression systems and mouse models have demonstrated altered sodium current properties. To investigate these mechanisms using a patient-specific model, we generated induced pluripotent stem cells from three patients with missense variants in SCN8A: p.R1872>L (Patient 1); p.V1592>L (Patient 2); and p.N1759>S (Patient 3). Using small molecule differentiation into excitatory neurons, induced pluripotent stem cell-derived neurons from all three patients displayed altered sodium currents. Patients 1 and 2 had elevated persistent current, while Patient 3 had increased resurgent current compared to controls. Neurons from all three patients displayed shorter axon initial segment lengths compared to controls. Further analyses focused on one of the patients with increased persistent sodium current (Patient 1) and the patient with increased resurgent current (Patient 3). Excitatory cortical neurons from both patients had prolonged action potential repolarization. Using doxycycline-inducible expression of the neuronal transcription factors neurogenin 1 and 2 to synchronize differentiation of induced excitatory cortical-like neurons, we investigated network activity and response to pharmacotherapies. Both small molecule differentiated and induced patient neurons displayed similar abnormalities in action potential repolarization. Patient induced neurons showed increased burstiness that was sensitive to phenytoin, currently a standard treatment for SCN8A-related epilepsy patients, or riluzole, an FDA-approved drug used in amyotrophic lateral sclerosis and known to block persistent and resurgent sodium currents, at pharmacologically relevant concentrations. Patch-clamp recordings showed that riluzole suppressed spontaneous firing and increased the action potential firing threshold of patient-derived neurons to more depolarized potentials. Two of the patients in this study were prescribed riluzole off-label. Patient 1 had a 50% reduction in seizure frequency. Patient 3 experienced an immediate and dramatic seizure reduction with months of seizure freedom. An additional patient with a SCN8A variant in domain IV of Nav1.6 (p.V1757>I) had a dramatic reduction in seizure frequency for several months after starting riluzole treatment, but then seizures recurred. Our results indicate that patient-specific neurons are useful for modelling SCN8A-related epilepsy and demonstrate SCN8A variant-specific mechanisms. Moreover, these findings suggest that patient-specific neuronal disease modelling offers a useful platform for discovering precision epilepsy therapies.}, }
@article {pmid32963657, year = {2020}, author = {Kang, SG and Song, SW and Kim, SH and Kang, YJ and Kim, YR and Eun, Y}, title = {Fatigue and Mental Status of Caregivers of Severely Chronically Ill Patients.}, journal = {Pain research &amp; management}, volume = {2020}, number = {}, pages = {6372857}, pmid = {32963657}, issn = {1918-1523}, mesh = {Aged ; Anxiety/epidemiology/*etiology ; Caregivers/*psychology ; Chronic Disease ; Depression/epidemiology/*etiology ; Fatigue/epidemiology/*etiology ; Female ; Humans ; Long-Term Care/*psychology ; Male ; Middle Aged ; Republic of Korea ; }, abstract = {BACKGROUND AND AIMS: Fatigue is an unpleasant experience accompanied by functional deterioration involving both mental and physical factors. Caregivers of patients with severe illnesses who require long-term treatment often experience marked physical and mental fatigue. This study investigated the factors affecting fatigue among caregivers of patients with severe chronic diseases.<br><br>METHODS: The study enrolled 100 caregivers of patients providing home care nursing at a university hospital in Gyeonggi-do of Korea, including 47 caregivers caring for cancer patients and 53 caregivers caring for chronic disease patients (e.g., dementia, amyotrophic lateral sclerosis, and Parkinson's disease). The degree of fatigue was measured using the Korean version of the multidimensional fatigue inventory (MFI-K). Caregiver depression and anxiety were examined using the Hospital Anxiety and Depression Scale.<br><br>RESULTS: The average MFI-K score of all caregivers was 60.43&#x2009;&#xb1;&#x2009;13.77 and did not differ significantly between those caring for cancer patients and those caring for patients with severe chronic diseases (62.15&#x2009;&#xb1;&#x2009;13.27 vs. 58.49&#x2009;&#xb1;&#x2009;14.20, respectively, p=0.186). The longer the disease duration, the greater the general and physical fatigue of the caregiver (r&#x2009;=&#x2009;0.284, p=0.004). However, caregiver mental fatigue did not differ according to disease duration (r&#x2009;=&#x2009;0.169, p=0.094). The main factors affecting caregiver general and physical fatigue were caregiver anxiety and depression and patient's disease duration.<br><br>CONCLUSIONS: The caregivers of patients with cancer or chronic severe illnesses experience high levels of fatigue: the longer the disease duration, the greater the degrees of depression, anxiety, and physical fatigue experienced by the caregivers. Such caregivers need strategies to manage their fatigue and depression.}, }
@article {pmid32961448, year = {2021}, author = {Liu, Z and Huang, X and Jiang, Z and Tuo, X}, title = {Investigation of the binding properties between levamlodipine and HSA based on MCR-ALS and computer modeling.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {245}, number = {}, pages = {118929}, doi = {10.1016/j.saa.2020.118929}, pmid = {32961448}, issn = {1873-3557}, mesh = {Binding Sites ; Circular Dichroism ; Computers ; Humans ; Hydrogen Bonding ; Least-Squares Analysis ; Molecular Docking Simulation ; Niacin/analogs &amp; derivatives ; Protein Binding ; *Serum Albumin/metabolism ; *Serum Albumin, Human ; Spectrometry, Fluorescence ; Thermodynamics ; }, abstract = {Levamlodipine (LEE) is a drug commonly used for antihypertensive treatment in clinical therapy. The overlapping fluorescence spectra of LEE and human serum albumin (HSA) cause some trouble in analysis of interactions between them by using the classic fluorescence method. Here, the multivariate curve resolution-alternating least squares (MCR-ALS) approach was used to overcome this disadvantage. Meanwhile, the binding properties of LEE-HSA complex were then explored through computer modeling. The MCR-ALS results suggested that LEE-HSA complex was present in the mixture solution of LEE and HSA. This conclusion was then confirmed by the Stern-Volmer equation and time-resolved fluorescence experiment. The binding constant (Ka) was 2.139 × 10[4] L·mol[-1] at 298 K. LEE was located close to the Trp-214 residue of HSA, with van der Waals forces and hydrogen bonding as main driving forces for this interaction. LEE can alter the conformation of HSA, in which the content of α-helix reduced from 57.2% to 52.3%. The Pi-Alkyl interactions contributed to maintaining the stability of the LEE-HSA complex. The results of molecular dynamics simulations showed that LEE-HSA complex was formed within 5 ns, and the particle size (Rg) of HSA was altered by the binding reaction. This study would promote better understanding of the transportation and distribution mechanisms of LEE in the human body.}, }
@article {pmid32956536, year = {2020}, author = {Garrison, SR and Korownyk, CS and Kolber, MR and Allan, GM and Musini, VM and Sekhon, RK and Dugré, N}, title = {Magnesium for skeletal muscle cramps.}, journal = {The Cochrane database of systematic reviews}, volume = {9}, number = {9}, pages = {CD009402}, pmid = {32956536}, issn = {1469-493X}, support = {//CIHR/Canada ; }, mesh = {Adult ; Age Factors ; Aged ; Cross-Over Studies ; Female ; Humans ; Magnesium/adverse effects/*therapeutic use ; Male ; Middle Aged ; Muscle Cramp/*drug therapy/etiology ; *Muscle, Skeletal ; Placebos/therapeutic use ; Pregnancy ; Pregnancy Complications/*drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Skeletal muscle cramps are common and often occur in association with pregnancy, advanced age, exercise or motor neuron disorders (such as amyotrophic lateral sclerosis). Typically, such cramps have no obvious underlying pathology, and so are termed idiopathic. Magnesium supplements are marketed for the prophylaxis of cramps but the efficacy of magnesium for this purpose remains unclear. This is an update of a Cochrane Review first published in 2012, and performed to identify and incorporate more recent studies.<br><br>OBJECTIVES: To assess the effects of magnesium supplementation compared to no treatment, placebo control or other cramp therapies in people with skeletal muscle cramps. &#xa0; SEARCH METHODS: On 9 September 2019, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, CINAHL Plus, AMED, and SPORTDiscus. We also searched WHO-ICTRP and ClinicalTrials.gov for registered trials that might be ongoing or unpublished, and ISI Web of Science for studies citing the studies included in this review.<br><br>SELECTION CRITERIA: Randomized controlled trials (RCTs) of magnesium supplementation (in any form) to prevent skeletal muscle cramps in any patient group (i.e. all clinical presentations of cramp). We considered comparisons of magnesium with no treatment, placebo control, or other therapy.<br><br>DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted data. Two review authors assessed risk of bias. We attempted to contact all study authors when questions arose and obtained participant-level data for four of the included trials, one of which was unpublished. We collected all data on adverse effects from the included RCTs.<br><br>MAIN RESULTS: We identified 11 trials (nine parallel-group, two cross-over) enrolling a total of 735 individuals, amongst whom 118 cross-over participants additionally served as their own controls. Five trials enrolled women with pregnancy-associated leg cramps (408 participants) and five trials enrolled people with idiopathic cramps (271 participants, with 118 additionally crossed over to control). Another study enrolled 29 people with liver cirrhosis, only some of whom suffered muscle cramps. All trials provided magnesium as an oral supplement, except for one trial which provided magnesium as a series of slow intravenous infusions. Nine trials compared magnesium to placebo, one trial compared magnesium to no treatment, calcium carbonate or vitamin B, and another trial compared magnesium to vitamin E or calcium. We judged the single trial in people with liver cirrhosis and all five trials in participants with pregnancy-associated leg cramps to be at high risk of bias. In contrast, we rated the risk of bias high in only one of five trials in participants with idiopathic rest cramps. For idiopathic cramps, largely in older adults (mean age 61.6 to 69.3 years) presumed to have nocturnal leg cramps (the commonest presentation), differences in measures of cramp frequency when comparing magnesium to placebo were small, not statistically significant, and showed minimal heterogeneity (I&#xb2; = 0% to 12%). This includes the primary endpoint, percentage change from baseline in the number of cramps per week at four weeks (mean difference (MD) -9.59%, 95% confidence interval (CI) -23.14% to 3.97%; 3 studies, 177 participants; moderate-certainty evidence); and the difference in the number of cramps per week at four weeks (MD -0.18 cramps/week, 95% CI -0.84 to 0.49; 5 studies, 307 participants; moderate-certainty evidence). The percentage of individuals experiencing a 25% or better reduction in cramp rate from baseline was also no different (RR 1.04, 95% CI 0.84 to 1.29; 3 studies, 177 participants; high-certainty evidence). Similarly, no statistically significant difference was found at four weeks in measures of cramp intensity or cramp duration. This includes the number of participants rating their cramps as moderate or severe at four weeks (RR 1.33, 95% CI 0.81 to 2.21; 2 studies, 91 participants; moderate-certainty evidence); and the percentage of participants with the majority of cramp durations of one minute or more at four weeks (RR 1.83, 95% CI 0.74 to 4.53, 1 study, 46 participants; low-certainty evidence). We were unable to perform meta-analysis for trials of pregnancy-associated leg cramps. The single study comparing magnesium to no treatment failed to find statistically significant benefit on a three-point ordinal scale of overall treatment efficacy. Of the three trials comparing magnesium to placebo, one found no benefit on frequency or intensity measures, another found benefit for both, and a third reported inconsistent results for frequency that could not be reconciled. The single study in people with liver cirrhosis was small and had limited reporting of cramps, but found no difference in terms of cramp frequency or cramp intensity. Our analysis of adverse events pooled all studies, regardless of the setting in which cramps occurred. Major adverse events (occurring in 2 out of 72 magnesium recipients and 3 out of 68 placebo recipients), and withdrawals due to adverse events, were not significantly different from placebo. However, in the four studies for which it could be determined, more participants experienced minor adverse events in the magnesium group than in the placebo group (RR 1.51, 95% CI 0.98 to 2.33; 4 studies, 254 participants; low-certainty evidence). Overall, oral magnesium was associated with mostly gastrointestinal adverse events (e.g. diarrhoea), experienced by 11% (10% in control) to 37% (14% in control) of participants.<br><br>AUTHORS' CONCLUSIONS: It is unlikely that magnesium supplementation provides clinically meaningful cramp prophylaxis to older adults experiencing skeletal muscle cramps. In contrast, for those experiencing pregnancy-associated rest cramps the literature is conflicting and further research in this population is needed. We found no RCTs evaluating magnesium for exercise-associated muscle cramps or disease-state-associated muscle cramps (for example amyotrophic lateral sclerosis/motor neuron disease) other than a single small (inconclusive) study in people with liver cirrhosis, only some of whom suffered cramps.}, }
@article {pmid32951348, year = {2020}, author = {Zhang, QJ and Chen, Y and Zou, XH and Hu, W and Ye, ML and Guo, QF and Lin, XL and Feng, SY and Wang, N}, title = {Promoting identification of amyotrophic lateral sclerosis based on label-free plasma spectroscopy.}, journal = {Annals of clinical and translational neurology}, volume = {7}, number = {10}, pages = {2010-2018}, pmid = {32951348}, issn = {2328-9503}, mesh = {Amyotrophic Lateral Sclerosis/*blood/*diagnosis ; Biomarkers/*analysis ; Disease Progression ; Female ; Humans ; Middle Aged ; Neurodegenerative Diseases/*diagnosis/metabolism ; Plasma/metabolism ; ROC Curve ; Severity of Illness Index ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal neurodegenerative disease which lacks identified biological markers. A label-free plasma surface-enhanced Raman spectroscopy (SERS) method was developed to explore a simple and noninvasive test for ALS.<br><br>METHODS: ALS patients were enrolled serially and plasma samples were collected at the time of diagnosis prior to the start of ALS treatment. SERS spectra were recorded using a Renishaw micro-Raman system.<br><br>RESULTS: To exclude the interference by varying disease severity, we enrolled three groups of ALS patients, including ALS-1 (n&#xa0;=&#xa0;60; ALSFRS-R&#xa0;&#x2265;&#xa0;42 and time interval&#xa0;&#x2264;&#xa0;12&#xa0;months), ALS-2 (n&#xa0;=&#xa0;61; ALSFRS-R&#xa0;<&#xa0;42 and time interval&#xa0;&#x2264;&#xa0;12&#xa0;months), and ALS-3 (n&#xa0;=&#xa0;61; ALSFRS-R&#xa0;&#x2265;&#xa0;38 and time interval>&#xa0;12&#xa0;months). The SERS spectra were analyzed using principal component analysis (PCA), which showed that ALS-1, ALS-2, ALS-3, and control groups were separated significantly. Then, decision tree (DT) models and receiver operating characteristic curves were employed and identified that bands at 722 and 739&#xa0;cm[-1] , and ratios of 635-722&#xa0;cm[-1] and 635-739&#xa0;cm[-1] were able to distinguish ALS from controls significantly. Finally, we highlighted six metabolism pathways correlated with ALS, including phenylalanine-tyrosine-tryptophan biosynthesis, aminoacyl-tRNA biosynthesis, phenylalanine metabolism, pantothenate and CoA biosynthesis, porphyrin and chlorophyll metabolism, and pyrimidine metabolism.<br><br>INTERPRETATION: Plasma SERS could be a promising tool for the detection of ALS. The bands at 722 and 739&#xa0;cm[-1] , and the ratios of 635-722&#xa0;cm[-1] and 635-739&#xa0;cm[-1] could serve as potential indicator for ALS.}, }
@article {pmid32950644, year = {2020}, author = {Johnson, MA and Deng, Q and Taylor, G and McEachin, ZT and Chan, AWS and Root, J and Bassell, GJ and Kukar, T}, title = {Divergent FUS phosphorylation in primate and mouse cells following double-strand DNA damage.}, journal = {Neurobiology of disease}, volume = {146}, number = {}, pages = {105085}, pmid = {32950644}, issn = {1095-953X}, support = {K99 AG032362/AG/NIA NIH HHS/United States ; R01 NS105971/NS/NINDS NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; R01 NS093362/NS/NINDS NIH HHS/United States ; R00 AG032362/AG/NIA NIH HHS/United States ; T32 NS096050/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain/*metabolism ; DNA/*metabolism ; DNA Damage/*physiology ; Frontotemporal Lobar Degeneration/genetics/*metabolism ; Humans ; Inclusion Bodies/genetics/metabolism ; Mice ; Mutation/genetics ; Neurons/metabolism ; Phosphorylation ; RNA-Binding Protein FUS/*genetics ; TATA-Binding Protein Associated Factors/genetics ; }, abstract = {Fused in sarcoma (FUS) is a RNA/DNA protein involved in multiple nuclear and cytoplasmic functions including transcription, splicing, mRNA trafficking, and stress granule formation. To accomplish these many functions, FUS must shuttle between cellular compartments in a highly regulated manner. When shuttling is disrupted, FUS abnormally accumulates into cytoplasmic inclusions that can be toxic. Disrupted shuttling of FUS into the nucleus is a hallmark of ~10% of frontotemporal lobar degeneration (FTLD) cases, the neuropathology that underlies frontotemporal dementia (FTD). Multiple pathways are known to disrupt nuclear/cytoplasmic shuttling of FUS. In earlier work, we discovered that double-strand DNA breaks (DSBs) trigger DNA-dependent protein kinase (DNA-PK) to phosphorylate FUS (p-FUS) at N-terminal residues leading to the cytoplasmic accumulation of FUS. Therefore, DNA damage may contribute to the development of FTLD pathology with FUS inclusions. In the present study, we examined how DSBs effect FUS phosphorylation in various primate and mouse cellular models. All cell lines derived from human and non-human primates exhibit N-terminal FUS phosphorylation following calicheamicin γ1 (CLM) induced DSBs. In contrast, we were unable to detect FUS phosphorylation in mouse-derived primary neurons or immortalized cell lines regardless of CLM treatment, duration, or concentration. Despite DNA damage induced by CLM treatment, we find that mouse cells do not phosphorylate FUS, likely due to reduced levels and activity of DNA-PK compared to human cells. Taken together, our work reveals that mouse-derived cellular models regulate FUS in an anomalous manner compared to primate cells. This raises the possibility that mouse models may not fully recapitulate the pathogenic cascades that lead to FTLD with FUS pathology.}, }
@article {pmid32944919, year = {2021}, author = {Eyileten, C and Sharif, L and Wicik, Z and Jakubik, D and Jarosz-Popek, J and Soplinska, A and Postula, M and Czlonkowska, A and Kaplon-Cieslicka, A and Mirowska-Guzel, D}, title = {The Relation of the Brain-Derived Neurotrophic Factor with MicroRNAs in Neurodegenerative Diseases and Ischemic Stroke.}, journal = {Molecular neurobiology}, volume = {58}, number = {1}, pages = {329-347}, pmid = {32944919}, issn = {1559-1182}, support = {2017/25/N/NZ5/00545//Narodowe Centrum Nauki/ ; }, mesh = {Animals ; Brain-Derived Neurotrophic Factor/*metabolism ; Humans ; Ischemic Stroke/*genetics/therapy ; MicroRNAs/genetics/*metabolism ; Models, Biological ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*genetics/therapy ; }, abstract = {Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that plays a crucial role in the development of the nervous system while supporting the survival of existing neurons and instigating neurogenesis. Altered levels of BDNF, both in the circulation and in the central nervous system (CNS), have been reported to be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), multiple sclerosis (MS), and ischemic stroke. MicroRNAs (miRNAs) are a class of non-coding RNAs found in body fluids such as peripheral blood and cerebrospinal fluid. Several different miRNAs, and their target genes, are recognized to be involved in the pathophysiology of neurodegenerative and neurovascular diseases. Thus, they present as promising biomarkers and a novel treatment approach for CNS disorders. Currently, limited studies provide viable evidence of miRNA-mediated post-transcriptional regulation of BDNF. The aim of this review is to provide a comprehensive assessment of the current knowledge regarding the potential diagnostic and prognostic values of miRNAs affecting BDNF expression and its role as a CNS disorders and neurovascular disease biomarker. Moreover, a novel therapeutic approach in neurodegenerative diseases and ischemic stroke targeting miRNAs associated with BDNF will be discussed.}, }
@article {pmid32937436, year = {2020}, author = {Wang, Y and Liu, Y and Nham, A and Sherbaf, A and Quach, D and Yahya, E and Ranburger, D and Bi, X and Baudry, M}, title = {Calpain-2 as a therapeutic target in repeated concussion-induced neuropathy and behavioral impairment.}, journal = {Science advances}, volume = {6}, number = {27}, pages = {}, pmid = {32937436}, issn = {2375-2548}, mesh = {Amyotrophic Lateral Sclerosis ; Animals ; Brain/physiopathology ; *Brain Concussion/complications/drug therapy ; *Calpain/antagonists &amp; inhibitors/genetics ; Frontotemporal Dementia ; Mice ; }, abstract = {Repeated concussion represents a serious health problem as it can result in various brain pathologies, ranging from minor focal tissue injury to severe chronic traumatic encephalopathy. The calcium-dependent protease, calpain, participates in the development of neurodegeneration following concussion, but there is no information regarding the relative contribution of calpain-1 and calpain-2, the major calpain isoforms in the brain. We used a mouse model of repeated concussions, which reproduces most of the behavioral and neuropathological features of the human condition, to address this issue. Deletion of calpain-2 or treatment with a selective calpain-2 inhibitor for 2 weeks prevented most of these neuropathological features. Changes in TAR DNA binding protein 43 (TDP-43) subcellular localization similar to those found in human amyotrophic lateral sclerosis and frontotemporal dementia were also prevented by deletion of calpain-2 or treatment with calpain-2 inhibitor. Our results indicate that a selective calpain-2 inhibitor represents a therapeutic approach for concussion.}, }
@article {pmid32924606, year = {2021}, author = {Wosiski-Kuhn, M and Caress, JB and Cartwright, MS and Hawkins, GA and Milligan, C}, title = {Interleukin 6 (IL6) level is a biomarker for functional disease progression within IL6R[358]Ala variant groups in amyotrophic lateral sclerosis patients.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {22}, number = {3-4}, pages = {248-259}, doi = {10.1080/21678421.2020.1813310}, pmid = {32924606}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Biomarkers ; Disease Progression ; Humans ; *Interleukin-6/genetics ; Longitudinal Studies ; Receptors, Interleukin-6/genetics ; }, abstract = {Interleukin-6 (IL6) expression increases in atrophying muscles and lung tissue during compromised function. Considering ALS patients undergo these same pathological changes, IL6 levels may be relevant for prognostication and treatment. The amount of soluble IL6 receptor, dictated by the IL6R[358]Ala variant, and local tissue environment in which IL6 signaling occurs is known to influence the ultimate effects of IL6 in multiple diseases. In this longitudinal study, we show that serum IL6 levels negatively correlate both with the patient's functional status as measured by the overall ALSFRS-R and subscores, and with respiratory function as measured by the percent predicted FVC (ppFVC). The correlations are only present in the two-thirds of patients who carry the IL6R[358]Ala variant that mediates pro-inflammatory transsignaling in the cases of ALSFRS-R limb and respiratory subscores and ppFVC. These results suggest that some observed associations between IL6 and ALS are driven by the subset of patients carrying the IL6R[358]Ala variant and thus that any IL6-targeted therapeutic approaches may be more advantageous when aimed at this group. Specifically, with relation to respiratory decline, these patients may benefit from closer respiratory follow-up and early initiation of noninvasive ventilation.}, }
@article {pmid32918993, year = {2021}, author = {Shin, Y and Lee, D and Ahn, J and Lee, M and Shin, SS and Yoon, M}, title = {The herbal extract ALS-L1023 from Melissa officinalis reduces weight gain, elevated glucose levels and β-cell loss in Otsuka Long-Evans Tokushima fatty rats.}, journal = {Journal of ethnopharmacology}, volume = {264}, number = {}, pages = {113360}, doi = {10.1016/j.jep.2020.113360}, pmid = {32918993}, issn = {1872-7573}, mesh = {Animals ; Blood Glucose/*drug effects/metabolism ; Diabetes Mellitus, Type 2 ; Diet, High-Fat/adverse effects ; Dose-Response Relationship, Drug ; Insulin-Secreting Cells/*drug effects/metabolism ; Lipid Metabolism/drug effects/physiology ; *Melissa ; Obesity/*drug therapy/etiology/metabolism ; Plant Extracts/pharmacology/*therapeutic use ; Rats ; Rats, Inbred OLETF ; Rats, Long-Evans ; Weight Gain/*drug effects/physiology ; }, abstract = {Melissa officinalis L. (Labiatae; lemon balm) is a traditional medicinal plant with hypoglycemic and hypolipidemic effects; however, how it imparts its beneficial effects remains unclear. We thus hypothesized that the herbal extract ALS-L1023, isolated from Melissa officinalis, inhibits obesity and diabetes, and tested our hypothesis using Otsuka Long-Evans Tokushima fatty (OLETF) rats, which are an established animal model of type 2 diabetes.<br><br>MATERIALS AND METHODS: In this study, 28-week-old OLETF rats were fed a high-fat diet for 4 weeks to induce a marked impairment of the insulin response and were treated with or without ALS-L1023. Subsequently, the variables and determinants of glucose metabolism and pancreatic function were assessed via blood analysis, histology, immunohistochemistry, and real-time polymerase chain reaction.<br><br>RESULTS: The administration of ALS-L1023 resulted in a weight reduction without changes in food intake. It also markedly inhibited hyperglycemia and hypoinsulinemia, and restored &#x3b2;-cell mass that was severely impaired in OLETF rats. There was a decrease in lipid accumulation in the liver and skeletal muscle of the obese rats after treatment with ALS-L1023. Concomitantly, there was an increase in the expression levels of fatty acid-oxidizing enzymes (AMPK&#x3b1;2, ACOX, MCAD, and VLCAD) in the liver and skeletal muscle after ALS-L1023 treatment. Furthermore, ALS-L1023 attenuated the pancreatic inflammation including the infiltration of CD68-positive macrophages and mast cells, in addition to attenuating the expression of inflammatory factors (IL-6 and CD68).<br><br>CONCLUSIONS: These results suggest that treatment with ALS-L1023 may reduce weight gain, elevated glucose levels, and &#x3b2;-cell loss, by changing the expression of fatty acid-oxidizing enzymes in the liver and skeletal muscle, including inflammatory factors in the pancreas. These findings indicate that ALS-L1023 may be an effective therapeutic strategy to treat human obesity and type 2 diabetes.}, }
@article {pmid32915525, year = {2020}, author = {Goldshtein, H and Muhire, A and Petel Légaré, V and Pushett, A and Rotkopf, R and Shefner, JM and Peterson, RT and Armstrong, GAB and Russek-Blum, N}, title = {Efficacy of Ciprofloxacin/Celecoxib combination in zebrafish models of amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {7}, number = {10}, pages = {1883-1897}, pmid = {32915525}, issn = {2328-9503}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Animals, Genetically Modified ; Celecoxib/*pharmacology ; Ciprofloxacin/*pharmacology ; DNA-Binding Proteins/genetics ; Disease Models, Animal ; Motor Neurons/*drug effects ; Mutation/genetics ; Neuromuscular Junction/drug effects ; Superoxide Dismutase/genetics ; Zebrafish/genetics ; Zebrafish Proteins/genetics ; }, abstract = {OBJECTIVE: To evaluate the efficacy of a fixed-dose combination of two approved drugs, Ciprofloxacin and Celecoxib, as a potential therapeutic treatment for amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Toxicity and efficacy of Ciprofloxacin and Celecoxib were tested, each alone and in distinct ratio combinations in SOD1 G93R transgenic zebrafish model for ALS. Quantification of swimming measures following stimuli, measurements of axonal projections from the spinal cord, neuromuscular junction structure and morphometric analysis of microglia cells were performed in the combination- treated vs nontreated mutant larvae. Additionally, quantifications of touch-evoked locomotor escape response were conducted in treated vs nontreated zebrafish expressing the TARDBP G348C ALS variant.<br><br>RESULTS: When administered individually, Ciprofloxacin had a mild effect and Celecoxib had no therapeutic effect. However, combined Ciprofloxacin and Celecoxib (Cipro/Celecox) treatment caused a significant increase of&#xa0;~&#xa0;84% in the distance the SOD1 G93R transgenic larvae swam. Additionally, Cipro/Celecox elicited recovery of impaired motor neurons morphology and abnormal neuromuscular junction structure and preserved the ramified morphology of microglia cells in the SOD1 mutants. Furthermore, larvae expressing the TDP-43 mutation displayed evoked touch responses that were significantly longer in swim distance (110% increase) and significantly higher in maximal swim velocity (~44% increase) when treated with Cipro/Celecox combination.<br><br>INTERPRETATION: Cipro/Celecox combination improved locomotor and cellular deficits of ALS zebrafish models. These results identify this novel combination as effective, and may prove promising for the treatment of ALS.}, }
@article {pmid32915460, year = {2021}, author = {Choi, HJ and Joo Cha, S and Do, HA and Kim, HJ and Lee, JW and Kim, K}, title = {SCF-Slimb is critical for Glycogen synthase kinase-3β-mediated suppression of TAF15-induced neurotoxicity in Drosophila.}, journal = {Journal of neurochemistry}, volume = {157}, number = {6}, pages = {2119-2127}, doi = {10.1111/jnc.15182}, pmid = {32915460}, issn = {1471-4159}, mesh = {Animals ; Animals, Genetically Modified ; Brain/*metabolism/pathology ; Cell Cycle Proteins/*biosynthesis/genetics ; Drosophila ; Drosophila Proteins/*biosynthesis/genetics ; Glycogen Synthase Kinase 3 beta/*biosynthesis/genetics ; Humans ; Locomotion/physiology ; Male ; TATA-Binding Protein Associated Factors/*biosynthesis/genetics/*toxicity ; Ubiquitin-Protein Ligases/*biosynthesis/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder characterized pathologically by motor neuron degeneration and associated with aggregation of RNA-binding proteins. TATA-binding protein-associated factor 15 (TAF15) accumulates as cytoplasmic aggregates in neuronal cells, and clearance of these aggregates is considered a potential therapeutic strategy for ALS. However, the exact pathogenic mechanism of TAF15-induced neurotoxicity remains to be elucidated. Glycogen synthase kinase-3 (GSK-3) plays a critical role in the protection of ALS pathology. In the present study, we use a transgenic fly model over-expressing human TAF15 to study the protective effects of Shaggy/GSK3β on TAF15-induced neuronal toxicity in Drosophila brain. Transgenic flies were examined for locomotor activity and lithium treatment. The expression level and solubility of TAF15 were assessed with western blotting, whereas immunohistochemistry was used to assess TAF15 aggregation in Drosophila brain. We have revealed that Shaggy/GSK3β was abnormally activated in neurons of TAF15-expressing flies and its inhibition can suppress the defective phenotypes, thereby preventing retinal degeneration and locomotive activity caused by TAF15. We have also found that Shaggy/GSK3β inhibition in neuronal cells leads to a reduction in TAF15 levels. Indeed, the F-box proteins Slimb and archipelago genetically interact with TAF15 and control TAF15 protein level in Drosophila. Importantly, SCF[slimb] is a critical regulator for Shaggy/GSK3β-mediated suppression of TAF15-induced toxicity in Drosophila. The present study has provided an in vivo evidence supporting the molecular mechanism of GSK3β inhibition for protection against TAF15-linked proteinopathies.}, }
@article {pmid32914778, year = {2020}, author = {Ciannameo, A and Chiarenza, A and Filippini, G and D'Amico, R and Grilli, R}, title = {[Engaging clinicians to identify and prioritize disinvestment opportunities in the treatment of neurodegenerative diseases: a qualitative study.].}, journal = {Recenti progressi in medicina}, volume = {111}, number = {9}, pages = {503-514}, doi = {10.1701/3421.34063}, pmid = {32914778}, issn = {2038-1840}, mesh = {Delivery of Health Care ; Humans ; *Neurodegenerative Diseases/diagnosis/therapy ; Qualitative Research ; }, abstract = {INTRODUCTION: The overuse of health care interventions is a problem which has clinical and economic implications. On a clinical level this means that ineffective interventions or effective interventions in inappropriate clinical indications are used. On an economic level it refers to allocative inefficiency which implies that these resources could possibly be used for interventions of major clinical utility. The contribution of health professionals in the context of reallocation disinvestment policies is still little investigated. This study involved 25 neurologists in the process of identifying low value interventions in the management of stroke, dementia, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis.<br><br>METHODS: The Nominal Group Technique was applied in the context of 5 Focus Groups (FG) in order to reach a consensus to identify and prioritize disinvestment opportunities in the treatment of the 5 neurodegenerative diseases. Qualitative data were coded, categorised, and analysed, applying the six-phase approach to thematic analysis, with the support of Atlas Ti7.<br><br>RESULTS: Within 5 categories of "low value intervention", 25 clinical interventions were identified: 6 pharmacological, 16 diagnostic, 3 clinical-therapeutic. FG findings describe: how clinicians view the issue of disinvestment, both in absolute and relative terms; the factors which contribute to the use of low-value interventions; the explicit link between the disinvestment process and the reallocation of resources.<br><br>DISCUSSION: This study revealed that factors that hinder the disinvestment of inappropriate practices involve elements that are not only technical or clinical, but also relational and care-related contexts.}, }
@article {pmid32911810, year = {2020}, author = {Sidorova, YA and Saarma, M}, title = {Small Molecules and Peptides Targeting Glial Cell Line-Derived Neurotrophic Factor Receptors for the Treatment of Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {21}, number = {18}, pages = {}, pmid = {32911810}, issn = {1422-0067}, support = {1325555//Academy of Finland/ ; }, mesh = {Animals ; Cells, Cultured ; Drug Delivery Systems/*methods ; Glial Cell Line-Derived Neurotrophic Factor/metabolism ; Glial Cell Line-Derived Neurotrophic Factor Receptors/*drug effects/metabolism ; Humans ; Ligands ; Neuralgia/metabolism ; Neurites/metabolism ; Neurodegenerative Diseases/drug therapy ; Neuroglia/drug effects/metabolism ; Neurons/metabolism ; Peptides/*pharmacology ; Receptors, Nerve Growth Factor/drug effects/metabolism ; Signal Transduction/drug effects ; Small Molecule Libraries/pharmacology ; }, abstract = {Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are able to promote the survival of multiple neuronal populations in the body and, therefore, hold considerable promise for disease-modifying treatments of diseases and conditions caused by neurodegeneration. Available data reveal the potential of GFLs for the therapy of Parkinson's disease, neuropathic pain and diseases caused by retinal degeneration but, also, amyotrophic lateral sclerosis and, possibly, Alzheimer's disease. Despite promising data collected in preclinical models, clinical translation of GFLs is yet to be conducted. The main reasons for the limited success of GFLs clinical development are the poor pharmacological characteristics of GFL proteins, such as the inability of GFLs to cross tissue barriers, poor diffusion in tissues, biphasic dose-response and activation of several receptors in the organism in different cell types, along with ethical limitations on patients' selection in clinical trials. The development of small molecules selectively targeting particular GFL receptors with improved pharmacokinetic properties can overcome many of the difficulties and limitations associated with the clinical use of GFL proteins. The current review lists several strategies to target the GFL receptor complex with drug-like molecules, discusses their advantages, provides an overview of available chemical scaffolds and peptides able to activate GFL receptors and describes the effects of these molecules in cultured cells and animal models.}, }
@article {pmid32910449, year = {2020}, author = {Schijven, D and Zinkstok, JR and Luykx, JJ}, title = {[From genetic findings to clinical practice in psychiatry: how genetics may enable Precision Psychiatry].}, journal = {Tijdschrift voor psychiatrie}, volume = {62}, number = {9}, pages = {776-783}, pmid = {32910449}, issn = {0303-7339}, mesh = {Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Phenotype ; *Psychiatry ; Psychotropic Drugs ; *Schizophrenia/genetics ; }, abstract = {Most psychiatric disorders are characterized by a complex genetic background where many common variants are involved. Nowadays, we are able to 'read' these variants, test for their association with phenotypes in genome-wide association studies (GWAS), and perform further downstream analyses. However, the impact of such findings on clinical psychiatry has remained largely unclear.<br/> AIM: To provide new insight into the degree of genetic overlap between psychiatric disorders and neurological disorders. And to investigate how genetic findings may impact clinical practice in psychiatry.<br/> METHOD: Bioinformatics and statistical methods were applied to perform analyses in large genetic datasets. In particular, we focused on: pathway analyses in schizophrenia; a multivariate GWAS of stress and trauma phenotypes; and genetic overlap analyses between amyotrophic lateral sclerosis (ALS) and schizophrenia. Finally, we assessed for which psychiatric disorders genetic findings are most likely to impact clinical practice in the near future.<br/> RESULTS: First, we found enrichment of common genetic variants associated with schizophrenia in synaptic signalling pathways relating to dopaminergic, acetylcholinergic and glutamatergic neurons. Second, we found that ALS and schizophrenia partly share common genetic risk. And third, we outline the clinical relevance of genetic cross-disorder studies in psychiatry, and posit that these studies have meaning for diagnostics, prognostics and treatment prediction in psychiatry.<br/> CONCLUSION: The summarized and previous genetic studies into psychiatric disorders will hopefully soon enable precision psychiatry, as genetics is a powerful tool to elucidate individualized risk profiles of patients and their responses to psychotropic medication. Genetic counselling allows clinicians to carefully balance the wide range of considerations in those patients and relatives with questions related to genetic underpinnings of disease and treatment response.}, }
@article {pmid32907630, year = {2020}, author = {Konopka, A and Whelan, DR and Jamali, MS and Perri, E and Shahheydari, H and Toth, RP and Parakh, S and Robinson, T and Cheong, A and Mehta, P and Vidal, M and Ragagnin, AMG and Khizhnyak, I and Jagaraj, CJ and Galper, J and Grima, N and Deva, A and Shadfar, S and Nicholson, GA and Yang, S and Cutts, SM and Horejsi, Z and Bell, TDM and Walker, AK and Blair, IP and Atkin, JD}, title = {Impaired NHEJ repair in amyotrophic lateral sclerosis is associated with TDP-43 mutations.}, journal = {Molecular neurodegeneration}, volume = {15}, number = {1}, pages = {51}, pmid = {32907630}, issn = {1750-1326}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; DNA Damage/*physiology ; DNA End-Joining Repair/*physiology ; DNA-Binding Proteins/*metabolism ; Female ; Humans ; Male ; Mice ; Middle Aged ; Motor Neurons/metabolism ; }, abstract = {BACKGROUND: Pathological forms of TAR DNA-binding protein 43 (TDP-43) are present in motor neurons of almost all amyotrophic lateral sclerosis (ALS) patients, and mutations in TDP-43 are also present in ALS. Loss and gain of TDP-43 functions are implicated in pathogenesis, but the mechanisms are unclear. While the RNA functions of TDP-43 have been widely investigated, its DNA binding roles remain unclear. However, recent studies have implicated a role for TDP-43 in the DNA damage response.<br><br>METHODS: We used NSC-34 motor neuron-like cells and primary cortical neurons expressing wildtype TDP-43 or TDP-43 ALS associated mutants (A315T, Q331K), in which DNA damage was induced by etoposide or H2O2 treatment. We investigated the consequences of depletion of TDP-43 on DNA repair using small interfering RNAs. Specific non homologous end joining (NHEJ) reporters (EJ5GFP and EJ2GFP) and cells lacking DNA-dependent serine/threonine protein kinase (DNA-PK) were used to investigate the role of TDP-43 in DNA repair. To investigate the recruitment of TDP-43 to sites of DNA damage we used single molecule super-resolution microscopy and a co-immunoprecipitation assay. We also investigated DNA damage in an ALS transgenic mouse model, in which TDP-43 accumulates pathologically in the cytoplasm. We also examined fibroblasts derived from ALS patients bearing the TDP-43 M337V mutation for evidence of DNA damage.<br><br>RESULTS: We demonstrate that wildtype TDP-43 is recruited to sites of DNA damage where it participates in classical NHEJ DNA repair. However, ALS-associated TDP-43 mutants lose this activity, which induces DNA damage. Furthermore, DNA damage is present in mice displaying TDP-43 pathology, implying an active role in neurodegeneration. Additionally, DNA damage triggers features typical of TDP-43 pathology; cytoplasmic mis-localisation and stress granule formation. Similarly, inhibition of NHEJ induces TDP-43 mis-localisation to the cytoplasm.<br><br>CONCLUSIONS: This study reveals that TDP-43 functions in DNA repair, but loss of this function triggers DNA damage and is associated with key pathological features of ALS.}, }
@article {pmid32903591, year = {2020}, author = {Zou, YH and Guan, PP and Zhang, SQ and Guo, YS and Wang, P}, title = {Rofecoxib Attenuates the Pathogenesis of Amyotrophic Lateral Sclerosis by Alleviating Cyclooxygenase-2-Mediated Mechanisms.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {817}, pmid = {32903591}, issn = {1662-4548}, abstract = {Cyclooxygenase-2 (COX-2) is reported to be activated during the course of amyotrophic lateral sclerosis (ALS) development and progression. However, the roles of COX-2 in aggravating ALS and the underlying mechanism have been largely overlooked. To reveal the mechanisms, the canonical SOD1[G93A] mouse model was used as an experimental model for ALS in the current study. In addition, a specific inhibitor of COX-2 activity, rofecoxib, was orally administered to SOD1[G93A] mice. With this in vivo approach, we revealed that COX-2 proinflammatory signaling cascades were inhibited by rofecoxib in SOD1[G93A] mice. Specifically, the protein levels of COX-2, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α were elevated as a result of activation of astrocytes and microglia during the course of ALS development and progression. These proinflammatory reactions may contribute to the death of neurons by triggering the movement of astrocytes and microglia to neurons in the context of ALS. Treatment with rofecoxib alleviated this close association between glial cells and neurons and significantly decreased the density of inflammatory cells, which helped to restore the number of motor neurons in SOD1[G93A] mice. Mechanistically, rofecoxib treatment decreased the expression of COX-2 and its downstream signaling targets, including IL-1β and TNF-α, by deactivating glial cells, which in turn ameliorated the progression of SOD1[G93A] mice by postponing disease onset and modestly prolonging survival. Collectively, these results provide novel insights into the mechanisms of ALS and aid in the development of new drugs to improve the clinical treatment of ALS.}, }
@article {pmid32892772, year = {2020}, author = {Versalovic, E and Klein, E}, title = {"Who Will I Be?": Relational Identity, Living with Amyotrophic Lateral Sclerosis, and Future-Oriented Decisionmaking.}, journal = {Cambridge quarterly of healthcare ethics : CQ : the international journal of healthcare ethics committees}, volume = {29}, number = {4}, pages = {617-629}, doi = {10.1017/S0963180120000365}, pmid = {32892772}, issn = {1469-2147}, mesh = {*Amyotrophic Lateral Sclerosis ; Caregivers ; Humans ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) face many difficult, timing-sensitive decisions over the course of their illness, weighing present versus future harms and benefits. Supplemented by interviews with people with ALS, we argue for a relational approach to understanding these decisions and their effects on identity. We highlight two critical aspects of the patient-caregiver relationship: (1) the extent to which each may rely on the other leaves their wellbeing intimately intertwined and (2) patients often require others to help with the imaginative task of considering possible futures for each therapeutic option. We show why family involvement in decisionmaking practices can be so critical, and shed light on the ways intimate others help preserve and protect people's identities amidst the destabilizing uncertainty illness and treatment can bring.}, }
@article {pmid32892745, year = {2020}, author = {Zhao, AD and Qin, H and Sun, ML and Ma, K and Fu, XB}, title = {Efficient and rapid conversion of human astrocytes and ALS mouse model spinal cord astrocytes into motor neuron-like cells by defined small molecules.}, journal = {Military Medical Research}, volume = {7}, number = {1}, pages = {42}, pmid = {32892745}, issn = {2054-9369}, mesh = {Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Animals ; Astrocytes/classification/*physiology ; Cell Differentiation/genetics ; Cells, Cultured ; Disease Models, Animal ; Humans ; Mice ; Motor Neurons/*classification ; Spinal Cord/growth &amp; development/*physiopathology ; }, abstract = {BACKGROUND: Motor neuron degeneration or loss in the spinal cord is the characteristic phenotype of motor neuron diseases or spinal cord injuries. Being proliferative and located near neurons, astrocytes are considered ideal cell sources for regenerating neurons.<br><br>METHODS: We selected and tested different combinations of the small molecules for inducing the conversion of human and mouse astrocytes into neurons. Microscopic imaging and immunocytochemistry analyses were used to characterize the morphology and phenotype of the induced neurons while RT-qPCR was utilized to analyze changes in gene expression. In addition, whole-cell patch-clamp recordings were measured to examine the electrophysiological properties of induced neurons.<br><br>RESULTS: The results showed that human astrocytes could be rapidly and efficiently converted into motor neuron-like cells by treatment with defined small molecules, with a yield of over 85% motor neuron-like cells attained. The induced motor neuron-like cells expressed the pan-neuronal markers TUJ1, MAP2, NeuN, and Synapsin 1 and motor neuron markers HB9, ISL1, CHAT, and VAChT. During the conversion process, the cells did not pass through a proliferative neural progenitor cell intermediate. The induced motor neurons were functional, showing the electrophysiological properties of neurons. The same chemical cocktail could induce spinal cord astrocytes from an amyotrophic lateral sclerosis mouse model carrying a SOD1 mutation to become motor neuron-like cells that exhibited a decrease in cell survival and an increase in oxidative stress compared to that observed in wild-type MNs derived from healthy mice. Moreover, the chemical induction reduced oxidative stress in the mutant astrocytes.<br><br>CONCLUSION: The results of the present study demonstrated the feasibility of chemically converting human and mouse astrocytes into motor neuron-like cells that are useful for neurodegenerative disease modeling and regenerative medicine.}, }
@article {pmid32869237, year = {2021}, author = {Schwerthöffer, D and Scholz, B and Longhi, S and Bäuml, J and Rentrop, M}, title = {[The Intensive Psychiatric Care Unit at a Hospital with Maximum Care - An Analysis of Treatment Variables in the Therapy of Psychiatric and comorbid Somatic Disorders].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {89}, number = {7-08}, pages = {346-353}, doi = {10.1055/a-1191-7637}, pmid = {32869237}, issn = {1439-3522}, mesh = {Germany ; *Hospitals ; Humans ; *Intensive Care Units ; }, abstract = {ZIEL DER STUDIE UND METHODIK: Alle 873 Behandlungsakten einer psychiatrischen Intensivstation aus einem Zeitraum von 5 Jahren gingen in eine Analyse des Patientenkollektivs, des Behandlungsoutcomes und von Prädiktoren für die stationäre Behandlungsdauer ein.<br><br>Auf der beschriebenen Station wurden sowohl Patienten mit psychiatrischen Notfallsyndromen als auch Patienten mit komorbiden psychischen und somatischen Erkrankungen behandelt. Somatische Zusatzerkrankungen beeinflussen den station&#xe4;ren Behandlungsverlauf psychisch Erkrankter erheblich, z.&#x2009;B. durch eine um durchschnittlich 2,4 Wochen k&#xfc;rzere intensivpsychiatrische station&#xe4;re Behandlungsdauer bei h&#xe4;ufiger Notwendigkeit (41,3%) einer station&#xe4;ren, z.&#x2009;B. rehabilitativen Anschlussbehandlung. Die Stationsauslastung von 110 % und die durchschnittliche Behandlungsdauer von 63 Tagen deuten auf einen hohen Bedarf an interdisziplin&#xe4;ren psychiatrisch-somatischen Behandlungsm&#xf6;glichkeiten hin. In Zukunft ist ein Zusammenwachsen von Psychiatrie und somatischer Medizin anzustreben. Untersuchungen zu Versorgungssituation und Wirtschaftlichkeit interdisziplin&#xe4;rer Behandlungsangebote stehen aus.<br><br>BACKGROUND AND METHOD: All 873 medical files of psychiatric inpatients treated over a 5 year period at a psychiatric intensive care unit were analyzed in regard to characteristics of the patient group, outcome and predictors for the length of stay.<br><br>RESULTS AND CONCLUSIONS: Patients with psychiatric emergency syndromes and patients with comorbid psychiatric and somatic disorders were treated on the described unit. Somatic comorbidities have a considerable effect on the course of treatment for patients with psychiatric disorders. They have to receive stationary treatment for a shorter period (2.4 weeks) but often need further stationary, e.&#x2009;g. rehabilitative treatment. The utilization of this specific unit (110%) and the above average length of stay (63 days) point to an increasing need in inpatient treatment capacities for patients with psychiatric and somatic comorbidities. In future a growing together of somatic medicine and psychiatry in Germany is worthwhile. The evaluation of the treatment situation and aspects of cost effectiveness are yet to come.}, }
@article {pmid32868378, year = {2020}, author = {Mokshagundam, D and Olivieri, LJ and McCarter, R and Kim, A and Sable, CA and Spurney, CF and Dham, N}, title = {Cardiac changes in pediatric cancer survivors.}, journal = {Journal of investigative medicine : the official publication of the American Federation for Clinical Research}, volume = {68}, number = {8}, pages = {1364-1369}, pmid = {32868378}, issn = {1708-8267}, support = {KL2 TR000076/TR/NCATS NIH HHS/United States ; R01 HL125918/HL/NHLBI NIH HHS/United States ; UL1 TR000075/TR/NCATS NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Anthracyclines/therapeutic use ; Biomarkers/blood ; *Cancer Survivors ; Child ; Echocardiography ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Myocardium/*pathology ; Young Adult ; }, abstract = {Cardiac damage from chemotherapy is a known phenomenon leading to significant morbidity and mortality in the cancer surviving population, and identifying high-risk pediatric patients early is challenging. The purpose of this pilot study was to evaluate whether echo strain, cardiac MRI (CMR), and serum biomarkers are more sensitive methods for detecting cardiac toxicity than standard echo and to examine the relationship between biomarkers in patients without decreased systolic function as determined by standard echo. In this pilot study, we prospectively enrolled pediatric subjects after completion of anthracycline inclusive chemotherapy. Each subject underwent a post-treatment echocardiogram (standard with strain), serum biomarkers (N-terminal brain natriuretic peptide (NT-pro-BNP) and interleukin 1 receptor-like 1 protein (ST2)), and CMR (standard and extracellular volumes (ECVs)). We correlated the markers using Pearson correlation. We enrolled 30 subjects, 11F/19M, aged 8-21 years. Cumulative anthracycline dose (CAD) correlated with BNP (p=0.06), CMR ECV 4-chamber (p=0.05) and sagittal (p=0.01), and mitral valve E/A (p=0.02). BNP correlated with CMR ECV 4-chamber (p=0.001) and sagittal (p=0.001) and with echo average longitudinal strain (ALS) (p=0.05). This study demonstrated a significant correlation of CAD with BNP and CMR ECV. There was also a significant correlation of NT-pro-BNP with CMR ECV and ALS. Combining these parameters with standard echo has the potential to identify high-risk patients early. Further studies are needed for long-term follow-up and management in this vulnerable population.}, }
@article {pmid32867756, year = {2020}, author = {Phokasem, P and Jantrapirom, S and Karinchai, J and Yoshida, H and Yamaguchi, M and Chantawannakul, P}, title = {Honeybee products and edible insect powders improve locomotive and learning abilities of Ubiquilin-knockdown Drosophila.}, journal = {BMC complementary medicine and therapies}, volume = {20}, number = {1}, pages = {267}, pmid = {32867756}, issn = {2662-7671}, mesh = {Animals ; Apitherapy/*methods ; Bees ; Drosophila ; *Edible Insects ; Female ; Locomotion/*drug effects ; Neurodegenerative Diseases/*drug therapy ; Powders ; Thailand ; }, abstract = {BACKGROUND: Mutations in the human Ubiquilin 2 gene are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD), the fatal neurodegenerative disease that progressively affected neuronal cells in both brain and spinal cord. There is currently no effective therapy for these diseases. Over the last decade, researchers have focused on the potential use of natural products especially in neurodegenerative studies. Insect products have been used as traditional medicines, however, scientific information is still lacking. Fruit fly is recently used as a model organism to investigate degenerative diseases related to the nervous system because it has a short life span and produces a large number of offspring.<br><br>METHODS: The present study investigated the effects of honeybee products and edible insect powders on the locomotive and learning abilities, neuromuscular junctions (NMJs) structure, and reactive oxygen species (ROS) in larval brains of Ubiquilin- knockdown Drosophila.<br><br>RESULTS: dUbqn knockdown flies showed defects in locomotive and learning abilities accompanied with structural defects in NMJs. The results obtained revealed that the recovery of locomotive defects was significantly greater in dUbqn knockdown flies fed with coffee honey from Apis cerana (1% v/v) or Apis dorsata melittin (0.5&#x2009;&#x3bc;g/ml) or wasp powder (2&#x2009;mg/ml) than that of in untreated dUbqn knockdown flies. Furthermore, dUbqn knockdown flies fed with coffee honey showed the partial rescue of structural defects in NMJs, improved learning ability, and reduced the accumulation of ROS caused by dUbqn depletion in the brain over the untreated group.<br><br>CONCLUSION: These results suggest that coffee honey from Apis cerana contains a neuroprotective agent that will contribute to the development of a novel treatment for ALS/FTD.}, }
@article {pmid32865792, year = {2020}, author = {Sathyaprakash, C and Manzano, R and Varela, MA and Hashimoto, Y and Wood, MJA and Talbot, K and Aoki, Y}, title = {Development of LNA Gapmer Oligonucleotide-Based Therapy for ALS/FTD Caused by the C9orf72 Repeat Expansion.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2176}, number = {}, pages = {185-208}, doi = {10.1007/978-1-0716-0771-8_14}, pmid = {32865792}, issn = {1940-6029}, support = {MC_PC_13073/MRC_/Medical Research Council/United Kingdom ; TALBOT-MUTIHAC/APR15/832-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/*genetics ; Cell Culture Techniques/*methods ; Cells, Cultured ; *DNA Repeat Expansion ; Extracellular Vesicles ; Fibroblasts ; Freezing ; Frontotemporal Dementia/genetics ; Genetic Therapy/*methods ; Humans ; Immunoblotting ; Oligonucleotides/*genetics ; Plasmids ; Reverse Transcriptase Polymerase Chain Reaction ; Skin/cytology ; Transfection/*methods ; }, abstract = {Several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), have a complex genetic background, in addition to cases where the disease appears to manifest sporadically. The recent discovery of the hexanucleotide repeat expansion in the C9orf72 gene as the causative agent of ALS (C9ALS) gives rise to the opportunity to develop new therapies directed at this mutation , which is responsible for a large proportion of ALS and/or frontotemporal dementia cases. Mammalian models conscientiously replicating the late-onset motor defects and cellular pathologies seen in human patients do not exist. In this context, patient-derived cells give us a platform to test potential antisense oligonucleotide therapies, which could be the key to treat this subtype of motor neuron disease. Recently, we described that locked nucleic acid gapmer oligonucleotide-based treatment targeting C9orf72 repeat expanded transcripts resulted in recovery from the disease-related phenotypes in patient-derived fibroblasts. Our findings highlight the therapeutic potential of C9ALS using this gapmer oligonucleotide-based approach.}, }
@article {pmid32864220, year = {2020}, author = {Musteikyte, G and Ziaunys, M and Smirnovas, V}, title = {Methylene blue inhibits nucleation and elongation of SOD1 amyloid fibrils.}, journal = {PeerJ}, volume = {8}, number = {}, pages = {e9719}, pmid = {32864220}, issn = {2167-8359}, abstract = {Protein aggregation into highly-structured amyloid fibrils is linked to several neurodegenerative diseases. Such fibril formation by superoxide dismutase I (SOD1) is considered to be related to amyotrophic lateral sclerosis, a late-onset and fatal disorder. Despite much effort and the discovery of numerous anti-amyloid compounds, no effective cure or treatment is currently available. Methylene blue (MB), a phenothiazine dye, has been shown to modulate the aggregation of multiple amyloidogenic proteins. In this work we show its ability to inhibit both the spontaneous amyloid aggregation of SOD1 as well as elongation of preformed fibrils.}, }
@article {pmid32862509, year = {2020}, author = {Zhou, N and Manser, P}, title = {Does including machine learning predictions in ALS clinical trial analysis improve statistical power?.}, journal = {Annals of clinical and translational neurology}, volume = {7}, number = {10}, pages = {1756-1765}, pmid = {32862509}, issn = {2328-9503}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Databases, Factual/*statistics &amp; numerical data ; Disease Progression ; Humans ; Linear Models ; *Machine Learning ; Neurodegenerative Diseases/*diagnosis ; Severity of Illness Index ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease which leads to progressive muscle weakness and eventually death. The increasing availability of large ALS clinical trial datasets have generated much interest in developing predictive models for disease progression. However, the utility of predictive modeling on clinical trial analysis has not been thoroughly evaluated.<br><br>METHODS: We evaluated a predictive modeling approach for ALS disease progression measured by ALSFRS-R using the PRO-ACT database and validated our findings in a novel test set from a former clinical trial. We examined clinical trial scenarios where model predictions could improve statistical power for detecting treatment effects with simulated clinical trials.<br><br>RESULTS: Models constructed with imputed PRO-ACT data have better external validation results than those fitted with complete observations. When fitted with imputed data, super learner (R[2] &#xa0;=&#xa0;0.71, MSPE&#xa0;=&#xa0;19.7) and random forest (R[2] &#xa0;=&#xa0;0.70, MSPE&#xa0;=&#xa0;19.6) have similar performance in the external validation and slightly outperform the linear mixed effects model (R[2] &#xa0;=&#xa0;0.69, MSPE&#xa0;=&#xa0;20.5). Simulation studies suggest including machine learning predictions as a covariate in the analysis model of a 12-month clinical study can increase the trial's effective sample size by 16% when there is a hypothetical treatment effect of 25% reduction in ALSFRS-R mean rate of change.<br><br>INTERPRETATION: Predictive modeling approaches for ALSFRS-R are able to explain a moderate amount of variability in longitudinal change, which is improved by robust missing data handling for baseline characteristics. Including ALSFRS-R post-baseline model prediction results as a covariate in the model for primary analysis may increase power under moderate treatment effects.}, }
@article {pmid32862101, year = {2020}, author = {Amporndanai, K and Rogers, M and Watanabe, S and Yamanaka, K and O'Neill, PM and Hasnain, SS}, title = {Novel Selenium-based compounds with therapeutic potential for SOD1-linked amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {59}, number = {}, pages = {102980}, pmid = {32862101}, issn = {2352-3964}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality/pathology ; Animals ; Azoles/chemistry/metabolism/therapeutic use ; Betacoronavirus/metabolism ; Binding Sites ; Cell Line, Tumor ; Crystallography, X-Ray ; Dimerization ; Disease Models, Animal ; Enzyme Stability ; Isoindoles ; Mice ; Mice, Transgenic ; Molecular Dynamics Simulation ; Neuroprotective Agents/chemistry/metabolism/therapeutic use ; Organoselenium Compounds/chemistry/metabolism/*therapeutic use ; Protein Structure, Tertiary ; Recombinant Proteins/biosynthesis/chemistry/isolation &amp; purification ; SARS-CoV-2 ; Superoxide Dismutase-1/genetics/*metabolism ; Survival Rate ; Viral Matrix Proteins/chemistry/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease as well as Lou Gehrig's disease, is a progressive neurological disorder selectively affecting motor neurons with no currently known cure. Around 20% of the familial ALS cases arise from dominant mutations in the sod1 gene encoding superoxide dismutase1 (SOD1) enzyme. Aggregation of mutant SOD1 in familial cases and of wild-type SOD1 in at least some sporadic ALS cases is one of the known causes of the disease. Riluzole, approved in 1995 and edaravone in 2017 remain the only drugs with limited therapeutic benefits.<br><br>METHODS: We have utilised the ebselen template to develop novel compounds that redeem stability of mutant SOD1 dimer and prevent aggregation. Binding modes of compounds have been visualised by crystallography. In vitro neuroprotection and toxicity of lead compounds have been performed in mouse neuronal cells and disease onset delay of ebselen has been demonstrated in transgenic ALS mice model.<br><br>FINDING: We have developed a number of ebselen-based compounds with improvements in A4V SOD1 stabilisation and in vitro therapeutic effects with significantly better potency than edaravone. Structure-activity relationship of hits has been guided by high resolution structures of ligand-bound A4V SOD1. We also show clear disease onset delay of ebselen in transgenic ALS mice model holding encouraging promise for potential therapeutic compounds.<br><br>INTERPRETATION: Our finding established the new generation of organo-selenium compounds with better in vitro neuroprotective activity than edaravone. The potential of this class of compounds may offer an alternative therapeutic agent for ALS treatment. The ability of these compounds to target cysteine 111 in SOD may have wider therapeutic applications targeting cysteines of enzymes involved in pathogenic and viral diseases including main protease of SARS-Cov-2 (COVID-19).<br><br>FUNDING: Project funding was supported by the ALS Association grant (WA1128) and Fostering Joint International Research (19KK0214) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.}, }
@article {pmid32862078, year = {2021}, author = {Mamián-López, MB and Bernardi Miguel, R and Araki, K and A Temperini, ML and da Costa Ferreira, AM}, title = {Multivariate probing of antitumor metal-based complexes damage on living cells through Raman imaging.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {244}, number = {}, pages = {118838}, doi = {10.1016/j.saa.2020.118838}, pmid = {32862078}, issn = {1873-3557}, mesh = {*Coordination Complexes/pharmacology ; Cytochromes c ; Cytoplasm ; *Spectrum Analysis, Raman ; }, abstract = {Intracellular modifications caused by two metal-based antitumor compounds were assessed by confocal Raman imaging assisted by multivariate curve resolution method, a very powerful deconvolution tool that can be used to extract the characteristic spectral profile of the individual or "purest" components from an image dataset. The use of this Raman methodology has the advantage of being non-invasive and totally label-free. Four main different intracellular processes were observed under the Raman imaging and multivariate approach combination, and even, significant differences could be identified between the treatments with both metallodrugs. Leakage of the nucleus and nucleolus content into the cytoplasm, along with releasing of cytochrome c were observed for the treatment with the Cu-based complex. At the same time, changes of hydrogen-bonding network were also evidenced, indicating an apoptotic cellular death process, consistent with complementary Total Reflection X-Ray fluorescence (TXRF) and fluorescence experiments attesting mitochondria and DNA as main targets after uptake of the complex by cells. For treatment with the Zn-based complex, changes associated with cytochrome c were not detected, neither a rapid leakage of nucleus content upon 24 h treatment. The hydrogen-bonding network also followed a quite different pattern, suggesting that with this metallodrug, the cellular death follows a different mechanism.}, }
@article {pmid32855905, year = {2020}, author = {Szczepanek, J}, title = {Role of microRNA dysregulation in childhood acute leukemias: Diagnostics, monitoring and therapeutics: A comprehensive review.}, journal = {World journal of clinical oncology}, volume = {11}, number = {6}, pages = {348-369}, pmid = {32855905}, issn = {2218-4333}, abstract = {MicroRNAs (miRNAs) are short noncoding RNAs that regulate the expression of genes by sequence-specific binding to mRNA to either promote or block its translation; they can also act as tumor suppressors (e.g., let-7b, miR-29a, miR-99, mir-100, miR-155, and miR-181) and/or oncogenes (e.g., miR-29a, miR-125b, miR-143-p3, mir-155, miR-181, miR-183, miR-196b, and miR-223) in childhood acute leukemia (AL). Differentially expressed miRNAs are important factors associated with the initiation and progression of AL. As shown in many studies, they can be used as noninvasive diagnostic and prognostic biomarkers, which are useful in monitoring early stages of AL development or during therapy (e.g., miR-125b, miR-146b, miR-181c, and miR-4786), accurate classification of different cellular or molecular AL subgroups (e.g., let-7b, miR-98, miR-100, miR-128b, and miR-223), and identification and development of new therapeutic agents (e.g., mir-10, miR-125b, miR-203, miR-210, miR-335). Specific miRNA patterns have also been described for commonly used AL therapy drugs (e.g., miR-125b and miR-223 for doxorubicin, miR-335 and miR-1208 for prednisolone, and miR-203 for imatinib), uncovering miRNAs that are associated with treatment response. In the current review, the role of miRNAs in the development, progression, and therapy monitoring of pediatric ALs will be presented and discussed.}, }
@article {pmid32854418, year = {2020}, author = {Ghemrawi, R and Khair, M}, title = {Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {21}, number = {17}, pages = {}, pmid = {32854418}, issn = {1422-0067}, mesh = {Activating Transcription Factor 6/metabolism ; Animals ; Endoplasmic Reticulum/*metabolism ; Endoplasmic Reticulum Stress ; Endoribonucleases/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; Protein Serine-Threonine Kinases/metabolism ; *Signal Transduction ; Unfolded Protein Response ; eIF-2 Kinase/metabolism ; }, abstract = {The endoplasmic reticulum (ER) is an important organelle involved in protein quality control and cellular homeostasis. The accumulation of unfolded proteins leads to an ER stress, followed by an adaptive response via the activation of the unfolded protein response (UPR), PKR-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) and activating transcription factor 6 (ATF6) pathways. However, prolonged cell stress activates apoptosis signaling leading to cell death. Neuronal cells are particularly sensitive to protein misfolding, consequently ER and UPR dysfunctions were found to be involved in many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and prions diseases, among others characterized by the accumulation and aggregation of misfolded proteins. Pharmacological UPR modulation in affected tissues may contribute to the treatment and prevention of neurodegeneration. The association between ER stress, UPR and neuropathology is well established. In this review, we provide up-to-date evidence of UPR activation in neurodegenerative disorders followed by therapeutic strategies targeting the UPR and ameliorating the toxic effects of protein unfolding and aggregation.}, }
@article {pmid32852645, year = {2021}, author = {Duarte, P and Cuadrado, A and León, R}, title = {Monoamine Oxidase Inhibitors: From Classic to New Clinical Approaches.}, journal = {Handbook of experimental pharmacology}, volume = {264}, number = {}, pages = {229-259}, pmid = {32852645}, issn = {0171-2004}, mesh = {Antidepressive Agents ; Humans ; Hydrogen Peroxide ; Monoamine Oxidase ; *Monoamine Oxidase Inhibitors/pharmacology/therapeutic use ; *Parkinson Disease/drug therapy ; }, abstract = {Monoamine oxidases (MAOs) are involved in the oxidative deamination of different amines and neurotransmitters. This pointed them as potential targets for several disorders and along the last 70 years a wide variety of MAO inhibitors have been developed as successful drugs for the treatment of complex diseases, being the first drugs approved for depression in the late 1950s. The discovery of two MAO isozymes (MAO-A and B) with different substrate selectivity and tissue expression patterns led to novel therapeutic approaches and to the development of new classes of inhibitors, such as selective irreversible and reversible MAO-B inhibitors and reversible MAO-A inhibitors. Significantly, MAO-B inhibitors constitute a widely studied group of compounds, some of them approved for the treatment of Parkinson's disease. Further applications are under development for the treatment of Alzheimer's disease, amyotrophic lateral sclerosis, and cardiovascular diseases, among others. This review summarizes the most important aspects regarding the development and clinical use of MAO inhibitors, going through mechanistic and structural details, new indications, and future perspectives. Monoamine oxidases (MAOs) catalyze the oxidative deamination of different amines and neurotransmitters. The two different isozymes, MAO-A and MAO-B, are located at the outer mitochondrial membrane in different tissues. The enzymatic reaction involves formation of the corresponding aldehyde and releasing hydrogen peroxide (H2O2) and ammonia or a substituted amine depending on the substrate. MAO's role in neurotransmitter metabolism made them targets for major depression and Parkinson's disease, among other neurodegenerative diseases. Currently, these compounds are being studied for other diseases such as cardiovascular ones.}, }
@article {pmid32849187, year = {2020}, author = {Lanznaster, D and Bejan-Angoulvant, T and Gandía, J and Blasco, H and Corcia, P}, title = {Is There a Role for Vitamin D in Amyotrophic Lateral Sclerosis? A Systematic Review and Meta-Analysis.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {697}, pmid = {32849187}, issn = {1664-2295}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by the progressive loss of motor neurons. Patients usually die 3-5 years after diagnosis from respiratory failure. Several studies investigated the role of vitamin D as a biomarker or a therapeutic option for ALS patients. To clarify the scientific evidence, we performed a systematic review and different meta-analyses regarding the potential role of vitamin D in ALS. Methods: We performed a systematic review of clinical trials, cohorts, and case-control studies retrieved from PubMed, EMBASE, and Cochrane databases reporting vitamin D levels as a putative biomarker for ALS diagnosis or prognosis or the effect of vitamin D supplementation in ALS patients. Whenever possible, data were pooled using a random-effects model, with an assessment of heterogeneity. Results: Out of 2,996 articles retrieved, we finally included 13 research articles, 12 observational studies (50% prospective), and 1 clinical trial. We found that ALS patients had slightly lower levels of vitamin D than controls (mean difference -6 ng/ml, 95% CI [-10.8; -1.3]), but important confounding factors were not considered in the studies analyzed. We found no relationship between vitamin D levels and ALS functional rate score-revised (ALSFRS-R), with highly heterogeneous results. Discordant results were reported in three studies regarding survival. Finally, five studies reported the effects of vitamin D supplementation with discordant results. Two of them showed a small improvement, whereas two others showed a deleterious effect on ALSFRS-R. One very small clinical trial with important methodological limitations showed some improvement in ALSFRS-R with high doses of vitamin D compared with normal doses. Conclusions: Our review did not find evidence to support the role of vitamin D on ALS diagnosis, prognosis, or treatment. Most studies had important limitations, mostly regarding the risk of bias for not considering confounding factors. Vitamin D supplementation should be offered to ALS patients to avoid other health issues related to vitamin D deficiency, but there is not enough evidence to support the use of vitamin D as a therapy for ALS.}, }
@article {pmid32848579, year = {2020}, author = {Izrael, M and Slutsky, SG and Revel, M}, title = {Rising Stars: Astrocytes as a Therapeutic Target for ALS Disease.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {824}, pmid = {32848579}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial disease, characterized by a progressive loss of motor neurons that eventually leads to paralysis and death. The current ALS-approved drugs modestly change the clinical course of the disease. The mechanism by which motor neurons progressively degenerate remains unclear but entails a non-cell autonomous process. Astrocytes impaired biological functionality were implicated in multiple neurodegenerative diseases, including ALS, frontotemporal dementia (FTD), Parkinson's disease (PD), and Alzheimer disease (AD). In ALS disease patients, A1 reactive astrocytes were found to play a key role in the pathology of ALS disease and death of motor neurons, via loss or gain of function or acquired toxicity. The contribution of astrocytes to the maintenance of motor neurons by diverse mechanisms makes them a promising therapeutic candidate for the treatment of ALS. Therapeutic approaches targeting at modulating the function of endogenous astrocytes or replacing lost functionality by transplantation of healthy astrocytes, may contribute to the development of therapies which might slow down or even halt the progression ALS diseases. The proposed mechanisms by which astrocytes can potentially ameliorate ALS progression and the status of ALS clinical studies involving astrocytes are discussed.}, }
@article {pmid32847483, year = {2020}, author = {Saitoh, Y and Takahashi, Y}, title = {Riluzole for the treatment of amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {10}, number = {6}, pages = {343-355}, doi = {10.2217/nmt-2020-0033}, pmid = {32847483}, issn = {1758-2032}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Excitatory Amino Acid Antagonists/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; Riluzole/*therapeutic use ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the death of motor neurons. Riluzole is a benzothiazole derivative that blocks glutamatergic neurotransmission in the CNS, which is thought to exert neuroprotective effects. Riluzole was approved by the US FDA in 1995 as the first drug to treat ALS. Although riluzole is generally safe and well tolerated in clinical practice, its efficacy in ALS is modest, prolonging tracheostomy-free survival by only 2-3 months. In this article, we will first provide an overview of the ALS field, followed by a discussion of riluzole regarding its physical properties; pharmacology; clinical efficacy in ALS; safety and tolerability; and recommended administration.}, }
@article {pmid32846148, year = {2020}, author = {Gromova, A and La Spada, AR}, title = {Harmony Lost: Cell-Cell Communication at the Neuromuscular Junction in Motor Neuron Disease.}, journal = {Trends in neurosciences}, volume = {43}, number = {9}, pages = {709-724}, doi = {10.1016/j.tins.2020.07.002}, pmid = {32846148}, issn = {1878-108X}, mesh = {*Amyotrophic Lateral Sclerosis ; Cell Communication ; Humans ; *Motor Neuron Disease ; Motor Neurons ; Neuromuscular Junction ; }, abstract = {The neuromuscular junction (NMJ) is a specialized synapse that is the point of connection between motor neurons and skeletal muscle. Although developmental studies have established the importance of cell-cell communication at the NMJ for the integrity and full functionality of this synapse, the contribution of this structure as a primary driver in motor neuron disease pathogenesis remains uncertain. Here, we consider the biology of the NMJ and review emerging lines of investigation that are highlighting the importance of cell-cell interaction at the NMJ in spinal muscular atrophy (SMA), X-linked spinal and bulbar muscular atrophy (SBMA), and amyotrophic lateral sclerosis (ALS). Ongoing research may reveal NMJ targets and pathways whose therapeutic modulation will help slow the progression of motor neuron disease, offering a novel treatment paradigm for ALS, SBMA, SMA, and related disorders.}, }
@article {pmid32840332, year = {2020}, author = {Chen, JJ}, title = {Overview of current and emerging therapies for amytrophic lateral sclerosis.}, journal = {The American journal of managed care}, volume = {26}, number = {9 Suppl}, pages = {S191-S197}, doi = {10.37765/ajmc.2020.88483}, pmid = {32840332}, issn = {1936-2692}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Antibodies, Monoclonal, Humanized/*therapeutic use ; Benzamides ; Edaravone ; Humans ; Mesenchymal Stem Cells ; Oligonucleotides/*therapeutic use ; Piperidines ; Pyridines ; Riluzole ; Thiazoles/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating, fatal neuromuscular disease. Most patients die within 2 to 5 years of diagnosis. The disease stems from death of upper and lower motor neurons leading to degeneration of motor pathways and the paralytic effects of the disease. The economic cost of the disease is not clear, with estimates ranging from about $64,000 per year to $200,000. Two drugs, riluzole and edaravone, are currently FDA approved for the treatment of ALS, and each provides modest benefits in mortality and/or function. Recent developments in the understanding of the underlying pathophysiologic processes that contribute to ALS have led to the development of numerous investigational therapies, with several now in phase 3 trials. This article highlights the oral tyrosine kinase inhibitor masitinib; the antisense drug tofersen; the humanized monoclonal antibody C5 complement inhibitor ravulizumab-cwvz; and mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells, a proprietary platform that induces autologous bone marrow-derived MSCs to secrete high levels of NTFs.}, }
@article {pmid32839928, year = {2020}, author = {Malek, EG and Salameh, JS and Makki, A}, title = {Kennedy's disease: an under-recognized motor neuron disorder.}, journal = {Acta neurologica Belgica}, volume = {120}, number = {6}, pages = {1289-1295}, pmid = {32839928}, issn = {2240-2993}, mesh = {*Bulbo-Spinal Atrophy, X-Linked ; Humans ; }, abstract = {Kennedy's disease or spinal bulbar muscular atrophy is a rare, inherited and slowly progressive multisystem disease mostly manifesting with a motor neuron disease phenotype leading to disability. The slow progression, partial androgen insensitivity, electrophysiological evidence of sensory neuronopathy, and relatively spared central nervous system pathways help differentiate it from amyotrophic lateral sclerosis. To date, there is no treatment or cure with clinical care mainly focused on accurate diagnosis, symptom management, patient education, and genetic counselling.}, }
@article {pmid32836016, year = {2020}, author = {Chen, PC and Wu, D and Hu, CJ and Chen, HY and Hsieh, YC and Huang, CC}, title = {Exosomal TAR DNA-binding protein-43 and neurofilaments in plasma of amyotrophic lateral sclerosis patients: A longitudinal follow-up study.}, journal = {Journal of the neurological sciences}, volume = {418}, number = {}, pages = {117070}, doi = {10.1016/j.jns.2020.117070}, pmid = {32836016}, issn = {1878-5883}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Biomarkers ; Child, Preschool ; DNA-Binding Proteins ; Follow-Up Studies ; Humans ; Infant ; Intermediate Filaments ; Neurofilament Proteins ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease with characteristic of progressive general muscle weakness and atrophy. ALS is still lack of efficient treatment and laboratory biomarkers. In this study, we longitudinally examined ALS patients' peripheral blood to search potential biomarkers. 18 ALS patients aged between 20 and 65 years were recruited in a clinical trial and longitudinal plasma samples were obtained and analyzed at baseline, 1, 3, 6 and 12 months follow up. Neurofilament light chain (NFL), phosphorylated neurofilament heavy chain (pNFH) by ELISA and exosomal TAR DNA-binding protein-43 (TDP-43) ratio were measured by flow cytometry assay in isolated exosomes RESULTS: Exosomal TDP-43 ratio significantly changed in 3-month (increased 60.8 ± 18.9%, p = 0.0005) and 6-month (increased 60.2 ± 32.6%, p = 0.0291) follow-up and close to significance at 12-month follow-up (increased 12.8 ± 10.8%, p = 0.0524). When subclassifying patients into rapid and slow progression groups, NFL but not pNFH is significantly higher in the rapid progression group at baseline (22.74 ± 1.66 pg/mL vs. 43.96 ± 12.87 pg/mL, p = 0.0136) and at 3-month follow-up (28.40 ± 3.39 pg/mL vs. 40.33 ± 5.44 pg/mL, p = 0.0356).<br><br>CONCLUSION: In this study, we found exosomal TDP-43 ratio was increasing along with follow-up at 3 and 6&#xa0;months and NFL levels in plasma was associated with rapid progression in ALS patients. In addition to NFL, exosomal TDP-43 ratio might be a potential candidate of biomarkers for ALS long-term follow-up studies.}, }
@article {pmid32828271, year = {2020}, author = {Kaifer, KA and Villalón, E and Smith, CE and Simon, ME and Marquez, J and Hopkins, AE and Morcos, TI and Lorson, CL}, title = {AAV9-DOK7 gene therapy reduces disease severity in Smn[2B/-] SMA model mice.}, journal = {Biochemical and biophysical research communications}, volume = {530}, number = {1}, pages = {107-114}, pmid = {32828271}, issn = {1090-2104}, support = {R21 NS106490/NS/NINDS NIH HHS/United States ; R25 GM064120/GM/NIGMS NIH HHS/United States ; T32 GM008396/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Dependovirus/genetics ; Disease Models, Animal ; Gene Deletion ; Genetic Therapy/methods ; Mice, Inbred C57BL ; Muscle Proteins/*genetics ; Muscular Atrophy, Spinal/*genetics/pathology/*therapy ; Neuromuscular Junction/genetics/pathology ; Severity of Illness Index ; Survival of Motor Neuron 1 Protein/genetics ; }, abstract = {Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disease caused by deletions or mutations in the survival motor neuron (SMN1) gene. An important hallmark of disease progression is the pathology of neuromuscular junctions (NMJs). Affected NMJs in the SMA context exhibit delayed maturation, impaired synaptic transmission, and loss of contact between motor neurons and skeletal muscle. Protection and maintenance of NMJs remains a focal point of therapeutic strategies to treat SMA, and the recent implication of the NMJ-organizer Agrin in SMA pathology suggests additional NMJ organizing molecules may contribute. DOK7 is an NMJ organizer that functions downstream of Agrin. The potential of DOK7 as a putative therapeutic target was demonstrated by adeno-associated virus (AAV)-mediated gene therapy delivery of DOK7 in Amyotrophic Lateral Sclerosis (ALS) and Emery Dreyefuss Muscular Dystrophy (EDMD). To assess the potential of DOK7 as a disease modifier of SMA, we administered AAV-DOK7 to an intermediate mouse model of SMA. AAV9-DOK7 treatment conferred improvements in NMJ architecture and reduced muscle fiber atrophy. Additionally, these improvements resulted in a subtle reduction in phenotypic severity, evidenced by improved grip strength and an extension in survival. These findings reveal DOK7 is a novel modifier of SMA.}, }
@article {pmid32820492, year = {2020}, author = {Lesman-Segev, OH and Edwards, L and Rabinovici, GD}, title = {Chronic Traumatic Encephalopathy: A Comparison with Alzheimer's Disease and Frontotemporal Dementia.}, journal = {Seminars in neurology}, volume = {40}, number = {4}, pages = {394-410}, doi = {10.1055/s-0040-1715134}, pmid = {32820492}, issn = {1098-9021}, support = {P30 AG062422/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/*diagnosis/genetics/metabolism/pathology ; Chronic Traumatic Encephalopathy/*diagnosis/genetics/metabolism/pathology ; Frontotemporal Dementia/*diagnosis/genetics/metabolism/pathology ; Humans ; }, abstract = {The clinical diagnosis of chronic traumatic encephalopathy (CTE) is challenging due to heterogeneous clinical presentations and overlap with other neurodegenerative dementias. Depending on the clinical presentation, the differential diagnosis of CTE includes Alzheimer's disease (AD), behavioral variant frontotemporal dementia (bvFTD), Parkinson's disease, amyotrophic lateral sclerosis, primary mood disorders, posttraumatic stress disorder, and psychotic disorders. The aim of this article is to compare the clinical aspects, genetics, fluid biomarkers, imaging, treatment, and pathology of CTE to those of AD and bvFTD. A detailed clinical evaluation, neurocognitive assessment, and structural brain imaging can inform the differential diagnosis, while molecular biomarkers can help exclude underlying AD pathology. Prospective studies that include clinicopathological correlations are needed to establish tools that can more accurately determine the cause of neuropsychiatric decline in patients at risk for CTE.}, }
@article {pmid32819425, year = {2020}, author = {Ng Kee Kwong, KC and Mehta, AR and Nedergaard, M and Chandran, S}, title = {Defining novel functions for cerebrospinal fluid in ALS pathophysiology.}, journal = {Acta neuropathologica communications}, volume = {8}, number = {1}, pages = {140}, pmid = {32819425}, issn = {2051-5960}, support = {MR/R001162/1/MRC_/Medical Research Council/United Kingdom ; RF1 NS110049/NS/NINDS NIH HHS/United States ; MEHTA/JUL17/948-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; R01 NS100366/NS/NINDS NIH HHS/United States ; RF1 AG057575/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*cerebrospinal fluid/*physiopathology ; Animals ; Humans ; }, abstract = {Despite the considerable progress made towards understanding ALS pathophysiology, several key features of ALS remain unexplained, from its aetiology to its epidemiological aspects. The glymphatic system, which has recently been recognised as a major clearance pathway for the brain, has received considerable attention in several neurological conditions, particularly Alzheimer's disease. Its significance in ALS has, however, been little addressed. This perspective article therefore aims to assess the possibility of CSF contribution in ALS by considering various lines of evidence, including the abnormal composition of ALS-CSF, its toxicity and the evidence for impaired CSF dynamics in ALS patients. We also describe a potential role for CSF circulation in determining disease spread as well as the importance of CSF dynamics in ALS neurotherapeutics. We propose that a CSF model could potentially offer additional avenues to explore currently unexplained features of ALS, ultimately leading to new treatment options for people with ALS.}, }
@article {pmid32815196, year = {2020}, author = {Boussicault, L and Laffaire, J and Schmitt, P and Rinaudo, P and Callizot, N and Nabirotchkin, S and Hajj, R and Cohen, D}, title = {Combination of acamprosate and baclofen (PXT864) as a potential new therapy for amyotrophic lateral sclerosis.}, journal = {Journal of neuroscience research}, volume = {98}, number = {12}, pages = {2435-2450}, pmid = {32815196}, issn = {1097-4547}, mesh = {Acamprosate/*administration &amp; dosage ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism/pathology ; Animals ; Baclofen/*administration &amp; dosage ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Cerebral Cortex/*drug effects/metabolism/pathology ; Coculture Techniques ; Drug Therapy, Combination ; Female ; GABA-B Receptor Agonists/administration &amp; dosage ; Motor Neurons/*drug effects/metabolism/pathology ; Pregnancy ; Rats ; Rats, Transgenic ; Rats, Wistar ; }, abstract = {There is currently no therapy impacting the course of amyotrophic lateral sclerosis (ALS). The only approved treatments are riluzole and edaravone, but their efficacy is modest and short-lasting, highlighting the need for innovative therapies. We previously demonstrated the ability of PXT864, a combination of low doses of acamprosate and baclofen, to synergistically restore cellular and behavioral activity in Alzheimer's and Parkinson's disease models. The overlapping genetic, molecular, and cellular characteristics of these neurodegenerative diseases supported investigating the effectiveness of PXT864 in ALS. As neuromuscular junction (NMJ) alterations is a key feature of ALS, the effects of PXT864 in primary neuron-muscle cocultures injured by glutamate were studied. PXT864 significantly and synergistically preserved NMJ and motoneuron integrity following glutamate excitotoxicity. PXT864 added to riluzole significantly improved such protection. PXT864 activity was then assessed in primary cultures of motoneurons derived from SOD1[G93A] rat embryos. These motoneurons presented severe maturation defects that were significantly improved by PXT864. In this model, glutamate application induced an accumulation of TDP-43 protein in the cytoplasm, a hallmark that was completely prevented by PXT864. The anti-TDP-43 aggregation effect was also confirmed in a cell line expressing TDP-43 fused to GFP. These results demonstrate the value of PXT864 as a promising therapeutic strategy for the treatment of ALS.}, }
@article {pmid32815157, year = {2021}, author = {Kukharsky, MS and Skvortsova, VI and Bachurin, SO and Buchman, VL}, title = {In a search for efficient treatment for amyotrophic lateral sclerosis: Old drugs for new approaches.}, journal = {Medicinal research reviews}, volume = {41}, number = {5}, pages = {2804-2822}, doi = {10.1002/med.21725}, pmid = {32815157}, issn = {1098-1128}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Pharmaceutical Preparations ; }, abstract = {Recent progress in understanding the pathological changes in the nervous system and in certain other body systems (e.g., immune system) that lead to the development and progression of amyotrophic lateral sclerosis (ALS) revealed a number of molecular and cellular processes that can potentially be used as therapeutic targets. Many of these processes are compromised not only in ALS but also in other diseases and a repertoire of drugs able to restore, at least partially, their functionality has been developed. In this review, we briefly describe current approaches to the repurposing of such "old" drugs for treatment of patients with ALS.}, }
@article {pmid32813409, year = {2021}, author = {Russell, RD and Black, LJ and Begley, A}, title = {Dietary education programs for adults with neurological diseases: a scoping review protocol.}, journal = {JBI evidence synthesis}, volume = {19}, number = {1}, pages = {170-176}, doi = {10.11124/JBISRIR-D-19-00394}, pmid = {32813409}, issn = {2689-8381}, mesh = {Adult ; *Diet ; Diet, Healthy ; Educational Status ; Humans ; *Nervous System Diseases ; Scoping Reviews As Topic ; }, abstract = {OBJECTIVE: The objective of this review is to identify and map the evidence on the types of dietary education programs that have been implemented and evaluated in any setting for adults with neurological diseases. This review will also examine program characteristics, including program duration, length, and number of sessions, and common behavior change techniques used.<br><br>INTRODUCTION: Up to 1 billion people are affected by neurological diseases, most commonly Alzheimer's disease and dementias, epilepsy, Huntington's disease, motor neurone disease, multiple sclerosis, Parkinson's disease, and stroke. Dietary recommendations for most of these diseases follow national dietary guidelines. Dietary education programs are recommended by the World Health Organization to promote adherence to a healthy diet, but it is not clear which dietary education programs have been conducted for adults with neurological diseases or the characteristics of such programs.<br><br>INCLUSION CRITERIA: This review will consider qualitative and intervention studies (randomized controlled trials, non-randomized controlled trials, and pre-post studies) evaluating dietary education programs for adults with neurological diseases. Programs can be any format in any setting, and may include a comparator group (waitlist control, treatment as usual, or another intervention) or have no comparator group.<br><br>METHODS: CINAHL, Cochrane Database of Systematic Reviews, Emcare, MEDLINE, ProQuest (ProQuest Central and ProQuest Dissertations &amp; Theses), PsycINFO, Cochrane Central Register of Controlled Trials, and Google Scholar will be searched for publications in English. Neurological organizations will be contacted for unpublished literature. Titles and abstracts will be screened, and full texts accessed for final inclusion. Intervention details, study outcomes, behavior change techniques, and findings will be extracted. Results will be presented in a table with accompanying description.}, }
@article {pmid32807149, year = {2020}, author = {Valko, L and Baglyas, S and Gyarmathy, VA and Gal, J and Lorx, A}, title = {Home mechanical ventilation: quality of life patterns after six months of treatment.}, journal = {BMC pulmonary medicine}, volume = {20}, number = {1}, pages = {221}, pmid = {32807149}, issn = {1471-2466}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/physiopathology ; Female ; *Home Care Services, Hospital-Based ; Humans ; Hungary ; Male ; Middle Aged ; Obesity Hypoventilation Syndrome/physiopathology ; Prospective Studies ; Pulmonary Disease, Chronic Obstructive/physiopathology ; Quality of Life/*psychology ; Respiration, Artificial/*methods/psychology ; Respiratory Function Tests ; Respiratory Insufficiency/physiopathology/psychology/*therapy ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: It has been shown that home mechanical ventilation improves quality of life, but it has not been widely studied which particular patient groups benefit the most from starting this type of therapy. The purpose of this prospective observational study was to evaluate quality of life change patterns 6 months after initiation of home mechanical ventilation in patients suffering from chronic respiratory failure using patient reported outcomes.<br><br>METHODS: We enrolled 74 chronic respiratory failure patients starting invasive or noninvasive home mechanical ventilation through the Semmelweis University Home Mechanical Ventilation Program. Quality of life was evaluated at baseline and at 6 months after initiation of home mechanical ventilation using the Severe Respiratory Insufficiency Questionnaire.<br><br>RESULTS: Overall quality of life showed 10.5% improvement 6 months after initiation of home mechanical ventilation (p&#xa0;<&#x2009;0.001). The greatest improvement was observed in Respiratory complaint (20.4%, p&#xa0;=&#x2009;0.015), Sleep and attendant symptoms (19.3%, p&#xa0;<&#x2009;0.001), and Anxiety related subscales (14.4%, p&#xa0;<&#x2009;0.001). Interface (invasive versus noninvasive ventilation) was not associated with improvement in quality of life (p&#xa0;=&#x2009;0.660). Severely impaired patients showed the greatest improvement (CC&#x2009;=&#x2009;-0.328, p&#xa0;<&#x2009;0.001). Initial diagnosis contributed to the observed change (p&#xa0;=&#x2009;0.025), with chronic obstructive pulmonary disease and obesity hypoventilation syndrome patients showing the greatest improvement, while amyotrophic lateral sclerosis patients showed no improvement in quality of life. We found that patients who were started on long term ventilation in an acute setting, required oxygen supplementation and had low baseline quality of life, showed the most improvement during the six-month study period.<br><br>CONCLUSIONS: Our study highlights the profound effect of home mechanical ventilation on quality of life in chronic respiratory failure patients that is indifferent of ventilation interface but is dependent on initial diagnosis and some baseline characteristics, like acute initiation, oxygen supplementation need and baseline quality of life.<br><br>TRIAL REGISTRATION: This study was approved by and registered at the ethics committee of Semmelweis University (SE TUKEB 251/2017; 20th of December, 2017).}, }
@article {pmid32806490, year = {2020}, author = {Khan, A and Jahan, S and Imtiyaz, Z and Alshahrani, S and Antar Makeen, H and Mohammed Alshehri, B and Kumar, A and Arafah, A and Rehman, MU}, title = {Neuroprotection: Targeting Multiple Pathways by Naturally Occurring Phytochemicals.}, journal = {Biomedicines}, volume = {8}, number = {8}, pages = {}, pmid = {32806490}, issn = {2227-9059}, abstract = {With the increase in the expectancy of the life span of humans, neurodegenerative diseases (NDs) have imposed a considerable burden on the family, society, and nation. In defiance of the breakthroughs in the knowledge of the pathogenesis and underlying mechanisms of various NDs, very little success has been achieved in developing effective therapies. This review draws a bead on the availability of the nutraceuticals to date for various NDs (Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, vascular cognitive impairment, Prion disease, Spinocerebellar ataxia, Spinal muscular atrophy, Frontotemporal dementia, and Pick's disease) focusing on their various mechanisms of action in various in vivo and in vitro models of NDs. This review is distinctive in its compilation to critically review preclinical and clinical studies of the maximum phytochemicals in amelioration and prevention of almost all kinds of neurodegenerative diseases and address their possible mechanism of action. PubMed, Embase, and Cochrane Library searches were used for preclinical studies, while ClinicalTrials.gov and PubMed were searched for clinical updates. The results from preclinical studies demonstrate the efficacious effects of the phytochemicals in various NDs while clinical reports showing mixed results with promise for phytochemical use as an adjunct to the conventional treatment in various NDs. These studies together suggest that phytochemicals can significantly act upon different mechanisms of disease such as oxidative stress, inflammation, apoptotic pathways, and gene regulation. However, further clinical studies are needed that should include the appropriate biomarkers of NDs and the effect of phytochemicals on them as well as targeting the appropriate population.}, }
@article {pmid32805742, year = {2021}, author = {Özdinler, PH}, title = {Expanded access: opening doors to personalized medicine for rare disease patients and patients with neurodegenerative diseases.}, journal = {The FEBS journal}, volume = {288}, number = {5}, pages = {1457-1461}, pmid = {32805742}, issn = {1742-4658}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/*drug therapy/metabolism/pathology ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Autophagy/drug effects ; Cerebral Cortex/drug effects/metabolism/pathology ; Drug Repositioning/methods ; Drugs, Investigational/*therapeutic use ; Health Services Accessibility/organization &amp; administration ; Humans ; Inflammation ; Mitochondria/drug effects/metabolism/pathology ; Neurons/drug effects/metabolism/pathology ; Parkinson Disease/*drug therapy/metabolism/pathology ; Precision Medicine/*trends ; Rare Diseases/*drug therapy/metabolism/pathology ; Unfolded Protein Response/drug effects ; }, abstract = {In neurodegenerative diseases, a select set of neuron population displays early vulnerability and undergoes progressive degeneration. The heterogeneity of the cerebral cortex and the heterogeneity of patient populations diagnosed with the same disease offer many challenges for developing effective and long-term treatment options. Currently, patients who are considered to have a 'rare' disease are left with no hopes for cure, and many of the neurodegenerative diseases progress fast without any effective solutions. However, as our understanding of disease mechanisms evolve, we begin to realize that the boundaries between diseases are not as sharp as once believed. There are many patients who develop disease due to common underlying causes and mechanisms. As we move forward with drug discovery effort, it becomes obvious that we will have to shift our focus from finding a cure for a disease, to finding solutions to the disease-causing cellular mechanisms so that patients can be treated by mechanism-based strategies. This paradigm shift will lay the foundation for personalized medicine approaches for neurodegenerative disease patients and patients diagnosed with a rare disease.}, }
@article {pmid32801000, year = {2020}, author = {West, RJH and Ugbode, C and Fort-Aznar, L and Sweeney, ST}, title = {Neuroprotective activity of ursodeoxycholic acid in CHMP2B[Intron5] models of frontotemporal dementia.}, journal = {Neurobiology of disease}, volume = {144}, number = {}, pages = {105047}, pmid = {32801000}, issn = {1095-953X}, support = {/WT_/Wellcome Trust/United Kingdom ; 204829/WT_/Wellcome Trust/United Kingdom ; SWEENEY/OCT15/884-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Animals ; Apoptosis/*drug effects ; Cell Survival/drug effects ; Dendrites/drug effects/pathology ; Disease Models, Animal ; Drosophila ; Drosophila Proteins/*genetics ; Endosomal Sorting Complexes Required for Transport/genetics ; Endosomes/drug effects/metabolism ; Frontotemporal Dementia/*genetics ; Glutathione/drug effects/metabolism ; Lysosomes/drug effects/metabolism ; Neurons/*drug effects ; Neuroprotective Agents/*pharmacology ; Presynaptic Terminals/drug effects/pathology ; Primary Cell Culture ; Rats ; Synapses/*drug effects/pathology ; Ubiquitinated Proteins/drug effects/metabolism ; Ursodeoxycholic Acid/*pharmacology ; Vesicular Transport Proteins/*genetics ; }, abstract = {Frontotemporal dementia (FTD) is one of the most prevalent forms of early-onset dementia. It represents part of the FTD-Amyotrophic Lateral Sclerosis (ALS) spectrum, a continuum of genetically and pathologically overlapping disorders. FTD-causing mutations in CHMP2B, a gene encoding a core component of the heteromeric ESCRT-III Complex, lead to perturbed endosomal-lysosomal and autophagic trafficking with impaired proteostasis. While CHMP2B mutations are rare, dysfunctional endosomal-lysosomal signalling is common across the FTD-ALS spectrum. Using our established Drosophila and mammalian models of CHMP2B[Intron5] induced FTD we demonstrate that the FDA-approved compound Ursodeoxycholic Acid (UDCA) conveys neuroprotection, downstream of endosomal-lysosomal dysfunction in both Drosophila and primary mammalian neurons. UDCA exhibited a dose dependent rescue of neuronal structure and function in Drosophila pan-neuronally expressing CHMP2B[Intron5]. Rescue of CHMP2B[Intron5] dependent dendritic collapse and apoptosis with UDCA in rat primary neurons was also observed. UDCA failed to ameliorate aberrant accumulation of endosomal and autophagic organelles or ubiquitinated neuronal inclusions in both models. We demonstrate the neuroprotective activity of UDCA downstream of endosomal-lysosomal and autophagic dysfunction, delineating the molecular mode of action of UDCA and highlighting its potential as a therapeutic for the treatment of FTD-ALS spectrum disorders.}, }
@article {pmid32800276, year = {2020}, author = {Shariati, A and Nemati, R and Sadeghipour, Y and Yaghoubi, Y and Baghbani, R and Javidi, K and Zamani, M and Hassanzadeh, A}, title = {Mesenchymal stromal cells (MSCs) for neurodegenerative disease: A promising frontier.}, journal = {European journal of cell biology}, volume = {99}, number = {6}, pages = {151097}, doi = {10.1016/j.ejcb.2020.151097}, pmid = {32800276}, issn = {1618-1298}, mesh = {Cell- and Tissue-Based Therapy/*methods ; Humans ; Mesenchymal Stem Cells/*metabolism ; Neurodegenerative Diseases/physiopathology/*therapy ; }, abstract = {Neurodegenerative disorders are a variety of diseases including Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) along with some other less common diseases generally described by the advanced deterioration of central or peripheral nervous system, structurally or functionally. In the last two decades, mesenchymal stromal cells (MSCs) due to their unique assets encompassing self-renewal, multipotency and accessibility in association with low ethical concern open new frontiers in the context of neurodegenerative diseases therapy. Interestingly, MSCs can be differentiated into endodermal and ectodermal lineages (e.g., neurons, oligodendrocyte, and astrocyte), and thus could be employed to advance cell-based therapeutic strategy. Additionally, as inflammation ordinarily ensues as a local response provoked by microglia in the neurodegenerative diseases, MSCs therapy because of their pronounced immunomodulatory properties is noticed as a rational approach for their treatment. Recently, varied types of studies have been mostly carried out in vitro and rodent models using MSCs upon their procurement from various sources and expansion. The promising results of the studies in rodent models have motivated researchers to design and perform several clinical trials, with a speedily rising number. In the current review, we aim to deliver a brief overview of MSCs sources, expansion strategies, and their immunosuppressive characteristics and discuss credible functional mechanisms exerted by MSCs to treat neurodegenerative disorders, covering AD, PD, ALS, MS, and HD.}, }
@article {pmid32799604, year = {2020}, author = {Dias, ML and Batista, CMP and Secomandi, VJK and Silva, AC and Monteiro, VRS and Faccioli, LA and Goldenberg, RCS}, title = {Surgical Models to Explore Acellular Liver Scaffold Transplantation: Step-by-Step.}, journal = {Organogenesis}, volume = {16}, number = {3}, pages = {95-112}, pmid = {32799604}, issn = {1555-8592}, mesh = {Animals ; Extracellular Matrix ; Female ; Liver/*surgery ; Liver Transplantation/*methods ; Male ; Microsurgery/*methods ; Models, Anatomic ; Rats ; Rats, Wistar ; Tissue Engineering/*methods ; *Tissue Scaffolds ; Transplantation, Heterotopic ; }, abstract = {Acellular liver scaffolds (ALS) have arisen as potential candidates for transplantation. Until now, all reports involving ALS transplantation failed in surgical method descriptions and do not offer support to scientists to reproduce the procedures used in experimental microsurgery to make the results comparable to literature. To overcome the lack of detail information, we described surgical steps details to perform heterotopic and partial orthotopic surgical models to promote ALS transplantation. After preservation and vessel cannulation steps, the liver grafts were decellularized. In addition, ex vivo blood perfusion tests were performed to obtain a successful anticoagulation treatment prior in vivo transplantation. Then, methods of partial liver resection, combination of hand-suture and cuff techniques to complete end-to-end anastomosis between the scaffold and the recipient animal were performed. These procedures which take 30-60 min and were efficient to allow acellular liver scaffold viability and recellularization of different types of cell post-surgery. In conclusion, our methods are practical and simple promising approach that provides the opportunity to investigate ways to achieve sufficient liver function post-transplantation in vivo.}, }
@article {pmid32797327, year = {2020}, author = {Matsuda, K and Hashiguchi, Y and Asako, K and Okada, Y and Ohno, K and Tsukamoto, M and Fukushima, Y and Shimada, R and Ozawa, T and Hayama, T and Nozawa, K and Fukagawa, T and Sasajima, Y}, title = {Afferent limb syndrome after total proctocolectomy and ileal pouch-anal canal anastomosis.}, journal = {Surgical case reports}, volume = {6}, number = {1}, pages = {209}, pmid = {32797327}, issn = {2198-7793}, abstract = {BACKGROUND: Small bowel obstruction (SBO) is a common postoperative complication of ulcerative colitis (UC). There have been a few recent reports of afferent limb syndrome (ALS) as a rare occurrence in cases of SBO. We present a case of ALS with recurrent SBO that was successfully managed surgically.<br><br>CASE PRESENTATION: When this male patient was 55&#x2009;years old, he underwent laparoscopy-assisted anus-preserving total proctocolectomy, the creation of a J-type ileal pouch, ileal pouch-anal canal anastomosis (IPAA), and creation of ileostomy for intractable UC. Three months later, ileostomy closure was performed. The first onset of SBO was observed 5 months after ileostomy closure. SBO occurred repeatedly, and the patient was hospitalized nine times in approximately 2 years. Each SBO was improved by non-surgical treatment. A computed tomography (CT) scan revealed that the afferent limb was narrowing and twisted, and gastrografin enema confirmed narrowing at the proximal portion of the pouch inlet. Endoscopy showed a sharp angulation at the pouch inlet. We suspected ALS and decided on a surgical policy and performed pouchopexy and ileopexy to the retroperitoneum by suturing with excision of the remaining blind end of the ileum. Endoscopy 3 days after surgery showed neither twist nor stricture in the fixed ileal pouch or the afferent limb. At the time of writing, the patient remains free of SBO symptoms.<br><br>CONCLUSION: Clinicians should consider ALS when examining a patient with recurrent intermittent SBO after IPAA surgery. When ALS is suspected, the patient is indicated for surgery such as surgical pexy.}, }
@article {pmid32796282, year = {2020}, author = {van Eijk, RPA and Kliest, T and van den Berg, LH}, title = {Current trends in the clinical trial landscape for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {33}, number = {5}, pages = {655-661}, pmid = {32796282}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; *Clinical Trials as Topic ; Humans ; Research Design ; }, abstract = {PURPOSE OF REVIEW: To review the current developments in the design and conduct of clinical trials for amyotrophic lateral sclerosis (ALS), illustrated by a critical appraisal of ClinicalTrials.gov.<br><br>RECENT FINDINGS: In total, 63 clinical trials were included in the analysis, of which 13 phase 1, 35 phase 2 and 15 phase 3. Virtually all phase 3 clinical trials can be classified as randomized, placebo controlled, whereas this is only true for 57% of the phase 2 clinical trials. There are promising developments in the routes of drug administration, eligibility criteria, efficacy endpoints and overall trial design. Some of these innovative approaches may, however, not fulfil clinical trial guidelines or regulatory requirements. This could delay the development of effective therapy or hamper our ability to determine whether a treatment is truly (in)effective. The initiation of trial consortia comprising patient organizations, academia, industry and funding bodies may significantly strengthen the future clinical trial landscape for ALS.<br><br>SUMMARY: The ALS clinical trial landscape is currently highly active with several promising innovative developments and therapeutic options. By further refinement of evidence-based guidelines, and alignment of our current endeavours, we may soon be able to positively impact the lives of people living with ALS.}, }
@article {pmid32795302, year = {2020}, author = {Zeman, M and Czarnecki, M and Chmielarz, A and Idasiak, A and Grajek, M and Czarniecka, A}, title = {Assessment of the risk of permanent stoma after low anterior resection in rectal cancer patients.}, journal = {World journal of surgical oncology}, volume = {18}, number = {1}, pages = {207}, pmid = {32795302}, issn = {1477-7819}, mesh = {Anastomosis, Surgical/adverse effects ; Anastomotic Leak/epidemiology/etiology/prevention &amp; control ; Humans ; Ileostomy/adverse effects ; Prognosis ; *Rectal Neoplasms/surgery ; Retrospective Studies ; Risk Factors ; *Surgical Stomas/adverse effects ; }, abstract = {BACKGROUND: One of the most severe complications of low anterior rectal resection is anastomotic leakage (AL). The creation of a loop ileostomy (LI) reduces the prevalence of AL requiring surgical intervention. However, up to one-third of temporary stomas may never be closed. The first aim of the study was to perform a retrospective assessment of the impact of LI on the risk of permanent stoma (PS) and symptomatic AL. The second aim of the study was to assess preoperative PS risk factors in patients with LI.<br><br>METHODS: A total of 286 consecutive patients who underwent low anterior rectal resection were subjected to retrospective analysis. In 101 (35.3%) patients, diverting LI was performed due to low anastomosis, while in the remaining 185 (64.7%) patients, no ileostomy was performed. LIs were reversed after adjuvant treatment. Analyses of the effect of LI on symptomatic AL and PS were performed. Among the potential risk factors for PS, clinical factors and the values of selected peripheral blood parameters were analysed.<br><br>RESULTS: PS occurred in 37.6% and 21.1% of the patients with LI and without LI, respectively (p < 0.01). Symptomatic ALs were significantly more common in patients without LI. In this group, symptomatic ALs occurred in 23.8% of patients, while in the LI group, they occurred in 5% of patients (p < 0.001). In the LI group, the only significant risk factor for PS in the multivariate analysis was preoperative plasma fibrinogen concentration (OR = 1.007, 97.5% CI 1.002-1.013, p = 0.013).<br><br>CONCLUSIONS: Although protective LI may reduce the incidence of symptomatic AL, it can be related to a higher risk of PS in this group of patients. The preoperative plasma fibrinogen concentration can be a risk factor for PS in LI patients and may be a useful variable in decision-making models.}, }
@article {pmid32792920, year = {2020}, author = {Guan, Y and Han, F}, title = {Key Mechanisms and Potential Targets of the NLRP3 Inflammasome in Neurodegenerative Diseases.}, journal = {Frontiers in integrative neuroscience}, volume = {14}, number = {}, pages = {37}, pmid = {32792920}, issn = {1662-5145}, abstract = {Neurodegenerative diseases are neuronal disorders characterized by the loss of a large number of neurons in the human brain. Innate immunity-mediated neuroinflammation actively contributes to the onset and progression of neurodegenerative diseases. Inflammasomes are involved in the progression of the innate immune response and are responsible for the maturation of caspase-1 and inflammatory cytokines during neuroinflammation. The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome, which is one of the most intensively investigated inflammasomes, has been reported to play a key role in neurodegenerative diseases. Here, we reviewed the mechanisms, role, and latest developments regarding the NLRP3 inflammasome with respect to three neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Patient and animal model studies have found that abnormal protein aggregation of Aβ, synuclein, or copper-zinc superoxide dismutase-1 (SOD1), which are the main proteins expressed in the three diseases, respectively, can activate microglial cells, induce increased interleukin-1β (IL-1β) release, and activate the NLRP3 pathway, leading to neurodegeneration. In contrast, a deficiency of the components of the NLRP3 pathway may inhibit Aβ, synuclein, or SOD1-induced microglial activation. These studies indicate a positive correlation between NLRP3 levels and abnormal protein aggregation. However, in the case of ALS, not only microglia but also astrocytes express increased NLRP3 levels and contribute to activation of the NLRP3 pathway. In addition, in this review article, we also focus on the therapeutic implications of targeting novel inhibitors of the NLRP3 inflammasome or of novel drugs that mediate the NLRP3 pathway, which could play a role via NLRP3 in the treatment of neurodegenerative diseases.}, }
@article {pmid32790644, year = {2020}, author = {Prudencio, M and Humphrey, J and Pickles, S and Brown, AL and Hill, SE and Kachergus, JM and Shi, J and Heckman, MG and Spiegel, MR and Cook, C and Song, Y and Yue, M and Daughrity, LM and Carlomagno, Y and Jansen-West, K and de Castro, CF and DeTure, M and Koga, S and Wang, YC and Sivakumar, P and Bodo, C and Candalija, A and Talbot, K and Selvaraj, BT and Burr, K and Chandran, S and Newcombe, J and Lashley, T and Hubbard, I and Catalano, D and Kim, D and Propp, N and Fennessey, S and ,  and Fagegaltier, D and Phatnani, H and Secrier, M and Fisher, EM and Oskarsson, B and van Blitterswijk, M and Rademakers, R and Graff-Radford, NR and Boeve, BF and Knopman, DS and Petersen, RC and Josephs, KA and Thompson, EA and Raj, T and Ward, M and Dickson, DW and Gendron, TF and Fratta, P and Petrucelli, L}, title = {Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia.}, journal = {The Journal of clinical investigation}, volume = {130}, number = {11}, pages = {6080-6092}, pmid = {32790644}, issn = {1558-8238}, support = {MR/M008606/1/MRC_/Medical Research Council/United Kingdom ; R35 NS097273/NS/NINDS NIH HHS/United States ; R56 AG055824/AG/NIA NIH HHS/United States ; FRATTA/JAN15/946-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; /DH_/Department of Health/United Kingdom ; RF1 AG062077/AG/NIA NIH HHS/United States ; //CIHR/Canada ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 ES020395/ES/NIEHS NIH HHS/United States ; RF1 NS120992/NS/NINDS NIH HHS/United States ; TALBOT/OCT15/886-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; P50 AG016574/AG/NIA NIH HHS/United States ; MR/P007023/1/MRC_/Medical Research Council/United Kingdom ; R01 NS088689/NS/NINDS NIH HHS/United States ; R21 NS084528/NS/NINDS NIH HHS/United States ; R01 AG037491/AG/NIA NIH HHS/United States ; P01 NS099114/NS/NINDS NIH HHS/United States ; U01 AG045390/AG/NIA NIH HHS/United States ; MR/N013255/1/MRC_/Medical Research Council/United Kingdom ; U01 AG006786/AG/NIA NIH HHS/United States ; }, mesh = {Biomarkers/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Female ; Frontal Lobe/*metabolism/pathology ; Frontotemporal Dementia/genetics/*metabolism/pathology ; Humans ; Induced Pluripotent Stem Cells/*metabolism/pathology ; Male ; Middle Aged ; Mutation ; Stathmin/genetics/*metabolism ; }, abstract = {No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.}, }
@article {pmid32788871, year = {2020}, author = {Pawlukowska, W and Baumert, B and Gołąb-Janowska, M and Pius-Sadowska, E and Litwińska, Z and Kotowski, M and Meller, A and Rotter, I and Peregud-Pogorzelski, J and Nowacki, P}, title = {Articulation recovery in ALS patients after lineage-negative adjuvant cell therapy - preliminary report.}, journal = {International journal of medical sciences}, volume = {17}, number = {13}, pages = {1927-1935}, pmid = {32788871}, issn = {1449-1907}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/genetics/pathology/*therapy ; Cell Lineage/genetics ; Cell- and Tissue-Based Therapy/*methods ; Female ; Humans ; Male ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology/metabolism ; Middle Aged ; Nerve Growth Factors/*cerebrospinal fluid/genetics ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is one of the most frequently occurring neurodegenerative diseases affecting speech and swallowing. This preliminary study aimed to investigate whether an autologous lineage-negative stem/progenitor cell therapy applied to ALS patients affects the level of selected trophic and proinflammatory factors, and subsequently improves the articulation. Methods: We enrolled 12 patients with sporadic ALS, who underwent autologous bone marrow-derived lineage negative (LIN[-]) cells administration into cerebrospinal fluid (CSF). We evaluated patients' articulation using the Frenchay Dysarthria Assessment on days 0 and 28 following the LIN[-] cells administration. Concentrations of various factors (BDNF, NGF, ANGP-2, VEGF, PDGF-AA, PEDF, COMP-FH, CRP, C3, C4) in CSF were quantified by multiplex fluorescent bead-based immunoassays in the samples collected on the day of LIN[-] cells administration and 28 days later. On top of this, we assessed levels of BDNF and NGF in the patients' plasma on the day of the injection, three, seven days and three months after the treatment. Results: Of the 12 patients who received the LIN[-] cell therapy 8 showed short-termed improvement in articulatory functions (group I), which was particularly noticeable in better phonation time, lips and soft palate performance, swallowing reflex and voice loudness. Four patients (group II) did not show substantial improvement. CSF concentrations of BDNF, ANGP-2 and PDGF-AA in group I decreased significantly 28 days after LIN[-] cells administration. The highest concentration levels of BDNF in group II and NGF in both groups in blood plasma were observed on day 3 following the injection. Conclusions: The outcomes of the LIN[-] cell application in ALS treatment of articulatory organs are promising. The procedure proved to be safe and feasible. A short-lasting trophic effect of autologous LIN[-] administration could encourage repeated cell's application in order to sustain their beneficial effects, however this approach needs further investigation.}, }
@article {pmid32787753, year = {2021}, author = {Shakkour, Z and Issa, H and Ismail, H and Ashekyan, O and Habashy, KJ and Nasrallah, L and Jourdi, H and Hamade, E and Mondello, S and Sabra, M and Zibara, K and Kobeissy, F}, title = {Drug Repurposing: Promises of Edaravone Target Drug in Traumatic Brain Injury.}, journal = {Current medicinal chemistry}, volume = {28}, number = {12}, pages = {2369-2391}, doi = {10.2174/0929867327666200812221022}, pmid = {32787753}, issn = {1875-533X}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; *Brain Injuries, Traumatic ; Drug Repositioning ; Edaravone ; Free Radical Scavengers/therapeutic use ; Humans ; *Neuroprotective Agents/therapeutic use ; *Pharmaceutical Preparations ; }, abstract = {Edaravone is a potent free-radical scavenger that has been in the market for more than 30 years. It was originally developed in Japan to treat strokes and has been used there since 2001. Aside from its anti-oxidative effects, edaravone demonstrated beneficial effects on proinflammatory responses, nitric oxide production, and apoptotic cell death. Interestingly, edaravone has shown neuroprotective effects in several animal models of diseases other than stroke. In particular, edaravone administration was found to be effective in halting amyotrophic lateral sclerosis (ALS) progression during the early stages. Accordingly, after its success in Phase III clinical studies, edaravone has been approved by the FDA as a treatment for ALS patients. Considering its promises in neurological disorders and its safety in patients, edaravone is a drug of interest that can be repurposed for traumatic brain injury (TBI) treatment. Drug repurposing is a novel approach in drug development that identifies drugs for purposes other than their original indication. This review presents the biochemical properties of edaravone along with its effects on several neurological disorders in the hope that it can be adopted for treating TBI patients.}, }
@article {pmid32784556, year = {2020}, author = {Chen, D and Zhang, T and Lee, TH}, title = {Cellular Mechanisms of Melatonin: Insight from Neurodegenerative Diseases.}, journal = {Biomolecules}, volume = {10}, number = {8}, pages = {}, pmid = {32784556}, issn = {2218-273X}, support = {81901071//National Natural Science Foundation of China/International ; 81970993//National Natural Science Foundation of China/International ; 2019J01297//Natural Science Foundation of Fujian Province/International ; 2019J05072//Natural Science Foundation of Fujian Province/International ; 2019-CX-36//Medical Innovation Grant of Fujian Province/International ; XRCZX2017007//Fujian Medical University/International ; XRCZX2017019//Fujian Medical University/International ; }, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; *Circadian Rhythm/drug effects ; Dementia, Vascular/metabolism ; Humans ; Huntington Disease/metabolism ; Melatonin/*physiology/therapeutic use ; Multiple Sclerosis/metabolism ; Neurodegenerative Diseases/drug therapy/*metabolism ; *Oxidative Stress/drug effects ; Parkinson Disease/metabolism ; }, abstract = {Neurodegenerative diseases are the second most common cause of death and characterized by progressive impairments in movement or mental functioning in the central or peripheral nervous system. The prevention of neurodegenerative disorders has become an emerging public health challenge for our society. Melatonin, a pineal hormone, has various physiological functions in the brain, including regulating circadian rhythms, clearing free radicals, inhibiting biomolecular oxidation, and suppressing neuroinflammation. Cumulative evidence indicates that melatonin has a wide range of neuroprotective roles by regulating pathophysiological mechanisms and signaling pathways. Moreover, melatonin levels are decreased in patients with neurodegenerative diseases. In this review, we summarize current knowledge on the regulation, molecular mechanisms and biological functions of melatonin in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, vascular dementia and multiple sclerosis. We also discuss the clinical application of melatonin in neurodegenerative disorders. This information will lead to a better understanding of the regulation of melatonin in the brain and provide therapeutic options for the treatment of various neurodegenerative diseases.}, }
@article {pmid32776498, year = {2020}, author = {Liu, L and Killoy, KM and Vargas, MR and Yamamoto, Y and Pehar, M}, title = {Effects of RAGE inhibition on the progression of the disease in hSOD1[G93A] ALS mice.}, journal = {Pharmacology research &amp; perspectives}, volume = {8}, number = {4}, pages = {e00636}, pmid = {32776498}, issn = {2052-1707}, support = {R01NS100835/NS/NINDS NIH HHS/United States ; S10 OD018113/OD/NIH HHS/United States ; R01 NS100835/NS/NINDS NIH HHS/United States ; P30 CA138313/CA/NCI NIH HHS/United States ; P20 GM103542/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/physiopathology ; Animals ; Astrocytes/*metabolism ; Disease Models, Animal ; Disease Progression ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Motor Neurons/pathology ; Receptor for Advanced Glycation End Products/*genetics ; Superoxide Dismutase-1/*genetics ; }, abstract = {Astrocytes play a key role in the progression of amyotrophic lateral sclerosis (ALS) by actively inducing the degeneration of motor neurons. Motor neurons isolated from receptor for advanced glycation end products (RAGE)-knockout mice are resistant to the neurotoxic signal derived from ALS-astrocytes. Here, we confirmed that in a co-culture model, the neuronal death induced by astrocytes over-expressing the ALS-linked mutant hSOD1[G93A] is prevented by the addition of the RAGE inhibitors FPS-ZM1 or RAP. These inhibitors also prevented the motor neuron death induced by spinal cord extracts from symptomatic hSOD1[G93A] mice. To evaluate the relevance of this neurotoxic mechanism in ALS pathology, we assessed the therapeutic potential of FPS-ZM1 in hSOD1[G93A] mice. FPS-ZM1 treatment significantly improved hind-limb grip strength in hSOD1[G93A] mice during the progression of the disease, reduced the expression of atrophy markers in the gastrocnemius muscle, improved the survival of large motor neurons, and reduced gliosis in the ventral horn of the spinal cord. However, we did not observe a statistically significant effect of the drug in symptoms onset nor in the survival of hSOD1[G93A] mice. Maintenance of hind-limb grip strength was also observed in hSOD1[G93A] mice with RAGE haploinsufficiency [hSOD1[G93A] ;RAGE(+/-)], further supporting the beneficial effect of RAGE inhibition on muscle function. However, no benefits were observed after complete RAGE ablation. Moreover, genetic RAGE ablation significantly shortened the median survival of hSOD1[G93A] mice. These results indicate that the advance of new therapies targeting RAGE in ALS demands a better understanding of its physiological role in a cell type/tissue-specific context.}, }
@article {pmid32772223, year = {2020}, author = {Palermo, G and Mazzucchi, S and Della Vecchia, A and Siciliano, G and Bonuccelli, U and Azuar, C and Ceravolo, R and Lista, S and Hampel, H and Baldacci, F}, title = {Different Clinical Contexts of Use of Blood Neurofilament Light Chain Protein in the Spectrum of Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {57}, number = {11}, pages = {4667-4691}, doi = {10.1007/s12035-020-02035-9}, pmid = {32772223}, issn = {1559-1182}, mesh = {Animals ; Biomarkers/blood ; Humans ; Mass Screening ; Neurodegenerative Diseases/*blood/diagnosis ; Neurofilament Proteins/*blood ; Prognosis ; Risk Factors ; }, abstract = {One of the most pressing challenges in the clinical research of neurodegenerative diseases (NDDs) is the validation and standardization of pathophysiological biomarkers for different contexts of use (CoUs), such as early detection, diagnosis, prognosis, and prediction of treatment response. Neurofilament light chain (NFL) concentration is a particularly promising candidate, an indicator of axonal degeneration, which can be analyzed in peripheral blood with advanced ultrasensitive methods. Serum/plasma NFL concentration is closely correlated with cerebrospinal fluid NFL and directly reflects neurodegeneration within the central nervous system. Here, we provide an update on the feasible CoU of blood NFL in NDDs and translate recent findings to potentially valuable clinical practice applications. As NFL is not a disease-specific biomarker, however, blood NFL is an easily accessible biomarker with promising different clinical applications for several NDDs: (1) early detection and diagnosis (i.e., amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, atypical parkinsonisms, sporadic late-onset ataxias), (2) prognosis (Huntington's disease and Parkinson's disease), and (3) prediction of time to symptom onset (presymptomatic mutation carriers in genetic Alzheimer's disease and spinocerebellar ataxia type 3).}, }
@article {pmid32769392, year = {2020}, author = {Cabras, S and Calvo, A and Moglia, C and Chiò, A and Canosa, A}, title = {Acute, Hemorrhagic, Necrotizing Pancreatitis Associated With Riluzole Treatment in a Patient With Amyotrophic Lateral Sclerosis.}, journal = {American journal of therapeutics}, volume = {29}, number = {2}, pages = {e265-e268}, doi = {10.1097/MJT.0000000000001217}, pmid = {32769392}, issn = {1536-3686}, }
@article {pmid32768089, year = {2020}, author = {Weimer, LH}, title = {Neuromuscular disorders in pregnancy.}, journal = {Handbook of clinical neurology}, volume = {172}, number = {}, pages = {201-218}, pmid = {32768089}, issn = {0072-9752}, mesh = {Animals ; Cesarean Section ; Female ; Humans ; *Muscular Diseases ; *Myasthenia Gravis ; *Neuromuscular Diseases/epidemiology/therapy ; Pregnancy ; *Pregnancy Complications/epidemiology/therapy ; Retrospective Studies ; }, abstract = {Many neuromuscular disorders preexist or occur during pregnancy. In some cases, pregnancy unmasks a latent hereditary disorder. Most available information is based on case reports or series or retrospective clinical experience or patient surveys. Of special interest are pregnancy-induced changes in disease course or severity and likelihood for baseline recovery of function postpartum. Labor and delivery present special challenges in many conditions that affect skeletal but not smooth (uterine) muscle; so labor complications must be anticipated. Anesthesia for cesarean section surgery requires special precautions in many disorders. The types of conditions reviewed are broad and include examples of autoimmune, hereditary, and compressive/mechanical processes. Disorders include carpal tunnel syndrome and other focal neuropathies, Bell palsy, myasthenia gravis, and other neuromuscular junction disorders, acute and chronic inflammatory neuropathy, hereditary and acquired muscle diseases, spinal muscular atrophy, amyotrophic lateral sclerosis, channelopathies, autonomic neuropathy, and dysautonomia. Many commonly used therapies have fetal animal but no proven human toxicity concerns, complicating treatment and risk decisions. Weaning off effective therapeutic agents or preemptive aggressive treatment or surgery prior to planned pregnancy is an option in some conditions.}, }
@article {pmid32766931, year = {2021}, author = {Spataro, R and La Bella, V}, title = {The capacity to consent to treatment in amyotrophic lateral sclerosis: a preliminary report.}, journal = {Journal of neurology}, volume = {268}, number = {1}, pages = {219-226}, pmid = {32766931}, issn = {1432-1459}, support = {841116//H2020 Marie Sk&#x142;odowska-Curie Actions/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Cognition ; *Cognition Disorders ; Humans ; Informed Consent ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Facing the relentless worsening of their condition, ALS patients are required to make decisions on treatments and end-of-life care. A cognitive impairment showed to be a negative prognostic factor in ALS patients, perhaps affecting the ability to make informed decisions. Notwithstanding its crucial role, the capacity to consent to treatment (CCT) has never been evaluated in these patients.<br><br>OBJECTIVES: To assess the CCT in an ALS cohort in comparison to a control group, and to study the effects of demographic and clinical variables on this high-level cognitive function.<br><br>METHODS: 102 ALS patients and 106 healthy controls (HC) were enrolled. CCT was assessed using the MacArthur Competence Assessment Tool for Treatment (MAC-CAT-T) and the performance was classified into the three CCT outcomes (full credit, partial credit, no credit). Cognitive and psychological variables were assessed by MMSE, phonemic fluencies, Frontal System Behavioural Scale (FrSBe), and ALS Depression Inventory (ADI). Clinical and demographic variables were analyzed as possible predictors of the MAC-CAT-T outcomes. After a 1-year follow-up, CCT and neuropsychological assessments were repeated.<br><br>RESULTS: Most ALS patients (i.e., from 75 to 83% according to the different sub-items) retain full CCT. However, a subpopulation of the ALS patients showed a reduced CCT with respect to the HC. Age, education, phonemic fluency, and depression appeared related to the CCT outcomes. After 1 year, only the reasoning items worsened.<br><br>CONCLUSIONS: This is a preliminary report suggesting that the large majority of ALS patients can retain full ability to choose between treatment options. However, demographic and neuropsychological variables may affect CCT, pointing to the need for special attention to the consent disclosure in this disease.}, }
@article {pmid32765151, year = {2020}, author = {Spencer, PS}, title = {Etiology of Retinal and Cerebellar Pathology in Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex.}, journal = {Eye and brain}, volume = {12}, number = {}, pages = {97-104}, pmid = {32765151}, issn = {1179-2744}, abstract = {PURPOSE: To reexamine the etiology of a unique retinal pathology (linear and vermiform sub-retinal tubular structures) described among subjects with and without neurodegenerative disease in former high-incidence foci of Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS/PDC) in Guam (USA) and the Kii peninsula of Honshu island (Japan).<br><br>METHODS: Analysis of published and unpublished reports of 1) ALS/PDC and the retinal and cerebellar pathology associated therewith and 2) exogenous neurotoxic factors associated with ALS/PDC and the developing retina and cerebellum.<br><br>RESULTS: ALS/PDC retinal and cerebellar pathology matches persistent retinal and cerebellar dysplasia found in laboratory animals given single in utero or postnatal systemic treatment with cycasin, the principal neurotoxic component in the seed of cycad plants traditionally used for food (Guam) or oral medicine (Kii-Japan), both of which have been linked to the human neurodegenerative disease.<br><br>CONCLUSION: ALS/PDC-associated retinal and cerebellar dysplasia could arise from in utero exposure to methylazoxymethanol, the genotoxic metabolite of cycasin that results from maternal ingestion of this azoxyglucoside. These results support the environmental toxic etiology of retinal and brain pathology in ALS/PDC.}, }
@article {pmid32763509, year = {2020}, author = {Richards, D and Morren, JA and Pioro, EP}, title = {Time to diagnosis and factors affecting diagnostic delay in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {417}, number = {}, pages = {117054}, doi = {10.1016/j.jns.2020.117054}, pmid = {32763509}, issn = {1878-5883}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Canada ; *Delayed Diagnosis ; Egypt ; Europe ; Humans ; Japan ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative neuromuscular disease with limited treatment options. The diagnosis of ALS can be challenging for numerous reasons, resulting in delays that may compromise optimal management and enrollment into clinical trials. Several studies have examined the process and challenges regarding the clinical diagnosis of ALS. Twenty-one studies that were almost exclusively from the English literature published between 1990 and 2020 were identified via PubMed using relevant search terms and included patient populations from the United States, Canada, Japan, Egypt, and several countries in South America and Europe. Probable or definitive ALS patients were identified using El Escorial or revised El Escorial/Airlie House Criteria. Time to diagnosis or diagnostic delay was defined as mean or median time from patient-reported first symptom onset to formal diagnosis by a physician, as recorded in medical records. The typical time to diagnosis was 10-16 months from symptom onset. Several points of delay in the diagnosis course were identified, including specialist referrals and misdiagnoses, often resulting in unnecessary procedures and surgeries. Bulbar onset was noted to significantly reduce time to ALS diagnosis. Future interventions and potential research opportunities were reviewed.}, }
@article {pmid32763254, year = {2020}, author = {Desai, P and Bandopadhyay, R}, title = {Pathophysiological implications of RNP granules in frontotemporal dementia and ALS.}, journal = {Neurochemistry international}, volume = {140}, number = {}, pages = {104819}, doi = {10.1016/j.neuint.2020.104819}, pmid = {32763254}, issn = {1872-9754}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*physiopathology ; Animals ; Brain/metabolism/physiopathology ; Frontotemporal Dementia/*metabolism/*physiopathology ; Humans ; Oxidative Stress/physiology ; Ribonucleoproteins/*metabolism ; }, abstract = {Neurodegenerative diseases are a group of chronic, progressive, age-related disorders that are becoming increasingly prevalent in the ageing population. Despite the variety of clinical features observed, neurodegenerative diseases are characterised by protein aggregation and deposition at the molecular level. The nature of such intracellular protein aggregates is dependent on disease type and specific to disease subtype. Frontotemporal dementia and amyotrophic lateral sclerosis (ALS) are two overlapping neurodegenerative diseases, exhibiting pathological aggregates commonly composed of the proteins: Fused in Sarcoma (FUS) or Transactive Response DNA Binding Protein of 43 KDa (TDP-43). The presence of these protein aggregates in late disease stages is suggestive of a converging underlying mechanism of pathology across diseases involving disrupted proteostasis. Despite this, at present there are no effective therapeutics for the diseases, with current treatment strategies generally tending to be only for symptom management. An area of research that has gained increased interest in recent years is the formation and maintenance of ribonucleoprotein (RNP) granules. These are membraneless organelles that consist of RNA and protein elements, which can be either constitutively expressed (such as nuclear paraspeckles) or upregulated under conditions of cellular stress as an adaptive response (such as cytoplasmic stress granules). RNA-binding proteins are a key component of RNP granules, and crucially some of which, for example FUS and TDP-43, are also neurodegenerative disease-associated proteins. Therefore, a better understanding of RNA-binding proteins in RNP granule formation and the regulation and maintenance of RNP granule biophysical properties and dynamics may provide insights into mechanisms contributing to disrupted proteostasis in neurodegenerative pathology; and thus open up new avenues for therapeutic discovery and development. This review will focus on stress granule and paraspeckle RNP granules, and discuss their possible contribution to pathology in cases of frontotemporal dementia and ALS.}, }
@article {pmid32760239, year = {2020}, author = {Calió, ML and Henriques, E and Siena, A and Bertoncini, CRA and Gil-Mohapel, J and Rosenstock, TR}, title = {Mitochondrial Dysfunction, Neurogenesis, and Epigenetics: Putative Implications for Amyotrophic Lateral Sclerosis Neurodegeneration and Treatment.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {679}, pmid = {32760239}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and devastating multifactorial neurodegenerative disorder. Although the pathogenesis of ALS is still not completely understood, numerous studies suggest that mitochondrial deregulation may be implicated in its onset and progression. Interestingly, mitochondrial deregulation has also been associated with changes in neural stem cells (NSC) proliferation, differentiation, and migration. In this review, we highlight the importance of mitochondrial function for neurogenesis, and how both processes are correlated and may contribute to the pathogenesis of ALS; we have focused primarily on preclinical data from animal models of ALS, since to date no studies have evaluated this link using human samples. As there is currently no cure and no effective therapy to counteract ALS, we have also discussed how improving neurogenic function by epigenetic modulation could benefit ALS. In support of this hypothesis, changes in histone deacetylation can alter mitochondrial function, which in turn might ameliorate cellular proliferation as well as neuronal differentiation and migration. We propose that modulation of epigenetics, mitochondrial function, and neurogenesis might provide new hope for ALS patients, and studies exploring these new territories are warranted in the near future.}, }
@article {pmid32758777, year = {2020}, author = {Sheikholeslami, MN and Gómez-Canela, C and Barron, LP and Barata, C and Vosough, M and Tauler, R}, title = {Untargeted metabolomics changes on Gammarus pulex induced by propranolol, triclosan, and nimesulide pharmaceutical drugs.}, journal = {Chemosphere}, volume = {260}, number = {}, pages = {127479}, doi = {10.1016/j.chemosphere.2020.127479}, pmid = {32758777}, issn = {1879-1298}, mesh = {Amphipoda/*physiology ; Animals ; Chromatography, Liquid/methods ; Least-Squares Analysis ; Mass Spectrometry/methods ; Metabolome ; Metabolomics/methods ; Pharmaceutical Preparations ; Propranolol/*toxicity ; Sulfonamides/*toxicity ; Triclosan/*toxicity ; Wastewater ; Water Pollutants, Chemical/*toxicity ; }, abstract = {The presence of pharmaceuticals and personal care products (PPCPs) in natural water resources due to incomplete removal in Wastewater Treatment Plants (WWTPs) is a serious environmental concern at present. In this work, the effects of three pharmaceuticals (propranolol, triclosan, and nimesulide) on Gammarus pulex metabolic profiles at different doses and times of exposure have been investigated by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). The complex data sets generated in the different exposure experiments were analyzed with the ROIMCR procedure, based on the selection of the MS regions of interest (ROI) data and on their analysis by the Multivariate Curve-Resolution Alternating Least Squares (MCR-ALS) chemometrics method. This approach, allowed the resolution and identification of the metabolites present in the analyzed samples, as well as the estimation of their concentration changes due to the exposure experiments. ANOVA Simultaneous Component Analysis (ASCA) and Partial Least Squares Discriminant Analysis (PLS-DA) were then conducted to assess the changes in the concentration of the metabolites for the three pharmaceuticals at the different conditions of exposure. The three tested pharmaceuticals changed the concentrations of metabolites, which were related to different KEGG functional classes. These changes summarize the biochemical response of Gammarus pulex to the exposure by the three investigated pharmaceuticals. Possible pathway alterations related to protein synthesis and oxidative stress were observed in the concentration of identified metabolites.}, }
@article {pmid32756308, year = {2020}, author = {Gil-Monreal, M and Royuela, M and Zabalza, A}, title = {Hypoxic Treatment Decreases the Physiological Action of the Herbicide Imazamox on Pisum sativum Roots.}, journal = {Plants (Basel, Switzerland)}, volume = {9}, number = {8}, pages = {}, pmid = {32756308}, issn = {2223-7747}, support = {AGL2016-77531-R//Ministerio de Econom&#xed;a, Industria y Competitividad, Gobierno de Espa&#xf1;a/ ; }, abstract = {The inhibition of acetolactate synthase (ALS; EC 2.2.1.6), an enzyme located in the biosynthetic pathway of branched-chain amino acids, is the target site of the herbicide imazamox. One of the physiological effects triggered after ALS inhibition is the induction of aerobic ethanol fermentation. The objective of this study was to unravel if fermentation induction is related to the toxicity of the herbicide or if it is a plant defense mechanism. Pea plants were exposed to two different times of hypoxia before herbicide application in order to induce the ethanol fermentation pathway, and the physiological response after herbicide application was evaluated at the level of carbohydrates and amino acid profile. The effects of the herbicide on total soluble sugars and starch accumulation, and changes in specific amino acids (branched-chain, amide, and acidic) were attenuated if plants were subjected to hypoxia before herbicide application. These results suggest that fermentation is a plant defense mechanism that decreases the herbicidal effect.}, }
@article {pmid32751486, year = {2020}, author = {Dörner, M and Schreiber, F and Stephanik, H and Tempelmann, C and Winter, N and Stahl, JH and Wittlinger, J and Willikens, S and Kramer, M and Heinze, HJ and Vielhaber, S and Schelle, T and Grimm, A and Schreiber, S}, title = {Peripheral Nerve Imaging Aids in the Diagnosis of Immune-Mediated Neuropathies-A Case Series.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {10}, number = {8}, pages = {}, pmid = {32751486}, issn = {2075-4418}, abstract = {BACKGROUND: Diagnosis of immune-mediated neuropathies and their differentiation from amyotrophic lateral sclerosis (ALS) can be challenging, especially at early disease stages. Accurate diagnosis is, however, important due to the different prognosis and available treatment options. We present one patient with a left-sided dorsal flexor paresis and initial suspicion of ALS and another with multifocal sensory deficits. In both, peripheral nerve imaging was the key for diagnosis.<br><br>METHODS: We performed high-resolution nerve ultrasound (HRUS) and 7T or 3T magnetic resonance neurography (MRN).<br><br>RESULTS: In both patients, HRUS revealed mild to severe, segmental or inhomogeneous, nerve enlargement at multiple sites, as well as an area increase of isolated fascicles. MRN depicted T2 hyperintense nerves with additional contrast-enhancement.<br><br>DISCUSSION: Peripheral nerve imaging was compatible with the respective diagnosis of an immune-mediated neuropathy, i.e., multifocal motor neuropathy (MMN) in patient 1 and multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) in patient 2. Peripheral nerve imaging, especially HRUS, should play an important role in the diagnostic work-up for immune-mediated neuropathies and their differentiation from ALS.}, }
@article {pmid32746649, year = {2020}, author = {Brimson, JM and Brimson, S and Chomchoei, C and Tencomnao, T}, title = {Using sigma-ligands as part of a multi-receptor approach to target diseases of the brain.}, journal = {Expert opinion on therapeutic targets}, volume = {24}, number = {10}, pages = {1009-1028}, doi = {10.1080/14728222.2020.1805435}, pmid = {32746649}, issn = {1744-7631}, mesh = {Animals ; Brain Diseases/*drug therapy/physiopathology ; Humans ; Ligands ; *Molecular Targeted Therapy ; Neurodegenerative Diseases/drug therapy ; Neuroprotective Agents/administration &amp; dosage/pharmacology ; Receptors, sigma/*agonists/metabolism ; }, abstract = {INTRODUCTION: The sigma receptors are found abundantly in the central nervous system and are targets for the treatment of various diseases, including Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), depression, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). However, for many of these diseases, other receptors and targets have been the focus of the most, such as acetylcholine esterase inhibitors in Alzheimer's and dopamine replacement in Parkinson's. The currently available drugs for these diseases have limited success resulting in the requirement of an alternative approach to their treatment.<br><br>AREAS COVERED: In this review, we discuss the potential role of the sigma receptors and their ligands as part of a multi receptor approach in the treatment of the diseases mentioned above. The literature reviewed was obtained through searches in databases, including PubMed, Web of Science, Google Scholar, and Scopus.<br><br>EXPERT OPINION: Given sigma receptor agonists provide neuroprotection along with other benefits such as potentiating the effects of other receptors, further development of multi-receptor targeting ligands, and or the development of multi-drug combinations to target multiple receptors may prove beneficial in the future treatment of degenerative diseases of the CNS, especially when coupled with better diagnostic techniques.}, }
@article {pmid32739295, year = {2020}, author = {Fujimoto, M and Andrew, M and Dauber, A}, title = {Disorders caused by genetic defects associated with GH-dependent genes: PAPPA2 defects.}, journal = {Molecular and cellular endocrinology}, volume = {518}, number = {}, pages = {110967}, pmid = {32739295}, issn = {1872-8057}, support = {R01 HD093622/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Female ; Genetic Diseases, Inborn/*genetics/metabolism ; Growth and Development/*genetics ; Human Growth Hormone/metabolism/physiology ; Humans ; Insulin-Like Growth Factor I/genetics/metabolism ; Male ; Mice ; Mutation ; Pregnancy-Associated Plasma Protein-A/*genetics/physiology ; Signal Transduction/genetics ; }, abstract = {Growth hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), have long been recognized as central to human growth physiology. IGF-1 is known to complex with IGF binding proteins as well as with the acid labile subunit (ALS) in order to prolong its half-life in circulation. Factors regulating the bioavailability of IGF-1 (i.e. the balance between free and bound IGF-1) were less well understood. Recently, pregnancy-associated plasma protein-A2 (PAPP-A2) was discovered as a protease which specifically cleaves IGF-binding protein (IGFBP)-3 and -5. PAPP-A2 deficient patients present with characteristic findings including growth failure, elevated total IGF-1 and -2, IGFBPs, and ALS, but decreased percentage of free to total IGF-1. Additionally, patients with PAPP-A2 deficiency have impairments in glucose metabolism and bone mineral density (BMD). Treatment with recombinant human IGF-1 (rhIGF-1) improved height SD scores, growth velocity, body composition, and dysglycemia. Mouse models recapitulate many of the human findings of PAPP-A2 deficiency. This review summarizes the function of PAPP-A2 and its contribution to the GH-IGF axis through an examination of PAPP-A2 deficient patients and mouse models, thereby emphasizing the importance of the regulation of IGF-1 bioavailability in human growth.}, }
@article {pmid32739173, year = {2020}, author = {Bouscary, A and Quessada, C and René, F and Spedding, M and Henriques, A and Ngo, S and Loeffler, JP}, title = {Drug repositioning in neurodegeneration: An overview of the use of ambroxol in neurodegenerative diseases.}, journal = {European journal of pharmacology}, volume = {884}, number = {}, pages = {173446}, doi = {10.1016/j.ejphar.2020.173446}, pmid = {32739173}, issn = {1879-0712}, mesh = {Ambroxol/*pharmacology ; Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/genetics/pathology ; Animals ; Disease Models, Animal ; Disease Progression ; *Drug Repositioning ; Enzyme Inhibitors/*pharmacology ; Glucosylceramidase/antagonists &amp; inhibitors/metabolism ; Humans ; Mutation ; *Nerve Degeneration ; Neuroprotective Agents/*pharmacology ; Spinal Cord/*drug effects/enzymology/pathology ; Superoxide Dismutase-1/genetics ; beta-Glucosidase/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. While it is primarily characterized by the death of upper and lower motor neurons, there is a significant metabolic component involved in the progression of the disease. Two-thirds of ALS patients have metabolic alterations that are associated with the severity of symptoms. In ALS, as in other neurodegenerative diseases, the metabolism of glycosphingolipids, a class of complex lipids, is strongly dysregulated. We therefore assume that this pathway constitutes an interesting avenue for therapeutic approaches. We have shown that the glucosylceramide degrading enzyme, glucocerebrosidase (GBA) 2 is abnormally increased in the spinal cord of the SOD1[G86R] mouse model of ALS. Ambroxol, a chaperone molecule that inhibits GBA2, has been shown to have beneficial effects by slowing the development of the disease in SOD1[G86R] mice. Currently used in clinical trials for Parkinson's and Gaucher disease, ambroxol could be considered as a promising therapeutic treatment for ALS.}, }
@article {pmid32737989, year = {2021}, author = {Palomo, V and Nozal, V and Rojas-Prats, E and Gil, C and Martinez, A}, title = {Protein kinase inhibitors for amyotrophic lateral sclerosis therapy.}, journal = {British journal of pharmacology}, volume = {178}, number = {6}, pages = {1316-1335}, doi = {10.1111/bph.15221}, pmid = {32737989}, issn = {1476-5381}, support = {B2017/BMD3813//Comunidad de Madrid/ ; LCF/BQ/PR18/11640007//La Caixa Banking Foundation/ ; FPU14-00204//MECD/ ; FPU16/04466//MECD/ ; CIBERNED, CB18/05/00040//ISCiii/ ; //FEDER/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Humans ; Motor Neurons ; *Neurodegenerative Diseases ; Protein Kinase Inhibitors/therapeutic use ; Ubiquitin ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that causes the progressive loss of motoneurons and, unfortunately, there is no effective treatment for this disease. Interconnecting multiple pathological mechanisms are involved in the neuropathology of this disease, including abnormal aggregation of proteins, neuroinflammation and dysregulation of the ubiquitin proteasome system. Such complex mechanisms, together with the lack of reliable animal models of the disease have hampered the development of drugs for this disease. Protein kinases, a key pharmacological target in several diseases, have been linked to ALS as they play a central role in the pathology of many diseases. Therefore several inhibitors are being currently trailed for clinical proof of concept in ALS patients. In this review, we examine the recent literature on protein kinase inhibitors currently in pharmaceutical development for this diseaseas future therapy for AS together with their involvement in the pathobiology of ALS. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.}, }
@article {pmid32727895, year = {2020}, author = {Rosbash, M}, title = {Metformin treatment of the C9orf72 ALS/FTD mouse: Almost too good for words.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {117}, number = {33}, pages = {19627-19628}, pmid = {32727895}, issn = {1091-6490}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein ; DNA Repeat Expansion ; *Frontotemporal Dementia/genetics ; *Metformin ; Disease Models, Animal ; }, }
@article {pmid32725516, year = {2020}, author = {Ahmad, A and Patel, V and Xiao, J and Khan, MM}, title = {The Role of Neurovascular System in Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {57}, number = {11}, pages = {4373-4393}, doi = {10.1007/s12035-020-02023-z}, pmid = {32725516}, issn = {1559-1182}, mesh = {Animals ; Blood-Brain Barrier/pathology/physiopathology ; Cerebrovascular Circulation ; Humans ; Models, Neurological ; Nervous System/*blood supply/physiopathology ; Neurodegenerative Diseases/*pathology/physiopathology/therapy ; }, abstract = {The neurovascular system (NVS), which consisted of neurons, glia, and vascular cells, is a functional and structural unit of the brain. The NVS regulates blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), thereby maintaining the brain's microenvironment for normal functioning, neuronal survival, and information processing. Recent studies have highlighted the role of vascular dysfunction in several neurodegenerative diseases. This is not unexpected since both nervous and vascular systems are functionally interdependent and show close anatomical apposition, as well as similar molecular pathways. However, despite extensive research, the precise mechanism by which neurovascular dysfunction contributes to neurodegeneration remains incomplete. Therefore, understanding the mechanisms of neurovascular dysfunction in disease conditions may allow us to develop potent and effective therapies for prevention and treatment of neurodegenerative diseases. This review article summarizes the current research in the context of neurovascular signaling associated with neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). We also discuss the potential implication of neurovascular factor as a novel therapeutic target and prognostic marker in patients with neurodegenerative conditions. Graphical Abstract.}, }
@article {pmid32725316, year = {2020}, author = {Barczewska, M and Maksymowicz, S and Zdolińska-Malinowska, I and Siwek, T and Grudniak, M}, title = {Umbilical Cord Mesenchymal Stem Cells in Amyotrophic Lateral Sclerosis: an Original Study.}, journal = {Stem cell reviews and reports}, volume = {16}, number = {5}, pages = {922-932}, pmid = {32725316}, issn = {2629-3277}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/pathology/*therapy ; Disease Progression ; Female ; Humans ; Male ; *Mesenchymal Stem Cell Transplantation/adverse effects ; Mesenchymal Stem Cells/*cytology ; Middle Aged ; Survival Analysis ; Treatment Outcome ; Umbilical Cord/*cytology ; Young Adult ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is still incurable. Although different therapies can affect the health and survival of patients. Our aim is to evaluate the effect of umbilical mesenchymal stem cells administrated intrathecally to patients with amyotrophic lateral sclerosis on disability development and survival.<br><br>METHODS: This case-control study involved 67 patients treated with Wharton's jelly mesenchymal stem cells (WJ-MSC). The treated patients were paired with 67 reference patients from the PRO-ACT database which contains patient records from 23 ALS clinical studies (phase 2/3). Patients in the treatment and reference groups were fully matched in terms of race, sex, onset of symptoms (bulbar/spinal), FT9 disease stage at the beginning of therapy and concomitant amyotrophic lateral sclerosis medications. Progression rates prior to treatment varied within a range of &#xb1;&#x2009;0.5 points. All patients received three intrathecal injections of Wharton's jelly-derived mesenchymal stem cells every two months at a dose of 30&#x2009;&#xd7;&#x2009;10[6] cells. Patients were assessed using the ALSFRS-R scale. Survival times were followed-up until March 2020.<br><br>RESULTS: Median survival time increased two-fold in all groups. In terms of progression, three response types measured in ALSFRS-R were observed: decreased progression rate (n&#xa0;=&#x2009;21, 31.3%), no change in progression rate (n&#xa0;=&#x2009;33, 49.3%) and increased progression rate (n&#xa0;=&#x2009;13, 19.4%). Risk-benefit ratios were favorable in all groups. No serious adverse drug reactions were observed.<br><br>INTERPRETATION: Wharton's jelly-derived mesenchymal stem cells therapy is safe and effective in some ALS patients, regardless of the clinical features and demographic factors excluding sex. The female sex and a good therapeutic response to the first administration are significant predictors of efficacy following further administrations. Graphical Abstract Medical therapeutic experiment with retrospective case-control analyses.}, }
@article {pmid32724029, year = {2020}, author = {Elbe, P and Markus, K and Valente, R and Ingre, C and Tsolakis, AV and Vujasinovic, M}, title = {Effectiveness of percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis.}, journal = {Minerva gastroenterologica e dietologica}, volume = {66}, number = {3}, pages = {219-224}, doi = {10.23736/S1121-421X.20.02695-1}, pmid = {32724029}, issn = {1827-1642}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications ; Deglutition Disorders/*etiology ; Female ; *Gastroscopy ; Gastrostomy/*methods ; Humans ; Male ; Middle Aged ; Nutritional Status ; Retrospective Studies ; Treatment Outcome ; Weight Loss ; }, abstract = {BACKGROUND: Weight loss and dysphagia are frequent features of amyotrophic lateral sclerosis (ALS) and influence prognosis. The aim of this study was to determine complications and outcomes in patients with percutaneous endoscopic gastrostomy (PEG) insertion in a high-volume center.<br><br>METHODS: A single center retrospective study on a prospectively collected cohort of 187 consecutive patients who have undergone PEG placement due to ALS was performed. Demographic and clinical parameters were analyzed.<br><br>RESULTS: There were 51.3% male; mean age at insertion was 65.7 years. Major complications occurred in 5 (2.7%) patients: 3 with local infections requiring intravenous antibiotic treatment, 1 patient with PEG dislocation required laparotomy and a new surgically introduced gastrostomy and 1 patient with buried-bumper syndrome. Improvement in Body Mass Index (BMI) and serum albumin levels were recorded in 37.3% and 51.9%, respectively. Mortality after 30 days, 6 months and 12 months was 5.3%, 38% and 64.3%, respectively. At the time of data collection, 78.9% of the patients had died. Mean survival after ALS diagnosis was 20.5 months.<br><br>CONCLUSIONS: PEG placement is as an effective, safe nutritional method with a low complication rate in patients with ALS, with or without non-invasive ventilation. The BMI and albumin levels stabilize after PEG placement, indicating benefits of early placement.}, }
@article {pmid32718499, year = {2020}, author = {Roggenbuck, J and Fong, JC}, title = {Genetic Testing for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: Impact on Clinical Management.}, journal = {Clinics in laboratory medicine}, volume = {40}, number = {3}, pages = {271-287}, doi = {10.1016/j.cll.2020.05.002}, pmid = {32718499}, issn = {1557-9832}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Frontotemporal Dementia/diagnosis/genetics ; Genetic Counseling ; *Genetic Testing ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative disorders that share clinical, pathologic, and genetic features. Persons and families affected by these conditions frequently question why they developed the disease, the expected disease course, treatment options, and the likelihood that family members will be affected. Genetic testing has the potential to answers these important questions. Despite the progress in gene discovery, the offer of genetic testing is not yet "standard of care" in ALS and FTD clinics. The authors review the current genetic landscape and present recommendations for the laboratory genetic evaluation of persons with these conditions.}, }
@article {pmid32709706, year = {2023}, author = {Wakefield, D and Hanson, SR}, title = {Requested withdrawal of gastrostomy feeding in motor neurone disease.}, journal = {BMJ supportive &amp; palliative care}, volume = {13}, number = {e1}, pages = {e88-e90}, doi = {10.1136/bmjspcare-2020-002428}, pmid = {32709706}, issn = {2045-4368}, mesh = {Humans ; *Gastrostomy/psychology ; Quality of Life ; Enteral Nutrition ; Palliative Care/psychology ; *Motor Neuron Disease/complications/therapy/psychology ; }, abstract = {NICE (National Institute for Health &amp; Care Excellence) guidance recommends that healthcare professionals with expertise in palliative care should be an integral part of the multidisciplinary team in managing patients with motor neuron disease (MND). Those in the poorest prognostic group may benefit from early referral to help manage rapidly progressive symptoms, psychological distress and offer additional support with complex decision-making and early robust advance care planning. Patients frequently develop dysphagia and gastrostomy feeding can be used to prolong survival and improve quality of life. As the disease progresses patients may request withdrawal of life-sustaining treatment such as gastrostomy feeding; however, a literature search found no evidence or guidance on how best to facilitate this. We present the case of a patient with MND admitted to the hospice inpatient unit requesting withdrawal of gastrostomy feeding, outline the challenges and need for further consensus guidelines to inform practice.}, }
@article {pmid32709255, year = {2020}, author = {Briese, M and Saal-Bauernschubert, L and Lüningschrör, P and Moradi, M and Dombert, B and Surrey, V and Appenzeller, S and Deng, C and Jablonka, S and Sendtner, M}, title = {Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function.}, journal = {Acta neuropathologica communications}, volume = {8}, number = {1}, pages = {116}, pmid = {32709255}, issn = {2051-5960}, mesh = {Animals ; Axons/*metabolism ; DNA-Binding Proteins/*metabolism ; Energy Metabolism ; Mice ; Mitochondria/*metabolism ; Motor Neurons/*metabolism ; Protein Biosynthesis ; TDP-43 Proteinopathies/metabolism ; Transcriptome ; }, abstract = {Protein inclusions containing the RNA-binding protein TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis and other neurodegenerative disorders. The loss of TDP-43 function that is associated with these inclusions affects post-transcriptional processing of RNAs in multiple ways including pre-mRNA splicing, nucleocytoplasmic transport, modulation of mRNA stability and translation. In contrast, less is known about the role of TDP-43 in axonal RNA metabolism in motoneurons. Here we show that depletion of Tdp-43 in primary motoneurons affects axon growth. This defect is accompanied by subcellular transcriptome alterations in the axonal and somatodendritic compartment. The axonal localization of transcripts encoding components of the cytoskeleton, the translational machinery and transcripts involved in mitochondrial energy metabolism were particularly affected by loss of Tdp-43. Accordingly, we observed reduced protein synthesis and disturbed mitochondrial functions in axons of Tdp-43-depleted motoneurons. Treatment with nicotinamide rescued the axon growth defect associated with loss of Tdp-43. These results show that Tdp-43 depletion in motoneurons affects several pathways integral to axon health indicating that loss of TDP-43 function could thus make a major contribution to axonal pathomechanisms in ALS.}, }
@article {pmid32708926, year = {2020}, author = {Scuderi, SA and Ardizzone, A and Paterniti, I and Esposito, E and Campolo, M}, title = {Antioxidant and Anti-inflammatory Effect of Nrf2 Inducer Dimethyl Fumarate in Neurodegenerative Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {7}, pages = {}, pmid = {32708926}, issn = {2076-3921}, abstract = {Neurodegenerative diseases (NDs) represents debilitating conditions characterized by degeneration of neuronal cells in specific brain areas, causing disability and death in patients. In the pathophysiology of NDs, oxidative stress, apoptosis and neuroinflammation have a key role, as demonstrated by in vivo and in vitro models. Therefore, the use of molecules with antioxidant and anti-inflammatory activities represents a possible strategy for the treatment of NDs. Many studies demonstrated the beneficial effects of fumaric acid esters (FAEs) to counteract neuroinflammation and oxidative stress. Among these molecules, dimethyl fumarate (DMF) showed a valid therapeutic approach to slow down neurodegeneration and relieve symptoms in patients with NDs. DMF is a methyl ester of fumaric acid and acts as modulator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation. Therefore, this review aims to examine the potential beneficial effects of DMF to counteract oxidative stress and inflammation in patients with NDs.}, }
@article {pmid32708667, year = {2020}, author = {Liu, Z and Chen, X and Li, Z and Ye, W and Ding, H and Li, P and Aung, LHH}, title = {Role of RNA Oxidation in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {21}, number = {14}, pages = {}, pmid = {32708667}, issn = {1422-0067}, support = {91849209; 81850410551//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Cell Death ; Humans ; Neurodegenerative Diseases/*metabolism ; Oxidation-Reduction ; *Oxidative Stress ; RNA/*metabolism ; }, abstract = {In the history of nucleic acid research, DNA has always been the main research focus. After the sketch of the human genome was completed in 2000, RNA has been started to gain more attention due to its abundancies in the cell and its essential role in cellular physiology and pathologies. Recent studies have shown that RNAs are susceptible to oxidative damage and oxidized RNA is able to break the RNA strand, and affect the protein synthesis, which can lead to cell degradation and cell death. Studies have shown that RNA oxidation is one of the early events in the formation and development of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. However, its molecular mechanism, as well as its impact on these diseases, are still unclear. In this article, we review the different types of RNA oxidative damage and the neurodegenerative diseases that are reported to be associated with RNA oxidative damage. In addition, we discuss recent findings on the association between RNA oxidative damage and the development of neurodegenerative diseases, which will have great significance for the development of novel strategies for the prevention and treatment of these diseases.}, }
@article {pmid32707914, year = {2020}, author = {Mignani, S and Majoral, JP and Desaphy, JF and Lentini, G}, title = {From Riluzole to Dexpramipexole via Substituted-Benzothiazole Derivatives for Amyotrophic Lateral Sclerosis Disease Treatment: Case Studies.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {15}, pages = {}, pmid = {32707914}, issn = {1420-3049}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Benzothiazoles/*chemical synthesis/chemistry/pharmacology ; Clinical Trials as Topic ; Drug Approval ; Drug Evaluation, Preclinical ; Humans ; Neuroprotective Agents/*chemical synthesis/pharmacology ; Pramipexole/*chemistry ; Riluzole/*chemistry ; Small Molecule Libraries/chemical synthesis/pharmacology ; Toluene/analogs &amp; derivatives/chemistry ; Treatment Outcome ; }, abstract = {The 1,3-benzothiazole (BTZ) ring may offer a valid option for scaffold-hopping from indole derivatives. Several BTZs have clinically relevant roles, mainly as CNS medicines and diagnostic agents, with riluzole being one of the most famous examples. Riluzole is currently the only approved drug to treat amyotrophic lateral sclerosis (ALS) but its efficacy is marginal. Several clinical studies have demonstrated only limited improvements in survival, without benefits to motor function in patients with ALS. Despite significant clinical trial efforts to understand the genetic, epigenetic, and molecular pathways linked to ALS pathophysiology, therapeutic translation has remained disappointingly slow, probably due to the complexity and the heterogeneity of this disease. Many other drugs to tackle ALS have been tested for 20 years without any success. Dexpramipexole is a BTZ structural analog of riluzole and was a great hope for the treatment of ALS. In this review, as an interesting case study in the development of a new medicine to treat ALS, we present the strategy of the development of dexpramipexole, which was one of the most promising drugs against ALS.}, }
@article {pmid32703476, year = {2020}, author = {Katzberg, HD}, title = {Case Studies in Management of Muscle Cramps.}, journal = {Neurologic clinics}, volume = {38}, number = {3}, pages = {679-696}, doi = {10.1016/j.ncl.2020.03.011}, pmid = {32703476}, issn = {1557-9875}, mesh = {Adult ; *Disease Management ; Female ; Humans ; Male ; Mexiletine/therapeutic use ; Middle Aged ; Muscle Cramp/*diagnosis/physiopathology/*therapy ; Pregnancy ; Voltage-Gated Sodium Channel Blockers/therapeutic use ; Young Adult ; }, abstract = {Muscle cramps, defined as a painful contraction of a muscle or muscle group, are a common symptom most people have experienced throughout their lifespan. In some cases cramps can be frequent, severe, and disabling, thus requiring medical assessment and intervention. Physiologic states such as pregnancy and exercise are associated with excessive muscle cramps, as are numerous medical and neurologic conditions, medications such as diuretics and statins, and peripheral nerve hyperexcitability syndromes. Treatment options for muscle cramps are limited, although recent studies have shown that mexiletine could be a safe and efficient alternative for patients with amyotrophic lateral sclerosis.}, }
@article {pmid32696574, year = {2020}, author = {Khosla, R and Rain, M and Chawathey, S and Modgil, S and Tyagi, R and Thakur, K and Pannu, V and Sharma, SK and Anand, A}, title = {Identifying putative cerebrospinal fluid biomarkers of amyotrophic lateral sclerosis in a north Indian population.}, journal = {Muscle &amp; nerve}, volume = {62}, number = {4}, pages = {528-533}, doi = {10.1002/mus.27026}, pmid = {32696574}, issn = {1097-4598}, support = {5/4-5/122Neuro/2013-NCD-I//Indian Council of Medical Research/International ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/*diagnosis ; Biomarkers/cerebrospinal fluid ; Case-Control Studies ; Cell Cycle Proteins/*cerebrospinal fluid ; Chemokine CCL2/*cerebrospinal fluid ; DNA-Binding Proteins/*cerebrospinal fluid ; Female ; Humans ; India ; Male ; Membrane Transport Proteins/*cerebrospinal fluid ; Middle Aged ; Ribonuclease, Pancreatic/*cerebrospinal fluid ; Vascular Endothelial Growth Factor A/*cerebrospinal fluid ; Vascular Endothelial Growth Factor Receptor-2/*cerebrospinal fluid ; }, abstract = {INTRODUCTION: Evidence-based information about cerebrospinal fluid (CSF) levels of biomarkers in patients with amyotrophic lateral sclerosis (ALS) is limited.<br><br>METHODS: Vascular endothelial growth factor (VEGF) and its receptor vascular endothelial growth factor receptor 2 (VEGFR2), optineurin (OPTN), monocyte chemoattractant protein-1 (MCP-1), angiogenin (ANG), and TAR DNA-binding protein (TDP-43) were quantified by enzyme-linked immunoassay in the CSF of 54 patients with sporadic ALS and 32 controls in a case-control study design.<br><br>RESULTS: CSF levels of VEGF (P = .014) and ANG (P = .009) were decreased, whereas VEGFR2 was higher (P = .002) in patients with ALS than in controls. TDP-43 positively correlated with MCP-1 (P = .003), VEGF (P&#x2009;<&#x2009;.001), and VEGFR2 (P&#x2009;<&#x2009;.001) in patients with ALS.<br><br>DISCUSSION: Our findings suggest possible utility of VEGF, VEGFR2, and ANG as biomarkers for use in ALS treatment trials.}, }
@article {pmid32691043, year = {2020}, author = {Arenas, A and Chen, J and Kuang, L and Barnett, KR and Kasarskis, EJ and Gal, J and Zhu, H}, title = {Lysine acetylation regulates the RNA binding, subcellular localization and inclusion formation of FUS.}, journal = {Human molecular genetics}, volume = {29}, number = {16}, pages = {2684-2697}, pmid = {32691043}, issn = {1460-2083}, support = {R01 NS115507/NS/NINDS NIH HHS/United States ; R01 NS077284/NS/NINDS NIH HHS/United States ; R21 NS095299/NS/NINDS NIH HHS/United States ; R01 GM129325/GM/NIGMS NIH HHS/United States ; T32 ES007266/ES/NIEHS NIH HHS/United States ; S10 RR029127/RR/NCRR NIH HHS/United States ; I01 BX002149/BX/BLRD VA/United States ; IS1 BX003561/BX/BLRD VA/United States ; }, mesh = {Acetylation/drug effects ; Adult ; Amyotrophic Lateral Sclerosis/*genetics/pathology ; Female ; Frontotemporal Dementia/*genetics/pathology ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/genetics ; Humans ; Lysine/genetics ; Male ; Middle Aged ; Nuclear Localization Signals/genetics ; Protein Domains/genetics ; RNA-Binding Protein FUS/*genetics ; RNA-Binding Proteins/genetics ; Sirtuins/genetics ; Young Adult ; beta Karyopherins/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the preferential death of motor neurons. Approximately 10% of ALS cases are familial and 90% are sporadic. Fused in sarcoma (FUS) is a ubiquitously expressed RNA-binding protein implicated in familial ALS and frontotemporal dementia (FTD). The physiological function and pathological mechanism of FUS are not well understood, particularly whether post-translational modifications play a role in regulating FUS function. In this study, we discovered that FUS was acetylated at lysine-315/316 (K315/K316) and lysine-510 (K510) residues in two distinct domains. Located in the nuclear localization sequence, K510 acetylation disrupted the interaction between FUS and Transportin-1, resulting in the mislocalization of FUS in the cytoplasm and formation of stress granule-like inclusions. Located in the RNA recognition motif, K315/K316 acetylation reduced RNA binding to FUS and decreased the formation of cytoplasmic inclusions. Treatment with deacetylase inhibitors also significantly reduced the inclusion formation in cells expressing ALS mutation P525L. More interestingly, familial ALS patient fibroblasts showed higher levels of FUS K510 acetylation as compared with healthy controls. Lastly, CREB-binding protein/p300 acetylated FUS, whereas both sirtuins and histone deacetylases families of lysine deacetylases contributed to FUS deacetylation. These findings demonstrate that FUS acetylation regulates the RNA binding, subcellular localization and inclusion formation of FUS, implicating a potential role of acetylation in the pathophysiological process leading to FUS-mediated ALS/FTD.}, }
@article {pmid32682829, year = {2020}, author = {van Onselen, R and Scott, LL and Downing, TG}, title = {Evaluating amino acids as protectants against β-N-methylamino-l-alanine-induced developmental neurotoxicity in a rat model.}, journal = {Toxicology and applied pharmacology}, volume = {403}, number = {}, pages = {115140}, doi = {10.1016/j.taap.2020.115140}, pmid = {32682829}, issn = {1096-0333}, mesh = {Amino Acids/*pharmacology ; Amino Acids, Diamino/*toxicity ; Animals ; Behavior, Animal/drug effects ; Central Nervous System Diseases/*chemically induced ; Cyanobacteria Toxins ; Female ; Maze Learning/drug effects ; Pregnancy ; Prenatal Exposure Delayed Effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {With accumulating evidence that supports the role of β-N-methylamino-l-alanine (BMAA) in neurodegeneration, it is necessary to elucidate the mechanisms and modes of BMAA toxicity so as to facilitate the search for potential preventative/therapeutic strategies. Daily supplementation with l-serine was suggested as a possible therapy to treat BMAA-induced neurotoxicity, based on the hypothesized mechanism of BMAA misincorporation into proteins for l-serine. As an alternative to misincorporation, it was hypothesized that BMAA toxicity may, in part, be due to its high affinity for associating with hydroxyl group-containing amino acids, and that a dietary excess of the hydroxyl-containing l-serine might offer protection by binding to BMAA and reducing its toxicity. Additionally, l-serine can also reduce the uptake of BMAA into human cells by competitive uptake at ASCT2, and l-phenylalanine, by competitive uptake at LAT1, and l-alanine, by competitive uptake at SNAT2, can also reduce BMAA uptake into human cells. The aim of this study was therefore to determine the protective value of l-serine, l-phenylalanine and l-alanine in reducing the effects of neonatal exposure to BMAA in a Sprague Dawley rat model. Pre-treatment with l-phenylalanine reduced the observed behavioral abnormalities and neuropathologies by 60-70% in most cases. l-serine was also effective in reducing some of the behavioral abnormalities and neuropathologies, most markedly spinal cord neuronal loss. However, the protective effect of l-serine was obfuscated by neuropathies that were observed in l-serine-treated control male rats. l-alanine had no effect in protecting against BMAA-induced neurotoxicity, suggesting that competitive amino acid uptake plays a minor role in protecting against BMAA-induced neurotoxicity.}, }
@article {pmid32676989, year = {2020}, author = {Lee, JD and McDonald, TS and Fung, JNT and Woodruff, TM}, title = {Absence of Receptor for Advanced Glycation End Product (RAGE) Reduces Inflammation and Extends Survival in the hSOD1[G93A] Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {57}, number = {10}, pages = {4143-4155}, doi = {10.1007/s12035-020-02019-9}, pmid = {32676989}, issn = {1559-1182}, support = {APP1082271//National Health and Medical Research Council/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Astrocytes/pathology ; Biomarkers/metabolism ; Cytokines/metabolism ; DNA-Binding Proteins/metabolism ; Denervation ; Disease Models, Animal ; Disease Progression ; Gene Deletion ; Hand Strength ; Hindlimb/physiopathology ; Inflammation/*pathology ; Macrophages/pathology ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/pathology ; Muscles/innervation/pathology ; RNA, Messenger/genetics/metabolism ; Receptor for Advanced Glycation End Products/*deficiency/genetics/metabolism ; Rotarod Performance Test ; Severity of Illness Index ; Spinal Cord/pathology ; Superoxide Dismutase-1/*genetics ; Survival Analysis ; Up-Regulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron degenerative disease that is without effective treatment. The receptor for advanced glycation end products (RAGE) is a major component of the innate immune system that has been implicated in ALS pathogenesis. However, the contribution of RAGE signalling to the neuroinflammation that underlies ALS neurodegeneration remains unknown. The present study therefore generated SOD1[G93A] mice lacking RAGE and compared them with SOD1[G93A] transgenic ALS mice in respect to disease progression (i.e. body weight, survival and muscle strength), neuroinflammation and denervation markers in the spinal cord and tibialis anterior muscle. We found that complete absence of RAGE signalling exerted a protective effect on SOD1[G93A] pathology, slowing disease progression and significantly extending survival by ~ 3 weeks and improving motor function (rotarod and grip strength). This was associated with reduced microgliosis, cytokines, innate immune factors (complement, TLRs, inflammasomes), and oxidative stress in the spinal cord, and a reduction of denervation markers in the tibialis anterior muscle. We also documented that RAGE mRNA expression was significantly increased in the spinal cord and muscles of preclinical SOD1 and TDP43 models of ALS, supporting a widespread involvement for RAGE in ALS pathology. In summary, our results indicate that RAGE signalling drives neuroinflammation and contributes to neurodegeneration in ALS and highlights RAGE as a potential immune therapeutic target for ALS.}, }
@article {pmid32661089, year = {2020}, author = {San Gil, R and Cox, D and McAlary, L and Berg, T and Walker, AK and Yerbury, JJ and Ooi, L and Ecroyd, H}, title = {Neurodegenerative disease-associated protein aggregates are poor inducers of the heat shock response in neuronal cells.}, journal = {Journal of cell science}, volume = {133}, number = {15}, pages = {}, doi = {10.1242/jcs.243709}, pmid = {32661089}, issn = {1477-9137}, mesh = {Heat Shock Transcription Factors/genetics ; Heat-Shock Response/genetics ; Humans ; *Neurodegenerative Diseases/genetics ; Protein Aggregates ; Superoxide Dismutase-1 ; }, abstract = {Protein aggregates that result in inclusion formation are a pathological hallmark common to many neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease. Under conditions of cellular stress, activation of the heat shock response (HSR) results in an increase in the levels of molecular chaperones and is a first line of cellular defence against inclusion formation. It remains to be established whether neurodegenerative disease-associated proteins and inclusions are themselves capable of inducing an HSR in neuronal cells. To address this, we generated a neuroblastoma cell line that expresses a fluorescent reporter protein under conditions of heat shock transcription factor 1 (HSF1)-mediated HSR induction. We show that the HSR is not induced by exogenous treatment with aggregated forms of recombinant α-synuclein or the G93A mutant of superoxide dismutase-1 (SOD1[G93A]) nor intracellular expression of SOD1[G93A] or a pathogenic form of polyglutamine-expanded huntingtin (Htt[72Q]). These results suggest that pathogenic proteins evade detection or impair induction of the HSR in neuronal cells. A failure of protein aggregation to induce an HSR might contribute to the development of inclusion pathology in neurodegenerative diseases.This article has an associated First Person interview with the first author of the paper.}, }
@article {pmid32657152, year = {2021}, author = {Zarotti, N and Mayberry, E and Ovaska-Stafford, N and Eccles, F and Simpson, J}, title = {Psychological interventions for people with motor neuron disease: a scoping review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {22}, number = {1-2}, pages = {1-11}, doi = {10.1080/21678421.2020.1788094}, pmid = {32657152}, issn = {2167-9223}, mesh = {Adaptation, Psychological ; *Amyotrophic Lateral Sclerosis ; *Cognitive Behavioral Therapy ; Humans ; *Motor Neuron Disease/therapy ; Psychosocial Intervention ; }, abstract = {Motor neuron disease (MND) is a rapidly progressive neurodegenerative condition with no known cure. MND can affect every aspect of a person's life and has been associated with a wide range of psychological difficulties, which can occur from pre-diagnosis through to the condition's later stages. However, very little research has been conducted on psychological interventions for people with MND (pwMND). This paper aimed to provide the first review specifically targeting psychological interventions in MND and offer potential directions for future research. Methods: A scoping review was carried out across five major databases (PubMed, PsycINFO, CINAHL, Academic Search Ultimate, and Cochrane Library) until 1st of March 2020. Results: From an initial return of 1278 citations, 10 papers were included in the review. These included three randomized controlled trials (RCTs), two quasi-experiments, three uncontrolled pretest-post-test designs, one single case study, and one qualitative secondary analysis. The existing studies focused on a limited number of psychological outcomes and did not take into account site of MND onset or level of depression/anxiety before intervention. Implications for clinical practice are discussed and suggestions for future research are provided. Conclusions: The literature on psychological interventions is still extremely sparse. Mindfulness-based stress reduction (MBSR) and cognitive behavioral therapy (CBT) based on the stress-coping model show promise in RCTs, but require further evaluation. The need for further development and evaluation of psychological interventions to improve the well-being of pwMND cannot be overstated, particularly as the struggle toward the discovery of an effective treatment for MND continues.}, }
@article {pmid32654149, year = {2021}, author = {Clark, CM and Clark, RM and Hoyle, JA and Dickson, TC}, title = {Pathogenic or protective? Neuropeptide Y in amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {156}, number = {3}, pages = {273-289}, doi = {10.1111/jnc.15125}, pmid = {32654149}, issn = {1471-4159}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Humans ; Neuropeptide Y/*metabolism ; Receptors, Neuropeptide Y/metabolism ; }, abstract = {Neuropeptide Y (NPY) is an endogenous peptide of the central and enteric nervous systems which has gained significant interest as a potential neuroprotective agent for treatment of neurodegenerative disease. Amyotrophic lateral sclerosis (ALS) is an aggressive and fatal neurodegenerative disease characterized by motor deficits and motor neuron loss. In ALS, recent evidence from ALS patients and animal models has indicated that NPY may have a role in the disease pathogenesis. Increased NPY levels were found to correlate with disease progression in ALS patients. Similarly, NPY expression is increased in the motor cortex of ALS mice by end stages of the disease. Although the functional consequence of increased NPY levels in ALS is currently unknown, NPY has been shown to exert a diverse range of neuroprotective roles in other neurodegenerative diseases; through modulation of potassium channel activity, increased production of neurotrophins, inhibition of endoplasmic reticulum stress and autophagy, reduction of excitotoxicity, oxidative stress, neuroinflammation and hyperexcitability. Several of these mechanisms and signalling pathways are heavily implicated in the pathogenesis of ALS. Therefore, in this review, we discuss possible effects of NPY and NPY-receptor signalling in the ALS disease context, as determining NPY's contribution to, or impact on, ALS disease mechanisms will be essential for future studies investigating the NPY system as a therapeutic strategy in this devastating disease.}, }
@article {pmid32651875, year = {2021}, author = {Ismail, II and Massoud, F and Kamel, WA and Al-Hashel, JY}, title = {Evaluation of clinical outcome and safety profile of edaravone in treatment of amyotrophic lateral sclerosis: a 72-week single-center experience.}, journal = {Acta neurologica Belgica}, volume = {121}, number = {6}, pages = {1591-1597}, pmid = {32651875}, issn = {2240-2993}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/*epidemiology ; Cohort Studies ; Edaravone/*therapeutic use ; Female ; Follow-Up Studies ; Free Radical Scavengers/*therapeutic use ; Humans ; Kuwait/epidemiology ; Male ; Middle Aged ; Neuroprotective Agents/therapeutic use ; Prospective Studies ; Time Factors ; Treatment Outcome ; }, abstract = {Edaravone is a free radical scavenger that has been recently approved for treatment of Amyotrophic lateral sclerosis (ALS) to delay functional decline. We aim to evaluate edaravone efficacy and safety in ALS patients in the main neurology tertiary center in Kuwait over 72-week period. We conducted a prospective observational cohort study in the main tertiary hospital over 72-week period from July 2018 until January 2020. Patients were assessed at baseline, 24, 48 and 72 weeks of therapy using ALSFRS-R score, MRC sum score, FVC value, among other parameters. Seventeen consecutive patients were evaluated. All patients were assessed at baseline, 24 and 48 weeks, while 9 patients (52.9%) were further assessed at 72 weeks. There was a statistically significant decline of ALSFRS-R at 72 weeks, MRC sum score at 48 and 72 weeks, while the decline in FVC was not statistically significant. Glycosuria was found in only one patient. Our study showed significant functional decline after 1 year of edaravone therapy with preserved respiratory function. The drug had a high level of dissatisfaction among our cohort despite having a high safety profile.}, }
@article {pmid32651161, year = {2020}, author = {Camu, W and Mickunas, M and Veyrune, JL and Payan, C and Garlanda, C and Locati, M and Juntas-Morales, R and Pageot, N and Malaspina, A and Andreasson, U and Kirby, J and Suehs, C and Saker, S and Masseguin, C and De Vos, J and Zetterberg, H and Shaw, PJ and Al-Chalabi, A and Leigh, PN and Tree, T and Bensimon, G}, title = {Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial.}, journal = {EBioMedicine}, volume = {59}, number = {}, pages = {102844}, pmid = {32651161}, issn = {2352-3964}, support = {ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/etiology/metabolism ; Antineoplastic Agents/*administration &amp; dosage ; Biomarkers ; Chemokines ; Cytokines ; Female ; Humans ; Immunophenotyping ; Interleukin-2/administration &amp; dosage/*analogs &amp; derivatives/metabolism ; Male ; Middle Aged ; Recombinant Proteins/administration &amp; dosage ; T-Lymphocyte Subsets/immunology/metabolism ; T-Lymphocytes, Regulatory/drug effects/immunology/metabolism ; Treatment Outcome ; }, abstract = {BACKGROUND: Low-dose interleukin-2 (ld-IL-2) enhances regulatory T-cell (Treg) function in auto-inflammatory conditions. Neuroinflammation being a pathogenic feature of amyotrophic lateral sclerosis (ALS), we evaluated the pharmacodynamics and safety of ld-IL-2 in ALS subjects.<br><br>METHODS: We performed a single centre, parallel three-arm, randomised, double-blind, placebo-controlled study. Eligibility criteria included age <&#xa0;75 years, disease duration <&#xa0;5 years, riluzole treatment >&#xa0;3 months, and a slow vital capacity &#x2265;&#xa0;70% of normal. Patients were randomised (1:1:1) to aldesleukin 2 MIU, 1 MIU, or placebo once daily for 5 days every 4 weeks for 3 cycles. Primary outcome was change from baseline in Treg percentage of CD4[+] T cells (%Tregs) following a first cycle. Secondary laboratory outcomes included: %Treg and Treg number following repeated cycles, and plasma CCL2 and neurofilament light chain protein (NFL) concentrations as surrogate markers of efficacy. Safety outcomes included motor-function (ALSFRS-R), slow vital capacity (SVC), and adverse event reports. This trial is registered with ClinicalTrials.gov, NCT02059759.<br><br>FINDINGS: All randomised patients (12 per group), recruited from October 2015 to December 2015, were alive at the end of follow-up and included in the intent-to-treat (ITT) analysis. No drug-related serious adverse event was observed. Non-serious adverse events occurred more frequently with the 1 and 2 MIU IL-2 doses compared to placebo, including injection site reactions and flu-like symptoms. Primary outcome analysis showed a significant increase (p&#xa0;<&#xa0;0&#xb7;0001) in %Tregs in the 2 MIU and 1 MIU arms (mean [SD]: 2 MIU: +6&#xb7;2% [2&#xb7;2]; 1 MIU: +3&#xb7;9% [1&#xb7;2]) as compared to placebo (mean [SD]: -0&#xb7;49% [1&#xb7;3]). Effect sizes (ES) were large in treated groups: 2 MIU ES=3&#xb7;7 (IC95%: 2&#xb7;3-4&#xb7;9) and 1 MIU ES=3&#xb7;5 (IC95%: 2&#xb7;1-4&#xb7;6). Secondary outcomes showed a significant increase in %Tregs following repeated cycles (p&#xa0;<&#xa0;0&#xb7;0001) as compared to placebo, and a dose-dependent decrease in plasma CCL2 (p&#xa0;=&#xa0;0&#xb7;0049). There were no significant differences amongst the three groups on plasma NFL levels.<br><br>INTERPRETATION: Ld-IL-2 is well tolerated and immunologically effective in subjects with ALS. These results warrant further investigation into their eventual therapeutic impact on slowing ALS disease progression.<br><br>FUNDING: The French Health Ministry (PHRC-I-14-056), EU H2020 (grant #633413), and the Association pour la Recherche sur la SLA (ARSLA).}, }
@article {pmid32645824, year = {2020}, author = {Wang, T and Zhang, J and Xu, Y}, title = {Epigenetic Basis of Lead-Induced Neurological Disorders.}, journal = {International journal of environmental research and public health}, volume = {17}, number = {13}, pages = {}, pmid = {32645824}, issn = {1660-4601}, mesh = {*Alzheimer Disease ; Animals ; DNA/*genetics ; DNA Methylation/drug effects ; Epigenesis, Genetic ; Histone Deacetylase Inhibitors ; Lead/*adverse effects ; Nervous System Diseases/*chemically induced/genetics ; Neurodegenerative Diseases/genetics ; }, abstract = {Environmental lead (Pb) exposure is closely associated with pathogenesis of a range of neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), attention deficit/hyperactivity disorder (ADHD), etc. Epigenetic machinery modulates neural development and activities, while faulty epigenetic regulation contributes to the diverse forms of CNS (central nervous system) abnormalities and diseases. As a potent epigenetic modifier, lead is thought to cause neurological disorders through modulating epigenetic mechanisms. Specifically, increasing evidence linked aberrant DNA methylations, histone modifications as well as ncRNAs (non-coding RNAs) with AD cases, among which circRNA (circular RNA) stands out as a new and promising field for association studies. In 23-year-old primates with developmental lead treatment, Zawia group discovered a variety of epigenetic changes relating to AD pathogenesis. This is a direct evidence implicating epigenetic basis in lead-induced AD animals with an entire lifespan. Additionally, some epigenetic molecules associated with AD etiology were also known to respond to chronic lead exposure in comparable disease models, indicating potentially interlaced mechanisms with respect to the studied neurotoxic and pathological events. Of note, epigenetic molecules acted via globally or selectively influencing the expression of disease-related genes. Compared to AD, the association of lead exposure with other neurological disorders were primarily supported by epidemiological survey, with fewer reports connecting epigenetic regulators with lead-induced pathogenesis. Some pharmaceuticals, such as HDAC (histone deacetylase) inhibitors and DNA methylation inhibitors, were developed to deal with CNS disease by targeting epigenetic components. Still, understandings are insufficient regarding the cause-consequence relations of epigenetic factors and neurological illness. Therefore, clear evidence should be provided in future investigations to address detailed roles of novel epigenetic factors in lead-induced neurological disorders, and efforts of developing specific epigenetic therapeutics should be appraised.}, }
@article {pmid32643415, year = {2020}, author = {van Eijk, RPA and Kliest, T and McDermott, CJ and Roes, KCB and Van Damme, P and Chio, A and Weber, M and Ingre, C and Corcia, P and Povedano, M and Reviers, E and van Es, MA and Al-Chalabi, A and Hardiman, O and van den Berg, LH}, title = {TRICALS: creating a highway toward a cure.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {7-8}, pages = {496-501}, doi = {10.1080/21678421.2020.1788092}, pmid = {32643415}, issn = {2167-9223}, support = {ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Biomarkers ; Humans ; Patient Selection ; Treatment Outcome ; }, abstract = {A change in our current approach toward drug development is required to improve the likelihood of finding effective treatment for patients with amyotrophic lateral sclerosis (ALS). The aim of the Treatment Research Initiative to Cure ALS (TRICALS) is to extend the collective effort with industry and consolidate drug development paths. TRICALS has begun a series of meetings on how to best move the field forward collaboratively, thereby addressing five major topics in ALS clinical trials: (1) preclinical research, (2) biomarker development, (3) eligibility criteria, (4) efficacy endpoints and (5) innovative trial design. There is an appetite for ongoing discussions of these major topics in clinical trials between representatives from academia, patient advocacy groups, industry partners and funding bodies. Industry is open to fundamentally change drug development for ALS and shorten the time to effective therapy for patients by implementing promising innovations in biomarker development, trial design, and patient selection. There is however, a pressing need from all stakeholders for regulatory discussions and amendments of current guidelines to successfully adopt innovation in future clinical development lines.}, }
@article {pmid32640422, year = {2020}, author = {Wilkins, JM and Gakh, O and Kabiraj, P and McCarthy, CB and Tobin, WO and Howe, CL and Lucchinetti, CF}, title = {Signatures of cell stress and altered bioenergetics in skin fibroblasts from patients with multiple sclerosis.}, journal = {Aging}, volume = {12}, number = {14}, pages = {15134-15156}, pmid = {32640422}, issn = {1945-4589}, mesh = {Activating Transcription Factor 4/*metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Biological Variation, Population ; *Endoplasmic Reticulum/metabolism/pathology ; Energy Metabolism/physiology ; Female ; Fibroblasts/*metabolism ; Gene Expression Profiling ; Humans ; Male ; Membrane Glycoproteins/*metabolism ; Middle Aged ; Mitochondrial Diseases/metabolism ; *Multiple Sclerosis/metabolism/pathology ; Precision Medicine ; Skin/pathology ; Transcription Factor CHOP/*metabolism ; }, abstract = {Multiple sclerosis (MS) is a central nervous system inflammatory demyelinating disease and the most common cause of non-traumatic disability in young adults. Despite progress in the treatment of the active relapsing disease, therapeutic options targeting irreversible progressive decline remain limited. Studies using skin fibroblasts derived from patients with neurodegenerative disorders demonstrate that cell stress pathways and bioenergetics are altered when compared to healthy individuals. However, findings in MS skin fibroblasts are limited. Here, we collected skin fibroblasts from 24 healthy control individuals, 30 patients with MS, and ten with amyotrophic lateral sclerosis (ALS) to investigate altered cell stress profiles. We observed endoplasmic reticulum swelling in MS skin fibroblasts, and increased gene expression of cell stress markers including BIP, ATF4, CHOP, GRP94, P53, and P21. When challenged against hydrogen peroxide, MS skin fibroblasts had reduced resiliency compared to ALS and controls. Mitochondrial and glycolytic functions were perturbed in MS skin fibroblasts while exhibiting a significant increase in lactate production over ALS and controls. Our results suggest that MS skin fibroblasts have an underlying stress phenotype, which may be disease specific. Interrogating MS skin fibroblasts may provide patient specific molecular insights and aid in prognosis, diagnosis, and therapeutic testing enhancing individualized medicine.}, }
@article {pmid32640133, year = {2020}, author = {Mueller, C and Berry, JD and McKenna-Yasek, DM and Gernoux, G and Owegi, MA and Pothier, LM and Douthwright, CL and Gelevski, D and Luppino, SD and Blackwood, M and Wightman, NS and Oakley, DH and Frosch, MP and Flotte, TR and Cudkowicz, ME and Brown, RH}, title = {SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS.}, journal = {The New England journal of medicine}, volume = {383}, number = {2}, pages = {151-158}, pmid = {32640133}, issn = {1533-4406}, support = {P30 AG062421/AG/NIA NIH HHS/United States ; P50 AG005134/AG/NIA NIH HHS/United States ; R01 NS111990/NS/NINDS NIH HHS/United States ; R01 NS088698/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/cerebrospinal fluid/genetics/*therapy ; Dependovirus ; Fatal Outcome ; Gene Silencing ; Genetic Therapy ; Genetic Vectors ; Humans ; Injections, Spinal ; Male ; Meningoencephalitis ; MicroRNAs/*therapeutic use ; Middle Aged ; Mutation ; Proof of Concept Study ; Spinal Cord/chemistry/pathology ; Superoxide Dismutase-1/analysis/*cerebrospinal fluid/genetics ; Vital Capacity ; Young Adult ; }, abstract = {Two patients with familial amyotrophic lateral sclerosis (ALS) and mutations in the gene encoding superoxide dismutase 1 (SOD1) were treated with a single intrathecal infusion of adeno-associated virus encoding a microRNA targeting SOD1. In Patient 1, SOD1 levels in spinal cord tissue as analyzed on autopsy were lower than corresponding levels in untreated patients with SOD1-mediated ALS and in healthy controls. Levels of SOD1 in cerebrospinal fluid were transiently and only slightly lower in Patient 1 but were not affected in Patient 2. In Patient 1, meningoradiculitis developed after the infusion; Patient 2 was pretreated with immunosuppressive drugs and did not have this complication. Patient 1 had transient improvement in the strength of his right leg, a measure that had been relatively stable throughout his disease course, but there was no change in his vital capacity. Patient 2 had stable scores on a composite measure of ALS function and a stable vital capacity during a 12-month period. This study showed that intrathecal microRNA can be used as a potential treatment for SOD1-mediated ALS.}, }
@article {pmid32640130, year = {2020}, author = {Miller, T and Cudkowicz, M and Shaw, PJ and Andersen, PM and Atassi, N and Bucelli, RC and Genge, A and Glass, J and Ladha, S and Ludolph, AL and Maragakis, NJ and McDermott, CJ and Pestronk, A and Ravits, J and Salachas, F and Trudell, R and Van Damme, P and Zinman, L and Bennett, CF and Lane, R and Sandrock, A and Runz, H and Graham, D and Houshyar, H and McCampbell, A and Nestorov, I and Chang, I and McNeill, M and Fanning, L and Fradette, S and Ferguson, TA}, title = {Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.}, journal = {The New England journal of medicine}, volume = {383}, number = {2}, pages = {109-119}, doi = {10.1056/NEJMoa2003715}, pmid = {32640130}, issn = {1533-4406}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/*drug therapy/genetics ; Disease Progression ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Headache/chemically induced ; Humans ; Injections, Spinal/adverse effects ; Intermediate Filaments ; Leukocytosis/chemically induced ; Male ; Middle Aged ; Mutation ; Oligonucleotides/*administration &amp; dosage/adverse effects/pharmacokinetics ; Oligonucleotides, Antisense/*administration &amp; dosage/adverse effects/pharmacokinetics ; Superoxide Dismutase-1/*cerebrospinal fluid/genetics ; Vital Capacity ; }, abstract = {BACKGROUND: Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations.<br><br>METHODS: We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured.<br><br>RESULTS: A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose.<br><br>CONCLUSIONS: In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.).}, }
@article {pmid32638706, year = {2020}, author = {Masoudi Asil, S and Ahlawat, J and Guillama Barroso, G and Narayan, M}, title = {Nanomaterial based drug delivery systems for the treatment of neurodegenerative diseases.}, journal = {Biomaterials science}, volume = {8}, number = {15}, pages = {4109-4128}, pmid = {32638706}, issn = {2047-4849}, support = {R16 GM145575/GM/NIGMS NIH HHS/United States ; SC3 GM111200/GM/NIGMS NIH HHS/United States ; }, mesh = {Aged ; Blood-Brain Barrier ; Drug Delivery Systems ; Humans ; *Nanoparticles ; Nanotechnology ; *Neurodegenerative Diseases/drug therapy ; }, abstract = {With an aging population that has been increasing in recent years, the need for the development of therapeutic approaches for treatment of neurodegenerative disorders (ND) has increased. ND, which are characterized by the progressive loss of the structure or function of neurons, are often associated with neuronal death. In spite of screening numerous drugs, currently there is no specific treatment that can cure these diseases or slow down their progression. Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Huntington's disease, and prion diseases belong to ND which affect enormous numbers of people globally. There are some main possible reasons for failure in the treatment of neurodegenerative diseases such as limitations introduced by the Blood-Brain Barrier (BBB), the Blood-Cerebrospinal Fluid Barrier (BCFB) and P-glycoproteins. Current advances in nanotechnology present opportunities to overcome the mentioned limitations by using nanotechnology and designing nanomaterials improving the delivery of active drug candidates. Some of the basic and developing strategies to overcome drug delivery impediments are the local delivery of drugs, receptor-mediated transcytosis, physicochemical disruption of the BBB, cell-penetrating peptides and magnetic disruption. Recently, the application of nanoparticles has been developed to improve the efficiency of drug delivery. Nanoengineered particles as nanodrugs possess the capacity to cross the BBB and also show decreased invasiveness. Examples include inorganic, magnetic, polymeric and carbonic nanoparticles that have been developed to improve drug delivery efficiency. Despite numerous papers published in this filed, there are some unsolved issues that need to be addressed for successful treatment of neurodegenerative diseases. These are discussed herein.}, }
@article {pmid32638230, year = {2020}, author = {Termsinsuk, P and Chantarojanasiri, T and Pausawasdi, N}, title = {Diagnosis and treatment of the afferent loop syndrome.}, journal = {Clinical journal of gastroenterology}, volume = {13}, number = {5}, pages = {660-668}, doi = {10.1007/s12328-020-01170-z}, pmid = {32638230}, issn = {1865-7265}, mesh = {*Afferent Loop Syndrome/diagnostic imaging/etiology ; Dilatation ; Gastrectomy ; *Gastric Bypass ; Humans ; }, abstract = {Afferent loop syndrome (ALS) is a mechanical complication that arises after gastric surgery with gastrojejunostomy reconstruction. This condition was first described in 1950 by Roux, Pedoussaut, and Marchal to post-gastrectomy patients with bilious vomiting. Acute ALS is associated with complete obstruction and considered a surgical emergency, whereas chronic ALS is mostly related to partial obstruction of the afferent loop. The delay in diagnosis may lead to intestinal ischemia, perforation and can be associated with a high mortality rate up to 60%. Surgery is usually the mainstay treatment of ALS, but endoscopic therapy, including stent placement in malignancy-related, anastomotic stricture dilation, has been evolving over the past recent years.}, }
@article {pmid32634871, year = {2020}, author = {Yamaguchi, A and Queralt-Rosinach, N}, title = {A proof-of-concept study of extracting patient histories for rare/intractable diseases from social media.}, journal = {Genomics &amp; informatics}, volume = {18}, number = {2}, pages = {e17}, pmid = {32634871}, issn = {1598-866X}, abstract = {The amount of content on social media platforms such as Twitter is expanding rapidly. Simultaneously, the lack of patient information seriously hinders the diagnosis and treatment of rare/intractable diseases. However, these patient communities are especially active on social media. Data from social media could serve as a source of patient-centric knowledge for these diseases complementary to the information collected in clinical settings and patient registries, and may also have potential for research use. To explore this question, we attempted to extract patient-centric knowledge from social media as a task for the 3-day Biomedical Linked Annotation Hackathon 6 (BLAH6). We selected amyotrophic lateral sclerosis and multiple sclerosis as use cases of rare and intractable diseases, respectively, and we extracted patient histories related to these health conditions from Twitter. Four diagnosed patients for each disease were selected. From the user timelines of these eight patients, we extracted tweets that might be related to health conditions. Based on our experiment, we show that our approach has considerable potential, although we identified problems that should be addressed in future attempts to mine information about rare/intractable diseases from Twitter.}, }
@article {pmid32628315, year = {2021}, author = {Vaca, G and Martinez-Gonzalez, L and Fernandez, A and Rojas-Prats, E and Porras, G and Cuevas, EP and Gil, C and Martinez, A and Martin-Requero, &#xc1;}, title = {Therapeutic potential of novel Cell Division Cycle Kinase 7 inhibitors on TDP-43-related pathogenesis such as Frontotemporal Lobar Degeneration (FTLD) and amyotrophic lateral sclerosis (ALS).}, journal = {Journal of neurochemistry}, volume = {156}, number = {3}, pages = {379-390}, doi = {10.1111/jnc.15118}, pmid = {32628315}, issn = {1471-4159}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*metabolism ; Cells, Cultured ; DNA-Binding Proteins/drug effects/*metabolism ; Female ; Frontotemporal Lobar Degeneration/*metabolism ; Humans ; Lymphocytes/drug effects/metabolism ; Male ; Middle Aged ; Protein Kinase Inhibitors/*pharmacology ; Protein Kinases/*metabolism ; }, abstract = {TDP-43 has been identified as the major component of protein aggregates found in affected neurons in FTLD-TDP and amyotrophic lateral sclerosis (ALS) patients. TDP-43 is hyperphosphorylated, ubiquitinated, and cleaved in the C-terminus. CDC-7 was reported to phosphorylate TDP-43. There are no effective treatments for either FTLD-TDP or ALS, being a pressing need for the search of new therapies. We hypothesized that modulating CDC-7 activity with small molecules that are able to interfere with TDP-43 phosphorylation could be a good therapeutic strategy for these diseases. Here, we have studied the effects of novel brain penetrant, thiopurine-based, CDC-7 inhibitors in TDP-43 homeostasis in immortalized lymphocytes from FTLD-TDP patients, carriers of a loss-of-function GRN mutation, as well as in cells derived from sporadic ALS patients. We found that selective CDC-7 inhibitors, ERP1.14a and ERP1.28a, are able to decrease the enhanced TDP-43 phosphorylation in cells derived from FTLD-TDP and ALS patients and to prevent cytosolic accumulation of TDP-43. Moreover, treatment of FTLD-TDP lymphoblasts with CDC-7 inhibitors leads to recovering the nuclear function of TDP-43-inducing CDK6 repression. We suggest that CDC-7 inhibitors, mainly the heterocyclic compounds here shown, may be considered as promising drug candidates for the ALS/FTD spectrum.}, }
@article {pmid32627599, year = {2020}, author = {Van Es, MA and Van Eijk, RPA and Bunte, TM and Van Den Berg, LH}, title = {A placebo-controlled trial to investigate the safety and efficacy of Penicillin G/Hydrocortisone in patients with ALS (PHALS trial).}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {7-8}, pages = {584-592}, doi = {10.1080/21678421.2020.1788093}, pmid = {32627599}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Humans ; Hydrocortisone ; Penicillin G ; Quality of Life ; }, abstract = {OBJECTIVE: A recent case-series described patients with ALS to improve and/or stabilize after treatment with intravenous high-dose Penicillin G/Hydrocortisone (PenGH). In this study, we determine the safety and efficacy of intravenous PenGH versus placebo in combination with riluzole in patients with ALS.<br><br>METHODS: Patients diagnosed with ALS according to the El Escorial criteria were randomized double-blind to four quarterly cycles of 21 d of intravenous PenGH or placebo in a 5:3 ratio. The primary outcome was change from baseline to week 48 in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). Secondary outcomes were lung function, muscle strength, plasma creatinine, clinical stage, gastrostomy placement, quality of life and occurrence of adverse of events.<br><br>RESULTS: In total, 16 patients were randomized (10 PenGH and 6 placebo), of which 6 (40%) completed the study. Patients treated with PenGH progressed with 2.2 (95% CI 1.1-3.3) ALSFRS-R points per month and PenGH treatment did not halt disease progression (p&#x2009;=&#x2009;0.002). No significant differences were found between PenGH or placebo (mean difference 0.5, 95% CI -1.01 to &#x221e;, p&#x2009;=&#x2009;0.28). Although PenGH was well-tolerated, 6 patients (38%, 3 in each arm) had thrombotic complications due to the intravenous administration method.<br><br>CONCLUSIONS: Treatment with PenGH does not halt disease or reverse progression in patients with ALS and showed no statistical difference with those who received placebo. Prolonged intravenous administration therapies may inflate thrombosis risk.}, }
@article {pmid32627229, year = {2020}, author = {Tan, HHG and Westeneng, HJ and van der Burgh, HK and van Es, MA and Bakker, LA and van Veenhuijzen, K and van Eijk, KR and van Eijk, RPA and Veldink, JH and van den Berg, LH}, title = {The Distinct Traits of the UNC13A Polymorphism in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {88}, number = {4}, pages = {796-806}, pmid = {32627229}, issn = {1531-8249}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*genetics/pathology ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Nerve Tissue Proteins/*genetics ; Phenotype ; Polymorphism, Single Nucleotide ; }, abstract = {OBJECTIVE: The rs12608932 single nucleotide polymorphism in UNC13A is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) susceptibility, and may underlie differences in treatment response. We aimed to characterize the clinical, cognitive, behavioral, and neuroimaging phenotype of UNC13A in patients with ALS.<br><br>METHODS: We included 2,216 patients with ALS without a C9orf72 mutation to identify clinical characteristics associated with the UNC13A polymorphism. A subcohort of 428 patients with ALS was used to study cognitive and behavioral profiles, and 375 patients to study neuroimaging characteristics. Associations were analyzed under an additive genetic model.<br><br>RESULTS: Genotyping rs12608932 resulted in 854 A/A, 988 A/C, and 374 C/C genotypes. The C allele was associated with a higher age at symptom onset (median years A/A 63.5, A/C 65.6, and C/C 65.5; p <&#x2009;0.001), more frequent bulbar onset (A/A 29.6%, A/C 31.8%, and C/C 43.1%; p <&#x2009;0.001), higher incidences of ALS-FTD (A/A 4.3%, A/C 5.2%, and C/C 9.5%; p =&#x2009;0.003), lower forced vital capacity at diagnosis (median percentage A/A 92.0, A/C 90.0, and C/C 86.5; p <&#x2009;0.001), and a shorter survival (median in months A/A 33.3, A.C 30.7, and C/C 26.6; p <&#x2009;0.001). UNC13A was associated with lower scores on ALS-specific cognition tests (means A/A 79.5, A/C 78.1, and C/C 76.6; p =&#x2009;0.037), and more frequent behavioral disturbances (A/A 16.7%, A/C 24.4%, and C/C 27.7%; p =&#x2009;0.045). Thinner left inferior temporal and right fusiform cortex were associated with the UNC13A single nucleotide polymorphism (SNP; p =&#x2009;0.045 and p =&#x2009;0.036).<br><br>INTERPRETATION: Phenotypical distinctions associated with UNC13A make it an important factor to take into account in clinical trial design, studies on cognition and behavior, and prognostic counseling. ANN NEUROL 2020;88:796-806.}, }
@article {pmid32625051, year = {2020}, author = {Gunes, ZI and Kan, VWY and Ye, X and Liebscher, S}, title = {Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {573}, pmid = {32625051}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the degeneration of both upper and lower motor neurons. Despite decades of research, we still to date lack a cure or disease modifying treatment, emphasizing the need for a much-improved insight into disease mechanisms and cell type vulnerability. Altered neuronal excitability is a common phenomenon reported in ALS patients, as well as in animal models of the disease, but the cellular and circuit processes involved, as well as the causal relevance of those observations to molecular alterations and final cell death, remain poorly understood. Here, we review evidence from clinical studies, cell type-specific electrophysiology, genetic manipulations and molecular characterizations in animal models and culture experiments, which argue for a causal involvement of complex alterations of structure, function and connectivity of different neuronal subtypes within the cortical and spinal cord motor circuitries. We also summarize the current knowledge regarding the detrimental role of astrocytes and reassess the frequently proposed hypothesis of glutamate-mediated excitotoxicity with respect to changes in neuronal excitability. Together, these findings suggest multifaceted cell type-, brain area- and disease stage- specific disturbances of the excitation/inhibition balance as a cardinal aspect of ALS pathophysiology.}, }
@article {pmid32621411, year = {2020}, author = {Wang, Y and Lu, Y}, title = {[Poly adenosine diphosphate-ribosylation and neurodegenerative diseases].}, journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences}, volume = {49}, number = {1}, pages = {100-106}, pmid = {32621411}, issn = {1008-9292}, mesh = {*ADP-Ribosylation ; Humans ; *Neurodegenerative Diseases/physiopathology ; *Poly Adenosine Diphosphate Ribose ; Poly(ADP-ribose) Polymerases/metabolism ; }, abstract = {The morbidity of neurodegenerative diseases are increased in recent years, however, the treatment is limited. Poly ADP-ribosylation (PARylation) is a post-translational modification of protein that catalyzed by poly(ADP-ribose) polymerase (PARP). Studies have shown that PARylation is involved in many neurodegenerative diseases such as stroke, Parkinson's diseases, Alzheimer's disease, amyotrophic lateral sclerosis and so on, by affecting intracellular translocation of protein molecules, protein aggregation, protein activity, and cell death. PARP inhibitors have showed neuroprotective efficacy for neurodegenerative diseases in pre-clinical studies and phase Ⅰ clinical trials. To find new PARP inhibitors with more specific effects and specific pharmacokinetic characteristics will be the new direction for the treatment of neurodegenerative diseases. This paper reviews the recent progress on PARylation in neurodegenerative diseases.}, }
@article {pmid32612503, year = {2020}, author = {Liu, Z and Cheng, X and Zhong, S and Zhang, X and Liu, C and Liu, F and Zhao, C}, title = {Peripheral and Central Nervous System Immune Response Crosstalk in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {575}, pmid = {32612503}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by muscle weakness due to the degeneration of the upper and lower motor neurons. Neuroinflammation is known as a prominent pathological feature of ALS. Although neuroinflammation cannot trigger ALS, activated central nervous system (CNS) microglia and astrocytes, proinflammatory periphery monocytes/macrophages and T lymphocytes, and infiltrated monocytes/macrophages and T lymphocytes, as well as the immunoreactive molecules they release, are closely related to disease progression. The crosstalk between the peripheral and CNS immune components mentioned above significantly correlates with survival in patients with ALS. This review provides an update on the role of this crosstalk between the CNS and peripheral immune responses in ALS. Additionally, we discuss changes in the composition of gut microbiota because these can directly or indirectly influence this crosstalk. These recent advances may well provide innovative ways for targeting the molecules associated with this crosstalk and breaking the current treatment impasse in ALS.}, }
@article {pmid32612057, year = {2020}, author = {Kawano, C and Isozaki, Y and Nakagawa, A and Hirayama, T and Nishiyama, K and Kuroyama, M}, title = {[Liver Injury Risk Factors in Amyotrophic Lateral Sclerosis Patients Treated with Riluzole].}, journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan}, volume = {140}, number = {7}, pages = {923-928}, doi = {10.1248/yakushi.20-00015}, pmid = {32612057}, issn = {1347-5231}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy ; Chemical and Drug Induced Liver Injury/*etiology ; Cytochrome P-450 CYP1A2 Inhibitors/adverse effects/therapeutic use ; Drug Therapy, Combination/adverse effects ; Female ; Humans ; Male ; Middle Aged ; Riluzole/*adverse effects/therapeutic use ; Risk Factors ; Smoking/adverse effects ; }, abstract = {Riluzole, a drug used in the management of amyotrophic lateral sclerosis (ALS), is associated with a high incidence of liver failure. It is imperative to determine risk factors and severity of liver injury in patients taking riluzole to devise an appropriate treatment regimen. We, therefore, studied risk factors for liver injury in ALS patients who were prescribed riluzole at Kitasato University East Hospital from 1999 to 2015. Of the 222 patients enrolled in this study, 113 and 109 patients were diagnosed with mild to moderate (grade 1 or 2) and without (grade 0) liver injury, respectively. Prediction of risk factors was determined using binary logistical regression analyses. The results showed that 50.9% (n=113) of ALS patients developed mild to moderate liver injury; 71.7% and 53.1% of patients were concurrently using CYP1A2 inhibitors (p=0.005) and diclofenac (p=0.032), respectively; 55.8% of patients with liver injury had a history of smoking (p=0.011). Multivariate analyses revealed that the concurrent use of CYP1A2 inhibitors [odds ratio (OR) 2.152, 95% confidence interval (CI) 1.225-3.780, p=0.008] and history of smoking (OR 1.938, 95% CI 1.125-3.340, p=0.017) were independent risk factors for liver injury in patients receiving riluzole. In conclusion, treatment of ALS patients with riluzole, smoking habits, and concurrent use of CYP1A2 inhibitors are independent liver injury risk factors. Further studies on liver injury are warranted in ALS patients treated with riluzole to comprehensively understand the underlying mechanisms of riluzole-associated liver toxicity.}, }
@article {pmid32612045, year = {2020}, author = {Kimura, M}, title = {[Consideration of Advanced Pharmaceutical Control Functions through Pharmacy-provided Home Pharmaceutical Care].}, journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan}, volume = {140}, number = {7}, pages = {841-850}, doi = {10.1248/yakushi.19-00237-1}, pmid = {32612045}, issn = {1347-5231}, mesh = {*Community Pharmacy Services ; *Delivery of Health Care ; *Home Care Services ; Humans ; Japan ; *Pharmacy ; }, abstract = {In October 2015, the Ministry of Health, Labour and Welfare of Japan newly included "health support functions" and "advanced pharmaceutical control functions" as part of "primary-care pharmacy" in the pharmacy vision for patients. "Health support functions" were defined as recommending that patients seek medical consultations, introducing them to relevant medical institutions, and contributing to disease prevention and health support among local residents, apart from health counseling and the consolidation of a framework for the appropriate selection and supply of and advice on pharmacist-only over-the-counter medications, etc. On the other hand, the term "advanced pharmaceutical control functions" is presumed to imply meeting the needs for advanced pharmaceutical control, e.g., cooperation with specialized medical institutions in addressing adverse reactions caused by anticancer drugs and support of the selection of anti-HIV drugs. However, the details remain unknown. Since the opening of the Akebono pharmacy group 22 years ago, our staff members have visited home-care patients, controlled and guided the use of pharmaceuticals, and supported all types of home-care patients including those with end-stage cancer and amyotrophic lateral sclerosis, undergoing home parenteral nutrition, and pediatric home-care patients. We have experienced many cases requiring sophisticated pharmaceutical control, e.g., pain control with opioids, sterile preparation of transfusions, and supply of special medical devices. We would like to consider the requirements for pharmacy-provided home healthcare that depends heavily on medical treatment as one advanced pharmaceutical control function.}, }
@article {pmid32610599, year = {2020}, author = {Connolly, O and Le Gall, L and McCluskey, G and Donaghy, CG and Duddy, WJ and Duguez, S}, title = {A Systematic Review of Genotype-Phenotype Correlation across Cohorts Having Causal Mutations of Different Genes in ALS.}, journal = {Journal of personalized medicine}, volume = {10}, number = {3}, pages = {}, pmid = {32610599}, issn = {2075-4426}, support = {EU Sustainable Competitiveness Programme for N. Ireland//European Regional Development Fund/ ; HSC//Northern Ireland Public Health Agency/ ; Ph.D Fellowship//ArSLA/ ; DELL fellowship//Ulster University/ ; 2019//IICN/ ; }, abstract = {Amyotrophic lateral sclerosis is a rare and fatal neurodegenerative disease characterised by progressive deterioration of upper and lower motor neurons that eventually culminates in severe muscle atrophy, respiratory failure and death. There is a concerning lack of understanding regarding the mechanisms that lead to the onset of ALS and as a result there are no reliable biomarkers that aid in the early detection of the disease nor is there an effective treatment. This review first considers the clinical phenotypes associated with ALS, and discusses the broad categorisation of ALS and ALS-mimic diseases into upper and lower motor neuron diseases, before focusing on the genetic aetiology of ALS and considering the potential relationship of mutations of different genes to variations in phenotype. For this purpose, a systematic review is conducted collating data from 107 original published clinical studies on monogenic forms of the disease, surveying the age and site of onset, disease duration and motor neuron involvement. The collected data highlight the complexity of the disease's genotype-phenotype relationship, and thus the need for a nuanced approach to the development of clinical assays and therapeutics.}, }
@article {pmid32610290, year = {2020}, author = {Miller, KJ and Hermes, D and Staff, NP}, title = {The current state of electrocorticography-based brain-computer interfaces.}, journal = {Neurosurgical focus}, volume = {49}, number = {1}, pages = {E2}, doi = {10.3171/2020.4.FOCUS20185}, pmid = {32610290}, issn = {1092-0684}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation ; Brain/*physiopathology ; *Brain-Computer Interfaces ; *Electroencephalography/methods ; Exoskeleton Device ; Humans ; Quadriplegia/*physiopathology ; Speech/physiology ; Stroke/physiopathology ; Stroke Rehabilitation ; }, abstract = {Brain-computer interfaces (BCIs) provide a way for the brain to interface directly with a computer. Many different brain signals can be used to control a device, varying in ease of recording, reliability, stability, temporal and spatial resolution, and noise. Electrocorticography (ECoG) electrodes provide a highly reliable signal from the human brain surface, and these signals have been used to decode movements, vision, and speech. ECoG-based BCIs are being developed to provide increased options for treatment and assistive devices for patients who have functional limitations. Decoding ECoG signals in real time provides direct feedback to the patient and can be used to control a cursor on a computer or an exoskeleton. In this review, the authors describe the current state of ECoG-based BCIs that are approaching clinical viability for restoring lost communication and motor function in patients with amyotrophic lateral sclerosis or tetraplegia. These studies provide a proof of principle and the possibility that ECoG-based BCI technology may also be useful in the future for assisting in the cortical rehabilitation of patients who have suffered a stroke.}, }
@article {pmid32610099, year = {2020}, author = {Soo, SK and Rudich, PD and Traa, A and Harris-Gauthier, N and Shields, HJ and Van Raamsdonk, JM}, title = {Compounds that extend longevity are protective in neurodegenerative diseases and provide a novel treatment strategy for these devastating disorders.}, journal = {Mechanisms of ageing and development}, volume = {190}, number = {}, pages = {111297}, pmid = {32610099}, issn = {1872-6216}, support = {R01 GM121756/GM/NIGMS NIH HHS/United States ; //CIHR/Canada ; }, mesh = {Aged ; Humans ; *Longevity/drug effects/physiology ; *Neurodegenerative Diseases/classification/genetics/prevention &amp; control ; Protective Agents/*pharmacology ; }, abstract = {While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is poorly understood. In the inherited forms of these diseases, the disease-causing mutation is present from birth but symptoms appear decades later. This indicates that these mutations are well tolerated in younger individuals but not in older adults. Based on this observation, we hypothesized that changes taking place during normal aging make the cells in the brain (and elsewhere) susceptible to the disease-causing mutations. If so, then delaying some of these age-related changes may be beneficial in the treatment of neurodegenerative disease. In this review, we examine the effects of five compounds that have been shown to extend longevity (metformin, rapamycin, resveratrol, N-acetyl-l-cysteine, curcumin) in four of the most common neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis). While not all investigations observe a beneficial effect of these compounds, there are multiple studies that show a protective effect of each of these lifespan-extending compounds in animal models of neurodegenerative disease. Combined with genetic studies, this suggests the possibility that targeting the aging process may be an effective strategy to treat neurodegenerative disease.}, }
@article {pmid32609300, year = {2020}, author = {Begovich, K and Vu, AQ and Yeo, G and Wilhelm, JE}, title = {Conserved metabolite regulation of stress granule assembly via AdoMet.}, journal = {The Journal of cell biology}, volume = {219}, number = {8}, pages = {}, pmid = {32609300}, issn = {1540-8140}, support = {R01 HG004659/HG/NHGRI NIH HHS/United States ; T32 GM007240/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Cytoplasmic Granules/genetics/*metabolism/pathology ; DNA-Binding Proteins/genetics/metabolism ; *Energy Metabolism ; HeLa Cells ; Humans ; Methionine Adenosyltransferase/genetics/metabolism ; Motor Neurons/drug effects/*metabolism/pathology ; S-Adenosylmethionine/*metabolism/pharmacology ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; *Stress, Physiological ; }, abstract = {Stress granules (SGs) are evolutionarily conserved condensates of ribonucleoproteins that assemble in response to metabolic stresses. Because aberrant SG formation is associated with amyotrophic lateral sclerosis (ALS), understanding the connection between metabolic activity and SG composition can provide therapeutic insights into neurodegeneration. Here, we identify 17 metabolic enzymes recruited to yeast SGs in response to physiological growth stress. Furthermore, the product of one of these enzymes, AdoMet, is a regulator of SG assembly and composition. Decreases in AdoMet levels increase SG formation, while chronic elevation of AdoMet produces SG remnants lacking proteins associated with the 5' end of transcripts. Interestingly, acute elevation of AdoMet blocks SG formation in yeast and motor neurons. Treatment of ALS-derived motor neurons with AdoMet also suppresses the formation of TDP-43-positive SGs, a hallmark of ALS. Together, these results argue that AdoMet is an evolutionarily conserved regulator of SG composition and assembly with therapeutic potential in neurodegeneration.}, }
@article {pmid32595261, year = {2019}, author = {Białkowska, J and Mroczkowska, D and Huflejt, ME and Wojtkiewicz, J and Siwek, T and Barczewska, M and Maksymowicz, W}, title = {COMPLEX TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS PATIENT.}, journal = {Acta clinica Croatica}, volume = {58}, number = {4}, pages = {757-766}, pmid = {32595261}, issn = {1333-9451}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*rehabilitation ; Humans ; Male ; Practice Guidelines as Topic ; Rehabilitation/*methods/*standards ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis is a progressive and fatal degenerative neuromuscular disease with few if any treatment options and physical rehabilitation addressing specific deficits is the most frequent form of therapy. Patients also suffer from depression and increased anxiety. Our purpose was to assess the neurorehabilitation effectiveness in a patient with amyotrophic lateral sclerosis who underwent stem cell transplantation but refused physiotherapy due to depression. Disease progression was followed using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale bimonthly for six months pre- and then post-stem cell transplantation. Psychological traits were assessed using six standardized tests. Quantitative electroencephalogram diagnostics was performed before the first and after the last neurofeedback session, and sessions were conducted on a 3-times-a-week basis. The physiotherapy protocol included proprioceptive neuromuscular facilitation, electrical modalities unit applied to the lumbar spine area, and breathing, relaxation and walking exercises, among others. Increased motivation and marked decrease in the pain level was associated with the patient's willingness to complete physiotherapy, which resulted in improvements in most neuromuscular deficits and in increased respiratory capacity. During the 12 post-rehabilitation months, progression of the disease decelerated, and a positive behavioral change was noted. The study suggested that neurofeedback could be used as a neurorehabilitation component of the personalized complex rehabilitation protocol in patients with amyotrophic lateral sclerosis.}, }
@article {pmid32593977, year = {2020}, author = {Spinelli, EG and Riva, N and Rancoita, PMV and Schito, P and Doretti, A and Poletti, B and Di Serio, C and Silani, V and Filippi, M and Agosta, F}, title = {Structural MRI outcomes and predictors of disease progression in amyotrophic lateral sclerosis.}, journal = {NeuroImage. Clinical}, volume = {27}, number = {}, pages = {102315}, pmid = {32593977}, issn = {2213-1582}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging ; Diffusion Tensor Imaging ; Disease Progression ; Humans ; Longitudinal Studies ; Magnetic Resonance Imaging ; Pyramidal Tracts/diagnostic imaging ; }, abstract = {BACKGROUND AND AIMS: Considering the great heterogeneity of amyotrophic lateral sclerosis (ALS), the identification of accurate prognostic predictors is fundamental for both the clinical practice and the design of treatment trials. This study aimed to explore the progression of clinical and structural brain changes in patients with ALS, and to assess magnetic resonance imaging (MRI) measures of brain damage as predictors of subsequent functional decline.<br><br>METHODS: 50 ALS patients underwent clinical evaluations and 3&#xa0;T MRI scans at regular intervals for a maximum of 2&#xa0;years (total MRI scans&#xa0;=&#xa0;164). MRI measures of cortical thickness, as well as diffusion tensor (DT) metrics of microstructural damage along white matter (WM) tracts were obtained. Voxel-wise regression models and longitudinal mixed-effects models were used to test the relationship between clinical decline and baseline and longitudinal MRI features.<br><br>RESULTS: The rate of decline of the ALS Functional Rating Scale revised (ALSFRS-r) was significantly associated with the rate of fractional anisotropy (FA) decrease in the body of the corpus callosum (CC). Corticospinal tract (CST) and CC-body alterations had a faster progression in patients with higher baseline ALSFRS-r scores and greater CC-body disruption at baseline. Lower FA of the cerebral peduncle was associated with faster subsequent clinical progression.<br><br>CONCLUSIONS: In this longitudinal study, we identified a significant association between measures of WM damage of the motor tracts and functional decline in ALS patients. Our data suggest that a multiparametric approach including DT MRI measures of brain damage would provide an optimal method for an accurate stratification of ALS patients into prognostic classes.}, }
@article {pmid32583744, year = {2020}, author = {Ireland, SC and Huang, H and Zhang, J and Li, J and Wang, Y}, title = {Hydrogen peroxide induces Arl1 degradation and impairs Golgi-mediated trafficking.}, journal = {Molecular biology of the cell}, volume = {31}, number = {17}, pages = {1931-1942}, pmid = {32583744}, issn = {1939-4586}, support = {R01 GM112786/GM/NIGMS NIH HHS/United States ; R35 GM130331/GM/NIGMS NIH HHS/United States ; R56 AG062225/AG/NIA NIH HHS/United States ; }, mesh = {ADP-Ribosylation Factors/drug effects/*metabolism ; Autoantigens/metabolism ; Biological Transport/physiology ; Golgi Apparatus/*metabolism/physiology ; Golgi Matrix Proteins/metabolism ; HeLa Cells ; Humans ; Hydrogen Peroxide/pharmacology ; Intracellular Membranes/metabolism ; Membrane Proteins/drug effects/*metabolism ; Mitochondria/metabolism ; Oxidative Stress/*physiology ; Protein Transport/physiology ; Reactive Oxygen Species/metabolism ; trans-Golgi Network/metabolism ; }, abstract = {Reactive oxygen species (ROS)-induced oxidative stress has been associated with diseases such as amyotrophic lateral sclerosis, stroke, and cancer. While the effect of ROS on mitochondria and endoplasmic reticulum (ER) has been well documented, its consequence on the Golgi apparatus is less well understood. In this study, we characterized the Golgi structure and function in HeLa cells after exposure to hydrogen peroxide (H2O2), a reagent commonly used to introduce ROS to cells. Treatment of cells with 1 mM H2O2 for 10 min resulted in the degradation of Arl1 and dissociation of GRIP domain-containing proteins Golgin-97 and Golgin-245 from the trans-Golgi. This effect could be rescued by treatment of cells with a ROS scavenger N-acetyl cysteine or protease inhibitors. Structurally, H2O2 treatment reduced the number of cisternal membranes per Golgi stack, suggesting a loss of trans-Golgi cisternae. Functionally, H2O2 treatment inhibited both anterograde and retrograde protein transport, consistent with the loss of membrane tethers on the trans-Golgi cisternae. This study revealed membrane tethers at the trans-Golgi as novel specific targets of ROS in cells.}, }
@article {pmid32583696, year = {2020}, author = {Blasco, H and Lanznaster, D and Veyrat-Durebex, C and Hergesheimer, R and Vourch, P and Maillot, F and Andres, CR and Pradat, PF and Corcia, P}, title = {Understanding and managing metabolic dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {20}, number = {9}, pages = {907-919}, doi = {10.1080/14737175.2020.1788389}, pmid = {32583696}, issn = {1744-8360}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Metabolic Diseases/*etiology/*therapy ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron disease that leads to death after a median survival of 36 months. The development of an effective treatment has proven to be extremely difficult due to the inadequate understanding of the pathogenesis of ALS. Energy metabolism is thoroughly involved in the disease based on the discoveries of hypermetabolism, lipid/glucose metabolism, the tricarboxylic acid (TCA) cycle, and mitochondrial impairment.<br><br>AREA COVERED: Many perturbed metabolites within these processes have been identified as promising therapeutic targets. However, the therapeutic strategies targeting these pathways have failed to produce clinically significant results. The authors present in this review the metabolic disturbances observed in ALS and the derived-therapeutics.<br><br>EXPERT OPINION: The authors suggest that this is due to the insufficient knowledge of the relationship between the metabolic targets and the type of ALS of the patient, depending on genetic and environmental factors. We must improve our understanding of the pathological mechanisms and pay attention to the subtle hidden effects of changing diet, for example, and to use this strategy in addition to other drugs or to use metabolism status to determine subgroups of patients.}, }
@article {pmid32574550, year = {2020}, author = {Banack, SA and Dunlop, RA and Cox, PA}, title = {An miRNA fingerprint using neural-enriched extracellular vesicles from blood plasma: towards a biomarker for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {Open biology}, volume = {10}, number = {6}, pages = {200116}, pmid = {32574550}, issn = {2046-2441}, mesh = {Amyotrophic Lateral Sclerosis/blood/*genetics ; DNA Fingerprinting ; Extracellular Vesicles/*genetics ; Female ; Gene Expression Regulation ; Genetic Markers ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; MicroRNAs/*genetics ; Motor Neuron Disease/blood/*genetics ; Pilot Projects ; Sequence Analysis, RNA/*methods ; }, abstract = {Biomarkers for amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) are currently not clinically available for disease diagnosis or analysis of disease progression. If identified, biomarkers could improve patient outcomes by enabling early intervention and assist in the determination of treatment efficacy. We hypothesized that neural-enriched extracellular vesicles could provide microRNA (miRNA) fingerprints with unequivocal signatures of neurodegeneration. Using blood plasma from ALS/MND patients and controls, we extracted neural-enriched extracellular vesicle fractions and conducted next-generation sequencing and qPCR of miRNA components of the transcriptome. We here report eight miRNA sequences which significantly distinguish ALS/MND patients from controls in a replicated experiment using a second cohort of patients and controls. miRNA sequences from patient blood samples using neural-enriched extracellular vesicles may yield unique insights into mechanisms of neurodegeneration and assist in early diagnosis of ALS/MND.}, }
@article {pmid32573277, year = {2020}, author = {Andrews, JA and Jackson, CE and Heiman-Patterson, TD and Bettica, P and Brooks, BR and Pioro, EP}, title = {Real-world evidence of riluzole effectiveness in treating amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {7-8}, pages = {509-518}, doi = {10.1080/21678421.2020.1771734}, pmid = {32573277}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {To compare the effect of riluzole on median survival in population studies of patients with amyotrophic lateral sclerosis (ALS) with that observed in clinical trials. Methods: Two independent PubMed searches were conducted, to identify population studies that reported median survival for ALS patients who were either treated with riluzole or remained riluzole-free. Results: We identified 14 studies that met the inclusion criteria of reporting median survival and an additional study that reported mean survival of both riluzole and riluzole-free patients. Analysis of the 15 studies found that a majority reported increased survival of riluzole vs. riluzole-free patients. In 8 studies, the median survival for patients treated with riluzole was 6-19 months longer compared with patients not treated with riluzole (p < 0.05). Three additional studies reported a clinically meaningful treatment effect (range 3-5.9 months) but did not meet statistical significance. The remaining 4 studies did not show a meaningful treatment effect between riluzole and riluzole-free groups (<3 months), and differences among the groups were not significant. Also, 5 of the studies used multivariate regression analysis to investigate the level of association between treatment with riluzole and survival; these analyses supported the positive effect of riluzole on survival. Conclusions: A majority of population studies that compared riluzole vs. riluzole-free ALS patients found significant differences in median survival between the two groups, ranging from 6 to 19 months. This is substantially longer than the 2- to 3-month survival benefit observed in the pivotal clinical trials of riluzole.}, }
@article {pmid32570926, year = {2020}, author = {Koza, LA and Winter, AN and Holsopple, J and Baybayon-Grandgeorge, AN and Pena, C and Olson, JR and Mazzarino, RC and Patterson, D and Linseman, DA}, title = {Protocatechuic Acid Extends Survival, Improves Motor Function, Diminishes Gliosis, and Sustains Neuromuscular Junctions in the hSOD1[G93A] Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Nutrients}, volume = {12}, number = {6}, pages = {}, pmid = {32570926}, issn = {2072-6643}, support = {PCA-ALS//Ralph L. Smith Foundation/ ; }, mesh = {Amyotrophic Lateral Sclerosis/complications/*drug therapy ; Animals ; Anticarcinogenic Agents/*pharmacology ; Disease Models, Animal ; Gliosis/complications/*prevention &amp; control ; Hydroxybenzoates/*pharmacology ; Mice ; Mice, Transgenic ; Motor Activity/*drug effects ; Motor Neurons/drug effects ; Neuromuscular Junction/*drug effects ; Superoxide Dismutase-1 ; Survival Rate ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by motor neuron apoptosis and subsequent skeletal muscle atrophy caused by oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation. Anthocyanins are polyphenolic compounds found in berries that possess neuroprotective and anti-inflammatory properties. Protocatechuic acid (PCA) is a phenolic acid metabolite of the parent anthocyanin, kuromanin, found in blackberries and bilberries. We explored the therapeutic effects of PCA in a transgenic mouse model of ALS that expresses mutant human Cu, Zn-superoxide dismutase 1 with a glycine to alanine substitution at position 93. These mice display skeletal muscle atrophy, hindlimb weakness, and weight loss. Disease onset occurs at approximately 90 days old and end stage is reached at approximately 120 days old. Daily treatment with PCA (100 mg/kg) by oral gavage beginning at disease onset significantly extended survival (121 days old in untreated vs. 133 days old in PCA-treated) and preserved skeletal muscle strength and endurance as assessed by grip strength testing and rotarod performance. Furthermore, PCA reduced astrogliosis and microgliosis in spinal cord, protected spinal motor neurons from apoptosis, and maintained neuromuscular junction integrity in transgenic mice. PCA lengthens survival, lessens the severity of pathological symptoms, and slows disease progression in this mouse model of ALS. Given its significant preclinical therapeutic effects, PCA should be further investigated as a treatment option for patients with ALS.}, }
@article {pmid32564745, year = {2020}, author = {Miller, JH and Das, V}, title = {Potential for Treatment of Neurodegenerative Diseases with Natural Products or Synthetic Compounds that Stabilize Microtubules.}, journal = {Current pharmaceutical design}, volume = {26}, number = {35}, pages = {4362-4372}, doi = {10.2174/1381612826666200621171302}, pmid = {32564745}, issn = {1873-4286}, mesh = {*Alzheimer Disease/drug therapy ; Animals ; *Biological Products/pharmacology ; Humans ; Microtubules ; *Neurodegenerative Diseases/drug therapy ; *Tauopathies ; tau Proteins ; }, abstract = {No effective therapeutics to treat neurodegenerative diseases exist, despite significant attempts to find drugs that can reduce or rescue the debilitating symptoms of tauopathies such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, or Pick's disease. A number of in vitro and in vivo models exist for studying neurodegenerative diseases, including cell models employing induced-pluripotent stem cells, cerebral organoids, and animal models of disease. Recent research has focused on microtubulestabilizing agents, either natural products or synthetic compounds that can prevent the axonal destruction caused by tau protein pathologies. Although promising results have come from animal model studies using brainpenetrant natural product microtubule-stabilizing agents, such as paclitaxel analogs that can access the brain, epothilones B and D, and other synthetic compounds such as davunetide or the triazolopyrimidines, early clinical trials in humans have been disappointing. This review aims to summarize the research that has been carried out in this area and discuss the potential for the future development of an effective microtubule stabilizing drug to treat neurodegenerative disease.}, }
@article {pmid32563294, year = {2020}, author = {Mariani, LL and Corvol, JC}, title = {Maximizing placebo response in neurological clinical practice.}, journal = {International review of neurobiology}, volume = {153}, number = {}, pages = {71-101}, doi = {10.1016/bs.irn.2020.04.003}, pmid = {32563294}, issn = {2162-5514}, mesh = {Humans ; Nervous System Diseases/*therapy ; Personality/*physiology ; *Placebo Effect ; Placebos/*therapeutic use ; }, abstract = {The placebo effect is a widely recognized phenomenon in clinical research, with a negative perception that it could hide the "true" drug effect. In clinical care its positive potential to increase known drug effects has been neglected for too long. The placebo and nocebo responses have been described in many neurologic disorders such as Parkinson's, Huntington's and Alzheimer's diseases, restless leg syndrome, tics, essential tremor, dystonia, functional movement disorders, neuropathic pain, headaches, migraine, amyotrophic lateral sclerosis, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis and epilepsy. Knowledge regarding placebo mechanisms and their consequences on clinical outcome have greatly improved over the last two decades. This evolution has led to reconsiderations of the importance of placebo response in the clinic and has given several clues on how to improve it in daily practice. In this chapter, we first illustrate "why," e.g. the reasons (relevance to clinical practice, help in differential diagnosis/treatment of psychogenic movements, clinical impact, proven neurobiological grounds, health economic potential), and "how," e.g. the means (increase patients' knowledge, increase learning, improve patient-doctor relationship, increase Hawthorne effect, increase positive/decrease negative expectations (the Rosenthal effect), personalize placebo response), the placebo should be maximized (and nocebo avoided) in neurological clinical practice. Future studies regarding more specific neurobiological mechanisms will allow a finer tuning of placebo response in clinical practice. The use of placebo in clinical practice raises ethical issues, and a recent expert consensus regarding placebo use in the clinic is a first step to future guidelines necessary to this field.}, }
@article {pmid32556567, year = {2020}, author = {Lunetta, C and Moglia, C and Lizio, A and Caponnetto, C and Dubbioso, R and Giannini, F and Matà, S and Mazzini, L and Sabatelli, M and Siciliano, G and Simone, IL and Sorarù, G and Toriello, A and Trojsi, F and Vedovello, M and D'Ovidio, F and Filippi, M and Calvo, A and , }, title = {The Italian multicenter experience with edaravone in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {267}, number = {11}, pages = {3258-3267}, doi = {10.1007/s00415-020-09993-z}, pmid = {32556567}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Disease Progression ; Edaravone ; Humans ; Italy ; Treatment Outcome ; }, abstract = {OBJECTIVES: The aim of the study is to analyze the ALS disease progression and respiratory function of Italian patients treated with edaravone (EVN), as well as the adherence to, and the effects of, the therapy.<br><br>METHODS: We performed an observational study of patients treated with EVN from May 2017 to May 2019, in 39 Italian ALS Centers. Taking into account ALS patients with at least 12&#xa0;months of EVN treatment, we compared the decline of ALSFRS-R and FVC with a group of matched historical controls from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, using both descriptive and survival analysis approaches.<br><br>RESULTS: A total of 331 ALS Italian patients treated with EVN and 290 matched historical controls were recruited in this study. No significant differences on disease progression or respiratory function were found comparing the two cohorts in both descriptive and survival analyses. The EVN treatment was overall well tolerated.<br><br>CONCLUSIONS: The study showed that EVN treatment was well tolerated. No significant differences were reported in ALS patients treated and not treated with EVN, in terms of both disease progression and respiratory function. These findings prove that further studies are required to better clarify whether EVN could be considered an effective treatment for ALS disease.}, }
@article {pmid32547681, year = {2020}, author = {Wang, J and Hu, WW and Jiang, Z and Feng, MJ}, title = {Advances in treatment of neurodegenerative diseases: Perspectives for combination of stem cells with neurotrophic factors.}, journal = {World journal of stem cells}, volume = {12}, number = {5}, pages = {323-338}, pmid = {32547681}, issn = {1948-0210}, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, are a group of incurable neurological disorders, characterized by the chronic progressive loss of different neuronal subtypes. However, despite its increasing prevalence among the ever-increasing aging population, little progress has been made in the coincident immense efforts towards development of therapeutic agents. Research interest has recently turned towards stem cells including stem cells-derived exosomes, neurotrophic factors, and their combination as potential therapeutic agents in neurodegenerative diseases. In this review, we summarize the progress in therapeutic strategies based on stem cells combined with neurotrophic factors and mesenchymal stem cells-derived exosomes for neurodegenerative diseases, with an emphasis on the combination therapy.}, }
@article {pmid32546652, year = {2020}, author = {Atanasov, P and Diamantaras, A and MacPherson, A and Vinarov, E and Benjamin, DM and Shrier, I and Paul, F and Dirnagl, U and Kimmelman, J}, title = {Wisdom of the expert crowd prediction of response for 3 neurology randomized trials.}, journal = {Neurology}, volume = {95}, number = {5}, pages = {e488-e498}, pmid = {32546652}, issn = {1526-632X}, support = {EOG 201303//CIHR/Canada ; }, mesh = {*Forecasting ; Humans ; *Neurology ; *Randomized Controlled Trials as Topic ; *Treatment Outcome ; }, abstract = {OBJECTIVE: To explore the accuracy of combined neurology expert forecasts in predicting primary endpoints for trials.<br><br>METHODS: We identified one major randomized trial each in stroke, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) that was closing within 6 months. After recruiting a sample of neurology experts for each disease, we elicited forecasts for the primary endpoint outcomes in the trial placebo and treatment arms. Our main outcome was the accuracy of averaged predictions, measured using ordered Brier scores. Scores were compared against an algorithm that offered noncommittal predictions.<br><br>RESULTS: Seventy-one neurology experts participated. Combined forecasts of experts were less accurate than a noncommittal prediction algorithm for the stroke trial (pooled Brier score = 0.340, 95% subjective probability interval [sPI] 0.340 to 0.340 vs 0.185 for the uninformed prediction), and approximately as accurate for the MS study (pooled Brier score = 0.107, 95% confidence interval [CI] 0.081 to 0.133 vs 0.098 for the noncommittal prediction) and the ALS study (pooled Brier score = 0.090, 95% CI 0.081 to 0.185 vs 0.090). The 95% sPIs of individual predictions contained actual trial outcomes among 44% of experts. Only 18% showed prediction skill exceeding the noncommittal prediction. Independent experts and coinvestigators achieved similar levels of accuracy.<br><br>CONCLUSION: In this first-of-kind exploratory study, averaged expert judgments rarely outperformed noncommittal forecasts. However, experts at least anticipated the possibility of effects observed in trials. Our findings, if replicated in different trial samples, caution against the reliance on simple approaches for combining expert opinion in making research and policy decisions.}, }
@article {pmid32546239, year = {2020}, author = {Di Gioia, D and Bozzi Cionci, N and Baffoni, L and Amoruso, A and Pane, M and Mogna, L and Gaggìa, F and Lucenti, MA and Bersano, E and Cantello, R and De Marchi, F and Mazzini, L}, title = {A prospective longitudinal study on the microbiota composition in amyotrophic lateral sclerosis.}, journal = {BMC medicine}, volume = {18}, number = {1}, pages = {153}, pmid = {32546239}, issn = {1741-7015}, support = {--//Probiotical S.p.A./International ; AGING Project for Department of Excellence at the Department of Translational Medicine (DIMET), Universit&#xe0; del Piemonte Orientale, Novara, Italy//Universit&#xe0; degli Studi del Piemonte Orientale/International ; }, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Female ; Gastrointestinal Microbiome/*physiology ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Prospective Studies ; Young Adult ; }, abstract = {BACKGROUND: A connection between amyotrophic lateral sclerosis (ALS) and altered gut microbiota composition has previously been reported in animal models. This work is the first prospective longitudinal study addressing the microbiota composition in ALS patients and the impact of a probiotic supplementation on the gut microbiota and disease progression.<br><br>METHODS: Fifty patients and 50 matched controls were enrolled. The microbial profile of stool samples from patients and controls was analyzed via PCR-Denaturing Gradient Gel Electrophoresis, and the main microbial groups quantified via qPCR. The whole microbiota was then analyzed via next generation sequencing after amplification of the V3-V4 region of 16S rDNA. Patients were then randomized to receive probiotic treatment or placebo and followed up for 6&#x2009;months with ALSFRS-R, BMI, and FVC%.<br><br>RESULTS: The results demonstrate that the gut microbiota of ALS patients is characterized by some differences with respect to controls, regardless of the disability degree. Moreover, the gut microbiota composition changes during the course of the disease as demonstrated by the significant decrease in the number of observed operational taxonomic unit during the follow-up. Interestingly, an unbalance between potentially protective microbial groups, such as Bacteroidetes, and other with potential neurotoxic or pro-inflammatory activity, such as Cyanobacteria, has been shown. The 6-month probiotic treatment influenced the gut microbial composition; however, it did not bring the biodiversity of intestinal microbiota of patients closer to that of control subjects and no influence on the progression of the disease measured by ALSFRS-R was demonstrated.<br><br>CONCLUSIONS: Our study poses the bases for larger clinical studies to characterize the microbiota changes as a novel ALS biomarker and to test new microbial strategy to ameliorate the health status of the gut.<br><br>TRIAL REGISTRATION: CE 107/14, approved by the Ethics Committee of the "Maggiore della Carit&#xe0;" University Hospital, Italy.}, }
@article {pmid32543233, year = {2020}, author = {Rothstock, S and Weiss, HR and Krueger, D and Kleban, V and Paul, L}, title = {Innovative decision support for scoliosis brace therapy based on statistical modelling of markerless 3D trunk surface data.}, journal = {Computer methods in biomechanics and biomedical engineering}, volume = {23}, number = {13}, pages = {923-933}, doi = {10.1080/10255842.2020.1773449}, pmid = {32543233}, issn = {1476-8259}, mesh = {Adolescent ; Algorithms ; Automation ; *Braces ; Child ; *Decision Support Systems, Clinical ; Female ; Humans ; *Imaging, Three-Dimensional ; Male ; *Models, Statistical ; Probability ; Scoliosis/*diagnostic imaging ; Torso/*diagnostic imaging ; }, abstract = {Recently markerless 3D scanning methods receive an increased interest for therapy planning and brace treatment of patients with scoliosis. This avoids repeated radiation known from standard X-Ray analysis. Several authors introduced the method of asymmetry distance maps in order to classify curve severity and progression. The current work extends this approach by statistical mean shape 3D models of the human trunk in order to classify patients. 50 patients were included in this study performing frontal X-ray and 3D scanning analysis. All patients were classified by a clinician according to their Cobb angle and spinal curve pattern (Augmented-Lehnert-Schroth ALS). 3D reconstructions of each patient trunk were processed in a way to elastically register a reference surface mesh with fixed number of data points. Mean 3D shape models were generated for each curve pattern. An asymmetry distance map was then calculated for each patient and mean shape model. Single patient 3D reconstructions were classified according to severity and ALS treatment group. Optimal sensitivity and specificity was 97%/39% thoracic and 87%/42% lumbar respectively for detecting mild and moderate-severe patients. Identifying a treatment group was possible for three combined groups allowing to support decisions during diagnosis and therapy planning.}, }
@article {pmid32542280, year = {2020}, author = {Vieira, S and Strymecka, P and Stanaszek, L and Silva-Correia, J and Drela, K and Fiedorowicz, M and Malysz-Cymborska, I and Rogujski, P and Janowski, M and Reis, RL and Lukomska, B and Walczak, P and Oliveira, JM}, title = {Methacrylated gellan gum and hyaluronic acid hydrogel blends for image-guided neurointerventions.}, journal = {Journal of materials chemistry. B}, volume = {8}, number = {27}, pages = {5928-5937}, doi = {10.1039/d0tb00877j}, pmid = {32542280}, issn = {2050-7518}, mesh = {Adipose Tissue/cytology ; Animals ; Cations, Divalent/chemistry ; Cell Transplantation/*methods ; Cells, Cultured ; Contrast Media/*chemistry ; Female ; Humans ; Hyaluronic Acid/*chemistry ; Hydrogels/*chemistry ; Injections ; Magnetic Resonance Imaging ; Male ; Manganese/*chemistry ; Methacrylates/chemistry ; Phantoms, Imaging ; Polysaccharides, Bacterial/*chemistry ; Rheology ; Stem Cells/cytology/metabolism ; }, abstract = {Cell-based therapies delivered via intrathecal injection are considered as one of the most promising solutions for the treatment of amyotrophic lateral sclerosis (ALS). Herein, injectable manganese-based biocompatible hydrogel blends were developed, that can allow image-guided cell delivery. The hydrogels can also provide physical support for cells during injection, and at the intrathecal space after transplantation, while assuring cell survival. In this regard, different formulations of methacrylated gellan gum/hyaluronic acid hydrogel blends (GG-MA/HA) were considered as a vehicle for cell delivery. The hydrogels blends were supplemented with paramagnetic Mn2+ to allow a real-time monitorization of hydrogel deposition via T1-weighted magnetic resonance imaging (MRI). The developed hydrogels were easily extruded and formed a stable fiber upon injection into the cerebrospinal fluid. Hydrogels prepared with a 75 : 25 GG-MA to HA ratio supplemented with MnCl2 at 0.1 mM showed controlled hydrogel degradation, suitable permeability, and a distinct MRI signal in vitro and in vivo. Additionally, human-derived adipose stem cells encapsulated in 75 : 25 GG-MA/HA hydrogels remained viable for up to 14 days of culture in vitro. Therefore, the engineered hydrogels can be an excellent tool for injectable image-guided cell delivery approaches.}, }
@article {pmid32538885, year = {2020}, author = {Ceravolo, MG}, title = {Is cell-based therapy more efficacious for people with amyotrophic lateral sclerosis/motor neuron disease than placebo or no treatment? - A Cochrane review summary with commentary.}, journal = {NeuroRehabilitation}, volume = {46}, number = {4}, pages = {613-615}, doi = {10.3233/NRE-209004}, pmid = {32538885}, issn = {1878-6448}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Mesenchymal Stem Cell Transplantation/*adverse effects/methods ; Placebo Effect ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Even if there is sparse evidence of efficacy of stem cell administration for amyotrophic lateral sclerosis (ALS) in preclinical studies, the clinical use of cell-based therapy is yet to be defined.<br><br>OBJECTIVE: To assess the efficacy, feasibility and safety of cell-based therapy in people with ALS/MND, compared with placebo or no treatment.<br><br>METHODS: A Cochrane Review on the topic was summarized with comments.<br><br>RESULTS: Two randomized controlled trials met the selection criteria, but only one provided data useful for the analysis. It compared autologous bone marrow-mesenchymal stem cells, combined with riluzole, to riluzole only, in 64 people with ALS. The ALS Functional Rating Scale-Revised score slightly improved 6 months after the intervention, though the change was not clinically meaningful. Respiratory function, overall survival and the risk of total adverse events or serious adverse events were not different in the two groups.<br><br>CONCLUSIONS: The available evidence does not support the use of bone marrow-mesenchymal stem cells to treat people with ALS/MND.}, }
@article {pmid32535554, year = {2020}, author = {Long, Z and Chen, J and Zhao, Y and Zhou, W and Yao, Q and Wang, Y and He, G}, title = {Dynamic changes of autophagic flux induced by Abeta in the brain of postmortem Alzheimer's disease patients, animal models and cell models.}, journal = {Aging}, volume = {12}, number = {11}, pages = {10912-10930}, pmid = {32535554}, issn = {1945-4589}, mesh = {Alzheimer Disease/metabolism/pathology ; Amyloid beta-Protein Precursor/genetics/metabolism ; Animals ; *Autophagy ; Autopsy ; Brain/*metabolism/pathology ; Cells, Cultured ; Disease Models, Animal ; Female ; Humans ; Lysosomes/*metabolism ; Male ; Mice ; Mice, Transgenic ; Plaque, Amyloid/*metabolism ; }, abstract = {Autophagy has been reported to play a dual "double-edged sword" role in the occurrence and development of Alzheimer's disease (AD). To assess the relationship between AD and autophagy, the dynamic changes of autophagic flux in the brain of postmortem AD patients, animal models and cell models were studied. The results showed that autophagosomes (APs) accumulation and expression of lysosomal markers were decreased in the brains of AD patients. In the brain of APP/PS1 double transgenic mice, APs did not accumulate before the formation of SPs but accumulated along with the deposition of SPs, as well as the level of lysosomal markers cathepsin B and Lamp1 protein decreased significantly. In the brains of APP/PS1/LC3 triple - transgenic mice, the number of APs increased with age, but the number of ALs did not increase accordingly. The activation of autophagy is mainly due to the increase in Aβ rather than the overexpression of mutated APP gene. However, both the treatment with exogenous Aβ25-35 and the mutation of the endogenous APP gene blocked the fusion of APs with lysosomes and decreased lysosomal functioning in AD model cells, which may be the main mechanism of autophagy dysregulation in AD.}, }
@article {pmid32532288, year = {2020}, author = {Schönfelder, E and Osmanovic, A and Müschen, LH and Petri, S and Schreiber-Katz, O}, title = {Costs of illness in amyotrophic lateral sclerosis (ALS): a cross-sectional survey in Germany.}, journal = {Orphanet journal of rare diseases}, volume = {15}, number = {1}, pages = {149}, pmid = {32532288}, issn = {1750-1172}, mesh = {*Amyotrophic Lateral Sclerosis ; Cost of Illness ; Cross-Sectional Studies ; Germany ; Health Care Costs ; Humans ; *Quality of Life ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. Consequently, patients undergo a multidisciplinary treatment that often requires intensive use of medical resources. This study provides an estimate on the cost of illness depending on the clinical severity while also analysing the patients' health-related quality of life.<br><br>METHODS: Primary data from patients and caregivers was collected through a standardised questionnaire. Direct medical, direct non-medical and indirect costs were calculated using the latest German health economic guidelines. Patients were divided into five groups according to the King's staging system. Health-related quality of life was assessed using EuroQoL Group EQ-5D-5L&#x2122; questionnaire. Influencing factors on both total cost and quality of life were examined.<br><br>RESULTS: The mean annual total cost of illness was 78,256&#x20ac; per patient while the lifetime cost per patient was estimated at 246,184&#x20ac;. The prevalence based total burden yearly therefore was 519,776,352&#x20ac; in Germany. Nearly half of the costs were attributable to informal care. With increase of the clinical severity stage, costs rose and quality of life decreased. The score of the revised Amyotrophic Laterals Sclerosis Functional Rating Scale was identified as one major influencing factor on total costs, while subjective impairment in daily activities and classification into a care level as opposed to having no care level influenced patients' quality of life.<br><br>CONCLUSION: It is essential to understand the socioeconomic burden of a disease. These data can be used to improve patient care standards and quality of life while also serving as a basis for cost-benefit analyses during the approval process of new treatments.}, }
@article {pmid32531783, year = {2020}, author = {Chee, WH and Gunasagaran, J and Ahmad, TS}, title = {A comparison of delta wire technique versus extension block pinning in the treatment of bony Mallet finger.}, journal = {Handchirurgie, Mikrochirurgie, plastische Chirurgie : Organ der Deutschsprachigen Arbeitsgemeinschaft fur Handchirurgie : Organ der Deutschsprachigen Arbeitsgemeinschaft fur Mikrochirurgie der Peripheren Nerven und Gefasse : Organ der V...}, volume = {52}, number = {3}, pages = {176-181}, doi = {10.1055/a-1170-5590}, pmid = {32531783}, issn = {1439-3980}, mesh = {*Hand Deformities, Acquired ; Humans ; }, abstract = {UNLABELLED: ZIEL: Diese Studie vergleicht die klinischen Ergebnisse nach Delta-Draht-Technik (Gruppe 1 = 7 Patienten) mit den Ergebnissen nach Extensions-Block-Pinning (Gruppe 2 = 11 Patienten) in der Behandlung des knöchernen Mallet-Fingers.<br><br>PATIENTEN UND METHODEN: Sechs Monate postoperativ wurde bei allen Patienten das klinische Ergebnis nach den Crawford-Kriterien, die Schmerzen anhand einer visuellen Analogskale (VAS) und der DASH-Score ermittelt. Zus&#xe4;tzlich wurden die aktive Beweglichkeit und das Extensionsdefizit im Endgelenk sowie aufgetretene Komplikationen festgehalten.<br><br>ERGEBNISSE: Patienten der Gruppe 1 hatten eine signifikant bessere Beugung im Fingerendgelenk, aber auch ein signifikant gr&#xf6;&#xdf;eres Extensionsdefizit, obwohl sie signifikant fr&#xfc;her ihre Arbeit wiederaufnahmen. Nach den Crawford-Kriterien erzielten 71 % der Patienten der Gruppe 1 und 100 % der Gruppe 2 ein exzellentes und gutes Ergebnis. Keine Unterschiede konnten bzgl. der OP-Dauer, der Schmerzen, dem DASH-Score und der Zeit bis zur kn&#xf6;chernen Heilung festgestellt werden.<br><br>SCHLUSSFOLGERUNG: In der Kurzzeitbeobachtung werden mit Extension-Block-Pinning bessere Ergebnisse in der Behandlung des kn&#xf6;chernen Strecksehnenausriss am Fingerendglied erzielt als mit der Delta-Draht-Technik.}, }
@article {pmid32528400, year = {2020}, author = {Alessenko, AV and Albi, E}, title = {Exploring Sphingolipid Implications in Neurodegeneration.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {437}, pmid = {32528400}, issn = {1664-2295}, abstract = {Over the past decade, it was found that relatively simple sphingolipids, such as ceramide, sphingosine, sphingosine-1-phosphate, and glucosylceramide play important roles in neuronal functions by regulating rates of neuronal growth and differentiation. Homeostasis of membrane sphingolipids in neurons and myelin is essential to prevent the loss of synaptic plasticity, cell death and neurodegeneration. In our review we summarize data about significant brain cell alterations of sphingolipids in different neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, Amyotrophic Lateral Sclerosis, Gaucher's, Farber's diseases, etc. We reported results obtained in brain tissue from both animals in which diseases were induced and humans in autopsy samples. Moreover, attention was paid on sphingolipids in biofluids, liquor and blood, from patients. In Alzheimer's disease sphingolipids are involved in the processing and aggregation of β-amyloid and in the transmission of the cytotoxic signal β-amyloid and TNFα-induced. Recently, the gangliosides metabolism in transgenic animals and the relationship between blood sphingolipids changes and cognitive impairment in Alzheimer's disease patients have been intensively studied. Numerous experiments have highlighted the involvement of ceramide and monohexosylceramide metabolism in the pathophysiology of the sporadic forms of Parkinson's disease. Moreover, gene mutations of the glucocerebrosidase enzyme were considered as responsible for Parkinson's disease via transition of the monomeric form of α-synuclein to an oligomeric, aggregated toxic form. Disturbances in the metabolism of ceramides were also associated with the appearance of Lewy's bodies. Changes in sphingolipid metabolism were found as a manifestation of Amyotrophic Lateral Sclerosis, both sporadic and family forms, and affected the rate of disease development. Currently, fingolimod (FTY720), a sphingosine-1-phosphate receptor modulator, is the only drug undergoing clinical trials of phase II safety for the treatment of Amyotrophic Lateral Sclerosis. The use of sphingolipids as new diagnostic markers and as targets for innovative therapeutic strategies in different neurodegenerative disorders has been included.}, }
@article {pmid32526057, year = {2020}, author = {Masrori, P and Van Damme, P}, title = {Amyotrophic lateral sclerosis: a clinical review.}, journal = {European journal of neurology}, volume = {27}, number = {10}, pages = {1918-1929}, pmid = {32526057}, issn = {1468-1331}, support = {C1-C14-17-107//KU Leuven/International ; //Opening the Future Fund (KU Leuven)/International ; //the Fund for Scientific Research Flanders (FWO-Flanders)/International ; //the ALS Liga Belgium/International ; //Een Hart voor ALS/International ; //'/International ; //Laeversfonds voor ALS Onderzoek/International ; //Val&#xe9;ry Perrier Race against ALS Fund/International ; SAO-FRA 2017/023//the Alzheimer Research Foundation/International ; VIND 135043//the Flemish Government initiated Flanders Impulse Program on Networks for Dementia Research/International ; //Flanders Innovation and Enterpreneurship (IWT grants Project MinE and iPSCAF)/International ; //the Belgian National Lottery/International ; //the Latran Foundation/International ; 755094//the European Union's Horizon 2020 research and innovation programme/International ; //the European Union's ERA-Net for Research Programmes on Rare Diseases (INTEGRALS)/International ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; C9orf72 Protein/genetics ; DNA-Binding Proteins ; *Frontotemporal Dementia/epidemiology/genetics/therapy ; Humans ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily the motor system, but in which extra-motor manifestations are increasingly recognized. The loss of upper and lower motor neurons in the motor cortex, the brain stem nuclei and the anterior horn of the spinal cord gives rise to progressive muscle weakness and wasting. ALS often has a focal onset but subsequently spreads to different body regions, where failure of respiratory muscles typically limits survival to 2-5 years after disease onset. In up to 50% of cases, there are extra-motor manifestations such as changes in behaviour, executive dysfunction and language problems. In 10%-15% of patients, these problems are severe enough to meet the clinical criteria of frontotemporal dementia (FTD). In 10% of ALS patients, the family history suggests an autosomal dominant inheritance pattern. The remaining 90% have no affected family members and are classified as sporadic ALS. The causes of ALS appear to be heterogeneous and are only partially understood. To date, more than 20 genes have been associated with ALS. The most common genetic cause is a hexanucleotide repeat expansion in the C9orf72 gene, responsible for 30%-50% of familial ALS and 7% of sporadic ALS. These expansions are also a frequent cause of frontotemporal dementia, emphasizing the molecular overlap between ALS and FTD. To this day there is no cure or effective treatment for ALS and the cornerstone of treatment remains multidisciplinary care, including nutritional and respiratory support and symptom management. In this review, different aspects of ALS are discussed, including epidemiology, aetiology, pathogenesis, clinical features, differential diagnosis, investigations, treatment and future prospects.}, }
@article {pmid32520676, year = {2021}, author = {Liu, YD and Tang, G and Qian, F and Liu, L and Huang, JR and Tang, FR}, title = {Astroglial Connexins in Neurological and Neuropsychological Disorders and Radiation Exposure.}, journal = {Current medicinal chemistry}, volume = {28}, number = {10}, pages = {1970-1986}, doi = {10.2174/0929867327666200610175037}, pmid = {32520676}, issn = {1875-533X}, mesh = {*Astrocytes ; *Connexins ; Endothelial Cells ; Humans ; *Nervous System Diseases ; *Radiation Exposure ; }, abstract = {Radiotherapy is a common treatment for brain and spinal cord tumors and also a risk factor for neuropathological changes in the brain leading to different neurological and neuropsychological disorders. Astroglial connexins are involved in brain inflammation, development of Alzheimer's Disease (AD), depressive, epilepsy, and amyotrophic lateral sclerosis, and are affected by radiation exposure. Therefore, it is speculated that radiation-induced changes of astroglial connexins may be related to the brain neuropathology and development of neurological and neuropsychological disorders. In this paper, we review the functional expression and regulation of astroglial connexins expressed between astrocytes and different types of brain cells (including oligodendrocytes, microglia, neurons and endothelial cells). The roles of these connexins in the development of AD, depressive, epilepsy, amyotrophic lateral sclerosis and brain inflammation have also been summarized. The radiation-induced astroglial connexins changes and development of different neurological and neuropsychological disorders are then discussed. Based on currently available data, we propose that radiation-induced astroglial connexins changes may be involved in the genesis of different neurological and neuropsychological disorders which depends on the age, brain regions, and radiation doses/dose rates. The abnormal astroglial connexins may be novel therapeutic targets for the prevention of radiation-induced cognitive impairment, neurological and neuropsychological disorders.}, }
@article {pmid32515902, year = {2020}, author = {Huang, F and Zhu, Y and Hsiao-Nakamoto, J and Tang, X and Dugas, JC and Moscovitch-Lopatin, M and Glass, JD and Brown, RH and Ladha, SS and Lacomis, D and Harris, JM and Scearce-Levie, K and Ho, C and Bowser, R and Berry, JD}, title = {Longitudinal biomarkers in amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {7}, number = {7}, pages = {1103-1116}, pmid = {32515902}, issn = {2328-9503}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/genetics/*metabolism/physiopathology ; Biological Specimen Banks ; Biomarkers/blood/cerebrospinal fluid ; C9orf72 Protein/genetics ; Cytokines/blood/cerebrospinal fluid/*metabolism ; *Disease Progression ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Neurofilament Proteins/blood/cerebrospinal fluid/*metabolism ; Prognosis ; }, abstract = {OBJECTIVE: To investigate neurodegenerative and inflammatory biomarkers in people with amyotrophic lateral sclerosis (PALS), evaluate their predictive value for ALS progression rates, and assess their utility as pharmacodynamic biomarkers for monitoring treatment effects.<br><br>METHODS: De-identified, longitudinal plasma, and cerebrospinal fluid (CSF) samples from PALS (n&#xa0;=&#xa0;108; 85 with samples from &#x2265;2 visits) and controls without neurological disease (n&#xa0;=&#xa0;41) were obtained from the Northeast ALS Consortium (NEALS) Biofluid Repository. Seventeen of 108 PALS had familial ALS, of whom 10 had C9orf72 mutations. Additional healthy control CSF samples (n&#xa0;=&#xa0;35) were obtained from multiple sources. We stratified PALS into fast- and slow-progression subgroups using the ALS Functional Rating Scale-Revised change rate. We compared cytokines/chemokines and neurofilament (NF) levels between PALS and controls, among progression subgroups, and in those with C9orf72 mutations.<br><br>RESULTS: We found significant elevations of cytokines, including MCP-1, IL-18, and neurofilaments (NFs), indicators of neurodegeneration, in PALS versus controls. Among PALS, these cytokines and NFs were significantly higher in fast-progression and C9orf72 mutation subgroups versus slow progressors. Analyte levels were generally stable over time, a key feature for monitoring treatment effects. We demonstrated that CSF/plasma neurofilament light chain (NFL) levels may predict disease progression, and stratification by NFL levels can enrich for more homogeneous patient groups.<br><br>INTERPRETATION: Longitudinal stability of cytokines and NFs in PALS support their use for monitoring responses to immunomodulatory and neuroprotective treatments. NFs also have prognostic value for fast-progression patients and may be used to select similar patient subsets in clinical trials.}, }
@article {pmid32512363, year = {2020}, author = {Martínez-Blay, V and Taberner, V and Pérez-Gago, MB and Palou, L}, title = {Control of major citrus postharvest diseases by sulfur-containing food additives.}, journal = {International journal of food microbiology}, volume = {330}, number = {}, pages = {108713}, doi = {10.1016/j.ijfoodmicro.2020.108713}, pmid = {32512363}, issn = {1879-3460}, mesh = {Antifungal Agents/*pharmacology ; Citrus/*microbiology ; Food Additives/chemistry/*pharmacology ; Food Preservation/methods ; Fruit/microbiology ; Fungi/drug effects/growth &amp; development ; Plant Diseases/microbiology/*prevention &amp; control ; Sulfur/*pharmacology ; Temperature ; Time Factors ; }, abstract = {Sodium metabisulfite (SMBS), potassium metabisulfite (PMBS), aluminum sulfate (AlS) and aluminum potassium sulfate (AlPS), common sulfur-containing salts used as food additives, were evaluated for their antifungal activity against Penicillium digitatum, Penicillium italicum and Geotrichum citri-aurantii, the most economically important pathogens causing postharvest diseases of citrus fruits. In vitro radial mycelial growth was measured on potato dextrose agar (PDA) Petri dishes amended with five different concentrations of the salts (10, 20, 30, 50, 100 mM) after 7 d of incubation at 25 °C. SMBS and PMBS at all concentrations, and AIS and AIPS above 20 mM, completely inhibited the growth of these fungi. The curative antifungal activity of the four salts to control citrus green (GM) and blue (BM) molds and sour rot (SR) was evaluated on 'Valencia' oranges artificially inoculated in rind wounds with P. digitatum, P. italicum and G. citri-aurantii, respectively. In vivo primary screenings showed no significant antifungal activity of AlS and AlPS to control the three diseases at any dose tested, but SMBS and PMBS reduced the incidence and severity of GM, BM and SR at various concentrations. Effective salts and concentrations were selected for in vivo dip treatments in small-scale trials. Dips at room temperature (20 °C) in SMBS and PMBS at 20 and 50 mM for 60 or 120 s significantly reduced the incidence and severity of GM and BM, with PMBS at 50 mM for 120 s the most effective treatment. Conversely, dips in SMBS and PMBS at 50 mM for 60 or 120 s did not reduce SR incidence and severity. SMBS and PMBS treatments are potentially new tools to be included in reduced-risk non-polluting strategies to control Penicillium diseases, but not SR, on citrus fruits.}, }
@article {pmid32511278, year = {2020}, author = {Hayashi, H and Wang, T and Tanaka, M and Ogiwara, S and Okada, C and Ito, M and Fukunishi, N and Iida, Y and Nakamura, A and Sasaki, A and Amano, S and Yoshida, K and Otomo, A and Ohtsuka, M and Hadano, S}, title = {Monitoring the autophagy-endolysosomal system using monomeric Keima-fused MAP1LC3B.}, journal = {PloS one}, volume = {15}, number = {6}, pages = {e0234180}, pmid = {32511278}, issn = {1932-6203}, mesh = {Animals ; Autophagy/*physiology ; Cells, Cultured ; Culture Media/pharmacology ; Endosomes/genetics/*metabolism ; Female ; Fibroblasts/cytology/drug effects/physiology ; Humans ; Hydrogen-Ion Concentration ; Luminescent Proteins/*genetics/metabolism ; Lysosomes/genetics/*metabolism ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Microtubule-Associated Proteins/*genetics/metabolism ; Mutation ; Recombinant Fusion Proteins/genetics/metabolism ; Starvation ; Superoxide Dismutase-1/genetics ; Time-Lapse Imaging ; }, abstract = {The autophagy-endolysosomal pathway is an evolutionally conserved degradation system that is tightly linked to a wide variety of physiological processes. Dysfunction of this system is associated with many pathological conditions such as cancer, inflammation and neurodegenerative diseases. Therefore, monitoring the cellular autophagy-endolysosomal activity is crucial for studies on the pathogenesis as well as therapeutics of such disorders. To this end, we here sought to create a novel means exploiting Keima, an acid-stable fluorescent protein possessing pH-dependent fluorescence excitation spectra, for precisely monitoring the autophagy-endolysosomal system. First, we generated three lines of transgenic (tg) mouse expressing monomeric Keima-fused MAP1LC3B (mKeima-LC3B). Then, these tg mice were subjected to starvation by food-restriction, and also challenged to neurodegeneration by genetically crossing with a mouse model of amyotrophic lateral sclerosis; i.e., SOD1H46R transgenic mouse. Unexpectedly, despite that a lipidated-form of endogenous LC3 (LC3-II) was significantly increased, those of mKeima-LC3B (mKeima-LC3B-II) were not changed under both stressed conditions. It was also noted that mKeima-LC3B-positive aggregates were progressively accumulated in the spinal cord of SOD1H46R;mKeima-LC3B double-tg mice, suggestive of acid-resistance and aggregate-prone natures of long-term overexpressed mKeima-LC3B in vivo. Next, we characterized mouse embryonic fibroblasts (MEFs) derived from mKeima-LC3B-tg mice. In contrast with in vivo, levels of mKeima-LC3B-I were decreased under starved conditions. Furthermore, when starved MEFs were treated with chloroquine (CQ), the abundance of mKeima-LC3B-II was significantly increased. Remarkably, when cultured medium was repeatedly changed between DMEM (nutrient-rich) and EBSS (starvation), acidic/neutral signal ratios of mKeima-LC3B-positive compartments were rapidly and reversibly shifted, which were suppressed by the CQ treatment, indicating that intraluminal pH of mKeima-LC3B-positive vesicles was changeable upon nutritional conditions of culture media. Taken together, although mKeima-LC3B-tg mice may not be an appropriate tool to monitor the autophagy-endolysosomal system in vivo, mKeima-LC3B must be one of the most sensitive reporter molecules for monitoring this system under in vitro cultured conditions.}, }
@article {pmid32508590, year = {2020}, author = {Jara, JH and Sheets, PL and Nigro, MJ and Perić, M and Brooks, C and Heller, DB and Martina, M and Andjus, PR and Ozdinler, PH}, title = {The Electrophysiological Determinants of Corticospinal Motor Neuron Vulnerability in ALS.}, journal = {Frontiers in molecular neuroscience}, volume = {13}, number = {}, pages = {73}, pmid = {32508590}, issn = {1662-5099}, abstract = {The brain is complex and heterogeneous. Even though numerous independent studies indicate cortical hyperexcitability as a potential contributor to amyotrophic lateral sclerosis (ALS) pathology, the mechanisms that are responsible for upper motor neuron (UMN) vulnerability remain elusive. To reveal the electrophysiological determinants of corticospinal motor neuron (CSMN, a.k.a UMN in mice) vulnerability, we investigated the motor cortex of hSOD1[G93A] mice at P30 (postnatal day 30), a presymptomatic time point. Glutamate uncaging by laser scanning photostimulation (LSPS) revealed altered dynamics especially within the inhibitory circuitry and more specifically in L2/3 of the motor cortex, whereas the excitatory microcircuits were unchanged. Observed microcircuitry changes were specific to CSMN in the motor column. Electrophysiological evaluation of the intrinsic properties in response to the microcircuit changes, as well as the exon microarray expression profiles of CSMN isolated from hSOD1[G93A] and healthy mice at P30, revealed the presence of a very dynamic set of events, ultimately directed to establish, maintain and retain the balance at this early stage. Also, the expression profile of key voltage-gated potassium and sodium channel subunits as well as of the inhibitory GABA receptor subunits and modulatory proteins began to suggest the challenges CSMN face at this early age. Since neurodegeneration is initiated when neurons can no longer maintain balance, the complex cellular events that occur at this critical time point help reveal how CSMN try to cope with the challenges of disease manifestation. This information is critically important for the proper modulation of UMNs and for developing effective treatment strategies.}, }
@article {pmid32507583, year = {2021}, author = {López-Gómez, JJ and Ballesteros-Pomar, MD and Torres-Torres, B and De la Maza, BP and Penacho-Lázaro, M&#xc1; and Palacio-Mures, JM and Abreu-Padín, C and López-Guzmán, A and De Luis-Román, DA}, title = {Malnutrition at diagnosis in amyotrophic lateral sclerosis (als) and its influence on survival: Using glim criteria.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {40}, number = {1}, pages = {237-244}, doi = {10.1016/j.clnu.2020.05.014}, pmid = {32507583}, issn = {1532-1983}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*mortality/physiopathology ; Anthropometry ; Body Mass Index ; Female ; Humans ; Longitudinal Studies ; Male ; Malnutrition/*diagnosis/etiology/mortality ; Middle Aged ; *Nutrition Assessment ; Nutritional Status ; Predictive Value of Tests ; Prognosis ; Risk Assessment/*methods ; Risk Factors ; *Severity of Illness Index ; Spain ; Time Factors ; Weight Loss ; }, abstract = {BACKGROUND: Malnutrition is a prognostic factor in Amyotrophic Lateral Sclerosis (ALS). Sometimes, this condition is underdiagnosed, and it might influence on disease progression.<br><br>AIMS: To evaluate a) nutritional status at the beginning of specialized nutritional treatment and b) the influence of initial nutritional status on disease evolution and survival in a group of patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: An interhospital registry of patients with motor neuron disease treated at the Clinical Nutrition Clinics of six hospitals in the region of Castilla y Le&#xf3;n in Spain was created. The study was developed from January 2015 to December 2017. An anamnesis, affiliation data, past medical history, disease evolution, nutritional history and an anthropometry and bioelectrical impedance analysis were performed at baseline. The mortality rate was compared among those patients with worse nutritional status at the beginning of the follow-up against those with a better nutritional situation using two tools: The Subjective Global Assessment (SGA) and the criteria of the Global Leadership Initiative for Malnutrition (GLIM).<br><br>RESULTS: A total of 93 patients were analysed. The median age of the patients was 67 (57.5-75.5) years. The median Body Mass Index was 24.4 (21.7-25.9) kg/m[2] and the median percentage of weight loss was 9.32 (2.7-17.6)% without differences between the onset type. According to the SGA, 27 (29%) patients were in grade A; 43 (46.3%) patients were in grade B and 23 (24.7%) were in grade C. According to the new GLIM malnutrition criteria, 45 patients (48.4%) had malnutrition. Patients with worse nutritional status had a lower survival median with both SGA (SGA A: 20.5 (10.2-35) months vs SGA B-C: 12 (5.2-23.7) months (p&#xa0;=&#xa0;0.03)) or the new GLIM criteria according to severity (severe malnutrition: 18 (5-24) months vs. no severe malnutrition: 20 (12-33) months (p&#xa0;=&#xa0;0.01)). In the multivariate analysis, malnutrition measured by SGA was an independent risk factor (HR: 4.6 (1.5-13.9) p&#xa0;=&#xa0;0.007) for survival over 15 months when adjusted for age, sex and type of onset of ALS.<br><br>CONCLUSIONS: Patients with ALS have a severe deterioration in nutritional status when analysed using a classical malnutrition test (SGA) or a new one (GLIM criteria). Patients with a better nutritional situation according to SGA and GLIM severity classification were associated with a longer survival time.}, }
@article {pmid32503641, year = {2020}, author = {Machhi, J and Kevadiya, BD and Muhammad, IK and Herskovitz, J and Olson, KE and Mosley, RL and Gendelman, HE}, title = {Harnessing regulatory T cell neuroprotective activities for treatment of neurodegenerative disorders.}, journal = {Molecular neurodegeneration}, volume = {15}, number = {1}, pages = {32}, pmid = {32503641}, issn = {1750-1326}, support = {P01 DA028555/DA/NIDA NIH HHS/United States ; P30 MH062261/MH/NIMH NIH HHS/United States ; T32 NS105594/NS/NINDS NIH HHS/United States ; R01 AG043540/AG/NIA NIH HHS/United States ; R01 NS034239/NS/NINDS NIH HHS/United States ; R01 MH115860/MH/NIMH NIH HHS/United States ; P01 NS043985/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/immunology/metabolism/*therapy ; Animals ; Humans ; Inflammation/metabolism ; Neurodegenerative Diseases/immunology/*therapy ; *Neuroprotection ; Parkinson Disease/immunology/metabolism ; T-Lymphocytes, Regulatory/*immunology ; }, abstract = {Emerging evidence demonstrates that adaptive immunity influences the pathobiology of neurodegenerative disorders. Misfolded aggregated self-proteins can break immune tolerance leading to the induction of autoreactive effector T cells (Teffs) with associated decreases in anti-inflammatory neuroprotective regulatory T cells (Tregs). An imbalance between Teffs and Tregs leads to microglial activation, inflammation and neuronal injury. The cascade of such a disordered immunity includes the drainage of the aggregated protein antigens into cervical lymph nodes serving to amplify effector immune responses. Both preclinical and clinical studies demonstrate transformation of this altered immunity for therapeutic gain. We posit that the signs and symptoms of common neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and stroke can be attenuated by boosting Treg activities.}, }
@article {pmid32502186, year = {2020}, author = {Sell, SL and Widen, SG and Prough, DS and Hellmich, HL}, title = {Principal component analysis of blood microRNA datasets facilitates diagnosis of diverse diseases.}, journal = {PloS one}, volume = {15}, number = {6}, pages = {e0234185}, pmid = {32502186}, issn = {1932-6203}, mesh = {*Diagnosis ; Humans ; MicroRNAs/*blood ; *Principal Component Analysis ; Risk ; }, abstract = {Early, ideally pre-symptomatic, recognition of common diseases (e.g., heart disease, cancer, diabetes, Alzheimer's disease) facilitates early treatment or lifestyle modifications, such as diet and exercise. Sensitive, specific identification of diseases using blood samples would facilitate early recognition. We explored the potential of disease identification in high dimensional blood microRNA (miRNA) datasets using a powerful data reduction method: principal component analysis (PCA). Using Qlucore Omics Explorer (QOE), a dynamic, interactive visualization-guided bioinformatics program with a built-in statistical platform, we analyzed publicly available blood miRNA datasets from the Gene Expression Omnibus (GEO) maintained at the National Center for Biotechnology Information at the National Institutes of Health (NIH). The miRNA expression profiles were generated from real time PCR arrays, microarrays or next generation sequencing of biologic materials (e.g., blood, serum or blood components such as platelets). PCA identified the top three principal components that distinguished cohorts of patients with specific diseases (e.g., heart disease, stroke, hypertension, sepsis, diabetes, specific types of cancer, HIV, hemophilia, subtypes of meningitis, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, mild cognitive impairment, aging, and autism), from healthy subjects. Literature searches verified the functional relevance of the discriminating miRNAs. Our goal is to assemble PCA and heatmap analyses of existing and future blood miRNA datasets into a clinical reference database to facilitate the diagnosis of diseases using routine blood draws.}, }
@article {pmid32500377, year = {2020}, author = {Wen, X and An, P and Li, H and Zhou, Z and Sun, Y and Wang, J and Ma, L and Lu, B}, title = {Tau Accumulation via Reduced Autophagy Mediates GGGGCC Repeat Expansion-Induced Neurodegeneration in Drosophila Model of ALS.}, journal = {Neuroscience bulletin}, volume = {36}, number = {12}, pages = {1414-1428}, pmid = {32500377}, issn = {1995-8218}, mesh = {Adaptor Proteins, Signal Transducing ; *Amyotrophic Lateral Sclerosis/genetics ; Animals ; Apoptosis Regulatory Proteins ; *Autophagy ; C9orf72 Protein/genetics ; *DNA Repeat Expansion ; Disease Models, Animal ; Drosophila/metabolism ; *Frontotemporal Dementia/genetics ; Humans ; tau Proteins/*metabolism ; }, abstract = {Expansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders, including Huntington disease [caused by expanded CAG repeats (CAGr) in the HTT gene], and amyotrophic lateral sclerosis [ALS, possibly caused by expanded GGGGCC repeats (G4C2r) in the C9ORF72 gene], of which the molecular mechanisms remain unclear. Here, we demonstrated that lowering the Drosophila homologue of tau protein (dtau) significantly rescued in vivo neurodegeneration, motor performance impairments, and the shortened life-span in Drosophila expressing expanded CAGr or expanded G4C2r. Expression of human tau (htau4R) restored the disease-related phenotypes that had been mitigated by the loss of dtau, suggesting an evolutionarily-conserved role of tau in neurodegeneration. We further revealed that G4C2r expression increased tau accumulation by inhibiting autophagosome-lysosome fusion, possibly due to lowering the level of BAG3, a regulator of autophagy and tau. Taken together, our results reveal a novel mechanism by which expanded G4C2r causes neurodegeneration via an evolutionarily-conserved mechanism. Our findings provide novel autophagy-related mechanistic insights into C9ORF72-ALS and possible entry points to disease treatment.}, }
@article {pmid32498636, year = {2020}, author = {Lind, LA and Andel, EM and McCall, AL and Dhindsa, JS and Johnson, KA and Stricklin, OE and Mueller, C and ElMallah, MK and Lever, TE and Nichols, NL}, title = {Intralingual Administration of AAVrh10-miR[SOD1] Improves Respiratory But Not Swallowing Function in a Superoxide Dismutase-1 Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Human gene therapy}, volume = {31}, number = {15-16}, pages = {828-838}, pmid = {32498636}, issn = {1557-7422}, support = {K99 HL119606/HL/NHLBI NIH HHS/United States ; R00 HL119606/HL/NHLBI NIH HHS/United States ; R21 DC016071/DC/NIDCD NIH HHS/United States ; R21 NS098131/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Animals ; *Deglutition ; Dependovirus/*genetics ; Disease Models, Animal ; Female ; *Genetic Therapy ; Genetic Vectors/*administration &amp; dosage ; Male ; Mice ; Mice, Inbred C57BL ; MicroRNAs/*genetics ; Phenotype ; Respiratory Insufficiency/etiology/metabolism/pathology/*therapy ; Superoxide Dismutase-1/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by degeneration of motor neurons and muscles, and death is usually a result of impaired respiratory function due to loss of motor neurons that control upper airway muscles and/or the diaphragm. Currently, no cure for ALS exists and treatments to date do not significantly improve respiratory or swallowing function. One cause of ALS is a mutation in the superoxide dismutase-1 (SOD1) gene; thus, reducing expression of the mutated gene may slow the progression of the disease. Our group has been studying the SOD1[G93A] transgenic mouse model of ALS that develops progressive respiratory deficits and dysphagia. We hypothesize that solely treating the tongue in SOD1 mice will preserve respiratory and swallowing function, and it will prolong survival. At 6 weeks of age, 11 SOD1[G93A] mice (both sexes) received a single intralingual injection of gene therapy (AAVrh10-miR[SOD1]). Another 29 mice (both sexes) were divided into two control groups: (1) 12 SOD1[G93A] mice that received a single intralingual vehicle injection (saline); and (2) 17 non-transgenic littermates. Starting at 13 weeks of age, plethysmography (respiratory parameters) at baseline and in response to hypoxia (11% O2) + hypercapnia (7% CO2) were recorded and videofluoroscopic swallow study testing were performed twice monthly until end-stage disease. Minute ventilation during hypoxia + hypercapnia and mean inspiratory flow at baseline were significantly reduced (p < 0.05) in vehicle-injected, but not AAVrh10-miR[SOD1]-injected SOD1[G93A] mice as compared with wild-type mice. In contrast, swallowing function was unchanged by AAVrh10-miR[SOD1] treatment (p > 0.05). AAVrh10-miR[SOD1] injections also significantly extended survival in females by ∼1 week. In conclusion, this study indicates that intralingual AAVrh10-miR[SOD1] treatment preserved respiratory (but not swallowing) function potentially via increasing upper airway patency, and it is worthy of further exploration as a possible therapy to preserve respiratory capacity in ALS patients.}, }
@article {pmid32497448, year = {2020}, author = {Perrone, B and Conforti, FL}, title = {Common mutations of interest in the diagnosis of amyotrophic lateral sclerosis: how common are common mutations in ALS genes?.}, journal = {Expert review of molecular diagnostics}, volume = {20}, number = {7}, pages = {703-714}, doi = {10.1080/14737159.2020.1779060}, pmid = {32497448}, issn = {1744-8352}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/ethnology/*genetics ; C9orf72 Protein/genetics ; DNA Mutational Analysis/methods ; DNA Repeat Expansion ; DNA-Binding Proteins/genetics ; Ethnicity/genetics ; Gene Frequency ; Genetic Predisposition to Disease ; High-Throughput Nucleotide Sequencing ; Humans ; Molecular Diagnostic Techniques ; *Mutation ; Mutation, Missense ; Protein Aggregation, Pathological/genetics ; RNA-Binding Protein FUS/genetics ; Sequence Analysis, DNA/methods ; Superoxide Dismutase-1/genetics ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease predominantly affecting upper and lower motor neurons. Diagnosis of this devastating pathology is very difficult because the high degree of clinical heterogeneity with which it occurs and until now, no truly effective treatment exists.<br><br>AREAS COVERED: Molecular diagnosis may be a valuable tool for dissecting out ALS complex heterogeneity and for identifying new molecular mechanisms underlying the characteristic selective degeneration and death of motor neurons. To date, pathogenic variants in ALS genes are known to be present in up to 70% of familial and 10% of apparently sporadic ALS cases and can be associated with risks for ALS only or risks for other neurodegenerative diseases. This paper shows the procedure currently used in diagnostic laboratories to investigate most frequent mutations in ALS and evaluating the utility of involved molecular techniques as potential tools to discriminate 'common mutations' in ALS patients.<br><br>EXPERT OPINION: Genetic testing may allow for establishing an accurate pathological diagnosis and a more precise stratification of patient groups in future drug trials.}, }
@article {pmid32487123, year = {2020}, author = {Liscic, RM and Alberici, A and Cairns, NJ and Romano, M and Buratti, E}, title = {From basic research to the clinic: innovative therapies for ALS and FTD in the pipeline.}, journal = {Molecular neurodegeneration}, volume = {15}, number = {1}, pages = {31}, pmid = {32487123}, issn = {1750-1326}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Atrophy/genetics ; Frontotemporal Dementia/genetics/*therapy ; Humans ; Mutation/genetics ; Neurodegenerative Diseases/*therapy ; *Therapies, Investigational/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and Frontotemporal Degeneration (FTD) are neurodegenerative disorders, related by deterioration of motor and cognitive functions and short survival. Aside from cases with an inherited pathogenic mutation, the causes of the disorders are still largely unknown and no effective treatment currently exists. It has been shown that FTD may coexist with ALS and this overlap occurs at clinical, genetic, and molecular levels. In this work, we review the main pathological aspects of these complex diseases and discuss how the integration of the novel pathogenic molecular insights and the analysis of molecular interaction networks among all the genetic players represents a critical step to shed light on discovering novel therapeutic strategies and possibly tailoring personalized medicine approaches to specific ALS and FTD patients.}, }
@article {pmid32485268, year = {2020}, author = {Smaga, I and Fierro, D and Mesa, J and Filip, M and Knackstedt, LA}, title = {Molecular changes evoked by the beta-lactam antibiotic ceftriaxone across rodent models of substance use disorder and neurological disease.}, journal = {Neuroscience and biobehavioral reviews}, volume = {115}, number = {}, pages = {116-130}, pmid = {32485268}, issn = {1873-7528}, support = {R01 DA033436/DA/NIDA NIH HHS/United States ; }, mesh = {Amyloid beta-Peptides ; Animals ; Anti-Bacterial Agents ; *Ceftriaxone ; Excitatory Amino Acid Transporter 2 ; Glutamic Acid ; Rodentia ; *Substance-Related Disorders ; }, abstract = {Ceftriaxone is a beta-lactam antibiotic that increases the expression of the major glutamate transporter, GLT-1. As such, ceftriaxone ameliorates symptoms across multiple rodent models of neurological diseases and substance use disorders. However, the mechanism behind GLT-1 upregulation is unknown. The present review synthesizes this literature in order to identify commonalities in molecular changes. We find that ceftriaxone (200 mg/kg for at least two days) consistently restores GLT-1 expression in multiple rodent models of neurological disease, especially when GLT-1 is decreased in the disease model. The same dose given to healthy/drug-naive rodents does not reliably upregulate GLT-1 in any brain region except the hippocampus. Increased GLT-1 expression does not consistently arise from transcriptional regulation, and is likely to be due to trafficking changes. In addition to altered transporter expression, ceftriaxone ameliorates neuropathologies (e.g. tau, amyloid beta, cell death) and aberrant protein expression associated with a number of neurological disease models. Taken together, these results indicate that ceftriaxone remains a strong candidate for treatment of multiple disorders in the clinic.}, }
@article {pmid32483988, year = {2020}, author = {Inglet, S and Winter, B and Yost, SE and Entringer, S and Lian, A and Biksacky, M and Pitt, RD and Mortensen, W}, title = {Clinical Data for the Use of Cannabis-Based Treatments: A Comprehensive Review of the Literature.}, journal = {The Annals of pharmacotherapy}, volume = {54}, number = {11}, pages = {1109-1143}, doi = {10.1177/1060028020930189}, pmid = {32483988}, issn = {1542-6270}, mesh = {Clinical Trials as Topic ; Drug Utilization Review/*trends ; Humans ; Medical Marijuana/administration &amp; dosage/adverse effects/*therapeutic use ; Multiple Sclerosis/drug therapy ; Nausea/drug therapy ; Pain/drug therapy ; Practice Guidelines as Topic ; Vomiting/drug therapy ; }, abstract = {OBJECTIVE: To compile and synthesize the available literature describing medical cannabis use across various disease states.<br><br>DATA SOURCES: PubMed, EBSCO, and Google Scholar searches were conducted using MeSH and/or keywords.<br><br>Studies were included if they described the use of cannabis-based products and medications in the treatment of a predefined list of disease states in humans and were published in English. The extraction period had no historical limit and spanned through April 2019.<br><br>DATA SYNTHESIS: Evidence was compiled and summarized for the following medical conditions: Alzheimer disease, amyotrophic lateral sclerosis, autism, cancer and cancer-associated adverse effects, seizure disorders, human immunodeficiency virus, inflammatory bowel disease, multiple sclerosis (MS), nausea, pain, posttraumatic stress disorder, and hospice care.<br><br>Based on identified data, the most robust evidence suggests that medical cannabis may be effective in the treatment of chemotherapy-induced nausea and vomiting, seizure disorders, MS-related spasticity, and pain (excluding diabetic neuropathy). Overall, the evidence is inconsistent and generally limited by poor quality. The large variation in cannabis-based products evaluated in studies limits the ability to make direct comparisons. Regardless of the product, a gradual dose titration was utilized in most studies. Cannabis-based therapies were typically well tolerated, with the most common adverse effects being dizziness, somnolence, dry mouth, nausea, and euphoria.<br><br>CONCLUSIONS: As more states authorize medical cannabis use, there is an increasing need for high-quality clinical evidence describing its efficacy and safety. This review is intended to serve as a reference for clinicians, so that the risks and realistic benefits of medical cannabis are better understood.}, }
@article {pmid32481440, year = {2020}, author = {Chen, PC and Hsieh, YC and Huang, CC and Hu, CJ}, title = {Tamoxifen for amyotrophic lateral sclerosis: A randomized double-blind clinical trial.}, journal = {Medicine}, volume = {99}, number = {22}, pages = {e20423}, doi = {10.1097/MD.0000000000020423}, pmid = {32481440}, issn = {1536-5964}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Autophagy/drug effects ; Disease Progression ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Severity of Illness Index ; Tamoxifen/*therapeutic use ; Treatment Outcome ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is the most common cause of motor neuron disease, and effective treatment for ALS is still lacking. Transactive response (TAR) -DNA-binding protein-43 (TDP-43) is aggregated in the neurons of ALS patients. Animal studies shown TDP-43 aggregation can be attenuated by enhancing autophagy by tamoxifen. However, its beneficial effects for ALS patients remain unknown.<br><br>METHODS: Eighteen patients with ALS without mutations in superoxide dismutase-1 (SOD-1) or fused in sarcoma (FUS) genes were randomly assigned into the tamoxifen 40&#x200a;mg/day or placebo group in a double-blinded manner and all were given riluzole twice daily. Participants were followed up at 1, 3, 6, and 12 months. The primary end point was time to death or dependence on mechanical ventilation. Secondary end points were decline of the revised ALS Functional Rating Scale (ALSFRS-R) score and pulmonary function measured by forced vital capacity (FVC).<br><br>RESULTS: Ten participants were randomly assigned in the treatment group with tamoxifen, 7 finished trial, 1 reach primary endpoint; while 8 participants in the placebo group, 2 finished trial and 2 reach primary end point. The proportion of participants reaching the primary end point was lower in the tamoxifen group but did not reach statistical significance. At the 1-, 3-, and 6-month follow-up, the average decline rates of the ALSFRS-R score were slower in the tamoxifen group. No significant difference was observed in FVC and ALSFRS-R score at 12 months between groups.<br><br>CONCLUSION: Tamoxifen exerted only a modest effect on attenuate progression for 6 months in this small trial. Additional larger scale studies should be necessary to confirm whether enhancing autophagy can attenuate ALS progression.}, }
@article {pmid32479211, year = {2020}, author = {Reyhani, S and Abbaspanah, B and Mousavi, SH}, title = {Umbilical cord-derived mesenchymal stem cells in neurodegenerative disorders: from literature to clinical practice.}, journal = {Regenerative medicine}, volume = {15}, number = {4}, pages = {1561-1578}, doi = {10.2217/rme-2019-0119}, pmid = {32479211}, issn = {1746-076X}, mesh = {Animals ; Cell- and Tissue-Based Therapy/*methods ; Humans ; Mesenchymal Stem Cell Transplantation/*methods ; Mesenchymal Stem Cells/*cytology ; Neurodegenerative Diseases/*therapy ; Umbilical Cord/*cytology ; }, abstract = {Mesenchymal stem cells (MSCs) have provided a promising tool for cell therapy. Umbilical cord (UC) is one of the best sources of MSCs since its collection is noninvasive, and effortless, and the cells from this source are more capable and prolific. It has been proven that the differentiation, migration and protective properties of UC-MSCs are superior compared with other kinds of stem cells. Moreover, incurable neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and Huntington, encourage scientists to apply UC-MSCs transplantation in order to find a definite treatment. This review will focus on the preclinical and clinical use of mesenchymal stem cells derived from human umbilical cord in the treatment of neurodegenerative disorders.}, }
@article {pmid32477070, year = {2020}, author = {Paez-Colasante, X and Figueroa-Romero, C and Rumora, AE and Hur, J and Mendelson, FE and Hayes, JM and Backus, C and Taubman, GF and Heinicke, L and Walter, NG and Barmada, SJ and Sakowski, SA and Feldman, EL}, title = {Cytoplasmic TDP43 Binds microRNAs: New Disease Targets in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {14}, number = {}, pages = {117}, pmid = {32477070}, issn = {1662-5102}, support = {P30 AG053760/AG/NIA NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R01 GM081025/GM/NIGMS NIH HHS/United States ; K99 DK119366/DK/NIDDK NIH HHS/United States ; R00 DK119366/DK/NIDDK NIH HHS/United States ; F32 DK112642/DK/NIDDK NIH HHS/United States ; R01 GM062357/GM/NIGMS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, and incurable neurodegenerative disease. Recent studies suggest that dysregulation of gene expression by microRNAs (miRNAs) may play an important role in ALS pathogenesis. The reversible nature of this dysregulation makes miRNAs attractive pharmacological targets and a potential therapeutic avenue. Under physiological conditions, miRNA biogenesis, which begins in the nucleus and includes further maturation in the cytoplasm, involves trans-activation response element DNA/RNA-binding protein of 43 kDa (TDP43). However, TDP43 mutations or stress trigger TDP43 mislocalization and inclusion formation, a hallmark of most ALS cases, that may lead to aberrant protein/miRNA interactions in the cytoplasm. Herein, we demonstrated that TDP43 exhibits differential binding affinity for select miRNAs, which prompted us to profile miRNAs that preferentially bind cytoplasmic TDP43. Using cellular models expressing TDP43 variants and miRNA profiling analyses, we identified differential levels of 65 cytoplasmic TDP43-associated miRNAs. Of these, approximately 30% exhibited levels that differed by more than 3-fold in the cytoplasmic TDP43 models relative to our control model. The hits included both novel miRNAs and miRNAs previously associated with ALS that potentially regulate several predicted genes and pathways that may be important for pathogenesis. Accordingly, these findings highlight specific miRNAs that may shed light on relevant disease pathways and could represent potential biomarkers and reversible treatment targets for ALS.}, }
@article {pmid32471460, year = {2020}, author = {Paulin, J and Kurola, J and Salanterä, S and Moen, H and Guragain, N and Koivisto, M and Käyhkö, N and Aaltonen, V and Iirola, T}, title = {Changing role of EMS -analyses of non-conveyed and conveyed patients in Finland.}, journal = {Scandinavian journal of trauma, resuscitation and emergency medicine}, volume = {28}, number = {1}, pages = {45}, pmid = {32471460}, issn = {1757-7241}, support = {315376//Academy of Finland/ ; }, mesh = {Aged ; Aged, 80 and over ; *Decision Making ; Emergency Medical Services/*methods ; Female ; Finland ; Humans ; Male ; Middle Aged ; Patient Safety ; Prospective Studies ; *Rural Population ; }, abstract = {BACKGROUND: Emergency Medical Services (EMS) and Emergency Departments (ED) have seen increasing attendance rates in the last decades. Currently, EMS are increasingly assessing and treating patients without the need to convey patients to health care facility. The aim of this study was to describe and compare the patient case-mix between conveyed and non-conveyed patients and to analyze factors related to non-conveyance decision making.<br><br>METHODS: This was a prospective study design of EMS patients in Finland, and data was collected between 1st June and 30th November 2018. Adjusted ICPC2-classification was used as the reason for care. NEWS2-points were collected and analyzed both statistically and with a semi-supervised information extraction method. EMS patients' geographic location and distance to health care facilities were analyzed by urban-rural classification.<br><br>RESULTS: Of the EMS patients (40,263), 59.8% were over 65&#x2009;years of age and 46.0% of the patients had zero NEWS2 points. The most common ICPC2 code was weakness/tiredness, general (A04), as seen in 13.5% of all patients. When comparing patients between the non-conveyance and conveyance group, a total of 35,454 EMS patients met the inclusion criteria and 14,874 patients (42.0%) were not conveyed to health care facilities. According the multivariable logistic regression model, the non-conveyance decision was more likely made by ALS units, when the EMS arrival time was in the evening or night and when the distance to the health care facility was 21-40&#x2009;km. Furthermore, younger patients, female gender, whether the patient had used alcohol and a rural area were also related to the non-conveyance decision. If the patient's NEWS2 score increased by one or two points, the likelihood of conveyance increased. When there was less than 1 h to complete a shift, this did not associate with either non-conveyance or conveyance decisions.<br><br>CONCLUSIONS: The role of EMS might be changing. This warrants to redesign the chain-of-survival in EMS to include not only high-risk patient groups but also non-critical and general acute patients with non-specific reasons for care. Assessment and on-scene treatment without conveyance can be called the "stretched arm of the emergency department", but should be planned carefully to ensure patient safety.}, }
@article {pmid32471290, year = {2020}, author = {Zwilling, M and Theiss, C and Matschke, V}, title = {Caffeine and NAD[+] Improve Motor Neural Integrity of Dissociated Wobbler Cells In Vitro.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {6}, pages = {}, pmid = {32471290}, issn = {2076-3921}, support = {F976-20//Ruhr-Universit&#xe4;t Bochum/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a common degenerative disease of the central nervous system concerning a progressive loss of upper and lower motor neurons. While 5%-10% of patients are diagnosed with the inherited form of the disease, the vast majority of patients suffer from the less characterized sporadic form of ALS (sALS). As the wobbler mouse and the ALS show striking similarities in view of phenotypical attributes, the mouse is rated as an animal model for the disease. Recent investigations show the importance of nicotinamide adenine dinucleotide (NAD[+]) and its producing enzyme nicotinic acid mononucleotide transferase 2 (Nmnat2) for neurodegeneration as well as for the preservation of health of the neuronal cells. Furthermore, it is newly determined that these molecules show significant downregulations in the spinal cord of wobbler mice in the stable phase of disease development. Here, we were able to prove a positive benefit on affected motor neurons from an additional NAD[+] supply as well as an increase in the Nmnat2 level through caffeine treatment in cells in vitro. In addition, first assumptions about the importance of endogenous and exogenous factors that have an influence on the wellbeing of motor nerve cells in the model of ALS can be considered.}, }
@article {pmid32468595, year = {2020}, author = {Mir, BA and Mason, SA and May, AK and Russell, AP and Foletta, VC}, title = {Overexpression of NDRG2 in skeletal muscle does not ameliorate the effects of stress in vivo.}, journal = {Experimental physiology}, volume = {105}, number = {8}, pages = {1326-1338}, doi = {10.1113/EP088620}, pmid = {32468595}, issn = {1469-445X}, support = {//Institute for Physical Activity and Nutrition (IPAN)/ ; //Deakin University/ ; }, mesh = {Adaptor Proteins, Signal Transducing/*genetics ; Animals ; Chronic Disease ; Disease Models, Animal ; Endoplasmic Reticulum Stress ; Fasting ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondria ; Muscle, Skeletal/*metabolism ; Oxidative Stress ; Signal Transduction ; *Stress, Physiological ; Superoxide Dismutase/metabolism ; }, abstract = {NEW FINDINGS: What is the central question of this study? Do elevated levels of the stress-response protein NDRG2 protect against fasting and chronic disease in mouse skeletal muscle? What is the main finding and its importance? NDRG2 levels increased in the tibialis anterior muscle in response to fasting and the effects of motor neurone disease. No alleviation of the stress-related and proteasomal pathways, mitochondrial dysfunction or muscle mass loss was observed even with the addition of exogenous NDRG2 indicating that the increase in NDRG2 is a normal adaptive response.<br><br>ABSTRACT: Skeletal muscle mass loss and dysfunction can arise from stress, which leads to enhanced protein degradation and metabolic impairment. The expression of N-myc downstream-regulated gene&#xa0;2 (NDRG2) is induced in response to different stressors and is protective against the effects of stress in some tissues and cell types. Here, we investigated the endogenous NDRG2 response to the stress of fasting and chronic disease in mice and whether exogenous NDRG2 overexpression through adeno-associated viral (AAV) treatment ameliorated the response of skeletal muscle to these conditions. Endogenous levels of NDRG2 increased in the tibialis anterior muscle in response to 24&#xa0;h fasting and with the development of the motor neurone disease, amyotrophic lateral sclerosis, in SOD1[G93A] transgenic mice. Despite AAV-induced overexpression and increased expression with fasting, NDRG2 was unable to protect against the activation of proteasomal and stress pathways in response to fasting. Furthermore, NDRG2 was unable to reduce muscle mass loss, mitochondrial dysfunction and elevated oxidative and endoplasmic reticulum stress levels in SOD1[G93A] mice. Conversely, elevated NDRG2 levels did not exacerbate these stress responses. Overall, increasing NDRG2 levels might not be a useful therapeutic strategy to alleviate stress-related disease pathologies in skeletal muscle.}, }
@article {pmid32468479, year = {2020}, author = {Krokidis, MG}, title = {Transcriptomics and Metabolomics in Amyotrophic Lateral Sclerosis.}, journal = {Advances in experimental medicine and biology}, volume = {1195}, number = {}, pages = {205-212}, pmid = {32468479}, issn = {0065-2598}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism ; Gene Expression Profiling ; Humans ; *Metabolomics ; *Transcriptome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive and selective loss of motor neurons, muscle weakness, paralysis and death. The pathogenesis of ALS is not clearly understood, while reliable prognostic markers have not been identified to detect symptoms at earlier time points. The rapid development of microarray technology offers great potential for simultaneous analysis of the transcriptional expression of thousands of genes, aiming to determine novel candidate targets for efficient treatment. Additionally, metabolomics, as a high-throughput approach, is gaining significant attention in ALS research providing an opportunity to develop predictive biomarkers that may be utilized as indicators of clinical symptoms of ALS. In this review, recent evidences from gene expression profiling studies in ALS are illustrated in order to examine molecular signatures related to the disease's pathogenesis and potential discovery of therapeutic targets. Moreover, potent challenges are presented regarding the utilization of the metabolomics approach as a diagnostic tool in context with distinctive biomarkers' identification.}, }
@article {pmid32467611, year = {2019}, author = {Arnold, C}, title = {Tailored treatment for ALS poised to move ahead.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, doi = {10.1038/d41591-019-00013-w}, pmid = {32467611}, issn = {1546-170X}, }
@article {pmid32464743, year = {2020}, author = {Uddin, MS and Hossain, MF and Mamun, AA and Shah, MA and Hasana, S and Bulbul, IJ and Sarwar, MS and Mansouri, RA and Ashraf, GM and Rauf, A and Abdel-Daim, MM and Bin-Jumah, MN}, title = {Exploring the multimodal role of phytochemicals in the modulation of cellular signaling pathways to combat age-related neurodegeneration.}, journal = {The Science of the total environment}, volume = {725}, number = {}, pages = {138313}, doi = {10.1016/j.scitotenv.2020.138313}, pmid = {32464743}, issn = {1879-1026}, mesh = {Humans ; Mitochondria ; *Neurodegenerative Diseases ; *Neuroprotective Agents ; Oxidative Stress ; Phytochemicals ; }, abstract = {Neurodegeneration is the progressive loss of neuronal structures and functions that lead to copious disorders like Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), amyotrophic lateral sclerosis (ALS), and other less recurring diseases. Aging is the prime culprit for most neurodegenerative events. Moreover, the shared pathogenic factors of many neurodegenerative processes are inflammatory responses and oxidative stress (OS). Unfortunately, it is very complicated to treat neurodegeneration and there is no effective remedy. The rapid progression of the neurodegenerative diseases that exacerbate the burden and the concurrent absence of effective treatment strategies force the researchers to investigate more therapeutic approaches that ultimately target the causative factors of the neurodegeneration. Phytochemicals have great potential to exert their neuroprotective effects by targeting various mechanisms, such as OS, neuroinflammation, abnormal protein aggregation, neurotrophic factor deficiency, disruption in mitochondrial function, and apoptosis. Therefore, this review represents the molecular mechanisms of neuroprotection by multifunctional phytochemicals to combat age-linked neurodegenerative disorders.}, }
@article {pmid32462331, year = {2020}, author = {Boentert, M}, title = {Sleep and Sleep Disruption in Amyotrophic Lateral Sclerosis.}, journal = {Current neurology and neuroscience reports}, volume = {20}, number = {7}, pages = {25}, pmid = {32462331}, issn = {1534-6293}, mesh = {*Amyotrophic Lateral Sclerosis/complications/epidemiology/therapy ; Humans ; Polysomnography ; Quality of Life ; *Respiratory Insufficiency ; Sleep ; }, abstract = {PURPOSE OF REVIEW: In amyotrophic lateral sclerosis (ALS), sleep disruption is frequently present and substantially adds to disease burden. This review aims to summarize current knowledge on causes, pathophysiology, and treatment of sleep disturbances in ALS.<br><br>RECENT FINDINGS: Motor neuron degeneration and muscle weakness may lead to muscle cramps, pain, spasticity, immobilization, restless legs, sleep-disordered breathing, and difficulties to clear secretions. Furthermore, existential fears and depression may promote insomnia. Sleep-disordered breathing, and nocturnal hypoventilation in particular, requires ventilatory support which meaningfully prolongs survival and improves health-related quality of life albeit respiratory failure is inevitable. Early indication for non-invasive ventilation can be achieved by inclusion of capnometry in diagnostic sleep studies. Sleep disruption is extremely common in ALS and may arise from different etiologies. The absence of causative therapeutic options for ALS underlines the importance of symptomatic and palliative treatment strategies that acknowledge sleep-related complaints.}, }
@article {pmid32462265, year = {2021}, author = {Zhao, Z and Li, R and Wang, X and Li, J and Yuan, M and Liu, E and Liu, T and Li, G}, title = {Attenuation of atrial remodeling by aliskiren via affecting oxidative stress, inflammation and PI3K/Akt signaling pathway.}, journal = {Cardiovascular drugs and therapy}, volume = {35}, number = {3}, pages = {587-598}, pmid = {32462265}, issn = {1573-7241}, mesh = {Amides/*pharmacology ; Animals ; Atrial Remodeling/*drug effects ; Dogs ; Echocardiography ; Female ; Fumarates/*pharmacology ; Inflammation Mediators/metabolism ; Male ; Oxidative Stress/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Random Allocation ; Signal Transduction/drug effects ; Wortmannin/pharmacology ; }, abstract = {INTRODUCTION: Atrial fibrillation (AF) is the most common type of arrhythmia. Atrial remodeling is a major factor to the AF substrate. The purpose of the study is to explore whether aliskiren (ALS) has a cardioprotective effect and its potential molecular mechanisms on atrial remodeling.<br><br>METHODS: In acute experiments, dogs were randomly assigned to Sham, Paced and Paced+aliskiren (10&#xa0;mg&#xa0;kg[-1]) (Paced+ALS) groups, with 7 dogs in each group. Rapid atrial pacing (RAP) was maintained at 600&#xa0;bpm for 2&#xa0;h for paced and Paced+ALS groups and atrial effective refractory periods (AERPs), inducibility of AF (AFi) and average duration time (ADT) were measured. In chronic experiments, there were 5 groups: Sham, Sham+ALS, Paced, Paced+ALS and Paced+ALS+PI3K antagonist wortmannin (WM) (70&#xa0;&#x3bc;g&#xa0;kg[-1]&#xa0;day[-1]). RAP at 500 beats/min was maintained for 2&#xa0;weeks. Inflammation and oxidative stress indicators were measured by ELISA assay, echocardiogram and pathology were used to assess atrial structural remodeling, phosphatidylinositol 3-hydroxy kinase/protein kinase B (PI3K/Akt) signaling pathways were studied by RT-PCR and western blotting to evaluate whether the cardioprotective effect of ALS works through PI3K/Akt signaling pathway.<br><br>RESULTS: The electrophysiological changes were observed after 2-h pacing. The AERP shortened with increased AFi and ADT, which was attenuated by ALS (P&#x2009;<&#x2009;0.05). After pacing for 2&#xa0;weeks, oxidative stress and inflammation markers in the Paced group were significantly higher than those in the Sham group (P&#x2009;<&#x2009;0.01) and were reduced by ALS treatment (P&#x2009;<&#x2009;0.01). The reduced level of antioxidant enzymes caused by RAP was also found to be elevated in ALS-treated group (P&#x2009;<&#x2009;0.01). The results of pathology and echocardiography showed that RAP can cause atrial enlargement, fibrosis (P&#x2009;<&#x2009;0.01), and were attenuated in ALS treatment group. The PI3K/Akt signaling pathway were downregulated induced by RAP. ALS could upregulate the PI3K/Akt pathway expression (P&#x2009;<&#x2009;0.05). Furthermore, the cardioprotective effects in structural remodeling of ALS were suppressed by WM.<br><br>CONCLUSIONS: ALS may offer cardioprotection in RAP-induced atrial remodeling, which may partly be ascribed to its anti-inflammatory and anti-oxidative stress action and the regulation of PI3K/Akt signaling pathway.}, }
@article {pmid32459877, year = {2020}, author = {Zhu, J and Ou, N and Song, Y and Hu, R and Zhang, W and Liang, Z and Yang, Y and Liu, X}, title = {Identification and verification of key genes in varicocele rats through high-throughput sequencing and bioinformatics analysis.}, journal = {Andrologia}, volume = {52}, number = {9}, pages = {e13662}, doi = {10.1111/and.13662}, pmid = {32459877}, issn = {1439-0272}, support = {ZYYFY2018031//Zhao Yi-Cheng Medical Science Foundation/ ; 16JCZDJC34600//Tianjin Natural Science Foundation of China/ ; 17JCQNJC11900//Tianjin Natural Science Foundation of China/ ; }, mesh = {Animals ; *Computational Biology ; Gene Ontology ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Rats ; Software ; *Varicocele/genetics ; }, abstract = {Varicocele (VC) is the most common treatable cause of infertility, but it is difficult to distinguish fertile from infertile VC populations because the pathogenesis is unclear. In order to study the related mechanism of VC causing male sterility, we made VC rat model by surgery, analysed the rat epididymal spermatozoa and used the transcriptome sequencing to compare all the mRNA expression differences in testicular tissue between VC rats and control rats. The differentially expressed genes (DEGs) of testicular tissue were also screened by the limma package in R software (version 3.6.1). The 273 DEGs were identified from the four profile data sets including 124 up-regulated genes and 149 down-regulated genes in the VC group compared to control group. We found that Sod1, Casp9, Atg7, Casp3 and Sirt1 in module 1 had higher degrees of connectivity in the first 10 hub genes. Gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis demonstrated that Sod1, Casp9, Atg7, Casp3 and Sirt1 are enriched in regulation of oxidative stress-induced cell death (GO:1,903,201) and Amyotrophic lateral sclerosis (KEGG:05,014). From the above evidence, we speculate that hypoxia plays an important role in the occurrence and development of VC, and it induced the abnormal expression of autophagy and apoptosis-related proteins may involve in the development of VC-associated infertility. Sod1, Casp9, Atg7, Casp3 and Sirt1 as well as their module are hub genes for VC, which will have attractive applications to provide new treatment targets for VC.}, }
@article {pmid32456491, year = {2020}, author = {Barp, A and Gerardi, F and Lizio, A and Sansone, VA and Lunetta, C}, title = {Emerging Drugs for the Treatment of Amyotrophic Lateral Sclerosis: A Focus on Recent Phase 2 Trials.}, journal = {Expert opinion on emerging drugs}, volume = {25}, number = {2}, pages = {145-164}, doi = {10.1080/14728214.2020.1769067}, pmid = {32456491}, issn = {1744-7623}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Disease Progression ; *Drug Development ; Drug Discovery ; Edaravone/administration &amp; dosage/pharmacology ; Humans ; Neuroprotective Agents/*administration &amp; dosage/pharmacology ; Oxidative Stress/drug effects ; Riluzole/administration &amp; dosage/pharmacology ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease involving both upper and lower motor neurons and resulting in increasing disability and death 3-5 years after onset of symptoms. Over 40 large clinical trials for ALS have been negative, except for Riluzole that offers a modest survival benefit, and Edaravone that modestly reduces disease progression in patients with specific characteristics. Thus, the discovery of efficient disease modifying therapy is an urgent need.<br><br>AREAS COVERED: Although the cause of ALS remains unclear, many studies have demonstrated that neuroinflammation, proteinopathies, glutamate-induced excitotoxicity, microglial activation, oxidative stress, and mitochondrial dysfunction may play a key role in the pathogenesis. This review highlights recent discoveries relating to these diverse mechanisms and their implications for the development of therapy. Ongoing phase 2 clinical trials aimed to interfere with these pathophysiological mechanisms are discussed.<br><br>EXPERT OPINION: This review describes the challenges that the discovery of an efficient drug therapy faces and how these issues may be addressed. With the continuous advances coming from basic research, we provided possible suggestions that may be considered to improve performance of clinical trials and turn ALS research into a 'fertile ground' for drug development for this devastating disease.}, }
@article {pmid32456229, year = {2020}, author = {Obrenovich, M and Jaworski, H and Tadimalla, T and Mistry, A and Sykes, L and Perry, G and Bonomo, RA}, title = {The Role of the Microbiota-Gut-Brain Axis and Antibiotics in ALS and Neurodegenerative Diseases.}, journal = {Microorganisms}, volume = {8}, number = {5}, pages = {}, pmid = {32456229}, issn = {2076-2607}, abstract = {: The human gut hosts a wide and diverse ecosystem of microorganisms termed the microbiota, which line the walls of the digestive tract and colon where they co-metabolize digestible and indigestible food to contribute a plethora of biochemical compounds with diverse biological functions. The influence gut microbes have on neurological processes is largely yet unexplored. However, recent data regarding the so-called leaky gut, leaky brain syndrome suggests a potential link between the gut microbiota, inflammation and host co-metabolism that may affect neuropathology both locally and distally from sites where microorganisms are found. The focus of this manuscript is to draw connection between the microbiota-gut-brain (MGB) axis, antibiotics and the use of "BUGS AS DRUGS" for neurodegenerative diseases, their treatment, diagnoses and management and to compare the effect of current and past pharmaceuticals and antibiotics for alternative mechanisms of action for brain and neuronal disorders, such as Alzheimer disease (AD), Amyotrophic Lateral Sclerosis (ALS), mood disorders, schizophrenia, autism spectrum disorders and others. It is a paradigm shift to suggest these diseases can be largely affected by unknown aspects of the microbiota. Therefore, a future exists for applying microbial, chemobiotic and chemotherapeutic approaches to enhance translational and personalized medical outcomes. Microbial modifying applications, such as CRISPR technology and recombinant DNA technology, among others, echo a theme in shifting paradigms, which involve the gut microbiota (GM) and mycobiota and will lead to potential gut-driven treatments for refractory neurologic diseases.}, }
@article {pmid32455791, year = {2020}, author = {Bonafede, R and Turano, E and Scambi, I and Busato, A and Bontempi, P and Virla, F and Schiaffino, L and Marzola, P and Bonetti, B and Mariotti, R}, title = {ASC-Exosomes Ameliorate the Disease Progression in SOD1(G93A) Murine Model Underlining Their Potential Therapeutic Use in Human ALS.}, journal = {International journal of molecular sciences}, volume = {21}, number = {10}, pages = {}, pmid = {32455791}, issn = {1422-0067}, support = {FGBR_7/2016//AriSLA/ ; Grant 2017//Brain Research Fondation Verona Onlus/ ; }, mesh = {Adipose Tissue/cytology ; Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; Cells, Cultured ; Exosomes/*transplantation ; Mesenchymal Stem Cell Transplantation/*methods ; Mice ; Mice, Inbred C57BL ; Motor Neurons/metabolism/physiology ; Movement ; Mutation, Missense ; Neuromuscular Junction/metabolism/physiology ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motoneurons. To date, there is no effective treatment available. Exosomes are extracellular vesicles that play important roles in intercellular communication, recapitulating the effect of origin cells. In this study, we tested the potential neuroprotective effect of exosomes isolated from adipose-derived stem cells (ASC-exosomes) on the in vivo model most widely used to study ALS, the human SOD1 gene with a G93A mutation (SOD1(G93A)) mouse. Moreover, we compared the effect of two different routes of exosomes administration, intravenous and intranasal. The effect of exosomes administration on disease progression was monitored by motor tests and analysis of lumbar motoneurons and glial cells, neuromuscular junction, and muscle. Our results demonstrated that repeated administration of ASC-exosomes improved the motor performance; protected lumbar motoneurons, the neuromuscular junction, and muscle; and decreased the glial cells activation in treated SOD1(G93A) mice. Moreover, exosomes have the ability to home to lesioned ALS regions of the animal brain. These data contribute by providing additional knowledge for the promising use of ASC-exosomes as a therapy in human ALS.}, }
@article {pmid32455015, year = {2020}, author = {Matharan, M and Mathis, S and Bonabaud, S and Carla, L and Soulages, A and Le Masson, G}, title = {Minimizing the Diagnostic Delay in Amyotrophic Lateral Sclerosis: The Role of Nonneurologist Practitioners.}, journal = {Neurology research international}, volume = {2020}, number = {}, pages = {1473981}, pmid = {32455015}, issn = {2090-1852}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS), usually fatal in a few years, is a neurodegenerative disorder where the diagnostic delay, although variable according to the studies, remains too long. The main objective of this study was to determine the average time to diagnose ALS and the role of each physician, general practitioner (GP), or specialist (neurologist or not) involved in the management of these patients. The secondary objective was to propose some simple schemes to quickly identify an ALS suspicion with the aim to reduce this delay. Patients and Methods. This retrospective study evaluated the diagnostic delay (and other intermediate delays) of 90 ALS patients registered in the ALS Center of Bordeaux (France) in 2013. The main clinical signs encountered (and their order of appearance) were studied.<br><br>RESULTS: The average diagnostic delay was 17 months, with a median diagnostic delay of 12 months. The average diagnostic delay was 2.7 months between the first symptoms and the first complaint to GP, followed by an additional 6.5 month delay before the patient's first visit to a neurologist. This period could be shortened, especially if GP performed additional tests quickly (p=0.01), as the time spent consulting various specialists often extends this crucial step. Overall, diagnostic delay accounted for 40% of the total duration of the disease progression.<br><br>CONCLUSION: In relation to total survival time, the diagnostic delay of ALS appears to be proportionately very long, sometimes longer than that observed in previous studies (because it also included the total delay to diagnostic or treatment initiation). The rapid execution of useful additional tests by the first medical doctor, often GP (with the help of a neurologist), considerably reduces the diagnostic delay. The central role of GP seems to be crucial in the management of patients with ALS. The main objective is, of course, to initiate appropriate treatment and care as soon as possible. Finally, based on our results, we also provide a short practical diagram to help nonneurologist practitioners to quickly discuss the diagnosis of ALS in case of some specific symptoms ("red flags").}, }
@article {pmid32453150, year = {2020}, author = {Vacca, VM}, title = {Amyotrophic lateral sclerosis: Nursing care and considerations.}, journal = {Nursing}, volume = {50}, number = {6}, pages = {32-39}, doi = {10.1097/01.NURSE.0000662348.31823.44}, pmid = {32453150}, issn = {1538-8689}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*nursing/physiopathology ; Humans ; Nursing Diagnosis ; Terminal Care ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease that is always fatal, although treatment can help slow disease progression. This article discusses the etiology and pathophysiology, signs and symptoms, diagnosis, and clinical management of ALS, with special nursing considerations to help patients at the end of life.}, }
@article {pmid32453096, year = {2020}, author = {Shehee, L and O'Rourke, A and Garand, KL}, title = {The Role of Radiation Therapy and Botulinum Toxin Injections in the Management of Sialorrhea in Patients With Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Journal of clinical neuromuscular disease}, volume = {21}, number = {4}, pages = {205-221}, doi = {10.1097/CND.0000000000000273}, pmid = {32453096}, issn = {1537-1611}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*physiopathology ; Botulinum Toxins/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Neuromuscular Agents/*therapeutic use ; Sialorrhea/*drug therapy/*radiotherapy ; Treatment Outcome ; }, abstract = {OBJECTIVES: Half of patients with amyotrophic lateral sclerosis experience sialorrhea due to facial weakness. Although anticholinergic medications are first-line therapy, they often lead to unacceptable side effects. Radiation therapy and botulinum toxin may be considered when medical management fails. In this systematic review, we investigated the effectiveness of these interventions.<br><br>METHODS: Eligible studies were retrieved from PubMed and Scopus databases up to March 2017 along with hand-searching of references from primary articles.<br><br>RESULTS: Fourteen studies (N = 138) examined the benefits of botulinum toxin. Studies varied in salivary glands treated, dosages used, and the use of botulinum toxin subtype A or B. A majority of studies showed benefit after treatment. Although most studies reported only mild adverse effects, 2 case studies revealed severe complications including recurrent TMJ dislocations and rapid deterioration in bulbar function. Ten studies (N = 171) examined the benefits of radiation. Most studies reported improvement with only mild adverse events reported.<br><br>CONCLUSIONS: Both radiation and botulinum toxin are effective treatments for sialorrhea in patients with amyotrophic lateral sclerosis and should be considered when medical management fails. Radiation may offer longer duration of symptom improvement with fewer complications.}, }
@article {pmid32449677, year = {2020}, author = {Douglas, A and Baborie, A}, title = {Inappropriate antidiuretic hormone secretion in amyotrophic lateral sclerosis.}, journal = {Clinical neuropathology}, volume = {39}, number = {6}, pages = {275-281}, doi = {10.5414/NP301280}, pmid = {32449677}, issn = {0722-5091}, mesh = {Aged, 80 and over ; Amyotrophic Lateral Sclerosis/diagnosis/*pathology ; Bodily Secretions/*metabolism ; Brain/pathology ; Humans ; Hyponatremia/complications/drug therapy/*pathology ; Inappropriate ADH Syndrome/complications/diagnosis/*pathology ; Male ; Vasopressins/therapeutic use ; }, abstract = {Only a few cases of syndrome of inappropriate antidiuretic hormone secretion (SIADH) in the setting of amyotrophic lateral sclerosis (ALS) have been described in the literature. We present the case of an 81-year-old male who developed severe hyponatremia following elective total hip replacement. His past medical history included prostate cancer, which was under surveillance, and ischemic heart disease. He reported recent weight loss, worsening shortness of breath, and lethargy. SIADH was diagnosed on the basis of hyponatremia, elevated urinary sodium, and decreased serum osmolality, presumed secondary to surgery. Investigations revealed no occult malignancy and no other cause for hyponatremia. He was discharged when sodium levels had normalized, however, he then had several further admissions for hyponatremia, general fatigue, and breathlessness. His condition continued to decline, and he developed dysphagia, weakness, and tongue fasciculations. Neurological examination showed globally decreased power, increased tone, and fasciculations. MRI of the brain was normal. He did not respond to neostigmine treatment, and a presumed diagnosis of motor neuron disease was made. The patient passed away shortly after this, and a post-mortem confirmed the diagnosis of ALS. Drug, post-operative, and cancer-related causes were precluded by the timing of onset of hyponatremia. We present this case and an analysis of previously published cases alongside a discussion on the potential causative mechanisms.}, }
@article {pmid32447548, year = {2020}, author = {Jayaprakash, K and Glasmacher, SA and Pang, B and Beswick, E and Mehta, AR and Dakin, R and Newton, J and Chandran, S and Pal, S and , }, title = {Riluzole prescribing, uptake and treatment discontinuation in people with amyotrophic lateral sclerosis in Scotland.}, journal = {Journal of neurology}, volume = {267}, number = {8}, pages = {2459-2461}, pmid = {32447548}, issn = {1432-1459}, support = {MEHTA/JUL17/948-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R001162/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/*epidemiology ; Drug Prescriptions ; Female ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*administration &amp; dosage ; Registries ; Riluzole/*administration &amp; dosage ; Scotland/epidemiology ; Withholding Treatment/*trends ; }, }
@article {pmid32446009, year = {2020}, author = {Ohta, Y and Yamashita, T and Nomura, E and Hishikawa, N and Ikegami, K and Osakada, Y and Matsumoto, N and Kawahara, Y and Yunoki, T and Takahashi, Y and Takamiya, M and Tadokoro, K and Sasaki, R and Nakano, Y and Tsunoda, K and Sato, K and Omote, Y and Takemoto, M and Abe, K}, title = {Improvement of a decreased anti-oxidative activity by edaravone in amyotrophic lateral sclerosis patients.}, journal = {Journal of the neurological sciences}, volume = {415}, number = {}, pages = {116906}, doi = {10.1016/j.jns.2020.116906}, pmid = {32446009}, issn = {1878-5883}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Antipyrine/therapeutic use ; Edaravone ; Free Radical Scavengers/therapeutic use ; Humans ; Oxidation-Reduction ; }, abstract = {BACKGROUND: The free radical scavenger edaravone is a proven neuroprotective drug for patients with amyotrophic lateral sclerosis (ALS). Our objective was to evaluate the therapeutic effects of edaravone for oxidative stress and anti-oxidative activity in ALS patients.<br><br>METHODS: Twenty-two ALS patients with a disease duration of 2&#xa0;years, treated by edaravone, and 25 control participants were evaluated according to their clinical scores, including ALS functional rating scale-revised (ALSFRS-R), and serum and cerebrospinal fluid (CSF) markers of oxidative stress dROM and anti-oxidative activity OXY.<br><br>RESULTS: Serum and CSF markers of anti-oxidative activity OXY were significantly decreased in ALS patients at pre-treatment compared with controls ([##]p&#xa0;<&#xa0;.01), which was improved in the course of edaravone treatment. Both serum and CSF OXY were significantly correlated with ALS clinical scores including ALSFRS-R (*p&#xa0;<&#xa0;.05, **p&#xa0;<&#xa0;.01, ***p&#xa0;<&#xa0;.001). Furthermore, serum OXY at pre-treatment was significantly correlated with a change in the ALSFRS-R score in the sixth cycle of edaravone treatment (*p&#xa0;<&#xa0;.05).<br><br>CONCLUSIONS: The present study suggests significant correlations between anti-oxidative activity and ALS clinical severity, and the therapeutic efficacy of edaravone for decreased anti-oxidative activity in ALS.}, }
@article {pmid32445195, year = {2020}, author = {Andrews, JA and Berry, JD and Baloh, RH and Carberry, N and Cudkowicz, ME and Dedi, B and Glass, J and Maragakis, NJ and Miller, TM and Paganoni, S and Rothstein, JD and Shefner, JM and Simmons, Z and Weiss, MD and Bedlack, RS}, title = {Amyotrophic lateral sclerosis care and research in the United States during the COVID-19 pandemic: Challenges and opportunities.}, journal = {Muscle &amp; nerve}, volume = {62}, number = {2}, pages = {182-186}, pmid = {32445195}, issn = {1097-4598}, support = {S10 OD020007/OD/NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*therapy ; Betacoronavirus ; Biomedical Research ; COVID-19 ; Clinical Trials as Topic ; Coronavirus Infections/*epidemiology ; Enteral Nutrition ; *Health Services Accessibility ; *Home Care Services ; *Hospice Care ; Humans ; Pandemics ; Pneumonia, Viral/*epidemiology ; SARS-CoV-2 ; Spirometry ; *Telemedicine ; United States/epidemiology ; Ventilators, Mechanical ; Wheelchairs ; }, abstract = {Coronavirus disease 2019 has created unprecedented challenges for amyotrophic lateral sclerosis (ALS) clinical care and research in the United States. Traditional evaluations for making an ALS diagnosis, measuring progression, and planning interventions rely on in-person visits that may now be unsafe or impossible. Evidence- and experience-based treatment options, such as multidisciplinary team care, feeding tubes, wheelchairs, home health, and hospice, have become more difficult to obtain and in some places are unavailable. In addition, the pandemic has impacted ALS clinical trials by impairing the ability to obtain measurements for trial eligibility, to monitor safety and efficacy outcomes, and to dispense study drug, as these also often rely on in-person visits. We review opportunities for overcoming some of these challenges through telemedicine and novel measurements. These can reoptimize ALS care and research in the current setting and during future events that may limit travel and face-to-face interactions.}, }
@article {pmid32441587, year = {2022}, author = {Adami, R and Bottai, D}, title = {Curcumin and neurological diseases.}, journal = {Nutritional neuroscience}, volume = {25}, number = {3}, pages = {441-461}, doi = {10.1080/1028415X.2020.1760531}, pmid = {32441587}, issn = {1476-8305}, mesh = {*Alzheimer Disease/drug therapy ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Curcumin/pharmacology/therapeutic use ; Humans ; *Multiple Sclerosis ; *Parkinson Disease/drug therapy ; }, abstract = {Objectives: The beneficial effects of many substances have been discovered because of regular dietary consumption. This is also the case with curcumin, whose effects have been known for more than 4,000 years in Eastern countries such as China and India. A curcumin-rich diet has been known to counteract many human diseases, including cancer and diabetes, and has been shown to reduce inflammation. The effect of a curcumin treatment for neurological diseases, such as spinal muscular atrophy; Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; multiple sclerosis; and others, has only recently been brought to the attention of researchers and the wider population.Methods: In this paper, we summarise the studies on this natural product, from its isolation two centuries ago to its characterisation a century later.Results: We describe its role in the treatment of neurological diseases, including its cellular and common molecular mechanisms, and we report on the clinical trials of curcumin with healthy people and patients.Discussion: Commenting on the different approaches adopted by the efforts made to increase its bioavailability.}, }
@article {pmid32440312, year = {2020}, author = {Rajabian, A and Sadeghnia, H and Fanoudi, S and Hosseini, A}, title = {Genus Boswellia as a new candidate for neurodegenerative disorders.}, journal = {Iranian journal of basic medical sciences}, volume = {23}, number = {3}, pages = {277-286}, pmid = {32440312}, issn = {2008-3866}, abstract = {Neurodegenerative diseases, characterized by progressive loss of neurons, share common mechanisms such as apoptotic cell death, mitochondrial dysfunction, inflammation, and oxidative stress. Genus Boswellia is a genus in the Burseraceae family. It comprises several species traditionally used for treatment of chronic inflammatory diseases, cerebral edema, chronic pain syndrome, gastrointestinal diseases, tumors, as well as enhancing intelligence. Many studies have been carried out to discover therapeutic approaches for neurodegenerative diseases such as Alzheimer's diseases, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis, stroke, and concomitant cognitive deficits. However, no curative treatment has been developed. This paper provides an overview of evidence about the potential of the Boswellia species and their main constituents, boswellic acids, as modulators of several mechanisms involved in the pathology of the neurodegenerative diseases. In vitro, animal, and clinical studies have confirmed that Boswellia species contain bioactive components that may enhance cognitive activity and protect against neurodegeneration. They exert the beneficial effects via targeting multiple pathological causes by antioxidative, anti-inflammatory, antiamyloidogenic, and anti-apoptotic properties. The Boswellia species, having neuroprotective potential, makes them a promising candidate to cure or prevent the neurodegenerative disorders.}, }
@article {pmid32440158, year = {2020}, author = {Tan, J and Xu, W and Lei, L and Liu, H and Wang, H and Cao, X and Xu, M}, title = {Inhibition of Aurora Kinase A by Alisertib Reduces Cell Proliferation and Induces Apoptosis and Autophagy in HuH-6 Human Hepatoblastoma Cells.}, journal = {OncoTargets and therapy}, volume = {13}, number = {}, pages = {3953-3963}, pmid = {32440158}, issn = {1178-6930}, abstract = {PURPOSE: Aurora kinase A (AURKA), which belongs to the serine/threonine protein kinase family, has been identified as a key driver of the genesis and progression of diverse tumors. The aim of this study was to determine the clinical significance of AURKA in patients with hepatoblastoma (HB) and the effect of inhibiting AURKA in the HB cell line HuH-6.<br><br>METHODS: The expression of AURKA in HB tissue and adjacent normal liver tissue was detected by immunohistochemistry. Then, statistical analysis was performed to evaluate the association between AURKA expression and the clinicopathological characteristics of HB. The effect of AURKA knockdown on cell viability was assessed by CCK-8 assay. EdU and CCK-8 assays, Western blotting, flow cytometry, and transmission electron microscopy (TEM) were used to examine the effect of alisertib (ALS), a selective AURKA small-molecule inhibitor, on the cell cycle, proliferation, apoptosis, and autophagy in HuH-6 human hepatoblastoma cells.<br><br>RESULTS: The expression of AURKA was significantly higher in HB tissue than in adjacent normal tissue. Furthermore, high AURKA expression was associated with advanced Children's Oncology Group (COG) stage and tumor metastasis of HB. In vitro, AURKA knockdown significantly reduced the viability of HuH-6 cells, while ALS treatment significantly suppressed HuH-6 cell proliferation and induced G1-phase cell cycle arrest by reducing cyclin-D1 expression. Moreover, ALS promoted apoptosis and autophagy by decreasing the activity of p38 MAPK in HuH-6 cells.<br><br>CONCLUSION: High expression of AURKA is a potential predictor of poor prognosis in HB patients. AURKA knockdown reduced the viability of HuH-6 cells, and ALS treatment inhibited cell proliferation and induced apoptosis and autophagy via the p38 MAPK signaling pathway. Our results suggest that AURKA may be a novel therapeutic target and ALS a potential therapeutic drug for the treatment of HB.}, }
@article {pmid32439581, year = {2020}, author = {Takizawa, M and Nakano, M and Fukami, T and Nakajima, M}, title = {Decrease in ADAR1 expression by exposure to cigarette smoke enhances susceptibility to oxidative stress.}, journal = {Toxicology letters}, volume = {331}, number = {}, pages = {22-32}, doi = {10.1016/j.toxlet.2020.05.019}, pmid = {32439581}, issn = {1879-3169}, mesh = {A549 Cells ; Adenosine Deaminase/*genetics ; Cell Culture Techniques ; Cell Survival/drug effects/genetics ; Humans ; Oxidative Stress/*drug effects/genetics ; RNA Editing/*drug effects ; RNA-Binding Proteins/*genetics ; Smoke/*adverse effects ; *Tobacco Products ; }, abstract = {Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes, is the most frequent type of post-transcriptional nucleotide conversion in humans. It is known that innate abnormalities of A-to-I RNA editing are associated with the risk of certain diseases, such as amyotrophic lateral sclerosis. Extrinsic factors that modulate ADAR-mediated RNA editing remain to be clarified. In this study, we investigated the possibility that cigarette smoking may influence the expression of ADAR and that the changes may be biologically significant. Treatment of human lung adenocarcinoma A549 cells with cigarette smoke extract (CSE) induced a significant 50% decrease in ADAR1 protein levels. Since the decrease was counteracted by cotreatment with chloroquine, the CSE-dependent decrease in the ADAR1 protein levels may be due to the activation of autophagy. In addition to the in vitro study, we performed an in vivo study in mice and found a decrease in pulmonary Adar1 protein expression induced by cigarette smoking. Then, we investigated the biological significance of decreased ADAR1 expression. We found that knockdown of ADAR1 in A549 cells by siRNA resulted in an increase in the levels of protein carbonyl, a marker of oxidative stress. Moreover, knockdown of ADAR1 triggered a decrease in super oxide dismutase activity and heme oxygenase-1 expression, suggesting that ADAR1 plays a role to suppress oxidative stress. In conclusion, we show that ADAR1 expression is decreased by cigarette smoking and is a factor that contributes to the enhanced intracellular oxidative stress caused by cigarette smoking.}, }
@article {pmid32437029, year = {2020}, author = {Yousefi, N and Abdollahii, S and Kouhbanani, MAJ and Hassanzadeh, A}, title = {Induced pluripotent stem cells (iPSCs) as game-changing tools in the treatment of neurodegenerative disease: Mirage or reality?.}, journal = {Journal of cellular physiology}, volume = {235}, number = {12}, pages = {9166-9184}, doi = {10.1002/jcp.29800}, pmid = {32437029}, issn = {1097-4652}, mesh = {Cell Differentiation/physiology ; *Cell- and Tissue-Based Therapy/methods ; Humans ; Induced Pluripotent Stem Cells/*cytology ; Motor Neurons/pathology ; Neurodegenerative Diseases/pathology/*therapy ; Pluripotent Stem Cells/*cytology ; }, abstract = {Based on investigations, there exist tight correlations between neurodegenerative diseases' incidence and progression and aberrant protein aggregreferates in nervous tissue. However, the pathology of these diseases is not well known, leading to an inability to find an appropriate therapeutic approach to delay occurrence or slow many neurodegenerative diseases' development. The accessibility of induced pluripotent stem cells (iPSCs) in mimicking the phenotypes of various late-onset neurodegenerative diseases presents a novel strategy for in vitro disease modeling. The iPSCs provide a valuable and well-identified resource to clarify neurodegenerative disease mechanisms, as well as prepare a promising human stem cell platform for drug screening. Undoubtedly, neurodegenerative disease modeling using iPSCs has established innovative opportunities for both mechanistic types of research and recognition of novel disease treatments. Most important, the iPSCs have been considered as a novel autologous cell origin for cell-based therapy of neurodegenerative diseases following differentiation to varied types of neural lineage cells (e.g. GABAergic neurons, dopamine neurons, cortical neurons, and motor neurons). In this review, we summarize iPSC-based disease modeling in neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. Moreover, we discuss the efficacy of cell-replacement therapies for neurodegenerative disease.}, }
@article {pmid32436077, year = {2021}, author = {Quarracino, C and Bendersky, M and Rey, R and Rodríguez, GE}, title = {Logistics and safety of edaravone treatment for amyotrophic lateral sclerosis: experience in Argentina.}, journal = {Acta neurologica Belgica}, volume = {121}, number = {6}, pages = {1519-1523}, pmid = {32436077}, issn = {2240-2993}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/*epidemiology ; Argentina/epidemiology ; Drug Administration Routes ; Edaravone/*administration &amp; dosage ; Female ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*administration &amp; dosage ; }, abstract = {Since 2015, edaravone is the second drug available for the treatment of Amyotrophic lateral sclerosis (ALS). In this study we analyzed the characteristics and experience of ALS patients treated with this new medication in our country. Sixteen ALS patients were treated with edaravone infusions in three ALS clinics. Most of them were male, had a spinal onset of the disease and a definite diagnosis of ALS. Mean age at first infusion was 53.5 years. Since the diagnosis of ALS, delay in starting treatment with edaravone was five times greater than that of riluzole. Edaravone therapy was usually initiated at a health care facility and was followed by domiciliary cycles. Adverse effects and the need of a special catheter for infusion were rare. Access to edaravone through health insurance was possible in only 43.8% of patients. Altogether, treatment access was limited but feasible and edaravone was well tolerated.}, }
@article {pmid32435914, year = {2020}, author = {Pierozan, P and Piras, E and Brittebo, E and Karlsson, O}, title = {The cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) targets the olfactory bulb region.}, journal = {Archives of toxicology}, volume = {94}, number = {8}, pages = {2799-2808}, pmid = {32435914}, issn = {1432-0738}, mesh = {Administration, Intranasal ; Amino Acids, Diamino/administration &amp; dosage/metabolism/*toxicity ; Animals ; Bacterial Toxins/administration &amp; dosage/metabolism/*toxicity ; Cell Survival/drug effects ; Cells, Cultured ; Cyanobacteria/*metabolism ; Cyanobacteria Toxins ; Glutamic Acid/metabolism ; Male ; Mice, Inbred C57BL ; Neuroglia/*drug effects/metabolism/pathology ; Neuronal Outgrowth/drug effects ; Neurons/*drug effects/metabolism/pathology ; Olfactory Bulb/*drug effects/metabolism/pathology ; Olfactory Mucosa/metabolism ; }, abstract = {Olfactory dysfunction is implicated in neurodegenerative disorders and typically manifests years before other symptoms. The cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) is suggested as a risk factor for neurodegenerative disease. Detection of BMAA in air filters has increased the concern that aerosolization may lead to human BMAA exposure through the air. The aim of this study was to determine if BMAA targets the olfactory system. Autoradiographic imaging showed a distinct localization of radioactivity in the right olfactory mucosa and bulb following a unilateral intranasal instillation of [3]H-BMAA (0.018 µg) in mice, demonstrating a direct transfer of BMAA via the olfactory pathways to the brain circumventing the blood-brain barrier, which was confirmed by liquid scintillation. Treatment of mouse primary olfactory bulb cells with 100 µM BMAA for 24 h caused a disruption of the neurite network, formation of dendritic varicosities and reduced cell viability. The NMDA receptor antagonist MK-801 and the metabotropic glutamate receptor antagonist MCPG protected against the BMAA-induced alterations, demonstrating the importance of glutamatergic mechanisms. The ionotropic non-NMDA receptor antagonist CNQX prevented the BMAA-induced decrease of cell viability in mixed cultures containing both neuronal and glial cells, but not in cultures with neurons only, suggesting a role of neuron-glial interactions and glial AMPA receptors in the BMAA-induced toxicity. The results show that the olfactory region may be a target for BMAA following inhalation exposure. Further studies on the relations between environmental olfactory toxicants and neurodegenerative disorders are warranted.}, }
@article {pmid32434076, year = {2020}, author = {Thompson, AJ and Ma, LJ and Major, T and Jeakle, M and Lautner-Csorba, O and Goudie, MJ and Handa, H and Rojas-Peña, A and Potkay, JA}, title = {Assessing and improving the biocompatibility of microfluidic artificial lungs.}, journal = {Acta biomaterialia}, volume = {112}, number = {}, pages = {190-201}, pmid = {32434076}, issn = {1878-7568}, support = {I01 RX000390/RX/RRD VA/United States ; }, mesh = {Animals ; Blood Platelets ; Humans ; Hydrophobic and Hydrophilic Interactions ; Lung ; *Microfluidics ; *Quality of Life ; Rabbits ; }, abstract = {Microfluidic artificial lungs (µALs) have the potential to improve the treatment and quality of life for patients with acute or chronic lung injury. In order to realize the full potential of this technology (including as a destination therapy), the biocompatibility of these devices needs to be improved to produce long-lasting devices that are safe for patient use with minimal or no systemic anticoagulation. Many studies exist which probe coagulation and thrombosis on polydimethyl siloxane (PDMS) surfaces, and many strategies have been explored to improve surface biocompatibility. As the field of µALs is young, there are few studies which investigate biocompatibility of functioning µALs; and even fewer which were performed in vivo. Here, we use both in vitro and in vivo models to investigate two strategies to improve µAL biocompatibility: 1) a hydrophilic surface coating (polyethylene glycol, PEG) to prevent surface fouling, and 2) the addition of nitric oxide (NO) to the sweep gas to inhibit platelet activation locally within the µAL. In this study, we challenge µALs with clottable blood or platelet-rich plasma (PRP) and monitor the resistance to blood flow over time. Device lifetime (the amount of time the µAL remains patent and unobstructed by clot) is used as the primary indicator of biocompatibility. This study is the first study to: 1) investigate the effect of NO release on biocompatibility in a microfluidic network; 2) combine a hydrophilic PEG coating with NO release to improve blood compatibility; and 3) perform extended in vivo biocompatibility testing of a µAL. We found that µALs challenged in vitro with PRP remained patent significantly longer when the sweep gas contained NO than without NO. In the in vivo rabbit model, neither approach alone (PEG coating nor NO sweep gas) significantly improved biocompatibility compared to controls (though with larger sample size significance may become apparent); while the combination of a PEG coating with NO sweep gas resulted in significant improvement of device lifetime. STATEMENT OF SIGNIFICANCE: The development of microfluidic artificial lungs (µALs) can potentially have a massive impact on the treatment of patients with acute and chronic lung impairments. Before these devices can be deployed clinically, the biocompatibility of µALs must be improved and more comprehensively understood. This work explores two strategies for improving biocompatibility, a hydrophilic surface coating (polyethylene glycol) for general surface passivation and the addition of nitric oxide (NO) to the sweep gas to quell platelet and leukocyte activation. These two strategies are investigated separately and as a combined device treatment. Devices are challenged with clottable blood using in vitro testing and in vivo testing in rabbits. This is the first study to our knowledge that allows statistical comparisons of biocompatible µALs in animals, a key step towards eventual clinical use.}, }
@article {pmid32429516, year = {2020}, author = {Moreno-Martinez, L and de la Torre, M and Muñoz, MJ and Zaragoza, P and Aguilera, J and Calvo, AC and Osta, R}, title = {Neuroprotective Fragment C of Tetanus Toxin Modulates IL-6 in an ALS Mouse Model.}, journal = {Toxins}, volume = {12}, number = {5}, pages = {}, pmid = {32429516}, issn = {2072-6651}, support = {PI17/00949//Instituto de Salud Carlos III/International ; .//Fondo Europeo de Desarrollo Regional (FEDER) "Una manera de hacer Europa"/International ; .//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED-612)/International ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Caspase 1/metabolism ; Disease Models, Animal ; Down-Regulation ; Female ; Inflammasomes/metabolism ; Inflammation Mediators/*metabolism ; Interleukin-6/*metabolism ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Muscle, Skeletal/drug effects/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Neuroprotective Agents/*pharmacology ; Peptide Fragments/*pharmacology ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase-1/genetics ; Tetanus Toxin/*pharmacology ; }, abstract = {Neuroinflammation plays a significant role in amyotrophic lateral sclerosis (ALS) pathology, leading to the development of therapies targeting inflammation in recent years. Our group has studied the tetanus toxin C-terminal fragment (TTC) as a therapeutic molecule, showing neuroprotective properties in the SOD1G93A mouse model. However, it is unknown whether TTC could have some effect on inflammation. The objective of this study was to assess the effect of TTC on the regulation of inflammatory mediators to elucidate its potential role in modulating inflammation occurring in ALS. After TTC treatment in SOD1G93A mice, levels of eotaxin-1, interleukin (IL)-2, IL-6 and macrophage inflammatory protein (MIP)-1 alpha (α) and galectin-1 were analyzed by immunoassays in plasma samples, whilst protein expression of caspase-1, IL-1β, IL-6 and NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) was measured in the spinal cord, extensor digitorum longus (EDL) muscle and soleus (SOL) muscle. The results showed reduced levels of IL-6 in spinal cord, EDL and SOL in treated SOD1G93A mice. In addition, TTC showed a different role in the modulation of NLRP3 and caspase-1 depending on the tissue analyzed. In conclusion, our results suggest that TTC could have a potential anti-inflammatory effect by reducing IL-6 levels in tissues drastically affected by the disease. However, further research is needed to study more in depth the anti-inflammatory effect of TTC in ALS.}, }
@article {pmid32421156, year = {2020}, author = {De Vocht, J and Blommaert, J and Devrome, M and Radwan, A and Van Weehaeghe, D and De Schaepdryver, M and Ceccarini, J and Rezaei, A and Schramm, G and van Aalst, J and Chiò, A and Pagani, M and Stam, D and Van Esch, H and Lamaire, N and Verhaegen, M and Mertens, N and Poesen, K and van den Berg, LH and van Es, MA and Vandenberghe, R and Vandenbulcke, M and Van den Stock, J and Koole, M and Dupont, P and Van Laere, K and Van Damme, P}, title = {Use of Multimodal Imaging and Clinical Biomarkers in Presymptomatic Carriers of C9orf72 Repeat Expansion.}, journal = {JAMA neurology}, volume = {77}, number = {8}, pages = {1008-1017}, pmid = {32421156}, issn = {2168-6157}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/genetics/metabolism/pathology ; Biomarkers ; C9orf72 Protein/*genetics ; Case-Control Studies ; Cerebral Cortex/*diagnostic imaging/metabolism/pathology ; DNA Repeat Expansion ; Female ; Fluorodeoxyglucose F18 ; Frontotemporal Dementia/*diagnosis/genetics/metabolism/pathology ; Heterozygote ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Multimodal Imaging ; Positron-Emission Tomography/*standards ; *Prodromal Symptoms ; Prospective Studies ; }, abstract = {IMPORTANCE: During a time with the potential for novel treatment strategies, early detection of disease manifestations at an individual level in presymptomatic carriers of a hexanucleotide repeat expansion in the C9orf72 gene (preSxC9) is becoming increasingly relevant.<br><br>OBJECTIVES: To evaluate changes in glucose metabolism before symptom onset of amyotrophic lateral sclerosis or frontotemporal dementia in preSxC9 using simultaneous fluorine 18-labeled fluorodeoxyglucose ([18F]FDG positron emission tomographic (PET) and magnetic resonance imaging as well as the mutation's association with clinical and fluid biomarkers.<br><br>A prospective, case-control study enrolled 46 participants from November 30, 2015, until December 11, 2018. The study was conducted at the neuromuscular reference center of the University Hospitals Leuven, Leuven, Belgium.<br><br>MAIN OUTCOMES AND MEASURES: Neuroimaging data were spatially normalized and analyzed at the voxel level at a height threshold of P&#x2009;<&#x2009;.001, cluster-level familywise error-corrected threshold of P&#x2009;<&#x2009;.05, and statistical significance was set at P&#x2009;<&#x2009;.05 for the volume-of-interest level analysis, using Benjamini-Hochberg correction for multiple correction. W-score maps were computed using the individuals serving as controls as a reference to quantify the degree of [18F]FDG PET abnormality. The threshold for abnormality on the W-score maps was designated as an absolute W-score greater than or equal to 1.96. Neurofilament levels and performance on cognitive and neurologic examinations were determined. All hypothesis tests were 1-sided.<br><br>RESULTS: Of the 42 included participants, there were 17 with the preSxC9 mutation (12 women [71%]; mean [SD] age, 51 [9] years) and 25 healthy controls (12 women [48%]; mean [SD] age, 47 [10] years). Compared with control participants, significant clusters of relative hypometabolism were found in frontotemporal regions, basal ganglia, and thalami of preSxC9 participants and relative hypermetabolism in the peri-Rolandic region, superior frontal gyrus, and precuneus cortex. W-score frequency maps revealed reduced glucose metabolism with local maxima in the insular cortices, central opercular cortex, and thalami in up to 82% of preSxC9 participants and increased glucose metabolism in the precentral gyrus and precuneus cortex in up to 71% of preSxC9 participants. Other findings in the preSxC9 group were upper motor neuron involvement in 10 participants (59%), cognitive abnormalities in 5 participants (29%), and elevated neurofilament levels in 3 of 16 individuals (19%) who underwent lumbar puncture.<br><br>CONCLUSIONS AND RELEVANCE: The results suggest that [18F]FDG PET can identify glucose metabolic changes in preSxC9 at an individual level, preceding significantly elevated neurofilament levels and onset of symptoms.}, }
@article {pmid32419904, year = {2020}, author = {Jenkins, K and Mateeva, T and Szabó, I and Melnik, A and Picotti, P and Csikász-Nagy, A and Rosta, E}, title = {Combining data integration and molecular dynamics for target identification in α-Synuclein-aggregating neurodegenerative diseases: Structural insights on Synaptojanin-1 (Synj1).}, journal = {Computational and structural biotechnology journal}, volume = {18}, number = {}, pages = {1032-1042}, pmid = {32419904}, issn = {2001-0370}, abstract = {Parkinson's disease (PD), Alzheimer's disease (AD) and Amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases hallmarked by the formation of toxic protein aggregates. However, targeting these aggregates therapeutically have thus far shown no success. The treatment of AD has remained particularly problematic since no new drugs have been approved in the last 15 years. Therefore, novel therapeutic targets need to be identified and explored. Here, through the integration of genomic and proteomic data, a set of proteins with strong links to α-synuclein-aggregating neurodegenerative diseases was identified. We propose 17 protein targets that are likely implicated in neurodegeneration and could serve as potential targets. The human phosphatidylinositol 5-phosphatase synaptojanin-1, which has already been independently confirmed to be implicated in Parkinson's and Alzheimer's disease, was among those identified. Despite its involvement in PD and AD, structural aspects are currently missing at the molecular level. We present the first atomistic model of the 5-phosphatase domain of synaptojanin-1 and its binding to its substrate phosphatidylinositol 4,5-bisphosphate (PIP2). We determine structural information on the active site including membrane-embedded molecular dynamics simulations. Deficiency of charge within the active site of the protein is observed, which suggests that a second divalent cation is required to complete dephosphorylation of the substrate. The findings in this work shed light on the protein's binding to phosphatidylinositol 4,5-bisphosphate (PIP2) and give additional insight for future targeting of the protein active site, which might be of interest in neurodegenerative diseases where synaptojanin-1 is overexpressed.}, }
@article {pmid32411331, year = {2020}, author = {Kosuge, Y and Nango, H and Kasai, H and Yanagi, T and Mawatari, T and Nishiyama, K and Miyagishi, H and Ishige, K and Ito, Y}, title = {Generation of Cellular Reactive Oxygen Species by Activation of the EP2 Receptor Contributes to Prostaglandin E2-Induced Cytotoxicity in Motor Neuron-Like NSC-34 Cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {6101838}, pmid = {32411331}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Animals ; Caspase 3/metabolism ; Cell Death/drug effects ; Cell Differentiation/drug effects ; Cell Line ; Cyclic AMP/metabolism ; Dinoprostone/*toxicity ; L-Lactate Dehydrogenase/metabolism ; Mice ; Motor Neurons/drug effects/metabolism/*pathology ; Protein Isoforms/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, Prostaglandin E, EP2 Subtype/agonists/*metabolism ; Receptors, Prostaglandin E, EP3 Subtype/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease characterized by progressive degeneration of motor neurons in the central nervous system. Prostaglandin E2 (PGE2) plays a pivotal role in the degeneration of motor neurons in human and transgenic models of ALS. We have shown previously that PGE2 directly induces neuronal death through activation of the E-prostanoid (EP) 2 receptor in differentiated NSC-34 cells, a motor neuron-like cell line. In the present study, to clarify the mechanisms underlying PGE2-induced neurotoxicity, we focused on generation of intracellular reactive oxygen species (ROS) and examined the effects of N-acetylcysteine (NAC), a cell-permeable antioxidant, on PGE2-induced cell death in differentiated NSC-34 cells. Dichlorofluorescein (DCF) fluorescence analysis of PGE2-treated cells showed that intracellular ROS levels increased markedly with time, and that this effect was antagonized by a selective EP2 antagonist (PF-04418948) but not a selective EP3 antagonist (L-798,106). Although an EP2-selective agonist, butaprost, mimicked the effect of PGE2, an EP1/EP3 agonist, sulprostone, transiently but significantly decreased the level of intracellular ROS in these cells. MTT reduction assay and lactate dehydrogenase release assay revealed that PGE2- and butaprost-induced cell death were each suppressed by pretreatment with NAC in a concentration-dependent manner. Western blot analysis revealed that the active form of caspase-3 was markedly increased in the PGE2- and butaprost-treated cells. These increases in caspase-3 protein expression were suppressed by pretreatment with NAC. Moreover, dibutyryl-cAMP treatment of differentiated NSC-34 cells caused intracellular ROS generation and cell death. Our data reveal the existence of a PGE2-EP2 signaling-dependent intracellular ROS generation pathway, with subsequent activation of the caspase-3 cascade, in differentiated NSC-34 cells, suggesting that PGE2 is likely a key molecule linking inflammation to oxidative stress in motor neuron-like NSC-34 cells.}, }
@article {pmid32411012, year = {2020}, author = {Momtaz, S and Memariani, Z and El-Senduny, FF and Sanadgol, N and Golab, F and Katebi, M and Abdolghaffari, AH and Farzaei, MH and Abdollahi, M}, title = {Targeting Ubiquitin-Proteasome Pathway by Natural Products: Novel Therapeutic Strategy for Treatment of Neurodegenerative Diseases.}, journal = {Frontiers in physiology}, volume = {11}, number = {}, pages = {361}, pmid = {32411012}, issn = {1664-042X}, abstract = {Misfolded proteins are the main common feature of neurodegenerative diseases, thereby, normal proteostasis is an important mechanism to regulate the neural survival and the central nervous system functionality. The ubiquitin-proteasome system (UPS) is a non-lysosomal proteolytic pathway involved in numerous normal functions of the nervous system, modulation of neurotransmitter release, synaptic plasticity, and recycling of membrane receptors or degradation of damaged and regulatory intracellular proteins. Aberrant accumulation of intracellular ubiquitin-positive inclusions has been implicated to a variety of neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington disease (HD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Myeloma (MM). Genetic mutation in deubiquitinating enzyme could disrupt UPS and results in destructive effects on neuron survival. To date, various agents were characterized with proteasome-inhibitory potential. Proteins of the ubiquitin-proteasome system, and in particular, E3 ubiquitin ligases, may be promising molecular targets for neurodegenerative drug discovery. Phytochemicals, specifically polyphenols (PPs), were reported to act as proteasome-inhibitors or may modulate the proteasome activity. PPs modify the UPS by means of accumulation of ubiquitinated proteins, suppression of neuronal apoptosis, reduction of neurotoxicity, and improvement of synaptic plasticity and transmission. This is the first comprehensive review on the effect of PPs on UPS. Here, we review the recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders. This review attempts to summarize the latest reports on the neuroprotective properties involved in the proper functioning of natural polyphenolic compounds with implication for targeting ubiquitin-proteasome pathway in the neurodegenerative diseases. We highlight the evidence suggesting that polyphenolic compounds have a dose and disorder dependent effects in improving neurological dysfunctions, and so their mechanism of action could stimulate the UPS, induce the protein degradation or inhibit UPS and reduce protein degradation. Future studies should focus on molecular mechanisms by which PPs can interfere this complex regulatory system at specific stages of the disease development and progression.}, }
@article {pmid32409664, year = {2020}, author = {Sanna, S and Esposito, S and Masala, A and Sini, P and Nieddu, G and Galioto, M and Fais, M and Iaccarino, C and Cestra, G and Crosio, C}, title = {HDAC1 inhibition ameliorates TDP-43-induced cell death in vitro and in vivo.}, journal = {Cell death &amp; disease}, volume = {11}, number = {5}, pages = {369}, pmid = {32409664}, issn = {2041-4889}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; Cell Death/*drug effects/physiology ; DNA-Binding Proteins/genetics/metabolism/*pharmacology ; Frontotemporal Lobar Degeneration/metabolism/pathology ; Histone Deacetylase 1/genetics/*metabolism ; Humans ; Inclusion Bodies/metabolism ; Mice ; Mutation/genetics ; }, abstract = {TDP-43 pathology is a disease hallmark that characterizes both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). TDP-43 undergoes several posttranslational modifications that can change its biological activities and its aggregative propensity, which is a common hallmark of different neurodegenerative conditions. New evidence is provided by the current study pointing at TDP-43 acetylation in ALS cellular models. Using both in vitro and in vivo approaches, we demonstrate that TDP-43 interacts with histone deacetylase 1 (HDAC1) via RRM1 and RRM2 domains, that are known to contain the two major TDP-43 acetylation sites, K142 and K192. Moreover, we show that TDP-43 is a direct transcriptional activator of CHOP promoter and this activity is regulated by acetylation. Finally and most importantly, we observe both in cell culture and in Drosophila that a HDCA1 reduced level (genomic inactivation or siRNA) or treatment with pan-HDAC inhibitors exert a protective role against WT or pathological mutant TDP-43 toxicity, suggesting TDP-43 acetylation as a new potential therapeutic target. HDAC inhibition efficacy in neurodegeneration has long been debated, but future investigations are warranted in this area. Selection of more specific HDAC inhibitors is still a promising option for neuronal protection especially as HDAC1 appears as a downstream target of both TDP- 43 and FUS, another ALS-related gene.}, }
@article {pmid32408605, year = {2020}, author = {Shavit-Stein, E and Abu Rahal, I and Bushi, D and Gera, O and Sharon, R and Gofrit, SG and Pollak, L and Mindel, K and Maggio, N and Kloog, Y and Chapman, J and Dori, A}, title = {Brain Protease Activated Receptor 1 Pathway: A Therapeutic Target in the Superoxide Dismutase 1 (SOD1) Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {21}, number = {10}, pages = {}, pmid = {32408605}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Astrocytes/metabolism ; Body Weight/drug effects ; Brain/*metabolism ; *Disease Models, Animal ; Farnesol/analogs &amp; derivatives/pharmacology ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism ; Mutation ; Pyrroles/pharmacology ; Quinazolines/pharmacology ; Receptor, PAR-1/*metabolism ; Salicylates/pharmacology ; Signal Transduction/drug effects ; Superoxide Dismutase-1/genetics/*metabolism ; Survival Analysis ; Tosyllysine Chloromethyl Ketone/pharmacology ; }, abstract = {Glia cells are involved in upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Protease activated receptor 1 (PAR1) pathway is related to brain pathologies. Brain PAR1 is located on peri-synaptic astrocytes, adjacent to pyramidal motor neurons, suggesting possible involvement in ALS. Brain thrombin activity in superoxide dismutase 1 (SOD1) mice was measured using a fluorometric assay, and PAR1 levels by western blot. PAR1 was localized using immunohistochemistry staining. Treatment targeted PAR1 pathway on three levels; thrombin inhibitor TLCK (N-Tosyl-Lys-chloromethylketone), PAR1 antagonist SCH-79797 and the Ras intracellular inhibitor FTS (S-trans-trans-farnesylthiosalicylic acid). Mice were weighed and assessed for motor function and survival. SOD1 brain thrombin activity was increased (p < 0.001) particularly in the posterior frontal lobe (p = 0.027) and hindbrain (p < 0.01). PAR1 levels were decreased (p < 0.001, brain, spinal cord, p < 0.05). PAR1 and glial fibrillary acidic protein (GFAP) staining decreased in the cerebellum and cortex. SOD1 mice lost weight (≥17 weeks, p = 0.047), and showed shorter rotarod time (≥14 weeks, p < 0.01). FTS 40mg/kg significantly improved rotarod scores (p < 0.001). Survival improved with all treatments (p < 0.01 for all treatments). PAR1 antagonism was the most efficient, with a median survival improvement of 10 days (p < 0.0001). Our results support PAR1 pathway involvement in ALS.}, }
@article {pmid32396393, year = {2020}, author = {Brizzi, KT and Bridges, JFP and Yersak, J and Balas, C and Thakur, N and Galvin, M and Hardiman, O and Heatwole, C and Ravits, J and Simmons, Z and Bruijn, L and Chan, J and Bedlack, R and Berry, JD}, title = {Understanding the needs of people with ALS: a national survey of patients and caregivers.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {5-6}, pages = {355-363}, doi = {10.1080/21678421.2020.1760889}, pmid = {32396393}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/therapy ; *Caregivers ; Humans ; Mood Disorders ; Quality of Life ; Surveys and Questionnaires ; }, abstract = {Objective: Amyotrophic lateral sclerosis (ALS) has profound effects on people with ALS (PALS) and caregivers. There is a paucity of research detailing and comparing PALS and caregiver day-to-day perspectives of ALS. Methods: A survey developed collaboratively by The ALS Association and a panel of experts in ALS care was designed to broadly sample the experience of PALS and caregivers with respect to physical and emotional symptoms, the efficacy of treatment approaches, and goals for future treatments. Specific physical symptoms assessed consisted of fatigue, pain, weakness, shortness of breath, difficulty sleeping, speech problems, depression and other mood changes, and cognitive changes. PALS, caregivers of living patients with ALS (C-LPALS), and caregivers of deceased patients with ALS (C-DPALS) were contacted by email to participate in a 30-minute online survey. Results: 887 PALS, 444 C-LPALS, and 193 C-DPALS responded to the survey. In comparison to PALS, C-LPALS perceived that PALS had significantly higher rates of all surveyed symptoms except for pain and weakness. Caregivers self-reported higher stress levels than PALS (p < 0.001). 35% (135/383) of caregivers reported experiencing a devastating or near devastating financial impact of ALS and 64% (247/383) of caregivers felt their own health had worsened. Caregivers were significantly less likely to perceive a positive response to treatment in comparison to PALS (p < 0.001). Conclusions: PALS and caregivers report a number of symptoms beyond weakness that affect daily life which may be targets of future interventions. There are opportunities to improve services and care for caregivers to reduce the burden of illness.}, }
@article {pmid32390927, year = {2020}, author = {Yang, JS and Xu, HL and Chen, PP and Sikandar, A and Qian, MZ and Lin, HX and Lin, MT and Chen, WJ and Wang, N and Wu, H and Gan, SR}, title = {Ataxic Severity Is Positively Correlated With Fatigue in Spinocerebellar Ataxia Type 3 Patients.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {266}, pmid = {32390927}, issn = {1664-2295}, abstract = {Background: Spinocerebellar ataxia type 3 (SCA3) is an inherited form of ataxia that leads to progressive neurodegeneration. Fatigue is a common non-motor symptom in SCA3 and other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Although risk factors to fatigue in these diseases have been thoroughly studied, whether or not fatigue can affect clinical phenotypes has yet to be investigated. Methods: Ninety-one molecularly confirmed SCA3 patients and 85 age- and sex-matched controls were recruited for this study. The level of fatigue was measured using the 14-item Fatigue Scale (FS-14), and the risk factors to fatigue and how fatigue correlates with clinical phenotypes were studied using multivariable linear regression models. Results: We found that the severity was significantly higher in the SCA3 group than in the control group (9.30 ± 3.04% vs. 3.94 ± 2.66, P = 0.000). Daytime somnolence (β = 0.209, P = 0.002), severity of ataxia (β = 0.081, P = 0.006), and poor sleep quality (β = 0.187, P = 0.037) were found to have a positive relationship with fatigue. Although fatigue had no relationship with age at onset or ataxic progression, we found that it did have a positive relationship with the severity of ataxia (β = 7.009, P = 0.014). Conclusions: The high level of fatigue and the impact of fatigue on the clinical manifestation of SCA3 patients suggest that fatigue plays a large role in the pathogenesis of SCA3, thus demonstrating the need for intervention and treatment options in this patient cohort.}, }
@article {pmid32385188, year = {2020}, author = {Benatar, M and Zhang, L and Wang, L and Granit, V and Statland, J and Barohn, R and Swenson, A and Ravits, J and Jackson, C and Burns, TM and Trivedi, J and Pioro, EP and Caress, J and Katz, J and McCauley, JL and Rademakers, R and Malaspina, A and Ostrow, LW and Wuu, J and , }, title = {Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS.}, journal = {Neurology}, volume = {95}, number = {1}, pages = {e59-e69}, pmid = {32385188}, issn = {1526-632X}, support = {U01 NS107027/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; UL1 TR002366/TR/NCATS NIH HHS/United States ; UL1 TR000001/TR/NCATS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*blood ; Biomarkers/*blood ; Female ; Humans ; Intermediate Filaments/*metabolism ; Male ; Middle Aged ; Prognosis ; }, abstract = {OBJECTIVE: To identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development.<br><br>METHODS: In this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations.<br><br>RESULTS: For serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in &#x223c;4% and &#x223c;10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both &#x223c;3%. Mean coefficients of variation for pNfH in serum and CSF were &#x223c;4%-5% and &#x223c;2%-3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of &#x223c;8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings.<br><br>CONCLUSIONS: Serum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect.}, }
@article {pmid32383122, year = {2020}, author = {Ustyantseva, EI and Medvedev, SP and Zakian, SM}, title = {Studying ALS: Current Approaches, Effect on Potential Treatment Strategy.}, journal = {Advances in experimental medicine and biology}, volume = {1241}, number = {}, pages = {195-217}, doi = {10.1007/978-3-030-41283-8_11}, pmid = {32383122}, issn = {0065-2598}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Biomedical Research ; Disease Progression ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, characterized by inevitable progressive paralysis. To date, only two disease modifying therapeutic options are available for the patients with ALS, although they show very modest effect on disease course. The main reason of failure in the field of pharmacological correction of ALS is inability to untangle complex relationships taking place during ALS initiation and progression. Traditional methods of research, based on morphology or transgenic animal models studying provided lots of information about ALS throughout the years. However, translation of these results to humans was unsuccessful due to incomplete recapitulation of molecular pathology and overall inadequacy of the models used in the research.In this review we summarize current knowledge regarding ALS molecular pathology with depiction of novel methods applied recently for the studies. Furthermore we describe present and potential treatment strategies that are based on the recent findings in ALS disease mechanisms.}, }
@article {pmid32377479, year = {2020}, author = {Gonzalez Trujillo, F and Parra Cortes, K and Álvarez Pareja, Y and Onate, J}, title = {Human T-cell Lymphotropic Virus Type I Associated with Amyotrophic Lateral Sclerosis Syndrome: Immunopathological Aspects and Treatment Options.}, journal = {Cureus}, volume = {12}, number = {4}, pages = {e7531}, pmid = {32377479}, issn = {2168-8184}, abstract = {Human T-cell lymphotropic virus type I (HTLV-I) is a retrovirus related to infectious myelopathies, neoplasms, lymphomas, leukemias, and amyotrophic lateral sclerosis (ALS). It is acquired through sexual transmission, transfusion of blood products, and breastfeeding. The increased expression of human endogenous retrovirus K (HERV-K) in the brain tissue of patients with ALS has been demonstrated, a finding that supports the relationship between the virus and this disease. Therapeutic options include supportive measures and symptomatic treatment with anti-inflammatory medications including steroids, cyclosporines, pentoxifylline, danazol, interferons, and vitamin C. New management proposals are being implemented with valproic acid that acts to facilitate the recognition of the virus by the immune system and with zidovudine antivirals focused on reducing viral load. The purpose of this paper is to describe a clinical case that exhibits clinical signs and evidence of motor neuron compromise as described in electrophysiology studies along with positive laboratory tests for the HTLV-I virus.}, }
@article {pmid32372737, year = {2020}, author = {Høegh, MC and Melle, I and Aminoff, SR and Laskemoen, JF and Büchmann, CB and Ueland, T and Lagerberg, TV}, title = {Affective lability across psychosis spectrum disorders.}, journal = {European psychiatry : the journal of the Association of European Psychiatrists}, volume = {63}, number = {1}, pages = {e53}, pmid = {32372737}, issn = {1778-3585}, mesh = {Adult ; Bipolar Disorder/*psychology ; Borderline Personality Disorder/*psychology ; Female ; Humans ; Male ; Psychological Tests ; Psychotic Disorders/*psychology ; Risk Factors ; Schizophrenia/complications ; }, abstract = {BACKGROUND: Despite apparent clinical remission, individuals with psychotic disorders often experience significant impairments across functional domains. Thus, there is a need to search beyond management of core symptoms to optimize treatment outcomes. Affective dysregulation is considered a risk factor for poor clinical and functional outcomes in many mental disorders, but research investigating such features in psychosis, particularly in schizophrenia, is limited. We aimed to investigate the level of affective lability (AL) in participants with schizophrenia- and bipolar spectrum disorders (n = 222) compared to healthy controls (n = 140), as well as clinical correlates of AL in the diagnostic groups.<br><br>METHODS: The Affective Lability Scale (ALS-SF) was used to measure total score of AL and subscores covering the domains of anxiety/depression, depression/elation, and anger. An analysis of covariance was performed to compare the ALS-SF total score between groups, correcting for potential confounders, as well as standard multiple regression analyses for diagnosis-specific investigations of the relationship between AL and demographic and clinical features.<br><br>RESULTS: Both the schizophrenia- and bipolar spectrum group had significantly higher ALS-SF total score compared to controls (p < 0.001), and no significant differences between the patient groups were found. In the schizophrenia group, current psychotic and depressive symptoms were significantly and independently associated with AL (p = 0.012 and p = 0.024, respectively).<br><br>CONCLUSIONS: The findings indicate that AL is elevated in psychotic disorders and that it transcends diagnostic boundaries. Further research into the causal relationship between psychotic and affective symptoms and AL, as well as its role as a potential therapeutic target in psychosis spectrum disorders, is warranted.}, }
@article {pmid32371370, year = {2020}, author = {Scaricamazza, S and Salvatori, I and Giacovazzo, G and Loeffler, JP and Renè, F and Rosina, M and Quessada, C and Proietti, D and Heil, C and Rossi, S and Battistini, S and Giannini, F and Volpi, N and Steyn, FJ and Ngo, ST and Ferraro, E and Madaro, L and Coccurello, R and Valle, C and Ferri, A}, title = {Skeletal-Muscle Metabolic Reprogramming in ALS-SOD1[G93A] Mice Predates Disease Onset and Is A Promising Therapeutic Target.}, journal = {iScience}, volume = {23}, number = {5}, pages = {101087}, pmid = {32371370}, issn = {2589-0042}, abstract = {Patients with ALS show, in addition to the loss of motor neurons in the spinal cord, brainstem, and cerebral cortex, an abnormal depletion of energy stores alongside hypermetabolism. In this study, we show that bioenergetic defects and muscle remodeling occur in skeletal muscle of the SOD1[G93A] mouse model of ALS mice prior to disease onset and before the activation of muscle denervation markers, respectively. These changes in muscle physiology were followed by an increase in energy expenditure unrelated to physical activity. Finally, chronic treatment of SOD1[G93A] mice with Ranolazine, an FDA-approved inhibitor of fatty acid β-oxidation, led to a decrease in energy expenditure in symptomatic SOD1[G93A] mice, and this occurred in parallel with a robust, albeit temporary, recovery of the pathological phenotype.}, }
@article {pmid32371051, year = {2020}, author = {Chan, G and van Hummel, A and van der Hoven, J and Ittner, LM and Ke, YD}, title = {Neurodegeneration and Motor Deficits in the Absence of Astrogliosis upon Transgenic Mutant TDP-43 Expression in Mature Mice.}, journal = {The American journal of pathology}, volume = {190}, number = {8}, pages = {1713-1722}, doi = {10.1016/j.ajpath.2020.04.009}, pmid = {32371051}, issn = {1525-2191}, mesh = {Animals ; Brain/*metabolism/pathology ; DNA-Binding Proteins/*genetics/metabolism ; Gliosis/*pathology ; Mice ; Mice, Transgenic ; Motor Disorders/*genetics/metabolism/pathology ; Muscular Atrophy/*genetics/metabolism/pathology ; Nerve Degeneration/*genetics/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis is a rapidly progressing and fatal disease characterized by muscular atrophy due to loss of upper and lower motor neurons. Pathogenic mutations in the TARDBP gene encoding TAR DNA binding protein-43 (TDP-43) have been identified in familial amyotrophic lateral sclerosis. We have previously reported transgenic mice with neuronal expression of human TDP-43 carrying the pathogenic A315T mutation (iTDP-43[A315T] mice) using a tetracycline-controlled inducible promotor system. Constitutive expression of transgenic TDP-43[A315T] in the absence of doxycycline resulted in pronounced early-onset and progressive neurodegeneration, and motor and memory deficits. Here, delayed transgene expression of TDP-43[A315T] by oral doxycycline treatment of iTDP-43[A315T] mice from birth till weaning was analyzed. After doxycycline withdrawal, transgenic TDP-43[A315T] expression gradually increased and resulted in cytoplasmic TDP-43, widespread ubiquitination, and cortical and hippocampal atrophy. In addition, these mice developed motor and gait deficits with underlying muscle atrophy, similar to that observed in the constitutive iTDP-43[A315T] mice. Surprisingly, in contrast to the constitutive iTDP-43[A315T] mice, these mice did not develop astrogliosis. In summary, delayed activation coupled with gradual increase in TDP-43[A315T] expression in the central nervous system of mature mice resulted in progressive functional deficits with neuron and muscle loss, but in the absence of a glial response. This suggests that astrocytosis does not contribute to functional deficits and neuronal loss upon TDP-43[A315T] expression in mature mice.}, }
@article {pmid32370112, year = {2020}, author = {Crespo-Castrillo, A and Arevalo, MA}, title = {Microglial and Astrocytic Function in Physiological and Pathological Conditions: Estrogenic Modulation.}, journal = {International journal of molecular sciences}, volume = {21}, number = {9}, pages = {}, pmid = {32370112}, issn = {1422-0067}, support = {BFU2017-82754-R//Agencia Estatal de Investigaci&#xf3;n/ ; CB16/10/00383//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red Fragilidad y Envejecimiento Saludable/ ; }, mesh = {Alzheimer Disease/metabolism/*pathology ; Astrocytes/*pathology ; Depressive Disorder, Major/metabolism/*pathology ; Estrogens/metabolism ; Female ; Humans ; Male ; Microglia/*pathology ; Multiple Sclerosis/metabolism/*pathology ; Sex Factors ; }, abstract = {There are sexual differences in the onset, prevalence, and outcome of numerous neurological diseases. Thus, in Alzheimer's disease, multiple sclerosis, and major depression disorder, the incidence in women is higher than in men. In contrast, men are more likely to present other pathologies, such as amyotrophic lateral sclerosis, Parkinson's disease, and autism spectrum. Although the neurological contribution to these diseases has classically always been studied, the truth is that neurons are not the only cells to be affected, and there are other cells, such as glial cells, that are also involved and could be key to understanding the development of these pathologies. Sexual differences exist not only in pathology but also in physiological processes, which shows how cells are differentially regulated in males and females. One of the reasons these sexual differences may occur could be due to the different action of sex hormones. Many studies have shown an increase in aromatase levels in the brain, which could indicate the main role of estrogens in modulating proinflammatory processes. This review will highlight data about sex differences in glial physiology and how estrogenic compounds, such as estradiol and tibolone, could be used as treatment in neurological diseases due to their anti-inflammatory effects and the ability to modulate glial cell functions.}, }
@article {pmid32369618, year = {2020}, author = {Petrozziello, T and Mills, AN and Farhan, SMK and Mueller, KA and Granucci, EJ and Glajch, KE and Chan, J and Chew, S and Berry, JD and Sadri-Vakili, G}, title = {Lipocalin-2 is increased in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {62}, number = {2}, pages = {272-283}, doi = {10.1002/mus.26911}, pmid = {32369618}, issn = {1097-4598}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/physiopathology ; Blotting, Western ; Case-Control Studies ; Cell Death ; Cell Line, Tumor ; Cytokines/drug effects/metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Fluorescent Antibody Technique ; Humans ; In Vitro Techniques ; Inflammation/*metabolism ; Lipocalin-2/antagonists &amp; inhibitors/*genetics/metabolism/pharmacology ; Male ; Middle Aged ; Motor Cortex/*metabolism ; Polymorphism, Single Nucleotide ; Real-Time Polymerase Chain Reaction ; Spinal Cord/*metabolism ; }, abstract = {BACKGROUND: The exact mechanisms underlying neuroinflammation and how they contribute to amyotrophic lateral sclerosis (ALS) pathogenesis remain unclear. One possibility is the secretion of neurotoxic factors, such as lipocalin-2 (LCN2), that lead to neuronal death.<br><br>METHODS: LCN2 levels were measured in human postmortem tissue using Western blot, quantitative real time polymerase chain reaction, and immunofluorescence, and in plasma by enzyme-linked immunosorbent assay. SH-SY5Y cells were used to test the pro-inflammatory effects of LCN2.<br><br>RESULTS: LCN2 is increased in ALS postmortem motor cortex, spinal cord, and plasma. Furthermore, we identified several LCN2 variants in ALS patients that may contribute to disease pathogenesis. Lastly, while LCN2 treatment caused cell death and increased pro-inflammatory markers, treatment with an anti-LCN2 antibody prevented these responses in vitro.<br><br>CONCLUSIONS: LCN2 upregulation in ALS postmortem samples and plasma may be an upstream event for triggering neuroinflammation and neuronal death.}, }
@article {pmid32369036, year = {2020}, author = {Pot-Kolder, R and Veling, W and Geraets, C and Lokkerbol, J and Smit, F and Jongeneel, A and Ising, H and van der Gaag, M}, title = {Cost-Effectiveness of Virtual Reality Cognitive Behavioral Therapy for Psychosis: Health-Economic Evaluation Within a Randomized Controlled Trial.}, journal = {Journal of medical Internet research}, volume = {22}, number = {5}, pages = {e17098}, pmid = {32369036}, issn = {1438-8871}, mesh = {Adolescent ; Adult ; Aged ; Cognitive Behavioral Therapy/*methods ; Cost-Benefit Analysis/*methods ; Female ; Humans ; Male ; Middle Aged ; Psychotic Disorders/*therapy ; *Virtual Reality ; Young Adult ; }, abstract = {BACKGROUND: Evidence was found for the effectiveness of virtual reality-based cognitive behavioral therapy (VR-CBT) for treating paranoia in psychosis, but health-economic evaluations are lacking.<br><br>OBJECTIVE: This study aimed to determine the short-term cost-effectiveness of VR-CBT.<br><br>METHODS: The health-economic evaluation was embedded in a randomized controlled trial evaluating VR-CBT in 116 patients with a psychotic disorder suffering from paranoid ideation. The control group (n=58) received treatment as usual (TAU) for psychotic disorders in accordance with the clinical guidelines. The experimental group (n=58) received TAU complemented with add-on VR-CBT to reduce paranoid ideation and social avoidance. Data were collected at baseline and at 3 and 6 months postbaseline. Treatment response was defined as a pre-post improvement of symptoms of at least 20% in social participation measures. Change in quality-adjusted life years (QALYs) was estimated by using Sanderson et al's conversion factor to map a change in the standardized mean difference of Green's Paranoid Thoughts Scale score on a corresponding change in utility. The incremental cost-effectiveness ratios were calculated using 5000 bootstraps of seemingly unrelated regression equations of costs and effects. The cost-effectiveness acceptability curves were graphed for the costs per treatment responder gained and per QALY gained.<br><br>RESULTS: The average mean incremental costs for a treatment responder on social participation ranged between &#x20ac;8079 and &#x20ac;19,525, with 90.74%-99.74% showing improvement. The average incremental cost per QALY was &#x20ac;48,868 over the 6 months of follow-up, with 99.98% showing improved QALYs. Sensitivity analyses show costs to be lower when relevant baseline differences were included in the analysis. Average costs per treatment responder now ranged between &#x20ac;6800 and &#x20ac;16,597, while the average cost per QALY gained was &#x20ac;42,030.<br><br>CONCLUSIONS: This study demonstrates that offering VR-CBT to patients with paranoid delusions is an economically viable approach toward improving patients' health in a cost-effective manner. Long-term effects need further research.<br><br>TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) 12929657; http://www.isrctn.com/ISRCTN12929657.}, }
@article {pmid32364065, year = {2021}, author = {Catalano, A and Franchini, C and Carocci, A}, title = {Voltage-Gated Sodium Channel Blockers: Synthesis of Mexiletine Analogues and Homologues.}, journal = {Current medicinal chemistry}, volume = {28}, number = {8}, pages = {1535-1548}, doi = {10.2174/0929867327666200504080530}, pmid = {32364065}, issn = {1875-533X}, mesh = {Anti-Arrhythmia Agents/therapeutic use ; Arrhythmias, Cardiac/drug therapy ; Humans ; *Mexiletine/therapeutic use ; Sodium Channel Blockers/pharmacology/therapeutic use ; *Voltage-Gated Sodium Channel Blockers/pharmacology/therapeutic use ; }, abstract = {Mexiletine is an antiarrhythmic drug belonging to IB class, acting as sodium channel blocker. Besides its well-known activity on arrhythmias, its usefulness in the treatment of myotonia, myotonic dystrophy and amyotrophic lateral sclerosis is now widely recognized. Nevertheless, it has been retired from the market in several countries because of its undesired effects. Thus, several papers were reported in the last years about analogues and homologues of mexiletine being endowed with a wider therapeutic ratio and a more selectivity of action. Some of them showed sodium channel blocking activity higher than the parent compound. It is noteworthy that mexiletine is used in therapy as a racemate even though a difference in the activities of the two enantiomers was widely demonstrated, with (-)-(R)-enantiomer being more active: this finding led several research groups to study mexiletine and its analogues and homologues in their optically active forms. This review summarizes the different synthetic routes used to obtain these compounds. They could represent an interesting starting point to new mexiletine-like compounds without common side effects related to the use of mexiletine.}, }
@article {pmid32362075, year = {2020}, author = {Frydrýšková, K and Mašek, T and Pospíšek, M}, title = {Changing faces of stress: Impact of heat and arsenite treatment on the composition of stress granules.}, journal = {Wiley interdisciplinary reviews. RNA}, volume = {11}, number = {6}, pages = {e1596}, doi = {10.1002/wrna.1596}, pmid = {32362075}, issn = {1757-7012}, mesh = {Animals ; Arsenites/*metabolism ; Cytoplasmic Granules/*metabolism ; *Hot Temperature ; Humans ; Protein Processing, Post-Translational ; Stress, Physiological ; }, abstract = {Stress granules (SGs), hallmarks of the cellular adaptation to stress, promote survival, conserve cellular energy, and are fully dissolved upon the cessation of stress treatment. Different stresses can initiate the assembly of SGs, but arsenite and heat are the best studied of these stresses. The composition of SGs and posttranslational modifications of SG proteins differ depending on the type and severity of the stress insult, methodology used, cell line, and presence of overexpressed and tagged proteins. A group of 18 proteins showing differential localization to SGs in heat- and arsenite-stressed mammalian cell lines is described. Upon severe and prolonged stress, physiological SGs transform into more solid protein aggregates that are no longer reversible and do not contain mRNA. Similar pathological inclusions are hallmarks of neurodegenerative diseases. SGs induced by heat stress are less dynamic than SGs induced by arsenite and contain a set of unique proteins and linkage-specific polyubiquitinated proteins. The same types of ubiquitin linkages have been found to contribute to the development of neurodegenerative disorders such as Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (ALS). We propose heat stress-induced SGs as a possible model of an intermediate stage along the transition from dynamic, fully reversible arsenite stress-induced SGs toward aberrant SGs, the hallmark of neurodegenerative diseases. Stress- and methodology-specific differences in the compositions of SGs and the transition of SGs to aberrant protein aggregates are discussed. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Export and Localization > RNA Localization.}, }
@article {pmid32353332, year = {2020}, author = {Yerbury, JJ and Farrawell, NE and McAlary, L}, title = {Proteome Homeostasis Dysfunction: A Unifying Principle in ALS Pathogenesis.}, journal = {Trends in neurosciences}, volume = {43}, number = {5}, pages = {274-284}, doi = {10.1016/j.tins.2020.03.002}, pmid = {32353332}, issn = {1878-108X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Proteome/metabolism ; Motor Neurons ; Proteostasis ; Homeostasis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease but currently has no effective treatment. Growing evidence suggests that proteome homeostasis underlies ALS pathogenesis. Protein production, trafficking, and degradation all shape the proteome. We present a hypothesis that proposes all genetic lesions associated with ALS (including in mRNA-binding proteins) cause widespread imbalance to an already metastable proteome. The impact of such dysfunction is felt across the entire proteome and is not restricted to a small subset of proteins. Proteome imbalance may cause functional defects, such as excitability alterations, and eventually cell death. While this idea is a unifying principle for all of ALS, we propose that stratification will appear that might dictate the efficacy of therapeutics based on the proteostasis network.}, }
@article {pmid32351395, year = {2020}, author = {Hong, C and Jeong, B and Park, HJ and Chung, JY and Lee, JE and Kim, J and Shin, YC and So, I}, title = {TRP Channels as Emerging Therapeutic Targets for Neurodegenerative Diseases.}, journal = {Frontiers in physiology}, volume = {11}, number = {}, pages = {238}, pmid = {32351395}, issn = {1664-042X}, abstract = {The development of treatment for neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis is facing medical challenges due to the increasingly aging population. However, some pharmaceutical companies have ceased the development of therapeutics for NDs, and no new treatments for NDs have been established during the last decade. The relationship between ND pathogenesis and risk factors has not been completely elucidated. Herein, we review the potential involvement of transient receptor potential (TRP) channels in NDs, where oxidative stress and disrupted Ca[2+] homeostasis consequently lead to neuronal apoptosis. Reactive oxygen species (ROS) -sensitive TRP channels can be key risk factors as polymodal sensors, since progressive late onset with secondary pathological damage after initial toxic insult is one of the typical characteristics of NDs. Recent evidence indicates that the dysregulation of TRP channels is a missing link between disruption of Ca[2+] homeostasis and neuronal loss in NDs. In this review, we discuss the latest findings regarding TRP channels to provide insights into the research and quests for alternative therapeutic candidates for NDs. As the structures of TRP channels have recently been revealed by cryo-electron microscopy, it is necessary to develop new TRP channel antagonists and reevaluate existing drugs.}, }
@article {pmid32350120, year = {2020}, author = {Tavassoly, O and Sato, T and Tavassoly, I}, title = {Inhibition of Brain Epidermal Growth Factor Receptor Activation: A Novel Target in Neurodegenerative Diseases and Brain Injuries.}, journal = {Molecular pharmacology}, volume = {98}, number = {1}, pages = {13-22}, doi = {10.1124/mol.120.119909}, pmid = {32350120}, issn = {1521-0111}, mesh = {Adult ; Animals ; Blood-Brain Barrier/drug effects ; Brain Injuries/drug therapy/*metabolism ; Central Nervous System/*growth &amp; development/metabolism ; Child ; Drug Repositioning ; ErbB Receptors/antagonists &amp; inhibitors/metabolism ; Gene Expression Regulation, Developmental ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/drug therapy/*metabolism ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; Spinal Cord Injuries/drug therapy/*metabolism ; Up-Regulation/drug effects ; }, abstract = {Several reports have been published recently demonstrating a beneficial effect of epidermal growth factor receptor (EGFR) inhibitors in improving pathologic and behavioral conditions in neurodegenerative diseases (NDDs) such as Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS) as well as the brain and spinal cord injuries (SCI). Despite successful therapeutic effects of EGFR inhibition in these pathologic conditions, there is still no report of proof-of-concept studies in well-characterized animal models using recently developed blood-brain barrier (BBB)-penetrating EGFR inhibitors, which is due to previous conflicting reports concerning the level of EGFR or activated EGFR in normal and pathologic conditions that caused target engagement to be a concern in any future EGFR inhibition therapy. In this review, the level of EGFR expression and activation in the developing central nervous system (CNS) compared with the adult CNS will be explained as well as how neuronal injury or pathologic conditions, especially inflammation and amyloid fibrils, induce reactive astrocytes leading to an increase in the expression and activation of EGFR and, finally, neurodegeneration. Furthermore, in this review, we will discuss two main molecular mechanisms that can be proposed as the neuroprotective effects of EGFR inhibition in these pathologic conditions. We will also review the recent advances in the development of BBB-penetrating EGFR inhibitors in cancer therapy, which may eventually be repositioned for NDDs and SCI therapy in the future. SIGNIFICANCE STATEMENT: Based on the lessons from the applications of EGFR inhibitors in oncology, it is concluded that EGFR inhibitors can be beneficial in treatment of neurodegenerative diseases and spinal cord injuries. They carry their therapeutic potentials through induction of autophagy and attenuation of reactive astrocytes.}, }
@article {pmid32345721, year = {2020}, author = {Petit, CS and Lee, JJ and Boland, S and Swarup, S and Christiano, R and Lai, ZW and Mejhert, N and Elliott, SD and McFall, D and Haque, S and Huang, EJ and Bronson, RT and Harper, JW and Farese, RV and Walther, TC}, title = {Inhibition of sphingolipid synthesis improves outcomes and survival in GARP mutant wobbler mice, a model of motor neuron degeneration.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {117}, number = {19}, pages = {10565-10574}, pmid = {32345721}, issn = {1091-6490}, support = {R37 NS083524/NS/NINDS NIH HHS/United States ; //CIHR/Canada ; R01 NS110395/NS/NINDS NIH HHS/United States ; P30 CA006516/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; I01 BX002978/BX/BLRD VA/United States ; }, mesh = {Animals ; Disease Models, Animal ; Endosomes/metabolism ; Fatty Acids, Monounsaturated/pharmacology ; Female ; Fibroblasts/metabolism ; Golgi Apparatus/metabolism ; Male ; Membrane Proteins/*genetics/*metabolism ; Mice ; Mice, Neurologic Mutants ; Motor Neuron Disease/genetics/metabolism/pathology ; Motor Neurons/metabolism ; Mouse Embryonic Stem Cells ; Mutation ; Nervous System Malformations/metabolism ; Neurodegenerative Diseases/metabolism/physiopathology ; Protein Transport ; Proteomics ; Sphingolipids/*metabolism ; Vesicular Transport Proteins/metabolism ; }, abstract = {Numerous mutations that impair retrograde membrane trafficking between endosomes and the Golgi apparatus lead to neurodegenerative diseases. For example, mutations in the endosomal retromer complex are implicated in Alzheimer's and Parkinson's diseases, and mutations of the Golgi-associated retrograde protein (GARP) complex cause progressive cerebello-cerebral atrophy type 2 (PCCA2). However, how these mutations cause neurodegeneration is unknown. GARP mutations in yeast, including one causing PCCA2, result in sphingolipid abnormalities and impaired cell growth that are corrected by treatment with myriocin, a sphingolipid synthesis inhibitor, suggesting that alterations in sphingolipid metabolism contribute to cell dysfunction and death. Here we tested this hypothesis in wobbler mice, a murine model with a homozygous partial loss-of-function mutation in Vps54 (GARP protein) that causes motor neuron disease. Cytotoxic sphingoid long-chain bases accumulated in embryonic fibroblasts and spinal cords from wobbler mice. Remarkably, chronic treatment of wobbler mice with myriocin markedly improved their wellness scores, grip strength, neuropathology, and survival. Proteomic analyses of wobbler fibroblasts revealed extensive missorting of lysosomal proteins, including sphingolipid catabolism enzymes, to the Golgi compartment, which may contribute to the sphingolipid abnormalities. Our findings establish that altered sphingolipid metabolism due to GARP mutations contributes to neurodegeneration and suggest that inhibiting sphingolipid synthesis might provide a useful strategy for treating these disorders.}, }
@article {pmid32344747, year = {2020}, author = {Basile, MS and Battaglia, G and Bruno, V and Mangano, K and Fagone, P and Petralia, MC and Nicoletti, F and Cavalli, E}, title = {The Dichotomic Role of Macrophage Migration Inhibitory Factor in Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {21}, number = {8}, pages = {}, pmid = {32344747}, issn = {1422-0067}, mesh = {Animals ; Biomarkers ; Central Nervous System/metabolism/pathology ; Clinical Studies as Topic ; Disease Management ; Disease Models, Animal ; *Disease Susceptibility ; Humans ; Intramolecular Oxidoreductases/*genetics/*metabolism ; Macrophage Migration-Inhibitory Factors/*genetics/*metabolism ; Neurodegenerative Diseases/diagnosis/*etiology/*metabolism/therapy ; }, abstract = {Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine expressed by different cell types and exerting multiple biological functions. It has been shown that MIF may be involved in several disorders, including neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), and Huntington disease (HD), that represent an unmet medical need. Therefore, further studies are needed to identify novel pathogenetic mechanisms that may translate into tailored therapeutic approaches so to improve patients' survival and quality of life. Here, we reviewed the preclinical and clinical studies investigating the role of MIF in ALS, PD, and HD. The emerging results suggest that MIF might play a dichotomic role in these disorders, exerting a protective action in ALS, a pathogenetic action in HD, and a yet undefined and debated role in PD. The better understanding of the role of MIF in these diseases could allow its use as a novel diagnostic and therapeutic tool for the monitoring and treatment of the patients and for eventual biomarker-driven therapeutic approaches.}, }
@article {pmid32342825, year = {2021}, author = {Alam, M and Yadav, RK and Minj, E and Tiwari, A and Mehan, S}, title = {Exploring Molecular Approaches in Amyotrophic Lateral Sclerosis: Drug Targets from Clinical and Pre-Clinical Findings.}, journal = {Current molecular pharmacology}, volume = {14}, number = {3}, pages = {263-280}, doi = {10.2174/1566524020666200427214356}, pmid = {32342825}, issn = {1874-4702}, mesh = {*Amyotrophic Lateral Sclerosis/complications/drug therapy/pathology ; Humans ; Mitochondria/pathology ; *Motor Neuron Disease/complications/metabolism/pathology ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterized by the death of upper and lower motor neurons (corticospinal tract) in the motor cortex, basal ganglia, brain stem, and spinal cord. The patient experiences the sign and symptoms between 55 to 75 years of age, which include impaired motor movement, difficulty in speaking and swallowing, grip loss, muscle atrophy, spasticity, and sometimes associated with memory and cognitive impairments. Median survival is 3 to 5 years after diagnosis and 5 to 10% of the patients live for more than 10 years. The limited intervention of pharmacologically active compounds, that are used clinically, is majorly associated with the narrow therapeutic index. Pre-clinically established experimental models, where neurotoxin methyl mercury mimics the ALS like behavioural and neurochemical alterations in rodents associated with neuronal mitochondrial dysfunctions and downregulation of adenyl cyclase mediated cAMP/CREB, is the main pathological hallmark for the progression of ALS in central as well in the peripheral nervous system. Despite the considerable investigation into neuroprotection, it still constrains treatment choices to strong care and organization of ALS complications. Therefore, this current review specially targeted the investigation of clinical and pre-clinical features available for ALS to understand the pathogenic mechanisms and to explore the pharmacological interventions associated with the up-regulation of intracellular adenyl cyclase/cAMP/ CREB and activation of mitochondrial-ETC coenzyme-Q10 as a future drug target in the amelioration of ALS mediated motor neuronal dysfunctions.}, }
@article {pmid32342435, year = {2020}, author = {Ahmadian-Moghadam, H and Sadat-Shirazi, MS and Zarrindast, MR}, title = {Therapeutic potential of stem cells for treatment of neurodegenerative diseases.}, journal = {Biotechnology letters}, volume = {42}, number = {7}, pages = {1073-1101}, doi = {10.1007/s10529-020-02886-1}, pmid = {32342435}, issn = {1573-6776}, support = {36034-159-03-96//Iran's National Elites Foundation/ ; }, mesh = {Animals ; Humans ; Induced Pluripotent Stem Cells/transplantation ; Mice ; Neural Stem Cells/transplantation ; Neurodegenerative Diseases/*surgery ; *Stem Cell Transplantation ; }, abstract = {Neurodegenerative diseases are caused by a loss of neurons within the peripheral or central nervous system. Inadequate repairability in the central nervous system and failure of treatments are the significant hurdles for several neurological diseases. The regenerative potential of stem cells drew the attention of researchers to cell-based therapy for treating neurodegenerative diseases. The clinical application of stem cells may help to substitute new cells and overcome the inability of the endogenous repairing system to repair the damaged brain. However, the clinical application induced pluripotent stem cells are restricted due to the risk of tumor formation by residual undifferentiated upon transplantation. In this focused review, we briefly discussed different stem cells currently being studied for therapeutic development. Moreover, we present supporting evidence for the utilization of stem cell therapy for the treatment of neurodegenerative diseases. Also, we described the key issues that should be considered to transplantation of stem cells for different neurodegenerative diseases. In our conclusion, stem cell therapy probably would be the only treatment strategy that offers a cure for neurodegenerative disease. Although, further study is required to identify ideal stem cells candidate, dosing and the ideal method of cell transplantation. We suggest that all grafted cells would be transgenically armed with a molecular kill-switch that could be activated by the event of adverse side effects.}, }
@article {pmid32341983, year = {2019}, author = {Nguyen, KV}, title = {β-Amyloid precursor protein (APP) and the human diseases.}, journal = {AIMS neuroscience}, volume = {6}, number = {4}, pages = {273-281}, pmid = {32341983}, issn = {2373-7972}, abstract = {Several pathophysiological functions of the human β-amyloid precursor protein (APP) have been recently proposed in different human diseases such as neurodevelopmental and neurodegenerative disorders including rare diseases such as autism, fragile X syndrome, amyotrophic lateral sclerosis, multiple sclerosis, Lesch-Nyhan disease; common and complex disorders such as Alzheimer's disease; metabolic disorders such as diabetes; and also cancer. APP as well as all of its proteolytic fragments including the amyloid-β (Aβ) peptide, are part of normal physiology. The targeting of the components of APP proteolytic processing as a pharmacologic strategy will not be without consequences. Recent research results highlight the impact of alternative splicing (AS) process on human disease, and may provide new directions for the research on the impact of the human APP on human diseases. The identification of molecules capable of correcting and/or inhibiting pathological splicing events is therefore an important issue for future therapeutic approaches. To this end, the defective APP-mRNA isoform responsible for the disease in cells and tissues appears as an ideal target for epigenetic therapeutic intervention and antisense drugs are potential treatment.}, }
@article {pmid32338103, year = {2021}, author = {Tu, J and Lin, G and Gong, F}, title = {Additional luteal support might improve IVF outcomes in patients with low progesterone level in middle luteal phase following a GnRH agonist protocol.}, journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology}, volume = {37}, number = {2}, pages = {132-136}, doi = {10.1080/09513590.2020.1756252}, pmid = {32338103}, issn = {1473-0766}, mesh = {Dydrogesterone/*administration &amp; dosage ; Female ; Fertilization in Vitro ; Humans ; Luteal Phase/*blood ; Ovulation Induction/*methods ; Pregnancy ; Pregnancy Rate ; Progesterone/*blood ; Progestins/*administration &amp; dosage ; Retrospective Studies ; }, abstract = {AIM: The purpose of the study was to explore the efficacy of additional luteal support (ALS) for patients with low progesterone (P4) level in the middle luteal phase.<br><br>METHODS: A retrospective study of 1401 women who underwent their first in vitro fertilization (IVF) treatment with a GnRH agonist protocol was analyzed. Patients were divided into five groups according to P4 level in the middle luteal phase (group I>40ng/mL, group II 31-40&#x2009;ng/mL, group III 21-30&#x2009;ng/mL, group IV 11-20&#x2009;ng/mL and group V 0-10&#x2009;ng/mL. Besides routine luteal support, the group V was offered with additional oral dydrogesterone 10&#x2009;mg twice daily to HCG test (ALS group).<br><br>RESULTS: After a multiple regression analysis, a similar higher hCG positive rate, clinic pregnancy rate and lower early pregnancy loss rate were achieved in group I and group V. In contrast to group I, group IV demonstrated significant lower HCG positive rate (OR&#x2009;=&#x2009;0.65 [0.43; 0.99], p&#x2009;=&#x2009;.05), lower clinic pregnancy rate (OR&#x2009;=&#x2009;0.60 [0.41; 0.88], p&#x2009;<&#x2009;.01) and significant higher early pregnancy loss rate (OR&#x2009;=&#x2009;1.80 [1.08; 2.99], p&#x2009;=&#x2009;.02). The group III also resulted in significant lower clinic pregnancy rate (OR&#x2009;=&#x2009;0.56 [0.36; 0.87], p&#x2009;=&#x2009;.01). The live birth rate tended to be higher in group I and group V but without a significant difference.<br><br>CONCLUSION: Following agonist protocol, additional luteal support might improve IVF outcomes in patients with low serum P4 level in the middle luteal phase.}, }
@article {pmid32338076, year = {2020}, author = {Sokratous, M and Lucia, S and Bourinaris, T and Marogianni, C and Arnaoutoglou, M and Patrikiou, E and Ralli, S and Markou, A and Dardiotis, E and Houlden, H and Hadjigeorgiou, GM and Xiromerisiou, G}, title = {Prevalence of C9orf72 hexanucleotide repeat expansion in Greek patients with sporadic ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {5-6}, pages = {470-472}, doi = {10.1080/21678421.2020.1757115}, pmid = {32338076}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/genetics ; C9orf72 Protein/genetics ; Cohort Studies ; DNA Repeat Expansion/genetics ; Female ; Greece/epidemiology ; Humans ; Middle Aged ; Prevalence ; Proteins/genetics ; }, abstract = {A total of 178 consecutive patients with definite sALS without frontotemporal dementia (FTD) were enrolled in this study, after complete clinical evaluation. A Repeat-Primed Polymerase Chain Reaction (RP-PCR) protocol was applied to detect the G4C2 repeats expansions. In the studied sALS patients, 5.06% (n = 9) carried the C9orf72 mutation. Among carriers, 2/3 of them were females and spinal onset accounted for 78% and bulbar for 22%, while the mean age of onset was about 60 years. Our study showed that the prevalence of C9orf72 repeat expansion in Greek sALS patients is similar to the overall frequency of the mutation in European populations. The pathogenic mutation remains a promising biomarker for genetic testing and targeted treatment.}, }
@article {pmid32335272, year = {2020}, author = {Loffreda, A and Nizzardo, M and Arosio, A and Ruepp, MD and Calogero, RA and Volinia, S and Galasso, M and Bendotti, C and Ferrarese, C and Lunetta, C and Rizzuti, M and Ronchi, AE and Mühlemann, O and Tremolizzo, L and Corti, S and Barabino, SML}, title = {miR-129-5p: A key factor and therapeutic target in amyotrophic lateral sclerosis.}, journal = {Progress in neurobiology}, volume = {190}, number = {}, pages = {101803}, doi = {10.1016/j.pneurobio.2020.101803}, pmid = {32335272}, issn = {1873-5118}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*metabolism ; Animals ; Disease Models, Animal ; Down-Regulation ; ELAV-Like Protein 4 ; Humans ; Mice ; MicroRNAs/*antagonists &amp; inhibitors/genetics/*metabolism ; Oligonucleotides, Antisense/pharmacology ; Superoxide Dismutase-1 ; Up-Regulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentless and fatal neurological disease characterized by the selective degeneration of motor neurons. No effective therapy is available for this disease. Several lines of evidence indicate that alteration of RNA metabolism, including microRNA (miRNA) processing, is a relevant pathogenetic factor and a possible therapeutic target for ALS. Here, we showed that the abundance of components in the miRNA processing machinery is altered in a SOD1-linked cellular model, suggesting consequent dysregulation of miRNA biogenesis. Indeed, high-throughput sequencing of the small RNA fraction showed that among the altered miRNAs, miR-129-5p was increased in different models of SOD1-linked ALS and in peripheral blood cells of sporadic ALS patients. We demonstrated that miR-129-5p upregulation causes the downregulation of one of its targets: the RNA-binding protein ELAVL4/HuD. ELAVL4/HuD is predominantly expressed in neurons, where it controls several key neuronal mRNAs. Overexpression of pre-miR-129-1 inhibited neurite outgrowth and differentiation via HuD silencing in vitro, while its inhibition with an antagomir rescued the phenotype. Remarkably, we showed that administration of an antisense oligonucleotide (ASO) inhibitor of miR-129-5p to an ALS animal model, SOD1 (G93A) mice, result in a significant increase in survival and improved the neuromuscular phenotype in treated mice. These results identify miR-129-5p as a therapeutic target that is amenable to ASO modulation for the treatment of ALS patients.}, }
@article {pmid32331311, year = {2020}, author = {D'Amico, AG and Maugeri, G and Saccone, S and Federico, C and Cavallaro, S and Reglodi, D and D'Agata, V}, title = {PACAP Modulates the Autophagy Process in an In Vitro Model of Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {21}, number = {8}, pages = {}, pmid = {32331311}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*metabolism ; Animals ; *Autophagy/drug effects ; Cell Line ; Cell Survival/genetics ; Disease Models, Animal ; Disease Susceptibility ; Humans ; Hypoxia/genetics/metabolism ; MAP Kinase Signaling System/drug effects ; Mutation ; Pituitary Adenylate Cyclase-Activating Polypeptide/*metabolism/pharmacology ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of complex etiology leading to motor neuron degeneration. Many gene alterations cause this pathology, including mutation in Cu, Zn superoxide dismutase (SOD1), which leads to its gain of function. Mutant SOD1 proteins are prone to aberrant misfolding and create aggregates that impair autophagy. The hypoxic stress is strictly linked to the disease progression since it induces uncontrolled autophagy activation and the consequent high rates of cell death. Previously, we showed that pituitary adenylate cyclase-activating polypeptide (PACAP) exerts neurotrophic activity in cultured mSOD1 motor neurons exposed to serum deprivation. To date, no studies have examined whether the protective effect of PACAP on mSOD1 cells exposed to hypoxic insult is mediated through the regulation of the autophagy process. In the present study, we used the neuroblastoma-spinal cord-34 (NSC-34) cell line, stably expressing human wild type or mutant SOD1 G93A, to represent a well characterized in vitro model of a familial form of ALS. These cells were exposed to 100-µM desferrioxamine mesylate salt for 24h, to mimic the hypoxic stress affecting motor neurons during the disease progression. Our results showed that PACAP treatment significantly reduced cell death and hypoxia-induced mSOD1 accumulation by modulating the autophagy process in G93A motor neurons, as revealed by the decreased LC3II and the increased p62 levels, two autophagy indicators. These results were also confirmed by evaluating the vacuole formation detected through light chain 3 (LC3) immunofluorescence. Furthermore, the PACAP effects on autophagy seem to be mediated through the activation of the MAPK/ERK signaling pathway. Overall, our data demonstrated that PACAP exerts an ameliorative effect on the mSOD1 motor neuron viability by modulating a hypoxia-induced autophagy process through activation of MAPK/ERK signaling cascade.}, }
@article {pmid32328834, year = {2020}, author = {Zhang, H and Wang, T and Han, Z and Liu, G}, title = {Mendelian randomization study to evaluate the effects of interleukin-6 signaling on four neurodegenerative diseases.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {41}, number = {10}, pages = {2875-2882}, pmid = {32328834}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Interleukin-6/genetics ; Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics ; Signal Transduction ; }, abstract = {BACKGROUND: Multiple sclerosis (MS) is a complex neurological disease and chronic inflammatory disease. Until now, observational studies have reported positive association between serum interleukin-6 (IL-6) levels and MS risk. In order to develop effective therapies, we should establish the causal link between IL-6 signaling and MS. However, it is currently unknown whether IL-6 signaling is causally associated with the risk of MS.<br><br>METHODS: Here, we selected the increased soluble IL-6R (s-IL-6R) levels as the indirect markers for reduced IL-6 signaling, and performed a Mendelian randomization (MR) study using the rs2228145 variant as the instrumental variable to evaluate and quantify the effect of IL-6 signaling on the risk of MS. To be a comparison, we also evaluated the causal association of IL-6 signaling with the risk of other three neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).<br><br>RESULTS: We found that the increased s-IL-6R levels (per 1 standard deviation) were significantly associated with decreased MS risk (OR&#x2009;=&#x2009;0.96, 95% CI 0.94-0.98, P&#x2009;=&#x2009;1.69E-04), but not associated with the risk of AD (OR&#x2009;=&#x2009;1.01, 95% CI 0.92-1.11, P&#x2009;=&#x2009;0.835), PD (OR&#x2009;=&#x2009;0.94, 95% CI 0.84-1.05, P&#x2009;=&#x2009;0.261), or ALS (OR&#x2009;=&#x2009;1.00, 95% CI 0.92-1.10, P&#x2009;=&#x2009;0.9411).<br><br>CONCLUSION: Our findings have the similar directional effects to an existing humanized anti-IL-6R monoclonal antibody Tocilizumab which could bind to the IL-6 binding site of human IL-6R and competitively inhibit IL-6 signaling. Hence, we provided genetic evidence that inhibiting the IL-6 signaling such as tocilizumab treatment might represent a novel therapy for MS.}, }
@article {pmid32315694, year = {2020}, author = {Berhe, DF and Gebre, AK and Assefa, BT}, title = {Orexins role in neurodegenerative diseases: From pathogenesis to treatment.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {194}, number = {}, pages = {172929}, doi = {10.1016/j.pbb.2020.172929}, pmid = {32315694}, issn = {1873-5177}, mesh = {Alzheimer Disease/pathology/therapy ; Animals ; Epilepsy/pathology/therapy ; Humans ; Narcolepsy/pathology/therapy ; Neurodegenerative Diseases/metabolism/*pathology/*therapy ; Neurotransmitter Agents/metabolism ; Orexins/adverse effects/*metabolism ; Parkinson Disease/pathology/therapy ; Sleep ; Wakefulness ; }, abstract = {Orexin is a neurotransmitter that mainly regulates sleep/wake cycle. In addition to its sleep cycle regulatory role, it is involved in regulation of attention, energy homeostasis, neurogenesis and cognition. Several evidences has shown the involvement of orexin in narcolepsy, but there are also growing evidences that shows the disturbance in orexin system in neurodegenerative diseases including Alzheimer's, Parkinson's, Epilepsy, Huntington's diseases and Amyotrophic lateral sclerosis. Pathogenesis and clinical symptoms of these disorders can be partly attributed from orexin system imbalance. However, there are controversial reports on the exact relationship between orexin and these neurodegenerative diseases. Therefore, the aim of this review is to summarize the current evidences regarding the role of orexin in these neurodegenerative diseases.}, }
@article {pmid32311420, year = {2020}, author = {Rei, N and Rombo, DM and Ferreira, MF and Baqi, Y and Müller, CE and Ribeiro, JA and Sebastião, AM and Vaz, SH}, title = {Hippocampal synaptic dysfunction in the SOD1[G93A] mouse model of Amyotrophic Lateral Sclerosis: Reversal by adenosine A2AR blockade.}, journal = {Neuropharmacology}, volume = {171}, number = {}, pages = {108106}, doi = {10.1016/j.neuropharm.2020.108106}, pmid = {32311420}, issn = {1873-7064}, mesh = {Adenosine A2 Receptor Antagonists/*therapeutic use ; Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; Excitatory Postsynaptic Potentials/drug effects ; Hippocampus/*drug effects/*pathology ; Humans ; Long-Term Potentiation/drug effects ; Mice ; Mice, Transgenic ; Neuronal Plasticity/drug effects ; Purines/therapeutic use ; Receptor, Adenosine A2A/*drug effects ; Receptors, N-Methyl-D-Aspartate/drug effects ; Superoxide Dismutase-1/*genetics ; Synapses/*drug effects/*pathology ; Synaptic Transmission/drug effects ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) mostly affects motor neurons, but non-motor neural and cognitive alterations have been reported in ALS mouse models and patients. Here, we evaluated if time-dependent biphasic changes in synaptic transmission and plasticity occur in hippocampal synapses of ALS SOD1[G93A] mice. Recordings were performed in hippocampal slices of SOD1[G93A] and age-matched WT mice, in the pre-symptomatic and symptomatic stages. We found an enhancement of pre-synaptic function and increased adenosine A2A receptor levels in the hippocampus of pre-symptomatic mice. In contrast, in symptomatic mice, there was an impairment of long-term potentiation (LTP) and a decrease in NMDA receptor-mediated synaptic currents, with A2AR levels also being increased. Chronic treatment with the A2AR antagonist KW-6002, rescued LTP and A2AR values. Altogether, these findings suggest an increase in synaptic function during the pre-symptomatic stage, followed by a decrease in synaptic plasticity in the symptomatic stage, which involves over-activation of A2AR from early disease stages.}, }
@article {pmid32309896, year = {2020}, author = {Strom, SA and Hager, AG and Seiter, NJ and Davis, AS and Riechers, DE}, title = {Metabolic resistance to S-metolachlor in two waterhemp (Amaranthus tuberculatus) populations from Illinois, USA.}, journal = {Pest management science}, volume = {76}, number = {9}, pages = {3139-3148}, doi = {10.1002/ps.5868}, pmid = {32309896}, issn = {1526-4998}, support = {//Syngenta Ltd./ ; //University of Illinois/ ; }, mesh = {*4-Hydroxyphenylpyruvate Dioxygenase ; Acetamides ; *Amaranthus ; Herbicide Resistance ; *Herbicides/pharmacology ; Illinois ; }, abstract = {BACKGROUND: Two waterhemp (Amaranthus tuberculatus) populations from Illinois demonstrating multiple-resistance to acetolactate synthase (ALS)-, 4-hydroxyphenylpyruvate dioxygenase, and photosystem II (PSII)-inhibiting herbicides (designated CHR and SIR) also displayed reduced sensitivity to very-long-chain fatty acid-inhibiting herbicides, including S-metolachlor. We hypothesized that a physiological mechanism, such as enhanced metabolism, could be responsible for the reduced efficacy of S-metolachlor.<br><br>RESULTS: Metabolism experiments indicated that resistant populations degraded S-metolachlor more rapidly than sensitive populations and equally as rapidly as corn 2-24&#x2009;h after treatment (HAT). Resistant waterhemp and corn metabolized 90% (DT90) of absorbed S-metolachlor in less than 3.2 h whereas DT90 values for sensitive waterhemp exceeded 6 h. The glutathione S-transferase inhibitor 4-chloro-7-nitrobenzofurazon and cytochrome P450-inhibitor malathion decreased the amount of S-metolachlor metabolized in resistant waterhemp at 4 HAT but not in sensitive waterhemp or corn, and altered the abundance of certain metabolites in resistant waterhemp.<br><br>CONCLUSION: Results from this research demonstrate that resistance to S-metolachlor in these waterhemp populations is due to enhanced herbicide metabolism relative to sensitive populations. In addition, our results indicate that resistant waterhemp might utilize metabolic pathway(s) more intricate than either sensitive waterhemp or corn based on their metabolite profiles. &#xa9; 2020 Society of Chemical Industry.}, }
@article {pmid32309251, year = {2020}, author = {Martín, FJM and Fernández, MG and González, MC and Escudero, JCM}, title = {Urea Treatment of Syndrome of Inappropriate Antidiuretic Hormone Secretion Secondary to Amyotrophic Lateral Sclerosis.}, journal = {European journal of case reports in internal medicine}, volume = {7}, number = {4}, pages = {001444}, pmid = {32309251}, issn = {2284-2594}, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) rarely presents with hyponatraemia caused by syndrome of inappropriate antidiuretic hormone secretion (SIADH). We present a patient with hyponatraemia of multifactorial aetiology, in whom, after withdrawal of the drugs that contributed to this ionic alteration, SIADH secondary to ALS was confirmed. After initiating treatment with urea, sodium levels were normalized.<br><br>LEARNING POINTS: Amyotrophic lateral sclerosis (ALS) is rarely associated with syndrome of inappropriate antidiuretic hormone secretion (SIADH).In a patient with chronic hyponatraemia due to SIADH, administration of urea, as recommended by clinical practice guidelines, increases sodium levels.We present the case of a patient with SIADH due to ALS where hyponatraemia was resolved using urea.}, }
@article {pmid32307753, year = {2020}, author = {McDonald, TS and McCombe, PA and Woodruff, TM and Lee, JD}, title = {The potential interplay between energy metabolism and innate complement activation in amyotrophic lateral sclerosis.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {34}, number = {6}, pages = {7225-7233}, doi = {10.1096/fj.201901781}, pmid = {32307753}, issn = {1530-6860}, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Animals ; Complement Activation/*immunology ; Complement System Proteins/*immunology ; Disease Progression ; Energy Metabolism/*immunology ; Humans ; Immunity, Innate/*immunology ; Motor Neurons/immunology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. Although the precise mechanisms leading to ALS are yet to be determined, there is now increasing evidence implicating the defective energy metabolism and components of the innate immune complement system in the onset and progression of its motor phenotypes. This review will survey the mechanisms by which the energy metabolism and the complement system are altered during the disease progression of ALS and how it can contribute to disease. Furthermore, it will also examine how complement activation can modify the energy metabolism in metabolic disorders, in order to highlight how the complement system and energy metabolism may be linked in ALS.}, }
@article {pmid32307524, year = {2020}, author = {Scoles, DR and Dansithong, W and Pflieger, LT and Paul, S and Gandelman, M and Figueroa, KP and Rigo, F and Bennett, CF and Pulst, SM}, title = {ALS-associated genes in SCA2 mouse spinal cord transcriptomes.}, journal = {Human molecular genetics}, volume = {29}, number = {10}, pages = {1658-1672}, pmid = {32307524}, issn = {1460-2083}, support = {R37 NS033123/NS/NINDS NIH HHS/United States ; U01 NS103883/NS/NINDS NIH HHS/United States ; R21 NS081182/NS/NINDS NIH HHS/United States ; R56 NS033123/NS/NINDS NIH HHS/United States ; R01 NS097903/NS/NINDS NIH HHS/United States ; R21 NS103009/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Ataxin-2/antagonists &amp; inhibitors/*genetics ; Cerebellum/metabolism/pathology ; DNA-Binding Proteins/*genetics ; Disease Models, Animal ; Humans ; Mice ; Motor Neurons/pathology ; Oligonucleotides, Antisense/genetics/pharmacology ; Spinal Cord/metabolism/pathology ; Spinocerebellar Ataxias/*genetics/pathology ; Superoxide Dismutase-1/*genetics ; Transcriptome/genetics ; }, abstract = {The spinocerebellar ataxia type 2 (SCA2) gene ATXN2 has a prominent role in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS). In addition to cerebellar ataxia, motor neuron disease is often seen in SCA2, and ATXN2 CAG repeat expansions in the long normal range increase ALS risk. Also, lowering ATXN2 expression in TDP-43 ALS mice prolongs their survival. Here we investigated the ATXN2 relationship with motor neuron dysfunction in vivo by comparing spinal cord (SC) transcriptomes reported from TDP-43 and SOD1 ALS mice and ALS patients with those from SCA2 mice. SC transcriptomes were determined using an SCA2 bacterial artificial chromosome mouse model expressing polyglutamine expanded ATXN2. SCA2 cerebellar transcriptomes were also determined, and we also investigated the modification of gene expression following treatment of SCA2 mice with an antisense oligonucleotide (ASO) lowering ATXN2 expression. Differentially expressed genes (DEGs) defined three interconnected pathways (innate immunity, fatty acid biosynthesis and cholesterol biosynthesis) in separate modules identified by weighted gene co-expression network analysis. Other key pathways included the complement system and lysosome/phagosome pathways. Of all DEGs in SC, 12.6% were also dysregulated in the cerebellum. Treatment of mice with an ATXN2 ASO also modified innate immunity, the complement system and lysosome/phagosome pathways. This study provides new insights into the underlying molecular basis of SCA2 SC phenotypes and demonstrates annotated pathways shared with TDP-43 and SOD1 ALS mice and ALS patients. It also emphasizes the importance of ATXN2 in motor neuron degeneration and confirms ATXN2 as a therapeutic target.}, }
@article {pmid32306171, year = {2020}, author = {Falzone, YM and Domi, T and Agosta, F and Pozzi, L and Schito, P and Fazio, R and Del Carro, U and Barbieri, A and Comola, M and Leocani, L and Comi, G and Carrera, P and Filippi, M and Quattrini, A and Riva, N}, title = {Serum phosphorylated neurofilament heavy-chain levels reflect phenotypic heterogeneity and are an independent predictor of survival in motor neuron disease.}, journal = {Journal of neurology}, volume = {267}, number = {8}, pages = {2272-2280}, pmid = {32306171}, issn = {1432-1459}, support = {#RF-2011-02351193//Italian Ministry of Health/ ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Biomarkers ; Humans ; Intermediate Filaments ; *Motor Neuron Disease ; Neurofilament Proteins ; Phenotype ; }, abstract = {To investigate the prognostic role and the major determinants of serum phosphorylated neurofilament heavy -chain (pNfH) concentration across a large cohort of motor neuron disease (MND) phenotypes. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum pNfH concentration in 219 MND patients consecutively enrolled in our tertiary MND clinic. A multifactorial analysis was carried out to investigate the major clinical determinants of serum pNfH. Kaplan-Meier survival curves and Cox regression analysis were performed to explore the prognostic value of serum pNfH. Serum pNfH levels were not homogenous among MND phenotypes; higher concentrations in pyramidal, bulbar, and classic phenotypes were observed. C9orf72-MND exhibited higher pNfH concentrations compared to non-C9orf72 MND. Multiple linear regression analysis revealed mean MEP/cMAP and disease progression rate as the two major predictors of serum pNfH levels (R[2] = 0.188; p ≤ 0.001). Kaplan-Meier curves showed a significant difference of survival among MND subgroups when divided into quartiles based on pNfH concentrations, log-rank X[2] = 53.0, p ≤ 0.0001. Our study evidenced that higher serum pNfH concentration is a negative independent prognostic factor for survival. In Cox multivariate model, pNfH concentration showed the highest hazard ratio compared to the other factors influencing survival included in the analysis. pNfH differs among the MND phenotypes and is an independent prognostic factor for survival. This study provides supporting evidence of the role of pNfH as useful prognostic biomarker for MND patients. Neurofilament measurements should be considered in the future prognostic models and in clinical trials for biomarker-based stratification, and to evaluate treatment response.}, }
@article {pmid32305638, year = {2020}, author = {Zahiruddin, S and Basist, P and Parveen, A and Parveen, R and Khan, W and Gaurav,  and Ahmad, S}, title = {Ashwagandha in brain disorders: A review of recent developments.}, journal = {Journal of ethnopharmacology}, volume = {257}, number = {}, pages = {112876}, doi = {10.1016/j.jep.2020.112876}, pmid = {32305638}, issn = {1872-7573}, mesh = {Animals ; Brain/*drug effects/metabolism/pathology/physiopathology ; Brain Diseases/*drug therapy/metabolism/pathology/physiopathology ; Drug Development/legislation &amp; jurisprudence ; Drug Discovery/legislation &amp; jurisprudence ; Humans ; Neuroprotective Agents/adverse effects/isolation &amp; purification/*therapeutic use ; Patents as Topic ; *Phytotherapy ; Plant Extracts/adverse effects/chemistry/isolation &amp; purification/*therapeutic use ; Plant Roots ; Signal Transduction ; }, abstract = {Withania somnifera (Family: Solanaceae), commonly known as Ashwagandha or Indian ginseng is distributed widely in India, Nepal, China and Yemen. The roots of plant consist of active phytoconstituents mainly withanolides, alkaloids and sitoindosides and are conventionally used for the treatment of multiple brain disorders.<br><br>AIM OF THE REVIEW: This review aims to critically assess and summarize the current state and implication of Ashwagandha in brain disorders. We have mainly focussed on the reported neuroactive phytoconstituents, available marketed products, pharmacological studies, mechanism of action and recent patents published related to neuroprotective effects of Ashwagandha in brain disorders.<br><br>MATERIALS AND METHODS: All the information and data was collected on Ashwagandha using keywords "Ashwagandha" along with "Phytoconstituents", "Ayurvedic, Unani and Homeopathy marketed formulation", "Brain disorders", "Mechanism" and "Patents". Following sources were searched for data collection: electronic scientific databases such as Science Direct, Google Scholar, Elsevier, PubMed, Wiley On-line Library, Taylor and Francis, Springer; books such as AYUSH Pharmacopoeia; authentic textbooks and formularies.<br><br>RESULTS: Identified neuroprotective phytoconstituents of Ashwagandha are sitoindosides VII-X, withaferin A, withanosides IV, withanols, withanolide A, withanolide B, anaferine, beta-sitosterol, withanolide D with key pharmacological effects in brain disorders mainly anxiety, Alzheimer's, Parkinson's, Schizophrenia, Huntington's disease, dyslexia, depression, autism, addiction, amyotrophic lateral sclerosis, attention deficit hyperactivity disorder and bipolar disorders. The literature survey does not highlight any toxic effects of Ashwagandha. Further, multiple available marketed products and patents recognized its beneficial role in various brain disorders; however, very few data is available on mechanistic pathway and clinical studies of Ashwagandha for various brain disorders is scarce and not promising.<br><br>CONCLUSION: The review concludes the results of recent studies on Ashwagandha suggesting its extensive potential as neuroprotective in various brain disorders as supported by preclinical studies, clinical trials and published patents. However vague understanding of the mechanistic pathways involved in imparting the neuroprotective effect of Ashwagandha warrants further study to promote it as a promising drug candidate.}, }
@article {pmid32301341, year = {2020}, author = {Chami, AA and Beltran, S and Corcia, P and Andres, CR and Laumonnier, F and Blasco, H and Vourc'H, P}, title = {A novel mutation in the cleavage site N291 of TDP-43 protein in a familial case of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {5-6}, pages = {463-466}, doi = {10.1080/21678421.2020.1752243}, pmid = {32301341}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Brain/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Humans ; Motor Neurons/metabolism ; Mutation/genetics ; }, abstract = {Cytoplasmic aggregation of TAR-DNA binding protein (TDP-43) in Amyotrophic Lateral Sclerosis (ALS) and fronto-temporal lobar dementia (FTLD) is associated with post-translational modifications (PTM) and delocalization. Studies on postmortem brains of ALS and FTLD patients showed the existence of TDP-43 fragments that end at position N291. We report a new heterozygous mutation p.N291H in a familial case of ALS. Expression of the mutant protein in cell lines and primary motor neurons induces aggregate formation in the cytoplasm and reduces cell viability. The discovery of mutations at cleavage sites in TDP-43 in patients, which we reviewed here, is valuable for understanding the true role of the various TDP-43 fragments identified in patients and thus, for developing effective targeted therapies for ALS and FTLD treatment.}, }
@article {pmid32292776, year = {2020}, author = {Medina, DX and Chung, EP and Teague, CD and Bowser, R and Sirianni, RW}, title = {Intravenously Administered, Retinoid Activating Nanoparticles Increase Lifespan and Reduce Neurodegeneration in the SOD1[G93A] Mouse Model of ALS.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {8}, number = {}, pages = {224}, pmid = {32292776}, issn = {2296-4185}, abstract = {Dysregulation of the retinoic acid (RA) signaling pathway is observed in amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Here, we investigated the therapeutic potential of retinoid activation via the RA receptor β (RARβ) in the SOD1 [G93A] mouse model of ALS. Our approach utilized the RARβ agonist adapalene, which we previously found to be neuroprotective in vitro. Adapalene, like most retinoids, is poorly water soluble, which has thus far prevented effective drug delivery in vivo. To address this challenge, we encapsulated adapalene within nanoparticles (Adap-NPs) composed of poly(lactic acid)-poly(ethylene glycol) (PLA-PEG). Our data demonstrate that intravenous administration of Adap-NPs robustly activates retinoid signaling in the CNS. Chronic administration of Adap-NPs resulted in improved motor performance, prolonged lifespan, and neuroprotection in SOD1 [G93A] mice. This study highlights retinoid signaling as a valuable therapeutic approach and presents a novel nanoparticle platform for the treatment of ALS.}, }
@article {pmid32284138, year = {2020}, author = {Anthimidou, E and Ntoanidou, S and Madesis, P and Eleftherohorinos, I}, title = {Mechanisms of Lolium rigidum multiple resistance to ALS- and ACCase-inhibiting herbicides and their impact on plant fitness.}, journal = {Pesticide biochemistry and physiology}, volume = {164}, number = {}, pages = {65-72}, doi = {10.1016/j.pestbp.2019.12.010}, pmid = {32284138}, issn = {1095-9939}, mesh = {Acetyl-CoA Carboxylase/antagonists &amp; inhibitors ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Lolium/drug effects/genetics ; Mutation ; Acetolactate Synthase/antagonists &amp; inhibitors ; Plant Proteins/antagonists &amp; inhibitors/genetics ; }, abstract = {Three putative resistant (R1, R2, R3) and one susceptible (S) Lolium rigidum populations originating from Greece were studied for resistance to ALS and ACCase inhibiting herbicides, using whole plant, sequencing of als and accase gene, and in vitro ALS activity assays. The S and two R (R1, R2) populations were also evaluated for fitness in competition with wheat. The whole plant assay indicated unsatisfactory control of the R populations with mesosulfuron-methyl + iodosulfuron-methyl or pinoxaden application, whereas sequencing of the als gene revealed that all ALS-resistant individuals had a Pro-197 substitution by Leu, Glu, Ser, Ala, Thr, or Gln. In addition, the accase gene of all pinoxaden resistant individuals had an Ile-2041 substitution by Asn or Thr. Furthermore, sequencing of the individuals surviving mesosulfuron-methyl + iodosulfuron-methyl or pinoxaden treatment revealed co-existence of point mutations in the accase or als genes, respectively, demonstrating multiple resistance. The in vitro activity of the ALS enzyme confirmed that resistance to mesosulfuron-methyl + iodosulfuron-methyl was due altered target-site. The recorded higher vigor and greater competitive ability of S population against wheat as compared with that of the R populations suggests an associated fitness cost with multiple resistance.}, }
@article {pmid32278047, year = {2020}, author = {Paudel, YN and Angelopoulou, E and Piperi, C and Othman, I and Shaikh, MF}, title = {Implication of HMGB1 signaling pathways in Amyotrophic lateral sclerosis (ALS): From molecular mechanisms to pre-clinical results.}, journal = {Pharmacological research}, volume = {156}, number = {}, pages = {104792}, doi = {10.1016/j.phrs.2020.104792}, pmid = {32278047}, issn = {1096-1186}, mesh = {Amyotrophic Lateral Sclerosis/immunology/*metabolism/pathology ; Animals ; Brain/immunology/*metabolism/pathology ; HMGB1 Protein/*metabolism ; Humans ; Immunity, Innate ; Ligands ; Motor Neurons/immunology/*metabolism/pathology ; Receptor for Advanced Glycation End Products/*metabolism ; Signal Transduction ; Spinal Cord/immunology/*metabolism/pathology ; Toll-Like Receptor 4/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and rapidly progressing neurodegenerative disorder with no effective disease-modifying treatment up to date. The underlying molecular mechanisms of ALS are not yet completely understood. However, the critical role of the innate immune system and neuroinflammation in ALS pathogenesis has gained increased attention. High mobility group box 1 (HMGB1) is a typical damage-associated molecular pattern (DAMP) molecule, acting as a pro-inflammatory cytokine mainly through activation of its principal receptors, the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4) which are crucial components of the innate immune system. HMGB1 is an endogenous ligand for both RAGE and TLR4 that mediate its biological effects. Herein, on the ground of pre-clinical findings we unravel the underlying mechanisms behind the plausible contribution of HMGB1 and its receptors (RAGE and TLR4) in the ALS pathogenesis. Furthermore, we provide an account of the therapeutic outcomes associated with inhibition/blocking of HMGB1 receptor signalling in preventing motor neuron's death and delaying disease progression in ALS experimental models. There is strong evidence that HMGB1, RAGE and TLR4 signaling axes might present potential targets against ALS, opening a novel headway in ALS research that could plausibly bridge the current treatment gap.}, }
@article {pmid32277283, year = {2020}, author = {Bagal, B and Kumar, R and Gaur, T and Talreja, V and Bonda, A and Patkar, N and Shetty, D and Kowtal, P and Subramanian, PG and Gupta, S and Sarin, R and Hasan, SK}, title = {Characterization of therapy-related acute leukemia in hereditary breast-ovarian carcinoma patients: role of BRCA1 mutation and topoisomerase II-directed therapy.}, journal = {Medical oncology (Northwood, London, England)}, volume = {37}, number = {5}, pages = {48}, pmid = {32277283}, issn = {1559-131X}, mesh = {Adult ; Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use ; BRCA1 Protein/*genetics ; Carcinoma/*drug therapy/genetics/pathology ; Female ; Germ-Line Mutation ; Hereditary Breast and Ovarian Cancer Syndrome/*drug therapy/genetics/pathology ; Humans ; Leukemia, Myeloid, Acute/*chemically induced/drug therapy/genetics/pathology ; Middle Aged ; Oncogene Proteins, Fusion/genetics ; Topoisomerase II Inhibitors/*adverse effects/therapeutic use ; Translocation, Genetic ; Treatment Outcome ; }, abstract = {Therapy-related acute leukemias (t-ALs) represent approximately 10-20% of all acute leukemias, are frequently resistant to chemotherapy, and are associated with guarded outcomes. The national comprehensive cancer network data suggest that t-AL cases are diagnosed at increasing rates in breast cancer patients treated with chemotherapeutic agents targeting topoisomerase II. Two cases of BRCA1-mutated ovarian and breast carcinoma who developed therapy-related APL and ALL, respectively, following topoisomerase II-directed therapy were characterized. Genomic characterization of therapy-related acute promyelocytic leukemia (t-APL) revealed a unique RARA intron 2 breakpoint (Chr17: 40347487) at 3'-end of RARA corroborating breakpoint clustering in t-APL following topoisomerase II inhibition. Both cases of this series harbored germline BRCA1 mutations. The germline BRCA1 mutation in patient with t-APL was detected in exon 8 (HGVS nucleotide: c.512dupT). This mutation in t-APL is extremely rare. Interestingly, t-ALL patient in this series had a BRCA1 mutation (HGVS nucleotide: c.68_69delAG; BIC designation: 187delAG) identical to a previously reported case after the treatment of same primary disease. It is unlikely that two breast cancer patients with identical BRCA1 mutation receiving topoisomerase II-targeted agents for the primary disease developed t-AL by chance. This report highlights the development of t-AL in BRAC1-mutated hereditary breast and ovarian cancer patients and warrants further studies on functional consequences of topoisomerase inhibition in this setting.}, }
@article {pmid32271694, year = {2020}, author = {Chen, S and Liao, Q and Lu, K and Zhou, J and Huang, C and Bi, F}, title = {Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis.}, journal = {Current neurovascular research}, volume = {17}, number = {3}, pages = {275-285}, doi = {10.2174/1567202617666200409125227}, pmid = {32271694}, issn = {1875-5739}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/pathology ; Animals ; DNA-Binding Proteins/*genetics ; *Disease Models, Animal ; Humans ; Neuroprotective Agents/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Rats, Transgenic ; Riluzole/*therapeutic use ; Treatment Outcome ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurological disorder clinically characterized by motor system dysfunction, with intraneuronal accumulation of the TAR DNAbinding protein 43 (TDP-43) being a pathological hallmark. Riluzole is a primarily prescribed medicine for ALS patients, while its therapeutical efficacy appears limited. TDP-43 transgenic mice are existing animal models for mechanistic/translational research into ALS.<br><br>METHODS: We developed a transgenic rat model of ALS expressing a mutant human TDP-43 transgene (TDP-43M337V) and evaluated the therapeutic effect of Riluzole on this model. Relative to control, rats with TDP-43M337V expression promoted by the neurofilament heavy subunit (NEF) gene or specifically in motor neurons promoted by the choline acetyltransferase (ChAT) gene showed progressive worsening of mobility and grip strength, along with loss of motor neurons, microglial activation, and intraneuronal accumulation of TDP-43 and ubiquitin aggregations in the spinal cord.<br><br>RESULTS: Compared to vehicle control, intragastric administration of Riluzole (30 mg/kg/d) did not mitigate the behavioral deficits nor alter the neuropathologies in the transgenics.<br><br>CONCLUSION: These findings indicate that transgenic rats recapitulate the basic neurological and neuropathological characteristics of human ALS, while Riluzole treatment can not halt the development of the behavioral and histopathological phenotypes in this new transgenic rodent model of ALS.}, }
@article {pmid32266160, year = {2020}, author = {Vendrik, KEW and Ooijevaar, RE and de Jong, PRC and Laman, JD and van Oosten, BW and van Hilten, JJ and Ducarmon, QR and Keller, JJ and Kuijper, EJ and Contarino, MF}, title = {Fecal Microbiota Transplantation in Neurological Disorders.}, journal = {Frontiers in cellular and infection microbiology}, volume = {10}, number = {}, pages = {98}, pmid = {32266160}, issn = {2235-2988}, mesh = {Animals ; *Autism Spectrum Disorder ; *Clostridium Infections/therapy ; Fecal Microbiota Transplantation ; Feces ; *Gastrointestinal Microbiome ; Humans ; *Nervous System Diseases/therapy ; Treatment Outcome ; }, abstract = {Background: Several studies suggested an important role of the gut microbiota in the pathophysiology of neurological disorders, implying that alteration of the gut microbiota might serve as a treatment strategy. Fecal microbiota transplantation (FMT) is currently the most effective gut microbiota intervention and an accepted treatment for recurrent Clostridioides difficile infections. To evaluate indications of FMT for patients with neurological disorders, we summarized the available literature on FMT. In addition, we provide suggestions for future directions. Methods: In July 2019, five main databases were searched for studies and case descriptions on FMT in neurological disorders in humans or animal models. In addition, the ClinicalTrials.gov website was consulted for registered planned and ongoing trials. Results: Of 541 identified studies, 34 were included in the analysis. Clinical trials with FMT have been performed in patients with autism spectrum disorder and showed beneficial effects on neurological symptoms. For multiple sclerosis and Parkinson's disease, several animal studies suggested a positive effect of FMT, supported by some human case reports. For epilepsy, Tourette syndrome, and diabetic neuropathy some studies suggested a beneficial effect of FMT, but evidence was restricted to case reports and limited numbers of animal studies. For stroke, Alzheimer's disease and Guillain-Barré syndrome only studies with animal models were identified. These studies suggested a potential beneficial effect of healthy donor FMT. In contrast, one study with an animal model for stroke showed increased mortality after FMT. For Guillain-Barré only one study was identified. Whether positive findings from animal studies can be confirmed in the treatment of human diseases awaits to be seen. Several trials with FMT as treatment for the above mentioned neurological disorders are planned or ongoing, as well as for amyotrophic lateral sclerosis. Conclusions: Preliminary literature suggests that FMT may be a promising treatment option for several neurological disorders. However, available evidence is still scanty and some contrasting results were observed. A limited number of studies in humans have been performed or are ongoing, while for some disorders only animal experiments have been conducted. Large double-blinded randomized controlled trials are needed to further elucidate the effect of FMT in neurological disorders.}, }
@article {pmid32265627, year = {2020}, author = {Geijo-Barrientos, E and Pastore-Olmedo, C and De Mingo, P and Blanquer, M and Gómez Espuch, J and Iniesta, F and Iniesta, NG and García-Hernández, A and Martín-Estefanía, C and Barrios, L and Moraleda, JM and Martínez, S}, title = {Intramuscular Injection of Bone Marrow Stem Cells in Amyotrophic Lateral Sclerosis Patients: A Randomized Clinical Trial.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {195}, pmid = {32265627}, issn = {1662-4548}, abstract = {BACKGROUND: Preclinical studies suggest that stem cells may be a valuable therapeutic tool in amyotrophic lateral sclerosis (ALS). As it has been demonstrated that there are molecular changes at the end-plate during the early stages of motorneuron degeneration in animal models, we hypothesize that the local effect of this stem cell delivery method could slow the progressive loss of motor units (MUs) in ALS patients.<br><br>METHODS: We designed a Phase I/II clinical trial to study the safety of intramuscularly implanting autologous bone marrow mononuclear cells (BMMCs), including stem cells, in ALS patients and their possible effects on the MU of the tibialis anterior (TA) muscle. Twenty-two patients participated in a randomized, double-blind, placebo-controlled trial that consisted of a baseline visit followed by one intramuscular injection of BMNCs, follow-up visits at 30, 90, 180, and 360 days, and an additional year of clinical follow-up. In each patient, one TA muscle was injected with a single dose of BMMCs while the contralateral muscle was given a placebo; the sides were selected randomly. All visits included a complete EMG study of both TA muscles.<br><br>RESULTS: Our results show that (1) the intramuscular injection of BMMCs is a safe procedure; (2) ALS patients show heterogeneities in the degree of TA injury; (3) a comparison of placebo-injected muscles with BMMC-injected muscles showed significant differences in only one parameter, the D50 index used to quantify the Compound Muscle Action Potential (CMAP) scan curve. This parameter was higher in the BMMC-injected TA muscle at both 90 days (placebo side: 29.55 &#xb1; 2.89, n = 20; experimental side: 39.25 &#xb1; 3.21, n = 20; p < 0.01) and 180 days (placebo side: 29.35 &#xb1; 3.29, n = 17; experimental side: 41.24 &#xb1; 3.34, n = 17; p < 0.01).<br><br>CONCLUSION: This procedure had no effect on the TA muscle MU properties, with the exception of the D50 index. Finding differences in just this index supports the fact that it may be much more sensitive than other electrophysiological parameters when studying treatment effects. Given the low number of patients and their heterogeneity, these results justify exploring the efficacy of this procedure in further patients and other muscles, through Phase II trials.<br><br>CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov (identifier NCT02286011); EudraCT number 2011-004801-25.}, }
@article {pmid32258847, year = {2020}, author = {Ligresti, D and Amata, M and Messina, M and Traina, M and Tarantino, I}, title = {Single-step EUS-guided jejunojejunostomy with a lumen-apposing metal stent as treatment for malignant afferent limb syndrome.}, journal = {VideoGIE : an official video journal of the American Society for Gastrointestinal Endoscopy}, volume = {5}, number = {4}, pages = {154-156}, pmid = {32258847}, issn = {2468-4481}, }
@article {pmid32257625, year = {2020}, author = {Moos, WH and Faller, DV and Glavas, IP and Harpp, DN and Kanara, I and Mavrakis, AN and Pernokas, J and Pernokas, M and Pinkert, CA and Powers, WR and Sampani, K and Steliou, K and Vavvas, DG and Zamboni, RJ and Kodukula, K and Chen, X}, title = {Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs.}, journal = {BioResearch open access}, volume = {9}, number = {1}, pages = {94-105}, pmid = {32257625}, issn = {2164-7844}, support = {R01 EY025362/EY/NEI NIH HHS/United States ; R13 EY027184/EY/NEI NIH HHS/United States ; R13 EY029551/EY/NEI NIH HHS/United States ; }, abstract = {In this review we outline a rationale for identifying neuroprotectants aimed at inducing endogenous Klotho activity and expression, which is epigenetic action, by definition. Such an approach should promote remyelination and/or stimulate myelin repair by acting on mitochondrial function, thereby heralding a life-saving path forward for patients suffering from neuroinflammatory diseases. Disorders of myelin in the nervous system damage the transmission of signals, resulting in loss of vision, motion, sensation, and other functions depending on the affected nerves, currently with no effective treatment. Klotho genes and their single-pass transmembrane Klotho proteins are powerful governors of the threads of life and death, true to the origin of their name, Fates, in Greek mythology. Among its many important functions, Klotho is an obligatory co-receptor that binds, activates, and/or potentiates critical fibroblast growth factor activity. Since the discovery of Klotho a little over two decades ago, it has become ever more apparent that when Klotho pathways go awry, oxidative stress and mitochondrial dysfunction take over, and age-related chronic disorders are likely to follow. The physiological consequences can be wide ranging, potentially wreaking havoc on the brain, eye, kidney, muscle, and more. Central nervous system disorders, neurodegenerative in nature, and especially those affecting the myelin sheath, represent worthy targets for advancing therapies that act upon Klotho pathways. Current drugs for these diseases, even therapeutics that are disease modifying rather than treating only the symptoms, leave much room for improvement. It is thus no wonder that this topic has caught the attention of biomedical researchers around the world.}, }
@article {pmid32257544, year = {2020}, author = {Zhang, F and Niu, L and Liu, X and Liu, Y and Li, S and Yu, H and Le, W}, title = {Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Diseases: An Update.}, journal = {Aging and disease}, volume = {11}, number = {2}, pages = {315-326}, pmid = {32257544}, issn = {2152-5250}, abstract = {Rapid eye movement sleep behavior disorder (RBD) is a sleep behavior disorder characterized by abnormal behaviors and loss of muscle atonia during rapid eye movement (REM) sleep. RBD is generally considered to be associated with synucleinopathies, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), and usually precedes years before the first symptom of these diseases. It is believed that RBD predicts the neurodegeneration in synucleinopathy. However, increasing evidences have shown that RBD is also found in non-synucleinopathy neurodegenerative diseases, including Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), etc. Sleep disturbance such as RBD may be an early sign of neurodegeneration in these diseases, and also serve as an assessment of cognitive impairments. In this review, we updated the clinical characteristics, diagnosis, and possible mechanisms of RBD in neurogenerative diseases. A better understanding of RBD in these neurogenerative diseases will provide biomarkers and novel therapeutics for the early diagnosis and treatment of the diseases.}, }
@article {pmid32244957, year = {2020}, author = {De Nicola, AF and Meyer, M and Guennoun, R and Schumacher, M and Hunt, H and Belanoff, J and de Kloet, ER and Gonzalez Deniselle, MC}, title = {Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {21}, number = {6}, pages = {}, pmid = {32244957}, issn = {1422-0067}, support = {Salaries for argentine researchers//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; Ubacyt # 20020170100224BA//Universidad de Buenos Aires/ ; purchase of reagents//Corcept Therapeutics, California, USA/ ; }, mesh = {Animals ; Corticosterone/blood/chemistry ; Disease Models, Animal ; Humans ; Inflammation/blood/complications ; Models, Biological ; Neurodegenerative Diseases/blood/*drug therapy ; Receptors, Glucocorticoid/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Glucocorticoids are crucial for stress-coping, resilience, and adaptation. However, if the stress hormones become dysregulated, the vulnerability to stress-related diseases is enhanced. In this brief review, we discuss the role of glucocorticoids in the pathogenesis of neurodegenerative disorders in both human and animal models, and focus in particular on amyotrophic lateral sclerosis (ALS). For this purpose, we used the Wobbler animal model, which mimics much of the pathology of ALS including a dysfunctional hypothalamic-pituitary-adrenal axis. We discuss recent studies that demonstrated that the pathological cascade characteristic for motoneuron degeneration of ALS is mimicked in the genetically selected Wobbler mouse and can be attenuated by treatment with the selective glucocorticoid receptor antagonist (GRA) CORT113176. In long-term treatment (3 weeks) GRA attenuated progression of the behavioral, inflammatory, excitatory, and cell-death-signaling pathways while increasing the survival signal of serine-threonine kinase (pAkt). The action mechanism of the GRA may be either by interfering with GR deactivation or by restoring the balance between pro- and anti-inflammatory signaling pathways driven by the complementary mineralocorticoid receptor (MR)- and GR-mediated actions of corticosterone. Accordingly, GR antagonism may have clinical relevance for the treatment of neurodegenerative diseases.}, }
@article {pmid32244295, year = {2020}, author = {Bonfanti, E and Bonifacino, T and Raffaele, S and Milanese, M and Morgante, E and Bonanno, G and Abbracchio, MP and Fumagalli, M}, title = {Abnormal Upregulation of GPR17 Receptor Contributes to Oligodendrocyte Dysfunction in SOD1 G93A Mice.}, journal = {International journal of molecular sciences}, volume = {21}, number = {7}, pages = {}, pmid = {32244295}, issn = {1422-0067}, support = {GPR17ALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; PSR2017//Universit&#xe0; degli Studi di Milano/ ; Department of Excellence 2018-2022//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Cell Differentiation ; Cell Proliferation ; Disease Models, Animal ; Female ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism ; Myelin Sheath/metabolism ; Nerve Tissue Proteins/*metabolism ; Neurodegenerative Diseases/metabolism ; Oligodendrocyte Precursor Cells/metabolism ; Oligodendroglia/*metabolism ; Receptors, G-Protein-Coupled/*metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase/*metabolism ; Superoxide Dismutase-1/*metabolism ; Up-Regulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons (MN). Importantly, MN degeneration is intimately linked to oligodendrocyte dysfunction and impaired capacity of oligodendrocyte precursor cells (OPCs) to regenerate the myelin sheath enwrapping and protecting neuronal axons. Thus, improving OPC reparative abilities represents an innovative approach to counteract MN loss. A pivotal regulator of OPC maturation is the P2Y-like G protein-coupled receptor 17 (GPR17), whose role in ALS has never been investigated. In other models of neurodegeneration, an abnormal increase of GPR17 has been invariably associated to myelin defects and its pharmacological manipulation succeeded in restoring endogenous remyelination. Here, we analyzed GPR17 alterations in the SOD1[G93A] ALS mouse model and assessed in vitro whether this receptor could be targeted to correct oligodendrocyte alterations. Western-blot and immunohistochemical analyses showed that GPR17 protein levels are significantly increased in spinal cord of ALS mice at pre-symptomatic stage; this alteration is exacerbated at late symptomatic phases. Concomitantly, mature oligodendrocytes degenerate and are not successfully replaced. Moreover, OPCs isolated from spinal cord of SOD1[G93A] mice display defective differentiation compared to control cells, which is rescued by treatment with the GPR17 antagonist montelukast. These data open novel therapeutic perspectives for ALS management.}, }
@article {pmid32243913, year = {2020}, author = {Memon, AA and Coleman, JJ and Amara, AW}, title = {Effects of exercise on sleep in neurodegenerative disease.}, journal = {Neurobiology of disease}, volume = {140}, number = {}, pages = {104859}, pmid = {32243913}, issn = {1095-953X}, support = {R25 NS079188/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Disease Progression ; *Exercise Therapy ; Humans ; Huntington Disease/therapy ; Neurodegenerative Diseases/*therapy ; Parkinson Disease/therapy ; Quality of Life ; Sleep/*physiology ; Sleep Wake Disorders/*therapy ; }, abstract = {As the population ages, the incidence and prevalence of neurodegenerative disorders will continue to increase. Persons with neurodegenerative disease frequently experience sleep disorders, which not only affect quality of life, but potentially accelerate progression of the disease. Unfortunately, pharmacological interventions are often futile or have adverse effects. Therefore, investigation of non-pharmacological interventions has the potential to expand the treatment landscape for these disorders. The last decade has observed increasing recognition of the beneficial role of exercise in brain diseases, and neurodegenerative disorders in particular. In this review, we will focus on the therapeutic role of exercise for sleep dysfunction in four neurodegenerative diseases, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Available data suggest that exercise may have the potential to improve sleep disorders and attenuate neurodegeneration, particularly in Alzheimer's disease and Parkinson's disease. However, additional research is required in order to understand the most effective exercise therapy for these indications; the best way to monitor the response to interventions; the influence of exercise on sleep dysfunction in Huntington's disease and amyotrophic lateral sclerosis; and the mechanisms underlying exercise-induced sleep modifications.}, }
@article {pmid32242755, year = {2020}, author = {Hergesheimer, R and Lanznaster, D and Vourc'h, P and Andres, C and Bakkouche, S and Beltran, S and Blasco, H and Corcia, P and Couratier, P}, title = {Advances in disease-modifying pharmacotherapies for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert opinion on pharmacotherapy}, volume = {21}, number = {9}, pages = {1103-1110}, doi = {10.1080/14656566.2020.1746270}, pmid = {32242755}, issn = {1744-7666}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {INTRODUCTION: To date, riluzole and edaravone are the only two drugs that have successfully passed clinical trials for the treatment of Amyotrophic Lateral Sclerosis (ALS). Unfortunately, both drugs exhibit very modest effects. Most other drugs have failed at phase III to show significant effects in phase III when tested in larger cohorts. This pattern necessitates improvements in the approach to ALS pharmacotherapy.<br><br>AREAS COVERED: The authors discuss the two approved drugs, as well as several examples of drug candidates whose clinical trials did not demonstrate efficacy in phase III. Post-hoc analyses reveal that future clinical trials should include disease-staging procedures, longer-term trials to correctly assess survival, genetic studies of participants to aid in stratification, and more similarity between the protocols on preclinical models and clinical trials. Finally, they discuss the trials in process that demonstrate some of these suggestions and improvements.<br><br>EXPERT OPINION: The approval of riluzole and edaravone was essentially a desperate attempt to provide urgent pharmacotherapy to the ALS community. To evolve toward more efficient therapies, we must conduct clinical trials with optimal stratification based on rapid/slow progressors and cognitive decline. Pharmaco-metabolomics should allow for the identification of biomarkers that are adapted for a given drug.}, }
@article {pmid32242285, year = {2021}, author = {Dunlop, RA and Carney, JM}, title = {Mechanisms of L-Serine-Mediated Neuroprotection Include Selective Activation of Lysosomal Cathepsins B and L.}, journal = {Neurotoxicity research}, volume = {39}, number = {1}, pages = {17-26}, pmid = {32242285}, issn = {1476-3524}, mesh = {Cathepsin B/*metabolism ; Cathepsin L/*metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Humans ; Lysosomes/drug effects/*metabolism ; Neuroprotective Agents/*administration &amp; dosage/metabolism ; Serine/administration &amp; dosage/*metabolism ; }, abstract = {L-serine is a naturally occurring dietary amino acid that has recently received renewed attention as a potential therapy for the treatment of amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), hereditary sensory autonomic neuropathy type I (HSAN1), and sleep induction and maintenance. We have previously reported L-serine functions as a competitive inhibitor of L-BMAA toxicity in cell cultures and have since progressed to examine the neuroprotective effects of L-serine independent of L-BMAA-induced neurotoxicity. For example, in a Phase I, FDA-approved human clinical trial of 20 ALS patients, our lab reported 30 g L-serine/day was safe, well-tolerated, and slowed the progression of the disease in a group of 5 patients. Despite increasing evidence for L-serine being useful in the clinic, little is known about the mechanism of action of the observed neuroprotection. We have previously reported, in SH-SY5Y cell cultures, that L-serine alone can dysregulate the unfolded protein response (UPR) and increase the translation of the chaperone protein disulfide isomerase (PDI), and these mechanisms may contribute to the clearance of mis- or unfolded proteins. Here, we further explore the pathways involved in protein clearance when L-serine is present in low and high concentrations in cell culture. We incubated SH-SY5Y cells in the presence and absence of L-serine and measured changes in the activity of proteolytic enzymes from the autophagic-lysosomal system, cathepsin B, cathepsin L, and arylsulfatase and specific activities of the proteasome, peptidylglutamyl-peptide hydrolyzing (PGPH) (also called caspase-like), chymotrypsin, and trypsin-like. Under our conditions, we report that L-serine selectively induced the activity of autophagic-lysosomal enzymes, cathepsins B and L, but not any of the proteasome-hydrolyzing activities. To enable comparison with previous work, we also incubated cells with L-BMAA and report no effect on the activity of the autophagic lysosomes or the proteasomes. We also developed an open-source script for the automation of linear regression calculations of kinetic data. Autophagy impairment or failure is characteristic of many neurodegenerative disease; thus, activation of autophagic-lysosomal proteolysis may contribute to the neuroprotective effect of L-serine, which has been reported in cell culture and human clinical trials.}, }
@article {pmid32241621, year = {2020}, author = {Bailly, C and Hecquet, PE and Kouach, M and Thuru, X and Goossens, JF}, title = {Chemical reactivity and uses of 1-phenyl-3-methyl-5-pyrazolone (PMP), also known as edaravone.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {28}, number = {10}, pages = {115463}, doi = {10.1016/j.bmc.2020.115463}, pmid = {32241621}, issn = {1464-3391}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Edaravone/chemical synthesis/chemistry/*therapeutic use ; Humans ; Molecular Structure ; Neuroprotective Agents/chemical synthesis/chemistry/*therapeutic use ; Stroke/*drug therapy ; }, abstract = {1-Phenyl-3-methyl-5-pyrazolone is a reagent, known as PMP, used to derivatize monosaccharides for the study of polysaccharides composition and structure, and for the dosage of carbohydrates in complex media. The same molecule is also known as edaravone, a drug approved for the treatment of stroke and amyotrophic lateral sclerosis. It is also a reactive molecule susceptible to form stable adducts with aromatic aldehydes, such as formylpterin and vanillin. In addition, the molecule serves as a scaffold to design of edaravone analogs and drug conjugates, with various pharmacological properties (antioxidant, anticancer, antiviral). We have analyzed the multiple usages of PMP/edaravone to highlight the reactivity of the molecule and its wide range of applications. This phenyl-pyrazolone compound, considered by many as a biochemical reagent and by other as a clinically useful drug, has not yet revealed the full extent of its capacities and benefits.}, }
@article {pmid32231713, year = {2020}, author = {Sun, L and Wu, C and Ming, J and Nie, X and Guo, E and Zhang, W and Hu, G}, title = {Riluzole Enhances the Response of Human Nasopharyngeal Carcinoma Cells to Ionizing Radiation via ATM/P53 Signalling Pathway.}, journal = {Journal of Cancer}, volume = {11}, number = {11}, pages = {3089-3098}, pmid = {32231713}, issn = {1837-9664}, abstract = {Riluzole is approved by the FDA as an amyotrophic lateral sclerosis (ALS) drug. Previous studies showed that treatment with riluzole suppressed the proliferation of many cancer cells. However, little is known about its effects on nasopharyngeal carcinoma (NPC) and its molecular mode of action. In this study, we determined the effect of riluzole on apoptosis, cell cycle, migration, and invasion in NPC cell lines and investigated its mechanism at the molecular level. By using the human NPC cell lines CNE1, CNE2, and HNE1, we revealed that riluzole effectively inhibited viability of the NPC cell lines in dose- and time-dependent manners. Furthermore, riluzole dose-dependently induced apoptosis and G2/M cell cycle arrest in the NPC cell lines. After combination with radiotherapy (RT), greater cytotoxicity was achieved than with riluzole or RT alone in vitro and vivo. This was associated with the activation of ataxia telangiectasia mutated (ATM) and phosphoinositide p53 pathways. P53 silencing reduced cell reactiveness to riluzole therapy. These observations demonstrate that the riluzole-activated ATM/P53 pathway is directly involved in radiation-induced apoptosis of NPC cells. Given the acceptable side effect, combining of riluzole and radiotherapy is promising in NPC treatment.}, }
@article {pmid32231638, year = {2020}, author = {Koch, JC and Kuttler, J and Maass, F and Lengenfeld, T and Zielke, E and Bähr, M and Lingor, P}, title = {Compassionate Use of the ROCK Inhibitor Fasudil in Three Patients With Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {173}, pmid = {32231638}, issn = {1664-2295}, abstract = {The Rho kinase (ROCK) inhibitor Fasudil is a promising drug for a disease-modifying therapy of amyotrophic lateral sclerosis (ALS). In preclinical models, Fasudil was shown to increase motor neuron survival, inhibit axonal degeneration, enhance axonal regeneration and modulate microglial function in vitro and in vivo. It prolonged survival and improved motor function of SOD1-G93A-mice. Recently, a phase IIa clinical trial has been commenced to investigate the safety, tolerability, and efficacy of Fasudil in ALS patients at an early stage of disease (ROCK-ALS trial, NCT03792490, Eudra-CT-Nr.: 2017-003676-31). Although Fasudil has been approved in Japan for many years for the treatment of vasospasms following subarachnoid hemorrhage and is known to have a favorable side effect profile in these patients, there is no data on its use in human patients with ALS or any other neurodegenerative conditions. Here, we report the first three cases of compassionate use of Fasudil in patients with ALS. Between May 2017 and February 2019, one male (66 years old) and two female (62 and 68 years old) subjects with probable or definite ALS according to the El Escorial criteria (one of the females having a pathogenic SOD1 mutation) were administered Fasudil 30 mg intravenously twice daily over 45 min on 20 consecutive working days. Blood pressure, heart rate and routine laboratory tests were constantly controlled. All three subjects tolerated the Fasudil infusions well without any obvious side effects. Interestingly, the slow vital capacity showed a significant increase in one of the patients. Taken together, we report here the first compassionate use of the ROCK inhibitor Fasudil in three ALS patients, which was well-tolerated.}, }
@article {pmid32227134, year = {2020}, author = {Vijayaraghavan, M}, title = {Improving Access to Clinical Trials for Amyotrophic Lateral Sclerosis Treatment.}, journal = {JAMA neurology}, volume = {77}, number = {6}, pages = {671-672}, doi = {10.1001/jamaneurol.2020.0421}, pmid = {32227134}, issn = {2168-6157}, mesh = {*Amyotrophic Lateral Sclerosis ; Clinical Trials as Topic/*standards ; Humans ; }, }
@article {pmid32217641, year = {2020}, author = {Masaki, K and Sonobe, Y and Ghadge, G and Pytel, P and Lépine, P and Pernin, F and Cui, QL and Antel, JP and Zandee, S and Prat, A and Roos, RP}, title = {RNA-binding protein altered expression and mislocalization in MS.}, journal = {Neurology(R) neuroimmunology &amp; neuroinflammation}, volume = {7}, number = {3}, pages = {}, pmid = {32217641}, issn = {2332-7812}, support = {R21 NS096569/NS/NINDS NIH HHS/United States ; }, mesh = {*Active Transport, Cell Nucleus ; Adult ; Cells, Cultured ; Child ; DNA-Binding Proteins/*metabolism ; Female ; Humans ; Male ; Middle Aged ; Multiple Sclerosis/*metabolism/*pathology ; Oligodendroglia/*metabolism ; Polypyrimidine Tract-Binding Protein/*metabolism ; RNA-Binding Protein FUS/*metabolism ; *Stress, Physiological ; }, abstract = {OBJECTIVE: To determine whether there are nuclear depletion and cellular mislocalization of RNA-binding proteins (RBPs) transactivation response DNA-binding protein of 43 kDa (TDP-43), fused in sarcoma (FUS), and polypyrimidine tract-binding protein (PTB) in MS, as is the case in amyotrophic lateral sclerosis (ALS) and oligodendrocytes infected with Theiler murine encephalomyelitis virus (TMEV), we examined MS lesions and in vitro cultured primary human brain-derived oligodendrocytes.<br><br>METHODS: Nuclear depletion and mislocalization of TDP-43, FUS, and PTB are thought to contribute to the pathogenesis of ALS and TMEV demyelination. The latter findings prompted us to investigate these RBPs in the demyelinated lesions of MS and in in vitro cultured human brain-derived oligodendrocytes under metabolic stress conditions.<br><br>RESULTS: We found (1) mislocalized TDP-43 in oligodendrocytes in active lesions in some patients with MS; (2) decreased PTB1 expression in oligodendrocytes in mixed active/inactive demyelinating lesions; (3) decreased nuclear expression of PTB2 in neurons in cortical demyelinating lesions; and (4) nuclear depletion of TDP-43 in oligodendrocytes under metabolic stress induced by low glucose/low nutrient conditions compared with optimal culture conditions.<br><br>CONCLUSION: TDP-43 has been found to have a key role in oligodendrocyte function and viability, whereas PTB is important in neuronal differentiation, suggesting that altered expression and mislocalization of these RBPs in MS lesions may contribute to the pathogenesis of demyelination and neurodegeneration. Our findings also identify nucleocytoplasmic transport as a target for treatment.}, }
@article {pmid32215816, year = {2020}, author = {Smith, DL and Pavela, G}, title = {Energy Balance as a Moderator of Neurologic Disease Risk and Progression.}, journal = {Neurotoxicity research}, volume = {38}, number = {1}, pages = {242-248}, pmid = {32215816}, issn = {1476-3524}, support = {P30 AG050886/AG/NIA NIH HHS/United States ; P30 DK056336/DK/NIDDK NIH HHS/United States ; P30AG050886/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*etiology/*metabolism ; Animals ; *Disease Progression ; *Energy Metabolism ; *Environmental Exposure ; Humans ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating disease that like multiple other neurologic diseases has no curative treatment currently available. Environmental exposures to known neurotoxic compounds (e.g., pesticides, heavy metals, cyanobacterial toxins, etc.) are identified as risk factors associated with ALS. Assuming these environmental factors have causative roles in disease risk and given the ubiquity of these types of exposures for the modern human, why are not more people afflicted with ALS? Herein is proposed an energy balance moderation framework (EBMF)-a framework that postulates energy balance as a key moderator of neurologic disease risk. The EBMF proposes that the ability of the body to handle toxic compound exposures through excretion, metabolism, and/or storage impacts the acute and chronic tissue-specific toxicity which is moderated by energy balance. In this model, positive energy balance (weight gain or excess body weight/mass) would be protective against acute neurotoxic exposure permitting the assimilation and sequestration of toxic compounds within body stores separate from the nervous system. However, this protective buffering could be lost during sustained negative energy balance (weight loss) with the release of sequestered compounds redistributing to the nervous system. The EBMF may have relevance beyond ALS for other neurologic diseases with demonstrated environmental risks (such as Alzheimer's and Parkinson's disease) and offers new insights into potential strategies to reduce disease risk and develop novel treatments.}, }
@article {pmid32210783, year = {2020}, author = {Zhao, Y and Long, Z and Ding, Y and Jiang, T and Liu, J and Li, Y and Liu, Y and Peng, X and Wang, K and Feng, M and He, G}, title = {Dihydroartemisinin Ameliorates Learning and Memory in Alzheimer's Disease Through Promoting Autophagosome-Lysosome Fusion and Autolysosomal Degradation for Aβ Clearance.}, journal = {Frontiers in aging neuroscience}, volume = {12}, number = {}, pages = {47}, pmid = {32210783}, issn = {1663-4365}, abstract = {Dihydroartemisinin (DHA) is an active metabolite of sesquiterpene trioxane lactone extracted from Artemisia annua, which is used to treat malaria worldwide. DHA can activate autophagy, which is the main mechanism to remove the damaged cell components and recover the harmful or useless substances from eukaryotic cells and maintain cell viability through the autophagy lysosomal degradation system. Autophagy activation and autophagy flux correction are playing an important neuroprotective role in the central nervous system, as they accelerate the removal of toxic protein aggregates intracellularly and extracellularly to prevent neurodegenerative processes, such as Alzheimer's disease (AD). In this study, we explored whether this mechanism can mediate the neuroprotective effect of DHA on the AD model in vitro and in vivo. Three months of DHA treatment improved the memory and cognitive impairment, reduced the deposition of amyloid β plaque, reduced the levels of Aβ40 and Aβ42, and ameliorated excessive neuron apoptosis in APP/PS1 mice brain. In addition, DHA treatment increased the level of LC3 II/I and decreased the expression of p62. After Bafilomycin A1 and Chloroquine (CQ) blocked the fusion of autophagy and lysosome, as well as the degradation of autolysosomes (ALs), DHA treatment increased the level of LC3 II/I and decreased the expression of p62. These results suggest that DHA treatment can correct autophagic flux, improve autophagy dysfunction, inhibit abnormal death of neurons, promote the clearance of amyloid-β peptide (Aβ) fibrils, and have a multi-target effect on the neuropathological process, memory and cognitive deficits of AD.}, }
@article {pmid32209625, year = {2020}, author = {Salamone, P and Fuda, G and Casale, F and Marrali, G and Lunetta, C and Caponnetto, C and Mazzini, L and La Bella, V and Mandrioli, J and Simone, IL and Moglia, C and Calvo, A and Tarella, C and Chio, A and , }, title = {G-CSF (filgrastim) treatment for amyotrophic lateral sclerosis: protocol for a phase II randomised, double-blind, placebo-controlled, parallel group, multicentre clinical study (STEMALS-II trial).}, journal = {BMJ open}, volume = {10}, number = {3}, pages = {e034049}, pmid = {32209625}, issn = {2044-6055}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Clinical Trials, Phase II as Topic ; Double-Blind Method ; Filgrastim/*therapeutic use ; Humans ; Italy ; Multicenter Studies as Topic ; Quality of Life ; Randomized Controlled Trials as Topic ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurological disorder characterised by a selective degeneration of motor neurons (MNs). Stem cell transplantation is considered as a promising strategy in neurological disorders therapy and the possibility of inducing bone marrow cells (BMCs) to circulate in the peripheral blood is suggested to investigate stem cells migration in degenerated ALS nerve tissues where potentially repair MN damage. Granulocyte-colony stimulating factor (G-CSF) is a growth factor which stimulates haematopoietic progenitor cells, mobilises BMCs into injured brain and it is itself a neurotrophic factor for MN. G-CSF safety in humans has been demonstrated and many observations suggest that it may affect neural cells. Therefore, we decided to use G-CSF to mobilise BMCs into the peripheral circulation in patients with ALS, planning a clinical trial to evaluate the effect of G-CSF administration in ALS patients compared with placebo.<br><br>METHODS AND ANALYSIS: STEMALS-II is a phase II multicentre, randomised double-blind, placebo-controlled, parallel group clinical trial on G-CSF (filgrastim) and mannitol in ALS patients. Specifically, we investigate safety, tolerability and efficacy of four repeated courses of intravenous G-CSF and mannitol administered in 76 ALS patients in comparison with placebo (indistinguishable glucose solution 5%). We determine increase of G-CSF levels in serum and cerebrospinal fluid as CD34[+] cells and leucocyte count after treatment; reduction in ALS Functional Rating Scale-Revised Score, forced vital capacity, Scale for Testing Muscle Strength Score and quality of life; the adverse events/reactions during the treatment; changes in neuroinflammation biomarkers before and after treatment.<br><br>ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Azienda Ospedaliera Universitaria 'Citt&#xe0; della Salute e della Scienza', Torino, Italy. Results will be presented during scientific symposia or published in scientific journals.<br><br>TRIAL REGISTRATION NUMBER: Eudract 2014-002228-28.}, }
@article {pmid32207340, year = {2020}, author = {Garbuzova-Davis, S and Shell, R and Mustafa, H and Hailu, S and Willing, AE and Sanberg, PR and Borlongan, CV}, title = {Advancing Stem Cell Therapy for Repair of Damaged Lung Microvasculature in Amyotrophic Lateral Sclerosis.}, journal = {Cell transplantation}, volume = {29}, number = {}, pages = {963689720913494}, pmid = {32207340}, issn = {1555-3892}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Humans ; Lung/pathology ; Microvessels/*pathology ; Motor Neurons/*metabolism ; Spinal Cord/pathology ; *Stem Cell Transplantation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration in the brain and spinal cord. Progressive paralysis of the diaphragm and other respiratory muscles leading to respiratory dysfunction and failure is the most common cause of death in ALS patients. Respiratory impairment has also been shown in animal models of ALS. Vascular pathology is another recently recognized hallmark of ALS pathogenesis. Central nervous system (CNS) capillary damage is a shared disease element in ALS rodent models and ALS patients. Microvascular impairment outside of the CNS, such as in the lungs, may occur in ALS, triggering lung damage and affecting breathing function. Stem cell therapy is a promising treatment for ALS. However, this therapeutic strategy has primarily targeted rescue of degenerated motor neurons. We showed functional benefits from intravenous delivery of human bone marrow (hBM) stem cells on restoration of capillary integrity in the CNS of an superoxide dismutase 1 (SOD1) mouse model of ALS. Due to the widespread distribution of transplanted cells via this route, administered cells may enter the lungs and effectively restore microvasculature in this respiratory organ. Here, we provided preliminary evidence of the potential role of microvasculature dysfunction in prompting lung damage and treatment approaches for repair of respiratory function in ALS. Our initial studies showed proof-of-principle that microvascular damage in ALS mice results in lung petechiae at the late stage of disease and that systemic transplantation of mainly hBM-derived endothelial progenitor cells shows potential to promote lung restoration via re-established vascular integrity. Our new understanding of previously underexplored lung competence in this disease may facilitate therapy targeting restoration of respiratory function in ALS.}, }
@article {pmid32204915, year = {2020}, author = {Chen, Y and Wang, H and Ying, Z and Gao, Q}, title = {Ibudilast enhances the clearance of SOD1 and TDP-43 aggregates through TFEB-mediated autophagy and lysosomal biogenesis: The new molecular mechanism of ibudilast and its implication for neuroprotective therapy.}, journal = {Biochemical and biophysical research communications}, volume = {526}, number = {1}, pages = {231-238}, doi = {10.1016/j.bbrc.2020.03.051}, pmid = {32204915}, issn = {1090-2104}, mesh = {Amyotrophic Lateral Sclerosis/pathology ; Autophagosomes/drug effects/metabolism ; *Autophagy/drug effects ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Cell Death/drug effects ; Cell Nucleus/drug effects/metabolism ; DNA-Binding Proteins/*metabolism ; HEK293 Cells ; Humans ; Lysosomes/drug effects/*metabolism ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Membrane Fusion/drug effects ; Neuroprotection/drug effects ; Neuroprotective Agents/*pharmacology ; *Protein Aggregates/drug effects ; Protein Transport/drug effects ; Pyridines/*pharmacology ; Superoxide Dismutase-1/*metabolism ; }, abstract = {A key feature of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders including Alzheimer disease (AD), Parkinson disease (PD) and Huntington's disease (HD) is abnormal aggregation and deposition of misfolded proteins. Previous studies have shown that autophagy plays an important role in the clearance of disease-linked protein aggregates. In the current study, we report that ibudilast, which is a non-selective inhibitor of phosphodiesterases (PDEs) and an anti-inflammation drug, can induce autophagy and lysosomal biogenesis through mammalian target of rapamycin complex 1 - transcription factor EB (mTORC1-TFEB) signaling. We have found that ibudilast significantly enhances the clearance of disease-linked TAR DNA binding protein (TDP-43) and superoxide dismutase 1 (SOD1) protein aggregates in transfected cellular models carrying corresponding gene mutations. The mechanistic study revealed that ibudilast could markedly enhance TFEB nuclear translocation and increase the autolysosomes by inhibiting mTORC1 activity. We have also demonstrated that ibudilast could protect TDP-43-induced cytotoxicity in motor neuron-like NSC-34 cells. Collectively, our study identifies ibudilast as an autophagy enhancer and provides insights into the molecular basis of ibudilast for the potential treatment of several neurodegenerative disorders.}, }
@article {pmid32203578, year = {2020}, author = {Khademullah, CS and Aqrabawi, AJ and Place, KM and Dargaei, Z and Liang, X and Pressey, JC and Bedard, S and Yang, JW and Garand, D and Keramidis, I and Gasecka, A and Côté, D and De Koninck, Y and Keith, J and Zinman, L and Robertson, J and Kim, JC and Woodin, MA}, title = {Cortical interneuron-mediated inhibition delays the onset of amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {143}, number = {3}, pages = {800-810}, doi = {10.1093/brain/awaa034}, pmid = {32203578}, issn = {1460-2156}, mesh = {Adenoviridae ; Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Disease Progression ; Female ; Interneurons/*physiology ; Male ; Mice ; Mice, Transgenic ; Motor Cortex/*physiology ; Motor Skills/physiology ; Neural Inhibition/*physiology ; Patch-Clamp Techniques ; Pyramidal Cells/physiology ; Superoxide Dismutase-1/genetics ; Transfection ; }, abstract = {Amyotrophic lateral sclerosis is a fatal disease resulting from motor neuron degeneration in the cortex and spinal cord. Cortical hyperexcitability is a hallmark feature of amyotrophic lateral sclerosis and is accompanied by decreased intracortical inhibition. Using electrophysiological patch-clamp recordings, we revealed parvalbumin interneurons to be hypoactive in the late pre-symptomatic SOD1*G93A mouse model of amyotrophic lateral sclerosis. We discovered that using adeno-associated virus-mediated delivery of chemogenetic technology targeted to increase the activity of the interneurons within layer 5 of the primary motor cortex, we were able to rescue intracortical inhibition and reduce pyramidal neuron hyperexcitability. Increasing the activity of interneurons in the layer 5 of the primary motor cortex was effective in delaying the onset of amyotrophic lateral sclerosis-associated motor deficits, slowing symptom progression, preserving neuronal populations, and increasing the lifespan of SOD1*G93A mice. Taken together, this study provides novel insights into the pathogenesis and treatment of amyotrophic lateral sclerosis.}, }
@article {pmid32200527, year = {2020}, author = {Lameth, J and Arnaud-Cormos, D and Lévêque, P and Boillée, S and Edeline, JM and Mallat, M}, title = {Effects of a Single Head Exposure to GSM-1800 MHz Signals on the Transcriptome Profile in the Rat Cerebral Cortex: Enhanced Gene Responses Under Proinflammatory Conditions.}, journal = {Neurotoxicity research}, volume = {38}, number = {1}, pages = {105-123}, pmid = {32200527}, issn = {1476-3524}, support = {grants 2015/2 RF/12 and 2018/2 RF/16//Agence Nationale de S&#xe9;curit&#xe9; Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; }, mesh = {Animals ; Cerebral Cortex/*metabolism/*radiation effects ; *Electromagnetic Fields ; Encephalitis/chemically induced/*metabolism ; Female ; Gene Expression/radiation effects ; Lipopolysaccharides/administration &amp; dosage ; Male ; Radiometry ; Rats, Sprague-Dawley ; Sequence Analysis, RNA ; Transcriptome/*radiation effects ; }, abstract = {Mobile communications are propagated by electromagnetic fields (EMFs), and since the 1990s, they operate with pulse-modulated signals such as the GSM-1800 MHz. The biological effects of GSM-EMF in humans affected by neuropathological processes remain seldom investigated. In this study, a 2-h head-only exposure to GSM-1800 MHz was applied to (i) rats undergoing an acute neuroinflammation triggered by a lipopolysaccharide (LPS) treatment, (ii) age-matched healthy rats, or (iii) transgenic hSOD1[G93A] rats that modeled a presymptomatic phase of human amyotrophic lateral sclerosis (ALS). Gene responses were assessed 24 h after the GSM head-only exposure in a motor area of the cerebral cortex (mCx) where the mean specific absorption rate (SAR) was estimated to be 3.22 W/kg. In LPS-treated rats, a genome-wide mRNA profiling was performed by RNA-seq analysis and revealed significant (adjusted p value < 0.05) but moderate (fold changes < 2) upregulations or downregulations affecting 2.7% of the expressed genes, including genes expressed predominantly in neuronal or in glial cell types and groups of genes involved in protein ubiquitination or dephosphorylation. Reverse transcription-quantitative PCR analyses confirmed gene modulations uncovered by RNA-seq data and showed that in a set of 15 PCR-assessed genes, significant gene responses to GSM-1800 MHz depended upon the acute neuroinflammatory state triggered in LPS-treated rats, because they were not observed in healthy or in hSOD1[G93A] rats. Together, our data specify the extent of cortical gene modulations triggered by GSM-EMF in the course of an acute neuroinflammation and indicate that GSM-induced gene responses can differ according to pathologies affecting the CNS.}, }
@article {pmid32198305, year = {2020}, author = {Bortolasci, CC and Marx, W and Walker, AJ and Hasebe, K and Kavanagh, BE and Morris, MJ and Mohebbi, M and Turner, A and Gray, L and Berk, L and Walder, K and Berk, M and Dean, OM}, title = {Minocycline for the treatment of mental health and neurological conditions: study protocol of a systematic review and meta-analysis.}, journal = {BMJ open}, volume = {10}, number = {3}, pages = {e035080}, pmid = {32198305}, issn = {2044-6055}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; *Anti-Inflammatory Agents ; *Antioxidants ; Humans ; Mental Disorders/*drug therapy ; Meta-Analysis as Topic ; *Minocycline ; Systematic Reviews as Topic ; }, abstract = {INTRODUCTION: Due to the anti-inflammatory, antioxidant and anti-apoptotic properties of minocycline, clinical trials have evaluated the potential of this drug to treat several psychiatric and neurological disorders, including major depressive disorder, schizophrenia, bipolar disorder, stroke and amyotrophic lateral sclerosis. This protocol proposes a systematic review (and potential meta-analysis) that aims to identify and critically evaluate randomised controlled trials of minocycline for treating psychiatric and neurological disorders.<br><br>METHODS AND ANALYSIS: PubMed, Embase, Cochrane Central Register of Controlled Clinical Trials, PsycINFO and Cumulative Index to Nursing and Allied Health Literature (CINAHL) will be used to identify randomised controlled trials that used minocycline to treat psychiatric and neurological disorders. Double-blind, randomised, controlled, clinical trials of participants aged 18 years or older and written in English will be included in the review. Data will be extracted by two independent reviewers. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed and the Cochrane Collaboration's 'Risk of Bias' tool will be used to assess the risk of bias in all studies included in the systematic review. The Grading of Recommendations, Assessment, Development and Evaluation system will be used to access the overall quality of the level of evidence of the studies. If sufficient evidence is identified, a meta-analysis will be conducted using the standardised mean difference approach and reported with 95% CIs. Heterogeneity of evidence will be evaluated using the I[2] model.<br><br>ETHICS AND DISSEMINATION: This systematic review will evaluate only published data; therefore, ethical approval is not required. The systematic review will be published in a peer-reviewed journal and presented at relevant research conferences.<br><br>TRIAL REGISTRATION NUMBER: CRD42020153292.}, }
@article {pmid32188741, year = {2020}, author = {Valsecchi, V and Boido, M and Montarolo, F and Guglielmotto, M and Perga, S and Martire, S and Cutrupi, S and Iannello, A and Gionchiglia, N and Signorino, E and Calvo, A and Fuda, G and Chiò, A and Bertolotto, A and Vercelli, A}, title = {The transcription factor Nurr1 is upregulated in amyotrophic lateral sclerosis patients and SOD1-G93A mice.}, journal = {Disease models &amp; mechanisms}, volume = {13}, number = {5}, pages = {}, pmid = {32188741}, issn = {1754-8411}, mesh = {Amyotrophic Lateral Sclerosis/blood/*genetics ; Animals ; Astrocytes/metabolism/pathology ; Brain-Derived Neurotrophic Factor/metabolism ; Female ; Gene Expression Regulation ; Humans ; Male ; Mice ; Mice, Transgenic ; Middle Aged ; Motor Neurons/metabolism/pathology ; NF-kappa B/genetics/metabolism ; Nitric Oxide Synthase Type II/genetics/metabolism ; Nuclear Receptor Subfamily 4, Group A, Member 2/blood/*genetics/metabolism ; Promoter Regions, Genetic/genetics ; RNA, Messenger/genetics/metabolism ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase-1/*genetics ; Transcription Factors/*genetics/metabolism ; Transcriptional Activation/genetics ; Up-Regulation/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both lower and upper motor neurons (MNs) in the central nervous system. ALS etiology is highly multifactorial and multifarious, and an effective treatment is still lacking. Neuroinflammation is a hallmark of ALS and could be targeted to develop new therapeutic approaches. Interestingly, the transcription factor Nurr1 has been demonstrated to have an important role in the inflammatory process in several neurological disorders, such as Parkinson's disease and multiple sclerosis. In the present paper, we demonstrate for the first time that Nurr1 expression levels are upregulated in the peripheral blood of ALS patients. Moreover, we investigated Nurr1 function in the SOD1-G93A mouse model of ALS. Nurr1 was strongly upregulated in the spinal cord during the asymptomatic and early symptomatic phases of the disease, where it promoted the expression of brain-derived neurotrophic factor mRNA and the repression of NFκB pro-inflammatory targets, such as inducible nitric oxide synthase. Therefore, we hypothesize that Nurr1 is activated in an early phase of the disease as a protective endogenous anti-inflammatory mechanism, although not sufficient to reverse disease progression. On the basis of these observations, Nurr1 could represent a potential biomarker for ALS and a promising target for future therapies.}, }
@article {pmid32184709, year = {2020}, author = {Luo, S and Ma, C and Zhu, MQ and Ju, WN and Yang, Y and Wang, X}, title = {Application of Iron Oxide Nanoparticles in the Diagnosis and Treatment of Neurodegenerative Diseases With Emphasis on Alzheimer's Disease.}, journal = {Frontiers in cellular neuroscience}, volume = {14}, number = {}, pages = {21}, pmid = {32184709}, issn = {1662-5102}, abstract = {Neurodegenerative diseases are characterized by chronic progressive degeneration of the structure and function of the nervous system, which brings an enormous burden on patients, their families, and society. It is difficult to make early diagnosis, resulting from the insidious onset and progressive development of neurodegenerative diseases. The drugs on the market cannot cross the blood-brain barrier (BBB) effectively, which leads to unfavorable prognosis and less effective treatments. Therefore, there is an urgent demand to develop a novel detection method and therapeutic strategies. Recently, nanomedicine has aroused considerable attention for diagnosis and therapy of central nervous system (CNS) diseases. Nanoparticles integrate targeting, imaging, and therapy in one system and facilitate the entry of drug molecules across the blood-brain barrier, offering new hope to patients. In this review, we summarize the application of iron oxide nanoparticles (IONPs) in the diagnosis and treatment of neurodegenerative disease, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We focus on IONPs as magnetic resonance imaging (MRI) contrast agents (CAs) and drug carriers in AD. What most neurodegenerative diseases have in common is that hall marker lesions are represented by protein aggregates (Soto and Pritzkow, 2018). These diseases are of unknown etiology and unfavorable prognosis, and the treatments toward them are less effective (Soto and Pritzkow, 2018). Such diseases usually develop in aged people, and early clinical manifestations are atypical, resulting in difficulty in early diagnosis. Recently, nanomedicine has aroused considerable attention for therapy and diagnosis of CNS diseases because it integrates targeting, imaging, and therapy in one system (Gupta et al., 2019). In this review article, we first introduce the neurodegenerative diseases and commonly used MRI CAs. Then we review the application of IONPs in the diagnosis and treatment of neurodegenerative diseases with the purpose of assisting early theranostics (therapy and diagnosis).}, }
@article {pmid32175837, year = {2020}, author = {Morello, M and Pieri, M and Zenobi, R and Talamo, A and Stephan, D and Landel, V and Féron, F and Millet, P}, title = {The Influence of Vitamin D on Neurodegeneration and Neurological Disorders: A Rationale for its Physio-pathological Actions.}, journal = {Current pharmaceutical design}, volume = {26}, number = {21}, pages = {2475-2491}, doi = {10.2174/1381612826666200316145725}, pmid = {32175837}, issn = {1873-4286}, mesh = {*Alzheimer Disease ; Humans ; *Multiple Sclerosis ; Vitamin D ; Vitamins ; }, abstract = {Vitamin D is a steroid hormone implicated in the regulation of neuronal integrity and many brain functions. Its influence, as a nutrient and a hormone, on the physiopathology of the most common neurodegenerative diseases is continuously emphasized by new studies. This review addresses what is currently known about the action of vitamin D on the nervous system and neurodegenerative diseases such as Multiple Sclerosis, Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis. Further vitamin D research is necessary to understand how the action of this "neuroactive" steroid can help to optimize the prevention and treatment of several neurological diseases.}, }
@article {pmid32168734, year = {2020}, author = {Kasthuri, M and Li, C and Verma, K and Russell, OO and Dickson, L and McCormick, L and Bassit, L and Amblard, F and Schinazi, RF}, title = {Synthesis of 4'-Substituted-2'-Deoxy-2'-α-Fluoro Nucleoside Analogs as Potential Antiviral Agents.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {6}, pages = {}, pmid = {32168734}, issn = {1420-3049}, support = {1-R01-AI-132833/NH/NIH HHS/United States ; 5P30-AI-50409//Center for AIDS Research, Emory University/ ; }, mesh = {Animals ; Antiviral Agents/*chemical synthesis/pharmacology ; Cell Line, Tumor ; Chikungunya virus/drug effects/growth &amp; development ; Cricetulus ; Dengue Virus/drug effects/growth &amp; development ; Deoxycytidine/*analogs &amp; derivatives/chemical synthesis/pharmacology ; Deoxyribonucleosides/*chemical synthesis/pharmacology ; Epithelial Cells/drug effects/virology ; Hepatocytes/drug effects/virology ; Humans ; Leukocytes, Mononuclear/drug effects/virology ; Microbial Sensitivity Tests ; Primary Cell Culture ; Prodrugs/*chemical synthesis/pharmacology ; Respiratory Syncytial Virus, Human/drug effects/growth &amp; development ; T-Lymphocytes/drug effects/virology ; Treatment Failure ; Virus Replication/drug effects ; West Nile virus/drug effects/growth &amp; development ; Zika Virus/drug effects/growth &amp; development ; }, abstract = {Nucleoside analogs are widely used for the treatment of viral diseases (Hepatitis B/C, herpes and human immunodeficiency virus, HIV) and various malignancies. ALS-8176, a prodrug of the 4'-chloromethyl-2'-deoxy-2'-fluoro nucleoside ALS-8112, was evaluated in hospitalized infants for the treatment of respiratory syncytial virus (RSV), but was abandoned for unclear reasons. Based on the structure of ALS-8112, a series of novel 4'-modified-2'-deoxy-2'-fluoro nucleosides were synthesized. Newly prepared compounds were evaluated against RSV, but also against a panel of RNA viruses, including Dengue, West Nile, Chikungunya, and Zika viruses. Unfortunately, none of the compounds showed marked antiviral activity against these viruses.}, }
@article {pmid32157143, year = {2020}, author = {Martínez-González, L and Rodríguez-Cueto, C and Cabezudo, D and Bartolomé, F and Andrés-Benito, P and Ferrer, I and Gil, C and Martín-Requero, &#xc1; and Fernández-Ruiz, J and Martínez, A and de Lago, E}, title = {Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {4449}, pmid = {32157143}, issn = {2045-2322}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/*pathology ; Animals ; Case-Control Studies ; Casein Kinase Idelta/*antagonists &amp; inhibitors ; DNA-Binding Proteins/*metabolism ; Female ; Humans ; Male ; Mice ; Mice, Transgenic ; Middle Aged ; Motor Neurons/*cytology/drug effects/metabolism ; Phosphorylation ; Protein Kinase Inhibitors/*pharmacology ; Spinal Cord/*cytology/drug effects/metabolism ; }, abstract = {Pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease where no treatment exists, involves the compartmentalization of the nuclear protein TDP-43 (TAR DNA-binding protein 43) in the cytoplasm which is promoted by its aberrant phosphorylation and others posttranslational modifications. Recently, it was reported that CK-1δ (protein casein kinase-1δ) is able to phosphorylate TDP-43. Here, the preclinical efficacy of a benzothiazole-based CK-1δ inhibitor IGS-2.7, both in a TDP-43 (A315T) transgenic mouse and in a human cell-based model of ALS, is shown. Treatment with IGS-2.7 produces a significant preservation of motor neurons in the anterior horn at lumbar level, a decrease in both astroglial and microglial reactivity in this area, and in TDP-43 phosphorylation in spinal cord samples. Furthermore, the recovery of TDP-43 homeostasis (phosphorylation and localization) in a human-based cell model from ALS patients after treatment with IGS-2.7 is also reported. Moreover, we have shown a trend to increase in CK-1δ mRNA in spinal cord and significantly in frontal cortex of sALS cases. All these data show for the first time the in vivo modulation of TDP-43 toxicity by CK-1δ inhibition with IGS-2.7, which may explain the benefits in the preservation of spinal motor neurons and point to the relevance of CK-1δ inhibitors in a future disease-modifying treatment for ALS.}, }
@article {pmid32154900, year = {2020}, author = {Ingre, C and Nygren, I and Zachau, A and Staaf, G}, title = {[Quality of life the goal of care for patients with ALS].}, journal = {Lakartidningen}, volume = {117}, number = {}, pages = {}, pmid = {32154900}, issn = {1652-7518}, mesh = {*Amyotrophic Lateral Sclerosis/complications/therapy ; Goals ; Humans ; *Quality of Life ; Sweden ; }, abstract = {ALS is characterized by the degeneration of upper and lower motor neurons. In about 70% of patients with ALS the disease has an spinal onset, while about 30% of the patients have a bulbar onset. Cognitive dysfunction and behavioral changes are seen in about 50% of the patients, and 15% develop frontotemporal dementia. There is no single test that provides the ALS diagnosis. The diagnosis is based on clinical and electrophysiological signs, and the exclusion of other diseases. The only disease modulating treatment approved for ALS in Sweden is Riluzole, sadly only with limited effect. Other treatments are symptomatic and the goal is to help patients achieve the best possible quality of life through multidiciplinary ALS teams.}, }
@article {pmid32153351, year = {2020}, author = {Kaku, H and Ludlow, AV and Gutknecht, MF and Rothstein, TL}, title = {FAIM Opposes Aggregation of Mutant SOD1 That Typifies Some Forms of Familial Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {110}, pmid = {32153351}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative illness that is unremittingly fatal and for which no effective treatment exists. All forms of ALS are characterized by protein aggregation. In familial forms of ALS, specific and heritable aggregation-prone proteins have been identified, such as mutant superoxide dismutase (SOD1). It has been suggested that a factor capable of preventing mutant SOD1 protein aggregation and/or disassembling mutant SOD1 protein aggregates would ameliorate SOD1-associated forms of familial ALS. Here we identify Fas Apoptosis Inhibitory Molecule (FAIM), a highly evolutionarily conserved 20 kDa protein, as an agent with this activity. We show FAIM counteracts intracellular accumulation of mutant SOD1 protein aggregates, which is increased in the absence of FAIM, as determined by pulse-shape analysis and filter trap assays. In a cell-free system, FAIM inhibits aggregation of mutant SOD1, and further disassembles and solubilizes established mutant SOD1 protein aggregates, as determined by thioflavin T (ThT), filter trap, and sedimentation assays. In sum, we report here a previously unknown activity of FAIM that opposes ALS disease-related protein aggregation and promotes proteostasis of an aggregation-prone ALS protein.}, }
@article {pmid32148547, year = {2020}, author = {Mohd Sairazi, NS and Sirajudeen, KNS}, title = {Natural Products and Their Bioactive Compounds: Neuroprotective Potentials against Neurodegenerative Diseases.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2020}, number = {}, pages = {6565396}, pmid = {32148547}, issn = {1741-427X}, abstract = {In recent years, natural products, which originate from plants, animals, and fungi, together with their bioactive compounds have been intensively explored and studied for their therapeutic potentials for various diseases such as cardiovascular, diabetes, hypertension, reproductive, cancer, and neurodegenerative diseases. Neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis are characterized by the progressive dysfunction and loss of neuronal structure and function that resulted in the neuronal cell death. Since the multifactorial pathological mechanisms are associated with neurodegeneration, targeting multiple mechanisms of actions and neuroprotection approach, which involves preventing cell death and restoring the function to damaged neurons, could be promising strategies for the prevention and therapeutic of neurodegenerative diseases. Natural products have emerged as potential neuroprotective agents for the treatment of neurodegenerative diseases. This review focused on the therapeutic potential of natural products and their bioactive compounds to exert a neuroprotective effect on the pathologies of neurodegenerative diseases.}, }
@article {pmid32146096, year = {2020}, author = {Hlavnička, J and Tykalová, T and Ulmanová, O and Dušek, P and Horáková, D and Růžička, E and Klempíř, J and Rusz, J}, title = {Characterizing vocal tremor in progressive neurological diseases via automated acoustic analyses.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {131}, number = {5}, pages = {1155-1165}, doi = {10.1016/j.clinph.2020.02.005}, pmid = {32146096}, issn = {1872-8952}, mesh = {Adult ; Aged ; Aged, 80 and over ; *Disease Progression ; Electromyography/methods ; Essential Tremor/diagnosis/*physiopathology ; Female ; *Fourier Analysis ; Humans ; Male ; Middle Aged ; Nervous System Diseases/diagnosis/physiopathology ; *Speech Acoustics ; Voice Disorders/diagnosis/*physiopathology ; Voice Quality/*physiology ; }, abstract = {OBJECTIVE: Voice tremor represents a common but frequently overlooked clinical feature of neurological disease. Therefore, we aimed to quantitatively and objectively assess the characteristics of voice tremor in a large sample of patients with various progressive neurological diseases.<br><br>METHODS: Voice samples were acquired from 240 patients with neurological disease and 40 healthy controls. The robust automated method was designed, allowing precise tracking of multiple tremor frequencies and distinguish pathological from the physiological tremor.<br><br>RESULTS: Abnormal tremor was revealed in Huntington's disease (65%), essential tremor (50%), multiple system atrophy (40%), cerebellar ataxia (40%), amyotrophic lateral sclerosis (40%), progressive supranuclear palsy (25%), Parkinson's disease (20%), cervical dystonia (10%), and multiple sclerosis (8%) but not in controls. Low-frequency voice tremor (<4 Hz) was common in all investigated diseases, whereas medium tremor frequencies (4-7&#xa0;Hz) were specific for movement disorders of Parkinson's disease, multiple system atrophy, essential tremor, and cervical dystonia.<br><br>CONCLUSIONS: Careful estimation of vocal tremor may help with accurate diagnosis and tailored treatment.<br><br>SIGNIFICANCE: This study provides (i) more insights into the pathophysiology of vocal tremor in a wide range of neurological diseases and (ii) an accurate method for estimation of vocal tremor suitable for clinical practice.}, }
@article {pmid32145336, year = {2020}, author = {Vogt, S and Schreiber, S and Pfau, G and Kollewe, K and Heinze, HJ and Dengler, R and Petri, S and Vielhaber, S and Brinkers, M}, title = {Dyspnea as a Fatigue-Promoting Factor in ALS and the Role of Objective Indicators of Respiratory Impairment.}, journal = {Journal of pain and symptom management}, volume = {60}, number = {2}, pages = {430-438.e1}, doi = {10.1016/j.jpainsymman.2020.02.021}, pmid = {32145336}, issn = {1873-6513}, mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis/therapy ; Dyspnea/diagnosis/etiology/therapy ; Fatigue/diagnosis/etiology/therapy ; Humans ; Quality of Life ; *Respiratory Insufficiency ; }, abstract = {CONTEXT: There is no evidence-based treatment for fatigue in amyotrophic lateral sclerosis (ALS), and identification of treatable causes determines management strategies. Although dyspnea is a key symptom of ALS and effectively treatable, it has not been sufficiently investigated whether dyspnea may be a fatigue-promoting factor.<br><br>OBJECTIVES: To determine the level of fatigue in dyspneic ALS patients and whether fatigue is promoted by dyspnea. We further evaluated the correlation of fatigue with respiratory function tests.<br><br>METHODS: About 101 dyspneic patients and 20 matched controls completed the ALS Functional Rating Scale-Extension and the Fatigue Severity Scale. Dyspneic patients additionally completed the Dyspnea-ALS Scale and the ALS Assessment Questionnaire and underwent respiratory function tests (forced vital capacity, sniff nasal inspiratory pressure, mean inspiratory and expiratory pressure with respective relaxation rates, and blood gases). Multiple regression and correlation analyses were conducted.<br><br>RESULTS: Dyspneic patients had significantly higher fatigue scores than nondyspneic patients, and their fatigue significantly affected quality of life. Dyspnea alone explained up to 24% of the variance in fatigue. No associations were observed between fatigue and respiratory function tests. Patients with noninvasive ventilation reported significantly more dyspnea and fatigue.<br><br>CONCLUSION: Fatigue is a frequent and bothersome symptom in dyspneic ALS patients. Dyspnea-related distress is, in contrast to objective indicators of respiratory impairment, a determining factor of experienced fatigue. There is an urgent need for further symptom relief beyond noninvasive ventilation. Adequate treatment of dyspnea has the potential for synergies in symptom management arising from the association between fatigue and dyspnea.}, }
@article {pmid32142134, year = {2020}, author = {Ikenaka, K and Ishigaki, S and Iguchi, Y and Kawai, K and Fujioka, Y and Yokoi, S and Abdelhamid, RF and Nagano, S and Mochizuki, H and Katsuno, M and Sobue, G}, title = {Characteristic Features of FUS Inclusions in Spinal Motor Neurons of Sporadic Amyotrophic Lateral Sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {79}, number = {4}, pages = {370-377}, doi = {10.1093/jnen/nlaa003}, pmid = {32142134}, issn = {1554-6578}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/metabolism/*pathology ; DNA-Binding Proteins/*metabolism ; Dynactin Complex/metabolism ; Female ; HEK293 Cells ; Humans ; Inclusion Bodies/metabolism/*pathology ; Male ; Middle Aged ; Motor Neurons/metabolism/*pathology ; RNA-Binding Protein FUS/*metabolism ; }, abstract = {Alterations of RNA metabolism caused by mutations in RNA-binding protein genes, such as transactivating DNA-binding protein-43 (TDP-43) and fused in sarcoma (FUS), have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Unlike the accumulation of TDP43, which is accepted as a pathological hall mark of sporadic ALS (sALS), FUS pathology in sALS is still under debate. Although immunoreactive inclusions of FUS have been detected in sALS patients previously, the technical limitation of signal detection, including the necessity of specific antigen retrieval, restricts our understanding of FUS-associated ALS pathology. In this study, we applied a novel detection method using a conventional antigen retrieval technique with Sudan Black B treatment to identify FUS-positive inclusions in sALS patients. We classified pathological motor neurons into 5 different categories according to the different aggregation characteristics of FUS and TDP-43. Although the granular type was more dominant for inclusions with TDP-43, the skein-like type was more often observed in FUS-positive inclusions, suggesting that these 2 proteins undergo independent aggregation processes. Moreover, neurons harboring FUS-positive inclusions demonstrated substantially reduced expression levels of dynactin-1, a retrograde motor protein, indicating that perturbation of nucleocytoplasmic transport is associated with the formation of cytoplasmic inclusions of FUS in sALS.}, }
@article {pmid32140672, year = {2020}, author = {Juntas-Morales, R and Pageot, N and Bendarraz, A and Alphandéry, S and Sedel, F and Seigle, S and Camu, W}, title = {High-dose pharmaceutical grade biotin (MD1003) in amyotrophic lateral sclerosis: A pilot study.}, journal = {EClinicalMedicine}, volume = {19}, number = {}, pages = {100254}, pmid = {32140672}, issn = {2589-5370}, abstract = {BACKGROUND: Oligodendrocytes (OGs) provide metabolic support to motor neurons (MNs) and are implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS). MD1003, or high-dose Pharmaceutical grade Biotin (hdPB), may improve disability in progressive multiple sclerosis patients via augmentation of OG or MN energy levels. Here, we assessed the safety and efficacy of MD1003 in ALS patients.<br><br>METHODS: This single centre, randomised, double-blind, placebo-controlled trial included patients aged 25-80 years with probable or definite ALS. Patients were assigned (2:1), using a computer-generated randomisation list, to receive oral MD1003 (300&#xa0;mg/day) or placebo treatment for 24 weeks. The primary outcome, safety, was analysed in all patients who received at least one dose of study drug. This study, registered with ClinicalTrials.gov, NCT03114215, has been completed.<br><br>FINDINGS: Between June and December 2016, 30 patients were enrolled (MD1003, n&#xa0;=&#xa0;20; placebo, n&#xa0;=&#xa0;10). Baseline characteristics were representative of the ALS population. MD1003 and placebo groups were not well balanced at screening, with the MD1003-treated group having a higher rate of ALSFRS-R decline prior to screening versus placebo (-6&#xb7;0 IQR [-8&#xb7;5, -5&#xb7;0] vs. -5&#xb7;0 IQR [-5&#xb7;0, -3&#xb7;0]) and a predominance of ALS with upper limb onset compared to placebo (35% vs. 10%). MD1003 had a favourable safety profile and was well tolerated. The occurrence of adverse events was similar in both groups (60%). Two deaths occurred in the MD1003 group versus 1 in the placebo group. ALSFRS-R median change from baseline to month 6 was not significantly different between the two groups (p&#xa0;=&#xa0;0&#xb7;49); the mean difference between groups was -1&#xb7;6 (SEM=3&#xb7;3).<br><br>INTERPRETATION: MD1003 treatment was safe and well tolerated. It was not possible to establish MD1003 efficacy in this relatively small study. Given the favourable safety profile of MD1003 and an imbalance between treatment groups favouring placebo, additional, larger studies in ALS are warranted.<br><br>FUNDING: MedDay Pharmaceuticals.}, }
@article {pmid32123048, year = {2020}, author = {Olesen, MN and Wuolikainen, A and Nilsson, AC and Wirenfeldt, M and Forsberg, K and Madsen, JS and Lillevang, ST and Brandslund, I and Andersen, PM and Asgari, N}, title = {Inflammatory profiles relate to survival in subtypes of amyotrophic lateral sclerosis.}, journal = {Neurology(R) neuroimmunology &amp; neuroinflammation}, volume = {7}, number = {3}, pages = {}, pmid = {32123048}, issn = {2332-7812}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/classification/*genetics/*immunology/*mortality ; Cytokines/*blood ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Young Adult ; }, abstract = {OBJECTIVE: To investigate inflammatory cytokines in patients with motor neuron disease (MND) evaluating the putative contribution of amyotrophic lateral sclerosis (ALS)-causing gene variants.<br><br>METHODS: This study is a retrospective case series with prospective follow-up (1994-2016) of 248 patients with MND, of whom 164 had ALS who were screened for mutations in the genes for SOD1 and C9orf72. Paired CSF and plasma were collected at the diagnostic evaluation before treatment. A panel of cytokines were measured blindly via digital ELISA on the Simoa platform.<br><br>RESULTS: Time from disease onset to death was longer for patients with ALS-causing SOD1 mutations (mSOD1, n = 24) than those with C9orf72 hexanucleotide repeat expansion (C9orf72HRE) ALS (n = 19; q = 0.001) and other ALS (OALS) (n = 119; q = 0.0008). Patients with OALS had higher CSF tumor necrosis factor alpha (TNF-&#x3b1;) compared with those with C9orf72HRE ALS (q = 0.014). Patients with C9orf72HRE ALS had higher CSF interferon alpha compared with those with OALS and mSOD1 ALS (q = 0.042 and q = 0.042). In patients with ALS, the survival was negatively correlated with plasma interleukin (IL) 10 (hazard ratio [HR] 1.17, 95% CI 1.05-1.30). Plasma TNF-&#x3b1;, IL-10, and TNF-related apoptosis-inducing ligand (TRAIL) (HR 1.01 [1.00-1.02], 1.15 [1.02-1.30], and 1.01 [1.00-1.01], respectively) of patients with OALS, plasma IL-1&#x3b2; (HR 5.90 [1.27-27.5]) of patients with C9orf72HRE ALS, and CSF TRAIL (10.5 [1.12-98.6]) of patients with mSOD1 ALS all correlated negatively with survival.<br><br>CONCLUSIONS: Differences in survival times in ALS subtypes were correlated with cytokine levels, suggesting specific immune responses related to ALS genetic variants.}, }
@article {pmid32119873, year = {2020}, author = {Casterton, RL and Hunt, RJ and Fanto, M}, title = {Pathomechanism Heterogeneity in the Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Disease Spectrum: Providing Focus Through the Lens of Autophagy.}, journal = {Journal of molecular biology}, volume = {432}, number = {8}, pages = {2692-2713}, doi = {10.1016/j.jmb.2020.02.018}, pmid = {32119873}, issn = {1089-8638}, support = {FANTO/APR17/855-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; *Autophagy ; Frontotemporal Dementia/*pathology ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) constitute aggressive neurodegenerative pathologies that lead to the progressive degeneration of upper and lower motor neurons and of neocortical areas, respectively. In the past decade, the identification of several genes that cause these disorders indicated that the two diseases overlap in a multifaceted spectrum of conditions. The autophagy-lysosome system has been identified as a main intersection for the onset and progression of neurodegeneration in ALS/FTD. Genetic evidence has revealed that several genes with a mechanistic role at different stages of the autophagy process are mutated in patients with ALS/FTD. Moreover, the three main proteins aggregating in ALS/FTD, including in sporadic cases, are also targeted by autophagy and affect this process. Here, we examine the varied dysfunctions and degrees of involvement of the autophagy-lysosome system that have been discovered in ALS/FTD. We argue that these findings shed light on the pathological mechanisms in the ALS/FTD spectrum and conclude that they have important consequences both for treatment options and for the basic biomolecular understanding of how this process intersects with RNA metabolism, the other major cellular process reported to be dysfunctional in part of the ALS/FTD spectrum.}, }
@article {pmid32116773, year = {2020}, author = {Carrera-Juliá, S and Moreno, ML and Barrios, C and de la Rubia Ortí, JE and Drehmer, E}, title = {Antioxidant Alternatives in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review.}, journal = {Frontiers in physiology}, volume = {11}, number = {}, pages = {63}, pmid = {32116773}, issn = {1664-042X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that produces a selective loss of the motor neurons of the spinal cord, brain stem and motor cortex. Oxidative stress (OS) associated with mitochondrial dysfunction and the deterioration of the electron transport chain has been shown to be a factor that contributes to neurodegeneration and plays a potential role in the pathogenesis of ALS. The regions of the central nervous system affected have high levels of reactive oxygen species (ROS) and reduced antioxidant defenses. Scientific studies propose treatment with antioxidants to combat the characteristic OS and the regeneration of nicotinamide adenine dinucleotide (NAD[+]) levels by the use of precursors. This review examines the possible roles of nicotinamide riboside and pterostilbene as therapeutic strategies in ALS.}, }
@article {pmid32114585, year = {2019}, author = {Reyhani, A and Benbir Senel, G and Karadeniz, D}, title = {Effects of Sleep-Related Disorders on the Prognosis of Amyotrophic Lateral Sclerosis.}, journal = {Neuro-degenerative diseases}, volume = {19}, number = {3-4}, pages = {148-154}, doi = {10.1159/000505575}, pmid = {32114585}, issn = {1660-2862}, mesh = {Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/mortality ; Female ; Humans ; *Hypoxia/epidemiology/etiology ; Longitudinal Studies ; Male ; Middle Aged ; *Parasomnias/epidemiology/etiology ; Prognosis ; Restless Legs Syndrome/epidemiology/etiology ; Retrospective Studies ; *Sleep Apnea Syndromes/epidemiology/etiology ; Sleep Apnea, Central/epidemiology/etiology ; Sleep Apnea, Obstructive/epidemiology/etiology ; }, abstract = {BACKGROUND/OBJECTIVE: In this study, we demonstrated the effects of obstructive sleep apnea syndrome (OSAS) on the prognosis of amyotrophic lateral sclerosis (ALS). However, the effects of sleep-related disorders other than breathing problems are still waiting to be delineated.<br><br>METHODS: In this longitudinal retrospective and prospective study, we investigated 73 patients with ALS compared to 20 healthy subjects, to determine sleep-related disorders and their impact on disease prognosis.<br><br>RESULTS: In patients with ALS, the mean respiratory disturbance index (RDI) was 28.0/h, which was significantly higher than that in the controls (p < 0.001). OSAS was present in 67% of the patients, sleep-related hypoxemia was observed in 13.7% of the patients, and 5.4% had central sleep apnea syndrome. In patients with bulbar-onset disease, higher RDI was almost significantly associated with lower survival (p = 0.056). The mean index of periodic leg movements in sleep was significantly higher in patients with ALS (34.0 &#xb1; 19.9/h) than that in the controls (12.5 &#xb1; 15.5/h; p < 0.001). Periodic leg movements disorder (PLMD) was diagnosed in 23 patients with ALS (31.5%); fragmentary myoclonus was present in 13.7% of patients, and REM-sleep behavior disorder was diagnosed in 4 patients (5.4%). The presence of PLMD in addition to OSAS was significantly associated with worse prognosis and poorer survival (p = 0.040).<br><br>CONCLUSIONS: These findings emphasize that sleep-related disorders other than OSAS deserve attention in ALS. ALS is a catastrophic and frustrating disease for both patients and physicians; thus, the diagnosis and treatment of comorbid sleep disorders could improve the survival of patients with ALS.}, }
@article {pmid32105239, year = {2020}, author = {Brodell, JD and Sulovari, A and Bernstein, DN and Mongiovi, PC and Ciafaloni, E and Rubery, PT and Mesfin, A}, title = {Dropped Head Syndrome: An Update on Etiology and Surgical Management.}, journal = {JBJS reviews}, volume = {8}, number = {1}, pages = {e0068}, doi = {10.2106/JBJS.RVW.19.00068}, pmid = {32105239}, issn = {2329-9185}, mesh = {*Cervical Vertebrae ; Humans ; Kyphosis/*etiology/rehabilitation/surgery ; *Neck Muscles ; Neuromuscular Diseases/complications ; Orthotic Devices ; }, abstract = {» Dropped head syndrome is a group of disorders with diverse etiologies involving different anatomical components of the neck, ultimately resulting in a debilitating, flexible, anterior curvature of the cervical spine. » Causes of dropped head syndrome include myasthenia gravis, amyotrophic lateral sclerosis, Parkinson disease, radiation therapy, and cumulative age-related changes. Idiopathic cases have also been reported. » Nonoperative treatment of dropped head syndrome includes orthotic bracing and physical therapy. » Surgical treatment of dropped head syndrome consists of cervical spine fusion to correct the deformity. » The limited data available examining the clinical and radiographic outcomes of surgical intervention indicate a higher rate of complications with the majority having favorable outcomes in the long term.}, }
@article {pmid32104476, year = {2019}, author = {Niu, X and Chen, J and Gao, J}, title = {Nanocarriers as a powerful vehicle to overcome blood-brain barrier in treating neurodegenerative diseases: Focus on recent advances.}, journal = {Asian journal of pharmaceutical sciences}, volume = {14}, number = {5}, pages = {480-496}, pmid = {32104476}, issn = {2221-285X}, abstract = {Neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington disease and amyotrophic lateral sclerosis throw a heavy burden on families and society. Related scientific researches make tardy progress. One reason is that the known pathogeny is just the tip of the iceberg. Another reason is that various physiological barriers, especially blood-brain barrier (BBB), hamper effective therapeutic substances from reaching site of action. Drugs in clinical treatment of neurodegenerative diseases are basically administered orally. And generally speaking, the brain targeting efficiency is pretty low. Nano-delivery technology brings hope for neurodegenerative diseases. The use of nanocarriers encapsulating molecules such as peptides and genomic medicine may enhance drug transport through the BBB in neurodegenerative disease and target relevant regions in the brain for regenerative processes. In this review, we discuss BBB composition and applications of nanocarriers -liposomes, nanoparticles, nanomicelles and new emerging exosomes in neurodegenerative diseases. Furthermore, the disadvantages and the potential neurotoxicity of nanocarriers according pharmacokinetics theory are also discussed.}, }
@article {pmid32097525, year = {2020}, author = {Mariosa, D and Kamel, F and Bellocco, R and Ronnevi, LO and Almqvist, C and Larsson, H and Ye, W and Fang, F}, title = {Antidiabetics, statins and the risk of amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {27}, number = {6}, pages = {1010-1016}, pmid = {32097525}, issn = {1468-1331}, support = {Z01 ES049005/ImNIH/Intramural NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/epidemiology ; Case-Control Studies ; Diabetes Mellitus, Type 2 ; Female ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects ; Hypoglycemic Agents ; Risk Factors ; Sweden/epidemiology ; }, abstract = {BACKGROUND: Medications that are used for treatment of metabolic disorders have been suggested to be associated with the development of amyotrophic lateral sclerosis (ALS).<br><br>METHODS: To examine the associations of antidiabetics and statins with the subsequent risk of ALS we conducted a population-based nested case-control study of 2475 Swedish residents diagnosed with ALS during July 2006 to December 2013 and 12&#xa0;375 population controls (five for each ALS case). We extracted information on filled prescriptions of antidiabetics and statins for both cases and controls from the Swedish Prescribed Drug Register during the years before ALS diagnosis. Conditional logistic regression was used to calculate odds ratios (ORs) for the associations of these medications with ALS risk.<br><br>RESULTS: Patients with ALS were less likely to have been prescribed with antidiabetics compared with controls [OR, 0.76; 95% confidence intervals (CI), 0.65-0.90]. Conversely, statins were not associated with ALS risk overall (OR, 1.08; 95% CI, 0.98-1.19), although a positive association was noted among women (OR, 1.28; 95% CI, 1.10-1.48). The latter association was mostly explained by ALS cases being more likely to have a first prescription of statins during the year before diagnosis compared with controls (OR, 2.54; 95% CI, 1.84-3.49).<br><br>CONCLUSIONS: The inverse association of antidiabetics with ALS is consistent with the previously reported inverse association between type 2 diabetes and ALS risk. The increase in prescription of statins during the year before ALS diagnosis deserves attention because it might reflect an acceleration of the course of ALS due to statin use.}, }
@article {pmid32096049, year = {2019}, author = {Cruz, A and Verma, M and Wolozin, B}, title = {The Pathophysiology of Tau and Stress Granules in Disease.}, journal = {Advances in experimental medicine and biology}, volume = {1184}, number = {}, pages = {359-372}, pmid = {32096049}, issn = {0065-2598}, support = {R01 AG064932/AG/NIA NIH HHS/United States ; RF1 AG056318/AG/NIA NIH HHS/United States ; R01 AG050471/AG/NIA NIH HHS/United States ; R01 NS089544/NS/NINDS NIH HHS/United States ; R21 AG059925/AG/NIA NIH HHS/United States ; RF1 AG061706/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/pathology ; Cytoplasmic Granules/*metabolism/pathology ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; RNA-Binding Proteins/metabolism ; Tauopathies/metabolism/pathology ; tau Proteins/*metabolism ; }, abstract = {This chapter discusses the relationship between tau, RNA binding proteins and stress granules, which exhibit an intimate bidirectional relationship affecting the functions of both tau and the translational stress response. We describe how tau becomes hyperphosphorylated and oligomerized as part of an endogenous mechanism to promote the translational stress response through interaction with RNA binding proteins. Prior studies demonstrate that dysfunction of RNA binding proteins biology is sufficient to cause neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia. Emerging evidence indicates that tau-mediated neurodegeneration also occurs through a mechanism that is mediated by RNA binding proteins and the translational stress response. Discovery of the role of RNA metabolism in tauopathy opens a wide variety of novel therapeutic approaches. Multiple studies have already shown that approaches reducing the levels of selected RNA binding proteins or inhibiting the translational stress response can intervene in the pathophysiology of motoneuron diseases. Emerging studies show that reducing the levels of selected RNA binding proteins or inhibiting the translational stress response also reduces neurodegeneration in models of tauopathy and Aβ mediated degeneration. The combined impact of these studies indicate that RNA binding proteins and RNA metabolism represent a valuable new frontier for the investigation and treatment tauopathies.}, }
@article {pmid32089764, year = {2020}, author = {Kosuge, Y and Kaneko, E and Nango, H and Miyagishi, H and Ishige, K and Ito, Y}, title = {Bidens pilosa Extract Administered after Symptom Onset Attenuates Glial Activation, Improves Motor Performance, and Prolongs Survival in a Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {1020673}, pmid = {32089764}, issn = {1942-0994}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Animals ; Bidens ; Disease Models, Animal ; Drugs, Chinese Herbal/*chemistry ; Humans ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects ; Survival Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder characterized by progressive paralysis resulting from the death of upper and lower motor neurons. There is currently no effective pharmacological treatment for ALS, and the two approved drugs riluzole and edaravone have limited effects on the symptoms and only slightly prolong the life of patients. Therefore, the development of effective therapeutic strategies is of paramount importance. In this study, we investigated whether Miyako Island Bidens pilosa (MBP) can alleviate the neurological deterioration observed in a superoxide dismutase-1 G93A mutant transgenic mouse (G93A mouse) model of ALS. We orally administered 2 g/kg/day of MBP to G93A mice at the onset of symptoms of neurodegeneration (15 weeks old) until death. Treatment with MBP markedly prolonged the life of ALS model mice by approximately 20 days compared to that of vehicle-treated ALS model mice and significantly improved motor performance. MBP treatment prevented the reduction in SMI32 expression, a neuronal marker protein, and attenuated astrocyte (detected by GFAP) and microglia (detected by Iba-1) activation in the spinal cord of G93A mice at the end stage of the disease (18 weeks old). Our results indicate that MBP administered after the onset of ALS symptoms suppressed the inflammatory activation of microglia and astrocytes in the spinal cord of the G93A ALS model mice, thus improving their quality of life. MBP may be a potential therapeutic agent for ALS.}, }
@article {pmid32085981, year = {2020}, author = {Duque, T and Gromicho, M and Pronto-Laborinho, AC and de Carvalho, M}, title = {Transforming growth factor-β plasma levels and its role in amyotrophic lateral sclerosis.}, journal = {Medical hypotheses}, volume = {139}, number = {}, pages = {109632}, doi = {10.1016/j.mehy.2020.109632}, pmid = {32085981}, issn = {1532-2777}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; *Neurodegenerative Diseases ; *Pharmaceutical Preparations ; Plasma ; *Transforming Growth Factor beta/metabolism ; Transforming Growth Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle paralysis. Respiratory complications are the main cause of death in ALS. For this reason, initial respiratory status and its decline over disease progression are strong independent predictors of survival. Riluzole, a glutamatergic neurotransmission inhibitor, is the only drug that has shown to extend survival. Therefore, both novel molecular biomarkers and treatment strategies are needed. Transforming growth factor-β (TGF-β) family cytokines are important regulators of cell fate affecting both neurogenesis and neurodegeneration. Several studies demonstrate that TGF-β signalling protects neurons from glutamate-mediated excitotoxicity, a recognized mechanism underlying the pathogenesis of various neurodegenerative disorders such as ALS. Recent studies report dysregulations of the TGF-β system as a common feature of neurodegenerative disorders. The upregulation of this system has been linked with ALS progression. We have quantified TGF-β1, TGF-β2 and TGF-β3 serum levels in 23 ALS patients and 12 healthy controls, our preliminary results support the hypothesis that TGF-β3 levels can be a marker disease severity ALS. Further results are necessary to confirm this hypothesis.}, }
@article {pmid32082115, year = {2020}, author = {Theunissen, F and Flynn, LL and Anderton, RS and Mastaglia, F and Pytte, J and Jiang, L and Hodgetts, S and Burns, DK and Saunders, A and Fletcher, S and Wilton, SD and Akkari, PA}, title = {Structural Variants May Be a Source of Missing Heritability in sALS.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {47}, pmid = {32082115}, issn = {1662-4548}, abstract = {The underlying genetic and molecular mechanisms that drive amyotrophic lateral sclerosis (ALS) remain poorly understood. Structural variants within the genome can play a significant role in neurodegenerative disease risk, such as the repeat expansion in C9orf72 and the tri-nucleotide repeat in ATXN2, both of which are associated with familial and sporadic ALS. Many such structural variants reside in uncharacterized regions of the human genome, and have been under studied. Therefore, characterization of structural variants located in and around genes associated with ALS could provide insight into disease pathogenesis, and lead to the discovery of highly informative genetic tools for stratification in clinical trials. Such genomic variants may provide a deeper understanding of how gene expression can affect disease etiology, disease severity and trajectory, patient response to treatment, and may hold the key to understanding the genetics of sporadic ALS. This article outlines the current understanding of amyotrophic lateral sclerosis genetics and how structural variations may underpin some of the missing heritability of this disease.}, }
@article {pmid32077821, year = {2020}, author = {Spasić, S and Nikolić-Kokić, A and Miletić, S and Oreščanin-Dušić, Z and Spasić, MB and Blagojević, D and Stević, Z}, title = {Edaravone May Prevent Ferroptosis in ALS.}, journal = {Current drug targets}, volume = {21}, number = {8}, pages = {776-780}, doi = {10.2174/1389450121666200220123305}, pmid = {32077821}, issn = {1873-5592}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Drug Therapy, Combination ; Edaravone/*pharmacology/therapeutic use ; Ferroptosis/*drug effects ; Humans ; Motor Neurons/drug effects/metabolism ; Neuroprotective Agents/*pharmacology/therapeutic use ; }, abstract = {Radicava™ (Edaravone) was approved the Food and Drug Administration (FDA) as a new treatment for amyotrophic lateral sclerosis (ALS). Edaravone is a synthetic antioxidant that specifically targets oxidative damage interacting with lipid radicals in the cell. In ALS disease the multiple cell types are involved in devastating loss of motor neurons. Mutations and biochemical changes in various cell types jointly contribute to motor neuron death, disease onset, and disease progression. The overall mechanism of neurodegeneration in ALS is still not completely understood. Dying motor neurons have been reported to exhibit features of apoptosis. However, non-apoptotic features of dying motor neurons have also been reported such as ferroptosis. The role of Edaravone in the prevention of ferroptosis in parallel with other therapeutic approaches to ALS therapy is discussed.}, }
@article {pmid32076756, year = {2020}, author = {Brenner, D and Freischmidt, A and Ludolph, AC and Weishaupt, JH}, title = {[Gene-specific treatment approaches in amyotrophic lateral sclerosis in the present and future].}, journal = {Der Nervenarzt}, volume = {91}, number = {4}, pages = {287-293}, pmid = {32076756}, issn = {1433-0407}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; Animals ; C9orf72 Protein/genetics ; Disease Models, Animal ; *Genetic Therapy/trends ; Germany ; Mice ; Mutation ; Oligonucleotides, Antisense/therapeutic use ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is monogenic in up to 10% of cases. Various mutation types result in a loss of function, a gain of toxicity or a combination of both. Due to the continuous development of gene-specific approaches, the treatment of the various ALS forms is no longer a dream. Depending on the underlying mutation type and pathomechanism, different antisense oligonucleotide (ASO)-based or viral strategies are available. The SOD1 and C9ORF72 genes are the most frequently mutated ALS genes in Germany and their mutations most likely predominantly lead to a gain of toxicity. For both genes, specific ASOs were developed binding to the respective mRNAs and leading to their degradation and are now being tested in clinical trials after excellent efficacy in the related ALS mouse models, with promising interim results. For the sporadic form of ALS there are also gene-specific approaches that compensate pathomechanisms and are a promising therapeutic option. In this article, gene-specific therapeutic developments in ALS as well as possible pitfalls and challenges are discussed in detail.}, }
@article {pmid32065105, year = {2020}, author = {Estrada, JA and Contreras, I}, title = {Endocannabinoid Receptors in the CNS: Potential Drug Targets for the Prevention and Treatment of Neurologic and Psychiatric Disorders.}, journal = {Current neuropharmacology}, volume = {18}, number = {8}, pages = {769-787}, pmid = {32065105}, issn = {1875-6190}, mesh = {Animals ; Brain/drug effects/metabolism/physiopathology ; Cannabinoid Receptor Agonists/pharmacology ; Cannabinoid Receptor Antagonists/pharmacology ; Cannabinoid Receptor Modulators/physiology ; Endocannabinoids ; Humans ; Inflammation/metabolism ; Mental Disorders/*drug therapy/physiopathology/*prevention &amp; control ; Nervous System Diseases/*drug therapy/physiopathology/*prevention &amp; control ; Neuronal Plasticity/physiology ; Neurons/metabolism ; Receptors, Cannabinoid/*drug effects/*physiology ; }, abstract = {The endocannabinoid system participates in the regulation of CNS homeostasis and functions, including neurotransmission, cell signaling, inflammation and oxidative stress, as well as neuronal and glial cell proliferation, differentiation, migration and survival. Endocannabinoids are produced by multiple cell types within the CNS and their main receptors, CB1 and CB2, are expressed in both neurons and glia. Signaling through these receptors is implicated in the modulation of neuronal and glial alterations in neuroinflammatory, neurodegenerative and psychiatric conditions, including Alzheimer's, Parkinson's and Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, epilepsy, anxiety and depression. The therapeutic potential of endocannabinoid receptors in neurological disease has been hindered by unwelcome side effects of current drugs used to target them; however, due to their extensive expression within the CNS and their involvement in physiological and pathological process in nervous tissue, they are attractive targets for drug development. The present review highlights the potential applications of the endocannabinoid system for the prevention and treatment of neurologic and psychiatric disorders.}, }
@article {pmid32056896, year = {2020}, author = {Garakani, A and Buono, FD and Larkin, K and Goldberg, JF}, title = {Parsing the effects of comorbid adult ADHD and substance misuse on affective lability in bipolar disorder.}, journal = {Journal of affective disorders}, volume = {266}, number = {}, pages = {338-340}, doi = {10.1016/j.jad.2020.01.087}, pmid = {32056896}, issn = {1573-2517}, mesh = {Adult ; Affect ; *Attention Deficit Disorder with Hyperactivity/epidemiology ; *Bipolar Disorder/epidemiology ; Comorbidity ; Female ; Humans ; Male ; *Substance-Related Disorders/epidemiology ; }, abstract = {INTRODUCTION: Attentional deficits, substance misuse, and affective lability are all common features among adults with bipolar disorder, but little research has attempted to parse their inter-relationships.<br><br>METHODS: Using standardized scales and semi-structured interviews, we evaluated adult ADHD features and affective lability in 113 dually-diagnosed mood/substance use disorder inpatients (mean age 32.6 years, 63% female) drawn from one private suburban academically affiliated inpatient treatment program.<br><br>RESULTS: 24% of bipolar subjects had above-threshold ADHD screens. Affective Lability Scale (ALS) total and subscores were significantly associated with ADHD scores (univariate r's ranging from 0.38-0.63). ALS total and most subscale scores were significantly higher among bipolar subjects having above- (versus below-) threshold ADHD ratings. Linear regressions to predict affective lability revealed significant partial correlations between bipolar diagnoses and ALS total, depression, elation, and anger subscores, while controlling for significant effects from ADHD comorbidity. Inclusion of current substances of abuse did not change goodness-of-fit.<br><br>LIMITATIONS: Subjects were drawn from a single private institution, potentially limiting generalizability.<br><br>CONCLUSIONS: Comorbid ADHD appears to moderate multiple domains of affective lability in bipolar disorder inpatients, independent of current substance misuse.}, }
@article {pmid32052202, year = {2020}, author = {Patel, A and Lynch, F and Shepherd, SA}, title = {Newer Immunotherapies for the Treatment of Acute Neuromuscular Disease in the Critical Care Unit.}, journal = {Current treatment options in neurology}, volume = {22}, number = {3}, pages = {7}, pmid = {32052202}, issn = {1092-8480}, abstract = {OPINION STATEMENT: PURPOSE OF REVIEW: In this review, we discuss current treatment options for commonly encountered neuromuscular disorders in intensive care units. We will discuss epidemiology, pathophysiology, and acute and chronic treatment options for myasthenia gravis, Guillain-Barré syndrome, West Nile virus, Botulism, and amyotrophic lateral sclerosis.<br><br>RECENT FINDINGS: Eculizumab is the newest immunomodulator therapy approved by the Food and Drug Administration in treatment of myasthenia gravis, shown to improve long-term functional outcomes. Edaravone is the newest therapy in management of amyotrophic lateral sclerosis, shown to slow functional deterioration. Efgartigimod showed great promise in a phase 2 safety and efficacy trial in the treatment of stable generalized myasthenia gravis. Eculizumab was found to be safe in a small phase 2 trial for use in Guillain-Barr&#xe9; syndrome. Currently, therapies such as plasma exchange, intravenous immunoglobulins, and steroids remain the mainstay of treatment in the ICU for many neuromuscular disorders. While there are some newer immunotherapies available, few have been studied in the acute setting. However, with the advent of new immunotherapies and biologics, changes in these approaches may be on the horizon.}, }
@article {pmid32048886, year = {2021}, author = {Yao, RQ and Ren, C and Xia, ZF and Yao, YM}, title = {Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles.}, journal = {Autophagy}, volume = {17}, number = {2}, pages = {385-401}, pmid = {32048886}, issn = {1554-8635}, mesh = {Autophagy/*physiology ; Endoribonucleases/*metabolism ; Humans ; Inflammation/*metabolism ; Mitophagy/physiology ; Organelles/*metabolism ; Prohibitins ; Quality Control ; }, abstract = {The structural integrity and functional stability of organelles are prerequisites for the viability and responsiveness of cells. Dysfunction of multiple organelles is critically involved in the pathogenesis and progression of various diseases, such as chronic obstructive pulmonary disease, cardiovascular diseases, infection, and neurodegenerative diseases. In fact, those organelles synchronously present with evident structural derangement and aberrant function under exposure to different stimuli, which might accelerate the corruption of cells. Therefore, the quality control of multiple organelles is of great importance in maintaining the survival and function of cells and could be a potential therapeutic target for human diseases. Organelle-specific autophagy is one of the major subtypes of autophagy, selectively targeting different organelles for quality control. This type of autophagy includes mitophagy, pexophagy, reticulophagy (endoplasmic reticulum), ribophagy, lysophagy, and nucleophagy. These kinds of organelle-specific autophagy are reported to be beneficial for inflammatory disorders by eliminating damaged organelles and maintaining homeostasis. In this review, we summarized the recent findings and mechanisms covering different kinds of organelle-specific autophagy, as well as their involvement in various diseases, aiming to arouse concern about the significance of the quality control of multiple organelles in the treatment of inflammatory diseases.Abbreviations: ABCD3: ATP binding cassette subfamily D member 3; AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; ARIH1: ariadne RBR E3 ubiquitin protein ligase 1; ATF: activating transcription factor; ATG: autophagy related; ATM: ATM serine/threonine kinase; BCL2: BCL2 apoptosis regulator; BCL2L11/BIM: BCL2 like 11; BCL2L13: BCL2 like 13; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CANX: calnexin; CAT: catalase; CCPG1: cell cycle progression 1; CHDH: choline dehydrogenase; COPD: chronic obstructive pulmonary disease; CSE: cigarette smoke exposure; CTSD: cathepsin D; DDIT3/CHOP: DNA-damage inducible transcript 3; DISC1: DISC1 scaffold protein; DNM1L/DRP1: dynamin 1 like; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; EIF2S1/eIF2α: eukaryotic translation initiation factor 2 alpha kinase 3; EMD: emerin; EPAS1/HIF-2α: endothelial PAS domain protein 1; ER: endoplasmic reticulum; ERAD: ER-associated degradation; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FBXO27: F-box protein 27; FKBP8: FKBP prolyl isomerase 8; FTD: frontotemporal dementia; FUNDC1: FUN14 domain containing 1; G3BP1: G3BP stress granule assembly factor 1; GBA: glucocerebrosidase beta; HIF1A/HIF1: hypoxia inducible factor 1 subunit alpha; IMM: inner mitochondrial membrane; LCLAT1/ALCAT1: lysocardiolipin acyltransferase 1; LGALS3/Gal3: galectin 3; LIR: LC3-interacting region; LMNA: lamin A/C; LMNB1: lamin B1; LPS: lipopolysaccharide; MAPK8/JNK: mitogen-activated protein kinase 8; MAMs: mitochondria-associated membranes; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MFN1: mitofusin 1; MOD: multiple organelles dysfunction; MTPAP: mitochondrial poly(A) polymerase; MUL1: mitochondrial E3 ubiquitin protein ligase 1; NBR1: NBR1 autophagy cargo receptor; NLRP3: NLR family pyrin domain containing 3; NUFIP1: nuclear FMR1 interacting protein 1; OMM: outer mitochondrial membrane; OPTN: optineurin; PD: Parkinson disease; PARL: presenilin associated rhomboid like; PEX3: peroxisomal biogenesis factor 3; PGAM5: PGAM family member 5; PHB2: prohibitin 2; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RETREG1/FAM134B: reticulophagy regulator 1; RHOT1/MIRO1: ras homolog family member T1; RIPK3/RIP3: receptor interacting serine/threonine kinase 3; ROS: reactive oxygen species; RTN3: reticulon 3; SEC62: SEC62 homolog, preprotein translocation factor; SESN2: sestrin2; SIAH1: siah E3 ubiquitin protein ligase 1; SNCA: synuclein alpha; SNCAIP: synuclein alpha interacting protein; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; TICAM1/TRIF: toll-like receptor adaptor molecule 1; TIMM23: translocase of inner mitochondrial membrane 23; TNKS: tankyrase; TOMM: translocase of the outer mitochondrial membrane; TRIM: tripartite motif containing; UCP2: uncoupling protein 2; ULK1: unc-51 like autophagy activating kinase; UPR: unfolded protein response; USP10: ubiquitin specific peptidase 10; VCP/p97: valosin containing protein; VDAC: voltage dependent anion channels; XIAP: X-linked inhibitor of apoptosis; ZNHIT3: zinc finger HIT-type containing 3.}, }
@article {pmid32044139, year = {2020}, author = {Theoharides, TC and Tsilioni, I}, title = {Amyotrophic Lateral Sclerosis, Neuroinflammation, and Cromolyn.}, journal = {Clinical therapeutics}, volume = {42}, number = {3}, pages = {546-549}, doi = {10.1016/j.clinthera.2020.01.010}, pmid = {32044139}, issn = {1879-114X}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Cromolyn Sodium/*pharmacology ; Cytokines/metabolism ; Disease Models, Animal ; Humans ; Inflammation/*metabolism ; Mast Cells/drug effects/metabolism ; Mice ; Spinal Cord/drug effects/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an upper motor neuron disease with an unknown pathogenesis and no effective treatment. A recent study found that treatment of a mouse model of ALS (TgSOD1 mice) intraperitoneally with the mast-cell blocker disodium chromoglycate (cromolyn) had a small but significant effect on disease onset, improvement of neurologic symptoms, and decrease in the expression of proinflammatory cytokines and chemokines in the spinal cord and plasma of the TgSOD1 mice. Treatment with cromolyn also reduced degranulation of mast cells in the tibialis anterior muscle. There was no effect on survival. These findings are important in their support of the involvement of mast cells in the pathogenesis of ALS but are limited by the small effect of cromolyn, which was given intraperitoneally and is poorly absorbed after oral administration. Instead, use of the structurally related flavonoid tetramethoxyluteolin, which is a more potent inhibitor of proinflammatory cytokine release from mast cells and also inhibits activated microglia, may offer significant advantages over cromolyn. Development of mast cell inhibitors could benefit not only allergic disorders but also inflammatory and neurodegenerative disorders.}, }
@article {pmid32043626, year = {2020}, author = {Wobst, HJ and Mack, KL and Brown, DG and Brandon, NJ and Shorter, J}, title = {The clinical trial landscape in amyotrophic lateral sclerosis-Past, present, and future.}, journal = {Medicinal research reviews}, volume = {40}, number = {4}, pages = {1352-1384}, pmid = {32043626}, issn = {1098-1128}, support = {R21 NS090205/NS/NINDS NIH HHS/United States ; R21 AG061784/AG/NIA NIH HHS/United States ; R21 AG065854/AG/NIA NIH HHS/United States ; R21 NS102687/NS/NINDS NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Anti-Inflammatory Agents/chemistry/pharmacology/therapeutic use ; Autophagy/drug effects ; *Clinical Trials as Topic ; Drug Approval ; Humans ; Immunologic Factors/chemistry/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive loss of muscle function. It is the most common adult-onset form of motor neuron disease, affecting about 16 000 people in the United States alone. The average survival is about 3 years. Only two interventional drugs, the antiglutamatergic small-molecule riluzole and the more recent antioxidant edaravone, have been approved for the treatment of ALS to date. Therapeutic strategies under investigation in clinical trials cover a range of different modalities and targets, and more than 70 different drugs have been tested in the clinic to date. Here, we summarize and classify interventional therapeutic strategies based on their molecular targets and phenotypic effects. We also discuss possible reasons for the failure of clinical trials in ALS and highlight emerging preclinical strategies that could provide a breakthrough in the battle against this relentless disease.}, }
@article {pmid32035419, year = {2020}, author = {Vallée, A and Vallée, JN and Guillevin, R and Lecarpentier, Y}, title = {Riluzole: a therapeutic strategy in Alzheimer's disease by targeting the WNT/β-catenin pathway.}, journal = {Aging}, volume = {12}, number = {3}, pages = {3095-3113}, pmid = {32035419}, issn = {1945-4589}, mesh = {Alzheimer Disease/*drug therapy ; Gene Expression Regulation/drug effects ; Humans ; Neuroprotective Agents/therapeutic use ; Riluzole/*therapeutic use ; Wnt Proteins/genetics/*metabolism ; beta Catenin/genetics/*metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease, where the etiology remains unclear. AD is characterized by amyloid-(Aβ) protein aggregation and neurofibrillary plaques deposits. Oxidative stress and chronic inflammation have been suggested as causes of AD. Glutamatergic pathway dysregulation is also mainly associated with AD process. In AD, the canonical WNT/β-catenin pathway is downregulated. Downregulation of WNT/β-catenin, by activation of GSK-3β-induced Aβ, and inactivation of PI3K/Akt pathway involve oxidative stress in AD. The downregulation of the WNT/β-catenin pathway decreases the activity of EAAT2, the glutamate receptors, and leads to neuronal death. In AD, oxidative stress, neuroinflammation and glutamatergic pathway operate in a vicious circle driven by the dysregulation of the WNT/β-catenin pathway. Riluzole is a glutamate modulator and used as treatment in amyotrophic lateral sclerosis. Recent findings have highlighted its use in AD and its potential increase power on the WNT pathway. Nevertheless, the mechanism by which Riluzole can operate in AD remains unclear and should be better determine. The focus of our review is to highlight the potential action of Riluzole in AD by targeting the canonical WNT/β-catenin pathway to modulate glutamatergic pathway, oxidative stress and neuroinflammation.}, }
@article {pmid32032731, year = {2020}, author = {Mòdol-Caballero, G and Herrando-Grabulosa, M and García-Lareu, B and Solanes, N and Verdés, S and Osta, R and Francos-Quijorna, I and López-Vales, R and Calvo, AC and Bosch, A and Navarro, X}, title = {Gene therapy for overexpressing Neuregulin 1 type I in skeletal muscles promotes functional improvement in the SOD1[G93A] ALS mice.}, journal = {Neurobiology of disease}, volume = {137}, number = {}, pages = {104793}, doi = {10.1016/j.nbd.2020.104793}, pmid = {32032731}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*therapy ; Animals ; Disease Models, Animal ; *Genetic Therapy ; Mice, Transgenic ; Motor Neurons/*metabolism ; Muscle, Skeletal/metabolism ; Neuregulin-1/*genetics ; Neuroglia/metabolism ; Neuromuscular Junction/metabolism ; Spinal Cord/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motoneurons (MNs), with no effective treatment currently available. The molecular mechanisms that are involved in MN death are complex and not fully understood, with partial contributions of surrounding glial cells and skeletal muscle to the disease. Neuregulin 1 (NRG1) is a trophic factor highly expressed in MNs and neuromuscular junctions. Recent studies have suggested a crucial role of the isoform I (NRG1-I) in the collateral reinnervation process in skeletal muscle, and NRG1-III in the preservation of MNs in the spinal cord, opening a window for developing novel therapies for neuromuscular diseases like ALS. In this study, we overexpressed NRG1-I widely in the skeletal muscles of the SOD1[G93A] transgenic mouse. The results show that NRG1 gene therapy activated the survival pathways in muscle and spinal cord, increasing the number of surviving MNs and neuromuscular junctions and reducing the astroglial reactivity in the spinal cord of the treated SOD1[G93A] mice. Furthermore, NRG1-I overexpression preserved motor function and delayed the onset of clinical disease. In summary, our data indicates that NRG1 plays an important role on MN survival and muscle innervation in ALS, and that viral-mediated overexpression of NRG1 isoforms may be considered as a promising approach for ALS treatment.}, }
@article {pmid32030995, year = {2021}, author = {Yeung, AWK and Tzvetkov, NT and Georgieva, MG and Ognyanov, IV and Kordos, K and Jóźwik, A and Kühl, T and Perry, G and Petralia, MC and Mazzon, E and Atanasov, AG}, title = {Reactive Oxygen Species and Their Impact in Neurodegenerative Diseases: Literature Landscape Analysis.}, journal = {Antioxidants &amp; redox signaling}, volume = {34}, number = {5}, pages = {402-420}, doi = {10.1089/ars.2019.7952}, pmid = {32030995}, issn = {1557-7716}, mesh = {Animals ; *Disease Susceptibility ; Humans ; Medicine in Literature ; Neurodegenerative Diseases/diagnosis/*etiology/*metabolism/therapy ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; }, abstract = {Significance: The excessive production of reactive oxygen species (ROS) has been linked to neurodegenerative diseases (NDs), and, therefore, many scientific works were published on the impact of ROS on the development of prevalent NDs, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Since quantitative and qualitative bibliometric analyses in this research area have not yet been done, the aim of this work is to explore the scientific literature implying ROS in NDs and to identify the major contributors, mainstream research themes, and topics on the rise. Recent Advances: Overall, 22,885 publications were identified and analyzed within the Web of Science (WoS) Core Collection electronic database (Clarivate Analytics, Philadelphia, PA). Most of the manuscripts were published in the 21st century. The publications were mainly related to the WoS categories Neurosciences and Biochemistry molecular biology. The United States is the major contributor, harboring the most productive authors and institutions. China, South Korea, and India have emerged as upcoming major contributors in the 2010s. Two most productive journals were Journal of Neurochemistry and Free Radical Biology and Medicine. Critical Issues: AD, PD, and amyotrophic lateral sclerosis were much more investigated than multiple sclerosis and Huntington's disease. Vitamin E and curcumin were frequently mentioned as potential antioxidant therapeutics, but their efficacy in treating NDs requires more clinical studies, since the existing evidence was mainly from in vitro experiments and in vivo animal studies. Future Directions: Mitochondrial dysfunction, autophagy, and nuclear factor erythroid 2-related factor 2 were among the author keywords with rising prevalence. Further research in these directions should advance our understanding of the mechanism and treatment of NDs. Antioxid. Redox Signal. 34, 402-420.}, }
@article {pmid32027997, year = {2020}, author = {Lee, D and Shin, Y and Jang, J and Park, Y and Ahn, J and Jeong, S and Shin, SS and Yoon, M}, title = {The herbal extract ALS-L1023 from Melissa officinalis alleviates visceral obesity and insulin resistance in obese female C57BL/6J mice.}, journal = {Journal of ethnopharmacology}, volume = {253}, number = {}, pages = {112646}, doi = {10.1016/j.jep.2020.112646}, pmid = {32027997}, issn = {1872-7573}, mesh = {Adipocytes/drug effects/pathology ; Animals ; Anti-Obesity Agents/*therapeutic use ; Blood Glucose/analysis ; Fatty Acids, Nonesterified/blood ; Female ; Fibrosis ; Insulin Resistance ; *Melissa ; Mice, Inbred C57BL ; Obesity, Abdominal/blood/*drug therapy/pathology ; Pancreas/drug effects/pathology ; Plant Extracts/*therapeutic use ; Triglycerides/blood ; }, abstract = {Melissa officinalis L. (Labiatae; lemon balm) has traditionally been used as a medicinal herb to treat stress, anxiety, and insomnia. Current reports suggest that not only chronic stress stimulates angiogenesis, but angiogenesis also regulates adipogenesis and obesity. Because the herbal extract ALS-L1023 from Melissa officinalis inhibits angiogenesis, we hypothesized that ALS-L1023 could suppress visceral obesity and insulin resistance in obese female C57BL/6J mice, a mouse model of obese premenopausal women.<br><br>MATERIALS AND METHODS: The mice were grouped and fed for 16 weeks as follows: 1) low-fat diet (LFD), 2) high-fat diet (HFD), or 3) HFD supplemented with 0.4 or 0.8% ALS-L1023. Variables and determinants of visceral obesity, insulin resistance, and pancreatic dysfunction were then assessed via blood analysis, histology, immunohistochemistry, and real-time polymerase chain reaction.<br><br>RESULTS: ALS-L1023 decreased weight gain, visceral adipocyte size, and serum lipid levels in HFD-fed obese mice. ALS-L1023 also normalized hyperglycemia and hyperinsulinemia and concomitantly reduced blood glucose levels during oral glucose tolerance tests. The pancreatic islet size and insulin-positive &#x3b2;-cell area were significantly reduced in ALS-L1023-treated mice compared with untreated obese controls, reaching a level similar to that of LFD-fed lean mice. ALS-L1023 suppressed pancreatic lipid accumulation, infiltration of inflammatory cells, and collagen levels. ALS-L1023 treatment altered the pancreatic expression of genes involved in steatosis, inflammation, and fibrosis.<br><br>CONCLUSIONS: Our findings indicate that the herbal extract ALS-L1023 from Melissa officinalis not only inhibits visceral obesity, but also attenuates the increased fasting blood glucose, impaired glucose tolerance, and pancreatic dysfunction seen in female obese mice. These results suggest that ALS-L1023 may be effective in the prevention of visceral obesity and insulin resistance in obese premenopausal women.}, }
@article {pmid32022482, year = {2020}, author = {Carreau, C and Lenglet, T and Mosnier, I and Lahlou, G and Fargeot, G and Weiss, N and Demeret, S and Salachas, F and Veauville-Merllié, A and Acquaviva, C and Nadjar, Y}, title = {A juvenile ALS-like phenotype dramatically improved after high-dose riboflavin treatment.}, journal = {Annals of clinical and translational neurology}, volume = {7}, number = {2}, pages = {250-253}, pmid = {32022482}, issn = {2328-9503}, mesh = {Adolescent ; Age of Onset ; Amyotrophic Lateral Sclerosis/drug therapy ; Bulbar Palsy, Progressive/drug therapy ; Female ; Hearing Loss, Sensorineural/drug therapy ; Humans ; Membrane Transport Proteins/*deficiency ; Motor Neuron Disease/*drug therapy ; Riboflavin/administration &amp; dosage/*pharmacology ; Vitamin B Complex/administration &amp; dosage/*pharmacology ; }, abstract = {Riboflavin transporter deficiency (RTD) was recently characterized as a cause of genetic recessive childhood-onset motor neuron disease (MND) with hearing loss, formerly described as Brown-Vialetto-Van-Lear syndrome. We describe a 18-year-old woman with probable RTD mimicking juvenile Amyotrophic Lateral Sclerosis (ALS) who presented with an inaugural respiratory failure and moderate distal four limbs weakness. Only one heterozygous SLC52A3 mutation was detected, but presence of a sub-clinical auditory neuropathy and dramatic improvement under high dose riboflavin argued for a RTD. As RTD probably has a larger phenotypic spectrum than expected, a high dose riboflavin trial should be discussed in young-onset MND.}, }
@article {pmid32008542, year = {2019}, author = {Sahu, M and Vishwal, S and Usha Srivalli, S and Nagwani, NK and Verma, S and Shukla, S}, title = {Applying Auto-Regressive Model's Yule-Walker Approach to Amyotrophic Lateral Sclerosis (ALS) patients' Data.}, journal = {Current medical imaging reviews}, volume = {15}, number = {8}, pages = {749-760}, doi = {10.2174/1573405614666180322143503}, pmid = {32008542}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Electroencephalography/*methods ; Female ; Humans ; Male ; *Models, Statistical ; }, abstract = {OBJECTIVE: The purpose of this study is to identifying time series analysis and mathematical model fitting on electroencephalography channels that are placed on Amyotrophic Lateral Sclerosis (ALS) patients with P300 based brain-computer interface (BCI).<br><br>METHODS: Amyotrophic Lateral Sclerosis (ALS) or motor neuron diseases are a rapidly progressing neurological disease that attacks and kills neurons responsible for controlling voluntary muscles. There is no cure and treatment effective to reverse, to halt the disease progression. A Brain- Computer Interface enables disable person to communicate &amp; interact with each other and with the environment. To bypass the important motor difficulties present in ALS patient, BCI is useful. An input for BCI system is patient's brain signals and these signals are converted into external operations, for brain signals detection, Electroencephalography (EEG) is normally used. P300 based BCI is used to record the reading of EEG brain signals with the help of non-invasive placement of channels. In EEG, channel analysis Autoregressive (AR) model is a widely used. In the present study, Yule-Walker approach of AR model has been used for channel data fitting. Model fitting as a form of digitization is majorly required for good understanding of the dataset, and also for data prediction.<br><br>RESULTS: Fourth order of the mathematical curve for this dataset is selected. The reason is the high accuracy obtained in the 4th order of Autoregressive model (97.51&#xb1;0.64).<br><br>CONCLUSION: In proposed Auto Regressive (AR) model has been used for Amyotrophic Lateral Sclerosis (ALS) patient data analysis. The 4th order of Yule Walker auto-regressive model is giving best fitting on this problem.}, }
@article {pmid32006533, year = {2020}, author = {Pennuto, M and Pandey, UB and Polanco, MJ}, title = {Insulin-like growth factor 1 signaling in motor neuron and polyglutamine diseases: From molecular pathogenesis to therapeutic perspectives.}, journal = {Frontiers in neuroendocrinology}, volume = {57}, number = {}, pages = {100821}, doi = {10.1016/j.yfrne.2020.100821}, pmid = {32006533}, issn = {1095-6808}, support = {R21 NS111768/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/physiopathology ; Animals ; Glutamine/genetics ; Humans ; Insulin-Like Growth Factor I/genetics/*physiology ; MAP Kinase Signaling System/physiology ; Motor Neurons/*metabolism ; Muscular Atrophy, Spinal/physiopathology ; Neurodegenerative Diseases/drug therapy/*physiopathology ; *Peptides ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/*physiology ; ras Proteins/metabolism ; }, abstract = {The pleiotropic peptide insulin-like growth factor 1 (IGF-I) regulates human body homeostasis and cell growth. IGF-I activates two major signaling pathways, namely phosphoinositide-3-kinase (PI3K)/protein kinase B (PKB/Akt) and Ras/extracellular signal-regulated kinase (ERK), which contribute to brain development, metabolism and function as well as to neuronal maintenance and survival. In this review, we discuss the general and tissue-specific effects of the IGF-I pathways. In addition, we present a comprehensive overview examining the role of IGF-I in neurodegenerative diseases, such as spinal and muscular atrophy, amyotrophic lateral sclerosis, and polyglutamine diseases. In each disease, we analyze the disturbances of the IGF-I pathway, the modification of the disease protein by IGF-I signaling, and the therapeutic strategies based on the use of IGF-I developed to date. Lastly, we highlight present and future considerations in the use of IGF-I for the treatment of these disorders.}, }
@article {pmid31994601, year = {2020}, author = {Zhao, Z and Liu, H and Guo, D}, title = {Aliskiren attenuates cardiac dysfunction by modulation of the mTOR and apoptosis pathways.}, journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas}, volume = {53}, number = {2}, pages = {e8793}, pmid = {31994601}, issn = {1414-431X}, mesh = {Amides/*administration &amp; dosage ; Angiotensin II/pharmacology ; Animals ; Apoptosis/*drug effects ; Blotting, Western ; Cardiomegaly/chemically induced/metabolism/*prevention &amp; control ; Disease Models, Animal ; Fibrosis/chemically induced/prevention &amp; control ; Flow Cytometry ; Fumarates/*administration &amp; dosage ; Isoproterenol/pharmacology ; Male ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/drug effects/*metabolism ; }, abstract = {Aliskiren (ALS) is well known for its antihypertensive properties. However, the potential underlying the molecular mechanism and the anti-hypertrophic effect of ALS have not yet been fully elucidated. The aim of the present study was to investigate the role of ALS in mammalian target of rapamycin (mTOR) and apoptosis signaling using in vivo and in vitro models of cardiac hypertrophy. A rat model of cardiac hypertrophy was induced by isoproterenol treatment (5 mg·kg-1·day-1) for 4 weeks, with or without ALS treatment at 20 mg·kg-1·day-1. The expression of hypertrophic, fibrotic, and apoptotic markers was determined by RT-qPCR. The protein expression of apoptotic markers mTOR and p-mTOR was assessed by western blot analysis. The proliferation of H9C2 cells was monitored using the MTS assay. Cell apoptosis was analyzed using flow cytometry. In vivo, isoproterenol-treated rats exhibited worse cardiac function, whereas ALS treatment reversed these dysfunctions, which were associated with changes in p-mTOR, Bcl-2, Bax, and cleaved caspase-3 expression, as well as the number of apoptotic cells. In vitro, H9C2 cardiomyocyte viability was significantly inhibited and cardiac hypertrophy was induced by Ang II administration, but ALS reversed Ang II-induced H9C2 cardiomyocyte hypertrophy and death. Furthermore, Ang II triggered the activation of the mTOR and apoptosis pathways in hypertrophic cardiomyocytes that were inhibited by ALS treatment. These results indicated that ALS alleviated cardiac hypertrophy through inhibition of the mTOR and apoptosis pathways in cardiomyocytes.}, }
@article {pmid31993129, year = {2020}, author = {Caplliure-Llopis, J and Peralta-Chamba, T and Carrera-Juliá, S and Cuerda-Ballester, M and Drehmer-Rieger, E and López-Rodriguez, MM and de la Rubia Ortí, JE}, title = {Therapeutic alternative of the ketogenic Mediterranean diet to improve mitochondrial activity in Amyotrophic Lateral Sclerosis (ALS): A Comprehensive Review.}, journal = {Food science &amp; nutrition}, volume = {8}, number = {1}, pages = {23-35}, pmid = {31993129}, issn = {2048-7177}, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease which is pathogenically based on the mitochondrial alteration of motor neurons, causing progressive neuron death. While ALS is characterized by enormous oxidative stress, the Mediterranean diet has been seen to have high antioxidant power. Therefore, the aim of this study is to determine how the Mediterranean diet can improve mitochondrial activity, establishing the specific nutrients and, in addition, observing the pathogenic mechanisms related to the disease that would achieve this improvement. To this end, a comprehensive review of the literature was performed using PubMed. KBs have been observed to have a neuroprotective effect to improve energy balance, increasing survival and the number of motor neurons. This ketogenesis can be achieved after following a Mediterranean diet which is associated with great benefits in other neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and ALS. These benefits are due to the high antioxidant power especially based on polyphenols contained mainly in olive oil, wine, nuts, or berries. In short, KBs could be considered as a promising option to treat ALS, representing an alternative source to glucose in motor neurons by providing neuroprotection. In addition, treatment results can be improved as ketogenesis can be achieved (increase in KBs) by following a Mediterranean diet, thanks to the high antioxidant properties which, at the same time, would improve the high oxidative stress that characterizes the disease.}, }
@article {pmid31991801, year = {2020}, author = {Božič, T and Zalar, M and Rogelj, B and Plavec, J and Šket, P}, title = {Structural Diversity of Sense and Antisense RNA Hexanucleotide Repeats Associated with ALS and FTLD.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {3}, pages = {}, pmid = {31991801}, issn = {1420-3049}, support = {P1-0242//Javna Agencija za Raziskovalno Dejavnost RS/ ; P4-0127//Javna Agencija za Raziskovalno Dejavnost RS/ ; J1-7108//Javna Agencija za Raziskovalno Dejavnost RS/ ; J1-1704//Javna Agencija za Raziskovalno Dejavnost RS/ ; J3-9263//Javna Agencija za Raziskovalno Dejavnost RS/ ; }, mesh = {Amyotrophic Lateral Sclerosis/etiology ; Base Pairing ; C9orf72 Protein/chemistry/genetics ; Disease Susceptibility ; Frontotemporal Dementia/etiology ; Humans ; Hydrogen-Ion Concentration ; Magnetic Resonance Spectroscopy ; *Nucleic Acid Conformation ; Oligonucleotides/*chemistry/genetics ; Oligonucleotides, Antisense/*chemistry/genetics ; RNA, Antisense/*chemistry/genetics ; *Repetitive Sequences, Nucleic Acid ; Spectrum Analysis ; Structure-Activity Relationship ; Temperature ; }, abstract = {The hexanucleotide expansion GGGGCC located in C9orf72 gene represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Since the discovery one of the non-exclusive mechanisms of expanded hexanucleotide G4C2 repeats involved in ALS and FTLD is RNA toxicity, which involves accumulation of pathological sense and antisense RNA transcripts. Formed RNA foci sequester RNA-binding proteins, causing their mislocalization and, thus, diminishing their biological function. Therefore, structures adopted by pathological RNA transcripts could have a key role in pathogenesis of ALS and FTLD. Utilizing NMR spectroscopy and complementary methods, we examined structures adopted by both guanine-rich sense and cytosine-rich antisense RNA oligonucleotides with four hexanucleotide repeats. While both oligonucleotides tend to form dimers and hairpins, the equilibrium of these structures differs with antisense oligonucleotide being more sensitive to changes in pH and sense oligonucleotide to temperature. In the presence of K[+] ions, guanine-rich sense RNA oligonucleotide also adopts secondary structures called G-quadruplexes. Here, we also observed, for the first time, that antisense RNA oligonucleotide forms i-motifs under specific conditions. Moreover, simultaneous presence of sense and antisense RNA oligonucleotides promotes formation of heterodimer. Studied structural diversity of sense and antisense RNA transcripts not only further depicts the complex nature of neurodegenerative diseases but also reveals potential targets for drug design in treatment of ALS and FTLD.}, }
@article {pmid31991108, year = {2020}, author = {Lim, CKW and Gapinske, M and Brooks, AK and Woods, WS and Powell, JE and Zeballos C, MA and Winter, J and Perez-Pinera, P and Gaj, T}, title = {Treatment of a Mouse Model of ALS by In Vivo Base Editing.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {28}, number = {4}, pages = {1177-1189}, pmid = {31991108}, issn = {1525-0024}, support = {R01 GM127497/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; CRISPR-Associated Protein 9/*metabolism ; Codon, Nonsense ; Dependovirus/*genetics ; Disease Models, Animal ; Gene Editing ; Genetic Vectors/administration &amp; dosage ; HEK293 Cells ; Humans ; Injections, Spinal ; Inteins ; Male ; Mice ; Mice, Transgenic ; Streptococcus pyogenes/enzymology ; Superoxide Dismutase-1/*genetics ; Trans-Splicing ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal disorder that can be caused by mutations in the superoxide dismutase 1 (SOD1) gene. Although ALS is currently incurable, CRISPR base editors hold the potential to treat the disease through their ability to create nonsense mutations that can permanently disable the expression of the mutant SOD1 gene. However, the restrictive carrying capacity of adeno-associated virus (AAV) vectors has limited their therapeutic application. In this study, we establish an intein-mediated trans-splicing system that enables in vivo delivery of cytidine base editors (CBEs) consisting of the widely used Cas9 protein from Streptococcus pyogenes. We show that intrathecal injection of dual AAV particles encoding a split-intein CBE engineered to trans-splice and introduce a nonsense-coding substitution into a mutant SOD1 gene prolonged survival and markedly slowed the progression of disease in the G93A-SOD1 mouse model of ALS. Adult animals treated by this split-intein CRISPR base editor had a reduced rate of muscle atrophy, decreased muscle denervation, improved neuromuscular function, and up to 40% fewer SOD1 immunoreactive inclusions at end-stage mice compared to control mice. This work expands the capabilities of single-base editors and demonstrates their potential for gene therapy.}, }
@article {pmid31982574, year = {2020}, author = {Teixeira, MI and Lopes, CM and Amaral, MH and Costa, PC}, title = {Current insights on lipid nanocarrier-assisted drug delivery in the treatment of neurodegenerative diseases.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {149}, number = {}, pages = {192-217}, doi = {10.1016/j.ejpb.2020.01.005}, pmid = {31982574}, issn = {1873-3441}, mesh = {Animals ; Blood-Brain Barrier/metabolism ; Brain/metabolism/physiopathology ; Drug Carriers/chemistry ; *Drug Delivery Systems ; Humans ; Lipids/chemistry ; *Nanoparticles ; Nanotechnology ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Tissue Distribution ; }, abstract = {The central nervous system (CNS) is vulnerable to pathologic processes that lead to the development of neurodegenerative disorders like Alzheimer's, Parkinson's and Huntington's diseases, Multiple sclerosis or Amyotrophic lateral sclerosis. These are chronic and progressive pathologies characterized by the loss of neurons and the formation of misfolded proteins. Additionally, neurodegenerative diseases are accompanied by a structural and functional dysfunction of the blood-brain barrier (BBB). Although serving as a protection for the CNS, the existence of physiological barriers, especially the BBB, limits the access of several therapeutic agents to the brain, constituting a major hindrance in neurotherapeutics advancement. In this regard, nanotechnology-based approaches have arisen as a promising strategy to not only improve drug targeting to the brain, but also to increase bioavailability. Lipid nanocarriers such as liposomes, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), microemulsions and nanoemulsions, have already proven their potential for enhancing brain transport, crossing more easily into the CNS and allowing the administration of medicines that could benefit the treatment of neurological pathologies. Given the socioeconomic impact of such conditions and the advent of nanotechnology that inevitably leads to more effective and superior therapeutics for their management, it is imperative to constantly update on the current knowledge of these topics. Herein, we provide insight on the BBB and the pathophysiology of the main neurodegenerative disorders. Moreover, this review seeks to highlight the several approaches that can be used to improve the delivery of therapeutic agents to the CNS, while also offering an extensive overview of the latest efforts regarding the use of lipid-based nanocarriers in the management of neurodegenerative diseases.}, }
@article {pmid31981074, year = {2020}, author = {Thapa, S and Abdelaziz, DH and Abdulrahman, BA and Schatzl, HM}, title = {Sephin1 Reduces Prion Infection in Prion-Infected Cells and Animal Model.}, journal = {Molecular neurobiology}, volume = {57}, number = {5}, pages = {2206-2219}, pmid = {31981074}, issn = {1559-1182}, support = {201600010//Alberta Innovates/Alberta Prion Research Institute/ ; PhD Fellowship//Alberta Innovates - Health Solutions/ ; PDF Fellowship//Alberta Innovates - Health Solutions/ ; PhD Fellowship//University of Calgary Eyes High/ ; PhD Fellowship//Killam Trusts/ ; }, mesh = {Animals ; Cell Line, Tumor ; Drug Evaluation, Preclinical ; Drug Synergism ; Endoplasmic Reticulum Stress/drug effects ; Eukaryotic Initiation Factor-2/metabolism ; Guanabenz/administration &amp; dosage/*analogs &amp; derivatives/pharmacology/therapeutic use ; Metformin/administration &amp; dosage/pharmacology/therapeutic use ; Mice ; Neuroblastoma/pathology ; Neuroprotective Agents/administration &amp; dosage/pharmacology/therapeutic use ; Phosphorylation/drug effects ; PrPC Proteins/*metabolism ; PrPSc Proteins/*metabolism ; Prions/*drug effects ; Protein Phosphatase 1/antagonists &amp; inhibitors ; Protein Processing, Post-Translational/drug effects ; Protein Serine-Threonine Kinases/metabolism ; Scrapie/*drug therapy/pathology ; Unfolded Protein Response/*drug effects ; }, abstract = {Prion diseases are fatal infectious neurodegenerative disorders in human and animals caused by misfolding of the cellular prion protein (PrP[C]) into the infectious isoform PrP[Sc]. These diseases have the potential to transmit within or between species, and no cure is available to date. Targeting the unfolded protein response (UPR) as an anti-prion therapeutic approach has been widely reported for prion diseases. Here, we describe the anti-prion effect of the chemical compound Sephin1 which has been shown to protect in mouse models of protein misfolding diseases including amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) by selectively inhibiting the stress-induced regulatory subunit of protein phosphatase 1, thus prolonging eIF2α phosphorylation. We show here that Sephin1 dose and time dependently reduced PrP[Sc] in different neuronal cell lines which were persistently infected with various prion strains. In addition, prion seeding activity was reduced in Sephin1-treated cells. Importantly, we found that Sephin1 significantly overcame the endoplasmic reticulum (ER) stress induced in treated cells, as measured by lower expression of stress-induced aberrant prion protein. In a mouse model of prion infection, intraperitoneal treatment with Sephin1 significantly prolonged survival of prion-infected mice. When combining Sephin1 with the neuroprotective drug metformin, the survival of prion-infected mice was also prolonged. These results suggest that Sephin1 could be a potential anti-prion drug selectively targeting one component of the UPR pathway.}, }
@article {pmid31963681, year = {2020}, author = {Filipi, T and Hermanova, Z and Tureckova, J and Vanatko, O and Anderova, AM}, title = {Glial Cells-The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment.}, journal = {Journal of clinical medicine}, volume = {9}, number = {1}, pages = {}, pmid = {31963681}, issn = {2077-0383}, support = {19-02046S//Grantov&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, which is characterized by the degeneration of motor neurons in the motor cortex and the spinal cord and subsequently by muscle atrophy. To date, numerous gene mutations have been linked to both sporadic and familial ALS, but the effort of many experimental groups to develop a suitable therapy has not, as of yet, proven successful. The original focus was on the degenerating motor neurons, when researchers tried to understand the pathological mechanisms that cause their slow death. However, it was soon discovered that ALS is a complicated and diverse pathology, where not only neurons, but also other cell types, play a crucial role via the so-called non-cell autonomous effect, which strongly deteriorates neuronal conditions. Subsequently, variable glia-based in vitro and in vivo models of ALS were established and used for brand-new experimental and clinical approaches. Such a shift towards glia soon bore its fruit in the form of several clinical studies, which more or less successfully tried to ward the unfavourable prognosis of ALS progression off. In this review, we aimed to summarize current knowledge regarding the involvement of each glial cell type in the progression of ALS, currently available treatments, and to provide an overview of diverse clinical trials covering pharmacological approaches, gene, and cell therapies.}, }
@article {pmid31954073, year = {2020}, author = {Lewis, KEA and Bennett, W and Blizzard, CL and West, AK and Chung, RS and Chuah, MI}, title = {The influence of metallothionein treatment and treadmill running exercise on disease onset and survival in SOD1[G93A] amyotrophic lateral sclerosis mice.}, journal = {The European journal of neuroscience}, volume = {52}, number = {4}, pages = {3223-3241}, doi = {10.1111/ejn.14682}, pmid = {31954073}, issn = {1460-9568}, support = {//Motor Neurone Disease Research Institute of Australia/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Disease Models, Animal ; Female ; Metallothionein/*therapeutic use ; Mice ; Mice, Transgenic ; *Physical Conditioning, Animal ; Quality of Life ; *Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterised by the degeneration of motor neurons innervating skeletal muscle. The mechanisms underlying neurodegeneration in ALS are not yet fully elucidated, and with current therapeutics only able to extend lifespan by a matter of months there is a clear need for novel therapies to increase lifespan and patient quality of life. Here, we evaluated whether moderate-intensity treadmill exercise and/or treatment with metallothionein-2 (MT2), a neuroprotective protein, could improve survival, behavioural or neuropathological outcomes in SOD1[G93A] familial ALS mice. Six-week-old female SOD1[G93A] mice were allocated to one of four treatment groups: MT2 injection, i.m.; moderate treadmill exercise; neither MT2 nor exercise; or both MT2 and exercise. MT2-treated mice survived around 3% longer than vehicle-treated mice, with this mild effect reaching statistical significance in Cox proportional hazards analysis once adjusted for potential confounders. Mixed model body weight trajectories over time indicated that MT2-treated mice, with or without exercise, reached maximum body weight at a later age, suggesting a delay in disease onset of around 4% compared to saline-treated mice. Exercise alone did not significantly increase survival or delay disease onset, and neither exercise nor MT2 substantially ameliorated gait abnormalities or muscle strength loss. We conclude that neither exercise nor MT2 treatment was detrimental in female SOD1[G93A] mice, and further study could determine whether the mild effect of peripheral MT2 administration on disease onset and survival could be improved via direct administration of MT2 to the central nervous system.}, }
@article {pmid31948361, year = {2021}, author = {Pathak, S and Tripathi, S and Deori, N and Ahmad, B and Verma, H and Lokhande, R and Nagotu, S and Kale, A}, title = {Effect of tetracycline family of antibiotics on actin aggregation, resulting in the formation of Hirano bodies responsible for neuropathological disorders.}, journal = {Journal of biomolecular structure &amp; dynamics}, volume = {39}, number = {1}, pages = {236-253}, doi = {10.1080/07391102.2020.1717629}, pmid = {31948361}, issn = {1538-0254}, mesh = {*Actins ; *Anti-Bacterial Agents/pharmacology ; Humans ; Inclusion Bodies/metabolism ; Kinetics ; Tetracycline ; }, abstract = {Actin, an ATPase superfamily protein, regulates some vital biological functions like cell locomotion, cytokinesis, synaptic plasticity and cell signaling in higher eukaryotes, and is dependent on the dynamics of actin polymerization process. Impaired regulation of actin polymerization has been implicated in the formation and deposition of rod-like paracrystalline structures called as Hirano bodies in neuronal cells of patients suffering from Alzheimer's disease, Pick's disease, Guam amyotrophic lateral sclerosis and parkinsonism-dementia complex. Aggregation of actin forming amorphous deposition in the brain cells is also associated with chronic alcoholism and aging of the neurons. In the current article, we propose the breaking of the highly amorphous and dysregulated actin aggregates using generic compounds like tetracycline, oxytetracycline, doxycycline and minocycline which are used as antibiotics against tuberculosis and infection caused due to various Gram-negative bacteria. We have investigated the effect and affinity of binding of these four compounds to that of actin aggregates using 90° light scattering, size exclusion chromatography, dynamic light scattering, circular dichroism, scanning electron microscopy, transmission electron microscopy imaging and kinetic analysis. The isothermal calorimetric measurements showed that the binding constant for the cycline family molecules used in this study range from 9.8 E4 M[-1] to 1.3 E4 M[-1]. To understand the in vivo effect, we also studied the effect of these drugs on Saccharomyces cerevisiae Δend3 mutant cells. Our data suggest that these generic compounds can plausibly be used for the treatment of various neurodegenerative diseases occurring due to Hirano body formation in brain cells.Communicated by Ramaswamy H. Sarma.}, }
@article {pmid31944180, year = {2020}, author = {Vagnozzi, AN and Garg, K and Dewitz, C and Moore, MT and Cregg, JM and Jeannotte, L and Zampieri, N and Landmesser, LT and Philippidou, P}, title = {Phrenic-specific transcriptional programs shape respiratory motor output.}, journal = {eLife}, volume = {9}, number = {}, pages = {}, pmid = {31944180}, issn = {2050-084X}, support = {F30HD096788//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R00 NS085037/NS/NINDS NIH HHS/United States ; R01NS114510/NS/NINDS NIH HHS/United States ; R00NS085037/NS/NINDS NIH HHS/United States ; R01 NS114510/NS/NINDS NIH HHS/United States ; T32GM007250/GM/NIGMS NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; P30 CA043703/CA/NCI NIH HHS/United States ; F30 HD096788/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; *Genes, Homeobox ; Mice ; Motor Neurons/*physiology ; Phrenic Nerve/*physiology ; Respiration/*genetics ; *Transcription, Genetic ; }, abstract = {The precise pattern of motor neuron (MN) activation is essential for the execution of motor actions; however, the molecular mechanisms that give rise to specific patterns of MN activity are largely unknown. Phrenic MNs integrate multiple inputs to mediate inspiratory activity during breathing and are constrained to fire in a pattern that drives efficient diaphragm contraction. We show that Hox5 transcription factors shape phrenic MN output by connecting phrenic MNs to inhibitory premotor neurons. Hox5 genes establish phrenic MN organization and dendritic topography through the regulation of phrenic-specific cell adhesion programs. In the absence of Hox5 genes, phrenic MN firing becomes asynchronous and erratic due to loss of phrenic MN inhibition. Strikingly, mice lacking Hox5 genes in MNs exhibit abnormal respiratory behavior throughout their lifetime. Our findings support a model where MN-intrinsic transcriptional programs shape the pattern of motor output by orchestrating distinct aspects of MN connectivity.}, }
@article {pmid31936257, year = {2020}, author = {Rivas-Ramírez, P and Reboreda, A and Rueda-Ruzafa, L and Herrera-Pérez, S and Lamas, JA}, title = {PIP2 Mediated Inhibition of TREK Potassium Currents by Bradykinin in Mouse Sympathetic Neurons.}, journal = {International journal of molecular sciences}, volume = {21}, number = {2}, pages = {}, pmid = {31936257}, issn = {1422-0067}, support = {CONSOLIDER CSD2008-00005, BFU2014-58999-P//Ministerio de Ciencia e Innovaci&#xf3;n/ ; INBIOMED CN2012/273, INB1-131H-2//Secretaria Xeral de Investigaci&#xf3;n e Desenvolvemento, Xunta de Galicia/ ; }, mesh = {Action Potentials/drug effects ; Animals ; Bradykinin/administration &amp; dosage/analogs &amp; derivatives/genetics/*metabolism/pharmacology ; Cells, Cultured ; Humans ; Mice ; Muscarinic Agonists/pharmacology ; Neurons/*drug effects/pathology ; Patch-Clamp Techniques ; Phosphatidylinositol 4,5-Diphosphate/genetics/*metabolism ; Potassium/metabolism ; Potassium Channels, Tandem Pore Domain/*genetics/metabolism ; Receptors, Muscarinic/genetics ; Riluzole/pharmacology ; Sodium Channel Blockers/pharmacology ; Superior Cervical Ganglion/drug effects ; Sympathetic Nervous System/*drug effects/metabolism ; Type C Phospholipases ; }, abstract = {Bradykinin (BK), a hormone inducing pain and inflammation, is known to inhibit potassium M-currents (IM) and to increase the excitability of the superior cervical ganglion (SCG) neurons by activating the Ca[2+]-calmodulin pathway. M-current is also reduced by muscarinic agonists through the depletion of membrane phosphatidylinositol 4,5-biphosphate (PIP2). Similarly, the activation of muscarinic receptors inhibits the current through two-pore domain potassium channels (K2P) of the "Tandem of pore-domains in a Weakly Inward rectifying K[+] channel (TWIK)-related channels" (TREK) subfamily by reducing PIP2 in mouse SCG neurons (mSCG). The aim of this work was to test and characterize the modulation of TREK channels by bradykinin. We used the perforated-patch technique to investigate riluzole (RIL) activated currents in voltage- and current-clamp experiments. RIL is a drug used in the palliative treatment of amyotrophic lateral sclerosis and, in addition to blocking voltage-dependent sodium channels, it also selectively activates the K2P channels of the TREK subfamily. A cell-attached patch-clamp was also used to investigate TREK-2 single channel currents. We report here that BK reduces spike frequency adaptation (SFA), inhibits the riluzole-activated current (IRIL), which flows mainly through TREK-2 channels, by about 45%, and reduces the open probability of identified single TREK-2 channels in cultured mSCG cells. The effect of BK on IRIL was precluded by the bradykinin receptor (B2R) antagonist HOE-140 (d-Arg-[Hyp[3], Thi[5], d-Tic[7], Oic[8]]BK) but also by diC8PIP2 which prevents PIP2 depletion when phospholipase C (PLC) is activated. On the contrary, antagonizing inositol triphosphate receptors (IP3R) using 2-aminoethoxydiphenylborane (2-APB) or inhibiting protein kinase C (PKC) with bisindolylmaleimide did not affect the inhibition of IRIL by BK. In conclusion, bradykinin inhibits TREK-2 channels through the activation of B2Rs resulting in PIP2 depletion, much like we have demonstrated for muscarinic agonists. This mechanism implies that TREK channels must be relevant for the capture of information about pain and visceral inflammation.}, }
@article {pmid31931694, year = {2020}, author = {Binvignat, O and Olloquequi, J}, title = {Excitotoxicity as a Target Against Neurodegenerative Processes.}, journal = {Current pharmaceutical design}, volume = {26}, number = {12}, pages = {1251-1262}, doi = {10.2174/1381612826666200113162641}, pmid = {31931694}, issn = {1873-4286}, mesh = {*Alzheimer Disease ; *Glutamic Acid ; Humans ; Memantine/pharmacology ; Neurons/physiology ; }, abstract = {The global burden of neurodegenerative diseases is alarmingly increasing in parallel to the aging of population. Although the molecular mechanisms leading to neurodegeneration are not completely understood, excitotoxicity, defined as the injury and death of neurons due to excessive or prolonged exposure to excitatory amino acids, has been shown to play a pivotal role. The increased release and/or decreased uptake of glutamate results in dysregulation of neuronal calcium homeostasis, leading to oxidative stress, mitochondrial dysfunctions, disturbances in protein turn-over and neuroinflammation. Despite the anti-excitotoxic drug memantine has shown modest beneficial effects in some patients with dementia, to date, there is no effective treatment capable of halting or curing neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, Huntington's disease or amyotrophic lateral sclerosis. This has led to a growing body of research focusing on understanding the mechanisms associated with the excitotoxic insult and on uncovering potential therapeutic strategies targeting these mechanisms. In the present review, we examine the molecular mechanisms related to excitotoxic cell death. Moreover, we provide a comprehensive and updated state of the art of preclinical and clinical investigations targeting excitotoxic- related mechanisms in order to provide an effective treatment against neurodegeneration.}, }
@article {pmid31931138, year = {2020}, author = {Stankiewicz, TR and Pena, C and Bouchard, RJ and Linseman, DA}, title = {Dysregulation of Rac or Rho elicits death of motor neurons and activation of these GTPases is altered in the G93A mutant hSOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {136}, number = {}, pages = {104743}, pmid = {31931138}, issn = {1095-953X}, support = {R01 NS062766/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Cell Death/physiology ; Female ; GTP Phosphohydrolases/genetics/*metabolism ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/*metabolism/pathology ; Mutation/physiology ; Proto-Oncogene Proteins c-akt/genetics/*metabolism ; Superoxide Dismutase/*physiology ; rho-Associated Kinases/genetics/*metabolism ; }, abstract = {Rho GTPases play a central role in neuronal survival; however, the antagonistic relationship between Rac and Rho in the regulation of motor neuron survival remains poorly defined. In the current study, we demonstrate that treatment with NSC23766, a selective inhibitor of the Rac-specific guanine nucleotide exchange factors, Tiam1 and Trio, is sufficient to induce the death of embryonic stem cell (ESC)-derived motor neurons. The mode of cell death is primarily apoptotic and is characterized by caspase-3 activation, de-phosphorylation of ERK5 and AKT, and nuclear translocation of the BH3-only protein Bad. As opposed to the inhibition of Rac, motor neuron cell death is also induced by constitutive activation of Rho, via a mechanism that depends on Rho kinase (ROCK) activity. Investigation of Rac and Rho in the G93A mutant, human Cu, Zn-superoxide dismutase (hSOD1) mouse model of amyotrophic lateral sclerosis (ALS), revealed that active Rac1-GTP is markedly decreased in spinal cord motor neurons of transgenic mice at disease onset and end-stage, when compared to age-matched wild type (WT) littermates. Furthermore, although there is no significant change in active RhoA-GTP, total RhoB displays a striking redistribution from motor neuron nuclei in WT mouse spinal cord to motor neuron axons in end-stage G93A mutant hSOD1 mice. Collectively, these data suggest that the intricate balance between pro-survival Rac signaling and pro-apoptotic Rho/ROCK signaling is critical for motor neuron survival and therefore, disruption in the balance of their activities and/or localization may contribute to the death of motor neurons in ALS.}, }
@article {pmid31930364, year = {2020}, author = {Isaacson, SH and Ondo, W and Jackson, CE and Trosch, RM and Molho, E and Pagan, F and Lew, M and Dashtipour, K and Clinch, T and Espay, AJ and , }, title = {Safety and Efficacy of RimabotulinumtoxinB for Treatment of Sialorrhea in Adults: A Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {77}, number = {4}, pages = {461-469}, pmid = {31930364}, issn = {2168-6157}, mesh = {Acetylcholine Release Inhibitors/adverse effects/*therapeutic use ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Botulinum Toxins, Type A/adverse effects/*therapeutic use ; Deglutition Disorders/*chemically induced ; Dental Caries/*chemically induced ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Sialorrhea/*drug therapy ; Treatment Outcome ; Young Adult ; }, abstract = {IMPORTANCE: RimabotulinumtoxinB (RIMA) may be preferable as an anti-sialorrhea treatment compared with current oral anticholinergic drugs in people with neurological disorders.<br><br>OBJECTIVE: To assess the safety, efficacy, and tolerability of RIMA injections for the treatment of sialorrhea in adults.<br><br>This randomized, parallel, double-blind, placebo-controlled clinical trial of RIMA 2500 U and 3500 U was conducted from November 14, 2013, to January 23, 2017. A total of 249 adult patients with troublesome sialorrhea secondary to any disorder or cause were screened. Of them, 13 refused further participation in the study or were lost to follow-up and 49 did not fulfill the criteria for participation; 187 were ultimately enrolled. Patients had to have a minimum unstimulated salivary flow rate (USFR) of 0.2 g/min and a minimum Drooling Frequency and Severity Scale score of 4.<br><br>EXPOSURES: Patients were randomized 1:1:1 to RIMA, 2500 U (n&#x2009;=&#x2009;63); RIMA, 3500 U (n&#x2009;=&#x2009;64); or placebo (n&#x2009;=&#x2009;60).<br><br>MAIN OUTCOMES AND MEASURES: Primary outcomes were the change in USFR from baseline to week 4 and the Clinical Global Impression of Change (CGI-C) at week 4. The CGI-C scores were recorded on a 7-point scale ranging from very much improved to very much worse. Adverse events were recorded throughout the trial period.<br><br>RESULTS: Of 187 patients enrolled (147 men [78.6%]; mean [SD] age, 63.9 [13.3] years), 122 patients had Parkinson disease (65.2%), 13 (7.0%) were stroke survivors, 12 had amyotrophic lateral sclerosis (6.4%), 6 had medication-induced sialorrhea (3.2%), 4 had adult cerebral palsy (2.1%), and 30 had sialorrhea owing to other causes (16.0%). A total of 176 completed the study. Treatment with both doses of RIMA significantly reduced USFR at week 4 vs placebo (mean treatment difference, -0.30 g/min [95% CI, -0.39 to -0.21] for both doses vs placebo, P&#x2009;<&#x2009;.001). The CGI-C scores were statistically significantly improved at week 4 for both treatment groups vs placebo (-1.21 [95% CI, -1.56 to -0.87] for 2500 U, -1.14 [95% CI, -1.49 to -0.80] for 3500 U, both P&#x2009;<&#x2009;.001). Treatment benefits were seen as early as 1 week after injection and were maintained over the treatment cycle of approximately 13 weeks. The RIMA injections were well tolerated compared with placebo. The most common adverse events were self-limited mild to moderate dry mouth, dysphagia, and dental caries.<br><br>CONCLUSIONS AND RELEVANCE: Treatment with RIMA (2500 U and 3500 U) in adults was well tolerated and reduced sialorrhea, with the onset of the effect at 1 week after the injection. These data support the clinical use of RIMA in the management of sialorrhea in adults.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01994109.}, }
@article {pmid31929756, year = {2020}, author = {Zhou, Q and Zhu, L and Qiu, W and Liu, Y and Yang, F and Chen, W and Xu, R}, title = {Nicotinamide Riboside Enhances Mitochondrial Proteostasis and Adult Neurogenesis through Activation of Mitochondrial Unfolded Protein Response Signaling in the Brain of ALS SOD1[G93A] Mice.}, journal = {International journal of biological sciences}, volume = {16}, number = {2}, pages = {284-297}, pmid = {31929756}, issn = {1449-2288}, mesh = {Animals ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Brain/drug effects/metabolism ; Mice, Transgenic ; *Mitochondria/drug effects/metabolism ; Motor Neurons/drug effects/metabolism ; Neural Stem Cells/drug effects/metabolism ; *Niacinamide/analogs &amp; derivatives/pharmacology ; Pyridinium Compounds ; Signal Transduction/drug effects ; Superoxide Dismutase-1/metabolism ; *Unfolded Protein Response/drug effects ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is caused by the progressive degeneration of motor neurons in the spinal cord, the brain stem, and the motor cortex. So far, there is still a lack of effective drugs. Nicotinamide adenine dinucleotide (NAD+) takes part in redox reactions and the NAD-dependent signaling pathway. The NAD+ decline is related with many neurological diseases, leading to the accumulation of neurotoxic protein in the central nervous system. Moreover, the NAD+ supplementation is shown to promote neural stem cells/neuronal precursor cells (NSCs/NPCs) pool maintenance. Regulatory mechanisms and functions of NAD+ metabolism in ALS are still unknown. Thus, we hypothesized the aggregation of human SOD1 toxic protein and the fate of NSCs/NPCs in the ALS disease could be improved by the administration of nicotinamide riboside (NR), an NAD+ precursor. In this study, we treated SOD1[G93A] transgenic and wild-type mice by the oral administration of 20 mg/ml NR starting at 50 days of age. Effects of NR on the body weight, the motor function, the onset and the survival were assessed during the experiment. The expression of mutant hSOD1 protein, mitochondrial unfolded protein response (UPR[mt]) related protein, mitophagy markers and NAD+ metabolism related protein were detected by immunoblotting. Effects of NR on the NSCs/NPCs in neurogenic niches of brain were identified by the immunofluorescence staining. Our investigation elucidated that the NR treatment exhibited better hanging wire endurance but did not postpone the onset or extend the life span of SOD1[G93A] mice. Besides, we observed that the NR repletion promoted the clearance of mitochondrial hSOD1 neurotoxic protein. Meanwhile, the mitochondrial function pathway was disrupted in the brain of SOD1[G93A] mice. What's more, we demonstrated that the inadequate function of NAD+ salvage synthesis pathway was the primary explanation behind the decline of NAD+, and the NR treatment enhanced the proliferation and migration of NSCs/NPCs in the brain of SOD1[G93A] mice. At last, we found that levels of UPR[mt] related protein were significantly increased in the brain of SOD1[G93A] mice after the NR treatment. In summary, these findings reveal that the administration of NR activates UPR[mt] signaling, modulates mitochondrial proteostasis and improves the adult neurogenesis in the brain of SOD1[G93A] mice.}, }
@article {pmid31929366, year = {2020}, author = {Wei, HY and Dong, CK and Zhu, YT and Zhou, J and Yi, P and Yang, F and Tan, MS}, title = {A modified posterior wedge osteotomy with interbody fusion for the treatment of thoracolumbar kyphosis with Andersson lesions in ankylosing spondylitis: a 5-year follow-up study.}, journal = {Chinese medical journal}, volume = {133}, number = {2}, pages = {165-173}, pmid = {31929366}, issn = {2542-5641}, mesh = {Adult ; Aged ; Female ; Follow-Up Studies ; Humans ; Kyphosis/*surgery ; Lumbar Vertebrae/surgery ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Osteotomy ; Quality of Life ; Retrospective Studies ; Spinal Fusion ; Spondylitis, Ankylosing/*surgery ; Thoracic Vertebrae/surgery ; }, abstract = {BACKGROUND: Andersson lesions (ALs), also known as spondylodiscities, destructive vertebral lesions and spinal pseudarthrosis, usually occur in patients with ankylosing spondylitis (AS). Inflammatory and traumatic causes have been proposed to define this lesion. Different surgical approaches including anterior, posterior, and combined anterior and posterior procedure have been used to address the complications, consisting of mechanical pain, kyphotic deformity, and neurologic deficits. However, the preferred surgical procedure remains controversial. The aim of this study was to illustrate the safety, efficacy, and feasibility of a modified posterior wedge osteotomy for the ALs with kyphotic deformity in AS.<br><br>METHODS: From June 2008 to January 2013, 23 patients (18 males, 5 females) at an average age of 44.8 years (range 25-69 years) were surgically treated for thoracolumbar kyphosis with ALs in AS via a modified posterior wedge osteotomy in our department. All sagittal balance parameters were assessed by standing lateral radiography of the whole spine before surgery and during the follow-up period. Assessment of radiologic fusion at follow-up was based on the Bridwell interbody fusion grading system. Ankylosing spondylitis quality of life (ASQoL) and visual analog scale (VAS) scores were performed to evaluate improvements in daily life function and back pain pre-operatively and post-operatively. Paired t tests were used to compare clinical data change in parametric values before and after surgery and the Mann-Whitney U test was employed for non-parametric comparisons. The radiographic data change was evaluated by repeated measure analysis of variance.<br><br>RESULTS: The mean operative duration was 205.4 min (range 115-375 min), with an average blood loss of 488.5 mL (range 215-880 mL). Radiographical and clinical outcomes were assessed after a mean of 61.4 months of follow-up. The VAS back pain and ASQoL scores improved significantly in all patients (7.52&#x200a;&#xb1;&#x200a;1.31 vs. 1.70&#x200a;&#xb1;&#x200a;0.70, t&#x200a;=&#x200a;18.30, P&#x200a;<&#x200a;0.001; 13.87&#x200a;&#xb1;&#x200a;1.89 vs. 7.22&#x200a;&#xb1;&#x200a;1.24, t&#x200a;=&#x200a;18.53, P&#x200a;<&#x200a;0.001, respectively). The thoracolumbar kyphosis (TLK) changed from 40.03&#x200a;&#xb1;&#x200a;17.61&#xb0; pre-operatively to 13.86&#x200a;&#xb1;&#x200a;6.65&#xb0; post-operatively, and 28.45&#x200a;&#xb1;&#x200a;6.63&#xb0; at final follow-up (F&#x200a;=&#x200a;57.54, P&#x200a;<&#x200a;0.001), the thoracic kyphosis (TK) changed from 52.30&#x200a;&#xb1;&#x200a;17.62&#xb0; pre-operatively to 27.76&#x200a;&#xb1;&#x200a;6.50&#xb0; post-operatively, and 28.45&#x200a;&#xb1;&#x200a;6.63&#xb0; at final follow-up (F&#x200a;=&#x200a;57.29, P&#x200a;<&#x200a;0.001), and lumbar lordosis (LL) changed from -29.56&#x200a;&#xb1;&#x200a;9.73&#xb0; pre-operatively to -20.58&#x200a;&#xb1;&#x200a;9.71&#xb0; post-operatively, and -20.73&#x200a;&#xb1;&#x200a;10.27&#xb0; at final follow-up (F&#x200a;=&#x200a;42.50, P&#x200a;<&#x200a;0.001). Mean sagittal vertical axis (SVA) was improved from 11.82&#x200a;&#xb1;&#x200a;4.55 cm pre-operatively to 5.12&#x200a;&#xb1;&#x200a;2.42 cm post-operatively, and 5.03&#x200a;&#xb1;&#x200a;2.29 cm at final follow-up (F&#x200a;=&#x200a;79.36, P&#x200a;<&#x200a;0.001). No obvious loss of correction occurred, according to the lack of significant differences in the sagittal balance parameters between post-operatively and the final follow-up in all patients (TK: 27.76&#x200a;&#xb1;&#x200a;6.50&#xb0; vs. 28.45&#x200a;&#xb1;&#x200a;6.63&#xb0;, TLK: 13.86&#x200a;&#xb1;&#x200a;6.65&#xb0; vs. 14.42&#x200a;&#xb1;&#x200a;6.7&#xb0;, LL: -20.58&#x200a;&#xb1;&#x200a;9.71&#xb0; vs. -20.73&#x200a;&#xb1;&#x200a;10.27&#xb0;, and SVA: 5.12&#x200a;&#xb1;&#x200a;2.42 cm vs. 5.03&#x200a;&#xb1;&#x200a;2.29 cm, all P&#x200a;>&#x200a;0.05, respectively).<br><br>CONCLUSIONS: The modified posterior wedge osteotomy is an accepted surgical procedure for treating thoracolumbar kyphosis with ALs in AS and results in satisfactory local kyphosis correction, solid fusion, and good clinical outcomes.}, }
@article {pmid31928838, year = {2020}, author = {Mathew, B and Ruiz, P and Pathak, V and Suto, MJ}, title = {Development of novel small molecules for the treatment of ALS.}, journal = {Bioorganic &amp; medicinal chemistry letters}, volume = {30}, number = {4}, pages = {126950}, doi = {10.1016/j.bmcl.2020.126950}, pmid = {31928838}, issn = {1464-3405}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/*pathology ; Gene Expression Regulation/drug effects ; Humans ; NF-kappa B/genetics/metabolism ; Small Molecule Libraries/*chemistry/pharmacology/therapeutic use ; Structure-Activity Relationship ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare and progressive neurodegenerative disease with unknown etiology. It is caused by the degeneration of motor neurons responsible for controlling voluntary muscles. It has been reported that mutations in the superoxide dismutase (SOD) 1 gene can lead to ALS. SOD1 abnormalities have been identified in both familial, as well as sporadic ALS cases. SOD2 is a highly inducible SOD that works in conjunction with SOD1. SOD2 can be induced through activation of NF-κBs. We previously reported that the novel small molecule, SRI-22818, increases NF-κB expression and activation and SOD2 levels in vitro and has activity in vivo in the SOD1-G93A reference model of ALS. We report herein the synthesis and biological evaluation of SRI-22818 analogs.}, }
@article {pmid31926602, year = {2020}, author = {Okano, H and Yasuda, D and Fujimori, K and Morimoto, S and Takahashi, S}, title = {Ropinirole, a New ALS Drug Candidate Developed Using iPSCs.}, journal = {Trends in pharmacological sciences}, volume = {41}, number = {2}, pages = {99-109}, doi = {10.1016/j.tips.2019.12.002}, pmid = {31926602}, issn = {1873-3735}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Indoles/pharmacology ; *Induced Pluripotent Stem Cells ; *Pharmaceutical Preparations ; }, abstract = {Induced pluripotent stem cells (iPSCs) are increasingly used in the study of disease mechanisms and the development of effective disease-modifying therapies for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Recently, three candidate anti-ALS drugs - ropinirole (ROPI), retigabine, and bosutinib - have been identified in iPSC-based drug screens and are now being evaluated in clinical trials for safety and effectiveness. We review the preclinical data, clinical research design, and rationale for ROPI as an anti-ALS drug candidate compared with those of the other two drugs. We also discuss the use of iPSCs for understanding and monitoring treatment response as well as for new insights into the development of new drugs and therapeutic interventions for major neurodegenerative diseases.}, }
@article {pmid31920478, year = {2019}, author = {Trageser, KJ and Smith, C and Herman, FJ and Ono, K and Pasinetti, GM}, title = {Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {1298}, pmid = {31920478}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with overlapping pathomechanisms, neurobehavioral features, and genetic etiologies. Individuals diagnosed with either disorder exhibit symptoms within a clinical spectrum. Symptoms of ALS involve neuromusculature deficits, reflecting upper and lower motor neurodegeneration, while the primary clinical features of FTD are behavioral and cognitive impairments, reflecting frontotemporal lobar degeneration. An intronic G4C2 hexanucleotide repeat expansion (HRE) within the promoter region of chromosome 9 open reading frame 72 (C9orf72) is the predominant monogenic cause of both ALS and FTD. While the heightened risk to develop ALS/FTD in response to C9orf72 expansions is well-established, studies continue to define the precise mechanisms by which this mutation elicits neurodegeneration. Studies show that G4C2 expansions undergo repeat-associated non-ATG dependent (RAN) translation, producing dipeptide repeat proteins (DRPs) with varying toxicities. Accumulation of DRPs in neurons, in particular arginine containing DRPs, have neurotoxic effects by potently impairing nucleocytoplasmic transport, nucleotide metabolism, lysosomal processes, and cellular metabolic pathways. How these pathophysiological effects of C9orf72 expansions engage and elicit immune activity with additional neurobiological consequences is an important line of future investigations. Immunoreactive microglia and elevated levels of peripheral inflammatory cytokines noted in individuals with C9orf72 ALS/FTD provide evidence that persistent immune activation has a causative role in the progression of each disorder. This review highlights the current understanding of the cellular, proteomic and genetic substrates through which G4C2 HREs may elicit detrimental immune activity, facilitating region-specific neurodegeneration in C9orf72 mediated ALS/FTD. We in particular emphasize interactions between intracellular pathways induced by C9orf72 expansions and innate immune inflammasome complexes, intracellular receptors responsible for eliciting inflammation in response to cellular stress. A further understanding of the intricate, reciprocal relationship between the cellular and molecular pathologies resulting from C9orf72 HREs and immune activation may yield novel therapeutics for ALS/FTD, which currently have limited treatment strategies.}, }
@article {pmid31919375, year = {2020}, author = {Lombardi, V and Carassiti, D and Giovannoni, G and Lu, CH and Adiutori, R and Malaspina, A}, title = {The potential of neurofilaments analysis using dry-blood and plasma spots.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {97}, pmid = {31919375}, issn = {2045-2322}, support = {MALASPINA/APR13/817-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; U54 NS092091/NS/NINDS NIH HHS/United States ; 17-CReA-382//Amyotrophic Lateral Sclerosis Association (ALS Association)/International ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/blood/*diagnosis ; Biomarkers/*blood ; Blood Specimen Collection/*methods ; Case-Control Studies ; Dried Blood Spot Testing/*methods ; Female ; Humans ; Male ; Middle Aged ; Neurofilament Proteins/*blood ; Specimen Handling/*methods ; }, abstract = {The lack of biomarkers for an early diagnosis of neurodegenerative disorders (NDs) has hampered the development of therapeutics whose effect would be enhanced by a timely intervention. Neurofilaments light chain (Nf-L), an integral part of the axonal structure, has emerged as a robust fluid biomarker for fatal neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). To facilitate large-scale studies into early-stage neurodegeneration, reduce costs of samples collection/processing and cold-chain storage, we describe the measurement of Nf-L in blood fractions obtained from dry blood spots (DBS) and dry plasma spots (DPS), two filter paper-based remote blood collection tools. To test the feasibility of using this approach, Nf-L analysis in DBS/DPS is compared to that in plasma obtained from the same blood sample, looking at Nf-L discriminatory power in the clinical stratification of ALS compared to healthy controls. With the best pre-analytical treatment for total protein recovery and using highly sensitive immunoassays, we report the detection of different Nf-L levels in DBS elute compared to reference plasma and DPS from the same blood samples. However, Nf-L measurement in DBS elutes provides a very good discrimination of ALS from healthy controls which is comparable to that obtained using plasma Nf-L assays. With the available immunodetection methods, we show that Nf-L measurement based on DPS microsampling is similar to that in plasma. The filter-paper biophysical characteristics and the interference of high haemoglobin concentration released by erythrocyte lysis is likely to perturb Nf-L detection in DBS elute. Further studies into DBS-based Nf-L detection and its analytical optimization are needed to make this method suitable for routine Nf-L blood analyses in neurodegeneration.}, }
@article {pmid31917162, year = {2020}, author = {Rosa Silva, JP and Santiago Júnior, JB and Dos Santos, EL and de Carvalho, FO and de França Costa, IMP and Mendonça, DMF}, title = {Quality of life and functional independence in amyotrophic lateral sclerosis: A systematic review.}, journal = {Neuroscience and biobehavioral reviews}, volume = {111}, number = {}, pages = {1-11}, doi = {10.1016/j.neubiorev.2019.12.032}, pmid = {31917162}, issn = {1873-7528}, mesh = {*Activities of Daily Living ; Amyotrophic Lateral Sclerosis/*physiopathology/*rehabilitation ; Humans ; *Quality of Life ; *Severity of Illness Index ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) leads to functional capacity decline, generating great impact in quality of life. Quality of life is directly related to physical integrity and functional independence. This systematic review aimed to analyze treatment protocols and their outcomes from clinical trials with focus on ALS rehabilitation that evaluated the effects on quality of life and functional independence from their intervention process. A literature search was conducted through MEDLINE-PubMed, Science Direct, Web of Science and Scopus databases. A total of 3630 articles were identified. Eleven studies met the inclusion criteria. They focused on different aspects of quality of life or functional independence, which are: respiratory care, mental health, communication skills and exercises. Use of bipap and inspiratory muscle training, anxiety and depression, communication devices implementation and exercises safety and tolerability were considered as key points. However, the drastic evolution of the disease is a limiting factor to the perception of quality of life improvement by patients. Further studies should be done to validate the benefits on patients' quality of life.}, }
@article {pmid31916190, year = {2020}, author = {Zhao, A and Pan, Y and Cai, S}, title = {Patient-Specific Cells for Modeling and Decoding Amyotrophic Lateral Sclerosis: Advances and Challenges.}, journal = {Stem cell reviews and reports}, volume = {16}, number = {3}, pages = {482-502}, doi = {10.1007/s12015-019-09946-8}, pmid = {31916190}, issn = {2629-3277}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Cellular Reprogramming ; Drug Discovery ; Humans ; *Models, Biological ; Motor Neurons/pathology ; Mutation/genetics ; }, abstract = {Motor neuron loss or degeneration is the typical characteristic of amyotrophic lateral sclerosis (ALS), which often leads to weakness, paralysis, or even death. The underlying mechanisms of motor neuron degeneration and ALS progression remain elusive, and there is no effective treatment for ALS. The advances of stem cells and reprogramming techniques has made it possible to generate patient-specific motor neurons as cell models for studying disease mechanisms and drug discovery. This review comprehensively discusses recent approaches to generate motor neurons from stem cells and somatic cells and highlights the application of induced motor neurons to modeling ALS diseases, dissecting the pathogenesis, and screening new drugs. New perspectives are also discussed on generating patient-specific motor neuron subtypes that are affected by ALS or creating 3D spinal cord organoid models for better recapitulating and understanding ALS.}, }
@article {pmid31914904, year = {2020}, author = {Rahman, MA and Rahman, MR and Zaman, T and Uddin, MS and Islam, R and Abdel-Daim, MM and Rhim, H}, title = {Emerging Potential of Naturally Occurring Autophagy Modulators Against Neurodegeneration.}, journal = {Current pharmaceutical design}, volume = {26}, number = {7}, pages = {772-779}, doi = {10.2174/1381612826666200107142541}, pmid = {31914904}, issn = {1873-4286}, mesh = {Animals ; *Autophagy ; Biological Products/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy ; Signal Transduction ; }, abstract = {BACKGROUND: Naturally-occurring products derived from living organisms have been shown to modulate various pharmacological and biological activities. Natural products protect against various diseases, which could be used for therapeutic assistance. Autophagy, a lysosome-mediated self-digestion pathway, has been implicated in a range of pathophysiological conditions and has recently gained attention for its role in several neurodegenerative diseases.<br><br>METHODS: In this current review, we emphasized the recent progress made in our understanding of the molecular mechanism of autophagy in different cellular and mouse models using naturally-occurring autophagy modulators for the management of several neurodegenerative diseases.<br><br>RESULTS: Accumulating evidence has revealed that a wide variety of natural compounds such as alkaloids, polyphenols, terpenoids, xanthonoids, flavonoids, lignans, disaccharides, glycolipoproteins, and saponins are involved in the modulation of the autophagy signaling pathway. These natural products have been used to treat various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, spinocerebellar ataxia, neuroblastoma, and glioblastoma. Although a number of synthetic autophagy regulators have been recognized as encouraging neurodegenerative therapeutic candidates, natural autophagy- regulating compounds have been of further interest as potential disease therapeutics, as they cause insignificant side effects.<br><br>CONCLUSION: Existing in vitro and in vivo data are promising and highlight that naturally-occurring autophagyregulating compounds play an important role in the prevention and treatment of neurodegenerative disorders.}, }
@article {pmid31914903, year = {2020}, author = {Gulla, S and Lomada, D and Lade, A and Pallu, R and Reddy, MC}, title = {Role of Prostaglandins in Multiple Sclerosis.}, journal = {Current pharmaceutical design}, volume = {26}, number = {7}, pages = {730-742}, doi = {10.2174/1381612826666200107141328}, pmid = {31914903}, issn = {1873-4286}, mesh = {Central Nervous System/physiopathology ; Humans ; Inflammation ; Multiple Sclerosis/*physiopathology ; Prostaglandins/*physiology ; }, abstract = {Multiple sclerosis (MS) is an autoimmune demyelinating disorder with chronic inflammation in the central nervous system, manifested by both physical and cognitive disability. Neuroinflammation and neurodegeneration are the phenomena that appear in the central nervous system associated with various neurodegenerative disorders, including MS, Alzheimer's diseases, amyotrophic lateral sclerosis and Parkinson's disease. Prostaglandins are one of the major mediators of inflammation that exhibit an important function in enhancing neuroinflammatory and neurodegenerative processes. These mediators would help understand the pathophysiology of MS as the combination of antagonists or agonists of prostaglandins receptors could be beneficial during the treatment of MS. The present review focuses on the role played by different prostaglandins and the enzymes which produced them in the etiopathogenesis of MS.}, }
@article {pmid31914343, year = {2020}, author = {Bandookwala, M and Sengupta, P}, title = {3-Nitrotyrosine: a versatile oxidative stress biomarker for major neurodegenerative diseases.}, journal = {The International journal of neuroscience}, volume = {130}, number = {10}, pages = {1047-1062}, doi = {10.1080/00207454.2020.1713776}, pmid = {31914343}, issn = {1563-5279}, mesh = {*Alzheimer Disease/diagnosis/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism/pathology ; Biomarkers/*metabolism ; Humans ; *Huntington Disease/diagnosis/metabolism/pathology ; *Parkinson Disease/diagnosis/metabolism/pathology ; *Prion Diseases/diagnosis/metabolism/pathology ; Tyrosine/*analogs &amp; derivatives/metabolism ; }, abstract = {Reactive oxygen species are generated as a by-product of routine biochemical reactions. However, dysfunction of the antioxidant system or mutations in gene function may result in the elevated production of the pro-oxidant species. Modified endogenous molecules due to chemical interactions with increased levels of reactive oxygen and nitrogen species in the cellular microenvironment can be termed as biomarkers of oxidative stress. 3-Nitrotyrosine is one such promising biomarker of oxidative stress formed due to nitration of protein-bound and free tyrosine residues by reactive peroxynitrite molecules. Nitration of proteins at the subcellular level results in conformational alterations that damage the cytoskeleton and result in neurodegeneration. In this review, we summarized the role of oxidative/nitrosative processes as a contributing factor for progressive neurodegeneration in Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease and Prion disease. The selective tyrosine protein nitration of the major marker proteins in related pathologies has been discussed. The alteration in 3-Nitrotyrosine profile occurs well before any symptoms appear and can be considered as a potential target for early diagnosis of neurodegenerative diseases. Furthermore, the reduction in 3-Nitrotyrosine levels in response to treatment with neuroprotective has been highlighted which is indicative of the importance of this particular marker in oxidative stress-related brain and central nervous system pathologies.}, }
@article {pmid31913476, year = {2020}, author = {Kuang, L and Hashimoto, K and Huang, EJ and Gentry, MS and Zhu, H}, title = {Frontotemporal dementia non-sense mutation of progranulin rescued by aminoglycosides.}, journal = {Human molecular genetics}, volume = {29}, number = {4}, pages = {624-634}, pmid = {31913476}, issn = {1460-2083}, support = {R01 NS115507/NS/NINDS NIH HHS/United States ; I01 BX002978/BX/BLRD VA/United States ; R01 NS077284/NS/NINDS NIH HHS/United States ; I01 BX002149/BX/BLRD VA/United States ; IS1 BX003561/BX/BLRD VA/United States ; R01 AA027074/AA/NIAAA NIH HHS/United States ; R01 NS070899/NS/NINDS NIH HHS/United States ; }, mesh = {Aminoglycosides/*pharmacology ; Animals ; *Codon, Nonsense ; Frontotemporal Dementia/*genetics ; Gentamicins/pharmacology ; Mice ; Neuroblastoma/*drug therapy/genetics/metabolism/pathology ; Neurons/*drug effects/metabolism ; Neuroprotective Agents/*pharmacology ; Progranulins/*genetics ; Protein Synthesis Inhibitors/pharmacology ; Tumor Cells, Cultured ; }, abstract = {Frontotemporal dementia (FTD) is an early onset dementia characterized by progressive atrophy of the frontal and/or temporal lobes. FTD is highly heritable with mutations in progranulin accounting for 5-26% of cases in different populations. Progranulin is involved in endocytosis, secretion and lysosomal processes, but its functions under physiological and pathological conditions remains to be defined. Many FTD-causing non-sense progranulin mutations contain a premature termination codon (PTC), thus progranulin haploinsufficiency has been proposed as a major disease mechanism. Currently, there is no effective FTD treatment or therapy. Aminoglycosides are a class of antibiotics that possess a less-known function to induce eukaryotic ribosomal readthrough of PTCs to produce a full-length protein. The aminoglycoside-induced readthrough strategy has been utilized to treat multiple human diseases caused by PTCs. In this study, we tested the only clinically approved readthrough small molecule PTC124 and 11 aminoglycosides in a cell culture system on four PTCs responsible for FTD or a related neurodegenerative disease amyotrophic lateral sclerosis. We found that the aminoglycosides G418 and gentamicin rescued the expression of the progranulin R493X mutation. G418 was more effective than gentamicin (~50% rescue versus <10%), and the effect was dose- and time-dependent. The progranulin readthrough protein displayed similar subcellular localization as the wild-type progranulin protein. These data provide an exciting proof-of-concept that aminoglycosides or other readthrough-promoting compounds are a therapeutic avenue for familial FTD caused by progranulin PTC mutations.}, }
@article {pmid31912279, year = {2020}, author = {Devos, D and Cabantchik, ZI and Moreau, C and Danel, V and Mahoney-Sanchez, L and Bouchaoui, H and Gouel, F and Rolland, AS and Duce, JA and Devedjian, JC and , }, title = {Conservative iron chelation for neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {127}, number = {2}, pages = {189-203}, pmid = {31912279}, issn = {1435-1463}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; *Chelation Therapy/methods/standards ; Deferiprone/*pharmacology ; Humans ; Iron/*metabolism ; Iron Chelating Agents/*pharmacology ; Parkinson Disease/*drug therapy/metabolism ; }, abstract = {Focal iron accumulation associated with brain iron dyshomeostasis is a pathological hallmark of various neurodegenerative diseases (NDD). The application of iron-sensitive sequences in magnetic resonance imaging has provided a useful tool to identify the underlying NDD pathology. In the three major NDD, degeneration occurs in central nervous system (CNS) regions associated with memory (Alzheimer's disease, AD), automaticity (Parkinson's disease, PD) and motor function (amyotrophic lateral sclerosis, ALS), all of which require a high oxygen demand for harnessing neuronal energy. In PD, a progressive degeneration of the substantia nigra pars compacta (SNc) is associated with the appearance of siderotic foci, largely caused by increased labile iron levels resulting from an imbalance between cell iron import, storage and export. At a molecular level, α-synuclein regulates dopamine and iron transport with PD-associated mutations in this protein causing functional disruption to these processes. Equally, in ALS, an early iron accumulation is present in neurons of the cortico-spinal motor pathway before neuropathology and secondary iron accumulation in microglia. High serum ferritin is an indicator of poor prognosis in ALS and the application of iron-sensitive sequences in magnetic resonance imaging has become a useful tool in identifying pathology. The molecular pathways that cascade down from such dyshomeostasis still remain to be fully elucidated but strong inroads have been made in recent years. Far from being a simple cause or consequence, it has recently been discovered that these alterations can trigger susceptibility to an iron-dependent cell-death pathway with unique lipoperoxidation signatures called ferroptosis. In turn, this has now provided insight into some key modulators of this cell-death pathway that could be therapeutic targets for the NDD. Interestingly, iron accumulation and ferroptosis are highly sensitive to iron chelation. However, whilst chelators that strongly scavenge intracellular iron protect against oxidative neuronal damage in mammalian models and are proven to be effective in treating systemic siderosis, these compounds are not clinically suitable due to the high risk of developing iatrogenic iron depletion and ensuing anaemia. Instead, a moderate iron chelation modality that conserves systemic iron offers a novel therapeutic strategy for neuroprotection. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred (conservatively) either to higher affinity acceptors in cells or extracellular transferrin. Promising preclinical and clinical proof of concept trials has led to several current large randomized clinical trials that aim to demonstrate the efficacy and safety of conservative iron chelation for NDD, notably in a long-term treatment regimen.}, }
@article {pmid31910072, year = {2020}, author = {Adam, E}, title = {A Systematic Review of the Effectiveness of Oral Baclofen in the Management of Hiccups in Adult Palliative Care Patients.}, journal = {Journal of pain &amp; palliative care pharmacotherapy}, volume = {34}, number = {1}, pages = {43-54}, doi = {10.1080/15360288.2019.1705457}, pmid = {31910072}, issn = {1536-0539}, mesh = {Adult ; Baclofen/*therapeutic use ; Hiccup/*drug therapy/etiology/physiopathology ; Humans ; Palliative Care ; Publications ; Quality of Life ; Randomized Controlled Trials as Topic ; }, abstract = {Hiccup is a recognised symptom amongst the palliative care population. It can be debilitating, with significant impact on quality of life. The pathophysiology is poorly understood and the list of aetiological factors is extensive. The current treatment recommendations are based on a small body of evidence and there remains uncertainty regarding optimal management. The aim of this study was to systematically review the evidence for oral baclofen in the management of hiccups in adult palliative care patients. A search was conducted using MEDLINE, Embase, the Cochrane library and CINAHL, as well as a hand search and review of the grey literature. Relevant articles were identified using pre-defined eligibility criteria. Quality assessment was guided by the SIGN grading system, CASP, Hawker et al's checklist and Cochrane's risk of bias tool. A narrative approach was used for data synthesis. Four relevant articles were identified; one randomised controlled trial and three case series. This gave a combined total of 22 patients, all of whom benefited from the use of oral baclofen in the treatment of hiccups, with few reports of side effects. The dose ranged from 10mg once only to 20mg TDS, and the duration from 1-24 days. However, the overall quality of the evidence was low. While baclofen is an option in the management of hiccups, it is difficult to make recommendations based on the body of evidence presented in this systematic review. There is a lack of RCTs in this field and further research is warranted.}, }
@article {pmid31905174, year = {2020}, author = {Thanh, LT and Dao, NTA and Dung, NV and Trung, NL and Abed-Meraim, K}, title = {Multi-channel EEG epileptic spike detection by a new method of tensor decomposition.}, journal = {Journal of neural engineering}, volume = {17}, number = {1}, pages = {016023}, doi = {10.1088/1741-2552/ab5247}, pmid = {31905174}, issn = {1741-2552}, mesh = {Action Potentials/*physiology ; Adolescent ; Adult ; Aged ; Brain/*physiopathology ; Child ; Child, Preschool ; Electroencephalography/*methods ; Epilepsy/diagnosis/*physiopathology ; Female ; Humans ; Male ; *Signal Processing, Computer-Assisted ; Young Adult ; }, abstract = {OBJECTIVE: Epilepsy is one of the most common brain disorders. For epilepsy diagnosis or treatment, the neurologist needs to observe epileptic spikes from electroencephalography (EEG) data. Since multi-channel EEG records can be naturally represented by multi-way tensors, it is of interest to see whether tensor decomposition is able to analyze EEG epileptic spikes.<br><br>APPROACH: In this paper, we first proposed the problem of simultaneous multilinear low-rank approximation of tensors (SMLRAT) and proved that SMLRAT can obtain local optimum solutions by using two well-known tensor decomposition algorithms (HOSVD and Tucker-ALS). Second, we presented a new system for automatic epileptic spike detection based on SMLRAT.<br><br>MAIN RESULTS: We propose to formulate the problem of feature extraction from a set of EEG segments, represented by tensors, as the SMLRAT problem. Efficient EEG features were obtained, based on estimating the 'eigenspikes' derived from nonnegative GSMLRAT. We compared the proposed tensor analysis method with other common tensor methods in analyzing EEG signal and compared the proposed feature extraction method with the state-of-the-art methods. Experimental results indicated that our proposed method is able to detect epileptic spikes with high accuracy.<br><br>SIGNIFICANCE: Our method, for the first time, makes a step forward for automatic detection EEG epileptic spikes based on tensor decomposition. The method can provide a practical solution to distinguish epileptic spikes from artifacts in real-life EEG datasets.}, }
@article {pmid31901592, year = {2020}, author = {Saitoh, Y and Aoshima, Y and Mukai, T and Abe, H and Ariga, H and Mori-Yoshimura, M and Okamoto, T and Takahashi, Y}, title = {Riluzole-induced interstitial lung disease is a rare and potentially life-threatening adverse event successfully treated with high-dose steroid therapy: Case reports and review of the literature.}, journal = {Journal of the neurological sciences}, volume = {410}, number = {}, pages = {116650}, doi = {10.1016/j.jns.2019.116650}, pmid = {31901592}, issn = {1878-5883}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; *Lung Diseases, Interstitial/chemically induced/drug therapy ; Riluzole/adverse effects ; }, abstract = {Riluzole (RZ)-induced interstitial lung disease (RZ-ILD) is a rare and potentially life-threatening adverse event in amyotrophic lateral sclerosis (ALS) patients, which is rarely reported. Therefore, the optimal treatment for RZ-ILD is unclear. We describe herein three Japanese cases of ALS complicated with RZ-ILD, of which two were successfully treated with high-dose steroid therapy. In our all ALS cases with RZ-ILD, the duration of RZ exposure until RZ-ILD onset was within 2 months. All three cases showed respiratory symptoms, dorsal predominant ground-glass opacities by imaging analysis, and abnormal laboratory findings associated with interstitial lung diseases, such as Krebs von den Lungen-6 and surfactant protein-D. Intravenous high-dose steroid therapy together with the discontinuation of RZ in two cases with respiratory symptoms markedly ameliorated their symptoms and abnormal findings of RZ-ILD. One case showed mild respiratory symptoms compared with the others and recovered after the withdrawal of RZ only. According to previous case reports and our cases, RZ-ILD may develop 2 months after initiating RZ and exacerbate respiratory symptoms rapidly in ALS patients with severe respiratory muscle involvement or complicating aspiration pneumonia. Transient high-dose steroid therapy in addition to discontinuation of RZ might be a good therapeutic option for RZ-ILD.}, }
@article {pmid31900865, year = {2020}, author = {Kuta, R and Larochelle, N and Fernandez, M and Pal, A and Minotti, S and Tibshirani, M and St Louis, K and Gentil, BJ and Nalbantoglu, JN and Hermann, A and Durham, HD}, title = {Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models.}, journal = {Cell stress &amp; chaperones}, volume = {25}, number = {1}, pages = {173-191}, pmid = {31900865}, issn = {1466-1268}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Cells, Cultured ; HSP70 Heat-Shock Proteins/metabolism ; Heat-Shock Proteins/*drug effects/metabolism ; Heat-Shock Response/drug effects ; Histone Deacetylase Inhibitors/pharmacology ; Hydroxylamines/*pharmacology ; Mice ; Motor Neurons/*drug effects/metabolism ; Spinal Cord/*drug effects/metabolism ; Transcriptional Activation/drug effects ; Up-Regulation/drug effects ; }, abstract = {Upregulation of heat shock proteins (HSPs) is an approach to treatment of neurodegenerative disorders with impaired proteostasis. Many neurons, including motor neurons affected in amyotrophic lateral sclerosis (ALS), are relatively resistant to stress-induced upregulation of HSPs. This study demonstrated that histone deacetylase (HDAC) inhibitors enable the heat shock response in cultured spinal motor neurons, in a stress-dependent manner, and can improve the efficacy of HSP-inducing drugs in murine spinal cord cultures subjected to thermal or proteotoxic stress. The effect of particular HDAC inhibitors differed with the stress paradigm. The HDAC6 (class IIb) inhibitor, tubastatin A, acted as a co-inducer of Hsp70 (HSPA1A) expression with heat shock, but not with proteotoxic stress induced by expression of mutant SOD1 linked to familial ALS. Certain HDAC class I inhibitors (the pan inhibitor, SAHA, or the HDAC1/3 inhibitor, RGFP109) were HSP co-inducers comparable to the hydroxyamine arimoclomol in response to proteotoxic stress, but not thermal stress. Regardless, stress-induced Hsp70 expression could be enhanced by combining an HDAC inhibitor with either arimoclomol or with an HSP90 inhibitor that constitutively induced HSPs. HDAC inhibition failed to induce Hsp70 in motor neurons expressing ALS-linked mutant FUS, in which the heat shock response was suppressed; yet SAHA, RGFP109, and arimoclomol did reduce loss of nuclear FUS, a disease hallmark, and HDAC inhibition rescued the DNA repair response in iPSC-derived motor neurons carrying the FUS[P525L]mutation, pointing to multiple mechanisms of neuroprotection by both HDAC inhibiting drugs and arimoclomol.}, }
@article {pmid31897946, year = {2020}, author = {Chełstowska, B and Kuźma-Kozakiewicz, M}, title = {Biochemical parameters in determination of nutritional status in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {41}, number = {5}, pages = {1115-1124}, doi = {10.1007/s10072-019-04201-x}, pmid = {31897946}, issn = {1590-3478}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*blood/complications/*diagnosis ; Body Mass Index ; Deglutition Disorders/blood/complications ; Female ; Humans ; Inflammation/blood ; Male ; Middle Aged ; *Nutritional Status ; Young Adult ; }, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disorder without effective treatment. Progressive dysphagia, depression, and hypermetabolism may lead to malnutrition. The aim of the present study was to analyze the potential utility of readily available, relatively inexpensive, and rapid strategy for using laboratory parameters to assess nutritional status of ALS patients.<br><br>METHODS: This study included 203 patients with ALS. The analysis of inflammatory parameters: C Reactive Protein (CRP), erythrocyte sedimentation rate (ESR), white blood cell count (WBC), lymphocytes number (LN), and fibrinogen concentration (FC) was followed by nutritional markers: serum concentration of albumin (ALB), prealbumin (PALB), transferrin (TRNF), and creatinine (CREA), which were correlated with demographic and clinical parameters: body mass index (BMI), ALS phenotype, disease duration, diagnosis delay, and functional and respiratory assessment.<br><br>RESULTS: Nearly 20% of patients had biochemical features of inflammation. Among patients without inflammation (n&#x2009;=&#x2009;163), a decreased serum TRNF concentration was found in 84% of cases, PALB in 39%, ALB in 25%, and CREA in 53%. The median of PALB was the highest in patients with PMA (23.5&#xa0;mg/dL) and the lowest in PBP (16.6&#xa0;mg/dL) (p&#x2009;<&#x2009;0.05). The CREA concentration correlated with the BMI (r&#x2009;=&#x2009;0.25; p&#x2009;<&#x2009;0.01), while PALB and TRNF significantly varied depending on the severity of dysphagia. Patients with dysphagia qualified to enteral nutrition showed significantly decreased concentration of PALB, triglycerides, as well as reduced forced vital capacity, BMI, and functional status.<br><br>CONCLUSIONS: CREA, PALB, ALB, and TNFR are easily accessible, accurate, and low-cost parameters useful in assessment of the nutritional status in ALS.}, }
@article {pmid31888221, year = {2019}, author = {Wang, W and Gopal, S and Pocock, R and Xiao, Z}, title = {Glycan Mimetics from Natural Products: New Therapeutic Opportunities for Neurodegenerative Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {24}, number = {24}, pages = {}, pmid = {31888221}, issn = {1420-3049}, mesh = {Animals ; *Biological Mimicry ; Biological Products/*chemistry ; *Biomimetics/methods ; Drug Discovery/methods ; Glycosylation ; Humans ; Molecular Structure ; Neurodegenerative Diseases/drug therapy ; Polysaccharides/biosynthesis/*chemistry/*pharmacology/therapeutic use ; }, abstract = {Neurodegenerative diseases (NDs) affect millions of people worldwide. Characterized by the functional loss and death of neurons, NDs lead to symptoms (dementia and seizures) that affect the daily lives of patients. In spite of extensive research into NDs, the number of approved drugs for their treatment remains limited. There is therefore an urgent need to develop new approaches for the prevention and treatment of NDs. Glycans (carbohydrate chains) are ubiquitous, abundant, and structural complex natural biopolymers. Glycans often covalently attach to proteins and lipids to regulate cellular recognition, adhesion, and signaling. The importance of glycans in both the developing and mature nervous system is well characterized. Moreover, glycan dysregulation has been observed in NDs such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Therefore, glycans are promising but underexploited therapeutic targets. In this review, we summarize the current understanding of glycans in NDs. We also discuss a number of natural products that functionally mimic glycans to protect neurons, which therefore represent promising new therapeutic approaches for patients with NDs.}, }
@article {pmid31888078, year = {2019}, author = {Lanznaster, D and Bourgeais, J and Bruno, C and Hergesheimer, RC and Thepault, RA and Vourc'h, P and Corcia, P and Andres, CR and Herault, O and Blasco, H}, title = {TDP-43-Mediated Toxicity in HEK293T Cells: A Fast and Reproducible Protocol To Be Employed in the Search of New Therapeutic Options against Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {9}, number = {1}, pages = {}, pmid = {31888078}, issn = {2073-4409}, support = {LabEx MAbImprove ANR-10-LABX-53-01//Minist&#xe8;re de l'Enseignement Sup&#xe9;rieur et de la Recherche/ ; ARD2020 Biom&#xe9;dicaments - INTRABALS//Conseil R&#xe9;gional du Centre-Val de Loire/ ; }, mesh = {Amyloid/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/etiology/metabolism/pathology ; Apoptosis/drug effects/genetics ; Cell Cycle/drug effects/genetics ; Cell Death ; Cell Survival/drug effects/genetics ; DNA-Binding Proteins/genetics/*metabolism ; Drug Discovery ; HEK293 Cells ; Humans ; Metabolome ; Metabolomics ; Mitochondria/drug effects/genetics/metabolism ; *Protein Aggregates ; *Protein Aggregation, Pathological ; Protein Binding ; Protein Transport ; Reactive Oxygen Species/metabolism ; }, abstract = {Cytoplasmic TDP-43 aggregates are a hallmark of amyotrophic lateral sclerosis (ALS). Today, only two drugs are available for ALS treatment, and their modest effect prompts researchers to search for new therapeutic options. TDP-43 represents one of the most promising targets for therapeutic intervention, but reliable and reproducible in vitro protocols for TDP-43-mediated toxicity are lacking. Here, we used HEK293T cells transfected with increasing concentrations of TDP-43-expressing plasmid to evaluate different parameters of toxicity and alterations in cellular metabolism. Overexpression of TDP-43 induced aggregates occurrence followed by the detection of 25- and 35-kDa forms of TDP-43. TDP-43 overexpression decreased cell viability and increased cells arrested at G2/M phase and nuclear fragmentation. Analysis of the energetic metabolism showed a tendency to decrease oxidative phosphorylation and increase glycolysis, but no statistical differences were observed. Metabolomics revealed alterations in different metabolites (mainly sphingolipids and glycerophospholipids) in cells overexpressing TDP-43. Our data reveal the main role of TDP-43 aggregation in cellular death and highlight novel insight into the mechanism of cellular toxicity induced by TDP-43. Here, we provide a simple, sensitive, and reliable protocol in a human-derived cell line to be used in high-throughput screenings of potential therapeutic molecules for ALS treatment.}, }
@article {pmid31883180, year = {2020}, author = {Niida-Kawaguchi, M and Kakita, A and Noguchi, N and Kazama, M and Masui, K and Kato, Y and Yamamoto, T and Sawada, T and Kitagawa, K and Watabe, K and Shibata, N}, title = {Soluble iron accumulation induces microglial glutamate release in the spinal cord of sporadic amyotrophic lateral sclerosis.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {40}, number = {2}, pages = {152-166}, doi = {10.1111/neup.12632}, pmid = {31883180}, issn = {1440-1789}, support = {2018-12//Brain Research Institute, Niigata University/ ; 2017-15//Brain Research Institute, Niigata University/ ; 2016-02//Brain Research Institute, Niigata University/ ; //TWMU Career Development Center/ ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*metabolism ; Cadaver ; Female ; Glutamic Acid/*metabolism ; Humans ; Iron/*metabolism ; Male ; Microglia/*metabolism ; Middle Aged ; Spinal Cord/metabolism/pathology ; }, abstract = {Previous studies on sporadic amyotrophic lateral sclerosis (SALS) demonstrated iron accumulation in the spinal cord and increased glutamate concentration in the cerebrospinal fluid. To clarify the relationship between the two phenomena, we first performed quantitative and morphological analyses of substances related to iron and glutamate metabolism using spinal cords obtained at autopsy from 12 SALS patients and 12 age-matched control subjects. Soluble iron content determined by the Ferrozine method as well as ferritin (Ft) and glutaminase C (GLS-C) expression levels on Western blots were significantly higher in the SALS group than in the control group, while ferroportin (FPN) levels on Western blots were significantly reduced in the SALS group as compared to the control group. There was no significant difference in aconitase 1 (ACO1) and tumor necrosis factor-alpha (TNFα)-converting enzyme (TACE) levels on Western blots between the two groups. Immunohistochemically, Ft, ACO1, TACE, TNFα, and GLS-C were proven to be selectively expressed in microglia. Immunoreactivities for FPN and hepcidin were localized in neuronal and glial cells. Based on these observations, it is predicted that soluble iron may stimulate microglial glutamate release. To address this issue, cell culture experiments were carried out on a microglial cell line (BV-2). Treatment of BV-2 cells with ferric ammonium citrate (FAC) brought about significant increases in intracellular soluble iron and Ft expression levels and conditioned medium glutamate and TNFα concentrations. Glutamate concentration was also significantly increased in conditioned media of TNFα-treated BV-2 cells. While the FAC-driven increases in glutamate and TNFα release were completely canceled by pretreatment with ACO1 and TACE inhibitors, respectively, the TNFα-driven increase in glutamate release was completely canceled by GLS-C inhibitor pretreatment. Moreover, treatment of BV-2 cells with hepcidin resulted in a significant reduction in FPN expression levels on Western blots of the intracellular total protein extracts. The present results provide in vivo and in vitro evidence that microglial glutamate release in SALS spinal cords is enhanced by intracellular soluble iron accumulation-induced activation of ACO1 and TACE and by increased extracellular TNFα-stimulated GLS-C upregulation, and suggest a positive feedback mechanism to maintain increased intracellular soluble iron levels, involving TNFα, hepcidin, and FPN.}, }
@article {pmid31877540, year = {2020}, author = {Qiao, Y and Maiti, K and Sultana, Z and Fu, L and Smith, R}, title = {Inhibition of vertebrate aldehyde oxidase as a therapeutic treatment for cancer, obesity, aging and amyotrophic lateral sclerosis.}, journal = {European journal of medicinal chemistry}, volume = {187}, number = {}, pages = {111948}, doi = {10.1016/j.ejmech.2019.111948}, pmid = {31877540}, issn = {1768-3254}, mesh = {Aldehyde Oxidase/*antagonists &amp; inhibitors/metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Antineoplastic Agents/chemistry/*pharmacology ; Enzyme Inhibitors/chemistry/*pharmacology ; Humans ; Neoplasms/*drug therapy/metabolism ; Neuroprotective Agents/chemistry/*pharmacology ; Obesity/*drug therapy/metabolism ; }, abstract = {The aldehyde oxidases (AOXs) are a small sub-family of cytosolic molybdo-flavoenzymes, which are structurally conserved proteins and broadly distributed from plants to animals. AOXs play multiple roles in both physiological and pathological processes and AOX inhibition is of increasing significance in the development of novel drugs and therapeutic strategies. This review provides an overview of the evolution and the action mechanism of AOX and the role of each domain. The review provides an update of the polymorphisms in the human AOX. This review also summarises the physiology of AOX in different organs and its role in drug metabolism. The inhibition of AOX is a promising therapeutic treatment for cancer, obesity, aging and amyotrophic lateral sclerosis.}, }
@article {pmid31873312, year = {2020}, author = {Bravo-Hernandez, M and Tadokoro, T and Navarro, MR and Platoshyn, O and Kobayashi, Y and Marsala, S and Miyanohara, A and Juhas, S and Juhasova, J and Skalnikova, H and Tomori, Z and Vanicky, I and Studenovska, H and Proks, V and Chen, P and Govea-Perez, N and Ditsworth, D and Ciacci, JD and Gao, S and Zhu, W and Ahrens, ET and Driscoll, SP and Glenn, TD and McAlonis-Downes, M and Da Cruz, S and Pfaff, SL and Kaspar, BK and Cleveland, DW and Marsala, M}, title = {Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS.}, journal = {Nature medicine}, volume = {26}, number = {1}, pages = {118-130}, pmid = {31873312}, issn = {1546-170X}, support = {R01 CA134633/CA/NCI NIH HHS/United States ; R01 EB024015/EB/NIBIB NIH HHS/United States ; R01 NS027036/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/physiopathology/*therapy ; Animals ; Atrophy ; Dependovirus/*metabolism ; Disease Progression ; Evoked Potentials, Motor ; Female ; Gene Expression Regulation ; *Gene Silencing ; *Gene Transfer Techniques ; Humans ; Inflammation/pathology ; Interneurons/pathology ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/*pathology ; Muscle Development ; Nerve Degeneration/genetics/physiopathology/*therapy ; Pia Mater/*pathology/physiopathology ; Primates ; Protein Folding ; RNA, Messenger/genetics/metabolism ; RNA, Small Interfering/administration &amp; dosage ; Spinal Cord/diagnostic imaging/*pathology/physiopathology ; Superoxide Dismutase-1/genetics/metabolism ; Swine ; }, abstract = {Gene silencing with virally delivered shRNA represents a promising approach for treatment of inherited neurodegenerative disorders. In the present study we develop a subpial technique, which we show in adult animals successfully delivers adeno-associated virus (AAV) throughout the cervical, thoracic and lumbar spinal cord, as well as brain motor centers. One-time injection at cervical and lumbar levels just before disease onset in mice expressing a familial amyotrophic lateral sclerosis (ALS)-causing mutant SOD1 produces long-term suppression of motoneuron disease, including near-complete preservation of spinal α-motoneurons and muscle innervation. Treatment after disease onset potently blocks progression of disease and further α-motoneuron degeneration. A single subpial AAV9 injection in adult pigs or non-human primates using a newly designed device produces homogeneous delivery throughout the cervical spinal cord white and gray matter and brain motor centers. Thus, spinal subpial delivery in adult animals is highly effective for AAV-mediated gene delivery throughout the spinal cord and supraspinal motor centers.}, }
@article {pmid31867846, year = {2020}, author = {de Munter, JPJM and Shafarevich, I and Liundup, A and Pavlov, D and Wolters, EC and Gorlova, A and Veniaminova, E and Umriukhin, A and Kalueff, A and Svistunov, A and Kramer, BW and Lesch, KP and Strekalova, T}, title = {Neuro-Cells therapy improves motor outcomes and suppresses inflammation during experimental syndrome of amyotrophic lateral sclerosis in mice.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {26}, number = {5}, pages = {504-517}, pmid = {31867846}, issn = {1755-5949}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*therapy ; Animals ; Anti-Inflammatory Agents/*administration &amp; dosage ; Cells, Cultured ; Hematopoietic Stem Cell Transplantation/*methods ; Inflammation Mediators/*antagonists &amp; inhibitors/metabolism ; Injections, Intraventricular/methods ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Motor Skills Disorders/genetics/metabolism/*therapy ; Superoxide Dismutase/genetics/metabolism ; Treatment Outcome ; }, abstract = {AIMS: Mutations in DNA/RNA-binding factor (fused-in-sarcoma) FUS and superoxide dismutase-1 (SOD-1) cause amyotrophic lateral sclerosis (ALS). They were reproduced in SOD-1-G93A (SOD-1) and new FUS[1-359]-transgenic (FUS-tg) mice, where inflammation contributes to disease progression. The effects of standard disease therapy and anti-inflammatory treatments were investigated using these mutants.<br><br>METHODS: FUS-tg mice or controls received either vehicle, or standard ALS treatment riluzole (8&#xa0;mg/kg/day), or anti-inflammatory drug a selective blocker of cyclooxygenase-2 celecoxib (30&#xa0;mg/kg/day) for six weeks, or a single intracerebroventricular (i.c.v.) infusion of Neuro-Cells (a preparation of 1.39&#xa0;&#xd7;&#xa0;10[6] mesenchymal and hemopoietic human stem cells, containing 5&#xa0;&#xd7;&#xa0;10[5] of CD34[+] cells), which showed anti-inflammatory properties. SOD-1 mice received i.c.v.-administration of Neuro-Cells or vehicle.<br><br>RESULTS: All FUS-tg-treated animals displayed less marked reductions in weight gain, food/water intake, and motor deficits than FUS-tg-vehicle-treated mice. Neuro-Cell-treated mutants had reduced muscle atrophy and lumbar motor neuron degeneration. This group but not celecoxib-FUS-tg-treated mice had ameliorated motor performance and lumbar expression of microglial activation marker, ionized calcium-binding adapter molecule-1 (Iba-1), and glycogen-synthase-kinase-3&#xdf; (GSK-3&#xdf;). The Neuro-Cells-treated-SOD-1 mice showed better motor functions than vehicle-treated-SOD-1 group.<br><br>CONCLUSION: The neuropathology in FUS-tg mice is sensitive to standard ALS treatments and Neuro-Cells infusion. The latter improves motor outcomes in two ALS models possibly by suppressing microglial activation.}, }
@article {pmid31866818, year = {2019}, author = {Mejzini, R and Flynn, LL and Pitout, IL and Fletcher, S and Wilton, SD and Akkari, PA}, title = {ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {1310}, pmid = {31866818}, issn = {1662-4548}, abstract = {The scientific landscape surrounding amyotrophic lateral sclerosis (ALS) continues to shift as the number of genes associated with the disease risk and pathogenesis, and the cellular processes involved, continues to grow. Despite decades of intense research and over 50 potentially causative or disease-modifying genes identified, etiology remains unexplained and treatment options remain limited for the majority of ALS patients. Various factors have contributed to the slow progress in understanding and developing therapeutics for this disease. Here, we review the genetic basis of ALS, highlighting factors that have contributed to the elusiveness of genetic heritability. The most commonly mutated ALS-linked genes are reviewed with an emphasis on disease-causing mechanisms. The cellular processes involved in ALS pathogenesis are discussed, with evidence implicating their involvement in ALS summarized. Past and present therapeutic strategies and the benefits and limitations of the model systems available to ALS researchers are discussed with future directions for research that may lead to effective treatment strategies outlined.}, }
@article {pmid31863499, year = {2020}, author = {Krzykalla, J and Benner, A and Kopp-Schneider, A}, title = {Exploratory identification of predictive biomarkers in randomized trials with normal endpoints.}, journal = {Statistics in medicine}, volume = {39}, number = {7}, pages = {923-939}, doi = {10.1002/sim.8452}, pmid = {31863499}, issn = {1097-0258}, mesh = {*Amyotrophic Lateral Sclerosis ; Biomarkers ; Computer Simulation ; Databases, Factual ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {One of the main endeavours in present-day medicine, especially in oncological research, is to provide evidence for individual treatment decisions ("stratified medicine"). In the pursuit of optimal treatment decision rules, the identification of predictive biomarkers that modify the treatment effect is essential. Proposed methods have often been based on recursive partitioning since a wide variety of interaction patterns can be captured automatically and the results are easily interpretable. Furthermore, these methods are readily extendable to high-dimensional settings by means of ensemble learning. In this article, we present predMOB, an adaptation of the model-based recursive partitioning (MOB) for subgroup analysis approach specifically tailored to the identification of predictive factors. In a simulation study, predMOB outperforms the original MOB with respect to the number of false detections and shows to be more robust in moderately complex settings. Furthermore, we compare the results of predMOB for the application to a public data base of amyotrophic lateral sclerosis patients to those obtained from the original MOB and are able to elucidate the nature of the biomarkers' effects.}, }
@article {pmid31858811, year = {2020}, author = {Kacem, I and Sghaier, I and Bougatef, S and Nasri, A and Gargouri, A and Ajroud-Driss, S and Gouider, R}, title = {Epidemiological and clinical features of amyotrophic lateral sclerosis in a Tunisian cohort.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {1-2}, pages = {131-139}, doi = {10.1080/21678421.2019.1704012}, pmid = {31858811}, issn = {2167-9223}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/*epidemiology ; Cohort Studies ; Delayed Diagnosis ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Phenotype ; Riluzole/*therapeutic use ; Survival Rate ; }, abstract = {Objective: To describe the phenotypic heterogeneity of amyotrophic lateral sclerosis (ALS) in Tunisian patients, and to define the sociodemographic features, treatments, and survival rate with ALS. Methodology: The study included 210 patients with ALS diagnosed between 2003 and 2019 in The Neurology department, Razi Hospital Tunisia. ALS patients were phenotyped and followed until their death. Results: median age of ALS onset was 54.93 ± 14.08 years (men = 56.21 ± 12.58, women = 52.36 ± 16.49). The sex-ratio was 2.0 with obvious male predominance. Juvenile ALS form was found in 5.71% of our cohort and 94, 76% of the patients had the classic ALS form. In the latter, 76.3% had spinal onset whereas bulbar onset was seen in 20.1% of patients. Spinal onset was most frequent in Juvenile ALS patients. Approximately half of the ALS patients used Riluzole (58.5%). Median survival rate was 60 months (5 years). According to univariate analysis, the factors related to survival rate of ALS patient were: age at onset, diagnostic delay, site of onset, phenotype and treatment use. The multivariate analysis revealed that age at onset, gender, diagnostic delay, superior muscles atrophy, treatment use, consanguinity, cognitive signs, dysautonomia, and ALSFRS-R score were independent prognostic factors of survival among ALS patients. Conclusion: Our Tunisian cohort was characterized by a slower disease progression and a better prognosis. Juvenile ALS patients were more common. Initial ALSFRS-R scores were higher in our population. Age at onset of Bulbar ALS was younger. Our study highlights the possible presence of genetic and environmental factors that may influence the clinical phenotype of ALS in Tunisia.}, }
@article {pmid31857831, year = {2019}, author = {Kargbo, RB}, title = {Approaches for Prevention and Treatment of Neurodegenerative Diseases: ALS and Alzheimer's.}, journal = {ACS medicinal chemistry letters}, volume = {10}, number = {12}, pages = {1588-1589}, pmid = {31857831}, issn = {1948-5875}, }
@article {pmid31853962, year = {2019}, author = {Abdul Wahid, SF and Law, ZK and Ismail, NA and Lai, NM}, title = {Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {12}, number = {12}, pages = {CD011742}, pmid = {31853962}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/complications/*therapy ; *Cell- and Tissue-Based Therapy ; Disease Progression ; Humans ; Quality of Life ; Randomized Controlled Trials as Topic ; Vital Capacity ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND), is a fatal disease associated with rapidly progressive disability, for which no definitive treatment exists. Current treatment approaches largely focus on relieving symptoms to improve the quality of life of those affected. The therapeutic potential of cell-based therapies in ALS/MND has not been fully evaluated, given the paucity of high-quality clinical trials. Based on data from preclinical studies, cell-based therapy is a promising treatment for ALS/MND. This review was first published in 2015 when the first clinical trials of cell-based therapies were still in progress. We undertook this update to incorporate evidence now available from randomised controlled trials (RCTs).<br><br>OBJECTIVES: To assess the effects of cell-based therapy for people with ALS/MND, compared with placebo or no treatment.<br><br>SEARCH METHODS: On 31 July 2019, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched two clinical trials registries for ongoing or unpublished studies.<br><br>SELECTION CRITERIA: We included RCTs that assigned people with ALS/MND to receive cell-based therapy versus a placebo or no additional treatment. Co-interventions were allowed, provided that they were given to each group equally.<br><br>DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology.<br><br>MAIN RESULTS: Two RCTs involving 112 participants were eligible for inclusion in this review. One study compared autologous bone marrow-mesenchymal stem cells (BM-MSC) plus riluzole versus control (riluzole only), while the other study compared combined intramuscular and intrathecal administration of autologous mesenchymal stem cells secreting neurotrophic factors (MSC-NTF) to placebo. The latter study was reported as an abstract and provided no numerical data. Both studies were funded by biotechnology companies. The only study that contributed to the outcome data in the review involved 64 participants, comparing BM-MSC plus riluzole versus control (riluzole only). It reported outcomes after four to six months. It had a low risk of selection bias, detection bias and reporting bias, but a high risk of performance bias and attrition bias. The certainty of evidence was low for all major efficacy outcomes, with imprecision as the main downgrading factor, because the range of plausible estimates, as shown by the 95% confidence intervals (CIs), encompassed a range that would likely result in different clinical decisions. Functional impairment, expressed as the mean change in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score from baseline to six months after cell injection was slightly reduced (better) in the BM-MSC group compared to the control group (mean difference (MD) 3.38, 95% CI 1.22 to 5.54; 1 RCT, 56 participants; low-certainty evidence). ALSFRS-R has a range from 48 (normal) to 0 (maximally impaired); a change of 4 or more points is considered clinically important. The trial did not report outcomes at 12 months. There was no clear difference between the BM-MSC and the no treatment group in change in respiratory function (per cent predicted forced vital capacity; FVC%; MD -0.53, 95% CI -5.37 to 4.31; 1 RCT, 56 participants; low-certainty evidence); overall survival at six months (risk ratio (RR) 1.07, 95% CI 0.94 to 1.22; 1 RCT, 64 participants; low-certainty evidence); risk of total adverse events (RR 0.86, 95% CI 0.62 to 1.19; 1 RCT, 64 participants; low-certainty evidence) or serious adverse events (RR 0.47, 95% CI 0.13 to 1.72; 1 RCT, 64 participants; low-certainty evidence). The study did not measure muscle strength.<br><br>AUTHORS' CONCLUSIONS: Currently, there is a lack of high-certainty evidence to guide practice on the use of cell-based therapy to treat ALS/MND. Uncertainties remain as to whether this mode of therapy is capable of restoring muscle function, slowing disease progression, and improving survival in people with ALS/MND. Although one RCT provided low-certainty evidence that BM-MSC may slightly reduce functional impairment measured on the ALSFRS-R after four to six months, this was a small phase II trial that cannot be used to establish efficacy. We need large, prospective RCTs with long-term follow-up to establish the efficacy and safety of cellular therapy and to determine patient-, disease- and cell treatment-related factors that may influence the outcome of cell-based therapy. The major goals of future research are to determine the appropriate cell source, phenotype, dose and method of delivery, as these will be key elements in designing an optimal cell-based therapy programme for people with ALS/MND. Future research should also explore novel treatment strategies, including combinations of cellular therapy and standard or novel neuroprotective agents, to find the best possible approach to prevent or reverse the neurological deficit in ALS/MND, and to prolong survival in this debilitating and fatal condition.}, }
@article {pmid31846303, year = {2020}, author = {Laos, V and Bishop, D and Lang, CA and Marsh, NM and Cantrell, KL and Buratto, SK and Singh, AK and Bowers, MT}, title = {Modulating ALS-Related Amyloidogenic TDP-43307-319 Oligomeric Aggregates with Computationally Derived Therapeutic Molecules.}, journal = {Biochemistry}, volume = {59}, number = {4}, pages = {499-508}, doi = {10.1021/acs.biochem.9b00905}, pmid = {31846303}, issn = {1520-4995}, mesh = {Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Blood-Brain Barrier/metabolism ; Computational Biology/methods ; DNA-Binding Proteins/*chemistry/*metabolism ; Drug Design ; Frontotemporal Dementia/metabolism/pathology ; Humans ; Ion Mobility Spectrometry/methods ; Microscopy, Atomic Force/methods ; Mutation ; TDP-43 Proteinopathies/*metabolism ; }, abstract = {TDP-43 aggregates are a salient feature of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and a variety of other neurodegenerative diseases, including Alzheimer's disease (AD). With an anticipated growth in the most susceptible demographic, projections predict neurodegenerative diseases will potentially affect 15 million people in the United States by 2050. Currently, there are no cures for ALS, FTD, or AD. Previous studies of the amyloidogenic core of TDP-43 have demonstrated that oligomers greater than a trimer are associated with toxicity. Utilizing a joint pharmacophore space (JPS) method, potential drugs have been designed specifically for amyloid-related diseases. These molecules were generated on the basis of key chemical features necessary for blood-brain barrier permeability, low adverse side effects, and target selectivity. Combining ion-mobility mass spectrometry and atomic force microscopy with the JPS computational method allows us to more efficiently evaluate a potential drug's efficacy in disrupting the development of putative toxic species. Our results demonstrate the dissociation of higher-order oligomers in the presence of these novel JPS-generated inhibitors into smaller oligomer species. Additionally, drugs approved by the Food and Drug Administration for the treatment of ALS were also evaluated and demonstrated to maintain higher-order oligomeric assemblies. Possible mechanisms for the observed action of the JPS molecules are discussed.}, }
@article {pmid31839873, year = {2019}, author = {Gajewski, BJ and Statland, J and Barohn, R}, title = {Using Adaptive Designs to Avoid Selecting the Wrong Arms in Multiarm Comparative Effectiveness Trials.}, journal = {Statistics in biopharmaceutical research}, volume = {11}, number = {4}, pages = {375-386}, pmid = {31839873}, issn = {1946-6315}, support = {UL1 TR002366/TR/NCATS NIH HHS/United States ; }, abstract = {Limited resources are a challenge when planning comparative effectiveness studies of multiple promising treatments, often prompting study planners to reduce the sample size to meet the financial constraints. The practical solution is often to increase the efficiency of this sample size by selecting a pair of treatments among the pool of promising treatments before the clinical trial begins. The problem with this approach is that the investigator may inadvertently leave out the most beneficial treatment. This paper demonstrates a possible solution to this problem by using Bayesian adaptive designs. We use a planned comparative effectiveness clinical trial of treatments for sialorrhea in amyotrophic lateral sclerosis as an example of the approach. Rather than having to guess at the two best treatments to compare based on limited data, we suggest putting more arms in the trial and letting response adaptive randomization (RAR) determine better arms. To ground this study relative to previous literature we first compare RAR, adaptive equal randomization (ER), arm(s) dropping, and a fixed design. Given the goals of this trial we demonstrate that we may avoid 'type III errors' - inadvertently leaving out the best treatment - with little loss in power compared to a two-arm design, even when choosing the correct two arms for the two-armed design. There are appreciable gains in power when the two arms are prescreened at random.}, }
@article {pmid31832125, year = {2019}, author = {Yap, TE and Balendra, SI and Almonte, MT and Cordeiro, MF}, title = {Retinal correlates of neurological disorders.}, journal = {Therapeutic advances in chronic disease}, volume = {10}, number = {}, pages = {2040622319882205}, pmid = {31832125}, issn = {2040-6223}, abstract = {Considering the retina as an extension of the brain provides a platform from which to study diseases of the nervous system. Taking advantage of the clear optical media of the eye and ever-increasing resolution of modern imaging techniques, retinal morphology can now be visualized at a cellular level in vivo. This has provided a multitude of possible biomarkers and investigative surrogates that may be used to identify, monitor and study diseases until now limited to the brain. In many neurodegenerative conditions, early diagnosis is often very challenging due to the lack of tests with high sensitivity and specificity, but, once made, opens the door to patients accessing the correct treatment that can potentially improve functional outcomes. Using retinal biomarkers in vivo as an additional diagnostic tool may help overcome the need for invasive tests and histological specimens, and offers the opportunity to longitudinally monitor individuals over time. This review aims to summarise retinal biomarkers associated with a range of neurological conditions including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and prion diseases from a clinical perspective. By comparing their similarities and differences according to primary pathological processes, we hope to show how retinal correlates can aid clinical decisions, and accelerate the study of this rapidly developing area of research.}, }
@article {pmid31831863, year = {2020}, author = {Cristino, L and Bisogno, T and Di Marzo, V}, title = {Cannabinoids and the expanded endocannabinoid system in neurological disorders.}, journal = {Nature reviews. Neurology}, volume = {16}, number = {1}, pages = {9-29}, pmid = {31831863}, issn = {1759-4766}, mesh = {Analgesics/metabolism/therapeutic use ; Animals ; Cannabidiol/metabolism/therapeutic use ; Cannabinoids/*metabolism/therapeutic use ; Dronabinol/metabolism/therapeutic use ; Drug Combinations ; Endocannabinoids/*metabolism/therapeutic use ; Humans ; Nervous System Diseases/*drug therapy/*metabolism ; Receptor, Cannabinoid, CB1/metabolism ; Receptor, Cannabinoid, CB2/metabolism ; }, abstract = {Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ[9]-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics. These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor. The discovery of CB2 and of endogenous cannabinoid receptor ligands (endocannabinoids) raised new possibilities for safe targeting of this endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded endocannabinoid system - known as the endocannabinoidome - that includes several mediators that are biochemically related to the endocannabinoids, and their receptors and metabolic enzymes. The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and endocannabinoids in neurological diseases into the limelight. In this Review, we provide an overview of the endocannabinoid system and the endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma.}, }
@article {pmid31831332, year = {2020}, author = {Nguyen, L and Montrasio, F and Pattamatta, A and Tusi, SK and Bardhi, O and Meyer, KD and Hayes, L and Nakamura, K and Banez-Coronel, M and Coyne, A and Guo, S and Laboissonniere, LA and Gu, Y and Narayanan, S and Smith, B and Nitsch, RM and Kankel, MW and Rushe, M and Rothstein, J and Zu, T and Grimm, J and Ranum, LPW}, title = {Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model.}, journal = {Neuron}, volume = {105}, number = {4}, pages = {645-662.e11}, pmid = {31831332}, issn = {1097-4199}, support = {K08 NS104273/NS/NINDS NIH HHS/United States ; R01 NS098819/NS/NINDS NIH HHS/United States ; R37 NS040389/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Animals ; Antibodies, Monoclonal/administration &amp; dosage/*genetics/metabolism ; Brain/metabolism ; C9orf72 Protein/*genetics/metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Female ; Frontotemporal Dementia/*genetics/metabolism ; Gene Targeting/methods ; Genetic Therapy/*methods ; HEK293 Cells ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Phenotype ; Random Allocation ; Recombinant Proteins/administration &amp; dosage/genetics/metabolism ; ran GTP-Binding Protein/antagonists &amp; inhibitors/*metabolism ; }, abstract = {The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA1 interacts with TRIM21, and α-GA1 treatment reduced GA levels, increased GA turnover, and decreased RAN toxicity and co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA1 reduced GA as well as GP and GR proteins, improved behavioral deficits, decreased neuroinflammation and neurodegeneration, and increased survival. Glycosylation of the Fc region of α-GA1 is important for cell entry and efficacy. These data demonstrate that RAN proteins drive C9-ALS/FTD in C9-BAC transgenic mice and establish a novel therapeutic approach for C9orf72 ALS/FTD and other RAN-protein diseases.}, }
@article {pmid31830646, year = {2020}, author = {Ustyantseva, EI and Medvedev, SP and Vetchinova, AS and Illarioshkin, SN and Leonov, SV and Zakian, SM}, title = {Generation of an induced pluripotent stem cell line, ICGi014-A, by reprogramming peripheral blood mononuclear cells from a patient with homozygous D90A mutation in SOD1 causing Amyotrophic lateral sclerosis.}, journal = {Stem cell research}, volume = {42}, number = {}, pages = {101675}, doi = {10.1016/j.scr.2019.101675}, pmid = {31830646}, issn = {1876-7753}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Cellular Reprogramming/*genetics ; Humans ; Induced Pluripotent Stem Cells/*metabolism ; Leukocytes, Mononuclear/*metabolism ; Mutation ; Superoxide Dismutase-1/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by death of motor neurons. To date, neither etiology nor pathogenesis of ALS are known, which leads to the absence of an effective treatment strategy. ALS patient-specific induced pluripotent stem cells (iPSCs) represent an excellent tool for the disease study. We obtained iPSCs line from peripheral blood mononuclear cells of the patient with homozygous Asp90Ala mutation in the SOD1 gene using non-integrating episomal vectors. The iPSCs line retained pathological genotype and expressed pluripotency markers. It also displayed a normal karyotype and the ability to differentiate into derivatives of three germ layers.}, }
@article {pmid31826954, year = {2019}, author = {Shi, Y and Park, KS and Kim, SH and Yu, J and Zhao, K and Yu, L and Oh, KW and Lee, K and Kim, J and Chaggar, K and Li, Y and Dolphin, AC and Catterall, WA and Ryu, SH and Yang, SN and Berggren, PO}, title = {IgGs from patients with amyotrophic lateral sclerosis and diabetes target CaVα2δ1 subunits impairing islet cell function and survival.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {116}, number = {52}, pages = {26816-26822}, pmid = {31826954}, issn = {1091-6490}, support = {206279/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) often show hallmarks of type 2 diabetes mellitus (T2DM). However, the causal link between ALS and T2DM has remained a mystery. We now demonstrate that 60% of ALS patients with T2DM (ALS-T2DM) have sera that exaggerated K[+]-induced increases in cytosolic free Ca[2+] concentration ([Ca[2+]]i) in mouse islet cells. The effect was attributed to the presence of pathogenic immunoglobulin Gs (IgGs) in ALS-T2DM sera. The pathogenic IgGs immunocaptured the voltage-dependent Ca[2+] (CaV) channel subunit CaVα2δ1 in the plasma membrane enhancing CaV1 channel-mediated Ca[2+] influx and [Ca[2+]]i, resulting in impaired mitochondrial function. Consequently, impairments in [Ca[2+]]i dynamics, insulin secretion, and cell viability occurred. These data reveal that patients with ALS-T2DM carry cytotoxic ALS-T2DM-IgG autoantibodies that serve as a causal link between ALS and T2DM by immunoattacking CaVα2δ1 subunits. Our findings may lay the foundation for a pharmacological treatment strategy for patients suffering from a combination of these diseases.}, }
@article {pmid31826134, year = {2019}, author = {Abreu Filho, AG and Tardivo, LSPC and Oliveira, ASB and Silva, HCAD}, title = {Brazilian Nursing and Psychology students' visits to patients with amyotrophic lateral sclerosis: prospective analysis.}, journal = {Arquivos de neuro-psiquiatria}, volume = {77}, number = {11}, pages = {782-791}, doi = {10.1590/0004-282X20190134}, pmid = {31826134}, issn = {1678-4227}, mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Amyotrophic Lateral Sclerosis/*psychology ; Brazil ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; *Psychology ; Quality of Life/*psychology ; Sex Factors ; Statistics, Nonparametric ; Students/*psychology ; Students, Nursing/*psychology ; Surveys and Questionnaires ; Time Factors ; Visitors to Patients/*psychology ; Young Adult ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease without a cure, but multidisciplinary treatment can maintain the quality of life (QOL) of persons with ALS (PALS). Despite health professionals possibly being affected by ALS in their care roles, little is known about the impact of ALS care on these professionals.<br><br>OBJECTIVE: To analyze the effects of interactions between PALS and Nursing/Psychology students.<br><br>METHODS: Over 12 weeks, 16 student pairs performed weekly 60-minute home visits to 16 PALS. Instruments used for analyses were the McGill Quality of Life Questionnaire for the PALS; and the Draw-a-Person test and the Desiderative Questionnaire for the students. All instruments were applied twice: at the beginning (pre-first visit) and at the end of the study (post-12 visits).<br><br>RESULTS: After 12 weeks, there was not a significant change in total QOL or its five domains (existential wellbeing, physical wellbeing, psychological wellbeing, physical symptoms, and support). Existential wellbeing/support domains contributed most to the QOL of the PALS (pre-first visit and post-12 visits). Students showed anxiety/impulsivity but preserved adequacy to reality, logical thinking and global perception with regard to the PALS. We found that students were psychologically fragile in some subgroups/moments.<br><br>CONCLUSIONS: Students' visits to PALS may contribute to the maintenance of the QOL of the patients. Additionally, visits, with psychological support for the students, seem safe and could contribute to the students' psychological maturation as health professionals. Additional psychological support may be necessary for some students in fragile subgroups/moments.}, }
@article {pmid31819203, year = {2020}, author = {Duan, W and Guo, M and Yi, L and Liu, Y and Li, Z and Ma, Y and Zhang, G and Liu, Y and Bu, H and Song, X and Li, C}, title = {The deletion of mutant SOD1 via CRISPR/Cas9/sgRNA prolongs survival in an amyotrophic lateral sclerosis mouse model.}, journal = {Gene therapy}, volume = {27}, number = {3-4}, pages = {157-169}, pmid = {31819203}, issn = {1476-5462}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; *CRISPR-Cas Systems ; Female ; *Gene Deletion ; Gene Editing/*methods ; Genetic Therapy/*methods ; HEK293 Cells ; Humans ; Male ; Mice ; Muscle, Skeletal/metabolism/pathology ; Mutation, Missense ; RNA, Guide, CRISPR-Cas Systems/genetics/metabolism ; Superoxide Dismutase-1/*genetics/metabolism ; }, abstract = {The superoxide dismutase 1 (SOD1) mutation is one of the most notable causes of amyotrophic lateral sclerosis (ALS), and modifying the mutant SOD1 gene is the best approach for the treatment of patients with ALS linked to the mutations in this gene. Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas9)/sgRNA delivered by the adeno-associated virus (AAV) system is a powerful tool for genome editing in the central nervous system (CNS). Here, we tested the capacity of the AAV-SaCas9-sgRNA system to modify mutant SOD1 in SOD1G93A transgenic mice and found that AAV9-SaCas9-sgRNA5 deleted the SOD1 gene, improved the lifespan of SOD1G93A mice by 54.6%, and notably ameliorated the performance of ALS transgenic mice. An immunochemical analysis showed that the expression of mutant SOD1 was very weak in motor neurons expressing SaCas9-sgRNA5. Consequently, the area showing muscle atrophy was more notably restored in the group treated with SaCas9-sgRNA5 compared with the group treated with SaCas9-sgLacZ. In addition, deep sequencing did not show the indel mutation in the gene highly matched to sgRNA5. Hence, AAV9-SaCas9-sgRNA-based gene editing is a feasible potential treatment for patients with ALS linked to SOD1 mutations.}, }
@article {pmid31817379, year = {2019}, author = {Schellino, R and Boido, M and Vercelli, A}, title = {JNK Signaling Pathway Involvement in Spinal Cord Neuron Development and Death.}, journal = {Cells}, volume = {8}, number = {12}, pages = {}, pmid = {31817379}, issn = {2073-4409}, mesh = {Animals ; Cell Death ; Cell Differentiation ; Central Nervous System/embryology/metabolism ; Disease Susceptibility ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; *MAP Kinase Signaling System ; Neurodegenerative Diseases/etiology/metabolism/pathology ; Neurogenesis ; Neurons/*metabolism ; Organogenesis ; Spinal Cord/embryology/*metabolism ; }, abstract = {The c-Jun NH2-terminal protein kinase (JNK) is a Janus-faced kinase, which, in the nervous system, plays important roles in a broad range of physiological and pathological processes. Three genes, encoding for 10 JNK isoforms, have been identified: jnk1, jnk2, and jnk3. In the developing spinal cord, JNK proteins control neuronal polarity, axon growth/pathfinding, and programmed cell death; in adulthood they can drive degeneration and regeneration, after pathological insults. Indeed, recent studies have highlighted a role for JNK in motor neuron (MN) diseases, such as amyotrophic lateral sclerosis and spinal muscular atrophy. In this review we discuss how JNK-dependent signaling regulates apparently contradictory functions in the spinal cord, in both the developmental and adult stages. In addition, we examine the evidence that the specific targeting of JNK signaling pathway may represent a promising therapeutic strategy for the treatment of MN diseases.}, }
@article {pmid31816444, year = {2020}, author = {Ji, T and Zhang, X and Xin, Z and Xu, B and Jin, Z and Wu, J and Hu, W and Yang, Y}, title = {Does perturbation in the mitochondrial protein folding pave the way for neurodegeneration diseases?.}, journal = {Ageing research reviews}, volume = {57}, number = {}, pages = {100997}, doi = {10.1016/j.arr.2019.100997}, pmid = {31816444}, issn = {1872-9649}, mesh = {Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Caenorhabditis elegans/metabolism ; Humans ; Mammals/metabolism ; Mitochondria/*metabolism ; Neurodegenerative Diseases/*metabolism ; Parkinson Disease/metabolism ; *Protein Folding ; Signal Transduction ; *Unfolded Protein Response ; }, abstract = {Mitochondria, which are cell compartments that are widely present in eukaryotic cells, have been shown to be involved in a variety of synthetic, metabolic, and signaling processes, thereby playing a vital role in cells. The mitochondrial unfolded protein response (mtUPR) is a response in which mitochondria reverse the signal to the nucleus and maintain mitochondrial protein homeostasis when unfolded and misfolded proteins continue to accumulate. Multiple neurodegeneration diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and familial amyotrophic lateral sclerosis (fALS), are public health challenges. Every year, countless efforts are expended trying to clarify the pathogenesis and treatment of neurological disorders, which are associated with mitochondrial dysfunction to some extent. Numerous studies have shown that mtUPR is involved in and plays an important role in the pathogenesis of neurological disorders, but the exact mechanism of the disorders is still unclear. Further study of the process of mtUPR in neurological disorders can help us more accurately understand their pathogenesis in order to provide new therapeutic targets. In this paper, we briefly review mtUPR signaling in Caenorhabditis elegans (C. elegans) and mammals and summarize the role of mtUPR in neurodegeneration diseases, including AD, PD and fALS.}, }
@article {pmid31811965, year = {2020}, author = {Woodhouse, C and Slobodian, O and Nebor, I and Xu, A and Zhebrykov, D and Montemagno, K and Kashyrina, O and Matern, T and Hoang, S and Mendez-Rosito, D and Cheng, J and Forbes, J}, title = {Risk of Infection Associated with Transmucosal Placement of Instrumentation in Clean-Contaminated Field: Systematic Analysis.}, journal = {World neurosurgery}, volume = {135}, number = {}, pages = {330-334}, doi = {10.1016/j.wneu.2019.11.168}, pmid = {31811965}, issn = {1878-8769}, mesh = {Atlanto-Axial Joint/*surgery ; Atlanto-Occipital Joint/*surgery ; Device Removal/statistics &amp; numerical data ; Humans ; *Mouth Mucosa ; *Nasal Mucosa ; Odontoid Process/*surgery ; Reoperation/statistics &amp; numerical data ; Spinal Cord Compression/surgery ; Spinal Fusion/*methods ; Surgical Wound Infection/*epidemiology ; }, abstract = {Instability of the craniovertebral junction (CVJ) following odontoidectomy is relatively common. Traditionally, separate stage posterior atlantoaxial ± occipitocervical fusion is used for treatment. A transmucosal approach using a clean-contaminated route is associated with hypothetical risks of infectious complications. There is a paucity of information in the literature assessing the risk of surgical site infection (SSI) using the transmucosal approach for hardware placement. The authors conducted a literature search through PubMed identifying patients with pathology requiring transmucosal (i.e., transnasal or transoral) CVJ fixation. Studies that described 1) cases requiring a transmucosal approach and 2) associated infectious complications were included. Rates of SSIs, device removal, unplanned reoperation, and hardware failures were analyzed. Descriptive statistics and odds ratios (ORs) were used to compare complications. Nine studies with a total of 431 patients were identified. There were 4 (0.93%) superficial SSIs and 4 (0.93%) deep SSIs. In total, 1.86% of patients experienced SSI. There were 18 (4.18%) cases of unplanned reoperation, 4 (0.93%) related to SSI. Five (1.16%) patients required removal of their anterior fixation device, 4 (0.93%) related to SSI. ORs comparing our results with Medvedev et al's retrospective National Surgical Quality Improvement Program study assessing the risk associated with posterior cervical fixation showed no statistical difference between postoperative infection rates (OR = 0.72, P = 0.36). An extensive review of the literature found no evidence to suggest placement of spinal hardware via transmucosal corridor is associated with an increased risk of SSI.}, }
@article {pmid31800978, year = {2020}, author = {Marsala, M and Kamizato, K and Tadokoro, T and Navarro, M and Juhas, S and Juhasova, J and Marsala, S and Studenovska, H and Proks, V and Hazel, T and Johe, K and Kakinohana, M and Driscoll, S and Glenn, T and Pfaff, S and Ciacci, J}, title = {Spinal parenchymal occupation by neural stem cells after subpial delivery in adult immunodeficient rats.}, journal = {Stem cells translational medicine}, volume = {9}, number = {2}, pages = {177-188}, pmid = {31800978}, issn = {2157-6580}, support = {P30 NS047101/NS/NINDS NIH HHS/United States ; R01 OD018272/OD/NIH HHS/United States ; }, mesh = {Animals ; Neural Stem Cells/*metabolism ; Parenchymal Tissue/cytology/*metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Neural precursor cells (NSCs) hold great potential to treat a variety of neurodegenerative diseases and injuries to the spinal cord. However, current delivery techniques require an invasive approach in which an injection needle is advanced into the spinal parenchyma to deliver cells of interest. As such, this approach is associated with an inherent risk of spinal injury, as well as a limited delivery of cells into multiple spinal segments. Here, we characterize the use of a novel cell delivery technique that employs single bolus cell injections into the spinal subpial space. In immunodeficient rats, two subpial injections of human NSCs were performed in the cervical and lumbar spinal cord, respectively. The survival, distribution, and phenotype of transplanted cells were assessed 6-8 months after injection. Immunofluorescence staining and mRNA sequencing analysis demonstrated a near-complete occupation of the spinal cord by injected cells, in which transplanted human NSCs (hNSCs) preferentially acquired glial phenotypes, expressing oligodendrocyte (Olig2, APC) or astrocyte (GFAP) markers. In the outermost layer of the spinal cord, injected hNSCs differentiated into glia limitans-forming astrocytes and expressed human-specific superoxide dismutase and laminin. All animals showed normal neurological function for the duration of the analysis. These data show that the subpial cell delivery technique is highly effective in populating the entire spinal cord with injected NSCs, and has a potential for clinical use in cell replacement therapies for the treatment of ALS, multiple sclerosis, or spinal cord injury.}, }
@article {pmid31800202, year = {2020}, author = {Mulholland, K and Sullivan, HJ and Garner, J and Cai, J and Chen, B and Wu, C}, title = {Three-Dimensional Structure of RNA Monomeric G-Quadruplex Containing ALS and FTD Related G4C2 Repeat and Its Binding with TMPyP4 Probed by Homology Modeling based on Experimental Constraints and Molecular Dynamics Simulations.}, journal = {ACS chemical neuroscience}, volume = {11}, number = {1}, pages = {57-75}, doi = {10.1021/acschemneuro.9b00572}, pmid = {31800202}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis ; C9orf72 Protein/chemistry ; DNA Repeat Expansion ; *Frontotemporal Dementia ; *G-Quadruplexes ; Humans ; *Molecular Dynamics Simulation ; }, abstract = {The G-quadruplex-forming hexanucleotide repeat expansion (HRE), d(G4C2)n, within the human C9orf72 gene is the root cause for familial amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). A recent study has shown that TMPyP4 has good potential to work as a RNA G-quadruplex binder in treating ALS and FTD. Although the high-resolution structure of the monomeric DNA antiparallel G-quadruplex form of the monomeric hexanucleotide repeat was recently solved, the RNA parallel G-quadruplex structure and its complex with TMPyP4 are not available yet. In this study, we first constructed the homology model for the parallel monomeric RNA G-quadruplex of r(G4C2)3G4 based on experimental constraints and the parallel monomeric G-quadruplex DNA crystal structure. Although the G-tetra core of the homology model was stable observed in 15 μs molecular dynamics (MD) simulations, we observed that the loops adopt additional conformations besides the initial crystal conformation, where TMPyP4 binding was found to reduce the loop fluctuation of the RNA monomeric G-quadruplex. Next, we probed the elusive binding behavior of TMPyP4 to the RNA monomeric G-quadruplex. Encouragingly, the binding modes observed are similar to the modes observed in two experimental complexes of a parallel DNA G-quadruplex with TMPyP4. We also constructed a Markov state model to provide insights into the binding pathways. Together, the findings from our study may assist future development of G-quadruplex-specific ligands in the treatment of neurodegenerative diseases like ALS and FTD.}, }
@article {pmid31798922, year = {2019}, author = {Russell, T and Paul, D and Scott-Morgan, P and Wright, M and Kenefick, N}, title = {Thriving, not just surviving, with motor neurone disease. The outcome of the first pre-emptive 'triple-ostomy'.}, journal = {Oxford medical case reports}, volume = {2019}, number = {10}, pages = {omz109}, pmid = {31798922}, issn = {2053-8855}, abstract = {The following report details the multidisciplinary treatment of a patient with motor neurone disease. The patient, who requested publication of this case, is a highly intelligent and distinguished robotic scientist. He was diagnosed with amyotrophic lateral sclerosis in 2017 and his personal approach to his condition has been to use modern technology and all treatment options to maximise his quality and duration of life. After his research, the patient decided that his life would be significantly improved by formation of an elective 'triple-ostomy', this being an end colostomy and suprapubic catheter (for continence), and a percutaneous gastrostomy (for nutrition). We report the peri-operative multidisciplinary approach taken with this case, the surgical procedures, the potential risks and the outcome. The patient is delighted with the result and aims to raise awareness that this may be a treatment option in highly selected patients.}, }
@article {pmid31796494, year = {2019}, author = {Imamura, K and Izumi, Y and Banno, H and Uozumi, R and Morita, S and Egawa, N and Ayaki, T and Nagai, M and Nishiyama, K and Watanabe, Y and Hanajima, R and Oki, R and Fujita, K and Takahashi, N and Ikeda, T and Shimizu, A and Morinaga, A and Hirohashi, T and Fujii, Y and Takahashi, R and Inoue, H}, title = {Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic lateral sclerosis Medicine (iDReAM) study: protocol for a phase I dose escalation study of bosutinib for amyotrophic lateral sclerosis patients.}, journal = {BMJ open}, volume = {9}, number = {12}, pages = {e033131}, pmid = {31796494}, issn = {2044-6055}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy ; Aniline Compounds/*administration &amp; dosage ; Clinical Trials, Phase I as Topic ; Drug Repositioning/methods ; Female ; Humans ; Male ; Molecular Targeted Therapy/methods ; Motor Neurons/drug effects ; Nitriles/*administration &amp; dosage ; Pluripotent Stem Cells/drug effects ; Protein Kinase Inhibitors/*administration &amp; dosage ; Quinolines/*administration &amp; dosage ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and severe neurodegenerative disease caused by motor neuron death. There have as yet been no fundamental curative medicines, and the development of a medicine for ALS is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified an Src/c-Abl inhibitor, bosutinib, as a candidate molecular targeted therapy for ALS. The objectives of this study are to evaluate the safety and tolerability of bosutinib for the treatment of patients with ALS and to explore the efficacy of bosutinib on ALS. This study is the first clinical trial of administered bosutinib for patients with ALS.<br><br>METHODS AND ANALYSIS: An open-label, multicentre phase I dose escalation study has been designed. The study consists of a 12-week observation period, a 1-week transitional period, a 12-week study treatment period and a 4-week follow-up period. After completion of the transitional period, subjects whose total ALS Functional Rating Scale-Revised (ALSFRS-R) score decreased by 1-3 points during the 12-week observation period receive bosutinib for 12 weeks. Three to six patients with ALS are enrolled in each of the four bosutinib dose levels (100, 200, 300 or 400&#x2009;mg/day) to evaluate the safety and tolerability under a 3+3&#x2009;dose escalation study design. Dose escalation and maximum tolerated dose are determined by the safety assessment committee comprising oncologists/haematologists and neurologists based on the incidence of dose-limiting toxicity in the first 4 weeks of the treatment at each dose level. A recommended phase II dose is determined by the safety assessment committee on completion of the 12-week study treatment in all subjects at all dose levels. The efficacy of bosutinib is also evaluated exploratorily using ALS clinical scores and biomarkers.<br><br>ETHICS AND DISSEMINATION: This study received full ethical approval from the institutional review board of each participating site. The findings of the study will be disseminated in peer-reviewed journals and at scientific conferences.<br><br>TRIAL REGISTRATION NUMBER: UMIN000036295; Pre-results, JMA-IIA00419; Pre-results.}, }
@article {pmid31792092, year = {2020}, author = {Feustel, AC and MacPherson, A and Fergusson, DA and Kieburtz, K and Kimmelman, J}, title = {Risks and benefits of unapproved disease-modifying treatments for neurodegenerative disease.}, journal = {Neurology}, volume = {94}, number = {1}, pages = {e1-e14}, pmid = {31792092}, issn = {1526-632X}, mesh = {Humans ; *Neurodegenerative Diseases ; Risk Assessment ; United States ; }, abstract = {OBJECTIVE: To determine whether patients randomized to unapproved, disease-modifying interventions in neurodegenerative disease trials have better outcomes than patients randomized to placebo by performing a systematic review and meta-analysis of risk and benefit experienced by patients in randomized placebo-controlled trials testing investigational treatments for Alzheimer disease, Parkinson disease, Huntington disease, or amyotrophic lateral sclerosis (ALS).<br><br>METHODS: We searched MEDLINE, Embase, and ClinicalTrials.gov for results of randomized trials testing non-Food and Drug Administration-approved, putatively disease-modifying interventions from January 2005 to May 2018. Trial characteristics were double-extracted. Coprimary endpoints were the treatment advantage over placebo on efficacy (standardized mean difference in outcomes) and safety (risk ratios of serious adverse events and withdrawals due to adverse events), calculated with random effects meta-analyses. The study was registered on PROSPERO (CRD42018103798).<br><br>RESULTS: We included 113 trials (n = 39,875 patients). There was no significant efficacy advantage associated with assignment to putatively disease-modifying interventions compared to placebo for Alzheimer disease (standardized mean difference [SMD] -0.03, 95% confidence interval [CI] -0.07 to 0.01), Parkinson disease (SMD -0.09, 95% CI -0.32 to 0.15), ALS (SMD 0.02, 95% CI -0.25 to 0.30), or Huntington disease (0.02, 95% CI -0.27 to 0.31). Patients with Alzheimer disease assigned to active treatment were at higher risk of experiencing serious adverse events (risk ratio [RR] 1.15, 95% CI 1.04-1.27) and withdrawals due to adverse events (RR 1.44, 95% CI 1.21-1.70).<br><br>CONCLUSIONS: Assignment to active treatment was not beneficial for any of the indications examined and may have been slightly disadvantageous for patients with Alzheimer disease. Our findings suggest that patients with neurodegenerative diseases are not, on the whole, harmed by assignment to placebo when participating in trials.}, }
@article {pmid31789770, year = {2020}, author = {Unal, E and Anderson, B and Helber, A and Marks, JH}, title = {Cannabinoids: A Guide for Use in the World of Gastrointestinal Disease.}, journal = {Journal of clinical gastroenterology}, volume = {54}, number = {9}, pages = {769-788}, doi = {10.1097/MCG.0000000000001287}, pmid = {31789770}, issn = {1539-2031}, mesh = {*Cannabinoids/adverse effects ; *Cannabis ; Endocannabinoids ; *Gastrointestinal Diseases/drug therapy ; Humans ; Receptors, Cannabinoid ; }, abstract = {Cannabinoids have been known as the primary component of cannabis for decades, but the characterization of the endocannabinoid system (ECS) in the 1990s opened the doors for cannabis' use in modern medicine. The 2 main receptors of this system, cannabinoid receptors 1 and 2, are found on cells of various tissues, with significant expression in the gastrointestinal (GI) tract. The characterization of the ECS also heralded the understanding of endocannabinoids, naturally occurring compounds synthesized in the human body. Via secondary signaling pathways acting on vagal nerves, nociceptors, and immune cells, cannabinoids have been shown to have both palliative and detrimental effects on the pathophysiology of GI disorders. Although research on the effects of both endogenous and exogenous cannabinoids has been slow due to the complicated legal history of cannabis, discoveries of cannabinoids' treatment potential have been found in various fields of medicine, including the GI world. Medical cannabis has since been offered as a treatment for a myriad of conditions and malignancies, including cancer, human immunodeficiency virus/acquired immunodeficiency syndrome, multiple sclerosis, chronic pain, nausea, posttraumatic stress disorder, amyotrophic lateral sclerosis, cachexia, glaucoma, and epilepsy. This article hopes to create an overview of current research on cannabinoids and the ECS, detail the potential advantages and pitfalls of their use in GI diseases, and explore possible future developments in this field.}, }
@article {pmid31788795, year = {2020}, author = {Rajabinejad, M and Ranjbar, S and Afshar Hezarkhani, L and Salari, F and Gorgin Karaji, A and Rezaiemanesh, A}, title = {Regulatory T cells for amyotrophic lateral sclerosis/motor neuron disease: A clinical and preclinical systematic review.}, journal = {Journal of cellular physiology}, volume = {235}, number = {6}, pages = {5030-5040}, doi = {10.1002/jcp.29401}, pmid = {31788795}, issn = {1097-4652}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*immunology/pathology ; Humans ; Inflammation/*immunology/pathology ; Motor Neuron Disease/genetics/*immunology/pathology ; Motor Neurons/immunology/metabolism/pathology ; Quality of Life ; T-Lymphocytes, Regulatory/*immunology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by neuronal degeneration and inflammation in the nerves. The role of the immune system has been concentrated by researchers in the etiopathogenesis of the disease. Given the inhibitory roles of regulatory T cells (Tregs), it is expected that increasing or activating their populations in patients with ALS can have significant therapeutic effects. Here we searched databases, including CENTRAL, MEDLINE, CINAHL Plus, clinicaltrials.gov, and ICTRP for randomized clinical trials (RCTs) and non-RCTs until March 2019. For preclinical studies, we searched PubMed, Scopus, and Google Scholar up to June 2019. We also included preclinical studies, due to the lack of clinical information available, which used Tregs (or directly targeting them) for treating mice models of ALS. We identified 29 records (CENTRAL 7, MEDLINE 4, CINAHL Plus 8, and clinicaltrials.gov 10) and removed 10 duplicated publications. After screening, we identified one RCT which had been published as an abstract, three non-RCTs, and four ongoing studies. We also identified 551 records (PubMed 446, Google Scholar 68, and Scopus 37) for preclinical studies and performed a meta-analysis. Finally, we found three papers that matched our inclusion criteria for preclinical studies. Results indicated the effectiveness of the application of Tregs in the treatment of ALS. Our meta-analysis on preclinical studies revealed that Tregs significantly prolonged survival in mice models of ALS. Overall, our analysis testified that exertion of Tregs in the treatment of ALS is a promising approach, that notwithstanding, requires further evaluations.}, }
@article {pmid31788329, year = {2019}, author = {Zhang, X and Chen, S and Lu, K and Wang, F and Deng, J and Xu, Z and Wang, X and Zhou, Q and Le, W and Zhao, Y}, title = {Verapamil Ameliorates Motor Neuron Degeneration and Improves Lifespan in the SOD1[G93A] Mouse Model of ALS by Enhancing Autophagic Flux.}, journal = {Aging and disease}, volume = {10}, number = {6}, pages = {1159-1173}, pmid = {31788329}, issn = {2152-5250}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, paralytic disorder caused by selective degeneration of motor neurons in the brain and spinal cord. Our previous studies indicated that abnormal protein aggregation and dysfunctional autophagic flux might contribute to the disease pathogenesis. In this study, we have detected the role of the Ca[2+] dependent autophagic pathway in ALS by using the L-type channel Ca[2+] blocker, verapamil. We have found that verapamil significantly delayed disease onset, prolonged the lifespan and extended disease duration in SOD1[G93A] mice. Furthermore, verapamil administration rescued motor neuron survival and ameliorated skeletal muscle denervation in SOD1[G93A] mice. More interestingly, verapamil significantly reduced SOD1 aggregation and improved autophagic flux, which might be mediated the inhibition of calpain 1 activation in the spinal cord of SOD1[G93A] mice. Furthermore, we have demonstrated that verapamil reduced endoplasmic reticulum stress and suppressed glia activation in SOD1[G93A] mice. Collectively, our study indicated that verapamil is neuroprotective in the ALS mouse model and the Ca[2+]-dependent autophagic pathway is a possible therapeutic target for the treatment of ALS.}, }
@article {pmid31782132, year = {2020}, author = {Rekatsina, M and Paladini, A and Piroli, A and Zis, P and Pergolizzi, JV and Varrassi, G}, title = {Pathophysiology and Therapeutic Perspectives of Oxidative Stress and Neurodegenerative Diseases: A Narrative Review.}, journal = {Advances in therapy}, volume = {37}, number = {1}, pages = {113-139}, pmid = {31782132}, issn = {1865-8652}, mesh = {Central Nervous System Agents/administration &amp; dosage/adverse effects/*therapeutic use ; Humans ; Inflammation/*physiopathology ; Neurodegenerative Diseases/*drug therapy/*physiopathology ; Oxidative Stress/*physiology ; }, abstract = {INTRODUCTION: Neurodegeneration is the term describing the death of neurons both in the central nervous system and periphery. When affecting the central nervous system, it is responsible for diseases like Alzheimer's disease, Parkinson's disease, Huntington's disorders, amyotrophic lateral sclerosis, and other less frequent pathologies. There are several common pathophysiological elements that are shared in the neurodegenerative diseases. The common denominators are oxidative stress (OS) and inflammatory responses. Unluckily, these conditions are difficult to treat. Because of the burden caused by the progression of these diseases and the simultaneous lack of efficacious treatment, therapeutic approaches that could target the interception of development of the neurodegeneration are being widely investigated. This review aims to highlight the most recent proposed novelties, as most of the previous approaches have failed. Therefore, older approaches may currently be used by healthcare professionals and are not being presented.<br><br>METHODS: This review was based on an electronic search of existing literature, using PubMed as primary source for important review articles, and important randomized clinical trials, published in the last 5&#xa0;years. Reference lists from the most recent reviews, as well as additional sources of primary literature and references cited by relevant articles, were used.<br><br>RESULTS: Eighteen natural pharmaceutical substances and 24 extracted or recombinant products, and artificial agents that can be used against OS, inflammation, and neurodegeneration were identified. After presenting the most common neurodegenerative diseases and mentioning some of the basic mechanisms that lead to neuronal loss, this paper presents up to date information that could encourage the development of better therapeutic strategies.<br><br>CONCLUSIONS: This review shares the new potential pharmaceutical and not pharmaceutical options that have been recently introduced regarding OS and inflammatory responses in neurodegenerative diseases.}, }
@article {pmid31776380, year = {2019}, author = {Granucci, EJ and Griciuc, A and Mueller, KA and Mills, AN and Le, H and Dios, AM and McGinty, D and Pereira, J and Elmaleh, D and Berry, JD and Paganoni, S and Cudkowicz, ME and Tanzi, RE and Sadri-Vakili, G}, title = {Cromolyn sodium delays disease onset and is neuroprotective in the SOD1[G93A] Mouse Model of amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {17728}, pmid = {31776380}, issn = {2045-2322}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Cromolyn Sodium/pharmacology/*therapeutic use ; Cytokines/blood/genetics/metabolism ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Motor Neurons/drug effects ; Neuromuscular Junction/drug effects ; Neuroprotective Agents/pharmacology/*therapeutic use ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Accumulating evidence suggests that neuroinflammatory processes are implicated in the initiation and progression of amyotrophic lateral sclerosis (ALS). Previous reports have demonstrated an increase in microgliosis and astrogliosis in the lumbar spinal cord of SOD1[G93A] transgenic mice before the onset of symptoms, a neuroinflammatory response which correlated with disease progression. Importantly, early stage homeostatic microglia enhanced motor neuron survival, while pro-inflammatory microglia were toxic to motor neurons in the SOD1[G93A] mice. Recent studies from our group have demonstrated that cromolyn sodium, an FDA approved compound, exerts neuroprotective effects in mouse models of Alzheimer's disease by altering microglial cell activation. Here, we tested the neuroprotective and anti-inflammatory effects of cromolyn sodium in the SOD1[G93A] mouse model of ALS. Our results indicate that cromolyn sodium treatment significantly delayed the onset of neurological symptoms, and improved deficits in PaGE performance in both male and female mice, however, there was only an effect on survival in female mice. Furthermore, there was a significant increase in motor neuron survival in the lumbar spinal cord as well as a significant decrease in the denervation of the neuromuscular junction of the tibialis anterior muscle in cromolyn treated transgenic SOD1[G93A] mice. Lastly, cromolyn treatment decreased the expression of pro-inflammatory cytokines/chemokines in the lumbar spinal cord and plasma and decreased mast cell degranulation in the tibialis anterior muscle of transgenic SOD1[G93A] mice. Together, these findings suggest that cromolyn sodium provides neuroprotection in the SOD1[G93A] mice by decreasing the inflammatory response.}, }
@article {pmid31774307, year = {2020}, author = {Montalvo, RN and Doerr, V and Min, K and Szeto, HH and Smuder, AJ}, title = {Doxorubicin-induced oxidative stress differentially regulates proteolytic signaling in cardiac and skeletal muscle.}, journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, volume = {318}, number = {2}, pages = {R227-R233}, doi = {10.1152/ajpregu.00299.2019}, pmid = {31774307}, issn = {1522-1490}, support = {17GRNT33661052/AHA/American Heart Association-American Stroke Association/United States ; }, mesh = {Activating Transcription Factor 4/metabolism ; Animals ; Antibiotics, Antineoplastic/*toxicity ; CCAAT-Enhancer-Binding Proteins/metabolism ; Cardiotoxicity ; Diaphragm/*drug effects/metabolism ; Doxorubicin/*toxicity ; Eukaryotic Initiation Factor-2/metabolism ; Female ; Heart Diseases/*chemically induced/metabolism ; Lysosomes/drug effects/metabolism ; Mitochondria, Heart/drug effects/metabolism ; Mitochondria, Muscle/drug effects/metabolism ; Myocytes, Cardiac/*drug effects/metabolism ; Oxidative Stress/*drug effects ; Proteasome Endopeptidase Complex/drug effects/metabolism ; Proteolysis/*drug effects ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Unfolded Protein Response/drug effects ; }, abstract = {Doxorubicin (DOX) is a highly effective antineoplastic agent used in cancer treatment. Unfortunately, clinical use of DOX is limited due to the development of dose-dependent toxicity to cardiac and respiratory (i.e., diaphragm) muscles. After administration, DOX preferentially localizes to the inner mitochondrial membrane, where it promotes cellular toxicity via enhanced mitochondrial reactive oxygen species (ROS) production. Although recent evidence suggests that amelioration of mitochondrial ROS emission preserves cardiorespiratory muscle function following DOX treatment, the mechanisms responsible for this protection remain unknown. Therefore, we tested the hypothesis that DOX-induced mitochondrial ROS production is required to stimulate pathological signaling by the autophagy/lysosomal system (ALS), the ubiquitin-proteasome pathway (UPP), and the unfolded protein response (UPR). Cause and effect were determined by administration of the mitochondria-targeted peptide SS-31 to DOX-treated animals. Interestingly, while SS-31 abrogated aberrant ROS emission in cardiorespiratory muscles of DOX-treated animals, our results revealed muscle-specific regulation of effector pathways. In the heart, SS-31 prevented DOX-induced proteolytic signaling through the ALS and UPP. In contrast, ALS signaling was inhibited by SS-31 in the diaphragm, but the UPP was not affected. UPR signaling was activated in both muscles at eukaryotic translation initiation factor 2α (eIF2α) S51 in the heart and diaphragm of DOX-treated animals and was attenuated with SS-31 treatment in both tissues. However, downstream signaling of eIF2α (activating transcription factor 4 and CCAAT/enhancer-binding protein homologous protein) was diminished in the heart but upregulated in the diaphragm with DOX. Collectively, these results show that DOX-induced ROS production plays distinct roles in the regulation of cardiac and diaphragm muscle proteolysis.}, }
@article {pmid31763099, year = {2019}, author = {Andrade, FC and Vergetti, V and Cozza, G and Falcao, MC and Azevedo, G}, title = {Amyotrophic Lateral Sclerosis-like Syndrome after Chikungunya.}, journal = {Cureus}, volume = {11}, number = {10}, pages = {e5876}, pmid = {31763099}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS)-like syndrome refers to a group of conditions whose outcome is similar to that of amyotrophic lateral sclerosis, but with different characteristics in the initial phase and response to therapy. The involvement of an earlier age group, the subacute course, and the stabilization or improvement of the clinical condition during the treatment are most important. There is still no evidence of an association between amyotrophic lateral sclerosis-like syndrome and chikungunya (CHK) infection in the literature. This report was intended to review this syndrome and present a case that occurred after the epidemic of CHK in Pernambuco in 2016. CHK is a fast-onset febrile illness characterized by intense asthenia, arthralgia, myalgia, headache, and skin rash. Reports range from encephalitis, optic neuritis, myeloradiculitis to Guillain-Barré syndrome, generating drastic sequelae such as mental deficiency, blindness, and persistent paralysis. This is the first case report of a possible association of ALS-like syndrome and chikungunya infection. CHK infection may cause ALS-like syndrome. There is a need for further research in this field to develop therapies for neurological complications such as that of CHK.}, }
@article {pmid31752240, year = {2019}, author = {Mammana, S and Cavalli, E and Gugliandolo, A and Silvestro, S and Pollastro, F and Bramanti, P and Mazzon, E}, title = {Could the Combination of Two Non-Psychotropic Cannabinoids Counteract Neuroinflammation? Effectiveness of Cannabidiol Associated with Cannabigerol.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {55}, number = {11}, pages = {}, pmid = {31752240}, issn = {1648-9144}, support = {-//Current research funds 2019. IRCCS Centro Neurolesi "Bonino Pulejo"/ ; }, mesh = {Cannabidiol/standards/therapeutic use ; Cannabinoids/*standards/therapeutic use ; Cell Culture Techniques/methods ; Drug Therapy, Combination/methods/*standards/statistics &amp; numerical data ; Humans ; Inflammation/*prevention &amp; control ; Neurons/*drug effects ; Protective Factors ; }, abstract = {Background and Objectives: Neuroinflammation is associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this study, we investigate the anti-inflammatory, anti-oxidant, and anti-apoptotic properties of two non-psychoactive phytocannabinoids, cannabigerol (CBG) and cannabidiol (CBD). Materials and Methods: The motoneuron-like cell line NSC-34 differentiated by serum deprivation and with the additional treatment of all-trans retinoic acid (RA) is a valid model to investigate molecular events linked to neurodegeneration in ALS. Results: Pre-treatment with CBG (at 2.5 and 5 µM doses) alone and in combination with CBD (at 2.5 and 5 µM doses) was able to reduce neuroinflammation induced by a culture medium of LPS-stimulated macrophages. In particular, the pre-treatment with CBD at a 5 µM dose decreased TNF-α levels and increased IL10 and IL-37 expression. CBG-CBD association at a 5 µM dose also reduced NF-kB nuclear factor activation with low degradation of the inhibitor of kappaB alpha (IkBα). CBG and CBD co-administered at a 5 µM dose decreased iNOS expression and increased Nrf2 levels. Furthermore, the pre-treatment with the association of two non-psychoactive cannabinoids downregulated Bax protein expression and upregulated Bcl-2 expression. Our data show the anti-inflammatory, anti-oxidant, and anti-apoptotic effects PPARγ-mediated. Conclusions: Our results provide preliminary support on the potential therapeutic application of a CBG-CBD combination for further preclinical studies.}, }
@article {pmid31745214, year = {2020}, author = {Wang, T and Perera, ND and Chiam, MDF and Cuic, B and Wanniarachchillage, N and Tomas, D and Samson, AL and Cawthorne, W and Valor, EN and Murphy, JM and Turner, BJ}, title = {Necroptosis is dispensable for motor neuron degeneration in a mouse model of ALS.}, journal = {Cell death and differentiation}, volume = {27}, number = {5}, pages = {1728-1739}, pmid = {31745214}, issn = {1476-5403}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Brain/pathology ; Disease Models, Animal ; Disease Progression ; Humans ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/metabolism/*pathology ; *Necroptosis ; Nerve Degeneration/*pathology ; Neuroglia/metabolism/pathology ; Protein Kinases/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Spinal Cord/pathology ; Superoxide Dismutase/metabolism ; Up-Regulation ; }, abstract = {Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is proposed to occur by necroptosis, an inflammatory form of regulated cell death. Prior studies implicated necroptosis in ALS based on accumulation of necroptotic markers in affected tissues of patients and mouse models, and amelioration of disease in mutant superoxide dismutase 1 (SOD1[G93A]) mice with inhibition of the upstream necroptotic mediators, receptor interacting protein kinase 1 (RIPK1), and RIPK3. To definitively address the pathogenic role of necroptosis in ALS, we genetically ablated the critical terminal executioner of necroptosis, mixed lineage kinase domain-like protein (MLKL), in SOD1[G93A] mice. Disease onset, progression, and survival were not affected in SOD1[G93A] mice lacking MLKL. Motor neuron degeneration and activation of neuroinflammatory cells, astrocytes, and microglia, were independent of MLKL expression in SOD1[G93A] mice. While RIPK1 accumulation occurred in spinal cords of SOD1[G93A] mice in late stage disease, RIPK3 and MLKL expression levels were not detected in central nervous system tissues from normal or SOD1[G93A] mice at any disease stage. These findings demonstrate that necroptosis does not play an important role in motor neuron death in ALS, which may limit the potential of therapeutic targeting of necroptosis in the treatment of neurological disorders.}, }
@article {pmid33654921, year = {2019}, author = {Pérez-Berlanga, M and Laferrière, F and Polymenidou, M}, title = {SarkoSpin: A Technique for Biochemical Isolation and Characterization of Pathological TDP-43 Aggregates.}, journal = {Bio-protocol}, volume = {9}, number = {22}, pages = {e3424}, pmid = {33654921}, issn = {2331-8325}, abstract = {TDP-43 is the main aggregating protein in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Aggregated TDP-43 is resistant to diverse detergent solubilization, yet physiological TDP-43 and other abundant proteins commonly co-purify with pathological TDP-43. This mixed isolation has precluded the elucidation of the biochemical and structural features of the pathological TDP-43 and its role in disease. Here we describe SarkoSpin, a method for the isolation of pure pathological TDP-43 from patient autopsy brain by sample solubilization with Sarkosyl after nuclease treatment. This purification, which is also applicable to cell culture material, permits the study of biochemical properties of exclusively pathological TDP-43, allowing for the first time the determination of their link to the clinical presentation of FTLD. This method opens up a path for the study of pathological TDP-43 at the molecular and structural level in the heterogeneous spectrum of ALS and FTLD cases.}, }
@article {pmid31740545, year = {2019}, author = {Berry, JD and Cudkowicz, ME and Windebank, AJ and Staff, NP and Owegi, M and Nicholson, K and McKenna-Yasek, D and Levy, YS and Abramov, N and Kaspi, H and Mehra, M and Aricha, R and Gothelf, Y and Brown, RH}, title = {NurOwn, phase 2, randomized, clinical trial in patients with ALS: Safety, clinical, and biomarker results.}, journal = {Neurology}, volume = {93}, number = {24}, pages = {e2294-e2305}, pmid = {31740545}, issn = {1526-632X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*therapy ; Double-Blind Method ; Female ; Humans ; Male ; Mesenchymal Stem Cell Transplantation/*methods ; Middle Aged ; Nerve Growth Factors/*cerebrospinal fluid ; Transplantation, Autologous ; }, abstract = {OBJECTIVE: To determine the safety and efficacy of mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells (NurOwn®, autologous bone marrow-derived MSCs, induced to secrete NTFs) delivered by combined intrathecal and intramuscular administration to participants with amyotrophic lateral sclerosis (ALS) in a phase 2 randomized controlled trial.<br><br>METHODS: The study enrolled 48 participants randomized 3:1 (treatment: placebo). After a 3-month pretransplant period, participants received 1 dose of MSC-NTF cells (n = 36) or placebo (n = 12) and were followed for 6 months. CSF was collected before and 2 weeks after transplantation.<br><br>RESULTS: The study met its primary safety endpoint. The rate of disease progression (Revised ALS Functional Rating Scale [ALSFRS-R] slope change) in the overall study population was similar in treated and placebo participants. In a prespecified rapid progressor subgroup (n = 21), rate of disease progression was improved at early time points (p < 0.05). To address heterogeneity, a responder analysis showed that a higher proportion of treated participants experienced &#x2265;1.5 points/month ALSFRS-R slope improvement compared to placebo at all time points, and was significant in rapid progressors at 4 and 12 weeks (p = 0.004 and 0.046, respectively). CSF neurotrophic factors increased and CSF inflammatory biomarkers decreased in treated participants (p < 0.05) post-transplantation. CSF monocyte chemoattractant protein-1 levels correlated with ALSFRS-R slope improvement up to 24 weeks (p < 0.05).<br><br>CONCLUSION: A single-dose transplantation of MSC-NTF cells is safe and demonstrated early promising signs of efficacy. This establishes a clear path forward for a multidose randomized clinical trial of intrathecal autologous MSC-NTF cell transplantation in ALS.<br><br>CLASSIFICATION OF EVIDENCE: This phase II study provides Class I evidence.}, }
@article {pmid31732449, year = {2019}, author = {Peng, S and Jia, J and Sun, J and Xie, Q and Zhang, X and Deng, Y and Yi, L}, title = {LXW7 attenuates inflammation via suppressing Akt/nuclear factor kappa B and mitogen-activated protein kinases signaling pathways in lipopolysaccharide-stimulated BV2 microglial cells.}, journal = {International immunopharmacology}, volume = {77}, number = {}, pages = {105963}, doi = {10.1016/j.intimp.2019.105963}, pmid = {31732449}, issn = {1878-1705}, mesh = {Animals ; Anti-Inflammatory Agents/*pharmacology ; Cell Line ; Cytokines/metabolism ; Inflammation/*drug therapy/metabolism ; Inflammation Mediators/metabolism ; Lipopolysaccharides/pharmacology ; Mice ; Microglia/*drug effects/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; NF-kappa B/*metabolism ; Protective Agents/pharmacology ; Proto-Oncogene Proteins c-akt/*metabolism ; Signal Transduction/*drug effects ; Up-Regulation/drug effects ; }, abstract = {Microglia activation is closely linked to ischemia, various chronic neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis), and many other central nervous system diseases. Accumulating evidence suggests that depressing the microglial inflammatory response could be an effective treatment for inflammatory disorders. The integrin αvβ3 inhibitor LXW7 has a neuroprotective effect; however, its anti-inflammatory effects and underlying mechanism remain unclear. Thus, we examined whether LXW7 would inhibit inflammatory cytokines and mediators, and we evaluated the potential mechanisms of its neuroprotective effects. Nitrite analysis revealed LXW7 reduced the nitric oxide (NO) level. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) suggested that LXW7 suppressed the expression of proinflammatory genes for tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and anti-inflammatory gene interleukin 10 (IL-10) at the messenger ribonucleic acid level. Enzyme-linked immunosorbent assay results demonstrated that LXW7 treatment reduced the expression of prostaglandin E2 (PGE2), TNF-α, IL-1β and IL-10 at the protein level. Western blotting was conducted to confirm the upregulation of inflammatory factors, including iNOS and COX-2 at the protein level. LXW7 inhibited major genes in the Akt/NF-κB and c-Jun NH2-terminal kinase/ mitogen-activated protein kinases (JNK/MAPK) signaling pathways. Immunofluorescence revealed that LXW7 inhibited the nuclear translocation of nuclear factor kappa B (NF-κB). Thus, LXW7 effectively alleviated LPS-induced inflammatory damage and had neuroprotective effects. The anti-inflammatory effects of LXW7 may be associated with the inhibition of microglial activation via Akt/NF-κB and JNK/MAPK signaling pathways by blocking integrin αvβ3 receptor. The present study's findings suggest that LXW7 has a substantial therapeutic potential for treating inflammatory and neurodegenerative diseases.}, }
@article {pmid31730560, year = {2019}, author = {Al-Chalabi, A and Heunks, LMA and Papp, Z and Pollesello, P}, title = {Potential of the Cardiovascular Drug Levosimendan in the Management of Amyotrophic Lateral Sclerosis: An Overview of a Working Hypothesis.}, journal = {Journal of cardiovascular pharmacology}, volume = {74}, number = {5}, pages = {389-399}, doi = {10.1097/FJC.0000000000000728}, pmid = {31730560}, issn = {1533-4023}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology/physiopathology ; Animals ; Diaphragm/*innervation ; Disease Progression ; Humans ; Motor Neurons/*drug effects/pathology ; Muscle Strength/*drug effects ; Neuromuscular Agents/*therapeutic use ; Recovery of Function ; Respiration/*drug effects ; Respiratory Insufficiency/*drug therapy/pathology/physiopathology ; Simendan/*therapeutic use ; Treatment Outcome ; }, abstract = {Levosimendan is a calcium sensitizer that promotes myocyte contractility through its calcium-dependent interaction with cardiac troponin C. Administered intravenously, it has been used for nearly 2 decades to treat acute and advanced heart failure and to support the heart function in various therapy settings characterized by low cardiac output. Effects of levosimendan on noncardiac muscle suggest a possible new application in the treatment of people with amyotrophic lateral sclerosis (ALS), a neuromuscular disorder characterized by progressive weakness, and eventual paralysis. Previous attempts to improve the muscle response in ALS patients and thereby maintain respiratory function and delay progression of disability have produced some mixed results. Continuing this line of investigation, levosimendan has been shown to enhance in vitro the contractility of the diaphragm muscle fibers of non-ALS patients and to improve in vivo diaphragm neuromuscular efficiency in healthy subjects. Possible positive effects on respiratory function in people with ALS were seen in an exploratory phase 2 study, and a phase 3 clinical trial is now underway to evaluate the potential benefit of an oral form of levosimendan on both respiratory and overall functions in patients with ALS. Here, we will review the various known pharmacologic effects of levosimendan, considering their relevance to people living with ALS.}, }
@article {pmid31727215, year = {2019}, author = {Nguyen, L and Matsumoto, RR}, title = {The psychopharmacology of pseudobulbar affect.}, journal = {Handbook of clinical neurology}, volume = {165}, number = {}, pages = {243-251}, doi = {10.1016/B978-0-444-64012-3.00014-9}, pmid = {31727215}, issn = {0072-9752}, mesh = {Affective Symptoms/*drug therapy/*physiopathology/psychology ; Brain Stem/drug effects/physiopathology ; Clinical Trials as Topic/methods ; Humans ; Mood Disorders/*drug therapy/*physiopathology/psychology ; Motor Cortex/drug effects/physiopathology ; Pseudobulbar Palsy/*drug therapy/*physiopathology/psychology ; Psychopharmacology ; Psychotropic Drugs/pharmacology/therapeutic use ; }, abstract = {Pseudobulbar affect (PBA) is characterized by uncontrollable emotional episodes disconnected or disproportionate with mood, in association with an array of neurologic conditions. PBA is associated with disruption of descending control of brainstem motor circuitry and dysregulation of serotonergic and glutamatergic function. PBA has been historically under recognized, though advances resulting in more specific diagnostic criteria, validated rating scales, and an approved pharmacotherapy offer opportunities for improved treatment outcomes.}, }
@article {pmid31727149, year = {2019}, author = {Chiarotto, GB and Cartarozzi, LP and Perez, M and Biscola, NP and Spejo, AB and Gubert, F and França Junior, M and Mendez-Otero, R and de Oliveira, ALR}, title = {Tempol improves neuroinflammation and delays motor dysfunction in a mouse model (SOD1[G93A]) of ALS.}, journal = {Journal of neuroinflammation}, volume = {16}, number = {1}, pages = {218}, pmid = {31727149}, issn = {1742-2094}, support = {2014/06892-3//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 2013/16168-8//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 2017/02895-6//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 2018/05006-0//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 300553/2013-9//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 303085/2017-7//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/pathology/*physiopathology ; Animals ; Cell Survival/drug effects ; Cyclic N-Oxides/pharmacology/*therapeutic use ; Disease Models, Animal ; Female ; Inflammation/*drug therapy/metabolism/pathology ; Interleukin-1beta/metabolism ; Male ; Mice ; Motor Neurons/drug effects/metabolism/pathology ; Motor Skills/*drug effects/physiology ; Neuroprotective Agents/pharmacology/*therapeutic use ; Rotarod Performance Test ; Spin Labels ; Spinal Cord/*drug effects/metabolism/pathology ; Superoxide Dismutase-1/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {BACKGROUND: The development of new therapeutic strategies to treat amyotrophic lateral sclerosis (ALS) is of utmost importance. The use of cyclic nitroxides such as tempol may provide neuroprotection and improve lifespan. We investigated whether tempol (50 mg/kg) presents therapeutic potential in SOD1[G93A] transgenic mice.<br><br>METHODS: Tempol treatment began at the asymptomatic phase of the disease (10th week) and was administered every other day until week 14, after which it was administered twice a week until the final stage of the disease. The animals were sacrificed at week 14 (initial stage of symptoms-ISS) and at the end stage (ES) of the disease. The lumbar spinal cord of the animals was dissected and processed for use in the following techniques: Nissl staining to evaluate neuronal survival; immunohistochemistry to evaluate astrogliosis and microgliosis (ISS and ES); qRT-PCR to evaluate the expression of neurotrophic factors and pro-inflammatory cytokines (ISS); and transmission electron microscopy to evaluate the alpha-motoneurons (ES). Behavioral analyses considering the survival of animals, bodyweight loss, and Rotarod motor performance test started on week 10 and were performed every 3&#x2009;days until the end-stage of the disease.<br><br>RESULTS: The results revealed that treatment with tempol promoted greater neuronal survival (23%) at ISS compared to untreated animals, which was maintained until ES. The intense reactivity of astrocytes and microglia observed in vehicle animals was reduced in the lumbar spinal cords of the animals treated with tempol. In addition, the groups treated with tempol showed reduced expression of proinflammatory cytokines (IL1&#x3b2; and TNF&#x3b1;) and a three-fold decrease in the expression of TGF&#x3b2;1 at ISS compared with the group treated with vehicle.<br><br>CONCLUSIONS: Altogether, our results indicate that treatment with tempol has beneficial effects, delaying the onset of the disease by enhancing neuronal survival and decreasing glial cell reactivity during ALS progression in SOD1[G93A] mice.}, }
@article {pmid31726042, year = {2020}, author = {Meyer, M and Kruse, MS and Garay, L and Lima, A and Roig, P and Hunt, H and Belanoff, J and de Kloet, ER and Deniselle, MCG and De Nicola, AF}, title = {Long-term effects of the glucocorticoid receptor modulator CORT113176 in murine motoneuron degeneration.}, journal = {Brain research}, volume = {1727}, number = {}, pages = {146551}, doi = {10.1016/j.brainres.2019.146551}, pmid = {31726042}, issn = {1872-6240}, mesh = {Animals ; Astrocytes/drug effects/pathology ; Cell Death/drug effects ; Cell Survival/drug effects ; Encephalitis/pathology ; Female ; Glutamic Acid/toxicity ; Isoquinolines/*administration &amp; dosage ; Male ; Mice ; Microglia/drug effects/pathology ; Motor Neurons/*drug effects/*pathology ; Pyrazoles/*administration &amp; dosage ; Receptors, Glucocorticoid/*antagonists &amp; inhibitors ; Spinal Cord/*drug effects/*pathology ; }, abstract = {The Wobbler mouse spinal cord shows vacuolated motoneurons, glial reaction, inflammation and abnormal glutamatergic parameters. Wobblers also show deficits of motor performance. These conditions resemble amyotrophic lateral sclerosis (ALS). Wobbler mice also show high levels of corticosterone in blood, adrenals and brain plus adrenal hypertrophy, suggesting that chronically elevated glucocorticoids prime spinal cord neuroinflammation. Therefore, we analyzed if treatment of Wobbler mice with the glucocorticoid receptor (GR) antagonist CORT113176 mitigated the mentioned abnormalities. 30 mg/kg CORT113176 given daily for 3 weeks reduced motoneuron vacuolation, decreased astro and microgliosis, lowered the inflammatory mediators high mobility group box 1 protein (HMGB1), toll-like receptor 4, myeloid differentiation primary response 88 (MyD88), p50 subunit of nuclear factor kappa B (NFκB), tumor necrosis factor (TNF) receptor, and interleukin 18 (IL18) compared to untreated Wobblers. CORT113176 increased the survival signal pAKT (serine-threonine kinase) and decreased the death signal phosphorylated Junk-N-terminal kinase (pJNK), symptomatic of antiapoptosis. There was a moderate positive effect on glutamine synthase and astrocyte glutamate transporters, suggesting decreased glutamate excitotoxicity. In this pre-clinical study, Wobblers receiving CORT113176 showed enhanced resistance to fatigue in the rota rod test and lower forelimb atrophy at weeks 2-3. Therefore, long-term treatment with CORT113176 attenuated degeneration and inflammation, increased motor performance and decreased paw deformity. Antagonism of the GR may be of potential therapeutic value for neurodegenerative diseases.}, }
@article {pmid31722313, year = {2019}, author = {Aizawa, H and Kwak, S}, title = {[Perampanel for Sporadic Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {71}, number = {11}, pages = {1270-1278}, doi = {10.11477/mf.1416201437}, pmid = {31722313}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Motor Neurons/pathology ; Nitriles ; Pyridones/*therapeutic use ; }, abstract = {Disease-specific and site-selective deficiency of an RNA editing enzyme, adenosine deaminase acting on RNA 2 (ADAR2), has been demonstrated in sporadic amyotrophic lateral sclerosis (sALS) motor neurons. ADAR2 regulates Ca[2+] influx through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors via adenosine-to-inosine conversion at the glutamine/arginine site of GluA2 mRNA, which makes ADAR2 a key factor in acquired Ca[2+] resistance in motor neurons. Deficient ADAR2 of sALS motor neurons is supposed to lead to excessive Ca[2+] influx through AMPA receptors, resulting in TDP-43 pathology and nuclear pore complex pathology, and eventually motor neuronal death. We considered that AMPA receptor antagonists could strongly prevent excessive Ca[2+] influx through AMPA receptors and block motor neuronal degeneration in sALS. Perampanel, a selective non-competitive AMPA receptor antagonist, has been reported to prevent deterioration in a mouse model for sALS, in which ADAR2 is conditionally knocked out in motor neurons. Because of the therapeutic potency of perampanel for sporadic ALS, we have performed a multicenter randomized, double-blinded, placebo-controlled, parallel-group phase 2 clinical trial. The primary outcome measure is the change in ALS functional rating scale-revised after 48 weeks of treatment. The results of this study will be available in early 2020.}, }
@article {pmid31722311, year = {2019}, author = {Aoki, M and Warita, H and Kato, M and Suzuki, N}, title = {[Application of Hepatocyte Growth Factor for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {71}, number = {11}, pages = {1253-1260}, doi = {10.11477/mf.1416201435}, pmid = {31722311}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Clinical Trials, Phase I as Topic ; Disease Models, Animal ; Hepatocyte Growth Factor/*pharmacology ; Humans ; Injections, Spinal ; Japan ; Motor Neurons/pathology ; Rats ; Rats, Transgenic ; Recombinant Proteins/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. About 10% of all ALS cases are familial, and we have identified SOD1 and FUS mutations as the most common causes in a consecutive series of 111 familial ALS pedigrees in Japan (Nishiyama A, 2017). From studies of the TDP43, FUS, and C9orf72 genes, perturbations of RNA processing can be highly adverse in motor neurons. Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. We administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to transgenic rats at onset of paralysis for 4 weeks. Intrathecal administration of hrHGF attenuated motor neuron degeneration and prolonged the duration of the disease by 63% (Ishigaki A, 2007). To translate this strategy to human treatment, we induced a contusive cervical spinal cord injury in the common marmoset, a primate, and then administered hrHGF intrathecally. We conducted a first-in-human phase I trial of intrathecal hrHGF in 15 Japanese patients with ALS (Warita H, 2019). Based on the results, we are conducting a phase II trial of intrathecal hrHGF for patients with ALS.}, }
@article {pmid31722310, year = {2019}, author = {Yamashita, T and Abe, K}, title = {[Edaravone: A New Treatment for ALS].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {71}, number = {11}, pages = {1245-1251}, doi = {10.11477/mf.1416201434}, pmid = {31722310}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Edaravone/*therapeutic use ; Humans ; }, abstract = {In 1993, a mutation in the superoxyde dismutase gene, SOD1, was found causative for familial ALS, suggesting that free radical-related injury may be involved in ALS pathogenesis. Therefore, clinical trials were conducted with ALS patients using a free radical scavenger, edaravone, which was already approved for acute phase treatment of cerebral infarction in Japan. Because edaravone showed a therapeutic effect in suppressing the progression of ALS symptoms, it was approved as a new therapeutic agent in Japan, in June, 2015. In this article, we discuss the recent progress of basic and clinical research for the development of new ALS treatments.}, }
@article {pmid31719190, year = {2020}, author = {Sancho, J and Burés, E and Ferrer, S and Bondía, E and Servera, E}, title = {Usefulness of Oscillations Added to Mechanical In-Exsufflation in Amyotrophic Lateral Sclerosis.}, journal = {Respiratory care}, volume = {65}, number = {5}, pages = {596-602}, doi = {10.4187/respcare.07202}, pmid = {31719190}, issn = {1943-3654}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*therapy ; Bronchoscopy/statistics &amp; numerical data ; Cough ; Female ; Follow-Up Studies ; Humans ; Insufflation/*methods ; Male ; Middle Aged ; Prospective Studies ; Respiratory Insufficiency/therapy ; Respiratory Tract Infections/epidemiology ; Tracheostomy/statistics &amp; numerical data ; }, abstract = {BACKGROUND: Assisted coughing via mechanical in-exsufflation (MI-E) is a first-line treatment for secretion management in patients with amyotrophic lateral sclerosis (ALS) with unassisted CPF < 4.25 L/s. Some devices enable oscillations to be added to MI-E (MI-E+O). We sought to determine whether adding oscillations to MI-E enables a reduction in the use of invasive secretion management procedures (ie, bronchoscopy or tracheostomy) in subjects with ALS.<br><br>METHODS: We conducted a 12-month, prospective, randomized follow-up study of subjects with ALS for whom assisted coughing techniques were indicated. One group was treated with oscillations in addition to MI-E (MI-E+O), and the other group was treated with conventional MI-E.<br><br>RESULTS: 29 subjects were included in the MI-E group and 27 subjects were included in the MI-E+O group. Five subjects (8.9%) required invasive techniques for secretion management (3 in the MI-E group and 2 in the MI-E+O group, P = .70). Treatment with MI-E+O did not alter the risk of invasive procedures (odds ratio 0.69, 95% CI 0.10-4.50, P = .70). The mean number of respiratory infections was 0.58 &#xb1; 0.16 in the MI-E group and 0.025 &#xb1; 0.08 in the MI-E+O group (P = .10). Survival was 8.96 &#xb1; 0.18 months in the MI-E group and 7.70 &#xb1; 0.70 months in the MI-E+O group (P = .10).<br><br>CONCLUSION: Adding oscillations to MI-E did not enable a reduction in the need to perform invasive procedures for secretion management in subjects with ALS.}, }
@article {pmid31719072, year = {2019}, author = {Urbi, B and Broadley, S and Bedlack, R and Russo, E and Sabet, A}, title = {Study protocol for a randomised, double-blind, placebo-controlled study evaluating the Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease: the EMERALD trial.}, journal = {BMJ open}, volume = {9}, number = {11}, pages = {e029449}, pmid = {31719072}, issn = {2044-6055}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy ; Australia ; Disease Progression ; Double-Blind Method ; Female ; Humans ; Male ; Medical Marijuana/*therapeutic use ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Phytotherapy/*methods ; Quality of Life ; Randomized Controlled Trials as Topic ; Time Factors ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no known cure and with an average life expectancy of 3-5 years post diagnosis. The use of complementary medicine such as medicinal cannabis in search for a potential treatment or cure is common in ALS. Preclinical studies have demonstrated the efficacy of cannabinoids in extending the survival and slowing of disease progression in animal models with ALS. There are anecdotal reports of cannabis slowing disease progression in persons with ALS (pALS) and that cannabis alleviated the symptoms of spasticity and pain. However, a clinical trial in pALS with these objectives has not been conducted.<br><br>METHODS AND ANALYSIS: The Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease trial is a randomised, double-blind, placebo-controlled cannabis trial in pALS conducted at the Gold Coast University Hospital, Australia. The investigational product will be a cannabis-based medicine extract (CBME) supplied by CannTrust Inc., Canada, with a high-cannabidiol-low-tetrahydrocannabinol concentration. A total of 30 pALS with probable or definite ALS diagnosis based on the El Escorial criteria, with a symptom duration of <2 years, age between 25 and 75years and with at least 70% forced vital capacity (FVC) will be treated for 6 months. The primary objective of the study is to evaluate the efficacy of CBME compared with placebo in slowing the disease progression measured by differences in mean ALS Functional Rating Scale-Revised and FVC score between the groups at the end of treatment. The secondary objectives are to evaluate the safety and tolerability of CBME by summarising adverse events, the effects of CBME on spasticity, pain, weight loss and quality of life assessed by the differences in mean Numeric Rating Scale for spasticity and Numeric Rating Scale for pain, percentage of total weight loss and ALS specific quality of life-Revised questionnaire.<br><br>ETHICS AND DISSEMINATION: The study has been approved by the local Institutional Review Board. The results of this study will be published in a peer-reviewed journal.<br><br>TRIAL REGISTRATION NUMBER: NCT03690791.}, }
@article {pmid31709624, year = {2021}, author = {Sun, R and He, X and Jiang, X and Tao, H}, title = {The new role of riluzole in the treatment of pancreatic cancer through the apoptosis and autophagy pathways.}, journal = {Journal of cellular biochemistry}, volume = {122}, number = {9}, pages = {934-944}, doi = {10.1002/jcb.29533}, pmid = {31709624}, issn = {1097-4644}, support = {C, Foundation of Zhejiang Provincial Health Bureau (N), National Natural Science Foundation of China (81803087) Natural Science Foundation of Zhejiang Province, Outstanding Young Personnel Research Fund of Zheji//Rulin Sun/ ; }, mesh = {Humans ; Riluzole/pharmacology/therapeutic use ; Reproducibility of Results ; *Amyotrophic Lateral Sclerosis ; Apoptosis ; *Pancreatic Neoplasms/metabolism ; Autophagy ; Cell Line, Tumor ; }, abstract = {Pancreatic cancer is always diagnosed at an advanced stage. Hence, chemotherapy becomes the best choice for patients. Therefore, new anticancer drugs for pancreatic cancer are needed. Riluzole (RIL) is mainly used to treat amyotrophic lateral sclerosis clinically, but many previous studies have shown that RIL could inhibit tumors. However, no report has explored the association between RIL and pancreatic cancer. To validate this association, we performed this study. Our data showed that RIL could induce cytotoxicity, block the cell cycle, and inhibit clone formation, apoptosis, and migration in pancreatic cancer cells. Moreover, we demonstrated that RIL could suppress autophagy. However, more experiments will be needed to validate the reliability of our conclusions. In summary, our data suggest that RIL might provide clues for the development of a treatment for human pancreatic cancer in the future.}, }
@article {pmid31702465, year = {2019}, author = {Roggenbuck, J and Doyle, C and Lincoln, T and Glass, J}, title = {Theme 2 Genetics and genomics.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {sup1}, pages = {114-134}, doi = {10.1080/21678421.2019.1646990}, pmid = {31702465}, issn = {2167-9223}, abstract = {Background: A genetic basis is found in ∼70% of familial and ∼15% of sporadic ALS, in research cohorts. Clinical trials of gene-targeted therapies are underway, heralding a new era of personalized medicine in ALS treatment. However, ALS management guidelines do not include recommendations for the offer of genetic testing. Many persons with ALS who desire genetic testing are not currently offered it, and the yield of genetic testing in clinic-based ALS populations is unknown. The ALS GAP program, sponsored by the Northeast ALS (NEALS) Consortium, provides free genetic testing for patients with ALS who have a family history of ALS or dementia. We report genetic testing outcomes in the first 142 patients tested in the program.Objectives: 1) To create a pilot ALS genetic testing program for NEALS clinics, 2) To study the rate of ALS gene identification in a US clinic-based populationMethods: Persons with ALS and a family history of ALS (fALS) or dementia (dALS) who receive care at a US NEALS clinic are eligible for testing. Patients classified as fALS (having a positive family history of ALS in a 1[st], 2[nd], or 3[rd] degree relative) are eligible for C9orf72 testing, with the option to reflex to a 5 gene (SOD1, FUS, TARDBP, TBK1, VCP) panel. Patients classified as dALS (having a positive family history of dementia of any type in a 1[st] or 2[nd] degree relative) are eligible for C9orf72 testing only.Results: Currently, 29.5% (34/115) of US NEALS clinics have participated in the program. Of 142 patients who have completed testing to date, 78 (54.9%) were classified as fALS and 64 (45.1%) as dALS. Among fALS cases, 42/78 (53.9%) tested positive, including 32/78 (41%) with a C9orf72 repeat expansion, and 10/78 (12.8%) with other pathogenic or likely pathogenic variants in SOD, FUS, TARDP or VCP. Variants of uncertain significance (VUS) in FUS were identified in 2/78 (2.6%). Among dALS cases, 12/60 (20%) tested positive for C9orf72.Discussion and conclusions: Participation in ALS-GAP indicates significant clinician and patient interest in ALS genetic testing. This program addresses several current barriers to testing access, including cost, identifying appropriate candidates for testing, and appropriate test selection. Although 38% of patients who participated in the program have thus far received a genetic diagnosis, our testing outcome data suggests that the gene identification rate in fALS cases may be lower in clinic-based patients than in research cohorts, particularly for genes other than C9orf72. This program may serve as a model for the practice of ALS genetic testing in the clinic setting. Consistent, equitable testing policies, as well as an accurate understanding of the genetic profile of clinic-based ALS populations, are needed as gene-targeted therapies reach patient care.}, }
@article {pmid31702462, year = {2019}, author = {Garnaas, KR and Kittelsrud, J and Behnke, M}, title = {Theme 6 Tissue biomarkers.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {sup1}, pages = {206-216}, doi = {10.1080/21678421.2019.1646994}, pmid = {31702462}, issn = {2167-9223}, abstract = {Background: Glutamate excitotoxicity is a longstanding hypothesis in the pathophysiology of ALS. Prior studies have demonstrated increased plasma glutamate levels in ALS patients, which suggest a systemic defect in glutamate metabolism (1). The most abundant amino acid consumed in our diet is glutamate. Studies in healthy human subjects have demonstrated efficient metabolism of dietary glutamate via metabolism by enzymes present in the liver, gut lumen and residential gut bacteria. There is increasing evidence that the gut microbiota has significant CNS effects and intestinal dysbiosis has been found in the ALS transgenic SOD1[G93A] mouse model (2). If intestinal dysbiosis altered the prevalence of glutamine synthetase (GS) producing bacteria, dietary glutamate homeostasis could be impaired, leading to elevated plasma glutamate levels.Objectives: This study examined the degree of fluctuation in plasma glutamate levels seen with consumption of a protein shake in a cohort of ALS patients and family members from a single ALS center.Methods: Twenty six patients (87% of total cohort followed in the ALS center) underwent measurement of plasma amino acid analysis prior to and 1 hour following consumption of a 75 gm protein shake. A subset of 16 patients went on to receive a probiotic with high GS activity and completed serial protein challenges and amino acid analysis during the study. Ten unaffected family members of ALS patients underwent a similar protein challenge. Glutamate Metabolism Dysfunction (GMD) was defined as >30 umol difference post-prandially compared to fasting, and graded as mild (>30-60), moderate (>60-90) or severe (>90).Results: At baseline, 65.4% (17/26) ALS patients screened were GMD positive, compared to 30% (3/10) of tested family members. The severity of GMD in ALS patients was 41% mild, 29% moderate, 29% severe with only mild severity identified in family members. In the six month treatment phase, 75% (6/8) of patients with stable or improving GMD status saw significant improvements in their ALSFRS-R rate of decline, while 71.4% (5/7) with worsening or remaining severe GMD status experienced worsening of their rate of progression.Discussion and conclusions: Although limited by small sample size, this study does represent an excellent sampling within a single ALS center and is the first of its kind to investigate whether impairment in dietary glutamate metabolism exists in ALS patients. If validated in a larger ALS population, detection of glutamate metabolism dysfunction (GMD) could represent a novel biomarker linked to a potential therapeutic target in ALS patients. Planned microbiome analysis will also help in validating this hypothesis.}, }
@article {pmid31694449, year = {2021}, author = {Burk, BG and Nelson, LA}, title = {Psychotropic-Induced Priapism in a Treatment-Refractory Patient: A Case Report.}, journal = {Journal of pharmacy practice}, volume = {34}, number = {2}, pages = {309-313}, doi = {10.1177/0897190019885233}, pmid = {31694449}, issn = {1531-1937}, mesh = {Adult ; *Antipsychotic Agents/adverse effects ; *Clozapine ; Humans ; Male ; *Priapism/chemically induced ; Quetiapine Fumarate ; Risperidone ; }, abstract = {PURPOSE: A case report of multiple episodes of priapism associated with the use of 4 different psychotropic medications.<br><br>SUMMARY: A 34-year-old African American male with treatment-refractory schizoaffective disorder suffered priapism on 6 separate occasions. His medical history is relatively unremarkable, with the exception of possible undiagnosed thalassemia. All incidences were potentially attributable to psychotropic medications, with chlorpromazine, risperidone, trazodone, and quetiapine being the most likely culprits. The onset of priapism ranged from hours after a single injection of chlorpromazine, to years after multiple injections of risperidone, with nothing to indicate a medication dose or duration relationship to priapism. While on clozapine, fluphenazine, haloperidol, lurasidone, and olanzapine at varying times, the patient did not appear to develop priapism. The commonality of high-affinity alpha-1 antagonism with these psychotropics may be to blame. No pharmacokinetic or pharmacodynamic interactions were noted, which would have produced elevations in the levels of these psychotropics, nor was the patient on any phosphodiesterase type 5 (PDE-5) inhibitors or antihypertensives known to cause priapism. Depending on the offending agent, the Naranjo et al's Adverse-Reaction Probability Scale scores ranged from 5 to 8 (probable).<br><br>CONCLUSION: A man suffered from multiple episodes of priapism attributed to psychotropic medications. This is not the first case to describe this effect, but will give clinicians a timeline of events and medications that did and did not appear to elicit priapism in a patient with treatment-refractory schizoaffective disorder. Knowledge of which psychotropic medications may be more likely to induce priapism is crucial to preventing long-term penile damage.}, }
@article {pmid31692944, year = {2019}, author = {Tabassum, R and Jeong, NY}, title = {Potential for therapeutic use of hydrogen sulfide in oxidative stress-induced neurodegenerative diseases.}, journal = {International journal of medical sciences}, volume = {16}, number = {10}, pages = {1386-1396}, pmid = {31692944}, issn = {1449-1907}, mesh = {Animals ; Antioxidants/*administration &amp; dosage ; Brain/cytology/*drug effects/pathology ; Calcium Channels/drug effects/metabolism ; Clinical Trials, Phase III as Topic ; Disease Models, Animal ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Humans ; Hydrogen Sulfide/*adverse effects ; Lipid Peroxidation/drug effects ; Mitochondria/*drug effects/metabolism/pathology ; Mitochondrial Dynamics/drug effects ; Neurodegenerative Diseases/*drug therapy/etiology/pathology ; Neurons/cytology/drug effects/pathology ; Oxidative Stress/drug effects ; Potassium Channels/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Treatment Outcome ; }, abstract = {Oxidative phosphorylation is a source of energy production by which many cells satisfy their energy requirements. Endogenous reactive oxygen species (ROS) are by-products of oxidative phosphorylation. ROS are formed due to the inefficiency of oxidative phosphorylation, and lead to oxidative stress that affects mitochondrial metabolism. Chronic oxidative stress contributes to the onset of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The immediate consequences of oxidative stress include lipid peroxidation, protein oxidation, and mitochondrial deoxyribonucleic acid (mtDNA) mutation, which induce neuronal cell death. Mitochondrial binding of amyloid-β (Aβ) protein has been identified as a contributing factor in AD. In PD and HD, respectively, α-synuclein (α-syn) and huntingtin (Htt) gene mutations have been reported to exacerbate the effects of oxidative stress. Similarly, abnormalities in mitochondrial dynamics and the respiratory chain occur in ALS due to dysregulation of mitochondrial complexes II and IV. However, oxidative stress-induced dysfunctions in neurodegenerative diseases can be mitigated by the antioxidant function of hydrogen sulfide (H2S), which also acts through the potassium (KATP/K[+]) ion channel and calcium (Ca[2+]) ion channels to increase glutathione (GSH) levels. The pharmacological activity of H2S is exerted by both inorganic and organic compounds. GSH, glutathione peroxidase (Gpx), and superoxide dismutase (SOD) neutralize H2O2-induced oxidative damage in mitochondria. The main purpose of this review is to discuss specific causes and effects of mitochondrial oxidative stress in neurodegenerative diseases, and how these are impacted by the antioxidant functions of H2S to support the development of advancements in neurodegenerative disease treatment.}, }
@article {pmid31692669, year = {2019}, author = {Cai, M and Yang, EJ}, title = {Complementary and alternative medicine for treating amyotrophic lateral sclerosis: A narrative review.}, journal = {Integrative medicine research}, volume = {8}, number = {4}, pages = {234-239}, pmid = {31692669}, issn = {2213-4220}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that is characterized by selective motor neuron cell death in the motor cortex, brainstem, and spinal cord. Two drugs for ALS, riluzole and edaravone, have been approved by FDA for the treatment of ALS patients. However, they have many side effects, and riluzole extends the patient's life by only 2-3 months. Therefore, ALS patients seek an effective therapy for treating the symptoms or delaying the progression of ALS. Based on this, we review the effects of complementary and alternative medicine (CAM) in ALS animals or patients to verify the efficacy of CAM in incurable diseases. For this review, we searched published papers focusing on the effect of CAM in pre-clinical and clinical study in ALS.<br><br>METHODS: The search keywords included amyotrophic lateral sclerosis, acupuncture, herbal medicine, Traditional Chinese medicine, CAM, animals, and clinical study through electronic databases PubMed and Google Scholar from their inception until March 2019.<br><br>RESULTS: In the ALS animal model, CAM modulated the immune system to increase motor function by reducing the expression levels of neuroinflammatory proteins in the spinal cord. Besides this, ALS patients treated with herbal medicine showed improved disease symptoms, but clinical trials with larger sample sizes are needed to develop a treatment with this herbal medicine.<br><br>CONCLUSION: This review shows that CAM may be useful for ALS treatment, but more evidence regarding the efficacy and molecular mechanisms is required to establish CAM as a good therapy for the treatment of ALS patients.}, }
@article {pmid31690614, year = {2020}, author = {Chatwin, M and Simonds, AK}, title = {Long-Term Mechanical Insufflation-Exsufflation Cough Assistance in Neuromuscular Disease: Patterns of Use and Lessons for Application.}, journal = {Respiratory care}, volume = {65}, number = {2}, pages = {135-143}, doi = {10.4187/respcare.06882}, pmid = {31690614}, issn = {1943-3654}, mesh = {Adolescent ; Adult ; *Cough ; Female ; Humans ; Insufflation/*instrumentation ; Male ; Middle Aged ; Neuromuscular Diseases/*therapy ; Peak Expiratory Flow Rate ; Young Adult ; }, abstract = {BACKGROUND: Mechanical insufflation-exsufflation (MI-E) devices increase expiratory air flow and thereby promote increased cough peak flow (CPF) in conjunction with a cough. There is little research looking at long-term use of MI-E in subjects with neuromuscular disease (NMD), and no long-term study has reported CPF, MI-E device settings, and adherence.<br><br>METHODS: We evaluated 181 patient records (130 adults, 51 children) of individuals who received a MI-E device from our center between February 2014 and February 2018. Median age (interquartile range [IQR]) was 27 (14-51) y. Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and amyotrophic lateral sclerosis (ALS) were the 3 most common diagnoses.<br><br>RESULTS: MI-E devices were provided to the weakest subjects with a CPF < 160 L/min. Median (IQR) settings were insufflation, 25 (23-30) cm H2O, exsufflation -35 (-30 to -40) cm H2O, insufflation time 1.5 (1.3-1.7) s, exsufflation time 1.8 (1.5-2.0) s, and pause 1.5 (1.3-2.0) s. The inspiratory flow profile was set to high in all subjects, and no subject used supplemental oxygen with the MI-E device. When comparing insufflation pressures to exsufflation pressures, a greater negative pressure was used relative to positive pressure (P < .001). When comparing insufflation to exsufflation time, there was a significantly longer exsufflation duration (P < .001). Median (IQR) CPF at the start of MI-E was 60 (10-100) L/min. There was no correlation between either insufflation or exsufflation pressures and CPF. Median (IQR) usage for the group was 60% (13.5-100%) of days for the total days. Subjects with tracheostomies or SMA type I had the greatest adherence to treatment. Median (IQR) duration of MI-E use was 17 (8.5-32) months. Ninety-six percent of subjects were receiving ventilatory support.<br><br>CONCLUSIONS: Greater exsufflation pressures than insufflation pressures, together with a shorter insufflation time than exsufflation time, were used. Predicting good adherence among the subjects was difficult. Subjects who produced daily secretions were more likely to use MI-E every day.}, }
@article {pmid31689925, year = {2019}, author = {Cai, M and Yang, EJ}, title = {Hochu-Ekki-To Improves Motor Function in an Amyotrophic Lateral Sclerosis Animal Model.}, journal = {Nutrients}, volume = {11}, number = {11}, pages = {}, pmid = {31689925}, issn = {2072-6643}, support = {C18040//Korea Institute of Oriental Medicine/ ; KSN1621051//Korea Institute of Oriental Medicine/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Drugs, Chinese Herbal/*therapeutic use ; Female ; Male ; Mice ; Mice, Transgenic ; Oxidative Stress ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Hochu-ekki-to (Bojungikgi-Tang (BJIGT) in Korea; Bu-Zhong-Yi-Qi Tang in Chinese), a traditional herbal prescription, has been widely used in Asia. Hochu-ekki-to (HET) is used to enhance the immune system in respiratory disorders, improve the nutritional status associated with chronic diseases, enhance the mucosal immune system, and improve learning and memory. Amyotrophic lateral sclerosis (ALS) is pathologically characterized by motor neuron cell death and muscle paralysis, and is an adult-onset motor neuron disease. Several pathological mechanisms of ALS have been reported by clinical and in vitro/in vivo studies using ALS models. However, the underlying mechanisms remain elusive, and the critical pathological target needs to be identified before effective drugs can be developed for patients with ALS. Since ALS is a disease involving both motor neuron death and skeletal muscle paralysis, suitable therapy with optimal treatment effects would involve a motor neuron target combined with a skeletal muscle target. Herbal medicine is effective for complex diseases because it consists of multiple components for multiple targets. Therefore, we investigated the effect of the herbal medicine HET on motor function and survival in hSOD1[G93A] transgenic mice. HET was orally administered once a day for 6 weeks from the age of 2 months (the pre-symptomatic stage) of hSOD1[G93A] transgenic mice. We used the rota-rod test and foot printing test to examine motor activity, and Western blotting and H&amp;E staining for evaluation of the effects of HET in the gastrocnemius muscle and lumbar (L4-5) spinal cord of mice. We found that HET treatment dramatically inhibited inflammation and oxidative stress both in the spinal cord and gastrocnemius of hSOD1[G93A] transgenic mice. Furthermore, HET treatment improved motor function and extended the survival of hSOD1[G93A] transgenic mice. Our findings suggest that HET treatment may modulate the immune reaction in muscles and neurons to delay disease progression in a model of ALS.}, }
@article {pmid31684770, year = {2020}, author = {Pfeiffer, RM and Mayer, B and Kuncl, RW and Check, DP and Cahoon, EK and Rivera, DR and Freedman, DM}, title = {Identifying potential targets for prevention and treatment of amyotrophic lateral sclerosis based on a screen of medicare prescription drugs.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {3-4}, pages = {235-245}, pmid = {31684770}, issn = {2167-9223}, support = {Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/diagnosis/*epidemiology/*prevention &amp; control ; Anti-Bacterial Agents/therapeutic use ; Antihypertensive Agents/therapeutic use ; Case-Control Studies ; Female ; Humans ; Hypoglycemic Agents/therapeutic use ; Male ; Medicare/*trends ; Medicare Part D/trends ; Prescription Drugs/*therapeutic use ; United States/epidemiology ; }, abstract = {Background: Few well-established factors are associated with risk of amyotrophic lateral sclerosis (ALS). We comprehensively evaluate prescription drugs use in administrative health claims from U.S. Medicare beneficiaries in relation to ALS risk to generate hypotheses for further research. Methods: This is a population-based case-control study of 10,450 U.S. Medicare participants (ages 66-89 years) diagnosed with ALS, based on Medicare Parts A and B fee-for-service claims, between 1 January 2008, and 31 December 2014, and 104,500 controls (1:10 ratio) frequency-matched on age, sex, and selection year. Odds ratios (ORs) for the ALS association with 685 prescription drugs were estimated using logistic regression models for both a one- and three-year lag period. Covariates included demographic characteristics and key comorbidities, among other factors. Prescription drug use was based on Medicare Part D claims. We adjusted for multiple comparisons using a Bonferroni correction. Additional a priori analyses of sex hormone drugs were also undertaken. Results: In the large drug screen, we found 10 drugs significantly associated with lower ALS risk after the multiple-testing correction in a one-year and three-year lag analysis. These included several drugs for hypertension, diabetes, and cardiovascular disease. In a separate a priori inquiry of sex hormone drugs, tamoxifen was related to lower ALS risk, and testosterone to a higher risk in women. Conclusions: These associations warrant replication in databases that include information on the severity and duration of medical conditions underlying drug use, and drug use over a longer portion of individuals' lifespans, to further help evaluate confounding by indication.}, }
@article {pmid31674217, year = {2020}, author = {Zeng, SL and Sudlow, LC and Berezin, MY}, title = {Using Xenopus oocytes in neurological disease drug discovery.}, journal = {Expert opinion on drug discovery}, volume = {15}, number = {1}, pages = {39-52}, pmid = {31674217}, issn = {1746-045X}, support = {R01 CA208623/CA/NCI NIH HHS/United States ; R21 CA269099/CA/NCI NIH HHS/United States ; U54 CA199092/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System Agents/*pharmacology ; Central Nervous System Diseases/*drug therapy ; Drug Discovery/*methods ; Drug Evaluation, Preclinical/*methods ; Oocytes/*drug effects ; Xenopus ; }, abstract = {Introduction: Neurological diseases present a difficult challenge in drug discovery. Many of the current treatments have limited efficiency or result in a variety of debilitating side effects. The search of new therapies is of a paramount importance, since the number of patients that require a better treatment is growing rapidly. As an in vitro model, Xenopus oocytes provide the drug developer with many distinct advantages, including size, durability, and efficiency in exogenous protein expression. However, there is an increasing need to refine the recent breakthroughs.Areas covered: This review covers the usage and recent advancements of Xenopus oocytes for drug discovery in neurological diseases from expression and functional measurement techniques to current applications in Alzheimer's disease, painful neuropathies, and amyotrophic lateral sclerosis (ALS). The existing limitations of Xenopus oocytes in drug discovery are also discussed.Expert opinion: With the rise of aging population and neurological disorders, Xenopus oocytes, will continue to play an important role in understanding the mechanism of the disease, identification and validation of novel molecular targets, and drug screening, providing high-quality data despite the technical limitations. With further advances in oocytes-related techniques toward an accurate modeling of the disease, the diagnostics and treatment of neuropathologies will be becoming increasing personalized.}, }
@article {pmid31673451, year = {2019}, author = {Yang, M and Lee, S and Wang, T and Cha, E and Jang, J and Kim, D and Song, BK and Son, I and Kim, J and Kang, HW and Kim, S}, title = {26-Week Repeated Dose Oral Toxicity Study of KCHO-1 in Sprague-Dawley Rats.}, journal = {Journal of pharmacopuncture}, volume = {22}, number = {3}, pages = {192-199}, pmid = {31673451}, issn = {2093-6966}, abstract = {OBJECTIVES: KCHO-1(Mecasin), also called Gamijakyakgamchobuja-tang originally, is a combination of some traditional herbal medicines in East Asia. This medicine has been used mainly for alleviating neuropathic pains for centuries in Korean traditional medicine. KCHO-1 was developed to treat pain, joint contracture and muscular weakness in patients with amyotrophic lateral sclerosis. This study was carried out to investigate the chronic toxicity of KCHO-1 oral administration in rats for 26 weeks.<br><br>METHODS: Sprague-Dawely rats were divided into four groups and 10 rats were placed in the control group and the high-dose group, respectively. Group 1 was the control group and the remaining groups were the experimental groups. In the oral toxicity study, 500 mg/kg, 1,000 mg/kg, and 2,000 mg/kg of KCHO-1 were administered to the experimental group, and 10 ml/kg of sterile distilled water was administered to the control group. Survival rate, body weight, feed intake, clinical signs, and visual findings were examined. Urinalysis, ophthalmologic examination, necropsy, organ weight, hematologic examination, blood chemical examination and histopathologic examination were performed.<br><br>RESULTS: Mortality and toxicological lesions associated with the administration of test substance were not observed in all groups.<br><br>CONCLUSION: NOAEL(No observed adverse effect level) of KCHO-1 is higher than 2000 mg/kg/day. And, the above findings suggest that treatment with KCHO-1 is relatively safe.}, }
@article {pmid31671515, year = {2019}, author = {Totzeck, A and Stolte, B and Kizina, K and Bolz, S and Schlag, M and Thimm, A and Kleinschnitz, C and Hagenacker, T}, title = {Neurofilament Heavy Chain and Tau Protein Are Not Elevated in Cerebrospinal Fluid of Adult Patients with Spinal Muscular Atrophy during Loading with Nusinersen.}, journal = {International journal of molecular sciences}, volume = {20}, number = {21}, pages = {}, pmid = {31671515}, issn = {1422-0067}, mesh = {Adult ; Aged ; Biomarkers/blood/cerebrospinal fluid ; Female ; Humans ; Male ; Middle Aged ; Neurofilament Proteins/blood/*cerebrospinal fluid ; Oligonucleotides/pharmacology/*therapeutic use ; Phosphopyruvate Hydratase/blood/cerebrospinal fluid ; Pilot Projects ; Prospective Studies ; S100 Calcium Binding Protein beta Subunit/blood/cerebrospinal fluid ; Spinal Muscular Atrophies of Childhood/cerebrospinal fluid/*drug therapy ; Young Adult ; tau Proteins/blood/*cerebrospinal fluid ; }, abstract = {Nusinersen is the first approved drug for the treatment of spinal muscular atrophy (SMA). Treatment of SMA with nusinersen is based on a fixed dosing regimen. For other motoneuron diseases, such as amyotrophic lateral sclerosis (ALS), biomarkers are available for clinical diagnostics; however, no such biomarkers have yet been found for SMA. Serum and cerebrospinal fluid (CSF) samples of 11 patients with adult SMA type 3 were prospectively collected and analyzed during loading with nusinersen. Neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase were investigated as potential biomarkers of motor neuron destruction. No significant pathological alterations in levels of neurofilament heavy chain, tau protein, or S100B protein were detected in the CSF or blood samples under baseline conditions or during loading with nusinersen. Neuron-specific enolase was marginally elevated in CSF and blood samples without significant alteration during treatment. In a mixed cohort of adult patients with SMA type 3, neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase do not serve as potential biomarkers during the loading phase of nusinersen. The slow progression rate of SMA type 3 may not lead to detectable elevation of levels of these common markers of axonal degradation.}, }
@article {pmid31670091, year = {2019}, author = {Bailly, C}, title = {Potential use of edaravone to reduce specific side effects of chemo-, radio- and immuno-therapy of cancers.}, journal = {International immunopharmacology}, volume = {77}, number = {}, pages = {105967}, doi = {10.1016/j.intimp.2019.105967}, pmid = {31670091}, issn = {1878-1705}, mesh = {Animals ; Antioxidants/metabolism ; Edaravone/*adverse effects/*therapeutic use ; Free Radical Scavengers/adverse effects/therapeutic use ; Humans ; Inflammation/metabolism ; Neoplasms/*drug therapy/metabolism ; Oxidative Stress/drug effects ; }, abstract = {The drug edaravone (EDA) is prescribed for the treatment of patients with amyotrophic lateral sclerosis or after an acute cerebral infarction. This synthetic pyrazolone derivative is a potent scavenger of oxygen free radicals and also functions as a modulator of transcription factors, repressing NFκB and activating Nrf2, to regulate oxidative stress. EDA displays complementary anti-oxidative and anti-inflammatory effects. The injectable small molecule is currently investigated for the treatment of several non-neurological diseases. The potential interest of EDA in oncology is reviewed here. EDA is a mild antiproliferative agent but has been found to enhance significantly the anticancer and antimetastatic activities of irinotecan in a colon cancer model. Anticancer derivatives of EDA have been designed but they generally display a limited antiproliferative activity. The antioxidant and anti-inflammatory activity of EDA can be best exploited to protect non-tumor cells from damages induced by chemotherapeutic drugs and radiations. Notably EDA can reduce the renal dysfunction induced by cisplatin, the neurotoxicity of cyclophosphamide and the cardiotoxicity of doxorubicin. Upon treatment with EDA, a significant improvement in neurologic symptoms has been observed in patients with nasopharyngeal carcinoma after radiotherapy. The drug could be used to limit radiation-induced brain injury or oral mucositis. EDA was found to ameliorate autoimmune thyroiditis (Hashimoto thyroiditis), which is a frequent side effect observed after treatment of cancer patients with monoclonal antibodies targeting the immune checkpoint PD-1. Therefore, EDA could also be useful to reduce specific side effects of immuno-therapy. Collectively, the information suggests that the medical use of EDA, a drug with a proven safety after 18 years of use in brain-related Human diseases, could be extended to cancer-related conditions.}, }
@article {pmid31669671, year = {2020}, author = {Messer, A and Butler, DC}, title = {Optimizing intracellular antibodies (intrabodies/nanobodies) to treat neurodegenerative disorders.}, journal = {Neurobiology of disease}, volume = {134}, number = {}, pages = {104619}, doi = {10.1016/j.nbd.2019.104619}, pmid = {31669671}, issn = {1095-953X}, mesh = {Animals ; Genetic Therapy/*methods ; Humans ; Immunotherapy/*methods ; *Neurodegenerative Diseases ; *Single-Domain Antibodies ; }, abstract = {Intrabodies (both single-chain Fv and single-domain VH, VHH, and VL nanobodies) offer unique solutions to some of the challenges of delivery and target engagement posed by immunotherapeutics for the brain and other areas of the nervous system. The specificity, which includes the recognition of post-translational modifications, and capacity for engineering that characterize these antibody fragments can be especially well-focused when the genes encoding only the binding sites of the antibody are expressed intracellularly. Multifunctional constructs use fusions with peptides that can re-target antigen-antibody complexes to enhance both pharmacodynamic activity and intracellular solubility simultaneously. Fusions with proteolytic targeting signals, such as the PEST degron, greatly enhance potency in some cases. Stem cell transplants can be protected from exogenous misfolded proteins by stable transfection with intrabodies. Tandem expression to target two or more misfolding proteins in one treatment may be especially valuable for proteostatic disruptions due to genetic, aging, or toxic triggers. Advances in bioinformatics, screening protocols, and especially gene therapy are showing great promise for intrabody/ nanobody treatments of a full range of neurological disorders, including Alzheimer's disease and related tau dementias, Parkinson's disease and Lewy body diseases, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases, among others.}, }
@article {pmid31668517, year = {2019}, author = {Du, Z and Valtierra, S and Cardona, LR and Dunne, SF and Luan, CH and Li, L}, title = {Identifying Anti-prion Chemical Compounds Using a Newly Established Yeast High-Throughput Screening System.}, journal = {Cell chemical biology}, volume = {26}, number = {12}, pages = {1664-1680.e4}, pmid = {31668517}, issn = {2451-9448}, support = {R01 GM110045/GM/NIGMS NIH HHS/United States ; R01 GM126318/GM/NIGMS NIH HHS/United States ; S10 OD023681/OD/NIH HHS/United States ; }, mesh = {Alzheimer Disease/drug therapy ; High-Throughput Screening Assays/*methods ; Humans ; Mannose-Binding Lectins/genetics ; Methyltransferases/genetics/metabolism ; Prions/*antagonists &amp; inhibitors/genetics/metabolism ; Promoter Regions, Genetic ; Saccharomyces cerevisiae/growth &amp; development/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Small Molecule Libraries/*chemistry/metabolism/therapeutic use ; }, abstract = {Prion-like protein aggregation underlies the pathology of a group of fatal neurodegenerative diseases in humans, including Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy. At present, few high-throughput screening (HTS) systems are available for anti-prion small-molecule identification. Here we describe an innovative phenotypic HTS system in yeast that allows for efficient identification of chemical compounds that eliminate the yeast prion [SWI[+]]. We show that some identified anti-[SWI[+]] compounds can destabilize other non-[SWI[+]] prions, and their antagonizing effects can be prion- and/or variant specific. Intriguingly, among the identified hits are several previously identified anti-PrP[Sc] compounds and a couple of US Food and Drug Administration-approved drugs for AD treatment, validating the efficacy of this HTS system. Moreover, a few hits can reduce proteotoxicity induced by expression of several pathogenic mammalian proteins. Thus, we have established a useful HTS system for identifying compounds that can potentially antagonize prionization and human proteinopathies.}, }
@article {pmid31666087, year = {2019}, author = {Jara, JH and Gautam, M and Kocak, N and Xie, EF and Mao, Q and Bigio, EH and Özdinler, PH}, title = {MCP1-CCR2 and neuroinflammation in the ALS motor cortex with TDP-43 pathology.}, journal = {Journal of neuroinflammation}, volume = {16}, number = {1}, pages = {196}, pmid = {31666087}, issn = {1742-2094}, support = {P30 AG013854/AG/NIA NIH HHS/United States ; R21 NS085750/NS/NINDS NIH HHS/United States ; Milton Safenowitz Postdoctoral Fellowship//ALS Association/ ; R21-NS085750/GF/NIH HHS/United States ; AG13854//NIH/NIA/ ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*metabolism/*pathology ; Animals ; DNA-Binding Proteins/*metabolism ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Middle Aged ; Motor Cortex/*metabolism/*pathology ; Receptors, CCR2/*metabolism ; }, abstract = {BACKGROUND: The involvement of non-neuronal cells and the cells of innate immunity has been attributed to the initiation and progression of ALS. TDP-43 pathology is observed in a broad spectrum of ALS cases and is one of the most commonly shared pathologies. The potential involvement of the neuroimmune axis in the motor cortex of ALS patients with TDP-43 pathology needs to be revealed. This information is vital for building effective treatment strategies.<br><br>METHODS: We investigated the presence of astrogliosis and microgliosis in the motor cortex of ALS patients with TDP-43 pathology. prpTDP-43[A315T]-UeGFP mice, corticospinal motor neuron (CSMN) reporter line with TDP-43 pathology, are utilized to reveal the timing and extent of neuroimmune interactions and the involvement of non-neuronal cells to neurodegeneration. Electron microscopy and immunolabeling techniques are used to mark and monitor cells of interest.<br><br>RESULTS: We detected both activated astrocytes and microglia, especially rod-like microglia, in the motor cortex of patients and TDP-43 mouse model. Besides, CCR2+ TMEM119- infiltrating monocytes were detected as they penetrate the brain parenchyma. Interestingly, Betz cells, which normally do not express MCP1, were marked with high levels of MCP1 expression when diseased.<br><br>CONCLUSIONS: There is an early contribution of a neuroinflammatory response for upper motor neuron (UMN) degeneration with respect to TDP-43 pathology, and MCP1-CCR2 signaling is important for the recognition of diseased upper motor neurons by infiltrating monocytes. The findings are conserved among species and are observed in both ALS and ALS-FTLD patients.}, }
@article {pmid31658762, year = {2019}, author = {Leskelä, S and Huber, N and Rostalski, H and Natunen, T and Remes, AM and Takalo, M and Hiltunen, M and Haapasalo, A}, title = {C9orf72 Proteins Regulate Autophagy and Undergo Autophagosomal or Proteasomal Degradation in a Cell Type-Dependent Manner.}, journal = {Cells}, volume = {8}, number = {10}, pages = {}, pmid = {31658762}, issn = {2073-4409}, mesh = {Acetylcysteine/analogs &amp; derivatives/pharmacology ; Animals ; Autophagosomes/*metabolism ; Autophagy/drug effects ; C9orf72 Protein/*chemistry/genetics/*metabolism ; Cell Line ; Gene Expression Regulation/drug effects ; Gene Knockout Techniques ; Macrolides/pharmacology ; Mice ; Neurons/*cytology/metabolism ; Organ Specificity ; Proteasome Endopeptidase Complex/*metabolism ; Proteolysis ; Sirolimus/pharmacology ; }, abstract = {Dysfunctional autophagy or ubiquitin-proteasome system (UPS) are suggested to underlie abnormal protein aggregation in neurodegenerative diseases. Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS)-associated C9orf72 is implicated in autophagy, but whether it activates or inhibits autophagy is partially controversial. Here, we utilized knockdown or overexpression of C9orf72 in mouse N2a neuroblastoma cells or cultured neurons to elucidate the potential role of C9orf72 proteins in autophagy and UPS. Induction of autophagy in C9orf72 knockdown N2a cells led to decreased LC3BI to LC3BII conversion, p62 degradation, and formation of LC3-containing autophagosomes, suggesting compromised autophagy. Proteasomal activity was slightly decreased. No changes in autophagy nor proteasomal activity in C9orf72-overexpressing N2a cells were observed. However, in these cells, autophagy induction by serum starvation or rapamycin led to significantly decreased C9orf72 levels. The decreased levels of C9orf72 in serum-starved N2a cells were restored by the proteasomal inhibitor lactacystin, but not by the autophagy inhibitor bafilomycin A1 (BafA1) treatment. These data suggest that C9orf72 undergoes proteasomal degradation in N2a cells during autophagy. Lactacystin significantly elevated C9orf72 levels in N2a cells and neurons, further suggesting UPS-mediated regulation. In rapamycin and BafA1-treated neurons, C9orf72 levels were significantly increased. Altogether, these findings corroborate the previously suggested regulatory role for C9orf72 in autophagy and suggest cell type-dependent regulation of C9orf72 levels via UPS and/or autophagy.}, }
@article {pmid31655003, year = {2020}, author = {Southon, A and Szostak, K and Acevedo, KM and Dent, KA and Volitakis, I and Belaidi, AA and Barnham, KJ and Crouch, PJ and Ayton, S and Donnelly, PS and Bush, AI}, title = {Cu[II] (atsm) inhibits ferroptosis: Implications for treatment of neurodegenerative disease.}, journal = {British journal of pharmacology}, volume = {177}, number = {3}, pages = {656-667}, pmid = {31655003}, issn = {1476-5381}, support = {//FightMND/International ; //Motor Neurone Disease Research Institute of Australia/International ; 1103703//National Health and Medical Research Council/International ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Disease Models, Animal ; *Ferroptosis ; Humans ; Lipid Peroxidation ; Mice ; *Neurodegenerative Diseases/drug therapy ; *Organometallic Compounds ; *Thiosemicarbazones/pharmacology ; }, abstract = {BACKGROUND AND PURPOSE: Diacetyl-bis(4-methyl-3-thiosemicarbazonato)copper[II] (Cu[II] (atsm)) ameliorates neurodegeneration and delays disease progression in mouse models of amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), yet the mechanism of action remains uncertain. Promising results were recently reported for separate Phase 1 studies in ALS patients and PD patients. Affected tissue in these disorders shares features of elevated Fe, low glutathione and increased lipid peroxidation consistent with ferroptosis, a novel form of regulated cell death. We therefore evaluated the ability of Cu[II] (atsm) to inhibit ferroptosis.<br><br>EXPERIMENTAL APPROACH: Ferroptosis was induced in neuronal cell models by inhibition of glutathione peroxidase-4 activity with RSL3 or by blocking cystine uptake with erastin. Cell viability and lipid peroxidation were assessed and the efficacy of Cu[II] (atsm) was compared to the known antiferroptotic compound liproxstatin-1.<br><br>KEY RESULTS: Cu[II] (atsm) protected against lipid peroxidation and ferroptotic lethality in primary and immortalised neuronal cell models (EC50 : &#x2248;130 nM, within an order of magnitude of liproxstatin-1). Ni[II] (atsm) also prevented ferroptosis with similar potency, whereas ionic Cu[II] did not. In cell-free systems, Cu[II] (atsm) and Ni[II] (atsm) inhibited Fe[II] -induced lipid peroxidation, consistent with these compounds quenching lipid radicals.<br><br>CONCLUSIONS AND IMPLICATIONS: The antiferroptotic activity of Cu[II] (atsm) could therefore be the disease-modifying mechanism being tested in ALS and PD trials. With potency in vitro approaching that of liproxstatin-1, Cu[II] (atsm) possesses favourable properties such as oral bioavailability and entry into the brain that make it an attractive investigational product for clinical trials of ferroptosis-related diseases.}, }
@article {pmid31650248, year = {2019}, author = {Acevedo, K and Masaldan, S and Opazo, CM and Bush, AI}, title = {Redox active metals in neurodegenerative diseases.}, journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry}, volume = {24}, number = {8}, pages = {1141-1157}, doi = {10.1007/s00775-019-01731-9}, pmid = {31650248}, issn = {1432-1327}, mesh = {Alzheimer Disease/drug therapy/*physiopathology ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Brain/metabolism ; Copper/*metabolism ; Humans ; Iron/*metabolism ; Neuroprotective Agents/therapeutic use ; Parkinson Disease/drug therapy/*physiopathology ; alpha-Synuclein/metabolism ; }, abstract = {Copper (Cu) and iron (Fe) are redox active metals essential for the regulation of cellular pathways that are fundamental for brain function, including neurotransmitter synthesis and release, neurotransmission, and protein turnover. Cu and Fe are tightly regulated by sophisticated homeostatic systems that tune the levels and localization of these redox active metals. The regulation of Cu and Fe necessitates their coordination to small organic molecules and metal chaperone proteins that restrict their reactions to specific protein centres, where Cu and Fe cycle between reduced (Fe[2+], Cu[+]) and oxidised states (Fe[3+], Cu[2+]). Perturbation of this regulation is evident in the brain affected by neurodegeneration. Here we review the evidence that links Cu and Fe dyshomeostasis to neurodegeneration as well as the promising preclinical and clinical studies reporting pharmacological intervention to remedy Cu and Fe abnormalities in the treatment of Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS).}, }
@article {pmid31632942, year = {2019}, author = {Chisti, MJ and Shahid, ASMSB and Shahunja, KM and Banu, S and Raqib, R and Shahrin, L and Islam, SB and Sharifuzzaman,  and Saha, H and Alam, T and Rahman, MW and Nuzhat, S and Afroze, F and Sarmin, M and Ahmed, T}, title = {Comparative Performance of Modified Kenneth Jones Criteria Scoring, World Health Organization Criteria, and Antibodies in Lymphocyte Supernatant for Diagnosing Tuberculosis in Severely Malnourished Children Presenting With Pneumonia.}, journal = {Frontiers in pediatrics}, volume = {7}, number = {}, pages = {406}, pmid = {31632942}, issn = {2296-2360}, abstract = {Background: The diagnosis of childhood tuberculosis (TB) can be difficult in severely malnourished children. This is mainly due to the fact of our perceived notion that clinical signs of TB are often subtle in severely malnourished children and we may rely on laboratory investigation for the diagnosis. However, comparative data on the performance of clinical and laboratory diagnostics of TB in such population are also very limited. Objectives: To compare the performance of composite clinical criteria and a technique that measures antibodies in lymphocyte supernatant (ALS) for the diagnosis of TB in severely malnourished children with pneumonia. Methods: Severely malnourished children under five with radiological pneumonia admitted to the Dhaka Hospital of International Centre for Diarrhoeal Disease Research, Bangladesh were enrolled consecutively following informed consent. We collected venous blood for ALS, gastric lavage fluid and induced sputum for microscopy, mycobacterial culture, and real-time PCR by Xpert MTB/RIF. We compared the sensitivity, specificity, positive, and negative predictive values, and accuracy of modified Kenneth Jones criteria (MKJC) score, World Health Organization (WHO) criteria, and ALS in diagnosing TB in severely malnourished children with pneumonia for "Confirmed TB" and "All TB" ("Confirmed TB" plus "Probable TB") vs. "Not TB." Results: Compared to culture confirmed TB, the sensitivity, and specificity (95% CI) for MKJC were 60 (27-86) and 84 (79-87)% and for WHO criteria were 40 (14-73) and 84 (80-87)%, respectively. Compared to culture and/or Xpert MTB/RIF positive TB, the sensitivity and specificity (95% CI) for the criteria were 37 (20-58) and 84 (79-87)%; and 22 (9-43) and 83 (79-87)%, respectively. For both these comparisons, the sensitivity and specificity of ALS were 50 (14-86) and 60 (53-67)%, respectively. Conclusion: Our data suggest that WHO criteria and MKJC scoring mainly based on clinical criteria are more useful than ALS in diagnosing TB in young severely malnourished children with pneumonia. The results underscore the importance of using clinical criteria for the diagnosis of TB in severely malnourished children that may help to minimize the chance of over treatment with anti-TB in such population, especially in resource limited TB endemic settings.}, }
@article {pmid31632458, year = {2019}, author = {Bañares, R and Ibáñez-Samaniego, L and Torner, JM and Pavesi, M and Olmedo, C and Catalina, MV and Albillos, A and Larsen, FS and Nevens, F and Hassanein, T and Schmidt, H and Heeman, U and Jalan, R and Moreau, R and Arroyo, V}, title = {Meta-analysis of individual patient data of albumin dialysis in acute-on-chronic liver failure: focus on treatment intensity.}, journal = {Therapeutic advances in gastroenterology}, volume = {12}, number = {}, pages = {1756284819879565}, pmid = {31632458}, issn = {1756-283X}, abstract = {BACKGROUND: Acute-on-chronic liver failure (ACLF) is a common complication of cirrhosis characterized by single or multiple organ failures and high short-term mortality. Treatment of ACLF consists of standard medical care (SMC) and organ(s) support. Whether the efficacy of artificial liver support (ALS) depends on the severity of ACLF or on the intensity of this treatment, or both, is unclear. This study aimed to further assess these issues.<br><br>METHODS: We performed an individual patient data meta-analysis assessing the efficacy of Molecular Adsorbent Recirculating System (MARS) in ACLF patients enrolled in prior randomized control trials (RCTs). The meta-analysis was designed to assess the effect of patient severity (ACLF grade) and treatment intensity [low-intensity therapy (LIT), SMC alone or SMC plus&#x2009;&#x2a7d;&#x2009;4 MARS sessions, high-intensity therapy (HIT), SMC plus&#x2009;>&#x2009;4 MARS sessions] on mortality.<br><br>RESULTS: Three RCTs suitable for the meta-analysis (n&#x2009;=&#x2009;285, ACLF patients&#x2009;=&#x2009;165) were identified in a systematic review. SMC plus MARS (irrespective of the number of sessions) did not improve survival compared with SMC alone, neither in the complete population nor in the ACLF patients. Survival, however, was significantly improved in the subgroup of patients receiving HIT both in the entire cohort (10-day survival: 98.6% versus 82.8%, p&#x2009;=&#x2009;0.001; 30-day survival: 73.9% versus 64.3%, p&#x2009;=&#x2009;0.032) and within the ACLF patients (10-day survival: 97.8% versus 78.6%, p&#x2009;=&#x2009;0.001; 30-day survival: 73.3% versus 58.5%, p&#x2009;=&#x2009;0.041). Remarkably, HIT increased survival independently of ACLF grade. Independent predictors of survival were age, Model for End-Stage Liver Disease (MELD), ACLF grade, number of MARS sessions received, and intensity of MARS therapy.<br><br>CONCLUSION: HIT with albumin dialysis may improve survival in patients with ACLF. Appropriate treatment schedules should be determined in future clinical trials.}, }
@article {pmid31631821, year = {2020}, author = {Gontijo, VS and Viegas, FPD and Ortiz, CJC and de Freitas Silva, M and Damasio, CM and Rosa, MC and Campos, TG and Couto, DS and Tranches Dias, KS and Viegas, C}, title = {Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases.}, journal = {Current neuropharmacology}, volume = {18}, number = {5}, pages = {348-407}, pmid = {31631821}, issn = {1875-6190}, mesh = {Animals ; *Drug Design ; Humans ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/*chemistry/*therapeutic use ; }, abstract = {Neurodegenerative Diseases (NDs) are progressive multifactorial neurological pathologies related to neuronal impairment and functional loss from different brain regions. Currently, no effective treatments are available for any NDs, and this lack of efficacy has been attributed to the multitude of interconnected factors involved in their pathophysiology. In the last two decades, a new approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDLs) strategy, has emerged and has been used in the design and for the development of a variety of hybrid compounds capable to act simultaneously in diverse biological targets. Based on the polypharmacology concept, this new paradigm has been thought as a more secure and effective way for modulating concomitantly two or more biochemical pathways responsible for the onset and progress of NDs, trying to overcome low therapeutical effectiveness. As a complement to our previous review article (Curr. Med. Chem. 2007, 14 (17), 1829-1852. https://doi.org/10.2174/092986707781058805), herein we aimed to cover the period from 2008 to 2019 and highlight the most recent advances of the exploitation of Molecular Hybridization (MH) as a tool in the rational design of innovative multifunctional drug candidate prototypes for the treatment of NDs, specially focused on AD, PD, HD and ALS.}, }
@article {pmid31624333, year = {2020}, author = {van Eijk, RPA and Eijkemans, MJC and Nikolakopoulos, S and Jansen, MD and Westeneng, HJ and van Eijk, KR and van der Spek, RAA and van Vugt, JJFA and Piepers, S and Groeneveld, GJ and Veldink, JH and van den Berg, LH and van Es, MA}, title = {Pharmacogenetic interactions in amyotrophic lateral sclerosis: a step closer to a cure?.}, journal = {The pharmacogenomics journal}, volume = {20}, number = {2}, pages = {220-226}, doi = {10.1038/s41397-019-0111-3}, pmid = {31624333}, issn = {1473-1150}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/*genetics ; C9orf72 Protein/*genetics ; Double-Blind Method ; Epistasis, Genetic/*genetics ; Humans ; Mutation/genetics ; Myelin Proteins/*genetics ; Nerve Tissue Proteins/*genetics ; Netherlands/epidemiology ; Pharmacogenetics/*methods ; Pharmacogenomic Testing/methods ; }, abstract = {Genetic mutations related to amyotrophic lateral sclerosis (ALS) act through distinct pathophysiological pathways, which may lead to varying treatment responses. Here we assess the genetic interaction between C9orf72, UNC13A, and MOBP with creatine and valproic acid treatment in two clinical trials. Genotypic data was available for 309 of the 338 participants (91.4%). The UNC13A genotype affected mortality (p = 0.012), whereas C9orf72 repeat-expansion carriers exhibited a faster rate of decline in overall (p = 0.051) and bulbar functioning (p = 0.005). A dose-response pharmacogenetic interaction was identified between creatine and the A allele of the MOBP genotype (p = 0.027), suggesting a qualitative interaction in a recessive model (HR 3.96, p = 0.015). Not taking genetic information into account may mask evidence of response to treatment or be an unrecognized source of bias. Incorporating genetic data could help investigators to identify critical treatment clues in patients with ALS.}, }
@article {pmid31621933, year = {2020}, author = {Shefner, J and Heiman-Patterson, T and Pioro, EP and Wiedau-Pazos, M and Liu, S and Zhang, J and Agnese, W and Apple, S}, title = {Long-term edaravone efficacy in amyotrophic lateral sclerosis: Post-hoc analyses of Study 19 (MCI186-19).}, journal = {Muscle &amp; nerve}, volume = {61}, number = {2}, pages = {218-221}, pmid = {31621933}, issn = {1097-4598}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Disease Progression ; Double-Blind Method ; Edaravone/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Treatment Outcome ; }, abstract = {BACKGROUND: In a Phase 3 study, amyotrophic lateral sclerosis (ALS) patients experienced significantly less physical functional decline with 24-week edaravone vs placebo, followed by open-label treatment for an additional 24 weeks.<br><br>METHODS: Outcome (the change in ALS Functional Rating Scale-Revised, ALSFRS-R, from baseline) was projected for placebo patients through 48&#x2009;weeks and compared with 48-week edaravone or 24-week edaravone after switching from placebo.<br><br>RESULTS: A total of 123 patients received open-label treatment (65 edaravone-edaravone; 58 placebo-edaravone). The projected ALSFRS-R decline for placebo from baseline through week 48 was greater than for 48-week edaravone (P&#x2009;<&#x2009;.0001). For patients switching from placebo to edaravone, ALSFRS-R slope approached that of continued edaravone for 48&#x2009;weeks. ALSFRS-R decline did not differ between actual and projected edaravone through week 48.<br><br>CONCLUSIONS: Compared with placebo, these analyses suggest that edaravone is beneficial in ALS patients even after 6 mo of receiving placebo, and efficacy is maintained for up to 1&#x2009;year.}, }
@article {pmid31617094, year = {2020}, author = {Allaix, ME and Rebecchi, F and Famiglietti, F and Arolfo, S and Arezzo, A and Morino, M}, title = {Long-term oncologic outcomes following anastomotic leak after anterior resection for rectal cancer: does the leak severity matter?.}, journal = {Surgical endoscopy}, volume = {34}, number = {9}, pages = {4166-4176}, doi = {10.1007/s00464-019-07189-9}, pmid = {31617094}, issn = {1432-2218}, mesh = {Aged ; Aged, 80 and over ; Anastomotic Leak/*etiology ; C-Reactive Protein/metabolism ; Chemotherapy, Adjuvant ; Disease-Free Survival ; Female ; Humans ; Inflammation/etiology ; Male ; Middle Aged ; Neoplasm Metastasis ; Neoplasm Recurrence, Local ; Postoperative Complications ; Proctectomy/*adverse effects ; Prognosis ; Rectal Neoplasms/drug therapy/pathology/*surgery ; Retrospective Studies ; }, abstract = {BACKGROUND: The evidence regarding the impact of anastomotic leak (AL) after anterior resection (AR) for rectal cancer on oncologic outcomes is controversial, and there are no data about the prognostic relevance of the International Study Group of Rectal Cancer (ISREC) AL classification. The aim was to evaluate the oncologic outcomes in patients with AL after AR for rectal cancer. The prognostic value of the ISREC AL grading system was also investigated.<br><br>METHODS: It is a retrospective analysis of a prospectively collected database including all patients undergoing curative elective AR for rectal cancer (April 1998-September 2013). AL severity was defined according to the ISREC criteria. A multivariable analysis was performed to identify predictors of poor survival.<br><br>RESULTS: A total of 532 patients underwent curative AR (69% laparoscopic) for rectal cancer. The overall AL rate was 7.9%: 15 grade B and 27 grade C ALs. With a median follow-up of 80 (range 12-266) months, 5-year overall survival (OS) was 67.2% in patients with AL and 86.5% in those without AL (P&#x2009;=&#x2009;0.001). Five-year disease-free survival (DFS) was 50.5% and 80.3%, respectively (P&#x2009;<&#x2009;0.001). Local recurrence and distant metastases developed more frequently in AL patients (P&#x2009;<&#x2009;0.05). Grade B AL and no administration or delay of adjuvant chemotherapy were independent predictors for poorer OS and DFS. Grade B AL independently affected also the administration of adjuvant chemotherapy. Circulating C-reactive protein levels at 2&#xa0;weeks after AL treatment were higher in grade B than grade C patients (P&#x2009;=&#x2009;0.006) and in patients with tumor relapse (P&#x2009;=&#x2009;0.011).<br><br>CONCLUSION: AL after curative AR for rectal cancer and impaired use of adjuvant chemotherapy are associated with poor survival. Postoperative systemic inflammation seems to be more sustained in grade B than that in grade C AL patients, with possible adverse impact on long-term survival.}, }
@article {pmid31611772, year = {2019}, author = {Brettle, M and Stefen, H and Djordjevic, A and Fok, SYY and Chan, JW and van Hummel, A and van der Hoven, J and Przybyla, M and Volkerling, A and Ke, YD and Delerue, F and Ittner, LM and Fath, T}, title = {Developmental Expression of Mutant PFN1 in Motor Neurons Impacts Neuronal Growth and Motor Performance of Young and Adult Mice.}, journal = {Frontiers in molecular neuroscience}, volume = {12}, number = {}, pages = {231}, pmid = {31611772}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment and no cure. Mutations in profilin 1 were identified as a cause of familial ALS (fALS) in 2012. We investigated the functional impact of mutant profilin 1 expression in spinal cords during mouse development. We developed a novel mouse model with the expression of profilin 1 C71G under the control of the Hb9 promoter, targeting expression to α-motor neurons in the spinal cord during development. Embryos of transgenic mice showed evidence of a significant reduction of brachial nerve diameter and a loss of Mendelian inheritance. Despite the lack of transgene expression, adult mice presented with significant motor deficits. Transgenic mice had a significant reduction in the number of motor neurons in the spinal cord. Further analysis of these motor neurons in aged transgenic mice revealed reduced levels of TDP-43 and ChAT expression. Although profilin 1 C71G was only expressed during development, adult mice presented with some ALS-associated pathology and motor symptoms. This study highlights the effect of profilin 1 during neurodevelopment and the impact that this may have in later ALS.}, }
@article {pmid31610856, year = {2019}, author = {VanItallie, TB}, title = {Traumatic brain injury (TBI) in collision sports: Possible mechanisms of transformation into chronic traumatic encephalopathy (CTE).}, journal = {Metabolism: clinical and experimental}, volume = {100S}, number = {}, pages = {153943}, doi = {10.1016/j.metabol.2019.07.007}, pmid = {31610856}, issn = {1532-8600}, mesh = {Animals ; Brain Injuries, Traumatic/*complications ; Chronic Traumatic Encephalopathy/*etiology ; Humans ; Neurodegenerative Diseases/etiology ; Neuropathology ; *Sports ; }, abstract = {Traumatic brain injury (TBI) is a leading cause of death and disability, contributing to ~30% of all injury-related deaths in the US. TBI occurs when a force transmitted to the head causes neuropathologic damage and impairment of brain function. TBI doubles risk of suicide and is the major determinant of acquired seizure disorders. TBI arising from closed head trauma (CHT) significantly increases the risk of developing Alzheimer's disease (AD), Parkinson's disease (PD) and chronic traumatic encephalopathy (CTE). Evidence for a possible role of TBI as a risk factor for sporadic amyotrophic lateral sclerosis (sALS) has been provided by studies of professional players of European football. Depending on age, genetic make-up (in particular, being a carrier of one or two ApoE4 alleles), the number of TBIs sustained, their severity, the time periods involved, and many other factors that affect vulnerability, decades may pass after occurrence of one or more TBIs before sequelae such as AD, PD, sALS or CTE become clinically evident. Among college and professional football players who experience repeated concussions and sub-concussive blows to the head, the risk of developing CTE increases with the number of years actively devoted to the sport, and the degree of exposure to physical impacts inherent in the position played. Following a moderate or severe concussion, or a series of mild blows to the head, the brain may undergo subtle pathophysiological changes that are unlikely to be detected with confidence using available diagnostic methods. Biomarkers are being sought that can help the attending physician infer the likely presence of an ongoing occult neurodegenerative process. One example of the adverse effect of collision on the brain is "heading" the soccer ball-a feat that, repeated over years of competition, has been found to produce severe brain damage in veteran players. CTE has attracted increasing national attention because of its devastating effects in a high proportion of retired professional players of American football. In a study of brains from deceased former football players, contributed mostly by family members, CTE was neuropathologically diagnosed in 110 of 111 of National Football League (NFL) veterans. In the CTE-positive subjects, the authors observed extensive brain atrophy, astrogliosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. CTE's neuropathology has been formally defined as a tauopathy characterized by a distinct perivascular accumulation of hyperphosphorylated tau in neurons and astrocytes within cerebral sulci. Although the mechanism that underlies the unforeseen emergence of CTE long after the occurrence of one or more closed head traumas is unknown, an explanation proposed by Albayram and associates is persuasive. They discovered TBI-induced neuronal production of the toxic compound cis P-tau, an abnormal and destructive isomer of the normal and benign trans P-tau, in mouse models of CTE. Cis P-tau produced a CTE-like syndrome via a process they termed cistauosis. Cistauosis can be blocked in laboratory animals by cis P-tau monoclonal antibody, which prevents later development of tau tangles, brain atrophy and virtual CTE. In a subsequent study, the same group found in human samples obtained post-TBI from a variety of causes, that cis P-tau is induced in cortical axons and cerebrospinal fluid and positively correlates with axonal injury and clinical outcome. Thus, cis P-tau appears to contribute to short-term and long-term sequelae after TBI, but may be subject to neutralization by cis-antibody treatment.}, }
@article {pmid31608899, year = {2019}, author = {Zhang, L and Gong, Y and Wang, S and Gao, F}, title = {Anti-Colorectal Cancer Mechanisms of Formononetin Identified by Network Pharmacological Approach.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {25}, number = {}, pages = {7709-7714}, pmid = {31608899}, issn = {1643-3750}, mesh = {Cluster Analysis ; Colorectal Neoplasms/*drug therapy/*genetics ; *Gene Regulatory Networks ; Humans ; Isoflavones/*therapeutic use ; Protein Interaction Maps ; }, abstract = {BACKGROUND The network pharmacological approach was used to identity the anti-colorectal cancer (CRC) targets of formononetin (FN) and the molecular mechanisms of FN against CRC. MATERIAL AND METHODS A tool of the DisGeNET database was used for collection of CRC-based targets. Other tools of SuperPred, herbal ingredients target (HIT), and SwissTargetPrediction databases were applied in prediction of pharmacological targets of FN against cancer. A protein-protein interaction (PPI) network of FN against CRC was obtained by using a STRING database. All top biological functional processes and signaling pathways of FN against CRC were identified by using Database for Annotation, Visualization and Integrated Discovery (DAVID) software and Omicshare cloud platform. RESULTS The most key anti-CRC targets of FN were identified as tumor protein p53 (TP53), cytochrome P450 3A4 (CYP3A4), ATP binding cassette subfamily G member 2 (ABCG2), tumor necrosis factor (TNF), epidermal growth factor receptor (EGFR), Erb-B2 receptor tyrosine kinase 2 (ERBB2), and cytochrome P450 1A1 (CYP1A1). In further assays, the treatment of CRC by FN was mainly involved in biological functional processes of reactive oxygen species metabolic process, positive regulation of transcription, DNA-templated, positive regulation of nucleic acid-templated transcription, and positive regulation of RNA metabolic process. anti-CRC by FN of signaling pathways were associated with amyotrophic lateral sclerosis (ALS), allograft rejection, cytokine-cytokine receptor interaction, asthma, mitogen-activated protein kinase (MAPK) signaling pathways, and others. CONCLUSIONS The anti-CRC molecular mechanisms of FN are implicated in suppression of cellular proliferation and regulation of cancer-related metabolic pathways. Interestingly, 8 optimal biological targets may be used as potential molecular markers for predicting and treating CRC.}, }
@article {pmid31608711, year = {2020}, author = {Babu, S and Macklin, EA and Jackson, KE and Simpson, E and Mahoney, K and Yu, H and Walker, J and Simmons, Z and David, WS and Barkhaus, PE and Simionescu, L and Dimachkie, MM and Pestronk, A and Salameh, JS and Weiss, MD and Brooks, BR and Schoenfeld, D and Shefner, J and Aggarwal, S and Cudkowicz, ME and Atassi, N}, title = {Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {1-2}, pages = {15-23}, doi = {10.1080/21678421.2019.1672750}, pmid = {31608711}, issn = {2167-9223}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Creatine/adverse effects/*therapeutic use ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Muscle Strength ; Tamoxifen/*administration &amp; dosage/*therapeutic use ; Vital Capacity/drug effects/physiology ; }, abstract = {Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. Methods: Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. Results: CRE participants experienced higher rates of drug-related AEs (82% vs. 43% T40, 47% T80) and EDD (50% vs. 24% T40, 29% T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (-0.80 vs. -0.84 T40, -0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. Conclusion: Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design.}, }
@article {pmid31603947, year = {2019}, author = {Darbà, J}, title = {Current status and direct medical cost of amyotrophic lateral sclerosis in the region of Catalonia: A population-based analysis.}, journal = {PloS one}, volume = {14}, number = {10}, pages = {e0223772}, pmid = {31603947}, issn = {1932-6203}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*economics/*mortality ; Disease Management ; Female ; Health Care Costs ; Hospitalization/economics/statistics &amp; numerical data ; Humans ; Male ; Medical Records ; Middle Aged ; Primary Health Care/economics/statistics &amp; numerical data ; Retrospective Studies ; Spain/epidemiology ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis is a neurodegenerative disease that leads to motor weakness. There is no cure, and treatment focuses on slowing down progression, which is achieved by a multidisciplinary approach. Hence, it is vital to understand the population needs for an optimal management of the disease.<br><br>OBJECTIVES: To evaluate the current status of amyotrophic lateral sclerosis in the region of Catalonia, how the disease is managed and its direct medical costs.<br><br>METHODS: Records corresponding to 841 patients diagnosed between the year 2007 and 2017 were analysed in a retrospective population-based study, including data from primary care centres, hospitals (inpatient and outpatient care), extended care facilities and mental health centres.<br><br>RESULTS: Mean diagnosis age was 66.11 years (SD = 12.61) and 52.79% of admitted patients were males. On average, 14.91 months elapsed between diagnosis and death, and the mean age of death was 72.64 years (SD = 12.00). Patients were admitted 10.70 times per year, mostly into primary care (86.50%), although most expenses were concentrated in hospital inpatient care. The mean cost per patient per year was &#x20ac;1,168. The 83.24% of patients had more than 4 systems affected by chronic conditions.<br><br>CONCLUSIONS: Primary care is of utmost importance in ALS attention in Catalonia, which may have a direct impact in reducing hospitalisation costs. Nonetheless, the expenses linked to inpatient care represent the biggest portion of total costs. Patients' healthcare usage patterns and the high proportion of patients with multiple chronic conditions should be taken into account in order to adapt and improve guidelines and healthcare systems.}, }
@article {pmid31603904, year = {2019}, author = {Posavi, M and Diaz-Ortiz, M and Liu, B and Swanson, CR and Skrinak, RT and Hernandez-Con, P and Amado, DA and Fullard, M and Rick, J and Siderowf, A and Weintraub, D and McCluskey, L and Trojanowski, JQ and Dewey, RB and Huang, X and Chen-Plotkin, AS}, title = {Characterization of Parkinson's disease using blood-based biomarkers: A multicohort proteomic analysis.}, journal = {PLoS medicine}, volume = {16}, number = {10}, pages = {e1002931}, pmid = {31603904}, issn = {1549-1676}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; T32 AG000255/AG/NIA NIH HHS/United States ; U24 NS095871/NS/NINDS NIH HHS/United States ; P50 NS053488/NS/NINDS NIH HHS/United States ; R01 NS115139/NS/NINDS NIH HHS/United States ; U19 AG062418/AG/NIA NIH HHS/United States ; U01 NS112008/NS/NINDS NIH HHS/United States ; U01 NS082134/NS/NINDS NIH HHS/United States ; U01 NS082151/NS/NINDS NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; U01 NS082148/NS/NINDS NIH HHS/United States ; U01 NS097056/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Algorithms ; Amidohydrolases/blood ; Biomarkers/*blood ; Carrier Proteins/blood ; Disease Progression ; Extracellular Matrix Proteins/blood ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Neurodegenerative Diseases ; Osteopontin/blood ; Parkinson Disease/*blood ; Proportional Hazards Models ; Proteoglycans/blood ; *Proteomics ; Reproducibility of Results ; }, abstract = {BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disease affecting about 5 million people worldwide with no disease-modifying therapies. We sought blood-based biomarkers in order to provide molecular characterization of individuals with PD for diagnostic confirmation and prediction of progression.<br><br>METHODS AND FINDINGS: In 141 plasma samples (96 PD, 45 neurologically normal control [NC] individuals; 45.4% female, mean age 70.0 years) from a longitudinally followed Discovery Cohort based at the University of Pennsylvania (UPenn), we measured levels of 1,129 proteins using an aptamer-based platform. We modeled protein plasma concentration (log10 of relative fluorescence units [RFUs]) as the effect of treatment group (PD versus NC), age at plasma collection, sex, and the levodopa equivalent daily dose (LEDD), deriving first-pass candidate protein biomarkers based on p-value for PD versus NC. These candidate proteins were then ranked by Stability Selection. We confirmed findings from our Discovery Cohort in a Replication Cohort of 317 individuals (215 PD, 102 NC; 47.9% female, mean age 66.7 years) from the multisite, longitudinally followed National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) Cohort. Analytical approach in the Replication Cohort mirrored the approach in the Discovery Cohort: each protein plasma concentration (log10 of RFU) was modeled as the effect of group (PD versus NC), age at plasma collection, sex, clinical site, and batch. Of the top 10 proteins from the Discovery Cohort ranked by Stability Selection, four associations were replicated in the Replication Cohort. These blood-based biomarkers were bone sialoprotein (BSP, Discovery false discovery rate [FDR]-corrected p = 2.82 &#xd7; 10-2, Replication FDR-corrected p = 1.03 &#xd7; 10-4), osteomodulin (OMD, Discovery FDR-corrected p = 2.14 &#xd7; 10-2, Replication FDR-corrected p = 9.14 &#xd7; 10-5), aminoacylase-1 (ACY1, Discovery FDR-corrected p = 1.86 &#xd7; 10-3, Replication FDR-corrected p = 2.18 &#xd7; 10-2), and growth hormone receptor (GHR, Discovery FDR-corrected p = 3.49 &#xd7; 10-4, Replication FDR-corrected p = 2.97 &#xd7; 10-3). Measures of these proteins were not significantly affected by differences in sample handling, and they did not change comparing plasma samples from 10 PD participants sampled both on versus off dopaminergic medication. Plasma measures of OMD, ACY1, and GHR differed in PD versus NC but did not differ between individuals with amyotrophic lateral sclerosis (ALS, n = 59) versus NC. In the Discovery Cohort, individuals with baseline levels of GHR and ACY1 in the lowest tertile were more likely to progress to mild cognitive impairment (MCI) or dementia in Cox proportional hazards analyses adjusting for age, sex, and disease duration (hazard ratio [HR] 2.27 [95% CI 1.04-5.0, p = 0.04] for GHR, and HR 3.0 [95% CI 1.24-7.0, p = 0.014] for ACY1). GHR's association with cognitive decline was confirmed in the Replication Cohort (HR 3.6 [95% CI 1.20-11.1, p = 0.02]). The main limitations of this study were its reliance on the aptamer-based platform for protein measurement and limited follow-up time available for some cohorts.<br><br>CONCLUSIONS: In this study, we found that the blood-based biomarkers BSP, OMD, ACY1, and GHR robustly associated with PD across multiple clinical sites. Our findings suggest that biomarkers based on a peripheral blood sample may be developed for both disease characterization and prediction of future disease progression in PD.}, }
@article {pmid31598254, year = {2019}, author = {Eriksson, M and Nylin, S and Carlsson, MA}, title = {Insect brain plasticity: effects of olfactory input on neuropil size.}, journal = {Royal Society open science}, volume = {6}, number = {8}, pages = {190875}, pmid = {31598254}, issn = {2054-5703}, abstract = {Insect brains are known to express a high degree of experience-dependent structural plasticity. One brain structure in particular, the mushroom body (MB), has been attended to in numerous studies as it is implicated in complex cognitive processes such as olfactory learning and memory. It is, however, poorly understood to what extent sensory input per se affects the plasticity of the mushroom bodies. By performing unilateral blocking of olfactory input on immobilized butterflies, we were able to measure the effect of passive sensory input on the volumes of antennal lobes (ALs) and MB calyces. We showed that the primary and secondary olfactory neuropils respond in different ways to olfactory input. ALs show absolute experience-dependency and increase in volume only if receiving direct olfactory input from ipsilateral antennae, while MB calyx volumes were unaffected by the treatment and instead show absolute age-dependency in this regard. We therefore propose that cognitive processes related to behavioural expressions are needed in order for the calyx to show experience-dependent volumetric expansions. Our results indicate that such experience-dependent volumetric expansions of calyces observed in other studies may have been caused by cognitive processes rather than by sensory input, bringing some causative clarity to a complex neural phenomenon.}, }
@article {pmid31597644, year = {2019}, author = {Figueroa-Romero, C and Guo, K and Murdock, BJ and Paez-Colasante, X and Bassis, CM and Mikhail, KA and Pawlowski, KD and Evans, MC and Taubman, GF and McDermott, AJ and O'Brien, PD and Savelieff, MG and Hur, J and Feldman, EL}, title = {Temporal evolution of the microbiome, immune system and epigenome with disease progression in ALS mice.}, journal = {Disease models &amp; mechanisms}, volume = {13}, number = {2}, pages = {}, pmid = {31597644}, issn = {1754-8411}, support = {R21 NS102960/NS/NINDS NIH HHS/United States ; }, mesh = {5-Methylcytosine/analogs &amp; derivatives/metabolism ; Amyotrophic Lateral Sclerosis/*genetics/*microbiology/pathology ; Animals ; Bacteria/classification ; Brain/metabolism/pathology ; *Disease Progression ; *Epigenome ; Feces/microbiology ; Female ; Gastrointestinal Microbiome/*genetics ; Immune System/*microbiology ; Inflammation/pathology ; Leukocytes/metabolism ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Myeloid Cells/metabolism ; Phenotype ; Phylogeny ; Superoxide Dismutase-1/genetics ; Time Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease. Genetic predisposition, epigenetic changes, aging and accumulated life-long environmental exposures are known ALS risk factors. The complex and dynamic interplay between these pathological influences plays a role in disease onset and progression. Recently, the gut microbiome has also been implicated in ALS development. In addition, immune cell populations are differentially expanded and activated in ALS compared to healthy individuals. However, the temporal evolution of both the intestinal flora and the immune system relative to symptom onset in ALS is presently not fully understood. To better elucidate the timeline of the various potential pathological factors, we performed a longitudinal study to simultaneously assess the gut microbiome, immunophenotype and changes in ileum and brain epigenetic marks relative to motor behavior and muscle atrophy in the mutant superoxide dismutase 1 (SOD1[G93A]) familial ALS mouse model. We identified alterations in the gut microbial environment early in the life of SOD1[G93A] animals followed by motor dysfunction and muscle atrophy, and immune cell expansion and activation, particularly in the spinal cord. Global brain cytosine hydroxymethylation was also altered in SOD1[G93A] animals at disease end-stage compared to control mice. Correlation analysis confirmed interrelationships with the microbiome and immune system. This study serves as a starting point to more deeply comprehend the influence of gut microorganisms and the immune system on ALS onset and progression. Greater insight may help pinpoint novel biomarkers and therapeutic interventions to improve diagnosis and treatment for ALS patients.This article has an associated First Person interview with the joint first authors of the paper.}, }
@article {pmid31594243, year = {2019}, author = {Walter, MC and Wenninger, S and Thiele, S and Stauber, J and Hiebeler, M and Greckl, E and Stahl, K and Pechmann, A and Lochmüller, H and Kirschner, J and Schoser, B}, title = {Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 - A Prospective Observational Study.}, journal = {Journal of neuromuscular diseases}, volume = {6}, number = {4}, pages = {453-465}, pmid = {31594243}, issn = {2214-3602}, mesh = {Adolescent ; Adult ; Cohort Studies ; Female ; Humans ; Injections, Spinal/methods ; Male ; Middle Aged ; Muscular Atrophy, Spinal/*drug therapy ; Oligonucleotides/*pharmacology ; Outcome Assessment, Health Care ; Prospective Studies ; Spinal Muscular Atrophies of Childhood/*drug therapy/physiopathology ; *Treatment Outcome ; Young Adult ; }, abstract = {OBJECTIVE: Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease caused by loss of the SMN1 gene. Based on randomized clinical trials in children with SMA type 1 and 2, Nusinersen has been approved as the first treatment for all types of SMA, including adults with SMA type 3.<br><br>METHODS: We evaluated the safety and treatment effects of Nusinersen in longstanding adult 5q-SMA type 3. Patients were treated with intrathecal loading doses at day 1, 14, 28 and 63, followed by maintenance dose every four months up to 300 days. We monitored the patients within SMArtCARE, a prospective open-label outcome study for disease progression, side effects and treatment efficacy, encompassing clinical examination including MRC sum score, vital capacity in sitting position (VC, VC % pred.), ALS Functional Rating Scale (ALS-FRS), 6-Minute-Walk-Test (6MWT), Revised Upper Limb Module (RULM), and Hammersmith Functional Rating Scale (HFMSE). We also measured biomarkers in the spinal fluid (phosphorylated neurofilament heavy chain pNFH, neuron-specific enolase NSE, proteins, &#xdf;-Amyloid 1-40, &#xdf;-Amyloid 1-42, tau and phospho-tau) and creatine kinase (CK). Assessments were performed at baseline, day 63 (V4), day 180 (V5) and day 300 (V6). For statistical analysis, we compared baseline to V4, V5 and V6, using the paired sample t-test. When there were significant differences, we added cohen's d and effect size r for evaluation of clinical meaningfulness.<br><br>RESULTS: 19 patients were included, 17 of them have completed the observation period of 10 months (day 300, V6). Patients were aged 18 to 59 years with disease duration ranging from 6 to 53 years. Except for the 6MWT, the RULM and the peak cough flow, there were no relevant significant changes in all functional outcome assessments at V4, V5 or V6, compared to baseline. For the 6MWT, there was a statistically significant improvement at visit 5 and at visit 6. RULM-score increased significantly at V6, and peak cough flow at visit 5. In biomarker studies, there was a significant decline in NSE and pTAU as well as a slight increase in proteins. In safety analysis, overall, Nusinersen applications were well tolerated. Eleven patients reported adverse events that were related to the study procedures, comprising back pain in seven patients and post-lumbar-puncture headache following intrathecal administration in four patients. Post-lumbar-puncture headache was reported in three females and one male, in total eleven times of 108 punctures (10%). No serious adverse events occurred.<br><br>CONCLUSIONS: This prospective observational study indicates a mild treatment effect in adults with long-standing SMA3 after 10 months of treatment with Nusinersen, which had never occurred in the natural history of the disease. In our cohort, the most significant outcome measures were the 6MWT with statistically significant changes after day 180 and day 300, RULM after day 300 and peak cough flow after day 180.}, }
@article {pmid31584809, year = {2019}, author = {Ye, F and Zhai, Y and Guo, KL and Liu, YX and Li, N and Gao, S and Zhao, LX and Fu, Y}, title = {Safeners Improve Maize Tolerance under Herbicide Toxicity Stress by Increasing the Activity of Enzymes in Vivo.}, journal = {Journal of agricultural and food chemistry}, volume = {67}, number = {42}, pages = {11568-11576}, doi = {10.1021/acs.jafc.9b03587}, pmid = {31584809}, issn = {1520-5118}, mesh = {Acetolactate Synthase/chemistry/metabolism ; Glutathione Transferase/chemistry/metabolism ; Herbicides/*toxicity ; Kinetics ; Molecular Docking Simulation ; Plant Proteins/chemistry/*metabolism ; Protective Agents/*pharmacology ; Sulfonylurea Compounds/toxicity ; Zea mays/chemistry/*drug effects/*enzymology ; }, abstract = {Tribenuron-methyl (TM), as one of the sulfonylurea (SU) herbicides, has been widely and effectively applied for many kinds of plants. SUs inhibit plant growth by restraining the biosynthetic pathway of branched-chain amino acids (BCAAs) catalyzed by acetolactate synthase (ALS). Safeners are agrochemicals that protect crops from herbicide injuries. To improve the crop tolerance under TM toxicity stress, this paper evaluated the protective effect of N-tosyloxazolidine-3-carboxamide. It turned out that most of the tested compounds showed significant protection against TM via enhancing the glutathione (GSH) content and glutathione S-transferase (GST) activity. Among all of the tested compounds, compound 16 exhibited more excellent protection than the contrast safener R-28725 and other target compounds. A positive correlation between the growth level, endogenous GSH content, and GST activity was observed in this research. The GST kinetic parameter Vmax of the maize was increased by 29.6% after treatment with compound 16, while Km was decreased by 51.9% compared to the untreated control. The molecular docking model indicated that compound 16 could compete with TM in the active site of ALS, which could interpret the protective effects of safeners. The present work demonstrated that N-tosyloxazolidine-3-carboxamide derivatives could be considered as potential candidates for developing new safeners in the future.}, }
@article {pmid31579294, year = {2019}, author = {Stopford, MJ and Allen, SP and Ferraiuolo, L}, title = {A High-throughput and Pathophysiologically Relevant Astrocyte-motor Neuron Co-culture Assay for Amyotrophic Lateral Sclerosis Therapeutic Discovery.}, journal = {Bio-protocol}, volume = {9}, number = {17}, pages = {}, pmid = {31579294}, issn = {2331-8325}, support = {ALLEN/OCT15/956-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; BONANNO/APR16/848-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; SBF002\1142/AMS_/Academy of Medical Sciences/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult onset neurological disorder characterized by loss of motor neurons leading to progressive muscle wasting and eventually death. Astrocytes play a key role in disease pathogenesis. However, the ability to study astrocytic support towards motor neurons in ALS has been limited by a lack of sustainable high-throughput human cell models. Moreover, the ability to assess how astrocytic support of motor neurons is influenced by drug treatment or nutritional supplementation has been hampered by the lack of robust methodology. We have developed a high-throughput astrocyte motor neuron co-culture assay, which, by using Hb9-GFP+ motor neurons enables researchers to assess how ALS affects the ability of astrocytes to support motor neurons in 384-well plates. Moreover, astrocyte function can be manipulated by nutritional supplementation or drug treatment to identify possible therapeutic targets.}, }
@article {pmid31577933, year = {2019}, author = {Lautrup, S and Sinclair, DA and Mattson, MP and Fang, EF}, title = {NAD[+] in Brain Aging and Neurodegenerative Disorders.}, journal = {Cell metabolism}, volume = {30}, number = {4}, pages = {630-655}, pmid = {31577933}, issn = {1932-7420}, support = {R21 DE027490/DE/NIDCR NIH HHS/United States ; R37 AG028730/AG/NIA NIH HHS/United States ; DP1 AG058605/AG/NIA NIH HHS/United States ; R01 DK100263/DK/NIDDK NIH HHS/United States ; R01 AG019719/AG/NIA NIH HHS/United States ; }, mesh = {Aging/*metabolism ; Animals ; Brain/*metabolism ; Cell Line ; Humans ; Mice ; NAD/*metabolism ; Neurodegenerative Diseases/drug therapy/*metabolism ; Neurons/cytology/*metabolism/pathology ; Rats ; }, abstract = {NAD[+] is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD[+]-dependent enzymes are involved in synaptic plasticity and neuronal stress resistance. Here, we review emerging findings that reveal key roles for NAD[+] and related metabolites in the adaptation of neurons to a wide range of physiological stressors and in counteracting processes in neurodegenerative diseases, such as those occurring in Alzheimer's, Parkinson's, and Huntington diseases, and amyotrophic lateral sclerosis. Advances in understanding the molecular and cellular mechanisms of NAD[+]-based neuronal resilience will lead to novel approaches for facilitating healthy brain aging and for the treatment of a range of neurological disorders.}, }
@article {pmid31571171, year = {2019}, author = {Liu, L and Liu, X}, title = {Contributions of Drug Transporters to Blood-Brain Barriers.}, journal = {Advances in experimental medicine and biology}, volume = {1141}, number = {}, pages = {407-466}, doi = {10.1007/978-981-13-7647-4_9}, pmid = {31571171}, issn = {0065-2598}, mesh = {Biological Transport ; *Blood-Brain Barrier/metabolism ; Brain/metabolism ; Humans ; *Membrane Transport Proteins/metabolism ; *Pharmaceutical Preparations/administration &amp; dosage/metabolism ; }, abstract = {Blood-brain interfaces comprise the cerebral microvessel endothelium forming the blood-brain barrier (BBB) and the epithelium of the choroid plexuses forming the blood-cerebrospinal fluid barrier (BCSFB). Their main functions are to impede free diffusion between brain fluids and blood; to provide transport processes for essential nutrients, ions, and metabolic waste products; and to regulate the homeostasis of central nervous system (CNS), all of which are attributed to absent fenestrations, high expression of tight junction proteins at cell-cell contacts, and expression of multiple transporters, receptors, and enzymes. Existence of BBB is an important reason that systemic drug administration is not suitable for the treatment of CNS diseases. Some diseases, such epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and diabetes, alter BBB function via affecting tight junction proteins or altering expression and function of these transporters. This chapter will illustrate function of BBB, expression of transporters, as well as their alterations under disease status.}, }
@article {pmid31562633, year = {2019}, author = {Trostchansky, A}, title = {Overview of Lipid Biomarkers in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Advances in experimental medicine and biology}, volume = {1161}, number = {}, pages = {233-241}, doi = {10.1007/978-3-030-21735-8_18}, pmid = {31562633}, issn = {0065-2598}, mesh = {*Amyotrophic Lateral Sclerosis/blood/diagnosis ; Animals ; *Biomarkers/blood ; Disease Progression ; Humans ; Lipid Metabolism ; *Lipids/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease involving motor neuron (MN) degeneration in the spinal cord, brain stem and primary motor cortex. The existence of inflammatory processes around MN and axonal degeneration in ALS has been shown. Unfortunately, none of the successful therapies in ALS animal models has improved clinical outcomes in patients with ALS. Therefore, the detection of blood biomarkers to be used as screening tools for disease onset and progression has been an expanding research area with few advances in the development of drugs for the treatment of ALS. In this review, we will address the available data analyzing regarding the relationship of lipid metabolism and lipid derived- products with ALS. We will address the advances on the studies about the role that lipids plays at the onset, progression and lifespan extension of ALS patients.}, }
@article {pmid31561888, year = {2019}, author = {Ji, Y and Karbaschi, M and Cooke, MS}, title = {Mycoplasma infection of cultured cells induces oxidative stress and attenuates cellular base excision repair activity.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {845}, number = {}, pages = {403054}, pmid = {31561888}, issn = {1879-3592}, support = {R15 ES027196/ES/NIEHS NIH HHS/United States ; R41 ES030274/ES/NIEHS NIH HHS/United States ; }, mesh = {Cell Line, Tumor/*microbiology ; Comet Assay ; DNA Breaks ; DNA Damage ; DNA Glycosylases/metabolism ; DNA Repair ; Guanine/analogs &amp; derivatives/analysis ; Humans ; Hydrogen Peroxide/toxicity ; *Mycoplasma ; Neuroblastoma/pathology ; Oxidative Stress ; Propidium ; Purines/analysis ; Single-Cell Analysis ; Staining and Labeling/methods ; }, abstract = {Mycoplasma contamination is a major concern for in vitro cell culture models as its resistance to most antibiotics, which makes the prevention and treatment of infection challenging. Furthermore, numerous studies show that Mycoplasma infection alters a variety of cellular processes, in a wide range of cell lines. However, there is a lack of information pertaining to the effects of Mycoplasma infection on genomic stability. In this study, a dopaminergic neuronal cell line (BE-M17), a popular in vitro model for Parkinson's disease, was used to evaluate the effect of Mycoplasma infection on genomic instability, and base excision repair (BER) activity, using single cell gel electrophoresis (the comet assay). The results showed that Mycoplasma infection induced oxidative stress in the absence of an inflammatory response, with markedly increased levels of DNA damage [strand breaks/alkali-labile sites (SB/ALS), and oxidised purines], compared to uninfected cells. The source of the oxidative stress may have been increased ROS generation, or attenuation of cellular antioxidant capacity (or a combination of both). Uninfected cells initially repaired SB/ALS more rapidly than infected cells, although SB/ALS were fully repaired in both uninfected and infected cells 2 h after H2O2 challenge. However, while uninfected cells showed complete repair of oxidised purines within 24 h, for the infected cells, these were not fully repaired even after 30 h. In conclusion, this study showed that not only does Mycoplasma infection induce oxidative stress and DNA damage, but it also decreases the efficiency of the main pathway responsible for the repair of oxidatively damaged DNA i.e. BER. In this in vitro model, there is no mechanism for infection-induced inflammation, which could be a source of increased ROS production. Therefore, further studies are needed to evaluate how Mycoplasma infection causes oxidatively damaged DNA, and how it modulates cellular DNA repair.}, }
@article {pmid31561715, year = {2020}, author = {Braun, N and Macklin, EA and Sinani, E and Sherman, A and Weber, M and , }, title = {The revised El Escorial criteria "clinically probable laboratory supported ALS"-once a promising now a superfluous category?.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {1-2}, pages = {24-28}, doi = {10.1080/21678421.2019.1666875}, pmid = {31561715}, issn = {2167-9223}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*diagnosis ; *Bias ; *Delayed Diagnosis ; Disease Progression ; *Early Diagnosis ; Electromyography ; Female ; Humans ; Laboratories ; Male ; Middle Aged ; }, abstract = {Over the past two decades, the El Escorial criteria (EEC) have been used as eligibility criteria in major randomized controlled trials. One of the goals of the revised EEC was to allow earlier diagnosis and, thus earlier trial inclusion by introducing a new category, namely "clinically probable laboratory supported" ALS. This category allowed EMG findings to be taken into account assuming that EMG is more sensitive than the clinical examination in detecting lower motor neuron signs. Recently, Edaravone has been licensed in several countries for the treatment of ALS based on a randomized controlled trial in a selected group of ALS patients excluding the EEC category "clinically probable laboratory supported". The major reason was that in a post hoc analysis of the first Edaravone trial this group comprised many slow progressors. As it is unclear whether this bias towardslow progressors was a study-specific problem or related to the category itself, we performed an analysis in the PRO-ACT dataset. In the PRO-ACT dataset, progression in ALS patients included at baseline into the "clinically probable laboratory supported" category was significantly slower (-0.53 in ALSFRS/month) compared to the other EEC categories (-0.68 in ALSFRS/month; p < 0.001) and exhibited a significantly longer diagnostic delay (13.5 months vs. 11.7 months, p < 0.001). This suggests that the bias toward slow progressors in the "clinically probable laboratory supported" category is an inherent problem of the category and thus does not fulfill the previous goal of earlier diagnosis, raising several questions concerning the application of this category.}, }
@article {pmid31552889, year = {2020}, author = {Zhang, FQ and Jiang, JL and Zhang, JT and Niu, H and Fu, XQ and Zeng, LL}, title = {Current status and future prospects of stem cell therapy in Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {15}, number = {2}, pages = {242-250}, pmid = {31552889}, issn = {1673-5374}, abstract = {Alzheimer's disease is a common progressive neurodegenerative disorder, pathologically characterized by the presence of β-amyloid plaques and neurofibrillary tangles. Current treatment approaches using drugs only alleviate the symptoms without curing the disease, which is a serious issue and influences the quality of life of the patients and their caregivers. In recent years, stem cell technology has provided new insights into the treatment of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Currently, the main sources of stem cells include neural stem cells, embryonic stem cells, mesenchymal stem cells, and induced pluripotent stem cells. In this review, we discuss the pathophysiology and general treatment of Alzheimer's disease, and the current state of stem cell transplantation in the treatment of Alzheimer's disease. We also assess future challenges in the clinical application and drug development of stem cell transplantation as a treatment for Alzheimer's disease.}, }
@article {pmid31552549, year = {2020}, author = {Wurster, CD and Steinacker, P and Günther, R and Koch, JC and Lingor, P and Uzelac, Z and Witzel, S and Wollinsky, K and Winter, B and Osmanovic, A and Schreiber-Katz, O and Al Shweiki, R and Ludolph, AC and Petri, S and Hermann, A and Otto, M and , }, title = {Neurofilament light chain in serum of adolescent and adult SMA patients under treatment with nusinersen.}, journal = {Journal of neurology}, volume = {267}, number = {1}, pages = {36-44}, pmid = {31552549}, issn = {1432-1459}, support = {project FTLDc 01GI1007A//Bundesministerium f&#xfc;r Bildung und Forschung/ ; 01ED1512//PreFrontAls/ ; }, mesh = {Adolescent ; Adult ; Child ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Muscular Atrophy, Spinal/*blood/*drug therapy/physiopathology ; Neurofilament Proteins/*blood/*drug effects ; Oligonucleotides/*pharmacology ; *Outcome Assessment, Health Care ; Severity of Illness Index ; Spinal Muscular Atrophies of Childhood/*blood/*drug therapy/physiopathology ; Young Adult ; }, abstract = {OBJECTIVE: To determine the diagnostic and monitoring value of serum neurofilament light chain (NfL) in spinal muscular atrophy (SMA).<br><br>METHODS: We measured serum NfL in 46 SMA patients at baseline and over 14&#xa0;months of treatment with the antisense-oligonucleotide (ASO) nusinersen using the ultrasensitive single molecule array (Simoa) technology. Serum NfL levels of SMA patients were compared to controls and related to cerebrospinal fluid (CSF) NfL, blood-CSF barrier function quantified by the albumin blood/CSF ratio (Qalb) and motor scores (Hammersmith Functional Motor Scale Expanded, HFMSE; Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, ALSFRS-R).<br><br>RESULTS: Serum NfL levels of SMA patients were in the range of controls (p&#x2009;=&#x2009;0.316) and did not correlate with CSF NfL (&#x3c1;&#x2009;=&#x2009;0.302, p&#x2009;=&#x2009;0.142) or Qalb (&#x3c1;&#x2009;=&#x2009;-&#x2009;0.160, p&#x2009;=&#x2009;0.293). During therapy, serum NfL levels were relatively stable with notable concentration changes in single SMA patients, however, within the control range. Higher NfL levels were associated with worse motor performance in SMA (baseline: HFMSE &#x3c1;&#x2009;=&#x2009;-&#x2009;0.330, p&#x2009;=&#x2009;0.025, ALSFRS-R &#x3c1;&#x2009;=&#x2009;-&#x2009;0.403, p&#x2009;=&#x2009;0.005; after 10&#xa0;months: HFMSE &#x3c1;&#x2009;=&#x2009;-&#x2009;0.525, p&#x2009;=&#x2009;0.008, ALSFRS-R &#x3c1;&#x2009;=&#x2009;-&#x2009;0.537, p&#x2009;=&#x2009;0.007), but changes in motor scores did not correlate with changes in serum NfL.<br><br>CONCLUSION: Diagnostic and monitoring performance of serum NfL measurement seems to differ between SMA subtypes. Unlike to SMA type 1, in adolescent and adult SMA type 2 and 3 patients, neurodegeneration is not reflected by increased NfL levels and short-term therapeutic effects cannot be observed. Long-term follow-up has to be performed to see if even low levels of NfL might be good prognostic markers.}, }
@article {pmid31551693, year = {2019}, author = {Bauer, PO and Dunmore, JH and Sasaguri, H and Matoska, V}, title = {Neurons Induced From Fibroblasts of c9ALS/FTD Patients Reproduce the Pathology Seen in the Central Nervous System.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {935}, pmid = {31551693}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative conditions. A non-coding hexanucleotide (GGGGCC) repeat expansion in the c9orf72 gene is the most common genetic cause of ALS/FTD. We present a cellular model of c9ALS/FTD where induced neurons (iNeurons) are generated within 2 weeks by direct conversion of patients' dermal fibroblasts through down-regulation of polypyrimidine-tract-binding protein 1 (PTB1). While sense (S) and anti-sense (AS) intranuclear RNA foci were observed in both fibroblasts and iNeurons, the accumulation of (S) and (AS) repeat-associated non-ATG translation (RANT) products were detected only in iNeurons. Importantly, anti-sense oligonucleotides (ASOs) against the (S) repeat transcript lead to decreased (S) RNA foci staining and a reduction of the corresponding RANT products without affecting its (AS) counterparts. ASOs treatment also rescued the cell viability upon stressful stimulus. The results indicate that iNeurons is an advantageous model that not only recapitulates c9ALS/FTD hallmark features but can also help uncover promising therapeutics.}, }
@article {pmid31548223, year = {2020}, author = {Goldman, JS}, title = {Predictive Genetic Counseling for Neurodegenerative Diseases: Past, Present, and Future.}, journal = {Cold Spring Harbor perspectives in medicine}, volume = {10}, number = {7}, pages = {}, pmid = {31548223}, issn = {2157-1422}, mesh = {Alzheimer Disease/*genetics ; Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics ; Genetic Counseling/ethics/*methods/trends ; Genetic Testing/*methods ; Humans ; Huntington Disease/diagnosis/*genetics ; Parkinson Disease/genetics ; }, abstract = {Predictive genetic counseling for neurodegenerative diseases commenced with Huntington's disease (HD). Because the psychological issues and outcomes have been best studied in HD, the HD genetic counseling and testing protocol is still accepted as the gold standard for genetic counseling for these diseases. Yet, advances in genomic technology have produced an abundance of new information about the genetics of diseases such as Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Parkinson's disease. The resulting expansion of genetic tests together with the availability of direct-to-consumer testing and clinical trials for treatment of these diseases present new ethical and practical issues requiring modifications to the protocol for HD counseling and new demands on both physicians and genetic counselors. This work reviews the history of genetic counseling for neurodegenerative diseases, its current practice, and the future direction of genetic counseling for these conditions.}, }
@article {pmid31547555, year = {2019}, author = {Fuke, N and Nagata, N and Suganuma, H and Ota, T}, title = {Regulation of Gut Microbiota and Metabolic Endotoxemia with Dietary Factors.}, journal = {Nutrients}, volume = {11}, number = {10}, pages = {}, pmid = {31547555}, issn = {2072-6643}, mesh = {Animals ; Diet, High-Fat/adverse effects ; Dietary Fats/*adverse effects ; Dysbiosis/blood/etiology/*microbiology ; Endotoxemia/blood/etiology/*microbiology ; Gastrointestinal Microbiome/*physiology ; Humans ; Lipopolysaccharides/*blood ; Mice ; }, abstract = {Metabolic endotoxemia is a condition in which blood lipopolysaccharide (LPS) levels are elevated, regardless of the presence of obvious infection. It has been suggested to lead to chronic inflammation-related diseases such as obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease (NAFLD), pancreatitis, amyotrophic lateral sclerosis, and Alzheimer's disease. In addition, it has attracted attention as a target for the prevention and treatment of these chronic diseases. As metabolic endotoxemia was first reported in mice that were fed a high-fat diet, research regarding its relationship with diets has been actively conducted in humans and animals. In this review, we summarize the relationship between fat intake and induction of metabolic endotoxemia, focusing on gut dysbiosis and the influx, kinetics, and metabolism of LPS. We also summarize the recent findings about dietary factors that attenuate metabolic endotoxemia, focusing on the regulation of gut microbiota. We hope that in the future, control of metabolic endotoxemia using dietary factors will help maintain human health.}, }
@article {pmid31547425, year = {2019}, author = {Bastings, JJAJ and van Eijk, HM and Olde Damink, SW and Rensen, SS}, title = {d-amino Acids in Health and Disease: A Focus on Cancer.}, journal = {Nutrients}, volume = {11}, number = {9}, pages = {}, pmid = {31547425}, issn = {2072-6643}, mesh = {Amino Acids/*physiology ; Humans ; Neoplasms/*metabolism ; Synaptic Transmission/*physiology ; }, abstract = {d-amino acids, the enantiomeric counterparts of l-amino acids, were long considered to be non-functional or not even present in living organisms. Nowadays, d-amino acids are acknowledged to play important roles in numerous physiological processes in the human body. The most commonly studied link between d-amino acids and human physiology concerns the contribution of d-serine and d-aspartate to neurotransmission. These d-amino acids and several others have also been implicated in regulating innate immunity and gut barrier function. Importantly, the presence of certain d-amino acids in the human body has been linked to several diseases including schizophrenia, amyotrophic lateral sclerosis, and age-related disorders such as cataract and atherosclerosis. Furthermore, increasing evidence supports a role for d-amino acids in the development, pathophysiology, and treatment of cancer. In this review, we aim to provide an overview of the various sources of d-amino acids, their metabolism, as well as their contribution to physiological processes and diseases in man, with a focus on cancer.}, }
@article {pmid31542756, year = {2019}, author = {Burke, T and Wilson O'Raghallaigh, J and Maguire, S and Galvin, M and Heverin, M and Hardiman, O and Pender, N}, title = {Group interventions for amyotrophic lateral sclerosis caregivers in Ireland: a randomised controlled trial protocol.}, journal = {BMJ open}, volume = {9}, number = {9}, pages = {e030684}, pmid = {31542756}, issn = {2044-6055}, mesh = {*Amyotrophic Lateral Sclerosis ; Anxiety/etiology/*therapy ; Caregivers/*psychology ; *Cost of Illness ; Depression/etiology/*therapy ; Humans ; Ireland ; Randomized Controlled Trials as Topic/*methods ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapid and fatal motor disease marked by progressive physical impairment due to muscle weakness and wasting. It is multidimensional with many patients presenting with cognitive and/or behavioural impairment. Caregivers of patients with ALS, commonly non-paid immediate family members, often take primary responsibility for the complex care needs of patients in non-medicalised setting, and many as a consequence experience caregiver burden, anxiety, and/or depression.<br><br>METHODS AND ANALYSIS: This randomised controlled trial (RCT) will use randomisation to allocate n=75 caregivers of patients with ALS from the national ALS clinic into three groups with an equal distribution. The RCT consists of two intervention groups and a wait list control (treatment as usual [TAU]) group. The intervention arms of the trial consist of a 'mindfulness-based stress reduction' and 'building better caregivers' manualised group-based intervention, with 9 and 6 weekly sessions, respectively. The TAU group will have access to intervention at the end of the trial period. Primary outcomes are self-report questionnaires on anxiety and depression symptoms, with caregiver burden and quality of life considered secondary outcomes. Assessment will commence at baseline, immediately following the intervention period, and after a period of 12 weeks to assess the effectiveness and efficacy of participating in an intervention. Patient cognitive and behavioural data will also be considered. Means of treatment and control groups at Time 0 and 1 will be analysed using mixed model multivariate analysis of variance followed by analysis of variance, and treatment effect-sizes will be calculated. This RCT protocol is pre-results and has been registered with an international database resulting in an International Standard Randomised Controlled Trials Number (ISRCTN53226941).<br><br>ETHICS AND DISSEMINATION: Ethics approval was obtained from the Beaumont Hospital Medical Research Ethics Committee. Results of the main trial will be submitted for publication in a peer-reviewed journal.}, }
@article {pmid31540100, year = {2019}, author = {Bonafede, R and Brandi, J and Manfredi, M and Scambi, I and Schiaffino, L and Merigo, F and Turano, E and Bonetti, B and Marengo, E and Cecconi, D and Mariotti, R}, title = {The Anti-Apoptotic Effect of ASC-Exosomes in an In Vitro ALS Model and Their Proteomic Analysis.}, journal = {Cells}, volume = {8}, number = {9}, pages = {}, pmid = {31540100}, issn = {2073-4409}, mesh = {Adipocytes/*metabolism ; Animals ; *Apoptosis ; Cells, Cultured ; Exosomes/*metabolism ; Mice ; Mice, Inbred C57BL ; *Models, Biological ; Neuroprotective Agents/metabolism ; *Proteomics ; Stem Cells/*metabolism ; }, abstract = {Stem cell therapy represents a promising approach in the treatment of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). The beneficial effect of stem cells is exerted by paracrine mediators, as exosomes, suggesting a possible potential use of these extracellular vesicles as non-cell based therapy. We demonstrated that exosomes isolated from adipose stem cells (ASC) display a neuroprotective role in an in vitro model of ALS. Moreover, the internalization of ASC-exosomes by the cells was shown and the molecules and the mechanisms by which exosomes could exert their beneficial effect were addressed. We performed for the first time a comprehensive proteomic analysis of exosomes derived from murine ASC. We identified a total of 189 proteins and the shotgun proteomics analysis revealed that the exosomal proteins are mainly involved in cell adhesion and negative regulation of the apoptotic process. We correlated the protein content to the anti-apoptotic effect of exosomes observing a downregulation of pro-apoptotic proteins Bax and cleaved caspase-3 and upregulation of anti-apoptotic protein Bcl-2 α, in an in vitro model of ALS after cell treatment with exosomes. Overall, this study shows the neuroprotective effect of ASC-exosomes after their internalization and their global protein profile, that could be useful to understand how exosomes act, demonstrating that they can be employed as therapy in neurodegenerative diseases.}, }
@article {pmid31537598, year = {2019}, author = {Wagner-Altendorf, TA and Heldmann, M and Hanssen, H and Münte, TF}, title = {Permanent lesion to the corticospinal tract after therapy with capecitabine.}, journal = {BMJ case reports}, volume = {12}, number = {9}, pages = {}, pmid = {31537598}, issn = {1757-790X}, mesh = {Antimetabolites, Antineoplastic/*adverse effects/therapeutic use/toxicity ; Capecitabine/*adverse effects/therapeutic use/toxicity ; Colorectal Neoplasms/complications/drug therapy ; Diagnosis, Differential ; Fatal Outcome ; Humans ; Leukoencephalopathies/*chemically induced/complications/diagnostic imaging ; Magnetic Resonance Imaging/methods ; Male ; Middle Aged ; Motor Neuron Disease/diagnosis ; Pneumonia, Aspiration/etiology ; Pyramidal Tracts/diagnostic imaging/*drug effects/pathology ; Quadriplegia/chemically induced/diagnosis ; }, abstract = {Capecitabine is an oral fluoropyrimidine used to treat solid tumours such as colorectal and breast cancer. A rare but severe side effect is capecitabine-induced leukoencephalopathy, including bilateral lesion to the corticospinal tract. However, neurological symptoms due to capecitabine treatment are usually reported to be reversible after discontinuation of capecitabine. Here, we present the case of a patient with bilateral degeneration of the corticospinal tract and progressive spastic tetraplegia after chemotherapy with capecitabine mimicking primary lateral sclerosis. Although therapy with capecitabine was ended, symptoms substantially worsened over the following years and the patient finally died from aspiration pneumonia almost 3 years after the application of capecitabine.}, }
@article {pmid31530644, year = {2019}, author = {Seki, S and Yamamoto, T and Quinn, K and Spigelman, I and Pantazis, A and Olcese, R and Wiedau-Pazos, M and Chandler, SH and Venugopal, S}, title = {Circuit-Specific Early Impairment of Proprioceptive Sensory Neurons in the SOD1[G93A] Mouse Model for ALS.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {39}, number = {44}, pages = {8798-8815}, pmid = {31530644}, issn = {1529-2401}, support = {R01 CA196263/CA/NCI NIH HHS/United States ; R01 HL134346/HL/NHLBI NIH HHS/United States ; R21 NS095157/NS/NINDS NIH HHS/United States ; }, mesh = {Action Potentials ; Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Disease Models, Animal ; Female ; Jaw/innervation/physiopathology ; Male ; Mechanoreceptors/physiology ; Mice, Transgenic ; Models, Neurological ; Nociception/physiology ; Proprioception/*physiology ; Sensory Receptor Cells/*physiology ; Superoxide Dismutase-1/genetics ; Tegmentum Mesencephali/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons degenerate, resulting in muscle atrophy, paralysis, and fatality. Studies using mouse models of ALS indicate a protracted period of disease development with progressive motor neuron pathology, evident as early as embryonic and postnatal stages. Key missing information includes concomitant alterations in the sensorimotor circuit essential for normal development and function of the neuromuscular system. Leveraging unique brainstem circuitry, we show in vitro evidence for reflex circuit-specific postnatal abnormalities in the jaw proprioceptive sensory neurons in the well-studied SOD1[G93A] mouse. These include impaired and arrhythmic action potential burst discharge associated with a deficit in Nav1.6 Na[+] channels. However, the mechanoreceptive and nociceptive trigeminal ganglion neurons and the visual sensory retinal ganglion neurons were resistant to excitability changes in age-matched SOD1[G93A] mice. Computational modeling of the observed disruption in sensory patterns predicted asynchronous self-sustained motor neuron discharge suggestive of imminent reflexive defects, such as muscle fasciculations in ALS. These results demonstrate a novel reflex circuit-specific proprioceptive sensory abnormality in ALS.SIGNIFICANCE STATEMENT Neurodegenerative diseases have prolonged periods of disease development and progression. Identifying early markers of vulnerability can therefore help devise better diagnostic and treatment strategies. In this study, we examined postnatal abnormalities in the electrical excitability of muscle spindle afferent proprioceptive neurons in the well-studied SOD1[G93A] mouse model for neurodegenerative motor neuron disease, amyotrophic lateral sclerosis. Our findings suggest that these proprioceptive sensory neurons are exclusively afflicted early in the disease process relative to sensory neurons of other modalities. Moreover, they presented Nav1.6 Na[+] channel deficiency, which contributed to arrhythmic burst discharge. Such sensory arrhythmia could initiate reflexive defects, such as muscle fasciculations in amyotrophic lateral sclerosis, as suggested by our computational model.}, }
@article {pmid31529340, year = {2019}, author = {Yin, X and Wang, S and Wang, X and Yang, Y and Jiang, H and Wang, T and Wang, Y and Zhang, C and Feng, H}, title = {Lithium facilitates removal of misfolded proteins and attenuated faulty interaction between mutant SOD1 and p-CREB (Ser133) through enhanced autophagy in mutant hSOD1[G93A] transfected neuronal cell lines.}, journal = {Molecular biology reports}, volume = {46}, number = {6}, pages = {6299-6309}, pmid = {31529340}, issn = {1573-4978}, support = {81571227//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Autophagy ; Cell Line ; Cell Survival/drug effects ; Cyclic AMP Response Element-Binding Protein/genetics/*metabolism ; Lithium/*pharmacology ; Mice ; *Mutation ; Neurons/*cytology/drug effects/metabolism ; Phosphorylation ; Protein Folding/drug effects ; Signal Transduction ; Superoxide Dismutase-1/chemistry/genetics/*metabolism ; Transfection ; }, abstract = {Abnormally protein aggregation and deposition are key pathological features of ALS, which may related with dysfunctional cellular autophagy. In the current study, we found that, compared with wtSOD1 cells, serum starvation treatment resulted in significant higher percentage of apoptosis in mutSOD1 cells; Lithium treatment exerted protection for those mutSOD1 cells, with decreased GFP-tagged mutant SOD1 protein aggregates deposition; Whereas, pre-treatment with Baf or 3-MA (autophagy inhibitors) blocked protection of lithium for mutant SOD1 cells, and induced increased GFP-tagged mutant SOD1 protein aggregation. Further, Western blots results showed that lithium treatment led to decrease of mutant hSOD1 protein levels in both Triton X-100 soluble and Triton X-100 insoluble fraction of mutSOD1 cells. Besides, improper binding of mutant SOD1 proteins' aggregates with p-CREB (Ser133) (transcription factor) in mutSOD1 cells were demonstrated; whereas lithium treatment attenuated this fault interaction. In conclusion, our results showed that, in mutSOD1 cells, mutSOD1 protein aggregates were related with abnormal autophagic regulation. Lithium treatment could induce autophagy and enhance clearance of protein aggregates, further exerting protection on mutSOD1 cells. More importantly, we uncovered another distinct pathological role of mutSOD1 protein aggregates, that is abnormal binding with p-CREB (Ser133), an important transcription factor, which may play crucial role in the PI3K-Akt-CREB-AEG-1 signaling pathway.}, }
@article {pmid31521619, year = {2019}, author = {Zhang, C and Liang, W and Wang, H and Yang, Y and Wang, T and Wang, S and Wang, X and Wang, Y and Feng, H}, title = {γ-Oryzanol mitigates oxidative stress and prevents mutant SOD1-Related neurotoxicity in Drosophila and cell models of amyotrophic lateral sclerosis.}, journal = {Neuropharmacology}, volume = {160}, number = {}, pages = {107777}, doi = {10.1016/j.neuropharm.2019.107777}, pmid = {31521619}, issn = {1873-7064}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Antioxidants/pharmacology ; Cell Line ; Disease Models, Animal ; Drosophila ; Drosophila Proteins/genetics/metabolism ; Humans ; Male ; Mice ; Motor Neurons/drug effects ; Mutation ; Neuroprotective Agents/administration &amp; dosage/*pharmacology ; Oxidative Stress/*drug effects ; Phenylpropionates/administration &amp; dosage/*pharmacology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/*genetics/metabolism ; }, abstract = {Oxidative stress plays a critical role in mutant copper/zinc superoxide dismutase 1 (SOD1)-linked amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by selective loss of motor neurons. Thus, an anti-oxidative stress remedy might be a promising means for the treatment of ALS. The aim of the present study is to investigate the neuroprotective effects of γ-oryzanol (Orz) and elucidate its relevant molecular mechanisms in mutant hSOD1-linked Drosophila and cell models of ALS. Orz treatment provided neuroprotection in flies with expression of hSOD1-G85R in motor neurons, as demonstrated by the prolonged survival, improvement of motor deficits, reduced oxidative damage and regulated redox homeostasis when compared with those in controls. Moreover, Orz significantly decreased neuronal apoptosis and upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutamate-cysteine ligase catalytic subunit (GCLC) antioxidant pathway via activating Akt in hSOD1-G93A-expressing NSC-34 cells. In addition, our results showed that both in vivo and in vitro, Akt served as an upstream regulator of signal transducers and activators of transcription (Stat) 3 stimulated by Orz, which further increased the level of another anti-oxidative stress factor heat-shock protein 70 (HSP70). Altogether, these findings provide evidence that Orz has potential neuroprotective effects that may be beneficial in the treatment of ALS disease with SOD1 mutations.}, }
@article {pmid31507117, year = {2019}, author = {Ralli, M and Lambiase, A and Artico, M and de Vincentiis, M and Greco, A}, title = {Amyotrophic Lateral Sclerosis: Autoimmune Pathogenic Mechanisms, Clinical Features, and Therapeutic Perspectives.}, journal = {The Israel Medical Association journal : IMAJ}, volume = {21}, number = {7}, pages = {438-443}, pmid = {31507117}, issn = {1565-1088}, mesh = {Age Factors ; Aged ; Amyotrophic Lateral Sclerosis/drug therapy/epidemiology/*physiopathology ; Diagnosis, Differential ; Disease Progression ; Female ; Humans ; Immunosuppressive Agents/therapeutic use ; Male ; Motor Neurons/*pathology ; *Quality of Life ; Riluzole/therapeutic use ; Risk Factors ; Sex Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive death of motor neurons leading to fatal paralysis. The causes of ALS remain unknown; however, evidence supports the presence of autoimmune mechanisms contributing to pathogenesis. Although several environmental factors have been proposed, the only established risk factors are older age, male gender, and a family history of ALS. To date, there are no diagnostic test for ALS, and clinicians rely on the combination of upper motor neuron and lower motor neuron signs in the same body region. The aim of this paper was to provide a comprehensive review of current clinical literature with special focus on the role of autoimmunity in ALS, differential diagnosis, and available therapeutic approaches. Current evidence suggests a contribution of the innate immune system in ALS, with a role of microglial cell activation at the sites of neurodegeneration. The median time from symptom onset to diagnosis of ALS is 14 months, and this time estimate is mainly based on specific clinical signs and exclusion of ALS-like conditions. Several therapeutic approaches have been proposed, including immunosuppressive drugs, to reduce disease progression. Riluzole has been established as the only, although modestly effective, disease modifying therapy, extending mean patient survival by 3to 6 months. Recent advances in understanding the pathophysiology mechanisms of ALS encourage realistic hope for new treatment approaches. To date, the cornerstones of the management of patients with ALS are focused on symptom control, maintaining quality of life and improving survival.}, }
@article {pmid31506396, year = {2019}, author = {Takahashi, S and Morimoto, S and Okano, H}, title = {[Ropinirole Hydrochloride, a Candidate Drug for ALS Treatment].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {71}, number = {9}, pages = {943-952}, doi = {10.11477/mf.1416201386}, pmid = {31506396}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Double-Blind Method ; Humans ; Indoles/*therapeutic use ; Motor Neurons/drug effects ; }, abstract = {We performed drug screening using motor neurons derived from disease-specific induced pluripotent stem cells (iPSCs) for amyotrophic lateral sclerosis (ALS) and found that ropinirole hydrochloride prevented motor neuron death. We have started a randomized clinical trial testing ropinirole hydrochloride in ALS patients in December 2018. This is a phase I/IIa randomized, double-blind, placebo-controlled, single-center, open-label continuation clinical trial. The primary aim is to assess the safety and tolerability of ropinirole hydrochloride in patients with ALS. Secondary aims include the following effectiveness evaluations: ALSFRS-R, quantitative muscle strength by a hand-held dynamometer, muscle volume by CT scan, forced vital capacity, physical activity by an activity tracker, survival, ALSAQ40 scale, and a Zarit Caregiver Burden Interview. Moreover, we will perform an efficacy evaluation using subjects-derived iPSCs/motor neurons and assess plasma/CSF biomarkers (TDP-43, and ALS-related RNA/micro RNA) as exploratory research questions. Ropinirole hydrochloride potentially targets multiple mechanisms of ALS pathology (i.e., oxidative stress, mitochondrial dysfunction, and abnormal aggregation of TDP-43/FUS protein, which is representative of the ALS phenotype), with promising preclinical study results based on iPSC research. The availability of the drug suggests that rapid translation to daily clinical use might be possible. Our trial will provide reliable and important data for further potential trials. The results will appear in March 2021.}, }
@article {pmid31500113, year = {2019}, author = {Cappella, M and Ciotti, C and Cohen-Tannoudji, M and Biferi, MG}, title = {Gene Therapy for ALS-A Perspective.}, journal = {International journal of molecular sciences}, volume = {20}, number = {18}, pages = {}, pmid = {31500113}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/*therapy ; Animals ; C9orf72 Protein/genetics ; Disease Models, Animal ; Gene Editing ; Gene Expression ; Gene Transfer Techniques ; Genetic Predisposition to Disease ; *Genetic Therapy/adverse effects/methods ; Genetic Vectors/administration &amp; dosage/genetics ; Humans ; Molecular Targeted Therapy ; Motor Neurons/metabolism ; Mutation ; Superoxide Dismutase-1/genetics ; Transgenes ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) with no cure. Recent advances in gene therapy open a new perspective to treat this disorder-particularly for the characterized genetic forms. Gene therapy approaches, involving the delivery of antisense oligonucleotides into the central nervous system (CNS) are being tested in clinical trials for patients with mutations in SOD1 or C9orf72 genes. Viral vectors can be used to deliver therapeutic sequences to stably transduce motor neurons in the CNS. Vectors derived from adeno-associated virus (AAV), can efficiently target genes and have been tested in several pre-clinical settings with promising outcomes. Recently, the Food and Drug Administration (FDA) approved Zolgensma, an AAV-mediated treatment for another MND-the infant form of spinal muscular atrophy. Given the accelerated progress in gene therapy, it is potentially a promising avenue to develop an efficient and safe cure for ALS.}, }
@article {pmid31499409, year = {2019}, author = {van der Burgh, HK and Westeneng, HJ and Meier, JM and van Es, MA and Veldink, JH and Hendrikse, J and van den Heuvel, MP and van den Berg, LH}, title = {Cross-sectional and longitudinal assessment of the upper cervical spinal cord in motor neuron disease.}, journal = {NeuroImage. Clinical}, volume = {24}, number = {}, pages = {101984}, pmid = {31499409}, issn = {2213-1582}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/diagnostic imaging/*pathology ; Cervical Cord/diagnostic imaging/*pathology ; Cross-Sectional Studies ; *Disease Progression ; Female ; Humans ; Longitudinal Studies ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Motor Neuron Disease/diagnostic imaging/*pathology ; Muscular Atrophy, Spinal/diagnostic imaging/*pathology ; Neuroimaging ; Young Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease characterized by both upper and lower motor neuron degeneration. While neuroimaging studies of the brain can detect upper motor neuron degeneration, these brain MRI scans also include the upper part of the cervical spinal cord, which offers the possibility to expand the focus also towards lower motor neuron degeneration. Here, we set out to investigate cross-sectional and longitudinal disease effects in the upper cervical spinal cord in patients with ALS, progressive muscular atrophy (PMA: primarily lower motor neuron involvement) and primary lateral sclerosis (PLS: primarily upper motor neuron involvement), and their relation to disease severity and grey and white matter brain measurements.<br><br>METHODS: We enrolled 108 ALS patients without C9orf72 repeat expansion (ALS C9-), 26 ALS patients with C9orf72 repeat expansion (ALS C9+), 28 PLS patients, 56 PMA patients and 114 controls. During up to five visits, longitudinal T1-weighted brain MRI data were acquired and used to segment the upper cervical spinal cord (UCSC, up to C3) and individual cervical segments (C1 to C4) to calculate cross-sectional areas (CSA). Using linear (mixed-effects) models, the CSA differences were assessed between groups and correlated with disease severity. Furthermore, a relationship between CSA and brain measurements was examined in terms of cortical thickness of the precentral gyrus and white matter integrity of the corticospinal tract.<br><br>RESULTS: Compared to controls, CSAs at baseline showed significantly thinner UCSC in all groups in the MND spectrum. Over time, ALS C9- patients demonstrated significant thinning of the UCSC and, more specifically, of segment C3 compared to controls. Progressive thinning over time was also observed in C1 of PMA patients, while ALS C9+ and PLS patients did not show any longitudinal changes. Longitudinal spinal cord measurements showed a significant relationship with disease severity and we found a significant correlation between spinal cord and motor cortex thickness or corticospinal tract integrity for PLS and PMA, but not for ALS patients.<br><br>DISCUSSION: Our findings demonstrate atrophy of the upper cervical spinal cord in the motor neuron disease spectrum, which was progressive over time for all but PLS patients. Cervical spinal cord imaging in ALS seems to capture different disease effects than brain neuroimaging. Atrophy of the cervical spinal cord is therefore a promising additional biomarker for both diagnosis and disease progression and could help in the monitoring of treatment effects in future clinical trials.}, }
@article {pmid31497116, year = {2019}, author = {Yamada, Y and Ansari, A and Sae-Ngow, T and Tanaka, R and Kawase, T and Kalyan, S and Kato, Y}, title = {Microsurgical Treatment of Paraclinoid Aneurysms by Extradural Anterior Clinoidectomy: The Fujita Experience.}, journal = {Asian journal of neurosurgery}, volume = {14}, number = {3}, pages = {868-872}, pmid = {31497116}, issn = {1793-5482}, abstract = {INTRODUCTION: Paraclinoid aneurysms pose technical difficulty in their approach, mainly because of their close proximity to neurovascular structures, deeper location, and a smaller corridor. Extradural anterior clinoidectomy is a highly beneficial technique in such cases, making more space to deal with these aneurysms. We describe our method of performing extradural anterior clinoidectomy in such patients.<br><br>MATERIALS AND METHODS: A total of 33 cases of paraclinoid internal carotid artery aneurysms presenting to Fujita Health University Banbuntane Hospital, Japan, were included. Females comprised the majority with 32 cases; the mean age was 54.8 years (range: 35-74 years). The mean size of the paraclinoid aneurysm was 5.3 mm (range: 3-12 mm).<br><br>RESULTS: Nine paraclinoid aneurysms were found projecting dorsally, 7 laterally, and 17 medially (Kazuhiko Kyoshim et al's. classification). An immediate complete occlusion rate of 100% was present. Visual disturbance was found in 6.2% of our patients. One of our patients developed permanent loss of vision.<br><br>CONCLUSION: Extradural anterior clinoidectomy enables a better exposure to paraclinoid aneurysms. Precise anatomical knowledge along with microsurgical tactics is required to prevent and manage potential complications to achieve good outcomes.}, }
@article {pmid31496852, year = {2019}, author = {Boentert, M}, title = {Sleep disturbances in patients with amyotrophic lateral sclerosis: current perspectives.}, journal = {Nature and science of sleep}, volume = {11}, number = {}, pages = {97-111}, pmid = {31496852}, issn = {1179-1608}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease inevitably leading to generalized muscle weakness and premature death. Sleep disturbances are extremely common in patients with ALS and substantially add to the burden of disease for both patients and caregivers. Disruption of sleep can be caused by physical symptoms, such as muscle cramps, pain, reduced mobility, spasticity, mucus retention, and restless legs syndrome. In addition, depression and anxiety may lead to significant insomnia. In a small subset of patients, rapid eye movement (REM) sleep behavioral disorder may be present, reflecting neurodegeneration of central nervous system pathways which are involved in REM sleep regulation. With regard to overall prognosis, sleep-disordered breathing (SDB) and nocturnal hypoventilation (NH) are of utmost importance, particularly because NH precedes respiratory failure. Timely mechanical ventilation is one of the most significant therapeutic measures to prolong life span in ALS, and transcutaneous capnometry is superior to pulse oxymetry to detect NH early. In addition, it has been shown that in patients on home ventilatory support, survival time depends on whether normocapnia, normoxia, and elimination of apneic events during sleep can be reliably achieved. Several studies have investigated sleep patterns and clinical determinants of sleep disruption in ALS, but exact prevalence numbers are unknown. Thus, constant awareness for sleep-related symptoms is appropriate. Since no curative treatment can be offered to affected patients, sleep complaints should be thoroughly investigated in order to identify any treatable etiology and improve or stabilize quality of life as much as possible. The use of hypnotics should be confined to palliation during the terminal phase and refractory insomnia in earlier stages of the disease, taking into account that most compounds potentially aggravate SDB.}, }
@article {pmid31493784, year = {2019}, author = {Meyer, T and Funke, A and Münch, C and Kettemann, D and Maier, A and Walter, B and Thomas, A and Spittel, S}, title = {Real world experience of patients with amyotrophic lateral sclerosis (ALS) in the treatment of spasticity using tetrahydrocannabinol:cannabidiol (THC:CBD).}, journal = {BMC neurology}, volume = {19}, number = {1}, pages = {222}, pmid = {31493784}, issn = {1471-2377}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*drug therapy ; Cannabidiol/*administration &amp; dosage ; Cohort Studies ; Dronabinol/*administration &amp; dosage ; Drug Combinations ; Female ; Humans ; Male ; Middle Aged ; Muscle Spasticity/*drug therapy ; Patient Satisfaction ; Retrospective Studies ; }, abstract = {BACKGROUND: Treatment of spasticity poses a major challenge in amyotrophic lateral sclerosis (ALS) patient management. Delta-9-tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (THC:CBD), approved for the treatment of spasticity in multiple sclerosis, serves as a complementary off-label treatment option in ALS-related spasticity. However, few structured data are available on THC:CBD in the treatment of spasticity in ALS.<br><br>METHOD: A retrospective mono-centric cohort study was realised in 32 patients that meet the following criteria: 1) diagnosis of ALS, 2) ALS-related spasticity; 3) treatment with THC:CBD. Spasticity was rated using the Numeric Rating Scale (NRS). Patient's experience with THC:CBD was assessed using the net promoter score (NPS) and treatment satisfaction questionnaire for medication (TSMQ-9) as captured through telephone survey or online assessment.<br><br>RESULTS: The mean dose THC:CBD were 5.5 daily actuations (range&#x2009;<&#x2009;1 to 20). Three subgroups of patients were identified: 1) high-dose daily use (&#x2265; 7 daily actuations, 34%, n&#x2009;=&#x2009;11), 2) low-dose daily use (<&#x2009;7 daily actuations, 50%, n&#x2009;=&#x2009;16), 3) infrequent use (<&#x2009;1 daily actuation, 16%, n&#x2009;=&#x2009;5). Overall NPS was +&#x2009;4.9 (values above 0 express a positive recommendation to fellow patients). Remarkably, patients with moderate to severe spasticity (NRS&#x2009;&#x2265;&#x2009;4) reported a high recommendation rate (NPS: +&#x2009;29) in contrast to patients with mild spasticity (NRS&#x2009;<&#x2009;4; NPS: -&#x2009;44). For the three main domains of TSQM-9 high mean satisfaction levels were found (maximum value 100): effectiveness 70.5 (&#xb1;22.3), convenience 76.6 (&#xb1;23.3) and global satisfaction 75.0 (&#xb1;24.7).<br><br>CONCLUSION: THC:CBD is used in a wide dose range suggesting that the drug was applied on the basis of individual patients' needs and preferences. Contributing to this notion, moderate to severe spasticity was associated with an elevated number of daily THC:CBD actuations and stronger recommendation rate (NPS) as compared to patients with mild spasticity. Overall, treatment satisfaction (TSQM-9) was high. The results suggest that THC:CBD may serve as a valuable addition in the spectrum of symptomatic therapy in ALS. However, prospective studies and head-to-head comparisons to other spasticity medications are of interest to further explore the effectiveness of THC:CBD in the management of spasticity, and other ALS-related symptoms.}, }
@article {pmid31487757, year = {2019}, author = {Silva, IS and Pedrosa, R and Azevedo, IG and Forbes, AM and Fregonezi, GA and Dourado Junior, ME and Lima, SR and Ferreira, GM}, title = {Respiratory muscle training in children and adults with neuromuscular disease.}, journal = {The Cochrane database of systematic reviews}, volume = {9}, number = {9}, pages = {CD011711}, pmid = {31487757}, issn = {1469-493X}, mesh = {Adult ; Breathing Exercises/*methods ; Child ; Exhalation/physiology ; Humans ; Muscle Weakness ; Neuromuscular Diseases/*rehabilitation ; Quality of Life ; Randomized Controlled Trials as Topic ; Vital Capacity ; }, abstract = {BACKGROUND: Neuromuscular diseases (NMDs) are a heterogeneous group of diseases affecting the anterior horn cell of spinal cord, neuromuscular junction, peripheral nerves and muscles. NMDs cause physical disability usually due to progressive loss of strength in limb muscles, and some NMDs also cause respiratory muscle weakness. Respiratory muscle training (RMT) might be expected to improve respiratory muscle weakness; however, the effects of RMT are still uncertain. This systematic review will synthesize the available trial evidence on the effectiveness and safety of RMT in people with NMD, to inform clinical practice.<br><br>OBJECTIVES: To assess the effects of respiratory muscle training (RMT) for neuromuscular disease (NMD) in adults and children, in comparison to sham training, no training, standard treatment, breathing exercises, or other intensities or types of RMT.<br><br>SEARCH METHODS: On 19 November 2018, we searched the Cochrane Neuromuscular Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. On 23 December 2018, we searched the US National Institutes for Health Clinical Trials Registry (ClinicalTrials.gov), the World Health Organization International Clinical Trials Registry Platform, and reference lists of the included studies.<br><br>SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs, including cross-over trials, of RMT in adults and children with a diagnosis of NMD of any degree of severity, who were living in the community, and who did not need mechanical ventilation. We compared trials of RMT (inspiratory muscle training (IMT) or expiratory muscle training (EMT), or both), with sham training, no training, standard treatment, different intensities of RMT, different types of RMT, or breathing exercises.<br><br>DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodological procedures.<br><br>MAIN RESULTS: We included 11 studies involving 250 randomized participants with NMDs: three trials (N = 88) in people with amyotrophic lateral sclerosis (ALS; motor neuron disease), six trials (N = 112) in Duchenne muscular dystrophy (DMD), one trial (N = 23) in people with Becker muscular dystrophy (BMD) or limb-girdle muscular dystrophy, and one trial (N = 27) in people with myasthenia gravis.Nine of the trials were at high risk of bias in at least one domain and many reported insufficient information for accurate assessment of the risk of bias. Populations, interventions, control interventions, and outcome measures were often different, which largely ruled out meta-analysis. All included studies assessed lung capacity, our primary outcome, but four did not provide data for analysis (1 in people with ALS and three cross-over studies in DMD). None provided long-term data (over a year) and only one trial, in ALS, provided information on adverse events. Unscheduled hospitalisations for chest infection or acute exacerbation of chronic respiratory failure were not reported and physical function and quality of life were reported in one (ALS) trial.Amyotrophic lateral sclerosis (ALS)Three trials compared RMT versus sham training in ALS. Short-term (8 weeks) effects of RMT on lung capacity in ALS showed no clear difference in the change of the per cent predicted forced vital capacity (FVC%) between EMT and sham EMT groups (mean difference (MD) 0.70, 95% confidence interval (CI) -8.48 to 9.88; N = 46; low-certainty evidence). The mean difference (MD) in FVC% after four months' treatment was 10.86% in favour of IMT (95% CI -4.25 to 25.97; 1 trial, N = 24; low-certainty evidence), which is larger than the minimal clinically important difference (MCID, as estimated in people with idiopathic pulmonary fibrosis). There was no clear difference between IMT and sham IMT groups, measured on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALFRS; range of possible scores 0 = best to 40 = worst) (MD 0.85, 95% CI -2.16 to 3.85; 1 trial, N = 24; low-certainty evidence) or quality of life, measured on the EuroQol-5D (0 = worst to 100 = best) (MD 0.77, 95% CI -17.09 to 18.62; 1 trial, N = 24; low-certainty evidence) over the medium term (4 months). One trial report stated that the IMT protocol had no adverse effect (very low-certainty evidence).Duchenne muscular dystrophy (DMD)Two DMD trials compared RMT versus sham training in young males with DMD. In one study, the mean post-intervention (6-week) total lung capacity (TLC) favoured RMT (MD 0.45 L, 95% CI -0.24 to 1.14; 1 trial, N = 16; low-certainty evidence). In the other trial there was no clear difference in post-intervention (18 days) FVC between RMT and sham RMT (MD 0.16 L, 95% CI -0.31 to 0.63; 1 trial, N = 20; low-certainty evidence). One RCT and three cross-over trials compared a form of RMT with no training in males with DMD; the cross-over trials did not provide suitable data. Post-intervention (6-month) values showed no clear difference between the RMT and no training groups in per cent predicted vital capacity (VC%) (MD 3.50, 95% CI -14.35 to 21.35; 1 trial, N = 30; low-certainty evidence).Becker or limb-girdle muscular dystrophyOne RCT (N = 21) compared 12 weeks of IMT with breathing exercises in people with Becker or limb-girdle muscular dystrophy. The evidence was of very low certainty and conclusions could not be drawn.Myasthenia gravisIn myasthenia gravis, there may be no clear difference between RMT and breathing exercises on measures of lung capacity, in the short term (TLC MD -0.20 L, 95% CI -1.07 to 0.67; 1 trial, N = 27; low-certainty evidence). Effects of RMT on quality of life are uncertain (1 trial; N = 27).Some trials reported effects of RMT on inspiratory and/or expiratory muscle strength; this evidence was also of low or very low certainty.<br><br>AUTHORS' CONCLUSIONS: RMT may improve lung capacity and respiratory muscle strength in some NMDs. In ALS there may not be any clinically meaningful effect of RMT on physical functioning or quality of life and it is uncertain whether it causes adverse effects. Due to clinical heterogeneity between the trials and the small number of participants included in the analysis, together with the risk of bias, these results must be interpreted very cautiously.}, }
@article {pmid31484034, year = {2019}, author = {Gicalone, AR and Heckman, MG and Otto, E and McVeigh, KH}, title = {Shoulder Pain Among Patients With Amyotrophic Lateral Sclerosis: A Case Series.}, journal = {The American journal of occupational therapy : official publication of the American Occupational Therapy Association}, volume = {73}, number = {5}, pages = {7305345020p1-7305345020p6}, doi = {10.5014/ajot.2019.031757}, pmid = {31484034}, issn = {0272-9490}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Quality of Life ; Range of Motion, Articular ; Retrospective Studies ; Scapula ; *Shoulder Pain/therapy ; }, abstract = {IMPORTANCE: Evidence has demonstrated that shoulder pain constitutes a functional impairment for patients with amyotrophic lateral sclerosis (ALS). No studies have yet examined the efficacy of scapular mobilization of the painful shoulder among patients with ALS.<br><br>OBJECTIVE: Our retrospective case series evaluated the effects of scapular mobilization on pain and shoulder motion among patients with ALS.<br><br>DESIGN: Retrospective case series over 2 yr.<br><br>SETTING: A multidisciplinary outpatient clinic at an academic medical institution.<br><br>PARTICIPANTS: Twenty-eight patients with ALS who had shoulder pain and range of motion (ROM) limitations. Patients were excluded if information on visual analog scale (VAS) score for pain and shoulder ROM was not available.<br><br>INTERVENTION: Scapular mobilization, ROM, and caregiver education. All patients also received standard occupational therapy treatment for this patient population.<br><br>OUTCOMES AND MEASURES: The primary outcome was VAS shoulder pain scores; the secondary outcome was shoulder flexion ROM.<br><br>RESULTS: The median VAS pain score was 2 before treatment and 0 after treatment, with a significant median reduction of 2. Median shoulder flexion ROM was 100&#xb0; before mobilization treatment and 130&#xb0; after treatment, with a significant median increase of 25&#xb0;.<br><br>CONCLUSION AND RELEVANCE: The results provide strong evidence that both VAS pain score and shoulder ROM noticeably improve after mobilization treatment.<br><br>WHAT THIS ARTICLE ADDS: Occupational therapists can effectively promote shoulder care techniques such as scapular mobilization to both patients and care providers to reduce pain and improve quality of life for patients with ALS.}, }
@article {pmid31483911, year = {2020}, author = {Smith, AB and Bamgboje-Ayodele, A and Butow, P and Klein, B and Turner, J and Sharpe, L and Fardell, J and Beatty, L and Pearce, A and Thewes, B and Beith, J and ,  and Girgis, A}, title = {Development and usability evaluation of an online self-management intervention for fear of cancer recurrence (iConquerFear).}, journal = {Psycho-oncology}, volume = {29}, number = {1}, pages = {98-106}, doi = {10.1002/pon.5218}, pmid = {31483911}, issn = {1099-1611}, mesh = {Breast Neoplasms/*psychology ; Cancer Survivors/*psychology ; Female ; Humans ; *Internet-Based Intervention ; Male ; Middle Aged ; Neoplasm Recurrence, Local/*psychology ; *Outcome and Process Assessment, Health Care ; Phobic Disorders/*therapy ; *Self-Management ; }, abstract = {OBJECTIVE: To develop and evaluate the usability of iConquerFear, an online self-management adaptation of an efficacious face-to-face therapist-delivered treatment for fear of cancer recurrence (FCR).<br><br>METHODS: iConquerFear development was theory based and person based. Development was guided by Ritterband et al's behaviour change model for internet interventions. iConquerFear end users (cancer survivors) provided iterative feedback in accordance with Yardley et al's person-based approach to maximise engagement and usability. Online focus groups and cognitive interviews were conducted to evaluate the usability of iConquerFear. Discussions were recorded, transcribed verbatim, and thematically analysed.<br><br>RESULTS: Five online FCR modules were developed. Twenty-three cancer survivors (47% of those eligible) participated; 11/23 (58%) were breast cancer survivors, and average age was 53 years (SD = 10.8). Thematic saturation was reached after six focus groups (n = 16) and seven individual think-aloud interviews. Thematic analysis produced five overarching themes: easy navigation essential; satisfaction and engagement with content; flexible access is key; normalising and empowering; and a useful first step.<br><br>CONCLUSIONS: Online self-management interventions like iConquerFear have the potential to address the unmet supportive care needs reported by burgeoning numbers of cancer survivors. However, that potential may not be realised unless interventions are rigorously developed and user tested, as benefits are constrained by limited engagement. Themes from the usability testing of iConquerFear highlight the importance of developing flexible, tailored, interactive, and contextual online self-management interventions for people with cancer.}, }
@article {pmid31479686, year = {2019}, author = {Homma, T and Kobayashi, S and Sato, H and Fujii, J}, title = {Edaravone, a free radical scavenger, protects against ferroptotic cell death in vitro.}, journal = {Experimental cell research}, volume = {384}, number = {1}, pages = {111592}, doi = {10.1016/j.yexcr.2019.111592}, pmid = {31479686}, issn = {1090-2422}, mesh = {Animals ; Apoptosis/*drug effects ; Cell Death/*drug effects ; Cell Line, Tumor ; Cysteine/metabolism ; Edaravone/pharmacology ; Ferroptosis/*drug effects ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Iron/metabolism ; Lipid Peroxidation/drug effects ; Mice ; Mice, Knockout ; Protective Agents/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Ferroptosis is characterized by an iron-dependent cell death with increased lipid peroxidation and is typically induced by either a decrease in glutathione (GSH) levels due to an insufficient supply of cysteine (Cys) or the inhibition of phospholipid hydroperoxide glutathione peroxidase (Gpx4). While lipid peroxides are the direct trigger for ferroptosis, the issue of how radical species involve in the cytocidal process remains unclear. To gain insights into this issue, we employed edaravone, a free radical scavenger that is clinically approved for the treatment of acute ischemic strokes and amyotrophic lateral sclerosis (ALS), against ferroptotic cell death caused by various situations, notably under cystine deprivation. We initially investigated the effects of edaravone on ferroptosis in mouse hepatoma Hepa 1-6 cells cultivated in cystine-free medium and found that edaravone largely suppressed ferroptosis. Ferroptosis that was induced in the cells by the use of inhibitors for xCT or Gpx4 was also suppressed by edaravone. Moreover, edaravone also suppressed ferroptosis in xCT-knockout mouse-derived embryonic fibroblasts, which usually die in normal cultivating conditions due to the depletion of intracellular Cys and GSH. Although the edaravone treatment had no effects on the intracellular levels of Cys and GSH, both of which remained low in Hepa 1-6 cells under conditions of cystine deprivation, the causative factors for ferroptosis, including ferrous iron and lipid peroxide levels, were significantly suppressed. Collectively, these results indicate that radical species produced at the initial stage of the cytocidal process under Cys-deprived conditions trigger ferroptosis and scavenging these radicals by edaravone represents a promising treatment.}, }
@article {pmid31476356, year = {2019}, author = {Lyon, MS and Milligan, C}, title = {Extracellular heat shock proteins in neurodegenerative diseases: New perspectives.}, journal = {Neuroscience letters}, volume = {711}, number = {}, pages = {134462}, doi = {10.1016/j.neulet.2019.134462}, pmid = {31476356}, issn = {1872-7972}, mesh = {Animals ; Heat-Shock Proteins/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; }, abstract = {One pathological hallmark of neurodegenerative diseases and CNS trauma is accumulation of insoluble, hydrophobic molecules and protein aggregations found both within and outside cells. These may be the consequences of an inadequate or overburdened cellular response to stresses resulting from potentially toxic changes in extra- and intracellular environments. The upregulated expression of heat shock proteins (HSPs) is one example of a highly conserved cellular response to both internal and external stress. Intracellularly these proteins act as chaperones, playing vital roles in the folding of nascent polypeptides, the translocation of proteins between subcellular locations, and the disaggregation of misfolded or aggregated proteins in an attempt to maintain cellular proteostasis during both homeostatic and stressful conditions. While the predominant study of the HSPs has focused on their intracellular chaperone functions, it remains unclear if all neuronal populations can mount a complete stress response. Alternately, it is now well established that some members of this family of proteins can be secreted by nearby, non-neuronal cells to act in the extracellular environment. This review addresses the current literature detailing the use of exogenous and extracellular HSPs in the treatment of cellular and animal models of neurodegenerative disease. These findings offer a new measure of therapeutic potential to the HSPs, but obstacles must be overcome before they can be efficiently used in a clinical setting.}, }
@article {pmid31473983, year = {2020}, author = {Teti, C and Talco, M and Albertelli, M and Albanese, V and Minuto, M and Aglialoro, A and Monachesi, M and Viviani, G and Gatto, F and Ferone, D and Boschetti, M}, title = {Dipeptidyl peptidase-4 inhibitors do not alter GH/IGF-I axis in adult diabetic patients.}, journal = {Journal of endocrinological investigation}, volume = {43}, number = {3}, pages = {389-393}, pmid = {31473983}, issn = {1720-8386}, mesh = {Adult ; Aged ; Aged, 80 and over ; Diabetes Mellitus, Type 2/blood/*drug therapy ; Dipeptidyl-Peptidase IV Inhibitors/*therapeutic use ; Exenatide/therapeutic use ; Female ; Human Growth Hormone/*blood ; Humans ; Hypoglycemic Agents/*therapeutic use ; Insulin-Like Growth Factor I/*metabolism ; Liraglutide/therapeutic use ; Male ; Metformin/therapeutic use ; Middle Aged ; }, abstract = {PURPOSE: Incretin-based therapies have been introduced in clinical practice for type 2 diabetes mellitus (T2DM) treatment in the last few years. Current available medications of this class include glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. In addition to GLP-1, DPP-4 is able to inactivate many others peptides as hypothalamic growth hormone-releasing hormone (GHRH). The aim of this exploratory study was to evaluate, on adult diabetic patients, the impact of therapy with incretins, particularly DPP-4 inhibitors on GH/IGF-I axis.<br><br>METHODS: 60 patients with T2DM were included in the study and they were divided into three groups (age and sex comparable) on the basis of their hypoglycemic drugs in the last 4&#xa0;months: group 1 (17 patients, exenatide or liraglutide&#x2009;+&#x2009;metformin), group 2 (18 patients, sitagliptin or vildagliptin&#x2009;+&#x2009;metformin), group 3 (25 patients, metformin). Anthropometric data, glycemia, glycosylated hemoglobin (HbA1c), IGF-I and acid-labile subunit (ALS) were collected in all patients.<br><br>RESULTS: Weight, waist circumference and BMI of group 1 were significantly higher (P&#x2009;<&#x2009;0.05) compared to the other groups. Fasting plasma glucose and HbA1c of the group 1 were similar compared to those of group 3 (P ns) and higher compared to those of group 2 (P&#x2009;<&#x2009;0.05). IGF-I absolute values, IGF-I SDS were not significantly different in the three groups.<br><br>CONCLUSIONS: Our data evidence that DPP-4 inhibition does not influence significantly GH/IGF-I system, confirming what was observed in animal models. Further studies&#xa0;are needed to better characterize the properties of these molecules on endocrine system.}, }
@article {pmid31471712, year = {2020}, author = {Park, JM and Kim, SY and Park, D and Park, JS}, title = {Effect of edaravone therapy in Korean amyotrophic lateral sclerosis (ALS) patients.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {41}, number = {1}, pages = {119-123}, pmid = {31471712}, issn = {1590-3478}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/*epidemiology/metabolism ; Edaravone/pharmacology/*therapeutic use ; Female ; Free Radical Scavengers/pharmacology/*therapeutic use ; Humans ; Male ; Middle Aged ; Oxidative Stress/drug effects/physiology ; Republic of Korea/epidemiology ; Treatment Outcome ; }, abstract = {Oxidative stress caused by free radicals has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Edaravone (also known as MCI-186), a free radical scavenger, was approved as an ALS treatment in 2015 in Japan. However, the therapeutic effects of edaravone on patients with ALS outside of Japan are not yet reported. This study aims to investigate effects of edaravone on ALS patients in the Korean population. The study included 22 patients with ALS who were treated with edaravone. Of the 16 patients who finished six cycles of treatment, a mean decline of ALSFRS-R after the treatments was 5.75 ± 6.07 points and the average change of FVC was - 8.7 ± 17.0%. Patients experienced only minor adverse events. This study reports on the open-label study of edaravone on patients in Korea for ALS patients, which showed a modest effect of edaravone in this population of ALS patients.}, }
@article {pmid31471029, year = {2019}, author = {Liu, W and Ke, M and Zhang, Z and Lu, T and Zhu, Y and Li, Y and Pan, X and Qian, H}, title = {Effects of imazethapyr spraying on plant growth and leaf surface microbial communities in Arabidopsis thaliana.}, journal = {Journal of environmental sciences (China)}, volume = {85}, number = {}, pages = {35-45}, doi = {10.1016/j.jes.2019.04.020}, pmid = {31471029}, issn = {1001-0742}, mesh = {Arabidopsis/drug effects/*growth &amp; development/microbiology ; Herbicides/*toxicity ; Microbiota/*drug effects ; Nicotinic Acids/*toxicity ; Plant Leaves/drug effects/*microbiology ; }, abstract = {Imazethapyr (IM) is an acetolactate synthase (ALS)-inhibiting herbicide that has been widely used in recent years. However, IM spraying can lead to the accumulation of herbicide residues in leaves. Here, we determined the effects of IM spraying on the plant growth and leaf surface microbial communities of Arabidopsis thaliana after 7 and 14 days of exposure. The results suggested that IM spraying inhibited plant growth. Fresh weight decreased to 48% and 26% of the control value after 7 and 14 days, respectively, of 0.035 kg/ha IM exposure. In addition, anthocyanin content increased 9.2-fold and 37.2-fold relative to the control content after 7 and 14 days of treatment, respectively. Furthermore, IM spraying destroyed the cell structures of the leaves, as evidenced by increases in the number of starch granules and the stomatal closure rate. Reductions in photosynthetic efficiency and antioxidant enzyme activity were observed after IM spraying, especially after 14 days of exposure. The diversity and evenness of the leaf microbiota were not affected by IM treatment, but the composition of community structure at the genus level was altered by IM spraying. Imazethapyr application increased the abundance of Pseudomonas, a genus that includes species pathogenic to plants and humans, indicating that IM potentially increased the abundance of pathogenic bacteria on leaves. Our findings increase our understanding of the relationships between herbicide application and the microbial community structures on plant leaves, and they provide a new perspective for studying the ecological safety of herbicide usage.}, }
@article {pmid31470106, year = {2019}, author = {Guo, W and Pang, K and Chen, Y and Wang, S and Li, H and Xu, Y and Han, F and Yao, H and Liu, H and Lopes-Rodrigues, V and Sun, D and Shao, J and Shen, J and Dou, Y and Zhang, W and You, H and Wu, W and Lu, B}, title = {TrkB agonistic antibodies superior to BDNF: Utility in treating motoneuron degeneration.}, journal = {Neurobiology of disease}, volume = {132}, number = {}, pages = {104590}, doi = {10.1016/j.nbd.2019.104590}, pmid = {31470106}, issn = {1095-953X}, mesh = {Animals ; Antibodies, Monoclonal/*pharmacology ; Brain-Derived Neurotrophic Factor/metabolism ; Humans ; Motor Neurons/*drug effects/pathology ; Nerve Degeneration/*pathology ; Neuroprotective Agents/*pharmacology ; Receptor, trkB/*agonists ; }, abstract = {While Brain-derived Neurotrophic Factor (BDNF) has long been implicated in treating neurological diseases, recombinant BDNF protein has failed in multiple clinical trials. In addition to its unstable and adhesive nature, BDNF can activate p75[NTR], a receptor mediating cellular functions opposite to those of TrkB. We have now identified TrkB agonistic antibodies (TrkB-agoAbs) with several properties superior to BDNF: They exhibit blood half-life of days instead of hours, diffuse centimeters in neural tissues instead millimeters, and bind and activate TrkB, but not p75[NTR]. In addition, TrkB-agoAbs elicit much longer TrkB activation, reduced TrkB internalization and less intracellular degradation, compared with BDNF. More importantly, some of these TrkB-agoAbs bind TrkB epitopes distinct from that by BDNF, and work cooperatively with endogenous BDNF. Unlike BDNF, the TrkB-agoAbs exhibit a half-life of days/weeks and diffused readily in nerve tissues. We tested one of TrkB-agoAbs further and showed that it enhanced motoneuron survival in the spinal-root avulsion model for motoneuron degeneration in vivo. Thus, TrkB-agoAbs are promising drug candidates for the treatment of neural injury.}, }
@article {pmid31469402, year = {2019}, author = {Chernyshova, K and Inoue, K and Yamashita, SI and Fukuchi, T and Kanki, T}, title = {Glaucoma-Associated Mutations in the Optineurin Gene Have Limited Impact on Parkin-Dependent Mitophagy.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {60}, number = {10}, pages = {3625-3635}, doi = {10.1167/iovs.19-27184}, pmid = {31469402}, issn = {1552-5783}, mesh = {Cell Cycle Proteins/*genetics ; Cells, Cultured ; Gene Expression Regulation/physiology ; Gene Knockout Techniques ; Glaucoma, Open-Angle/*genetics ; HeLa Cells ; Humans ; Membrane Transport Proteins/*genetics ; Mitophagy/*physiology ; Mutagenesis, Site-Directed ; *Mutation ; Plasmids ; Transfection ; Ubiquitin-Protein Ligases/*genetics ; }, abstract = {PURPOSE: Glaucoma results in progressive degeneration of the optic nerve and irreversible vision loss. Several mutations in the gene encoding optineurin (OPTN), the receptor for Parkin-dependent mitochondrial autophagy (mitophagy), are associated with glaucoma and amyotrophic lateral sclerosis (ALS). ALS mutations in the ubiquitin-binding domain of OPTN impair Parkin-dependent mitophagy. However, the effects of glaucoma mutations in this region remain unknown. We examined the impact of glaucoma-associated OPTN mutations on Parkin-dependent mitophagy.<br><br>METHODS: The mitochondria-localized, pH-sensitive fluorescent protein mito-Keima was used to monitor mitophagy. HeLa cells expressing Parkin were treated with carbonyl cyanide 3-chlorophenylhydrazone (CCCP) or oligomycin/antimycin A (O/A) to induce Parkin-dependent mitophagy. Two complementary mitophagy receptors, OPTN and NDP52, were deleted in HeLa cells expressing mito-Keima and Parkin (DKO_HeLa). The mutant OPTN genes were re-introduced into DKO_HeLa cells using retroviruses or through transfection. Mitophagy activity and OPTN localization were evaluated via microscopic analyses. OPTN binding to ubiquitin was examined using an immunoprecipitation assay.<br><br>RESULTS: Parkin-dependent mitophagy was inhibited in DKO_HeLa cells. Introduction of two glaucoma mutations in the ubiquitin-interacting region of OPTN restored mitophagy in CCCP-treated DKO_HeLa cells, whereas the two ALS mutations failed to replicate this effect. Under treatment with CCCP, the two glaucoma-mutant OPTN proteins normally translocated to mitochondria and bound to ubiquitinated proteins. Furthermore, five additional glaucoma-mutant OPTN proteins restored CCCP-induced mitophagy. Moreover, treatment with O/A exhibited similar results.<br><br>CONCLUSIONS: Glaucoma-mutant OPTN proteins retain their normal properties as mitophagy receptors, suggesting that mutations in the OPTN gene cause glaucoma through a mechanism independent of mitophagy defects.}, }
@article {pmid31456666, year = {2019}, author = {Pradhan, J and Noakes, PG and Bellingham, MC}, title = {The Role of Altered BDNF/TrkB Signaling in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {13}, number = {}, pages = {368}, pmid = {31456666}, issn = {1662-5102}, abstract = {Brain derived neurotrophic factor (BDNF) is well recognized for its neuroprotective functions, via activation of its high affinity receptor, tropomysin related kinase B (TrkB). In addition, BDNF/TrkB neuroprotective functions can also be elicited indirectly via activation of adenosine 2A receptors (A2 a Rs), which in turn transactivates TrkB. Evidence suggests that alterations in BDNF/TrkB, including TrkB transactivation by A2 a Rs, can occur in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although enhancing BDNF has been a major goal for protection of dying motor neurons (MNs), this has not been successful. Indeed, there is emerging in vitro and in vivo evidence suggesting that an upregulation of BDNF/TrkB can cause detrimental effects on MNs, making them more vulnerable to pathophysiological insults. For example, in ALS, early synaptic hyper-excitability of MNs is thought to enhance BDNF-mediated signaling, thereby causing glutamate excitotoxicity, and ultimately MN death. Moreover, direct inhibition of TrkB and A2 a Rs has been shown to protect MNs from these pathophysiological insults, suggesting that modulation of BDNF/TrkB and/or A2 a Rs receptors may be important in early disease pathogenesis in ALS. This review highlights the relevance of pathophysiological actions of BDNF/TrkB under certain circumstances, so that manipulation of BDNF/TrkB and A2 a Rs may give rise to alternate neuroprotective therapeutic strategies in the treatment of neural diseases such as ALS.}, }
@article {pmid31456211, year = {2019}, author = {Xiong, H and Tuo, QZ and Guo, YJ and Lei, P}, title = {Diagnostics and Treatments of Iron-Related CNS Diseases.}, journal = {Advances in experimental medicine and biology}, volume = {1173}, number = {}, pages = {179-194}, doi = {10.1007/978-981-13-9589-5_10}, pmid = {31456211}, issn = {0065-2598}, mesh = {Homeostasis ; Humans ; Iron ; Iron Metabolism Disorders/*diagnosis/*therapy ; Neurodegenerative Diseases/*diagnosis/*therapy ; }, abstract = {Iron has been proposed to be responsible for neuronal loss in several diseases of the central nervous system, including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Friedreich's ataxia (FRDA), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS). In many diseases, abnormal accumulation of brain iron in disease-affected area has been observed, without clear knowledge of the contribution of iron overload to pathogenesis. Recent evidences implicate that key proteins involved in the disease pathogenesis may also participate in cellular iron metabolism, suggesting that the imbalance of brain iron homeostasis is associated with the diseases. Considering the complicated regulation of iron homeostasis within the brain, a thorough understanding of the molecular events leading to this phenotype is still to be investigated. However, current understanding has already provided the basis for the diagnosis and treatment of iron-related CNS diseases, which will be reviewed here.}, }
@article {pmid31450993, year = {2020}, author = {Thakore, NJ and Lapin, BR and Pioro, EP and , }, title = {Stage-specific riluzole effect in amyotrophic lateral sclerosis: a retrospective study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {1-2}, pages = {140-143}, doi = {10.1080/21678421.2019.1655060}, pmid = {31450993}, issn = {2167-9223}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy ; Female ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Retrospective Studies ; Riluzole/*therapeutic use ; Time Factors ; Treatment Outcome ; }, abstract = {Objectives: To estimate the effect of riluzole on the stage-specific risk of progression of ALS. Methods: Patients from the PRO-ACT dataset were staged employing two methods (King's and FT9). Hazard ratios associated with riluzole treatment were estimated for forward transition between stages, using unadjusted and adjusted Markov multistate models. Results: Of 1903 patients, 1587 had received riluzole. Riluzole-treated patients survived non-significantly longer than those who did not (median 22.9 months vs. 18.3 months from time of initial observation, log rank p = 0.16). After adjusting for age and ALSFRS-R slope at first visit, riluzole significantly reduced risk of the following transitions: (1) King's stages: 1->2 (hazard ratio (HR) = 0.81), and 2->3 (HR = 0.82), 4->death (HR = 0.57), and (2) FT9 stages: 1->2 (HR = 0.84), 3->4 (HR = 0.71), and 4->death (HR = 0.67). In contrast, the beneficial effect of riluzole in bulbar-onset patients was in early rather than late King's stages. Conclusions: This examination of cohorts closely followed in clinical trials finds a beneficial effect of riluzole that is predominantly but not exclusively in later stages of ALS. This analytic framework has utility to discern stage-specific treatment effects, and for refined health economic analyses.}, }
@article {pmid31450265, year = {2019}, author = {Vu, L and Penter, C and Platell, C}, title = {Long-term significance of an anastomotic leak in patients undergoing an ultra-low anterior resection for rectal cancer.}, journal = {ANZ journal of surgery}, volume = {89}, number = {10}, pages = {1291-1295}, doi = {10.1111/ans.15373}, pmid = {31450265}, issn = {1445-2197}, mesh = {Adult ; Aged ; Aged, 80 and over ; *Anastomotic Leak/epidemiology/etiology/mortality/therapy ; Female ; Follow-Up Studies ; Humans ; Incidence ; Logistic Models ; Male ; Middle Aged ; Prevalence ; Proctectomy/*methods ; Rectal Neoplasms/mortality/*surgery ; Reoperation ; Retrospective Studies ; Risk Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: Australia has one of the highest rates of colorectal cancer worldwide. Despite technological advances in colorectal surgery, anastomotic leaks (ALs) continue to cause significant morbidity and mortality. Ultra-low anterior resections (ULARs) carry the highest prevalence of AL. The aim of the study is to evaluate the incidence, treatment and consequences of AL following ULAR for colorectal cancer from a single colorectal unit.<br><br>METHODS: This is a retrospective evaluation of prospectively collected data on patients undergoing ULAR following rectal cancer. The main end points include the prevalence and management of AL following initial operation and the morbidity, re-operation and mortality rates associated with AL. A stepwise logistic regression analysis and a multivariate analysis were performed to identify independent risk factors.<br><br>RESULTS: A total of 467 patients underwent an ULAR. There were 32 (6.8%) ALs. Average follow-up time was 79&#x2009;months. There were five subclinical leaks and only one (20%) required intervention. The overall survival rate at 5 years was 80% (95% confidence interval 58-91). On univariate analysis male sex was a risk factor for AL (P = 0.03). On multivariate analysis patients who had a complete response to radiotherapy were more likely to have a leak than the patients who had no radiotherapy (grade 4, odds ratio 4.0, 95% confidence interval 1.4-10.9, P = 0.01).<br><br>CONCLUSION: This study has highlighted the relevance of subclinical leaks and their associated morbidity. It identified that radiotherapy a risk factor for AL, but the response to radiotherapy is an even better predictor of leakage.}, }
@article {pmid31449739, year = {2019}, author = {Zarotti, N and Coates, E and McGeachan, A and Williams, I and Beever, D and Hackney, G and Norman, P and Stavroulakis, T and White, D and White, S and Halliday, V and McDermott, C and , }, title = {Health care professionals' views on psychological factors affecting nutritional behaviour in people with motor neuron disease: A thematic analysis.}, journal = {British journal of health psychology}, volume = {24}, number = {4}, pages = {953-969}, doi = {10.1111/bjhp.12388}, pmid = {31449739}, issn = {2044-8287}, support = {ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; RP-PG-1016-20006/DH_/Department of Health/United Kingdom ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Adaptation, Psychological ; Adult ; *Attitude of Health Personnel ; Female ; Focus Groups ; Health Behavior ; Health Personnel/*psychology ; Health Promotion/*methods ; Humans ; Malnutrition/complications/*diet therapy/psychology ; Motor Neuron Disease/*complications/*psychology ; Patient Participation/psychology ; Quality of Life ; United Kingdom ; Weight Loss ; }, abstract = {UNLABELLED: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis, is a neurodegenerative disorder that causes progressive muscle paralysis and typically leads to death within 3 years. As no cure is currently available, symptomatic management is the mainstay of treatment. An important part of this is optimizing nutritional intake with evidence that this may positively affect survival and quality of life. Health care professionals (HCPs) play a pivotal role in nutritional management of people with MND (pwMND) but, to date, their views on the psychological barriers faced by pwMND have not been explored. Such an exploration may identify ways in which the delivery of nutritional care for pwMND can be optimized.<br><br>METHODS: Five qualitative focus groups were carried out across the United Kingdom in June 2018 with 51 participants, including 47 HCPs involved with MND care and four service user representatives. Data were analysed through thematic analysis.<br><br>RESULTS: Four overarching themes were identified: psychological adjustment and patient engagement; nutrition and the need for control; knowledge of nutrition and the complexity of MND; and the psychosocial nature of eating.<br><br>CONCLUSIONS: The findings suggest that the nutritional management of pwMND should be mindful of factors such as the impact of distress at the time of diagnosis, the availability of clear information on nutrition and MND, as well as the importance of illness perceptions and coping strategies. Moreover, tailored psychological interventions should be considered to mitigate the impact on MND on the experience of eating. Statement of contribution What is already known on this subject? Since weight loss and reduced body mass index (BMI) have been identified as independent risk factors for prognosis and survival in motor neuron disease (MND), nutritional management represents an important component of the symptomatic care of people with MND (pwMND) aimed at prolonging survival and maintaining or improving quality of life. However, the current guidelines and quantitative and qualitative literature on the topic are mainly focused on issues around enteral feeding and gastrostomy insertion, and very little is currently known about potential psychological enablers or barriers to earlier nutritional management, especially from the perspectives of health care professionals (HCPs) involved in the delivery of nutritional care in pwMND. What does this study add? First qualitative investigation of enablers or barriers to nutritional care in pwMND from the perspective of HCPs. New insight into psychological factors (e.g., adjustment, avoidance, loss of control) in nutritional care for pwMND. Practical implications and novel clinical suggestions for HCPs involved in nutritional care of pwMND.}, }
@article {pmid31441732, year = {2020}, author = {Kolagar, TA and Farzaneh, M and Nikkar, N and Khoshnam, SE}, title = {Human Pluripotent Stem Cells in Neurodegenerative Diseases: Potentials, Advances and Limitations.}, journal = {Current stem cell research &amp; therapy}, volume = {15}, number = {2}, pages = {102-110}, doi = {10.2174/1574888X14666190823142911}, pmid = {31441732}, issn = {2212-3946}, mesh = {Animals ; Humans ; Nerve Regeneration/*physiology ; Neurodegenerative Diseases/pathology/*therapy ; Pluripotent Stem Cells/*cytology/*physiology/transplantation ; *Stem Cell Transplantation/methods/trends ; Tissue Engineering/methods/trends ; }, abstract = {Neurodegenerative diseases are progressive and uncontrolled gradual loss of motor neurons function or death of neuron cells in the central nervous system (CNS) and the mechanisms underlying their progressive nature remain elusive. There is urgent need to investigate therapeutic strategies and novel treatments for neural regeneration in disorders like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Currently, the development and identification of pluripotent stem cells enabling the acquisition of a large number of neural cells in order to improve cell recovery after neurodegenerative disorders. Pluripotent stem cells which consist of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are characterized by their ability to indefinitely self-renew and the capacity to differentiate into different types of cells. The first human ESC lines were established from donated human embryos; while, because of a limited supply of donor embryos, human ESCs derivation remains ethically and politically controversial. Hence, hiPSCs-based therapies have been shown as an effective replacement for human ESCs without embryo destruction. Compared to the invasive methods for derivation of human ESCs, human iPSCs has opened possible to reprogram patient-specific cells by defined factors and with minimally invasive procedures. Human pluripotent stem cells are a good source for cell-based research, cell replacement therapies and disease modeling. To date, hundreds of human ESC and human iPSC lines have been generated with the aim of treating various neurodegenerative diseases. In this review, we have highlighted the recent potentials, advances, and limitations of human pluripotent stem cells for the treatment of neurodegenerative disorders.}, }
@article {pmid31439839, year = {2019}, author = {García-Morales, V and Rodríguez-Bey, G and Gómez-Pérez, L and Domínguez-Vías, G and González-Forero, D and Portillo, F and Campos-Caro, A and Gento-Caro, &#xc1; and Issaoui, N and Soler, RM and Garcera, A and Moreno-López, B}, title = {Sp1-regulated expression of p11 contributes to motor neuron degeneration by membrane insertion of TASK1.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {3784}, pmid = {31439839}, issn = {2041-1723}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*pathology ; Animals ; Annexin A2/*metabolism ; Cell Membrane/pathology ; Disease Models, Animal ; Female ; Gene Expression Regulation ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Male ; Membrane Potentials ; Mice ; Mice, Transgenic ; Motor Neurons/cytology/*pathology ; Nerve Degeneration/etiology/*pathology ; Nerve Tissue Proteins/*genetics/metabolism ; Potassium Channels, Tandem Pore Domain/*genetics/metabolism ; Primary Cell Culture ; Promoter Regions, Genetic ; Rats ; S100 Proteins/*metabolism ; Sp1 Transcription Factor/genetics/*metabolism ; Spinal Cord/cytology/pathology ; }, abstract = {Disruption in membrane excitability contributes to malfunction and differential vulnerability of specific neuronal subpopulations in a number of neurological diseases. The adaptor protein p11, and background potassium channel TASK1, have overlapping distributions in the CNS. Here, we report that the transcription factor Sp1 controls p11 expression, which impacts on excitability by hampering functional expression of TASK1. In the SOD1-G93A mouse model of ALS, Sp1-p11-TASK1 dysregulation contributes to increased excitability and vulnerability of motor neurons. Interference with either Sp1 or p11 is neuroprotective, delaying neuron loss and prolonging lifespan in this model. Nitrosative stress, a potential factor in human neurodegeneration, stimulated Sp1 expression and human p11 promoter activity, at least in part, through a Sp1-binding site. Disruption of Sp1 or p11 also has neuroprotective effects in a traumatic model of motor neuron degeneration. Together our work suggests the Sp1-p11-TASK1 pathway is a potential target for treatment of degeneration of motor neurons.}, }
@article {pmid31439573, year = {2019}, author = {Lynch, E and Semrad, T and Belsito, VS and FitzGibbons, C and Reilly, M and Hayakawa, K and Suzuki, M}, title = {C9ORF72-related cellular pathology in skeletal myocytes derived from ALS-patient induced pluripotent stem cells.}, journal = {Disease models &amp; mechanisms}, volume = {12}, number = {8}, pages = {}, pmid = {31439573}, issn = {1754-8411}, support = {R01 NS091540/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; C9orf72 Protein/*metabolism ; Cell Differentiation ; Cell Line ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation ; Haploinsufficiency/genetics ; Humans ; Induced Pluripotent Stem Cells/metabolism/*pathology ; Mitochondria/metabolism ; Muscle Fibers, Skeletal/*metabolism/*pathology/ultrastructure ; Oxidative Stress ; Protein Aggregates ; RNA/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset neuromuscular disease with no cure and limited treatment options. Patients experience a gradual paralysis leading to death from respiratory complications on average only 2-5 years after diagnosis. There is increasing evidence that skeletal muscle is affected early in the disease process, yet the pathological processes occurring in the skeletal muscle of ALS patients are still mostly unknown. Specifically, the most common genetic cause of ALS, a hexanucleotide repeat expansion in the C9ORF72 gene, has yet to be fully characterized in the context of skeletal muscle. In this study, we used the protocol previously developed in our lab to differentiate skeletal myocytes from induced pluripotent stem cells (iPSCs) of C9ORF72 ALS (C9-ALS) patients in order to create an in vitro disease model of C9-ALS skeletal muscle pathology. Of the three C9ORF72 mutation hallmarks, we did not see any evidence of haploinsufficiency, but we did detect RNA foci and dipeptide repeat (DPR) proteins. Additional abnormalities included changes in the expression of mitochondrial genes and a susceptibility to oxidative stress, indicating that mitochondrial dysfunction may be a critical feature of C9-ALS skeletal muscle pathology. Finally, the C9-ALS myocytes had increased expression and aggregation of TDP-43. Together, these data show that skeletal muscle cells experience pathological changes due to the C9ORF72 mutation. Our in vitro model could facilitate further study of cellular and molecular pathology in ALS skeletal muscle in order to discover new therapeutic targets against this devastating disease.This article has an associated First Person interview with the first author of the paper.}, }
@article {pmid31430861, year = {2019}, author = {Wehbe, R and Frangieh, J and Rima, M and El Obeid, D and Sabatier, JM and Fajloun, Z}, title = {Bee Venom: Overview of Main Compounds and Bioactivities for Therapeutic Interests.}, journal = {Molecules (Basel, Switzerland)}, volume = {24}, number = {16}, pages = {}, pmid = {31430861}, issn = {1420-3049}, mesh = {Animals ; Bee Venoms/*chemistry/*pharmacology ; Bees/*chemistry ; Central Nervous System Diseases/drug therapy ; Humans ; Inflammation/drug therapy ; }, abstract = {Apitherapy is an alternate therapy that relies on the usage of honeybee products, most importantly bee venom for the treatment of many human diseases. The venom can be introduced into the human body by manual injection or by direct bee stings. Bee venom contains several active molecules such as peptides and enzymes that have advantageous potential in treating inflammation and central nervous system diseases, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Moreover, bee venom has shown promising benefits against different types of cancer as well as anti-viral activity, even against the challenging human immunodeficiency virus (HIV). Many studies described biological activities of bee venom components and launched preclinical trials to improve the potential use of apitoxin and its constituents as the next generation of drugs. The aim of this review is to summarize the main compounds of bee venom, their primary biological properties, mechanisms of action, and their therapeutic values in alternative therapy strategies.}, }
@article {pmid31428170, year = {2019}, author = {Kim, S and Mun, S and Park, J and Choi, S and Lee, S and Kim, S}, title = {Complementary and Alternative Medicine Use in Amyotrophic Lateral Sclerosis Cases in South Korea.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2019}, number = {}, pages = {4217057}, pmid = {31428170}, issn = {1741-427X}, abstract = {Patients with amyotrophic lateral sclerosis (ALS) sometimes consider complementary and alternative medicine (CAM) because of ineffective treatment. This study investigated the prevalence and utilization pattern of CAM among patients with ALS in South Korea. Participants were recruited through homecare services for mechanical ventilation in South Korea. This study comprised a face-to-face cross-sectional survey with staff members available to address any queries. Fifty-five participants were included; all had used >1 CAM treatment option for ALS symptoms. Dietary treatments were most common, followed by functional food and massages. Most participants had obtained relevant information from family members or friends. The main reason for CAM use was an expectation that symptoms will improve with CAM; most patients were unsure of the effects. CAM use was previously discontinued by the majority of patients because of unsatisfactory effects. The mean expenditure on CAM was 288,385.28 ± 685,265.14 won per month, and the mean duration of CAM use was 11.54 ± 20.09 months. The results indicate that there is a high prevalence of CAM use among ALS patients. Healthcare providers should inquire about CAM use and openly provide accurate CAM information. Further evidence of CAM efficacy is required, as is specific guidance for consulting ALS patients regarding CAM.}, }
@article {pmid31428042, year = {2019}, author = {Gouel, F and Rolland, AS and Devedjian, JC and Burnouf, T and Devos, D}, title = {Past and Future of Neurotrophic Growth Factors Therapies in ALS: From Single Neurotrophic Growth Factor to Stem Cells and Human Platelet Lysates.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {835}, pmid = {31428042}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that typically results in death within 3-5 years after diagnosis. To date, there is no curative treatment and therefore an urgent unmet need of neuroprotective and/or neurorestorative treatments. Due to their spectrum of capacities in the central nervous system-e.g., development, plasticity, maintenance, neurogenesis-neurotrophic growth factors (NTF) have been exploited for therapeutic strategies in ALS for decades. In this review we present the initial strategy of using single NTF by different routes of administration to the use of stem cells transplantation to express a multiple NTFs-rich secretome to finally focus on a new biotherapy based on the human platelet lysates, the natural healing system containing a mix of pleitropic NTF and having immunomodulatory function. This review highlights that this latter treatment may be crucial to power the neuroprotection and/or neurorestoration therapy requested in this devastating disease.}, }
@article {pmid31422561, year = {2020}, author = {Oh-Hashi, K and Hirata, Y}, title = {Elucidation of the Molecular Characteristics of Wild-Type and ALS-Linked Mutant SOD1 Using the NanoLuc Complementation Reporter System.}, journal = {Applied biochemistry and biotechnology}, volume = {190}, number = {2}, pages = {674-685}, doi = {10.1007/s12010-019-03114-x}, pmid = {31422561}, issn = {1559-0291}, support = {no. 17K19901//Grant-in-aid from the Japan Society for the Promotion of Science/ ; no. 19H04030//Grant-in-aid from the Japan Society for the Promotion of Science/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology ; Animals ; COS Cells ; Chlorocebus aethiops ; Endoplasmic Reticulum Chaperone BiP ; *Genes, Reporter ; Humans ; *Mutation ; Superoxide Dismutase-1/*genetics ; }, abstract = {Previously, we evaluated human SOD1 (hSOD1) dimerization in living cells using the NanoLuc complementation reporter system and found that homodimerization of G85R and G93A mutant SOD1 was lower than that of wild-type hSOD1. Since these assays were performed only using N-terminal NanoBiT-tagged hSOD1 constructs in our previous study, we constructed additional hSOD1 genes with NanoBiT-tags at the C-terminus and evaluated the NanoBiT luciferase activities. Among the tested combinations, the luciferase activity in cells expressing NanoBiT-tagged wild-type hSOD1 was higher than that in cells expressing G85R or G93A mutant hSOD1. The NanoBiT luciferase activities were detected both inside and outside of cells; however, the extracellular luciferase activities were minimally dampened by treatment with brefeldin A, which inhibits canonical ER-Golgi transport. In addition to studies on the homodimerization of SOD1, we investigated the interaction between hSOD1 and three chaperone proteins, copper chaperone for SOD1 (CCS), FKBP, and GRP78. The NanoBiT luciferase activities in cells expressing NanoBiT-tagged SOD1 and CCS were relatively high, but weak signals were also observed in cells expressing SOD1 together with FKBP or GRP78. These luciferase activities were different between wild-type and mutant hSOD1. Finally, we investigated the effects of two selenocompounds, ebselen and Se-methylselenocysteine, on SOD1 dimerization and found that ebselen increased the NanoBiT luciferase activity in cells expressing wild-type and mutant hSOD1. In conclusion, we show the differential molecular characteristics of wild-type and mutant hSOD1 in live cells by transfection with NanoBiT-tagged hSOD1 and chaperone genes and demonstrate that this assay might be useful for the development and re-evaluation of chemical compounds modulating the SOD1 conformation.}, }
@article {pmid31417253, year = {2019}, author = {Yavarpour-Bali, H and Ghasemi-Kasman, M and Pirzadeh, M}, title = {Curcumin-loaded nanoparticles: a novel therapeutic strategy in treatment of central nervous system disorders.}, journal = {International journal of nanomedicine}, volume = {14}, number = {}, pages = {4449-4460}, pmid = {31417253}, issn = {1178-2013}, mesh = {Central Nervous System Diseases/*drug therapy ; Clinical Trials as Topic ; Curcumin/administration &amp; dosage/pharmacology/*therapeutic use ; Drug Delivery Systems ; Humans ; Nanoparticles/*chemistry ; Neuroprotective Agents/therapeutic use ; }, abstract = {Curcumin as a hydrophobic polyphenol is extracted from the rhizome of Curcuma longa. Curcumin is widely used as a dietary spice and a topical medication for the treatment of inflammatory disorders in Asia. This compound also possesses remarkable anti-inflammatory and neuroprotective effects with the ability to pass from the blood brain barrier. Based on several pharmacological activities of curcumin, it has been introduced as an ideal candidate for different neurological disorders. Despite the pleiotropic activities of curcumin, poor solubility, rapid clearance and low stability have limited its clinical application. In recent years, nano-based drug delivery system has effectively improved the aqueous solubility and bioavailability of curcumin. In this review article, the effects of curcumin nanoparticles and their possible mechanism/s of action has been elucidated in various central nervous system (CNS)-related diseases including Parkinson's disease, Huntington disease, Alzheimer's disease, Multiple sclerosis, epilepsy and Amyotrophic Lateral Sclerosis. Furthermore, recent evidences about administration of nano-curcumin in the clinical trial phase have been described in the present review article.}, }
@article {pmid31408496, year = {2019}, author = {Eastwood, K and Morgans, A and Stoelwinder, J and Smith, K}, title = {The appropriateness of low-acuity cases referred for emergency ambulance dispatch following ambulance service secondary telephone triage: A retrospective cohort study.}, journal = {PloS one}, volume = {14}, number = {8}, pages = {e0221158}, pmid = {31408496}, issn = {1932-6203}, mesh = {*Ambulance Diversion ; *Ambulances ; *Emergency Medical Services ; *Emergency Medical Technicians ; Humans ; Retrospective Studies ; *Triage ; Victoria ; }, abstract = {OBJECTIVE: Ambulance-based secondary telephone triage systems have been established in ambulance services to divert low-acuity cases away from emergency ambulance dispatch. However, some low-acuity cases still receive an emergency ambulance dispatch following secondary triage. To date, no evidence exists identifying whether these cases required an emergency ambulance. The aim of this study was to investigate whether cases were appropriately referred for emergency ambulance dispatch following secondary telephone triage.<br><br>METHODS: A retrospective cohort analysis was conducted of cases referred for emergency ambulance dispatch in Melbourne, Australia following secondary telephone triage between September 2009 and June 2012. Appropriateness was measured by assessing the frequency of advanced life support (ALS) treatment by paramedics, and paramedic transport to hospital.<br><br>RESULTS: There were 23,696 cases included in this study. Overall, 54% of cases received paramedic treatment, which was similar to the state-wide rate for emergency ambulance cases (55.5%). All secondary telephone triage cases referred for emergency ambulance dispatch had transportation rates higher than all metropolitan emergency ambulance cases (82.2% versus 71.1%). Two-thirds of the cases that were transported were also treated by paramedics (66.5%), and 17.7% of cases were not transported to hospital by ambulance following paramedic assessment.<br><br>CONCLUSIONS: Overall, the cases returned for emergency ambulance dispatch following secondary telephone triage were appropriate. Nevertheless, the paramedic treatment rates in particular indicate a considerable rate of overtriage requiring further investigation to optimize the efficacy of secondary telephone triage.}, }
@article {pmid31398791, year = {2019}, author = {Mouzat, K and Chudinova, A and Polge, A and Kantar, J and Camu, W and Raoul, C and Lumbroso, S}, title = {Regulation of Brain Cholesterol: What Role Do Liver X Receptors Play in Neurodegenerative Diseases?.}, journal = {International journal of molecular sciences}, volume = {20}, number = {16}, pages = {}, pmid = {31398791}, issn = {1422-0067}, mesh = {Animals ; Brain/*metabolism ; Cholesterol/*metabolism ; Disease Susceptibility ; Homeostasis ; Humans ; Ligands ; *Lipid Metabolism ; Liver X Receptors/chemistry/metabolism ; Neurodegenerative Diseases/etiology/metabolism/pathology ; Oxysterols/metabolism ; Structure-Activity Relationship ; }, abstract = {Liver X Receptors (LXR) alpha and beta are two members of nuclear receptor superfamily documented as endogenous cholesterol sensors. Following conversion of cholesterol in oxysterol, both LXR isoforms detect intracellular concentrations and act as transcription factors to promote expression of target genes. Among their numerous physiological roles, they act as central cholesterol-lowering factors. In the central nervous system (CNS), cholesterol has been shown to be an essential determinant of brain function, particularly as a major constituent of myelin and membranes. In the brain, LXRs act as cholesterol central regulators, and, beyond this metabolic function, LXRs have additional roles such as providing neuroprotective effects and lowering neuroinflammation. In many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and multiple sclerosis (MS), dysregulations of cholesterol and oxysterol have been reported. In this paper, we propose to focus on recent advances in the knowledge of the LXRs roles on brain cholesterol and oxysterol homeostasis, neuroinflammation, neuroprotection, and their putative involvement in neurodegenerative disorders. We will discuss their potential use as candidates for both molecular diagnosis and as promising pharmacological targets in the treatment of ALS, AD, or MS patients.}, }
@article {pmid31397342, year = {2019}, author = {Bissaro, M and Moro, S}, title = {Rethinking to riluzole mechanism of action: the molecular link among protein kinase CK1δ activity, TDP-43 phosphorylation, and amyotrophic lateral sclerosis pharmacological treatment.}, journal = {Neural regeneration research}, volume = {14}, number = {12}, pages = {2083-2085}, pmid = {31397342}, issn = {1673-5374}, }
@article {pmid31397052, year = {2019}, author = {Bean, MK and Ingersoll, KS and Powell, P and Stern, M and Evans, RK and Wickham, EP and Mazzeo, SE}, title = {Response to Vorland et al's Letter to the Editor about "Impact of motivational interviewing on outcomes of an adolescent obesity treatment: Results from the MI Values randomized controlled pilot trial".}, journal = {Clinical obesity}, volume = {9}, number = {5}, pages = {e12333}, doi = {10.1111/cob.12333}, pmid = {31397052}, issn = {1758-8111}, support = {UL1TR000058//Eunice Kennedy Shriver National Institute of Child Health and Human Development/International ; K23HD053742//Eunice Kennedy Shriver National Institute of Child Health and Human Development/International ; //Virginia Premier/International ; PFT-08-144-01-CPPB//American Cancer Society/International ; }, mesh = {Adolescent ; Body Mass Index ; Humans ; *Motivational Interviewing ; *Pediatric Obesity ; Pilot Projects ; }, }
@article {pmid31384636, year = {2019}, author = {Morimoto, S and Takahashi, S and Fukushima, K and Saya, H and Suzuki, N and Aoki, M and Okano, H and Nakahara, J}, title = {Ropinirole hydrochloride remedy for amyotrophic lateral sclerosis - Protocol for a randomized, double-blind, placebo-controlled, single-center, and open-label continuation phase I/IIa clinical trial (ROPALS trial).}, journal = {Regenerative therapy}, volume = {11}, number = {}, pages = {143-166}, pmid = {31384636}, issn = {2352-3204}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an intractable and incurable neurological disease. It is a progressive disease characterized by muscle atrophy and weakness caused by selective vulnerability of upper and lower motor neurons. In disease research, it has been common to use mouse models carrying mutations in responsible genes for familial ALS as pathological models of ALS. However, there is no model that has reproduced the actual conditions of human spinal cord pathology. Thus, we developed a method of producing human spinal motor neurons using human induced pluripotent stem cells (iPSCs) and an innovative experimental technique for drug screening. As a result, ropinirole hydrochloride was eventually discovered after considering such results as its preferable transitivity in the brain and tolerability, including possible adverse reactions. Therefore, we explore the safety, tolerability and efficacy of ropinirole hydrochloride as an ALS treatment in this clinical trial.<br><br>METHODS: The ROPALS trial is a single-center double-blind randomized parallel group-controlled trial of the safety, tolerability, and efficacy of the ropinirole hydrochloride extended-release tablet (Requip CR) at 2- to 16-mg doses in patients with ALS. Twenty patients will be recruited for the active drug group (fifteen patients) and placebo group (five patients). All patients will be able to receive the standard ALS treatment of riluzole if not changed the dosage during this trial. The primary outcome will be safety and tolerability at 24 weeks, defined from the date of randomization. Secondary outcome will be the efficacy, including any change in the ALS Functional Rating Scale-Revised (ALSFRS-R), change in the Combined Assessment of Function and Survival (CAFS), and the composite endpoint as a sum of Z-transformed scores on various clinical items. Notably, we will perform an explorative search for a drug effect evaluation using the patient-derived iPSCs to prove this trial concept. Eligible patients will have El Escorial Possible, clinically possible and laboratory-supported, clinically probable, or clinically definite amyotrophic lateral sclerosis with disease duration less than 60 months (inclusive), an ALSFRS-R score &#x2265;2 points on all items and age from 20 to 80 years.<br><br>CONCLUSION: Patient recruitment began in December 2018 and the last patient is expected to complete the trial protocol in November 2020.<br><br>TRIAL REGISTRATION: Current controlled trials UMIN000034954 and JMA-IIA00397.<br><br>PROTOCOL VERSION: version 1.6 (Date; 5/Apr/2019).}, }
@article {pmid31383794, year = {2019}, author = {Crivello, M and Hogg, MC and Jirström, E and Halang, L and Woods, I and Rayner, M and Coughlan, KS and Lewandowski, SA and Prehn, JHM}, title = {Vascular regression precedes motor neuron loss in the FUS (1-359) ALS mouse model.}, journal = {Disease models &amp; mechanisms}, volume = {12}, number = {8}, pages = {}, pmid = {31383794}, issn = {1754-8411}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Blood Vessels/*pathology ; Cell Count ; Disease Models, Animal ; Humans ; Mice, Inbred C57BL ; Mice, Transgenic ; MicroRNAs/metabolism ; Motor Neurons/metabolism/*pathology ; RNA-Binding Protein FUS/*genetics/metabolism ; Ribonuclease, Pancreatic/pharmacology ; Sialoglycoproteins/metabolism ; Survival Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) presents a poorly understood pathogenesis. Evidence from patients and mutant SOD1 mouse models suggests vascular damage may precede or aggravate motor dysfunction in ALS. We have previously shown angiogenin (ANG) treatment enhances motor neuron survival, delays motor dysfunction and prevents vascular regression in the SOD1[G93A] ALS model. However, the existence of vascular defects at different stages of disease progression remains to be established in other ALS models. Here, we assessed vascular integrity in vivo throughout different disease stages, and investigated whether ANG treatment reverses vascular regression and prolongs motor neuron survival in the FUS (1-359) mouse model of ALS. Lumbar spinal cord tissue was collected from FUS (1-359) and non-transgenic control mice at postnatal day (P)50, P90 and P120. We found a significant decrease in vascular network density in lumbar spinal cords from FUS (1-359) mice by day 90, at which point motor neuron numbers were unaffected. ANG treatment did not affect survival or counter vascular regression. Endogenous Ang1 and Vegf expression were unchanged at P50 and P90; however, we found a significant decrease in miRNA 126 at P50, indicating vascular integrity in FUS mice may be compromised via an alternative pathway. Our study demonstrates that vascular regression occurs before motor neuron degeneration in FUS (1-359) mice, and highlights that heterogeneity in responses to novel ALS therapeutics can already be detected in preclinical mouse models of ALS.This article has an associated First Person interview with the joint first authors of the paper.}, }
@article {pmid31382568, year = {2019}, author = {Apolloni, S and Caputi, F and Pignataro, A and Amadio, S and Fabbrizio, P and Ammassari-Teule, M and Volonté, C}, title = {Histamine Is an Inducer of the Heat Shock Response in SOD1-G93A Models of ALS.}, journal = {International journal of molecular sciences}, volume = {20}, number = {15}, pages = {}, pmid = {31382568}, issn = {1422-0067}, support = {Flagship Project NanoMAX (B81J13000310005)//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; }, mesh = {Amyotrophic Lateral Sclerosis ; Animals ; Astrocytes/drug effects/pathology ; Cell Death/drug effects ; Dendritic Spines/drug effects/genetics ; Disease Models, Animal ; Endoplasmic Reticulum Chaperone BiP ; Heat-Shock Response/*drug effects/genetics ; Histamine/*pharmacology ; Humans ; Mice ; Microglia/metabolism/pathology ; Motor Neurons/*drug effects/pathology ; Mutation ; Neuroglia/drug effects/pathology ; Spinal Cord/drug effects/pathology ; Superoxide Dismutase-1/*genetics ; }, abstract = {(1) Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial non-cell autonomous disease where activation of microglia and astrocytes largely contributes to motor neurons death. Heat shock proteins have been demonstrated to promote neuronal survival and exert a strong anti-inflammatory action in glia. Having previously shown that the pharmacological increase of the histamine content in the central nervous system (CNS) of SOD1-G93A mice decreases neuroinflammation, reduces motor neuron death, and increases mice life span, here we examined whether this effect could be mediated by an enhancement of the heat shock response. (2) Methods: Heat shock protein expression was analyzed in vitro and in vivo. Histamine was provided to primary microglia and NSC-34 motor neurons expressing the SOD1-G93A mutation. The brain permeable histamine precursor histidine was chronically administered to symptomatic SOD1-G93A mice. Spine density was measured by Golgi-staining in motor cortex of histidine-treated SOD1-G93A mice. (3) Results: We demonstrate that histamine activates the heat shock response in cultured SOD1-G93A microglia and motor neurons. In SOD1-G93A mice, histidine augments the protein content of GRP78 and Hsp70 in spinal cord and cortex, where the treatment also rescues type I motor neuron dendritic spine loss. (4) Conclusion: Besides the established histaminergic neuroprotective and anti-inflammatory effects, the induction of the heat shock response in the SOD1-G93A model by histamine confirms the importance of this pathway in the search for successful therapeutic solutions to treat ALS.}, }
@article {pmid31378345, year = {2019}, author = {Yan, B and Zhang, Y and Li, J and Fang, J and Liu, T and Dong, L}, title = {Transcriptome profiling to identify cytochrome P450 genes involved in penoxsulam resistance in Echinochloa glabrescens.}, journal = {Pesticide biochemistry and physiology}, volume = {158}, number = {}, pages = {112-120}, doi = {10.1016/j.pestbp.2019.04.017}, pmid = {31378345}, issn = {1095-9939}, mesh = {Cytochrome P-450 Enzyme System/genetics/*metabolism ; Echinochloa/*drug effects/genetics/*metabolism ; Gene Expression Profiling/*methods ; Herbicide Resistance/genetics ; Malathion/pharmacology ; Piperonyl Butoxide/pharmacology ; Sulfonamides/*pharmacology ; Uridine/*analogs &amp; derivatives/pharmacology ; }, abstract = {Cytochrome P450s (P450s) confer resistance against herbicides, and this is increasingly becoming a concern for weed control. As a widespread Gramineae weed in paddy fields, Echinocloa glabrescens has become resistant to the acetolactate synthase (ALS)-inhibiting triazolopyrimidine herbicide penoxsulam. In this study, we found that the GR50 of the resistant population (SHQP-R) decreased substantially from 25.6 to 5.0 and 6.2 g a.i. ha[-1] after treatment with the P450 inhibitors piperonyl butoxide (PBO) and malathion, respectively. However, P450 inhibitors almost had no effects on the susceptibility of the sensitive population (JYJD-S) to penoxsulam. To investigate the mechanisms of metabolic resistance, transcriptome sequencing analysis was performed to find candidate genes that may confer resistance to penoxsulam in E. glabrescens. A total of 233 P450 differentially expressed genes (DEGs) were identified by transcriptome sequencing. We found that the metabolic process and metabolic pathways were the most highly enriched in DEGs. Further, twenty-seven candidate P450 DEGs were selected for qPCR validation analyses. After penoxsulam treatment, the relative expression levels were significantly higher in SHQP-R than in JYJD-S. Among these, the relative expression of twenty-three P450 DEGs (eighteen from the CYP72A-71C-74A-96A-734A subfamily; five from CYP81E1-94C1-94B3-714C1-714C2) were upregulated and four P450 DEGs (from CYP724B1-711A1-707A7-97B2) were downregulated. Changes in the expression of these candidate P450 genes in E. glabrescens were in response to penoxsulam, which provides preliminary evidence for the role of P450s in herbicide metabolism in E. glabrescens. However, further functional studies on metabolic resistance to penoxsulam in a resistant E. glabrescens population are required.}, }
@article {pmid31376190, year = {2020}, author = {Fabbrizio, P and Apolloni, S and Bianchi, A and Salvatori, I and Valle, C and Lanzuolo, C and Bendotti, C and Nardo, G and Volonté, C}, title = {P2X7 activation enhances skeletal muscle metabolism and regeneration in SOD1G93A mouse model of amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {30}, number = {2}, pages = {272-282}, pmid = {31376190}, issn = {1750-3639}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Muscle, Skeletal/*metabolism/*pathology ; Neuromuscular Junction/*metabolism/pathology ; Receptors, Purinergic P2X7/*metabolism ; Regeneration ; Superoxide Dismutase/genetics ; }, abstract = {Muscle weakness plays an important role in neuromuscular disorders comprising amyotrophic lateral sclerosis (ALS). However, it is not established whether muscle denervation originates from the motor neurons, the muscles or more likely both. Previous studies have shown that the expression of the SOD1G93A mutation in skeletal muscles causes denervation of the neuromuscular junctions, inability to regenerate and consequent atrophy, all clear symptoms of ALS. In this work, we used SOD1G93A mice, a model that best mimics some pathological features of both familial and sporadic ALS, and we investigated some biological effects induced by the activation of the P2X7 receptor in the skeletal muscles. The P2X7, belonging to the ionotropic family of purinergic receptors for extracellular ATP, is abundantly expressed in the healthy skeletal muscles, where it controls cell duplication, differentiation, regeneration or death. In particular, we evaluated whether an in vivo treatment in SOD1G93A mice with the P2X7 specific agonist 2'(3')-O-(4-Benzoylbenzoyl) adenosine5'-triphosphate (BzATP) just before the onset of a pathological neuromuscular phenotype could exert beneficial effects in the skeletal muscles. Our findings indicate that stimulation of P2X7 improves the innervation and metabolism of myofibers, moreover elicits the proliferation/differentiation of satellite cells, thus preventing the denervation atrophy of skeletal muscles in SOD1G93A mice. Overall, this study suggests that a P2X7-targeted and site-specific modulation might be a strategy to interfere with the complex multifactorial and multisystem nature of ALS.}, }
@article {pmid31375848, year = {2019}, author = {Leussink, VI}, title = {[Aspects of nutrition for prevention and treatment of chronic neurological diseases].}, journal = {Der Nervenarzt}, volume = {90}, number = {8}, pages = {843-857}, pmid = {31375848}, issn = {1433-0407}, mesh = {Chronic Disease ; Humans ; *Nervous System Diseases/diet therapy/prevention &amp; control ; }, abstract = {Chronic neurodegenerative and neuroinflammatory diseases, such as idiopathic Parkinson's syndrome, amyotrophic lateral sclerosis and multiple sclerosis, represent a therapeutic challenge. Their pathophysiology is not well understood and a cure for any of these diseases is not possible. Over the past decades lifestyle and nutritional habits in modern industrial nations have changed and evidence is increasing that the prevalence of chronic diseases as well their clinical presentation are also changing. Epidemiological investigations indicate that nutritional components might have an impact on the pathogenesis of chronic neurological diseases. A profound understanding of these correlations could foster a better prevention as well as treatment of such chronic disabling diseases. This continuing medical education article summarizes the current understanding of selected nutritional components and their effect on the development and clinical course of chronic neurological disorders.}, }
@article {pmid31364409, year = {2019}, author = {Jackson, C and Heiman-Patterson, T and Kittrell, P and Baranovsky, T and McAnanama, G and Bower, L and Agnese, W and Martin, M}, title = {Radicava (edaravone) for amyotrophic lateral sclerosis: US experience at 1 year after launch.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {7-8}, pages = {605-610}, doi = {10.1080/21678421.2019.1645858}, pmid = {31364409}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*epidemiology ; Double-Blind Method ; Edaravone/*administration &amp; dosage/adverse effects ; Fatigue/chemically induced ; Free Radical Scavengers/*administration &amp; dosage/adverse effects ; Humans ; Infusions, Intravenous ; Muscle Weakness/chemically induced ; *Physicians ; Product Surveillance, Postmarketing/*methods ; Surveys and Questionnaires ; Time Factors ; United States/epidemiology ; }, abstract = {Background: Radicava[®] (edaravone), approved for the treatment of amyotrophic lateral sclerosis (ALS) in 2017, may be administered intravenously at clinic sites, infusion centers or at home. Objective: To gain insights into the utilization of Radicava[®] at 1 year post-launch. Methods: Radicava[®] usage data were collected, and a survey was conducted among 75 physicians. Adverse events (AEs) were identified from a post-marketing safety database from 8 August 2017 through 3 August 2018 (cutoff date). Results: As of 6 August 2018, 3007 ALS patients were treated with Radicava[®]. Survey results indicated that 43% of patients received infusions at home, 32% in a clinician's office, and 26% at a referred site. Infusions were administered mainly via implanted port. The most commonly reported AEs were drug ineffective, death (not specified), therapeutic response unexpected, asthenia, fatigue, gait disturbance, disease progression, muscular weakness, fall, and dyspnea. Conclusions: The first year of Radicava[®] availability to ALS patients in the US provided many key learnings that will help shape strategies for improved patient care.}, }
@article {pmid31354794, year = {2019}, author = {Gruchot, J and Kremer, D and Küry, P}, title = {Neural Cell Responses Upon Exposure to Human Endogenous Retroviruses.}, journal = {Frontiers in genetics}, volume = {10}, number = {}, pages = {655}, pmid = {31354794}, issn = {1664-8021}, abstract = {Human endogenous retroviruses (HERVs) are ancient retroviral elements, which invaded the human germ line several million years ago. Subsequent retrotransposition events amplified these sequences, resulting in approximately 8% of the human genome being composed of HERV sequences today. These genetic elements, normally dormant within human genomes, can be (re)-activated by environmental factors such as infections with other viruses, leading to the expression of viral proteins and, in some instances, even to viral particle production. Several studies have shown that the expression of these retroviral elements correlates with the onset and progression of neurological diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Further studies provided evidence on additional roles for HERVs in schizophrenia (SCZ). Since these diseases are still not well understood, HERVs might constitute a new category of pathogenic components that could significantly change our understanding of these pathologies. Moreover, knowledge about their mode of action might also help to develop novel and more powerful approaches for the treatment of these complex diseases. Therefore, the main scope of this review is a description of the current knowledge on the involvement of HERV-W and HERV-K in neurological disease specifically focusing on the effects they exert on neural cells of the central nervous system.}, }
@article {pmid31350742, year = {2019}, author = {Graf, D and Häussinger, D}, title = {[Standards and recent advancements in esophageal cancer treatment].}, journal = {Deutsche medizinische Wochenschrift (1946)}, volume = {144}, number = {15}, pages = {1023-1028}, doi = {10.1055/a-0597-7575}, pmid = {31350742}, issn = {1439-4413}, mesh = {*Esophageal Neoplasms/diagnosis/mortality/surgery ; Esophagectomy ; Humans ; Prognosis ; }, abstract = {Das Ösophaguskarzinom macht ca. 1 % aller malignen Erkrankungen aus und besitzt trotz aller Fortschritte in der Diagnostik und Therapie eine sehr schlechte Prognose. In der Therapie sind multimodale Konzepte fest verankert und es bedarf der interdisziplinären Zusammenarbeit der Gastroenterologen, Onkologen, Chirurgen und Strahlentherapeuten.Bei mukosalen Karzinomen stellt die endoskopische Resektion die Therapie der Wahl da. Im Falle von cT1b- oder cT2- Tumoren erfolgt die primäre chirurgische Resektion, demgegenüber wird bei lokal fortgeschrittenen Karzinomen cT3- oder N+-Tumoren erst nach neoadjuvanter Vorbehandlung mittels Radiochemotherapie oder alleiniger Chemotherapie die operative Resektion durchgeführt. In der metastasierten Situation stehen nur palliative Radio- bzw. Chemotherapien als Behandlungskonzepte zur Verfügung, wobei die Effizienz dieser Therapien eingeschränkt ist. Dieser Übersichtsartikel fasst die aktuellen multimodalen Therapiekonzepte zusammen.}, }
@article {pmid31345972, year = {2019}, author = {von Vopelius-Feldt, J and Powell, J and Benger, JR}, title = {Cost-effectiveness of advanced life support and prehospital critical care for out-of-hospital cardiac arrest in England: a decision analysis model.}, journal = {BMJ open}, volume = {9}, number = {7}, pages = {e028574}, pmid = {31345972}, issn = {2044-6055}, support = {DRF-2015-08-040/DH_/Department of Health/United Kingdom ; }, mesh = {Adult ; Advanced Cardiac Life Support/*economics ; Cost-Benefit Analysis ; *Decision Support Techniques ; Emergency Medical Services/*economics/statistics &amp; numerical data ; England ; Humans ; Out-of-Hospital Cardiac Arrest/economics/mortality/*therapy ; }, abstract = {OBJECTIVES: This research aimed to answer the following questions: What are the costs of prehospital advanced life support (ALS) and prehospital critical care for out-of-hospital cardiac arrest (OHCA)? What is the cost-effectiveness of prehospital ALS? What improvement in survival rates from OHCA would prehospital critical care need to achieve in order to be cost-effective?<br><br>SETTING: A single National Health Service ambulance service and a charity-funded prehospital critical care service in England.<br><br>PARTICIPANTS: The patient population is adult, non-traumatic OHCA.<br><br>METHODS: We combined data from previously published research with data provided by a regional ambulance service and air ambulance charity to create a decision tree model, coupled with a Markov model, of costs and outcomes following OHCA. We compared no treatment for OHCA to the current standard of care of prehospital ALS, and prehospital ALS to prehospital critical care. To reflect the uncertainty in the underlying data, we used probabilistic and two-way sensitivity analyses.<br><br>RESULTS: Costs of prehospital ALS and prehospital critical care were &#xa3;347 and &#xa3;1711 per patient, respectively. When costs and outcomes of prehospital, in-hospital and postdischarge phase of OHCA care were combined, prehospital ALS was estimated to be cost-effective at &#xa3;11 407/quality-adjusted life year. In order to be cost-effective in addition to ALS, prehospital critical care for OHCA would need to achieve a minimally economically important difference (MEID) in survival to hospital discharge of 3%-5%.<br><br>CONCLUSION: This is the first economic analysis to address the question of cost-effectiveness of prehospital critical care following OHCA. While costs of either prehospital ALS and/or critical care per patient with OHCA are relatively low, significant costs are incurred during hospital treatment and after discharge in patients who survive. Knowledge of the MEID for prehospital critical care can guide future research in this field.<br><br>TRIAL REGISTRATION NUMBER: ISRCTN18375201.}, }
@article {pmid31344397, year = {2019}, author = {Nomura, E and Ohta, Y and Tadokoro, K and Shang, J and Feng, T and Liu, X and Shi, X and Matsumoto, N and Sasaki, R and Tsunoda, K and Sato, K and Takemoto, M and Hishikawa, N and Yamashita, T and Kuchimaru, T and Kizaka-Kondoh, S and Abe, K}, title = {Imaging Hypoxic Stress and the Treatment of Amyotrophic Lateral Sclerosis with Dimethyloxalylglycine in a Mice Model.}, journal = {Neuroscience}, volume = {415}, number = {}, pages = {31-43}, doi = {10.1016/j.neuroscience.2019.06.025}, pmid = {31344397}, issn = {1873-7544}, mesh = {Amino Acids, Dicarboxylic/*pharmacology ; Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/pathology ; Animals ; Apoptosis ; Female ; Gene Expression Regulation ; Gliosis ; Hypoxia/*metabolism ; Hypoxia-Inducible Factor 1 ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Kaplan-Meier Estimate ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Muscle, Skeletal/metabolism ; Quadriceps Muscle/pathology ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase-1 ; }, abstract = {Hypoxia inducible factor-1α (HIF-1α) is a key transcription factor that maintains oxygen homeostasis. Hypoxic stress is related to the pathogenesis of amyotrophic lateral sclerosis (ALS), and impaired HIF-1α induces motor neuron degeneration in ALS. Dimethyloxalylglycine (DMOG) upregulates the stability of HIF-1α expression and shows neuroprotective effects, but has not been used in ALS as an anti-hypoxic stress treatment. In the present study, we investigated hypoxic stress in ALS model mice bearing G93A-human Cu/Zn superoxide dismutase by in vivo HIF-1α imaging, and treated the ALS mice with DMOG. In vivo HIF-1α imaging analysis showed enhanced hypoxic stress in both the spinal cord and muscles of lower limbs of ALS mice, even at the pre-symptomatic stage. HIF-1α expression decreased as the disease progressed until 126 days of age. DMOG treatment significantly ameliorated the decrease in HIF-1α expression, the degeneration of both spinal motor neurons and myofibers in lower limbs, gliosis and apoptosis in the spinal cord. This was accompanied by prolonged survival. The present study suggests that in vivo bioluminescence resonance energy transfer (BRET) HIF-1α imaging is useful for evaluating hypoxic stress in ALS, and that the enhancement of HIF-1α is a therapeutic target for ALS patients.}, }
@article {pmid31342410, year = {2019}, author = {Bose, P and Tremblay, E and Maios, C and Narasimhan, V and Armstrong, GAB and Liao, M and Parker, JA and Robitaille, R and Wen, XY and Barden, C and Drapeau, P}, title = {The Novel Small Molecule TRVA242 Stabilizes Neuromuscular Junction Defects in Multiple Animal Models of Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {16}, number = {4}, pages = {1149-1166}, pmid = {31342410}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/metabolism ; Animals ; Animals, Genetically Modified ; C9orf72 Protein/*genetics ; Caenorhabditis elegans ; DNA-Binding Proteins/administration &amp; dosage/metabolism ; *Disease Models, Animal ; Humans ; Locomotion/drug effects/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuromuscular Junction/drug effects/*genetics/metabolism ; Organ Culture Techniques ; Pimozide/administration &amp; dosage/metabolism ; Superoxide Dismutase-1/*genetics ; Zebrafish ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder in which the neuromuscular junction progressively degenerates, leading to movement difficulties, paralysis, and eventually death. ALS is currently being treated by only two FDA-approved drugs with modest efficacy in slowing disease progression. Often, the translation of preclinical findings to bedside terminates prematurely as the evaluation of potential therapeutic compounds focuses on a single study or a single animal model. To circumscribe these issues, we screened 3,765 novel small molecule derivatives of pimozide, a recently identified repurposed neuroleptic for ALS, in Caenorhabditis elegans, confirmed the hits in zebrafish and validated the most active compounds in mouse genetic models. Out of the 27 small molecules identified from the high-throughput screen in worms, 4 were found to recover locomotor defects in C. elegans and genetic zebrafish models of ALS. TRVA242 was identified as the most potent compound as it significantly improved efficiency in rescuing locomotor, motorneuron, and neuromuscular junction synaptic deficits in a C. elegans TDP-43 model and in multiple zebrafish genetic (TDP-43, SOD1, and C9ORF72) models of ALS. The actions of TRVA242 were also conserved in a mammalian model as it also stabilized neuromuscular junction deficits in a mouse SOD1 model of ALS. Compounds such as TRVA242 therefore represent new potential therapeutics for the treatment of ALS.}, }
@article {pmid31340904, year = {2022}, author = {Castillo-Álvarez, F and Marzo-Sola, ME}, title = {Role of the gut microbiota in the development of various neurological diseases.}, journal = {Neurologia}, volume = {37}, number = {6}, pages = {492-498}, doi = {10.1016/j.nrl.2019.03.017}, pmid = {31340904}, issn = {2173-5808}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Parkinson Disease/pathology ; *Alzheimer Disease ; *Neuromyelitis Optica ; *Amyotrophic Lateral Sclerosis ; *Multiple Sclerosis ; }, abstract = {INTRODUCTION: In recent years, the scientific evidence supporting a relationship between the microbiota and various diseases has increased significantly; this trend has also been observed for neurological diseases. This has given rise to the concept of the gut-brain axis and the idea of a relationship between the gut microbiota and several neurological diseases whose aetiopathogenesis is yet to be clearly defined.<br><br>DEVELOPMENT: We review the role of the gut microbiota in the gut-brain axis and analyse those neurological diseases in which alterations in the gut microbiota have been described as a result of human studies: specifically, Parkinson's disease, Alzheimer disease, amyotrophic lateral sclerosis, neuromyelitis optica, and multiple sclerosis.<br><br>CONCLUSIONS: The body of evidence linking the gut microbiota to various neurological diseases has grown considerably. Several interesting studies show a relationship between the gut microbiota and Parkinson's disease, Alzheimer disease, neuromyelitis optica, and multiple sclerosis, whereas other controversial studies implicate it in amyotrophic lateral sclerosis. Many of these studies place considerable emphasis on modulation of inflammation, particularly by bacteria capable of producing short-chain fatty acids. Despite these encouraging results, many questions remain, and there is a need to demonstrate causality, determine the role of fungi or viruses, and research possible treatment through diet, probiotics, or faecal microbiota transplantation.}, }
@article {pmid31339079, year = {2020}, author = {Liu, C and Li, J and Shi, W and Zhang, L and Liu, S and Lian, Y and Liang, S and Wang, H}, title = {Progranulin Regulates Inflammation and Tumor.}, journal = {Anti-inflammatory &amp; anti-allergy agents in medicinal chemistry}, volume = {19}, number = {2}, pages = {88-102}, pmid = {31339079}, issn = {1875-614X}, mesh = {Animals ; Carcinogenesis ; Cell Cycle ; Cell Movement ; Cell Proliferation ; Cell Transformation, Neoplastic ; Cytokines/metabolism ; Humans ; Inflammation/*metabolism ; Neoplasms/*metabolism ; Neurodegenerative Diseases/*metabolism ; Progranulins/genetics/*metabolism ; }, abstract = {Progranulin (PGRN) mediates cell cycle progression and cell motility as a pleiotropic growth factor and acts as a universal regulator of cell growth, migration and transformation, cell cycle, wound healing, tumorigenesis, and cytotoxic drug resistance as a secreted glycoprotein. PGRN overexpression can induce the secretion of many inflammatory cytokines, such as IL-8, -6,-10, TNF-α. At the same time, this protein can promote tumor proliferation and the occurrence and development of many related diseases such as gastric cancer, breast cancer, cervical cancer, colorectal cancer, renal injury, neurodegeneration, neuroinflammatory, human atherosclerotic plaque, hepatocarcinoma, acute kidney injury, amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease. In short, PGRN plays a very critical role in injury repair and tumorigenesis, it provides a new direction for succeeding research and serves as a target for clinical diagnosis and treatment, thus warranting further investigation. Here, we discuss the potential therapeutic utility and the effect of PGRN on the relationship between inflammation and cancer.}, }
@article {pmid31337114, year = {2019}, author = {Wang, J and Zuzzio, K and Walker, CL}, title = {Systemic Dental Pulp Stem Cell Secretome Therapy in a Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {9}, number = {7}, pages = {}, pmid = {31337114}, issn = {2076-3425}, support = {IK2 RX002688/RX/RRD VA/United States ; IK2RX002688//U.S. Department of Veterans Affairs/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron (MN) disease with no cure. Accumulating evidence indicates ALS involves a complex interaction between central glia and the peripheral immune response and neuromuscular interface. Stem cell secretomes contain various beneficial trophic factors and cytokines, and we recently demonstrated that administration of the secretome of adipose-derived stem cells (ASCs) during early neuromuscular junction (NMJ) denervation in the mutant superoxide dismutase (mSOD1[G93A]) ALS mouse ameliorated NMJ disruption. In the present study, we hypothesized that administration of dental pulp stem cell secretome in the form of conditioned medium (DPSC-CM) at different stages of disease would promote NMJ innervation, prevent MN loss and extend lifespan. Our findings show that DPSC-CM significantly improved NMJ innervation at postnatal day (PD) 47 compared to vehicle treated mSOD1[G93A] mice (p < 0.05). During late pre-symptomatic stages (PD70-P91), DPSC-CM significantly increased MN survival (p < 0.01) and NMJ preservation (p < 0.05), while reactive gliosis in the ventral horn remained unaffected. For DPSC-CM treated mSOD1[G93A] mice beginning at symptom onset, post-onset days of survival as well as overall lifespan was significantly increased compared to vehicle treated mice (p < 0.05). This is the first study to show therapeutic benefits of systemic DPSC secretome in experimental ALS, and establishes a foundation for future research into the treatment effects and mechanistic analyses of DPSC and other stem cell secretome therapies in ALS.}, }
@article {pmid31336872, year = {2019}, author = {Sivandzade, F and Bhalerao, A and Cucullo, L}, title = {Cerebrovascular and Neurological Disorders: Protective Role of NRF2.}, journal = {International journal of molecular sciences}, volume = {20}, number = {14}, pages = {}, pmid = {31336872}, issn = {1422-0067}, support = {R01 DA029121/DA/NIDA NIH HHS/United States ; 2R01-DA029121/DA/NIDA NIH HHS/United States ; }, mesh = {Aging/genetics/metabolism ; Animals ; Biomarkers ; Cerebrovascular Disorders/diagnosis/*etiology/*genetics ; Comorbidity ; *Disease Susceptibility ; Humans ; NF-E2-Related Factor 2/*genetics/*metabolism ; Nervous System Diseases/diagnosis/*etiology/*metabolism ; Oxidative Stress ; Protein Binding ; Risk Factors ; Signal Transduction ; Smoking/adverse effects ; }, abstract = {Cellular defense mechanisms, intracellular signaling, and physiological functions are regulated by electrophiles and reactive oxygen species (ROS). Recent works strongly considered imbalanced ROS and electrophile overabundance as the leading cause of cellular and tissue damage, whereas oxidative stress (OS) plays a crucial role for the onset and progression of major cerebrovascular and neurodegenerative pathologies. These include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and aging. Nuclear factor erythroid 2-related factor (NRF2) is the major modulator of the xenobiotic-activated receptor (XAR) and is accountable for activating the antioxidative response elements (ARE)-pathway modulating the detoxification and antioxidative responses of the cells. NRF2 activity, however, is also implicated in carcinogenesis protection, stem cells regulation, anti-inflammation, anti-aging, and so forth. Herein, we briefly describe the NRF2-ARE pathway and provide a review analysis of its functioning and system integration as well as its role in major CNS disorders. We also discuss NRF2-based therapeutic approaches for the treatment of neurodegenerative and cerebrovascular disorders.}, }
@article {pmid31334681, year = {2019}, author = {Goutman, SA and Brown, MB and Cudkowicz, M and Atassi, N and Feldman, EL}, title = {ALS/SURV: a modification of the CAFS statistic.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {7-8}, pages = {576-583}, pmid = {31334681}, issn = {2167-9223}, support = {K23 ES027221/ES/NIEHS NIH HHS/United States ; U01 NS049640/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*mortality ; Humans ; *Recovery of Function ; *Severity of Illness Index ; Survival Rate/trends ; }, abstract = {We present a composite endpoint that can be used in amyotrophic lateral sclerosis (ALS) trials, which combines functional status (via the ALS functional rating scale) and survival, denoted ALS/SURV. ALS/SURV modifies and extends the combined assessment of function and survival (CAFS) score and assigns rankings to participants that withdraw or are lost to follow up in a way that does not disproportionately lower and skew ranks for those participants that reach study endpoint (either death or study completion). ALS/SURV has properties of: (1) ordering participants that completed the study from the shortest surviving participant to the last observed death followed by worst function to best function; (2) ordering participants withdrawing at time of withdrawal by their decline in functional status relative to all the participants still in the study; and (3) then maintaining this ordering at time of withdrawal relative to participants still in the study. These properties allow ALS/SURV to better account for participant drop out compared to CAFS. We derive and compare the rankings of participants from the ceftriaxone treatment trial for ALS/SURV and CAFS and demonstrate that ALS/SURV does not modify the ordering of participants that complete a study by the results of participants who withdraw. Additionally, ALS/SURV can be summarized as either median functional status or median survival along with interquartile range, thereby adding clinical meaning to the statistic. Finally, by applying normal deviates, confidence intervals can be computed and used to estimate power for future studies. In summary, the above properties support the role for ALS/SURV as a new ALS composite statistic.}, }
@article {pmid31332433, year = {2019}, author = {Park, JH and Elpers, C and Reunert, J and McCormick, ML and Mohr, J and Biskup, S and Schwartz, O and Rust, S and Grüneberg, M and Seelhöfer, A and Schara, U and Boltshauser, E and Spitz, DR and Marquardt, T}, title = {SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {142}, number = {8}, pages = {2230-2237}, pmid = {31332433}, issn = {1460-2156}, support = {R01 CA182804/CA/NCI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis ; Child ; Child, Preschool ; Frameshift Mutation ; Heredodegenerative Disorders, Nervous System/*genetics ; Humans ; Male ; Pedigree ; Superoxide Dismutase-1/*deficiency/*genetics ; Syndrome ; }, abstract = {Superoxide dismutase 1 (SOD1) is the principal cytoplasmic superoxide dismutase in humans and plays a major role in redox potential regulation. It catalyses the transformation of the superoxide anion (O2•-) into hydrogen peroxide. Heterozygous variants in SOD1 are a common cause of familial amyotrophic lateral sclerosis. In this study we describe the homozygous truncating variant c.335dupG (p.C112Wfs*11) in SOD1 that leads to total absence of enzyme activity. The resulting phenotype is severe and marked by progressive loss of motor abilities, tetraspasticity with predominance in the lower extremities, mild cerebellar atrophy, and hyperekplexia-like symptoms. Heterozygous carriers have a markedly reduced enzyme activity when compared to wild-type controls but show no overt neurologic phenotype. These results are in contrast with the previously proposed theory that a loss of function is the underlying mechanism in SOD1-related motor neuron disease and should be considered before application of previously proposed SOD1 silencing as a treatment option for amyotrophic lateral sclerosis.}, }
@article {pmid31331820, year = {2019}, author = {Abugable, AA and Morris, JLM and Palminha, NM and Zaksauskaite, R and Ray, S and El-Khamisy, SF}, title = {DNA repair and neurological disease: From molecular understanding to the development of diagnostics and model organisms.}, journal = {DNA repair}, volume = {81}, number = {}, pages = {102669}, doi = {10.1016/j.dnarep.2019.102669}, pmid = {31331820}, issn = {1568-7856}, support = {103844/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Alzheimer Disease/genetics/metabolism ; *DNA Repair ; Dementia/genetics/metabolism ; Humans ; Huntington Disease/genetics/metabolism ; Nervous System Diseases/*genetics/metabolism ; Neurons/metabolism ; Parkinson Disease/genetics/metabolism ; Trinucleotide Repeat Expansion ; }, abstract = {In both replicating and non-replicating cells, the maintenance of genomic stability is of utmost importance. Dividing cells can repair DNA damage during cell division, tolerate the damage by employing potentially mutagenic DNA polymerases or die via apoptosis. However, the options for accurate DNA repair are more limited in non-replicating neuronal cells. If DNA damage is left unresolved, neuronal cells die causing neurodegenerative disorders. A number of pathogenic variants of DNA repair proteins have been linked to multiple neurological diseases. The current challenge is to harness our knowledge of fundamental properties of DNA repair to improve diagnosis, prognosis and treatment of such debilitating disorders. In this perspective, we will focus on recent efforts in identifying novel DNA repair biomarkers for the diagnosis of neurological disorders and their use in monitoring the patient response to therapy. These efforts are greatly facilitated by the development of model organisms such as zebrafish, which will also be summarised.}, }
@article {pmid31330533, year = {2019}, author = {Blacher, E and Bashiardes, S and Shapiro, H and Rothschild, D and Mor, U and Dori-Bachash, M and Kleimeyer, C and Moresi, C and Harnik, Y and Zur, M and Zabari, M and Brik, RB and Kviatcovsky, D and Zmora, N and Cohen, Y and Bar, N and Levi, I and Amar, N and Mehlman, T and Brandis, A and Biton, I and Kuperman, Y and Tsoory, M and Alfahel, L and Harmelin, A and Schwartz, M and Israelson, A and Arike, L and Johansson, MEV and Hansson, GC and Gotkine, M and Segal, E and Elinav, E}, title = {Potential roles of gut microbiome and metabolites in modulating ALS in mice.}, journal = {Nature}, volume = {572}, number = {7770}, pages = {474-480}, pmid = {31330533}, issn = {1476-4687}, support = {/HHMI/Howard Hughes Medical Institute/United States ; /ERC_/European Research Council/International ; }, mesh = {Akkermansia ; Amyotrophic Lateral Sclerosis/metabolism/*microbiology/pathology/*physiopathology ; Animals ; Anti-Bacterial Agents/pharmacology ; Disease Models, Animal ; Dysbiosis ; Female ; Gastrointestinal Microbiome/drug effects/*physiology ; Germ-Free Life ; Humans ; Longevity ; Male ; Mice ; Mice, Transgenic ; Niacinamide/biosynthesis/*metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Survival Rate ; Symbiosis/drug effects ; Verrucomicrobia/metabolism/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder, in which the clinical manifestations may be influenced by genetic and unknown environmental factors. Here we show that ALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. We correlate eleven distinct commensal bacteria at our vivarium with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1-Tg mice we demonstrate that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice. In humans, we identify distinct microbiome and metabolite configurations-including reduced levels of nicotinamide systemically and in the cerebrospinal fluid-in a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiome-brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.}, }
@article {pmid31329627, year = {2019}, author = {Bender, H and Noyes, N and Annis, JL and Hitpas, A and Mollnow, L and Croak, K and Kane, S and Wagner, K and Dow, S and Zabel, M}, title = {PrPC knockdown by liposome-siRNA-peptide complexes (LSPCs) prolongs survival and normal behavior of prion-infected mice immunotolerant to treatment.}, journal = {PloS one}, volume = {14}, number = {7}, pages = {e0219995}, pmid = {31329627}, issn = {1932-6203}, support = {R01 NS075214/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Antigens, Viral/chemistry/metabolism ; Blood-Brain Barrier/metabolism ; Female ; Liposomes/chemistry/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; PrPC Proteins/*genetics/metabolism ; Prion Diseases/*therapy ; RNAi Therapeutics/*methods ; Viral Envelope Proteins/chemistry/metabolism ; }, abstract = {Prion diseases are members of neurodegenerative protein misfolding diseases (NPMDs) that include Alzheimer's, Parkinson's and Huntington diseases, amyotrophic lateral sclerosis, tauopathies, traumatic brain injuries, and chronic traumatic encephalopathies. No known therapeutics extend survival or improve quality of life of humans afflicted with prion disease. We and others developed a new approach to NPMD therapy based on reducing the amount of the normal, host-encoded protein available as substrate for misfolding into pathologic forms, using RNA interference, a catabolic pathway that decreases levels of mRNA encoding a particular protein. We developed a therapeutic delivery system consisting of small interfering RNA (siRNA) complexed to liposomes and addressed to the central nervous system using a targeting peptide derived from rabies virus glycoprotein. These liposome-siRNA-peptide complexes (LSPCs) cross the blood-brain barrier and deliver PrP siRNA to neuronal cells to decrease expression of the normal cellular prion protein, PrPC, which acts as a substrate for prion replication. Here we show that LSPCs can extend survival and improve behavior of prion-infected mice that remain immunotolerant to treatment. LSPC treatment may be a viable therapy for prion and other NPMDs that can improve the quality of life of patients at terminal disease stages.}, }
@article {pmid31327120, year = {2019}, author = {Duma, C and Kopyov, O and Kopyov, A and Berman, M and Lander, E and Elam, M and Arata, M and Weiland, D and Cannell, R and Caraway, C and Berman, S and Scord, K and Stemler, L and Chung, K and Khoudari, S and McRory, R and Duma, C and Farmer, S and Bravo, A and Yassa, C and Sanathara, A and Singh, E and Rapaport, B}, title = {Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction (ADSVF) for neurodegenerative disorders: results of a 3-year phase 1 study of 113 injections in 31 patients.}, journal = {Molecular biology reports}, volume = {46}, number = {5}, pages = {5257-5272}, pmid = {31327120}, issn = {1573-4978}, mesh = {Adipose Tissue/*cytology ; Adult ; Aged ; Aged, 80 and over ; Female ; Hematopoietic Stem Cell Transplantation/adverse effects/instrumentation/*methods ; Hematopoietic Stem Cells ; Humans ; Infusions, Intraventricular ; Male ; Mesenchymal Stem Cell Transplantation/adverse effects/instrumentation/*methods ; Middle Aged ; Neurodegenerative Diseases/*therapy ; Transplantation, Autologous ; Treatment Outcome ; Ventriculoperitoneal Shunt ; }, abstract = {We have chosen to test the safety of human intracerebroventricular (ICV) brain injections of autologous non-genetically-modified adipose-derived stromal vascular fraction (ADSVF). In this IRB-approved trial, 24 patients received ICV ADSVF via an implanted reservoir between 5/22/14 and 5/22/17. Seven others were injected via their ventriculo-peritoneal shunts. Ten patients had Alzheimer's disease (AD), 6 had amyotrophic lateral sclerosis (ALS), 6 had progressive multiple sclerosis (MS-P), 6 had Parkinson's "Plus" (PD+), 1 had spinal cord injury, 1 had traumatic brain injury, and 1 had stroke. Median age was 74 (range 41-83). Injections were planned every 2-3 months. Thirty-one patients had 113 injections. Patients received SVF injection volumes of 3.5-20 cc (median:4 cc) containing 4.05 × 10[5] to 6.2 × 10[7] cells/cc, which contained an average of 8% hematopoietic and 7.5% adipose stem cells. Follow-up ranged from 0 to 36 months (median: 9.2 months). MRIs post injection(s) were unchanged, except for one AD patient whose hippocampal volume increased from < 5th percentile to 48th percentile (NeuroQuant[®] volumetric MRI). Of the 10 AD patients, 8 were stable or improved in tests of cognition. Two showed improvement in P-tau and ß-amyloid levels. Of the 6 MS-P patients all are stable or improved. Four of 6 ALS patients died of disease progression. Twelve of 111 injections (11%) led to 1-4 days of transient meningismus, and mild temperature elevation, which resolved with acetaminophen and/or dexamethasone. Two (1.8% of injections) required hospitalization for these symptoms. One patient (0.9% of injections) had his reservoir removed and later replaced for presumed infection. In this Phase 1 safety trial, ADSVF was safely injected into the human brain ventricular system in patients with no other treatment options. Secondary endpoints of clinical improvement or stability were particularly promising in the AD and MS-P groups. These results will be submitted for a Phase 2 FDA-approved trial.}, }
@article {pmid31327044, year = {2019}, author = {Cali, CP and Patino, M and Tai, YK and Ho, WY and McLean, CA and Morris, CM and Seeley, WW and Miller, BL and Gaig, C and Vonsattel, JPG and White, CL and Roeber, S and Kretzschmar, H and Troncoso, JC and Troakes, C and Gearing, M and Ghetti, B and Van Deerlin, VM and Lee, VM and Trojanowski, JQ and Mok, KY and Ling, H and Dickson, DW and Schellenberg, GD and Ling, SC and Lee, EB}, title = {C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy.}, journal = {Acta neuropathologica}, volume = {138}, number = {5}, pages = {795-811}, pmid = {31327044}, issn = {1432-0533}, support = {R25 GM071745/GM/NIGMS NIH HHS/United States ; P01 AG017586/NH/NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; MR/L016397/1/MRC_/Medical Research Council/United Kingdom ; P30 AG012300/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; U19 AG062418/AG/NIA NIH HHS/United States ; G0400074/MRC_/Medical Research Council/United Kingdom ; UG3 NS104095/NS/NINDS NIH HHS/United States ; U54 NS100693/NS/NINDS NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; P50 AG005146/AG/NIA NIH HHS/United States ; P01 AG017586/AG/NIA NIH HHS/United States ; R01 NS095793/NS/NINDS NIH HHS/United States ; P50 NS038377/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics ; Amyotrophic Lateral Sclerosis/pathology ; Autophagy/*genetics ; Basal Ganglia Diseases/genetics ; Brain/*pathology ; C9orf72 Protein/*genetics ; Frontotemporal Dementia/genetics ; Humans ; Neurodegenerative Diseases/*genetics ; Parkinson Disease/genetics ; Parkinsonian Disorders/genetics ; }, abstract = {Microsatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions in C9orf72 (100s-1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Parkinson's disease patients, but the association was not found in autopsy-confirmed cases. We hypothesized that intermediate C9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson's but has distinct tau protein pathology. Indeed, intermediate C9orf72 repeats were significantly enriched in autopsy-proven CBD (n = 354 cases, odds ratio = 3.59, p = 0.00024). While large C9orf72 repeat expansions are known to decrease C9orf72 expression, intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC-derived neural progenitor cells. In contrast to cases of FTD/ALS with large C9orf72 expansions, CBD with intermediate C9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionally, overexpression of C9orf72 without the repeat expansion leads to defects in autophagy under nutrient starvation conditions. These results raise the possibility that therapeutic strategies to reduce C9orf72 expression may be beneficial for the treatment of CBD.}, }
@article {pmid31322097, year = {2019}, author = {Nugent, K and Matthews, P and Gissendaner, J and Papas, M and Occident, D and Patel, A and Johnson, M and Megargel, RE and Nomura, JT}, title = {A Comparison of Efficacy of Treatment and Time to Administration of Naloxone by BLS and ALS Providers.}, journal = {Prehospital and disaster medicine}, volume = {34}, number = {4}, pages = {350-355}, doi = {10.1017/S1049023X19004527}, pmid = {31322097}, issn = {1945-1938}, mesh = {Adult ; Advanced Cardiac Life Support/*methods ; Aged ; Cardiopulmonary Resuscitation/*methods ; Chi-Square Distribution ; Emergency Medical Services/*methods ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Naloxone/*administration &amp; dosage/adverse effects ; Narcotic Antagonists/*administration &amp; dosage/adverse effects ; Opioid-Related Disorders/*therapy ; Patient Safety ; Pilot Projects ; Retrospective Studies ; Risk Assessment ; Treatment Outcome ; United States ; Young Adult ; }, abstract = {INTRODUCTION: The administration of naloxone therapy is restricted by scope of practice to Advanced Life Support (ALS) in many Emergency Medical Services (EMS) systems throughout the United States. In Delaware's two-tiered EMS system, Basic Life Support (BLS) often arrives on-scene prior to ALS, but BLS providers were not previously authorized to administer naloxone. Through a BLS naloxone pilot study, the researchers sought to evaluate BLS naloxone administration and timing compared to ALS.<br><br>HYPOTHESIS: After undergoing specialized training, BLS providers would be able to appropriately administer naloxone to opioid overdose patients in a more timely manner than ALS providers.<br><br>METHODS: This was a retrospective, observational study using data collected from February 2014 through May 2015 throughout a state BLS naloxone pilot program. A total of 14 out of 72 state BLS agencies participated in the study. Pilot BLS agencies attended a training session on the indications and administration of naloxone, and then were authorized to carry and administer naloxone. Researchers then compared vital signs and the time of BLS arrival to administration of naloxone by BLS and ALS. Data were analyzed using paired and independent sample t-tests, as well as chi-square, as appropriate.<br><br>RESULTS: A total of 131 incidents of naloxone administration were reviewed. Of those, 62 patients received naloxone by BLS (pilot group) and 69 patients received naloxone by ALS (control group). After naloxone administration, BLS patients showed improvements in heart rate (HR; P < .01), respiratory rate (RR; P < .01), and pulse oximetry (spO2; P < .01); ALS patients also showed improvement in RR (P < .01), and in spO2 (P = .005). There was no significant improvement in HR for ALS providers (P = .189).There was a significant difference in arrival time of BLS to the time of naloxone administration between the two groups, with shorter times in the BLS group compared to the ALS group (1.9 minutes versus 9.8 minutes; P < .01); BLS administration was 7.8 minutes faster when compared to ALS administration (95% CI, 6.2-9.3 minutes).<br><br>CONCLUSIONS: Patients improved similarly and received naloxone therapy sooner when treated by BLS agencies carrying naloxone than those who awaited ALS arrival. All EMS systems should consider allowing BLS to carry and administer naloxone for an effective and potentially faster naloxone administration when treating respiratory compromise related to opiate overdose.}, }
@article {pmid31321663, year = {2019}, author = {Zhao, Z and Fu, J and Li, S and Li, Z}, title = {Neuroprotective Effects of Genistein in a SOD1-G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {14}, number = {4}, pages = {688-696}, pmid = {31321663}, issn = {1557-1904}, support = {None//Inter Funding Source/International ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics/*prevention &amp; control ; Animals ; *Disease Models, Animal ; Female ; Genistein/*therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuroprotective Agents/*therapeutic use ; Phytoestrogens/therapeutic use ; Superoxide Dismutase/*genetics ; }, abstract = {Oxidant toxicity has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), an insidiously progressive neurodegenerative disorder involving upper and lower motor neurons. Here, we investigated the cellular and molecular mechanisms underlying the neuroprotective effects of an anti-oxidant genistein in SOD1-G93A transgenic mouse model of ALS. Rotarod test, hanging wire test and hindlimb clasping test were used to determined disease onset and assess motor performance. Immunostaining together with neuronal size measurement were used to count viable motor neurons. In addition, immunostaining procedure and ELISA kit were used to assess the inflammatory response in the spinal cord. Our results showed that Genistein administration suppressed the production of pro-inflammatory cytokines and alleviated gliosis in the spinal cord of SOD1-G93A mice. In addition, genistein administration induced autophagic processes and enhanced the viability of spinal motor neurons. As a result, genistein alleviated ALS-related symptoms and slightly prolonged the lifespan of SOD1-G93A mice. Taken together, our results indicate that genistein is neuroprotective in SOD1-G93A mice, suggesting genistein could be a promising treatment for human ALS. Graphical Abstract Genistein protects impariments in SOD1-G93A transgenic mouse model.}, }
@article {pmid31318169, year = {2020}, author = {Shang, HY and Zhang, JJ and Fu, ZF and Liu, YF and Li, S and Chen, S and Le, WD}, title = {Therapeutic effects of hirsutella sinensis on the disease onset and progression of amyotrophic lateral sclerosis in SOD1[G93A] transgenic mouse model.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {26}, number = {1}, pages = {90-100}, pmid = {31318169}, issn = {1755-5949}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics ; Animals ; Astrocytes/drug effects/pathology ; Cell Survival/drug effects ; *Cordyceps ; Cytokines/metabolism ; Encephalitis/drug therapy/etiology ; Humans ; Life Expectancy ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/pathology ; Motor Activity ; Motor Neurons/pathology ; Muscle, Skeletal/pathology ; Postural Balance ; Spinal Cord/pathology ; Superoxide Dismutase-1/*genetics ; }, abstract = {AIMS: Although the pathophysiology of amyotrophic lateral sclerosis (ALS) is still not completely understood, the deregulated microglia polarization and neuroinflammation have been shown to contribute to the pathogenesis and progression of this disease. In the present study, we aimed to determine whether hirsutella sinensis (HS) could reduce neuroinflammatory and pathological changes in the spinal cord of SOD1[G93A] model mice of ALS and consequently ameliorate disease onset and progression.<br><br>METHODS: SOD1[G93A] mice were chronically treated with HS by gavage. Their lifespan was recorded, and motor behavior was evaluated by rotarod test. The pathological changes in skeletal muscles and motor neurons in spinal cords were assessed by immunofluorescent staining and hematoxylin-eosin staining. The microglia activation and neuroinflammation were determined by immunofluorescent staining and RT-PCR.<br><br>RESULTS: Our data suggested that repeated HS administration prolonged the lifespan and extended disease duration of ALS mice without significant delay on disease onset. HS ameliorated the pathological changes in the motor neurons and gastrocnemius muscles. Moreover, HS promoted the transition of microglia from pro-inflammatory M1 to anti-inflammatory M2 phenotype in the spinal cord of ALS mice.<br><br>CONCLUSION: All these findings indicate that HS may serve as a potential therapeutic candidate for the treatment of ALS.}, }
@article {pmid31310593, year = {2019}, author = {Shi, Y and Hung, ST and Rocha, G and Lin, S and Linares, GR and Staats, KA and Seah, C and Wang, Y and Chickering, M and Lai, J and Sugawara, T and Sagare, AP and Zlokovic, BV and Ichida, JK}, title = {Identification and therapeutic rescue of autophagosome and glutamate receptor defects in C9ORF72 and sporadic ALS neurons.}, journal = {JCI insight}, volume = {5}, number = {15}, pages = {}, pmid = {31310593}, issn = {2379-3708}, support = {R01 NS097850/NS/NINDS NIH HHS/United States ; R01 NS090904/NS/NINDS NIH HHS/United States ; UM1 HG006493/HG/NHGRI NIH HHS/United States ; U24 HG008956/HG/NHGRI NIH HHS/United States ; T32 HD060549/HD/NICHD NIH HHS/United States ; R37 AG023084/AG/NIA NIH HHS/United States ; S10 OD021553/OD/NIH HHS/United States ; R00 NS077435/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/immunology/pathology ; Animals ; Autophagosomes/*drug effects/immunology ; Autophagy/genetics ; C9orf72 Protein/genetics/metabolism ; CHO Cells ; Cells, Cultured ; Cricetulus ; Disease Models, Animal ; Female ; Gain of Function Mutation ; Humans ; Induced Pluripotent Stem Cells ; Loss of Function Mutation ; Lymphocytes ; Male ; Mice ; Middle Aged ; Motor Neurons/*drug effects/immunology/pathology ; Primary Cell Culture ; Protein C/*administration &amp; dosage/genetics ; Proteostasis/drug effects/immunology ; Receptor, PAR-1/agonists/metabolism ; Receptors, Glutamate/metabolism ; Recombinant Proteins/administration &amp; dosage/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with diverse etiologies. Therefore, the identification of common disease mechanisms and therapeutics targeting these mechanisms could dramatically improve clinical outcomes. To this end, we developed induced motor neuron (iMN) models from C9ORF72 and sporadic ALS (sALS) patients to identify targets that are effective against these types of cases, which together comprise ~90% of patients. We find that iMNs from C9ORF72 and several sporadic ALS patients share two common defects - impaired autophagosome formation and the aberrant accumulation of glutamate receptors. Moreover, we show that an anticoagulation-deficient form of activated protein C, 3K3A-APC, rescues these defects in both C9ORF72 and sporadic ALS iMNs. As a result, 3K3A-APC treatment lowers C9ORF72 dipeptide repeat protein (DPR) levels, restores nuclear TDP-43 localization, and rescues the survival of both C9ORF72 and sporadic ALS iMNs. Importantly, 3K3A-APC also lowers glutamate receptor levels and rescues proteostasis in vivo in C9ORF72 gain- and loss-of-function mouse models. Thus, motor neurons from C9ORF72 and at least a subset of sporadic ALS patients share common, early defects in autophagosome formation and glutamate receptor homeostasis and a single therapeutic approach may be efficacious against these disease processes.}, }
@article {pmid31300701, year = {2019}, author = {Ikenaka, K and Tsukada, Y and Giles, AC and Arai, T and Nakadera, Y and Nakano, S and Kawai, K and Mochizuki, H and Katsuno, M and Sobue, G and Mori, I}, title = {A behavior-based drug screening system using a Caenorhabditis elegans model of motor neuron disease.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {10104}, pmid = {31300701}, issn = {2045-2322}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Caenorhabditis elegans/drug effects/genetics ; Caenorhabditis elegans Proteins/genetics ; Disease Models, Animal ; Drug Evaluation, Preclinical/*methods ; Dynactin Complex/genetics ; Humans ; Motor Neurons/pathology ; Neuroprotective Agents/*pharmacology ; Nifedipine/*pharmacology ; Riluzole/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, for which there is no effective treatment. Previously, we generated a Caenorhabditis elegans model of ALS, in which the expression of dnc-1, the homologous gene of human dynactin-1, is knocked down (KD) specifically in motor neurons. This dnc-1 KD model showed progressive motor defects together with axonal and neuronal degeneration, as observed in ALS patients. In the present study, we established a behavior-based, automated, and quantitative drug screening system using this dnc-1 KD model together with Multi-Worm Tracker (MWT), and tested whether 38 candidate neuroprotective compounds could improve the mobility of the dnc-1 KD animals. We found that 12 compounds, including riluzole, which is an approved medication for ALS patients, ameliorated the phenotype of the dnc-1 KD animals. Nifedipine, a calcium channel blocker, most robustly ameliorated the motor deficits as well as axonal degeneration of dnc-1 KD animals. Nifedipine also ameliorated the motor defects of other motor neuronal degeneration models of C. elegans, including dnc-1 mutants and human TAR DNA-binding protein of 43 kDa overexpressing worms. Our results indicate that dnc-1 KD in C. elegans is a useful model for the screening of drugs against motor neuron degeneration, and that MWT is a powerful tool for the behavior-based screening of drugs.}, }
@article {pmid31290185, year = {2019}, author = {Kim, S and Chung, AY and Na, JE and Lee, SJ and Jeong, SH and Kim, E and Sun, W and Rhyu, IJ and Park, HC}, title = {Myelin degeneration induced by mutant superoxide dismutase 1 accumulation promotes amyotrophic lateral sclerosis.}, journal = {Glia}, volume = {67}, number = {10}, pages = {1910-1921}, doi = {10.1002/glia.23669}, pmid = {31290185}, issn = {1098-1136}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*enzymology/pathology ; Animals ; Animals, Genetically Modified ; Cell Death/drug effects/physiology ; Disease Models, Animal ; Humans ; Monocarboxylic Acid Transporters/metabolism ; Motor Neurons/drug effects/enzymology/pathology ; Myelin Sheath/drug effects/*enzymology/pathology ; Nerve Degeneration/drug therapy/*metabolism/pathology ; Neuroprotective Agents/pharmacology ; Potassium Channel Blockers/pharmacology ; Superoxide Dismutase-1/genetics/*metabolism ; Zebrafish ; Zebrafish Proteins/metabolism ; }, abstract = {Myelin is a specialized membrane that wraps around nerve fibers and is essential for normal axonal conduction in neurons. In the central nervous system, oligodendrocytes are responsible for myelin formation. Recent studies have reported pathological abnormalities in oligodendrocytes in human patients with amyotrophic lateral sclerosis (ALS) and a mouse model of ALS expressing the G93A mutation of the human superoxide dismutase 1 (mtSOD1). However, it is unclear whether oligodendrocyte pathology in ALS represents the primary dysfunction induced by mtSOD1 and how mtSOD1 contributes to oligodendrocyte degeneration and ALS pathogenesis. We analyzed GAL4-VP16-UAS transgenic zebrafish selectively expressing mtSOD1 in mature oligodendrocytes. We observed that mtSOD1 directly induced oligodendrocyte degeneration by disrupting the myelin sheath and downregulating monocarboxylate transporter 1 (MCT1), thereby causing spinal motor neuron degeneration. Pathological changes observed in this transgenic zebrafish were similar to the pathology observed in the SOD1[G93A] mouse model of ALS, which is characterized by expression of mtSOD1 in all cells. In addition, oligodendrocyte dysfunction induced by mtSOD1 was associated with anxiety-related behavioral abnormalities, learning impairments, and motor defects in the early symptomatic stage. We also found that treatment with potassium channel inhibitors rescued behavioral abnormalities without rescuing MCT1 expression, suggesting that myelin disruption induces behavioral abnormalities independently of MCT1. These results indicate that mtSOD1-induced dysfunction of mature oligodendrocytes is sufficient to induce motor neuron degeneration, thus informing future therapeutic strategies targeted at oligodendrocytes in ALS.}, }
@article {pmid31287226, year = {2019}, author = {Ozanne, A and Sawatzky, R and Håkanson, C and Alvariza, A and Fürst, CJ and Årestedt, K and Öhlén, J}, title = {Symptom relief during last week of life in neurological diseases.}, journal = {Brain and behavior}, volume = {9}, number = {8}, pages = {e01348}, pmid = {31287226}, issn = {2162-3279}, mesh = {Adult ; *Central Nervous System Neoplasms/physiopathology/psychology/therapy ; Emotional Adjustment ; Female ; Humans ; Male ; Middle Aged ; *Motor Neuron Disease/physiopathology/psychology/therapy ; *Nervous System Diseases/physiopathology/psychology/therapy ; *Pain/epidemiology/etiology ; Pain Measurement ; *Palliative Care/methods/psychology ; Prevalence ; Sweden/epidemiology ; Symptom Assessment ; *Terminal Care/methods/psychology ; }, abstract = {OBJECTIVES: The aim of this study was to investigate symptom prevalence, symptom relief, and palliative care indicators during the last week of life, comparing them for patients with motor neuron disease (MND), central nervous system tumors (CNS tumor), and other neurological diseases (OND).<br><br>MATERIAL &amp; METHODS: Data were obtained from the Swedish Register for Palliative Care, which documents care during the last week of life. Logistic regression was used to compare patients with MND (n&#xa0;=&#xa0;419), CNS tumor (n&#xa0;=&#xa0;799), and OND (n&#xa0;=&#xa0;1,407) as the cause of death.<br><br>RESULTS: The most prevalent symptoms for all neurological disease groups were pain (52.7% to 72.2%) and rattles (58.1% to 65.6%). Compared to MND and OND, patients with CNS tumors were more likely to have totally relieved pain, shortness of breath, rattles, and anxiety. They were also more likely to have their pain assessed with a validated tool; to receive symptom treatment for anxiety, nausea, rattles, and pain; to have had family members receive end-of-life discussions; to have someone present at death; and to have had their family members offered bereavement support. Both patients with CNS tumor and MND were more likely than patients with OND to receive consultation with a pain unit and to have had end-of-life discussions.<br><br>CONCLUSIONS: The study reveals high symptom burden and differences in palliative care between the groups during the last week of life. There is a need for person-centered care planning based on a palliative approach, focused on improving symptom assessments, relief, and end-of-life conversations.}, }
@article {pmid31284774, year = {2019}, author = {Gold, J and Rowe, DB and Kiernan, MC and Vucic, S and Mathers, S and van Eijk, RPA and Nath, A and Garcia Montojo, M and Norato, G and Santamaria, UA and Rogers, ML and Malaspina, A and Lombardi, V and Mehta, PR and Westeneng, HJ and van den Berg, LH and Al-Chalabi, A}, title = {Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the Lighthouse trial.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {7-8}, pages = {595-604}, doi = {10.1080/21678421.2019.1632899}, pmid = {31284774}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Biomarkers/analysis ; Cohort Studies ; Dideoxynucleosides/adverse effects/*pharmacology ; Disease Progression ; Drug Combinations ; Female ; Heterocyclic Compounds, 3-Ring/adverse effects/*pharmacology ; Humans ; Lamivudine/adverse effects/*pharmacology ; Male ; Middle Aged ; Oxazines ; Piperazines ; Pyridones ; Young Adult ; }, abstract = {Background: Neuroinflammation and human endogenous retroviruses (HERV) are thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Therapy directed against endogenous retroviruses has demonstrated positive effects during in vitro and biomarker studies. Consequently, the present study was undertaken to assess the safety and tolerability of long-term antiretroviral therapy (ART), Triumeq (abacavir, lamivudine, and dolutegravir) exposure in patients with ALS, and efficacy against biomarkers of disease progression. Methods: Patients were observed during a 10-week lead-in period before receiving Triumeq treatment for 24 weeks at four specialist ALS centers. The primary outcomes were safety and tolerability. Secondary outcomes included HERV-K expression levels, urinary p75[ECD] levels, neurophysiological parameters, and clinical indicators. The ENCALS prediction model was applied to provide an estimate of the cohort survival. The trial was registered (NCT02868580). Findings: 40 patients with ALS received Triumeq and 35 (88%) completed treatment. There were no drug-related serious adverse events; one patient was withdrawn from the study due to a drug-associated increase in liver enzymes. A favorable response on HERV-K expression levels was observed, accompanied by a decline in ALSFRS-R progression rate of 21.8% (95% CI -4.8%-48.6%) and the amount of urinary p75[ECD] measured. One patient died five months after stopping treatment, while five were expected to have died during the treatment period (interquartile range 2-8). Interpretation: Long-term Triumeq exposure was safe and well tolerated in this cohort. There was suggestive indication for a possible biological response in some pharmacodynamic and clinical biomarkers. A larger international phase 3 trial will be deployed to assess the effect of Triumeq on overall survival and disease progression. Funding: Funding was provided by the FightMND Foundation; MND Research Institute of Australia; MND Association, United Kingdom, and GSK. ViiV Healthcare provided the Triumeq.}, }
@article {pmid31283931, year = {2019}, author = {Weber, JJ and Clemensson, LE and Schiöth, HB and Nguyen, HP}, title = {Olesoxime in neurodegenerative diseases: Scrutinising a promising drug candidate.}, journal = {Biochemical pharmacology}, volume = {168}, number = {}, pages = {305-318}, doi = {10.1016/j.bcp.2019.07.002}, pmid = {31283931}, issn = {1873-2968}, mesh = {Animals ; Calcium/metabolism ; Calpain/metabolism ; Cholestenones/chemistry/*pharmacology/*therapeutic use ; Cholesterol/metabolism ; Homeostasis/drug effects ; Humans ; Mice ; Mitochondria/drug effects/metabolism ; Mitochondrial Transmembrane Permeability-Driven Necrosis/drug effects ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/chemistry/*pharmacology/*therapeutic use ; Oxidative Stress/drug effects ; Rats ; }, abstract = {Over the last years, the experimental compound olesoxime, a mitochondria-targeting cholesterol derivative, has emerged as a promising drug candidate for neurodegenerative diseases. Numerous preclinical studies have successfully proved olesoxime's neuroprotective properties in cell and animal models of clinical conditions such as amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, peripheral neuropathy and spinal muscular atrophy. The beneficial effects were attributed to olesoxime's potential impact on oxidative stress, mitochondrial permeability transition or cholesterol homoeostasis. Although no significant benefits have been demonstrated in patients of amyotrophic lateral sclerosis, and only the first 12 months of a phase II/III clinical trial showed an improvement in motor symptoms of spinal muscular atrophy, this orphan drug may still offer undiscovered potential in the treatment of neurological diseases. In our earlier preclinical studies, we demonstrated that administration of olesoxime in mouse and rat models of Huntington disease improved psychiatric and molecular phenotypes. Aside from stabilising mitochondrial function, the drug reduced the overactivation of calpains, a class of calcium-dependent proteases entangled in neurodegenerative conditions. This observation may be credited to olesoxime's action on calcium dyshomeostasis, a further hallmark in neurodegeneration, and linked to its targets TSPO and VDAC, two proteins of the outer mitochondrial membrane associated with mitochondrial calcium handling. Further research into the mode of action of olesoxime under pathological conditions, including its effect on neuronal calcium homeostasis, may strengthen the untapped potential of olesoxime or other similar compounds as a therapeutic for neurodegenerative diseases.}, }
@article {pmid31283897, year = {2019}, author = {Bennett, CF and Krainer, AR and Cleveland, DW}, title = {Antisense Oligonucleotide Therapies for Neurodegenerative Diseases.}, journal = {Annual review of neuroscience}, volume = {42}, number = {}, pages = {385-406}, pmid = {31283897}, issn = {1545-4126}, support = {R37 GM042699/GM/NIGMS NIH HHS/United States ; R01 NS027036/NS/NINDS NIH HHS/United States ; R01 GM042699/GM/NIGMS NIH HHS/United States ; P01 CA013106/CA/NCI NIH HHS/United States ; R01 NS112503/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain/metabolism/pathology ; Humans ; Muscular Atrophy, Spinal/*drug therapy ; Neurodegenerative Diseases/*drug therapy/genetics ; Oligonucleotides/*pharmacology ; Oligonucleotides, Antisense/*therapeutic use ; Tissue Distribution/*genetics ; }, abstract = {Antisense oligonucleotides represent a novel therapeutic platform for the discovery of medicines that have the potential to treat most neurodegenerative diseases. Antisense drugs are currently in development for the treatment of amyotrophic lateral sclerosis, Huntington's disease, and Alzheimer's disease, and multiple research programs are underway for additional neurodegenerative diseases. One antisense drug, nusinersen, has been approved for the treatment of spinal muscular atrophy. Importantly, nusinersen improves disease symptoms when administered to symptomatic patients rather than just slowing the progression of the disease. In addition to the benefit to spinal muscular atrophy patients, there are discoveries from nusinersen that can be applied to other neurological diseases, including method of delivery, doses, tolerability of intrathecally delivered antisense drugs, and the biodistribution of intrathecal dosed antisense drugs. Based in part on the early success of nusinersen, antisense drugs hold great promise as a therapeutic platform for the treatment of neurological diseases.}, }
@article {pmid31280619, year = {2020}, author = {Mora, JS and Genge, A and Chio, A and Estol, CJ and Chaverri, D and Hernández, M and Marín, S and Mascias, J and Rodriguez, GE and Povedano, M and Paipa, A and Dominguez, R and Gamez, J and Salvado, M and Lunetta, C and Ballario, C and Riva, N and Mandrioli, J and Moussy, A and Kinet, JP and Auclair, C and Dubreuil, P and Arnold, V and Mansfield, CD and Hermine, O and , }, title = {Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {21}, number = {1-2}, pages = {5-14}, doi = {10.1080/21678421.2019.1632346}, pmid = {31280619}, issn = {2167-9223}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Benzamides ; Disease Progression ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Piperidines ; Pyridines ; Riluzole/*therapeutic use ; Thiazoles/*therapeutic use ; Treatment Outcome ; Young Adult ; }, abstract = {Objective: To assess masitinib in the treatment of ALS. Methods: Double-blind study, randomly assigning 394 patients (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg/d. Following a blinded transition from phase 2 to phase 2/3, a prospectively defined two-tiered design was implemented based on ALSFRS-R progression rate from disease-onset to baseline (ΔFS). This approach selects a more homogeneous primary efficacy population ("Normal Progressors", ΔFS < 1.1 points/month) while concurrently permitting secondary assessment of the broader population. Primary endpoint was decline in ALSFRS-R at week-48 (ΔALSFRS-R), with the high-dose "Normal Progressor" cohort being the prospectively declared primary efficacy population. Missing data were imputed via last observation carried forward (LOCF) methodology with sensitivity analyses performed to test robustness. Results: For the primary efficacy population, masitinib (n = 99) showed significant benefit over placebo (n = 102) with a ΔALSFRS-R between-group difference (ΔLSM) of 3.4 (95% CI 0.65-6.13; p = 0.016), corresponding to a 27% slowing in rate of functional decline (LOCF methodology). Sensitivity analyses were all convergent, including the conservative multiple imputation technique of FCS-REGPMM with a ΔLSM of 3.4 (95% CI 0.53-6.33; p = 0.020). Secondary endpoints (ALSAQ-40, FVC, and time-to-event analysis) were also significant. Conversely, no significant treatment-effect according to ΔALSFRS-R was seen for the broader "Normal and Fast Progressor" masitinib 4.5 mg/kg/d cohort, or either of the low-dose (masitinib 3.0 mg/kg/d) cohorts. Rates of treatment-emergent adverse events (AEs) (regardless of causality or post-onset ΔFS) were 88% with masitinib 4.5 mg/kg/d, 85% with 3.0 mg/kg/d, and 79% with placebo. Likewise, rates of serious AE were 31, 23, and 18%, respectively. No distinct event contributed to the higher rate observed for masitinib and no deaths were related to masitinib. Conclusions: Results show that masitinib at 4.5 mg/kg/d can benefit patients with ALS. A confirmatory phase 3 study will be initiated to substantiate these data.}, }
@article {pmid31277703, year = {2019}, author = {Rossaert, E and Pollari, E and Jaspers, T and Van Helleputte, L and Jarpe, M and Van Damme, P and De Bock, K and Moisse, M and Van Den Bosch, L}, title = {Restoration of histone acetylation ameliorates disease and metabolic abnormalities in a FUS mouse model.}, journal = {Acta neuropathologica communications}, volume = {7}, number = {1}, pages = {107}, pmid = {31277703}, issn = {2051-5960}, support = {G.0431.12N and G.0440.12N//Fund for Scientific Research Flanders/International ; P7/16//Interuniversity Attraction Poles Programme/International ; 577668//Muscular Dystrophy Association/International ; FP7/2007-2013//European Community's Health Seventh Framework Programme/International ; 14-LGCA-181//Amyotrophic Lateral Sclerosis Association/International ; }, mesh = {Acetylation/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy/genetics/*metabolism ; Animals ; *Disease Models, Animal ; Female ; Histone Deacetylase Inhibitors/pharmacology/*therapeutic use ; Histones/genetics/*metabolism ; Humans ; Hydroxamic Acids/pharmacology/therapeutic use ; Male ; Metabolomics/*methods ; Mice ; Mice, Transgenic ; Pyrimidines/pharmacology/therapeutic use ; RNA-Binding Protein FUS/*biosynthesis/genetics ; Random Allocation ; }, abstract = {Dysregulation of epigenetic mechanisms is emerging as a central event in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). In many models of neurodegeneration, global histone acetylation is decreased in the affected neuronal tissues. Histone acetylation is controlled by the antagonistic actions of two protein families -the histone acetyltransferases (HATs) and the histone deacetylases (HDACs). Drugs inhibiting HDAC activity are already used in the clinic as anti-cancer agents. The aim of this study was to explore the therapeutic potential of HDAC inhibition in the context of ALS. We discovered that transgenic mice overexpressing wild-type FUS ("Tg FUS+/+"), which recapitulate many aspects of human ALS, showed reduced global histone acetylation and alterations in metabolic gene expression, resulting in a dysregulated metabolic homeostasis. Chronic treatment of Tg FUS+/+ mice with ACY-738, a potent HDAC inhibitor that can cross the blood-brain barrier, ameliorated the motor phenotype and substantially extended the life span of the Tg FUS+/+ mice. At the molecular level, ACY-738 restored global histone acetylation and metabolic gene expression, thereby re-establishing metabolite levels in the spinal cord. Taken together, our findings link epigenetic alterations to metabolic dysregulation in ALS pathology, and highlight ACY-738 as a potential therapeutic strategy to treat this devastating disease.}, }
@article {pmid31272349, year = {2019}, author = {Lushington, GH and Barnes, AC}, title = {Protein Glycation: An Old Villain is Shedding Secrets.}, journal = {Combinatorial chemistry &amp; high throughput screening}, volume = {22}, number = {6}, pages = {362-369}, doi = {10.2174/1386207322666190704094356}, pmid = {31272349}, issn = {1875-5402}, mesh = {Glycosylation ; Humans ; Proteins/chemistry/*metabolism ; }, abstract = {The glycation of proteins is non-physiological post-translational incorporation of carbohydrates onto the free amines or guanidines of proteins and some lipids. Although the existence of glycated proteins has been known for forty years, a full understanding of their pathogenic nature has been slow in accruing. In recent years, however, glycation has gained widespread acceptance as a contributing factor in numerous metabolic, autoimmune, and neurological disorders, tying together several confounding aspects of disease etiology. From diabetes, arthritis, and lupus, to multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's diseases, an emerging glycation/inflammation paradigm now offers significant new insight into a physiologically important toxicological phenomenon. It exposes novel drug targets and treatment options, and may even lay foundations for long-awaited breakthroughs. This 'current frontier' article briefly profiles current knowledge regarding the underlying causes of glycation, the structural biology implications of such modifications, and their pathological consequences. Although several emerging therapeutic strategies for addressing glycation pathologies are introduced, the primary purpose of this mini-review is to raise awareness of the challenges and opportunities inherent in this emerging new medicinal target area.}, }
@article {pmid31270933, year = {2019}, author = {Huber, C and Benda, N and Friede, T}, title = {A comparison of subgroup identification methods in clinical drug development: Simulation study and regulatory considerations.}, journal = {Pharmaceutical statistics}, volume = {18}, number = {5}, pages = {600-626}, pmid = {31270933}, issn = {1539-1612}, mesh = {Algorithms ; Amyotrophic Lateral Sclerosis/drug therapy ; Biomarkers/metabolism ; *Computer Simulation ; Data Interpretation, Statistical ; Drug Development/*methods ; Humans ; *Models, Statistical ; Precision Medicine/*methods ; Research Design ; Sample Size ; Sensitivity and Specificity ; }, abstract = {With advancement of technologies such as genomic sequencing, predictive biomarkers have become a useful tool for the development of personalized medicine. Predictive biomarkers can be used to select subsets of patients, which are most likely to benefit from a treatment. A number of approaches for subgroup identification were proposed over the last years. Although overviews of subgroup identification methods are available, systematic comparisons of their performance in simulation studies are rare. Interaction trees (IT), model-based recursive partitioning, subgroup identification based on differential effect, simultaneous threshold interaction modeling algorithm (STIMA), and adaptive refinement by directed peeling were proposed for subgroup identification. We compared these methods in a simulation study using a structured approach. In order to identify a target population for subsequent trials, a selection of the identified subgroups is needed. Therefore, we propose a subgroup criterion leading to a target subgroup consisting of the identified subgroups with an estimated treatment difference no less than a pre-specified threshold. In our simulation study, we evaluated these methods by considering measures for binary classification, like sensitivity and specificity. In settings with large effects or huge sample sizes, most methods perform well. For more realistic settings in drug development involving data from a single trial only, however, none of the methods seems suitable for selecting a target population. Using the subgroup criterion as alternative to the proposed pruning procedures, STIMA and IT can improve their performance in some settings. The methods and the subgroup criterion are illustrated by an application in amyotrophic lateral sclerosis.}, }
@article {pmid31266172, year = {2019}, author = {Marvulli, R and Megna, M and Citraro, A and Vacca, E and Napolitano, M and Gallo, G and Fiore, P and Ianieri, G}, title = {Botulinum Toxin Type A and Physiotherapy in Spasticity of the Lower Limbs Due to Amyotrophic Lateral Sclerosis.}, journal = {Toxins}, volume = {11}, number = {7}, pages = {}, pmid = {31266172}, issn = {2072-6651}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy/*rehabilitation ; Botulinum Toxins, Type A/*therapeutic use ; Female ; Humans ; Lower Extremity ; Male ; Middle Aged ; Muscle Spasticity/*drug therapy/*rehabilitation ; Neuromuscular Agents/*therapeutic use ; *Physical Therapy Modalities ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease (unknown pathogenesis) of the central nervous system that causes death within 1-5 years. Clinically, flabby paralysis, areflexia, muscular atrophy, and muscle fasciculations, signs of II motor neuron damage, appear. Sometimes, clinical manifestations of damage of the I motor neuron come out in lower limbs; spastic paralysis, iperflexia, and clonus emerge, and they impair deambulation and management of activities of daily living, such as personal hygiene or dressing. Thus, the first therapeutic approach in these patients involves antispasmodic drugs orally followed by botulinum toxin type A injection (BTX-A). In this study, we study the efficacy of BTX-A and physiotherapy in lower limb spasticity due to ALS and no response to treatment with oral antispastic drugs. We evaluated 15 patients (10 male and five female), with a mean age of 48.06 ± 5.2 with spasticity of adductor magnus (AM), at baseline (T0, before BTX-A treatment) and in the following three follow-up visits (T1 30 days, T2 60 days, and T3 90 days after infiltration). We evaluated myometric measure of muscle tone, the Modified Ashworth Scale of AM, Barthel Index, Adductor Tone Rating Scale, and Hygiene Score. The study was conducted between November 2018 and April 2019. We treated AM with incobotulinum toxin type A (Xeomin[®], Merz). Spasticity (myometric measurement, Adductor Tone Rating Scale, and Modified Ashworth Scale) and clinical (Barthel Index and Hygiene Score) improvements were obtained for 90 days after injection (p < 0.05). Our study shows the possibility of using BTX-A in the treatment of spasticity in patients with ALS and no response to oral antispastic drugs, with no side effects. The limitation of the study is the small number of patients and the limited time of observation; therefore, it is important to increase both the number of patients and the observation time in future studies.}, }
@article {pmid31258624, year = {2019}, author = {Dorst, J and Ludolph, AC}, title = {Non-invasive ventilation in amyotrophic lateral sclerosis.}, journal = {Therapeutic advances in neurological disorders}, volume = {12}, number = {}, pages = {1756286419857040}, pmid = {31258624}, issn = {1756-2856}, abstract = {Non-invasive ventilation (NIV) has become an important cornerstone of symptomatic treatment in amyotrophic lateral sclerosis (ALS), improving survival and quality of life. In this review, we summarize the most important recent developments and insights, including evidence of efficacy, indication criteria and time of initiation, ventilation parameters and adaptation strategies, treatment of complicating factors, transition from NIV to invasive ventilation, termination of NIV and end-of-life management. Recent publications have questioned former conventions and guideline recommendations, especially with regard to timing and prognostic factors; therefore, a fresh look and re-evaluation of current evidence is needed.}, }
@article {pmid31257384, year = {2019}, author = {El Khoury, Y and Collongues, N and De Sèze, J and Gulsari, V and Patte-Mensah, C and Marcou, G and Varnek, A and Mensah-Nyagan, AG and Hellwig, P}, title = {Serum-based differentiation between multiple sclerosis and amyotrophic lateral sclerosis by Random Forest classification of FTIR spectra.}, journal = {The Analyst}, volume = {144}, number = {15}, pages = {4647-4652}, doi = {10.1039/c9an00754g}, pmid = {31257384}, issn = {1364-5528}, mesh = {Adult ; Aged ; Aged, 80 and over ; Algorithms ; Amyotrophic Lateral Sclerosis/*diagnosis/drug therapy ; Biomarkers/*blood ; Biotin/therapeutic use ; Decision Trees ; Diagnosis, Differential ; Female ; Humans ; Male ; Middle Aged ; Multiple Sclerosis/*diagnosis/drug therapy ; Pilot Projects ; Spectroscopy, Fourier Transform Infrared/methods ; }, abstract = {The challenging diagnosis and differentiation between multiple sclerosis and amyotrophic lateral sclerosis relies on the clinical assessment of the symptoms along with magnetic resonance imaging and sampling cerebrospinal fluid for the search of biomarkers for either disease. Despite the progress made in imaging techniques and biomarker identification, misdiagnosis still occurs. Here we used 2.5 μL of serum samples to obtain the infrared spectroscopic signatures of sera of multiple sclerosis and amyotrophic lateral sclerosis patients and compared them to those of healthy controls. The spectra are then classified with the help of a two-fold Random Forest cross-validation algorithm. This approach shows that infrared spectroscopy is powerful in discriminating between the two diseases and healthy controls by offering high specificity for multiple sclerosis (100%) and amyotrophic lateral sclerosis (98%). In addition, data after six and twelve months of treatment of the multiple sclerosis patients with biotin are discussed.}, }
@article {pmid31256630, year = {2019}, author = {Schoenfeld, DA and Finkelstein, DM and Macklin, E and Zach, N and Ennist, DL and Taylor, AA and Atassi, N and , }, title = {Design and analysis of a clinical trial using previous trials as historical control.}, journal = {Clinical trials (London, England)}, volume = {16}, number = {5}, pages = {531-538}, pmid = {31256630}, issn = {1740-7753}, support = {K23 NS083715/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/therapy ; Bayes Theorem ; Clinical Trials, Phase II as Topic/methods/statistics &amp; numerical data ; *Control Groups ; Humans ; Randomized Controlled Trials as Topic/*methods/statistics &amp; numerical data ; *Sample Size ; }, abstract = {BACKGROUND/AIMS: For single arm trials, a treatment is evaluated by comparing an outcome estimate to historically reported outcome estimates. Such a historically controlled trial is often analyzed as if the estimates from previous trials were known without variation and there is no trial-to-trial variation in their estimands. We develop a test of treatment efficacy and sample size calculation for historically controlled trials that considers these sources of variation.<br><br>METHODS: We fit a Bayesian hierarchical model, providing a sample from the posterior predictive distribution of the outcome estimand of a new trial, which, along with the standard error of the estimate, can be used to calculate the probability that the estimate exceeds a threshold. We then calculate criteria for statistical significance as a function of the standard error of the new trial and calculate sample size as a function of difference to be detected. We apply these methods to clinical trials for amyotrophic lateral sclerosis using data from the placebo groups of 16 trials.<br><br>RESULTS: We find that when attempting to detect the small to moderate effect sizes usually assumed in amyotrophic lateral sclerosis clinical trials, historically controlled trials would require a greater total number of patients than concurrently controlled trials, and only when an effect size is extraordinarily large is a historically controlled trial a reasonable alternative. We also show that utilizing patient level data for the prognostic covariates can reduce the sample size required for a historically controlled trial.<br><br>CONCLUSION: This article quantifies when historically controlled trials would not provide any sample size advantage, despite dispensing with a control group.}, }
@article {pmid31252669, year = {2019}, author = {Hosaka, T and Yamashita, T and Tamaoka, A and Kwak, S}, title = {Extracellular RNAs as Biomarkers of Sporadic Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {20}, number = {13}, pages = {}, pmid = {31252669}, issn = {1422-0067}, support = {16jm0310026h0004//Strategic International Collaborative Research Program/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*blood/genetics ; Animals ; Biomarkers/blood ; Cell-Free Nucleic Acids/*blood/genetics ; Humans ; RNA Editing ; }, abstract = {Recent progress in the research for underlying mechanisms in neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) has led to the development of potentially effective treatment, and hence increased the need for useful biomarkers that may enable early diagnosis and therapeutic monitoring. The deposition of abnormal proteins is a pathological hallmark of neurodegenerative diseases, including β-amyloid in AD, α-synuclein in PD, and the transactive response DNA/RNA binding protein of 43kDa (TDP-43) in ALS. Furthermore, progression of the disease process accompanies the spreading of abnormal proteins. Extracellular proteins and RNAs, including mRNA, micro RNA, and circular RNA, which are present as a composite of exosomes or other forms, play a role in cell-cell communication, and the role of extracellular molecules in the cell-to-cell spreading of pathological processes in neurodegenerative diseases is now in the spotlight. Therefore, extracellular proteins and RNAs are considered potential biomarkers of neurodegenerative diseases, in particular ALS, in which RNA dysregulation has been shown to be involved in the pathogenesis. Here, we review extracellular proteins and RNAs that have been scrutinized as potential biomarkers of neurodegenerative diseases, and discuss the possibility of extracellular RNAs as diagnostic and therapeutic monitoring biomarkers of sporadic ALS.}, }
@article {pmid31251338, year = {2019}, author = {Nainu, F and Salim, E and Asri, RM and Hori, A and Kuraishi, T}, title = {Neurodegenerative disorders and sterile inflammation: lessons from a Drosophila model.}, journal = {Journal of biochemistry}, volume = {166}, number = {3}, pages = {213-221}, doi = {10.1093/jb/mvz053}, pmid = {31251338}, issn = {1756-2651}, mesh = {Animals ; *Disease Models, Animal ; *Drosophila/immunology ; Inflammation/drug therapy/immunology/*metabolism ; Neurodegenerative Diseases/drug therapy/immunology/*metabolism ; }, abstract = {Central nervous system (CNS)-related disorders, including neurodegenerative diseases, are common but difficult to treat. As effective medical interventions are limited, those diseases will likely continue adversely affecting people's health. There is evidence that the hyperactivation of innate immunity is a hallmark of most neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and polyglutamine diseases. In mammalian and fly CNS, the presence of noninfectious ligands, including danger-associated molecular patterns, is recognized by (micro)glial cells, inducing the expression of proinflammatory cytokines. Such inflammation may contribute to the onset and progression of neurodegenerative states. Studies using fruit flies have shed light on the types of signals, receptors and cells responsible for inducing the inflammation that leads to neurodegeneration. Researchers are using fly models to assess the mechanisms of sterile inflammation in the brain and its link to progressive neurodegeneration. Given the similarity of its physiological system and biochemical function to those of mammals, especially in activating and regulating innate immune signalling, Drosophila can be a versatile model system for studying the mechanisms and biological significance of sterile inflammatory responses in the pathogenesis of neurodegenerative diseases. Such knowledge would greatly facilitate the quest for a novel effective treatment for neurodegenerative diseases.}, }
@article {pmid31245396, year = {2019}, author = {Gillespie, &#xcd; and Fletcher, DJ and Stevenson, MA and Boller, M}, title = {The Compliance of Current Small Animal CPR Practice With RECOVER Guidelines: An Internet-Based Survey.}, journal = {Frontiers in veterinary science}, volume = {6}, number = {}, pages = {181}, pmid = {31245396}, issn = {2297-1769}, abstract = {In 2012 the Reassessment Campaign on Veterinary Resuscitation (RECOVER) published evidence-based treatment recommendations for dogs and cats with cardiopulmonary arrest (CPA), to optimize the clinical practice of small animal CPR and positively impact outcomes. Six years after the release of these guidelines, we aimed to determine the compliance of small animal veterinary CPR practices with these RECOVER guidelines. To identify current CPR practices in clinically active small animal veterinarians and their awareness of the RECOVER guidelines, we conducted an internet-based survey. Survey invitations were disseminated internationally via veterinary professional organizations and their social media outlets. Questions explored respondent demographics, CPR preparedness, BLS and ALS techniques and awareness of RECOVER guidelines. Responding small animal veterinarians (n = 770) in clinical practice were grouped by level of expertise: board-certified specialists (BCS, n = 216) and residents (RES, n = 69) in anesthesia or emergency and critical care, practitioners in emergency (GPE, n = 299) or general practice (GPG, n = 186). Large disparities in preparedness measures, BLS and ALS techniques emerged among levels of expertise. Only 32% (95% CI: 29-36%) of respondents complied with BLS practice guidelines, varying from 49% (95% CI: 42-55%) of BCS to 15% (95% CI: 10-20%) of GPG. While incompliances in BCS, RES, and GPE were predominantly due to knowledge gaps, GPG compliance was further compromised by limitations in the resuscitation environment (e.g., defibrillator availability, team size). Those aware of RECOVER guidelines (100% of BCS and RES; 77% of GPE; 35% of GPG) were more likely to comply with recommended preparedness (OR = 2.4; 95% CI: 1.2-4.8), BLS (OR = 4.5; 95% CI: 2.4-9.1), and ALS techniques (OR = 7.8; 95% CI: 2.4-9.1) independent of age, gender, region of practice or level of expertise. We conclude that awareness of RECOVER guidelines is high in specialists and residents, but incomplete among general practitioners. This awareness positively influenced compliance with CPR guidelines, but CPR practices continue to be variable and largely not in agreement with guidelines. A widely accessible educational strategy is required to broadly improve compliance with best practices in small animal CPR.}, }
@article {pmid31241246, year = {2019}, author = {Zhang, G and Li, Y and Reuss, JL and Liu, N and Wu, C and Li, J and Xu, S and Wang, F and Hazel, TG and Cunningham, M and Zhang, H and Dai, Y and Hong, P and Zhang, P and He, J and Feng, H and Lu, X and Ulmer, JL and Johe, KK and Xu, R}, title = {Stable Intracerebral Transplantation of Neural Stem Cells for the Treatment of Paralysis Due to Ischemic Stroke.}, journal = {Stem cells translational medicine}, volume = {8}, number = {10}, pages = {999-1007}, pmid = {31241246}, issn = {2157-6580}, mesh = {Adult ; Aged ; Brain Ischemia/*complications/*therapy ; Female ; Humans ; Male ; Middle Aged ; Neural Stem Cells/*transplantation ; Paralysis/*therapy ; Stroke/*complications/*therapy ; Treatment Outcome ; }, abstract = {NSI-566 is a stable, primary adherent neural stem cell line derived from a single human fetal spinal cord and expanded epigenetically with no genetic modification. This cell line is being tested in clinical trials in the U.S. for treatment of amyotrophic lateral sclerosis and spinal cord injury. In a single-site, phase I study, we evaluated the feasibility and safety of NSI-566 transplantation for the treatment of hemiparesis due to chronic motor stroke and determined the maximum tolerated dose for future trials. Three cohorts (n = 3 per cohort) were transplanted with one-time intracerebral injections of 1.2 × 10[7] , 2.4 × 10[7] , or 7.2 × 10[7] cells. Immunosuppression therapy with tacrolimus was maintained for 28 days. All subjects had sustained chronic motor strokes, verified by magnetic resonance imaging (MRI), initiated between 5 and 24 months prior to surgery with modified Rankin Scores [MRSs] of 2, 3, or 4 and Fugl-Meyer Motor Scores of 55 or less. At the 12-month visit, the mean Fugl-Meyer Motor Score (FMMS, total score of 100) for the nine participants showed 16 points of improvement (p = .0078), the mean MRS showed 0.8 points of improvement (p = .031), and the mean National Institutes of Health Stroke Scale showed 3.1 points of improvement (p = .020). For six participants who were followed up for 24 months, these mean changes remained stable. The treatment was well tolerated at all doses. Longitudinal MRI studies showed evidence indicating cavity-filling by new neural tissue formation in all nine patients. Although this was a small, one-arm study of feasibility, the results are encouraging to warrant further studies. Stem Cells Translational Medicine 2019;8:999-1007.}, }
@article {pmid31239865, year = {2019}, author = {Wang, T and Lee, S and Yang, M and Cha, E and Jang, J and Kim, S}, title = {Analytical Method Validation of Gamijakyakgamchobuja-Tang (KCHO-1, Mecasin) Preparation.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2019}, number = {}, pages = {7824146}, pmid = {31239865}, issn = {1741-427X}, abstract = {Previous studies have confirmed that KCHO-1 (Mecasin) was developed to alleviate the symptoms of Amyotrophic Lateral Sclerosis (ALS). And its toxicity test has also been carried out. The aim of this study is confirming the validation and stability of concentration analysis method of the Mecasin preparations using HPLC. As a conclusion, we found that the preparations at the concentrations of 50mg/ml and 200mg/ml in sterilized distilled water were homogeneous and it was stable for 4 hours at room temperature and 7 days refrigerated condition (2~8°C). And this method for analyzing the concentration of the Mecasin preparations has been found to be suitable. This study is helpful to promote development of reliable manufacturing medicine and good researches through definitive quality control of Mecasin as complex herbal medicine, aiming to provide help for the treatment of ALS.}, }
@article {pmid31234550, year = {2019}, author = {Maher, P}, title = {The Potential of Flavonoids for the Treatment of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {20}, number = {12}, pages = {}, pmid = {31234550}, issn = {1422-0067}, support = {AG046153, AI104034 and NS106305//National Institutes of Health/ ; }, mesh = {Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Apoptosis ; Brain/drug effects/metabolism/physiopathology ; Flavonoids/pharmacology/*therapeutic use ; Humans ; Huntington Disease/drug therapy ; Inflammation ; Neurodegenerative Diseases/*drug therapy/metabolism/physiopathology ; Oxidative Stress ; Parkinson Disease/drug therapy ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), currently affect more than 6 million people in the United States. Unfortunately, there are no treatments that slow or prevent disease development and progression. Regardless of the underlying cause of the disorder, age is the strongest risk factor for developing these maladies, suggesting that changes that occur in the aging brain put it at increased risk for neurodegenerative disease development. Moreover, since there are a number of different changes that occur in the aging brain, it is unlikely that targeting a single change is going to be effective for disease treatment. Thus, compounds that have multiple biological activities that can impact the various age-associated changes in the brain that contribute to neurodegenerative disease development and progression are needed. The plant-derived flavonoids have a wide range of activities that could make them particularly effective for blocking the age-associated toxicity pathways associated with neurodegenerative diseases. In this review, the evidence for beneficial effects of multiple flavonoids in models of AD, PD, HD, and ALS is presented and common mechanisms of action are identified. Overall, the preclinical data strongly support further investigation of specific flavonoids for the treatment of neurodegenerative diseases.}, }
@article {pmid31233766, year = {2019}, author = {Volonté, C and Apolloni, S and Sabatelli, M}, title = {Histamine beyond its effects on allergy: Potential therapeutic benefits for the treatment of Amyotrophic Lateral Sclerosis (ALS).}, journal = {Pharmacology &amp; therapeutics}, volume = {202}, number = {}, pages = {120-131}, doi = {10.1016/j.pharmthera.2019.06.006}, pmid = {31233766}, issn = {1879-016X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Histamine/*pharmacology/*therapeutic use ; Humans ; Hypersensitivity/*drug therapy ; Immunologic Factors/pharmacology/therapeutic use ; Motor Neurons/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {ALS currently remains a challenge despite many efforts in performing successful clinical trials and formulating therapeutic solutions. By learning from current failures and striving for success, scientists and clinicians are checking every possibility to search for missing hints and efficacious treatments. Because the disease is very complex and heterogeneous and, moreover, targeting not only motor neurons but also several different cell types including muscle, glial, and immune cells, the right answer to ALS is conceivably a multidrug strategy or the use of broad-spectrum molecules. The aim of the present work is to gather evidence about novel perspectives on ALS pathogenesis and to present recent and innovative paradigms for therapy. In particular, we describe how an old molecule possessing immunomodulatory and neuroprotective functions beyond its recognized effects on allergy, histamine, might have a renewed and far-reaching momentum in ALS.}, }
@article {pmid31229177, year = {2019}, author = {Cortés, A and Casadó-Anguera, V and Moreno, E and Casadó, V}, title = {The heterotetrameric structure of the adenosine A1-dopamine D1 receptor complex: Pharmacological implication for restless legs syndrome.}, journal = {Advances in pharmacology (San Diego, Calif.)}, volume = {84}, number = {}, pages = {37-78}, doi = {10.1016/bs.apha.2019.01.001}, pmid = {31229177}, issn = {1557-8925}, mesh = {Adenosine/metabolism ; Animals ; Dopamine/metabolism ; Humans ; *Protein Multimerization ; Receptor, Adenosine A1/*chemistry/metabolism ; Receptors, Dopamine/*chemistry/metabolism ; Restless Legs Syndrome/*drug therapy ; }, abstract = {Dopaminergic and purinergic signaling play a pivotal role in neurological diseases associated with motor symptoms, including Parkinson's disease (PD), multiple sclerosis, amyotrophic lateral sclerosis, Huntington disease, Restless Legs Syndrome (RLS), spinal cord injury (SCI), and ataxias. Extracellular dopamine and adenosine exert their functions interacting with specific dopamine (DR) or adenosine (AR) receptors, respectively, expressed on the surface of target cells. These receptors are members of the family A of G protein-coupled receptors (GPCRs), which is the largest protein superfamily in mammalian genomes. GPCRs are target of about 40% of all current marketed drugs, highlighting their importance in clinical medicine. The striatum receives the densest dopamine innervations and contains the highest density of dopamine receptors. The modulatory role of adenosine on dopaminergic transmission depends largely on the existence of antagonistic interactions mediated by specific subtypes of DRs and ARs, the so-called A2AR-D2R and A1R-D1R interactions. Due to the dopamine/adenosine antagonism in the CNS, it was proposed that ARs and DRs could form heteromers in the neuronal cell surface. Therefore, adenosine can affect dopaminergic signaling through receptor-receptor interactions and by modulations in their shared intracellular pathways in the striatum and spinal cord. In this work we describe the allosteric modulations between GPCR protomers, focusing in those of adenosine and dopamine within the A1R-D1R heteromeric complex, which is involved in RLS. We also propose that the knowledge about the intricate allosteric interactions within the A1R-D1R heterotetramer, may facilitate the treatment of motor alterations, not only when the dopamine pathway is hyperactivated (RLS, chorea, etc.) but also when motor function is decreased (SCI, aging, PD, etc.).}, }
@article {pmid31229078, year = {2019}, author = {Jiménez-Carvelo, AM and González-Casado, A and Bagur-González, MG and Cuadros-Rodríguez, L}, title = {Alternative data mining/machine learning methods for the analytical evaluation of food quality and authenticity - A review.}, journal = {Food research international (Ottawa, Ont.)}, volume = {122}, number = {}, pages = {25-39}, doi = {10.1016/j.foodres.2019.03.063}, pmid = {31229078}, issn = {1873-7145}, mesh = {Data Mining/*methods ; Decision Trees ; Food Analysis/*methods ; *Food Quality ; *Machine Learning ; Statistics as Topic ; }, abstract = {In recent years, the variety and volume of data acquired by modern analytical instruments in order to conduct a better authentication of food has dramatically increased. Several pattern recognition tools have been developed to deal with the large volume and complexity of available trial data. The most widely used methods are principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA), soft independent modelling by class analogy (SIMCA), k-nearest neighbours (kNN), parallel factor analysis (PARAFAC), and multivariate curve resolution-alternating least squares (MCR-ALS). Nevertheless, there are alternative data treatment methods, such as support vector machine (SVM), classification and regression tree (CART) and random forest (RF), that show a great potential and more advantages compared to conventional ones. In this paper, we explain the background of these methods and review and discuss the reported studies in which these three methods have been applied in the area of food quality and authenticity. In addition, we clarify the technical terminology used in this particular area of research.}, }
@article {pmid31212179, year = {2019}, author = {Mousavi, SF and Fatemi, MH}, title = {Probing the binding mechanism of capecitabine to human serum albumin using spectrometric methods, molecular modeling, and chemometrics approach.}, journal = {Bioorganic chemistry}, volume = {90}, number = {}, pages = {103037}, doi = {10.1016/j.bioorg.2019.103037}, pmid = {31212179}, issn = {1090-2120}, mesh = {Binding Sites ; Capecitabine/chemistry/*metabolism ; Humans ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Prodrugs/chemistry/*metabolism ; Protein Binding ; Serum Albumin, Human/chemistry/*metabolism ; Spectrometry, Fluorescence ; Spectrophotometry, Ultraviolet ; Thermodynamics ; }, abstract = {Capecitabine as a prodrug of 5-Fluorouracil plays an important role in the treatment of breast and gastrointestinal cancers. Herein, in view of the importance of this drug in chemotherapy, interaction mechanism between Capecitabine (CAP) and human serum albumin (HSA) as a major transport protein in the blood circulatory system has been investigated by using a combination of spectroscopic and molecular modeling methods. The fluorescence spectroscopic results revealed that capecitabine could effectively quench the intrinsic fluorescence of HSA through a static quenching mechanism. Evaluation of the thermodynamic parameters suggested that the binding process was spontaneous while hydrogen bonds and van der Waals forces played a major role in this interaction. The value of the binding constant (Kb = 1.820 × 10[4]) suggested a moderate binding affinity between CAP and HSA which implies its easy diffusion from the circulatory system to the target tissue. The efficiency of energy transfer and the binding distance between the donor (HSA) and acceptor (CAP) were determined according to forster theory of nonradiation energy transfer as 0.410 and 4.135 nm, respectively. Furthermore, UV-Vis spectroscopic results confirmed that the interaction was occurred between HSA and CAP and caused conformational and micro-environmental changes of HSA during the interaction. Multivariate curve resolution-alternating least square (MCR-ALS) methodology as an efficient chemometric tool was used to separate the overlapped spectra of the species. The MCR-ALS result was exploited to estimate the stoichiometry of interaction and to provide concentration and structural information about HSA-CAP interactions. Molecular docking studies suggested that CAP binds mainly to the subdomain IIA of HSA, which were compatible with those obtained by experimental data. Finally, molecular dynamics simulation (MD) was performed on the best docked complex by considering the permanence and flexibility of HSA-CAP complex in the binding site. MD result showed that CAP could steadily bind to HSA in the site I based on the formation of hydrogen bond and π-π stacking interaction in addition to hydrophobic force.}, }
@article {pmid31205106, year = {2019}, author = {Chen, XQ and Qiu, K and Liu, H and He, Q and Bai, JH and Lu, W}, title = {Application and prospects of butylphthalide for the treatment of neurologic diseases.}, journal = {Chinese medical journal}, volume = {132}, number = {12}, pages = {1467-1477}, pmid = {31205106}, issn = {2542-5641}, mesh = {Animals ; Benzofurans/*therapeutic use ; Humans ; Nervous System Diseases/*drug therapy/metabolism ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {OBJECTIVE: The 3-N-butylphthalide (NBP) comprises one of the chemical constituents of celery oil. It has a series of pharmacologic mechanisms including reconstructing microcirculation, protecting mitochondrial function, inhibiting oxidative stress, inhibiting neuronal apoptosis, etc. Based on the complex multi-targets of pharmacologic mechanisms of NBP, the clinical application of NBP is increasing and more clinical researches and animal experiments are also focused on NBP. The aim of this review was to comprehensively and systematically summarize the application of NBP on neurologic diseases and briefly summarize its application to non-neurologic diseases. Moreover, recent progress in experimental models of NBP on animals was summarized.<br><br>DATA SOURCES: Literature was collected from PubMed and Wangfang database until November 2018, using the search terms including "3-N-butylphthalide," "microcirculation," "mitochondria," "ischemic stroke," "Alzheimer disease," "vascular dementia," "Parkinson disease," "brain edema," "CO poisoning," "traumatic central nervous system injury," "autoimmune disease," "amyotrophic lateral sclerosis," "seizures," "diabetes," "diabetic cataract," and "atherosclerosis."<br><br>STUDY SELECTION: Literature was mainly derived from English articles or articles that could be obtained with English abstracts and partly derived from Chinese articles. Article type was not limited. References were also identified from the bibliographies of identified articles and the authors' files.<br><br>RESULTS: NBP has become an important adjunct for ischemic stroke. In vascular dementia, the clinical application of NBP to treat severe cognitive dysfunction syndrome caused by the hypoperfusion of brain tissue during cerebrovascular disease is also increasing. Evidence also suggests that NBP has a therapeutic effect for neurodegenerative diseases. Many animal experiments have found that it can also improve symptoms in other neurologic diseases such as epilepsy, cerebral edema, and decreased cognitive function caused by severe acute carbon monoxide poisoning. Moreover, NBP has therapeutic effects for diabetes, diabetes-induced cataracts, and non-neurologic diseases such as atherosclerosis. Mechanistically, NBP mainly improves microcirculation and protects mitochondria. Its broad pharmacologic effects also include inhibiting oxidative stress, nerve cell apoptosis, inflammatory responses, and anti-platelet and anti-thrombotic effects.<br><br>CONCLUSIONS: The varied pharmacologic mechanisms of NBP involve many complex molecular mechanisms; however, there many unknown pharmacologic effects await further study.}, }
@article {pmid31202664, year = {2019}, author = {Hashimoto, S and Yasuda, M and Fujiwara, K and Ueda, E and Hata, J and Hirakawa, Y and Ninomiya, T and Sonoda, KH}, title = {Association between Axial Length and Myopic Maculopathy: The Hisayama Study.}, journal = {Ophthalmology. Retina}, volume = {3}, number = {10}, pages = {867-873}, doi = {10.1016/j.oret.2019.04.023}, pmid = {31202664}, issn = {2468-6530}, mesh = {Axial Length, Eye/*diagnostic imaging ; Cross-Sectional Studies ; Female ; Humans ; Japan/epidemiology ; Macular Degeneration/diagnosis/epidemiology/*etiology ; Male ; Middle Aged ; Myopia, Degenerative/*complications/diagnosis/epidemiology ; Population Surveillance/*methods ; Prevalence ; Retrospective Studies ; Risk Factors ; *Visual Acuity ; }, abstract = {PURPOSE: To assess the association between axial length (AL) and the prevalence of myopic maculopathy in a general Japanese population.<br><br>DESIGN: Population-based cross-sectional study.<br><br>PARTICIPANTS: A total of 2790 Hisayama residents 40 years of age or older who consented to participate and had available data of AL and fundus photographs for the right eyes were enrolled in this study.<br><br>METHODS: Myopic maculopathy was defined as the presence of diffuse chorioretinal atrophy, patchy chorioretinal atrophy, or macular degeneration. The optimal cutoff values of axial length for identifying myopic maculopathy were estimated from the receiver operating characteristic curve. The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a logistic regression analysis.<br><br>MAIN OUTCOME MEASURES: Odds ratios of AL for prevalent myopic maculopathy and the optimal cutoff values of AL for detecting myopic maculopathy.<br><br>RESULTS: Longer AL was associated significantly with prevalence of myopic maculopathy in both genders. The optimal cutoff values of AL for identifying myopic maculopathy were 25.9 mm in men and 25.3 mm in women. Participants with ALs of these values or longer showed a significantly higher OR for myopic maculopathy than those with AL of less than these values (men: OR, 21.23; 95% CI, 8.74-51.57; women: OR, 38.49; 95% CI, 18.03-86.49).<br><br>CONCLUSIONS: The present study found that there was a positive association between AL and the likelihood of myopic maculopathy, and the cutoff levels of AL for identifying myopic maculopathy were 25.9 mm in men and 25.3 mm in women. Our findings suggest that patients with AL close to or longer than these values should undergo intensive treatment and detailed ophthalmic follow-up.}, }
@article {pmid31197405, year = {2019}, author = {Rivera, S and García-González, L and Khrestchatisky, M and Baranger, K}, title = {Metalloproteinases and their tissue inhibitors in Alzheimer's disease and other neurodegenerative disorders.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {76}, number = {16}, pages = {3167-3191}, pmid = {31197405}, issn = {1420-9071}, mesh = {ADAM Proteins/metabolism ; Alzheimer Disease/metabolism/*pathology ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Humans ; Huntington Disease/metabolism/pathology ; Matrix Metalloproteinases/*metabolism ; Neurodegenerative Diseases/metabolism/*pathology ; Parkinson Disease/metabolism/pathology ; Tissue Inhibitor of Metalloproteinases/*metabolism ; }, abstract = {As life expectancy increases worldwide, age-related neurodegenerative diseases will increase in parallel. The lack of effective treatment strategies may soon lead to an unprecedented health, social and economic crisis. Any attempt to halt the progression of these diseases requires a thorough knowledge of the pathophysiological mechanisms involved to facilitate the identification of new targets and the application of innovative therapeutic strategies. The metzincin superfamily of metalloproteinases includes matrix metalloproteinases (MMP), a disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin motifs (ADAMTS). These multigenic and multifunctional proteinase families regulate the functions of an increasing number of signalling and scaffolding molecules involved in neuroinflammation, blood-brain barrier disruption, protein misfolding, synaptic dysfunction or neuronal death. Metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are therefore, at the crossroads of molecular and cellular mechanisms that support neurodegenerative processes, and emerge as potential new therapeutic targets. We provide an overview of current knowledge on the role and regulation of metalloproteinases and TIMPs in four major neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease.}, }
@article {pmid31197218, year = {2020}, author = {Trojsi, F and Siciliano, M and Passaniti, C and Bisecco, A and Russo, A and Lavorgna, L and Esposito, S and Ricciardi, D and Monsurrò, MR and Tedeschi, G and Santangelo, G}, title = {Vitamin D supplementation has no effects on progression of motor dysfunction in amyotrophic lateral sclerosis (ALS).}, journal = {European journal of clinical nutrition}, volume = {74}, number = {1}, pages = {167-175}, pmid = {31197218}, issn = {1476-5640}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Cholecalciferol ; Dietary Supplements ; *Persons with Disabilities ; Humans ; *Motor Disorders ; Vitamin D ; *Vitamin D Deficiency/complications/drug therapy ; }, abstract = {OBJECTIVES: To investigate the effects of cholecalciferol supplementation on the progression of motor disability in a cohort of amyotrophic lateral sclerosis (ALS) patients with low blood 25-hydroxyvitamin D3 [25(OH)D] levels, on the basis of the hypothesis of potential neuroprotective effects of vitamin D supplementation.<br><br>METHODS: Forty-eight ALS patients, 34 with deficient (<20&#x2009;ng/mL) and 14 with insufficient (20-29&#x2009;ng/mL) serum levels of 25(OH)D, were randomized and treated by 3 different doses of cholecalciferol [50.000, 75.000 and 100.000 international units (IU) /month] and evaluated after 6-months. Assessment of motor dysfunction at baseline and after 6 months included ALS Functional Rating Scale-Revised (ALFRS-R) and upper motor neuron (UMN) scores and blood samples for 25(OH)D levels.<br><br>RESULTS: Clinical data of 33 patients were available after 6 months. Analysis of Covariance (ANCOVA), with pre-treatment measurements included as covariate, did not show statistically significant differences in the ALSFRS-R (p&#x2009;>&#x2009;0.05) and UMN (p&#x2009;>&#x2009;0.05) among the patient groups who underwent 3 different doses of cholecalciferol. Conversely, the treatment with 75.000&#x2009;IU/month or 100.000&#x2009;IU/month induced a significant increase in serum levels of 25(OH)D in comparison with the supplementation with 50.000 IU/month; no significant differences were found between 75.000&#x2009;IU/month and 100.000&#x2009;IU/month.<br><br>CONCLUSIONS: Our findings highlighted that 6-month supplementation of vitamin D in ALS patients had no significant effects on motor dysfunction. However, it is recommended to prevent medical complications of vitamin D deficiency in ALS patients as well as in other populations of neurodegenerative patients, characterized by low mobility and decreased sun exposure.}, }
@article {pmid31196046, year = {2019}, author = {Seeber, AA and Pols, AJ and Hijdra, A and Grupstra, HF and Willems, DL and de Visser, M}, title = {Advance care planning in progressive neurological diseases: lessons from ALS.}, journal = {BMC palliative care}, volume = {18}, number = {1}, pages = {50}, pmid = {31196046}, issn = {1472-684X}, support = {project sj.152.005//ZonMw/ ; }, mesh = {Adult ; Advance Care Planning/*trends ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/psychology/*therapy ; Female ; Humans ; Interviews as Topic/methods ; Male ; Middle Aged ; Muscular Atrophy, Spinal/psychology/*therapy ; Netherlands ; Qualitative Research ; }, abstract = {BACKGROUND: There is increasing awareness of the need for an integrated palliative care approach in chronic progressive neurological diseases. Advance care planning (ACP) is an integral part of this approach. As a systematically organized and ongoing communication process about patients' values, goals and preferences regarding medical care during serious and chronic illness, ACP aims to involve patients in decision-making before they become cognitively and communicatively incapable. However, it remains underutilized in daily neurological practice except for speciality clinics such as ALS centers. Our aim was to study ACP in the tertiary ALS center Amsterdam and to investigate patients' reflections on it. Subsequently we used this knowledge to formulate recommendations for integration of ACP in the care of patients with other chronic progressive neurological diseases.<br><br>METHODS: Non-participating observations of all appointments of patients with amyotrophic lateral sclerosis (ALS) or progressive muscular atrophy (PMA) with the treating physician, in various stages of disease, during 6 consecutive months, followed by single in-depth interviews, and an inductive analysis.<br><br>RESULTS: Twenty-eight Dutch patients participated, varying in age, gender, disease onset and severity of physical decline. ACP started directly when the diagnosis was given, by means of a general outlook on the future with progressive disability and immediate introduction to a customized multidisciplinary team. During follow-up ACP was realized by regular appointments in which monitoring of the patient's status and clear communication strategies formed the basis of tailor-made discussions on treatment options. Patients accepted this policy as careful professional guidance.<br><br>CONCLUSIONS: ACP is a professional communication process throughout the whole course of progressive disease. It is feasible to integrate ACP into follow-up of patients with ALS and PMA from diagnosis onwards. Supported by recent literature, we argue that such a well-structured approach would also enhance the quality of care and life of patients with other chronic progressive neurological diseases.}, }
@article {pmid31195838, year = {2020}, author = {Pena, SA and Iyengar, R and Eshraghi, RS and Bencie, N and Mittal, J and Aljohani, A and Mittal, R and Eshraghi, AA}, title = {Gene therapy for neurological disorders: challenges and recent advancements.}, journal = {Journal of drug targeting}, volume = {28}, number = {2}, pages = {111-128}, doi = {10.1080/1061186X.2019.1630415}, pmid = {31195838}, issn = {1029-2330}, mesh = {Animals ; CRISPR-Cas Systems/genetics ; *Gene Transfer Techniques ; Genetic Therapy/*methods ; Genetic Vectors ; Humans ; Nanoparticles ; Nervous System Diseases/genetics/physiopathology/*therapy ; Polymers/chemistry ; }, abstract = {Major advancements in targeted gene therapy have opened up avenues for the treatment of major neurological disorders through a range of versatile modalities varying from expression of exogenous to suppression of endogenous genes. Recent technological innovations for improved gene sequence delivery have focussed on highly specific viral vector designs, plasmid transfection, nanoparticles, polymer-mediated gene delivery, engineered microRNA and in vivo clustered regulatory interspaced short palindromic repeats (CRISPR)-based therapeutics. These advanced techniques have profound applications in treating highly prevalent neurological diseases and neurodevelopmental disorders including Parkinson's disease, Alzheimer's disease and autism spectrum disorder, as well as rarer diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, lysosomal storage diseases, X-linked adrenoleukodystrophy and oncological diseases. In this article, we present an overview of the latest advances in targeted gene delivery and discuss the challenges and future direction of gene therapy in the treatment of neurological disorders.}, }
@article {pmid31195629, year = {2019}, author = {Moreno-Martinez, L and Calvo, AC and Muñoz, MJ and Osta, R}, title = {Are Circulating Cytokines Reliable Biomarkers for Amyotrophic Lateral Sclerosis?.}, journal = {International journal of molecular sciences}, volume = {20}, number = {11}, pages = {}, pmid = {31195629}, issn = {1422-0067}, support = {PI17/00949//Instituto de Salud Carlos III/ ; PI17/00949//European Regional Development Fund/ ; 612//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red sobre Enfermedades Neurodegenerativas/ ; A19_17R//Consolidated Groups from Gobierno de Arag&#xf3;n/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*blood/immunology/therapy ; Animals ; Biomarkers/*blood ; Body Fluids/metabolism ; Cytokines/*blood ; Humans ; Immune System/metabolism ; Inflammation/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that has no effective treatment. The lack of any specific biomarker that can help in the diagnosis or prognosis of ALS has made the identification of biomarkers an urgent challenge. Multiple panels have shown alterations in levels of numerous cytokines in ALS, supporting the contribution of neuroinflammation to the progressive motor neuron loss. However, none of them is fully sensitive and specific enough to become a universal biomarker for ALS. This review gathers the numerous circulating cytokines that have been found dysregulated in both ALS animal models and patients. Particularly, it highlights the opposing results found in the literature to date, and points out another potential application of inflammatory cytokines as therapeutic targets.}, }
@article {pmid31193360, year = {2019}, author = {Subaraja, M and Vanisree, AJ}, title = {Counter effects of Asiaticosids-D through putative neurotransmission on rotenone induced cerebral ganglionic injury in Lumbricus terrestris.}, journal = {IBRO reports}, volume = {6}, number = {}, pages = {160-175}, pmid = {31193360}, issn = {2451-8301}, abstract = {Asiaticoside-D (AD) was shown to efficacy of ganglionic degenerated Lumbricus terrestris as a pioneering observation in our earlier research. Though, extract molecular mechanisms of AD for degenerative diseases (DDs) remains largely unknown. We investigated the neuroprotective effects of AD against ROT in cerebral ganglions (CGs) of degenerative L. terrestris. Worms were exposed to 0.4 ppm ROT for 7 days were subjected to co- treatment with 15 ppm of AD. After, CGs was removed. The levels oxidant, non-antioxidant, antioxidant status, ganglioside, ceramide and ceramide glycanase (CGase) were estimated. The m-RNA levels of dopamine transporter (DAT), octopamine transporter (OAT), innexins-9 (inx-9), ionotropic glutamate receptor 3 (iGlu3), heat shock proteins (hsp70), XPRLamide neuropeptide precursor, tyramine beta-hydroxylase (tbh-1) and β- adrenergic receptor kinase-2 (β-ARK2-3) by semi-qRT- PCR. The expression pattern of tyramine beta hydroxylase (TBH), glutamate receptor (iGluR), serotonin transporter (SERT), dopamine transporters (DAT), nerve growth factors (NGF), cytochrome C oxidase (COC), NADH dehydogenase subunit-1 (ND-1), neurotrophin receptor p75 (p75NTR), neuronal nitric oxiside synthase (nNOs) interleukin 1- beta (IL1-β) and tumor necrosis factor alpha (TNF-α) by western blotting. Glutaminergic, serotogenic and dopaminergic toxicity variations were also performed. The levels of oxidant, non-antioxidant, antioxidant status, lipids, proteins and m-RNAs were significantly altered (p < 0.001) on ROT-induced (group II) and their levels were significantly changes (p < 0.05) by ROT+AD in CGs. The sensitive study plan concluded the neuroprotective effects of AD against ROT induced degeneration in worms and suggest that the AD deserves future studies for its use as an effective alternative medicine that could minimize the morbidity of ganglionic degenerative diseases patients.}, }
@article {pmid31189468, year = {2019}, author = {Lee, SH and Kim, S and Lee, N and Lee, J and Yu, SS and Kim, JH and Kim, S}, title = {Intrathecal delivery of recombinant AAV1 encoding hepatocyte growth factor improves motor functions and protects neuromuscular system in the nerve crush and SOD1-G93A transgenic mouse models.}, journal = {Acta neuropathologica communications}, volume = {7}, number = {1}, pages = {96}, pmid = {31189468}, issn = {2051-5960}, support = {HI16C1222//Korea Health Industry Development Institute/International ; }, mesh = {Animals ; Cells, Cultured ; Dependovirus/*genetics ; HEK293 Cells ; Hepatocyte Growth Factor/administration &amp; dosage/*genetics ; Humans ; Injections, Spinal ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Skills/drug effects/*physiology ; Nerve Crush/methods ; Neuromuscular Junction/drug effects/*physiology ; Recombinant Proteins/administration &amp; dosage/genetics ; Sciatic Neuropathy/drug therapy/*genetics/physiopathology ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease resulting from motor neuron degeneration that causes muscle weakness, paralysis, and eventually respiratory failure. We investigated whether recombinant adeno-associated virus encoding human hepatocyte growth factor (rAAV-HGF) could generate beneficial effects in two mouse models with neuromuscular problems when intrathecally delivered to the subarachnoid space. We chose AAV serotype 1 (rAAV1) based on the expression levels and distribution of HGF protein in the lumbar spinal cord (LSC). After a single intrathecal (IT) injection of rAAV1-HGF, the protein level of HGF in the LSC peaked on day 14 and thereafter gradually decreased over the next 14 weeks. rAAV1-HGF was initially tested in the mouse nerve crush model. IT injection of rAAV1-HGF improved mouse hindlimb strength and rotarod performance, while histological analyses showed that the length of regenerated axons was increased and the structure of the neuromuscular junction (NMJ) was restored. rAAV1-HGF was also evaluated in the SOD1-G93A transgenic (TG) mouse model. Again, rAAV1-HGF not only improved motor performance but also increased the survival rate. Moreover, the number and diameter of spinal motor neurons (SMNs) were increased, and the shape of the NMJs restored. Data from in vitro motor cortical culture experiments indicated that treatment with recombinant HGF protein (rHGF) increased the axon length of corticospinal motor neurons (CSMNs). When cultures were treated with an ERK inhibitor, the effects of HGF on axon elongation, protein aggregation, and oxidative stress were suppressed, indicating that ERK phosphorylation played an important role(s). Taken together, our results suggested that HGF might play an important role(s) in delaying disease progression in the SOD1-G93A TG mouse model by reducing oxidative stress through the control of ERK phosphorylation.}, }
@article {pmid31189354, year = {2019}, author = {Goutman, SA and Savelieff, MG and Sakowski, SA and Feldman, EL}, title = {Stem cell treatments for amyotrophic lateral sclerosis: a critical overview of early phase trials.}, journal = {Expert opinion on investigational drugs}, volume = {28}, number = {6}, pages = {525-543}, pmid = {31189354}, issn = {1744-7658}, support = {K23 ES027221/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Animals ; Clinical Trials as Topic/methods ; Humans ; Motor Neurons ; Research Design ; Stem Cell Transplantation/*methods ; Stem Cells/*cytology ; Treatment Outcome ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of cortical, brainstem, and spinal motor neurons; it causes progressive muscle weakness and atrophy, respiratory failure, and death. No currently available treatment either stops or reverses this disease. Therapeutics to slow, stop, and reverse ALS are needed. Stem cells may be a viable solution to sustain and nurture diseased motor neurons. Several early-stage clinical trials have been launched to assess the potential of stem cells for ALS treatment. Areas covered: Expert opinion:<br><br>AREAS COVERED: This review covers the key advances from early phase clinical trials of stem cell therapy for ALS and identifies promising avenues and key challenges.<br><br>EXPERT OPINION: Clinical trials in humans are still in the nascent stages of development. It will be critical to ensure that powered, well-controlled trials are conducted, that optimal treatment windows are identified, and that the ideal cell type, cell dose, and delivery site and method are determined. Several trials have used more invasive procedures, and ethical concerns of sham procedures on patients in the control arm and on their safety should be considered.}, }
@article {pmid31189016, year = {2019}, author = {Bk, B and Skuntz, S and Prochazkova, M and Kesavapany, S and Amin, ND and Shukla, V and Grant, P and Kulkarni, AB and Pant, HC}, title = {Overexpression of the Cdk5 inhibitory peptide in motor neurons rescue of amyotrophic lateral sclerosis phenotype in a mouse model.}, journal = {Human molecular genetics}, volume = {28}, number = {19}, pages = {3175-3187}, pmid = {31189016}, issn = {1460-2083}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*therapy ; Animals ; Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/*cytology/metabolism ; Nerve Tissue Proteins/*genetics ; Peptide Fragments/*genetics ; Phenotype ; Phosphorylation ; Superoxide Dismutase-1/genetics ; tau Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor nerve cells in the brain and the spinal cord. Etiological mechanisms underlying the disease remain poorly understood; recent studies suggest that deregulation of p25/Cyclin-dependent kinase 5 (Cdk5) activity leads to the hyperphosphorylation of Tau and neurofilament (NF) proteins in ALS transgenic mouse model (SOD1G37R). A Cdk5 involvement in motor neuron degeneration is supported by analysis of three SOD1G37R mouse lines exhibiting perikaryal inclusions of NF proteins and hyperphosphorylation of Tau. Here, we tested the hypothesis that inhibition of Cdk5/p25 hyperactivation in vivo is a neuroprotective factor during ALS pathogenesis by crossing the new transgenic mouse line that overexpresses Cdk5 inhibitory peptide (CIP) in motor neurons with the SOD1G37R, ALS mouse model (TriTg mouse line). The overexpression of CIP in the motor neurons significantly improves motor deficits, extends survival and delays pathology in brain and spinal cord of TriTg mice. In addition, overexpression of CIP in motor neurons significantly delays neuroinflammatory responses in TriTg mouse. Taken together, these data suggest that CIP may serve as a novel therapeutic agent for the treatment of neurodegenerative diseases.}, }
@article {pmid31187709, year = {2019}, author = {Yadav, K and Yadav, A and Vashistha, P and Pandey, VP and Dwivedi, UN}, title = {Protein Misfolding Diseases and Therapeutic Approaches.}, journal = {Current protein &amp; peptide science}, volume = {20}, number = {12}, pages = {1226-1245}, doi = {10.2174/1389203720666190610092840}, pmid = {31187709}, issn = {1875-5550}, mesh = {Acyl-CoA Dehydrogenases/metabolism ; Animals ; Endoplasmic Reticulum/metabolism ; High-Throughput Screening Assays/methods ; Humans ; Mitochondria/metabolism ; Molecular Chaperones/*chemistry/pharmacology ; Protein Conformation ; Protein Folding/drug effects ; Proteostasis Deficiencies/*drug therapy ; Signal Transduction ; Small Molecule Libraries/chemistry ; Structure-Activity Relationship ; }, abstract = {Protein folding is the process by which a polypeptide chain acquires its functional, native 3D structure. Protein misfolding, on the other hand, is a process in which protein fails to fold into its native functional conformation. This misfolding of proteins may lead to precipitation of a number of serious diseases such as Cystic Fibrosis (CF), Alzheimer's Disease (AD), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS) etc. Protein Quality-control (PQC) systems, consisting of molecular chaperones, proteases and regulatory factors, help in protein folding and prevent its aggregation. At the same time, PQC systems also do sorting and removal of improperly folded polypeptides. Among the major types of PQC systems involved in protein homeostasis are cytosolic, Endoplasmic Reticulum (ER) and mitochondrial ones. The cytosol PQC system includes a large number of component chaperones, such as Nascent-polypeptide-associated Complex (NAC), Hsp40, Hsp70, prefoldin and T Complex Protein-1 (TCP-1) Ring Complex (TRiC). Protein misfolding diseases caused due to defective cytosolic PQC system include diseases involving keratin/collagen proteins, cardiomyopathies, phenylketonuria, PD and ALS. The components of PQC system of Endoplasmic Reticulum (ER) include Binding immunoglobulin Protein (BiP), Calnexin (CNX), Calreticulin (CRT), Glucose-regulated Protein GRP94, the thiol-disulphide oxidoreductases, Protein Disulphide Isomerase (PDI) and ERp57. ER-linked misfolding diseases include CF and Familial Neurohypophyseal Diabetes Insipidus (FNDI). The components of mitochondrial PQC system include mitochondrial chaperones such as the Hsp70, the Hsp60/Hsp10 and a set of proteases having AAA+ domains similar to the proteasome that are situated in the matrix or the inner membrane. Protein misfolding diseases caused due to defective mitochondrial PQC system include medium-chain acyl-CoA dehydrogenase (MCAD)/Short-chain Acyl-CoA Dehydrogenase (SCAD) deficiency diseases, hereditary spastic paraplegia. Among therapeutic approaches towards the treatment of various protein misfolding diseases, chaperones have been suggested as potential therapeutic molecules for target based treatment. Chaperones have been advantageous because of their efficient entry and distribution inside the cells, including specific cellular compartments, in therapeutic concentrations. Based on the chemical nature of the chaperones used for therapeutic purposes, molecular, chemical and pharmacological classes of chaperones have been discussed.}, }
@article {pmid31184206, year = {2019}, author = {Sanberg, PR and Ehrhart, J}, title = {A Hallmark Clinical Study of Cord Blood Therapy in Adults with Ischemic Stroke.}, journal = {Cell transplantation}, volume = {28}, number = {9-10}, pages = {1329-1332}, pmid = {31184206}, issn = {1555-3892}, mesh = {Adult ; Allografts ; *Brain Ischemia/metabolism/pathology/therapy ; *Cord Blood Stem Cell Transplantation ; Humans ; Neurodegenerative Diseases/metabolism/pathology/therapy ; *Stroke/metabolism/pathology/therapy ; }, abstract = {The therapeutic application of human umbilical cord blood cells has been an area of great interest for at least the last 25 years. Currently, cord blood cells are approved for reconstitution of the bone marrow following myeloablation in both young and old patients with myeloid malignancies and other blood cancers. Translational studies investigating alternative uses of cord blood have also shown that these cells not only stimulate neurogenesis in the aged brain but are also potentially therapeutic in the treatment of adult neurodegenerative disorders including amyotrophic lateral sclerosis, Alzheimer's disease, ischemic stroke, traumatic brain injury, and Parkinson's disease. Recent advances in the clinical application of cord blood cells by Dr. Joanne Kurtzberg and colleagues have found that non-HLA matched allogeneic banked cord blood units in immunocompetent patients with ischemic stroke are safe and well tolerated. Although the exact mechanism(s) of action that provide the beneficial effects observed from a cord blood cell-based therapy are currently unknown, several studies using models of neurodegenerative disease have shown these cells are immune-modulatory and anti-inflammatory. Thus, any future clinical studies investigating the efficacy of this cord blood cell therapeutic would strongly benefit from the inclusion of methodologies to determine changes in both markers of inflammation and the response of immune tissues, such as the spleen, in subjects receiving cell infusion.}, }
@article {pmid31182448, year = {2019}, author = {Kerckhove, N and Busserolles, J and Stanbury, T and Pereira, B and Plence, V and Bonnetain, F and Krakowski, I and Eschalier, A and Pezet, D and Balayssac, D}, title = {Effectiveness assessment of riluzole in the prevention of oxaliplatin-induced peripheral neuropathy: RILUZOX-01: protocol of a randomised, parallel, controlled, double-blind and multicentre study by the UNICANCER-AFSOS Supportive Care intergroup.}, journal = {BMJ open}, volume = {9}, number = {6}, pages = {e027770}, pmid = {31182448}, issn = {2044-6055}, mesh = {Antineoplastic Agents/*adverse effects ; Double-Blind Method ; Humans ; Multicenter Studies as Topic/methods ; Neuroprotective Agents/*therapeutic use ; Neurotoxicity Syndromes/etiology/*prevention &amp; control ; Oxaliplatin/*administration &amp; dosage ; Peripheral Nervous System Diseases/chemically induced/*prevention &amp; control ; Randomized Controlled Trials as Topic/methods ; Riluzole/*therapeutic use ; Treatment Outcome ; }, abstract = {INTRODUCTION: Most patients (>70%) experience acute neuropathic symptoms shortly after oxaliplatin infusions. These symptoms are not always resolved between infusions. Overall, 30%-50% of patients suffer from chronic oxaliplatin-induced peripheral neuropathy (OIPN). This cumulative and dose-dependent sensory neuropathy limits compliance or results in oxaliplatin-based chemotherapies to be substituted with less neurotoxic agents. These treatment changes impair clinical outcomes, and may be associated with comorbidities, such as distress, depression and anxiety. Currently, no drug used to prevent or treat OIPN is sufficiently effective to be used routinely in clinical practice. There is, thus, an unmet therapeutic need to reduce the intensity of and/or prevent OIPN. We hypothesised that riluzole would be an excellent candidate to address this public health issue. Riluzole is approved for treating amyotrophic lateral sclerosis. In animals, there is a beneficial effect on sensorimotor and pain disorders, as well as related comorbidities, after repeated administration of oxaliplatin. In humans, riluzole has shown neuroprotective, anxiolytic and antidepressive effects.<br><br>METHODS AND ANALYSIS: RILUZOX-01 trial was designed as a randomised, controlled, double-blind study to evaluate the efficacy of riluzole to prevent OIPN. Patients with colorectal cancer and initiating adjuvant oxaliplatin-based chemotherapy are eligible. Patients (n=210) will be randomly assigned to either riluzole or placebo, concomitantly with chemotherapy. The primary endpoint is the change in OIPN intensity, assessed by the sensory scale of the QLQ-CIPN20, after six 2-week cycles of chemotherapy. Secondary endpoints include incidence and severity of neuropathy, grade of sensory neuropathy, intensity and features of neuropathic pain, health-related quality of life, disease-free survival, overall survival and safety.<br><br>ETHICS AND DESSIMINATION: The study was approved by a French ethics committee (ref:39/18_1, 'Comit&#xe9; de Protection des Personnes' Ouest-IV, France) and plans to start enroling patients in September 2019. The trial is registered in EudraCT and clinicaltrials.gov.<br><br>TRIAL REGISTRATION NUMBER: N&#xb0;2017-002320-25; NCT03722680.}, }
@article {pmid31182245, year = {2019}, author = {McGurk, L and Rifai, OM and Bonini, NM}, title = {Poly(ADP-Ribosylation) in Age-Related Neurological Disease.}, journal = {Trends in genetics : TIG}, volume = {35}, number = {8}, pages = {601-613}, pmid = {31182245}, issn = {0168-9525}, support = {R35 NS097275/NS/NINDS NIH HHS/United States ; }, mesh = {ADP-Ribosylation/*drug effects ; Aging ; Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Brain/pathology ; Cells, Cultured ; Drosophila ; Frontotemporal Lobar Degeneration/*genetics/pathology ; Humans ; Neurodegenerative Diseases/*genetics/pathology ; Neurons/pathology ; Poly Adenosine Diphosphate Ribose/metabolism ; Poly(ADP-ribose) Polymerase Inhibitors/*pharmacology ; Protein Aggregation, Pathological ; Protein Processing, Post-Translational ; }, abstract = {A central and causative feature of age-related neurodegenerative disease is the deposition of misfolded proteins in the brain. To devise novel approaches to treatment, regulatory pathways that modulate these aggregation-prone proteins must be defined. One such pathway is post-translational modification by the addition of poly(ADP-ribose) (PAR), which promotes protein recruitment and localization in several cellular contexts. Mounting evidence implicates PAR in seeding the abnormal localization and accumulation of proteins that are causative of neurodegenerative disease. Inhibitors of PAR polymerase (PARP) activity have been developed as cancer therapeutics, raising the possibility that they could be used to treat neurodegenerative disease. We focus on pathways regulated by PAR in neurodegenerative disease, with emphasis on amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD).}, }
@article {pmid31181282, year = {2019}, author = {Kuo, MTH and Beckman, JS and Shaw, CA}, title = {Neuroprotective effect of CuATSM on neurotoxin-induced motor neuron loss in an ALS mouse model.}, journal = {Neurobiology of disease}, volume = {130}, number = {}, pages = {104495}, doi = {10.1016/j.nbd.2019.104495}, pmid = {31181282}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Copper/*pharmacology ; Disease Models, Animal ; Mice ; Motor Neurons/*drug effects/*pathology ; Nerve Degeneration/pathology ; Neuroprotective Agents/*pharmacology ; Neurotoxins/toxicity ; }, abstract = {CuATSM is a PET-imaging agent that has recently received attention for its success in extending the lifespan in animals in several neurodegenerative disease models. In the SOD1[G93A] model of ALS, CuATSM prolonged mouse longevity far longer than any previously tested therapeutic agents. The mechanism underlying this outcome has not been fully understood, but studies suggest that this copper complex contributes to maintaining copper homeostasis in mitochondria. More specifically for the SOD1 model, the molecule supplies copper back to the SOD1 protein. Additionally, CuATSM demonstrated similar protective effects in various in vivo Parkinson's disease mouse models. In the current pilot study, we utilized a neurodegenerative mouse model of motor neuron degeneration induced by the neurotoxin β-sitosterol β-D-glucoside. In this model, slow but distinct and progressive features of sporadic ALS occur. Treatment with CuATSM kept animal behavioural performance on par with the controls and prevented the extensive motor neuron degeneration and microglia activation seen in the untreated animals. These outcomes support a broader neuroprotective role for CuATSM beyond mutant SOD models of ALS.}, }
@article {pmid31178951, year = {2019}, author = {Wang, M and Hu, R and Wang, Y and Liu, L and You, H and Zhang, J and Wu, X and Pei, T and Wang, F and Lu, L and Xiao, W and Wei, L}, title = {Atractylenolide III Attenuates Muscle Wasting in Chronic Kidney Disease via the Oxidative Stress-Mediated PI3K/AKT/mTOR Pathway.}, journal = {Oxidative medicine and cellular longevity}, volume = {2019}, number = {}, pages = {1875471}, pmid = {31178951}, issn = {1942-0994}, mesh = {Animals ; Cholinergic Antagonists/pharmacology/*therapeutic use ; Humans ; Lactones/pharmacology/*therapeutic use ; Male ; Oxidative Stress ; Phosphatidylinositol 3-Kinases/*metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Rats ; Rats, Sprague-Dawley ; Renal Insufficiency, Chronic/*drug therapy/pathology ; Sesquiterpenes/pharmacology/*therapeutic use ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {Oxidative stress contributes to muscle wasting in advanced chronic kidney disease (CKD) patients. Atractylenolide III (ATL-III), the major active constituent of Atractylodes rhizome, has been previously reported to function as an antioxidant. This study is aimed at investigating whether ATL-III has protective effects against CKD-induced muscle wasting by alleviating oxidative stress. The results showed that the levels of serum creatinine (SCr), blood urea nitrogen (BUN), and urinary protein significantly decreased in the ATL-III treatment group compared with the 5/6 nephrectomy (5/6 Nx) model group but were higher than those in the sham operation group. Skeletal muscle weight was increased, while inflammation was alleviated in the ATL-III administration group compared with the 5/6 Nx model group. ATL-III-treated rats also showed reduced dilation of the mitochondria, increased CAT, GSH-Px, and SOD activity, and decreased levels of MDA both in skeletal muscles and serum compared with 5/6 Nx model rats, suggesting that ATL-III alleviated mitochondrial damage and increased the activity of antioxidant enzymes, thus reducing the production of ROS. Furthermore, accumulated autophagosomes (APs) and autolysosomes (ALs) were reduced in the gastrocnemius (Gastroc) muscles of ATL-III-treated rats under transmission electron microscopy (TEM) together with the downregulation of LC3-II and upregulation of p62 according to Western blotting. This evidence indicated that ATL-III improved skeletal muscle atrophy and alleviated oxidative stress and autophagy in CKD rats. Furthermore, ATL-III could also increase the protein levels of p-PI3K, p-AKT, and p-mTOR in skeletal muscles in CKD rats. To further reveal the relevant mechanism, the oxidative stress-mediated PI3K/AKT/mTOR pathway was assessed, which showed that a reduced expression of p-PI3K, p-AKT, and p-mTOR in C2C12 myoblast atrophy induced by TNF-α could be upregulated by ATL-III; however, after the overexpression of Nox2 to increase ROS production, the attenuated effect was reversed. Our findings indicated that ATL-III is a potentially protective drug against muscle wasting via activation of the oxidative stress-mediated PI3K/AKT/mTOR pathway.}, }
@article {pmid31171958, year = {2019}, author = {Olavarria, OA and Kress, RL and Shah, SK and Agarwal, AK}, title = {Novel technique for anastomotic salvage using transanal minimally invasive surgery: A case report.}, journal = {World journal of gastrointestinal surgery}, volume = {11}, number = {5}, pages = {271-278}, pmid = {31171958}, issn = {1948-9366}, abstract = {BACKGROUND: Anastomotic leak (AL) after low anterior resection (LAR) can be a highly morbid complication. The incidence of AL ranges from 5% to 20% depending on patient characteristics and the distance of the anastomosis from the anal verge. Low anastomoses and leaks pose technical challenges for endoscopic treatment. The aim of this report was to describe the use of a commercially available laparoscopic energy device through a transanal minimally invasive surgery (TAMIS) port for the management of a symptomatic leak not requiring relaparotomy (grade B) after a LAR with diverting loop ileostomy.<br><br>CASE SUMMARY: A TAMIS GelPOINT Path port was inserted into the anus to access the distal rectum. Pneumorectum was achieved with AirSeal insufflation and a 30 degree laparoscope was introduced through a trocar. A LigaSure[TM] Retractable L-Hook device was then used to perform a septotomy of the chronic sinus tract identified posterior to the coloproctostomy. The procedure was then repeated twice in three weeks intervals with ultimate resolution of the chronic leak cavity. Several months after serial TAMIS septotomies, barium enema demonstrated a patent anastomosis with no evidence of persistent leak or stricture. The patient subsequently underwent ileostomy reversal and has had no significant post-operative issues.<br><br>CONCLUSION: TAMIS septotomy with the LigaSure[TM] Retractable L-Hook is a feasible and effective, minimally invasive salvage technique for the treatment of grade B ALs. Larger studies are needed to assess the generalizability and long-term results of this technique.}, }
@article {pmid31169327, year = {2019}, author = {Nemr, MTM and Yousif, MNM and Barciszewski, J}, title = {Interaction of small molecules with polynucleotide repeats and frameshift site RNA.}, journal = {Archiv der Pharmazie}, volume = {352}, number = {8}, pages = {e1900062}, doi = {10.1002/ardp.201900062}, pmid = {31169327}, issn = {1521-4184}, mesh = {Aptamers, Nucleotide/chemical synthesis/chemistry ; Hormones/analysis ; Pharmaceutical Preparations/analysis ; Polynucleotides/*chemistry ; RNA/*chemistry ; Small Molecule Libraries/*chemistry ; Toxins, Biological/analysis ; }, abstract = {This mini-review describes the interaction between small molecules and RNA, in addition to its application either in treating RNA-associated diseases or detecting target molecules. In the case of RNA-associated disease treatment, the designed small molecules interact with RNA sites, forming adducts and providing successful therapeutic strategies over oligonucleotides. On the other hand, synthetically designed RNA moieties (aptamers) interact with target molecules like toxins, drugs, hormones; these interactions are useful in the detection, quantification or separation of these target moieties.}, }
@article {pmid31159830, year = {2019}, author = {Vogt, S and Schreiber, S and Heinze, HJ and Dengler, R and Petri, S and Vielhaber, S}, title = {The Dyspnea-ALS-Scale (DALS-15) optimizes individual treatment in patients with amyotrophic lateral sclerosis (ALS) suffering from dyspnea.}, journal = {Health and quality of life outcomes}, volume = {17}, number = {1}, pages = {95}, pmid = {31159830}, issn = {1477-7525}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*physiopathology/therapy ; Disease Progression ; Dyspnea/*diagnosis/etiology/therapy ; Female ; Humans ; Male ; Middle Aged ; *Patient Reported Outcome Measures ; *Quality of Life ; Respiratory Insufficiency/*diagnosis/etiology/therapy ; }, abstract = {BACKGROUND: Dyspnea is frequent in amyotrophic lateral sclerosis (ALS) and one of the most bothersome symptoms. The recently developed Dyspnea-ALS-Scale (DALS-15) is a disease-specific patient-reported outcome to detect and quantify dyspnea.<br><br>OBJECTIVES: To analyze in a case-based approach the diagnostic and clinical implications and the benefit of the DALS-15 for individual patients in daily clinical routine.<br><br>METHODS: Dyspnea was assessed by the 15-item comprising DALS-15 in two patients with ALS. Spirometry was performed and blood gases were analyzed. Results were evaluated in the clinical context of the respective patients.<br><br>RESULTS: In one patient the presence of dyspnea detected by the DALS-15 indicated noninvasive ventilation (NIV) although forced vital capacity (FVC) and blood gas analysis were well preserved. After NIV implementation, the DALS-15 was helpful to determine the patient's need for medication, the timing of NIV titration and the adaptation of NIV sessions. In another patient, who was anarthric and no longer able to perform spirometry due to severe bulbar impairment, the DALS-15 allowed a standardized assessment of dyspnea-related distress independently of bulbar dysfunction.<br><br>CONCLUSION: The DALS-15 provides a deeper insight into the respiratory status of individual patients. It helps to diagnose respiratory impairment in patients in whom NIV should be considered although FVC and blood gas results do not reveal indication for NIV. It is also valuable for the guidance of patients in later stages of respiratory impairment when NIV is already implemented, and in patients with severe bulbar dysfunction. The DALS-15 can improve specific symptom management and coordination of care and therefore has the potential to optimize individual treatment in ALS patients with dyspnea.}, }
@article {pmid31152038, year = {2019}, author = {Mandrioli, J and Crippa, V and Cereda, C and Bonetto, V and Zucchi, E and Gessani, A and Ceroni, M and Chio, A and D'Amico, R and Monsurrò, MR and Riva, N and Sabatelli, M and Silani, V and Simone, IL and Sorarù, G and Provenzani, A and D'Agostino, VG and Carra, S and Poletti, A}, title = {Proteostasis and ALS: protocol for a phase II, randomised, double-blind, placebo-controlled, multicentre clinical trial for colchicine in ALS (Co-ALS).}, journal = {BMJ open}, volume = {9}, number = {5}, pages = {e028486}, pmid = {31152038}, issn = {2044-6055}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/physiopathology ; Autophagy/drug effects/*physiology ; Biomarkers ; Clinical Trials, Phase II as Topic ; Colchicine/pharmacokinetics/*therapeutic use ; DNA-Binding Proteins/antagonists &amp; inhibitors ; Disease Progression ; Double-Blind Method ; Female ; HSP20 Heat-Shock Proteins/*metabolism ; Heat-Shock Proteins ; Humans ; Male ; Middle Aged ; Molecular Chaperones ; Motor Neurons/drug effects/physiology ; Neuroprotective Agents/pharmacokinetics/*therapeutic use ; Proteostasis/*drug effects ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Young Adult ; }, abstract = {INTRODUCTION: Disruptions of proteasome and autophagy systems are central events in amyotrophic lateral sclerosis (ALS) and support the urgent need to find therapeutic compounds targeting these processes. The heat shock protein B8 (HSPB8) recognises and promotes the autophagy-mediated removal of misfolded mutant SOD1 and TDP-43 fragments from ALS motor neurons (MNs), as well as aggregating species of dipeptides produced in C9ORF72-related diseases. In ALS-SOD1 mice and in human ALS autopsy specimens, HSPB8 is highly expressed in spinal cord MNs that survive at the end stage of disease. Moreover, the HSPB8-BAG3-HSP70 complex maintains granulostasis, which avoids conversion of dynamic stress granules (SGs) into aggregation-prone assemblies. We will perform a randomised clinical trial (RCT) with colchicine, which enhances the expression of HSPB8 and of several autophagy players, blocking TDP-43 accumulation and exerting crucial activities for MNs function.<br><br>METHODS AND ANALYSIS: Colchicine in amyotrophic lateral sclerosis (Co-ALS) is a double-blind, placebo-controlled, multicentre, phase II RCT. ALS patients will be enrolled in three groups (placebo, colchicine 0.01&#x2009;mg/day and colchicine 0.005&#x2009;mg/day) of 18 subjects treated with riluzole; treatment will last 30 weeks, and follow-up will last 24 weeks. The primary aim is to assess whether colchicine decreases disease progression as measured by ALS Functional Rating Scale - Revised (ALSFRS-R) at baseline and at treatment end. Secondary aims include assessment of (1) safety and tolerability of Colchicine in patiets with ALS; (2) changes in cellular activity (autophagy, protein aggregation, and SG and exosome secretion) and in biomarkers of disease progression (neurofilaments); (3) survival and respiratory function and (4) quality of life. Preclinical studies with a full assessment of autophagy and neuroinflammation biomarkers in fibroblasts, peripheral blood mononuclear cells and lymphoblasts will be conducted in parallel with clinic assessment to optimise time and resources.<br><br>ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Area Vasta Emilia Nord and by Agenzia Italiana del Farmaco (EUDRACT N.2017-004459-21) based on the Declaration of Helsinki. This research protocol was written without patient involvement. Patients' association will be involved in disseminating the study design and results. Results will be presented during scientific symposia or published in scientific journals.<br><br>TRIAL REGISTRATION NUMBER: EUDRACT 2017-004459-21; NCT03693781; Pre-results.}, }
@article {pmid31150830, year = {2019}, author = {Gargiulo-Monachelli, G and Meyer, M and Lara, A and Garay, L and Lima, A and Roig, P and De Nicola, AF and Gonzalez Deniselle, MC}, title = {Comparative effects of progesterone and the synthetic progestin norethindrone on neuroprotection in a model of spontaneous motoneuron degeneration.}, journal = {The Journal of steroid biochemistry and molecular biology}, volume = {192}, number = {}, pages = {105385}, doi = {10.1016/j.jsbmb.2019.105385}, pmid = {31150830}, issn = {1879-1220}, mesh = {Animals ; Contraceptives, Oral, Synthetic/pharmacology ; *Disease Models, Animal ; Mice ; Motor Neurons/*drug effects/pathology ; Neurodegenerative Diseases/*drug therapy ; Neuroprotection/*drug effects ; Norethindrone/*pharmacology ; Progesterone/*pharmacology ; Progestins/*pharmacology ; }, abstract = {The Wobbler mouse has been proposed as an experimental model of the sporadic form of amyotrophic lateral sclerosis (ALS). The administration of natural progesterone (PROG) to Wobbler mice attenuates neuropathology, inhibits oxidative stress, enhances the expression of genes involved in motoneuron function, increases survival and restores axonal transport. However, current pharmacological treatments for ALS patients are still partially effective. This encouraged us to investigate if the synthetic progestin norethindrone (NOR), showing higher potency than PROG and used for birth control and hormone therapy might also afford neuroprotection. Two-month-old Wobbler mice (wr/wr) were left untreated or received either a 20 mg pellet of PROG or a 1 mg pellet of NOR for 18 days. Untreated control NFR/NFR mice (background strain for Wobbler) were also employed. Wobblers showed typical clinical and spinal cord abnormalities, while these abnormalities were normalized with PROG treatment. Surprisingly, we found that NOR did not increase immunoreactivity and gene expression for choline-acetyltransferase, drastically decreased GFAP + astrogliosis, favored proinflammatory mediators, promoted the inflammatory phenotype of IBA1+ microglia, increased the receptor for advanced glycation end products (RAGE) mRNA and protein expression and the activity of nitric oxide synthase (NOS)/NADPH diaphorase in the cervical spinal cord. Additionally, NOR treatment produced atrophy of the thymus. The combined negative effects of NOR on clinical assessments (forelimb atrophy and rotarod performance) suggest a detrimental effect on muscle trophism and motor function. These findings reinforce the evidence that the type of progestin used for contraception, endometriosis or replacement therapy, may condition the outcome of preclinical and clinical studies targeting neurodegenerative diseases.}, }
@article {pmid31146513, year = {2020}, author = {Nicolini, A and Parrinello, L and Grecchi, B and Braido, F and Baiardini, I and Ghirotti, C and Banfi, P}, title = {Diurnal mouthpiece ventilation and nocturnal non-invasive ventilation versus tracheostomy invasive ventilation in patients with amyotrophic lateral sclerosis.}, journal = {Panminerva medica}, volume = {62}, number = {1}, pages = {19-25}, doi = {10.23736/S0031-0808.19.03644-9}, pmid = {31146513}, issn = {1827-1898}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/physiopathology/psychology/*therapy ; Humans ; Middle Aged ; Noninvasive Ventilation/*instrumentation/*methods ; Proportional Hazards Models ; Quality of Life ; Respiration ; Respiratory Insufficiency/therapy ; Tracheostomy/*instrumentation/*methods ; Treatment Outcome ; }, abstract = {BACKGROUND: Respiratory disorders are a major cause of morbidity and mortality in amyotrophic lateral sclerosis (ALS). Current guidelines suggest the provision of noninvasive ventilation (NIV) for symptomatic hypoventilation in patients with ALS. Inspite of these results the proportion of ALS patients on tracheostomy invasive ventilation (TIV) is relatively high.<br><br>METHODS: Thirty-two patients were included in the study: 16 patients were treated with nocturnal NIV associated with diurnal mouthpiece ventilation (MPV) and 16 with TIV .The primary endpoint of the study was to evaluate survival in the two groups. Secondary endpoints were to evaluate differences in the two populations in terms of clinical outcomes and quality of life (HRQoL).<br><br>RESULTS: Cox analysis survival data shows no statically difference in the hazard function of the two groups. The comparison between the two groups showed a significant improvement in the average value of gas indices (paO2, paCO2) in the group treated with TIV in comparison to the group treated with MPV/NIV. Conversely, the evaluation of the questionnaires on HRQoL showed a higher score in patients treated with MPV/NIV compared to those treated with TIV.<br><br>CONCLUSIONS: Ventilatory treatment with MPV and TIV did not demonstrate significant differences in survival. Patients treated with MPV reported a better HRQoL, although TIV group showed higher ventilatory parameters improvement than MPV group.}, }
@article {pmid31144179, year = {2019}, author = {Omar, NA and Abu-Almaaty, AH and Abd El-Aziz, YM and Abdeen, AM and Mohamed, FEZA and Hashem, MMM and Hammad, S}, title = {Impacts of Egyptian propolis extract on rat cerebellum intoxicated by aluminum silicate: histopathological studies.}, journal = {Environmental science and pollution research international}, volume = {26}, number = {21}, pages = {22061-22068}, pmid = {31144179}, issn = {1614-7499}, mesh = {Aluminum Compounds ; Aluminum Silicates/*toxicity ; Animals ; Cerebellum/*drug effects ; Egypt ; Humans ; Male ; Neuroprotective Agents/*pharmacology ; Neurotoxicity Syndromes ; Propolis/*pharmacology ; Rats ; }, abstract = {Human is exposed to traces of aluminum silicate (AlS), i.e., cosmetics, pesticides. Accumulation of aluminum compounds including AlS is associated with neuropathological diseases, e.g., Alzheimer's disease. The aim of the current study is to investigate the neuroprotective effects of propolis extracts in AlS-induced cerebellum intoxication in rats. Forty adult rats were randomly divided into four groups (n = 10). The first group served as a control; the second group treated with 200 ml propolis/kg bwt. every other day by stomach gavage tube, third group was intraperitoneally injected with AIS (20 mg/kg) twice a week for 8 weeks, and the fourth group received propolis extract and AIS. At the end of 8 weeks, the cerebellum was harvested for further ultrastructure, histological, and histochemical investigations. Using electron microscopy, the ultrastructure of the cerebellar cortex of AlS intoxicated rats showed Purkinje cells with an irregular euchromatic nucleus and extremely increased invagination of the nuclear envelope. In addition, the cytoplasm revealed numerous damaged mitochondria (> 20%) as well as swollen lysosomes (> 40%) compared to controls. These AlS-related ultrastructure changes were to some extent normalized to < 10% and < 30% in case of mitochondria and lysosomes, respectively, if rats were co-treated with propolis extract. Further, histopathological examination showed that AlS-exposed rats revealed abnormal Purkinje cells with irregular size and shrank shape, evidence of pre-necrotic stage in the form of nuclear pyknosis, and condensed and frequent darkly stained cells in cerebellar layers. However, propolis extract co-administration reversed from 35 to 25% (p < 0.05) these alterations. The carbohydrate and protein contents were reduced in case of AlS treatment and surprisingly propolis co-treatment was able to rescue these neurotoxic effects. Propolis extract might have neuroprotective effects against AIS-induced toxicity. Further studies are required to identify the mechanism of the pharmacological action and optimal settings for medical testing of propolis extract.}, }
@article {pmid31141951, year = {2019}, author = {Nowicka, N and Juranek, J and Juranek, JK and Wojtkiewicz, J}, title = {Risk Factors and Emerging Therapies in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {20}, number = {11}, pages = {}, pmid = {31141951}, issn = {1422-0067}, support = {OPUS/2017/25/B/NZ4/00435//Narodowym Centrum Nauki/ ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/therapy ; Animals ; C9orf72 Protein/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Genetic Predisposition to Disease ; Genetic Therapy ; Humans ; Molecular Targeted Therapy ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease characterized by a permanent degeneration of both upper and lower motor neurons. Many different genes and pathophysiological processes contribute to this disease, however its exact cause remains unclear. Therefore, it is necessary to understand this heterogeneity to find effective treatments. In this review, we focus on selected environmental and genetic risk factors predisposing to ALS and highlight emerging treatments in ALS therapy. Of numerous defective genes associated with ALS, we focus on four principal genes that have been identified as definite causes of ALS: the SOD1 gene, C9orf72, TDP-43, as well as the recently identified TBK1. We also provide up-to-date information on selected environmental factors that have historically been considered as key players in ALS development and pathogenesis. In parallel to our survey of known risk factors, we also discuss emerging ALS stem cell therapies and experimental medicines currently undergoing phase II and III clinical trials.}, }
@article {pmid31139687, year = {2019}, author = {Zucchi, E and Vinceti, M and Malagoli, C and Fini, N and Gessani, A and Fasano, A and Rizzi, R and Sette, E and Cavazza, S and Fiocchi, A and Buja, S and Faccioli, T and Storani, S and Mandrioli, J}, title = {High-frequency motor rehabilitation in amyotrophic lateral sclerosis: a randomized clinical trial.}, journal = {Annals of clinical and translational neurology}, volume = {6}, number = {5}, pages = {893-901}, pmid = {31139687}, issn = {2328-9503}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*therapy ; Exercise Therapy/*methods ; Fatigue ; Female ; Humans ; Male ; Middle Aged ; Quality of Life ; }, abstract = {OBJECTIVE: Exercise may be physically and psychologically important for people with ALS, especially in the earlier stages of the disease, and, as a consequence, current ALS clinical management includes individualized rehabilitation as part of multidisciplinary care because. However, while recent studies focused on which type of exercise is more indicated to ALS patients, there is no evidence at which frequency training sessions should be performed.<br><br>METHODS: We performed an assessor blinded randomized clinical trial to investigate the superiority of two different frequencies of exercise on rate of progression in ALS. We enrolled 65 patients in two groups: intensive exercise regimen (IER, five sessions/week) versus usual exercise regimen (UER, two sessions/week). The primary aim was to assess if IER decreased disease progression, measured through Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, with respect to UER. Secondary aims included assessment of adverse events, tracheostomy-free survival, motor and respiratory functions, fatigue, quality of life and caregiver burden. Treatment regimen consisted for both groups of the same kind of exercise including aerobic training, endurance training, stretching or assisted active mobilization, differing for frequency of intervention.<br><br>RESULTS: No significant changes in disease progression were found in patients under IER versus UER. At the end of the study, there were no significant differences between the two groups in survival, respiratory function, time to supporting procedures, and quality of life. Adverse events, fatigue, and caregiver burden were not different between the two treatment regimens.<br><br>CONCLUSIONS: Despite some limitations, our trial demonstrated that high-frequency physical exercise was not superior to UER on ALSFRS-R scores, motor and respiratory functions, survival, fatigue, and quality of life of ALS patients.}, }
@article {pmid31139131, year = {2019}, author = {Vijayakumar, UG and Milla, V and Cynthia Stafford, MY and Bjourson, AJ and Duddy, W and Duguez, SM}, title = {A Systematic Review of Suggested Molecular Strata, Biomarkers and Their Tissue Sources in ALS.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {400}, pmid = {31139131}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is an incurable neurodegenerative condition, characterized by the loss of upper and lower motor neurons. It affects 1-1.8/100,000 individuals worldwide, and the number of cases is projected to increase as the population ages. Thus, there is an urgent need to identify both therapeutic targets and disease-specific biomarkers-biomarkers that would be useful to diagnose and stratify patients into different sub-groups for therapeutic strategies, as well as biomarkers to follow the efficacy of any treatment tested during clinical trials. There is a lack of knowledge about pathogenesis and many hypotheses. Numerous "omics" studies have been conducted on ALS in the past decade to identify a disease-signature in tissues and circulating biomarkers. The first goal of the present review was to group the molecular pathways that have been implicated in monogenic forms of ALS, to enable the description of patient strata corresponding to each pathway grouping. This strategy allowed us to suggest 14 strata, each potentially targetable by different pharmacological strategies. The second goal of this review was to identify diagnostic/prognostic biomarker candidates consistently observed across the literature. For this purpose, we explore previous biomarker-relevant "omics" studies of ALS and summarize their findings, focusing on potential circulating biomarker candidates. We systematically review 118 papers on biomarkers published during the last decade. Several candidate markers were consistently shared across the results of different studies in either cerebrospinal fluid (CSF) or blood (leukocyte or serum/plasma). Although these candidates still need to be validated in a systematic manner, we suggest the use of combinations of biomarkers that would likely reflect the "health status" of different tissues, including motor neuron health (e.g., pNFH and NF-L, cystatin C, Transthyretin), inflammation status (e.g., MCP-1, miR451), muscle health (miR-338-3p, miR-206) and metabolism (homocysteine, glutamate, cholesterol). In light of these studies and because ALS is increasingly perceived as a multi-system disease, the identification of a panel of biomarkers that accurately reflect features of pathology is a priority, not only for diagnostic purposes but also for prognostic or predictive applications.}, }
@article {pmid31137614, year = {2019}, author = {Spalloni, A and Greco, V and Ciriminna, G and Corasolla Carregari, V and Marini, F and Pieroni, L and Mercuri, NB and Urbani, A and Longone, P}, title = {Impact of Pharmacological Inhibition of Hydrogen Sulphide Production in the SOD1G93A-ALS Mouse Model.}, journal = {International journal of molecular sciences}, volume = {20}, number = {10}, pages = {}, pmid = {31137614}, issn = {1422-0067}, support = {PRIN 20158EB2CM//Italian Department of Education and Research/ ; Ricerca Corrente (2017-2018)//Italian Ministry of Health/ ; }, mesh = {Aminooxyacetic Acid/*pharmacology/therapeutic use ; Amyotrophic Lateral Sclerosis/drug therapy/genetics/*metabolism ; Animals ; Brain/drug effects/metabolism ; Cells, Cultured ; Cystathionine beta-Synthase/*antagonists &amp; inhibitors ; Enzyme Inhibitors/*pharmacology/therapeutic use ; Female ; Hydrogen Sulfide/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neuroglia/drug effects ; Sex Factors ; Superoxide Dismutase-1/genetics ; }, abstract = {A number of factors can trigger amyotrophic lateral sclerosis (ALS), although its precise pathogenesis is still uncertain. In a previous study done by us, poisonous liquoral levels of hydrogen sulphide (H2S) in sporadic ALS patients were reported. In the same study very high concentrations of H2S in the cerebral tissues of the familial ALS (fALS) model of the SOD1G93A mouse, were measured. The objective of this study was to test whether decreasing the levels of H2S in the fALS mouse could be beneficial. Amino-oxyacetic acid (AOA)-a systemic dual inhibitor of cystathionine-β-synthase and cystathionine-γ lyase (two key enzymes in the production of H2S)-was administered to fALS mice. AOA treatment decreased the content of H2S in the cerebral tissues, and the lifespan of female mice increased by approximately ten days, while disease progression in male mice was not affected. The histological evaluation of the spinal cord of the females revealed a significant increase in GFAP positivity and a significant decrease in IBA1 positivity. In conclusion, the results of the study indicate that, in the animal model, the inhibition of H2S production is more effective in females. The findings reinforce the need to adequately consider sex as a relevant factor in ALS.}, }
@article {pmid31133804, year = {2019}, author = {Jones, MK and Nair, A and Gupta, M}, title = {Mast Cells in Neurodegenerative Disease.}, journal = {Frontiers in cellular neuroscience}, volume = {13}, number = {}, pages = {171}, pmid = {31133804}, issn = {1662-5102}, abstract = {Neurodegenerative diseases affect millions of people worldwide, yet there are currently no effective treatments. Because risk of neurodegenerative disease substantially increases with age, greater life expectancy with a concomitant aging population means more individuals will be affected in the coming decades. Thus, there is an urgent need for understanding the mechanisms driving neurodegenerative diseases in order to develop improved treatment strategies. Inflammation in the nervous system, termed "neuroinflammation," has become increasingly recognized as being associated with neurodegenerative diseases. Early attention focused primarily on morphological changes in astrocytes and microglia; however, brain and CNS resident mast cells are now receiving attention as a result of being "first responders" to injury. Mast cells also exert profound effects on their microenvironment and neighboring cells including behavior and/or activation of astrocytes, microglia, and neurons, which, in turn, are implicated in neuroinflammation, neurogenesis and neurodegeneration. Mast cells also affect disruption/permeability of the blood brain barrier enabling toxin and immune cell entry exacerbating an inflammatory microenvironment. Here, we discuss the roles of mast cells in neuroinflammation and neurodegeneration with a focus on development and progression of four prominent neurodegenerative diseases: Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Huntington's Disease.}, }
@article {pmid31130623, year = {2019}, author = {Obál, I and Nógrádi, B and Meszlényi, V and Patai, R and Ricken, G and Kovacs, GG and Tripolszki, K and Széll, M and Siklós, L and Engelhardt, JI}, title = {Experimental Motor Neuron Disease Induced in Mice with Long-Term Repeated Intraperitoneal Injections of Serum from ALS Patients.}, journal = {International journal of molecular sciences}, volume = {20}, number = {10}, pages = {}, pmid = {31130623}, issn = {1422-0067}, support = {GINOP-2.3.2-15-2016-00001//Ministry for the National Economy of Hungary/ ; GINOP-2.3.2-15-2016-00034//Ministry for the National Economy of Hungary/ ; GINOP-2.3.3.-15-2016-00001//Ministry for the National Economy of Hungary/ ; 13725-2/2018/INTFIN//Ministry of Human Capacities/ ; NTP-NFT&#xd6;-18-B-0208//Ministry of Human Capacities/ ; UNKP-18-2//Ministry of Human Capacities/ ; }, mesh = {Amyotrophic Lateral Sclerosis/blood/*metabolism ; Animals ; Calcium/metabolism ; Disease Models, Animal ; Female ; Humans ; Immunoglobulin G/administration &amp; dosage/blood/metabolism ; Injections, Intraperitoneal ; Male ; Mice ; Mice, Inbred BALB C ; Motor Neuron Disease/*metabolism/pathology ; Motor Neurons/metabolism/*pathology ; Serum/*metabolism ; }, abstract = {In an earlier study, signs of commencing degeneration of spinal motor neurons were induced in mice with short-term intraperitoneal injections of immunoglobulin G (IgG) taken from patients with amyotrophic lateral sclerosis (ALS). Since in that study, neither weakness nor loss of motor neurons was noted, to test whether the ALS IgG in this paradigm has the potential to evoke relentless degeneration of motor neurons, treatment with repeated injections over a longer period was carried out. Mice were systematically injected intraperitoneally with serum taken from ALS patients over a 75-day period. At selected time points, the isometric force of the limbs, number of spinal motor neurons and their intracellular calcium levels were determined. Furthermore, markers of glial activation and the motoneuronal uptake of human IgG were monitored. During this period, gliosis and progressive motoneuronal degeneration developed, which led to gradual loss of spinal motor neurons, more than 40% at day 21, along with decreasing muscle strength in the limbs. The inclusion-like accumulation of IgG appeared in the perikarya with the increase of intracellular calcium in the cell bodies and motor nerve terminals. Our results demonstrate that ALS serum can transfer motor neuron disease to mice.}, }
@article {pmid31129201, year = {2019}, author = {Yan, L and Qi, W and Liu, Y and Zhou, F and Wang, Y and Bai, L and Zhou, X and Sun, C and Nie, X and Duan, S and Ran, J and Chen, J and Ji, Y and Liu, Y and Li, Z and Li, Y and Wang, Q}, title = {The Protective Effect of Aromatase on NSC-34 Cells with Stably Expressed hSOD1-G93A.}, journal = {Neuroscience}, volume = {411}, number = {}, pages = {37-46}, doi = {10.1016/j.neuroscience.2019.05.022}, pmid = {31129201}, issn = {1873-7544}, mesh = {Animals ; Apoptosis/drug effects/*physiology ; Aromatase/genetics/*metabolism ; Cell Line ; Cell Survival/drug effects/physiology ; Estradiol/pharmacology ; Estrogen Receptor Antagonists/pharmacology ; Gene Knockdown Techniques ; Mice ; Motor Neurons/drug effects/*metabolism ; Superoxide Dismutase/genetics/*metabolism ; }, abstract = {As an adult-onset neurodegenerative disease, amyotrophic lateral sclerosis (ALS) results in progressive muscular atrophy and paralysis. However, the mechanism of ALS has not yet been elucidated, and no cure has been found. Research has revealed that a mutation of the Cu/Zn superoxide dismutase (SOD1) gene is linked to familial ALS and that potential sex discrepancies exist in ALS incidence. Here, NSC-34 cells stably expressing hSOD1-G93A (hSOD1-G93A cells) were transiently transfected with Cyp19a1 mouse open reading frame (ORF) cDNA or a short hairpin RNA (ShRNA) plasmid. Overexpression of aromatase resulting from Cyp19a1 mouse ORF cDNA plasmid transfection enhanced cell proliferation and reduced cell damage in hSOD1-G93A cells. This protective effect occurred through anti-apoptotic pathways related to estrogen receptor-alpha (ER-α) activation. Meanwhile, knockdown of aromatase with Cyp19a1 ShRNA plasmid transfection reduced cell proliferation, increased cell damage, promoted apoptosis, and decreased ER-α expression in hSOD1-G93A cells, and the induced apoptotic effects could be reversed by estradiol (E2). In brief, the results of our study suggest that aromatase plays a neuroprotective role against apoptosis in hSOD1-G93A cells by activating ER-α and may become a new intervention target for ALS treatment.}, }
@article {pmid31128285, year = {2020}, author = {Tacconelli, E and Górska, A and De Angelis, G and Lammens, C and Restuccia, G and Schrenzel, J and Huson, DH and Carević, B and Preoţescu, L and Carmeli, Y and Kazma, M and Spanu, T and Carrara, E and Malhotra-Kumar, S and Gladstone, BP}, title = {Estimating the association between antibiotic exposure and colonization with extended-spectrum β-lactamase-producing Gram-negative bacteria using machine learning methods: a multicentre, prospective cohort study.}, journal = {Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases}, volume = {26}, number = {1}, pages = {87-94}, doi = {10.1016/j.cmi.2019.05.013}, pmid = {31128285}, issn = {1469-0691}, mesh = {Adolescent ; Adult ; Aged ; Anti-Bacterial Agents/*therapeutic use ; Drug Therapy, Combination ; Female ; Gram-Negative Bacteria/*drug effects/enzymology ; Gram-Negative Bacterial Infections/*epidemiology/microbiology ; Hospitalization/statistics &amp; numerical data ; Humans ; Incidence ; Italy ; *Machine Learning ; Male ; Middle Aged ; Prospective Studies ; Risk Factors ; Romania ; Serbia ; Young Adult ; beta-Lactamases ; }, abstract = {OBJECTIVES: The aim of the study was to measure the impact of antibiotic exposure on the acquisition of colonization with extended-spectrum β-lactamase-producing Gram-negative bacteria (ESBL-GNB) accounting for individual- and group-level confounding using machine-learning methods.<br><br>METHODS: Patients hospitalized between September 2010 and June 2013 at six medical and six surgical wards in Italy, Serbia and Romania were screened for ESBL-GNB at hospital admission, discharge, antibiotic start, and after 3, 7, 15 and 30&#xa0;days. Primary outcomes were the incidence rate and predictive factors of new ESBL-GNB colonization. Random forest algorithm was used to rank antibiotics according to the risk of selection of ESBL-GNB colonization in patients not colonized before starting antibiotics.<br><br>RESULTS: We screened 10&#xa0;034 patients collecting 28&#xa0;322 rectal swab samples. New ESBL-GNB colonization incidence with and without antibiotic treatment was 22/1000 and 9/1000 exposure-days, respectively. In the adjusted regression analyses, antibiotic exposure (hazard ratio (HR) 2.38; 95% CI 1.29-4.40), age 60-69&#xa0;years (HR 1.19; 95% CI 1.05-1.34), and spring season (HR 1.25; 95% CI 1.14-1.38) were independently associated with new colonization. Monotherapy ranked higher als combination therapy in promoting ESBL-GNB colonization. Among monotherapy, cephalosporins ranked first followed by tetracycline (second), macrolide (fourth) and cotrimoxazole (seventh). Overall the ranking of cephalosporins was lower when used in combination. Among combinations not including cephalosporins, quinolones plus carbapenems ranked highest (eighth). Among sequential therapies, quinolones ranked highest (tenth) when prescribed within 30 days of therapy with cephalosporins.<br><br>CONCLUSIONS: Impact of antibiotics on selecting ESBL-GNB at intestinal level varies if used in monotherapy or combination and according to previous antibiotic exposure. These finding should be explored in future clinical trials on antibiotic stewardship interventions.<br><br>CLINICAL TRIAL REGISTRATION: NCT01208519.}, }
@article {pmid31125839, year = {2019}, author = {Flint, AE and Waterman, MG and Siddell, P and Houston, AL and Vadlamani, G and Chumas, P and Morrall, MCHJ}, title = {Assessing evidence quality in research reporting neurocognitive outcomes following paediatric temporal lobe surgery for epilepsy.}, journal = {Epilepsy research}, volume = {154}, number = {}, pages = {116-123}, doi = {10.1016/j.eplepsyres.2019.03.013}, pmid = {31125839}, issn = {1872-6844}, mesh = {Child ; Cross-Sectional Studies ; Epilepsy, Temporal Lobe/*diagnosis/psychology/*surgery ; Humans ; Mental Status and Dementia Tests/*standards ; Neurocognitive Disorders/*diagnosis/etiology/psychology ; Psychosurgery/adverse effects/psychology/*standards ; *Qualitative Research ; Retrospective Studies ; Temporal Lobe/surgery ; Treatment Outcome ; }, abstract = {PURPOSE: RCTs are the gold standard in determining intervention efficacy with journal impact factor assumed to index research quality. Flint et al's (2017) systematic review examined neurocognitive outcomes following paediatric temporal lobe epilepsy surgery. Retrieved evidence was restricted to non-RCTs, which pose greater risk of bias and thus diminish research quality. The current study evaluated risk of bias in sources retrieved by Flint et al. and explored whether impact factor related to research quality within this selected field.<br><br>METHODS: Methodological and reporting bias was evaluated using categories of bias specified by Cochrane. The relationship between the identified number of biases and journal impact factors of retrieved sources was examined.<br><br>RESULTS: All studies carried substantial risk for bias. Methodology bias included low sample size (76.71%; 56/73), risk of confounding cognitive outcomes due to failure to report pre-surgery neurocognitive data (21.92%; 16/73) and to determine whether patients were prescribed antiepileptic drugs at follow-up (53.42%; 39/73). Reporting bias included overstating claims based on findings (53.42%; 39/73), failure to report individual patient characteristics (66%; 33/50) and omitting the nature of surgical interventions (15.07%; 11/73). The number of sources of common bias within studies was not associated significantly with journal impact factor (p&#x2009;=&#x2009;.878).<br><br>CONCLUSION: This evaluation highlights risk of bias when sources are predominantly uncontrolled non-RCTs and provides evidence that journal impact factor is not a reliable indicator of quality within this field. Authors should limit bias in their methods and reporting of results, to ensure the highest quality evidence possible is used to inform treatment decisions and prognosis.}, }
@article {pmid31121863, year = {2019}, author = {Hsu, SK and Chiu, CC and Dahms, HU and Chou, CK and Cheng, CM and Chang, WT and Cheng, KC and Wang, HD and Lin, IL}, title = {Unfolded Protein Response (UPR) in Survival, Dormancy, Immunosuppression, Metastasis, and Treatments of Cancer Cells.}, journal = {International journal of molecular sciences}, volume = {20}, number = {10}, pages = {}, pmid = {31121863}, issn = {1422-0067}, mesh = {Animals ; Cell Survival ; Disease Progression ; Humans ; Immune Tolerance ; Neoplasm Metastasis/immunology/pathology/therapy ; Neoplasms/immunology/metabolism/*pathology/therapy ; Neovascularization, Pathologic/immunology/metabolism/pathology/therapy ; *Unfolded Protein Response ; }, abstract = {The endoplasmic reticulum (ER) has diverse functions, and especially misfolded protein modification is in the focus of this review paper. With a highly regulatory mechanism, called unfolded protein response (UPR), it protects cells from the accumulation of misfolded proteins. Nevertheless, not only does UPR modify improper proteins, but it also degrades proteins that are unable to recover. Three pathways of UPR, namely PERK, IRE-1, and ATF6, have a significant role in regulating stress-induced physiological responses in cells. The dysregulated UPR may be involved in diseases, such as atherosclerosis, heart diseases, amyotrophic lateral sclerosis (ALS), and cancer. Here, we discuss the relation between UPR and cancer, considering several aspects including survival, dormancy, immunosuppression, angiogenesis, and metastasis of cancer cells. Although several moderate adversities can subject cancer cells to a hostile environment, UPR can ensure their survival. Excessive unfavorable conditions, such as overloading with misfolded proteins and nutrient deprivation, tend to trigger cancer cell death signaling. Regarding dormancy and immunosuppression, cancer cells can survive chemotherapies and acquire drug resistance through dormancy and immunosuppression. Cancer cells can also regulate the downstream of UPR to modulate angiogenesis and promote metastasis. In the end, regulating UPR through different molecular mechanisms may provide promising anticancer treatment options by suppressing cancer proliferation and progression.}, }
@article {pmid31118868, year = {2019}, author = {Garuti, G and Rao, F and Ribuffo, V and Sansone, VA}, title = {Sialorrhea in patients with ALS: current treatment options.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {9}, number = {}, pages = {19-26}, pmid = {31118868}, issn = {1179-9900}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the motor neuron, which selectively affects it both at central (first motor-neuron) and peripheral level (second motor-neuron). The disease shows up at a mean age of 56 years and the most affected are males. Although ALS may start as a bulbar or spinal disease, with the progression of the disease typically both become evident. Pharmacological approved treatments for ALS are still limited and include riluzole and edaravone which improve survival over time. Despite this, ALS leads to progressive muscle involvement and requires a complex multidisciplinary approach to manage increasing disability which goes beyond motor neurons. Sialorrhea is, amongst others, one of the most disabling symptoms in ALS. The complexity in managing saliva is due to a muscular spasticity and to a scarce palatino-lingual muscles control, rather than to an overproduction of saliva. These features could increase the risk of aspiration pneumonia and limit the use of noninvasive mechanical ventilation. We reviewed the treatment for sialorrhea in ALS patients that are available at this time, emphasizing pros and cons for each approach. Our purpose is to create a practical tool for the diagnosis, in order to facilitate the quantification and management of sialorrhea in everyday practice.}, }
@article {pmid31118040, year = {2019}, author = {Swindell, WR and Kruse, CPS and List, EO and Berryman, DE and Kopchick, JJ}, title = {ALS blood expression profiling identifies new biomarkers, patient subgroups, and evidence for neutrophilia and hypoxia.}, journal = {Journal of translational medicine}, volume = {17}, number = {1}, pages = {170}, pmid = {31118040}, issn = {1479-5876}, support = {R01 AG059779/AG/NIA NIH HHS/United States ; }, mesh = {Altitude Sickness/blood/genetics ; Amyotrophic Lateral Sclerosis/*blood/*genetics/immunology ; Biomarkers/*blood ; Cell Lineage/genetics ; Erythrocytes/metabolism ; Exosomes/metabolism ; Female ; *Gene Expression Profiling ; Gene Expression Regulation ; Genetic Loci ; Genetic Predisposition to Disease ; Humans ; Hypoxia/blood/*complications/genetics ; Leukocyte Disorders/blood/*complications/genetics ; Male ; Middle Aged ; Neutrophils/metabolism/*pathology ; Superoxide Dismutase ; Support Vector Machine ; Survival Analysis ; Transcriptome/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a debilitating disease with few treatment options. Progress towards new therapies requires validated disease biomarkers, but there is no consensus on which fluid-based measures are most informative.<br><br>METHODS: This study analyzed microarray data derived from blood samples of patients with ALS (n&#x2009;=&#x2009;396), ALS mimic diseases (n&#x2009;=&#x2009;75), and healthy controls (n&#x2009;=&#x2009;645). Goals were to provide in-depth analysis of differentially expressed genes (DEGs), characterize patient-to-patient heterogeneity, and identify candidate biomarkers.<br><br>RESULTS: We identified 752 ALS-increased and 764 ALS-decreased DEGs (FDR&#x2009;<&#x2009;0.10 with&#x2009;>&#x2009;10% expression change). Gene expression shifts in ALS blood broadly resembled acute high altitude stress responses. ALS-increased DEGs had high exosome expression, were neutrophil-specific, associated with translation, and overlapped significantly with genes near ALS susceptibility loci (e.g., IFRD1, TBK1, CREB5). ALS-decreased DEGs, in contrast, had low exosome expression, were erythroid lineage-specific, and associated with anemia and blood disorders. Genes encoding neurofilament proteins (NEFH, NEFL) had poor diagnostic accuracy (50-53%). However, support vector machines distinguished ALS patients from ALS mimics and controls with 87% accuracy (sensitivity: 86%, specificity: 87%). Expression profiles were heterogeneous among patients and we identified two subgroups: (i) patients with higher expression of IL6R and myeloid lineage-specific genes and (ii) patients with higher expression of IL23A and lymphoid-specific genes. The gene encoding copper chaperone for superoxide dismutase (CCS) was most strongly associated with survival (HR&#x2009;=&#x2009;0.77; P&#x2009;=&#x2009;1.84e-05) and other survival-associated genes were linked to mitochondrial respiration. We identify a 61 gene signature that significantly improves survival prediction when added to Cox proportional hazard models with baseline clinical data (i.e., age at onset, site of onset and sex). Predicted median survival differed 2-fold between patients with favorable and risk-associated gene expression signatures.<br><br>CONCLUSIONS: Peripheral blood analysis informs our understanding of ALS disease mechanisms and genetic association signals. Our findings are consistent with low-grade neutrophilia and hypoxia as ALS phenotypes, with heterogeneity among patients partly driven by differences in myeloid and lymphoid cell abundance. Biomarkers identified in this study require further validation but may provide new tools for research and clinical practice.}, }
@article {pmid31110103, year = {2019}, author = {Srinivasapura Venkateshmurthy, N and Mc Namara, K and Koorts, H and Mohan, S and S Ajay, V and Jindal, D and Malipeddi, BR and Roy, A and Tandon, N and Prabhakaran, D and Worsley, T and Maddison, R and O'Reilly, S}, title = {Process evaluation protocol for a cluster randomised trial of a complex, nurse-led intervention to improve hypertension management in India.}, journal = {BMJ open}, volume = {9}, number = {5}, pages = {e027841}, pmid = {31110103}, issn = {2044-6055}, mesh = {Blood Pressure ; Community Health Services/*methods ; Disease Management ; Female ; Humans ; Hypertension/*nursing/*therapy ; India ; Male ; Process Assessment, Health Care/*methods ; }, abstract = {INTRODUCTION: India has high prevalence of hypertension but low awareness, treatment and control rate. A cluster randomised trial entitled 'm-Power Heart Project' is being implemented to test the effectiveness of a nurse care coordinator (NCC) led complex intervention to address uncontrolled hypertension in the community health centres (CHCs). The trial's process evaluation will assess the fidelity and quality of implementation, clarify the causal mechanisms and identify the contextual factors associated with variation in the outcomes. The trial will use a theory-based mixed-methods process evaluation, guided by the Consolidated Framework for Implementation Research.<br><br>METHODS AND ANALYSIS: The process evaluation will be conducted in the CHCs of Visakhapatnam (southern India). The key stakeholders involved in the intervention development and implementation will be included as participants. In-depth interviews will be conducted with intervention developers, doctors, NCCs and health department officials and focus groups with patients and their caregivers. NCC training will be evaluated using Kirkpatrick's model for training evaluation. Key process evaluation indicators (number of patients recruited and retained; concordance between the treatment plans generated by the electronic decision support system and treatment prescribed by the doctor and so on) will be assessed. Fidelity will be assessed using Borrelli et al's framework. Qualitative data will be analysed using the template analysis technique. Quantitative data will be summarised as medians (IQR), means (SD) and proportions as appropriate. Mixed-methods analysis will be conducted to assess if the variation in the mean reduction of systolic blood pressure between the intervention CHCs is influenced by patient satisfaction, training outcome, attitude of doctors, patients and NCCs about the intervention, process indicators etc. ETHICS AND DISSEMINATION: Ethical approval for this study was obtained from the ethics committees at Public Health Foundation of India and Deakin University. Findings will be disseminated via peer-reviewed publications, national and international conference presentations.<br><br>TRIAL REGISTRATION NUMBER: NCT03164317; Pre-results.}, }
@article {pmid31110036, year = {2019}, author = {Benditt, JO}, title = {Respiratory Care of Patients With Neuromuscular Disease.}, journal = {Respiratory care}, volume = {64}, number = {6}, pages = {679-688}, doi = {10.4187/respcare.06827}, pmid = {31110036}, issn = {1943-3654}, mesh = {Cough ; Deglutition ; Humans ; Hypoventilation/physiopathology/therapy ; Insufflation/methods ; Laryngeal Masks ; Neuromuscular Diseases/*physiopathology ; Noninvasive Ventilation/methods ; Oxygen Inhalation Therapy ; Respiratory Therapy/*methods ; Sleep Apnea Syndromes/physiopathology/therapy ; }, abstract = {Neuromuscular diseases are a heterogeneous group of neurologic diseases that affect a number of neural structures including the motor nerves, neuromuscular junctions, or the muscles themselves. Although many of the diseases are rare, the total number of individuals who present to a pulmonologist or respiratory care provider is significant. Approaches to care include regular and careful clinical follow-up of symptoms of sleep-disordered breathing, daytime hypoventilation, as well as cough and swallowing effectiveness. Noninvasive support with nocturnal mask ventilation and a pressure support device can be extraordinarily helpful and delay daytime ventilatory failure. When daytime ventilatory failure develops, other noninvasive methods are available for portable assistance. Support of cough function with manual assistance, a resuscitator bag, and/or mechanical insufflation-exsufflation can help prevent and treat infection. Referral for swallowing evaluation and treatment is very important for those with impaired bulbar function. This comprehensive respiratory care approach to individuals with neuromuscular disease and respiratory system involvement is essential to maintaining the health and longevity of these individuals.}, }
@article {pmid31105519, year = {2019}, author = {Shah, EJ and Gurdziel, K and Ruden, DM}, title = {Mammalian Models of Traumatic Brain Injury and a Place for Drosophila in TBI Research.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {409}, pmid = {31105519}, issn = {1662-4548}, support = {UH3 OD023285/OD/NIH HHS/United States ; R01 ES012933/ES/NIEHS NIH HHS/United States ; S10 OD025170/OD/NIH HHS/United States ; P30 ES020957/ES/NIEHS NIH HHS/United States ; UG3 OD023285/OD/NIH HHS/United States ; }, abstract = {Traumatic brain injury (TBI), caused by a sudden blow or jolt to the brain that disrupts normal function, is an emerging health epidemic with ∼2.5 million cases occurring annually in the United States that are severe enough to cause hospitalization or death. Most common causes of TBI include contact sports, vehicle crashes and domestic violence or war injuries. Injury to the central nervous system is one of the most consistent candidates for initiating the molecular and cellular cascades that result in Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Not every TBI event is alike with effects varying from person to person. The majority of people recover from mild TBI within a short period of time, but repeated incidents can have deleterious long-lasting effects which depend on factors such as the number of TBIs sustained, time till medical attention, age, gender and genetics of the individual. Despite extensive research, many questions still remain regarding diagnosis, treatment, and prevention of long-term effects from TBI as well as recovery of brain function. In this review, we present an overview of TBI pathology, discuss mammalian models for TBI and focus on current methods using Drosophila melanogaster as a model for TBI study. The relatively small brain size (∼100,000 neurons and glia), conserved neurotransmitter signaling mechanisms and sophisticated genetics of Drosophila allows for cell biological, molecular and genetic analyses that are impractical in mammalian models of TBI.}, }
@article {pmid31104357, year = {2019}, author = {Mazzini, L and Gelati, M and Profico, DC and Sorarù, G and Ferrari, D and Copetti, M and Muzi, G and Ricciolini, C and Carletti, S and Giorgi, C and Spera, C and Frondizi, D and Masiero, S and Stecco, A and Cisari, C and Bersano, E and De Marchi, F and Sarnelli, MF and Querin, G and Cantello, R and Petruzzelli, F and Maglione, A and Zalfa, C and Binda, E and Visioli, A and Trombetta, D and Torres, B and Bernardini, L and Gaiani, A and Massara, M and Paolucci, S and Boulis, NM and Vescovi, AL and , }, title = {Results from Phase I Clinical Trial with Intraspinal Injection of Neural Stem Cells in Amyotrophic Lateral Sclerosis: A Long-Term Outcome.}, journal = {Stem cells translational medicine}, volume = {8}, number = {9}, pages = {887-897}, pmid = {31104357}, issn = {2157-6580}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/pathology/*therapy ; Brain/diagnostic imaging ; Brain-Derived Neurotrophic Factor/analysis ; Female ; Glial Fibrillary Acidic Protein/cerebrospinal fluid ; Humans ; Injections, Spinal ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Neural Stem Cells/cytology/metabolism/*transplantation ; Pain/etiology ; Pilot Projects ; Spinal Cord/diagnostic imaging ; Stem Cell Transplantation/adverse effects ; Treatment Outcome ; Vascular Endothelial Growth Factor A/analysis ; Young Adult ; }, abstract = {The main objective of this phase I trial was to assess the feasibility and safety of microtransplanting human neural stem cell (hNSC) lines into the spinal cord of patients with amyotrophic lateral sclerosis (ALS). Eighteen patients with a definite diagnosis of ALS received microinjections of hNSCs into the gray matter tracts of the lumbar or cervical spinal cord. Patients were monitored before and after transplantation by clinical, psychological, neuroradiological, and neurophysiological assessment. For up to 60 months after surgery, none of the patients manifested severe adverse effects or increased disease progression because of the treatment. Eleven patients died, and two underwent tracheotomy as a result of the natural history of the disease. We detected a transitory decrease in progression of ALS Functional Rating Scale Revised, starting within the first month after surgery and up to 4 months after transplantation. Our results show that transplantation of hNSC is a safe procedure that causes no major deleterious effects over the short or long term. This study is the first example of medical transplantation of a highly standardized cell drug product, which can be reproducibly and stably expanded ex vivo, comprising hNSC that are not immortalized, and are derived from the forebrain of the same two donors throughout this entire study as well as across future trials. Our experimental design provides benefits in terms of enhancing both intra- and interstudy reproducibility and homogeneity. Given the potential therapeutic effects of the hNSCs, our observations support undertaking future phase II clinical studies in which increased cell dosages are studied in larger cohorts of patients. Stem Cells Translational Medicine 2019;8:887&amp;897.}, }
@article {pmid31104055, year = {2019}, author = {Hümmer, H and Wiecken, T and Pachmann, K}, title = {[Unmittelbare Remission eines mit großzelligem B-Non-Hodgkin-Lymphom befallenen inguinalen Lymphknotens unter alleiniger homöopathischer Behandlung mit Conium: Wann ist eine alleinige adjuvant-homöopathische Tumortherapie zulässig und sinnvoll?].}, journal = {Complementary medicine research}, volume = {26}, number = {5}, pages = {361-366}, pmid = {31104055}, issn = {2504-2106}, mesh = {Adjuvants, Immunologic/*therapeutic use ; *Conium ; Female ; Groin ; Homeopathy/*methods ; Humans ; Lymphoma, B-Cell/*drug therapy ; Lymphoma, Non-Hodgkin/*drug therapy ; Middle Aged ; }, abstract = {A large-cell B-cell non-Hodgkin Lymphoma (LCBCL) was diagnosed bioptically in a female patient (age 63 years) in one left inguinal lymph node. Immediately after beginning homeopathic treatment with Conium C 30, the lymph node started to show a reduction in size. Two weeks after starting homeopathic therapy, histological examination of the excised lymph node showed no evidence of a residual tumor – suggestive of a complete remission. The patient remains disease free until now. The homeopathic remedy Conium (hemlock) is frequently applied for adjuvant homeopathic tumor therapy as well as for the treatment of enlarged lymph nodes.}, }
@article {pmid31100684, year = {2019}, author = {Iberl, S and Meyer, AL and Müller, G and Peters, S and Johannesen, S and Kobor, I and Beier, F and Brümmendorf, TH and Hart, C and Schelker, R and Herr, W and Bogdahn, U and Grassinger, J}, title = {Effects of continuous high-dose G-CSF administration on hematopoietic stem cell mobilization and telomere length in patients with amyotrophic lateral sclerosis - a pilot study.}, journal = {Cytokine}, volume = {120}, number = {}, pages = {192-201}, doi = {10.1016/j.cyto.2019.05.003}, pmid = {31100684}, issn = {1096-0023}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/blood/*drug therapy/*genetics ; Antigens, CD34/metabolism ; Blood Cell Count ; Colony-Forming Units Assay ; Cytokines/blood ; Dose-Response Relationship, Drug ; Female ; Granulocyte Colony-Stimulating Factor/*administration &amp; dosage ; *Hematopoietic Stem Cell Mobilization ; Hematopoietic Stem Cells/drug effects/metabolism ; Humans ; Male ; Middle Aged ; Pilot Projects ; *Telomere Homeostasis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of complex and still poorly understood etiology. Loss of upper and lower motoneurons results in death within few years after diagnosis. Recent studies have proposed neuroprotective and disease-slowing effects of granulocyte-colony stimulating factor (G-CSF) treatment in ALS mouse models as well as humans. In this study, six ALS patients were monitored up to 3.5 years during continuous high-dose G-CSF administration. Repetitive analyses were performed including blood count parameters, CD34[+] hematopoietic stem and progenitor cell (HSPC) and colony forming cell (CFC) counts, serum cytokine levels and leukocyte telomere length. We demonstrate that continuous G-CSF therapy was well tolerated and safe resulting in only mild adverse events during the observation period. However, no mobilization of CD34[+] HSPC was detected as compared to baseline values. CFC mobilization was equally low and even a decrease of myeloid precursors was observed in some patients. Assessment of telomere length within ALS patients' leukocytes revealed that G-CSF did not significantly shorten telomeres, while those of ALS patients were shorter compared to age-matched healthy controls, irrespective of G-CSF treatment. During G-CSF stimulation, TNF-alpha, CRP, IL-16, sVCAM-1, sICAM-1, Tie-2 and VEGF were significantly increased in serum whereas MCP-1 levels decreased. In conclusion, our data show that continuous G-CSF treatment fails to increase circulating CD34[+] HSPC in ALS patients. Cytokine profiles revealed G-CSF-mediated immunomodulatory and proteolytic effects. Interestingly, despite intense G-CSF stimulation, telomere length was not significantly shortened.}, }
@article {pmid31096690, year = {2019}, author = {Chiricosta, L and Gugliandolo, A and Tardiolo, G and Bramanti, P and Mazzon, E}, title = {Transcriptomic Analysis of MAPK Signaling in NSC-34 Motor Neurons Treated with Vitamin E.}, journal = {Nutrients}, volume = {11}, number = {5}, pages = {}, pmid = {31096690}, issn = {2072-6643}, support = {RF-2013-02359594//Ministry of Health/ ; }, mesh = {Animals ; Cell Line ; Cell Survival/drug effects ; Gene Expression Regulation/drug effects ; Mice ; Mitogen-Activated Protein Kinase Kinases/genetics/*metabolism ; Motor Neurons/*drug effects/*metabolism ; Transcriptome/*drug effects ; Up-Regulation ; Vitamin E/*pharmacology ; }, abstract = {Vitamin E family is composed of different tocopherols and tocotrienols that are well-known as antioxidants but that exert also non-antioxidant effects. Oxidative stress may be involved in the progression of neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), characterized by motor neuron death. The aim of the study was the evaluation of the changes induced in the transcriptional profile of NSC-34 motor neurons treated with α-tocopherol. In particular, cells were treated for 24 h with 10 µM α-tocopherol, RNA was extracted and transcriptomic analysis was performed using Next Generation Sequencing. Vitamin E treatment modulated MAPK signaling pathway. The evaluation revealed that 34 and 12 genes, respectively belonging to "Classical MAP kinase pathway" and "JNK and p38 MAP kinase pathway", were involved. In particular, a downregulation of the genes encoding for p38 (Log2 fold change -0.87 and -0.67) and JNK (Log2 fold change -0.16) was found. On the contrary, the gene encoding for ERK showed a higher expression in cells treated with vitamin E (Log2 fold change 0.30). Since p38 and JNK seem more involved in cell death, while ERK in cell survival, the data suggested that vitamin E treatment may exert a protective role in NSC-34 motor neurons. Moreover, Vitamin E treatment reduced the expression of the genes which encode proteins involved in mitophagy. These results indicate that vitamin E may be an efficacious therapy in preventing motor neuron death, opening new strategies for those diseases that involve motor neurons, including ALS.}, }
@article {pmid31096430, year = {2019}, author = {Liao, Q and Li, Z and Zeng, H and Feng, X and Huang, W and Fu, C and Liang, X and Li, T}, title = {Is the evidence strong enough for acupuncture ameliorates clinical symptoms in patients with amyotrophic lateral sclerosis: A protocol for a systematic review and meta-analysis.}, journal = {Medicine}, volume = {98}, number = {20}, pages = {e15218}, pmid = {31096430}, issn = {1536-5964}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Acupuncture Therapy/adverse effects/methods ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/mortality/therapy ; China ; Data Collection ; Databases, Factual ; Hand Strength/physiology ; Outcome Assessment, Health Care ; Pinch Strength/physiology ; Vital Capacity/physiology ; Meta-Analysis as Topic ; Systematic Reviews as Topic ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron diseases. Until now, it lacks effective drugs for its treatment, and the median survival time of ALS is reported as only 20 to 48 months after the onset of symptoms. Acupuncture served as part of traditional Chinese therapy, has been widely applied to clinical practice for patients with ALS but lacks studies to verify its efficacy. This study provides a protocol of systematic review, with which we will comprehensively verify the effects of acupuncture on ALS with evidence-based studies.<br><br>METHODS: The eligible studies will be collected from 4 English databases (the MEDLINE via PubMed, the Cochrane Library, EMBASE, the Web of Science, and Ovid database), and 4 Chinese databases (China Science and Technology Journal Database, Chinese Biomedical Literature Database, Wan-fang Database, China National Knowledge Infrastructure) from October 2000 to October 2022. The primary outcome measure is the change in amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) scores. We will use RevMan V.5.3 software to calculate the data synthesis and will conduct meta-analysis based on the collected data.<br><br>RESULTS: The primary outcome measure is the change in ALSFRS-R scores, and secondary outcome measures included changes in forced vital capacity, grasping power, pinch strength, modified Norris Scale, ALS assessment questionnaire-40, and time to activity of daily living-independent will be measured and comprehensively assessed to evaluate the effect of acupuncture on ALS from this systematic review and meta-analysis.<br><br>CONCLUSION: The systematic review and meta-analysis will assess the effect of acupuncture in the treatment of ALS with up-to-date clinical evidence.<br><br>PROSPERO REGISTRATION NUMBER: PROSPERO CRD 42019124785.}, }
@article {pmid31092730, year = {2019}, author = {Gertsman, I and Wuu, J and McAlonis-Downes, M and Ghassemian, M and Ling, K and Rigo, F and Bennett, F and Benatar, M and Miller, TM and Da Cruz, S}, title = {An endogenous peptide marker differentiates SOD1 stability and facilitates pharmacodynamic monitoring in SOD1 amyotrophic lateral sclerosis.}, journal = {JCI insight}, volume = {4}, number = {10}, pages = {}, pmid = {31092730}, issn = {2379-3708}, support = {R01 NS078398/NS/NINDS NIH HHS/United States ; R01 NS097816/NS/NINDS NIH HHS/United States ; R21 NS099766/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/therapy ; Animals ; *Biomarkers/cerebrospinal fluid ; Disease Models, Animal ; Gene Silencing ; Humans ; Mutation ; Peptides/cerebrospinal fluid/*pharmacology ; Rats ; Spinal Cord ; Superoxide Dismutase-1/*genetics ; }, abstract = {The discovery of novel biomarkers has emerged as a critical need for therapeutic development in amyotrophic lateral sclerosis (ALS). For some subsets of ALS, such as the genetic superoxide dismutase 1 (SOD1) form, exciting new treatment strategies, such as antisense oligonucleotide-mediated (ASO-mediated) SOD1 silencing, are being tested in clinical trials, so the identification of pharmacodynamic biomarkers for therapeutic monitoring is essential. We identify increased levels of a 7-amino acid endogenous peptide of SOD1 in cerebrospinal fluid (CSF) of human SOD1 mutation carriers but not in other neurological cases or nondiseased controls. Levels of peptide elevation vary based on the specific SOD1 mutation (ranging from 1.1-fold greater than control in D90A to nearly 30-fold greater in V148G) and correlate with previously published measurements of SOD1 stability. Using a mass spectrometry-based method (liquid chromatography-mass spectrometry), we quantified peptides in both extracellular samples (CSF) and intracellular samples (spinal cord from rat) to demonstrate that the peptide distinguishes mutation-specific differences in intracellular SOD1 degradation. Furthermore, 80% and 63% reductions of the peptide were measured in SOD1G93A and SOD1H46R rat CSF samples, respectively, following treatment with ASO, with an improved correlation to mRNA levels in spinal cords compared with the ELISA measuring intact SOD1 protein. These data demonstrate the potential of this peptide as a pharmacodynamic biomarker.}, }
@article {pmid31089048, year = {2019}, author = {Walker, CL}, title = {Adipose-derived stem cell conditioned medium for the treatment of amyotrophic lateral sclerosis: pre-clinical evidence and potential for clinical application.}, journal = {Neural regeneration research}, volume = {14}, number = {9}, pages = {1522-1524}, pmid = {31089048}, issn = {1673-5374}, support = {IK2 RX002688/RX/RRD VA/United States ; }, }
@article {pmid31089037, year = {2019}, author = {French, PW and Ludowyke, RI and Guillemin, GJ}, title = {Fungal-contaminated grass and well water and sporadic amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {14}, number = {9}, pages = {1490-1493}, pmid = {31089037}, issn = {1673-5374}, abstract = {Fungi are important infectious disease-causing agents, but are often overlooked as environmental factors in disease. We review several lines of evidence that point to a potential fungal origin of sporadic amyotrophic lateral sclerosis (ALS), the most common form of motor neurone disease. Approximately 90% cases of ALS are sporadic, and the aetiology of sporadic ALS is still unknown. We have previously postulated that grass or soil-associated fungal infections may be a leading cause of sporadic ALS. Herein we extend this proposal to water-associated fungi. A wide variety of fungi have been reported in drinking water including Acremonium, Alternaria, Aspergillus, Cladosporium, Fusarium, Penicillium and Trichoderma. Some of these are known to produce neurotoxic mycotoxins. Despite this, drinking water is not routinely monitored for fungal contamination. Fungal contamination could explain the close correlation between distribution of well water and cases of sporadic ALS in the United States. We propose several mechanisms by which an opportunistic fungal infection from environmental exposure (to water, soil or plants) can lead to long term neuronal degradation resulting in the hallmarks of ALS. If confirmed, the association between fungal infection and sporadic ALS could lead to novel treatment strategies for this progressive and fatal disease.}, }
@article {pmid31084461, year = {2019}, author = {Howard, I}, title = {Cannabis Hyperemesis Syndrome in Palliative Care: A Case Study and Narrative Review.}, journal = {Journal of palliative medicine}, volume = {22}, number = {10}, pages = {1227-1231}, doi = {10.1089/jpm.2018.0531}, pmid = {31084461}, issn = {1557-7740}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/therapy ; Humans ; Male ; Medical Marijuana/*adverse effects ; *Palliative Care ; Syndrome ; Vomiting/*chemically induced ; }, abstract = {Background: Cannabis is increasingly used by persons at end of life to ameliorate symptoms such as pain, spasticity, anorexia, or anxiety. Cannabis hyperemesis is a distressing adverse effect of chronic use and may cause significant morbidity. Unfortunately, the clinical presentation of this syndrome may be subtle in a person with complex medical issues or disability. Providers must remain vigilant for possible variations in presentation in these populations. Aim: To assess literature on cannabis hyperemesis and present unique considerations for clinical assessment and treatment for patients at end of life. Design: Initial literature scoping yielded limited evidence on the subject in the setting of chronic disease and disability. A case of cannabis hyperemesis in a person with advanced amyotrophic lateral sclerosis is presented to illustrate challenges in diagnosis and management in this setting. A narrative synthesis of current literature on assessment and management and special considerations for evaluation and treatment for patients under palliative care was performed. Results: Several unique considerations for the diagnosis and management of cannabis hyperemesis in palliative care patients are highlighted in the case presented, including: (1) Symptoms may possibly be abolished through decrease rather than complete abstinence from cannabis, (2) Frequent hot baths may not be present in patients with physical impairments in activities of daily living, and (3) Management of primary symptoms (pain, spasticity, nausea, and anxiety) in the end-of-life care patient must be considered to maximize comfort. Conclusion: The presentation of cannabis hyperemesis may be atypical in palliative care patients due to disability. More work is needed to improve risk stratification for patients using cannabis for palliative care.}, }
@article {pmid31081694, year = {2019}, author = {Shefner, JM and Cudkowicz, ME and Hardiman, O and Cockcroft, BM and Lee, JH and Malik, FI and Meng, L and Rudnicki, SA and Wolff, AA and Andrews, JA and , }, title = {A phase III trial of tirasemtiv as a potential treatment for amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {0}, number = {0}, pages = {1-11}, doi = {10.1080/21678421.2019.1612922}, pmid = {31081694}, issn = {2167-9223}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy ; Disease Progression ; Double-Blind Method ; Female ; Humans ; Imidazoles/*pharmacology ; Male ; Middle Aged ; Muscle Strength/*drug effects ; Muscle, Skeletal/*drug effects ; Pyrazines/*pharmacology ; Treatment Outcome ; }, abstract = {OBJECTIVE: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo in patients with amyotrophic lateral sclerosis. Methods: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled clinical trial. Participants tolerating 2 weeks of open-label tirasemtiv (125 mg twice daily) were randomized 3:2:2:2 to placebo or one of three target tirasemtiv dose levels, using an escalating dosage protocol lasting 28 days. The primary outcome measure was changed in slow vital capacity (SVC) at 24 weeks. Secondary endpoints included a change in muscle strength and time to respiratory milestones of disease progression.<br><br>RESULTS: Of 744 participants, 565 tolerated open-label tirasemtiv and received randomized treatment. By 24 weeks, 23 (12.2%) placebo-treated participants discontinued study treatment vs. 129 (34.2%) randomized to tirasemtiv. SVC declined by 14.4% (95% CI: &#x2212;16.8, &#x2212;11.9) in the placebo group and 13.4% (95% CI: &#x2212;15.3, &#x2212;11.6) in the tirasemtiv group (p&#x2009;=&#x2009;0.56). Secondary endpoints did not show significant differences. However, participants who tolerated tirasemtiv at their randomized dose showed a numeric trend toward a dose-related slowing of decline in SVC (p&#x2009;=&#x2009;0.11). Dizziness, fatigue, nausea, weight loss, and insomnia occurred more frequently on tirasemtiv. Serious adverse events were similar across groups.<br><br>CONCLUSIONS: Tirasemtiv did not alter the decline of SVC or significantly impact secondary outcome measures. Poor tolerability of tirasemtiv may have contributed to this result. However, participants tolerating their intended dose exhibited a trend toward treatment benefit on SVC, suggesting the underlying mechanism of action may still hold promise, as is being tested with a different fast skeletal muscle troponin activator (NCT03160898).}, }
@article {pmid31077796, year = {2019}, author = {Subhramanyam, CS and Wang, C and Hu, Q and Dheen, ST}, title = {Microglia-mediated neuroinflammation in neurodegenerative diseases.}, journal = {Seminars in cell &amp; developmental biology}, volume = {94}, number = {}, pages = {112-120}, doi = {10.1016/j.semcdb.2019.05.004}, pmid = {31077796}, issn = {1096-3634}, mesh = {Animals ; Humans ; Inflammation/*metabolism/pathology ; Microglia/*metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology ; }, abstract = {Microglia, being the resident immune cells of the central nervous system, play an important role in maintaining tissue homeostasis and contributes towards brain development under normal conditions. However, when there is a neuronal injury or other insult, depending on the type and magnitude of stimuli, microglia will be activated to secrete either proinflammatory factors that enhance cytotoxicity or anti-inflammatory neuroprotective factors that assist in wound healing and tissue repair. Excessive microglial activation damages the surrounding healthy neural tissue, and the factors secreted by the dead or dying neurons in turn exacerbate the chronic activation of microglia, causing progressive loss of neurons. It is the case observed in many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. This review gives a detailed account of the microglia-mediated neuroinflammation in various neurodegenerative diseases. Hence, resolving chronic inflammation mediated by microglia bears great promise as a novel treatment strategy to reduce neuronal damage and to foster a permissive environment for further regeneration effort.}, }
@article {pmid31068973, year = {2019}, author = {Silva, PR and Nieva, GV and Igaz, LM}, title = {Suppression of Conditional TDP-43 Transgene Expression Differentially Affects Early Cognitive and Social Phenotypes in TDP-43 Mice.}, journal = {Frontiers in genetics}, volume = {10}, number = {}, pages = {369}, pmid = {31068973}, issn = {1664-8021}, abstract = {Dysregulation of TAR DNA-binding protein 43 (TDP-43) is a hallmark feature of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two fatal neurodegenerative diseases. TDP-43 is a ubiquitously expressed RNA-binding protein with many physiological functions, playing a role in multiple aspects of RNA metabolism. We developed transgenic mice conditionally overexpressing human wild-type TDP-43 protein (hTDP-43-WT) in forebrain neurons, a model that recapitulates several key features of FTD. After post-weaning transgene (TG) induction during 1 month, these mice display an early behavioral phenotype, including impaired cognitive and social function with no substantial motor abnormalities. In order to expand the analysis of this model, we took advantage of the temporal and regional control of TG expression possible in these mice. We behaviorally evaluated mice at two different times: after 2 weeks of post-weaning TG induction (0.5 month group) and after subsequent TG suppression for 2 weeks following that time point [1 month (sup) group]. We found no cognitive abnormalities after 0.5 month of hTDP-43 expression, evaluated with a spatial working memory task (Y-maze test). Suppression of TG expression with doxycycline (Dox) at this time point prevented the development of cognitive deficits previously observed at 1 month post-induction, as revealed by the performance of the 1 month (sup) group. On the other hand, sociability deficits (assessed through the social interaction test) appeared very rapidly after Dox removal (0.5 month) and TG suppression was not sufficient to reverse this phenotype, indicating differential vulnerability to hTDP-43 expression and suppression. Animals evaluated at the early time point (0.5 month) post-induction do not display a motor phenotype, in agreement with the results obtained after 1 month of TG expression. Moreover, all motor tests (open field, accelerated rotarod, limb clasping, hanging wire grip) showed identical responses in both control and bigenic animals in the suppressed group, demonstrating that this protocol and treatment do not cause non-specific effects in motor behavior, which could potentially mask the phenotypes in other domains. Our results show that TDP-43-WT mice have a phenotype that qualifies them as a useful model of FTD and provide valuable information for susceptibility windows in therapeutic strategies for TDP-43 proteinopathies.}, }
@article {pmid31059788, year = {2019}, author = {Jin, X and Liu, MY and Zhang, DF and Zhong, X and Du, K and Qian, P and Gao, H and Wei, MJ}, title = {Natural products as a potential modulator of microglial polarization in neurodegenerative diseases.}, journal = {Pharmacological research}, volume = {145}, number = {}, pages = {104253}, doi = {10.1016/j.phrs.2019.104253}, pmid = {31059788}, issn = {1096-1186}, mesh = {Animals ; Biological Products/*therapeutic use ; Humans ; Microglia/*drug effects/physiology ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/*therapeutic use ; Phenotype ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by the progressive loss of structure and function of neurons most common in elderly population, mainly including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Neuroinflammation caused by microglia as the resident macrophages of the central nervous system (CNS) plays a contributory role in the onset and progression of NDs. Activated microglia, as in macrophages, to be heterogeneous, can polarize into M1 (pro-inflammatory) and M2 (anti-inflammatory) functional phenotypes. The former elaborate pro-inflammatory mediators promoting neuroinflammation and neuronal damage. In contrast, the latter generate anti-inflammatory mediators and neurotrophins that inhibit neuroinflammation and promote neuronal healing. Consistently, the regulation of microglial polarization from M1 to M2 phenotype appears as an outstanding therapeutic and preventive approach for NDs treatment. Although non-steroidal anti-inflammatory drugs (NSAIDs) currently used to alleviate M1 microglia-associated neuroinflammation responsible for the development of NDs, these drugs have different degrees of adverse effects and limited efficacy. As the advantages of novel structure, multi-target, high efficiency and low toxicity, natural products as the modulators of microglial polarization have attracted considerable concerns in the therapeutic areas of NDs. In this review, we mainly summarized the therapeutic potential of natural products and their various molecular mechanisms for NDs treatment through modulating microglial polarization. The aim of the current review is expected to be useful to develop innovative modulators of microglial polarization from natural products for the amelioration and treatment of NDs.}, }
@article {pmid31048504, year = {2019}, author = {Degterev, A and Ofengeim, D and Yuan, J}, title = {Targeting RIPK1 for the treatment of human diseases.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {116}, number = {20}, pages = {9714-9722}, pmid = {31048504}, issn = {1091-6490}, support = {R21 AG059073/AG/NIA NIH HHS/United States ; R01 CA190542/CA/NCI NIH HHS/United States ; RF1 AG055521/AG/NIA NIH HHS/United States ; R21 AI124049/AI/NIAID NIH HHS/United States ; R56 AG058642/AG/NIA NIH HHS/United States ; R01 AG047231/AG/NIA NIH HHS/United States ; }, mesh = {Apoptosis ; Central Nervous System Diseases/*drug therapy ; Drug Development ; Gene Expression ; Humans ; Inflammation/metabolism ; *Molecular Targeted Therapy ; Necroptosis ; Receptor-Interacting Protein Serine-Threonine Kinases/*antagonists &amp; inhibitors ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {RIPK1 kinase has emerged as a promising therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases. This was supported by extensive studies which demonstrated that RIPK1 is a key mediator of apoptotic and necrotic cell death as well as inflammatory pathways. Furthermore, human genetic evidence has linked the dysregulation of RIPK1 to the pathogenesis of ALS as well as other inflammatory and neurodegenerative diseases. Importantly, unique allosteric small-molecule inhibitors of RIPK1 that offer high selectivity have been developed. These molecules can penetrate the blood-brain barrier, thus offering the possibility to target neuroinflammation and cell death which drive various neurologic conditions including Alzheimer's disease, ALS, and multiple sclerosis as well as acute neurological diseases such as stroke and traumatic brain injuries. We discuss the current understanding of RIPK1 regulatory mechanisms and emerging evidence for the pathological roles of RIPK1 in human diseases, especially in the context of the central nervous systems.}, }
@article {pmid31038230, year = {2019}, author = {Peikert, K and Naumann, M and Günther, R and Wegner, F and Hermann, A}, title = {Off-Label Treatment of 4 Amyotrophic Lateral Sclerosis Patients With 4-Aminopyridine.}, journal = {Journal of clinical pharmacology}, volume = {59}, number = {10}, pages = {1400-1404}, doi = {10.1002/jcph.1437}, pmid = {31038230}, issn = {1552-4604}, mesh = {4-Aminopyridine/*therapeutic use ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Female ; Humans ; Male ; Off-Label Use ; Quality of Life ; Retrospective Studies ; Superoxide Dismutase/metabolism ; Young Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by degeneration of the upper and lower motor neuron. Among the at least 25 known genes associated with familial (hereditary) and sporadic ALS, mutations in fused-in-sarcoma (FUS) and superoxide dismutase 1 (SOD1) have been extensively investigated in the past years, with emphasis on altered excitability of affected neurons. Recently, we reported on hypoexcitability and increased cell death in a FUS/SOD1-ALS-induced pluripotent stem cell-derived motor neuron model, which was partly reversible by a treatment with the potassium channel blocker 4-aminopyridine (4-AP). Based on this study, we aimed to examine this US Food and Drug Administration-approved drug as a potential individualized treatment for patients with ALS. We therefore retrospectively investigated 4 FUS/SOD1-ALS patients who were prescribed 4-AP. Two patients expressed an improved quality of life due to regain of facial muscle motor function and decreased disease progression rate, respectively. Together with recent pathophysiologic findings, this case series supports the need for clinical trials to examine the efficacy of this potential treatment in distinct ALS subgroups and disease stages.}, }
@article {pmid31037649, year = {2019}, author = {Brennan, S and Keon, M and Liu, B and Su, Z and Saksena, NK}, title = {Panoramic Visualization of Circulating MicroRNAs Across Neurodegenerative Diseases in Humans.}, journal = {Molecular neurobiology}, volume = {56}, number = {11}, pages = {7380-7407}, pmid = {31037649}, issn = {1559-1182}, mesh = {Circulating MicroRNA/genetics/*metabolism ; Down-Regulation/genetics ; Gene Expression Profiling ; Gene Ontology ; Genome, Human ; Humans ; Neurodegenerative Diseases/*blood/*genetics ; Phylogeny ; }, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and dementia pose one of the greatest health challenges this century. Although these NDs have been looked at as single entities, the underlying molecular mechanisms have never been collectively visualized to date. With the advent of high-throughput genomic and proteomic technologies, we now have the opportunity to visualize these diseases in a whole new perspective, which will provide a clear understanding of the primary and secondary events vital in achieving the final resolution of these diseases guiding us to new treatment strategies to possibly treat these diseases together. We created a knowledge base of all microRNAs known to be differentially expressed in various body fluids of ND patients. We then used several bioinformatic methods to understand the functional intersections and differences between AD, PD, ALS, and MS. These results provide a unique panoramic view of possible functional intersections between AD, PD, MS, and ALS at the level of microRNA and their cognate genes and pathways, along with the entities that unify and separate them. While the microRNA signatures were apparent for each ND, the unique observation in our study was that hsa-miR-30b-5p overlapped between all four NDS, and has significant functional roles described across NDs. Furthermore, our results also show the evidence of functional convergence of miRNAs which was associated with the regulation of their cognate genes represented in pathways that included fatty acid synthesis and metabolism, ECM receptor interactions, prion diseases, and several signaling pathways critical to neuron differentiation and survival, underpinning their relevance in NDs. Envisioning this group of NDs together has allowed us to propose new ways of utilizing circulating miRNAs as biomarkers and in visualizing diverse NDs more holistically . The critical molecular insights gained through the discovery of ND-associated miRNAs, overlapping miRNAs, and the functional convergence of microRNAs on vital pathways strongly implicated in neurodegenerative processes can prove immensely valuable in the identifying new generation of biomarkers, along with the development of miRNAs into therapeutics.}, }
@article {pmid31037421, year = {2019}, author = {Luo, W and Li, Y and Xu, Q and Gu, R and Zhao, J}, title = {Cervical spondylotic amyotrophy: a systematic review.}, journal = {European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society}, volume = {28}, number = {10}, pages = {2293-2301}, pmid = {31037421}, issn = {1432-0932}, mesh = {*Cervical Vertebrae/surgery ; Conservative Treatment ; Decompression, Surgical ; Diagnosis, Differential ; Humans ; Immobilization ; Physical Therapy Modalities ; Prognosis ; Spinal Fusion ; Spondylosis/classification/*diagnosis/*therapy ; Traction ; }, abstract = {PURPOSE: Cervical spondylotic amyotrophy (CSA) is characterized by upper limb muscle weakness and atrophy, without sensory deficits. The pathophysiology of CSA has been attributed to selective injury to the ventral nerve root and/or anterior horn of the spinal cord. This review aimed to delineate the history of CSA and to describe the epidemiology, etiology, pathophysiology, classification, clinical features, radiological and electrophysiological assessment, diagnosis, differential diagnosis, natural history and treatment of CSA.<br><br>METHODS: A comprehensive search of PubMed, EMBASE, Cochrane library and Web of Science databases was conducted, from their inception to April 3, 2018.<br><br>RESULTS: Clinically, CSA is classified into three types: a proximal-type (involving the scapular muscles, deltoid and biceps), a distal-type (involving the triceps and muscles of the forearm and hand) and a diffuse-type (involving features of both the distal- and proximal-type). Diagnosis requires documentation of muscle atrophy, without significant sensory deficits, supported by careful neurological, radiological and neurophysiological assessments, with amyotrophic lateral sclerosis, Parsonage-Turner syndrome, rotator cuff tear and Hirayama disease being the principle differential diagnoses. Conservative management of CSA includes cervical traction, neck immobilization and physical therapy, with vitamin B12 or E administration being useful in some patients. Surgical treatment, including anterior decompression and fusion or laminoplasty, with or without foraminotomy, is indicated after conservative treatment failure. Factors associated with a poor outcome include the distal-type CSA, long symptom duration, older age and greater preoperative muscle weakness.<br><br>CONCLUSION: Although the disease process of CSA is self-limited, treatment remains challenging, leaving scope for future studies. These slides can be retrieved under Electronic Supplementary Material.}, }
@article {pmid31036551, year = {2019}, author = {Jiang, T and Handley, E and Brizuela, M and Dawkins, E and Lewis, KEA and Clark, RM and Dickson, TC and Blizzard, CA}, title = {Amyotrophic lateral sclerosis mutant TDP-43 may cause synaptic dysfunction through altered dendritic spine function.}, journal = {Disease models &amp; mechanisms}, volume = {12}, number = {5}, pages = {}, pmid = {31036551}, issn = {1754-8411}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Axons/metabolism/pathology ; Cerebral Cortex/pathology ; DNA-Binding Proteins/*genetics ; Dendritic Spines/metabolism/*pathology ; Humans ; Mice, Transgenic ; Mutation/*genetics ; Synapses/metabolism/*pathology ; }, abstract = {Altered cortical excitability and synapse dysfunction are early pathogenic events in amyotrophic lateral sclerosis (ALS) patients and animal models. Recent studies propose an important role for TAR DNA-binding protein 43 (TDP-43), the mislocalization and aggregation of which are key pathological features of ALS. However, the relationship between ALS-linked TDP-43 mutations, excitability and synaptic function is not fully understood. Here, we investigate the role of ALS-linked mutant TDP-43 in synapse formation by examining the morphological, immunocytochemical and excitability profile of transgenic mouse primary cortical pyramidal neurons that over-express human TDP-43[A315T] In TDP-43[A315T] cortical neurons, dendritic spine density was significantly reduced compared to wild-type controls. TDP-43[A315T] over-expression increased the total levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropinionic acid (AMPA) glutamate receptor subunit GluR1, yet the localization of GluR1 to the dendritic spine was reduced. These postsynaptic changes were coupled with a decrease in the amount of the presynaptic marker synaptophysin that colocalized with dendritic spines. Interestingly, action potential generation was reduced in TDP-43[A315T] pyramidal neurons. This work reveals a crucial effect of the over-expression mutation TDP-43[A315T] on the formation of synaptic structures and the recruitment of GluR1 to the synaptic membrane. This pathogenic effect may be mediated by cytoplasmic mislocalization of TDP-43[A315T] Loss of synaptic GluR1, and reduced excitability within pyramidal neurons, implicates hypoexcitability and attenuated synaptic function in the pathogenic decline of neuronal function in TDP-43-associated ALS. Further studies into the mechanisms underlying AMPA receptor-mediated excitability changes within the ALS cortical circuitry may yield novel therapeutic targets for treatment of this devastating disease.}, }
@article {pmid31029113, year = {2019}, author = {Inoue-Shibui, A and Kato, M and Suzuki, N and Kobayashi, J and Takai, Y and Izumi, R and Kawauchi, Y and Kuroda, H and Warita, H and Aoki, M}, title = {Interstitial pneumonia and other adverse events in riluzole-administered amyotrophic lateral sclerosis patients: a retrospective observational study.}, journal = {BMC neurology}, volume = {19}, number = {1}, pages = {72}, pmid = {31029113}, issn = {1471-2377}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy ; Chemical and Drug Induced Liver Injury/epidemiology/etiology ; Disease Progression ; Female ; Humans ; Lung Diseases, Interstitial/chemically induced/epidemiology ; Male ; Middle Aged ; Neuroprotective Agents/*adverse effects ; Retrospective Studies ; Riluzole/*adverse effects ; }, abstract = {BACKGROUND: Riluzole is the only approved oral drug for amyotrophic lateral sclerosis (ALS). We performed a retrospective study including ALS patients treated with riluzole, focusing on adverse events.<br><br>METHODS: Patients diagnosed with ALS according to the revised El Escorial criteria (World Federation of Neurology) in our center and who were administered 50&#x2009;mg oral riluzole twice daily between January 2011 and September 2017 and followed up for at least 6&#x2009;months from treatment initiation or until death were included. Data regarding sex, age, disease type, initial symptoms, biochemical analyses performed before and after riluzole administration, and medical history were collected. In case of withdrawal, cause of discontinuation and durations of disease and drug administration were recorded.<br><br>RESULTS: A total of 92 cases were enrolled. Riluzole administration was discontinued in 20 cases (21.7%). The most frequent reason for discontinuation was elevated liver enzymes (n&#xa0;=&#x2009;5, 5.4%), followed interstitial pneumonia (IP), nausea and appetite loss, dizziness, general malaise, tongue paresthesia, and urinary urgency. In two cases, administration was discontinued primarily because of progression of bulbar palsy. All adverse events occurred within 6&#x2009;months from treatment initiation and improved soon after its discontinuation. Three IP cases developed severe respiratory failure and required steroid treatment.<br><br>CONCLUSION: Riluzole administration was discontinued in 20 cases among total of 92 cases. Careful follow-up is important for the first six months after the initiation of riluzole administration, including through interviews, chemical analyses, and chest X-rays, as required.}, }
@article {pmid31024256, year = {2019}, author = {Vaz, AR and Pinto, S and Ezequiel, C and Cunha, C and Carvalho, LA and Moreira, R and Brites, D}, title = {Phenotypic Effects of Wild-Type and Mutant SOD1 Expression in N9 Murine Microglia at Steady State, Inflammatory and Immunomodulatory Conditions.}, journal = {Frontiers in cellular neuroscience}, volume = {13}, number = {}, pages = {109}, pmid = {31024256}, issn = {1662-5102}, abstract = {Accumulation of mutated superoxide dismutase 1 (mSOD1) in amyotrophic lateral sclerosis (ALS) involves injury to motor neurons (MNs), activation of glial cells and immune unbalance. However, neuroinflammation, besides its detrimental effects, also plays beneficial roles in ALS pathophysiology. Therefore, the targeting of microglia to modulate the release of inflammatory neurotoxic mediators and their exosomal dissemination, while strengthening cell neuroprotective properties, has gained growing interest. We used the N9 microglia cell line to identify phenotype diversity upon the overexpression of wild-type (WT; hSOD1[WT]) and mutated G93A (hSOD1[G93A]) protein. To investigate how each transduced cell respond to an inflammatory stimulus, N9 microglia were treated with lipopolysaccharide (LPS). Glycoursodeoxycholic acid (GUDCA) and dipeptidyl vinyl sulfone (VS), known to exert neuroprotective properties, were tested for their immunoregulatory properties. Reduced Fizz1, IL-10 and TLR4 mRNAs were observed in both transduced cells. However, in contrast with hSOD1[WT]-induced decreased of inflammatory markers, microglia transduced with hSOD1[G93A] showed upregulation of pro-inflammatory (TNF-α/IL-1β/HMGB1/S100B/iNOS) and membrane receptors (MFG-E8/RAGE). Importantly, their derived exosomes were enriched in HMGB1 and SOD1. When inflammatory-associated miRNAs were evaluated, increased miR-146a in cells with overexpressed hSOD1[WT] was not recapitulated in their exosomes, whereas hSOD1[G93A] triggered elevated exosomal miR-155/miR-146a, but no changes in cells. LPS stimulus increased M1/M2 associated markers in the naïve microglia, including MFG-E8, miR-155 and miR-146a, whose expression was decreased in both hSOD1[WT] and hSOD1[G93A] cells treated with LPS. Treatment with GUDCA or VS led to a decrease of TNF-α, IL-1β, HMGB1, S100B and miR-155 in hSOD1[G93A] microglia. Only GUDCA was able to increase cellular IL-10, RAGE and TLR4, together with miR-21, while decreased exosomal miR-155 cargo. Conversely, VS reduced MMP-2/MMP-9 activation, as well as upregulated MFG-E8 and miR-146a, while producing miR-21 shuttling into exosomes. The current study supports the powerful role of overexpressed hSOD1[WT] in attenuating M1/M2 activation, and that of hSOD1[G93A] in switching microglia from the steady state into a reactive phenotype with low responsiveness to stimuli. This work further reveals GUDCA and VS as promising modulators of microglia immune response by eliciting common and compound-specific molecular mechanisms that may promote neuroregeneration.}, }
@article {pmid31020811, year = {2019}, author = {Apolloni, S and Amadio, S and Fabbrizio, P and Morello, G and Spampinato, AG and Latagliata, EC and Salvatori, I and Proietti, D and Ferri, A and Madaro, L and Puglisi-Allegra, S and Cavallaro, S and Volonté, C}, title = {Histaminergic transmission slows progression of amyotrophic lateral sclerosis.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {10}, number = {4}, pages = {872-893}, pmid = {31020811}, issn = {2190-6009}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Disease Models, Animal ; Disease Progression ; Gene Expression/*genetics ; Histamine/pharmacology/*therapeutic use ; Humans ; Mice ; }, abstract = {BACKGROUND: Histamine is an immune modulator, neuroprotective, and remyelinating agent, beneficially acting on skeletal muscles and promoting anti-inflammatory features in amyotrophic lateral sclerosis (ALS) microglia. Drugs potentiating the endogenous release of histamine are in trial for neurological diseases, with a role not systematically investigated in ALS. Here, we examine histamine pathway associations in ALS patients and the efficacy of a histamine-mediated therapeutic strategy in ALS mice.<br><br>METHODS: We adopted an integrative multi-omics approach combining gene expression profiles, copy number variants, and single nucleotide polymorphisms of ALS patients. We treated superoxide dismutase 1 (SOD1)-G93A mice that recapitulate key ALS features, with the brain-permeable histamine precursor histidine in the symptomatic phase of the disease and analysed the rescue from disease pathological signs. We examined the action of histamine in cultured SOD1-G93A motor neuron-like cells.<br><br>RESULTS: We identified 13 histamine-related genes deregulated in the spinal cord of two ALS patient subgroups, among which genes involved in histamine metabolism, receptors, transport, and secretion. Some histamine-related genes overlapped with genomic regions disrupted by DNA copy number and with ALS-linked pathogenic variants. Histidine treatment in SOD1-G93A mice proved broad efficacy in ameliorating ALS features, among which most importantly lifespan, motor performance, microgliosis, muscle atrophy, and motor neurons survival in vivo and in vitro.<br><br>CONCLUSIONS: Our gene set/pathway enrichment analyses and preclinical studies started at the onset of symptoms establish that histamine-related genes are modifiers in ALS, supporting their role as candidate biomarkers and therapeutic targets. We disclose a novel important role for histamine in the characterization of the multi-gene network responsible for ALS and, furthermore, in the drug development process.}, }
@article {pmid31014130, year = {2020}, author = {Åkerblom, Y and Jakobsson Larsson, B and Zetterberg, L and Åsenlöf, P}, title = {The multiple faces of pain in motor neuron disease: a qualitative study to inform pain assessment and pain management.}, journal = {Disability and rehabilitation}, volume = {42}, number = {15}, pages = {2123-2132}, doi = {10.1080/09638288.2018.1555615}, pmid = {31014130}, issn = {1464-5165}, mesh = {Activities of Daily Living ; Humans ; *Motor Neuron Disease/complications ; Pain ; *Pain Management ; Pain Measurement ; Quality of Life ; }, abstract = {Purpose: The aim was to explore personal experiences of pain in people with motor neuron disease.Materials and methods: Sixteen participants were individually interviewed on one occasion concerning their experiences of presentation, consequences, and management of pain. Qualitative content analysis with researcher triangulation was used to synthesize and interpret data.Results: Four themes emerged as the result of the analysis: (1) The multiple faces of pain, (2) The thin line between experience of pain and no pain, (3) The negative effects of pain on role functioning (4) Successful coping with pain requiring personal effort and competent engagement. The important findings were the experiences of unpredictability of pain breakthroughs, the efforts required to manage pain, consequences for activity and quality of life, and the suffering induced by diminishment and neglect of pain from both patients and staff.Conclusions: Pain in motor neuron disease seems to have certain and multiple characteristics, which is why there is a need to develop and implement pain assessment methods adapted to this population. Such methods may help make pain more predictable, and increase the possibilities to provide effective and individually tailored pain treatment.IMPLICATIONS FOR REHABILITATIONPain is a common, but often neglected, ailment in motor neuro disease, which deserves more attention from health care.Staff should provide information about the pain being possible to treat successfully with medication, by contrast to the possibility of curing the disease itself.Pain assessments should be implemented during the entire course of the disease, covering a time frame long enough to cover characteristic fluctuations of pain.Whenever possible, facilitate the performance of painful activities of daily living as much as possible to make room for engagement in other personally valued activities of importance for individual quality of life.}, }
@article {pmid31011884, year = {2019}, author = {Raikwar, SP and Kikkeri, NS and Sakuru, R and Saeed, D and Zahoor, H and Premkumar, K and Mentor, S and Thangavel, R and Dubova, I and Ahmed, ME and Selvakumar, GP and Kempuraj, D and Zaheer, S and Iyer, SS and Zaheer, A}, title = {Next Generation Precision Medicine: CRISPR-mediated Genome Editing for the Treatment of Neurodegenerative Disorders.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {14}, number = {4}, pages = {608-641}, pmid = {31011884}, issn = {1557-1904}, support = {I01 BX002477/BX/BLRD VA/United States ; R01 AG048205/AG/NIA NIH HHS/United States ; RO1 AG048205/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; CRISPR-Associated Protein 9/*genetics ; CRISPR-Cas Systems/*genetics ; Gene Editing/methods/*trends ; Genetic Therapy/methods/trends ; Humans ; Neurodegenerative Diseases/*genetics/*therapy ; Precision Medicine/methods/*trends ; Treatment Outcome ; }, abstract = {Despite significant advancements in the field of molecular neurobiology especially neuroinflammation and neurodegeneration, the highly complex molecular mechanisms underlying neurodegenerative diseases remain elusive. As a result, the development of the next generation neurotherapeutics has experienced a considerable lag phase. Recent advancements in the field of genome editing offer a new template for dissecting the precise molecular pathways underlying the complex neurodegenerative disorders. We believe that the innovative genome and transcriptome editing strategies offer an excellent opportunity to decipher novel therapeutic targets, develop novel neurodegenerative disease models, develop neuroimaging modalities, develop next-generation diagnostics as well as develop patient-specific precision-targeted personalized therapies to effectively treat neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Frontotemporal dementia etc. Here, we review the latest developments in the field of CRISPR-mediated genome editing and provide unbiased futuristic insights regarding its translational potential to improve the treatment outcomes and minimize financial burden. However, despite significant advancements, we would caution the scientific community that since the CRISPR field is still evolving, currently we do not know the full spectrum of CRISPR-mediated side effects. In the wake of the recent news regarding CRISPR-edited human babies being born in China, we urge the scientific community to maintain high scientific and ethical standards and utilize CRISPR for developing in vitro disease in a dish model, in vivo testing in nonhuman primates and lower vertebrates and for the development of neurotherapeutics for the currently incurable neurodegenerative disorders. Graphical Abstract.}, }
@article {pmid31000441, year = {2019}, author = {Conde, B and Martins, N and Brandão, M and Pimenta, AC and Winck, JC}, title = {Upper Airway Video Endoscopy: Assessment of the response to positive pressure ventilation and mechanical in-exsufflation.}, journal = {Pulmonology}, volume = {25}, number = {5}, pages = {299-304}, doi = {10.1016/j.pulmoe.2019.02.008}, pmid = {31000441}, issn = {2531-0437}, mesh = {Airway Obstruction/*diagnostic imaging ; Deep Sedation ; Endoscopy ; Humans ; *Insufflation ; Larynx/diagnostic imaging ; Nasal Cavity/diagnostic imaging ; Noninvasive Ventilation ; Pharynx/diagnostic imaging ; *Positive-Pressure Respiration ; Sleep ; Vocal Cord Dysfunction/*diagnostic imaging/etiology ; }, abstract = {Upper airways (UA) include the nasal cavities, pharynx, and larynx, and its main function is to warm and filter the inspired air. UA dysfunction is in the pathogenesis of various disorders, such as obstructive sleep apnea syndrome (OSAS) and vocal cord dysfunction. In addition, in some neurodegenerative diseases (e.g. Amyotrophic Lateral Sclerosis - ALS), UA dysfunction may also compromise the effective use of ventilatory support (VS). In this context, the endoscopic evaluation of UA may be useful in understanding the OSAS mechanisms, in determining the causes for treatment-induced airway obstruction and even in helping to titrate noninvasive ventilation (NIV) in ALS patients with bulbar or pseudo-bulbar (spastic) dysfunction. Specifically, in OSAS patients, when residual obstructive events persist, although an optimal ventilatory mode has been apparently achieved, along with interface and equipment, the endoscopic evaluation of UA seems to be a valuable tool in understanding its mechanisms, even assisting adjustments to NIV parameters. In addition, it has also been described as being useful in laryngeal response to mechanical in-exsufflation (MI-E) and Exercise-Induced Laryngeal Obstruction (EILO). However, no protocol has yet been published or validated for this. For this reason, a literature review was conducted on UA function and its response to positive pressure and MI-E. Special emphasis has also been given to the current indication for video endoscopy in chronically ventilated patients.}, }
@article {pmid30999379, year = {2019}, author = {Haensch, CA and Hilz, M and Jost, W and Kaufmann, A and Kessler, T and Lahrmann, H}, title = {[S1-Guideline for Diagnosis and Treatment of Erectile Dysfunction].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {87}, number = {4}, pages = {225-233}, doi = {10.1055/a-0747-5892}, pmid = {30999379}, issn = {1439-3522}, mesh = {Erectile Dysfunction/*diagnosis/*therapy ; Humans ; Male ; Practice Guidelines as Topic ; }, abstract = {Die S1-Leitlinie "Diagnostik und Therapie der erektilen Dysfunktion" (AWMF-Registernummer 030 / 112) steht in einer vollständig überarbeiteten Neufassung zur Verfügung. Erektile Dysfunktion ist definiert als die fortwährende Unfähigkeit, eine penile Erektion, die für einen befriedigenden Geschlechtsverkehr ausreicht, zu erreichen oder aufrechtzuerhalten. Betroffen sind Millionen Bundesbürger: Bei Männern mit regelmäßiger sexueller Aktivität nimmt die erektile Dysfunktion von 2,3 Prozent in der dritten Lebensdekade auf 53,4 Prozent in der siebten Lebensdekade zu. Die Leitlinie gibt dezidierte Empfehlungen zur adäquaten Diagnose und zur Therapie der erektilen Dysfunktion, die seit der Einführung der Phosphodiesterase-5-(PDE-5-)Hemmer häufig unkritisch erfolgt.}, }
@article {pmid30986029, year = {2019}, author = {Cheng, CS and Liu, TP and Chien, FC and Mou, CY and Wu, SH and Chen, YP}, title = {Codelivery of Plasmid and Curcumin with Mesoporous Silica Nanoparticles for Promoting Neurite Outgrowth.}, journal = {ACS applied materials &amp; interfaces}, volume = {11}, number = {17}, pages = {15322-15331}, doi = {10.1021/acsami.9b02797}, pmid = {30986029}, issn = {1944-8252}, mesh = {Actin Cytoskeleton/drug effects ; Animals ; Cell Line, Tumor ; Curcumin/chemistry/*pharmacology ; Drug Carriers/*chemistry ; GTP Phosphohydrolases/genetics ; Mice ; Nanoparticles/*chemistry ; Neuronal Outgrowth/*drug effects ; Oxidative Stress ; Particle Size ; Peptide Fragments/chemistry ; Plasmids/chemistry/*metabolism ; Porosity ; Reactive Oxygen Species/metabolism ; Silicon Dioxide/*chemistry ; tat Gene Products, Human Immunodeficiency Virus/chemistry ; }, abstract = {Reactive oxygen species (ROS)-induced oxidative stress leads to neuron damage and is involved in the pathogenesis of chronic inflammation in neurodegenerative diseases (NDs), such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Researchers, therefore, are looking for antiinflammatory drugs and gene therapy approaches to slow down or even prevent neurological disorders. Combining therapeutics has shown a synergistic effect in the treatment of human diseases. Many nanocarriers could be designed for the simultaneous codelivery of drugs with genes to fight diseases. However, only a few researches have been performed in NDs. In this study, we developed a mesoporous silica nanoparticle (MSN)-based approach for neurodegenerative therapy. This MSN-based platform involved multiple designs in the targeted codelivery of (1) curcumin, a natural antioxidant product, to protect ROS-induced cell damage and (2) plasmid RhoG-DsRed, which is associated with the formation of lamellipodia and filopodia for promoting neurite outgrowth. At the same time, TAT peptide was introduced to the plasmid RhoG-DsRed via electrostatic interaction to elevate the efficiency of nonendocytic pathways and the nuclear plasmid delivery of RhoG-DsRed in cells for enhanced gene expression. Besides, such a plasmid RhoG-DsRed/TAT complex could work as a noncovalent gatekeeper. The release of curcumin inside the channel of the MSN could be triggered when the complex was dissociated from the MSN surface. Taken together, this MSN-based platform combining genetic and pharmacological manipulations of an actin cytoskeleton as well as oxidative stress provides an attractive way for ND therapy.}, }
@article {pmid30982356, year = {2019}, author = {Palumbo, JM and Hubble, J and Apple, S and Takei, K and Tsuda, K and Liu, S and Zhang, J and Agnese, W}, title = {Post-hoc analyses of the edaravone clinical trials Study 16 and Study 19: a step toward more efficient clinical trial designs in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {5-6}, pages = {421-431}, doi = {10.1080/21678421.2019.1599955}, pmid = {30982356}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Clinical Trials, Phase II as Topic/*methods ; Clinical Trials, Phase III as Topic/*methods ; Disease Progression ; Double-Blind Method ; Edaravone/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; Randomized Controlled Trials as Topic/*methods ; Treatment Outcome ; }, abstract = {Objectives: The edaravone development program established a study design in which a treatment effect slowing functional loss in amyotrophic lateral sclerosis (ALS) could be documented within a 24-week time frame. This report elucidates the strategic enrichment design utilized to create efficiency and precision in the development program. Methods: Post-hoc analyses describe learning, sequential iteration, and evolution in study design. Results: The first Phase 3 study of edaravone in ALS (Study MCI186-16) included a large proportion (35%) of placebo patients who were minimal progressors. These patients demonstrated high heterogeneity in change in ALSFRS-R score (-4 median with interquartile range [IQR] 7.5) and a modal distribution score of 0, suggesting evidence of minimal change in ALSFRS-R during the study. This level of variability and rate of progression may have made it difficult to detect a prospective treatment effect in the study. A strategic enrichment strategy provided the second Phase 3 study (Study MCI186-19) with the ability to detect a treatment effect. In Study MCI186-19, only 13% of the placebo patients were minimal progressors. Further, these placebo patients demonstrated less heterogeneity and greater functional progression of ALS, thereby providing greater likelihood of detecting a treatment effect. The enrichment strategy may have excluded some rapidly progressing patients, potentially supporting the detection of a treatment effect. As previously published, Study MCI186-19 prospectively documented a 33% reduction in rate of progression of ALS (p = 0.0013). Conclusions: Strategic choices in the design of Study MCI186-19 reduced the proportion of minimally progressing patients and supported detection of a treatment effect.}, }
@article {pmid30976725, year = {2019}, author = {Taule, T and Spilde Morland, A and Arnevik Renså, M and Aßmus, J and Tysnes, OB and Rekand, T}, title = {Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS) in Norway: Protocol for validation and a prospective cohort study.}, journal = {Contemporary clinical trials communications}, volume = {14}, number = {}, pages = {100347}, pmid = {30976725}, issn = {2451-8654}, abstract = {In amyotrophic lateral sclerosis (ALS) cognitive impairment may occur. This could detrimentally influence communication between patient and health-care professionals and make clinical assessment difficult. Given the short life expectancy after diagnosis, it is crucial to accurately identify ALS patients early. Although suitable cognitive screening tools for patients with ALS are available, they have not been evaluated in a Norwegian population. Interpretation of scores for available tests and practical application of scoring is also not well established. The protocol described here involves two related studies that aim to improve the quality of ALS clinical testing instruments used in the Norwegian population. The first is a validation study that evaluates the psychometric properties of the ECAS-Norwegian. The second is a prospective cohort study that evaluates the ECAS-Norwegian as a tool to predict early changes in ability to work, drive a car and the need for advanced therapy. Study 1 is a multicenter study using international quality criteria. Patients with ALS, healthy control subjects, and control subjects with dementia will be included. Primary outcome is ECAS-Norwegian scores. In study 2, patients with ALS will be included. ECAS-Norwegian compared to Clinical Dementia Rating score and Montreal Cognitive Assessment scores will be used as a prognostic tool for working, driving, and initiating advanced life-prolonging therapy. Before clinical implementation, the ECAS-Norwegian needs to be evaluated and validated. Successful validation and implementation of the ECAS-Norwegian may provide early identification of cognitive impairment in ALS, leading to more proactive, individualized treatment.}, }
@article {pmid30974280, year = {2019}, author = {Bretonnier, M and Hénaux, PL and Gaberel, T and Roualdes, V and Kerdiles, G and Le Reste, PJ and Morandi, X}, title = {Spinal Dural Arteriovenous Fistulas: Clinical Outcome After Surgery Versus Embolization: A Retrospective Study.}, journal = {World neurosurgery}, volume = {127}, number = {}, pages = {e943-e949}, doi = {10.1016/j.wneu.2019.04.005}, pmid = {30974280}, issn = {1878-8769}, mesh = {Adult ; Aged ; Central Nervous System Vascular Malformations/*surgery ; Disability Evaluation ; *Embolization, Therapeutic/methods ; Endovascular Procedures/methods ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; *Neurosurgical Procedures/methods ; Retrospective Studies ; Spinal Cord/blood supply/*surgery ; Treatment Outcome ; }, abstract = {OBJECTIVE: Spinal dural arteriovenous fistulas (SDAVFs) are rare vascular spinal malformations. According to the reported data, surgery seems to result in better occlusion rates than endovascular treatment. However, the post-treatment evolution of neurological symptoms stratified by the treatment remains unknown. The main objective of the present study was to compare the clinical outcomes for patients according to the treatment method.<br><br>METHODS: The data from 63 patients with SDAVFs from 2000 to 2017 at 4 academic neurosurgical departments were retrospectively analyzed. Preoperative and postoperative examination neurological status was assessed using the Aminoff-Logue scale (ALS), which evaluates gait and micturition disturbances. Initial occlusion, late recurrence, and complications of the 2 techniques were also reviewed.<br><br>RESULTS: Patients who had undergone surgery and embolization improved clinically on the ALS (P&#xa0;= 0.0009), and no significant differences were found between the 2 techniques. Subgroup analysis using the ALS showed that patients who had undergone surgery and embolization without late recurrence improved (P < 0.0001 and P&#xa0;=&#xa0;0.0334, respectively) and that patients who had undergone surgery or embolization with late recurrence did not improve. The initial occlusion rate was in favor of surgery, with 91.3% versus 70% for endovascular treatment (P&#xa0;= 0.050). The late recurrence rate was higher for embolization (21.4% vs. 9.1% for surgery; P&#xa0;= 0.28).<br><br>CONCLUSIONS: Surgery can be proposed as first-line treatment of SDAVFs after multidisciplinary discussion between neurosurgeons and neuroradiologists. The development of late recurrence negatively affects the neurological outcome of patients.}, }
@article {pmid30973284, year = {2019}, author = {Forsberg, U and Jonsson, P and Stegmayr, B}, title = {Air contamination during medical treatment results in deposits of microemboli in the lungs: An autopsy study.}, journal = {The International journal of artificial organs}, volume = {42}, number = {9}, pages = {477-481}, doi = {10.1177/0391398819840363}, pmid = {30973284}, issn = {1724-6040}, mesh = {Aged ; Aged, 80 and over ; Autopsy ; Case-Control Studies ; Embolism, Air/*pathology ; Female ; Humans ; Lung/*pathology ; Male ; Renal Dialysis/*adverse effects ; }, abstract = {INTRODUCTION: Microbubbles of air may enter into patients during conventional hemodialysis, infusions of fluids, or by injections. The aim of this study was to investigate whether the air that enters the patient during hemodialysis can be detected in the lungs after death, and if so, whether this may be related to tissue damage.<br><br>METHODS: The material consisted of lung tissue from five chronic hemodialysis patients who died either during (two) or after hemodialysis (range 10&#x2009;min from start until 3333&#x2009;min after the last hemodialysis session); as reference group tissue was taken from seven patients who died due to amyotrophic lateral sclerosis. The lung tissue was investigated by microscopy after autopsy using a fluorescein-marked polyclonal antibody against fibrinogen as a marker for clots preformed before death.<br><br>RESULTS: All five hemodialysis patients had microbubbles of air in the lung tissue, whereas two of seven amyotrophic lateral sclerosis patients had such findings (Fisher's test p&#x2009;=&#x2009;0.0278, relative risk&#x2009;=&#x2009;3.5, confidence interval: 1.08-11.3). There were more microbubbles of air/10 randomly investigated microscopic fields of tissue in the hemodialysis patients than the amyotrophic lateral sclerosis patients (Student's test, p&#x2009;<&#x2009;0.05). All hemodialysis patients had a medium graded extent of pulmonary fibrosis that was not found in any of the ALS patients. The microbubbles of air were surrounded by fibrin as a sign of development of clots around the air bubbles while the patients were still alive.<br><br>CONCLUSION: Exposure to microbubbles of air during various treatments such as hemodialysis may result in microemboli. Future studies should clarify whether microbubbles of air contribute to tissue scarring. We suggest preventive measures against the exposure to microbubbles of air during especially repeated exposures such as hemodialysis.}, }
@article {pmid30972662, year = {2019}, author = {Quarracino, C and Segamarchi, MC and Rodríguez, GE}, title = {Predictors of amyotrophic lateral sclerosis mimic syndrome.}, journal = {Acta neurologica Belgica}, volume = {119}, number = {2}, pages = {253-256}, doi = {10.1007/s13760-019-01135-1}, pmid = {30972662}, issn = {2240-2993}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis ; Diagnosis, Differential ; *Diagnostic Errors/prevention &amp; control ; Electromyography/methods ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*diagnosis ; *Predictive Value of Tests ; Retrospective Studies ; Syndrome ; }, abstract = {The term amyotrophic lateral sclerosis mimic syndrome (ALSms) includes pathologies that present signs or symptoms similar to those caused by amyotrophic lateral sclerosis (ALS), which can lead to misdiagnosis. In general, any kind of misdiagnosis can result in negative clinical, psychological and economic consequences as well diagnostic and treatment delay. The objectives were to determine the frequency and to compare the demographic and clinical characteristics of patients with ALS and ALSms in our ALS clinic. We retrospectively studied all patients evaluated from 2007 to 2017 including only patients with a definite final diagnosis. Out of 368 patients with motor neuron disease symptomatology, 43 (11.7%) had an ALSms. The most frequent etiology was compressive myelopathy (32.6%). Multivariate analysis considering positive associations was statistically significant for patients having only upper or lower motor neuron signs in the physical examination, a non-compatible electromyogram (EMG), as well as atypical first symptoms. ALS misdiagnosis is an ongoing and not infrequent problem. From our series of patients, atypical symptoms, absence of EMG pathological findings or isolated upper or lower motor neuron disease should prompt suspicion of a differential diagnosis.}, }
@article {pmid30972018, year = {2019}, author = {Lingor, P and Weber, M and Camu, W and Friede, T and Hilgers, R and Leha, A and Neuwirth, C and Günther, R and Benatar, M and Kuzma-Kozakiewicz, M and Bidner, H and Blankenstein, C and Frontini, R and Ludolph, A and Koch, JC and , }, title = {ROCK-ALS: Protocol for a Randomized, Placebo-Controlled, Double-Blind Phase IIa Trial of Safety, Tolerability and Efficacy of the Rho Kinase (ROCK) Inhibitor Fasudil in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {293}, pmid = {30972018}, issn = {1664-2295}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; }, abstract = {Objectives: Disease-modifying therapies for amyotrophic lateral sclerosis (ALS) are still not satisfactory. The Rho kinase (ROCK) inhibitor fasudil has demonstrated beneficial effects in cell culture and animal models of ALS. For many years, fasudil has been approved in Japan for the treatment of vasospasm in patients with subarachnoid hemorrhage with a favorable safety profile. Here we describe a clinical trial protocol to repurpose fasudil as a disease-modifying therapy for ALS patients. Methods: ROCK-ALS is a multicenter, double-blind, randomized, placebo-controlled phase IIa trial of fasudil in ALS patients (EudraCT: 2017-003676-31, NCT: 03792490). Safety and tolerability are the primary endpoints. Efficacy is a secondary endpoint and will be assessed by the change in ALSFRS-R, ALSAQ-5, slow vital capacity (SVC), ECAS, and the motor unit number index (MUNIX), as well as survival. Efficacy measures will be assessed before (baseline) and immediately after the infusion therapy as well as on days 90 and 180. Patients will receive a daily dose of either 30 or 60 mg fasudil, or placebo in two intravenous applications for a total of 20 days. Regular assessments of safety will be performed throughout the treatment period, and in the follow-up period until day 180. Additionally, we will collect biological fluids to assess target engagement and evaluate potential biomarkers for disease progression. A total of 120 patients with probable or definite ALS (revised El Escorial criteria) and within 6-18 months of the onset of weakness shall be included in 16 centers in Germany, Switzerland and France. Results and conclusions: The ROCK-ALS trial is a phase IIa trial to evaluate the ROCK-inhibitor fasudil in early-stage ALS-patients that started patient recruitment in 2019.}, }
@article {pmid30967892, year = {2019}, author = {Verdile, V and De Paola, E and Paronetto, MP}, title = {Aberrant Phase Transitions: Side Effects and Novel Therapeutic Strategies in Human Disease.}, journal = {Frontiers in genetics}, volume = {10}, number = {}, pages = {173}, pmid = {30967892}, issn = {1664-8021}, abstract = {Phase separation is a physiological process occurring spontaneously when single-phase molecular complexes separate in two phases, a concentrated phase and a more diluted one. Eukaryotic cells employ phase transition strategies to promote the formation of intracellular territories not delimited by membranes with increased local RNA concentration, such as nucleolus, paraspeckles, P granules, Cajal bodies, P-bodies, and stress granules. These organelles contain both proteins and coding and non-coding RNAs and play important roles in different steps of the regulation of gene expression and in cellular signaling. Recently, it has been shown that most human RNA-binding proteins (RBPs) contain at least one low-complexity domain, called prion-like domain (PrLD), because proteins harboring them display aggregation properties like prion proteins. PrLDs support RBP function and contribute to liquid-liquid phase transitions that drive ribonucleoprotein granule assembly, but also render RBPs prone to misfolding by promoting the formation of pathological aggregates that lead to toxicity in specific cell types. Protein-protein and protein-RNA interactions within the separated phase can enhance the transition of RBPs into solid aberrant aggregates, thus causing diseases. In this review, we highlight the role of phase transition in human disease such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and in cancer. Moreover, we discuss novel therapeutic strategies focused to control phase transitions by preventing the conversion into aberrant aggregates. In this regard, the stimulation of chaperone machinery to disassemble membrane-less organelles, the induction of pathways that could inhibit aberrant phase separation, and the development of antisense oligonucleotides (ASOs) to knockdown RNAs could be evaluated as novel therapeutic strategies for the treatment of those human diseases characterized by aberrant phase transition aggregates.}, }
@article {pmid30967373, year = {2019}, author = {D'Alesio, C and Bellese, G and Gagliani, MC and Lechiara, A and Dameri, M and Grasselli, E and Lanfrancone, L and Cortese, K and Castagnola, P}, title = {The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2[+] breast cancer cells.}, journal = {Biology open}, volume = {8}, number = {4}, pages = {}, pmid = {30967373}, issn = {2046-6390}, abstract = {The chromodomain helicase DNA-binding 4 (CHD4), a member of the nucleosome remodeling and deacetylases (NuRD) complex, has been identified as an oncogene that modulates proliferation and migration of breast cancers (BC). ERBB2 is an oncogenic driver in 20-30% of BC in which its overexpression leads to increased chemoresistance. Here we investigated whether CHD4 depletion affects the ERBB2 cascade and autophagy, which represents a mechanism of resistance against Trastuzumab (Tz), a therapeutic anti-ERBB2 antibody. We show that CHD4 depletion in two ERBB2[+] BC cell lines strongly inhibits cell proliferation, induces p27[KIP1] upregulation, Tyr[1248] ERBB2 phosphorylation, ERK1/2 and AKT dephosphorylation, and downregulation of both ERBB2 and PI3K levels. Moreover, CHD4 silencing impairs late stages of autophagy, resulting in increased levels of LC3 II and SQSTM1/p62, lysosomal enlargement and accumulation of autolysosomes (ALs). Importantly, we show that CHD4 depletion and concomitant treatment with Tz prevent cell proliferation in vitro Our results suggest that CHD4 plays a critical role in modulating cell proliferation, ERBB2 signaling cascade and autophagy and provide new insights on CHD4 as a potential target for the treatment of ERBB2[+] BC.}, }
@article {pmid30964420, year = {2019}, author = {Haack, SE and Walse, SS and Nguyen, K and Adaskaveg, JE}, title = {Management of Xanthomonas fragariae with Pre- and Postharvest Treatments to Overcome Trade Barriers for California Strawberries.}, journal = {Plant disease}, volume = {103}, number = {6}, pages = {1256-1263}, doi = {10.1094/PDIS-08-18-1395-RE}, pmid = {30964420}, issn = {0191-2917}, mesh = {Agriculture/*methods ; Animals ; Anti-Bacterial Agents/pharmacology ; California ; Commerce ; *Fragaria/microbiology ; Fruit/microbiology ; Fumigation ; *Xanthomonas/drug effects/physiology ; }, abstract = {Xanthomonas fragariae, the causal agent of angular leaf spot (ALS) of strawberry, is a quarantine pathogen in some export markets, causing trade restrictions and economic loss to the California fresh-market strawberry industry. Preharvest chemical management options are limited to copper, and there are no postharvest treatments available that reduce populations of the pathogen if ALS is detected at an export destination. Here, we report high preharvest efficacy for the experimental bactericide amino thiadiazole and the commercial product zinc thiadiazole, alone and in mixtures with low rates of copper or the antibiotic kasugamycin, with average disease incidence reduction of up to 92.8% compared with the control. Although effective against quarantine insect pests of strawberry, postharvest methyl bromide fumigation was ineffective against X. fragariae in diseased plant tissue at a standard commercial rate. Postharvest propylene oxide fumigation, used for decades by the California nut industries for insect and microbial disinfestation, significantly reduced X. fragariae populations in infected leaflet tissues by at least 2.5-log compared with controls at a dose of ≥142 µg/ml for 2 h at 15 to 20°C. Fumigated leaflets showed little to no phytotoxicity at effective rates, and fumigated fruit were not significantly affected in appearance or susceptibility to postharvest gray mold or Rhizopus rot following storage at 2°C for 3 days and at 15°C for an additional 5 days. Together, these new treatments offer potential strategies for establishing a systems approach with preharvest treatments significantly reducing the risk of ALS on plants and, in response to quarantine detections, a postharvest fumigation treatment that reduces viable pathogen populations in existing lesions.}, }
@article {pmid30963986, year = {2019}, author = {Li, L and Liu, J and She, H}, title = {Targeting Macrophage for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {18}, number = {5}, pages = {366-371}, doi = {10.2174/1871527318666190409103831}, pmid = {30963986}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Drug Delivery Systems/*methods ; Humans ; Macrophages/*drug effects ; Neuromuscular Junction/drug effects ; }, abstract = {BACKGROUND &amp; OBJECTIVE: Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that specifically affects motor neurons in the brain and in the spinal cord. Patients with amyotrophic lateral sclerosis usually die from respiratory failure within 3 to 5 years from when the symptoms first appear. Currently, there is no cure for amyotrophic lateral sclerosis. Accumulating evidence suggests that dismantling of neuromuscular junction is an early event in the pathogenesis of amyotrophic lateral sclerosis.<br><br>CONCLUSION: It is starting to realized that macrophage malfunction contributes to the disruption of neuromuscular junction. Modulation of macrophage activation states may stabilize neuromuscular junction and provide protection against motor neuron degeneration in amyotrophic lateral sclerosis.}, }
@article {pmid30961394, year = {2019}, author = {Gowland, A and Opie-Martin, S and Scott, KM and Jones, AR and Mehta, PR and Batts, CJ and Ellis, CM and Leigh, PN and Shaw, CE and Sreedharan, J and Al-Chalabi, A}, title = {Predicting the future of ALS: the impact of demographic change and potential new treatments on the prevalence of ALS in the United Kingdom, 2020-2116.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {3-4}, pages = {264-274}, pmid = {30961394}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; G0900635/MRC_/Medical Research Council/United Kingdom ; MC_PC_17115/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; G1100695/MRC_/Medical Research Council/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Age Distribution ; Age Factors ; Aged ; Amyotrophic Lateral Sclerosis/*epidemiology/genetics/*therapy ; C9orf72 Protein/genetics ; Demography ; Female ; *Forecasting ; Humans ; Incidence ; Male ; Middle Aged ; Prevalence ; Sex Factors ; Survival Analysis ; Treatment Outcome ; United Kingdom/epidemiology ; }, abstract = {Objective: To model the effects of demographic change under various scenarios of possible future treatment developments in ALS. Methods: Patients diagnosed with ALS at the King's College Hospital Motor Nerve Clinic between 2004 and 2017, and living within the London boroughs of Lambeth, Southwark, and Lewisham (LSL), were included as incident cases. We also ascertained incident cases from the Canterbury region over the same period. Future incidence of ALS was estimated by applying the calculated age- and sex-specific incidence rates to the UK population projections from 2020 to 2116. The number of prevalent cases for each future year was estimated based on an established method. Assuming constant incidence, we modelled four possible future prevalence scenarios by altering the median disease duration for varying subsets of the population, to represent the impact of new treatments. Results: The total number of people newly diagnosed with ALS per year in the UK is projected to rise from a baseline of 1415 UK cases in 2010 to 1701 in 2020 and 2635 in 2116. Overall prevalence of ALS was predicted to increase from 8.58 per 100,000 persons in 2020 to 9.67 per 100,000 persons in 2116. Halting disease progression in patients with C9orf72 mutations would yield the greatest impact of the modelled treatment scenarios, increasing prevalence in the year 2066 from a baseline of 9.50 per 100,000 persons to 15.68 per 100,000 persons. Conclusions: Future developments in treatment would combine with the effects of demographic change to result in more people living longer with ALS.}, }
@article {pmid30958470, year = {2019}, author = {Bennett, SA and Cobos, SN and Meykler, M and Fallah, M and Rana, N and Chen, K and Torrente, MP}, title = {Characterizing Histone Post-translational Modification Alterations in Yeast Neurodegenerative Proteinopathy Models.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {145}, pages = {}, pmid = {30958470}, issn = {1940-087X}, support = {K22 NS091314/NS/NINDS NIH HHS/United States ; }, mesh = {Disease Progression ; Epigenesis, Genetic ; *Genomics ; Histones/*metabolism ; Neurodegenerative Diseases/*genetics/*metabolism/pathology ; *Protein Processing, Post-Translational ; *Saccharomyces cerevisiae ; }, abstract = {Neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), cause the loss of hundreds of thousands of lives each year. Effective treatment options able to halt disease progression are lacking. Despite the extensive sequencing efforts in large patient populations, the majority of ALS and PD cases remain unexplained by genetic mutations alone. Epigenetics mechanisms, such as the post-translational modification of histone proteins, may be involved in neurodegenerative disease etiology and progression and lead to new targets for pharmaceutical intervention. Mammalian in vivo and in vitro models of ALS and PD are costly and often require prolonged and laborious experimental protocols. Here, we outline a practical, fast, and cost-effective approach to determining genome-wide alterations in histone modification levels using Saccharomyces cerevisiae as a model system. This protocol allows for comprehensive investigations into epigenetic changes connected to neurodegenerative proteinopathies that corroborate previous findings in different model systems while significantly expanding our knowledge of the neurodegenerative disease epigenome.}, }
@article {pmid30956667, year = {2019}, author = {Gugliandolo, A and Bramanti, P and Mazzon, E}, title = {Mesenchymal Stem Cells: A Potential Therapeutic Approach for Amyotrophic Lateral Sclerosis?.}, journal = {Stem cells international}, volume = {2019}, number = {}, pages = {3675627}, pmid = {30956667}, issn = {1687-966X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons. Patients show both motor and extra-motor symptoms. A cure is not available at this time, and the disease leads to death within 3-5 years, mainly due to respiratory failure. Stem cell therapy is arising as a new promising approach for the treatment of neurodegenerative disorders. In particular, mesenchymal stem cells (MSCs) seem the most suitable type of stem cells, thanks to their demonstrated beneficial effects in different experimental models, to the easy availability, and to the lack of ethical problems. In this review, we focused on the studies involving ALS rodent models and clinical trials in order to understand the potential beneficial effects of MSC transplantation. In different ALS rodent models, the administration of MSCs induced a delay in disease progression and at least a partial recovery of the motor function. In addition, clinical trials evidenced the feasibility and safety of MSC transplantation in ALS patients, given that no major adverse events were recorded. However, only partial improvements were shown. For this reason, more studies and trials are needed to clarify the real effectiveness of MSC-based therapy in ALS.}, }
@article {pmid30942089, year = {2019}, author = {Jésus, P and Blasco, H and Patin, F and Bakkouche, SE and Beltran, S and Andrés, CR and Vourc'h, P and Maillot, F and Corcia, P}, title = {Ferritin and LDL-cholesterol as biomarkers of fat-free mass loss in ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {5-6}, pages = {441-444}, doi = {10.1080/21678421.2019.1597126}, pmid = {30942089}, issn = {2167-9223}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*blood/*diagnosis ; Biomarkers/blood ; Body Composition/*physiology ; Cholesterol, LDL/*blood ; *Electric Impedance ; Female ; Ferritins/*blood ; Follow-Up Studies ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Retrospective Studies ; }, abstract = {The availability of longitudinal clinical and biological data led us to wonder whether these parameters could be used to predict disturbances in body composition during ALS progression. Bioelectrical impedance analysis (BIA), as well as clinical and biological parameters (blood lipids and ferritin), were collected one year after diagnosis in ALS patients. The correlations were evaluated by the Spearman test. Performances to predict the evolution of BIA parameters during ALS evolution were evaluated by ROC analysis. Forty-two ALS patients were enrolled. Variations in FFM over one year were correlated to the variations in LDL-cholesterol (r = 0.53, p = 0.002) and ferritin (r = -0.58, p = 0.0002). To predict FFM loss, an increase in ferritin over 9 µg/L had a sensitivity of 90.0% and a specificity of 80.0% (p < 0.0001). Ferritine evolution would allow to easily follow the FFM without BIA during ALS. In addition, an adapted nutritional treatment based on this biological parameter might slow down ALS progression.}, }
@article {pmid30940071, year = {2019}, author = {Lian, JL and Ren, LS and Zhang, C and Yu, CY and Huang, Z and Xu, AX and Dong, JG}, title = {How exposure to ALS-inhibiting gametocide tribenuron-methyl induces male sterility in rapeseed.}, journal = {BMC plant biology}, volume = {19}, number = {1}, pages = {124}, pmid = {30940071}, issn = {1471-2229}, support = {2016YFD0101300//National Key R&amp;D Program of China/ ; 2018NY-055//Key R&amp;D Program of Shaanxi Province/ ; 2018ZX08020001-011//the National Transgenic Research Projects of China/ ; }, mesh = {Acetolactate Synthase/*antagonists &amp; inhibitors/metabolism ; Arylsulfonates/*pharmacology ; Brassica napus/*drug effects/enzymology/physiology ; Down-Regulation/drug effects ; Gene Expression Regulation, Developmental/drug effects ; Gene Expression Regulation, Plant/*drug effects ; Herbicides/*pharmacology ; Photosynthesis/drug effects ; Plant Infertility/*drug effects ; Plant Leaves/drug effects/enzymology/physiology ; Plant Proteins/antagonists &amp; inhibitors/metabolism ; }, abstract = {BACKGROUND: Acetolactate synthase (ALS)-inhibiting herbicide tribenuron-methyl (TBM) is an efficient gametocide that can cause rapeseed (Brassica napus L.) to become male sterile and outcrossing. To find the reason the TBM treatment leads to male sterility, an integrated study using cytological, physiological, and transcriptomic methods was conducted.<br><br>RESULTS: Some temporary symptoms, including the discoloration of young leaves and a short halt of raceme elongation, were observed in the rapeseed plants exposed to TBM at an application rate of 1&#x2009;&#x3bc;g per plant. Both chloroplasts in young leaves and plastids in anthers were deformed. TBM also reduced the leaf photosynthetic rate and the contents of chlorophyll, soluble sugar and pyruvate. Both the tapetal cells and uni-nucleate microspores in the treated plants showed large autophagic vacuoles, and the tissue degenerated quickly. A transcriptomic comparison with the control identified 200 upregulated and 163 downregulated differential expression genes in the small flower buds of the TBM treatment. The genes encoding functionally important proteins, including glucan endo-1,3-beta-glucosidase A6, QUARTET3 (QRT3), ARABIDOPSIS ANTHER 7 (ATA7), non-specific lipid-transfer protein LTP11 and LTP12, histone-lysine N-methyltransferase ATXR6, spermidine coumaroyl-CoA acyltransferase (SCT), and photosystem II reaction centre protein psbB, were downregulated by TBM exposure. Some important genes encoding autophagy-related protein ATG8a and metabolic detoxification related proteins, including DTX1, DTX6, DTX35, cytosolic sulfotransferase SOT12, and six members of glutathione S-transferase, were upregulated. In addition, several genes related to hormone stimulus, such as 1-aminocyclopropane-1-carboxylate synthase 8 (ACS8), ethylene-responsive factor ERF1A, ERF1, ERF71, CRF6, and RAP2-3, were also upregulated. The transcriptional regulation is in accordance with the functional abnormalities of pollen wall formation, lipid metabolism, chloroplast structure, ethylene generation, cell cycle, and tissue autophagy.<br><br>CONCLUSION: The results suggested that except for ALS, the metabolic pathways related to lipid metabolism, pollen exine formation, photosynthesis and hormone response are associated with male sterility induced by TBM. The results provide new insight into the molecular mechanisms of inducing male sterility by sulfonylurea.}, }
@article {pmid30938419, year = {2019}, author = {Xu, W and Bao, P and Jiang, X and Wang, H and Qin, M and Wang, R and Wang, T and Yang, Y and Lorenzini, I and Liao, L and Sattler, R and Xu, J}, title = {Reactivation of nonsense-mediated mRNA decay protects against C9orf72 dipeptide-repeat neurotoxicity.}, journal = {Brain : a journal of neurology}, volume = {142}, number = {5}, pages = {1349-1364}, pmid = {30938419}, issn = {1460-2156}, support = {R01 NS085207/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics/*metabolism ; Animals ; Animals, Genetically Modified ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use ; C9orf72 Protein/*genetics/*metabolism ; Cell Line, Tumor ; Dipeptides/genetics/metabolism ; Drosophila ; Female ; HeLa Cells ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Nonsense Mediated mRNA Decay/drug effects/*physiology ; ortho-Aminobenzoates/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis is a deleterious neurodegenerative disease without effective treatment options. Recent studies have indicated the involvement of the dysregulation of RNA metabolism in the pathogenesis of amyotrophic lateral sclerosis. Among the various RNA regulatory machineries, nonsense-mediated mRNA decay (NMD) is a stress responsive cellular surveillance system that degrades selected mRNA substrates to prevent the translation of defective or harmful proteins. Whether this pathway is affected in neurodegenerative diseases is unclear. Here we report the inhibition of NMD by arginine-rich dipeptide repeats derived from C9orf72 hexanucleotide repeat expansion, the most common cause of familial amyotrophic lateral sclerosis. Bioinformatic analysis of multiple transcriptome profiles revealed significant overlap of upregulated genes in NMD-defective cells with those in the brain tissues, micro-dissected motor neurons, or induced pluripotent stem cell-derived motor neurons specifically from amyotrophic lateral sclerosis patients carrying C9orf72 hexanucleotide repeat expansion, suggesting the suppression of NMD pathway in these patients. Using Drosophila as a model, we have validated that the C9orf72 hexanucleotide repeat expansion products could lead to the accumulation of the NMD substrates and identified arginine-rich dipeptide repeats, including poly glycine-arginine and poly proline-arginine, as the main culprits of NMD inhibition. Furthermore, in human SH-SY5Y neuroblastoma cells and in mouse brains, expression of glycine-arginine with 36 repeats (GR36) was sufficient to cause NMD inhibition. In cells expressing GR36, stress granule accumulation was accompanied by decreased processing body formation, which contributed to the inhibition of NMD. Remarkably, expression of UPF1, a core gene in the NMD pathway, efficiently blocked neurotoxicity caused by arginine-rich dipeptide repeats in both cellular and Drosophila models. Although not as effective as UPF1, expression of another NMD gene UPF2 also ameliorated the degenerative phenotypes in dipeptide repeat-expressing flies, indicating that genetically reactivating the NMD pathway could suppress dipeptide repeat toxicity. Finally, after validating tranilast as an NMD-activating drug, we demonstrated the therapeutic potential of this asthma drug in cellular and Drosophila models of C9orf72 dipeptide repeat neurotoxicity. Therefore, our study has revealed a cellular mechanism whereby arginine-rich C9orf72 dipeptide repeats could inhibit NMD activities by reducing the abundance of processing bodies. Furthermore, our results suggested that activation of the NMD pathway could be a potential therapeutic strategy for amyotrophic lateral sclerosis with defective RNA metabolism.}, }
@article {pmid30935380, year = {2019}, author = {Kapiriri, L and Lee, NM and Wallace, LJ and Kwesiga, B}, title = {Beyond cost-effectiveness, morbidity and mortality: a comprehensive evaluation of priority setting for HIV programming in Uganda.}, journal = {BMC public health}, volume = {19}, number = {1}, pages = {359}, pmid = {30935380}, issn = {1471-2458}, support = {001/WHO_/World Health Organization/International ; }, mesh = {Cost-Benefit Analysis ; *Decision Making ; *Delivery of Health Care ; Developing Countries ; HIV ; HIV Infections/prevention &amp; control/*therapy ; Health Planning/standards ; *Health Priorities ; Health Resources ; Humans ; Morbidity ; Mortality ; Poverty ; Qualitative Research ; Social Responsibility ; Uganda/epidemiology ; }, abstract = {BACKGROUND: While there has been progress in controlling the HIV epidemic, HIV still remains a disease of global concern. Some of the progress has been attributed to increased public awareness and uptake of public health interventions, as well as increased access to anti- retroviral treatment and the prevention of vertical HIV transmission. These interventions would not have been possible without substantial investments in HIV programs. However, donor fatigue introduces the need for low income countries to maximize the benefits of the available resources. This necessitates identification of priorities that should be funded. Evaluating prioritization processes would enable decision makers to assess the effectiveness of their processes, thereby designing intervention strategies. To date most evaluations have focused on cost-benefit analyses, which overlooks additional critical impacts of priority setting decisions. Kapiriri &amp; Martin (2010) developed and validated a comprehensive framework for evaluating PS in low income countries. The objective of this paper report findings from a comprehensive evaluation of priority setting for HIV in Uganda, using the framework; and to identify lessons of good practice and areas for improvement.<br><br>METHODS: This was a qualitative study based on forty interviews with decision makers and policy document review. Data were analysed using INVIVO 10, and based on the parameters in Kapiriri et al's evaluation framework.<br><br>RESULTS: We found that HIV enjoys political support, which contributes to the availability of resources, strong planning institutions, and participatory prioritization process based on some criteria. Some of the identified limitations included; undue donor and political influence, priorities not being publicized, and lack of mechanisms for appealing the decisions. HIV prioritization had both positive and negative impacts on the health system.<br><br>CONCLUSIONS: The framework facilitated a more comprehensive evaluation of HIV priority setting. While there were successful areas, the process could be strengthened by minimizing undue influence of external actors, and support the legitimate institutions to set priorities and implement them. These should also institute mechanisms for publicizing the decisions, appeals and increased accountability. While this paper looked at HIV, the framework is flexible enough to be used in evaluating priority setting for other health programs within similar context.}, }
@article {pmid30930396, year = {2019}, author = {Kusama-Eguchi, K}, title = {[Research in Motor Neuron Diseases Caused by Natural Substances: Focus on Pathological Mechanisms of Neurolathyrism].}, journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan}, volume = {139}, number = {4}, pages = {609-615}, doi = {10.1248/yakushi.18-00202}, pmid = {30930396}, issn = {1347-5231}, mesh = {Animals ; Cell Death/drug effects ; Disease Models, Animal ; Fabaceae/*adverse effects/chemistry ; Humans ; Lathyrism/*etiology/pathology ; Lathyrus/*adverse effects/chemistry ; Motor Neuron Disease/etiology/pathology ; Motor Neurons/pathology ; Rats ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid ; beta-Alanine/*analogs &amp; derivatives/isolation &amp; purification/toxicity ; }, abstract = {Diseases of the motor-conducting system that cause moving disability affect socio-economic activity as well as human dignity. Neurolathyrism, konzo, and amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC) have attracted researchers to study the pathology of motor neuron (MN) diseases such as ALS. I have been studying neurolathyrism, which is caused by overconsumption of a legume grass pea (Lathyrys sativus L.). Among people who consume the legume as a food staple, many developed life-long paraparesis in their legs. β-N-oxalyl-l-α,β- diaminopropionic (l-β-ODAP; BOAA), contained in this plant, is a neurotoxic analog of l-glutamic acid. We have clarified that in addition to the causal involvement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type glutamatergic receptor in MN death, a toxic role of group I metabotropic glutamate receptors as well as transient receptor potential channels were involved in the MN insult by l-β-ODAP using primary MN culture. We have also established a neurolathyrism rat model by repeated, peripheral l-β-ODAP treatment to newborn rats under mild stress. Rats showing hind-leg paraparesis with an incidence rate of around 25% were useful to study the in vivo pathology of MN disease. MNs of these rats were greatly decreased at their lumbo/sacral segments at various ages. Intra-parenchymal hemorrhage was consistently observed in paraparetic rats but not in cripple-free, treated rats. MN were depleted even at an acute period around bleeding spots, suggesting catastrophic neuro-vascular-glial interaction in this MN disease. Summaries of konzo and ALS-PDCs studies are also introduced.}, }
@article {pmid30928161, year = {2019}, author = {Leibowitz-Amit, R}, title = {Reply to Joe O'Sullivan, Daniel Heinrich, Nicholas D. James, et al's Letter to the Editor re: The Case Against the European Medicines Agency's Change to the Label for Radium-223 for the Treatment of Metastatic Castration-resistant Prostate Cancer. Eur Urol 2019;75:e53.}, journal = {European urology}, volume = {76}, number = {1}, pages = {e19}, doi = {10.1016/j.eururo.2019.03.013}, pmid = {30928161}, issn = {1873-7560}, mesh = {Humans ; Male ; *Prostatic Neoplasms ; *Prostatic Neoplasms, Castration-Resistant ; *Radium ; }, }
@article {pmid30924108, year = {2019}, author = {Chen, Y and Xu, S and Wang, N and Ma, Q and Peng, P and Yu, Y and Zhang, L and Ying, Z and Wang, H}, title = {Dynasore Suppresses mTORC1 Activity and Induces Autophagy to Regulate the Clearance of Protein Aggregates in Neurodegenerative Diseases.}, journal = {Neurotoxicity research}, volume = {36}, number = {1}, pages = {108-116}, pmid = {30924108}, issn = {1476-3524}, support = {31571053//National Natural Science Foundation of China/ ; 31771117//National Natural Science Foundation of China/ ; 2017YFC0909100//National Key Plan for Scientific Research and Development of China/ ; BM2013003//Jiangsu KeyLavoratory of Neuropsychiatric Diseases/ ; }, mesh = {Autophagy/*drug effects ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Dynamins/*antagonists &amp; inhibitors ; HEK293 Cells ; Humans ; Huntingtin Protein/metabolism ; Hydrazones/*administration &amp; dosage ; Lysosomes/drug effects/metabolism ; Mechanistic Target of Rapamycin Complex 1/*metabolism ; Neurodegenerative Diseases/*metabolism/pathology ; Protein Aggregation, Pathological/*metabolism ; }, abstract = {Autophagy is an important cellular protein control process, which plays a key role in the regulation of cell homeostasis and pathogenesis of many human diseases including neurodegenerative diseases. Reduced autophagic activity and abnormal protein aggregation are common features of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Therefore, pharmacological regulation of overall autophagy may be helpful for effective treatment of neurodegenerative diseases. In the present study, we find Dynasore, a potent inhibitor of dynamin, can repress the lysosomal localization of mTOR and block the activity of mTORC1, which in turn enhances the nuclear translocation of the master regulators of autophagy including TFE3 and TFEB. We find that autophagic flux is upregulated in Dynasore-treated cells. Moreover, treatment of Dynasore significantly promotes the clearance of protein aggregates formed by mutant huntingtin protein containing expanded polyglutamine (polyQ), but not damaged mitochondria. In contrast, treatment with Dynasore has no effect on the clearance of polyQ aggregates of mutant huntingtin in ATG5-depleted cells, in which autophagy is defective. Taken together, our results indicate that Dynasore affects autophagic degradation of neurodegenerative disease-associated proteins by regulating mTORC1-TFEB signaling.}, }
@article {pmid30912216, year = {2019}, author = {Morelot-Panzini, C and Bruneteau, G and Gonzalez-Bermejo, J}, title = {NIV in amyotrophic lateral sclerosis: The 'when' and 'how' of the matter.}, journal = {Respirology (Carlton, Vic.)}, volume = {24}, number = {6}, pages = {521-530}, doi = {10.1111/resp.13525}, pmid = {30912216}, issn = {1440-1843}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/psychology/therapy ; Cognition ; Humans ; Noninvasive Ventilation/*methods ; Prognosis ; *Quality of Life ; }, abstract = {Non-invasive ventilation (NIV) has become an essential part of the treatment of amyotrophic lateral sclerosis (ALS) since 2006. NIV very significantly improves survival, quality of life and cognitive performances. The initial NIV settings are simple, but progression of the disease, ventilator dependence and upper airway involvement sometimes make long-term adjustment of NIV more difficult, with a major impact on survival. Unique data concerning the long-term adjustment of NIV in ALS show that correction of leaks, management of obstructive apnoea and adaptation to the patient's degree of ventilator dependence improve the prognosis. Non-ventilatory factors also impact the efficacy of NIV and various solutions have been described and must be applied, including cough assist techniques, control of excess salivation and renutrition. NIV in ALS has been considerably improved as a result of application of all of these measures, avoiding the need for tracheostomy in the very great majority of cases. More advanced use of NIV also requires pulmonologists to master the associated end-of-life palliative care, as well as the modalities of discontinuing ventilation when it becomes unreasonable.}, }
@article {pmid30911936, year = {2019}, author = {Abati, E and Bresolin, N and Comi, G and Corti, S}, title = {Advances, Challenges, and Perspectives in Translational Stem Cell Therapy for Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {56}, number = {10}, pages = {6703-6715}, pmid = {30911936}, issn = {1559-1182}, support = {778003//Ministero della Salute/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Clinical Trials as Topic ; Humans ; Research Design ; *Stem Cell Transplantation ; *Translational Research, Biomedical ; }, abstract = {Finding an effective therapeutic approach is a primary goal for current and future research for amyotrophic lateral sclerosis (ALS), a fatal neurological disease characterized by degeneration and loss of upper and lower motor neurons. Transplantation approaches based on stem cells have been attempted in virtue of their potential to contrast simultaneously different ALS pathogenic aspects including either the replacement of lost cells or the protection of motor neurons from degeneration and toxic microenvironment. Here, we critically review the recent translational research aimed at the assessment of stem cell transplantation safety and feasibility in the treatment of ALS. Most of these efforts aim to exert a neuroprotective action rather than cell replacement. Critical aspects that emerge in these studies are the need for the identification of the most effective therapeutic cell source (mesenchymal stem cells, immune, or neural stem cells), the definition of the optimal injection site (cortical area, spinal cord, or muscles) with a suitable administration protocol (local or systemic injection), and the analysis of therapeutic mechanisms, which are necessary steps in order to overcome the hurdles posed by previous in vivo human studies. New perspectives will also be offered by the increasing number of induced pluripotent stem cell-based therapies that are now being tested in clinical trials. A thorough analysis of recently completed trials is the foundation for continued progress in cellular therapy for ALS and other neurodegenerative disorders.}, }
@article {pmid30909602, year = {2019}, author = {Geisler, JG}, title = {2,4 Dinitrophenol as Medicine.}, journal = {Cells}, volume = {8}, number = {3}, pages = {}, pmid = {30909602}, issn = {2073-4409}, mesh = {2,4-Dinitrophenol/*metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Calcium/metabolism ; Cognition ; Humans ; *Medicine ; Reactive Oxygen Species/metabolism ; }, abstract = {In the sanctity of pure drug discovery, objective reasoning can become clouded when pursuing ideas that appear unorthodox, but are spot on physiologically. To put this into historical perspective, it was an unorthodox idea in the 1950's to suggest that warfarin, a rat poison, could be repositioned into a breakthrough drug in humans to protect against strokes as a blood thinner. Yet it was approved in 1954 as Coumadin[®] and has been prescribed to billions of patients as a standard of care. Similarly, no one can forget the horrific effects of thalidomide, prescribed or available without a prescription, as both a sleeping pill and "morning sickness" anti-nausea medication targeting pregnant women in the 1950's. The "thalidomide babies" became the case-in-point for the need of strict guidelines by the U.S. Food &amp; Drug Administration (FDA) or full multi-species teratogenicity testing before drug approval. More recently it was found that thalidomide is useful in graft versus host disease, leprosy and resistant tuberculosis treatment, and as an anti-angiogenesis agent as a breakthrough drug for multiple myeloma (except for pregnant female patients). Decades of diabetes drug discovery research has historically focused on every possible angle, except, the energy-out side of the equation, namely, raising mitochondrial energy expenditure with chemical uncouplers. The idea of "social responsibility" allowed energy-in agents to be explored and the portfolio is robust with medicines of insulin sensitizers, insulin analogues, secretagogues, SGLT2 inhibitors, etc., but not energy-out medicines. The primary reason? It appeared unorthodox, to return to exploring a drug platform used in the 1930s in over 100,000 obese patients used for weight loss. This is over 80-years ago and prior to Dr Peter Mitchell explaining the mechanism of how mitochondrial uncouplers, like 2,4-dinitrophenol (DNP) even worked by three decades later in 1961. Although there is a clear application for metabolic disease, it was not until recently that this platform was explored for its merit at very low, weight-neutral doses, for treating insidious human illnesses and completely unrelated to weight reduction. It is known that mitochondrial uncouplers specifically target the entire organelle's physiology non-genomically. It has been known for years that many neuromuscular and neurodegenerative diseases are associated with overt production of reactive oxygen species (ROSs), a rise in isoprostanes (biomarker of mitochondrial ROSs in urine or blood) and poor calcium (Ca[2+]) handing. It has also been known that mitochondrial uncouplers lower ROS production and Ca[2+] overload. There is evidence that elevation of isoprostanes precedes disease onset, in Alzheimer's Disease (AD). It is also curious, why so many neurodegenerative diseases of known and unknown etiology start at mid-life or later, such as Multiple Sclerosis (MS), Huntington Disease (HD), AD, Parkinson Disease, and Amyotrophic Lateral Sclerosis (ALS). Is there a relationship to a buildup of mutations that are sequestered over time due to ROSs exceeding the rate of repair? If ROS production were managed, could disease onset due to aging be delayed or prevented? Is it possible that most, if not all neurodegenerative diseases are manifested through mitochondrial dysfunction? Although DNP, a historic mitochondrial uncoupler, was used in the 1930s at high doses for obesity in well over 100,000 humans, and so far, it has never been an FDA-approved drug. This review will focus on the application of using DNP, but now, repositioned as a potential disease-modifying drug for a legion of insidious diseases at much lower and paradoxically, weight neutral doses. DNP will be addressed as a treatment for "metabesity", an emerging term related to the global comorbidities associated with the over-nutritional phenotype; obesity, diabetes, nonalcoholic steatohepatitis (NASH), metabolic syndrome, cardiovascular disease, but including neurodegenerative disorders and accelerated aging. Some unexpected drug findings will be discussed, such as DNP's induction of neurotrophic growth factors involved in neuronal heath, learning and cognition. For the first time in 80's years, the FDA has granted (to Mitochon Pharmaceutical, Inc., Blue Bell, PA, USA) an open Investigational New Drug (IND) approval to begin rigorous clinical testing of DNP for safety and tolerability, including for the first ever, pharmacokinetic profiling in humans. Successful completion of Phase I clinical trial will open the door to explore the merits of DNP as a possible treatment of people with many truly unmet medical needs, including those suffering from HD, MS, PD, AD, ALS, Duchenne Muscular Dystrophy (DMD), and Traumatic Brain Injury (TBI).}, }
@article {pmid30909571, year = {2019}, author = {Marcuzzo, S and Isaia, D and Bonanno, S and Malacarne, C and Cavalcante, P and Zacheo, A and Laquintana, V and Denora, N and Sanavio, B and Salvati, E and Andreozzi, P and Stellacci, F and Krol, S and Mellado-López, M and Mantegazza, R and Moreno-Manzano, V and Bernasconi, P}, title = {FM19G11-Loaded Gold Nanoparticles Enhance the Proliferation and Self-Renewal of Ependymal Stem Progenitor Cells Derived from ALS Mice.}, journal = {Cells}, volume = {8}, number = {3}, pages = {}, pmid = {30909571}, issn = {2073-4409}, mesh = {Amyotrophic Lateral Sclerosis ; Animals ; Benzamides/*pharmacology ; Biomarkers/metabolism ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Cell Self Renewal/*drug effects ; Ependyma/*cytology ; Gene Expression Regulation/drug effects ; Gold/*chemistry ; Humans ; Metal Nanoparticles/*chemistry ; Mice, Transgenic ; MicroRNAs/genetics/metabolism ; Octamer Transcription Factor-3/metabolism ; PTEN Phosphohydrolase/metabolism ; Pluripotent Stem Cells/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; SOXB1 Transcription Factors/metabolism ; Stem Cells/*cytology/drug effects ; Superoxide Dismutase-1/metabolism ; Uncoupling Protein 2/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. In ALS mice, neurodegeneration is associated with the proliferative restorative attempts of ependymal stem progenitor cells (epSPCs) that normally lie in a quiescent in the spinal cord. Thus, modulation of the proliferation of epSPCs may represent a potential strategy to counteract neurodegeneration. Recent studies demonstrated that FM19G11, a hypoxia-inducible factor modulator, induces epSPC self-renewal and proliferation. The aim of the study was to investigate whether FM19G11-loaded gold nanoparticles (NPs) can affect self-renewal and proliferation processes in epSPCs isolated from G93A-SOD1 mice at disease onset. We discovered elevated levels of SOX2, OCT4, AKT1, and AKT3, key genes associated with pluripotency, self-renewal, and proliferation, in G93A-SOD1 epSPCs at the transcriptional and protein levels after treatment with FM19G11-loaded NPs. We also observed an increase in the levels of the mitochondrial uncoupling protein (UCP) gene in treated cells. FM19G11-loaded NPs treatment also affected the expression of the cell cycle-related microRNA (miR)-19a, along with its target gene PTEN, in G93A-SOD1 epSPCs. Overall our findings establish the significant impact of FM19G11-loaded NPs on the cellular pathways involved in self-renewal and proliferation in G93A-SOD1 epSPCs, thus providing an impetus to the design of novel tailored approaches to delay ALS disease progression.}, }
@article {pmid30906528, year = {2019}, author = {Lemon, R}, title = {Recent advances in our understanding of the primate corticospinal system.}, journal = {F1000Research}, volume = {8}, number = {}, pages = {}, pmid = {30906528}, issn = {2046-1402}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Humans ; Mice ; *Motor Cortex ; *Primates/physiology ; *Pyramidal Tracts/physiology ; Species Specificity ; }, abstract = {The last few years have seen major advances in our understanding of the organisation and function of the corticospinal tract (CST). These have included studies highlighting important species-specific variations in the different functions mediated by the CST. In the primate, the most characteristic feature is direct cortico-motoneuronal (CM) control of muscles, particularly of hand and finger muscles. This system, which is unique to dexterous primates, is probably at its most advanced level in humans. We now know much more about the origin of the CM system within the cortical motor network, and its connectivity within the spinal cord has been quantified. We have learnt much more about how the CM system works in parallel with other spinal circuits receiving input from the CST and how the CST functions alongside other brainstem motor pathways. New work in the mouse has provided fascinating insights into the contribution of the CM system to dexterity. Finally, accumulating evidence for the involvement of CM projections in motor neuron disease has highlighted the importance of advances in basic neuroscience for our understanding and possible treatment of a devastating neurological disease.}, }
@article {pmid30898538, year = {2020}, author = {Zhang, X and Hu, D and Shang, Y and Qi, X}, title = {Using induced pluripotent stem cell neuronal models to study neurodegenerative diseases.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1866}, number = {4}, pages = {165431}, pmid = {30898538}, issn = {1879-260X}, support = {R01 AG065240/AG/NIA NIH HHS/United States ; R01 NS088192/NS/NINDS NIH HHS/United States ; R21 NS107897/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Induced Pluripotent Stem Cells/*metabolism/pathology ; *Models, Neurological ; Neurodegenerative Diseases/*metabolism/pathology ; }, abstract = {Current application of human induced pluripotent stem cells (hiPSCs) technology in patient-specific models of neurodegenerative disorders recapitulate some of key phenotypes of diseases, representing disease-specific cellular modeling and providing a unique platform for therapeutics development. We review recent efforts toward advancing hiPSCs-derived neuronal cell types and highlight their potential use for the development of more complex in vitro models of neurodegenerative diseases by focusing on Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. We present evidence from previous works on the important phenotypic changes of various neuronal types in these neurological diseases. We also summarize efforts on conducting low- and high-throughput screening experiments with hiPSCs toward developing potential therapeutics for treatment of neurodegenerative diseases. Lastly, we discuss the limitations of hiPSCs culture system in studying neurodegenerative diseases and alternative strategies to overcome these hurdles.}, }
@article {pmid30892090, year = {2019}, author = {Bhattacharya, R and Harvey, RA and Abraham, K and Rosen, J and Mehta, P}, title = {Amyotrophic lateral sclerosis among patients with a Medicare Advantage prescription drug plan; prevalence, survival and patient characteristics.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {3-4}, pages = {251-259}, doi = {10.1080/21678421.2019.1582674}, pmid = {30892090}, issn = {2167-9223}, mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Algorithms ; Amyotrophic Lateral Sclerosis/epidemiology/mortality/*therapy ; Comorbidity ; Female ; Humans ; *Insurance, Pharmaceutical Services/statistics &amp; numerical data ; Male ; *Medicare/statistics &amp; numerical data ; Middle Aged ; Motor Neuron Disease/epidemiology/mortality/therapy ; Patients ; Prevalence ; Retrospective Studies ; Socioeconomic Factors ; Survival Analysis ; United States/epidemiology ; Young Adult ; }, abstract = {Objective: To estimate amyotrophic lateral sclerosis (ALS) prevalence, 5-year survival, and explore factors associated with survival in a Medicare population. Methods: A validated administrative claims algorithm was used to classify individual's ages 18-89 years at index date (first claim with a diagnosis of motor neuron disease or ALS between 1 January 2007 and 31 December 2011) with Medicare Advantage prescription drug coverage into mutually exclusive categories: ALS, no ALS, and possible ALS. Crude prevalence and cumulative survival from index date to the date of death, disenrollment or end of the study were calculated. Cox-proportional hazards were used to estimate and explore factors associated with survival. Results: Of 2631 eligible individuals, the algorithm identified 1271 (48 %), 1157 (44 %), 203 (8 %) as ALS, no ALS and possible ALS, respectively. The 5-year period prevalence and the 2011 point prevalence of ALS were 20.5 and 11.8 per 100,000, respectively. Evidence of death was documented in 81%, 35%, and 1.6% of the ALS, no ALS or possible ALS groups, respectively. Unadjusted median survival time was 388, 542 and 1473 days for the ALS, no ALS and possible ALS groups, respectively. Seeing a psychiatrist or neurologist at the index visit, having respiratory or genitourinary comorbidities, and the number of pre-index acute inpatient admissions were associated with shorter survival. Conclusions: Surveillance data from a Medicare population demonstrated a higher prevalence of ALS. Results highlight the need for effective ALS treatment options and resources for patients with ALS who will likely face limited therapeutic choices and care options at the end of life.}, }
@article {pmid30892087, year = {2019}, author = {Benatar, M and Turner, MR and Wuu, J}, title = {Defining pre-symptomatic amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {5-6}, pages = {303-309}, pmid = {30892087}, issn = {2167-9223}, support = {R01 NS105479/NS/NINDS NIH HHS/United States ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*blood/*diagnosis/epidemiology ; Animals ; *Asymptomatic Diseases/epidemiology ; Biomarkers/blood ; Humans ; }, abstract = {Successful treatment of neurodegenerative disease may hinge on early therapeutic intervention. This requires an understanding of early/pre-symptomatic disease, a need that is underscored by advances in antisense oligonucleotide, and viral-vector-based gene therapies. In amyotrophic lateral sclerosis (ALS), the study of pre-symptomatic disease requires a cohesive conceptual framework for describing this phase of disease. Informed by the literature in other neurodegenerative diseases and extensive personal experience, a model is proposed that distinguishes ALS as a clinical syndrome from ALS as a disease, and characterizes pre-symptomatic ALS as having two identifiable stages: pre-manifest and prodromal. The unique and critical importance of biomarker development is articulated and an operational definition of phenoconversion is provided. It is hoped that this framework will accelerate collective efforts to study pre-symptomatic ALS, and aid in the design and implementation of an early intervention- or disease-prevention trial.}, }
@article {pmid30889483, year = {2019}, author = {Zhang, Q and An, Y and Chen, ZS and Koon, AC and Lau, KF and Ngo, JCK and Chan, HYE}, title = {A Peptidylic Inhibitor for Neutralizing r(GGGGCC)exp-Associated Neurodegeneration in C9ALS-FTD.}, journal = {Molecular therapy. Nucleic acids}, volume = {16}, number = {}, pages = {172-185}, pmid = {30889483}, issn = {2162-2531}, abstract = {One drug, two diseases is a rare and economical therapeutic strategy that is highly desirable in the pharmaceutical industry. We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide toxicity in polyglutamine (polyQ) diseases. Here we report that BIND also effectively inhibits GGGGCC repeat-mediated neurodegeneration in vitro and in vivo. When fused with a cell-penetrating peptide derived from the transactivator of transcription (TAT) protein of the HIV, TAT-BIND reduces cell death, formation of GGGGCC RNA foci, and levels of poly-GR, poly-GA, and poly-GP dipeptide proteins in cell models of C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS-FTD). We showed that TAT-BIND disrupts the interaction between GGGGCC RNA and nucleolin protein, restores rRNA maturation, and inhibits mislocalization of nucleolin and B23, which eventually suppresses nucleolar stress in C9ALS-FTD. In a Drosophila model of C9ALS-FTD, TAT-BIND suppresses retinal degeneration, rescues climbing ability, and extends the lifespan of flies. In contrast, TAT-BIND has no effect on UAS-poly-glycine-arginine (poly-GR)100-expressing flies, which generate only poly-GR protein toxicity, indicating BIND ameliorates toxicity in C9ALS-FTD models via a r(GGGGCC)exp-dependent inhibitory mechanism. Our findings demonstrated that, apart from being a potential therapeutic for polyQ diseases, BIND is also a potent peptidylic inhibitor that suppresses expanded GGGGCC RNA-mediated neurodegeneration, highlighting its potential application in C9ALS-FTD treatment.}, }
@article {pmid30881332, year = {2019}, author = {Chew, S and Atassi, N}, title = {Positron Emission Tomography Molecular Imaging Biomarkers for Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {135}, pmid = {30881332}, issn = {1664-2295}, support = {K23 NS083715/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with limited treatment options. Despite decades of therapeutic development, only two modestly efficacious disease-modifying drugs-riluzole and edaravone-are available to ALS patients. Biomarkers that can facilitate ALS diagnosis, aid in prognosis, and measure drug pharmacodynamics are needed to accelerate therapeutic development for patients with ALS. Positron emission tomography (PET) imaging has promise as a biomarker for ALS because it permits visualization of central nervous system (CNS) pathology in individuals living with ALS. The availability of PET radioligands that target a variety of potential pathophysiological mechanisms-including cerebral metabolism, neuroinflammation, neuronal dysfunction, and oxidative stress-has enabled dynamic interrogation of molecular changes in ALS, in both natural history studies and human clinical trials. PET imaging has potential as a diagnostic biomarker that can establish upper motor neuron (UMN) pathology in ALS patients without overt UMN symptoms, as a prognostic biomarker that might help stratify patients for clinical trials, and as a pharmacodynamic biomarker that measures the biological effect of investigational drugs in the brain and spinal cord. In this Review, we discuss progress made with 30 years of PET imaging studies in ALS and consider future research needed to establish PET imaging biomarkers for ALS therapeutic development.}, }
@article {pmid30879475, year = {2019}, author = {Valko, K and Ciesla, L}, title = {Amyotrophic lateral sclerosis.}, journal = {Progress in medicinal chemistry}, volume = {58}, number = {}, pages = {63-117}, doi = {10.1016/bs.pmch.2018.12.001}, pmid = {30879475}, issn = {0079-6468}, mesh = {Amino Acid Transport System X-AG/chemistry/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/*pathology ; Animals ; Anti-Inflammatory Agents/therapeutic use ; Disease Models, Animal ; Humans ; Immunotherapy ; Neuroprotective Agents/therapeutic use ; Polymorphism, Single Nucleotide ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is caused by selective and progressive loss of spinal, bulbar and cortical motoneurons and leads to irreversible paralysis, loss of speech, inability to swallow and respiratory malfunctions with the eventual death of the affected individual in a rapid disease course. Several suggested molecular pathways are reviewed including SOD1 gene mutation, protein nitrosylation, phosphorylation and oxidative stress, excitotoxicity, glutamate transporter deprivation, mitochondrial involvement, protein aggregation and motor neuron trophic factors. The role of insulin and its receptor in the brain is described. It is very possible that in 90% of the sporadic ALS cases, the cause of the motor neuron degeneration is different or that multiple mechanisms are involved that would need drugs with multiple mechanisms or action. Several marketed drugs have been selected for clinical trials. Only two drugs have been approved by the FDA as showing positive effect in ALS: Riluzole and Edaravone. Two other drugs that have a significant benefit in ALS are Talampanel and Tamoxifen. The results for modulation of the neurotrophic factor Insulin Growth Factor-1 (IGF1) as a potential treatment are inconclusive. Several compounds are discussed that show a positive effect in the mouse model but which have failed in clinical trials. New approaches using different modalities such as peptides, proteins and stem cells are promising. Our ability to design better drugs would be enhanced by investigating the endogenous factors in neuron death, protein aggregation and oxidative stress that would improve our understanding of the potential pathways that result in neurodegeneration.}, }
@article {pmid30877731, year = {2019}, author = {Kiousi, V and Arnaoutoglou, M and Printza, A}, title = {Speech and language intervention for language impairment in patients in the FTD-ALS spectrum.}, journal = {Hellenic journal of nuclear medicine}, volume = {22 Suppl}, number = {}, pages = {133-146}, pmid = {30877731}, issn = {1790-5427}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Frontotemporal Dementia/*physiopathology ; Humans ; *Speech ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease that belongs to the group of motor neuron diseases. Motor deficits like reduce in tongue strength, may coexist with cognitive deficits compatible with frontotemporal dementia (FTD), also known as frontotemporal lobar degeneration (FTLD). FTD is a neurodegenerative syndrome with two main clinical variants: behavioral (bvFTD) and language or Primary Progressive Aphasia (PPA). ALS and FTD have significant clinical and neuropathological overlapping so that for some researchers they are "the ends of the same disease spectrum". A key intervention in this patient population is the speech language therapy (SLT), a specific form of cognitive intervention, which evaluates communication skills and designs a personalized intervention plan to improve communication abilities. It has been used in patients with aphasia of different etiologies and has been shown to be effective. There is limited research in SLT interventions in patients in FTD-ALS spectrum, and the initial findings indicate success to some extent. Due to progressive neurodegeneration in FTD-ALS spectrum, the main goal of the intervention is not the complete rehabilitation of linguistic deficits but the reduction and, if possible, the delay of language decline in order to improve patient's communication and the quality of his/her life. In this paper, we critically review the reported approaches of speech language therapy (SLT) for monitoring language impairments and the impact of interventions in patients with FTD-ALS spectrum. Initial findings are supporting more systematic treatment of speech and language impairment in patients in the FTD-ALS spectrum.}, }
@article {pmid30872628, year = {2019}, author = {Leoni, E and Bremang, M and Mitra, V and Zubiri, I and Jung, S and Lu, CH and Adiutori, R and Lombardi, V and Russell, C and Koncarevic, S and Ward, M and Pike, I and Malaspina, A}, title = {Combined Tissue-Fluid Proteomics to Unravel Phenotypic Variability in Amyotrophic Lateral Sclerosis.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {4478}, pmid = {30872628}, issn = {2045-2322}, support = {//Wellcome Trust/United Kingdom ; MALASPINA/APR13/817-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; 103208/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*diagnosis/metabolism ; Apolipoproteins E/*metabolism ; Biomarkers/*metabolism ; Case-Control Studies ; Early Diagnosis ; Female ; Humans ; Intermediate Filaments/*metabolism ; Male ; Middle Aged ; Phenotype ; Principal Component Analysis ; Proteomics/*methods ; Workflow ; }, abstract = {The lack of biomarkers for early diagnosis, clinical stratification and to monitor treatment response has hampered the development of new therapies for amyotrophic lateral sclerosis (ALS), a clinically heterogeneous neurodegenerative disorder with a variable site of disease initiation and rate of progression. To identify new biomarkers and therapeutic targets, two separate proteomic workflows were applied to study the immunological response and the plasma/brain proteome in phenotypic variants of ALS. Conventional multiplex (TMT) proteomic analysis of peripheral blood mononuclear cells (PBMCs) was performed alongside a recently introduced method to profile neuronal-derived proteins in plasma using brain tissue-enhanced isobaric tagging (TMTcalibrator). The combined proteomic analysis allowed the detection of regulated proteins linked to ALS pathogenesis (RNA-binding protein FUS, superoxide dismutase Cu-Zn and neurofilaments light polypeptide) alongside newly identified candidate biomarkers (myosin-9, fructose-bisphosphate aldolase and plectin). In line with the proteomic results, orthogonal immunodetection showed changes in neurofilaments and ApoE in bulbar versus limb onset fast progressing ALS. Functional analysis of significantly regulated features showed enrichment of pathways involved in regulation of the immune response, Rho family GTPases, semaphorin and integrin signalling. Our cross-phenotype investigation of PBMCs and plasma/brain proteins provides a more sensitive biomarker exploratory platform than conventional case-control studies in a single matrix. The reported regulated proteins may represent novel biomarker candidates and potentially druggable targets.}, }
@article {pmid31583314, year = {2017}, author = {Munakata, S and Ito, S and Sugimoto, K and Kojima, Y and Goto, M and Tomiki, Y and Sakamoto, K}, title = {Defunctioning loop ileostomy with restorative proctocolectomy for rectal cancer: Friend or foe?.}, journal = {Journal of the anus, rectum and colon}, volume = {1}, number = {4}, pages = {136-140}, pmid = {31583314}, issn = {2432-3853}, abstract = {OBJECTIVES: Temporary ileostomy is used to decrease morbidity from anastomotic leakages (ALs). However, ileostomies are associated with complications (i.e., stoma-related complications; SRCs), ileus due to stenosis, dehydration, and the need for a second operation. Here we retrospectively evaluated the impact of SRCs on the treatment of rectal cancer.<br><br>METHODS: We identified 180 consecutive patients who underwent curative resection for rectal cancer at Juntendo University Hospital between January 2006 and December 2014. We divided the patients into groups with and without defunctioning stoma (DS), and we compared the patient age and gender, tumor location, approach (laparotomy/laparoscopy), surgical procedure, distance of the tumor from the margin of the anus, T factor, stage, duration of postoperative hospital stay, and postoperative complications between these groups. Univariate and multivariate analyses were performed to determine the risk factors for postoperative hospital stay.<br><br>RESULTS: The symptomatic leakage rate in the DS group (n = 92) was not significantly different from that of the non-DS group (n = 88; p = 0.29). However, Grade &#x2265; 4 AL occurred significantly less frequently in the DS group (0%) than in the non-DS group (5.7%; p = 0.02). SRCs occurred in 14 DS-group patients (15.2%). The multivariate analysis demonstrated that both AL (odds ratio [OR] 9.24; confidence interval [CI] 4.91-19.4) and SRC (OR 1.84; CI 1.03-3.54) were independently predictive of short-term outcomes.<br><br>CONCLUSIONS: The benefit of a DS is balanced against the risk of leakage and SRCs at rectal resection. Surgeons should focus on not only the consequences of AL, but also SRC risk.}, }
@article {pmid32669907, year = {2014}, author = {Brown, KE and Neva, JL and Ledwell, NM and Boyd, LA}, title = {Use of transcranial magnetic stimulation in the treatment of selected movement disorders.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {4}, number = {}, pages = {133-151}, pmid = {32669907}, issn = {1179-9900}, abstract = {Transcranial magnetic stimulation (TMS) is a valuable technique for assessing the underlying neurophysiology associated with various neuropathologies, and is a unique tool for establishing potential neural mechanisms responsible for disease progression. Recently, repetitive TMS (rTMS) has been advanced as a potential therapeutic technique to treat selected neurologic disorders. In healthy individuals, rTMS can induce changes in cortical excitability. Therefore, targeting specific cortical areas affected by movement disorders theoretically may alter symptomology. This review discusses the evidence for the efficacy of rTMS in Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. It is hoped that gaining a more thorough understanding of the timing and parameters of rTMS in individuals with neurodegenerative disorders may advance both clinical care and research into the most effective uses of this technology.}, }
@article {pmid30867054, year = {2019}, author = {Bohaciakova, D and Hruska-Plochan, M and Tsunemoto, R and Gifford, WD and Driscoll, SP and Glenn, TD and Wu, S and Marsala, S and Navarro, M and Tadokoro, T and Juhas, S and Juhasova, J and Platoshyn, O and Piper, D and Sheckler, V and Ditsworth, D and Pfaff, SL and Marsala, M}, title = {A scalable solution for isolating human multipotent clinical-grade neural stem cells from ES precursors.}, journal = {Stem cell research &amp; therapy}, volume = {10}, number = {1}, pages = {83}, pmid = {30867054}, issn = {1757-6512}, support = {F32 NS093938/NS/NINDS NIH HHS/United States ; }, mesh = {Cell Line ; *Flow Cytometry ; Humans ; Multipotent Stem Cells/*cytology ; Neural Stem Cells/*cytology ; }, abstract = {BACKGROUND: A well-characterized method has not yet been established to reproducibly, efficiently, and safely isolate large numbers of clinical-grade multipotent human neural stem cells (hNSCs) from embryonic stem cells (hESCs). Consequently, the transplantation of neurogenic/gliogenic precursors into the CNS for the purpose of cell replacement or neuroprotection in humans with injury or disease has not achieved widespread testing and implementation.<br><br>METHODS: Here, we establish an approach for the in vitro isolation of a highly expandable population of hNSCs using the manual selection of neural precursors based on their colony morphology (CoMo-NSC). The purity and NSC properties of established and extensively expanded CoMo-NSC were validated by expression of NSC markers (flow cytometry, mRNA sequencing), lack of pluripotent markers and by their tumorigenic/differentiation profile after in vivo spinal grafting in three different animal models, including (i) immunodeficient rats, (ii) immunosuppressed ALS rats (SOD1G93A), or (iii) spinally injured immunosuppressed minipigs.<br><br>RESULTS: In vitro analysis of established CoMo-NSCs showed a consistent expression of NSC markers (Sox1, Sox2, Nestin, CD24) with lack of pluripotent markers (Nanog) and stable karyotype for more than 15 passages. Gene profiling and histology revealed that spinally grafted CoMo-NSCs differentiate into neurons, astrocytes, and oligodendrocytes over a 2-6-month period in vivo without forming neoplastic derivatives or abnormal structures. Moreover, transplanted CoMo-NSCs formed neurons with synaptic contacts and glia in a variety of host environments including immunodeficient rats, immunosuppressed ALS rats (SOD1G93A), or spinally injured minipigs, indicating these cells have favorable safety and differentiation characteristics.<br><br>CONCLUSIONS: These data demonstrate that manually selected CoMo-NSCs represent a safe and expandable NSC population which can effectively be used in prospective human clinical cell replacement trials for the treatment of a variety of neurodegenerative disorders, including ALS, stroke, spinal traumatic, or spinal ischemic injury.}, }
@article {pmid30861116, year = {2019}, author = {Joshi, AR and Muke, I and Bobylev, I and Lehmann, HC}, title = {ROCK inhibition improves axonal regeneration in a preclinical model of amyotrophic lateral sclerosis.}, journal = {The Journal of comparative neurology}, volume = {527}, number = {14}, pages = {2334-2340}, doi = {10.1002/cne.24679}, pmid = {30861116}, issn = {1096-9861}, mesh = {Amides/pharmacology/*therapeutic use ; Amyotrophic Lateral Sclerosis/drug therapy/*enzymology/genetics ; Animals ; Axons/drug effects/*enzymology ; Disease Models, Animal ; Enzyme Inhibitors/pharmacology/therapeutic use ; Female ; Male ; Mice ; Mice, Transgenic ; Nerve Regeneration/drug effects/*physiology ; Pyridines/pharmacology/*therapeutic use ; Sciatic Neuropathy/drug therapy/*enzymology/genetics ; Superoxide Dismutase/genetics ; rho-Associated Kinases/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Alteration of the RhoA/ROCK (Rho kinase) pathway has been shown to be neuroprotective in SOD1[G93A] mice, the most commonly used animal model of ALS. Since previous studies indicate that, apart from neuroprotection, ROCK inhibitor Y-27632 can also accelerate regeneration of motor axons, we here assessed the regenerative capability of axons in SOD1[G93A] mice with and without treatment with Y-27632. Regeneration of axons was examined after sciatic nerve crush in pre- and symptomatic SOD1[G93A] mice. Proregenerative effects of Y-27632 were studied during the disease course in the SOD1[G93A] mouse model. In symptomatic SOD1[G93A] mice, axonal regeneration was markedly reduced compared to presymptomatic SOD1[G93A] mice and wild types. Treatment with Y-27632 improved functional and morphological measures of motor axons after sciatic crush in all tested conditions. Y-27632 treatment did not increase the lifespan of symptomatic SOD1[G93A] mice, but did improve axonal (re)innervation of neuromuscular junctions. Our study provides proof of concept that axonal regeneration of motor neurons harboring SOD1[G93A] is impaired, but amenable for pharmacological interventions aiming to accelerate axonal regeneration. Given the lack of treatments for ALS, approaches to improve axonal regeneration, including by inhibiting ROCK, should be further explored.}, }
@article {pmid30855105, year = {2019}, author = {Ward, RJ and Crichton, RR}, title = {Ironing out the Brain.}, journal = {Metal ions in life sciences}, volume = {19}, number = {}, pages = {}, doi = {10.1515/9783110527872-010}, pmid = {30855105}, issn = {1559-0836}, mesh = {Aging ; Alzheimer Disease ; Amyotrophic Lateral Sclerosis ; Animals ; Brain/*physiology/physiopathology ; *Chelation Therapy ; Friedreich Ataxia ; Homeostasis ; Humans ; Huntington Disease ; Iron/*physiology/toxicity ; Neurodegenerative Diseases/*drug therapy ; Parkinson Disease ; }, abstract = {Our understanding of the broad principles of cellular and systemic iron homeostasis in man are well established with the exception of the brain. Most of the proteins involved in mammalian iron metabolism are present in the brain, although their distribution and precise roles in iron uptake, intracellular metabolism and export are still uncertain, as is the way in which systemic iron is transferred across the blood-brain barrier. We briefly review current concepts concerning the uptake and distribution of iron in the brain, before turning to the ways in which brain iron homeostasis might be regulated. The distribution of iron between different brain regions is then discussed as is the increase in brain iron with normal aging, and the different forms in which iron is present. The increased levels of iron found in specific brain regions and their potential contribution to neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease and other polyglutamine expansion diseases, amyotrophic lateral sclerosis, Friedreich's ataxia, as well as a number of neurodegenerative diseases with iron accumulation, are discussed. The interactions between neuroinflammation and iron are presented, and the chapter concludes with a review of current clinical studies and discussion of the potential and efficacy of iron chelation therapy in the treatment of neurodegenerative diseases.}, }
@article {pmid30851309, year = {2019}, author = {Pajarillo, E and Rizor, A and Lee, J and Aschner, M and Lee, E}, title = {The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics.}, journal = {Neuropharmacology}, volume = {161}, number = {}, pages = {107559}, pmid = {30851309}, issn = {1873-7064}, support = {R01 ES020852/ES/NIEHS NIH HHS/United States ; R01 ES024756/ES/NIEHS NIH HHS/United States ; R01 ES031282/ES/NIEHS NIH HHS/United States ; R01 ES007331/ES/NIEHS NIH HHS/United States ; R01 ES010563/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Astrocytes/drug effects/*metabolism ; Excitatory Amino Acid Transporter 1/drug effects/*genetics/*metabolism ; Excitatory Amino Acid Transporter 2/drug effects/*genetics/*metabolism ; Gene Expression Regulation ; Humans ; Nervous System Diseases/*drug therapy/*genetics/metabolism ; }, abstract = {Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS) which initiates rapid signal transmission in the synapse before its re-uptake into the surrounding glia, specifically astrocytes. The astrocytic glutamate transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) and their human homologs excitatory amino acid transporter 1 (EAAT1) and 2 (EAAT2), respectively, are the major transporters which take up synaptic glutamate to maintain optimal extracellular glutamic levels, thus preventing accumulation in the synaptic cleft and ensuing excitotoxicity. Growing evidence has shown that excitotoxicity is associated with various neurological disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), manganism, ischemia, schizophrenia, epilepsy, and autism. While the mechanisms of neurological disorders are not well understood, the dysregulation of GLAST/GLT-1 may play a significant role in excitotoxicity and associated neuropathogenesis. The expression and function of GLAST/GLT-1 may be dysregulated at the genetic, epigenetic, transcriptional or translational levels, leading to high levels of extracellular glutamate and excitotoxicity. Consequently, understanding the regulatory mechanisms of GLAST/GLT-1 has been an area of interest in developing therapeutics for the treatment of neurological disorders. Pharmacological agents including β-lactam antibiotics, estrogen/selective estrogen receptor modulators (SERMs), growth factors, histone deacetylase inhibitors (HDACi), and translational activators have shown significant efficacy in enhancing the expression and function of GLAST/GLT-1 and glutamate uptake both in vitro and in vivo. This comprehensive review will discuss the regulatory mechanisms of GLAST/GLT-1, their association with neurological disorders, and the pharmacological agents which mediate their expression and function. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.}, }
@article {pmid30849511, year = {2019}, author = {Parker, SE and Hanton, AM and Stefanou, SN and Noakes, PG and Woodruff, TM and Lee, JD}, title = {Revisiting the role of the innate immune complement system in ALS.}, journal = {Neurobiology of disease}, volume = {127}, number = {}, pages = {223-232}, doi = {10.1016/j.nbd.2019.03.003}, pmid = {30849511}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/metabolism ; Animals ; Complement System Proteins/*metabolism ; Humans ; Immunity, Innate/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. Although the precise mechanisms leading to ALS are yet to be determined, there is now increasing evidence implicating components of the innate immune complement system in the onset and progression of its motor phenotypes. This review will survey the clinical and experimental evidence for the role of the complement system in driving neuroinflammation and contributing to ALS disease progression. Specifically, it will explore findings regarding the different complement activation pathways involved in ALS, with a focus on the terminal pathway. It will also examine potential future research directions for complement in ALS, highlighting the targeting of specific molecular components of the system.}, }
@article {pmid30849180, year = {2019}, author = {McLeod, VM and Lau, CL and Chiam, MDF and Rupasinghe, TW and Roessner, U and Djouma, E and Boon, WC and Turner, BJ}, title = {Androgen receptor antagonism accelerates disease onset in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {British journal of pharmacology}, volume = {176}, number = {13}, pages = {2111-2130}, pmid = {30849180}, issn = {1476-5381}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology/physiopathology ; Androgen Receptor Antagonists/*pharmacology ; Animals ; Disease Models, Animal ; Disease Progression ; Embryonic Stem Cells ; Female ; Flutamide/*pharmacology ; Humans ; Male ; Mice, Transgenic ; Motor Neurons/drug effects ; Muscle, Skeletal/drug effects/metabolism/pathology ; Muscular Atrophy/metabolism/pathology ; Neuroglia/drug effects ; Prostate/drug effects/pathology ; Receptors, Androgen/metabolism ; Seminal Vesicles/drug effects/pathology ; Spinal Cord/drug effects/metabolism/pathology ; Testosterone/blood ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease typically more common in males, implicating androgens in progression of both patients and mouse models. Androgen effects are mediated by androgen receptor which is highly expressed in spinal motor neurons and skeletal muscles. To clarify the role of androgen receptors in ALS, we therefore examined the effect of androgen receptor antagonism in the SOD1[G93A] mouse model.<br><br>EXPERIMENTAL APPROACH: The androgen receptor antagonist, flutamide, was administered to presymptomatic SOD1[G93A] mice as a slow-release subcutaneous implant (5&#xa0;mg&#xb7;day[-1]). Testosterone, flutamide, and metabolite levels were measured in blood and spinal cord tissue by LC-MS-MS. Effects on disease onset and progression were assessed using motor function tests, survival, muscle, and neuropathological analyses.<br><br>KEY RESULTS: Flutamide was metabolised to 2-hydroxyflutamide achieving steady-state plasma levels across the study duration and reached the spinal cord at pharmacologically active concentrations. Flutamide treatment accelerated disease onset and locomotor dysfunction in male SOD1[G93A] mice, but not female mice, without affecting survival. Analysis of hindlimb muscles revealed exacerbation of myofibre atrophy in male SOD1[G93A] mice treated with flutamide, although motor neuron pathology was not affected.<br><br>CONCLUSION AND IMPLICATIONS: The androgen receptor antagonist accelerated disease onset in male SOD1[G93A] mice, leading to exacerbated muscle pathology, consistent with a role of androgens in modulating disease severity, sexual dimorphism, and peripheral pathology in ALS. These results also demonstrate a key contribution of skeletal muscle pathology to disease onset, but not outcome, in this mouse model of ALS.}, }
@article {pmid30844858, year = {2019}, author = {Drain, JP and Virk, SS and Jain, N and Yu, E}, title = {Dropped Head Syndrome: A Systematic Review.}, journal = {Clinical spine surgery}, volume = {32}, number = {10}, pages = {423-429}, doi = {10.1097/BSD.0000000000000811}, pmid = {30844858}, issn = {2380-0194}, mesh = {Aged ; Female ; Humans ; Logistic Models ; Male ; Middle Aged ; Spinal Diseases/*pathology/surgery ; Syndrome ; Treatment Outcome ; }, abstract = {STUDY DESIGN: This study was a systematic review.<br><br>OBJECTIVES: To reveal demographic factors, etiologies, response to treatment, and to propose a novel treatment algorithm for dropped head syndrome (DHS).<br><br>SUMMARY OF BACKGROUND DATA: DHS is a rare condition defined by weakness of the cervical paraspinal muscles resulting in passively correctable flexion of the cervical spine. Patients present with neck pain, difficulty eating, and impaired horizontal gaze. Because of the rarity of DHS, a paucity of information exists with regard to demographics, etiology, and relative superiority of medical and surgical treatment.<br><br>MATERIALS AND METHODS: We conducted a systematic literature review by searching PubMed for "dropped head syndrome," "chin on chest," "isolated neck extensor myopathy" (INEM), and "camptocephalia." Inclusion criteria were English-language articles that applied a specific treatment regimen with outcome data. A binomial logistic regression analysis was then performed to determine which covariates (age, sex, and treatments) were predictive of a positive response to treatment.<br><br>RESULTS: A total of 129 patients were described in 74 studies. Mean age was 63.6 and 63% were female. More than two-thirds of all patients fell into just 4 diagnostic categories (isolated neck extensor myopathy, 31.8%; Parkinson's, 20.2%; myasthenia gravis, 12.4%; amyotrophic lateral sclerosis, 7.0%). Overall positive response to treatment was 64.3%; primary medical treatment (73.5%), immune suppression (78.9%), and a combination of both (87.5%). Surgery was 93.8% successful. A treatment algorithm focused on appropriate diagnosis, initial medical management, with surgical evaluation only after failure of medical treatment was proposed.<br><br>CONCLUSIONS: Treatment for DHS starts with accurate diagnosis of the underlying etiology and is often associated with neuromuscular disease. A treatment algorithm for appropriate management of these patients was proposed. A trial of medical management and/or immunomodulators is warranted. Failing nonoperative management, surgery is predictive of a positive outcome.<br><br>LEVEL OF EVIDENCE: Level V.}, }
@article {pmid30841754, year = {2019}, author = {Harlan, BA and Pehar, M and Killoy, KM and Vargas, MR}, title = {Enhanced SIRT6 activity abrogates the neurotoxic phenotype of astrocytes expressing ALS-linked mutant SOD1.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {33}, number = {6}, pages = {7084-7091}, pmid = {30841754}, issn = {1530-6860}, support = {R01 NS089640/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Antioxidant Response Elements ; Astrocytes/drug effects/*metabolism ; Gene Expression Regulation/drug effects ; Mice ; Mutation ; Niacinamide/*analogs &amp; derivatives/pharmacology ; Nicotinamide Mononucleotide/*pharmacology ; Pyridinium Compounds ; Sirtuins/genetics/*metabolism ; Superoxide Dismutase-1/genetics/*metabolism ; }, abstract = {Sirtuins (SIRTs) are NAD[+]-dependent deacylases that play a key role in transcription, DNA repair, metabolism, and oxidative stress resistance. Increasing NAD[+] availability regulates endogenous SIRT activity, leading to increased resistance to oxidative stress and decreased mitochondrial reactive oxygen production in multiple cell types and disease models. This protection, at least in part, depends on the activation of antioxidant mitochondrial proteins. We now show that increasing total NAD[+] content in astrocytes leads to the activation of the transcription factor nuclear factor, erythroid-derived 2, like 2 (Nfe2l2 or Nrf2) and up-regulation of the antioxidant proteins heme oxygenase 1 (HO-1) and sulfiredoxin 1 (SRXN1). Nrf2 activation also occurs as a result of SIRT6 overexpression. Mutations in Cu-Zn superoxide dismutase 1 (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS). Astrocytes isolated from mutant human SOD1-overexpressing mice induce motor neuron death in coculture. Treatment with nicotinamide mononucleotide or nicotinamide riboside increases total NAD[+] content in ALS astrocytes and abrogates their toxicity toward cocultured motor neurons. The observed neuroprotection depends on SIRT6 expression in astrocytes. Moreover, overexpression of SIRT6 in astrocytes by itself abrogates the neurotoxic phenotype of ALS astrocytes. Our results identify SIRT6 as a potential therapeutic target to prevent astrocyte-mediated motor neuron death in ALS.-Harlan, B. A., Pehar, M., Killoy, K. M., Vargas, M. R. Enhanced SIRT6 activity abrogates the neurotoxic phenotype of astrocytes expressing ALS-linked mutant SOD1.}, }
@article {pmid30839376, year = {2019}, author = {Cimpoesu, D and Corlade-Andrei, M and Popa, TO and Grigorasi, G and Bouros, C and Rotaru, L and Nedelea, PL}, title = {Cardiac Arrest in Special Circumstances-Recent Advances in Resuscitation.}, journal = {American journal of therapeutics}, volume = {26}, number = {2}, pages = {e276-e283}, doi = {10.1097/MJT.0000000000000927}, pmid = {30839376}, issn = {1536-3686}, mesh = {Cardiopulmonary Resuscitation/*methods/trends ; Extracorporeal Membrane Oxygenation/methods ; Heart Arrest/*therapy ; Humans ; }, abstract = {BACKGROUND: Cardiopulmonary resuscitation (CPR) in special circumstances includes the emergency intervention for special causes, special environments, and special patients. Special causes cover the potential reversible causes of cardiac arrest that must be identified or excluded during any resuscitation act. The special environments section includes recommendations for the treatment of cardiac arrest occurring in specific locations: cardiac surgery, catheterization laboratory, dialysis unit, dental surgery, commercial airplanes or air ambulances, playing field, difficult environment (eg, drowning, high altitude, avalanche, and electrical injuries) or mass casualty incident. CPR for special patients gives guidance for the patients with severe comorbidities (asthma, heart failure with ventricular assist devices, neurological disease, and obesity) and pregnant women or older people.<br><br>AREAS OF UNCERTAINTY: There are no generally worldwide accepted resuscitation guidelines for special circumstance, and there are still few studies investigating the safety and outcome of cardiac arrest in special circumstances. Applying standard advanced life support (ALS) guidelines in this situation is not enough to obtain better results from CPR, for example, cardiac arrest caused by electrolyte abnormalities require also the treatment of that electrolyte disturbance, not only standard CPR, or in the case of severe hypothermia, when standard ALS approach is not recommended until a temperature threshold is reached after warming measures. Data sources for this article are scientific articles describing retrospective studies conducted in CPR performed in special circumstances, experts' consensus, and related published opinion of experts in CPR.<br><br>THERAPEUTIC ADVANCES: The newest advance in therapeutics applied to resuscitation field for these particular situations is the use of extracorporeal life support/extracorporeal membrane oxygenation devices during CPR.<br><br>CONCLUSIONS: In special circumstances, ALS guidelines require modification and special attention for causes, environment, and patient particularities, with specific therapeutic intervention concomitant with standard ALS.}, }
@article {pmid30835675, year = {2019}, author = {Srinivas, S and Wali, AR and Pham, MH}, title = {Efficacy of riluzole in the treatment of spinal cord injury: a systematic review of the literature.}, journal = {Neurosurgical focus}, volume = {46}, number = {3}, pages = {E6}, doi = {10.3171/2019.1.FOCUS18596}, pmid = {30835675}, issn = {1092-0684}, mesh = {Adolescent ; Adult ; Aged ; Animals ; Biological Availability ; Clinical Trials as Topic ; Drug Evaluation ; Drug Evaluation, Preclinical ; Excitatory Amino Acid Antagonists/pharmacokinetics/therapeutic use ; Glutamic Acid/metabolism ; Humans ; Middle Aged ; Neuroprotective Agents/pharmacokinetics/*therapeutic use ; Rabbits ; Rats ; Recovery of Function ; Riluzole/pharmacokinetics/*therapeutic use ; Spinal Cord Injuries/complications/*drug therapy ; Trauma Severity Indices ; Treatment Outcome ; Young Adult ; }, abstract = {OBJECTIVERiluzole is a glutamatergic modulator that has recently shown potential for neuroprotection after spinal cord injury (SCI). While the effects of riluzole are extensively documented in animal models of SCI, there remains heterogeneity in findings. Moreover, there is a paucity of data on the pharmacology of riluzole and its effects in humans. For the present study, the authors systematically reviewed the literature to provide a comprehensive understanding of the effects of riluzole in SCI.METHODSThe PubMed database was queried from 1996 to September 2018 to identify animal studies and clinical trials involving riluzole administration for SCI. Once articles were identified, they were processed for year of publication, study design, subject type, injury model, number of subjects in experimental and control groups, dose, timing/route of administration, and outcomes.RESULTSA total of 37 studies were included in this study. Three placebo-controlled clinical trials were included with a total of 73 patients with a mean age of 39.1 years (range 18-70 years). For the clinical trials included within this study, the American Spinal Injury Association Impairment Scale distributions for SCI were 42.6% grade A, 25% grade B, 26.6% grade C, and 6.2% grade D. Key findings from studies in humans included decreased nociception, improved motor function, and attenuated spastic reflexes. Twenty-six animal studies (24 in vivo, 1 in vitro, and 1 including both in vivo and in vitro) were included. A total of 520 animals/in vitro specimens were exposed to riluzole and 515 animals/in vitro specimens underwent other treatment for comparison. The average dose of riluzole for intraperitoneal, in vivo studies was 6.5 mg/kg (range 1-10 mg/kg). Key findings from animal studies included behavioral improvement, histopathological tissue sparing, and modified electrophysiology after SCI. Eight studies examined the pharmacology of riluzole in SCI. Key findings from pharmacological studies included riluzole dose-dependent effects on glutamate uptake and its modified bioavailability after SCI in both animal and clinical models.CONCLUSIONSSCI has many negative sequelae requiring neuroprotective intervention. While still relatively new in its applications for SCI, both animal and human studies demonstrate riluzole to be a promising pharmacological intervention to attenuate the devastating effects of this condition.}, }
@article {pmid30832324, year = {2019}, author = {Christ, MG and Huesmann, H and Nagel, H and Kern, A and Behl, C}, title = {Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo.}, journal = {Cells}, volume = {8}, number = {3}, pages = {}, pmid = {30832324}, issn = {2073-4409}, mesh = {Animals ; *Autophagy/drug effects ; Caenorhabditis elegans/drug effects/metabolism ; Furans/pharmacology ; HEK293 Cells ; HeLa Cells ; Humans ; Paralysis/pathology ; Phosphorylation/drug effects ; Protein Aggregates/drug effects ; *Proteostasis/drug effects ; Receptors, sigma/agonists/*metabolism ; Sigma-1 Receptor ; }, abstract = {Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and memory, and the described pleiotropic neuroprotective effects in various experimental paradigms, Sig-1R activation is recognized as one potential approach for prevention and therapy of neurodegeneration and, interestingly, in amyotrophic lateral sclerosis associated with mutated Sig-1R, autophagy is disturbed. Here we analyzed the effects of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), a muscarinic receptor ligand and Sig-1R agonist, on autophagy and proteostasis. We describe, at the molecular level, for the first time, that pharmacological Sig-1R activation a) enhances the autophagic flux in human cells and in Caenorhabditis elegans and b) increases proteostasis capacity, ultimately ameliorating paralysis caused by protein aggregation in C. elegans. ANAVEX2-73 is already in clinical investigation for the treatment of Alzheimer's disease, and the novel activities of this compound on autophagy and proteostasis described here may have consequences for the use and further development of the Sig-1R as a drug target in the future. Moreover, our study defines the Sig-1R as an upstream modulator of canonical autophagy, which may have further implications for various conditions with dysfunctional autophagy, besides neurodegeneration.}, }
@article {pmid30828191, year = {2019}, author = {Kumar, M and Bhoi, S and Sharma, K}, title = {Human-induced pluripotent stem cells derived hematopoietic progenitor cells for treatment of hematopoietic failure among trauma hemorrhagic shock patients.}, journal = {Journal of clinical orthopaedics and trauma}, volume = {10}, number = {2}, pages = {269-273}, pmid = {30828191}, issn = {0976-5662}, abstract = {Hematopoietic failure (HF) has been observed in trauma hemorrhagic shock (T/HS) patients. Multiple factors are involved. Elevated serum levels of cytokines, catecholamine, granulocyte colony stimulating factor, peripheral blood hematopoietic progenitor cells (HPCs) and decreased expression of erythropoietin receptor are associated with HF among T/HS. HF leads to anaemia, susceptibility to infection, sepsis and multi-organ failure. There is a lack of molecular understanding of HF and its potential therapeutic strategies. Cell-based therapy has ability to modulate the production of inflammatory cytokines, vascular dysfunction, tissue damage and apoptosis. Human-induced pluripotent stem cells (iPSC) derived HPCs may have the ability to restore HF in T/HS. Autologous cell-based iPSC have great promises for various diseases such as Alzheimer's disease, Parkinson's disease, cardiovascular disease, diabetes, amyotrophic lateral sclerosis, and spinal cord injury without ethical concerns. Similarly, treatment with iPSC derived hematopoietic stem cells can used for the treatment of HF among T/HS and may also improve the outcome. Here, we review the potential of human iPSC derived HSC to reversed HF following T/HS.}, }
@article {pmid30826182, year = {2019}, author = {Mann, JR and Gleixner, AM and Mauna, JC and Gomes, E and DeChellis-Marks, MR and Needham, PG and Copley, KE and Hurtle, B and Portz, B and Pyles, NJ and Guo, L and Calder, CB and Wills, ZP and Pandey, UB and Kofler, JK and Brodsky, JL and Thathiah, A and Shorter, J and Donnelly, CJ}, title = {RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43.}, journal = {Neuron}, volume = {102}, number = {2}, pages = {321-338.e8}, pmid = {30826182}, issn = {1097-4199}, support = {R21 NS090205/NS/NINDS NIH HHS/United States ; P30 DK079307/DK/NIDDK NIH HHS/United States ; T32 NS007433/NS/NINDS NIH HHS/United States ; T32 GM132039/GM/NIGMS NIH HHS/United States ; R21 NS098379/NS/NINDS NIH HHS/United States ; P50 AG005133/AG/NIA NIH HHS/United States ; R01 GM075061/GM/NIGMS NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; R01 NS105756/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Cytoplasmic Granules/*metabolism ; DNA-Binding Proteins/*metabolism ; Frontotemporal Dementia/metabolism ; HEK293 Cells ; Humans ; Inclusion Bodies ; Neurons/*metabolism ; Oligonucleotides ; Optogenetics ; *Phase Transition ; RNA/*metabolism ; *Stress, Physiological ; TDP-43 Proteinopathies/*metabolism ; }, abstract = {TDP-43 proteinopathy is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia where cytoplasmic TDP-43 inclusions are observed within degenerating regions of patient postmortem tissue. The mechanism by which TDP-43 aggregates has remained elusive due to technological limitations, which prevent the analysis of specific TDP-43 interactions in live cells. We present an optogenetic approach to reliably induce TDP-43 proteinopathy under spatiotemporal control. We show that the formation of pathologically relevant inclusions is driven by aberrant interactions between low-complexity domains of TDP-43 that are antagonized by RNA binding. Although stress granules are hypothesized to be a conduit for seeding TDP-43 proteinopathy, we demonstrate pathological inclusions outside these RNA-rich structures. Furthermore, we show that aberrant phase transitions of cytoplasmic TDP-43 are neurotoxic and that treatment with oligonucleotides composed of TDP-43 target sequences prevent inclusions and rescue neurotoxicity. Collectively, these studies provide insight into the mechanisms that underlie TDP-43 proteinopathy and present a potential avenue for therapeutic intervention.}, }
@article {pmid30825670, year = {2019}, author = {Martier, R and Liefhebber, JM and García-Osta, A and Miniarikova, J and Cuadrado-Tejedor, M and Espelosin, M and Ursua, S and Petry, H and van Deventer, SJ and Evers, MM and Konstantinova, P}, title = {Targeting RNA-Mediated Toxicity in C9orf72 ALS and/or FTD by RNAi-Based Gene Therapy.}, journal = {Molecular therapy. Nucleic acids}, volume = {16}, number = {}, pages = {26-37}, pmid = {30825670}, issn = {2162-2531}, abstract = {A hexanucleotide GGGGCC expansion in intron 1 of chromosome 9 open reading frame 72 (C9orf72) gene is the most frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The corresponding repeat-containing sense and antisense transcripts cause a gain of toxicity through the accumulation of RNA foci in the nucleus and deposition of dipeptide-repeat (DPR) proteins in the cytoplasm of the affected cells. We have previously reported on the potential of engineered artificial anti-C9orf72-targeting miRNAs (miC) targeting C9orf72 to reduce the gain of toxicity caused by the repeat-containing transcripts. In the current study, we tested the silencing efficacy of adeno-associated virus (AAV)5-miC in human-derived induced pluripotent stem cell (iPSC) neurons and in an ALS mouse model. We demonstrated that AAV5-miC transduces different types of neuronal cells and can reduce the accumulation of repeat-containing C9orf72 transcripts. Additionally, we demonstrated silencing of C9orf72 in both the nucleus and cytoplasm, which has an added value for the treatment of ALS and/or FTD patients. A proof of concept in an ALS mouse model demonstrated the significant reduction in repeat-containing C9orf72 transcripts and RNA foci after treatment. Taken together, these findings support the feasibility of a gene therapy for ALS and FTD based on the reduction in toxicity caused by the repeat-containing C9orf72 transcripts.}, }
@article {pmid30824685, year = {2019}, author = {Ionescu, A and Gradus, T and Altman, T and Maimon, R and Saraf Avraham, N and Geva, M and Hayden, M and Perlson, E}, title = {Targeting the Sigma-1 Receptor via Pridopidine Ameliorates Central Features of ALS Pathology in a SOD1[G93A] Model.}, journal = {Cell death &amp; disease}, volume = {10}, number = {3}, pages = {210}, pmid = {30824685}, issn = {2041-4889}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Axonal Transport/drug effects/genetics ; Cell Death/drug effects ; Cell Survival/drug effects/genetics ; Cells, Cultured ; Coculture Techniques ; Disease Models, Animal ; Female ; MAP Kinase Signaling System/drug effects ; Mice ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Mice, Transgenic ; Motor Neurons/*drug effects/metabolism ; Muscle Cells/drug effects/metabolism/pathology ; Myoblasts, Smooth Muscle ; Neuromuscular Junction/drug effects/genetics/physiology ; Piperidines/*pharmacology/*therapeutic use ; Receptors, sigma/genetics/*metabolism ; Spinal Cord/*drug effects/metabolism/pathology ; Superoxide Dismutase-1/genetics/*metabolism ; Sigma-1 Receptor ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting both the upper and lower motor neurons (MNs), with no effective treatment currently available. Early pathological events in ALS include perturbations in axonal transport (AT), formation of toxic protein aggregates and Neuromuscular Junction (NMJ) disruption, which all lead to axonal degeneration and motor neuron death. Pridopidine is a small molecule that has been clinically developed for Huntington disease. Here we tested the efficacy of pridopidine for ALS using in vitro and in vivo models. Pridopidine beneficially modulates AT deficits and diminishes NMJ disruption, as well as motor neuron death in SOD1[G93A] MNs and in neuromuscular co-cultures. Furthermore, we demonstrate that pridopidine activates the ERK pathway and mediates its beneficial effects through the sigma-1 receptor (S1R). Strikingly, in vivo evaluation of pridopidine in SOD1[G93A] mice reveals a profound reduction in mutant SOD1 aggregation in the spinal cord, and attenuation of NMJ disruption, as well as subsequent muscle wasting. Taken together, we demonstrate for the first time that pridopidine improves several cellular and histological hallmark pathologies of ALS through the S1R.}, }
@article {pmid30819665, year = {2019}, author = {Paidi, SK and Diaz, PM and Dadgar, S and Jenkins, SV and Quick, CM and Griffin, RJ and Dings, RPM and Rajaram, N and Barman, I}, title = {Label-Free Raman Spectroscopy Reveals Signatures of Radiation Resistance in the Tumor Microenvironment.}, journal = {Cancer research}, volume = {79}, number = {8}, pages = {2054-2064}, pmid = {30819665}, issn = {1538-7445}, support = {DP2 GM128198/GM/NIGMS NIH HHS/United States ; P20 GM103625/GM/NIGMS NIH HHS/United States ; P30 GM145393/GM/NIGMS NIH HHS/United States ; P41 EB015871/EB/NIBIB NIH HHS/United States ; }, mesh = {Animals ; Carcinoma, Squamous Cell/*pathology/radiotherapy ; Head and Neck Neoplasms/*pathology/radiotherapy ; Humans ; Lung Neoplasms/*pathology/radiotherapy ; Mice ; Mice, Nude ; *Radiation Tolerance ; Spectrum Analysis, Raman/*methods ; Tumor Cells, Cultured ; Tumor Microenvironment/*radiation effects ; Xenograft Model Antitumor Assays ; }, abstract = {Delay in the assessment of tumor response to radiotherapy continues to pose a major challenge to quality of life for patients with nonresponsive tumors. Here, we exploited label-free Raman spectroscopic mapping to elucidate radiation-induced biomolecular changes in tumors and uncovered latent microenvironmental differences between treatment-resistant and -sensitive tumors. We used isogenic radiation-resistant and -sensitive A549 human lung cancer cells and human head and neck squamous cell carcinoma (HNSCC) cell lines (UM-SCC-47 and UM-SCC-22B, respectively) to grow tumor xenografts in athymic nude mice and demonstrated the molecular specificity and quantitative nature of Raman spectroscopic tissue assessments. Raman spectra obtained from untreated and treated tumors were subjected to chemometric analysis using multivariate curve resolution-alternating least squares (MCR-ALS) and support vector machine (SVM) to quantify biomolecular differences in the tumor microenvironment. The Raman measurements revealed significant and reliable differences in lipid and collagen content postradiation in the tumor microenvironment, with consistently greater changes observed in the radiation-sensitive tumors. In addition to accurately evaluating tumor response to therapy, the combination of Raman spectral markers potentially offers a route to predicting response in untreated tumors prior to commencing treatment. Combined with its noninvasive nature, our findings provide a rationale for in vivo studies using Raman spectroscopy, with the ultimate goal of clinical translation for patient stratification and guiding adaptation of radiotherapy during the course of treatment. SIGNIFICANCE: These findings highlight the sensitivity of label-free Raman spectroscopy to changes induced by radiotherapy and indicate the potential to predict radiation resistance prior to commencing therapy.}, }
@article {pmid30811816, year = {2019}, author = {Bursch, F and Rath, KJ and Sarikidi, A and Böselt, S and Kefalakes, E and Osmanovic, A and Thau-Habermann, N and Klöß, S and Köhl, U and Petri, S}, title = {Analysis of the therapeutic potential of different administration routes and frequencies of human mesenchymal stromal cells in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of tissue engineering and regenerative medicine}, volume = {13}, number = {4}, pages = {649-663}, doi = {10.1002/term.2846}, pmid = {30811816}, issn = {1932-7005}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Animals ; Body Weight ; Brain/pathology/physiopathology ; Disease Models, Animal ; Female ; Humans ; Injections, Intraventricular ; Male ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*cytology ; Mice, Transgenic ; Motor Activity ; Nerve Growth Factors/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Rotarod Performance Test ; Spinal Cord/pathology/physiopathology ; Superoxide Dismutase-1/*genetics ; Survival Analysis ; }, abstract = {Cellular therapy represents a novel option for the treatment of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Its major aim is the generation of a protective environment for degenerating motor neurons. Mesenchymal stromal cells secrete different growth factors and have antiapoptotic and immunomodulatory properties. They can easily and safely be isolated from human bone marrow and are therefore considered promising therapeutic candidates. In the present study, we compared intraventricular application of human mesenchymal stromal cells (hMSCs) versus single and repeated intraspinal injections in the mutant SOD1[G93A] transgenic ALS mouse model. We observed significant reduction of lifespan of animals treated by intraventricular hMSC injection compared with the vehicle treated control group, accompanied by changes in weight, general condition, and behavioural assessments. A potential explanation for these rather surprising deleterious effects lies in increased microgliosis detected in the hMSC treated animals. Repeated intraspinal injection at two time points resulted in a slight but not significant increase in survival and significant improvement of motor performance although no hMSC-induced changes of motor neuron numbers, astrogliosis, and microgliosis were detected. Quantitative real time polymerase chain reaction showed reduced expression of endothelial growth factor in animals having received hMSCs twice compared with the vehicle treated control group. hMSCs were detectable at the injection site at Day 20 after injection into the spinal cord but no longer at Day 70. Intraspinal injection of hMSCs may therefore be a more promising option for the treatment of ALS than intraventricular injection and repeated injections might be necessary to obtain substantial therapeutic benefit.}, }
@article {pmid30810406, year = {2019}, author = {Yoshino, H}, title = {Edaravone for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {19}, number = {3}, pages = {185-193}, doi = {10.1080/14737175.2019.1581610}, pmid = {30810406}, issn = {1744-8360}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Cognitive Dysfunction/drug therapy/etiology ; Edaravone/pharmacokinetics/pharmacology/*therapeutic use ; Free Radical Scavengers/pharmacokinetics/pharmacology/*therapeutic use ; Humans ; Neuroprotective Agents/pharmacokinetics/pharmacology/*therapeutic use ; Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive fatal disorder that affects all skeletal muscles, leading to death, mostly within 2-4 years from onset. To date, the anti-glutamatergic drug riluzole is the only drug that has been approved for the treatment of this disease; however, its efficacy is modest. Oxidative stress is considered to be involved in the pathology of ALS, and in this regard, the free radical scavenger edaravone, which was originally developed for the treatment of acute ischemic stroke, has also been developed for the treatment of ALS. Areas covered: This review describes the pharmacological properties of edaravone and the progress of clinical trials conducted to evaluate the efficacy of this drug in the treatment of ALS. Expert commentary: Edaravone is the first drug to show effective inhibition of the motor function deterioration experienced by ALS patients with early-stage probable and definite types. In order to effectively prolong the quality of motor function, edaravone treatment should be initiated as soon as the diagnosis has been confirmed; however, the respiratory function should be carefully monitored when a deterioration in breathing capacity is detected.}, }
@article {pmid30802001, year = {2019}, author = {Řehořová, M and Vargová, I and Forostyak, S and Vacková, I and Turnovcová, K and Kupcová Skalníková, H and Vodička, P and Kubinová, &#x160; and Syková, E and Jendelová, P}, title = {A Combination of Intrathecal and Intramuscular Application of Human Mesenchymal Stem Cells Partly Reduces the Activation of Necroptosis in the Spinal Cord of SOD1[G93A] Rats.}, journal = {Stem cells translational medicine}, volume = {8}, number = {6}, pages = {535-547}, pmid = {30802001}, issn = {2157-6580}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Beclin-1/metabolism ; Caspase 9/metabolism ; Disease Models, Animal ; Humans ; Injections, Intramuscular ; Injections, Spinal ; Longevity ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology/metabolism ; Motor Neurons/metabolism ; *Necroptosis ; Protein Serine-Threonine Kinases/metabolism ; Quadriceps Muscle/cytology/metabolism ; Rats ; Rats, Sprague-Dawley ; Rats, Transgenic ; Receptor-Interacting Protein Serine-Threonine Kinases ; Spinal Cord/cytology/*metabolism ; Superoxide Dismutase-1/*genetics/metabolism ; }, abstract = {An increasing number of studies have demonstrated the beneficial effects of human mesenchymal stem cells (hMSC) in the treatment of amyotrophic lateral sclerosis (ALS). We compared the effect of repeated intrathecal applications of hMSC or their conditioned medium (CondM) using lumbar puncture or injection into the muscle (quadriceps femoris), or a combination of both applications in symptomatic SOD1[G93A] rats. We further assessed the effect of the treatment on three major cell death pathways (necroptosis, apoptosis, and autophagy) in the spinal cord tissue. All the animals were behaviorally tested (grip strength test, Basso Beattie Bresnahan (BBB) test, and rotarod), and the tissue was analyzed immunohistochemically, by qPCR and Western blot. All symptomatic SOD1 rats treated with hMSC had a significantly increased lifespan, improved motor activity and reduced number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells. Moreover, a combined hMSC delivery increased motor neuron survival, maintained neuromuscular junctions in quadriceps femoris and substantially reduced the levels of proteins involved in necroptosis (Rip1, mixed lineage kinase-like protein, cl-casp8), apoptosis (cl-casp 9) and autophagy (beclin 1). Furthermore, astrogliosis and elevated levels of Connexin 43 were decreased after combined hMSC treatment. The repeated application of CondM, or intramuscular injections alone, improved motor activity; however, this improvement was not supported by changes at the molecular level. Our results provide new evidence that a combination of repeated intrathecal and intramuscular hMSC applications protects motor neurons and neuromuscular junctions, not only through a reduction of apoptosis and autophagy but also through the necroptosis pathway, which is significantly involved in cell death in rodent SOD1[G93A] model of ALS. Stem Cells Translational Medicine 2019;8:535-547.}, }
@article {pmid30797953, year = {2019}, author = {Vissers, C and Ming, GL and Song, H}, title = {Nanoparticle technology and stem cell therapy team up against neurodegenerative disorders.}, journal = {Advanced drug delivery reviews}, volume = {148}, number = {}, pages = {239-251}, pmid = {30797953}, issn = {1872-8294}, support = {R01 AG057497/AG/NIA NIH HHS/United States ; T32 GM007445/GM/NIGMS NIH HHS/United States ; R37 NS047344/NS/NINDS NIH HHS/United States ; U19 MH106434/MH/NIMH NIH HHS/United States ; U19 AI131130/AI/NIAID NIH HHS/United States ; P01 NS097206/NS/NINDS NIH HHS/United States ; R35 NS097370/NS/NINDS NIH HHS/United States ; R35 NS116843/NS/NINDS NIH HHS/United States ; R01 MH105128/MH/NIMH NIH HHS/United States ; }, mesh = {Animals ; Drug Delivery Systems ; Humans ; Nanostructures/*chemistry ; *Nanotechnology ; Neurodegenerative Diseases/*therapy ; Neuroprotective Agents/chemistry/*therapeutic use ; *Stem Cell Transplantation ; }, abstract = {The convergence of nanoparticles and stem cell therapy holds great promise for the study, diagnosis, and treatment of neurodegenerative disorders. Researchers aim to harness the power of nanoparticles to regulate cellular microenvironment, improve the efficiency of cell and drug delivery to the brain, and enhance the survival of stem cell transplants. Understanding the various properties of different nanoparticles is key to applying them to clinical therapies; the many distinct types of nanoparticles offer unique capacities for medical imaging, diagnosis, and treatment of neurodegeneration disorders. In this review we introduce the biology of Alzheimer's, Parkinson's Disease, and amyotrophic lateral sclerosis, and discuss the potentials and shortcomings of metal, silica, lipid-based, polymeric, and hydrogel nanoparticles for diagnosis and treatment of neurodegenerative disorders. We then provide an overview of current strategies in stem cell therapies and how they can be combined with nanotechnology to improve clinical outcomes.}, }
@article {pmid30794116, year = {2020}, author = {Zhao, Z and Yao, M and Wei, L and Ge, S}, title = {Obesity caused by a high-fat diet regulates the Sirt1/PGC-1α/FNDC5/BDNF pathway to exacerbate isoflurane-induced postoperative cognitive dysfunction in older mice.}, journal = {Nutritional neuroscience}, volume = {23}, number = {12}, pages = {971-982}, doi = {10.1080/1028415X.2019.1581460}, pmid = {30794116}, issn = {1476-8305}, mesh = {Animals ; Brain-Derived Neurotrophic Factor/metabolism ; Cognitive Dysfunction/*chemically induced/*metabolism ; *Diet, High-Fat ; Fibronectins/metabolism ; Hippocampus/metabolism ; Isoflurane/*administration &amp; dosage ; Male ; Mice, Inbred C57BL ; Obesity/*metabolism ; Postoperative Complications/*chemically induced/*metabolism ; *Signal Transduction ; Sirtuin 1/metabolism ; Transcription Factors/metabolism ; }, abstract = {Objectives: To investigate the effects of obesity caused by high-fat diet (HFD) on postoperative cognitive dysfunction (POCD) and expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampus of older mice. Methods: Fifty-six 15-month-old male C57BL/6 mice were randomly divided into eight groups - ad libitum control (ALC), ad libitum surgery (ALS), ad libitum surgery with PBS (ALS + PBS), ad libitum surgery with resveratrol (ALS + Res), HFD control (HFC), HFD surgery (HFS), HFD surgery with PBS (HFS + PBS), HFD surgery with resveratrol (HFS + Res). Surgery group mice were exposed to isoflurane before tibial fracture internal fixation. Open field tests and fear conditioning were performed to test motor ability and memory. The levels of expression of Sirt1, PGC-1α, FNDC5, and BDNF were detected using western blot and immunofluorescence. Results: The results of the open field tests indicated there were no between-group differences in motor ability and anxiety. The results of the fear conditioning indicated that the memory of the HFC group and HFS group mice were significantly worse compared with the ALC group and ALS group mice, respectively. There were parallel decreases in expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampi of the HFC and HFS group mice. Resveratrol treatment attenuated the memory loss by increasing hippocampal Sirt1 expression. Expression of the PGC-1α/FNDC5/ BDNF pathway in the CA1 area of the hippocampus was upregulated after resveratrol treatment. Conclusion: An HFD exacerbates POCD in older mice. This change was related to HFD inhibition of expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampus. Resveratrol pretreatment reversed the memory loss via upregulation of this pathway.}, }
@article {pmid30786027, year = {2019}, author = {Zhou, LY and Tian, ZR and Yao, M and Chen, XQ and Song, YJ and Ye, J and Yi, NX and Cui, XJ and Wang, YJ}, title = {Riluzole promotes neurological function recovery and inhibits damage extension in rats following spinal cord injury: a meta-analysis and systematic review.}, journal = {Journal of neurochemistry}, volume = {150}, number = {1}, pages = {6-27}, doi = {10.1111/jnc.14686}, pmid = {30786027}, issn = {1471-4159}, mesh = {Animals ; Neuroprotective Agents/*pharmacology ; Rats ; Recovery of Function/*drug effects ; Riluzole/*pharmacology ; Spinal Cord/*drug effects/pathology ; *Spinal Cord Injuries/pathology ; }, abstract = {Spinal cord injury (SCI) is a devastating condition that has few treatment options. Riluzole, a sodium channel blocker used to treat amyotrophic lateral sclerosis, has been initially trialed in human SCI. We performed a systematic review to critically assess the efficacy of riluzole in locomotor recovery and damage extension in SCI rat models, and the potential for clinical translation. PubMed, Embase, Cochrane Library, and Chinese databases were searched from their inception date to March 2018. Two reviewers independently selected animal studies that evaluated neurological recovery and lesion area following riluzole treatment in SCI rat models, extracted data and assessed methodological quality. Pairwise meta-analysis, subgroup analysis, and network meta-analysis were performed to assess the effects of riluzole on SCI. Ten eligible studies were included. Two studies had high methodological quality. Overall, the Basso, Beattie, and Bresnahan scores were increased in riluzole-treated animals versus controls, and effect sizes showed a gradual increase from the 1st (five studies, n = 104, mean difference = 1.24, 95% CI = 0.11 to 2.37, p = 0.03) to 6th week after treatment (five studies, n = 120, mean difference = 2.34, 95% CI = 1.26 to 3.42, p < 0.0001). Riluzole was associated with improved outcomes in the inclined plane test and the tissue preservation area. Subgroup analyses suggested an association of locomotor recovery with riluzole dose. Network meta-analysis showed that 5 mg/kg riluzole exhibited greater protection than 2.5 and 8 mg/kg riluzole. Collectively, this review suggests that riluzole has a protective effect on SCI, with good safety and a clear mechanism of action and may be suitable for future clinical trials or applications. However, animal results should be interpreted with caution given the known limitations in animal experimental design and methodological quality.}, }
@article {pmid30785719, year = {2019}, author = {Palomo, V and Tosat-Bitrian, C and Nozal, V and Nagaraj, S and Martin-Requero, A and Martinez, A}, title = {TDP-43: A Key Therapeutic Target beyond Amyotrophic Lateral Sclerosis.}, journal = {ACS chemical neuroscience}, volume = {10}, number = {3}, pages = {1183-1196}, doi = {10.1021/acschemneuro.9b00026}, pmid = {30785719}, issn = {1948-7193}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Animals ; DNA-Binding Proteins/genetics/*metabolism ; Frontotemporal Dementia/genetics/metabolism/therapy ; Humans ; Neuroprotective Agents/pharmacology ; }, abstract = {Accumulation of TDP-43 in the cytoplasm of diseased neurons is the pathological hallmark of frontotemporal dementia-TDP (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), two diseases that lack efficacious medicine to prevent or to stop disease progression. The discovery of mutations in the TARDBP gene (encoding the nuclear protein known as TDP-43) in both FTLD and ALS patients provided evidence for a link between TDP-43 alterations and neurodegeneration. Our understanding of TDP-43 function has advanced profoundly in the past several years; however, its complete role and the molecular mechanisms that lead to disease are not fully understood. Here we summarize the recent studies of this protein, its relation to neurodegenerative diseases, and the therapeutic strategies for restoring its homeostasis with small molecules. Finally, we briefly discuss the available cellular and animal models that help to shed light on TDP-43 pathology and could serve as tools for the discovery of pharmacological agents for the treatment of TDP-43-related diseases.}, }
@article {pmid30784320, year = {2019}, author = {Abraham, A and Nefussy, B and Fainmesser, Y and Ebrahimi, Y and Karni, A and Drory, VE}, title = {Early post-marketing experience with edaravone in an unselected group of patients with ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {3-4}, pages = {260-263}, doi = {10.1080/21678421.2019.1572191}, pmid = {30784320}, issn = {2167-9223}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Cohort Studies ; Disease Progression ; Edaravone/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Muscle Strength ; Neuroprotective Agents/*therapeutic use ; Product Surveillance, Postmarketing ; Respiration Disorders/etiology/physiopathology ; Respiratory Function Tests ; Retrospective Studies ; Socioeconomic Factors ; Treatment Outcome ; }, abstract = {Introduction: Treatment with edaravone has shown efficacy in a subgroup of patients with amyotrophic lateral sclerosis (ALS). However, it has been estimated that <7% of ALS patients fulfill the stringent inclusion criteria of the trial. In the current study, we aimed to explore retrospectively the efficacy of edaravone in unselected ALS patients. Methods: Demographic and clinical data were retrospectively collected for 22 patients who opted for treatment with edaravone and 71 untreated ALS patients attending the ALS clinic at Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, between May 2017 and January 2018. Clinical data were extracted for a baseline visit at treatment onset, and for pre-baseline and post-baseline visits, roughly 6 months apart from the baseline visit. Results: Baseline demographic and clinical characteristics were similar between edaravone treated and untreated patients, except for shorter disease duration in edaravone treated patients. Muscle strength, ALS Functional rating scale (ALSFRS-R), and respiratory function were similar between edaravone treated and untreated patients, including monthly rate of decline before and after baseline visit. Among treated patients, 7 had major respiratory complications occurring between 8 days to 7 months after treatment initiation, during or within hours following infusions. Discussion: Results of our study comparing edaravone treated and untreated patients in a real-life setting showed no differences in the rate of monthly decline of ALSFRS-R, in line with previous reports in ALS patients not treated with edaravone, and a previous clinical trial. Our findings might suggest that edaravone is not effective in unselected ALS patients.}, }
@article {pmid30782181, year = {2019}, author = {Lee, JD and Liu, N and Levin, SC and Ottosson, L and Andersson, U and Harris, HE and Woodruff, TM}, title = {Therapeutic blockade of HMGB1 reduces early motor deficits, but not survival in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {16}, number = {1}, pages = {45}, pmid = {30782181}, issn = {1742-2094}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/physiopathology ; Animals ; Disease Models, Animal ; HMGB1 Protein/*antagonists &amp; inhibitors ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Activity/physiology ; Muscle Strength/physiology ; Mutation ; Spinal Cord/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disease without effective treatment. The receptor for advanced glycation end products (RAGE) and the toll-like receptor (TLR) system are major components of the innate immune system, which have been implicated in ALS pathology. Extracellularly released high-mobility group box 1 (HMGB1) is a pleiotropic danger-associated molecular pattern (DAMP), and is an endogenous ligand for both RAGE and TLR4.<br><br>METHODS: The present study examined the effect of HMGB1 inhibition on disease progression in the preclinical SOD1[G93A] transgenic mouse model of ALS using a potent anti-HMGB1 antibody (2G7), which targets the extracellular DAMP form of HMGB1.<br><br>RESULTS: We found that chronic intraperitoneal dosing of the anti-HMGB1 antibody to SOD1[G93A] mice transiently improved hind-limb grip strength early in the disease, but did not extend survival. Anti-HMGB1 treatment also reduced tumour necrosis factor &#x3b1; and complement C5a receptor 1 gene expression in the spinal cord, but did not affect overall glial activation.<br><br>CONCLUSIONS: In summary, our results indicate that therapeutic targeting of an extracellular DAMP, HMGB1, improves early motor dysfunction, but overall has limited efficacy in the SOD1[G93A] mouse model of ALS.}, }
@article {pmid30772963, year = {2019}, author = {Abboud, WA and Nadel, S and Hassin-Baer, S and Arad, A and Dobriyan, A and Yahalom, R}, title = {Ultrasound-Guided Botulinum Toxin Injections into the Salivary Glands for the Treatment of Drooling.}, journal = {The Israel Medical Association journal : IMAJ}, volume = {21}, number = {2}, pages = {116-119}, pmid = {30772963}, issn = {1565-1088}, mesh = {Adult ; Aged ; Aged, 80 and over ; Botulinum Toxins, Type A/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Neurotoxins/therapeutic use ; Retrospective Studies ; Salivary Glands/*diagnostic imaging/*drug effects ; Sialorrhea/*drug therapy ; Treatment Outcome ; Ultrasonography, Interventional/*methods ; Young Adult ; }, abstract = {BACKGROUND: Drooling is the unintentional loss of saliva from the mouth, usually caused by poor coordination of the swallowing mechanism. It is commonly seen in patients with chronic neurologic disorders, such as Parkinson's disease, amyotrophic lateral sclerosis (ALS), cerebral palsy, and stroke, as well as in patients with cognitive impairment and dementia.<br><br>OBJECTIVES: To evaluate the efficacy and safety of ultrasound-guided botulinum toxin injections into the parotid and submandibular salivary glands for the treatment of drooling.<br><br>METHODS: We conducted a retrospective analysis of the medical records of 12 consecutive patients treated with botulinum toxin injections into the parotid and submandibular glands for the first time. The primary outcome variable was the subjective improvement of drooling on a 5-point scale. Secondary outcome variables were duration of the therapeutic effect, request to undergo additional treatment, and adverse events.<br><br>RESULTS: Of 12 patients, 8 (67%) reported considerable improvement after treatment, 3 reported slight improvement, and 1 reported development of dry mouth. All patients stated that they felt the effects 1 week after the injections; the mean duration of the therapeutic effect was 4.5 months (range 3-9 months). One patient suffered from local hematoma and ecchymosis that did not require medical care. Another patient complained of difficulty swallowing, which did not require medical treatment and resolved spontaneously within 1 month.<br><br>CONCLUSIONS: Ultrasound-guided botulinum toxin injections into the parotid and submandibular glands seem to be a safe and effective therapy for the treatment of drooling. Further long-term prospective studies with varying doses are warranted.}, }
@article {pmid30763568, year = {2019}, author = {Haukedal, H and Freude, K}, title = {Implications of Microglia in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Journal of molecular biology}, volume = {431}, number = {9}, pages = {1818-1829}, doi = {10.1016/j.jmb.2019.02.004}, pmid = {30763568}, issn = {1089-8638}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*immunology/pathology ; Animals ; Autophagy/genetics/*immunology ; C9orf72 Protein/genetics/immunology ; DNA-Binding Proteins/genetics/immunology ; Disease Models, Animal ; Disease Progression ; Frontotemporal Dementia/genetics/*immunology/pathology ; Gene Expression Regulation/*immunology ; Humans ; Immunity, Innate ; Membrane Glycoproteins/genetics/immunology ; Mice ; Microglia/*immunology/pathology ; RNA-Binding Protein FUS/genetics/immunology ; Receptors, Immunologic/genetics/immunology ; Superoxide Dismutase-1/genetics/immunology ; tau Proteins/genetics/immunology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with clear similarities regarding their clinical, genetic and pathological features. Both are progressive, lethal disorders, with no current curative treatment available. Several genes that correlated with ALS and FTD are implicated in the same molecular pathways. Strikingly, many of these genes are not exclusively expressed in neurons, but also in glial cells, suggesting a multicellular pathogenesis. Moreover, chronic inflammation is a common feature observed in ALS and FTD, indicating an essential role of microglia, the resident immune cells of the central nervous system, in disease development and progression. In this review, we will provide a comprehensive overview of the implications of microglia in ALS and FTD. Specifically, we will focus on the role of impaired phagocytosis and increased inflammatory responses and their impact on microglial function. Several genes associated with the disorders can directly be linked to microglial activation, phagocytosis and neuroinflammation. Other genes associated with the disorders are implicated in biological pathways involved in protein degradation and autophagy. In general such mutations have been shown to cause abnormal protein accumulation and impaired autophagy. These impairments have previously been linked to affect the innate immune system in the central nervous system through inappropriate activation of microglia and neuroinflammation, highlighted in this review. Although it has been well established that microglia play essential roles in neurodegenerative disorders, the precise underlying mechanisms remain to be elucidated.}, }
@article {pmid30753166, year = {2019}, author = {Amanzadeh, E and Esmaeili, A and Rahgozar, S and Nourbakhshnia, M}, title = {Application of quercetin in neurological disorders: from nutrition to nanomedicine.}, journal = {Reviews in the neurosciences}, volume = {30}, number = {5}, pages = {555-572}, doi = {10.1515/revneuro-2018-0080}, pmid = {30753166}, issn = {2191-0200}, mesh = {Animals ; Antioxidants/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Humans ; Nanoparticles/chemistry ; Nervous System Diseases/*drug therapy ; Neuroprotective Agents/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Quercetin/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Tissue Distribution ; }, abstract = {Quercetin is a polyphenolic flavonoid, which is frequently found in fruits and vegetables. The antioxidant potential of quercetin has been studied from subcellular compartments, that is, mitochondria to tissue levels in the brain. The neurodegeneration process initiates alongside aging of the neurons. It appears in different parts of the brain as Aβ plaques, neurofibrillary tangles, Lewy bodies, Pick bodies, and others, which leads to Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and other diseases. So far, no specific treatment has been identified for these diseases. Despite common treatments that help to prevent the development of disease, the condition of patients with progressive neurodegenerative diseases usually do not completely improve. Currently, the use of flavonoids, especially quercetin for the treatment of neurodegenerative diseases, has been expanded in animal models. It has also been used to treat animal models of neurodegenerative diseases. In addition, improvements in behavioral levels, as well as in cellular and molecular levels, decreased activity of antioxidant and apoptotic proteins, and increased levels of antiapoptotic proteins have been observed. Low bioavailability of quercetin has also led researchers to construct various quercetin-involved nanoparticles. The treatment of animal models of neurodegeneration using quercetin-involved nanoparticles has shown that improvements are observed in shorter periods and with use of lower concentrations. Indeed, intranasal administration of quercetin-involved nanoparticles, constructing superparamagnetic nanoparticles, and combinational treatment using nanoparticles such as quercetin and other drugs are suggested for future studies.}, }
@article {pmid30742586, year = {2019}, author = {Gandhi, J and Antonelli, AC and Afridi, A and Vatsia, S and Joshi, G and Romanov, V and Murray, IVJ and Khan, SA}, title = {Protein misfolding and aggregation in neurodegenerative diseases: a review of pathogeneses, novel detection strategies, and potential therapeutics.}, journal = {Reviews in the neurosciences}, volume = {30}, number = {4}, pages = {339-358}, doi = {10.1515/revneuro-2016-0035}, pmid = {30742586}, issn = {2191-0200}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/diagnosis/drug therapy/pathology ; Proteasome Endopeptidase Complex/metabolism ; *Protein Folding ; Proteolysis ; *Proteostasis Deficiencies/diagnosis/drug therapy/pathology ; Treatment Outcome ; }, abstract = {Protein folding is a complex, multisystem process characterized by heavy molecular and cellular footprints. Chaperone machinery enables proper protein folding and stable conformation. Other pathways concomitant with the protein folding process include transcription, translation, post-translational modifications, degradation through the ubiquitin-proteasome system, and autophagy. As such, the folding process can go awry in several different ways. The pathogenic basis behind most neurodegenerative diseases is that the disruption of protein homeostasis (i.e. proteostasis) at any level will eventually lead to protein misfolding. Misfolded proteins often aggregate and accumulate to trigger neurotoxicity through cellular stress pathways and consequently cause neurodegenerative diseases. The manifestation of a disease is usually dependent on the specific brain region that the neurotoxicity affects. Neurodegenerative diseases are age-associated, and their incidence is expected to rise as humans continue to live longer and pursue a greater life expectancy. We presently review the sequelae of protein misfolding and aggregation, as well as the role of these phenomena in several neurodegenerative diseases including Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, transmissible spongiform encephalopathies, and spinocerebellar ataxia. Strategies for treatment and therapy are also conferred with respect to impairing, inhibiting, or reversing protein misfolding.}, }
@article {pmid30735638, year = {2019}, author = {Gubert, F and Bonacossa-Pereira, I and Decotelli, AB and Furtado, M and Vasconcelos-Dos-Santos, A and Mendez-Otero, R and Santiago, MF}, title = {Bone-marrow mononuclear cell therapy in a mouse model of amyotrophic lateral sclerosis: Functional outcomes from different administration routes.}, journal = {Brain research}, volume = {1712}, number = {}, pages = {73-81}, doi = {10.1016/j.brainres.2019.02.003}, pmid = {30735638}, issn = {1872-6240}, mesh = {Administration, Intravenous/methods ; Amyotrophic Lateral Sclerosis/*metabolism/physiopathology ; Animals ; Bone Marrow/metabolism ; Cell- and Tissue-Based Therapy/*methods ; Disease Models, Animal ; Disease Progression ; Injections, Intramuscular/methods ; Mice ; Mice, Transgenic ; Microglia/metabolism ; Motor Neurons/drug effects/metabolism ; Neuromuscular Junction/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic degenerative disease that mainly affects motor neurons, leading to progressive paralysis and death. Recently, cell therapy has emerged as a therapeutic alternative for several neurological diseases, including ALS, and bone-marrow cells are one of the major cell sources. Considering the importance of pre-clinical trials to determine the best therapeutic protocol and the hope of translating this protocol to the clinical setting, we tested bone-marrow mononuclear cell (BMMC) therapy administered by different routes in the SOD1[G93A] model of ALS. BMMCs were isolated from non-transgenic, age matched animals and administered intravenously (IV), intramuscularly (IM), and intravenously and intramuscular concomitantly (IV + IM). BMMC therapy had no significant beneficial effects when injected IV or IM, but delayed disease progression when these two routes were used concomitantly. BMMC IV + IM treatment reduced the number of microglia cells in the spinal cord and partially protected of neuromuscular-junction innervation, but had no effect in preventing motor-neuron loss. This study showed that injection of BMMC IV + IM had better results when compared to each route in isolation, highlighting the importance of targeting multiple anatomical regions in the treatment of ALS.}, }
@article {pmid30733525, year = {2019}, author = {van de Stolpe, A and Holtzer, L and van Ooijen, H and Inda, MA and Verhaegh, W}, title = {Enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {1603}, pmid = {30733525}, issn = {2045-2322}, mesh = {Bayes Theorem ; Computational Biology/*methods ; Estrogen Receptor alpha/metabolism ; Forkhead Transcription Factors/metabolism ; Humans ; Phosphatidylinositol 3-Kinases/metabolism ; *Precision Medicine ; RNA, Messenger/genetics ; *Signal Transduction ; Wnt Signaling Pathway ; }, abstract = {Signal transduction pathways are important in physiology and pathophysiology. Targeted drugs aim at modifying pathogenic pathway activity, e.g., in cancer. Optimal treatment choice requires assays to measure pathway activity in individual patient tissue or cell samples. We developed a method enabling quantitative measurement of functional pathway activity based on Bayesian computational model inference of pathway activity from measurements of mRNA levels of target genes of the pathway-associated transcription factor. Oestrogen receptor, Wnt, and PI3K-FOXO pathway assays have been described previously. Here, we report model development for androgen receptor, Hedgehog, TGFβ, and NFκB pathway assays, biological validation on multiple cell types, and analysis of data from published clinical studies (multiple sclerosis, amyotrophic lateral sclerosis, contact dermatitis, Ewing sarcoma, lymphoma, medulloblastoma, ependymoma, skin and prostate cancer). Multiple pathway analysis of clinical prostate cancer (PCa) studies showed increased AR activity in hyperplasia and primary PCa but variable AR activity in castrate resistant (CR) PCa, loss of TGFβ activity in PCa, increased Wnt activity in TMPRSS2:ERG fusion protein-positive PCa, active PI3K pathway in advanced PCa, and active PI3K and NFκB as potential hormonal resistance pathways. Potential value for future clinical practice includes disease subtyping and prediction and targeted therapy response prediction and monitoring.}, }
@article {pmid30732430, year = {2019}, author = {Hakimi, M and Maurer, CW}, title = {Pseudobulbar Affect in Parkinsonian Disorders: A Review.}, journal = {Journal of movement disorders}, volume = {12}, number = {1}, pages = {14-21}, pmid = {30732430}, issn = {2005-940X}, abstract = {Pseudobulbar affect (PBA) is a neurological symptom of inappropriate and uncontrollable laughter or crying that occurs secondary to a variety of neurological conditions, including parkinsonian disorders. PBA is a socially and emotionally debilitating symptom that has been estimated to affect 3.6% to 42.5% of the population with Parkinson's disease. While indexing measures and treatment options for PBA have been extensively studied in neurological conditions such as amyotrophic lateral sclerosis and multiple sclerosis, there has been considerably less attention given in the literature to PBA in parkinsonian disorders. The purpose of this review is to discuss the pathophysiology of PBA, its prevalence and impact on quality of life in parkinsonian disorders, and the treatment options currently available. Areas requiring further study, including the development of standardized, cross-culturally validated methods of symptom assessment, and evidence-based studies exploring the efficacy of current treatment options in parkinsonian disorders, are also highlighted.}, }
@article {pmid30729795, year = {2020}, author = {Craenen, K and Verslegers, M and Baatout, S and Abderrafi Benotmane, M}, title = {An appraisal of folates as key factors in cognition and ageing-related diseases.}, journal = {Critical reviews in food science and nutrition}, volume = {60}, number = {5}, pages = {722-739}, doi = {10.1080/10408398.2018.1549017}, pmid = {30729795}, issn = {1549-7852}, mesh = {Aging/drug effects/*metabolism ; *Cognition/drug effects ; Dietary Supplements ; Folic Acid/*metabolism/therapeutic use ; Folic Acid Deficiency/complications/diet therapy/drug therapy/metabolism ; Humans ; Neurodegenerative Diseases/complications/drug therapy/*metabolism ; }, abstract = {Folic acid (FA) is often consumed as a food supplement and can be found in fortified staple foods in various western countries. Even though FA supplementation during pregnancy is known to prevent severe congenital anomalies in the developing child (e.g., neural tube defects), much less is known about its influence on cognition and neurological functioning. In this review, we address the advances in this field and situate how folate intake during pregnancy, postnatal life, adulthood and in the elderly affects cognition. In addition, an association between folate status and ageing, dementia and other neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis is discussed. While its role in the incidence and severity of these diseases is becoming apparent, the underlying action of folates and related metabolites remains elusive. Finally, the potential of FA as a nutraceutical has been proposed, although the efficacy will highly depend on the interplay with other micronutrients, the disease stage and the duration of supplementation. Hence, the lack of consistent data urges for more animal studies and (pre)clinical trials in humans to ascertain a potential beneficial role for folates in the treatment or amelioration of cognitive decline and ageing-related disorders.}, }
@article {pmid30713520, year = {2018}, author = {Poesen, K and Van Damme, P}, title = {Diagnostic and Prognostic Performance of Neurofilaments in ALS.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {1167}, pmid = {30713520}, issn = {1664-2295}, abstract = {There is a need for biomarkers for amyotrophic lateral sclerosis (ALS), to support the diagnosis of the disease, to predict disease progression and to track disease activity and treatment responses. Over the last decade multiple studies have investigated the potential of neurofilament levels, both in cerebrospinal fluid and blood, as biomarker for ALS. The most widely studied neurofilament subunits are neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH). Neurofilament levels are reflecting neuronal injury and therefore potentially of value in ALS and other neurological disorders. In this mini-review, we summarize and discuss the available evidence about neurofilaments as diagnostic and prognostic biomarker for human ALS.}, }
@article {pmid30713114, year = {2019}, author = {Pigna, E and Simonazzi, E and Sanna, K and Bernadzki, KM and Proszynski, T and Heil, C and Palacios, D and Adamo, S and Moresi, V}, title = {Histone deacetylase 4 protects from denervation and skeletal muscle atrophy in a murine model of amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {40}, number = {}, pages = {717-732}, pmid = {30713114}, issn = {2352-3964}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*etiology/metabolism/mortality ; Animals ; Cell Survival ; Disease Models, Animal ; Disease Progression ; Gene Deletion ; Gene Expression Regulation ; Histone Deacetylases/*genetics/metabolism ; Metabolic Networks and Pathways ; Mice ; Mice, Knockout ; Motor Neurons/metabolism ; Muscle Denervation ; Muscle, Skeletal/innervation/*metabolism/pathology ; Muscular Atrophy/*genetics/metabolism/pathology ; Neuromuscular Junction/genetics/metabolism ; Phenotype ; Weight Loss ; }, abstract = {BACKGROUND: Histone deacetylase 4 (HDAC4) has been proposed as a target for Amyotrophic Lateral Sclerosis (ALS) because it mediates nerve-skeletal muscle interaction and since its expression in skeletal muscle correlates with the severity of the disease. However, our recent studies on the skeletal muscle response upon long-term denervation highlighted the importance of HDAC4 in maintaining muscle integrity.<br><br>METHODS: To fully identify the yet uncharacterized HDAC4 functions in ALS, we genetically deleted HDAC4 in skeletal muscles of a mouse model of ALS. Body weight, skeletal muscle, innervation and spinal cord were analyzed over time by morphological and molecular analyses. Transcriptome analysis was also performed to delineate the signaling modulated by HDAC4 in skeletal muscle of a mouse model of ALS.<br><br>FINDINGS: HDAC4 deletion in skeletal muscle caused earlier ALS onset, characterized by body weight loss, muscle denervation and atrophy, and compromised muscle performance, although the main catabolic pathways were not activated. Transcriptome analysis identified the gene networks modulated by HDAC4 in ALS, revealing UCP1 as a top regulator that may be implicated in worsening ALS features.<br><br>INTERPRETATION: HDAC4 plays an important role in preserving innervations and skeletal muscle in ALS, likely by modulating the UCP1 gene network. Our study highlights a possible risk in considering HDAC inhibitors for the treatment of ALS. FUND: This work was supported by FIRB grant (RBFR12BUMH) from Ministry of Education, Universities and Research, by Fondazione Veronesi, by Sapienza research project 2017 (RM11715C78539BD8) and Polish National Science Center grant (UMO-2016/21/B/NZ3/03638).}, }
@article {pmid30710110, year = {2019}, author = {Ferguson, R and Holloway, DE and Chandrasekhar, A and Acharya, KR and Subramanian, V}, title = {The catalytic activity and secretion of zebrafish RNases are essential for their in vivo function in motor neurons and vasculature.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {1107}, pmid = {30710110}, issn = {2045-2322}, support = {/WT_/Wellcome Trust/United Kingdom ; 083191/WT_/Wellcome Trust/United Kingdom ; 085969/WT_/Wellcome Trust/United Kingdom ; 083191/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Blood Vessels/*metabolism/physiology ; Catalysis ; Cell Movement ; Humans ; Motor Neurons/*metabolism/physiology ; Mutation/genetics ; Neurogenesis ; Neurons, Efferent/*physiology ; Ribonuclease, Pancreatic/genetics/*metabolism ; Ribonucleases/genetics/*metabolism ; Zebrafish ; Zebrafish Proteins/genetics/*metabolism ; }, abstract = {Angiogenin (hANG), a member of the Ribonuclease A superfamily has angiogenic, neurotrophic and neuroprotective activities. Mutations in hANG have been found in patients with Amyotrophic lateral sclerosis (ALS). The zebrafish (Danio rerio) rnasel-1, 2 and 3 are orthologues of hANG and of these only Rnasel-1 and Rnasel-2 have been shown to be angiogenic. Herein we show that NCI-65828, a potent and specific small molecule inhibitor of hANG inhibits Rnasel-1 to a similar extent. Treatment of early zebrafish embryos with NCI-65828, or with terrein, a fungal metabolite which prevents the secretion of hANG, resulted in spinal neuron aberrations as well defects in trunk vasculature. Our detailed expression analysis and inhibitor studies suggest that Rnasel-1 plays important roles in neuronal migration and pathfinding as well as in angiogenesis in zebrafish. Our studies suggest the usefulness of the zebrafish as a model to dissect the molecular consequences of the ANG ALS variants.}, }
@article {pmid30705990, year = {2019}, author = {Korhonen, P and Pollari, E and Kanninen, KM and Savchenko, E and Lehtonen, &#x160; and Wojciechowski, S and Pomeshchik, Y and Van Den Bosch, L and Goldsteins, G and Koistinaho, J and Malm, T}, title = {Long-term interleukin-33 treatment delays disease onset and alleviates astrocytic activation in a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {IBRO reports}, volume = {6}, number = {}, pages = {74-86}, pmid = {30705990}, issn = {2451-8301}, abstract = {Inflammation is a prominent feature of the neuropathology of amyotrophic lateral sclerosis (ALS). Emerging evidence suggests that inflammatory cascades contributing to the disease progression are not restricted to the central nervous system (CNS) but also occur peripherally. Indeed, alterations in T cell responses and their secreted cytokines have been detected in ALS patients and in animal models of ALS. One key cytokine responsible for the shift in T cell responses is interleukin-33 (IL-33), which stimulates innate type 2 immune cells to produce a large amount of Th2 cytokines that are possibly beneficial in the recovery processes of CNS injuries. Since the levels of IL-33 have been shown to be decreased in patients affected with ALS, we sought to determine whether a long-term recombinant IL-33 treatment of a transgenic mouse model of ALS expressing G93A-superoxide dismutase 1 (SOD1-G93A) alters the disease progression and ameliorates the ALS-like disease pathology. SOD1-G93A mice were treated with intraperitoneal injections of IL-33 and effects on disease onset and inflammatory status were determined. Spinal cord (SC) neurons, astrocytes and T-cells were exposed to IL-33 to evaluate the cell specific responses to IL-33. Treatment of SOD1-G93A mice with IL-33 delayed the disease onset in female mice, decreased the proportion of CD4+ and CD8 + T cell populations in the spleen and lymph nodes, and alleviated astrocytic activation in the ventral horn of the lumbar SC. Male SOD1-G93A mice were unresponsive to the treatment. In vitro studies showed that IL-33 is most likely not acting directly on neurons and astrocytes, but rather conveying its effects through peripheral T-cells. Our results suggest that strategies directed to the peripheral immune system may have therapeutic potential in ALS. The effect of gender dimorphisms to the treatment efficacy needs to be taken into consideration when designing new therapeutic strategies for CNS diseases.}, }
@article {pmid30692571, year = {2019}, author = {Majchrzak, M and Drela, K and Andrzejewska, A and Rogujski, P and Figurska, S and Fiedorowicz, M and Walczak, P and Janowski, M and Lukomska, B and Stanaszek, L}, title = {SOD1/Rag2 Mice with Low Copy Number of SOD1 Gene as a New Long-Living Immunodeficient Model of ALS.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {799}, pmid = {30692571}, issn = {2045-2322}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/genetics/immunology/physiopathology ; Animals ; *DNA Copy Number Variations ; DNA-Binding Proteins/*genetics/metabolism ; Disease Models, Animal ; Disease Progression ; Female ; Gene Knockout Techniques ; Humans ; Immunocompromised Host ; Male ; Mice ; Mice, Transgenic ; Protein Folding ; Severity of Illness Index ; Spinal Cord/diagnostic imaging/metabolism ; Superoxide Dismutase-1/chemistry/*genetics/metabolism ; Trigeminal Motor Nucleus/diagnostic imaging/metabolism ; }, abstract = {The most recent research concerning amyotrophic lateral sclerosis (ALS) emphasizes the role of glia in disease development. Thus, one can suspect that the effective therapeutic strategy in treatment of ALS would be replacement of defective glia. One of the basic problems with human glial progenitors (hGRPs) replacement strategies is the time needed for the cells to become fully functional in vivo. The lifespan of most popular high copy number SOD1 mutant mice might be too short to acknowledge benefits of transplanted cells. We focused on developing immunodeficient rag2[-]/[-] model of ALS with lower number of transgene copies and longer lifespan. The obtained hSOD1/rag2 double mutant mice have been characterized. QPCR analysis revealed that copy number of hSOD1 transgene varied in our colony (4-8 copies). The difference in transgene copy number may be translated to significant impact on the lifespan. The death of long- and short-living hSOD1/rag2 mice is preceded by muscular weakness as early as one month before death. Importantly, based on magnetic resonance imaging we identified that mutant mice demonstrated abnormalities within the medullar motor nuclei. To conclude, we developed long-living double mutant hSOD1/rag2 mice, which could be a promising model for testing therapeutic utility of human stem cells.}, }
@article {pmid30690059, year = {2019}, author = {Zhang, C and Yang, Y and Liang, W and Wang, T and Wang, S and Wang, X and Wang, Y and Jiang, H and Feng, H}, title = {Neuroprotection by urate on the mutant hSOD1-related cellular and Drosophila models of amyotrophic lateral sclerosis: Implication for GSH synthesis via activating Akt/GSK3β/Nrf2/GCLC pathways.}, journal = {Brain research bulletin}, volume = {146}, number = {}, pages = {287-301}, doi = {10.1016/j.brainresbull.2019.01.019}, pmid = {30690059}, issn = {1873-2747}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Antioxidants/pharmacology ; Cell Line, Tumor ; Disease Models, Animal ; Drosophila Proteins/metabolism ; Drosophila melanogaster/metabolism ; Glutamate-Cysteine Ligase/metabolism ; Glutathione/genetics/*metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Male ; Mice ; Motor Neurons/metabolism ; NF-E2-Related Factor 2/metabolism ; Neurodegenerative Diseases/metabolism ; Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Uric Acid/metabolism/*pharmacology ; }, abstract = {Oxidative stress has been considered as a principal mechanism of motor neuron death in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease which could be caused by dominant mutations in an antioxidant enzyme superoxide dismutase-1 (SOD1). The aim of the present study was to investigate the potential neuroprotective effects and mechanisms of urate, an important endogenous antioxidant and a biomarker of favorable ALS progression rates, in the mutant human SOD1-related cellular and Drosophila models of ALS. Our results showed that urate treatment provided neuroprotective effects as confirmed by enhanced survival, attenuated motor impairments, reduced oxidative damage and increased antioxidant defense in hSOD1-G85R-expressing Drosophila models of ALS. In vitro studies, we demonstrated that urate protected motor neurons (NSC-34 cells) against hSOD1-G93A-induced cell damage and apoptosis by decreasing reactive oxygen specials (ROS) production and oxidative damage. Moreover, urate markedly increased the expression and activation of nuclear factor erythroid 2-related factor 2 (Nrf2), stimulated Nrf2-targeted antioxidant gene glutathione cysteine ligase catalytic subunit (GCLC) expression and glutathione (GSH) synthesis by upregulating Akt/GSK3β pathway. Furthermore, the inhibition of Akt pathway with LY294002 abolished urate-mediated elevation of GSH synthesis and neuroprotective effects both in vivo and in vitro. Overall, these results suggested that, in addition to its direct scavenging of ROS, urate markedly enhanced GSH expression by activating Akt/GSK3β/Nrf2/GCLC pathway, and thus offering neuroprotective effects on motor neurons against oxidative stress.}, }
@article {pmid30689195, year = {2019}, author = {Gonzalez, D and Brandan, E}, title = {CTGF/CCN2 from Skeletal Muscle to Nervous System: Impact on Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {56}, number = {8}, pages = {5911-5916}, pmid = {30689195}, issn = {1559-1182}, support = {AFB170005//Basal CARE UC CHILE/ ; 1150106//FONDECYT/ ; 1//Beca de Doctorado/ ; }, mesh = {Animals ; Connective Tissue Growth Factor/*metabolism ; Humans ; Models, Biological ; Muscle, Skeletal/*metabolism ; Nervous System/*metabolism ; Neurodegenerative Diseases/*metabolism ; }, abstract = {Connective tissue growth factor (CTGF/CCN2) is a matricellular protein that belongs to the CCN family of proteins. Since its discovery, it has been linked to cellular processes such as cell proliferation, differentiation, adhesion, migration, and synthesis of extracellular matrix (ECM) components, among others. The pro-fibrotic role of CTGF/CCN2 has been well-studied in several pathologies characterized by the development of fibrosis. Reduction of CTGF/CCN2 levels in mdx mice, a murine model for Duchenne muscular dystrophy (DMD), decreases fibrosis and improves skeletal muscle phenotype and function. Recently, it has been shown that skeletal muscle of symptomatic hSOD1[G93A] mice, a model for Amyotrophic lateral sclerosis (ALS), shows up-regulation of CTGF/CCN2 accompanied by excessive deposition ECM molecules. Elevated levels of CTGF/CCN2 in spinal cord from ALS patients have been previously reported. However, there is no evidence regarding the role of CTGF/CCN2 in neurodegenerative diseases such as ALS, in which alterations in skeletal muscle seem to be the consequence of early pathological denervation. In this regard, the emerging evidence shows that CTGF/CCN2 also exerts non-fibrotic roles in the central nervous system (CNS), specifically impairing oligodendrocyte maturation and regeneration, and inhibiting axon myelination. Despite these striking observations, there is no evidence showing the role of CTGF/CCN2 in peripheral nerves. Therefore, even though more studies are needed to elucidate its precise role, CTGF/CCN2 is starting to emerge as a novel therapeutic target for the treatment of neurodegenerative diseases where demyelination and axonal degeneration occurs.}, }
@article {pmid30677752, year = {2019}, author = {Crimi, C and Pierucci, P and Carlucci, A and Cortegiani, A and Gregoretti, C}, title = {Long-Term Ventilation in Neuromuscular Patients: Review of Concerns, Beliefs, and Ethical Dilemmas.}, journal = {Respiration; international review of thoracic diseases}, volume = {97}, number = {3}, pages = {185-196}, doi = {10.1159/000495941}, pmid = {30677752}, issn = {1423-0356}, mesh = {Follow-Up Studies ; Humans ; Neuromuscular Diseases/*therapy ; *Quality of Life ; Respiration, Artificial/*ethics ; Respiratory Insufficiency/etiology/therapy ; Respiratory Therapy/*ethics/methods ; Time Factors ; }, abstract = {BACKGROUND: Noninvasive mechanical ventilation (NIV) is an effective treatment in patients with neuromuscular diseases (NMD) to improve symptoms, quality of life, and survival.<br><br>SUMMARY: NIV should be used early in the course of respiratory muscle involvement in NMD patients and its requirements may increase over time. Therefore, training on technical equipment at home and advice on problem solving are warranted. Remote monitoring of ventilator parameters using built-in ventilator software is recommended. Telemedicine may be helpful in reducing hospital admissions. Anticipatory planning and palliative care should be carried out to lessen the burden of care, to maintain or withdraw from NIV, and to guarantee the most respectful management in the last days of NMD patients' life. Key Message: Long-term NIV is effective but challenging in NMD patients. Efforts should be made by health care providers in arranging a planned transition to home and end-of-life discussions for ventilator-assisted individuals and their families.}, }
@article {pmid30668199, year = {2019}, author = {de la Rubia, JE and Drehmer, E and Platero, JL and Benlloch, M and Caplliure-Llopis, J and Villaron-Casales, C and de Bernardo, N and AlarcÓn, J and Fuente, C and Carrera, S and Sancho, D and GarcÍa-Pardo, P and Pascual, R and JuÁrez, M and Cuerda-Ballester, M and Forner, A and Sancho-Castillo, S and Barrios, C and Obrador, E and Marchio, P and Salvador, R and Holmes, HE and Dellinger, RW and Guarente, L and Estrela, JM}, title = {Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {1-2}, pages = {115-122}, doi = {10.1080/21678421.2018.1536152}, pmid = {30668199}, issn = {2167-9223}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Disease Progression ; Double-Blind Method ; Drug Combinations ; Electromyography ; Female ; Humans ; Male ; Middle Aged ; Muscle Strength ; Niacinamide/*analogs &amp; derivatives/therapeutic use ; Pilot Projects ; Ribonucleosides/*therapeutic use ; Stilbenes/*therapeutic use ; Treatment Outcome ; Vital Capacity ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by progressive loss of spinal and cortical motor neurons, leading to muscular atrophy, respiratory failure, and ultimately death. There is no known cure, and the clinical benefit of the two drugs approved to treat ALS remains unclear. Novel disease-modifying therapeutics that are able to modulate the disease course are desperately needed. Our objective was to evaluate the efficacy and tolerability of Elysium Health's candidate drug EH301 in people with ALS (PALS).<br><br>METHODS: This was a single-center, prospective, double-blind, randomized, placebo-controlled pilot study. Thirty-two PALS were recruited thanks to the collaboration of the Spanish Foundation for ALS Research (FUNDELA). Study participants were randomized to receive either EH301 or placebo and underwent evaluation for 4 months. Differences between EH301 and placebo-treated participants were evaluated based on standard clinical endpoints, including the revised ALS functional rating scale (ALSFRS-R), forced vital capacity (FVC), and the Medical Research Council (MRC) grading scale.<br><br>RESULTS: Compared to placebo, participants treated with EH301 demonstrated significant improvements in the ALSFRS-R score, pulmonary function, muscular strength, and in skeletal muscle/fat weight ratio. EH301 was shown to significantly slow the progression of ALS relative to placebo, and even showed improvements in several key outcome measures compared with baseline.<br><br>CONCLUSIONS: This study provides evidence in support of the disease-modifying effects of EH301 for the treatment of ALS.}, }
@article {pmid30667370, year = {2019}, author = {Pozzi, S and Thammisetty, SS and Codron, P and Rahimian, R and Plourde, KV and Soucy, G and Bareil, C and Phaneuf, D and Kriz, J and Gravel, C and Julien, JP}, title = {Virus-mediated delivery of antibody targeting TAR DNA-binding protein-43 mitigates associated neuropathology.}, journal = {The Journal of clinical investigation}, volume = {129}, number = {4}, pages = {1581-1595}, pmid = {30667370}, issn = {1558-8238}, support = {//CIHR/Canada ; }, mesh = {Amino Acid Motifs ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/*therapy ; Animals ; Cell Line ; *DNA-Binding Proteins/antagonists &amp; inhibitors/genetics/metabolism ; *Dependovirus ; Disease Models, Animal ; Frontotemporal Dementia/genetics/metabolism/pathology/*therapy ; Mice ; Mice, Transgenic ; Mutation ; *Single-Chain Antibodies/biosynthesis/genetics ; *Transduction, Genetic ; }, abstract = {The cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of degenerating neurons in amyotrophic lateral sclerosis (ALS) and subsets of frontotemporal dementia (FTD). In order to reduce TDP-43 pathology, we generated single-chain (scFv) antibodies against the RNA recognition motif 1 (RRM1) of TDP-43, which is involved in abnormal protein self-aggregation and interaction with p65 NF-κB. Virus-mediated delivery into the nervous system of a scFv antibody, named VH7Vk9, reduced microgliosis in a mouse model of acute neuroinflammation and mitigated cognitive impairment, motor defects, TDP-43 proteinopathy, and neuroinflammation in transgenic mice expressing ALS-linked TDP-43 mutations. These results suggest that antibodies targeting the RRM1 domain of TDP-43 might provide new therapeutic avenues for the treatment of ALS and FTD.}, }
@article {pmid30663902, year = {2019}, author = {Bedlack, RS and Wicks, P and Vaughan, T and Opie, A and Blum, R and Dios, A and Sadri-Vakili, G}, title = {Lunasin does not slow ALS progression: results of an open-label, single-center, hybrid-virtual 12-month trial.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {3-4}, pages = {285-293}, doi = {10.1080/21678421.2018.1556698}, pmid = {30663902}, issn = {2167-9223}, mesh = {Acetylation ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials as Topic ; Computer Simulation ; Disease Progression ; Female ; Histone Deacetylase Inhibitors/*therapeutic use ; Histones/metabolism ; Humans ; Male ; Middle Aged ; Negative Results ; Research Design ; Self Report ; Soybean Proteins/*therapeutic use ; Treatment Failure ; }, abstract = {Objective: Lunasin, a soy peptide that reportedly alters histone acetylation in vitro, was associated with a single ALS reversal in the media. Following an ALSUntangled report, we sought to determine whether Lunasin altered histone acetylation and improved progression in people with ALS, and whether patient-centric trial design features might improve enrollment and retention. Methods: This single-center, year-long trial (NCT02709330) featured broad inclusion criteria, historical controls, primarily virtual data collection, and real-time results. Participants measured their own ALSFRS-R score, weight and perceived efficacy, and recorded these monthly on PatientsLikeMe. Blood tests at screening and month 1 assessed alterations in histone H3 and H4 acetylation. The protocol was published online, empowering patients outside the study to self-experiment. Results: Fifty participants enrolled in 5.5 months. Although this population had more advanced disease compared to other trials, retention and adherence were very high. There was no significant effect of Lunasin treatment on histone acetylation or disease progression. A cohort following our protocol outside the trial reported similar side effects and perceived effectiveness; however, their compliance with data entry was markedly lower. Conclusions: While Lunasin's lack of efficacy is disappointing, our novel trial design had the highest ALS trial enrollment rate ever recorded, with excellent retention and adherence. Low data density from patients who are self-experimenting outside a formal protocol casts doubt on the possibility of gathering useful information from unsupervised expanded access programs or "right to try" initiatives.}, }
@article {pmid30662429, year = {2018}, author = {Huynh, W and Dharmadasa, T and Vucic, S and Kiernan, MC}, title = {Functional Biomarkers for Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {1141}, pmid = {30662429}, issn = {1664-2295}, abstract = {The clinical diagnosis of amyotrophic lateral sclerosis (ALS) relies on determination of progressive dysfunction of both cortical as well as spinal and bulbar motor neurons. However, the variable mix of upper and lower motor neuron signs result in the clinical heterogeneity of patients with ALS, resulting frequently in delay of diagnosis as well as difficulty in monitoring disease progression and treatment outcomes particularly in a clinical trial setting. As such, the present review provides an overview of recently developed novel non-invasive electrophysiological techniques that may serve as biomarkers to assess UMN and LMN dysfunction in ALS patients.}, }
@article {pmid30657305, year = {2019}, author = {Ma, S and Attarwala, IY and Xie, XQ}, title = {SQSTM1/p62: A Potential Target for Neurodegenerative Disease.}, journal = {ACS chemical neuroscience}, volume = {10}, number = {5}, pages = {2094-2114}, pmid = {30657305}, issn = {1948-7193}, support = {P30 DA035778/DA/NIDA NIH HHS/United States ; R56 AG074951/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Autophagy/*physiology ; Brain/*metabolism/pathology ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Sequestosome-1 Protein/*metabolism ; Signal Transduction/physiology ; }, abstract = {Neurodegenerative diseases, characterized by a progressive loss of brain function, affect the lives of millions of individuals worldwide. The complexity of the brain poses a challenge for scientists trying to map the biochemical and physiological pathways to identify areas of pathological errors. Brain samples of patients with neurodegenerative diseases have been shown to contain large amounts of misfolded and abnormally aggregated proteins, resulting in dysfunction in certain brain centers. Removal of these abnormal molecules is essential in maintaining protein homeostasis and overall neuronal health. Macroautophagy is a major route by which cells achieve this. Administration of certain autophagy-enhancing compounds has been shown to provide therapeutic effects for individuals with neurodegenerative conditions. SQSTM1/p62 is a scaffold protein closely involved in the macroautophagy process. p62 functions to anchor the ubiquitinated proteins to the autophagosome membrane, promoting degradation of unwanted molecules. Modulators targeting p62 to induce autophagy and promote its protective pathways for aggregate protein clearance have high potential in the treatment of these conditions. Additionally, causal relationships have been found between errors in regulation of SQSTM1/p62 and the development of a variety of neurodegenerative disorders, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. Furthermore, SQSTM1/p62 also serves as a signaling hub for multiple pathways associated with neurodegeneration, providing a potential therapeutic target in the treatment of neurodegenerative diseases. However, rational design of a p62-oriented autophagy modulator that can balance the negative and positive functions of multiple domains in p62 requires further efforts in the exploration of the protein structure and pathological basis.}, }
@article {pmid30656911, year = {2018}, author = {Węgrzyn, G and Pierzynowska, K and Podlacha, M and Brokowska, J and Gaffke, L and Mantej, J and Cyske, Z and Rintz, E and Osiadły, M and Bartkowski, M and Puchalski, M and Grabski, M and Pierzynowski, M and Pankanin, D and Piotrowska, E and Tukaj, S}, title = {[Molecular mechanisms of genistein action in the light of therapies for genetic and immunological diseases].}, journal = {Postepy biochemii}, volume = {64}, number = {4}, pages = {262-276}, doi = {10.18388/pb.2018_140}, pmid = {30656911}, issn = {0032-5422}, mesh = {Alzheimer Disease/drug therapy/genetics ; Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Genistein/*pharmacology/*therapeutic use ; Humans ; Huntington Disease/drug therapy/genetics ; Immune System Diseases/*drug therapy ; Mucopolysaccharidosis III/drug therapy ; Parkinson Disease/drug therapy/genetics ; }, abstract = {Genetic and immunological diseases, despite many attempts to develop effective treatments, still remain a great challenge for medicine. Current therapies of these diseases consist of pharmacological alleviation of symptoms, rehabilitation and psychological help which, although very important, are not sufficient. Therefore, searching for new therapeutics which could remove the major causes of these diseases is of particular importance for the society. Natural compounds reveal many biological activities which makes them candidates for drugs in such diseases. One of them is genistein, a compound from the group of flavonoids. As it affects multiple processes, genistein has become in the center of interest of many scientists working on diseases of various etiology, course and inheritance. It was used in experimental therapies of some genetic diseases (Huntington's disease, amyotrophic lateral sclerosis Parkinson disease, cystic fibrosis), as well as autoimmunological diseases and allergies. Clinical trials with the use of genistein in treatment of patients suffering from Alzheimer's diseases and mucopolysaccharidosis type III are ongoing. The employment of differential properties of genistein in attempts to treat each of these diseases is of special interest. In this review, detailed molecular mechanisms of genistein action are summarized in the light of therapies of the above mentioned genetic and immunological diseases, including description of therapeutic potentials of each activity of this isoflavone, efficiency of its action, and its potential use as a drug in the future.}, }
@article {pmid30640943, year = {2019}, author = {Rando, A and de la Torre, M and Martinez-Muriana, A and Zaragoza, P and Musaro, A and Hernández, S and Navarro, X and Toivonen, JM and Osta, R}, title = {Chemotherapeutic agent 5-fluorouracil increases survival of SOD1 mouse model of ALS.}, journal = {PloS one}, volume = {14}, number = {1}, pages = {e0210752}, pmid = {30640943}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/physiopathology ; Animals ; Antimetabolites, Antineoplastic/*therapeutic use ; Bone Marrow Cells/drug effects ; Disease Models, Animal ; Drug Repositioning ; Female ; Fluorouracil/*therapeutic use ; Humans ; Leukocyte Count ; Male ; Mice ; Mice, Transgenic ; Motor Activity/drug effects ; Motor Neurons/drug effects/pathology/physiology ; Muscles/drug effects/physiopathology ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal motor neuron disease with no cure. Currently there are only two ALS drugs approved by the FDA, both with a limited therapeutic effect. In the search for drug candidates for ALS, we studied the effect of known stem cell mobilizing agents (treatment) and antimetabolite 5-fluorouracil (5-FU) (anti-treatment) in SOD1G93A model of ALS. Surprisingly, we found that anti-cancer drug 5-FU increases lifespan, delays the disease onset and improves motor performance in ALS mice. Although we were not able to demonstrate the mechanistic basis of the beneficial 5-FU action in ALS mice, our findings suggest that 5-FU or similar drugs are possible drug candidates for the treatment of motor neuron diseases through drug repurposing.}, }
@article {pmid30637316, year = {2017}, author = {Lavado, A and Guo, X and Smith, AS and Akanda, N and Martin, C and Cai, Y and Elbrecht, D and Tran, M and Bryant, JP and Colon, A and Long, CJ and Lambert, S and Morgan, D and Hickman, JJ}, title = {Evaluation of Holistic Treatment for ALS Reveals Possible Mechanism and Therapeutic Potential.}, journal = {International journal of pharmacy and pharmaceutical research}, volume = {11}, number = {1}, pages = {348-374}, pmid = {30637316}, issn = {2349-7203}, support = {R01 NS050452/NS/NINDS NIH HHS/United States ; }, abstract = {There has been a tremendous amount of research into the causes of Amyotrophic Lateral Sclerosis (ALS), but yet very few treatment options beyond amelioration of symptoms. A holistic approach has shown anecdotal evidence of slowing disease progression and this treatment, known as the Deanna protocol (DP), postulates that ALS is a metabolic disease caused by glutamate that induces toxicity. In this study, glutamate exposure to human motoneurons was investigated and found not to significantly affect cell viability or electrophysiological properties. However, varicosities were observed in axons suggestive of transport impairment that was dose dependent for glutamate exposure. Surprisingly, a subset of the components of the DP eliminated these varicosities. To verify this finding a human SOD1 patient-derived iPSC line was examined and significant numbers of varicosities were present without glutamate treatment, compared to the iPSC control, indicating the possibility of a common mechanism despite different origins for the varicosities. Importantly, the DP ameliorated these varicosities by over 70% in the patient derived cells as well. These results are consistent with much of the literature on ALS and give hope for treatment not only for arresting disease progression using compounds considered safe but also the potential for restoration of function.}, }
@article {pmid30636888, year = {2019}, author = {Sariko, M and Maro, A and Gratz, J and Houpt, E and Kisonga, R and Mpagama, S and Heysell, S and Mmbaga, BT and Thomas, TA}, title = {Evaluation of cytokines in peripheral blood mononuclear cell supernatants for the diagnosis of tuberculosis.}, journal = {Journal of inflammation research}, volume = {12}, number = {}, pages = {15-22}, pmid = {30636888}, issn = {1178-7031}, support = {D43 TW006578/TW/FIC NIH HHS/United States ; D43 TW008270/TW/FIC NIH HHS/United States ; K23 AI097197/AI/NIAID NIH HHS/United States ; U01 AI115594/AI/NIAID NIH HHS/United States ; }, abstract = {INTRODUCTION: There is active interest in leveraging host immune responses as biomarkers of tuberculosis (TB) disease activity. We had previously evaluated an immunodiagnostic test called the antibody in lymphocyte supernatant (ALS) assay. Here, we aimed to evaluate a panel of inflammatory mediators and associate the responses with the ALS results to identify a biosignature to distinguish TB cases from controls.<br><br>METHODOLOGY: In this case-control study, adults with TB were compared to controls who were hospitalized for non-infectious conditions. Blood was collected at baseline and after 4 weeks of TB treatment (from TB cases only). Peripheral blood mononuclear cells were isolated and cultured without antigenic stimulation for 72 hours. Inflammatory mediators were measured using the Multiplex cytokine kit and compared between TB cases and controls; among TB cases, responses were compared over time. ALS and inflammatory mediator results were evaluated using generalized discriminant analysis to identify the optimal biosignature to predict TB.<br><br>RESULTS: When comparing inflammatory mediators between groups, IL-1ra, IL-1&#x3b2;, and granulocyte macrophage-colony stimulating factor (GM-CSF) were lower in TB cases (P<0.002). Fibroblast growth factor-basic significantly increased from baseline to week-4 (P=0.002). Generalized discriminant analysis yielded a model with IL-2, tumor necrosis factor-alpha, vascular endothelial growth factor, and ALS, providing a sensitivity of 82.2% and specificity of 76.2%.<br><br>CONCLUSION: Our results suggest that IL-1ra, IL-1&#x3b2;, and GM-CSF might be used as diagnostic biomarkers to distinguish between TB cases and non-TB cases. We could not identify a group of mediators that outperformed the diagnostic accuracy of the ALS alone.}, }
@article {pmid30636701, year = {2019}, author = {Kaji, R and Imai, T and Iwasaki, Y and Okamoto, K and Nakagawa, M and Ohashi, Y and Takase, T and Hanada, T and Shimizu, H and Tashiro, K and Kuzuhara, S}, title = {Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {90}, number = {4}, pages = {451-457}, pmid = {30636701}, issn = {1468-330X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Double-Blind Method ; Female ; Humans ; Injections, Intramuscular ; Male ; Middle Aged ; Respiration, Artificial ; Survival Rate ; Vitamin B 12/administration &amp; dosage/*analogs &amp; derivatives/therapeutic use ; }, abstract = {OBJECTIVE: To evaluate the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: 373 patients with ALS (El Escorial definite or probable; laboratory-supported probable; duration &#x2264;36 months) were randomly assigned to placebo, 25 mg or 50 mg of methylcobalamin groups. The primary endpoints were the time interval to primary events (death or full ventilation support) and changes in the Revised ALS Functional Rating Scale (ALSFRS-R) score from baseline to week 182. Efficacy was also evaluated using post-hoc analyses in patients diagnosed early (entered &#x2264;12 months after symptom onset).<br><br>RESULTS: No significant differences were detected in either primary endpoint (minimal p value=0.087). However, post-hoc analyses of methylcobalamin-treated patients diagnosed and entered early (&#x2264;12 months' duration) showed longer time intervals to the primary event (p<0.025) and less decreases in the ALSFRS-R score (p<0.025) than the placebo group. The incidence of treatment-related adverse events was similar and low in all groups.<br><br>CONCLUSION: Although ultra-high-dose methylcobalamin did not show significant efficacy in the whole cohort, this treatment may prolong survival and retard symptomatic progression without major side effects if started early.<br><br>TRIAL REGISTRATION NUMBER: NCT00444613.}, }
@article {pmid30631300, year = {2018}, author = {Pawlitzki, M and Schreiber, S and Bittner, D and Kreipe, J and Leypoldt, F and Rupprecht, K and Carare, RO and Meuth, SG and Vielhaber, S and Körtvélyessy, P}, title = {CSF Neurofilament Light Chain Levels in Primary Progressive MS: Signs of Axonal Neurodegeneration.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {1037}, pmid = {30631300}, issn = {1664-2295}, abstract = {Objectives: Elevated neurofilament light chain (NFL) levels within the cerebrospinal fluid (CSF) are a biomarker representing axonal neurodegeneration in rapid progressive neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). It is unclear to what extent the levels of NFL increase in the CSF (CSF-NFL) in a chronic neuroinflammatory process with axonal neurodegeneration, as found in primary progressive multiple sclerosis (PPMS). Methods: We used a multicenter approach to statistically compare CSF-NFL levels between PPMS patients (n = 50), ALS patients (n = 50), and healthy controls (n = 50). Clinical findings, including disease duration, expanded disability status scale (EDSS), electrophysiological recordings such as visual evoked potentials or spinal and cerebral MRI, and previously administered treatment were selected as experimental parameters retrospectively. Results: Median [range] CSF-NFL concentrations in PPMS patients were significantly higher than in the controls [1724 (799-4275) pg/ml vs. 1202 (612-2934) pg/ml, p = 0.015], and significantly lower compared to ALS patients [1724 (799-4275) pg/ml vs. 10238 (2610-35138) pg/ml, p < 0.001]. There was no correlation between CSF-NFL and disease duration (p = 0.5), EDSS (p = 0.2) or treatment (p = 0.3). Conclusion: We conclude that CSF-NFL may mirror the proposed slow axonal degeneration in PPMS, but does not reflect the disease severity.}, }
@article {pmid30622763, year = {2018}, author = {Marcu, IR and Patru, S and Bighea, AC}, title = {Diagnosis Particularities of Amyotrophic Lateral Sclerosis in an Elderly Patient.}, journal = {Current health sciences journal}, volume = {44}, number = {1}, pages = {92-96}, pmid = {30622763}, issn = {2067-0656}, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease (MND) which prognosis is poor. Early diagnosis permits to set up immediately adapted treatment. Available diagnostic criteria are based on the detection of both central and peripheral motor neuron injury in bulbar, cervical, thoracic and lumbar regions. Electrodiagnostic tests are key tools to identify peripheral motor neuron involvement. In the absence of a diagnostic biomarker of ALS, a careful clinical and neurophysiological work-up is essential to rule the differential diagnosis. The study presents the case of a 74 years-old woman who was diagnosed with ALS using clinical examination and electromyography.}, }
@article {pmid30619076, year = {2018}, author = {Lanznaster, D and de Assis, DR and Corcia, P and Pradat, PF and Blasco, H}, title = {Metabolomics Biomarkers: A Strategy Toward Therapeutics Improvement in ALS.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {1126}, pmid = {30619076}, issn = {1664-2295}, abstract = {Biomarkers research in amyotrophic lateral sclerosis (ALS) holds the promise of improving ALS diagnosis, follow-up of patients, and clinical trials outcomes. Metabolomics have a big impact on biomarkers identification. In this mini-review, we provide the main findings of metabolomics studies in ALS and discuss the most relevant therapeutics attempts that targeted some prominent alterations found in ALS, like glutamate excitotoxicity, oxidative stress, alterations in energetic metabolism, and creatinine levels. Metabolomics studies have reported putative diagnosis or prognosis biomarkers, but discrepancies among these studies did not allow validation of metabolic biomarkers for clinical use in ALS. In this context, we wonder whether metabolomics knowledge could improve ALS therapeutics. As metabolomics identify specific metabolic pathways modified by disease progression and/or treatment, we support that adjuvant or combined treatment should be used to rescue these pathways, creating a new perspective for ALS treatment. Some ongoing clinical trials are already trying to target these pathways. As clinical trials in ALS have been disappointing and considering the heterogeneity of the disease presentation, we support the application of a pharmacometabolomic approach to evaluate the individual response to drug treatments and their side effects, enabling the development of personalized treatments for ALS. We suggest that the best strategy to apply metabolomics for ALS therapeutics progress is to establish a metabolic signature for ALS patients in order to improve the knowledge of patient metabotypes, to choose the most adequate pharmacological treatment, and to follow the drug response and side effects, based on metabolomics biomarkers.}, }
@article {pmid30618638, year = {2018}, author = {Jordan, K and Murphy, J and Singh, A and Mitchell, CS}, title = {Astrocyte-Mediated Neuromodulatory Regulation in Preclinical ALS: A Metadata Analysis.}, journal = {Frontiers in cellular neuroscience}, volume = {12}, number = {}, pages = {491}, pmid = {30618638}, issn = {1662-5102}, support = {K01 NS069616/NS/NINDS NIH HHS/United States ; R03 NS098228/NS/NINDS NIH HHS/United States ; R21 NS081426/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive degradation of motoneurons in the central nervous system (CNS). Astrocytes are key regulators for inflammation and neuromodulatory signaling, both of which contribute to ALS. The study goal was to ascertain potential temporal changes in astrocyte-mediated neuromodulatory regulation with transgenic ALS model progression: glutamate, GTL-1, GluR1, GluR2, GABA, ChAT activity, VGF, TNFα, aspartate, and IGF-1. We examine neuromodulatory changes in data aggregates from 42 peer-reviewed studies derived from transgenic ALS mixed cell cultures (neurons + astrocytes). For each corresponding experimental time point, the ratio of transgenic to wild type (WT) was found for each compound. ANOVA and a student's t-test were performed to compare disease stages (early, post-onset, and end stage). Glutamate in transgenic SOD1-G93A mixed cell cultures does not change over time (p > 0.05). GLT-1 levels were found to be decreased 23% over WT but only at end-stage (p < 0.05). Glutamate receptors (GluR1, GluR2) in SOD1-G93A were not substantially different from WT, although SOD1-G93A GluR1 decreased by 21% from post-onset to end-stage (p < 0.05). ChAT activity was insignificantly decreased. VGF is decreased throughout ALS (p < 0.05). Aspartate is elevated by 25% in SOD1-G93A but only during end-stage (p < 0.05). TNFα is increased by a dramatic 362% (p < 0.05). Furthermore, principal component analysis identified TNFα as contributing to 55% of the data variance in the first component. Thus, TNFα, which modulates astrocyte regulation via multiple pathways, could be a strategic treatment target. Overall results suggest changes in neuromodulator levels are subtle in SOD1-G93A ALS mixed cell cultures. If excitotoxicity is present as is often presumed, it could be due to ALS cells being more sensitive to small changes in neuromodulation. Hence, seemingly unsubstantial or oscillatory changes in neuromodulators could wreak havoc in ALS cells, resulting in failed microenvironment homeostasis whereby both hyperexcitability and hypoexcitability can coexist. Future work is needed to examine local, spatiotemporal neuromodulatory homeostasis and assess its functional impact in ALS.}, }
@article {pmid30615021, year = {2019}, author = {Fralick, M and Sacks, CA and Kesselheim, AS}, title = {Assessment of Use of Combined Dextromethorphan and Quinidine in Patients With Dementia or Parkinson Disease After US Food and Drug Administration Approval for Pseudobulbar Affect.}, journal = {JAMA internal medicine}, volume = {179}, number = {2}, pages = {224-230}, pmid = {30615021}, issn = {2168-6114}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications ; Dementia/*drug therapy ; Dextromethorphan/*therapeutic use ; Drug Combinations ; Excitatory Amino Acid Antagonists/therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Multiple Sclerosis/complications ; Parkinson Disease/*drug therapy ; Pseudobulbar Palsy/*drug therapy/etiology ; Quinidine/*therapeutic use ; United States ; United States Food and Drug Administration ; }, abstract = {IMPORTANCE: In 2010, the US Food and Drug Administration (FDA) approved a combination of dextromethorphan hydrobromide and quinidine sulfate for the treatment of pseudobulbar affect after studies in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). This medication, however, may be commonly prescribed in patients with dementia and/or Parkinson disease (PD).<br><br>OBJECTIVE: To investigate the prescribing patterns of dextromethorphan-quinidine, including trends in associated costs.<br><br>This population-based cohort study of patients prescribed dextromethorphan-quinidine used data from 2 commercial insurance databases, Optum Clinformatics Data Mart and Truven Health MarketScan. The Medicare Part D Prescription Drug Program data set was used to evaluate numbers of prescriptions and total reported spending by the Centers for Medicare &amp; Medicaid Services. Patients were included if they were prescribed dextromethorphan-quinidine from October 29, 2010, when the drug was approved, through March 1, 2017, for Optum and December 31, 2015, for Truven. Data were analyzed from December 1, 2017, through August 1, 2018.<br><br>MAIN OUTCOMES AND MEASURES: The proportion of patients prescribed dextromethorphan-quinidine with a diagnosis of MS, ALS, or dementia and/or PD, as well as the number of patients with a history of heart failure (a contraindication for the drug).<br><br>RESULTS: In the commercial health care databases, 12 858 patients filled a prescription for dextromethorphan-quinidine during the study period. Mean (SD) age was 66.0 (18.5) years, 66.7% were women, and 13.3% had a history of heart failure. Combining results from both databases, few patients had a diagnosis of MS (8.4%) or ALS (6.8%); most (57.0%) had a diagnosis of dementia and/or PD. In the Medicare Part D database, the number of patients prescribed dextromethorphan-quinidine increased 15.3-fold, from 3296 in 2011 to 50 402 in 2016. Reported spending by Centers for Medicare &amp; Medicaid Services on this medication increased from $3.9 million in 2011 to $200.4 million in 2016.<br><br>CONCLUSIONS AND RELEVANCE: Despite approval by the FDA for pseudobulbar affect based on studies of patients with ALS or MS, dextromethorphan-quinidine appears to be primarily prescribed for patients with dementia and/or PD.}, }
@article {pmid30614231, year = {2019}, author = {Xu, L and Shou, JY and Gill, RA and Guo, X and Najeeb, U and Zhou, WJ}, title = {Effects of ZJ0273 on barley and growth recovery of herbicide-stressed seedlings through application of branched-chain amino acids.}, journal = {Journal of Zhejiang University. Science. B}, volume = {20}, number = {1}, pages = {71-83}, pmid = {30614231}, issn = {1862-1783}, mesh = {Amino Acids, Branched-Chain/*administration &amp; dosage ; Antioxidants/metabolism ; Benzoates/administration &amp; dosage/*pharmacology ; Biomass ; Chlorophyll/metabolism ; Herbicides/administration &amp; dosage/*pharmacology ; Hordeum/*drug effects/*growth &amp; development/metabolism ; Photosynthesis/drug effects ; Plant Leaves/metabolism ; Reactive Oxygen Species/metabolism ; Seedlings/drug effects/growth &amp; development/metabolism ; }, abstract = {In this study, we evaluated the effect of the herbicide propyl 4-(2-(4,6-dimethoxypyrimidin-2-yloxy)benzylamino) benzoate (ZJ0273) on barley growth and explored the potential to trigger growth recovery through the application of branched-chain amino acids (BCAAs). Barley plants were foliar-sprayed with various concentrations of ZJ0273 (100, 500, or 1000 mg/L) at the four-leaf stage. Increasing either the herbicide concentration or measurement time after herbicide treatment significantly impaired plant morphological parameters such as plant height and biomass, and affected physiological indexes, i.e. maximal photochemical efficiency (Fv/Fm), quantum yield of photosystem II (ФPSII), net photosynthetic rate (Pn), and chlorophyll meter value (soil and plant analyzer development (SPAD)). Cellular injury of herbicide-treated plants was also evidenced by increased levels of reactive oxygen species (ROS) and antioxidative enzyme activity. Elevated levels of herbicide significantly reduced the activity of acetolactate synthase (ALS)-a key enzyme in the biosynthesis of BCAAs. In a separate experiment, growth recovery in herbicide-stressed barley plants was studied using various concentrations of BCAAs (10, 50, 100, and 200 mg/L). Increasing BCAA concentration in growth media significantly increased the biomass of herbicide-stressed barley seedlings, but had no significant effect on non-stressed plants. Further, BCAAs (100 mg/L) significantly down-regulated ROS and consequently antioxidant enzyme levels in herbicide-stressed plants. Our results showed that exogenous application of BCAAs could reverse the inhibitory effects of ZJ0273 by restoring protein biosynthesis in barley seedlings.}, }
@article {pmid30606512, year = {2019}, author = {Corcia, P and Beltran, S and Lautrette, G and Bakkouche, S and Couratier, P}, title = {Staging amyotrophic lateral sclerosis: A new focus on progression.}, journal = {Revue neurologique}, volume = {175}, number = {5}, pages = {277-282}, doi = {10.1016/j.neurol.2018.09.017}, pmid = {30606512}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Disease Progression ; Forms as Topic ; Humans ; Symptom Assessment/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogenous motoneuronal neurodegenerative condition with a panel of phenotypes exhibiting different clinical patterns. Two compounds are currently available for the treatment of ALS but the majority of trials have failed to show a positive effect on prognosis. One of the explanations which could be put forward involves the way efficacy is evaluated: clinicians agree that the ALSFRS-revised scale used in all trials does not fit with highlighting a positive effect. So, the development and validation of new tools allowing a reliable assessment of ALS has become a key issue in clinical research. Over the last three years, two functional scales (the King's College and MiToS staging systems) have been proposed. These scales rely on two different approaches to ALS: an anatomical and prognostic concept, and loss of autonomy. Both scales propose five stages. We will discuss below the contribution of these two scales to clinical evaluation and the questions which remain to be resolved in the future.}, }
@article {pmid30606510, year = {2019}, author = {García Santos, JM and García Martínez-Lozano, M and Vázquez Olmos, C and Blanquer, M}, title = {Neuroimaging and clinical trials with stem cells in amyotrophic lateral sclerosis: present and future perspectives.}, journal = {Radiologia}, volume = {61}, number = {3}, pages = {183-190}, doi = {10.1016/j.rx.2018.11.004}, pmid = {30606510}, issn = {2173-5107}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/*surgery ; Cell Survival ; Forecasting ; Humans ; Injections, Spinal ; Magnetic Resonance Imaging ; Mesenchymal Stem Cell Transplantation/adverse effects/methods ; Motor Cortex/diagnostic imaging ; Neural Stem Cells/*transplantation ; Neuroimaging/*methods ; Postoperative Complications/diagnostic imaging ; Spinal Cord/diagnostic imaging ; Stem Cell Transplantation/adverse effects/*methods ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis is a rare neurodegenerative disease with a rapid fatal course. The absence of effective treatments has led to new lines of research, some of which are based on stem cells. Surgical injection into the spinal cord, the most common route of administration of stem cells, has proven safe in trials to test the safety of the procedure. Nevertheless, challenges remain, such as determining the best route of administration or the way of checking the survival of the cells and their interaction with the therapeutic target. To date, the mission of neuroimaging techniques has been to detect lesions and complications in the spine and spinal cord, but neuroimaging also has the potential to supplant histologic study in analyzing the relations between the implanted cells and the therapeutic target, and as biomarkers of the disease, by measuring morphological and functional changes after treatment. These developments would increase the role of radiologists in the clinical management of patients with amyotrophic lateral sclerosis.}, }
@article {pmid30605685, year = {2019}, author = {Naguib, A and Sandmann, T and Yi, F and Watts, RJ and Lewcock, JW and Dowdle, WE}, title = {SUPT4H1 Depletion Leads to a Global Reduction in RNA.}, journal = {Cell reports}, volume = {26}, number = {1}, pages = {45-53.e4}, doi = {10.1016/j.celrep.2018.12.004}, pmid = {30605685}, issn = {2211-1247}, mesh = {A549 Cells ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Gene Knockdown Techniques ; HEK293 Cells ; HeLa Cells ; Humans ; RNA/biosynthesis/genetics/*metabolism ; RNA Interference ; RNA, Messenger/genetics/metabolism ; Repressor Proteins/*deficiency/genetics/metabolism ; Ribosomes/genetics/metabolism ; Transcriptional Elongation Factors/genetics/metabolism ; }, abstract = {SUPT4H1 is a transcription elongation factor that makes up part of the RNA polymerase II complex. Recent studies propose a selective role for SUPT4H1 in the transcription of repeat-containing DNA, the translated products of which contribute to neurodegenerative disorders such as C9orf72-amyotrophic lateral sclerosis. To investigate the potential of SUPT4H1 as a therapeutic target in repeat-associated neurodegeneration, we depleted SUPT4H1 by RNA interference to inhibit the function of the SUPT4H1/SUPT5H transcription elongation complex. Depletion of SUPT4H1 leads to a global reduction in all cellular RNA, highlighting the significant challenges that are associated with targeting this molecule for the treatment of human disease. Any requirement of SUPT4H1 for transcription of specific transcripts should be interpreted in the context of global modulatory effects on the transcriptome.}, }
@article {pmid30604238, year = {2019}, author = {Kunou, H and Kanzaki, R and Kawamura, T and Kanou, T and Ose, N and Funaki, S and Shintani, Y and Minami, M and Okumura, M}, title = {Two cases of air leak syndrome after bone marrow transplantation successfully treated by the pleural covering technique.}, journal = {General thoracic and cardiovascular surgery}, volume = {67}, number = {11}, pages = {987-990}, pmid = {30604238}, issn = {1863-6713}, mesh = {Adult ; Bone Marrow Transplantation/*adverse effects ; Female ; Humans ; Male ; Pleura/*surgery ; Pneumothorax/etiology/*surgery ; Postoperative Complications/*etiology/*surgery ; Recurrence ; Syndrome ; }, abstract = {Air leak syndrome (ALS) is a rare complication after bone marrow transplantation (BMT) and usually has a fatal outcome because of the high recurrence rate and treatment-refractory nature. A 32-year-old man with a history of BMT for acute lymphoblastic leukemia suffered from metachronous bilateral ALS. Bullectomy and the pleural covering procedure (PLC) were successfully performed for each side of the thorax. After surgery, no relapse of pneumothorax was seen for 2 years on the right side and for 1 year on the left side. A 38-year-old man with a history of BMT for acute myelogenous leukemia (AML) suffered from ALS at the thorax on the left side. Bullectomy and the PLC were successfully performed. After that no recurrence of left pneumothorax for 7 years. We experienced two cases of ALS after BMT successfully treated by the PLC. This technique may be a viable treatment option for future lung transplantation.}, }
@article {pmid30602569, year = {2019}, author = {Malik, R and Meng, H and Wongkongkathep, P and Corrales, CI and Sepanj, N and Atlasi, RS and Klärner, FG and Schrader, T and Spencer, MJ and Loo, JA and Wiedau, M and Bitan, G}, title = {The molecular tweezer CLR01 inhibits aberrant superoxide dismutase 1 (SOD1) self-assembly in vitro and in the G93A-SOD1 mouse model of ALS.}, journal = {The Journal of biological chemistry}, volume = {294}, number = {10}, pages = {3501-3513}, pmid = {30602569}, issn = {1083-351X}, support = {F32 NS087858/NS/NINDS NIH HHS/United States ; P30 AR057230/AR/NIAMS NIH HHS/United States ; R01 GM103479/GM/NIGMS NIH HHS/United States ; S10 RR028893/RR/NCRR NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/physiopathology ; Animals ; Binding Sites ; Body Weight/drug effects ; Bridged-Ring Compounds/metabolism/*pharmacology ; Disease Models, Animal ; Mice ; Muscle Strength/drug effects ; *Mutation ; Organophosphates/metabolism/*pharmacology ; Protein Aggregates/drug effects ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase-1/*chemistry/*genetics/metabolism ; Survival Analysis ; }, abstract = {Mutations in superoxide dismutase 1 (SOD1) cause 15-20% of familial amyotrophic lateral sclerosis (fALS) cases. The resulting amino acid substitutions destabilize SOD1's protein structure, leading to its self-assembly into neurotoxic oligomers and aggregates, a process hypothesized to cause the characteristic motor-neuron degeneration in affected individuals. Currently, effective disease-modifying therapy is not available for ALS. Molecular tweezers prevent formation of toxic protein assemblies, yet their protective action has not been tested previously on SOD1 or in the context of ALS. Here, we tested the molecular tweezer CLR01-a broad-spectrum inhibitor of the self-assembly and toxicity of amyloid proteins-as a potential therapeutic agent for ALS. Using recombinant WT and mutant SOD1, we found that CLR01 inhibited the aggregation of all tested SOD1 forms in vitro Next, we examined whether CLR01 could prevent the formation of misfolded SOD1 in the G93A-SOD1 mouse model of ALS and whether such inhibition would have a beneficial therapeutic effect. CLR01 treatment decreased misfolded SOD1 in the spinal cord significantly. However, these histological findings did not correlate with improvement of the disease phenotype. A small, dose-dependent decrease in disease duration was found in CLR01-treated mice, relative to vehicle-treated animals, yet motor function did not improve in any of the treatment groups. These results demonstrate that CLR01 can inhibit SOD1 misfolding and aggregation both in vitro and in vivo, but raise the question whether such inhibition is sufficient for achieving a therapeutic effect. Additional studies in other less aggressive ALS models may be needed to determine the therapeutic potential of this approach.}, }
@article {pmid30597421, year = {2019}, author = {Moodley, K and Bill, PLA and Bhigjee, AI and Patel, VB}, title = {A comparative study of motor neuron disease in HIV-infected and HIV-uninfected patients.}, journal = {Journal of the neurological sciences}, volume = {397}, number = {}, pages = {96-102}, doi = {10.1016/j.jns.2018.12.030}, pmid = {30597421}, issn = {1878-5883}, mesh = {Adult ; Age Factors ; Aged ; Anti-Retroviral Agents/therapeutic use ; Female ; HIV Infections/*complications/drug therapy/mortality ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*complications/mortality ; Retrospective Studies ; South Africa ; Survival Rate ; Treatment Outcome ; }, abstract = {BACKGROUND: This study is a descriptive review of the clinical and treatment outcome differences in HIV-infected patients with motor neuron syndrome (MNS) and HIV-uninfected patients with motor neuron disease (MND).<br><br>METHODS: A retrospective analysis of patients with MND/S was performed at Inkosi Albert Luthuli Central Hospital (IALCH), Durban, South Africa between 2003 and 2017.<br><br>RESULTS: One hundred and thirty six patients were included in the study, 101 (76%) were HIV-uninfected and 35 (26%) were HIV-infected. Ninety four percent of the HIV-infected cohort were <50&#x202f;years, median 41, IQR (33-45), p&#x202f;<&#x202f;0.001, had median ALS functional rating scale revised (ALSFRS-R) score of 28, IQR [24-30] and 40% of these patients on anti-retroviral therapy (ART) survived longer than 10&#x202f;years. Ninety one percent of the HIV-uninfected cohort were >50&#x202f;years, median 66, IQR(57-74), P&#x202f;<&#x202f;0.001, had median ALSFRS-R score of 44 (IQR 42-45) and 93% died within 5&#x202f;years of their illness.<br><br>CONCLUSION: HIV-infected MNS patients were younger, had more severe disease at presentation and survived longer if treated with ART with possible reversal of the disease process, compared to patients with MND.}, }
@article {pmid30594990, year = {2018}, author = {Bosisio, F and Jox, RJ and Jones, L and Rubli Truchard, E}, title = {Planning ahead with dementia: what role can advance care planning play? A review on opportunities and challenges.}, journal = {Swiss medical weekly}, volume = {148}, number = {}, pages = {w14706}, doi = {10.4414/smw.2018.14706}, pmid = {30594990}, issn = {1424-3997}, mesh = {*Advance Care Planning ; *Attitude to Death ; *Communication ; *Decision Making ; Dementia/*nursing/psychology ; Health Personnel ; Humans ; Palliative Care/methods ; Switzerland ; }, abstract = {Advance directives emerged in the 1960s with the goal of empowering people to exert control over their future medical decisions. However, it has become apparent, over recent years, that advance directives do not sufficiently capture the temporal and relational aspects of planning treatment and care. Advance care planning (ACP) has been suggested as a way to emphasise communication between the patient, their surrogate decision maker and healthcare professional(s) in order to anticipate healthcare decisions in the event that the patient loses decision-making capacity, either temporarily or permanently. In more and more countries, ACP has become common practice in planning the treatment of terminal diseases such as cancer or amyotrophic lateral sclerosis. However, even though neurodegenerative dementia results in the gradual loss of decision-making capacity, ACP is still extremely rare. There are several reasons for this. Firstly, some people have difficulties talking about illness and death, especially when this involves anticipation. Secondly, lay people and professionals alike struggle to consider Alzheimer’s disease and similar forms of dementia as terminal diseases. Thirdly, although patient decision-making capacity gradually decreases with the progression of dementia, the patient retains the ability to communicate and interact with surrogates and professionals until the later stages of the disease. Therefore, surrogates and professionals may feel unsure or even ambivalent when enforcing advance directives, in particular when those decisions may shorten a patient’s life expectancy. Finally, to be effective, existing ACP interventions should be adapted to patient’s cognitive impairments and lay out dementia-specific scenarios. Current WHO estimates indicate that by 2050 one out of four people will potentially have to take care of a relative with cognitive and communication impairments for several years. In Switzerland, the Federal Office of Public Health and the regional states have established national strategies on dementia and palliative care. These strategies emphasise the need for ACP as a means to prepare patients and their relatives for future decisions, as soon as someone is diagnosed with dementia. This moment is thus especially conducive to develop appropriate processes to prompt the elderly and people diagnosed with dementia to engage in ACP. Therefore, the aim of the present paper is to identify the benefits and challenges of ACP in dementia care, outline strategies to design appropriate procedures and tools, and provide professionals, patients and their relatives with opportunities to engage in ACP.}, }
@article {pmid30591087, year = {2019}, author = {El Sayed, M and El Tawil, C and Tamim, H and Mailhac, A and Mann, NC}, title = {Emergency Medical Services Experience With Barb Removal After Taser Use By Law Enforcement: A Descriptive National Study.}, journal = {Prehospital and disaster medicine}, volume = {34}, number = {1}, pages = {38-45}, doi = {10.1017/S1049023X18001176}, pmid = {30591087}, issn = {1945-1938}, abstract = {BACKGROUND: Conducted electrical weapons (CEWs), including Thomas A. Swift Electric Rifles (TASERs), are increasingly used by law enforcement officers (LEOs) in the US and world-wide. Little is known about the experience of Emergency Medical Service (EMS) providers with these incidents.<br><br>OBJECTIVES: This study describes EMS encounters with documented TASER use and barb removal, characteristics of resulting injuries, and treatment provided.<br><br>METHODS: This retrospective study used five combined, consecutive National Emergency Medical Services Information System (NEMSIS; Salt Lake City, Utah USA) public-release datasets (2011-2015). All EMS activations with documented TASER barb removal were included. Descriptive analyses were carried out.<br><br>RESULTS: The study included 648 EMS activations with documented TASER barb removal, yielding a prevalence rate of 4.55 per 1,000,000 EMS activations. Patients had a mean age of 35.9 years (SD=18.2). The majority were males (80.2%) and mainly white (71.3%). Included EMS activations were mostly in urban or suburban areas (78.3%). Over one-half received Advanced Life Support (ALS)-level of service (58.2%). The most common chief complaint reported by dispatch were burns (29.9%), followed by traumatic injury (16.1%). Patients had pain (45.6%) or wound (17.2%) as a primary symptom, with most having possible injury (77.8%). Reported causes of injury were mainly fire and flames (29.8%) or excessive heat (16.7%). The provider's primary impressions were traumatic injury (66.3%) and behavioral/psychiatric disorder (16.8%). Only one cardiac arrest (0.2%) was reported. Over one-half of activations resulted in patient transports (56.3%), mainly to a hospital (91.2%). These encounters required routine EMS care (procedures and medications). An increase in the prevalence of EMS activations with documented TASER barb removal over the study period was not significant (P=.27).<br><br>CONCLUSION: At present, EMS activations with documented TASER barb removal are rare. Routine care by EMS is expected, and life-threatening emergencies are not common. All EMS providers should be familiar with local policies and procedures related to TASER use and barb removal.El SayedM, El TawilC, TamimH, MailhacA, MannNC. Emergency Medical Services experience with barb removal after TASER use by law enforcement: a descriptive national study. Prehosp Disaster Med. 2019;34(1):38-45.}, }
@article {pmid30588220, year = {2018}, author = {Fu, T and Kim, JO and Han, JH and Gumilang, A and Lee, YH and Kim, KS}, title = {A Small GTPase RHO2 Plays an Important Role in Pre-infection Development in the Rice Blast Pathogen Magnaporthe oryzae.}, journal = {The plant pathology journal}, volume = {34}, number = {6}, pages = {470-479}, pmid = {30588220}, issn = {1598-2254}, abstract = {The rice blast pathogen Magnaporthe oryzae is a global threat to rice production. Here we characterized RHO2 gene (MGG_02457) that belongs to the Rho GTPase family, using a deletion mutant. This mutant ΔMorho2 exhibited no defects in conidiation and germination but developed only 6% of appressoria in response to a hydrophobic surface when compared to the wild-type progenitor. This result indicates that MoRHO2 plays a role in appressorium development. Furthermore, exogenous cAMP treatment on the mutant led to appressoria that exhibited abnormal morphology on both hydrophobic and hydrophilic surfaces. These outcomes suggested the involvement of MoRHO2 in cAMP-mediated appressorium development. ΔMorho2 mutation also delayed the development of appressorium-like structures (ALS) at hyphal tips on hydrophobic surface, which were also abnormally shaped. These results suggested that MoRHO2 is involved in morphological development of appressoria and ALS from conidia and hyphae, respectively. As expected, ΔMorho2 mutant was defective in plant penetration, but was still able to cause lesions, albeit at a reduced rate on wounded plants. These results implied that MoRHO2 plays a role in M. oryzae virulence as well.}, }
@article {pmid30586030, year = {2019}, author = {Zhang, Q and Cao, B and Chen, Y and Liang, Y and Wei, Q and Zhou, D and Shang, H}, title = {Facial Onset Motor and Sensory Neuronopathy Syndrome With a Novel TARDBP Mutation.}, journal = {The neurologist}, volume = {24}, number = {1}, pages = {22-25}, doi = {10.1097/NRL.0000000000000201}, pmid = {30586030}, issn = {2331-2637}, mesh = {Adult ; DNA-Binding Proteins/*genetics ; Facial Nerve Diseases/*genetics/*physiopathology ; Humans ; Male ; Motor Neuron Disease ; Mutation/*genetics ; }, abstract = {INTRODUCTION: Facial onset sensory and motor neuronopathy (FOSMN) syndrome was a rare and slowly progressive neurodegenerative disorder, which heralded by sensory symptoms within the face, and followed by evolution of sensory and motor deficits in the face and limbs. The underlying pathogenesis of FOSMN remains to be fully elucidated.<br><br>CASE REPORT: A 40-year-old man was admitted to our hospital with facial sensory deficits spreading in a rostral-caudal manner. He then developed diffuse fasciculation, bulbar signs, atrophy and weakness of facial, neck, and limb muscles progressively, a process resembling amyotrophic lateral sclerosis. Neurophysiological studies demonstrated abnormal blink reflexes and some denervation-reinnervation changes in electromyogram. He was diagnosed with FOSMN syndrome clinically. A novel heterozygous Gly386Glu mutation in the transactive response DNA-binding protein (TARDBP) gene was found. The patient had no response to immunologic treatment and finally died of respiratory failure.<br><br>CONCLUSIONS: This is the first time that a novel mutation in TARDBP gene was identified in a patient with FOSMN syndrome, which further suggested a link between FOSMN and amyotrophic lateral sclerosis. Our findings widen the spectrum of TARDBP-related motor neuron diseases.}, }
@article {pmid30578866, year = {2019}, author = {Elfawy, HA and Das, B}, title = {Crosstalk between mitochondrial dysfunction, oxidative stress, and age related neurodegenerative disease: Etiologies and therapeutic strategies.}, journal = {Life sciences}, volume = {218}, number = {}, pages = {165-184}, doi = {10.1016/j.lfs.2018.12.029}, pmid = {30578866}, issn = {1879-0631}, mesh = {Age Factors ; Animals ; Humans ; Mitochondria/metabolism/*pathology ; Neurodegenerative Diseases/etiology/metabolism/*therapy ; *Oxidative Stress ; Signal Transduction ; }, abstract = {Mitochondrial function is vital for normal cellular processes. Mitochondrial damage and oxidative stress have been greatly implicated in the progression of aging, along with the pathogenesis of age-related neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Although antioxidant therapy has been proposed for the prevention and treatment of age-related NDs, unraveling the molecular mechanisms of mitochondrial dysfunction can lead to significant progress in the development of effective treatments against such diseases. Aging is associated with the generation and accumulation of reactive oxygen species (ROS) that are the major contributors to oxidative stress. Oxidative stress is caused because of the imbalance between the production of ROS and their oxidation, which can affect the mitochondrial respiratory chain function, thereby altering the membrane permeability and calcium homeostasis, along with increasing the heteroplasmic mtDNA and weakening the mitochondrial defense systems. Mitochondrial dysfunction mainly affects mitochondrial biogenesis and dynamics that are prominent in several age-related NDs. Mitochondrial dysfunction has a crucial role in the pathophysiology of age-related NDs. Several mitochondria targeted strategies, such as enhancing the antioxidant bioavailability via novel delivery systems, identifying unique mitochondrial proteins as specific drug targets, investigating the signaling pathways of mitochondrial biogenesis and dynamics, and identifying effective natural products are potentially effective to counteract mitochondrial dysfunction-related NDs.}, }
@article {pmid30578206, year = {2018}, author = {Oki, R and Izumi, Y and Nodera, H and Sato, Y and Nokihara, H and Kanai, K and Sonoo, M and Urushitani, M and Nishinaka, K and Atsuta, N and Kohara, N and Shimizu, T and Kikuchi, H and Oda, M and Ikeda, K and Nagai, M and Komai, K and Kojima, Y and Kuzume, D and Isose, S and Shimohama, S and Abe, K and Ito, H and Noda, K and Ishihara, T and Morita, M and Shimohata, T and Teramukai, S and Kagimura, T and Noma, K and Yanagawa, H and Kuwabara, S and Kaji, R and , }, title = {The Japanese Early-Stage Trial of High-Dose Methylcobalamin for Amyotrophic Lateral Sclerosis (JETALS): Protocol for a Randomized Controlled Trial.}, journal = {JMIR research protocols}, volume = {7}, number = {12}, pages = {e12046}, pmid = {30578206}, issn = {1929-0748}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Currently, only riluzole and edaravone are approved as drugs to treat ALS and new agents with larger effect sizes are warranted. Exploratory analyses in our previous study (study ID #E0302-J081-761) have suggested that high-dose methylcobalamin (E0302) prolonged the overall survival of ALS patients and suppressed ALS progression in patients with a disease duration of less than 12 months.<br><br>OBJECTIVE: This clinical trial aims to evaluate the efficacy and safety of E0302 for treatment of ALS patients within one year of onset.<br><br>METHODS: The Japanese early-stage trial of high-dose methylcobalamin for ALS (JETALS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase III study conducted at 24 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 128 ALS patients within one year of onset were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 16 weeks. If patients wish to receive E0302 50 mg after the double-blind administration period, E0302 will be provided to them until March 2020 during the continuous administration period.<br><br>RESULTS: This study began in October 2017 and is being conducted at 24 participating institutions in Japan. The study is in progress and the patient enrollment period is scheduled to end in August 2019, with follow-up scheduled to end in March 2020.<br><br>CONCLUSIONS: This study is being performed to revalidate the efficacy and safety of E0302 in patients with early-stage ALS in the first year of symptom onset. If positive results are obtained, the aim is to apply for E0302 approval as a new drug for the treatment of ALS.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT03548311; https://clinicaltrials.gov/ct2/show/NCT03548311 (Archived by WebCite at http://www.webcitation.org/74Fw3rDzb).<br><br>PRR1-10.2196/12046.}, }
@article {pmid30576920, year = {2019}, author = {Sivandzade, F and Prasad, S and Bhalerao, A and Cucullo, L}, title = {NRF2 and NF-қB interplay in cerebrovascular and neurodegenerative disorders: Molecular mechanisms and possible therapeutic approaches.}, journal = {Redox biology}, volume = {21}, number = {}, pages = {101059}, pmid = {30576920}, issn = {2213-2317}, support = {R01 DA029121/DA/NIDA NIH HHS/United States ; }, mesh = {Aging/metabolism ; Animals ; Cerebrovascular Disorders/drug therapy/*etiology/*metabolism ; *Disease Susceptibility ; Humans ; Hyperglycemia/complications/etiology/metabolism ; Inflammation/etiology/metabolism ; Molecular Targeted Therapy ; NF-E2-Related Factor 2/agonists/*metabolism ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Neurodegenerative Diseases/drug therapy/*etiology/*metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Smoking/adverse effects ; }, abstract = {Electrophiles and reactive oxygen species (ROS) play a major role in modulating cellular defense mechanisms as well as physiological functions, and intracellular signaling. However, excessive ROS generation (endogenous and exogenous) can create a state of redox imbalance leading to cellular and tissue damage (Ma and He, 2012) [1]. A growing body of research data strongly suggests that imbalanced ROS and electrophile overproduction are among the major prodromal factors in the onset and progression of several cerebrovascular and neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), stroke, Alzheimer's disease (AD), Parkinson's disease (PD), and aging (Ma and He, 2012; Ramsey et al., 2017; Salminen et al., 2012; Sandberg et al., 2014; Sarlette et al., 2008; Tanji et al., 2013) [1-6]. Cells offset oxidative stress by the action of housekeeping antioxidative enzymes (such as superoxide dismutase, catalase, glutathione peroxidase) as well direct and indirect antioxidants (Dinkova-Kostova and Talalay, 2010) [7]. The DNA sequence responsible for modulating the antioxidative and cytoprotective responses of the cells has been identified as the antioxidant response element (ARE), while the nuclear factor erythroid 2-related factor (NRF2) is the major regulator of the xenobiotic-activated receptor (XAR) responsible for activating the ARE-pathway, thus defined as the NRF2-ARE system (Ma and He, 2012) [1]. In addition, the interplay between the NRF2-ARE system and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB, a protein complex that controls cytokine production and cell survival), has been further investigated in relation to neurodegenerative and neuroinflammatory disorders. On these premises, we provide a review analysis of current understanding of the NRF2-NF-ĸB interplay, their specific role in major CNS disorders, and consequent therapeutic implication for the treatment of neurodegenerative and cerebrovascular diseases.}, }
@article {pmid30574410, year = {2018}, author = {Wei, QQ and Chen, Y and Chen, X and Cao, B and Ou, R and Zhang, L and Hou, Y and Shang, H}, title = {Prognostic Nomogram Associated with Longer Survival in Amyotrophic Lateral Sclerosis Patients.}, journal = {Aging and disease}, volume = {9}, number = {6}, pages = {965-975}, pmid = {30574410}, issn = {2152-5250}, abstract = {Better understanding of survival factors in amyotrophic lateral sclerosis (ALS) could help physicians and patients schedule therapeutic interventions. We conducted a study to evaluate the predictive factors associated with longer survival and construct prognostic nomogram in ALS patients. A total of 553 ALS patients were enrolled and divided into 2 groups: a training set and a validation set. Risk factors for survival were identified using logistic regression analysis, and a nomogram created by R program was performed to predict the probability of longer survival in the training set; then receiver operating characteristic (ROC) analysis was applied to assess predictive value of the nomogram model. The median survival time was 3.2 years for all patients. Multivariate analyses revealed that age of onset, rate of disease progression, hemoglobin A1c (HbA1c) level, body mass index, creatinine, creatine kinase (CK), and non-invasive positive pressure ventilation (NIPPV) were independent predictors of longer survival. A nomogram based on the above seven predictive factors was developed to predict the possibility of longer survival. The ROC curve of the nomogram demonstrated good discrimination ability with an AUC of 0.92 (95% CI: 0.88-0.96) in the validation set. In ALS, serum CK, creatinine and HbA1c levels at baseline were independent biomarkers of longer survival. The prognostic nomogram model that integrated all significant independent factors for those who survived longer than 3 years provides an effective way to predict the probability of longer survival and can help doctors evaluate the disease progression and give personalized treatment recommendations.}, }
@article {pmid30567526, year = {2018}, author = {Yu, CJ and Wang, L and Mao, SL and Zhang, Y and Song, LL and Cai, LY and Tao, Y}, title = {The clinical assessment of amyotrophic lateral sclerosis patients' prognosis by ZNF512B gene, neck flexor muscle power score and body mass index (BMI).}, journal = {BMC neurology}, volume = {18}, number = {1}, pages = {211}, pmid = {30567526}, issn = {1471-2377}, support = {QC2012C007//the Youth Foundation of the Heilongjiang Province of China/ ; 12531304//the Science and Technology Research Project of Education Department of Heilongjiang Province of China/ ; LBH-Q15100//the postdoctoral scientific research developmental fund of Heilongjiang Province/ ; }, mesh = {Aged ; Alleles ; Amyotrophic Lateral Sclerosis/*genetics ; Body Mass Index ; Carrier Proteins/*genetics ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Muscle Strength/*genetics ; Muscle, Skeletal ; Neck ; Polymorphism, Single Nucleotide ; Prognosis ; }, abstract = {BACKGROUND: Assessment on the prognosis of amyotrophic lateral sclerosis (ALS) is becoming a focus of research in recent years since there is no effective treatment. The aim of the research is to explore the major factors involving in prognosis of ALS patients through long-term follow-up.<br><br>METHODS: ALS patients' DNA extracted from peripheral blood white cells were detected for the risk allele by single nucleotide polymorphism (SNP) analysis. Neck flexor muscle score and body mass index (BMI) were recorded during Medical Research Council follow-up using manual muscle testing method.<br><br>RESULTS: ALS patients with risk alleles (C) deteriorated rapidly with poor clinical outcome. It seemed that the higher neck flexor muscle strength score in ALS patients with the longer survival time but without significant correlation (p&#x2009;>&#x2009;0.05). The lower the basal body mass index, the shorter the survival time and the faster deterioration (p&#x2009;<&#x2009;0.05). The patients with body mass index less than 22.04 seemed to have short survival time than those with BMI more than 22.04 (p&#x2009;<&#x2009;0.05), however, the speed of deterioration in two groups of patients had no significant difference (p&#x2009;>&#x2009;0.05).<br><br>CONCLUSION: The risk (C) allele of the SNP (rs2275294) in the ZNF512B gene, cervical flexor muscle power and body weight index might have clinical potential for ALS prognostication, since these indicators is so simple to perform that they might be very suitable for primary clinics and even community medical institutions to carry out.}, }
@article {pmid30565312, year = {2019}, author = {Ohta, Y and Nomura, E and Shang, J and Feng, T and Huang, Y and Liu, X and Shi, X and Nakano, Y and Hishikawa, N and Sato, K and Takemoto, M and Yamashita, T and Abe, K}, title = {Enhanced oxidative stress and the treatment by edaravone in mice model of amyotrophic lateral sclerosis.}, journal = {Journal of neuroscience research}, volume = {97}, number = {5}, pages = {607-619}, doi = {10.1002/jnr.24368}, pmid = {30565312}, issn = {1097-4547}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism/pathology ; Animals ; Atrophy ; Edaravone/*pharmacology ; Female ; Histone Deacetylases/metabolism ; Humans ; Longevity/drug effects ; Male ; Mice ; Mice, Transgenic ; NF-E2-Related Factor 2/metabolism ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/*drug effects ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/metabolism ; }, abstract = {Oxidative stress is associated with the degeneration of both motor neurons and skeletal muscles in amyotrophic lateral sclerosis (ALS). A free radical scavenger edaravone has been proven as a therapeutic drug for ALS patients, but the neuroprotective mechanism for the oxidative stress of ALS has not been fully investigated. In this study, we investigated oxidative stress in ALS model mice bearing both oxidative stress sensor nuclear erythroid 2-related factor 2 (Nrf2) and G93A-human Cu/Zn superoxide dismutase (Nrf2/G93A) treated by edaravone. In vivo Nrf2 imaging analysis showed the accelerated oxidative stress both in spinal motor neurons and lower limb muscles of Nrf2/G93A mice according to disease progression in addition to the enhancement of serum oxidative stress marker dROMS. These were significantly alleviated by edaravone treatment accompanied by clinical improvements (rotarod test). The present study suggests that in vivo optical imaging of Nrf2 is useful for detecting oxidative stress in ALS, and edaravone alleviates the degeneration of both motor neurons and muscles related to oxidative stress in ALS patients.}, }
@article {pmid30564619, year = {2018}, author = {Nicholson, K and Chan, J and Macklin, EA and Levine-Weinberg, M and Breen, C and Bakshi, R and Grasso, DL and Wills, AM and Jahandideh, S and Taylor, AA and Beaulieu, D and Ennist, DL and Andronesi, O and Ratai, EM and Schwarzschild, MA and Cudkowicz, M and Paganoni, S}, title = {Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {5}, number = {12}, pages = {1522-1533}, pmid = {30564619}, issn = {2328-9503}, abstract = {OBJECTIVE: To test the safety, tolerability, and urate-elevating capability of the urate precursor inosine taken orally or by feeding tube in people with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: This was a pilot, open-label trial in 25 participants with ALS. Treatment duration was 12 weeks. The dose of inosine was titrated at pre-specified time points to elevate serum urate levels to 7-8 mg/dL. Primary outcomes were safety (as assessed by the occurrence of adverse events [AEs]) and tolerability (defined as the ability to complete the 12-week study on study drug). Secondary outcomes included biomarkers of oxidative stress and damage. As an exploratory analysis, observed outcomes were compared with a virtual control arm built using prediction algorithms to estimate ALSFRS-R scores.<br><br>RESULTS: Twenty-four out of 25 participants (96%) completed 12 weeks of study drug treatment. One participant was unable to comply with study visits and was lost to follow-up. Serum urate rose to target levels in 6 weeks. No serious AEs attributed to study drug and no AEs of special concern, such as urolithiasis and gout, occurred. Selected biomarkers of oxidative stress and damage had significant changes during the study period. Observed changes in ALSFRS-R did not differ from baseline predictions.<br><br>INTERPRETATION: Inosine appeared safe, well tolerated, and effective in raising serum urate levels in people with ALS. These findings, together with epidemiological observations and preclinical data supporting a neuroprotective role of urate in ALS models, provide the rationale for larger clinical trials testing inosine as a potential disease-modifying therapy for ALS.}, }
@article {pmid30564616, year = {2018}, author = {Self, WK and Schoch, KM and Alex, J and Barthélemy, N and Bollinger, JG and Sato, C and Cole, T and Kordasiewicz, HB and Swayze, E and Bateman, RJ and Miller, TM}, title = {Protein production is an early biomarker for RNA-targeted therapies.}, journal = {Annals of clinical and translational neurology}, volume = {5}, number = {12}, pages = {1492-1504}, pmid = {30564616}, issn = {2328-9503}, support = {R21 NS084870/NS/NINDS NIH HHS/United States ; R01 NS095773/NS/NINDS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; TL1 TR002344/TR/NCATS NIH HHS/United States ; R21 NS098716/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVES: Clinical trials for progressive neurodegenerative disorders such as Alzheimer's Disease and Amyotrophic Lateral Sclerosis have been hindered due to the absence of effective pharmacodynamics markers to assay target engagement. We tested whether measurements of new protein production would be a viable pharmacodynamics tool for RNA-targeted therapies.<br><br>METHODS: Transgenic animal models expressing human proteins implicated in neurodegenerative disorders - microtubule-associated protein tau (hTau) or superoxide dismutase-1 (hSOD1) - were treated with antisense oligonucleotides (ASOs) delivered to the central nervous system to target these human mRNA transcripts. Simultaneously, animals were administered [13]C6-leucine via drinking water to measure new protein synthesis after ASO treatment. Measures of new protein synthesis and protein concentration were assayed at designated time points after ASO treatment using targeted proteomics.<br><br>RESULTS: ASO treatment lowered hTau mRNA and protein production (measured by [13]C6-leucine-labeled hTau protein) earlier than total hTau protein concentration in transgenic mouse cortex. In the CSF of hSOD1 transgenic rats, ASO treatment lowered newly generated hSOD1 protein driven by decreases in newly synthesized hSOD1 protein, not overall protein concentration, 30&#xa0;days after treatment. At later time points, decreases in newly generated protein were still observed after mRNA lowering reached a steady state after ASO treatment.<br><br>INTERPRETATION: Measures of newly generated protein show earlier pharmacodynamics changes for RNA-lowering therapeutics compared with total protein concentration. Early in ASO treatment, decreases in newly generated protein are driven by changes in newly synthesized protein. Measuring new protein production in CSF may be a promising early pharmacodynamics marker for RNA-targeted therapeutics.}, }
@article {pmid30554828, year = {2019}, author = {Riva, N and Mora, G and Sorarù, G and Lunetta, C and Ferraro, OE and Falzone, Y and Leocani, L and Fazio, R and Comola, M and Comi, G and , }, title = {Safety and efficacy of nabiximols on spasticity symptoms in patients with motor neuron disease (CANALS): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial.}, journal = {The Lancet. Neurology}, volume = {18}, number = {2}, pages = {155-164}, doi = {10.1016/S1474-4422(18)30406-X}, pmid = {30554828}, issn = {1474-4465}, mesh = {Adult ; Aged ; Cannabidiol/adverse effects/*therapeutic use ; Double-Blind Method ; Dronabinol/adverse effects/*therapeutic use ; Drug Combinations ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/complications/*drug therapy ; Muscle Spasticity/*drug therapy/etiology ; Quality of Life ; Treatment Outcome ; }, abstract = {BACKGROUND: Spasticity is a major determinant of disability and decline in quality of life in patients with motor neuron disease. Cannabinoids have been approved for symptomatic treatment of spasticity in multiple sclerosis. We investigated whether cannabinoids might also reduce spasticity in patients with motor neuron disease.<br><br>METHODS: We did an investigator-initiated, randomised, double-blind, placebo-controlled, phase 2 clinical trial at four tertiary motor neuron disease centres in Italy. Eligible patients were aged 18-80 years; had possible, laboratory-supported probable, probable, or definite amyotrophic lateral sclerosis as defined by revised El Escorial criteria, or primary lateral sclerosis according to Pringle's criteria; had spasticity symptoms due to motor neuron disease for at least 3 months; had spasticity scores of 1 or greater in at least two muscle groups on the Modified Ashworth Scale; and were taking an antispasticity regimen that was maintained at a stable dose for 30 days before enrolment. Participants were assigned (1:1) by an independent statistician via a computer-generated randomisation sequence to a standardised oromucosal spray (nabiximols) containing a defined combination of delta-9-tetrahydrocannabinol and cannabidiol (each 100 &#x3bc;L actuation contained 2&#xb7;7 mg delta-9-tetrahydrocannabinol and 2&#xb7;5 mg cannabidiol) or to placebo for 6 weeks. Participants self-titrated during the first 14 treatment days according to a predefined escalation scheme (maximum 12 actuations per 24 h), then maintained that dose for 4 weeks. The primary endpoint was the change in the score on the Modified Ashworth Scale, which was assessed at baseline and after 6 weeks. Safety and tolerability were also monitored. Participants, investigators, site personnel, and the study statistician were masked to treatment allocation. All randomised participants who received at least one dose of study drug were included in the analysis. This trial is registered with ClinicalTrials.gov, number NCT01776970. The trial is closed to new participants with follow-up completed.<br><br>FINDINGS: Between Jan 19, 2013, and Dec 15, 2014, 60 participants were randomly assigned, and 59 participants were included in the final analysis (29 in the nabiximols group and 30 in the placebo group). Modified Ashworth Scale scores improved by a mean of 0&#xb7;11 (SD 0&#xb7;48) in the nabiximols group and deteriorated by a mean of 0&#xb7;16 (0&#xb7;47) in the placebo group (adjusted effect estimate -0&#xb7;32 [95% CI -0&#xb7;57 to -0&#xb7;069]; p=0&#xb7;013). Nabiximols was well tolerated, and no participants withdrew from the double-blind phase of the study. No serious adverse effects occurred.<br><br>INTERPRETATION: In this proof-of-concept trial, nabiximols had a positive effect on spasticity symptoms in patients with motor neuron disease and had an acceptable safety and tolerability profile. These findings should be investigated further in larger clinical trials.<br><br>FUNDING: Italian Research Foundation for Amyotrophic Lateral Sclerosis.}, }
@article {pmid30551677, year = {2018}, author = {Morgan, S and Duguez, S and Duddy, W}, title = {Personalized Medicine and Molecular Interaction Networks in Amyotrophic Lateral Sclerosis (ALS): Current Knowledge.}, journal = {Journal of personalized medicine}, volume = {8}, number = {4}, pages = {}, pmid = {30551677}, issn = {2075-4426}, abstract = {Multiple genes and mechanisms of pathophysiology have been implicated in amyotrophic lateral sclerosis (ALS), suggesting it is a complex systemic disease. With this in mind, applying personalized medicine (PM) approaches to tailor treatment pipelines for ALS patients may be necessary. The modelling and analysis of molecular interaction networks could represent valuable resources in defining ALS-associated pathways and discovering novel therapeutic targets. Here we review existing omics datasets and analytical approaches, in order to consider how molecular interaction networks could improve our understanding of the molecular pathophysiology of this fatal neuromuscular disorder.}, }
@article {pmid30548150, year = {2019}, author = {Orts, J and Aulikki Wälti, M and Ghosh, D and Campioni, S and Saupe, SJ and Riek, R}, title = {Rational Structure-Based Design of Fluorescent Probes for Amyloid Folds.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {20}, number = {9}, pages = {1161-1166}, doi = {10.1002/cbic.201800664}, pmid = {30548150}, issn = {1439-7633}, mesh = {Amyloid beta-Peptides/*metabolism ; Fluorescence ; Fluorescent Dyes/chemistry/*metabolism ; Fungal Proteins/*metabolism ; Humans ; Molecular Structure ; Peptide Fragments/*metabolism ; Podospora/chemistry ; Protein Binding ; Spectrometry, Fluorescence ; alpha-Synuclein/*metabolism ; }, abstract = {Amyloid fibrils are pathological hallmarks of various human diseases, including Parkinson's, Alzheimer's, amyotrophic lateral sclerosis (ALS or motor neurone disease), and prion diseases. Treatment of the amyloid diseases are hindered, among other factors, by timely detection and therefore, early detection of the amyloid fibrils would be beneficial for treatment against these disorders. Here, a small molecular fluorescent probe is reported that selectively recognize the fibrillar form of amyloid beta(1-42), α-synuclein, and HET-s(218-289) protein over their monomeric conformation. The rational design of the reporters relies on the well-known cross-β-sheet repetition motif, the key structural feature of amyloids.}, }
@article {pmid30524706, year = {2018}, author = {Swindell, WR and Bojanowski, K and Kindy, MS and Chau, RMW and Ko, D}, title = {GM604 regulates developmental neurogenesis pathways and the expression of genes associated with amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {7}, number = {}, pages = {30}, pmid = {30524706}, issn = {2047-9158}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is currently an incurable disease without highly effective pharmacological treatments. The peptide drug GM604 (GM6 or Alirinetide) was developed as a candidate ALS therapy, which has demonstrated safety and good drug-like properties with a favorable pharmacokinetic profile. GM6 is hypothesized to bolster neuron survival through the multi-target regulation of developmental pathways, but mechanisms of action are not fully understood.<br><br>METHODS: This study used RNA-seq to evaluate transcriptome responses in SH-SY5Y neuroblastoma cells following GM6 treatment (6, 24 and 48&#xa0;h).<br><br>RESULTS: We identified 2867 protein-coding genes with expression significantly altered by GM6 (FDR&#x2009;<&#x2009;0.10). Early (6&#xa0;h) responses included up-regulation of Notch and hedgehog signaling components, with increased expression of developmental genes mediating neurogenesis and axon growth. Prolonged GM6 treatment (24 and 48&#xa0;h) altered the expression of genes contributing to cell adhesion and the extracellular matrix. GM6 further down-regulated the expression of genes associated with mitochondria, inflammatory responses, mRNA processing and chromatin organization. GM6-increased genes were located near GC-rich motifs interacting with C2H2 zinc finger transcription factors, whereas GM6-decreased genes were located near AT-rich motifs associated with helix-turn-helix homeodomain factors. Such motifs interacted with a diverse network of transcription factors encoded by GM6-regulated genes (STAT3, HOXD11, HES7, GLI1). We identified 77 ALS-associated genes with expression significantly altered by GM6 treatment (FDR&#x2009;<&#x2009;0.10), which were known to function in neurogenesis, axon guidance and the intrinsic apoptosis pathway.<br><br>CONCLUSIONS: Our findings support the hypothesis that GM6 acts through developmental-stage pathways to influence neuron survival. Gene expression responses were consistent with neurotrophic effects, ECM modulation, and activation of the Notch and hedgehog neurodevelopmental pathways. This multifaceted mechanism of action is unique among existing ALS drug candidates and may be applicable to multiple neurodegenerative diseases.}, }
@article {pmid30522774, year = {2019}, author = {Aragonès, JM and Altimiras, J and Molist, N and Roura, P and Amblàs-Novellas, J}, title = {[Under-diagnosis of neuromuscular diseases in patients of 80 years and older].}, journal = {Revista espanola de geriatria y gerontologia}, volume = {54}, number = {2}, pages = {99-102}, doi = {10.1016/j.regg.2018.10.004}, pmid = {30522774}, issn = {1578-1747}, mesh = {Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*diagnosis/epidemiology ; Female ; Guillain-Barre Syndrome/*diagnosis/epidemiology ; Humans ; Male ; Myasthenia Gravis/*diagnosis/epidemiology ; Spain/epidemiology ; }, abstract = {Myasthenia gravis (MG), amyotrophic lateral sclerosis and Guillain-Barre syndrome (GBS) have been classically considered as exceptional or unusual diseases in people with a geriatric profile. Over the past 25 years, several population-based studies have been conducted in the Osona area (Barcelona), which, for the first time, has led to describing the high global incidences in the elderly, especially those over 80 years-old. The results suggest the possibility of underdiagnosis of these neuromuscular diseases in the elderly, a fact that could be especially relevant in the case of MG and GBS, since they are 2potentially reversible entities with high mortality in the event of underdiagnosis and absence of treatment.}, }
@article {pmid30538761, year = {2018}, author = {Kim, SJ and Park, YC and Baek, YH and Seo, BK}, title = {Traditional Korean Medicine Treatment for Patients with Wilting Disorder: A Literature Review of In Vivo Studies.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2018}, number = {}, pages = {5601846}, pmid = {30538761}, issn = {1741-427X}, abstract = {Wilting disorder is an abnormal condition characterized by weakness and paralysis of the upper and lower extremities. Pathogenesis and treatment target of the disorder are unclear; hence, allopathic treatment is generally used to relieve the symptoms. To investigate the treatment mechanism and effect of Traditional Korean Medicine (TKM) in patients with wilting disorder, we reviewed in vivo studies that focused on the effect of TKM on the main symptoms of wilting disorder and treatment of the diseases that can cause these symptoms. We electronically searched the PubMed, Cochrane, and CNKI (China National Knowledge Infrastructure) databases using the following search terms: (weakness OR motor function disorder) (myasthenia gravis OR Guillain-Barre syndrome OR amyotrophic lateral sclerosis OR paralysis OR polymyositis OR muscular dystrophy) AND (herbal medicine OR acupuncture OR bee-venom OR pharmacoacupuncture OR electro-acupuncture OR moxibustion). We selected 11 studies that demonstrated the effect of TKM treatment on the main symptoms of wilting disorder. In these studies, inducted models of amyotrophic lateral sclerosis, myasthenia gravis, Duchenne muscular atrophy, polymyositis, and Guillain-Barre syndrome were used. With regard to treatment, herbal medicine was used in five studies, and acupuncture and bee-venom pharmacoacupuncture were used in three studies each. Future research is needed to determine the effectiveness of TKM treatment in patients with diseases that can cause the main symptoms of wilting disorder.}, }
@article {pmid30534107, year = {2018}, author = {Johannesen, S and Budeus, B and Peters, S and Iberl, S and Meyer, AL and Kammermaier, T and Wirkert, E and Bruun, TH and Samara, VC and Schulte-Mattler, W and Herr, W and Schneider, A and Grassinger, J and Bogdahn, U}, title = {Biomarker Supervised G-CSF (Filgrastim) Response in ALS Patients.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {971}, pmid = {30534107}, issn = {1664-2295}, abstract = {Objective: To evaluate safety, tolerability and feasibility of long-term treatment with Granulocyte-colony stimulating factor (G-CSF), a well-known hematopoietic stem cell factor, guided by assessment of mobilized bone marrow derived stem cells and cytokines in the serum of patients with amyotrophic lateral sclerosis (ALS) treated on a named patient basis. Methods: 36 ALS patients were treated with subcutaneous injections of G-CSF on a named patient basis and in an outpatient setting. Drug was dosed by individual application schemes (mean 464 Mio IU/month, range 90-2160 Mio IU/month) over a median of 13.7 months (range from 2.7 to 73.8 months). Safety, tolerability, survival and change in ALSFRS-R were observed. Hematopoietic stem cells were monitored by flow cytometry analysis of circulating CD34[+] and CD34[+]CD38[-] cells, and peripheral cytokines were assessed by electrochemoluminescence throughout the intervention period. Analysis of immunological and hematological markers was conducted. Results: Long term and individually adapted treatment with G-CSF was well tolerated and safe. G-CSF led to a significant mobilization of hematopoietic stem cells into the peripheral blood. Higher mobilization capacity was associated with prolonged survival. Initial levels of serum cytokines, such as MDC, TNF-beta, IL-7, IL-16, and Tie-2 were significantly associated with survival. Continued application of G-CSF led to persistent alterations in serum cytokines and ongoing measurements revealed the multifaceted effects of G-CSF. Conclusions: G-CSF treatment is feasible and safe for ALS patients. It may exert its beneficial effects through neuroprotective and -regenerative activities, mobilization of hematopoietic stem cells and regulation of pro- and anti-inflammatory cytokines as well as angiogenic factors. These cytokines may serve as prognostic markers when measured at the time of diagnosis. Hematopoietic stem cell numbers and cytokine levels are altered by ongoing G-CSF application and may potentially serve as treatment biomarkers for early monitoring of G-CSF treatment efficacy in ALS in future clinical trials.}, }
@article {pmid30531015, year = {2019}, author = {Barczewska, M and Grudniak, M and Maksymowicz, S and Siwek, T and Ołdak, T and Jezierska-Woźniak, K and Gładysz, D and Maksymowicz, W}, title = {Safety of intrathecal injection of Wharton's jelly-derived mesenchymal stem cells in amyotrophic lateral sclerosis therapy.}, journal = {Neural regeneration research}, volume = {14}, number = {2}, pages = {313-318}, pmid = {30531015}, issn = {1673-5374}, abstract = {Animal experiments have confirmed that mesenchymal stem cells can inhibit motor neuron apoptosis and inflammatory factor expression and increase neurotrophic factor expression. Therefore, mesenchymal stem cells have been shown to exhibit prospects in the treatment of amyotrophic lateral sclerosis. However, the safety of their clinical application needs to be validated. To investigate the safety of intrathecal injection of Wharton's jelly-derived mesenchymal stem cells in amyotrophic lateral sclerosis therapy, 43 patients (16 females and 27 males, mean age of 57.3 years) received an average dose of 0.42 × 10[6] cells/kg through intrathecal administration at the cervical, thoracic or lumbar region depending on the clinical symptoms. There was a 2 month interval between two injections. The adverse events occurring during a 6-month treatment period were evaluated. No adverse events occurred. Headache occurred in one case only after first injection of stem cells. This suggests that intrathecal injection of Wharton's Jelly-derived mesenchymal stem cells is well tolerated in patients with amyotrophic lateral sclerosis. This study was approved by the Bioethical Committee of School of Medicine, University of Warmia and Mazury in Olsztyn, Poland (approval No. 36/2014 and approval No. 8/2016). This study was registered with the ClinicalTrials.gov (identifier: NCT02881476) on August 29, 2016.}, }
@article {pmid30531003, year = {2019}, author = {Matschke, V and Theiss, C and Matschke, J}, title = {Oxidative stress: the lowest common denominator of multiple diseases.}, journal = {Neural regeneration research}, volume = {14}, number = {2}, pages = {238-241}, pmid = {30531003}, issn = {1673-5374}, abstract = {Oxygen is essential to the human life and life of all aerobic organisms. The complete oxidation of nutrients for the biological energy supply is one of the most important prerequisites for the formation of higher life forms. However, cells that benefit from oxidative respiration also suffer from reactive oxygen species because they adapted to oxygen as an energy source. Healthy cells balance the formation and elimination of reactive oxygen species thereby creating and keeping reactive oxygen species-homeostasis. When the concentration of free radicals exceeds a critical level and homeostasis is disturbed, oxidative stress occurs leading to damage of multiple cellular molecules and compartments. Therefore, oxidative stress plays an important role in the physiology and pathology of various diseases. Often, the antioxidant protection system becomes pathologically unbalanced in the genesis of several diseases, leading to functional losses of the organism, as in the case of amyotrophic lateral sclerosis, or cells develop metabolic mechanisms to use this system as protection against external influences, such as in the case of glioblastoma cells. Either way, understanding the underlying deregulated mechanisms of the oxidative protection system would allow the development of novel treatment strategies for various diseases. Thus, regardless of the direction in which the reactive oxygen species-homeostasis disequilibrate, the focus should be on the oxidative protection system.}, }
@article {pmid30530996, year = {2019}, author = {Riancho, J and Gil-Bea, FJ and Santurtun, A and López de Munaín, A}, title = {Amyotrophic lateral sclerosis: a complex syndrome that needs an integrated research approach.}, journal = {Neural regeneration research}, volume = {14}, number = {2}, pages = {193-196}, pmid = {30530996}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis, the most common neurodegenerative disease affecting motor neurons, lacks an effective treatment. A small fraction of amyotrophic lateral sclerosis cases have a familial origin, related to mutations in causative genes, while the vast majority of amyotrophic lateral sclerosis cases are considered to be sporadic, resulting from the interaction between genes and environmental factors in predisposed individuals. During the past few years, dozens of drugs have been postulated as promising strategies for the disease after showing some beneficial effects in preclinical cellular and murine models. However, the translation into clinical practice has been largely unsuccessful and the compounds failed when were tested in clinical trials. This might be explained, at least partially, by the enormous complexity of the disease both from clinico-epidemiological and a pathogenic points of view. In this review, we will briefly comment on the complexity of the disease focusing on some recent findings, and we will suggest how amyotrophic lateral sclerosis research might be reoriented to foster the advance in the diagnostic and therapeutic questions.}, }
@article {pmid30528741, year = {2019}, author = {Günther, R and Neuwirth, C and Koch, JC and Lingor, P and Braun, N and Untucht, R and Petzold, D and Weber, M and Hermann, A}, title = {Motor Unit Number Index (MUNIX) of hand muscles is a disease biomarker for adult spinal muscular atrophy.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {130}, number = {2}, pages = {315-319}, doi = {10.1016/j.clinph.2018.11.009}, pmid = {30528741}, issn = {1872-8952}, mesh = {Adult ; Aged ; Female ; Hand/*innervation/*physiology ; Humans ; Male ; Middle Aged ; Muscle, Skeletal/*innervation/*physiology ; Muscular Atrophy, Spinal/diagnosis/*physiopathology ; Recruitment, Neurophysiological/*physiology ; Young Adult ; }, abstract = {OBJECTIVE: There is still insufficient knowledge about natural history in adult spinal muscular atrophy, thus valid markers for treatment and disease monitoring are urgently needed.<br><br>METHODS: We studied hand muscle innervation pattern of 38 adult genetically confirmed 5q spinal muscular atrophy (SMA) patients by the motor unit number index (MUNIX) method. Data were compared to healthy controls and amyotrophic lateral sclerosis (ALS) patients and systematically correlated to typical disease-relevant scores and other clinical as well as demographic characteristics.<br><br>RESULTS: Denervation of hand muscles in adult SMA was not evenly distributed. By calculation of the MUNIX ratios, we identified a specific hand muscle wasting pattern for SMA which is different to the split hand in ALS. Furthermore, MUNIX parameters strongly correlated with established disease course parameters independent of disease stages.<br><br>CONCLUSION: We found a pathophysiological remarkable denervation pattern of hand muscles, a 'reversed split hand'. MUNIX of single hand muscles correlated well with disease severity and thus represents an easily available biomarker for adult SMA.<br><br>SIGNIFICANCE: Our data show the power of the MUNIX method as a biomarker for upcoming questions in adult SMA.}, }
@article {pmid30528255, year = {2019}, author = {Sengupta-Ghosh, A and Dominguez, SL and Xie, L and Barck, KH and Jiang, Z and Earr, T and Imperio, J and Phu, L and Budayeva, HG and Kirkpatrick, DS and Cai, H and Eastham-Anderson, J and Ngu, H and Foreman, O and Hedehus, M and Reichelt, M and Hotzel, I and Shang, Y and Carano, RAD and Ayalon, G and Easton, A}, title = {Muscle specific kinase (MuSK) activation preserves neuromuscular junctions in the diaphragm but is not sufficient to provide a functional benefit in the SOD1[G93A] mouse model of ALS.}, journal = {Neurobiology of disease}, volume = {124}, number = {}, pages = {340-352}, doi = {10.1016/j.nbd.2018.12.002}, pmid = {30528255}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/pathology/*physiopathology ; Animals ; Diaphragm/pathology/*physiopathology ; Disease Models, Animal ; Enzyme Activation/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/pathology ; Neuromuscular Junction/pathology/*physiopathology ; Receptor Protein-Tyrosine Kinases/*agonists ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons, is characterized by rapid decline of motor function and ultimately respiratory failure. As motor neuron death occurs late in the disease, therapeutics that prevent the initial disassembly of the neuromuscular junction may offer optimal functional benefit and delay disease progression. To test this hypothesis, we treated the SOD1[G93A] mouse model of ALS with an agonist antibody to muscle specific kinase (MuSK), a receptor tyrosine kinase required for the formation and maintenance of the neuromuscular junction. Chronic MuSK antibody treatment fully preserved innervation of the neuromuscular junction when compared with control-treated mice; however, no preservation of diaphragm function, motor neurons, or survival benefit was detected. These data show that anatomical preservation of neuromuscular junctions in the diaphragm via MuSK activation does not correlate with functional benefit in SOD1[G93A] mice, suggesting caution in employing MuSK activation as a therapeutic strategy for ALS patients.}, }
@article {pmid30520038, year = {2019}, author = {Urbi, B and Owusu, MA and Hughes, I and Katz, M and Broadley, S and Sabet, A}, title = {Effects of cannabinoids in Amyotrophic Lateral Sclerosis (ALS) murine models: a systematic review and meta-analysis.}, journal = {Journal of neurochemistry}, volume = {149}, number = {2}, pages = {284-297}, doi = {10.1111/jnc.14639}, pmid = {30520038}, issn = {1471-4159}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Cannabinoids/*pharmacology ; Disease Models, Animal ; Mice ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that results from motor neuron damage. Cannabinoids have been proposed as treatments for ALS because of their anti-excitotoxicity, anti-oxidant and anti-inflammatory effects. Preclinical studies in mice models of ALS have been published using a range of cannabinoid formulations and doses. To date, there has been no rigorous evaluation of these trials to assess a potential cannabinoid treatment effect. This review and meta-analysis was undertaken to provide evidence for or against a treatment effect of cannabinoids in murine ALS models. Evidence of a treatment effect in mice may provide motivation for trials in human ALS. We identified a total of 10 studies; nine studies using cannabinoid treatment in transgenic SOD1-G93A ALS-model mice and one study in TDP-43 transgenic mice. Eight of the nine studies that used SOD1-G93A mice expressed similarly high copy numbers of the transgene while one study used a low-copy number line. Outcomes evaluated were survival time and disease progression. The latter was measured by motor function and bodyweight decline. Meta-analysis of the mean difference in survival time across the seven studies showed an increase in survival of 3.84 days (95% CI: 0.35-7.32 days; p = 0.031) for cannabinoid treated compared to control SOD1-G93A mice. It was not possible to conduct meta-analyses for motor function decline or weight loss. However, eight of nine studies reported significant improvements in measures of motor function decline and one reported non-significant improvements. Weight loss was significantly attenuated in four of five studies reporting this measure while the other study reported a non-significant attenuation. This review provides some evidence for the efficacy of cannabinoids in prolonging survival time in an ALS mouse model. A delay in disease progression is also suggested following cannabinoid treatment though it was not possible to consolidate the results from reviewed studies. However, studies have moderate to high risk of bias and are highly heterogeneous. Although this review provides some evidence to support the conduct of a cannabinoid trial in human ALS, more standardized studies on specific cannabinoids are necessary before supporting therapeutic potential of cannabinoids in treating patients with ALS. OPEN SCIENCE BADGES: This article has received a badge for *Preregistration* because the study was pre-registered at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=89274. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Read the Editorial Highlight for this article on page 168.}, }
@article {pmid30519240, year = {2018}, author = {Liu, Z and Li, H and Hong, C and Chen, M and Yue, T and Chen, C and Wang, Z and You, Q and Li, C and Weng, Q and Xie, H and Hu, R}, title = {ALS-Associated E478G Mutation in Human OPTN (Optineurin) Promotes Inflammation and Induces Neuronal Cell Death.}, journal = {Frontiers in immunology}, volume = {9}, number = {}, pages = {2647}, pmid = {30519240}, issn = {1664-3224}, mesh = {Amino Acid Substitution ; Amyotrophic Lateral Sclerosis/genetics/*immunology/pathology ; Animals ; Cell Cycle Proteins ; Cell Death/genetics/immunology ; Embryo, Mammalian ; Eye Proteins/genetics/immunology ; Fibroblasts/immunology/pathology ; Humans ; Membrane Transport Proteins ; Mice ; *Mutation, Missense ; Neurons/*immunology/pathology ; Transcription Factor TFIIIA/genetics/*immunology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a group of neurodegenerative disorders that featured with the death of motor neurons, which leads to loss of voluntary control on muscles. The etiologies vary among different subtypes of ALS, and no effective management or medication could be provided to the patients, with the underlying mechanisms incompletely understood yet. Mutations in human Optn (Optineurin), particularly E478G, have been found in many ALS patients. In this work, we report that NF-κB activity was increased in Optn knockout (Optn[-/-]) MEF (mouse embryonic fibroblast) cells expressing OPTN of different ALS-associated mutants especially E478G. Inflammation was significantly activated in mice infected with lenti-virus that allowed overexpression of OPTN[E478G] mutation in the motor cortex, with marked increase in the secretion of pro-inflammatory cytokines as well as neuronal cell death. Our work with both cell and animal models strongly suggested that anti-inflammation treatment could represent a powerful strategy to intervene into disease progression in ALS patients who possess the distinctive mutations in OPTN gene.}, }
@article {pmid30518612, year = {2018}, author = {Maier, M and Welt, T and Wirth, F and Montrasio, F and Preisig, D and McAfoose, J and Vieira, FG and Kulic, L and Späni, C and Stehle, T and Perrin, S and Weber, M and Hock, C and Nitsch, RM and Grimm, J}, title = {A human-derived antibody targets misfolded SOD1 and ameliorates motor symptoms in mouse models of amyotrophic lateral sclerosis.}, journal = {Science translational medicine}, volume = {10}, number = {470}, pages = {}, doi = {10.1126/scitranslmed.aah3924}, pmid = {30518612}, issn = {1946-6242}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology/*physiopathology ; Animals ; Antibodies/administration &amp; dosage/pharmacology/*therapeutic use ; Disease Models, Animal ; Disease Progression ; Humans ; Inflammation/pathology ; Injections, Intraperitoneal ; Injections, Intraventricular ; Mice, Transgenic ; *Motor Activity/drug effects ; Protein Folding/*drug effects ; Recombinant Proteins/pharmacology/therapeutic use ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase-1/*chemistry/*metabolism ; Survival Analysis ; }, abstract = {Mutations in the gene encoding superoxide dismutase 1 (SOD1) lead to misfolding and aggregation of SOD1 and cause familial amyotrophic lateral sclerosis (FALS). However, the implications of wild-type SOD1 misfolding in sporadic forms of ALS (SALS) remain unclear. By screening human memory B cells from a large cohort of healthy elderly subjects, we generated a recombinant human monoclonal antibody (α-miSOD1) that selectively bound to misfolded SOD1, but not to physiological SOD1 dimers. On postmortem spinal cord sections from 121 patients with ALS, α-miSOD1 antibody identified misfolded SOD1 in a majority of cases, regardless of their SOD1 genotype. In contrast, the α-miSOD1 antibody did not bind to its epitope in most of the 41 postmortem spinal cord sections from non-neurological control (NNC) patients. In transgenic mice overexpressing disease-causing human SOD1[G37R] or SOD1[G93A] mutations, treatment with the α-miSOD1 antibody delayed the onset of motor symptoms, extended survival by up to 2 months, and reduced aggregation of misfolded SOD1 and motor neuron degeneration. These effects were obtained whether α-miSOD1 antibody treatment was administered by direct brain infusion or peripheral administration. These results support the further development of α-miSOD1 antibody as a candidate treatment for ALS involving misfolding of SOD1.}, }
@article {pmid30508770, year = {2019}, author = {Gao, N and Huang, YP and Chu, TT and Li, QQ and Zhou, B and Chen, YX and Zhao, YF and Li, YM}, title = {TDP-43 specific reduction induced by Di-hydrophobic tags conjugated peptides.}, journal = {Bioorganic chemistry}, volume = {84}, number = {}, pages = {254-259}, doi = {10.1016/j.bioorg.2018.11.042}, pmid = {30508770}, issn = {1090-2120}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Cell Line, Tumor ; Cell Survival/drug effects ; DNA-Binding Proteins/chemistry/*metabolism ; Drosophila melanogaster/metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Mice ; Peptides/*chemistry/metabolism/pharmacology ; }, abstract = {TAR DNA binding protein 43 (TDP-43) is a key target in amyotrophic lateral sclerosis (ALS) treatment. Here, based on hydrophobic tagging strategy, we designed and synthesized a series of single or double hydrophobic tags conjugated peptides D1-D8. Among them, it was found that D4 displayed strongest ability to induce TDP-43 degradation in cells. D4 could reduce TDP-43 induced cytotoxicity. Besides, D4 could reduce TDP-43 levels in a transgenic drosophila model.}, }
@article {pmid30507302, year = {2019}, author = {Jones, RM and Hynynen, K}, title = {Advances in acoustic monitoring and control of focused ultrasound-mediated increases in blood-brain barrier permeability.}, journal = {The British journal of radiology}, volume = {92}, number = {1096}, pages = {20180601}, pmid = {30507302}, issn = {1748-880X}, support = {R01 EB003268/EB/NIBIB NIH HHS/United States ; }, mesh = {Blood-Brain Barrier/*metabolism ; Humans ; *Microbubbles ; Monitoring, Physiologic/*methods ; Permeability ; *Ultrasonic Waves ; }, abstract = {Transcranial focused ultrasound (FUS) combined with intravenously circulating microbubbles can transiently and selectively increase blood-brain barrier permeability to enable targeted drug delivery to the central nervous system, and is a technique that has the potential to revolutionize the way neurological diseases are managed in medical practice. Clinical testing of this approach is currently underway in patients with brain tumors, early Alzheimer's disease, and amyotrophic lateral sclerosis. A major challenge that needs to be addressed in order for widespread clinical adoption of FUS-mediated blood-brain barrier permeabilization to occur is the development of systems and methods for real-time treatment monitoring and control, to ensure that safe and effective acoustic exposure levels are maintained throughout the procedures. This review gives a basic overview of the oscillation dynamics, acoustic emissions, and biological effects associated with ultrasound-stimulated microbubbles in vivo, and provides a summary of recent advances in acoustic-based strategies for detecting, controlling, and mapping microbubble activity in the brain. Further development of next-generation clinical FUS brain devices tailored towards microbubble-mediated applications is warranted and required for translation of this potentially disruptive technology into routine clinical practice.}, }
@article {pmid30506635, year = {2019}, author = {Liu, LM and Wang, N and Lu, Y and Wang, WP}, title = {Edaravone acts as a potential therapeutic drug against pentylenetetrazole-induced epilepsy in male albino rats by downregulating cyclooxygenase-II.}, journal = {Brain and behavior}, volume = {9}, number = {1}, pages = {e01156}, pmid = {30506635}, issn = {2162-3279}, mesh = {Animals ; Antioxidants/pharmacology ; Brain/drug effects/metabolism ; Convulsants/pharmacology ; *Cyclooxygenase 2/genetics/metabolism ; Disease Models, Animal ; Down-Regulation ; Edaravone/*pharmacology ; *Epilepsy/drug therapy/etiology ; Gene Expression Profiling ; Male ; Neuroprotective Agents/pharmacology ; Nitric Oxide/metabolism ; Pentylenetetrazole/pharmacology ; Rats ; Rats, Wistar ; Treatment Outcome ; }, abstract = {INTRODUCTION: The effects of edaravone against pentylenetetrazole (PTZ)-induced epilepsy in male albino rats were investigated. Edaravone is a well-known commercial drug used in the treatment of strokes and amyotrophic lateral sclerosis (ALS). Antioxidant and free radical scavenging activities of edaravone have been reported in patients with ALS.<br><br>METHODS: In this study, the experimental groups were as follows: sham, control, 5&#xa0;mg/kg edaravone, and 10&#xa0;mg/kg edaravone. Behavioral assessment, determination of biochemical markers, apoptosis, nitric oxide (NO), and mRNA and protein expression of cyclooxygenase-II (COX-II) were carried out. Seizure incidence, including generalized tonic-clonic seizure (GTCS) and minimal clonic seizure (MCS), was directly associated with PTZ administration in rats.<br><br>RESULTS: Edaravone supplementation substantially increased MCS and GTCS latency in rats, and biochemical markers were significantly altered in the brain tissue of PTZ-treated rats. Edaravone treatment normalized altered biochemical markers compared with the untreated control. Apoptosis and NO levels were significantly reduced by more than 50% compared to their respective controls. COX-II mRNA was increased by 130% in PTZ-treated rats, while edaravone supplementation reduced mRNA and protein expression of COX-II by more than 20% and 40%, respectively. Immunohistochemistry indicated that COX-II protein expression was reduced by 13.2% and 33.7% following supplementation with 5 and 10&#xa0;mg/kg edaravone, respectively.<br><br>CONCLUSION: Taken together, our results suggest that edaravone functions by downregulating the levels of COX-II and NO and is a potential candidate for the treatment of PTZ-induced epilepsy.}, }
@article {pmid30503815, year = {2019}, author = {Laudati, G and Mascolo, L and Guida, N and Sirabella, R and Pizzorusso, V and Bruzzaniti, S and Serani, A and Di Renzo, G and Canzoniero, LMT and Formisano, L}, title = {Resveratrol treatment reduces the vulnerability of SH-SY5Y cells and cortical neurons overexpressing SOD1-G93A to Thimerosal toxicity through SIRT1/DREAM/PDYN pathway.}, journal = {Neurotoxicology}, volume = {71}, number = {}, pages = {6-15}, doi = {10.1016/j.neuro.2018.11.009}, pmid = {30503815}, issn = {1872-9711}, mesh = {Animals ; Cell Death/drug effects ; Cell Line, Tumor ; Cerebral Cortex/*drug effects/*metabolism ; Enkephalins/metabolism ; Humans ; Kv Channel-Interacting Proteins/metabolism ; Neurons/*drug effects/*metabolism ; Protein Precursors/metabolism ; Rats, Wistar ; Repressor Proteins/metabolism ; Resveratrol/*administration &amp; dosage ; *Signal Transduction ; Sirtuin 1/metabolism ; Superoxide Dismutase/*metabolism ; Superoxide Dismutase-1/metabolism ; Thimerosal/*toxicity ; }, abstract = {In humans, mutation of glycine 93 to alanine of Cu[++]/Zn[++] superoxide dismutase type-1 (SOD1-G93 A) has been associated to some familial cases of Amyotrophic Lateral Sclerosis (ALS). Several evidence proposed the involvement of environmental pollutants that like mercury could accelerate ALS symptoms. SH-SY5Y cells stably transfected with SOD1 and G93 A mutant of SOD1 constructs were exposed to non-toxic concentrations (0.01 μM) of ethylmercury thiosalicylate (thimerosal) for 24 h. Interestingly, we found that thimerosal, in SOD1-G93 A cells, but not in SOD1 cells, reduced cell survival. Furthermore, thimerosal-induced cell death occurred in a concentration dependent-manner and was prevented by the Sirtuin 1 (SIRT1) activator Resveratrol (RSV). Moreover, thimerosal decreased the protein expression of transcription factor Downstream Regulatory Element Antagonist Modulator (DREAM), but not DREAM gene. Interestingly, DREAM reduction was blocked by co-treatment with RSV, suggesting the participation of SIRT1 in determining this effect. Immunoprecipitation experiments in SOD1-G93 A cells exposed to thimerosal demonstrated that RSV increased DREAM deacetylation and reduced its polyubiquitination. In addition, RSV counteracted thimerosal-enhanced prodynorphin (PDYN) mRNA, a DREAM target gene. Furthermore, cortical neurons transiently transfected with SOD1-G93 A construct and exposed to thimerosal (0.5 μM/24 h) showed a reduction of DREAM and an up-regulation of the prodynorphin gene. Importantly, both the treatment with RSV or the transfection of siRNA against prodynorphin significantly reduced thimerosal-induced neurotoxicity, while DREAM knocking-down potentiated thimerosal-reduced cell survival. These results demonstrate the particular vulnerability of SOD1-G93 A neuronal cells to thimerosal and that RSV via SIRT1 counteracts the neurodetrimental effect of this toxicant by preventing DREAM reduction and prodynorphin up-regulation.}, }
@article {pmid30503152, year = {2019}, author = {Riera-Punet, N and Martinez-Gomis, J and Zamora-Olave, C and Willaert, E and Peraire, M}, title = {Satisfaction of patients with amyotrophic lateral sclerosis with an oral appliance for managing oral self-biting injuries and alterations in their masticatory system: A case-series study.}, journal = {The Journal of prosthetic dentistry}, volume = {121}, number = {4}, pages = {631-636}, doi = {10.1016/j.prosdent.2018.06.010}, pmid = {30503152}, issn = {1097-6841}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Personal Satisfaction ; Stomatognathic System ; *Temporomandibular Joint Disorders ; Tongue ; }, abstract = {STATEMENT OF PROBLEM: About 10% of patients with amyotrophic lateral sclerosis (ALS) are candidates for oral treatment specifically because of traumatic injuries in the lips, cheeks, or tongue due to self-biting. However, patients with ALS have a prevalence of temporomandibular disorder (TMD) similar to that in the general population.<br><br>PURPOSE: The purpose of this case-series study was to determine the degree of satisfaction of patients with ALS with an oral appliance for managing oral self-biting lesions or symptoms related to TMDs. This study also assessed the degree of improvement of the chief complaint and the compliance with and adverse effects of this treatment.<br><br>MATERIAL AND METHODS: Eleven patients with ALS who sought oral treatment because of oral self-biting or TMD-related symptoms were included. A custom complete-coverage acrylic resin device was fabricated and fitted to each participant. A follow-up visit was planned for 3 months after the placement of the oral appliance, at which point the patients would rate the degree of improvement or worsening of the chief complaint and their degree of satisfaction with the treatment. A 1-sample t test was used to assess whether the degree of improvement of the chief complaint was significant.<br><br>RESULTS: Participants reported a mean of 61% (95% confidence interval [CI] 38% to 84%) improvement of the chief complaint and a mean of 84% (95% CI 72% to 97%) satisfaction with the treatment. The mean rate of compliance was 62% (95% CI 40% to 84%) of the recommended time, and only a few adverse effects were reported.<br><br>CONCLUSIONS: Participants with ALS were highly satisfied with the use of an oral appliance to manage oral self-biting or TMD-related symptoms. Adherence to this treatment was high, and no major adverse effects were observed.}, }
@article {pmid30515715, year = {2019}, author = {French, PW and Ludowyke, R and Guillemin, GJ}, title = {Fungal Neurotoxins and Sporadic Amyotrophic Lateral Sclerosis.}, journal = {Neurotoxicity research}, volume = {35}, number = {4}, pages = {969-980}, pmid = {30515715}, issn = {1476-3524}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*metabolism/*microbiology ; Animals ; Brain/metabolism/*microbiology ; DNA-Binding Proteins/metabolism ; Glutamic Acid/metabolism ; Humans ; Motor Neurons/drug effects/metabolism ; Mycoses/*complications ; Mycotoxins/*metabolism ; Neurotoxins/*metabolism ; Superoxide Dismutase-1/metabolism ; }, abstract = {We review several lines of evidence that point to a potential fungal origin of sporadic amyotrophic lateral sclerosis (ALS). ALS is the most common form of motor neuron disease (MND) in adults. It is a progressive and fatal disease. Approximately 90% cases of ALS are sporadic, and 5-10% are due to genetic mutations (familial). About 25 genes implicated in familial ALS have been identified so far, including SOD1 and TARDBP, the gene encoding 43 kDa transactive response (TAR) DNA-binding protein (TDP-43). Despite intensive research over many decades, the aetiology of sporadic ALS is still unknown. An environmental cause, including grass or soil-associated fungal infections, is suggested from a range of widely diverse lines of evidence. Clusters of ALS have been reported in soccer players, natives of Guam and farmers. Grass-associated fungi are known to produce a range of neurotoxins and, in symbiotic associations, high levels of fungal SOD1. Exposure of neurons to fungal neurotoxins elicits a significant increase in glutamate production. High levels of glutamate stimulate TDP-43 translocation and modification, providing a link between fungal infection and one of the molecular and histologic hallmarks of sporadic ALS. A recent study provided evidence of a variety of fungi in the cerebrospinal fluid and brain tissue of ALS patients. This review provides a rational explanation for this observation. If a fungal infection could be confirmed as a potential cause of ALS, this could provide a straightforward treatment strategy for this fatal and incurable disease.}, }
@article {pmid30509290, year = {2018}, author = {Jawaid, A and Khan, R and Polymenidou, M and Schulz, PE}, title = {Disease-modifying effects of metabolic perturbations in ALS/FTLD.}, journal = {Molecular neurodegeneration}, volume = {13}, number = {1}, pages = {63}, pmid = {30509290}, issn = {1750-1326}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Diabetes Mellitus, Type 2/*genetics/metabolism ; Frontotemporal Dementia/*genetics/metabolism ; Frontotemporal Lobar Degeneration/*genetics ; Humans ; Inclusion Bodies/metabolism ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two fatal neurodegenerative disorders with considerable clinical, pathological and genetic overlap. Both disorders are characterized by the accumulation of pathological protein aggregates that contain a number of proteins, most notably TAR DNA binding protein 43 kDa (TDP-43). Surprisingly, recent clinical studies suggest that dyslipidemia, high body mass index, and type 2 diabetes mellitus are associated with better clinical outcomes in ALS. Moreover, ALS and FTLD patients have a significantly lower incidence of cardiovascular disease, supporting the idea that an unfavorable metabolic profile may be beneficial in ALS and FTLD. The two most widely studied ALS/FTLD models, super-oxide dismutase 1 (SOD1) and TAR DNA binding protein of 43 kDA (TDP-43), reveal metabolic dysfunction and a positive effect of metabolic strategies on disease onset and/or progression. In addition, molecular studies reveal a role for ALS/FTLD-associated proteins in the regulation of cellular and whole-body metabolism. Here, we systematically evaluate these observations and discuss how changes in cellular glucose/lipid metabolism may result in abnormal protein aggregations in ALS and FTLD, which may have important implications for new treatment strategies for ALS/FTLD and possibly other neurodegenerative conditions.}, }
@article {pmid30498914, year = {2019}, author = {Vogrig, A and Joubert, B and Maureille, A and Thomas, L and Bernard, E and Streichenberger, N and Cotton, F and Ducray, F and Honnorat, J}, title = {Motor neuron involvement in anti-Ma2-associated paraneoplastic neurological syndrome.}, journal = {Journal of neurology}, volume = {266}, number = {2}, pages = {398-410}, pmid = {30498914}, issn = {1432-1459}, support = {ANR-14-CE15-0001-MECANO//Agence Nationale de la Recherche/ ; DQ20170336751//Fondation pour la recherche m&#xe9;dicale/ ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Antigens, Neoplasm/*immunology ; Autoantibodies/blood/cerebrospinal fluid ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; *Motor Neuron Disease/immunology/pathology/physiopathology ; Nerve Tissue Proteins/*immunology ; *Paraneoplastic Syndromes, Nervous System/immunology/pathology/physiopathology ; *Radiculopathy/immunology/pathology/physiopathology ; Retrospective Studies ; *Spinal Cord Diseases/immunology/pathology/physiopathology ; }, abstract = {OBJECTIVE: To present clinical, radiological, and pathological features of a cohort of patients with motor neuron involvement in association with anti-Ma2 antibodies (Ma2-Ab).<br><br>METHODS: Retrospective case-series of patients with definite paraneoplastic neurological syndrome (PNS) and Ma2-Ab, and cases identified from a review of the literature.<br><br>RESULTS: Among 33 Ma2-Ab patients referred between 2002 and 2016, we retrospectively identified three patients (9.1%) with a motor neuron syndrome (MNS). Seven additional cases were retrieved among the 75 Ma2-patients reported in the literature (9.3%). A total of ten patients are, therefore, described herein. MNS was evident as combined upper and lower MNS in four patients, isolated upper MNS in two, and isolated lower MNS in one; three patients were diagnosed with myeloradiculopathy. The most common MNS signs/symptoms were: hyperreflexia (80%), proximal weakness (60%), proximal upper-limb fasciculations (50%), head drop (40%), and dysarthria/dysphagia (30%). Brain MRI abnormalities included bilateral pyramidal tract T2-weighted/FLAIR hyperintensities (three patients). Spine MRI found bilateral, symmetric, T2-weighted signal abnormalities in the anterior horn in two patients. CSF examination was abnormal in nine patients. Cancer was found in seven patients (four testicular, two lung, and one mesothelioma). Eight patients underwent first-line immunotherapy. Second-line immunotherapy was adopted in all our patients and in none of those identified in the literature. Motor improvement was observed in 33% of our patients, and 20% in the literature series.<br><br>CONCLUSIONS: Motor neuron involvement could complicate Ma2-Ab-associated PNS in almost 10% of patients and must be carefully studied to adapt treatment. This disorder differs from amyotrophic lateral sclerosis.}, }
@article {pmid30487362, year = {2018}, author = {Mitsumoto, H and Saito, T}, title = {[A prognostic biomarker in amyotrophic lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {58}, number = {12}, pages = {729-736}, doi = {10.5692/clinicalneurol.cn-001220}, pmid = {30487362}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/diagnostic imaging/*drug therapy ; Biomarkers/blood/cerebrospinal fluid/urine ; Brain/*diagnostic imaging ; Creatinine/*blood ; Disease Progression ; Electric Impedance ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Myography ; Neurofilament Proteins/*blood/cerebrospinal fluid ; *Neuroimaging ; Positron-Emission Tomography ; Prognosis ; Transcranial Magnetic Stimulation ; Uric Acid/*blood ; }, abstract = {Although we currently have two, approved, disease-modifying drugs for the treatment of amyotrophic lateral sclerosis (ALS), we are in disperate need for more efficacious treatment. To aggressively test for newer therapies, we must develop reliable objective biomarkers to supplement clinical outcome measures. Many biomarker candidates have been actively and vigorously investigated. Among neurophysiological biomarkers, transcranial magnetic stimulation (TMS)-based biomarkers show potential in exploring disease mechanisms. Neuroimaging biomarkers have high specificity in diagnosing ALS but are an expensive endeavor and are not sensitive enough to detect changes over time of the disease. Among fluid-based biochemical biomarkers, creatinine (Crn) and uric acids (UA), which have been known for decades, may prove to be highly promising biomarkers that can predict disease progression. They can be easily tested in any clinical trials because the costs are minimal. Although known for some time, neurofilaments (NF), either phosphorylated-NF heavy subunit (pNFH) or NF light subunit (NFL), have emerged as "new" biomarkers using specific antibodies. They appear to be highly specific and sensitive in diagnosing ALS, yet they may be insensitive to assess changes in disease over time. These two NF biomarkers along with Crn and UA should be explored extensively in future clinical trials and any other clinical studies in ALS. Yet, we still need newer, more innovative, and reliable biomarkers for future ALS research. Fortunatley, aggressive investigations appear to be currently underway.}, }
@article {pmid30483992, year = {2019}, author = {Luo, L and Song, Z and Li, X and Huiwang,  and Zeng, Y and Qinwang,  and Meiqi,  and He, J}, title = {Efficacy and safety of edaravone in treatment of amyotrophic lateral sclerosis-a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {40}, number = {2}, pages = {235-241}, pmid = {30483992}, issn = {1590-3478}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Edaravone/*adverse effects/*therapeutic use ; Humans ; Neuroprotective Agents/*adverse effects/*therapeutic use ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Based on the results of randomized, double-blind, placebo-controlled trials, the benefit and safety of edaravone in the treatment of amyotrophic lateral sclerosis remain controversial. We performed a meta-analysis to evaluate the efficacy and safety of edaravone in the treatment of this disease.<br><br>METHODS: We searched PubMed, the Cochrane Library, and Embase from the inception of electronic data to April 2018. We included randomized, double-blind, placebo-controlled trials reporting amyotrophic lateral sclerosis patients receiving 60-mg intravenous edaravone or intravenous saline placebo for 24&#xa0;weeks. The primary efficacy evaluation was changed in Amyotrophic Lateral Sclerosis Functional Rating Scale score from baseline to after the trial. Measure of safety was the frequency of investigated adverse events and serious adverse events. Data synthesis and analysis and evaluation of risk of bias were performed using RevMan 5.3 software. Heterogeneity among studies was evaluated with the I[2] statistic.<br><br>RESULTS: A total of 367 patients were analyzed across three randomized controlled trials (183 patients receiving intravenous edaravone; 184 receiving placebo). A difference in ALSFRS-R score between groups at 24&#xa0;weeks was found (mean difference [MD]&#x2009;=&#x2009;1.63, 95% confidence interval [CI] 0.26-3.00, P&#x2009;=&#x2009;.02). No differences in the frequency of adverse events (odds ratio [OR]&#x2009;=&#x2009;1.22, 95% CI 0.68-2.19, P&#x2009;=&#x2009;.50) or serious adverse events (OR&#x2009;=&#x2009;0.71, 95% CI 0.43-1.19, P&#x2009;=&#x2009;.20) were found.<br><br>CONCLUSION: Intravenous edaravone is efficacious in amyotrophic lateral sclerosis patients, with no severe adverse effects. Additional reliable randomized controlled trials with larger sample sizes will further assess the efficacy and safety of edaravone in amyotrophic lateral sclerosis.<br><br>CLINICAL TRIAL REGISTRATION: The systematic review and meta-analysis was registered in the international prospective register of systematic reviews. (PROSPERO registration number: CRD42018096191; http://www.crd.york.ac.uk/PROSPERO .).}, }
@article {pmid30479062, year = {2019}, author = {Yun, YC and Jeong, SG and Kim, SH and Cho, GW}, title = {Reduced sirtuin 1/adenosine monophosphate-activated protein kinase in amyotrophic lateral sclerosis patient-derived mesenchymal stem cells can be restored by resveratrol.}, journal = {Journal of tissue engineering and regenerative medicine}, volume = {13}, number = {1}, pages = {110-115}, doi = {10.1002/term.2776}, pmid = {30479062}, issn = {1932-7005}, support = {2018//Chosun University/International ; }, mesh = {AMP-Activated Protein Kinases/*metabolism ; Amyotrophic Lateral Sclerosis/*enzymology/pathology ; Cell Differentiation/*drug effects ; Dendrites/enzymology ; Female ; Humans ; Male ; Mesenchymal Stem Cells/*enzymology/pathology ; Resveratrol/*pharmacology ; Sirtuin 1/*biosynthesis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neuron system. Our previous study has shown that bone marrow-mesenchymal stem cells (BM-MSCs) from ALS patients have functional limitations in releasing neurotrophic factors and exhibit the senescence phenotype. In this study, we examined sirtuin 1/adenosine monophosphate-activated protein kinase (SIRT1/AMPK) activities and identified significant decreases in the ALS-MSCs compared with normal healthy control originated BM-MSCs. This decline was restored by pretreatment with resveratrol (RSV), measured using quantitative polymerase chain reaction, NAD/NADH assay, and immunoblot analysis. Neuroprogenitor markers were increased in RSV-treated ALS-MSCs (RSV/ALS-MSCs). The differentiated ALS-MSCs (ALS-dMSCs) exhibited a cell body and dendritic shape similar to neurons. RSV/ALS-MSCs showed significantly increased differentiation rate as compared with the untreated ALS-dMSCs. The neurite numbers and lengths were also significantly increased. This was confirmed with immunoblot analysis using neuron specific markers such as nestin, NF-M, Tuj-1, and Map-2 in RSV/ALS-dMSCs. Thus, this study shows that ALS-MSCs showed down-regulation of AMPK/SIRT1 signalling, which was recovered by treatment with RSV. This data suggest that RSV can be one of the candidate agents for improving therapeutic efficacy of ALS patients' originated MSCs.}, }
@article {pmid30476904, year = {2018}, author = {Cai, HY and Tian, KW and Zhang, YY and Jiang, H and Han, S}, title = {Angiopoietin-1 and ανβ3 integrin peptide promote the therapeutic effects of L-serine in an amyotrophic lateral sclerosis/Parkinsonism dementia complex model.}, journal = {Aging}, volume = {10}, number = {11}, pages = {3507-3527}, pmid = {30476904}, issn = {1945-4589}, mesh = {Amino Acids, Diamino/toxicity ; Amyotrophic Lateral Sclerosis/*chemically induced/*drug therapy ; Angiopoietin-1/*pharmacology ; Animals ; Cyanobacteria Toxins ; Gene Expression Regulation ; Integrin alpha Chains/*therapeutic use ; Male ; Parkinsonian Disorders/*chemically induced/*drug therapy ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult disorder of neurodegeneration that manifests as the destruction of upper and lower motor neurons. Beta-N-methylamino-L-alanine (L-BMAA), an amino acid not present in proteins, was found to cause intraneuronal protein misfolding and to induce ALS/Parkinsonism dementia complex (PDC), which presents symptoms analogous to those of Alzheimer's-like dementia and Parkinsonism. L-serine suppresses the erroneous incorporation of L-BMAA into proteins in the human nervous system. In this study, angiopoietin-1, an endothelial growth factor crucial for vascular development and angiogenesis, and the integrin αvβ3 binding peptide C16, which inhibits inflammatory cell infiltration, were utilized to improve the local microenvironment within the central nervous system of an ALS/PDC rodent model by minimizing inflammation. Our results revealed that L-serine application yielded better effects than C16+ angiopoietin-1 treatment alone for alleviating apoptotic and autophagic changes and improving cognition and electrophysiological dysfunction, but not for improving the inflammatory micro-environment in the central nerve system, while further advances in attenuating the functional disability and pathological impairment induced by L-BMAA could be achieved by co-treatment with C16 and angiopoietin-1 in addition to L-serine. Therefore, C16+ angiopoietin-1 could be beneficial as a supplement to promote the effects of L-serine treatment.}, }
@article {pmid30463642, year = {2018}, author = {Kim, SH and Oh, KW and Jin, HK and Bae, JS}, title = {Immune inflammatory modulation as a potential therapeutic strategy of stem cell therapy for ALS and neurodegenerative diseases.}, journal = {BMB reports}, volume = {51}, number = {11}, pages = {545-546}, doi = {10.5483/BMBRep.2018.51.11.255}, pmid = {30463642}, issn = {1976-670X}, mesh = {Amyotrophic Lateral Sclerosis/immunology/pathology/*therapy ; Cell Death/immunology ; Humans ; *Immunomodulation ; Inflammation/*immunology ; *Mesenchymal Stem Cell Transplantation/methods ; Mesenchymal Stem Cells/*physiology ; Motor Neurons/pathology/physiology ; Neurodegenerative Diseases/immunology/pathology/*therapy ; T-Lymphocytes, Regulatory/physiology/transplantation ; Th2 Cells/physiology/transplantation ; }, abstract = {With emerging evidence on the importance of non-cell autonomous toxicity in neurodegenerative diseases, therapeutic strategies targeting modulation of key immune cells. including microglia and Treg cells, have been designed for treatment of ALS and other neurodegenerative diseases. Strategy switching the patient's environment from a pro-inflammatory toxic to an anti-inflammatory, and neuroprotective condition, could be potential therapy for neurodegenerative diseases. Mesenchymal stem cells (MSCs) regulate innate and adaptive immune cells, through release of soluble factors such as TGF-β and elevation of regulatory T cells (Tregs) and T helper-2 cells (Th2 cells), would play important roles, in the neuroprotective effect on motor neuronal cell death mechanisms in ALS. Single cycle of repeated intrathecal injections of BM-MSCs demonstrated a clinical benefit lasting at least 6 months, with safety, in ALS patients. Cytokine profiles of CSF provided evidence that BM-MSCs, have a role in switching from pro-inflammatory to anti-inflammatory conditions. Inverse correlation of TGF-β1 and MCP-1 levels, could be a potential biomarker to responsiveness. Thus, additional cycles of BM-MSC treatment are required, to confirm long-term efficacy and safety. [BMB Reports 2018; 51(11): 545-546].}, }
@article {pmid30462490, year = {2019}, author = {Farrawell, NE and Yerbury, MR and Plotkin, SS and McAlary, L and Yerbury, JJ}, title = {CuATSM Protects Against the In Vitro Cytotoxicity of Wild-Type-Like Copper-Zinc Superoxide Dismutase Mutants but not Mutants That Disrupt Metal Binding.}, journal = {ACS chemical neuroscience}, volume = {10}, number = {3}, pages = {1555-1564}, doi = {10.1021/acschemneuro.8b00527}, pmid = {30462490}, issn = {1948-7193}, support = {2682/CAPMC/CIHR/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Animals ; Chelating Agents/pharmacology ; Copper/*metabolism ; Humans ; Mice ; Mutation/*genetics ; Neurons/drug effects/metabolism ; Protective Agents/pharmacology ; Superoxide Dismutase/*genetics/metabolism ; Zinc/*metabolism ; }, abstract = {Mutations in the SOD1 gene are associated with some forms of familial amyotrophic lateral sclerosis (fALS). There are more than 150 different mutations in the SOD1 gene that have various effects on the copper-zinc superoxide dismutase (SOD1) enzyme structure, including the loss of metal binding and a decrease in dimer affinity. The copper-based therapeutic CuATSM has been proven to be effective at rescuing neuronal cells from SOD1 mutant toxicity and has also increased the life expectancy of mice expressing the human transgenes SOD1[G93A] and SOD1[G37R]. Furthermore, CuATSM is currently the subject of a phase I/II clinical trial in Australia as a treatment for ALS. To determine if CuATSM protects against a broad variety of SOD1 mutations, we used a well-established cell culture model of SOD1-fALS. NSC-34 cells expressing SOD1-EGFP constructs were treated with CuATSM and examined by time-lapse microscopy. Our results show a concentration-dependent protection of cells expressing mutant SOD1[A4V] over the experimental time period. We tested the efficacy of CuATSM on 10 SOD1-fALS mutants and found that while protection was observed in cells expressing pathogenic wild-type-like mutants, cells expressing a truncation mutant or metal binding region mutants were not. We also show that CuATSM rescue is associated with an increase in human SOD1 activity and a decrease in the level of SOD1 aggregation in vitro. In conclusion, CuATSM has shown to be a promising therapeutic for SOD1-associated ALS; however, our in vitro results suggest that the protection afforded varies depending on the SOD1 variant, including negligible protection to mutants with deficient copper binding.}, }
@article {pmid30458231, year = {2019}, author = {Spiller, KJ and Khan, T and Dominique, MA and Restrepo, CR and Cotton-Samuel, D and Levitan, M and Jafar-Nejad, P and Zhang, B and Soriano, A and Rigo, F and Trojanowski, JQ and Lee, VM}, title = {Reduction of matrix metalloproteinase 9 (MMP-9) protects motor neurons from TDP-43-triggered death in rNLS8 mice.}, journal = {Neurobiology of disease}, volume = {124}, number = {}, pages = {133-140}, pmid = {30458231}, issn = {1095-953X}, support = {P01 AG017586/AG/NIA NIH HHS/United States ; R01 NS110688/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology/physiopathology ; Animals ; DNA-Binding Proteins/genetics/*metabolism ; Disease Models, Animal ; Female ; Gene Knockdown Techniques ; Male ; Matrix Metalloproteinase 9/genetics/*metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/*metabolism/*pathology ; Muscle, Skeletal/innervation/physiopathology ; }, abstract = {Therapeutic strategies are needed for the treatment of amyotrophic lateral sclerosis (ALS). One potential target is matrix metalloproteinase-9 (MMP-9), which is expressed only by fast motor neurons (MNs) that are selectively vulnerable to various ALS-relevant triggers. Previous studies have shown that reduction of MMP-9 function delayed motor dysfunction in a mouse model of familial ALS. However, given that the majority of ALS cases are sporadic, we propose preclinical testing in a mouse model which may be more clinically translatable: rNLS8 mice. In rNLS8 mice, neurodegeneration is triggered by the major pathological hallmark of ALS, TDP-43 mislocalization and aggregation. MMP-9 was targeted in 3 different ways in rNLS8 mice: by AAV9-mediated knockdown, using antisense oligonucleotide (ASO) technology, and by genetic modification. All 3 strategies preserved the motor unit during disease, as measured by MN counts, tibialis anterior (TA) muscle innervation, and physiological recordings from muscle. However, the strategies that reduced MMP-9 beyond the motor unit lead to premature deaths in a subset of rNLS8 mice. Therefore, selective targeting of MMP-9 in MNs could be beneficial in ALS, but side effects outside of the motor circuit may limit the most commonly used clinical targeting strategies.}, }
@article {pmid30458059, year = {2019}, author = {Paganoni, S and Alshikho, MJ and Luppino, S and Chan, J and Pothier, L and Schoenfeld, D and Andres, PL and Babu, S and Zürcher, NR and Loggia, ML and Barry, RL and Luotti, S and Nardo, G and Trolese, MC and Pantalone, S and Bendotti, C and Bonetto, V and De Marchi, F and Rosen, B and Hooker, J and Cudkowicz, M and Atassi, N}, title = {A pilot trial of RNS60 in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {59}, number = {3}, pages = {303-308}, pmid = {30458059}, issn = {1097-4598}, support = {K23 NS083715/NS/NINDS NIH HHS/United States ; S10 OD023517/OD/NIH HHS/United States ; S10 RR026666/RR/NCRR NIH HHS/United States ; //MGH ALS Therapy Fund/International ; }, mesh = {Administration, Inhalation ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnostic imaging/*drug therapy/physiopathology ; Anti-Inflammatory Agents, Non-Steroidal/administration &amp; dosage/*therapeutic use ; Biomarkers/analysis ; Brain/diagnostic imaging ; Female ; Healthy Volunteers ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Muscle Strength ; Neuroimaging ; Pilot Projects ; Positron-Emission Tomography ; Sodium Chloride/adverse effects/therapeutic use ; Treatment Outcome ; Young Adult ; }, abstract = {INTRODUCTION: RNS60 is a novel immune-modulatory agent that has shown neuroprotective effects in amytrophic lateral sclerosis (ALS) preclinical models. RNS60 is administered by weekly intravenous infusion and daily nebulization. The objective of this pilot open-label trial was to test the feasibility, safety, and tolerability of long-term RNS60 administration in ALS patients.<br><br>METHODS: The planned treatment duration was 23 weeks and the primary outcomes were safety and tolerability. Secondary outcomes included PBR28 positron emission tomography (PET) imaging and plasma biomarkers of inflammation.<br><br>RESULTS: Sixteen participants with ALS received RNS60 and 13 (81%) completed 23 weeks of RNS60 treatment. There were no serious adverse events and no participants withdrew from the trial due to drug-related adverse events. There were no significant changes in the biomarkers.<br><br>DISCUSSION: Long-term RNS60 administration was safe and well-tolerated. A large, multicenter, phase II trial of RNS60 is currently enrolling participants to test the effects of RNS60 on ALS biomarkers and disease progression. Muscle Nerve 59:303-308, 2019.}, }
@article {pmid30445611, year = {2019}, author = {Zeng, P and Zhou, X}, title = {Causal effects of blood lipids on amyotrophic lateral sclerosis: a Mendelian randomization study.}, journal = {Human molecular genetics}, volume = {28}, number = {4}, pages = {688-697}, pmid = {30445611}, issn = {1460-2083}, support = {R01 HG009124/HG/NHGRI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*blood/*genetics/physiopathology ; Cholesterol/blood/genetics ; Female ; Humans ; Lipids/blood/*genetics ; Lipoproteins, HDL/blood/genetics ; Lipoproteins, LDL/blood/*genetics ; Male ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide/genetics ; Triglycerides/blood/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disorder that is predicted to increase across the globe by ~70% in the following decades. Understanding the disease causal mechanism underlying ALS and identifying modifiable risks factors for ALS hold the key for the development of effective preventative and treatment strategies. Here, we investigate the causal effects of four blood lipid traits that include high-density lipoprotein, low-density lipoprotein (LDL), total cholesterol and triglycerides on the risk of ALS. By leveraging instrument variables from multiple large-scale genome-wide association studies in both European and East Asian populations, we carry out one of the largest and most comprehensive Mendelian randomization analyses performed to date on the causal relationship between lipids and ALS. Among the four lipids, we found that only LDL is causally associated with ALS and that higher LDL level increases the risk of ALS in both the European and East Asian populations. Specifically, the odds ratio of ALS per 1 standard deviation (i.e. 39.0 mg/dL) increase of LDL is estimated to be 1.14 [95% confidence interval (CI), 1.05-1.24; P = 1.38E-3] in the European population and 1.06 (95% CI, 1.00-1.12; P = 0.044) in the East Asian population. The identified causal relationship between LDL and ALS is robust with respect to the choice of statistical methods and is validated through extensive sensitivity analyses that guard against various model assumption violations. Our study provides important evidence supporting the causal role of higher LDL on increasing the risk of ALS, paving ways for the development of preventative strategies for reducing the disease burden of ALS across multiple nations.}, }
@article {pmid30439413, year = {2019}, author = {Grottelli, S and Mezzasoma, L and Scarpelli, P and Cacciatore, I and Cellini, B and Bellezza, I}, title = {Cyclo(His-Pro) inhibits NLRP3 inflammasome cascade in ALS microglial cells.}, journal = {Molecular and cellular neurosciences}, volume = {94}, number = {}, pages = {23-31}, doi = {10.1016/j.mcn.2018.11.002}, pmid = {30439413}, issn = {1095-9327}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Disease Models, Animal ; Inflammasomes/*drug effects/metabolism ; Mice ; Mice, Transgenic ; Microglia/*drug effects/metabolism ; Motor Neurons/drug effects ; NLR Family, Pyrin Domain-Containing 3 Protein/*drug effects/genetics/metabolism ; Oxidative Stress/drug effects ; Superoxide Dismutase/pharmacology ; }, abstract = {Neuroinflammation, i.e. self-propelling progressive cycle of microglial activation and neuron damage, as well as improper protein folding, are recognized as major culprits of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Mutations in several proteins have been linked to ALS pathogenesis, including the G93A mutation in the superoxide dismutase 1 (SOD1) enzyme. SOD1(G93A) mutant is prone to aggregate thus inducing both oxidative stress and neuroinflammation. In this study we used hSOD1(G93A) microglial cells to investigate the effects of the antioxidant and anti-inflammatory cyclic dipeptide (His-Pro) on LPS-induced inflammasome activation. We found that cyclo(His-Pro) inhibits NLRP3 inflammasome activation by reducing protein nitration via reduction in NO and ROS levels, indicative of lower peroxynitrite generation by LPS. Low levels in peroxynitrite are related to NF-κB inhibition responsible for iNOS down-regulation and NO dampening. On the other hand, cyclo(His-Pro)-mediated ROS attenuation, not linked to Nrf2 activation in this cellular model, is ascribed to increased soluble SOD1 activity due to the up-regulation of Hsp70 and Hsp27 expression. Conclusively, our results, besides corroborating the anti-inflammatory properties of cyclo(His-Pro), highlight a novel role of the cyclic dipeptide as a proteostasis regulator, and therefore a good candidate for the treatment of ALS and other misfolding diseases.}, }
@article {pmid30430868, year = {2019}, author = {Verschueren, A and Kianimehr, G and Belingher, C and Salort-Campana, E and Loundou, A and Grapperon, AM and Attarian, S}, title = {Wish to die and reasons for living among patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {20}, number = {1-2}, pages = {68-73}, doi = {10.1080/21678421.2018.1530265}, pmid = {30430868}, issn = {2167-9223}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*psychology ; Cohort Studies ; Depression/*psychology ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; *Suicidal Ideation ; }, abstract = {OBJECTIVE: In Amyotrophic lateral sclerosis (ALS), disease severity, ineffective treatment, and increasing dependence on caregivers may give rise to hopelessness and suicidal ideation among patients. In clinical practice, the desire for death among patients with ALS often accompanies the desire to live and fear of death. Thus, we decided to study suicidal ideation among patients with ALS and examine protective factors and reasons for living.<br><br>METHODS: We conducted a prospective, observational cohort study that recruited patients during routine visits to the outpatient multidisciplinary reference center for ALS. Depression was measured using the Beck Depression Inventory, suicidal ideation was assessed using the Columbia Suicide Severity Rating Scale, and reasons for living were assessed using the Reasons for Living inventory for adults.<br><br>RESULTS: Among the 71 patients included, 39% expressed either passive (wish to die) or active suicidal ideation. Patients who expressed suicidal ideation were more likely to report depressive symptoms and have worse disability scores. A significant difference in the survival and coping beliefs subscore of the RFL inventory, which was negatively associated with suicidal ideation, had been found between those who did and did not have suicidal ideation.<br><br>CONCLUSION: These findings have stressed the need for caregivers to recognize depression and other distressing expressions as well as provide adequate treatment. Therefore, close attention should be given to those suffering from depression while providing optimal care in terms of not only drug treatment but also psychological support.}, }
@article {pmid30425026, year = {2018}, author = {Meyer, R and Spittel, S and Steinfurth, L and Funke, A and Kettemann, D and Münch, C and Meyer, T and Maier, A}, title = {Patient-Reported Outcome of Physical Therapy in Amyotrophic Lateral Sclerosis: Observational Online Study.}, journal = {JMIR rehabilitation and assistive technologies}, volume = {5}, number = {2}, pages = {e10099}, pmid = {30425026}, issn = {2369-2529}, abstract = {BACKGROUND: Physical therapy is an essential component of multidisciplinary treatment in amyotrophic lateral sclerosis (ALS). However, the meaning of physical therapy beside preservation of muscular strength and functional maintenance is not fully understood.<br><br>OBJECTIVE: The purpose of this study was to examine patients' perception of physical therapy during symptom progression using an internet assessment approach.<br><br>METHODS: A prospective, longitudinal, observational study was performed. Recruitment took place in an ALS center in Berlin, Germany. Online self-assessment was established on a case management platform over 6 months. Participants self-assessed the progression of the disease with the ALS Functional Rating Scale-Revised (ALSFRS-R) and tracked the efficacy of targeted physical therapy using Measure Yourself Medical Outcome Profile (MYMOP). We used the net promoter score (NPS) to inquire into recommendation levels of physical therapy.<br><br>RESULTS: Forty-five participants with ALS were included in the study. Twenty-seven (60.0%) started the online assessment. The mean duration of physical therapy sessions per week was 142.7 minutes (SD 60.4) with a mean frequency of 2.9 (SD 1.2) per week. As defined by MYMOP input, the most concerning symptoms were reported in the legs (62.2%), arms (31.1%), and less frequently in the torso (6.7%). As expected for a progressive disease, there was a functional decline of 3 points in the ALSFRS-R at the end of the observation period (n=20). Furthermore, the MYMOP showed a significant loss of 0.8 in the composite score, 0.9 in the activity score and 0.8 in the targeted symptom. In spite of functional decline, the recommendation for physical therapy jumped from a baseline value of 20 NPS points to a very high 50 points at the end of study (P=.05).<br><br>CONCLUSIONS: Physical therapy is perceived as an important treatment method by patients with ALS. Despite functional deterioration, patients are satisfied with physical therapy and recommend this intervention. The results also underline how the meaning of physical therapy changes throughout the disease. Physical therapy in ALS has to be regarded as a supportive and palliative health care intervention beyond functional outcome parameters.}, }
@article {pmid30424824, year = {2018}, author = {Haney, MM and Ericsson, AC and Lever, TE}, title = {Effects of Intraoperative Vagal Nerve Stimulation on the Gastrointestinal Microbiome in a Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Comparative medicine}, volume = {68}, number = {6}, pages = {452-460}, pmid = {30424824}, issn = {2769-819X}, support = {K01 OD019924/OD/NIH HHS/United States ; T32 OD011126/OD/NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*microbiology ; Analysis of Variance ; Animals ; Disease Models, Animal ; *Gastrointestinal Microbiome ; Mice ; Multivariate Analysis ; Signal Transduction ; Vagus Nerve Stimulation/*adverse effects ; }, abstract = {The gastrointestinal microbiota (GM) plays a fundamental role in health and disease and contributes to the bidirectional signaling between the gastrointestinal system and brain. The direct line of communication between these organ systems is through the vagus nerve. Therefore, vagal nerve stimulation (VNS), a commonly used technique for multiple disorders, has potential to modulate the enteric microbiota, enabling investigation and possibly treatment of numerous neurologic disorders in which the microbiota has been linked with disease. Here we investigate the effect of VNS in a mouse model of amyotrophic lateral sclerosis (ALS). B6SJL-Tg(SOD1*G93A)[dl]1Gur (SOD1[dl]) and wildtype mice underwent ventral neck surgery to access the vagus nerve. During surgery, the experimental group received 1 h of VNS, whereas the sham group underwent 1 h of sham treatment. The third (control) group did not undergo any surgical manipulation. Fecal samples were collected before surgery and at 8 d after the initial collection. Microbial DNA was sequenced to determine the GM profiles at both time points. GM profiles did not differ between genotypes at either the initial or end point. In addition, VNS did not alter GM populations, according to the parameters chosen in this study, indicating that this short intraoperative treatment is safe and has no lasting effects on the GM. Future studies are warranted to determine whether different stimulation parameters or chronic use of VNS affect GM profiles.}, }
@article {pmid30422329, year = {2019}, author = {Zetterberg, H and van Swieten, JC and Boxer, AL and Rohrer, JD}, title = {Review: Fluid biomarkers for frontotemporal dementias.}, journal = {Neuropathology and applied neurobiology}, volume = {45}, number = {1}, pages = {81-87}, doi = {10.1111/nan.12530}, pmid = {30422329}, issn = {1365-2990}, support = {MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; MR/M023664/1/MRC_/Medical Research Council/United Kingdom ; R01AG038791/GF/NIH HHS/United States ; }, mesh = {Biomarkers/*metabolism ; Frontotemporal Dementia/*diagnosis/*metabolism ; Humans ; }, abstract = {Frontotemporal dementias (FTDs) are clinically, genetically and pathologically heterogeneous neurodegenerative disorders that affect the frontal and anterior temporal lobes of the brain. They are relatively common causes of young-onset dementia and usually present with behavioural disturbance (behavioural variant FTD) or language impairment (primary progressive aphasia), but there is also overlap with motor neurone disease and the atypical parkinsonian disorders, corticobasal syndrome and progressive supranuclear palsy. At post mortem, neuronal inclusions containing tau, TDP-43 or infrequently FUS protein are seen in most cases. However, a poor correlation between clinical syndrome and underlying pathology means that it is difficult to diagnose the underlying molecular basis using clinical criteria. At this point, biomarkers for the underlying pathology come into play. This paper provides a brief update on fluid biomarkers for FTDs that may be useful to dissect the underlying molecular changes in patients presenting with signs of frontal and/or temporal lobe dysfunction. The hope is that such biomarkers, together with genetics and imaging, would be useful in clinical trials of novel drug candidates directed against specific pathologies and, in the long run, helpful in clinical practice to select the most appropriate treatment at the right dose for individual patients.}, }
@article {pmid30414993, year = {2019}, author = {Wen, D and Cui, C and Duan, W and Wang, W and Wang, Y and Liu, Y and Li, Z and Li, C}, title = {The role of insulin-like growth factor 1 in ALS cell and mouse models: A mitochondrial protector.}, journal = {Brain research bulletin}, volume = {144}, number = {}, pages = {1-13}, doi = {10.1016/j.brainresbull.2018.09.015}, pmid = {30414993}, issn = {1873-2747}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/physiopathology ; Animals ; Apoptosis/physiology ; Cell Line ; DNA-Binding Proteins/metabolism ; Disease Models, Animal ; Disease Progression ; Female ; Humans ; Insulin-Like Growth Factor I/*metabolism/physiology ; Male ; Membrane Potential, Mitochondrial/physiology ; Mice ; Mice, Transgenic ; Mitochondria/metabolism ; Mitophagy/physiology ; Motor Neurons/metabolism ; Neurodegenerative Diseases/metabolism ; Peptide Fragments/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disorder, but little is known about the exact causes and pathophysiology of this disease. In transgenic mouse models of ALS, mitochondrial abnormalities develop during the disease and might contribute to the progression of ALS. Gene therapy was recently shown to induce beneficial effects. For example, the delivery of human insulin-like growth factor-1 (hIGF-1) by self-complementary adeno-associated virus (AAV) vectors has been shown to prolong the lifespan of ALS transgenic mice. However, the function of IGF-1 in mitochondria has not been systematically studied in ALS models. In this study, scAAV9-hIGF-1 was intramuscularly injected into transgenic SOD1[G93A] mice and administered to cell lines expressing the ∼25-kDa C-terminal fragment of transactive response DNA-binding protein (TDP-25). The mitochondrial electrical transmembrane potential was hyperpolarized, and electron microscopy findings revealed that the abnormal mitochondria were transformed. Moreover, the intrinsic mitochondrial apoptotic process was modified through the upregulation of anti-apoptotic proteins (B-cell lymphoma-extra large (Bcl-xl) and B-cell lymphoma-2 (Bcl-2)), the downregulation of pro-apoptotic proteins (Bcl-2-associated x protein (Bax) and Bcl-2 homologous antagonist killer (Bak)) and a reduction in mitochondrial cytochrome c release. Mitophagy was also increased after scAAV9-hIGF-1 treatment, as evidenced by a decrease in the p62 level and an increase in the LC3-II level. Furthermore, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) system was used to delete the IGF-1 gene in SOD1[G93A] model mice via an intrathecal injection of scAAV9-sgRNA-IGF1-Cas9 to confirm these findings. The protective effect of IGF-1 on the mitochondria decreased after genetic deletion. These novel findings demonstrate that IGF-1 strongly protects mitochondria from apoptosis and upregulates mitophagy in mouse and cell models of ALS. Therefore, therapies that specifically protect mitochondrial function might be promising strategies for treating ALS.}, }
@article {pmid30414815, year = {2018}, author = {Fitzgerald, DA and Doumit, M and Abel, F}, title = {Changing respiratory expectations with the new disease trajectory of nusinersen treated spinal muscular atrophy [SMA] type 1.}, journal = {Paediatric respiratory reviews}, volume = {28}, number = {}, pages = {11-17}, doi = {10.1016/j.prrv.2018.07.002}, pmid = {30414815}, issn = {1526-0550}, mesh = {Early Medical Intervention ; Humans ; Hypoventilation/etiology/physiopathology/*therapy ; Life Expectancy ; Oligonucleotides/*therapeutic use ; Phenotype ; *Physical Therapy Modalities ; Pneumonia/etiology/physiopathology ; *Respiration, Artificial ; Respiratory Aspiration/etiology/physiopathology ; Respiratory Insufficiency/etiology/physiopathology/*therapy ; *Respiratory Therapy ; Spinal Muscular Atrophies of Childhood/complications/physiopathology/*therapy ; }, abstract = {Spinal muscular atrophy [SMA] is the most common genetic cause of childhood mortality, primarily from the most severe form SMA type 1. It is a severe, progressive motor neurone disease, affecting the lower brainstem nuclei and the spinal cord. There is a graded level of severity with SMA children from a practical viewpoint described as "Non-sitters", "Sitters" and less commonly, "Ambulant" correlating with SMA Type 0/Type 1, Type 2 and Type 3 respectively. Children with SMA Type 0 have a severe neonatal form whilst those with SMA Type 1 develop hypoventilation, pulmonary aspiration, recurrent lower respiratory tract infections, dysphagia and failure to thrive before usually succumbing to respiratory failure and death before the age of 2 years. The recent introduction of the antisense oligonucleotide nusinersen into clinical practice in certain countries, following limited trials of less than two years duration, has altered the treatment landscape and improved the outlook considerably for SMN1 related SMA. Approximately 70% of infants appear to have a clinically significant response to nusinersen with improved motor function. It appears the earlier the treatment is initiated the better the response. There are other rarer genetic forms of SMA that are not treated with nusinersen. Clinical expectations will change although it is unclear as yet what the extent of response will mean in terms of screening initiatives [e.g., newborn screening], "preventative strategies" to maintain respiratory wellbeing, timing of introduction of respiratory supports, and prolonged life expectancy for the subcategory of children with treated SMA type 1. This article provides a review of the strategies available for supporting children with respiratory complications of SMA, with a particular emphasis on SMA Type 1.}, }
@article {pmid30410953, year = {2018}, author = {Yane, K and Katanuma, A and Hayashi, T and Takahashi, K and Kin, T and Nagai, K and Tanaka, K and Komatsu, N and Endo, M and Kobayashi, Y and Takigawa, Y and Utsunomiya, R}, title = {Enteral self-expandable metal stent placement for malignant afferent limb syndrome using single-balloon enteroscope: report of five cases.}, journal = {Endoscopy international open}, volume = {6}, number = {11}, pages = {E1330-E1335}, pmid = {30410953}, issn = {2364-3722}, abstract = {Endoscopic enteral self-expandable metal stent (SEMS) placement is a useful alternative treatment option for malignant afferent limb syndrome (ALS). We investigated the safety, efficacy, and follow-up results of enteral SEMS placement using a single-balloon enteroscope for the treatment of malignant ALS.}, }
@article {pmid30407295, year = {2018}, author = {Portaro, S and Morini, E and Santoro, ME and Accorinti, M and Marzullo, P and Naro, A and Calabrò, RS}, title = {Breathlessness in amyotrophic lateral sclerosis: A case report on the role of osteoporosis in the worsening of respiratory failure.}, journal = {Medicine}, volume = {97}, number = {45}, pages = {e13026}, pmid = {30407295}, issn = {1536-5964}, mesh = {Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*complications ; Disease Progression ; Dyspnea/*etiology ; Humans ; Male ; Osteoporosis/*complications ; Respiratory Insufficiency/*etiology ; }, abstract = {RATIONALE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative multisystem disorder, presenting with limb or bulbar onset. To date, there is no cure for ALS. At some stage of the disease, patients may complain of breathlessness due to respiratory failure, thus needing a noninvasive mechanical ventilation (NIMV) support. However, breathlessness is a symptom that may be induced by different causes that must be taken into consideration in ALS management.<br><br>PATIENTS CONCERNS: We report the case of an 81-year-old man, with a spinal onset ALS, who was admitted to our clinic to start NIMV because of respiratory involvement. After 3 weeks from NIMV performed at night time, with beneficial effects, he suddenly complained of breathlessness even at rest and in standing position.<br><br>DIAGNOSIS: Respiratory and cardiac assessments did not show new clinical events, indicating the worsening respiratory function. Due to a history of osteoporosis which was treated with biphosphonates and even though no previous bone trauma or falls were reported, we performed a spine computed tomography scan. The findings indicated multiple dorsal vertebral fractures which was a probable cause for breathlessness.<br><br>INTERVENTIONS AND OUTCOMES: Considering the neurodegenerative disease associated to respiratory failure, the cardiovascular risk factors and the age, the patient refused to undergo a surgery with kyphoplasty. A spine support was then prescribed, together with analgesic medications, with significant alleviation of pain and breathlessness.<br><br>LESSONS: The occurrence of breathlessness in a patient with ALS cannot always be related to the bulbar involvement. Other causes should be taken into account, especially when there is sudden worsening of symptoms in spite of good clinical response and compliance to NIMV treatment.}, }
@article {pmid30401437, year = {2018}, author = {Oskarsson, B and Gendron, TF and Staff, NP}, title = {Amyotrophic Lateral Sclerosis: An Update for 2018.}, journal = {Mayo Clinic proceedings}, volume = {93}, number = {11}, pages = {1617-1628}, doi = {10.1016/j.mayocp.2018.04.007}, pmid = {30401437}, issn = {1942-5546}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/physiopathology/therapy ; C9orf72 Protein ; Diagnosis, Differential ; Edaravone/therapeutic use ; Female ; Humans ; Male ; Mesenchymal Stem Cell Transplantation ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons and other neuronal cells, leading to severe disability and eventually death from ventilatory failure. It has a prevalence of 5 in 100,000, with an incidence of 1.7 per 100,000, reflecting short average survival. The pathogenesis is incompletely understood, but defects of RNA processing and protein clearance may be fundamental. Repeat expansions in the chromosome 9 open reading frame 72 gene (C9orf72) are the most common known genetic cause of ALS and are seen in approximately 40% of patients with a family history and approximately 10% of those without. No environmental risk factors are proved to be causative, but many have been proposed, including military service. The diagnosis of ALS rests on a history of painless progressive weakness coupled with examination findings of upper and lower motor dysfunction. No diagnostic test is yet available, but electromyography and genetic tests can support the diagnosis. Care for patients is best provided by a multidisciplinary team, and most interventions are directed at managing symptoms. Two medications with modest benefits have Food and Drug Administration approval for the treatment of ALS: riluzole, a glutamate receptor antagonist, and, new in 2017, edaravone, a free radical scavenger. Many other encouraging treatment strategies are being explored in clinical trials for ALS; herein we review stem cell and antisense oligonucleotide gene therapies.}, }
@article {pmid30391475, year = {2019}, author = {Bennett, SA and Tanaz, R and Cobos, SN and Torrente, MP}, title = {Epigenetics in amyotrophic lateral sclerosis: a role for histone post-translational modifications in neurodegenerative disease.}, journal = {Translational research : the journal of laboratory and clinical medicine}, volume = {204}, number = {}, pages = {19-30}, pmid = {30391475}, issn = {1878-1810}, support = {K22 NS091314/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylation ; Amyotrophic Lateral Sclerosis/etiology/*genetics ; Animals ; Chromatin Assembly and Disassembly ; DNA Methylation ; *Epigenesis, Genetic ; Histones/*metabolism ; Humans ; MicroRNAs/physiology ; *Protein Processing, Post-Translational ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the third most common adult onset neurodegenerative disorder worldwide. It is generally characterized by progressive paralysis starting at the limbs ultimately leading to death caused by respiratory failure. There is no cure and current treatments fail to slow the progression of the disease. As such, new treatment options are desperately needed. Epigenetic targets are an attractive possibility because they are reversible. Epigenetics refers to heritable changes in gene expression unrelated to changes in DNA sequence. Three main epigenetic mechanisms include the methylation of DNA, microRNAs and the post-translational modification of histone proteins. Histone modifications occur in many amino acid residues and include phosphorylation, acetylation, methylation as well as other chemical moieties. Recent evidence points to a possible role for epigenetic mechanisms in the etiology of ALS. Here, we review recent advances linking ALS and epigenetics, with a strong focus on histone modifications. Both local and global changes in histone modification profiles are associated with ALS drawing attention to potential targets for future diagnostic and treatment approaches.}, }
@article {pmid30390594, year = {2018}, author = {Peng, Y and Ye, Y and Jia, J and He, Y and Yang, Z and Zhu, X and Huang, H and Wang, W and Geng, L and Yin, S and Zhou, L and Zheng, S}, title = {Galectin-1-induced tolerogenic dendritic cells combined with apoptotic lymphocytes prolong liver allograft survival.}, journal = {International immunopharmacology}, volume = {65}, number = {}, pages = {470-482}, doi = {10.1016/j.intimp.2018.10.019}, pmid = {30390594}, issn = {1878-1705}, mesh = {Allografts/immunology ; Animals ; Apoptosis ; Cell Proliferation ; Cells, Cultured ; Dendritic Cells/*immunology/transplantation ; Galectin 1/*therapeutic use ; Graft Rejection/*immunology/prevention &amp; control ; Histocompatibility Antigens/immunology ; Humans ; Immune Tolerance ; Liver/*immunology/pathology ; *Liver Transplantation ; Lymphocyte Transfusion ; Male ; Rats ; Rats, Inbred Lew ; T-Lymphocyte Subsets/*immunology ; T-Lymphocytes, Regulatory/*immunology ; Transplantation, Homologous ; }, abstract = {Donor-derived tolerogenic dendritic cells (DCs) and apoptotic lymphocytes (ALs) are practical tools for controlling rejection after transplantation by targeting direct and indirect allorecognition pathways, respectively. To date, few studies have investigated the combination of donor-derived tolerogenic DCs and ALs infusion in organ transplantation protection. In the present study, we generated galectin-1-induced tolerogenic DCs (DCgal-1s) and ultraviolet irradiation-induced ALs with stable immune characteristics in vitro and potential immune regulatory activity in vivo. A rat model of acute liver transplant rejection was established, and the intrinsic tolerogenic profiles associated with the short-term alleviation of rejection and the long-term maintenance of tolerance in the absence of immunosuppressive drugs were evaluated. The DCgal-1-AL treatment prolonged allograft survival more significantly than a transfusion of DCgal-1s or ALs alone. This benefit was associated with CD4[+] Treg cell expansion and decreased interferon (IFN)-γ[+] T cell levels. Moreover, DCgal-1-AL treatment led to different cytokine/chemokine changes in the allograft and peripheral blood, that indicated an alleviation of local and systemic inflammation on day 7 post-transplantation. TGF-β1 and TGF-β2 were significantly increased in the long-term surviving allografts after DCgal-1-AL treatment. Our results indicate that the combination of DCgal-1s with ALs effectively prolongs liver allograft survival and represents a novel therapeutic strategy for liver transplant rejection.}, }
@article {pmid30388515, year = {2018}, author = {Dong, QX and Zhu, J and Liu, SY and Yu, XL and Liu, RT}, title = {An oligomer-specific antibody improved motor function and attenuated neuropathology in the SOD1-G93A transgenic mouse model of ALS.}, journal = {International immunopharmacology}, volume = {65}, number = {}, pages = {413-421}, doi = {10.1016/j.intimp.2018.10.032}, pmid = {30388515}, issn = {1878-1705}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; Antibodies/*therapeutic use ; Disease Models, Animal ; Gliosis/genetics/*therapy ; Humans ; Immunotherapy/*methods ; Male ; Mice ; Mice, Transgenic ; Motor Activity/drug effects ; Motor Neurons/pathology ; Neurogenic Inflammation/genetics/*therapy ; Spinal Cord/*pathology ; Superoxide Dismutase/*genetics/immunology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by motor neuron loss in the brain and spinal cord. Mutations in Cu-Zn superoxide dismutase (SOD1) are the first identified genetic mutations that are causative for familial ALS. Soluble SOD1 oligomers are considered the most toxic species and play a key role in the pathologic process of ALS. Here we present a therapeutic strategy for ALS with an oligomer-specific antibody (W20) targeting toxic SOD1 oligomers. Our study showed that W20 significantly improved motor neuron survival and motor performance in SOD1-G93A mouse model of ALS when administrated even at low dose within short time. Further investigation demonstrated that the beneficial effects of W20 resulted from the reduction of SOD1 oligomer levels and the inhibition of gliosis and neuroinflammation in the spinal cords and brain stems of ALS model mice. These findings for the first time suggest that an oligomer-specific antibody has promising therapeutic potential for ALS and open a new way for ALS treatment.}, }
@article {pmid30381409, year = {2018}, author = {Borel, F and Gernoux, G and Sun, H and Stock, R and Blackwood, M and Brown, RH and Mueller, C}, title = {Safe and effective superoxide dismutase 1 silencing using artificial microRNA in macaques.}, journal = {Science translational medicine}, volume = {10}, number = {465}, pages = {}, doi = {10.1126/scitranslmed.aau6414}, pmid = {30381409}, issn = {1946-6242}, mesh = {Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Brain/metabolism ; Dependovirus/metabolism ; *Gene Silencing ; Green Fluorescent Proteins/metabolism ; Immunity ; Injections, Spinal ; Liver/enzymology ; Lumbar Vertebrae/pathology ; Macaca ; MicroRNAs/genetics/*metabolism ; Motor Neurons/metabolism ; Superoxide Dismutase-1/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease caused by degeneration of motor neurons leading to rapidly progressive paralysis. About 10% of cases are caused by gain-of-function mutations that are transmitted as dominant traits. A potential therapy for these cases is to suppress the expression of the mutant gene. Here, we investigated silencing of SOD1, a gene commonly mutated in familial ALS, using an adeno-associated virus (AAV) encoding an artificial microRNA (miRNA) that targeted SOD1 In a superoxide dismutase 1 (SOD1)-mediated mouse model of ALS, we have previously demonstrated that SOD1 silencing delayed disease onset, increased survival time, and reduced muscle loss and motor and respiratory impairments. Here, we describe the preclinical characterization of this approach in cynomolgus macaques (Macaca fascicularis) using an AAV serotype for delivery that has been shown to be safe in clinical trials. We optimized AAV delivery to the spinal cord by preimplantation of a catheter and placement of the subject with head down at 30° during intrathecal infusion. We compared different promoters for the expression of artificial miRNAs directed against mutant SOD1 Results demonstrated efficient delivery and effective silencing of the SOD1 gene in motor neurons. These results support the notion that gene therapy with an artificial miRNA targeting SOD1 is safe and merits further development for the treatment of mutant SOD1-linked ALS.}, }
@article {pmid30376079, year = {2019}, author = {Patel, K and Kirkpatrick, CM and Nieforth, KA and Chanda, S and Zhang, Q and McClure, M and Fry, J and Symons, JA and Blatt, LM and Beigelman, L and DeVincenzo, JP and Huntjens, DR and Smith, PF}, title = {Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans.}, journal = {The Journal of antimicrobial chemotherapy}, volume = {74}, number = {2}, pages = {442-452}, doi = {10.1093/jac/dky415}, pmid = {30376079}, issn = {1460-2091}, mesh = {Adult ; Antiviral Agents/blood/*pharmacokinetics/*therapeutic use ; Deoxycytidine/*analogs &amp; derivatives/blood/pharmacokinetics/therapeutic use ; Double-Blind Method ; Healthy Volunteers ; Humans ; Models, Theoretical ; Nasopharynx/virology ; Respiratory Syncytial Virus Infections/*drug therapy ; Respiratory Syncytial Virus, Human/*drug effects/physiology ; Viral Load/drug effects ; Virus Replication/*drug effects ; }, abstract = {BACKGROUND: Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5'-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection.<br><br>OBJECTIVES: To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment.<br><br>METHODS: Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-cell-limited model that included a physiological delay.<br><br>RESULTS: The estimated clearances of ALS-8112 and ALS-8144 were 54.2 and 115&#x2009;L/h/70&#x2009;kg, respectively. A semi-physiological model was linked to predict ALS-8112 conversion to active intracellular NTP. Extensive and rapid RSV reduction occurred after lumicitabine treatment (EC50&#x2009;=&#x2009;1.79&#x2009;&#x3bc;M), with >99% viral inhibition at 2&#x2009;h after loading dose. Simulated NTP exposures and time to EC50 attainment suggested that rapid therapeutic effects and reduced dosing frequency are achievable in adult and paediatric patients.<br><br>CONCLUSIONS: The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients.}, }
@article {pmid30375462, year = {2018}, author = {Maccioni, R and Setzu, MD and Talani, G and Solari, P and Kasture, A and Sucic, S and Porru, S and Muroni, P and Sanna, E and Kasture, S and Acquas, E and Liscia, A}, title = {Standardized phytotherapic extracts rescue anomalous locomotion and electrophysiological responses of TDP-43 Drosophila melanogaster model of ALS.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {16002}, pmid = {30375462}, issn = {2045-2322}, support = {P 31255/FWF_/Austrian Science Fund FWF/Austria ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics/*physiopathology ; Animals ; Disease Models, Animal ; Drosophila melanogaster ; Electrophysiological Phenomena/*drug effects ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Locomotion/*drug effects ; Motor Neurons/drug effects/metabolism ; Mutation ; Phytochemicals/chemistry/*pharmacology ; Plant Extracts/chemistry/*pharmacology ; TDP-43 Proteinopathies/drug therapy/*genetics/*physiopathology ; }, abstract = {Findings from studies using animal models expressing amyotrophic lateral sclerosis (ALS) mutations in RNA-binding proteins, such as Transactive Response DNA-binding protein-43 (TDP-43), indicate that this protein, which is involved in multiple functions, including transcriptional regulation and pre-mRNA splicing, represents a key candidate in ALS development. This study focuses on characterizing, in a Drosophila genetic model of ALS (TDP-43), the effects of Mucuna pruriens (Mpe) and Withania somnifera (Wse). Electrophysiological and behavioural data in TDP-43 mutant flies revealed anomalous locomotion (i.e. impaired climbing with unexpected hyperactivity) and sleep dysregulation. These features, in agreement with previous findings with a different ALS model, were at least partially, rescued by treatment with Mpe and Wse. In addition, electrophysiological recordings from dorsal longitudinal muscle fibers and behavioral observations of TDP-43 flies exposed to the volatile anaesthetics, diethyl ether or chloroform, showed paradoxical responses, which were normalized upon Mpe or Wse treatment. Hence, given the involvement of some potassium channels in the effects of anaesthetics, our results also hint toward a possible dysregulation of some potassium channels in the ALS-TDP-43 Drosophila model, that might shed new light on future therapeutic strategies pertaining to ALS.}, }
@article {pmid30373594, year = {2018}, author = {Cao, YF and Wang, SF and Li, X and Zhang, YL and Qiao, YJ}, title = {The anticancer mechanism investigation of Tanshinone IIA by pharmacological clustering in protein network.}, journal = {BMC systems biology}, volume = {12}, number = {1}, pages = {90}, pmid = {30373594}, issn = {1752-0509}, mesh = {Abietanes/*pharmacology/therapeutic use ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Autophagy/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; *Computational Biology ; Gene Ontology ; Humans ; Neovascularization, Pathologic/drug therapy ; }, abstract = {BACKGROUND: Cancer is the second most common cause of death globally. The anticancer effects of Tanshinone IIA (Tan IIA) has been confirmed by numerous researches. However, the underlying mechanism remained to be integrated in systematic format. Systems biology embraced the complexity of cancer; therefore, a system study approach was proposed in the present study to explore the anticancer mechanism of Tan IIA based on network pharmacology.<br><br>METHOD: Agilent Literature Search (ALS), a text-mining tool, was used to pull protein targets of Tan IIA. Then, pharmacological clustering was applied to classify obtained hits, the anticancer module was analysed further. The top ten essential nodes in the anticancer module were obtained by ClusterONE. Functional units in the anticancer module were catalogued and validated by Gene Ontology (GO) analysis. Meanwhile, KEGG and Cell Signalling Technology Pathway were employed to provide pathway data for potential anticancer pathways construction. Finally, the pathways were plotted using Cytoscape 3.5.1. Furthermore, in vitro experiments with five carcinoma cell lines were conducted.<br><br>RESULTS: A total of 258 proteins regulated by Tan IIA were identified through ALS and were visualized by protein network. Pharmacological clustering further sorted 68 proteins that intimately involved in cancer pathogenesis based on Gene Ontology. Subsequently, pathways on anticancer effect of Tan IIA were delineated. Five functional units were clarified according to literature: including regulation on apoptosis, proliferation, sustained angiogenesis, autophagic cell death, and cell cycle. The GO analysis confirmed the classification was statistically significant. The inhibiting influence of Tan IIA on p70 S6K/mTOR pathway was revealed for the first time. The in vitro experiments displayed the selectivity of Tan IIA on HeLa, MDA-MB-231, HepG2, A549, and ACHN cell lines, the IC50 values were 0.54&#xa0;&#x3bc;M, 4.63&#xa0;&#x3bc;M, 1.42&#xa0;&#x3bc;M, 17.30&#xa0;&#x3bc;M and 204.00&#xa0;&#x3bc;M, respectively. This result further reinforced the anticancer effect of Tan IIA treatment.<br><br>CONCLUSIONS: The current study provides a systematic methodology for discovering the coordination of the anticancer pathways regulated by Tan IIA via protein network. And it also offers a valuable guidance for systematic study on the therapeutic values of other herbs and their active compounds.}, }
@article {pmid30373406, year = {2018}, author = {Turnbull, J}, title = {Is edaravone harmful? (A placebo is not a control).}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {19}, number = {7-8}, pages = {477-482}, doi = {10.1080/21678421.2018.1517179}, pmid = {30373406}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Edaravone/*adverse effects ; Humans ; Neuroprotective Agents/*adverse effects ; *Placebo Effect ; }, abstract = {Edaravone is delivered by long-term daily intravenous infusions, yet the risk of infusion was not considered in the design or analysis of studies examining the efficacy of edaravone in ALS. A reappraisal of the pivotal edaravone study (Study 19) on which claims of efficacy are based suggests that this risk cannot be dismissed, that the efficacy of edaravone may be over-estimated, and that some differences between edaravone and placebo may not implicate the ALS disease process. When trial conditions may be harmful to both arms of a placebo-controlled trial, not only is it necessary that treatment prove superior to placebo, but also that treatment is better than no intervention. In Study 19, edaravone performed better than placebo, but both placebo and edaravone likely did worse than no intervention, an interpretation more in keeping with previous trial experience of drugs with similar mechanisms of action, and with previous trial experience with edaravone. Edaravone, as presently delivered, may be both ineffective and harmful.}, }
@article {pmid30372689, year = {2018}, author = {Tilanus, TBM and Groothuis, JT and Ten Broek-Pastoor, JMC and Doorduin, J and van Engelen, BGM and Kampelmacher, MJ and Raaphorst, J}, title = {Respiratory Assessment of ALS Patients: A Nationwide Survey of Current Dutch Practice.}, journal = {Journal of neuromuscular diseases}, volume = {5}, number = {4}, pages = {431-438}, doi = {10.3233/JND-180302}, pmid = {30372689}, issn = {2214-3599}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Netherlands ; Noninvasive Ventilation/methods/statistics &amp; numerical data ; Referral and Consultation/statistics &amp; numerical data ; Respiratory Function Tests ; Respiratory Insufficiency/*etiology/*therapy ; Surveys and Questionnaires ; }, abstract = {BACKGROUND AND OBJECTIVE: Non-invasive ventilation (NIV) is an established treatment for respiratory failure in patients with amyotrophic lateral sclerosis (ALS). Several studies have shown room for improvement with regard to respiratory care for ALS patients, including latency of referral. These studies focused on the time period starting at the moment of referral to a home ventilation service (HVS) onwards. In the current study we performed a nationwide survey to gain insight in the trajectory before referral. We questioned the assessment of respiratory impairment by ALS physicians/care teams, including criteria for referral to an HVS.<br><br>METHODS: We requested 40 ALS care teams in the Netherlands to fill in an online questionnaire on respiratory management in ALS patients.<br><br>RESULTS: Thirty-two ALS care teams (80%) responded. Forced vital capacity was the most frequently used test at each outpatient visit (72%) and often served as a criterion (78%) for referral to an HVS. Other respiratory function measurements that were performed less often included peak cough flow (50%), maximum inspiratory/expiratory pressure (31% /28%) and sniff nasal inspiratory pressure (13%). Morning headache was the most frequently questioned complaint (94%), followed by daytime sleepiness (91%). Dyspnoea and orthopnoea were reported by 38% and 59% as important complaints. Out of all patients under the care of the ALS care teams, the mean estimated proportion of patients that was referred to an HVS was 69% (range 20-100%). When physicians refrained from referral, the most often cited reasons were patient's decision to withhold NIV (94%) and cognitive impairment (50%). Sixteen percent of the respondents stated bulbar impairment as a reason to refrain from referral.<br><br>CONCLUSION: Despite findings in previous studies on the superiority of SNIP and PCF as compared to FVC, our study shows that a majority of ALS care teams still prefers to use FVC for the assessment of respiratory dysfunction and for the timing of referral to an HVS. Another finding is that bulbar impairment is not an obstacle for referral for NIV.}, }
@article {pmid30371865, year = {2019}, author = {Ash, PEA and Dhawan, U and Boudeau, S and Lei, S and Carlomagno, Y and Knobel, M and Al Mohanna, LFA and Boomhower, SR and Newland, MC and Sherr, DH and Wolozin, B}, title = {Heavy Metal Neurotoxicants Induce ALS-Linked TDP-43 Pathology.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {167}, number = {1}, pages = {105-115}, pmid = {30371865}, issn = {1096-0929}, support = {R01 AG064932/AG/NIA NIH HHS/United States ; R01 NS089544/NS/NINDS NIH HHS/United States ; RF1 AG056318/AG/NIA NIH HHS/United States ; S10 OD023663/OD/NIH HHS/United States ; }, mesh = {Animals ; Rats ; *Amyotrophic Lateral Sclerosis/chemically induced/metabolism/pathology ; Cell Nucleus/drug effects/metabolism ; *Cerebral Cortex/drug effects/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; Green Fluorescent Proteins/genetics ; *Hippocampus/drug effects/metabolism/pathology ; *Metals, Heavy/toxicity ; Mice, Inbred BALB C ; *Neurons/drug effects/metabolism ; PC12 Cells ; Primary Cell Culture ; RNA Splicing ; Mice ; Disease Models, Animal ; }, abstract = {Heavy metals, such as lead, mercury, and selenium, have been epidemiologically linked with a risk of ALS, but a molecular mechanism proving the connection has not been shown. A screen of putative developmental neurotoxins demonstrated that heavy metals (lead, mercury, and tin) trigger accumulation of TDP-43 into nuclear granules with concomitant loss of diffuse nuclear TDP-43. Lead (Pb) and methyl mercury (MeHg) disrupt the homeostasis of TDP-43 in neurons, resulting in increased levels of transcript and increased splicing activity of TDP-43. TDP-43 homeostasis is tightly regulated, and positively or negatively altering its splicing-suppressive activity has been shown to be deleterious to neurons. These changes are associated with the liquid-liquid phase separation of TDP-43 into nuclear bodies. We show that lead directly facilitates phase separation of TDP-43 in a dose-dependent manner in vitro, possibly explaining the means by which lead treatment results in neuronal nuclear granules. Metal toxicants also triggered the accumulation of insoluble TDP-43 in cultured cells and in the cortices of exposed mice. These results provide novel evidence of a direct mechanistic link between heavy metals, which are a commonly cited environmental risk of ALS, and molecular changes in TDP-43, the primary pathological protein accumulating in ALS.}, }
@article {pmid30369270, year = {2018}, author = {Caga, J and Hsieh, S and Highton-Williamson, E and Zoing, MC and Ramsey, E and Devenney, E and Ahmed, RM and Hogden, A and Kiernan, MC}, title = {The burden of apathy for caregivers of patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {19}, number = {7-8}, pages = {599-605}, doi = {10.1080/21678421.2018.1497659}, pmid = {30369270}, issn = {2167-9223}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/nursing ; *Apathy ; Australia ; Caregivers/*psychology ; Cognitive Dysfunction/*etiology ; Female ; Humans ; Male ; Mental Disorders/*etiology ; Middle Aged ; Mood Disorders/etiology ; Neuropsychological Tests ; Psychiatric Status Rating Scales ; Retrospective Studies ; }, abstract = {OBJECTIVES: Apathy is the most common behavioral symptom of amyotrophic lateral sclerosis (ALS). Despite its known impact on caregiver wellbeing, apathy is typically considered a unitary construct making assessment and targeting treatment problematic. The aim of this study was to explore the relationship between caregiver burden and the behavioral, cognitive, and emotional symptoms of apathy in ALS.<br><br>METHODS: Fifty-one ALS patient-caregiver dyads from an ALS/frontotemporal dementia Clinic were assessed with the Apathy Evaluation Scale which measured the cognitive, behavioral, emotional, and nonspecific symptoms of apathy as well as the Zarit Burden Interview, a measure of perceived burden among caregivers of cognitively impaired older adults. The relationship between apathy and caregiver burden were analyzed using univariate and multivariate methods.<br><br>RESULTS: Apathy was identified in 18% of ALS patients. Greater behavioral (p&#x2009;=&#x2009;0.011) and nonspecific (p&#x2009;=&#x2009;0.010) symptoms of apathy exhibited by patients were reported by caregivers with higher levels of burden compared to caregivers with lower levels of burden. Of the cognitive, behavioral, emotional, and nonspecific symptoms of apathy, only the behavioral symptoms explained a significant amount of variance in caregiver burden (p&#x2009;=&#x2009;0.031).<br><br>CONCLUSIONS: Apathy, specifically the behavioral symptoms of apathy was associated with higher burden of care among ALS caregivers, highlighting the importance of multidimensional assessment of apathy and provision of behavior management support as part of ALS care.}, }
@article {pmid30368196, year = {2018}, author = {Weerasekera, A and Sima, DM and Dresselaers, T and Van Huffel, S and Van Damme, P and Himmelreich, U}, title = {Non-invasive assessment of disease progression and neuroprotective effects of dietary coconut oil supplementation in the ALS SOD1[G93A] mouse model: A [1]H-magnetic resonance spectroscopic study.}, journal = {NeuroImage. Clinical}, volume = {20}, number = {}, pages = {1092-1105}, pmid = {30368196}, issn = {2213-1582}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*pathology/physiopathology ; Animals ; Behavior, Animal/drug effects/physiology ; Coconut Oil/*pharmacology ; Disease Models, Animal ; *Disease Progression ; Magnetic Resonance Imaging/methods ; Magnetic Resonance Spectroscopy/methods ; Mice, Transgenic ; Neuroprotective Agents ; Spinal Cord/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease primarily characterized by progressive degeneration of motor neurons in the motor cortex, brainstem and spinal cord. Due to relatively fast progression of ALS, early diagnosis is essential for possible therapeutic intervention and disease management. To identify potential diagnostic markers, we investigated age-dependent effects of disease onset and progression on regional neurochemistry in the SOD1[G93A] ALS mouse model using localized in vivo magnetic resonance spectroscopy (MRS). We focused mainly on the brainstem region since brainstem motor nuclei are the primarily affected regions in SOD1[G93A] mice and ALS patients. In addition, metabolite profiles of the motor cortex were also assessed. In the brainstem, a gradual decrease in creatine levels were detected starting from the pre-symptomatic age of 70 days postpartum. During the early symptomatic phase (day 90), a significant increase in the levels of the inhibitory neurotransmitter γ- aminobutyric acid (GABA) was measured. At later time points, alterations in the form of decreased NAA, glutamate, glutamine and increased myo-inositol were observed. Also, decreased glutamate, NAA and increased taurine levels were seen at late stages in the motor cortex. A proof-of-concept (PoC) study was conducted to assess the effects of coconut oil supplementation in SOD[G93A] mice. The PoC revealed that the coconut oil supplementation together with the regular diet delayed disease symptoms, enhanced motor performance, and prolonged survival in the SOD1[G93A] mouse model. Furthermore, MRS data showed stable metabolic profile at day 120 in the coconut oil diet group compared to the group receiving a standard diet without coconut oil supplementation. In addition, a positive correlation between survival and the neuronal marker NAA was found. To the best of our knowledge, this is the first study that reports metabolic changes in the brainstem using in vivo MRS and effects of coconut oil supplementation as a prophylactic treatment in SOD1[G93A] mice.}, }
@article {pmid30359484, year = {2018}, author = {Bissaro, M and Federico, S and Salmaso, V and Sturlese, M and Spalluto, G and Moro, S}, title = {Targeting Protein Kinase CK1δ with Riluzole: Could It Be One of the Possible Missing Bricks to Interpret Its Effect in the Treatment of ALS from a Molecular Point of View?.}, journal = {ChemMedChem}, volume = {13}, number = {24}, pages = {2601-2605}, doi = {10.1002/cmdc.201800632}, pmid = {30359484}, issn = {1860-7187}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Astrocytes/metabolism ; Casein Kinase Idelta/*antagonists &amp; inhibitors ; Glutamic Acid/metabolism ; Humans ; Molecular Docking Simulation ; Molecular Targeted Therapy ; Neuroprotective Agents/*chemistry/pharmacology ; Protein Binding ; Protein Conformation ; Riluzole/*chemistry/pharmacology ; Thermodynamics ; }, abstract = {Riluzole, approved by the US Food and Drug Administration (FDA) in 1995, is the most widespread oral treatment for the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). The drug, whose mechanism of action is still obscure, mitigates progression of the illness, but unfortunately with only limited improvements. Herein we report the first demonstration, using a combination of computational and in vitro studies, that riluzole is an ATP-competitive inhibitor of the protein kinase CK1 isoform δ, with an IC50 value of 16.1 μm. This allows us to rewrite its possible molecular mechanism of action in the treatment of ALS. The inhibition of CK1δ catalytic activity indeed links the two main pathological hallmarks of ALS: transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy and glutamate excitotoxicity, exacerbated by the loss of expression of glial excitatory amino acid transporter-2 (EAAT2).}, }
@article {pmid30352453, year = {2019}, author = {Chen, HR and Kao, CC and Tsao, CW and Tang, SH and En, M and Cha, TL and Sun, GH and Wu, ST and Yu, DS}, title = {Comparison of Different Treatment Schedules of Mitomycin C Intravesical Instillation in High-Risk Superficial Bladder Cancer Patients.}, journal = {Aktuelle Urologie}, volume = {50}, number = {3}, pages = {292-297}, doi = {10.1055/a-0750-5595}, pmid = {30352453}, issn = {1438-8820}, mesh = {Administration, Intravesical ; Adult ; Aged ; Aged, 80 and over ; Chemotherapy, Adjuvant ; Cohort Studies ; Combined Modality Therapy ; Drug Administration Schedule ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Mitomycin/*administration &amp; dosage ; Neoplasm Recurrence, Local/prevention &amp; control ; Neoplasm Staging ; Retrospective Studies ; Risk Factors ; Taiwan ; Urinary Bladder Neoplasms/*drug therapy/pathology/surgery ; Young Adult ; }, abstract = {UNLABELLED: ZIEL: Diese Studie erfolgte zum Vergleich der Wirksamkeit einer intravesikalen Instillation von Mitomycin C (MMC) zur Prävention eines nicht muskelinvasiven Ta- oder T1-High-Risk-Harnblasenkarzinoms (NMIBC) unter Verwendung verschiedener Schemata.<br><br>MATERIAL UND METHODEN: &#x2002;Diese retrospektive Kohortenstudie wurde bei 152 Patienten durchgef&#xfc;hrt, die zwischen April 2009 und September 2016 mit einer intravesikalen MMC-Injektion behandelt wurden. Der mittlere Nachbeobachtungszeitraum lag bei 32,67 Monaten. Alle Patienten unterzogen sich einer vollst&#xe4;ndigen transurethralen Resektion des Blasentumors (TURBT), an die sich innerhalb von 24 Stunden eine postoperative Instillation von MMC anschloss. Die Patienten wurden in 4 Behandlungsgruppen unterteilt: Bei Gruppe 1 erfolgte die Nachbeobachtung ohne MMC-Erhaltungsdosis; Gruppe 2 erhielt in den ersten 8 Wochen einmal pro Woche eine MMC-Instillation; Gruppe 3 erhielt in den ersten 8 Wochen einmal pro Woche und in den darauffolgenden 6 Monaten einmal pro Monat eine MMC-Instillation; Gruppe 4 erhielt in den ersten 8 Wochen einmal pro Woche und in den darauffolgenden 12 Monaten einmal pro Monat eine MMC-Instillation.<br><br>ERGEBNISSE: &#x2002;Die allgemeine Rezidivrate lag bei 27,6&#x200a;%. Gruppe 1 zeigte eine signifikant hohe (p&#x200a;<&#x200a;0,05) Rezidivrate von 50&#x200a;%, w&#xe4;hrend sich bei den Rezidivraten der &#xfc;brigen 3 Schemata kein Unterschied fand (Gruppe 2: 15&#x200a;%; Gruppe 3: 24,1&#x200a;%; Gruppe 4: 27,2&#x200a;%). Dar&#xfc;ber hinaus zeigte sich zwischen diesen Patientengruppen kein statistischer Unterschied bei den Rezidivraten von Ta- oder T1-Tumoren sowie niedrig- oder hochgradigen Tumoren.<br><br>SCHLUSSFOLGERUNG: &#x2002;Unser Vergleich der verschiedenen Schemata einer intravesikalen MMC-Instillation ergab bei einer einzigen MMC-Instillation nach TURBT eine signifikant h&#xf6;here Rezidivrate als bei Patienten, die nach 8 Wochen, 6 Monaten und 12 Monaten eine Erhaltungsdosis erhielten. Zeitlich fanden sich beim MMC-Erhaltungsschema keine signifikanten Unterschiede zwischen der 8.&#x200a;Woche und dem 12.&#x200a;Monat. Daraus folgern wir, dass bei T1- oder Ta-High-Risk-NMIBC nach TURBT einmalig eine MMC-Instillation mit anschlie&#xdf;ender Erhaltungstherapie mit einmal w&#xf6;chentlicher Verabreichung &#xfc;ber 8 Wochen durchgef&#xfc;hrt werden kann.}, }
@article {pmid30349065, year = {2018}, author = {Pokrishevsky, E and McAlary, L and Farrawell, NE and Zhao, B and Sher, M and Yerbury, JJ and Cashman, NR}, title = {Tryptophan 32-mediated SOD1 aggregation is attenuated by pyrimidine-like compounds in living cells.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {15590}, pmid = {30349065}, issn = {2045-2322}, mesh = {Amino Acid Substitution ; Flow Cytometry ; HEK293 Cells ; Humans ; Mass Spectrometry ; Mutant Proteins/chemistry/*metabolism ; *Protein Aggregation, Pathological ; Protein Stability ; Pyrimidines/*metabolism ; Superoxide Dismutase-1/chemistry/genetics/*metabolism ; Tryptophan/*metabolism ; }, abstract = {Over 160 mutations in superoxide dismutase 1 (SOD1) are associated with familial amyotrophic lateral sclerosis (fALS), where the main pathological feature is deposition of SOD1 into proteinaceous cytoplasmic inclusions. We previously showed that the tryptophan residue at position 32 (W32) mediates the prion-like propagation of SOD1 misfolding in cells, and that a W32S substitution blocks this phenomenon. Here, we used in vitro protein assays to demonstrate that a W32S substitution in SOD1-fALS mutants significantly diminishes their propensity to aggregate whilst paradoxically decreasing protein stability. We also show SOD1-W32S to be resistant to seeded aggregation, despite its high abundance of unfolded protein. A cell-based aggregation assay demonstrates that W32S substitution significantly mitigates inclusion formation. Furthermore, this assay reveals that W32 in SOD1 is necessary for the formation of a competent seed for aggregation under these experimental conditions. Following the observed importance of W32 for aggregation, we established that treatment of living cells with the W32-interacting 5-Fluorouridine (5-FUrd), and its FDA approved analogue 5-Fluorouracil (5-FU), substantially attenuate inclusion formation similarly to W32S substitution. Altogether, we highlight W32 as a significant contributor to SOD1 aggregation, and propose that 5-FUrd and 5-FU present promising lead drug candidates for the treatment of SOD1-associated ALS.}, }
@article {pmid30342424, year = {2019}, author = {Nozal, V and Martinez, A}, title = {Tau Tubulin Kinase 1 (TTBK1), a new player in the fight against neurodegenerative diseases.}, journal = {European journal of medicinal chemistry}, volume = {161}, number = {}, pages = {39-47}, doi = {10.1016/j.ejmech.2018.10.030}, pmid = {30342424}, issn = {1768-3254}, mesh = {Dose-Response Relationship, Drug ; Humans ; Models, Molecular ; Molecular Structure ; Neurodegenerative Diseases/*drug therapy/metabolism ; Neuroprotective Agents/chemistry/*pharmacology ; Phosphorylation/drug effects ; Protein Serine-Threonine Kinases/*antagonists &amp; inhibitors/metabolism ; Structure-Activity Relationship ; }, abstract = {Tau-tubuline kinases (TTBK) are a family of serine/threonine and tyrosine kinases recently discovered and implicated in the phosphorylation of important substrates such as tau, tubuline or TDP-43. Its two homologs, TTBK1 and TTBK2, show different expression patterns and different involvements in physiological mechanisms of great importance such as mitosis, ciliogenesis and neurotransmission. Their phosphorylation activity has also linked them to the development of neurodegenerative diseases like Alzheimer's disease, amyotrophic lateral sclerosis or spinocerebellar ataxia type 11. There are currently only three inhibitors of these kinases described in the literature. This review intends to give an overview of the structure, expression, physiological and pathological mechanisms of both kinases as well as an extended analysis on the molecules that can inhibit them. The final analysis of all this information led us to propose TTBK1 as a new target for the treatment of neurodegenerative diseases and its selective inhibitors as potential effective drugs for the treatment of these severe unmet disorders.}, }
@article {pmid30334916, year = {2018}, author = {Nur Yilmaz, RB and Germeç Çakan, D and Nalbantgil, D}, title = {Aesthetic Assessment of Infants With Different Cleft Types Before, During, and After Orthopedic Treatment.}, journal = {The Journal of craniofacial surgery}, volume = {29}, number = {8}, pages = {2081-2087}, doi = {10.1097/SCS.0000000000004888}, pmid = {30334916}, issn = {1536-3732}, mesh = {Adult ; Cleft Lip/*surgery ; Cleft Palate/*surgery ; *Dentistry ; *Esthetics ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Orthodontics ; Photography ; Postoperative Period ; Preoperative Period ; Plastic Surgery Procedures/instrumentation/methods ; Stents ; }, abstract = {OBJECTIVE: The aim of the present study is to compare the aesthetic assessments of infants with different types of cleft before (T1), during (T2), and after (T3) orthopedic therapy (OT) by orthodontists, dentists, and laypersons.<br><br>METHODS: Photographs of 3 patients (incomplete lip [C1], complete unilateral [C2], and complete bilateral cleft [C3]) at T1 (C1, C2, C3 chronologic age: 5, 2, 2 days), T2 (C1, C2, C3 chronologic age: 32, 28, 35 days; using forehead anchoraged nasal stent or conventional nasoalveolar therapy plates), and T3 (C1, C2, C3 chronologic age: 80, 91, 105 days) were collected from the archive. The nasolabial region at stage T3 were masked and also added to the evaluation form (T4). Fifty-one evaluators (17 orthodontists, 17 dentists, and 17 laypersons; mean age&#x200a;=&#x200a;30.1&#x200a;&#xb1;&#x200a;3.63) assessed 21 frontal photographs using Asher-McDade et al's 5-point scale.<br><br>RESULTS: The scores of the orthodontists for T1 photographs were statistically lower than the dentists and laypersons (P&#x200a;<&#x200a;0.05). The scores of T3 and T4 were similar in all groups (P&#x200a;>&#x200a;0.05). The assessment scores progressively decreased from T1 to T3 (P&#x200a;>&#x200a;0.05). The scores of both treatment methods were similar in the orthodontist group (P&#x200a;>&#x200a;0.05), whereas the scores were lower for forehead anchored nasal stent in the other groups (P&#x200a;<&#x200a;0.05).<br><br>CONCLUSION: Orthodontists are familiar with cleft patients. Therefore, the aesthetic of infants at any therapy stage with different treatment methods was not categorized as poor. The enhanced scores at post-OT stage and the similar scores of masked and nonmasked post-OT photographs may underline the recognition of the rehabilitation period by not only specialists but also laypersons.}, }
@article {pmid30328519, year = {2018}, author = {Garcia-Santibanez, R and Burford, M and Bucelli, RC}, title = {Hereditary Motor Neuropathies and Amyotrophic Lateral Sclerosis: a Molecular and Clinical Update.}, journal = {Current neurology and neuroscience reports}, volume = {18}, number = {12}, pages = {93}, pmid = {30328519}, issn = {1534-6293}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/metabolism ; Animals ; Biomarkers/metabolism ; Humans ; Motor Neuron Disease/*drug therapy/*genetics/metabolism ; Randomized Controlled Trials as Topic ; }, abstract = {PURPOSE OF REVIEW: This article provides an overview of recent advancements in the fields of hereditary motor neuropathies and ALS.<br><br>RECENT FINDINGS: There has been a robust growth in our knowledge and understanding of hereditary and degenerative motor neuronopathies/neuropathies over the last decade. Many breakthroughs in the field of hereditary motor neuropathies (HMN) have been associated with identification and characterization of the genes and molecular mechanisms underlying these disorders. Similar recent breakthroughs on the genetic and molecular underpinnings of the degenerative motor neuronopathy, amyotrophic lateral sclerosis (ALS), have been accompanied by advancements in biomarker research and the development and FDA approval of novel therapies. There is a reasonable hope that the marked and continued growth in our understanding of the molecular pathophysiology of the HMNs will translate into novel therapeutic approaches in the decade to come. Such breakthroughs have already begun in ALS, where novel biomarkers and treatment strategies have translated into a new FDA-approved therapy with a number of promising agents in development and/or in definitive phase 2/3 trials.}, }
@article {pmid30325939, year = {2018}, author = {McClure, MW and Berliba, E and Tsertsvadze, T and Streinu-Cercel, A and Vijgen, L and Astruc, B and Patat, A and Westland, C and Chanda, S and Zhang, Q and Kakuda, TN and Vuong, J and Khorlin, N and Beigelman, L and Blatt, LM and Fry, J}, title = {Safety, tolerability, and pharmacokinetics of AL-335 in healthy volunteers and hepatitis C virus-infected subjects.}, journal = {PloS one}, volume = {13}, number = {10}, pages = {e0204974}, pmid = {30325939}, issn = {1932-6203}, mesh = {Adult ; Alanine/adverse effects/*analogs &amp; derivatives/pharmacokinetics/therapeutic use ; Antiviral Agents/adverse effects/pharmacokinetics/*therapeutic use ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Genotype ; Half-Life ; Hepacivirus/genetics ; Hepatitis C/complications/*drug therapy ; Humans ; Liver Cirrhosis/complications ; Male ; Middle Aged ; Phosphoramides ; Placebo Effect ; RNA, Viral/blood ; Uridine/adverse effects/*analogs &amp; derivatives/pharmacokinetics/therapeutic use ; }, abstract = {BACKGROUND: The nucleotide analog AL-335 is a pangenotypic hepatitis C virus (HCV) nonstructural protein (NS)5B inhibitor being evaluated as treatment for chronic HCV infection.<br><br>METHODS: This three-part randomized, double-blind study evaluated the safety and pharmacokinetics of single and multiple ascending oral doses of AL-335. Healthy volunteers (HVs) received single doses of AL-335 (100-1,200 mg) or placebo in a fasted or fed (400 mg) state. Non-cirrhotic subjects (HCV genotype [GT]1-4) and GT1-infected subjects with Child Pugh A cirrhosis received multiple doses of AL-335 (400, 800, 1,200 mg) or placebo once daily (QD) for 7 days.<br><br>RESULTS: Forty-eight HVs and 64 subjects with HCV GT1-4 were randomized and received treatment. AL-335 was well tolerated in HVs and HCV-infected subjects with/without cirrhosis. AL-335 was rapidly absorbed and converted to the metabolites ALS-022399 and ALS-022227. ALS-022227 exposure increased less than dose-proportionally and was unaffected by food, while AL-335 and ALS-022399 exposure increased with food by 85% and 50%, respectively, in HVs. Rapid and dose-dependent reductions in HCV-RNA were observed in GT1-infected subjects. In non-cirrhotic, GT1-4-infected subjects receiving AL-335 800 mg QD, potent antiviral activity was observed, regardless of genotype (mean maximum reductions in HCV-RNA of 4.0-4.8 log10 IU/mL). The same dose in GT1-infected cirrhotic subjects resulted in a 3.5 log10 IU/mL mean maximum reduction in HCV-RNA.<br><br>CONCLUSIONS: AL-335 was well tolerated when administered as single and multiple doses, with an acceptable pharmacokinetic profile. The drug also demonstrated potent antiviral activity in HCV GT1-4-infected subjects, including GT1-infected subjects with cirrhosis.}, }
@article {pmid30324134, year = {2018}, author = {Osaki, T and Uzel, SGM and Kamm, RD}, title = {Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons.}, journal = {Science advances}, volume = {4}, number = {10}, pages = {eaat5847}, pmid = {30324134}, issn = {2375-2548}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Calcium Signaling ; Electric Stimulation ; Gene Expression ; Glutamic Acid/metabolism/pharmacology ; Humans ; Induced Pluripotent Stem Cells/*cytology ; Lab-On-A-Chip Devices ; Mice ; Motor Neurons/drug effects/*pathology/physiology ; Muscle Contraction ; Muscle Fibers, Skeletal/physiology ; Muscle, Skeletal/*cytology/physiopathology ; Neuromuscular Junction/cytology/physiology ; Optogenetics ; Spheroids, Cellular ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease involving loss of motor neurons (MNs) and muscle atrophy, still has no effective treatment, despite much research effort. To provide a platform for testing drug candidates and investigating the pathogenesis of ALS, we developed an ALS-on-a-chip technology (i.e., an ALS motor unit) using three-dimensional skeletal muscle bundles along with induced pluripotent stem cell (iPSC)-derived and light-sensitive channelrhodopsin-2-induced MN spheroids from a patient with sporadic ALS. Each tissue was cultured in a different compartment of a microfluidic device. Axon outgrowth formed neuromuscular junctions on the muscle fiber bundles. Light was used to activate muscle contraction, which was measured on the basis of pillar deflections. Compared to a non-ALS motor unit, the ALS motor unit generated fewer muscle contractions, there was MN degradation, and apoptosis increased in the muscle. Furthermore, the muscle contractions were recovered by single treatments and cotreatment with rapamycin (a mechanistic target of rapamycin inhibitor) and bosutinib (an Src/c-Abl inhibitor). This recovery was associated with up-regulation of autophagy and degradation of TAR DNA binding protein-43 in the MNs. Moreover, administering the drugs via an endothelial cell barrier decreased the expression of P-glycoprotein (an efflux pump that transports bosutinib) in the endothelial cells, indicating that rapamycin and bosutinib cotreatment has considerable potential for ALS treatment. This ALS-on-a-chip and optogenetics technology could help to elucidate the pathogenesis of ALS and to screen for drug candidates.}, }
@article {pmid30322255, year = {2018}, author = {Shaik, I and Bhojraj, SY and Prasad, G and Nagad, PB and Patel, PM and Kashikar, AD and Kumar, N}, title = {Management of Andersson Lesion in Ankylosing Spondylitis Using the Posterior-Only Approach: A Case Series of 18 Patients.}, journal = {Asian spine journal}, volume = {12}, number = {6}, pages = {1017-1027}, pmid = {30322255}, issn = {1976-1902}, abstract = {STUDY DESIGN: This retrospective study was conducted including 18 patients who underwent posterior-only stabilization and fusion procedure for pseudoarthrosis in the ankylosed spine from October 2007 to May 2015.<br><br>PURPOSE: This study aimed to describe the treatment outcomes in 18 patients with Andersson lesion (AL) who were managed using the posterior-only approach. Literature Review: AL is an unstable, localized, vertebral, or discovertebral lesion of the spine. It is observed in patients with ankylosing spondylitis. The exact etiology of this disorder remains unclear, and the treatment guidelines are not clearly described.<br><br>METHODS: We analyzed 18 patients with AL who were treated with posterior long segment spinal fusion without any anterior interbody grafting or posterior osteotomy. Pre- and postoperative radiography, computed tomography, and recent follow-up images were examined. The pre- and postoperative Visual Analog Scale score and the Oswestry Disability Index score were evaluated for all patients. Whiteclouds' outcome analysis criteria were applied at the follow-up. Moreover, at study completion, patient feedback was collected; all the patients were asked to provide their opinion regarding the surgery and were asked whether they would recommend this procedure to other patients and them self undergo the same procedure again if required.<br><br>RESULTS: The most common site was the thoracolumbar junction. The symptom duration ranged from 1 month to 10 years preoperatively. Most patients experienced fusion by the end of 1 year, and the fusion mass could be observed as early as 4 months. Pseudoarthrosis void of up to 2.5 cm was noted to be healed in subsequent imaging. In addition, clinically, the patients reported good symptomatic relief. No patient required revision surgery. Whiteclouds' outcome analysis score at the latest follow-up revealed goodto- excellent outcomes in all patients.<br><br>CONCLUSIONS: ALs can be treated using the posterior-only approach with long segment fixation and posterior spinal fusion. This is a safe, simple, and quick procedure that prevents the morbidity of anterior surgery.}, }
@article {pmid30318168, year = {2018}, author = {Gerretsen, HE and Capone, S and Vitelli, A and Reyes, LS and Thompson, A and Jones, C and Green, CA and Pollard, AJ and Sande, CJ}, title = {Antibodies in lymphocyte supernatants can distinguish between neutralising antibodies induced by RSV vaccination and pre-existing antibodies induced by natural infection.}, journal = {Vaccine}, volume = {36}, number = {46}, pages = {6988-6994}, pmid = {30318168}, issn = {1873-2518}, support = {/WT_/Wellcome Trust/United Kingdom ; 091663/WT_/Wellcome Trust/United Kingdom ; 203077/WT_/Wellcome Trust/United Kingdom ; WT 091663MA/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Adolescent ; Adult ; Antibodies, Neutralizing/blood/*immunology ; Antibodies, Viral/blood/*immunology ; Cells, Cultured ; Culture Media/chemistry ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Lymphocytes/*immunology ; Male ; Middle Aged ; Nasal Mucosa/immunology ; Neutralization Tests ; Respiratory Syncytial Virus Infections/*immunology ; Respiratory Syncytial Virus Vaccines/administration &amp; dosage/*immunology ; Respiratory Syncytial Virus, Human/*immunology ; Serum/immunology ; Young Adult ; }, abstract = {INTRODUCTION: Respiratory syncytial virus (RSV) is the single most important cause of severe respiratory illness in infants. There is no effective vaccine and the only effective treatment available is the monoclonal antibody palivizumab which reduces the risk of severe RSV disease in prematurely born infants. However, palivizumab is too costly to allow for wide implementation and thus treatment is restricted to supportive care. Despite extensive efforts to develop a vaccine, progress has been hindered by the difficulty in measuring and assessing immunological correlates of RSV vaccine efficacy in the presence of high levels of pre-existing RSV antibodies.<br><br>METHODS: Here we describe a new method for measuring the functional activity of antibodies induced by vaccination distinct from pre-existing antibodies. Antibodies in lymphocyte supernatants (ALS) from the cultured peripheral blood mononuclear cells (PBMCs) of young adults who had recently been vaccinated with a novel RSV candidate vaccine were directly assayed for virus neutralising activity. An ELISA method was used to measure antibodies in nasal and serum samples and then compared with the adapted ALS based method.<br><br>RESULTS: There was a wide background distribution of RSV-specific antibodies in serum and nasal samples that obscured vaccine-specific responses measured two weeks after vaccination. No RSV-specific antibodies were observed at baseline in ALS samples, but a clear vaccine-specific antibody response was observed in ALS seven days after the administration of each dose of vaccine. These vaccine-specific antibodies in ALS displayed functional activity in vitro, and quantification of this functional activity was unperturbed by pre-existing antibodies from natural exposure. The results demonstrate a promising new approach for assessing functional immune responses attributed to RSV vaccines.}, }
@article {pmid30317895, year = {2018}, author = {McGown, A and Stopford, MJ}, title = {High-throughput drug screens for amyotrophic lateral sclerosis drug discovery.}, journal = {Expert opinion on drug discovery}, volume = {13}, number = {11}, pages = {1015-1025}, doi = {10.1080/17460441.2018.1533953}, pmid = {30317895}, issn = {1746-045X}, support = {MR/P027989/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Artificial Intelligence ; Computer Simulation ; Disease Models, Animal ; Drug Discovery/*methods ; High-Throughput Screening Assays/*methods ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapid adult-onset neurodegenerative disorder characterised by the progressive loss of upper and lower motor neurons. Current treatment options are limited for ALS, with very modest effects on survival. Therefore, there is a unmet need for novel therapeutics to treat ALS. Areas covered: This review highlights the many diverse high-throughput screening platforms that have been implemented in ALS drug discovery. The authors discuss cell free assays including in silico and protein interaction models. The review also covers classical in vitro cell studies and new cell technologies, such as patient derived cell lines. Finally, the review looks at novel in vivo models and their use in high-throughput ALS drug discovery Expert opinion: Greater use of patient-derived in vitro cell models and development of better animal models of ALS will improve translation of lead compounds into clinic. Furthermore, AI technology is being developed to digest and interpret obtained data and to make 'hidden knowledge' usable to researchers. As a result, AI will improve target selection for high-throughput drug screening (HTDS) and aid lead compound optimisation. Furthermore, with greater genetic characterisation of ALS patients recruited to clinical trials, AI may help identify responsive genetic subtypes of patients from clinical trials.}, }
@article {pmid30317421, year = {2018}, author = {Liu, C and Leng, B and Li, Y and Jiang, H and Duan, W and Guo, Y and Li, C and Hong, K}, title = {Diallyl Trisulfide Protects Motor Neurons from the Neurotoxic Protein TDP-43 via Activating Lysosomal Degradation and the Antioxidant Response.}, journal = {Neurochemical research}, volume = {43}, number = {12}, pages = {2304-2312}, pmid = {30317421}, issn = {1573-6903}, support = {30900460//National Natural Science Foundation of China/ ; 81171210//National Natural Science Foundation of China/ ; 11966122D//Hebei Science and Technology Department/ ; }, mesh = {Allyl Compounds/*pharmacology ; Antioxidant Response Elements/drug effects/physiology ; Antioxidants/*pharmacology ; Cell Line ; Cell Survival/drug effects/physiology ; DNA-Binding Proteins/*biosynthesis/toxicity ; Dose-Response Relationship, Drug ; Humans ; Lysosomes/drug effects/*metabolism/pathology ; Motor Neurons/drug effects/*metabolism/pathology ; Neuroprotective Agents/*pharmacology ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Sulfides/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disease for which only limited effective therapeutics are available. Currently, TAR DNA-binding protein 43 (TDP-43) is recognized as a pathological and biochemical marker for ALS. Increases in the levels of aggregated or mislocalized forms of TDP-43 might result in ALS pathology. Therefore, clearance pathways for intracellular protein aggregates have been suggested as potential therapeutic targets for the treatment of ALS. Here we report that treatment of motor neuron-like NSC34 cells overexpressing TDP-43 with diallyl trisulfide (DATS) induced neuronal autophagy and lysosomal clearance of TDP-43 and C-terminal TDP-43 fragments. We also observed that the antioxidant transcription factor NF-E2-related factor 2 (Nrf2) was accumulated in the nucleus and the expression of the antioxidant enzymes heme oxygenase1 (HO-1) and NAD(P)H:quinone oxidoreductase (NQO1) was increased. Consequently, DATS suppressed the increase in the levels of reactive oxygen species induced by TDP-43 expression. This study extends the findings of prior reports indicating that lower doses of DATS mediate cell survival in part by inducing autophagy and activating the Nrf2/antioxidant response element pathway.}, }
@article {pmid30315929, year = {2018}, author = {Massenzio, F and Peña-Altamira, E and Petralla, S and Virgili, M and Zuccheri, G and Miti, A and Polazzi, E and Mengoni, I and Piffaretti, D and Monti, B}, title = {Microglial overexpression of fALS-linked mutant SOD1 induces SOD1 processing impairment, activation and neurotoxicity and is counteracted by the autophagy inducer trehalose.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1864}, number = {12}, pages = {3771-3785}, doi = {10.1016/j.bbadis.2018.10.013}, pmid = {30315929}, issn = {1879-260X}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics/pathology ; Animals ; *Autophagy/drug effects ; Cells, Cultured ; Disease Models, Animal ; Microglia/drug effects/metabolism/*pathology ; Neuroprotective Agents/pharmacology ; *Point Mutation/drug effects ; Rats ; Rats, Wistar ; Superoxide Dismutase-1/*genetics ; Trehalose/pharmacology ; *Up-Regulation/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. Mutations in the gene encoding copper/zinc superoxide dismutase-1 (SOD1) are responsible for most familiar cases, but the role of mutant SOD1 protein dysfunction in non-cell autonomous neurodegeneration, especially in relation to microglial activation, is still unclear. Here, we focused our study on microglial cells, which release SOD1 also through exosomes. We observed that in rat primary microglia the overexpression of the most-common SOD1 mutations linked to fALS (G93A and A4V) leads to SOD1 intracellular accumulation, which correlates to autophagy dysfunction and microglial activation. In primary contact co-cultures, fALS mutant SOD1 overexpression by microglial cells appears to be neurotoxic by itself. Treatment with the autophagy-inducer trehalose reduced mutant SOD1 accumulation in microglial cells, decreased microglial activation and abrogated neurotoxicity in the co-culture model. These data suggest that i) the alteration of the autophagic pathway due to mutant SOD1 overexpression is involved in microglial activation and neurotoxicity; ii) the induction of autophagy with trehalose reduces microglial SOD1 accumulation through proteasome degradation and activation, leading to neuroprotection. Our results provide a novel contribution towards better understanding key cellular mechanisms in non-cell autonomous ALS neurodegeneration.}, }
@article {pmid30306833, year = {2019}, author = {Wang, J and Luo, S}, title = {Joint modeling of multiple repeated measures and survival data using multidimensional latent trait linear mixed model.}, journal = {Statistical methods in medical research}, volume = {28}, number = {10-11}, pages = {3392-3403}, pmid = {30306833}, issn = {1477-0334}, support = {R01 NS091307/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*mortality ; Bayes Theorem ; Ceftriaxone/*therapeutic use ; Disease Progression ; Humans ; *Linear Models ; Markov Chains ; Monte Carlo Method ; Proportional Hazards Models ; *Survival Analysis ; }, abstract = {Impairment caused by Amyotrophic lateral sclerosis (ALS) is multidimensional (e.g. bulbar, fine motor, gross motor) and progressive. Its multidimensional nature precludes a single outcome to measure disease progression. Clinical trials of ALS use multiple longitudinal outcomes to assess the treatment effects on overall improvement. A terminal event such as death or dropout can stop the follow-up process. Moreover, the time to the terminal event may be dependent on the multivariate longitudinal measurements. In this article, we develop a joint model consisting of a multidimensional latent trait linear mixed model (MLTLMM) for the multiple longitudinal outcomes, and a proportional hazards model with piecewise constant baseline hazard for the event time data. Shared random effects are used to link together two models. The model inference is conducted using a Bayesian framework via Markov chain Monte Carlo simulation implemented in Stan language. Our proposed model is evaluated by simulation studies and is applied to the Ceftriaxone study, a motivating clinical trial assessing the effect of ceftriaxone on ALS patients.}, }
@article {pmid30303328, year = {2018}, author = {Fries, S and Schweizer, V}, title = {[Salivary management in amyotrophic lateral sclerosis].}, journal = {Revue medicale suisse}, volume = {14}, number = {621}, pages = {1758-1762}, pmid = {30303328}, issn = {1660-9379}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; Humans ; Quality of Life ; Salivary Glands/physiopathology ; *Sialorrhea/etiology/therapy ; }, abstract = {80 % of patients suffering from amyotrophic lateral sclerosis present bulbar involvement and 50 % have salivary symptoms, which are often poorly managed. They present either with drooling or thick secretions. This elevates the risk of bronchoaspiration leading to pneumonia, second cause of death in this population. It is hence paramount to treat, while enhancing the patient's quality of life. The first line of treatment is a salivary drying agent such as an atropine-based medication. These treatments have a low adverse effect rate, are reversible and easy to dose. Management of thick secretions is possible with mucolytics. Taking into account the severity of the bulbar involvement, the second line of treatment, once controversial, is salivary gland injections of botulinium toxin.}, }
@article {pmid30298513, year = {2018}, author = {Gu, X and Chen, Y and Shang, H}, title = {[Roles of exosomes in Parkinson's disease and amyotrophic lateral sclerosis].}, journal = {Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics}, volume = {35}, number = {5}, pages = {757-761}, doi = {10.3760/cma.j.issn.1003-9406.2018.05.032}, pmid = {30298513}, issn = {1003-9406}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Exosomes/genetics/*metabolism ; Humans ; Parkinson Disease/genetics/*metabolism ; }, abstract = {Exosomes, as a kind of extracellular vesicles generated by inward budding of the endosomes to form multi-vesicular bodies (MVBs), are secreted into the extracellular milieu and the systemic circulation thereafter. By endocytosis, direct fusion or receptor-ligand interactions, exosomes can interact with receptor cells and involve in various pathophysiological processes. Accumulating evidence have indicated that exosomes may play crucial roles in the pathogenesis of many neurodegenerative diseases including Parkinson's disease (PD), Huntington's disease (HD), Alzheimer disease (AD) and amyotrophic lateral sclerosis (ALS). In this paper, the roles of exosomes in the pathogenesis, diagnosis and treatment of PD and ALS are reviewed.}, }
@article {pmid30293622, year = {2018}, author = {Howard, IM and Rad, N}, title = {Electrodiagnostic Testing for the Diagnosis and Management of Amyotrophic Lateral Sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {29}, number = {4}, pages = {669-680}, doi = {10.1016/j.pmr.2018.06.003}, pmid = {30293622}, issn = {1558-1381}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Disease Management ; *Electrodiagnosis ; Humans ; }, abstract = {Electrodiagnostic testing provides insight into subclinical aspects of disease in amyotrophic lateral sclerosis and helps to diagnose and exclude other diagnoses. It may also help to manage or track disease progression. Mapping the extent of subclinical disease may guide the clinician to supportive interventions. There is considerable interest in establishing electrodiagnostic biomarkers to monitor disease progression. This article details the usefulness of electrodiagnostic testing across the disease spectrum. A review of clinical presentations and differential diagnoses, diagnostic evaluation, and emerging applications of electrodiagnostic studies to guide management and assess response to treatment interventions are presented with considerations for clinical practice.}, }
@article {pmid30291374, year = {2019}, author = {Müller Herde, A and Schibli, R and Weber, M and Ametamey, SM}, title = {Metabotropic glutamate receptor subtype 5 is altered in LPS-induced murine neuroinflammation model and in the brains of AD and ALS patients.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {46}, number = {2}, pages = {407-420}, pmid = {30291374}, issn = {1619-7089}, mesh = {Alzheimer Disease/diagnostic imaging/*metabolism ; Amyotrophic Lateral Sclerosis/diagnostic imaging/*metabolism ; Animals ; Brain/diagnostic imaging/*drug effects/*metabolism ; Inflammation/chemically induced/diagnostic imaging/metabolism ; Lipopolysaccharides/*pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Positron Emission Tomography Computed Tomography ; Receptor, Metabotropic Glutamate 5/*metabolism ; Receptors, GABA/metabolism ; }, abstract = {PURPOSE: The aim of the present study was to determine the expression levels of mGluR5 in different mouse strains after induction of neuroinflammation by lipopolysaccharide (LPS) challenge and in the brains of patients with Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) post mortem to investigate mGluR5 expression in human neurodegenerative diseases.<br><br>METHODS: C57BL/6 and CD1 mice were injected intraperitoneally with either 10&#xa0;mg/kg LPS or saline. mGluR5 and TSPO mRNA levels were measured after 1 and 5&#xa0;days by qPCR, and mGluR5 protein levels were determined by PET imaging with the mGluR5-specific radiotracer [[18]F]PSS232. mGluR5 expression was evaluated in the post-mortem brain slices from AD and ALS patients using in vitro autoradiography.<br><br>RESULTS: mGluR5 and TSPO mRNA levels were increased in brains of C57BL/6 and CD1 mice 1&#xa0;day after LPS treatment and remained significantly increased after 5&#xa0;days in C57BL/6 mice but not in CD1 mice. Brain PET imaging with [[18]F]PSS232 confirmed increased mGluR5 levels in the brains of both mouse strains 1&#xa0;day after LPS treatment. After 5&#xa0;days, mGluR5 levels in CD1 mice declined to the levels in vehicle-treated mice but remained high in C57BL/6 mice. Autoradiograms revealed a severalfold higher binding of [[18]F]PSS232 in post-mortem brain slices from AD and ALS patients compared with the binding in control brains.<br><br>CONCLUSION: LPS-induced neuroinflammation increased mGluR5 levels in mouse brain and is dependent on the mouse strain and time after LPS treatment. mGluR5 levels were also increased in human AD and ALS brains in vitro. PET imaging of mGluR5 levels could potentially be used to diagnose and monitor therapy outcomes in patients with AD and ALS.}, }
@article {pmid30289025, year = {2020}, author = {Çekici, H and Acar Tek, N}, title = {Determining energy requirement and evaluating energy expenditure in neurological diseases.}, journal = {Nutritional neuroscience}, volume = {23}, number = {7}, pages = {543-553}, doi = {10.1080/1028415X.2018.1530180}, pmid = {30289025}, issn = {1476-8305}, mesh = {*Energy Metabolism ; Exercise ; Humans ; Nervous System Diseases/diagnosis/*metabolism ; *Nutritional Physiological Phenomena ; Nutritional Requirements ; Nutritional Status ; }, abstract = {Objectives: It has been reported that in most neurological patients, resting energy expenditure due to hypermetabolism is increased. Physical activity, which is another component of energy expenditure, varies depending on the course of the disease. Different mechanisms are used to explain changes in energy expenditure in this population. Pathological problems of centers that regulate energy balance in the brain, endocrine and metabolic dysfunction, mitochondrial damage, autonomic dysfunction and inflammatory anomalies are thought to be at the root of this situation. In this review study, studies about energy expenditure and energy requirement in neurological diseases have been examined and suggested practices in this field have been presented. Methods: We reviewed articles regarding selected from PubMed, Science Direct, EBSCO, and databases about energy expenditure and neurological diseases. Results: Based on the type of neurological diseases; factors such as stage of the disease, disease complications, metabolic status, mechanical ventilation, body composition, movement restrictions or hyperactivity change energy expenditure and, as a result, nutrition requirement. Determination of the energy requirement is the basic variable for adjusting medical nutrition therapy. Despite an increase in resting energy expenditure as a result of metabolic processes in most neurological disorders, the daily energy expenditure is reported to change based on the restriction of physical activity due to the disorder. Discussion: Determining patient's energy expenditure and energy requirements is regarded as the right approach in terms of improving the patient's quality of life, regulating appropriate medical nutrition treatment and increasing the effectiveness of other treatments.}, }
@article {pmid30284267, year = {2019}, author = {Laidlaw, TM and Prussin, C and Panettieri, RA and Lee, S and Ferguson, BJ and Adappa, ND and Lane, AP and Palumbo, ML and Sullivan, M and Archibald, D and Dworetzky, SI and Hebrank, GT and Bozik, ME}, title = {Dexpramipexole depletes blood and tissue eosinophils in nasal polyps with no change in polyp size.}, journal = {The Laryngoscope}, volume = {129}, number = {2}, pages = {E61-E66}, doi = {10.1002/lary.27564}, pmid = {30284267}, issn = {1531-4995}, support = {//Knopp Biosciences, LLC./International ; }, mesh = {Adult ; Antioxidants/*therapeutic use ; Chronic Disease ; Eosinophilia/*drug therapy ; Eosinophils/*drug effects ; Female ; Humans ; Male ; Nasal Polyps/*drug therapy ; Pramipexole/*therapeutic use ; Prospective Studies ; Rhinitis/*drug therapy ; Sinusitis/*drug therapy ; Treatment Outcome ; }, abstract = {OBJECTIVE: Chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilia is a disease of the upper respiratory tract for which few therapies are available. Because the oral investigational drug dexpramipexole serendipitously decreased blood eosinophils in amyotrophic lateral sclerosis studies, we assessed its safety, eosinophil-lowering activity, and preliminary clinical efficacy in patients with CRSwNP and eosinophilia.<br><br>METHODS: Sixteen subjects with CRSwNP, absolute eosinophil count (AEC)&#x2009;&#x2265;&#x2009;0.300&#x2009;&#xd7;&#x2009;10[9] /L, and polyp tissue eosinophils were evaluable for efficacy in a 6-month open-label, multi-center study of dexpramipexole 150&#x2009;mg twice daily. The coprimary endpoints were change in AEC and change in total polyp score (TPS) from baseline to month 6, with additional clinical and histologic endpoints assessed.<br><br>RESULTS: Thirteen of 16 subjects completed 6 months of dexpramipexole treatment. Geometric mean baseline AEC was 0.525&#x2009;&#xb1;&#x2009;0.465 eosinophils&#x2009;&#xd7;&#x2009;10[9] /L and decreased to 0.031&#x2009;&#xb1;&#x2009;0.019 after 6 months of dexpramipexole treatment, a 94% reduction (P&#x2009;<&#x2009;0.001). Ten of 16 subjects had eosinophil counts reduced to&#x2009;&#x2264;&#x2009;0.020&#x2009;&#xd7;&#x2009;10[9] /L at month 6. In 12 subjects with nasal polyp biopsies at baseline and month 6, tissue eosinophils were reduced from a mean of 168&#x2009;&#xb1;&#x2009;134 to 5&#x2009;&#xb1;&#x2009;2 per high-power field (HPF) (P&#x2009;=&#x2009;0.001), a 97% reduction from baseline. There was no significant reduction in TPS or improvement in other clinical endpoints. Dexpramipexole was well tolerated, with no drug-related serious adverse events.<br><br>CONCLUSION: Dexpramipexole treatment produced profound eosinophil-lowering in peripheral blood and nasal polyp tissue. Despite the near-elimination of polyp eosinophils, decreased TPS and nasal symptom improvement were not observed.<br><br>LEVEL OF EVIDENCE: 2 Laryngoscope, 129:E61-E66, 2019.}, }
@article {pmid30283511, year = {2018}, author = {Ghadirpour, R and Nasi, D and Iaccarino, C and Romano, A and Motti, L and Farneti, M and Pascarella, R and Servadei, F}, title = {Intraoperative Neurophysiological Monitoring in Surgical Treatment of Spinal Dural Arteriovenous Fistulas: Technique and Results.}, journal = {Asian journal of neurosurgery}, volume = {13}, number = {3}, pages = {595-606}, pmid = {30283511}, issn = {1793-5482}, abstract = {OBJECTIVE AND BACKGROUND: Data on intraoperative neurophysiological monitoring (IOM) during surgery of spinal dural arteriovenous fistulas (SDAVFs) are lacking. The purpose of this study was to evaluate the role of IOM during microsurgery for SDAVFs.<br><br>MATERIALS AND METHODS: From March 2007 to March 2013, 12 patients had microsurgery with IOM for SDAVFs. The IOM included somatosensory-evoked potentials, motor-evoked potentials (MEPs), and - in selected cases - D-Waves. All patients were evaluated at admission and at follow-up (6, 12, and 24 months) with Aminoff-Logue Disability Scale for Gait-Aminoff-Logue Disability Scale (G-ALS) and Micturition-Aminoff-Logue Disability Scale (M-ALS).<br><br>STATISTICAL ANALYSIS USED: Logistic regression was used for detecting the clinical risk factors influencing neurological functions after the treatment.<br><br>RESULTS: During surgery, we registered the absence of significant modifications of evoked potentials in nine cases (75%), while improvement of MEPs occurred in three cases (25%). No false-negative case was registered, and IOM predicted the absence of new postoperative neurological deficit in all patients. At 24-month follow-up, nine patients improved their overall neurological status, while three patients remained stable. At univariate analysis, Aminoff-Logue Disability Scales for Gait and Micturition (G + M-ALS) score at 24-month follow-up was directly associated with the duration of symptom before the surgery (P = 0.024), preoperative G-ALS (P = 0.02), M-ALS (P = 0.022), and G + M-ALS scores (P = 0.045), and improvement of IOM after occlusion of the fistula (P = 0.025).<br><br>CONCLUSIONS: In our series, no significant worsening of evoked potentials occurred and subsequently the surgical strategy was not changed by IOM. However, no false-negative case was registered, and IOM predicted the absence of new postoperative neurological deficit in all patients. Patients with improvement of IOM parameters after occlusion of the fistula had greater chances of postsurgical improvement at the univariate analysis.}, }
@article {pmid30283000, year = {2018}, author = {Dervishi, I and Gozutok, O and Murnan, K and Gautam, M and Heller, D and Bigio, E and Ozdinler, PH}, title = {Protein-protein interactions reveal key canonical pathways, upstream regulators, interactome domains, and novel targets in ALS.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {14732}, pmid = {30283000}, issn = {2045-2322}, mesh = {14-3-3 Proteins/genetics ; Amyotrophic Lateral Sclerosis/*genetics/pathology/therapy ; Humans ; *Molecular Targeted Therapy ; Motor Cortex/*metabolism/pathology ; Mutation/genetics ; PPAR gamma/genetics ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics ; Protein Interaction Maps/*genetics ; Pyramidal Cells/metabolism ; Signal Transduction/genetics ; Vesicular Transport Proteins ; }, abstract = {Developing effective treatment strategies for neurodegenerative diseases require an understanding of the underlying cellular pathways that lead to neuronal vulnerability and progressive degeneration. To date, numerous mutations in 147 distinct genes are identified to be "associated" with, "modifier" or "causative" of amyotrophic lateral sclerosis (ALS). Protein products of these genes and their interactions helped determine the protein landscape of ALS, and revealed upstream modulators, key canonical pathways, interactome domains and novel therapeutic targets. Our analysis originates from known human mutations and circles back to human, revealing increased PPARG and PPARGC1A expression in the Betz cells of sALS patients and patients with TDP43 pathology, and emphasizes the importance of lipid homeostasis. Downregulation of YWHAZ, a 14-3-3 protein, and cytoplasmic accumulation of ZFYVE27 especially in diseased Betz cells of ALS patients reinforce the idea that perturbed protein communications, interactome defects, and altered converging pathways will reveal novel therapeutic targets in ALS.}, }
@article {pmid30282815, year = {2018}, author = {Trias, E and King, PH and Si, Y and Kwon, Y and Varela, V and Ibarburu, S and Kovacs, M and Moura, IC and Beckman, JS and Hermine, O and Barbeito, L}, title = {Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALS.}, journal = {JCI insight}, volume = {3}, number = {19}, pages = {}, pmid = {30282815}, issn = {2379-3708}, support = {I01 BX001148/BX/BLRD VA/United States ; I01 BX004419/BX/BLRD VA/United States ; P30 CA013148/CA/NCI NIH HHS/United States ; R01 NS092651/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*immunology/pathology ; Animals ; Axons/drug effects/immunology/pathology ; Benzamides ; Cell Degranulation/drug effects/immunology ; Disease Models, Animal ; Humans ; Male ; Mast Cells/drug effects/*immunology ; Motor Neurons/cytology/immunology/*pathology ; Muscle, Skeletal/cytology/innervation/pathology ; Neuromuscular Junction/drug effects/immunology/*pathology ; Neutrophil Infiltration/drug effects ; Neutrophils/drug effects/*immunology ; Piperidines ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; Pyridines ; Rats ; Rats, Transgenic ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics ; Thiazoles/pharmacology/therapeutic use ; Treatment Outcome ; }, abstract = {Neuroinflammation is a recognized pathogenic mechanism underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS), but the inflammatory mechanisms influencing peripheral motor axon degeneration remain largely unknown. A recent report showed a pathogenic role for c-Kit-expressing mast cells mediating inflammation and neuromuscular junction denervation in muscles from SOD1G93A rats. Here, we have explored whether mast cells infiltrate skeletal muscles in autopsied muscles from ALS patients. We report that degranulating mast cells were abundant in the quadriceps muscles from ALS subjects but not in controls. Mast cells were associated with myofibers and motor endplates and, remarkably, interacted with neutrophils forming large extracellular traps. Mast cells and neutrophils were also abundant around motor axons in the extensor digitorum longus muscle, sciatic nerve, and ventral roots of symptomatic SOD1G93A rats, indicating that immune cell infiltration extends along the entire peripheral motor pathway. Postparalysis treatment of SOD1G93A rats with the tyrosine kinase inhibitor drug masitinib prevented mast cell and neutrophil infiltration, axonal pathology, secondary demyelination, and the loss of type 2B myofibers, compared with vehicle-treated rats. These findings provide further evidence for a yet unrecognized contribution of immune cells in peripheral motor pathway degeneration that can be therapeutically targeted by tyrosine kinase inhibitors.}, }
@article {pmid30267401, year = {2018}, author = {Lawal, IO and Ankrah, AO and Mokoala, KMG and Popoola, GO and Kaoma, CA and Maes, A and Mokgoro, NP and Van de Wiele, C and Sathekge, MM}, title = {Prognostic Value of Pre-treatment F-18 FDG PET Metabolic Metrics in Patients with Locally Advanced Carcinoma of the Anus with and without HIV Infection.}, journal = {Nuklearmedizin. Nuclear medicine}, volume = {57}, number = {5}, pages = {190-197}, doi = {10.3413/Nukmed-0965-18-03}, pmid = {30267401}, issn = {2567-6407}, mesh = {Adult ; Age Factors ; Aged ; Anus Neoplasms/complications/*diagnosis/diagnostic imaging/pathology ; Carcinoma, Squamous Cell/complications/*diagnosis/diagnostic imaging/pathology ; Female ; Fluorodeoxyglucose F18/*administration &amp; dosage ; Follow-Up Studies ; HIV/physiology ; HIV Infections/*complications/virology ; Humans ; Male ; Middle Aged ; Neoplasm Metastasis ; Positron-Emission Tomography/*methods ; Prognosis ; Radiopharmaceuticals/*administration &amp; dosage ; Survival Rate ; }, abstract = {AIM: To investigate the prognostic value of F-18 FDG PET metabolic parameters in patients with anal carcinoma with and without human immunodeficiency virus infection (HIV).<br><br>METHODS: Maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were obtained on F-18 FDG PET/CT images of treatment-na&#xef;ve patients with locally advanced anal squamous cell carcinoma (ASSC). We compared patients' characteristics and F-18 FDG PET metabolic metrics between the HIV-infected patients and the HIV-uninfected patients. We did a simple Cox regression analysis followed by a multiple Cox regression analysis to determine factors predictive of death.<br><br>RESULTS: We studied 33 patients including 21 HIV-infected individuals, mean age = 46.06 &#xb1; 12.59, female = 16, males = 17. Median CD4 count among HIV-infected patients was 400.50 cells/mm[3] (IQR: 304.0 - 642.25). HIV-infected patients were younger than the HIV-uninfected patients at the time of diagnosis; 38.71 &#xb1; 7.98 vs. 58.92 &#xb1; 7.88 respectively, p < 0.001. No significant difference in the TNM stage and F-18 FDG metabolic parameters between the two groups. In a simple Cox regression analysis, MTV and TLG were significant predictors of death. Following a multiple Cox regression analysis, MTV and SUVmean were significant predictors of death. The median overall survival was 44.63 (95 % CI: 34.12 - 55.14) among HIV-infected patients versus 54.65 (95 % CI: 45.73 - 63.57) among HIV-uninfected patients, p = 0.415.<br><br>CONCLUSION: HIV-infected patients are diagnosed with ASSC at a younger age compared with HIV-uninfected patients. F-18 FDG PET metabolic metrics especially MTV predicts overall survival in patients with ASCC. There is no difference in the overall survival of HIV-infected and HIV-uninfected patients treated similarly for ASSC. ZIEL:: Die Untersuchung der prognostischen Bedeutung der F-18 FDG PET metabolischen Aktivit&#xe4;t bei HIV-negativen und positiven Analkarzinom-Patienten.<br><br>METHODEN: Bestimmt wurden maximale standardisierten Uptake-Werte (SUVmax), mittlere standardisierte Uptake-Werte (SUVmean), das metabolische Tumorvolumen (MTV) sowie die gesamte Tumorlyse-Glukose (TLG) mittels F-18 FDG PET/CT bei behandlungsnaiven Patienten mit lokal fortgeschrittenem Anal-Plattenepithelkarzinom (ASSC). Die Patientencharakteristika und F-18 FDG PET metabolischen Ergebnisse der HIV-positiven und HIV-negativen Patienten wurden verglichen. Eine einfache Cox-Regressionsanalyse gefolgt von einer multiplen Cox-Regressionsanalyse diente der Bestimmung von Faktoren f&#xfc;r Tod.<br><br>ERGEBNISSE: Wir untersuchten 33 Patienten, davon 21 HIV-Infizierte, mittleres Alter = 46,06 &#xb1; 12,59, Frauen = 16, M&#xe4;nner = 17. Die mediane CD4-Zahl unter den HIV-Patienten war 400,50 Zellen/mm[3] (IRQ: 304,0 - 642,25). Die HIV-infizierten Patienten waren j&#xfc;nger als die HIV-negativen Patienten zum Zeitpunkt der Diagnose; 38,71 &#xb1; 7,98 vs. 58,92 &#xb1; 7,88, p < 0,001. Es gab keinen signifikanten Unterschied in der TNM-Klassifikation und in den F-18 FDG metabolischen Werten zwischen den beiden Gruppen. In einer einfachen Cox-Regressionsanalyse waren MTV und TLG signifikante Pr&#xe4;diktoren f&#xfc;r Tod. Das mediane Gersamt&#xfc;berleben lag bei 44,63 (95 % CI: 34,12 - 55,14) unter den HIV-infizierten Patienten vs. 54,65 (95 % CI: 45,73 - 63,57) unter den HIV-negativen Patienten, p = 0,415.<br><br>SCHLUSSFOLGERUNGEN: HIV-infizierte Patienten werden in j&#xfc;ngeren Jahren mit ASSC diagnostiziert im Vergleich zu HIV-negativen Patienten. F-18 FDG PET metabolische Aktivit&#xe4;t, insbesondere MTV, kann das Gesamt&#xfc;berleben von Patienten mit ASCC vorhersagen. Es gibt keinen Unterschied im Gesamt&#xfc;berleben von HIV-infizierten und HIV-negativen Patienten bei gleicher Therapie des ASSC.}, }
@article {pmid30266516, year = {2018}, author = {Mitsutake, H and Castro, SR and de Paula, E and Poppi, RJ and Rutledge, DN and Breitkreitz, MC}, title = {Comparison of different chemometric methods to extract chemical and physical information from Raman images of homogeneous and heterogeneous semi-solid pharmaceutical formulations.}, journal = {International journal of pharmaceutics}, volume = {552}, number = {1-2}, pages = {119-129}, doi = {10.1016/j.ijpharm.2018.09.058}, pmid = {30266516}, issn = {1873-3476}, mesh = {Ethylene Glycols/chemistry ; Excipients/*chemistry ; Least-Squares Analysis ; Palmitates/chemistry ; Pharmaceutical Preparations/*chemistry ; Polyethylene Glycols/chemistry ; Polysorbates/chemistry ; Principal Component Analysis ; *Spectrum Analysis, Raman ; }, abstract = {In formulations of nanostructured lipid carriers, lipid solid dispersions and self-emulsifying drug delivery systems, it is common that a solid or semi-solid lipid excipient is mixed with a liquid solvent or liquid lipid. Even when the excipients are visually miscible upon melting, they might have microscopic non-homogeneities which could lead to instability over time and future phase separation. Raman mapping associated with chemometric methods can be useful to evaluate spatial distribution of compounds, however it has not been extensively applied to the formulations mentioned above. The aim of this work was to compare the outcomes of three different chemometric methods - principal components analysis (PCA), multivariate curve resolution with alternating least squares (MCR-ALS) and independent components analysis (ICA) - to study two systems of very different degrees of microscopic miscibility: cetyl palmitate + Transcutol[©] (heterogeneous) and polyethylene glycol 6000 (PEG 6000) + Tween 80[©] (homogeneous). These two samples were chosen due to large differences in spatial distribution of the compounds over the pixels which could require different approaches for data treatment. The three methods were compared regarding recovered concentrations (or scores), signals (or loadings) and the need for matrix augmentation to obtain reliable results. Results showed that PCA loadings were the mathematical differences of the spectra of pure compounds for both samples, and therefore only 'contrast images' could be generated. MCR and ICA provided signals that could be related to the chemical components, however MCR presented rotational ambiguities even for the very heterogeneous sample, a situation in which ICA performed better as a blind search method. For the homogeneous sample, both methods showed rank deficiency and therefore the use of a matrix augmentation was necessary. ICA and PCA allowed identifying physical modifications in the homogeneous semi-solid PEG 6000/Tween 80[®] sample over the time, probably due to the folding/unfolding of the crystalline chains of PEG 6000. Therefore, this work discusses the ability of the three chemometrics methods to extract information from Raman spectra in order to characterize the chemical, spatial and even physical aspects of semi-solid pharmaceutical formulations, which could be of much use for stability studies of different drug delivery systems.}, }
@article {pmid30258257, year = {2018}, author = {Singh, N and Ray, S and Srivastava, A}, title = {Clinical Mimickers of Amyotrophic Lateral Sclerosis-Conditions We Cannot Afford to Miss.}, journal = {Annals of Indian Academy of Neurology}, volume = {21}, number = {3}, pages = {173-178}, pmid = {30258257}, issn = {0972-2327}, abstract = {Giving a diagnosis of amyotrophic lateral sclerosis to a patient is akin to handing out a death certificate. However, not all patients presenting with the classical dysphagia, wasting, and weakness may have motor neuron diseases. In these cases, it is extremely important not to miss little cues which can suggest an alternative diagnosis and in many cases a lease of life in terms of a treatment option. In this review, we consider some clinical scenarios that can present with the same symptom complex as diseases involving motor neurons but have a different anatomical or etiopathological basis and in many cases even a therapeutic option.}, }
@article {pmid30257805, year = {2018}, author = {Lai, X and Gu, X and Yang, X and Sun, J and Jiang, M and Bu, B and Feng, G and Li, L}, title = {Motor neurone disease-associated neck pain misdiagnosed as cervical spondylosis: A case report and literature review.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {55}, number = {}, pages = {112-115}, doi = {10.1016/j.jocn.2018.06.048}, pmid = {30257805}, issn = {1532-2653}, mesh = {*Diagnostic Errors ; Disease Progression ; Humans ; Intracranial Hypertension/etiology ; Male ; Middle Aged ; Motor Neuron Disease/complications/*diagnosis ; Neck Pain/*etiology ; Neurologic Examination ; Respiratory Insufficiency/etiology ; Spondylosis/complications/*diagnosis ; }, abstract = {BACKGROUND: Motor neurone disease (MND) is a chronic, progressive and currently incurable neurodegenerative disorder. Although pain as a symptom appears in many patients with MND, it is often misdiagnosed as other diseases when occurs before the onset of weakness. Patients are often assigned to non-neurological departments due to the atypical symptoms, which can lead to diagnostic delay and inappropriate treatment.<br><br>OBJECTIVE: To analyze the causes of misdiagnosis and improve the clinician's understanding of neck pain in patients with MND.<br><br>METHODS: We reviewed relevant literature and retrospectively reported a misdiagnosis case of MND-associated neck pain.<br><br>RESULTS: A case of MND presenting prominently as neck pain was suspected of suffering from cervical spondylosis and wrongly assigned to orthopedic clinic. When eventually being diagnosed as MND, his neck pain was found to be caused by intracranial hypertension (ICH) resulting from hypoxia via insidious respiratory failure through ventilator insufficiency.<br><br>CONCLUSION: Careful evaluation of the clinical progression of the symptoms, extensive EMG and nerve conduction study, as well as the establishment of better clinical approach to the diagnosis and higher public awareness allow a reduction of misdiagnosis.}, }
@article {pmid30257722, year = {2018}, author = {Barbeito, L}, title = {Astrocyte-based cell therapy: new hope for amyotrophic lateral sclerosis patients?.}, journal = {Stem cell research &amp; therapy}, volume = {9}, number = {1}, pages = {241}, pmid = {30257722}, issn = {1757-6512}, mesh = {Amyotrophic Lateral Sclerosis/genetics/physiopathology/*therapy ; Animals ; Astrocytes/cytology/*transplantation ; *Cell- and Tissue-Based Therapy ; Disease Models, Animal ; Gene Expression Regulation, Enzymologic/genetics ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons ; Superoxide Dismutase-1/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disease with no cure or treatment to stop disease progression. Because ALS represents an urgent unmet medical need, a significant number of therapeutics are being tested in preclinical and clinical studies. A recent publication in Stem Cell Research &amp; Therapy by Izrael and colleagues reports about embryonic stem cell-derived astrocytes as a potential cell therapy for ALS. Such cells behave as highly trophic "young astrocytes", being able to delay disease onset and prolong survival when injected intrathechally in murine models of ALS overexpressing the SOD1[G93A] mutation. The safety and therapeutic potential of these cells are currently being evaluated in a clinical trial in ALS patients. This commentary discusses the mechanisms of action and potential therapeutic effects of these "young astrocytes" in ALS.}, }
@article {pmid30255159, year = {2018}, author = {Caggiu, E and Paulus, K and Mameli, G and Arru, G and Sechi, GP and Sechi, LA}, title = {Differential expression of miRNA 155 and miRNA 146a in Parkinson's disease patients.}, journal = {eNeurologicalSci}, volume = {13}, number = {}, pages = {1-4}, pmid = {30255159}, issn = {2405-6502}, abstract = {Parkinson's disease is a neurodegenerative disorder and its etiology is unknown, numerous studies show how different environmental factors can influence the development of disease. miRNAs are involved in several pathologies and their dysregulation contribute to different pathologies, also in neurodegenerative such as Parkinson's disease, Alzheimer's disease, Huntington's disease and Amyotrophic lateral sclerosis. In this study, we profiled the expression of different candidate miRNAs: miR-155, miR-26a, miR-146a, and miR132, in PBMCs of L-dopa treated Parkinson patients and unaffected controls (HCs).We investigated the expression of miRNAs by RT-real time PCR, the results were subjected to statistical analysis. miRNA-155-5p was generally up-regulated in PD patients compared to HCs whereas miRNA-146a-5p was down-regulated in PD patients in comparison to HCs. It is interesting to point out that the expression of miR-155-5p was modified by levodopa treatment, in fact a down-regulation of miR-155-5p in PD patients with the highest dosage was observed. In conclusion, miRNA 155 could not only be a promising target for the anti-inflammatory therapy in PD but also a good candidate as a disease progression biomarker. The role of levodopa in modulating the levels of miRNA 155 requires further studies.}, }
@article {pmid30244551, year = {2018}, author = {Lau, FS and Brennan, FP and Gardiner, MD}, title = {Multidisciplinary management of motor neurone disease.}, journal = {Australian journal of general practice}, volume = {47}, number = {9}, pages = {593-597}, doi = {10.31128/AJGP-02-18-4495}, pmid = {30244551}, issn = {2208-7958}, mesh = {Dyspnea/drug therapy/etiology ; Humans ; Interdisciplinary Communication ; Motor Neuron Disease/*complications/*drug therapy/epidemiology ; Muscle Spasticity/drug therapy/etiology ; Neuroprotective Agents/adverse effects/therapeutic use ; Pain/drug therapy/etiology ; Palliative Care/methods ; Riluzole/adverse effects/therapeutic use ; }, abstract = {BACKGROUND: Motor neurone disease (MND) is the term for a group of progressive, debilitating, neurodegenerative disorders that affect various aspects of a patient's life, including speech, swallowing, breathing and limb function.<br><br>OBJECTIVE: This review outlines the common symptoms and issues in MND and the latest available treatment options. A multidisciplinary approach to MND, involving the general practitioner (GP) and rehabilitation, palliative care and allied health services, is discussed.<br><br>DISCUSSION: The complexity of care for patients with MND and their families is best managed using a multidisciplinary team approach, with the GP as an important member of that team. The biopsychosocial care model discussed can improve the quality of life for patients and carers, as well as the life&#xa0;expectancy of patients with MND.}, }
@article {pmid30242613, year = {2019}, author = {Javorkova, E and Matejckova, N and Zajicova, A and Hermankova, B and Hajkova, M and Bohacova, P and Kossl, J and Krulova, M and Holan, V}, title = {Immunomodulatory Properties of Bone Marrow Mesenchymal Stem Cells from Patients with Amyotrophic Lateral Sclerosis and Healthy Donors.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {14}, number = {2}, pages = {215-225}, pmid = {30242613}, issn = {1557-1904}, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Bone Marrow Cells/*immunology ; Cytokines/metabolism ; Female ; Healthy Volunteers ; Humans ; Immunologic Factors/pharmacology ; Immunomodulation ; Leukocytes, Mononuclear/drug effects/immunology ; Male ; Mesenchymal Stem Cells/*immunology ; Middle Aged ; Mitogens/pharmacology ; T-Lymphocytes, Helper-Inducer/drug effects/immunology ; Tumor Necrosis Factor-alpha/biosynthesis ; }, abstract = {Pathogenesis of amyotrophic lateral sclerosis (ALS) involves several mechanisms resulting in a shift from a neuroprotective to a neurotoxic immune reaction. A promising tool for ALS treatment is represented by mesenchymal stem cells (MSCs), which possess both regenerative potential and immunomodulatory properties. In this study, we aimed to compare the immunomodulatory properties of MSCs isolated from the bone marrow of patients suffering from ALS and healthy donors. Moreover, the influence of proinflammatory cytokines on the immunoregulatory functions of MSCs was also evaluated. We found that MSCs from ALS patients and healthy donors comparably affected mitogen-stimulated peripheral blood mononuclear cells and reduced the percentage of T helper (Th)1, Th17 and CD8[+]CD25[+] lymphocytes. These MSCs also equally increased the percentage of Th2 and CD4[+]FOXP3[+] T lymphocytes. On the other hand, MSCs from ALS patients decreased more strongly the production of tumour necrosis factor-α than MSCs from healthy donors, but this difference was abrogated in the case of MSCs stimulated with cytokines. Significant differences between cytokine-treated MSCs from ALS patients and healthy donors were detected in the effects on the percentage of CD8[+]CD25[+] and CD4[+]FOXP3[+] T lymphocytes. In general, treatment of MSCs with cytokines results in a potentiation of their effects, but in the case of MSCs from ALS patients, it causes stagnation or even restriction of some of their immunomodulatory properties. We conclude that MSCs from ALS patients exert comparable immunomodulatory effects to MSCs from healthy donors, but respond differently to stimulation with proinflammatory cytokines. Graphical Abstract Treatment of mesenchymal stem cells (MSCs) with cytokines results in a potentiation of their effects, but in the case of MSCs from amyotrophic lateral sclerosis (ALS) patients, it causes stagnation (an equal reduction of the percentage of CD8[+]CD25[+] T lymphocytes) or even restriction (no increase of proportion of CD4[+]FOXP3[+] T lymphocytes) of some of their immunomodulatory properties. It means that MSCs from ALS patients exert comparable immunomodulatory effects to MSCs from healthy donors, but respond differently to stimulation with proinflammatory cytokines.}, }
@article {pmid30242088, year = {2019}, author = {Luna, J and Diagana, M and Ait Aissa, L and Tazir, M and Ali Pacha, L and Kacem, I and Gouider, R and Henning, F and Basse, A and Cisse, O and Balogou, AAK and Kombate, D and Agbetou, M and Houinato, D and Millogo, A and Agba, T and Belo, M and Penoty, M and Raymondeau-Moustafa, M and Hamidou, B and Couratier, P and Preux, PM and Marin, B and , }, title = {Clinical features and prognosis of amyotrophic lateral sclerosis in Africa: the TROPALS study.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {90}, number = {1}, pages = {20-29}, doi = {10.1136/jnnp-2018-318469}, pmid = {30242088}, issn = {1468-330X}, mesh = {Adult ; Africa, Northern/epidemiology ; Africa, Southern/epidemiology ; Africa, Western/epidemiology ; Age of Onset ; Aged ; Amyotrophic Lateral Sclerosis/drug therapy/epidemiology/mortality/*physiopathology ; Cohort Studies ; Humans ; Middle Aged ; Neuroprotective Agents/therapeutic use ; Prognosis ; Proportional Hazards Models ; Riluzole/therapeutic use ; Sex Distribution ; Survival Rate ; }, abstract = {OBJECTIVE: We describe and compare the sociodemographic and clinical features, treatments, and prognoses and survival times of patients with amyotrophic lateral sclerosis (ALS) in Africa.<br><br>METHODOLOGY: We conducted a multicentre, hospital-based cohort study in Africa. Patients with ALS diagnosed in the neurology departments of participating hospitals from 2005 to 2017 were included. Subgroup analysis was performed by subcontinent. Survival analyses were conducted using the Cox proportional hazards model.<br><br>RESULTS: Nine centres from eight African countries participated. A total of 185 patients with ALS were included: 114 from Northern Africa, 41 from Western Africa and 30 from Southern Africa. A male predominance (male to female ratio 2.9) was evident. The median age at onset was 53.0 years (IQR 44.5-64.0 years). The onset was bulbar in 22.7%. Only 47 patients (26.3%) received riluzole, mainly in Northern and Western Africa. The median survival from the time of diagnosis was 14.0 months (95%&#x2009;CI 10.7 to 17.2 months). The median survival was longer in Northern Africa (19.0 months, 95%&#x2009;CI 10.8 to 27.2 months) than in Western (4.0 months, 95%&#x2009;CI 0.8 to 7.1 months) and Southern (11.0 months, 95%&#x2009;CI 5.6 to 16.4 months) Africa (Breslow test, p<0.0001). Both subcontinental location and riluzole treatment independently affected survival.<br><br>CONCLUSION: More African patients with ALS were male and younger and exhibited a lower proportion of bulbar onset compared with patients with ALS from Western nations. Survival was consistent with that in Western registers but far shorter than what would be expected for young patients with ALS. The research improves our understanding of the disease in Africa.}, }
@article {pmid30241688, year = {2018}, author = {Wang, J and Chen, X and Yuan, B and Wang, W and Xu, C and Zhao, W and Zhao, P and Wang, Y and Zhao, X and Wang, Y}, title = {Bioavailability of Edaravone Sublingual Tablet Versus Intravenous Infusion in Healthy Male Volunteers.}, journal = {Clinical therapeutics}, volume = {40}, number = {10}, pages = {1683-1691}, doi = {10.1016/j.clinthera.2018.08.009}, pmid = {30241688}, issn = {1879-114X}, mesh = {Administration, Sublingual ; Adult ; Area Under Curve ; Biological Availability ; China ; Cross-Over Studies ; Edaravone/*administration &amp; dosage/pharmacokinetics ; Humans ; Infusions, Intravenous ; Male ; Neuroprotective Agents/*administration &amp; dosage/pharmacokinetics ; Tablets ; Young Adult ; }, abstract = {PURPOSE: Edaravone is a free-radical scavenger. Edaravone 30mg IV has been approved for use in the treatment of acute ischemic stroke in Japan and China, and for amyotrophic lateral sclerosis in Japan and the United States. Considering the inconvenience of IV infusion in clinical practice, an oral tablet formulation of edaravone was developed but failed in 2011 due to poor bioavailability. More recently, a sublingual (SL) tablet formulation of edaravone 30mg was developed by a Good Manufacturing Practices-compliant manufacturer in China. This study explored the bioavailability of the SL tablet of edaravone and aimed to provide evidence to support decision making in future clinical development.<br><br>METHODS: This 2-way crossover study was conducted in 10 healthy male volunteers. Eligible subjects were randomized, in a 1:1 ratio, to 1 of 2 dosing sequences: (1) SL edaravone 30mg, followed by edaravone 30mg IV infusion given over 30 minutes; or (2) edaravone 30mg IV infusion given over 30 minutes, followed by SL edaravone 30mg. The washout period between the 2 dosing periods was at least 24hours. Serial blood samples were collected in each dosing period. The bioavailability of the SL tablet was assessed using bioavailability analysis. Tolerability was evaluated throughout the study.<br><br>FINDINGS: The plasma concentration-time profile of the SL tablet was similar to that with the IV infusion. Amean (SD) Cmax of 2030.2 (517.2) ng/mL was reached within a median Tmax of 0.875hour, which was statistically significantly longer than the median Tmax with IV administration (0.5 hour). The Cmax with SL administration corresponded to 83.92% (90% CI, 73.22%-96.18%) of the Cmax with the start of IV infusion (2354.0 [336.6] ng/mL). The mean AUC0-t with SL dosing was 5420.07 (1429.75) h &#xb7; ng/mL, which corresponded to 91.94% (90% CI, 86.81%-97.39%) of the AUC0-t with IV administration (5824.42 [1338.48] h &#xb7; ng/mL). Two cases of adverse events were reported during the study; both were considered by the investigator to have been possibly not related to the study treatment.<br><br>IMPLICATIONS: The bioavailability of the SL tablet of edaravone was 91.94%. Compared with IV administration, Cmax with SL administration was &#x223c;17% lower and Tmax was statistically significantly longer. The exposure differences can be addressed by modifying the strength of the SL tablet, and then conducting a second study to demonstrate the pharmacokinetic bioavailability of the sublingually administered new strength versus IV infusion of edaravone.}, }
@article {pmid30233272, year = {2018}, author = {Fiorentino, G and Annunziata, A and Gaeta, AM and Lanza, M and Esquinas, A}, title = {Continuous noninvasive ventilation for respiratory failure in patients with amyotrophic lateral sclerosis: current perspectives.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {8}, number = {}, pages = {55-61}, pmid = {30233272}, issn = {1179-9900}, abstract = {Respiratory failure is a recognized late complication of amyotrophic lateral sclerosis. It is related to the neurological progression of the diseases with the impairment of the respiratory musculature. Survival and quality of life of amyotrophic lateral sclerosis patients is improved by using noninvasive mechanical ventilation. The rate of long-term mechanical ventilation is different within and between countries. Cultural factors, socioeconomic conditions, and physician attitude often influence the decision to start noninvasive ventilation. Technical elements, like the choice of the correct interface, solid caregivers support, and the communication between the patient and the physician are essential for achieving therapeutic goals, especially in the case of continuous treatment.}, }
@article {pmid30232045, year = {2018}, author = {Wei, QQ and Chen, Y and Chen, X and Cao, B and Ou, R and Zhang, L and Hou, Y and Shang, H}, title = {Clinical and prognostic features of ALS/MND in different phenotypes-data from a hospital-based registry.}, journal = {Brain research bulletin}, volume = {142}, number = {}, pages = {403-408}, doi = {10.1016/j.brainresbull.2018.09.005}, pmid = {30232045}, issn = {1873-2747}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*diagnosis/*epidemiology/physiopathology ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Phenotype ; Prognosis ; Prospective Studies ; Registries ; Survival Analysis ; Young Adult ; }, abstract = {OBJECTIVES: To explore the natural history, clinical features, and survival relevance of patients presenting with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) with different phenotypes.<br><br>METHODS: All patients were prospectively enrolled in a hospital-based register from 2006 to 2015. Cases were classified according to established phenotypes: classic, bulbar, flail arm, flail leg, upper motor neuron dominate, respiratory, pure lower motor neuron and pure upper motor neuron. Survival was analyzed using Kaplan-Meier curves and Cox regression analysis.<br><br>RESULTS: A total of 1157 patients with complete clinical information were registered in the current cohort study. The classic phenotype was the most frequent phenotype. The mean age of onset, diagnostic delay, smoking status, exposure to pesticides and mean survival time were significantly different among different phenotypes. The median survival time was 3.1&#x2009;years for all patients. At the end of the analysis, the 3-year survival rate was 62.1%, the 5-year survival rate was 39.6%, and the 10-year survival rate was 22.0%. The Cox analysis revealed that the disease phenotype was an independent predictor of survival (hazard ratio&#x2009;=&#x2009;0.825, P&#x2009;<&#x2009;0.001), after adjusting for other factors.<br><br>CONCLUSIONS: This study showed the natural history data of ALS/MND and supported the theory that varied disease phenotypes had different clinical, demographic and prognostic characteristics, which provided the basis for analysis of future management and treatment for ALS/MND. Furthermore, the phenotypic expression of ALS/MND with distinctive characteristics is important for providing complementary information for identifying the underlying mechanisms of the diseases.}, }
@article {pmid30222983, year = {2018}, author = {Lazarevic, V and Yang, Y and Ivanova, D and Fejtova, A and Svenningsson, P}, title = {Riluzole attenuates the efficacy of glutamatergic transmission by interfering with the size of the readily releasable neurotransmitter pool.}, journal = {Neuropharmacology}, volume = {143}, number = {}, pages = {38-48}, doi = {10.1016/j.neuropharm.2018.09.021}, pmid = {30222983}, issn = {1873-7064}, mesh = {Animals ; CD146 Antigen/metabolism ; Cells, Cultured ; Cerebral Cortex/drug effects/metabolism ; Excitatory Amino Acid Antagonists/*pharmacology ; Glutamic Acid/*metabolism ; Male ; Mice, Inbred C57BL ; Neuronal Plasticity/drug effects/physiology ; Neuroprotective Agents/*pharmacology ; Presynaptic Terminals/drug effects/metabolism ; Protein Kinase C/metabolism ; Rats, Wistar ; Riluzole/*pharmacology ; Synaptic Transmission/*drug effects/physiology ; Synaptic Vesicles/*drug effects/metabolism ; }, abstract = {Riluzole is a potent neuroprotective agent which primarily inhibits excitatory neurotransmission interfering with presynaptic release, uptake and postsynaptic actions of glutamate by mechanisms that are not well understood. Riluzole and related prodrugs with improved blood brain barrier penetrance, are shown to be effective for the treatment of amyotrophic lateral sclerosis, ataxias, epilepsy and mood disorders. Our study was undertaken to decipher molecular and subcellular mechanisms of riluzole's antiglutamatergic effect, particularly focusing on presynaptic active zone structure and function. Applying multifarious live cell imaging techniques and amperometric glutamate recordings, we measured the impact of riluzole on presynaptic activity, synaptic vesicle recycling and glutamate release. Our in vitro and in vivo data revealed a unique mechanism whereby riluzole reduces the efficacy of glutamatergic transmission by selectively lowering the size of the readily releasable pool. This effect was correlated with the inhibition of protein kinase C-dependent Munc18-1 phosphorylation which is known to interfere with neurotransmitter release.}, }
@article {pmid30220791, year = {2018}, author = {Volk, AE and Weishaupt, JH and Andersen, PM and Ludolph, AC and Kubisch, C}, title = {Current knowledge and recent insights into the genetic basis of amyotrophic lateral sclerosis.}, journal = {Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V}, volume = {30}, number = {2}, pages = {252-258}, pmid = {30220791}, issn = {0936-5931}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease, affecting the upper and/or lower motor neurons. However, extramotor symptoms can also occur; cognitive deficits are present in more than 40% of patients and 5-8% of ALS patients develop frontotemporal dementia. There is no effective treatment for ALS and median survival is 2-3 years after onset. Amyotrophic lateral sclerosis is a genetically heterogeneous disorder with monogenic forms as well as complex genetic etiology. Currently, complex genetic risk factors are of minor interest for routine diagnostic testing or counseling of patients and their families. By contrast, a monogenic cause can be identified in 70% of familial and 10% of sporadic ALS cases. The most frequent genetic cause is a noncoding hexanucleotide repeat expansion in the C9orf72 gene. In recent years, high-throughput sequencing technologies have helped to identify additional monogenic and complex risk factors of ALS. Genetic counseling should be offered to all ALS patients and their first- and possibly second-degree relatives, and should include information about the possibilities and limitations of genetic testing. Routine diagnostic testing should at least encompass the most frequently mutated disease genes (C9orf72, SOD1, TDP-43, FUS). Targeted sequencing approaches including further disease genes may be applied. Caution is warranted as the C9orf72 repeat expansion cannot be detected by routine sequencing technologies and testing by polymerase chain reaction (PCR) is failure-prone. Predictive testing is possible in families in which a genetic cause has been identified, but the limitations of genetic testing (i. e., the problems of incomplete penetrance, variable expressivity and possible oligogenic inheritance) have to be explained to the families.}, }
@article {pmid30219376, year = {2019}, author = {Nguyen, H and Zarriello, S and Coats, A and Nelson, C and Kingsbury, C and Gorsky, A and Rajani, M and Neal, EG and Borlongan, CV}, title = {Stem cell therapy for neurological disorders: A focus on aging.}, journal = {Neurobiology of disease}, volume = {126}, number = {}, pages = {85-104}, pmid = {30219376}, issn = {1095-953X}, support = {R01 NS071956/NS/NINDS NIH HHS/United States ; R01 NS090962/NS/NINDS NIH HHS/United States ; R21 NS089851/NS/NINDS NIH HHS/United States ; R21 NS094087/NS/NINDS NIH HHS/United States ; }, mesh = {*Aging ; Animals ; Cell- and Tissue-Based Therapy/*methods/trends ; Humans ; Nervous System Diseases/*therapy ; Stem Cells ; }, abstract = {Age-related neurological disorders continue to pose a significant societal and economic burden. Aging is a complex phenomenon that affects many aspects of the human body. Specifically, aging can have detrimental effects on the progression of brain diseases and endogenous stem cells. Stem cell therapies possess promising potential to mitigate the neurological symptoms of such diseases. However, aging presents a major obstacle for maximum efficacy of these treatments. In this review, we discuss current preclinical and clinical literature to highlight the interactions between aging, stem cell therapy, and the progression of major neurological disease states such as Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and multiple system atrophy. We raise important questions to guide future research and advance novel treatment options.}, }
@article {pmid30212959, year = {2018}, author = {Huang, Q and Wang, Y and Xia, Y and Li, L and Luo, J and Xia, S and Sun, Y and Miao, Y and Wang, K and Chen, Y}, title = {Testing the neutral theory of biodiversity with the microbiome dataset from cystic fibrosis patients.}, journal = {Medicine}, volume = {97}, number = {37}, pages = {e12248}, pmid = {30212959}, issn = {1536-5964}, mesh = {Anti-Bacterial Agents/*pharmacology ; Cystic Fibrosis/*pathology ; Humans ; Lung/*drug effects/*microbiology ; *Microbiota ; Models, Statistical ; Sputum/microbiology ; }, abstract = {Cystic fibrosis (CF) is a hereditary disease that is characterized by defective mucociliary clearance, airway obstruction, chronic infection, and persistent inflammation. Cystic fibrosis pulmonary exacerbation (CFPE) majorly causes the morbidity of CF patients. Although CF has been demonstrated to change the composition of lung microbial community, previous studies have not made efforts to study the differences in the mechanism of assembly and diversity maintenance of lung microbial community in CF patients. In this study, we applied the neutral theory of biodiversity to comparatively investigate the assembly and diversity maintenance of the lung microbial community before and after the antibiotic treatment by reanalyzing the dataset from Fodor et al's study. We found that no one sample in the lung microbial communities of the sputum samples of Exacerbation group, nor those of End-of-treatment group satisfied the predictions of neutral model, suggesting that the neutral-process does not dominate in CF patients before and after antibiotic treatments. By comparing the biodiversity parameter between Exacerbation and End-of-treatment group, we found that the former had the significantly higher biodiversity, but the change in diversity parameter is slight and the P value is close to.05 (P value = .41). Therefore, our second finding is that although CFPE may increase the biodiversity of lung microbial community, the change is not essential.}, }
@article {pmid30207671, year = {2018}, author = {Schultz, J}, title = {Disease-modifying treatment of amyotrophic lateral sclerosis.}, journal = {The American journal of managed care}, volume = {24}, number = {15 Suppl}, pages = {S327-S335}, pmid = {30207671}, issn = {1936-2692}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Edaravone/therapeutic use ; Humans ; Neuroprotective Agents/therapeutic use ; Quality of Life ; Riluzole/therapeutic use ; }, abstract = {Currently, there is no cure for amyotrophic lateral sclerosis (ALS) and the foundation of ALS management revolves around symptomatic and palliative care. Early diagnosis offers the best prognosis for a longer, quality life while living with the disease. Many medications are used to relieve symptoms but there are only 2 pharmacologic agents indicated for the management of ALS. For 2 decades, riluzole had been the mainstay of disease-modifying therapy, but in 2017, edaravone became the second agent approved in the management of patients with ALS. The mechanism of either agent is not well known. Riluzole is thought to reduce damage to motor neurons through an inhibitory effect on glutamate release, while edaravone is thought to act as a neuroprotective agent that prevents oxidative stress damage as a free radical scavenger. With the lack of treatment options, it is imperative for healthcare professionals to understand the nuances of using these 2 agents to optimize therapy and quality of life for patients with ALS.}, }
@article {pmid30203797, year = {2018}, author = {Li, D and Li, YP and Li, YX and Zhu, XH and Du, XG and Zhou, M and Li, WB and Deng, HY}, title = {Effect of Regulatory Network of Exosomes and microRNAs on Neurodegenerative Diseases.}, journal = {Chinese medical journal}, volume = {131}, number = {18}, pages = {2216-2225}, pmid = {30203797}, issn = {2542-5641}, mesh = {Alzheimer Disease ; Amyloid beta-Peptides ; *Exosomes ; Humans ; *MicroRNAs ; Neurodegenerative Diseases/*genetics/metabolism ; }, abstract = {OBJECTIVE: A comprehensive review of the network regulation of exosomes and microRNAs (miRNAs) in neurodegenerative diseases was done, centering on the mechanism of the formation of exosomes and miRNAs and the sorting mechanism of exosomal miRNAs, with the aim to provide a theoretical basis in the search of biomarkers and the treatment of neurodegenerative diseases.<br><br>DATA SOURCES: The comprehensive search used online literature databases including NCBI PubMed, Web of Science, Google Scholar, and Baidu Scholar.<br><br>STUDY SELECTION: The study selection was based on the following keywords: exosomes, miRNAs, central nervous system (CNS), and neurodegenerative diseases. The time limit for literature retrieval was from the year 2000 to 2018, with language restriction in English. Relevant articles were carefully reviewed, with no exclusions applied to study design and publication type.<br><br>RESULTS: Exosomes are the smallest nanoscale membranous microvesicles secreted by cells and contain important miRNAs, among other rich contents. In the CNS, exosomes can transport amyloid &#x3b2;-protein, &#x3b1;-synuclein, Huntington-associated protein 1, and superoxide dismutase I to other cells. These events relieve the abnormal accumulation of proteins and aggravating neurological diseases. In some neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, miRNAs are pathologically altered as an inexorable course, suggesting that miRNAs may contribute neurodegeneration. Exosomes and miRNAs form a network to regulate the homeostasis of the CNS, both synergistically and individually.<br><br>CONCLUSION: The network of exosomes and miRNAs that regulates CNS homeostasis is a promising biomarker for the diagnosis and treatment of neurodegenerative diseases.}, }
@article {pmid30195799, year = {2018}, author = {Iannitti, T and Scarrott, JM and Likhite, S and Coldicott, IRP and Lewis, KE and Heath, PR and Higginbottom, A and Myszczynska, MA and Milo, M and Hautbergue, GM and Meyer, K and Kaspar, BK and Ferraiuolo, L and Shaw, PJ and Azzouz, M}, title = {Translating SOD1 Gene Silencing toward the Clinic: A Highly Efficacious, Off-Target-free, and Biomarker-Supported Strategy for fALS.}, journal = {Molecular therapy. Nucleic acids}, volume = {12}, number = {}, pages = {75-88}, pmid = {30195799}, issn = {2162-2531}, support = {/WT_/Wellcome Trust/United Kingdom ; BONANNO/APR16/848-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; G1001492/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Of familial amyotrophic lateral sclerosis (fALS) cases, 20% are caused by mutations in the gene encoding human cytosolic Cu/Zn superoxide dismutase (hSOD1). Efficient translation of the therapeutic potential of RNAi for the treatment of SOD1-ALS patients requires the development of vectors that are free of significant off-target effects and with reliable biomarkers to discern sufficient target engagement and correct dosing. Using adeno-associated virus serotype 9 to deliver RNAi against hSOD1 in the SOD1[G93A] mouse model, we found that intrathecal injection of the therapeutic vector via the cisterna magna delayed onset of disease, decreased motor neuron death at end stage by up to 88%, and prolonged the median survival of SOD1[G93A] mice by up to 42%. To our knowledge, this is the first report to demonstrate no significant off-target effects linked to hSOD1 silencing, providing further confidence in the specificity of this approach. We also report the measurement of cerebrospinal fluid (CSF) hSOD1 protein levels as a biomarker of effective dosing and efficacy of hSOD1 knockdown. Together, these data provide further confidence in the safety of the clinical therapeutic vector. The CSF biomarker will be a useful measure of biological activity for translation into human clinical trials.}, }
@article {pmid30192007, year = {2019}, author = {Statland, JM and Moore, D and Wang, Y and Walsh, M and Mozaffar, T and Elman, L and Nations, SP and Mitsumoto, H and Fernandes, JA and Saperstein, D and Hayat, G and Herbelin, L and Karam, C and Katz, J and Wilkins, HM and Agbas, A and Swerdlow, RH and Santella, RM and Dimachkie, MM and Barohn, RJ and , }, title = {Rasagiline for amyotrophic lateral sclerosis: A randomized, controlled trial.}, journal = {Muscle &amp; nerve}, volume = {59}, number = {2}, pages = {201-207}, pmid = {30192007}, issn = {1097-4598}, support = {P30 AG035982/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; UL1 TR000001/TR/NCATS NIH HHS/United States ; R01 FD003739/FD/FDA HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; UL1 TR002366/TR/NCATS NIH HHS/United States ; KL2 TR000119/TR/NCATS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy/psychology ; DNA-Binding Proteins/metabolism ; Double-Blind Method ; Female ; Humans ; Indans/*therapeutic use ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Outcome Assessment, Health Care ; Quality of Life ; Retrospective Studies ; Severity of Illness Index ; Treatment Outcome ; United States ; Young Adult ; }, abstract = {INTRODUCTION: Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with possible neuroprotective effects in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: We performed a randomized, double-blind, placebo-controlled trial of 80 ALS participants with enrichment of the placebo group with historical controls (n&#x2009;=&#x2009;177) at 10 centers in the United States. Participants were randomized in a 3:1 ratio to 2&#x2009;mg/day rasagiline or placebo. The primary outcome was average slope of decline on the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary measures included slow vital capacity, survival, mitochondrial and molecular biomarkers, and adverse-event reporting.<br><br>RESULTS: There was no difference in the average 12-month ALSFRS-R slope between rasagiline and the mixed placebo and historical control cohorts. Rasagiline did not show signs of drug-target engagement in urine and blood biomarkers. Rasagiline was well tolerated with no serious adverse events.<br><br>DISCUSSION: Rasagiline did not alter disease progression compared with controls over 12 months of treatment. Muscle Nerve 59:201-207, 2019.}, }
@article {pmid30175978, year = {2018}, author = {Garzón, F and Coimbra, D and Parcerisas, A and Rodriguez, Y and García, JC and Soriano, E and Rama, R}, title = {NeuroEPO Preserves Neurons from Glutamate-Induced Excitotoxicity.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {65}, number = {4}, pages = {1469-1483}, doi = {10.3233/JAD-180668}, pmid = {30175978}, issn = {1875-8908}, mesh = {Anilides/pharmacology ; Animals ; Caspase 3/metabolism ; Cells, Cultured ; Cerebral Cortex/cytology ; Cytochromes c/metabolism ; Embryo, Mammalian ; Erythropoietin/*pharmacology ; Excitatory Amino Acid Agonists/*pharmacology ; Glial Fibrillary Acidic Protein/metabolism ; Glutamic Acid/*toxicity ; Microtubule-Associated Proteins/metabolism ; Neurons/*drug effects ; Neuroprotective Agents/*pharmacology ; Oligopeptides/pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Rats ; Rats, Wistar ; Time Factors ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Many experimental studies show that erythropoietin (EPO) has a neuroprotective action in the brain. EPO in acute and chronic neurological disorders, particularly in stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, has neuroprotective effects. We previously reported the neuroprotective effect of NeuroEPO, a low sialic form of EPO, against oxidative stress induced by glutamate excitotoxicity. In this paper, we analyze the effect of NeuroEPO against apoptosis induced by glutamate excitotoxicity in primary neuronal cultures obtained from the forebrains of Wistar rat embryos after 17 days of gestation. Excitotoxicity was induced after nine days of in vitro culture by treatment with a culture medium containing 100μM glutamate for 15 min. To withdraw glutamate, a new medium containing 100 ng NeuroEPO/mL was added. Apoptosis was analyzed after 24 h. Images obtained by phase contrast microscopy show that neurons treated with glutamate exhibit cell body shrinkage, loss of dendrites that do not make contact with neighboring cells, and that NeuroEPO was able to preserve the morphological characteristics of the control. Immunocytochemistry images show that the culture is essentially pure in neurons; that glutamate causes cell mortality, and that this is partially avoided when the culture medium is supplemented with NeuroEPO. Activation of intrinsic apoptotic pathways was analyzed. The decreases in Bcl-2/Bax ratio, increase in the release of cytochrome c, and in the expression and activity of caspase-3 observed in cells treated with glutamate, were restored by NeuroEPO. The results from this study show that NeuroEPO protects cortical neurons from glutamate-induced apoptosis via upregulation of Bcl-2 and inhibit glutamate-induced activation of caspase-3.}, }
@article {pmid30172620, year = {2018}, author = {Garbuzova-Davis, S and Haller, E and Navarro, S and Besong, TE and Boccio, KJ and Hailu, S and Khatib, M and Sanberg, PR and Appel, SH and Borlongan, CV}, title = {Transplantation of human bone marrow stem cells into symptomatic ALS mice enhances structural and functional blood-spinal cord barrier repair.}, journal = {Experimental neurology}, volume = {310}, number = {}, pages = {33-47}, pmid = {30172620}, issn = {1090-2430}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/chemically induced/*surgery ; Animals ; Antigens, CD34/metabolism ; Blood-Brain Barrier/*physiopathology/ultrastructure ; Bone Marrow Cells/*physiology ; Bone Marrow Transplantation/*methods ; Capillary Permeability ; Disease Models, Animal ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microscopy, Electron ; Spinal Cord/*physiopathology/ultrastructure ; Spinal Cord Regeneration/*physiology ; Superoxide Dismutase/genetics/metabolism ; Treatment Outcome ; }, abstract = {Accumulating evidence shows alterations in the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) in ALS patients and in animal models of disease, mainly by endothelial cell (EC) damage. Repair of the altered barrier in the CNS by replacement of ECs via cell transplantation may be a new therapeutic approach for ALS. Recently, we demonstrated positive effects towards BSCB repair by intravenous administration of unmodified human bone marrow CD34[+] (hBM34[+]) cells at different doses into symptomatic ALS mice. However, particular benefits of these transplanted cells on microvascular integrity in symptomatic ALS mice are still unclear. The aim of the present study was to determine the structural and functional spinal cord capillary integrity in symptomatic ALS mice after intravenous administration of hBM34[+] cells. The G93A mice at 13 weeks of age intravenously received one of three different cell doses (5 × 10[4], 5 × 10[5], or 1 × 10[6]) and were euthanized at 17 weeks of age (4 weeks post-transplant). Control groups were media-treated and non-carrier mutant SOD1 gene mice. Capillary ultrastructural (electron microscopy), immunohistochemical (laminin and HuNu), and histological (myelin and capillary density) analyses were performed in the cervical and lumbar spinal cords. Capillary permeability in the spinal cords was determined by Evans Blue (EB) injection. Results showed significant restoration of ultrastructural capillary morphology, improvement of basement membrane integrity, enhancement of axonal myelin coherence, and stabilization of capillary density in the spinal cords primarily of ALS mice receiving the high dose of 1 × 10[6] cells. Moreover, substantial reduction of parenchymal EB levels was determined in these mice, confirming our previous results on capillary permeability. Additionally, transplanted cells were detected in blood smears of sacrificed late symptomatic mice by HuNu marker. Altogether, these results provide novel evidence that unmodified bone marrow hematopoietic stem cell treatment at optimal dose might be beneficial for structural and functional repair of the damaged BSCB in advanced stage of ALS, potentially resulting in delayed disease progression by increased motor neuron survival.}, }
@article {pmid30171200, year = {2018}, author = {Khalil, M and Teunissen, CE and Otto, M and Piehl, F and Sormani, MP and Gattringer, T and Barro, C and Kappos, L and Comabella, M and Fazekas, F and Petzold, A and Blennow, K and Zetterberg, H and Kuhle, J}, title = {Neurofilaments as biomarkers in neurological disorders.}, journal = {Nature reviews. Neurology}, volume = {14}, number = {10}, pages = {577-589}, doi = {10.1038/s41582-018-0058-z}, pmid = {30171200}, issn = {1759-4766}, mesh = {Aging/*metabolism ; Amyotrophic Lateral Sclerosis/diagnosis/*metabolism ; Biomarkers/*metabolism ; Bipolar Disorder/diagnosis/*metabolism ; Brain Injuries, Traumatic/diagnosis/*metabolism ; Dementia/diagnosis/*metabolism ; Humans ; Huntington Disease/diagnosis/*metabolism ; Immunoassay/*methods ; Multiple Sclerosis/diagnosis/*metabolism ; Neurofilament Proteins/blood/cerebrospinal fluid/*metabolism ; Parkinson Disease/diagnosis/*metabolism ; Stroke/diagnosis/*metabolism ; }, abstract = {Neuroaxonal damage is the pathological substrate of permanent disability in various neurological disorders. Reliable quantification and longitudinal follow-up of such damage are important for assessing disease activity, monitoring treatment responses, facilitating treatment development and determining prognosis. The neurofilament proteins have promise in this context because their levels rise upon neuroaxonal damage not only in the cerebrospinal fluid (CSF) but also in blood, and they indicate neuroaxonal injury independent of causal pathways. First-generation (immunoblot) and second-generation (enzyme-linked immunosorbent assay) neurofilament assays had limited sensitivity. Third-generation (electrochemiluminescence) and particularly fourth-generation (single-molecule array) assays enable the reliable measurement of neurofilaments throughout the range of concentrations found in blood samples. This technological advancement has paved the way to investigate neurofilaments in a range of neurological disorders. Here, we review what is known about the structure and function of neurofilaments, discuss analytical aspects and knowledge of age-dependent normal ranges of neurofilaments and provide a comprehensive overview of studies on neurofilament light chain as a marker of axonal injury in different neurological disorders, including multiple sclerosis, neurodegenerative dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis and Parkinson disease. We also consider work needed to explore the value of this axonal damage marker in managing neurological diseases in daily practice.}, }
@article {pmid30168894, year = {2019}, author = {Swash, M and Czesnik, D and de Carvalho, M}, title = {Muscular cramp: causes and management.}, journal = {European journal of neurology}, volume = {26}, number = {2}, pages = {214-221}, doi = {10.1111/ene.13799}, pmid = {30168894}, issn = {1468-1331}, mesh = {Adolescent ; Aged ; Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Exercise/physiology ; Humans ; Motor Neurons/physiology ; Muscle Cramp/*etiology/physiopathology/*therapy ; }, abstract = {Muscular cramp is a common symptom in healthy people, especially among the elderly and in young people after vigorous or peak exercise. It is prominent in a number of benign neurological syndromes. It is a particular feature of chronic neurogenic disorders, especially amyotrophic lateral sclerosis. A literature review was undertaken to understand the diverse clinical associations of cramp and its neurophysiological basis, taking into account recent developments in membrane physiology and modulation of motor neuronal excitability. Many aspects of cramping remain incompletely understood and require further study. Current treatment options are correspondingly limited.}, }
@article {pmid30159850, year = {2019}, author = {Martínez-Palma, L and Miquel, E and Lagos-Rodríguez, V and Barbeito, L and Cassina, A and Cassina, P}, title = {Mitochondrial Modulation by Dichloroacetate Reduces Toxicity of Aberrant Glial Cells and Gliosis in the SOD1G93A Rat Model of Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {16}, number = {1}, pages = {203-215}, pmid = {30159850}, issn = {1878-7479}, support = {1104//Comisi&#xf3;n Sectorial de Investigaci&#xf3;n Cient&#xed;fica/International ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Dichloroacetic Acid/*pharmacology ; Disease Models, Animal ; *Gliosis/metabolism/pathology ; *Mitochondria/drug effects/metabolism ; Neuroglia/drug effects/metabolism/ultrastructure ; Rats ; Spinal Cord/drug effects/metabolism/pathology ; *Superoxide Dismutase ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron (MN) degeneration and gliosis. Neonatal astrocytes obtained from the SOD1G93A rat model of ALS exhibit mitochondrial dysfunction and neurotoxicity that can be reduced by dichloroacetate (DCA), a metabolic modulator that has been used in humans, and shows beneficial effects on disease outcome in SOD1G93A mice. Aberrant glial cells (AbGC) isolated from the spinal cords of adult paralytic SOD1G93A rats exhibit highly proliferative and neurotoxic properties and may contribute to disease progression. Here we analyze the mitochondrial activity of AbGC and whether metabolic modulation would modify their phenotypic profile. Our studies revealed fragmented mitochondria and lower respiratory control ratio in AbGC compared to neonatal SOD1G93A and nontransgenic rat astrocytes. DCA (5 mM) exposure improved AbGC mitochondrial function, reduced their proliferative rate, and importantly, decreased their toxicity to MNs. Furthermore, oral DCA administration (100 mg/kg, 10 days) to symptomatic SOD1G93A rats reduced MN degeneration, gliosis, and the number of GFAP/S100β double-labeled hypertrophic glial cells in the spinal cord. DCA treatment of AbGC reduced extracellular lactate levels indicating that the main recognized DCA action, targeting the pyruvate dehydrogenase kinase/pyruvate dehydrogenase complex, may underlie our findings. Our results show that AbGC metabolic phenotype is related to their toxicity to MNs and indicate that its modulation can reduce glial mediated pathology in the spinal cord. Together with previous findings, these results further support glial metabolic modulation as a valid therapeutic strategy in ALS.}, }
@article {pmid30158984, year = {2018}, author = {Kuzma-Kozakiewicz, M and Marchel, A and Kaminska, A and Gawel, M and Sznajder, J and Figiel-Dabrowska, A and Nowak, A and Maj, E and Krzesniak, NE and Noszczyk, BH and Domanska-Janik, K and Sarnowska, A}, title = {Intraspinal Transplantation of the Adipose Tissue-Derived Regenerative Cells in Amyotrophic Lateral Sclerosis in Accordance with the Current Experts' Recommendations: Choosing Optimal Monitoring Tools.}, journal = {Stem cells international}, volume = {2018}, number = {}, pages = {4392017}, pmid = {30158984}, issn = {1687-966X}, abstract = {Stem cells (SCs) may constitute a perspective alternative to pharmacological treatment in neurodegenerative diseases. Although the safety of SC transplantation has been widely shown, their clinical efficiency in amyotrophic lateral sclerosis (ALS) is still to be proved. It is not only due to a limited number of studies, small treatment groups, and fast but nonlinear disease progression but also due to lack of objective methods able to show subtle clinical changes. Preliminary guidelines for cell therapy have recently been proposed by a group of ALS experts. They combine clinical, neurophysiological, and functional assessment together with monitoring of the cytokine level. Here, we describe a pilot study on transplantation of autologous adipose-derived regenerative cells (ADRC) into the spinal cord of the patients with ALS and monitoring of the results in accordance with the current recommendations. To show early and/or subtle changes within the muscles of interest, a wide range of clinical and functional tests were used and compared in order to choose the most sensitive and optimal set. Additionally, an analysis of transplanted ADRC was provided to develop standards ensuring the derivation and verification of adequate quality of transplanted cells and to correlate ADRC properties with clinical outcome.}, }
@article {pmid30158264, year = {2018}, author = {Poorthuis, MHF and Battjes, S and Dorigo-Zetsma, JW and de Kruijk, JR}, title = {Primary Epstein-Barr virus infection in immunocompetent patients with acute transverse myelitis and a combination of polyradiculitis and anterior horn syndrome as neurological manifestations.}, journal = {BMJ case reports}, volume = {2018}, number = {}, pages = {}, pmid = {30158264}, issn = {1757-790X}, mesh = {Adolescent ; Antiviral Agents/therapeutic use ; Diagnosis, Differential ; Epstein-Barr Virus Infections/complications/*diagnosis/diagnostic imaging/drug therapy ; Humans ; Immunocompetence ; Male ; Middle Aged ; Motor Neuron Disease/complications/*diagnosis/diagnostic imaging/drug therapy ; Myelitis, Transverse/complications/*diagnosis/diagnostic imaging/drug therapy ; Polyradiculopathy/complications/*diagnosis/diagnostic imaging/drug therapy ; Syndrome ; Tomography, X-Ray Computed ; }, abstract = {Neurological manifestations of a primary Epstein-Barr virus (EBV) infection are rare. We describe a case with acute transverse myelitis and another case with a combination of polyradiculitis and anterior horn syndrome as manifestations of a primary EBV infection.The first case is a 50-year-old immunocompetent male diagnosed with acute transverse myelitis, 2 weeks after he was clinically diagnosed with infectious mononucleosis. The second case is an 18-year-old immunocompetent male diagnosed with a combination of polyradiculitis and anterior horn syndrome while he had infectious mononucleosis. The first patient was treated with methylprednisolone. After 1 year, he was able to stop performing clean intermittent self-catheterisation. The second patient completely recovered within 6 weeks without treatment.Primary EBV infection should be considered in immunocompetent patients presenting with acute transverse myelitis and a combination of polyradiculitis and anterior horn syndrome. Antiviral treatment and steroids are controversial, and the prognosis of neurological sequelae is largely unknown.}, }
@article {pmid30157956, year = {2018}, author = {McGurk, L and Mojsilovic-Petrovic, J and Van Deerlin, VM and Shorter, J and Kalb, RG and Lee, VM and Trojanowski, JQ and Lee, EB and Bonini, NM}, title = {Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {6}, number = {1}, pages = {84}, pmid = {30157956}, issn = {2051-5960}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; R21 NS093439/NS/NINDS NIH HHS/United States ; R21 NS090205/NS/NINDS NIH HHS/United States ; P01 AG017586/AG/NIA NIH HHS/United States ; R01 NS096746/NS/NINDS NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; R01 NS095793/NS/NINDS NIH HHS/United States ; R35 NS097275/NS/NINDS NIH HHS/United States ; R21 NS087077/NS/NINDS NIH HHS/United States ; R01 NS073660/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; Ataxin-2/genetics/metabolism ; Bacterial Proteins/genetics/metabolism ; Benzimidazoles/pharmacology ; C9orf72 Protein/genetics/metabolism ; COS Cells ; Cell Nucleus/*metabolism ; Cells, Cultured ; Chlorocebus aethiops ; Cohort Studies ; DNA-Binding Proteins ; Dose-Response Relationship, Drug ; Female ; Humans ; Luminescent Proteins/genetics/metabolism ; Male ; Middle Aged ; Motor Neurons/metabolism/*ultrastructure ; Mutation/genetics ; Poly Adenosine Diphosphate Ribose/*metabolism ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Rats ; Saponins/pharmacology ; Spinal Cord/pathology ; Transfection ; Triterpenes/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and fatal motor neuron disease. Diagnosis typically occurs in the fifth decade of life and the disease progresses rapidly leading to death within ~ 2-5 years of symptomatic onset. There is no cure, and the few available treatments offer only a modest extension in patient survival. A protein central to ALS is the nuclear RNA/DNA-binding protein, TDP-43. In > 95% of ALS patients, TDP-43 is cleared from the nucleus and forms phosphorylated protein aggregates in the cytoplasm of affected neurons and glia. We recently defined that poly(ADP-ribose) (PAR) activity regulates TDP-43-associated toxicity. PAR is a posttranslational modification that is attached to target proteins by PAR polymerases (PARPs). PARP-1 and PARP-2 are the major enzymes that are active in the nucleus. Here, we uncovered that the motor neurons of the ALS spinal cord were associated with elevated nuclear PAR, suggesting elevated PARP activity. Veliparib, a small-molecule inhibitor of nuclear PARP-1/2, mitigated the formation of cytoplasmic TDP-43 aggregates in mammalian cells. In primary spinal-cord cultures from rat, Veliparib also inhibited TDP-43-associated neuronal death. These studies uncover that PAR activity is misregulated in the ALS spinal cord, and a small-molecular inhibitor of PARP-1/2 activity may have therapeutic potential in the treatment of ALS and related disorders associated with abnormal TDP-43 homeostasis.}, }
@article {pmid30157547, year = {2018}, author = {Zhao, M and Kim, JR and van Bruggen, R and Park, J}, title = {RNA-Binding Proteins in Amyotrophic Lateral Sclerosis.}, journal = {Molecules and cells}, volume = {41}, number = {9}, pages = {818-829}, pmid = {30157547}, issn = {0219-1032}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism ; Animals ; Animals, Genetically Modified ; Cytoplasmic Granules/metabolism ; Humans ; Models, Animal ; Mutation ; Neurons/metabolism ; RNA/metabolism ; RNA-Binding Proteins/*genetics/*metabolism ; }, abstract = {Significant research efforts are ongoing to elucidate the complex molecular mechanisms underlying amyotrophic lateral sclerosis (ALS), which may in turn pinpoint potential therapeutic targets for treatment. The ALS research field has evolved with recent discoveries of numerous genetic mutations in ALS patients, many of which are in genes encoding RNA binding proteins (RBPs), including TDP-43, FUS, ATXN2, TAF15, EWSR1, hnRNPA1, hnRNPA2/B1, MATR3 and TIA1. Accumulating evidence from studies on these ALS-linked RBPs suggests that dysregulation of RNA metabolism, cytoplasmic mislocalization of RBPs, dysfunction in stress granule dynamics of RBPs and increased propensity of mutant RBPs to aggregate may lead to ALS pathogenesis. Here, we review current knowledge of the biological function of these RBPs and the contributions of ALS-linked mutations to disease pathogenesis.}, }
@article {pmid30157377, year = {2018}, author = {Zhao, N and Yan, Y and Wang, H and Bai, S and Wang, Q and Liu, W and Wang, J}, title = {Acetolactate Synthase Overexpression in Mesosulfuron-Methyl-Resistant Shortawn Foxtail (Alopecurus aequalis Sobol.): Reference Gene Selection and Herbicide Target Gene Expression Analysis.}, journal = {Journal of agricultural and food chemistry}, volume = {66}, number = {37}, pages = {9624-9634}, doi = {10.1021/acs.jafc.8b03054}, pmid = {30157377}, issn = {1520-5118}, mesh = {Acetolactate Synthase/*genetics/metabolism ; Acetyl-CoA Carboxylase/genetics/metabolism ; China ; Gene Expression Regulation, Plant/drug effects ; *Herbicide Resistance ; Herbicides/*pharmacology ; Plant Proteins/*genetics/metabolism ; Plant Weeds/*drug effects/enzymology/genetics ; Poaceae/*drug effects/*enzymology/genetics ; Sulfonylurea Compounds/*pharmacology ; }, abstract = {Severe infestations of shortawn foxtail (Alopecurus aequalis Sobol.), a noxious weed in wheat and canola cropping systems in China, remain standing even after the application of the herbicides, fenoxaprop- P-ethyl and mesosulfuron-methyl. Analysis of gene expression in weed plants subjected to herbicide treatment is a key step toward more mechanistic studies. Since such an analysis often involves quantitative real-time PCR (qRT-PCR), endogenous reference genes with stable expression are required. Herein, we identified specific gene sets, suitable as references for qRT-PCR data normalization in A. aequalis plants under different experimental conditions, using geNorm, NormFinder, BestKeeper, and RefFinder software. Additionally, the reliability of reference genes was verified by analyzing the expression of genes encoding two major herbicide target enzymes: acetyl-CoA carboxylase (ACCase) and acetolactate synthase (ALS). Furthermore, functional ALS gene amplification was likely present in resistant plants, although it may make no contribution to the resistant phenotypes.}, }
@article {pmid30154826, year = {2018}, author = {De Felice, B and Manfellotto, F and Fiorentino, G and Annunziata, A and Biffali, E and Pannone, R and Federico, A}, title = {Wide-Ranging Analysis of MicroRNA Profiles in Sporadic Amyotrophic Lateral Sclerosis Using Next-Generation Sequencing.}, journal = {Frontiers in genetics}, volume = {9}, number = {}, pages = {310}, pmid = {30154826}, issn = {1664-8021}, abstract = {MicroRNA (miRNA) has emerged as an important regulator of gene expression in neurodegenerative disease as amyotrophic lateral sclerosis (ALS). In the nervous system, dysregulation in miRNA-related pathways is subordinated to neuronal damage and cell death, which contributes to the expansion of neurodegenerative disorders, such as ALS. In the present research, we aimed to profile dysregulation of miRNAs in ALS blood and neuromuscular junction as well as healthy blood control by next-generation sequencing (NGS). The expression of three upregulated miRNAs, as miR-338-3p, miR-223-3p, and miR-326, in the ALS samples compared to healthy controls, has been validated by qRT-PCR in a cohort of 45 samples collected previously. Bioinformatics tools were used to perform ALS miRNAs target analysis and to predict novel miRNAs secondary structure. The analysis of the NGS data identified 696 and 49 novel miRNAs which were differentially expressed in ALS tissues. In particular, in neuromuscular junction the differential expression of miR-338-3p, which we previously found upregulated in different types of ASL tissues, miR-223-3p, and miR-326 was elevated compared to normal control. ALS miRNAs gene target were significantly involved in neuronal related pathway as BDFN1 and HIF-1genes. This study presents the direct experimental evidence that, overall, miR-338-3p is highly expressed in ALS tissues including neuromuscular junction characterizing ALS from normal tissues. Beside, our analysis identified, for the first time, novel miRNAs highly expressed in ALS tissues. In conclusion, the results indicate that miRNAs has an important role in the diagnosis and treatment of ALS.}, }
@article {pmid30154300, year = {2018}, author = {Zhou, L and Ouyang, R and Chen, P and Luo, H and Wu, B and Liu, G}, title = {[Obstructive sleep apnea hypopnea syndrome and alveolar hypoventilation syndrome in motor neuron disease: A case report and literature review].}, journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences}, volume = {43}, number = {1}, pages = {106-112}, doi = {10.11817/j.issn.1672-7347.2018.01.017}, pmid = {30154300}, issn = {1672-7347}, mesh = {Hemosiderosis/diagnosis/*etiology/physiopathology ; Humans ; Lung Diseases/diagnosis/*etiology/physiopathology ; Male ; Middle Aged ; Motor Neuron Disease/*complications/physiopathology ; Polysomnography ; Retrospective Studies ; Sleep Apnea, Obstructive/diagnosis/*etiology/physiopathology ; Hemosiderosis, Pulmonary ; }, abstract = {To investigate the clinical characteristics of a patient with motor neuron disease, which caused sleep-disordered breathing (SDB) and alveolar hypoventilation syndrome, and to improve the diagnosis rate for this disease. Methods: Retrospectively analyze the diagnosis and treatment process for a 52 year-old male patient, who was accepted by the Second Xiangya Hospital, Central South University because of dyspnea, shortness of breath and malaise for 4 months, and eventually was diagnosed as motor neuron disease associated with obstructive sleep apnea hypopnea syndrome and alveolar hypoventilation syndrome. In addition, we searched CNKI, Wanfang and PubMed databases to review relevant literature with keywords (motor neuron disease or amyotrophic lateral sclerosis or progressive bulbar palsy or progressive muscular atrophy or primary lateral sclerosis) AND (sleep apnea or sleep disordered breathing) from January 1990 to May 2017. Results: The major clinical manifestation of motor neuron disease included impaired upper and lower motor neuron displayed with proximal muscle weakness, muscle tremor, amyotrophy, bulbar symptoms and pyramidal sign. It was a chronic, progressive disease with worse prognosis, low survival and difficult in diagnosis. Electroneuromyography was a vital way for diagnosis. Furthermore, sleep disordered breathing was common in patients with motor neuron disease, which was featured as decreased rapid eye movement sleep, increased awaking time, apnea and hypopnea. The main mechanism for sleep disordered breathing in motor neuron disease might be due to the disturbed central nervous system and paralysis of diaphragm and respiratory muscle. Moreover, the patient suffered from restrictive ventilatory dysfunction, alveolar hypoventilation and subsequent partial pressure of carbon dioxide and hypoxemia. Therefore, respiratory failure was the most frequent cause of death for patients with motor neuron disease. Non-invasive positive pressure ventilation was suggested to apply to such patients, whose forced vital capability was less than 75 percent of predicted value. Conclusion: Sleep disordered breathing is common in patients with motor neuron disease. Hence, polysomnography is suggested as a routine examination to confirm the potential complications and give timely therapy. Treatment with non-invasive positive pressure ventilation is important for patients to improve life quality, survival rate and prognosis.}, }
@article {pmid30150770, year = {2018}, author = {Schiaffino, L and Bonafede, R and Scambi, I and Parrella, E and Pizzi, M and Mariotti, R}, title = {Acetylation state of RelA modulated by epigenetic drugs prolongs survival and induces a neuroprotective effect on ALS murine model.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {12875}, pmid = {30150770}, issn = {2045-2322}, mesh = {Acetylation ; Amyotrophic Lateral Sclerosis/drug therapy/etiology/*metabolism/*mortality ; Animals ; Biomarkers ; Disease Models, Animal ; Epigenesis, Genetic/*drug effects ; Histones/metabolism ; Mice ; Motor Neurons/metabolism ; Neurodegenerative Diseases/etiology/metabolism/pathology ; Neuroprotective Agents/*pharmacology ; Prognosis ; Resveratrol/pharmacology ; Signal Transduction ; Spinal Cord/metabolism ; Superoxide Dismutase/metabolism ; Transcription Factor RelA/*metabolism ; Treatment Outcome ; }, abstract = {Dysregulation in acetylation homeostasis has been implicated in the pathogenesis of the amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. It is known that the acetylation of transcriptional factors regulates their activity. The acetylation state of NF-kB RelA has been found to dictate the neuroprotective versus the neurotoxic effect of p50/RelA. Here we showed that the pro-apoptotic acetylation mode of RelA, involving a general lysine deacetylation of the subunit with the exclusion of the lysine 310, is evident in the lumbar spinal cord of SOD1(G93A) mice, a murine model of ALS. The administration of the HDAC inhibitor MS-275 and the AMPK/sirtuin 1 activator resveratrol restored the normal RelA acetylation in SOD1(G93A) mice. The SOD1(G93A) mice displayed a 3 weeks delay of the disease onset, associated with improvement of motor performance, and 2 weeks increase of lifespan. The epigenetic treatment rescued the lumbar motor neurons affected in SOD1(G93A) mice, accompanied by increased levels of protein products of NF-kB-target genes, Bcl-xL and brain-derived neurotrophic factor. In conclusion, we here demonstrate that MS-275 and resveratrol restore the acetylation state of RelA in the spinal cord, delaying the onset and increasing the lifespan of SOD1(G93A) mice.}, }
@article {pmid30139772, year = {2018}, author = {Rose, L and McKim, D and Leasa, D and Nonoyama, M and Tandon, A and Bai, YQ and Amin, R and Katz, S and Goldstein, R and Gershon, A}, title = {Patterns of healthcare utilisation for respiratory complications of adults with neuromuscular disease: a population study.}, journal = {The European respiratory journal}, volume = {52}, number = {3}, pages = {}, doi = {10.1183/13993003.00754-2018}, pmid = {30139772}, issn = {1399-3003}, support = {//CIHR/Canada ; }, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/complications/epidemiology ; Databases, Factual ; Emergency Service, Hospital/*statistics &amp; numerical data ; Female ; Hospitalization/*statistics &amp; numerical data ; Humans ; Linear Models ; Longitudinal Studies ; Male ; Middle Aged ; Neuromuscular Diseases/complications/epidemiology/*therapy ; Ontario/epidemiology ; Patient Acceptance of Health Care/*statistics &amp; numerical data ; Respiration Disorders/epidemiology/etiology/*therapy ; Retrospective Studies ; Severity of Illness Index ; Time Factors ; Young Adult ; }, abstract = {Our objective was to quantify health service utilisation including monitoring and treatment of respiratory complications for adults with neuromuscular disease (NMD), identifying practice variation and adherence to guideline recommendations at a population level.We conducted a population-based longitudinal cohort study (2003-2015) of adults with NMD using hospital diagnostic and health insurance billing codes within administrative health databases.We identified 185 586 adults with NMD. Mean age 52 years, 59% female. 41 173 (22%) went to an emergency department for respiratory complications on average 1.6 times every 3 years; 14 947 (8%) individuals were admitted to hospital 1.4 times every 3 years. Outpatient respiratory specialist visits occurred for 64 084 (35%) with four visits every 3 years, although substantial variation in visit frequency was found. 157 285 (85%) went to the emergency department (all-cause) almost 4 times every 3 years, 100 052 (54%) were admitted to hospital. Individuals with amyotrophic lateral sclerosis/motor neurone disease (ALS/MND) had more emergency department visits compared with other types of NMD (p<0.0001).One-third of adults with NMD received respiratory specialist care at a frequency recommended by professional guidelines, although substantial variation exists. Emergent healthcare utilisation was substantial, emphasising the burden of NMD on the healthcare system and urgent need to improve community and social supports, particularly for ALS/MND patients.}, }
@article {pmid30135644, year = {2018}, author = {Varidaki, A and Hong, Y and Coffey, ET}, title = {Repositioning Microtubule Stabilizing Drugs for Brain Disorders.}, journal = {Frontiers in cellular neuroscience}, volume = {12}, number = {}, pages = {226}, pmid = {30135644}, issn = {1662-5102}, abstract = {Microtubule stabilizing agents are among the most clinically useful chemotherapeutic drugs. Mostly, they act to stabilize microtubules and inhibit cell division. While not without side effects, new generations of these compounds display improved pharmacokinetic properties and brain penetrance. Neurological disorders are intrinsically associated with microtubule defects, and efforts to reposition microtubule-targeting chemotherapeutic agents for treatment of neurodegenerative and psychiatric illnesses are underway. Here we catalog microtubule regulators that are associated with Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, schizophrenia and mood disorders. We outline the classes of microtubule stabilizing agents used for cancer treatment, their brain penetrance properties and neuropathy side effects, and describe efforts to apply these agents for treatment of brain disorders. Finally, we summarize the current state of clinical trials for microtubule stabilizing agents under evaluation for central nervous system disorders.}, }
@article {pmid30134203, year = {2018}, author = {Masala, A and Sanna, S and Esposito, S and Rassu, M and Galioto, M and Zinellu, A and Carru, C and Carrì, MT and Iaccarino, C and Crosio, C}, title = {Epigenetic Changes Associated with the Expression of Amyotrophic Lateral Sclerosis (ALS) Causing Genes.}, journal = {Neuroscience}, volume = {390}, number = {}, pages = {1-11}, doi = {10.1016/j.neuroscience.2018.08.009}, pmid = {30134203}, issn = {1873-7544}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism ; Animals ; Cell Line, Tumor ; DNA Methylation ; DNA-Binding Proteins/metabolism ; *Epigenesis, Genetic ; HEK293 Cells ; Histones/metabolism ; Humans ; Mice, Transgenic ; *Protein Processing, Post-Translational ; RNA-Binding Protein FUS/metabolism ; Superoxide Dismutase-1/metabolism ; }, abstract = {Neurodegenerative disorders, including Amyotrophic Lateral Sclerosis (ALS), have been associated to alterations in chromatin structure resulting in long-lasting changes in gene expression. ALS is predominantly a sporadic disease and environmental triggers may be involved in its onset. In this respect, alterations in the epigenome can provide the key to transform the genetic information into phenotype. In this paper, we demonstrate that two modifications associated with transcriptional activation, namely dimethylation of lysine 4 on H3 tail (H3K4me2) and phospho-acetylation of serine 10 and lysine 14 on H3 tail (H3K14ac-S10ph), and two modifications associated to transcriptional repression, namely trimethylation of lysine 9 on H3 tail (H3K9me3) and DNA methylation are selectively altered in cellular and animal model of ALS. These results reinforce the idea that epigenetic therapy may represent a potential and attractive approach for ALS treatment.}, }
@article {pmid30134145, year = {2018}, author = {Dutta, K and Patel, P and Julien, JP}, title = {Protective effects of Withania somnifera extract in SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {309}, number = {}, pages = {193-204}, doi = {10.1016/j.expneurol.2018.08.008}, pmid = {30134145}, issn = {1090-2430}, support = {//CIHR/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/pathology ; Animals ; Autophagy/drug effects ; Body Weight/drug effects/genetics ; Calcium-Binding Proteins/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Ganglia, Spinal/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microfilament Proteins/metabolism ; Motor Neurons/drug effects ; Nerve Tissue Proteins/metabolism ; Neuroprotective Agents/*therapeutic use ; Plant Extracts/*therapeutic use ; Psychomotor Performance/drug effects ; Reflex/drug effects/genetics ; Spinal Cord/pathology ; Superoxide Dismutase/genetics/*metabolism ; Withania/*chemistry ; }, abstract = {Withania somnifera (WS; commonly known as Ashwagandha or Indian ginseng) is a medicinal plant whose extracts have been in use for centuries in various regions of the world as a rejuvenator. There is now a growing body of evidence documenting neuroprotective functions of the plant extracts or its purified compounds in several models of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Based on the extract's beneficial effect in a mouse model of ALS with TDP-43 proteinopathy, the current study was designed to test its efficacy in another model of familial ALS. Our results show that administration of WS extracts by gavage to mice expressing G93A mutant form of superoxide dismutase (SOD1) resulted in increased longevity, improved motor performance and increased number of motor neurons in lumbar spinal cord. The WS treatment caused substantial reduction in levels of misfolded SOD1whereas it enhanced expression of cellular chaperons in spinal cord of SOD1[G93A] mice. WS markedly reduced glial activation and prevented phosphorylation of nuclear factor kappaB (NF-κB). The overall immunomodulatory effect of WS was further evidenced by changes in expression of multiple cytokines/chemokines. WS also served as an autophagy inducer which may be beneficial at early stages of the disease. These results suggest that WS extracts might constitute promising therapeutics for treatment of ALS with involvement of misfolded SOD1.}, }
@article {pmid30131665, year = {2018}, author = {Sirabella, R and Valsecchi, V and Anzilotti, S and Cuomo, O and Vinciguerra, A and Cepparulo, P and Brancaccio, P and Guida, N and Blondeau, N and Canzoniero, LMT and Franco, C and Amoroso, S and Annunziato, L and Pignataro, G}, title = {Ionic Homeostasis Maintenance in ALS: Focus on New Therapeutic Targets.}, journal = {Frontiers in neuroscience}, volume = {12}, number = {}, pages = {510}, pmid = {30131665}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most threatening neurodegenerative disease since it causes muscular paralysis for the loss of Motor Neurons in the spinal cord, brainstem and motor cortex. Up until now, no effective pharmacological treatment is available. Two forms of ALS have been described so far: 90% of the cases presents the sporadic form (sALS) whereas the remaining 10% of the cases displays the familiar form (fALS). Approximately 20% of fALS is associated with inherited mutations in the Cu, Zn-superoxide dismutase 1 (SOD1) gene. In the last decade, ionic homeostasis dysregulation has been proposed as the main trigger of the pathological cascade that brings to motor-neurons loss. In the light of these premises, the present review will analyze the involvement in ALS pathophysiology of the most well studied metal ions, i.e., calcium, sodium, iron, copper and zinc, with particular focus to the role of ionic channels and transporters able to contribute in the regulation of ionic homeostasis, in order to propose new putative molecular targets for future therapeutic strategies to ameliorate the progression of this devastating neurodegenerative disease.}, }
@article {pmid30127392, year = {2018}, author = {Fujimori, K and Ishikawa, M and Otomo, A and Atsuta, N and Nakamura, R and Akiyama, T and Hadano, S and Aoki, M and Saya, H and Sobue, G and Okano, H}, title = {Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent.}, journal = {Nature medicine}, volume = {24}, number = {10}, pages = {1579-1589}, pmid = {30127392}, issn = {1546-170X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Cell Differentiation/genetics ; Humans ; Indoles/therapeutic use ; Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism/*pathology ; Mutation ; Nerve Degeneration/*genetics/metabolism/pathology ; Phenotype ; Protein Aggregation, Pathological/*genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous motor neuron disease for which no effective treatment is available, despite decades of research into SOD1-mutant familial ALS (FALS). The majority of ALS patients have no familial history, making the modeling of sporadic ALS (SALS) essential to the development of ALS therapeutics. However, as mutations underlying ALS pathogenesis have not yet been identified, it remains difficult to establish useful models of SALS. Using induced pluripotent stem cell (iPSC) technology to generate stem and differentiated cells retaining the patients' full genetic information, we have established a large number of in vitro cellular models of SALS. These models showed phenotypic differences in their pattern of neuronal degeneration, types of abnormal protein aggregates, cell death mechanisms, and onset and progression of these phenotypes in vitro among cases. We therefore developed a system for case clustering capable of subdividing these heterogeneous SALS models by their in vitro characteristics. We further evaluated multiple-phenotype rescue of these subclassified SALS models using agents selected from non-SOD1 FALS models, and identified ropinirole as a potential therapeutic candidate. Integration of the datasets acquired in this study permitted the visualization of molecular pathologies shared across a wide range of SALS models.}, }
@article {pmid30125805, year = {2018}, author = {Riancho, J and Gil-Bea, FJ and Castanedo-Vazquez, D and Sedano, MJ and Zufiría, M and de Eulate, GFG and Poza, JJ and Lopez de Munain, A}, title = {Clinical evidences supporting the Src/c-Abl pathway as potential therapeutic target in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {393}, number = {}, pages = {80-82}, doi = {10.1016/j.jns.2018.08.013}, pmid = {30125805}, issn = {1878-5883}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/*enzymology ; Cell Survival/drug effects ; Cells, Cultured ; Fibroblasts/drug effects/enzymology ; Humans ; Male ; Middle Aged ; Protein Kinase Inhibitors/*therapeutic use ; Proto-Oncogene Proteins c-abl/*metabolism ; Signal Transduction ; Stress, Physiological/drug effects ; Sunitinib/*therapeutic use ; src-Family Kinases/*metabolism ; }, }
@article {pmid30124008, year = {2019}, author = {Nabavi, SM and Arab, L and Jarooghi, N and Bolurieh, T and Abbasi, F and Mardpour, S and Azimyian, V and Moeininia, F and Maroufizadeh, S and Sanjari, L and Hosseini, SE and Aghdami, N}, title = {Safety, Feasibility of Intravenous and Intrathecal Injection of Autologous Bone Marrow Derived Mesenchymal Stromal Cells in Patients with Amyotrophic Lateral Sclerosis: An Open Label Phase I Clinical Trial.}, journal = {Cell journal}, volume = {20}, number = {4}, pages = {592-598}, pmid = {30124008}, issn = {2228-5806}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is the most severe disorder within the spectrum of motor neuron diseases (MND) that has no effective treatment and a progressively fatal outcome. We have conducted two clinical trials to assess the safety and feasibility of intravenous (IV) and intrathecal (IT) injections of bone marrow derived mesenchymal stromal cells (BM-MSCs) in patients with ALS.<br><br>MATERIALS AND METHODS: This is an interventional/experimental study. We enrolled 14 patients that met the following inclusion criteria: definitive diagnosis of sporadic ALS, ALS Functional Rating Scale (ALS-FRS) &#x2265;24, and &#x2265;40% predicted forced vital capacity (FVC). All patients underwent bone marrow (BM) aspiration to obtain an adequate sample for cell isolation and culture. Patients in group 1 (n=6) received an IV and patients in group 2 (n=8) received an IT injection of the cell suspension. All patients in both groups were followed at 24 hours and 2, 4, 6, and 12 months after the injection with ALS-FRS, FVC, laboratory tests, check list of side effects and brain/spinal cord magnetic resonance imaging (MRI). In each group, one patient was lost to follow up one month after cell injection and one patient from IV group died due to severe respiratory insufficiency and infection.<br><br>RESULTS: During the follow up there were no reports of adverse events in terms of clinical and laboratory assessments. In MRI, there was not any new abnormal finding. The ALS-FRS score and FVC percentage significantly reduced in all patients from both groups.<br><br>CONCLUSION: This study has shown that IV and IT transplantation of BM-derived stromal cells is safe and feasible (Registration numbers: NCT01759797 and NCT01771640).}, }
@article {pmid30121249, year = {2018}, author = {Aymerich, MS and Aso, E and Abellanas, MA and Tolon, RM and Ramos, JA and Ferrer, I and Romero, J and Fernández-Ruiz, J}, title = {Cannabinoid pharmacology/therapeutics in chronic degenerative disorders affecting the central nervous system.}, journal = {Biochemical pharmacology}, volume = {157}, number = {}, pages = {67-84}, doi = {10.1016/j.bcp.2018.08.016}, pmid = {30121249}, issn = {1873-2968}, mesh = {Alzheimer Disease/drug therapy/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Cannabinoids/pharmacology/*therapeutic use ; Chronic Disease ; Endocannabinoids/metabolism ; Humans ; Huntington Disease/drug therapy/metabolism ; Mice ; Neurodegenerative Diseases/*drug therapy ; Parkinson Disease/drug therapy/metabolism ; }, abstract = {The endocannabinoid system (ECS) exerts a modulatory effect of important functions such as neurotransmission, glial activation, oxidative stress, or protein homeostasis. Dysregulation of these cellular processes is a common neuropathological hallmark in aging and in neurodegenerative diseases of the central nervous system (CNS). The broad spectrum of actions of cannabinoids allows targeting different aspects of these multifactorial diseases. In this review, we examine the therapeutic potential of the ECS for the treatment of chronic neurodegenerative diseases of the CNS focusing on Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. First, we describe the localization of the molecular components of the ECS and how they are altered under neurodegenerative conditions, either contributing to or protecting cells from degeneration. Second, we address recent advances in the modulation of the ECS using experimental models through different strategies including the direct targeting of cannabinoid receptors with agonists or antagonists, increasing the endocannabinoid tone by the inhibition of endocannabinoid hydrolysis, and activation of cannabinoid receptor-independent effects. Preclinical evidence indicates that cannabinoid pharmacology is complex but supports the therapeutic potential of targeting the ECS. Third, we review the clinical evidence and discuss the future perspectives on how to bridge human and animal studies to develop cannabinoid-based therapies for each neurodegenerative disorder. Finally, we summarize the most relevant opportunities of cannabinoid pharmacology related to each disease and the multiple unexplored pathways in cannabinoid pharmacology that could be useful for the treatment of neurodegenerative diseases.}, }
@article {pmid30120006, year = {2019}, author = {Tsunoda, K and Takazawa, M and Chong, T and Morita, Y}, title = {Slow, slurred speech as an initial complaint in amyotrophic lateral sclerosis.}, journal = {Auris, nasus, larynx}, volume = {46}, number = {2}, pages = {193-195}, doi = {10.1016/j.anl.2018.07.007}, pmid = {30120006}, issn = {1879-1476}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/complications/diagnosis/*physiopathology ; Cough/etiology/physiopathology ; Dysarthria/etiology/*physiopathology ; Fasciculation/etiology/physiopathology ; Female ; Hoarseness/etiology/*physiopathology ; Humans ; Male ; Middle Aged ; Multiple System Atrophy/complications/diagnosis/physiopathology ; Speech Disorders/etiology/physiopathology ; Tongue/physiopathology ; }, abstract = {OBJECTIVE: Otorhinolaryngologic examinations at an early stage, particularly those conducted by vocal specialists, can make potentially important contributions to the diagnosis of bulbar-onset ALS patients.<br><br>METHODS: We analyzed 2623 patients (2010-2017) visited the ENT Voice Clinic, National Hospital Organization Tokyo Medical Center, with the primary complaint of speech or vocal dysfunction at the initial visit. Among those, 12 patients visited the voice clinic after consultations with other physicians but before receiving a diagnosis and we initially suspected bulbar-onset ALS due to slow, slurred speech (SSS). We analyzed the detail of those suspected ALS cases.<br><br>RESULTS: Every patient suspected ALS patients consulted an average of 2.2 physicians before visiting the voice clinic and a total of 3.2 physicians before receiving the final diagnosis. The mean speech symptom duration before visiting the vocal clinic was 7.83 months in ALS, 24 months in MSA patients. The duration until final diagnosis after we referred them to neurologists was 2.16 months and 15.3 months, respectively.<br><br>CONCLUSION: Otolaryngologists and primary care physicians to consider the possibility of ALS when patients present even with an only symptom of SSS. They should then refer such patients to neurologists for definitive diagnoses, leading to early detection and treatment of ALS.}, }
@article {pmid30116051, year = {2018}, author = {Boland, B and Yu, WH and Corti, O and Mollereau, B and Henriques, A and Bezard, E and Pastores, GM and Rubinsztein, DC and Nixon, RA and Duchen, MR and Mallucci, GR and Kroemer, G and Levine, B and Eskelinen, EL and Mochel, F and Spedding, M and Louis, C and Martin, OR and Millan, MJ}, title = {Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing.}, journal = {Nature reviews. Drug discovery}, volume = {17}, number = {9}, pages = {660-688}, pmid = {30116051}, issn = {1474-1784}, support = {MR/M02492X/1/MRC_/Medical Research Council/United Kingdom ; P01 AG017617/AG/NIA NIH HHS/United States ; UKDRI-2002/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Aging/*metabolism ; Animals ; Autophagy/physiology ; Humans ; Neurodegenerative Diseases/*metabolism ; Neurotoxins/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin/metabolism ; }, abstract = {Neurodegenerative disorders of ageing (NDAs) such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and amyotrophic lateral sclerosis represent a major socio-economic challenge in view of their high prevalence yet poor treatment. They are often called 'proteinopathies' owing to the presence of misfolded and aggregated proteins that lose their physiological roles and acquire neurotoxic properties. One reason underlying the accumulation and spread of oligomeric forms of neurotoxic proteins is insufficient clearance by the autophagic-lysosomal network. Several other clearance pathways are also compromised in NDAs: chaperone-mediated autophagy, the ubiquitin-proteasome system, extracellular clearance by proteases and extrusion into the circulation via the blood-brain barrier and glymphatic system. This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs.}, }
@article {pmid30115018, year = {2018}, author = {Clarke, G and Fistein, E and Holland, A and Tobin, J and Barclay, S and Barclay, S}, title = {Planning for an uncertain future in progressive neurological disease: a qualitative study of patient and family decision-making with a focus on eating and drinking.}, journal = {BMC neurology}, volume = {18}, number = {1}, pages = {115}, pmid = {30115018}, issn = {1471-2377}, support = {G0900035/MRC_/Medical Research Council/United Kingdom ; R317/1113//Dunhill Medical Trust/ ; }, mesh = {Adult ; *Advance Care Planning ; Aged ; Aged, 80 and over ; *Decision Making ; *Drinking ; *Eating ; Family/psychology ; Female ; Humans ; Male ; Middle Aged ; Nervous System Diseases/*psychology ; Patients/*psychology ; Qualitative Research ; }, abstract = {BACKGROUND: Dysphagia and other eating and drinking difficulties are common in progressive neurological diseases. Mealtimes can become a major source of difficulty and anxiety for patients and their families. Decisions about eating, drinking and care can become challenging as disease progresses, and the person in question loses the capacity to participate in decisions about their own care. We sought to investigate how patients and their family members make decisions about their future care as their condition deteriorates, with a particular focus on mealtimes, eating and drinking.<br><br>METHODS: Longitudinal qualitative in-depth interviews were undertaken with patients and their family members (N&#x2009;=&#x2009;29) across a range of disease groups, including: dementia, Parkinson's Disease, Huntington's Disease, Progressive Supranuclear Palsy, Motor Neurone Disease, Multiple Sclerosis. Patients had varying degrees of eating and drinking difficulties, and levels of decision-making capacity. Interviews were 'participant led' and undertaken in the patients' own homes or a place of their choosing. Follow-up interviews were three months to one year later depending upon disease trajectory. Interviews were audio recorded and analysed in NVivo using a Thematic Analysis approach.<br><br>RESULTS: Twenty-nine&#xa0;participants were interviewed between 2015 and 2017. Two key themes emerged from the analysis: 1) Health Literacy: the extent to which patients and relatives appeared to know about the condition and its treatment. Patients and their family members varied in their ability to speak and communicate about their condition and prognosis. 2) Planning style: the extent to which participants appeared to value involvement in advance care-planning. Patients and their family members varied in the way in which they made decisions: some preferred to 'take each day as it comes', while others wished to plan extensively for the future.<br><br>CONCLUSIONS: Issues with eating and drinking are often overlooked. Clinicians need to understand both the patient's level of health literacy and their style of planning before communicating with patients and their families about these sensitive issues.}, }
@article {pmid30109997, year = {2018}, author = {Liao, D and Liao, Q and Huang, C and Bi, F}, title = {[Mutations of G38R and D40G cause amyotrophic lateral sclerosis by reducing Annexin A11 protein stability].}, journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences}, volume = {43}, number = {6}, pages = {577-582}, doi = {10.11817/j.issn.1672-7347.2018.06.001}, pmid = {30109997}, issn = {1672-7347}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Annexins/chemistry/*genetics/metabolism ; HEK293 Cells ; Humans ; *Mutation ; Plasmids/genetics ; Protein Stability ; Solubility ; Transfection ; }, abstract = {To explore the role of the mutations G38R and D40G of Annexin A11 (ANXA11) in the onset of amyotrophic lateral sclerosis (ALS). Methods: The plasmids expressing ANXA11 wild type protein, ANXA11 G38R protein and ANXA11 D40G protein were constructed, respectively. The recombinant plasmids were then transfected into HEK293 cells respectively followed by cycloheximide (CHX) treatment for 0, 2, 4 and 8 h. The protein expressions of ANXA11 wild type, ANXA11 G38R and ANXA11 D40G mutations were determined by Western blot. Gray analysis by Image J was performed to compare the half-life of each protein. The NSC-34 cell lines constantly expressing ANXA11 wild type protein, ANXA11 G38R protein and ANXA11 D40G protein were established. The cells were treated with NP-40 lysis buffer to examine the protein solubility by Western blot. Results: Both ANXA11 G38R protein and ANXA11 D40G protein showed a shorter half-life than ANXA11 wild type protein (P<0.05), while there was no difference between ANXA11 G38R protein and ANXA11 D40G protein (P>0.05). There was no visible insoluble substance in the NP-40 lysates for ANXA11 wild type protein, ANXA11 G38R protein and ANXA11 D40G protein. Conclusion: G38R and D40G mutations reduce the stability of ANXA11 protein. G38R and D40G mutations do not alter ANXA11 solubility.}, }
@article {pmid30108288, year = {2018}, author = {Fyfe, I}, title = {Antisense treatment alleviates ALS in animals.}, journal = {Nature reviews. Neurology}, volume = {14}, number = {9}, pages = {508}, doi = {10.1038/s41582-018-0059-y}, pmid = {30108288}, issn = {1759-4766}, }
@article {pmid30105628, year = {2018}, author = {Ratliff, WA and Saykally, JN and Kane, MJ and Citron, BA}, title = {Neuromuscular Junction Morphology and Gene Dysregulation in the Wobbler Model of Spinal Neurodegeneration.}, journal = {Journal of molecular neuroscience : MN}, volume = {66}, number = {1}, pages = {114-120}, pmid = {30105628}, issn = {1559-1166}, support = {I01 RX001520/RX/RRD VA/United States ; I01RX001520/VA/Department of Veterans Affairs/United States ; 4KB14//Florida Department of Health/ ; W81XWH-16-1-0626//Department of Defense/ ; }, mesh = {Animals ; Calcitonin Gene-Related Peptide/genetics/metabolism ; Mice ; Motor Endplate/metabolism/*pathology ; Motor Neurons/metabolism/pathology ; Neurodegenerative Diseases/genetics/metabolism/*pathology ; Receptors, Cholinergic/genetics/metabolism ; Vesicular Transport Proteins/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset neuromuscular disease for which there is currently no effective treatment. The progression of ALS includes loss of motor neurons controlling the voluntary muscles, with much of this loss occurring at the neuromuscular junction. In an effort to better understand changes at the neuromuscular junction, we utilized the wobbler mouse model of motor neuron loss. We examined biceps and end plate morphologies and monitored selected factors involved in end plate function. Structural volumes were determined from 3D reconstructions that were generated for the end plates. Wobbler mice exhibited size reductions of both the muscle fibers and the end plates within the biceps, and we found that the end plate volumes were the most sensitive indicator of the degeneration. Concurrently, we found increases in calcitonin gene-related peptide (CGRP) and its receptor in wobbler biceps and spinal cord. We also found increases in gene expression of two acetylcholine receptors within the wobbler biceps, which may be a result of altered CGRP/CALCRL (calcitonin receptor-like receptor) expression.}, }
@article {pmid30101561, year = {2018}, author = {Snowden, A and Young, J and Savinc, J}, title = {Proactive community support tailored to holistic needs: A cohort study.}, journal = {Cancer medicine}, volume = {7}, number = {9}, pages = {4836-4845}, pmid = {30101561}, issn = {2045-7634}, mesh = {Adult ; Aged ; Aged, 80 and over ; Cohort Studies ; Female ; Humans ; Male ; Middle Aged ; Needs Assessment/*statistics &amp; numerical data ; Neoplasms/*epidemiology/*psychology ; Quality of Life ; *Social Support ; Young Adult ; }, abstract = {BACKGROUND: It is increasingly internationally recognized that a cancer diagnosis impacts on people practically and financially as well as physically and psychologically. It is less clear what to do about this. This study introduces an original community service designed to mitigate this wider impact. Nonclinical "link officers" use holistic needs assessment (HNA) to help newly diagnosed people identify and quantify the severity of their physical, psychological, practical, financial, and social concerns. A care plan is then agreed, usually involving community interventions from partner agencies. Following intervention, assessment is repeated. The primary aim of this study was to establish whether there was a significant difference between initial assessment and follow-up, postintervention. Secondary aim was to identify potential predictors of increased levels of concern at baseline and follow-up.<br><br>METHOD: Pre- and postintervention observational cohort study. Paired t test examined the difference in mean (SD) concern severity between baseline and follow-up. Multiple linear regression models were computed to hypothesize potential predictors of initial concern severity and severity change.<br><br>RESULTS: The service saw 2413 people 2014-2017. Participants identified average 5.5 (4.7) concerns, financial concerns being most frequent. Mean severity at baseline was 7.12 (out of 10) (2.50), reducing to 3.83 (3.49) post-treatment, paired t(4454)&#xa0;=&#xa0;64.68, P&#xa0;<&#xa0;0.0001, reduction of 3.31 (95% CI 3.21-3.41). Factors associated with higher initial concern included unemployment and caring responsibilities. Unemployment was also associated with a smaller reduction of concern severity at follow-up.<br><br>CONCLUSION: Patient level of concern went from a level associated with specialist referral to a much more manageable level. This original finding is internationally significant because it extends Khera et&#xa0;al's (2017) "provocative idea" that all patients should be screened for financial problems to show that they can be helped with all their concerns. This article describes a successful, transferable model of community care.}, }
@article {pmid30101496, year = {2019}, author = {Jaiswal, MK}, title = {Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs.}, journal = {Medicinal research reviews}, volume = {39}, number = {2}, pages = {733-748}, doi = {10.1002/med.21528}, pmid = {30101496}, issn = {1098-1128}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Antioxidants/therapeutic use ; Clinical Trials as Topic ; Disease Models, Animal ; Disease Progression ; Drug Design ; Edaravone/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Riluzole/*therapeutic use ; }, abstract = {Over the past decades, a multitude of experimental drugs have been shown to delay disease progression in preclinical animal models of amyotrophic lateral sclerosis (ALS) but failed to show efficacy in human clinical trials or are still waiting for approval under Phase I-III trials. Riluzole, a glutamatergic neurotransmission inhibitor, is the only drug approved by the USA Food and Drug Administration for ALS treatment with modest benefits on survival. Recently, an antioxidant drug, edaravone, developed by Mitsubishi Tanabe Pharma was found to be effective in halting ALS progression during early stages. The newly approved drug edaravone is a force multiplier for ALS treatment. This short report provides an overview of the two drugs that have been approved for ALS treatment and highlights an update on the timeline of drug development, how clinical trials were done, the outcome of these trials, primary endpoint, mechanism of actions, dosing information, administration, side effects, and storage procedures. Moreover, we also discussed the pressing issues and challenges of ALS clinical trials and drug developments as well as future outlook.}, }
@article {pmid30099415, year = {2018}, author = {Hübner, J and Hübner, I and Kroczka, S}, title = {Correlation of electrophysiological parameters of peripheral nerves and manual dexterity in patients with amyotrophic lateral sclerosis.}, journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)}, volume = {71}, number = {4}, pages = {807-814}, pmid = {30099415}, issn = {0043-5147}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*physiopathology ; Female ; Humans ; Male ; Middle Aged ; Motor Neurons/physiology ; Muscle Strength/physiology ; Muscle, Skeletal/innervation/*physiopathology ; Neural Conduction/physiology ; Neurologic Examination ; Upper Extremity/*physiopathology ; }, abstract = {OBJECTIVE: Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, presenting with various manifestations, leading to progressing disability, with poor prognosis, and with no options for successful treatment. In its classic form the central and peripheral motor neurons are simultaneously affected at the beginning; the bulbar-onset ALS successively involving other parts of the nervous system is slightly less common. The aim: To demonstrate a correlation between electrophysiological parameters of peripheral nerves and loss of manual dexterity in the ALS.<br><br>PATIENTS AND METHODS: Materials and methods: The analysis covered results of electrophysiological tests of motor conductivity in median and ulnar nerves, and results of the Mira Stambak and Rene Zazzo tests normally used to evaluate lateralisation, while in this study they were adapted to verify manual dexterity. The study covered 20 patients with clinically confirmed or possible ALS determined on the basis of the EI Escorial criteria. Half (10 people) of the studied group had limb-onset ALS, while the other half had the bulbar-onset ALS.<br><br>RESULTS: Results: When evaluating a correlation between the results of electrophysiological tests and the results of the Mira Stambak and Rene Zazzo tests, a significant relationship was found between a reduction in an amplitude of the compound muscle action potential (CMAP) and deterioration in manual dexterity in the subjects, with a tendency for progression in these deviations, but with their interdependency maintained.<br><br>CONCLUSION: Conclusions: 1. A loss of motor cells in the anterior horns of the spinal cord is reflected in the deterioration of manual dexterity in ALS patients. 2. A significant correlation is found between a loss in manual dexterity and an increase in changes in motor conductivity.}, }
@article {pmid30097809, year = {2018}, author = {Siddiqi, KS and Husen, A and Sohrab, SS and Yassin, MO}, title = {Recent Status of Nanomaterial Fabrication and Their Potential Applications in Neurological Disease Management.}, journal = {Nanoscale research letters}, volume = {13}, number = {1}, pages = {231}, pmid = {30097809}, issn = {1931-7573}, abstract = {Nanomaterials (NMs) are receiving remarkable attention due to their unique properties and structure. They vary from atoms and molecules along with those of bulk materials. They can be engineered to act as drug delivery vehicles to cross blood-brain barriers (BBBs) and utilized with better efficacy and safety to deliver specific molecules into targeted cells as compared to conventional system for neurological disorders. Depending on their properties, various metal chelators, gold nanoparticles (NPs), micelles, quantum dots, polymeric NPs, liposomes, solid lipid NPs, microparticles, carbon nanotubes, and fullerenes have been utilized for various purposes including the improvement of drug delivery system, treatment response assessment, diagnosis at early stage, and management of neurological disorder by using neuro-engineering. BBB regulates micro- and macromolecule penetration/movement, thus protecting it from many kinds of illness. This phenomenon also prevents drug delivery for the neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis, amyotrophic lateral sclerosis, and primary brain tumors. For some neurological disorders (AD and PD), the environmental pollution was considered as a major cause, as observed that metal and/or metal oxide from different sources are inhaled and get deposited in the lungs/brain. Old age, obesity, diabetes, and cardiovascular disease are other factors for rapid deterioration of human health and onset of AD. In addition, gene mutations have also been examined to cause the early onset familial forms of AD. AD leads to cognitive impairment and plaque deposits in the brain leading to neuronal cell death. Based on these facts and considerations, this review elucidates the importance of frequently used metal chelators, NMs and/or NPs. The present review also discusses the current status and future challenges in terms of their application in drug delivery for neurological disease management.}, }
@article {pmid30097696, year = {2018}, author = {Cheng, J and Korte, N and Nortley, R and Sethi, H and Tang, Y and Attwell, D}, title = {Targeting pericytes for therapeutic approaches to neurological disorders.}, journal = {Acta neuropathologica}, volume = {136}, number = {4}, pages = {507-523}, pmid = {30097696}, issn = {1432-0533}, support = {A1188//Rosetrees Trust/International ; 099222/Z/12/Z//Wellcome Trust/United Kingdom ; 2017YFC1307500//National Key R&amp;D Program of China/International ; M153F2//Rosetrees Trust (GB) and Stoneygate Trust/International ; 2017YFC1307504//National Key R&amp;D Program of China/International ; 81622041//National Natural Science Foundation of China/International ; //Wellcome Trust/United Kingdom ; //Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; Blood-Brain Barrier/pathology ; Capillaries/pathology ; Humans ; Nervous System Diseases/genetics/*pathology ; Pericytes/*pathology ; }, abstract = {Many central nervous system diseases currently lack effective treatment and are often associated with defects in microvascular function, including a failure to match the energy supplied by the blood to the energy used on neuronal computation, or a breakdown of the blood-brain barrier. Pericytes, an under-studied cell type located on capillaries, are of crucial importance in regulating diverse microvascular functions, such as angiogenesis, the blood-brain barrier, capillary blood flow and the movement of immune cells into the brain. They also form part of the "glial" scar isolating damaged parts of the CNS, and may have stem cell-like properties. Recent studies have suggested that pericytes play a crucial role in neurological diseases, and are thus a therapeutic target in disorders as diverse as stroke, traumatic brain injury, migraine, epilepsy, spinal cord injury, diabetes, Huntington's disease, Alzheimer's disease, diabetes, multiple sclerosis, glioma, radiation necrosis and amyotrophic lateral sclerosis. Here we report recent advances in our understanding of pericyte biology and discuss how pericytes could be targeted to develop novel therapeutic approaches to neurological disorders, by increasing blood flow, preserving blood-brain barrier function, regulating immune cell entry to the CNS, and modulating formation of blood vessels in, and the glial scar around, damaged regions.}, }
@article {pmid30085001, year = {2019}, author = {Esposito, R and Galderisi, M and Santoro, C and Imbriaco, M and Riccio, E and Maria Pellegrino, A and Sorrentino, R and Lembo, M and Citro, R and Angela Losi, M and Spinelli, L and Trimarco, B and Pisani, A}, title = {Prominent longitudinal strain reduction of left ventricular basal segments in treatment-naïve Anderson-Fabry disease patients.}, journal = {European heart journal. Cardiovascular Imaging}, volume = {20}, number = {4}, pages = {438-445}, doi = {10.1093/ehjci/jey108}, pmid = {30085001}, issn = {2047-2412}, mesh = {Adolescent ; Adult ; Aged ; Cardiomyopathies/*diagnostic imaging/physiopathology ; Cross-Sectional Studies ; Echocardiography, Doppler ; Fabry Disease/*diagnostic imaging/physiopathology ; Female ; Heart Ventricles/*diagnostic imaging/physiopathology ; Humans ; Male ; Middle Aged ; Young Adult ; }, abstract = {AIMS: Little is known about regional longitudinal strain (LS) distribution in early stages of Anderson-Fabry disease (AFD) cardiomyopathy. We investigated regional left ventricular (LV) patterns of LS strain and base-to-apex behaviour of LS in treatment-naïve AFD patients.<br><br>METHODS AND RESULTS: Twenty-three consecutive AFD patients at diagnosis and 23 healthy controls without cardiovascular risk factors and matched for age and sex to the patients, underwent a comprehensive evaluation of target organs. An echo-Doppler exam, including determination of regional and global LS strain (GLS) was obtained. The average LS of 6 basal (BLS), 6 middle (MLS), and 5 apical (ALS) segments and relative regional strain ratio [ALS/(BLS + MLS)] were also calculated. Ejection fraction and diastolic indices did not differ between the two groups. LV mass index was greater in AFD (P&#x2009;<&#x2009;0.01). GLS (P&#x2009;=&#x2009;0.006), BLS (P&#x2009;<&#x2009;0.0001), and MLS (P&#x2009;=&#x2009;0.003), but not ALS, were lower in AFD patients and relative regional strain ratio was higher in AFD (P&#x2009;<&#x2009;0.01) than in controls. These analyses were confirmed separately in the two genders and even after excluding patients with wall hypertrophy. By subdividing AFD patients according to lysoGB3 levels, 9 patients with lysoGB3&#x2009;&#x2265;&#x2009;1.8&#x2009;ng/L had lower ALS compared to 11 patients with lysoGB3&#x2009;<&#x2009;1.8 ng/L (P&#x2009;<&#x2009;0.01).<br><br>CONCLUSION: In na&#xef;ve AFD patients, we observed an early reduction of LV LS, involving mainly LV basal myocardial segments. Nevertheless, the association found between the higher lysoGB3 levels and the lower apical cap LS demonstrates that apical segments LS, despite still normal, is not spared at diagnosis.}, }
@article {pmid30080715, year = {2018}, author = {Vucic, S and Rutkove, SB}, title = {Neurophysiological biomarkers in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {31}, number = {5}, pages = {640-647}, doi = {10.1097/WCO.0000000000000593}, pmid = {30080715}, issn = {1473-6551}, support = {K24 NS060951/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; *Biomarkers ; Electrodiagnosis ; Electromyography ; Humans ; Transcranial Magnetic Stimulation ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the motor neurons, characterized by upper motor neuron (UMN) and lower motor neuron (LMN) dysfunction. There have been significant technological advances in the development of neurophysiological biomarkers of UMN and LMN dysfunction in ALS. In this review, we discuss major advances in development of neurophysiological biomarkers in ALS, critiquing their potential in diagnosis and prognosis of ALS, as well as utility in monitoring treatment effects.<br><br>RECENT FINDINGS: The threshold tracking transcranial magnetic stimulation (TMS) technique has established cortical hyperexcitability as an early and specific biomarker of UMN dysfunction in ALS, and associated with neurodegeneration. In addition to establishing cortical hyperexcitability as a pathophysiological mechanism, threshold tracking TMS has enabled an earlier diagnosis of ALS and provided a means of monitoring effects of therapeutic agents. Biomarkers of LMN dysfunction, including motor unit number estimation, the neurophysiological index, electrical impedance myography and axonal excitability techniques, have all exhibited utility in monitoring disease progression.<br><br>SUMMARY: In addition to enhancing ALS diagnosis, the development of novel neurophysiological biomarkers has implications for clinical trials research and drug development, enabling the assessment of biological efficacy of agents in early stages of drug development.}, }
@article {pmid30076846, year = {2018}, author = {Rodríguez-Cueto, C and Santos-García, I and García-Toscano, L and Espejo-Porras, F and Bellido, M and Fernández-Ruiz, J and Muñoz, E and de Lago, E}, title = {Neuroprotective effects of the cannabigerol quinone derivative VCE-003.2 in SOD1[G93A] transgenic mice, an experimental model of amyotrophic lateral sclerosis.}, journal = {Biochemical pharmacology}, volume = {157}, number = {}, pages = {217-226}, doi = {10.1016/j.bcp.2018.07.049}, pmid = {30076846}, issn = {1873-2968}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism/pathology ; Animals ; Astrocytes/drug effects/metabolism ; Cannabinoids/*therapeutic use ; Cells, Cultured ; Disease Models, Animal ; Gene Expression/drug effects ; Male ; Mice ; Mice, Transgenic ; Neuroprotective Agents/*therapeutic use ; Quinones/therapeutic use ; Superoxide Dismutase/genetics ; }, abstract = {Antioxidant phytocannabinoids, synthetic compounds targeting the CB2 receptor, and inhibitors of the endocannabinoid inactivation afforded neuroprotection in SOD1[G93A] mutant mice, a model of ALS. These effects may involve the activation of PPAR-γ too. Here, we have investigated the neuroprotective effects in SOD1[G93A] mutant mice of the cannabigerol derivative VCE-003.2, which works as neuroprotectant by activating PPAR-γ. Mice were treated with VCE-003.2 from 60 days up to an advanced stage in disease progression (18 weeks), when they were euthanized and used for analysis of neuropathological signs. As expected, SOD1[G93A] transgenic mice experienced a progressive weight loss and neurological deterioration, which was associated with a marked loss of spinal cholinergic motor neurons, glial reactivity, and elevations in several biochemical markers (cytokines, glutamate transporters) that indirectly reflect the glial proliferation and activation in the spinal cord. The treatment with VCE-003.2 improved most of these neuropathological signs. It attenuated the weight loss and the anomalies in neurological parameters, preserved spinal cholinergic motor neurons, and reduced astroglial reactivity. VCE-003.2 also reduced the elevations in IL-1β and glial glutamate transporters. Lastly, VCE-003.2 attenuated the LPS-induced generation of TNF-α and IL-1β in cultured astrocytes obtained from SOD1[G93A] transgenic newborns, an effect also produced by rosiglitazone, then indicating a probable PPAR-γ activation as responsible of its neuroprotective effects. In summary, our results showed benefits with VCE-003.2 in SOD1[G93A] transgenic mice supporting PPAR-γ as an additional neuroprotective target available for cannabinoids in ALS. Such benefits would need to be validated in other ALS models prior to be translated to the clinical level.}, }
@article {pmid30075221, year = {2018}, author = {Maya, S and Prakash, T and Goli, D}, title = {Evaluation of neuroprotective effects of wedelolactone and gallic acid on aluminium-induced neurodegeneration: Relevance to sporadic amyotrophic lateral sclerosis.}, journal = {European journal of pharmacology}, volume = {835}, number = {}, pages = {41-51}, doi = {10.1016/j.ejphar.2018.07.058}, pmid = {30075221}, issn = {1879-0712}, mesh = {Aluminum/*adverse effects ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism/pathology ; Animals ; Body Weight/drug effects ; Brain-Derived Neurotrophic Factor/genetics ; Caspase 3/metabolism ; Coumarins/*pharmacology/therapeutic use ; Female ; Gallic Acid/*pharmacology/therapeutic use ; Gene Expression Regulation/drug effects ; Glutamic Acid/metabolism ; Interleukin-6/genetics ; Male ; Mice ; Neuroprotective Agents/*pharmacology/therapeutic use ; Rats ; Rotarod Performance Test ; Tumor Necrosis Factor-alpha/genetics ; }, abstract = {Al exposure causes an alteration in the several ions in the body and causes toxicity. Such as apoptosis, oxidative stress, disruption in neuronal transport, mitochondrial damage, excitotoxicity, generation of inflammatory mediators, and microglial activation. These multiple mechanisms lead to the several neurodegenerative diseases, including sporadic amyotrophic lateral sclerosis (sALS). The study aims to unravel the mechanisms behind the neuroprotective effects of wedelolactone (WL) and gallic acid (GA) against aluminium-induced neurodegeneration and thereby to unlock a platform to find a cure for sALS. We studied the neuroprotective effects of WL (100 &amp; 200 mg/kg) and GA (100 &amp; 200 mg/kg) using aluminium chloride (AlCl3)-induced neurodegeneration model. The study was conducted using male Wistar rats. We assessed the effects of WL and GA on motor learning ability, motor coordination, locomotor activity, cytokine production, BDNF, glutathione peroxidase (GPx), m-calpain, caspase-3 inhibition and L-glutamate level. The study suggests that the treatment with WL and GA could protect the motor neurons from the toxicity that caused by Al via improving the antioxidant status, BDNF, and by preventing glutamate excitotoxicity. Also, WL and GA are found to be effective in inhibiting caspase-3 activation and downregulating inflammatory cytokines. WL and GA also found effective in improving the motor learning abilities and motor coordination in rats. The protective effects of the WL and GA were further confirmed from histopathological results. WL and GA prevent the neurofibrillary tangle formation and neuronal damage. The study concluded that the WL and GA were dose-dependently effective in managing the AlCl3-induced neurodegeneration.}, }
@article {pmid30066793, year = {2018}, author = {Nasimbera, A and Rosales, J and Silva, B and Alonso, R and Bohorquez, N and Lepera, S and Garretto, N and Arakaki, T and Garcea, O and Rey, R and Quarracino, C and Rodriguez, GE}, title = {Everything you always wanted to know about sex and Neurology: neurological disability and sexuality.}, journal = {Arquivos de neuro-psiquiatria}, volume = {76}, number = {7}, pages = {430-435}, doi = {10.1590/0004-282X20180061}, pmid = {30066793}, issn = {1678-4227}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Case-Control Studies ; Chronic Disease ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; Multiple Sclerosis/*complications ; Nervous System Diseases/*complications ; Parkinson Disease/*complications ; Severity of Illness Index ; Stroke/*complications ; }, abstract = {OBJECTIVE: Chronic neurological disorders generate disabilities affecting multiple aspects of life, including sexuality.<br><br>OBJECTIVE: To describe the presence of sexual dysfunction and comorbidities in a population with chronic neurological disorders. To analyze the relationship between disability and sexual dysfunction.<br><br>METHODS: A cross-sectional case-control study was carried out. Patients with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson's disease (PD), and stroke of at least one year since the onset of symptoms were included, and compared with controls with no neurological disease, matched by age and sex.<br><br>RESULTS: We included 71 participants: 29 controls, with a mean age of 49.4 years, and 42 patients with a mean age of 53.8 years. Sexual dysfunction was present in 22.5% of the controls and 77.5% of the patients. A statistically significant relationship between sexual dysfunction and disability was found in the logistic regression analysis (OR = 20.38, 95%CI: 2.5 -165.86).<br><br>CONCLUSIONS: Disability proved to be the main variable related to the presence of sexual dysfunction. Patients with ALS had the worst rates of sexual dysfunction. Patients with MS were similar to the control group. As for the PD group, no patient had normal sexuality. Finally, in stroke patients, the presence of comorbidities and their treatment may have negatively influenced sexuality. These findings showed that patients with chronic neurological diseases have sexual dysfunction and underscore the need for neurologists to know and address this problem.}, }
@article {pmid30056192, year = {2018}, author = {Hyung, S and Jeong, YS and Yeo, J and Song, YK and Kim, MS and Im, YJ and Maeng, HJ and Chung, SJ}, title = {Identification of the primary determining factor(s) governing the oral absorption of edaravone in rats.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {123}, number = {}, pages = {312-320}, doi = {10.1016/j.ejps.2018.07.052}, pmid = {30056192}, issn = {1879-0720}, mesh = {Administration, Oral ; Animals ; Biological Availability ; Dogs ; Drug Stability ; Edaravone/*administration &amp; dosage/chemistry/*pharmacokinetics ; Free Radical Scavengers/*administration &amp; dosage/chemistry/*pharmacokinetics ; *Intestinal Absorption ; Kidney/metabolism ; Liver/metabolism ; Madin Darby Canine Kidney Cells ; Male ; Metabolic Clearance Rate ; Permeability ; Rats, Sprague-Dawley ; Solubility ; }, abstract = {This study was performed to determine the primary factor(s) governing the oral absorption of edaravone, a novel anti-oxidant for the treatment of amyotrophic lateral sclerosis, in rats. While the aqueous solubility of edaravone widely varied depending on the vehicle used, the oral bioavailability of the drug was not low when it was adequately solubilized, as evidenced by the fact that the oral exposure was high (in terms of the absolute bioavailability of 50-90%) at all dose ranges (i.e., 0.5-27 mg/kg) under solubilized conditions in rats. The sum of the in vitro clearance values for edaravone, 12.7 mL/(min × kg), obtained from metabolic stability studies with tissue-homogenates from the rat liver, kidney, intestine, and with the rat plasma, was found to be virtually identical to the systemic clearance of the drug in rats. It was noted that the liver represented over 83.9% of the total elimination with a hepatic extraction ratio of approximately 0.137, indicative of the minor role of hepatic first pass metabolism in the systemic absorption of edaravone after its oral administration. In studies with Ussing chamber with rat intestinal segments and Madin-Darby canine kidney (MDCKII) cells, edaravone was found to be highly permeable (i.e., Papp over 10 × 10[-6] cm/s), and appeared to be a substrate for rat P-glycoprotein (P-gp; estimated Km of 421 μM). In contrast, however, the drug did not appear to be a substrate for human P-gp in transport studies with MDCKII-hMDR1 cells. Collectively, these observations suggest that the primary determining factor for the intestinal absorption of edaravone is its solubilization in vehicle/intestinal fluids, rather than permeability, pre-systemic first-pass metabolism, or efflux transport. Considering the fact that the newly approved indication of the drug would require prolonged administration, probably via oral administration, the findings reported herein provide relevant information regarding its use.}, }
@article {pmid30054789, year = {2018}, author = {Talbot, K and Feneberg, E and Scaber, J and Thompson, AG and Turner, MR}, title = {Amyotrophic lateral sclerosis: the complex path to precision medicine.}, journal = {Journal of neurology}, volume = {265}, number = {10}, pages = {2454-2462}, pmid = {30054789}, issn = {1432-1459}, support = {MR/L002167/1/MRC_/Medical Research Council/United Kingdom ; TALBOT/APR11/811-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; SCABER/JULY13/945-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; FENEBERG/AUG17/949-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/P007023/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; TALBOT-GORDON/APR15/831-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; 107/516/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/physiopathology/*therapy ; Animals ; Humans ; *Precision Medicine ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the corticomotorneuronal network responsible for voluntary movement. There are well-established clinical, genetic and pathological overlaps between ALS and frontotemporal dementia (FTD), which together constitute the 'TDP-43 proteinopathies'. An ever-expanding list of genes in which mutation leads to typical ALS have implicated abnormalities in RNA processing, protein homoeostasis and axonal transport. How these apparently distinct pathways converge to cause the characteristic clinical syndrome of ALS remains unclear. Although there are major gaps in our understanding of the essential nature of ALS pathophysiology, the identification of genetic causes in up to 15% of ALS patients, coupled with advances in biotechnology and biomarker research provide a foundation for approaches to treatment based on 'precision medicine', and even prevention of the disease in pre-symptomatic mutation carriers in the future. Currently, multidisciplinary care remains the bedrock of management and this is increasingly being put onto an evidence-based footing.}, }
@article {pmid30053042, year = {2019}, author = {Yogaratnam, J and Rito, J and Kakuda, TN and Fennema, H and Gupta, K and Jekle, CA and Mitchell, T and Boyce, M and Sahgal, O and Balaratnam, G and Chanda, S and Van Remoortere, P and Symons, JA and Fry, J}, title = {Antiviral Activity, Safety, and Pharmacokinetics of AL-794, a Novel Oral Influenza Endonuclease Inhibitor: Results of an Influenza Human Challenge Study.}, journal = {The Journal of infectious diseases}, volume = {219}, number = {2}, pages = {177-185}, doi = {10.1093/infdis/jiy410}, pmid = {30053042}, issn = {1537-6613}, mesh = {Administration, Oral ; Adolescent ; Adult ; Antiviral Agents/adverse effects/*pharmacology/*therapeutic use ; Double-Blind Method ; Endonucleases/*antagonists &amp; inhibitors ; Female ; Humans ; Influenza A Virus, H3N2 Subtype ; Influenza, Human/*drug therapy/enzymology ; Male ; Middle Aged ; Serine Endopeptidases/*pharmacology/*therapeutic use ; Viral Load/drug effects ; Young Adult ; }, abstract = {BACKGROUND: AL-794 is an orally active prodrug of ALS-033719, which selectively inhibits the endonuclease domain of influenza virus A and B polymerase.<br><br>METHODS: In a phase 1, double-blinded, randomized, placebo-controlled study, healthy subjects were inoculated intranasally with influenza virus (A/Perth/16/2009 H3N2) after confirmation of infection or on day 4. Subjects received 50 mg of AL-794, 150 mg of AL-794, or placebo twice daily for 5 days. Viral load, influenza symptoms, pharmacokinetics, and safety were evaluated.<br><br>RESULTS: A total of 61 subjects were inoculated. In 42 infected subjects, the mean peak viral load for 50-mg AL-794 recipients, 150-mg AL-794 recipients, and placebo recipients was 3.54, 2.77, and 3.72 log10 50% tissue culture infectious doses (TCID50)/mL, respectively. The mean influenza viral load area under the curve in the corresponding treatment groups was 137, 87.5, and 142 log10 TCID50/mL&#xb7;h, respectively, and the median time to virus nondetection was 117, 75.3, and 108 hours, respectively. AL-794 was well tolerated, and no viral resistance to ALS-033719 was identified.<br><br>CONCLUSION: Following oral administration of AL-794, significant dose-dependent antiviral activity was noted, with a greater decrease in viral load, symptoms, and mucus weight at the 150-mg dose, compared with the 50-mg dose, and no safety concerns for either dose or placebo.<br><br>CLINICAL TRIALS REGISTRATION: NCT02588521.}, }
@article {pmid30050381, year = {2017}, author = {Ngo, ST and Mi, JD and Henderson, RD and McCombe, PA and Steyn, FJ}, title = {Exploring targets and therapies for amyotrophic lateral sclerosis: current insights into dietary interventions.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {7}, number = {}, pages = {95-108}, pmid = {30050381}, issn = {1179-9900}, abstract = {A growing number of preclinical and human studies demonstrate a disease-modifying effect of nutritional state in amyotrophic lateral sclerosis (ALS). The management of optimal nutrition in ALS is complicated, as physiological, physical, and psychological effects of the disease need to be considered and addressed accordingly. In this regard, multidisciplinary care teams play an integral role in providing dietary guidance to ALS patients and their carers. However, with an increasing research focus on the use of dietary intervention strategies to manage disease symptoms and improve prognosis in ALS, many ALS patients are now seeking or are actively engaged in using complementary and alternative therapies that are dietary in nature. In this article, we review the aspects of appetite control, energy balance, and the physiological effects of ALS relative to their impact on overall nutrition. We then provide current insights into dietary interventions for ALS, considering the mechanisms of action of some of the common dietary interventions used in ALS, discussing their validity in the context of clinical trials.}, }
@article {pmid30048339, year = {2018}, author = {Thonhoff, JR and Simpson, EP and Appel, SH}, title = {Neuroinflammatory mechanisms in amyotrophic lateral sclerosis pathogenesis.}, journal = {Current opinion in neurology}, volume = {31}, number = {5}, pages = {635-639}, doi = {10.1097/WCO.0000000000000599}, pmid = {30048339}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/immunology/*pathology ; Animals ; Disease Models, Animal ; Humans ; Inflammation/*complications/immunology/*pathology ; Mice ; T-Lymphocytes, Regulatory/immunology ; }, abstract = {PURPOSE OF REVIEW: Neuroinflammation is increasingly recognized as an important mediator of disease progression in patients with amyotrophic lateral sclerosis (ALS), and is characterized by reactive central nervous system (CNS) microglia and astroglia as well as infiltrating peripheral monocytes and lymphocytes. Anti-inflammatory and neuroprotective factors sustain the early phase of the disease whereas inflammation becomes proinflammatory and neurotoxic as disease progression accelerates. Initially, motor neurons sustain injuries through multiple mechanisms resulting from harmful mutations causing disruptions of critical intracellular pathways. Injured motor neurons release distress signal(s), which induce inflammatory processes produced by surrounding glial cells in the CNS as well as peripheral innate and adaptive immune cells. This review will focus on mechanisms of neuroinflammation and their essential contributions in ALS pathogenesis.<br><br>RECENT FINDINGS: Regulatory T lymphocytes (Tregs) are a subpopulation of immunosuppressive T lymphocytes that become reduced and dysfunctional as the disease progresses in ALS patients. Their degree of dysfunction correlates with the extent and rapidity of the disease. Treg numbers are boosted in transgenic mutant SOD1 (mSOD1) mice through the passive transfer of Tregs or through treatment with an interleukin-2/ interleukin-2 monoclonal antibody complex and rapamycin. Treating the transgenic mice with either of these modalities delays disease progression and prolongs survival. In addition, Treg function is restored when dysfunctional Tregs are isolated from ALS patients and expanded ex vivo in the presence of interleukin-2 and rapamycin. Based on these findings, a first-in-human phase 1 trial has been completed in which expanded autologous Tregs were infused back into ALS patients as a potential treatment. The infusions were safe and shown to 'hit target' by enhancing both Treg numbers and suppressive functions.<br><br>SUMMARY: A delicate balance between anti-inflammatory and proinflammatory factors modulates the rates of disease progression and survival times in ALS. Tipping the balance toward the anti-inflammatory mediators shows promise in slowing the progression of this devastating disease.}, }
@article {pmid30048006, year = {2018}, author = {Oh, KW and Noh, MY and Kwon, MS and Kim, HY and Oh, SI and Park, J and Kim, HJ and Ki, CS and Kim, SH}, title = {Repeated Intrathecal Mesenchymal Stem Cells for Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {84}, number = {3}, pages = {361-373}, pmid = {30048006}, issn = {1531-8249}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*therapy ; Biomarkers/metabolism ; *Cell- and Tissue-Based Therapy/methods ; Cytokines/metabolism ; Double-Blind Method ; Female ; Humans ; Male ; *Mesenchymal Stem Cell Transplantation/methods ; Mesenchymal Stem Cells/*cytology ; Middle Aged ; }, abstract = {OBJECTIVE: To assess the safety and efficacy of 2 repeated intrathecal injections of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: In a phase 2 randomized controlled trial (NCT01363401), 64 participants with ALS were randomly assigned treatments (1:1) of riluzole alone (control group, n = 31) or combined with 2 BM-MSC injections (MSC group, n = 33). Safety was assessed based on the occurrence of adverse events. The primary efficacy outcome was changes in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score from baseline to 4 and 6 months postinjection. Post hoc analysis includes investigation of cerebrospinal fluid biomarkers and long-term survival analysis.<br><br>RESULTS: Safety rating showed no groupwise difference with absence of serious treatment-related adverse events. Mean changes in ALSFRS-R scores from baseline to 4 and 6 months postinjection were reduced in the MSC group compared with the control group (4 months: 2.98, 95% confidence interval [CI] = 1.48-4.47, p < 0.001; 6 months: 3.38, 95% CI = 1.23-5.54, p = 0.003). The MSC group showed decreased proinflammatory and increased anti-inflammatory cytokines. In good responders, transforming growth factor &#x3b2;1 significantly showed inverse correlation with monocyte chemoattractant protein-1. There was no significant difference in long-term survival between groups.<br><br>INTERPRETATION: Repeated intrathecal injections of BM-MSCs demonstrated a possible clinical benefit lasting at least 6 months, with safety, in ALS patients. A plausible action mechanism is that BM-MSCs mediate switching from pro- to anti-inflammatory conditions. A future randomized, double-blind, large-scale phase 3 clinical trial with additional BM-MSC treatments is required to evaluate long-term efficacy and safety. Ann Neurol 2018;84:361-373.}, }
@article {pmid30047795, year = {2018}, author = {Gaipa, G and Buracchi, C and Biondi, A}, title = {Flow cytometry for minimal residual disease testing in acute leukemia: opportunities and challenges.}, journal = {Expert review of molecular diagnostics}, volume = {18}, number = {9}, pages = {775-787}, doi = {10.1080/14737159.2018.1504680}, pmid = {30047795}, issn = {1744-8352}, mesh = {Acute Disease ; Flow Cytometry/methods ; Humans ; Immunophenotyping/methods ; Leukemia, Myeloid, Acute/*pathology ; Neoplasm, Residual/*pathology ; }, abstract = {Flow cytometric quantification of minimal residual disease (MRD) in acute leukemia (AL) represents an indispensable tool to guide modern therapeutic protocols toward a precision medicine approach, being a powerful predictor of the overall response to treatment. This review covers the most challenging aspects and developments of this method, aiming at supporting further its implementation in clinical practices. Area covered: Flow cytometric MRD is based on the discrimination of leukemia cells from their physiological counterparts by the recognition of the leukemia-associated immunophenotypes. Technical and standardization advances along the last decades have been implemented allowing flow cytometric MRD to consolidate its role in modern therapeutic protocols for ALs. However, gaps in sensitivity and data interpretation are still present together with the need for further optimization of MRD-based clinical protocols. In this review, we critically analyze and discuss the most relevant and representative contributions in the field by accurate selection of the literature available in PubMed. Expert commentary: Further research in flow cytometric MRD can bring this technology toward wider and consistent applications in multiple acute leukemia settings rendering this tool a future golden standard and providing clinicians with more reliable and accurate tools for clinical decisions.}, }
@article {pmid30046279, year = {2018}, author = {Cai, M and Yang, EJ}, title = {Gamisoyo-San Ameliorates Neuroinflammation in the Spinal Cord of hSOD1[G93A] Transgenic Mice.}, journal = {Mediators of inflammation}, volume = {2018}, number = {}, pages = {5897817}, pmid = {30046279}, issn = {1466-1861}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Astrocytes/cytology/metabolism ; Disease Models, Animal ; Drugs, Chinese Herbal/pharmacology/*therapeutic use ; Female ; Heme Oxygenase-1/metabolism ; Immune System ; Inflammation/*drug therapy/metabolism ; Membrane Proteins/metabolism ; Mice ; Mice, Transgenic ; Microglia/metabolism ; Nervous System Diseases/pathology ; Neuroglia/metabolism ; Neurons/metabolism ; Oxidative Stress ; Plant Preparations/*pharmacology ; Quality of Life ; Signal Transduction ; Spinal Cord/*drug effects/pathology ; Superoxide Dismutase-1/*genetics ; Toll-Like Receptor 4/metabolism ; Transferrin/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a progressive disorder, causes motor neuron degeneration and neuromuscular synapse denervation. Because this is a complex disease, there are no effective drugs for the treatment of patients with ALS. For example, riluzole is used in many countries but has many side effects and only increases the lifespan of patients by approximately 2-3 months. Therefore, patients with ALS often turn to complementary and alternative medicine, such as acupuncture, homeopathy, and herbal medicine, with the hope and belief of recovery, despite the lack of definite evidence on the efficacy of these methods. Gamisoyo-San (GSS), a herbal medicine known to improve health, has been used for stress-related neuropsychological disorders, including anorexia, in Asian countries, such as China, Korea, and Japan. To evaluate the effects of GSS on the spinal cord, we investigated the expression of neuroinflammatory and metabolic proteins in symptomatic hSOD1[G93A] mice. We observed that GSS reduces the expression of glial markers, including those for microglia and astrocytes, and prevents neuronal loss. Moreover, we found that GSS inhibits the expression of proteins related to Toll-like receptor 4 signaling and oxidative stress, known to cause neuroinflammation. Notably, GSS also regulates metabolism in the spinal cord of transgenic mice. These results suggest that GSS could be used for improving the immune system and increasing the life quality of patients with ALS.}, }
@article {pmid30040804, year = {2018}, author = {Levitsky, GN and Chub, RV and Kryachkov, AV}, title = {[The quality of medical care of patients with amyotrophic lateral sclerosis in the Russian Federation].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {118}, number = {6}, pages = {72-75}, doi = {10.17116/jnevro20181186172}, pmid = {30040804}, issn = {1997-7298}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Neurologists ; Russia ; }, abstract = {The quality of medical care for patients with amyotrophic lateral sclerosis (ALS) in the Russian Federation is analyzed taking into account the cooperation of patients. Two hundred and fifty-one patients with ALS were observed. Ninety-nine patients, including 16 who were followed up, were examined. Other patients (n=152) were consulted indirectly including 28 followed up. It has been shown that 79.8% of the patients are characterized by the low level of cooperation with neurologists regardless of the quality of medical care; 8.3% of patients are managed in facilities (or by physicians), which don't use the International standard of ALS management. Only 11.9% of patients receive medical care in accordance with this standard and in these cases, the high level of cooperation of the patients with medical services was recorded. A dual system that combines the services provided by medical insurance, private treatment facilities, charity organizations, structures of medical/social care with different levels of availability and methods of consumer-provider interactions is the most effective.}, }
@article {pmid30039719, year = {2018}, author = {Thomas, PT and Warrier, MG and Sadasivan, A and Balasubramanium, B and Preethish-Kumar, V and Nashi, S and Polavarapu, K and Krishna, G and Vengalil, S and Rajaram, P and Nalini, A}, title = {Caregiver burden and quality of life of patients with amyotrophic lateral sclerosis in India.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {19}, number = {7-8}, pages = {606-610}, doi = {10.1080/21678421.2018.1482353}, pmid = {30039719}, issn = {2167-9223}, mesh = {Adaptation, Psychological ; Amyotrophic Lateral Sclerosis/*epidemiology/*psychology ; Caregivers/*psychology ; Cross-Sectional Studies ; Disease Progression ; Female ; Humans ; India/epidemiology ; Male ; Middle Aged ; Quality of Life/*psychology ; }, abstract = {AIM: Amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND) is a progressive degenerative disorder that can have significant debilitating impact. Few studies have explored living with ALS in the developing countries. The study aims to understand the relationship between functionality, quality of life, and caregiver burden in ALS in the sociocultural scenario in India.<br><br>METHODS: A cross-sectional descriptive study was performed among 30 persons with ALS and their caregivers (men&#x2009;=&#x2009;19; women&#x2009;=&#x2009;11) receiving treatment from a national quaternary referral care center for Neurological disorders in Southern India. All patients were diagnosed as Definite ALS according to El Escorial Criteria. The mean age at onset of illness was 51.6&#xa0;years and mean duration of illness at presenting to hospital was 11&#xa0;months. The caregivers were spouses, offspring, or siblings. Variables were assessed with ALS Functional Rating Scale Revised (ALSFRS- R), ALS Specific Quality of Life Scale (ALSSQOL-R) with the patients and Zarit Burden Interview (ZBI) with the caregiver.<br><br>RESULTS: Functionality and quality of life negatively correlated with caregiver burden. Caregiver burden was negatively associated with "negative emotional state" and "interaction of the patient with family and environment", sub domains in ALSQOL scale. No significant association was noted between caregiver burden and intimacy, religiosity as well as physical symptoms domains of quality of life.<br><br>CONCLUSION: ALS patients and caregivers would benefit from structured care plan that is sensitive to the impact of the illness on the specific domains of quality of life as well as the deterioration in the neurological functioning.}, }
@article {pmid30039158, year = {2018}, author = {Curfman, GD}, title = {Prediction of Cardiovascular Risk to Guide Primary Prevention.}, journal = {JAMA internal medicine}, volume = {178}, number = {9}, pages = {1240-1241}, pmid = {30039158}, issn = {2168-6114}, mesh = {*Cardiovascular Diseases ; Cohort Studies ; Female ; Humans ; Primary Prevention ; Risk Factors ; Women's Health ; }, abstract = {IMPORTANCE: In 2010, the US Food and Drug Administration approved a combination of dextromethorphan hydrobromide and quinidine sulfate with an Orphan Drug Act designation for the treatment of pseudobulbar affect in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). This medication, however, is commonly prescribed off-label for behavioral symptoms in patients with dementia and/or Parkinson disease (PD).<br><br>OBJECTIVE: To investigate the prescribing patterns of dextromethorphan-quinidine, including off-label prescribing, and trends in associated costs.<br><br>This population-based cohort study of patients prescribed dextromethorphan-quinidine used data from 2 commercial insurance databases. The Medicare Part D Prescription Drug Program data set was used to evaluate prescription number and total spending by the Centers for Medicare &amp; Medicaid Services. Patients were included if they were prescribed dextromethorphan-quinidine from October 29, 2010, when the drug was approved, through March 1, 2017.<br><br>MAIN OUTCOMES AND MEASURES: The proportion of patients prescribed dextromethorphan-quinidine with a diagnosis of MS, ALS, or dementia and/or PD, as well as the number of patients with a history of heart failure (a contraindication for the drug).<br><br>RESULTS: In the commercial health care databases, 12&#x2009;858 patients filled a prescription for dextromethorphan-quinidine during the study period. Mean (SD) age was 66.0 (18.5) years; 67.0% were women; and 13.3% had a history of heart failure. Combining results from both databases, few patients had a diagnosis of MS (8.4%) or ALS (6.8%); most (57.0%) had a diagnosis of dementia and/or PD. In the Medicare Part D database, the number of patients prescribed dextromethorphan-quinidine increased approximately 12-fold, from 3296 in 2011 to 40&#x2009;448 in 2015. Centers for Medicare &amp; Medicaid Services spending on this medication increased from $4.3 million in 2011 to $137.5 million by 2015.<br><br>CONCLUSIONS AND RELEVANCE: Despite approval by the US Food and Drug Administration as an orphan-designated drug for pseudobulbar affect related to ALS or MS, this study suggests that dextromethorphan-quinidine appears to be primarily prescribed off-label for patients with dementia and/or PD.}, }
@article {pmid30033879, year = {2018}, author = {Chico, L and Ienco, EC and Bisordi, C and Lo Gerfo, A and Petrozzi, L and Petrucci, A and Mancuso, M and Siciliano, G}, title = {Amyotrophic Lateral Sclerosis and Oxidative Stress: A Double-Blind Therapeutic Trial After Curcumin Supplementation.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {17}, number = {10}, pages = {767-779}, doi = {10.2174/1871527317666180720162029}, pmid = {30033879}, issn = {1996-3181}, mesh = {Advanced Oxidation Protein Products/blood ; Aged ; Amyotrophic Lateral Sclerosis/*diet therapy/genetics ; Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use ; Antioxidants/metabolism ; Body Mass Index ; Curcumin/*therapeutic use ; *Dietary Supplements ; Double-Blind Method ; Exercise Test ; Female ; Follow-Up Studies ; Hand Strength/physiology ; Humans ; Lactic Acid ; Male ; Middle Aged ; Mutation/genetics ; Oxidative Stress/*drug effects ; Severity of Illness Index ; Sulfhydryl Compounds/metabolism ; Superoxide Dismutase-1/genetics ; Time Factors ; Treatment Outcome ; }, abstract = {OBJECTIVE: To investigate the efficacy of curcumin oral supplementation (600 mg/day, Brainoil), a natural antioxidant compound, in Amyotrophic Lateral Sclerosis (ALS).<br><br>METHODS: Patients were randomized into two groups: Group A received placebo for 3 months, then Brainoil for the following 3 months, Group B took Brainoil for 6 months. The evaluations were conducted at basal (T0), after 3 months of double blinded Brainoil or placebo treatment (T1), and after the 3 month open-label phase (T2). Clinical evaluations and oxidative stress biomarkers, including oxidative protein products (AOPPs), ferric reducing ability (FRAP), total thiols (T-SH) and lactate, were evaluated, compared to a control group, during an incremental forearm exercise test.<br><br>RESULTS: Over the entire study Group B showed a stable score of the ALS-FRS-r which decreased in Group A (p<0.01), in parallel with a reduction of AOPPs (p<0.01) which was not detected into Group A. Also FRAP exercise values remained stable in Group B, while in Group A they were reduced without treatment at T1 (0.05<p<0.01), for then increase at T2 with introduction of therapy (p<0.05). In Group B T1>T0 exercise lactate was lower compared to Group A (p<0.01). Compared to controls, the whole ALS population showed a greater oxidative stress (p<0.001), those treated with curcumin (Group B) exhibiting decreased exercise AOPPs at T2 with values approaching those of controls.<br><br>CONCLUSION: Although further studies are needed to confirm these data, treatment with curcumin shows encouraging results indicating a slight slowdown in disease progression, improving aerobic metabolism and oxidative damage, this also contributing to deepen knowledge into the pathogenic mechanisms of ALS.}, }
@article {pmid30033758, year = {2018}, author = {Lee, JH and Liu, JW and Lin, SZ and Harn, HJ and Chiou, TW}, title = {Advances in Patient-Specific Induced Pluripotent Stem Cells Shed Light on Drug Discovery for Amyotrophic Lateral Sclerosis.}, journal = {Cell transplantation}, volume = {27}, number = {9}, pages = {1301-1312}, pmid = {30033758}, issn = {1555-3892}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Drug Discovery/*methods ; Drug Evaluation, Preclinical/*methods ; Genotype ; Humans ; Induced Pluripotent Stem Cells/*cytology/drug effects/metabolism ; Motor Neurons/*cytology/drug effects/metabolism ; Neurogenesis/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Small Molecule Libraries/pharmacology/therapeutic use ; }, abstract = {Induced pluripotent stem cells (iPSCs), which are generated through reprogramming adult somatic cells by expressing specific transcription factors, can differentiate into derivatives of the three embryonic germ layers and accelerate rapid advances in stem cell research. Neurological diseases such as amyotrophic lateral sclerosis (ALS) have benefited enormously from iPSC technology. This approach can be particularly important for creating iPSCs from patients with familial or sporadic forms of ALS. Motor neurons differentiated from the ALS-patient-derived iPSC can help to determine the relationship between cellular phenotype and genotype. Patient-derived iPSCs facilitate the development of new drugs and/or drug screening for ALS treatment and allow the exploration of the possible mechanism of ALS disease. In this article, we reviewed ALS-patient-specific iPSCs with various genetic mutations, progress in drug development for ALS disease, functional assays showing the differentiation of iPSCs into mature motor neurons, and promising biomarkers in ALS patients for the evaluation of drug candidates.}, }
@article {pmid30030751, year = {2019}, author = {Cai, M and Lee, SH and Yang, EJ}, title = {Bojungikgi-tang Improves Muscle and Spinal Cord Function in an Amyotrophic Lateral Sclerosis Model.}, journal = {Molecular neurobiology}, volume = {56}, number = {4}, pages = {2394-2407}, pmid = {30030751}, issn = {1559-1182}, support = {C16051and C18040//Korea Institute of Oriental Medicine/ ; NRF-2015R1C1A2A01053248//National Research Foundation of Korea/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology/*physiopathology ; Animals ; Antioxidants/pharmacology ; Autophagy/drug effects ; Drugs, Chinese Herbal/pharmacology/*therapeutic use ; Humans ; Inflammation/pathology ; Mice, Transgenic ; Mitochondria/drug effects/metabolism/ultrastructure ; Motor Activity/drug effects ; Muscle, Skeletal/drug effects/*physiopathology ; Muscular Atrophy/pathology ; Neuromuscular Junction/drug effects/ultrastructure ; Spinal Cord/drug effects/pathology/*physiopathology ; Superoxide Dismutase-1/metabolism ; Survival Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive motor function impairment, dysphagia, and respiratory failure. Owing to the complexity of its pathogenic mechanisms, an effective therapy for ALS is lacking. Herbal medicines with multiple targets have good efficacy and low adverse reactions for the treatment of neurodegenerative diseases. In this study, the effects of Bojungikgi-tang (BJIGT), an herbal medicine with eight component herbs, on muscle and spinal cord function were evaluated in an ALS animal model. Animals were randomly divided into three groups: a non-transgenic group (nTg, n = 24), a hSOD1[G93A] transgenic group (Tg, n = 24), and a hSOD1[G93A] transgenic group in which 8-week-old mice were orally administered BJIGT (1 mg/g) once daily for 6 weeks (Tg+BJIGT, n = 24). The effects of BJIGT were evaluated using a rotarod test, foot-printing, and survival analyses based on Kaplan-Meier survival curves. To determine the biological mechanism underlying the effects of BJIGT in hSOD1[G93A] mice, western blotting, transmission electron microscopy, and Bungarotoxin staining were used. BJIGT improved motor function and extended the survival duration of hSOD1[G93A] mice. In addition, BJIGT had protective effects, including anti-oxidative and anti-inflammatory effects, in both the spinal cord and muscle of hSOD1[G93A] mice. Our results demonstrated that BJIGT causes muscle atrophy and the denervation of neuromuscular junctions in the gastrocnemius of hSOD1[G93A] mice. The components of BJIGT may alleviate the symptoms of ALS via different mechanisms, and accordingly, BJIGT treatment may be an effective therapeutic approach.}, }
@article {pmid30030591, year = {2018}, author = {Dhouafli, Z and Cuanalo-Contreras, K and Hayouni, EA and Mays, CE and Soto, C and Moreno-Gonzalez, I}, title = {Inhibition of protein misfolding and aggregation by natural phenolic compounds.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {75}, number = {19}, pages = {3521-3538}, pmid = {30030591}, issn = {1420-9071}, mesh = {Amyloidosis/drug therapy/metabolism/pathology ; Animals ; Biological Products/*pharmacology/therapeutic use ; Diabetes Mellitus, Type 2/drug therapy/metabolism/pathology ; Humans ; Phenols/*pharmacology/therapeutic use ; Prion Diseases/drug therapy/metabolism/pathology ; Protein Aggregation, Pathological/*prevention &amp; control ; Protein Folding/*drug effects ; Proteostasis Deficiencies/drug therapy/*prevention &amp; control ; }, abstract = {Protein misfolding and aggregation into fibrillar deposits is a common feature of a large group of degenerative diseases affecting the central nervous system or peripheral organs, termed protein misfolding disorders (PMDs). Despite their established toxic nature, clinical trials aiming to reduce misfolded aggregates have been unsuccessful in treating or curing PMDs. An interesting possibility for disease intervention is the regular intake of natural food or herbal extracts, which contain active molecules that inhibit aggregation or induce the disassembly of misfolded aggregates. Among natural compounds, phenolic molecules are of particular interest, since most have dual activity as amyloid aggregation inhibitors and antioxidants. In this article, we review many phenolic natural compounds which have been reported in diverse model systems to have the potential to delay or prevent the development of various PMDs, including Alzheimer's and Parkinson's diseases, prion diseases, amyotrophic lateral sclerosis, systemic amyloidosis, and type 2 diabetes. The lower toxicity of natural compounds compared to synthetic chemical molecules suggest that they could serve as a good starting point to discover protein misfolding inhibitors that might be useful for the treatment of various incurable diseases.}, }
@article {pmid30029769, year = {2019}, author = {Driskell, LD and York, MK and Heyn, PC and Sanjak, M and MacAdam, C}, title = {A Guide to Understanding the Benefits of a Multidisciplinary Team Approach to Amyotrophic Lateral Sclerosis (ALS) Treatment.}, journal = {Archives of physical medicine and rehabilitation}, volume = {100}, number = {3}, pages = {583-586}, doi = {10.1016/j.apmr.2018.05.002}, pmid = {30029769}, issn = {1532-821X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; *Patient Care Team ; }, }
@article {pmid30027910, year = {2018}, author = {Arneson, D and Zhang, Y and Yang, X and Narayanan, M}, title = {Shared mechanisms among neurodegenerative diseases: from genetic factors to gene networks.}, journal = {Journal of genetics}, volume = {97}, number = {3}, pages = {795-806}, pmid = {30027910}, issn = {0973-7731}, support = {R01 DK104363/DK/NIDDK NIH HHS/United States ; R21 NS103088/NS/NINDS NIH HHS/United States ; }, mesh = {Gene Expression Profiling ; Gene Expression Regulation ; *Gene Regulatory Networks ; *Genetic Predisposition to Disease ; Humans ; Neurodegenerative Diseases/*genetics ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are pressing health concerns in modern societies for which effective therapies are still lacking. Recent high-throughput genomic technologies have enabled genome-scale, multidimensional investigations to facilitate a better understanding of the underlying mechanisms and the identification of novel targets. Here we review the molecular insights gained through such studies, and compare the similarities and differences between neurodegenerative diseases revealed by systems genomics and gene network modelling approaches. We focus specifically on the shared mechanisms at multiple molecular scales ranging from genetic factors to gene expression to network-level features of gene regulation, and whenever possible also point out mechanisms that distinguish one disease from another. Our review sets the stage for similar genomewide inspection in the future on shared/distinct features of neurodegenerative diseases at the levels of cellular, proteomic or epigenomic signatures, and how these features may interact to determine the progression and treatment response of different diseases afflicting the same individual.}, }
@article {pmid30027900, year = {2018}, author = {Kumar, S and Yadav, N and Pandey, S and Thelma, BK}, title = {Advances in the discovery of genetic risk factors for complex forms of neurodegenerative disorders: contemporary approaches, success, challenges and prospects.}, journal = {Journal of genetics}, volume = {97}, number = {3}, pages = {625-648}, pmid = {30027900}, issn = {0973-7731}, mesh = {*Genetic Predisposition to Disease ; Humans ; Neurodegenerative Diseases/*genetics ; Risk Factors ; }, abstract = {Neurodegenerative diseases constitute a large proportion of disorders in elderly, majority being sporadic in occurrence with ∼5-10% familial. A strong genetic component underlies the Mendelian forms but nongenetic factors together with genetic vulnerability contributes to the complex sporadic forms. Several gene discoveries in the familial forms have provided novel insights into the pathogenesis of neurodegeneration with implications for treatment. Conversely, findings from genetic dissection of the sporadic forms, despite large genomewide association studies and more recently whole exome and whole genome sequencing, have been limited. This review provides a concise account of the genetics that we know, the pathways that they implicate, the challenges that are faced and the prospects that are envisaged for the sporadic, complex forms of neurodegenerative diseases, taking four most common conditions, namely Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington disease as examples. Poor replication across studies, inability to establish genotype-phenotype correlations and the overall failure to predict risk and/or prevent disease in this group poses a continuing challenge. Among others, clinical heterogeneity emerges as the most important impediment warranting newer approaches. Advanced computational and system biology tools to analyse the big data are being generated and the alternate strategy such as subgrouping of case-control cohorts based on deep phenotyping using the principles of Ayurveda to overcome current limitation of phenotype heterogeneity seem to hold promise. However, at this point, with advances in discovery genomics and functional analysis of putative determinants with translation potential for the complex forms being minimal, stem cell therapies are being attempted as potential interventions. In this context, the possibility to generate patient derived induced pluripotent stem cells, mutant/gene/genome correction through CRISPR/Cas9 technology and repopulating the specific brain regions with corrected neurons, which may fulfil the dream of personalized medicine have been mentioned briefly. Understanding disease pathways/biology using this technology, with implications for development of novel therapeutics are optimistic expectations in the near future.}, }
@article {pmid30019764, year = {2018}, author = {Greene, M and Lomen-Hoerth, C}, title = {Navigating a fine balance in the treatment of amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {58}, number = {6}, pages = {745-746}, doi = {10.1002/mus.26302}, pmid = {30019764}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; *Noninvasive Ventilation ; Respiration ; Ventilation ; }, }
@article {pmid30013324, year = {2018}, author = {Parikh, A and Kathawala, K and Tan, CC and Garg, S and Zhou, XF}, title = {Self-nanomicellizing solid dispersion of edaravone: part I - oral bioavailability improvement.}, journal = {Drug design, development and therapy}, volume = {12}, number = {}, pages = {2051-2069}, pmid = {30013324}, issn = {1177-8881}, mesh = {Administration, Oral ; Biological Availability ; Dose-Response Relationship, Drug ; Drug Carriers/chemistry ; Drug Compounding ; Edaravone/administration &amp; dosage/chemistry/*pharmacokinetics ; Free Radical Scavengers/administration &amp; dosage/chemistry/*pharmacokinetics ; Humans ; Kinetics ; Polymers/chemistry ; Solubility ; }, abstract = {BACKGROUND: Edaravone (EDR) is known for its free radical scavenging, antiapoptotic, antinecrotic, and anticytokine effects in neurological and non-neurological diseases. It is currently available clinically as Radicava[®] and Radicut[®], intravenous medications, recently approved for the treatment of amyotrophic lateral sclerosis and cerebral infarction. However, the oral use of EDR is still restricted by its poor oral bioavailability (BA) due to poor aqueous solubility, stability, rapid metabolism, and low permeability. The present study reports the development of novel EDR formulation (NEF) using self-nanomicellizing solid dispersion (SNMSD) strategy with the aim to enable its oral use.<br><br>MATERIALS AND METHODS: The selection of a suitable carrier for the development of NEF was performed based on the miscibility study. The optimization of EDR-to-carrier ratio was conducted via kinetic solubility study after preparing SNMSDs using solvent evaporation technique. The drug-polymer carrier interaction and self-nanomicellizing properties of NEF were investigated with advanced characterization studies. In vitro permeation, metabolism, and dissolution study was carried out to examine the effect of the presence of a carrier on physico-chemical properties of EDR. Additionally, the dose-dependent pharmacokinetic study of NEF was conducted and compared with the EDR suspension.<br><br>RESULTS: Soluplus[&#xae;] (SOL) as a carrier was selected based on the potential for improving aqueous solubility. The NEF containing EDR and SOL (1:5) resulted in the highest enhancement in aqueous solubility (17.53-fold) due to amorphization, hydrogen bonding interaction, and micellization. Moreover, the NEF demonstrated significant improvement in metabolism, permeability, and dissolution profile of EDR. Furthermore, the oral BA of NEF showed 10.2-, 16.1-, and 14.8-fold enhancement compared to EDR suspension at 46, 138, and 414 &#xb5;mol/kg doses.<br><br>CONCLUSION: The results demonstrated that SNMSD strategy could serve as a promising way to enhance EDR oral BA and NEF could be a potential candidate for the treatment of diseases in which oxidative stress plays a key role in their pathogenesis.}, }
@article {pmid30010155, year = {2018}, author = {Walker, CL and Meadows, RM and Merfeld-Clauss, S and Du, Y and March, KL and Jones, KJ}, title = {Adipose-derived stem cell conditioned medium impacts asymptomatic peripheral neuromuscular denervation in the mutant superoxide dismutase (G93A) transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Restorative neurology and neuroscience}, volume = {36}, number = {5}, pages = {621-627}, pmid = {30010155}, issn = {1878-3627}, support = {R01 ES027078/ES/NIEHS NIH HHS/United States ; T32 HL079995/HL/NHLBI NIH HHS/United States ; T32 HL79995/NH/NIH HHS/United States ; }, mesh = {Adipocytes/*metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology/physiopathology ; Animals ; Culture Media, Conditioned/*pharmacology ; Disease Models, Animal ; Humans ; Mice, Transgenic ; Molybdoferredoxin ; Muscle, Skeletal/drug effects/innervation/pathology/physiopathology ; Nerve Degeneration/drug therapy/pathology/physiopathology ; Neuromuscular Junction/*drug effects/pathology/physiopathology ; Neuroprotective Agents/*pharmacology ; Random Allocation ; Receptors, Cholinergic/metabolism ; Stem Cells/*metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is devastating, leading to paralysis and death. Disease onset begins pre-symptomatically through spinal motor neuron (MN) axon die-back from musculature at ∼47 days of age in the mutant superoxide dismutase 1 (mSOD1G93A) transgenic ALS mouse model. This period may be optimal to assess potential therapies. We previously demonstrated that post-symptomatic adipose-derived stem cell conditioned medium (ASC-CM) treatment is neuroprotective in mSOD1G93A mice. We hypothesized that early disease onset treatment could ameliorate neuromuscular junction (NMJ) disruption.<br><br>OBJECTIVE: To determine whether pre-symptom administration of ASC-CM prevents early NMJ disconnection.<br><br>METHODS: We confirmed the NMJ denervation time course in mSOD1G93A mice using co-labeling of neurofilament and post-synaptic acetylcholine receptors (AchR) by &#x3b1;-bungarotoxin. We determined whether ASC-CM ameliorates early NMJ loss in mSOD1G93A mice by systemically administering 200&#x3bc;l ASC-CM or vehicle medium daily from post-natal days 35 to 47 and quantifying intact NMJs through co-labeling of neurofilament and synaptophysin with &#x3b1;-bungarotoxin in gastrocnemius muscle.<br><br>RESULTS: Intact NMJs were significantly decreased in 47 day old mSOD1G93A mice (p&#x200a;<&#x200a;0.05), and daily systemic ASC-CM prevented disease-induced NMJ denervation compared to vehicle treated mice (p&#x200a;<&#x200a;0.05).<br><br>CONCLUSIONS: Our results lay the foundation for testing the long-term neurological benefits of systemic ASC-CM therapy in the mSOD1G93A mouse model of ALS.}, }
@article {pmid30005051, year = {2019}, author = {Sarnicola, C and Farooq, AV and Colby, K}, title = {Fuchs Endothelial Corneal Dystrophy: Update on Pathogenesis and Future Directions.}, journal = {Eye &amp; contact lens}, volume = {45}, number = {1}, pages = {1-10}, doi = {10.1097/ICL.0000000000000469}, pmid = {30005051}, issn = {1542-233X}, mesh = {*Corneal Transplantation ; Endothelium, Corneal/*pathology ; *Fuchs' Endothelial Dystrophy/diagnosis/epidemiology/surgery ; Global Health ; Humans ; Incidence ; }, abstract = {Fuchs endothelial corneal dystrophy (FECD) is the most common indication for corneal transplantation in the United States, accounting 36% of the almost 47,000 transplants performed in 2016. Although the surgical management of FECD has undergone a revolution over the past 20 years, its pathogenesis remains elusive, with multiple putative disease pathways and an ever increasing number of candidate genes thought to play a role. This review will summarize the recent advancements in our understanding of the biology of FECD, including potential parallels with neurodegenerative disease like amyotrophic lateral sclerosis and will highlight prospects for future treatment advances.}, }
@article {pmid30001159, year = {2018}, author = {Thakore, NJ and Lapin, BR and Kinzy, TG and Pioro, EP}, title = {Deconstructing progression of amyotrophic lateral sclerosis in stages: a Markov modeling approach.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {19}, number = {7-8}, pages = {483-494}, doi = {10.1080/21678421.2018.1484925}, pmid = {30001159}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology/therapy ; Clinical Studies as Topic ; *Disease Progression ; Female ; Humans ; Male ; *Markov Chains ; Severity of Illness Index ; Survival Analysis ; }, abstract = {OBJECTIVES: Propose an empirical amyotrophic lateral sclerosis (ALS) staging approach called Fine'til 9 (FT9) based on how many of the patient's ALS functional rating scale (ALSFRS-R) subscores are 9 or less (of normal 12). Gain insights into progression of ALS by applying Markov models to ALS stages by multiple systems (King's, Milan-Torino system (MITOS) and FT9).<br><br>METHODS: Patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) dataset were staged using ALSFRS-R responses. Risks of progression through stages and death were estimated, as were effects of prognostic variables on these risks.<br><br>RESULTS: A total of 29,947 time points in 3199 patients from the PRO-ACT dataset were assigned stages. Although the three systems were moderately correlated, MITOS stages were heavily skewed toward advanced disease, whereas King's and FT9 stages were more balanced. Non-sequential progression was observed with King's system. Markov models adequately described transitions from stage to stage in the first year of observation, but underestimated risks beyond that point. Regardless of staging method, initial rate of ALSFRS-R decline had a powerful effect on rate of progression through sequential stages, whereas age predominantly influenced stage-specific mortality.<br><br>CONCLUSION: King's and FT9 are more sensitive to observed progression of disease in clinical trials than MITOS. FT9 can partition the course similar to King's, and may have advantages of sequential progression and easy applicability to retrospective data. Markov transition intensity estimates may be of value for counseling, health economic studies, and research design. In particular, this framework permits estimation of multidimensional effects of variables (including treatment) on outcome.}, }
@article {pmid29998226, year = {2018}, author = {Bhandari, R and Kuhad, A and Kuhad, A}, title = {Edaravone: a new hope for deadly amyotrophic lateral sclerosis.}, journal = {Drugs of today (Barcelona, Spain : 1998)}, volume = {54}, number = {6}, pages = {349-360}, doi = {10.1358/dot.2018.54.6.2828189}, pmid = {29998226}, issn = {1699-3993}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Antipyrine/adverse effects/*analogs &amp; derivatives/pharmacokinetics/pharmacology/therapeutic use ; Edaravone ; Free Radical Scavengers/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a fatal motor neuron degenerative disorder leading to paralysis and eventual death. At present, we do not have any specific cure for this deadly disorder. Current drug therapy can only reduce morbidity in ALS patients. In 1995, riluzole was the first drug approved by the U.S. Food and Drug Administration (FDA) for ALS. After a long gap of 22 years, Mitsubishi Tanabe Pharma America got U.S. FDA approval for edaravone (Radicava) in May 2017 for the management of ALS. Edaravone, a novel neuroprotective agent, is indicated to slow down progression of ALS. In 2015, Mitsubishi Tanabe Pharma launched edaravone (Radicut) for the treatment of stroke and ALS in Japan. The U.S. FDA approved edaravone following clinical evidence from three clinical trials conducted in 368 ALS patients in Japan. Edaravone is awaiting approval by the European Medicines Agency (EMA) in Europe. Edaravone (60 mg) is administered by very slow intravenous infusion (60 minutes) in 28-day cycles. It has been shown to slow down the loss of physical function in ALS patients by 33% as compared to placebo. Edaravone is a strong antioxidant that prevents oxidative stress from inducing motor neuron death in ALS patients. Being a potent free radical scavenger, it has been shown to inhibit nitration of tyrosine residues in the cerebrospinal fluid and improve motor functions in mouse models of ALS. The product has been patented and the FDA has not approved any generic version of edaravone. This article discusses the preclinical pharmacology, pharmacokinetics, safety profile, clinical studies and drug interactions of edaravone (Radicava) in ALS.}, }
@article {pmid29996549, year = {2018}, author = {Greco, V and Spalloni, A and Corasolla Carregari, V and Pieroni, L and Persichilli, S and Mercuri, NB and Urbani, A and Longone, P}, title = {Proteomics and Toxicity Analysis of Spinal-Cord Primary Cultures upon Hydrogen Sulfide Treatment.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {7}, number = {7}, pages = {}, pmid = {29996549}, issn = {2076-3921}, abstract = {Hydrogen sulfide (H2S) is an endogenous gasotransmitter recognized as an essential body product with a dual, biphasic action. It can function as an antioxidant and a cytoprotective, but also as a poison with a high probability of causing brain damage when present at noxious levels. In a previous study, we measured toxic liquoral levels of H2S in sporadic amyotrophic lateral sclerosis (ALS) patients and in the familial ALS (fALS) mouse model, SOD1G93A. In addition, we experimentally demonstrated that H2S is extremely and selectively toxic to motor neurons, and that it is released by glial cells and increases Ca[2+] concentration in motor neurons due to a lack of ATP. The presented study further examines the effect of toxic concentrations of H2S on embryonic mouse spinal-cord cultures. We performed a proteomic analysis that revealed a significant H2S-mediated activation of pathways related to oxidative stress and cell death, particularly the Nrf-2-mediated oxidative stress response and peroxiredoxins. Furthermore, we report that Na2S (a stable precursor of H2S) toxicity is, at least in part, reverted by the Bax inhibitor V5 and by necrostatin, a potent necroptosis inhibitor.}, }
@article {pmid29991716, year = {2018}, author = {Tsuburaya, N and Homma, K and Higuchi, T and Balia, A and Yamakoshi, H and Shibata, N and Nakamura, S and Nakagawa, H and Ikeda, SI and Umezawa, N and Kato, N and Yokoshima, S and Shibuya, M and Shimonishi, M and Kojima, H and Okabe, T and Nagano, T and Naguro, I and Imamura, K and Inoue, H and Fujisawa, T and Ichijo, H}, title = {A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model.}, journal = {Nature communications}, volume = {9}, number = {1}, pages = {2668}, pmid = {29991716}, issn = {2041-1723}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*prevention &amp; control ; Animals ; Brain/drug effects/metabolism ; *Disease Models, Animal ; HEK293 Cells ; Humans ; Male ; Membrane Proteins/genetics/*metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Protein Binding/drug effects ; Small Molecule Libraries/*pharmacology ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase-1/genetics/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder. Despite its severity, there are no effective treatments because of the complexity of its pathogenesis. As one of the underlying mechanisms of Cu, Zn superoxide dismutase (SOD1) gene mutation-induced ALS, SOD1 mutants (SOD1[mut]) commonly interact with an endoplasmic reticulum-resident membrane protein Derlin-1, triggering motoneuron death. However, the importance of SOD1-Derlin-1 interaction in in vitro human model and in vivo mouse model remains to be elucidated. Here, we identify small-molecular-weight compounds that inhibit the SOD1-Derlin-1 interaction by screening approximately 160,000 compounds. The inhibitor prevents 122 types of SOD1[mut] from interacting with Derlin-1, and significantly ameliorates the ALS pathology both in motoneurons derived from patient induced pluripotent stem cells and in model mice. Our data suggest that the SOD1-Derlin-1 interaction contributes to the pathogenesis of ALS and is a promising drug target for ALS treatment.}, }
@article {pmid29991087, year = {2019}, author = {Perdigão, APL and Antunes, NJ and Juni, LT and de Freitas, NL and Rojas-Moscoso, J and Corrêa, SVM and da Costa, RC and Moreno, RA and Mendes, GD and De Nucci, G}, title = {Pharmacokinetics of Riluzole in Beagle Dogs.}, journal = {Drug research}, volume = {69}, number = {1}, pages = {40-45}, doi = {10.1055/a-0645-1248}, pmid = {29991087}, issn = {2194-9387}, mesh = {Administration, Oral ; Animals ; Area Under Curve ; Chromatography, Liquid/methods ; Dogs ; Female ; Male ; Plasma/metabolism ; Riluzole/blood/*pharmacokinetics/pharmacology ; Spinal Cord Injuries/blood/drug therapy/metabolism ; Tandem Mass Spectrometry/methods ; }, abstract = {BACKGROUND: Riluzole is a benzothiazole anticonvulsant used in the treatment of patients with amyotrophic lateral sclerosis and it is being investigated for clinical use in patients with spinal cord injury. The present study evaluated the pharmacokinetics of riluzole in beagle dogs after oral dose administration.<br><br>METHODS: The oral doses (1.5, 5, 15 and 50&#x2009;mg/kg) of riluzole were administered to beagle dogs and blood samples were collected from 0&#x2009;h to 24&#x2009;h post drug administration. Riluzole was quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS).<br><br>RESULTS: The method was sensitive, precise, accurate and selective to riluzole quantification in plasma of beagle dogs. The pharmacokinetics following oral administration was linear from 1.5 to 15&#x2009;mg/kg and the t1/2 was 2.16, 1.5, 1.8 and 3.0&#x2009;h after oral administration of 1.5, 5.0, 15 and 50&#x2009;mg/kg riluzole.<br><br>CONCLUSION: The riluzole pharmacokinetics was linear up to 15&#x2009;mg/kg and had a significantlyshorter t1/2 in beagle dogs than in humans.}, }
@article {pmid29990478, year = {2019}, author = {Niedermeyer, S and Murn, M and Choi, PJ}, title = {Respiratory Failure in Amyotrophic Lateral Sclerosis.}, journal = {Chest}, volume = {155}, number = {2}, pages = {401-408}, doi = {10.1016/j.chest.2018.06.035}, pmid = {29990478}, issn = {1931-3543}, mesh = {Airway Management ; Amyotrophic Lateral Sclerosis/*complications/mortality/*therapy ; Humans ; Respiratory Insufficiency/*etiology/mortality/*therapy ; Respiratory Therapy ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neuromuscular disease characterized by both lower motor neuron and upper motor neuron dysfunction. Although clinical presentations can vary, there is no cure for ALS, and the disease is universally terminal, with most patients dying of respiratory complications. Patients die, on average, within 3 to 5 years of diagnosis, unless they choose to undergo tracheostomy, in which case, they may live, on average, 2 additional years. Up to 95% of patients with ALS in the United States choose not to undergo tracheostomy; management of respiratory failure is therefore aimed at both prolonging survival as well as improving quality of life. Standard of care for patients with ALS includes treatment from multidisciplinary teams, but many patients do not have consistent access to a pulmonary physician who regularly sees patients with this disease. The goal of this review was to serve as an overview of respiratory considerations in the management of ALS. This article discusses noninvasive ventilation in the management of respiratory muscle weakness, mechanical insufflation/exsufflation devices for airway clearance, and treatment of aspiration, including timing of placement of a percutaneous endoscopic gastrostomy tube, as well as secretion management. In addition, it is important for physicians to consider end-of-life issues such as advanced directives, hospice referral, and ventilator withdrawal.}, }
@article {pmid29981425, year = {2018}, author = {Cocozza, G and di Castro, MA and Carbonari, L and Grimaldi, A and Antonangeli, F and Garofalo, S and Porzia, A and Madonna, M and Mainiero, F and Santoni, A and Grassi, F and Wulff, H and D'Alessandro, G and Limatola, C}, title = {Ca[2+]-activated K[+] channels modulate microglia affecting motor neuron survival in hSOD1[G93A] mice.}, journal = {Brain, behavior, and immunity}, volume = {73}, number = {}, pages = {584-595}, pmid = {29981425}, issn = {1090-2139}, support = {R56 NS098328/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/pathology ; Animals ; Cell Death ; Disease Models, Animal ; Disease Progression ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/metabolism/*physiology ; Motor Neurons/*physiology ; Phenotype ; Potassium Channels, Calcium-Activated/antagonists &amp; inhibitors/metabolism/*physiology ; Pyrazoles/pharmacology ; Spinal Cord/pathology ; Superoxide Dismutase/genetics/metabolism/physiology ; }, abstract = {Recent studies described a critical role for microglia in amyotrophic lateral sclerosis (ALS), where these CNS-resident immune cells participate in the establishment of an inflammatory microenvironment that contributes to motor neuron degeneration. Understanding the mechanisms leading to microglia activation in ALS could help to identify specific molecular pathways which could be targeted to reduce or delay motor neuron degeneration and muscle paralysis in patients. The intermediate-conductance calcium-activated potassium channel KCa3.1 has been reported to modulate the "pro-inflammatory" phenotype of microglia in different pathological conditions. We here investigated the effects of blocking KCa3.1 activity in the hSOD1[G93A]ALS mouse model, which recapitulates many features of the human disease. We report that treatment of hSOD1[G93A] mice with a selective KCa3.1 inhibitor, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), attenuates the "pro-inflammatory" phenotype of microglia in the spinal cord, reduces motor neuron death, delays onset of muscle weakness, and increases survival. Specifically, inhibition of KCa3.1 channels slowed muscle denervation, decreased the expression of the fetal acetylcholine receptor γ subunit and reduced neuromuscular junction damage. Taken together, these results demonstrate a key role for KCa3.1 in driving a pro-inflammatory microglia phenotype in ALS.}, }
@article {pmid29981392, year = {2018}, author = {Ramalho, TC and de Castro, AA and Tavares, TS and Silva, MC and Silva, DR and Cesar, PH and Santos, LA and da Cunha, EFF and Nepovimova, E and Kuca, K}, title = {Insights into the pharmaceuticals and mechanisms of neurological orphan diseases: Current Status and future expectations.}, journal = {Progress in neurobiology}, volume = {169}, number = {}, pages = {135-157}, doi = {10.1016/j.pneurobio.2018.06.011}, pmid = {29981392}, issn = {1873-5118}, mesh = {Animals ; Humans ; *Nervous System Diseases/drug therapy/genetics/physiopathology ; *Pharmaceutical Preparations ; *Rare Diseases/drug therapy/genetics/physiopathology ; }, abstract = {Several rare or orphan diseases have been characterized that singly affect low numbers of people, but cumulatively reach ∼6%-10% of the population in Europe and in the United States. Human genetics has shown to be broadly effective when evaluating subjacent genetic defects such as orphan genetic diseases, but on the other hand, a modest progress has been achieved toward comprehending the molecular pathologies and designing new therapies. Chemical genetics, placed at the interface of chemistry and genetics, could be employed to understand the molecular mechanisms of subjacent illnesses and for the discovery of new remediation processes. This review debates current progress in chemical genetics, and how a variety of compounds and reaction mechanisms can be used to study and ultimately treat rare genetic diseases. We focus here on a study involving Amyotrophic lateral sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Spinal muscular atrophy (SMA) and Familial Amyloid Polyneuropathy (FAP), approaching different treatment methods and the reaction mechanisms of several compounds, trying to elucidate new routes capable of assisting in the treatment profile.}, }
@article {pmid29981346, year = {2018}, author = {S, M and T, P and Goli, D}, title = {Effect of wedelolactone and gallic acid on quinolinic acid-induced neurotoxicity and impaired motor function: significance to sporadic amyotrophic lateral sclerosis.}, journal = {Neurotoxicology}, volume = {68}, number = {}, pages = {1-12}, doi = {10.1016/j.neuro.2018.06.015}, pmid = {29981346}, issn = {1872-9711}, mesh = {Amyotrophic Lateral Sclerosis/*chemically induced/metabolism ; Animals ; Antioxidants/administration &amp; dosage ; Apoptosis ; Brain/*drug effects/metabolism ; Coumarins/*administration &amp; dosage ; Disease Models, Animal ; Encephalitis/chemically induced/metabolism ; Gallic Acid/*administration &amp; dosage ; Learning/*drug effects ; Male ; Motor Activity/*drug effects ; Neuroprotective Agents/*administration &amp; dosage ; Quinolinic Acid/*toxicity ; Rats, Wistar ; }, abstract = {Quinolinic acid (QUIN) is a well-known neuroactive metabolite of tryptophan degradation pathway or kynurenine pathway. The QUIN is involved in the development of several toxic cascades which leads to the neuronal degeneration processes. The QUIN-induced toxicity is also responsible for the impairment of the motor function and motor learning ability. This study seeks to investigate the several mechanisms which are involved in the intrastriatal administration of QUIN-induced neurodegeneration and the neuroprotective effects of wedelolactone (WL) and gallic acid (GA) over QUIN-induced toxicity. The Wistar rats were used for the study and conducted behavioral model to evaluate the effects of WL (100 &amp; 200 mg/kg) and GA (100 &amp; 200 mg/kg) on impaired motor function and motor learning ability. We also assessed the effects of WL and GA on the antioxidant profile, cytotoxicity, apoptosis, excitotoxicity, inflammatory cascades, and on growth factors which helps in neurogenesis. The compounds effectively improved the motor function, motor learning memory in the rats. Similarly, enhanced the activity of Glutathione peroxidase, SOD, catalase, and declined the lipid peroxidation and nitrite production in the brain. The treatment with WL and GA lowered the activities of LDH, m-calpain, and caspase-3. The reports strongly support that both compounds are useful in the prevention of glutamate excitotoxicity induced by QUIN. The NAA, IGF-1, and VEGF levels in the brain were improved after treatment with WL and GA. The neuroprotective effects of WL and GA further proved through the anti-inflammatory effects. The compounds significantly down-regulated the expression of TNF-α, IL-6, and IL-β in the brain. Immunohistochemical analysis shows that the WL and GA reduced the expression of NF-κB. The histopathological studies for cerebellum, hippocampus, striatum, and spinal cord confirms the toxic effects of QUIN and neuroprotective effects of WL and GA. The results suggest that WL and GA could ameliorate the toxic events triggered by QUIN and might be effective in the prevention and progression of several cascades which lead to the development of sALS.}, }
@article {pmid29981250, year = {2019}, author = {Plowman, EK and Tabor-Gray, L and Rosado, KM and Vasilopoulos, T and Robison, R and Chapin, JL and Gaziano, J and Vu, T and Gooch, C}, title = {Impact of expiratory strength training in amyotrophic lateral sclerosis: Results of a randomized, sham-controlled trial.}, journal = {Muscle &amp; nerve}, volume = {59}, number = {1}, pages = {40-46}, doi = {10.1002/mus.26292}, pmid = {29981250}, issn = {1097-4598}, support = {R21 HD075327/HD/NICHD NIH HHS/United States ; 1R21 HDO75327//National Institutes of Child Health and Development/International ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*rehabilitation ; Deglutition/physiology ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Muscle Strength/*physiology ; Prospective Studies ; Resistance Training/*methods ; Respiratory Muscles/physiology ; Single-Blind Method ; Spirometry ; }, abstract = {INTRODUCTION: The purpose of this study was to determine the impact of an in-home expiratory muscle strength training (EMST) program on pulmonary, swallow, and cough function in individuals with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: EMST was tested in a prospective, single-center, double-blind, randomized, controlled trial of 48 ALS individuals who completed 8 weeks of either active EMST (n&#x2009;=&#x2009;24) or sham EMST (n&#x2009;=&#x2009;24). The primary outcome to assess treatment efficacy was change in maximum expiratory pressure (MEP). Secondary outcomes included: cough spirometry; swallowing; forced vital capacity; and scoring on the ALS Functional Rating Scale-Revised.<br><br>RESULTS: Treatment was well tolerated with 96% of patients completing the protocol. Significant differences in group change scores were noted for MEP and Dynamic Imaging Grade of Swallowing Toxicity scores (P&#x2009;<&#x2009;0.02). No differences were noted for other secondary measures.<br><br>DISCUSSION: This respiratory training program was well-tolerated and led to improvements in respiratory and bulbar function in ALS. Muscle Nerve 59:40-46, 2019.}, }
@article {pmid29973287, year = {2018}, author = {Mordes, DA and Prudencio, M and Goodman, LD and Klim, JR and Moccia, R and Limone, F and Pietilainen, O and Chowdhary, K and Dickson, DW and Rademakers, R and Bonini, NM and Petrucelli, L and Eggan, K}, title = {Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients.}, journal = {Acta neuropathologica communications}, volume = {6}, number = {1}, pages = {55}, pmid = {29973287}, issn = {2051-5960}, support = {R01 NS089742/NS/NINDS NIH HHS/United States ; R35 NS097273/NS/NINDS NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R21 NS084528/NS/NINDS NIH HHS/United States ; R01 ES020395/ES/NIEHS NIH HHS/United States ; R35 NS097275/NS/NINDS NIH HHS/United States ; R01 NS077402/NS/NINDS NIH HHS/United States ; R01 NS063964/NS/NINDS NIH HHS/United States ; P50 AG005134/AG/NIA NIH HHS/United States ; T32 CA009216/CA/NCI NIH HHS/United States ; R01 NS088689/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain/*metabolism/pathology ; C9orf72 Protein/*genetics ; Cohort Studies ; DNA Repeat Expansion/*genetics ; Dipeptides ; Disease Models, Animal ; Drosophila ; Eye/pathology ; Female ; Frontotemporal Lobar Degeneration/*genetics/pathology ; Gene Expression Regulation/*genetics ; Glial Fibrillary Acidic Protein/metabolism ; Heat Shock Transcription Factors/genetics/metabolism ; Heat-Shock Response/*physiology ; Humans ; Male ; Neurons/metabolism ; Signal Transduction/physiology ; Stem Cells/metabolism ; }, abstract = {A hexanucleotide (GGGGCC) repeat expansion in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Reduced expression of the C9ORF72 gene product has been proposed as a potential contributor to disease pathogenesis. Additionally, repetitive RNAs and dipeptide repeat proteins (DPRs), such as poly-GR, can be produced by this hexanucleotide expansion that disrupt a number of cellular processes, potentially contributing to neural degeneration. To better discern which of these mechanisms leads to disease-associated changes in patient brains, we analyzed gene expression data generated from the cortex and cerebellum. We found that transcripts encoding heat shock proteins (HSPs) regulated by the HSF1 transcription factor were significantly induced in C9ORF72-ALS/FTLD patients relative to both sporadic ALS/FTLD cases and controls. Treatment of human neurons with chemically synthesized DPRs was sufficient to activate a similar transcriptional response. Expression of GGGGCC repeats and also poly-GR in the brains of Drosophila lead to the upregulation of HSF1 and the same highly-conserved HSPs. Additionally, HSF1 was a modifier of poly-GR toxicity in Drosophila. Our results suggest that the expression of DPRs are associated with upregulation of HSF1 and activation of a heat shock response in C9ORF72-ALS/FTLD.}, }
@article {pmid29971035, year = {2018}, author = {Chen, X and Wei, QQ and Chen, Y and Cao, B and Ou, R and Hou, Y and Yuan, X and Zhang, L and Liu, H and Shang, H}, title = {Clinical Staging of Amyotrophic Lateral Sclerosis in Chinese Patients.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {442}, pmid = {29971035}, issn = {1664-2295}, abstract = {Objective: It is important to explore the utility of clinical staging systems in the management of amyotrophic lateral sclerosis (ALS). Our aim was to assess the validity of King's College in a Chinese ALS cohort, by evaluating the duration and informativeness of each stage and examining the association between stage and prognosis. Methods: From May 2008 to December 2016, patients with a likely diagnosis of ALS were registered. We prospectively assessed the progression of the patients through the stages and calculated the duration of each stage. Results: The median duration in Stage 1 was 12.00 months, Stage 2 7.50 months, Stage 3 6.50 months, and Stage 4 4.10 months. Subset analysis revealed that the spinal-onset and early-onset patients had a longer median time in Stage 1 compared to bulbar-onset and late-onset patients, respectively. Riluzole treatment extended the durations of Stages 1 and 2, and the effect was maintained in patients with long-term use of riluzole (>6 months). Patients who initiated long-term riluzole therapy early, in Stage 1 or 2, had a longer Stage 2. Patients who received percutaneous gastrostomy endoscopy (PEG) or non-invasive positive-pressure ventilation (NIPPV) showed longer durations of Stage 4. The differences in survival time measured from each stage to death or censor date were significant. Conclusions: We validated the King's College staging system in a Chinese population, and showed this system to be useful in clinical practice. Patients with bulbar-onset or an age of onset>45 years tended to have rapidly progressing ALS. Riluzole may be more effective when initiated in an early disease stage and continued long-term. PEG and NIPPV treatments can extend disease duration of Stage 4.}, }
@article {pmid29970123, year = {2018}, author = {Gustafsson, JR and Katsioudi, G and Degn, M and Ejlerskov, P and Issazadeh-Navikas, S and Kornum, BR}, title = {DNMT1 regulates expression of MHC class I in post-mitotic neurons.}, journal = {Molecular brain}, volume = {11}, number = {1}, pages = {36}, pmid = {29970123}, issn = {1756-6606}, support = {Fellowship//Lundbeckfonden/International ; CIG PCIG12-GA-2012-334443//FP7 People: Marie-Curie Actions/International ; }, mesh = {Animals ; Biomarkers/metabolism ; Cell Line, Tumor ; DNA (Cytosine-5-)-Methyltransferase 1/*metabolism ; *Gene Expression Regulation ; Gene Knockdown Techniques ; *Genes, MHC Class I ; Interferon-gamma/metabolism ; Mice ; Mitosis/*genetics ; Neurons/*cytology/*metabolism ; RNA, Small Interfering/metabolism ; Synapses/metabolism ; }, abstract = {Major Histocompability Complex I (MHC-I) molecules present cellularly derived peptides to the adaptive immune system. Generally MHC-I is not expressed on healthy post-mitotic neurons in the central nervous system, but it is known to increase upon immune activation such as viral infections and also during neurodegenerative processes. MHC-I expression is known to be regulated by the DNA methyltransferase DNMT1 in non-neuronal cells. Interestingly DNMT1 expression is high in neurons despite these being non-dividing. This suggests a role for DNMT1 in neurons beyond the classical re-methylation of DNA after cell division. We thus investigated whether DNMT1 regulates MHC-I in post-mitotic neurons. For this we used primary cultures of mouse cerebellar granule neurons (CGNs). Our results showed that knockdown of DNMT1 in CGNs caused upregulation of some, but not all subtypes of MHC-I genes. This effect was synergistically enhanced by subsequent IFNγ treatment. Overall MHC-I protein level was not affected by knockdown of DNMT1 in CGNs. Instead our results show that the relative MHC-I expression levels among the different MHC subtypes is regulated by DNMT1 activity. In conclusion, we show that while the mouse H2-D1/L alleles are suppressed in neurons by DNMT1 activity under normal circumstances, the H2-K1 allele is not. This finding is particularly important in two instances. One: in the context of CNS autoimmunity with epitope presentation by specific MHC-I subtypes where this allele specific regulation might become important; and two: in amyotropic lateral sclerosis (ALS) where H2-K but not H2-D protects motor neurons from ALS astrocyte-induced toxicity in a mouse model of ALS.}, }
@article {pmid29964212, year = {2018}, author = {Zorowitz, RD and Alexander, DN and Formella, AE and Ledon, F and Davis, C and Siffert, J}, title = {Dextromethorphan/Quinidine for Pseudobulbar Affect Following Stroke: Safety and Effectiveness in the PRISM II Trial.}, journal = {PM &amp; R : the journal of injury, function, and rehabilitation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.pmrj.2018.06.003}, pmid = {29964212}, issn = {1934-1563}, abstract = {BACKGROUND: Dextromethorphan (DM) / quinidine (Q) was approved for pseudobulbar affect (PBA) treatment based on efficacy and safety trials in patients with PBA caused by amyotrophic lateral sclerosis or multiple sclerosis. The PRISM II trial evaluated DM/Q as PBA treatment in patients with stroke, dementia, or traumatic brain injury.<br><br>OBJECTIVE: To report results from the stroke cohort of PRISM II, including the Stroke Impact Scale (SIS).<br><br>DESIGN: Open-label trial evaluating twice-daily DM/Q over 90 days.<br><br>STUDY PARTICIPANTS: Adults (n = 113) with a clinical diagnosis of PBA secondary to stroke; stable psychiatric medications were allowed.<br><br>METHODS: PRISM II was an open-label, 12-week trial enrolling adults with PBA caused by dementia, stroke (reported here), or TBI. All study participants received DM/Q 20/10 mg twice daily. Study visits occurred at baseline and at days 30 and&#xa0;90.<br><br>SETTING: 150 U.S. centers.<br><br>MAIN OUTCOME MEASUREMENTS: Primary efficacy measure was changed from baseline to day 90 in Center for Neurologic Study-Lability Scale (CNS-LS) scores. Secondary outcomes included PBA episodes (estimated over 7 days), Clinical and Patient/Caregiver Global Impression of Change (CGI-C and PGI-C), Quality of Life-Visual Analog Scale (QOL-VAS), SIS, Patient Health Questionnaire (PHQ-9), and Mini-Mental State Examination (MMSE).<br><br>RESULTS: Compared with baseline, CNS-LS scores (SD) improved by -6.2 (6.1, P&#xa0;<&#xa0;.001) at day 30 and -7.6 (6.7, P&#xa0;<&#xa0;.001) at day 90. PBA episodes were reduced by 65% and 75% at day 30 and 90, respectively. Seventy-five percent of clinicians and 67% of patients/caregivers rated PBA as "much" or "very much improved." All SIS items significantly improved from baseline (P < .05, all). Adverse events included diarrhea (4.4%), headache (3.5%), constipation (2.7%), and dizziness (2.7%); 5.3% had adverse events leading to study discontinuation.<br><br>CONCLUSIONS: DM/Q effectively treated PBA and was associated with global and functional improvement; adverse events were consistent with the known safety profile of DM/Q.}, }
@article {pmid29961357, year = {2018}, author = {Neal, EG and Liska, MG and Lippert, T and Lin, R and Gonzalez, M and Russo, E and Xu, K and Ji, X and Vale, FL and Van Loveren, H and Borlongan, CV}, title = {An update on intracerebral stem cell grafts.}, journal = {Expert review of neurotherapeutics}, volume = {18}, number = {7}, pages = {557-572}, doi = {10.1080/14737175.2018.1491309}, pmid = {29961357}, issn = {1744-8360}, support = {R01 NS071956/NS/NINDS NIH HHS/United States ; R01 NS090962/NS/NINDS NIH HHS/United States ; R21 NS089851/NS/NINDS NIH HHS/United States ; R21 NS094087/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Blood-Brain Barrier ; Central Nervous System Diseases/metabolism/*therapy ; Graft vs Host Reaction ; Humans ; Risk Factors ; Stem Cell Transplantation/adverse effects/*methods ; }, abstract = {Primary neurological disorders are notoriously debilitating and deadly, and over the past four decades stem cell therapy has emerged as a promising treatment. Translation of stem cell therapies from the bench to the clinic requires a better understanding of delivery protocols, safety profile, and efficacy in each disease. Areas covered: In this review, benefits and risks of intracerebral stem cell transplantation are presented for consideration. Milestone discoveries in stem cell applications are reviewed to examine the efficacy and safety of intracerebral stem cell transplant therapy for disorders of the central nervous system and inform design of translatable protocols for clinically feasible stem cell-based treatments. Expert commentary: Intracerebral administration, compared to peripheral delivery, is more invasive and carries the risk of open brain surgery. However, direct cell implantation bypasses the blood-brain barrier and reduces the first-pass effect, effectively increasing the therapeutic cell deposition at its intended site of action. These benefits must be weighed with the risk of graft-versus-host immune response. Rigorous clinical trials are underway to assess the safety and efficacy of intracerebral transplants, and if successful will lead to widely available stem cell therapies for neurologic diseases in the coming years.}, }
@article {pmid29960237, year = {2018}, author = {Calvo, NL and Balzaretti, NM and Antonio, M and Kaufman, TS and Maggio, RM}, title = {Chemometrics-assisted study of the interconversion between the crystalline forms of nimodipine.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {158}, number = {}, pages = {461-470}, doi = {10.1016/j.jpba.2018.06.019}, pmid = {29960237}, issn = {1873-264X}, mesh = {Calcium Channel Blockers/*chemistry ; Chemistry, Pharmaceutical ; Crystallization ; Drug Compounding/*standards ; Drug Storage ; Least-Squares Analysis ; Nimodipine/*chemistry ; Quality Control ; Solubility ; Spectroscopy, Fourier Transform Infrared/instrumentation/methods ; Transition Temperature ; Water ; }, abstract = {Nimodipine (NIM) is a calcium channel-blocking agent, which in the solid state exhibits two crystalline modifications, Mode I and Mode II. The first one is a racemic mixture, while the second is a conglomerate. Because the drug has poor aqueous solubility and Mode I is twice as soluble as Mode II, the former is widely preferred for the development of pharmaceutical forms. In order to study the effect of thermal stimuli on the behavior of NIM, an analytical method was developed coupling ATR-FTIR spectroscopy to Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS). The method allowed to monitor the transformations of each polymorph, their respective mixtures and commercial samples, during the thermal treatment. It was observed that Mode II experienced changes during the experiments and the chemometric technique provided the abundance profile and the pure spectra of the different species involved. In this way, it was established that Mode II has two transitions, at 116.8 °C and 131.9 °C, which reflect that Mode II is first transformed into Mode I, which then melts. The liquid phase solidifies to give an amorphous (AM) vitreous solid, which does not revert to the crystalline state. The analysis of a commercial sample of NIM exhibited the similar transformations than Mode II; however, a pronounced decrease was noted in the first transition temperature (95 °C), whereas the second remained essentially unchanged (131.6 °C). This could be a result of the presence of mixtures of Mode I and Mode II (0.32:0.68) in the bulk solid, as confirmed by the analysis of a physical mixture of crystals of Modes I and II. Therefore, it was concluded that the developed ATR-FTIR/MCR-ALS method is suitable for the detailed analysis of the crystalline forms of NIM in bulk drug and enables de study of their possible thermally promoted interconversions.}, }
@article {pmid29940336, year = {2018}, author = {Wong, SQ and Pontifex, MG and Phelan, MM and Pidathala, C and Kraemer, BC and Barclay, JW and Berry, NG and O'Neill, PM and Burgoyne, RD and Morgan, A}, title = {α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a C. elegans model of TDP-43 proteinopathy.}, journal = {Neurobiology of disease}, volume = {118}, number = {}, pages = {40-54}, pmid = {29940336}, issn = {1095-953X}, support = {MR/M009114/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Animals, Genetically Modified ; Anticonvulsants/chemistry/therapeutic use ; Caenorhabditis elegans ; Caenorhabditis elegans Proteins/*genetics ; *Disease Models, Animal ; Female ; Male ; Neurodegenerative Diseases/drug therapy/genetics/pathology ; Succinimides/chemistry/*therapeutic use ; TDP-43 Proteinopathies/*drug therapy/*genetics/pathology ; }, abstract = {The antiepileptic drug ethosuximide has recently been shown to be neuroprotective in various Caenorhabditis elegans and rodent neurodegeneration models. It is therefore a promising repurposing candidate for the treatment of multiple neurodegenerative diseases. However, high concentrations of the drug are required for its protective effects in animal models, which may impact on its translational potential and impede the identification of its molecular mechanism of action. Therefore, we set out to develop more potent neuroprotective lead compounds based on ethosuximide as a starting scaffold. Chemoinformatic approaches were used to identify compounds with structural similarity to ethosuximide and to prioritise these based on good predicated blood-brain barrier permeability and C. elegans bioaccumulation properties. Selected compounds were initially screened for anti-convulsant activity in a C. elegans pentylenetetrazol-induced seizure assay, as a rapid primary readout of bioactivity; and then assessed for neuroprotective properties in a C. elegans TDP-43 proteinopathy model based on pan-neuronal expression of human A315T mutant TDP-43. The most potent compound screened, α-methyl-α-phenylsuccinimide (MPS), ameliorated the locomotion defects and extended the shortened lifespan of TDP-43 mutant worms. MPS also directly protected against neurodegeneration by reducing the number of neuronal breaks and cell body losses in GFP-labelled GABAergic motor neurons. Importantly, optimal neuroprotection was exhibited by external application of 50 μM MPS, compared to 8 mM for ethosuximide. This greater potency of MPS was not due to bioaccumulation to higher internal levels within the worm, based on [1]H-nuclear magnetic resonance analysis. Like ethosuximide, the activity of MPS was abolished by mutation of the evolutionarily conserved FOXO transcription factor, daf-16, suggesting that both compounds act via the same neuroprotective pathway(s). In conclusion, we have revealed a novel neuroprotective activity of MPS that is >100-fold more potent than ethosuximide. This increased potency will facilitate future biochemical studies to identify the direct molecular target(s) of both compounds, as we have shown here that they share a common downstream DAF-16-dependent mechanism of action. Furthermore, MPS is the active metabolite of another approved antiepileptic drug, methsuximide. Therefore, methsuximide may have repurposing potential for treatment of TDP-43 proteinopathies and possibly other human neurodegenerative diseases.}, }
@article {pmid29939872, year = {2018}, author = {Wang, JS and Bojovic, D and Chen, Y and Lindgren, CA}, title = {Homocysteine sensitizes the mouse neuromuscular junction to oxidative stress by nitric oxide.}, journal = {Neuroreport}, volume = {29}, number = {12}, pages = {1030-1035}, pmid = {29939872}, issn = {1473-558X}, support = {R15 NS072735/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Excitatory Postsynaptic Potentials/drug effects/physiology ; Homocysteine/*pharmacology ; Mice ; Mice, Inbred C57BL ; Neuromuscular Junction/drug effects/*metabolism ; Nitric Oxide/agonists/antagonists &amp; inhibitors/*metabolism ; Nitric Oxide Donors/pharmacology ; Organ Culture Techniques ; Oxidative Stress/drug effects/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Homocysteine (HCY), a redox-active metabolite of the methionine cycle, is of particular clinical interest because of its association with various neurodegenerative diseases including amyotrophic lateral sclerosis. It has been previously established that HCY exacerbates damage to motor neurons from reactive oxygen species (ROS) such as hydrogen peroxide. To assess the role of HCY at the mammalian neuromuscular junction, neurotransmission was monitored by electrophysiology at the mouse epitrochleoanconeus muscle. Preparations were preincubated in HCY before inducing ROS and recordings were taken before and after ROS treatment. In this study, HCY was observed to sensitize the neuromuscular junction to ROS-induced depression of spontaneous transmission frequency, an effect we found to be mediated by a N-methyl-D-aspartate receptor (NMDAR) and nitric oxide (NO). The NMDAR antagonist D, L-2-amino-5-phosphonopentanoic acid prevented the HCY-induced sensitization to oxidative stress. Disrupting NO activity with either the nitric oxide synthase I antagonist Nω-nitro-L-arginine methyl ester hydrochloride or the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide potassium salt also prevented sensitization. Moreover, replacing HCY with the exogenous NO donor Diethylamine NONOate diethylammonium was sufficient to reconstitute the effects of HCY-induced sensitization to ROS. Interestingly, a novel secondary effect was observed where HCY itself depresses quantal content, an effect found to be mediated by NMDARs independently of nitric oxide and ROS. Collectively, these data present a novel model of two distinct pathways through which HCY alters neurotransmission at the neuromuscular junction. Characterizing HCY's mechanism of action is of particular clinical relevance as many treatments for amyotrophic lateral sclerosis are centered on mitigating HCY-induced pathologies.}, }
@article {pmid29934198, year = {2018}, author = {Ludolph, AC and Schuster, J and Dorst, J and Dupuis, L and Dreyhaupt, J and Weishaupt, JH and Kassubek, J and Weiland, U and Petri, S and Meyer, T and Grosskreutz, J and Schrank, B and Boentert, M and Emmer, A and Hermann, A and Zeller, D and Prudlo, J and Winkler, AS and Grehl, T and Heneka, MT and Wollebæk Johannesen, S and Göricke, B and , }, title = {Safety and efficacy of rasagiline as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomised, double-blind, parallel-group, placebo-controlled, phase 2 trial.}, journal = {The Lancet. Neurology}, volume = {17}, number = {8}, pages = {681-688}, doi = {10.1016/S1474-4422(18)30176-5}, pmid = {29934198}, issn = {1474-4465}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Body Mass Index ; Disease Progression ; Double-Blind Method ; Female ; Humans ; Indans/*therapeutic use ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Retrospective Studies ; Riluzole/*therapeutic use ; Treatment Outcome ; Vital Capacity/drug effects ; }, abstract = {BACKGROUND: Rasagiline, a monoamine oxidase B inhibitor with neuroprotective potential in Parkinson's disease, has shown a disease-modifying effect in the SOD1-Gly93Ala low-expressing mouse model of amyotrophic lateral sclerosis, both alone and in combination with riluzole. We sought to test whether or not rasagiline 1 mg/day can prolong survival in patients with amyotrophic lateral sclerosis also receiving riluzole.<br><br>METHODS: Patients with possible, probable, or definite amyotrophic lateral sclerosis were enrolled to our randomised, placebo-controlled, parallel-group, double-blind, phase 2 trial from 15 German network for motor neuron diseases (MND-NET) centres (university hospitals or clinics). Eligible patients were aged at least 18 years, had onset of progressive weakness within the 36 months before the study, had disease duration of more than 6 months and less than 3 years, and had a best-sitting slow vital capacity of at least 50%. After a 4-week screening period, eligible patients were randomly assigned (1:1) to receive either rasagiline (1 mg/day) or placebo in addition to riluzole (100 mg/day), after stratification for site of onset (bulbar or spinal) and study centre. Patients and all personnel assessing outcome parameters were masked to treatment allocation. Patients were followed up 2, 6, 12, and 18 months after randomisation. The primary endpoint was survival time, defined as the time to death or time to study cutoff date (ie, the last patient's last visit plus 14 days). Analyses of primary outcome and safety measures were done in all patients who received at least one dose of trial treatment (intention-to-treat population). The trial is registered with ClinicalTrials.gov, number NCT01879241.<br><br>FINDINGS: Between July 2, 2013, and Nov 11, 2014, 273 patients were screened for eligibility, and 252 patients were randomly assigned to receive rasagiline (n=127) or placebo (n=125). 126 patients taking rasagiline and 125 taking placebo were included in the intention-to-treat analysis. For the primary outcome, the survival probability at the end of the study was 0&#xb7;43 (95% CI 0&#xb7;25-0&#xb7;59) in the rasagiline group (n=126) and 0&#xb7;53 (0&#xb7;43-0&#xb7;62) in the placebo group (n=125). The estimated effect size (hazard ratio) was 0&#xb7;91 (one-sided 97&#xb7;5% CI -infinity to 1&#xb7;34; p=0&#xb7;31). Rasagiline was well tolerated, and most adverse events were due to amyotrophic lateral sclerosis disease progression rather than treatment; the most frequent of these were dysphagia (32 [25%] taking rasagiline vs 24 [19%] taking placebo) and respiratory failure (25 [20%] vs 31 [25%]). Frequency of adverse events were comparable between both groups.<br><br>INTERPRETATION: Rasagiline was safe in patients with amyotrophic lateral sclerosis. There was no difference between groups in the primary outcome of survival, although post-hoc analysis suggested that rasagiline might modify disease progression in patients with an initial slope of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised greater than 0&#xb7;5 points per month at baseline. This should be confirmed in another clinical trial.<br><br>FUNDING: Teva Pharmaceutical Industries.}, }
@article {pmid29933890, year = {2018}, author = {Kjældgaard, AL and Pilely, K and Olsen, KS and Pedersen, SW and Lauritsen, A&#xd8; and Møller, K and Garred, P}, title = {Amyotrophic lateral sclerosis: The complement and inflammatory hypothesis.}, journal = {Molecular immunology}, volume = {102}, number = {}, pages = {14-25}, doi = {10.1016/j.molimm.2018.06.007}, pmid = {29933890}, issn = {1872-9142}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/*physiopathology ; Animals ; Complement System Proteins/*physiology ; Humans ; Immunity, Innate/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating, neurodegenerative motor neuron disease. The aetiology of ALS remains an enigma which hinders the design of an effective treatment to prevent, postpone, or reverse the pathophysiological changes occurring during the aggressive progression of this disease. During the last decade, basic research within the innate immune system, and in particular the complement system, has revealed new, important roles of the innate immune system during development, homeostasis, and ageing within as well as outside the central nervous system. Several lines of evidence indicate that aberrant activation of the complement system locally in the central nervous system as well as systemically may be involved in the pathophysiology of ALS. This exciting new knowledge could point towards the innate immune system as a potential target of medical intervention in ALS. Recently, the historic perception of ALS as a central neurodegenerative disease has been challenged due to the significant amount of evidence of a dying-back mechanism causing the selective destruction of the motor neurons, indicating that disease onset occurs outside the borders of the blood-brain-barrier. This review addresses the function of the innate immune system during ALS. We emphasize the role of the complement system and specifically suggest the involvement of ficolin-3 from the lectin pathway in the pathophysiology of ALS.}, }
@article {pmid29932880, year = {2018}, author = {Shijo, T and Warita, H and Suzuki, N and Ikeda, K and Mitsuzawa, S and Akiyama, T and Ono, H and Nishiyama, A and Izumi, R and Kitajima, Y and Aoki, M}, title = {Antagonizing bone morphogenetic protein 4 attenuates disease progression in a rat model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {307}, number = {}, pages = {164-179}, doi = {10.1016/j.expneurol.2018.06.009}, pmid = {29932880}, issn = {1090-2430}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/drug therapy/genetics/*metabolism ; Animals ; Bone Morphogenetic Protein 4/*antagonists &amp; inhibitors/*biosynthesis ; *Disease Models, Animal ; *Disease Progression ; Female ; Humans ; Injections, Spinal ; Male ; Middle Aged ; Oligonucleotides, Antisense/administration &amp; dosage ; Rats ; Rats, Transgenic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative syndrome characterized by the systemic loss of motor neurons with prominent astrocytosis and microgliosis in the spinal cord and brain. Astrocytes play an essential role in maintaining extracellular microenvironments that surround motor neurons, and are activated by various insults. Growing evidence points to a non-cell autonomous neurotoxicity caused by chronic and sustained astrocytic activation in patients with neurodegenerative diseases, including ALS. However, the mechanisms that underlie the harmful effects of astrocytosis in patients with ALS remain unresolved. We focused on bone morphogenetic proteins as a major soluble factor that promotes astrocytogenesis and its activation in the adult spinal cord. In a transgenic rat model with ALS-linked mutant Cu/Zn superoxide dismutase gene, BMP4 was progressively up-regulated in reactive astrocytes of the spinal ventral horns, whereas the BMP-antagonist noggin was decreased in association with neuronal degeneration. Continuous intrathecal noggin supplementation after disease onset significantly ameliorated motor dysfunction symptoms, neurogenic muscle atrophy, and extended survival of symptomatic ALS model rats, despite lack of deterrence against neuronal death itself. The exogenous noggin inhibited astrocytic hypertrophy, astrocytogenesis, and neuroinflammation by inactivating both Smad1/5/8 and p38 mitogen-activated protein kinase pathways. Moreover, intrathecal infusion of a Bmp4-targeted antisense oligonucleotides and provided selective Bmp4 knockdown in vivo, which suppressed astrocyte and microglia activation, reproducing the aforementioned results by noggin treatment. Collectively, we clarified the involvement of BMP4 in the processes of excessive gliosis that exacerbate the disease progression of the ALS model rats. Our study demonstrated that BMP4, with its downstream signaling, might be a novel therapeutic target for disease-modifying therapies in ALS.}, }
@article {pmid29931492, year = {2018}, author = {Teke, K and Yilmaz, H and Uslubas, AK and Akpinar, G and Kasap, M and Mutlu, O and Yildiz, DK and Guzel, N and Dillioglugil, O}, title = {Histopathologic and molecular comparative analyses of intravesical Aurora kinase-A inhibitor Alisertib with bacillus Calmette-Guérin on precancerous lesions of bladder in a rat model.}, journal = {International urology and nephrology}, volume = {50}, number = {8}, pages = {1417-1425}, pmid = {29931492}, issn = {1573-2584}, support = {Grant number 2015/035//Kocaeli &#xdc;niversitesi/ ; }, mesh = {Adjuvants, Immunologic/*administration &amp; dosage ; Administration, Intravesical ; Animals ; Aurora Kinase A/*antagonists &amp; inhibitors ; Azepines/*administration &amp; dosage ; BCG Vaccine/*administration &amp; dosage ; Disease Models, Animal ; Female ; Precancerous Conditions/*drug therapy/*pathology ; Pyrimidines/*administration &amp; dosage ; Rats ; Rats, Wistar ; Urinary Bladder Neoplasms/*pathology/*prevention &amp; control ; }, abstract = {PURPOSE: Recent studies have shown that Aurora-A expression is associated with bladder cancer initiation and progression. In this study, the effects of intravesical Aurora-A inhibitor Alisertib (ALS) and bacillus Calmette-Guérin (BCG) were compared on bladder carcinogenesis.<br><br>METHODS: Two mg N-Methyl-N-nitrosourea was administered intravesically to forty of Wistar-albino rats every other week for 8&#xa0;weeks. At week 10, rats were divided into four groups (10/group): No-treatment (vehicle), ALS-alone, BCG-alone, and ALS&#x2009;+&#x2009;BCG. The intravesical treatment of ALS, BCG, and ALS plus BCG was performed once a week for 6&#xa0;weeks. At week 16, bladders were collected for immunohistopathological and Western blot analysis. The cell cycle regulators p53, p21, Aurora-A, phosphorylated Aurora-A (p-Aurora-A), and apoptotic marker cleavage of poly [ADP-ribose] polymerase (c-PARP) were determined by Western blot.<br><br>RESULTS: Histopathologically relatively healthy urothelium was observed in ALS&#x2009;+&#x2009;BCG group (87.5%) compared to the ALS-alone (50%) and the BCG-alone (50%) groups. The lowest expression of p21 and p53 was detected in the BCG-alone, while the highest level of expression was evident in no-treatment group. The ALS treatment alone caused a slight decrease in Aurora-A while there was a dramatic decrease in p-Aurora-A in comparison to no-treatment group. In overall combined treatment with ALS&#x2009;+&#x2009;BCG significantly increased c-PARP compared to all mono-treatments, and decreased all cell cycle parameters compared to no-treatment group.<br><br>CONCLUSIONS: Although intravesical ALS treatment has similar antiproliferative effects like BCG, ALS&#x2009;+&#x2009;BCG combined treatment led to a best histopathologic and apoptotic response. Consequently, BCG combined with Aurora-A inhibition may provide a new intravesical treatment modality in the&#xa0;prevention of bladder carcinogenesis.}, }
@article {pmid29928711, year = {2018}, author = {Okada, M and Yamashita, S and Ueyama, H and Ishizaki, M and Maeda, Y and Ando, Y}, title = {Long-term effects of edaravone on survival of patients with amyotrophic lateral sclerosis.}, journal = {eNeurologicalSci}, volume = {11}, number = {}, pages = {11-14}, pmid = {29928711}, issn = {2405-6502}, abstract = {BACKGROUND AND PURPOSE: Oxidative stress has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Edaravone, a free radical scavenger, was approved as a therapeutic drug for ALS in 2015 in Japan. A phase 3 clinical trial demonstrated a smaller decline in ALS functional scale scores compared with placebo. However, the long-term effects of edaravone on ALS patients remain unclear. This study aimed to retrospectively investigate the long-term effects of edaravone on the survival of ALS patients.<br><br>METHODS: We retrospectively analyzed 27 consecutive patients with ALS who were treated with edaravone and 30 consecutive ALS patients who were not treated with edaravone between 2010 and 2016.<br><br>RESULTS: The differences of ALSFRS-R scores from baseline to 6&#x202f;months was significantly reduced in the edaravone group, compared to the control group. The changes in serum creatinine, as a possible marker of ALS severity, from baseline to 6 and 12&#x202f;months were significantly improved in the edaravone group, compared to the control group. The survival rate was significantly improved in the edaravone group compared with control patients.<br><br>CONCLUSION: Our retrospective single-center analysis suggests slower progression and better prognosis of ALS patients with edaravone treatment. Further investigation, including prospective multicenter analysis, is warranted to confirm the usefulness of edaravone for a better prognosis of ALS.}, }
@article {pmid29927386, year = {2018}, author = {Kakuda, TN and Yogaratnam, J and Rito, J and Boyce, M and Mitchell, T and Gupta, K and Symons, JA and Chanda, S and Van Remoortere, P and Fry, J}, title = {Phase I study on safety and pharmacokinetics of a novel influenza endonuclease inhibitor, AL-794 (JNJ-64155806), following single- and multiple-ascending doses in healthy adults.}, journal = {Antiviral therapy}, volume = {23}, number = {7}, pages = {555-566}, doi = {10.3851/IMP3244}, pmid = {29927386}, issn = {2040-2058}, mesh = {Administration, Oral ; Adult ; Antiviral Agents/adverse effects/blood/*pharmacokinetics ; Area Under Curve ; Dizziness/diagnosis/etiology ; Double-Blind Method ; Drug Administration Schedule ; Endonucleases/antagonists &amp; inhibitors ; Enzyme Inhibitors/adverse effects/blood/*pharmacokinetics ; Fasting ; Headache/diagnosis/etiology ; Healthy Volunteers ; Humans ; Influenza, Human/prevention &amp; control ; Male ; Patient Safety ; Serine Endopeptidases/adverse effects/blood/*pharmacokinetics ; Viral Proteins/antagonists &amp; inhibitors ; }, abstract = {BACKGROUND: This double-blind, first-in-human Phase I study evaluated pharmacokinetics, safety and tolerability of AL-794 (prodrug of ALS-033719), a potent endonuclease inhibitor of influenza A and B in healthy volunteers.<br><br>METHODS: Healthy adult volunteers were randomized to AL-794 (50-2,000 mg single ascending doses, fasting) or placebo (5 cohorts, n=6:2 AL-794: placebo/cohort) in part 1, and AL-794 (50-600 mg multiple ascending doses, twice-daily, fed or fasted) or placebo (3 cohorts, n=8:2 AL-794: placebo/cohort) for 7 days in part 2. In part 3, 8 healthy volunteers from part 1 received 450 mg AL-794 (n=6) or placebo (n=2) following a high-fat meal. All dosing was done with an oral suspension. Blood and urine samples for pharmacokinetics were collected at scheduled times and analysed for ALS-033719 and ALS-033927 (inactive glucuronide) plasma concentrations using LC-MS/MS.<br><br>RESULTS: ALS-033719 plasma concentrations increased dose proportionately up to 150 mg but less than proportionately above 150 mg. Steady-state was generally achieved by the third dose. ALS-033719 exposure increased following administration with a standard meal (19%-33%) or high-fat meal (3-3.6-fold). ALS-033927 was the major metabolite observed. Renal elimination was negligible (0.2%). Seventeen AL-794-treated healthy volunteers reported &#x2265;1 treatment-emergent adverse event (TEAE; part 1: n=6, 24%; part 2: n=11, 69%). The most common TEAEs were headache (part 1: n=3; part 2: n=5) and dizziness (part 1: n=2; part 2: n=6).<br><br>CONCLUSIONS: AL-794 up to 200 mg twice daily achieved ALS-033719 exposures which are expected to be efficacious and were generally tolerated. Further studies are planned to characterize safety and antiviral activity.}, }
@article {pmid29921193, year = {2018}, author = {Niazi, ZR and Khan, N and Khan, S and Alam, M and Kamal, MA}, title = {Potential Application of Venom Proteins in Designing of Medicines for Treating Human Neurodegenerative Disorders.}, journal = {Protein and peptide letters}, volume = {25}, number = {7}, pages = {633-642}, doi = {10.2174/0929866525666180614120407}, pmid = {29921193}, issn = {1875-5305}, mesh = {Animals ; *Bee Venoms/genetics/therapeutic use ; *Drug Design ; Humans ; Mice ; Neurodegenerative Diseases/*drug therapy ; Rats ; *Wasp Venoms/genetics/therapeutic use ; }, abstract = {BACKGROUND: Neurodegenerative disorder are persistently increasing and relentlessly affecting the individuals, families and society as whole. Regrettably these disorders are resistant to the available drugs, the outcomes are only palliative while the side effects of the therapy harm the patient compliance as well as treatment. Drugs from venomous source have been considered as an effective alternative for such types of disorders, particularly neurodegenerative diseases. Due to emerging advancement in the field of proteomics, genomics and molecular biology, characterization and screening of these novel compounds become more assessable.<br><br>CONCLUSION: In this reverence, the present study reviews the current consideration of the mode of action and the future prediction concerning the use of novel compounds isolated from arthropods and other venomous animals in the treatment of major neurodegenerative diseases such as Parkinson disease, Alzheimer disease, Multiple Sclerosis, Epilepsy and Amyotrophic Lateral Sclerosis.}, }
@article {pmid29916014, year = {2018}, author = {Ebbert, MTW and Lank, RJ and Belzil, VV}, title = {An Epigenetic Spin to ALS and FTD.}, journal = {Advances in neurobiology}, volume = {20}, number = {}, pages = {1-29}, doi = {10.1007/978-3-319-89689-2_1}, pmid = {29916014}, issn = {2190-5215}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; DNA Methylation ; *Epigenesis, Genetic ; Frontotemporal Dementia/*genetics ; Humans ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating and lethal neurodegenerative diseases seen comorbidly in up to 15% of patients. Despite several decades of research, no effective treatment or disease-modifying strategies have been developed. We now understand more than before about the genetics and biology behind ALS and FTD, but the genetic etiology for the majority of patients is still unknown and the phenotypic variability observed across patients, even those carrying the same mutation, is enigmatic. Additionally, susceptibility factors leading to neuronal vulnerability in specific central nervous system regions involved in disease are yet to be identified. As the inherited but dynamic epigenome acts as a cell-specific interface between the inherited fixed genome and both cell-intrinsic mechanisms and environmental input, adaptive epigenetic changes might contribute to the ALS/FTD aspects we still struggle to comprehend. This chapter summarizes our current understanding of basic epigenetic mechanisms, how they relate to ALS and FTD, and their potential as therapeutic targets. A clear understanding of the biological mechanisms driving these two currently incurable diseases is urgent-well-needed therapeutic strategies need to be developed soon. Disease-specific epigenetic changes have already been observed in patients and these might be central to this endeavor.}, }
@article {pmid29915483, year = {2018}, author = {An, V and Chandra, R and Lawrence, M}, title = {Anastomotic Failure in Colorectal Surgery: Where Are We at?.}, journal = {The Indian journal of surgery}, volume = {80}, number = {2}, pages = {163-170}, pmid = {29915483}, issn = {0972-2068}, abstract = {Anastomotic leak (AL) can be a devastating complication in colorectal surgery. While it is less frequent in the modern era, it still results in significant morbidity and mortality, prolonged hospital stays and increases the costs and demands on health services. There is inevitable interplay between patient physiology and technical factors that predispose a patient to AL. Obesity, preoperative total proteins, male gender, ongoing anticoagulant treatment, intraoperative complication and number of hospital beds have been identified as independent risk factors. This has led to an online risk calculator for AL. Non-steroidal anti-inflammatory drugs and neoadjuvant chemoradiotherapy have also been implicated, but no significant evidence has yet been found to support causation. In addition, technical factors such as type of anastomosis, mechanical bowel preparation, drains, omentoplasty and faecal diversion have failed to show significant differences in AL rates. Early diagnosis and intervention in AL is essential in reducing the rates of morbidity and mortality. Clinical assessment has high sensitivity but low specificity and should be used in combination with imaging techniques to get a diagnosis. C-reactive protein is also a useful marker. The management will depend on the grade of AL and the clinical state of the patient. Management options include conservative measures such as antibiotics and/or percutaneous drainage to more invasion procedures such as open drainage and/or Hartmann's procedure. In conclusion, ALs will forever pose challenges to the surgeon in diagnosis and management. It is often the yardstick by which each surgeon is measured and is the source of significant morbidity to patients and health care services worldwide. As a result, a low threshold for investigation and intervention is mandatory to ensure better outcomes and lower overall mortality and morbidity.}, }
@article {pmid29909652, year = {2018}, author = {Hare, N and Georgopoulos, P and Philips, KE and Johnson, JE and Seary, C and Panicker, JN and Stevenson, VL}, title = {Improvement in overactive bladder symptoms in patients using functional electrical stimulation of the common peroneal nerve for walking.}, journal = {Clinical rehabilitation}, volume = {32}, number = {10}, pages = {1357-1362}, doi = {10.1177/0269215518780974}, pmid = {29909652}, issn = {1477-0873}, mesh = {Accidental Falls/prevention &amp; control ; Adult ; Aged ; Electric Stimulation Therapy/methods ; Female ; Humans ; Male ; Middle Aged ; Multiple Sclerosis/physiopathology/rehabilitation ; Peroneal Nerve/*physiopathology ; Surveys and Questionnaires ; Tibial Nerve ; Urinary Bladder, Overactive/physiopathology/*rehabilitation ; Walking Speed/*physiology ; }, abstract = {OBJECTIVE: Functional electrical stimulation is used to improve walking speed and reduces falls in people with upper motor neurone foot-drop. Following anecdotal observations of changes in bladder symptoms, an observational study was performed to explore this association further.<br><br>DESIGN: A total of 47 consecutive patients attending for setup with functional electrical stimulation during a six-month period were asked to complete a questionnaire assessing bladder symptoms (ICIQ-OAB (International Consultation on Incontinence Questionnaire Overactive Bladder)) at baseline and three&#x2009; months during routine appointments.<br><br>SUBJECTS: In all, 35 (75%) had multiple sclerosis and the other 12 subjects had a total of 9 diagnoses including 3 with stroke. Other conditions included cerebral palsy, motor neurone disease, hereditary spastic paraparesis, meningioma and spinocerebellar ataxias.<br><br>RESULTS: Improvement in overactive bladder symptoms was not significant in the whole cohort, however, was significant in patients with multiple sclerosis (n&#x2009; =&#x2009; 35; mean change in ICIQ-OAB score 1.0, P&#x2009; =&#x2009; 0.043). Specifically, significant improvements were seen in urgency and urge incontinence in multiple sclerosis patients. There was a significant negative correlation of moderate strength within the multiple sclerosis cohort between baseline walking speed and subsequent change in ICIQ-OAB score (correlation coefficient of r&#x2009; =&#x2009; -0.40, P&#x2009; =&#x2009; 0.046). Thus, greater changes in bladder symptoms were seen with lower baseline walking speeds.<br><br>CONCLUSION: The results of this exploratory study suggest that functional electrical stimulation use does improve overactive bladder symptoms in people with multiple sclerosis. Further exploration is needed to study this association and explore whether the mechanism is similar to that of percutaneous tibial nerve stimulation, a recognized treatment for the overactive bladder.}, }
@article {pmid29906423, year = {2018}, author = {Hilton, JB and Kysenius, K and White, AR and Crouch, PJ}, title = {The accumulation of enzymatically inactive cuproenzymes is a CNS-specific phenomenon of the SOD1[G37R] mouse model of ALS and can be restored by overexpressing the human copper transporter hCTR1.}, journal = {Experimental neurology}, volume = {307}, number = {}, pages = {118-128}, doi = {10.1016/j.expneurol.2018.06.006}, pmid = {29906423}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Cation Transport Proteins/*biosynthesis/genetics ; Central Nervous System/metabolism/pathology ; Copper Transporter 1 ; *Disease Models, Animal ; Gene Expression ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/*biosynthesis/genetics ; }, abstract = {Mutations to the copper-dependent enzyme Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) in humans, and transgenic overexpression of mutant SOD1 represents a robust murine model of the disease. We have previously shown that the copper-containing compound Cu[II](atsm) phenotypically improves mutant SOD1 mice and delivers copper to copper-deficient SOD1 in the CNS to restore its physiological function. Cu[II](atsm) is now in clinical trials for the treatment of ALS. In this study, we demonstrate that cuproenzyme dysfunction extends beyond SOD1 in SOD1[G37R] mice to also affect the endogenous copper-dependent ferroxidase ceruloplasmin. We show that SOD1 and ceruloplasmin both accumulate progressively in the SOD1[G37R] mouse spinal cord as the animals' ALS-like symptoms progress, yet the biochemical activity of the two cuproenzymes does not increase commensurately, indicating that, as per mutant SOD1, ceruloplasmin accumulates in a copper-deficient form. Consistent with this finding, we show that expression of the human copper transporter 1 (hCTR1) in SOD1[G37R] mice increases copper levels in the spinal cord and concurrently restores SOD1 and ceruloplasmin activity. Soluble misfolded SOD1, a proposed driver of pathology in this model, is readily detectable in the SOD1[G37R] mouse spinal cord. However, misfolded SOD1[G37R] levels do not change in abundance with disease progression and are less abundant than misfolded SOD1 in the spinal cords of age-matched transgenic SOD1[WT] mice which do not exhibit an evident ALS-like phenotype. Collectively, these outcomes support a copper malfunction phenomenon in mutant SOD1 mouse models of ALS and a copper-related mechanism of action for the therapeutic agent Cu[II](atsm).}, }
@article {pmid29904049, year = {2019}, author = {Portaro, S and Cimino, V and Accorinti, M and Pidalà, A and Naro, A and Calabrò, RS}, title = {A promising tool for flail arm in amyotrophic lateral sclerosis rehabilitation: a case report.}, journal = {European journal of physical and rehabilitation medicine}, volume = {55}, number = {4}, pages = {515-518}, doi = {10.23736/S1973-9087.18.05249-8}, pmid = {29904049}, issn = {1973-9095}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*rehabilitation ; Female ; Humans ; Muscle Weakness/etiology/*rehabilitation ; *Neurological Rehabilitation ; *Physical Therapy Modalities ; *Upper Extremity ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis flail arm (ALS-FA) is a motor neuron disease form confined to the upper limbs (cervical spinal cord region), often with asymmetric onset. To date, there is no defined neurorehabilitation strategy for ALS patients, although aerobic exercises may be of some help.<br><br>CASE REPORT: A 69-year-old woman affected by ALS-FA was admitted to our research institute because of upper limb muscle weakness. She was then submitted to two different conventional physiotherapy programs, the first stand-alone and the second combined to a robotic treatment. The patient gained an important motor improvement only after a 2-month treatment of physiotherapy plus Armeo-Power (AP), a robotic rehabilitation exoskeleton for upper limbs training, providing intelligent arm support in a 3D workspace.<br><br>Even though this is a single case, our combined neurorehabilitation approach (i.e. conventional physiotherapy plus robotics) could be considered a promising tool in improving upper limb function in patients affected by motoneurons disease, including ALS. Further studies involving a larger cohort of ALS-FA patients and long-term follow-up are needed, in order to evaluate the efficacy of robotics in prolonging patient's independence in active daily living.}, }
@article {pmid29901635, year = {2018}, author = {Mandrioli, J and D'Amico, R and Zucchi, E and Gessani, A and Fini, N and Fasano, A and Caponnetto, C and Chiò, A and Dalla Bella, E and Lunetta, C and Mazzini, L and Marinou, K and Sorarù, G and de Biasi, S and Lo Tartaro, D and Pinti, M and Cossarizza, A and , }, title = {Rapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial).}, journal = {Medicine}, volume = {97}, number = {24}, pages = {e11119}, pmid = {29901635}, issn = {1536-5964}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Biomarkers ; Double-Blind Method ; Humans ; Immunosuppressive Agents/adverse effects/*therapeutic use ; Italy ; Quality of Life ; Research Design ; Sirolimus/adverse effects/*therapeutic use ; Survival Rate ; TOR Serine-Threonine Kinases/drug effects/metabolism ; Treatment Outcome ; }, abstract = {INTRODUCTION: Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions. Rapamycin also expands regulatory T lymphocytes (Treg) and increased Treg levels are associated with slow progression in ALS patients.Therefore, we planned a randomized clinical trial testing Rapamycin treatment in ALS patients.<br><br>METHODS: RAP-ALS is a phase II randomized, double-blind, placebo-controlled, multicenter (8 ALS centers in Italy), clinical trial. The primary aim is to assess whether Rapamycin administration increases Tregs number in treated patients compared with control arm. Secondary aims include the assessment of safety and tolerability of Rapamycin in patients with ALS; the minimum dosage to have Rapamycin in cerebrospinal fluid; changes in immunological (activation and homing of T, B, NK cell subpopulations) and inflammatory markers, and on mTOR downstream pathway (S6RP phosphorylation); clinical activity (ALS Functional Rating Scale-Revised, survival, forced vital capacity); and quality of life (ALSAQ40 scale).<br><br>DISCUSSION: Rapamycin potentially targets mechanisms at play in ALS (i.e., autophagy and neuroinflammation), with promising preclinical studies. It is an already approved drug, with known pharmacokinetics, already available and therefore with significant possibility of rapid translation to daily clinics. Findings will provide reliable data for further potential trials.<br><br>ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Azienda Ospedaliero Universitaria of Modena and by the Ethics Committees of participating centers (Eudract n. 2016-002399-28) based on the Helsinki declaration.}, }
@article {pmid29896864, year = {2018}, author = {Pearson, JL and Villanti, AC}, title = {Recommendations for linking client data with clinic services to improve our ability to make inferences.}, journal = {Addiction (Abingdon, England)}, volume = {113}, number = {8}, pages = {1393-1395}, pmid = {29896864}, issn = {1360-0443}, support = {K01 DA037950/DA/NIDA NIH HHS/United States ; P20 GM103644/GM/NIGMS NIH HHS/United States ; }, mesh = {*Smoking ; *Tobacco Use Cessation Devices ; }, abstract = {Concise statement: Skinner et al’s proposed minimum dataset for global stop-smoking services is an essential tool for improving tobacco dependence treatment. We suggest insertion of additional items on treatment cost and cessation aids, including e-cigarettes, as well as items linking program- and individual-level to allow for stronger inferences about the effectiveness of specific services and cessation aids.}, }
@article {pmid29891363, year = {2018}, author = {Guo, W and Chi, Y and Feng, L and Tian, X and Liu, W and Wang, J}, title = {Fenoxaprop-P-ethyl and mesosulfuron-methyl resistance status of shortawn foxtail (Alopecurus aequalis Sobol.) in eastern China.}, journal = {Pesticide biochemistry and physiology}, volume = {148}, number = {}, pages = {126-132}, doi = {10.1016/j.pestbp.2018.04.013}, pmid = {29891363}, issn = {1095-9939}, mesh = {Acetolactate Synthase/chemistry/genetics ; Acetyl-CoA Carboxylase/chemistry/genetics ; Amino Acid Substitution ; China ; Dose-Response Relationship, Drug ; Herbicide Resistance/*genetics ; Herbicides/*pharmacology ; Mutation ; Oxazoles/*pharmacology ; Poaceae/*drug effects/enzymology/genetics ; Propionates/*pharmacology ; Sulfonylurea Compounds/*pharmacology ; }, abstract = {Resistance to the acetyl-coenzyme A carboxylase (ACCase)- and acetolactate synthase (ALS)- inhibiting herbicides in shortawn foxtail (Alopecurus aequalis) has been reported in wheat fields of eastern China. To better understand the distribution of the resistant populations and the occurrence of the target-site mutations, 74 populations collected from Anhui, Jiangsu and Shandong province were surveyed, and the ACCase and ALS gene fragments, encompassing all the documented mutant codon positions, were amplified and sequenced. Plants from 37 and 34 populations survived fenoxaprop-P-ethyl and mesosulfuron-methyl treatment at 62.1 g a.i. ha[-1] and 9 g a.i. ha[-1] respectively, with different survival rates. Twenty-seven populations exhibited multiple resistance to fenoxaprop-P-ethyl and mesosulfuron-methyl. Whole-plant dose-response experiments showed that the resistance index ranged from 6.2 to 167.8 for fenoxaprop-P-ethyl, and from 7.8 to 139.5 for mesosulfuron-methyl. Four ACCase (I1781L, I2041N, I2041T and D2078G) and four ALS (P197R, P197S, P197T and W574 L) resistance mutations were detected respectively. Individuals containing two amino acid substitutions were also found. D2078G and W574 L were predominant ACCase and ALS gene mutations respectively. This study has shown that fenoxaprop-P-ethyl and mesosulfuron-methyl resistance was prevalent in A. aequalis in eastern China, and target site mutations in the ACCase and ALS gene were one of the most common mechanisms.}, }
@article {pmid29890290, year = {2018}, author = {Meyer, M and Lara, A and Hunt, H and Belanoff, J and de Kloet, ER and Gonzalez Deniselle, MC and De Nicola, AF}, title = {The Selective Glucocorticoid Receptor Modulator Cort 113176 Reduces Neurodegeneration and Neuroinflammation in Wobbler Mice Spinal Cord.}, journal = {Neuroscience}, volume = {384}, number = {}, pages = {384-396}, doi = {10.1016/j.neuroscience.2018.05.042}, pmid = {29890290}, issn = {1873-7544}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Astrocytes/drug effects/metabolism/pathology ; Disease Models, Animal ; Glial Fibrillary Acidic Protein/metabolism ; Inflammation/*drug therapy/metabolism/pathology ; Isoquinolines/pharmacology/*therapeutic use ; Mice ; Mice, Neurologic Mutants ; Nerve Degeneration/*drug therapy/metabolism/pathology ; Neuroprotective Agents/pharmacology/*therapeutic use ; Pyrazoles/pharmacology/*therapeutic use ; Receptors, Glucocorticoid/*antagonists &amp; inhibitors ; Spinal Cord/*drug effects/metabolism/pathology ; Treatment Outcome ; }, abstract = {Wobbler mice are experimental models for amyotrophic lateral sclerosis. As such they show motoneuron degeneration, motor deficits, and astrogliosis and microgliosis of the spinal cord. Additionally, Wobbler mice show increased plasma, spinal cord and brain corticosterone levels and focal adrenocortical hyperplasia, suggesting a pathogenic role for glucocorticoids in this disorder. Considering this endocrine background, we examined whether the glucocorticoid receptor (GR) modulator CORT 113176 prevents spinal cord neuropathology of Wobblers. CORT 113176 shows high affinity for the GR, with low or null affinity for other steroid receptors. We employed five-month-old genotyped Wobbler mice that received s.c. vehicle or 30 mg/kg/day for 4 days of CORT 113176 dissolved in sesame oil. The mice were used on the 4th day, 2 h after the last dose of CORT 113176. Vehicle-treated Wobbler mice presented vacuolated motoneurons, increased glial fibrillary acidic protein (GFAP)+ astrocytes and decreased glutamine synthase (GS)+ cells. There was strong neuroinflammation, shown by increased staining for IBA1+ microglia and CD11b mRNA, enhanced expression of tumor necrosis factor-α, its cognate receptor TNFR1, toll-like receptor 4, the inducible nitric oxide synthase, NFkB and the high-mobility group box 1 protein (HMGB1). Treatment of Wobbler mice with CORT 113176 reversed the abnormalities of motoneurons and down-regulated proinflammatory mediators and glial reactivity. Expression of glutamate transporters GLT1 and GLAST mRNAs and GLT1 protein was significantly enhanced over untreated Wobblers. In summary, antagonism of GR with CORT 113176 prevented neuropathology and showed anti-inflammatory and anti-glutamatergic effects in the spinal cord of Wobbler mice.}, }
@article {pmid29879656, year = {2018}, author = {Chen, YT and Chen, WR and Lin, TF}, title = {Oxidation of cyanobacterial neurotoxin beta-N-methylamino-L-alanine (BMAA) with chlorine, permanganate, ozone, hydrogen peroxide and hydroxyl radical.}, journal = {Water research}, volume = {142}, number = {}, pages = {187-195}, doi = {10.1016/j.watres.2018.05.056}, pmid = {29879656}, issn = {1879-2448}, mesh = {Amino Acids, Diamino/*chemistry ; Chlorine/chemistry ; Cyanobacteria/*chemistry ; Cyanobacteria Toxins ; Drinking Water/*chemistry ; Halogenation ; Hydrogen Peroxide/chemistry ; Hydrogen-Ion Concentration ; Hydroxyl Radical/chemistry ; Manganese Compounds/chemistry ; Neurotoxins/chemistry ; Oxidants/*chemistry ; Oxidation-Reduction ; Oxides/chemistry ; Ozone/chemistry ; Water Purification/methods ; }, abstract = {Beta-N-methylamino-L-alanine (BMAA), a new cyanobacterial neurotoxin produced by more than 20 genera of cyanobacteria, has been associated with amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) or Alzheimer's disease. Although BMAA has been shown to be removed in drinking water treatment plants (DWTPs), studies regarding the reactions between BMAA and the commonly used oxidants in DWTPs are limited to chlorine under specific conditions. In this study, the reaction kinetics between BMAA and five oxidants commonly used in DWTPs, including chlorine, potassium permanganate, ozone, hydrogen peroxide and hydroxyl radical were investigated. The oxidation of BMAA by chlorine, ozone or OH radical followed the second order reaction rate law, and the reaction rate was in the order of OH radicals > ozone >> chlorine. The rate constants increased by 20 times from 2 × 10[3] M[-1]s[-1] at pH 5.8 to 4.93 × 10[4] M[-1]s[-1] at pH 7, and kept in a relatively stable level at pH 7-9.5; rate constants of OH radicals were 1.11 × 10[8] M[-1]s[-1] at pH 6.5 and 5.51 × 10[9]- 1.35 × 10[10] M[-1]s[-1] at pH > 6.5. For both permanganate and H2O2 only, the removal of BMAA was negligible. The pH dependency of chlorine and the OH radical may be attributed to the neutral form of BMAA with free lone pair electrons readily to be attacked by oxidants. However, for ozonation of BMAA, the rate constants were 1.88 × 10[6]-3.72 × 10[10] M[-1]s[-1], with a linear dependency on pH, implying that the hydroxide concentration governs the reaction. In addition, the rate of BMAA degradation was found to be slower in natural water if compared with that in deionized water.}, }
@article {pmid29871694, year = {2018}, author = {Izrael, M and Slutsky, SG and Admoni, T and Cohen, L and Granit, A and Hasson, A and Itskovitz-Eldor, J and Krush Paker, L and Kuperstein, G and Lavon, N and Yehezkel Ionescu, S and Solmesky, LJ and Zaguri, R and Zhuravlev, A and Volman, E and Chebath, J and Revel, M}, title = {Safety and efficacy of human embryonic stem cell-derived astrocytes following intrathecal transplantation in SOD1[G93A] and NSG animal models.}, journal = {Stem cell research &amp; therapy}, volume = {9}, number = {1}, pages = {152}, pmid = {29871694}, issn = {1757-6512}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism/pathology ; Animals ; Astrocytes/*metabolism ; Disease Models, Animal ; Human Embryonic Stem Cells/*metabolism ; Humans ; Injections, Spinal/*methods ; Mice ; Rats ; Superoxide Dismutase-1/*genetics/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a motor neuron (MN) disease characterized by the loss of MNs in the central nervous system. As MNs die, patients progressively lose their ability to control voluntary movements, become paralyzed and eventually die from respiratory/deglutition failure. Despite the selective MN death in ALS, there is growing evidence that malfunctional astrocytes play a crucial role in disease progression. Thus, transplantation of healthy astrocytes may compensate for the diseased astrocytes.<br><br>METHODS: We developed a good manufacturing practice-grade protocol for generation of astrocytes from human embryonic stem cells (hESCs). The first stage of our protocol is derivation of astrocyte progenitor cells (APCs) from hESCs. These APCs can be expanded in large quantities and stored frozen as cell banks. Further differentiation of the APCs yields an enriched population of astrocytes with more than 90% GFAP expression (hES-AS). hES-AS were injected intrathecally into hSOD1[G93A] transgenic mice and rats to evaluate their therapeutic potential. The safety and biodistribution of hES-AS were evaluated in a 9-month study conducted in immunodeficient NSG mice under good laboratory practice conditions.<br><br>RESULTS: In vitro, hES-AS possess the activities of functional healthy astrocytes, including glutamate uptake, promotion of axon outgrowth and protection of MNs from oxidative stress. A secretome analysis shows that these hES-AS also secrete several inhibitors of metalloproteases as well as a variety of neuroprotective factors (e.g. TIMP-1, TIMP-2, OPN, MIF and Midkine). Intrathecal injections of the hES-AS into transgenic hSOD1[G93A] mice and rats significantly delayed disease onset and improved motor performance compared to sham-injected animals. A safety study in immunodeficient mice showed that intrathecal transplantation of hES-AS is safe. Transplanted hES-AS attached to the meninges along the neuroaxis and survived for the entire duration of the study without formation of tumors or teratomas. Cell-injected mice gained similar body weight to the sham-injected group and did not exhibit clinical signs that could be related to the treatment. No differences from the vehicle control were observed in hematological parameters or blood chemistry.<br><br>CONCLUSION: Our findings demonstrate the safety and potential therapeutic benefits of intrathecal injection of hES-AS for the treatment of ALS.}, }
@article {pmid29870584, year = {2018}, author = {Saracoglu, E and Kılıç, S and Vuruşkan, E and Düzen, I and Çekici, Y and Kuzu, Z and Yıldırım, A and Küçükosmanoğlu, M and Çetin, M}, title = {Prediction of subtle left ventricular systolic dysfunction in homozygous and heterozygous familial hypercholesterolemia: Genetic analyses and speckle tracking echocardiography study.}, journal = {Echocardiography (Mount Kisco, N.Y.)}, volume = {35}, number = {9}, pages = {1289-1299}, doi = {10.1111/echo.14021}, pmid = {29870584}, issn = {1540-8175}, mesh = {Adult ; Apolipoprotein B-100/genetics ; Echocardiography/*methods ; Female ; Heart Ventricles/diagnostic imaging/physiopathology ; Humans ; Hyperlipoproteinemia Type II/*diagnostic imaging/*genetics ; Male ; Proprotein Convertase 9/genetics ; Receptors, LDL/genetics ; Reproducibility of Results ; Ventricular Dysfunction, Left/*complications/*diagnostic imaging/genetics ; }, abstract = {BACKGROUND AND AIMS: Few studies have shown the direct effect of familial hypercholesterolemia (FH) on myocardial systolic function. Studies focused on heterozygote FH patients but not homozygote ones, and they did not perform genetic analyses. We aimed to evaluate all types of patients with FH using the potentially more sensitive speckle tracking echocardiography (STE) technique to identify early left ventricular (LV) dysfunction.<br><br>METHODS: Genetic analyses of patients with FH were conducted for LDL-receptor, PCSK9, and ApoB100. Nine homozygote, two compound heterozygote, and 82 heterozygote FH patients and 85 healthy subjects were prospectively studied. Longitudinal and circumferential strain measurements and conventional echocardiography findings were obtained.<br><br>RESULTS: LV ejection fractions were similar for all (homozygote, heterozygote, and control) groups. The LV average longitudinal strain (aLS) and average circumferential strain (aCS) levels were significantly reduced in the homozygote and heterozygote groups when compared with the controls (for aLS, P&#xa0;=&#xa0;.008 (<.001); for aCS, P&#xa0;=<&#xa0;.001). A significant inverse correlation was found between LDL-C levels and LS (P&#xa0;<&#xa0;.001, r&#xa0;=&#xa0;.728) and CS (P&#xa0;<&#xa0;.001, r&#xa0;=&#xa0;.642) for all FH patients.<br><br>CONCLUSIONS: This study demonstrates the potential of using systolic strain values obtained using 2D STE for determining lipotoxicity in the myocardium owing to hypercholesterolemia. Our study found that cardiac functions of homozygote patients who had the highest cholesterol levels were disrupted at very early ages. Therefore, starting lipid reduction treatment and early reverse LV remodelling therapy at early ages may be beneficial for high-risk patients.}, }
@article {pmid29870556, year = {2018}, author = {Blasco, H and Patin, F and Descat, A and Garçon, G and Corcia, P and Gelé, P and Lenglet, T and Bede, P and Meininger, V and Devos, D and Gossens, JF and Pradat, PF}, title = {A pharmaco-metabolomics approach in a clinical trial of ALS: Identification of predictive markers of progression.}, journal = {PloS one}, volume = {13}, number = {6}, pages = {e0198116}, pmid = {29870556}, issn = {1932-6203}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy/*metabolism/pathology ; Biomarkers, Pharmacological/analysis/*metabolism ; Cholestenones/*therapeutic use ; Disease Progression ; Double-Blind Method ; Drug Resistance/drug effects ; Female ; Humans ; Male ; Metabolome/drug effects ; Metabolomics/*methods ; Middle Aged ; Placebos ; Prognosis ; }, abstract = {There is an urgent and unmet need for accurate biomarkers in Amyotrophic Lateral Sclerosis. A pharmaco-metabolomics study was conducted using plasma samples from the TRO19622 (olesoxime) trial to assess the link between early metabolomic profiles and clinical outcomes. Patients included in this trial were randomized into either Group O receiving olesoxime (n = 38) or Group P receiving placebo (n = 36). The metabolomic profile was assessed at time-point one (V1) and 12 months (V12) after the initiation of the treatment. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites (Biocrates® commercial kit). Multivariate analysis based on machine learning approaches (i.e. Biosigner algorithm) was performed. Metabolomic profiles at V1 and V12 and changes in metabolomic profiles between V1 and V12 accurately discriminated between Groups O and P (p<5×10-6), and identified glycine, kynurenine and citrulline/arginine as the best predictors of group membership. Changes in metabolomic profiles were closely linked to clinical progression, and correlated with glutamine levels in Group P and amino acids, lipids and spermidine levels in Group O. Multivariate models accurately predicted disease progression and highlighted the discriminant role of sphingomyelins (SM C22:3, SM C24:1, SM OH C22:2, SM C16:1). To predict SVC from SM C24:1 in group O and SVC from SM OH C22:2 and SM C16:1 in group P+O, we noted a median sensitivity between 67% and 100%, a specificity between 66.7 and 71.4%, a positive predictive value between 66 and 75% and a negative predictive value between 70% and 100% in the test sets. This proof-of-concept study demonstrates that the metabolomics has a role in evaluating the biological effect of an investigational drug and may be a candidate biomarker as a secondary outcome measure in clinical trials.}, }
@article {pmid29868568, year = {2018}, author = {Li, J and Chen, JY and Deng, YL and Zhou, Q and Wu, Y and Wu, D and Luo, HB}, title = {Structure-Based Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel PDE10 Inhibitors With Antioxidant Activities.}, journal = {Frontiers in chemistry}, volume = {6}, number = {}, pages = {167}, pmid = {29868568}, issn = {2296-2646}, abstract = {Phosphodiesterase 10 is a promising target for the treatment of a series of central nervous system (CNS) diseases. Imbalance between oxidative stress and antioxidant defense systems as a universal condition in neurodegenerative disorders is widely studied as a potential therapy for CNS diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). To discover multifunctional pharmaceuticals as a treatment for neurodegenerative diseases, a series of quinazoline-based derivatives with PDE10 inhibitory activities and antioxidant activities were designed and synthesized. Nine out of 13 designed compounds showed good PDE10 inhibition at the concentration of 1.0 μM. Among these compounds, eight exhibited moderate to excellent antioxidant activity with ORAC (oxygen radical absorbance capacity) value above 1.0. Molecular docking was performed for better understanding of the binding patterns of these compounds with PDE10. Compound 11e, which showed remarkable inhibitory activity against PDE10 and antioxidant activity may serve as a lead for the further modification.}, }
@article {pmid29863511, year = {2018}, author = {Jeffery, D and Fish, AF}, title = {A Journey with Amyotrophic Lateral Sclerosis.}, journal = {Journal of Christian nursing : a quarterly publication of Nurses Christian Fellowship}, volume = {35}, number = {3}, pages = {152-159}, doi = {10.1097/CNJ.0000000000000502}, pmid = {29863511}, issn = {0743-2550}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/*nursing/physiopathology ; Attitude of Health Personnel ; *Christianity ; *Curriculum ; Education, Nursing, Continuing/organization &amp; administration ; Female ; Humans ; Male ; Middle Aged ; Nursing Care/*psychology ; Nursing Staff, Hospital/*education/*psychology ; Surveys and Questionnaires ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Motor neurons are affected in certain patterns, such as cervical, thoracic, lumbar, and bulbar (facial) regions. Although initial presentations can vary, eventually upper and lower motor neurons are lost in the two types of ALS: familial and sporadic. A case study highlighting the reality of living with bulbar ALS relays Sister A's journey from early to late ALS. Etiology, pathophysiology, diagnosis, treatment, and clinical care are discussed.}, }
@article {pmid29863360, year = {2018}, author = {Siu, M and Sengupta Ghosh, A and Lewcock, JW}, title = {Dual Leucine Zipper Kinase Inhibitors for the Treatment of Neurodegeneration.}, journal = {Journal of medicinal chemistry}, volume = {61}, number = {18}, pages = {8078-8087}, doi = {10.1021/acs.jmedchem.8b00370}, pmid = {29863360}, issn = {1520-4804}, mesh = {Animals ; Calcium-Binding Proteins ; Humans ; Intercellular Signaling Peptides and Proteins ; MAP Kinase Kinase Kinases/*antagonists &amp; inhibitors ; Membrane Proteins/*antagonists &amp; inhibitors ; Neurodegenerative Diseases/*drug therapy ; Protein Kinase Inhibitors/*therapeutic use ; }, abstract = {Dual leucine zipper kinase (DLK, MAP3K12) is an essential driver of the neuronal stress response that regulates neurodegeneration in models of acute neuronal injury and chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. In this review, we provide an overview of DLK signaling mechanisms and describe selected small molecules that have been utilized to inhibit DLK kinase activity in vivo. These compounds represent valuable tools for understanding the role of DLK signaling and evaluating the potential for DLK inhibition as a therapeutic strategy to prevent neuronal degeneration.}, }
@article {pmid29860398, year = {2018}, author = {Gonzalez, D and Rebolledo, DL and Correa, LM and Court, FA and Cerpa, W and Lipson, KE and van Zundert, B and Brandan, E}, title = {The inhibition of CTGF/CCN2 activity improves muscle and locomotor function in a murine ALS model.}, journal = {Human molecular genetics}, volume = {27}, number = {16}, pages = {2913-2926}, doi = {10.1093/hmg/ddy204}, pmid = {29860398}, issn = {1460-2083}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/pathology ; Animals ; Antibodies, Neutralizing/administration &amp; dosage ; Astrocytes/drug effects/pathology ; Connective Tissue Growth Factor/*genetics ; Disease Models, Animal ; Fibrosis/drug therapy/genetics/pathology ; Gene Expression Regulation/drug effects ; Humans ; Locomotion/drug effects ; Mice ; Mice, Inbred mdx ; Mice, Transgenic ; Muscle, Skeletal/drug effects/pathology ; Muscular Dystrophy, Duchenne/*drug therapy/genetics/pathology ; Neuromuscular Junction/drug effects/pathology ; Neurons/drug effects/pathology ; Superoxide Dismutase-1/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset progressive neurodegenerative disease characterized by upper and lower motoneuron degeneration. A total of 20% of familial ALS (fALS) cases are explained by mutations in the superoxide dismutase 1 (SOD1) enzyme. Although more than 20 years have passed since the generation of the first ALS mouse model, the precise molecular mechanisms of ALS pathogenesis remain unknown. CTGF/CCN2 is a matricellular protein with associated fibrotic activity that is up-regulated in several chronic diseases. The inhibition of CTGF/CCN2 with the monoclonal neutralizing antibody FG-3019 reduces fibrosis in several chronic disorders including the mdx mice, a murine model for Duchenne muscular dystrophy (DMD). In this work, we show that there are increased levels of CTGF/CCN2 in skeletal muscle and spinal cord of hSOD1G93A mice. In this scenario, we show evidence that FG-3019 not only reduces fibrosis in skeletal muscle of hSOD1G93A mice, but also improves muscle and locomotor performance. We demonstrate that treatment with FG-3019 reduces muscle atrophy in hSOD1G93A mice. We also found improvement of neuromuscular junction (NMJ) innervation together with a reduction in myelin degeneration in the sciatic nerve, suggesting that alterations in nerve-muscle communication are partially improved in FG-3019-treated hSOD1G93A mice. Moreover, we also found that CTGF/CCN2 is expressed in astrocytes and neurons, predominantly in dorsal areas of spinal cord from symptomatic hSOD1G93A mice. Together, these results reveal that CTGF/CCN2 might be a novel therapeutic target to ameliorate symptoms and improve the quality of life of ALS patients.}, }
@article {pmid29857945, year = {2019}, author = {Jouffroy, R and Saade, A and Alexandre, P and Philippe, P and Carli, P and Vivien, B}, title = {Epinephrine administration in non-shockable out-of-hospital cardiac arrest.}, journal = {The American journal of emergency medicine}, volume = {37}, number = {3}, pages = {387-390}, doi = {10.1016/j.ajem.2018.05.055}, pmid = {29857945}, issn = {1532-8171}, mesh = {Aged ; Cardiopulmonary Resuscitation ; Dose-Response Relationship, Drug ; Electric Countershock ; Emergency Medical Services ; Epinephrine/*administration &amp; dosage ; Female ; Humans ; Male ; Middle Aged ; Out-of-Hospital Cardiac Arrest/classification/*drug therapy ; Paris ; Propensity Score ; Registries ; Retrospective Studies ; Time-to-Treatment ; Vasoconstrictor Agents/*administration &amp; dosage ; }, abstract = {BACKGROUND: Epinephrine is recommended for the treatment of non-shockable out of hospital cardiac arrest (OHCA) to obtain return of spontaneous circulation (ROSC). Epinephrine efficiency and safety remain under debate.<br><br>OBJECTIVE: We propose to describe the association between the cumulative dose of epinephrine and the failure of ROSC during the first 30&#x202f;min of advanced life support (ALS).<br><br>METHODOLOGY: A retrospective observational cohort study using the Paris SAMU 75 registry including all non-traumatic OHCA. All OHCA receiving epinephrine during the first 30&#x202f;min of ALS were enrolled. Cumulative epinephrine dose given during ALS to ROSC was retrieved from medical reports.<br><br>RESULTS: Among 1532 patients with OHCA, 776 (51%) had initial non-shockable rhythm. Fifty-four patients were excluded for missing data. The mean value of cumulative dose of epinephrine was 10&#x202f;&#xb1;&#x202f;4&#x202f;mg in patients who failed to achieve ROSC (ROSC-) and 4&#x202f;&#xb1;&#x202f;3&#x202f;mg (p&#x202f;=&#x202f;0.04) for those who achieved ROSC. ROC curve analysis indicated a cut-off point of 7&#x202f;mg total cumulative epinephrine associated with ROSC- (AUC&#x202f;=&#x202f;0.89 [0.86-0.92]). Using propensity score analysis including age, sex and no-flow duration, association with ROSC- only remained significant for epinephrine&#x202f;>&#x202f;7&#x202f;mg (p&#x202f;&#x2264;10-3, OR [CI95]&#x202f;=&#x202f;1.53 [1.42-1.65]).<br><br>CONCLUSION: An association between total cumulative epinephrine dose administered during OHCA resuscitation and ROSC- was reported with a threshold of 7&#x202f;mg, best identifying patients with refractory OHCA. We suggest using this threshold in this context to guide the termination of ALS and early decide on the implementation of extracorporeal life support or organ harvesting in the first 30&#x202f;min of ALS.}, }
@article {pmid29854003, year = {2018}, author = {Wurster, CD and Ludolph, AC}, title = {Antisense oligonucleotides in neurological disorders.}, journal = {Therapeutic advances in neurological disorders}, volume = {11}, number = {}, pages = {1756286418776932}, pmid = {29854003}, issn = {1756-2856}, abstract = {The introduction of genetics revolutionized the field of neurodegenerative and neuromuscular diseases and has provided considerable insight into the underlying pathomechanisms. Nevertheless, effective treatment options have been limited. This changed recently when antisense oligonucleotides (ASOs) could be translated from in vitro and experimental animal studies into clinical practice. In 2016, two ASOs were approved by the United States US Food and Drug Administration (FDA) and demonstrated remarkable efficacy in Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). ASOs are synthetic single-stranded strings of nucleic acids. They selectively bind to specific premessenger ribonucleic acid (pre-mRNA)/mRNA sequences and alter protein synthesis by several mechanisms of action. Thus, apart from gene replacement, ASOs may therefore provide the most direct therapeutic strategy for influencing gene expression. In this review, we shall discuss basic mechanisms of ASO action, the role of chemical modifications needed to improve the pharmacodynamic and pharmacokinetic properties of ASOs, and we shall then focus on several ASOs developed for the treatment of neurodegenerative and neuromuscular disorders, including SMA, DMD, myotonic dystrophies, Huntington's disease, amyotrophic lateral sclerosis and Alzheimer's disease.}, }
@article {pmid29852219, year = {2019}, author = {Cortes, CJ and La Spada, AR}, title = {TFEB dysregulation as a driver of autophagy dysfunction in neurodegenerative disease: Molecular mechanisms, cellular processes, and emerging therapeutic opportunities.}, journal = {Neurobiology of disease}, volume = {122}, number = {}, pages = {83-93}, pmid = {29852219}, issn = {1095-953X}, support = {R01 AG033082/AG/NIA NIH HHS/United States ; R01 NS100023/NS/NINDS NIH HHS/United States ; R03 AG063215/AG/NIA NIH HHS/United States ; RF1 AG057264/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Autophagy/*physiology ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/*therapy ; }, abstract = {Two decades ago, the recognition of protein misfolding and aggregate accumulation as defining features of neurodegenerative disease set the stage for a thorough examination of how protein quality control is maintained in neurons and in other non-neuronal cells in the central nervous system (CNS). Autophagy, a pathway of cellular self-digestion, has emerged as especially important for CNS proteostasis, and autophagy dysregulation has been documented as a defining feature of neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Transcription factor EB (TFEB) is one of the main transcriptional regulators of autophagy, as it promotes the expression of genes required for autophagosome formation, lysosome biogenesis, and lysosome function, and it is highly expressed in CNS. Over the last 7 years, TFEB has received considerable attention and TFEB dysfunction has been implicated in the pathogenesis of numerous neurodegenerative disorders. In this review, we delineate the current understanding of how TFEB dysregulation is involved in neurodegeneration, highlighting work done on AD, PD, HD, X-linked spinal &amp; bulbar muscular atrophy, and amyotrophic lateral sclerosis. Because TFEB is a central node in defining autophagy activation status, efforts at understanding the basis for TFEB dysfunction are yielding insights into how TFEB might be targeted for therapeutic application, which may represent an exciting opportunity for the development of a treatment modality with broad application to neurodegeneration.}, }
@article {pmid29848047, year = {2018}, author = {Gwyther, L and Heap, M and London, L}, title = {Access to palliative care in HIV services in Cape Town.}, journal = {AIDS care}, volume = {30}, number = {sup2}, pages = {11-15}, doi = {10.1080/09540121.2018.1470307}, pmid = {29848047}, issn = {1360-0451}, mesh = {Adult ; Antiretroviral Therapy, Highly Active ; Female ; HIV Infections/psychology/*therapy ; *Health Services Accessibility ; Humans ; Male ; Middle Aged ; Neoplasms/psychology/*therapy ; Pain ; Palliative Care/*methods/*psychology ; Prospective Studies ; Quality of Life/*psychology ; *Referral and Consultation ; South Africa ; Surveys and Questionnaires ; }, abstract = {UNLABELLED: This paper examines access to palliative care (PC) for patients with HIV, part of a study investigating access to PC for patients with chronic diseases. Studies highlight gaps in symptom management and psychosocial care for People living with HIV (PLHIV) and thus the need to integrate PC into HIV services. The aim of the study was to describe the access of patients with advanced chronic illness to PC services.<br><br>METHODOLOGY: this was a prospective cohort study conducted over six months. Participants were recruited from patients living with HIV with CD4 counts of <200&#x2005;cells/mm[3], patients with advanced cancer and patients diagnosed with motor neurone disease. All HIV patients were on anti-retroviral treatment. Participants responded to a questionnaire including the APCA African Palliative Outcome Scale (POS), a validated palliative outcome scale, as a measure of care at first visit and telephonically once a month for 6 months.<br><br>RESULTS: Seventy-nine HIV patients were recruited to the study. During the study 6 PLHIV died and no HIV patients were referred to PC services. A significant finding is that most patient outcomes improved for HIV patients. Pain reduced from 1.83 to 0.86; symptoms reduced from 2.41 to 0.49; worry reduced from 2.17 to 0.35. Spiritual well-being also improved&#xa0;- life worthwhile from 3.56 to 4.74 and at peace from 3.63 to 4.86; all measures out of 5.&#xa0;A small sub-set of this cohort (7.7%) experienced high pain levels not controlled during the study.<br><br>DISCUSSION: Few patients were referred to PC services despite 6 HIV deaths during the study. Patients attending HIV clinics received good PC in conjunction with HAART, suggesting that PC appears to be well integrated into routine HIV care. It is suggested that patients with severe problems including those who died would have benefitted from referral to PC.}, }
@article {pmid29845377, year = {2019}, author = {Castanedo-Vazquez, D and Bosque-Varela, P and Sainz-Pelayo, A and Riancho, J}, title = {Infectious agents and amyotrophic lateral sclerosis: another piece of the puzzle of motor neuron degeneration.}, journal = {Journal of neurology}, volume = {266}, number = {1}, pages = {27-36}, pmid = {29845377}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/*microbiology/virology ; Animals ; Bacterial Infections/*immunology ; Humans ; Motor Neurons/immunology/microbiology/parasitology/virology ; Virus Diseases/*immunology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MN). This fatal disease is characterized by progressive muscle wasting and lacks an effective treatment. ALS pathogenesis has not been elucidated yet. In a small proportion of ALS patients, the disease has a familial origin, related to mutations in specific genes, which directly result in MN degeneration. By contrast, the vast majority of cases are though to be sporadic, in which genes and environment interact leading to disease in genetically predisposed individuals. Lately, the role of the environment has gained relevance in this field and an extensive list of environmental conditions have been postulated to be involved in ALS. Among them, infectious agents, particularly viruses, have been suggested to play an important role in the pathogenesis of the disease. These agents could act by interacting with some crucial pathways in MN degeneration, such as gene processing, oxidative stress or neuroinflammation. In this article, we will review the main studies about the involvement of microorganisms in ALS, subsequently discussing their potential pathogenic effect and integrating them as another piece in the puzzle of ALS pathogenesis.}, }
@article {pmid29842900, year = {2018}, author = {Wang, T and Cheng, J and Wang, S and Wang, X and Jiang, H and Yang, Y and Wang, Y and Zhang, C and Liang, W and Feng, H}, title = {α-Lipoic acid attenuates oxidative stress and neurotoxicity via the ERK/Akt-dependent pathway in the mutant hSOD1 related Drosophila model and the NSC34 cell line of amyotrophic lateral sclerosis.}, journal = {Brain research bulletin}, volume = {140}, number = {}, pages = {299-310}, doi = {10.1016/j.brainresbull.2018.05.019}, pmid = {29842900}, issn = {1873-2747}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Animals, Genetically Modified ; Cell Line ; Disease Models, Animal ; Drosophila melanogaster ; Enzyme Inhibitors/pharmacology ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors/*metabolism ; Humans ; MAP Kinase Signaling System/drug effects/physiology ; Male ; Mice ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/*drug effects/physiology ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/*metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Thioctic Acid/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative disease with a progressive loss of motor neurons in the central nervous system (CNS). However, there are unsolved problems with the therapies for this disease. α-Lipoic acid (LA) is a natural, universal antioxidant capable of scavenging hydroxyl radicals as well as regenerating a series of antioxidant enzymes that has been widely used in clinical settings. This study aimed to evaluate the antioxidant and neuroprotective effects of LA in ALS cell and Drosophila models with mutant G85R and G93A hSOD1 genes. The biological effects of LA and the protein levels of several antioxidant factors were examined, as were those of phospho-Akt and phospho-ERK. Furthermore, specific inhibitors of the PI3K/Akt and MEK/ERK signaling pathways were used to analyze their effects on LA-induced antioxidant expression in vivo and in vitro. Evidences showed that the mutant hSOD1 resulted in the increased oxidative stress, abnormal antioxidant signaling and pathological behaviors in motor performance and survival compared with non-mutant hSOD1 models, treatment with LA improved motor activity and survival in transgenic flies, prevented NSC34 cells from mutant hSOD1 or H2O2 induced decreased antioxidant enzymes as well as increased ROS levels. In addition, LA regulated the expression levels of antioxidant proteins in a dose- and periodical time-dependent manner, which might be mediated by ERK/Akt pathway activation and independent from the mutant hSOD1 gene. Our observations suggest that LA exerts strong and positive antioxidant and neuroprotective effects through the activation of the ERK-Akt pathway in hSOD1 ALS models.}, }
@article {pmid29808621, year = {2019}, author = {Zhao, N and Yan, Y and Ge, L and Zhu, B and Liu, W and Wang, J}, title = {Target site mutations and cytochrome P450s confer resistance to fenoxaprop-P-ethyl and mesosulfuron-methyl in Alopecurus aequalis.}, journal = {Pest management science}, volume = {75}, number = {1}, pages = {204-214}, doi = {10.1002/ps.5089}, pmid = {29808621}, issn = {1526-4998}, support = {201303031//Special Fund for Agro-scientific Research in the Public Interest/ ; 31772181//National Natural Science Foundation of China/ ; }, mesh = {Cytochrome P-450 Enzyme System/*genetics/metabolism ; Herbicide Resistance/*genetics ; Herbicides/*pharmacology ; Mutation ; Oxazoles/*pharmacology ; Plant Proteins/*genetics/metabolism ; Poaceae/drug effects/*genetics/physiology ; Propionates/*pharmacology ; Sulfonylurea Compounds/*pharmacology ; }, abstract = {BACKGROUND: Shortawn foxtail (Alopecurus aequalis Sobol.) is a competitive grass weed infesting winter wheat- and canola-growing fields in China. In May 2016, a suspected A. aequalis resistant population AHTC-06 that survived fenoxaprop-P-ethyl and mesosulfuron-methyl applied at their field-recommended rates was collected from a wheat field in Jinji County, Anhui Province, China. This study aimed to determine the resistance profile of this AHTC-06 population to ACCase- and ALS-inhibitors, and to investigate its mechanisms of resistance to fenoxaprop-P-ethyl and mesosulfuron-methyl.<br><br>RESULTS: Two mutations, a common Ile-2041-Asn (ACCase gene) and a very rare Pro-197-Tyr (ALS1 gene), were both identified in resistant individual plants. The homozygous subpopulation AHTC-06F1 for the two mutations was generated, and it showed broad-spectrum resistance to APPs, DENs, and ALS-inhibiting herbicides of all five chemical families tested, with resistance index (RI) values that ranged from 2.2 to 36.5. In vitro ALS activity assays showed the ALS from the resistant population was insensitive to all the tested ALS inhibitors, with RI values ranging from 3.10 to 22.51. Pre-treatment with piperonyl butoxide (PBO) and malathion significantly (P < 0.05) reversed the weed's resistance to fenoxaprop-P-ethyl and mesosulfuron-methyl, respectively. Two P450 genes, c21190_g1 and c43350_g3, were constitutively overexpressed and mesosulfuron-methyl-induced upregulated in resistant plants, for which c43350_g3 was also fenoxaprop-P-ethyl-induced upregulated.<br><br>CONCLUSION: This study confirms the first case of a grass weed featuring broad-spectrum resistance to ALS-inhibiting herbicides due to a Pro-197-Tyr mutation in the ALS gene. Fenoxaprop-P-ethyl and mesosulfuron-methyl resistances in AHTC-06 plants were conferred by target site mutations and P450s-based metabolism. &#xa9; 2018 Society of Chemical Industry.}, }
@article {pmid29807145, year = {2018}, author = {Zhou, F and Dong, H and Liu, Y and Yan, L and Sun, C and Hao, P and Liu, Y and Zhai, J and Liu, Y}, title = {Raloxifene, a promising estrogen replacement, limits TDP-25 cell death by enhancing autophagy and suppressing apoptosis.}, journal = {Brain research bulletin}, volume = {140}, number = {}, pages = {281-290}, doi = {10.1016/j.brainresbull.2018.05.017}, pmid = {29807145}, issn = {1873-2747}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Apoptosis/*drug effects/physiology ; Autophagy/*drug effects/physiology ; Cell Line ; Cell Survival/drug effects/physiology ; DNA-Binding Proteins/genetics/metabolism ; Estrogen Replacement Therapy ; Neuroprotective Agents/pharmacology ; Peptide Fragments/genetics/metabolism ; Raloxifene Hydrochloride/*pharmacology ; Receptors, Estrogen/metabolism ; Selective Estrogen Receptor Modulators/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease, and at present, therapies for ALS are limited. Estrogen is a potential therapeutic agent for ALS but has undesirable effects that might increase the risk of breast and uterine cancers or stroke. Raloxifene (Ral) has estrogenic properties but does not exhibit these adverse effects. However, the mechanism of Ral in ALS has not been studied. We thus investigated the effects of Ral in an NSC34 model of ALS that stably expresses the 25-kDa C-terminal fragment of TDP-43 (i.e., TDP-25 cells) and found that GPR30 (G protein-coupled receptor 30) and ER (estrogen receptor) α/ERβ were expressed in TDP-25 cells, which show significantly different morphology compared with controls. Both E2 (17β-estradiol) and Ral increased the expression of ERα and GPR30 and enhanced TDP-25 cell viability, and these effects were completely abolished by treatment with an ERα/β antagonist (ICI 182,780) or GPR30 antagonist (G15). The P62, caspase-9 and Bax levels were significantly decreased in TDP-25 cells treated with Ral or E2, and the LC3-II levels were elevated in E2-treated cells but reduced in Ral-treated cells. All these changes were abolished by treatment with ICI 182,780 or G15. These data suggest that Ral, similar to E2, enhances autophagy and suppresses apoptosis to limit motor neuron death by binding to ERα/β or GPR30 in TDP-25 cells. These results demonstrate the protective effects of Ral in an ALS cell model and suggest that Ral is a promising replacement for estrogen and a promising therapeutic strategy for ALS.}, }
@article {pmid29801610, year = {2018}, author = {Dalmau, N and Bedia, C and Tauler, R}, title = {Validation of the Regions of Interest Multivariate Curve Resolution (ROIMCR) procedure for untargeted LC-MS lipidomic analysis.}, journal = {Analytica chimica acta}, volume = {1025}, number = {}, pages = {80-91}, doi = {10.1016/j.aca.2018.04.003}, pmid = {29801610}, issn = {1873-4324}, mesh = {Cell Line, Tumor ; Chromatography, Liquid/*methods ; Humans ; Least-Squares Analysis ; Lipid Metabolism ; Lipids/*analysis ; Mass Spectrometry/*methods ; Metabolomics/*methods ; Multivariate Analysis ; }, abstract = {Untargeted liquid chromatography coupled to mass spectrometry (LC-MS) analysis generates massive amounts of information-rich mass data which presents storage and processing challenges. In this work, the validation of a recently proposed procedure for LC-MS data compression and processing is presented, using as example the analysis of lipid mixtures. This method consists of a preliminary selection of the Regions of Interest of the LC-MS data (MSROI) coupled to their throughout chemometric analysis by the Multivariate Curve Resolution Alternating Least Squares method (MCR-ALS). The proposed data selection procedure is based on the search of the most significant mass traces regions with high mass densities. This allows for a drastic reduction of the MS data size and of the computer storage requirements, without any significant loss neither of spectral resolution nor of accuracy on m/z measures. The combination of the MSROI data compression and MCR-ALS data analysis procedures in the new ROIMCR procedure has the main advantage of not requiring neither the chromatographic peak alignment nor the chromatographic peak shape modelling used in many other procedures as a pre-treatment step of the data analysis. The proposed ROIMCR procedure is tested in the analysis of the LC-MS experimental data coming from different lipid mixtures and of a melanoma cell line culture sample with satisfactory results. The proposed strategy is shown to be a general, fast, reliable and easy to use method for general untargeted LC-MS metabolic and lipidomic data analysis type of studies.}, }
@article {pmid29791943, year = {2018}, author = {Julian, K and Yuhasz, N and Hollingsworth, E and Imitola, J}, title = {The "Growing" Reality of the Neurological Complications of Global "Stem Cell Tourism".}, journal = {Seminars in neurology}, volume = {38}, number = {2}, pages = {176-181}, doi = {10.1055/s-0038-1649338}, pmid = {29791943}, issn = {1098-9021}, mesh = {*Global Health ; Humans ; Nervous System Diseases/epidemiology/*surgery ; Stem Cell Transplantation/*methods ; Stem Cells/*physiology ; }, abstract = {"Stem cell tourism" is defined as the unethical practice of offering unproven cellular preparations to patients suffering from various medical conditions. This phenomenon is rising in the field of neurology as patients are requesting information and opportunities for treatment with stem cells for incurable conditions such as multiple sclerosis and amyotrophic lateral sclerosis, despite their clinical research and experimental designation. Here, we review the recent trends in "stem cell tourism" in both the United States and abroad, and discuss the recent reports of neurological complications from these activities. Finally, we frame critical questions for the field of neurology regarding training in the ethical, legal, and societal issues of the global "stem cell tourism," as well as suggest strategies to alleviate this problem. Although there are ongoing legitimate clinical trials with stem cells for neurological diseases, procedures offered by "stem cell clinics" cannot be defined as clinical research. They lack the experimental and state-of-the-art framework defined by peers and the FDA that focus on human research that safeguard the protection of human subjects against economical exploitation, unwanted side effects, and futility of unproven procedures. "Stem cell tourism" ultimately exploits therapeutic hope of patients and families with incurable neurological diseases and can put in danger the legitimacy of stem cell research as a whole. We posit that an improvement in education, regulation, legislation, and involvement of authorities in global health in neurology and neurosurgery is required.}, }
@article {pmid29790082, year = {2018}, author = {Pozzi, S and Thammisetty, SS and Julien, JP}, title = {Chronic Administration of Pimozide Fails to Attenuate Motor and Pathological Deficits in Two Mouse Models of Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {15}, number = {3}, pages = {715-727}, pmid = {29790082}, issn = {1878-7479}, support = {W81XWH-11-1-0573//U.S. Department of Defense/International ; FDN143275//Institute of Neurosciences, Mental Health and Addiction/International ; }, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*complications/genetics/*pathology ; Animals ; Anti-Dyskinesia Agents/*administration &amp; dosage ; Body Weight/drug effects/genetics ; Botulinum Toxins, Type A/therapeutic use ; DNA-Binding Proteins/genetics/metabolism ; Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Mice, Transgenic ; Motor Activity/drug effects/genetics ; Movement Disorders/*drug therapy/*etiology ; Muscle Strength/drug effects/genetics ; Mutation/genetics ; Neuromuscular Agents/therapeutic use ; Neuromuscular Junction/drug effects/pathology ; Phosphopyruvate Hydratase/metabolism ; Pimozide/*adverse effects ; Statistics, Nonparametric ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which presently does not have any efficient therapeutic approach. Pimozide, a Food and Drug Administration (FDA)-approved neuroepileptic drug, has been recently proposed as a promising treatment for ALS patients based on apparent stabilization of right hand muscles after a short-time administration. A new clinical trial started at the end of 2017 to recruit patients with a prolonged drug delivery schedule. Here, our aim was to investigate the effects of chronic administration of pimozide on disease progression and pathological events in two mouse models of ALS. Pimozide was administered every 2 days to transgenic mice bearing the ALS-linked A315T mutation on the human TAR DNA-binding protein 43 (TDP-43) gene and to mice carrying the human superoxide dismutase 1 (SOD1) gene with the ALS-linked G93A mutation. Chronic administration of pimozide exacerbated motor performances in both animal models and reduced survival in SOD1[G93A] mice. In TDP-43[A315]T, it decreased the percentage of innervated neuromuscular junctions (NMJs) and increased the accumulation of insoluble TDP-43. In SOD1[G93A] mice, pimozide had no effects on NMJ innervation or motoneuron loss, but it increased the levels of misfolded SOD1. We conclude that a chronic administration of pimozide did not confer beneficial effects on disease progression in two mouse models of ALS. In light of a new clinical trial on ALS patients with a chronic regime of pimozide, these results with mouse models suggest prudence and careful monitoring of ALS patients subjected to pimozide treatment.}, }
@article {pmid29789529, year = {2018}, author = {Gibbs, KL and Kalmar, B and Rhymes, ER and Fellows, AD and Ahmed, M and Whiting, P and Davies, CH and Greensmith, L and Schiavo, G}, title = {Inhibiting p38 MAPK alpha rescues axonal retrograde transport defects in a mouse model of ALS.}, journal = {Cell death &amp; disease}, volume = {9}, number = {6}, pages = {596}, pmid = {29789529}, issn = {2041-4889}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Acetylcarnitine/pharmacology ; Amyotrophic Lateral Sclerosis/*enzymology/*pathology ; Animals ; *Axonal Transport/drug effects ; Disease Models, Animal ; Enzyme Activation/drug effects ; Hindlimb/drug effects/physiopathology ; Imidazoles/pharmacology ; JNK Mitogen-Activated Protein Kinases/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/drug effects/metabolism ; Muscles/drug effects/physiopathology ; Protein Kinase Inhibitors/pharmacology ; Pyrimidines/pharmacology ; Quinazolinones/pharmacology ; Receptors, Nerve Growth Factor/metabolism ; Superoxide Dismutase/metabolism ; Tetanus Toxin/metabolism ; p38 Mitogen-Activated Protein Kinases/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the degeneration of upper and lower motor neurons. Defects in axonal transport have been observed pre-symptomatically in the SOD1[G93A] mouse model of ALS, and have been proposed to play a role in motor neuron degeneration as well as in other pathologies of the nervous system, such as Alzheimer's disease and hereditary neuropathies. In this study, we screen a library of small-molecule kinase inhibitors towards the identification of pharmacological enhancers of the axonal retrograde transport of signalling endosomes, which might be used to normalise the rate of this process in diseased neurons. Inhibitors of p38 mitogen-activated protein kinases (p38 MAPK) were identified in this screen and were found to correct deficits in axonal retrograde transport of signalling endosomes in cultured primary SOD1[G93A] motor neurons. In vitro knockdown experiments revealed that the alpha isoform of p38 MAPK (p38 MAPKα) was the sole isoform responsible for SOD1[G93A]-induced transport deficits. Furthermore, we found that acute treatment with p38 MAPKα inhibitors restored the physiological rate of axonal retrograde transport in vivo in early symptomatic SOD1[G93A] mice. Our findings demonstrate the pathogenic effect of p38 MAPKα on axonal retrograde transport and identify a potential therapeutic strategy for ALS.}, }
@article {pmid29789410, year = {2018}, author = {Trainer, PJ and Newell-Price, JDC and Ayuk, J and Aylwin, SJB and Rees, A and Drake, W and Chanson, P and Brue, T and Webb, SM and Fajardo, C and Aller, J and McCormack, AI and Torpy, DJ and Tachas, G and Atley, L and Ryder, D and Bidlingmaier, M}, title = {A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly.}, journal = {European journal of endocrinology}, volume = {179}, number = {2}, pages = {97-108}, pmid = {29789410}, issn = {1479-683X}, mesh = {Acromegaly/drug therapy ; Adult ; Aged ; Female ; Human Growth Hormone/blood ; Humans ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/analysis ; Male ; Middle Aged ; Oligonucleotides/administration &amp; dosage/adverse effects/*therapeutic use ; *Oligonucleotides, Antisense ; RNA, Messenger/antagonists &amp; inhibitors ; Receptors, Somatotropin/antagonists &amp; inhibitors/*genetics ; Treatment Outcome ; }, abstract = {OBJECTIVE: ATL1103 is a second-generation antisense oligomer targeting the human growth hormone (GH) receptor. This phase 2 randomised, open-label, parallel-group study assessed the potential of ATL1103 as a treatment for acromegaly.<br><br>DESIGN: Twenty-six patients with active acromegaly (IGF-I >130% upper limit of normal) were randomised to subcutaneous ATL1103 200&#x2009;mg either once or twice weekly for 13 weeks and monitored for a further 8-week washout period.<br><br>METHODS: The primary efficacy measures were change in IGF-I at week 14, compared to baseline and between cohorts. For secondary endpoints (IGFBP3, acid labile subunit (ALS), GH, growth hormone-binding protein (GHBP)), comparison was between baseline and week 14. Safety was assessed by reported adverse events.<br><br>RESULTS AND CONCLUSIONS: Baseline median IGF-I was 447 and 649&#x2009;ng/mL in the once- and twice-weekly groups respectively. Compared to baseline, at week 14, twice-weekly ATL1103 resulted in a median fall in IGF-I of 27.8% (P&#x2009;=&#x2009;0.0002). Between cohort comparison at week 14 demonstrated the median fall in IGF-I to be 25.8% (P&#x2009;=&#x2009;0.0012) greater with twice-weekly dosing. In the twice-weekly cohort, IGF-I was still declining at week 14, and remained lower at week 21 than at baseline by a median of 18.7% (P&#x2009;=&#x2009;0.0005). Compared to baseline, by week 14, IGFBP3 and ALS had declined by a median of 8.9% (P&#x2009;=&#x2009;0.027) and 16.7% (P&#x2009;=&#x2009;0.017) with twice-weekly ATL1103; GH had increased by a median of 46% at week 14 (P&#x2009;=&#x2009;0.001). IGFBP3, ALS and GH did not change with weekly ATL1103. GHBP fell by a median of 23.6% and 48.8% in the once- and twice-weekly cohorts (P&#x2009;=&#x2009;0.027 and P&#x2009;=&#x2009;0.005) respectively. ATL1103 was well tolerated, although 84.6% of patients experienced mild-to-moderate injection-site reactions. This study provides proof of concept that ATL1103 is able to significantly lower IGF-I in patients with acromegaly.}, }
@article {pmid29787578, year = {2018}, author = {Scherz, B and Rabl, R and Flunkert, S and Rohler, S and Neddens, J and Taub, N and Temmel, M and Panzenboeck, U and Niederkofler, V and Zimmermann, R and Hutter-Paier, B}, title = {mTh1 driven expression of hTDP-43 results in typical ALS/FTLD neuropathological symptoms.}, journal = {PloS one}, volume = {13}, number = {5}, pages = {e0197674}, pmid = {29787578}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/physiopathology ; Animals ; Cell Nucleus/metabolism ; Cytosol/metabolism ; DNA-Binding Proteins/*genetics/*metabolism ; Disease Models, Animal ; Frontotemporal Lobar Degeneration/*genetics/metabolism/physiopathology ; Hippocampus/metabolism ; Humans ; Hypothalamus/metabolism ; Medulla Oblongata/metabolism ; Mice ; Mice, Transgenic ; Motor Neurons/physiology ; Phosphoric Monoester Hydrolases/*genetics ; Promoter Regions, Genetic ; Spinal Cord/metabolism ; *Up-Regulation ; }, abstract = {Transgenic mouse models are indispensable tools to mimic human diseases and analyze the effectiveness of related new drugs. For a long time amyotrophic lateral sclerosis (ALS) research depended on only a few mouse models that exhibit a very strong and early phenotype, e.g. SOD1 mice, resulting in a short treatment time window. By now, several models are available that need to be characterized to highlight characteristics of each model. Here we further characterized the mThy1-hTDP-43 transgenic mouse model TAR6/6 that overexpresses wild type human TARDBP, also called TDP-43, under control of the neuronal Thy-1 promoter presented by Wils and colleagues, 2010, by using biochemical, histological and behavioral readouts. Our results show that TAR6/6 mice exhibit a strong TDP-43 expression in the hippocampus, spinal cord, hypothalamus and medulla oblongata. Apart from prominent protein expression in the nucleus, TDP-43 protein was found at lower levels in the cytosol of transgenic mice. Additionally, we detected insoluble TDP-43 in the cortex, motoneuron loss, and increased neuroinflammation in the central nervous system of TAR6/6 animals. Behavioral analyses revealed early motor deficits in the clasping- and wire suspension test as well as decreased anxiety in the elevated plus maze. Further motor tests showed differences at later time points compared to non-transgenic littermates, thus allowing the observation of onset and severity of such deficits. Together, TAR6/6 mice are a valuable tool to test new ALS/FTLD drugs that target TDP-43 expression and insolubility, neuroinflammation, motoneuron loss or other TDP-43 related downstream signaling pathways since these mice exhibit a later pathology as previously used ALS/FTLD mouse models.}, }
@article {pmid29786645, year = {2018}, author = {Di Pietro, L and Lattanzi, W and Bernardini, C}, title = {Skeletal Muscle MicroRNAs as Key Players in the Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {19}, number = {5}, pages = {}, pmid = {29786645}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics ; Animals ; Humans ; MicroRNAs/*genetics/metabolism ; Muscle, Skeletal/*metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, for which, to date, no effective treatment to ameliorate the clinical manifestations is available. The long-standing view of ALS as affecting only motor neurons has been challenged by the finding that the skeletal muscle plays an active role in the disease pathogenesis and can be a valuable target for therapeutic strategies. In recent years, non-coding RNAs, including microRNAs, have emerged as important molecules that play key roles in several cellular mechanisms involved in the pathogenic mechanisms underlying various human conditions. In this review, we summarize how the expression of some microRNAs is dysregulated in the skeletal muscle of ALS mouse models and patients. Shedding light on the mechanisms underlying microRNAs dysregulation in the skeletal muscle could clarify some of the processes involved in the pathogenesis of ALS and especially identify new promising therapeutic targets in patients.}, }
@article {pmid29784843, year = {2018}, author = {Norman, G and Campeau, J and Sim, VL}, title = {High Dose and Delayed Treatment with Bile Acids Ineffective in RML Prion-Infected Mice.}, journal = {Antimicrobial agents and chemotherapy}, volume = {62}, number = {8}, pages = {}, pmid = {29784843}, issn = {1098-6596}, mesh = {Animals ; Anti-Infective Agents/*pharmacology ; Disease Models, Animal ; Drug Administration Schedule ; Female ; Male ; Mice ; PrPSc Proteins/*drug effects/pathogenicity ; Prion Diseases/*drug therapy/mortality/pathology ; Survival Analysis ; Taurochenodeoxycholic Acid/*pharmacology ; Time-to-Treatment ; Treatment Failure ; Ursodeoxycholic Acid/*pharmacology ; }, abstract = {Prion diseases are a group of neurodegenerative diseases associated with the misfolding of the cellular prion protein (PrP[C]) into the infectious form (PrP[Sc]). There are currently no treatments for prion disease. Bile acids have the ability to protect hepatocytes from apoptosis and are neuroprotective in animal models of other protein-folding neurodegenerative diseases, including Huntington's, Parkinson's, and Alzheimer's disease. Importantly, bile acids are approved for clinical use in patients with cirrhosis and have recently been shown to be safe and possibly effective in pilot trials of patients with amyotrophic lateral sclerosis (ALS). We previously reported that the bile acid ursodeoxycholic acid (UDCA), given early in disease, prolonged incubation periods in male RML-infected mice. Here, we expand on this result to include tauro-ursodeoxycholic acid (TUDCA) treatment trials and delayed UDCA treatment. We demonstrate that despite a high dose of TUDCA given early in disease, there was no significant difference in incubation periods between treated and untreated cohorts, regardless of sex. In addition, delayed treatment with a high dose of UDCA resulted in a significant shortening of the average survival time for both male and female mice compared to their sex-matched controls, with evidence of increased BiP, a marker of apoptosis, in treated female mice. Our findings suggest that treatment with high-dose TUDCA provides no therapeutic benefit and that delayed treatment with high-dose UDCA is ineffective and could worsen outcomes.}, }
@article {pmid29782468, year = {2018}, author = {Mazzini, L and Mogna, L and De Marchi, F and Amoruso, A and Pane, M and Aloisio, I and Cionci, NB and Gaggìa, F and Lucenti, A and Bersano, E and Cantello, R and Di Gioia, D and Mogna, G}, title = {Potential Role of Gut Microbiota in ALS Pathogenesis and Possible Novel Therapeutic Strategies.}, journal = {Journal of clinical gastroenterology}, volume = {52 Suppl 1, Proceedings from the 9th Probiotics, Prebiotics and New Foods, Nutraceuticals and Botanicals for Nutrition &amp; Human and Microbiota Health Meeting, held in Rome, Italy from September 10 to 12, 2017}, number = {}, pages = {S68-S70}, doi = {10.1097/MCG.0000000000001042}, pmid = {29782468}, issn = {1539-2031}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*microbiology/therapy ; Bifidobacterium/growth &amp; development ; Colony Count, Microbial ; Double-Blind Method ; Enterobacteriaceae/growth &amp; development ; Escherichia coli/growth &amp; development ; Feces/microbiology ; Female ; *Gastrointestinal Microbiome ; Gastrointestinal Tract/microbiology ; Humans ; Lactobacillus ; Male ; Phenotype ; Probiotics/*administration &amp; dosage ; Yeasts/growth &amp; development ; }, abstract = {BACKGROUND: Recent preclinical studies suggest that dysfunction of gastrointestinal tract may play a role in amyotrophic lateral sclerosis (ALS) pathogenesis through a modification of the gut microbiota brain axis. Our study is the first focused on microbiota analysis in ALS patients.<br><br>AIM: Our aim was to study the main human gut microbial groups and the overall microbial diversity in ALS and healthy subjects. Moreover we have examined the influence of a treatment with a specific bacteriotherapy composed of Lactobacillus strains (Lactobacillus fermentum, Lactobacillus delbrueckii, Lactobacillus plantarum, Lactobacillus salivarius) acting on the gastrointestinal barrier.<br><br>METHODS: We enrolled 50 ALS patients and 50 healthy controls, matched for sex, age, and origin. Fecal samples were used for total genomic DNA extraction. Enterobacteria, Bifidobacterium spp., Lactobacillus spp., Clostridium sensu stricto, Escherichia coli and yeast were quantified using quantitative polymerase chain reaction approach. Denaturing gradient gel electrophoresis analyses were performed to investigate total eubacteria and yeasts populations. Patients were randomized to double-blind treatment either with microorganisms or placebo for 6 months and monitored for clinical progression and microbiota composition.<br><br>RESULTS: The comparison between ALS subjects and healthy group revealed a variation in the intestinal microbial composition with a higher abundance of E. coli and enterobacteria and a low abundance of total yeast in patients. Polymerase chain reaction denaturing gradient gel electrophoresis analysis showed a cluster distinction between the bacterial profiles of ALS patients and the healthy subjects. The complexity of the profiles in both cases may indicate that a real dysbiosis status is not evident in the ALS patients although differences between healthy and patients exist. The effects of the progression of the disease and of the bacteriotherapy on the bacterial and yeast populations are currently in progress.<br><br>CONCLUSIONS: Our preliminary results confirm that there is a difference in the microbiota profile in ALS patients.}, }
@article {pmid29777602, year = {2018}, author = {Silberberg, AA and Robetto, J and Achával, M}, title = {[Suspension of Respiratory Support in Patients with Amyotrophic Lateral Sclerosis].}, journal = {Cuadernos de bioetica : revista oficial de la Asociacion Espanola de Bioetica y Etica Medica}, volume = {29}, number = {96}, pages = {137-146}, pmid = {29777602}, issn = {1132-1989}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Respiration, Artificial/*ethics ; Withholding Treatment/*ethics ; }, abstract = {Decision making in advanced Amyotrophic Lateral Sclerosis (ALS) patients keeps on being a controversial issue. The aim of this work is to discuss ethical implications of withdrawing respiratory support treatment in patients with ALS. Through a bibliographic search on Pubmed database (2010-2016) we investigated whether or not the use of Non-Invasive Ventilation (NIV) and Mechanical Ventilation (MV) would increase survival and quality of life. We included 38 review articles. From these papers, results and ethical implications of initiating and mainly withdrawing respiratory support were analyzed. Survival time increased with NIV and with MV. Quality of life, above all according to physiological criteria, improved with NIV but regarding MV it remained controversial. Implementation and future withdrawal of MV seemed open to medical and ethical discussion. From a perspective of the intrinsic dignity of every human being, whatever its quality of life was, and knowing that no effective therapies for the underlying disease are available, the decision to remove MV in a patient with advanced ALS requires: knowledge of the will of the patient and, above all, evaluating whether this respiratory support measure is becoming objectively disproportionate.}, }
@article {pmid29773756, year = {2018}, author = {Maimon, R and Ionescu, A and Bonnie, A and Sweetat, S and Wald-Altman, S and Inbar, S and Gradus, T and Trotti, D and Weil, M and Behar, O and Perlson, E}, title = {miR126-5p Downregulation Facilitates Axon Degeneration and NMJ Disruption via a Non-Cell-Autonomous Mechanism in ALS.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {38}, number = {24}, pages = {5478-5494}, pmid = {29773756}, issn = {1529-2401}, support = {R01 NS044292/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Axons/metabolism/pathology ; Down-Regulation ; Gene Expression Regulation ; Humans ; Mice ; MicroRNAs/genetics/*metabolism ; Nerve Degeneration/genetics/*metabolism/pathology ; Neuromuscular Junction/metabolism/pathology ; Neuropilin-1/biosynthesis/genetics ; Semaphorin-3A/biosynthesis/genetics ; }, abstract = {Axon degeneration and disruption of neuromuscular junctions (NMJs) are key events in amyotrophic lateral sclerosis (ALS) pathology. Although the disease's etiology is not fully understood, it is thought to involve a non-cell-autonomous mechanism and alterations in RNA metabolism. Here, we identified reduced levels of miR126-5p in presymptomatic ALS male mice models, and an increase in its targets: axon destabilizing Type 3 Semaphorins and their coreceptor Neuropilins. Using compartmentalized in vitro cocultures, we demonstrated that myocytes expressing diverse ALS-causing mutations promote axon degeneration and NMJ dysfunction, which were inhibited by applying Neuropilin1 blocking antibody. Finally, overexpressing miR126-5p is sufficient to transiently rescue axon degeneration and NMJ disruption both in vitro and in vivo Thus, we demonstrate a novel mechanism underlying ALS pathology, in which alterations in miR126-5p facilitate a non-cell-autonomous mechanism of motor neuron degeneration in ALS.SIGNIFICANCE STATEMENT Despite some progress, currently no effective treatment is available for amyotrophic lateral sclerosis (ALS). We suggest a novel regulatory role for miR126-5p in ALS and demonstrate, for the first time, a mechanism by which alterations in miR126-5p contribute to axon degeneration and NMJ disruption observed in ALS. We show that miR126-5p is altered in ALS models and that it can modulate Sema3 and NRP protein expression. Furthermore, NRP1 elevations in motor neurons and muscle secretion of Sema3A contribute to axon degeneration and NMJ disruption in ALS. Finally, overexpressing miR126-5p is sufficient to transiently rescue NMJ disruption and axon degeneration both in vitro and in vivo.}, }
@article {pmid29772957, year = {2019}, author = {Slutzky, MW}, title = {Brain-Machine Interfaces: Powerful Tools for Clinical Treatment and Neuroscientific Investigations.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {25}, number = {2}, pages = {139-154}, pmid = {29772957}, issn = {1089-4098}, support = {R01NS09474/NS/NINDS NIH HHS/United States ; R01 NS094748/NS/NINDS NIH HHS/United States ; F32 NS009474/NS/NINDS NIH HHS/United States ; UL1 RR025741/RR/NCRR NIH HHS/United States ; UL1 TR001422/TR/NCATS NIH HHS/United States ; K08 NS060223/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain/*physiology/physiopathology ; *Brain-Computer Interfaces ; Humans ; Learning ; Membrane Potentials ; *Movement ; Nervous System Diseases/*rehabilitation ; }, abstract = {Brain-machine interfaces (BMIs) have exploded in popularity in the past decade. BMIs, also called brain-computer interfaces, provide a direct link between the brain and a computer, usually to control an external device. BMIs have a wide array of potential clinical applications, ranging from restoring communication to people unable to speak due to amyotrophic lateral sclerosis or a stroke, to restoring movement to people with paralysis from spinal cord injury or motor neuron disease, to restoring memory to people with cognitive impairment. Because BMIs are controlled directly by the activity of prespecified neurons or cortical areas, they also provide a powerful paradigm with which to investigate fundamental questions about brain physiology, including neuronal behavior, learning, and the role of oscillations. This article reviews the clinical and neuroscientific applications of BMIs, with a primary focus on motor BMIs.}, }
@article {pmid29766296, year = {2018}, author = {Kadi, AA and Amer, SM and Darwish, HW and Attwa, MW}, title = {Characterization of in vivo metabolites in rat urine following an oral dose of masitinib by liquid chromatography tandem mass spectrometry.}, journal = {Chemistry Central journal}, volume = {12}, number = {1}, pages = {61}, pmid = {29766296}, issn = {1752-153X}, support = {Research Group Project No. RGP- 322//Deanship of Scientific Research at the King Saud University/ ; }, abstract = {Masitinib (MST) is an orally administered drug that targets mast cells and macrophages, important cells for immunity, by inhibiting a limited number of tyrosine kinases. It is currently registered in Europe and USA for the treatment of mast cell tumors in dogs. AB Science announced that the European Medicines Agency has accepted a conditional marketing authorization application for MST to treat amyotrophic lateral sclerosis. In our work, we focused on studying in vivo metabolism of MST in Sprague-Dawley rats. Single oral dose of MST (33 mg kg[-1]) was given to Sprague-Dawley rats (kept in metabolic cages) using oral gavage. Urine was collected and filtered at 0, 6, 12, 18, 24, 48, 72 and 96 h from MST dosing. An equal amount of ACN was added to urine samples. Both organic and aqueous layers were injected into liquid chromatography-tandem mass spectrometry (LC-MS/MS) to detect in vivo phase I and phase II MST metabolites. The current work reports the identification and characterization of twenty in vivo phase I and four in vivo phase II metabolites of MST by LC-MS/MS. Phase I metabolic pathways were reduction, demethylation, hydroxylation, oxidative deamination, oxidation and N-oxide formation. Phase II metabolic pathways were the direct conjugation of MST, N-demethyl metabolites and oxidative metabolites with glucuronic acid. Part of MST dose was excreted unchanged in urine. The literature review showed no previous articles have been made on in vivo metabolism of MST or detailed structural identification of the formed in vivo phase I and phase II metabolites.}, }
@article {pmid29760648, year = {2018}, author = {Trostchansky, A and Mastrogiovanni, M and Miquel, E and Rodríguez-Bottero, S and Martínez-Palma, L and Cassina, P and Rubbo, H}, title = {Profile of Arachidonic Acid-Derived Inflammatory Markers and Its Modulation by Nitro-Oleic Acid in an Inherited Model of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {11}, number = {}, pages = {131}, pmid = {29760648}, issn = {1662-5099}, abstract = {The lack of current treatments for amyotrophic lateral sclerosis (ALS) highlights the need of a comprehensive understanding of the biological mechanisms of the disease. A consistent neuropathological feature of ALS is the extensive inflammation around motor neurons and axonal degeneration, evidenced by accumulation of reactive astrocytes and activated microglia. Final products of inflammatory processes may be detected as a screening tool to identify treatment response. Herein, we focus on (a) detection of arachidonic acid (AA) metabolization products by lipoxygenase (LOX) and prostaglandin endoperoxide H synthase in SOD1[G93A] mice and (b) evaluate its response to the electrophilic nitro-oleic acid (NO2-OA). Regarding LOX-derived products, a significant increase in 12-hydroxyeicosatetraenoic acid (12-HETE) levels was detected in SOD1[G93A] mice both in plasma and brain whereas no changes were observed in age-matched non-Tg mice at the onset of motor symptoms (90 days-old). In addition, 15-hydroxyeicosatetraenoic acid (15-HETE) levels were greater in SOD1[G93A] brains compared to non-Tg. Prostaglandin levels were also increased at day 90 in plasma from SOD1[G93A] compared to non-Tg being similar in both types of animals at later stages of the disease. Administration of NO2-OA 16 mg/kg, subcutaneously (s/c) three times a week to SOD1[G93A] female mice, lowered the observed increase in brain 12-HETE levels compared to the non-nitrated fatty acid condition, and modified many others inflammatory markers. In addition, NO2-OA significantly improved grip strength and rotarod performance compared to vehicle or OA treated animals. These beneficial effects were associated with increased hemeoxygenase 1 (HO-1) expression in the spinal cord of treated mice co-localized with reactive astrocytes. Furthermore, significant levels of NO2-OA were detected in brain and spinal cord from NO2-OA -treated mice indicating that nitro-fatty acids (NFA) cross brain-blood barrier and reach the central nervous system to induce neuroprotective actions. In summary, we demonstrate that LOX-derived oxidation products correlate with disease progression. Overall, we are proposing that key inflammatory mediators of AA-derived pathways may be useful as novel footprints of ALS onset and progression as well as NO2-OA as a promising therapeutic compound.}, }
@article {pmid29755644, year = {2018}, author = {Asai, H and Inoue, K and Sakuma, E and Shinohara, Y and Ueki, T}, title = {Potential implication of SGK1-dependent activity change in BV-2 microglial cells.}, journal = {International journal of physiology, pathophysiology and pharmacology}, volume = {10}, number = {2}, pages = {115-123}, pmid = {29755644}, issn = {1944-8171}, abstract = {It has recently been established that microglial activation is involved in the pathophysiology of various neurological and psychiatric disorders such as amyotrophic lateral sclerosis and schizophrenia. The pathological molecular machineries underlying microglial activation and its accelerating molecules have been precisely described in the diseased central nervous system (CNS). However, to date, the details of physiological mechanism, which represses microglial activation, are still to be elucidated. Our latest report demonstrated that serum- and glucocorticoid-inducible kinases (SGK1 and SGK3) were expressed in multiple microglial cell lines, and their inhibitor enhanced the toxic effect of lipopolysaccharide on microglial production of inflammatory substances such as TNFα and iNOS. In the present report, we prepared SGK1-lacked microglial cell line (BV-2) and demonstrated that deficiency of SGK1 in microglia induced its toxic conversion, in which it took amoeboid morphology characteristic of reactive microglia, increased CD68 expression, quickened its proliferation, and showed higher susceptibility to ATP and subsequent cell death. Our data indicate that SGK1 plays pivotal roles in inhibiting its pathological activation, and suggest its potential function as a therapeutic target for the treatment of various disorders related to the inflammation in the CNS.}, }
@article {pmid29743351, year = {2018}, author = {Strnadel, J and Carromeu, C and Bardy, C and Navarro, M and Platoshyn, O and Glud, AN and Marsala, S and Kafka, J and Miyanohara, A and Kato, T and Tadokoro, T and Hefferan, MP and Kamizato, K and Yoshizumi, T and Juhas, S and Juhasova, J and Ho, CS and Kheradmand, T and Chen, P and Bohaciakova, D and Hruska-Plochan, M and Todd, AJ and Driscoll, SP and Glenn, TD and Pfaff, SL and Klima, J and Ciacci, J and Curtis, E and Gage, FH and Bui, J and Yamada, K and Muotri, AR and Marsala, M}, title = {Survival of syngeneic and allogeneic iPSC-derived neural precursors after spinal grafting in minipigs.}, journal = {Science translational medicine}, volume = {10}, number = {440}, pages = {}, doi = {10.1126/scitranslmed.aam6651}, pmid = {29743351}, issn = {1946-6242}, support = {P01 HL066941/HL/NHLBI NIH HHS/United States ; R21 MH107771/MH/NIMH NIH HHS/United States ; R01 MH094753/MH/NIMH NIH HHS/United States ; U19 MH107367/MH/NIMH NIH HHS/United States ; R01 OD018272/OD/NIH HHS/United States ; }, mesh = {Aging ; Animals ; Cell Differentiation ; Cellular Reprogramming ; Chronic Disease ; Fibroblasts/cytology ; Gene Expression Regulation ; Immune Tolerance ; Immunity, Humoral ; Immunosuppression Therapy ; Induced Pluripotent Stem Cells/*cytology ; Neostriatum/pathology ; Neural Stem Cells/cytology/*transplantation ; Neurons/cytology ; Rats ; Skin/cytology ; Spinal Cord/*transplantation ; Spinal Cord Injuries/pathology/therapy ; Survival Analysis ; Swine ; Swine, Miniature ; Transplantation, Homologous ; Transplantation, Isogeneic ; }, abstract = {The use of autologous (or syngeneic) cells derived from induced pluripotent stem cells (iPSCs) holds great promise for future clinical use in a wide range of diseases and injuries. It is expected that cell replacement therapies using autologous cells would forego the need for immunosuppression, otherwise required in allogeneic transplantations. However, recent studies have shown the unexpected immune rejection of undifferentiated autologous mouse iPSCs after transplantation. Whether similar immunogenic properties are maintained in iPSC-derived lineage-committed cells (such as neural precursors) is relatively unknown. We demonstrate that syngeneic porcine iPSC-derived neural precursor cell (NPC) transplantation to the spinal cord in the absence of immunosuppression is associated with long-term survival and neuronal and glial differentiation. No tumor formation was noted. Similar cell engraftment and differentiation were shown in spinally injured transiently immunosuppressed swine leukocyte antigen (SLA)-mismatched allogeneic pigs. These data demonstrate that iPSC-NPCs can be grafted into syngeneic recipients in the absence of immunosuppression and that temporary immunosuppression is sufficient to induce long-term immune tolerance after NPC engraftment into spinally injured allogeneic recipients. Collectively, our results show that iPSC-NPCs represent an alternative source of transplantable NPCs for the treatment of a variety of disorders affecting the spinal cord, including trauma, ischemia, or amyotrophic lateral sclerosis.}, }
@article {pmid29736243, year = {2018}, author = {Kakuda, TN and McClure, MW and Westland, C and Vuong, J and Homery, MC and Poizat, G and Viguerie, L and Denot, C and Patat, A and Zhang, Q and Hui, J and Apelian, D and Smith, DB and Chanda, SM and Fry, J}, title = {Pharmacokinetics, safety, and tolerability of the 2- and 3-direct-acting antiviral combination of AL-335, odalasvir, and simeprevir in healthy subjects.}, journal = {Pharmacology research &amp; perspectives}, volume = {6}, number = {3}, pages = {e00395}, pmid = {29736243}, issn = {2052-1707}, mesh = {Administration, Oral ; Adult ; Alanine/adverse effects/*analogs &amp; derivatives/pharmacokinetics ; Antiviral Agents/adverse effects/*pharmacokinetics ; Area Under Curve ; Benzimidazoles/adverse effects/*pharmacokinetics ; Carbamates/adverse effects/*pharmacokinetics ; Drug Administration Schedule ; Drug Therapy, Combination/*adverse effects ; Female ; Healthy Volunteers ; Humans ; Indoles/adverse effects/*pharmacokinetics ; Male ; Middle Aged ; Phosphoramides ; Prodrugs/adverse effects/*pharmacokinetics ; Simeprevir/adverse effects/*pharmacokinetics ; Uridine/adverse effects/*analogs &amp; derivatives/pharmacokinetics ; Viral Nonstructural Proteins/antagonists &amp; inhibitors ; Young Adult ; }, abstract = {This Phase I, open-label, two-group, fixed-sequence study evaluated the pharmacokinetics and safety of AL-335, odalasvir, and simeprevir in healthy subjects. Group 1 (n = 16) received AL-335 800 mg once daily (QD) (days 1-3, 11-13, and 21-23), simeprevir 150 mg QD (days 4-23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15-23). Group 2 (n = 16) received the same AL-335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5-23) and simeprevir 150 mg QD (days 14-23). Blood samples were collected to determine plasma concentrations of AL-335 (prodrug) and its metabolites, ALS-022399 (monophosphate precursor) and ALS-022227 (parent nucleoside), odalasvir, and simeprevir. Thirty-two subjects were enrolled. Odalasvir and simeprevir given alone, or in combination, increased AL-335 area under plasma concentration-time curve over 24 hours (AUC 0-24 h) 3-, 4-, and 7- to 8-fold, respectively; ALS-022399 AUC 0-24 h increased 2-, 2-, and 3-fold, respectively. Simeprevir had no effect on ALS-022227 AUC 0-24 h, whereas odalasvir with/without simeprevir increased ALS-022227 AUC 0-24 h 1.5-fold. AL-335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC 0-24 h increased 1.5- to 2-fold for both drugs when coadministered irrespective of AL-335 coadministration. Study medications were well tolerated with no serious adverse events. One subject prematurely discontinued study drugs (unrelated event). This study defined the preliminary pharmacokinetic and safety profiles of the combination of AL-335, odalasvir, and simeprevir in healthy subjects. These data support the further evaluation of this combination for the treatment of chronic hepatitis C virus infection.}, }
@article {pmid29735472, year = {2018}, author = {Wicks, P and Mack Thorley, E and Simacek, K and Curran, C and Emmas, C}, title = {Scaling PatientsLikeMe via a "Generalized Platform" for Members with Chronic Illness: Web-Based Survey Study of Benefits Arising.}, journal = {Journal of medical Internet research}, volume = {20}, number = {5}, pages = {e175}, pmid = {29735472}, issn = {1438-8871}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology ; Chronic Disease ; Cross-Sectional Studies ; Female ; Humans ; Internet/*instrumentation ; Male ; Middle Aged ; Patient Participation/*methods ; Retrospective Studies ; Social Support ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Launched in 2006 for patients with amyotrophic lateral sclerosis, PatientsLikeMe is an online community offering patient-reported outcomes, symptom tracking, and social features. Every member of the site can see all the data reported by every other member, view aggregated reports, identify "patients like them," and learn about treatment options in order to live better with their condition. In previous studies, members reported benefits such as improved condition knowledge, increased medication adherence, and better management of side effects. However, the site evolved in 2011 from condition-specific "vertical" communities consisting only of people with the same disease to a "generalized platform," in which every patient could connect with every other patient regardless of condition and with generic, rather than condition-specific, data tools. Some, but not all, communities received further custom tracking tools.<br><br>OBJECTIVE: We aimed to understand (1) whether members of PatientsLikeMe using the generalized platform still reported similar benefits and (2) assess factors associated with benefits, such as community customization, site use, and patient activation.<br><br>METHODS: A cross-sectional retrospective custom survey was fielded to 377,625 members between 2016 and 2017 including the Patient Activation Measure (PAM). A benefit index was developed for comparability across conditions.<br><br>RESULTS: The invitation was viewed by 26,048 members of whom 11,915 did not respond, 5091 opted out, 1591 provided partial data, and 17 were screened out. Complete responses were received from 7434 participants. Users perceived greatest benefit in understanding how their condition may affect them (4530/6770, 66.91% participants, excluding "does not apply" answers), understanding what might help them live better with their condition (4247/6750, 62.92%), which treatments were available (4143/6898, 60.06%), understanding treatment side effects (4182/6902, 60.59%), and important factors in making treatment decisions (3919/6813, 57.52%). The benefit index was 29% higher for the "most activated" patients (PAM level 4 vs PAM level 1; relative risk [RR]=1.29, P<.001), 21% higher for conditions with some community customization versus none (RR=1.21, P<.001), and 11% higher in those using the site most often versus least (RR=1.11, P<.001).<br><br>CONCLUSIONS: Members of the generalized platform reported a range of benefits related to improved knowledge and understanding of their condition and treatment management. Condition-specific customization may improve their experience still further. Future studies will explore longitudinal changes to patient activation.}, }
@article {pmid29734735, year = {2018}, author = {Metaxakis, A and Ploumi, C and Tavernarakis, N}, title = {Autophagy in Age-Associated Neurodegeneration.}, journal = {Cells}, volume = {7}, number = {5}, pages = {}, pmid = {29734735}, issn = {2073-4409}, abstract = {The elimination of abnormal and dysfunctional cellular constituents is an essential prerequisite for nerve cells to maintain their homeostasis and proper function. This is mainly achieved through autophagy, a process that eliminates abnormal and dysfunctional cellular components, including misfolded proteins and damaged organelles. Several studies suggest that age-related decline of autophagy impedes neuronal homeostasis and, subsequently, leads to the progression of neurodegenerative disorders due to the accumulation of toxic protein aggregates in neurons. Here, we discuss the involvement of autophagy perturbation in neurodegeneration and present evidence indicating that upregulation of autophagy holds potential for the development of therapeutic interventions towards confronting neurodegenerative diseases in humans.}, }
@article {pmid29732485, year = {2019}, author = {Esparza, JL and Gómez, M and Domingo, JL}, title = {Role of Melatonin in Aluminum-Related Neurodegenerative Disorders: a Review.}, journal = {Biological trace element research}, volume = {188}, number = {1}, pages = {60-67}, doi = {10.1007/s12011-018-1372-4}, pmid = {29732485}, issn = {1559-0720}, mesh = {Aluminum/metabolism/*toxicity ; Animals ; Antioxidants/*therapeutic use ; Humans ; Melatonin/*therapeutic use ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neurotoxicity Syndromes/drug therapy/metabolism ; Oxidative Stress/drug effects ; }, abstract = {Aluminum (Al), a potentially neurotoxic element, provokes various adverse effects on human health such as dialysis dementia, osteomalacia, and microcytic anemia. It has been also associated with serious neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, and Parkinsonism dementia of Guam. The "aluminum hypothesis" of AD assumes that the metal complexes can potentiate the rate of aggregation of amyloid-β (Aβ), enhancing the toxicity of this peptide, and being able of contributing to the pathogenesis of AD. It has been supported by a number of analytical, epidemiological, and neurotoxicological studies. On the other hand, melatonin (Mel) is a potent direct free radical scavenger and indirect antioxidant, which acts increasing the activity of important related antioxidant enzymes, and preventing oxidative stress and cell death of neurons exposed to Aβ-induced neurotoxicity. Therefore, Mel might be useful in the treatment of AD by reducing the Aβ generation and by inhibiting mitochondrial cell death pathways. The present review on the role of Mel in Al-related neurodegenerative disorders concludes that the protective effects of this hormone, together with its low toxicity, support the administration of Mel as a potential supplement in the treatment of neurological disorders, in which oxidative stress is involved.}, }
@article {pmid29725842, year = {2018}, author = {Mélé, N and Berzero, G and Maisonobe, T and Salachas, F and Nicolas, G and Weiss, N and Beaudonnet, G and Ducray, F and Psimaras, D and Lenglet, T}, title = {Motor neuron disease of paraneoplastic origin: a rare but treatable condition.}, journal = {Journal of neurology}, volume = {265}, number = {7}, pages = {1590-1599}, pmid = {29725842}, issn = {1432-1459}, mesh = {Action Potentials/physiology ; Adult ; Aged ; Aged, 80 and over ; Cytokines/cerebrospinal fluid ; Electromyography ; Female ; Humans ; Immunoglobulins, Intravenous/therapeutic use ; Immunologic Factors/therapeutic use ; Male ; Middle Aged ; Motor Neuron Disease/*diagnosis/*etiology/therapy ; Neurologic Examination ; Paraneoplastic Syndromes, Nervous System/*complications/therapy ; Retrospective Studies ; }, abstract = {Paraneoplastic motor neuron disorders (MND) are rare conditions; their exact clinical and electrophysiological phenotype have not been exhaustively described yet. The purpose of this study is to depict the main characteristics of paraneoplastic MND to highlight the features that may allow its diagnosis. Based on the description of eight original cases, and on the revision of 21 patients identified from a systematic review of the literature, the main features of paraneoplastic MND can be summarized as follows: (1) subacute; (2) lower motor neuron syndrome, associated or not with upper motor neuron involvement; (3) predominant asymmetric upper limb involvement; (4) presence of other non-motor neurological manifestations, including sensory neuronopathy; (5) signs of inflammation in the cerebrospinal fluid (CSF); (6) neurological improvement or stabilization after immunotherapy and tumor treatment. The diagnosis of paraneoplastic MND may be difficult because of its rarity, the absence of pathognomonic clinical features, and the frequent absence of prior tumor history. However, it is of capital importance to correctly identify patients with paraneoplastic MND, as this represents a potentially treatable condition. In the presence of subacute lower motor neuron impairment, especially when atypical clinical features for degenerative MND or other non-motor neurological manifestations are present, we recommend testing for onconeural antibodies. In the case, the search for onconeural antibodies is negative, but it exists a strong clinical suspicion for a paraneoplastic etiology; CSF analysis and total-body 18FDG-PET/CT imaging should be performed to circumstantiate diagnosis.}, }
@article {pmid29723609, year = {2018}, author = {Kurz, MC and Schmicker, RH and Leroux, B and Nichol, G and Aufderheide, TP and Cheskes, S and Grunau, B and Jasti, J and Kudenchuk, P and Vilke, GM and Buick, J and Wittwer, L and Sahni, R and Straight, R and Wang, HE and , }, title = {Advanced vs. Basic Life Support in the Treatment of Out-of-Hospital Cardiopulmonary Arrest in the Resuscitation Outcomes Consortium.}, journal = {Resuscitation}, volume = {128}, number = {}, pages = {132-137}, doi = {10.1016/j.resuscitation.2018.04.031}, pmid = {29723609}, issn = {1873-1570}, support = {U01 HL077863/HL/NHLBI NIH HHS/United States ; }, mesh = {Adult ; Advanced Cardiac Life Support/methods/*mortality ; Aged ; Aged, 80 and over ; Cardiopulmonary Resuscitation/methods/mortality ; Defibrillators ; Electric Countershock ; Emergency Medical Services/statistics &amp; numerical data ; Female ; Humans ; Male ; Middle Aged ; Out-of-Hospital Cardiac Arrest/*mortality/therapy ; Retrospective Studies ; Time Factors ; }, abstract = {BACKGROUND: Prior observational studies suggest no additional benefit from advanced life support (ALS) when compared with providing basic life support (BLS) for patients with out-of-hospital cardiac arrest (OHCA). We compared the association of ALS care with OHCA outcomes using prospective clinical data from the Resuscitation Outcomes Consortium (ROC).<br><br>METHODS: Included were consecutive adults OHCA treated by participating emergency medical services (EMS) agencies between June 1, 2011, and June 30, 2015. We defined BLS as receipt of cardiopulmonary resuscitation (CPR) and/or automated defibrillation and ALS as receipt of an advanced airway, manual defibrillation, or intravenous drug therapy. We compared outcomes among patients receiving: 1) BLS-only; 2) BLS&#x202f;+&#x202f;late ALS; 3) BLS&#x202f;+&#x202f;early ALS; and 4) ALS-first care. Using multivariable logistic regression, we evaluated the associations between level of care and return of spontaneous circulation (ROSC), survival to hospital discharge, and survival with good functional status, adjusting for age, sex, witnessed arrest, bystander CPR, shockable initial rhythm, public location, EMS response time, CPR quality, and ROC site.<br><br>RESULTS: Among 35,065 patients with OHCA, characteristics were median age 68 years (IQR 56-80), male 63.9%, witnessed arrest 43.8%, bystander CPR 50.6%, and shockable initial rhythm 24.2%. Care delivered was: 4.0% BLS-only, 31.5% BLS&#x202f;+&#x202f;late ALS, 17.2% BLS&#x202f;+&#x202f;early ALS, and 47.3% ALS-first. ALS care with or without initial BLS care was independently associated with increased adjusted ROSC and survival to hospital discharge unless delivered greater than 6&#x202f;min after BLS arrival (BLS&#x202f;+&#x202f;late ALS). Regardless of when it was delivered, ALS care was not associated with significantly greater functional outcome.<br><br>CONCLUSION: ALS care was associated with survival to hospital discharge when provided initially or within six minutes of BLS arrival. ALS care, with or without initial BLS care, was associated with increased ROSC, however it was not associated with functional outcome.}, }
@article {pmid29713302, year = {2018}, author = {Oberstadt, MCF and Esser, P and Classen, J and Mehnert, A}, title = {Alleviation of Psychological Distress and the Improvement of Quality of Life in Patients With Amyotrophic Lateral Sclerosis: Adaptation of a Short-Term Psychotherapeutic Intervention.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {231}, pmid = {29713302}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is inevitably fatal. To be diagnosed with a terminal illness such as ALS deeply affects one's personal existence and goes along with significant changes regarding the physical, emotional, and social domains of the patients' life. ALS patients have to face a rapidly debilitating physical decline which restrains mobility and impairs all activities of daily living. This progressive loss of autonomy may lead to a sense of hopelessness and loss of quality of life, which in turn may even result in thoughts about physician-assisted suicide. Here, we would like to propose a psychotherapeutic manualized, individual, semi-structured intervention to relieve distress and promote psychological well-being in ALS patients. This short-term intervention was originally developed for advanced cancer patients. "Managing Cancer and Living Meaningfully (CALM)" focuses on the four dimensions: (i) symptom management and communication with healthcare providers, (ii) changes in self and relations with close others, (iii) spirituality, sense of meaning and purpose and (iv) thinking of the future, hope, and mortality. We suggest to supplement the concept by two additional dimensions which take into account specific issues of ALS patients: (v) communication skills, and (vi) emotional expression and control. This therapeutic concept named "ManagIng Burden in ALS and Living Meaningfully (mi-BALM)" may be a further treatment option to help improving quality of life of ALS patients.}, }
@article {pmid29704642, year = {2018}, author = {Yang, T and Ferrill, L and Gallant, L and McGillicuddy, S and Fernandes, T and Schields, N and Bai, S}, title = {Verapamil and riluzole cocktail liposomes overcome pharmacoresistance by inhibiting P-glycoprotein in brain endothelial and astrocyte cells: A potent approach to treat amyotrophic lateral sclerosis.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {120}, number = {}, pages = {30-39}, doi = {10.1016/j.ejps.2018.04.026}, pmid = {29704642}, issn = {1879-0720}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/*antagonists &amp; inhibitors/metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Astrocytes/*drug effects/metabolism/pathology ; Brain/*drug effects/metabolism/pathology ; Cell Line ; Dose-Response Relationship, Drug ; Drug Combinations ; Drug Liberation ; Drug Resistance/*drug effects ; Endothelial Cells/*drug effects/metabolism/pathology ; Kinetics ; Liposomes ; Mice ; Neuroprotective Agents/administration &amp; dosage/metabolism/*pharmacology ; Particle Size ; Riluzole/administration &amp; dosage/metabolism/*pharmacology ; Solubility ; Verapamil/administration &amp; dosage/*pharmacology ; }, abstract = {Riluzole is currently one of two approved medications for the treatment of amyotrophic lateral sclerosis (ALS). However, brain disposition of riluzole, as a substrate of P-glycoprotein (P-gp), is limited by the efflux transporters at the blood-brain barrier (BBB). We propose to develop a liposomal co-delivery system that could effectively transport riluzole to brain cells by reducing efflux pumps with a P-gp inhibitor, verapamil. Riluzole and verapamil cocktail liposomes were prepared by lipid film hydration. The average particle size of cocktail liposomes was 194.3 ± 6.0 nm and their polydispersity index (PDI) was 0.272 ± 0.017. The encapsulation efficiencies of verapamil and riluzole in the cocktail liposomes were 86.0 ± 1.4% and 85.6 ± 1.1%, respectively. The drug release from cocktail liposomes after 8 h in PBS at 37 °C was 78.4 ± 6.2% of riluzole and 76.7 ± 3.8% of verapamil. The average particle size of liposomes did not show significant changes at 4 °C after three months. Verapamil cocktail liposomes inhibited P-gp levels measured by western blotting in dose and time-dependent manners in brain endothelial bEND.3 cells. Increased drug efflux transporters were detected in bEND.3 and astrocytes C8D1A cells, promoted by tumor necrosis factor (TNF-α) or hydrogen peroxide (H2O2). Restored accumulations of riluzole and fluorescent dye rhodamine 123 were observed in bEND.3 cells after treatments with cocktail liposomes. It indicated that inhibitory potential of co-delivery liposome system towards P-gp could mediate the transport of both P-gp substrates. Verapamil and riluzole co-loaded liposomes may be used to overcome pharmacoresistance of riluzole for improving ALS therapy.}, }
@article {pmid29702606, year = {2018}, author = {Sobuś, A and Baumert, B and Litwińska, Z and Gołąb-Janowska, M and Stępniewski, J and Kotowski, M and Pius-Sadowska, E and Kawa, MP and Gródecka-Szwajkiewicz, D and Peregud-Pogorzelski, J and Dulak, J and Nowacki, P and Machaliński, B}, title = {Safety and Feasibility of Lin- Cells Administration to ALS Patients: A Novel View on Humoral Factors and miRNA Profiles.}, journal = {International journal of molecular sciences}, volume = {19}, number = {5}, pages = {}, pmid = {29702606}, issn = {1422-0067}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*immunology/*therapy ; Cerebrospinal Fluid/chemistry ; Female ; *Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/chemistry/immunology ; Humans ; Immunity, Humoral/*immunology ; Male ; MicroRNAs/blood/cerebrospinal fluid/*genetics ; Middle Aged ; Prospective Studies ; Spinal Puncture ; Subarachnoid Space ; Transcriptome/*genetics ; Transplantation, Autologous ; }, abstract = {Therapeutic options for amyotrophic lateral sclerosis (ALS) are still limited. Great hopes, however, are placed in growth factors that show neuroprotective abilities (e.g., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF)) and in the immune modulating features, in particular, the anti-inflammatory effects. In our study we aimed to investigate whether a bone marrow-derived lineage-negative (Lin-) cells population, after autologous application into cerebrospinal fluid (CSF), is able to produce noticeable concentrations of trophic factors and inflammatory-related proteins and thus influence the clinical course of ALS. To our knowledge, the evaluation of Lin- cells transplantation for ALS treatment has not been previously reported. Early hematopoietic Lin- cells were isolated from twelve ALS patients’ bone marrow, and later, the suspension of cells was administered into the subarachnoid space by lumbar puncture. Concentrations of selected proteins in the CSF and plasma were quantified by multiplex fluorescent bead-based immunoassays at different timepoints post-transplantation. We also chose microRNAs (miRNAs) related to muscle biology (miRNA-1, miRNA-133a, and miRNA-206) and angiogenesis and inflammation (miRNA-155 and miRNA-378) and tested, for the first time, their expression profiles in the CSF and plasma of ALS patients after Lin- cells transplantation. The injection of bone marrow cells resulted in decreased concentration of selected inflammatory proteins (C3) after Lin- cells injection, particularly in patients who had a better clinical outcome. Moreover, several analyzed miRNAs have changed expression levels in the CSF and plasma of ALS patients subsequent to Lin- cells administration. Interestingly, the expression of miR-206 increased in ALS patients, while miR-378 decreased both in the CSF and plasma one month after the cells’ injection. We propose that autologous lineage-negative early hematopoietic cells injected intrathecally may be a safe and feasible source of material for transplantations to the central nervous system (CNS) environment aimed at anti-inflammatory support provision for ALS adjuvant treatment strategies. Further research is needed to evaluate whether the observed effects could significantly influence the ALS progression.}, }
@article {pmid29697388, year = {2018}, author = {Kvirkvelia, N and Shakarishvili, R and Kanashvili, T}, title = {[TRANSFORMATION OF MYASTHENIA GRAVIS INTO AMYOTROPHIC LATERAL SCLEROSIS, OR THEIR CONCOMITANCE? (CASE REVIEW)].}, journal = {Georgian medical news}, volume = {}, number = {276}, pages = {86-92}, pmid = {29697388}, issn = {1512-0112}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*diagnosis/drug therapy/physiopathology ; Humans ; Male ; Myasthenia Gravis/complications/*diagnosis/drug therapy/physiopathology ; }, abstract = {The authors present a case of 75-year-old male patient with typical clinical and electroneuromyographic signs of Amyotrophic Lateral Sclerosis (ALS), manifested in 4 years after a diagnosis of generalized Myasthenia Gravis (MG) had been made. The aim of the article is to assess the possibility of pathogenetic integrated comorbidity of MG and ALS, which may have resulted from a common aberrant immune process and to emphasize the importance of detailed clinical analysis and adequate diagnostic methods essential for correct diagnosis and treatment. Only several cases of coexistence of MG and ALS have been described in medical literature. Exploring the pathogenetic association between MG and ALS may lead to dysregulation of thea immune system. Deficiency of T-regulatory cells, increased activity of atrophy-related atrogenes, anomalies of neuronal nitric oxide synthase can be found in both diseases. Immunoglobulin isolated from ALS patients can affect neuromuscular junction and activate AChRs, which plays an important role in the innervation and re-innervation of muscle fibers. Immunoglobulin also changes the function of Ca2+ channels. Blood level of circulatory Heat Shock Protein 70 (HSP70) antibodies in MG patients is elevated. HSP70 maintains normal conformation of cell proteins. Conversely, HSP70 antibodies cause HSP70's dysfunction and therefore, abnormal protein synthesis, which can be the main reason of neurodegenerative diseases, such as ALS. Experimental evidence indicates, that muscle and neuromuscular junctions may be initial targets of ALS. According to the "dying-back" hypothesis, neuromuscular junction damage and failure in MG patients may precede lower and upper motor neuron loss, and thus increase risk of developing ALS. Pathogenetic mechanisms of MG and ALS are the subjects of further studies. Refining the etiology of these two diseases will answer the question whether it is a transformation or a coexistence of MG and ALS in our case. The presented case demonstrates, that in spite of meeting all diagnostic criteria it is, sometimes, impossible to make the correct diagnosis. Only a detailed clinical analysis and adequate diagnostic methods contribute to correct diagnosis and adequate therapy.}, }
@article {pmid29693363, year = {2018}, author = {Brooks, BR and Jorgenson, JA and Newhouse, BJ and Shefner, JM and Agnese, W}, title = {Edaravone in the treatment of amyotrophic lateral sclerosis: efficacy and access to therapy - a roundtable discussion.}, journal = {The American journal of managed care}, volume = {24}, number = {9 Suppl}, pages = {S175-S186}, pmid = {29693363}, issn = {1936-2692}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Disease Progression ; Dose-Response Relationship, Drug ; Edaravone/*therapeutic use ; Free Radical Scavengers/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease affecting approximately 5 out of every 100,000 individuals living in the United States. ALS is associated with 50% mortality within 30 months of initial symptom onset. The rarity of the disease, along with the significant inter- and intra-patient variability in clinical course and a lack of reliable biomarkers, have rendered the development of effective agents to treat ALS a challenge. Because oxidative stress is considered a contributing factor to ALS onset and progression, drugs that eliminate free radicals may protect motor neurons from damage potentially caused by free-radical and oxidative stress. Edaravone is an antioxidant free-radical scavenger approved by the FDA in 2017 for the treatment of ALS. A review of the edaravone clinical development program offers a clearer view of the clinical utility of this agent. Broader treatment success is also influenced by factors such as limited patient access and the restrictive payer environment. Cooperation within the healthcare community, among clinicians, patient advocacy groups, pharmaceutical companies, and managed care payers, must occur to advance ALS management and treatment and improve patient access. Moreover, collaborative discussions are useful in identifying potential solutions to problems currently surrounding patient access.}, }
@article {pmid29687024, year = {2018}, author = {Berry, JD and Taylor, AA and Beaulieu, D and Meng, L and Bian, A and Andrews, J and Keymer, M and Ennist, DL and Ravina, B}, title = {Improved stratification of ALS clinical trials using predicted survival.}, journal = {Annals of clinical and translational neurology}, volume = {5}, number = {4}, pages = {474-485}, pmid = {29687024}, issn = {2328-9503}, abstract = {INTRODUCTION: In small trials, randomization can fail, leading to differences in patient characteristics across treatment arms, a risk that can be reduced by stratifying using key confounders. In ALS trials, riluzole use (RU) and bulbar onset (BO) have been used for stratification. We hypothesized that randomization could be improved by using a multifactorial prognostic score of predicted survival as a single stratifier.<br><br>METHODS: We defined a randomization failure as a significant difference between treatment arms on a characteristic. We compared randomization failure rates when stratifying for RU and BO ("traditional stratification") to failure rates when stratifying for predicted survival using a predictive algorithm. We simulated virtual trials using the PRO-ACT database without application of a treatment effect to assess balance between cohorts. We performed 100 randomizations using each stratification method - traditional and algorithmic. We applied these stratification schemes to a randomization simulation with a treatment effect using survival as the endpoint and evaluated sample size and power.<br><br>RESULTS: Stratification by predicted survival met with fewer failures than traditional stratification. Stratifying predicted survival into tertiles performed best. Stratification by predicted survival was validated with an external dataset, the placebo arm from the BENEFIT-ALS trial. Importantly, we demonstrated a substantial decrease in sample size required to reach statistical power.<br><br>CONCLUSIONS: Stratifying randomization based on predicted survival using a machine learning algorithm is more likely to maintain balance between trial arms than traditional stratification methods. The methodology described here can translate to smaller, more efficient clinical trials for numerous neurological diseases.}, }
@article {pmid29686818, year = {2018}, author = {Merico, A and Cavinato, M and Gregorio, C and Lacatena, A and Gioia, E and Piccione, F and Angelini, C}, title = {Effects of combined endurance and resistance training in Amyotrophic Lateral Sclerosis: A pilot, randomized, controlled study.}, journal = {European journal of translational myology}, volume = {28}, number = {1}, pages = {7278}, pmid = {29686818}, issn = {2037-7452}, abstract = {Based on available evidence, muscle strengthening and cardiovascular exercises can help maintain function and not adversely affect the progression of disease in patients with ALS. However, this evidence is not sufficiently detailed to recommend a specific exercise prescription. The purpose of this project was to assess clinical outcomes of a combined exercise programme to increase knowledge of rehabilitation in ALS patients. 38 ALS patients were assigned randomly to two groups: one group underwent a specific exercise programme (ALS-EP) based on a moderate aerobic workout and isometric contractions, and the second group followed a standard neuromotor rehabilitation treatment. Objective evaluation consisted of cardiovascular measures, muscle strength and fatigue. Some positive effects of physical activity on ALS patients were found. Among the benefits, an overall improvement of functional independence in all patients, independently of the type of exercise conducted was seen. In addition, improvements in muscle power, oxygen consumption and fatigue were specifically observed in the ALS-EP group, all hallmarks of a training effect for the specific exercises. In conclusion, moderate intensity exercise is beneficial in ALS, helping in avoiding deconditioning and muscle atrophy resulting from progressive inactivity.}, }
@article {pmid29684335, year = {2018}, author = {Subramaniam, NS and Bawden, CS and Waldvogel, H and Faull, RML and Howarth, GS and Snell, RG}, title = {Emergence of breath testing as a new non-invasive diagnostic modality for neurodegenerative diseases.}, journal = {Brain research}, volume = {1691}, number = {}, pages = {75-86}, doi = {10.1016/j.brainres.2018.04.017}, pmid = {29684335}, issn = {1872-6240}, mesh = {Breath Tests/*methods ; Humans ; Neurodegenerative Diseases/*diagnosis/*physiopathology ; }, abstract = {Neurodegenerative diseases (NDDs) are incapacitating disorders that result in progressive motor and cognitive impairment. These diseases include Alzheimer's disease, the most common cause of dementia, frontotemporal dementia, amyotrophic lateral sclerosis, dementia with Lewy bodies, Parkinson's, Huntington's, Friedreich's ataxia, and prion disease. Dementia causing NDDs impose a high social and economic burden on communities around the world. Rapid growth in knowledge regarding the pathogenic mechanisms and disease-associated biomarkers of these diseases in the past few decades have accelerated the development of new diagnostic methods and therapeutic opportunities. Continuous effort is being applied to the development of more advanced, easy-to-apply and reliable methods of diagnosis, that are able to identify disease manifestation at its earliest stages and before clinical symptoms become apparent. Development of these diagnostic tools are essential in aiding effective disease management through accurate monitoring of disease progression, timely application of therapeutics and evaluation of treatment efficacy. Recently, several studies have identified novel biomarkers based on compounds in exhaled breath associated with specific NDDs. The use of breath testing, as a means of monitoring neurodegenerative disease onset and progression, has the potential to have a significant impact on augmenting the diagnosis of NDDs as the approach is non-invasive, relatively cost effective and straight forward to implement. This review highlights key features of current diagnostic methods utilised to identify NDDs, and describes the potential application and limitations associated with the use of breath analysis for disease diagnosis and progression monitoring.}, }
@article {pmid29679377, year = {2018}, author = {Hirose, T and Kimura, F and Tani, H and Ota, S and Tsukahara, A and Sano, E and Shigekiyo, T and Nakamura, Y and Kakiuchi, K and Motoki, M and Unoda, K and Ishida, S and Nakajima, H and Arawaka, S}, title = {Clinical characteristics of long-term survival with noninvasive ventilation and factors affecting the transition to invasive ventilation in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {58}, number = {6}, pages = {770-776}, doi = {10.1002/mus.26149}, pmid = {29679377}, issn = {1097-4598}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*mortality/*therapy ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Respiration, Artificial/classification/*methods ; Retrospective Studies ; Survival Analysis ; Time Factors ; Tracheostomy/*methods ; Treatment Outcome ; Vital Capacity ; }, abstract = {INTRODUCTION: We evaluated post-noninvasive ventilation survival and factors for the transition to tracheostomy in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: We analyzed 197 patients using a prospectively collected database with 114 patients since 2000.<br><br>RESULTS: Among 114 patients, 59 patients underwent noninvasive ventilation (NIV), which prolonged the total median survival time to 43 months compared with 32 months without treatment. The best post-NIV survival was associated with a lack of bulbar symptoms, higher measured pulmonary function, and a slower rate of progression at diagnosis. The transition rate from NIV to tracheostomy gradually decreased over the years. Patients using NIV for more than 6 months were more likely to refuse tracheostomy and to be women.<br><br>DISCUSSION: This study confirmed a positive survival effect with NIV, which was less effective in patients with bulbar dysfunction. Additional studies are required to determine the best timing for using NIV with ALS in patients with bulbar dysfunction. Muscle Nerve 58:770-776 2018.}, }
@article {pmid29676670, year = {2018}, author = {Safaee, MM and Clark, AJ and Burkhardt, JK and Winkler, EA and Lawton, MT}, title = {Timing, severity of deficits, and clinical improvement after surgery for spinal dural arteriovenous fistulas.}, journal = {Journal of neurosurgery. Spine}, volume = {29}, number = {1}, pages = {85-91}, doi = {10.3171/2017.11.SPINE17988}, pmid = {29676670}, issn = {1547-5646}, mesh = {Adult ; Aged ; Aged, 80 and over ; Central Nervous System Vascular Malformations/*diagnosis/*surgery ; Embolization, Therapeutic ; Female ; Humans ; Ligation ; Male ; Middle Aged ; Prospective Studies ; Retrospective Studies ; Severity of Illness Index ; Spinal Cord/blood supply ; Time Factors ; Treatment Outcome ; }, abstract = {OBJECTIVE Spinal dural arteriovenous fistulas (dAVFs) are rare vascular abnormalities caused by arteriovenous shunting. They often form at the dural root sleeve between a radicular feeding artery and draining medullary vein causing venous congestion and edema, decreased perfusion, and ischemia of the spinal cord. Treatment consists of either surgical ligation of the draining vein or selective embolization via an endovascular approach. There is a paucity of data on which modality provides more durable and effective outcomes. METHODS The authors performed a retrospective review of a prospectively maintained database by the senior author to assess clinical outcomes in patients undergoing surgical treatment of spinal dAVFs. Preoperative and postoperative motor and Aminoff-Logue Scale (ALS) scores were collected. RESULTS A total of 41 patients with 44 spinal dAVFs were identified, with a mean patient age of 64 years. The mean symptom duration was 14 months, with weakness (82%), urinary symptoms (47%), and sensory symptoms (29%) at presentation. The fistula locations were as follows: 30 thoracic, 9 lumbar, 3 sacral, and 2 cervical. Five patients had normal motor and ALS scores at presentation. Among the remaining 36 patients with motor deficits or abnormal gait and micturition at presentation, 78% experienced an improvement while the remaining 22% continued to be stable. There was a trend toward improved outcomes in patients with shorter symptom duration; mean symptom duration among patients with clinical improvement was 13 months compared with 22 months among those without improvement. Additionally, rates of improvement were higher for lower thoracic and lumbosacral dAVFs (85% and 83%) compared with those in the upper thoracic spine (57%). No patient developed recurrent fistulas or worsening neurological deficits. CONCLUSIONS Surgery is associated with excellent outcomes in the treatment of spinal dAVFs. Early diagnosis and treatment are critical, with a trend toward improved outcomes. No patient in this study had fistula recurrence or worsening of symptoms. Among patients with abnormal motor or ALS scores, 78% improved after surgery. Therapeutic embolization is an option for some lesions, but for cases with unfavorable anatomy where embolization is not feasible, surgery is a safe option associated with high success.}, }
@article {pmid29676181, year = {2018}, author = {Lee, SH and Suk, K}, title = {Identification of glia phenotype modulators based on select glial function regulatory signaling pathways.}, journal = {Expert opinion on drug discovery}, volume = {13}, number = {7}, pages = {627-641}, doi = {10.1080/17460441.2018.1465925}, pmid = {29676181}, issn = {1746-045X}, mesh = {Animals ; Humans ; Microglia/*metabolism ; *Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neuroglia/metabolism ; Phenotype ; Severity of Illness Index ; Signal Transduction/drug effects ; }, abstract = {Despite the considerable social and economic burden on the healthcare system worldwide due to neurodegenerative diseases, there are currently few disease-altering treatment options for many of these conditions. Therefore, new approaches for both prevention and intervention for neurodegenerative diseases are urgently required. Microglia-mediated neurotoxicity is one of the pathologic hallmarks common to Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Current therapeutic approaches to target microglia-mediated neurotoxicity are focused on the identification of glia phenotype modulators (GPMs), which can inhibit the 'classical' pro-inflammatory and neurotoxic phenotypes of microglia. Areas covered: This article reviews selected microglial molecular targets and pathways involved in either neurotoxicity or neuroprotection and how their identification. Expert opinion: Microglial activation and their signaling pathways have important implications in the neurotoxicity and brain disorders. Pharmacological modulation of microglial activation may serve as a potential therapeutic approach for targeting microglia-mediated neurotoxicity. However, given that microglia change their activation states depending on the timing, stage, and severity of disease, and even aging, the appropriate window should be considered for this approach to be clinically effective. In the future, the identification of unknown extracellular signals and intracellular molecular switches that control phenotypic shifts may facilitate the development of novel therapeutics targeting microglia-mediated neurotoxicity.}, }
@article {pmid29674987, year = {2018}, author = {Carelli, L and Solca, F and Faini, A and Madotto, F and Lafronza, A and Monti, A and Zago, S and Doretti, A and Ciammola, A and Ticozzi, N and Silani, V and Poletti, B}, title = {The Complex Interplay Between Depression/Anxiety and Executive Functioning: Insights From the ECAS in a Large ALS Population.}, journal = {Frontiers in psychology}, volume = {9}, number = {}, pages = {450}, pmid = {29674987}, issn = {1664-1078}, abstract = {Introduction: The observed association between depressive symptoms and cognitive performances has not been previously clarified in patients with amyotrophic lateral sclerosis (pALS). In fact, the use of cognitive measures often not accommodating for motor disability has led to heterogeneous and not conclusive findings about this issue. The aim of the present study was to evaluate the relationship between cognitive and depressive/anxiety symptoms by means of the recently developed Edinburgh Cognitive and Behavioral ALS Screen (ECAS), a brief assessment specifically designed for pALS. Methods: Sample included 168 pALS (114 males, 54 females); they were administered two standard cognitive screening tools (FAB; MoCA) and the ECAS, assessing different cognitive domains, including ALS-specific (executive functions, verbal fluency, and language tests) and ALS non-specific subtests (memory and visuospatial tests). Two psychological questionnaires for depression and anxiety (BDI; STAI/Y) were also administered to patients. Pearson's correlation coefficient was used to assess the degree of association between cognitive and psychological measures. Results: Depression assessment negatively correlated with the ECAS, more significantly with regard to the executive functions subdomain. In particular, Sentence Completion and Social Cognition subscores were negatively associated with depression levels measured by BDI total score and Somatic-Performance symptoms subscore. Conversely, no significant correlations were observed between depression level and cognitive functions as measured by traditional screening tools for frontal abilities (FAB) and global cognition (MoCA) assessment. Finally, no significant correlations were observed between state/trait anxiety and the ECAS. Discussion and conclusion: This represents the first study focusing on the relationship between cognitive and psychological components in pALS by means of the ECAS, the current gold standard for ALS cognitive-behavioral assessment. If confirmed by further investigations, the observed association between depression and executive functions suggests the need for a careful screening and treatment of depression, to avoid overestimation of cognitive involvement and possibly improve cognitive performances in ALS.}, }
@article {pmid29671581, year = {2018}, author = {Is, YS and Durdagi, S and Aksoydan, B and Yurtsever, M}, title = {Proposing Novel MAO-B Hit Inhibitors Using Multidimensional Molecular Modeling Approaches and Application of Binary QSAR Models for Prediction of Their Therapeutic Activity, Pharmacokinetic and Toxicity Properties.}, journal = {ACS chemical neuroscience}, volume = {9}, number = {7}, pages = {1768-1782}, doi = {10.1021/acschemneuro.8b00095}, pmid = {29671581}, issn = {1948-7193}, mesh = {Drug Discovery ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Monoamine Oxidase/chemistry/metabolism ; Monoamine Oxidase Inhibitors/chemistry/pharmacokinetics/*pharmacology/toxicity ; Structure-Activity Relationship ; }, abstract = {Monoamine oxidase (MAO) enzymes MAO-A and MAO-B play a critical role in the metabolism of monoamine neurotransmitters. Hence, MAO inhibitors are very important for the treatment of several neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). In this study, 256 750 molecules from Otava Green Chemical Collection were virtually screened for their binding activities as MAO-B inhibitors. Two hit molecules were identified after applying different filters such as high docking scores and selectivity to MAO-B, desired pharmacokinetic profile predictions with binary quantitative structure-activity relationship (QSAR) models. Therapeutic activity prediction as well as pharmacokinetic and toxicity profiles were investigated using MetaCore/MetaDrug platform which is based on a manually curated database of molecular interactions, molecular pathways, gene-disease associations, chemical metabolism, and toxicity information. Particular therapeutic activity and toxic effect predictions are based on the ChemTree ability to correlate structural descriptors to that property using recursive partitioning algorithm. Molecular dynamics (MD) simulations were also performed to make more detailed assessments beyond docking studies. All these calculations were made not only to determine if studied molecules possess the potential to be a MAO-B inhibitor but also to find out whether they carry MAO-B selectivity versus MAO-A. The evaluation of docking results and pharmacokinetic profile predictions together with the MD simulations enabled us to identify one hit molecule (ligand 1, Otava ID: 3463218) which displayed higher selectivity toward MAO-B than a positive control selegiline which is a commercially used drug for PD therapeutic purposes.}, }
@article {pmid29670700, year = {2018}, author = {Collibee, SE and Bergnes, G and Muci, A and Browne, WF and Garard, M and Hinken, AC and Russell, AJ and Suehiro, I and Hartman, J and Kawas, R and Lu, PP and Lee, KH and Marquez, D and Tomlinson, M and Xu, D and Kennedy, A and Hwee, D and Schaletzky, J and Leung, K and Malik, FI and Morgans, DJ and Morgan, BP}, title = {Discovery of Tirasemtiv, the First Direct Fast Skeletal Muscle Troponin Activator.}, journal = {ACS medicinal chemistry letters}, volume = {9}, number = {4}, pages = {354-358}, pmid = {29670700}, issn = {1948-5875}, abstract = {The identification and optimization of the first activators of fast skeletal muscle are reported. Compound 1 was identified from high-throughput screening (HTS) and subsequently found to improve muscle function via interaction with the troponin complex. Optimization of 1 for potency, metabolic stability, and physical properties led to the discovery of tirasemtiv (25), which has been extensively characterized in clinical trials for the treatment of amyotrophic lateral sclerosis.}, }
@article {pmid29666294, year = {2018}, author = {Andersen, TM and Sandnes, A and Fondenes, O and Nilsen, RM and Tysnes, OB and Heimdal, JH and Clemm, HH and Halvorsen, T and Vollsæter, M and Røksund, OD}, title = {Laryngeal Responses to Mechanically Assisted Cough in Progressing Amyotrophic Lateral Sclerosis.}, journal = {Respiratory care}, volume = {63}, number = {5}, pages = {538-549}, doi = {10.4187/respcare.05924}, pmid = {29666294}, issn = {1943-3654}, mesh = {Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/physiopathology ; *Cough/etiology/physiopathology ; Disease Progression ; Female ; Humans ; Insufflation/*methods ; Laryngoscopy/*methods ; Larynx/*physiopathology ; Longitudinal Studies ; Male ; Middle Aged ; Neurologic Examination/methods ; Outcome Assessment, Health Care ; Prospective Studies ; Respiratory Function Tests/methods ; Respiratory Insufficiency/etiology/physiopathology/prevention &amp; control ; Respiratory Therapy/*methods ; Video Recording/methods ; }, abstract = {BACKGROUND: Respiratory complications represent the major cause of death in amyotrophic lateral sclerosis (ALS). Noninvasive respiratory support is the mainstay therapy, but treatment becomes challenging as the disease progresses, possibly due to a malfunctioning larynx, which is the entrance to the airways. We studied laryngeal response patterns to mechanically assisted cough (mechanical insufflation-exsufflation) as ALS progresses.<br><br>METHODS: This prospective longitudinal study of 13 consecutively included subjects with ALS were followed up during 2011-2016 with repeated tests of lung function, neurological status, and laryngeal responses to mechanical insufflation-exsufflation using video-recorded flexible transnasal fiberoptic laryngoscopy.<br><br>RESULTS: Follow-up time was median 17 (range 6-59) months. In total, 751 laryngoscopy recordings from 67 individual examinations (median 4 per subject, range 2-11 per subject) were analyzed. Adverse laryngeal events that developed with disease progression during insufflation included adduction of true vocal folds in 8 of 9 spinal-onset subjects and adduction of aryepiglottic folds in all subjects, initially at the highest positive pressure and prior to onset of other bulbar symptoms in spinal-onset subjects. As cough became less expulsive with disease progression, laryngeal adduction occurred at lower insufflation pressures. Retroflex movement of the epiglottis was observed in 7 of 13 subjects regardless of insufflation pressures and independent of bulbar involvements. Backward movement of the tongue base occurred regardless of insufflation pressures in all but 1 subject. During exsufflation, constriction of the hypopharynx was observed in all subjects regardless of the presence of bulbar symptoms, after the adverse events that occurred during insufflation.<br><br>CONCLUSIONS: Applying high insufflation pressures during mechanically assisted cough in ALS can become counterproductive as the disease progresses as well as prior to the onset of bulbar symptoms. The application of positive inspiratory pressures should be tailored to the individual patient, and laryngoscopy during ongoing treatment appears to be a feasible tool.}, }
@article {pmid29656576, year = {2018}, author = {Zhang, JJ and Zhou, QM and Chen, S and Le, WD}, title = {Repurposing carbamazepine for the treatment of amyotrophic lateral sclerosis in SOD1-G93A mouse model.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {24}, number = {12}, pages = {1163-1174}, pmid = {29656576}, issn = {1755-5949}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/pathology ; Analgesics, Non-Narcotic/*therapeutic use ; Animals ; Autophagy/drug effects/genetics ; Beclin-1/metabolism ; Carbamazepine/*therapeutic use ; Disease Models, Animal ; *Drug Repositioning ; Gene Expression Regulation/drug effects/genetics ; Humans ; Mice ; Mice, Transgenic ; Muscle, Skeletal/drug effects/pathology ; NAD/metabolism ; Protein Aggregation, Pathological/drug therapy/etiology ; Signal Transduction/drug effects/genetics ; Superoxide Dismutase/*genetics/metabolism ; }, abstract = {AIMS: To investigate the effect and mechanisms of carbamazepine (CBZ) on the onset and progression of amyotrophic lateral sclerosis (ALS) in SOD1-G93A mouse model.<br><br>METHODS: Starting from 64&#xa0;days of age, SOD1-G93A mice were orally administered with CBZ at 200&#xa0;mg/kg once daily until death. The disease onset and life span of SOD1-G93A mice were recorded. Motor neurons (MNs) in anterior horn of spinal cord were quantified by Nissl staining and SMI-32 immunostaining. Hematoxylin and eosin (H&amp;E), nicotinamide adenine dinucleotide hydrogen (NADH), modified Gomori trichrome (MGT), and &#x3b1;-bungarotoxin-ATTO-488 staining were also performed to evaluate muscle and neuromuscular junction (NMJ) damage. Expressions of aggregated SOD1 protein and autophagy-related proteins were further detected by Western blot and immunofluorescent staining.<br><br>RESULTS: Carbamazepine treatment could delay the disease onset and extend life span of SOD1-G93A mice by about 14.5% and 13.9%, respectively. Furthermore, CBZ treatment reduced MNs loss by about 46.6% and ameliorated the altered muscle morphology and NMJ. Much more interestingly, mechanism study revealed that CBZ treatment activated autophagy via AMPK-ULK1 pathway and promoted the clearance of mutant SOD1 aggregation.<br><br>CONCLUSION: Our findings uncovered the therapeutic effects of CBZ against disease pathogenesis in SOD1-G93A mice, indicating a promising clinical utilization of CBZ in ALS therapy.}, }
@article {pmid29653550, year = {2018}, author = {Kim, S and Kim, JK and Son, MJ and Kim, D and Song, B and Son, I and Kang, HW and Lee, J and Kim, S}, title = {Mecasin treatment in patients with amyotrophic lateral sclerosis: study protocol for a randomized controlled trial.}, journal = {Trials}, volume = {19}, number = {1}, pages = {225}, pmid = {29653550}, issn = {1745-6215}, support = {HI11C2142//Korea Health Industry Development Institute/Republic of Korea ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/physiopathology ; Anti-Inflammatory Agents/*administration &amp; dosage/adverse effects ; Clinical Trials, Phase II as Topic ; Disease Progression ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Health Status ; Humans ; Male ; Middle Aged ; Multicenter Studies as Topic ; Neuroprotective Agents/*administration &amp; dosage/adverse effects ; Plant Extracts/*therapeutic use ; Randomized Controlled Trials as Topic ; Republic of Korea ; Riluzole/administration &amp; dosage ; Time Factors ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes paralysis of limb, swallowing, and breathing muscles. Riluzole, the Food and Drug Administration-approved drug for ALS, provides minimal benefit, prolonging patient life by only 2-3 months. Previous studies have found a neuro-protective and anti-neuroinflammatory effect of Mecasin, with retrospective studies providing suggestive evidence for a beneficial effect of Mecasin. The aim of this study was to develop a protocol to determine the proper dosage of Mecasin.<br><br>METHODS: This is a phase II-A, multi-center, randomized study with three arms. Thirty-six patients with ALS will be randomly assigned to one of three groups, each receiving the standard treatment with 100 mg of riluzole in addition to one of 1.6 g of Mecasin, 2.4 g of Mecasin, or a placebo. The Primary outcome is the Korean version of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised result after 12 weeks of treatment. Secondary outcomes include results of the Short Form Health Survey-8, Medical Research Council Scale, Visual Analogue Scale for Pain, Hamilton Rating Scale for Depression, Fatigue Severity Scale, Patient Global Impression of Change, pulmonary function test, forced expiratory volume in 1 s and its ratio to forced vital capacity, creatine kinase, and body weight. The frequencies of total adverse events and serious adverse events will be described and documented. The trial protocol has been approved by the Institutional Review Board of the Wonkwang University Gwangju and Sanbon Hospital (2016-5-4 and 2016-34-01, respectively). An Investigational New Drug status (30731) was granted by the Korea Food and Drug Administration.<br><br>DISCUSSION: This trial will aim to identify the optimal dosage of Mecasin. Additionally, it will test the efficacy and safety of Mecasin in conjunction with standard treatment, riluzole, for alleviating the functional decline in patients with ALS.<br><br>TRIAL REGISTRATION: Korean National Clinical Trial Registry CRIS; KCT0001984 . Registered on 28 July 2016.}, }
@article {pmid29653372, year = {2018}, author = {Argente, J and Pérez-Jurado, LA}, title = {Letter to the Editor: History and clinical implications of PAPP-A2 in human growth: When reflecting on idiopathic short stature leads to a specific and new diagnosis: Understanding the concept of "low IGF-I availability".}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {40}, number = {}, pages = {17-19}, doi = {10.1016/j.ghir.2018.04.001}, pmid = {29653372}, issn = {1532-2238}, mesh = {Biomarkers/*analysis ; Child ; Dwarfism/blood/*diagnosis/genetics ; Female ; Humans ; Insulin-Like Growth Factor I/*analysis ; *Mutation ; Pregnancy-Associated Plasma Protein-A/*genetics ; Prognosis ; }, abstract = {As a result of our publication of the first patients with short stature due to a mutation in the gene for PAPP-A2 the question, "Why did you continue to study these patients when they were not more than 2 SDS below normal?" has been proposed surprisingly frequently. We would like to communicate our opinions on why these patients were studied and share the experience on how this process took place. In addition, the choice of treatment is also discussed. We believe that this discovery process is a good example of good clinical practice and international collaboration.}, }
@article {pmid29648683, year = {2018}, author = {Shoop-Worrall, SJW and Verstappen, SMM and McDonagh, JE and Baildam, E and Chieng, A and Davidson, J and Foster, H and Ioannou, Y and McErlane, F and Wedderburn, LR and Thomson, W and Hyrich, KL}, title = {Long-Term Outcomes Following Achievement of Clinically Inactive Disease in Juvenile Idiopathic Arthritis: The Importance of Definition.}, journal = {Arthritis &amp; rheumatology (Hoboken, N.J.)}, volume = {70}, number = {9}, pages = {1519-1529}, pmid = {29648683}, issn = {2326-5205}, support = {20542/VAC_/Versus Arthritis/United Kingdom ; 20380/ARC_/Arthritis Research UK/United Kingdom ; /DH_/Department of Health/United Kingdom ; 20542/ARC_/Arthritis Research UK/United Kingdom ; MR/R013926/1/MRC_/Medical Research Council/United Kingdom ; 20164/ARC_/Arthritis Research UK/United Kingdom ; MR/K501311/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Adolescent ; Antirheumatic Agents/*therapeutic use ; Arthritis, Juvenile/drug therapy/*pathology ; Child ; Female ; Humans ; Induction Chemotherapy/*statistics &amp; numerical data ; Male ; Outcome Assessment, Health Care/*methods ; Prospective Studies ; Quality of Life ; *Severity of Illness Index ; Time Factors ; Treatment Outcome ; }, abstract = {OBJECTIVE: Potential targets for treat-to-target strategies in juvenile idiopathic arthritis are minimal disease activity (MDA) and clinically inactive disease (CID). We undertook this study to compare short- and long-term outcomes following achievement of MDA and CID on the 10-joint clinical Juvenile Arthritis Disease Activity Score (cJADAS10) and following achievement of CID on Wallace et al's preliminary criteria.<br><br>METHODS: Children recruited to the Childhood Arthritis Prospective Study, a UK multicenter inception cohort, were selected if they were recruited prior to January 2011 and diagnosed as having oligoarthritis or rheumatoid factor-negative or -positive polyarthritis. One year following diagnosis, children were assessed for MDA on the cJADAS10 and for CID on both Wallace et al's preliminary criteria and the cJADAS10. Associations were tested between those disease states and functional ability, absence of joints with limited range of motion, psychosocial health, and pain at 1 year and annually to 5 years.<br><br>RESULTS: Of 832 children, 70% were female and the majority had oligoarthritis (68%). At 1 year, 21% had achieved CID according to both definitions, 7% according to Wallace et al's preliminary criteria alone, and 16% according to the cJADAS10 alone; 56% had not achieved CID. Only 10% of children in the entire cohort achieved MDA without also achieving CID. Achieving either early CID state was associated with a greater absence of joints with limited range of motion. However, only CID according to the cJADAS10 was associated with improved functional ability and psychosocial health. Achieving CID was superior to achieving MDA in terms of short- and long-term pain and the absence of joints with limited range of motion.<br><br>CONCLUSION: CID on the cJADAS10 may be preferable as a treatment target to CID on Wallace et al's preliminary criteria in terms of both feasibility of application and long-term outcomes.}, }
@article {pmid29648589, year = {2018}, author = {Sentandreu, R and Caminero, A and Rentería, I and León-Ramirez, C and González-de-la-Vara, L and Valentin-Gomez, E and Ruiz-Herrera, J}, title = {Analysis of the 3H8 antigen of Candida albicans reveals new aspects of the organization of fungal cell wall proteins.}, journal = {FEMS yeast research}, volume = {18}, number = {4}, pages = {}, doi = {10.1093/femsyr/foy035}, pmid = {29648589}, issn = {1567-1364}, mesh = {Antibodies, Fungal/immunology ; Antibodies, Monoclonal/immunology ; Antigens, Fungal/*analysis/chemistry/immunology/metabolism ; Candida albicans/*chemistry ; Cell Wall/*chemistry ; Electrophoresis, Polyacrylamide Gel ; Macromolecular Substances/*analysis/chemistry/immunology/metabolism ; Mass Spectrometry ; Microscopy, Electron ; }, abstract = {The walls of both, yeast and mycelial cells of Candida albicans possess a species-specific antigen that is recognized by a monoclonal antibody (MAb 3H8). This antigen can be extracted in the form of a very high Mr complex, close or over 106 Da, by treatment, with β-1,3-glucanase, β mercaptoethanol or dithothreitol, or mild alkali, but not by saturated hydrogen fluoride (HF) in pyridine, suggesting that the complex is bound to wall β-1,3 glucans, and to proteins by disulfide bonds, but not to β-1,6 glucans. Through its sensitivity to trypsin and different deglycosylation procedures, it was concluded that the epitope is associated to a glycoprotein containing N-glycosidic, but not O-glycosidic mannan moieties. By means of electrophoresis in polycrylamide gradient gels, followed by mass spectrometric analysis, the epitope was pinpointed to a very high MW complex containing Agglutinin-Like Sequence (ALS) family proteins, and other cytoplasmic, membrane and secreted proteins. The components of this complex are bound by unknown covalent bonds. The material extracted with β mercaptoethanol or dilute alkali appeared under the electron microscope as large aggregates in the form of spheroidal and mostly web-like structures of large sizes. These, and additional data, suggest that this protein complex may constitute an important part of the basic glycoprotein structure of C. albicans. The possibility that similar complexes exist in the wall of other fungi is an attractive, although yet untested possibility.}, }
@article {pmid29641956, year = {2018}, author = {Al-Chalabi, A and Brown, RH}, title = {Finding a Treatment for ALS - Will Gene Editing Cut It?.}, journal = {The New England journal of medicine}, volume = {378}, number = {15}, pages = {1454-1456}, doi = {10.1056/NEJMcibr1716741}, pmid = {29641956}, issn = {1533-4406}, support = {ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; *CRISPR-Cas Systems ; Dependovirus ; Disease Models, Animal ; *Gene Editing ; Gene Expression ; Genetic Therapy/*methods ; Humans ; Mice ; Mice, Transgenic ; Mutation ; Superoxide Dismutase/*genetics ; }, }
@article {pmid29635557, year = {2018}, author = {Benov, A and Antebi, B and Wenke, JC and Batchinsky, AI and Murray, CK and Nachman, D and Haim, P and Tarif, B and Glassberg, E and Yitzhak, A}, title = {Antibiotic Treatment - What Can Be Learned from Point of Injury Experience?.}, journal = {Military medicine}, volume = {183}, number = {suppl_1}, pages = {466-471}, doi = {10.1093/milmed/usx144}, pmid = {29635557}, issn = {1930-613X}, mesh = {Adult ; Anti-Bacterial Agents/*administration &amp; dosage/therapeutic use ; Female ; Guidelines as Topic/standards ; Humans ; Male ; Military Medicine/methods ; Military Personnel/statistics &amp; numerical data ; Point-of-Care Systems/*standards/statistics &amp; numerical data ; Registries/statistics &amp; numerical data ; Retrospective Studies ; *Time Factors ; Wounds and Injuries/drug therapy ; }, abstract = {INTRODUCTION: Early antibiotic administration after trauma reduces infection rates of open wounds. A clinical practice guideline (CPG) was created to ensure that wounded personnel who are not expected to arrive at the hospital within an hour receive antibiotic treatment in the field. This study evaluated how well-advanced life saver (ALS) providers complied with Israeli Defense Force (IDF) CPG.<br><br>MATERIALS AND METHODS: A retrospective review of all trauma patients between November 2011 and January 2015 was conducted. All casualties who suffered from penetrating injuries with evacuation times greater than 60 min were examined. Casualties who should have received antibiotic treatment in accordance with the IDF CPG were further divided into those who received antibiotics (i.e., "Antibiotic" group) and those who did not receive antibiotic treatment (i.e., "No Antibiotics" group).<br><br>RESULTS: For a 3-yr period, a total of 5,142 casualties occurred in the pre-hospital environment. According to parameters established in the CPG, 600 casualties should have received antibiotic treatment. Of these patients, only 49 (8.2%) received antibiotic treatment. Comparative analysis between these groups revealed no significant differences in regards to gender, age, and time to MTF; however, significant differences were found in regards to injury severity score (ISS) (p < 0.01), care under fire (i.e., treatment at a combat zone) criteria (p < 0.00001), and life-saving interventions (p < 0.005).<br><br>DISCUSSION: Although the reasons for poor adherence to IDF CPG's are not entirely clear, the data suggest that the severity of the injuries sustained by these casualties requiring a greater number of LSIs, longer evacuation distances, and a more hostile battlefield environment may each contribute to poor adherence. Since this has been identified as a training gap, the importance of antibiotic administration at point of injury in delayed evacuation scenarios has been reinforced.}, }
@article {pmid29627580, year = {2018}, author = {Riehm, JJ and Wang, L and Ghadge, G and Teng, M and Correa, AM and Marks, JD and Roos, RP and Allen, MJ}, title = {Poloxamer 188 decreases membrane toxicity of mutant SOD1 and ameliorates pathology observed in SOD1 mouse model for ALS.}, journal = {Neurobiology of disease}, volume = {115}, number = {}, pages = {115-126}, pmid = {29627580}, issn = {1095-953X}, support = {R01 NS056313/NS/NINDS NIH HHS/United States ; R01 NS067247/NS/NINDS NIH HHS/United States ; U54 GM087519/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/pathology ; Animals ; Cell Membrane/drug effects/pathology/*physiology ; Humans ; Male ; Mice ; Mice, Transgenic ; Mutation/drug effects/*physiology ; Poloxamer/pharmacology/*therapeutic use ; Superoxide Dismutase-1/*genetics ; Surface-Active Agents/pharmacology/therapeutic use ; }, abstract = {Here we report a gain in function for mutant (mt) superoxide dismutase I (SOD1), a cause of familial amyotrophic lateral sclerosis (FALS), wherein small soluble oligomers of mtSOD1 acquire a membrane toxicity. Phosphatidylglycerol (PG) lipid domains are selectively targeted, which could result in membrane damage or "toxic channels" becoming active in the bilayer. This PG-selective SOD1-mediated membrane toxicity is largely reversible in vitro by a widely-available FDA-approved surfactant and membrane-stabilizer P188. Treatment of G93ASOD1 transgenic mice with P188 significantly delayed symptoms onset, extended survival and decreased motoneuron death. The use of P188 or an analogue, which targets mtSOD1 misfolding-induced membrane toxicity, may provide a new direction for ALS treatment.}, }
@article {pmid29625589, year = {2018}, author = {Rando, A and Pastor, D and Viso-León, MC and Martínez, A and Manzano, R and Navarro, X and Osta, R and Martínez, S}, title = {Intramuscular transplantation of bone marrow cells prolongs the lifespan of SOD1[G93A] mice and modulates expression of prognosis biomarkers of the disease.}, journal = {Stem cell research &amp; therapy}, volume = {9}, number = {1}, pages = {90}, pmid = {29625589}, issn = {1757-6512}, mesh = {Animals ; Female ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Biomarkers/metabolism ; *Bone Marrow Transplantation/methods ; Cells, Cultured ; Motor Neurons/metabolism ; *Muscle, Skeletal/cytology/metabolism ; Mutation, Missense ; Nerve Growth Factors/metabolism ; Neuromuscular Junction/metabolism ; Superoxide Dismutase-1/genetics ; Disease Models, Animal ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle weakness, paralysis and death. There is no effective treatment for ALS and stem cell therapy has arisen as a potential therapeutic approach.<br><br>METHODS: SOD1 mutant mice were used to study the potential neurotrophic effect of bone marrow cells grafted into quadriceps femoris muscle.<br><br>RESULTS: Bone marrow intramuscular transplants resulted in increased longevity with improved motor function and decreased motoneuron degeneration in the spinal cord. Moreover, the increment of the glial-derived neurotrophic factor and neurotrophin 4 observed in the grafted muscles suggests that this partial neuroprotective effect is mediated by neurotrophic factor release at the neuromuscular junction level. Finally, certain neurodegeneration and muscle disease-specific markers, which are altered in the SOD1[G93A] mutant mouse and may serve as molecular biomarkers for the early detection of ALS in patients, have been studied with encouraging results.<br><br>CONCLUSIONS: This work demonstrates that stem cell transplantation in the muscle prolonged the lifespan, increased motoneuron survival and slowed disease progression, which was also assessed by genetic expression analysis.}, }
@article {pmid29625458, year = {2018}, author = {Li, M and Chen, Y and Jiang, Z and Chen, X and Chen, J and Sun, X}, title = {What Are the Characteristics of Primary Angle Closure With Longer Axial Length?.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {59}, number = {3}, pages = {1354-1359}, doi = {10.1167/iovs.17-23711}, pmid = {29625458}, issn = {1552-5783}, mesh = {Aged ; Anterior Chamber/pathology ; Axial Length, Eye/*pathology ; Biometry ; Ciliary Body/pathology ; Cross-Sectional Studies ; Female ; Glaucoma, Angle-Closure/diagnostic imaging/*pathology ; Humans ; Lens, Crystalline/pathology ; Male ; Middle Aged ; Prospective Studies ; Tomography, Optical Coherence ; }, abstract = {PURPOSE: To compare biometric parameters between primary angle closure with longer axial length (AL) and those with medium or shorter AL.<br><br>METHODS: We prospectively recruited 138 primary angle-closure patients. Low-coherence interferometry and ultrasound biomicroscopy examinations were performed before laser peripheral iridotomy and pilocarpine treatment. AL was categorized as shorter (<22.5 mm), medium (&#x2265;22.5 to <23.5 mm), or longer (&#x2265;23.5 mm). Anterior chamber depth and width (ACD and ACW), lens vault (LV), anterior vault (AV), relative AV (AV/AL), relative lens position (RLP, [ACD + 1/2 lens thickness]/AL), trabecular-ciliary angle (TCA), keratometry, and other biometric parameters were compared among different AL groups.<br><br>RESULTS: Among 138 angle-closure patients, 15 (10.9%) patients had longer ALs, of which 11 (73.3%) were male. These angle-closure eyes with longer AL had flatter cornea (P = 0.006 and 0.022 for flat and steep keratometry) and larger ACW (P = 0.006), but smaller RLP (P = 0.019) than those with medium AL; similarly, they had flatter cornea (P < 0.001 for both flat and steep keratometry), and larger ACW (P < 0.001), AV (P = 0.004), and TCA (P = 0.024), but smaller relative AV (P = 0.040) and RLP (P = 0.005) than those with shorter AL. No significant differences were found in the other parameters.<br><br>CONCLUSIONS: Primary angle closure with longer AL was uncommon. Causes of angle closure in these atypical patients were manifold. These patients were predominantly male; they had smaller relative dimension of the anterior segment, flatter cornea, and more anterior RLP and less anteriorly rotated ciliary body compared with those angle-closure patients with relatively shorter AL.}, }
@article {pmid29615863, year = {2018}, author = {Lai, CY and Liu, YJ and Lai, HL and Chen, HM and Kuo, HC and Liao, YP and Chern, Y}, title = {The D2 Dopamine Receptor Interferes With the Protective Effect of the A2A Adenosine Receptor on TDP-43 Mislocalization in Experimental Models of Motor Neuron Degeneration.}, journal = {Frontiers in neuroscience}, volume = {12}, number = {}, pages = {187}, pmid = {29615863}, issn = {1662-4548}, abstract = {The A2A adenosine receptor (A2AR) and D2 dopamine receptor (D2R) are two G-protein-coupled receptors that can form dimers and negatively regulate their partners. TAR DNA-binding protein (TDP-43) is a nuclear protein that has been implicated in amyotrophic lateral sclerosis (ALS). Mislocalization of TDP-43 from the nucleus to the cytoplasm is an early step of TDP-43 proteinopathy. Our previous studies indicated that A2AR is a potential drug target for ALS because treatment with an A2AR agonist (JMF1907; a T1-11 analog) prevents reactive oxygen species (ROS)-induced TDP-43 mislocalization in a motor neuron cell line (NSC34) and delays motor impairment in a TDP-43 transgenic ALS mouse model. Here, we set out to assess whether activation of D2R interferes with the beneficial effects of an A2AR agonist on motor neurons. We first demonstrated that A2AR and D2R are both located in motor neurons of mouse and human spinal cords and human iPSC-derived motor neurons. Expression of A2AR and D2R in NSC34 cells led to dimer formation without affecting the binding affinity of A2AR toward T1-11. Importantly, activation of D2R reduced T1-11-mediated activation of cAMP/PKA signaling and subsequent inhibition of TDP-43 mislocalization in NSC34 cells. Treatment with quinpirole (a D2 agonist) blunted the rescuing effect of T1-11 on TDP-43 mislocalization and impaired grip strength in a mouse model of ALS. Our findings suggest that D2R activation may limit the beneficial responses of an A2AR agonist in motor neurons and may have an important role in ALS pathogenesis.}, }
@article {pmid29599075, year = {2019}, author = {Carbó Perseguer, J and Madejón Seiz, A and Romero Portales, M and Martínez Hernández, J and Mora Pardina, JS and García-Samaniego, J}, title = {Percutaneous endoscopic gastrostomy in patients with amyotrophic lateral sclerosis: Mortality and complications.}, journal = {Neurologia}, volume = {34}, number = {9}, pages = {582-588}, doi = {10.1016/j.nrl.2018.01.003}, pmid = {29599075}, issn = {2173-5808}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*mortality/therapy ; *Endoscopy ; *Enteral Nutrition ; Female ; *Gastrostomy ; Hospitals ; Humans ; Male ; Middle Aged ; Prospective Studies ; Spain ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes severe dysphagia and weight loss. Percutaneous endoscopic gastrostomy (PEG) is currently the technique of choice for the enteral nutrition of these patients.<br><br>OBJECTIVES: To analyse mortality and complications in a series of patients diagnosed with ALS who underwent PEG, and to evaluate factors related to patient survival after the procedure.<br><br>MATERIAL AND METHODS: We performed a prospective, observational study including all patients diagnosed with ALS and treated by our hospital's Gastroenterology Department in the period 1997-2013. We studied mortality, complications, and clinical and biochemical parameters, and correlated these with the survival rate.<br><br>RESULTS: The study included a total of 57 patients, of whom 49 were ultimately treated with PEG. ALS onset was bulbar in 30 patients and spinal in 19. Mortality during the procedure and at 30 days was 2% (n&#xa0;=&#xa0;1). Six patients (12.2%) experienced major complications; 17 (34.7%) experienced less serious complications which were easily resolved with conservative treatment. No significant differences were observed in forced vital capacity, albumin level, or age between patients with (n&#xa0;=&#xa0;6) and without (n&#xa0;=&#xa0;43) major complications.<br><br>CONCLUSIONS: PEG is an effective, relatively safe procedure for the enteral nutrition of patients with ALS, although not without morbidity and mortality. Neither forced vital capacity nor the form of presentation of ALS were associated with morbidity in PEG.}, }
@article {pmid29593492, year = {2018}, author = {Xue, YC and Feuer, R and Cashman, N and Luo, H}, title = {Enteroviral Infection: The Forgotten Link to Amyotrophic Lateral Sclerosis?.}, journal = {Frontiers in molecular neuroscience}, volume = {11}, number = {}, pages = {63}, pmid = {29593492}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily attacks motor neurons in the brain and spinal cord, leading to progressive paralysis and ultimately death. Currently there is no effective therapy. The majority of ALS cases are sporadic, with no known family history; unfortunately the etiology remains largely unknown. Contribution of Enteroviruses (EVs), a family of positive-stranded RNA viruses including poliovirus, coxsackievirus, echovirus, enterovirus-A71 and enterovirus-D68, to the development of ALS has been suspected as they can target motor neurons, and patients with prior poliomyelitis show a higher risk of motor neuron disease. Multiple efforts have been made to detect enteroviral genome in ALS patient tissues over the past two decades; however the clinical data are controversial and a causal relationship has not yet been established. Recent evidence from in vitro and animal studies suggests that enterovirus-induced pathology remarkably resembles the cellular and molecular phenotype of ALS, indicating a possible link between enteroviral infection and ALS pathogenesis. In this review, we summarize the nature of enteroviral infection, including route of infection, cells targeted, and viral persistence within the central nervous system (CNS). We review the molecular mechanisms underlying viral infection and highlight the similarity between viral pathogenesis and the molecular and pathological features of ALS, and finally, discuss the potential role of enteroviral infection in frontotemporal dementia (FTD), a disease that shares common clinical, genetic, and pathological features with ALS, and the significance of anti-viral therapy as an option for the treatment of ALS.}, }
@article {pmid29593436, year = {2018}, author = {van Eijk, RP and Eijkemans, MJ and Rizopoulos, D and van den Berg, LH and Nikolakopoulos, S}, title = {Comparing methods to combine functional loss and mortality in clinical trials for amyotrophic lateral sclerosis.}, journal = {Clinical epidemiology}, volume = {10}, number = {}, pages = {333-341}, pmid = {29593436}, issn = {1179-1349}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) clinical trials based on single end points only partially capture the full treatment effect when both function and mortality are affected, and may falsely dismiss efficacious drugs as futile. We aimed to investigate the statistical properties of several strategies for the simultaneous analysis of function and mortality in ALS clinical trials.<br><br>METHODS: Based on the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we simulated longitudinal patterns of functional decline, defined by the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and conditional survival time. Different treatment scenarios with varying effect sizes were simulated with follow-up ranging from 12 to 18 months. We considered the following analytical strategies: 1) Cox model; 2) linear mixed effects (LME) model; 3) omnibus test based on Cox and LME models; 4) composite time-to-6-point decrease or death; 5) combined assessment of function and survival (CAFS); and 6) test based on joint modeling framework. For each analytical strategy, we calculated the empirical power and sample size.<br><br>RESULTS: Both Cox and LME models have increased false-negative rates when treatment exclusively affects either function or survival. The joint model has superior power compared to other strategies. The composite end point increases false-negative rates among all treatment scenarios. To detect a 15% reduction in ALSFRS-R decline and 34% decline in hazard with 80% power after 18 months, the Cox model requires 524 patients, the LME model 794 patients, the omnibus test 526 patients, the composite end point 1,274 patients, the CAFS 576 patients and the joint model 464 patients.<br><br>CONCLUSION: Joint models have superior statistical power to analyze simultaneous effects on survival and function and may circumvent pitfalls encountered by other end points. Optimizing trial end points is essential, as selecting suboptimal outcomes may disguise important treatment clues.}, }
@article {pmid29590676, year = {2018}, author = {Maucksch, U and Runge, R and Oehme, L and Kotzerke, J and Freudenberg, R}, title = {Radiotoxicity of alpha particles versus high and low energy electrons in hypoxic cancer cells.}, journal = {Nuklearmedizin. Nuclear medicine}, volume = {57}, number = {2}, pages = {56-63}, doi = {10.3413/Nukmed-0950-17-12}, pmid = {29590676}, issn = {2567-6407}, mesh = {Alpha Particles/*therapeutic use ; Cell Line, Tumor ; Cell Survival/radiation effects ; Electrons/*therapeutic use ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Linear Energy Transfer ; Neoplasms/metabolism/*radiotherapy ; Oxygen/metabolism ; Radiation Tolerance ; Radioisotopes/pharmacokinetics/therapeutic use ; Radiopharmaceuticals/pharmacokinetics/therapeutic use ; Radiotherapy Dosage ; Radium/pharmacokinetics/therapeutic use ; Rhenium/pharmacokinetics/therapeutic use ; Technetium Tc 99m Exametazime/pharmacokinetics/therapeutic use ; Tumor Hypoxia/*radiation effects ; }, abstract = {PURPOSE: Hypoxic regions of tumors are less sensitive to radio- and chemotherapy, leading to poor prognosis of patients. One option to overcome the radioresistance is the irradiation of hypoxic tumors with high linear energy transfer (LET) α- or Auger electronemitters assuming their radiotoxicity would be less dependent on the cellular oxygenation status. Therefore, the aim of the present study was to determine whether irradiation with the intracellularly distributed Auger electron/γ-emitter [99m]Tc using the tracer [[99m]Tc]TcHMPAO is a promising therapeutic option for the treatment of hypoxic tumor cells. Thus, the high LET α-particleemitter [223]Ra ([[223]Ra]RaCl2) and the low LET β-emitter [188]Re ([[188]Re]NaReO4) were studied in comparison to [99mTc]Tc-HMPAO.<br><br>MATERIALS AND METHODS: A431 tumor cells were incubated with [[99m]Tc]Tc-HMPAO (1-20 MBq/2 mL), [[223]Ra]RaCl2 (1.4-16.3 kBq/2 mL) or [[188]Re]NaReO4 (0.3-13.7 MBq/2 mL) under normoxic or hypoxic conditions. The degree of radiotoxicity was analyzed using the colony forming assay (CFA), and the intracellular radionuclide uptake of the radiotracers was quantified.<br><br>RESULTS: Hypoxic A431 cells are less radiosensitive to irradiation with [[99m]Tc]Tc-HMPAO or [[188]Re]NaReO4 than normoxic ones. In contrast, the radiosensitivity of A431 cells is almost independent of the oxygen status when treated with the [[223]Ra]RaCl2.<br><br>CONCLUSIONS: We demonstrate that the Auger electron/&#x3b3;-emitter [99m]Tc ([[99m]Tc]Tc-HMPAO), which does not bound directly to the DNA, is not a promising therapeutic option for hypoxic tumor cells. But the high LET &#x3b1;-particle-emitter [223]Ra is more suitable for the treatment of hypoxic tumor cells than irradiation with [[99m]Tc]Tc-HMPAO or the low LET bemitter [188]Re.<br><br>ZIELSETZUNG: Hypoxische Tumorregionen sind bei Radio- und Chemotherapie weniger sensitiv als Tumorregionen mit ausreichender Sauerstoffversorgung. Dies verursacht eine schlechte Prognose f&#xfc;r Tumorpatienten. Eine Option die Radioresistenz zu &#xfc;berwinden, stellt die Bestrahlung mit &#x3b1;-Partikel-Emittern oder Auger-Elektronen-Emittern mit einem hohen linearen Energietransfer (LET) dar. In dieser Studie soll untersucht werden, ob die Bestrahlung von hypoxischen Tumorzellen mit dem intrazellul&#xe4;r aufgenommenen &#x3b3;- sowie Auger-Elektronen-Emitter [99m]Tc unter Verwendung des Radiotracers [[99m]Tc]Tc-HMPAO eine vielversprechende Therapieoption darstellen k&#xf6;nnte. Vergleichend wurde der Hoch-LET &#x3b1;-Partikel-Emitter [223]Ra ([[223]Ra]RaCl2) und der Niedrig-LET &#x3b2;-Emitter [188]Re ([[188]Re]NaReO4) eingesetzt.<br><br>METHODEN: A431 Tumorzellen wurden unter normoxischen oder hypoxischen Kulturbedingungen mit [[99m]Tc]Tc-HMPAO (1-20 MBq/2 ml), [[223]Ra]RaCl2 (1,4-16,3 kBq/2 ml) und [[188]Re]NaReO4 (0,3-13,7 MBq/2 ml) inkubiert. Zur Detektion der resultierenden strahlenbiologischen Wirkung wurde der Koloniebildungsassay angewendet. Zus&#xe4;tzlich wurde die intrazellul&#xe4;re Aufnahme der Radiotracer quantifiziert.<br><br>ERGEBNISSE: Nach Inkubation von [[99m]Tc]Tc-HMPAO sind hypoxische A431-Zellen weniger strahlensensitiv als normoxische Zellen. Im Gegensatz zur Behandlung mit [[99m]Tc]Tc-HMPAO oder [[188]Re]NaReO4 wurde bei Behandlung mit [[223]Ra]RaCl2 ein geringerer Einfluss des Sauerstoffstatus auf die Radiosensitivit&#xe4;t von A431-Zellen gefunden.<br><br>SCHLUSSFOLGERUNG: Damit konnte gezeigt werden, dass der nicht direkt an die DNA gebundene Auger-Elektronen-/ &#x3b3;-Emitter [99m]Tc ([[99m]Tc]Tc-HMPAO) die Radioresistenz von hypoxischen Tumorzellen nicht &#xfc;berwinden kann. Jedoch stellt der Hoch-LET &#x3b1;-Partikel-Emitter [223]Ra ([[223]Ra]RaCl2) eine bessere Behandlungsoption dar.}, }
@article {pmid29588251, year = {2018}, author = {Buonvicino, D and Felici, R and Ranieri, G and Caramelli, R and Lapucci, A and Cavone, L and Muzzi, M and Di Pietro, L and Bernardini, C and Zwergel, C and Valente, S and Mai, A and Chiarugi, A}, title = {Effects of Class II-Selective Histone Deacetylase Inhibitor on Neuromuscular Function and Disease Progression in SOD1-ALS Mice.}, journal = {Neuroscience}, volume = {379}, number = {}, pages = {228-238}, doi = {10.1016/j.neuroscience.2018.03.022}, pmid = {29588251}, issn = {1873-7544}, mesh = {Animals ; Female ; Male ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals, Genetically Modified ; Cell Survival/drug effects ; Cells, Cultured ; *Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/metabolism ; *Hydroxamic Acids/pharmacology ; Motor Activity/drug effects/physiology ; *Motor Neurons/drug effects/metabolism/pathology ; *Muscle, Skeletal/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; *Pyrroles/pharmacology ; Random Allocation ; Sciatic Nerve/drug effects/metabolism/pathology ; Superoxide Dismutase/metabolism ; Disease Models, Animal ; }, abstract = {Emerging evidence indicates that transcriptome alterations due to epigenetic deregulation concur to ALS pathogenesis. Accordingly, pan-histone deacetylase (HDAC) inhibitors delay ALS development in mice, but these compounds failed when tested in ALS patients. Possibly, lack of selectivity toward specific classes of HDACs weakens the therapeutic effects of pan-HDAC inhibitors. Here, we tested the effects of the HDAC Class II selective inhibitor MC1568 on disease evolution, motor neuron survival as well as skeletal muscle function in SOD1G93A mice. We report that HDACs did not undergo expression changes during disease evolution in isolated motor neurons of adult mice. Conversely, increase in specific Class II HDACs (-4, -5 and -6) occurs in skeletal muscle of mice with severe neuromuscular impairment. Importantly, treatment with MC1568 causes early improvement of motor performances that vanishes at later stages of disease. Notably, motor improvement is not paralleled by reduced motor neuron degeneration but by increased skeletal muscle electrical potentials, reduced activation of mir206/FGFBP1-dependent muscle reinnervation signaling, and increased muscle expression of myogenic genes.}, }
@article {pmid29579332, year = {2018}, author = {Brookes, DW and Coates, M and Allen, H and Daly, L and Constant, S and Huang, S and Hows, M and Davis, A and Cass, L and Ayrton, J and Knowles, I and Strong, P and Rapeport, G and Ito, K}, title = {Late therapeutic intervention with a respiratory syncytial virus L-protein polymerase inhibitor, PC786, on respiratory syncytial virus infection in human airway epithelium.}, journal = {British journal of pharmacology}, volume = {175}, number = {12}, pages = {2520-2534}, pmid = {29579332}, issn = {1476-5381}, mesh = {Antiviral Agents/chemistry/*pharmacology ; Benzamides ; Benzazepines ; DNA-Directed RNA Polymerases/antagonists &amp; inhibitors/metabolism ; Dose-Response Relationship, Drug ; Epithelium/*drug effects/metabolism/virology ; HeLa Cells ; Humans ; Microbial Sensitivity Tests ; Respiratory Mucosa/*drug effects/metabolism/virology ; Respiratory Syncytial Virus Infections/*drug therapy/metabolism ; Respiratory Syncytial Virus, Human/*drug effects ; Spiro Compounds/chemistry/*pharmacology ; Structure-Activity Relationship ; Virus Replication/drug effects ; }, abstract = {BACKGROUND AND PURPOSE: Effective anti-respiratory syncytial virus (RSV) agents are still not available for clinical use. Current major targets are virus surface proteins, such as a fusion protein involved in viral entry, but agents effective after RSV infection is established are required. Here we have investigated the effects of late therapeutic intervention with a novel inhaled RSV polymerase inhibitor, PC786, on RSV infection in human airway epithelium.<br><br>EXPERIMENTAL APPROACH: Air liquid interface-cultured bronchial or small airway epithelium was infected with RSVA2. PC786 was applied apically or basolaterally once daily following peak virus load on Day 3 post inoculation. Apical wash was collected daily for determination of viral burden by PCR and plaque assay (primary endpoints) and biomarker analyses. The effects were compared with those of ALS-8112, an anti-RSV nucleoside analogue, and GS-5806, a fusion-protein inhibitor, which were treated basolaterally.<br><br>KEY RESULTS: Late intervention with GS-5806 did not show significant anti-viral effects, but PC786 produced potent, concentration-dependent inhibition of viral replication with viral load falling below detectable limits 3&#xa0;days after treatment commenced in airway epithelium. These effects were superior to those of ALS-8112. PC786 showed inhibitory activities against RSV-induced increases of CCL5, IL-6, double-strand DNA and mucin. The effects of PC786 were also confirmed in small airway epithelium.<br><br>CONCLUSION AND IMPLICATIONS: Late therapeutic intervention with the RSV polymerase inhibitor, PC786, reduced the viral burden quickly in human airway epithelium. Thus, PC786 demonstrates the potential to be an effective therapeutic agent to treat active RSV infection.}, }
@article {pmid29577362, year = {2018}, author = {Jokubauskas, L and Baltrušaitytė, A}, title = {Efficacy of biofeedback therapy on sleep bruxism: A systematic review and meta-analysis.}, journal = {Journal of oral rehabilitation}, volume = {45}, number = {6}, pages = {485-495}, doi = {10.1111/joor.12628}, pmid = {29577362}, issn = {1365-2842}, mesh = {Biofeedback, Psychology/*methods/*physiology ; Controlled Clinical Trials as Topic ; Electric Stimulation Therapy ; Humans ; Mandibular Advancement ; Sleep Bruxism/*physiopathology/rehabilitation/*therapy ; Treatment Outcome ; }, abstract = {This study updates the review published by Wang et al in 2014 (Sleep Breath 2014;18(2):235-242). The review focuses on the most recent literature on management of sleep bruxism (SB) with biofeedback. An electronic search was conducted in five databases searching for articles published later than the date of Wang et al's search, viz., October 2012. Six articles of 2320 identified citations involving 86 adult participants were included in the qualitative synthesis. Of them, 4 were randomised controlled trials (RCTs) and 2 were uncontrolled before-after studies. Different feedback modalities (electrical, auditory and vibratory stimulus) were investigated. The overall quality of the selected studies was assessed using the GRADE criteria. Due to heterogeneity between studies, the quantitative synthesis was performed out of three RCTs, of which two were retrieved from the previous review. The meta-analysis indicated a non-significant difference in electromyographic-measured SB episodes per hour after one night of contingent electrical stimulation (CES) compared with placebo control, yet a significant difference was shown after five nights of CES. The quality of evidence identified through GRADEpro was from low to moderate, due to imprecision and inconsistency between studies. Qualitative synthesis did not present a reliable reduction in clinical pain levels; however, no substantial sleep disturbances were indicated following the intervention. In conclusion, one of the biofeedback modalities, CES, is effective in reducing SB-related motor activities after a short-term treatment period. However, evidence of long-term effects is lacking. Further longitudinal studies with larger samples are necessary to acknowledge the clinical application of biofeedback.}, }
@article {pmid29571747, year = {2018}, author = {Zhang, Q and Zhang, P and Qi, GJ and Zhang, Z and He, F and Lv, ZX and Peng, X and Cai, HW and Li, TX and Wang, XM and Tian, B}, title = {Cdk5 suppression blocks SIRT1 degradation via the ubiquitin-proteasome pathway in Parkinson's disease models.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {1862}, number = {6}, pages = {1443-1451}, doi = {10.1016/j.bbagen.2018.03.021}, pmid = {29571747}, issn = {0304-4165}, mesh = {Animals ; Behavior, Animal ; Cells, Cultured ; Cyclin-Dependent Kinase 5/genetics/*metabolism ; *Disease Models, Animal ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Neurons/metabolism/pathology ; *Neuroprotective Agents ; Parkinson Disease/etiology/*metabolism/pathology ; Proteasome Endopeptidase Complex/genetics/*metabolism ; Rats, Sprague-Dawley ; Sirtuin 1/*physiology ; Ubiquitins/*metabolism ; }, abstract = {The NAD[+]-dependent protein deacetylase sirtuin 1 (SIRT1), a member of the sirtuin family, may have a neuroprotective effect in multiple neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Many studies have suggested that overexpression-induced or resveratrol-treated activation of SIRT1 could significantly ameliorate several neurodegenerative diseases in mouse models. However, the type of SIRT1, protein expression levels and underlying mechanisms remain unclear, especially in PD. In this study, the results demonstrated that SIRT1 knockout markedly worsened the movement function in MPTP-lesioned animal model of PD. SIRT1 expression was found to be markedly decreased not only in environmental factor PD models, neurotoxin MPP[+]-treated primary culture neurons and MPTP-induced mice but also in genetic factor PD models, overexpressed α-synuclein-A30PA53T SH-SY5Y stable cell line and hm[2]α-SYN-39 transgenic mouse strain. Importantly, the degradation of SIRT1 during MPP[+] treatment was mediated by the ubiquitin-proteasome pathway. Furthermore, the results indicated that cyclin-dependent kinase 5 (Cdk5) was also involved in the decrease of SIRT1 expression, which could be efficiently blocked by the inhibition of Cdk5. In conclusion, our findings revealed that the Cdk5-dependent ubiquitin-proteasome pathway mediated degradation of SIRT1 plays a vital role in the progression of PD.}, }
@article {pmid29571701, year = {2018}, author = {Kuźma-Kozakiewicz, M}, title = {Edaravone in the treatment of amyotrophic lateral sclerosis.}, journal = {Neurologia i neurochirurgia polska}, volume = {52}, number = {2}, pages = {124-128}, doi = {10.1016/j.pjnns.2018.03.004}, pmid = {29571701}, issn = {0028-3843}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Edaravone/*therapeutic use ; Humans ; }, }
@article {pmid29569624, year = {2018}, author = {Ahmed, RM and Ke, YD and Vucic, S and Ittner, LM and Seeley, W and Hodges, JR and Piguet, O and Halliday, G and Kiernan, MC}, title = {Physiological changes in neurodegeneration - mechanistic insights and clinical utility.}, journal = {Nature reviews. Neurology}, volume = {14}, number = {5}, pages = {259-271}, pmid = {29569624}, issn = {1759-4766}, mesh = {*Alzheimer Disease/metabolism/physiopathology ; *Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; Animals ; *Autonomic Nervous System/physiopathology ; *Frontotemporal Dementia/metabolism/physiopathology ; Humans ; *Hypothalamus/metabolism/physiopathology ; *Nerve Net/physiopathology ; *Parkinsonian Disorders/metabolism/physiopathology ; *Sleep Wake Disorders/physiopathology ; }, abstract = {The effects of neurodegenerative syndromes extend beyond cognitive function to involve key physiological processes, including eating and metabolism, autonomic nervous system function, sleep, and motor function. Changes in these physiological processes are present in several conditions, including frontotemporal dementia, amyotrophic lateral sclerosis, Alzheimer disease and the parkinsonian plus conditions. Key neural structures that mediate physiological changes across these conditions include neuroendocrine and hypothalamic pathways, reward pathways, motor systems and the autonomic nervous system. In this Review, we highlight the key changes in physiological processing in neurodegenerative syndromes and the similarities in these changes between different progressive neurodegenerative brain conditions. The changes and similarities between disorders might provide novel insights into the human neural correlates of physiological functioning. Given the evidence that physiological changes can arise early in the neurodegenerative process, these changes could provide biomarkers to aid in the early diagnosis of neurodegenerative diseases and in treatment trials.}, }
@article {pmid29564728, year = {2018}, author = {Chen, Y and Cao, B and Ou, R and Wei, Q and Chen, X and Zhao, B and Wu, Y and Song, W and Shang, HF}, title = {Determining the Effect of the HNMT, STK39, and NMD3 Polymorphisms on the Incidence of Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Multiple System Atrophy in Chinese Populations.}, journal = {Journal of molecular neuroscience : MN}, volume = {64}, number = {4}, pages = {574-580}, pmid = {29564728}, issn = {1559-1166}, support = {81571247//the funding of the National Science Fund of China/ ; 81701249//the funding of the National Science Fund of China/ ; 2017YFC0909101//the National Key Research and Development Program of China/ ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*genetics ; China ; Female ; Histamine N-Methyltransferase/*genetics ; Humans ; Male ; Middle Aged ; Multiple System Atrophy/*genetics ; Parkinson Disease/*genetics ; *Polymorphism, Single Nucleotide ; Protein Serine-Threonine Kinases/*genetics ; RNA-Binding Proteins/*genetics ; }, abstract = {Large-scale meta-analyses of genome-wide association studies have identified several loci linked to sporadic Parkinson's disease (PD). However, the roles of some important loci, such as HNMT Thr105Ile, STK39 rs2390669, and NMD3 rs34016896, have not been clarified in Chinese populations. Accumulating evidence indicates that some common clinicopathological characteristics are shared by different neurodegenerative diseases. Consequently, we conducted a large sample study to investigate associations between these variants and PD, multiple system atrophy (MSA), and amyotrophic lateral sclerosis (ALS) in Chinese populations. A total of 2417 patients, including 1237 PD, 850 SALS, and 330 MSA patients, along with 836 healthy controls (HCs) were examined in this study. All patients were genotyped for SNPs using the Sequenom iPLEX assay. No significant differences were found in the genotype and allele frequency distributions between the three neurodegenerative diseases and three candidate variants investigated. In subgroup analysis, compared with PD patients with initial symptom of tremor and HCs, the minor allele frequency of NMD3 rs34016896 in PD patients with initial symptoms of rigidity/bradykinesia was significantly lower. In addition, female patients carrying the rs34016896 minor allele had an increased risk of developing MSA (OR 1.25, 95% CI [1.09-1.43]), and ALS patients carrying the Ile105 polymorphism on the Thr105Ile allele in the HNMT gene exhibited a trend toward a delay in symptom onset of 3.010 ± 1.629 years. Our results indicate that the presence of the rs34016896 allele in the NMD3 gene may contribute to the development of synucleinopathies and that the Thr105Ile allele in the HNMT gene could potentially be an important therapeutic target for the treatment of ALS.}, }
@article {pmid29562705, year = {2018}, author = {Kruminis-Kaszkiel, E and Juranek, J and Maksymowicz, W and Wojtkiewicz, J}, title = {CRISPR/Cas9 Technology as an Emerging Tool for Targeting Amyotrophic Lateral Sclerosis (ALS).}, journal = {International journal of molecular sciences}, volume = {19}, number = {3}, pages = {}, pmid = {29562705}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; CRISPR-Cas Systems/*genetics ; *Genetic Techniques ; Humans ; Models, Biological ; }, abstract = {The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) is a genome editing tool that has recently caught enormous attention due to its novelty, feasibility, and affordability. This system naturally functions as a defense mechanism in bacteria and has been repurposed as an RNA-guided DNA editing tool. Unlike zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), CRISPR/Cas9 takes advantage of an RNA-guided DNA endonuclease enzyme, Cas9, which is able to generate double-strand breaks (DSBs) at specific genomic locations. It triggers cellular endogenous DNA repair pathways, contributing to the generation of desired modifications in the genome. The ability of the system to precisely disrupt DNA sequences has opened up new avenues in our understanding of amyotrophic lateral sclerosis (ALS) pathogenesis and the development of new therapeutic approaches. In this review, we discuss the current knowledge of the principles and limitations of the CRISPR/Cas9 system, as well as strategies to improve these limitations. Furthermore, we summarize novel approaches of engaging the CRISPR/Cas9 system in establishing an adequate model of neurodegenerative disease and in the treatment of SOD1-linked forms of ALS. We also highlight possible applications of this system in the therapy of ALS, both the inherited type as well as ALS of sporadic origin.}, }
@article {pmid29560813, year = {2018}, author = {Scoles, DR and Pulst, SM}, title = {Oligonucleotide therapeutics in neurodegenerative diseases.}, journal = {RNA biology}, volume = {15}, number = {6}, pages = {707-714}, pmid = {29560813}, issn = {1555-8584}, support = {R01 NS097903/NS/NINDS NIH HHS/United States ; R21 NS081182/NS/NINDS NIH HHS/United States ; R37 NS033123/NS/NINDS NIH HHS/United States ; U01 NS103883/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Ataxin-2/antagonists &amp; inhibitors/genetics/metabolism ; Humans ; Mice ; *Neurodegenerative Diseases/drug therapy/genetics/metabolism ; *Oligonucleotides, Antisense/genetics/therapeutic use ; }, abstract = {Therapeutics that directly target RNAs are promising for a broad spectrum of disorders, including the neurodegenerative diseases. This is exemplified by the FDA approval of Nusinersen, an antisense oligonucleotide (ASO) therapeutic for spinal muscular atrophy (SMA). RNA targeting therapeutics are currently under development for amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias. We have used an ASO approach toward developing a treatment for spinocerebellar ataxia type 2 (SCA2), for targeting the causative gene ATXN2. We demonstrated that reduction of ATXN2 expression in SCA2 mice treated by intracerebroventicular injection (ICV) of ATXN2 ASO delayed motor phenotype onset, improved the expression of several genes demonstrated abnormally reduced by transcriptomic profiling of SCA2 mice, and restored abnormal Purkinje cell firing frequency in acute cerebellar sections. Here we discuss RNA abnormalities in disease and the prospects of targeting neurodegenerative diseases at the level of RNA control using ASOs and other RNA-targeted therapeutics.}, }
@article {pmid29559895, year = {2018}, author = {Bucchia, M and Merwin, SJ and Re, DB and Kariya, S}, title = {Limitations and Challenges in Modeling Diseases Involving Spinal Motor Neuron Degeneration in Vitro.}, journal = {Frontiers in cellular neuroscience}, volume = {12}, number = {}, pages = {61}, pmid = {29559895}, issn = {1662-5102}, support = {R21 AG052011/AG/NIA NIH HHS/United States ; }, abstract = {Pathogenic conditions involving degeneration of spinal motor neurons (MNs), such as amyotrophic lateral sclerosis, sarcopenia, and spinal cord injury, mostly occur in individuals whose spinal MNs are fully mature. There is currently no effective treatment to prevent death or promote axonal regeneration of the spinal MNs affected in these patients. To increase our understanding and find a cure for such conditions, easily controllable and monitorable cell culture models allow for a better dissection of certain molecular and cellular events that cannot be teased apart in whole organism models. To date, various types of spinal MN cultures have been described. Yet these models are all based on the use of immature neurons or neurons uncharacterized for their degree of maturity after being isolated and cultured. Additionally, studying only MNs cannot give a comprehensive and complete view of the neurodegenerative processes usually involving other cell types. To date, there is no confirmed in vitro model faithfully emulating disease or injury of the mature spinal MNs. In this review, we summarize the different limitations of currently available culture models, and discuss the challenges that have to be overcome for developing more reliable and translational platforms for the in vitro study of spinal MN degeneration.}, }
@article {pmid29559385, year = {2018}, author = {Wang, TH and Wang, SY and Wang, XD and Jiang, HQ and Yang, YQ and Wang, Y and Cheng, JL and Zhang, CT and Liang, WW and Feng, HL}, title = {Fisetin Exerts Antioxidant and Neuroprotective Effects in Multiple Mutant hSOD1 Models of Amyotrophic Lateral Sclerosis by Activating ERK.}, journal = {Neuroscience}, volume = {379}, number = {}, pages = {152-166}, doi = {10.1016/j.neuroscience.2018.03.008}, pmid = {29559385}, issn = {1873-7544}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Animals, Genetically Modified ; Antioxidants/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Disease Models, Animal ; Drosophila melanogaster ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Flavonoids/*pharmacology ; Flavonols ; Free Radicals/metabolism ; Humans ; Male ; Mice ; Motor Activity/drug effects ; Mutation ; Neuroprotective Agents/*pharmacology ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Oxidative stress exhibits a central role in the course of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease commonly found to include a copper/zinc superoxide dismutase (SOD1) gene mutation. Fisetin, a natural antioxidant, has shown benefits in varied neurodegenerative diseases. The possible effect of fisetin in ALS has not been clarified as of yet. We investigated whether fisetin affected mutant hSOD1 ALS models. Three different hSOD1-related mutant models were used: Drosophila expressing mutant hSOD1[G85R], hSOD1[G93A] NSC34 cells, and transgenic mice. Fisetin treatment provided neuroprotection as demonstrated by an improved survival rate, attenuated motor impairment, reduced ROS damage and regulated redox homeostasis compared with those in controls. Furthermore, fisetin increased the expression of phosphorylated ERK and upregulated antioxidant factors, which were reversed by MEK/ERK inhibition. Finally, fisetin reduced the levels of both mutant and wild-type hSOD1 in vivo and in vitro, as well as the levels of detergent-insoluble hSOD1 proteins. The results indicate that fisetin protects cells from ROS damage and improves the pathological behaviors caused by oxidative stress in disease models related to SOD1 gene mutations probably by activating ERK, thereby providing a potential treatment for ALS.}, }
@article {pmid29552439, year = {2018}, author = {Fujisaki, N and Suwazono, S and Suehara, M and Nakachi, R and Kido, M and Fujiwara, Y and Oshiro, S and Tokashiki, T and Takashima, H and Nakagawa, M}, title = {The natural history of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) in 97 Japanese patients.}, journal = {Intractable &amp; rare diseases research}, volume = {7}, number = {1}, pages = {7-12}, pmid = {29552439}, issn = {2186-3644}, abstract = {Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is a motor and sensory neuronopathy with autosomal dominant inheritance, adult onset, slowly progressive course, and is associated with TRK-fused gene (TFG) mutation. At advanced stages, respiratory failure and dysphagia becomes life-threatoning, and patients typically die by their 70s. Although there is currently no evidence for effective treatment, a therapy may be found by elucidation of the function of TFG. Recently its pathomechanism has been proposed to be associated with abnormalities in protein transfer from the endoplasmic reticulum. Such pathomechanisms might involve a similar process in amyotrophic lateral sclerosis; thus, its pathomechanisms and treatment strategy might make it a good model for neurodegenerative disorders. It is of great value to clarify the natural history of HMSN-P, in oder to judge the treatment effect. By evaluating 97 patients (79 out of 97 were examined and all confirmed with p.Pro 285 Leu mutation) in this study, it was confirmed that this disease follows a uniform course in the earlier stages, and there are individual differences in the onset between 20 and 30 years. Such uniformity might be due to the proposed single gene abnormality. At advanced stages, there are larger individual differences in the progression, but the reasons for these are unknown. Longer survival might be achieved with a better care for respiratory failure and dysphagia if such cares were undertaken at appropriate times.}, }
@article {pmid29549424, year = {2018}, author = {Vandoorne, T and De Bock, K and Van Den Bosch, L}, title = {Energy metabolism in ALS: an underappreciated opportunity?.}, journal = {Acta neuropathologica}, volume = {135}, number = {4}, pages = {489-509}, pmid = {29549424}, issn = {1432-0533}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/therapy ; Animals ; *Energy Metabolism ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative disorder that primarily affects motor neurons. Despite our increased understanding of the genetic factors contributing to ALS, no effective treatment is available. A growing body of evidence shows disturbances in energy metabolism in ALS. Moreover, the remarkable vulnerability of motor neurons to ATP depletion has become increasingly clear. Here, we review metabolic alterations present in ALS patients and models, discuss the selective vulnerability of motor neurons to energetic stress, and provide an overview of tested and emerging metabolic approaches to treat ALS. We believe that a further understanding of the metabolic biology of ALS can lead to the identification of novel therapeutic targets.}, }
@article {pmid29547745, year = {2018}, author = {Santhanam, N and Kumanchik, L and Guo, X and Sommerhage, F and Cai, Y and Jackson, M and Martin, C and Saad, G and McAleer, CW and Wang, Y and Lavado, A and Long, CJ and Hickman, JJ}, title = {Stem cell derived phenotypic human neuromuscular junction model for dose response evaluation of therapeutics.}, journal = {Biomaterials}, volume = {166}, number = {}, pages = {64-78}, pmid = {29547745}, issn = {1878-5905}, support = {R01 NS050452/NS/NINDS NIH HHS/United States ; R44 TR001326/TR/NCATS NIH HHS/United States ; }, mesh = {Coculture Techniques ; *Dose-Response Relationship, Drug ; *Drug Evaluation, Preclinical/methods ; Electric Stimulation ; Humans ; Induced Pluripotent Stem Cells/cytology ; Motor Neurons/cytology ; Muscle Contraction ; Muscle Fibers, Skeletal/cytology ; *Neuromuscular Junction ; *Tissue Engineering ; }, abstract = {There are currently no functional neuromuscular junction (hNMJ) systems composed of human cells that could be used for drug evaluations or toxicity testing in vitro. These systems are needed to evaluate NMJs for diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy or other neurodegenerative diseases or injury states. There are certainly no model systems, animal or human, that allows for isolated treatment of motoneurons or muscle capable of generating dose response curves to evaluate pharmacological activity of these highly specialized functional units. A system was developed in which human myotubes and motoneurons derived from stem cells were cultured in a serum-free medium in a BioMEMS construct. The system is composed of two chambers linked by microtunnels to enable axonal outgrowth to the muscle chamber that allows separate stimulation of each component and physiological NMJ function and MN stimulated tetanus. The muscle's contractions, induced by motoneuron activation or direct electrical stimulation, were monitored by image subtraction video recording for both frequency and amplitude. Bungarotoxin, BOTOX[®] and curare dose response curves were generated to demonstrate pharmacological relevance of the phenotypic screening device. This quantifiable functional hNMJ system establishes a platform for generating patient-specific NMJ models by including patient-derived iPSCs.}, }
@article {pmid29545836, year = {2018}, author = {Geffard, M and Mangas, A and Bedat, D and Coveñas, R}, title = {GEMALS: A promising therapy for amyotrophic lateral sclerosis.}, journal = {Experimental and therapeutic medicine}, volume = {15}, number = {4}, pages = {3203-3210}, pmid = {29545836}, issn = {1792-0981}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that currently has no cure. At present, the only approved treatment for ALS is Riluzole, a glutamate release blocker that improves life expectancy by 3-6 months. ALS-Endotherapia (GEMALS) is a novel therapeutic approach to treat ALS and the aim of the present study was to investigate the potential beneficial effects of this novel treatment. A total of 31 patients with ALS were assessed in the current study. Deceleration of the disease was observed in 83.87% (P<0.0001) of patients and mean life expectancy was increased by 38 months. Motor functions, including breathing, walking, salivation, speech, swallowing and writing, were also improved in patients treated with GEMALS. The results of the present study demonstrate that long-term treatment with GEMALS has a curative effect in patients with ALS. Furthermore, the overall effectiveness of GEMALS was assessed using the ALS Assessment Questionnaire. The score improvement was 76.2 and 100% for men and women, respectively (P<0.0001), compared with the worldwide reference score. The present study provides a promising basis for the use of GEMALS as a therapeutic treatment for patients with ALS; however, these results must be confirmed in a double-blinded and randomized clinical trial.}, }
@article {pmid29540819, year = {2018}, author = {Sun, J and Mu, Y and Jiang, Y and Song, R and Yi, J and Zhou, J and Sun, J and Jiao, X and Prinz, RA and Li, Y and Xu, X}, title = {Inhibition of p70 S6 kinase activity by A77 1726 induces autophagy and enhances the degradation of superoxide dismutase 1 (SOD1) protein aggregates.}, journal = {Cell death &amp; disease}, volume = {9}, number = {3}, pages = {407}, pmid = {29540819}, issn = {2041-4889}, support = {R01 AR057404/AR/NIAMS NIH HHS/United States ; }, mesh = {AMP-Activated Protein Kinase Kinases ; Amino Acid Motifs ; Aniline Compounds/*pharmacology ; Animals ; Autophagy/*drug effects ; Autophagy-Related Protein 7/genetics/metabolism ; Autophagy-Related Protein-1 Homolog/genetics/metabolism ; Cell Line ; Crotonates ; Hydroxybutyrates/*pharmacology ; MAP Kinase Kinase Kinases/genetics/metabolism ; Mice ; Nitriles ; Protein Aggregates/drug effects ; Protein Kinases/genetics/metabolism ; Proteolysis/drug effects ; Ribosomal Protein S6 Kinases, 70-kDa/*antagonists &amp; inhibitors/chemistry/genetics/metabolism ; Superoxide Dismutase-1/genetics/*metabolism ; TOR Serine-Threonine Kinases/genetics/metabolism ; Toluidines ; }, abstract = {Autophagy plays a central role in degrading misfolded proteins such as mutated superoxide dismutase 1 (SOD1), which forms aggregates in motor neurons and is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Autophagy is activated when UNC-51-like kinase 1 (ULK1) is phosphorylated at S555 and activated by AMP-activated protein kinase (AMPK). Autophagy is suppressed when ULK1 is phosphorylated at S757 by the mechanistic target of rapamycin (mTOR). Whether p70 S6 kinase 1 (S6K1), a serine/threonine kinase downstream of mTOR, can also regulate autophagy remains uncertain. Here we report that inhibition of S6K1 by A77 1726, the active metabolite of an anti-inflammatory drug leflunomide, induced mTOR feedback activation and ULK1[S757] phosphorylation in NSC34 cells, a hybrid mouse motoneuron cell line. Unexpectedly, A77 1726 did not suppress but rather induced autophagy by increasing AMPK[T172] and ULK1[S555] phosphorylation. Similar observations were made with PF-4708671, a specific S6K1 inhibitor, or with S6K1 siRNA. Further studies showed that A77 1726 induced AMPK phosphorylation by activating the TGF-β-activated kinase 1 (TAK1). Functional studies revealed that A77 1726 induced co-localization of mutant SOD1[G93A] protein aggregates with autophagosomes and accelerated SOD1[G93A] protein degradation, which was blocked by inhibition of autophagy through autophagy-related protein 7 (ATG7) siRNA. Our study suggests that S6K1 inhibition induces autophagy through TAK1-mediated AMPK activation in NSC34 cells, and that blocking S6K1 activity by a small molecule inhibitor such as leflunomide may offer a new strategy for ALS treatment.}, }
@article {pmid29535831, year = {2018}, author = {Eve, DJ and Steiner, G and Mahendrasah, A and Sanberg, PR and Kurien, C and Thomson, A and Borlongan, CV and Garbuzova-Davis, S}, title = {Reduction of microhemorrhages in the spinal cord of symptomatic ALS mice after intravenous human bone marrow stem cell transplantation accompanies repair of the blood-spinal cord barrier.}, journal = {Oncotarget}, volume = {9}, number = {12}, pages = {10621-10634}, pmid = {29535831}, issn = {1949-2553}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; }, abstract = {Blood-spinal cord barrier (BSCB) alterations, including capillary rupture, have been demonstrated in animal models of amyotrophic lateral sclerosis (ALS) and ALS patients. To date, treatment to restore BSCB in ALS is underexplored. Here, we evaluated whether intravenous transplantation of human bone marrow CD34[+] (hBM34[+]) cells into symptomatic ALS mice leads to restoration of capillary integrity in the spinal cord as determined by detection of microhemorrhages. Three different doses of hBM34[+] cells (5 × 10[4], 5 × 10[5] or 1 × 10[6]) or media were intravenously injected into symptomatic G93A SOD1 mice at 13 weeks of age. Microhemorrhages were determined in the cervical and lumbar spinal cords of mice at 4 weeks post-treatment, as revealed by Perls' Prussian blue staining for ferric iron. Numerous microhemorrhages were observed in the gray and white matter of the spinal cords in media-treated mice, with a greater number of capillary ruptures within the ventral horn of both segments. In cell-treated mice, microhemorrhage numbers in the cervical and lumbar spinal cords were inversely related to administered cell doses. In particular, the pervasive microvascular ruptures determined in the spinal cords in late symptomatic ALS mice were significantly decreased by the highest cell dose, suggestive of BSCB repair by grafted hBM34[+] cells. The study results provide translational outcomes supporting transplantation of hBM34[+] cells at an optimal dose as a potential therapeutic strategy for BSCB repair in ALS patients.}, }
@article {pmid29533975, year = {2018}, author = {Mammana, S and Fagone, P and Cavalli, E and Basile, MS and Petralia, MC and Nicoletti, F and Bramanti, P and Mazzon, E}, title = {The Role of Macrophages in Neuroinflammatory and Neurodegenerative Pathways of Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis: Pathogenetic Cellular Effectors and Potential Therapeutic Targets.}, journal = {International journal of molecular sciences}, volume = {19}, number = {3}, pages = {}, pmid = {29533975}, issn = {1422-0067}, mesh = {Alzheimer Disease/drug therapy/etiology/*metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/etiology/*metabolism ; Animals ; Central Nervous System/metabolism/pathology ; Humans ; Macrophages/*metabolism ; Molecular Targeted Therapy ; Multiple Sclerosis/drug therapy/etiology/*metabolism ; }, abstract = {In physiological conditions, different types of macrophages can be found within the central nervous system (CNS), i.e., microglia, meningeal macrophages, and perivascular (blood-brain barrier) and choroid plexus (blood-cerebrospinal fluid barrier) macrophages. Microglia and tissue-resident macrophages, as well as blood-borne monocytes, have different origins, as the former derive from yolk sac erythromyeloid precursors and the latter from the fetal liver or bone marrow. Accordingly, specific phenotypic patterns characterize each population. These cells function to maintain homeostasis and are directly involved in the development and resolution of neuroinflammatory processes. Also, following inflammation, circulating monocytes can be recruited and enter the CNS, therefore contributing to brain pathology. These cell populations have now been identified as key players in CNS pathology, including autoimmune diseases, such as multiple sclerosis, and degenerative diseases, such as Amyotrophic Lateral Sclerosis and Alzheimer's disease. Here, we review the evidence on the involvement of CNS macrophages in neuroinflammation and the advantages, pitfalls, and translational opportunities of pharmacological interventions targeting these heterogeneous cellular populations for the treatment of brain diseases.}, }
@article {pmid29529498, year = {2018}, author = {Battaglia, G and Bruno, V}, title = {Metabotropic glutamate receptor involvement in the pathophysiology of amyotrophic lateral sclerosis: new potential drug targets for therapeutic applications.}, journal = {Current opinion in pharmacology}, volume = {38}, number = {}, pages = {65-71}, doi = {10.1016/j.coph.2018.02.007}, pmid = {29529498}, issn = {1471-4973}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism ; Animals ; Humans ; Receptors, Metabotropic Glutamate/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex genetic, late age-onset, progressive neurodegenerative disorder leading to the death of upper and lower motor neurons. Life expectancy after diagnosis is short due to the ongoing degeneration and to the lack of effective treatments. Axonal alterations, mitochondrial deficits, RNA changes, protein misfolding and turnover, glial dysfunction and hyperexcitability are key players in molecular mechanisms involved in the degeneration of motor neurons. In the context of hyperexcitability, metabotropic glutamate (mGlu) receptors, which are widely distributed throughout the central nervous system and act through many intracellular signaling pathways, are emerging as novel potential drug targets for the therapeutic treatment of ALS, as they are able to counteract excitotoxicity by reducing glutamate release and inducing the production of neurotrophic factors.}, }
@article {pmid29525492, year = {2018}, author = {Fang, T and Al Khleifat, A and Meurgey, JH and Jones, A and Leigh, PN and Bensimon, G and Al-Chalabi, A}, title = {Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study.}, journal = {The Lancet. Neurology}, volume = {17}, number = {5}, pages = {416-422}, pmid = {29525492}, issn = {1474-4465}, support = {ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; JONES/OCT15/958-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; *Disease Progression ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Antagonists/*administration &amp; dosage ; Humans ; *Outcome Assessment, Health Care ; Retrospective Studies ; Riluzole/*administration &amp; dosage ; *Severity of Illness Index ; *Survival Analysis ; Time Factors ; }, abstract = {BACKGROUND: Riluzole is the only drug to prolong survival for amyotrophic lateral sclerosis (ALS) and, at a dose of 100 mg, was associated with a 35% reduction in mortality in a clinical trial. A key question is whether the survival benefit occurs at an early stage of disease, late stage, or is spread throughout the course of the disease. To address this question, we used the King's clinical staging system to do a retrospective analysis of data from the original dose-ranging clinical trial of riluzole.<br><br>METHODS: In the original dose-ranging trial, patients were enrolled between December, 1992, and November, 1993, in Belgium, France, Germany, Spain, Canada, the USA, and the UK if they had probable or definite ALS as defined by the El Escorial criteria. The censor date for the riluzole survival data was set as the original study end date of Dec 31, 1994. For this analysis, King's clinical ALS stage was estimated from the electronic case record data of the modified Norris scale, UK Medical Research Council score for muscle strength, El Escorial category, vital capacity, and gastrostomy insertion data. The lowest allocated stage was 2 because the original trial only included patients with probable or definite ALS. We used a &#x3c7;[2] test to assess the independence of stage at trial enrolment and treatment group, Kaplan-Meier product limit distribution to test the transition from each stage to subsequent stages, and Cox regression to confirm an effect of treatment group on time in stage, controlling for covariates. We did sensitivity analyses by combining treatment groups, using alternative strategies to stage, stratifying by stage at trial enrolment, and using multistate outcome analysis of treatments (MOAT).<br><br>FINDINGS: We analysed the case records of all 959 participants from the original dose-ranging trial, 237 assigned to 50 mg/day riluzole, 236 to 100 mg/day, 244 to 200 mg/day, and 242 to daily placebo. Clinical stage at enrolment did not significantly differ between treatment groups (p=0&#xb7;22). Time in stage 4 was longer for patients receiving 100 mg/day riluzole than for those receiving placebo (hazard ratio [HR] 0&#xb7;55, 95% CI 0&#xb7;36-0&#xb7;83; log-rank p=0&#xb7;037). Combining treatment groups and stratifying by stage at enrolment showed a similar result (HR 0&#xb7;638, 95% CI 0&#xb7;464-0&#xb7;878; p=0&#xb7;006), as did analysis with MOAT where the mean number of days spent in stage 4 was numerically higher for patients given riluzole at higher doses compared with patients receiving placebo. Time from stages 2 or 3 to subsequent stages or death did not differ between riluzole treatment groups and placebo (p=0&#xb7;83 for stage 2 and 0&#xb7;88 for stage 3).<br><br>INTERPRETATION: We showed that riluzole prolongs survival in the last clinical stage of ALS; this finding needs to be confirmed in a prospective study, and treatment effects at stage 1 still need to be analysed. The ALS stage at which benefit occurs is important for counselling of patients before starting treatment. Staging should be used in future ALS clinical trials to assess the stage at which survival benefit occurs, and a similar approach could be used for other neurodegenerative diseases.<br><br>FUNDING: NIHR Maudsley Biomedical Research Centre, The European Union Joint Programme on Neurodegeneration, and the King's Summer Undergraduate Studentship.}, }
@article {pmid29519253, year = {2018}, author = {Neal, ML and Boyle, AM and Budge, KM and Safadi, FF and Richardson, JR}, title = {The glycoprotein GPNMB attenuates astrocyte inflammatory responses through the CD44 receptor.}, journal = {Journal of neuroinflammation}, volume = {15}, number = {1}, pages = {73}, pmid = {29519253}, issn = {1742-2094}, support = {R01 ES026057/ES/NIEHS NIH HHS/United States ; U01 NS079249/NS/NINDS NIH HHS/United States ; R01ES026057//National Institute of Environmental Health Sciences/ ; R01 ES021800/ES/NIEHS NIH HHS/United States ; None//Michael J. Fox Foundation for Parkinson's Research/ ; R01ES021800//National Institute of Environmental Health Sciences/ ; U01NS079249//National Institute of Neurological Disorders and Stroke/ ; }, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology ; Analysis of Variance ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; Astrocytes/*drug effects ; Case-Control Studies ; Cells, Cultured ; Cytokines/genetics/metabolism ; Databases, Chemical ; Female ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Hyaluronan Receptors/*metabolism ; Inflammation/*drug therapy/etiology ; Male ; Membrane Glycoproteins/*therapeutic use ; Mice ; Neurotoxins/toxicity ; Nitric Oxide/metabolism ; Parkinson Disease/complications/*pathology ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {BACKGROUND: Neuroinflammation is one of the hallmarks of neurodegenerative diseases, such as Parkinson's disease (PD). Activation of glial cells, including microglia and astrocytes, is a characteristic of the inflammatory response. Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane glycoprotein that releases a soluble signaling peptide when cleaved by ADAM10 or other extracellular proteases. GPNMB has demonstrated a neuroprotective role in animal models of ALS and ischemia. However, the mechanism of this protection has not been well established. CD44 is a receptor expressed on astrocytes that can bind GPNMB, and CD44 activation has been demonstrated to reduce NFκB activation and subsequent inflammatory responses in macrophages. GPNMB signaling has not been investigated in models of PD or specifically in astrocytes. More recently, genetic studies have linked polymorphisms in GPNMB with risk for PD. Therefore, it is important to understand the role this signaling protein plays in PD.<br><br>METHODS: We used data mining techniques to evaluate mRNA expression of GPNMB and its receptor CD44 in the substantia nigra of PD and control brains. Immunofluorescence and qPCR techniques were used to assess GPNMB and CD44 levels in mice treated with MPTP. In vitro experiments utilized the immortalized mouse astrocyte cell line IMA2.1 and purified primary mouse astrocytes. The effects of recombinant GPNMB on cytokine-induced astrocyte activation was determined by qPCR, immunofluorescence, and measurement of nitric oxide and reactive oxygen production.<br><br>RESULTS: Increased GPNMB and CD44 expression was observed in the substantia nigra of human PD brains and in GFAP-positive astrocytes in an animal model of PD. GPNMB treatment attenuated cytokine-induced levels of inducible nitric oxide synthase, nitric oxide, reactive oxygen species, and the inflammatory cytokine IL-6 in an astrocyte cell line and primary mouse astrocytes. Using primary mouse astrocytes from CD44 knockout mice, we found that the anti-inflammatory effects of GPNMB are CD44-mediated.<br><br>CONCLUSIONS: These results demonstrate that GPNMB may exert its neuroprotective effect through reducing astrocyte-mediated neuroinflammation in a CD44-dependent manner, providing novel mechanistic insight into the neuroprotective properties of GPNMB.}, }
@article {pmid29511163, year = {2018}, author = {Delprat, B and Maurice, T and Delettre, C}, title = {Wolfram syndrome: MAMs' connection?.}, journal = {Cell death &amp; disease}, volume = {9}, number = {3}, pages = {364}, pmid = {29511163}, issn = {2041-4889}, mesh = {Endoplasmic Reticulum/*metabolism ; Endoplasmic Reticulum Stress ; Humans ; Intracellular Membranes/*metabolism ; Mitochondria/*metabolism ; Models, Biological ; Wolfram Syndrome/*metabolism/*pathology/physiopathology ; }, abstract = {Wolfram syndrome (WS) is a rare neurodegenerative disease, the main pathological hallmarks of which associate with diabetes, optic atrophy, and deafness. Other symptoms may be identified in some but not all patients. Prognosis is poor, with death occurring around 35 years of age. To date, no treatment is available. WS was first described as a mitochondriopathy. However, the localization of the protein on the endoplasmic reticulum (ER) membrane challenged this hypothesis. ER contacts mitochondria to ensure effective Ca[2+] transfer, lipids transfer, and apoptosis within stabilized and functionalized microdomains, termed "mitochondria-associated ER membranes" (MAMs). Two types of WS are characterized so far and Wolfram syndrome type 2 is due to mutation in CISD2, a protein mostly expressed in MAMs. The aim of the present review is to collect evidences showing that WS is indeed a mitochondriopathy, with established MAM dysfunction, and thus share commonalities with several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as metabolic diseases, such as diabetes.}, }
@article {pmid29510799, year = {2018}, author = {Mazibuko, Z and Indermun, S and Govender, M and Kumar, P and Du Toit, LC and Choonara, YE and Modi, G and Naidoo, D and Pillay, V}, title = {Targeted Delivery of Amantadine-loaded Methacrylate Nanosphere-ligands for the Potential Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Journal of pharmacy &amp; pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques}, volume = {21}, number = {1}, pages = {94-109}, doi = {10.18433/jpps29595}, pmid = {29510799}, issn = {1482-1826}, mesh = {Amantadine/chemistry/*therapeutic use ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Antiparkinson Agents/chemistry/*therapeutic use ; Cells, Cultured ; Drug Delivery Systems ; Ligands ; Methacrylates/*chemistry ; Mice ; Nanospheres/*chemistry ; Pentetic Acid/*chemistry ; Polyesters/chemistry ; }, abstract = {PURPOSE: This study aimed to develop and analyse poly(DL-lactic acid)-methacrylic acid nanospheres bound to the chelating ligand diethylenetriaminepentaacetic acid (DTPA) for the targeted delivery of amantadine in Amyotrophic Lateral Sclerosis (ALS).<br><br>METHODS: The nanospheres were prepared by a double emulsion solvent evaporation technique statistically optimized employing a 3-Factor Box-Behnken experimental design. Analysis of the particle size, zeta potential, polydispersity (Pdl), morphology, drug entrapment and drug release kinetics were carried out.<br><br>RESULTS: The prepared nanospheres were determined to have particle sizes ranging from 68.31 to 113.6 nm (Pdl &#x2264; 0.5). An initial burst release (50% of amantadine released in 24 hr) was also obtained, followed by a prolonged release phase of amantadine over 72 hr. Successful conjugation of the chelating ligand onto the surface of the optimised nanospheres was thereafter achieved and confirmed by TEM. The synthesized modified nanospheres were spherical in shape, 105.6 nm in size, with a PdI of 0.24 and zeta potential of -28.0 mV. Conjugation efficiency was determined to be 74%. In vitro and ex vivo cell study results confirmed the intracellular uptake of the modified nanospheres by the NSC-34 cell line and the non-cytotoxicity of the synthesized nanospheres.<br><br>CONCLUSIONS: Biocompatible amantadine-loaded nanospheres were successfully designed, characterized and optimized employing the randomized Box-Behnken statistical design. Delivery of amantadine over 72 hrs was achieved, with the nanospheres being of a size capable of internalization by the NSC- 34 cells.&#xa0;This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.}, }
@article {pmid29510461, year = {2018}, author = {Oskarsson, B and Moore, D and Mozaffar, T and Ravits, J and Wiedau-Pazos, M and Parziale, N and Joyce, NC and Mandeville, R and Goyal, N and Cudkowicz, ME and Weiss, M and Miller, RG and McDonald, CM}, title = {Mexiletine for muscle cramps in amyotrophic lateral sclerosis: A randomized, double-blind crossover trial.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, pmid = {29510461}, issn = {1097-4598}, support = {KL2 TR000134/TR/NCATS NIH HHS/United States ; UL1 RR024146/RR/NCRR NIH HHS/United States ; UL1 TR000002/TR/NCATS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; }, abstract = {INTRODUCTION: More than 90% of amyotrophic lateral sclerosis (ALS) patients have muscle cramps, but evidence-based treatments have not been available.<br><br>METHODS: A multicenter, double-blind, placebo-controlled crossover trial of mexiletine 150&#x2009;mg twice daily was conducted in ALS patients requesting treatment of symptomatic muscle cramps.<br><br>RESULTS: Muscle cramp frequency was reduced in 18 of 20 patients; 13 reductions were attributed to treatment (P&#x2009;<&#x2009;0.05). The average reduction, based on t tests, was 1.8 cramps per day (a reduction from 5.3 with placebo to 3.5 with mexiletine). The estimated reduction of cramp severity was 15 units on a 100-unit scale (P&#x2009;=&#x2009;0.01) from a baseline average of 46. No effect on fasciculations was noted. One patient discontinued the study because of dizziness, and another patient discontinued the study to start open-label mexiletine therapy. No serious adverse event occurred.<br><br>DISCUSSION: Mexiletine is a well tolerated and effective medication for controlling the symptom of muscle cramps in ALS. Muscle Nerve, 2018.}, }
@article {pmid29506970, year = {2018}, author = {Hijikata, Y and Katsuno, M and Suzuki, K and Hashizume, A and Araki, A and Yamada, S and Inagaki, T and Ito, D and Hirakawa, A and Kinoshita, F and Gosho, M and Sobue, G}, title = {Treatment with Creatine Monohydrate in Spinal and Bulbar Muscular Atrophy: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial.}, journal = {JMIR research protocols}, volume = {7}, number = {3}, pages = {e69}, pmid = {29506970}, issn = {1929-0748}, abstract = {BACKGROUND: Although spinal and bulbar muscular atrophy (SBMA) has been classified as a motor neuron disease, several reports have indicated the primary involvement of skeletal muscle in the pathogenesis of this devastating disease. Recent studies reported decreased intramuscular creatine levels in skeletal muscles in both patients with SBMA and transgenic mouse models of SBMA, which appears to contribute to muscle weakness.<br><br>OBJECTIVE: The present study aimed to examine the efficacy and safety of oral creatine supplementation to improve motor function in patients with SBMA.<br><br>METHODS: A randomized, double-blind, placebo-controlled, three-armed clinical trial was conducted to assess the safety and efficacy of creatine therapy in patients with SBMA. Patients with SBMA eligible for this study were assigned randomly in a 1:1:1 ratio to each group of placebo, 10 g, or 15 g daily dose of creatine monohydrate in a double-blind fashion. Participants took creatine or placebo orally 3 times a day for 8 weeks. Outcome measurements were results of neurological assessments, examinations, and questionnaires collected at baseline and at weeks 4, 8, and 16 after a washout period. The primary endpoint was the change in handgrip strength values from baseline to week 8. The secondary endpoints included the following: results of maximum voluntary isometric contraction tests of extremities; tongue pressure; results of the 15-foot timed walk test and the rise from bed test; modified quantitative myasthenia gravis score; respiratory function test results; activities of daily living assessed with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale and the Spinal and Bulbar Muscular Atrophy Functional Rating Scale; skeletal muscle mass measured with dual-energy X-ray absorptiometry; urinary 8-hydroxydeoxyguanosine levels; and questionnaires examining the quality of life, swallowing function, and fatigue.<br><br>RESULTS: Participant enrollment in the trial started from June 2014 and follow-up was completed in July 2015. The study is currently being analyzed.<br><br>CONCLUSIONS: This is the first clinical trial evaluating creatine therapy in SBMA. Given that creatine serves as an energy source in skeletal muscles, recovery of intramuscular creatine concentration is expected to improve muscle strength.<br><br>TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000012503; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014611 (Archived by WebCite at http://www.webcitation.org/6xOlbPkg3).}, }
@article {pmid29505320, year = {2018}, author = {Patel, N and Combs, H and York, M and Phan, C and Jimenez-Shahed, J}, title = {Pseudobulbar Affect Correlates With Mood Symptoms in Parkinsonian Disorders but Not Amyotrophic Lateral Sclerosis.}, journal = {The Journal of neuropsychiatry and clinical neurosciences}, volume = {30}, number = {3}, pages = {214-219}, doi = {10.1176/appi.neuropsych.17070131}, pmid = {29505320}, issn = {1545-7222}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*psychology ; Analysis of Variance ; Comorbidity ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; Mood Disorders/*complications/epidemiology ; Parkinsonian Disorders/*complications/epidemiology/*psychology ; Psychiatric Status Rating Scales ; Regression Analysis ; Self Report ; Severity of Illness Index ; }, abstract = {Pseudobulbar affect (PBA) is a syndrome of affective disturbance associated with inappropriate laughter and crying, independent of mood. PBA is common in amyotrophic lateral sclerosis (ALS) and increasingly recognized in Parkinson's disease (PD) and atypical parkinsonism (aP). Correlates of PBA have not been systematically studied. The purpose of this study was to determine whether cognitive and psychiatric comorbidities correlated with patient-reported symptoms of PBA by using the Center for Neurological Study-Lability Scale among patients with ALS, PD, and aP. A total of 108 patients (PD, N=53; aP, N=29; ALS, N=26) completed a cognitive screener and self-reported measures of lability, depression, anxiety, apathy, and quality of life. Statistical analyses included one- and two-way analyses of covariance to evaluate group differences, Pearson's correlations to determine relationships between PBA symptoms and comorbidities, multiple regression for predicting PBA symptom severity in clinical correlates, and chi-square t tests for predicting demographic variables. PBA symptom severity did not vary between the three groups. Younger age and worse anxiety correlated with PBA symptom severity in all three groups, whereas depression and poor mental health/quality of life only correlated with PBA symptom severity in the PD and aP groups. PD and aP patients may be more likely to benefit from treatment with antidepressants. Increased PBA symptoms were associated with declines in cognitive functioning in the aP group, but sufficient numbers of PD and ALS patients with cognitive dysfunction may not have been recruited. The results suggest the possibility of an alternate pathophysiologic mechanism for PBA, which may vary between neurological disorders and disease progression. Mood and cognition are of particular relevance and should be evaluated when symptoms of PBA are suspected.}, }
@article {pmid29504729, year = {2018}, author = {Holecek, V and Rokyta, R}, title = {Possible etiology and treatment of amyotrophic lateral sclerosis.}, journal = {Neuro endocrinology letters}, volume = {38}, number = {8}, pages = {528-531}, pmid = {29504729}, issn = {0172-780X}, mesh = {Amyotrophic Lateral Sclerosis/classification/*etiology/*therapy ; Animals ; Humans ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is one of the most dangerous and least understood diseases with a pathophysiology that is still largely unknown. In this article we try to provide a pathophysiological explanation of the etiological, pathogenetic, and clinical aspects of ALS. After a description of the rather complicated classification of the disease, we continue with an evaluation of its clinical presentation. The bibliography reveals several suspect etiological factors including atherosclerosis, inflammation, tumors, cataracts, diabetes mellitus type 2, aging, and degeneration of the nervous system. One of the more intriguing factors involves changes associated with oxidative damage to both neurons and glial cells. It is known that astrocytes support the development of motor neurons. Oxidative damage is known to lead to the expression of stress sensitive genes, proteins, as well as inflammation of glial cells. Chronic inflammation could be a key factor in ALS since it has been linked to the death of motor neurons. Pathophysiological research has confirmed the influence of certains proteins on the prognosis of ALS. ALS is typically a proteinopathy in which proteins aggregate in motoneurons. Additionally, glutamate excitotoxicity has also been linked to ALS, with mutated superoxide dismutase (SOD1) having been shown to be responsible for familial ALS. As concerns the pathogenesis of ALS, we discussed several phenomenon such as increased levels of specific serum compounds, reduced concentrations of myelin, and changes in 5-hydroxytryptamine that could represent key indicators of the pathogenesis, prognosis, and therapy of ALS. Concerning ALS therapy; treatment with antioxidatives is potentially very important. Exposure to heavy metals is also thought to negatively influence ALS. Evidence also suggests that good nutrition is a very important factor in the treatment of ALS. From a pharmacological perspective, serotonin treatment appears to be a useful therapeutic agent.}, }
@article {pmid29504292, year = {2018}, author = {Tae, WS and Ham, BJ and Pyun, SB and Kang, SH and Kim, BJ}, title = {Current Clinical Applications of Diffusion-Tensor Imaging in Neurological Disorders.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {14}, number = {2}, pages = {129-140}, pmid = {29504292}, issn = {1738-6586}, abstract = {Diffusion-tensor imaging (DTI) is a noninvasive medical imaging tool used to investigate the structure of white matter. The signal contrast in DTI is generated by differences in the Brownian motion of the water molecules in brain tissue. Postprocessed DTI scalars can be used to evaluate changes in the brain tissue caused by disease, disease progression, and treatment responses, which has led to an enormous amount of interest in DTI in clinical research. This review article provides insights into DTI scalars and the biological background of DTI as a relatively new neuroimaging modality. Further, it summarizes the clinical role of DTI in various disease processes such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's dementia, epilepsy, ischemic stroke, stroke with motor or language impairment, traumatic brain injury, spinal cord injury, and depression. Valuable DTI postprocessing tools for clinical research are also introduced.}, }
@article {pmid29501436, year = {2018}, author = {Hidalgo Carvajal, R and Sánchez Casado, M and de Miguel-Díez, J and López Gabaldón, E}, title = {Beneficial effect of nocturnal oximetric control on the clinical and gasometric situation and the prognosis of patients with home non-invasive mechanical ventilation.}, journal = {Medicina clinica}, volume = {151}, number = {11}, pages = {435-440}, doi = {10.1016/j.medcli.2018.01.018}, pmid = {29501436}, issn = {1578-8989}, mesh = {Aged ; Blood Gas Analysis ; Cohort Studies ; Female ; Home Care Services ; Humans ; Male ; Middle Aged ; *Monitoring, Ambulatory ; *Noninvasive Ventilation ; *Oximetry ; Prognosis ; Respiratory Insufficiency/*blood/mortality/*therapy ; Retrospective Studies ; Survival Rate ; }, abstract = {INTRODUCTION AND OBJECTIVE: The effectiveness of home non-invasive mechanical ventilation (NIMV) is assessed by determining blood gas values in wakefulness, the evolution of their symptoms, and the monitoring of ventilation at night. The aim of our study is to evaluate whether defined values reached with outpatient monitoring by oximetry is related to the clinical, arterial gases and survival of a sample of patients with home NIMV.<br><br>MATERIAL AND METHOD: Retrospective observational cohort study of a series of patients receiving home NIMV treatment for different causes. Patients with amyotrophic lateral sclerosis and less than 3 months of follow-up were excluded. The evolution of the patient's symptoms, their baseline arterial blood gases in wakefulness, and home nocturnal oximetry records, are evaluated at each outpatient visit. Good maintained oximetry control (MOC) was defined when mean O2 saturation values were reached and maintained until the last revision. Patient groups were considered, according to whether or not a good MOC was achieved during follow-up.<br><br>RESULT: Four hundred patients were evaluated. Three hundred and sixty four (91%) were included in the study; their median age was 68 years, 51% were male. 37.6% had a good MOC during follow-up. Compared to patients with not good MOC, a better long-term mortality was obtained (16.8% vs 28.2%, P=.013), and an improvement in symptoms (33.8% vs 18.6%, P=.002) and a lower proportion of patients with persistently>50mmHg PaCO2 (14.2% vs. 33.9%, P<.001) was observed.<br><br>CONCLUSION: In the follow-up of patients with home NIMV in our context, values defined in home nocturnal oximetry (good MOC) are positively associated with clinical, gasometric and longer-term survival.}, }
@article {pmid29499577, year = {2018}, author = {Brewer Gutierrez, OI and Irani, SS and Ngamruengphong, S and Aridi, HD and Kunda, R and Siddiqui, A and Dollhopf, M and Nieto, J and Chen, YI and Sahar, N and Bukhari, MA and Sanaei, O and Canto, MI and Singh, VK and Kozarek, R and Khashab, MA}, title = {Endoscopic ultrasound-guided entero-enterostomy for the treatment of afferent loop syndrome: a multicenter experience.}, journal = {Endoscopy}, volume = {50}, number = {9}, pages = {891-895}, doi = {10.1055/s-0044-102254}, pmid = {29499577}, issn = {1438-8812}, mesh = {*Afferent Loop Syndrome/epidemiology/etiology/physiopathology/surgery ; Endosonography/*methods ; *Enterostomy/adverse effects/instrumentation/methods ; Female ; Humans ; Jaundice/diagnosis/etiology ; Male ; Middle Aged ; Outcome and Process Assessment, Health Care ; Pancreaticoduodenectomy/adverse effects ; *Postoperative Complications/diagnosis/epidemiology/surgery ; *Reoperation/methods/statistics &amp; numerical data ; Retrospective Studies ; *Stents ; Symptom Assessment/methods/statistics &amp; numerical data ; Treatment Outcome ; United States/epidemiology ; Vomiting/diagnosis/etiology ; }, abstract = {BACKGROUND: Afferent loop syndrome (ALS) is traditionally managed surgically and, more recently, endoscopically. The role of endoscopic ultrasound-guided entero-enterostomy (EUS-EE) has not been well described. The aim of this study was to assess the technical and clinical success and safety of EUS-EE.<br><br>METHODS: This was a multicenter, retrospective series at six centers in patients with ALS treated by EUS-EE. Data on patients treated with enteroscopy-assisted luminal stenting (EALS) at a single center were also collected.<br><br>RESULTS: 18 patients (mean age 64.2 years, 72&#x200a;% post-pancreaticoduodenectomy, 10 female) underwent EUS-EE. The most common symptoms were vomiting (27.8&#x200a;%) and jaundice (33.3&#x200a;%). Clinical success included resolution of symptoms in 88.9&#x200a;% and improvement to allow hospital discharge in 11.1&#x200a;%. Technical success was achieved in 100&#x200a;% of cases, with a mean procedure time of 29.7 minutes. The most common procedure was a gastro-jejunostomy (72.2&#x200a;%). Three adverse events (16.7&#x200a;%) occurred (two mild, one moderate). When compared with data on EALS, patients treated with EUS-EE needed fewer re-interventions (16.6&#x200a;% vs. 76.5&#x200a;%; P&#x200a;<&#x200a;0.001).<br><br>CONCLUSION: EUS-EE seems to be safe and effective in the treatment of ALS.&#x200a;Indirect comparison with EALS suggested that EUS-EE is associated with a reduced need for re-intervention.}, }
@article {pmid29499331, year = {2018}, author = {Wang, W and Wen, D and Duan, W and Yin, J and Cui, C and Wang, Y and Li, Z and Liu, Y and Li, C}, title = {Systemic administration of scAAV9-IGF1 extends survival in SOD1[G93A] ALS mice via inhibiting p38 MAPK and the JNK-mediated apoptosis pathway.}, journal = {Brain research bulletin}, volume = {139}, number = {}, pages = {203-210}, doi = {10.1016/j.brainresbull.2018.02.015}, pmid = {29499331}, issn = {1873-2747}, mesh = {Amyotrophic Lateral Sclerosis/genetics/mortality/pathology/*therapy ; Animals ; Apoptosis/*physiology ; Calcium-Binding Proteins/metabolism ; Dependovirus/physiology ; Disease Models, Animal ; Female ; Green Fluorescent Proteins/genetics/metabolism ; Humans ; Insulin-Like Growth Factor I/genetics/*metabolism ; JNK Mitogen-Activated Protein Kinases/genetics/*metabolism ; Mice ; Mice, Transgenic ; Microfilament Proteins/metabolism ; Muscle, Skeletal/metabolism/pathology ; Mutation/genetics ; Phosphopyruvate Hydratase/metabolism ; Phosphorylation ; Spinal Cord/metabolism ; Statistics, Nonparametric ; Superoxide Dismutase/genetics ; p38 Mitogen-Activated Protein Kinases/genetics/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is closely associated with a reduction of neurotrophic factors in the central nervous system (CNS). Insulin-like growth factor 1 (IGF1)-encoding vectors delivered via intramuscular and intraparenchymal spinal cord injections have conferred therapeutic benefits in ALS model mice, although the development of a noninvasive delivery route is still needed. Intravenous administration of adeno-associated virus (AAV) vectors has been used to induce expression of neurotrophic genes in the lumbar spinal cords of adult mice. Therefore, the aim of this study was to investigate the effect of intravenous delivery of human IGF1 by self-complementary adeno-associated virus (scAAV) vectors in 90-day-old SOD1-G93A ALS mice. We found that IGF1 treatment decreased motor neuron death, mitigated myelin pathology in the ventral root, and prolonged the lifespan in SOD1-G93A mice. We also discovered that IGF1 inhibited phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and the c-Jun-N-terminal kinase (JNK) pathway in the lumbar spinal cord, as evidenced by downregulated phosphorylated p38 and phosphorylated JNK. Furthermore, we detected the levels of proteins involved in the apoptosis pathway and found that the apoptotic inhibitor Bcl2 increased and the apoptotic promoter Bax, caspase 3, and caspase 9 decreased. In addition, the pro-inflammatory factor TNF-α was reduced after IGF1 treatment. In conclusion, we report a convenient and noninvasive ALS treatment method. Our results revealed a previously unrecognized role of IGF1 in p38 MAPK and the JNK-mediated pathway and its potential role as a therapeutic target for ALS.}, }
@article {pmid29497380, year = {2018}, author = {Sokolov, ME and Bashirov, FV and Markosyan, VA and Povysheva, TV and Fadeev, FO and Izmailov, AA and Kuztetsov, MS and Safiullov, ZZ and Shmarov, MM and Naroditskyi, BS and Palotás, A and Islamov, RR}, title = {Triple-Gene Therapy for Stroke: A Proof-of-Concept in Vivo Study in Rats.}, journal = {Frontiers in pharmacology}, volume = {9}, number = {}, pages = {111}, pmid = {29497380}, issn = {1663-9812}, abstract = {Natural brain repair after stroke is extremely limited, and current therapeutic options are even more scarce with no clinical break-through in sight. Despite restricted regeneration in the central nervous system, we have previously proved that human umbilical cord blood mono-nuclear cells (UCB-MC) transduced with adenoviral vectors carrying genes encoding vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF), and neural cell adhesion molecule (NCAM) successfully rescued neurons in amyotrophic lateral sclerosis and spinal cord injury. This proof-of-principle project was aimed at evaluating the beneficial effects of the same triple-gene approach in stroke. Rats subjected to distal occlusion of the middle cerebral artery were treated intrathecally with a combination of these genes either directly or using our cell-based (UCB-MC) approach. Various techniques and markers were employed to evaluate brain injury and subsequent recovery after treatment. Brain repair was most prominent when therapeutic genes were delivered via adenoviral vector- or UCB-MC-mediated approach. Remodeling of brain cortex in the stroke area was confirmed by reduction of infarct volume and attenuated neural cell death, depletion of astrocytes and microglial cells, and increase in the number of oligodendroglial cells and synaptic proteins expression. These results imply that intrathecal injection of genetically engineered UCB-MC over-expressing therapeutic molecules (VEGF, GDNF, and NCAM) following cerebral blood vessel occlusion might represent a novel avenue for future research into treating stroke.}, }
@article {pmid29497049, year = {2018}, author = {Sheykhansari, S and Kozielski, K and Bill, J and Sitti, M and Gemmati, D and Zamboni, P and Singh, AV}, title = {Redox metals homeostasis in multiple sclerosis and amyotrophic lateral sclerosis: a review.}, journal = {Cell death &amp; disease}, volume = {9}, number = {3}, pages = {348}, pmid = {29497049}, issn = {2041-4889}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Cadmium/*metabolism ; Copper/*metabolism ; Gene Expression ; Homeostasis ; Humans ; Iron/*metabolism ; Multiple Sclerosis/genetics/*metabolism ; Oxidation-Reduction ; }, abstract = {The effect of redox metals such as iron and copper on multiple sclerosis and amyotrophic lateral sclerosis has been intensively studied. However, the origin of these disorders remains uncertain. This review article critically describes the physiology of redox metals that produce oxidative stress, which in turn leads to cascades of immunomodulatory alteration of neurons in multiple sclerosis and amyotrophic lateral sclerosis. Iron and copper overload has been well established in motor neurons of these diseases' lesions. On the other hand, the role of other metals like cadmium participating indirectly in the redox cascade of neurobiological mechanism is less studied. In the second part of this review, we focus on this less conspicuous correlation between cadmium as an inactive-redox metal and multiple sclerosis and amyotrophic lateral sclerosis, providing novel treatment modalities and approaches as future prospects.}, }
@article {pmid29493465, year = {2018}, author = {Lemieszek, MK and Stepulak, A and Sawa-Wejksza, K and Czerwonka, A and Ikonomidou, C and Rzeski, W}, title = {Riluzole Inhibits Proliferation, Migration and Cell Cycle Progression and Induces Apoptosis in Tumor Cells of Various Origins.}, journal = {Anti-cancer agents in medicinal chemistry}, volume = {18}, number = {4}, pages = {565-572}, doi = {10.2174/1871520618666180228152713}, pmid = {29493465}, issn = {1875-5992}, mesh = {Animals ; Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/*drug effects ; Cell Cycle/drug effects ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Humans ; Molecular Structure ; Rats ; Riluzole/chemistry/*pharmacology ; Structure-Activity Relationship ; Tumor Cells, Cultured ; }, abstract = {BACKGROUND: Regardless of contemporary improvements in cancer treatment, the results of drug treatment are not always efficacious. Thus, the development of novel approaches that affect cancer cell-specific metabolic pathways is needed. Since much evidence has shown that tumor cell proliferation and motility are stimulated by glutamate via activation of its receptors, use of antagonists to these receptors may be the key to control cancer cell progression. Riluzole noncompetitive metabotropic glutamate receptor 1 (mGluR1) antagonist, commonly used to treat patients with amyotrophic lateral sclerosis (ALS), has shown some antineoplastic properties against melanoma, breast and prostate cancer. Yet little is known about its molecular mode of action.<br><br>AIMS: The current study aims at evaluating the abilities of Riluzole to inhibit proliferation of several cancer cell lines, as well as resolve the mechanism of its action.<br><br>METHOD: We demonstrated antiproliferative and antimigrative properties of Riluzole in rhabdomyosarcomamedulloblastoma, neuroblastoma, astrocytoma, glioma, colon cancer, lung cancer, thyroid carcinoma, leukemia, erythroleukemia and multiple myeloma. Our studies revealed apoptosis induction and G2-M cell cycle arrest in Riluzole treated A549, C6 and HT-29 cells.<br><br>RESULT: At the molecular level, we found that these cells treated with Riluzole had a decrease of Cyclin B and an increase of p21 Waf1/Cip1 and p53 expression. We also observed an enhancement of CDK1 and Chk2 phosphorylation. Reported changes may suggest the involvement of these proteins in G2-M arrest, observed in flow cytometry analysis. These data indicated the potential use of Riluzole in the treatment of different types of cancers.}, }
@article {pmid29486281, year = {2018}, author = {van Eijk, RPA and Nikolakopoulos, S and Ferguson, TA and Liu, D and Eijkemans, MJC and van den Berg, LH}, title = {Increasing the efficiency of clinical trials in neurodegenerative disorders using group sequential trial designs.}, journal = {Journal of clinical epidemiology}, volume = {98}, number = {}, pages = {80-88}, doi = {10.1016/j.jclinepi.2018.02.013}, pmid = {29486281}, issn = {1878-5921}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Central Nervous System Agents/therapeutic use ; Confidence Intervals ; *Early Termination of Clinical Trials ; Equivalence Trials as Topic ; Humans ; *Medical Futility ; Neurodegenerative Diseases/drug therapy ; Placebos/therapeutic use ; Pramipexole/therapeutic use ; Randomized Controlled Trials as Topic/*methods ; Research Design ; Time Factors ; }, abstract = {OBJECTIVES: Clinical trials in neurodegenerative disorders are facing high futility rates and rising development costs. We aim to review and exemplify the value of group sequential trial designs (i.e., designs with one or more prospectively planned interim analyses) within the field of amyotrophic lateral sclerosis.<br><br>STUDY DESIGN AND SETTING: We reviewed the literature to identify sequentially conducted trials. Subsequently, we reanalyzed the dexpramipexole trial (EMPOWER), a classically designed and conducted trial involving 942 participants, by sequentially monitoring the functional questionnaire and survival endpoint. Finally, we simulated the performance of the sequential methodology under different treatment effects.<br><br>RESULTS: Only six (12%) randomized, placebo-controlled trials incorporated stopping rules for both futility and superiority. Despite its high enrollment rate, sequential reanalysis of the EMPOWER study reduced the total trial duration with 140&#xa0;days (23.4%, 95% confidence interval [CI] 13.2-34.4%), the number of follow-ups with 2,688 visits (23.6%, 95% CI 11.3-38.6%), and the total drug exposure time with 73,377&#xa0;days (20.6%, 95% CI 9.8-35.9%). The functional questionnaire considerably increased the heterogeneity in the test statistics, which may negatively affect sequential monitoring.<br><br>CONCLUSION: Group sequential trials can result in important reductions in the trial duration, which could make clinical trials more ethical by reducing the patients' exposure to noneffective treatments or by limiting their time on placebo.}, }
@article {pmid29486168, year = {2018}, author = {Crivello, M and O'Riordan, SL and Woods, I and Cannon, S and Halang, L and Coughlan, KS and Hogg, MC and Lewandowski, SA and Prehn, JHM}, title = {Pleiotropic activity of systemically delivered angiogenin in the SOD1[G93A] mouse model.}, journal = {Neuropharmacology}, volume = {133}, number = {}, pages = {503-511}, doi = {10.1016/j.neuropharm.2018.02.022}, pmid = {29486168}, issn = {1873-7064}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/blood/complications/*drug therapy/*genetics ; Angiogenesis Inducing Agents/*therapeutic use ; Animals ; Astrocytes/drug effects/metabolism ; Disease Models, Animal ; Endothelial Cells/drug effects/pathology ; Female ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/pathology ; Movement Disorders/drug therapy/etiology ; Ribonuclease, Pancreatic/blood/*therapeutic use ; Rotarod Performance Test ; Superoxide Dismutase/genetics/metabolism ; Survival Analysis ; Time Factors ; }, abstract = {Loss-of-function mutations in the angiogenin (ANG) gene have been identified in familial and sporadic ALS patients. Previous work from our group identified human ANG (huANG) to protect motoneurons in vitro, and provided proof-of-concept that daily intraperitoneal (i.p.) huANG injections post-symptom onset increased lifespan and delayed disease progression in SOD1[G93A] mice. huANG's mechanism of action remains less well understood. Here, we implemented a preclinical in vivo design to validate our previous results, provide pharmacokinetic and protein distribution data after systemic administration, and explore potential pleiotropic activities of huANG in vivo. SOD1[G93A] mice (n = 45) and non-transgenic controls (n = 31) were sex- age- and litter-matched according to the 2010 European ALS/MND group guidelines, and treated with huANG (1 μg, i.p., 3 times/week) or vehicle from 90 days on. huANG treatment increased survival and delayed motor dysfunction as assessed by rotarod in SOD1[G93A] mice. Increased huANG serum levels were detectable 2 and 24 h after i.p. injection equally in transgenic and non-transgenic mice. Exogenous huANG localized to spinal cord astrocytes, supporting a glia-mediated, paracrine mechanism of action; uptake into endothelial cells was also observed. 1 μg huANG or vehicle were administered from 90 to 115 days of age for histological analysis. Vehicle-treated SOD1[G93A] mice showed decreased motoneuron numbers and vascular length per ventral horn area, while huANG treatment resulted in improved vascular network maintenance and motoneuron survival. Our data suggest huANG represents a new class of pleiotropic ALS therapeutic that acts on the spinal cord vasculature and glia to delay motoneuron degeneration and disease progression.}, }
@article {pmid29486049, year = {2018}, author = {Gao, J and Wang, L and Huntley, ML and Perry, G and Wang, X}, title = {Pathomechanisms of TDP-43 in neurodegeneration.}, journal = {Journal of neurochemistry}, volume = {}, number = {}, pages = {}, pmid = {29486049}, issn = {1471-4159}, support = {R01 NS089604/NS/NINDS NIH HHS/United States ; }, abstract = {Neurodegeneration, a term that refers to the progressive loss of structure and function of neurons, is a feature of many neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). There is no cure or treatment available that can prevent or reverse neurodegenerative conditions. The causes of neurodegeneration in these diseases remain largely unknown; yet, an extremely small proportion of these devastating diseases are associated with genetic mutations in proteins involved in a wide range of cellular pathways and processes. Over the past decade, it has become increasingly clear that the most notable neurodegenerative diseases, such as ALS, FTLD, and AD, share a common prominent pathological feature known as TAR DNA-binding protein 43 (TDP-43) proteinopathy, which is usually characterized by the presence of aberrant phosphorylation, ubiquitination, cleavage and/or nuclear depletion of TDP-43 in neurons and glial cells. The role of TDP-43 as a neurotoxicity trigger has been well documented in different in vitro and in vivo experimental models. As such, the investigation of TDP-43 pathomechanisms in various major neurodegenerative diseases is on the rise. Here, after a discussion of stages of TDP-43 proteinopathy during disease progression in various major neurodegenerative diseases, we review previous and most recent studies about the potential pathomechanisms with a particular emphasis on ALS, FTLD, and AD, and discuss the possibility of targeting TDP-43 as a common therapeutic approach to treat neurodegenerative diseases.}, }
@article {pmid29478603, year = {2018}, author = {Goutman, SA and Chen, KS and Paez-Colasante, X and Feldman, EL}, title = {Emerging understanding of the genotype-phenotype relationship in amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {148}, number = {}, pages = {603-623}, doi = {10.1016/B978-0-444-64076-5.00039-9}, pmid = {29478603}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; Autophagy/genetics ; DNA-Binding Proteins/genetics ; *Genetic Association Studies ; Genetic Counseling ; Genotype ; Humans ; Motor Neurons/*pathology ; Mutation/*genetics ; Proteins/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, noncurable neurodegenerative disorder of the upper and lower motor neurons causing weakness and death within a few years of symptom onset. About 10% of patients with ALS have a family history of the disease; however, ALS-associated genetic mutations are also found in sporadic cases. There are over 100 ALS-associated mutations, and importantly, several genetic mutations, including C9ORF72, SOD1, and TARDBP, have led to mechanistic insight into this complex disease. In the clinical realm, knowledge of ALS genetics can also help explain phenotypic heterogeneity, aid in genetic counseling, and in the future may help direct treatment efforts.}, }
@article {pmid29477412, year = {2018}, author = {Hammond, FM and Sauve, W and Ledon, F and Davis, C and Formella, AE}, title = {Safety, Tolerability, and Effectiveness of Dextromethorphan/Quinidine for Pseudobulbar Affect Among Study Participants With Traumatic Brain Injury: Results From the PRISM-II Open Label Study.}, journal = {PM &amp; R : the journal of injury, function, and rehabilitation}, volume = {10}, number = {10}, pages = {993-1003}, doi = {10.1016/j.pmrj.2018.02.010}, pmid = {29477412}, issn = {1934-1563}, mesh = {Adult ; Brain Injuries, Traumatic/*complications/diagnosis ; Dextromethorphan/*administration &amp; dosage ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Humans ; Injury Severity Score ; Male ; Maximum Tolerated Dose ; Middle Aged ; Neuropsychological Tests ; *Patient Safety ; Patient Selection ; Prognosis ; Prospective Studies ; Pseudobulbar Palsy/*drug therapy/*etiology/physiopathology ; Quinidine/*administration &amp; dosage ; Risk Assessment ; Severity of Illness Index ; Treatment Outcome ; }, abstract = {BACKGROUND: Dextromethorphan 20 mg / quinidine 10 mg (DM/Q) was approved to treat pseudobulbar affect (PBA) based on phase 3 trials conducted in participants with amyotrophic lateral sclerosis or multiple sclerosis. PRISM II evaluated DM/Q effectiveness, safety, and tolerability for PBA following stroke, dementia, or traumatic brain injury (TBI).<br><br>OBJECTIVE: To report results from the TBI cohort of PRISM II, including a TBI-specific functional scale.<br><br>DESIGN: Open-label trial evaluating twice-daily DM/Q over 90 days.<br><br>STUDY PARTICIPANTS: Adults (n = 120) with a clinical diagnosis of PBA secondary to nonpenetrating TBI; stable psychiatric medications were allowed.<br><br>METHODS: PRISM II was an open-label, 12-week trial enrolling adults with PBA secondary to dementia, stroke, or TBI (NCT01799941). All study participants received DM/Q 20/10 mg twice daily. Study visits occurred at baseline and at day 30 and day&#xa0;90.<br><br>SETTING: 150 U.S. centers.<br><br>MAIN OUTCOME MEASUREMENTS: Primary endpoint was change in Center for Neurologic Study-Lability Scale (CNS-LS) score from baseline to day 90. Secondary outcomes included PBA episode count, Clinical and Patient Global Impression of Change (CGI-C; PGI-C), Quality of Life-Visual Analog Scale (QOL-VAS), treatment satisfaction, Neurobehavioral Functioning Inventory (NFI), Patient Health Questionnaire (PHQ-9), and Mini Mental State Examination (MMSE).<br><br>RESULTS: DM/Q-treated participants showed significant mean (SD) reductions in CNS-LS from baseline (day 30, -5.6 [5.2]; day 90, -8.5 [5.2]; both, P<.001). Compared with baseline, PBA episodes were reduced by 61.3% and 78.5% at days 30 and 90 (both, P<.001). At day 90, 78% and 73% of study participants had "much improved" or "very much improved" on the CGI-C and PGI-C. QOL-VAS scores were significantly reduced from baseline (-3.7 [3.3], P<.001). Mean (SD) PHQ-9 scores improved compared to baseline at day 30 (-3.2 [5.3], P<.001) and 90 (-5.2 [6.4], P<.001). NFI T scores were significantly improved (P<.001), whereas MMSE scores were unchanged. Adverse events (AEs) were consistent with the known DM/Q safety profile; the most common AE was diarrhea (8.3%).<br><br>CONCLUSIONS: DM/Q was well tolerated, and it significantly reduced PBA episodes in study participants with TBI. Changes in CNS-LS and PBA episode count were similar to changes with DM/Q in phase 3 trials.<br><br>LEVEL OF EVIDENCE: II.}, }
@article {pmid29475576, year = {2018}, author = {Sridharan, K and Sivaramakrishnan, G}, title = {Pharmacological interventions for treating sialorrhea associated with neurological disorders: A mixed treatment network meta-analysis of randomized controlled trials.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {51}, number = {}, pages = {12-17}, doi = {10.1016/j.jocn.2018.02.011}, pmid = {29475576}, issn = {1532-2653}, mesh = {Benztropine/therapeutic use ; Botulinum Toxins, Type A/therapeutic use ; Child ; Child, Preschool ; Female ; Glycopyrrolate/therapeutic use ; Humans ; Muscarinic Antagonists/therapeutic use ; Nervous System Diseases/*complications/*drug therapy ; Network Meta-Analysis ; Randomized Controlled Trials as Topic ; Scopolamine/therapeutic use ; Sialorrhea/*drug therapy/*etiology ; }, abstract = {Sialorrhea is a common distress associated with certain neurological disorders. The aim of this study is to compare the pharmacological agents used for treating sialorrhea by network meta-analysis. Electronic databases were searched for randomized clinical trials comparing active drugs with either placebo or other active drugs. Total drooling scores was the primary outcome measure. Inverse variance heterogeneity model was used for both direct and mixed treatment comparison analysis. Twenty one studies were included in the systematic review and 15 in the meta-analysis. Compared to placebo, benztropine, botulinum toxins A and B are associated with a significant reduction in the frequency and severity of drooling both in the overall neurological disorders as well as for children with cerebral palsy. Only botulinum toxin A and B were associated with significant therapeutic effects in Parkinson's disease. Benztropine and botulinum toxins A and B were observed to be effective in reducing sialorrhea associated with neurological disorders.}, }
@article {pmid29472887, year = {2018}, author = {Briones, MRS and Snyder, AM and Ferreira, RC and Neely, EB and Connor, JR and Broach, JR}, title = {A Possible Role for Platelet-Activating Factor Receptor in Amyotrophic Lateral Sclerosis Treatment.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {39}, pmid = {29472887}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is the third most prevalent neurodegenerative disease affecting upper and lower motor neurons. An important pathway that may lead to motor neuron degeneration is neuroinflammation. Cerebrospinal Fluids of ALS patients have increased levels of the inflammatory cytokine IL-18. Because IL-18 is produced by dendritic cells stimulated by the platelet-activating factor (PAF), a major neuroinflammatory mediator, it is expected that PAF is involved in ALS. Here we show pilot experimental data on amplification of PAF receptor (PAFR) mRNA by RT-PCR. PAFR is overexpressed, as compared to age matched controls, in the spinal cords of transgenic ALS SOD1-G93A mice, suggesting PAF mediation. Although anti-inflammatory drugs have been tested for ALS before, no clinical trial has been conducted using PAFR specific inhibitors. Therefore, we hypothesize that administration of PAFR inhibitors, such as Ginkgolide B, PCA 4248 and WEB 2086, have potential to function as a novel therapy for ALS, particularly in SOD1 familial ALS forms. Because currently there are only two approved drugs with modest effectiveness for ALS therapy, a search for novel drugs and targets is essential.}, }
@article {pmid29453639, year = {2018}, author = {Schellhas, V and Glatz, C and Beecken, I and Okegwo, A and Heidbreder, A and Young, P and Boentert, M}, title = {Upper airway obstruction induced by non-invasive ventilation using an oronasal interface.}, journal = {Sleep &amp; breathing = Schlaf &amp; Atmung}, volume = {22}, number = {3}, pages = {781-788}, pmid = {29453639}, issn = {1522-1709}, mesh = {Airway Obstruction/*etiology ; Female ; Humans ; Male ; Middle Aged ; Neuromuscular Diseases/*therapy ; Noninvasive Ventilation/*adverse effects/*instrumentation ; Polysomnography ; Retrospective Studies ; }, abstract = {BACKGROUND: On initiation of long-term non-invasive ventilation (NIV), intermittent upper airway obstruction has rarely been described as possibly treatment-induced. Inspiratory pressure effects and the use of an oronasal interface may promote obstructive events in some patients with neuromuscular disease (NMD) and amyotrophic lateral sclerosis (ALS) in particular.<br><br>METHODS: We evaluated clinical data from 212 patients in whom NIV was initiated using an oronasal mask. Treatment-induced upper airway obstruction (TAO) was defined as an AHI >&#x2009;5/h along with a relative increase of the AHI in the first treatment night compared to diagnostic sleep studies.<br><br>RESULTS: Prevalence of TAO was 14.2% in the entire cohort, 17.0% in patients with NMD (n&#x2009;=&#x2009;165), 20.4% in the ALS subgroup (n&#x2009;=&#x2009;93), and 4.3% in non-NMD patients (n&#x2009;=&#x2009;47). Fixed expiratory positive airway pressure (EPAP, n&#x2009;=&#x2009;192) was significantly correlated with AHI reduction (r&#x2009;=&#x2009;0.50; p&#x2009;<&#x2009;0.001). The inspiratory-expiratory pressure interval (&#x2206;PAP, n&#x2009;=&#x2009;191) showed inverse correlation with the AHI change achieved in the first treatment night (r&#x2009;=&#x2009;-&#x2009;0.28; p&#x2009;<&#x2009;0.001). However, &#x2206;PAP and the effective pressure range between EPAP and the highest inspiratory PAP achieved were not predictive of TAO. In patients with ALS, TAO was associated with better bulbar function. Study results were limited by initial EPAP being significantly lower in NMD patients reflecting that sleep apnea was less frequent and severe in this subgroup.<br><br>CONCLUSIONS: Initiation of NIV using an oronasal interface may be associated with TAO in a subset of patients. Since both EPAP and &#x2206;PAP appear to play a causative role, careful titration of ventilator settings is recommended.}, }
@article {pmid29450726, year = {2018}, author = {Herrmann, D and Parlato, R}, title = {C9orf72-associated neurodegeneration in ALS-FTD: breaking new ground in ribosomal RNA and nucleolar dysfunction.}, journal = {Cell and tissue research}, volume = {373}, number = {2}, pages = {351-360}, doi = {10.1007/s00441-018-2806-1}, pmid = {29450726}, issn = {1432-0878}, support = {DFG PA 1529/2-1//DFG-Deutsche Forschungsgemeinschaft/International ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; C9orf72 Protein/genetics/*metabolism ; Cell Nucleolus/*pathology ; Frontotemporal Dementia/*pathology ; Humans ; Nerve Degeneration/*pathology ; RNA, Ribosomal/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) are neurodegenerative diseases with distinct clinical appearance. However, both share as major genetic risk factor a C9orf72 locus intronic hexanucleotide expansion. The pathogenic pathways associated with the expansion-dependent neuronal toxicity are still poorly understood. Recent efforts to identify common threads of neuronal dysfunction have pointed towards deficits of ribosomal RNA (rRNA) biogenesis and loss of nucleolar integrity, a condition known as nucleolar stress that is an emerging shared feature among neurodegenerative diseases. Intriguingly, the C9orf72 mutation in ALS-FTD interferes with the function of the nucleolus by transcripts and dipeptide repeats (DPRs) produced by the hexanucleotide expansion. Experimental discrepancies have given rise to different hypotheses with regard to the connection of C9orf72 and nucleolar activity. In this review, we present and discuss emerging concepts concerning the impact of C9orf72 expansion on nucleolar biology. Moreover, we discuss the "nucleolar stress hypothesis," according to which nucleolar malfunction accompanies, exacerbates, or potentially triggers a degenerative phenotype. Upcoming awareness of the involvement of nucleolar stress in C9orf72 ALS-FTD could shed light into its pathogenesis, enabling potential treatment options aimed at shielding an "Achilles' heel" of neurons.}, }
@article {pmid29447051, year = {2018}, author = {Singh, N and Vijayanti, S and Saha, L}, title = {Targeting crosstalk between Nuclear factor (erythroid-derived 2)-like 2 and Nuclear factor kappa beta pathway by Nrf2 activator dimethyl fumarate in epileptogenesis.}, journal = {The International journal of neuroscience}, volume = {128}, number = {10}, pages = {987-994}, doi = {10.1080/00207454.2018.1441149}, pmid = {29447051}, issn = {1563-5279}, mesh = {Animals ; Dimethyl Fumarate/*pharmacology/therapeutic use ; Epilepsy/*drug therapy/*metabolism ; Humans ; Immunologic Factors/*pharmacology/therapeutic use ; Inflammation/*drug therapy ; NF-E2-Related Factor 2/*metabolism ; NF-kappa B/*metabolism ; Oxidative Stress/*drug effects ; *Signal Transduction/drug effects ; }, abstract = {UNLABELLED: Purpose/Aim: Epilepsy is a complex, chronic neurological disorder characterized by increased and abnormal synchronization of neuronal electrical activity, which is manifested as seizures. It is associated with many comorbid conditions such as depression, anxiety, sleep disorder, psychiatric disorder etc., which consequently causes higher mortality rate. The understanding of its cellular and molecular mechanism is partial, because of which it remains an ongoing health problem, despite the increasing availability of newer antiepileptic drugs. Although recurrent seizures are the clinical indication of epilepsy, the disease process (epileptogenesis) begins before the onset of the first seizure. This dormant phase before the onset of first seizure provides an opportune time window for modifying the epileptogenic process by intervening in its progression with an appropriate treatment.<br><br>MATERIAL AND METHODS: Studies have shown that in epilepsy, there is a chronic state of oxidative stress and inflammation, which plays a key role in epileptic pathogenesis. Various antioxidant mechanisms maintain the redox balance in the body by either scavenging or regulating the generation of free radicals. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway is a well-established antioxidant pathway in various diseases such as diabetes, renal disease, various neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, etc. Results: It has been observed that single-target therapies are inefficient in providing anticonvulsant and disease-modifying effects in epilepsy.<br><br>CONCLUSIONS: So, preventing the progression of epilepsy by targeting Nrf2-activated antioxidant pathway along with the other established antiepileptic pathways can prove beneficial in epilepsy treatment.}, }
@article {pmid29441840, year = {2018}, author = {Brenner, JM and Aswegan, AL and Vearrier, LE and Basford, JB and Iserson, KV}, title = {The Ethics of Real-Time EMS Direction: Suggested Curricular Content.}, journal = {Prehospital and disaster medicine}, volume = {33}, number = {2}, pages = {201-212}, doi = {10.1017/S1049023X18000110}, pmid = {29441840}, issn = {1945-1938}, mesh = {*Decision Support Techniques ; Emergency Medical Services/*ethics ; Humans ; Practice Patterns, Physicians'/*ethics ; United States ; }, abstract = {Ethical dilemmas can create moral distress in even the most experienced emergency physicians (EPs). Following reasonable and justified approaches can help alleviate such distress. The purpose of this article is to guide EPs providing Emergency Medical Services (EMS) direction to navigate through common ethical issues confronted in the prehospital delivery of care, including protecting privacy and confidentiality, decision-making capacity and refusal of treatment, withholding of treatment, and termination of resuscitation (TOR). This requires a strong foundation in the principles and theories underlying sound ethical decisions that EPs and prehospital providers make every day in good faith, but will now also make with more awareness and conscientiousness. Brenner JM , Aswegan AL , Vearrier LE , Basford JB , Iserson KV . The ethics of real-time EMS direction: suggested curricular content. Prehosp Disaster Med. 2018;33(2):201-212.}, }
@article {pmid29438867, year = {2018}, author = {Bastidas, CY and von Plessing, C and Troncoso, J and Del P Castillo, R}, title = {Evaluation of the microscopic distribution of florfenicol in feed pellets for salmon by Fourier Transform infrared imaging and multivariate analysis.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {152}, number = {}, pages = {257-263}, doi = {10.1016/j.jpba.2018.02.002}, pmid = {29438867}, issn = {1873-264X}, mesh = {Animals ; Least-Squares Analysis ; Multivariate Analysis ; Principal Component Analysis/methods ; Salmon/*metabolism ; Spectroscopy, Fourier Transform Infrared/methods ; Thiamphenicol/*analogs &amp; derivatives/metabolism ; }, abstract = {Fourier Transform infrared imaging and multivariate analysis were used to identify, at the microscopic level, the presence of florfenicol (FF), a heavily-used antibiotic in the salmon industry, supplied to fishes in feed pellets for the treatment of salmonid rickettsial septicemia (SRS). The FF distribution was evaluated using Principal Component Analysis (PCA) and Augmented Multivariate Curve Resolution with Alternating Least Squares (augmented MCR-ALS) on the spectra obtained from images with pixel sizes of 6.25 μm × 6.25 μm and 1.56 μm × 1.56 μm, in different zones of feed pellets. Since the concentration of the drug was 3.44 mg FF/g pellet, this is the first report showing the powerful ability of the used of spectroscopic techniques and multivariate analysis, especially the augmented MCR-ALS, to describe the FF distribution in both the surface and inner parts of feed pellets at low concentration, in a complex matrix and at the microscopic level. The results allow monitoring the incorporation of the drug into the feed pellets.}, }
@article {pmid29430494, year = {2018}, author = {Govindasamy, R and Gnanasundaram, R and Kasirajan, S and Ibrahim, S and Melepuram, JJ}, title = {Elastic Stable Intramedullary Nailing of Femoral Shaft Fracture-Experience in 48 Children.}, journal = {The archives of bone and joint surgery}, volume = {6}, number = {1}, pages = {39-46}, pmid = {29430494}, issn = {2345-4644}, abstract = {BACKGROUND: Femoral shaft fractures are an incapacitating pediatric injury accounting for 1.6% of all pediatric bony injuries. Management of these fractures is largely directed by age, fracture pattern, associated injuries, built of the child and socioeconomic status of the family. We retrospectively evaluated the use of elastic stable intramedullary nail (ESIN) in surgical management of femoral shaft fractures in children and its complications.<br><br>METHODS: Fifty two children were treated with titanium elastic nails (TEN) from June 2009 to June 2014 at our institution. At the end of the study there were 48 children. Fractures were classified according to Winquest and Hansen's as Grade I (n=32), Grade II (n=10), Grade III (n=6) and compound fractures by Gustilo and Anderson's classification, Grade I (n=5), Grade II (n=3). There were 36 mid-shaft fractures, 7 proximal third shaft fractures, 5 distal third shaft fractures. The final results were clinically evaluated by using Flynn's criteria and radiologically by Anthony et al's criteria.<br><br>RESULTS: The mean duration of follow-up was 20 months (range 12 - 40 months). All fractures healed radiologically with grade III callus formation at 9 - 12 weeks (mean 9.7 weeks). The results were analyzed using Flynn's criteria and were excellent in 40 children (83%) and satisfactory in 8 children (17%). The soft tissue discomfort near the knee produced by nail ends was the most common problem in our study (25%). Other complications include limb shortening (n=5), Varus malunion (n=4), Nail protruding site infection (n=4) and nail migration (n=2). There was no delayed union, non-union or refractures.<br><br>CONCLUSION: TEN is minimally invasive, safe, relatively easy to use and an effective treatment for fracture shaft of femur in properly selected children.Level of evidence: III.}, }
@article {pmid29428550, year = {2018}, author = {Leão, R and Nayan, M and Punjani, N and Jewett, MAS and Fadaak, K and Garisto, J and Lewin, J and Atenafu, EG and Sweet, J and Anson-Cartwright, L and Boström, P and Chung, P and Warde, P and Bedard, PL and Bagrodia, A and Freifeld, Y and Power, N and Winquist, E and Hamilton, RJ}, title = {A New Model to Predict Benign Histology in Residual Retroperitoneal Masses After Chemotherapy in Nonseminoma.}, journal = {European urology focus}, volume = {4}, number = {6}, pages = {995-1001}, doi = {10.1016/j.euf.2018.01.015}, pmid = {29428550}, issn = {2405-4569}, mesh = {Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Chemotherapy, Adjuvant ; Humans ; Logistic Models ; *Lymph Node Excision ; Lymph Nodes/*pathology ; Lymphatic Metastasis ; Male ; Multivariate Analysis ; Neoplasms, Germ Cell and Embryonal/*drug therapy/metabolism/pathology ; *Orchiectomy ; Retroperitoneal Space ; Retrospective Studies ; Testicular Neoplasms/*drug therapy/metabolism/pathology ; Tumor Burden ; alpha-Fetoproteins/metabolism ; }, abstract = {BACKGROUND: Postchemotherapy retroperitoneal lymph node dissection (pcRPLND) is indicated in testicular cancer patients with normalised or plateaued serum tumour markers and residual retroperitoneal lesions >1cm. Challenges remain in predicting postchemotherapy residual mass (pcRM) histology, which may lead to unnecessary surgery.<br><br>OBJECTIVE: To develop an accurate model to predict pcRM histology in patients with nonseminomatous germ cell tumours (NSGCTs).<br><br>A retrospective review of 335 patients undergoing pcRPLND for metastatic NSGCTs to develop a model to predict benign histology in retroperitoneal pcRM. Our model was compared with others and externally validated.<br><br>INTERVENTION: Chemotherapy and pcRPLND.<br><br>Multivariable logistic regression to evaluate the presence of benign histology, and fractional polynomials to allow for a nonlinear association between continuous variables and the outcome. The final Princess Margaret model (PMM) was selected based on the number of variables used, reliability, and discriminative capacity to predict benign pcRM.<br><br>RESULTS AND LIMITATIONS: PMM included the presence of teratoma in the orchiectomy, prechemotherapy &#x3b1;-fetoprotein, prechemotherapy mass size, and change in mass size during chemotherapy. Model specificity was 99.3%. Compared with Vergouwe et al's model, PMM had significantly better accuracy (C statistic 0.843 vs 0.783). PMM appropriately identified a larger number of patients for whom pcRPLND can safely be avoided (13.9% vs 0%). Validated in external cohorts, the model retained high discrimination (C statistic 0.88 and 0.80). Larger and prospective studies are needed to further validate this model.<br><br>CONCLUSIONS: Our clinical model, externally validated, showed improved discriminative ability in predicting pcRM histology when compared with other models. The higher accuracy and reduced number of variables make this a novel and appealing model to use for patient counselling and treatment strategies.<br><br>PATIENT SUMMARY: Princess Margaret model accurately predicted postchemotherapy benign histology. These results might have clinical impact by avoiding unnecessary retroperitoneal lymph node dissection and consequently changing the paradigm of advanced testicular cancer treatment.}, }
@article {pmid29425472, year = {2018}, author = {Ryan, K and George, D and Liu, J and Mitchell, P and Nelson, K and Kue, R}, title = {The Use of Field Triage in Disaster and Mass Casualty Incidents: A Survey of Current Practices by EMS Personnel.}, journal = {Prehospital emergency care}, volume = {22}, number = {4}, pages = {520-526}, doi = {10.1080/10903127.2017.1419323}, pmid = {29425472}, issn = {1545-0066}, mesh = {Adolescent ; Adult ; Algorithms ; Boston ; Disaster Planning/methods ; *Emergency Medical Services ; *Emergency Medical Technicians ; Female ; Health Care Surveys ; Humans ; Male ; *Mass Casualty Incidents ; Middle Aged ; Triage/*methods ; Young Adult ; }, abstract = {BACKGROUND: Mass casualty incident (MCI) triage and the use of triage tags to assign treatment priorities are not fully implemented despite emergency medical services (EMS) personnel training during drills and exercises.<br><br>OBJECTIVES: To compare current field triage practices during both training and actual MCIs and identify any potential barriers to use.<br><br>METHODS: During training sessions from November 2015 through March 2016, an anonymous survey was distributed to personnel in 3 distinct types of paid full-time EMS systems: Boston EMS (2-tiered, municipal third-service); Portland Fire Department (fire department-based ALS); and Stokes County EMS (county-based ALS) combined with Forsyth County EMS (county-based ALS). Data included personnel demographics and previous participation experiences in both drill and actual MCIs. Personnel with any prior MCI experience were queried regarding triage tag use and type of algorithm used. Data on barriers to use of triage tags and methods of communication of patient information were also collected. Descriptive statistics were used to analyze responses.<br><br>RESULTS: Overall survey participation rate was 77.9% (464/596). Among all respondents, 38.7% (179/464) reported participating in both a drill and actual MCI's. In these cases, respondents reported less likely use of triage tags during actual MCI's compared to drills, (34.1&#xa0;vs. 91.8%, p < 0.01), less likely to complete full triage (16.3&#xa0;vs. 68.7%, p < 0.01) and less likely to employ geographical triage (56.8&#xa0;vs. 90.4% p < 0.01). Verbal report was the most common communication method to hospitals (93.1%) when triage tags were not used. Responders reported proximity to the hospital as the most common reason for not using triage tags during an actual MCI (29.5%).<br><br>CONCLUSIONS: Despite being a fundamental skill in MCI response, triage and other standard practices have not always been utilized in actual events despite training. EMS educators and disaster planners should consider strategies to better incorporate MCI practices during real world events.}, }
@article {pmid29416499, year = {2018}, author = {Bond, L and Bernhardt, K and Madria, P and Sorrentino, K and Scelsi, H and Mitchell, CS}, title = {A Metadata Analysis of Oxidative Stress Etiology in Preclinical Amyotrophic Lateral Sclerosis: Benefits of Antioxidant Therapy.}, journal = {Frontiers in neuroscience}, volume = {12}, number = {}, pages = {10}, pmid = {29416499}, issn = {1662-4548}, support = {R03 NS098228/NS/NINDS NIH HHS/United States ; }, abstract = {Oxidative stress, induced by an imbalance of free radicals, incites neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). In fact, a mutation in antioxidant enzyme superoxide dismutase 1 (SOD1) accounts for 20% of familial ALS cases. However, the variance among individual studies examining ALS oxidative stress clouds corresponding conclusions. Therefore, we construct a comprehensive, temporal view of oxidative stress and corresponding antioxidant therapy in preclinical ALS by mining published quantitative experimental data and performing metadata analysis of 41 studies. In vitro aggregate analysis of innate oxidative stress inducers, glutamate and hydrogen peroxide, revealed 70-90% of cell death coincides to inducer exposure equivalent to 30-50% peak concentration (p < 0.05). A correlative plateau in cell death suggests oxidative stress impact is greatest in early-stage neurodegeneration. In vivo SOD1-G93A transgenic ALS mouse aggregate analysis of heat shock proteins (HSPs) revealed HSP levels are 30% lower in muscle than spine (p < 0.1). Overall spine HSP levels, including HSP70, are mildly upregulated in SOD1-G93A mice compared to wild type, but not significantly (p > 0.05). Thus, innate HSP compensatory responses to oxidative stress are simply insufficient, a result supportive of homeostatic system instability as central to ALS etiology. In vivo aggregate analysis of antioxidant therapy finds SOD1-G93A ALS mouse survival duration significantly increases by 11.2% (p << 0.001) but insignificantly decreases onset age by 2%. Thus, the aggregate antioxidant treatment effect on survival in preclinical ALS is not sufficient to overcome clinical heterogeneity, which explains the literature disparity between preclinical and clinical antioxidant survival benefit. The aggregate effect sizes on preclinical ALS survival and onset illustrate that present antioxidants, alone, are not sufficient to halt ALS, which underscores its multi-factorial nature. Nonetheless, antioxidant-treated SOD1-G93A ALS mice have significantly increased motor performance (p < 0.05) measured via rotarod. With a colossal aggregate preclinical effect size average of 59.6%, antioxidants are promising for increasing function/quality of life in clinical ALS patients, a premise worth exploration via low-risk nutritional supplements. Finally, more direct, quantitative measures of oxidative stress, antioxidant levels and bioavailability are key to developing powerful antioxidant therapeutics that can assert measurable impacts on redox homeostasis in the brain and spinal cord.}, }
@article {pmid29411640, year = {2018}, author = {Zhang, H and Cai, W and Chen, S and Liang, J and Wang, Z and Ren, Y and Liu, W and Zhang, X and Sun, Z and Huang, X}, title = {Screening for possible oligogenic pathogenesis in Chinese sporadic ALS patients.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {19}, number = {5-6}, pages = {419-425}, doi = {10.1080/21678421.2018.1432659}, pmid = {29411640}, issn = {2167-9223}, mesh = {Adolescent ; Adult ; Age of Onset ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*diagnosis/epidemiology/*genetics ; Asian People/genetics ; Chi-Square Distribution ; Female ; Gene Frequency ; Genetic Association Studies ; *Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Multifactorial Inheritance/*genetics ; Retrospective Studies ; Young Adult ; }, abstract = {We investigated all coding regions of 17 known amyotrophic lateral sclerosis (ALS)-related genes in 311 sporadic ALS patients who were of Chinese ancestry using next-generation sequencing technology. All nonsynonymous variants identified were confirmed by Sanger sequencing. 29 (9.32%) patients harbored at least one pathogenic or likely pathogenic variants. Nine (2.8%) patients harbored two or three variants which frequency <1% in population databases that may be related to oligogenic pathogenesis. A higher allele frequency was observed in East Asian than in European patients for the majority variants identified in this screening, which may indicate that genetic factors are responsible for the different clinical characteristics between Chinese and European ALS patients. Our study reports the results of extensive genetic screening and is the first to investigate the possible oligogenic pathogenesis in Chinese sporadic ALS patients. These findings are useful for exploring ALS pathogenesis and treatment strategies.}, }
@article {pmid29411264, year = {2018}, author = {Kay, L and Pienaar, IS and Cooray, R and Black, G and Soundararajan, M}, title = {Understanding Miro GTPases: Implications in the Treatment of Neurodegenerative Disorders.}, journal = {Molecular neurobiology}, volume = {55}, number = {9}, pages = {7352-7365}, pmid = {29411264}, issn = {1559-1182}, mesh = {Animals ; Disease Models, Animal ; GTP Phosphohydrolases/chemistry/*metabolism ; Homeostasis ; Humans ; Mitochondria/metabolism ; Mitochondrial Dynamics ; Neurodegenerative Diseases/*enzymology/*therapy ; }, abstract = {The Miro GTPases represent an unusual subgroup of the Ras superfamily and have recently emerged as important mediators of mitochondrial dynamics and for maintaining neuronal health. It is now well-established that these enzymes act as essential components of a Ca[2+]-sensitive motor complex, facilitating the transport of mitochondria along microtubules in several cell types, including dopaminergic neurons. The Miros appear to be critical for both anterograde and retrograde mitochondrial transport in axons and dendrites, both of which are considered essential for neuronal health. Furthermore, the Miros may be significantly involved in the development of several serious pathological processes, including the development of neurodegenerative and psychiatric disorders. In this review, we discuss the molecular structure and known mitochondrial functions of the Miro GTPases in humans and other organisms, in the context of neurodegenerative disease. Finally, we consider the potential human Miros hold as novel therapeutic targets for the treatment of such disease.}, }
@article {pmid29405033, year = {2017}, author = {Silani, V}, title = {Therapy in Amyotrophic Lateral Sclerosis (ALS): an unexpected evolving scenario.}, journal = {Archives italiennes de biologie}, volume = {155}, number = {4}, pages = {118-130}, doi = {10.12871/00039829201747}, pmid = {29405033}, issn = {0003-9829}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Humans ; Molecular Targeted Therapy/methods ; Neuroprotective Agents/*therapeutic use ; Precision Medicine/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease resulting in increasing disability, being uniformly fatal. Since its approval in the 1990s, riluzole remained for long time the unique treatment, offering modest survival benefit. Most recently a second drug has been approved by the US Food and Drug Administration for treatment of ALS: edaravone. Significant advances have been made in the symptomatic management of the disease but more effective drug therapy targeting disease progression is still dreadfully needed, the success appearing almost a miracle. Recent discoveries related to genetics indicate divergent mechanisms of disease encouraging precision medicine leading to molecularly tailored interventions. The search for effective therapy still faces important challenges in the areas of both basic science and animal research, adequate translation of results into human clinical trials, inherent bias in human studies, and issues related to delays in clinical diagnosis. It is interesting to point out that ALS research may speed up drug development not only for this disease, but also for other more prevalent neurodegenerative diseases: the reverse is also conceivable.}, }
@article {pmid29404735, year = {2018}, author = {Mandrioli, J and Malerba, SA and Beghi, E and Fini, N and Fasano, A and Zucchi, E and De Pasqua, S and Guidi, C and Terlizzi, E and Sette, E and Ravasio, A and Casmiro, M and Salvi, F and Liguori, R and Zinno, L and Handouk, Y and Rizzi, R and Borghi, A and Rinaldi, R and Medici, D and Santangelo, M and Granieri, E and Mussuto, V and Aiello, M and Ferro, S and Vinceti, M and , }, title = {Riluzole and other prognostic factors in ALS: a population-based registry study in Italy.}, journal = {Journal of neurology}, volume = {265}, number = {4}, pages = {817-827}, pmid = {29404735}, issn = {1432-1459}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/epidemiology/mortality/*therapy ; Community Health Planning ; Delayed Diagnosis ; Female ; Follow-Up Studies ; Gastrostomy ; Humans ; Italy ; Longitudinal Studies ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Prognosis ; Registries ; Riluzole/*therapeutic use ; Survival ; Time Factors ; *Treatment Outcome ; }, abstract = {OBJECTIVE: In this prospective population-based registry study on ALS survival, we investigated the role of riluzole treatment, together with other clinical factors, on the prognosis in incident ALS cases in Emilia Romagna Region (ERR), Italy.<br><br>METHODS: A registry for ALS has been collecting all incident cases in ERR since 2009. Detailed clinical data from all patients diagnosed with ALS between 1.1.2009 and 31.12.2014 have been analyzed for this study, with last follow up date set at 31.12.2015.<br><br>RESULTS: During the 6&#xa0;years of the study, there were 681 incident cases with a median tracheostomy-free survival of 40&#xa0;months (95% CI 36-44) from onset and of 26&#xa0;months (95% CI 24-30) from diagnosis; 573 patients (84.14%) were treated with riluzole, 207 (30.39%) patients underwent gastrostomy, 246 (36.12%) non invasive ventilation, and 103 (15.15%) invasive ventilation. Patients who took treatment for&#xa0;&#x2265;&#xa0;75% of disease duration from diagnosis had a median survival of 29&#xa0;months compared to 18&#xa0;months in patients with&#xa0;<&#xa0;75% treatment duration. In multivariable analysis, factors independently influencing survival were age at onset (HR 1.04, 95% CI 1.02-1.05, p&#xa0;<&#xa0;0.001), dementia (HR 1.56, 95% CI 1.05-2.32, p&#xa0;=&#xa0;0.027), degree of diagnostic certainty (HR 0.88, 95% CI 0.78-0.98, p&#xa0;=&#xa0;0.021), gastrostomy (HR 1.46, 95% CI 1.14-1.88, p&#xa0;=&#xa0;0.003), NIV (HR 1.43, 95% CI 1.12-1.82, p&#xa0;=&#xa0;0.004), and weight loss at diagnosis (HR 1.05, 95% CI 1.03-1.07, p&#xa0;<&#xa0;0.001), diagnostic delay (HR 0.98, 95% CI 0.97-0.99, p&#xa0;=&#xa0;0.004), and % treatment duration (HR 0.98, 95% CI 0.98-0.99, p&#xa0;<&#xa0;0.001).<br><br>CONCLUSIONS: Independently from other prognostic factors, patients who received riluzole for a longer period of time survived longer, but further population based studies are needed to verify if long-tem use of riluzole prolongs survival.}, }
@article {pmid29402141, year = {2018}, author = {Andrews, JA and Cudkowicz, ME and Hardiman, O and Meng, L and Bian, A and Lee, J and Wolff, AA and Malik, FI and Shefner, JM}, title = {VITALITY-ALS, a phase III trial of tirasemtiv, a selective fast skeletal muscle troponin activator, as a potential treatment for patients with amyotrophic lateral sclerosis: study design and baseline characteristics.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {19}, number = {3-4}, pages = {259-266}, doi = {10.1080/21678421.2018.1426770}, pmid = {29402141}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Imidazoles/*therapeutic use ; Male ; Pyrazines/*therapeutic use ; Severity of Illness Index ; Troponin/metabolism ; }, abstract = {OBJECTIVE: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo on respiratory function and other functional measures in patients with amyotrophic lateral sclerosis (ALS). This study was designed to confirm and extend results from a large phase IIb trial and maximize tolerability with a slower dose escalation.<br><br>METHODS: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled, parallel-group study in ALS patients. Participants who tolerated two weeks of open-label tirasemtiv (125&#x2009;mg twice a day) were randomized 3:2:2:2 to placebo or one of three target total daily dose levels of tirasemtiv (250, 375, or 500&#x2009;mg). Participants randomized to tirasemtiv escalated their dose every two weeks to their target dose level or maximum tolerated dose. The primary outcome measure was change in slow vital capacity from baseline to 24 weeks. Secondary endpoints assessed the effect of tirasemtiv on muscle strength and certain respiratory milestones of disease progression. A four-week randomized withdrawal phase followed 48 weeks of treatment to evaluate the possibility of sustained benefit or rebound decline.<br><br>RESULTS: Data collection will be complete in the fourth quarter of 2017.<br><br>CONCLUSIONS: VITALITY-ALS was a phase III trial designed to evaluate the efficacy, safety, and tolerability of tirasemtiv in ALS.}, }
@article {pmid29400298, year = {2018}, author = {Morlet, &#xc9; and Hozer, F and Costemale-Lacoste, JF}, title = {Neuroprotective effects of lithium: what are the implications in humans with neurodegenerative disorders?.}, journal = {Geriatrie et psychologie neuropsychiatrie du vieillissement}, volume = {16}, number = {1}, pages = {78-86}, doi = {10.1684/pnv.2017.0718}, pmid = {29400298}, issn = {2115-7863}, mesh = {Aged ; Aged, 80 and over ; Aging ; Humans ; Lithium/*therapeutic use ; Neurodegenerative Diseases/*prevention &amp; control ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Lithium is used as a first line treatment in bipolar disorder. The neuroprotective effects of lithium in this indication tend to be well known and are mediated by its action on two enzymes: glycogen synthase kinase-3 and inositol monophosphatase-1. Preclinical and clinical studies seek to evaluate the neuroprotective effect of lithium in neurodegenerative disorders. The aims of this literature review is to gather clinical studies that investigated the efficacy of lithium in neurodegenerative diseases, using a systematic method based on PubMed data. Results were found concerning Alzheimer's disease and related dementias, Huntington's disease, amyotrophic lateral sclerosis and spino-cerebellar ataxia. Lithium exposure showed a potential neuroprotective effect in studies on psychiatric populations with a lower prevalence of Alzheimer's disease in exposed patients. In patients with mild cognitive impairment, lithium would be associated with clinical improvement and a lower level of cerebrospinal phosphorylated tau protein. Lithium would allow at least a partial improvement in symptoms, including suicidal thoughts, in Huntington's disease. Despite several positive case reports and short studies, further controlled researches have failed to substantiate any positive effects of lithium exposure in amyotrophic lateral sclerosis. In spinocerebellar ataxia, introduction of lithium may be of benefits in terms of improvement of cerebellar symptoms. Large randomized controlled trials are required to asses the effect of early exposure lithium in these indications, based on reliable biological markers of disease.}, }
@article {pmid29399337, year = {2018}, author = {Abdanipour, A and Jafari Anarkooli, I and Shokri, S and Ghorbanlou, M and Bayati, V and Nejatbakhsh, R}, title = {Neuroprotective effects of selegiline on rat neural stem cells treated with hydrogen peroxide.}, journal = {Biomedical reports}, volume = {8}, number = {1}, pages = {41-46}, pmid = {29399337}, issn = {2049-9434}, abstract = {Oxidative stress and reactive oxygen species generation have been implicated in the pathogenesis of several neurological disorders including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. In the present study, the neuroprotective effects of selegiline against hydrogen peroxide-induced oxidative stress in hippocampus-derived neural stem cells (NSCs) were evaluated. NSCs isolated from neonatal Wistar rats were pretreated with different doses of selegiline for 48 h and then exposed to 125 µM H2O2 for 30 min. Using MTT and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays, acridine orange/ethidium bromide staining and reverse transcription-quantitative polymerase chain reaction, the effects of selegiline on cell survival, apoptosis and the expression of B-cell lymphoma 2 (Bcl-2) and heat shock protein 4 (Hspa4) in pretreated stem cells were assessed compared with a control group lacking pretreatment. The results indicated that the viability of cells pretreated with 20 µM selegiline was significantly increased compared with the control group (P<0.05). Additionally, 20 µM selegiline increased the mRNA expression of Bcl-2 and Hspa4 (P<0.05 vs. control) and suppressed oxidative stress-induced cell death (apoptosis and necrosis; P<0.05 vs. control and 10 µM groups). From these findings, it was concluded that selegiline may be a therapeutic candidate for the treatment of neurological diseases mediated by oxidative stress.}, }
@article {pmid29399045, year = {2018}, author = {Dorst, J and Ludolph, AC and Huebers, A}, title = {Disease-modifying and symptomatic treatment of amyotrophic lateral sclerosis.}, journal = {Therapeutic advances in neurological disorders}, volume = {11}, number = {}, pages = {1756285617734734}, pmid = {29399045}, issn = {1756-2856}, abstract = {In this review, we summarize the most important recent developments in the treatment of amyotrophic lateral sclerosis (ALS). In terms of disease-modifying treatment options, several drugs such as dexpramipexole, pioglitazone, lithium, and many others have been tested in large multicenter trials, albeit with disappointing results. Therefore, riluzole remains the only directly disease-modifying drug. In addition, we discuss antisense oligonucleotides (ASOs) as a new and potentially causal treatment option. Progress in symptomatic treatments has been more important. Nutrition and ventilation are now an important focus of ALS therapy. Several studies have firmly established that noninvasive ventilation improves patients' quality of life and prolongs survival. On the other hand, there is still no consensus regarding best nutritional management, but big multicenter trials addressing this issue are currently ongoing. Evidence regarding secondary symptoms like spasticity, muscle cramps or sialorrhea remains generally scarce, but some new insights will also be discussed. Growing evidence suggests that multidisciplinary care in specialized clinics improves survival.}, }
@article {pmid29396541, year = {2018}, author = {Oberstadt, M and Stieler, J and Simpong, DL and Römuß, U and Urban, N and Schaefer, M and Arendt, T and Holzer, M}, title = {TDP-43 self-interaction is modulated by redox-active compounds Auranofin, Chelerythrine and Riluzole.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {2248}, pmid = {29396541}, issn = {2045-2322}, mesh = {Amyotrophic Lateral Sclerosis/pathology/prevention &amp; control ; Animals ; Auranofin/*pharmacology ; Benzophenanthridines/*pharmacology ; Cell Line, Tumor ; DNA-Binding Proteins/*metabolism ; Glutathione/analysis ; Mice ; Motor Neurons/pathology ; Oxidation-Reduction/drug effects ; Protein Aggregates/*drug effects ; Protein Aggregation, Pathological/*drug therapy/pathology ; Riluzole/*pharmacology ; Thioredoxin-Disulfide Reductase/antagonists &amp; inhibitors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) represents a fatal neurodegenerative disease, which is characterized by a rapid loss of lower and upper motor neurons. As a major neuropathological hallmark, protein aggregates containing the Transactivating Response Region (TAR) DNA Binding Protein (TDP-43) are detectable in about 95% of sporadic ALS patients. TDP-43 interacts with itself physiologically to form liquid droplets, which may progress to pathological aggregates. In this study, we established the NanoBit luciferase complementation assay to measure TDP-43 self-interaction and found the fusion of the split luciferase subunits to the N-terminus of the protein as the strongest interacting partners. A screen of pharmacologically active compounds from the LOPAC[®1280] library identified auranofin, chelerythrine and riluzole as dose-dependent inhibitors of TDP-43 self-interaction. Further analysis of drug action of the gold-containing thioredoxin reductase inhibitor auranofin revealed a redistribution from insoluble TDP-43 protein pool to PBS-soluble protein pool in N2a cells. In addition, auranofin treatment diminished reduced glutathione as a sign for oxidative modulation.}, }
@article {pmid29394876, year = {2018}, author = {Qosa, H and Volpe, DA}, title = {The development of biological therapies for neurological diseases: moving on from previous failures.}, journal = {Expert opinion on drug discovery}, volume = {13}, number = {4}, pages = {283-293}, doi = {10.1080/17460441.2018.1437142}, pmid = {29394876}, issn = {1746-045X}, mesh = {Animals ; Biological Products/adverse effects/*therapeutic use ; Biological Therapy/*methods ; Disease Progression ; Drug Design ; Humans ; Nervous System Diseases/*drug therapy/physiopathology ; }, abstract = {Although years of research have expanded the use of biologics for several clinical conditions, such development has not yet occurred in the treatment of neurological diseases. With the advancement of biologic technologies, there is promise for these therapeutics as novel therapeutic approaches for neurological diseases. Areas covered: In this article, the authors review the therapeutic potential of different types of biologics for the treatment of neurological diseases. Preclinical and clinical studies that investigate the efficacy and safety of biologics in the treatment of neurological diseases, namely Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson disease, multiple sclerosis, and stroke, were reviewed. Moreover, the authors describe the key challenges in the development of therapeutically safe and effective biologics for the treatment of neurological diseases. Expert opinion: Several biologics have shown promise in the treatment of neurological diseases. However, the complexity of the CNS, as well as a limited understanding of disease progression, and restricted access of biologics to the CNS has limited successful development. Therefore, more research needs to be conducted to overcome these hurdles before developing effective and safe biologics for neurological diseases. The emergence of new technologies for the design, production and delivery of biologics will accelerate translating biologics to the clinic.}, }
@article {pmid29394243, year = {2018}, author = {Yan, L and Liu, Y and Sun, C and Zheng, Q and Hao, P and Zhai, J and Liu, Y}, title = {Effects of Ovariectomy in an hSOD1-G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis (ALS).}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {24}, number = {}, pages = {678-686}, pmid = {29394243}, issn = {1643-3750}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; Anti-Inflammatory Agents/metabolism ; Apoptosis/genetics ; Arginase/metabolism ; Aromatase/metabolism ; Behavior, Animal ; Disease Models, Animal ; Down-Regulation/genetics ; Female ; Humans ; Lumbar Vertebrae/enzymology/pathology ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; *Ovariectomy ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Receptors, Estrogen/metabolism ; Superoxide Dismutase/*metabolism ; }, abstract = {BACKGROUND Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive muscular dystrophy and paralysis; most ALS patients die from respiratory failure within 3 to 5 years, and there is currently no effective treatment. Some studies have indicated sex differences in the incidence of ALS, and evidence suggests a neuroprotective role for estrogen. MATERIAL AND METHODS We used human Cu/Zn superoxide dismutase (hSOD1-G93A) transgenic mice to determine the effects of ovariotomy on the onset of disease and behavior; we also used Western blotting to measure the expression of aromatase and estrogen receptors, as well as the inflammatory cytokines and apoptosis markers, in the lumbar spinal cord to determine the mechanism of estrogen-mediated neuroprotection. RESULTS Ovariectomy advanced the onset of disease, down-regulated aromatase and estrogen receptor alpha (ER-a) expression, and inhibited expression of the anti-inflammatory factors arginase-1 and the anti-apoptotic factor B-cell lymphoma-2 (Bcl-2) in the lumbar spinal cord of hSOD1-G93A transgenic mice. CONCLUSIONS Ovariectomy resulted in earlier disease onset and attenuated the anti-inflammatory and anti-apoptotic actions of estrogen in hSOD1-G93A transgenic mice. Therefore, estrogen may play an important role in protecting spinal cord motor neurons.}, }
@article {pmid29393015, year = {2018}, author = {Kiers, D and Meermans, M and Verstraete, E and van Leeuwen, HJ}, title = {[Weak respiratory muscles as a first sign of ALS: symptoms may put the physician on the wrong track].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {162}, number = {}, pages = {D2189}, pmid = {29393015}, issn = {1876-8784}, mesh = {Aged, 80 and over ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/physiopathology ; Delayed Diagnosis/*prevention &amp; control ; Diagnosis, Differential ; Exercise Tolerance ; Fatal Outcome ; Humans ; Male ; Muscle Weakness/etiology/physiopathology ; Neurologic Examination/methods ; *Respiratory Insufficiency/diagnosis/etiology/physiopathology ; Respiratory Muscles/physiopathology ; }, abstract = {BACKGROUND: Patients with decreased exercise tolerance and orthopnoea are often referred to an internist, a cardiologist or a pulmonologist. These symptoms can also be caused by weakness of the respiratory muscles, as an indication of a neuromuscular disease. If these symptoms are not recognized as such, this may result in a delay in timely diagnosis.<br><br>CASE DESCRIPTION: An 82-year-old man had suffered from decreased exercise tolerance for 18 months. For the last months he had been sleeping upright and had lost 20 kg in weight. Analyses by the cardiologist and the internist had not led to a definitive diagnosis. He was finally brought to the emergency department with loss of consciousness and hypercapnic respiratory insufficiency. Neurological examination was suggestive of motor neuron disease such as progressive spinal muscular atrophy or amyotrophic lateral sclerosis. The patient died within 24 hours of admission.<br><br>CONCLUSION: Patients with symptoms resulting from respiratory muscle weakness are commonly referred to non-neurological specialists, leading to a delay in diagnosis and treatment of an underlying neuromuscular disease.}, }
@article {pmid29387280, year = {2017}, author = {Boumil, EF and Vohnoutka, RB and Liu, Y and Lee, S and Shea, TB}, title = {Omega-3 Hastens and Omega-6 Delays the Progression of Neuropathology in a Murine Model of Familial ALS.}, journal = {The open neurology journal}, volume = {11}, number = {}, pages = {84-91}, pmid = {29387280}, issn = {1874-205X}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive disease of motor neurons that has no cure or effective treatment. Any approach that could sustain minor motor function during terminal stages would improve quality of life.<br><br>OBJECTIVE: We examined the impact of omega-3 (&#x3a9;-3) and &#x3a9;-6, on motor neuron function in mice expressing mutant human superoxide dismutase-1 (SOD-1), which dominantly confers familial ALS and induces a similar sequence of motor neuron decline and eventual death when expressed in mice.<br><br>METHOD: Mice received standard diets supplemented with equivalent amounts of &#x3a9;-3 and &#x3a9;-6 or a 10x increase in &#x3a9;-6 with no change in &#x3a9;-3 commencing at 4 weeks of age. Motor function and biochemical/histological parameters were assayed by standard methodologies.<br><br>RESULTS: Supplementation with equivalent &#x3a9;-3 and &#x3a9;-6 hastened motor neuron pathology and death, while 10x &#x3a9;-6 with no change in &#x3a9;-3 significantly delayed motor neuron pathology, including preservation of minor motor neuron function during the terminal stage.<br><br>CONCLUSION: In the absence of a cure or treatment, affected individuals may resort to popular nutritional supplements such as &#x3a9;-3 as a form of "self-medication". However, our findings and those of other laboratories indicate that such an approach could be harmful. Our findings suggest that a critical balance of &#x3a9;-6 and &#x3a9;-3 may temporarily preserve motor neuron function during the terminal stages of ALS, which could provide a substantial improvement in quality of life for affected individuals and their caregivers.}, }
@article {pmid29383655, year = {2018}, author = {Wang, Y and Liu, FT and Wang, YX and Guan, RY and Chen, C and Li, DK and Bu, LL and Song, J and Yang, YJ and Dong, Y and Chen, Y and Wang, J}, title = {Autophagic Modulation by Trehalose Reduces Accumulation of TDP-43 in a Cell Model of Amyotrophic Lateral Sclerosis via TFEB Activation.}, journal = {Neurotoxicity research}, volume = {34}, number = {1}, pages = {109-120}, pmid = {29383655}, issn = {1476-3524}, support = {81571232//National Natural Science Foundation of China/International ; 81371413//National Natural Science Foundation of China/International ; 2016YFC1306500//project from Ministry of Science and technology of China;/International ; 2016QD01//Scientific Research Project from Huashan Hospital affiliated to Fudan University/International ; }, mesh = {Animals ; Autophagy/*drug effects ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Glucose/pharmacology ; Green Fluorescent Proteins/genetics/metabolism ; Humans ; Microtubule-Associated Proteins/genetics/metabolism ; Neuroblastoma/pathology ; Time Factors ; Transfection ; Trehalose/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease characterized by the formation of protein inclusion and progressive loss of motor neurons, finally leading to muscle weakness and respiratory failure. So far, the effective drugs for ALS are yet to be developed. Impairment of transcriptional activator transcription factor EB (TFEB) has been demonstrated as a key element in the pathogenesis of ALS. Trehalose is an mechanistic target of rapamycin-independent inducer for autophagy, which showed autophagic activation and neuroprotective effect in a variety of neurodegenerative diseases. The mechanism for trehalose-induced autophagy enhancement is not clear, and its therapeutic effect on TAR DNA-binding protein-43 (TDP-43) proteinopathies has been poorly investigated. Here we examined the effect of trehalose on TDP-43 clearance in a cell culture model and identified that trehalose treatment significantly reduced TDP-43 accumulation in vitro through modulation of the autophagic degradation pathway. Further studies revealed that activation of TFEB induced by trehalose was responsible for the enhancement of autophagy and clearance of TDP-43 level. These results gave us the notion that TFEB is a central regular in trehalose-mediated autophagic clearance of TDP-43 aggregates, representing an important step forward in the treatment of TDP-43 related ALS diseases.}, }
@article {pmid29382225, year = {2018}, author = {Funke, A and Spittel, S and Grehl, T and Grosskreutz, J and Kettemann, D and Petri, S and Weyen, U and Weydt, P and Dorst, J and Ludolph, AC and Baum, P and Oberstadt, M and Jordan, B and Hermann, A and Wolf, J and Boentert, M and Walter, B and Gajewski, N and Maier, A and Münch, C and Meyer, T}, title = {Provision of assistive technology devices among people with ALS in Germany: a platform-case management approach.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {19}, number = {5-6}, pages = {342-350}, doi = {10.1080/21678421.2018.1431786}, pmid = {29382225}, issn = {2167-9223}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/epidemiology/psychology/*therapy ; *Case Management ; Cohort Studies ; Delivery of Health Care ; Female ; Germany/epidemiology ; Health Services Accessibility ; Humans ; Male ; Middle Aged ; *Self-Help Devices ; }, abstract = {OBJECTIVE: The procurement of assistive technology devices (ATD) is an essential component of managed care in ALS. The objective was to analyze the standards of care for ATD and to identify challenges in the provision process.<br><br>METHODS: A cohort study design was used. We investigated the provision of 11,364 ATD in 1494 patients with ALS at 12 ALS centers in Germany over four years. Participants were patients that entered a case management program for ATD including systematic assessment of ATD on a digital management platform.<br><br>RESULTS: Wheelchairs (requested in 65% of patients), orthoses (52%), bathroom adaptations (49%), and communication devices (46%) were the most needed ATD. There was a wide range in the number of indicated ATD per patient: 1 to 4 ATD per patient in 45% of patients, 5 to 20 ATD in 48%, and&#x2009;>20 ATD in 7% of patients. Seventy percent of all requested ATD were effectively delivered. However, an alarming failure rate during procurement was found in ATD that are crucial for ALS patients such as powered wheelchairs (52%), communication devices (39%), or orthoses (21%). Leading causes for not providing ATD were the refusal by health insurances, the decision by patients, and the death of the patient before delivery of the device.<br><br>CONCLUSIONS: The need for ATD was highly prevalent among ALS patients. Failed or protracted provision posed substantial barriers to ATD procurement. Targeted national strategies and the incorporation of ATD indication criteria in international ALS treatment guidelines are urgently needed to overcome these barriers.}, }
@article {pmid29380557, year = {2018}, author = {Halon-Golabek, M and Borkowska, A and Kaczor, JJ and Ziolkowski, W and Flis, DJ and Knap, N and Kasperuk, K and Antosiewicz, J}, title = {hmSOD1 gene mutation-induced disturbance in iron metabolism is mediated by impairment of Akt signalling pathway.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {9}, number = {3}, pages = {557-569}, pmid = {29380557}, issn = {2190-6009}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Cell Line ; Disease Models, Animal ; Forkhead Box Protein O3/*metabolism ; Humans ; Insulin/metabolism ; Iron/*metabolism ; Male ; Mice ; Muscle Proteins/metabolism ; Muscle, Skeletal/metabolism ; Mutation ; Proto-Oncogene Proteins c-akt/*metabolism ; Rats, Sprague-Dawley ; Rats, Transgenic ; SKP Cullin F-Box Protein Ligases/metabolism ; Signal Transduction ; Superoxide Dismutase-1/*genetics ; }, abstract = {BACKGROUND: Recently, skeletal muscle atrophy, impairment of iron metabolism, and insulin signalling have been reported in rats suffering from amyotrophic lateral sclerosis (ALS). However, the interrelationship between these changes has not been studied. We hypothesize that an impaired Akt-FOXO3a signalling pathway triggers changes in the iron metabolism in the muscles of transgenic animals.<br><br>METHODS: In the present study, we used transgenic rats bearing the G93A hmSOD1 gene and their non-transgenic littermates. The study was performed on the muscles taken from animals at three different stages of the disease: asymptomatic (ALS I), the onset of the disease (ALS II), and the terminal stage of the disease (ALS III). In order to study the molecular mechanism of changes in iron metabolism, we used SH-SY5Y and C2C12 cell lines stably transfected with pcDNA3.1, SOD1 WT and SOD1 G93A, or FOXO3a TM-ER.<br><br>RESULTS: A significant decrease in P-Akt level and changes in iron metabolism were observed even in the group of ALS I animals. This was accompanied by an increase in the active form of FOXO3a, up-regulation of atrogin-1, and catalase. However, significant muscle atrophy was observed in ALS II animals. An increase in ferritin L and H was accompanied by a rise in PCBP1 and APP protein levels. In SH-SY5Y cells stably expressing SOD1 or SOD1 G93A, we observed elevated levels of ferritin L and H and non-haem iron. Interestingly, insulin treatment significantly down-regulated ferritin L and H proteins in the cell. Conversely, cells transfected with small interfering RNA against Akt 1, 2, 3, respectively, showed a significant increase in the ferritin and FOXO3a levels. In order to assess the role of FOXO3a in the ferritin expression, we constructed a line of SH-SY5Y cells that expressed a fusion protein made of FOXO3a fused at the C-terminus with the ligand-binding domain of the oestrogen receptor (TM-ER) being activated by 4-hydroxytamoxifen. Treatment of the cells with 4-hydroxytamoxifen significantly up-regulated ferritin L and H proteins level.<br><br>CONCLUSIONS: Our data suggest that impairment of insulin signalling and iron metabolism in the skeletal muscle precedes muscle atrophy and is mediated by changes in Akt/FOXO3a signalling pathways.}, }
@article {pmid29380402, year = {2018}, author = {Clark, JA and Blizzard, CA and Breslin, MC and Yeaman, EJ and Lee, KM and Chuckowree, JA and Dickson, TC}, title = {Epothilone D accelerates disease progression in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {Neuropathology and applied neurobiology}, volume = {44}, number = {6}, pages = {590-605}, doi = {10.1111/nan.12473}, pmid = {29380402}, issn = {1365-2990}, support = {D0019780//Masonic Centenary Medical Research Foundation of Tasmania/International ; C0021192//Motor Neurone Disease Research Institute of Australia/International ; K0020795//Motor Neurone Disease Research Institute of Australia/International ; D0018642//National Health and Medical Research Council/International ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; Axons/pathology ; Disease Models, Animal ; Disease Progression ; Epothilones/*pharmacology ; Hand Strength ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/*pathology ; Motor Skills/drug effects ; Neuromuscular Junction/*pathology ; Superoxide Dismutase-1/*genetics ; }, abstract = {AIMS: Degeneration of the distal neuromuscular circuitry is a hallmark pathology of Amyotrophic Lateral Sclerosis (ALS). The potential for microtubule dysfunction to be a critical pathophysiological mechanism in the destruction of this circuitry is increasingly being appreciated. Stabilization of microtubules to improve neuronal integrity and pathology has been shown to be a particularly favourable approach in other neurodegenerative diseases. We present evidence here that treatment with the microtubule-targeting compound Epothilone D (EpoD) both positively and negatively affects the spinal neuromuscular circuitry in the SOD1[G93A] mouse model of ALS.<br><br>METHODS: SOD1[G93A] mice were treated every 5 days with 2 mg/kg EpoD. Evaluation of motor behaviour, neurological phenotype and survival was completed, with age-dependent histological characterization also conducted, using the thy1-YFP mouse. Motor neuron degeneration, axonal integrity, neuromuscular junction (NMJ) health and gliosis were also assessed.<br><br>RESULTS: EpoD treatment prevented loss of the spinal motor neuron soma, and distal axon degeneration, early in the disease course. This, however, was not associated with protection of the NMJ synapse and did not improve motor phenotype or clinical progression. EpoD administration was also found to be neurotoxic at later disease stages. This was evidenced by accelerated motor neuron cell body loss, increasing gliosis, and was associated with detrimental outcomes to motor behaviour, clinical assessment and survival.<br><br>CONCLUSIONS: The results suggest that EpoD accelerates disease progression in the SOD1[G93A] mouse model of ALS, and highlights that the pathophysiological involvement of microtubules in ALS is an evolving and underappreciated phenomenon.}, }
@article {pmid29379292, year = {2018}, author = {Introna, A and D'Errico, E and Modugno, B and Scarafino, A and Fraddosio, A and Distaso, E and Tempesta, I and Mastronardi, A and Simone, IL}, title = {Adherence to riluzole in patients with amyotrophic lateral sclerosis: an observational study.}, journal = {Neuropsychiatric disease and treatment}, volume = {14}, number = {}, pages = {193-203}, pmid = {29379292}, issn = {1176-6328}, abstract = {OBJECTIVE: Riluzole is the first drug approved to treat amyotrophic lateral sclerosis (ALS). Recently, an oral suspension (OS) of riluzole was made available. Thus, the aim of our study was to evaluate the adherence to 2 formulations of riluzole in patients with ALS.<br><br>PATIENTS AND METHODS: We enrolled 45 consecutive patients with ALS. At disease diagnosis, riluzole was prescribed in 2 different formulations depending on the severity of dysphagia (27/45 patients received tablets and 18/45 patients received OS). Side effects (SEs) and treatment adherence were investigated using a clinical questionnaire including the &#xa9;Morisky 8-item Medication Adherence Questionnaire.<br><br>RESULTS: Gastroenteric complaints were the most frequent SEs (58% in the tablet group and 48% in the OS group), followed by those at the nervous system (29% and 40%, respectively). No serious SEs related to treatment were reported. The rate of adherence to riluzole was independent of the formulation of the drug and consistent with other medications assumed for comorbidities (p=0.004). In the tablet group, low adherence was caused by SEs in 55.6% and by dysphagia in 44.4% of patients. In the OS group, SEs caused low adherence in 75% of patients. Independently of the drug formulation, patients with high or medium adherence to riluzole had a higher progression rate (p=0.002 and p=0.009, respectively) and a shorter time to generalization (TTG; p=0.01), compared to those with low adherence.<br><br>CONCLUSION: Gastroenteric symptoms were the most frequent SE related to tablet as well as OS. The rate of adherence was independent of the formulation of riluzole and the number of medications assumed for comorbidities, and it was consistent with the severity of the disease. The low adherence was caused by dysphagia and SEs in the tablet group, whereas it was caused prevalently by SEs in the OS group.}, }
@article {pmid29375317, year = {2017}, author = {Mòdol-Caballero, G and Santos, D and Navarro, X and Herrando-Grabulosa, M}, title = {Neuregulin 1 Reduces Motoneuron Cell Death and Promotes Neurite Growth in an in Vitro Model of Motoneuron Degeneration.}, journal = {Frontiers in cellular neuroscience}, volume = {11}, number = {}, pages = {431}, pmid = {29375317}, issn = {1662-5102}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder with no effective treatment currently available. Although the mechanisms of motoneuron (MN) death are still unclear, glutamate excitotoxicity and neuroinflammatory reaction are two main features in the neurodegenerative process of ALS. Neuregulin 1 (NRG1) is a trophic factor highly expressed in MNs and neuromuscular junctions. Several recent evidences suggest that NRG1 and their ErbB receptors are involved in ALS. However, further knowledge is still needed to clarify the role of the NRG1-ErbB pathway on MN survival. In this study we used an in vitro model of spinal cord organotypic cultures (SCOCs) subject to chronic excitotoxicity caused by DL-threo-β-hydroxyaspartic acid (THA) to characterize the effect of NRG1 on MN survival. Our results show that addition of recombinant human NRG1 (rhNRG1) to the medium significantly increased MN survival through the activation of ErbB receptors which was ablated with lapatinib (LP), an ErbB inhibitor, and reduced microglial reactivity overcoming the excitotoxicity effects. rhNRG1 activated the pro-survival PI3K/AKT pathway and restored the autophagic flux in the spinal cord culture. Moreover, addition of rhNRG1 to the medium promoted motor and sensory neurite outgrowth. These findings indicate that increasing NRG1 at the spinal cord is an interesting approach for promoting MN protection and regeneration.}, }
@article {pmid29375039, year = {2017}, author = {Csobonyeiova, M and Polak, S and Nicodemou, A and Danisovic, L}, title = {Induced pluripotent stem cells in modeling and cell-based therapy of amyotrophic lateral sclerosis.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {68}, number = {5}, pages = {649-657}, pmid = {29375039}, issn = {1899-1505}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Animals ; Cell Differentiation/physiology ; Cell- and Tissue-Based Therapy/*methods/trends ; *Disease Models, Animal ; Humans ; Induced Pluripotent Stem Cells/physiology/*transplantation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by neuromuscular degeneration and the progressive loss of upper and lower motor neurons (MNs), causing weakness and paralysis. However, the underlying mechanisms of this disease are still unknown and there is no cure, or even treatment to stop or reverse its pathology. Consequently, most ALS patients die within 3 - 5 years after disease onset. While considerable progress has been made in studying animal models of ALS, they lack clinical suitability due to genetic differences. However, the recent development of induced pluripotent stem cells (iPSCs) has made it possible to study human disease-specific neuronal and glial cells to identify disease mechanisms and develop phenotypic screens for drug discovery. iPSCs provide researchers with a model of naturally occurring pathology under the human genetic background and MNs differentiated from human iPSCs bearing ALS-associated mutations offer a powerful model to study disease pathology. This paper reviews recent methods of differentiating iPSCs into neuronal cells and suggests further applications of these iPSCs-derived cells for ALS disease modeling, drug screening, and possible cell-based therapy.}, }
@article {pmid29374221, year = {2018}, author = {Zhou, Q and Wang, Y and Zhang, J and Shao, Y and Li, S and Wang, Y and Cai, H and Feng, Y and Le, W}, title = {Fingerprint analysis of Huolingshengji Formula and its neuroprotective effects in SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {1668}, pmid = {29374221}, issn = {2045-2322}, support = {ZIA AG000959/ImNIH/Intramural NIH HHS/United States ; ZIA AG000959/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Chromatography, High Pressure Liquid ; Disease Models, Animal ; Drugs, Chinese Herbal/*administration &amp; dosage/*chemistry ; Mice ; Muscle, Skeletal/pathology ; Mutation, Missense ; *Neuroprotective Agents ; Spinal Cord/pathology ; Superoxide Dismutase-1/*genetics ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by progressive loss of motor neurons. There are no definitive pathogenic mechanisms and effective treatments for ALS now. Traditional Chinese medicine (TCM) plays an important role in Chinese health care system. Huolingshengji Formula (HLSJ) is a TCM formula which is applied for treating flaccid syndrome. Our previous clinical study has indicated that HLSJ may have therapeutic effects in ALS patients. In the present study, we analyzed the chemical profile of HLSJ by the high-performance liquid chromatographic (HPLC) fingerprint analysis. And we investigated the therapeutic effects and neuroprotective mechanisms of HLSJ against ALS in SOD1[G93A] mouse model. Eleven typical peaks were identified by the fingerprint analysis of HLSJ, and the HPLC method had good precision, repeatability and stability. Consistent with our clinical studies, HLSJ significantly prolonged the lifespan, extended the disease duration, and prevented the motor neuron loss in the anterior horn of the lumbar spinal cords in SOD1[G93A] ALS model mice. Additionally, HLSJ alleviated the atrophy of the gastrocnemius muscles and ameliorated the apoptotic and inflammatory levels in the spinal cords of SOD1[G93A] mice. Collectively, our study indicated that HLSJ might be a novel candidate for the treatment of ALS.}, }
@article {pmid29371752, year = {2018}, author = {Watanabe, K and Tanaka, M and Yuki, S and Hirai, M and Yamamoto, Y}, title = {How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis?.}, journal = {Journal of clinical biochemistry and nutrition}, volume = {62}, number = {1}, pages = {20-38}, pmid = {29371752}, issn = {0912-0009}, abstract = {Edaravone is a low-molecular-weight antioxidant drug targeting peroxyl radicals among many types of reactive oxygen species. Because of its amphiphilicity, it scavenges both lipid- and water-soluble peroxyl radicals by donating an electron to the radical. Thus, it inhibits the oxidation of lipids by scavenging chain-initiating water-soluble peroxyl radicals and chain-carrying lipid peroxyl radicals. In 2001, it was approved in Japan as a drug to treat acute-phase cerebral infarction, and then in 2015 it was approved for amyotrophic lateral sclerosis (ALS). In 2017, the U.S. Food and Drug Administration also approved edaravone for treatment of patients with ALS. Its mechanism of action was inferred to be scavenging of peroxynitrite. In this review, we focus on the radical-scavenging characteristics of edaravone in comparison with some other antioxidants that have been studied in clinical trials, and we summarize its pharmacological action and clinical efficacy in patients with acute cerebral infarction and ALS.}, }
@article {pmid29371591, year = {2018}, author = {Shvil, N and Banerjee, V and Zoltsman, G and Shani, T and Kahn, J and Abu-Hamad, S and Papo, N and Engel, S and Bernhagen, J and Israelson, A}, title = {MIF inhibits the formation and toxicity of misfolded SOD1 amyloid aggregates: implications for familial ALS.}, journal = {Cell death &amp; disease}, volume = {9}, number = {2}, pages = {107}, pmid = {29371591}, issn = {2041-4889}, mesh = {Active Transport, Cell Nucleus/drug effects ; Amyloid/*chemistry ; Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Biocatalysis ; Cell Line ; Cell Nucleus/drug effects/metabolism ; Humans ; Macrophage Migration-Inhibitory Factors/*pharmacology ; Models, Biological ; Mutant Proteins/metabolism/toxicity ; Protein Aggregates/*drug effects ; Protein Binding/drug effects ; *Protein Folding/drug effects ; Protein Multimerization/drug effects ; Recombinant Proteins/pharmacology ; Superoxide Dismutase-1/*chemistry/*toxicity ; }, abstract = {Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the progressive loss of motor neurons in the brain and spinal cord. It has been suggested that toxicity of mutant SOD1 results from its misfolding, however, it is yet unclear why misfolded SOD1 accumulates specifically within motor neurons. We recently demonstrated that macrophage migration inhibitory factor (MIF)-a multifunctional protein with cytokine/chemokine activity and cytosolic chaperone-like properties-inhibits the accumulation of misfolded SOD1. Here, we show that MIF inhibits mutant SOD1 nuclear clearance when overexpressed in motor neuron-like NSC-34 cells. In addition, MIF alters the typical SOD1 amyloid aggregation pathway in vitro, and, instead, promotes the formation of disordered aggregates, as measured by Thioflavin T (ThT) assay and transmission electron microscopy (TEM) imaging. Moreover, we report that MIF reduces the toxicity of misfolded SOD1 by directly interacting with it, and that the chaperone function and protective effect of MIF in neuronal cultures do not require its intrinsic catalytic activities. Importantly, we report that the locked-trimeric MIF[N110C] mutant, which exhibits strongly impaired CD74-mediated cytokine functions, has strong chaperone activity, dissociating, for the first time, these two cellular functions. Altogether, our study implicates MIF as a potential therapeutic candidate in the treatment of ALS.}, }
@article {pmid29367439, year = {2018}, author = {Benatar, M and Wuu, J and Andersen, PM and Atassi, N and David, W and Cudkowicz, M and Schoenfeld, D}, title = {Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS.}, journal = {Neurology}, volume = {90}, number = {7}, pages = {e565-e574}, pmid = {29367439}, issn = {1526-632X}, support = {R01 FD003517/FD/FDA HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Disease Progression ; Double-Blind Method ; Female ; Humans ; Hydroxylamines/adverse effects/*therapeutic use ; Male ; Middle Aged ; Neuroprotective Agents/adverse effects/*therapeutic use ; Severity of Illness Index ; Superoxide Dismutase-1/genetics ; Survival Analysis ; Treatment Outcome ; }, abstract = {OBJECTIVE: To examine the safety and tolerability as well as the preliminary efficacy of arimoclomol, a heat shock protein co-inducer that promotes nascent protein folding, in patients with rapidly progressive SOD1 amyotrophic lateral sclerosis (ALS).<br><br>METHODS: This was a double-blind, placebo-controlled trial in which patients with rapidly progressive SOD1-mutant ALS were randomized 1:1 to receive arimoclomol 200 mg tid or matching placebo for up to 12 months. Study procedures were performed using a mix of in-person and remote assessments. Primary outcome was safety and tolerability. Secondary outcome was efficacy, with survival as the principal measure. Additional efficacy measures were the rates of decline of the Revised ALS Functional Rating Scale (ALSFRS-R) and percent predicted forced expiratory volume in 6 seconds (FEV6), and the Combined Assessment of Function and Survival (CAFS).<br><br>RESULTS: Thirty-eight participants were randomized. Thirty-six (19 placebo, 17 arimoclomol) were included in the prespecified intent-to-treat analysis. Apart from respiratory function, groups were generally well-balanced at baseline. Adverse events occurred infrequently, and were usually mild and deemed unlikely or not related to study drug. Adjusting for riluzole and baseline ALSFRS-R, survival favored arimoclomol with a hazard ratio of 0.77 (95% confidence interval [CI] 0.32-1.80). ALSFRS-R and FEV6 declined more slowly in the arimoclomol group, with treatment differences of 0.5 point/month (95% CI -0.63 to 1.63) and 1.24 percent predicted/month (95% CI -2.77 to 5.25), respectively, and the CAFS similarly favored arimoclomol.<br><br>CONCLUSIONS: This study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. Although not powered for therapeutic effect, the consistency of results across the range of prespecified efficacy outcome measures suggests a possible therapeutic benefit of arimoclomol.<br><br>CLINICALTRIALSGOV IDENTIFIER: NCT00706147.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. The study lacked the precision to conclude, or to exclude, an important therapeutic benefit of arimoclomol.}, }
@article {pmid29365034, year = {2018}, author = {Kuehn, BM}, title = {Simple Models and Ice Bucket Challenge Fuel Progress in ALS Treatment.}, journal = {JAMA}, volume = {319}, number = {6}, pages = {535-537}, doi = {10.1001/jama.2017.20704}, pmid = {29365034}, issn = {1538-3598}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Antipsychotic Agents/*therapeutic use ; Caenorhabditis elegans/physiology ; Clinical Trials, Phase II as Topic/economics ; Disease Models, Animal ; Fund Raising/*methods ; Humans ; Neuromuscular Junction/drug effects ; Pimozide/*therapeutic use ; *Research Support as Topic ; *Social Media ; }, }
@article {pmid29357791, year = {2017}, author = {Ridolfi, B and Abdel-Haq, H}, title = {Neurodegenerative Disorders Treatment: The MicroRNA Role.}, journal = {Current gene therapy}, volume = {17}, number = {5}, pages = {327-363}, doi = {10.2174/1566523218666180119120726}, pmid = {29357791}, issn = {1875-5631}, mesh = {Alzheimer Disease/genetics/therapy ; Amyotrophic Lateral Sclerosis/genetics/therapy ; Exosomes/*genetics ; Gene Expression Regulation ; Genetic Therapy/*methods/trends ; Humans ; MicroRNAs/*genetics ; Neurodegenerative Diseases/genetics/*therapy ; Parkinson Disease/genetics/therapy ; RNA Interference ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and prion disease are not timely and effectively treated using conventional therapies. This emphasizes the need for alternative therapeutic approaches. In this respect, gene-based therapies have been adopted as potentially feasible alternative therapies, where the microRNA (miRNA) approach has experienced a great explosion in recent years. Because miRNAs have been shown to be implicated in the pathogenesis of several diseases including neurodegenerative diseases, they are intensely studied as candidates for diagnostic and prognostic biomarkers, as predictors of drug response and as therapeutic agents. In this review, we evaluate the feasibility of both direct and indirect miRNA mimics and inhibitors toward the regulation of neurodegenerative-related genes both in vivo and in vitro models, highlight the advantages and drawbacks associated with miRNA-based therapy, and summarize the relevant techniques and approaches attempted to deliver miRNAs to the central nervous system for therapeutic purposes, with particular regard to the exosomes. Additionally, we describe a new approach that holds great promise for the treatment of a wide range of diseases including neurodegenerative disorders. This approach is based on addressing the incorporation of miRNAs into exosomes to increase the quantity and quality of miRNA packed and delivered to the central nervous system and other sites of action.}, }
@article {pmid29352425, year = {2018}, author = {Ahmadi, M and Agah, E and Nafissi, S and Jaafari, MR and Harirchian, MH and Sarraf, P and Faghihi-Kashani, S and Hosseini, SJ and Ghoreishi, A and Aghamollaii, V and Hosseini, M and Tafakhori, A}, title = {Safety and Efficacy of Nanocurcumin as Add-On Therapy to Riluzole in Patients With Amyotrophic Lateral Sclerosis: A Pilot Randomized Clinical Trial.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {15}, number = {2}, pages = {430-438}, pmid = {29352425}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Anti-Inflammatory Agents/*therapeutic use ; Antioxidants/*therapeutic use ; Curcumin/*therapeutic use ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Pilot Projects ; Riluzole/*therapeutic use ; Treatment Outcome ; }, abstract = {The objective of present study was to assess the safety and efficacy of nanocurcumin as an anti-inflammatory and antioxidant agent in adults with amyotrophic lateral sclerosis (ALS). We conducted a 12-month, double-blind, randomized, placebo-controlled trial at a neurological referral center in Iran. Eligible patients with a definite or probable ALS diagnosis were randomly assigned to receive either nanocurcumin (80 mg daily) or placebo in a 1:1 ratio. A computerized random number generator was used to prepare the randomization list. All patients and research investigators were blinded to treatment allocation. The primary outcome was survival, and event was defined to be death or mechanical ventilation dependency. Analysis was by intention-to-treat and included all patients who received at least one dose of study drug. A total of 54 patients were randomized to receive either nanocurcumin (n = 27) or placebo (n = 27). After 12 months, events occurred in 1 patient (3.7%) in the nanocurcumin group and in 6 patients (22.2%) in the placebo group. Kaplan-Meier analysis revealed a significant difference between the study groups regarding their survival curves (p = 0.036). No significant between-group differences were observed for any other outcome measures. No serious adverse events or treatment-related deaths were detected. No patients withdrew as a result of drug adverse events. The results suggest that nanocurcumin is safe and might improve the probability of survival as an add-on treatment in patients with ALS, especially in those with existing bulbar symptoms. Future studies with larger sample sizes and of longer duration are needed to confirm these findings.}, }
@article {pmid29351637, year = {2018}, author = {Smith, JS and Shaffrey, CI and Kim, HJ and Passias, P and Protopsaltis, T and Lafage, R and Mundis, GM and Klineberg, E and Lafage, V and Schwab, FJ and Scheer, JK and Miller, E and Kelly, M and Hamilton, DK and Gupta, M and Deviren, V and Hostin, R and Albert, T and Riew, KD and Hart, R and Burton, D and Bess, S and Ames, CP and , }, title = {Prospective Multicenter Assessment of All-Cause Mortality Following Surgery for Adult Cervical Deformity.}, journal = {Neurosurgery}, volume = {83}, number = {6}, pages = {1277-1285}, doi = {10.1093/neuros/nyx605}, pmid = {29351637}, issn = {1524-4040}, mesh = {Adult ; Aged ; Cervical Vertebrae/surgery ; Comorbidity ; Female ; Humans ; Male ; Middle Aged ; Osteotomy/*methods/*mortality ; Prospective Studies ; Spinal Curvatures/*mortality/*surgery ; }, abstract = {BACKGROUND: Surgical treatments for adult cervical spinal deformity (ACSD) are often complex and have high complication rates.<br><br>OBJECTIVE: To assess all-cause mortality following ACSD surgery.<br><br>METHODS: ACSD patients presenting for surgical treatment were identified from a prospectively collected multicenter database. Clinical and surgical parameters and all-cause mortality were assessed.<br><br>RESULTS: Of 123 ACSD patients, 120 (98%) had complete baseline data (mean age, 60.6 yr). The mean number of comorbidities per patient was 1.80, and 80% had at least 1 comorbidity. Surgical approaches included anterior only (15.8%), posterior only (50.0%), and combined anterior/posterior (34.2%). The mean number of vertebral levels fused was 8.0 (standard deviation [SD]&#xa0;=&#xa0;4.5), and 23.3% had a 3-column osteotomy. Death was reported for 11 (9.2%) patients at a mean of 1.1 yr (SD&#xa0;=&#xa0;0.76 yr; range&#xa0;=&#xa0;7 d to 2 yr). Mean follow-up for living patients was 1.2 yr (SD&#xa0;=&#xa0;0.64 yr). Causes of death included myocardial infarction (n&#xa0;=&#xa0;2), pneumonia/cardiopulmonary failure (n&#xa0;=&#xa0;2), sepsis (n&#xa0;=&#xa0;1), obstructive sleep apnea/narcotics (n&#xa0;=&#xa0;1), subsequently diagnosed amyotrophic lateral sclerosis (n&#xa0;=&#xa0;1), burn injury related to home supplemental oxygen (n&#xa0;=&#xa0;1), and unknown (n&#xa0;=&#xa0;3). Deceased patients did not significantly differ from alive patients based on demographic, clinical, or surgical parameters assessed, except for a higher major complication rate (excluding mortality; 63.6% vs 22.0%, P&#xa0;=&#xa0;.006).<br><br>CONCLUSION: All-cause mortality at a mean of 1.2 yr following surgery for ACSD was 9.2% in this prospective multicenter series. Causes of death were reflective of the overall high level of comorbidities. These findings may prove useful for treatment decision making and patient counseling in the context of the substantial impact of ACSD.}, }
@article {pmid29350907, year = {2018}, author = {Ramírez-Jarquín, UN and Tapia, R}, title = {Excitatory and Inhibitory Neuronal Circuits in the Spinal Cord and Their Role in the Control of Motor Neuron Function and Degeneration.}, journal = {ACS chemical neuroscience}, volume = {9}, number = {2}, pages = {211-216}, doi = {10.1021/acschemneuro.7b00503}, pmid = {29350907}, issn = {1948-7193}, mesh = {Animals ; Humans ; Motor Neurons/*physiology ; Nerve Degeneration/physiopathology ; Neural Inhibition/*physiology ; Neural Pathways/physiology/physiopathology ; Spinal Cord/*physiology/*physiopathology ; }, abstract = {The complex neuronal networks of the spinal cord coordinate a wide variety of motor functions, including walking, running, and voluntary and involuntary movements. This is accomplished by different groups of neurons, called center pattern generators, which control left-right alternation and flexor-extensor patterns. These spinal circuits, located in the ventral horns, are formed by several neuronal types, and the specific function of most of them has been identified by means of studies in vivo and in the isolated spinal cord of mice harboring genetically induced ablation of specific neuronal populations. These studies have shown that the coordinated activity of several interneuron types, mainly GABAergic and glycinergic inhibitory neurons, have a crucial role in the modulation of motor neurons activity that finally excites the corresponding muscles. A pharmacological experimental approach by administering in the spinal cord agonists and antagonists of glutamate, GABA, glycine, and acetylcholine receptors to alter their synaptic action has also produced important results, linking the deficits in the synaptic function with the resulting motor alterations. These results have also increased the knowledge of the mechanisms of motor neuron degeneration, which is characteristic of diseases such as amyotrophic lateral sclerosis, and therefore open the possibility of designing new strategies for the prevention and treatment of these diseases.}, }
@article {pmid29338427, year = {2018}, author = {Battaglia, L and Panciani, PP and Muntoni, E and Capucchio, MT and Biasibetti, E and De Bonis, P and Mioletti, S and Fontanella, M and Swaminathan, S}, title = {Lipid nanoparticles for intranasal administration: application to nose-to-brain delivery.}, journal = {Expert opinion on drug delivery}, volume = {15}, number = {4}, pages = {369-378}, doi = {10.1080/17425247.2018.1429401}, pmid = {29338427}, issn = {1744-7593}, mesh = {Administration, Intranasal ; Animals ; Biological Transport ; Blood-Brain Barrier ; Brain/*metabolism ; Central Nervous System Agents/*administration &amp; dosage ; Drug Delivery Systems/*methods ; Humans ; Lipids/chemistry ; Nanoparticles/*administration &amp; dosage ; Nasal Mucosa/*drug effects/metabolism ; Neurodegenerative Diseases/*drug therapy ; }, abstract = {INTRODUCTION: The blood brain barrier is a functional barrier allowing the entry into the brain of only essential nutrients, excluding other molecules. Its structure, although essential to keep the harmful entities out, is also a major roadblock for pharmacological treatment of brain diseases. Several alternative invasive drug delivery approaches, such as transcranial drug delivery and disruption of blood brain barrier have been explored, with limited success and several challenges. Intranasal delivery is a non-invasive methodology, which bypasses the systemic circulation, and, through the intra- and extra- neuronal pathways, provides direct brain drug delivery. Colloidal drug delivery systems, particularly lipidic nanoparticles offer several unique advantages for this goal.<br><br>AREAS COVERED: This review focuses on key brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, and provide a detailed overview of the current lipid nanoparticle based treatment options explored thus far. The review also delves into basic preparation, challenges and evaluation methods of lipid drug delivery systems.<br><br>EXPERT OPINION: Brain diseases present complex pathophysiology, in addition to the practically inaccessible brain tissues, hence according to the authors, a two-pronged approach utilizing new target discovery coupled with new drug delivery systems such as lipid carriers must be adopted.}, }
@article {pmid29335339, year = {2018}, author = {Joshi, AU and Saw, NL and Vogel, H and Cunnigham, AD and Shamloo, M and Mochly-Rosen, D}, title = {Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis.}, journal = {EMBO molecular medicine}, volume = {10}, number = {3}, pages = {}, pmid = {29335339}, issn = {1757-4684}, support = {P30 NS069375/NS/NINDS NIH HHS/United States ; R37 AA011147/AA/NIAAA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology ; Animals ; Apoptosis/drug effects ; Autophagy/drug effects ; Behavior, Animal ; Cell Differentiation/drug effects ; Disease Models, Animal ; *Disease Progression ; Dynamins ; Fibroblasts/drug effects/metabolism/pathology ; GTP Phosphohydrolases/*metabolism/pharmacology ; Humans ; Membrane Proteins/*metabolism ; Mice ; Microtubule-Associated Proteins/*metabolism ; Mitochondria/drug effects/metabolism/ultrastructure ; Mitochondrial Dynamics/drug effects ; Mitochondrial Proteins/*metabolism ; Models, Biological ; Motor Activity/drug effects ; Motor Neurons/drug effects/metabolism/pathology ; Muscular Atrophy/pathology ; Mutation/genetics ; Oxidative Stress/drug effects ; Peptide Fragments/pharmacology ; Protein Binding/drug effects ; Stress, Physiological/drug effects ; Superoxide Dismutase/metabolism ; }, abstract = {Bioenergetic failure and oxidative stress are common pathological hallmarks of amyotrophic lateral sclerosis (ALS), but whether these could be targeted effectively for novel therapeutic intervention needs to be determined. One of the reported contributors to ALS pathology is mitochondrial dysfunction associated with excessive mitochondrial fission and fragmentation, which is predominantly mediated by Drp1 hyperactivation. Here, we determined whether inhibition of excessive fission by inhibiting Drp1/Fis1 interaction affects disease progression. We observed mitochondrial excessive fragmentation and dysfunction in several familial forms of ALS patient-derived fibroblasts as well as in cultured motor neurons expressing SOD1 mutant. In both cell models, inhibition of Drp1/Fis1 interaction by a selective peptide inhibitor, P110, led to a significant reduction in reactive oxygen species levels, and to improvement in mitochondrial structure and functions. Sustained treatment of mice expressing G93A SOD1 mutation with P110, beginning at the onset of disease symptoms at day 90, produced an improvement in motor performance and survival, suggesting that Drp1 hyperactivation may be an attractive target in the treatment of ALS patients.}, }
@article {pmid29334251, year = {2018}, author = {Yeo, CJJ and Simmons, Z}, title = {Discussing edaravone with the ALS patient: an ethical framework from a U.S. perspective.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {19}, number = {3-4}, pages = {167-172}, doi = {10.1080/21678421.2018.1425455}, pmid = {29334251}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/psychology ; Antipyrine/adverse effects/*analogs &amp; derivatives/economics/therapeutic use ; Clinical Trials as Topic/*ethics/methods ; Cost-Benefit Analysis ; Edaravone ; *Ethics, Clinical ; Free Radical Scavengers/adverse effects/economics/*therapeutic use ; Humans ; Professional-Patient Relations ; Quality of Life ; United States ; }, abstract = {The recent approval of edaravone by the United States Food and Drug Administration has generated a mix of hope tempered by reality. The costs of the drug, both monetarily and with regard to intensity of treatment, are high. The benefits, while modest, will be viewed through a very different lens by individuals depending on their goals of care. By virtue of our training and experience, physicians are ideally suited to understand and explain new treatments to our patients. As healthcare providers with a fiduciary responsibility to our patients, we must make sure they are fully informed about both the costs and benefits of non-curative therapies such as edaravone, and be prepared to discuss these in the context of their goals of care and potential impact on quality of life. Respect for our patients' autonomy is critical when discussing these issues, but we should always be guided by the ethical principles of beneficence and non-maleficence.}, }
@article {pmid29326641, year = {2017}, author = {Peters, S and Zitzelsperger, E and Kuespert, S and Iberl, S and Heydn, R and Johannesen, S and Petri, S and Aigner, L and Thal, DR and Hermann, A and Weishaupt, JH and Bruun, TH and Bogdahn, U}, title = {The TGF-β System As a Potential Pathogenic Player in Disease Modulation of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {8}, number = {}, pages = {669}, pmid = {29326641}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) represents a fatal orphan disease with high unmet medical need, and a life time risk of approx. 1/400 persons per population. Based on increasing knowledge on pathophysiology including genetic and molecular changes, epigenetics, and immune dysfunction, inflammatory as well as fibrotic processes may contribute to the heterogeneity and dynamics of ALS. Animal and human studies indicate dysregulations of the TGF-β system as a common feature of neurodegenerative disorders in general and ALS in particular. The TGF-β system is involved in different essential developmental and physiological processes and regulates immunity and fibrosis, both affecting neurogenesis and neurodegeneration. Therefore, it has emerged as a potential therapeutic target for ALS: a persistent altered TGF-β system might promote disease progression by inducing an imbalance of neurogenesis and neurodegeneration. The current study assessed the activation state of the TGF-β system within the periphery/in life disease stage (serum samples) and a late stage of disease (central nervous system tissue samples), and a potential influence upon neuronal stem cell (NSC) activity, immune activation, and fibrosis. An upregulated TGF-β system was suggested with significantly increased TGF-β1 protein serum levels, enhanced TGF-β2 mRNA and protein levels, and a strong trend toward an increased TGF-β1 protein expression within the spinal cord (SC). Stem cell activity appeared diminished, reflected by reduced mRNA expression of NSC markers Musashi-1 and Nestin within SC-paralleled by enhanced protein contents of Musashi-1. Doublecortin mRNA and protein expression was reduced, suggesting an arrested neurogenesis at late stage ALS. Chemokine/cytokine analyses suggest a shift from a neuroprotective toward a more neurotoxic immune response: anti-inflammatory chemokines/cytokines were unchanged or reduced, expression of proinflammatory chemokines/cytokines were enhanced in ALS sera and SC postmortem tissue. Finally, we observed upregulated mRNA and protein expression for fibronectin in motor cortex of ALS patients which might suggest increased fibrotic changes. These data suggest that there is an upregulated TGF-β system in specific tissues in ALS that might lead to a "neurotoxic" immune response, promoting disease progression and neurodegeneration. The TGF-β system therefore may represent a promising target in treatment of ALS patients.}, }
@article {pmid29319397, year = {2018}, author = {Ishida, N and Hongo, S and Kumano, A and Hatta, H and Zakoji, N and Hirutani, M and Yamamoto, Y and Aono, H and Tuigi, M and Suzuki, R and Hanamitsu, H and Wakasugi, E and Takahashi, M and Yamatani, A}, title = {Relationship between Pain and Functional Status in Patients with Amyotrophic Lateral Sclerosis: A Multicenter Cross-Sectional Study.}, journal = {Journal of palliative medicine}, volume = {21}, number = {5}, pages = {588-591}, doi = {10.1089/jpm.2017.0503}, pmid = {29319397}, issn = {1557-7740}, mesh = {Activities of Daily Living/*psychology ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*physiopathology/*psychology ; Analgesics, Opioid/*therapeutic use ; Cross-Sectional Studies ; Female ; Humans ; Japan ; Male ; Middle Aged ; Pain/*drug therapy ; Quality of Life/*psychology ; }, abstract = {BACKGROUND: Pain is a widely neglected symptom in patients with amyotrophic lateral sclerosis (ALS), even though it may be common and have a significant impact on the quality of life.<br><br>OBJECTIVE: The aim of this study was to determine the frequency and characteristics of pain and its treatment in ALS patients.<br><br>DESIGN: A multicenter cross-sectional study.<br><br>SETTING/SUBJECTS: Eighty patients with ALS from eight hospitals.<br><br>MEASUREMENTS: Data on demographics, functional status, and pharmacological treatment were collected. The Barthel Index (BI) was used to assess functional status. Pain was measured using the 0-5-point Wong-Baker FACES Pain Rating Scale.<br><br>RESULTS: Pain was reported by 53.8% of ALS patients, and 36.3% reported receiving pain medication. Opioids were the drugs most commonly used to treat pain. The differences in pain frequency according to functional status were not statistically significant (p&#x2009;=&#x2009;0.38). The pain intensity in patients whose functional status was total dependence (BI 0-20, 2.5&#x2009;&#xb1;&#x2009;1.2) was significantly worse than that in those with better functional status (BI 21-60, 1.4&#x2009;&#xb1;&#x2009;0.7; BI 61-99, 1.4&#x2009;&#xb1;&#x2009;0.5; p&#x2009;<&#x2009;0.01).<br><br>CONCLUSIONS: Our study indicates that all patients with ALS have the potential to suffer from pain, the intensity of which increases with decreased functional status.}, }
@article {pmid29319015, year = {2018}, author = {Karacam, V and Sanli, A and Tertemiz, KC and Ulugun, I}, title = {A practical technique in laparoscopic diaphragm pacing surgery: Retrospective analyse of 43 patients.}, journal = {Journal of minimal access surgery}, volume = {14}, number = {4}, pages = {273-276}, pmid = {29319015}, issn = {0972-9941}, abstract = {INTRODUCTION: Diaphragm pacing stimulation (DPS) is a treatment method used in respiratory failure occurs in diseases such as high-level cervical spinal cord injury, central hypoventilation syndrome and amyotrophic lateral sclerosis.<br><br>MATERIALS AND METHODS: A total of 43 patients, who had undergone DPS implantation surgery were evaluated retrospectively. The patients were divided into two groups according to the surgical technique (Group 1: classical surgical technic and Group 2: modified surgical technic) applied. The patients with previous abdominal surgery or percutaneous endoscopic gastrostomy were excluded from the study.<br><br>RESULTS: The mean operation duration was significantly shorter in modified DPS implantation technic (105.1 min in Group 1 and 87.4 min in Group 2) (P < 0.001). Capnothorax is seen 11% of the cases in classical surgery procedure. In the modified group, capnothorax was not observed. Pneumothorax rate was found similar in both groups. Post-operative atelectasis was determined 16% of the cases in classical surgery procedure and also in the modified group atelectasis was not observed. The complications were higher in classical surgery procedure group but not differed statistically in this study. Total hospitalisation duration was significantly shorter in the modified surgical technique group compared to the other group (8.0 days in Group 1 and 6.0 days in Group 2) (P = 0.03).<br><br>CONCLUSION: With modification in DPS implantation surgery, shorter operation and hospitalisation durations, and less complications may be achieved.}, }
@article {pmid29317338, year = {2018}, author = {Gorshkov, K and Aguisanda, F and Thorne, N and Zheng, W}, title = {Astrocytes as targets for drug discovery.}, journal = {Drug discovery today}, volume = {23}, number = {3}, pages = {673-680}, pmid = {29317338}, issn = {1878-5832}, support = {ZIA TR000018-02//Intramural NIH HHS/United States ; ZIA TR000269-01//Intramural NIH HHS/United States ; }, mesh = {Animals ; Astrocytes/*drug effects ; Drug Discovery/methods ; Humans ; Neurodegenerative Diseases/*drug therapy ; Neurons/drug effects ; Pharmaceutical Preparations/*administration &amp; dosage ; }, abstract = {Recent studies have illuminated the crucial role of astrocytes in maintaining proper neuronal health and function. Abnormalities in astrocytic functions have now been implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Historically, drug development programs for neurodegenerative diseases generally target only neurons, overlooking the contributions of astrocytes. Therefore, targeting both disease neurons and astrocytes offers a new approach for drug development for the treatment of neurological diseases. Looking forward, the co-culturing of human neurons with astrocytes could be the next evolutionary step in drug discovery for neurodegenerative diseases.}, }
@article {pmid29316798, year = {2018}, author = {Desai, S and Juncker, M and Kim, C}, title = {Regulation of mitophagy by the ubiquitin pathway in neurodegenerative diseases.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {243}, number = {6}, pages = {554-562}, pmid = {29316798}, issn = {1535-3699}, support = {R21 NS060960/NS/NINDS NIH HHS/United States ; }, mesh = {Cytokines/metabolism ; Humans ; *Mitophagy ; Neurodegenerative Diseases/*physiopathology ; Proteasome Endopeptidase Complex/*metabolism ; Protein Aggregation, Pathological ; Ubiquitin/*metabolism ; Ubiquitins/metabolism ; }, abstract = {Mitophagy is a cellular process by which dysfunctional mitochondria are degraded via autophagy. Increasing empirical evidence proposes that this mitochondrial quality-control mechanism is defective in neurons of patients with various neurodegenerative diseases such as Ataxia Telangiectasia, Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Accumulation of defective mitochondria and the production of reactive oxygen species due to defective mitophagy have been identified as causes underlying neurodegenerative disease pathogenesis. However, the reason mitophagy is defective in most neurodegenerative diseases is unclear. Like mitophagy, defects in the ubiquitin/26S proteasome pathway have been linked to neurodegeneration, resulting in the characteristic protein aggregates often seen in neurons of affected patients. Although initiation of mitophagy requires a functional ubiquitin pathway, whether defects in the ubiquitin pathway are causally responsible for defective mitophagy is not known. In this mini-review, we introduce mitophagy and ubiquitin pathways and provide a summary of our current understanding of the regulation of mitophagy by the ubiquitin pathway. We will then briefly review empirical evidence supporting mitophagy defects in neurodegenerative diseases. The review will conclude with a discussion of the constitutively elevated expression of ubiquitin-like protein Interferon-Stimulated Gene 15 (ISG15), an antagonist of the ubiquitin pathway, as a potential cause of defective mitophagy in neurodegenerative diseases. Impact statement Neurodegenerative diseases place an enormous burden on patients and caregivers globally. Over six million people in the United States alone suffer from neurodegenerative diseases, all of which are chronic, incurable, and with causes unknown. Identifying a common molecular mechanism underpinning neurodegenerative disease pathology is urgently needed to aid in the design of effective therapies to ease suffering, reduce economic cost, and improve the quality of life for these patients. Although the development of neurodegeneration may vary between neurodegenerative diseases, they have common cellular hallmarks, including defects in the ubiquitin-proteasome system and mitophagy. In this review, we will provide a summary of our current understanding of the regulation of mitophagy by the ubiquitin pathway and discuss the potential of targeting mitophagy and ubiquitin pathways for the treatment of neurodegeneration.}, }
@article {pmid29312526, year = {2017}, author = {Maguire, G}, title = {Amyotrophic lateral sclerosis as a protein level, non-genomic disease: Therapy with S2RM exosome released molecules.}, journal = {World journal of stem cells}, volume = {9}, number = {11}, pages = {187-202}, pmid = {29312526}, issn = {1948-0210}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that leads to death. No effective treatments are currently available. Based on data from epidemiological, etiological, laboratory, and clinical studies, I offer a new way of thinking about ALS and its treatment. This paper describes a host of extrinsic factors, including the exposome, that disrupt the extracellular matrix and protein function such that a spreading, prion-like disease leads to neurodegeneration in the motor tracts. A treatment regimen is described using the stem cell released molecules from a number of types of adult stem cells to provide tissue dependent molecules that restore homeostasis, including proteostasis, in the ALS patient. Because stem cells themselves as a therapeutic are cumbersome and expensive, and when implanted in a host cause aging of the host tissue and often fail to engraft or remain viable, only the S2RM molecules are used. Rebuilding of the extracellular matrix and repair of the dysfunctional proteins in the ALS patient ensues.}, }
@article {pmid29308669, year = {2018}, author = {Fournier, CN and Schoenfeld, D and Berry, JD and Cudkowicz, ME and Chan, J and Quinn, C and Brown, RH and Salameh, JS and Tansey, MG and Beers, DR and Appel, SH and Glass, JD}, title = {An open label study of a novel immunosuppression intervention for the treatment of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {19}, number = {3-4}, pages = {242-249}, doi = {10.1080/21678421.2017.1421666}, pmid = {29308669}, issn = {2167-9223}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/immunology ; Anti-Inflammatory Agents/therapeutic use ; Antibodies, Monoclonal/*therapeutic use ; Basiliximab ; Female ; Humans ; Immunosuppressive Agents/*therapeutic use ; Male ; Middle Aged ; Prednisone/therapeutic use ; Recombinant Fusion Proteins/*therapeutic use ; Treatment Outcome ; Young Adult ; }, abstract = {Neuroinflammation is increasingly tied to disease progression in amyotrophic lateral sclerosis (ALS). Participants in the first-in-human trial of intra-spinal allogeneic stem cell therapy for ALS received immunosuppression, and one participant saw dramatic improvement across multiple outcome measures. The primary objective of this study (NCT01884571) was to assess the rate of clinical response to the same immunosuppressive regimen using basiliximab, tacrolimus, mycophenolate, and prednisone in people with ALS. A clinical response was defined as an improvement on the revised ALS Functional Rating Scale (ALSFRS-R) by six points over a 6-month period. Thirty-one participants were enrolled in this 15-month open label study and received an identical immunosuppression regimen. Clinical outcome measures and biospecimens were collected before, during, and after the treatment regimen. No patients met the pre-defined responder criteria. No difference in mean ALSFRS-R slope was seen in the treatment period compared to the pretreatment period (p = 0.200). The regimen was generally safe in an ALS population, although only 18 out of 31 patients completed the full 6 months of immunosuppression. Analyses of immune markers showed no change in peripheral regulatory T-cell populations during treatment compared to pretreatment (p = 0.200). Analysis of cerebrospinal fluid (CSF) cytokine levels showed an increase in IL-2 levels with immunosuppression (p = 0.004) followed by decrease during post-treatment follow-up (p = 0.031). Further studies are needed to understand how manipulation of the immune system may affect disease progression in ALS.}, }
@article {pmid29305926, year = {2018}, author = {Fisk, CA and Olsufka, M and Yin, L and McCoy, AM and Latimer, AJ and Maynard, C and Nichol, G and Larsen, J and Cobb, LA and Sayre, MR}, title = {Lower-dose epinephrine administration and out-of-hospital cardiac arrest outcomes.}, journal = {Resuscitation}, volume = {124}, number = {}, pages = {43-48}, doi = {10.1016/j.resuscitation.2018.01.004}, pmid = {29305926}, issn = {1873-1570}, mesh = {Adult ; Cardiopulmonary Resuscitation/methods ; Dose-Response Relationship, Drug ; Electric Countershock/statistics &amp; numerical data ; Emergency Medical Services/methods ; Epinephrine/*administration &amp; dosage ; Female ; Humans ; Male ; Middle Aged ; Out-of-Hospital Cardiac Arrest/classification/*drug therapy ; Time-to-Treatment/statistics &amp; numerical data ; Vasoconstrictor Agents/*administration &amp; dosage ; }, abstract = {BACKGROUND: International guidelines recommend administration of 1 mg of intravenous epinephrine every 3-5 min during cardiac arrest. The optimal dose of epinephrine is not known. We evaluated the association of reduced frequency and dose of epinephrine with survival after out-of-hospital cardiac arrest (OHCA).<br><br>METHODS: Included were patients with non-traumatic OHCA treated by advanced life support (ALS) providers from January 1, 2008 to June 30, 2016. During the before period, providers were instructed to give epinephrine 1&#x202f;mg intravenously at 4&#x202f;min followed by additional 1&#x202f;mg doses every eight minutes to patients with OHCA with a shockable rhythm and 1&#x202f;mg doses every two minutes to patients with a non-shockable rhythm (higher dose). On October 1, 2012, providers were instructed to reduce the dose of epinephrine treatment during out-of-hospital cardiac arrest (OHCA): 0.5&#x202f;mg at 4 and 8&#x202f;min followed by additional doses of 0.5&#x202f;mg every 8&#x202f;min for shockable rhythms and 0.5&#x202f;mg every 2&#x202f;min for non-shockable rhythms (lower dose). Patients with shockable initial rhythms were analyzed separately from those with non-shockable initial rhythms. The primary outcome was survival to hospital discharge with a secondary outcome of favorable neurological status (Cerebral Performance Category [CPC] 1 or 2) at hospital discharge. Multiple logistic regression modeling was used to adjust for age, sex, presence of a witness, bystander CPR, and response interval.<br><br>RESULTS: 2255 patients with OHCA were eligible for analysis. Of these, 24.6% had an initially shockable rhythm. Total epinephrine dose per patient decreased from a mean&#x202f;&#xb1;&#x202f;standard deviation of 3.4&#x202f;&#xb1;&#x202f;2.3&#x202f;mg-2.6&#x202f;&#xb1;&#x202f;1.9&#x202f;mg (p&#x202f;<&#x202f;0.001) in the shockable group and 3.5&#x202f;&#xb1;&#x202f;1.9&#x202f;mg-2.8&#x202f;&#xb1;&#x202f;1.7&#x202f;mg (p&#x202f;<&#x202f;0.001) in the non-shockable group. Among those with a shockable rhythm, survival to hospital discharge was 35.0% in the higher dose group vs. 34.2% in the lower dose group. Among those with a non-shockable rhythm, survival was 4.2% in the higher dose group vs. 5.1% in the lower dose group. Lower dose vs. higher dose was not significantly associated with survival: adjusted odds ratio, aOR 0.91 (95% CI 0.62-1.32, p&#x202f;=&#x202f;0.61) if shockable and aOR 1.26 (95% CI 0.79-2.01, p&#x202f;=&#x202f;0.33) if non-shockable. Lower dose vs. higher dose was not significantly associated with favorable neurological status at discharge: aOR 0.84 (95% CI 0.57-1.24, p&#x202f;=&#x202f;0.377) if shockable and aOR 1.17 (95% CI 0.68-2.02, p&#x202f;=&#x202f;0.577) if non-shockable.<br><br>CONCLUSION: Reducing the dose of epinephrine administered during out-of-hospital cardiac arrest was not associated with a change in survival to hospital discharge or favorable neurological outcomes after OHCA.}, }
@article {pmid29302360, year = {2017}, author = {Kanzaki, M and Takagi, R and Washio, K and Kokubo, M and Yamato, M}, title = {Bio-artificial pleura using an autologous dermal fibroblast sheet.}, journal = {NPJ Regenerative medicine}, volume = {2}, number = {}, pages = {26}, pmid = {29302360}, issn = {2057-3995}, abstract = {Air leaks (ALs) are observed after pulmonary resections, and without proper treatment, can produce severe complications. AL prevention is a critical objective for managing patients after pulmonary resection. This study applied autologous dermal fibroblast sheets (DFS) to close ALs. For sealing ALs in a 44-year-old male human patient with multiple bullae, a 5 × 15-mm section of skin was surgically excised. From this skin specimen, primary dermal fibroblasts were isolated and cultured for 4 weeks to produce DFSs that were harvested after a 10-day culture. ALs were completely sealed using surgical placement of these autologous DFSs. DFS were found to be a durable long-term AL sealant, exhibiting requisite flexibility, elasticity, durability, biocompatibility, and usability, resulting reliable AL closure. DFS should prove to be an extremely useful tissue-engineered pleura substitute.}, }
@article {pmid29298618, year = {2018}, author = {Seibold, H and Zeileis, A and Hothorn, T}, title = {Individual treatment effect prediction for amyotrophic lateral sclerosis patients.}, journal = {Statistical methods in medical research}, volume = {27}, number = {10}, pages = {3104-3125}, doi = {10.1177/0962280217693034}, pmid = {29298618}, issn = {1477-0334}, mesh = {Algorithms ; Amyotrophic Lateral Sclerosis/*drug therapy ; Anticonvulsants/administration &amp; dosage ; Databases, Factual ; *Forecasting ; Humans ; Models, Statistical ; Precision Medicine/statistics &amp; numerical data ; Randomized Controlled Trials as Topic ; Riluzole/administration &amp; dosage ; Treatment Outcome ; }, abstract = {A treatment for a complicated disease might be helpful for some but not all patients, which makes predicting the treatment effect for new patients important yet challenging. Here we develop a method for predicting the treatment effect based on patient characteristics and use it for predicting the effect of the only drug (Riluzole) approved for treating amyotrophic lateral sclerosis. Our proposed method of model-based random forests detects similarities in the treatment effect among patients and on this basis computes personalised models for new patients. The entire procedure focuses on a base model, which usually contains the treatment indicator as a single covariate and takes the survival time or a health or treatment success measurement as primary outcome. This base model is used both to grow the model-based trees within the forest, in which the patient characteristics that interact with the treatment are split variables, and to compute the personalised models, in which the similarity measurements enter as weights. We applied the personalised models using data from several clinical trials for amyotrophic lateral sclerosis from the Pooled Resource Open-Access Clinical Trials database. Our results indicate that some amyotrophic lateral sclerosis patients benefit more from the drug Riluzole than others. Our method allows gradually shifting from stratified medicine to personalised medicine and can also be used in assessing the treatment effect for other diseases studied in a clinical trial.}, }
@article {pmid29297656, year = {2017}, author = {Demler, TL}, title = {Introduction to pseudobulbar affect: setting the stage for recognition and familiarity with this challenging disorder.}, journal = {The American journal of managed care}, volume = {23}, number = {18 Suppl}, pages = {S339-S344}, pmid = {29297656}, issn = {1936-2692}, mesh = {Alzheimer Disease/*complications/diagnosis/therapy ; Amyotrophic Lateral Sclerosis/*complications/diagnosis/therapy ; Female ; Humans ; Male ; Middle Aged ; Nervous System Diseases/complications/epidemiology ; Parkinson Disease/*complications/diagnosis/therapy ; Prevalence ; Pseudobulbar Palsy/*diagnosis/etiology/psychology/*therapy ; Quality of Life ; Risk Assessment ; Severity of Illness Index ; United States ; }, abstract = {Pseudobulbar affect (PBA), despite its prevalence and distinctive symptoms, is widely underrecognized and undertreated. It is characterized by uncontrollable laughing or crying that can occur in an exaggerated manner or inappropriately to a given situation or stimuli. PBA is thought to center around preexisting neurological conditions, which include Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer disease, traumatic brain injury, and stroke. The PBA Registry Series trial was created to measure the prevalence of PBA among patients with these underlying neurological conditions. Through greater awareness, recognition, and diagnosis, treatment for patients with PBA can be improved.}, }
@article {pmid29294332, year = {2018}, author = {Ji, Y and Duan, W and Liu, Y and Liu, Y and Liu, C and Li, Y and Wen, D and Li, Z and Li, C}, title = {IGF1 affects macrophage invasion and activation and TNF-α production in the sciatic nerves of female SOD1G93A mice.}, journal = {Neuroscience letters}, volume = {668}, number = {}, pages = {1-6}, doi = {10.1016/j.neulet.2017.12.062}, pmid = {29294332}, issn = {1872-7972}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Disease Models, Animal ; Female ; Insulin-Like Growth Factor I/deficiency/*pharmacology ; Macrophages/*drug effects ; Mice ; Mice, Knockout ; *Neuritis/drug therapy/immunology/metabolism ; *Sciatic Nerve/drug effects/immunology/metabolism ; Superoxide Dismutase-1/genetics ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease leading to paralysis and death within 3-5 years of its diagnosis. The SOD1G93A mouse is used extensively as an ALS animal model. Increasing evidence shows that non-neuronal cellscontribute to the pathogenesis and progression of ALS. Among them, many studies focus on microgliosis in the spinal cord (SC); while few on macrophage activation in the sciatic nerves. Substantial evidence shows that insulin-like growth factor 1 (IGF1) delays disease progression and increases the lifespan of SOD1G93A mice, and some studies indicate that IGF1 reduces inflammation in the SC of ALS mice. However, no studies have focused on the effect of IGF on sciatic nerve inflammation. Here, we find that ALS progression is characterized by increasing macrophage invasion and activation accompanied by significant TNF-α production in the sciatic nerve. Furthermore, IGF1 treatment and knockdown alleviate and aggravate these responses, respectively. Collectively, our findings show the first time that IGF1 has an anti-inflammatory effect in the sciatic nerves of SOD1G93A mice.}, }
@article {pmid29293261, year = {2018}, author = {Gibbons, C and Pagnini, F and Friede, T and Young, CA}, title = {Treatment of fatigue in amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {1}, number = {1}, pages = {CD011005}, pmid = {29293261}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Benzhydryl Compounds/*therapeutic use ; Breathing Exercises/*methods ; Fatigue/etiology/*therapy ; Humans ; Modafinil ; Randomized Controlled Trials as Topic ; Resistance Training/*methods ; Transcranial Magnetic Stimulation/*methods ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is terminal, progressive neurological condition for which there are no curative treatments. Among people with ALS/MND, fatigue is a common and debilitating symptom, which is characterised by reversible motor weakness and whole-body tiredness that is only partially relieved by rest. The effectiveness of pharmacological or non-pharmacological treatments for fatigue in ALS/MND is not yet established.<br><br>OBJECTIVES: To assess the effects of pharmacological and non-pharmacological interventions for fatigue in ALS/MND.<br><br>SEARCH METHODS: We searched the following databases on 5 September 2017: Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL Plus, and ERIC. We also searched two clinical trials registries.<br><br>SELECTION CRITERIA: We selected randomised and quasi-randomised controlled trials of any intervention which sought to reduce fatigue for people with ALS/MND. We included studies if reduction in fatigue was a primary or secondary outcome of the trial.<br><br>DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane.<br><br>MAIN RESULTS: We included one pharmacological (modafinil) study and three non-pharmacological studies (resistance exercise, respiratory exercise, and repetitive transcranial magnetic stimulation (rTMS)), involving a total of 86 participants with ALS/MND. None of the included studies were free from risk of bias. Since there was only one trial for each intervention, no meta-analysis was possible. All studies assessed fatigue using the Fatigue Severity Scale (FSS; scale from 9 to 63, higher scores indicate more fatigue). Information for assessing bias was often lacking in study reports, making the risk of bias unclear across several domains in all trials. Blinding of participants was not possible in exercise trials, but the outcome assessment was blinded.We found very low-quality evidence suggesting possible improvements in fatigue for modafinil treatment versus placebo (MD -11.00, 95% CI -23.08 to 1.08), respiratory exercise versus a sham intervention (MD -9.65, 95% CI -22.04 to 2.73), and rTMS versus sham rTMS (data not provided), which warrant further investigation to clarify the efficacy of these treatments for fatigue in ALS/MND. We found no clear improvements in fatigue for resistance exercise versus usual care (MD 0.20, 95% CI -10.98 to 11.38; very low-quality evidence).Three participants in the modafinil group dropped out of the modafinil study, two citing issues with headache and one with chest tightness; other adverse effects were anxiety, nausea, dizziness, and sialorrhoea (probably ALS-related). The trials reported no adverse effects of exercise or rTMS.We cannot be certain about the effects of any of the interventions studied because of imprecision (small numbers of participants, wide CI), and possible study limitations.<br><br>AUTHORS' CONCLUSIONS: It is impossible to draw firm conclusions about the effectiveness of interventions to improve fatigue for people with ALS/MND as there are few randomised studies, and the quality of available evidence is very low.}, }
@article {pmid29290672, year = {2018}, author = {Cruz, MP}, title = {Edaravone (Radicava): A Novel Neuroprotective Agent for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {P &amp; T : a peer-reviewed journal for formulary management}, volume = {43}, number = {1}, pages = {25-28}, pmid = {29290672}, issn = {1052-1372}, abstract = {Edaravone (Radicava): a novel neuroprotective agent for the treatment of amyotrophic lateral sclerosis.}, }
@article {pmid29287521, year = {2018}, author = {Moreau, C and Danel, V and Devedjian, JC and Grolez, G and Timmerman, K and Laloux, C and Petrault, M and Gouel, F and Jonneaux, A and Dutheil, M and Lachaud, C and Lopes, R and Kuchcinski, G and Auger, F and Kyheng, M and Duhamel, A and Pérez, T and Pradat, PF and Blasco, H and Veyrat-Durebex, C and Corcia, P and Oeckl, P and Otto, M and Dupuis, L and Garçon, G and Defebvre, L and Cabantchik, ZI and Duce, J and Bordet, R and Devos, D}, title = {Could Conservative Iron Chelation Lead to Neuroprotection in Amyotrophic Lateral Sclerosis?.}, journal = {Antioxidants &amp; redox signaling}, volume = {29}, number = {8}, pages = {742-748}, pmid = {29287521}, issn = {1557-7716}, support = {J-1203/PUK_/Parkinson's UK/United Kingdom ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Deferiprone/administration &amp; dosage/*therapeutic use ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Humans ; Iron Chelating Agents/administration &amp; dosage/*therapeutic use ; Male ; Mice ; Mice, Transgenic ; Middle Aged ; Neuroprotective Agents/administration &amp; dosage/*therapeutic use ; Oxidative Stress/drug effects ; Young Adult ; }, abstract = {Iron accumulation has been observed in mouse models and in both sporadic and familial forms of amyotrophic lateral sclerosis (ALS). Iron chelation could reduce iron accumulation and the related excess of oxidative stress in the motor pathways. However, classical iron chelation would induce systemic iron depletion. We assess the safety and efficacy of conservative iron chelation (i.e., chelation with low risk of iron depletion) in a murine preclinical model and pilot clinical trial. In Sod1[G86R] mice, deferiprone increased the mean life span compared with placebo. The safety was good, without anemia after 12 months of deferiprone in the 23 ALS patients enrolled in the clinical trial. The decreases in the ALS Functional Rating Scale and the body mass index were significantly smaller for the first 3 months of deferiprone treatment (30 mg/kg/day) than for the first treatment-free period. Iron levels in the cervical spinal cord, medulla oblongata, and motor cortex (according to magnetic resonance imaging), as well as cerebrospinal fluid levels of oxidative stress and neurofilament light chains were lower after deferiprone treatment. Our observation leads to the hypothesis that moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality of neuroprotection for ALS. Antioxid. Redox Signal. 29, 742-748.}, }
@article {pmid29285622, year = {2018}, author = {Miró, &#xd2; and Hazlitt, M and Escalada, X and Llorens, P and Gil, V and Martín-Sánchez, FJ and Harjola, P and Rico, V and Herrero-Puente, P and Jacob, J and Cone, DC and Möckel, M and Christ, M and Freund, Y and di Somma, S and Laribi, S and Mebazaa, A and Harjola, VP and , }, title = {Effects of the intensity of prehospital treatment on short-term outcomes in patients with acute heart failure: the SEMICA-2 study.}, journal = {Clinical research in cardiology : official journal of the German Cardiac Society}, volume = {107}, number = {4}, pages = {347-361}, doi = {10.1007/s00392-017-1190-2}, pmid = {29285622}, issn = {1861-0692}, mesh = {Acute Disease ; Advanced Cardiac Life Support/adverse effects/mortality ; Aged ; Aged, 80 and over ; Chi-Square Distribution ; Combined Modality Therapy ; *Emergency Medical Services ; Female ; Heart Failure/diagnosis/mortality/physiopathology/*therapy ; Hospital Mortality ; Humans ; Length of Stay ; Logistic Models ; Male ; Odds Ratio ; Registries ; Risk Factors ; Spain ; Time Factors ; Treatment Outcome ; }, abstract = {OBJECTIVE: Little is known about treatments provided by advanced life support (ALS) ambulance teams to patients with acute heart failure (AHF) during the prehospital phase, and their influence on short-term outcome. We evaluated the effect of prehospital care in consecutive patients diagnosed with AHF in Spanish emergency departments (EDs).<br><br>METHODS: We selected patients from the EAHFE registry arriving at the ED by ALS ambulances with available follow-up data. We recorded specific prehospital ALS treatments (supplemental oxygen, diuretics, nitroglycerin, non-invasive ventilation) and patients were grouped according to whether they received low- (LIPHT; 0/1 treatments) or high-intensity prehospital therapy (HIPHT; >&#xa0;1 treatment) for AHF. We also recorded 46 covariates. The primary endpoint was all-cause 7-day mortality, and secondary endpoints were prolonged hospitalisation (>&#x2009;10&#xa0;days) and in-hospital and 30-day mortality. Unadjusted and adjusted odds ratios were calculated to compare the groups.<br><br>RESULTS: We included 1493 patients [mean age 80.7 (10) years; women 54.8%]. Prehospital treatment included supplemental oxygen in 71.2%, diuretics in 27.9%, nitroglycerin in 13.5%, and non-invasive ventilation in 5.3%. The LIPHT group included 1041 patients (70.0%) with an unadjusted OR for 7-day mortality of 1.770 (95% CI 1.115-2.811; p&#x2009;=&#x2009;0.016), and 1.939 (95% CI 1.114-3.287, p&#x2009;=&#x2009;0.014) after adjustment for 16 discordant covariables. The adjusted ORs for all secondary endpoints were always&#x2009;>&#x2009;1 in the LIPHT group, but none reached statistical significance.<br><br>CONCLUSIONS: Patients finally diagnosed with AHF at then ED that have received LIPHT by the ALS ambulance teams have a poorer short-term outcome, especially during the first 7&#xa0;days.}, }
@article {pmid29284475, year = {2017}, author = {Weber, C and Fijalkowska, B and Ciecwierska, K and Lindblad, A and Badura-Lotter, G and Andersen, PM and Kuźma-Kozakiewicz, M and Ludolph, AC and Lulé, D and Pasierski, T and Lynöe, N}, title = {Existential decision-making in a fatal progressive disease: how much do legal and medical frameworks matter?.}, journal = {BMC palliative care}, volume = {16}, number = {1}, pages = {80}, pmid = {29284475}, issn = {1472-684X}, support = {MND-Net (#01GM1103A)//Bundesministerium f&#xfc;r Bildung und Forschung/ ; JPND 01ED1405)//EU Joint Programme - Neurological Disease Research/ ; }, mesh = {Advance Directives/legislation &amp; jurisprudence ; Amyotrophic Lateral Sclerosis/complications/psychology ; *Decision Making ; Existentialism/*psychology ; Germany ; Humans ; Poland ; Sweden ; Terminal Care/legislation &amp; jurisprudence/methods ; Withholding Treatment/*legislation &amp; jurisprudence ; }, abstract = {BACKGROUND: Healthcare legislation in European countries is similar in many respects. Most importantly, the framework of informed consent determines that physicians have the duty to provide detailed information about available therapeutic options and that patients have the right to refuse measures that contradict their personal values. However, when it comes to end-of-life decision-making a number of differences exist in the more specific regulations of individual countries. These differences and how they might nevertheless impact patient's choices will be addressed in the current debate.<br><br>MAIN TEXT: In this article we show how the legal and medical frameworks of Germany, Poland and Sweden differ with regard to end-of-life decisions for patients with a fatal progressive disease. Taking Amyotrophic Lateral Sclerosis (ALS) as an example, we systematically compare clinical guidelines and healthcare law, pointing out the country-specific differences most relevant for existential decision-making. A fictional case report discusses the implications of these differences for a patient with ALS living in either of the three countries. Patients with ALS in Germany, Poland and Sweden are confronted with a similar spectrum of treatment options. However, the analysis of the normative frameworks shows that the conditions for making existential decisions differ considerably in Germany, Poland and Sweden. Specifically, these differences concern (1) the legal status of advance directives, (2) the conditions under which life-sustaining therapies are started or withheld, and (3) the legal regulations on assisted dying.<br><br>CONCLUSION: According to the presented data, regulations of terminating life-sustaining treatments and the framework of "informed consent" are quite differently understood and implemented in the legal setting of the three countries. It is possible, and even likely, that these differences in the legal and medical frameworks have a considerable influence on existential decisions of patients with ALS.}, }
@article {pmid29278738, year = {2018}, author = {Liu, J and Allender, E and Wang, J and Simpson, EH and Loeb, JA and Song, F}, title = {Slowing disease progression in the SOD1 mouse model of ALS by blocking neuregulin-induced microglial activation.}, journal = {Neurobiology of disease}, volume = {111}, number = {}, pages = {118-126}, doi = {10.1016/j.nbd.2017.12.012}, pmid = {29278738}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Disease Models, Animal ; Disease Progression ; Dose-Response Relationship, Drug ; ErbB Receptors/antagonists &amp; inhibitors/metabolism ; Female ; Injections, Intraventricular ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/*drug effects/metabolism/pathology ; Motor Neurons/drug effects/metabolism/pathology ; Neuregulins/*antagonists &amp; inhibitors/metabolism ; Neuroprotective Agents/*pharmacology ; Recombinant Fusion Proteins/pharmacology ; Signal Transduction/drug effects ; Species Specificity ; Spinal Cord/drug effects/metabolism/pathology ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {There are no effective treatments to slow disease progression in ALS. We previously reported that neuregulin (NRG) receptors are constitutively activated on microglia in the ventral horns in both ALS patients and SOD1 mice and in the corticospinal tracts of ALS patients, and that NRG receptor activation occurs prior to significant clinical disease onset in SOD1 mice. Here, we hypothesize that blocking NRG signaling on microglia would slow disease progression in SOD1 mice using a targeted NRG antagonist (HBD-S-H4). Recombinant HBD-S-H4 directly delivered into the central nervous system (CNS) through implanted intracerebroventricular cannulas showed no signs of toxicity and significantly inhibited NRG receptor activation on microglia resulting in reduced microglial activation and motor neuron loss. The treatment also resulted in a delay in disease onset and an increase in survival. The therapeutic effect was dose-dependent that varied as a function of genetic background in two different strains of SOD1 mice. As a complementary drug delivery approach, transgenic mice expressing HBD-S-H4 driven by an astrocytic promoter (GFAP) had slower disease progression in a dose dependent manner, based on the level of HBD-S-H4 expression. These studies provide mechanistic insights into how NRG signaling on microglia may lead to disease progression and demonstrate the utility of a humanized fusion protein that blocks NRG as a novel therapeutic for human ALS.}, }
@article {pmid29270590, year = {2017}, author = {Li, YH and Liu, SB and Zhang, HY and Zhou, FH and Liu, YX and Lu, Q and Yang, L}, title = {[Antioxidant effects of celastrol against hydrogen peroxide-induced oxidative stress in the cell model of amyotrophic lateral sclerosis].}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {69}, number = {6}, pages = {751-758}, pmid = {29270590}, issn = {0371-0874}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Antioxidants/*pharmacology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Glutamate-Cysteine Ligase/genetics ; Hydrogen Peroxide/*pharmacology ; Mice ; Oxidative Stress/*drug effects ; Pentacyclic Triterpenes ; Phosphorylation ; Triterpenes/*pharmacology/therapeutic use ; }, abstract = {To investigate the anti-oxidative effect of celastrol on H2O2-induced oxidative stress in the cell model of amyotrophic lateral sclerosis (ALS) and its molecular mechanism, NSC34 motor neuron-like cells were transfected with EGFP-G93A-SOD1 plasmid and used as in vitro ALS cell model. SOD1[G93A] transfected NSC34 cells were treated with different doses of H2O2 and celastrol. The survival rate of the cells was detected by CCK-8 assay, and malondialdehyde (MDA) content was detected by corresponding kit. The mRNA expression of glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione S-transferases (GST) were detected by real-time PCR. The activation of intracellular MEK/ERK and PI3K/Akt signal pathways was detected by Western blot. The results showed that pre-incubation of celastrol (50 nmol/L) for 4 h prior to H2O2 (10 μmol/L) co-treatment for another 24 h significantly attenuated H2O2-induced cell death and MDA level in SOD1[G93A] transfected NSC34 cells. Real-time PCR showed that the mRNA expressions of GCLC and GST were enhanced with pre-incubation of celastrol. Celastrol quickly induced phosphorylation of ERK1/2 and Akt within 30 min and 1 h respectively in SOD1[G93A] transfected NSC34 cells. Pharmacological inhibitors of MEK (PD98059, 10 μmol/L) or Akt (MK2206, 10 μmol/L) could reverse the phosphorylation of ERK1/2 and Akt, and abolish up-regulation of GCLC and GST induced by celastrol at mRNA levels. Taken together, we conclude that celastrol exerts a beneficial antioxidant effect in SOD1[G93A]NSC34 cells, which might be dependent on MEK/ERK and PI3K/Akt signaling pathway activation.}, }
@article {pmid29270111, year = {2017}, author = {Tosolini, AP and Sleigh, JN}, title = {Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {405}, pmid = {29270111}, issn = {1662-5099}, support = {//Wellcome Trust/United Kingdom ; }, abstract = {Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are severe nervous system diseases characterized by the degeneration of lower motor neurons. They share a number of additional pathological, cellular, and genetic parallels suggesting that mechanistic and clinical insights into one disorder may have value for the other. While there are currently no clinical ALS gene therapies, the splice-switching antisense oligonucleotide, nusinersen, was recently approved for SMA. This milestone was achieved through extensive pre-clinical research and patient trials, which together have spawned fundamental insights into motor neuron gene therapy. We have thus tried to distil key information garnered from SMA research, in the hope that it may stimulate a more directed approach to ALS gene therapy. Not only must the type of therapeutic (e.g., antisense oligonucleotide vs. viral vector) be sensibly selected, but considerable thought must be applied to the where, which, what, and when in order to enhance treatment benefit: to where (cell types and tissues) must the drug be delivered and how can this be best achieved? Which perturbed pathways must be corrected and can they be concurrently targeted? What dosing regime and concentration should be used? When should medication be administered? These questions are intuitive, but central to identifying and optimizing a successful gene therapy. Providing definitive solutions to these quandaries will be difficult, but clear thinking about therapeutic testing is necessary if we are to have the best chance of developing viable ALS gene therapies and improving upon early generation SMA treatments.}, }
@article {pmid29262737, year = {2018}, author = {Horton, DK and Graham, S and Punjani, R and Wilt, G and Kaye, W and Maginnis, K and Webb, L and Richman, J and Bedlack, R and Tessaro, E and Mehta, P}, title = {A spatial analysis of amyotrophic lateral sclerosis (ALS) cases in the United States and their proximity to multidisciplinary ALS clinics, 2013.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {19}, number = {1-2}, pages = {126-133}, pmid = {29262737}, issn = {2167-9223}, support = {CC999999//Intramural CDC HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Ambulatory Care Facilities/statistics &amp; numerical data ; Amyotrophic Lateral Sclerosis/*epidemiology ; Female ; Humans ; Male ; Middle Aged ; Prevalence ; Racial Groups ; *Registries ; United States ; Young Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that typically results in death within 2-5 years of initial symptom onset. Multidisciplinary ALS clinics (MDCs) have been established to provide specialty care to people living with the disease.<br><br>OBJECTIVE: To estimate the proximity of ALS prevalence cases to the nearest MDC in the US to help evaluate one aspect of access to care.<br><br>METHODS: Using 2013 prevalence data from the National ALS Registry, cases were geocoded by city using geographic information system (GIS) software, along with the locations of all MDCs in operation during 2013. Case-to-MDC proximity was calculated and analyzed by sex, race, and age group.<br><br>RESULTS: During 2013, there were 72 MDCs in operation in 30 different states. A total of 15,633 ALS cases were geocoded and were distributed throughout all 50 states. Of these, 62.6% were male, 77.9% were white, and 76.2% were 50-79 years old. For overall case-to-MDC proximity, nearly half (44.9%) of all geocoded cases in the US lived >50 miles from an MDC, including approximately a quarter who lived >100 miles from an MDC. There was a statistically significant difference between distance to MDC by race and age group.<br><br>CONCLUSIONS: The high percentage of those living more than 50 miles from the nearest specialized clinic underscores one of the many challenges of ALS. Having better access to care, whether at MDCs or through other modalities, is likely key to increasing survivability and obtaining appropriate end-of-life treatment and support for people with ALS.}, }
@article {pmid29249625, year = {2018}, author = {Domené, HM and Fierro-Carrión, G}, title = {Genetic disorders of GH action pathway.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {38}, number = {}, pages = {19-23}, doi = {10.1016/j.ghir.2017.12.004}, pmid = {29249625}, issn = {1532-2238}, mesh = {*Genetic Markers ; Growth Disorders/*diagnosis/*genetics/metabolism ; Human Growth Hormone/*deficiency ; Humans ; *Signal Transduction ; }, abstract = {While insensitivity to GH (GHI) is characterized by low IGF-I levels, normal or elevated GH levels, and lack of IGF-I response to GH treatment, IGF-I resistance is characterized by elevated IGF-I levels with normal/high GH levels. Several genetic defects are responsible for impairment of GH and IGF-I actions resulting in short stature that could affect intrauterine growth or be present in the postnatal period. The genetic defects affecting GH and/or IGF-I action can be divided into five different groups: GH insensitivity by defects affecting the GH receptor (GHR), the intracellular GH signaling pathway (STAT5B, STAT3, IKBKB, IL2RG, PIK3R1), the synthesis of insulin-like growth factors (IGF1, IGF2), the transport/bioavailability of IGFs (IGFALS, PAPPA2), and defects affecting IGF-I sensitivity (IGF1R). Complete GH insensitivity (GHI) was first reported by Zvi Laron and his colleagues in patients with classical appearance of GH deficiency, but presenting elevated levels of GH. The association of GH insensitivity with several clinical sings of immune-dysfunction and autoimmune dysregulation are characteristic of molecular defects in the intracellular GH signaling pathway (STAT5B, STAT3, IKBKB, IL2RG, PIK3R1). Gene mutations in the IGF1 and IGF2 genes have been described in patients presenting intrauterine growth retardation and postnatal short stature. Molecular defects have also been reported in the IGFALS gene, that encodes the acid-labile subunit (ALS), responsible to stabilize circulating IGF-I in ternary complexes, and more recently in the PAPPA2 gen that encodes the pregnancy-associated plasma protein-A2, a protease that specifically cleaves IGFBP-3 and IGFBP-5 regulating the accessibility of IGFs to their target tissues. Mutations in the IGF1R gene resulted in IGF-I insensitivity in patients with impaired intrauterine and postnatal growth. These studies have revealed novel molecular mechanisms of GH insensitivity/primary IGF-I deficiency beyond the GH receptor gene. In addition, they have also underlined the importance of several players of the GH-IGF axis in the complex system that promotes human growth.}, }
@article {pmid29246232, year = {2017}, author = {Mishra, PS and Vijayalakshmi, K and Nalini, A and Sathyaprabha, TN and Kramer, BW and Alladi, PA and Raju, TR}, title = {Etiogenic factors present in the cerebrospinal fluid from amyotrophic lateral sclerosis patients induce predominantly pro-inflammatory responses in microglia.}, journal = {Journal of neuroinflammation}, volume = {14}, number = {1}, pages = {251}, pmid = {29246232}, issn = {1742-2094}, support = {BT/PR5384/MED/30/817/2012//Department of Biotechnology , Ministry of Science and Technology/ ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*cerebrospinal fluid ; Cells, Cultured ; Cerebrospinal Fluid/*chemistry/*immunology ; Female ; Humans ; Inflammation/cerebrospinal fluid/immunology ; Male ; Microglia/drug effects/*metabolism ; Middle Aged ; }, abstract = {BACKGROUND: Microglial cell-associated neuroinflammation is considered as a potential contributor to the pathophysiology of sporadic amyotrophic lateral sclerosis. However, the specific role of microglia in the disease pathogenesis remains to be elucidated.<br><br>METHODS: We studied the activation profiles of the microglial cultures exposed to the cerebrospinal fluid from these patients which recapitulates the neurodegeneration seen in sporadic amyotrophic lateral sclerosis. This was done by investigating the morphological and functional changes including the expression levels of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), TNF-&#x3b1;, IL-6, IFN-&#x3b3;, IL-10, inducible nitric oxide synthase (iNOS), arginase, and trophic factors. We also studied the effect of chitotriosidase, the inflammatory protein found upregulated in the cerebrospinal fluid from amyotrophic lateral sclerosis patients, on these cultures.<br><br>RESULTS: We report that the cerebrospinal fluid from amyotrophic lateral sclerosis patients could induce an early and potent response in the form of microglial activation, skewed primarily towards a pro-inflammatory profile. It was seen in the form of upregulation of the pro-inflammatory cytokines and factors including IL-6, TNF-&#x3b1;, iNOS, COX-2, and PGE2. Concomitantly, a downregulation of beneficial trophic factors and anti-inflammatory markers including VEGF, glial cell line-derived neurotrophic factor, and IFN-&#x3b3; was seen. In addition, chitotriosidase-1 appeared to act specifically via the microglial cells.<br><br>CONCLUSION: Our findings demonstrate that the cerebrospinal fluid from amyotrophic lateral sclerosis patients holds enough cues to induce microglial inflammatory processes as an early event, which may contribute to the neurodegeneration seen in the sporadic amyotrophic lateral sclerosis. These findings highlight the dynamic role of microglial cells in the pathogenesis of the disease, thus suggesting the need for a multidimensional and temporally guarded therapeutic approach targeting the inflammatory pathways for its treatment.}, }
@article {pmid29244892, year = {2018}, author = {Riera-Punet, N and Martinez-Gomis, J and Paipa, A and Povedano, M and Peraire, M}, title = {Alterations in the Masticatory System in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Journal of oral &amp; facial pain and headache}, volume = {32}, number = {1}, pages = {84&#x2013;90}, doi = {10.11607/ofph.1882}, pmid = {29244892}, issn = {2333-0384}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*physiopathology ; Bite Force ; Case-Control Studies ; Cross-Sectional Studies ; Female ; Humans ; Jaw/physiology/physiopathology ; Male ; Mastication/physiology ; Masticatory Muscles/physiopathology ; Middle Aged ; Range of Motion, Articular ; Stomatognathic System/physiology/*physiopathology ; }, abstract = {AIMS: To determine the effect of amyotrophic lateral sclerosis (ALS) on aspects of masticatory function and to assess the relationship between ALS and the prevalence of traumatic mucosal lesions caused by oral self-injury.<br><br>METHODS: A total of 153 ALS patients and 23 control subjects participated in this cross-sectional study. Clinical characteristics including site of onset, medication, type of feeding, and use of noninvasive mechanical ventilation were recorded. The Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) protocol and a specific questionnaire to assess aspects of masticatory dysfunction and frequency of self-injury of the oral mucosa were applied to all participants. Maximum mandibular range of motion, maximum bite force, and maximum finger-thumb grip force were determined and tested with Mann Whitney, Kruskal-Wallis, or chi-square tests. P < .05 was considered significant.<br><br>RESULTS: Maximum unassisted and assisted mouth opening, protrusion, left laterotrusion, and finger-thumb grip force were significantly reduced in both spinal- (n = 102) and bulbar-onset (n = 40) patients compared to the control group; however, bite force was reduced only in bulbar-onset patients. ALS patients with tube feeding (n = 16) had the greatest reduction in maximum bite force and mandibular opening. There was no relationship between TMD and ALS. Oral self-injury due to biting was more frequent in the ALS group (29.9%) than in the control group (8.7%) and in the bulbar-onset group (55.0%) compared to the spinal- (20.8%) and respiratory-onset (18.2%) groups. Of the ALS patients in the study, 10% sought dental treatment related to the condition.<br><br>CONCLUSION: The ALS patients in this study had a reduction in finger-thumb grip force that was twice as great as the reduction in bite force. The maximum range of mandibular movement was also reduced, especially in bulbar-onset patients. ALS patients did not have a higher prevalence of TMD but did have more traumatic mucosal injury than controls. The dentist should be an integral part of the multidisciplinary team to manage ALS patients.}, }
@article {pmid29241420, year = {2018}, author = {von Ranke, NL and Bello, ML and Cabral, LM and Castro, HC and Rodrigues, CR}, title = {Molecular modeling and dynamic simulations of agglutinin-like family members from Candida albicans: New insights into potential targets for the treatment of candidiasis.}, journal = {Journal of biomolecular structure &amp; dynamics}, volume = {36}, number = {16}, pages = {4352-4365}, doi = {10.1080/07391102.2017.1417159}, pmid = {29241420}, issn = {1538-0254}, mesh = {Agglutinins/*chemistry/metabolism ; Antifungal Agents/chemistry/metabolism/*pharmacology ; Binding Sites ; Candida albicans/*drug effects/metabolism/pathogenicity ; Candidiasis/microbiology/*prevention &amp; control ; Fungal Proteins/*chemistry/metabolism ; Humans ; Ligands ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Molecular Structure ; Protein Binding ; Protein Domains ; Virulence ; }, abstract = {Infections by Candida albicans in immune compromised patients cause significant morbidity and mortality. In the search for potential molecular targets for drug development, the family of agglutinin-like proteins (Als) in C. albicans have been identified due to numerous attributes associated with high virulence, most prominently due to their role in adherence. Here, molecular models of individual members of the Als family illustrated common and unique structure features. Additionally, dynamic simulations were performed to display regions of high mobility. The results showed variations between Als members in the fluctuation of the A1B1 protein loop, which is located at the entrance to the peptide binding cavity, suggesting that this feature may be a factor contributing to observed differences in affinities to ligands and adhesion properties. Molecular docking results further suggested that ligand affinity could be influenced by movements in the A1B1 loop. In addition, a new site was identified in Als in an area adjacent to the peptide binding cavity that could serve as a new binding site for the design of future anti-adhesion ligands that provide increased specificity inhibiting Als proteins from C. albicans.}, }
@article {pmid29241087, year = {2018}, author = {Vosough, M and Tehrani, SM}, title = {Development of a fast HPLC-DAD method for simultaneous quantitation of three immunosuppressant drugs in whole blood samples using intelligent chemometrics resolving of coeluting peaks in the presence of blood interferences.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {1073}, number = {}, pages = {69-79}, doi = {10.1016/j.jchromb.2017.12.012}, pmid = {29241087}, issn = {1873-376X}, mesh = {Chromatography, High Pressure Liquid/*methods ; Computational Biology ; Cyclosporine/blood ; Everolimus/blood ; Humans ; Immunosuppressive Agents/*blood ; Least-Squares Analysis ; Limit of Detection ; Linear Models ; Reproducibility of Results ; Tacrolimus/blood ; }, abstract = {The present study describes a fast high performance liquid chromatography-diode array detection analytical methodology for quantification of tacrolimus, everolimus and cyclosporine A in whole blood samples, with minimum sample preparation steps. A short isocratic chromatographic elution was coupled with second-order calibration using multivariate curve resolution to stablish a smart and green methodology. Due to presence of matrix effect, a sample-added calibration strategy was used for quantification purposes. The serious issues related to background drift, chromatographic shifts and co-elution of non-calibrated blood components, were resolved by a proper background correction and multivariate curve resolution-alternating least squares (MCR/ALS) methods The main features of this study were based on the fact that the acquired data matrices were handled intelligently and all features of the concerned target analytes were taken into account. Satisfactory resolution and quantification results in the presence of matrix interferences were achieved and the second-order advantage was fully exploited. The average recoveries in therapeutic concentration ranges were 102±10%, 99±11% and 104±12% for TAC, EVR and CsA, with average relative prediction errors of less than 7%. Considering the advantages of the present strategy, such as increased selectivity, sensitivity and sufficiency of lower limit of quantification through multivariate advantage, simplicity of sample treatment steps, a fast elution pattern and also a low-cost instrumentation compared with LC-MS/MS, the proposed method has the significant merits as an alternative for simultaneous therapeutic monitoring of immunosuppressants.}, }
@article {pmid29228563, year = {2017}, author = {Sperling, S and Aung, T and Martin, S and Rohde, V and Ninkovic, M}, title = {Riluzole: a potential therapeutic intervention in human brain tumor stem-like cells.}, journal = {Oncotarget}, volume = {8}, number = {57}, pages = {96697-96709}, pmid = {29228563}, issn = {1949-2553}, abstract = {A small subpopulation of tumor stem-like cells has the capacity to initiate tumors and mediate radio- and chemoresistance in diverse cancers hence also in glioblastoma (GBM). It has been reported that this capacity of tumor initiation in the brain is mainly dependent on the body's nutrient supply. This population of so-called brain tumor initiating or brain tumor stem-like cells (BTSCs) is able to extract nutrients like glucose with a higher affinity. Riluzole, a drug approved for treating amyotrophic lateral sclerosis (ALS), was reported to possess anticancer properties, affecting the glutamate metabolism. We report that riluzole treatment inhibits the growth of brain tumor stem-like cells enriched cultures isolated from two human glioblastomas. The effects of riluzole on these cells were associated with an inhibition of a poor prognostic indicator: glucose transporter 3 (GLUT3). A decrease in GLUT3 is associated with a decrease in the p-Akt/HIF1α pathway. Further, downregulation of the DNA (Cytosine-5-)-methyltransferase 1 (DNMT1) gene that causes hypermethylation of various tumor-suppressor genes and leads to a poor prognosis in GBM, was detected. Two hallmarks of cancer cells-proliferation and cell death-were positively influenced by riluzole treatment. Finally, we observed that riluzole reduced the tumor growth in in vivo CAM assay, suggesting it could be a possible synergistic drug for the treatment of glioblastoma.}, }
@article {pmid29221425, year = {2018}, author = {Hogg, MC and Halang, L and Woods, I and Coughlan, KS and Prehn, JHM}, title = {Riluzole does not improve lifespan or motor function in three ALS mouse models.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {19}, number = {5-6}, pages = {438-445}, doi = {10.1080/21678421.2017.1407796}, pmid = {29221425}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*mortality ; Animals ; DNA-Binding Proteins/genetics ; Disease Models, Animal ; Disease Progression ; Kaplan-Meier Estimate ; Longevity/*drug effects/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuroprotective Agents/*therapeutic use ; RNA-Binding Protein FUS/genetics ; Riluzole/*therapeutic use ; Superoxide Dismutase/genetics ; }, abstract = {BACKGROUND: Riluzole is the most widespread therapeutic for treatment of the progressive degenerative disease amyotrophic lateral sclerosis (ALS). Riluzole gained FDA approval in 1995 before the development of ALS mouse models. We assessed riluzole in three transgenic ALS mouse models: the SOD1[G93A] model, the TDP-43[A315T] model, and the recently developed FUS (1-359) model.<br><br>METHODS: Age, sex and litter-matched mice were treated with riluzole (22&#x2009;mg/kg) in drinking water or vehicle (DMSO) from symptom onset. Lifespan was assessed and motor function tests were carried out twice weekly to determine whether riluzole slowed disease progression.<br><br>RESULTS: Riluzole treatment had no significant benefit on lifespan in any of the ALS mouse models tested. Riluzole had no significant impact on decline in motor performance in the FUS (1-359) and SOD1[G93A] transgenic mice as assessed by Rotarod and stride length analysis.<br><br>CONCLUSIONS: Riluzole is widely prescribed for ALS patients despite questions surrounding its efficacy. Our data suggest that if riluzole was identified as a therapeutic candidate today it would not progress past pre-clinical assessment. This raises questions about the standards used in pre-clinical assessment of therapeutic candidates for the treatment of ALS.}, }
@article {pmid29218631, year = {2018}, author = {Barbieri, L and Luchinat, E and Banci, L}, title = {Intracellular metal binding and redox behavior of human DJ-1.}, journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry}, volume = {23}, number = {1}, pages = {61-69}, pmid = {29218631}, issn = {1432-1327}, mesh = {Calcium/*chemistry ; Catalytic Domain ; Cysteine/chemistry ; HEK293 Cells ; Humans ; Oxidation-Reduction ; Protein Deglycase DJ-1/*chemistry ; Superoxide Dismutase-1/chemistry ; Zinc/*chemistry ; }, abstract = {DJ-1 is a conserved, ubiquitous protein associated to a large number of intracellular processes. Human DJ-1 has been linked to several pathologies, including hereditary forms of Parkinson's disease, cancer, and amyotrophic lateral sclerosis. Several cytoprotective functions of DJ-1 have been reported, however, its actual mechanisms of action remain elusive. In vitro, DJ-1 has been shown to bind zinc and copper(II) at its active site, which contains a conserved cysteine (C106), and copper(I) at a different binding site. C106 is essential to DJ-1 function, and is easily oxidized upon oxidative stress. Here, we investigated the metal-binding- and redox properties of DJ-1 in living human cells by in-cell NMR. Intracellular DJ-1 is surprisingly free from interactions with any other cellular components and as such is clearly detectable by NMR. Metal-bound forms of DJ-1 were not observed upon treating the cells with excess zinc or copper. No copper binding was observed when co-expressing DJ-1 with the copper chaperone for superoxide dismutase 1 (SOD1). Co-expression of DJ-1 with SOD1 itself did not promote copper binding to SOD1, excluding a previously suggested function of DJ-1 as a copper chaperone. Overall, our data do not support the role of DJ-1 as a metalloprotein. Conversely, oxidative treatment to the cells caused the complete and selective oxidation of C106 to sulfinic acid, consistent with the reported role of DJ-1 as a redox sensor.}, }
@article {pmid29218049, year = {2017}, author = {Milošević, M and Milićević, K and Božić, I and Lavrnja, I and Stevanović, I and Bijelić, D and Dubaić, M and Živković, I and Stević, Z and Giniatullin, R and Andjus, P}, title = {Immunoglobulins G from Sera of Amyotrophic Lateral Sclerosis Patients Induce Oxidative Stress and Upregulation of Antioxidative System in BV-2 Microglial Cell Line.}, journal = {Frontiers in immunology}, volume = {8}, number = {}, pages = {1619}, pmid = {29218049}, issn = {1664-3224}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with a very fast progression, no diagnostic tool for the presymptomatic phase, and still no effective treatment of the disease. Although ALS affects motor neurons, the overall pathophysiological condition points out to the non-cell autonomous mechanisms, where astrocytes and microglia play crucial roles in the disease progression. We have already shown that IgG from sera of ALS patients (ALS IgG) induce calcium transients and an increase in the mobility of acidic vesicles in cultured rat astrocytes. Having in mind the role of microglia in neurodegeneration, and a well-documented fact that oxidative stress is one of the many components contributing to the disease, we decided to examine the effect of ALS IgG on activation, oxidative stress and antioxidative system of BV-2 microglia, and to evaluate their acute effect on cytosolic peroxide, pH, and on reactive oxygen species (ROS) generation. All tested ALS IgGs (compared to control IgG) induced oxidative stress (rise in nitric oxide and the index of lipid peroxidation) followed by release of TNF-α and higher antioxidative defense (elevation of Mn- and CuZn-superoxide dismutase, catalase, and glutathione reductase with a decrease of glutathione peroxidase and glutathione) after 24 h treatment. Both ALS IgG and control IgG showed same localization on the membrane of BV-2 cells following 24 h treatment. Cytosolic peroxide and pH alteration were evaluated with fluorescent probes HyPer and SypHer, respectively, having in mind that HyPer also reacts to pH changes. Out of 11 tested IgGs from ALS patients, 4 induced slow exponential rise of HyPer signal, with maximal normalized fluorescence in the range 0.2-0.5, also inducing similar increase of SypHer intensity, but of a lower amplitude. None of the control IgGs induced changes with neither of the indicators. Acute ROS generation was detected in one out of three tested ALS samples with carboxy-H2DCFDA. The observed phenomena demonstrate the potential role of inflammatory humoral factors, IgGs, as potential triggers of the activation in microglia, known to occur in later stages of ALS. Therefore, revealing the ALS IgG signaling cascade in microglial cells could offer a valuable molecular biomarker and/or a potential therapeutic target.}, }
@article {pmid29202456, year = {2017}, author = {Patten, SA and Aggad, D and Martinez, J and Tremblay, E and Petrillo, J and Armstrong, GA and La Fontaine, A and Maios, C and Liao, M and Ciura, S and Wen, XY and Rafuse, V and Ichida, J and Zinman, L and Julien, JP and Kabashi, E and Robitaille, R and Korngut, L and Parker, JA and Drapeau, P}, title = {Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis.}, journal = {JCI insight}, volume = {2}, number = {22}, pages = {}, pmid = {29202456}, issn = {2379-3708}, support = {R00 NS077435/NS/NINDS NIH HHS/United States ; R01 NS097850/NS/NINDS NIH HHS/United States ; //CIHR/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Antipsychotic Agents/*pharmacokinetics/*therapeutic use ; Caenorhabditis elegans ; Calcium Channels/drug effects ; Calcium Channels, T-Type/drug effects ; DNA-Binding Proteins/metabolism ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Drug Tolerance ; Female ; Mice ; Neuromuscular Junction/drug effects ; Neuromuscular Junction Diseases/*drug therapy ; Pimozide/pharmacology ; Zebrafish ; Zebrafish Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal disorder with no effective treatment. We used simple genetic models of ALS to screen phenotypically for potential therapeutic compounds. We screened libraries of compounds in C. elegans, validated hits in zebrafish, and tested the most potent molecule in mice and in a small clinical trial. We identified a class of neuroleptics that restored motility in C. elegans and in zebrafish, and the most potent was pimozide, which blocked T-type Ca2+ channels in these simple models and stabilized neuromuscular transmission in zebrafish and enhanced it in mice. Finally, a short randomized controlled trial of sporadic ALS subjects demonstrated stabilization of motility and evidence of target engagement at the neuromuscular junction. Simple genetic models are, thus, useful in identifying promising compounds for the treatment of ALS, such as neuroleptics, which may stabilize neuromuscular transmission and prolong survival in this disease.}, }
@article {pmid29187690, year = {2017}, author = {Yokoi, K and Ando, T and Ishikawa, S}, title = {[Treatment for paroxysmal sympathetic hyperactivity in amyotrophic lateral sclerosis patient].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {57}, number = {12}, pages = {782-784}, doi = {10.5692/clinicalneurol.cn-001093}, pmid = {29187690}, issn = {1882-0654}, mesh = {Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*complications ; Autonomic Nervous System Diseases/*drug therapy/*etiology/metabolism ; Catecholamines/metabolism ; Diazepam/*therapeutic use ; Humans ; Male ; Treatment Outcome ; }, abstract = {We report a case of an 80-year-old man who contracted amyotrophic lateral sclerosis (ALS) 15 years ago, was put on a ventilator 8 years ago, and became locked in 3 years ago. Two years ago, he began to suffer from sudden symptoms of paroxysmal sympathetic hyperactivity (PSH) attacks (hot flushes, abnormal sweating, tachycardia, and increased blood pressure). One day, he developed multiple-organ failure. This failure healed in a few days, but PSH attacks remained. His catecholamine levels were abnormal: adrenaline, 215 pg/ml; noradrenaline, 5,960 pg/ml; and dopamine, 606 pg/ml. Diazepam was administered, which decreased both the number of PSH attacks and the catecholamine levels. When the dose was increased to 3 mg, the attacks stopped, whereas when the dose was reduced to 2 mg, the attacks relapsed. When the dose of 3 mg was continued, there was no relapse of the attacks and no re-rise in the catecholamine levels. These results show that diazepam alone has an effect on PSH attacks in ALS.}, }
@article {pmid29182055, year = {2019}, author = {Hwang, WJ and Huang, K and Huang, JS}, title = {Amyotrophic lateral sclerosis presenting as the temporomandibular disorder: A case report and literature review.}, journal = {Cranio : the journal of craniomandibular practice}, volume = {37}, number = {3}, pages = {196-200}, doi = {10.1080/08869634.2017.1407117}, pmid = {29182055}, issn = {2151-0903}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Masticatory Muscles ; Quality of Life ; *Temporomandibular Joint Disorders ; }, abstract = {BACKGROUND: Spasticity and pain in the masticatory muscles or mouth opening limitation have been reported as early signs and symptoms of amyotrophic lateral sclerosis (ALS). These signs and symptoms are also frequently seen in, and thus mistaken for, temporomandibular disorders (TMD).<br><br>CLINICAL PRESENTATION: The authors report a case of ALS initially presenting with signs and symptoms of TMD. The TMD was followed by dysarthria of insidious onset, leading to the diagnosis of ALS. This case highlights the importance of considering TMD as a potential early form of presentation of ALS, requiring multidisciplinary treatment, especially by dental professionals.<br><br>CONCLUSION: A review of the literature was conducted to elucidate the oral and facial signs and symptoms of ALS and to identify ways of improving the quality of life of patients through a multidisciplinary approach.}, }
@article {pmid29178260, year = {2018}, author = {Kolin, DL and Dinulescu, DM and Crum, CP}, title = {Origin of clear cell carcinoma: nature or nurture?.}, journal = {The Journal of pathology}, volume = {244}, number = {2}, pages = {131-134}, doi = {10.1002/path.5009}, pmid = {29178260}, issn = {1096-9896}, mesh = {Adenocarcinoma, Clear Cell/*genetics ; Carcinoma, Endometrioid/*genetics ; *Endometriosis ; Female ; Humans ; Ovarian Neoplasms/*genetics ; United Kingdom ; }, abstract = {A rare but serious complication of endometriosis is the development of carcinoma, and clear cell and endometrioid carcinomas of the ovary are the two most common malignancies which arise from endometriosis. They are distinct diseases, characterized by unique morphologies, immunohistochemical profiles, and responses to treatment. However, both arise in endometriosis and can share common mutations. The overlapping mutational profiles of clear cell and endometrioid carcinomas suggest that their varied histologies may be due to a different cell of origin which gives rise to each type of cancer. Cochrane and colleagues address this question in a recent article in this journal. They show that a marker of ovarian clear cell carcinoma, cystathionine gamma lyase, is expressed in ciliated cells. Similarly, they show that markers of secretory cells (estrogen receptor and methylenetetrahydrofolate dehydrogenase 1) are expressed in ovarian endometrioid carcinoma. Taken together, they suggest that endometrioid and clear cell carcinomas arise from cells related to secretory and ciliated cells, respectively. We discuss Cochrane et al's work in the context of other efforts to determine the cell of origin of gynecological malignancies, with an emphasis on recent developments and challenges unique to the area. These limitations complicate our interpretation of tumor differentiation; does it reflect nature imposed by a specific cell of origin or nurture, by either mutation(s) or environment? Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.}, }
@article {pmid29175945, year = {2018}, author = {Schludi, MH and Edbauer, D}, title = {Targeting RNA G-quadruplexes as new treatment strategy for C9orf72 ALS/FTD.}, journal = {EMBO molecular medicine}, volume = {10}, number = {1}, pages = {4-6}, pmid = {29175945}, issn = {1757-4684}, mesh = {*Amyotrophic Lateral Sclerosis ; C9orf72 Protein ; *G-Quadruplexes ; Humans ; Proteins/genetics ; }, abstract = {The recent discovery of a pathogenic expansion of a (GGGGCC)n repeat in the C9orf72 gene in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) led to a burst of mechanistic discoveries. In this issue, Simone et al (2018) describe novel compounds targeting the G‐quadruplex (G‐Q) structure of the (GGGGCC)n repeat RNA that alleviate the hallmarks of C9orf72 disease in patient‐derived neurons and increase survival in a Drosophila model. Lack of overt off‐target effects and toxicity suggest that these small molecules are promising lead compounds to the development of a therapy.}, }
@article {pmid29169899, year = {2018}, author = {Liu, Z and Wang, H and Fan, D and Wang, W}, title = {Comparison of optical coherence tomography findings and visual field changes in patients with primary open-angle glaucoma and amyotrophic lateral sclerosis.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {48}, number = {}, pages = {233-237}, doi = {10.1016/j.jocn.2017.10.080}, pmid = {29169899}, issn = {1532-2653}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/pathology/*physiopathology ; Case-Control Studies ; Disease Progression ; Female ; Glaucoma, Open-Angle/*physiopathology ; Humans ; Macula Lutea/pathology ; Male ; Middle Aged ; Nerve Fibers/pathology ; Retina/pathology ; Retinal Ganglion Cells/pathology ; Tomography, Optical Coherence/*methods ; Visual Fields/*physiology ; }, abstract = {Recent studies revealing genetic connection of primary open angle glaucoma (POAG) and amyotrophic lateral sclerosis (ALS) have received particular attention. Exploring the evidence for common pathogenesis of these two progressive neurological disorders may assist in understanding the mechanism and searching for new treatment. Retinal nerve fiber layer (RNFL) defect and corresponding visual field (VF) impairment are well known neuropathy signs in glaucoma. In our study, thickness of certain retinal layer in ALS patients was analyzed to detect ganglion cell's soma and axon, and for first time visual field was examined for ALS. The correlation of retinal involvement and ALS progression were also investigated. The results were compared with those of POAG. The study may provide new knowledge for these two neurodegenerative diseases.}, }
@article {pmid29162978, year = {2017}, author = {Lembke, KM and Morton, DB}, title = {Exploring the Interaction of Drosophila TDP-43 and the Type II Voltage-Gated Calcium Channel, Cacophony, in Regulating Motor Function and Behavior.}, journal = {Journal of experimental neuroscience}, volume = {11}, number = {}, pages = {1179069517740892}, pmid = {29162978}, issn = {1179-0695}, support = {R21 NS071186/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult onset motor neurodegenerative disease. The cause of the disease remains obscure, and as such there is no effective treatment or cure. Amyotrophic lateral sclerosis and other neurodegenerative diseases are frequently characterized by dysfunction of the RNA-binding protein, TDP-43. Using model systems to understand the mechanisms underlying TDP-43 dysfunction should accelerate identification of therapeutic targets. A recent report has shown that motor defects caused by the deletion of the Drosophila TDP-43 ortholog, tbph, are not driven by changes in the physiology at the neuromuscular junction. Rather, defective motor burst rhythmicity and coordination, displayed by tbph mutants, are rescued by genetically restoring a voltage-gated calcium channel to either motor neurons or just a single pair of neurons in the brain. If these effects are mirrored in human TDP-43 proteinopathies, these observations could open new avenues to investigate alternative therapeutic targets for these neurodegenerative diseases.}, }
@article {pmid29162476, year = {2018}, author = {McKimm-Breschkin, JL and Jiang, S and Hui, DS and Beigel, JH and Govorkova, EA and Lee, N}, title = {Prevention and treatment of respiratory viral infections: Presentations on antivirals, traditional therapies and host-directed interventions at the 5th ISIRV Antiviral Group conference.}, journal = {Antiviral research}, volume = {149}, number = {}, pages = {118-142}, pmid = {29162476}, issn = {1872-9096}, support = {HHSN261200800001C/CA/NCI NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; HHSN272201400006C/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Respiratory Tract Infections/*prevention &amp; control/*therapy/*virology ; }, abstract = {The International Society for Influenza and other Respiratory Virus Diseases held its 5th Antiviral Group (isirv-AVG) Conference in Shanghai, China, in conjunction with the Shanghai Public Health Center and Fudan University from 14-16 June 2017. The three-day programme encompassed presentations on some of the clinical features, management, immune responses and virology of respiratory infections, including influenza A(H1N1)pdm09 and A(H7N9) viruses, MERS-CoV, SARS-CoV, adenovirus Type 80, enterovirus D68, metapneumovirus and respiratory syncytial virus (RSV). Updates were presented on several therapeutics currently in clinical trials, including influenza polymerase inhibitors pimodivir/JNJ6362387, S033188, favipiravir, monoclonal antibodies MHAA45449A and VIS410, and host directed strategies for influenza including nitazoxanide, and polymerase ALS-008112 and fusion inhibitors AK0529, GS-5806 for RSV. Updates were also given on the use of the currently licensed neuraminidase inhibitors. Given the location in China, there were also presentations on the use of Traditional Chinese Medicines. Following on from the previous conference, there were ongoing discussions on appropriate endpoints for severe influenza in clinical trials from regulators and clinicians, an issue which remains unresolved. The aim of this conference summary is to provide information for not only conference participants, but a detailed referenced review of the current status of clinical trials, and pre-clinical development of therapeutics and vaccines for influenza and other respiratory diseases for a broader audience.}, }
@article {pmid29156920, year = {2018}, author = {Cheng, HWB and Chan, KY and Chung, YKJ and Choi, CW and Chan, CH and Cheng, SC and Chan, WH and Fung, KS and Wong, KY and Chan, OMI and Man, CW}, title = {Supportive &amp; palliative interventions in motor neurone disease: what we know from current literature?.}, journal = {Annals of palliative medicine}, volume = {7}, number = {3}, pages = {320-331}, doi = {10.21037/apm.2017.10.01}, pmid = {29156920}, issn = {2224-5839}, mesh = {Cost-Benefit Analysis ; Hospitalization ; Humans ; Motor Neuron Disease/economics/physiopathology/*therapy ; Nutritional Support ; *Palliative Care/methods ; Patient Care Team ; Quality of Life ; Respiratory Therapy ; Social Support ; Survival Analysis ; }, abstract = {Although there is no cure for motor neurone disease (MND), the advent of supportive interventions including multidisciplinary care (MDC) has improved treatment interventions and enhanced quality of life (QOL) for MND patients and their carers. Our integrative review showed evidence-based MDC, respiratory management and disease-modifying therapy that have improved the outcomes of patients diagnosed with MND. Supportive approaches to nutritional maintenance and optimization of symptomatic treatments, including management of communication and neuropsychiatric issues, improve the QOL for MND patients. Notwithstanding improvement to care and QOL, survival benefit has become evident with the advent of a MDC framework, early treatment with non-invasive ventilation (NIV). In addition, weight maintenance remains critical, as weight loss is associated with more rapid disease progression. The endof- life phase is poorly defined in MND patients and treatment remains challenging, yet effective symptom control through palliative care (PC) is achievable and essential.}, }
@article {pmid29154925, year = {2018}, author = {Antonini, A and Caioli, S and Saba, L and Vindigni, G and Biocca, S and Canu, N and Zona, C}, title = {Membrane cholesterol depletion in cortical neurons highlights altered NMDA receptor functionality in a mouse model of amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1864}, number = {2}, pages = {509-519}, doi = {10.1016/j.bbadis.2017.11.008}, pmid = {29154925}, issn = {0925-4439}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Cell Membrane/metabolism ; Cell Survival ; Cholesterol/*metabolism ; Disease Models, Animal ; Electrophysiology ; Female ; Glutamic Acid/metabolism ; Humans ; Male ; Membrane Microdomains/*chemistry ; Mice ; Mice, Transgenic ; Motor Neurons/*cytology/metabolism ; N-Methylaspartate/*pharmacology ; Proteomics ; Receptors, AMPA/metabolism ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Signal Transduction ; Superoxide Dismutase-1/genetics ; beta-Cyclodextrins/pharmacology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a chronic neurodegenerative disease affecting upper and lower motor neurons, with unknown aetiology. Lipid rafts, cholesterol enriched microdomains of the plasma membrane, have been linked to neurodegenerative disorders like ALS. The NMDA-receptor subcellular localization in lipid rafts is known to play many roles, from modulating memory strength to neurotoxicity. In this study, performed on the widely used G93A mouse model of ALS, we have shown an equal content of total membrane cholesterol in Control and G93A cortical cultures. Moreover, by electrophysiological studies, we have recorded NMDA- and AMPA-evoked currents which were not significantly different between the two neuronal populations. To study the role of membrane cholesterol on glutamate receptor functionality, we have analysed NMDA and AMPA receptors following cholesterol membrane depletion by methyl-β-cyclodextrin (MβCD). Interestingly, MβCD chronic treatment has provoked a significant reduction of NMDA-evoked currents in both cellular populations which was dose- and time-dependent but significantly higher in ALS neurons compared to Control. The different MβCD effect on NMDA-evoked currents was not due to a different membrane receptor subunit composition but seemed to cause in both neuronal populations a NMDA receptor membrane redistribution. MβCD treatment effect was receptor-specific since no alterations in the two neuronal populations were detected on AMPA receptors. These results lead us to speculate for an altered proteomic composition of lipid rafts in cortical mutated neurons and suggest the need for further studies on the lipid rafts composition and on their interaction with membrane receptors in ALS cortices.}, }
@article {pmid29154076, year = {2017}, author = {Sironi, F and Vallarola, A and Violatto, MB and Talamini, L and Freschi, M and De Gioia, R and Capelli, C and Agostini, A and Moscatelli, D and Tortarolo, M and Bigini, P and Introna, M and Bendotti, C}, title = {Multiple intracerebroventricular injections of human umbilical cord mesenchymal stem cells delay motor neurons loss but not disease progression of SOD1G93A mice.}, journal = {Stem cell research}, volume = {25}, number = {}, pages = {166-178}, doi = {10.1016/j.scr.2017.11.005}, pmid = {29154076}, issn = {1876-7753}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics/*therapy ; Animals ; Female ; Humans ; Male ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/*cytology/metabolism ; Point Mutation ; Superoxide Dismutase-1/*genetics/metabolism ; Umbilical Cord/cytology/metabolism/*transplantation/ultrastructure ; }, abstract = {Stem cell therapy is considered a promising approach in the treatment of amyotrophic lateral sclerosis (ALS) and mesenchymal stem cells (MSCs) seem to be the most effective in ALS animal models. The umbilical cord (UC) is a source of highly proliferating fetal MSCs, more easily collectable than other MSCs. Recently we demonstrated that human (h) UC-MSCs, double labeled with fluorescent nanoparticles and Hoechst-33258 and transplanted intracerebroventricularly (ICV) into SOD1G93A transgenic mice, partially migrated into the spinal cord after a single injection. This prompted us to assess the effect of repeated ICV injections of hUC-MSCs on disease progression in SOD1G93A mice. Although no transplanted cells migrated to the spinal cord, a partial but significant protection of motor neurons (MNs) was found in the lumbar spinal cord of hUC-MSCs-treated SOD1G93A mice, accompanied by a shift from a pro-inflammatory (IL-6, IL-1β) to anti-inflammatory (IL-4, IL-10) and neuroprotective (IGF-1) environment in the lumbar spinal cord, probably linked to the activation of p-Akt survival pathway in both motor neurons and reactive astrocytes. However, this treatment neither prevented the muscle denervation nor delayed the disease progression of mice, emphasizing the growing evidence that protecting the motor neuron perikarya is not sufficient to delay the ALS progression.}, }
@article {pmid29153328, year = {2017}, author = {Berson, A and Sartoris, A and Nativio, R and Van Deerlin, V and Toledo, JB and Porta, S and Liu, S and Chung, CY and Garcia, BA and Lee, VM and Trojanowski, JQ and Johnson, FB and Berger, SL and Bonini, NM}, title = {TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling.}, journal = {Current biology : CB}, volume = {27}, number = {23}, pages = {3579-3590.e6}, pmid = {29153328}, issn = {1879-0445}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; P01 AG017586/AG/NIA NIH HHS/United States ; R01 NS078283/NS/NINDS NIH HHS/United States ; P01 CA196539/CA/NCI NIH HHS/United States ; P01 AG031862/AG/NIA NIH HHS/United States ; P30 ES013508/ES/NIEHS NIH HHS/United States ; R01 GM110174/GM/NIGMS NIH HHS/United States ; R35 NS097275/NS/NINDS NIH HHS/United States ; F32 NS084667/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/physiopathology ; Animals ; *Chromatin Assembly and Disassembly ; DNA-Binding Proteins/*genetics/metabolism ; Disease Models, Animal ; Drosophila Proteins/*genetics/metabolism ; Drosophila melanogaster/*genetics/metabolism ; Frontotemporal Dementia/*genetics/metabolism/physiopathology ; HEK293 Cells ; Heat-Shock Proteins/metabolism ; Humans ; Male ; Middle Aged ; }, abstract = {Regulation of chromatin structure is critical for brain development and function. However, the involvement of chromatin dynamics in neurodegeneration is less well understood. Here we find, launching from Drosophila models of amyotrophic lateral sclerosis and frontotemporal dementia, that TDP-43 impairs the induction of multiple key stress genes required to protect from disease by reducing the recruitment of the chromatin remodeler Chd1 to chromatin. Chd1 depletion robustly enhances TDP-43-mediated neurodegeneration and promotes the formation of stress granules. Conversely, upregulation of Chd1 restores nucleosomal dynamics, promotes normal induction of protective stress genes, and rescues stress sensitivity of TDP-43-expressing animals. TDP-43-mediated impairments are conserved in mammalian cells, and, importantly, the human ortholog CHD2 physically interacts with TDP-43 and is strikingly reduced in level in temporal cortex of human patient tissue. These findings indicate that TDP-43-mediated neurodegeneration causes impaired chromatin dynamics that prevents appropriate expression of protective genes through compromised function of the chromatin remodeler Chd1/CHD2. Enhancing chromatin dynamics may be a treatment approach to amyotrophic lateral scleorosis (ALS)/frontotemporal dementia (FTD).}, }
@article {pmid29150766, year = {2018}, author = {Squires, A and Oshinski, JN and Boulis, NM and Tse, ZTH}, title = {SpinoBot: An MRI-Guided Needle Positioning System for Spinal Cellular Therapeutics.}, journal = {Annals of biomedical engineering}, volume = {46}, number = {3}, pages = {475-487}, pmid = {29150766}, issn = {1573-9686}, support = {1617340 (I-Corps Team Grant)//National Science Foundation/ ; Center for Interventional Oncology Grant/NH/NIH HHS/United States ; Inter-Institutional Seed Funding//AU/UGA Medical Partnership/ ; UL1 TR000454/TR/NCATS NIH HHS/United States ; Bench-to-Bedside Award/NH/NIH HHS/United States ; UL1 TR002378/TR/NCATS NIH HHS/United States ; Dr. Richard J. Schlesinger Grant//American Society for Quality/ ; UL1TR000454 (PHS Grant)/TR/NCATS NIH HHS/United States ; 1359095 (REU site program)//National Science Foundation/ ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnostic imaging/therapy ; Animals ; Humans ; *Imaging, Three-Dimensional ; *Injections, Spinal/instrumentation/methods ; *Magnetic Resonance Imaging ; *Needles ; *Robotic Surgical Procedures/instrumentation/methods ; Swine ; }, abstract = {The neurodegenerative disease amyotrophic lateral sclerosis (ALS) results in the death of motor neurons in voluntary muscles. There are no cures for ALS and few available treatments. In studies with small animal models, injection of cellular therapeutics into the anterior horn of the spinal cord has been shown to inhibit the progression of ALS. It was hypothesized that spinal injection could be made faster and less invasive with the aid of a robot. The robotic system presented-SpinoBot-uses MRI guidance to position a needle for percutaneous injection into the spinal cord. With four degrees of freedom (DOF) provided by two translation stages and two rotational axes, SpinoBot proved capable of advanced targeting with a mean error of 1.12 mm and standard deviation of 0.97 mm in bench tests, and a mean error of 2.2 mm and standard deviation of 0.85 mm in swine cadaver tests. SpinoBot has shown less than 3% signal-to-noise ratio reduction in 3T MR imaging quality, demonstrating its compliance to the MRI environment. With the aid of SpinoBot, the length of the percutaneous injection procedure is reduced to less than 60 min with 10 min for each additional insertion. Although SpinoBot is designed for ALS treatment, it could potentially be used for other procedures that require precise access to the spine.}, }
@article {pmid29149916, year = {2017}, author = {Gratten, J and Zhao, Q and Benyamin, B and Garton, F and He, J and Leo, PJ and Mangelsdorf, M and Anderson, L and Zhang, ZH and Chen, L and Chen, XD and Cremin, K and Deng, HW and Edson, J and Han, YY and Harris, J and Henders, AK and Jin, ZB and Li, Z and Lin, Y and Liu, X and Marshall, M and Mowry, BJ and Ran, S and Reutens, DC and Song, S and Tan, LJ and Tang, L and Wallace, RH and Wheeler, L and Wu, J and Yang, J and Xu, H and Visscher, PM and Bartlett, PF and Brown, MA and Wray, NR and Fan, D}, title = {Whole-exome sequencing in amyotrophic lateral sclerosis suggests NEK1 is a risk gene in Chinese.}, journal = {Genome medicine}, volume = {9}, number = {1}, pages = {97}, pmid = {29149916}, issn = {1756-994X}, support = {81522014//National Natural Science Foundation of China/ ; R01 AR069055/AR/NIAMS NIH HHS/United States ; 1127440//National Health and Medical Research Council/ ; Linkage Grant//Australian Research Council/ ; Ross Maclean Senior Research Fellowship//Motor Neurone Disease Research Institute of Australia/ ; 81601105//National Natural Science Foundation of China/ ; U19 AG055373/AG/NIA NIH HHS/United States ; Ross Maclean Senior Research Fellowships//Motor Neurone Disease Research Institute of Australia/ ; 1103418//National Health and Medical Research Council/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Asian People/genetics ; Genetic Predisposition to Disease ; Humans ; NIMA-Related Kinase 1/*genetics ; Risk ; Exome Sequencing ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement. There remains limited understanding of disease aetiology, with median survival of ALS of three years and no effective treatment. Identifying genes that contribute to ALS susceptibility is an important step towards understanding aetiology. The vast majority of published human genetic studies, including for ALS, have used samples of European ancestry. The importance of trans-ethnic studies in human genetic studies is widely recognised, yet a dearth of studies of non-European ancestries remains. Here, we report analyses of novel whole-exome sequencing (WES) data from Chinese ALS and control individuals.<br><br>METHODS: WES data were generated for 610 ALS cases and 460 controls drawn from Chinese populations. We assessed evidence for an excess of rare damaging mutations at the gene level and the gene set level, considering only singleton variants filtered to have allele frequency less than 5&#x2009;&#xd7;&#x2009;10[-5] in reference databases. To meta-analyse our results with a published study of European ancestry, we used a Cochran-Mantel-Haenszel test to compare gene-level variant counts in cases vs controls.<br><br>RESULTS: No gene passed the genome-wide significance threshold with ALS in Chinese samples alone. Combining rare variant counts in Chinese with those from the largest WES study of European ancestry resulted in three genes surpassing genome-wide significance: TBK1 (p&#x2009;=&#x2009;8.3&#x2009;&#xd7;&#x2009;10[-12]), SOD1 (p&#x2009;=&#x2009;8.9&#x2009;&#xd7;&#x2009;10[-9]) and NEK1 (p&#x2009;=&#x2009;1.1&#x2009;&#xd7;&#x2009;10[-9]). In the Chinese data alone, SOD1 and NEK1 were nominally significantly associated with ALS (p&#x2009;=&#x2009;0.04 and p&#x2009;=&#x2009;7&#x2009;&#xd7;&#x2009;10[-3], respectively) and the case/control frequencies of rare coding variants in these genes were similar in Chinese and Europeans (SOD1: 1.5%/0.2% vs 0.9%/0.1%, NEK1 1.8%/0.4% vs 1.9%/0.8%). This was also true for TBK1 (1.2%/0.2% vs 1.4%/0.4%), but the association with ALS in Chinese was not significant (p&#x2009;=&#x2009;0.14).<br><br>CONCLUSIONS: While SOD1 is already recognised as an ALS-associated gene in Chinese, we provide novel evidence for association of NEK1 with ALS in Chinese, reporting variants in these genes not previously found in Europeans.}, }
@article {pmid29149058, year = {2017}, author = {Bianchi, VE and Locatelli, V and Rizzi, L}, title = {Neurotrophic and Neuroregenerative Effects of GH/IGF1.}, journal = {International journal of molecular sciences}, volume = {18}, number = {11}, pages = {}, pmid = {29149058}, issn = {1422-0067}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Brain Injuries/*therapy ; Drug Evaluation ; Growth Hormone/*therapeutic use ; Humans ; Insulin-Like Growth Factor I/*therapeutic use ; Male ; Mice ; Middle Aged ; Models, Animal ; Neurons/metabolism ; Neuroprotective Agents/*therapeutic use ; Rats ; Treatment Outcome ; }, abstract = {INTRODUCTION: Human neurodegenerative diseases increase progressively with age and present a high social and economic burden. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are both growth factors exerting trophic effects on neuronal regeneration in the central nervous system (CNS) and peripheral nervous system (PNS). GH and IGF-1 stimulate protein synthesis in neurons, glia, oligodendrocytes, and Schwann cells, and favor neuronal survival, inhibiting apoptosis. This study aims to evaluate the effect of GH and IGF-1 on neurons, and their possible therapeutic clinical applications on neuron regeneration in human subjects.<br><br>METHODS: In the literature, we searched the clinical trials and followed up studies in humans, which have evaluated the effect of GH/IGF-1 on CNS and PNS. The following keywords have been used: "GH/IGF-1" associated with "neuroregeneration", "amyotrophic lateral sclerosis", "Alzheimer disease", "Parkinson's disease", "brain", and "neuron".<br><br>RESULTS: Of the retrieved articles, we found nine articles about the effect of GH in healthy patients who suffered from traumatic brain injury (TBI), and six studies (four using IGF-1 and two GH therapy) in patients with amyotrophic lateral sclerosis (ALS). The administration of GH in patients after TBI showed a significantly positive recovery of brain and mental function. Treatment with GH and IGF-1 therapy in ALS produced contradictory results.<br><br>CONCLUSIONS: Although strong findings have shown the positive effects of GH/IGF-1 administration on neuroregeneration in animal models, a very limited number of clinical studies have been conducted in humans. GH/IGF-1 therapy had different effects in patients with TBI, evidencing a high recovery of neurons and clinical outcome, while in ALS patients, the results are contradictory. More complex clinical protocols are necessary to evaluate the effect of GH/IGF-1 efficacy in neurodegenerative diseases. It seems evident that GH and IGF-1 therapy favors the optimal recovery of neurons when a consistent residual activity is still present. Furthermore, the effect of GH/IGF-1 could be mediated by, or be overlapped with that of other hormones, such as estradiol and testosterone.}, }
@article {pmid29143574, year = {2018}, author = {Sohail, A and Bhat, WF and Bhat, SA and Furkan, M and Shah, A and Bano, B}, title = {Investigating the preventive effects of baicalin and gallocatechin against glyoxal-induced cystatin aggregation.}, journal = {Journal of biomolecular structure &amp; dynamics}, volume = {36}, number = {14}, pages = {3791-3802}, doi = {10.1080/07391102.2017.1400470}, pmid = {29143574}, issn = {1538-0254}, mesh = {Animals ; Catechin/*analogs &amp; derivatives/chemistry/pharmacology ; Cattle ; Cystatins/*chemistry/metabolism ; Flavonoids/*chemistry/pharmacology ; Glyoxal/*chemistry ; Molecular Structure ; Protein Aggregates/drug effects ; Protein Binding/drug effects ; Spectrum Analysis ; Structure-Activity Relationship ; }, abstract = {Several mammalian proteins form pathological deposits under nonphysiological conditions that are associated with many degenerative diseases. Protein aggregation is associated with aging, as well as a variety of diseases, including cystic fibrosis, amyotrophic lateral sclerosis (ALS), and hypertrophic cardiomyopathy. There is a lack of any potential anti-amyloidogenic agents and therapeutics till date. Polyphenols have been accredited with myriad biological effects. An analysis of the effects of natural agents like baicalin (BC) and gallocatechin (GC) on aggregation process can open new avenues for the treatment of protein misfolding diseases. Thus, investigation of the effects of these flavonoids on Buffalo Heart Cystatin (BHC) aggregation induced by a reactive metabolic dialdehyde, glyoxal (GO), was taken up. Results have shown that elevated concentration of GO forms aggregates of BHC, which was characterized by an increase in the ANS fluorescence intensity, an increase in ThT fluorescence intensity, red shift in Congo red absorbance, negative ellipticity peak at 217 nm in the far-UVCD and BHC aggregates displaying by TEM. Using fluorescence spectroscopic analysis with Thioflavin T, CD and electron microscopic studies, anti-aggregation effects of polyphenols, BC and GC were analyzed. The study showed that BC and GC produced concentration-dependent anti-aggregation effects with GC producing a more pronounced effect than BC. The study proposed a mechanistic approach assuming structural constraints and specific aromatic interactions of polyphenols with sheets of BHC aggregates.}, }
@article {pmid29137922, year = {2018}, author = {Croese, T and Furlan, R}, title = {Extracellular vesicles in neurodegenerative diseases.}, journal = {Molecular aspects of medicine}, volume = {60}, number = {}, pages = {52-61}, doi = {10.1016/j.mam.2017.11.006}, pmid = {29137922}, issn = {1872-9452}, mesh = {Animals ; Biomarkers ; Disease Progression ; Extracellular Vesicles/*metabolism ; Humans ; Neurodegenerative Diseases/*diagnosis/genetics/*metabolism/physiopathology ; }, abstract = {Extracellular vesicles (EVs) are released by all neural cells, including neurons, oligodendrocytes, astrocytes, and microglia. The lack of adequate technology has not halted neuroscientists from investigating EVs as a mean to decipher neurodegenerative disorders, still in search of comprehensible pathogenic mechanisms and efficient treatment. EVs are thought to be one of ways neurodegenerative pathologies spread in the brain, but also one of the ways the brain tries to displace toxic proteins, making their meaning in pathogenesis uncertain. EVs, however do reach biological fluids where they can be analyzed, and might therefore constitute clinically decisive biomarkers for neurodegenerative diseases in the future. Finally, if they constitute a physiological inter-cell communication system, they may represent also a very specific drug delivery tool for a difficult target such as the brain. We try to resume here available information on the role of EVs in neurodegeneration, with a special focus on Alzheimer's disease, progressive multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease.}, }
@article {pmid29132389, year = {2017}, author = {Ciervo, Y and Ning, K and Jun, X and Shaw, PJ and Mead, RJ}, title = {Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {12}, number = {1}, pages = {85}, pmid = {29132389}, issn = {1750-1326}, support = {MR/K008943/1/MRC_/Medical Research Council/United Kingdom ; MR/M010864/1/MRC_/Medical Research Council/United Kingdom ; SITRAN/APR13/983-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; 983-797//MND Association/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Humans ; Stem Cell Transplantation/*methods/*trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition where loss of motor neurons within the brain and spinal cord leads to muscle atrophy, weakness, paralysis and ultimately death within 3-5 years from onset of symptoms. The specific molecular mechanisms underlying the disease pathology are not fully understood and neuroprotective treatment options are minimally effective. In recent years, stem cell transplantation as a new therapy for ALS patients has been extensively investigated, becoming an intense and debated field of study. In several preclinical studies using the SOD1[G93A] mouse model of ALS, stem cells were demonstrated to be neuroprotective, effectively delayed disease onset and extended survival. Despite substantial improvements in stem cell technology and promising results in preclinical studies, several questions still remain unanswered, such as the identification of the most suitable and beneficial cell source, cell dose, route of delivery and therapeutic mechanisms. This review will cover publications in this field and comprehensively discuss advances, challenges and future direction regarding the therapeutic potential of stem cells in ALS, with a focus on mesenchymal stem cells. In summary, given their high proliferation activity, immunomodulation, multi-differentiation potential, and the capacity to secrete neuroprotective factors, adult mesenchymal stem cells represent a promising candidate for clinical translation. However, technical hurdles such as optimal dose, differentiation state, route of administration, and the underlying potential therapeutic mechanisms still need to be assessed.}, }
@article {pmid29125503, year = {2017}, author = {Landfeldt, E and Edström, J and Lindgren, P and Lochmüller, H}, title = {Patient Preferences for Treatments of Neuromuscular Diseases: A Systematic Literature Review.}, journal = {Journal of neuromuscular diseases}, volume = {4}, number = {4}, pages = {285-292}, doi = {10.3233/JND-170271}, pmid = {29125503}, issn = {2214-3599}, mesh = {Humans ; Neuromuscular Diseases/*psychology/*therapy ; *Patient Preference ; }, abstract = {BACKGROUND: Treatment decisions of neuromuscular diseases involve weighing clinical benefits and risks, as well as impact on patient social life, work status, other activities of daily living, and health-related quality of life.<br><br>OBJECTIVE: To conduct a systemic literature review of patient preferences for treatments of neuromuscular diseases.<br><br>METHODS: We searched Embase, Web of Science, and PubMed for full-text articles reporting results from studies of patient preferences for treatments of neuromuscular diseases. We excluded articles published before the year 2000, articles written in a language other than English, articles only reporting proxy-assessments of patient preferences, and studies reporting results for a sample comprising&#x200a;<5 patients.<br><br>RESULTS: The search resulted in the identification of 305 unique publications. Of these, 275 were excluded following title and abstract screening and 23 following full-text review. Seven articles were included for data synthesis. Preference data were identified for a hypothetical treatment with pulmonary benefits of Duchenne muscular dystrophy and Becker muscular dystrophy, pathways for different routes of opioid drug administration in motor neuron disease, wheelchair features in amyotrophic lateral sclerosis (ALS), ankle foot orthoses in patients with Charcot Marie Tooth disease, and mechanical ventilation in ALS and a mixed cohort of patients with neuromuscular diseases.<br><br>CONCLUSIONS: Despite considerable research into the development of new health technologies targeting neuromuscular diseases, little is known of patients' preferences for pharmacological interventions. More research is needed to help incorporate patient preferences in clinical decision-making to improve treatment satisfaction, medication compliance, and health outcomes.}, }
@article {pmid29123086, year = {2017}, author = {Challenger, JD and Bruxvoort, K and Ghani, AC and Okell, LC}, title = {Assessing the impact of imperfect adherence to artemether-lumefantrine on malaria treatment outcomes using within-host modelling.}, journal = {Nature communications}, volume = {8}, number = {1}, pages = {1373}, pmid = {29123086}, issn = {2041-1723}, support = {//Medical Research Council/United Kingdom ; }, mesh = {Antimalarials/pharmacokinetics/*therapeutic use ; Artemether, Lumefantrine Drug Combination ; Artemisinins/pharmacokinetics/*therapeutic use ; Drug Combinations ; Ethanolamines/pharmacokinetics/*therapeutic use ; Fluorenes/pharmacokinetics/*therapeutic use ; Host-Parasite Interactions/*drug effects ; Humans ; Malaria, Falciparum/*drug therapy ; Models, Biological ; *Patient Compliance ; Tanzania ; Treatment Outcome ; }, abstract = {Artemether-lumefantrine (AL) is the most widely-recommended treatment for uncomplicated Plasmodium falciparum malaria worldwide. Its safety and efficacy have been extensively demonstrated in clinical trials; however, its performance in routine health care settings, where adherence to drug treatment is unsupervised and therefore may be suboptimal, is less well characterised. Here we develop a within-host modelling framework for estimating the effects of sub-optimal adherence to AL treatment on clinical outcomes in malaria patients. Our model incorporates the data on the human immune response to the parasite, and AL's pharmacokinetic and pharmacodynamic properties. Utilising individual-level data of adherence to AL in 482 Tanzanian patients as input for our model predicted higher rates of treatment failure than were obtained when adherence was optimal (9% compared to 4%). Our model estimates that the impact of imperfect adherence was worst in children, highlighting the importance of advice to caregivers.}, }
@article {pmid29115515, year = {2018}, author = {Kume, K and Iwama, H and Deguchi, K and Ikeda, K and Takata, T and Kokudo, Y and Kamada, M and Fujikawa, K and Hirose, K and Masugata, H and Touge, T and Masaki, T}, title = {Serum microRNA expression profiling in patients with multiple system atrophy.}, journal = {Molecular medicine reports}, volume = {17}, number = {1}, pages = {852-860}, pmid = {29115515}, issn = {1791-3004}, mesh = {Aged ; Biomarkers ; Case-Control Studies ; *Circulating MicroRNA ; Cluster Analysis ; Computational Biology/methods ; Female ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Male ; MicroRNAs/*genetics ; Middle Aged ; Multiple System Atrophy/*blood/*genetics ; }, abstract = {Multiple system atrophy (MSA) is a sporadic neurodegenerative disease that is pathologically characterized by α‑synuclein positive glial cytoplasmic inclusions in oligodendrocytes. The clinical diagnosis of MSA is often challenging as there are no established biomarkers and diagnoses are now based on clinical findings alone. At present, the etiology and pathogenesis of MSA are unclear. It has been reported that dysregulation of microRNA (miRNA/miR) serves an important role in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The miRNA profile of patients with MSA remains to be established. The present study investigated the serum miRNA expression level of 10 patients with MSA, using microarray chips including 668 miRNAs. It was identified that 50 miRNAs were significantly upregulated and 17 miRNAs were significantly downregulated in the serum of the patients with MSA. The most upregulated miRNA was miR‑16, which may induce the accumulation of α‑synuclein. The target genes of some miRNAs upregulated in MSA (including miR‑17, 20a, 24, 25, 30d and 451) were associated with autophagy‑associated molecules. The present study concluded that the expression pattern of miRNAs may be a clinical biomarker for MSA and targeting these miRNAs may provide a novel treatment for MSA.}, }
@article {pmid29114200, year = {2017}, author = {Forostyak, S and Sykova, E}, title = {Neuroprotective Potential of Cell-Based Therapies in ALS: From Bench to Bedside.}, journal = {Frontiers in neuroscience}, volume = {11}, number = {}, pages = {591}, pmid = {29114200}, issn = {1662-4548}, abstract = {Motor neurons (MN) degeneration is a main feature of amyotrophic lateral sclerosis (ALS), a neurological disorder with a progressive course. The diagnosis of ALS is essentially a clinical one. Most common symptoms include a gradual neurological deterioration that reflect the impairment and subsequent loss of muscle functions. Up-to-date ALS has no therapy that would prevent or cure a disease. Modern therapeutic strategies comprise of neuroprotective treatment focused on antiglutamatergic, antioxidant, antiapoptotic, and anti-inflammatory molecules. Stem cells application and gene therapy has provided researchers with a powerful tool for discovery of new mechanisms and therapeutic agents, as well as opened new perspectives for patients and family members. Here, we review latest progress made in basic, translational and clinical stem cell research related to the ALS. We overviewed results of preclinical and clinical studies employing cell-based therapy to treat neurodegenerative disorders. A special focus has been made on the neuroprotective properties of adult mesenchymal stromal cells (MSC) application into ALS patients. Finally, we overviewed latest progress in the field of embryonic and induced pluripotent stem cells used for the modeling and application during neurodegeneration in general and in ALS in particular.}, }
@article {pmid29109704, year = {2017}, author = {Darton, TC and Jones, C and Dongol, S and Voysey, M and Blohmke, CJ and Shrestha, R and Karkey, A and Shakya, M and Arjyal, A and Waddington, CS and Gibani, M and Carter, MJ and Basnyat, B and Baker, S and Pollard, AJ}, title = {Assessment and Translation of the Antibody-in-Lymphocyte Supernatant (ALS) Assay to Improve the Diagnosis of Enteric Fever in Two Controlled Human Infection Models and an Endemic Area of Nepal.}, journal = {Frontiers in microbiology}, volume = {8}, number = {}, pages = {2031}, pmid = {29109704}, issn = {1664-302X}, support = {092661/WT_/Wellcome Trust/United Kingdom ; }, abstract = {New diagnostic tests for enteric fever are urgently needed to assist with timely antimicrobial treatment of patients and to measure the efficacy of prevention measures such as vaccination. In a novel translational approach, here we use two recently developed controlled human infection models (CHIM) of enteric fever to evaluate an antibody-in-lymphocyte supernatant (ALS) assay, which can detect recent IgA antibody production by circulating B cells in ex vivo mononuclear cell culture. We calculated the discriminative ability of the ALS assay to distinguish diagnosed cases in the two CHIM studies in Oxford, prior to evaluating blood culture-confirmed diagnoses of patients presenting with fever to hospital in an endemic areas of Kathmandu, Nepal. Antibody responses to membrane preparations and lipopolysaccharide provided good sensitivity (>90%) for diagnosing systemic infection after oral challenge with Salmonella Typhi or S. Paratyphi A. Assay specificity was moderate (~60%) due to imperfect sensitivity of blood culture as the reference standard and likely unrecognized subclinical infection. These findings were augmented through the translation of the assay into the endemic setting in Nepal. Anti-MP IgA responses again exhibited good sensitivity (86%) but poor specificity (51%) for detecting blood culture-confirmed enteric fever cases (ROC AUC 0.79, 95%CI 0.70-0.88). Patients with anti-MP IgA ALS titers in the upper quartile exhibited a clinical syndrome synonymous with enteric fever. While better reference standards are need to assess enteric fever diagnostics, routine use of this ALS assay could be used to rule out infection and has the potential to double the laboratory detection rate of enteric fever in this setting over blood culture alone.}, }
@article {pmid29107252, year = {2017}, author = {Ntoanidou, S and Madesis, P and Diamantidis, G and Eleftherohorinos, I}, title = {Trp574 substitution in the acetolactate synthase of Sinapis arvensis confers cross-resistance to tribenuron and imazamox.}, journal = {Pesticide biochemistry and physiology}, volume = {142}, number = {}, pages = {9-14}, doi = {10.1016/j.pestbp.2016.12.008}, pmid = {29107252}, issn = {1095-9939}, mesh = {Acetolactate Synthase/*genetics/metabolism ; Amino Acid Substitution ; Arylsulfonates/*pharmacology ; *Herbicide Resistance ; Herbicides/*pharmacology ; Imidazoles/*pharmacology ; Mutation, Missense ; Plant Proteins/*genetics/metabolism ; Sinapis/drug effects/*enzymology/genetics ; Tryptophan/chemistry/*genetics/metabolism ; }, abstract = {Rate-response experiments with nine putative resistant wild mustard (Sinapis arvensis) populations from Greece showed cross-resistance to tribenuron and imazamox. The calculated GR50 values [herbicide rate (gaiha[-1]) required for 50% reduction of fresh weight] of the nine resistant (R) populations ranged from 51.8 to 555.6gaitribenuronha[-1] and from 66.3 to 900.4gaiimazamoxha[-1]. Regarding the susceptible population, GR50 value was not estimated for tribenuron as its lower treatment reduced fresh weight by >95%, whereas the respective value for imazamox was 0.5gaiha[-1]. Gene sequencing of als revealed that a point mutation at Trp574 position, leading to amino acid substitution by Leu in the ALS enzyme was present and the likely cause of resistance. The in vitro activity of the ALS enzyme indicated I50 values (herbicide concentration required for 50% reduction of the ALS activity) ranging from 19.11 to 217.45μM for tribenuron, whereas the respective value for the S population was 1.17μM. All populations were susceptible to MCPA at the recommended rate. These results strongly support that cross-resistance of 9 S. arvensis populations was due a point mutation of the als gene, which resulted in a less sensitive ALS enzyme.}, }
@article {pmid29096137, year = {2017}, author = {Di Lazzaro, V and Mazzone, P and Insola, A and Florio, L and Capone, F and Ranieri, F}, title = {Spinal cord stimulation for pain treatment failed to modify disease progression in a patient with amyotrophic lateral sclerosis.}, journal = {Clinical neurology and neurosurgery}, volume = {163}, number = {}, pages = {108-109}, doi = {10.1016/j.clineuro.2017.10.010}, pmid = {29096137}, issn = {1872-6968}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/diagnosis/*therapy ; Disease Progression ; Humans ; Male ; Motor Neurons/physiology ; Pain/*surgery ; *Pain Management ; Spinal Cord/*surgery ; *Spinal Cord Stimulation/methods ; }, }
@article {pmid29095723, year = {2017}, author = {Brendish, NJ and Clark, TW}, title = {Antiviral treatment of severe non-influenza respiratory virus infection.}, journal = {Current opinion in infectious diseases}, volume = {30}, number = {6}, pages = {573-578}, doi = {10.1097/QCO.0000000000000410}, pmid = {29095723}, issn = {1473-6527}, support = {PDF-2016-09-061/DH_/Department of Health/United Kingdom ; }, mesh = {Adult ; Aged ; Antiviral Agents/*therapeutic use ; Child ; Hospitalization ; Humans ; Infant ; *Respiratory Tract Infections/drug therapy/virology ; *Virus Diseases/drug therapy/virology ; *Viruses ; }, abstract = {PURPOSE OF REVIEW: Non-influenza respiratory virus infections are a frequent cause of severe acute respiratory infections, especially in infants, the elderly, and the immunocompromised. We review here the current treatment options for non-influenza respiratory viruses and promising candidate antiviral agents currently in development.<br><br>RECENT FINDINGS: Small molecule antiviral agents active against respiratory syncytial virus (RSV), such as ALS-8176 and GS-5806, show considerable promise in challenge studies and are undergoing late-phase clinical trials in hospitalised adults and children. Monoclonal antibodies (mAbs) active against non-influenza respiratory viruses are broadly at a preclinical stage. Broad-spectrum antivirals, such as favipiravir and nitrazoxanide, have potential utility in treating illness caused by non-influenza respiratory viruses but further definitive clinical trials are needed.<br><br>SUMMARY: Severe non-influenza respiratory virus infection is common and current treatment is largely supportive. Ribavirin is used in immunocompromised patients but its use is limited by toxicity and the evidence for its efficacy is weak. Effective antiviral treatment for RSV may shortly become available, pending the results of ongoing clinical trials. For other non-influenza viruses, effective treatments may become available in the medium term. Early detection of respiratory viruses with rapid molecular test platforms will be crucial in differentiating virus types and directing the prompt initiation of novel treatments when available.}, }
@article {pmid29090256, year = {2017}, author = {You, TM and Kim, S}, title = {Pulseless electrical activity during general anesthesia induction in patients with amyotrophic lateral sclerosis.}, journal = {Journal of dental anesthesia and pain medicine}, volume = {17}, number = {3}, pages = {235-240}, pmid = {29090256}, issn = {2383-9309}, abstract = {Pulseless electrical activity (PEA) is a clinical condition characterized by unresponsiveness and lack of palpable pulse in the presence of organized cardiac electrical activity and is caused by a profound cardiovascular insult (e.g., severe prolonged hypoxia or acidosis, extreme hypovolemia, or flow-restricting pulmonary embolus). Amyotrophic lateral sclerosis (ALS) is a disease that is characterized by progressive degeneration of all levels of the motor nervous system. Damage to the respiratory system and weakness of the muscles may increase the likelihood of an emergency situation occurring in patients with ALS while under general anesthesia. We report a case of PEA during the induction of general anesthesia in a patient with ALS who presented for dental treatment and discuss the causes of PEA and necessary considerations for general anesthesia in patients with ALS.}, }
@article {pmid29085236, year = {2017}, author = {Zamani, M and Rahbar, A and Shokri-Shirvani, J}, title = {Resistance of Helicobacter pylori to furazolidone and levofloxacin: A viewpoint.}, journal = {World journal of gastroenterology}, volume = {23}, number = {37}, pages = {6920-6922}, pmid = {29085236}, issn = {2219-2840}, mesh = {Asia ; Drug Resistance, Bacterial/genetics ; Europe ; *Furazolidone ; Helicobacter Infections ; Helicobacter pylori/genetics ; *Levofloxacin ; Microbial Sensitivity Tests ; }, abstract = {In their review, Arslan et al[[1]] did not describe the status of Helicobacter pylori (H. pylori) treatment with furazolidone and the resistance to this antibiotic. We have presented different surveys showing the resistance of H. pylori to furazolidone from Asia and South America. The resistance rates varied but were mostly low (< 5%). There are not enough data on its efficacy and resistance in the United States and Europe. H. pylori mutations occurring in the oorD gene, including A041G, A122G, C349A(G), A78G, A112G, A335G, C156T and C165T, and in the porD gene, including G353A, A356G, C357T, C347T, C347G and C346A, have been indicated to be possibly related to the observed resistance. Additionally, to complete Arslan et al's statement regarding levofloxacin resistance, it should be noted that compound mutations of N87A, A88N and V65I at codon Asn-87 were recently observed in the gyrA gene for the first time. However, the results on these topics are not sufficient, and more worldwide studies are suggested.}, }
@article {pmid29084868, year = {2018}, author = {van Eijk, RPA and Eijkemans, MJC and Ferguson, TA and Nikolakopoulos, S and Veldink, JH and van den Berg, LH}, title = {Monitoring disease progression with plasma creatinine in amyotrophic lateral sclerosis clinical trials.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {89}, number = {2}, pages = {156-161}, pmid = {29084868}, issn = {1468-330X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*blood/mortality/physiopathology ; Clinical Trials as Topic ; Creatinine/*blood ; Disease Progression ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; *Muscle Strength ; Survival Rate ; }, abstract = {OBJECTIVES: Plasma creatinine is a predictor of survival in amyotrophic lateral sclerosis (ALS). It remains, however, to be established whether it can monitor disease progression and serve as surrogate endpoint in clinical trials.<br><br>METHODS: We used clinical trial data from three cohorts of clinical trial participants in the LITRA, EMPOWER and PROACT studies. Longitudinal associations between functional decline, muscle strength and survival with plasma creatinine were assessed. Results were translated to trial design in terms of sample size and power.<br><br>RESULTS: A total of 13&#x2009;564 measurements were obtained for 1241 patients. The variability between patients in rate of decline was lower in plasma creatinine than in ALS functional rating scale-Revised (ALSFRS-R; p<0.001). The average rate of decline was faster in the ALSFRS-R, with less between-patient variability at baseline (p<0.001). Plasma creatinine had strong longitudinal correlations with the ALSFRS-R (0.43 (0.39-0.46), p<0.001), muscle strength (0.55 (0.51-0.58), p<0.001) and overall mortality (HR 0.88 (0.86-0.91, p<0.001)). Using plasma creatinine as outcome could reduce the sample size in trials by 21.5% at 18 months. For trials up to 10 months, the ALSFRS-R required a lower sample size.<br><br>CONCLUSIONS: Plasma creatinine is an inexpensive and easily accessible biomarker that exhibits less variability between patients with ALS over time and is predictive for the patient's functional status, muscle strength and mortality risk. Plasma creatinine may, therefore, increase the power to detect treatment effects and could be incorporated in future ALS clinical trials as potential surrogate outcome.}, }
@article {pmid29081603, year = {2017}, author = {Morello, G and Spampinato, AG and Cavallaro, S}, title = {Neuroinflammation and ALS: Transcriptomic Insights into Molecular Disease Mechanisms and Therapeutic Targets.}, journal = {Mediators of inflammation}, volume = {2017}, number = {}, pages = {7070469}, pmid = {29081603}, issn = {1466-1861}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Female ; Gene Expression Profiling/*methods ; Humans ; Male ; Motor Neurons/metabolism ; Transcriptome/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor nervous system. Despite the mechanism underlying motor neuron death is not yet clarified, multiple pathogenic processes have been proposed to account for ALS. Among these, inflammatory/immune responses have recently gained particular interest, although there are conflicting reports on the role of these processes in ALS pathogenesis and treatment. This apparent discrepancy may be due to the absence of an effective stratification of ALS patients into subgroups with markedly different clinical, biological, and molecular features. Our research group recently described genome-wide characterization of motor cortex samples from sporadic ALS (SALS) patients, revealing the existence of molecular and functional heterogeneity in SALS. Here, we reexamine data coming from our previous work, focusing on transcriptomic changes of inflammatory-related genes, in order to investigate their potential contribution in ALS. A total of 1573 inflammatory genes were identified as differentially expressed between SALS patients and controls, characterizing distinct topological pathways and networks, suggestive of specific inflammatory molecular signatures for different patient subgroups. Besides providing promising insights into the intricate relationship between inflammation and ALS, this paper represents a starting point for the rationale design and development of novel and more effective diagnostic and therapeutic applications.}, }
@article {pmid29078263, year = {2017}, author = {Zhu, J and Shen, L and Lin, X and Hong, Y and Feng, Y}, title = {Clinical Research on Traditional Chinese Medicine compounds and their preparations for Amyotrophic Lateral Sclerosis.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {96}, number = {}, pages = {854-864}, doi = {10.1016/j.biopha.2017.09.135}, pmid = {29078263}, issn = {1950-6007}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Drugs, Chinese Herbal/*pharmacology/*therapeutic use ; Humans ; Medicine, Chinese Traditional/methods ; Phytotherapy/methods ; Plant Extracts/*therapeutic use ; Plants, Medicinal/chemistry ; Riluzole/pharmacology/therapeutic use ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a chronic, fatal neurodegenerative disease which leads to progressive muscle atrophy and paralysis. In order to summarize the characteristics of Traditional Chinese Medicine compounds and their preparations in the prevention and treatment of ALS through analyzing the mechanism, action site, and symptoms according to effective clinical research.<br><br>METHODS: We searched ALS, motor neuron disease, chemical drugs, herbal medicine, Chinese medicine, Traditional Chinese Medicine (TCM), and various combinations of these terms in databases including the PudMed, Springer, Ovid, Google, China National Knowledge Infrastructure, and Wanfang databases.<br><br>RESULT: It was found that the chemical drugs almost had not sufficient evidence to show their effectiveness in the treatment of ALS, except RILUZOLE. According to the characteristics of clinical symptoms of ALS, Chinese medicine practitioners believe that this disease belongs to the category of "atrophic disease". In clinical research, many Chinese herbal formulas had good clinical efficacies in the treatment of ALS with multiple targets, multiple links, and few side effects. And four kinds of dialectical treatment had been developed based on Clinical data analysis and the use of dialectical therapy: Benefiting the kidney; Declaring the lungs; Enhancing the Qi; and Dredging the meridian.<br><br>CONCLUSION: In this review, we provide an overview of chemical drugs and Traditional Chinese Medicine compound and its preparations in therapy of ALS as well as how they may contribute to the ALS pathogenesis, thereby offering some clues for further studies.}, }
@article {pmid29077801, year = {2017}, author = {Tröster, AI}, title = {Introduction to the Special Issue on Clinical Neuropsychology of Movement Disorders.}, journal = {Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists}, volume = {32}, number = {7}, pages = {767-768}, doi = {10.1093/arclin/acx087}, pmid = {29077801}, issn = {1873-5843}, mesh = {Humans ; Movement Disorders/diagnosis/*psychology/therapy ; Neuropsychological Tests ; }, abstract = {The special issue on the clinical neuropsychology of movement disorders provides an overview for the non-subspecialist clinical neuropsychologist and other clinical neuroscientists of the neuropsychological features, assessment and treatment of Parkinson's disease and Lewy body dementias, atypical parkinsonian disorders (corticobasal syndrome, progressive supranuclear palsy, and multiple system atrophy), Huntington's disease, dystonia, and amyotrophic lateral sclerosis. Additionally, articles provide overviews of neuropsychological and ethical issues related to deep brain stimulation and a discussion of non-pharamcologic and non-invasive treatment of cognitive dysfunction in Parkinson's disease. A search of PubMed using neuropsycholog* and parkinson* as search terms indicates that the number of articles dealing with neuropsychology of parkinsonian disorders has more than doubled in each of the past three decades (1990-99:269 entries, 2000-09:575 entries, 2010-17:967 entries). This rapid growth of research makes a special issue on the topic very timely.}, }
@article {pmid29076800, year = {2018}, author = {Trojsi, F and Sorrentino, P and Sorrentino, G and Tedeschi, G}, title = {Neurodegeneration of brain networks in the amyotrophic lateral sclerosis-frontotemporal lobar degeneration (ALS-FTLD) continuum: evidence from MRI and MEG studies.}, journal = {CNS spectrums}, volume = {23}, number = {6}, pages = {378-387}, doi = {10.1017/S109285291700075X}, pmid = {29076800}, issn = {1092-8529}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnostic imaging/physiopathology ; *Connectome ; Frontotemporal Lobar Degeneration/*diagnostic imaging/etiology/physiopathology ; Humans ; Magnetic Resonance Imaging ; Magnetoencephalography ; }, abstract = {Brain imaging techniques, especially those based on magnetic resonance imaging (MRI) and magnetoencephalography (MEG), have been increasingly applied to study multiple large-scale distributed brain networks in healthy people and neurological patients. With regard to neurodegenerative disorders, amyotrophic lateral sclerosis (ALS), clinically characterized by the predominant loss of motor neurons and progressive weakness of voluntary muscles, and frontotemporal lobar degeneration (FTLD), the second most common early-onset dementia, have been proven to share several clinical, neuropathological, genetic, and neuroimaging features. Specifically, overlapping or mildly diverging brain structural and functional connectivity patterns, mostly evaluated by advanced MRI techniques-such as diffusion tensor and resting-state functional MRI (DT-MRI, RS-fMRI)-have been described comparing several ALS and FTLD populations. Moreover, though only pioneering, promising clues on connectivity patterns in the ALS-FTLD continuum may derive from MEG investigations. We will herein overview the current state of knowledge concerning the most advanced neuroimaging findings associated with clinical and genetic patterns of neurodegeneration across the ALS-FTLD continuum, underlying the possibility that network-based approaches may be useful to develop novel biomarkers of disease for adequately designing and monitoring more appropriate treatment strategies.}, }
@article {pmid29070943, year = {2017}, author = {Almomani, FM and Bani-Issa, W}, title = {The incidence of depression among residents of assisted living: prevalence and related risk factors.}, journal = {Clinical interventions in aging}, volume = {12}, number = {}, pages = {1645-1653}, pmid = {29070943}, issn = {1178-1998}, mesh = {Aged ; Aged, 80 and over ; *Assisted Living Facilities ; Cognition ; Cognition Disorders/*epidemiology ; Depression/*epidemiology ; Depressive Disorder/epidemiology ; Persons with Disabilities/*statistics &amp; numerical data ; Female ; Humans ; Jordan/epidemiology ; Male ; Middle Aged ; Prevalence ; Risk Factors ; }, abstract = {AIM: This study aims to recognize and estimate the prevalence of depression and its risk factors among residents of assisted living facilities (ALs) in Jordan.<br><br>BACKGROUND: Depression is commonly experienced by residents of ALs. The condition is, however, often misunderstood as a part of normal aging and may be overlooked by health care professionals. Little is known about the extent of depression and its risk factors among AL residents in Jordan.<br><br>SUBJECTS AND METHODS: A national representative sample of 221 residents selected from all AL units across Jordan was recruited to the study. Data on expected risk factors for depression were collected, including sociodemographics; smoking status; number of roommates; number of family members; assessments for cognitive functioning, for lower limb functioning, for hand, shoulder, and arm impairments; and oral health status. Levels of depression among the sample respondents were also assessed.<br><br>RESULTS: The study found that around 60% of the participants reported depressive manifestations, with 48.0% of AL residents exhibiting impaired cognitive functions, one-third (33.2%) having >50% upper limb disability, two-thirds (63.2%) being at moderate risk of falls, and 69.7% having fair to poor oral health status. Being female, and having a higher level of education, disability of the upper limbs, and impairment of cognitive functions were found to be independent risk factors for depression in participants.<br><br>CONCLUSION: Depression is relatively common among residents of AL units in Jordan. Health care professionals, nurses, physiotherapists, and dentists working in these facilities need to work cooperatively to identify the manifestations of depression in residents and collaboratively implement the best practice in the treatment of depression and circumvent its long-term impacts on the health of residents.}, }
@article {pmid29067136, year = {2017}, author = {Sudhakaran, P}, title = {Amyotrophic Lateral Sclerosis: An Acupuncture Approach.}, journal = {Medical acupuncture}, volume = {29}, number = {5}, pages = {260-268}, pmid = {29067136}, issn = {1933-6586}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder that has no curative treatment and is usually fatal. Modern medicine treatment is mostly supportive. Acupuncture has much more to offer by way of symptomatic relief and improving quality of life (QoL). Useful points for the treatment of bulbar paralysis, paralysis of upper and lower extremities, and correction of underlying Disharmony Patterns are discussed and an illustrative case is presented to demonstrate the acupuncture approach for treating ALS. Case: A 55-year-old woman had weakness in her right arm and both legs for 4 months. She also had muscle cramps and clumsiness in the affected limbs, which rapidly progressed in the 4 months prior to presentation. She was diagnosed with ALS, given 50 mg of oral riluzole per day, and told that the condition was fatal. She sought acupuncture and was treated for two courses of 8 weeks each. Results: After acupuncture, this patient's symptomatic relief was near perfect in that she became free from disabling symptoms and is now leading a normal life. Conclusions: Acupuncture can be an effective modality of treatment for ALS, producing symptomatic relief and improving QoL.}, }
@article {pmid29053667, year = {2017}, author = {Lee, H and Radu, C and Han, JW and Grailhe, R}, title = {Assay Development for High Content Quantification of Sod1 Mutant Protein Aggregate Formation in Living Cells.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {128}, pages = {}, pmid = {29053667}, issn = {1940-087X}, mesh = {Humans ; Protein Aggregates/*physiology ; Superoxide Dismutase-1/*metabolism ; Transfection ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that can be caused by inherited mutations in the gene encoding copper-zinc superoxide dismutase 1 (SOD1). The structural instability of SOD1 and the detection of SOD1-positive inclusions in familial-ALS patients supports a potential causal role for misfolded and/or aggregated SOD1 in ALS pathology. In this study, we describe the development of a cell-based assay designed to quantify the dynamics of SOD1 aggregation in living cells by high content screening approaches. Using lentiviral vectors, we generated stable cell lines expressing wild-type and mutant A4V SOD1 tagged with yellow fluorescent protein and found that both proteins were expressed in the cytosol without any sign of aggregation. Interestingly, only SOD1 A4V stably expressed in HEK-293, but not in U2OS or SH-SY5Y cell lines, formed aggregates upon proteasome inhibitor treatment. We show that it is possible to quantify aggregation based on dose-response analysis of various proteasome inhibitors, and to track aggregate-formation kinetics by time-lapse microscopy. Our approach introduces the possibility of quantifying the effect of ALS mutations on the role of SOD1 in aggregate formation as well as screening for small molecules that prevent SOD1 A4V aggregation.}, }
@article {pmid29046475, year = {2017}, author = {Trias, E and Ibarburu, S and Barreto-Núñez, R and Varela, V and Moura, IC and Dubreuil, P and Hermine, O and Beckman, JS and Barbeito, L}, title = {Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS.}, journal = {JCI insight}, volume = {2}, number = {20}, pages = {}, pmid = {29046475}, issn = {2379-3708}, support = {I01 BX004419/BX/BLRD VA/United States ; R01 NS092651/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Axons/pathology ; Benzamides ; Disease Models, Animal ; Male ; Mast Cells/*pathology ; Muscle, Skeletal ; Neuromuscular Diseases/*pathology ; Neuromuscular Junction/pathology ; Piperidines ; Pyridines ; Rats ; Thiazoles/pharmacology ; }, abstract = {Evidence indicates that neuroinflammation contributes to motor neuron degeneration in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease leading to progressive muscular paralysis. However, it remains elusive whether inflammatory cells can interact with degenerating distal motor axons, influencing the progressive denervation of neuromuscular junctions (NMJs). By analyzing the muscle extensor digitorum longus (EDL) following paralysis onset in the SOD1G93A rat model, we have observed a massive infiltration and degranulation of mast cells, starting after paralysis onset and correlating with progressive NMJ denervation. Remarkably, mast cells accumulated around degenerating motor axons and NMJs, and were also associated with macrophages. Mast cell accumulation and degranulation in paralytic EDL muscle was prevented by systemic treatment over 15 days with masitinib, a tyrosine kinase inhibitor currently in clinical trials for ALS exhibiting pharmacological activity affecting mast cells and microglia. Masitinib-induced mast cell reduction resulted in a 35% decrease in NMJ denervation and reduced motor deficits as compared with vehicle-treated rats. Masitinib also normalized macrophage infiltration, as well as regressive changes in Schwann cells and capillary networks observed in advanced paralysis. These findings provide evidence for mast cell contribution to distal axonopathy and paralysis progression in ALS, a mechanism that can be therapeutically targeted by masitinib.}, }
@article {pmid29045376, year = {2017}, author = {Scott, A}, title = {Drug therapy: On the treatment trail for ALS.}, journal = {Nature}, volume = {550}, number = {7676}, pages = {S120-S121}, doi = {10.1038/550S120a}, pmid = {29045376}, issn = {1476-4687}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/physiopathology ; Antipyrine/analogs &amp; derivatives/therapeutic use ; Benzamides ; C9orf72 Protein/genetics/metabolism ; Clinical Trials as Topic ; Disease Progression ; Drug Therapy, Combination ; Edaravone ; Genetic Therapy ; Humans ; Imidazoles/therapeutic use ; Mesenchymal Stem Cells/cytology/metabolism ; Motor Neurons/drug effects/pathology ; Neuroglia/metabolism/pathology ; Off-Label Use ; Oligoribonucleotides, Antisense/therapeutic use ; Piperidines ; Precision Medicine/*methods/*trends ; Pyrazines/therapeutic use ; Pyridines ; RNAi Therapeutics ; Riluzole/therapeutic use ; Stem Cell Transplantation ; Superoxide Dismutase/antagonists &amp; inhibitors/biosynthesis/genetics/metabolism ; Thiazoles/therapeutic use ; United States ; United States Food and Drug Administration/legislation &amp; jurisprudence ; }, }
@article {pmid29031901, year = {2017}, author = {Liscic, RM}, title = {Als and Ftd: Insights into the disease mechanisms and therapeutic targets.}, journal = {European journal of pharmacology}, volume = {817}, number = {}, pages = {2-6}, doi = {10.1016/j.ejphar.2017.10.012}, pmid = {29031901}, issn = {1879-0712}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Animals ; *Frontotemporal Lobar Degeneration/drug therapy/genetics/pathology ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The causes are still largely unknown and no effective treatment currently exists. It has been shown that FTLD may coexist with ALS. The overlap between ALS and frontotemporal dementia (FTD), the clinical syndrome associated with FTLD, occurs at clinical, genetic, and pathological levels. The hallmark proteins of the pathognomonic inclusions are SOD-1, TDP-43 or FUS, rarely the disease is caused by mutations in the respective genes. Frontotemporal lobar degenerations (FTLD) is genetically, neuropathologically and clinically heterogeneous and may present with behavioural, language and occasionally motor disorder, respectively. Almost all cases of ALS, as well as tau-negative FTLD share a common neuropathology, neuronal and glial inclusion bodies containing abnormal TDP-43 protein, collectively called TDP-43 proteinopathy. Recent discoveries in genetics (e.g. C9orf72 hexanucleotide expansion) and the subsequent neuropathological characterization have revealed remarkable overlap between ALS and FTLD-TDP indicating common pathways in pathogenesis. For ALS, an anti-glutamate agent riluzole may be offered to slow disease progression (Level A), and a promising molecule, arimoclomol, is currently in clinical trials. Other compounds, however, are being trailed and some have shown encouraging results. As new therapeutic approaches continue to emerge by targeting SOD1, TDP-43, or GRN, we present some advances that are being made in our understanding of the molecular mechanisms of these diseases, which together with gene and stem cell therapies may translate into new treatment options.}, }
@article {pmid29028904, year = {2017}, author = {Woolley, SC and Rush, BK}, title = {Considerations for Clinical Neuropsychological Evaluation in Amyotrophic Lateral Sclerosis.}, journal = {Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists}, volume = {32}, number = {7}, pages = {906-916}, doi = {10.1093/arclin/acx089}, pmid = {29028904}, issn = {1873-5843}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology/*psychology ; Humans ; Neuropsychological Tests ; }, abstract = {The clinical neuropsychologist has the opportunity to be uniquely involved in the evaluation and treatment of individuals with amyotrophic lateral sclerosis (ALS). We review the current literature that defines cognitive and behavioral symptoms in ALS, including current knowledge of the neuropathological and genetic underpinning for these symptoms. There are unique considerations for clinical neuropsychological evaluation and clinical research in ALS and we highlight these in this review. Specifically, we shed light on special factors that contribute to our understanding of cognitive and behavioral impairment in ALS, including co-morbid symptoms, differential diagnosis, and considerations for longitudinal tracking of phenotypes. We discuss the rationale for proposing a specific approach to such as cognitive screening, test selection, response modality consideration, and test-retest intervals. With this didactic overview, the clinical neuropsychologist has the potential to learn more about the heterogeneous presentation of motor and neuropsychological symptoms in ALS. Furthermore, the reader has the opportunity to understand what it takes to develop a valid assessment approach particularly when the phenotype of ALS remains undefined in some regards. This clinical practice review sets the stage for the clinical neuropsychologist to further contribute to our clinical and scientific understanding of ALS and cognition.}, }
@article {pmid29021725, year = {2017}, author = {Purvis, MV and Rooks, H and Young Lee, J and Longerich, S and Kahn, SA}, title = {Prehospital hydroxocobalamin for inhalation injury and cyanide toxicity in the United States - analysis of a database and survey of ems providers.}, journal = {Annals of burns and fire disasters}, volume = {30}, number = {2}, pages = {126-128}, pmid = {29021725}, issn = {1592-9558}, abstract = {Prehospital use of hydroxocobalamin as an antidote for cyanide toxicity, a serious complication of smoke inhalation, has yet to be universally adopted in the United States though its efficacy and safety have been demonstrated since 2006. The purpose of this study was to characterize practices of prehospital hydroxocobalamin administration via a survey of emergency medical services (EMS) and to report a case series from an EMS database to track use of hydroxocobalamin. The Fire Smoke Coalition Newsletter emailed a voluntary survey to EMS subscribers regarding hydroxocobalamin use. Survey responses were analyzed in addition to survival data from the Smoke Inhalation Treatment Database (SITD), a publically available, self-reported, online database for EMS regarding smoke inhalation patient outcomes. Analysis was compared to current published data from PubMed. The survey had a 14% response rate (284/2000). Only 38% reported prehospital utilization of a hydrogen cyanide antidote with 46% using hydroxocobalamin. 20% of responders reported a formal ALS protocol was in place for hydroxocobalamin use. For the SITD, 12 of 13 (92%) patients who received hydroxocobalamin for suspected inhalation survived. Other studies found a survival rate of 72% and 42% after administration of hydroxocobalamin for smoke inhalation. Prehospital administration of hydroxocobalamin for cyanide toxicity is uncommon in the United States, as evidenced by this analysis, despite well-documented safety and efficacy. Although a small sample, patients who received prehospital hydroxocobalamin had improved survival. This survival rate is significantly greater than those reported previously.}, }
@article {pmid29018296, year = {2017}, author = {Kaufman, MB}, title = {Pharmaceutical Approval Update.}, journal = {P &amp; T : a peer-reviewed journal for formulary management}, volume = {42}, number = {10}, pages = {620-621}, pmid = {29018296}, issn = {1052-1372}, abstract = {L-glutamine oral powder (Endari) for reducing the acute complications of sickle cell disease; edaravone (Radicava) for the treatment of amyotrophic lateral sclerosis; and midostaurin (Rydapt) for the treatment of acute myeloid leukemia in combination with chemotherapy.}, }
@article {pmid29016670, year = {2017}, author = {Kanno, T and Yasutake, K and Tanaka, K and Hadano, S and Ikeda, JE}, title = {A novel function of N-linked glycoproteins, alpha-2-HS-glycoprotein and hemopexin: Implications for small molecule compound-mediated neuroprotection.}, journal = {PloS one}, volume = {12}, number = {10}, pages = {e0186227}, pmid = {29016670}, issn = {1932-6203}, mesh = {Acetamides/*administration &amp; dosage ; Animals ; Cattle ; Cell Death/drug effects ; Central Nervous System/*drug effects/pathology ; Culture Media/*chemistry ; Hemopexin/chemistry/*metabolism ; Humans ; Imidazoles/*administration &amp; dosage ; Mice ; Neurons/drug effects/pathology ; Neuroprotective Agents/administration &amp; dosage/chemistry ; Oxidative Stress/drug effects ; Small Molecule Libraries/*administration &amp; dosage/chemistry ; alpha-2-HS-Glycoprotein/chemistry/*metabolism ; }, abstract = {Therapeutic agents to the central nervous system (CNS) need to be efficiently delivered to the target site of action at appropriate therapeutic levels. However, a limited number of effective drugs for the treatment of neurological diseases has been developed thus far. Further, the pharmacological mechanisms by which such therapeutic agents can protect neurons from cell death have not been fully understood. We have previously reported the novel small-molecule compound, 2-[mesityl(methyl)amino]-N-[4-(pyridin-2-yl)-1H-imidazol-2-yl] acetamide trihydrochloride (WN1316), as a unique neuroprotectant against oxidative injury and a highly promising remedy for the treatment of amyotrophic lateral sclerosis (ALS). One of the remarkable characteristics of WN1316 is that its efficacious doses in ALS mouse models are much less than those against oxidative injury in cultured human neuronal cells. It is also noted that the WN1316 cytoprotective activity observed in cultured cells is totally dependent upon the addition of fetal bovine serum in culture medium. These findings led us to postulate some serum factors being tightly linked to the WN1316 efficacy. In this study, we sieved through fetal bovine serum proteins and identified two N-linked glycoproteins, alpha-2-HS-glycoprotein (AHSG) and hemopexin (HPX), requisites to exert the WN1316 cytoprotective activity against oxidative injury in neuronal cells in vitro. Notably, the removal of glycan chains from these molecules did not affect the WN1316 cytoprotective activity. Thus, two glycoproteins, AHSG and HPX, represent a pivotal glycoprotein of the cytoprotective activity for WN1316, showing a concrete evidence for the novel glycan-independent function of serum glycoproteins in neuroprotective drug efficacy.}, }
@article {pmid28993751, year = {2017}, author = {Khalid, SI and Ampie, L and Kelly, R and Ladha, SS and Dardis, C}, title = {Immune Modulation in the Treatment of Amyotrophic Lateral Sclerosis: A Review of Clinical Trials.}, journal = {Frontiers in neurology}, volume = {8}, number = {}, pages = {486}, pmid = {28993751}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. Though many molecular and genetic causes are thought to serve as predisposing or disease propagating factors, the underlying pathogenesis of the disease is not known. Recent discoveries have demonstrated the presence of inflammation propagating substrates in the central nervous system of patients afflicted with ALS. Over the past decade, this hypothesis has incited an effort to better understand the role of the immune system in ALS and has led to the trial of several potential immune-modulating therapies. Here, we briefly review advances in the role of such therapies. The clinical trials discussed here are currently ongoing or have been concluded at the time of writing.}, }
@article {pmid28983304, year = {2017}, author = {Liu, XQ and Yu, CY and Dong, JG and Hu, SW and Xu, AX}, title = {Acetolactate Synthase-Inhibiting Gametocide Amidosulfuron Causes Chloroplast Destruction, Tissue Autophagy, and Elevation of Ethylene Release in Rapeseed.}, journal = {Frontiers in plant science}, volume = {8}, number = {}, pages = {1625}, pmid = {28983304}, issn = {1664-462X}, abstract = {Background: Acetolactate synthase (ALS)-inhibiting herbicides amidosulfuron (Hoestar) is an efficient gametocide that can induce male sterility in rapeseed (Brassica napus L.). We conducted an integrated study of cytological, transcriptomic, and physiological analysis to decipher the gametocidal effect of amidosulfuron. Results: In the first several days after exposure to amidosulfuron at a gametocidal dose of ca. 1 μg per plant, the plants showed the earliest symptoms including short retard of raceme elongation, slight chlorosis on leaf, and decrease of photosynthesis rate. Chloroplasts in leaf and anther epidermis, and tapetal plastids were deformed. Both tapetal cell and uni-nucleate microspore showed autophagic vacuoles and degenerated quickly. The amidosulfuron treatment caused reduction of photosynthetic rate and the contents of leaf chlorophyll, soluble sugar and pyruvate, as well as content alteration of several free amino acids in the treated plants. A comparison of transcriptomic profiling data of the young flower buds of the treated plants with the control identified 142 up-regulated and 201 down-regulated differential expression transcripts with functional annotations. Down-regulation of several interesting genes encoding PAIR1, SDS, PPD2, HFM1, CSTF77, A6, ALA6, UGE1, FLA20, A9, bHLH91, and putative cell wall protein LOC106368794, and up-regulation of autophagy-related protein ATG8A indicated functional abnormalities about cell cycle, cell wall formation, chloroplast structure, and tissue autophagy. Ethylene-responsive transcription factor RAP2-11-like was up-regulated in the flower buds and ethylene release rate was also elevated. The transcriptional regulation in the amidosulfuron-treated plants was in line with the cytological and physiological changes. Conclusions: The results suggested that metabolic decrease related to photosynthesis and energy supply are associated with male sterility induced by amidosulfuron. The results provide insights into the molecular mechanisms of gametocide-induced male sterility and expand the knowledge on the transcriptomic complexity of the plants exposure to sulfonylurea herbicide.}, }
@article {pmid28982489, year = {2017}, author = {Robinson, MT and Holloway, RG}, title = {Palliative Care in Neurology.}, journal = {Mayo Clinic proceedings}, volume = {92}, number = {10}, pages = {1592-1601}, doi = {10.1016/j.mayocp.2017.08.003}, pmid = {28982489}, issn = {1942-5546}, mesh = {*Central Nervous System Diseases/diagnosis/physiopathology/psychology/therapy ; Humans ; *Palliative Care/ethics/methods/psychology ; Patient Care Planning/ethics/organization &amp; administration ; Prognosis ; *Quality of Life ; }, abstract = {Palliative medicine is a specialty that focuses on improving the quality of life for patients with serious or advanced medical conditions, and it is appropriate at any stage of disease, including at the time of diagnosis. Neurologic conditions tend to have high symptom burdens, variable disease courses, and poor prognoses that affect not only patients but also their families and caregivers. Patients with a variety of neurologic conditions such as Parkinson disease, dementia, amyotrophic lateral sclerosis, brain tumors, stroke, and acute neurologic illnesses have substantial unmet needs that can be addressed through a combination of primary and specialty palliative care. The complex needs of these patients are ideally managed with a comprehensive approach to care that addresses the physical, psychological, social, and spiritual aspects of care in an effort to reduce suffering. Early discussions about prognosis, goals of care, and advance care planning are critical as they can provide guidance for treatment decisions and allow patients to retain a sense of autonomy despite progressive cognitive or functional decline. With the rapid growth in palliative care across the United States, there are opportunities to improve the palliative care knowledge of neurology trainees, the delivery of palliative care to patients with neurologic disease by both neurologists and nonneurologists, and the research agenda for neuropalliative care.}, }
@article {pmid28980850, year = {2018}, author = {Perera, ND and Sheean, RK and Lau, CL and Shin, YS and Beart, PM and Horne, MK and Turner, BJ}, title = {Rilmenidine promotes MTOR-independent autophagy in the mutant SOD1 mouse model of amyotrophic lateral sclerosis without slowing disease progression.}, journal = {Autophagy}, volume = {14}, number = {3}, pages = {534-551}, pmid = {28980850}, issn = {1554-8635}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Autophagy/*drug effects ; DNA-Binding Proteins/metabolism ; Disease Models, Animal ; Humans ; Mice, Transgenic ; Motor Neurons/drug effects ; Rilmenidine/*pharmacology ; Superoxide Dismutase-1/genetics ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {Macroautophagy/autophagy is the main intracellular catabolic pathway in neurons that eliminates misfolded proteins, aggregates and damaged organelles associated with ageing and neurodegeneration. Autophagy is regulated by both MTOR-dependent and -independent pathways. There is increasing evidence that autophagy is compromised in neurodegenerative disorders, which may contribute to cytoplasmic sequestration of aggregation-prone and toxic proteins in neurons. Genetic or pharmacological modulation of autophagy to promote clearance of misfolded proteins may be a promising therapeutic avenue for these disorders. Here, we demonstrate robust autophagy induction in motor neuronal cells expressing SOD1 or TARDBP/TDP-43 mutants linked to amyotrophic lateral sclerosis (ALS). Treatment of these cells with rilmenidine, an anti-hypertensive agent and imidazoline-1 receptor agonist that induces autophagy, promoted autophagic clearance of mutant SOD1 and efficient mitophagy. Rilmenidine administration to mutant SOD1[G93A] mice upregulated autophagy and mitophagy in spinal cord, leading to reduced soluble mutant SOD1 levels. Importantly, rilmenidine increased autophagosome abundance in motor neurons of SOD1[G93A] mice, suggesting a direct action on target cells. Despite robust induction of autophagy in vivo, rilmenidine worsened motor neuron degeneration and symptom progression in SOD1[G93A] mice. These effects were associated with increased accumulation and aggregation of insoluble and misfolded SOD1 species outside the autophagy pathway, and severe mitochondrial depletion in motor neurons of rilmenidine-treated mice. These findings suggest that rilmenidine treatment may drive disease progression and neurodegeneration in this mouse model due to excessive mitophagy, implying that alternative strategies to beneficially stimulate autophagy are warranted in ALS.}, }
@article {pmid28978660, year = {2017}, author = {van Eijk, RPA and Jones, AR and Sproviero, W and Shatunov, A and Shaw, PJ and Leigh, PN and Young, CA and Shaw, CE and Mora, G and Mandrioli, J and Borghero, G and Volanti, P and Diekstra, FP and van Rheenen, W and Verstraete, E and Eijkemans, MJC and Veldink, JH and Chio, A and Al-Chalabi, A and van den Berg, LH and van Es, MA and , }, title = {Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials.}, journal = {Neurology}, volume = {89}, number = {18}, pages = {1915-1922}, pmid = {28978660}, issn = {1526-632X}, support = {AL-CHALABI/APR15/844-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; SHAW/APR15/933-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; JONES/OCT15/958-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MC_G1000733/MRC_/Medical Research Council/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; G0300329/MRC_/Medical Research Council/United Kingdom ; SHAW/NOV14/985-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; G0501573/MRC_/Medical Research Council/United Kingdom ; MR/L021803/1/MRC_/Medical Research Council/United Kingdom ; G0900635/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; G1100695/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics ; C9orf72 Protein ; Genotype ; Lithium Carbonate/therapeutic use ; Nerve Tissue Proteins/genetics ; Neuroprotective Agents/*therapeutic use ; *Pharmacogenetics ; Proportional Hazards Models ; Proteins/genetics ; *Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVE: To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders.<br><br>METHODS: Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype.<br><br>RESULTS: Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3).<br><br>CONCLUSIONS: This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials.}, }
@article {pmid28978653, year = {2017}, author = {Armon, C and Hardiman, O}, title = {The beginning of precision medicine in ALS? Treatment to fit the genes.}, journal = {Neurology}, volume = {89}, number = {18}, pages = {1850-1851}, doi = {10.1212/WNL.0000000000004612}, pmid = {28978653}, issn = {1526-632X}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Pharmacogenetics ; Pharmacogenomic Testing ; *Precision Medicine ; }, }
@article {pmid28977468, year = {2018}, author = {Dudley, LS and Konomos, D and Robbins, V and Qiu, L and Bauter, R and Merlin, MA}, title = {Opioid crisis at the Jersey Shore-special report.}, journal = {Journal of public health (Oxford, England)}, volume = {40}, number = {2}, pages = {e112-e117}, doi = {10.1093/pubmed/fdx106}, pmid = {28977468}, issn = {1741-3850}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Drug Overdose/drug therapy/epidemiology ; Drug Utilization ; Emergency Service, Hospital ; Female ; Humans ; Male ; Middle Aged ; Naloxone/*therapeutic use ; Narcotic Antagonists/*therapeutic use ; New Jersey/epidemiology ; Opioid-Related Disorders/*drug therapy/*epidemiology ; Police ; Retrospective Studies ; Young Adult ; }, abstract = {The USA is experiencing an epidemic of drug overdoses and deaths with a 200% increase in overdose deaths involving opioids including heroin. Legislation since 2013 has created paths to reduce opioid overdose deaths and since, basic life support (BLS) and police agencies have been administering naloxone to patients with suspected opioid overdoses as part of standard treatment protocols. Charts were reviewed from 1 January 2016 to 15 April 2016 on the de-identified electronic medical records of patients in a two-county system comprising the 'Jersey Shore' who received naloxone to determine the number of naloxone administrations and heroin overdoses. Additionally, narratives were examined for evidence of heroin use. Of the 312 patients, 213 received a first dose of naloxone by a family member or bystander, police, or by BLS; 99 received a first dose by a paramedic (ALS). About 233 were initially unresponsive or had altered mental status that improved after naloxone administration. About210 (67.3%) charts illustrated obvious opioid use. Of the note, 282 patients arrived to an emergency department alive. About 30 patients were pronounced dead. From 1 February 2016 to 31 March 2016, the number of opioid overdoses increased and the subsequent use of naloxone has increased by 176%.}, }
@article {pmid28973341, year = {2017}, author = {Akiyama, G and Azuchi, Y and Guo, X and Noro, T and Kimura, A and Harada, C and Namekata, K and Harada, T}, title = {Edaravone Prevents Retinal Degeneration in Adult Mice Following Optic Nerve Injury.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {58}, number = {11}, pages = {4908-4914}, doi = {10.1167/iovs.17-22250}, pmid = {28973341}, issn = {1552-5783}, mesh = {Animals ; Antipyrine/*analogs &amp; derivatives/pharmacology ; Disease Models, Animal ; Edaravone ; Free Radical Scavengers/*pharmacology ; Immunohistochemistry ; Injections, Intraocular ; MAP Kinase Kinase 1/metabolism ; MAP Kinase Kinase Kinase 5/metabolism ; Mice ; Mice, Inbred C57BL ; Optic Nerve Injuries/*drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Retina/metabolism ; Retinal Degeneration/pathology/*prevention &amp; control ; Retinal Ganglion Cells/pathology ; Tomography, Optical Coherence ; }, abstract = {PURPOSE: To assess the therapeutic potential of edaravone, a free radical scavenger that is used for the treatment of acute brain infarction and amyotrophic lateral sclerosis, in a mouse model of optic nerve injury (ONI).<br><br>METHODS: Two microliters of edaravone (7.2 mM) or vehicle were injected intraocularly 3 minutes after ONI. Optical coherence tomography, retrograde labeling of retinal ganglion cells (RGCs), histopathology, and immunohistochemical analyses of phosphorylated apoptosis signal-regulating kinase-1 (ASK1) and p38 mitogen-activated protein kinase (MAPK) in the retina were performed after ONI. Reactive oxygen species (ROS) levels were assessed with a CellROX Green Reagent.<br><br>RESULTS: Edaravone ameliorated ONI-induced ROS production, RGC death, and inner retinal degeneration. Also, activation of the ASK1-p38 MAPK pathway that induces RGC death following ONI was suppressed with edaravone treatment.<br><br>CONCLUSIONS: The results of this study suggest that intraocular administration of edaravone may be a useful treatment for posttraumatic complications.}, }
@article {pmid28973294, year = {2017}, author = {Tibshirani, M and Zhao, B and Gentil, BJ and Minotti, S and Marques, C and Keith, J and Rogaeva, E and Zinman, L and Rouaux, C and Robertson, J and Durham, HD}, title = {Dysregulation of chromatin remodelling complexes in amyotrophic lateral sclerosis.}, journal = {Human molecular genetics}, volume = {26}, number = {21}, pages = {4142-4152}, doi = {10.1093/hmg/ddx301}, pmid = {28973294}, issn = {1460-2083}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/*physiopathology ; Animals ; Cell Differentiation/genetics/physiology ; Chromatin Assembly and Disassembly/genetics/*physiology ; Cytoplasm/metabolism ; DNA Helicases/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Humans ; Mice ; Motor Neurons/metabolism ; Mutation ; Neurons/pathology ; Nuclear Proteins/genetics/metabolism ; Protein Subunits ; RNA-Binding Protein FUS/genetics/metabolism ; Spinal Cord/metabolism ; Transcription Factors/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with paralysis resulting from dysfunction and loss of motor neurons. A common neuropathological finding is attrition of motor neuron dendrites, which make central connections vital to motor control. The chromatin remodelling complex, neuronal Brahma-related gene 1 (Brg1)-associated factor complex (nBAF), is critical for neuronal differentiation, dendritic extension and synaptic function. We have identified loss of the crucial nBAF subunits Brg1, Brg1-associated factor 53b and calcium responsive transactivator in cultured motor neurons expressing FUS or TAR-DNA Binding Protein 43 (TDP-43) mutants linked to familial ALS. When plasmids encoding wild-type or mutant human FUS or TDP-43 were expressed in motor neurons of dissociated spinal cord cultures prepared from E13 mice, mutant proteins in particular accumulated in the cytoplasm. Immunolabelling of nBAF subunits was reduced in proportion to loss of nuclear FUS or TDP-43 and depletion of Brg1 was associated with nuclear retention of Brg1 mRNA. Dendritic attrition (loss of intermediate and terminal dendritic branches) occurred in motor neurons expressing mutant, but not wild-type, FUS or TDP-43. This attrition was delayed by ectopic over-expression of Brg1 and was reproduced by inhibiting Brg1 activity either through genetic manipulation or treatment with the chemical inhibitor, (E)-1-(2-Hydroxyphenyl)-3-((1R, 4R)-5-(pyridin-2-yl)-2, 5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one, demonstrating the importance of Brg1 to maintenance of dendritic architecture. Loss of nBAF subunits was also documented in spinal motor neurons in autopsy tissue from familial amyotrophic sclerosis (chromosome 9 open reading frame 72 with G4C2 nucleotide expansion) and from sporadic cases with no identified mutation, pointing to dysfunction of nBAF chromatin remodelling in multiple forms of ALS.}, }
@article {pmid28968371, year = {2017}, author = {Simmons, Z}, title = {Right-to-Try Investigational Therapies for Incurable Disorders.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {23}, number = {5, Peripheral Nerve and Motor Neuron Disorders}, pages = {1451-1457}, doi = {10.1212/CON.0000000000000515}, pmid = {28968371}, issn = {1538-6899}, mesh = {Compassionate Use Trials/*ethics/*legislation &amp; jurisprudence ; Humans ; Therapies, Investigational/*ethics ; United States ; }, abstract = {Patients with life-threatening disorders such as amyotrophic lateral sclerosis, for which only minimally effective medical therapies currently exist, often seek treatments not proven to be effective and not approved by regulatory agencies for use outside of experimental treatment trials. The expanded access (compassionate use) provisions of the US Food and Drug Administration (FDA) for access to such therapies are often perceived as being inadequate. In response, states have passed right-to-try laws designed to improve access to experimental therapies for patients willing to assume the risks associated with such treatments. This situation has resulted in conflicts between those who perceive access to such treatments as their right as autonomous individuals and those who believe that the principles of beneficence and nonmaleficence justify actions of physicians and regulators in controlling access to such treatments. A variety of factors also contribute to the inequitable distribution of such treatments. Better systems are needed to improve access to promising new treatments while protecting these vulnerable patients from the abuses associated with human research in the preregulatory era.}, }
@article {pmid28968365, year = {2017}, author = {Goutman, SA}, title = {Diagnosis and Clinical Management of Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {23}, number = {5, Peripheral Nerve and Motor Neuron Disorders}, pages = {1332-1359}, doi = {10.1212/CON.0000000000000535}, pmid = {28968365}, issn = {1538-6899}, support = {K23 ES027221/ES/NIEHS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Humans ; *Motor Neuron Disease/diagnosis/genetics/therapy ; }, abstract = {PURPOSE OF REVIEW: This article reviews the clinical features, diagnostic pathway, therapies, and current understanding of the pathophysiology of amyotrophic lateral sclerosis (ALS). The spectrum of motor neuron diseases is reviewed, and the clinical heterogeneity of ALS is described.<br><br>RECENT FINDINGS: ALS is increasingly recognized as a clinical spectrum disorder with pure upper and pure lower motor neuron presentations, supported by genetic links. The phenotypic variability is broad. Identification of ALS-related genes provides insights into disease mechanisms.<br><br>SUMMARY: ALS is a progressive fatal multisystem neurodegenerative disease primarily affecting motor neurons. Clinical recognition of suspicious symptoms and the appropriate laboratory evaluation are essential to limit diagnostic delay and avoid unnecessary testing and procedures. ALS has broad genetic and hypothesized environmental causes and phenotypic variability. Recognizing related motor neuron diseases will prevent misdiagnosis while allowing proper disease counseling. Although ALS cannot be cured, implementation of appropriate symptomatic treatment is valuable.}, }
@article {pmid28968162, year = {2017}, author = {Podsiadło, P and Darocha, T and Kosiński, S and Sałapa, K and Ziętkiewicz, M and Sanak, T and Turner, R and Brugger, H}, title = {Severe Hypothermia Management in Mountain Rescue: A Survey Study.}, journal = {High altitude medicine &amp; biology}, volume = {18}, number = {4}, pages = {411-416}, pmid = {28968162}, issn = {1557-8682}, mesh = {Advanced Cardiac Life Support ; Cardiopulmonary Resuscitation/instrumentation ; Education, Medical ; Emergency Medical Services/methods/organization &amp; administration/*standards ; Equipment and Supplies/standards ; Extracorporeal Membrane Oxygenation ; *Guideline Adherence ; Heart Arrest/*therapy ; Humans ; Hypothermia/*therapy ; Patient Care Team/organization &amp; administration/*standards ; Practice Guidelines as Topic ; Rescue Work/methods/organization &amp; administration/*standards ; Rewarming/instrumentation/methods ; Surveys and Questionnaires ; Thermometers ; Transportation of Patients ; }, abstract = {UNLABELLED: Podsiadło, Paweł, Tomasz Darocha, Sylweriusz Kosiński, Kinga Sałapa, Mirosław Ziętkiewicz, Tomasz Sanak, Rachel Turner, and Hermann Brugger. Severe hypothermia management in mountain rescue: A survey study. High Alt Med Biol 18:411-416, 2017.<br><br>INTRODUCTION: Severe hypothermia is a rare but demanding medical emergency. Although mortality is high, if well managed, the neurological outcome of survivors can be excellent. The aim of the study was to assess whether mountain rescue teams (MRTs) are able to meet the guidelines in the management of severe hypothermia, regarding their equipment and procedures.<br><br>METHODS: Between August and December 2016, an online questionnaire, with 24 questions to be completed using Google Forms, was sent to 123&#x2009;MRTs in 27 countries.<br><br>RESULTS: Twenty-eight MRTs from 10 countries returned the completed questionnaire. Seventy-five percent of MRTs reportedly provide advanced life support (ALS) on-site and 89% are regularly trained in hypothermia management. Thirty-two percent of MRTs transport hypothermic patients in cardiac arrest to the nearest hospital instead of an Extracorporeal Life Support facility; 39% are equipped with mechanical chest compression devices; 36% measure core body temperature on-site and no MRT is equipped with a device to measure serum potassium concentration on-site in avalanche victims.<br><br>CONCLUSIONS: Most MRTs are regularly trained in the treatment of severe hypothermia and provide ALS. The majority are not equipped to follow standard procedural guidelines for the treatment of severely hypothermic patients, especially with cardiac arrest. However, the low response rate-23% (28/123)-could have induced a bias.}, }
@article {pmid28962574, year = {2017}, author = {Lagos-Cabré, R and Alvarez, A and Kong, M and Burgos-Bravo, F and Cárdenas, A and Rojas-Mancilla, E and Pérez-Nuñez, R and Herrera-Molina, R and Rojas, F and Schneider, P and Herrera-Marschitz, M and Quest, AFG and van Zundert, B and Leyton, L}, title = {αVβ3 Integrin regulates astrocyte reactivity.}, journal = {Journal of neuroinflammation}, volume = {14}, number = {1}, pages = {194}, pmid = {28962574}, issn = {1742-2094}, mesh = {Animals ; Animals, Genetically Modified ; Animals, Newborn ; Astrocytes/drug effects/*physiology ; Cell Movement/drug effects/genetics/*physiology ; Cells, Cultured ; Connexins/genetics/metabolism ; Disease Models, Animal ; Gene Expression Regulation/drug effects/*genetics ; Humans ; Integrin alphaVbeta3/genetics/*metabolism ; Mice ; Nerve Tissue Proteins/genetics/metabolism ; Neurodegenerative Diseases/genetics/pathology ; Rats ; Receptors, Purinergic P2/genetics/metabolism ; Signal Transduction/drug effects/genetics ; Superoxide Dismutase/genetics/metabolism ; Thy-1 Antigens/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; Wound Healing/physiology ; }, abstract = {BACKGROUND: Neuroinflammation involves cytokine release, astrocyte reactivity and migration. Neuronal Thy-1 promotes DITNC1 astrocyte migration by engaging αVβ3 Integrin and Syndecan-4. Primary astrocytes express low levels of these receptors and are unresponsive to Thy-1; thus, inflammation and astrocyte reactivity might be necessary for Thy-1-induced responses.<br><br>METHODS: Wild-type rat astrocytes (TNF-activated) or from human SOD1[G93A] transgenic mice (a neurodegenerative disease model) were used to evaluate cell migration, Thy-1 receptor levels, signaling molecules, and reactivity markers.<br><br>RESULTS: Thy-1 induced astrocyte migration only after TNF priming. Increased expression of &#x3b1;V&#x3b2;3 Integrin, Syndecan-4, P2X7R, Pannexin-1, Connexin-43, GFAP, and iNOS were observed in TNF-treated astrocytes. Silencing of &#x3b2;3 Integrin prior to TNF treatment prevented Thy-1-induced migration, while &#x3b2;3 Integrin over-expression was sufficient to induce astrocyte reactivity and allow Thy-1-induced migration. Finally, hSOD1[G93A] astrocytes behave as TNF-treated astrocytes since they were reactive and responsive to Thy-1.<br><br>CONCLUSIONS: Therefore, inflammation induces expression of &#x3b1;V&#x3b2;3 Integrin and other proteins, astrocyte reactivity, and Thy-1 responsiveness. Importantly, ectopic control of &#x3b2;3 Integrin levels modulates these responses regardless of inflammation.}, }
@article {pmid28956014, year = {2017}, author = {Figuera-Losada, M and Thomas, AG and Stathis, M and Stockwell, BR and Rojas, C and Slusher, BS}, title = {Development of a primary microglia screening assay and its use to characterize inhibition of system xc[-] by erastin and its analogs.}, journal = {Biochemistry and biophysics reports}, volume = {9}, number = {}, pages = {266-272}, pmid = {28956014}, issn = {2405-5808}, support = {P30 MH075673/MH/NIMH NIH HHS/United States ; R35 CA209896/CA/NCI NIH HHS/United States ; }, abstract = {The inflammatory response in the central nervous system involves activated microglia. Under normal conditions they remove damaged neurons by phagocytosis. On the other hand, neurodegenerative diseases are thought to involve chronic microglia activation resulting in release of excess glutamate, proinflammatory cytokines and reactive oxygen species, leading to neuronal death. System xC[-] cystine/glutamate antiporter (SXC), a sodium independent heterodimeric transporter found in microglia and astrocytes in the CNS, imports cystine into the cell and exports glutamate. SXC has been shown to be upregulated in neurodegenerative diseases including multiple sclerosis, ALS, neuroAIDS Parkinson's disease and Alzheimer's disease. Consequently, SXC inhibitors could be of use in the treatment of diseases characterized by neuroinflammation and glutamate excitotoxicity. We report on the optimization of a primary microglia-based assay to screen for SXC inhibitors. Rat primary microglia were activated using lipopolysaccharides (LPS) and glutamate release and cystine uptake were monitored by fluorescence and radioactivity respectively. LPS-induced glutamate release increased with increasing cell density, time of incubation and LPS concentration. Conditions to screen for SXC inhibitors were optimized in 96-well format and subsequently used to evaluate SXC inhibitors. Known SXC inhibitors sulfasalazine, S-4CPG and erastin blocked glutamate release and cystine uptake while R-4CPG, the inactive enantiomer of S-4CPG, failed to inhibit glutamate release or cystine transport. In addition, several erastin analogs were evaluated using primary microglia and found to have EC50 values in agreement with previous studies using established cell lines.}, }
@article {pmid28955370, year = {2017}, author = {Torra, J and Rojano-Delgado, AM and Rey-Caballero, J and Royo-Esnal, A and Salas, ML and De Prado, R}, title = {Enhanced 2,4-D Metabolism in Two Resistant Papaver rhoeas Populations from Spain.}, journal = {Frontiers in plant science}, volume = {8}, number = {}, pages = {1584}, pmid = {28955370}, issn = {1664-462X}, abstract = {Corn poppy (Papaver rhoeas), the most problematic broadleaf weed in winter cereals in Southern Europe, has developed resistance to the widely-used herbicide, 2,4-D. The first reported resistance mechanism in this species to 2,4-D was reduced translocation from treated leaves to the rest of the plant. However, the presence of other non-target site resistance (NTSR) mechanisms has not been investigated up to date. Therefore, the main objective of this research was to reveal if enhanced 2,4-D metabolism is also present in two Spanish resistant (R) populations to synthetic auxins. With this aim, HPLC experiments at two 2,4-D rates (600 and 2,400 g ai ha[-1]) were conducted to identify and quantify the metabolites produced and evaluate possible differences in 2,4-D degradation between resistant (R) and susceptible (S) plants. Secondarily, to determine the role of cytochrome P450 in the resistance response, dose-response experiments were performed using malathion as its inhibitor. Three populations were used: S, only 2,4-D R (R-703) and multiple R to 2,4-D and ALS inhibitors (R-213). HPLC studies indicated the presence of two hydroxy metabolites in these R populations in shoots and roots, which were not detected in S plants, at both rates. Therefore, enhanced metabolism becomes a new NTSR mechanism in these two P. rhoeas populations from Spain. Results from the dose-response experiments also showed that pre-treatment of R plants with the cytochrome P450 (P450) inhibitor malathion reversed the phenotype to 2,4-D from resistant to susceptible in both R populations. Therefore, it could be hypothesized that a malathion inhibited P450 is responsible of the formation of the hydroxy metabolites detected in the metabolism studies. This and previous research indicate that two resistant mechanisms to 2,4-D could be present in populations R-703 and R-213: reduced translocation and enhanced metabolism. Future experiments are required to confirm these hypotheses, understand the role of P450, and the relationship between both NTSR mechanisms. On this basis, selection pressure with synthetic auxins bears the risk of promoting the evolution enhanced metabolism in Papaver rhoeas.}, }
@article {pmid28952073, year = {2018}, author = {Srinivasan, E and Rajasekaran, R}, title = {Cysteine to Serine Conversion at 111th Position Renders the Disaggregation and Retains the Stabilization of Detrimental SOD1 A4V Mutant Against Amyotrophic Lateral Sclerosis in Human-A Discrete Molecular Dynamics Study.}, journal = {Cell biochemistry and biophysics}, volume = {76}, number = {1-2}, pages = {231-241}, doi = {10.1007/s12013-017-0830-5}, pmid = {28952073}, issn = {1559-0283}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Humans ; *Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Protein Aggregates/physiology ; Protein Stability ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Superoxide Dismutase-1/chemistry/genetics/*metabolism ; Thermodynamics ; }, abstract = {Protein aggregation is a hallmark of various neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS) in humans. Mutations in Cu/Zn superoxide dismutase (SOD1) protein were found to be a prominent cause behind the majority of the familial ALS cases with abnormal protein aggregates. Herein, we report the biophysical characterization of the beneficial mutation C111S that stabilizes the SOD1 harboring A4V mutation, one of the most lethal diseases causing mutant that leads to protein destabilization and aggregation. In this study, we utilized discrete molecular dynamics (DMD) simulations, which stipulated an outlook over the systematic action of C111S mutation in the A4V mutant that stabilizes the protein and impedes the formation of protein aggregation. Herewith, the findings from our study manifested that the mutation of C111S in SOD1 could aid in regaining the protein structural conformations that protect against the formation of toxic aggregates, thereby hindering the disease pathogenicity subtly. Hence, our study provides a feasible pharmaceutical strategy in developing the treatment for incurable ALS affecting the mankind.}, }
@article {pmid28951720, year = {2017}, author = {Galieva, LR and Mukhamedshina, YO and Arkhipova, SS and Rizvanov, AA}, title = {Human Umbilical Cord Blood Cell Transplantation in Neuroregenerative Strategies.}, journal = {Frontiers in pharmacology}, volume = {8}, number = {}, pages = {628}, pmid = {28951720}, issn = {1663-9812}, abstract = {At present there is no effective treatment of pathologies associated with the death of neurons and glial cells which take place as a result of physical trauma or ischemic lesions of the nervous system. Thus, researchers have high hopes for a treatment based on the use of stem cells (SC), which are potentially able to replace dead cells and synthesize neurotrophic factors and other molecules that stimulate neuroregeneration. We are often faced with ethical issues when selecting a source of SC. In addition to precluding these, human umbilical cord blood (hUCB) presents a number of advantages when compared with other sources of SC. In this review, we consider the key characteristics of hUCB, the results of various studies focused on the treatment of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), ischemic (stroke) and traumatic injuries of the nervous system and the molecular mechanisms of hUCB-derived mononuclear and stem cells.}, }
@article {pmid28951257, year = {2017}, author = {Meyer, M and Garay, LI and Kruse, MS and Lara, A and Gargiulo-Monachelli, G and Schumacher, M and Guennoun, R and Coirini, H and De Nicola, AF and Gonzalez Deniselle, MC}, title = {Protective effects of the neurosteroid allopregnanolone in a mouse model of spontaneous motoneuron degeneration.}, journal = {The Journal of steroid biochemistry and molecular biology}, volume = {174}, number = {}, pages = {201-216}, doi = {10.1016/j.jsbmb.2017.09.015}, pmid = {28951257}, issn = {1879-1220}, mesh = {Amyotrophic Lateral Sclerosis ; Animals ; Brain-Derived Neurotrophic Factor/genetics ; Choline O-Acetyltransferase/metabolism ; Disease Models, Animal ; Female ; Male ; Mice ; Motor Neurons/drug effects/pathology ; Nerve Degeneration/*drug therapy/genetics/metabolism ; Neuroprotective Agents/blood/pharmacology/*therapeutic use ; Nitric Oxide Synthase/metabolism ; Pregnanolone/blood/pharmacology/*therapeutic use ; Progesterone/blood/pharmacology/therapeutic use ; Receptor, trkB/genetics ; Receptors, Nerve Growth Factor/metabolism ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by progressive death of motoneurons. The Wobbler (WR) mouse is a preclinical model sharing neuropathological similarities with human ALS. We have shown that progesterone (PROG) prevents the progression of motoneuron degeneration. We now studied if allopregnanolone (ALLO), a reduced metabolite of PROG endowed with gabaergic activity, also prevents WR neuropathology. Sixty-day old WRs remained untreated or received two steroid treatment regimens in order to evaluate the response of several parameters during early or prolonged steroid administration. ALLO was administered s.c. daily for 5days (4mg/kg) or every other day for 32days (3, 3mg/kg), while another group of WRs received a 20mg PROG pellet s.c. for 18 or 60days. ALLO administration to WRs increased ALLO serum levels without changing PROG and 5 alpha dihydroprogesterone (5α-DHP), whereas PROG treatment increased PROG, 5α-DHP and ALLO. Untreated WRs showed higher basal levels of serum 5α-DHP than controls. In the cervical spinal cord we studied markers of oxidative stress or associated to trophic responses. These included nitric oxide synthase (NOS) activity, motoneuron vacuolation, MnSOD immunoreactivity (IR), brain derived neurotrophic factor (BDNF) and TrkB mRNAs, p75 neurotrophin receptor (p75NTR) and, cell survival or death signals such as pAKT and the stress activated kinase JNK. Untreated WRs showed a reduction of MnSOD-IR and BDNF/TrkB mRNAs, associated to high p75NTR in motoneurons, neuronal and glial NOS hyperactivity and neuronal vacuolation. Also, low pAKT, mainly in young WRs, and a high pJNK in the old stage characterized WŔs spinal cord. Except for MnSOD and BDNF, these alterations were prevented by an acute ALLO treatment, while short-term PROG elevated MnSOD. Moreover, after chronic administration both steroids enhanced MnSOD-IR and BDNF mRNA, while attenuated pJNK and NOS in glial cells. Long-term PROG also increased pAKT and reduced neuronal NOS, parameters not modulated by chronic ALLO. Clinically, both steroids improved muscle performance. Thus, ALLO was able to reduce neuropathology in this model. Since high oxidative stress activates p75NTR and pJNK in neurodegeneration, steroid reduction of these molecules may provide adequate neuroprotection. These data yield the first evidence that ALLO, a gabaergic neuroactive steroid, brings neuroprotection in a model of motoneuron degeneration.}, }
@article {pmid28938599, year = {2017}, author = {Wu, T and Wang, Y and Jiang, R and Lu, X and Tian, J}, title = {A pathways-based prediction model for classifying breast cancer subtypes.}, journal = {Oncotarget}, volume = {8}, number = {35}, pages = {58809-58822}, pmid = {28938599}, issn = {1949-2553}, abstract = {Breast cancer is highly heterogeneous and is classified into four subtypes characterized by specific biological traits, treatment responses, and clinical prognoses. We performed a systemic analysis of 698 breast cancer patient samples from The Cancer Genome Atlas project database. We identified 136 breast cancer genes differentially expressed among the four subtypes. Based on unsupervised clustering analysis, these 136 core genes efficiently categorized breast cancer patients into the appropriate subtypes. Functional enrichment based on Kyoto Encyclopedia of Genes and Genomes analysis identified six functional pathways regulated by these genes: JAK-STAT signaling, basal cell carcinoma, inflammatory mediator regulation of TRP channels, non-small cell lung cancer, glutamatergic synapse, and amyotrophic lateral sclerosis. Three support vector machine (SVM) classification models based on the identified pathways effectively classified different breast cancer subtypes, suggesting that breast cancer subtype-specific risk assessment based on disease pathways could be a potentially valuable approach. Our analysis not only provides insight into breast cancer subtype-specific mechanisms, but also may improve the accuracy of SVM classification models.}, }
@article {pmid28937029, year = {2017}, author = {Tao, QQ and Wu, ZY}, title = {Amyotrophic Lateral Sclerosis: Precise Diagnosis and Individualized Treatment.}, journal = {Chinese medical journal}, volume = {130}, number = {19}, pages = {2269-2272}, pmid = {28937029}, issn = {2542-5641}, mesh = {Adaptor Proteins, Signal Transducing ; Amyotrophic Lateral Sclerosis/*diagnosis/drug therapy/metabolism ; Antipyrine/analogs &amp; derivatives/therapeutic use ; Autophagy-Related Proteins ; C9orf72 Protein/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Edaravone ; Humans ; Membrane Transport Proteins ; Mitochondrial Proteins/genetics/metabolism ; Profilins/genetics/metabolism ; Protein Serine-Threonine Kinases/genetics/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Transcription Factor TFIIIA/genetics/metabolism ; Ubiquitins/genetics/metabolism ; Valosin Containing Protein/genetics/metabolism ; }, }
@article {pmid28926110, year = {2018}, author = {Bonaventura, G and Iemmolo, R and D'Amico, AG and La Cognata, V and Costanzo, E and Zappia, M and D'Agata, V and Conforti, FL and Aronica, E and Cavallaro, S}, title = {PACAP and PAC1R are differentially expressed in motor cortex of amyotrophic lateral sclerosis patients and support survival of iPSC-derived motor neurons.}, journal = {Journal of cellular physiology}, volume = {233}, number = {4}, pages = {3343-3351}, doi = {10.1002/jcp.26182}, pmid = {28926110}, issn = {1097-4652}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Motor Cortex/*metabolism ; Motor Neurons/*metabolism ; Pituitary Adenylate Cyclase-Activating Polypeptide/*metabolism ; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I/*metabolism ; Signal Transduction/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and disabling neurodegenerative disease characterized by upper and lower motor neurons depletion. In our previous work, comprehensive genomic profiling of 41 motor cortex samples enabled to discriminate controls from sporadic ALS patients, and segregated these latter into two distinct subgroups (SALS1 and SALS2), each associated with different deregulated genes. In the present study, we focused our attention on two of them, Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and its type 1 receptor (PAC1R), and validated the results of the transcriptome experiments by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), immunohistochemistry and Western blot analysis. To assess the functional role of PACAP and PAC1R in ALS, we developed an in vitro model of human induced pluripotent stem cells (iPSC)-derived motor neurons and examined the trophic effects of exogenous PACAP following neurodegenerative stimuli. Treatment with 100 nm PACAP was able to effectively rescue iPSC-derived motor neurons from apoptosis, as shown by cell viability assay and protein dosage of the apoptotic marker (BAX). All together, these data suggest that perturbations in the PACAP-PAC1R pathway may be involved in ALS pathology and represent a potential drug target to enhance motor neuron viability.}, }
@article {pmid28926091, year = {2018}, author = {Lo Furno, D and Mannino, G and Giuffrida, R}, title = {Functional role of mesenchymal stem cells in the treatment of chronic neurodegenerative diseases.}, journal = {Journal of cellular physiology}, volume = {233}, number = {5}, pages = {3982-3999}, doi = {10.1002/jcp.26192}, pmid = {28926091}, issn = {1097-4652}, mesh = {Alzheimer Disease/physiopathology/therapy ; Amyotrophic Lateral Sclerosis/physiopathology/therapy ; *Cell- and Tissue-Based Therapy ; Humans ; Huntington Disease/pathology/therapy ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology/physiology ; Neurodegenerative Diseases/physiopathology/*therapy ; Neurogenesis/*physiology ; Neurons/transplantation ; Parkinson Disease/physiopathology/therapy ; Umbilical Cord/transplantation ; }, abstract = {Mesenchymal stem cells (MSCs) can differentiate into not only cells of mesodermal lineages, but also into endodermal and ectodermal derived elements, including neurons and glial cells. For this reason, MSCs have been extensively investigated to develop cell-based therapeutic strategies, especially in pathologies whose pharmacological treatments give poor results, if any. As in the case of irreversible neurological disorders characterized by progressive neuronal death, in which behavioral and cognitive functions of patients inexorably decline as the disease progresses. In this review, we focus on the possible functional role exerted by MSCs in the treatment of some disabling neurodegenerative disorders such as Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, and Parkinson's Disease. Investigations have been mainly performed in vitro and in animal models by using MSCs generally originated from umbilical cord, bone marrow, or adipose tissue. Positive results obtained have prompted several clinical trials, the number of which is progressively increasing worldwide. To date, many of them have been primarily addressed to verify the safety of the procedures but some improvements have already been reported, fortunately. Although the exact mechanisms of MSC-induced beneficial activities are not entirely defined, they include neurogenesis and angiogenesis stimulation, antiapoptotic, immunomodulatory, and anti-inflammatory actions. Most effects would be exerted through their paracrine expression of neurotrophic factors and cytokines, mainly delivered at damaged regions, given the innate propensity of MSCs to home to injured sites. Hopefully, in the near future more efficacious cell-replacement therapies will be developed to substantially restore disease-disrupted brain circuitry.}, }
@article {pmid28923312, year = {2017}, author = {Moloudizargari, M and Asghari, MH and Ghobadi, E and Fallah, M and Rasouli, S and Abdollahi, M}, title = {Autophagy, its mechanisms and regulation: Implications in neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {40}, number = {}, pages = {64-74}, doi = {10.1016/j.arr.2017.09.005}, pmid = {28923312}, issn = {1872-9649}, mesh = {Alzheimer Disease/genetics/metabolism/pathology ; Animals ; Autophagy/*physiology ; Clinical Trials as Topic/methods ; Humans ; Neurodegenerative Diseases/genetics/*metabolism/*pathology ; Parkinson Disease/genetics/metabolism/pathology ; }, abstract = {Autophagy is a major regulatory cellular mechanism which gives the cell an ability to cope with some of the destructive events that normally occur within a metabolically living cell. This is done by maintaining the cellular homeostasis, clearance of damaged organelles and proteins and recycling necessary molecules like amino acids and fatty acids. There is a wide array of factors that influence autophagy in the state of health and disease. Disruption of these mechanisms may not only give rise to several autophagy-related disease, but also it can occur as the result of intracellular changes induced during disease pathogenesis causing exacerbation of the disease. Our knowledge is increasing regarding the role of autophagy and its mechanisms in the pathogenesis of various neurodegenerative diseases such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease and Amyotrophic lateral sclerosis. Indeed, getting to know about the pathways of autophagy and its regulation can provide the basis for designing therapeutic interventions. In the present paper, we review the pathways of autophagy, its regulation and the possible autophagy-targeting interventions for the treatment of neurodegenerative disorders.}, }
@article {pmid28920880, year = {2017}, author = {Mora, JS}, title = {Edaravone for treatment of early-stage ALS.}, journal = {The Lancet. Neurology}, volume = {16}, number = {10}, pages = {772}, doi = {10.1016/S1474-4422(17)30289-2}, pmid = {28920880}, issn = {1474-4465}, mesh = {*Amyotrophic Lateral Sclerosis ; *Antipyrine/analogs &amp; derivatives ; Edaravone ; Free Radical Scavengers ; Humans ; }, }
@article {pmid28920878, year = {2017}, author = {Akimoto, M and Nakamura, K and , }, title = {Edaravone for treatment of early-stage ALS - Authors' reply.}, journal = {The Lancet. Neurology}, volume = {16}, number = {10}, pages = {772}, doi = {10.1016/S1474-4422(17)30290-9}, pmid = {28920878}, issn = {1474-4465}, mesh = {*Amyotrophic Lateral Sclerosis ; *Antipyrine/analogs &amp; derivatives ; Edaravone ; Free Radical Scavengers ; Humans ; }, }
@article {pmid28914735, year = {2017}, author = {de Visser, M and Oliver, DJ}, title = {Palliative care in neuromuscular diseases.}, journal = {Current opinion in neurology}, volume = {30}, number = {6}, pages = {686-691}, doi = {10.1097/WCO.0000000000000493}, pmid = {28914735}, issn = {1473-6551}, mesh = {Humans ; Neuromuscular Diseases/*therapy ; Palliative Care/*methods ; }, abstract = {PURPOSE OF REVIEW: Palliative care is an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness. Neuromuscular disorders (NMDs) are characterized by progressive muscle weakness, leading to pronounced and incapacitating physical disabilities. Most NMDs are not amenable to curative treatment and would thus qualify for palliative care. Amyotrophic lateral sclerosis is a relentlessly progressive disease, which leads to death about 2 years after onset due to respiratory muscle weakness. Increasingly, neurologists caring for these patients learn to apply the principles of palliative care. However, this does not yet apply to other well known and frequently occurring NMDs.<br><br>RECENT FINDINGS: There is sparse literature on palliative care in NMDs such as Duchenne muscular dystrophy, spinal muscular atrophy, muscular dystrophies, some congenital myopathies, Pompe's disease and myotonic dystrophy type 1. These NMDs are often associated with imminent respiratory insufficiency and/or heart failure leading to a reduced life expectancy. Reasons for underutilization may include misconceptions about palliative care amongst patients, family carers and healthcare professionals or lack of awareness of the usefulness of this approach in these severely affected patients and the possibilities of integration of palliative principles into care for children and adults with NMDs.<br><br>SUMMARY: There is an urgent need for increased attention to the development of palliative care in chronic progressive neuromuscular diseases associated with increasing functional incapacities and premature death. This will require education and training of the healthcare professionals, involvement of patient associations and funding to perform research.}, }
@article {pmid28911903, year = {2017}, author = {Sui, X and Yan, L and Jiang, YY}, title = {The vaccines and antibodies associated with Als3p for treatment of Candida albicans infections.}, journal = {Vaccine}, volume = {35}, number = {43}, pages = {5786-5793}, doi = {10.1016/j.vaccine.2017.08.082}, pmid = {28911903}, issn = {1873-2518}, mesh = {Animals ; Antibodies, Fungal/*immunology ; Antibodies, Monoclonal/*immunology ; Antigens, Fungal/immunology ; Candida albicans/*immunology ; Candidiasis/*immunology ; Humans ; Vaccines/*immunology ; }, abstract = {Candida albicans is the most common fungal microorganism in healthy individuals, as well as the cause of high mortality infections in high-risk hosts such as immunocompromised patients. Antifungal vaccines and monoclonal antibodies useful for active or passive immunizations have recently generated considerable excitement for the treatment of fungal infections. The cell wall proteins of C. albicans, which are crucial for virulence and pathogenicity, are attractive target antigens. Als3p, a member of the C. albicans agglutinin-like sequence (ALS) family, is a hyphal-specific glycophosphatidylinositol cell wall protein that plays a key role in the interaction with host cells. The abundance of Als3p on the hyphal surface makes it an attractive target. For example, the NDV-3 vaccine, targeted at the N-terminus of Als3p, has entered a preparation of Phase 2 clinical trial. The Als3p-specific antibodies include monoclonal antibodies (MAbs) 3-A5, MAb 113, and scFv3. In addition, MAb C7, MAb 3D9.3 and MAb 2G8, which were supposed to be identifying other targets, have also provided good protection by recognizing Als3p. In this review, we summarize the functions of Als3p and highlight the development of the vaccines and the antibodies that are associated, directly or indirectly, with this protein.}, }
@article {pmid28884711, year = {2017}, author = {Kovrazhkina, EA and Razinskaya, OD and Gubsky, LV}, title = {[Clinical polymorphism of amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {117}, number = {8}, pages = {4-10}, doi = {10.17116/jnevro2017117814-10}, pmid = {28884711}, issn = {1997-7298}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*diagnosis/pathology/physiopathology/psychology ; Cognitive Dysfunction/diagnosis/etiology ; Disease Progression ; Electromyography ; Female ; Humans ; Male ; Middle Aged ; Motor Neurons/pathology/physiology ; }, abstract = {AIM: To clarify clinical polymorphism of amyotrophic lateral sclerosis (ALS).<br><br>MATERIAL AND METHODS: The study was based on records of a hospital personalized register. Ninety-four patients, aged from 25 to 81 years, diagnosed with ALS according to El Escorial criteria were included. Electromyography and, if necessary, transcranial magnetic stimulation and magnetic-resonance tomography were used to confirm the diagnosis. Disease progression was assessed with the ARSFRS. Age at disease onset, progression rate and duration of survival of patients, rare symptoms of ALS ('extramotor'), time for palliative care (gastrostomy, non-invasive and invasive lung ventilation) and provision of the care to the patient, family history were recorded in a specially designed questionnaire.<br><br>RESULTS: Most of the patients had sporadic ALS, only two familial cases were identified. Spinal onset ALS was found in 66.0% of the patients, bulbar onset in 29.8%, diffuse onset (spinal and bulbar motor neurons were affected simultaneously) in 4.2%. Moderate ALS progression was observed in 42.6% of the patients, mean time till death was 3.0&#xb1;1.2 years. A slow progression was found in patients with cervical, low back and bulbar onset. A rapid and even 'momentary' type of progression was in diffuse and breast onset. An extremely slow progression with the long-term hospital treatment and survival >5 years was found in 9.7%. Rare ALS symptoms were represented by specific cognitive and psychological impairments, a type of frontal/temporal dysfunction, but only 5 (5.3%) patients were diagnosed with ALS-dementia. Signs of pathological muscle fatigue (myasthenic syndrome) were identified in 18 (19.1%), extrapyramidal disorders in 5 (5.3%), coordination disorders in 4 (4.3%), pain in 12 (12.8%), sensory symptoms in 5 (5.3%) of the patients.<br><br>CONCLUSION: ALS is a multisystemic neurodegeneration disease though the progressive motor neuron death determines the fatal outcome.}, }
@article {pmid28884318, year = {2018}, author = {Brasil, AA and Magalhães, RSS and De Carvalho, MDC and Paiva, I and Gerhardt, E and Pereira, MD and Outeiro, TF and Eleutherio, ECA}, title = {Implications of fALS Mutations on Sod1 Function and Oligomerization in Cell Models.}, journal = {Molecular neurobiology}, volume = {55}, number = {6}, pages = {5269-5281}, pmid = {28884318}, issn = {1559-1182}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/*genetics ; Cell Line, Tumor ; Cell Nucleus/metabolism ; DNA Damage ; Humans ; *Models, Biological ; Mutation/*genetics ; *Protein Multimerization ; Protein Transport ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/*genetics ; }, abstract = {Among the familial forms of amyotrophic lateral sclerosis (fALS), 20% are associated with the Cu,Zn-superoxide dismutase (Sod1). fALS is characterized by the accumulation of aggregated proteins and the increase in oxidative stress markers. Here, we used the non-invasive bimolecular fluorescence complementation (BiFC) assay in human H4 cells to investigate the kinetics of aggregation and subcellular localization of Sod1 mutants. We also studied the effect of the different Sod1 mutants to respond against oxidative stress by following the levels of reactive oxygen species (ROS) after treatment with hydrogen peroxide. Our results showed that only 30% of cells transfected with A4VSod1 showed no inclusions while for the other Sod1 mutants tested (L38V, G93A and G93C), this percentage was at least 70%. In addition, we found that 10% of cells transfected with A4VSod1 displayed more than five inclusions per cell and that A4V and G93A Sod1 formed inclusions more rapidly than L38V and G93C Sod1. Expression of WTSod1 significantly decreased the intracellular oxidation levels in comparison with expression of fALS Sod1 mutants, suggesting the mutations induce a functional impairment. All fALS mutations impaired nuclear localization of Sod1, which is important for maintaining genomic stability. Consistently, expression of WTSod1, but not of fALS Sod1 mutants, reduced DNA damage, as measured by the comet assay. Altogether, our study sheds light into the effects of fALS Sod1 mutations on inclusion formation, dynamics, and localization as well as on antioxidant response, opening novel avenues for investigating the role of fALS Sod1 mutations in pathogenesis.}, }
@article {pmid28872920, year = {2017}, author = {, }, title = {Open-label 24-week extension study of edaravone (MCI-186) in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {sup1}, pages = {55-63}, doi = {10.1080/21678421.2017.1364269}, pmid = {28872920}, issn = {2167-9223}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy/mortality ; Antipyrine/adverse effects/*analogs &amp; derivatives/therapeutic use ; Double-Blind Method ; Edaravone ; Female ; Free Radical Scavengers/adverse effects/*therapeutic use ; Humans ; Male ; Middle Aged ; Nasopharyngitis/chemically induced ; Respiration Disorders/chemically induced ; Survival Rate/trends ; }, abstract = {We aimed to explore the longer-term efficacy and safety of edaravone in an active-treatment extension period following the double-blind period of the second phase III study. Patients who met all the following criteria (scores ≥2 points on all 12 items of the revised amyotrophic lateral sclerosis functional rating scale [ALSFRS-R], forced vital capacity ≥80%, definite or probable ALS, and disease duration ≤2 years) were randomised to 60 mg intravenous edaravone or placebo for six cycles in the double-blind period, and then offered the opportunity to proceed to this 24-week open-label extension period. One hundred and twenty-three of 137 patients continued to the extension period: 65 edaravone-edaravone (E-E group) and 58 placebo-edaravone (P-E group). Change (mean ± standard deviation; SD) in the ALSFRS-R score from baseline in the double-blind period was -4.1 ± 3.4 and -6.9 ± 5.1 in the E-E group and P-E group, respectively, while it was -8.0 ± 5.6 in the E-E group and -10.9 ± 6.9 in the P-E group over the whole 48-week period. The ALSFRS-R score changed almost linearly throughout Cycles 1-12 in the E-E group. The most commonly reported adverse events were constipation, dysphagia, and contusion. There was no sudden deterioration in the ALSFRS-R score of the E-E group. No safety concerns related to edaravone were detected.}, }
@article {pmid28872919, year = {2017}, author = {Kalin, A and Medina-Paraiso, E and Ishizaki, K and Kim, A and Zhang, Y and Saita, T and Wasaki, M}, title = {A safety analysis of edaravone (MCI-186) during the first six cycles (24 weeks) of amyotrophic lateral sclerosis (ALS) therapy from the double-blind period in three randomized, placebo-controlled studies.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {sup1}, pages = {71-79}, doi = {10.1080/21678421.2017.1362440}, pmid = {28872919}, issn = {2167-9223}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy/epidemiology ; Antipyrine/adverse effects/*analogs &amp; derivatives/therapeutic use ; Double-Blind Method ; Edaravone ; Female ; Free Radical Scavengers/adverse effects/*therapeutic use ; Humans ; Male ; Middle Aged ; *Patient Safety/standards ; Respiration Disorders/chemically induced/epidemiology ; }, abstract = {BACKGROUND: There continues to be a need for new therapies to treat ALS.<br><br>OBJECTIVE: Provide an overview of safety for edaravone in ALS patients during the first six cycles of treatment.<br><br>METHODS: Analysis was based on three randomised, placebo-controlled clinical trials. Endpoints included treatment-emergent adverse events (TEAEs), including AEs leading to discontinuation, serious adverse events (SAEs), and deaths.<br><br>RESULTS: The analysis included a total of 368 patients (184 in the edaravone group and placebo group, respectively). Of those, 94.6% of the edaravone group and 90.2% of placebo group completed six cycles of therapy. Baseline characteristics were comparable between the two groups. TEAE incidence in the edaravone group and placebo group was 87.5% and 87.0%, respectively. TEAEs ocurring at &#x2265;2% incidence in the edaravone group compared to placebo were contusion (14.7% vs. 8.7%), gait disturbance (12.5% vs. 9.2%), headache (8.2% vs. 5.4%), eczema (6.5% vs. 2.2%), dermatitis contact (6.0% vs. 3.3%), respiratory disorder (4.3% vs. 1.1%), and glucose urine present (3.8% vs. 1.6%). There was no imbalance in TEAEs leading to discontinuation (2.2% [edaravone], and 5.4% [placebo]). SAE incidence was 17.4% in the edaravone group and 22.3% in placebo group. Treatment-emergent deaths occurred in 2.2% in the edaravone group and 1.1% in placebo group, all respiratory in nature and attributed to worsening ALS.<br><br>CONCLUSION: Data collected from three double-blind assessments found that while some TEAEs were more common in the edaravone group compared to placebo, the overall incidences of SAEs, deaths, and discontinuations due to AEs were similar or less for edaravone compared to placebo.}, }
@article {pmid28872917, year = {2017}, author = {, }, title = {A post-hoc subgroup analysis of outcomes in the first phase III clinical study of edaravone (MCI-186) in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {sup1}, pages = {11-19}, doi = {10.1080/21678421.2017.1363780}, pmid = {28872917}, issn = {2167-9223}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Antipyrine/*analogs &amp; derivatives/therapeutic use ; Double-Blind Method ; Edaravone ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Middle Aged ; Treatment Outcome ; }, abstract = {Our first phase III study failed to demonstrate efficacy of edaravone for amyotrophic lateral sclerosis (ALS) compared to placebo. Here, we performed post-hoc subgroup analysis to identify a subgroup in which edaravone might be expected to show efficacy. We focussed on two newly defined subgroups, EESP and dpEESP2y. The EESP was defined as the efficacy-expected subpopulation with % forced vital capacity of ≥80%, and ≥2 points for all item scores in the revised ALS functional rating scale (ALSFRS-R) score before treatment. The dpEESP2y was defined as the greater-efficacy-expected subpopulation within EESP having a diagnosis of 'definite' or 'probable' ALS according to the El Escorial revised Airlie House diagnostic criteria and onset of disease within two years. The primary endpoint of the post-hoc analysis was the change in the ALSFRS-R score during the 24-week treatment period. The intergroup differences of the least-squares mean change in the ALSFRS-R score ± standard error during treatment were 0.65 ± 0.78 (p = 0.4108) in the full analysis set, 2.20 ± 1.03 (p = 0.0360) in the EESP, and 3.01 ± 1.33 (p = 0.0270) in the dpEESP2y. Edaravone exhibited efficacy in the dpEESP2y subgroup. A further clinical study in patients meeting dpEESP2y criteria is warranted.}, }
@article {pmid28872916, year = {2017}, author = {Takei, K and Tsuda, K and Takahashi, F and Palumbo, J}, title = {Post-hoc analysis of open-label extension period of study MCI186-19 in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {sup1}, pages = {64-70}, doi = {10.1080/21678421.2017.1365372}, pmid = {28872916}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy/physiopathology ; Antipyrine/*analogs &amp; derivatives/pharmacology/therapeutic use ; Double-Blind Method ; Edaravone ; Female ; Free Radical Scavengers/pharmacology/*therapeutic use ; Hand Strength/physiology ; Humans ; Male ; Prospective Studies ; }, abstract = {Study MCI186-19 investigated the safety and efficacy of edaravone in the treatment of ALS. The 24-week, double-blind period was followed by a 24-week, open-label, active extension period. Patients originally receiving edaravone continued edaravone (E-E group, n = 65), and patients originally receiving placebo switched to edaravone (P-E group, n = 58). Because no statistical tests had been prospectively planned in the open-label period, we performed post-hoc analyses to assist in the interpretation of efficacy data. A mixed model for repeated measures (MMRM) and the Combined Assessment of Function and Survival (CAFS) were assessed. Additionally, slopes of time-dependent change between baseline in cycle 1 and the end of cycle 6 (24 weeks double-blind) and between the end of cycle 6 and end of cycle 12 (24 weeks open-label) were calculated using a random coefficient model including all available data during each period. At week 48, the MMRM analysis showed significantly less decline in ALS Functional Rating Scale-Revised (ALSFRS-R) total score in the E-E group than in the P-E group (least-squares mean change from baseline ± standard error, 4.17 ± 1.40, p = 0.0037), meaning that the differences in the ALSFRS-R total score during the 24-week double-blind period were maintained in patients receiving edaravone for an additional 24 weeks. The CAFS endpoint (p = 0.0089) supported this finding. The slope analysis during the double-blind period showed a significant difference between the treatment groups, while there was no significant difference between the groups during the active extension period. These analyses suggest a potential benefit of early and continued edaravone treatment over delayed edaravone treatment.}, }
@article {pmid28872915, year = {2017}, author = {, }, title = {Exploratory double-blind, parallel-group, placebo-controlled study of edaravone (MCI-186) in amyotrophic lateral sclerosis (Japan ALS severity classification: Grade 3, requiring assistance for eating, excretion or ambulation).}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {sup1}, pages = {40-48}, doi = {10.1080/21678421.2017.1361441}, pmid = {28872915}, issn = {2167-9223}, mesh = {*Activities of Daily Living ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy/physiopathology ; Antipyrine/*analogs &amp; derivatives/pharmacology/therapeutic use ; Double-Blind Method ; Eating/*drug effects/physiology ; Edaravone ; Female ; Free Radical Scavengers/pharmacology/*therapeutic use ; Humans ; Japan/epidemiology ; Male ; Middle Aged ; *Mobility Limitation ; Placebo Effect ; Severity of Illness Index ; }, abstract = {Our objective was to explore the efficacy and safety of edaravone in amyotrophic lateral sclerosis (ALS) patients with a Japan ALS severity classification of Grade 3. In a 24-week, double-blind, randomized study, 25 patients who met all of the following criteria were enrolled: Japan ALS severity classification Grade 3; definite, probable, or probable-laboratory supported ALS (El Escorial/revised Airlie House); forced vital capacity (%FVC) ≥60%; duration of disease ≤3 years at consent; and change in the revised ALS functional rating scale (ALSFRS-R) score of -1 to -4 points during the 12-week pre-observation period. Patients received edaravone (n = 13) or placebo (n = 12) for six cycles. The efficacy outcome was change in the ALSFRS-R score. The least-squares mean change in the ALSFRS-R score ± standard error during the 24-week treatment was -6.52 ± 1.78 in the edaravone group and -6.00 ± 1.83 in the placebo group; the difference of -0.52 ± 2.46 was not statistically significant (p = 0.835). Incidence of adverse events was 92.3% (12/13) in the edaravone group and 100.0% (12/12) in the placebo group. There was no intergroup difference in the changes in the ALSFRS-R score. The incidences of adverse events were similar in the two groups.}, }
@article {pmid28872913, year = {2017}, author = {Takei, K and Takahashi, F and Liu, S and Tsuda, K and Palumbo, J}, title = {Post-hoc analysis of randomised, placebo-controlled, double-blind study (MCI186-19) of edaravone (MCI-186) in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {sup1}, pages = {49-54}, doi = {10.1080/21678421.2017.1361443}, pmid = {28872913}, issn = {2167-9223}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy/physiopathology ; Antipyrine/*analogs &amp; derivatives/therapeutic use ; Double-Blind Method ; Edaravone ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Middle Aged ; }, abstract = {Post-hoc analyses of the ALS Functional Rating Scale-Revised (ALSFRS-R) score data, the primary endpoint in the 24-week double-blind placebo-controlled study of edaravone (MCI186-19, NCT01492686), were performed to confirm statistical robustness of the result. The previously reported original analysis had used a last observation carried forward (LOCF) method and also excluded patients with fewer than three completed treatment cycles. The post-hoc sensitivity analyses used different statistical methods as follows: 1) including all patients regardless of treatment cycles received (ALL LOCF); 2) a mixed model for repeated measurements (MMRM) analysis; and 3) the Combined Assessment of Function and Survival (CAFS) endpoint. Findings were consistent with the original primary analysis in showing superiority of edaravone over placebo. We also investigated the distribution of change in ALSFRS-R total score across all patients in the study as well as which ALSFRS-R items and domains may have contributed to the overall efficacy findings. The distribution of changes in ALSFRS-R total score from baseline to the end of cycle 6 (ALL LOCF) shifted in favour of edaravone compared to placebo. Edaravone was descriptively favoured for each ALSFRS-R item and each of the four ALSFRS-R domains at the end of cycle 6 (ALL LOCF), suggesting a generalised effect of edaravone in slowing functional decline across all anatomical regions. The effect of edaravone appeared to be similar in patients with bulbar onset and limb onset. Together, these observations would be consistent with its putative neuroprotective effects against the development of oxidative damage unspecific to anatomical regions.}, }
@article {pmid28872912, year = {2017}, author = {Takei, K and Tsuda, K and Takahashi, F and Hirai, M and Palumbo, J}, title = {An assessment of treatment guidelines, clinical practices, demographics, and progression of disease among patients with amyotrophic lateral sclerosis in Japan, the United States, and Europe.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {sup1}, pages = {88-97}, doi = {10.1080/21678421.2017.1361445}, pmid = {28872912}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/drug therapy/*epidemiology ; Clinical Trials as Topic/methods/standards ; Demography/methods/*standards ; *Disease Progression ; Europe/epidemiology ; Female ; Humans ; Japan/epidemiology ; Male ; Neuroprotective Agents/therapeutic use ; Practice Guidelines as Topic/*standards ; United States/epidemiology ; }, abstract = {BACKGROUND: There is an increasing clinical research focus on neuroprotective agents in amyotrophic lateral sclerosis (ALS). However, it is unclear how generalisable clinical study trial results are between different countries and regions.<br><br>OBJECTIVE: To assess similarities and differences in clinical practice and treatment guidelines for ALS, and also to compare the demographics and rate of progression of disease in patients with ALS enrolled in clinical trials in Japan, the US, and Europe.<br><br>METHODS: We performed a review of clinical studies published since 2000 to compare the demographics and characteristics of patients with ALS. Progression of ALS disease was assessed in patients receiving placebo. The changes per month in ALSFRS-R score were calculated and compared between the studies.<br><br>RESULTS: Overall, diagnostic criteria, recognition of ALS symptoms, comorbidities, use of riluzole, and nutritional, and respiratory support were similar. Regarding demographics and characteristics, there were no clear differences in the incidence of sporadic ALS (range 91-98%), bulbar onset (range 11-41%), and median time from onset to diagnosis (range 9-14 months) among the populations despite the difference in race between regions. However, use of tracheostomy-based invasive respiratory support was higher in Japan (29-38%) than in the US (4%) and Europe (1-31%). Rate of progression of disease was similar between the US and Europe study populations (range -0.89 to -1.60 points/month), and the Japanese study populations (range -1.03 to -1.21 points/month).<br><br>CONCLUSION: There is evidence to support the generalisability of data from the Japanese ALS trial experience to the US and Europe populations in early to mid-stage of ALS.}, }
@article {pmid28872911, year = {2017}, author = {Maragakis, NJ}, title = {What can we learn from the edaravone development program for ALS?.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {sup1}, pages = {98-103}, doi = {10.1080/21678421.2017.1361446}, pmid = {28872911}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/*drug therapy ; Antipyrine/*analogs &amp; derivatives/therapeutic use ; Clinical Trials as Topic/methods/standards ; Edaravone ; Free Radical Scavengers/*therapeutic use ; Humans ; Program Development/*methods/standards ; }, abstract = {Edaravone's development into an ALS therapeutic has been a process which began with preclinical studies regarding its potential in targeting ALS. Despite edaravone's inability to show benefit in a general ALS population, an important post-hoc analysis showed that a clinical subset of patients had benefit. Most importantly, a subsequent study examining the capacity of edaravone to have benefit in this specific subset of ALS patients was successful in meeting its primary outcome measures. Questions regarding whether the dosing regimen could be simplified or improved, the duration of the effects, and the timing of the potential treatment to different stages of disease remain to be answered. However, the benefit of this compound in delivering a meaningful therapy to ALS patients and the lessons learned with regard to its development should widen interest in clinical research so that additional strategies for treating ALS may become available to patients.}, }
@article {pmid28872909, year = {2017}, author = {Miller, RG and Appel, SH}, title = {Introduction to supplement: the current status of treatment for ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {sup1}, pages = {1-4}, doi = {10.1080/21678421.2017.1361447}, pmid = {28872909}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Anti-Inflammatory Agents/therapeutic use ; Dietary Supplements ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Quality of Health Care/standards ; Riluzole/therapeutic use ; Treatment Outcome ; }, abstract = {ALS is a lethal neurodegenerative disease wherein the diagnosis is often delayed. Our understanding of the pathobiology is slowly expanding, and the number of new genes is rapidly increasing. The development of potential treatments targeting specific mechanisms is beginning to offer hope. Evidence-based treatments and the development of quality measures have raised the standard of care. The current status of treatment for ALS includes one drug riluzole that slows progression modestly, and another drug edaravone that was recently approved by FDA to slow ALS progression. Multidisciplinary clinics and symptomatic treatments ease the burden of ALS and prolong life. An overview of these treatments is provided here.}, }
@article {pmid28872907, year = {2017}, author = {Takei, K and Watanabe, K and Yuki, S and Akimoto, M and Sakata, T and Palumbo, J}, title = {Edaravone and its clinical development for amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {sup1}, pages = {5-10}, doi = {10.1080/21678421.2017.1353101}, pmid = {28872907}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/*metabolism ; Antipyrine/*analogs &amp; derivatives/pharmacology/therapeutic use ; Clinical Trials as Topic/methods ; Edaravone ; Free Radical Scavengers/pharmacology/*therapeutic use ; Humans ; Oxidative Stress/*drug effects/physiology ; }, abstract = {The etiology of amyotrophic lateral sclerosis (ALS) is unknown. Oxidative stress may be one of the major mechanisms involved. In vitro and in vivo data of edaravone suggest that it may possess broad free radical scavenging activity and protect neurons, glia, and vascular endothelial cells against oxidative stress. During the 1980s and 1990s, edaravone was developed for the treatment of acute ischemic stroke. In 2001, a clinical program in ALS was initiated and five clinical studies were conducted in Japan. Phase III studies were designed to rapidly evaluate (within a 24-week double-blind study window) functional changes using the Revised ALS Functional Rating Scale (ALSFRS-R) as a primary endpoint. The study populations were selected according to these considerations and were further refined as the studies proceeded. Although the first phase III study did not meet its primary endpoint, post-hoc analyses showed an apparent effect of edaravone, when additional patient inclusion criteria defined by ALSFRS-R score, pulmonary function, certainty of ALS diagnosis, and duration of disease were applied. This population was hypothesized not only to have retained broad functionality and normal respiratory function at study baseline but also to be likely to show measurable disease progression over 24 weeks. A second confirmatory phase III study applying these refinements in patient selection was prospectively designed and successfully documented a statistically significant difference between the edaravone and placebo groups in the ALSFRS-R primary endpoint. This paper describes and reviews data pertinent to the potential mechanism of action of edaravone, and reviews the development history of edaravone for the treatment of ALS.}, }
@article {pmid28872050, year = {2017}, author = {Fang, S and Wang, H and Liu, Y and Zhang, M and Yang, W and Feng, Q and Chen, W and Zhang, Y}, title = {Super-resolution reconstruction of 4D-CT lung data via patch-based low-rank matrix reconstruction.}, journal = {Physics in medicine and biology}, volume = {62}, number = {20}, pages = {7925-7937}, doi = {10.1088/1361-6560/aa8a48}, pmid = {28872050}, issn = {1361-6560}, mesh = {*Algorithms ; Disease Progression ; Four-Dimensional Computed Tomography/*methods ; Humans ; Image Processing, Computer-Assisted/*methods ; Lung Neoplasms/*diagnostic imaging ; Movement/*physiology ; Radionuclide Imaging ; }, abstract = {Lung 4D computed tomography (4D-CT), which is a time-resolved CT data acquisition, performs an important role in explicitly including respiratory motion in treatment planning and delivery. However, the radiation dose is usually reduced at the expense of inter-slice spatial resolution to minimize radiation-related health risk. Therefore, resolution enhancement along the superior-inferior direction is necessary. In this paper, a super-resolution (SR) reconstruction method based on a patch low-rank matrix reconstruction is proposed to improve the resolution of lung 4D-CT images. Specifically, a low-rank matrix related to every patch is constructed by using a patch searching strategy. Thereafter, the singular value shrinkage is employed to recover the high-resolution patch under the constraints of the image degradation model. The output high-resolution patches are finally assembled to output the entire image. This method is extensively evaluated using two public data sets. Quantitative analysis shows that the proposed algorithm decreases the root mean square error by 9.7%-33.4% and the edge width by 11.4%-24.3%, relative to linear interpolation, back projection (BP) and Zhang et al's algorithm. A new algorithm has been developed to improve the resolution of 4D-CT. In all experiments, the proposed method outperforms various interpolation methods, as well as BP and Zhang et al's method, thus indicating the effectivity and competitiveness of the proposed algorithm.}, }
@article {pmid28871219, year = {2017}, author = {Fabbrizio, P and Amadio, S and Apolloni, S and Volonté, C}, title = {P2X7 Receptor Activation Modulates Autophagy in SOD1-G93A Mouse Microglia.}, journal = {Frontiers in cellular neuroscience}, volume = {11}, number = {}, pages = {249}, pmid = {28871219}, issn = {1662-5102}, abstract = {Autophagy and inflammation play determinant roles in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), an adult-onset neurodegenerative disease characterized by deterioration and final loss of upper and lower motor neurons (MN) priming microglia to sustain neuroinflammation and a vicious cycle of neurodegeneration. Given that extracellular ATP through P2X7 receptor constitutes a neuron-to-microglia alarm signal implicated in ALS, and that P2X7 affects autophagy in immune cells, we have investigated if autophagy can be directly triggered by P2X7 activation in primary microglia from superoxide dismutase 1 (SOD1)-G93A mice. We report that P2X7 enhances the expression of the autophagic marker microtubule-associated protein 1 light chain 3 (LC3)-II, via mTOR pathway and concomitantly with modulation of anti-inflammatory M2 microglia markers. We also demonstrate that the autophagic target SQSTM1/p62 is decreased in SOD1-G93A microglia after a short stimulation of P2X7, but increased after a sustained challenge. These effects are prevented by the P2X7 antagonist A-804598, and the autophagy/phosphoinositide-3-kinase inhibitor wortmannin (WM). Finally, a chronic in vivo treatment with A-804598 in SOD1-G93A mice decreases the expression of SQSTM1/p62 in lumbar spinal cord at end stage of disease. These data identify the modulation of the autophagic flux as a novel mechanism by which P2X7 activates ALS-microglia, to be considered for further investigations in ALS.}, }
@article {pmid28867362, year = {2017}, author = {Falcão de Campos, C and de Carvalho, M}, title = {Riluzole-induced recurrent pancreatitis.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {45}, number = {}, pages = {153-154}, doi = {10.1016/j.jocn.2017.08.032}, pmid = {28867362}, issn = {1532-2653}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/adverse effects ; Pancreatitis/*chemically induced ; Riluzole/*adverse effects/therapeutic use ; }, abstract = {Riluzole is the only drug approved for the treatment of patients with Amyotrophic Lateral Sclerosis (ALS). It is well tolerated, being the most frequent adverse effects asthenia, nausea and reversible increase of liver enzymes levels. Severe adverse effects are extremely rare. We report for the first time, two patients with sporadic limb-onset ALS who developed recurrent acute pancreatitis (AP), with portal vein thrombosis as complication, during treatment with riluzole. We suggest that AP should be considered asa probable rare and severe side effect of treatment with riluzole in patients with ALS. We believe that in patients who develop AP during treatment with riluzole, its withdrawn may prevent recurrent AP and should be discussed with patients.}, }
@article {pmid28864675, year = {2017}, author = {McDonnell, E and Schoenfeld, D and Paganoni, S and Atassi, N}, title = {Causal inference methods to study gastric tube use in amyotrophic lateral sclerosis.}, journal = {Neurology}, volume = {89}, number = {14}, pages = {1483-1489}, pmid = {28864675}, issn = {1526-632X}, support = {U01 NS049640/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/epidemiology/*psychology/*therapy ; Disease Progression ; Enteral Nutrition/*methods ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; *Quality of Life ; Respiration, Artificial/methods ; *Survival/psychology ; Survival Analysis ; Vital Capacity ; }, abstract = {OBJECTIVE: To estimate effects of gastric tube (G-tube) on survival and quality of life (QOL) in people with amyotrophic lateral sclerosis (ALS) correcting for confounding by indication inherent in nonrandomized observational data.<br><br>METHODS: To complement a recent causal inference analysis, which concluded that G-tube placement increases the hazard of death, permanent assisted ventilation, or tracheostomy by 28%, we fit causal inference models on a different sample of 481 patients with ALS enrolled in a recent clinical trial of ceftriaxone. Forward selection identified predictors of G-tube placement. Effects of G-tube on survival and QOL were estimated using structural nested models and marginal structural models, accounting for predictors of G-tube treatment.<br><br>RESULTS: Forced vital capacity and the total score and bulbar subscale of the revised ALS Functional Rating Scale best predicted G-tube placement. Correcting for these confounders, G-tube placement decreased survival time by 46% (p < 0.001) and had no effect on QOL (p = 0.078). Sensitivity survival analyses varied in significance, but none revealed a survival benefit.<br><br>CONCLUSIONS: In the absence of randomization, causal inference methods are necessary to correct for time-varying confounding. G-tube placement may have a negative effect on survival with no QOL-related benefit for people with ALS. A randomized controlled trial is warranted to further evaluate the efficacy of this widely used intervention.<br><br>CLINICALTRIALSGOV IDENTIFIER: NCT00349622.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with ALS, G-tube placement decreases survival time and does not affect QOL.}, }
@article {pmid28861496, year = {2016}, author = {Haug, NA and Kieschnick, D and Sottile, JE and Babson, KA and Vandrey, R and Bonn-Miller, MO}, title = {Training and Practices of Cannabis Dispensary Staff.}, journal = {Cannabis and cannabinoid research}, volume = {1}, number = {1}, pages = {244-251}, pmid = {28861496}, issn = {2578-5125}, abstract = {Introduction: The proliferation of cannabis dispensaries within the United States has emerged from patient demand for the legalization of cannabis as an alternative treatment for a number of conditions and symptoms. Unfortunately, nothing is known about the practices of dispensary staff with respect to recommendation of cannabis strains/concentrations for specific patient ailments. To address this limitation, the present study assessed the training and practices of cannabis dispensary staff. Materials and Methods: Medical and nonmedical dispensary staff (n=55) were recruited via e-mail and social media to complete an online survey assessing their demographic characteristics, dispensary features, patient characteristics, formal training, and cannabis recommendation practices. Results: Fifty-five percent of dispensary staff reported some formal training for their position, with 20% reporting medical/scientific training. A majority (94%) indicated that they provide specific cannabis advice to patients. In terms of strains, dispensary staff trended toward recommendations of Indica for anxiety, chronic pain, insomnia, nightmares, and Tourette's syndrome. They were more likely to recommend Indica and hybrid plants for post-traumatic stress disorder (PTSD)/trauma and muscle spasms. In contrast, staff were less likely to recommend Indica for depression; hybrid strains were most often recommended for amyotrophic lateral sclerosis (ALS). In terms of cannabinoid concentrations, dispensary staff were most likely to recommend a 1:1 ratio of delta-9-tetrahydrocannabinol (THC):cannabidiol (CBD) for patients suffering from anxiety, Crohn's disease, hepatitis C, and PTSD/trauma, while patients seeking appetite stimulation were most likely to be recommended THC. Staff recommended high CBD for arthritis and Alzheimer's disease and a high CBD or 1:1 ratio for ALS, epilepsy, and muscle spasms. Conclusions: Although many dispensary staff are making recommendations consistent with current evidence, some are recommending cannabis that has either not been shown effective for, or could exacerbate, a patient's condition. Findings underscore the importance of consistent, evidence-based, training of dispensary staff who provide specific recommendations for patient medical conditions.}, }
@article {pmid28861148, year = {2017}, author = {Zhu, Q and Luo, M and Zhou, C and Zhou, Z and He, Z and Yu, X and Zhou, S}, title = {A proteomics-based investigation on the anticancer activity of alisertib, an Aurora kinase A inhibitor, in hepatocellular carcinoma Hep3B cells.}, journal = {American journal of translational research}, volume = {9}, number = {8}, pages = {3558-3572}, pmid = {28861148}, issn = {1943-8141}, abstract = {Targeted therapy may provide survival benefit for advanced hepatocellular carcinoma (HCC) and Aurora A kinase (AURKA) represents a feasible target in cancer treatment. The purpose of this study is to investigate the anticancer activity of alisertib (ALS) on Hep3B cells based on a proteomic study conducted with the stable-isotope labeling by amino acids in cell culture (SILAC). The proteomic response to ALS was obtained with SILAC-based proteomic study. Cell cycle distribution and apoptosis were assessed using flow cytometry and autophagy was determined using flow cytometry and confocal microscopy. ALS inhibited the proliferation of Hep3B cells, with IC50 values for 24- and 48-h exposure of 46.8 and 28.0 μM, respectively. Our SILAC study demonstrated that there were at least 565 proteins responding to ALS treatment, with 256 upregulated, 275 downregulated and 35 stable. Ninety-four signaling pathways, majority of which involved cell proliferation and survival, programmed cell death, and nutrition and energy metabolism, were regulated by ALS. ALS significantly inhibited the phosphorylation of AURKA at Thr288 in a concentration-dependent manner. Subsequent study showed that ALS remarkably arrested Hep3B cells in G2/M phase via regulating the expression of key cell cycle regulators, and induced a marked autophagy via the PI3K/Akt/mTOR axis. Inhibition of autophagy enhanced the anticancer activity of ALS in Hep3B cells. Overall, ALS leads to comprehensive proteomic response, inhibits cellular proliferation, and induces cell cycle arrest and autophagy in Hep3B cells. Further studies are warranted to explore the role of ALS in the treatment of HCC.}, }
@article {pmid28856541, year = {2018}, author = {Budge, KM and Neal, ML and Richardson, JR and Safadi, FF}, title = {Glycoprotein NMB: an Emerging Role in Neurodegenerative Disease.}, journal = {Molecular neurobiology}, volume = {55}, number = {6}, pages = {5167-5176}, pmid = {28856541}, issn = {1559-1182}, mesh = {Animals ; Humans ; Immune System/metabolism ; Membrane Glycoproteins/chemistry/*metabolism ; Nerve Degeneration/pathology ; Neurodegenerative Diseases/*metabolism/therapy ; }, abstract = {Neurodegeneration is characterized by severe neuronal loss leading to the cognitive and physical impairments that define various neurodegenerative diseases. Neuroinflammation is one hallmark of neurodegenerative diseases and can ultimately contribute to disease progression. Increased inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1β (IL-1 β), and tumor necrosis factor-α (TNF-α) are associated with Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Unfortunately, current therapeutic options lack ability to stop or effectively slow progression of these diseases and are primarily aimed at alleviating symptoms. Thus, it is crucial to discover novel treatment candidates for neurodegenerative diseases. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type-I transmembrane glycoprotein first identified in a melanoma cell line. GPNMB augments bone mineral deposition by stimulating osteoblast differentiation. Aside from its anabolic function in the bone, emerging evidence suggests that GPNMB has anti-inflammatory and reparative functions. GPNMB has also been demonstrated to be neuroprotective in an animal model of ALS, cerebral ischemia, and other disease models. Given these discoveries, GPNMB should be investigated as a potential therapeutic option for multiple neurodegenerative diseases.}, }
@article {pmid28855568, year = {2017}, author = {Tan, SH and Lee, A and Pascovici, D and Care, N and Birzniece, V and Ho, K and Molloy, MP and Khan, A}, title = {Plasma biomarker proteins for detection of human growth hormone administration in athletes.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {10039}, pmid = {28855568}, issn = {2045-2322}, mesh = {Adolescent ; Adult ; Apolipoprotein L1/*blood ; Athletes ; Biomarkers/blood ; Female ; Human Growth Hormone/administration &amp; dosage/*blood ; Humans ; Male ; Proteome/chemistry ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Substance Abuse Detection/*methods ; alpha-2-HS-Glycoprotein/*analysis ; }, abstract = {Human growth hormone (GH) is a naturally occurring hormone secreted by the pituitary gland with anabolic and growth-promoting activities. Since an increased availability of recombinant GH (rGH) for the treatment of GH-deficient patients, GH has been abused in sports and it is prohibited. "GH-isoform" and "biomarkers" tests are currently available for detection of GH abuse in sports, however both methods suffer from shortcomings. Here, we report on a proteomic approach to search for novel protein biomarkers associated with rGH administration in non-elite athletes. In this study, participants received either placebo or rGH for 8 weeks, and were followed over a 6-week washout period. We used 2-D DIGE and iTRAQ LC-MS/MS analyses to expose rGH-dependent marker proteins. Eight rGH-dependent plasma proteins namely apolipoproptein-L1, alpha-HS-glycoprotein, vitamin D-binding protein, afamin, insulin-like growth factor-binding protein-3, insulin-like growth factor-binding protein-ALS, lumican and extracellular matrix proteins 1 were identified. Apolipoprotein L1 and alpha-HS-glycoprotein were validated by Western blots to confirm their identities and expression patterns in rGH- and placebo-treated subject cohorts. Independent confirmation of these putative GH-responsive biomarkers would be of value for clinical practices and may have sports anti-doping utility.}, }
@article {pmid28848566, year = {2017}, author = {Duhoux, A and Pernin, F and Desserre, D and Délye, C}, title = {Herbicide Safeners Decrease Sensitivity to Herbicides Inhibiting Acetolactate-Synthase and Likely Activate Non-Target-Site-Based Resistance Pathways in the Major Grass Weed Lolium sp. (Rye-Grass).}, journal = {Frontiers in plant science}, volume = {8}, number = {}, pages = {1310}, pmid = {28848566}, issn = {1664-462X}, abstract = {Herbicides are currently pivotal to control weeds and sustain food security. Herbicides must efficiently kill weeds while being as harmless as possible for crops, even crops taxonomically close to weeds. To increase their selectivity toward crops, some herbicides are sprayed in association with safeners that are bioactive compounds exacerbating herbicide-degrading pathways reputedly specifically in crops. However, exacerbated herbicide metabolism is also a key mechanism underlying evolved non-target-site-based resistance to herbicides (NTSR) in weeds. This raised the issue of a possible role of safeners on NTSR evolution in weeds. We investigated a possible effect of the respective field rates of the two broadly used safeners cloquintocet-mexyl and mefenpyr-diethyl on the sensitivity of the troublesome global weed Lolium sp. (rye-grass) to the major herbicides inhibiting acetolactate-synthase (ALS) pyroxsulam and iodosulfuron + mesosulfuron, respectively. Three Lolium sp. populations were studied in three series of experiments. The first experiment series compared the frequencies of plants surviving application of each herbicide alone or in association with its safener. Safener co-application caused a net increase ranging from 5.0 to 46.5% in the frequency of plants surviving the field rate of their associated herbicide. In a second series of experiments, safener effect was assessed on individual plant sensitivity using vegetative propagation. A reduction in sensitivity to pyroxsulam and to iodosulfuron + mesosulfuron was observed for 44.4 and 11.1% of the plants in co-treatment with cloquintocet-mexyl and mefenpyr-diethyl, respectively. A third series of experiments investigated safener effect on the expression level of 19 Lolium sp. NTSR marker genes. Safeners showed an enhancing effect on the expression level of 10 genes. Overall, we demonstrated that cloquintocet-mexyl and mefenpyr-diethyl both reduced the sensitivity of Lolium sp. to their associated ALS-inhibiting herbicide and most likely exacerbated herbicide-degrading secondary metabolism pathways. This suggests that genetic variation for safener response is present in Lolium sp. Thus, a possible, uninvestigated way to NTSR evolution could be selection for increased responsiveness to safener action. Delivering safeners exclusively to the crop could mitigate the risk for NTSR evolution in weeds.}, }
@article {pmid28842862, year = {2018}, author = {Tan, VX and Lassus, B and Lim, CK and Tixador, P and Courte, J and Bessede, A and Guillemin, GJ and Peyrin, JM}, title = {Neurotoxicity of the Cyanotoxin BMAA Through Axonal Degeneration and Intercellular Spreading.}, journal = {Neurotoxicity research}, volume = {33}, number = {1}, pages = {62-75}, pmid = {28842862}, issn = {1476-3524}, support = {43449247//Macquarie University/ ; }, mesh = {Amino Acids, Diamino/*toxicity ; Analysis of Variance ; Animals ; Axons/*drug effects/pathology ; Brain/cytology ; Cells, Cultured ; Cyanobacteria Toxins ; Dose-Response Relationship, Drug ; Embryo, Mammalian ; Glial Fibrillary Acidic Protein/metabolism ; Lab-On-A-Chip Devices ; Mice ; Microtubule-Associated Proteins/metabolism ; Nerve Degeneration/*chemically induced/*pathology ; Nerve Net/drug effects/metabolism ; Neurons/cytology/*drug effects ; Neurotoxins/*toxicity ; Transcytosis/drug effects ; Tubulin/metabolism ; }, abstract = {β-Methylamino-L-alanine (BMAA) is implicated in neurodegeneration and neurotoxicity, particularly in ALS-Parkinson Dementia Complex. Neurotoxic properties of BMAA have been partly elucidated, while its transcellular spreading capacity has not been examined. Using reconstructed neuronal networks in microfluidic chips, separating neuronal cells into two subcompartments-(1) the proximal, containing first-order neuronal soma and dendrites, and (2) a distal compartment, containing either only axons originating from first-order neurons or second-order striatal neurons-creates a cortico-striatal network. Using this system, we investigated the toxicity and spreading of BMAA in murine primary neurons. We used a newly developed antibody to detect BMAA in cells. After treatment with 10 μM BMAA, the cyanotoxin was incorporated in first-degree neurons. We also observed a rapid trans-neuronal spread of BMAA to unexposed second-degree neurons in 48 h, followed by axonal degeneration, with limited somatic death. This in vitro study demonstrates BMAA axonal toxicity at sublethal concentrations and, for the first time, the transcellular spreading abilities of BMAA. This neuronal dying forward spread that could possibly be associated with progression of some neurodegenerative diseases especially amyotrophic lateral sclerosis.}, }
@article {pmid28840457, year = {2017}, author = {Friedman, MJ and Huber, BR and Brady, CB and Ursano, RJ and Benedek, DM and Kowall, NW and McKee, AC and , }, title = {VA's National PTSD Brain Bank: a National Resource for Research.}, journal = {Current psychiatry reports}, volume = {19}, number = {10}, pages = {73}, pmid = {28840457}, issn = {1535-1645}, mesh = {Biomedical Research/*organization &amp; administration ; Brain/*pathology ; Humans ; Stress Disorders, Post-Traumatic/*pathology ; Tissue Banks/*organization &amp; administration ; United States ; *United States Department of Veterans Affairs ; }, abstract = {The National PTSD Brain Bank (NPBB) is a brain tissue biorepository established to support research on the causes, progression, and treatment of PTSD. It is a six-part consortium led by VA's National Center for PTSD with participating sites at VA medical centers in Boston, MA; Durham, NC; Miami, FL; West Haven, CT; and White River Junction, VT along with the Uniformed Services University of Health Sciences. It is also well integrated with VA's Boston-based brain banks that focus on Alzheimer's disease, ALS, chronic traumatic encephalopathy, and other neurological disorders. This article describes the organization and operations of NPBB with specific attention to: tissue acquisition, tissue processing, diagnostic assessment, maintenance of a confidential data biorepository, adherence to ethical standards, governance, accomplishments to date, and future challenges. Established in 2014, NPBB has already acquired and distributed brain tissue to support research on how PTSD affects brain structure and function.}, }
@article {pmid28834910, year = {2017}, author = {Park, D}, title = {Application of different ventilator modes in patients with amyotrophic lateral sclerosis according to certain clinical situations: A Case Report.}, journal = {Medicine}, volume = {96}, number = {34}, pages = {e7899}, pmid = {28834910}, issn = {1536-5964}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Male ; Middle Aged ; Respiration, Artificial/*methods ; Respiratory Insufficiency/*etiology/*therapy ; }, abstract = {RATIONALE: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that involves limb, axial, bulbar, and respiratory muscles. Fatigue and weakness of the respiratory muscles eventually induce respiratory insufficiency, which is one of the main causes of death in patients with ALS. In ALS patients with respiratory insufficiency, application of a ventilator is indispensable. Although there are various modes of ventilation, these modes are classified roughly into volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV). There have been several reports that VCV is preferable to PCV in neuromuscular disorder patients, such as ALS patients, but there is still debate on which ventilator mode is better.<br><br>PATIENT CONCERNS: Respiratory difficulty despite ventilator application.<br><br>DIAGNOSIS: Three ALS patients with respiratory difficulty.<br><br>INTERVENTION: Changing ventilator mode to improve symptoms of respiratory difficulty.<br><br>OUTCOMES: Considering case 1 shows that the VCV mode may have an advantage in managing respiratory insufficiency of patients in situations where the inner diameter of the airway decreases because of increased sputum. In contrast, cases 2 and 3, it is shown that changing to the PCV mode may be one of the treatment options if not enough tidal volume can be supplied to resolve respiratory insufficiency because of an increase in leakage volume.<br><br>LESSONS: Therefore, in this study, through considering several cases of ALS patients whose clinical symptoms were improved by changing ventilation mode, we tried to investigate the adequacy of each ventilation mode under certain clinical situations.}, }
@article {pmid28823891, year = {2017}, author = {Andreasen, SR and Lundbye, CJ and Christensen, TB and Thielsen, KD and Schmitt-John, T and Holm, MM}, title = {Excitatory-inhibitory imbalance in the brain of the wobbler mouse model of amyotrophic lateral sclerosis substantiated by riluzole and diazepam.}, journal = {Neuroscience letters}, volume = {658}, number = {}, pages = {85-90}, doi = {10.1016/j.neulet.2017.08.033}, pmid = {28823891}, issn = {1872-7972}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Diazepam/*pharmacology ; Disease Models, Animal ; Hippocampus/*drug effects ; Mice, Inbred C57BL ; Neurodegenerative Diseases/drug therapy ; Riluzole/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. So far, no cure exists, prompting studies in disease mechanisms to facilitate development of new treatment strategies. In this study, we employed the wobbler mouse model of ALS focusing on a symptomatic group of animals. We studied the neurophysiological changes conferred by riluzole or diazepam application, two drugs employed in ALS. Riluzole is an antiglutamatergic agent and the only drug to offer some effect on the life expectancy of ALS patients. To target the inhibitory system, we utilized diazepam as a GABAergic modulator. Acute brain slices were prepared from the wobbler mouse model and analyzed using extracellular field recordings in the hippocampus. During Schaffer collateral stimulation, riluzole caused a marked reduction in the paired-pulse ratio (p<0.0001). Importantly, this reduction was more pronounced in wobbler slices (e.g. 184.2±8.9% at 20ms interval without riluzole, and 124.3±9.8% in the presence of riluzole) compared to control slices (at 20ms: from 198.7±5.8% to 160.5±6.7%). Diazepam caused less pronounced effects at wobbler slices and reduced the paired-pulse ratio more in control animals compared to wobbler individuals (p<0.0001). Comparable results were obtained during trains of stimulations (10 pulses at 20Hz). Importantly, paired-pulse ratios as well as synaptic facilitation were overall similar in control and wobbler slices, without the drugs present, indicating that the differences were only revealed pharmacologically. In summary, the present data support excitatory-inhibitory imbalances in the brain of the wobbler mouse and further consolidate this mouse as an animal model of ALS.}, }
@article {pmid28818672, year = {2018}, author = {Chen, T and Turner, BJ and Beart, PM and Sheehan-Hennessy, L and Elekwachi, C and Muyderman, H}, title = {Glutathione monoethyl ester prevents TDP-43 pathology in motor neuronal NSC-34 cells.}, journal = {Neurochemistry international}, volume = {112}, number = {}, pages = {278-287}, doi = {10.1016/j.neuint.2017.08.009}, pmid = {28818672}, issn = {1872-9754}, mesh = {Animals ; Cell Line ; Cell Survival/drug effects/physiology ; DNA-Binding Proteins/antagonists &amp; inhibitors/*metabolism ; Glutathione/*analogs &amp; derivatives/antagonists &amp; inhibitors/*metabolism/pharmacology ; Mice ; Motor Neurons/drug effects/*metabolism ; Oxidative Stress/drug effects/*physiology ; }, abstract = {Oxidative stress is recognised as central in a range of neurological diseases including Amyotrophic lateral sclerosis (ALS), a disease characterised by fast progressing death of motor neurons in the brain and spinal cord. Cellular pathology includes cytosolic protein aggregates in motor neurons and glia of which potentially cytotoxic hyper-phosphorylated fragments of the Transactive response DNA Binding Protein 43 kDa (TDP-43) constitute a major component. This is closely associated with an additional loss of nuclear TDP-43 expression indicating a "loss of function" mechanism, accelerating motor neuron (MN) loss. Furthermore, mutations in TDP-43 cause familial ALS and ALS-like disease in animal models. In this study, we investigated the role of glutathione (GSH) in modulating oxidative stress responses in TDP-43 pathology in motor neuron NSC-34 cells. Results demonstrate that depletion of GSH produces pathology similar to that of mutant TDP-43, including occurrence of cytosolic aggregates, TDP-43 phosphorylation and nuclear clearing of endogenous TDP-43. We also demonstrate that introduction of mutant TDP-43[A315T] and silencing of endogenous TDP-43, but not overexpression of wild-type TDP-43, result in similar pathology, including depletion of intracellular GSH, possibly resulting from a decreased expression of a regulatory subunit of ɣ-glutamylcysteine ligase (GCLM), a rate limiting enzyme in GSH synthesis. Importantly, treatment of mutant cells with GSH monoethyl ester (GSHe) that directly increases intracellular GSH and bypasses the need for GSH synthesis, protected against mutant-induced TDP-43 pathology, including reducing aggregate formation, nuclear clearance, reactive oxygen species (ROS) production and cell death. Our data strongly suggest that oxidative stress is central to TDP-43 pathology and may result from a loss of function affecting GSH synthesis and that treatments directly aimed at restoring cellular GSH content may be beneficial in preventing cell death in TDP-43-mediated ALS.}, }
@article {pmid28811143, year = {2017}, author = {Sorce, S and Stocker, R and Seredenina, T and Holmdahl, R and Aguzzi, A and Chio, A and Depaulis, A and Heitz, F and Olofsson, P and Olsson, T and Duveau, V and Sanoudou, D and Skosgater, S and Vlahou, A and Wasquel, D and Krause, KH and Jaquet, V}, title = {NADPH oxidases as drug targets and biomarkers in neurodegenerative diseases: What is the evidence?.}, journal = {Free radical biology &amp; medicine}, volume = {112}, number = {}, pages = {387-396}, doi = {10.1016/j.freeradbiomed.2017.08.006}, pmid = {28811143}, issn = {1873-4596}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/*enzymology/pathology ; Animals ; Antioxidants/therapeutic use ; Biomarkers/blood ; Central Nervous System/drug effects/enzymology/pathology ; Creutzfeldt-Jakob Syndrome/diagnosis/drug therapy/*enzymology/pathology ; Disease Models, Animal ; Europe ; Gene Expression ; Humans ; Hydrogen Peroxide/metabolism ; International Cooperation ; Microglia/drug effects/enzymology/pathology ; Multiple Sclerosis/diagnosis/drug therapy/*enzymology/pathology ; NADPH Oxidase 2/antagonists &amp; inhibitors/blood/*genetics ; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis/drug therapy/*enzymology/pathology ; Superoxides/metabolism ; }, abstract = {Neurodegenerative disease are frequently characterized by microglia activation and/or leukocyte infiltration in the parenchyma of the central nervous system and at the molecular level by increased oxidative modifications of proteins, lipids and nucleic acids. NADPH oxidases (NOX) emerged as a novel promising class of pharmacological targets for the treatment of neurodegeneration due to their role in oxidant generation and presumably in regulating microglia activation. The unique function of NOX is the generation of superoxide anion (O2[•-]) and hydrogen peroxide (H2O2). However in the context of neuroinflammation, they present paradoxical features since O2[•-]/H2O2 generated by NOX and/or secondary reactive oxygen species (ROS) derived from O2[•-]/H2O2 can either lead to neuronal oxidative damage or resolution of inflammation. The role of NOX enzymes has been investigated in many models of neurodegenerative diseases by using either genetic or pharmacological approaches. In the present review we provide a critical assessment of recent findings related to the role of NOX in the CNS as well as how the field has advanced over the last 5 years. In particular, we focus on the data derived from the work of a consortium (Neurinox) funded by the European Commission's Programme 7 (FP7). We discuss the evidence gathered from animal models and human samples linking NOX expression/activity with neuroinflammation in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Creutzfeldt-Jakob disease as well as autoimmune demyelinating diseases like multiple sclerosis (MS) and chronic inflammatory demyelinating polyneuropathy (CIDP). We address the possibility to use measurement of the activity of the NOX2 isoform in blood samples as biomarker of disease severity and treatment efficacy in neurodegenerative disease. Finally we clarify key controversial aspects in the field of NOX, such as NOX cellular expression in the brain, measurement of NOX activity, impact of genetic deletion of NOX in animal models of neurodegeneration and specificity of NOX inhibitors.}, }
@article {pmid28805578, year = {2017}, author = {Fang, T and Jozsa, F and Al-Chalabi, A}, title = {Nonmotor Symptoms in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {International review of neurobiology}, volume = {134}, number = {}, pages = {1409-1441}, doi = {10.1016/bs.irn.2017.04.009}, pmid = {28805578}, issn = {2162-5514}, support = {MR/L501529/1//Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology/therapy ; Autonomic Nervous System Diseases/diagnosis/physiopathology/therapy ; Gastrointestinal Diseases/diagnosis/physiopathology/therapy ; Humans ; Mental Disorders/diagnosis/physiopathology/therapy ; Prospective Studies ; Randomized Controlled Trials as Topic/*methods ; Retrospective Studies ; }, abstract = {BACKGROUND: ALS is a progressive neurodegenerative disease with no curative treatment. Nonmotor symptoms presenting in ALS may cause significant distress, worsen prognosis, and affect survival.<br><br>OBJECTIVE: To systematically review evidence for the prevalence of nonmotor ALS symptoms, and treatment options.<br><br>METHODS: Multiple medical literature databases were searched and studies screened using predefined inclusion criteria. Of 4580 studies, 44 were eligible for inclusion with 25 relating to treatment and 19 to the prevalence of nonmotor symptoms in ALS.<br><br>RESULTS: Nonmotor symptoms involve neuropsychiatric, autonomic, gastrointestinal, and vascular systems, and affect between 5% and 80% of people with ALS. Screening tools for individual nonmotor symptoms are useful in classifying symptom severity and to compare between treatment options. Several methods to relieve nonmotor symptoms have been trialed with varying success rates.<br><br>CONCLUSIONS: Many of the current studies of nonmotor symptoms in ALS have small sample sizes, requiring more evidence to increase precision in prevalence estimates. Further research is needed to assess the efficacy of current treatments and to find new therapies. Symptom relief or treatment of these nonmotor symptoms should therefore be considered during the clinical management of ALS.}, }
@article {pmid28798369, year = {2017}, author = {Rusconi, M and Gerardi, F and Santus, W and Lizio, A and Sansone, VA and Lunetta, C and Zanoni, I and Granucci, F}, title = {Inflammatory role of dendritic cells in Amyotrophic Lateral Sclerosis revealed by an analysis of patients' peripheral blood.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {7853}, pmid = {28798369}, issn = {2045-2322}, support = {P30 DK034854/DK/NIDDK NIH HHS/United States ; R01 AI121066/AI/NIAID NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*physiopathology ; Chemokine CCL2/metabolism ; Dendritic Cells/chemistry/*immunology ; Humans ; Inflammation/*pathology/*physiopathology ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; L-Selectin/analysis ; Receptors, CCR2/analysis ; }, abstract = {Chronic inflammation is one of the causes of neurodegeneration in Amyotrophic lateral sclerosis (ALS). Here we examined whether circulating dendritic cells (DCs) can contribute to disease progression. We found ALS patients show a significant reduction in the number of circulating DCs. Also, patients' DCs present an increased expression of CD62L and a tendency to overexpress CCR2 compared with healthy donors. Moreover, DCs derived from a subpopulation of ALS patients produced higher levels of IL-8 and CCL-2 upon lipopolysaccharide (LPS)-stimulation. Finally, we found a significant inverse correlation between the time from onset of the pathology to its diagnosis and the levels of IL-6 secretion induced by LPS. Our data support the hypothesis, in a subpopulation of patients, DCs recruited at the diseased tissue produce high levels of CCL-2 and IL-8 and contribute to the inflammatory process promoting the recruitment of other inflammatory cells. An increased efficiency of IL-6 production may accelerate only the initial phases of disease progression. Blood DC analysis can be used to identify ALS patients with an altered course of inflammatory cell recruitment at the diseased central nervous system (CNS). The high levels of CD62L expression suggests this molecule could be a target for treatment of CNS inflammation.}, }
@article {pmid28792504, year = {2017}, author = {Sagar, V and Pilakka-Kanthikeel, S and Martinez, PC and Atluri, VSR and Nair, M}, title = {Common gene-network signature of different neurological disorders and their potential implications to neuroAIDS.}, journal = {PloS one}, volume = {12}, number = {8}, pages = {e0181642}, pmid = {28792504}, issn = {1932-6203}, support = {R01 DA034547/DA/NIDA NIH HHS/United States ; R01 DA040537/DA/NIDA NIH HHS/United States ; R03 DA037782/DA/NIDA NIH HHS/United States ; R21 MH101025/MH/NIMH NIH HHS/United States ; }, mesh = {AIDS Dementia Complex/*genetics/*metabolism ; Cell Line ; Computational Biology ; *Gene Regulatory Networks ; HIV-1 ; Humans ; Microarray Analysis ; Monocytes/metabolism ; Nervous System Diseases/*genetics/*metabolism ; RNA, Messenger/metabolism ; }, abstract = {The neurological complications of AIDS (neuroAIDS) during the infection of human immunodeficiency virus (HIV) are symptomized by non-specific, multifaceted neurological conditions and therefore, defining a specific diagnosis/treatment mechanism(s) for this neuro-complexity at the molecular level remains elusive. Using an in silico based integrated gene network analysis we discovered that HIV infection shares convergent gene networks with each of twelve neurological disorders selected in this study. Importantly, a common gene network was identified among HIV infection, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and age macular degeneration. An mRNA microarray analysis in HIV-infected monocytes showed significant changes in the expression of several genes of this in silico derived common pathway which suggests the possible physiological relevance of this gene-circuit in driving neuroAIDS condition. Further, this unique gene network was compared with another in silico derived novel, convergent gene network which is shared by seven major neurological disorders (Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Age Macular Degeneration, Amyotrophic Lateral Sclerosis, Vascular Dementia, and Restless Leg Syndrome). These networks differed in their gene circuits; however, in large, they involved innate immunity signaling pathways, which suggests commonalities in the immunological basis of different neuropathogenesis. The common gene circuits reported here can provide a prospective platform to understand how gene-circuits belonging to other neuro-disorders may be convoluted during real-time neuroAIDS condition and it may elucidate the underlying-and so far unknown-genetic overlap between HIV infection and neuroAIDS risk. Also, it may lead to a new paradigm in understanding disease progression, identifying biomarkers, and developing therapies.}, }
@article {pmid28791401, year = {2017}, author = {Zhou, T and Ahmad, TK and Gozda, K and Truong, J and Kong, J and Namaka, M}, title = {Implications of white matter damage in amyotrophic lateral sclerosis (Review).}, journal = {Molecular medicine reports}, volume = {16}, number = {4}, pages = {4379-4392}, pmid = {28791401}, issn = {1791-3004}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/*pathology ; Animals ; Disease Progression ; Humans ; Models, Biological ; White Matter/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which involves the progressive degeneration of motor neurons. ALS has long been considered a disease of the grey matter; however, pathological alterations of the white matter (WM), including axonal loss, axonal demyelination and oligodendrocyte death, have been reported in patients with ALS. The present review examined motor neuron death as the primary cause of ALS and evaluated the associated WM damage that is guided by neuronal‑glial interactions. Previous studies have suggested that WM damage may occur prior to the death of motor neurons, and thus may be considered an early indicator for the diagnosis and prognosis of ALS. However, the exact molecular mechanisms underlying early‑onset WM damage in ALS have yet to be elucidated. The present review explored the detailed anatomy of WM and identified several pathological mechanisms that may be implicated in WM damage in ALS. In addition, it associated the pathophysiological alterations of WM, which may contribute to motor neuron death in ALS, with similar mechanisms of WM damage that are involved in multiple sclerosis (MS). Furthermore, the early detection of WM damage in ALS, using neuroimaging techniques, may lead to earlier therapeutic intervention, using immunomodulatory treatment strategies similar to those used in relapsing‑remitting MS, aimed at delaying WM damage in ALS. Early therapeutic approaches may have the potential to delay motor neuron damage and thus prolong the survival of patients with ALS. The therapeutic interventions that are currently available for ALS are only marginally effective. However, early intervention with immunomodulatory drugs may slow the progression of WM damage in the early stages of ALS, thus delaying motor neuron death and increasing the life expectancy of patients with ALS.}, }
@article {pmid28790177, year = {2017}, author = {Monahan, Z and Ryan, VH and Janke, AM and Burke, KA and Rhoads, SN and Zerze, GH and O'Meally, R and Dignon, GL and Conicella, AE and Zheng, W and Best, RB and Cole, RN and Mittal, J and Shewmaker, F and Fawzi, NL}, title = {Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity.}, journal = {The EMBO journal}, volume = {36}, number = {20}, pages = {2951-2967}, pmid = {28790177}, issn = {1460-2075}, support = {T32 MH020068/MH/NIMH NIH HHS/United States ; T32 GM007601/GM/NIGMS NIH HHS/United States ; P30 GM122732/GM/NIGMS NIH HHS/United States ; P30 GM103410/GM/NIGMS NIH HHS/United States ; P20 GM104937/GM/NIGMS NIH HHS/United States ; R01 GM118530/GM/NIGMS NIH HHS/United States ; S10 RR027027/RR/NCRR NIH HHS/United States ; P30 RR031153/RR/NCRR NIH HHS/United States ; S10 RR020923/RR/NCRR NIH HHS/United States ; R35 GM119790/GM/NIGMS NIH HHS/United States ; P20 RR018728/RR/NCRR NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/pathology ; Cell Line ; Frontotemporal Dementia/pathology ; Humans ; Magnetic Resonance Spectroscopy ; Phosphorylation ; Protein Aggregation, Pathological ; Protein Conformation ; *Protein Processing, Post-Translational ; RNA-Binding Protein FUS/chemistry/*metabolism ; }, abstract = {Neuronal inclusions of aggregated RNA-binding protein fused in sarcoma (FUS) are hallmarks of ALS and frontotemporal dementia subtypes. Intriguingly, FUS's nearly uncharged, aggregation-prone, yeast prion-like, low sequence-complexity domain (LC) is known to be targeted for phosphorylation. Here we map in vitro and in-cell phosphorylation sites across FUS LC We show that both phosphorylation and phosphomimetic variants reduce its aggregation-prone/prion-like character, disrupting FUS phase separation in the presence of RNA or salt and reducing FUS propensity to aggregate. Nuclear magnetic resonance spectroscopy demonstrates the intrinsically disordered structure of FUS LC is preserved after phosphorylation; however, transient domain collapse and self-interaction are reduced by phosphomimetics. Moreover, we show that phosphomimetic FUS reduces aggregation in human and yeast cell models, and can ameliorate FUS-associated cytotoxicity. Hence, post-translational modification may be a mechanism by which cells control physiological assembly and prevent pathological protein aggregation, suggesting a potential treatment pathway amenable to pharmacologic modulation.}, }
@article {pmid28782538, year = {2017}, author = {Shimizu, M and Dickhoff, WW}, title = {Circulating insulin-like growth factor binding proteins in fish: Their identities and physiological regulation.}, journal = {General and comparative endocrinology}, volume = {252}, number = {}, pages = {150-161}, doi = {10.1016/j.ygcen.2017.08.002}, pmid = {28782538}, issn = {1095-6840}, mesh = {Amino Acid Sequence ; Animals ; Environment ; Fishes/*blood ; Hormones/metabolism ; Insulin-Like Growth Factor Binding Proteins/*blood/chemistry/genetics/isolation &amp; purification ; Insulin-Like Growth Factor I/metabolism ; }, abstract = {Insulin-like growth factor binding proteins (IGFBPs) play crucial roles in regulating the availability of IGFs to receptors and prolong the half-lives of IGFs. There are six IGFBPs present in the mammalian circulation with IGFBP-3 being most abundant. In mammals IGFBP-3 is the major carrier of circulating IGFs, facilitated by forming a ternary complex with IGF and an acid-labile subunit (ALS). IGFBP-1 is generally inhibitory to IGF action by preventing it from interacting with its receptors. In teleosts, the third-round of vertebrate whole genome duplication created paralogs of each IGFBP, except IGFBP-4. In the fish circulation, three major IGFBPs are typically detected at molecular ranges of 20-25, 28-32 and 40-50kDa. However, their identities are not well established. Three major circulating IGFBPs in Chinook salmon have been identified through protein purification and cDNA cloning. Salmon 28- and 22-kDa IGFBPs are co-orthologs of IGFBP-1, termed IGFBP-1a and -1b, respectively. They are induced under catabolic conditions such as stress and fasting but their responses are somewhat different, with IGFBP-1b being the most sensitive of the two. Cortisol stimulates production and secretion of these IGFBP-1 subtypes while, unlike in mammals, insulin may not be a primary suppressor. Salmon 41-kDa IGFBP, a major carrier of IGF-I, is not IGFBP-3, as might be expected extrapolating from mammals, but is in fact IGFBP-2b. Salmon IGFBP-2b levels in plasma are high when fish are fed, and GH treatment increases its circulating levels similar to mammalian IGFBP-3. These findings suggest that salmon IGFBP-2b acquired the role and regulation similar to mammalian IGFBP-3. Multiple replications of fish IGFBPs offer a unique opportunity to investigate molecular evolution of IGFBPs.}, }
@article {pmid28780701, year = {2017}, author = {Speyer, CL and Bukhsh, MA and Jafry, WS and Sexton, RE and Bandyopadhyay, S and Gorski, DH}, title = {Riluzole synergizes with paclitaxel to inhibit cell growth and induce apoptosis in triple-negative breast cancer.}, journal = {Breast cancer research and treatment}, volume = {166}, number = {2}, pages = {407-419}, pmid = {28780701}, issn = {1573-7217}, support = {P30 CA022453/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/*administration &amp; dosage/pharmacology ; Cell Cycle/drug effects ; Cell Cycle Proteins/*genetics ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drug Synergism ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mice ; Paclitaxel/*administration &amp; dosage/pharmacology ; Riluzole/*administration &amp; dosage/pharmacology ; Triple Negative Breast Neoplasms/*drug therapy ; Xenograft Model Antitumor Assays ; }, abstract = {PURPOSE: One in eight women will develop breast cancer, 15-20% of whom will have triple-negative breast cancer (TNBC), an aggressive breast cancer with no current targeted therapy. We have demonstrated that riluzole, an FDA-approved drug for treating amyotrophic lateral sclerosis, inhibits growth of TNBC. In this study, we explore potential synergism between riluzole and paclitaxel, a chemotherapeutic agent commonly used to treat TNBC, in regulating TNBC proliferation, cell cycle arrest, and apoptosis.<br><br>METHODS: TNBC cells were treated with paclitaxel and/or riluzole and synergistic effects on cell proliferation were quantified via MTT assay and CompuSyn analysis. Apoptosis was observed morphologically and by measuring cleaved PARP/caspase three products. Microarray analysis was performed using MDA-MB-231 cells to examine cell cycle genes regulated by riluzole and any enhanced effects on paclitaxel-mediated cell cycle arrest, determined by FACS analysis. These results were confirmed in vivo using a MDA-MB-231 xenograft model.<br><br>RESULTS: Strong enhanced or synergistic effects of riluzole on paclitaxel regulation of cell cycle progression and apoptosis was demonstrated in all TNBC cells tested as well as in the xenograft model. The MDA-MB-231, SUM149, and SUM229 cells, which are resistant to paclitaxel treatment, demonstrated the strongest synergistic or enhanced effect. Key protein kinases were shown to be upregulated in this study by riluzole as well as downstream cell cycle genes regulated by these kinases.<br><br>CONCLUSIONS: All TNBC cells tested responded synergistically to riluzole and paclitaxel strongly suggesting the usefulness of this combinatorial treatment strategy in TNBC, especially for patients whose tumors are relatively resistant to paclitaxel.}, }
@article {pmid28780536, year = {2017}, author = {Hashizume, A and Katsuno, M and Suzuki, K and Hirakawa, A and Hijikata, Y and Yamada, S and Inagaki, T and Banno, H and Sobue, G}, title = {Long-term treatment with leuprorelin for spinal and bulbar muscular atrophy: natural history-controlled study.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {88}, number = {12}, pages = {1026-1032}, doi = {10.1136/jnnp-2017-316015}, pmid = {28780536}, issn = {1468-330X}, mesh = {Adult ; Aged ; Antineoplastic Agents, Hormonal/adverse effects/*therapeutic use ; Disease Progression ; Disease-Free Survival ; Endpoint Determination ; Female ; Humans ; Kaplan-Meier Estimate ; Leuprolide/adverse effects/*therapeutic use ; Long-Term Care ; Male ; Middle Aged ; Muscular Atrophy, Spinal/complications/*drug therapy/genetics ; Pneumonia/complications/prevention &amp; control ; Prognosis ; }, abstract = {OBJECTIVE: To evaluate the prognosis and progression of spinal and bulbar muscular atrophy (SBMA), a rare X-linked motor neuron disorder caused by trinucleotide repeat expansion in the AR (androgen receptor) gene, after long-term androgen suppression with leuprorelin acetate treatment.<br><br>METHODS: In the present natural history-controlled study, 36 patients with SBMA treated with leuprorelin acetate for up to 84 months (leuprorelin acetate-treated group; LT group) and 29 patients with SBMA with no specific treatment (non-treated group; NT group) were analysed. Disease progression was evaluated by longitudinal quantitative assessment of motor functioning using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and the modified Norris score. In addition, we selected two major clinical endpoint events, namely the occurrence of pneumonia requiring hospitalisation and death, to evaluate disease prognosis following long-term leuprorelin acetate treatment.<br><br>RESULTS: In our analysis of the longitudinal disease progression using the random slope model, we observed a significant difference in the ALSFRS-R total score, the Limb Norris Score, and the Norris Bulbar Score (p=0.005, 0.026 and 0.020, respectively), with the LT group exhibiting a slower per-12-months decline compared with the NT group. As for the event analysis, the prognosis of the LT group was better in comparison to the NT group as for the event-free survival period (p=0.021).<br><br>CONCLUSION: Long-term treatment with leuprorelin acetate appears to delay the functional decline and suppress the incidence of pneumonia and death in subjects with SBMA.}, }
@article {pmid28779378, year = {2017}, author = {Mohamed, LA and Markandaiah, S and Bonanno, S and Pasinelli, P and Trotti, D}, title = {Blood-Brain Barrier Driven Pharmacoresistance in Amyotrophic Lateral Sclerosis and Challenges for Effective Drug Therapies.}, journal = {The AAPS journal}, volume = {19}, number = {6}, pages = {1600-1614}, pmid = {28779378}, issn = {1550-7416}, support = {R01 NS074886/NS/NINDS NIH HHS/United States ; }, mesh = {ATP Binding Cassette Transporter, Subfamily B/genetics ; ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists &amp; inhibitors/physiology ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; *Blood-Brain Barrier ; Brain/blood supply ; Clinical Trials as Topic ; Drug Resistance ; Humans ; }, abstract = {The blood-brain barrier (BBB) is essential for proper neuronal function, homeostasis, and protection of the central nervous system (CNS) microenvironment from blood-borne pathogens and neurotoxins. The BBB is also an impediment for CNS penetration of drugs. In some neurologic conditions, such as epilepsy and brain tumors, overexpression of P-glycoprotein, an efflux transporter whose physiological function is to expel catabolites and xenobiotics from the CNS into the blood stream, has been reported. Recent studies reported that overexpression of P-glycoprotein and increase in its activity at the BBB drives a progressive resistance to CNS penetration and persistence of riluzole, the only drug approved thus far for treatment of amyotrophic lateral sclerosis (ALS), rapidly progressive and mostly fatal neurologic disease. This review will discuss the impact of transporter-mediated pharmacoresistance for ALS drug therapy and the potential therapeutic strategies to improve the outcome of ALS clinical trials and efficacy of current and future drug treatments.}, }
@article {pmid28777179, year = {2017}, author = {Ju, YS and Videnovic, A and Vaughn, BV}, title = {Comorbid Sleep Disturbances in Neurologic Disorders.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {23}, number = {4, Sleep Neurology}, pages = {1117-1131}, doi = {10.1212/CON.0000000000000501}, pmid = {28777179}, issn = {1538-6899}, mesh = {Comorbidity ; Humans ; Nervous System Diseases/complications/diagnosis/*therapy ; Restless Legs Syndrome/diagnosis/*therapy ; Sleep/*physiology ; Sleep Apnea Syndromes/complications/therapy ; Sleep Wake Disorders/complications/diagnosis/*therapy ; }, abstract = {PURPOSE OF REVIEW: This article provides a review of disturbances of sleep comorbid with common neurologic disorders.<br><br>RECENT FINDINGS: A wide variety of neurologic disorders are frequently complicated by comorbid sleep disturbances. In many cases, a bidirectional relationship appears to occur between sleep function and the neurologic disease, such that treatment of comorbid sleep disturbances may improve the symptoms of the neurologic disease.<br><br>SUMMARY: Neurologic disorders are often associated with abnormalities of sleep. Sleep influences the severity of both epilepsy and headache, and treatment of comorbid sleep disorders may improve seizure and headache frequency. Alzheimer disease is characterized by circadian phase delay and poor nighttime sleep and is strongly associated with obstructive sleep apnea. Parkinson disease is associated with several sleep disorders, including insomnia, restless legs syndrome, rapid eye movement (REM) sleep behavior disorder, daytime hypersomnia, and sleep-disordered breathing. Hypoventilation in amyotrophic lateral sclerosis and other neuromuscular disorders often presents initially with sleep problems, and treatment with noninvasive ventilation improves survival and quality of life.}, }
@article {pmid28767243, year = {2017}, author = {Panozzo, S and Milani, A and Scarabel, L and Balogh, &#xc1; and Dancza, I and Sattin, M}, title = {Occurrence of Different Resistance Mechanisms to Acetolactate Synthase Inhibitors in European Sorghum halepense.}, journal = {Journal of agricultural and food chemistry}, volume = {65}, number = {34}, pages = {7320-7327}, doi = {10.1021/acs.jafc.7b01243}, pmid = {28767243}, issn = {1520-5118}, mesh = {Acetolactate Synthase/*antagonists &amp; inhibitors/genetics/metabolism ; Europe ; *Herbicide Resistance ; Herbicides/*pharmacology ; Plant Proteins/*antagonists &amp; inhibitors/genetics/metabolism ; Sorghum/*drug effects/*enzymology/genetics ; Zea mays/growth &amp; development ; }, abstract = {Four Hungarian and two Italian Sorghum halepense populations harvested in maize fields were investigated to elucidate the levels and mechanisms underlying acetolactate synthase (ALS) inhibitors resistance. The two Italian populations were highly cross-resistant to all ALS inhibitors tested, and the variant ALS allele Leu574 was identified in most of the plants; no differences were observed when the plants were treated with herbicide plus malathion. This suggests that the main resistance mechanism is target-site mediated. The Hungarian populations proved to be controlled by imazamox, while they were resistant to sulfonylureas and bispyribac-Na. All Hungarian populations, but not all plants of population 12-49H, presented the variant allele Glu376. This is the first documented occurrence of the Asp-376-Glu substitution in S. halepense. ALS enzyme bioassay and treatment with malathion confirmed that at least in plants of two populations the resistance is very likely due to both target-site and enhanced metabolism of P450 enzymes.}, }
@article {pmid28763002, year = {2017}, author = {Fellner, A and Barhum, Y and Angel, A and Perets, N and Steiner, I and Offen, D and Lev, N}, title = {Toll-Like Receptor-4 Inhibitor TAK-242 Attenuates Motor Dysfunction and Spinal Cord Pathology in an Amyotrophic Lateral Sclerosis Mouse Model.}, journal = {International journal of molecular sciences}, volume = {18}, number = {8}, pages = {}, pmid = {28763002}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/blood/*drug therapy/pathology/*physiopathology ; Animals ; Astrocytes/drug effects/metabolism/pathology ; Behavior, Animal/drug effects ; Cell Proliferation/drug effects ; Disease Models, Animal ; Disease Progression ; Female ; Humans ; Interleukin-1beta/blood ; Lipopolysaccharides/pharmacology ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/drug effects/metabolism/pathology ; *Motor Activity/drug effects ; Motor Neurons/drug effects/metabolism/pathology ; Spinal Cord/drug effects/*pathology/physiopathology ; Spleen/pathology ; Sulfonamides/pharmacology/*therapeutic use ; Superoxide Dismutase-1/metabolism ; Toll-Like Receptor 4/*antagonists &amp; inhibitors/metabolism ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Neuroinflammation contributes to amyotrophic lateral sclerosis (ALS) progression. TLR4, a transmembrane protein that plays a central role in activation of the innate immune system, has been shown to induce microglial activation in ALS models. TLR4 is up-regulated in the spinal cords of hSOD1[G93A] mice. We aimed to examine the effects of specific TLR4 inhibition on disease progression and survival in the hSOD1[G93A] mouse model of ALS. Immunologic effect of TLR4 inhibition in vitro was measured by the effect of TAK-242 treatment on LPS-induced splenocytes proliferation. hSOD1[G93A] transgenic mice were treated with TAK-242, a selective TLR4 inhibitor, or vehicle. Survival, body weight, and motor behavior were monitored. To evaluate in vivo immunologic modifications associated with TAK-242 treatment, we measured serum IL-1β in the plasma, as well as IL-1β and TNF-α mRNAs in the spinal cord in wild-type mice and in TAK-242-treated and vehicle-treated early symptomatic hSOD1[G93A] mice. Immunohistochemical analysis of motor neurons, astrocytes, and microglial reactivity in the spinal cords were performed on symptomatic (100 days old) TAK-242-treated and vehicle-treated hSOD1[G93A] mice. In vitro, splenocytes taken from 100 days old hSOD1[G93A] mice showed significantly increased proliferation when exposed to LPS (p = 0.0002), a phenomenon that was reduced by TAK-242 (p = 0.0179). TAK-242 treatment did not attenuate body weight loss or significantly affect survival. However, TAK-242-treated hSOD1[G93A] mice showed temporary clinical delay in disease progression evident in the ladder test and hindlimb reflex measurements. Plasma IL-1β levels were significantly reduced in TAK-242-treated compared to vehicle-treated hSOD1[G93A] mice (p = 0.0023). TAK-242 treatment reduced spinal cord astrogliosis and microglial activation and significantly attenuated spinal cord motor neuron loss at early disease stage (p = 0.0259). Compared to wild-type animals, both IL-1β and TNF-α mRNAs were significantly upregulated in the spinal cords of hSOD1[G93A] mice. Spinal cord analysis in TAK-242-treated hSOD1[G93A] mice revealed significant attenuation of TNF-α mRNA (p = 0.0431), but no change in IL-1β mRNA. TLR4 inhibition delayed disease progression, attenuated spinal cord astroglial and microglial reaction, and reduced spinal motor neuron loss in the ALS hSOD1[G93A] mouse model. However, this effect did not result in increased survival. To our knowledge, this is the first report on TAK-242 treatment in a neurodegenerative disease model. Further studies are warranted to assess TLR4 as a therapeutic target in ALS.}, }
@article {pmid28762306, year = {2018}, author = {Fatima, MT and Islam, Z and Ahmad, E and Salahuddin, P}, title = {Emerging Targets and Latest Proteomics Based Therapeutic Approaches in Neurodegenerative Diseases.}, journal = {Current protein &amp; peptide science}, volume = {19}, number = {9}, pages = {858-875}, doi = {10.2174/1389203718666170731114757}, pmid = {28762306}, issn = {1875-5550}, mesh = {Drug Design ; Humans ; Molecular Chaperones/metabolism ; Molecular Targeted Therapy ; Neurodegenerative Diseases/etiology/metabolism/*therapy ; Protein Folding ; Protein Multimerization ; Proteins/antagonists &amp; inhibitors/*metabolism ; Proteolysis ; Proteomics/*methods ; Proteostasis ; }, abstract = {Protein homeostasis (proteostasis) is achieved by the interplay among various components and pathways inside a cell. Dysfunction in proteostasis leads to protein misfolding and aggregation which is ubiquitously associated with many neurodegenerative disorders, although the exact role of these aggregate in the pathogenesis remains unknown. Many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and others are characterized by the conversion of specific protein aggregates into protein inclusions and/or plaques in degenerating brains. Apart from the conventional disease specific proteins, such as amyloid-β, α - synuclein, huntingtin protein, and prions that are known to aggregate, a number of other proteins play a vital role in aggravating the disease condition. In this review, we discuss the disease etiology, mechanism, the role of various pathways, molecular machinery including molecular chaperones, protein degradation pathways, and the active formation of inclusions in various neurodegenerative diseases. We also highlight the approaches, strategies, and methods that have been used for the treatment of these complex diseases over the years and the efforts that have potential in the near future.}, }
@article {pmid28758631, year = {2017}, author = {Carroll, JA and Race, B and Phillips, K and Striebel, JF and Chesebro, B}, title = {Statins are ineffective at reducing neuroinflammation or prolonging survival in scrapie-infected mice.}, journal = {The Journal of general virology}, volume = {98}, number = {8}, pages = {2190-2199}, pmid = {28758631}, issn = {1465-2099}, mesh = {Animals ; Humans ; Mice ; Mice, Inbred C57BL ; Neurodegenerative Diseases/*drug therapy/*immunology/mortality ; Pravastatin/*administration &amp; dosage ; Scrapie ; Simvastatin/*administration &amp; dosage ; }, abstract = {Neuroinflammation is a prominent component of several neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, tauopathies, amyotrophic lateral sclerosis and prion diseases. In such conditions, the ability to decrease neuroinflammation by drug therapy may influence disease progression. Statins have been used to treat hyperlipidemia as well as reduce neuroinflammation and oxidative stress in various tissues. In previous studies, treatment of scrapie-infected mice with the type 1 statins, simvastatin or pravastatin, showed a small beneficial effect on survival time. In the current study, to increase the effectiveness of statin therapy, we treated infected mice with atorvastatin, a type 2 statin that has improved pharmacokinetics over many type 1 statins. Treatments with either simvastatin or pravastatin were tested for comparison. We evaluated scrapie-infected mice for protease-resistant PrP (PrPres) accumulation, gliosis, neuroinflammation and time until advanced clinical disease requiring euthanasia. All three statin treatments reduced total serum cholesterol ≥40 % in mice. However, gliosis and PrPres deposition were similar in statin-treated and untreated infected mice. Time to euthanasia due to advanced clinical signs was not changed in statin-treated mice relative to untreated mice, a finding at odds with previous reports. Expression of 84 inflammatory genes involved in neuroinflammation was also quantitated. Seven genes were reduced by pravastatin, and one gene was reduced by atorvastatin. In contrast, simvastatin therapy did not reduce any of the tested genes, but did slightly increase the expression of Ccl2 and Cxcl13. Our studies indicate that none of the three statins tested were effective in reducing scrapie-induced neuroinflammation or neuropathogenesis.}, }
@article {pmid28755697, year = {2017}, author = {Burns, EE and Keith, BK and Refai, MY and Bothner, B and Dyer, WE}, title = {Proteomic and biochemical assays of glutathione-related proteins in susceptible and multiple herbicide resistant Avena fatua L.}, journal = {Pesticide biochemistry and physiology}, volume = {140}, number = {}, pages = {69-78}, doi = {10.1016/j.pestbp.2017.06.007}, pmid = {28755697}, issn = {1095-9939}, mesh = {Avena/*drug effects ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Plant/*drug effects/physiology ; Glutathione/*metabolism ; Glutathione Peroxidase/genetics/metabolism ; Glutathione Transferase/genetics/metabolism ; Herbicide Resistance/*genetics ; Herbicides/*pharmacology ; Plant Proteins/genetics/metabolism ; *Proteomics ; }, abstract = {Extensive herbicide usage has led to the evolution of resistant weed populations that cause substantial crop yield losses and increase production costs. The multiple herbicide resistant (MHR) Avena fatua L. populations utilized in this study are resistant to members of all selective herbicide families, across five modes of action, available for A. fatua control in U.S. small grain production, and thus pose significant agronomic and economic threats. Resistance to ALS and ACCase inhibitors is not conferred by target site mutations, indicating that non-target site resistance mechanisms are involved. To investigate the potential involvement of glutathione-related enzymes in the MHR phenotype, we used a combination of proteomic, biochemical, and immunological approaches to compare their constitutive activities in herbicide susceptible (HS1 and HS2) and MHR (MHR3 and MHR4) A. fatua plants. Proteomic analysis identified three tau and one phi glutathione S-transferases (GSTs) present at higher levels in MHR compared to HS plants, while immunoassays revealed elevated levels of lambda, phi, and tau GSTs. GST specific activity towards 1-chloro-2,4-dinitrobenzene was 1.2-fold higher in MHR4 than in HS1 plants and 1.3- and 1.2-fold higher in MHR3 than in HS1 and HS2 plants, respectively. However, GST specific activities towards fenoxaprop-P-ethyl and imazamethabenz-methyl were not different between untreated MHR and HS plants. Dehydroascorbate reductase specific activity was 1.4-fold higher in MHR than HS plants. Pretreatment with the GST inhibitor NBD-Cl did not affect MHR sensitivity to fenoxaprop-P-ethyl application, while the herbicide safener and GST inducer mefenpyr reduced the efficacy of low doses of fenoxaprop-P-ethyl on MHR4 but not MHR3 plants. Mefenpyr treatment also partially reduced the efficacy of thiencarbazone-methyl or mesosulfuron-methyl on MHR3 or MHR4 plants, respectively. Overall, the GSTs described here are not directly involved in enhanced rates of fenoxaprop-P-ethyl or imazamethabenz-methyl metabolism in MHR A. fatua. Instead, we propose that the constitutively elevated GST proteins and related enzymes in MHR plants are representative of a larger, more global suite of abiotic stress-related changes.}, }
@article {pmid28732762, year = {2017}, author = {Lapucci, A and Cavone, L and Buonvicino, D and Felici, R and Gerace, E and Zwergel, C and Valente, S and Mai, A and Chiarugi, A}, title = {Effect of Class II HDAC inhibition on glutamate transporter expression and survival in SOD1-ALS mice.}, journal = {Neuroscience letters}, volume = {656}, number = {}, pages = {120-125}, doi = {10.1016/j.neulet.2017.07.033}, pmid = {28732762}, issn = {1872-7972}, mesh = {Amino Acid Transport System X-AG/*metabolism ; Amyotrophic Lateral Sclerosis/*metabolism/mortality ; Animals ; Astrocytes/drug effects/metabolism ; Cells, Cultured ; Excitatory Amino Acid Transporter 2/metabolism ; Female ; Glutamic Acid/metabolism ; Histone Deacetylase Inhibitors/*pharmacology ; Histone Deacetylases/*metabolism ; Hydroxamic Acids/*pharmacology ; Male ; Mice, Transgenic ; Pyrroles/*pharmacology ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase-1/*genetics ; }, abstract = {Transcriptional deregulation emerges as a key pathogenetic mechanism in ALS pathogenesis, and non-class-specific histone deacetylase (HDACs) inhibitors proved of therapeutic efficacy in preclinical models of ALS. When tested in patients, however, these drugs failed, probably because of a lack of selectivity toward pathogenetic HDACs. Here, we studied the effects of MC1568, an inhibitor of Class-II HDACs which have been reported to contribute to ALS pathogenesis. We focused on transcriptional regulation of glutamate transporter EAAT2, whose reduced expression may contribute to motor neuron degeneration in ALS. We report that MC1568 highly increased EAAT2 transcripts in primary cultures of mouse glia, but these increases did not correlate with increased glutamate uptake capacity. Accordingly, we found that MC1568 augmented protein expression of EAAT2 together with its sumoylation, a post-translational modification typically altering protein function and localization. When tested in SOD1G93A mice, however, MC1568 fully restored the reduced spinal cord expression of EAAT2 and glutamate uptake up to control levels. A prolonged treatment with MC1568 (from onset to end stage) was unable to prolong survival of mice. Data reveal a key role of Class-II HDACs in expression and function of glutamate transporter, further corroborating preclinical and clinical evidence that the sole restoration of glutamate uptake is not of therapeutic relevance to ALS therapy.}, }
@article {pmid28721826, year = {2017}, author = {Sanchez-Barcelo, EJ and Rueda, N and Mediavilla, MD and Martinez-Cue, C and Reiter, RJ}, title = {Clinical Uses of Melatonin in Neurological Diseases and Mental and Behavioural Disorders.}, journal = {Current medicinal chemistry}, volume = {24}, number = {35}, pages = {3851-3878}, doi = {10.2174/0929867324666170718105557}, pmid = {28721826}, issn = {1875-533X}, mesh = {Animals ; Clinical Trials as Topic ; Humans ; Melatonin/pharmacology/*therapeutic use ; Mental Disorders/*drug therapy ; Nervous System Diseases/*drug therapy ; Oxidative Stress/drug effects ; Receptors, Melatonin/agonists/metabolism ; }, abstract = {BACKGROUND: Melatonin is a molecule with numerous properties applicable to the treatment of neurological diseases. Among these properties are the following: potent scavenger of oxygen and nitrogen reactive species, anti-inflammatory features, immuno-enhancing nature, and modulation of circadian rhythmicity. Furthermore, low concentrations of melatonin are usually found in patients with neurological diseases and mental disorders. The positive results obtained in experimental models of diverse pathologies, including diseases of the nervous system (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, headaches, etc.) as well as mental and behavioural disordes (e.g., autism spectrum disorders, attention-deficit hyperactivity disorders, etc.), have served as a basis for the design of clinical trials to study melatonin's possible usefulness in human pathology, although the satisfactory results obtained from the laboratory "bench" are not always applicable to the patient's "bedside".<br><br>OBJECTIVE: In this article, we review those papers describing the results of the administration of melatonin to humans for various therapeutic purposes in the field of neuropathology.<br><br>CONCLUSION: Clinical trials with strong methodologies and appropriate doses of melatonin are necessary to support or reject the usefulness of melatonin in neurological diseases.}, }
@article {pmid28714393, year = {2017}, author = {Caballero-Villarraso, J and Galvan, A and Escribano, BM and Tunez, I}, title = {Interrelationships Among Gut Microbiota and Host: Paradigms, Role in Neurodegenerative Diseases and Future Prospects.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {16}, number = {8}, pages = {945-964}, doi = {10.2174/1871527316666170714120118}, pmid = {28714393}, issn = {1996-3181}, mesh = {Animals ; Gastrointestinal Microbiome/*physiology ; Host Microbial Interactions/*physiology ; Humans ; Neurodegenerative Diseases/*microbiology/*physiopathology ; }, abstract = {BACKGROUND &amp; OBJECTIVE: Advances in the knowledge of the microbiota and concepts related to it have triggered a wake-up call in biomedicine. The development in various scientific areas has enabled a better and broader approach to everything concerning the set of families of microorganisms that coexist with an individual and are able to function as one or more organs in its body. Among the aforementioned scientific areas, those worth mentioning are the advances/progress in biotechnological resources and, in particular, molecular biology and related areas. This has given rise to the era of "omics", marking a turning point in the understanding of numerous physiologic and pathophysiologic processes of the organism. The current theory is that the microbiota and the host maintain an intimate relationship that is of a markedly bilateral nature. This continuous feedback has different connotations between one individual and another, but also within the same individual throughout its life span, which is determined by its own conditioning factors (such as its genetic profile), and environmental ones (mainly diet and lifestyles). Both elements (microbiota and host) coexist harmoniously, maintaining a balance, which can be altered and give rise to different morbid entities. Among these is its relation to chronic processes, and especially those of an autoimmune origin. Such may be neurological diseases situations and, specifically, those of a neurodegenerative nature. In disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington's chorea and Alzheimer's disease, among others, it has been found that a disharmonic coexistence between microbiota and host may have implications in their etiology and pathogenesis. A better understanding of those implications has led to the development of actions on the gut microbiota as a target to slow down the advancement or establishment of neurodegeneration.<br><br>CONCLUSION: In this scenario, several treatment strategies have emerged, such as probiotic food intake and stool transplantation. Their real potentialities remain to be elucidated, although current scientific evidence infers that the development of those therapeutic approaches could offer a ray of hope in the prospects of tackling neurodegenerative diseases.}, }
@article {pmid28711998, year = {2017}, author = {Kuczmarski, T and Stommel, EW and Riley, K and Tandan, R and Chaudhry, V and Clawson, L and Caller, TA and Henegan, PL and Facciponte, DN and Bradley, WG and Andrew, AS}, title = {Medical history of chemotherapy or immunosuppressive drug treatment and risk of amyotrophic lateral sclerosis (ALS).}, journal = {Journal of neurology}, volume = {264}, number = {8}, pages = {1763-1767}, pmid = {28711998}, issn = {1432-1459}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*epidemiology ; *Antineoplastic Agents/adverse effects/therapeutic use ; Case-Control Studies ; Female ; Humans ; *Immunosuppressive Agents/adverse effects/therapeutic use ; Male ; Middle Aged ; Odds Ratio ; Risk Factors ; Sex Factors ; Smoking/epidemiology ; United States ; }, abstract = {A recent population-based analysis demonstrated lower risk of the lethal degenerative neuromuscular disease, amyotrophic lateral sclerosis (ALS) associated with history of the use of 'antineoplastic agents' and 'immunosuppressants'. To see if this finding was generalizable to other ALS cohorts, we examined associations between use of these agents and ALS risk in an independent case-control study of n = 414 ALS patients and n = 361 controls in an Eastern US population. Controls were sampled from the general population and among non-neurodegenerative disease patients. A history of chemotherapy treatment was significantly associated with a decreased ALS risk (OR 0.46, 95% CI 0.22-0.89, P = 0.026). We did not observe an association between risk of ALS and immunosuppressant therapy use (OR 0.78, 95% CI 0.50-1.02, P = 0.23). Analyses were adjusted for age, gender, and smoking. Our results support the prior report for chemotherapy treatment and lead to further discussion of the underlying mechanism.}, }
@article {pmid28710685, year = {2017}, author = {Coatti, GC and Frangini, M and Valadares, MC and Gomes, JP and Lima, NO and Cavaçana, N and Assoni, AF and Pelatti, MV and Birbrair, A and de Lima, ACP and Singer, JM and Rocha, FMM and Da Silva, GL and Mantovani, MS and Macedo-Souza, LI and Ferrari, MFR and Zatz, M}, title = {Pericytes Extend Survival of ALS SOD1 Mice and Induce the Expression of Antioxidant Enzymes in the Murine Model and in IPSCs Derived Neuronal Cells from an ALS Patient.}, journal = {Stem cell reviews and reports}, volume = {13}, number = {5}, pages = {686-698}, pmid = {28710685}, issn = {2629-3277}, mesh = {Adipose Tissue/cytology/metabolism ; Amyotrophic Lateral Sclerosis/genetics/mortality/pathology/*therapy ; Animals ; Blood-Brain Barrier/metabolism/pathology ; Brain Stem/metabolism/pathology ; Catalase/genetics/metabolism ; Cerebral Cortex/metabolism/pathology ; Disease Models, Animal ; Female ; Gene Expression ; Humans ; Induced Pluripotent Stem Cells/metabolism/*pathology ; Male ; Mesenchymal Stem Cells/cytology/metabolism ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism/*pathology ; Mutation ; Pericytes/cytology/metabolism/*transplantation ; RNA-Binding Protein FUS/genetics/metabolism ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase-1/deficiency/*genetics ; Survival Analysis ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is one of the most common adult-onset motor neuron disease causing a progressive, rapid and irreversible degeneration of motor neurons in the cortex, brain stem and spinal cord. No effective treatment is available and cell therapy clinical trials are currently being tested in ALS affected patients. It is well known that in ALS patients, approximately 50% of pericytes from the spinal cord barrier are lost. In the central nervous system, pericytes act in the formation and maintenance of the blood-brain barrier, a natural defense that slows the progression of symptoms in neurodegenerative diseases. Here we evaluated, for the first time, the therapeutic effect of human pericytes in vivo in SOD1 mice and in vitro in motor neurons and other neuronal cells derived from one ALS patient. Pericytes and mesenchymal stromal cells (MSCs) were derived from the same adipose tissue sample and were administered to SOD1 mice intraperitoneally. The effect of the two treatments was compared. Treatment with pericytes extended significantly animals survival in SOD1 males, but not in females that usually have a milder phenotype with higher survival rates. No significant differences were observed in the survival of mice treated with MSCs. Gene expression analysis in brain and spinal cord of end-stage animals showed that treatment with pericytes can stimulate the host antioxidant system. Additionally, pericytes induced the expression of SOD1 and CAT in motor neurons and other neuronal cells derived from one ALS patient carrying a mutation in FUS. Overall, treatment with pericytes was more effective than treatment with MSCs. Our results encourage further investigations and suggest that pericytes may be a good option for ALS treatment in the future. Graphical Abstract ᅟ.}, }
@article {pmid28703923, year = {2018}, author = {Guo, F and Liu, X and Cai, H and Le, W}, title = {Autophagy in neurodegenerative diseases: pathogenesis and therapy.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {28}, number = {1}, pages = {3-13}, pmid = {28703923}, issn = {1750-3639}, support = {Z01 AG000941-01//Intramural NIH HHS/United States ; Z01 AG000942-01//Intramural NIH HHS/United States ; Z01 AG000944-01//Intramural NIH HHS/United States ; }, mesh = {Animals ; Autophagy/*physiology ; Humans ; Neurodegenerative Diseases/*physiopathology ; }, abstract = {The most prevalent pathological features of many neurodegenerative diseases are the aggregation of misfolded proteins and the loss of certain neuronal populations. Autophagy, as major intracellular machinery for degrading aggregated proteins and damaged organelles, has been reported to be involved in the occurrence of pathological changes in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. In this review, we summarize most recent research progress in this topic and provide a new perspective regarding autophagy regulation on the pathogenesis of neurodegenerative diseases. Finally, we discuss the signaling molecules in autophagy-related pathways as therapeutic targets for the treatment of these diseases.}, }
@article {pmid28703795, year = {2017}, author = {Akaiwa, K and Namekata, K and Azuchi, Y and Guo, X and Kimura, A and Harada, C and Mitamura, Y and Harada, T}, title = {Edaravone suppresses retinal ganglion cell death in a mouse model of normal tension glaucoma.}, journal = {Cell death &amp; disease}, volume = {8}, number = {7}, pages = {e2934}, pmid = {28703795}, issn = {2041-4889}, mesh = {Animals ; Antipyrine/*analogs &amp; derivatives/pharmacology/therapeutic use ; Apoptosis/*drug effects ; Disease Models, Animal ; Edaravone ; Electroretinography ; Excitatory Amino Acid Transporter 3/deficiency/genetics ; Intraocular Pressure/drug effects ; Low Tension Glaucoma/metabolism/*pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neuroprotective Agents/*pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Retina/diagnostic imaging/metabolism/pathology ; Retinal Ganglion Cells/*drug effects/metabolism/pathology ; Tomography, Optical Coherence ; Vision Disorders/prevention &amp; control ; }, abstract = {Glaucoma, one of the leading causes of irreversible blindness, is characterized by progressive degeneration of optic nerves and retinal ganglion cells (RGCs). In the mammalian retina, excitatory amino-acid carrier 1 (EAAC1) is expressed in neural cells, including RGCs. Loss of EAAC1 leads to RGC degeneration without elevated intraocular pressure (IOP) and exhibits glaucomatous pathology including glutamate neurotoxicity and oxidative stress. In the present study, we found that edaravone, a free radical scavenger that is used for treatment of acute brain infarction and amyotrophic lateral sclerosis (ALS), reduces oxidative stress and prevents RGC death and thinning of the inner retinal layer in EAAC1-deficient (KO) mice. In addition, in vivo electrophysiological analyses demonstrated that visual impairment in EAAC1 KO mice was ameliorated with edaravone treatment, clearly establishing that edaravone beneficially affects both histological and functional aspects of the glaucomatous retina. Our findings raise intriguing possibilities for the management of glaucoma by utilizing a widely prescribed drug for the treatment of acute brain infarction and ALS, edaravone, in combination with conventional treatments to lower IOP.}, }
@article {pmid28694091, year = {2017}, author = {Zhong, SJ and Gong, YH and Lin, YC}, title = {Combined intranasal nerve growth factor and ventricle neural stem cell grafts prolong survival and improve disease outcome in amyotrophic lateral sclerosis transgenic mice.}, journal = {Neuroscience letters}, volume = {656}, number = {}, pages = {1-8}, doi = {10.1016/j.neulet.2017.07.005}, pmid = {28694091}, issn = {1872-7972}, mesh = {Administration, Intranasal ; Amyotrophic Lateral Sclerosis/metabolism/pathology/*therapy ; Animals ; Brain/metabolism/pathology ; Cell Proliferation ; Combined Modality Therapy ; Lateral Ventricles/cytology ; Mice, Transgenic ; Motor Neurons/pathology ; Nerve Growth Factor/metabolism/*therapeutic use ; Neural Stem Cells/*transplantation ; Receptor, trkA/metabolism ; Spinal Cord/pathology ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease that selectively involves motor neurons. Neurotrophic factor supplementation and neural stem cell (NSC) alternative therapy have been used to treat ALS. The two approaches can affect each other in their pathways of action, and there is a possibility for synergism. However, to date, there have been no studies demonstrating the effects of combined therapy in the treatment of ALS. In this study, for the first time, we adopted a method involving the intranasal administration of nerve growth factor combined with lateral ventricle NSC transplantation using G93A-SOD1 transgenic mice as experimental subjects to explore the treatment effect of this combined therapy in ALS. We discover that the combined therapy increase the quantity of TrkA receptors, broaden the migration of exogenous NSCs, further promote active proliferation in neurogenic regions of the brain and enhance the preservation of motor neurons in the spinal cord. Regarding physical activity, the combined therapy improved motor functions, further postponed ALS onset and extended the survival time of the mice.}, }
@article {pmid28684305, year = {2017}, author = {Lee, SH and Suk, K}, title = {Emerging roles of protein kinases in microglia-mediated neuroinflammation.}, journal = {Biochemical pharmacology}, volume = {146}, number = {}, pages = {1-9}, doi = {10.1016/j.bcp.2017.06.137}, pmid = {28684305}, issn = {1873-2968}, mesh = {Central Nervous System Diseases/*enzymology/*pathology ; Gene Expression Regulation, Enzymologic ; Humans ; Inflammation/*enzymology/*pathology ; Microglia/*enzymology ; Protein Kinases/genetics/*metabolism ; }, abstract = {Neuroinflammation is mediated by resident central nervous system glia, neurons, peripherally derived immune cells, blood-brain barrier, and inflammatory mediators secreted from these cells. Neuroinflammation has been implicated in stroke and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Protein kinases have been one of the most exploited therapeutic targets in the current pharmacological research, especially in studies on cancer and inflammation. To date, 32 small-molecule protein kinase inhibitors have been approved by the United States Food and Drug Administration for the treatment of cancer and inflammation. However, there is no drug effectively targeting neuroinflammation and/or neurodegenerative diseases. Recent studies have advanced several protein kinases as important drug targets in neuroinflammation and/or neurodegenerative diseases. Here, we review emerging protein kinases potentially involved in neuroinflammation and subsequent neurodegenerative diseases.}, }
@article {pmid28677731, year = {2017}, author = {Che, F and Wang, G and Yu, J and Wang, X and Lu, Y and Fu, Q and Su, Q and Jiang, J and Du, Y}, title = {Effects of epigallocatechin‑3‑gallate on iron metabolism in spinal cord motor neurons.}, journal = {Molecular medicine reports}, volume = {16}, number = {3}, pages = {3010-3014}, doi = {10.3892/mmr.2017.6919}, pmid = {28677731}, issn = {1791-3004}, mesh = {Animals ; Catechin/*analogs &amp; derivatives/pharmacology ; Female ; Iron/*metabolism ; Lipid Peroxidation/drug effects ; Male ; Motor Neurons/*metabolism ; Rats, Sprague-Dawley ; Spinal Cord/*cytology ; }, abstract = {Accumulating evidence suggests that iron homeostasis is disordered in amyotrophic lateral sclerosis (ALS). In view of the promising performance of epigallocatechin‑3‑gallate (EGCG) in neuroprotection studies, the present study aimed to verify whether EGCG protects motor neurons in an ALS model, and whether it has any effects on iron metabolism using an ELISA and western blotting. The results demonstrated that EGCG decreased oxidative stress and protected motor neurons in the organotypic culture of the rat spinal cord. Furthermore, total iron levels increased significantly in the spinal cord following 3 weeks of treatment with threo‑hydroxyaspartate. In addition, the expression of influx proteins (transferrin receptor and divalent metal‑ion transporter 1) increased significantly. However, EGCG demonstrated no effect on total iron levels and the expression of influx proteins. In conclusion, EGCG leads to a decrease in oxidative stress levels, leading to motor neuron protection in the organotypic culture of a rat spinal cord; however, EGCG does not alter iron metabolism protein expression regulation.}, }
@article {pmid28673891, year = {2017}, author = {Lagman, C and Chung, LK and Chitale, RV and Yang, I}, title = {Dural Arteriovenous Fistula and Foix-Alajouanine Syndrome: Assessment of Functional Scores with Review of Pathogenesis.}, journal = {World neurosurgery}, volume = {106}, number = {}, pages = {206-210}, doi = {10.1016/j.wneu.2017.06.141}, pmid = {28673891}, issn = {1878-8769}, mesh = {Central Nervous System Vascular Malformations/complications/physiopathology/*therapy ; *Embolization, Therapeutic ; Gait Disorders, Neurologic/etiology/physiopathology ; Humans ; *Neurosurgical Procedures ; Paraplegia/etiology/physiopathology ; Spinal Cord Diseases/etiology/physiopathology/*therapy ; Syndrome ; Treatment Outcome ; Urination/physiology ; }, abstract = {OBJECTIVE: To assess the use of functional scores in the evaluation of patients with dural arteriovenous fistula and Foix-Alajouanine syndrome.<br><br>METHODS: We systematically surveyed the literature to identify relevant patients. Aminoff-Logue Scale (ALS) and modified Rankin Scale (mRS) scores were ascertained and combined to form a novel functional score, the Aminoff-Rankin Composite (ARC) score. We compared functional scores between surgery and embolization groups and ran one-sided point-biserial analyses to test our expectation that positive correlations exist between functional scores and treatment outcomes. Finally, we reviewed the pathogenesis of dural arteriovenous fistula formation.<br><br>RESULTS: The quantitative synthesis included 18 patients. Surgery alone was performed in 11 patients (61.11%); 7&#xa0;patients&#xa0;underwent embolization alone (38.89%). There were no significant differences in functional scores or symptom outcomes when we compared surgery to embolization. The pre-intervention ALS gait, mRS, and ARC scores were correlated with improved symptoms (rpb = 0.43, P = 0.04; rpb = 0.47, P = 0.02; rpb = 0.48, P = 0.04, respectively). In patients whose symptoms were improved, post-intervention ALS gait and micturition scores (2.55 vs. 4.43, P = 0.02 and 1.09 vs. 2.71, P = 0.01, respectively) and post-intervention ARC scores (6.66 vs. 11.57, P = 0.01) were on average lower than in patients whose symptoms were unimproved.<br><br>CONCLUSIONS: We believe that patients with dAVF and Foix-Alajouanine syndrome present with worse function (higher functional scores) as a result of an acute myelopathic episode, and that if diagnosed and treated appropriately, will experience some level of symptom improvement that is evidenced by reduced post-intervention functional scores.}, }
@article {pmid28671060, year = {2017}, author = {Milsten, AM and Tennyson, J and Weisberg, S}, title = {Retrospective Analysis of Mosh-Pit-Related Injuries.}, journal = {Prehospital and disaster medicine}, volume = {32}, number = {6}, pages = {636-641}, doi = {10.1017/S1049023X17006689}, pmid = {28671060}, issn = {1945-1938}, mesh = {*Crowding ; *Dancing ; Emergency Medical Services/*statistics &amp; numerical data ; Female ; Humans ; Male ; Massachusetts/epidemiology ; Retrospective Studies ; Wounds and Injuries/*epidemiology/etiology ; Young Adult ; }, abstract = {OBJECTIVES: Moshing is a violent form of dancing found world-wide at rock concerts, festivals, and electronic dance music events. It involves crowd surfing, shoving, and moving in a circular rotation. Moshing is a source of increased morbidity and mortality. The goal of this study was to report epidemiologic information on patient presentation rate (PPR), transport to hospital rate (TTHR), and injury patterns from patients who participated in mosh-pits. Materials and Methods Subjects were patrons from mosh-pits seeking medical care at a single venue. The events reviewed were two national concert tours which visited this venue during their tour. The eight distinct events studied occurred between 2011 and 2014. Data were collected retrospectively from prehospital patient care reports (PCRs). A single Emergency Medical Service (EMS) provided medical care at this venue. The following information was gathered from each PCR: type of injury, location of injury, treatment received, alcohol or drug use, Advanced Life Support/ALS interventions required, age and gender, disposition, minor or parent issues, as well as type of activity engaged in when injured.<br><br>RESULTS: Attendance for the eight events ranged from 5,100 to 16,000. Total patient presentations ranged from 50 to 206 per event. Patient presentations per ten thousand (PPTT) ranged from 56 to 130. The TTHR per 10,000 ranged from seven to 20. The mean PPTT was 99 (95% CI, 77-122) and the median was 98. The mean TTHR was 16 (95% CI, 12-29) and the median TTHR was 17. Patients presenting from mosh-pits were more frequently male (57.6%; P<.004). The mean age was 20 (95% CI, 19-20). Treatment received was overwhelmingly at the Basic Life Support (BLS) level (96.8%; P<.000001). General moshing was the most common activity leading to injury. Crowd surfing was the next most significant, accounting for 20% of presentations. The most common body part injured was the head (64% of injuries).<br><br>CONCLUSIONS: This retrospective review of mosh-pit-associated injury patterns demonstrates a high rate of injuries and presentations for medical aid at the evaluated events. General moshing was the most commonly associated activity and the head was the most common body part injured. Milsten AM , Tennyson J , Weisberg S , Retrospective analysis of mosh-pit-related injuries. Prehosp Disaster Med. 2017;32(6):636-641.}, }
@article {pmid28663100, year = {2017}, author = {Biferi, MG and Cohen-Tannoudji, M and Cappelletto, A and Giroux, B and Roda, M and Astord, S and Marais, T and Bos, C and Voit, T and Ferry, A and Barkats, M}, title = {A New AAV10-U7-Mediated Gene Therapy Prolongs Survival and Restores Function in an ALS Mouse Model.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {25}, number = {9}, pages = {2038-2052}, pmid = {28663100}, issn = {1525-0024}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*genetics/mortality/physiopathology/therapy ; Animals ; Dependovirus/*genetics ; Disease Models, Animal ; Exons ; Gene Order ; Gene Transfer Techniques ; *Genetic Therapy/methods ; Genetic Vectors/administration &amp; dosage/*genetics ; Humans ; Mice ; Mice, Transgenic ; Motor Activity/genetics ; Oligonucleotides, Antisense ; RNA Splice Sites ; RNA, Messenger/genetics/metabolism ; Recovery of Function ; Superoxide Dismutase-1/*genetics/metabolism ; Survival Rate ; Transduction, Genetic ; }, abstract = {One of the most promising therapeutic approaches for familial amyotrophic lateral sclerosis linked to superoxide dismutase 1 (SOD1) is the suppression of toxic mutant SOD1 in the affected tissues. Here, we report an innovative molecular strategy for inducing substantial, widespread, and sustained reduction of mutant human SOD1 (hSOD1) levels throughout the body of SOD1[G93A] mice, leading to therapeutic effects in animals. Adeno-associated virus serotype rh10 vectors (AAV10) were used to mediate exon skipping of the hSOD1 pre-mRNA by expression of exon-2-targeted antisense sequences embedded in a modified U7 small-nuclear RNA (AAV10-U7-hSOD). Skipping of hSOD1 exon 2 led to the generation of a premature termination codon, inducing production of a deleted transcript that was subsequently degraded by the activation of nonsense-mediated decay. Combined intravenous and intracerebroventricular delivery of AAV10-U7-hSOD increased the survival of SOD1[G93A] mice injected either at birth or at 50 days of age (by 92% and 58%, respectively) and prevented weight loss and the decline of neuromuscular function. This study reports the effectiveness of an exon-skipping approach in SOD1-ALS mice, supporting the translation of this technology to the treatment of this as yet incurable disease.}, }
@article {pmid28662296, year = {2017}, author = {Berry, JD and Paganoni, S and Atassi, N and Macklin, EA and Goyal, N and Rivner, M and Simpson, E and Appel, S and Grasso, DL and Mejia, NI and Mateen, F and Gill, A and Vieira, F and Tassinari, V and Perrin, S}, title = {Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability.}, journal = {Muscle &amp; nerve}, volume = {56}, number = {6}, pages = {1077-1084}, pmid = {28662296}, issn = {1097-4598}, support = {UL1 TR001414/TR/NCATS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Bradycardia/chemically induced ; Fatigue/chemically induced ; Female ; Fingolimod Hydrochloride/adverse effects/*therapeutic use ; Humans ; Immunosuppressive Agents/adverse effects/*therapeutic use ; Male ; Middle Aged ; Single-Blind Method ; }, abstract = {INTRODUCTION: Immune activation has been implicated in progression of amytrophic lateral sclerosis (ALS). Oral fingolimod reduces circulating lymphocytes. The objective of this phase IIa, randomized, controlled trial was to test the short-term safety, tolerability, and target engagement of fingolimod in ALS.<br><br>METHODS: Randomization was 2:1 (fingolimod:placebo). Treatment duration was 4 weeks. Primary outcomes were safety and tolerability. Secondary outcomes included circulating lymphocytes and whole-blood gene expression.<br><br>RESULTS: Thirty participants were randomized; 28 were administered a drug (fingolimod 18, placebo 10). No serious adverse events occurred. Adverse events were similar by treatment arm, as was study discontinuation (2 fingolimod vs. 0 placebo, with no statistical difference). Forced expiratory volume in 1 second (FEV1) and FEV1 /slow vital capacity changes were similar in the fingolimod and placebo arms. Circulating lymphocytes decreased significantly in the fingolimod arm (P&#x2009;<&#x2009;0.001). Nine immune-related genes were significantly downregulated in the fingolimod arm, including forkhead box P3 (P&#x2009;<&#x2009;0.001) and CD40 ligand (P&#x2009;=&#x2009;0.003).<br><br>DISCUSSION: Fingolimod is safe and well-tolerated and can reduce circulating lymphocytes in ALS patients. Muscle Nerve 56: 1077-1084, 2017.}, }
@article {pmid28645622, year = {2017}, author = {Bonifacino, T and Cattaneo, L and Gallia, E and Puliti, A and Melone, M and Provenzano, F and Bossi, S and Musante, I and Usai, C and Conti, F and Bonanno, G and Milanese, M}, title = {In-vivo effects of knocking-down metabotropic glutamate receptor 5 in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {Neuropharmacology}, volume = {123}, number = {}, pages = {433-445}, doi = {10.1016/j.neuropharm.2017.06.020}, pmid = {28645622}, issn = {1873-7064}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Astrocytes/metabolism/pathology ; Cell Death/physiology ; Cell Survival/physiology ; Disease Models, Animal ; Disease Progression ; Female ; Glutamic Acid/metabolism ; Humans ; Male ; Mice, Transgenic ; Microglia/metabolism/pathology ; Motor Neurons/metabolism/pathology ; Motor Skills/physiology ; Receptor, Metabotropic Glutamate 5/genetics/*metabolism ; Receptors, Metabotropic Glutamate/metabolism ; Sex Factors ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder due to loss of upper and lower motor neurons (MNs). The mechanisms of neuronal death are largely unknown, thus prejudicing the successful pharmacological treatment. One major cause for MN degeneration in ALS is represented by glutamate(Glu)-mediated excitotoxicity. We have previously reported that activation of Group I metabotropic Glu receptors (mGluR1 and mGluR5) at glutamatergic spinal cord nerve terminals produces abnormal Glu release in the widely studied SOD1[G93A] mouse model of ALS. We also demonstrated that halving mGluR1 expression in the SOD1[G93A] mouse had a positive impact on survival, disease onset, disease progression, and on a number of cellular and biochemical readouts of ALS. We generated here SOD1[G93A] mice with reduced expression of mGluR5 (SOD1[G93A]Grm5[-/+]) by crossing the SOD1[G93A] mutant mouse with the mGluR5 heterozigous Grm5[-/+] mouse. SOD1[G93A]Grm5[-/+] mice showed prolonged survival probability and delayed pathology onset. These effects were associated to enhanced number of preserved MNs, decreased astrocyte and microglia activation, reduced cytosolic free Ca[2+] concentration, and regularization of abnormal Glu release in the spinal cord of SOD1[G93A]Grm5[-/+] mice. Unexpectedly, only male SOD1[G93A]Grm5[-/+] mice showed improved motor skills during disease progression vs. SOD1[G93A] mice, while SOD1[G93A]Grm5[-/+] females did not. These results demonstrate that a lower constitutive level of mGluR5 has a significant positive impact in mice with ALS and support the idea that blocking Group I mGluRs may represent a potentially effective pharmacological approach to the disease.}, }
@article {pmid28639617, year = {2017}, author = {Friedmann, T}, title = {Gene therapy for spinomuscular atrophy: a biomedical advance, a missed opportunity for more equitable drug pricing.}, journal = {Gene therapy}, volume = {24}, number = {9}, pages = {503-505}, doi = {10.1038/gt.2017.48}, pmid = {28639617}, issn = {1476-5462}, mesh = {Costs and Cost Analysis ; Genetic Therapy/*economics/methods ; Humans ; Muscular Atrophy, Spinal/economics/genetics/*therapy ; Oligonucleotides, Antisense/administration &amp; dosage/*economics ; }, abstract = {An experimental approach for gene therapy of spinomuscular atrophy has been reported to prevent development of the neuromuscular features of this lethal and previously untreatable disorder. The approach involves treatment of patients suffering from SMN1-associated infantile form of the disease with a splice-switching antisense oligonucleotide (ASO) that corrects aberrant splicing of the nearly identical SMN2 gene to allow the generation of functional SMN protein, thereby mitigating the development of the disease. This technique represents the first apparently effective therapy for spinal muscular atrophy (SMA) and an important documentation for ASO technology for therapy of neurodegenerative disease. These results with one form of SMA are likely to be relevant for similar applications to other SMA types and are likely to inspire application to a number of other intractable neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis and possibly even the extremely common Parkinson's and Alzheimer's diseases and others. Nevertheless, the scientific and medical importance of this advance is marred by a pricing policy by the corporate sponsors that may complicate accessibility of the drug for some desperate patients.}, }
@article {pmid28634653, year = {2018}, author = {Main, BJ and Rodgers, KJ}, title = {Assessing the Combined Toxicity of BMAA and Its Isomers 2,4-DAB and AEG In Vitro Using Human Neuroblastoma Cells.}, journal = {Neurotoxicity research}, volume = {33}, number = {1}, pages = {33-42}, pmid = {28634653}, issn = {1476-3524}, support = {GIA1431//Motor Neurone Disease Research Institute of Australia/ ; }, mesh = {Amino Acids, Diamino/*pharmacology ; Aminobutyrates/*pharmacology ; Apoptosis/*drug effects ; Caspases/metabolism ; Cathepsins/metabolism ; Cell Line, Transformed ; Cell Survival ; Cyanobacteria Toxins ; Dose-Response Relationship, Drug ; Drug Synergism ; Electron Transport Complex IV/metabolism ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; Membrane Proteins/metabolism ; Neuroblastoma/pathology ; Neurotoxins/*pharmacology ; RNA, Messenger/metabolism ; Time Factors ; Transaminases/metabolism ; Transcription Factor CHOP/metabolism ; }, abstract = {The non-protein amino acid (NPAA) ß-methylamino-L-alanine (BMAA) is produced by a diverse range of cyanobacteria, diatoms and dinoflagellates, and is present in both aquatic and terrestrial ecosystems globally. Exposure to BMAA has been implicated in the development of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD). BMAA is often found in nature along with its structural isomers 2,4-diaminobutyric acid (2,4-DAB) and aminoethylglycine (AEG); however, the toxicity of these NPAAs in combination has not been examined. We have previously demonstrated that BMAA induces endoplasmic reticulum (ER) stress and increases caspase and cathepsin activity in human neuroblastoma cells (SH-SY5Y), effects consistent with proteotoxic stress due to disturbances in protein synthesis, folding or turnover. The current study investigates whether 2,4-DAB and AEG share a similar mechanism of toxicity to BMAA, and if simultaneous exposure of cells to BMAA and its isomers results in increased toxicity in vitro. We show that a 48-h treatment with both 500 μM BMAA and 2,4-DAB decreases cell viability in vitro whereas AEG was not cytotoxic under the same conditions. Treatment of SH-SY5Y cells with 2,4-DAB did not increase expression of ER stress markers. Combined treatment of cells with BMAA and 2,4-DAB resulted in increased caspase activity and increased apoptosis above that of BMAA or 2,4-DAB on their own. These results suggest that 2,4-DAB does not share the same mechanism of toxicity as BMAA but the presence of 2,4-DAB increases the toxicity of BMAA to human cells in vitro.}, }
@article {pmid28631959, year = {2017}, author = {Levi, BH and Simmons, Z and Hanna, C and Brothers, A and Lehman, E and Farace, E and Bain, M and Stewart, R and Green, MJ}, title = {Advance care planning for patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {5-6}, pages = {388-396}, pmid = {28631959}, issn = {2167-9223}, support = {R21 NR008539/NR/NINR NIH HHS/United States ; }, mesh = {Adult ; *Advance Care Planning/trends ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/psychology/*therapy ; *Decision Making ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; *Patient Satisfaction ; *Physician-Patient Relations ; Terminal Care/*methods/trends ; }, abstract = {PURPOSE: To determine whether an advance care planning (ACP) decision-aid could improve communication about end-of-life treatment wishes between patients with amyotrophic lateral sclerosis (ALS) and their clinicians.<br><br>METHODS: Forty-four patients with ALS (>21, English-speaking, without dementia) engaged in ACP using an interactive computer based decision-aid. Before participants completed the intervention, and again three months later, their clinicians reviewed three clinical vignettes, and made treatment decisions (n&#x2009;=&#x2009;18) for patients. After patients indicated their agreement with the team's decisions, concordance was calculated.<br><br>RESULTS: The mean concordance between patient wishes and the clinical team decisions was significantly higher post-intervention (post&#x2009;=&#x2009;91.9%, 95% CI&#x2009;=&#x2009;87.8, 96.1, vs. pre&#x2009;=&#x2009;52.4%, 95% CI&#x2009;=&#x2009;41.9, 62.9; p&#x2009;<0.001). Clinical team members reported greater confidence that their decisions accurately represented each patient's wishes post-intervention (mean&#x2009;=&#x2009;6.5) compared to pre-intervention (mean&#x2009;=&#x2009;3.3, 1&#x2009;=&#x2009;low, 10&#x2009;=&#x2009;high, p <0.001). Patients reported high satisfaction (mean&#x2009;=&#x2009;26.4, SD&#x2009;=&#x2009;3.2; 6&#x2009;=&#x2009;low, 30&#x2009;=&#x2009;high) and low decisional conflict (mean&#x2009;=&#x2009;28.8, SD&#x2009;=&#x2009;8.2; 20&#x2009;=&#x2009;low, 80&#x2009;=&#x2009;high) with decisions about end-of-life care, and high satisfaction with the decision-aid (mean&#x2009;=&#x2009;52.7, SD&#x2009;=&#x2009;5.7, 20&#x2009;=&#x2009;low, 60&#x2009;=&#x2009;high). Patient knowledge regarding ACP increased post-intervention (pre&#x2009;=&#x2009;47.8% correct responses vs. post&#x2009;=&#x2009;66.3%; p&#x2009;<0.001) without adversely affecting patient anxiety or self-determination.<br><br>CONCLUSION: A computer based ACP decision-aid can significantly improve clinicians' understanding of ALS patients' wishes with regard to end-of-life medical care.}, }
@article {pmid28628244, year = {2017}, author = {Gendron, TF and ,  and Daughrity, LM and Heckman, MG and Diehl, NN and Wuu, J and Miller, TM and Pastor, P and Trojanowski, JQ and Grossman, M and Berry, JD and Hu, WT and Ratti, A and Benatar, M and Silani, V and Glass, JD and Floeter, MK and Jeromin, A and Boylan, KB and Petrucelli, L}, title = {Phosphorylated neurofilament heavy chain: A biomarker of survival for C9ORF72-associated amyotrophic lateral sclerosis.}, journal = {Annals of neurology}, volume = {82}, number = {1}, pages = {139-146}, pmid = {28628244}, issn = {1531-8249}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; R21 NS089979/NS/NINDS NIH HHS/United States ; R01 NS085207/NS/NINDS NIH HHS/United States ; K23 AG042856/AG/NIA NIH HHS/United States ; P01 AG017586/AG/NIA NIH HHS/United States ; R56 NS061867/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; R01 NS061867/NS/NINDS NIH HHS/United States ; R35 NS097261/NS/NINDS NIH HHS/United States ; R01 NS093865/NS/NINDS NIH HHS/United States ; R01 NS078398/NS/NINDS NIH HHS/United States ; R01 NS088689/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R21 NS084528/NS/NINDS NIH HHS/United States ; U54 NS092089/NS/NINDS NIH HHS/United States ; U54 NS091046/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/*genetics ; Biomarkers/cerebrospinal fluid ; C9orf72 Protein ; Case-Control Studies ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Neurofilament Proteins/*cerebrospinal fluid ; Phosphorylation ; Proteins/*genetics ; Survival Analysis ; Young Adult ; }, abstract = {As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions. These data support the use of CSF pNFH as a prognostic biomarker for clinical trials, which will increase the likelihood of successfully developing a treatment for c9ALS. Ann Neurol 2017;82:139-146.}, }
@article {pmid28620838, year = {2017}, author = {Prpar Mihevc, S and Pavlin, M and Darovic, S and Živin, M and Podbregar, M and Rogelj, B and Mars, T}, title = {Modelling FUS Mislocalisation in an In Vitro Model of Innervated Human Muscle.}, journal = {Journal of molecular neuroscience : MN}, volume = {62}, number = {3-4}, pages = {318-328}, pmid = {28620838}, issn = {1559-1166}, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Cells, Cultured ; Humans ; Muscle Fibers, Skeletal/*metabolism ; Neurons/metabolism ; Protein Transport ; RNA-Binding Protein FUS/*metabolism ; Rats ; Rats, Wistar ; Spinal Cord/cytology ; }, abstract = {Degeneration of distal axons and neuromuscular junctions is an early feature in the pathology of amyotrophic lateral sclerosis (ALS), which culminates in motor neuron loss due to axon retraction and muscle atrophy. The complex interactions in the pathogenesis of ALS between motor neurons, muscle cells and accompanying glia require an appropriate experimental model. Here, we have defined a co-culture model based on human myotubes innervated by neurons from embryonic rat spinal cord explants to investigate the pathology and treatment of ALS. This model was first characterised for endogenous expression and distribution of ALS-related proteins TDP-43 and FUS. Then, wild-type FUS and its mutants were introduced into these co-cultures to determine how FUS defects in nuclear transport modulate the pathological conditions. FUS-bearing plasmids were introduced by classical transfection and electroporation, as novel approaches to deliver plasmids into explants, and their cellular distributions were characterised. Endogenous nuclear expression of TDP-43 and FUS was observed in explants and myoblasts/myotubes. After transfection, wild-type FUS was expressed in nuclei of myoblasts, myotubes and explants, although with low transfection rates. Following successful electrotransfection into explants, the localisation of wild-type FUS was nuclear, and it was detected in neurons, astrocytes, Schwann cells and oligodendrocyte precursors, whereas the FUS∆Y, FUSY526A and FUSY526E mutants were cytoplasmic, and the FUSY526F mutant was nuclear and cytoplasmic. This co-culture model is applicable to the study of neuronal and non-neuronal cell contributions to ALS and other neurodegenerative diseases, and it can be used to investigate drug targets amenable to intervention.}, }
@article {pmid28619002, year = {2017}, author = {Peric, M and Mitrecic, D and Andjus, PR}, title = {Targeting Astrocytes for Treatment in Amyotrophic Lateral Sclerosis.}, journal = {Current pharmaceutical design}, volume = {23}, number = {33}, pages = {5037-5044}, doi = {10.2174/1381612823666170615110446}, pmid = {28619002}, issn = {1873-4286}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology/*therapy ; Animals ; Aquaporins/antagonists &amp; inhibitors/metabolism ; Astrocytes/drug effects/*metabolism/pathology ; Drug Delivery Systems/methods/*trends ; Humans ; Potassium Channel Blockers/administration &amp; dosage ; Potassium Channels, Inwardly Rectifying/antagonists &amp; inhibitors/metabolism ; Stem Cell Transplantation/methods/*trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder affecting upper and lower motoneurons. The two types, sporadic and familial differ in the aetiopathogenesis but have a similar neuropathology characterized by oxidative stress, excitotoxicity and inflammation. The disease is also characterized by a non-cell autonomous mechanism with astrocytes playing a central role by affecting synaptic glutamate, the blood-brain barrier, and metabolic and trophic support. Two types of therapeutic approaches focusing on astrocytes are presented: a) emerging molecular targets (potassium inward rectifier channels and aquaporins at the astrocyte endfeet, and IP3 receptor signaling pathway), and b) cell therapy with stem cell - generated and transplanted astrocytes.}, }
@article {pmid28616022, year = {2017}, author = {Jaiswal, MK}, title = {Therapeutic opportunities and challenges of induced pluripotent stem cells-derived motor neurons for treatment of amyotrophic lateral sclerosis and motor neuron disease.}, journal = {Neural regeneration research}, volume = {12}, number = {5}, pages = {723-736}, pmid = {28616022}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis (ALS) and motor neuron diseases (MNDs) are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons (UMNs/LMNs), brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons (MNs), muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3-5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for the first time to obtain substantial amounts of human cells to recapitulate in vitro "disease in dish" and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs.}, }
@article {pmid28612258, year = {2018}, author = {Cunha, C and Santos, C and Gomes, C and Fernandes, A and Correia, AM and Sebastião, AM and Vaz, AR and Brites, D}, title = {Downregulated Glia Interplay and Increased miRNA-155 as Promising Markers to Track ALS at an Early Stage.}, journal = {Molecular neurobiology}, volume = {55}, number = {5}, pages = {4207-4224}, pmid = {28612258}, issn = {1559-1182}, support = {PTDC/SAU-FAR/118787/2010//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; UID/DTP/04138/2013//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; SFRH/BPD/76590/2011//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; SFRH/BD/91316/2012//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; SFRH/BD/102718/2014//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; ELA-2015-002//Research Grant of the Santa Casa Scientific Research Program on ALS/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*pathology ; Animals ; Astrocytes/metabolism ; Biomarkers/metabolism ; Cell Communication ; Cell Count ; Disease Models, Animal ; *Down-Regulation ; Gene Expression Profiling ; HMGB1 Protein/metabolism ; Homeostasis ; Humans ; Inflammasomes/metabolism ; Inflammation/pathology ; Interleukin-6/metabolism ; Mice, Transgenic ; MicroRNAs/genetics/*metabolism ; Motor Neurons/metabolism/pathology ; NF-kappa B/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Neuroglia/metabolism/*pathology ; Phenotype ; Signal Transduction ; Superoxide Dismutase-1/genetics ; Tumor Necrosis Factor-alpha/metabolism ; Up-Regulation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown cause. Absence of specific targets and biomarkers compromise the development of new therapeutic strategies and of innovative tools to stratify patients and assess their responses to treatment. Here, we investigate changes in neuroprotective-neuroinflammatory actions in the spinal cord of SOD1 [G93A] mice, at presymptomatic and symptomatic stages to identify stage-specific biomarkers and potential targets. Results showed that in the presymptomatic stage, there are alterations in both astrocytes and microglia, which comprise decreased expression of GFAP and S100B and upregulation of GLT-1, as well as reduced expression of CD11b, M2-phenotype markers, and a set of inflammatory mediators. Reduced levels of Connexin-43, Pannexin-1, CCL21, and CX3CL1 further indicate the existence of a compromised intercellular communication. In contrast, in the symptomatic stage, increased markers of inflammation became evident, such as NF-κB/Nlrp3-inflammasome, Iba1, pro-inflammatory cytokines, and M1-polarizion markers, together with a decreased expression of M2-phenotypic markers. We also observed upregulation of the CX3CL1-CX3CR1 axis, Connexin-43, Pannexin-1, and of microRNAs (miR)-124, miR-125b, miR-146a and miR-21. Reduced motor neuron number and presence of reactive astrocytes with decreased GFAP, GLT-1, and GLAST further characterized this inflammatory stage. Interestingly, upregulation of miR-155 and downregulation of MFG-E8 appear as consistent biomarkers of both presymptomatic and symptomatic stages. We hypothesize that downregulated cellular interplay at the early stages may represent neuroprotective mechanisms against inflammation, SOD1 aggregation, and ALS onset. The present study identified a set of inflamma-miRNAs, NLRP3-inflammasome, HMGB1, CX3CL1-CX3CR1, Connexin-43, and Pannexin-1 as emerging candidates and promising pharmacological targets that may represent potential neuroprotective strategies in ALS therapy.}, }
@article {pmid28600459, year = {2017}, author = {Rushton, DJ and Andres, PL and Allred, P and Baloh, RH and Svendsen, CN}, title = {Patients with ALS show highly correlated progression rates in left and right limb muscles.}, journal = {Neurology}, volume = {89}, number = {2}, pages = {196-206}, pmid = {28600459}, issn = {1526-632X}, support = {R01 NS097545/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*physiopathology ; *Disease Progression ; Extremities/*physiopathology ; Follow-Up Studies ; Humans ; Models, Statistical ; Muscle Strength/*physiology ; Muscle, Skeletal/*physiopathology ; Neurologic Examination ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) progresses at different rates between patients, making clinical trial design difficult and dependent on large cohorts of patients. Currently, there are few data showing whether the left and right limbs progress at the same or different rates. This study addresses rates of decline in specific muscle groups of patients with ALS and assesses whether there is a relationship between left and right muscles in the same patient, regardless of overall progression.<br><br>METHODS: A large cohort of patients was used to assess decline in muscle strength in right and left limbs over time using 2 different methods: The Tufts Quantitative Neuromuscular Exam and Accurate Test of Limb Isometric Strength protocol. Then advanced linear regression statistical methods were applied to assess progression rates in each limb.<br><br>RESULTS: This report shows that linearized progression models can predict general slopes of decline with good accuracy. Critically, the data demonstrate that while overall decline is variable, there is a high degree of correlation between left and right muscle decline in ALS. This implies that irrespective of which muscle starts declining soonest or latest, their rates of decline following onset are more consistent.<br><br>CONCLUSIONS: First, this study demonstrates a high degree of power when using unilateral treatment approaches to detect a slowing in disease progression in smaller groups of patients, thus allowing for paired statistical tests. These findings will be useful in transplantation trials that use muscle decline to track disease progression in ALS. Second, these findings discuss methods, such as tactical selection of muscle groups, which can improve the power efficiency of all ALS clinical trials.}, }
@article {pmid28597807, year = {2017}, author = {Gil-Bea, FJ and Aldanondo, G and Lasa-Fernández, H and López de Munain, A and Vallejo-Illarramendi, A}, title = {Insights into the mechanisms of copper dyshomeostasis in amyotrophic lateral sclerosis.}, journal = {Expert reviews in molecular medicine}, volume = {19}, number = {}, pages = {e7}, doi = {10.1017/erm.2017.9}, pmid = {28597807}, issn = {1462-3994}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*metabolism ; Animals ; Biological Transport ; Central Nervous System/metabolism ; Copper/*metabolism ; Homeostasis ; Humans ; Mitochondria/genetics/metabolism ; Motor Neurons/metabolism ; Nervous System Diseases/etiology/metabolism ; Oxidation-Reduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neuromuscular disease characterised by a progressive loss of motor neurons that usually results in paralysis and death within 2 to 5 years after disease onset. The pathophysiological mechanisms involved in ALS remain largely unknown and to date there is no effective treatment for this disease. Here, we review clinical and experimental evidence suggesting that dysregulation of copper homeostasis in the central nervous system is a crucial underlying event in motor neuron degeneration and ALS pathophysiology. We also review and discuss novel approaches seeking to target copper delivery to treat ALS. These novel approaches may be clinically relevant not only for ALS but also for other neurological disorders with abnormal copper homeostasis, such as Parkinson's, Huntington's and Prion diseases.}, }
@article {pmid28597677, year = {2017}, author = {Alves, AR and Almeida, N and Ferreira, M and Tomé, L}, title = {Endoscopic management of afferent loop syndrome caused by enteroliths and anastomotic stricture. A case report.}, journal = {Revista espanola de enfermedades digestivas}, volume = {109}, number = {6}, pages = {457}, pmid = {28597677}, issn = {1130-0108}, mesh = {Afferent Loop Syndrome/*diagnostic imaging/*surgery ; Aged, 80 and over ; Calculi/*diagnostic imaging/*surgery ; Constriction, Pathologic ; Endoscopy, Gastrointestinal/*methods ; Gastric Bypass/adverse effects ; Humans ; Male ; Tomography, X-Ray Computed ; }, abstract = {Afferent loop syndrome (ALS) is a rare complication of Billroth-II gastrojejunostomy. Causes of afferent loop obstruction include adhesions, internal hernias, intestinal strictures or malignancy. Obstruction caused by enteroliths is rare and usually requires surgery. We present the case of a 90-year-old man with a Billroth-II performed 50 years earlier and three acute pancreatitis. He presented with acute abdominal pain, without signs of pancreatitis. Upper digestive endoscopy revealed a punctiform anastomotic stricture of the afferent loop. Fluoroscopy-guided contrast injection showed a dilated loop with multiple filling defects. After through-the-scope balloon dilation, multiple calculi similar to gallstones were observed in the afferent loop and were removed with a basket. There were no signs of choledochoduodenal fistula or abnormalities in the ampulla of Vater, leading us to assume the formation of intestinal calculi. This case represents a rare cause of ALS, emphasizing the possibility of solely endoscopic treatment. The stone was removed and the anastomotic stricture which was the underlying cause of the enterolith formation was treated by endoscopy. Endoscopic management of enterolith-related ALS is technically difficult and rarely reported. To our knowledge, there are two cases in which electrohydraulic lithotripsy was used to fragment a large enterolith in the afferent loop. This includes one report of failed endoscopic retrieval of an enterolith and in another case a perforation after an attempt to grasp the stone with a basket. ALS has multiple causes and non-specific clinical manifestations. We highlight the importance of high clinical suspicion and individualized treatment according to the patient's condition, severity, ALS etiology and locally available treatment possibilities.}, }
@article {pmid28593575, year = {2017}, author = {Fortunato, A}, title = {The role of hERG1 ion channels in epithelial-mesenchymal transition and the capacity of riluzole to reduce cisplatin resistance in colorectal cancer cells.}, journal = {Cellular oncology (Dordrecht, Netherlands)}, volume = {40}, number = {4}, pages = {367-378}, pmid = {28593575}, issn = {2211-3436}, mesh = {Animals ; Anticonvulsants/pharmacology ; Antineoplastic Agents/pharmacology ; Caco-2 Cells ; Cell Line, Tumor ; Cell Survival/drug effects/genetics ; Cisplatin/*pharmacology ; Colorectal Neoplasms/*drug therapy/genetics/metabolism/pathology ; Drug Resistance, Neoplasm/*drug effects/genetics ; Drug Synergism ; Epithelial-Mesenchymal Transition/*drug effects/genetics ; Ether-A-Go-Go Potassium Channels/*genetics/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; HCT116 Cells ; HT29 Cells ; Humans ; Mice, Nude ; RNA Interference ; Riluzole/*pharmacology ; Xenograft Model Antitumor Assays ; }, abstract = {PURPOSE: The transition of cells from the epithelial to the mesenchymal state (EMT) plays an important role in tumor progression. EMT allows cells to acquire mobility, stem-like behavior and resistance to apoptosis and drug treatment. These features turn EMT into a central process in tumor biology. Ion channels are attractive targets for the treatment of cancer since they play critical roles in controlling a wide range of physiological processes that are frequently deregulated in cancer. Here, we investigated the role of ether-a-go-go-related 1 (hERG1) ion channels in the EMT of colorectal cancer cells.<br><br>METHODS: We studied the epithelial-mesenchymal profile of different colorectal cancer-derived cell lines and the expression of hERG1 potassium channels in these cell lines using real-time PCR. Next, we knocked down hERG1 expression in HCT116 cells using lentivirus mediated RNA interference and characterized the hERG1 silenced cells in vitro and in vivo. Finally, we investigated the capacity of riluzole, an ion channel-modulating drug used in humans to treat amyotrophic lateral sclerosis, to reduce the resistance of the respective colorectal cancer cells to the chemotherapeutic drug cisplatin.<br><br>RESULTS: We found that of the colorectal cancer-derived cell lines tested, HCT116 showed the highest mesenchymal profile and a high hERG1 expression. Subsequent hERG1 expression knockdown induced a change in cell morphology, which was accompanied by a reduction in the proliferative and tumorigenic capacities of the cells. Notably, we found that hERG1expression knockdown elicited a reversion of the EMT profile in HCT116 cells with a reacquisition of the epithelial-like profile. We also found that riluzole increased the sensitivity of HCT116 cisplatin-resistant cells to cisplatin.<br><br>CONCLUSIONS: Our data indicate that hERG1 plays a role in the EMT of colorectal cancer cells and that its knockdown reduces the proliferative and tumorigenic capacities of these cells. In addition, we conclude that riluzole may be used in combination with cisplatin to reduce chemo-resistance in colorectal cancer cells.}, }
@article {pmid28591718, year = {2017}, author = {Dolfi, SC and Medina, DJ and Kareddula, A and Paratala, B and Rose, A and Dhami, J and Chen, S and Ganesan, S and Mackay, G and Vazquez, A and Hirshfield, KM}, title = {Riluzole exerts distinct antitumor effects from a metabotropic glutamate receptor 1-specific inhibitor on breast cancer cells.}, journal = {Oncotarget}, volume = {8}, number = {27}, pages = {44639-44653}, pmid = {28591718}, issn = {1949-2553}, support = {21140/CRUK_/Cancer Research UK/United Kingdom ; P30 CA072720/CA/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Agents/*pharmacology ; Breast Neoplasms/genetics/metabolism ; Cell Cycle/drug effects/genetics ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage ; Dose-Response Relationship, Drug ; Energy Metabolism ; Female ; G2 Phase Cell Cycle Checkpoints/drug effects ; Gene Expression ; Gene Expression Profiling ; Humans ; Mitosis/drug effects/genetics ; Oxidative Phosphorylation/drug effects ; Receptors, Metabotropic Glutamate/*antagonists &amp; inhibitors/genetics/metabolism ; Riluzole/*pharmacology ; Signal Transduction/drug effects ; }, abstract = {Recent evidence suggests that glutamate signaling plays an important role in cancer. Riluzole is a glutamate release inhibitor and FDA-approved drug for the treatment of amyotrophic lateral sclerosis. It has been investigated as an inhibitor of cancer cell growth and tumorigenesis with the intention of repurposing it for the treatment of cancer. Riluzole is thought to act by indirectly inhibiting glutamate signaling. However, the specific effects of riluzole in breast cancer cells are not well understood. In this study, the anti-cancer effects of riluzole were explored in a panel of breast cancer cell lines in comparison to the metabotropic glutamate receptor 1-specific inhibitor BAY 36-7620. While both drugs inhibited breast cancer cell proliferation, there were distinct functional effects suggesting that riluzole action may be metabotropic glutamate receptor 1-independent. Riluzole induced mitotic arrest independent of oxidative stress while BAY 36-7620 had no measurable effect on mitosis. BAY 36-7620 had a more pronounced and significant effect on DNA damage than riluzole. Riluzole altered cellular metabolism as demonstrated by changes in oxidative phosphorylation and cellular metabolite levels. These results provide a better understanding of the functional action of riluzole in the treatment of breast cancer.}, }
@article {pmid28588226, year = {2017}, author = {Ueda, T and Inden, M and Shirai, K and Sekine, SI and Masaki, Y and Kurita, H and Ichihara, K and Inuzuka, T and Hozumi, I}, title = {The effects of Brazilian green propolis that contains flavonols against mutant copper-zinc superoxide dismutase-mediated toxicity.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {2882}, pmid = {28588226}, issn = {2045-2322}, mesh = {AMP-Activated Protein Kinases/metabolism ; Animals ; Antioxidants/chemistry/pharmacology ; Autophagy ; Flavonols/chemistry/*pharmacology ; Kaempferols/pharmacology ; Mice ; Motor Neurons/drug effects/metabolism ; *Mutation ; Phosphorylation ; Propolis/chemistry/*pharmacology ; Protective Agents/chemistry/*pharmacology ; Protein Aggregates ; Superoxide Dismutase-1/*genetics/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective and progressive loss of motor neurons. The purpose of this study was to clarify effects of brazilian green propolis and the active ingredient against ALS-associated mutant copper-zinc superoxide dismutase (SOD1)-mediated toxicity. Ethanol extract of brazilian green propolis (EBGP) protected N2a cells against mutant SOD1-induced neurotoxicity and reduced aggregated mutant SOD1 by induction of autophagy. Kaempferide and kaempferol, the active ingredients of EBGP, also inhibited mutant SOD1-induced cell death and reduced the intracellular mutant SOD1 aggregates. Both kaempferide and kaempferol significantly suppressed mutant SOD1-induced superoxide in mitochondria. Western blot analysis showed that kaempferol potentially induced autophagy via the AMP-activated protein kinase (AMPK) - the mammalian target of rapamycin (mTOR) pathway. These results suggest that EBGP containing the active ingredient against mutant SOD1-mediated toxicity is a promising medicine or health food for prevention and treatment of ALS.}, }
@article {pmid28587920, year = {2018}, author = {Paino, L and Blasco, N}, title = {[What would you do with an adult patient who consults due to head muscle weakness and has dropped head?].}, journal = {Semergen}, volume = {44}, number = {2}, pages = {135-137}, doi = {10.1016/j.semerg.2017.04.009}, pmid = {28587920}, issn = {1578-8865}, mesh = {Aged, 80 and over ; Algorithms ; Diagnosis, Differential ; Female ; Humans ; Kyphosis/*diagnosis/etiology ; Muscle Weakness/*diagnosis/etiology ; Neck Muscles/*pathology ; Prognosis ; Syndrome ; }, abstract = {The dropped head syndrome, whether due to muscle weakness, rigidity, or ankylosis, is not uncommon in the elderly. It is characterised by a "chin-on-chest" reducible kyphosis, which is secondary to head muscle debility. It may be associated with a neuromuscular group of diseases such as polymyositis, chronic Inflammatory demyelinating polyneuropathy, myasthenia gravis, amyotrophic lateral sclerosis, and inclusion-body myositis. Some cases associated with hypothyroidism and hyperparathyroidism have also been described. Prognosis without treatment is poor. Therefore, familiarity with this condition, together with a complete anamnesis and physical examination, should lead us to the clinical suspicion and selection of the appropriate complementary tests. In this article, a case of dropped head syndrome is reported, as well as an algorithm for its diagnosis.}, }
@article {pmid28585888, year = {2017}, author = {Crook, A and Williams, K and Adams, L and Blair, I and Rowe, DB}, title = {Predictive genetic testing for amyotrophic lateral sclerosis and frontotemporal dementia: genetic counselling considerations.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {7-8}, pages = {475-485}, doi = {10.1080/21678421.2017.1332079}, pmid = {28585888}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics/*psychology ; Clinical Decision-Making/methods ; Evidence-Based Medicine ; Frontotemporal Dementia/diagnosis/*genetics/*psychology ; Genetic Counseling/methods/*psychology ; Genetic Testing/*methods ; Humans ; Patient Participation/methods/*psychology ; Physician-Patient Relations ; Prognosis ; Risk Assessment ; }, abstract = {Once a gene mutation that is causal of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) is identified in a family, relatives may decide to undergo predictive genetic testing to determine whether they are at risk of developing disease. Recent advances in gene discovery have led to a pressing need to better understand the implications of predictive genetic testing. Here we review the uptake of genetic counselling, predictive and reproductive testing, and the factors that impact the decision to undergo testing, for consideration in clinical practice. The literature suggests that the factors impacting the decision to undergo testing are complex due to the nature of these diseases, absence of available preventative medical treatment and variable age of onset in mutation carriers. Gaining further insight into the decision-making process and the impact of testing is critical as we seek to develop best-practice guidelines for predictive testing for familial ALS and FTD.}, }
@article {pmid28583309, year = {2017}, author = {Leone Roberti Maggiore, U and Ferrero, S and Candiani, M and Somigliana, E and Viganò, P and Vercellini, P}, title = {Reply to Rodolfo Montironi, Silvia Gasparrini, Antonio Lopez-Beltran, et al's Letter to the Editor re: Umberto Leone Roberti Maggiore, Simone Ferrero, Massimo Candiani, et al. Bladder Endometriosis: A Systematic Review of Pathogenesis, Diagnosis, Treatment, Impact on Fertility, and Risk of Malignant Transformation. Eur Urol 2017;71:790-807. Benign Müllerian Lesions in the Urinary Bladder: Endometriosis, Endocervicosis, Endosalpingiosis, and Müllerianosis.}, journal = {European urology}, volume = {72}, number = {5}, pages = {e142}, doi = {10.1016/j.eururo.2017.05.028}, pmid = {28583309}, issn = {1873-7560}, mesh = {*Endometriosis ; Female ; Fertility ; Humans ; *Urinary Bladder Diseases ; Urologic Diseases ; }, }
@article {pmid28579792, year = {2017}, author = {Hogden, A and Foley, G and Henderson, RD and James, N and Aoun, SM}, title = {Amyotrophic lateral sclerosis: improving care with a multidisciplinary approach.}, journal = {Journal of multidisciplinary healthcare}, volume = {10}, number = {}, pages = {205-215}, pmid = {28579792}, issn = {1178-2390}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, leading to death within an average of 2-3 years. A cure is yet to be found, and a single disease-modifying treatment has had a modest effect in slowing disease progression. Specialized multidisciplinary ALS care has been shown to extend survival and improve patients' quality of life, by providing coordinated interprofessional care that seeks to address the complex needs of this patient group. This review examines the nature of specialized multidisciplinary care in ALS and draws on a broad range of evidence that has shaped current practice. The authors explain how multidisciplinary ALS care is delivered. The existing models of care, the role of palliative care within multidisciplinary ALS care, and the costs of formal and informal care are examined. Critical issues of ALS care are then discussed in the context of the support rendered by multidisciplinary-based care. The authors situate the patient and family as key stakeholders and decision makers in the multidisciplinary care network. Finally, the current challenges to the delivery of coordinated interprofessional care in ALS are explored, and the future of coordinated interprofessional care for people with ALS and their family caregivers is considered.}, }
@article {pmid28579383, year = {2017}, author = {Gazzina, S and Manes, MA and Padovani, A and Borroni, B}, title = {Clinical and biological phenotypes of frontotemporal dementia: Perspectives for disease modifying therapies.}, journal = {European journal of pharmacology}, volume = {817}, number = {}, pages = {76-85}, doi = {10.1016/j.ejphar.2017.05.056}, pmid = {28579383}, issn = {1879-0712}, mesh = {Animals ; Frontotemporal Dementia/*drug therapy/genetics/metabolism ; Humans ; Phenotype ; }, abstract = {Frontotemporal Dementia (FTD) is a progressive neurodegenerative condition which encompasses a group of clinically, neuropathologically and genetically heterogeneous disorders characterized by selective involvement of the frontal and temporal lobes. FTD is characterized by changes in behaviour and personality, frontal executive deficits and language dysfunction. Different phenotypes have been defined on the basis of presenting clinical symptoms, behavioural variants of FTD (bvFTD) and primary progressive aphasia (PPA), which includes nonfluent/agrammatic variant PPA (avPPA) and semantic variant PPA (svPPA). These presentations can overlap with atypical parkinsonian disorders (i.e., corticobasal syndrome, progressive supranuclear palsy) and amyotrophic lateral sclerosis. Each syndrome can be associated with one or more neuropathological hallmark, and in some cases it may be due to autosomal inherited disorder caused by mutations in a number of genes. Currently, there is no specific treatment available to prevent disease progression. FTD treatment is based on symptomatic management, and most therapies lack quality evidence from randomized, placebo-controlled clinical trials. Recent advances in the understanding of FTD pathophysiology and genetics have led to the development of potentially disease-modifying therapies. In this review, we discussed current knowledge and recommendations with regards to symptomatic and disease-modifying therapies.}, }
@article {pmid28571556, year = {2017}, author = {Magri, A and Messina, A}, title = {Interactions of VDAC with Proteins Involved in Neurodegenerative Aggregation: An Opportunity for Advancement on Therapeutic Molecules.}, journal = {Current medicinal chemistry}, volume = {24}, number = {40}, pages = {4470-4487}, doi = {10.2174/0929867324666170601073920}, pmid = {28571556}, issn = {1875-533X}, mesh = {Alzheimer Disease/physiopathology ; Amyloid beta-Peptides/*metabolism ; Animals ; *Drug Delivery Systems ; Humans ; Parkinson Disease/physiopathology ; Protein Aggregation, Pathological/genetics/*physiopathology ; Protein Folding ; Protein Isoforms ; Voltage-Dependent Anion Channel 1/*metabolism ; }, abstract = {BACKGROUND: The Voltage Dependent Anion Channel (VDAC) proteins represent the most important pore-forming proteins of the mitochondrial outer membrane, directly involved in metabolism and apoptosis regulation. Literature has highlighted a key role of VDACs in mitochondrial dysfunction typical of many neurodegenerative disorders. In particular, the principal isoform VDAC1 represents the main mitochondrial docking site of many misfolded proteins, such as amyloid β and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease and several SOD1 mutants in Amyotrophic Lateral Sclerosis. The interaction of misfolded proteins with VDAC1 has a strong impact on both cellular bioenergetics and apoptosis' pathways alteration. Therefore, VDACs represent a promising therapeutic target in neurodegeneration.<br><br>OBJECTIVE: This review summarizes the roles of VDAC isoforms, and particularly of VDAC1, in the most common neurological disorders and analyzes in detail molecules and peptides available so far, able to interact and modulate VDAC1 in any considered pathological condition.<br><br>CONCLUSION: This review offers a description of the most promising therapeutic strategies acting on VDAC1, for the treatment of neurodegenerative diseases.}, }
@article {pmid28561886, year = {2018}, author = {Nicholson, K and Murphy, A and McDonnell, E and Shapiro, J and Simpson, E and Glass, J and Mitsumoto, H and Forshew, D and Miller, R and Atassi, N}, title = {Improving symptom management for people with amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {57}, number = {1}, pages = {20-24}, doi = {10.1002/mus.25712}, pmid = {28561886}, issn = {1097-4598}, mesh = {Age Factors ; Age of Onset ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/epidemiology/therapy ; Cohort Studies ; Disease Management ; Fatigue/etiology/physiopathology ; Female ; Health Care Surveys ; Humans ; Male ; Middle Aged ; Muscle Cramp ; Muscular Diseases/etiology/physiopathology ; Prevalence ; Severity of Illness Index ; Sex Factors ; United States/epidemiology ; }, abstract = {INTRODUCTION: Symptomatic management is the main focus of ALS clinical care. We aim to report the prevalence of ALS-related symptoms and characterize self-reported symptomatic management.<br><br>METHODS: A symptom management survey developed by the Muscular Dystrophy Association Clinical Research Network was completed by ALS registrants. Logistic regression identified potential predictors of symptom prevalence, severity, and treatment.<br><br>RESULTS: A total of 567 ALS participants reported fatigue (90%), muscle stiffness (84%), and muscle cramps (74%) as most prevalent symptoms. Fatigue (18%), muscle stiffness (14%), and shortness of breath (12%) were most bothersome. Although fatigue was the most prevalent symptom, it was also least treated (10%). Neither location of care nor disease duration was associated with symptom prevalence, severity, or probability of receiving treatment.<br><br>DISCUSSION: This large patient-reported symptom survey suggests that fatigue is the most prevalent, bothersome, and undertreated ALS symptom. Improving ALS symptom management is an unmet medical need and clinical trials of symptomatic treatments are needed. Muscle Nerve 57: 20-24, 2018.}, }
@article {pmid28560815, year = {2017}, author = {Han, B and Zhan, J and John Zhong, Z and Liu, D and Lindborg, S}, title = {Covariate-adjusted borrowing of historical control data in randomized clinical trials.}, journal = {Pharmaceutical statistics}, volume = {16}, number = {4}, pages = {296-308}, doi = {10.1002/pst.1815}, pmid = {28560815}, issn = {1539-1612}, mesh = {Bayes Theorem ; Control Groups ; Humans ; Models, Statistical ; *Randomized Controlled Trials as Topic ; }, abstract = {The borrowing of historical control data can be an efficient way to improve the treatment effect estimate of the current control group in a randomized clinical trial. When the historical and current control data are consistent, the borrowing of historical data can increase power and reduce Type I error rate. However, when these 2 sources of data are inconsistent, it may result in a combination of biased estimates, reduced power, and inflation of Type I error rate. In some situations, inconsistency between historical and current control data may be caused by a systematic variation in the measured baseline prognostic factors, which can be appropriately addressed through statistical modeling. In this paper, we propose a Bayesian hierarchical model that can incorporate patient-level baseline covariates to enhance the appropriateness of the exchangeability assumption between current and historical control data. The performance of the proposed method is shown through simulation studies, and its application to a clinical trial design for amyotrophic lateral sclerosis is described. The proposed method is developed for scenarios involving multiple imbalanced prognostic factors and thus has meaningful implications for clinical trials evaluating new treatments for heterogeneous diseases such as amyotrophic lateral sclerosis.}, }
@article {pmid28554396, year = {2017}, author = {Goldman, SA}, title = {Progenitor cell-based treatment of glial disease.}, journal = {Progress in brain research}, volume = {231}, number = {}, pages = {165-189}, pmid = {28554396}, issn = {1875-7855}, support = {R01 MH099578/MH/NIMH NIH HHS/United States ; R01 MH104701/MH/NIMH NIH HHS/United States ; R01 NS075345/NS/NINDS NIH HHS/United States ; }, mesh = {Demyelinating Diseases/*therapy ; Humans ; Myelin Sheath ; Neuroglia/*cytology ; Oligodendroglia/*cytology ; Pluripotent Stem Cells/*cytology ; }, abstract = {Diseases of glia, including astrocytes and oligodendrocytes, are among the most prevalent and disabling, yet least appreciated, conditions in neurology. In recent years, it has become clear that besides the overtly glial disorders of oligodendrocyte loss and myelin failure, such as the leukodystrophies and inflammatory demyelinations, a number of neurodegenerative and psychiatric disorders may also be causally linked to glial dysfunction and derive from astrocytic as well as oligodendrocytic pathology. The relative contribution of glial dysfunction to many of these disorders may be so great as to allow their treatment by the delivery of allogeneic glial progenitor cells, the precursors to both astroglia and myelin-producing oligodendrocytes. Given the development of new methods for producing and isolating these cells from pluripotent stem cells, both the myelin disorders and appropriate glial-based neurodegenerative conditions may now be compelling targets for cell-based therapy. As such, glial cell-based therapies may offer potential benefit to a broader range of diseases than ever before contemplated, including disorders such as Huntington's disease and the motor neuron degeneration of amyotrophic lateral sclerosis, which have traditionally been considered neuronal in nature.}, }
@article {pmid28554311, year = {2018}, author = {Penke, B and Fulop, L and Szucs, M and Frecska, E}, title = {The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases.}, journal = {Current neuropharmacology}, volume = {16}, number = {1}, pages = {97-116}, pmid = {28554311}, issn = {1875-6190}, mesh = {Animals ; Endoplasmic Reticulum/pathology ; Humans ; Molecular Chaperones/*metabolism ; Neurodegenerative Diseases/drug therapy/*metabolism/*pathology ; Receptors, sigma/agonists/*metabolism ; Sigma-1 Receptor ; }, abstract = {BACKGROUND: Widespread protein aggregation occurs in the living system under stress or during aging, owing to disturbance of endoplasmic reticulum (ER) proteostasis. Many neurodegenerative diseases may have a common mechanism: the failure of protein homeostasis. Perturbation of ER results in unfolded protein response (UPR). Prolonged chronical UPR may activate apoptotic pathways and cause cell death.<br><br>METHODS: Research articles on Sigma-1 receptor were reviewed.<br><br>RESULTS: ER is associated to mitochondria by the mitochondria-associated ER-membrane, MAM. The sigma-1 receptor (Sig-1R), a well-known ER-chaperone localizes in the MAM. It serves for Ca2+-signaling between the ER and mitochondria, involved in ion channel activities and especially important during neuronal differentiation. Sig-1R acts as central modulator in inter-organelle signaling. Sig-1R helps cell survival by attenuating ER-stress. According to sequence based predictions Sig-1R is a 223 amino acid protein with two transmembrane (2TM) domains. The X-ray structure of the Sig-1R [1] showed a membrane-bound trimeric assembly with one transmembrane (1TM) region. Despite the in vitro determined assembly, the results of in vivo studies are rather consistent with the 2TM structure. The receptor has unique and versatile pharmacological profile. Dimethyl tryptamine (DMT) and neuroactive steroids are endogenous ligands that activate Sig-1R. The receptor has a plethora of interacting client proteins. Sig-1R exists in oligomeric structures (dimer-trimer-octamer-multimer) and this fact may explain interaction with diverse proteins.<br><br>CONCLUSION: Sig-1R agonists have been used in the treatment of different neurodegenerative diseases, e.g. Alzheimer's and Parkinson's diseases (AD and PD) and amyotrophic lateral sclerosis. Utilization of Sig-1R agents early in AD and similar other diseases has remained an overlooked therapeutic opportunity.}, }
@article {pmid28553836, year = {2017}, author = {Mathew, SJ and Gueorguieva, R and Brandt, C and Fava, M and Sanacora, G}, title = {A Randomized, Double-Blind, Placebo-Controlled, Sequential Parallel Comparison Design Trial of Adjunctive Riluzole for Treatment-Resistant Major Depressive Disorder.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {42}, number = {13}, pages = {2567-2574}, pmid = {28553836}, issn = {1740-634X}, support = {R01 MH085055/MH/NIMH NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; }, mesh = {Adult ; Ambulatory Care ; Antidepressive Agents/adverse effects/*therapeutic use ; Depressive Disorder, Major/*drug therapy ; Depressive Disorder, Treatment-Resistant/*drug therapy ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/adverse effects/therapeutic use ; Psychiatric Status Rating Scales ; Riluzole/adverse effects/*therapeutic use ; Severity of Illness Index ; Treatment Outcome ; }, abstract = {Riluzole is a glutamate-modulating agent with neuroprotective properties approved for use in amyotrophic lateral sclerosis. The efficacy and safety of riluzole vs placebo as an adjunct to antidepressant medication in outpatients with major depressive disorder (MDD) was examined in a 3-site, 8-week, randomized, double-blind, placebo-controlled, fixed-dose trial using a sequential parallel comparison design comprised of two phases of 4 weeks. Patients with MDD in a current major depressive episode (N=104) with an inadequate response to either a prospective or a historical trial of an antidepressant medication were randomized in a 2 : 3 : 3 ratio to the treatment sequences of riluzole/riluzole, placebo/placebo, and placebo/riluzole, respectively. The primary outcome was change in depression severity, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary efficacy outcomes included the response rate, defined as at least a 50% improvement in MADRS, Clinical Global Impressions severity and improvement subscales, and patient-reported measures of depression and cognitive function. Eighty-five patients completed the randomized treatment phases. Treatment groups did not differ in mean change in MADRS scores, response rate, or in any secondary efficacy outcomes. Riluzole was generally well tolerated, with a side effect profile consistent with its clinical use. In conclusion, a fixed dose of riluzole (100 mg/day) did not show adjunctive antidepressant efficacy compared to placebo. The trial was adequately powered to detect a moderate riluzole effect, and the risk for exaggerated placebo responses was mitigated. The lack of efficacy suggests that mechanisms underlying riluzole's neuroprotective effects are insufficient for clinical response in treatment-resistant depression.}, }
@article {pmid28553083, year = {2017}, author = {Lin, JF and Lin, YC and Tsai, TF and Chen, HE and Chou, KY and Hwang, TI}, title = {Cisplatin induces protective autophagy through activation of BECN1 in human bladder cancer cells.}, journal = {Drug design, development and therapy}, volume = {11}, number = {}, pages = {1517-1533}, pmid = {28553083}, issn = {1177-8881}, mesh = {Antineoplastic Agents/administration &amp; dosage/*pharmacology ; Apoptosis/drug effects ; Autophagy/drug effects ; Beclin-1/*genetics ; Cell Line, Tumor ; Cell Survival/drug effects ; Cisplatin/administration &amp; dosage/*pharmacology ; DNA Fragmentation/drug effects ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm ; Gene Knockdown Techniques ; Humans ; Microscopy, Electron, Transmission ; RNA, Small Interfering ; Time Factors ; Urinary Bladder Neoplasms/*drug therapy/genetics/pathology ; }, abstract = {PURPOSE: Cisplatin-based chemotherapy is the first line treatment for several cancers including bladder cancer (BC). Autophagy induction has been implied to contribute to cisplatin resistance in ovarian cancer; and a high basal level of autophagy has been demonstrated in human bladder tumors. Therefore, it is reasonable to speculate that autophagy may account for the failure of cisplatin single treatment in BC. This study investigated whether cisplatin induces autophagy and the mechanism involved using human BC cell lines.<br><br>MATERIALS AND METHODS: Human BC cells (5637 and T24) were used in this study. Cell viability was detected using water soluble tetrazolium-8 reagents. Autophagy induction was detected by monitoring the levels of light chain 3 (LC3)-II and p62 by Western blot, LC3-positive puncta formation by immunofluorescence, and direct observation of the autophagolysosome (AL) formation by transmission electron microscopy. Inhibitors including bafilomycin A1 (Baf A1), chloroquine (CQ), and shRNA-based lentivirus against autophagy-related genes (ATG7 and ATG12) were utilized. Apoptosis level was detected by caspase 3/7 activity and DNA fragmentation.<br><br>RESULTS: Cisplatin decreased cell viability and induced apoptosis of 5637 and T24 cells in a dose-and time-dependent manner. The increased LC3-II accumulation, p62 clearance, the number of LC3-positive puncta, and ALs in cisplatin-treated cells suggested that cisplatin indeed induces autophagy. Inhibition of cisplatin-induced autophagy using Baf A1, CQ, or ATG7/ATG12 shRNAs significantly enhanced cytotoxicity of cisplatin toward BC cells. These results indicated that cisplatin induced protective autophagy which may contribute to the development of cisplatin resistance and resulted in treatment failure. Mechanistically, upregulation of beclin-1 (BECN1) was detected in cisplatin-treated cells, and knockdown of BECN1 using shRNA attenuated cisplatin-induced autophagy and subsequently enhanced cisplatin-induced apoptosis.<br><br>CONCLUSION: Collectively, the study results indicated that cisplatin-induced autophagy is mediated by BECN1 in BC cells. Therefore, combinative treatment using cisplatin and autophagy inhibitors could potentially overcome cisplatin resistance related to autophagy induction.}, }
@article {pmid28552237, year = {2017}, author = {Gowing, G and Svendsen, S and Svendsen, CN}, title = {Ex vivo gene therapy for the treatment of neurological disorders.}, journal = {Progress in brain research}, volume = {230}, number = {}, pages = {99-132}, doi = {10.1016/bs.pbr.2016.11.003}, pmid = {28552237}, issn = {1875-7855}, mesh = {Animals ; Cell- and Tissue-Based Therapy ; *Genetic Therapy ; Humans ; Mesenchymal Stem Cell Transplantation ; Nervous System Diseases/genetics/*therapy ; Neural Stem Cells ; Stem Cell Transplantation ; }, abstract = {Ex vivo gene therapy involves the genetic modification of cells outside of the body to produce therapeutic factors and their subsequent transplantation back into patients. Various cell types can be genetically engineered. However, with the explosion in stem cell technologies, neural stem/progenitor cells and mesenchymal stem cells are most often used. The synergy between the effect of the new cell and the additional engineered properties can often provide significant benefits to neurodegenerative changes in the brain. In this review, we cover both preclinical animal studies and clinical human trials that have used ex vivo gene therapy to treat neurological disorders with a focus on Parkinson's disease, Huntington's disease, Alzheimer's disease, ALS, and stroke. We highlight some of the major advances in this field including new autologous sources of pluripotent stem cells, safer ways to introduce therapeutic transgenes, and various methods of gene regulation. We also address some of the remaining hurdles including tunable gene regulation, in vivo cell tracking, and rigorous experimental design. Overall, given the current outcomes from researchers and clinical trials, along with exciting new developments in ex vivo gene and cell therapy, we anticipate that successful treatments for neurological diseases will arise in the near future.}, }
@article {pmid30050378, year = {2017}, author = {Hinchcliffe, M and Smith, A}, title = {Riluzole: real-world evidence supports significant extension of median survival times in patients with amyotrophic lateral sclerosis.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {7}, number = {}, pages = {61-70}, pmid = {30050378}, issn = {1179-9900}, abstract = {Amyotrophic lateral sclerosis (ALS) is the commonest form of motor neuron disease and is a fatal, degenerative, multisystem disorder affecting upper and/or lower motor neurons in the motor cortex, brain stem, and spinal cord. ALS is characterized by progressive atrophy of associated bulbar, limb, thoracic, and abdominal muscles and supporting cells manifesting in a range of muscular symptoms such as weakness and wasting and eventual paralysis; the majority of patients will die from respiratory failure within 2-5 years of onset. Riluzole, a synthetic benzothiazole drug with glutamine antagonist activity, is indicated for the treatment of patients with ALS and is the only drug that has been shown to slow the course of the disease and extend survival in ALS patients. The original analyses, and subsequent meta-analyses, of data obtained from randomized controlled trials (RCTs) suggest that riluzole typically extends survival by 2-3 months and increases the chance of an additional year of survival by ~9%. However, published real-world evidence (RWE) from 10 clinical ALS databases indicates that riluzole therapy may afford much greater extension of survival, and improvements in median survival times of more than 19 months have been reported in the overall ALS patient population. This article will review the available data from RCTs and RWE on riluzole therapy.}, }
@article {pmid28542233, year = {2017}, author = {Burkhardt, C and Neuwirth, C and Sommacal, A and Andersen, PM and Weber, M}, title = {Is survival improved by the use of NIV and PEG in amyotrophic lateral sclerosis (ALS)? A post-mortem study of 80 ALS patients.}, journal = {PloS one}, volume = {12}, number = {5}, pages = {e0177555}, pmid = {28542233}, issn = {1932-6203}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/complications/genetics/mortality/*therapy ; C9orf72 Protein ; Cause of Death ; Disease Progression ; Female ; *Gastrostomy ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; *Noninvasive Ventilation ; Nuclear Respiratory Factors ; Proportional Hazards Models ; Proteins/genetics ; Retrospective Studies ; Survival Analysis ; }, abstract = {BACKGROUND: Non-invasive ventilation (NIV) and percutaneous gastrostomy (PEG) are guideline-recommended interventions for symptom management in amyotrophic lateral sclerosis (ALS). Their effect on survival is controversial and the impact on causes of death is unknown.<br><br>OBJECTIVE: To investigate the effect of NIV and PEG on survival and causes of death in ALS patients.<br><br>METHODS: Eighty deceased ALS patients underwent a complete post mortem analysis for causes of death between 2003 and 2015. Forty-two of these patients consented for genetic testing. Effects of NIV and PEG on survival and causes of death were analyzed in a multivariable Cox proportional hazard regression.<br><br>RESULTS: Six patients, who requested assisted suicide causing drug-induced hypoxia, were excluded from final analysis. Respiratory failure was the main cause of death in 72 out of 74 patients. Fifteen out of 74 died of aspiration pneumonia 23/74 of bronchopneumonia and 8/74 of a combination of aspiration pneumonia and bronchopneumonia. Twenty died of hypoxia without concomitant infection, and six patients had pulmonary embolism alone or in combination with pneumonia. NIV (p = 0.01) and PEG (p<0.01) had a significant impact on survival. In patients using NIV bronchopneumonia was significantly more frequent (p <0.04) compared to non-NIV patients. This effect was even more pronounced in limb onset patients (p<0.002). Patients with C9orf72 hexanucleotide repeat expansions showed faster disease progression and shorter survival (p = 0.01).<br><br>CONCLUSION: The use of NIV and PEG prolongs survival in ALS. This study supports current AAN and EFNS guidelines which recommend NIV and PEG as a treatment option in ALS. The risk of bronchopneumonia as cause of death may be increased by NIV.}, }
@article {pmid28539470, year = {2017}, author = {Imamura, K and Izumi, Y and Watanabe, A and Tsukita, K and Woltjen, K and Yamamoto, T and Hotta, A and Kondo, T and Kitaoka, S and Ohta, A and Tanaka, A and Watanabe, D and Morita, M and Takuma, H and Tamaoka, A and Kunath, T and Wray, S and Furuya, H and Era, T and Makioka, K and Okamoto, K and Fujisawa, T and Nishitoh, H and Homma, K and Ichijo, H and Julien, JP and Obata, N and Hosokawa, M and Akiyama, H and Kaneko, S and Ayaki, T and Ito, H and Kaji, R and Takahashi, R and Yamanaka, S and Inoue, H}, title = {The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis.}, journal = {Science translational medicine}, volume = {9}, number = {391}, pages = {}, doi = {10.1126/scitranslmed.aaf3962}, pmid = {28539470}, issn = {1946-6242}, support = {F-0902/PUK_/Parkinson's UK/United Kingdom ; MR/K017047/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Humans ; Induced Pluripotent Stem Cells/cytology/metabolism ; Motor Neurons/cytology/metabolism ; Mutation/genetics ; Proto-Oncogene Proteins c-abl/genetics/*metabolism ; Proto-Oncogene Proteins pp60(c-src)/genetics/*metabolism ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro. Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration. One of the hits, bosutinib, boosted autophagy, reduced the amount of misfolded mutant SOD1 protein, and attenuated altered expression of mitochondrial genes. Bosutinib also increased survival in vitro of ALS iPSC-derived motor neurons from patients with sporadic ALS or other forms of familial ALS caused by mutations in TAR DNA binding protein (TDP-43) or repeat expansions in C9orf72 Furthermore, bosutinib treatment modestly extended survival of a mouse model of ALS with an SOD1 mutation, suggesting that Src/c-Abl may be a potentially useful target for developing new drugs to treat ALS.}, }
@article {pmid28536907, year = {2017}, author = {Grande, G and Morin, L and Vetrano, DL and Fastbom, J and Johnell, K}, title = {Drug Use in Older Adults with Amyotrophic Lateral Sclerosis Near the End of Life.}, journal = {Drugs &amp; aging}, volume = {34}, number = {7}, pages = {529-533}, pmid = {28536907}, issn = {1179-1969}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Disease Progression ; Drug Utilization/standards/statistics &amp; numerical data/*trends ; Female ; Humans ; Male ; Middle Aged ; Odds Ratio ; Prescription Drugs/administration &amp; dosage/*therapeutic use ; Prognosis ; Retrospective Studies ; Sweden ; Terminal Care/standards/statistics &amp; numerical data/*trends ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), with its certain prognosis and swift progression, raises concerns regarding the adequacy of pharmacological treatment, including the risk-benefit profiles of prescribed drugs.<br><br>OBJECTIVE: Our objective was to evaluate the use of prescription drugs over the course of the last year of life in older adults with ALS.<br><br>METHODS: We conducted a nationwide retrospective cohort study of older adults who died with ALS in Sweden between 2007 and 2013. The primary outcome was the number of prescription drugs to which individuals were exposed during the last 12 months before death.<br><br>RESULTS: The overall proportion of individuals receiving ten or more different prescription drugs increased from 19% at 12 months before death to 37% during the last month of life. Institutionalization was independently associated with polypharmacy near the end of life (odds ratio 1.84; 95% confidence interval 1.42-2.39).<br><br>CONCLUSION: Future research is needed to assess the time to benefit of treatments and to develop guidelines for medication discontinuation in advanced ALS.}, }
@article {pmid28533943, year = {2017}, author = {Rafael, H and David, JO and Vilca, AS}, title = {Etiology and treatment of amyotrophic lateral sclerosis.}, journal = {American journal of neurodegenerative disease}, volume = {6}, number = {1}, pages = {1-8}, pmid = {28533943}, issn = {2165-591X}, abstract = {BACKGROUND: To date all researchers conclude that the etiology of Amyotrophic lateral sclerosis (ALS) is not known. On the contrary, since August 2009, we believe that disease is of ischemic origin in the anterior surface of the medulla oblongata.<br><br>MATERIAL AND METHOD: We present our surgical experience into 45 patients with ALS (bulbar form in 36 cases and spinal form in 9). Preoperative MRI scans revealed microinfarcts in the medulla oblongata and/or cervical cord. During surgery we found: 1) poor quality of omentum in most cases; 2) degenerative changes in the cervical spine; 3) anatomical anomalies at the V4 segments of the vertebral arteries; 4) moderate to severe atherosclerosis at both V4 segments; 5) unilateral absence or stenosis in the anterior-ventral spinal arteries (AVSAs). All patients received omentum on the anterior, lateral and posterior surface of the medulla oblongata, and in 9 cases, an additional segment at the C5-C6 level.<br><br>RESULTS: Neurological improvement was better during the first days or weeks after surgery than in the following months or years, in all patients. However, 13 patients suffered neurological impairment in about 4 months later, due to greater deterioration of the cervical spine, by contrast, 7 patients with mild ALS have experienced neurological improvement by 80 to 100% during a follow-up of 4 and 6 years.<br><br>CONCLUSIONS: These results confirm that ALS is of ischemic origin in the intraparenchymal territory of the AVSAs and/or in anterior spinal artery caused by atherosclerosis and associated to anatomical variants in the V4 segments of the vertebral arteries. Because in contrast to this, its revascularization by means of omentum can cure (mild degree) or improve this disease.}, }
@article {pmid28532674, year = {2017}, author = {Michaelson, N and Facciponte, D and Bradley, W and Stommel, E}, title = {Cytokine expression levels in ALS: A potential link between inflammation and BMAA-triggered protein misfolding.}, journal = {Cytokine &amp; growth factor reviews}, volume = {37}, number = {}, pages = {81-88}, doi = {10.1016/j.cytogfr.2017.05.001}, pmid = {28532674}, issn = {1879-0305}, mesh = {Adaptive Immunity ; Amino Acids, Diamino/*toxicity ; Amyotrophic Lateral Sclerosis/*immunology/*metabolism/physiopathology/therapy ; Animals ; Cyanobacteria Toxins ; Cytokines/*genetics ; *Gene Expression ; Humans ; Immunity, Innate ; Inflammasomes/immunology ; Inflammation ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/immunology ; Neuroimmunomodulation ; Proteostasis Deficiencies/*immunology ; }, abstract = {Recently, it has been shown that proinflammatory cytokines play a complex and important role in the pathogenesis of many neurological disorders, including amyotrophic lateral sclerosis (ALS). To help facilitate future discoveries and more effective treatment strategies, we highlight the role that both innate and adaptive immune systems play in ALS and summarize the main observations that relate to cytokine expression levels in this disease. Furthermore, we propose a mechanism by which a known neurotoxin, β-N-methylamino-l-alanine (BMAA), may trigger this cytokine expression profile through motor neuron protein misfolding and subsequent NLRP3 (nucleotide-binding domain (NOD)-like receptor protein 3) inflammasome activation.}, }
@article {pmid28528135, year = {2017}, author = {Patai, R and Paizs, M and Tortarolo, M and Bendotti, C and Obál, I and Engelhardt, JI and Siklós, L}, title = {Presymptomatically applied AMPA receptor antagonist prevents calcium increase in vulnerable type of motor axon terminals of mice modeling amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1863}, number = {7}, pages = {1739-1748}, doi = {10.1016/j.bbadis.2017.05.016}, pmid = {28528135}, issn = {0925-4439}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/*metabolism/pathology ; Animals ; Benzodiazepines/*pharmacology ; Calcium/*metabolism ; Calcium Signaling/*drug effects ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Presynaptic Terminals/*metabolism/pathology ; Receptors, AMPA/*antagonists &amp; inhibitors/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Increased intracellular calcium (Ca), which might be the consequence of an excess influx through Ca-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, plays a crucial role in degeneration of motor neurons. Previously we demonstrated that the presymptomatic application of AMPA receptor antagonist, talampanel, could reduce Ca elevation in spinal motor neurons of mice carrying the G93A mutation of superoxide dismutase 1 (SOD1), modeling amyotrophic lateral sclerosis (ALS). It remained to be examined whether the remote, functionally semi-autonomous motor axon terminals could be rescued from the Ca overload, or if the terminals, where the degeneration possibly starts, already experience intractable changes at early time points. Thus using electron microscopic techniques, we measured the Ca level of motor axon terminals in the interosseus muscle of the SOD1 mutant animals, which are prototypes of vulnerable nerve endings in ALS. In line with the results obtained in the perikarya, talampanel treatment could reduce Ca increase evoked by the presence of mutant SOD1 in the axon terminals if the treatment was started presymptomatically but not at an early symptomatic stage. We also tested the Ca level in the cell bodies and axon terminals of the oculomotor neurons, which are resistant to the disease. Neither Ca increase, nor talampanel effect could be demonstrated at either time point. This is consistent with the observations that oculomotor neurons contain increased level of Ca buffer, which could reduce excess Ca load, and they also express glutamate receptor subunit type 2, which renders AMPA receptors impermeable to Ca.}, }
@article {pmid28527504, year = {2017}, author = {Tenforde, AS and Hefner, JE and Kodish-Wachs, JE and Iaccarino, MA and Paganoni, S}, title = {Telehealth in Physical Medicine and Rehabilitation: A Narrative Review.}, journal = {PM &amp; R : the journal of injury, function, and rehabilitation}, volume = {9}, number = {5S}, pages = {S51-S58}, doi = {10.1016/j.pmrj.2017.02.013}, pmid = {28527504}, issn = {1934-1563}, mesh = {Humans ; *Physical and Rehabilitation Medicine ; *Telemedicine ; }, abstract = {Telehealth refers to health care interactions that leverage telecommunication devices to provide medical care outside the traditional face-to-face, in-person medical encounter. Technology advances and research have expanded use of telehealth in health care delivery. Physical medicine and rehabilitation providers may use telehealth to deliver care to populations with neurologic and musculoskeletal conditions, commonly treated in both acute care and outpatient settings. Patients with impaired mobility and those living in locations with reduced access to care may particularly benefit. Video-teleconferencing has been shown to be effective for management of burn patients during acute rehabilitation, including reduced health care use expenses and less disruptions to care. Telehealth can facilitate developing interprofessional care plans. Patients with neurologic conditions including stroke, spinal cord injury, traumatic brain injury, and amyotrophic lateral sclerosis may use telehealth to monitor symptoms and response to treatment. Telehealth also may facilitate occupational and physical therapy programs as well as improve weight management and skin care in patients with chronic conditions. Other applications include imaging review in sports medicine, symptom management and counseling in concussion, traumatic brain injury, and pain management programs. Limitations of telehealth include barriers in establishing relationship between medical provider and patient, ability to perform limited physical examination, and differences in payment models and liability coverage. The expansion of telehealth services is expected to grow and has potential to improve patient satisfaction by delivering high quality and value of care.}, }
@article {pmid28527102, year = {2018}, author = {Bradley, WG and Miller, RX and Levine, TD and Stommel, EW and Cox, PA}, title = {Studies of Environmental Risk Factors in Amyotrophic Lateral Sclerosis (ALS) and a Phase I Clinical Trial of L-Serine.}, journal = {Neurotoxicity research}, volume = {33}, number = {1}, pages = {192-198}, pmid = {28527102}, issn = {1476-3524}, support = {Contract 200-2014-59046//Agency for Toxic Substances and Disease Registry/ ; R01TS000245-01//Agency for Toxic Substances and Disease Registry/ ; 15-IIP-213//Amyotrophic Lateral Sclerosis Association/ ; N/A//Institute for Ethnomedicine/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/epidemiology/*etiology ; Environmental Exposure/*adverse effects ; Female ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Risk Factors ; Serine/*therapeutic use ; }, abstract = {β-N-Methylamino-L-alanine (BMAA) has been linked to Guam ALS/PDC and shown to produce neurodegeneration in vitro and in vivo (Drosophila, mice, rats, primates). BMAA misincorporation into neuroproteins produces protein misfolding and is inhibited by L-serine. Case-control studies in Northern New England indicate that living near to water-bodies with cyanobacterial blooms increases the risk of developing amyotrophic lateral sclerosis (ALS). The distribution of addresses of ALS cases in New Hampshire, Vermont, and Florida was compared to that of controls. Areas of statistically significantly increased numbers of ALS cases were examined for sources of environmental toxins. A phase I trial of oral L-serine was performed in 20 ALS patients (0.5 to 15 g twice daily). Safety and tolerability were assessed by comparing the rate of deterioration with 430 matched placebo controls. The distribution of residential addresses of ALS cases in New England and Florida revealed many areas where the age- and gender-adjusted frequency of ALS was greater than expected (P < 0.01). GIS studies of these "hot spots" in relation to sources of environmental pollutants, like cyanobacterial blooms, Superfund and Brownfield sites, and landfills, are ongoing. In the phase I trial of L-serine, two patients withdrew from because of gastrointestinal side effects. Three patients died during the study, which was about the expected number. The ALSFRS-R in the L-serine-treated patients showed a dose-related decrease in the rate of progression (34% reduction in slope, P = 0.044). The non-random distribution of addresses of ALS patients suggests that residential exposure to environmental pollutants may play an important role in the etiology of ALS. L-Serine in doses up to 15 g twice daily appears to be safe in patients with ALS. Exploratory studies of efficacy suggested that L-serine might slow disease progression. A phase II trial is planned.}, }
@article {pmid28522961, year = {2017}, author = {Liu, YJ and Tsai, PY and Chern, Y}, title = {Energy Homeostasis and Abnormal RNA Metabolism in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {11}, number = {}, pages = {126}, pmid = {28522961}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that is clinically characterized by progressive muscle weakness and impaired voluntary movement due to the loss of motor neurons in the brain, brain stem and spinal cord. To date, no effective treatment is available. Ample evidence suggests that impaired RNA homeostasis and abnormal energy status are two major pathogenesis pathways in ALS. In the present review article, we focus on recent studies that report molecular insights of both pathways, and discuss the possibility that energy dysfunction might negatively regulate RNA homeostasis via the impairment of cytoplasmic-nuclear shuttling in motor neurons and subsequently contribute to the development of ALS.}, }
@article {pmid28522181, year = {2017}, author = {,  and , }, title = {Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.}, journal = {The Lancet. Neurology}, volume = {16}, number = {7}, pages = {505-512}, doi = {10.1016/S1474-4422(17)30115-1}, pmid = {28522181}, issn = {1474-4465}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Antipyrine/administration &amp; dosage/adverse effects/*analogs &amp; derivatives/pharmacology ; Double-Blind Method ; Edaravone ; Female ; Free Radical Scavengers/administration &amp; dosage/adverse effects/*pharmacology ; Humans ; Male ; Middle Aged ; *Outcome Assessment, Health Care ; *Severity of Illness Index ; Young Adult ; }, abstract = {BACKGROUND: In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating Scale (ALSFRS-R) score compared with placebo. Post-hoc analysis of these data revealed that patients in an early stage with definite or probable diagnosis of ALS, defined by the revised El Escorial criteria, who met a select set of inclusion criteria showed a greater magnitude of effect than did the full study population. We aimed to substantiate this post-hoc result and assess safety and efficacy of edaravone in a phase 3 trial that focused on patients with early stage ALS who met the post-hoc analysis inclusion criteria.<br><br>METHODS: In this phase 3, randomised, double-blind, parallel-group study, patients aged 20-75 years with ALS of grade 1 or 2 in the Japan ALS Severity Classification, scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, definite or probable ALS according to the revised El Escorial criteria, and disease duration of 2 years or less were recruited from 31 hospitals in Japan. Eligible patients also had a decrease of 1-4 points in the ALSFRS-R score during a 12-week observation period before randomisation. Patients meeting all criteria were then randomly assigned 1:1 to receive 60 mg intravenous edaravone or intravenous saline placebo for 6 cycles (4 weeks per cycle with 2 weeks on, 2 weeks off) for a total treatment duration of 24 weeks. In cycle 1, the study drug or placebo was administered once per day for 14 days within a 14 day period, followed by the drug-free period. In cycle 2 and thereafter, the study drug or placebo was administered for 10 days within a 14 day period, followed by a 2 week drug-free period. Participants and investigators, including those assessing outcomes, were masked to treatment allocation. The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation. The primary outcome was assessed in all patients who had received at least one treatment infusion, had at least one assessment post-baseline, and reached the end of cycle 3. For patients with missing values at the end of cycle 6, data were imputed by the last observation carried forward (LOCF) method, provided the patients had completed at least cycle 3. Safety was assessed in all patients who had received at least one treatment infusion and had at least one assessment post-baseline. This trial is registered with ClinicalTrials.gov, NCT01492686.<br><br>FINDINGS: Between Nov 28, 2011, and Sept 3, 2014, we screened 213 patients, and enrolled 192 as potential participants. Of these, 137 patients completed the observation period: 69 were randomly assigned to receive edaravone, and 68 were randomly assigned to receive placebo. 68 patients taking edaravone and 66 taking placebo were included in the primary efficacy analysis. For the primary outcome, the change in ALSFRS-R score was -5&#xb7;01 (SE 0&#xb7;64) in the edavarone group and -7&#xb7;50 (0&#xb7;66) in the placebo group. The least-squares mean difference between groups was 2&#xb7;49 (SE 0&#xb7;76, 95% CI 0&#xb7;99-3&#xb7;98; p=0&#xb7;0013) in favour of edaravone. Treatment-emergent adverse events were reported in 58 (84%) patients receiving edaravone and 57 (84%) patients receiving placebo. 11 (16%) patients taking edaravone and 16 (24%) taking placebo had serious adverse events, and one (1%) patient receiving edaravone and four (6%) patients receiving placebo had adverse events (one dysphagia in edaravone group and one dyspnoea, two respiratory disorder, and one rash in the placebo group) that led to withdrawal.<br><br>INTERPRETATION: Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria.<br><br>FUNDING: Mitsubishi Tanabe Pharma Corporation.}, }
@article {pmid28522180, year = {2017}, author = {Hardiman, O and van den Berg, LH}, title = {Edaravone: a new treatment for ALS on the horizon?.}, journal = {The Lancet. Neurology}, volume = {16}, number = {7}, pages = {490-491}, doi = {10.1016/S1474-4422(17)30163-1}, pmid = {28522180}, issn = {1474-4465}, mesh = {*Amyotrophic Lateral Sclerosis ; *Antipyrine/analogs &amp; derivatives ; Edaravone ; Free Radical Scavengers ; Humans ; }, }
@article {pmid28521184, year = {2017}, author = {Ling, T and Zhou, B and Zhu, C and Yang, X and Song, Y and Qiang, Z and Liu, L}, title = {One-stage posterior grade 4 osteotomy and bone graft fusion at pseudarthrosis for the treatment of kyphotic deformity with Andersson lesions in ankylosing spondylitis.}, journal = {Clinical neurology and neurosurgery}, volume = {159}, number = {}, pages = {19-24}, doi = {10.1016/j.clineuro.2017.05.017}, pmid = {28521184}, issn = {1872-6968}, mesh = {Adult ; Aged ; Bone Transplantation/*methods ; Female ; Follow-Up Studies ; Humans ; Kyphosis/diagnostic imaging/*surgery ; Male ; Middle Aged ; Osteotomy/*methods ; Pseudarthrosis/diagnostic imaging/*surgery ; Retrospective Studies ; Spondylitis, Ankylosing/diagnostic imaging/*surgery ; Treatment Outcome ; }, abstract = {OBJECTIVES: The optimal surgical procedure for treating kyphotic deformity with Andersson lesions (ALs) in ankylosing spondylitis (AS) patients is controversial. The one-stage posterior osteotomy and bone graft fusion approach is rarely reported. The aim of the present study was to report a new surgical procedure involving one-stage posterior grade 4 osteotomy and bone graft fusion for the treatment of kyphotic deformity with ALs in AS.<br><br>PATIENTS AND METHODS: Eleven patients with ALs in AS were enrolled. One-stage posterior grade 4 osteotomy and bone graft fusion was performed in all patients. Frankel classification and visual analog scale (VAS) were used to evaluate neurologic deficit and the level of back pain pre- and postoperatively, respectively. Radiographic and clinical outcomes were assessed with a mean of 31.5 months follow-up.<br><br>RESULTS: Local kyphosis was corrected from 19.1&#xb0; to 0.5&#xb0; after surgery with a mean correction rate of 95%. One Frankel C and 5 Frankel D patients changed to Frankel D and Frankel E, respectively. VAS was reduced from 6.7 to 0.27 at final follow-up. Bone graft fusion was observed at an average of 4.3 months and solid bony fusion was achieved at final follow-up. Average operation time and blood loss were 268.6min and 1009ml, respectively. Three patients developed dural tear complications. There were no neurological or instrumentation complications reported or observed at final follow-up.<br><br>CONCLUSION: One-stage posterior grade 4 osteotomy and bone graft fusion is an optional surgical procedure to treat ALs in AS patients. This approach results in reduced blood loss and operation time, satisfactory correction of local kyphosis, and good safety. Successful fusion and good clinical outcomes can also be achieved.}, }
@article {pmid28514335, year = {2017}, author = {Levitsky, GN and Chub, RV and Kryachkov, AV}, title = {[The quality of medical care and cooperation of patients with amyotrophic lateral sclerosis in the Russian Federation].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {117}, number = {1. Vyp. 2}, pages = {59-63}, doi = {10.17116/jnevro20171171259-63}, pmid = {28514335}, issn = {1997-7298}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Neurologists ; *Quality of Health Care ; Referral and Consultation ; Russia ; }, abstract = {The quality of medical care for patients with amyotrophic lateral sclerosis (ALS) in the Russian Federation is analyzed taking into account the cooperation of patients. Two hundred and fifty-one patients with ALS were observed. Ninety-nine patients, including 16 who were followed up, were examined. Other patients (n=152) were consulted indirectly including 28 followed up. It has been shown that 79,8% of the patients are characterized by the low level of cooperation with neurologists regardless of the quality of medical care; 8.3% of patients are managed in facilities (or by physicians), which don't use the International standard of ALS management. Only 11.9% of patients receive medical care in accordance with this standard and in these cases, the high level of cooperation of the patients with medical services was recorded. A dual system that combines the services provided by medical insurance, private treatment facilities, charity organizations, structures of medical/social care with different levels of availability and methods of consumer-provider interactions is the most effective.}, }
@article {pmid28511992, year = {2017}, author = {Ladd, AC and Brohawn, DG and Thomas, RR and Keeney, PM and Berr, SS and Khan, SM and Portell, FR and Shakenov, MZ and Antkowiak, PF and Kundu, B and Tustison, N and Bennett, JP}, title = {RNA-seq analyses reveal that cervical spinal cords and anterior motor neurons from amyotrophic lateral sclerosis subjects show reduced expression of mitochondrial DNA-encoded respiratory genes, and rhTFAM may correct this respiratory deficiency.}, journal = {Brain research}, volume = {1667}, number = {}, pages = {74-83}, doi = {10.1016/j.brainres.2017.05.010}, pmid = {28511992}, issn = {1872-6240}, support = {S10 RR019911/RR/NCRR NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Brain/diagnostic imaging/metabolism ; Cells, Cultured ; Cervical Cord/*metabolism ; DNA, Mitochondrial ; DNA-Binding Proteins/administration &amp; dosage/*metabolism ; Gene Expression ; Glucose/metabolism ; Humans ; Laser Capture Microdissection ; Male ; Mitochondrial Proteins/administration &amp; dosage/*metabolism ; Motor Neurons/*metabolism ; Neural Stem Cells/metabolism ; Rats, Sprague-Dawley ; Recombinant Proteins/administration &amp; dosage/metabolism ; Sequence Analysis, RNA ; Transcription Factors/administration &amp; dosage/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a generally fatal neurodegenerative disease of adults that produces weakness and atrophy due to dysfunction and death of upper and lower motor neurons. We used RNA-sequencing (RNA-seq) to analyze expression of all mitochondrial DNA (mtDNA)-encoded respiratory genes in ALS and CTL human cervical spinal cords (hCSC) and isolated motor neurons. We analyzed with RNA-seq mtDNA gene expression in human neural stem cells (hNSC) exposed to recombinant human mitochondrial transcription factor A (rhTFAM), visualized in 3-dimensions clustered gene networks activated by rhTFAM, quantitated their interactions with other genes and determined their gene ontology (GO) families. RNA-seq and quantitative PCR (qPCR) analyses showed reduced mitochondrial gene expression in ALS hCSC and ALS motor neurons isolated by laser capture microdissection (LCM), and revealed that hNSC and CTL human cervical spinal cords were similar. Rats treated with i.v. rhTFAM showed a dose-response increase in brain respiration and an increase in spinal cord mitochondrial gene expression. Treatment of hNSC with rhTFAM increased expression of mtDNA-encoded respiratory genes and produced one major and several minor clusters of gene interactions. Gene ontology (GO) analysis of rhTFAM-stimulated gene clusters revealed enrichment in GO families involved in RNA and mRNA metabolism, suggesting mitochondrial-nuclear signaling. In postmortem ALS hCSC and LCM-isolated motor neurons we found reduced expression of mtDNA respiratory genes. In hNSC's rhTFAM increased mtDNA gene expression and stimulated mRNA metabolism by unclear mechanisms. rhTFAM may be useful in improving bioenergetic function in ALS.}, }
@article {pmid28510586, year = {2017}, author = {Wobst, HJ and Delsing, L and Brandon, NJ and Moss, SJ}, title = {Truncation of the TAR DNA-binding protein 43 is not a prerequisite for cytoplasmic relocalization, and is suppressed by caspase inhibition and by introduction of the A90V sequence variant.}, journal = {PloS one}, volume = {12}, number = {5}, pages = {e0177181}, pmid = {28510586}, issn = {1932-6203}, support = {R01 NS087662/NS/NINDS NIH HHS/United States ; R01 MH097446/MH/NIMH NIH HHS/United States ; R21 NS080064/NS/NINDS NIH HHS/United States ; R01 NS051195/NS/NINDS NIH HHS/United States ; R21 MH106954/MH/NIMH NIH HHS/United States ; R01 NS056359/NS/NINDS NIH HHS/United States ; }, mesh = {Amino Acid Substitution ; Caspases/metabolism ; *Codon ; Cytoplasm/metabolism ; DNA-Binding Proteins/chemistry/*genetics/*metabolism ; *Genetic Variation ; HeLa Cells ; Humans ; Mutation ; Osmotic Pressure ; Oxidative Stress ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Transport/drug effects ; Proteolysis ; Sorbitol/pharmacology ; }, abstract = {The RNA-binding and -processing protein TAR DNA-binding protein 43 (TDP-43) is heavily linked to the underlying causes and pathology of neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In these diseases, TDP-43 is mislocalized, hyperphosphorylated, ubiquitinated, aggregated and cleaved. The importance of TDP-43 cleavage in the disease pathogenesis is still poorly understood. Here we detail the use of D-sorbitol as an exogenous stressor that causes TDP-43 cleavage in HeLa cells, resulting in a 35 kDa truncated product that accumulates in the cytoplasm within one hour of treatment. We confirm that the formation of this 35 kDa cleavage product is mediated by the activation of caspases. Inhibition of caspases blocks the cleavage of TDP-43, but does not prevent the accumulation of full-length protein in the cytoplasm. Using D-sorbitol as a stressor and caspase activator, we also demonstrate that the A90V variant of TDP-43, which lies adjacent to the caspase cleavage site within the nuclear localization sequence of TDP-43, confers partial resistance against caspase-mediated generation of the 35 kDa cleavage product.}, }
@article {pmid28510254, year = {2017}, author = {Tian, YP and Che, FY and Su, QP and Lu, YC and You, CP and Huang, LM and Wang, SG and Wang, L and Yu, JX}, title = {Effects of mutant TDP-43 on the Nrf2/ARE pathway and protein expression of MafK and JDP2 in NSC-34 cells.}, journal = {Genetics and molecular research : GMR}, volume = {16}, number = {2}, pages = {}, doi = {10.4238/gmr16029638}, pmid = {28510254}, issn = {1676-5680}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Cell Line ; DNA-Binding Proteins/genetics/*metabolism ; MafK Transcription Factor/genetics/*metabolism ; Mice ; *Mutation, Missense ; NAD(P)H Dehydrogenase (Quinone)/metabolism ; NF-E2-Related Factor 2/*metabolism ; Neurons/metabolism ; Oxidative Stress ; Repressor Proteins/genetics/*metabolism ; *Response Elements ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons and lacks an effective treatment. The disease pathogenesis has not been clarified at present. Pathological transactive response DNA-binding protein 43 (TDP-43) plays an important role in the pathogenesis of ALS. Nuclear translocation of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is found in a mutant TDP-43 transgenic cell model, but its downstream antioxidant enzyme expression is decreased. To elucidate the specific mechanism of Nrf2/ARE (antioxidant responsive element) signaling dysfunction, we constructed an ALS cell model with human mutant TDP-43 using the NSC-34 cell line to evaluate the impact of the TDP-43 mutation on the Nrf2/ARE pathway. We found the nuclear translocation of Nrf2, but the expression of total Nrf2, cytoplasmic Nrf2, and downstream phase II detoxifying enzyme (NQO1) was decreased in NSC-34 cells transfected with the TDP-43-M337V plasmid. Besides, TDP-43-M337V plasmid-transfected NSC-34 cells were rounded with reduced neurites, shortened axons, increased levels of intracellular lipid peroxidation products, and decreased viability, which suggests that the TDP-43-M337V plasmid weakened the antioxidant capacity of NSC-34 cells and increased their susceptibility to oxidative damage. We further showed that expression of the MafK protein and the Jun dimerization protein 2 (JDP2) was reduced in TDP-43-M337V plasmid-transfected NSC-34 cells, which might cause accumulation of Nrf2 in nuclei but a decrease in NQO1 expression. Taken together, our results confirmed that TDP-43-M337V impaired the Nrf2/ARE pathway by reducing the expression of MafK and JDP2 proteins, and provided information for further research on the molecular mechanisms of TDP-43-M337V in ALS.}, }
@article {pmid28495534, year = {2017}, author = {Settembre, N and Saba, C and Bouziane, Z and Jeannon, F and Mandry, D and Malikov, S}, title = {Hybrid Treatment of the Aberrant Right Subclavian Artery (Arteria Lusoria): Feasibility Study on 180 Angio-CTs.}, journal = {Annals of vascular surgery}, volume = {44}, number = {}, pages = {229-233}, doi = {10.1016/j.avsg.2017.03.172}, pmid = {28495534}, issn = {1615-5947}, mesh = {Adult ; Aged ; Aged, 80 and over ; Anatomic Landmarks ; Aneurysm/*diagnostic imaging/*surgery ; Blood Vessel Prosthesis ; Blood Vessel Prosthesis Implantation/instrumentation/*methods ; Cardiovascular Abnormalities/*diagnostic imaging/*surgery ; Carotid Artery, Common/diagnostic imaging/surgery ; *Computed Tomography Angiography ; Endovascular Procedures/instrumentation/*methods ; Feasibility Studies ; Female ; France ; Hospitals, University ; Humans ; Male ; Middle Aged ; Predictive Value of Tests ; Radiographic Image Interpretation, Computer-Assisted ; Software ; Stents ; Subclavian Artery/*abnormalities/diagnostic imaging/surgery ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: The aberrant right subclavian artery or arteria lusoria (AL) is the most frequent anatomical variation of the supra-aortic trunks (SAT). Treatment is only warranted in the presence of an aneurysm because of the risk of rupture, or in symptomatic cases with signs of compression of the esophagus or the trachea, with embolisms causing right upper limb ischemia of vertebrobasilar cerebrovascular accidents. The conventional surgical treatment of AL is the closure of the origin of AL and the revascularization of the right subclavian artery through a left thoracotomy. With the appearance of endovascular techniques, some of these patients can be treated with minimally invasive hybrid techniques. The aim of this study is to evaluate the feasibility of the endovascular treatment of AL based on the radioanatomical analysis of the thoracic angio-computed tomographies.<br><br>METHODS: We analyzed 180 thoracic angio-computed tomographies using millimeter cuts (<1.2 mm) performed between 2010 and 2015 in the Nancy University Hospital in which an AL was fortuitously discovered. Symptomatic ALs and pediatric patients were excluded. The diameters of the SATs and the aorta and the distances between the SATs were measured. The data were processed with the t-test using the SPSS 22 software.<br><br>RESULTS: Our results showed the presence of a Kommerell diverticulum in 36 cases (20%) and of a bi-carotid trunk in 91 cases (50.5%). The average distance between the left subclavian artery (LSCA) and AL was 5.4 &#xb1;&#xa0;4.3 mm. To obtain a proximal neck >20 mm for the implantation of a thoracic stent graft, a double transposition or bypass was always necessary (LSCA to left common carotid artery, AL to right common carotid). An additional debranching of the left common carotid artery was necessary in 33.8% of the cases and of all the SATs in 2.9% of the cases.<br><br>CONCLUSIONS: The radio-anatomical study showed that no patient was eligible for conventional thoracic endovascular aneurysm repair to treat an aneurysmal AL. The hybrid approach is feasible using a double transposition or a bypass before the implantation of a stent graft, if needed associated with a debranching of the common carotid arteries.}, }
@article {pmid28494742, year = {2017}, author = {Bangde, P and Atale, S and Dey, A and Pandit, A and Dandekar, P and Jain, R}, title = {Potential Gene Therapy Towards Treating Neurodegenerative Disea ses Employing Polymeric Nanosystems.}, journal = {Current gene therapy}, volume = {17}, number = {2}, pages = {170-183}, doi = {10.2174/1566523217666170510153845}, pmid = {28494742}, issn = {1875-5631}, mesh = {Animals ; Drug Carriers/chemistry ; Drug Delivery Systems/methods ; Gene Transfer Techniques ; Genetic Therapy/*methods ; Humans ; Nanoparticles/*administration &amp; dosage/chemistry ; Nanotechnology/methods ; Neurodegenerative Diseases/genetics/*therapy ; Polymers/*administration &amp; dosage/chemistry ; }, abstract = {BACKGROUND: Recent integrated approaches involving nanotechnology and gene therapy have accelerated development of efficient drug delivery to the central nervous system (CNS). Neurodegenerative disorders are closely associated with genetic inheritance and mutation.<br><br>MATERIALS: Nanotechnology has allowed effective engineering of various such polymeric structures. Moreover, availability of a wide array of polymeric materials has enabled fabrication of biocompatible and biodegradable delivery vehicles. Our manuscript focuses on the ideal features and properties of polymeric nanoparticles that have enabled successful gene therapy for neurodegenerative disorders, as well as the challenges that are posing difficulties in their practical application. We have highlighted these aspects through examples of polymeric nanoparticles that have exhibited therapeutic promise in the treatment of neurological disorders and mutations.<br><br>METHODS: Complete cure of these diseases is a challenging task and gene therapy appears as a realistic approach for their treatment. Gene therapy allows effective replacement or suppression of faulty genes, thereby increasing chances for neuron survival and repair. However, successful delivery of naked genetic material to CNS faces severe obstacles due to possible degradation and restricted transportation of these biological entities across the blood brain barrier (BBB). Structurally, the BBB is composed of several tight junctions, making the membrane highly selective towards the entry of molecules.<br><br>CONCLUSION: In order to target BBB for treating neurodegenerative diseases, it is essential to develop a tailor-made system that may not only cross this barrier, but also effectively modulate the expression of disease-causing genes. Stabilization of therapeutic genes and their effective, targeted delivery may be possible using polymeric nanoparticles as carriers.}, }
@article {pmid28490573, year = {2017}, author = {Miyoshi, S and Tezuka, T and Arimura, S and Tomono, T and Okada, T and Yamanashi, Y}, title = {DOK7 gene therapy enhances motor activity and life span in ALS model mice.}, journal = {EMBO molecular medicine}, volume = {9}, number = {7}, pages = {880-889}, pmid = {28490573}, issn = {1757-4684}, mesh = {Adenoviridae/genetics ; Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Disease Models, Animal ; *Genetic Therapy ; Genetic Vectors ; Humans ; Longevity ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; *Motor Activity ; Muscle Proteins/*genetics/*metabolism ; Nerve Degeneration/therapy ; Neuromuscular Junction/physiology ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, multifactorial motor neurodegenerative disease with severe muscle atrophy. The glutamate release inhibitor riluzole is the only medication approved by the FDA, and prolongs patient life span by a few months, testifying to a strong need for new treatment strategies. In ALS, motor neuron degeneration first becomes evident at the motor nerve terminals in neuromuscular junctions (NMJs), the cholinergic synapse between motor neuron and skeletal muscle; degeneration then progresses proximally, implicating the NMJ as a therapeutic target. We previously demonstrated that activation of muscle-specific kinase MuSK by the cytoplasmic protein Dok-7 is essential for NMJ formation, and forced expression of Dok-7 in muscle activates MuSK and enlarges NMJs. Here, we show that therapeutic administration of an adeno-associated virus vector encoding the human DOK7 gene suppressed motor nerve terminal degeneration at NMJs together with muscle atrophy in the SOD1-G93A ALS mouse model. Ultimately, we show that DOK7 gene therapy enhanced motor activity and life span in ALS model mice.}, }
@article {pmid28489755, year = {2017}, author = {Chen, Y and Luo, P and Li, Z and Hu, H and Wu, D and Xu, T and Wang, X and Xie, H}, title = {Kennedy disease with difficulty in differential diagnosis: A case report.}, journal = {Medicine}, volume = {96}, number = {19}, pages = {e6792}, pmid = {28489755}, issn = {1536-5964}, mesh = {Adult ; Bulbo-Spinal Atrophy, X-Linked/*diagnosis/genetics/pathology/physiopathology ; Diagnosis, Differential ; Humans ; Male ; }, abstract = {RATIONALE: Kennedy disease (KD) is also known as spinal bulbar muscular dystrophy. As KD has similar symptoms with most neuromuscular diseases, so it is difficult to make a rapid diagnosis clinically.<br><br>PATIENT CONCERNS: We report a case of a 43-year-old male with progressive limb proximal weakness without family history. Physical examination showed gynecomastia, erectile dysfunction, bilateral tendon reflex and quadriceps weakness, and tongue muscle atrophy.<br><br>DIAGNOSES: Laboratory examination found increased creatine kinase, impaired glucose tolerance, and abnormal lactic acid values. There was no mutation or copy number variant in SMN1 gene and related mitochondrion genes tested, even with the use of multiplex ligation probe- dependent amplification technique. Diagnosis was confirmed with genetic analysis which displayed trinucleotide CAG (glutamine)- repeat expansion in the androgen-receptor gene.<br><br>INTERVENTIONS AND OUTCOMES: The patient achieved good prognosis with symptomatic treatment after diagnosis.<br><br>LESSONS: To diagnose KD, clinicians should pay more attention to differentiate KD and myasthenia gravis, mitochondrial myopathy, and amyotrophic lateral sclerosis. Gene analysis was the key in detecting this rare confusing disease in the patient.}, }
@article {pmid28489058, year = {2017}, author = {Szwajgier, D and Borowiec, K and Pustelniak, K}, title = {The Neuroprotective Effects of Phenolic Acids: Molecular Mechanism of Action.}, journal = {Nutrients}, volume = {9}, number = {5}, pages = {}, pmid = {28489058}, issn = {2072-6643}, mesh = {Animals ; Central Nervous System Diseases/*prevention &amp; control ; Humans ; Molecular Structure ; Neuroprotective Agents/*pharmacology ; Phenols/chemistry/*pharmacology ; }, abstract = {The neuroprotective role of phenolic acids from food has previously been reported by many authors. In this review, the role of phenolic acids in ameliorating depression, ischemia/reperfusion injury, neuroinflammation, apoptosis, glutamate-induced toxicity, epilepsy, imbalance after traumatic brain injury, hyperinsulinemia-induced memory impairment, hearing and vision disturbances, Parkinson's disease, Huntington's disease, anti-amyotrophic lateral sclerosis, Chagas disease and other less distributed diseases is discussed. This review covers the in vitro, ex vivo and in vivo studies concerning the prevention and treatment of neurological disorders (on the biochemical and gene expression levels) by phenolic acids.}, }
@article {pmid28482434, year = {2017}, author = {Meng, YK and Zhang, J and Yang, Y and Zhou, LL and Yan, TF and Wang, Y and Yang, HS and Shi, GD and Chen, DY and Shi, JG and Guo, YF and Jia, LS}, title = {[Clinical diagnosis and management of cervical spondylotic amyotrophy].}, journal = {Zhonghua yi xue za zhi}, volume = {97}, number = {17}, pages = {1320-1323}, doi = {10.3760/cma.j.issn.0376-2491.2017.17.010}, pmid = {28482434}, issn = {0376-2491}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/diagnosis ; Cervical Vertebrae ; Female ; Humans ; Male ; Middle Aged ; Muscular Atrophy ; *Muscular Atrophy, Spinal/diagnosis/therapy ; Spondylosis ; Treatment Outcome ; }, abstract = {Objective: To investigate the clinical characteristics and surgical treatment of cervical spondylotic amyotrophy. Methods: Thirteen patients(13 man) with proximal (10) and distal(3) cervical spondylotic amyotrophy between November 2014 and September 2016 were included in this study. The average age of the patients was 55 (range, 47-66) years. The sex, age, clinical course, type of amyotrophy, lesion segment and postdecompression improvement in muscle power were reviewed. Results: Of 13 cervical spondylotic amyotrophy patients, 9 were performed on with cervical disectomy, 2 were performed on with cervical posterior operation, 2 remainding patients received nonoperative treatment. Cervical spondylotic amyotrophy patients were followed up 6-22 (average 10.6) months, muscle power of 4 patients (all proximal-type)were improved completely (the average recovery time were 4.4 months), muscle power of 6 patients were improved uncompletely, 1 patients failed to improve, the 2 remainding patients received nonoperative treatment had no change. Conclusion: Cervical spondylotic amyotrophy as a rare type of cervical spondylotic disorder, It should distinguish cervical spondylotic amyotrophy from amyotrophic lateral sclerosis, especially in the early stage of amyotrophic lateral sclerosis. A surgical treatment is recommended as the first line of proximal-type CSA, especially those with serious compression. It is important that clinicians should be aware that distal-type CSA had a poor results, resulting in a lower lower satisfaction, especially those with no, or insignificant, sensory disturbance.}, }
@article {pmid28480907, year = {2017}, author = {Navarro-Reig, M and Jaumot, J and Piña, B and Moyano, E and Galceran, MT and Tauler, R}, title = {Metabolomic analysis of the effects of cadmium and copper treatment in Oryza sativa L. using untargeted liquid chromatography coupled to high resolution mass spectrometry and all-ion fragmentation.}, journal = {Metallomics : integrated biometal science}, volume = {9}, number = {6}, pages = {660-675}, doi = {10.1039/c6mt00279j}, pmid = {28480907}, issn = {1756-591X}, mesh = {Cadmium/*pharmacology ; Chromatography, Liquid/methods ; Copper/*pharmacology ; Mass Spectrometry/methods ; Metabolomics/methods ; Oryza/*drug effects/growth &amp; development/*metabolism ; Proteome/drug effects/*metabolism ; }, abstract = {While the knowledge of plant metabolomes has increased in the last few years, their response to the presence of toxicants is still poorly understood. Here, we analyse the metabolomic changes in Japanese rice (Oryza sativa var. Japonica) upon exposure to heavy metals (Cd(ii) and Cu(ii)) in concentrations from 10 to 1000 μM. After harvesting, rice metabolites were extracted from aerial parts of the plants and analysed by HPLC (HILIC TSK gel amide-80 column) coupled to a mass spectrometer quadrupole-Orbitrap (Q-Exactive). Full scan and all ion fragmentation (AIF) mass spectrometry modes were used during the analysis. The proposed untargeted metabolomics data analysis strategy is based on the application of the multivariate curve resolution alternating least squares (MCR-ALS) method for feature detection, allowing the simultaneous resolution of pure chromatographic profiles and mass spectra of all metabolites present in the analysed rice extracts. All-ion fragmentation data were used to confirm the identification of MCR-ALS resolved metabolites. A total of 112 metabolites were detected, and 97 of them were subsequently identified and confirmed. Pathway analysis of the observed metabolic changes suggested an underlying similarity of the responses of the plant to Cd(ii) and Cu(ii), although the former treatment appeared to be the more severe of the two. In both cases, secondary metabolism and amino acid-, purine-, carbon- and glycerolipid-metabolism pathways were affected, in a pattern consistent with reduction in plant growth and/or photosynthetic capacity and with induction of defence mechanisms to reduce cell damage.}, }
@article {pmid28479121, year = {2017}, author = {Danel-Brunaud, V and Touzet, L and Chevalier, L and Moreau, C and Devos, D and Vandoolaeghe, S and Defebvre, L}, title = {Ethical considerations and palliative care in patients with amyotrophic lateral sclerosis: A review.}, journal = {Revue neurologique}, volume = {173}, number = {5}, pages = {300-307}, doi = {10.1016/j.neurol.2017.03.032}, pmid = {28479121}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Caregivers ; Ethics, Medical ; Humans ; Palliative Care/*ethics ; Quality of Life ; Terminal Care ; Withholding Treatment ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is not a curable disease, but it is treatable. By definition, much of the care provided to ALS patients is palliative, even though active life-sustaining strategies are available to prolong survival. Healthcare professionals must develop communication skills that help patients cope with the inexorable progression of the disease and the inevitability of death. Symptomatic treatments as well as respiratory insufficiency and nutritional life-sustaining therapies must be regularly evaluated as the disease progresses, without losing sight of the burden placed on the patient's non-professional caregivers. The decision-making process regarding tracheostomy with invasive ventilation (TIV) is of greater complexity. Providing full information is crucial. Several long interviews are necessary to explain, discuss and allow assimilation of the information. Also, physicians should be careful not to focus exclusively on the biomedical aspects of disease, as ALS patients generally welcome the opportunity to discuss end-of-life issues with their physicians. Psychological factors, education level and cognitive status (especially the level of executive dysfunction) have a major influence on their decisions. However, as many patients do not complete advance directives with regard to TIV, advance care planning may instead be suggested in anticipation of emergency interventions. This should be discussed by healthcare professionals and the patient, and based on the wishes of the patient and caregiver(s), and communicated to all healthcare professionals. Many healthcare professionals are involved in the management of an ALS patient: they include not only those at ALS centers who provide diagnosis, follow-up and treatment initiation (particularly for respiratory and nutritional care), but also the medical and social care networks involved in disability support and home care. Specialist palliative care teams can work in partnership with ALS centers early in the course of the disease, with the center coordinating information-sharing and collaborative discussions.}, }
@article {pmid28476168, year = {2017}, author = {Ash, PEA and Stanford, EA and Al Abdulatif, A and Ramirez-Cardenas, A and Ballance, HI and Boudeau, S and Jeh, A and Murithi, JM and Tripodis, Y and Murphy, GJ and Sherr, DH and Wolozin, B}, title = {Dioxins and related environmental contaminants increase TDP-43 levels.}, journal = {Molecular neurodegeneration}, volume = {12}, number = {1}, pages = {35}, pmid = {28476168}, issn = {1750-1326}, support = {P30 AG013846/AG/NIA NIH HHS/United States ; R01 AG050471/AG/NIA NIH HHS/United States ; R01 ES020395/ES/NIEHS NIH HHS/United States ; R01 NS089544/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis ; Animals ; Brain/*drug effects ; Cell Line ; DNA-Binding Proteins/biosynthesis/*drug effects ; Environmental Pollutants/*adverse effects ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Neurons/*drug effects ; Polychlorinated Dibenzodioxins/adverse effects ; Polycyclic Aromatic Hydrocarbons/adverse effects ; Receptors, Aryl Hydrocarbon/*agonists ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative condition that is characterized by progressive loss of motor neurons and the accumulation of aggregated TAR DNA Binding Protein-43 (TDP-43, gene: TARDBP). Increasing evidence indicates that environmental factors contribute to the risk of ALS. Dioxins, related planar polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) are environmental contaminants that activate the aryl hydrocarbon receptor (AHR), a ligand-activated, PAS family transcription factor. Recently, exposure to these toxicants was identified as a risk factor for ALS.<br><br>METHODS: We examined levels of TDP-43 reporter activity, transcript and protein. Quantification was done using cell lines, induced pluripotent stem cells (iPSCs) and mouse brain. The target samples were treated with AHR agonists, including 6-Formylindolo[3,2-b]carbazole (FICZ, a potential endogenous ligand, 2,3,7,8-tetrachlorodibenzo(p)dioxin, and benzo(a)pyrene, an abundant carcinogen in cigarette smoke). The action of the agonists was inhibited by concomitant addition of AHR antagonists or by AHR-specific shRNA.<br><br>RESULTS: We now report that AHR agonists induce up to a 3-fold increase in TDP-43 protein in human neuronal cell lines (BE-M17 cells), motor neuron differentiated iPSCs, and in murine brain. Chronic treatment with AHR agonists elicits over 2-fold accumulation of soluble and insoluble TDP-43, primarily because of reduced TDP-43 catabolism. AHR antagonists or AHR knockdown inhibits agonist-induced increases in TDP-43 protein and TARDBP transcription demonstrating that the ligands act through the AHR.<br><br>CONCLUSIONS: These results provide the first evidence that environmental AHR ligands increase TDP-43, which is the principle pathological protein associated with ALS. These results suggest novel molecular mechanisms through which a variety of prevalent environmental factors might directly contribute to ALS. The widespread distribution of dioxins, PCBs and PAHs is considered to be a risk factor for cancer and autoimmune diseases, but could also be a significant public health concern for ALS.}, }
@article {pmid28473732, year = {2017}, author = {Leonoudakis, D and Rane, A and Angeli, S and Lithgow, GJ and Andersen, JK and Chinta, SJ}, title = {Anti-Inflammatory and Neuroprotective Role of Natural Product Securinine in Activated Glial Cells: Implications for Parkinson's Disease.}, journal = {Mediators of inflammation}, volume = {2017}, number = {}, pages = {8302636}, pmid = {28473732}, issn = {1466-1861}, support = {P01 AG025901/AG/NIA NIH HHS/United States ; R01 AG029631/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Anti-Inflammatory Agents/therapeutic use ; Astrocytes/drug effects ; Azepines/*therapeutic use ; Blotting, Western ; Cell Survival/drug effects ; Heterocyclic Compounds, Bridged-Ring/*therapeutic use ; Interferon-Stimulated Gene Factor 3/metabolism ; Lactones/*therapeutic use ; Lipopolysaccharides/pharmacology ; Mice ; Microglia/drug effects ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/metabolism ; Neuroprotective Agents/therapeutic use ; Nitric Oxide Synthase Type II/metabolism ; Nitrites/metabolism ; Parkinson Disease/*drug therapy/immunology/*metabolism ; Phosphorylation/drug effects ; Piperidines/*therapeutic use ; Polymerase Chain Reaction ; }, abstract = {Glial activation and subsequent release of neurotoxic proinflammatory factors are believed to play an important role in the pathogenesis of several neurological disorders including Parkinson's disease (PD). Inhibition of glial activation and inflammatory processes may represent a therapeutic target to alleviate neurodegeneration. Securinine, a major natural alkaloid product from the root of the plant Securinega suffruticosa, has been reported to have potent biological activity and is used in the treatment of neurological conditions such as amyotrophic lateral sclerosis, poliomyelitis, and multiple sclerosis. In this study, we explored the underlying mechanisms of neuroprotection elicited by securinine, particularly its anti-inflammatory effects in glial cells. Our results demonstrate that securinine significantly and dose-dependently suppressed the nitric oxide production in microglia and astrocytic cultures. In addition, securinine inhibited the activation of the inflammatory mediator NF-κB, as well as mitogen-activated protein kinases in lipopolysaccharide- (LPS-) stimulated BV2 cells. Additionally, securinine also inhibited interferon-γ- (IFN-γ-) induced nitric oxide levels and iNOS mRNA expression. Furthermore, conditioned media (CM) from securinine pretreated BV2 cells significantly reduced mesencephalic dopaminergic neurotoxicity compared with CM from LPS stimulated microglia. These findings suggest that securinine may be a potential candidate for the treatment of neurodegenerative diseases related to neuroinflammation.}, }
@article {pmid28469667, year = {2017}, author = {Li, XY and Liang, ZH and Han, C and Wei, WJ and Song, CL and Zhou, LN and Liu, Y and Li, Y and Ji, XF and Liu, J}, title = {Transplantation of autologous peripheral blood mononuclear cells in the subarachnoid space for amyotrophic lateral sclerosis: a safety analysis of 14 patients.}, journal = {Neural regeneration research}, volume = {12}, number = {3}, pages = {493-498}, pmid = {28469667}, issn = {1673-5374}, abstract = {There is a small amount of clinical data regarding the safety and feasibility of autologous peripheral blood mononuclear cell transplantation into the subarachnoid space for the treatment of amyotrophic lateral sclerosis. The objectives of this retrospective study were to assess the safety and efficacy of peripheral blood mononuclear cell transplantation in 14 amyotrophic lateral sclerosis patients to provide more objective data for future clinical trials. After stem cell mobilization and collection, autologous peripheral blood mononuclear cells (1 × 10[9]) were isolated and directly transplanted into the subarachnoid space of amyotrophic lateral sclerosis patients. The primary outcome measure was incidence of adverse events. Secondary outcome measures were electromyography 1 week before operation and 4 weeks after operation, Functional Independence Measurement, Berg Balance Scale, and Dysarthria Assessment Scale 1 week preoperatively and 1, 2, 4 and 12 weeks postoperatively. There was no immediate or delayed transplant-related cytotoxicity. The number of leukocytes, serum alanine aminotransferase and creatinine levels, and body temperature were within the normal ranges. Radiographic evaluation showed no serious transplant-related adverse events. Muscle strength grade, results of Functional Independence Measurement, Berg Balance Scale, and Dysarthria Assessment Scale were not significantly different before and after treatment. These findings suggest that peripheral blood mononuclear cell transplantation into the subarachnoid space for the treatment of amyotrophic lateral sclerosis is safe, but its therapeutic effect is not remarkable. Thus, a large-sample investigation is needed to assess its efficacy further.}, }
@article {pmid28469644, year = {2017}, author = {Kinghorn, KJ and Asghari, AM and Castillo-Quan, JI}, title = {The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson's disease.}, journal = {Neural regeneration research}, volume = {12}, number = {3}, pages = {380-384}, pmid = {28469644}, issn = {1673-5374}, abstract = {Gaucher disease (GD), the commonest lysosomal storage disorder, results from the lack or functional deficiency of glucocerebrosidase (GCase) secondary to mutations in the GBA1 gene. There is an established association between GBA1 mutations and Parkinson's disease (PD), and indeed GBA1 mutations are now considered to be the greatest genetic risk factor for PD. Impaired lysosomal-autophagic degradation of cellular proteins, including α-synuclein (α-syn), is implicated in the pathogenesis of PD, and there is increasing evidence for this also in GD and GBA1-PD. Indeed we have recently shown in a Drosophila model lacking neuronal GCase, that there are clear lysosomal-autophagic defects in association with synaptic loss and neurodegeneration. In addition, we demonstrated alterations in mechanistic target of rapamycin complex 1 (mTORC1) signaling and functional rescue of the lifespan, locomotor defects and hypersensitivity to oxidative stress on treatment of GCase-deficient flies with the mTOR inhibitor rapamycin. Moreover, a number of other recent studies have shown autophagy-lysosomal system (ALS) dysfunction, with specific defects in both chaperone-mediated autophagy (CMA), as well as macroautophagy, in GD and GBA1-PD model systems. Lastly we discuss the possible therapeutic benefits of inhibiting mTOR using drugs such as rapamycin to reverse the autophagy defects in GD and PD.}, }
@article {pmid28469596, year = {2017}, author = {Morello, G and Spampinato, AG and Cavallaro, S}, title = {Molecular Taxonomy of Sporadic Amyotrophic Lateral Sclerosis Using Disease-Associated Genes.}, journal = {Frontiers in neurology}, volume = {8}, number = {}, pages = {152}, pmid = {28469596}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of upper and lower motor neurons. Despite intensive research, the origin and progression of ALS remain largely unknown, suggesting that the traditional clinical diagnosis and treatment strategies might not be adequate to completely capture the molecular complexity underlying the disease. In our previous work, comprehensive genomic profiling of 41 motor cortex samples enabled to discriminate control from sporadic ALS patients and segregated these latter into two distinct subgroups, each associated with different deregulated genes and pathways. Interestingly, some deregulated genes in sporadic ALS were previously associated with familiar ALS, indicating shared pathogenic mechanisms between the two forms of disease. In this, we performed cluster analysis on the same whole-genome expression profiles using a restricted (203) subset of genes extensively implicated in monogenic forms of ALS. Surprisingly, this short and unbiased gene list was sufficiently representative to allow the accurate separation of SALS patients from controls and the stratification of SALS patients into two molecularly distinct subgroups. Overall, our findings support the existence of a molecular taxonomy for ALS and represent a further step toward the establishment of a molecular-based diagnosis and patient-tailored therapies.}, }
@article {pmid28466394, year = {2017}, author = {Lawana, V and Singh, N and Sarkar, S and Charli, A and Jin, H and Anantharam, V and Kanthasamy, AG and Kanthasamy, A}, title = {Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {12}, number = {4}, pages = {624-660}, pmid = {28466394}, issn = {1557-1904}, support = {R01 NS078247/NS/NINDS NIH HHS/United States ; R01 NS088206/NS/NINDS NIH HHS/United States ; NS078247//National Institutes of Health/ ; NS088206//National Institutes of Health/ ; }, mesh = {Animals ; Cells, Cultured ; Inflammasomes/*metabolism ; Mice ; Mice, Inbred C57BL ; Microglia/*metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Oxidative Stress/physiology ; Parkinson Disease/metabolism/physiopathology ; Proto-Oncogene Proteins c-abl/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/*immunology ; }, abstract = {A growing body of evidence suggests that excessive microglial activation and pesticide exposure may be linked to the etiology of PD; however, the mechanisms involved remain elusive. Emerging evidence indicates that intracellular inflammasome complex namely NLRP3 complex is involved in the recognition and execution of host inflammatory response. Thus, in the present study, we investigated the hypothesis that NLRP3 inflammasome activation is linked to rotenone (ROT)-induced microglial activation which is dependent upon a priming stimulus by a pathogen-associated molecular pattern (PAMP) or damage associated molecular pattern (DAMP), respectively. Herein using both BV2 cells and primary microglial cells, we show that LPS priming and subsequent ROT stimulation enhanced NLRP3 inflammasome activation, c-Abl and PKCδ activation, mitochondrial dysfunction, NF-κB activation, and autophagic markers, while TFEB levels were decreased dramatically. Mechanistic studies revealed c-Abl acts as a proximal signal that exacerbated the activation of the afore mentioned markers. Intriguingly, siRNA-mediated depletion or pharmacological inhibition of c-Abl via dasatinib abrogated LPS and ROT-induced microglial activation response via attenuation of NLRP3 inflammasome activation, mitochondrial oxidative stress, and ALS dysfunction. Moreover, mitoTEMPO, a mitochondrial antioxidant, attenuated NLRP3 inflammasome activation effects via blockade of c-Abl and PKCδ activation. In LPS treated mice, dasatinib attenuated NLRP3 inflammasome activation, c-Abl and PKCδ activation; and sickness behavior. Together our findings identify an exaggerated ROS/c-Abl/NLRP3 signaling axis in the heightened microglial activation response evidenced in LPS-primed ROT-stimulated microglial cells and suggest that targeting c-Abl-regulated NLRP3 inflammasome signaling offers a novel therapeutic strategy for PD treatment. Graphical Abstract ᅟ.}, }
@article {pmid28461025, year = {2017}, author = {Lenglet, T and Camdessanché, JP}, title = {Amyotrophic lateral sclerosis or not: Keys for the diagnosis.}, journal = {Revue neurologique}, volume = {173}, number = {5}, pages = {280-287}, doi = {10.1016/j.neurol.2017.04.003}, pmid = {28461025}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Diagnosis, Differential ; Electrodiagnosis ; Evoked Potentials, Motor ; Humans ; Motor Neuron Disease/*diagnosis ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease (MND) which prognosis is poor. Early diagnosis permit to set up immediately adapted treatment and cares. Available diagnostic criteria are based on the detection of both central and peripheral motor neuron injury in bulbar, cervical, thoracic and lumbar regions. Electrodiagnostic (EDX) tests are the key tools to identify peripheral motor neuron involvement. Needle examination records abnormal activities at rest, and looks for neurogenic pattern during muscle contraction. Motor unit potentials morphology is modified primary to recruitment. Motor evoked potentials remain the test of choice to identify impairment of central motor neurons. In the absence of diagnostic biomarker of ALS and among essential investigations of suspected MND, a careful clinical and neurophysiological work-up is essential to rule out the differential diagnosis.}, }
@article {pmid28461024, year = {2017}, author = {Soriani, MH and Desnuelle, C}, title = {Care management in amyotrophic lateral sclerosis.}, journal = {Revue neurologique}, volume = {173}, number = {5}, pages = {288-299}, doi = {10.1016/j.neurol.2017.03.031}, pmid = {28461024}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/psychology/rehabilitation/*therapy ; Humans ; Nutritional Support ; Palliative Care ; *Patient Care Management ; Patient Care Team ; Respiration, Artificial ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative disease characterized by progressive weakness of voluntary muscles of movement as well as those for swallowing, speech and respiration. In the absence of curative treatment, care can improve quality of life, prolong survival, and support ALS patients and their families, and also help them to anticipate and prepare for the end of life. Multidisciplinary management in tertiary centers is recommended in close collaboration with general practitioners, home carers and a dedicated health network. Patients' follow-up deals mainly with motor impairment and physical disability, adaptation, nutrition and respiratory function. Involvement of palliative care as part of the multidisciplinary team management offers patients the possibility of discussing their end of life issues. This review summarizes the different aspects of ALS care, from delivering the diagnosis to the end of life, and the organization of its management.}, }
@article {pmid28458007, year = {2017}, author = {Srinivasan, E and Rajasekaran, R}, title = {Probing the inhibitory activity of epigallocatechin-gallate on toxic aggregates of mutant (L84F) SOD1 protein through geometry based sampling and steered molecular dynamics.}, journal = {Journal of molecular graphics &amp; modelling}, volume = {74}, number = {}, pages = {288-295}, doi = {10.1016/j.jmgm.2017.04.019}, pmid = {28458007}, issn = {1873-4243}, mesh = {Amyotrophic Lateral Sclerosis/enzymology ; Catalytic Domain ; Catechin/*analogs &amp; derivatives/chemistry ; Humans ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Molecular Dynamics Simulation ; Mutation, Missense ; Protein Aggregates ; Protein Binding ; Protein Conformation, alpha-Helical ; Superoxide Dismutase-1/antagonists &amp; inhibitors/chemistry/*genetics ; Thermodynamics ; }, abstract = {Amyloid formation and protein aggregation are considered to be at the core of the disease pathology for the various neurodegenerative disorders such as Amyotrophic lateral sclerosis (ALS). Considerable experimental reports have suggested that epigallocatechin-gallate (EGCG), a natural polyphenol from the green tea inhibits the amyloid formation in multiple neurodegenerative disease. Mutations in SOD1 protein are considered to a key factor that contributes towards the rapid disease progression and the pathogenesis in both, the sporadic and familial form. In our study, we computationally examined the inhibitory action of EGCG against the native and the mutant SOD1 through molecular docking, steered molecular dynamics and conformational sampling methods From the outcome, we could conjecture that the protein destabilization and increased β-sheet propensity that occurred due to mutation were regained upon the binding of EGCG. Moreover, the concepts of the free energy landscape analysis are introduced to establish the visual appearance of protein aggregation upon mutation. Altogether, we come to know that the binding of EGCG on mutant SOD1 has reduced the formation of the toxic aggregates upon mutation. Hence, our study could be an initiative in deciphering the inhibitory action of EGCG against the aggregated mutant SOD1, which could be a therapeutic potential against the treatment for the incurable neurodegenerative disorder (ALS) affecting the mankind.}, }
@article {pmid28456300, year = {2017}, author = {Paporisch, A and Rubin, B}, title = {Isoxadifen safening mechanism in sweet corn genotypes with differential response to P450-metabolized herbicides.}, journal = {Pesticide biochemistry and physiology}, volume = {138}, number = {}, pages = {22-28}, doi = {10.1016/j.pestbp.2017.02.002}, pmid = {28456300}, issn = {1095-9939}, mesh = {Cholinesterase Inhibitors/metabolism ; Cytochrome P-450 Enzyme System/genetics/*metabolism ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Plant ; *Genotype ; Herbicides/*toxicity ; Malathion/metabolism ; Oxazoles/*toxicity ; Pyrazoles/pharmacology ; Zea mays/classification/*genetics ; }, abstract = {Three sweet corn genotypes, two inbred lines (IBER001 and IBER002) and their hybrid (ER00X), differ in their phenotypic responses to several P450-metabolized herbicides, used in sweet corn, namely, foramsulfuron, iodosulfuron, rimsulfuron and tembotrione. Foramsulfuron is a sulfonylurea herbicide commonly formulated with the safener isoxadifen that is used for selective post-emergence weed control in corn. Our goal was to elucidate the mechanism of these genotypes' responses to foramsulfuron and safener isoxadifen and examine the heritability of those responses. IBER001 was sensitive to foramsulfuron+isoxadifen, with an ED50 of 3.6gaiha[-1], while IBER002 and ER00X were tolerant with ED50 values of 808 and 700gaiha[-1], respectively. ALS enzyme extracted from each of the different genotypes was equally sensitive to foramsulfuron. Pre-treatment with malathion, a known cytochrome P450 inhibitor, increased foramsulfuron injury in IBER002 and ER00X, but had no effect on those lines when isoxadifen was applied with the herbicide. Foramsulfuron-treated IBER001 was severely injured regardless of the presence of malathion and/or isoxadifen. Pre-treatment with malathion similarly increased the phytotoxicity of iodosulfuron+safener (mefenpyr) and rimsulfuron to the tolerant genotypes, but did not increase the level of injury caused by the tembotrione+isoxadifen treatment. Segregation of F2 and backcross progenies according to their responses to foramsulfuron+isoxadifen revealed a pattern of inheritance typical of a trait controlled by a single gene inheritance, with a recessive allele conferring sensitivity. Our results support the hypothesis that foramsulfuron selectivity is associated with P450 metabolism and that isoxadifen positively affects P450 activity. The sensitive genotype that does not respond to isoxadifen is presumably homozygous for a deficient or non-functioning P450 gene.}, }
@article {pmid28452633, year = {2017}, author = {Povysheva, T and Shmarov, M and Logunov, D and Naroditsky, B and Shulman, I and Ogurcov, S and Kolesnikov, P and Islamov, R and Chelyshev, Y}, title = {Post-spinal cord injury astrocyte-mediated functional recovery in rats after intraspinal injection of the recombinant adenoviral vectors Ad5-VEGF and Ad5-ANG.}, journal = {Journal of neurosurgery. Spine}, volume = {27}, number = {1}, pages = {105-115}, doi = {10.3171/2016.9.SPINE15959}, pmid = {28452633}, issn = {1547-5646}, mesh = {Adenoviridae/genetics ; Animals ; Astrocytes/pathology/*physiology ; Disease Models, Animal ; Female ; *Genetic Therapy ; Genetic Vectors ; Humans ; Injections, Spinal ; Male ; Motor Activity/physiology ; RNA, Messenger/metabolism ; Random Allocation ; Rats, Wistar ; Recovery of Function/*physiology ; Ribonuclease, Pancreatic/*administration &amp; dosage/genetics ; S100 Calcium Binding Protein beta Subunit/metabolism ; Spinal Cord/pathology/physiopathology ; Spinal Cord Injuries/pathology/physiopathology/*therapy ; Spinal Cord Regeneration/physiology ; Vascular Endothelial Growth Factor A/*administration &amp; dosage/metabolism ; }, abstract = {OBJECTIVE The most actively explored therapeutic strategy for overcoming spinal cord injury (SCI) is the delivery of genes encoding molecules that stimulate regeneration. In a mouse model of amyotrophic lateral sclerosis and in preliminary clinical trials in patients with amyotrophic lateral sclerosis, the combined administration of recombinant adenoviral vectors (Ad5-VEGF+Ad5-ANG) encoding the neurotrophic/angiogenic factors vascular endothelial growth factor (VEGF) and angiogenin (ANG) was found to slow the development of neurological deficits. These results suggest that there may be positive effects of this combination of genes in posttraumatic spinal cord regeneration. The objective of the present study was to determine the effects of Ad5-VEGF+Ad5-ANG combination therapy on motor function recovery and reactivity of astrocytes in a rat model of SCI. METHODS Spinal cord injury was induced in adult Wistar rats by the weight-drop method. Rats (n = 51) were divided into 2 groups: the experimental group (Ad5-VEGF+Ad5-ANG) and the control group (Ad5-GFP [green fluorescent protein]). Recovery of motor function was assessed using the Basso, Beattie, and Bresnahan scale. The duration and intensity of infectivity and gene expression from the injected vectors were assessed by immunofluorescent detection of GFP. Reactivity of glial cells was assessed by changes in the number of immunopositive cells expressing glial fibrillary acidic protein (GFAP), S100β, aquaporin 4 (AQP4), oligodendrocyte transcription factor 2, and chondroitin sulfate proteoglycan 4. The level of S100β mRNA expression in the spinal cord was estimated by real-time polymerase chain reaction. RESULTS Partial recovery of motor function was observed 30 days after surgery in both groups. However, Basso, Beattie, and Bresnahan scores were 35.9% higher in the Ad5-VEGF+Ad5-ANG group compared with the control group. Specific GFP signal was observed at distances of up to 5 mm in the rostral and caudal directions from the points of injection. A 1.5 to 2.0-fold increase in the number of GFAP[+], S100β[+], and AQP4[+] cells was observed in the white and gray matter at a distance of up to 5 mm from the center of the lesion site in the caudal and rostral directions. At 30 days after injury, a 2-fold increase in S100β transcripts was observed in the Ad5-VEGF+Ad5-ANG group compared with the control group. CONCLUSIONS Intraspinal injection of recombinant adenoviral vectors encoding VEGF and ANG stimulates functional recovery after traumatic SCI. The increased number of S100β[+] astrocytes induced by this approach may be a beneficial factor for maintaining the survival and function of neurons. Therefore, gene therapy with Ad5-VEGF+Ad5-ANG vectors is an effective therapeutic method for SCI treatment.}, }
@article {pmid28446118, year = {2017}, author = {Dharmadasa, T and Henderson, RD and Talman, PS and Macdonell, RA and Mathers, S and Schultz, DW and Needham, M and Zoing, M and Vucic, S and Kiernan, MC}, title = {Motor neurone disease: progress and challenges.}, journal = {The Medical journal of Australia}, volume = {206}, number = {8}, pages = {357-362}, doi = {10.5694/mja16.01063}, pmid = {28446118}, issn = {1326-5377}, mesh = {Australia ; Evidence-Based Practice ; Genetic Testing ; Genetic Therapy ; Humans ; *Interdisciplinary Communication ; Motor Neuron Disease/*therapy ; Neuroprotection ; Noninvasive Ventilation ; Nutritional Support ; Patient Acceptance of Health Care ; Quality of Life ; Randomized Controlled Trials as Topic ; *Standard of Care ; Stem Cell Transplantation ; }, abstract = {Major progress has been made over the past decade in the understanding of motor neurone disease (MND), changing the landscape of this complex disease. Through identifying positive prognostic factors, new evidence-based standards of care have been established that improve patient survival, reduce burden of disease for patients and their carers, and enhance quality of life. These factors include early management of respiratory dysfunction with non-invasive ventilation, maintenance of weight and nutritional status, as well as instigation of a multidisciplinary team including neurologists, general practitioners and allied health professionals. Advances in technology have enhanced our understanding of the genetic architecture of MND considerably, with implications for patients, their families and clinicians. Recognition of extra-motor involvement, particularly cognitive dysfunction, has identified a spectrum of disease from MND through to frontotemporal dementia. Although riluzole remains the only disease-modifying medication available in clinical practice in Australia, several new therapies are undergoing clinical trials nationally and globally, representing a shift in treatment paradigms. Successful translation of this clinical research through growth in community funding, awareness and national MND research organisations has laid the foundation for closing the research-practice gap on this debilitating disease. In this review, we highlight these recent developments, which have transformed treatment, augmented novel therapeutic platforms, and established a nexus between research and the MND community. This era of change is of significant relevance to both specialists and general practitioners who remain integral to the care of patients with MND.}, }
@article {pmid28445628, year = {2017}, author = {Scaglia, PA and Keselman, AC and Braslavsky, D and Martucci, LC and Karabatas, LM and Domené, S and Gutiérrez, ML and Ballerini, MG and Ropelato, MG and Spinola-Castro, A and Siviero-Miachon, AA and Tartuci, JS and Rodríguez Azrak, MS and Rey, RA and Jasper, HG and Bergadá, I and Domené, HM}, title = {Characterization of four Latin American families confirms previous findings and reveals novel features of acid-labile subunit deficiency.}, journal = {Clinical endocrinology}, volume = {87}, number = {3}, pages = {300-311}, doi = {10.1111/cen.13361}, pmid = {28445628}, issn = {1365-2265}, mesh = {Adolescent ; Adult ; Aged ; Animals ; Carrier Proteins/genetics ; Child ; Child, Preschool ; Cricetulus ; Family ; Female ; Fertility ; Genetic Variation ; Glycoproteins/*deficiency/genetics ; Growth Disorders/genetics ; Heterozygote ; Humans ; Infant ; Insulin-Like Growth Factor Binding Protein 3/*blood/deficiency ; Insulin-Like Growth Factor I/*analysis/deficiency ; Latin America ; Male ; Middle Aged ; Mutation ; Transfection ; Young Adult ; }, abstract = {OBJECTIVE: Acid-labile subunit deficiency (ACLSD), caused by inactivating mutations in both IGFALS gene alleles, is characterized by marked reduction in IGF-I and IGFBP-3 levels associated with mild growth retardation. The aim of this study was to expand the known phenotype and genetic characteristics of ACLSD by reporting data from four index cases and their families.<br><br>DESIGN: Auxological data, biochemical and genetic studies were performed in four children diagnosed with ACLSD and all available relatives.<br><br>METHODS: Serum levels of IGF-I, IGFBP-3, acid-labile subunit (ALS), and in vitro ternary complex formation (ivTCF) were determined. After sequencing the IGFALS gene, pathogenicity of novel identified variants was evaluated by in vitro expression in transfected Chinese hamster ovarian (CHO) cells. ALS protein was detected in patients' sera and CHO cells conditioned media and lysates by Western immunoblot (WIB).<br><br>RESULTS: Four index cases and four relatives were diagnosed with ACLSD. The following variants were found: p.Glu35Glyfs*17, p.Glu35Lysfs*87, p.Leu213Phe, p.Asn276Ser, p.Leu409Phe, p.Ala475Val and p.Ser490Trp. ACLSD patients presented low IGF-I and low or undetectable levels of IGFBP-3 and ALS. Seven out of 8 patients did not form ivTCF.<br><br>CONCLUSIONS: This study confirms previous findings in ACLSD, such as the low IGF-I and a more severe reduction in IGFBP-3 levels, and a gene dosage effect observed in heterozygous carriers (HC). In addition, father-to-son transmission (father compound heterozygous and mother HC), preservation of male fertility, and marginal ALS expression with potential involvement in preserved responsiveness to rhGH treatment, are all novel aspects, not previously reported in this condition.}, }
@article {pmid28443372, year = {2017}, author = {Garbuzova-Davis, S and Ehrhart, J and Sanberg, PR}, title = {Cord blood as a potential therapeutic for amyotrophic lateral sclerosis.}, journal = {Expert opinion on biological therapy}, volume = {17}, number = {7}, pages = {837-851}, doi = {10.1080/14712598.2017.1323862}, pmid = {28443372}, issn = {1744-7682}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/pathology/*therapy ; Animals ; Cell Differentiation ; Cell- and Tissue-Based Therapy ; Clinical Trials as Topic ; Disease Models, Animal ; Fetal Blood/cytology/metabolism/*transplantation ; Humans ; Neural Cell Adhesion Molecule L1/genetics/metabolism ; Tissue Distribution ; Vascular Endothelial Growth Factor A/genetics/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord. Treatment options are limited due to the complexity of underlying disease factors. Cell therapy, using human umbilical cord blood (hUCB) cells may be a promising new treatment for ALS, mainly by providing a protective microenvironment for motor neuron survival. Areas covered: Composition, in vitro and in vivo differentiation of hUCB cells, and the advantages of cord blood as a source of transplant cells are discussed. A brief history of hUCB in treatment of an ALS animal model and the feasibility of these cells in therapy for ALS patients is provided. Current ALS clinical trials are also deliberated. Expert opinion: Among multiple advantages, hUCB cells' production of various anti-inflammatory/growth/trophic factors makes them an attractive cell source for ALS therapy. Biodistribution and optimal hUCB cell dose for transplantation have been determined in preclinical studies. Repeated intravenous cell doses during disease progression may be the best approach for cell-based ALS treatment. Accumulated evidence shows the efficacy of naïve or genetically modified MNC hUCB cells in the treatment of ALS and provide a superior basis for the development of clinical trials in the near future.}, }
@article {pmid28443187, year = {2017}, author = {Tuk, B and Jousma, H and Gaillard, PJ}, title = {Treatment with penicillin G and hydrocortisone reduces ALS-associated symptoms: a case series of three patients.}, journal = {F1000Research}, volume = {6}, number = {}, pages = {410}, pmid = {28443187}, issn = {2046-1402}, abstract = {Three male Caucasian patients with ALS were admitted to the hospital due to progressive dysphagia and dysarthria. During two 21-day courses of penicillin G and hydrocortisone, these patients' dysphagia and dysarthria resolved. The patient's other ALS-associated symptoms also improved, including respiratory function, coordination, walking, and muscle strength. This is the first report of a treatment with a protocol for treating dysphagia, dysarthria, respiratory depression and other ALS-related symptoms. Furthermore, the observations are consistent with the recent hypothesis that the successful treatment of ALS symptoms with this treatment course in six patients with syphilitic ALS was not directly due to the treatment of syphilis; but that the administered penicillin G and/or hydrocortisone treated these patients' ALS symptoms due the off-target pharmacological activity of penicillin G and/or hydrocortisone. This report therefore underscores the need to evaluate the efficacy of this treatment course in a clinical trial.}, }
@article {pmid28434507, year = {2017}, author = {Verschueren, A}, title = {Motor neuropathies and lower motor neuron syndromes.}, journal = {Revue neurologique}, volume = {173}, number = {5}, pages = {320-325}, doi = {10.1016/j.neurol.2017.03.018}, pmid = {28434507}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Motor Neuron Disease/immunology/pathology/*physiopathology ; Muscular Atrophy, Spinal/physiopathology ; Peroneal Neuropathies/immunology/pathology/*physiopathology ; }, abstract = {Motor or motor-predominant neuropathies may arise from disease processes affecting the motor axon and/or its surrounding myelin. Lower motor neuron syndrome (LMNS) arises from a disease process affecting the spinal motor neuron itself. The term LMNS is more generally used, rather than motor neuronopathy, although both entities are clinically similar. Common features are muscle weakness (distal or proximal) with atrophy and hyporeflexia, but no sensory involvement. They can be acquired or hereditary. Immune-mediated neuropathies (multifocal motor neuropathy, motor-predominant chronic inflammatory demyelinating polyneuropathy) are important to identify, as effective treatments are available. Other acquired neuropathies, such as infectious, paraneoplastic and radiation-induced neuropathies are also well known. Focal LMNS is an amyotrophic lateral sclerosis (ALS)-mimicking syndrome especially affecting young adults. The main hereditary LMNSs in adulthood are Kennedy's disease, late-onset spinal muscular atrophy and distal hereditary motor neuropathies. Motor neuropathies and LMNS are all clinical entities that should be better known, despite being rare diseases. They can sometimes be difficult to differentially diagnose from other diseases, particularly from the more frequent ALS in its pure LMN form. Nevertheless, correct identification of these syndromes is important because their treatment and prognoses are definitely different.}, }
@article {pmid28429727, year = {2017}, author = {Chen, J and Huang, Z and Huang, H and Wei, S and Liu, Y and Jiang, C and Zhang, J and Zhang, C}, title = {Selection of relatively exact reference genes for gene expression studies in goosegrass (Eleusine indica) under herbicide stress.}, journal = {Scientific reports}, volume = {7}, number = {}, pages = {46494}, pmid = {28429727}, issn = {2045-2322}, mesh = {Acetolactate Synthase/genetics ; Chloroplast Proteins/genetics ; Eleusine/enzymology/*genetics ; Gene Expression Regulation, Plant/drug effects ; Glycine/*analogs &amp; derivatives/pharmacology ; Herbicide Resistance/*genetics ; Herbicides/*pharmacology ; *Selection, Genetic ; Stress, Physiological/drug effects/*genetics ; Glyphosate ; }, abstract = {Goosegrass (Eleusine indica) is one of the most serious annual grassy weeds worldwide, and its evolved herbicide-resistant populations are more difficult to control. Quantitative real-time PCR (qPCR) is a common technique for investigating the resistance mechanism; however, there is as yet no report on the systematic selection of stable reference genes for goosegrass. This study proposed to test the expression stability of 9 candidate reference genes in goosegrass in different tissues and developmental stages and under stress from three types of herbicide. The results show that for different developmental stages and organs (control), eukaryotic initiation factor 4 A (eIF-4) is the most stable reference gene. Chloroplast acetolactate synthase (ALS) is the most stable reference gene under glyphosate stress. Under glufosinate stress, eIF-4 is the best reference gene. Ubiquitin-conjugating enzyme (UCE) is the most stable reference gene under quizalofop-p-ethyl stress. The gene eIF-4 is the recommended reference gene for goosegrass under the stress of all three herbicides. Moreover, pairwise analysis showed that seven reference genes were sufficient to normalize the gene expression data under three herbicides treatment. This study provides a list of reliable reference genes for transcript normalization in goosegrass, which will facilitate resistance mechanism studies in this weed species.}, }
@article {pmid28428229, year = {2017}, author = {Gleeson, A and Johnson, F}, title = {Withdrawal of invasive ventilation in a patient with motor neurone disease and total locked-in syndrome.}, journal = {Practical neurology}, volume = {17}, number = {5}, pages = {383-386}, doi = {10.1136/practneurol-2016-001574}, pmid = {28428229}, issn = {1474-7766}, mesh = {Adult ; Humans ; Male ; Motor Neuron Disease/*complications ; Noninvasive Ventilation/*methods ; Palliative Care ; Quadriplegia/*complications ; Respiratory Insufficiency/etiology/*therapy ; Ventilation ; }, abstract = {Withdrawing invasive ventilation from a person with motor neurone disease who lacks the relevant mental capacity raises ethical issues such as the withdrawal of life-sustaining treatment and establishing best interests. There is little available information on providing optimal symptom management to these patients during the withdrawal process. We describe a man with motor neurone disease who also had total locked-in syndrome at the time of ventilation withdrawal, and we document the legal, ethical, emotional and symptom control issues encountered in supporting him.}, }
@article {pmid28422386, year = {2018}, author = {Fujiwara, K and Hida, S and Yasui, S and Yokosuka, O and Oda, S}, title = {Corticosteroid might reduce serum levels of pro-inflammatory cytokines in fulminant hepatitis: A case series.}, journal = {Hepatology research : the official journal of the Japan Society of Hepatology}, volume = {48}, number = {1}, pages = {106-112}, doi = {10.1111/hepr.12906}, pmid = {28422386}, issn = {1386-6346}, abstract = {AIM: There are no beneficial therapies except for emergency liver transplantation for acute liver failure (ALF). However, in Japan, which has a serious problem in the shortage of donor livers, therapies other than transplantation must be further investigated for patients with ALF. Pro-inflammatory cytokines promoting tissue destruction are predominant at an early phase of ALF. Corticosteroid (CS) influences monocyte/macrophage differentiation, by suppressing pro-inflammatory genes, indicating CS treatment might be beneficial during the early phase of ALF. Our aim was to elucidate the efficacy of CS pulse therapy in decreasing pro-inflammatory cytokine levels in the early stage of ALF.<br><br>METHODS: Ten consecutive adult Japanese patients with fulminant hepatitis in the early stage, three treated with artificial liver support (ALS) and CS pulse therapy (ALS&#x2009;+&#x2009;CS group) and seven treated with ALS (ALS group), were enrolled. Clinical and biochemical data on admission were matched between the groups and retrospectively analyzed for serum concentrations of interleukin-6, tumor necrosis factor-&#x3b1;, and interleukin-1&#x3b2; over a 2-week period.<br><br>RESULTS: Mean cytokine levels on admission were not different between the two groups. Tumor necrosis factor-&#x3b1; was significantly reduced on day 7 in patients with CS. Serum levels of pro-inflammatory cytokines tended to be reduced in patients with CS compared to those without during the observation period, although the differences were not significant.<br><br>CONCLUSIONS: It might be possible that introduction of CS pulse therapy in the early stage of ALF could reduce levels of pro-inflammatory cytokines, which might inhibit the cascade of progression of ALF.}, }
@article {pmid28420986, year = {2017}, author = {Roser, AE and Tönges, L and Lingor, P}, title = {Modulation of Microglial Activity by Rho-Kinase (ROCK) Inhibition as Therapeutic Strategy in Parkinson's Disease and Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {9}, number = {}, pages = {94}, pmid = {28420986}, issn = {1663-4365}, abstract = {Neurodegenerative diseases are characterized by the progressive degeneration of neurons in the central and peripheral nervous system (CNS, PNS), resulting in a reduced innervation of target structures and a loss of function. A shared characteristic of many neurodegenerative diseases is the infiltration of microglial cells into affected brain regions. During early disease stages microglial cells often display a rather neuroprotective phenotype, but switch to a more pro-inflammatory neurotoxic phenotype in later stages of the disease, contributing to the neurodegeneration. Activation of the Rho kinase (ROCK) pathway appears to be instrumental for the modulation of the microglial phenotype: increased ROCK activity in microglia mediates mechanisms of the inflammatory response and is associated with improved motility, increased production of reactive oxygen species (ROS) and release of inflammatory cytokines. Recently, several studies suggested inhibition of ROCK signaling as a promising treatment option for neurodegenerative diseases. In this review article, we discuss the contribution of microglial activity and phenotype switch to the pathophysiology of Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS), two devastating neurodegenerative diseases without disease-modifying treatment options. Furthermore, we describe how ROCK inhibition can influence the microglial phenotype in disease models and explore ROCK inhibition as a future treatment option for PD and ALS.}, }
@article {pmid28420164, year = {2017}, author = {Kim, J and Lee, H and Lim, J and Oh, J and Shin, SS and Yoon, M}, title = {The Angiogenesis Inhibitor ALS-L1023 from Lemon-Balm Leaves Attenuates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease through Regulating the Visceral Adipose-Tissue Function.}, journal = {International journal of molecular sciences}, volume = {18}, number = {4}, pages = {}, pmid = {28420164}, issn = {1422-0067}, mesh = {Adipocytes/drug effects/metabolism ; Angiogenesis Inhibitors/*pharmacology ; Animals ; Biomarkers ; Diet, High-Fat/*adverse effects ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; Humans ; Intra-Abdominal Fat/*drug effects/*metabolism ; Lipid Metabolism/drug effects ; Lipids/blood ; Male ; Melissa/chemistry ; Mice ; Neovascularization, Physiologic/drug effects ; Non-alcoholic Fatty Liver Disease/drug therapy/*etiology/*metabolism/pathology ; Organ Size/drug effects ; Plant Extracts/chemistry/*pharmacology ; Plant Leaves/chemistry ; }, abstract = {Similar to neoplastic tissues, growth and development of adipose tissue are thought to be angiogenesis-dependent. Since visceral adipose tissue (VAT) is associated with development and progression of nonalcoholic fatty liver disease (NAFLD), we hypothesized that angiogenesis inhibition would attenuate obesity-induced NAFLD. We fed C57BL/6J mice a low-fat diet (LFD, chow 10% kcal fat), a high-fat diet (HFD, 45% kcal fat) or HFD supplemented with the lemon-balm extract ALS-L1023 (HFD-ALS) for 15 weeks. ALS-L1023 reduced endothelial cell-tube formation in vitro. HFD increased VAT angiogenesis and induced weight gains including body weight, VAT mass and visceral adipocyte size compared with LFD. However, HFD-ALS led to weight reductions without affecting calorie intake compared with HFD. HFD-ALS also reduced serum ALT and AST levels and improved lipid metabolism. HFD-ALS suppressed steatosis, infiltration of inflammatory cells, and accumulation of collagen in livers. HFD-ALS modulated hepatic expression of genes involved in lipid metabolism, inflammation, fibrosis, antioxidation, and apoptosis. Concomitantly, analysis of VAT function revealed that HFD-ALS led to fewer CD68-positive macrophage numbers and lower expression of inflammatory cytokines compared with HFD. Our findings show that the anti-angiogenic herbal extract ALS-L1023 attenuates NAFLD by targeting VAT during obesity, suggesting that angiogenesis inhibitors could aid in the treatment and prevention of obesity-induced human NAFLD.}, }
@article {pmid28416816, year = {2017}, author = {Gonzales, DL and Badhiwala, KN and Vercosa, DG and Avants, BW and Liu, Z and Zhong, W and Robinson, JT}, title = {Scalable electrophysiology in intact small animals with nanoscale suspended electrode arrays.}, journal = {Nature nanotechnology}, volume = {12}, number = {7}, pages = {684-691}, pmid = {28416816}, issn = {1748-3395}, support = {P40 OD010440/OD/NIH HHS/United States ; R01 DA018341/DA/NIDA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; *Caenorhabditis elegans ; Disease Models, Animal ; Electrodes ; *Hydra ; *Lab-On-A-Chip Devices ; }, abstract = {Electrical measurements from large populations of animals would help reveal fundamental properties of the nervous system and neurological diseases. Small invertebrates are ideal for these large-scale studies; however, patch-clamp electrophysiology in microscopic animals typically requires invasive dissections and is low-throughput. To overcome these limitations, we present nano-SPEARs: suspended electrodes integrated into a scalable microfluidic device. Using this technology, we have made the first extracellular recordings of body-wall muscle electrophysiology inside an intact roundworm, Caenorhabditis elegans. We can also use nano-SPEARs to record from multiple animals in parallel and even from other species, such as Hydra littoralis. Furthermore, we use nano-SPEARs to establish the first electrophysiological phenotypes for C. elegans models for amyotrophic lateral sclerosis and Parkinson's disease, and show a partial rescue of the Parkinson's phenotype through drug treatment. These results demonstrate that nano-SPEARs provide the core technology for microchips that enable scalable, in vivo studies of neurobiology and neurological diseases.}, }
@article {pmid28410876, year = {2017}, author = {Lefaucheur, JP and Chalah, MA and Mhalla, A and Palm, U and Ayache, SS and Mylius, V}, title = {The treatment of fatigue by non-invasive brain stimulation.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {47}, number = {2}, pages = {173-184}, doi = {10.1016/j.neucli.2017.03.003}, pmid = {28410876}, issn = {1769-7131}, mesh = {Brain/physiology/*surgery ; Fatigue/complications/*therapy ; Humans ; Multiple Sclerosis/*complications/therapy ; *Pain Management ; *Transcranial Direct Current Stimulation/methods ; Treatment Outcome ; }, abstract = {The use of non-invasive brain neurostimulation (NIBS) techniques to treat neurological or psychiatric diseases is currently under development. Fatigue is a commonly observed symptom in the field of potentially treatable pathologies by NIBS, yet very little data has been published regarding its treatment. We conducted a review of the literature until the end of February 2017 to analyze all the studies that reported a clinical assessment of the effects of NIBS techniques on fatigue. We have limited our analysis to repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). We found only 15 studies on this subject, including 8 tDCS studies and 7 rTMS studies. Of the tDCS studies, 6 concerned patients with multiple sclerosis while 6 rTMS studies concerned fibromyalgia or chronic fatigue syndrome. The remaining 3 studies included patients with post-polio syndrome, Parkinson's disease and amyotrophic lateral sclerosis. Three cortical regions were targeted: the primary sensorimotor cortex, the dorsolateral prefrontal cortex and the posterior parietal cortex. In all cases, tDCS protocols were performed according to a bipolar montage with the anode over the cortical target. On the other hand, rTMS protocols consisted of either high-frequency phasic stimulation or low-frequency tonic stimulation. The results available to date are still too few, partial and heterogeneous as to the methods applied, the clinical profile of the patients and the variables studied (different fatigue scores) in order to draw any conclusion. However, the effects obtained, especially in multiple sclerosis and fibromyalgia, are really carriers of therapeutic hope.}, }
@article {pmid28406335, year = {2017}, author = {Sawada, H}, title = {Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert opinion on pharmacotherapy}, volume = {18}, number = {7}, pages = {735-738}, doi = {10.1080/14656566.2017.1319937}, pmid = {28406335}, issn = {1744-7666}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Antipyrine/*analogs &amp; derivatives/therapeutic use ; Disease Models, Animal ; Edaravone ; Free Radical Scavengers/*therapeutic use ; Humans ; Randomized Controlled Trials as Topic ; Time Factors ; Treatment Outcome ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disease. Although the pathogenesis remains unresolved, oxidative stress is known to play a pivotal role. Edaravone works in the central nervous system as a potent scavenger of oxygen radicals. In ALS mouse models, edaravone suppresses motor functional decline and nitration of tyrosine residues in the cerebrospinal fluid. Areas covered: Three clinical trials, one phase II open-label trial, and two phase III placebo-control randomized trials were reviewed. In all trials, the primary outcome measure was the changes in scores on the revised ALS functional rating scale (ALSFRS-R) to evaluate motor function of patients. Expert opinion: The phase II open label trial suggested that edaravone is safe and effective in ALS, markedly reducing 3-nitrotyrosine levels in the cerebrospinal fluid. One of the two randomized controlled trials showed beneficial effects in ALSFRS-R, although the differences were not significant. The last trial demonstrated that edaravone provided significant efficacy in ALSFRS-R scores over 24 weeks where concomitant use of riluzole was permitted. Eligibility was restricted to patients with a relatively short disease duration and preserved vital capacity. Therefore, combination therapy with edaravone and riluzole should be considered earlier.}, }
@article {pmid28405022, year = {2017}, author = {Becker, LA and Huang, B and Bieri, G and Ma, R and Knowles, DA and Jafar-Nejad, P and Messing, J and Kim, HJ and Soriano, A and Auburger, G and Pulst, SM and Taylor, JP and Rigo, F and Gitler, AD}, title = {Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice.}, journal = {Nature}, volume = {544}, number = {7650}, pages = {367-371}, pmid = {28405022}, issn = {1476-4687}, support = {P30 NS069375/NS/NINDS NIH HHS/United States ; R37 NS033123/NS/NINDS NIH HHS/United States ; R21 NS081182/NS/NINDS NIH HHS/United States ; R35 NS097974/NS/NINDS NIH HHS/United States ; R01 NS065317/NS/NINDS NIH HHS/United States ; T32 AG047126/AG/NIA NIH HHS/United States ; R01 NS073660/NS/NINDS NIH HHS/United States ; R01 NS097903/NS/NINDS NIH HHS/United States ; R35 NS097263/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/physiopathology/*therapy ; Animals ; Ataxin-2/*deficiency/genetics ; Central Nervous System/metabolism ; Cytoplasmic Granules/metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Disease Progression ; Female ; Gene Knockdown Techniques ; Humans ; *Longevity ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; Motor Skills/physiology ; Oligonucleotides, Antisense/administration &amp; dosage/genetics/*therapeutic use ; Protein Aggregation, Pathological/genetics/*therapy ; Stress, Physiological ; Survival Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that is characterized by motor neuron loss and that leads to paralysis and death 2-5 years after disease onset. Nearly all patients with ALS have aggregates of the RNA-binding protein TDP-43 in their brains and spinal cords, and rare mutations in the gene encoding TDP-43 can cause ALS. There are no effective TDP-43-directed therapies for ALS or related TDP-43 proteinopathies, such as frontotemporal dementia. Antisense oligonucleotides (ASOs) and RNA-interference approaches are emerging as attractive therapeutic strategies in neurological diseases. Indeed, treatment of a rat model of inherited ALS (caused by a mutation in Sod1) with ASOs against Sod1 has been shown to substantially slow disease progression. However, as SOD1 mutations account for only around 2-5% of ALS cases, additional therapeutic strategies are needed. Silencing TDP-43 itself is probably not appropriate, given its critical cellular functions. Here we present a promising alternative therapeutic strategy for ALS that involves targeting ataxin-2. A decrease in ataxin-2 suppresses TDP-43 toxicity in yeast and flies, and intermediate-length polyglutamine expansions in the ataxin-2 gene increase risk of ALS. We used two independent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model of TDP-43 proteinopathy. First, we crossed ataxin-2 knockout mice with TDP-43 (also known as TARDBP) transgenic mice. The decrease in ataxin-2 reduced aggregation of TDP-43, markedly increased survival and improved motor function. Second, in a more therapeutically applicable approach, we administered ASOs targeting ataxin-2 to the central nervous system of TDP-43 transgenic mice. This single treatment markedly extended survival. Because TDP-43 aggregation is a component of nearly all cases of ALS, targeting ataxin-2 could represent a broadly effective therapeutic strategy.}, }
@article {pmid28401371, year = {2017}, author = {Elmann, A and Telerman, A and Ofir, R and Kashman, Y}, title = {Glutamate Toxicity to Differentiated Neuroblastoma N2a Cells Is Prevented by the Sesquiterpene Lactone Achillolide A and the Flavonoid 3,5,4'-Trihydroxy-6,7,3'-Trimethoxyflavone from Achillea fragrantissima.}, journal = {Journal of molecular neuroscience : MN}, volume = {62}, number = {1}, pages = {99-105}, pmid = {28401371}, issn = {1559-1166}, mesh = {Achillea/*chemistry ; Animals ; Antioxidants/chemistry/*pharmacology ; Cell Line, Tumor ; Flavonoids/chemistry/*pharmacology ; Glutamic Acid/toxicity ; Mice ; Neurons/drug effects ; Neuroprotective Agents/chemistry/*pharmacology ; Sesquiterpenes/chemistry/*pharmacology ; }, abstract = {Glutamate toxicity is a major contributor to the pathophysiology of numerous neurodegenerative diseases including amyotrophic lateral sclerosis and Alzheimer's disease. Therefore, protecting neuronal cells against glutamate-induced cytotoxicity might be an effective approach for the treatment of these diseases. We have previously purified from the medicinal plant Achillea fragrantissima two bioactive compounds which were not studied before: the sesquiterpene lactone achillolide A and the flavonoid 3,5,4'-trihydroxy-6,7,3'-trimethoxyflavone (TTF). We have shown that these compounds protect astrocytes from oxidative stress-induced cell death and inhibit microglial activation. The current study examined for the first time their effects on differentiated mouse neuroblastoma N2a cells and on glutamate toxicity. We have found that, although these compounds belong to different chemical families, they protect neuronal cells from glutamate toxicity. We further demonstrate that this protective effect might be, at least partially, due to inhibitory effects of these compounds on the levels of reactive oxygen species produced following treatment with glutamate.}, }
@article {pmid28400790, year = {2017}, author = {Mathis, S and Couratier, P and Julian, A and Corcia, P and Le Masson, G}, title = {Current view and perspectives in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {12}, number = {2}, pages = {181-184}, pmid = {28400790}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis (ALS), identified as a distinct clinical entity by Charcot since the end of the nineteenth century, is a devastating and fatal neurodegenerative disorder that affects motor neurons in the brain, brainstem and spinal cord. Survival of patients with ALS is associated with several factors such as clinical phenotype, age at onset, gender, early presence of respiratory failure, weight loss and treatment with Riluzole (the only disease-modifying drug approved for this disease). Nowadays, there is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. Nevertheless, the scientific knowledge in the field of ALS motor neuron degeneration is growing, with the prospect of new treatments. Based on this physiopathological knowledge, several new therapeutic targets are being studied, involving various mechanisms such as excitotoxicity, neuroinflammation, mitochondrial dysfunction, oxidative stress, RNA metabolism and other attractive concepts. Moreover, it is also important to identify reliable biomarkers that will be essential components for future therapeutic development and study design in ALS. In this review, we present the main recent advances and promising therapeutics and biomarkers in the field of ALS.}, }
@article {pmid28387998, year = {2017}, author = {Apitz, SE and Vivian, C and Agius, S}, title = {Anatomy of a decision III: Evaluation of national disposal at sea program action level efficacy considering 2 chemical action levels.}, journal = {Integrated environmental assessment and management}, volume = {13}, number = {6}, pages = {1086-1099}, doi = {10.1002/ieam.1940}, pmid = {28387998}, issn = {1551-3793}, mesh = {Canada ; Ecotoxicology ; *Environmental Monitoring ; Geologic Sediments ; Hazardous Waste/*analysis/statistics &amp; numerical data ; Risk Assessment ; Waste Management/*methods/standards ; Water Pollutants, Chemical/*analysis/standards/toxicity ; }, abstract = {The potential performance (i.e., ability to separate nontoxic from toxic sediments) of a range of international Disposal at Sea (DaS) chemical Action Levels (ALs) was compared using a sediment chemical and toxicological database. The use of chemistry alone (without the use of further lines of evidence) did not perform well at reducing costs and protecting the environment. Although some approaches for interpreting AL1 results are very effective at filtering out the majority of acutely toxic sediments, without subsequent toxicological assessment, a large proportion of nontoxic sediments would be unnecessarily subjected to treatment and containment, and a number of sublethally toxic sediments would be missed. Even the best tiered systems that collect and evaluate information sequentially resulted in the failure to catch at least some sublethally or acutely toxic sediments. None of the AL2s examined were particularly effective in distinguishing between non-, sublethally, or acutely toxic sediments. Thus, this review did not support the use of chemical AL2s to predict the degree to which sediments will be toxic. Integr Environ Assess Manag 2017;13:1086-1099.© 2017 The Authors. Integrated Environmental Assessment and Management Published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology &amp; Chemistry (SETAC).}, }
@article {pmid28387380, year = {2017}, author = {Eleuteri, C and Olla, S and Veroni, C and Umeton, R and Mechelli, R and Romano, S and Buscarinu, MC and Ferrari, F and Calò, G and Ristori, G and Salvetti, M and Agresti, C}, title = {A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials.}, journal = {Scientific reports}, volume = {7}, number = {}, pages = {45780}, pmid = {28387380}, issn = {2045-2322}, mesh = {Animals ; Cell Differentiation ; Cell Proliferation ; Clinical Trials as Topic ; Drug Evaluation, Preclinical/*methods ; Mice ; Myelin Sheath/drug effects ; Neuroprotective Agents/*therapeutic use ; Oligodendrocyte Precursor Cells/*drug effects/metabolism ; *Remyelination ; }, abstract = {There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds' activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.}, }
@article {pmid28386317, year = {2017}, author = {Liu, Z and Wang, F and Zhou, ZW and Xia, HC and Wang, XY and Yang, YX and He, ZX and Sun, T and Zhou, SF}, title = {Alisertib induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt/mTOR- and p38 MAPK-mediated pathways in human glioblastoma cells.}, journal = {American journal of translational research}, volume = {9}, number = {3}, pages = {845-873}, pmid = {28386317}, issn = {1943-8141}, abstract = {Glioblastoma (GBM) is the most common brain tumor with poor response to current therapeutics. Alisertib (ALS), a second-generation selective Aurora kinase A (AURKA) inhibitor, has shown potent anticancer effects on solid tumors in animal studies. This study aimed to investigate the killing effect of ALS on GBM cell line DAOY and the possible underlying mechanisms using both bioinformatic and cell-based approaches. Our molecular docking showed that ALS preferentially bound AURKA over AURKB via hydrogen bond formation, charge interaction, and π-π stacking. ALS also bound key regulating proteins of cell cycle, apoptosis and autophagy, such as cyclin-dependent kinase 1 (CDK1/CDC2), CDK2, cyclin B1, p27 Kip1, p53, cytochrome C, cleaved caspase 3, Bax, Bcl-2, Bcl-xl, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), 5'-adenosine monophosphate-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (MAPK), beclin 1, phosphatase and tensin homolog (PTEN), and microtubule-associated protein light chain 3 (LC3). ALS exhibited potent growth-inhibitory, pro-apoptotic, and pro-autophagic effects on DAOY cells in a concentration-dependent manner. Notably, ALS remarkably induced G2/M arrest mainlyvia regulating the expression of CDK1/CDC2, CDK2, cyclin B1, p27 Kip1, and p53 in DAOY cells. ALS significantly induced the expression of mitochondria-mediated pro-apoptotic proteins such as Baxbut inhibited the expression of anti-apoptotic proteins such as Bcl-2 and Bcl-xl, with a significant increase in the release of cytochrome C and the activation of caspases 3 and 9. ALS also induced PI3K/Akt/mTOR and p38 MAPK signaling pathways while activating the AMPK signaling pathway. Taken together, these findings indicate that ALS exerts a potent inhibitory effect on cell proliferation and induces mitochondria-dependent apoptosis and autophagy with the involvement of PI3K/Akt/mTOR- and p38 MAPK-mediated signaling pathways in DAOY cells. ALS is a promising anticancer agent for GBM treatment.}, }
@article {pmid28386082, year = {2017}, author = {Wei, CC and Kong, YY and Li, GQ and Guan, YF and Wang, P and Miao, CY}, title = {Nicotinamide mononucleotide attenuates brain injury after intracerebral hemorrhage by activating Nrf2/HO-1 signaling pathway.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {717}, pmid = {28386082}, issn = {2045-2322}, support = {R21 AA020943/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Biomarkers ; Brain Injuries/drug therapy/*etiology/*metabolism/pathology ; Cell Death/drug effects ; Cerebral Hemorrhage/*complications ; Disease Models, Animal ; Heme Oxygenase-1/*metabolism ; Immunohistochemistry ; Inflammation Mediators/metabolism ; Mice ; Microglia/metabolism ; NAD/metabolism ; NF-E2-Related Factor 2/*metabolism ; Neuroprotection/drug effects ; Neutrophil Infiltration ; Nicotinamide Mononucleotide/*pharmacology ; Oxidative Stress/drug effects ; Protective Agents/pharmacology ; Signal Transduction/*drug effects ; Time Factors ; }, abstract = {Replenishment of NAD[+] has been shown to protect against brain disorders such as amyotrophic lateral sclerosis and ischemic stroke. However, whether this intervention has therapeutic effects in intracerebral hemorrhage (ICH) is unknown. In this study, we sought to determine the potential therapeutic value of replenishment of NAD[+] in ICH. In a collagenase-induced ICH (cICH) mouse model, nicotinamide mononucleotide (NMN), a key intermediate of nicotinamide adenine dinucleotide (NAD[+]) biosynthesis, was administrated at 30 minutes post cICH from tail vein to replenish NAD[+]. NMN treatment did not decrease hematoma volume and hemoglobin content. However, NMN treatment significantly reduced brain edema, brain cell death, oxidative stress, neuroinflammation, intercellular adhesion molecule-1 expression, microglia activation and neutrophil infiltration in brain hemorrhagic area. Mechanistically, NMN enhanced the expression of two cytoprotective proteins: heme oxygenase 1 (HO-1) and nuclear factor-like 2 (Nrf2). Moreover, NMN increased the nuclear translocation of Nrf2 for its activation. Finally, a prolonged NMN treatment for 7 days markedly promoted the recovery of body weight and neurological function. These results demonstrate that NMN treats brain injury in ICH by suppressing neuroinflammation/oxidative stress. The activation of Nrf2/HO-1 signaling pathway may contribute to the neuroprotection of NMN in ICH.}, }
@article {pmid28384752, year = {2017}, author = {Lunetta, C and Lizio, A and Maestri, E and Sansone, VA and Mora, G and Miller, RG and Appel, SH and Chiò, A}, title = {Serum C-Reactive Protein as a Prognostic Biomarker in Amyotrophic Lateral Sclerosis.}, journal = {JAMA neurology}, volume = {74}, number = {6}, pages = {660-667}, pmid = {28384752}, issn = {2168-6157}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*blood/*drug therapy ; Biomarkers/blood ; C-Reactive Protein/*metabolism ; *Disease Progression ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Immunologic Factors/administration &amp; dosage/*pharmacology ; Male ; Middle Aged ; *Registries ; }, abstract = {IMPORTANCE: Various factors have been proposed as possible candidates associated with the prognosis of amyotrophic lateral sclerosis (ALS); however, there is still no consensus on which biomarkers are reliable prognostic factors. C-reactive protein (CRP) is a biomarker of the inflammatory response that shows significant prognostic value for several diseases.<br><br>OBJECTIVE: To examine the prognostic significance of CRP in ALS.<br><br>Patients' serum CRP levels were evaluated from January 1, 2009, to June 30, 2015, in a large cohort of patients with ALS observed by an Italian tertiary multidisciplinary center. Results were replicated in an independent cohort obtained from a population-based registry of patients with ALS. A post hoc analysis was performed of the phase 2 trial of NP001 to determine whether stratification by levels of CRP improves differentiation of responders and nonresponders to the drug.<br><br>MAIN OUTCOMES AND MEASURES: Serum CRP levels from the first examination were recorded to assess their effect on disease progression and survival.<br><br>RESULTS: A total of 394 patients with ALS (168 women and 226 men; mean [SD] age at diagnosis, 60.18 [13.60] years) were observed in a tertiary multidisciplinary center, and the analysis was replicated in an independent cohort of 116 patients with ALS (50 women and 66 men; mean [SD] age at diagnosis, 67.00 [10.74] years) identified through a regional population-based registry. Serum CRP levels in the 394 patients with ALS correlated with severity of functional impairment, as measured by total score on the ALS Functional Rating Scale-Revised, at first evaluation (r&#x2009;=&#x2009;-0.14818; P&#x2009;=&#x2009;.004), and with patient survival (hazard ratio, 1.129; 95% CI, 1.033-1.234; P&#x2009;=&#x2009;.007). Similar results were found in the independent cohort (hazard ratio, 1.044; 95% CI, 1.016-1.056; P&#x2009;&#x2264;&#x2009;.001). Moreover, a post hoc analysis of the phase 2 trial of NP001 using the same CRP threshold showed that patients with elevated baseline CRP levels receiving the higher dose of NP001 had significantly less functional impairment after the treatment period compared with patients with normal baseline CRP, regardless of whether patients with normal CRP levels received NP001 or placebo (3.00 [3.62] vs -7.31 [6.23]; P&#x2009;=&#x2009;.04).<br><br>CONCLUSIONS AND RELEVANCE: These findings suggest that patients with ALS and elevated serum CRP levels progress more rapidly than do those with lower CRP levels and that this elevation may reflect a neuroinflammatory state potentially responsive to the immune regulators such as NP001.}, }
@article {pmid28382594, year = {2017}, author = {Shao, L and Yu, S and Ji, W and Li, H and Gao, Y}, title = {The Contribution of Necroptosis in Neurodegenerative Diseases.}, journal = {Neurochemical research}, volume = {42}, number = {8}, pages = {2117-2126}, pmid = {28382594}, issn = {1573-6903}, mesh = {Animals ; Apoptosis/*physiology ; Humans ; Necrosis/metabolism/pathology ; Neurodegenerative Diseases/*metabolism/*pathology ; Signal Transduction/physiology ; }, abstract = {Over the past decades, cell apoptosis has been significantly reputed as an accidental, redundant and alternative manner of cell demise which partakes in homeostasis in the development of extensive diseases. Nevertheless, necroptosis, another novel manner of cell death through a caspase-independent way, especially in neurodegenerative diseases remains ambiguous. The cognition of this form of cell demise is helpful to understand other forms of morphological resemblance of necrosis. Additionally, the concrete signal mechanism in the regulation of necroptosis is beneficial to the diagnosis and treatment of neurodegenerative diseases. Recent studies have demonstrated that necroptotic inhibitor, 24(S)-Hydroxycholesterol and partial specific histone deacetylase inhibitors could alleviate pathogenetic conditions of neurodegenerative diseases via necroptosis pathway. In this review, we summarize recent researches about mechanisms and modulation of necroptotic signaling pathways and probe into the role of programmed necroptotic cell demise in neurodegenerative diseases such as Parkinson's disease, Multiple sclerosis, Amyotrophic lateral sclerosis.}, }
@article {pmid28382000, year = {2017}, author = {Petrov, D and Mansfield, C and Moussy, A and Hermine, O}, title = {ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?.}, journal = {Frontiers in aging neuroscience}, volume = {9}, number = {}, pages = {68}, pmid = {28382000}, issn = {1663-4365}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating condition with an estimated mortality of 30,000 patients a year worldwide. The median reported survival time since onset ranges from 24 to 48 months. Riluzole is the only currently approved mildly efficacious treatment. Riluzole received marketing authorization in 1995 in the USA and in 1996 in Europe. In the years that followed, over 60 molecules have been investigated as a possible treatment for ALS. Despite significant research efforts, the overwhelming majority of human clinical trials (CTs) have failed to demonstrate clinical efficacy. In the past year, oral masitinib and intravenous edaravone have emerged as promising new therapeutics with claimed efficacy in CTs in ALS patients. Given their advanced phase of clinical development one may consider these drugs as the most likely near-term additions to the therapeutic arsenal available for patients with ALS. In terms of patient inclusion, CT with masitinib recruited a wider, more representative, less restrictive patient population in comparison to the only successful edaravone CT (edaravone eligibility criteria represents only 18% of masitinib study patients). The present manuscript reviews >50 CTs conducted in the last 20 years since riluzole was first approved. A special emphasis is put on the analysis of existing evidence in support of the clinical efficacy of edaravone and masitinib and the possible implications of an eventual marketing authorisation in the treatment of ALS.}, }
@article {pmid28381746, year = {2017}, author = {Inoue, Y and Murakami, T and Nakamura, T and Morita, K and Kaneda, D and Nishino, I and Hayashi, T and Shinoto, Y and Hatoko, T and Kato, T and Yonemitsu, S and Muro, S and Oki, S}, title = {Syndrome of Inappropriate Antidiuretic Hormone Secretion Associated with Amyotrophic Lateral Sclerosis in a Patient Developing Carbon Dioxide Narcosis.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {56}, number = {7}, pages = {797-803}, pmid = {28381746}, issn = {1349-7235}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications ; Carbon Dioxide/*adverse effects ; Humans ; Hyponatremia/complications ; Inappropriate ADH Syndrome/*complications ; Inert Gas Narcosis/*complications ; Male ; Osmolar Concentration ; }, abstract = {We report a rare case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) associated with amyotrophic lateral sclerosis (ALS). A 69-year-old man was admitted to our hospital with sustained hyponatremia. Hyposmolality with elevated urinary osmolality and sodium excretion was observed, which indicated SIADH. The treatment for SIADH was challenging; the patient developed carbon dioxide narcosis, which led to the diagnosis of ALS. After the initiation of noninvasive positive-pressure ventilation, the patient's serum sodium concentration normalized and became stable. Thus, ALS should be recognized as a possible cause of SIADH in the clinical setting.}, }
@article {pmid28380322, year = {2017}, author = {Libonati, L and Onesti, E and Gori, MC and Ceccanti, M and Cambieri, C and Fabbri, A and Frasca, V and Inghilleri, M}, title = {Vitamin D in amyotrophic lateral sclerosis.}, journal = {Functional neurology}, volume = {32}, number = {1}, pages = {35-40}, pmid = {28380322}, issn = {1971-3274}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*blood/*diagnosis/prevention &amp; control ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Vitamin D/*blood/therapeutic use ; }, abstract = {Vitamin D supplementation has been proposed as a potential treatment to delay amyotrophic lateral sclerosis (ALS) progression. The aims of this study were to compare retrospectively vitamin D blood levels in ALS patients with those in healthy subjects; to correlate vitamin D blood levels with clinical functions in patients; and to evaluate whether administration of vitamin D could modify the clinical progression of the disease. Vitamin D blood levels were evaluated in 57ALS patients and in 57 healthy subjects. In the ALS patients the following clinical variables were evaluated every 3 months: Medical Research Council scale (MRC) score; revised ALS functional rating scale (ALSFRS-R) score; forced vital capacity (FVC). Twentyfour patients were treated with high doses of cholecalciferol. No significant differences were found between the vitamin D blood levels in the ALS patients (18.8 ± 12.2) and the healthy subjects (20.7 ± 10.1). The vitamin D levels in the ALS patientsdid not correlate with recorded clinical parameters. No clinical differences in terms of ALSFRS-R, MRC or FVC were found between the treated and the untreated patients over time. In ALS, as in other chronic neurological diseases, levels of vitamin D in blood appeared reduced, but no difference was found between the levels in ALS patients and in healthy subjects. Oral vitamin D supplementation in ALS patients was not associated with better prognosis in comparison with untreated ALS patients. Further prospective controlled studies are needed to clarify the effect of vitamin D on the progression of ALS disease.}, }
@article {pmid28377696, year = {2017}, author = {Bonafede, R and Mariotti, R}, title = {ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles.}, journal = {Frontiers in cellular neuroscience}, volume = {11}, number = {}, pages = {80}, pmid = {28377696}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle paralysis determined by the degeneration of motoneurons in the motor cortex brainstem and spinal cord. The ALS pathogenetic mechanisms are still unclear, despite the wealth of studies demonstrating the involvement of several altered signaling pathways, such as mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress and neuroinflammation. To date, the proposed therapeutic strategies are targeted to one or a few of these alterations, resulting in only a minimal effect on disease course and survival of ALS patients. The involvement of different mechanisms in ALS pathogenesis underlines the need for a therapeutic approach targeted to multiple aspects. Mesenchymal stem cells (MSC) can support motoneurons and surrounding cells, reduce inflammation, stimulate tissue regeneration and release growth factors. On this basis, MSC have been proposed as promising candidates to treat ALS. However, due to the drawbacks of cell therapy, the possible therapeutic use of extracellular vesicles (EVs) released by stem cells is raising increasing interest. The present review summarizes the main pathological mechanisms involved in ALS and the related therapeutic approaches proposed to date, focusing on MSC therapy and their preclinical and clinical applications. Moreover, the nature and characteristics of EVs and their role in recapitulating the effect of stem cells are discussed, elucidating how and why these vesicles could provide novel opportunities for ALS treatment.}, }
@article {pmid28373073, year = {2017}, author = {Pasquarelli, N and Engelskirchen, M and Hanselmann, J and Endres, S and Porazik, C and Bayer, H and Buck, E and Karsak, M and Weydt, P and Ferger, B and Witting, A}, title = {Evaluation of monoacylglycerol lipase as a therapeutic target in a transgenic mouse model of ALS.}, journal = {Neuropharmacology}, volume = {124}, number = {}, pages = {157-169}, doi = {10.1016/j.neuropharm.2017.03.037}, pmid = {28373073}, issn = {1873-7064}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Arachidonic Acids/pharmacology ; Arginase/metabolism ; Benzodioxoles/pharmacology/*therapeutic use ; Brain-Derived Neurotrophic Factor/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Endocannabinoids/pharmacology ; Female ; Glycerides/pharmacology ; Male ; Mice ; Mice, Transgenic ; Molecular Targeted Therapy/*methods ; Monoacylglycerol Lipases/*antagonists &amp; inhibitors ; Neuroglia/metabolism ; Neurons/metabolism ; Piperidines/pharmacology/*therapeutic use ; Primary Cell Culture ; Spinal Cord/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neuron system with limited therapeutic options. While an increasing number of ALS patients can be linked to a small number of autosomal-dominantly inherited cases, most cases are termed sporadic. Both forms are clinically and histopathologically indistinguishable, raising the prospect that they share key pathogenic steps, including potential therapeutic intervention points. The endocannabinoid system is emerging as a versatile, druggable therapeutic target in the CNS and its dysregulation is an early hallmark of neurodegeneration. Whether this is a defense mechanism or part of the pathogenesis remains to be determined. The neuroprotective and anti-inflammatory endocannabinoid 2-arachidonoylglycerol (2-AG), which is degraded by monoacylglycerol lipase (MAGL), accumulates in the spinal cords of transgenic models of ALS. We tested the hypothesis that this 2-AG increase is a protective response in the low-copy SOD1[G93A] mouse model of ALS. We show that oral application of the MAGL inhibitor KML29 delays disease onset, progression and survival. Furthermore, we could demonstrate that KML29 reduced proinflammatory cytokines and increased brain-derived neurotrophic factor (BDNF) expression levels in the spinal cord, the major site of neurodegeneration in ALS. Moreover, treatment of primary mouse neurons and primary mousecroglia with 2-AG confirmed the neuroprotective and anti-inflammatory action by increasing BDNF and arginase-1 and decreasing proinflammatory cytokines in vitro. In summary, we show that elevating 2-AG levels by MAGL inhibition is a therapeutic target in ALS and demonstrate that the endocannabinoid defense mechanisms can be exploited therapeutically in neurodegenerative diseases. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".}, }
@article {pmid28359145, year = {2017}, author = {Jeon, YM and Lee, S and Kim, S and Kwon, Y and Kim, K and Chung, CG and Lee, S and Lee, SB and Kim, HJ}, title = {Neuroprotective Effects of Protein Tyrosine Phosphatase 1B Inhibition against ER Stress-Induced Toxicity.}, journal = {Molecules and cells}, volume = {40}, number = {4}, pages = {280-290}, pmid = {28359145}, issn = {0219-1032}, mesh = {Animals ; Cell Death ; Cerebral Cortex/enzymology ; Down-Regulation ; Drosophila/enzymology ; Endoplasmic Reticulum Stress/*drug effects ; Eukaryotic Initiation Factor-2/drug effects ; Humans ; Leupeptins/pharmacology ; Mice ; Neurodegenerative Diseases/*enzymology ; Neurons/*drug effects/enzymology ; *Neuroprotection ; Phosphorylation ; Protein Tyrosine Phosphatase, Non-Receptor Type 1/*antagonists &amp; inhibitors ; Reactive Oxygen Species/metabolism ; Rotenone/pharmacology ; Tumor Cells, Cultured ; Uncoupling Agents/pharmacology ; eIF-2 Kinase/drug effects ; }, abstract = {Several lines of evidence suggest that endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Protein tyrosine phosphatase 1B (PTP1B) is known to regulate the ER stress signaling pathway, but its role in neuronal systems in terms of ER stress remains largely unknown. Here, we showed that rotenone-induced toxicity in human neuroblastoma cell lines and mouse primary cortical neurons was ameliorated by PTP1B inhibition. Moreover, the increase in the level of ER stress markers (eIF2α phosphorylation and PERK phosphorylation) induced by rotenone treatment was obviously suppressed by concomitant PTP1B inhibition. However, the rotenone-induced production of reactive oxygen species (ROS) was not affected by PTP1B inhibition, suggesting that the neuroprotective effect of the PTP1B inhibitor is not associated with ROS production. Moreover, we found that MG132-induced toxicity involving proteasome inhibition was also ameliorated by PTP1B inhibition in a human neuroblastoma cell line and mouse primary cortical neurons. Consistently, downregulation of the PTP1B homologue gene in Drosophila mitigated rotenone- and MG132-induced toxicity. Taken together, these findings indicate that PTP1B inhibition may represent a novel therapeutic approach for ER stress-mediated neurodegenerative diseases.}, }
@article {pmid28356511, year = {2017}, author = {Gendron, TF and Chew, J and Stankowski, JN and Hayes, LR and Zhang, YJ and Prudencio, M and Carlomagno, Y and Daughrity, LM and Jansen-West, K and Perkerson, EA and O'Raw, A and Cook, C and Pregent, L and Belzil, V and van Blitterswijk, M and Tabassian, LJ and Lee, CW and Yue, M and Tong, J and Song, Y and Castanedes-Casey, M and Rousseau, L and Phillips, V and Dickson, DW and Rademakers, R and Fryer, JD and Rush, BK and Pedraza, O and Caputo, AM and Desaro, P and Palmucci, C and Robertson, A and Heckman, MG and Diehl, NN and Wiggs, E and Tierney, M and Braun, L and Farren, J and Lacomis, D and Ladha, S and Fournier, CN and McCluskey, LF and Elman, LB and Toledo, JB and McBride, JD and Tiloca, C and Morelli, C and Poletti, B and Solca, F and Prelle, A and Wuu, J and Jockel-Balsarotti, J and Rigo, F and Ambrose, C and Datta, A and Yang, W and Raitcheva, D and Antognetti, G and McCampbell, A and Van Swieten, JC and Miller, BL and Boxer, AL and Brown, RH and Bowser, R and Miller, TM and Trojanowski, JQ and Grossman, M and Berry, JD and Hu, WT and Ratti, A and Traynor, BJ and Disney, MD and Benatar, M and Silani, V and Glass, JD and Floeter, MK and Rothstein, JD and Boylan, KB and Petrucelli, L}, title = {Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis.}, journal = {Science translational medicine}, volume = {9}, number = {383}, pages = {}, pmid = {28356511}, issn = {1946-6242}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; DP1 NS096898/NS/NINDS NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; R21 NS089979/NS/NINDS NIH HHS/United States ; R01 NS085207/NS/NINDS NIH HHS/United States ; K23 AG042856/AG/NIA NIH HHS/United States ; P01 AG017586/AG/NIA NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; R25 NS065729/NS/NINDS NIH HHS/United States ; R01 NS078398/NS/NINDS NIH HHS/United States ; R01 NS088689/NS/NINDS NIH HHS/United States ; Z01 AG000949//Intramural NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R21 NS084528/NS/NINDS NIH HHS/United States ; U54 NS092089/NS/NINDS NIH HHS/United States ; U54 NS091046/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/*genetics/pathology ; Animals ; Biomarkers/*metabolism ; Brain/metabolism/pathology ; C9orf72 Protein/*genetics ; Cell Line ; Dinucleotide Repeats/*genetics ; Humans ; Induced Pluripotent Stem Cells/drug effects/metabolism ; Leukocytes, Mononuclear/drug effects/metabolism ; Longitudinal Studies ; Mice ; Middle Aged ; Neurons/metabolism ; Oligonucleotides, Antisense/pharmacology ; Prognosis ; RNA/genetics ; }, abstract = {There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.}, }
@article {pmid28355734, year = {2017}, author = {Wang, W and Wang, Y and Wang, D and Zhao, Y and Liu, H and Yang, XY and Zhu, SG and Xiao, FS and Wei, W and Zhu, T and Yang, XJ and Zhang, JN}, title = {[Application of hybrid operating room in the treatment of spinal dural arteriovenous fistulas].}, journal = {Zhonghua yi xue za zhi}, volume = {97}, number = {11}, pages = {814-816}, doi = {10.3760/cma.j.issn.0376-2491.2017.11.004}, pmid = {28355734}, issn = {0376-2491}, mesh = {Angiography, Digital Subtraction ; *Central Nervous System Vascular Malformations ; Humans ; Neurosurgery ; Neurosurgical Procedures ; *Operating Rooms ; Retrospective Studies ; Spinal Cord ; Spinal Cord Diseases ; }, abstract = {Objective: To explore the experience in the treatment of spinal dural arteriovenous fistulas with application of hybrid operating room. Method: A retrospective analysis was performed among 22 patients with spinal dural arteriovenous fistulas admitted to Department of Neurosurgery of Tianjin Medical University General Hospital who received operation in the hybrid operating room from March 2011 to February 2016. Modified Aminoff-Logue scores (ALS) for myelopathy was used to evaluate the spinal function.All the 22 patients were followed up 6-12 months after the operation. Result: All the patients were diagnosed by spinal digital subtraction angiography (DSA). The modified ALS pre-operation and post-operation 6 months were (4.7±1.8) and (2.0±1.5), respectively, with significant difference (P<0.01). There were 15 cases with mild dysfunction, 6 cases with moderate dysfunction, severe dysfunction in 1 case before operation.Fifteen cases were cured, 4 cases improved, 1 case had no change after 6 months follow-up.The improvement rate was 95.45%. Conclusion: The application of hybrid operating room in the treatment of spinal dural arteriovenous fistulas achieves good outcome and provides a convenient and effective approach, which embodies the idea of precision medicine.}, }
@article {pmid28351931, year = {2017}, author = {Zhou, Q and Lehmer, C and Michaelsen, M and Mori, K and Alterauge, D and Baumjohann, D and Schludi, MH and Greiling, J and Farny, D and Flatley, A and Feederle, R and May, S and Schreiber, F and Arzberger, T and Kuhm, C and Klopstock, T and Hermann, A and Haass, C and Edbauer, D}, title = {Antibodies inhibit transmission and aggregation of C9orf72 poly-GA dipeptide repeat proteins.}, journal = {EMBO molecular medicine}, volume = {9}, number = {5}, pages = {687-702}, pmid = {28351931}, issn = {1757-4684}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/*therapy ; Animals ; Antibodies/*therapeutic use ; Brain/metabolism/pathology ; C9orf72 Protein/*genetics ; Cells, Cultured ; HEK293 Cells ; Humans ; *Immunotherapy/methods ; Neurons/metabolism/pathology ; Protein Aggregation, Pathological/genetics/pathology/*therapy ; Rats ; }, abstract = {Cell-to-cell transmission of protein aggregates is an emerging theme in neurodegenerative disease. Here, we analyze the dipeptide repeat (DPR) proteins that form neuronal inclusions in patients with hexanucleotide repeat expansion C9orf72, the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Sense and antisense transcripts of the (G4C2)n repeat are translated by repeat-associated non-ATG (RAN) translation in all reading frames into five aggregating DPR proteins. We show that the hydrophobic DPR proteins poly-GA, poly-GP, and poly-PA are transmitted between cells using co-culture assays and cell extracts. Moreover, uptake or expression of poly-GA induces nuclear RNA foci in (G4C2)80-expressing cells and patient fibroblasts, suggesting an unexpected positive feedback loop. Exposure to recombinant poly-GA and cerebellar extracts of C9orf72 patients increases repeat RNA levels and seeds aggregation of all DPR proteins in receiver cells expressing (G4C2)80 Treatment with anti-GA antibodies inhibits intracellular poly-GA aggregation and blocks the seeding activity of C9orf72 brain extracts. Poly-GA-directed immunotherapy may thus reduce DPR aggregation and disease progression in C9orf72 ALS/FTD.}, }
@article {pmid28351750, year = {2017}, author = {Marcuzzo, S and Bonanno, S and Figini, M and Scotti, A and Zucca, I and Minati, L and Riva, N and Domi, T and Fossaghi, A and Quattrini, A and Galbardi, B and D'Alessandro, S and Bruzzone, MG and García-Verdugo, JM and Moreno-Manzano, V and Mantegazza, R and Bernasconi, P}, title = {A longitudinal DTI and histological study of the spinal cord reveals early pathological alterations in G93A-SOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {293}, number = {}, pages = {43-52}, doi = {10.1016/j.expneurol.2017.03.018}, pmid = {28351750}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/*genetics ; Animals ; Anthracenes ; *Diffusion Tensor Imaging ; Disease Models, Animal ; Gray Matter/diagnostic imaging/ultrastructure ; Humans ; Image Processing, Computer-Assisted ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microscopy, Electron, Transmission ; Mitochondria/pathology/ultrastructure ; Sensory Receptor Cells/pathology/ultrastructure ; Spinal Cord/*diagnostic imaging/pathology/ultrastructure ; Superoxide Dismutase/*genetics ; Time Factors ; White Matter/diagnostic imaging/ultrastructure ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron degeneration in the motor cortex, brainstem and spinal cord. It is generally accepted that ALS is caused by death of motor neurons, however the exact temporal cascade of degenerative processes is not yet completely known. To identify the early pathological changes in spinal cord of G93A-SOD1 ALS mice we performed a comprehensive longitudinal analysis employing diffusion-tensor magnetic resonance imaging alongside histology and electron microscopy, in parallel with peripheral nerve histology. We showed the gradient of degeneration appearance in spinal cord white and gray matter, starting earliest in the ventral white matter, due to a cascade of pathological events including axon dysfunction and mitochondrial changes. Notably, we found that even the main sensory regions are affected by the neurodegenerative process at symptomatic disease phase. Overall our results attest the applicability of DTI in determining disease progression in ALS mice. These findings suggest that DTI could be potentially adapted in humans to aid the assessment of ALS progression and eventually the evaluation of treatment efficacy.}, }
@article {pmid28337659, year = {2017}, author = {Perga, S and Martire, S and Montarolo, F and Navone, ND and Calvo, A and Fuda, G and Marchet, A and Leotta, D and Chiò, A and Bertolotto, A}, title = {A20 in Multiple Sclerosis and Parkinson's Disease: Clue to a Common Dysregulation of Anti-Inflammatory Pathways?.}, journal = {Neurotoxicity research}, volume = {32}, number = {1}, pages = {1-7}, pmid = {28337659}, issn = {1476-3524}, mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Alzheimer Disease/blood ; Amyotrophic Lateral Sclerosis/blood ; Female ; Gene Expression ; Humans ; Italy ; Male ; Middle Aged ; Multiple Sclerosis/*blood ; Parkinson Disease/*blood ; RNA, Messenger/metabolism ; Tumor Necrosis Factor alpha-Induced Protein 3/*blood/genetics ; }, abstract = {Chronic inflammation significantly contributes to the pathogenesis of several neurodegenerative disorders. In physiological conditions, a chronic inflammatory state is prevented through the termination of the acute inflammatory response once the triggering insult is eliminated. Several mechanisms regulate the resolution of inflammation. Among these, a potent inhibitor of the pro-inflammatory NF-kB signaling known as A20 has emerged as a key player. Recent studies have shown reduced blood levels of A20 in the patients of diverse chronic inflammatory diseases. Similar results have also been demonstrated in patients of multiple sclerosis (MS), a neurodegenerative disease characterized by persisting inflammation. In the present study, we investigate whether other similar neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) also demonstrate deregulated levels of A20 expression as compared to healthy controls (HC) and treatment-naive MS patients. Our results confirm previous data that the A20 expression is reduced in whole blood of MS patients as compared to HC. Additionally, we demonstrate that significantly diminished A20 expression is also evident in PD patients. The dysregulation of the A20 pathway could then contribute to the persistence of inflammation in these disorders. It would thus be interesting to investigate further whether such commonly deregulated pathways between different inflammatory diseases could represent novel targets for therapy.}, }
@article {pmid28337334, year = {2017}, author = {Zhang, Y and Benmohamed, R and Zhang, W and Kim, J and Edgerly, CK and Zhu, Y and Morimoto, RI and Ferrante, RJ and Kirsch, DR and Silverman, RB}, title = {Correction to "Chiral Cyclohexane 1,3-Diones as Inhibitors of Mutant SOD1-Dependent Protein Aggregation for the Treatment of ALS".}, journal = {ACS medicinal chemistry letters}, volume = {8}, number = {3}, pages = {377}, doi = {10.1021/acsmedchemlett.7b00070}, pmid = {28337334}, issn = {1948-5875}, abstract = {[This corrects the article DOI: 10.1021/ml3000963.].}, }
@article {pmid28330477, year = {2017}, author = {Tyagi, R and Li, W and Parades, D and Bianchet, MA and Nath, A}, title = {Inhibition of human endogenous retrovirus-K by antiretroviral drugs.}, journal = {Retrovirology}, volume = {14}, number = {1}, pages = {21}, pmid = {28330477}, issn = {1742-4690}, mesh = {Anti-Retroviral Agents/*pharmacology ; Endogenous Retroviruses/*drug effects ; HeLa Cells ; Humans ; Microbial Sensitivity Tests ; Real-Time Polymerase Chain Reaction ; Recombination, Genetic ; Vesiculovirus/genetics/growth &amp; development ; }, abstract = {BACKGROUND: Human endogenous retroviruses (HERVs) are genomic sequences of retroviral origin which were believed to be integrated into germline chromosomes millions of years ago and account for nearly 8% of the human genome. Although mostly defective and inactive, some of the HERVs may be activated under certain physiological and pathological conditions. While no drugs are designed specifically targeting HERVs, there are a panel of antiretroviral drugs designed against the human immunodeficiency virus and approved by the Federal Drug Administration (FDA).<br><br>RESULTS: We determined if these antiretroviral drugs may also be effective in inhibiting HERVs. We constructed a plasmid with consensus HERV-K sequence for testing the effect of antiretroviral drugs on HERV-K. We first determined the effects of nucleoside and non-nucleotide reverse transcriptase (RT) inhibitors on HERV-K by product enhanced reverse transcription assay. We found that all RT inhibitors could significantly inhibit HERV-K RT activity. To determine the effects of antiretroviral drugs on HERV-K infection and viral production, we pseudotyped HERV-K with VSV-G and used the pseudotyped HERV-K virus to infect HeLa cells. HERV-K production was measured by quantitative real time polymerase chain reaction. We found that RT inhibitors Abacavir and Zidovudine, and integrase inhibitor Raltegravir could effectively block HERV-K infection and production. However, protease inhibitors were not as effective as RT and integrase inhibitors.<br><br>CONCLUSIONS: In summary, we identified several FDA approved antiretroviral drugs that can effectively inhibit HERV-K. These antiretrovirals may open new prospects for studying HERV-K pathophysiology and potentially for exploring treatment of diseases in which HERV-K has been implicated.}, }
@article {pmid28320070, year = {2018}, author = {Muzzi, M and Gerace, E and Buonvicino, D and Coppi, E and Resta, F and Formentini, L and Zecchi, R and Tigli, L and Guasti, D and Ferri, M and Camaioni, E and Masi, A and Pellegrini-Giampietro, DE and Mannaioni, G and Bani, D and Pugliese, AM and Chiarugi, A}, title = {Dexpramipexole improves bioenergetics and outcome in experimental stroke.}, journal = {British journal of pharmacology}, volume = {175}, number = {2}, pages = {272-283}, pmid = {28320070}, issn = {1476-5381}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Benzothiazoles/pharmacokinetics/*pharmacology/*therapeutic use ; Calcium/metabolism ; Cell Death/drug effects ; Energy Metabolism/*drug effects ; Evoked Potentials/physiology ; Hippocampus/metabolism/physiology/ultrastructure ; Infarction, Middle Cerebral Artery ; Male ; Mice ; Mitochondria/metabolism ; Neurons/physiology ; Neuroprotective Agents/pharmacokinetics/pharmacology/*therapeutic use ; Pramipexole ; Primary Cell Culture ; Rats ; Stroke/*drug therapy/metabolism ; }, abstract = {BACKGROUND AND PURPOSE: Dexpramipexole, a drug recently tested in patients with amyotrophic lateral sclerosis (ALS,) is able to bind F1Fo ATP synthase and increase mitochondrial ATP production. Here, we have investigated its effects on experimental ischaemic brain injury.<br><br>EXPERIMENTAL APPROACH: The effects of dexpramipexole on bioenergetics, Ca[2+] fluxes, electrophysiological functions and death were evaluated in primary neural cultures and hippocampal slices exposed to oxygen-glucose deprivation (OGD). Effects on infarct volumes and neurological functions were also evaluated in mice following proximal or distal middle cerebral artery occlusion (MCAo). Distribution of dexpramipexole within the ischaemic brain was evaluated by means of mass spectrometry imaging.<br><br>KEY RESULTS: Dexpramipexole increased mitochondrial ATP production in cultured neurons or glia and reduces energy failure, prevents intracellular Ca[2+] overload and affords cytoprotection when cultures are exposed to OGD. This compound also counteracted ATP depletion, mitochondrial swelling, anoxic depolarization, loss of synaptic activity and neuronal death in hippocampal slices subjected to OGD. Post-ischaemic treatment with dexpramipexole, at doses consistent with those already used in ALS patients, reduced brain infarct size and ameliorated neuroscore in mice subjected to transient or permanent MCAo. Notably, the concentrations of dexpramipexole reached within the ischaemic penumbra equalled those found neuroprotective in vitro.<br><br>CONCLUSION AND IMPLICATIONS: Dexpramipexole, a compound able to increase mitochondrial F1Fo ATP-synthase activity reduced ischaemic brain injury. These findings, together with the excellent brain penetration and favourable safety profile in humans, make dexpramipexole a drug with realistic translational potential for the treatment of stroke.<br><br>LINKED ARTICLES: This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.}, }
@article {pmid28315276, year = {2017}, author = {Mavlyutov, TA and Baker, EM and Losenegger, TM and Kim, JR and Torres, B and Epstein, ML and Ruoho, AE}, title = {The Sigma-1 Receptor-A Therapeutic Target for the Treatment of ALS?.}, journal = {Advances in experimental medicine and biology}, volume = {964}, number = {}, pages = {255-265}, doi = {10.1007/978-3-319-50174-1_17}, pmid = {28315276}, issn = {0065-2598}, support = {NS075820/NH/NIH HHS/United States ; DK081634/NH/NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism ; Animals ; Cell Membrane/drug effects ; Endoplasmic Reticulum/drug effects/metabolism ; Humans ; Motor Neurons/drug effects/metabolism ; Receptors, sigma/*metabolism ; Sigma-1 Receptor ; }, abstract = {The membrane bound 223 amino acid Sigma-1 Receptor (S1R) serves as a molecular chaperone and functional regulator of many signaling proteins. Spinal cord motor neuron activation occurs, in part, via large ventral horn cholinergic synapses called C-boutons/C-terminals. Chronic excitation of motor neurons and alterations in C-terminals has been associated with Amyotrophic Lateral Sclerosis (ALS). The S1R has an important role in regulating motor neuron function. High levels of the S1R are localized in postsynaptic endoplasmic reticulum (ER) subsurface cisternae within 10-20 nm of the plasma membrane that contain muscarinic type 2 acetylcholine receptors (M2AChR), calcium activated potassium channels (Kv2.1) and slow potassium (SK) channels. An increase in action potentials in the S1R KO mouse motor neurons indicates a critical role for the S1R as a "brake" on motor neuron function possibly via calcium dependent hyperpolarization mechanisms involving the aforementioned potassium channels. The longevity of SOD-1/S1R KO ALS mice is significantly reduced compared to SOD-1/WT ALS controls. The S1R colocalizes in C-terminals with Indole(ethyl)amine-N-methyl transferase (INMT), the enzyme that produces the S1R agonist , N,N'- dimethyltryptamine (DMT). INMT methylation can additionally neutralize endogenous toxic sulfur and selenium derivatives thus providing functional synergism with DMT to reduce oxidative stress in motor neurons . Small molecule activation of the S1R and INMT thus provides a possible therapeutic strategy to treat ALS .}, }
@article {pmid28315275, year = {2017}, author = {Mancuso, R and Navarro, X}, title = {Sigma-1 Receptor in Motoneuron Disease.}, journal = {Advances in experimental medicine and biology}, volume = {964}, number = {}, pages = {235-254}, doi = {10.1007/978-3-319-50174-1_16}, pmid = {28315275}, issn = {0065-2598}, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Humans ; Motor Neuron Disease/*metabolism ; Motor Neurons/*metabolism ; Neuroglia/metabolism ; Receptors, sigma/*metabolism ; Sigma-1 Receptor ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease affecting spinal cord and brain motoneurons , leading to paralysis and early death. Multiple etiopathogenic mechanisms appear to contribute in the development of ALS , including glutamate excitotoxicity, oxidative stress , protein misfolding, mitochondrial defects, impaired axonal transport, inflammation and glial cell alterations. The Sigma-1 receptor is highly expressed in motoneurons of the spinal cord, particularly enriched in the endoplasmic reticulum (ER) at postsynaptic cisternae of cholinergic C-terminals. Several evidences point to participation of Sigma-1R alterations in motoneuron degeneration. Thus, mutations of the transmembrane domain of the Sigma-1R have been described in familial ALS cases. Interestingly, Sigma-1R KO mice display muscle weakness and motoneuron loss. On the other hand, Sigma-1R agonists promote neuroprotection and neurite elongation through activation of protein kinase C on motoneurons in vitro and in vivo after ventral root avulsion. Remarkably, treatment of SOD1 mice, the most usual animal model of ALS , with Sigma-1R agonists resulted in significantly enhanced motoneuron function and preservation, and increased animal survival. Sigma-1R activation also reduced microglial reactivity and increased the glial expression of neurotrophic factors. Two main interconnected mechanisms seem to underlie the effects of Sigma-1R manipulation on motoneurons: modulation of neuronal excitability and regulation of calcium homeostasis. In addition, Sigma-1R also contributes to regulating protein degradation, and reducing oxidative stress. Therefore, the multi-functional nature of the Sigma-1R represents an attractive target for treating aspects of ALS and other motoneuron diseases .}, }
@article {pmid28315269, year = {2017}, author = {Nguyen, L and Lucke-Wold, BP and Mookerjee, S and Kaushal, N and Matsumoto, RR}, title = {Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection.}, journal = {Advances in experimental medicine and biology}, volume = {964}, number = {}, pages = {133-152}, pmid = {28315269}, issn = {0065-2598}, support = {U54 GM104942/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Brain/drug effects/metabolism ; Humans ; Ligands ; Molecular Chaperones/*pharmacology ; Neurodegenerative Diseases/drug therapy/*metabolism ; Neuroprotection/drug effects ; Neuroprotective Agents/*pharmacology ; Receptors, sigma/*metabolism ; Sigma-1 Receptor ; }, abstract = {Sigma-1 receptors are molecular chaperones that may act as pathological mediators and targets for novel therapeutic applications in neurodegenerative diseases. Accumulating evidence indicates that sigma-1 ligands can either directly or indirectly modulate multiple neurodegenerative processes, including excitotoxicity, calcium dysregulation, mitochondrial and endoplasmic reticulum dysfunction, inflammation, and astrogliosis. In addition, sigma-1 ligands may act as disease-modifying agents in the treatment for central nervous system (CNS) diseases by promoting the activity of neurotrophic factors and neural plasticity. Here, we summarize their neuroprotective and neurorestorative effects in different animal models of acute brain injury and chronic neurodegenerative diseases, and highlight their potential role in mitigating disease. Notably, current data suggest that sigma-1 receptor dysfunction worsens disease progression, whereas enhancement amplifies pre-existing functional mechanisms of neuroprotection and/or restoration to slow disease progression. Collectively, the data support a model of the sigma-1 receptor as an amplifier of intracellular signaling, and suggest future clinical applications of sigma-1 ligands as part of multi-therapy approaches to treat neurodegenerative diseases.}, }
@article {pmid28315260, year = {2017}, author = {Smith, SB}, title = {Introduction to Sigma Receptors: Their Role in Disease and as Therapeutic Targets.}, journal = {Advances in experimental medicine and biology}, volume = {964}, number = {}, pages = {1-4}, doi = {10.1007/978-3-319-50174-1_1}, pmid = {28315260}, issn = {0065-2598}, support = {R01 EY014560/EY/NEI NIH HHS/United States ; R01 EY028103/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Depression/*metabolism ; Humans ; Neoplasms/*metabolism ; Neurodegenerative Diseases/*metabolism ; Receptors, sigma/*metabolism ; Substance-Related Disorders/*metabolism ; Sigma-1 Receptor ; }, abstract = {This book highlights contributions from leaders in the field of sigma receptor research. Sigma receptors represent a promising, novel target for the treatment of neurodegenerative diseases, retinal degenerations, pain and substance abuse. Information is presented about tracers for molecular imaging these receptors, the newly determined crystal structure of human sigma 1 receptor and information about sigma 2 receptor. New discoveries about the role of sigma 1 receptors in cancer, pain, neuropsychiatric disorders, learning and memory, neuronal networks and depression are described. The compendium offers important insights about the direction unfolding for this exciting field of research.}, }
@article {pmid28302022, year = {2017}, author = {Ahmed, S and Gull, A and Khuroo, T and Aqil, M and Sultana, Y}, title = {Glial Cell: A Potential Target for Cellular and Drug Based Therapy in Various CNS Diseases.}, journal = {Current pharmaceutical design}, volume = {23}, number = {16}, pages = {2389-2399}, doi = {10.2174/1381612823666170316124500}, pmid = {28302022}, issn = {1873-4286}, mesh = {Animals ; Blood-Brain Barrier/drug effects/pathology ; Central Nervous System Diseases/*drug therapy/pathology ; Humans ; Neuroglia/*drug effects/pathology ; }, abstract = {Glial cells are integrated part of neurovascular unit of blood brain barrier (BBB). They undergo mitosis and mainly classified as astrocytes, oligodendrocytes, microglia, ependymal cells and nerve glial antigen 2 cells. Being a most versatile glial cell, astrocytes provide structural support to neurons, maintain brain homeostasis, take part in neuronal communication, and perform some housekeeping functions. Oligodendrocytes myelinate the neuronal axons for proper transmission of nerve impulse and microglia are brain immune cells. Multiple sclerosis is a prototype glia mediated disease that manifests demyelination. Fingolimod is already being marketed for this disease, while guanabenz and ibudilast are facing clinical trials. Many researches revealed the role of glial cells in Alzheimer's disease, in which riluzole (a glutamate modulator already in market for amyotrophic lateral sclerosis-ALS) was found to be effective. Q-cells® are glial cell-based therapeutic agent to treat ALS that only produce astrocytes and oligodendrocytes, when transplanted in vivo. hIL13-PE is a gene based therapeutic agent that has been smartly designed for the treatment of glioma. Although for CNS diseases, drugs are available, still it is not easy to extract satisfactory therapeutic effect of most of the drugs due to the presence of BBB. This barrier can be overcome by implanting a drug reservoir in brain parenchyma (wafer), by judicious selection of drug delivery system (nanoparticulate system), or by using an alternative route of administration (intranasal route). This review revolves around cellular and drug based modulation of glial cells to achieve maximum therapeutic benefit for some of the CNS diseases.}, }
@article {pmid28300211, year = {2017}, author = {Rotem, N and Magen, I and Ionescu, A and Gershoni-Emek, N and Altman, T and Costa, CJ and Gradus, T and Pasmanik-Chor, M and Willis, DE and Ben-Dov, IZ and Hornstein, E and Perlson, E}, title = {ALS Along the Axons - Expression of Coding and Noncoding RNA Differs in Axons of ALS models.}, journal = {Scientific reports}, volume = {7}, number = {}, pages = {44500}, pmid = {28300211}, issn = {2045-2322}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Axons/*metabolism/pathology ; DNA-Binding Proteins/*genetics ; Disease Models, Animal ; Gene Expression Regulation/genetics ; Humans ; Mice ; Motor Neurons/metabolism/pathology ; Nerve Degeneration ; RNA, Untranslated/genetics ; Superoxide Dismutase-1/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial lethal motor neuron disease with no known treatment. Although the basic mechanism of its degenerative pathogenesis remains poorly understood, a subcellular spatial alteration in RNA metabolism is thought to play a key role. The nature of these RNAs remains elusive, and a comprehensive characterization of the axonal RNAs involved in maintaining neuronal health has yet to be described. Here, using cultured spinal cord (SC) neurons grown using a compartmented platform followed by next-generation sequencing (NGS) technology, we find that RNA expression differs between the somatic and axonal compartments of the neuron, for both mRNA and microRNA (miRNA). Further, the introduction of SOD1[G93A] and TDP43[A315T], established ALS-related mutations, changed the subcellular expression and localization of RNAs within the neurons, showing a spatial specificity to either the soma or the axon. Altogether, we provide here the first combined inclusive profile of mRNA and miRNA expression in two ALS models at the subcellular level. These data provide an important resource for studies on the roles of local protein synthesis and axon degeneration in ALS and can serve as a possible target pool for ALS treatment.}, }
@article {pmid28298842, year = {2017}, author = {Şanlı, A and Şengün, I&#x15e; and Karaçam, V and Alpaydın, A&#xd6; and Tertemiz, KC and Özalevli, S and Şanlı, BA and Kaya, A and Özdemir, N}, title = {Preoperative parameters and their prognostic value in amyotrophic lateral sclerosis patients undergoing implantation of a diaphragm pacing stimulation system.}, journal = {Annals of Indian Academy of Neurology}, volume = {20}, number = {1}, pages = {51-54}, pmid = {28298842}, issn = {0972-2327}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease with devastating and fatal respiratory complications. Diaphragm pacing stimulation (DPS) is a treatment option in diaphragm insufficient ALS patients. Ventilatory insufficiency depending on diaphragmatic failure is treated by the present study aimed to investigate prognostic value of preoperative clinical and functional characteristics of ALS patients undergoing implantation of a DPS system and to determine appropriate indications for the DPS system.<br><br>METHODS: The study included 34 ALS patients implanted with DPS system. All patients underwent multidisciplinary and laboratory evaluations before the surgery. The laboratory examinations included pulmonary function tests and arterial blood gas analysis. Survival rates were recorded in a 2-year follow-up after the surgery.<br><br>RESULTS: Twenty-eight of 34 patients with ALS survived after a 2-year follow-up. These patients were younger than those who died and had the disease for a longer time; however, the differences were not significant. Both right and left hemidiaghragms were thicker in the survived patients (P < 0.0001 for each). Pulmonary function tests revealed no significant differences between the patients who survived. Arterial blood gas analysis demonstrated lower partial pressure of carbon dioxide in the survived patients (P = 0.025).<br><br>CONCLUSIONS: DPS implantation was more efficacious in ALS patients with mild respiratory failure and thicker diaphragm. Predictors of long-term effectiveness of DPS system are needed to be addressed by large-scale studies.}, }
@article {pmid28293919, year = {2017}, author = {Gerth, HU and Pohlen, M and Pavenstädt, H and Schmidt, H}, title = {[Extracorporeal liver support of liver failure].}, journal = {Zeitschrift fur Gastroenterologie}, volume = {55}, number = {4}, pages = {383-393}, doi = {10.1055/s-0043-100020}, pmid = {28293919}, issn = {1439-7803}, mesh = {*Extracorporeal Circulation ; Humans ; Liver Failure/physiopathology/*therapy ; *Liver, Artificial ; Plasmapheresis/methods ; *Randomized Controlled Trials as Topic ; Sorption Detoxification ; }, abstract = {Extracorporeal liver support can be classified into cell-free, artificial methods (artificial liver support, ALS) and cell-based bioartificial methods (bioartificial liver support, BLS). ALS improves biochemical parameters of liver failure by the simultaneous removal of protein-bound and water-soluble substances. Here, the MARS therapy belongs to the most studied methods with a proved beneficial effect on hepatic encephalopathy (HE), hepatorenal syndrome (HRS) or hyperbilirubinemia. However, a general survival advantage of any liver support for liver failure has not been shown yet and is restricted to meta-analyses or patient subgroups. There are no prospective randomized studies on the treatment of liver failure by intoxication. However, several case series report positive treatment effects using the MARS system, particularly in mushroom poisoning or acetaminophen intoxication. In acute liver failure (ALF) studies, the usage of BLS showed no survival advantage. Using ALS systems, a positive effect on mortality could be demonstrated in patient subgroups after several consecutive MARS therapies. The first randomized controlled trial demonstrating a survival benefit used large-volume plasmapheresis. Apparently, immunomodulatory and hemodynamic effects of the treatment play a crucial role in this context. In patients with acute-on-chronic liver failure (ACLF) accompanied by hyperbilirubinemia without any further organ failure (singular hepatic dysfunction), prognostic favorable effects by using a BLS system have been shown. However, once other extrahepatic organ systems are affected, indicating a progressive transition to multi-organ failure, a survival advantage could be achieved with the MARS and Prometheus system. Decisive for a successful therapy is the exact indication of the respective liver dialysis procedure for this very heterogeneous disease. Future studies are needed to define more accurate patient selection criteria for each liver support.}, }
@article {pmid28292200, year = {2017}, author = {Brusilow, WS and Peters, TJ}, title = {Therapeutic effects of methionine sulfoximine in multiple diseases include and extend beyond inhibition of glutamine synthetase.}, journal = {Expert opinion on therapeutic targets}, volume = {21}, number = {5}, pages = {461-469}, doi = {10.1080/14728222.2017.1303484}, pmid = {28292200}, issn = {1744-7631}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Animals ; Brain Edema/*drug therapy/physiopathology ; Disease Models, Animal ; Drug Design ; Glutamate-Ammonia Ligase/*metabolism ; Hepatic Encephalopathy/drug therapy/physiopathology ; Humans ; Methionine Sulfoximine/*pharmacology ; Molecular Targeted Therapy ; Stroke/drug therapy/physiopathology ; }, abstract = {Methionine sulfoximine (MSO), a well-characterized inhibitor of glutamine synthetase, displays significant therapeutic benefits in animal models for several human diseases. This amino acid might therefore be a viable candidate for drug development to treat diseases for which there are few effective therapies. Areas covered: We describe the effects of MSO on brain swelling occurring in overt hepatic encephalopathy resulting from liver failure, the effects of MSO on excitotoxic damage involved in amyotrophic lateral sclerosis (ALS) or resulting from stroke, and the effects of MSO on a model for an inflammatory immune response involved in a range of diseases. We conclude that these results imply the existence of another therapeutic target for MSO in addition to glutamine synthetase. Expert opinion: We summarize the various diseases for which MSO treatment might be a candidate for drug development. We discuss why MSO has limited enthusiasm in the scientific and medical communities for use in humans, with a rebuttal to those negative opinions. And we conclude that MSO should be considered a candidate drug to treat brain swelling involved in overt hepatic encephalopathy and diseases involving an inflammatory immune response.}, }
@article {pmid30135932, year = {2017}, author = {Vieira, FG and Hatzipetros, T and Thompson, K and Moreno, AJ and Kidd, JD and Tassinari, VR and Levine, B and Perrin, S and Gill, A}, title = {CuATSM efficacy is independently replicated in a SOD1 mouse model of ALS while unmetallated ATSM therapy fails to reveal benefits.}, journal = {IBRO reports}, volume = {2}, number = {}, pages = {47-53}, pmid = {30135932}, issn = {2451-8301}, abstract = {A copper chelator known as diacetylbis(N(4)-methylthiosemicarbazonato) copper II (CuATSM), has been reported to be efficacious in multiple transgenic SOD1 models of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting motor neurons. Here we report that we also observed CuATSM efficacy on disease onset and progression in a standardized litter-matched and gender-balanced efficacy study using B6SJL-SOD1G93A/1Gur mice. We also report improved survival trends with CuATSM treatment. In addition, we report a lack of efficacy by unmetallated ATSM in the same model using the same standardized study design. These results add to existing evidence supporting an efficacious role for copper delivery using chaperone molecules in mouse models of ALS.}, }
@article {pmid28283968, year = {2017}, author = {Smith, R and Pioro, E and Myers, K and Sirdofsky, M and Goslin, K and Meekins, G and Yu, H and Wymer, J and Cudkowicz, M and Macklin, EA and Schoenfeld, D and Pattee, G}, title = {Erratum to: Enhanced Bulbar Function in Amyotrophic Lateral Sclerosis: The Nuedexta Treatment Trial.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {14}, number = {3}, pages = {830}, doi = {10.1007/s13311-017-0517-z}, pmid = {28283968}, issn = {1878-7479}, support = {UL1 TR000439/TR/NCATS NIH HHS/United States ; }, }
@article {pmid28281895, year = {2017}, author = {Lam, D and Koch, GG and Preisser, JS and Saville, BR and Hussey, MA}, title = {Randomization-based adjustment of multiple treatment hazard ratios for covariates with missing data.}, journal = {Journal of biopharmaceutical statistics}, volume = {27}, number = {3}, pages = {373-386}, doi = {10.1080/10543406.2017.1289954}, pmid = {28281895}, issn = {1520-5711}, mesh = {Computer Simulation ; Confidence Intervals ; Data Accuracy ; *Data Interpretation, Statistical ; Humans ; *Proportional Hazards Models ; *Randomized Controlled Trials as Topic ; *Research Design ; }, abstract = {Clinical trials are designed to compare treatment effects when applied to samples from the same population. Randomization is used so that the samples are not biased with respect to baseline covariates that may influence the efficacy of the treatment. We develop randomization-based covariance adjustment methodology to estimate the log hazard ratios and their confidence intervals of multiple treatments in a randomized clinical trial with time-to-event outcomes and missingness among the baseline covariates. The randomization-based covariance adjustment method is a computationally straight-forward method for handling missing baseline covariate values.}, }
@article {pmid28277881, year = {2017}, author = {Martinez, A and Palomo Ruiz, MD and Perez, DI and Gil, C}, title = {Drugs in clinical development for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert opinion on investigational drugs}, volume = {26}, number = {4}, pages = {403-414}, doi = {10.1080/13543784.2017.1302426}, pmid = {28277881}, issn = {1744-7658}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Antipyrine/analogs &amp; derivatives/therapeutic use ; Biological Therapy/methods ; Biomarkers/metabolism ; Cell- and Tissue-Based Therapy/methods ; *Drug Design ; Drug Repositioning ; Drugs, Investigational/*therapeutic use ; Edaravone ; Humans ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron progressive disorder for which no treatment exists to date. However, there are other investigational drugs and therapies currently under clinical development may offer hope in the near future. Areas covered: We have reviewed all the ALS ongoing clinical trials (until November 2016) and collected in Clinicaltrials.gov or EudraCT. We have described them in a comprehensive way and have grouped them in the following sections: biomarkers, biological therapies, cell therapy, drug repurposing and new drugs. Expert opinion: Despite multiple obstacles that explain the absence of effective drugs for the treatment of ALS, joint efforts among patient's associations, public and private sectors have fueled innovative research in this field, resulting in several compounds that are in the late stages of clinical trials. Drug repositioning is also playing an important role, having achieved the approval of some orphan drug applications, in late phases of clinical development. Endaravone has been recently approved in Japan and is pending in USA.}, }
@article {pmid28276271, year = {2018}, author = {Winter, AN and Ross, EK and Wilkins, HM and Stankiewicz, TR and Wallace, T and Miller, K and Linseman, DA}, title = {An anthocyanin-enriched extract from strawberries delays disease onset and extends survival in the hSOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {Nutritional neuroscience}, volume = {21}, number = {6}, pages = {414-426}, doi = {10.1080/1028415X.2017.1297023}, pmid = {28276271}, issn = {1476-8305}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/prevention &amp; control ; Animals ; Anthocyanins/*pharmacology ; Body Weight ; Disease Models, Animal ; Disease Progression ; Female ; Fragaria/*chemistry ; Gliosis/drug therapy/prevention &amp; control ; Immunohistochemistry ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/metabolism ; Muscle, Skeletal/drug effects/metabolism ; Plant Extracts/*pharmacology ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting from the death of motor neurons in the brain, brain stem, and spinal cord. Several processes such as oxidative stress, neuroinflammation, and neuronal apoptosis, contribute to disease progression. Anthocyanins are flavonoid compounds derived from fruits and vegetables that possess antioxidant, anti-inflammatory, and anti-apoptotic abilities. Thus, these unique compounds may provide therapeutic benefit for the treatment of ALS.<br><br>METHODS: We used the G93A mutant human SOD1 (hSOD1[G93A]) mouse model of ALS to assess the effects of an anthocyanin-enriched extract from strawberries (SAE) on disease onset and progression. Mice were administered SAE orally beginning at 60 days of age until end-stage such that mice received 2&#x2005;mg/kg/day of the extract's primary anthocyanin constituent. Clinical indices of disease were assessed until mice were sacrificed at end-stage. Histopathological indices of disease progression were also evaluated at 105 days of age.<br><br>RESULTS: hSOD1[G93A] mice supplemented with SAE experienced a marked (&#x223c;17 day) delay in disease onset and a statistically significant (&#x223c;11 day) extension in survival in comparison to their untreated mutant counterparts. Additionally, SAE-treated hSOD1[G93A] mice displayed significantly preserved grip strength throughout disease progression. Histopathological analysis demonstrated that SAE supplementation significantly reduced astrogliosis in spinal cord, and preserved neuromuscular junctions (NMJs) in gastrocnemius muscle.<br><br>DISCUSSION: These data are the first to demonstrate that anthocyanins have significant potential as therapeutic agents in a preclinical model of ALS due to their ability to reduce astrogliosis in spinal cord and preserve NMJ integrity and muscle function. Therefore, further study of these compounds is warranted in additional preclinical models of ALS and other neurodegenerative diseases.}, }
@article {pmid28265522, year = {2017}, author = {Bartlett, R and Sluyter, V and Watson, D and Sluyter, R and Yerbury, JJ}, title = {P2X7 antagonism using Brilliant Blue G reduces body weight loss and prolongs survival in female SOD1[G93A] amyotrophic lateral sclerosis mice.}, journal = {PeerJ}, volume = {5}, number = {}, pages = {e3064}, pmid = {28265522}, issn = {2167-8359}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterised by the accumulation of aggregated proteins, microglia activation and motor neuron loss. The mechanisms underlying neurodegeneration and disease progression in ALS are unknown, but the ATP-gated P2X7 receptor channel is implicated in this disease. Therefore, the current study aimed to examine P2X7 in the context of neurodegeneration, and investigate whether the P2X7 antagonist, Brilliant Blue G (BBG), could alter disease progression in a murine model of ALS.<br><br>METHODS: Human SOD1[G93A] transgenic mice, which normally develop ALS, were injected with BBG or saline, three times per week, from pre-onset of clinical disease (62-64 days of age) until end-stage. During the course of treatment mice were assessed for weight, clinical score and survival, and motor coordination, which was assessed by rotarod performance. Various parameters from end-stage mice were assessed as follows. Motor neuron loss and microgliosis were assessed by immunohistochemistry. Relative amounts of lumbar spinal cord SOD1 and P2X7 were quantified by immunoblotting. Serum monocyte chemoattractant protein-1 was measured by ELISA. Splenic leukocyte populations were assessed by flow cytometry. Relative expression of splenic and hepatic P2X7 mRNA was measured by quantitative real-time PCR. Lumbar spinal cord SOD1 and P2X7 were also quantified by immunoblotting in untreated female SOD1[G93A] mice during the course of disease.<br><br>RESULTS: BBG treatment reduced body weight loss in SOD1[G93A] mice of combined sex, but had no effect on clinical score, survival or motor coordination. BBG treatment reduced body weight loss in female, but not male, SOD1[G93A] mice. BBG treatment also prolonged survival in female, but not male, SOD1[G93A] mice, extending the mean survival time by 4.3% in female mice compared to female mice treated with saline. BBG treatment had no effect on clinical score or motor coordination in either sex. BBG treatment had no major effect on any end-stage parameters. Total amounts of lumbar spinal cord SOD1 and P2X7 in untreated female SOD1[G93A] mice did not change over time.<br><br>DISCUSSION: Collectively, this data suggests P2X7 may have a partial role in ALS progression in mice, but additional research is required to fully elucidate the contribution of this receptor in this disease.}, }
@article {pmid30057745, year = {2017}, author = {Kindy, M and Lupinacci, P and Chau, R and Shum, T and Ko, D}, title = {A Phase 2A randomized, double-blind, placebo-controlled pilot trial of GM604 in patients with Amyotrophic Lateral Sclerosis (ALS Protocol GALS-001) and a single compassionate patient treatment (Protocol GALS-C).}, journal = {F1000Research}, volume = {6}, number = {}, pages = {230}, pmid = {30057745}, issn = {2046-1402}, abstract = {Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that lacks effective treatment options. Genervon has discovered and developed GM604 (GM6) as a potential ALS therapy. GM6 has been modeled upon an insulin receptor tyrosine kinase binding motoneuronotrophic factor within the developing central nervous system. Methods This was a 2-center phase 2A, randomized, double-blind, placebo-controlled pilot trial with 12 definite ALS patients diagnosed within 2 years of disease onset. Patients received 6 doses of GM604 or placebo, administered as slow IV bolus injections (3x/week, 2 consecutive weeks). Objectives were to assess the safety and efficacy of GM604 based on ALSFRS-R, FVC and selected biomarkers (TDP-43, Tau and SOD1, pNFH). This report also includes results of compassionate treatment protocol GALS-C for an advanced ALS patient. Results Definite ALS patients were randomized to one of two treatment groups (GM604, n = 8; placebo, n = 4). 2 of 8 GM604-treated patients exhibited mild rash, but otherwise adverse event frequency was similar in treated and placebo groups. GM604 slowed functional decline (ALSFRS-R) when compared to a historical control (P = 0.005). At one study site, a statistically significant difference between treatment and control groups was found when comparing changes in respiratory function (FVC) between baseline and week 12 (P = 0.027). GM604 decreased plasma levels of key ALS biomarkers relative to the placebo group (TDP-43, P = 0.008; Tau, P = 0.037; SOD1, P = 0.009). The advanced ALS patient in compassionate treatment demonstrated improved speech, oral fluid consumption, mouth suction with GM604 treatment and biomarker improvements. Conclusions We observed favorable shifts in ALS biomarkers and improved functional measures during the Phase 2A study as well as in an advanced ALS patient. Although a larger trial is needed to confirm these findings, the present data are encouraging and support GM604 as an ALS drug candidate.}, }
@article {pmid28258384, year = {2017}, author = {Bausch, D and Keck, T}, title = {[Laparoscopic pancreatic resection].}, journal = {Der Chirurg; Zeitschrift fur alle Gebiete der operativen Medizen}, volume = {88}, number = {6}, pages = {484-489}, pmid = {28258384}, issn = {1433-0385}, mesh = {Cohort Studies ; Germany ; Hospitals, High-Volume/statistics &amp; numerical data ; Hospitals, Low-Volume/statistics &amp; numerical data ; Laparoscopy/instrumentation/*methods ; Pancreatectomy/instrumentation/*methods ; Pancreatic Neoplasms/mortality/*surgery ; Retrospective Studies ; Survival Analysis ; }, abstract = {INTRODUCTION AND PURPOSE: Despite being technically challenging, laparoscopic surgical procedures are increasingly being used also in pancreatic surgery. This review attempts to evaluate these procedures based on the currently available literature against the background of the high mortality of pancreatic surgery observed nationwide and the as yet unclear oncological validation of these procedures.<br><br>MATERIAL AND METHODS: Recently published retrospective cohort and register trials have evaluated not only perioperative outcome but also long-term survival after laparoscopic pancreatic resection.<br><br>RESULTS AND CONCLUSION: Laparoscopic interventions are increasingly being used for treatment of malignant tumors of the pancreas. The advantages of laparoscopy, such as less intraoperative blood loss, reduced postoperative pain and a&#xa0;shorter duration of hospital stay, have all been demonstrated in retrospective trials. Equivalent long-term survival after oncological laparoscopic pancreatic surgery compared to open procedures was also observed in these trials; however, mortality even after laparoscopic pancreatic surgery was found to be significantly increased in low-volume centers. Prospective trials are still needed to prove adequate oncological treatment. Laparoskopische Verfahren haben sich in den letzten Jahren in fast allen Bereichen der Chirurgie quasi zum Standard entwickelt und werden von Patienten zunehmend nachgefragt. Die kosmetischen Ergebnisse sind deutlich besser als bei konventionellem Vorgehen und sie reduzieren unter anderem den postoperativen Schmerz, Schmerzmittelbedarf sowie den Krankenhausaufenthalt [29]. Daher ist es wenig &#xfc;berraschend, dass minimal-invasive Verfahren auch bei technisch hochkomplexen Eingriffen, wie z.&#x2009;B. am Pankreas, zunehmend eingesetzt werden. Allerdings wird ihr Einsatz hier noch immer kontrovers diskutiert.}, }
@article {pmid28253479, year = {2017}, author = {von Vopelius-Feldt, J and Brandling, J and Benger, J}, title = {Systematic review of the effectiveness of prehospital critical care following out-of-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {114}, number = {}, pages = {40-46}, doi = {10.1016/j.resuscitation.2017.02.018}, pmid = {28253479}, issn = {1873-1570}, support = {DRF-2015-08-040/DH_/Department of Health/United Kingdom ; }, mesh = {Advanced Cardiac Life Support/*standards ; Critical Care/*standards ; Emergency Medical Services/*standards ; Female ; Humans ; Male ; Observational Studies as Topic ; Out-of-Hospital Cardiac Arrest/mortality/*therapy ; Outcome Assessment, Health Care ; Prospective Studies ; *Quality of Health Care ; }, abstract = {BACKGROUND: Improving survival after out-of-hospital cardiac arrest (OHCA) is a priority for modern emergency medical services (EMS) and prehospital research. Advanced life support (ALS) is now the standard of care in most EMS. In some EMS, prehospital critical care providers are also dispatched to attend OHCA. This systematic review presents the evidence for prehospital critical care for OHCA, when compared to standard ALS care.<br><br>METHODS: We searched the following electronic databases: PubMed, EmBASE, CINAHL Plus and AMED (via EBSCO), Cochrane Database of Systematic Reviews, DARE, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, NIHR Health Technology Assessment Database, Google Scholar and ClinicalTrials.gov. Search terms related to cardiac arrest and prehospital critical care. All studies that compared patient-centred outcomes between prehospital critical care and ALS for OHCA were included.<br><br>RESULTS: The review identified six full text publications that matched the inclusion criteria, all of which are observational studies. Three studies showed no benefit from prehospital critical care but were underpowered with sample sizes of 1028-1851. The other three publications showed benefit from prehospital critical care delivered by physicians. However, an imbalance of prognostic factors and hospital treatment in these studies systematically favoured the prehospital critical care group.<br><br>CONCLUSION: Current evidence to support prehospital critical care for OHCA is limited by the logistic difficulties of undertaking high quality research in this area. Further research needs an appropriate sample size with adjustments for confounding factors in observational research design.}, }
@article {pmid28243281, year = {2016}, author = {Shafaroodi, H and Shahbek, F and Faizi, M and Ebrahimi, F and Moezi, L}, title = {Creatine Revealed Anticonvulsant Properties on Chemically and Electrically Induced Seizures in Mice.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {15}, number = {4}, pages = {843-850}, pmid = {28243281}, issn = {1735-0328}, abstract = {Creatine exerts beneficial effects on a variety of pathologies in which energy metabolism and oxidative stress play an etiological role. Creatine supplements have shown beneficial effects on neurological disorders including Parkinson׳s disease, Huntington›s disease, amyotrophic lateral sclerosis, as well as Alzheimer›s disease and stroke. However, the potential benefits of creatine for patients with convulsive disorders remain poorly defined. While some authors did not suggest any anti- or pro-convulsant roles for creatine treatment, others suggest that creatine may be an anticonvulsant agent. In this study, we investigated the effects of creatine on seizures in mice. Three models were used to explore the role of creatine on seizures in mice including intravenous pentylenetetrazole (PTZ), intraperitoneal PTZ, and electroshock models. Acute creatine treatment (10, 20, 40 and 80 mg/Kg) significantly increased the clonic seizure threshold in the intravenous PTZ model. Sub-chronic administration of creatine (10 and 20 mg/Kg) revealed a significant anticonvulsant effect in intravenous PTZ model. Acute creatine administration (10, 20 and 40 mg/Kg) significantly decreased the frequency of clonic seizures in the intraperitoneal PTZ model. Besides, acute creatine (40 and 80 mg/Kg) decreased the incidence of tonic seizures after electroshock. In conclusion, creatine exerts anticonvulsant effects in three seizure models; therefore, it may act as a potential drug to help patients with convulsions. However, further investigations should be done to clarify these results more.}, }
@article {pmid28229532, year = {2017}, author = {Zhou, QM and Zhang, JJ and Li, S and Chen, S and Le, WD}, title = {n-butylidenephthalide treatment prolongs life span and attenuates motor neuron loss in SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {23}, number = {5}, pages = {375-385}, pmid = {28229532}, issn = {1755-5949}, mesh = {Administration, Oral ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology/physiopathology ; Animals ; Apoptosis/drug effects/physiology ; Autophagy/drug effects/physiology ; Cell Survival/drug effects/physiology ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Hindlimb/drug effects/pathology/physiopathology ; Humans ; Mice, Transgenic ; Motor Activity/drug effects/physiology ; Motor Neurons/*drug effects/pathology/physiology ; Muscle Strength/drug effects/physiology ; Muscle, Skeletal/drug effects/pathology/physiopathology ; Neuroimmunomodulation/drug effects/physiology ; Neuroprotective Agents/*pharmacology ; Phthalic Anhydrides/*pharmacology ; Random Allocation ; Spinal Cord/drug effects/pathology/physiopathology ; Superoxide Dismutase-1/genetics/*metabolism ; }, abstract = {AIMS: To evaluate the therapeutic effects of n-butylidenephthalide (BP) in SOD1[G93A] mouse model of amyotrophic lateral sclerosis and explore the possible mechanisms.<br><br>METHODS: The SOD1[G93A] mice were treated by oral administration of BP (q.d., 400&#xa0;mg/kg&#xa0;d) starting from 60&#xa0;days of age and continuing until death. The rotarod test was performed to assess the disease onset. The expression levels of apoptosis-related proteins, inflammatory molecules, and autophagy-associated proteins were determined. The number of apoptotic motor neurons and the extent of microglial and astroglial activation were also assessed in the lumbar spinal cords of BP-treated mice. Grip strength test, hematoxylin-eosin staining, nicotinamide adenine dinucleotide hydrogen staining, and malondialdehyde assay were conducted to evaluate the muscle function and pathology.<br><br>RESULTS: Although BP treatment did not delay the disease onset, it prolonged the life span and thereafter extended the disease duration in SOD1[G93A] mouse model of ALS. BP treatment also reduced the motor neuron loss through inhibiting apoptosis. We further demonstrated that the neuroprotective effects of BP might be resulted from the inhibition of inflammatory, oxidative stress, and autophagy.<br><br>CONCLUSION: Our study suggests that BP may be a promising candidate for the treatment of ALS.}, }
@article {pmid28229508, year = {2017}, author = {Pagnini, F and Marconi, A and Tagliaferri, A and Manzoni, GM and Gatto, R and Fabiani, V and Gragnano, G and Rossi, G and Volpato, E and Banfi, P and Palmieri, A and Graziano, F and Castelnuovo, G and Corbo, M and Molinari, E and Riva, N and Sansone, V and Lunetta, C}, title = {Meditation training for people with amyotrophic lateral sclerosis: a randomized clinical trial.}, journal = {European journal of neurology}, volume = {24}, number = {4}, pages = {578-586}, doi = {10.1111/ene.13246}, pmid = {28229508}, issn = {1468-1331}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*psychology ; Anxiety/psychology/therapy ; Depression/psychology/therapy ; Female ; Humans ; Male ; Meditation/*psychology ; Middle Aged ; Quality of Life/*psychology ; Stress, Psychological/psychology/*therapy ; Treatment Outcome ; }, abstract = {BACKGROUND AND PURPOSE: Studies investigating psychological interventions for the promotion of well-being in people with amyotrophic lateral sclerosis (ALS) are lacking. The purpose of the current study was to examine the use of an ALS-specific mindfulness-based intervention for improving quality of life in this population.<br><br>METHODS: A randomized, open-label and controlled clinical trial was conducted on the efficacy of an ALS-specific meditation programme in promoting quality of life. Adults who received a diagnosis of ALS within 18 months were randomly assigned either to usual care or to an 8-week meditation training based on the original mindfulness-based stress reduction programme and tailored for people with ALS. Quality of life, assessed with the ALS-Specific Quality of Life Revised scale, represented the primary outcome, whilst secondary outcomes included anxiety and depression, assessed with the Hospital Anxiety and Depression Scale, and specific quality of life domains. Participants were assessed at recruitment and after 2, 6 and 12 months. The efficacy of the treatment was assessed on an intention-to-treat basis of a linear mixed model.<br><br>RESULTS: A hundred participants were recruited between November 2012 and December 2014. Over time, there was a significant difference between the two groups in terms of quality of life (&#x3b2; = 0.24, P = 0.015, d = 0.89). Significant differences between groups over time were also found for anxiety, depression, negative emotions, and interaction with people and the environment.<br><br>CONCLUSIONS: An ALS-specific meditation programme is beneficial for the quality of life and psychological well-being of people with ALS.}, }
@article {pmid28225381, year = {2017}, author = {Oh, J and Kim, JA}, title = {Information-seeking Behavior and Information Needs in Patients With Amyotrophic Lateral Sclerosis: Analyzing an Online Patient Community.}, journal = {Computers, informatics, nursing : CIN}, volume = {35}, number = {7}, pages = {345-351}, doi = {10.1097/CIN.0000000000000333}, pmid = {28225381}, issn = {1538-9774}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Disease Management ; Family/*psychology ; Female ; Humans ; *Information Seeking Behavior ; *Internet ; Male ; Republic of Korea ; }, abstract = {A few studies have examined the specific informational needs of the population with amyotrophic lateral sclerosis. The aims of this study were to describe the information-seeking behavior and information needs of patients with amyotrophic lateral sclerosis and their families in Korea by analyzing messages from an online patient community. A total of 1047 messages from the question and answer forum of the "Lou Gehrig's Disease Network" (http://cafe.daum.net/alsfree) from January 2010 to September 2015 were collected. The word frequency, main questions, and asker of the messages were analyzed and coded. Terms such as "hospital," "mother," "father," "gastrostomy," and "ALS" were most frequently identified. The most commonly mentioned main topic was about disease-specific information, while the most frequent subcategory was symptoms or management of symptoms. Other prominent categories concerned information about treatment, rehabilitation, and the medical system. The people who wrote the questions were mostly the son/daughter of patients with amyotrophic lateral sclerosis. Patients with amyotrophic lateral sclerosis and their family members commonly obtained information by posting their inquiries online and have a variety of questions regarding amyotrophic lateral sclerosis in this study. The findings of this study can be used as a base of information for developing educational programs and resources for patients with amyotrophic lateral sclerosis and their families.}, }
@article {pmid28210978, year = {2017}, author = {Masdeu, JC}, title = {Future Directions in Imaging Neurodegeneration.}, journal = {Current neurology and neuroscience reports}, volume = {17}, number = {1}, pages = {9}, pmid = {28210978}, issn = {1534-6293}, mesh = {Alzheimer Disease/*diagnosis/metabolism ; Amyloid/analysis/metabolism ; Animals ; Humans ; Magnetic Resonance Imaging ; Neuroimaging/*methods ; Positron-Emission Tomography ; tau Proteins/analysis/metabolism ; }, abstract = {Neuroimaging comprises a powerful set of instruments to diagnose various neurodegenerative disorders, clarifies their neurobiology, and monitors their treatment. Magnetic resonance imaging depicts volume changes, as well as abnormalities in functional and structural connectivity. Positron emission tomography (PET) allows for the quantification of regional cerebral metabolism, characteristically altered in Alzheimer's disease, amyotrophic lateral sclerosis, diffuse Lewy-body disease, and the frontotemporal dementias. PET is also used to measure several neurotransmitters, such as dopamine, which is abnormal in Parkinson's disease, and to determine the abnormal brain deposition of amyloid-β and tau, as well as brain inflammation. These instruments allow for the quantification in vivo and the longitudinal follow-up of key neurobiological events in neurodegeneration. For instance, amyloid imaging is being used not only to determine who has excess amyloid in the brain but also to investigate whether removing it may slow the deposition of tau and delay cognitive impairment in Alzheimer's disease.}, }
@article {pmid28205575, year = {2017}, author = {Hilton, JB and Mercer, SW and Lim, NK and Faux, NG and Buncic, G and Beckman, JS and Roberts, BR and Donnelly, PS and White, AR and Crouch, PJ}, title = {Cu[II](atsm) improves the neurological phenotype and survival of SOD1[G93A] mice and selectively increases enzymatically active SOD1 in the spinal cord.}, journal = {Scientific reports}, volume = {7}, number = {}, pages = {42292}, pmid = {28205575}, issn = {2045-2322}, mesh = {Administration, Oral ; Animals ; Coordination Complexes ; Copper/metabolism ; Cytochromes c/metabolism ; Gliosis/metabolism/pathology ; Humans ; Liver/enzymology ; Mice, Transgenic ; Mitochondria/metabolism ; Motor Neurons/drug effects/metabolism/pathology ; Mutation/genetics ; Organometallic Compounds/administration &amp; dosage/*pharmacology ; Oxidative Stress/drug effects ; Phenotype ; Spinal Cord/*enzymology/*pathology ; Superoxide Dismutase/*metabolism ; Survival Analysis ; Thiosemicarbazones/administration &amp; dosage/*pharmacology ; Tissue Extracts ; }, abstract = {Ubiquitous expression of mutant Cu/Zn-superoxide dismutase (SOD1) selectively affects motor neurons in the central nervous system (CNS), causing the adult-onset degenerative disease amyotrophic lateral sclerosis (ALS). The CNS-specific impact of ubiquitous mutant SOD1 expression is recapitulated in transgenic mouse models of the disease. Here we present outcomes for the metallo-complex Cu[II](atsm) tested for therapeutic efficacy in mice expressing SOD1[G93A] on a mixed genetic background. Oral administration of Cu[II](atsm) delayed the onset of neurological symptoms, improved locomotive capacity and extended overall survival. Although the ALS-like phenotype of SOD1[G93A] mice is instigated by expression of the mutant SOD1, we show the improved phenotype of the Cu[II](atsm)-treated animals involves an increase in mature mutant SOD1 protein in the disease-affected spinal cord, where concomitant increases in copper and SOD1 activity are also evident. In contrast to these effects in the spinal cord, treating with Cu[II](atsm) had no effect in liver on either mutant SOD1 protein levels or its activity, indicating a CNS-selective SOD1 response to the drug. These data provide support for Cu[II](atsm) as a treatment option for ALS as well as insight to the CNS-selective effects of mutant SOD1.}, }
@article {pmid28197175, year = {2016}, author = {Giacoppo, S and Mazzon, E}, title = {Can cannabinoids be a potential therapeutic tool in amyotrophic lateral sclerosis?.}, journal = {Neural regeneration research}, volume = {11}, number = {12}, pages = {1896-1899}, pmid = {28197175}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system. Over the last years, a growing interest was aimed to discovery new innovative and safer therapeutic approaches in the ALS treatment. In this context, the bioactive compounds of Cannabis sativa have shown antioxidant, anti-inflammatory and neuroprotective effects in preclinical models of central nervous system disease. However, most of the studies proving the ability of cannabinoids in delay disease progression and prolong survival in ALS were performed in animal model, whereas the few clinical trials that investigated cannabinoids-based medicines were focused only on the alleviation of ALS-related symptoms, not on the control of disease progression. The aim of this report was to provide a short but important overview of evidences that are useful to better characterize the efficacy as well as the molecular pathways modulated by cannabinoids.}, }
@article {pmid28197100, year = {2017}, author = {Günther, R and Balck, A and Koch, JC and Nientiedt, T and Sereda, M and Bähr, M and Lingor, P and Tönges, L}, title = {Rho Kinase Inhibition with Fasudil in the SOD1[G93A] Mouse Model of Amyotrophic Lateral Sclerosis-Symptomatic Treatment Potential after Disease Onset.}, journal = {Frontiers in pharmacology}, volume = {8}, number = {}, pages = {17}, pmid = {28197100}, issn = {1663-9812}, abstract = {Despite an improved understanding of the genetic background and the pathomechanisms of amyotrophic lateral sclerosis (ALS) no novel disease-modifying therapies have been successfully implemented in clinical routine. Riluzole still remains the only clinically approved substance in human ALS treatment with limited efficacy. We have previously identified pharmacological rho kinase (ROCK) inhibitors as orally applicable substances in SOD1.G93A transgenic ALS mice (SOD1[G93A]), which are able to extend survival time and improve motor function after presymptomatic treatment. Here, we have evaluated the therapeutic effect of the orally administered ROCK inhibitor Fasudil starting at a symptomatic disease stage, more realistically reflecting the clinical situation. Oral Fasudil treatment was initiated at a symptomatic stage at 80 days of life (d80) with 30 or 100 mg/kg body weight in both female and male mice. While baseline neurological scoring and survival were not influenced, Fasudil significantly improved motor behavior in male mice. Spinal cord pathology of motoneurons (MN) and infiltrating microglial cells (MG) at disease end-stage were not significantly modified. Although treatment after symptom onset was less potent than treatment in asymptomatic animals, our study shows the therapeutic benefits of this well-tolerated substance, which is already in clinical use for other indications.}, }
@article {pmid28196613, year = {2017}, author = {Wu, B and De, SK and Kulinich, A and Salem, AF and Koeppen, J and Wang, R and Barile, E and Wang, S and Zhang, D and Ethell, I and Pellecchia, M}, title = {Potent and Selective EphA4 Agonists for the Treatment of ALS.}, journal = {Cell chemical biology}, volume = {24}, number = {3}, pages = {293-305}, pmid = {28196613}, issn = {2451-9448}, support = {P01 CA138390/CA/NCI NIH HHS/United States ; R01 CA168517/CA/NCI NIH HHS/United States ; P41 GM103311/GM/NIGMS NIH HHS/United States ; R01 MH067121/MH/NIMH NIH HHS/United States ; P30 CA030199/CA/NCI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Binding Sites ; Cells, Cultured ; Disease Models, Animal ; Drug Design ; Half-Life ; Humans ; Ligands ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; Molecular Docking Simulation ; Protein Binding ; Protein Isoforms/metabolism ; Protein Structure, Tertiary ; Receptor, EphA4/*agonists/chemistry/metabolism ; Small Molecule Libraries/chemistry/metabolism/pharmacokinetics/therapeutic use ; Structure-Activity Relationship ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease that affects motor neurons. Recent studies identified the receptor tyrosine kinase EphA4 as a disease-modifying gene that is critical for the progression of motor neuron degeneration. We report on the design and characterization of a family of EphA4 targeting agents that bind to its ligand binding domain with nanomolar affinity. The molecules exhibit excellent selectivity and display efficacy in a SOD1 mutant mouse model of ALS. Interestingly, the molecules appear to act as agonists for the receptor in certain surrogate cellular assays. While the exact mechanisms responsible for the therapeutic effect of the new agonists remain to be elucidated, we believe that the described agent represents both an invaluable pharmacological tool to further decipher the role of the EphA4 in ALS and potentially other human diseases, and a significant stepping stone for the development of novel treatments.}, }
@article {pmid28193696, year = {2017}, author = {Jo, M and Kim, JH and Song, GJ and Seo, M and Hwang, EM and Suk, K}, title = {Astrocytic Orosomucoid-2 Modulates Microglial Activation and Neuroinflammation.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {37}, number = {11}, pages = {2878-2894}, pmid = {28193696}, issn = {1529-2401}, mesh = {Animals ; Brain/*immunology/*pathology ; Cytokines/immunology ; Encephalitis/*immunology/pathology ; Humans ; Immunologic Factors/*immunology ; Male ; Mice ; Mice, Inbred C57BL ; Microglia/*immunology/pathology ; Orosomucoid/*immunology ; }, abstract = {Orosomucoid (ORM) is an acute-phase protein that belongs to the immunocalin subfamily, a group of small-molecule-binding proteins with immunomodulatory functions. Little is known about the role of ORM proteins in the CNS. The aim of the present study was to investigate the brain expression of ORM and its role in neuroinflammation. Expression of Orm2, but not Orm1 or Orm3, was highly induced in the mouse brain after systemic injection of lipopolysaccharide (LPS). Plasma levels of ORM2 were also significantly higher in patients with cognitive impairment than in normal subjects. RT-PCR, Western blot, and immunofluorescence analyses revealed that astrocytes are the major cellular sources of ORM2 in the inflamed mouse brain. Recombinant ORM2 protein treatment decreased microglial production of proinflammatory mediators and reduced microglia-mediated neurotoxicity in vitro LPS-induced microglial activation, proinflammatory cytokines in hippocampus, and neuroinflammation-associated cognitive deficits also decreased as a result of intracerebroventricular injection of recombinant ORM2 protein in vivo Moreover, lentiviral shRNA-mediated Orm2 knockdown enhanced LPS-induced proinflammatory cytokine gene expression and microglial activation in the hippocampus. Mechanistically, ORM2 inhibited C-C chemokine ligand 4 (CCL4)-induced microglial migration and activation by blocking the interaction of CCL4 with C-C chemokine receptor type 5. Together, the results from our cultured glial cells, mouse neuroinflammation model, and patient studies suggest that ORM2 is a novel mediator of astrocyte-microglial interaction. We also report that ORM2 exerts anti-inflammatory effects by modulating microglial activation and migration during brain inflammation. ORM2 can be exploited therapeutically for the treatment of neuroinflammatory diseases.SIGNIFICANCE STATEMENT Neural cell interactions are important for brain physiology and pathology. Particularly, the interaction between non-neuronal cells plays a central role in regulating brain inflammation, which is closely linked to many brain disorders. Here, we newly identified orosomucoid-2 (ORM2) as an endogenous protein that mediates such non-neuronal glial cell interactions. Based on the critical role of astrocyte-derived ORM2 in modulating microglia-mediated neuroinflammation, ORM2 can be exploited for the diagnosis, prevention, or treatment of devastating brain disorders that have a strong neuroinflammatory component, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis.}, }
@article {pmid28184974, year = {2017}, author = {Wolf, J and Safer, A and Wöhrle, JC and Palm, F and Nix, WA and Maschke, M and Grau, AJ}, title = {[Causes of death in amyotrophic lateral sclerosis : Results from the Rhineland-Palatinate ALS registry].}, journal = {Der Nervenarzt}, volume = {88}, number = {8}, pages = {911-918}, pmid = {28184974}, issn = {1433-0407}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*mortality ; *Cause of Death ; Cohort Studies ; Female ; Germany ; Humans ; Male ; Middle Aged ; Prospective Studies ; Registries/*statistics &amp; numerical data ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is associated with an increased mortality. Knowledge of possible causes of death could lead to an individualization of the palliative treatment concept and result in a differentiated palliative treatment pathway. Currently, only few systematic data are available on the heterogeneity of causes of death associated with ALS.<br><br>OBJECTIVE: Analysis of the various causes of death in a&#xa0;prospective population-based German cohort of ALS patients.<br><br>MATERIAL AND METHODS: Analysis of data of the Rhineland-Palatinate ALS registry in which newly diagnosed patients who had been identified between October 2009 and September 2012 were prospectively enrolled and followed up at regular intervals. From this prospective cohort study the causes of death were elicited based on information provided by the attending physicians, family members and by means of death certificates registered by the regional health authorities in Rhineland-Palatinate.<br><br>RESULTS: Out of 200 ALS patients registered 148 died between register initiation on 1 October 2009 and the end of follow-up on 30 September 2015 (78&#xa0;males and 70&#xa0;females, death rate 74%). The most frequent cause of death was respiratory failure as a&#xa0;consequence of weakness of respiratory muscles (n&#xa0;= 91, 61%). Less frequent causes of death were pneumonia (n&#xa0;= 13, 9%), terminal cachexia (n&#xa0;= 9, 6%) and death from cardiovascular causes including sudden death (n&#xa0;= 9, 6%). Cases of suicide were rare (n&#xa0;= 3, 2%) as were deaths due to concurrent diseases (n&#xa0;= 2). In 21&#xa0;cases (14%) the exact cause of death could not be clarified. Differences in the causes of death only showed a tendency towards the ALS phenotype. Respiratory failure was the cause of death in all patients with a respiratory phenotype and in 78% of patients with flail arm syndrome. Despite the low number of patients (8%) with additional frontotemporal dementia (FTD) a&#xa0;distinct difference in causes of death between those with and without FTD could be observed. Death due to respiratory failure was less frequent in ALS patients with FTD (33% vs. 65%) while pneumonia was more frequent (27% vs. 7%).<br><br>CONCLUSION: Respiratory failure was the most frequent cause of death in our cohort of ALS patients. In contrast, pneumonia and nutritional disorders played a&#xa0;less important role as the cause of death. The phenotypic expression of ALS might in part allow the cause of the prospective death to be predicted. Differentiation of ALS phenotypes is an important foundation for patient counseling on the process of dying to be expected and for the determination of an individual palliative concept.}, }
@article {pmid28181459, year = {2017}, author = {Naz, S and Beach, J and Heckert, B and Tummala, T and Pashchenko, O and Banerjee, T and Santra, S}, title = {Cerium oxide nanoparticles: a 'radical' approach to neurodegenerative disease treatment.}, journal = {Nanomedicine (London, England)}, volume = {12}, number = {5}, pages = {545-553}, doi = {10.2217/nnm-2016-0399}, pmid = {28181459}, issn = {1748-6963}, mesh = {Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Blood-Brain Barrier/drug effects ; Cerium/chemistry/*therapeutic use ; Humans ; Multiple Sclerosis/drug therapy ; Nanomedicine/*trends ; Nanoparticles/chemistry/*therapeutic use ; Neurodegenerative Diseases/*drug therapy ; Oxidative Stress/drug effects ; Parkinson Disease/drug therapy ; }, abstract = {Despite advances in understanding the factors that cause many neurodegenerative diseases (NDs), no current therapies have yielded significant results. Cerium oxide nanoparticles (CeONPs) have recently emerged as therapeutics for the treatment of NDs due to their antioxidant properties. This report summarizes the recent findings regarding CeONPs in treatment of various NDs, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, ischemic stroke and amyotrophic lateral sclerosis. Interest in CeONPs as a potential nanomedicine for NDs has increased due to: their ability to alter signaling pathways, small diameter allowing passage through the blood-brain barrier and scavenging of reactive oxygen species. Due to these properties, CeONPs could eventually revolutionize existing treatments for NDs.}, }
@article {pmid28178902, year = {2017}, author = {Silva Adaya, D and Aguirre-Cruz, L and Guevara, J and Ortiz-Islas, E}, title = {Nanobiomaterials' applications in neurodegenerative diseases.}, journal = {Journal of biomaterials applications}, volume = {31}, number = {7}, pages = {953-984}, doi = {10.1177/0885328216659032}, pmid = {28178902}, issn = {1530-8022}, mesh = {Animals ; Biocompatible Materials/administration &amp; dosage/chemical synthesis ; Blood-Brain Barrier/*chemistry ; Diffusion ; Drug Compounding/methods ; Evidence-Based Medicine ; Humans ; Nanocapsules/*administration &amp; dosage/*chemistry/ultrastructure ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/*administration &amp; dosage/*chemistry ; Particle Size ; Tissue Distribution ; }, abstract = {The blood-brain barrier is the interface between the blood and brain, impeding the passage of most circulating cells and molecules, protecting the latter from foreign substances, and maintaining central nervous system homeostasis. However, its restrictive nature constitutes an obstacle, preventing therapeutic drugs from entering the brain. Usually, a large systemic dose is required to achieve pharmacological therapeutic levels in the brain, leading to adverse effects in the body. As a consequence, various strategies are being developed to enhance the amount and concentration of therapeutic compounds in the brain. One such tool is nanotechnology, in which nanostructures that are 1-100 nm are designed to deliver drugs to the brain. In this review, we examine many nanotechnology-based approaches to the treatment of neurodegenerative diseases. The review begins with a brief history of nanotechnology, followed by a discussion of its definition, the properties of most reported nanomaterials, their biocompatibility, the mechanisms of cell-material interactions, and the current status of nanotechnology in treating Alzheimer's, Parkinson's diseases, and amyotrophic lateral sclerosis. Of all strategies to deliver drug to the brain that are used in nanotechnology, drug release systems are the most frequently reported.}, }
@article {pmid28178599, year = {2017}, author = {Dworetzky, SI and Hebrank, GT and Archibald, DG and Reynolds, IJ and Farwell, W and Bozik, ME}, title = {The targeted eosinophil-lowering effects of dexpramipexole in clinical studies.}, journal = {Blood cells, molecules &amp; diseases}, volume = {63}, number = {}, pages = {62-65}, doi = {10.1016/j.bcmd.2017.01.008}, pmid = {28178599}, issn = {1096-0961}, mesh = {Benzothiazoles/adverse effects/*pharmacology/therapeutic use ; Dose-Response Relationship, Drug ; Double-Blind Method ; Eosinophilia/drug therapy ; Eosinophils/cytology/*drug effects ; Humans ; Hypereosinophilic Syndrome/drug therapy ; Infections/chemically induced ; Leukocyte Count ; Pramipexole ; }, abstract = {Dexpramipexole, an orally bioavailable small molecule previously under clinical development in amyotrophic lateral sclerosis, was observed during routine safety hematology monitoring to demonstrate pronounced, dose- and time-dependent eosinophil-lowering effects, with minor reductions on other leukocyte counts. Analysis of hematology lab values across two double-blind, randomized placebo-controlled clinical trials at total daily doses ranging from 50mg to 300mg demonstrated that dexpramipexole consistently and markedly lowered peripheral blood eosinophils. This effect developed after 1month on treatment, required 3-4months to reach its maximum, remained constant throughout treatment, and partially recovered to baseline levels upon drug withdrawal. All doses tested were well tolerated. The overall adverse event rate was similar for dexpramipexole and placebo, and notably with no increase in infection-related adverse events associated with eosinophil-lowering effects. Given the reliance on and insufficiency of off-label chronic corticosteroid therapy for hypereosinophilic syndromes and other eosinophilic-associated diseases (EADs), a need exists for less toxic, more effective, targeted therapeutic alternatives. Further clinical studies are underway to assess the eosinophil-lowering effect of dexpramipexole in the peripheral blood and target tissues of EAD patients and whether such reductions, if observed, produce clinically important benefits.}, }
@article {pmid28178525, year = {2017}, author = {Rodriguez-Muela, N and Litterman, NK and Norabuena, EM and Mull, JL and Galazo, MJ and Sun, C and Ng, SY and Makhortova, NR and White, A and Lynes, MM and Chung, WK and Davidow, LS and Macklis, JD and Rubin, LL}, title = {Single-Cell Analysis of SMN Reveals Its Broader Role in Neuromuscular Disease.}, journal = {Cell reports}, volume = {18}, number = {6}, pages = {1484-1498}, pmid = {28178525}, issn = {2211-1247}, support = {P01 NS066888/NS/NINDS NIH HHS/United States ; R01 NS045523/NS/NINDS NIH HHS/United States ; R01 NS075672/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Disease Models, Animal ; Humans ; Mice ; Motor Neurons/metabolism ; Muscular Atrophy, Spinal/metabolism ; Neuromuscular Diseases/*metabolism ; SMN Complex Proteins/*metabolism ; Single-Cell Analysis/methods ; Spinal Cord/metabolism ; }, abstract = {The mechanism underlying selective motor neuron (MN) death remains an essential question in the MN disease field. The MN disease spinal muscular atrophy (SMA) is attributable to reduced levels of the ubiquitous protein SMN. Here, we report that SMN levels are widely variable in MNs within a single genetic background and that this heterogeneity is seen not only in SMA MNs but also in MNs derived from controls and amyotrophic lateral sclerosis (ALS) patients. Furthermore, cells with low SMN are more susceptible to cell death. These findings raise the important clinical implication that some SMN-elevating therapeutics might be effective in MN diseases besides SMA. Supporting this, we found that increasing SMN across all MN populations using an Nedd8-activating enzyme inhibitor promotes survival in both SMA and ALS-derived MNs. Altogether, our work demonstrates that examination of human neurons at the single-cell level can reveal alternative strategies to be explored in the treatment of degenerative diseases.}, }
@article {pmid28168522, year = {2017}, author = {Visser, AE and Pazoki, R and Pulit, SL and van Rheenen, W and Raaphorst, J and van der Kooi, AJ and Ricaño-Ponce, I and Wijmenga, C and Otten, HG and Veldink, JH and van den Berg, LH}, title = {No association between gluten sensitivity and amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {264}, number = {4}, pages = {694-700}, pmid = {28168522}, issn = {1432-1459}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*blood/epidemiology/genetics ; Antibodies/*blood ; Case-Control Studies ; Cohort Studies ; Diet, Gluten-Free/methods ; Female ; Glutens/*genetics/*metabolism ; Humans ; Male ; Middle Aged ; Netherlands/epidemiology ; Regression Analysis ; Surveys and Questionnaires ; Transglutaminases/immunology ; Young Adult ; }, abstract = {To examine evidence for a role of gluten sensitivity (GS) or celiac disease (CD) in ALS etiology, we included participants from a population-based case-control study in The Netherlands between January 2006 and December 2015. We compared levels and seroprevalence of IgA antibodies to tissue transglutaminase 6 (TG6) in 359 ALS patients and 359 controls, and to transglutaminase 2 (TG2) and endomysium (EMA) in 199 ALS patients and 199 controls. Questionnaire data on 1829 ALS patients and 3920 controls were examined for CD or gluten-free diets (GFD). Genetic correlation and HLA allele frequencies were analyzed using two genome-wide association studies: one on ALS (12,577 cases, 23,475 controls), and one on CD (4533 cases, 10,750 controls). We found one patient with TG6, TG2 and EMA antibodies who had typical ALS and no symptoms of GS. TG6 antibody concentrations and positivity, CD prevalence and adherence to a GFD were similar in patients and controls (p > 0.66) and in these patients disease progression was compatible with typical ALS. CD and ALS were not found to be genetically correlated (p > 0.37). CD-associated HLA allele frequencies were similar in patients and controls (p > 0.28). In conclusion, we found no serological evidence for involvement of gluten-related antibodies in ALS etiology nor did we observe an association between CD and ALS in medical history or genetic data, indicating that there is no evidence in our data for an association between the two diseases. Hence, a role for a GFD in the ALS treatment seems unlikely.}, }
@article {pmid28166654, year = {2017}, author = {Sufit, RL and Ajroud-Driss, S and Casey, P and Kessler, JA}, title = {Open label study to assess the safety of VM202 in subjects with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {3-4}, pages = {269-278}, doi = {10.1080/21678421.2016.1259334}, pmid = {28166654}, issn = {2167-9223}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology/physiopathology ; Female ; Genetic Therapy/*adverse effects ; Hepatocyte Growth Factor/*adverse effects/genetics/pharmacokinetics/*therapeutic use ; Humans ; Injections, Intramuscular ; Male ; Middle Aged ; Muscle Strength ; Muscle, Skeletal/pathology ; Plasmids ; Treatment Outcome ; Vital Capacity ; Young Adult ; }, abstract = {OBJECTIVE: To assess safety and define efficacy measures of hepatocyte growth factor (HGF) DNA plasmid, VM202, administered by intramuscular injections in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Eighteen participants were treated with VM202 administered in divided doses by injections alternating between the upper and lower limbs on d 0, 7, 14, and 21. Subjects were followed for nine months to evaluate possible adverse events. Functional outcome was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R) as well as by serially measuring muscle strength, muscle circumference, and forced vital capacity.<br><br>RESULTS: Seventeen of 18 participants completed the study. All participants tolerated 64&#x2009;mg of VM202 well with no serious adverse events (SAE) related to the drug. Twelve participants reported 26 mild or moderate injection site reactions. Three participants experienced five SAEs unrelated to VM202. One subject died from respiratory insufficiency secondary to ALS progression.<br><br>CONCLUSIONS: Multiple intramuscular injection of VM202 into the limbs appears safe in ALS subjects. Future trials with retreatment after three months will determine whether VM202 treatment alters the long-term course of ALS.}, }
@article {pmid28164765, year = {2017}, author = {Ahmad, K and Baig, MH and Mushtaq, G and Kamal, MA and Greig, NH and Choi, I}, title = {Commonalities in Biological Pathways, Genetics, and Cellular Mechanism between Alzheimer Disease and Other Neurodegenerative Diseases: An In Silico-Updated Overview.}, journal = {Current Alzheimer research}, volume = {14}, number = {11}, pages = {1190-1197}, pmid = {28164765}, issn = {1875-5828}, support = {Z99 AG999999//Intramural NIH HHS/United States ; ZIA AG000311-16//Intramural NIH HHS/United States ; }, mesh = {Computer Simulation ; Humans ; Neurodegenerative Diseases/*genetics/*metabolism/therapy ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common and well-studied neurodegenerative disease (ND). Biological pathways, pathophysiology and genetics of AD show commonalities with other NDs viz. Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Prion disease and Dentatorubral-pallidoluysian atrophy (DRPLA). Many of the NDs, sharing the common features and molecular mechanisms suggest that pathology may be directly comparable and be implicated in disease prevention and development of highly effective therapies.<br><br>METHOD: In this review, a brief description of pathophysiology, clinical symptoms and available treatment of various NDs have been explored with special emphasis on AD. Commonalities in these fatal NDs provide support for therapeutic advancements and enhance the understanding of disease manifestation.<br><br>CONCLUSION: The studies concentrating on the commonalities in biological pathways, cellular mechanisms and genetics may provide the scope to researchers to identify few novel common target(s) for disease prevention and development of effective common drugs for multi-neurodegenerative diseases.}, }
@article {pmid28163728, year = {2016}, author = {Mokhtari, F and Matin, M and Rajati, F}, title = {Pemphigus vulgaris and amyotrophic lateral sclerosis.}, journal = {Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences}, volume = {21}, number = {}, pages = {82}, pmid = {28163728}, issn = {1735-1995}, abstract = {Pemphigus vulgaris (PV) is an autoimmune bullous and erosive mucocutaneous disease. Rarely, it occurs in patients with other autoimmune disease. The relation between PV and neurological disorders is unclear and needs to be more studied. Here, we report a case of amyotrophic lateral sclerosis (ALS), followed by dermatologic involvement. Histopathological evidence and direct immunofluorescence are consistent with PV. Systemic corticosteroid and azathioprine were effective in the treatment of mucocutaneous lesions. PV seems to be accidentally associated with ALS. Expression of major histocompatibility complex Class II in autoimmune disease and production of autoantibodies have been proposed to describe the association of PV with ALS.}, }
@article {pmid28163382, year = {2017}, author = {Yamamoto, Y}, title = {Plasma marker of tissue oxidative damage and edaravone as a scavenger drug against peroxyl radicals and peroxynitrite.}, journal = {Journal of clinical biochemistry and nutrition}, volume = {60}, number = {1}, pages = {49-54}, pmid = {28163382}, issn = {0912-0009}, abstract = {The percentage of the plasma oxidized form of coenzyme Q10 in the total amount of coenzyme Q10 (%CoQ10) is a useful marker of oxidative stress in the circulation. Plasma free fatty acids and their composition can be used as markers of tissue oxidative damage, as demonstrated in patients suffering from a wide variety of diseases and in humans and rats under oxidative stress. Edaravone was approved for the treatment of stroke in Japan in 2001 and its mechanism of action is based on scavenging lipid peroxyl radicals. In 2015, edaravone was also approved for the treatment of ALS patients. Edaravone functions therapeutically as a scavenger of peroxynitrite, as demonstrated by the finding that its administration raises plasma uric acid levels and decreases 3-nitrotyrosine in cerebrospinal fluid.}, }
@article {pmid28161391, year = {2017}, author = {Tu, WY and Simpson, JE and Highley, JR and Heath, PR}, title = {Spinal muscular atrophy: Factors that modulate motor neurone vulnerability.}, journal = {Neurobiology of disease}, volume = {102}, number = {}, pages = {11-20}, doi = {10.1016/j.nbd.2017.01.011}, pmid = {28161391}, issn = {1095-953X}, mesh = {Animals ; Humans ; Motor Neurons/*physiology ; Muscular Atrophy, Spinal/*physiopathology ; }, abstract = {Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterised by the selective loss of particular groups of motor neurones in the anterior horn of the spinal cord with concomitant muscle weakness. To date, no effective treatment is available, however, there are ongoing clinical trials are in place which promise much for the future. However, there remains an ongoing problem in trying to link a single gene loss to motor neurone degeneration. Fortunately, given successful disease models that have been established and intensive studies on SMN functions in the past ten years, we are fast approaching the stage of identifying the underlying mechanisms of SMA pathogenesis Here we discuss potential disease modifying factors on motor neurone vulnerability, in the belief that these factors give insight into the pathological mechanisms of SMA and therefore possible therapeutic targets.}, }
@article {pmid28155653, year = {2016}, author = {Joshi, K and Goyal, S and Grover, S and Jamal, S and Singh, A and Dhar, P and Grover, A}, title = {Novel group-based QSAR and combinatorial design of CK-1δ inhibitors as neuroprotective agents.}, journal = {BMC bioinformatics}, volume = {17}, number = {Suppl 19}, pages = {515}, pmid = {28155653}, issn = {1471-2105}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; Casein Kinase Idelta/*antagonists &amp; inhibitors ; DNA-Binding Proteins/chemistry ; *Drug Design ; Drug Discovery ; Humans ; *Models, Molecular ; Molecular Docking Simulation ; Neuroprotective Agents/*chemistry/pharmacology ; Phosphorylation ; Protein Conformation ; Protein Kinase Inhibitors/*chemistry/pharmacology ; *Quantitative Structure-Activity Relationship ; }, abstract = {BACKGROUND: Tar DNA binding protein 43 (TDP-43) hyperphosphorylation, caused by Casein kinase 1 (CK-1) protein isoforms, is associated with the onset and progression of Amyotrophic Lateral Sclerosis (ALS). Among the reported isoforms and splice variants of CK-1 protein superfamily, CK-1δ is known to phosphorylate different serine and threonine sites on TDP-43 protein in vitro and thus qualifies as a potential target for ALS treatment.<br><br>RESULTS: The developed GQSAR (group based quantitative structure activity relationship) model displayed satisfactory statistical parameters for the dataset of experimentally reported N-Benzothiazolyl-2-Phenyl Acetamide derivatives. A combinatorial library of molecules was also generated and the activities were predicted using the statistically sound GQSAR model. Compounds with higher predicted inhibitory activity were screened against CK-1&#x3b4; that resulted in to the potential novel leads for CK-1&#x3b4; inhibition.<br><br>CONCLUSIONS: In this study, a robust fragment based QSAR model was developed on a congeneric set of experimentally reported molecules and using combinatorial library approach, a series of molecules were generated from which we report two top scoring, CK-1&#x3b4; inhibitors i.e., CHC (6-benzyl-2-cyclopropyl-4-{[(4-cyclopropyl-6-ethyl-1,3-benzothiazol-2-yl)carbamoyl]methyl}j-3-fluorophenyl hydrogen carbonate) and DHC (6-benzyl-4-{[(4-cyclopropyl-6-ethyl-1,3-benzothiazol-2-yl)carbamoyl]methyl}-2-(decahydronaphthalen-1-yl)-3-hydroxyphenyl hydrogen carbonate) with binding energy of -6.11 and -6.01&#xa0;kcal/mol, respectively.}, }
@article {pmid28139349, year = {2017}, author = {Meininger, V and Genge, A and van den Berg, LH and Robberecht, W and Ludolph, A and Chio, A and Kim, SH and Leigh, PN and Kiernan, MC and Shefner, JM and Desnuelle, C and Morrison, KE and Petri, S and Boswell, D and Temple, J and Mohindra, R and Davies, M and Bullman, J and Rees, P and Lavrov, A and , }, title = {Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled, phase 2 trial.}, journal = {The Lancet. Neurology}, volume = {16}, number = {3}, pages = {208-216}, doi = {10.1016/S1474-4422(16)30399-4}, pmid = {28139349}, issn = {1474-4465}, mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Antibodies, Monoclonal, Humanized/*therapeutic use ; Double-Blind Method ; Electrocardiography ; Female ; Humans ; Immunologic Factors/*therapeutic use ; International Cooperation ; Male ; Middle Aged ; Nogo Proteins/*immunology ; Survival Analysis ; *Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a positive effect in the SOD1[G93A] mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS.<br><br>METHODS: This randomised, double-blind, placebo-controlled, phase 2 trial was done in 34 centres in 11 countries. Patients aged 18-80 years with a diagnosis of familial or sporadic ALS were randomly assigned (1:1), centrally according to a computer-generated allocation schedule, to receive ozanezumab (15 mg/kg) or placebo as intravenous infusions over 1 h every 2 weeks for 46 weeks, followed by assessments at week 48 and week 60. Patients and study personnel were masked to treatment assignment. The primary outcome was a joint-rank analysis of function (ALS Functional Rating Scale-Revised) and overall survival, analysed at 48 weeks in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01753076, and with GSK-ClinicalStudyRegister.com, NOG112264, and is completed.<br><br>FINDINGS: Between Dec 20, 2012, and Nov 1, 2013, we recruited 307 patients, of whom 303 were randomly assigned to receive placebo (n=151) or ozanezumab (n=152). The adjusted mean of the joint-rank score was -14&#xb7;9 (SE 13&#xb7;5) for the ozanezumab group and 15&#xb7;0 (13&#xb7;6) for the placebo group, with a least squares mean difference of -30&#xb7;0 (95% CI -67&#xb7;9 to 7&#xb7;9; p=0&#xb7;12). Overall, reported adverse events, serious adverse events, and adverse events leading to permanent discontinuation of study drug or withdrawal from study were similar between the treatment groups, except for dyspepsia (ten [7%] in the ozanezumab group vs four [3%] in the placebo group), depression (11 [7%] vs five [3%]), and diarrhoea (25 [16%] vs 12 [8%]). Respiratory failure was the most common serious adverse event (12 [8%] vs seven [5%]). At week 60, the number of deaths was higher in the ozanezumab group (20 [13%]) than in the placebo group (16 [11%]), mainly as a result of respiratory failure (ten [7%] vs five [3%]). Two deaths were considered related to the study drug (bladder transitional cell carcinoma in the ozanezumab group and cerebrovascular accident in the placebo group).<br><br>INTERPRETATION: Ozanezumab did not show efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS.<br><br>FUNDING: GlaxoSmithKline.}, }
@article {pmid28129947, year = {2017}, author = {Zhang, YG and Wu, S and Yi, J and Xia, Y and Jin, D and Zhou, J and Sun, J}, title = {Target Intestinal Microbiota to Alleviate Disease Progression in Amyotrophic Lateral Sclerosis.}, journal = {Clinical therapeutics}, volume = {39}, number = {2}, pages = {322-336}, pmid = {28129947}, issn = {1879-114X}, support = {R01 AR057404/AR/NIAMS NIH HHS/United States ; R01 DK105118/DK/NIDDK NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Disease Models, Animal ; Disease Progression ; *Gastrointestinal Microbiome ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/pathology ; Quality of Life ; Superoxide Dismutase/*metabolism ; }, abstract = {PURPOSE: Emerging evidence has demonstrated that gut microbiome plays essential roles in the pathogenesis of human diseases in distal organs. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Treatment with the only drug approved by the US Food and Drug Administration for use in ALS, riluzole, extends a patient׳s life span by only a few months. Thus, there is an urgent need to develop novel interventions that for alleviate disease progression and improve quality of life in patients with ALS. Here we present evidence that intestinal dysfunction and dysbiosis may actively contribute to ALS pathophysiology.<br><br>METHODS: We used G93A transgenic mice as a model of human ALS. The G93A mice show abnormal intestinal microbiome and damaged tight junctions before ALS disease onset. The mice were given 2% butyrate, a natural bacterial product, in the drinking water.<br><br>RESULTS: In mice fed with butyrate, intestinal microbial homeostasis was restored, gut integrity was improved, and life span was prolonged compared with those in control mice. At the cellular level, abnormal Paneth cells-specialized intestinal epithelial cells that regulate the host-bacterial interactions-were significantly decreased in the ALS mice treated with butyrate. In both ALS mice and intestinal epithelial cells cultured from humans, butyrate treatment was associated with decreased aggregation of the G93A superoxide dismutase 1 mutated protein.<br><br>IMPLICATIONS: The findings from this study highlight the complex role of the gut microbiome and intestinal epithelium in the progression of ALS and present butyrate as a potential therapeutic reagent for restoring ALS-related dysbiosis.}, }
@article {pmid28128456, year = {2017}, author = {Lee, JD and Kumar, V and Fung, JN and Ruitenberg, MJ and Noakes, PG and Woodruff, TM}, title = {Pharmacological inhibition of complement C5a-C5a1 receptor signalling ameliorates disease pathology in the hSOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {British journal of pharmacology}, volume = {174}, number = {8}, pages = {689-699}, pmid = {28128456}, issn = {1476-5381}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; *Disease Models, Animal ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Peptides, Cyclic/administration &amp; dosage/*pharmacology ; Receptor, Anaphylatoxin C5a/*antagonists &amp; inhibitors/metabolism ; Signal Transduction/*drug effects ; Superoxide Dismutase-1/*metabolism ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. The complement system is up-regulated in ALS, with recent studies indicating that the activation product C5a accelerates disease progression via the C5a1 receptor (C5aR1). We therefore examined the therapeutic effect of C5a1 receptor antagonism in hSOD1[G93A] mice, the most widely used preclinical model of ALS.<br><br>EXPERIMENTAL APPROACH: The selective and orally active C5a1 receptor antagonist, PMX205, was administered to hSOD1[G93A] mice in drinking water, both pre- and post-disease onset. Blood, brain and spinal cord pharmacokinetics were performed using LC-MS/MS methods. Effects of PMX205 on hSOD1[G93A] disease progression was determined using body weight, hindlimb grip strength, survival time and blood analysis.<br><br>KEY RESULTS: PMX205 entered the intact CNS at pharmacologically active concentrations, with increased entry observed in hSOD1[G93A] mice as the disease progressed, in line with augmented blood-brain barrier breakdown. hSOD1[G93A] mice treated with PMX205 before disease onset had significantly improved hindlimb grip strength, slower disease progression and extended survival, compared with vehicle treatment. These improvements were associated with reductions in pro-inflammatory monocytes and granulocytes and increases in T-helper lymphocytes in peripheral blood. PMX205 treatment beginning 3&#xa0;weeks following disease onset also attenuated disease progression, significantly extending survival.<br><br>CONCLUSION AND IMPLICATIONS: These results confirm that C5a1 receptors play a pathogenic role in hSOD1[G93A] mice, further validating the C5a-C5a1 receptor signalling axis as a potential therapeutic target to slow disease progression in ALS.}, }
@article {pmid28127517, year = {2017}, author = {Mehl, T and Jordan, B and Zierz, S}, title = {"Patients with amyotrophic lateral sclerosis (ALS) are usually nice persons"-How physicians experienced in ALS see the personality characteristics of their patients.}, journal = {Brain and behavior}, volume = {7}, number = {1}, pages = {e00599}, pmid = {28127517}, issn = {2162-3279}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*psychology ; Female ; Humans ; Male ; Middle Aged ; Personality/*physiology ; *Physicians ; }, abstract = {INTRODUCTION: Physicians experienced in the treatment of patients with amyotrophic lateral sclerosis (ALS) occasionally describe these patients as "nice" persons.<br><br>METHODS: ALS experienced physicians (n&#xa0;=&#xa0;36) were asked to assess the personality characteristics of ALS patients using a multidimensional personality questionnaire based on the five-factor model of personality. Control groups consisted of physicians experienced in Myasthenia gravis (MG) (n&#xa0;=&#xa0;21) and lung cancer (LC) (n&#xa0;=&#xa0;36).<br><br>RESULTS: In the dimension Agreeableness ALS patients were rated significantly higher than the other groups (p&#xa0;<&#xa0;.001). This was mainly due to the high scores for converse adjective pairs "stubborn-compliant" and "selfish-helpful".<br><br>DISCUSSION: The dimension Agreeableness is very similar to "niceness". Results support the anecdotal description of ALS patients as "nice" persons. Personality characteristics of ALS patients differentiate them from other patient groups. It remains open whether the "nice" personality structure is linked to the susceptibility to the disease.}, }
@article {pmid28125293, year = {2017}, author = {Viswambharan, V and Thanseem, I and Vasu, MM and Poovathinal, SA and Anitha, A}, title = {miRNAs as biomarkers of neurodegenerative disorders.}, journal = {Biomarkers in medicine}, volume = {11}, number = {2}, pages = {151-167}, doi = {10.2217/bmm-2016-0242}, pmid = {28125293}, issn = {1752-0371}, mesh = {Alzheimer Disease/diagnosis/genetics/pathology ; Amyotrophic Lateral Sclerosis/diagnosis/genetics/pathology ; Biomarkers/*metabolism ; Friedreich Ataxia/diagnosis/genetics/pathology ; Humans ; Huntington Disease/diagnosis/genetics/pathology ; MicroRNAs/metabolism ; Multiple Sclerosis/diagnosis/genetics/pathology ; Muscular Atrophy, Spinal/diagnosis/genetics/pathology ; Neurodegenerative Diseases/*diagnosis/genetics/pathology ; Parkinson Disease/diagnosis/genetics/pathology ; Prion Diseases/diagnosis/genetics/pathology ; }, abstract = {Neurodegenerative diseases (NDDs) are the result of progressive deterioration of neurons, ultimately leading to disabilities. There is no effective cure for NDDs at present; ongoing therapies are mainly aimed at treating the most bothersome symptoms. Since early treatment is crucial in NDDs, there is an urgent need for specific and sensitive biomarkers that can aid in early diagnosis of these disorders. Recently, altered expression of miRNAs has been implicated in several neurological disorders, including NDDs. miRNA expression has been extensively investigated in the cells, tissues and body fluids of patients with different types of NDDs. The aim of this review is to provide a comprehensive overview of miRNAs as biomarkers and therapeutic targets for NDDs.}, }
@article {pmid28124594, year = {2017}, author = {Nguyen, KT and Pham, MN and Vo, TV and Duan, W and Tran, PH and Tran, TT}, title = {Strategies of Engineering Nanoparticles for Treating Neurodegenerative Disorders.}, journal = {Current drug metabolism}, volume = {18}, number = {9}, pages = {786-797}, doi = {10.2174/1389200218666170125114751}, pmid = {28124594}, issn = {1875-5453}, mesh = {Animals ; Blood-Brain Barrier/metabolism ; Humans ; Nanoparticles/*chemistry/*therapeutic use ; Nanotechnology ; Neurodegenerative Diseases/*drug therapy/metabolism ; }, abstract = {BACKGROUND: Neurodegenerative disorders (NDs) are typically referred to Alzheimer's disease, Parkinson's diseases, amyotrophic lateral sclerosis and prion disease. These are commonly debilitating and, unfortunately, have few therapeutic options.<br><br>OBJECTIVE: In this review, we describe some emerging advances in nanoengineering strategies for the treatment of NDs. One of the main difficulties in fighting against NDs is to overcome the shielding of blood-brain barrier (BBB), which greatly limits the penetration of various therapeutic drugs, which sometimes leads to severe side effects. Nanotechnology, by engineering materials of a size scale usually within 1-100 nm, fortunately offers an alternative approach for novel, promising and innovative solutions. Nanoparticles are capable of not only penetrating the BBB but also releasing active ingredients at a specific site due to its surface functionalization. Therefore, nanoengineered delivery systems potentially facilitate the targeted delivery of neuronal therapeutic drugs and genes to the central nervous system. Furthermore, recently developed nanomaterials are considered as therapeutic agents themselves since they exhibit important roles in promoting the protection of healthy neurons or the regeneration of neurons to repair damaged tissues.<br><br>CONCLUSION: There have been a variety of innovative approaches to designing therapeutic nanoparticles for NDs, and each has been associated with certain pros and cons.}, }
@article {pmid28122657, year = {2017}, author = {Maragh-Bass, AC and Fields, JC and McWilliams, J and Knowlton, AR}, title = {Challenges and Opportunities to Engaging Emergency Medical Service Providers in Substance Use Research: A Qualitative Study.}, journal = {Prehospital and disaster medicine}, volume = {32}, number = {2}, pages = {148-155}, doi = {10.1017/S1049023X16001424}, pmid = {28122657}, issn = {1945-1938}, support = {R01 DA019413/DA/NIDA NIH HHS/United States ; }, mesh = {Adult ; Drug Overdose/*prevention &amp; control ; *Emergency Medical Technicians ; Female ; Humans ; Interviews as Topic ; Male ; Naloxone/*administration &amp; dosage ; Narcotic Antagonists/*administration &amp; dosage ; Pilot Projects ; Research Design ; Substance Abuse, Intravenous/*prevention &amp; control ; }, abstract = {UNLABELLED: Introduction Research suggests Emergency Medical Services (EMS) over-use in urban cities is partly due to substance users with limited access to medical/social services. Recent efforts to deliver brief, motivational messages to encourage these individuals to enter treatment have not considered EMS providers. Problem Little research has been done with EMS providers who serve substance-using patients. The EMS providers were interviewed about participating in a pilot program where they would be trained to screen their patients for substance abuse and encourage them to enter drug treatment.<br><br>METHODS: Qualitative interviews were conducted with Baltimore City Fire Department (BCFD; Baltimore, Maryland USA) EMS providers (N=22). Topics included EMS misuse, work demands, and views on participating in the pilot program. Interviews were transcribed and analyzed using grounded theory and constant-comparison.<br><br>RESULTS: Participants were mostly white (68.1%); male (68.2%); with Advanced Life Skills training (90.9%). Mean age was 37.5 years. Providers described the "frequent flyer problem" (eg, EMS over-use by a few repeat non-emergent cases). Providers expressed disappointment with local health delivery due to resource limitations and being excluded from decision making within their administration, leading to reduced team morale and burnout. Nonetheless, providers acknowledged they are well-positioned to intervene with substance-using patients because they are in direct contact and have built rapport with them. They noted patients might be most receptive to motivational messages immediately after overdose revival, which several called "hitting their bottom." Several stated that involvement with the proposed study would be facilitated by direct incorporation into EMS providers' current workflow. Many recommended that research team members accompany EMS providers while on-call to observe their day-to-day work. Barriers identified by the providers included time constraints to intervene, limited knowledge of substance abuse treatment modalities, and fearing negative repercussions from supervisors and/or patients. Despite reservations, several EMS providers expressed inclination to deliver brief motivational messages to encourage substance-using patients to consider treatment, given adequate training and skill-building.<br><br>CONCLUSIONS: Emergency Medical Service providers may have many demands, including difficult case time/resource limitations. Even so, participants recognized their unique position as first responders to deliver motivational, harm-reduction messages to substance-using patients during transport. With incentivized training, implementing this program could be life- and cost-saving, improving emergency and behavioral health services. Findings will inform future efforts to connect substance users with drug treatment, potentially reducing EMS over-use in Baltimore. Maragh-Bass AC , Fields JC , McWilliams J , Knowlton AR . Challenges and opportunities to engaging Emergency Medical Service providers in substance use research: a qualitative study. Prehosp Disaster Med. 2017;32(2):148-155.}, }
@article {pmid28120377, year = {2017}, author = {Hoang, TT and Smith, TP and Raines, RT}, title = {A Boronic Acid Conjugate of Angiogenin that Shows ROS-Responsive Neuroprotective Activity.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {56}, number = {10}, pages = {2619-2622}, pmid = {28120377}, issn = {1521-3773}, support = {P41 GM103399/GM/NIGMS NIH HHS/United States ; R01 CA073808/CA/NCI NIH HHS/United States ; R01 GM044783/GM/NIGMS NIH HHS/United States ; T32 GM007215/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Boronic Acids/chemistry/*pharmacology ; Cell Proliferation/drug effects ; Humans ; Neovascularization, Pathologic/*drug therapy/metabolism/pathology ; Neuroprotective Agents/chemistry/*pharmacology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; Ribonuclease, Pancreatic/chemistry/*pharmacology ; }, abstract = {Angiogenin (ANG) is a human ribonuclease that is compromised in patients with amyotrophic lateral sclerosis (ALS). ANG also promotes neovascularization, and can induce hemorrhage and encourage tumor growth. The causal neurodegeneration of ALS is associated with reactive oxygen species, which are also known to elicit the oxidative cleavage of carbon-boron bonds. We have developed a synthetic boronic acid mask that restrains the ribonucleolytic activity of ANG. The masked ANG does not stimulate endothelial cell proliferation but protects astrocytes from oxidative stress. By differentiating between the two dichotomous biological activities of ANG, this strategy could provide a viable pharmacological approach for the treatment of ALS.}, }
@article {pmid28119559, year = {2016}, author = {Tefera, TW and Borges, K}, title = {Metabolic Dysfunctions in Amyotrophic Lateral Sclerosis Pathogenesis and Potential Metabolic Treatments.}, journal = {Frontiers in neuroscience}, volume = {10}, number = {}, pages = {611}, pmid = {28119559}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease primarily characterized by loss of motor neurons in brain and spinal cord. The death of motor neurons leads to denervation of muscle which in turn causes muscle weakness and paralysis, decreased respiratory function and eventually death. Growing evidence indicates disturbances in energy metabolism in patients with ALS and animal models of ALS, which are likely to contribute to disease progression. Particularly, defects in glucose metabolism and mitochondrial dysfunction limit the availability of ATP to CNS tissues and muscle. Several metabolic approaches improving mitochondrial function have been investigated in vitro and in vivo and showed varying effects in ALS. The effects of metabolic approaches in ALS models encompass delays in onset of motor symptoms, protection of motor neurons and extension of survival, which signifies an important role of metabolism in the pathogenesis of the disease. There is now an urgent need to test metabolic approaches in controlled clinical trials. In addition, more detailed studies to better characterize the abnormalities in energy metabolism in patients with ALS and ALS models are necessary to develop metabolically targeted effective therapies that can slow the progression of the disease and prolong life for patients with ALS.}, }
@article {pmid28116236, year = {2017}, author = {Devenney, EM and Landin-Romero, R and Irish, M and Hornberger, M and Mioshi, E and Halliday, GM and Kiernan, MC and Hodges, JR}, title = {The neural correlates and clinical characteristics of psychosis in the frontotemporal dementia continuum and the C9orf72 expansion.}, journal = {NeuroImage. Clinical}, volume = {13}, number = {}, pages = {439-445}, pmid = {28116236}, issn = {2213-1582}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/epidemiology/genetics ; C9orf72 Protein/*genetics ; Comorbidity ; Female ; Frontotemporal Dementia/epidemiology/genetics/pathology/*physiopathology ; Gray Matter/diagnostic imaging/*pathology ; Heterozygote ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Psychotic Disorders/epidemiology/genetics/pathology/*physiopathology ; Repetitive Sequences, Nucleic Acid ; }, abstract = {OBJECTIVE: This present study aims to address the gap in the literature regarding the severity and underlying neural correlates of psychotic symptoms in frontotemporal dementia with and without the C9orf72 gene expansion.<br><br>METHODS: Fifty-six patients with behavioural variant frontotemporal dementia (20 with concomitant amyotrophic lateral sclerosis) and 23 healthy controls underwent neuropsychological assessments, detailed clinical interview for assessment of psychosis symptoms, brain MRI and genetic testing. Carers underwent a clinical interview based upon the neuropsychiatric inventory. Patients were assessed at ForeFront, the Frontotemporal Dementia Research Group at Neuroscience Research Australia or at the Brain and Mind Centre, between January 2008 and December 2013. An index of psychosis was calculated, taking into account the degree and severity of psychosis in each case. Voxel-based morphometry analyses were used to explore relationships between the psychosis index and grey matter changes.<br><br>RESULTS: Thirty-four percent of frontotemporal dementia patients showed psychotic features. C9orf72 expansion cases were more likely to exhibit psychotic symptoms than non-carriers (64% vs. 26%; p&#xa0;=&#xa0;0.006), which were also more severe (psychotic index 23.1 vs. 8.1; p&#xa0;=&#xa0;0.002). Delusions comprised persecutory, somatic, jealous and grandiose types and were present in 57% of C9orf72 carriers and 19% of non-carriers (p&#xa0;=&#xa0;0.006). Auditory, visual or tactile hallucinations were present in 36% of C9orf72 carriers and 17% of non-carriers (p&#xa0;=&#xa0;0.13). Increased psychotic symptoms in C9orf72 expansion carriers correlated with atrophy in a distributed cortical and subcortical network that included discrete regions of the frontal, temporal and occipital cortices, as well as the thalamus, striatum and cerebellum.<br><br>CONCLUSIONS: This study underlines the need to consider and assess for psychotic symptoms in the frontotemporal dementia-amyotrophic lateral sclerosis continuum particularly in those with C9orf72 gene expansions. The network of brain regions identified in this study is strikingly similar to that identified in other psychotic disorders such as schizophrenia, which suggests that treatment strategies in psychiatry may be beneficial for the management of psychotic symptoms in frontotemporal dementia.}, }
@article {pmid28111633, year = {2016}, author = {Pandey, R and Yang, Y and Jackson, L and Ahmed, RP}, title = {MicroRNAs regulating meis1 expression and inducing cardiomyocyte proliferation.}, journal = {Cardiovascular regenerative medicine}, volume = {3}, number = {}, pages = {}, pmid = {28111633}, issn = {2378-3141}, support = {R01 HL106190/HL/NHLBI NIH HHS/United States ; }, abstract = {Cardiovascular disease has been the biggest killer in the United States for decades, with almost a million new cases each year. Even though mammalian rodent neonatal cardiomyocytes show proliferative potential for up to 5 days, adult cardiomyocytes lose this ability. Insufficient cardiomyocyte proliferation is one of the major reasons for the lack of regeneration of myocardial tissue, post injury. Several studies have looked at the mechanisms responsible for the arrest in proliferation at an adult stage. Following up on a recent study by Eulalio et al's study on functional screening of 875 miRNAs for neonatal cardiomyocyte proliferation, we recently identified several miRNAs that induce proliferation in naturally senescent adult cardiomyocytes. Additional studies by Mahmood et al 2013 have identified Meis1 as the major regulator of cardiomyocyte cell cycle. In our present study we have identified three of the adult cardiomyocyte proliferation inducing miRNAs to have binding sites on the 3'UTR of Meis1 gene by in-silico analysis and luciferase assay. Additionally we found these miRNAs; miR-548c-3p, miR-509-3p, and miR-23b-3p to induce significant proliferation in adult cardiomyocytes through translational inhibition of Meis1. We found a significant increase in the number of ACMs with each miRNA, in combination, and with siRNA mediated inhibition of Meis1 gene. We confirmed that these microRNAs, through inhibition of Meis1, affect its downstream targets and thereby regulate cell-cycle progression. Further investigating of the mechanism of action of these miRNAs can identify other treatment options for abnormalities associated with the lack of cardiac regeneration post myocardial injury.}, }
@article {pmid28103684, year = {2017}, author = {Jordan, PC and Stevens, SK and Tam, Y and Pemberton, RP and Chaudhuri, S and Stoycheva, AD and Dyatkina, N and Wang, G and Symons, JA and Deval, J and Beigelman, L}, title = {Activation Pathway of a Nucleoside Analog Inhibiting Respiratory Syncytial Virus Polymerase.}, journal = {ACS chemical biology}, volume = {12}, number = {1}, pages = {83-91}, doi = {10.1021/acschembio.6b00788}, pmid = {28103684}, issn = {1554-8937}, mesh = {*Activation, Metabolic ; Antiviral Agents/*metabolism/pharmacology ; Deoxycytidine/*analogs &amp; derivatives/metabolism/pharmacology ; Deoxycytidine Kinase/metabolism ; Drug Discovery ; Humans ; Phosphorylation ; Prodrugs/*metabolism/pharmacology ; Respiratory Syncytial Virus Infections/*drug therapy/metabolism/virology ; Respiratory Syncytial Viruses/drug effects/*enzymology/physiology ; Virus Replication/drug effects ; }, abstract = {Human respiratory syncytial virus (RSV) is a negative-sense RNA virus and a significant cause of respiratory infection in infants and the elderly. No effective vaccines or antiviral therapies are available for the treatment of RSV. ALS-8176 is a first-in-class nucleoside prodrug inhibitor of RSV replication currently under clinical evaluation. ALS-8112, the parent molecule of ALS-8176, undergoes intracellular phosphorylation, yielding the active 5'-triphosphate metabolite. The host kinases responsible for this conversion are not known. Therefore, elucidation of the ALS-8112 activation pathway is key to further understanding its conversion mechanism, particularly given its potent antiviral effects. Here, we have identified the activation pathway of ALS-8112 and show it is unlike other antiviral cytidine analogs. The first step, driven by deoxycytidine kinase (dCK), is highly efficient, while the second step limits the formation of the active 5'-triphosphate species. ALS-8112 is a 2'- and 4'-modified nucleoside analog, prompting us to investigate dCK recognition of other 2'- and 4'-modified nucleosides. Our biochemical approach along with computational modeling contributes to an enhanced structure-activity profile for dCK. These results highlight an exciting potential to optimize nucleoside analogs based on the second activation step and increased attention toward nucleoside diphosphate and triphosphate prodrugs in drug discovery.}, }
@article {pmid28102336, year = {2017}, author = {De Rose, F and Marotta, R and Talani, G and Catelani, T and Solari, P and Poddighe, S and Borghero, G and Marrosu, F and Sanna, E and Kasture, S and Acquas, E and Liscia, A}, title = {Differential effects of phytotherapic preparations in the hSOD1 Drosophila melanogaster model of ALS.}, journal = {Scientific reports}, volume = {7}, number = {}, pages = {41059}, pmid = {28102336}, issn = {2045-2322}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality/pathology ; Animals ; Animals, Genetically Modified/metabolism ; Behavior, Animal/drug effects ; Disease Models, Animal ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster ; Evoked Potentials/drug effects ; Ganglia/pathology/ultrastructure ; Humans ; Longevity/drug effects ; Microscopy, Electron, Transmission ; Mitochondria/drug effects/metabolism/pathology ; Motor Neurons/metabolism ; Mucuna/chemistry/metabolism ; Mutagenesis ; Plant Extracts/chemistry/pharmacology/*therapeutic use ; Superoxide Dismutase-1/genetics/*metabolism ; Survival Rate ; Transcription Factors/genetics/metabolism ; Withania/chemistry/metabolism ; }, abstract = {The present study was aimed at characterizing the effects of Withania somnifera (Wse) and Mucuna pruriens (Mpe) on a Drosophila melanogaster model for Amyotrophic Lateral Sclerosis (ALS). In particular, the effects of Wse and Mpe were assessed following feeding the flies selectively overexpressing the wild human copper, zinc-superoxide dismutase (hSOD1-gain-of-function) in Drosophila motoneurons. Although ALS-hSOD1 mutants showed no impairment in life span, with respect to GAL4 controls, the results revealed impairment of climbing behaviour, muscle electrophysiological parameters (latency and amplitude of ePSPs) as well as thoracic ganglia mitochondrial functions. Interestingly, Wse treatment significantly increased lifespan of hSDO1 while Mpe had not effect. Conversely, both Wse and Mpe significantly rescued climbing impairment, and also latency and amplitude of ePSPs as well as failure responses to high frequency DLM stimulation. Finally, mitochondrial alterations were any more present in Wse- but not in Mpe-treated hSOD1 mutants. Hence, given the role of inflammation in the development of ALS, the high translational impact of the model, the known anti-inflammatory properties of these extracts, and the viability of their clinical use, these results suggest that the application of Wse and Mpe might represent a valuable pharmacological strategy to counteract the progression of ALS and related symptoms.}, }
@article {pmid28100064, year = {2017}, author = {Thompson, AG and Blackwell, V and Marsden, R and Millard, E and Lawson, C and Nickol, AH and East, JE and Talbot, K and Allan, PJ and Turner, MR}, title = {A risk stratifying tool to facilitate safe late-stage percutaneous endoscopic gastrostomy in ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {3-4}, pages = {243-248}, pmid = {28100064}, issn = {2167-9223}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*epidemiology/*surgery ; Cohort Studies ; Disease Progression ; Endoscopy, Gastrointestinal/*methods ; Enteral Nutrition ; Female ; Gastrostomy/*methods ; Humans ; Hypnotics and Sedatives/administration &amp; dosage/therapeutic use ; Male ; Nutritional Support ; Respiratory Function Tests ; Retrospective Studies ; Risk Assessment ; Vital Capacity ; }, abstract = {BACKGROUND: The safety of percutaneous endoscopic gastrostomy (PEG) insertion in amyotrophic lateral sclerosis (ALS) patients with significant respiratory compromise has been questioned.<br><br>OBJECTIVES: To review the characteristics of an ALS clinic patient cohort undergoing PEG, and the introduction of a risk stratification tool with procedural adaptations for higher-risk individuals.<br><br>METHODS: Patients undergoing PEG insertion were analysed (n&#x2009;=&#x2009;107). Cases stratified as higher-risk underwent insertion in a semi-recumbent position, minimising sedation, with the option of nasal non-invasive ventilation.<br><br>RESULTS: All underwent successful PEG. One-third had pre-procedure FVC &#x2264;50% (mean, 64&#x2009;&#xb1;&#x2009;22%). Of those who underwent PEG insertion after introduction of risk stratification (n&#x2009;=&#x2009;58), 39 (67%) met criteria for being higher risk, 16 (41%) of whom had FVC &#x2264;50% (p&#x2009;=&#x2009;0.005). High-risk patients received lower sedative doses vs. the low-risk group (midazolam 2.1&#x2009;&#xb1;&#x2009;1.1 vs.2.8&#x2009;&#xb1;&#x2009;0.95mg, p&#x2009;=&#x2009;0.021; fentanyl 42&#x2009;&#xb1;&#x2009;16 vs. 60&#x2009;&#xb1;&#x2009;21&#x3bc;g, p&#x2009;=&#x2009;0.015). Four deaths occurred within one month of insertion (attributable to the natural disease course).<br><br>CONCLUSIONS: Risk stratification identified a greater number of patients with evidence of respiratory compromise than using the sole criterion of FVC &#x2264;50%. A modified PEG procedure enabled safe insertion despite respiratory compromise, in those who might not have tolerated attempted insertion by alternative means such as radiologically-inserted gastrostomy.}, }
@article {pmid28099475, year = {2017}, author = {Khanal, S and Elsey, H and King, R and Baral, SC and Bhatta, BR and Newell, JN}, title = {Development of a Patient-Centred, Psychosocial Support Intervention for Multi-Drug-Resistant Tuberculosis (MDR-TB) Care in Nepal.}, journal = {PloS one}, volume = {12}, number = {1}, pages = {e0167559}, pmid = {28099475}, issn = {1932-6203}, mesh = {Adult ; Aged ; Antitubercular Agents/*adverse effects/therapeutic use ; Female ; Focus Groups ; Humans ; Male ; Middle Aged ; Nepal ; Patient Education as Topic ; Patient-Centered Care/*methods ; *Psychosocial Support Systems ; Surveys and Questionnaires ; Tuberculosis, Multidrug-Resistant/*drug therapy/*psychology ; Tuberculosis, Pulmonary/*drug therapy/*psychology ; Young Adult ; }, abstract = {Multi-drug-resistant tuberculosis (MDR-TB) poses a major threat to public health worldwide, particularly in low-income countries. The current long (20 month) and arduous treatment regime uses powerful drugs with side-effects that include mental ill-health. It has a high loss-to-follow-up (25%) and higher case fatality and lower cure-rates than those with drug sensitive tuberculosis (TB). While some national TB programmes provide small financial allowances to patients, other aspects of psychosocial ill-health, including iatrogenic ones, are not routinely assessed or addressed. We aimed to develop an intervention to improve psycho-social well-being for MDR-TB patients in Nepal. To do this we conducted qualitative work with MDR-TB patients, health professionals and the National TB programme (NTP) in Nepal. We conducted semi-structured interviews (SSIs) with 15 patients (10 men and 5 women, aged 21 to 68), four family members and three frontline health workers. In addition, three focus groups were held with MDR-TB patients and three with their family members. We conducted a series of meetings and workshops with key stakeholders to design the intervention, working closely with the NTP to enable government ownership. Our findings highlight the negative impacts of MDR-TB treatment on mental health, with greater impacts felt among those with limited social and financial support, predominantly married women. Michie et al's (2011) framework for behaviour change proved helpful in identifying corresponding practice- and policy-level changes. The findings from this study emphasise the need for tailored psycho-social support. Recent work on simple psychological support packages for the general population can usefully be adapted for use with people with MDR-TB.}, }
@article {pmid28093437, year = {2017}, author = {Lee, CW and Chen, HJ and Liang, JA and Kao, CH}, title = {Risk of sepsis in patients with amyotrophic lateral sclerosis: a population-based retrospective cohort study in Taiwan.}, journal = {BMJ open}, volume = {7}, number = {1}, pages = {e013761}, pmid = {28093437}, issn = {2044-6055}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*epidemiology ; Cohort Studies ; Comorbidity ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Risk ; Sepsis/*epidemiology ; Taiwan/epidemiology ; Young Adult ; }, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and sepsis is a frequent cause of death in hospitalised patients. We investigated the relationship between ALS and the subsequent risk of sepsis.<br><br>DESIGN: A retrospective cohort analysis.<br><br>SETTING: Patients with ALSs diagnosed between 2000 and 2010 in Taiwan National Health Insurance Research Database.<br><br>PARTICIPANTS: We included 701 and 2804 patients as the ALS and the non-ALS groups, respectively.<br><br>OUTCOME MEASURES: The risk of sepsis was calculated by Cox proportional hazards regression model.<br><br>RESULTS: During the follow-up period, the incidence density rates were 77.8 and 11.1 per 1000 person-years in the ALS and non-ALS groups, respectively. After adjusting for sex, age, Charlson comorbidity index score, life-support measures, and &#x3b2;2-adrenoceptor agonists treatment, the ALS group had a higher risk of sepsis (HR=3.42; 95% CI 2.60 to 4.50) than the non-ALS group. An increase of the risk was observed in patients with ALS receiving life support treatment measures, whereas a decrease of the risk was associated with treatment of &#x3b2;2-adrenoceptor agonists.<br><br>CONCLUSIONS: The risk of sepsis is associated with a prior ALS diagnosis, and may be increased by the use of life support measures and decreased by &#x3b2;2-adrenoceptor agonists.}, }
@article {pmid28089419, year = {2017}, author = {Deng, X and Hao, Y and Xiao, B and Tan, EK and Lo, YL}, title = {Risk factors for respiratory failure of motor neuron disease in a multiracial Asian population.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {39}, number = {}, pages = {137-141}, doi = {10.1016/j.jocn.2016.12.018}, pmid = {28089419}, issn = {1532-2653}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/diagnosis/ethnology ; Asian People/ethnology ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/complications/*diagnosis/*ethnology ; *Population Surveillance ; Racial Groups/*ethnology ; Respiratory Insufficiency/complications/*diagnosis/*ethnology ; Retrospective Studies ; Risk Factors ; Singapore/ethnology ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a devastating degenerative disorder. Amyotrophic Lateral Sclerosis (ALS) is the most common and severe form of MND. Respiratory failure arising from ventilator musculature atrophy is the most common cause of death for ALS patients. Exploring the factors correlated with respiratory failure can contribute to disease management.<br><br>PURPOSE: To characterize the clinical features of MND and determine the factors that may affect respiratory failure of MND patients.<br><br>METHODS: The case records of all MND patients seen in Singapore General Hospital (SGH) between January 2004 and December 2014 were examined. Demographic, clinical information were collected by reviewing case records. Mortality data, if not available from records, were obtained via phone call interview of family members. Demographic data and clinical treatments were compared between Respiratory support group and Non-respiratory support group.<br><br>RESULTS: There were 73 patients included in our study. 49 (67.1%) patients died during follow-up. The mean age of onset was 58&#xb1;11.1years. With regard to treatment, 63% needed feeding support, and 42.5% required ventilation aid. The median overall survival was 36months from symptom onset. Chi-square tests showed there was significantly higher percentage of respiratory support needed in Chinese than in other races (P=0.016). Compared with non-feeding support patients, patients with feeding support were more likely to require assisted ventilation (P=0.001).<br><br>CONCLUSIONS: We report for the first time that the need of feeding support is significantly associated with assisted ventilation. Chinese MND patients may be more inclined to require respiratory support.}, }
@article {pmid28085899, year = {2017}, author = {Sariko, M and Anderson, C and Mujaga, BS and Gratz, J and Mpagama, SG and Heysell, S and Kibiki, G and Mmbaga, B and Houpt, E and Thomas, T}, title = {Evaluation of the Antibody in Lymphocyte Supernatant Assay to Detect Active Tuberculosis.}, journal = {PloS one}, volume = {12}, number = {1}, pages = {e0169118}, pmid = {28085899}, issn = {1932-6203}, support = {D43 TW006578/TW/FIC NIH HHS/United States ; K23 AI099019/AI/NIAID NIH HHS/United States ; U01 AI115594/AI/NIAID NIH HHS/United States ; K23 AI097197/AI/NIAID NIH HHS/United States ; D43 TW008270/TW/FIC NIH HHS/United States ; }, mesh = {Adult ; Antibodies, Bacterial/*analysis ; Biological Assay/*methods ; Case-Control Studies ; Enzyme-Linked Immunosorbent Assay ; Female ; HIV Infections/*etiology/pathology ; HIV Seropositivity/*complications ; HIV-1/physiology ; Humans ; Lymphocytes/*immunology ; Male ; Mycobacterium tuberculosis/*pathogenicity ; Sputum/microbiology ; Tanzania ; Tuberculosis, Pulmonary/*diagnosis/immunology/microbiology ; }, abstract = {BACKGROUND: We aimed to evaluate the antibody in lymphocyte supernatant (ALS) assay as a biomarker to diagnose tuberculosis among adults from Tanzania with and without HIV.<br><br>METHODS: Adults admitted with suspicion for tuberculosis had sputa obtained for GeneXpert MTB/RIF, acid-fast bacilli smear and mycobacterial culture; blood was obtained prior to treatment initiation and after 4 weeks. Adults hospitalized with non-infectious conditions served as controls. Peripheral blood mononuclear cells were cultured unstimulated for 72 hours. Anti-mycobacterial antibodies were measured from culture supernatants by ELISA, using BCG vaccine as the coating antigen. Median ALS responses were compared between cases and controls at baseline and between cases over time.<br><br>RESULTS: Of 97 TB cases, 85 were microbiologically confirmed and 12 were clinically diagnosed. Median ALS responses from TB cases (0.366 OD from confirmed cases and 0.285 from clinical cases) were higher compared to controls (0.085, p<0.001). ALS responses did not differ based on HIV status, CD4 count or sputum smear status. Over time, the median ALS values declined significantly (0.357 at baseline; 0.198 after 4-weeks, p<0.001).<br><br>CONCLUSIONS: Robust ALS responses were mounted by patients with TB regardless of HIV status, CD4 count, or low sputum bacillary burden, potentially conferring a unique niche for this immunologic biomarker for TB.}, }
@article {pmid28085149, year = {2017}, author = {Petrozziello, T and Secondo, A and Tedeschi, V and Esposito, A and Sisalli, M and Scorziello, A and Di Renzo, G and Annunziato, L}, title = {ApoSOD1 lacking dismutase activity neuroprotects motor neurons exposed to beta-methylamino-L-alanine through the Ca[2+]/Akt/ERK1/2 prosurvival pathway.}, journal = {Cell death and differentiation}, volume = {24}, number = {3}, pages = {511-522}, pmid = {28085149}, issn = {1476-5403}, mesh = {Amino Acids, Diamino/*toxicity ; Animals ; Apoproteins/chemistry/genetics/metabolism ; Calcium/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Cyanobacteria Toxins ; Endoplasmic Reticulum Chaperone BiP ; Flavonoids/pharmacology ; Heat-Shock Proteins/metabolism ; Humans ; MAP Kinase Kinase 1/antagonists &amp; inhibitors/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinase 1/*metabolism ; Mitogen-Activated Protein Kinase 3/*metabolism ; Motor Neurons/cytology/metabolism ; Neuroprotective Agents/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Proto-Oncogene Proteins c-akt/*metabolism ; Rats ; Recombinant Proteins/biosynthesis/isolation &amp; purification/pharmacology ; Superoxide Dismutase-1/chemistry/genetics/*metabolism ; Tretinoin/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe human adult-onset neurodegenerative disease affecting lower and upper motor neurons. In >20% of cases, the familial form of ALS is caused by mutations in the gene encoding Cu,Zn-superoxide dismutase (SOD1). Interestingly, administration of wild-type SOD1 to SOD1[G93A] transgenic rats ameliorates motor symptoms through an unknown mechanism. Here we investigated whether the neuroprotective effects of SOD1 are due to the Ca[2+]-dependent activation of such prosurvival signaling pathway and not to its catalytic activity. To this aim, we also examined the mechanism of neuroprotective action of ApoSOD1, the metal-depleted state of SOD1 that lacks dismutase activity, in differentiated motor neuron-like NSC-34 cells and in primary motor neurons exposed to the cycad neurotoxin beta-methylamino-L-alanine (L-BMAA). Preincubation of ApoSOD1 and SOD1, but not of human recombinant SOD1[G93A], prevented cell death in motor neurons exposed to L-BMAA. Moreover, ApoSOD1 elicited ERK1/2 and Akt phosphorylation in motor neurons through an early increase of intracellular Ca[2+] concentration ([Ca[2+]]i). Accordingly, inhibition of ERK1/2 by siMEK1 and PD98059 counteracted ApoSOD1- and SOD1-induced neuroprotection. Similarly, transfection of the dominant-negative form of Akt in NSC-34 motor neurons and treatment with the selective PI3K inhibitor LY294002 prevented ApoSOD1- and SOD1-mediated neuroprotective effects in L-BMAA-treated motor neurons. Furthermore, ApoSOD1 and SOD1 prevented the expression of the two markers of L-BMAA-induced ER stress GRP78 and caspase-12. Collectively, our data indicate that ApoSOD1, which is devoid of any catalytic dismutase activity, exerts a neuroprotective effect through an early activation of Ca[2+]/Akt/ERK1/2 pro-survival pathway that, in turn, prevents ER stress in a neurotoxic model of ALS.}, }
@article {pmid28079403, year = {2017}, author = {Bergendal, B and McAllister, A}, title = {Orofacial function and monitoring of oral care in amyotrophic lateral sclerosis.}, journal = {Acta odontologica Scandinavica}, volume = {75}, number = {3}, pages = {179-185}, doi = {10.1080/00016357.2016.1276212}, pmid = {28079403}, issn = {1502-3850}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*complications ; Female ; *Health Status ; Humans ; Male ; Mandibulofacial Dysostosis/etiology ; Middle Aged ; *Oral Health ; *Oral Hygiene ; Quality of Life ; }, abstract = {OBJECTIVE: The aim was to assess orofacial function and monitor oral care in patients with amyotrophic lateral sclerosis (ALS) to maintain oral comfort and oral health.<br><br>MATERIALS AND METHODS: A case series of 14 patients newly diagnosed with ALS accepted to participate in a quality improvement project. After initial examinations, baseline oral conditions were obtained and the patients were seen every 3 months. Nordic Orofacial Test-Screening (NOT-S) was used for evaluation of orofacial function.<br><br>RESULTS: Patients were grouped according to initial symptoms in a bulbar group and a spinal group with eight and six patients, respectively. The mean age at diagnosis was 62.8 years. All were dentate with a mean of 26.7 natural teeth. Most patients had very good oral and dental conditions. As expected, orofacial functions were differently affected in the two groups; at initial NOT-S registration, the mean total score was 5.6 (range 3-8 domains) in the bulbar group and 0.7 (0-2 domains) in the spinal group. At final registration, the corresponding figures were 6.1 and 3.2. Oral and dental aids were introduced according to need.<br><br>CONCLUSIONS: In the bulbar group, several orofacial functions became impaired at an early stage of disease development, and at final registrations many vital orofacial functions were severely compromised. The spinal group was less severely affected orally. However, all individuals irrespective of type of initial symptoms needed assistance in performing oral hygiene measures in the latter part of the disease period. Good oral health and oral comfort could be maintained in all participants and no other dental treatment was needed.}, }
@article {pmid28072907, year = {2017}, author = {Ng, L and Khan, F and Young, CA and Galea, M}, title = {Symptomatic treatments for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {1}, number = {1}, pages = {CD011776}, pmid = {28072907}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Enteral Nutrition ; Exercise Therapy ; Humans ; Motor Neuron Disease/complications ; Muscle Cramp/*drug therapy/etiology ; Muscle Spasticity/etiology/*therapy ; Noninvasive Ventilation ; Pain/*drug therapy/etiology ; Respiratory Insufficiency/etiology/*therapy ; Review Literature as Topic ; Sialorrhea/etiology/*therapy ; Transcranial Magnetic Stimulation ; }, abstract = {BACKGROUND: Motor neuron disease (MND), which is also known as amyotrophic lateral sclerosis (ALS), causes a wide range of symptoms but the evidence base for the effectiveness of the symptomatic treatment therapies is limited.<br><br>OBJECTIVES: To summarise the evidence from Cochrane Systematic Reviews of all symptomatic treatments for MND.<br><br>METHODS: We searched the Cochrane Database of Systematic Reviews (CDSR) on 15 November 2016 for systematic reviews of symptomatic treatments for MND. We assessed the methodological quality of the included reviews using the Assessment of Multiple Systematic Reviews (AMSTAR) tool and the GRADE approach. We followed standard Cochrane study (review) selection and data extraction procedures. We reported findings narratively and in tables.<br><br>MAIN RESULTS: We included nine Cochrane Systematic Reviews of interventions to treat symptoms in people with MND. Three were empty reviews with no included randomised controlled trials (RCTs); however, all three reported on non-RCT evidence and the remaining six included mostly one or two studies. We deemed all of the included reviews of high methodological quality. Drug therapy for painThere is no RCT evidence in a Cochrane Systematic Review exploring the efficacy of drug therapy for pain in MND. Treatment for crampsThere is evidence (13 RCTs, N = 4012) that for the treatment of cramps in MND, compared to placebo:- memantine and tetrahydrocannabinol (THC) are probably ineffective (moderate-quality evidence);- vitamin E may have little or no effect (low-quality evidence); and- the effects of L-threonine, gabapentin, xaliproden, riluzole, and baclofen are uncertain as the evidence is either very low quality or the trial specified the outcome but did not report numerical data.The review reported adverse effects of riluzole, but it is not clear whether other interventions had adverse effects. Treatment for spasticityIt is uncertain whether an endurance-based exercise programme improved spasticity or quality of life, measured at three months after the programme, as the quality of evidence is very low (1 RCT, comparison "usual activities", N = 25). The review did not evaluate other approaches, such as use of baclofen as no RCTs were available. Mechanical ventilation for supporting respiratory functionNon-invasive ventilation (NIV) probably improves median survival and quality of life in people with respiratory insufficiency and normal to moderately impaired bulbar function compared to standard care, and improves quality of life but not survival for people with poor bulbar function (1 RCT, N = 41, moderate-quality evidence; a second RCT did not provide data). The review did not evaluate other approaches such as tracheostomy-assisted ('invasive') ventilation, or assess timing of NIV initiation. Treatment for sialorrhoeaA single session of botulinum toxin type B injections to parotid and submandibular glands probably improves sialorrhoea and quality of life at up to 4 weeks compared to placebo injections, but not at 8 or 12 weeks after the injections (moderate-quality evidence from 1 placebo-controlled RCT, N = 20). The review authors found no trials of other approaches. Enteral tube feeding for supporting nutritionThere is no RCT evidence in a Cochrane Systematic Review to support benefit or harms of enteral tube feeding in supporting nutrition in MND. Repetitive transcranial magnetic stimulationIt is uncertain whether repetitive transcranial magnetic stimulation (rTMS) improves disability or limitation in activity in MND in comparison with sham rTMS (3 RCTs, very low quality evidence, N = 50). Therapeutic exerciseThere is evidence that exercise may improve disability in MND at three months after the exercise programme, but not quality of life, in comparison with "usual activities" or "usual care" including stretching (2 RCTs, low-quality evidence, N = 43). Multidisciplinary careThere is no RCT evidence in a Cochrane Systematic Review to demonstrate any benefit or harm for multidisciplinary care in MND.None of the reviews, other than the review of treatment for cramps, reported that adverse events occurred. However, the trials were too small for reliable adverse event reporting.<br><br>AUTHORS' CONCLUSIONS: This overview has highlighted the lack of robust evidence in Cochrane Systematic Reviews on interventions to manage symptoms resulting from MND. It is important to recognise that clinical trials may fail to demonstrate efficacy of an intervention for reasons other than a true lack of efficacy, for example because of insufficient statistical power, the wrong choice of dose, insensitive outcome measures or inappropriate participant eligibility. The trials were mostly too small to reliably assess adverse effects of the treatments. The nature of MND makes it difficult to research clinically accepted or recommended practice, regardless of the level of evidence supporting the practice. It would not be ethical, for example, to design a placebo-controlled trial for treatment of pain in MND or to withhold multidisciplinary care where such care is available. It is therefore highly unlikely that there will ever be classically designed placebo-controlled RCTs in these areas.We need more research with appropriate study designs, robust methodology, and of sufficient duration to address the changing needs-of people with MND and their caregivers-associated with MND disease progression and mortality. There is a significant gap in studies assessing the effectiveness of interventions for symptoms relating to MND, such as pseudobulbar emotional lability and cognitive and behavioural difficulties. Future studies should use appropriate outcome measures that are reliable, have internal and external validity, and are sensitive to change in what is being measured (such as quality of life).}, }
@article {pmid28070747, year = {2017}, author = {Smith, R and Pioro, E and Myers, K and Sirdofsky, M and Goslin, K and Meekins, G and Yu, H and Wymer, J and Cudkowicz, M and Macklin, EA and Schoenfeld, D and Pattee, G}, title = {Enhanced Bulbar Function in Amyotrophic Lateral Sclerosis: The Nuedexta Treatment Trial.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {14}, number = {3}, pages = {762-772}, pmid = {28070747}, issn = {1878-7479}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Cross-Over Studies ; Dextromethorphan/*therapeutic use ; Double-Blind Method ; Drug Combinations ; Female ; Humans ; Male ; Middle Aged ; Quinidine/*therapeutic use ; }, abstract = {The goal of this randomized, blinded, crossover clinical trial was to determine whether Nuedexta (dextromethorphan and quinidine) enhanced speech, swallowing, and salivation in patients with ALS. Sixty patients with amyotrophic lateral sclerosis (ALS) received either Nuedexta or placebo for 28 to 30 days, followed by a 10 to 15-day washout period. Subsequently, patients were switched to the opposite treatment arm for the remaining days of the trial. The primary endpoint was a reduction in the self-report Center for Neurologic Study Bulbar Function Scale (CNS-BFS) score. The rater-administered ALS Functional Rating Scale Revised was the principal secondary endpoint. The CNS-BFS score improved with active treatment, decreasing from a mean of 59.3 in the placebo arm of the trial to 53.5 during the drug-treatment arm (p < 0.001). Each of the individual domains of bulbar function interrogated by the CNS-BFS responded to treatment with Nuedexta as follows: salivation: 15.8 versus 14.3 (p = 0.004); speech: 24.6 versus 22.2 (p = 0.003); swallowing: 18.9 versus 17.1 (p = 0.009). Similarly, the bulbar component of the ALS Functional Rating Scale Revised improved with active treatment (p = 0.003), although the drug did not affect the motor and respiratory components of this scale. This study is unique for several reasons. Firstly, it was driven by patient reports of improved speech and swallowing while taking Nuedexta for control of emotional lability. Secondly, the study was conducted over a short duration (70 days), and thirdly, a self-report scale was selected as the principle outcome measure. Considering the importance of bulbar functions, these results, if confirmed, point to an additional use of Nuedexta as an adjunct to the management of ALS.}, }
@article {pmid28067943, year = {2017}, author = {Diana, A and Pillai, R and Bongioanni, P and O'Keeffe, AG and Miller, RG and Moore, DH}, title = {Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {1}, number = {1}, pages = {CD006049}, pmid = {28067943}, issn = {1469-493X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Baclofen/therapeutic use ; Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; GABA Agents/adverse effects/*therapeutic use ; Humans ; Randomized Controlled Trials as Topic ; Time Factors ; gamma-Aminobutyric Acid/adverse effects/*therapeutic use ; }, abstract = {BACKGROUND: Imbalance of gamma aminobutyric acid (GABA) and related modulators has been implicated as an important factor in the pathogenesis of amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND). In this context, the role and mechanism of action of gabapentin and baclofen have been extensively investigated, although with conflicting results. This is the first systematic review to assess clinical trials of GABA modulators for the treatment of ALS.<br><br>OBJECTIVES: To examine the efficacy of gabapentin, baclofen, or other GABA modulators in delaying the progression of ALS, and to evaluate adverse effects of these interventions<br><br>SEARCH METHODS: On 16 August 2016, we searched the Cochrane Neuromuscular Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL Plus, AMED, and LILACS. In addition, we checked the bibliographies of the trials found in order to identify any other trials, and contacted trial authors to identify relevant unpublished results or additional clinical trials. On 30 August 2016, we searched two clinical trials registries.<br><br>SELECTION CRITERIA: Types of studies: double-blind randomized controlled trials (RCTs) or quasi-RCTsTypes of participants: adults with a diagnosis of probable or definite ALSTypes of interventions: gabapentin, baclofen, or other GABA modulators compared with placebo, no treatment, or each otherPrimary outcome: survival at one year from study enrollmentSecondary outcomes: individual rate of decline of maximum voluntary isometric contraction (MVIC), expressed as arm megascore; rate of decline of per cent predicted forced vital capacity (FVC); rate of decline of ALS Functional Rating Scale (ALSFRS); health-related quality of life; survival evaluated by pooling hazards; and adverse events DATA COLLECTION AND ANALYSIS: At least two review authors independently checked titles and abstracts identified by the searches. The review authors obtained and independently analyzed original individual participant data from each included study; additional review authors and the Cochrane Neuromuscular Managing Editor checked the outcome data. Two authors independently assessed the risk of bias in included studies.<br><br>DATA COLLECTION AND ANALYSIS: At least two review authors independently checked titles and abstracts identified by the searches. The review authors obtained and independently analyzed original individual participant data from each included study; additional review authors and the Cochrane Neuromuscular Managing Editor checked the outcome data. Two authors independently assessed the risk of bias in included studies.<br><br>MAIN RESULTS: We identified two double-blind RCTs of gabapentin treatment in ALS for inclusion in this review. We found no eligible RCTs of baclofen or other GABA modulators. The selected studies were phase II and phase III trials, which lasted six and nine months, respectively. They were highly comparable because both were comparisons of oral gabapentin and placebo, performed by the same investigators. The trials enrolled 355 participants with ALS: 80 in the gabapentin group and 72 in the placebo group in the first (phase II) trial and 101 in the gabapentin group and 102 in the placebo group in the second (phase III) trial. Neither trial was long enough to report survival at one year, which was our primary outcome. We found little or no difference in estimated one-year survival between the treated group and the placebo group (78% versus 77%, P = 0.63 by log-rank test; high-quality evidence). We also found little or no difference in the rate of decline of MVIC expressed as arm megascore, or rate of FVC decline (high-quality evidence). One trial investigated monthly decline in the ALSFRS and quality of life measured using the 12-Item Short Form Survey (SF-12) and found little or no difference between groups (moderate-quality evidence). The trials reported similar adverse events. Complaints that were clearly elevated in those taking gabapentin, based on analyses of the combined data, were light-headedness, drowsiness, and limb swelling (high-quality evidence). Fatigue and falls occurred more frequently with gabapentin than with placebo in one trial, but when we combined the data for fatigue from both trials, there was no clear difference between the groups. We assessed the overall risk of bias in the included trials as low.<br><br>AUTHORS' CONCLUSIONS: According to high-quality evidence, gabapentin is not effective in treating ALS. It does not extend survival, slow the rate of decline of muscle strength, respiratory function and, based on moderate-quality evidence, probably does not improve quality of life or slow monthly decline in the ALSFRS. Other GABA modulators have not been studied in randomized trials.}, }
@article {pmid28060747, year = {2017}, author = {Kim, SM and Noh, MY and Kim, H and Cheon, SY and Lee, KM and Lee, J and Cha, E and Park, KS and Lee, KW and Sung, JJ and Kim, SH}, title = {25-Hydroxycholesterol is involved in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Oncotarget}, volume = {8}, number = {7}, pages = {11855-11867}, pmid = {28060747}, issn = {1949-2553}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Humans ; Hydroxycholesterols/*metabolism ; Mice ; Middle Aged ; }, abstract = {This study aimed to evaluate the levels of three major hydroxycholesterols (24-, 25-, and 27-hydroxycholesterols) in the serum and cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS), as well as to show their role in the pathogenesis of ALS experimental models. The level of 25-hydroxycholesterol were higher in untreated ALS patients (n = 30) than in controls without ALS (n = 33) and ALS patients treated with riluzole (n = 9) both in their serum and CSF. The level of 25-hydroxycholesterol in the serum of ALS patients were significantly associated with their disease severity and rate of progression. In the motor neuron-like cell line (NSC34) with the human mutant G93A superoxide dismutase 1 gene (mSOD1-G93A), 25-hydroxycholesterol induced motor neuronal death/ apoptosis via glycogen synthase kinase-3β and liver X receptor pathways; riluzole treatment attenuated these effects. The expressions of enzymes that synthesize 25-hydroxycholesterol were significantly increased in the brains of early symptomatic mSOD1G93A mice. Our data, obtained from patients with ALS, a cellular model of ALS, and an animal model of ALS, suggests that 25-hydroxycholesterol could be actively involved in the pathogenesis of ALS, mostly in the early symptomatic disease stage, by mediating neuronal apoptosis.}, }
@article {pmid28050984, year = {2017}, author = {Tatikonda, A and Sudheep, N and Biswas, KP and Gowtham, K and Pujari, S and Singh, P}, title = {Evaluation of Bacteriological Profile in the Apical Root Segment of the Patients with Primary Apical Periodontitis.}, journal = {The journal of contemporary dental practice}, volume = {18}, number = {1}, pages = {44-48}, doi = {10.5005/jp-journals-10024-1986}, pmid = {28050984}, issn = {1526-3711}, mesh = {Bacteroidetes/genetics/isolation &amp; purification ; Fusobacterium nucleatum/genetics/isolation &amp; purification ; Humans ; Periapical Periodontitis/*microbiology ; Polymerase Chain Reaction ; Porphyromonas endodontalis/genetics/isolation &amp; purification ; RNA, Ribosomal, 16S ; Streptococcus/genetics/isolation &amp; purification ; Tooth Apex/*microbiology ; Tooth Root/*microbiology ; Treponema denticola/genetics/isolation &amp; purification ; }, abstract = {INTRODUCTION: Apical periodontitis usually results from bacterial accumulation and contamination occurring in the root-canal system, and extending beyond the apical foramen to involve the periapical tissues. Literature has a paucity of the studies that stress on the division and analysis of the pulp canal segments. The reason for this disparity might be the technique used for collecting the samples from the pulp canals. Hence, we carried out the present study to evaluate the microbial flora in the apical part of the roots with necrotic pulp canals.<br><br>MATERIALS AND METHODS: The present study included the assessment of 40 freshly extracted teeth that had necrotized pulpal tissue along with the presence of periapical periodontal lesions. Removal of the soft tissue lesions attached to the root portion of the teeth along with apical periodontal lesions was done with the help of scalpel blade, after rinsing them with a sterile solution of saline. Thorough cleaning of the root surfaces was done with hydrogen peroxide followed by rapid disinfection with the help of sodium hypochlorite at varying concentrations. Sectioning of the root portion of all the specimens with the help of a disk was done perpendicular to the long axis of the teeth at a distance of roughly 5 to 6 mm from the teeth's apicalmost point. Cryotubes were used for transferring the specimens of apical portions containing 1 mL of buffer and were subjected to immediate frozen processing at a temperature of -20&#xb0;C. A 10 K-type file was used for the initial collection of the samples followed by subsequent incubation of the files and paper pints in the incubation cabinet. Subsequent deoxyribonucleic acid (DNA) extraction from the samples was done following the procedure described by Siqueira et al. Paster et al's modification of the reverse-capture checkerboard assay was used in the present study. Semiquantitative data were used for overcoming the difficulties arising due to obtaining the counts of the polymerase chain reaction (PCR)-based analysis of specimens.<br><br>RESULTS: A positive result for the 16S ribosomal ribonucleic acid (rRNA) gene primer was observed only in two examined specimens of all the samples of the apical portion of the root canals in the present study. Negative result was shown by all the control group specimens, which were sterile samples. Presence of bacteria was confirmed by PCR in 38 out of 40 examined specimens. Amount of bacterial taxa, out of these 24 samples, ranged up to 6. Pseudoramibacter alactolyticus, Porphyromonas endodontalis, Dialister oral species, Bacteroidetes species, Streptococcus species, Olsenella uli, Synergistes species, Fusobacterium nucleatum, Parvimonas micra, Treponema denticola, and Filifactor alocis were the specific species detected. Bacteroidetes species was the only species that were detected at levels at or above 10[5]. Heavy bacterial infections were noticed in more than 45% of the cases at the periradicular part of the root canals.<br><br>CONCLUSION: Microbial flora of the apical segment of the root with necrotized pulp tissue comprises a vast variety of pathogenic bacteria.<br><br>CLINICAL SIGNIFICANCE: For better prognosis of the treatment of such cases, adequate knowledge of the microbial flora of the root, especially the apical portion is necessary.}, }
@article {pmid28048973, year = {2017}, author = {Kassa, RM and Bonafede, R and Boschi, F and Bentivoglio, M and Mariotti, R}, title = {Effect of physical exercise and anabolic steroid treatment on spinal motoneurons and surrounding glia of wild-type and ALS mice.}, journal = {Brain research}, volume = {1657}, number = {}, pages = {269-278}, doi = {10.1016/j.brainres.2016.12.029}, pmid = {28048973}, issn = {1872-6240}, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology/*therapy ; Anabolic Agents/*pharmacology/toxicity ; Animals ; Anterior Horn Cells/drug effects/pathology/*physiology ; Body Weight ; Cell Survival/drug effects/physiology ; Choline O-Acetyltransferase/metabolism ; Disease Models, Animal ; *Exercise Therapy ; Lumbar Vertebrae ; Male ; Mice, Transgenic ; Nandrolone/*pharmacology/toxicity ; Neuroglia/drug effects/pathology/*physiology ; Random Allocation ; Running/physiology ; Sedentary Behavior ; }, abstract = {Motoneuron degeneration is the hallmark of amyotrophic lateral sclerosis (ALS). The cause and predisposing factors for sporadic ALS are still unknown. Exposure to a specific environmental risk factors in subjects with a susceptibility genotype may increase the risk of the disease. The role of physical activity and the use of anabolic steroids are still debated in epidemiological studies on patients and murine models of ALS. To assess at the cellular level the role (beneficial or detrimental) of physical exercise and the use of anabolic steroid, we here investigated, in SOD1(G93A) (mSOD1) mice and wild-type littermates, changes in the ventral horn after regular exercise, treatment with the anabolic androgenic steroid 19-nortestosterone (nandrolone), and their combination, compared with matched control sedentary mice. The experiments were pursued for several weeks until symptom onset in mSOD1 mice. Lumbar motoneurons, astrocytes and microglia were analyzed. In wild-type mice, cytological alterations of motoneurons were observed especially after nandrolone treatment. The following main findings were observed in treated mSOD1 mice versus untreated ones: i) nandrolone treatment markedly enhanced motoneuron loss; this detrimental effect was reverted by the combination with exercise, resulting in increased motoneuron survival; ii) astrocytic activation was most marked after nandrolone treatment when motoneuron damage was most severe; iii) microglia activation was most marked after physical exercise when motoneuron damage was less severe. The results indicate a vulnerability of mSOD1 motoneurons to nandrolone treatment, a potential neuroprotective effect of physical exercise, and a modulation by glial cells in the ALS murine model in the examined paradigms.}, }
@article {pmid28042779, year = {2017}, author = {Robert, MA and Gilbert, R and Gaillet, B}, title = {Antibody Delivery Mediated by Recombinant Adeno-associated Virus for the Treatment of Various Chronic and Infectious Diseases.}, journal = {Current gene therapy}, volume = {16}, number = {6}, pages = {363-374}, doi = {10.2174/1566523217666170102111251}, pmid = {28042779}, issn = {1875-5631}, mesh = {Antibodies/genetics/*therapeutic use ; Communicable Diseases/genetics/*therapy ; Dependovirus/*genetics ; *Genetic Therapy ; Genetic Vectors ; Humans ; Transduction, Genetic ; }, abstract = {Monoclonal antibodies (mAbs) based-therapies are currently one of the most successful strategies to treat immune disorders, cancer and infectious diseases. Vectors derived from adenoassociated virus (AAV) are very attractive to deliver the genes coding the mAbs because they allow long-term expression thus, reducing the number of administrations. They can also penetrate biological barriers such as the blood-brain-barrier to transduce cells localized in immunoprivileged organs. Recent animal studies with AAV have demonstrated the capacity of AAV to deliver sufficient quantity of antibodies to confer an efficient immunoprotection against chronic and infectious diseases for several months to years. The treatment was successfully applied either for prophylaxis or therapeutic use, depending on the disease and its progression. In this review, we discuss the advantages and the limitations of AAV for mAb and immunoadhesin delivery. Recent advances in vector design and antibody engineering are also presented. Optimization of the vector design can improve the kinetic and the level of mAbs expression whereas protein engineering can enhance transgene product properties. Furthermore, an exhaustive review of pre-clinical studies for chronic diseases including Alzheimer disease, amyotrophic lateral sclerosis and cancer is presented as well as for infectious diseases.}, }
@article {pmid29574475, year = {2017}, author = {Flader, M and Zalas, D and Niedziela, M}, title = {Is growth without IGF1 possible? A case report.}, journal = {Pediatric endocrinology, diabetes, and metabolism}, volume = {23}, number = {4}, pages = {215-220}, doi = {10.18544/PEDM-23.04.0096}, pmid = {29574475}, issn = {2083-8441}, mesh = {Child ; Child Development/*physiology ; Human Growth Hormone/*metabolism/*therapeutic use ; Humans ; Hypopituitarism/*drug therapy ; Insulin-Like Growth Factor Binding Protein 3/*blood/*metabolism ; Insulin-Like Growth Factor I/*metabolism ; Male ; Treatment Outcome ; }, abstract = {According to the growth hormone - insulin-like growth factor 1 axis (GH/IGF1 axis) theory, the actions of GH on promoting growth are mediated by IGF1. In the blood, IGF1, insulin-like growth factor 1 binding protein 3 (IGFBP3) and acid-labile subunit (ALS) form ternary complexes, hence the accumulation of IGF1. We report a case of 10-year-old male with short stature due to GH deficiency diagnosed with hypopituitarism. Therapy with recombinant human GH (rhGH) was initiated at 11 years and 4 months. After twenty three months on treatment clinical effects were as follows: increase in the patient's height by 19.2 cm (initial height 12.4 cm vs. 140.6 cm; hSDS -4.35 vs. -2.7; predicted adult height 176 cm vs. 182 cm, respectively). Despite good clinical response to the therapy, serum levels of IGF1 and IGFBP3 remained diminished: IGF1 - 28 ng/ml initially, vs. 23 ng/ml 19 months on therapy and IGFBP3 - 1116 ng/ml initially, vs. 1888 ng/ml after 11 months on therapy. We attempt to justify this phenomenon by reconsidering the IGF1-independent GH actions, assessing the endocrine role of hepatic IGF1 in comparison to the autocrine/paracrine role of its bone tissue fraction, and evaluating the functions of ALS. The exact explanation for the positive response to rhGH treatment without the expected increase in IGF1 in our patient remains unknown. Serum levels of IGF1 and IGFBP3 seem not always to be reliable markers of the response to rhGH treatment in GH-deficient patients.}, }
@article {pmid28038988, year = {2017}, author = {Srivastava, AK and Gross, SK and Almad, AA and Bulte, CA and Maragakis, NJ and Bulte, JWM}, title = {Serial in vivo imaging of transplanted allogeneic neural stem cell survival in a mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {289}, number = {}, pages = {96-102}, pmid = {28038988}, issn = {1090-2430}, support = {R01 NS045062/NS/NINDS NIH HHS/United States ; R01 NS076573/NS/NINDS NIH HHS/United States ; S10 OD010744/OD/NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/genetics/*surgery ; Animals ; Cell Survival ; Disease Models, Animal ; Disease Progression ; Embryo, Mammalian ; Follow-Up Studies ; Immunosuppressive Agents/pharmacology ; Luciferases/metabolism ; Male ; Mice ; Mice, Transgenic ; Motor Activity/drug effects/physiology ; Nerve Tissue Proteins/metabolism ; Neural Stem Cells/*transplantation ; Psychomotor Disorders/etiology/surgery ; Sirolimus/pharmacology ; Spinal Cord/diagnostic imaging/surgery ; Superoxide Dismutase/genetics/metabolism ; Tacrolimus/pharmacology ; Transplantation, Homologous ; }, abstract = {Neural stem cells (NSCs) are being investigated as a possible treatment for amyotrophic lateral sclerosis (ALS) through intraspinal transplantation, but no longitudinal imaging studies exist that describe the survival of engrafted cells over time. Allogeneic firefly luciferase-expressing murine NSCs (Luc[+]-NSCs) were transplanted bilaterally (100,000 cells/2μl) into the cervical spinal cord (C5) parenchyma of pre-symptomatic (63day-old) SOD1[G93A] ALS mice (n=14) and wild-type age-matched littermates (n=14). Six control SOD1[G93A] ALS mice were injected with saline. Mice were immunosuppressed using a combination of tacrolimus+sirolimus (1mg/kg each, i.p.) daily. Compared to saline-injected SOD1[G93A] ALS control mice, a transient improvement (p<0.05) in motor performance (rotarod test) was observed after NSC transplantation only at the early disease stage (weeks 2 and 3 post-transplantation). Compared to day one post-transplantation, there was a significant decline in bioluminescent imaging (BLI) signal in SOD1[G93A] ALS mice at the time of disease onset (71.7±17.9% at 4weeks post-transplantation, p<0.05), with a complete loss of BLI signal at endpoint (120day-old mice). In contrast, BLI signal intensity was observed in wild-type littermates throughout the entire study period, with only a 41.4±8.7% decline at the endpoint. In SOD1[G93A] ALS mice, poor cell survival was accompanied by accumulation of mature macrophages and the presence of astrogliosis and microgliosis. We conclude that the disease progression adversely affects the survival of engrafted murine Luc[+]-NSCs in SOD1[G93A] ALS mice as a result of the hostile ALS spinal cord microenvironment, further emphasizing the challenges that face successful cell therapy of ALS.}, }
@article {pmid28034792, year = {2017}, author = {Rae, CD and Williams, SR}, title = {Glutathione in the human brain: Review of its roles and measurement by magnetic resonance spectroscopy.}, journal = {Analytical biochemistry}, volume = {529}, number = {}, pages = {127-143}, doi = {10.1016/j.ab.2016.12.022}, pmid = {28034792}, issn = {1096-0309}, mesh = {Animals ; Brain/*metabolism ; Glutathione/*metabolism ; Humans ; Magnetic Resonance Imaging/*methods ; Magnetic Resonance Spectroscopy/*methods ; Models, Biological ; }, abstract = {We review the transport, synthesis and catabolism of glutathione in the brain as well as its compartmentation and biochemistry in different brain cells. The major reactions involving glutathione are reviewed and the factors limiting its availability in brain cells are discussed. We also describe and critique current methods for measuring glutathione in the human brain using magnetic resonance spectroscopy, and review the literature on glutathione measurements in healthy brains and in neurological, psychiatric, neurodegenerative and neurodevelopmental conditions In summary: Healthy human brain glutathione concentration is ∼1-2 mM, but it varies by brain region, with evidence of gender differences and age effects; in neurological disease glutathione appears reduced in multiple sclerosis, motor neurone disease and epilepsy, while being increased in meningiomas; in psychiatric disease the picture is complex and confounded by methodological differences, regional effects, length of disease and drug-treatment. Both increases and decreases in glutathione have been reported in depression and schizophrenia. In Alzheimer's disease and mild cognitive impairment there is evidence for a decrease in glutathione compared to age-matched healthy controls. Improved methods to measure glutathione in vivo will provide better precision in glutathione determination and help resolve the complex biochemistry of this molecule in health and disease.}, }
@article {pmid28034353, year = {2017}, author = {Wilkins, HM and Morris, JK}, title = {New Therapeutics to Modulate Mitochondrial Function in Neurodegenerative Disorders.}, journal = {Current pharmaceutical design}, volume = {23}, number = {5}, pages = {731-752}, pmid = {28034353}, issn = {1873-4286}, support = {K99 AG050490/AG/NIA NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Energy Metabolism/*drug effects ; Humans ; Mitochondria/*drug effects/*metabolism ; Neurodegenerative Diseases/*drug therapy/metabolism ; }, abstract = {BACKGROUND: Mitochondrial function and energy metabolism are impaired in neurodegenerative diseases. There is evidence for these functional declines both within the brain and systemically in Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Due to these observations, therapeutics targeted to alter mitochondrial function and energy pathways are increasingly studied in pre-clinical and clinical settings.<br><br>METHODS: The goal of this article was to review therapies with specific implications on mitochondrial energy metabolism published through May 2016 that have been tested for treatment of neurodegenerative diseases.<br><br>RESULTS: We discuss implications for mitochondrial dysfunction in neurodegenerative diseases and how this drives new therapeutic initiatives.<br><br>CONCLUSION: Thus far, treatments have achieved varying degrees of success. Further investigation into the mechanisms driving mitochondrial dysfunction and bioenergetic failure in neurodegenerative diseases is warranted.}, }
@article {pmid28031292, year = {2017}, author = {Ottaviani, D and Marin, O and Arrigoni, G and Franchin, C and Vilardell, J and Sandre, M and Li, W and Parfitt, DA and Pinna, LA and Cheetham, ME and Ruzzene, M}, title = {Protein kinase CK2 modulates HSJ1 function through phosphorylation of the UIM2 domain.}, journal = {Human molecular genetics}, volume = {26}, number = {3}, pages = {611-623}, pmid = {28031292}, issn = {1460-2083}, support = {MR/N004434/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amino Acid Sequence ; Casein Kinase II/genetics/metabolism ; Charcot-Marie-Tooth Disease/*genetics/physiopathology ; HSP40 Heat-Shock Proteins/*genetics/metabolism ; Humans ; Molecular Chaperones/*genetics/metabolism ; Muscular Atrophy, Spinal/*genetics/physiopathology ; Mutation ; Neurons/*metabolism/pathology ; Phosphorylation ; Proteasome Endopeptidase Complex/genetics ; Protein Domains/genetics ; Protein Folding ; Ubiquitin/genetics ; }, abstract = {HSJ1 (DNAJB2), a member of the DNAJ family of molecular chaperones, is a key player in neuronal proteostasis maintenance. It binds ubiquitylated proteins through its Ubiquitin Interacting Motifs (UIMs) and facilitates their delivery to the proteasome for degradation. Mutations in the DNAJB2 gene lead to inherited neuropathies such as Charcot-Marie-Tooth type-2, distal hereditary motor neuropathies, spinal muscular atrophy with parkinsonism and the later stages can resemble amyotrophic lateral sclerosis. HSJ1 overexpression can reduce aggregation of neurodegeneration-associated proteins in vitro and in vivo; however, the regulation of HSJ1 function is little understood. Here we show that CK2, a ubiquitous and constitutively active protein kinase, phosphorylates HSJ1 within its second UIM, at the dominant site Ser250 and the hierarchical site Ser247. A phospho-HSJ1 specific antibody confirmed phosphorylation of endogenous HSJ1a and HSJ1b. A tandem approach of phospho-site mutation and treatment with CK2 specific inhibitors demonstrated that phosphorylation at these sites is accompanied by a reduced ability of HSJ1 to bind ubiquitylated clients and to exert its chaperone activity. Our results disclose a novel interplay between ubiquitin- and phosphorylation-dependent signalling, and represent the first report of a regulatory mechanism for UIM-dependent function. They also suggest that CK2 inhibitors could release the full neuroprotective potential of HSJ1, and deserve future interest as therapeutic strategies for neurodegenerative disease.}, }
@article {pmid28025800, year = {2017}, author = {Wang, W and Duan, W and Wang, Y and Wen, D and Liu, Y and Li, Z and Hu, H and Cui, H and Cui, C and Lin, H and Li, C}, title = {Intrathecal Delivery of ssAAV9-DAO Extends Survival in SOD1[G93A] ALS Mice.}, journal = {Neurochemical research}, volume = {42}, number = {4}, pages = {986-996}, pmid = {28025800}, issn = {1573-6903}, mesh = {Amidohydrolases/administration &amp; dosage/*biosynthesis/genetics ; Amyotrophic Lateral Sclerosis/*drug therapy/*enzymology/genetics ; Animals ; *Dependovirus/genetics ; Female ; *Gene Transfer Techniques ; HEK293 Cells ; Humans ; Injections, Spinal ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; *Superoxide Dismutase/genetics ; Survival Rate/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset, irreversible neurodegenerative disease that leads to progressive paralysis and inevitable death 3-5 years after diagnosis. The mechanisms underlying this process remain unknown, but new evidence indicates that accumulating levels of D-serine result from the downregulation of D-amino acid oxidase (DAO) and that this is a novel mechanism that leads to motoneuronal death in ALS via N-methyl-D-aspartate receptor-mediated cell toxicity. Here, we explored a new therapeutic approach to ALS by overexpressing DAO in the lumbar region of the mouse spinal cord using a single stranded adeno-associated virus serotype 9 (ssAAV9) vector. A single intrathecal injection of ssAAV9-DAO was made in SOD1[G93A] mice, a well-established mouse model of ALS. Treatment resulted in moderate expression of exogenous DAO in motorneurons in the lumbar spinal cord, reduced immunoreactivity of D-serine, alleviated motoneuronal loss and glial activation, and extended survival. The potential mechanisms underlying these effects were associated with the down-regulation of NF-κB and the restoration of the phosphorylation of Akt. In conclusion, administering ssAAV9-DAO may be an effective complementary approach to gene therapy to extend lifespans in symptomatic ALS.}, }
@article {pmid28011744, year = {2017}, author = {Pasetto, L and Pozzi, S and Castelnovo, M and Basso, M and Estevez, AG and Fumagalli, S and De Simoni, MG and Castellaneta, V and Bigini, P and Restelli, E and Chiesa, R and Trojsi, F and Monsurrò, MR and Callea, L and Malešević, M and Fischer, G and Freschi, M and Tortarolo, M and Bendotti, C and Bonetto, V}, title = {Targeting Extracellular Cyclophilin A Reduces Neuroinflammation and Extends Survival in a Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {37}, number = {6}, pages = {1413-1427}, pmid = {28011744}, issn = {1529-2401}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/drug therapy/*metabolism/mortality ; Animals ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Coculture Techniques ; Cyclophilin A/antagonists &amp; inhibitors/*metabolism ; *Disease Models, Animal ; Drug Delivery Systems/methods ; Enzyme Inhibitors/administration &amp; dosage ; Extracellular Fluid/drug effects/*metabolism ; Female ; Humans ; Inflammation/drug therapy/metabolism ; Inflammation Mediators/antagonists &amp; inhibitors/*metabolism ; Male ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Transgenic ; Middle Aged ; Neurons/drug effects/metabolism ; Survival Rate/trends ; }, abstract = {Neuroinflammation is a major hallmark of amyotrophic lateral sclerosis (ALS), which is currently untreatable. Several anti-inflammatory compounds have been evaluated in patients and in animal models of ALS, but have been proven disappointing in part because effective targets have not yet been identified. Cyclophilin A, also known as peptidylprolyl cis-/trans-isomerase A (PPIA), as a foldase is beneficial intracellularly, but extracellularly has detrimental functions. We found that extracellular PPIA is a mediator of neuroinflammation in ALS. It is a major inducer of matrix metalloproteinase 9 and is selectively toxic for motor neurons. High levels of PPIA were found in the CSF of SOD1[G93A] mice and rats and sporadic ALS patients, suggesting that our findings may be relevant for familial and sporadic cases. A specific inhibitor of extracellular PPIA, MM218, given at symptom onset, rescued motor neurons and extended survival in the SOD1[G93A] mouse model of familial ALS by 11 d. The treatment resulted in the polarization of glia toward a prohealing phenotype associated with reduced NF-κB activation, proinflammatory markers, endoplasmic reticulum stress, and insoluble phosphorylated TDP-43. Our results indicates that extracellular PPIA is a promising druggable target for ALS and support further studies to develop a therapy to arrest or slow the progression of the disease in patients.SIGNIFICANCE STATEMENT We provide evidence that extracellular cyclophilin A, also known as peptidylprolyl cis-/trans-isomerase A (PPIA), is a mediator of the neuroinflammatory reaction in amyotrophic lateral sclerosis (ALS) and is toxic for motor neurons. Supporting this, a specific extracellular PPIA inhibitor reduced neuroinflammation, rescued motor neurons, and extended survival in the SOD1[G93A] mouse model of familial ALS. Our findings suggest selective pharmacological inhibition of extracellular PPIA as a novel therapeutic strategy, not only for SOD1-linked ALS, but possibly also for sporadic ALS. This approach aims to address the neuroinflammatory reaction that is a major hallmark of ALS. However, given the complexity of the disease, a combination of therapeutic approaches may be necessary.}, }
@article {pmid28009454, year = {2017}, author = {Lu, X and Johnson, BA}, title = {Direct estimation for adaptive treatment length policies: Methods and application to evaluating the effect of delayed PEG insertion.}, journal = {Biometrics}, volume = {73}, number = {3}, pages = {981-989}, pmid = {28009454}, issn = {1541-0420}, support = {P30 AI078498/AI/NIAID NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis ; *Deglutition Disorders ; Gastrostomy ; Humans ; Polyethylene Glycols ; Registries ; }, abstract = {Dysphagia is a primary cause of death among patients diagnosed with amyotrophic lateral sclerosis (ALS), and percutaneous endoscopic gastrostomy (PEG) is a procedure to insert a tube into the stomach to assist or replace oral feeding. It is believed that PEG is beneficial and, generally, earlier insertion is preferable to later. However, gathering clinical evidence to support these beliefs on the use and timing of PEG is challenging because controlled clinical trials are not feasible and clinical endpoints are confounded with PEG in observational data. Moreover, the confounders are time-varying and time to PEG insertion may be only partially observed. We show how one can view this problem as an adaptive treatment length policy and propose a new estimator via g-computation. We show that our estimator is consistent and asymptotically normal for the causal estimand and explore its finite sample properties in simulation studies. Finally, using more than 10 years of data from Emory ALS clinic registry, we found no evidence to suggest that earlier PEG reduced 4-year mortality; thus, our results do not support the hypothesis and belief that initiating palliative care earlier extends life, on average. At the same, we cannot be certain that all important confounding variables are collected and observed to ensure our modeling assumptions are correct, so more work is needed to address these important end-of-life questions for ALS patients.}, }
@article {pmid28004277, year = {2017}, author = {Launay, N and Ruiz, M and Grau, L and Ortega, FJ and Ilieva, EV and Martínez, JJ and Galea, E and Ferrer, I and Knecht, E and Pujol, A and Fourcade, S}, title = {Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy.}, journal = {Acta neuropathologica}, volume = {133}, number = {2}, pages = {283-301}, pmid = {28004277}, issn = {1432-0533}, mesh = {Adrenoleukodystrophy/*physiopathology ; Animals ; Axons/*drug effects/pathology ; Humans ; Mice ; Mice, Knockout ; Nerve Degeneration/*physiopathology ; Taurochenodeoxycholic Acid/*pharmacology ; Unfolded Protein Response/*physiology ; }, abstract = {The activation of the highly conserved unfolded protein response (UPR) is prominent in the pathogenesis of the most prevalent neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), which are classically characterized by an accumulation of aggregated or misfolded proteins. This activation is orchestrated by three endoplasmic reticulum (ER) stress sensors: PERK, ATF6 and IRE1. These sensors transduce signals that induce the expression of the UPR gene programme. Here, we first identified an early activator of the UPR and investigated the role of a chronically activated UPR in the pathogenesis of X-linked adrenoleukodystrophy (X-ALD), a neurometabolic disorder that is caused by ABCD1 malfunction; ABCD1 transports very long-chain fatty acids (VLCFA) into peroxisomes. The disease manifests as inflammatory demyelination in the brain or and/or degeneration of corticospinal tracts, thereby resulting in spastic paraplegia, with the accumulation of intracellular VLCFA instead of protein aggregates. Using X-ALD mouse model (Abcd1 [-] and Abcd1 [-] /Abcd2 [-/-] mice) and X-ALD patient's fibroblasts and brain samples, we discovered an early engagement of the UPR. The response was characterized by the activation of the PERK and ATF6 pathways, but not the IRE1 pathway, showing a difference from the models of AD, PD or ALS. Inhibition of PERK leads to the disruption of homeostasis and increased apoptosis during ER stress induced in X-ALD fibroblasts. Redox imbalance appears to be the mechanism that initiates ER stress in X-ALD. Most importantly, we demonstrated that the bile acid tauroursodeoxycholate (TUDCA) abolishes UPR activation, which results in improvement of axonal degeneration and its associated locomotor impairment in Abcd1 [-] /Abcd2 [-/-] mice. Altogether, our preclinical data provide evidence for establishing the UPR as a key drug target in the pathogenesis cascade. Our study also highlights the potential role of TUDCA as a treatment for X-ALD and other axonopathies in which similar molecular mediators are implicated.}, }
@article {pmid28000730, year = {2016}, author = {Prasad, A and Raju, G and Sivalingam, V and Girdhar, A and Verma, M and Vats, A and Taneja, V and Prabusankar, G and Patel, BK}, title = {An acridine derivative, [4,5-bis{(N-carboxy methyl imidazolium)methyl}acridine] dibromide, shows anti-TDP-43 aggregation effect in ALS disease models.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {39490}, pmid = {28000730}, issn = {2045-2322}, mesh = {Acridines/*chemistry ; Amyloid/chemistry ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Bromides/*chemistry ; Circular Dichroism ; DNA-Binding Proteins/*chemistry ; Drug Evaluation, Preclinical ; Escherichia coli ; Humans ; Imidazoles/*chemistry ; Microscopy, Atomic Force ; Microscopy, Fluorescence ; Motor Neurons/pathology ; Muscular Atrophy/pathology ; Mutation ; Neurons/metabolism ; Prions/chemistry ; Protein Domains ; Protein Structure, Secondary ; Recombinant Proteins/chemistry ; Saccharomyces cerevisiae/*drug effects/metabolism ; Ultraviolet Rays ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with aggregation of TAR DNA-binding protein-43 (TDP-43) in neuronal cells and manifests as motor neuron dysfunction &amp;muscle atrophy. The carboxyl-terminal prion-like domain of TDP-43 can aggregate in vitro into toxic β-sheet rich amyloid-like structures. So far, treatment options for ALS are very limited and Riluzole, which targets glutamate receptors, is the only but highly ineffective drug. Therefore, great interest exists in developing molecules for ALS treatment. Here, we have examined certain derivatives of acridine containing same side chains at position 4 &amp;5, for inhibitory potential against TDP-43 aggregation. Among several acridine derivatives examined, AIM4, which contains polar carboxyl groups in the side arms, significantly reduces TDP-43-YFP aggregation in the powerful yeast model cell and also abolishes in vitro amyloid-like aggregation of carboxyl terminal domain of TDP-43, as observed by AFM imaging. Thus, AIM4 can be a lead molecule potentiating further therapeutic research for ALS.}, }
@article {pmid27999308, year = {2016}, author = {Jiang, HZ and Wang, SY and Yin, X and Jiang, HQ and Wang, XD and Wang, J and Wang, TH and Qi, Y and Yang, YQ and Wang, Y and Zhang, CT and Feng, HL}, title = {Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid.}, journal = {International journal of molecular sciences}, volume = {17}, number = {12}, pages = {}, pmid = {27999308}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/*therapy ; Animals ; Apoptosis/genetics ; Cell Line ; Genetic Predisposition to Disease ; Homer Scaffolding Proteins/antagonists &amp; inhibitors/*biosynthesis/genetics ; Humans ; Lithium/*therapeutic use ; Mice ; Mice, Transgenic ; Proto-Oncogene Proteins c-bcl-2/metabolism ; RNA Interference ; RNA, Small Interfering/genetics ; Superoxide Dismutase/*genetics ; Valproic Acid/*therapeutic use ; }, abstract = {BACKGROUND: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important roles in neurological diseases. In this study, we explored whether Homer1b/c was involved in SOD1 mutation-linked ALS.<br><br>RESULTS: In vitro studies showed that the SOD1 G93A mutation induced an increase of Homer1b/c expression at both the mRNA and protein levels in NSC34 cells. Knockdown of Homer1b/c expression using its short interfering RNA (siRNA) (si-Homer1) protected SOD1 G93A NSC34 cells from apoptosis. The expressions of Homer1b/c and apoptosis-related protein Bax were also suppressed, while Bcl-2 was increased by lithium and valproic acid (VPA) in SOD1 G93A NSC34 cells. In vivo, both the mRNA and protein levels of Homer1b/c were increased significantly in the lumbar spinal cord in SOD1 G93A transgenic mice compared with wild type (WT) mice. Moreover, lithium and VPA treatment suppressed the expression of Homer1b/c in SOD1 G93A mice.<br><br>CONCLUSION: The suppression of SOD1 G93A mutation-induced Homer1b/c upregulation protected ALS against neuronal apoptosis, which is a novel mechanism of the neuroprotective effect of lithium and VPA. This study provides new insights into pathogenesis and treatment of ALS.}, }
@article {pmid27995572, year = {2018}, author = {Lin, H and Hu, H and Duan, W and Liu, Y and Tan, G and Li, Z and Liu, Y and Deng, B and Song, X and Wang, W and Wen, D and Wang, Y and Li, C}, title = {Intramuscular Delivery of scAAV9-hIGF1 Prolongs Survival in the hSOD1[G93A] ALS Mouse Model via Upregulation of D-Amino Acid Oxidase.}, journal = {Molecular neurobiology}, volume = {55}, number = {1}, pages = {682-695}, pmid = {27995572}, issn = {1559-1182}, support = {H0912-81171210//the Natural Science Foundation of China/International ; C090301-30870882//National Natural Science Foundation of China/International ; 0647007D//Science and Technological department of Hebei Province/International ; }, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Apoptosis ; D-Amino-Acid Oxidase/*metabolism ; Dependovirus/*metabolism ; Disease Models, Animal ; Disease Progression ; Female ; Gene Transfer Techniques ; Humans ; Injections, Intramuscular ; Insulin-Like Growth Factor I/*administration &amp; dosage ; Male ; Mice, Transgenic ; Motor Neurons/metabolism ; Muscle, Skeletal/metabolism ; Muscular Atrophy/pathology ; Phenotype ; RNA, Guide, CRISPR-Cas Systems/metabolism ; Serine/metabolism ; Superoxide Dismutase/*metabolism ; Survival Analysis ; Transduction, Genetic ; *Up-Regulation ; }, abstract = {Self-complementary adeno-associated viral vector 9 (scAAV9) has been confirmed to be an efficient AAV serotype for gene transfer to the central nervous system (CNS). Neurotrophic factors have been considered to be therapeutic targets for amyotrophic lateral sclerosis (ALS). In the present study, we intramuscularly injected scAAV9 encoding human insulin-like growth factor 1 (hIGF1) into an hSOD1[G93A] ALS mouse model. We observed that scAAV9-hIGF1 significantly reduced the loss of motor neurons of the anterior horn in the lumbar spinal cord and delayed muscle atrophy in ALS mice. Importantly, IGF1 significantly delayed disease onset and prolonged the life span of ALS mice. In addition, scAAV9-hIGF1 protected motor neurons from apoptosis through upregulation of D-amino acid oxidase (DAO), which controls the level of D-serine. Moreover, to further verify these results, we used CRISPR-Cas9 system to target the central nervous system knockdown of IGF1. This experiment supported the continued investigation of neurotrophic factor gene therapies targeting the central nervous system as a potential treatment for ALS.}, }
@article {pmid27986528, year = {2017}, author = {Winter, AN and Ross, EK and Khatter, S and Miller, K and Linseman, DA}, title = {Chemical basis for the disparate neuroprotective effects of the anthocyanins, callistephin and kuromanin, against nitrosative stress.}, journal = {Free radical biology &amp; medicine}, volume = {103}, number = {}, pages = {23-34}, doi = {10.1016/j.freeradbiomed.2016.12.012}, pmid = {27986528}, issn = {1873-4596}, mesh = {Animals ; Anthocyanins/*pharmacology ; Cells, Cultured ; Drug Evaluation, Preclinical ; Fragaria/chemistry ; Glucosides/*pharmacology ; Glutamic Acid/pharmacology ; Neurons/drug effects/*physiology ; Neuroprotective Agents/*pharmacology ; Nitric Oxide/physiology ; *Nitrosative Stress ; Plant Extracts/pharmacology ; Rats, Sprague-Dawley ; Rubus/chemistry ; Signal Transduction ; Superoxides/metabolism ; }, abstract = {Oxidative and nitrosative stress are major factors in neuronal cell death underlying neurodegenerative disease. Thus, supplementation of antioxidant defenses may be an effective therapeutic strategy for diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. In this regard, treatment with nutraceutical antioxidants has garnered increasing attention; however, the differential neuroprotective effects of structurally similar nutraceuticals, which may affect their suitability as therapeutic agents, has not been directly examined. In this study we compare the ability of two anthocyanins, callistephin (pelargonidin-3-O-glucoside) and kuromanin (cyanidin-3-O-glucoside) to protect cerebellar granule neurons from damage induced by either oxidative or nitrosative stress. These anthocyanins differ by the presence of a single hydroxyl group on the B-ring of kuromanin, forming a catechol moiety. While both compounds protected neurons from oxidative stress induced by glutamate excitotoxicity, a stark contrast was observed under conditions of nitrosative stress. Only kuromanin displayed the capacity to defend neurons from nitric oxide (NO)-induced apoptosis. This protective effect was blocked by addition of Cu, Zn-superoxide dismutase, indicating that the neuroprotective mechanism is superoxide dependent. Based on these observations, we suggest a unique mechanism by which slight structural variances, specifically the absence or presence of a catechol moiety, lend kuromanin the unique ability to generate superoxide, which acts as a scavenger of NO. These findings indicate that kuromanin and compounds that share similar chemical characteristics may be more effective therapeutic agents for treating neurodegenerative diseases than callistephin and related (non-catechol) compounds.}, }
@article {pmid27982040, year = {2017}, author = {Al-Chalabi, A and van den Berg, LH and Veldink, J}, title = {Gene discovery in amyotrophic lateral sclerosis: implications for clinical management.}, journal = {Nature reviews. Neurology}, volume = {13}, number = {2}, pages = {96-104}, pmid = {27982040}, issn = {1759-4766}, support = {ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MC_G1000733/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; AL-CHALABI/APR15/844-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*therapy ; Genetic Predisposition to Disease/*genetics ; Humans ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease predominantly affecting upper and lower motor neurons. The disease leads to relentlessly progressive weakness of voluntary muscles, with death typically resulting from diaphragmatic failure within 2-5 years. Since the discovery of mutations in SOD1, which account for ∼2% of ALS cases, increasing efforts have been made to understand the genetic component of ALS risk, with the expectation that this insight will not only aid diagnosis and classification, but also guide personalized treatment and reveal the mechanisms that cause motor neuron death. In this Review, we outline previous and current efforts to characterize genes that are associated with ALS, describe current knowledge about the genetic architecture of ALS - including the relevance of family history - and the probable nature of future gene discoveries, and explore how our understanding of ALS genetics affects present and future clinical decisions. We observe that many gene variants associated with ALS have effect sizes between those of mutations that greatly increase risk and those of common variants that have a small effect on risk, and combine this observation with insights from next-generation sequencing to explore the implications for genetic counselling.}, }
@article {pmid27981909, year = {2017}, author = {Bjelobaba, I and Savic, D and Lavrnja, I}, title = {Multiple Sclerosis and Neuroinflammation: The Overview of Current and Prospective Therapies.}, journal = {Current pharmaceutical design}, volume = {23}, number = {5}, pages = {693-730}, doi = {10.2174/1381612822666161214153108}, pmid = {27981909}, issn = {1873-4286}, mesh = {Animals ; Anti-Inflammatory Agents/*therapeutic use ; Humans ; Inflammation/*physiopathology ; Multiple Sclerosis/*drug therapy/etiology ; Neurodegenerative Diseases/*physiopathology ; Neuroimmunomodulation/*drug effects ; }, abstract = {Persistent neuroinflammation is now recognized as a chief pathological component of practically all neurodegenerative diseases. Neuroinflammation in the central nervous system (CNS), is accompanied with immune responses of glial cells. Glial cells respond to pathological stimuli through antigen presentation, and cytokine and chemokine signaling. Therefore, limiting CNS inflammation represents prospective therapeutic approach in diseases like Alzheimer's, amyotrophic lateral sclerosis, Parkinson's, ischemia, various psychiatric disorders and Multiple sclerosis (MS). As a complex disease, MS is characterized by neuroinflamation, demyelination and sequential axonal loss. Due to unknown etiology and the heterogeneous presentation of the disease, MS is hard to treat and the search for potential therapeutics is wide and meticulous. However, finding a proper antineuroinflammatory drug may bring an advance in selecting novel treatment regimens of ample of neurodegenerative diseases and neurological disorders. The present review gives the overview of the existing and potential therapies in MS, aimed to modulate neuroinflammation and ensure neuroprotection.}, }
@article {pmid27978764, year = {2017}, author = {Stephens, HE and Joyce, NC and Oskarsson, B}, title = {National Study of Muscle Cramps in ALS in the USA.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {1-2}, pages = {32-36}, pmid = {27978764}, issn = {2167-9223}, support = {U01 AR052170/AR/NIAMS NIH HHS/United States ; U01 AR057929/AR/NIAMS NIH HHS/United States ; U01 AR052181/AR/NIAMS NIH HHS/United States ; U01 AR057954/AR/NIAMS NIH HHS/United States ; U01 AR057940/AR/NIAMS NIH HHS/United States ; U01 AR057948/AR/NIAMS NIH HHS/United States ; U01 AR057956/AR/NIAMS NIH HHS/United States ; U01 AR057967/AR/NIAMS NIH HHS/United States ; U01 AR052155/AR/NIAMS NIH HHS/United States ; U54 AR057943/AR/NIAMS NIH HHS/United States ; UL1 TR000002/TR/NCATS NIH HHS/United States ; U01 AR052171/AR/NIAMS NIH HHS/United States ; U54 AR057951/AR/NIAMS NIH HHS/United States ; U54 AR057926/AR/NIAMS NIH HHS/United States ; U01 AR052177/AR/NIAMS NIH HHS/United States ; KL2 TR000134/TR/NCATS NIH HHS/United States ; U01 AR052158/AR/NIAMS NIH HHS/United States ; U01 AR057971/AR/NIAMS NIH HHS/United States ; U01 AR057936/AR/NIAMS NIH HHS/United States ; U01 AR052186/AR/NIAMS NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/epidemiology ; Female ; Humans ; Male ; Middle Aged ; Muscle Cramp/diagnosis/*epidemiology/*etiology/therapy ; Muscle Relaxants, Central/therapeutic use ; Registries/statistics &amp; numerical data ; Severity of Illness Index ; United States/epidemiology ; }, abstract = {The objective of this study was to describe muscle cramps in an US sample of amyotrophic lateral sclerosis (ALS) patients. Utilizing an anonymous web based questionnaire we queried ALS patients regarding the severity, frequency, time-course, treatment of muscle cramps and their relationship to pain. The survey had 282 respondents with 92% reporting that they had cramps. For 20% of the sample, cramps were stated to be the presenting ALS symptom. Cramp severity was rated at a mean of 5.2/10 and the mean cramp frequency was 5.3 cramps per day. Cramp intensity and frequency did not correlate with duration or severity of ALS. Pain as measured with the Patient Reported Outcome Measurement Information System (PROMIS) pain scales was not statistically different from the US general population. Cramp severity and frequency significantly and positively correlated with the PROMIS pain scales. Patients with more severe cramps were more likely to use prescription medications for their cramps compared to patients with milder symptoms. Treatments directed at cramps were tried by 57%. In conclusion, cramps are a common symptom in ALS and it does not correlate with disease duration or severity. The severity of cramps is on average moderate and many patients try treatments.}, }
@article {pmid27965247, year = {2016}, author = {Walker, VM and Davies, NM and Jones, T and Kehoe, PG and Martin, RM}, title = {Can commonly prescribed drugs be repurposed for the prevention or treatment of Alzheimer's and other neurodegenerative diseases? Protocol for an observational cohort study in the UK Clinical Practice Research Datalink.}, journal = {BMJ open}, volume = {6}, number = {12}, pages = {e012044}, pmid = {27965247}, issn = {2044-6055}, support = {MC_PC_13088/MRC_/Medical Research Council/United Kingdom ; MC_UU_12013/9/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Alzheimer Disease/*drug therapy/prevention &amp; control ; Amyotrophic Lateral Sclerosis/*drug therapy/prevention &amp; control ; Cohort Studies ; Cost-Benefit Analysis ; Databases, Factual ; Dementia/*drug therapy/prevention &amp; control ; *Drug Repositioning ; Humans ; Multivariate Analysis ; Parkinson Disease/*drug therapy/prevention &amp; control ; Proportional Hazards Models ; Research Design ; United Kingdom ; }, abstract = {INTRODUCTION: Current treatments for Alzheimer's and other neurodegenerative diseases have only limited effectiveness meaning that there is an urgent need for new medications that could influence disease incidence and progression. We will investigate the potential of a selection of commonly prescribed drugs, as a more efficient and cost-effective method of identifying new drugs for the prevention or treatment of Alzheimer's disease, non-Alzheimer's disease dementias, Parkinson's disease and amyotrophic lateral sclerosis. Our research will focus on drugs used for the treatment of hypertension, hypercholesterolaemia and type 2 diabetes, all of which have previously been identified as potentially cerebroprotective and have variable levels of preclinical evidence that suggest they may have beneficial effects for various aspects of dementia pathology.<br><br>METHODS AND ANALYSIS: We will conduct a hypothesis testing observational cohort study using data from the Clinical Practice Research Datalink (CPRD). Our analysis will consider four statistical methods, which have different approaches for modelling confounding. These are multivariable adjusted Cox regression; propensity matched regression; instrumental variable analysis and marginal structural models. We will also use an intention-to-treat analysis, whereby we will define all exposures based on the first prescription observed in the database so that the target parameter is comparable to that estimated by a randomised controlled trial.<br><br>ETHICS AND DISSEMINATION: This protocol has been approved by the CPRD's Independent Scientific Advisory Committee (ISAC). We will publish the results of the study as open-access peer-reviewed publications and disseminate findings through national and international conferences as are appropriate.}, }
@article {pmid27965018, year = {2017}, author = {Rinaldi, F and Motti, D and Ferraiuolo, L and Kaspar, BK}, title = {High content analysis in amyotrophic lateral sclerosis.}, journal = {Molecular and cellular neurosciences}, volume = {80}, number = {}, pages = {180-191}, pmid = {27965018}, issn = {1095-9327}, support = {R01 NS064492/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating disease characterized by the progressive loss of motor neurons. Neurons, astrocytes, oligodendrocytes and microglial cells all undergo pathological modifications in the onset and progression of ALS. A number of genes involved in the etiopathology of the disease have been identified, but a complete understanding of the molecular mechanisms of ALS has yet to be determined. Currently, people affected by ALS have a life expectancy of only two to five years from diagnosis. The search for a treatment has been slow and mostly unsuccessful, leaving patients in desperate need of better therapies. Until recently, most pre-clinical studies utilized the available ALS animal models. In the past years, the development of new protocols for isolation of patient cells and differentiation into relevant cell types has provided new tools to model ALS, potentially more relevant to the disease itself as they directly come from patients. The use of stem cells is showing promise to facilitate ALS research by expanding our understanding of the disease and help to identify potential new therapeutic targets and therapies to help patients. Advancements in high content analysis (HCA) have the power to contribute to move ALS research forward by combining automated image acquisition along with digital image analysis. With modern HCA machines it is possible, in a period of just a few hours, to observe changes in morphology and survival of cells, under the stimulation of hundreds, if not thousands of drugs and compounds. In this article, we will summarize the major molecular and cellular hallmarks of ALS, describe the advancements provided by the in vitro models developed in the last few years, and review the studies that have applied HCA to the ALS field to date.}, }
@article {pmid27957680, year = {2017}, author = {Heitzer, M and Kaiser, S and Kanagaratnam, M and Zendedel, A and Hartmann, P and Beyer, C and Johann, S}, title = {Administration of 17β-Estradiol Improves Motoneuron Survival and Down-regulates Inflammasome Activation in Male SOD1(G93A) ALS Mice.}, journal = {Molecular neurobiology}, volume = {54}, number = {10}, pages = {8429-8443}, pmid = {27957680}, issn = {1559-1182}, support = {START (SJ)//Medical Faculty, RWTH Aachen University (DE)/ ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Cell Survival/drug effects/physiology ; Down-Regulation/drug effects/*physiology ; Estradiol/*pharmacology/therapeutic use ; Female ; Humans ; Inflammasomes/antagonists &amp; inhibitors/genetics/*metabolism ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/*metabolism ; Superoxide Dismutase-1/genetics/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease manifested by the progressive loss of upper and lower motoneurons. The pathomechanism of ALS is complex and not yet fully understood. Neuroinflammation is believed to significantly contribute to disease progression. Inflammasome activation was recently shown in the spinal cord of human sporadic ALS patients and in the SOD1(G93A) mouse model for ALS. In the present study, we investigated the neuroprotective and anti-inflammatory effects of 17β-estradiol (E2) treatment in pre-symptomatic and symptomatic male SOD1(G93A) mice. Symptomatic mice with E2 substitution exhibited improved motor performance correlating with an increased survival of motoneurons in the lumbar spinal cord. Expression of NLRP3 inflammasome proteins and levels of activated caspase 1 and mature interleukin 1 beta were significantly reduced in SOD1(G93A) mice supplemented with E2.}, }
@article {pmid27940503, year = {2017}, author = {Li, Z and Vuong, JK and Zhang, M and Stork, C and Zheng, S}, title = {Inhibition of nonsense-mediated RNA decay by ER stress.}, journal = {RNA (New York, N.Y.)}, volume = {23}, number = {3}, pages = {378-394}, pmid = {27940503}, issn = {1469-9001}, support = {R00 MH096807/MH/NIMH NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Adenine/analogs &amp; derivatives/pharmacology ; Alternative Splicing/*drug effects ; Animals ; Carrier Proteins/genetics/metabolism ; Cell Line, Tumor ; Codon, Nonsense ; DNA-Binding Proteins/deficiency/genetics ; Disks Large Homolog 4 Protein ; Endoplasmic Reticulum/drug effects/genetics/metabolism ; Endoplasmic Reticulum Stress/*drug effects ; Enzyme Inhibitors/pharmacology ; Guanylate Kinases/genetics/metabolism ; Heterogeneous-Nuclear Ribonucleoproteins/genetics/metabolism ; High-Throughput Screening Assays ; Indoles/pharmacology ; Membrane Proteins/genetics/metabolism ; Mice ; Mice, Knockout ; Nerve Tissue Proteins/genetics/metabolism ; Neurons/cytology/*drug effects/metabolism ; Polypyrimidine Tract-Binding Protein/genetics/metabolism ; Protein Kinase Inhibitors/*pharmacology ; RNA Stability/*drug effects ; RNA-Binding Proteins ; Signal Transduction ; Thapsigargin/*pharmacology ; eIF-2 Kinase/antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {Nonsense-mediated RNA decay (NMD) selectively degrades mutated and aberrantly processed transcripts that contain premature termination codons (PTC). Cellular NMD activity is typically assessed using exogenous PTC-containing reporters. We overcame some inherently problematic aspects of assaying endogenous targets and developed a broadly applicable strategy to reliably and easily monitor changes in cellular NMD activity. Our new method was genetically validated for distinguishing NMD regulation from transcriptional control and alternative splicing regulation, and unexpectedly disclosed a different sensitivity of NMD targets to NMD inhibition. Applying this robust method for screening, we identified NMD-inhibiting stressors but also found that NMD inactivation was not universal to cellular stresses. The high sensitivity and broad dynamic range of our method revealed a strong correlation between NMD inhibition, endoplasmic reticulum (ER) stress, and polysome disassembly upon thapsigargin treatment in a temporal and dose-dependent manner. We found little evidence of calcium signaling mediating thapsigargin-induced NMD inhibition. Instead, we discovered that of the three unfolded protein response (UPR) pathways activated by thapsigargin, mainly protein kinase RNA-like endoplasmic reticulum kinase (PERK) was required for NMD inhibition. Finally, we showed that ER stress compounded TDP-43 depletion in the up-regulation of NMD isoforms that had been implicated in the pathogenic mechanisms of amyotrophic lateral sclerosis and frontotemporal dementia, and that the additive effect of ER stress was completely blocked by PERK deficiency.}, }
@article {pmid27939241, year = {2017}, author = {Choi, JA and Chung, YR and Byun, HR and Park, H and Koh, JY and Yoon, YH}, title = {The anti-ALS drug riluzole attenuates pericyte loss in the diabetic retinopathy of streptozotocin-treated mice.}, journal = {Toxicology and applied pharmacology}, volume = {315}, number = {}, pages = {80-89}, doi = {10.1016/j.taap.2016.12.004}, pmid = {27939241}, issn = {1096-0333}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Diabetic Retinopathy/*drug therapy/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Pericytes/*drug effects ; Protein Kinase C beta/metabolism ; Riluzole/metabolism/*pharmacology/therapeutic use ; Streptozocin ; }, abstract = {Loss of pericytes, considered an early hallmark of diabetic retinopathy, is thought to involve abnormal activation of protein kinase C (PKC). We previously showed that the anti-amyotrophic lateral sclerosis (ALS) drug riluzole functions as a PKC inhibitor. Here, we examined the effects of riluzole on pathological changes in diabetic retinopathy. Pathological endpoints examined in vivo included the number of pericytes and integrity of retinal vessels in streptozotocin (STZ)-induced diabetic mice. In addition, PKC activation and the induction of monocyte chemotactic protein (MCP1) were assessed in diabetic mice and in human retinal pericytes exposed to advanced glycation end product (AGE) or modified low-density lipoprotein (mLDL). The diameter of retinal vessels and the number of pericytes were severely reduced, and the levels of MCP1 and PKC were increased in STZ-induced diabetic mice. Administration of riluzole reversed all of these changes. Furthermore, the increased expression of MCP1 in AGE- or mLDL-treated cultured retinal pericytes was inhibited by treatment with riluzole or the PKC inhibitor GF109203X. In silico modeling showed that riluzole fits well within the catalytic pocket of PKC. Taken together, our results demonstrate that riluzole attenuates both MCP1 induction and pericyte loss in diabetic retinopathy, likely through its direct inhibitory effect on PKC.}, }
@article {pmid27938483, year = {2017}, author = {Syková, E and Rychmach, P and Drahorádová, I and Konrádová, &#x160; and Růžičková, K and Voříšek, I and Forostyak, S and Homola, A and Bojar, M}, title = {Transplantation of Mesenchymal Stromal Cells in Patients With Amyotrophic Lateral Sclerosis: Results of Phase I/IIa Clinical Trial.}, journal = {Cell transplantation}, volume = {26}, number = {4}, pages = {647-658}, pmid = {27938483}, issn = {1555-3892}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Female ; Follow-Up Studies ; Humans ; Male ; *Mesenchymal Stem Cell Transplantation/adverse effects ; Mesenchymal Stem Cells/*cytology ; Middle Aged ; Regression Analysis ; Treatment Outcome ; Vital Capacity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive untreatable neurodegenerative disorder, leading to the death of the cortical and spinal motoneurons (MNs). Bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) may represent a new approach to slowing down the progression of ALS by providing neurotrophic support to host MNs and by having an anti-inflammatory effect. We have designed a prospective, nonrandomized, open-label clinical trial (phase I/IIa, EudraCT No. 2011-000362-35) to assess the safety and efficacy of autologous multipotent BM-MSCs in ALS treatment. Autologous BM-MSCs were isolated and expanded under GMP conditions. Patients received 15 ± 4.5 × 106 of BM-MSCs via lumbar puncture into the cerebrospinal fluid. Patients were monitored for 6 months before treatment and then for an 18-month follow-up period. Potential adverse reactions were assessed, and the clinical outcome was evaluated by the ALS functional rating scale (ALSFRS), forced vital capacity (FVC), and weakness scales (WSs) to assess muscle strength on the lower and upper extremities. In total, 26 patients were enrolled in the study and were assessed for safety; 23 patients were suitable for efficacy evaluation. After intrathecal BM-MSC application, about 30% of the patients experienced a mild to moderate headache, resembling the headaches after a standard lumbar puncture. No suspected serious adverse reactions (SUSAR) were observed. We found a reduction in ALSFRS decline at 3 months after application (p < 0.02) that, in some cases, persisted for 6 months (p < 0.05). In about 80% of the patients, FVC values remained stable or above 70% for a time period of 9 months. Values of WS were stable in 75% of patients at 3 months after application. Our results demonstrate that the intrathecal application of BM-MSCs in ALS patients is a safe procedure and that it can slow down progression of the disease.}, }
@article {pmid27933485, year = {2017}, author = {Vu, LT and Bowser, R}, title = {Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {14}, number = {1}, pages = {119-134}, pmid = {27933485}, issn = {1878-7479}, support = {R01 NS061867/NS/NINDS NIH HHS/United States ; R56 NS061867/NS/NINDS NIH HHS/United States ; RC1 NS068179/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/*diagnosis/urine ; *Biomarkers/blood/cerebrospinal fluid/urine ; *Disease Progression ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process.}, }
@article {pmid27932790, year = {2016}, author = {Park, JH and Park, HS and Hong, S and Kang, S}, title = {Motor neurons derived from ALS-related mouse iPS cells recapitulate pathological features of ALS.}, journal = {Experimental &amp; molecular medicine}, volume = {48}, number = {12}, pages = {e276}, pmid = {27932790}, issn = {2092-6413}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology/physiopathology ; Animals ; Cells, Cultured ; Humans ; Induced Pluripotent Stem Cells/*pathology ; Mice ; Mice, Transgenic ; Motor Neurons/*pathology ; Mutation ; Neurogenesis ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disease characterized by the loss of motor neurons in the spinal cord and brain. Mutations in Cu/Zn superoxide dismutase 1 (SOD1) are known to induce ALS. Although many research models have been developed, the exact pathological mechanism of ALS remains unknown. The recently developed induced pluripotent stem (iPS) cell technology is expected to illuminate the pathological mechanisms and new means of treatment for neurodegenerative diseases. To determine the pathological mechanism of ALS, we generated mouse iPS (miPS) cells from experimental ALS transgenic mice and control mice and characterized the cells using molecular biological methods. The generated miPS cells expressed many pluripotent genes and differentiated into three germ layers in vitro and in vivo. Motor neurons derived from ALS-related miPS cells recapitulated the pathological features of ALS. The ALS-model motor neurons showed SOD1 aggregates, as well as decreased cell survival rate and neurite length compared with wild-type motor neurons. Our study will be helpful in revealing the mechanism of motor neuronal cell death in ALS.}, }
@article {pmid27928708, year = {2017}, author = {Dutta, K and Patel, P and Rahimian, R and Phaneuf, D and Julien, JP}, title = {Withania somnifera Reverses Transactive Response DNA Binding Protein 43 Proteinopathy in a Mouse Model of Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {14}, number = {2}, pages = {447-462}, pmid = {27928708}, issn = {1878-7479}, support = {//CIHR/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*physiopathology/prevention &amp; control ; Animals ; Avoidance Learning/drug effects ; Cells, Cultured ; Cytokines/metabolism ; DNA-Binding Proteins/*metabolism ; Disease Models, Animal ; Encephalitis/prevention &amp; control ; Female ; Frontotemporal Lobar Degeneration/metabolism/*physiopathology/prevention &amp; control ; Male ; Mice ; Mice, Transgenic ; Microglia/drug effects/metabolism ; Motor Activity/drug effects ; NF-kappa B/metabolism ; Neuromuscular Junction/drug effects ; Neurons/drug effects/metabolism ; Plant Extracts/*administration &amp; dosage/isolation &amp; purification/therapeutic use ; Rotarod Performance Test ; Spinal Cord/drug effects/metabolism ; TDP-43 Proteinopathies/metabolism/*physiopathology/prevention &amp; control ; Withania ; }, abstract = {Abnormal cytoplasmic mislocalization of transactive response DNA binding protein 43 (TARDBP or TDP-43) in degenerating neurons is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Our previous work suggested that nuclear factor kappa B (NF-κB) may constitute a therapeutic target for TDP-43-mediated disease. Here, we investigated the effects of root extract of Withania somnifera (Ashwagandha), an herbal medicine with anti-inflammatory properties, in transgenic mice expressing a genomic fragment encoding human TDP-43[A315T] mutant. Ashwagandha extract was administered orally to hTDP-43[A315T] mice for a period of 8 weeks starting at 64 and 48 weeks of age for males and females, respectively. The treatment of hTDP-43[A315T] mice ameliorated their motor performance on rotarod test and cognitive function assessed by the passive avoidance test. Microscopy examination of tissue samples revealed that Ashwagandha treatment of hTDP-43[A315T] mice improved innervation at neuromuscular junctions, attenuated neuroinflammation, and reduced NF-κB activation. Remarkably, Ashwagandha treatment reversed the cytoplasmic mislocalization of hTDP-43 in spinal motor neurons and in brain cortical neurons of hTDP-43[A315T] mice and it reduced hTDP-43 aggregation. In vitro evidence is presented that the neuronal rescue of TDP-43 mislocalization may be due to the indirect effect of factors released from microglial cells exposed to Ashwagandha. These results suggest that Ashwagandha and its constituents might represent promising therapeutics for TDP-43 proteinopathies.}, }
@article {pmid27927940, year = {2017}, author = {Goedee, HS and van der Pol, WL and van Asseldonk, JH and Franssen, H and Notermans, NC and Vrancken, AJ and van Es, MA and Nikolakopoulos, S and Visser, LH and van den Berg, LH}, title = {Diagnostic value of sonography in treatment-naive chronic inflammatory neuropathies.}, journal = {Neurology}, volume = {88}, number = {2}, pages = {143-151}, doi = {10.1212/WNL.0000000000003483}, pmid = {27927940}, issn = {1526-632X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnostic imaging/physiopathology ; Brachial Plexus/physiopathology ; Case-Control Studies ; Cohort Studies ; Edema/etiology ; Electromyography ; Female ; Humans ; Logistic Models ; Male ; Middle Aged ; Neural Conduction/physiology ; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/*diagnostic imaging/physiopathology ; Ultrasonography/*methods ; }, abstract = {OBJECTIVE: To determine the diagnostic value of high-resolution ultrasound (HRUS) for detection of chronic inflammatory demyelinating polyneuropathy (CIDP), Lewis-Sumner syndrome (LSS), and multifocal motor neuropathy (MMN).<br><br>METHODS: Between January 2013 and January 2015, we enrolled 75 consecutive treatment-naive patients with chronic inflammatory neuropathies and 70 disease controls. We performed extensive nerve conduction and standardized HRUS studies bilaterally of large arm and leg nerves and brachial plexus. We determined optimal sonographic cutoff values of nerve size and used receiver operating characteristic analysis and logistic regression models to identify nerve combinations with optimal diagnostic performance.<br><br>RESULTS: Enlargement of median nerve at forearm >10 mm[2], upper arm >13 mm[2], and any trunk of brachial plexus >8 mm[2] was 99% specific for chronic inflammatory neuropathies. A shortened HRUS protocol for detecting this abnormal nerve enlargement showed high sensitivity (83%-95%), positive predictive value (100%), and negative predictive value (98%) in discriminating CIDP, LSS, and MMN from clinical mimics.<br><br>CONCLUSIONS: Sonographic enlargement of proximal median nerve segments in the arms and brachial plexus is a key feature of chronic inflammatory neuropathies, which helps to reliably distinguish them from axonal neuropathies and amyotrophic lateral sclerosis.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, in absence of clinical features that suggest a hereditary demyelinating neuropathy, sonographic enlargement of proximal median nerve segments and brachial plexus accurately identifies patients with chronic inflammatory neuropathies.}, }
@article {pmid27925274, year = {2017}, author = {Galwey, NW}, title = {Supplementation of a clinical trial by historical control data: is the prospect of dynamic borrowing an illusion?.}, journal = {Statistics in medicine}, volume = {36}, number = {6}, pages = {899-916}, doi = {10.1002/sim.7180}, pmid = {27925274}, issn = {1097-0258}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; Bayes Theorem ; Bias ; Clinical Trials as Topic/*methods ; Data Interpretation, Statistical ; Humans ; Models, Statistical ; Sample Size ; Statistics as Topic ; }, abstract = {There are strong arguments, ethical, logistical and financial, for supplementing the evidence from a new clinical trial using data from previous trials with similar control treatments. There is a consensus that historical information should be down-weighted or discounted relative to information from the new trial, but the determination of the appropriate degree of discounting is a major difficulty. The degree of discounting can be represented by a bias parameter with specified variance, but a comparison between the historical and new data gives only a poor estimate of this variance. Hence, if no strong assumption is made concerning its value (i.e. if 'dynamic borrowing' is practiced), there may be little or no gain from using the historical data, in either frequentist terms (type I error rate and power) or Bayesian terms (posterior distribution of the treatment effect). It is therefore best to compare the consequences of a range of assumptions. This paper presents a clear, simple graphical tool for doing so on the basis of the mean square error, and illustrates its use with historical data from clinical trials in amyotrophic lateral sclerosis. This approach makes it clear that different assumptions can lead to very different conclusions. External information can sometimes provide strong additional guidance, but different stakeholders may still make very different judgements concerning the appropriate degree of discounting. Copyright © 2016 John Wiley &amp; Sons, Ltd.}, }
@article {pmid27923201, year = {2017}, author = {Mancini, A and Chelini, A and Di Capua, A and Castelli, L and Brogi, S and Paolino, M and Giuliani, G and Cappelli, A and Frosini, M and Ricci, L and Leonelli, E and Giorgi, G and Giordani, A and Magistretti, J and Anzini, M}, title = {Synthesis and biological evaluation of a new class of benzothiazines as neuroprotective agents.}, journal = {European journal of medicinal chemistry}, volume = {126}, number = {}, pages = {614-630}, doi = {10.1016/j.ejmech.2016.11.053}, pmid = {27923201}, issn = {1768-3254}, mesh = {Animals ; Brain/pathology ; Calcium Channels/drug effects ; Cell Death/drug effects ; Glutamic Acid/deficiency ; Humans ; Neuroblastoma/pathology ; Neuroprotective Agents/*chemical synthesis/pharmacology ; Oxygen/metabolism ; Reactive Oxygen Species ; Thiazines/chemical synthesis/*pharmacology ; Voltage-Gated Sodium Channels/drug effects ; }, abstract = {Neurodegenerative diseases are disorders related to the degeneration of central neurons that gradually lead to various, severe alterations of cognitive and/or motor functions. Currently, for no such diseases does any pharmacological treatment exist able to arrest its progression. Riluzole (1) is a small molecule able to interfere with multiple cellular and molecular mechanisms of neurodegeneration, and is the only approved treatment of amyotrophic lateral sclerosis (ALS), the progression of which proved to significantly slow, thus increasing somewhat average survival. Here we report the synthesis of differently functionalized 4H-3,1-benzothiazine (5-6) and 2H-1,4-benzothiazine (7) series as superior homologues of 1. Biological evaluation demonstrated that amidine 4H-3,1-benzothiazine derivatives 5b-d can reduce glutamate and LDH release in the oxygen/glucose deprivation and reperfusion model (OGD/R) applied to brain slices with a higher potency than 1. Moreover the mentioned compounds significantly reduce glutamate- and 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in neuroblastoma cells. In addition, the same compounds limit ROS formation in both neuronal preparations. Finally, 5c proved effective in inhibiting neuronal voltage-dependent Na[+] and Ca[2+]-channels, showing a profile comparable with that of 1.}, }
@article {pmid27922548, year = {2017}, author = {Ito, S and Izumi, Y and Niidome, T and Ono, Y}, title = {Methylcobalamin prevents mutant superoxide dismutase-1-induced motor neuron death in vitro.}, journal = {Neuroreport}, volume = {28}, number = {2}, pages = {101-107}, doi = {10.1097/WNR.0000000000000716}, pmid = {27922548}, issn = {1473-558X}, mesh = {Animals ; Cell Death/*drug effects/genetics ; Cells, Cultured ; Cerebral Cortex/cytology ; Embryo, Mammalian ; In Situ Nick-End Labeling ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects/*physiology ; Neuroprotective Agents/pharmacology ; Riluzole/pharmacology ; Superoxide Dismutase/*genetics/metabolism ; Vitamin B 12/*analogs &amp; derivatives/pharmacology ; Vitamin B Complex/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable progressive neurodegenerative disorder that causes motor dysfunction. Treatments and drugs that slow progression of ALS have garnered great interest. In the present study, we show that the vitamin B12 analog methylcobalamin (MBL) effectively and dose dependently prevented embryonic stem cell-derived motor neuron death induced by cocultivation with astrocytes expressing mutant human superoxide dismutase-1 (G93A). Moreover, cotreatment of MBL with a conventional ALS drug, riluzole, further enhanced survival of motor neurons in this in-vitro ALS model. Our results show the potential use of MBL as a treatment for ALS and suggest a possible combination therapy strategy with other types of approved ALS drugs.}, }
@article {pmid27909398, year = {2016}, author = {Mompeán, M and Baralle, M and Buratti, E and Laurents, DV}, title = {An Amyloid-Like Pathological Conformation of TDP-43 Is Stabilized by Hypercooperative Hydrogen Bonds.}, journal = {Frontiers in molecular neuroscience}, volume = {9}, number = {}, pages = {125}, pmid = {27909398}, issn = {1662-5099}, abstract = {TDP-43 is an essential RNA-binding protein forming aggregates in almost all cases of sporadic amyotrophic lateral sclerosis (ALS) and many cases of frontotemporal lobar dementia (FTLD) and other neurodegenerative diseases. TDP-43 consists of a folded N-terminal domain with a singular structure, two RRM RNA-binding domains, and a long disordered C-terminal region which plays roles in functional RNA regulatory assemblies as well as pernicious aggregation. Evidence from pathological mutations and seeding experiments strongly suggest that TDP-43 aggregates are pathologically relevant through toxic gain-of-harmful-function and/or harmful loss-of-native-function mechanisms. Recent, but not early, microscopy studies and the ability of TDP-43 aggregates to resist harsh treatment and to seed new pathological aggregates in vitro and in cells strongly suggest that TDP-43 aggregates have a self-templating, amyloid-like structure. Based on the importance of the Gln/Asn-rich 341-367 residue segment for efficient aggregation of endogenous TDP-43 when presented as a 12X-repeat and extensive spectroscopic and computational experiments, we recently proposed that this segment adopts a beta-hairpin structure that assembles in a parallel with a beta-turn configuration to form an amyloid-like structure. Here, we propose that this conformer is stabilized by an especially strong class of hypercooperative hydrogen bonding unique to Gln and Asn sidechains. The clinical existence of this conformer is supported by very recent LC-MS/MS characterization of TDP-43 from ex vivo aggregates, which show that residues 341-367 were protected in vivo from Ser phosphorylation, Gln/Asn deamidation and Met oxidation. Its distinct pattern of SDS-PAGE bands allows us to link this conformer to the exceptionally stable seed of the Type A TDP-43 proteinopathy.}, }
@article {pmid27908811, year = {2017}, author = {Ousaka, D and Fujii, Y and Oozawa, S and Nishibori, M and Kuroko, Y and Masuda, Z and Sano, S}, title = {Decreased Serum Levels of High Mobility Group Box 1 (HMGB-1) after Graft Replacement or Stenting of Abdominal Aortic Aneurysm.}, journal = {Annals of vascular surgery}, volume = {41}, number = {}, pages = {265-270}, doi = {10.1016/j.avsg.2016.08.017}, pmid = {27908811}, issn = {1615-5947}, mesh = {Adult ; Aged ; Aged, 80 and over ; Aortic Aneurysm, Abdominal/blood/diagnostic imaging/*surgery ; Biomarkers/blood ; *Blood Vessel Prosthesis ; Blood Vessel Prosthesis Implantation/*instrumentation ; Case-Control Studies ; Down-Regulation ; Endovascular Procedures/*instrumentation ; Female ; HMGB1 Protein/*blood ; Humans ; Male ; Middle Aged ; Prospective Studies ; *Stents ; Treatment Outcome ; }, abstract = {BACKGROUND: High-mobility group box 1 (HMGB-1) is a key substance mediating inflammation and development of atherosclerotic lesions (ALs), including abdominal aortic aneurysms (AAA). Serum levels of HMGB-1 are increased in patients with AAA than those in normal controls because the ALs in AAAs secrete HMGB-1. We therefore postulate that the serum HMGB-1 level should decrease after endovascular aortic repair (EVAR) or open aortic repair (OAR). However, there is no evidence of this in the literature. The purpose of this study was to investigate the changes in HMGB-1 levels after surgical intervention for AAA. We also aimed to determine if the HMGB-1 levels varied between the two procedures.<br><br>METHODS: Serum HMGB-1 levels were determined in 24 patients with AAA and 25 healthy controls. Twelve of the 24 AAA patients underwent EVAR, whereas the other half underwent OAR. The relationship between HMGB-1 levels and presence of AAA or influence of operative methods on the serum HMGB-1 level were prospectively investigated.<br><br>RESULTS: Serum HMGB-1 levels in AAA patients were significantly higher than those in healthy controls (9.4&#xa0;&#xb1;&#xa0;5.7 vs. 4.1&#xa0;&#xb1;&#xa0;2.0&#xa0;ng/mL, P&#xa0;<&#xa0;0.01). The serum HMGB-1 levels in both the EVAR group and the OAR group were significantly decreased from baseline at both 3&#xa0;mo and 1&#xa0;y after surgery.<br><br>CONCLUSIONS: Removal or isolation of AL via surgical intervention significantly decreases serum HMGB-1 levels. The significant postoperative reduction in HMGB-1 levels suggests that important endocrinological changes occur after surgical treatment of AAA.}, }
@article {pmid27906525, year = {2017}, author = {Eskreis-Winkler, S and Zhang, Y and Zhang, J and Liu, Z and Dimov, A and Gupta, A and Wang, Y}, title = {The clinical utility of QSM: disease diagnosis, medical management, and surgical planning.}, journal = {NMR in biomedicine}, volume = {30}, number = {4}, pages = {}, doi = {10.1002/nbm.3668}, pmid = {27906525}, issn = {1099-1492}, mesh = {Biomarkers/metabolism ; Brain/*diagnostic imaging/metabolism ; Brain Diseases/*diagnostic imaging/metabolism/*surgery ; Diffusion Magnetic Resonance Imaging/*methods ; Humans ; Image Enhancement/methods ; Molecular Imaging/*methods ; Preoperative Care/*methods ; Surgery, Computer-Assisted/*methods ; }, abstract = {Quantitative susceptibility mapping (QSM) is an MR technique that depicts and quantifies magnetic susceptibility sources. Mapping iron, the dominant susceptibility source in the brain, has many important clinical applications. Herein, we review QSM applications in the diagnosis, medical management, and surgical treatment of disease. To assist in early disease diagnosis, QSM can identify elevated iron levels in the motor cortex of amyotrophic lateral sclerosis patients, in the substantia nigra of Parkinson's disease (PD) patients, in the globus pallidus, putamen, and caudate of Huntington's disease patients, and in the basal ganglia of Wilson's disease patients. Additionally, QSM can distinguish between hemorrhage and calcification, which could prove useful in tumor subclassification, and can measure microbleeds in traumatic brain injury patients. In guiding medical management, QSM can be used to monitor iron chelation therapy in PD patients, to monitor smoldering inflammation of multiple sclerosis (MS) lesions after the blood-brain barrier (BBB) seals, to monitor active inflammation of MS lesions before the BBB seals without using gadolinium, and to monitor hematoma volume in intracerebral hemorrhage. QSM can also guide neurosurgical treatment. Neurosurgeons require accurate depiction of the subthalamic nucleus, a tiny deep gray matter nucleus, prior to inserting deep brain stimulation electrodes into the brains of PD patients. QSM is arguably the best imaging tool for depiction of the subthalamic nucleus. Finally, we discuss future directions, including bone QSM, cardiac QSM, and using QSM to map cerebral metabolic rate of oxygen. Copyright © 2016 John Wiley &amp; Sons, Ltd.}, }
@article {pmid27905515, year = {2016}, author = {Andrione, M and Vallortigara, G and Antolini, R and Haase, A}, title = {Neonicotinoid-induced impairment of odour coding in the honeybee.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {38110}, pmid = {27905515}, issn = {2045-2322}, mesh = {Animals ; Bees/*drug effects/*physiology ; Calcium Signaling/drug effects ; Evoked Potentials/drug effects/physiology ; Insecticides/*toxicity ; Learning/drug effects/physiology ; Memory/drug effects/physiology ; Mushroom Bodies/drug effects/physiology ; Neonicotinoids/*toxicity ; Nitro Compounds/toxicity ; *Odorants ; Olfactory Receptor Neurons/drug effects/physiology ; Smell/*drug effects/*physiology ; }, abstract = {Exposure to neonicotinoid pesticides is considered one of the possible causes of honeybee (Apis mellifera) population decline. At sublethal doses, these chemicals have been shown to negatively affect a number of behaviours, including performance of olfactory learning and memory, due to their interference with acetylcholine signalling in the mushroom bodies. Here we provide evidence that neonicotinoids can affect odour coding upstream of the mushroom bodies, in the first odour processing centres of the honeybee brain, i.e. the antennal lobes (ALs). In particular, we investigated the effects of imidacloprid, the most common neonicotinoid, in the AL glomeruli via in vivo two-photon calcium imaging combined with pulsed odour stimulation. Following acute imidacloprid treatment, odour-evoked calcium response amplitude in single glomeruli decreases, and at the network level the representations of different odours are no longer separated. This demonstrates that, under neonicotinoid influence, olfactory information might reach the mushroom bodies in a form that is already incorrect. Thus, some of the impairments in olfactory learning and memory caused by neonicotinoids could, in fact, arise from the disruption in odor coding and olfactory discrimination ability of the honey bees.}, }
@article {pmid27898033, year = {2016}, author = {Bezdjian, A and Kraaijenga, VJ and Ramekers, D and Versnel, H and Thomeer, HG and Klis, SF and Grolman, W}, title = {Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans.}, journal = {International journal of molecular sciences}, volume = {17}, number = {12}, pages = {}, pmid = {27898033}, issn = {1422-0067}, mesh = {Animals ; Cochlear Nerve/*drug effects ; Humans ; Nerve Growth Factors/administration &amp; dosage/adverse effects/*therapeutic use ; Neurodegenerative Diseases/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {Animal studies have evidenced protection of the auditory nerve by exogenous neurotrophic factors. In order to assess clinical applicability of neurotrophic treatment of the auditory nerve, the safety and efficacy of neurotrophic therapies in various human disorders were systematically reviewed. Outcomes of our literature search included disorder, neurotrophic factor, administration route, therapeutic outcome, and adverse event. From 2103 articles retrieved, 20 randomized controlled trials including 3974 patients were selected. Amyotrophic lateral sclerosis (53%) was the most frequently reported indication for neurotrophic therapy followed by diabetic polyneuropathy (28%). Ciliary neurotrophic factor (50%), nerve growth factor (24%) and insulin-like growth factor (21%) were most often used. Injection site reaction was a frequently occurring adverse event (61%) followed by asthenia (24%) and gastrointestinal disturbances (20%). Eighteen out of 20 trials deemed neurotrophic therapy to be safe, and six out of 17 studies concluded the neurotrophic therapy to be effective. Positive outcomes were generally small or contradicted by other studies. Most non-neurodegenerative diseases treated by targeted deliveries of neurotrophic factors were considered safe and effective. Hence, since local delivery to the cochlea is feasible, translation from animal studies to human trials in treating auditory nerve degeneration seems promising.}, }
@article {pmid27881068, year = {2016}, author = {Rodríguez, MJ and Mahy, N}, title = {Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited.}, journal = {Current medicinal chemistry}, volume = {23}, number = {42}, pages = {4753-4772}, doi = {10.2174/0929867324666161123091314}, pmid = {27881068}, issn = {1875-533X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology/therapy ; Animals ; Energy Metabolism ; Humans ; Inflammation/pathology ; Microglia/*pathology ; Motor Neurons/*pathology ; Protein Folding ; }, abstract = {Research onto the pathogenesis of amyotrophic lateral sclerosis (ALS) has obtained notable gene discoveries, although, to date, only progress with regard to treatment has been very modest. Currently ALS is considered a multifactorial disease that presents diverse clinical presentations, ranging from a monogenic inherited disease to an autoimmune pathology, and develops with misfolded protein aggregation and neuroinflammation. An important factor related to ALS pathogenesis is the microglial activation associated with degenerative motor neurons. This activation leads to changes in the expression of a wide range of genes related to phagocytosis and inflammation, and to profound modifications in the dynamic interactions between neurons and glial cells. Overactivation and deregulation of microglial activity causes deleterious effects and leads to neuronal death. However, the involvement of microglia in non-inflammatory functions challenges our concept of neuroinflammation and opens up new possibilities for the study of the pathophysiological mechanisms of ALS. In this review we summarize the current knowledge on the adaptive interactions between neurons and microglia in ALS. We also discuss the hypothesis that controlling the extent of microglial activation and neuroinflammation may have clinical and therapeutic benefits for the condition.}, }
@article {pmid27878793, year = {2016}, author = {Linnebank, M and McDougall, CG and Krueger, S and Biskup, S and Neumann, M and Weller, M and Valavanis, A and Prudlo, J}, title = {Novel cases of amyotrophic lateral sclerosis after treatment of cerebral arteriovenous malformationss.}, journal = {Swiss medical weekly}, volume = {146}, number = {}, pages = {w14361}, doi = {10.4414/smw.2016.14361}, pmid = {27878793}, issn = {1424-3997}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*etiology/pathology ; Embolization, Therapeutic/*adverse effects ; Female ; Humans ; Intracranial Arteriovenous Malformations/*complications ; Middle Aged ; Risk Factors ; Time Factors ; }, abstract = {Previous case studies reported nine patients with cerebral arteriovenous malformations (AVM) who developed amyotrophic lateral sclerosis (ALS) after AVM embolisation. Here, we describe three novel cases of ALS which developed 13-34 years after treatment, including embolisation, of cerebral AVM. This study provides further arguments supporting the thesis that embolisation of cerebral AVM might influence the risk of later ALS development.}, }
@article {pmid27873462, year = {2017}, author = {Golpich, M and Amini, E and Mohamed, Z and Azman Ali, R and Mohamed Ibrahim, N and Ahmadiani, A}, title = {Mitochondrial Dysfunction and Biogenesis in Neurodegenerative diseases: Pathogenesis and Treatment.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {23}, number = {1}, pages = {5-22}, pmid = {27873462}, issn = {1755-5949}, mesh = {Animals ; Histocompatibility Antigens/genetics/metabolism ; Humans ; Mitochondrial Diseases/*etiology ; Neurodegenerative Diseases/*complications/*metabolism ; *Organelle Biogenesis ; }, abstract = {Neurodegenerative diseases are a heterogeneous group of disorders that are incurable and characterized by the progressive degeneration of the function and structure of the central nervous system (CNS) for reasons that are not yet understood. Neurodegeneration is the umbrella term for the progressive death of nerve cells and loss of brain tissue. Because of their high energy requirements, neurons are especially vulnerable to injury and death from dysfunctional mitochondria. Widespread damage to mitochondria causes cells to die because they can no longer produce enough energy. Several lines of pathological and physiological evidence reveal that impaired mitochondrial function and dynamics play crucial roles in aging and pathogenesis of neurodegenerative diseases. As mitochondria are the major intracellular organelles that regulate both cell survival and death, they are highly considered as a potential target for pharmacological-based therapies. The purpose of this review was to present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) and the importance of mitochondrial biogenesis as a potential novel therapeutic target for their treatment. Likewise, we highlight a concise overview of the key roles of mitochondrial electron transport chain (ETC.) complexes as well as mitochondrial biogenesis regulators regarding those diseases.}, }
@article {pmid27866730, year = {2016}, author = {Stojkovic, T}, title = {Hereditary neuropathies: An update.}, journal = {Revue neurologique}, volume = {172}, number = {12}, pages = {775-778}, doi = {10.1016/j.neurol.2016.06.007}, pmid = {27866730}, issn = {0035-3787}, mesh = {Amyloid Neuropathies, Familial/epidemiology/genetics ; Charcot-Marie-Tooth Disease/epidemiology/genetics ; Humans ; Mutation ; Nervous System Diseases/epidemiology/*genetics ; Neuromuscular Diseases/epidemiology/*genetics ; Prealbumin/genetics ; Prevalence ; }, abstract = {Hereditary neuropathies are the most common inherited neuromuscular diseases. Charcot-Marie-Tooth (CMT) disease represents the most common form with an average prevalence ranging from 1/2500 to 1/1200, depending on the studies. To date and with the advances of the latest generation sequencing, more than 80 genes have been identified. Although the common clinical phenotype comprises a progressive distal muscle weakness and sensory loss, foot deformities and decreased or absent tendon reflexes, clinical and electrophysiological phenotypes exhibit great variability. Moreover, atypical phenotypes are arising, overlapping with spastic paraplegia, hereditary sensory neuropathies or amyotrophic lateral sclerosis. The causative genes are involved in various biological processes such as myelin development and maintenance, biosynthesis and degradation of proteins, neuronal structural maintenance, axonal transport, endocytosis, membrane dynamics, ion-channel function and the mitochondrial network. An accurate genetic diagnosis is important for appropriate genetic counselling and treatment options. Therapeutic advances, particularly small interfering RNA therapy, are encouraging in hereditary transthyretin amyloid neuropathy.}, }
@article {pmid27857748, year = {2016}, author = {}, title = {Correction: Prospects for bone marrow cell therapy in amyotrophic lateral sclerosis: how far are we from a clinical treatment?.}, journal = {Neural regeneration research}, volume = {11}, number = {9}, pages = {1449}, pmid = {27857748}, issn = {1673-5374}, abstract = {[This corrects the article on p. 1216 in vol. 11, PMID: 27651758.].}, }
@article {pmid27847465, year = {2016}, author = {Kojic, M and Wainwright, B}, title = {The Many Faces of Elongator in Neurodevelopment and Disease.}, journal = {Frontiers in molecular neuroscience}, volume = {9}, number = {}, pages = {115}, pmid = {27847465}, issn = {1662-5099}, abstract = {Development of the nervous system requires a variety of cellular activities, such as proliferation, migration, axonal outgrowth and guidance and synapse formation during the differentiation of neural precursors into mature neurons. Malfunction of these highly regulated and coordinated events results in various neurological diseases. The Elongator complex is a multi-subunit complex highly conserved in eukaryotes whose function has been implicated in the majority of cellular activities underlying neurodevelopment. These activities include cell motility, actin cytoskeleton organization, exocytosis, polarized secretion, intracellular trafficking and the maintenance of neural function. Several studies have associated mutations in Elongator subunits with the neurological disorders familial dysautonomia (FD), intellectual disability (ID), amyotrophic lateral sclerosis (ALS) and rolandic epilepsy (RE). Here, we review the various cellular activities assigned to this complex and discuss the implications for neural development and disease. Further research in this area has the potential to generate new diagnostic tools, better prevention strategies and more effective treatment options for a wide variety of neurological disorders.}, }
@article {pmid27831974, year = {2017}, author = {Alfwaress, FS and Bibars, AR and Hamasha, A and Maaitah, EA}, title = {Outcomes of Palatal Lift Prosthesis on Dysarthric Speech.}, journal = {The Journal of craniofacial surgery}, volume = {28}, number = {1}, pages = {30-35}, doi = {10.1097/SCS.0000000000003167}, pmid = {27831974}, issn = {1536-3732}, mesh = {Adolescent ; Adult ; Aged ; Child ; Dysarthria/*etiology/*surgery ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Palate/*surgery ; *Prosthesis Implantation ; Sound Spectrography ; Speech ; Speech Acoustics ; Speech Intelligibility ; *Speech Production Measurement ; Treatment Outcome ; Vital Capacity ; Young Adult ; }, abstract = {PURPOSE: This study was designed to investigate the effect of palatal lift prosthesis (PLP) on the speech of individuals with different types of dysarthria.<br><br>PARTICIPANTS: Thirty (19 males and 11 females) native speakers of Jordanian Arabic with dysarthria participated in the study. The age of the participants ranged from 8 to 67 years with an average of 34.1 years. Traumatic brain injury was the most common etiology of dysarthria among 12 participants, stroke among 11, multiple sclerosis among 3, and pseudobulbar palsy among 2; 1 participant had Parkinson disease, and another participant had amyotrophic lateral sclerosis.<br><br>METHODS: Five acoustic and aerodynamic measures were evaluated to determine the speech outcomes including nasalance scores, sequential motion rate, speech rate, vital capacity, and sound pressure level. The acoustic measures were obtained from the participants in PLP-out and PLP-in conditions.<br><br>RESULTS: Results showed statistically significant decrease in the nasalance scores of the syllable repetition, vowel prolongation, and sentence repetition tasks in the PLP-in condition below the 28% cutoff score. Furthermore, results revealed statistically significant increase in sequential motion rate, speech rate, vital capacity, and sound pressure level (P&#x200a;=&#x200a;0.000).<br><br>CONCLUSION: The use of PLP is an effective treatment option of dysarthric speech. Besides nasalance scores, the sequential motion rate, speech rate, vital capacity, and sound pressure level are considered reliable speech measures that may be used to evaluate the effect of PLP on dysarthria.}, }
@article {pmid27830059, year = {2016}, author = {Tuk, B}, title = {Syphilis may be a confounding factor, not a causative agent, in syphilitic ALS.}, journal = {F1000Research}, volume = {5}, number = {}, pages = {1904}, pmid = {27830059}, issn = {2046-1402}, abstract = {Based upon a review of published clinical observations regarding syphilitic amyotrophic lateral sclerosis (ALS), I hypothesize that syphilis is actually a confounding factor, not a causative factor, in syphilitic ALS. Moreover, I propose that the successful treatment of ALS symptoms in patients with syphilitic ALS using penicillin G and hydrocortisone is an indirect consequence of the treatment regimen and is not due to the treatment of syphilis. Specifically, I propose that the observed effect is due to the various pharmacological activities of penicillin G (e.g., a GABA receptor antagonist) and/or the multifaceted pharmacological activity of hydrocortisone. The notion that syphilis may be a confounding factor in syphilitic ALS is highly relevant, as it suggests that treating ALS patients with penicillin G and hydrocortisone-regardless of whether they present with syphilitic ALS or non-syphilitic ALS-may be effective at treating this rapidly progressive, highly devastating disease.}, }
@article {pmid27826939, year = {2017}, author = {Golko-Perez, S and Amit, T and Bar-Am, O and Youdim, MB and Weinreb, O}, title = {A Novel Iron Chelator-Radical Scavenger Ameliorates Motor Dysfunction and Improves Life Span and Mitochondrial Biogenesis in SOD1[G93A] ALS Mice.}, journal = {Neurotoxicity research}, volume = {31}, number = {2}, pages = {230-244}, pmid = {27826939}, issn = {1476-3524}, mesh = {Amyotrophic Lateral Sclerosis/diet therapy/*drug therapy ; Animals ; Cell Survival/drug effects ; Cells, Cultured ; Combined Modality Therapy ; DNA, Mitochondrial/*metabolism ; Denervation ; Electron Transport Complex I/metabolism ; Electron Transport Complex II/metabolism ; Female ; Gene Expression/drug effects ; Hydroxyquinolines/*pharmacology/*therapeutic use ; Iron/metabolism ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects ; Motor Skills/*drug effects ; Muscle, Skeletal/metabolism ; Myofibrils/drug effects ; Neuromuscular Junction/pathology ; Oxidative Stress/drug effects ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Spinal Cord/metabolism/physiology ; Superoxide Dismutase-1/genetics ; *Survival Rate ; Up-Regulation/drug effects ; }, abstract = {The aim of the present study was to evaluate the therapeutic effect of the novel neuroprotective multitarget brain permeable monoamine oxidase inhibitor/iron chelating-radical scavenging drug, VAR10303 (VAR), co-administered with high-calorie/energy-supplemented diet (ced) in SOD1[G93A] transgenic amyotrophic lateral sclerosis (ALS) mice. Administration of VAR-ced was initiated after the appearance of disease symptoms (at day 88), as this regimen is comparable with the earliest time at which drug therapy could start in ALS patients. Using this rescue protocol, we demonstrated in the current study that VAR-ced treatment provided several beneficial effects in SOD1[G93A] mice, including improvement in motor performance, elevation of survival time, and attenuation of iron accumulation and motoneuron loss in the spinal cord. Moreover, VAR-ced treatment attenuated neuromuscular junction denervation and exerted a significant preservation of myofibril regular morphology, associated with a reduction in the expression levels of genes related to denervation and atrophy in the gastrocnemius (GNS) muscle in SOD1[G93A] mice. These effects were accompanied by upregulation of mitochondrial DNA and elevated activities of complexes I and II in the GNS muscle. We have also demonstrated that VAR-ced treatment upregulated the mitochondrial biogenesis master regulator, peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) and increased PGC-1α-targeted metabolic genes and proteins, such as, PPARγ, UCP1/3, NRF1/2, Tfam, and ERRα in GNS muscle. These results provide evidence of therapeutic potential of VAR-ced in SOD1[G93A] mice with underlying molecular mechanisms, further supporting the importance role of multitarget iron chelators in ALS treatment.}, }
@article {pmid27822919, year = {2016}, author = {Abdul Wahid, SF and Law, ZK and Ismail, NA and Azman Ali, R and Lai, NM}, title = {Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {11}, number = {11}, pages = {CD011742}, pmid = {27822919}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Cell- and Tissue-Based Therapy/*methods ; Humans ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND) is a fatal disease associated with rapidly progressive disability, for which no definitive treatment as yet exists. Current treatment regimens largely focus on relieving symptoms to improve the quality of life of those affected. Based on data from preclinical studies, cell-based therapy is a promising treatment for ALS/MND.<br><br>OBJECTIVES: To assess the effects of cell-based therapy for people with ALS/MND, compared with placebo or no additional treatment.<br><br>SEARCH METHODS: On 21 June 2016, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched two clinical trials' registries for ongoing or unpublished studies.<br><br>SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs), quasi-RCTs and cluster RCTs that assigned people with ALS/MND to receive cell-based therapy versus a placebo or no additional treatment. Co-interventions were allowable, provided that they were given to each group equally.<br><br>DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology.<br><br>MAIN RESULTS: No studies were eligible for inclusion in the review. We identified four ongoing trials.<br><br>AUTHORS' CONCLUSIONS: Currently, there is a lack of high-quality evidence to guide practice on the use of cell-based therapy to treat ALS/MND.We need large, prospective RCTs to establish the efficacy of cellular therapy and to determine patient-, disease- and cell treatment-related factors that may influence the outcome of cell-based therapy. The major goals of future research should be to determine the appropriate cell source, phenotype, dose, and route of delivery, as these will be key elements in designing an optimal cell-based therapy programme for people with ALS/MND. Future research should also explore novel treatment strategies, including combinations of cellular therapy and standard or novel neuroprotective agents, to find the best possible approach to prevent or reverse the neurological deficit in ALS/MND, and to prolong survival in this debilitating and fatal condition.}, }
@article {pmid27815720, year = {2017}, author = {Xiang, C and Wang, Y and Zhang, H and Han, F}, title = {The role of endoplasmic reticulum stress in neurodegenerative disease.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {22}, number = {1}, pages = {1-26}, doi = {10.1007/s10495-016-1296-4}, pmid = {27815720}, issn = {1573-675X}, mesh = {Alzheimer Disease/genetics/pathology ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Apoptosis/*genetics ; Endoplasmic Reticulum/genetics ; Endoplasmic Reticulum Stress/*genetics ; Humans ; Huntington Disease/genetics/pathology ; Parkinson Disease/genetics/pathology ; Unfolded Protein Response/*genetics ; }, abstract = {The endoplasmic reticulum (ER) is an important organelle involved in cellular homeostasis and control of protein quality. Unfolded protein response (UPR) is a cellular response to ER stress and promotes cell survival. Severe or prolonged stress activates apoptosis signaling to trigger cell death. In mammals, the UPR is initiated by three major ER stress sensors, including inositol-requiring transmembrane kinase 1, double-stranded RNA-activated protein kinase-like ER kinase and activating transcription factor 6. UPR dysfunction plays an important role in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease, which is characterized by the accumulation and aggregation of misfolded proteins. ER stress mediates the pathogenesis of psychiatric diseases, such as depression, schizophrenia, sleep fragmentation and post-traumatic stress disorder. The role of UPR in the neuropathology of humans, cell lines and animal models, is established. Therefore, inhibition of specific ER mediators may contribute to the treatment and prevention of neurodegeneration. Preclinical studies have shed light on the potential therapeutic strategies. Here, we will review the evidence of UPR activation in neurodegenerative disorders and psychiatric diseases along with the methodology.}, }
@article {pmid27815125, year = {2017}, author = {Vere Hodge, RA}, title = {Meeting report: 29th International Conference on Antiviral Research in La Jolla, CA, USA.}, journal = {Antiviral research}, volume = {137}, number = {}, pages = {23-40}, pmid = {27815125}, issn = {1872-9096}, mesh = {Animals ; *Antiviral Agents ; Biomedical Research ; Congresses as Topic ; Disease Models, Animal ; Herpesviridae/drug effects ; Humans ; Mice ; Prodrugs ; Respiratory Syncytial Virus, Human/drug effects ; Virus Diseases/*diagnosis/*therapy ; Virus Replication/drug effects ; Viruses/genetics/pathogenicity ; Zika Virus/drug effects ; }, abstract = {The 29th International Conference on Antiviral Research (ICAR) was held in La Jolla, CA, USA from April 17 to 21, 2016. This report opens with a tribute to the late Chris McGuigan, a Past-President of ISAR, then continues with summaries of the principal invited lectures. Doug Richman (Elion Award) investigated HIV resistance, Bob Vince (Holý Award) showed how carbocyclic nucleoside analogs led to abacavir and Jerome Deval (Prusoff Award) explained how his group chose to seek a nucleoside analog to treat RSV. ALS-8176 was active in a human RSV-challenge study and is being evaluated in children. The first keynote address, by Richard H. Scheuermann, reported on the remarkable progress made in viral genomics. The second keynote address, by Heinz Feldmann, gave an overview of Ebola virus disease. There were four mini-symposia, Structural Biology, Diagnostic Technologies, DNA viruses and Zika virus. Diagnostic assays are approaching an ideal aim, a compact instrument, simple to use with any type of sample, no sample preparation and a result within an hour. The diversity of HCMV is far greater than for other herpesviruses, typically, an individual having >20,000 single nucleotide polymorphisms (SNPs). During antiviral treatment, there is rapid CMV evolution which is presumed to be due to preferential selection of already present variants rather than by the creation of new variants. A selection of contributor presentations includes oral prodrugs for nucleoside triphosphate analogs, a new method for the synthesis of phosphoramidate prodrugs and the clinical evaluation of brincidofovir for treating transplant recipients with adenovirus infections.}, }
@article {pmid27807401, year = {2016}, author = {Vallée, A and Lecarpentier, Y}, title = {Alzheimer Disease: Crosstalk between the Canonical Wnt/Beta-Catenin Pathway and PPARs Alpha and Gamma.}, journal = {Frontiers in neuroscience}, volume = {10}, number = {}, pages = {459}, pmid = {27807401}, issn = {1662-4548}, abstract = {The molecular mechanisms underlying the pathophysiology of Alzheimer's disease (AD) are still not fully understood. In AD, Wnt/beta-catenin signaling has been shown to be downregulated while the peroxisome proliferator-activated receptor (PPAR) gamma (mARN and protein) is upregulated. Certain neurodegenerative diseases share the same Wnt/beta-catenin/PPAR gamma profile, such as bipolar disorder and schizophrenia. Conversely, other NDs share an opposite profile, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis, and Friedreich's ataxia. AD is characterized by the deposition of extracellular Abeta plaques and the formation of intracellular neurofibrillary tangles in the central nervous system (CNS). Activation of Wnt signaling or inhibition of both glycogen synthase kinase-3beta and Dickkopf 1, two key negative regulators of the canonical Wnt pathway, are able to protect against Abeta neurotoxicity and to ameliorate cognitive performance in AD patients. Although PPAR gamma is upregulated in AD patients, and despite the fact that it has been shown that the PPAR gamma and Wnt/beta catenin pathway systems work in an opposite manner, PPAR gamma agonists diminish learning and memory deficits, decrease Abeta activation of microglia, and prevent hippocampal and cortical neurons from dying. These beneficial effects observed in AD transgenic mice and patients might be partially due to the anti-inflammatory properties of PPAR gamma agonists. Moreover, activation of PPAR alpha upregulates transcription of the alpha-secretase gene and represents a new therapeutic treatment for AD. This review focuses largely on the behavior of two opposing pathways in AD, namely Wnt/beta-catenin signaling and PPAR gamma. It is hoped that this approach may help to develop novel AD therapeutic strategies integrating PPAR alpha signaling.}, }
@article {pmid29441966, year = {2016}, author = {Zhao, H and Meng, W and Li, Y and Liu, W and Fu, B and Yang, Y and Zhang, Q and Chen, G}, title = {The protective effects of CHIR99021 against oxidative injury in LO2 cells.}, journal = {Die Pharmazie}, volume = {71}, number = {11}, pages = {629-635}, doi = {10.1691/ph.2016.6714}, pmid = {29441966}, issn = {0031-7144}, mesh = {Antioxidants/metabolism ; Apoptosis/drug effects ; Cell Line ; Cell Survival/drug effects ; Chemical and Drug Induced Liver Injury/enzymology/pathology/prevention &amp; control ; Cytoprotection/*drug effects ; Glycogen Synthase Kinase 3/biosynthesis/genetics ; Hepatocytes/*drug effects ; Humans ; Hydrogen Peroxide/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Necrosis ; Oxidative Stress/*drug effects ; Pyridines/*pharmacology ; Pyrimidines/*pharmacology ; }, abstract = {Hepatic ischemia-reperfusion injury is one of the most important factors for the prognosis of liver transplantation and hepatic surgery. It was reported that glycogen synthase kinase-3 (GSK-3) regulated injury response during ischemia-reperfusion. In this study, we investigated the protective effects of the GSK-3 inhibitor CHIR99021 against hepatic ischemia-reperfusion injury. A H2O2-induced oxidative injury model using LO2 cells was established. LO2 cells were divided into four groups, including blank control group, CHIR99021 control group treated with CHIR99021 alone, H2O2-injury group treated with H2O2 and protection group treated with H2O2 plus CHIR99021. Cell viability, cell apoptosis or necrosis was determined. Meanwhile, mitochondrial membrane potential, lipid peroxidation, cellular ROS levels, SOD activity, and serum contents of ALS and AST were measured. Protein and mRNA expressions were also detected. The results showed that a cell oxidative injury model was established by treating LO2 cells with 200 μmol/L H2O2 for 6 h. Cells exposed to H2O2 resulted in a significant decrease of cell viability and increase of cell apoptosis, which was accompanied by increasing ROS levels, disruption of mitochondrial membrane potential, excessive lipid peroxidation, reduction of SOD activity, and increased levels of ALT and AST. Treatment with CHIR99021 significantly protected LO2 cells against H2O2-induce oxidative injury by inhibiting the changes of above oxidative injury related indicators. Moreover, CHIR99021 treatment significantly reversed H2O2-induced decrease in p-GSK-3βSer9 , Bcl-2, Bcl-xl, survivin and β-catenin expression, whereas it significantly attenuated H2O2-induced increase in caspase-3, cleaved caspase-3 and p-JNK protein expression. In conclusion, CHIR99021 protected LO2 cells against H2O2-induced oxidative injury through reducing GSK-3β activity and apoptosis, with underlying mechanisms involved in stabilizing mitochondrial membrane potential, attenuating cellular ROS generation, suppressing mitochondria-mediated apoptotic pathway, and activation of GSK-3β/β-catenin signaling pathway.}, }
@article {pmid27764523, year = {2016}, author = {Simon, ST and Higginson, IJ and Booth, S and Harding, R and Weingärtner, V and Bausewein, C}, title = {Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults.}, journal = {The Cochrane database of systematic reviews}, volume = {10}, number = {10}, pages = {CD007354}, pmid = {27764523}, issn = {1469-493X}, support = {MCCC-RP-15-A18859/MCCC_/Marie Curie/United Kingdom ; PB-PG-0808-17311/DH_/Department of Health/United Kingdom ; }, mesh = {Adult ; Benzodiazepines/adverse effects/*therapeutic use ; Dyspnea/*drug therapy/etiology ; Humans ; Lung Neoplasms/*complications ; Pulmonary Disease, Chronic Obstructive/*complications ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: This is an updated version of the original Cochrane review published in Issue 1, 2010, on 'Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults'. Breathlessness is one of the most common symptoms experienced in the advanced stages of malignant and non-malignant disease. Benzodiazepines are widely used for the relief of breathlessness in advanced diseases and are regularly recommended in the literature. At the time of the previously published Cochrane review, there was no evidence for a beneficial effect of benzodiazepines for the relief of breathlessness in people with advanced cancer and chronic obstructive pulmonary disease (COPD).<br><br>OBJECTIVES: The primary objective of this review was to determine the efficacy of benzodiazepines for the relief of breathlessness in people with advanced disease. Secondary objectives were to determine the efficacy of different benzodiazepines, different doses of benzodiazepines, different routes of application, adverse effects of benzodiazepines, and the efficacy in different disease groups.<br><br>SEARCH METHODS: This is an update of a review published in 2010. We searched 14 electronic databases up to September 2009 for the original review. We checked the reference lists of all relevant studies, key textbooks, reviews, and websites. For the update, we searched CENTRAL, MEDLINE, and EMBASE and registers of clinical trials for further ongoing or unpublished studies, up to August 2016. We contacted study investigators and experts in the field of palliative care asking for further studies, unpublished data, or study details when necessary.<br><br>SELECTION CRITERIA: We included randomised controlled trials (RCTs) and controlled clinical trials (CCTs) assessing the effect of benzodiazepines compared with placebo or active control in relieving breathlessness in people with advanced stages of cancer, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), motor neurone disease (MND), and idiopathic pulmonary fibrosis (IPF).<br><br>DATA COLLECTION AND ANALYSIS: Two review authors independently assessed identified titles and abstracts. Three review authors independently performed assessment of all potentially relevant studies (full text), data extraction, and assessment of methodological quality. We carried out meta-analysis where appropriate.<br><br>MAIN RESULTS: Overall, we identified eight studies for inclusion: seven in the previous review and an additional study for this update. We also identified two studies awaiting classification in this update. The studies were small (a maximum number of 101 participants) and comprised data from a total of 214 participants with advanced cancer or COPD, which we analysed. There was only one study of low risk of bias. Most of the studies had an unclear risk of bias due to lack of information on random sequence generation, concealment, and attrition. Analysis of all studies did not show a beneficial effect of benzodiazepines for the relief of breathlessness (the primary outcome) in people with advanced cancer and COPD (8 studies, 214 participants) compared to placebo, midazolam, morphine, or promethazine. Furthermore, we observed no statistically significant effect in the prevention of episodic breathlessness (breakthrough dyspnoea) in people with cancer (after 48 hours: risk ratio of 0.76 (95% CI 0.53 to 1.09; 2 studies, 108 participants)) compared to morphine. Sensitivity analyses demonstrated no statistically significant differences regarding type of benzodiazepine, dose, route and frequency of delivery, duration of treatment, or type of control. Benzodiazepines caused statistically significantly more adverse events, particularly drowsiness and somnolence, when compared to placebo (risk difference 0.74 (95% CI 0.37, 1.11); 3 studies, 38 participants). In contrast, two studies reported that morphine caused more adverse events than midazolam (RD -0.18 (95% CI -0.31, -0.04); 194 participants).<br><br>AUTHORS' CONCLUSIONS: Since the last version of this review, we have identified one new study for inclusion, but the conclusions remain unchanged. There is no evidence for or against benzodiazepines for the relief of breathlessness in people with advanced cancer and COPD. Benzodiazepines caused more drowsiness as an adverse effect compared to placebo, but less compared to morphine. Benzodiazepines may be considered as a second- or third-line treatment, when opioids and non-pharmacological measures have failed to control breathlessness. There is a need for well-conducted and adequately powered studies.}, }
@article {pmid27581221, year = {2016}, author = {Jacobs, TL and Brown, DL and Baek, J and Migda, EM and Funckes, T and Gruis, KL}, title = {Trial of early noninvasive ventilation for ALS: A pilot placebo-controlled study.}, journal = {Neurology}, volume = {87}, number = {18}, pages = {1878-1883}, pmid = {27581221}, issn = {1526-632X}, support = {R01 NS070941/NS/NINDS NIH HHS/United States ; U10 NS086526/NS/NINDS NIH HHS/United States ; K23 NS055200/NS/NINDS NIH HHS/United States ; R01 HL123379/HL/NHLBI NIH HHS/United States ; R01 HL126700/HL/NHLBI NIH HHS/United States ; R01 DC012760/DC/NIDCD NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Double-Blind Method ; Female ; Humans ; Male ; Noninvasive Ventilation/*methods ; Pilot Projects ; Prospective Studies ; Treatment Outcome ; }, abstract = {OBJECTIVE: To evaluate the use and tolerability of noninvasive positive pressure ventilation (NIV) in patients with amyotrophic lateral sclerosis (ALS) early in their disease by comparing active NIV and sham NIV in patients not yet eligible for NIV use as recommended by practice guidelines.<br><br>METHODS: This was a single-center, prospective, double-blind, randomized, placebo (sham)-controlled pilot trial. Patients with ALS were randomized to receive either sham NIV or active NIV and underwent active surveillance approximately every 3 months until they reached a forced vital capacity (FVC) <50% or required NIV for clinical symptom management.<br><br>RESULTS: In total, 54 participants were randomized. The mean NIV use was 2.0 hours (95% confidence interval [CI] 1.1-3.0) per day in the sham NIV treatment group and 3.3 hours (CI 2.0-4.6) per day in the active NIV group, which did not differ by treatment group (p = 0.347). The majority of sham NIV participants (88%) and active NIV participants (73%) reported only mild or no problem with NIV use. Difference of change in FVC through the treatment period by group (0.44 per month) favored active NIV (p = 0.049). Survival and changes in maximal inspiratory or expiratory pressure did not differ between treatment groups.<br><br>CONCLUSIONS: The efficacy of early NIV in ALS should be tested in randomized, placebo-controlled trials. The trial is registered on clinicaltrials.gov (NCT00580593).<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with ALS, adherence with NIV and sham NIV are similar.}, }
@article {pmid27571131, year = {2016}, author = {Gonzalez Deniselle, MC and Liere, P and Pianos, A and Meyer, M and Aprahamian, F and Cambourg, A and Di Giorgio, NP and Schumacher, M and De Nicola, AF and Guennoun, R}, title = {Steroid Profiling in Male Wobbler Mouse, a Model of Amyotrophic Lateral Sclerosis.}, journal = {Endocrinology}, volume = {157}, number = {11}, pages = {4446-4460}, doi = {10.1210/en.2016-1244}, pmid = {27571131}, issn = {1945-7170}, mesh = {17-Ketosteroids/blood/metabolism ; Adrenal Glands/metabolism ; Amyotrophic Lateral Sclerosis/blood/*metabolism ; Androstanols/blood/metabolism ; Animals ; Brain/metabolism ; Corticosterone/blood/metabolism ; Disease Models, Animal ; Female ; Gas Chromatography-Mass Spectrometry ; Gonadotropin-Releasing Hormone/metabolism ; Luteinizing Hormone/blood ; Male ; Mice ; Motor Neurons/metabolism/physiology ; Pregnanolone/blood/metabolism ; Progesterone/blood/metabolism ; Spinal Cord/metabolism ; Testis/metabolism ; Testosterone/blood/metabolism ; }, abstract = {The Wobbler mouse is an animal model for human motoneuron diseases, especially amyotrophic lateral sclerosis (ALS), used in the investigation of both pathology and therapeutic treatment. ALS is a fatal neurodegenerative disease, characterized by the selective and progressive death of motoneurons, leading to progressive paralysis. Previous limited studies have reported steroidal hormone dysregulation in Wobbler mouse and in ALS patients, suggesting endocrine dysfunctions which may be involved in the pathogenesis of the disease. In this study, we established a steroid profiling in brain, spinal cord, plasma, adrenal glands, and testes in 2-month-old male Wobbler mice and their littermates by gas chromatography coupled to mass spectrometry. Our results show in Wobbler mice the following: 1) a marked up-regulation of corticosterone levels in adrenal glands, plasma, spinal cord regions (cervical, thoracic, lumbar) and brain; 2) a strong decrease in T levels in the testis, plasma, spinal cord, and brain; and 3) increased levels of progesterone and especially of its reduced metabolites 5α-dihydroprogesterone, allopregnanolone, and 20α-dihydroprogesterone in the brain, spinal cord, and adrenal glands. Furthermore, Wobbler mice showed a hypothalamic-pituitary-gonadal hypoactivity. Interestingly, plasma concentrations of corticosterone and T correlate well with their respective levels in cervical spinal cord in both control and Wobbler mice. T down-regulation is probably the consequence of adrenal hyperactivity, and the up-regulation of progesterone and its reduced metabolites may correspond to an endogenous protective mechanism in response to motoneuron degeneration. Our findings suggest that increased levels of corticosterone and decreased levels of T in plasma could be a signature of motoneuron degeneration.}, }
@article {pmid27544379, year = {2017}, author = {Rando, A and Gasco, S and de la Torre, M and García-Redondo, A and Zaragoza, P and Toivonen, JM and Osta, R}, title = {Granulocyte Colony-Stimulating Factor Ameliorates Skeletal Muscle Dysfunction in Amyotrophic Lateral Sclerosis Mice and Improves Proliferation of SOD1-G93A Myoblasts in vitro.}, journal = {Neuro-degenerative diseases}, volume = {17}, number = {1}, pages = {1-13}, doi = {10.1159/000446113}, pmid = {27544379}, issn = {1660-2862}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Cell Proliferation/*drug effects/physiology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Disease Models, Animal ; Female ; Filgrastim ; Granulocyte Colony-Stimulating Factor/*pharmacology ; Hematopoietic Stem Cells/drug effects/metabolism ; Humans ; Male ; Mice, Transgenic ; Motor Activity/drug effects/physiology ; Muscle, Skeletal/*drug effects/metabolism/pathology ; Myoblasts/drug effects/metabolism/pathology ; Neuromuscular Agents/*pharmacology ; Polyethylene Glycols ; Recombinant Proteins/pharmacology ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) causes loss of upper and lower motor neurons as well as skeletal muscle (SKM) dysfunction and atrophy. SKM is one of the tissues involved in the development of ALS pathology, and studies in a SOD1-G93A mouse model of ALS have demonstrated alterations in SKM degeneration/regeneration marker expression in vivo and defective mutant myoblast proliferation in vitro. Granulocyte colony-stimulating factor (G-CSF) has been shown to alleviate SOD1-G93A pathology. However, it is unknown whether G-CSF may have a direct effect on SKM or derived myoblasts.<br><br>OBJECTIVE: To investigate effects of G-CSF and its analog pegfilgrastim (PEGF) on SOD1-G93A- associated SKM markers in vivo and those of G-CSF on myoblast proliferation in vitro.<br><br>METHODS: The effect of PEGF treatment on hematopoietic stem cell mobilization, survival, and motor function was determined. RNA expression of SKM markers associated with mutant SOD1 expression was quantified in response to PEGF treatment in vivo, and the effect of G-CSF on the proliferation of myoblasts derived from mutant and control muscles was determined in vitro.<br><br>RESULTS: Positive effects of PEGF on hematopoietic stem cell mobilization, survival, and functional assays in SOD1-G93A animals were confirmed. In vivo PEGF treatment augmented the expression of its receptor Csf3r and alleviated typical markers for mutant SOD1 muscle. Additionally, G-CSF was found to directly increase the proliferation of SOD1-G93A, but not wild-type primary myoblasts in vitro.<br><br>CONCLUSION: Our results support the beneficial role of the G-CSF analog PEGF in a SOD1-G93A model of ALS. Thus, G-CSF and its analogs may be directly beneficial in diseases where the SKM function is compromised.}, }
@article {pmid27437724, year = {2016}, author = {Raglio, A and Giovanazzi, E and Pain, D and Baiardi, P and Imbriani, C and Imbriani, M and Mora, G}, title = {Active music therapy approach in amyotrophic lateral sclerosis: a randomized-controlled trial.}, journal = {International journal of rehabilitation research. Internationale Zeitschrift fur Rehabilitationsforschung. Revue internationale de recherches de readaptation}, volume = {39}, number = {4}, pages = {365-367}, doi = {10.1097/MRR.0000000000000187}, pmid = {27437724}, issn = {1473-5660}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/psychology/*rehabilitation ; Anxiety Disorders/psychology/rehabilitation ; Combined Modality Therapy ; Depressive Disorder/psychology/rehabilitation ; Disability Evaluation ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/psychology/rehabilitation ; Music Therapy/*methods ; Nonverbal Communication ; Quality of Life/psychology ; Surveys and Questionnaires ; }, abstract = {This randomized controlled study assessed the efficacy of active music therapy (AMT) on anxiety, depression, and quality of life in amyotrophic lateral sclerosis (ALS). Communication and relationship during AMT treatment were also evaluated. Thirty patients were assigned randomly to experimental [AMT plus standard of care (SC)] or control (SC) groups. AMT consisted of 12 sessions (three times a week), whereas the SC treatment was based on physical and speech rehabilitation sessions, occupational therapy, and psychological support. ALS Functional Rating Scale-Revised, Hospital Anxiety and Depression Scale, McGill Quality of Life Questionnaire, and Music Therapy Rating Scale were administered to assess functional, psychological, and music therapy outcomes. The AMT group improved significantly in McGill Quality of Life Questionnaire global scores (P=0.035) and showed a positive trend in nonverbal and sonorous-music relationship during the treatment. Further studies involving larger samples in a longer AMT intervention are needed to confirm the effectiveness of this approach in ALS.}, }
@article {pmid27791428, year = {2017}, author = {Pound, J and Verbeek, PR and Cheskes, S}, title = {CPR Induced Consciousness During Out-of-Hospital Cardiac Arrest: A Case Report on an Emerging Phenomenon.}, journal = {Prehospital emergency care}, volume = {21}, number = {2}, pages = {252-256}, doi = {10.1080/10903127.2016.1229823}, pmid = {27791428}, issn = {1545-0066}, mesh = {Algorithms ; Cardiopulmonary Resuscitation/*methods ; Consciousness/*physiology ; Delirium/therapy ; Humans ; Male ; Middle Aged ; Out-of-Hospital Cardiac Arrest/physiopathology/*psychology/*therapy ; Ventricular Fibrillation/therapy ; Vital Signs/*physiology ; }, abstract = {BACKGROUND: High quality cardiopulmonary resuscitation (CPR) has produced a relatively new phenomenon of consciousness in patients with vital signs absent. Further research is necessary to produce a viable treatment strategy during and post resuscitation.<br><br>OBJECTIVE: To provide a case study done by paramedics in the field illustrating the need for sedation in a patient whose presentation was consistent with CPR induced consciousness. Resuscitative challenges are provided as well as potential future treatment options to minimize harm to both patients and prehospital providers.<br><br>CASE REPORT: A 52-year-old male presented as a witnessed out-of-hospital cardiac arrest (OHCA). During CPR the patient began to exhibit signs of life including severe agitation and thrashing of his limbs while CPR was ongoing for ventricular fibrillation prior to defibrillation. Resuscitation became considerably more complicated due to the violent and counterintuitive motions done by the patient during their own resuscitation. Despite the atypical presentation of cardiac arrest the patient was successfully resuscitated employing high quality CPR, standard advanced life support (ALS) care as well as two double sequential external defibrillation shocks. The patient underwent emergency percutaneous coronary intervention (PCI) for a 100% occlusion of his left anterior descending artery (LAD). The patient returned home 3&#xa0;days later fully recovered with a Cerebral Performance Score of 1.<br><br>CONCLUSION: CPR induced consciousness is emerging as a new phenomenon challenging providers of high quality CPR during cardiac arrest resuscitation. Our case report describes the manifestations of CPR induced consciousness as well as the resuscitative challenges which occur during resuscitation. Further research is required to determine the true frequency of this condition as well as treatment algorithms that would allow for appropriate and safe management for both the patient and EMS providers.}, }
@article {pmid27688759, year = {2016}, author = {Ferraiuolo, L and Meyer, K and Sherwood, TW and Vick, J and Likhite, S and Frakes, A and Miranda, CJ and Braun, L and Heath, PR and Pineda, R and Beattie, CE and Shaw, PJ and Askwith, CC and McTigue, D and Kaspar, BK}, title = {Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {113}, number = {42}, pages = {E6496-E6505}, pmid = {27688759}, issn = {1091-6490}, support = {RC2 NS069476/NS/NINDS NIH HHS/United States ; R21 NS064412/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Animals ; Apoptosis ; Biomarkers ; C9orf72 Protein/genetics/metabolism ; Cell Communication ; Cell Death ; Cell Differentiation ; Cell Survival ; Disease Models, Animal ; Gene Expression Profiling ; Humans ; Lactic Acid/metabolism ; Mice ; Mice, Transgenic ; Motor Neurons/*metabolism ; Mutation ; Neural Stem Cells/cytology/metabolism ; Oligodendroglia/cytology/*metabolism ; Superoxide Dismutase-1/*genetics/metabolism ; }, abstract = {Oligodendrocytes have recently been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS). Here we show that, in vitro, mutant superoxide dismutase 1 (SOD1) mouse oligodendrocytes induce WT motor neuron (MN) hyperexcitability and death. Moreover, we efficiently derived human oligodendrocytes from a large number of controls and patients with sporadic and familial ALS, using two different reprogramming methods. All ALS oligodendrocyte lines induced MN death through conditioned medium (CM) and in coculture. CM-mediated MN death was associated with decreased lactate production and release, whereas toxicity in coculture was lactate-independent, demonstrating that MN survival is mediated not only by soluble factors. Remarkably, human SOD1 shRNA treatment resulted in MN rescue in both mouse and human cultures when knockdown was achieved in progenitor cells, whereas it was ineffective in differentiated oligodendrocytes. In fact, early SOD1 knockdown rescued lactate impairment and cell toxicity in all lines tested, with the exclusion of samples carrying chromosome 9 ORF 72 (C9orf72) repeat expansions. These did not respond to SOD1 knockdown nor did they show lactate release impairment. Our data indicate that SOD1 is directly or indirectly involved in ALS oligodendrocyte pathology and suggest that in this cell type, some damage might be irreversible. In addition, we demonstrate that patients with C9ORF72 represent an independent patient group that might not respond to the same treatment.}, }
@article {pmid27788555, year = {2016}, author = {Boentert, M and Young, P}, title = {[Ventilatory Support and Management of Secretions in Amyotrophic Lateral Sclerosis].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {84}, number = {10}, pages = {640-650}, doi = {10.1055/s-0042-117284}, pmid = {27788555}, issn = {1439-3522}, mesh = {Amyotrophic Lateral Sclerosis/complications/*therapy ; Humans ; Respiration, Artificial/*methods ; Respiratory Insufficiency/etiology/therapy ; Respiratory Muscles/physiopathology ; }, abstract = {The term amyotrophic lateral sclerosis (ALS) comprises a group of motor neuron diseases which are characterized by rapid disease progression and poor prognosis which is mostly due to severe respiratory muscle weakness and its sequelae. Since causative treatment options are limited it is crucial to offer comprehensive symptomatic therapies to affect patients. Symptoms of respiratory muscle weakness, sleep-disordered breathing and, subsequently, chronic hypercapnic respiratory failure are known to severely affect health-related quality of life and social functioning of patients with ALS. This review article delineates the clinical presentation of respiratory muscle weakness, diagnostic procedures to assess diaphragmatic function, and practical aspects of both mechanical ventilation and cough assistance, respectively. Various technical and electrophysiological methods allow for detection of diaphragmatic weakness and nocturnal hypoventilation. These include spiro-manometric tests of respiratory muscle strength, cardiorespiratory polygraphy and polysomnography, transcutaneous capnography, and blood gas analysis. Once the diagnosis of respiratory muscle weakness is established, non-invasive ventilation, tracheostomy-invasive ventilation (if the patient agrees to it), and management of secretions all become increasingly important in the course of the disease.}, }
@article {pmid27784774, year = {2016}, author = {Staff, NP and Madigan, NN and Morris, J and Jentoft, M and Sorenson, EJ and Butler, G and Gastineau, D and Dietz, A and Windebank, AJ}, title = {Safety of intrathecal autologous adipose-derived mesenchymal stromal cells in patients with ALS.}, journal = {Neurology}, volume = {87}, number = {21}, pages = {2230-2234}, pmid = {27784774}, issn = {1526-632X}, support = {K08 CA169443/CA/NCI NIH HHS/United States ; }, mesh = {Adipocytes/cytology ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/diagnostic imaging/*therapy ; Biomarkers/blood/cerebrospinal fluid ; Brain/diagnostic imaging ; Female ; Follow-Up Studies ; Humans ; Injections, Spinal/adverse effects ; Magnetic Resonance Imaging ; Male ; Mesenchymal Stem Cell Transplantation/adverse effects/*methods ; Mesenchymal Stem Cells ; Middle Aged ; Severity of Illness Index ; Spinal Cord/diagnostic imaging ; Surveys and Questionnaires ; Transplantation, Autologous/adverse effects/*methods ; Treatment Outcome ; }, abstract = {OBJECTIVE: To determine the safety of intrathecal autologous adipose-derived mesenchymal stromal cell treatment for amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Participants with ALS were enrolled and treated in this phase I dose-escalation safety trial, ranging from 1 &#xd7; 10[7] (single dose) to 1 &#xd7; 10[8] cells (2 monthly doses). After intrathecal treatments, participants underwent standardized follow-up, which included clinical examinations, revised ALS Functional Rating Scale (ALSFRS-R) questionnaire, blood and CSF sampling, and MRI of the neuroaxis.<br><br>RESULTS: Twenty-seven patients with ALS were enrolled and treated in this study. The safety profile was positive, with the most common side effects reported being temporary low back and radicular leg pain at the highest dose level. These clinical findings were associated with elevated CSF protein and nucleated cells with MRI of thickened lumbosacral nerve roots. Autopsies from 4 treated patients did not show evidence of tumor formation. Longitudinal ALSFRS-R questionnaires confirmed continued progression of disease in all treated patients.<br><br>CONCLUSIONS: Intrathecal treatment of autologous adipose-derived mesenchymal stromal cells appears safe at the tested doses in ALS. These results warrant further exploration of efficacy in phase II trials.<br><br>CLASSIFICATION OF EVIDENCE: This phase I study provides Class IV evidence that in patient with ALS, intrathecal autologous adipose-derived mesenchymal stromal cell therapy is safe.}, }
@article {pmid27780064, year = {2016}, author = {Politi, K and Przedborski, S}, title = {Axonal Degeneration: RIPK1 Multitasking in ALS.}, journal = {Current biology : CB}, volume = {26}, number = {20}, pages = {R932-R934}, doi = {10.1016/j.cub.2016.08.052}, pmid = {27780064}, issn = {1879-0445}, mesh = {*Amyotrophic Lateral Sclerosis ; Apoptosis ; Humans ; Inflammation ; *Neurodegenerative Diseases ; Receptor-Interacting Protein Serine-Threonine Kinases ; }, abstract = {A recent study reports that microglia and oligodendrocytes promote motor neuron degeneration by inducing inflammation and necroptosis in a manner dependent on receptor-interacting kinase 1 (RIPK1). These findings could be significant for our understanding of the neurobiology and treatment of neurodegenerative diseases like amyotrophic lateral sclerosis.}, }
@article {pmid27748814, year = {2016}, author = {Shen, H and Kim, K and Oh, Y and Yoon, KS and Baik, HH and Kim, SS and Ha, J and Kang, I and Choe, W}, title = {Neurotoxin β‑N‑methylamino‑L‑alanine induces endoplasmic reticulum stress‑mediated neuronal apoptosis.}, journal = {Molecular medicine reports}, volume = {14}, number = {5}, pages = {4873-4880}, doi = {10.3892/mmr.2016.5802}, pmid = {27748814}, issn = {1791-3004}, mesh = {Amino Acids, Diamino/*pharmacology ; Animals ; Apoptosis/drug effects/genetics ; Cell Line ; Cyanobacteria Toxins ; Endoplasmic Reticulum Stress/*drug effects/genetics ; HSP70 Heat-Shock Proteins/genetics/metabolism ; Humans ; MAP Kinase Signaling System/drug effects ; Mice ; Neurons/*drug effects/*metabolism ; Neurotoxins/*pharmacology ; Signal Transduction/drug effects ; Transcription Factor CHOP/genetics/metabolism ; Unfolded Protein Response/drug effects ; }, abstract = {β-N-methylamino-L-alanine (BMAA) is a neurotoxin that is closely associated with the incidence of amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease. In cultured neuronal cells, BMAA notably induces the upregulation of endoplasmic reticulum (ER) chaperons and activates the unfolded protein response (UPR) receptor pathways of protein kinase RNA‑like endoplasmic reticulum kinase, inositol‑requiring kinase 1 and transcription factor 6. The ER stress‑specific protein CCAAT/‑enhancer‑binding protein homologous protein (CHOP) affords pro‑apoptotic responses that cause mitochondrial damage and caspase activation. BMAA also induces the activation of mitogen‑activated protein kinase member c‑JUN N‑terminal kinase, p38 and extracellular signal‑regulated kinase, which have been suggested to be involved in the signaling pathway of UPR‑mediated apoptosis. Inhibition of ER stress using ER stress antagonist, salubrinal, attenuated the expression of CHOP and alleviated neuronal death. Overexpression of heat shock protein 70 suppressed the activation of UPR receptors and UPR‑evoked apoptotic signaling. The present findings demonstrated that ER stress induced by BMAA is the important mediator of neuronal injury and apoptotic death, and suggests development in novel therapeutic strategies for treatment.}, }
@article {pmid27718307, year = {2016}, author = {Sariki, SK and Sahu, PK and Golla, U and Singh, V and Azad, GK and Tomar, RS}, title = {Sen1, the homolog of human Senataxin, is critical for cell survival through regulation of redox homeostasis, mitochondrial function, and the TOR pathway in Saccharomyces cerevisiae.}, journal = {The FEBS journal}, volume = {283}, number = {22}, pages = {4056-4083}, doi = {10.1111/febs.13917}, pmid = {27718307}, issn = {1742-4658}, mesh = {Autophagy/genetics ; Cardiolipins/biosynthesis ; Cellular Senescence/genetics ; DNA Helicases/*genetics/metabolism ; Gene Expression Profiling/methods ; Gene Expression Regulation, Fungal ; Gene Regulatory Networks ; Homeostasis/genetics ; Humans ; Immunoblotting ; Membrane Potential, Mitochondrial/genetics ; Microbial Viability/genetics ; Microscopy, Fluorescence ; Mitochondria/*genetics/metabolism ; Models, Genetic ; Multifunctional Enzymes ; Mutation ; Oxidation-Reduction ; Protein Serine-Threonine Kinases/*genetics/metabolism ; RNA Helicases/*genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Saccharomyces cerevisiae/*genetics/growth &amp; development/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Signal Transduction/genetics ; Unfolded Protein Response/genetics ; }, abstract = {Mutations in the Senataxin gene, SETX are known to cause the neurodegenerative disorders, ataxia with oculomotor apraxia type 2 (AOA2), and amyotrophic lateral sclerosis 4 (ALS4). However, the mechanism underlying disease pathogenesis is still unclear. The Senataxin N-terminal protein-interaction and C-terminal RNA/DNA helicase domains are conserved in the Saccharomyces cerevisiae homolog, Sen1p. Using genome-wide expression analysis, we first show alterations in key cellular pathways such as: redox, unfolded protein response, and TOR in the yeast sen1 ΔN mutant (N-terminal truncation). This mutant exhibited growth defects on nonfermentable carbon sources, was sensitive to oxidative stress, and showed severe loss of mitochondrial DNA. The growth defect could be partially rescued upon supplementation with reducing agents and antioxidants. Furthermore, the mutant showed higher levels of reactive oxygen species, lower UPR activity, and alterations in mitochondrial membrane potential, increase in vacuole acidity, free calcium ions in the cytosol, and resistance to rapamycin treatment. Notably, the sen1 ∆N mutant showed increased cell death and shortened chronological life span. Given the strong similarity of the yeast and human Sen1 proteins, our study thus provides a mechanism for the progressive neurological disorders associated with mutations in human senataxin.}, }
@article {pmid27664983, year = {2016}, author = {Bowen, LN and Tyagi, R and Li, W and Alfahad, T and Smith, B and Wright, M and Singer, EJ and Nath, A}, title = {HIV-associated motor neuron disease: HERV-K activation and response to antiretroviral therapy.}, journal = {Neurology}, volume = {87}, number = {17}, pages = {1756-1762}, pmid = {27664983}, issn = {1526-632X}, support = {U24 MH100929/MH/NIMH NIH HHS/United States ; }, mesh = {Adult ; Antiretroviral Therapy, Highly Active/*methods ; Endogenous Retroviruses/*isolation &amp; purification ; HIV Infections/*complications/*drug therapy ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*etiology/virology ; }, abstract = {OBJECTIVE: To determine whether there is activation of human endogenous retrovirus K (HERV-K) in amyotrophic lateral sclerosis in HIV infection and whether it might respond to treatment with antiretroviral drugs.<br><br>METHODS: In this case series, we present 5 patients with HIV infection who subsequently developed motor neuron disease involving both upper and lower motor neurons. We monitored HERV-K levels in plasma of 4 of these patients.<br><br>RESULTS: Three patients who received antiretroviral therapy had reversal of symptoms within 6 months of onset of neurologic symptoms and the other 2 had slow neurologic progression over several years. Three patients in whom the levels were measured at onset of neurologic symptoms showed elevated HERV-K levels that responded to optimization of antiretroviral therapy for CNS penetration.<br><br>CONCLUSIONS: Thus, motor neuron disease in individuals with HIV infection may a treatable entity, but early treatment with CNS-penetrating antiretroviral therapy may be necessary. Monitoring of HERV-K levels may help guide treatment.}, }
@article {pmid27612558, year = {2016}, author = {Seol, HS and Lee, SE and Song, JS and Lee, HY and Park, S and Kim, I and Singh, SR and Chang, S and Jang, SJ}, title = {Glutamate release inhibitor, Riluzole, inhibited proliferation of human hepatocellular carcinoma cells by elevated ROS production.}, journal = {Cancer letters}, volume = {382}, number = {2}, pages = {157-165}, doi = {10.1016/j.canlet.2016.08.028}, pmid = {27612558}, issn = {1872-7980}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/metabolism ; Carcinoma, Hepatocellular/*drug therapy/metabolism/pathology ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Dose-Response Relationship, Drug ; Drug Repositioning ; Excitatory Amino Acid Antagonists/*pharmacology ; G2 Phase Cell Cycle Checkpoints/drug effects ; Glutamic Acid/*metabolism ; Glutathione/metabolism ; Humans ; Liver Neoplasms/*drug therapy/metabolism/pathology ; Male ; Mice, Inbred NOD ; Mice, Nude ; Mice, SCID ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; Riluzole/*pharmacology ; Signal Transduction/drug effects ; Tumor Burden/drug effects ; Tumor Cells, Cultured ; Up-Regulation ; Xenograft Model Antitumor Assays ; }, abstract = {Liver cancer is one of the common malignancies in many countries and an increasing cause of cancer death. Despite of that, there are few therapeutic options available with inconsistent outcome, raising a need for developing alternative therapeutic options. Through a drug repositioning screening, we identified and investigated the action mechanism of the Riluzole, an amyotrophic lateral sclerosis (ALS) drug, on hepatocellular carcinoma (HCC) therapy. Treatment of the Riluzole leads to a suppression of cell proliferation in liver primary cancer cells and cancer cell lines. In addition, Riluzole induced caspase-dependent apoptosis and G2/M cell cycle arrest in SNU449 and Huh7 cell lines. In a line with the known function of glutamate release inhibitor, we found Riluzole-treated cells have increased the level of inner cellular glutamate that in turn decrease the glutathione (GSH) level and finally augment the reactive oxygen species (ROS) production. We confirm this finding in vivo by showing the Riluzole-induced GSH and ROS changes in a Huh7 xenograft cancer model. Altogether, these data suggest the anti-cancer effect of Riluzole on hepatocellular carcinoma and the suppression of glutamate signaling might be a new target pathway for HCC therapy.}, }
@article {pmid27619542, year = {2016}, author = {Mouhid Al-Achbili, L and Moreno-Ortega, AJ and Matías-Guiu, J and Cano-Abad, MF and Ruiz-Nuño, A}, title = {ITH33/IQM9.21 provides neuroprotection in a novel ALS model based on TDP-43 and Na[+]/Ca[2+] overload induced by VTD.}, journal = {Neuroscience letters}, volume = {633}, number = {}, pages = {28-32}, doi = {10.1016/j.neulet.2016.09.009}, pmid = {27619542}, issn = {1872-7972}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Apoptosis ; Benzamides/*pharmacology ; Calcium/*metabolism ; Cations, Divalent ; Cations, Monovalent ; Cell Line ; Cell Survival ; DNA-Binding Proteins/*metabolism ; Glutamates/*pharmacology ; Humans ; Mice ; Motor Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/*pharmacology ; Sodium/*metabolism ; Veratridine/*toxicity ; }, abstract = {Therapeutic options for amyotrophic lateral sclerosis (ALS) are scarce and controversial. Although the aetiology of neuronal vulnerability is unknown, growing evidence supports a complex network in which multiple toxicity pathways, rather than a single mechanism, are involved in the pathogenesis of ALS. However, most cellular models only explain single pathogenic mechanisms. The present study proposes the two main cytotoxic mechanisms: (1) veratridine (VTD), which induced Na[+] and Ca[2+] overload; and (2) the TARD DNA-binding protein 43 (TDP-43) in NSC-34 cell line as an in vitro model of ALS. The study was carried out by MTT as an indirect measurement of cell viability and by flow cytometry to determine cell death stages. The impact of Ca[2+] overload combined with TDP-43 overexpression increased early apoptosis of NSC-34 cells. Furthermore, we found that ITH33/IQM9.21 (ITH33) exerted a neuroprotective effect in this model by reducing activation of the apoptotic pathway. Therefore, treatment with VTD in TDP-43 overexpressing NSC-34 cells is a good in vitro ALS model that makes it possible to test new neuroprotective compounds such as ITH33.}, }
@article {pmid27597727, year = {2016}, author = {Khanam, H and Ali, A and Asif, M and Shamsuzzaman, }, title = {Neurodegenerative diseases linked to misfolded proteins and their therapeutic approaches: A review.}, journal = {European journal of medicinal chemistry}, volume = {124}, number = {}, pages = {1121-1141}, doi = {10.1016/j.ejmech.2016.08.006}, pmid = {27597727}, issn = {1768-3254}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*complications/drug therapy/metabolism/*therapy ; Proteostasis Deficiencies/*complications ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, Creutzfeldt-Jacob, Huntington's diseases and amyotrophic lateral sclerosis, are mainly characterized by the massive deposition of misfolded protein aggregates consequent to aberrant production or overexpression of specific proteins. The development of new therapeutics for the treatment of neurodegenerative pathophysiologies currently stands at a crossroads. This presents an opportunity to transition future drug discovery efforts to target disease modification, an area in which much still remains unknown. In this review we examine recent progress in the area of neurodegenerative drug discovery, focusing on some of the most common targets.}, }
@article {pmid27456702, year = {2016}, author = {Potenza, RL and De Simone, R and Armida, M and Mazziotti, V and Pèzzola, A and Popoli, P and Minghetti, L}, title = {Fingolimod: A Disease-Modifier Drug in a Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {13}, number = {4}, pages = {918-927}, pmid = {27456702}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/complications/*drug therapy/genetics/pathology ; Animals ; Body Weight/drug effects/genetics ; Brain/metabolism/pathology ; Cytokines/genetics/metabolism ; Disease Models, Animal ; Fingolimod Hydrochloride/*pharmacology/*therapeutic use ; Forkhead Transcription Factors/genetics/metabolism ; Gene Expression Regulation/*drug effects/genetics ; Humans ; Immunosuppressive Agents/pharmacology/therapeutic use ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Movement Disorders/drug therapy/etiology ; Mutation/genetics ; Nitric Oxide Synthase Type II/genetics/metabolism ; Spinal Cord/drug effects/metabolism/pathology ; Superoxide Dismutase/genetics ; }, abstract = {Fingolimod phosphate (FTY720), the first approved oral therapy for multiple sclerosis, primarily acts as an immunomodulator. Its concomitant effects in the central nervous system, however, indicate a potentially broader spectrum of activity in neurodegenerative diseases. In the present study, we investigated the possible effects of fingolimod in a mouse model of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by a strong neuroinflammatory component. Fingolimod (0.1 and 1 mg/kg i.p.) was administered to mSOD1[G93A] mice, a well-characterized mouse model of ALS, starting from the onset of motor symptoms to the end stage of the disease. The drug was able to improve the neurological phenotype (p < 0.05) and to extend the survival (p < 0.01) of ALS mice. The beneficial effect of fingolimod administration was associated with a significant modulation of neuroinflammatory and protective genes (CD11b, Foxp3, iNOS, Il1β, Il10, Arg1, and Bdnf) in motor cortex and spinal cord of animals. Our data show, for the first time, that fingolimod is protective in ALS mice and that its beneficial effects are accompanied by a modulation of microglial activation and innate immunity. Considering that the treatment was started in already symptomatic mice, our data strongly support fingolimod as a potential new therapeutic approach to ALS.}, }
@article {pmid27753537, year = {2017}, author = {Casaca-Carreira, J and Temel, Y and Larrakoetxea, I and Jahanshahi, A}, title = {Distribution and Penetration of Intracerebroventricularly Administered 2'OMePS Oligonucleotide in the Mouse Brain.}, journal = {Nucleic acid therapeutics}, volume = {27}, number = {1}, pages = {4-10}, doi = {10.1089/nat.2016.0642}, pmid = {27753537}, issn = {2159-3345}, mesh = {Animals ; Blood-Brain Barrier/metabolism ; Brain/*metabolism ; Central Nervous System Diseases/*therapy ; *Infusions, Intraventricular ; Male ; Mice ; Mice, Inbred Strains ; Oligonucleotides, Antisense/*administration &amp; dosage/cerebrospinal fluid/*pharmacokinetics ; Optical Imaging ; Stereotaxic Techniques ; Tissue Distribution ; }, abstract = {Antisense oligonucleotide (AON) therapy is emerging as a potential treatment strategy for neurodegenerative diseases, such as spinal muscular atrophy, Huntington's disease, and amyotrophic lateral sclerosis. AONs function at the cellular level by, for example, direct interference with the expression of gene products or the molecular activation of neuroprotective pathways. However, AON therapy faces a major obstacle limiting its clinical application for central nervous system (CNS) disorders: the blood-brain barrier. Systemic administration of AONs leads to rapid clearance and breakdown of its molecules in the periphery. One way to overcome this obstacle is intracerebroventricular (ICV) delivery of the therapeutics directly to cerebrospinal fluid (CSF). Given the particular molecular structure of oligonucleotides, the (pharmaco) kinetic and distribution pattern of these compounds in the brain are yet to be clarified. In this study, 2'OMePS oligonucleotide delivered through ICV into CSF reached the most key structures in the brain. The distribution of this oligonucleotide differed when comparing specific brain structures and cell groups. After 48 h post-infusion, the distribution of the oligonucleotide reached its maximum and was found intracellularly in many key brain structures. These findings help understanding the kinetic and distribution pattern of 2'OMePS oligonucleotide in the brain and will direct more rational and effective use of ICV drug delivery and unleash its full therapeutic potential in managing CNS diseases.}, }
@article {pmid27752938, year = {2017}, author = {Menke, RA and Agosta, F and Grosskreutz, J and Filippi, M and Turner, MR}, title = {Neuroimaging Endpoints in Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {14}, number = {1}, pages = {11-23}, pmid = {27752938}, issn = {1878-7479}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; SHAW/APR15/933-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/pathology/physiopathology ; Animals ; Biomarkers ; Brain/diagnostic imaging/pathology/physiopathology ; Brain Mapping ; Clinical Trials as Topic ; Diffusion Tensor Imaging ; Disease Models, Animal ; *Disease Progression ; *Endpoint Determination ; Humans ; Image Interpretation, Computer-Assisted/methods ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; *Neuroimaging ; Positron-Emission Tomography ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative, clinically heterogeneous syndrome pathologically overlapping with frontotemporal dementia. To date, therapeutic trials in animal models have not been able to predict treatment response in humans, and the revised ALS Functional Rating Scale, which is based on coarse disability measures, remains the gold-standard measure of disease progression. Advances in neuroimaging have enabled mapping of functional, structural, and molecular aspects of ALS pathology, and these objective measures may be uniquely sensitive to the detection of propagation of pathology in vivo. Abnormalities are detectable before clinical symptoms develop, offering the potential for neuroprotective intervention in familial cases. Although promising neuroimaging biomarker candidates for diagnosis, prognosis, and disease progression have emerged, these have been from the study of necessarily select patient cohorts identified in specialized referral centers. Further multicenter research is now needed to establish their validity as therapeutic outcome measures.}, }
@article {pmid27752511, year = {2016}, author = {Eleftheriadou, I and Manolaras, I and Irvine, EE and Dieringer, M and Trabalza, A and Mazarakis, ND}, title = {αCAR IGF-1 vector targeting of motor neurons ameliorates disease progression in ALS mice.}, journal = {Annals of clinical and translational neurology}, volume = {3}, number = {10}, pages = {752-768}, pmid = {27752511}, issn = {2328-9503}, abstract = {OBJECTIVE: We have previously described the generation of coxsackievirus and adenovirus receptor (α CAR)-targeted vector, and shown that intramuscular delivery in mouse leg muscles resulted in specific retrograde transduction of lumbar-motor neurons (MNs). Here, we utilized the α CAR-targeted vector to investigate the in vivo neuroprotective effects of lentivirally expressed IGF-1 for inducing neuronal survival and ameliorating the neuropathology and behavioral phenotypes of the SOD1[G93A] mouse model of ALS.<br><br>METHODS: We produced cell factories of IGF-1 expressing lentiviral vectors (LVs) bearing &#x3b1; CAR or Vesicular Stomatitis Virus glycoprotein (VSV-G) on their surface so as to compare neuroprotection from MN transduced versus muscle transduced cells. We performed intramuscular delivery of either &#x3b1; CAR IGF-1 or VSVG IGF-1 LVs into key muscles of SOD1[G93A] mice prior to disease onset at day 28. Motor performance, coordination and gait analysis were assessed weekly.<br><br>RESULTS: We observed substantial therapeutic efficacy only with the &#x3b1; CAR IGF-1 LV pretreatment with up to 50% extension of survival compared to controls. &#x3b1; CAR IGF-1 LV-treated animals retained muscle tone and had better motor performance during their prolonged survival. Histological analysis of spinal cord samples at end-stage further confirmed that &#x3b1; CAR IGF-1 LV treatment delays disease onset by increasing MN survival compared with age-matched controls. Intrastriatal injection of &#x3b1; CAR eGFP LV in rats leads to transduction of neurons and glia locally and neurons in olfactory bulb distally.<br><br>INTERPRETATION: Our data are indicative of the efficacy of the &#x3b1; CAR IGF-1 LV in this model and support its candidacy for early noninvasive neuroprotective therapy in ALS.}, }
@article {pmid27751553, year = {2016}, author = {Gonzalez-Bermejo, J and Morélot-Panzini, C and Tanguy, ML and Meininger, V and Pradat, PF and Lenglet, T and Bruneteau, G and Forestier, NL and Couratier, P and Guy, N and Desnuelle, C and Prigent, H and Perrin, C and Attali, V and Fargeot, C and Nierat, MC and Royer, C and Ménégaux, F and Salachas, F and Similowski, T}, title = {Early diaphragm pacing in patients with amyotrophic lateral sclerosis (RespiStimALS): a randomised controlled triple-blind trial.}, journal = {The Lancet. Neurology}, volume = {15}, number = {12}, pages = {1217-1227}, doi = {10.1016/S1474-4422(16)30233-2}, pmid = {27751553}, issn = {1474-4465}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*therapy ; Diaphragm/innervation/*physiopathology ; Double-Blind Method ; *Early Termination of Clinical Trials ; Electric Stimulation Therapy/adverse effects/*methods ; Female ; Humans ; Laparoscopy ; Male ; Middle Aged ; *Phrenic Nerve ; Respiration Disorders ; Respiration, Artificial ; Respiratory Insufficiency/*prevention &amp; control ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with respiratory muscle weakness and respiratory failure. Non-invasive ventilation alleviates respiratory symptoms and prolongs life, but is a palliative intervention. Slowing the deterioration of diaphragm function before respiratory failure would be desirable. We aimed to assess whether early diaphragm pacing could slow down diaphragm deterioration and would therefore delay the need for non-invasive ventilation.<br><br>METHODS: We did a multicentre, randomised, controlled, triple-blind trial in patients with probable or definite ALS in 12 ALS centres in France. The main inclusion criterion was moderate respiratory involvement (forced vital capacity 60-80% predicted). Other key eligibility criteria were age older than 18 years and bilateral responses of the diaphragm to diagnostic phrenic stimulation. All patients were operated laparoscopically and received phrenic stimulators. Clinicians randomly assigned patients (1:1) to receive either active or sham stimulation with a central web-based randomisation system (computer-generated list). Investigators, patients, and an external outcome allocation committee were masked to treatment. The primary outcome was non-invasive ventilation-free survival, analysed in the intention-to-treat population. Safety outcomes were also assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01583088.<br><br>FINDINGS: Between Sept 27, 2012, and July 8, 2015, 74 participants were randomly assigned to receive either active (n=37) or sham (n=37) stimulation. On July 16, 2015, an unplanned masked analysis was done after another trial showed excess mortality with diaphragm pacing in patients with hypoventilation (DiPALS, ISRCTN 53817913). In view of this finding, we analysed mortality in our study and found excess mortality (death from any cause) in our active stimulation group. We therefore terminated the study on July, 16, 2015. Median non-invasive ventilation-free survival was 6&#xb7;0 months (95% CI 3&#xb7;6-8&#xb7;7) in the active stimulation group versus 8&#xb7;8 months (4&#xb7;2-not reached) in the control (sham stimulation) group (hazard ratio 1&#xb7;96 [95% CI 1&#xb7;08-3&#xb7;56], p=0&#xb7;02). Serious adverse events (mainly capnothorax or pneumothorax, acute respiratory failure, venous thromboembolism, and gastrostomy) were frequent (24 [65%] patients in the active stimulation group vs 22 [59%] patients in the control group). No treatment-related death was reported.<br><br>INTERPRETATION: Early diaphragm pacing in patients with ALS and incipient respiratory involvement did not delay non-invasive ventilation and was associated with decreased survival. Diaphragm pacing is not indicated at the early stage of the ALS-related respiratory involvement.<br><br>FUNDING: Hospital Program for Clinical Research, French Ministry of Health; French Patients' Association for ALS Research (Association pour la Recherche sur la Scl&#xe9;rose Lat&#xe9;rale Amyotrophique); and Thierry de Latran Foundation.}, }
@article {pmid27583801, year = {2016}, author = {Bronner, A and Guzek, J}, title = {Descemet Stripping Automated Endothelial Keratoplasty for a Patient With Combined Fuchs Dystrophy and Corneal Ectasia-A Follow-up on Vira et al's "Descemet Stripping Endothelial Keratoplasty for Treatment of Combined Fuchs Corneal Endothelial Dystrophy and Keratoconus," Cornea 2014;33: 1-5.}, journal = {Cornea}, volume = {35}, number = {11}, pages = {e37-e38}, doi = {10.1097/ICO.0000000000001013}, pmid = {27583801}, issn = {1536-4798}, mesh = {Cataract Extraction ; Corneal Topography ; *Descemet Stripping Endothelial Keratoplasty ; Dilatation, Pathologic/etiology ; Fuchs' Endothelial Dystrophy/*surgery ; Humans ; Keratoconus/etiology/*surgery ; Keratomileusis, Laser In Situ ; Lens Implantation, Intraocular ; Male ; Middle Aged ; Postoperative Complications ; }, }
@article {pmid27716798, year = {2016}, author = {Glajch, KE and Ferraiuolo, L and Mueller, KA and Stopford, MJ and Prabhkar, V and Gravanis, A and Shaw, PJ and Sadri-Vakili, G}, title = {MicroNeurotrophins Improve Survival in Motor Neuron-Astrocyte Co-Cultures but Do Not Improve Disease Phenotypes in a Mutant SOD1 Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {PloS one}, volume = {11}, number = {10}, pages = {e0164103}, pmid = {27716798}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*mortality ; Animals ; Astrocytes/*drug effects ; Coculture Techniques/methods ; Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic/genetics ; Motor Neurons/*drug effects ; Nerve Growth Factors/*pharmacology ; Neuroprotective Agents/pharmacology ; Phenotype ; Spinal Cord/drug effects ; Superoxide Dismutase-1/*genetics ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease caused by loss of motor neurons. ALS patients experience rapid deterioration in muscle function with an average lifespan of 3-5 years after diagnosis. Currently, the most effective therapeutic only extends lifespan by a few months, thus highlighting the need for new and improved therapies. Neurotrophic factors (NTFs) are important for neuronal development, maintenance, and survival. NTF treatment has previously shown efficacy in pre-clinical ALS models. However, clinical trials using NTFs produced no major improvements in ALS patients, due in part to the limited blood brain barrier (BBB) penetration. In this study we assessed the potential neuroprotective effects of a novel class of compounds known as MicroNeurotrophins (MNTs). MNTs are derivatives of Dehydroepiandrosterone (DHEA), an endogenous neurosteroid that can cross the BBB and bind to tyrosine kinase receptors mimicking the pro-survival effects of NTFs. Here we sought to determine whether MNTs were neuroprotective in two different models of ALS. Our results demonstrate that BNN27 (10 μM) attenuated loss of motor neurons co-cultured with astrocytes derived from human ALS patients with SOD1 mutations via the reduction of oxidative stress. Additionally, in the G93A SOD1 mouse, BNN27 (10 mg/kg) treatment attenuated motor behavioral impairment in the paw grip endurance and rotarod tasks at postnatal day 95 in female but not male mice. In contrast, BNN27 (10 mg/kg and 50 mg/kg) treatment did not alter any other behavioral outcome or neuropathological marker in male or female mice. Lastly, BNN27 was not detected in post-mortem brain or spinal cord tissue of treated mice due to the rapid metabolism of BNN27 by mouse hepatocytes relative to human hepatocytes. Together, these findings demonstrate that BNN27 treatment failed to yield significant neuroprotective effects in the G93A SOD1 model likely due to its rapid rate of metabolism in mice.}, }
@article {pmid27694488, year = {2016}, author = {Talman, P and Duong, T and Vucic, S and Mathers, S and Venkatesh, S and Henderson, R and Rowe, D and Schultz, D and Edis, R and Needham, M and Macdonnell, R and McCombe, P and Birks, C and Kiernan, M}, title = {Identification and outcomes of clinical phenotypes in amyotrophic lateral sclerosis/motor neuron disease: Australian National Motor Neuron Disease observational cohort.}, journal = {BMJ open}, volume = {6}, number = {9}, pages = {e012054}, pmid = {27694488}, issn = {2044-6055}, mesh = {Amyotrophic Lateral Sclerosis/classification/*mortality/*therapy ; Australia ; *Disease Progression ; Female ; Gastrostomy/statistics &amp; numerical data ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Neuroprotective Agents/therapeutic use ; Noninvasive Ventilation/statistics &amp; numerical data ; Phenotype ; Prospective Studies ; Registries ; Riluzole/therapeutic use ; Time Factors ; }, abstract = {OBJECTIVE: To capture the clinical patterns, timing of key milestones and survival of patients presenting with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) within Australia.<br><br>METHODS: Data were prospectively collected and were timed to normal clinical assessments. An initial registration clinical report form (CRF) and subsequent ongoing assessment CRFs were submitted with a completion CRF at the time of death.<br><br>DESIGN: Prospective observational cohort study.<br><br>PARTICIPANTS: 1834 patients with a diagnosis of ALS/MND were registered and followed in ALS/MND clinics between 2005 and 2015.<br><br>RESULTS: 5 major clinical phenotypes were determined and included ALS bulbar onset, ALS cervical onset and ALS lumbar onset, flail arm and leg and primary lateral sclerosis (PLS). Of the 1834 registered patients, 1677 (90%) could be allocated a clinical phenotype. ALS bulbar onset had a significantly lower length of survival when compared with all other clinical phenotypes (p<0.004). There were delays in the median time to diagnosis of up to 12&#x2005;months for the ALS phenotypes, 18&#x2005;months for the flail limb phenotypes and 19&#x2005;months for PLS. Riluzole treatment was started in 78-85% of cases. The median delays in initiating riluzole therapy, from symptom onset, varied from 10 to 12&#x2005;months in the ALS phenotypes and 15-18&#x2005;months in the flail limb phenotypes. Percutaneous endoscopic gastrostomy was implemented in 8-36% of ALS phenotypes and 2-9% of the flail phenotypes. Non-invasive ventilation was started in 16-22% of ALS phenotypes and 21-29% of flail phenotypes.<br><br>CONCLUSIONS: The establishment of a cohort registry for ALS/MND is able to determine clinical phenotypes, survival and monitor time to key milestones in disease progression. It is intended to expand the cohort to a more population-based registry using opt-out methodology and facilitate data linkage to other national registries.}, }
@article {pmid29624324, year = {2016}, author = {Yamashita, T and Kwak, S}, title = {[Abnormal RNA editing and treatment strategy in neurological diseases; towards cure for ALS].}, journal = {Seikagaku. The Journal of Japanese Biochemical Society}, volume = {88}, number = {5}, pages = {600-608}, pmid = {29624324}, issn = {0037-1017}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/therapy ; Animals ; Cell Death ; Humans ; Motor Neurons ; *RNA Editing ; }, }
@article {pmid29441921, year = {2016}, author = {Zhuo, H and Zhou, L}, title = {Gpnmb/osteoactivin: an indicator and therapeutic target in tumor and nontumorous lesions.}, journal = {Die Pharmazie}, volume = {71}, number = {10}, pages = {555-561}, doi = {10.1691/ph.2016.6683}, pmid = {29441921}, issn = {0031-7144}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Biomarkers/*analysis ; Biomarkers, Tumor/*analysis ; Humans ; Membrane Glycoproteins/*drug effects/*metabolism ; }, abstract = {Non-metastatic melanoma glycoprotein B (Gpnmb), a type I transmembrane glycoprotein, was first cloned and described in low-metastatic human melanoma and xenografts in 1995. Up to now a growing number of studies have confirmed that Gpnmb is expressed not only in numerous normal tissues but also at pathological sites and malignant tissues and often connected with the invasive and metastatic phenotypes, including breast cancer. Nowadays, immunotherapeutic approaches for cancer therapy, by which monoclonal antibodies (Mabs) target tumor specific antigens, have shown great potential. Glembatumumabvedotin, also called CR011-vcMMAE, is a Mab-drug conjugate which was developed for the treatment of Gpnmb-expressing cancers. Several phase I/II studies have confirmed the safety and activity of glembatumumabvedotin in patients with advanced/metastatic breast cancer and unresectable cutaneous melanoma. Moreover, increasing numbers of studies have supported the potential roles of targeting Gpnmb with glembatumumabvedotin in patients with recurrent osteosarcoma, uveal melanoma, ALS, Gaucher disease, pancreatic ductal adenocarcinoma etc. This review will summarize the latest understanding of Gpnmb in the aspects of diagnosis, progression and prognosis of pathological disorders and neoplasms, emphasizing the clinical advances in targeting Gpnmb-expressing malignancies.}, }
@article {pmid27687289, year = {2016}, author = {Spiller, KJ and Restrepo, CR and Khan, T and Stieber, AM and Kwong, LK and Trojanowski, JQ and Lee, VM}, title = {Progression of motor neuron disease is accelerated and the ability to recover is compromised with advanced age in rNLS8 mice.}, journal = {Acta neuropathologica communications}, volume = {4}, number = {1}, pages = {105}, pmid = {27687289}, issn = {2051-5960}, support = {P01 AG017586/AG/NIA NIH HHS/United States ; }, abstract = {In order to treat progressive paralysis in ALS patients, it is critical to develop a mouse that closely models human ALS in both pathology and also in the timing of these events. We have recently generated new TDP-43 bigenic mice (called rNLS8) with doxycycline (Dox)-suppressible expression of human TDP-43 (hTDP-43) harboring a defective nuclear localization signal (hTDP-43∆NLS) under the control of the NEFH promoter. Our previous studies characterized the pathology and disease course in young rNLS8 mice following induction of neuronal hTDP-43ΔNLS. We now seek to examine if the order and timing of pathologic events are changed in aged mice. We found that the expression of hTDP-43∆NLS in 12+ month old mice did not accelerate the appearance of neuromuscular abnormalities or motor neuron (MN) death in the lumbar spinal cord (SC), though disease progression was accelerated. However, following suppression of the transgene, important differences between young and aged rNLS8 mice emerged in functional motor recovery. We found that recovery was incomplete in aged mice relative to their younger treatment matched counterparts based on gross behavioral measures and physiological recordings from the animals' gastrocnemius (GC) muscles, despite muscle reinnervation by surviving MNs. This is likely because the reinnervation most often only resulted in partial nerve and endplate connections and the muscle's junctional folds were much more disorganized in aged rNLS8 mice. We believe that these studies will be an important basis for the future design and evaluation of therapies designed to slow denervation and promote re-innervation in adult ALS patients.}, }
@article {pmid27678294, year = {2016}, author = {Kurita, H and Okuda, R and Yokoo, K and Inden, M and Hozumi, I}, title = {Protective roles of SLC30A3 against endoplasmic reticulum stress via ERK1/2 activation.}, journal = {Biochemical and biophysical research communications}, volume = {479}, number = {4}, pages = {853-859}, doi = {10.1016/j.bbrc.2016.09.119}, pmid = {27678294}, issn = {1090-2104}, mesh = {Caspase 3/metabolism ; Cation Transport Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Endoplasmic Reticulum Chaperone BiP ; *Endoplasmic Reticulum Stress/drug effects ; Enzyme Activation ; Gene Knockdown Techniques ; HEK293 Cells ; Heat-Shock Proteins/genetics ; Humans ; *MAP Kinase Signaling System/drug effects ; Mitogen-Activated Protein Kinase 1/metabolism ; Neurodegenerative Diseases/etiology/metabolism/prevention &amp; control ; Phosphorylation/drug effects ; RNA, Messenger/genetics/metabolism ; RNA, Small Interfering/genetics ; Transcription Factor CHOP/genetics ; Tunicamycin/pharmacology ; }, abstract = {Endoplasmic reticulum (ER) stress has been thought to be involved to neurodegenerative diseases such as Alzheimer's disease (AD) or Amyotrophic lateral sclerosis (ALS). The previous studies have shown that SLC30A3 level is decreased in prefrontal cortex of AD patients. In addition, we have shown that level of zinc (Zn) is increased in cerebrospinal fluid and SLC30A3 level is decreased in spinal cord of ALS patients. It was thought that both SLC30A3 and ER stress could be related to the cause of AD and ALS, however the relationship between ER stress and SLC30A3 has not been elucidated. Therefore we investigated that the role of SLC30A3 against ER stress. The level of SLC30A3 mRNA was significantly increased by tunicamycin treatment in human neuroblastoma cell line (SH-SY5Y) and human embryonic kidney cell line (HEK293). Cell viability under tunicamycin treatment was significantly decreased in SLC30A3 knockdown cells by siRNA in comparison with negative control (NC) cells. Cleaved caspase-3 level was significantly increased in SLC30A3 knockdown cells, not in NC cells. These results showed that SLC30A3 has a protective role to ER stress-induced toxicities. The previous study has shown that SLC30A3 protect cells from oxidative stress in ERK1/2 signal dependent manner, thus we determined the activity of ERK1/2 in SLC30A3 knockdown cells under ER stress condition. The level of ERK1/2 phosphorylation was significantly increased by tunicamycin treatment in NC cells, not in SLC30A3 knockdown cells. The ERK1/2 pathway is thought to have an association with defensive effects of SLC30A3 on cellular stress such as ER stress. In conclusion, this study suggested that SLC30A3 is supposed to play a protective role against ER stress, which is related to ERK1/2 activation.}, }
@article {pmid27658510, year = {2017}, author = {Burnstock, G}, title = {Purinergic Signalling and Neurological Diseases: An Update.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {16}, number = {3}, pages = {257-265}, doi = {10.2174/1871527315666160922104848}, pmid = {27658510}, issn = {1996-3181}, mesh = {Animals ; Humans ; *Nervous System Diseases/drug therapy/metabolism/physiopathology ; Purinergic P2X Receptor Antagonists/*therapeutic use ; Receptors, Purinergic/*metabolism ; Signal Transduction/drug effects/*physiology ; }, abstract = {Purinergic signalling, i.e. ATP as an extracellular signalling molecule and cotransmitter in both peripheral and central neurons, is involved in the physiology of neurotransmission and neuromodulation. Receptors for purines have been cloned and characterised, including 4 subtypes of the P1(adenosine) receptor family, 7 subtypes of the P2X ion channel nucleotide receptor family and 8 subtypes of the P2Y G protein-coupled nucleotide receptor family. The roles of purinergic signalling in diseases of the central nervous system and the potential use of purinergic compounds for their treatment are attracting increasing attention. In this review, the focus is on the findings reported in recent papers and reviews to update knowledge in this field about the involvement of purinergic signalling in Alzheimer's, Parkinson's and Huntington's diseases, multiple sclerosis, amyotrophic lateral sclerosis, degeneration and regeneration after brain injury, stroke, ischaemia, inflammation, migraine, epilepsy, psychiatric disorders, schizophrenia, bipolar disorder, autism, addiction, sleep disorders and brain tumours. The use in particular of P2X7 receptor antagonists for the treatment of neurodegenerative diseases, cancer, depression, stroke and ischaemia, A2A receptor antagonists for Parkinson's disease and agonists for brain injury and depression and P2X3 receptor antagonists for migraine and seizures has been recommended. P2Y receptors have also been claimed to be involved in some central nervous disorders.}, }
@article {pmid27651843, year = {2016}, author = {Maggiani, A and Tremolizzo, L and Della Valentina, A and Mapelli, L and Sosio, S and Milano, V and Bianchi, M and Badi, F and Lavazza, C and Grandini, M and Corna, G and Prometti, P and Lunetta, C and Riva, N and Ferri, A and Lanfranconi, F and , }, title = {Osteopathic Manual Treatment for Amyotrophic Lateral Sclerosis: A Feasibility Pilot Study.}, journal = {The open neurology journal}, volume = {10}, number = {}, pages = {59-66}, pmid = {27651843}, issn = {1874-205X}, abstract = {BACKGROUND: Current interventions in amyotrophic lateral sclerosis (ALS) are focused on supporting quality of life (QoL) and easing pain with a multidisciplinary approach.<br><br>OBJECTIVE: Primary aim of this pilot work assessed feasibility, safety, tolerability and satisfaction of osteopathic manual treatment (OMT) in 14 ALS outpatients.<br><br>METHODS: Patients were randomized according to an initial single-blind design (12 weeks, T0-T1), in order to receive OMT (weekly for 4 weeks, and fortnightly for the following 8 weeks) versus usual-care (n=7 each group), followed by an OMT open period (T1-T2, once a week for 8 weeks, n=10). Secondary aims included blind osteopathic assessment of somatic dysfunctions (SD) for goal attainment scale (GAS) calculation, Brief Pain Inventory-short form and McGill QoL-16 items.<br><br>RESULTS: OMT was demonstrated feasible and safe and patients displayed high satisfaction (T1-VAS=8.34 &#xb1; 0.46; T2-VAS=8.52 &#xb1; 0.60). Considering secondary aims no significant differences emerged. Finally, at study entry (T0), a cervico-dorsal SD was found in 78% of ALS patients versus 28% of healthy matched controls (p<0.01).<br><br>CONCLUSION: OMT was found feasible, safe and satisfactory in ALS. The lack of secondary aim differences can be due to the limited sample size. OMT could be an interesting option to explore in ALS.}, }
@article {pmid27651758, year = {2016}, author = {Gubert, F and Satiago, MF}, title = {Prospects for bone marrow cell therapy in amyotrophic lateral sclerosis: how far are we from a clinical treatment?.}, journal = {Neural regeneration research}, volume = {11}, number = {8}, pages = {1216-1219}, pmid = {27651758}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive muscular atrophy and death within 3-5 years after its onset. Despite the significant advances in knowledge of ALS pathology, no effective treatment is available. Therefore, it is imperative to search for new alternatives to treat ALS. Cell therapy, especially using bone-marrow cells, has showed to be very useful to protect the neural tissue in different brain disease or traumatic lesions. In ALS, most published results show beneficial effects of the use bone marrow cells, especially mesenchymal stromal cells. However, until now, the best outcome extends animal's lifespan by only a few weeks. It is essential to continue the search for a really effective therapy, testing different cells, routes and time-windows of administration. Studying the mechanisms that initiate and spread the degenerative process is also important to find out an effective therapy. Therefore, we discussed here some progresses that have been made using bone-marrow cell therapy as a therapeutic tool for ALS.}, }
@article {pmid27644548, year = {2017}, author = {Mathis, S and Couratier, P and Julian, A and Vallat, JM and Corcia, P and Le Masson, G}, title = {Management and therapeutic perspectives in amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {17}, number = {3}, pages = {263-276}, doi = {10.1080/14737175.2016.1227705}, pmid = {27644548}, issn = {1744-8360}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/psychology/therapy ; Humans ; Nerve Degeneration ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder affecting both upper and lower motor neurons. Despite much research and effort, no clear insights into a unifying hypothesis for the pathogenesis has so far emerged for this disease. Areas covered: We review the main pathophysiological hypotheses and the potential therapeutic targets in ALS, as well as the management of these patients (in order to improve their survival and quality of life). Expert commentary: ALS is a complex neurodegenerative disease, these days considered as a multisystem disorder with predominant motor symptoms (and various clinical forms). Further comprehension of the pathophysiology of this disease is required, although pathophysiological mechanisms (such as TDP-43) show promise in the search for new therapies. There is still no curative treatment for ALS, but the emergence of multidisciplinary specialized ALS clinics has increased both the quality of life and the survival of these patients.}, }
@article {pmid27641665, year = {2016}, author = {Lee, M and Ban, JJ and Kim, KY and Jeon, GS and Im, W and Sung, JJ and Kim, M}, title = {Adipose-derived stem cell exosomes alleviate pathology of amyotrophic lateral sclerosis in vitro.}, journal = {Biochemical and biophysical research communications}, volume = {479}, number = {3}, pages = {434-439}, doi = {10.1016/j.bbrc.2016.09.069}, pmid = {27641665}, issn = {1090-2104}, mesh = {Adipocytes/*cytology ; Adipose Tissue/cytology ; Amyotrophic Lateral Sclerosis/*metabolism/*therapy ; Animals ; Cells, Cultured ; Cytoplasm/metabolism ; Disease Models, Animal ; Exosomes/*metabolism ; Humans ; Mice ; Mice, Transgenic ; Mitochondria/metabolism ; Motor Neurons/metabolism ; Neurons/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Phenotype ; Stem Cells/*cytology ; Superoxide Dismutase-1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative disorder that involves the death of motor neurons in the cortex, brain stem, and spinal cord. Adipose-derived stem cells (ADSCs) are considered as a perspective remedy for therapy of neurodegenerative diseases including ALS. Stem cells secrete various factors which can modulate a hostile environment, called paracrine effect. Exosomes are small extracellular vesicles containing cell derived factors and mediate paracrine effect of cells. Thus, exosomes from ADSCs (ADSC-exo) can be a potential candidate of therapeutic effects of stem cells. To investigate the effect of ADSC-exo on the cellular phenotypes of ALS, we used neuronal stem cells (NSCs), which can be differentiated into neuronal cells, isolated from wild type or G93A ALS mice model. ADSC-exo was treated to neuronal cells from G93A ALS mice model. Immunocytochemistry and dot-blot assay result showed that ADSC-exo alleviated aggregation of superoxide dismutase 1 (SOD1). Reduction of cytosolic SOD1 level by ADSC-exo was also confirmed by western blot. Mitochondria display various abnormalities in ALS and the decrease of phospho-CREB and PGC-1α were observed in the G93A cells. ADSC-exo treatment showed normalization of phospho-CREB/CREB ratio and PGC-1α expression level. Our results suggest that ADSC-exo modulates cellular phenotypes of ALS including SOD-1 aggregation and mitochondrial dysfunction, and can be a therapeutic candidate for ALS.}, }
@article {pmid27640365, year = {2016}, author = {Mishra-Kalyani, PS and Johnson, BA and Glass, JD and Long, Q}, title = {Estimating the palliative effect of percutaneous endoscopic gastrostomy in an observational registry using principal stratification and generalized propensity scores.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {33431}, pmid = {27640365}, issn = {2045-2322}, support = {R21 NS091630/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/surgery ; Body Mass Index ; *Endoscopy/adverse effects ; *Gastrostomy/adverse effects ; Humans ; Likelihood Functions ; *Palliative Care ; *Propensity Score ; *Registries ; }, abstract = {Clinical disease registries offer a rich collection of valuable patient information but also pose challenges that require special care and attention in statistical analyses. The goal of this paper is to propose a statistical framework that allows for estimating the effect of surgical insertion of a percutaneous endogastrostomy (PEG) tube for patients living with amyotrophic lateral sclerosis (ALS) using data from a clinical registry. Although all ALS patients are informed about PEG, only some patients agree to the procedure which, leads to the potential for selection bias. Assessing the effect of PEG is further complicated by the aggressively fatal disease, such that time to death competes directly with both the opportunity to receive PEG and clinical outcome measurements. Our proposed methodology handles the "censoring by death" phenomenon through principal stratification and selection bias for PEG treatment through generalized propensity scores. We develop a fully Bayesian modeling approach to estimate the survivor average causal effect (SACE) of PEG on BMI, a surrogate outcome measure of nutrition and quality of life. The use of propensity score methods within the principal stratification framework demonstrates a significant and positive effect of PEG treatment, particularly when time of treatment is included in the treatment definition.}, }
@article {pmid27640217, year = {2016}, author = {Fraess-Phillips, AJ}, title = {Can Paramedics Safely Refuse Transport of Non-Urgent Patients?.}, journal = {Prehospital and disaster medicine}, volume = {31}, number = {6}, pages = {667-674}, doi = {10.1017/S1049023X16000935}, pmid = {27640217}, issn = {1945-1938}, mesh = {*Decision Making ; *Emergency Medical Technicians ; Humans ; *Transportation of Patients ; }, abstract = {OBJECTIVE: The goal of this search was to review the current literature regarding paramedic triage of primary care patients and the safety of paramedic-initiated non-transport of non-urgent patients.<br><br>METHODS: A narrative literature review was conducted using the Medline (Medline Industries, Inc.; Mundelein, Illinois USA) database and a manual search of Google Scholar (Google; Mountain View, California USA).<br><br>RESULTS: Only 11 studies were found investigating paramedic triage and safety of non-transport of non-urgent patients. It was found that triage agreement between paramedic and emergency department staff generally is poor and that paramedics are limited in their abilities to predict the ultimate admission location of their patients. However, these triage decisions and admission predictions are much more accurate when the patient's condition is the result of trauma and when the patient requires critical care services. Furthermore, the literature provides very limited support for the safety of paramedic triage in the refusal of non-urgent patient transport, especially without physician oversight. Though many non-transported patients are satisfied with the quality of non-urgent treatment that they receive from paramedics, the rates of under-triage and subsequent hospitalization reported in the literature are too high to suggest that this practice can be adopted widely.<br><br>CONCLUSION: There is insufficient evidence to suggest that non-urgent patients can safely be refused transport based on paramedic triage alone. Further attempts to implement paramedic-initiated non-transport of non-urgent patients should be approached with careful triage protocol development, paramedic training, and pilot studies. Future primary research and systematic reviews also are required to build on the currently limited literature. Fraess-Phillips AJ . Can paramedics safely refuse transport of non-urgent patients? Prehosp Disaster Med. 2016;31(6):667-674.}, }
@article {pmid27639947, year = {2017}, author = {Sakhri, L and Saint-Raymond, C and Quetant, S and Pison, C and Lagrange, E and Hamidfar Roy, R and Janssens, JP and Maindet-Dominici, C and Garrouste-Orgeas, M and Levy-Soussan, M and Terzi, N and Toffart, AC}, title = {[Limitations of active therapeutic and palliative care in chronic respiratory disease].}, journal = {Revue des maladies respiratoires}, volume = {34}, number = {2}, pages = {102-120}, doi = {10.1016/j.rmr.2016.06.005}, pmid = {27639947}, issn = {1776-2588}, mesh = {Chronic Disease ; Critical Care/*statistics &amp; numerical data ; Decision Making ; Humans ; Palliative Care/*methods ; Patient Comfort/methods ; Prognosis ; Respiration Disorders/*complications/diagnosis/*therapy ; }, abstract = {The issue of intensive and palliative care in patients with chronic disease frequently arises. This review aims to describe the prognostic factors of chronic respiratory diseases in stable and in acute situations in order to improve the management of these complex situations. The various laws on patients' rights provide a legal framework and define the concept of unreasonable obstinacy. For patients with chronic obstructive pulmonary disease, the most robust decision factors are good knowledge of the respiratory disease, the comorbidities, the history of previous exacerbations and patient preferences. In the case of idiopathic pulmonary fibrosis, it is necessary to know if there is a prospect of transplantation and to assess the reversibility of the respiratory distress. In the case of amyotrophic lateral sclerosis, treatment decisions depend on the presence of advance directives about the use of intubation and tracheostomy. For lung cancer patients, general condition, cancer history and the tumor treatment plan are important factors. A multidisciplinary discussion that takes into account the patient's medical history, wishes and the current state of knowledge permits the taking of a coherent decision.}, }
@article {pmid27638636, year = {2016}, author = {Hazenberg, A and Kerstjens, HA and Prins, SC and Vermeulen, KM and Wijkstra, PJ}, title = {Is chronic ventilatory support really effective in patients with amyotrophic lateral sclerosis?.}, journal = {Journal of neurology}, volume = {263}, number = {12}, pages = {2456-2461}, pmid = {27638636}, issn = {1432-1459}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/psychology/*therapy ; Blood Gas Analysis ; Databases, Bibliographic/statistics &amp; numerical data ; Female ; Humans ; Male ; Middle Aged ; Noninvasive Ventilation/*methods/psychology ; Quality of Life/psychology ; Randomized Controlled Trials as Topic ; Respiratory Insufficiency/etiology/therapy ; Severity of Illness Index ; *Treatment Outcome ; }, abstract = {Most patients with amyotrophic lateral sclerosis (ALS) develop respiratory insufficiency in the advanced stage of their disease. Non-invasive ventilation (NIV) is commonly regarded to be a treatment that is effective in reducing these complaints. To assess whether the effect of NIV on gas exchange and quality of life (QOL) is different in patients with ALS versus without ALS. A post hoc analysis was done with data from a previously published trial, in which all patients were instituted on NIV. Arterial blood gasses were assessed next to QOL by generic as well as disease-specific questionnaires. 77 patients started NIV: 30 with ALS and 47 without. Both groups showed significant improvements in blood gasses after 2 and 6 months. Compared to the non-ALS group, the ALS group had significantly worse scores after 6 months in MRF-28, SRI, HADS and SF-36 than the non-ALS group. This study shows that NIV improves gas exchange, both in patients with and without ALS. QOL improves markedly more in patients without ALS than in those with ALS, in whom only some domains improve. Our observation of little or no effect in ALS patients warrants a large study limited to ALS patients only.}, }
@article {pmid27631495, year = {2016}, author = {de Munck, E and Palomo, V and Muñoz-Sáez, E and Perez, DI and Gómez-Miguel, B and Solas, MT and Gil, C and Martínez, A and Arahuetes, RM}, title = {Small GSK-3 Inhibitor Shows Efficacy in a Motor Neuron Disease Murine Model Modulating Autophagy.}, journal = {PloS one}, volume = {11}, number = {9}, pages = {e0162723}, pmid = {27631495}, issn = {1932-6203}, mesh = {Animals ; *Autophagy ; Cell Line ; *Disease Models, Animal ; Enzyme Inhibitors/*pharmacology/therapeutic use ; Glycogen Synthase Kinase 3/*antagonists &amp; inhibitors ; Mice ; Motor Neuron Disease/*drug therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron degenerative disease that has no effective treatment up to date. Drug discovery tasks have been hampered due to the lack of knowledge in its molecular etiology together with the limited animal models for research. Recently, a motor neuron disease animal model has been developed using β-N-methylamino-L-alanine (L-BMAA), a neurotoxic amino acid related to the appearing of ALS. In the present work, the neuroprotective role of VP2.51, a small heterocyclic GSK-3 inhibitor, is analysed in this novel murine model together with the analysis of autophagy. VP2.51 daily administration for two weeks, starting the first day after L-BMAA treatment, leads to total recovery of neurological symptoms and prevents the activation of autophagic processes in rats. These results show that the L-BMAA murine model can be used to test the efficacy of new drugs. In addition, the results confirm the therapeutic potential of GSK-3 inhibitors, and specially VP2.51, for the disease-modifying future treatment of motor neuron disorders like ALS.}, }
@article {pmid27622247, year = {2018}, author = {Park, JE and Koo, HW and Liu, H and Jung, SC and Park, D and Suh, DC}, title = {Clinical Characteristics and Treatment Outcomes of Spinal Arteriovenous Malformations.}, journal = {Clinical neuroradiology}, volume = {28}, number = {1}, pages = {39-46}, pmid = {27622247}, issn = {1869-1447}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Arteriovenous Malformations/diagnosis/pathology/therapy ; *Central Nervous System Vascular Malformations/diagnosis/pathology/therapy ; Child ; *Embolization, Therapeutic ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Treatment Outcome ; Young Adult ; }, abstract = {PURPOSE: Spinal arteriovenous malformations (SAVMs) are rare events. This study evaluated initial clinical presentations and treatment outcomes of SAVMs.<br><br>METHODS: In this study, 91 consecutive patients with SAVM between January 1993 and November 2014 were evaluated. Initial clinical presentations, radiological findings, treatment results, and follow-up outcomes were evaluated according to disease type and treatment modalities. Patient status was scored using the modified Rankin scale (mRS) and Aminoff-Logue Disability scale (ALS).<br><br>RESULTS: Of the SAVM patients 69&#x2009;% were male and 31&#x2009;% were female with a&#xa0;mean age of 49&#xa0;years (range 11-82&#xa0;years). At the time of initial imaging evaluation, myelopathy was the most common finding with main complaints of gait disturbance (69 out of 91, 76&#x2009;%), sensory disturbances (61/91, 67&#x2009;%), and bowel or bladder symptoms (51/91, 56&#x2009;%). Among the 80&#xa0;patients who received treatment 56 (62&#x2009;%) underwent endovascular embolization and 24 (26&#x2009;%) underwent surgery. Complete obliteration was achieved in 47&#xa0;patients (84&#x2009;%) after endovascular embolization and in 18 (75&#x2009;%) after surgical ligation. At the time of final follow-up 67&#xa0;patients (84&#x2009;%) showed improvement of more than 1&#xa0;point on the mRS, while 69 (86&#x2009;%) showed significant improvement on the ALS after treatment.<br><br>CONCLUSION: The SAVMs presented with diverse neurological deficits, including myelopathy. Endovascular or surgical treatment of SAVMs can result in good clinical outcomes in most patients.}, }
@article {pmid27603566, year = {2016}, author = {Mera-Adasme, R and Erdmann, H and Bereźniak, T and Ochsenfeld, C}, title = {Destabilization of the metal site as a hub for the pathogenic mechanism of five ALS-linked mutants of copper, zinc superoxide dismutase.}, journal = {Metallomics : integrated biometal science}, volume = {8}, number = {10}, pages = {1141-1150}, doi = {10.1039/c6mt00085a}, pmid = {27603566}, issn = {1756-591X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Binding Sites ; Enzyme Stability ; Humans ; Molecular Dynamics Simulation ; *Point Mutation ; Protein Conformation ; Superoxide Dismutase-1/*chemistry/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease, with no effective pharmacological treatment. Its pathogenesis is unknown, although a subset of the cases is linked to genetic mutations. A significant fraction of the mutations occur in one protein, copper, zinc superoxide dismutase (SOD1). The toxic function of mutant SOD1 has not been elucidated, but damage to the metal site of the protein is believed to play a major role. In this work, we study the electrostatic loop of SOD1, which we had previously proposed to work as a "solvent seal" isolating the metal site from water molecules. Out of the five contact points identified between the electrostatic loop and its dock in the rest of the protein, three points were found to be affected by ALS-linked mutations, with a total of five mutations identified. The effect of the five mutations was studied using methods of computational chemistry. We found that four of the mutations destabilize the proposed solvent seal, while the fifth mutation directly affects the metal-site stability. In the two contact points unaffected by ALS-linked mutations, the side chains of the residues were not found to play a stabilizing role. Our results show that the docking of the electrostatic loop to the rest of SOD1 plays a role in ALS pathogenesis, in support of that structure acting as a solvent barrier for the metal site. The results provide a unified pathogenic mechanism for five different ALS-linked mutations of SOD1.}, }
@article {pmid27590968, year = {2016}, author = {Chaudhary, U and Birbaumer, N and Ramos-Murguialday, A}, title = {Brain-computer interfaces in the completely locked-in state and chronic stroke.}, journal = {Progress in brain research}, volume = {228}, number = {}, pages = {131-161}, doi = {10.1016/bs.pbr.2016.04.019}, pmid = {27590968}, issn = {1875-7855}, mesh = {Brain/*physiology ; Brain Waves/physiology ; *Brain-Computer Interfaces ; Chronic Disease ; *Communication ; Conditioning, Classical/physiology ; Electroencephalography ; Female ; Humans ; Male ; Paralysis/*etiology/*rehabilitation ; Spectroscopy, Near-Infrared ; Stroke/*complications ; User-Computer Interface ; }, abstract = {Brain-computer interfaces (BCIs) use brain activity to control external devices, facilitating paralyzed patients to interact with the environment. In this chapter, we discuss the historical perspective of development of BCIs and the current advances of noninvasive BCIs for communication in patients with amyotrophic lateral sclerosis and for restoration of motor impairment after severe stroke. Distinct techniques have been explored to control a BCI in patient population especially electroencephalography (EEG) and more recently near-infrared spectroscopy (NIRS) because of their noninvasive nature and low cost. Previous studies demonstrated successful communication of patients with locked-in state (LIS) using EEG- and invasive electrocorticography-BCI and intracortical recordings when patients still showed residual eye control, but not with patients with complete LIS (ie, complete paralysis). Recently, a NIRS-BCI and classical conditioning procedure was introduced, allowing communication in patients in the complete locked-in state (CLIS). In severe chronic stroke without residual hand function first results indicate a possible superior motor rehabilitation to available treatment using BCI training. Here we present an overview of the available studies and recent results, which open new doors for communication, in the completely paralyzed and rehabilitation in severely affected stroke patients. We also reflect on and describe possible neuronal and learning mechanisms responsible for BCI control and perspective for future BMI research for communication in CLIS and stroke motor recovery.}, }
@article {pmid27579582, year = {2016}, author = {Bartolo, M and Chiò, A and Ferrari, S and Tassorelli, C and Tamburin, S and Avenali, M and Azicnuda, E and Calvo, A and Caraceni, AT and Defazio, G and DE Icco, R and Formisano, R and Franzoni, S and Greco, E and Jedrychowska, I and Magrinelli, F and Manera, U and Marchioni, E and Mariotto, S and Monaco, S and Pace, A and Saviola, D and Springhetti, I and Tinazzi, M and DE Tanti, A and , }, title = {Assessing and treating pain in movement disorders, amyotrophic lateral sclerosis, severe acquired brain injury, disorders of consciousness, dementia, oncology and neuroinfectivology. Evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.}, journal = {European journal of physical and rehabilitation medicine}, volume = {52}, number = {6}, pages = {841-854}, pmid = {27579582}, issn = {1973-9095}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Brain Diseases/*complications/*microbiology ; Brain Injuries/*complications ; Combined Modality Therapy ; Consciousness Disorders/*complications ; Dementia/*complications ; Evidence-Based Medicine ; Humans ; Italy ; Movement Disorders/*complications ; Neoplasms/*complications ; Neurological Rehabilitation/*methods ; Outcome Assessment, Health Care ; Pain/*etiology/*rehabilitation ; Pain Management/*methods ; *Pain Measurement ; Translational Research, Biomedical ; }, abstract = {Pain is an important non-motor symptom in several neurological diseases, such as Parkinson's disease, cervical dystonia, amyotrophic lateral sclerosis, severe acquired brain injury, disorders of consciousness and dementia, as well as in oncology and neuroinfectivology. To overcome the lack of evidence-based data on pain management in these diseases, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) has defined criteria for good clinical practice among Italian neurorehabilitation professionals. Here a review of the literature (PubMed, EMBASE and gray literature) on pain characteristics, treatment and impact of pain in a neurorehabilitation setting is provided. Despite the heterogeneity of data, a consensus was reached on pain management for patients with these diseases: it is an approach originating from an analysis of the available data on pain characteristics in each disease, the evolution of pain in relation to the natural course of the disease and the impact of pain on the overall process of rehabilitation. There was unanimous consensus regarding the utility of a multidisciplinary approach to pain therapy, combining the benefits of pharmacological therapy with the techniques of physiotherapy and neurorehabilitation for all the conditions considered. While some treatments could be different depending on pathology, a progressive approach to the pharmacological treatment of pain is advisable, starting with non-opioid analgesics (paracetamol) and nonsteroidal anti-inflammatory drugs as a first-line treatment, and opioid analgesics as a second-line treatment. In cases of pain secondary to spasticity, botulinum neurotoxin, and, in some cases, intrathecal baclofen infusion should be considered. Randomized controlled trials and prospective multicenter studies aimed at documenting the efficacy of pain treatment and their risk-benefit profile are recommended for these conditions.}, }
@article {pmid27579520, year = {2017}, author = {McGeachan, AJ and Hobson, EV and Al-Chalabi, A and Stephenson, J and Chandran, S and Crawley, F and Dick, D and Donaghy, C and Ellis, CM and Gorrie, G and Hanemann, CO and Harrower, T and Jung, A and Malaspina, A and Morrison, KE and Orrell, RW and Talbot, K and Turner, MR and Williams, TL and Young, CA and Shaw, PJ and McDermott, CJ}, title = {A multicentre evaluation of oropharyngeal secretion management practices in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {1-2}, pages = {1-9}, doi = {10.1080/21678421.2016.1221433}, pmid = {27579520}, issn = {2167-9223}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MALASPINA/APR13/817-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; DRF-2013-06-076/DH_/Department of Health/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Acetylcholine Release Inhibitors/therapeutic use ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*complications ; Botulinum Toxins/therapeutic use ; Cholinergic Antagonists/therapeutic use ; Cohort Studies ; *Disease Management ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Middle Aged ; Scopolamine/therapeutic use ; Sialorrhea/*etiology/*therapy ; Treatment Outcome ; }, abstract = {Failure to clear oral secretions can be debilitating for patients with amyotrophic lateral sclerosis (ALS), but the treatment of this symptom is poorly defined and there is no consensus on best practice. The objective of this study was to identify the treatments that are commonly prescribed, and to describe how experienced clinicians manage a patient with treatment resistant symptoms. Twenty-three clinicians were approached, of which 19 from 16 centres across the UK provided case report forms for a total of 119 ALS patients identified as having problematic oral secretions. The use of five anticholinergics, salivary gland botulinum toxin injections, conservative management approaches and carbocisteine were reported. Of the 72 patients who were evaluated following the initiation of a first anticholinergic, 61% had symptomatic improvement. Only 19% of patients achieved symptomatic improvement with the use of an alternative anticholinergic when an initial anticholinergic achieved no symptomatic improvement. Problems with thick and thin secretions often coexisted, with 37% of patients receiving treatment for both types of problem. In conclusion, a variety of treatment options are employed by expert clinicians for problematic oral secretions in ALS patients. The variation in management highlights the need for further prospective research in this area.}, }
@article {pmid27575793, year = {2016}, author = {Fearns, R and Deval, J}, title = {New antiviral approaches for respiratory syncytial virus and other mononegaviruses: Inhibiting the RNA polymerase.}, journal = {Antiviral research}, volume = {134}, number = {}, pages = {63-76}, doi = {10.1016/j.antiviral.2016.08.006}, pmid = {27575793}, issn = {1872-9096}, mesh = {Antiviral Agents/pharmacology/*therapeutic use ; Clinical Trials as Topic ; DNA-Directed RNA Polymerases/*antagonists &amp; inhibitors/drug effects/metabolism ; Deoxycytidine/analogs &amp; derivatives/therapeutic use ; Hemorrhagic Fever, Ebola/drug therapy ; Humans ; Measles/drug therapy ; Mononegavirales/*drug effects/enzymology/genetics ; Nucleosides/agonists ; RNA, Messenger ; RNA-Dependent RNA Polymerase/drug effects ; Respiratory Syncytial Virus Infections/drug therapy ; Respiratory Syncytial Virus, Human/*drug effects/enzymology/genetics ; Transcription, Genetic ; Virus Replication/drug effects ; }, abstract = {Worldwide, respiratory syncytial virus (RSV) causes severe disease in infants, the elderly, and immunocompromised people. No vaccine or effective antiviral treatment is available. RSV is a member of the non-segmented, negative-strand (NNS) group of RNA viruses and relies on its RNA-dependent RNA polymerase to transcribe and replicate its genome. Because of its essential nature and unique properties, the RSV polymerase has proven to be a good target for antiviral drugs, with one compound, ALS-8176, having already achieved clinical proof-of-concept efficacy in a human challenge study. In this article, we first provide an overview of the role of the RSV polymerase in viral mRNA transcription and genome replication. We then review past and current approaches to inhibiting the RSV polymerase, including use of nucleoside analogs and non-nucleoside inhibitors. Finally, we consider polymerase inhibitors that hold promise for treating infections with other NNS RNA viruses, including measles and Ebola.}, }
@article {pmid27564703, year = {2016}, author = {Tefera, TW and Wong, Y and Barkl-Luke, ME and Ngo, ST and Thomas, NK and McDonald, TS and Borges, K}, title = {Triheptanoin Protects Motor Neurons and Delays the Onset of Motor Symptoms in a Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {PloS one}, volume = {11}, number = {8}, pages = {e0161816}, pmid = {27564703}, issn = {1932-6203}, mesh = {Alanine Transaminase/genetics ; Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Animals ; Citric Acid Cycle/drug effects ; Female ; Hand Strength/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Motor Neurons/*drug effects ; Succinate Dehydrogenase/genetics ; Superoxide Dismutase-1/metabolism ; Triglycerides/*therapeutic use ; Weight Loss/drug effects ; }, abstract = {There is increasing evidence that energy metabolism is disturbed in Amyotrophic Lateral Sclerosis (ALS) patients and animal models. Treatment with triheptanoin, the triglyceride of heptanoate, is a promising approach to provide alternative fuel to improve oxidative phosphorylation and aid ATP generation. Heptanoate can be metabolized to propionyl-CoA, which after carboxylation can produce succinyl-CoA and thereby re-fill the tricarboxylic acid (TCA) cycle (anaplerosis). Here we tested the hypothesis that treatment with triheptanoin prevents motor neuron loss and delays the onset of disease symptoms in female mice overexpressing the mutant human SOD1G93A (hSOD1G93A) gene. When oral triheptanoin (35% of caloric content) was initiated at P35, motor neuron loss at 70 days of age was attenuated by 33%. In untreated hSOD1G93A mice, the loss of hind limb grip strength began at 16.7 weeks. Triheptanoin maintained hind limb grip strength for 2.8 weeks longer (p<0.01). Loss of balance on the rotarod and reduction of body weight were delayed by 13 and 11 days respectively (both p<0.01). Improved motor function occurred in parallel with alterations in the expression of genes associated with muscle metabolism. In gastrocnemius muscles, the mRNA levels of pyruvate, 2-oxoglutarate and succinate dehydrogenases and methyl-malonyl mutase were reduced by 24-33% in 10 week old hSOD1G93A mice when compared to wild-type mice, suggesting that TCA cycling in skeletal muscle may be slowed in this ALS mouse model at a stage when muscle strength is still normal. At 25 weeks of age, mRNA levels of succinate dehydrogenases, glutamic pyruvic transaminase 2 and the propionyl carboxylase β subunit were reduced by 69-84% in control, but not in triheptanoin treated hSOD1G93A animals. Taken together, our results suggest that triheptanoin slows motor neuron loss and the onset of motor symptoms in ALS mice by improving TCA cycling.}, }
@article {pmid27552392, year = {2016}, author = {Silvestri, NJ and Wolfe, GI and Lacomis, D and Bromberg, MB}, title = {What's in the Literature?.}, journal = {Journal of clinical neuromuscular disease}, volume = {18}, number = {1}, pages = {47-59}, doi = {10.1097/CND.0000000000000139}, pmid = {27552392}, issn = {1537-1611}, abstract = {The Guillain-Barré syndrome (GBS) is one of the few neuropathies well known to the general public, in part because of its association with swine flu vaccinations in 1976. GBS has again reached the general public with its possible association with Zika virus. The virus, borne by infected Aedes aegypti mosquitos, is being linked to birth defects when pregnant women are bitten and infected. There are early reports also linking GBS to Zika infection, which could expose a wider range of infected people to the neuropathy. This summer infected Aedes mosquitos will likely reach southern portions of the United States, and travelers to countries where Aedes is endemic will increase. It is important to appreciate that the neurologic consequences of Zika virus are being actively investigated, and firm associations and consequences are yet to be established. Small fiber neuropathies are common and can be due to a number of underlying diseases, and a recent review also indicates that many are idiopathic. One cause is Sjögren syndrome, and a case series reviews clinical features. The diagnosis and underlying features of primary lateral sclerosis are a clinical challenge. Similarities between primary lateral sclerosis and hereditary spastic paraparesis (HSP) have long been noted. With a wide spectrum of gene mutations associated with HSP, clinical distinction between the 2 disorders is problematic. A review covers the wide spectrum of HSP. With no cure, the progression of amyotrophic lateral sclerosis (ALS) to respiratory failure is predictable. This could easily result in marked depression among patients, and 2 studies have explored the frequency and severity of depression. The cause of ALS remains unknown, and when no hereditary factor is apparent, environmental questions arise as possible contributing factor(s). The most notable association is with military service, although specific occupational or environmental linkages are not well sorted out. Two recent reports address these issues. There is good news for ALS patients with muscle cramps with the results of a multicenter randomized and placebo-controlled trial showing that mexiletine is effective in reducing this common symptom. The treatment of myasthenia gravis with various agents, the use of patient-reported outcome measures in myasthenia gravis, and the occurrence of myocarditis in this disease are reviewed. Necrotizing autoimmune neuropathies, the co-occurrence of inclusion body myositis and a form of T-cell leukemia are discussed as are valosin-containing protein (VCP)-opathy and bone health in patients with dystrophinopathy.}, }
@article {pmid27549088, year = {2016}, author = {Apolloni, S and Fabbrizio, P and Amadio, S and Volonté, C}, title = {Actions of the antihistaminergic clemastine on presymptomatic SOD1-G93A mice ameliorate ALS disease progression.}, journal = {Journal of neuroinflammation}, volume = {13}, number = {1}, pages = {191}, pmid = {27549088}, issn = {1742-2094}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/*prevention &amp; control ; Animals ; Animals, Newborn ; Asymptomatic Diseases/therapy ; Autophagy/drug effects ; Cells, Cultured ; Clemastine/*therapeutic use ; Cytokines/metabolism ; Disease Models, Animal ; Disease Progression ; Histamine Antagonists/*therapeutic use ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/drug effects ; Motor Neurons/drug effects/pathology ; Receptors, Purinergic P2X4/metabolism ; Signal Transduction/drug effects ; Spinal Cord/cytology ; Superoxide Dismutase/*genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease with a strong neuroinflammatory component sustained by activated microglia contributing to motoneuron death. However, how to successfully balance neuroprotective versus neurotoxic actions by the use of antinflammatory agents is still under scrutiny. We have recently shown that the antihistamine clemastine, an FDA-approved drug, can influence the M1/M2 switch occurring in SOD1-G93A ALS microglia.<br><br>METHODS: Here, we have chronically treated female SOD1-G93A mice with clemastine, evaluated disease progression and performed mice lumbar spinal cord analysis at symptomatic and end stage of the disease. Moreover, we have studied the mechanism of action of clemastine in primary adult spinal SOD1-G93A microglia cultures and in NSC-G93A motor neuron-like cells.<br><br>RESULTS: We found that a short treatment with clemastine (50&#xa0;mg/kg) from asymptomatic (postnatal day 40) to symptomatic phase (postnatal day 120) significantly delayed disease onset and extended the survival of SOD1-G93A mice by about 10&#xa0;%. Under these conditions, clemastine induced protection of motor neurons, modulation of inflammatory parameters, reduction of SOD1 protein levels and SQSTM1/p62 autophagic marker, when analysed immediately at the end of the treatment (postnatal day 120). A long treatment with clemastine (from asymptomatic until the end stage) instead failed to ameliorate ALS disease progression. At the end stage of the disease, we found that clemastine short treatment decreased microgliosis and SOD1 protein and increased LC3-II autophagic marker, while the long treatment produced opposite effects. Finally, in spinal microglia cultures from symptomatic SOD1-G93A mice clemastine activated inflammatory parameters, stimulated autophagic flux via the mTOR signalling pathway and decreased SOD1 levels. Modulation of autophagy was also demonstrated in NSC34 SOD1-G93A motor neuron-like cells.<br><br>CONCLUSIONS: By gaining insights into the ameliorating actions of an antihistaminergic compound in ALS disease, our findings might represent an exploitable therapeutic approach for familial forms of ALS.}, }
@article {pmid27548576, year = {2016}, author = {Wang, Y and Zhao, Z and Rege, SV and Wang, M and Si, G and Zhou, Y and Wang, S and Griffin, JH and Goldman, SA and Zlokovic, BV}, title = {3K3A-activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice.}, journal = {Nature medicine}, volume = {22}, number = {9}, pages = {1050-1055}, pmid = {27548576}, issn = {1546-170X}, support = {P50 AG005142/AG/NIA NIH HHS/United States ; R01 MH104701/MH/NIMH NIH HHS/United States ; R01 NS075345/NS/NINDS NIH HHS/United States ; R01 MH099578/MH/NIMH NIH HHS/United States ; R01 NS090904/NS/NINDS NIH HHS/United States ; R01 HL052246/HL/NHLBI NIH HHS/United States ; R01 HL021544/HL/NHLBI NIH HHS/United States ; P01 HL031950/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Behavior, Animal ; Brain/*drug effects/metabolism ; Brain Ischemia ; Cell Proliferation/*drug effects ; Cerebral Cortex/drug effects/metabolism ; Flow Cytometry ; Humans ; Infarction, Middle Cerebral Artery/metabolism/*physiopathology ; Male ; Mice ; Neural Stem Cells/*drug effects/transplantation ; Protein C/*pharmacology ; Recombinant Proteins/*pharmacology ; Recovery of Function ; Regeneration/*drug effects ; Synapses ; }, abstract = {Activated protein C (APC) is a blood protease with anticoagulant activity and cell-signaling activities mediated by the activation of protease-activated receptor 1 (F2R, also known as PAR1) and F2RL1 (also known as PAR3) via noncanonical cleavage. Recombinant variants of APC, such as the 3K3A-APC (Lys191-193Ala) mutant in which three Lys residues (KKK191-193) were replaced with alanine, and/or its other mutants with reduced (>90%) anticoagulant activity, engineered to reduce APC-associated bleeding risk while retaining normal cell-signaling activity, have shown benefits in preclinical models of ischemic stroke, brain trauma, multiple sclerosis, amyotrophic lateral sclerosis, sepsis, ischemic and reperfusion injury of heart, kidney and liver, pulmonary, kidney and gastrointestinal inflammation, diabetes and lethal body radiation. On the basis of proof-of-concept studies and an excellent safety profile in humans, 3K3A-APC has advanced to clinical trials as a neuroprotectant in ischemic stroke. Recently, 3K3A-APC has been shown to stimulate neuronal production by human neural stem and progenitor cells (NSCs) in vitro via a PAR1-PAR3-sphingosine-1-phosphate-receptor 1-Akt pathway, which suggests the potential for APC-based treatment as a strategy for structural repair in the human central nervous (CNS) system. Here we report that late postischemic treatment of mice with 3K3A-APC stimulates neuronal production by transplanted human NSCs, promotes circuit restoration and improves functional recovery. Thus, 3K3A-APC-potentiated neuronal recruitment from engrafted NSCs might offer a new approach to the treatment of stroke and related neurological disorders.}, }
@article {pmid27534566, year = {2017}, author = {Kettemann, D and Funke, A and Maier, A and Rosseau, S and Meyer, R and Spittel, S and Münch, C and Meyer, T}, title = {Clinical characteristics and course of dying in patients with amyotrophic lateral sclerosis withdrawing from long-term ventilation.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {18}, number = {1-2}, pages = {53-59}, doi = {10.1080/21678421.2016.1214734}, pmid = {27534566}, issn = {2167-9223}, mesh = {Adult ; Aged ; Aged, 80 and over ; *Amyotrophic Lateral Sclerosis/diagnosis/mortality/therapy ; Cohort Studies ; Disease Progression ; Female ; Germany ; Humans ; Male ; Middle Aged ; Noninvasive Ventilation/*methods ; Palliative Care/methods ; Statistics, Nonparametric ; Terminal Care/*methods ; Tracheotomy/methods ; }, abstract = {Non-invasive ventilation (NIV) or tracheotomy with invasive ventilation (TIV) are treatment options in ALS. However, a proportion of patients receiving long-term ventilation decide to have it withdrawn. The objective of this study was to analyse the clinical characteristics and palliative approaches in ALS patients withdrawing from long-term ventilation (WLTV). In a cohort study, two different palliative concepts in WLTV were studied: (1) augmented symptom control (ASC; sedation not intended) in patients with ventilator-free tolerance; (2) continuous deep sedation (CDS; sedation intended) in patients without ventilator-free tolerance. Results showed that WLTV was realised in 49 ALS patients (NIV = 13; TIV = 36). Mean daily ventilation was 23.4 h. The ALS Functional Rating Scale (ALSFRS-R) was low (5.6 of 48). Forty-one per cent of patients (n = 20) presented with ophthalmoplegia. ASC was performed in 20 patients, CDS in 29 patients. The mean time to death following disconnection was 32 (0.3-164) h during ASC and 0.3 (0.2-0.6) h in CDS. In conclusion, a low ALSFRS-R, high incidence of ophthalmoplegia and extended ventilator dependency were found before WLTV. The presence or absence of ventilator-free tolerance determined the approach to the management of symptoms, the setting for immediate end-of-life care and the course of dying in WLTV.}, }
@article {pmid27524729, year = {2016}, author = {Lewandowski, SA and Fredriksson, L and Lawrence, DA and Eriksson, U}, title = {Pharmacological targeting of the PDGF-CC signaling pathway for blood-brain barrier restoration in neurological disorders.}, journal = {Pharmacology &amp; therapeutics}, volume = {167}, number = {}, pages = {108-119}, pmid = {27524729}, issn = {1879-016X}, support = {R01 HL055374/HL/NHLBI NIH HHS/United States ; R01 NS079639/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Blood-Brain Barrier/metabolism/pathology ; Drug Design ; Humans ; Lymphokines/*metabolism ; Mice ; Molecular Targeted Therapy ; Nervous System Diseases/*drug therapy/etiology/physiopathology ; Neurodegenerative Diseases/*drug therapy/etiology/physiopathology ; Neuroprotective Agents/pharmacology ; Platelet-Derived Growth Factor/*metabolism ; Risk Factors ; Signal Transduction ; }, abstract = {Neurological disorders account for a majority of non-malignant disability in humans and are often associated with dysfunction of the blood-brain barrier (BBB). Recent evidence shows that despite apparent variation in the origin of neural damage, the central nervous system has a common injury response mechanism involving platelet-derived growth factor (PDGF)-CC activation in the neurovascular unit and subsequent dysfunction of BBB integrity. Inhibition of PDGF-CC signaling with imatinib in mice has been shown to prevent BBB dysfunction and have neuroprotective effects in acute damage conditions, including traumatic brain injury, seizures or stroke, as well as in neurodegenerative diseases that develop over time, including multiple sclerosis and amyotrophic lateral sclerosis. Stroke and traumatic injuries are major risk factors for age-associated neurodegenerative disorders and we speculate that restoring BBB properties through PDGF-CC inhibition might provide a common therapeutic opportunity for treatment of both acute and progressive neuropathology in humans. In this review we will summarize what is known about the role of PDGF-CC in neurovascular signaling events and the variety of seemingly different neuropathologies it is involved in. We will also discuss the pharmacological means of therapeutic interventions for anti-PDGF-CC therapy and ongoing clinical trials. In summary: inhibition of PDGF-CC signaling can be protective for immediate injury and decrease the long-term neurodegenerative consequences.}, }
@article {pmid27514792, year = {2017}, author = {Hakeem, H and Uz Zaman, M and Khan, S}, title = {Hypoparathyroidism: A rare mimic of amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {55}, number = {3}, pages = {437-439}, doi = {10.1002/mus.25376}, pmid = {27514792}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Electromyography ; Humans ; Hypoparathyroidism/*diagnosis ; Male ; Middle Aged ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) carries a grim prognosis. Various ALS mimics have been reported and should be excluded before confirming this diagnosis.<br><br>METHODS: We report the case of a 61-year-old man who presented with progressively worsening limb weakness and dysphagia. His examination showed mixed upper and lower motor neuron signs without sensory impairment. ALS was suspected, however, atypical diffuse pain prompted diagnostic work-up to exclude other causes.<br><br>RESULTS: Electrodiagnostic testing was suggestive of a sensorimotor polyneuropathy with superimposed diffuse active denervation suspicious for anterior horn cell degeneration. Brain MRI showed bilateral basal ganglia and thalamic calcifications. Laboratory studies confirmed the diagnosis of hypoparathyroidism. Treatment with calcium and vitamin D resulted in significant improvement at 6 months follow-up.<br><br>CONCLUSIONS: Hypoparathyroidism, a treatable endocrinopathy, can rarely present clinically as ALS. In atypical cases, this should be ruled out before making a final diagnosis. Muscle Nerve, 2016 Muscle Nerve 55: 437-439, 2017.}, }
@article {pmid27514452, year = {2017}, author = {Agarwal, S and Yadav, A and Chaturvedi, RK}, title = {Peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders.}, journal = {Biochemical and biophysical research communications}, volume = {483}, number = {4}, pages = {1166-1177}, doi = {10.1016/j.bbrc.2016.08.043}, pmid = {27514452}, issn = {1090-2104}, mesh = {Animals ; Calcium/metabolism ; Homeostasis ; Humans ; Inflammation/metabolism ; Mitochondria/metabolism ; Neurodegenerative Diseases/metabolism/pathology/*therapy ; Oxidative Stress ; Peroxisome Proliferator-Activated Receptors/*drug effects/metabolism ; }, abstract = {Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and they serve to be a promising therapeutic target for several neurodegenerative disorders, which includes Parkinson disease, Alzheimer's disease, Huntington disease and Amyotrophic Lateral Sclerosis. PPARs play an important role in the downregulation of mitochondrial dysfunction, proteasomal dysfunction, oxidative stress, and neuroinflammation, which are the major causes of the pathogenesis of neurodegenerative disorders. In this review, we discuss about the role of PPARs as therapeutic targets in neurodegenerative disorders. Several experimental approaches suggest potential application of PPAR agonist as well as antagonist in the treatment of neurodegenerative disorders. Several epidemiological studies found that the regular usage of PPAR activating non-steroidal anti-inflammatory drugs is effective in decreasing the progression of neurodegenerative diseases including PD and AD. We also reviewed the neuroprotective effects of PPAR agonists and associated mechanism of action in several neurodegenerative disorders both in vitro as well as in vivo animal models.}, }
@article {pmid27504455, year = {2016}, author = {Faa, A and Faa, G and Papalois, A and Obinu, E and Locci, G and Pais, ME and Lelovas, P and Barouxis, D and Pantazopoulos, C and Vasileiou, PV and Iacovidou, N and Xanthos, T}, title = {Effects of Erythropoietin Administration on Adrenal Glands of Landrace/Large White Pigs after Ventricular Fibrillation.}, journal = {BioMed research international}, volume = {2016}, number = {}, pages = {7261960}, pmid = {27504455}, issn = {2314-6141}, mesh = {Adrenal Cortex/drug effects ; Adrenal Glands/*drug effects ; Adrenal Medulla/drug effects ; Animals ; Apoptosis/drug effects ; Cardiopulmonary Resuscitation/methods ; Disease Models, Animal ; Erythropoietin/*administration &amp; dosage ; Female ; Protective Agents/administration &amp; dosage ; Swine ; Ventricular Fibrillation/*drug therapy ; }, abstract = {Aim. To evaluate the effects of erythropoietin administration on the adrenal glands in a swine model of ventricular fibrillation and resuscitation. Methods. Ventricular fibrillation was induced via pacing wire forwarded into the right ventricle in 20 female Landrace/Large White pigs, allocated into 2 groups: experimental group treated with bolus dose of erythropoietin (EPO) and control group which received normal saline. Cardiopulmonary resuscitation (CPR) was performed immediately after drug administration as per the 2010 European Resuscitation Council (ERC) guidelines for Advanced Life Support (ALS) until return of spontaneous circulation (ROSC) or death. Animals who achieved ROSC were monitored, mechanically ventilated, extubated, observed, and euthanized. At necroscopy, adrenal glands samples were formalin-fixed, paraffin-embedded, and routinely processed. Sections were stained with hematoxylin-eosin. Results. Oedema and apoptosis were the most frequent histological changes and were detected in all animals in the adrenal cortex and in the medulla. Mild and focal endothelial lesions were also detected. A marked interindividual variability in the degree of the intensity of apoptosis and oedema at cortical and medullary level was observed within groups. Comparing the two groups, higher levels of pathological changes were detected in the control group. No significant difference between the two groups was observed regarding the endothelial changes. Conclusions. In animals exposed to ventricular fibrillation, EPO treatment has protective effects on the adrenal gland.}, }
@article {pmid27498188, year = {2016}, author = {Weishaupt, JH and Hyman, T and Dikic, I}, title = {Common Molecular Pathways in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Trends in molecular medicine}, volume = {22}, number = {9}, pages = {769-783}, doi = {10.1016/j.molmed.2016.07.005}, pmid = {27498188}, issn = {1471-499X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology/therapy ; Animals ; Autophagy ; Frontotemporal Dementia/genetics/metabolism/*pathology/therapy ; Humans ; Protein Aggregates ; RNA/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative diseases in which predominantly motor neurons and cerebral cortex neurons, respectively, are affected. Several novel ALS and FTD disease genes have been recently discovered, pointing toward a few overarching pathways in ALS/FTD pathogenesis. Nevertheless, a precise picture of how various cellular processes cause neuronal death, or how different routes leading to ALS and FTD are functionally connected is just emerging. Moreover, how the most recent milestone findings in the ALS/FTD field might lead to improved diagnosis and treatment is actively being explored. We highlight some of the most exciting recent topics in the field, which could potentially facilitate the identification of further links between the pathogenic ALS/FTD pathways related to autophagy, vesicle trafficking, and RNA metabolism.}, }
@article {pmid27498123, year = {2016}, author = {Bennett, JP and O'Brien, LC and Brohawn, DG}, title = {Pharmacological properties of microneurotrophin drugs developed for treatment of amyotrophic lateral sclerosis.}, journal = {Biochemical pharmacology}, volume = {117}, number = {}, pages = {68-77}, doi = {10.1016/j.bcp.2016.08.001}, pmid = {27498123}, issn = {1873-2968}, mesh = {ATP Binding Cassette Transporter, Subfamily B/antagonists &amp; inhibitors/genetics/metabolism ; Absorption, Physiological/drug effects ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Biotransformation ; Blood-Brain Barrier ; Caco-2 Cells ; Cell Line ; Cells, Cultured ; Dehydroepiandrosterone/*analogs &amp; derivatives/metabolism/pharmacokinetics/pharmacology ; Dogs ; Drugs, Investigational/metabolism/pharmacokinetics/*pharmacology ; Gene Expression Regulation/*drug effects ; Hepatocytes/cytology/drug effects/metabolism/pathology ; Humans ; Induced Pluripotent Stem Cells/cytology/drug effects ; Madin Darby Canine Kidney Cells ; Membrane Transport Modulators/pharmacology ; Mice ; Motor Neurons/cytology/*drug effects/metabolism/pathology ; Nerve Tissue Proteins/genetics/*metabolism ; Neural Stem Cells/cytology/drug effects ; Neuroprotective Agents/metabolism/pharmacokinetics/*pharmacology ; Recombinant Proteins/chemistry/metabolism ; Tissue Distribution ; }, abstract = {Microneurotrophins (MNT's) are small molecule derivatives of dehydroepiandrosterone (DHEA) and do not have significant interactions with sex steroid receptors. MNT's retain high-affinity binding to protein tyrosine kinase (Trk) receptors and can mimic many pleiotropic actions of neurotrophin (NT) proteins on neurons. MNT's offer therapeutic potential for diseases such as amyotrophic lateral sclerosis (ALS) where motor neurons (MN) degenerate. MNT's cross artificial membranes mimicking the blood-brain barrier, are not major substrates for ABC (ATP-binding cassette) transporters and are metabolized rapidly by mouse but more slowly by human hepatocytes. A lead MNT (BNN27) and its mono-oxidation metabolites enter mouse brain rapidly. RNA-sequencing measured gene expression profiles of human H9eSC-(embryonic stem cell)-derived or CTL (control) subject iPSC-(induced pluripotential stem cell)-derived MN's exposed to NT proteins or MNT molecules. Expression ratios (relative to DMSO (dimethylsulfoxide) vehicle) were calculated, and the resulting top 500 gene lists were analyzed for Gene Ontology (GO) grouping using DAVID (Database for Annotation, Visualization and Integrated Discovery). The MNT's BNN20, BNN23, and BNN27 showed overlap of GO terms with NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor) in the H9eSC-derived MN's. In the iPSC-derived MN's two (BNN20, BNN27) showed overlap of GO terms with NGF or BDNF. Each NT protein had GO terms that did not overlap with any MNT in the MN cell lines.}, }
@article {pmid27495938, year = {2017}, author = {Islamov, RR and Rizvanov, AA and Fedotova, VY and Izmailov, AA and Safiullov, ZZ and Garanina, EE and Salafutdinov, II and Sokolov, ME and Mukhamedyarov, MA and Palotás, A}, title = {Tandem Delivery of Multiple Therapeutic Genes Using Umbilical Cord Blood Cells Improves Symptomatic Outcomes in ALS.}, journal = {Molecular neurobiology}, volume = {54}, number = {6}, pages = {4756-4763}, pmid = {27495938}, issn = {1559-1182}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/*therapy ; Animals ; Behavior, Animal ; Cell Count ; Fetal Blood/*cytology ; Fluorescent Antibody Technique ; *Genetic Therapy ; Green Fluorescent Proteins/metabolism ; Humans ; Leukocytes, Mononuclear/metabolism ; Lumbar Vertebrae/pathology ; Mice, Transgenic ; Survival Analysis ; Treatment Outcome ; }, abstract = {Current treatment options of chronic, progressive degenerative neuropsychiatric conditions offer only marginal efficacy, and there is no therapy which arrests or even reverses these diseases. Interest in genetic engineering and cell-based approaches have constantly been increasing, although most of them so far proved to be fruitless or at best provided very slight clinical benefit. In the light of the highly complex patho-mechanisms of these maladies, the failure of drugs aimed at targeting single molecules is not surprising. In order to improve their effectiveness, the role of a unique triple-combination gene therapy was investigated in this study. Intravenous injection of human umbilical cord blood mononuclear cell (hUCBMC) cotransduced with adenoviral vectors expressing vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF), and neural cell adhesion molecule (NCAM) resulted in prominent increase of life span and performance in behavioral tests in amyotrophic lateral sclerosis (ALS). Expression of the recombinant genes in hUCBMCs was confirmed as soon as 5 days after transduction by RT-PCR, and cells were detectable for as long as 1 month after grafting in lumbar spinal cord by immunofluorescent staining. Xenotransplantation of cells into mice blood without any immunosuppression demonstrated a high level of hUCBMCs homing and survivability in the central nervous system (CNS), most conspicuously in the spinal cord, but not in the spleen or liver. This study confirms an increased addressed homing and notable survivability of triple-transfected cells in lumbar spinal cord, yielding a remarkably enhanced therapeutic potential of hUCBMCs overexpressing neurotrophic factors.}, }
@article {pmid27495204, year = {2016}, author = {Mestre, TA}, title = {Chorea.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {22}, number = {4 Movement Disorders}, pages = {1186-1207}, doi = {10.1212/CON.0000000000000349}, pmid = {27495204}, issn = {1538-6899}, mesh = {C9orf72 Protein/genetics ; Chorea/*diagnosis/genetics/physiopathology ; Humans ; Mutation/genetics ; }, abstract = {PURPOSE OF REVIEW: This article reviews the clinical approach to the diagnosis of adult patients presenting with chorea, using Huntington disease (HD) as a point of reference, and presents the clinical elements that help in the diagnostic workup. Principles of management for chorea and some of the associated features of other choreic syndromes are also described.<br><br>RECENT FINDINGS: Mutations in the C9orf72 gene, previously identified in families with a history of frontotemporal dementia, amyotrophic lateral sclerosis, or both, have been recognized as one of the most prevalent causes of HD phenocopies in the white population.<br><br>SUMMARY: The diagnosis of chorea in adult patients is challenging. A varied number of associated causes require a physician to prioritize the investigations, and a detailed history of chorea and associated findings will help. For chorea presenting as part of a neurodegenerative syndrome, the consideration of a mutation in the C9orf72 gene is a new recommendation after excluding HD. There are no new treatment options for chorea, aside from dopamine blockers and tetrabenazine. There are no disease-modifying treatments for HD or other neurodegenerative choreic syndromes.}, }
@article {pmid27493188, year = {2016}, author = {Ito, Y and Ofengeim, D and Najafov, A and Das, S and Saberi, S and Li, Y and Hitomi, J and Zhu, H and Chen, H and Mayo, L and Geng, J and Amin, P and DeWitt, JP and Mookhtiar, AK and Florez, M and Ouchida, AT and Fan, JB and Pasparakis, M and Kelliher, MA and Ravits, J and Yuan, J}, title = {RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS.}, journal = {Science (New York, N.Y.)}, volume = {353}, number = {6299}, pages = {603-608}, pmid = {27493188}, issn = {1095-9203}, support = {R01 AG047231/AG/NIA NIH HHS/United States ; 1R01AG047231/AG/NIA NIH HHS/United States ; R01 AI075118/AI/NIAID NIH HHS/United States ; 1R01NS082257/NS/NINDS NIH HHS/United States ; R01 NS082257/NS/NINDS NIH HHS/United States ; 323040/ERC_/European Research Council/International ; 2R01AI075118/AI/NIAID NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; *Apoptosis/genetics ; Axons/*pathology ; Cell Cycle Proteins ; Humans ; Inflammation/genetics/pathology ; Membrane Transport Proteins ; Mice ; Mice, Transgenic ; Necrosis ; Nerve Degeneration/*genetics ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics/*physiology ; Spinal Cord/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Suppression, Genetic ; Transcription Factor TFIIIA/genetics/*metabolism ; }, abstract = {Mutations in the optineurin (OPTN) gene have been implicated in both familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of this protein in the central nervous system (CNS) and how it may contribute to ALS pathology are unclear. Here, we found that optineurin actively suppressed receptor-interacting kinase 1 (RIPK1)-dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1(G93A) transgenic mice and pathological samples from human ALS patients. Thus, RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration. Furthermore, inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration.}, }
@article {pmid27490513, year = {2016}, author = {Mehta, P and Kaye, W and Bryan, L and Larson, T and Copeland, T and Wu, J and Muravov, O and Horton, K}, title = {Prevalence of Amyotrophic Lateral Sclerosis - United States, 2012-2013.}, journal = {Morbidity and mortality weekly report. Surveillance summaries (Washington, D.C. : 2002)}, volume = {65}, number = {8}, pages = {1-12}, doi = {10.15585/mmwr.ss6508a1}, pmid = {27490513}, issn = {1545-8636}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*epidemiology/ethnology ; Female ; Humans ; Male ; Middle Aged ; *Population Surveillance ; Prevalence ; Registries ; Risk Factors ; United States/epidemiology ; Young Adult ; }, abstract = {PROBLEM/CONDITION: Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a progressive and fatal neuromuscular disease for which no cure or viable treatment has been identified. ALS, like most noncommunicable diseases, is not a nationally notifiable disease in the United States. The prevalence of ALS in the United States during 2010-2011 was estimated to be 3.9 cases per 100,000 persons in the general population. Updated prevalence estimates are needed to help monitor disease status, better understand etiology, and identify risk factors for ALS.<br><br>PERIOD COVERED: 2012-2013.<br><br>DESCRIPTION OF SYSTEM: The National ALS Registry, established in 2009, collects data on ALS patients in the United States to better describe the incidence and prevalence of ALS, examine risk factors such as environmental and occupational exposures, and characterize the demographics of those living with ALS. To identify prevalent cases of ALS, data are compiled from four national administrative databases (maintained by the Centers for Medicare and Medicaid Services, the Veterans Health Administration, and the Veterans Benefits Administration). To identify cases not included in these databases and to better understand risk-factors associated with ALS and disease progression, the Registry also includes data that are collected from patients who voluntarily enroll and complete online surveys.<br><br>RESULTS: During 2012 and 2013, the Registry identified 14,713 and 15,908 persons, respectively, who met the surveillance case definition of ALS. The estimated ALS prevalence rate was 4.7 cases per 100,000 U.S. population for 2012 and 5.0 per 100,000 for 2013. Due to revisions to the algorithm and use of death data from the National Death Index, an updated prevalence estimate has been calculated retrospectively for October 19, 2010-December 31, 2011. This updated estimate showed a prevalence rate of 4.3 per 100,000 population and a total of 13,282 cases. Since the inception of the Registry, the pattern of characteristics (e.g., age, sex, and race/ethnicity) among persons with ALS have remained unchanged. Overall, ALS was more common among whites, males, and persons aged 60-69 years. The age groups with the lowest number of ALS cases were persons aged 18-39 years and those aged &#x2265;80 years. Males had a higher prevalence rate of ALS than females overall and across all data sources. These findings remained consistent during October 2010-December 2013.<br><br>INTERPRETATION: The Registry is the only available data source that can be used to estimate the national prevalence for ALS in the United States. Use of both administrative national databases and self-report from patients enables a comprehensive approach to estimate ALS prevalence. The overall increase in the prevalence rate from 4.3 per 100,000 persons (revised) during 2010-2011 to 4.7 and 5.0 per 100,000 persons, respectively, during 2012-2013 likely is not an actual increase in the number of ALS cases. Rather, this increase might be attributed to improved case ascertainment due to the refinement of the algorithm used to identify definite ALS cases, along with an increased public awareness of the Registry. Registry estimates of ALS prevalence are consistent with findings from long-established ALS registries in Europe and from smaller-scale epidemiologic studies previously conducted in the United States.<br><br>PUBLIC HEALTH ACTIONS: Data collected by the National ALS Registry are being used to better describe the epidemiology of ALS in the United States and to help facilitate research. The combined approach of using national administrative databases and a self-enrollment web portal to collect data is novel and potentially could be used for other non-notifiable diseases such as Parkinson's disease or multiple sclerosis. Increased public awareness of the Registry might lead to more ALS cases being identified from the secure web portal (https://www.cdc.gov/als), which can ascertain cases apart from the national administrative databases. For example, in 2014, the ALS Ice Bucket Challenge, a social media-centered campaign, received extensive public visibility and created increased awareness of ALS. The Agency for Toxic Substances and Disease Registry (ATSDR) works closely with ALS advocacy and support groups, researchers, health care professionals, and others to promote the National ALS Registry and to identify all cases of ALS in the United States. In addition to estimating the prevalence of ALS, the Registry is being used to collect specimens from patient enrollees through a new biorepository, connect patient enrollees with new clinical trials and epidemiologic studies, and fund studies to help learn more about the etiology of ALS. Additional information about the National ALS Registry is available at http://www.cdc.gov/als or by calling toll-free at 1-877-442-9719.}, }
@article {pmid27481264, year = {2016}, author = {Gal, J and Kuang, L and Barnett, KR and Zhu, BZ and Shissler, SC and Korotkov, KV and Hayward, LJ and Kasarskis, EJ and Zhu, H}, title = {ALS mutant SOD1 interacts with G3BP1 and affects stress granule dynamics.}, journal = {Acta neuropathologica}, volume = {132}, number = {4}, pages = {563-576}, pmid = {27481264}, issn = {1432-0533}, support = {I01 BX002149/BX/BLRD VA/United States ; R01 NS077284/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Carrier Proteins/*genetics ; DNA Helicases ; Disease Models, Animal ; Inclusion Bodies/*metabolism/pathology ; Mice, Transgenic ; Motor Neurons/pathology ; Mutation/*genetics ; Poly-ADP-Ribose Binding Proteins ; RNA Helicases ; RNA Recognition Motif Proteins ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase-1/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Mutations in Cu/Zn superoxide dismutase (SOD1) are responsible for approximately 20 % of the familial ALS cases. ALS-causing SOD1 mutants display a gain-of-toxicity phenotype, but the nature of this toxicity is still not fully understood. The Ras GTPase-activating protein-binding protein G3BP1 plays a critical role in stress granule dynamics. Alterations in the dynamics of stress granules have been reported in several other forms of ALS unrelated to SOD1. To our surprise, the mutant G93A SOD1 transgenic mice exhibited pathological cytoplasmic inclusions that co-localized with G3BP1-positive granules in spinal cord motor neurons. The co-localization was also observed in fibroblast cells derived from familial ALS patient carrying SOD1 mutation L144F. Mutant SOD1, unlike wild-type SOD1, interacted with G3BP1 in an RNA-independent manner. Moreover, the interaction is specific for G3BP1 since mutant SOD1 showed little interaction with four other RNA-binding proteins implicated in ALS. The RNA-binding RRM domain of G3BP1 and two particular phenylalanine residues (F380 and F382) are critical for this interaction. Mutant SOD1 delayed the formation of G3BP1- and TIA1-positive stress granules in response to hyperosmolar shock and arsenite treatment in N2A cells. In summary, the aberrant mutant SOD1-G3BP1 interaction affects stress granule dynamics, suggesting a potential link between pathogenic SOD1 mutations and RNA metabolism alterations in ALS.}, }
@article {pmid27477403, year = {2016}, author = {Nakane, S and Izumi, Y and Oda, M and Kaji, R and Matsuo, H}, title = {A Potential Link between Amyotrophic Lateral Sclerosis and Bullous Pemphigoid: Six New Cases and a Systematic Review of the Literature.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {55}, number = {15}, pages = {1985-1990}, doi = {10.2169/internalmedicine.55.5578}, pmid = {27477403}, issn = {1349-7235}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications ; *Pemphigoid, Bullous/complications ; Time Factors ; }, abstract = {Objective Bullous pemphigoid in amyotrophic lateral sclerosis (BP-ALS) is rare and poorly understood. We herein assessed the association between ALS and BP using clinical and biological findings. Methods The clinical features of six new BP-ALS cases were described and collated with cases from a systematic literature review. Results Our six cases were combined with three other published cases. The mean disease duration (from ALS onset to the occurrence of BP) was 5.6±3.1 years. All patients had limb-onset ALS. Four of the 9 patients received riluzole, with the use of riluzole ranging from a few days to 3 years. When BP occurred, the status of the ALS patients was paretic and/or bedridden in all cases. BP occurred throughout the body, and we confirmed that the bullous lesions were located not only at the compression site, but also at the anterior part of the chest, abdomen, and limbs. Treatment for BP was successful, as oral prednisone and/or local corticosteroids were effective in 8 cases. Conclusion These six new cases, in combination with previous cases, expand our knowledge of the relationship between dermatological lesions and ALS. The pathogenesis of BP-ALS is poorly understood, however, some immunological aberrance is likely.}, }
@article {pmid27473339, year = {2016}, author = {Wise, JP and Cannon, J}, title = {From the Cover: Alterations in Optineurin Expression and Localization in Pre-clinical Parkinson's Disease Models.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {153}, number = {2}, pages = {372-381}, pmid = {27473339}, issn = {1096-0929}, support = {R00 ES019879/ES/NIEHS NIH HHS/United States ; R01 ES025750/ES/NIEHS NIH HHS/United States ; R03 ES022819/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Autophagy/drug effects ; Cell Cycle Proteins ; Corpus Striatum/metabolism ; *Disease Models, Animal ; Membrane Transport Proteins ; Mesencephalon/metabolism ; Parkinson Disease/*metabolism ; Rats ; Rats, Inbred Lew ; Rotenone/pharmacology ; Substantia Nigra/metabolism ; Transcription Factor TFIIIA/*metabolism ; alpha-Synuclein/metabolism ; }, abstract = {Parkinson's disease (PD) is a progressive neurodegenerative disease that affects ∼5 million people around the world. PD etiopathogenesis is poorly understood and curative or disease modifying treatments are not available. Mechanistic studies have identified numerous pathogenic pathways that overlap with many other neurodegenerative diseases. Mutations in the protein optineurin (OPTN) have recently been identified as causative factors for glaucoma and amyotrophic lateral sclerosis. OPTN has multiple recognized roles in neurons, notably in mediating autophagic flux, which has been found to be disrupted in most neurodegenerative diseases. OPTN(+)aggregates have preliminarily been identified in cytoplasmic inclusions in numerous neurodegenerative diseases, however, whether OPTN has a role in PD pathogenesis has yet to be tested. Thus, we chose to test the hypothesis that OPTN expression and localization would be modulated in pre-clinical PD models. To test our hypothesis, we characterized midbrain OPTN expression in normal rats and in a rat rotenone PD model. For the first time, we show that OPTN is enriched in dopamine neurons in the midbrain, and its expression is modulated by rotenone treatment in vivo Here, animals were sampled at time-points both prior to overt neurodegeneration and after severe behavioral deficits, where a lesion to the nigrostriatal dopamine system is present. The effect and magnitude of OPTN expression changes are dependent on duration of treatment. Furthermore, OPTN colocalizes with LC3 (autophagic vesicle marker) and alpha-synuclein positive puncta in rotenone-treated animals, potentially indicating an important role in autophagy and PD pathogenesis.}, }
@article {pmid27473302, year = {2016}, author = {Zheng, Q and Chu, L and Tan, L and Zhang, H}, title = {Facial onset sensory and motor neuronopathy.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {37}, number = {12}, pages = {1905-1909}, pmid = {27473302}, issn = {1590-3478}, mesh = {Databases, Bibliographic ; Face/*innervation ; Humans ; Motor Neuron Disease/*complications/*pathology ; Trigeminal Nerve/*physiopathology ; }, abstract = {Facial onset sensory and motor neuronopathy (FOSMN) is a recently defined slowly progressive motor neuron disorder. It is characterized by facial onset sensory abnormalities which may spread to the scalp, neck, upper trunk and extremities, followed by lower motor neuron deficits. Bulbar symptoms, such as dysarthria and dysphagia, muscle weakness, cramps and fasciculations, can present later in the course of the disease. We search the PubMed database for articles published in English from 2006 to 2016 using the term of "Facial onset sensory and motor neuronopathy". Reference lists of the identified articles were selected and reviewed. Only 38 cases of FOSMN have been reported in the Pubmed database since it was first reported in 2006. Typically, FOSMN present with slowly evolving numbness of the face followed by neck and arm weakness. Reduced or absent of corneal reflexes and blink reflex is the main pathognomonic features of FOSMN. In this review, we summarize the epidemiology, clinical presentation, auxiliary examination, and treatment of all the reported cases of FOSMN. Moreover, we discuss the pathogenesis of this rare disorder. In addition, we propose diagnostic criteria for FOSMN.}, }
@article {pmid27473149, year = {2016}, author = {Liachko, NF and Saxton, AD and McMillan, PJ and Strovas, TJ and Currey, HN and Taylor, LM and Wheeler, JM and Oblak, AL and Ghetti, B and Montine, TJ and Keene, CD and Raskind, MA and Bird, TD and Kraemer, BC}, title = {The phosphatase calcineurin regulates pathological TDP-43 phosphorylation.}, journal = {Acta neuropathologica}, volume = {132}, number = {4}, pages = {545-561}, pmid = {27473149}, issn = {1432-0533}, support = {P40 OD010440/OD/NIH HHS/United States ; R01 NS064131/NS/NINDS NIH HHS/United States ; T32 AG000057/AG/NIA NIH HHS/United States ; IK2 BX002243/BX/BLRD VA/United States ; I01 BX002619/BX/BLRD VA/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; P01 AG001751/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Brain/metabolism/pathology ; Caenorhabditis elegans ; Calcineurin/*metabolism ; DNA-Binding Proteins/metabolism ; Inclusion Bodies/pathology ; Neurons/metabolism/pathology ; Phosphoric Monoester Hydrolases/*metabolism ; Phosphorylation ; TDP-43 Proteinopathies/*metabolism/pathology ; }, abstract = {Detergent insoluble inclusions of TDP-43 protein are hallmarks of the neuropathology in over 90 % of amyotrophic lateral sclerosis (ALS) cases and approximately half of frontotemporal dementia (FTLD-TDP) cases. In TDP-43 proteinopathy disorders, lesions containing aggregated TDP-43 protein are extensively post-translationally modified, with phosphorylated TDP-43 (pTDP) being the most consistent and robust marker of pathological TDP-43 deposition. Abnormally phosphorylated TDP-43 has been hypothesized to mediate TDP-43 toxicity in many neurodegenerative disease models. To date, several different kinases have been implicated in the genesis of pTDP, but no phosphatases have been shown to reverse pathological TDP-43 phosphorylation. We have identified the phosphatase calcineurin as an enzyme binding to and catalyzing the removal of pathological C-terminal phosphorylation of TDP-43 in vitro. In C. elegans models of TDP-43 proteinopathy, genetic elimination of calcineurin results in accumulation of excess pTDP, exacerbated motor dysfunction, and accelerated neurodegenerative changes. In cultured human cells, treatment with FK506 (tacrolimus), a calcineurin inhibitor, results in accumulation of pTDP species. Lastly, calcineurin co-localizes with pTDP in degenerating areas of the central nervous system in subjects with FTLD-TDP and ALS. Taken together, these findings suggest calcineurin acts on pTDP as a phosphatase in neurons. Furthermore, patient treatment with calcineurin inhibitors may have unappreciated adverse neuropathological consequences.}, }
@article {pmid27470447, year = {2016}, author = {Riancho, J}, title = {Retinoids and PPAR agonists: Promising partners in neurodegenerative diseases?.}, journal = {Free radical biology &amp; medicine}, volume = {97}, number = {}, pages = {616-617}, doi = {10.1016/j.freeradbiomed.2016.07.024}, pmid = {27470447}, issn = {1873-4596}, mesh = {Animals ; Bexarotene ; Disease Models, Animal ; Gene Expression Regulation ; Humans ; Mice ; Neurodegenerative Diseases/*drug therapy/genetics/metabolism/pathology ; Neuroprotective Agents/*pharmacology ; PPAR gamma/*agonists/genetics/metabolism ; Receptors, Retinoic Acid/*agonists/genetics/metabolism ; Retinoid X Receptors/*agonists/genetics/metabolism ; Tetrahydronaphthalenes/*pharmacology ; Vitamin A/metabolism/pharmacology ; }, }
@article {pmid27464072, year = {2016}, author = {Tortelli, R and Seripa, D and Panza, F and Solfrizzi, V and Logroscino, G}, title = {Pharmacogenetics in Neurodegenerative Diseases: Implications for Clinical Trials.}, journal = {Frontiers of neurology and neuroscience}, volume = {39}, number = {}, pages = {124-135}, doi = {10.1159/000445453}, pmid = {27464072}, issn = {1662-2804}, mesh = {Cytochrome P-450 Enzyme System/*genetics ; Humans ; Neurodegenerative Diseases/*drug therapy/*therapy ; Neuroprotective Agents/*therapeutic use ; *Pharmacogenetics ; *Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Pharmacogenetics has become extremely important over the last 20 years for identifying individuals more likely to be responsive to pharmacological interventions. The role of genetic background as a predictor of drug response is a young and mostly unexplored field in neurodegenerative diseases.<br><br>SUMMARY: Mendelian mutations in neurodegenerative diseases have been used as models for early diagnosis and intervention. On the other hand, genetic polymorphisms or risk factors for late-onset Alzheimer's disease (AD) or other neurodegenerative diseases, probably influencing drug response, are hardly taken into account in randomized clinical trial (RCT) design. The same is true for genetic variants in cytochrome P450 (CYP), the principal enzymes influencing drug metabolism. A better characterization of individual genetic background may optimize clinical trial design and personal drug response. This chapter describes the state of the art about the impact of genetic factors in RCTs on neurodegenerative disease, with AD, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease as examples. Furthermore, a brief description of the genetic bases of drug response focusing on neurodegenerative diseases will be conducted.<br><br>KEY MESSAGES: The role of pharmacogenetics in RCTs for neurodegenerative diseases is still a young, unexplored, and promising field. Genetic tools allow increased sophistication in patient profiling and treatment optimization. Pharmaceutical companies are aware of the value of collecting genetic data during their RCTs. Pharmacogenetic research is bidirectional with RCTs: efficacy data are correlated with genetic polymorphisms, which in turn define subjects for treatment stratification.}, }
@article {pmid27463686, year = {2016}, author = {Beghi, E and Pupillo, E and Giussani, G}, title = {Peculiarities of Neurological Disorders and Study Designs.}, journal = {Frontiers of neurology and neuroscience}, volume = {39}, number = {}, pages = {8-23}, doi = {10.1159/000445409}, pmid = {27463686}, issn = {1662-2804}, mesh = {Clinical Trials as Topic/*methods ; Humans ; Nervous System Diseases/diagnosis/*therapy ; *Research Design ; }, abstract = {BACKGROUND: Neurological disorders are heterogeneous clinical conditions with variable course and outcome.<br><br>SUMMARY: The basic aspects of the commonest neurological disorders are addressed along with the proposed structure of randomized clinical trials (RCTs). Dementing disorders, including Alzheimer's disease (AD), are clinical conditions in which altered cognitive functions are associated with behavioral and personality changes. Parkinson's disease (PD) is a multisystem disorder characterized by motor dysfunction associated with dysautonomia, sleep and olfactory disturbances, cognitive changes, and depression. Amyotrophic lateral sclerosis (ALS) is an invariably fatal clinical condition involving motor neurons. The available treatments are purely symptomatic for PD but virtually ineffective for AD and ALS. Headache disorders, multiple sclerosis, and epilepsy, three diseases characterized by recurrent symptoms and chronic or episodic course, can be fairly easily controlled by current treatments, but cannot be prevented nor cured. The objectives of treatments of neurodegenerative disorders include primary prevention, slowing or arrest of disease progression, and control of symptoms. Stroke is an acute clinical condition causing frequent disability and death, with only one approved treatment. There are many challenges to acute stroke clinical trials; among them, the very short therapeutic window and the issue of stroke heterogeneity. In this chapter, only the core elements of the study designs are outlined.<br><br>KEY MESSAGES: The design of an RCT must be adapted to the basic characteristics of each clinical condition.}, }
@article {pmid27462978, year = {2016}, author = {Bruijn, LI and Kolb, S}, title = {The Right Therapy for Neurological Disorders: From Randomized Trials to Clinical Practice - Patients versus Investigator Expectations and Needs.}, journal = {Frontiers of neurology and neuroscience}, volume = {39}, number = {}, pages = {147-153}, doi = {10.1159/000445455}, pmid = {27462978}, issn = {1662-2804}, mesh = {Health Services Needs and Demand/*statistics &amp; numerical data ; Humans ; Nervous System Diseases/*psychology/*therapy ; *Randomized Controlled Trials as Topic ; Research Personnel/*psychology ; }, abstract = {BACKGROUND: People living with amyotrophic lateral sclerosis (ALS) are now more proactive in making decisions about their treatment options, in particular with increased awareness through social media and the Internet. Together with increased awareness about the disease comes increased frustration that there is still only one Food and Drug Administration (FDA)-approved drug that modestly improves survival.<br><br>SUMMARY: While efforts are underway to improve clinical trial design, patient involvement in trial design, clinical outcomes, and risk/benefit evaluations have become more recognized and will play a major role in the future success of clinical trials. This chapter addresses the perspective of people living with ALS and their perceptions of clinical trials. We describe various organizations and programs available that provide increased education and patient involvement.<br><br>KEY MESSAGE: Stronger partnerships between those living with ALS, clinicians, government, nonprofit organizations, and regulatory agencies will significantly impact treatment development.}, }
@article {pmid27454577, year = {2016}, author = {Dharmadasa, T and Matamala, JM and Kiernan, MC}, title = {Treatment approaches in motor neurone disease.}, journal = {Current opinion in neurology}, volume = {29}, number = {5}, pages = {581-591}, doi = {10.1097/WCO.0000000000000369}, pmid = {27454577}, issn = {1473-6551}, mesh = {*Disease Management ; Disease Progression ; Evidence-Based Medicine ; Humans ; Motor Neuron Disease/diagnosis/*drug therapy ; Neuroprotective Agents/*therapeutic use ; Noninvasive Ventilation ; *Quality of Life ; }, abstract = {PURPOSE OF REVIEW: Although there is no cure for motor neurone disease (MND), the advent of multidisciplinary care and neuroprotective agents has improved treatment interventions and enhanced quality of life for MND patients and their carers.<br><br>RECENT FINDINGS: Evidence-based multidisciplinary care, respiratory management and disease-modifying therapy have improved the outcomes of patients diagnosed with MND. Supportive approaches to nutritional maintenance and optimization of symptomatic treatments, including management of communication and neuropsychiatric issues, improve the quality of life for MND patients.<br><br>SUMMARY: Recent progress in the understanding of the clinical, pathophysiological and genetic heterogeneity of MND has improved the approach of clinicians to treatment. Notwithstanding improvement to care and quality of life, survival benefit has become evident with the advent of a multidisciplinary care framework, early treatment with riluzole and noninvasive ventilation. Weight maintenance remains critical, with weight loss associated with more rapid disease progression. The end-of-life phase is poorly defined and treatment is challenging, but effective symptom control through palliative care is achievable and essential. Encouragingly, current progress of clinical trials continues to close the gap towards the successful development of curative treatment in MND.}, }
@article {pmid27450455, year = {2016}, author = {Morgan, S and Orrell, RW}, title = {Pathogenesis of amyotrophic lateral sclerosis.}, journal = {British medical bulletin}, volume = {119}, number = {1}, pages = {87-98}, doi = {10.1093/bmb/ldw026}, pmid = {27450455}, issn = {1471-8391}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/drug therapy/*genetics/pathology/*physiopathology ; Anticonvulsants/therapeutic use ; C9orf72 Protein ; DNA-Binding Proteins ; Executive Function/drug effects ; Genome-Wide Association Study ; Humans ; Molecular Targeted Therapy/*trends ; Mutation/genetics ; Proteins ; RNA-Binding Protein FUS ; Riluzole/therapeutic use ; Superoxide Dismutase-1 ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) or motor neuron disease is a rapidly progressive neurodegenerative disorder. The primary involvement is of motor neurons in the brain, spinal cord and peripherally. There is secondary weakness of muscles and primary involvement of other brain regions, especially involving cognition.<br><br>SOURCES OF DATA: Peer-reviewed journal articles and reviews. PubMed.gov<br><br>AREAS OF AGREEMENT: The pathogenesis of ALS remains largely unknown. There are a wide range of potential mechanisms related to neurodegeneration. An increasing number of genetic factors are recognized.<br><br>AREAS OF CONTROVERSY: There remains controversy, or lack of knowledge, in explaining how cellular events manifest as the complex human disease. There is controversy as to how well cellular and animal models of disease relate to the human disease.<br><br>GROWING POINTS: Large-scale international collaborative genetic epidemiological studies are replacing local studies. Therapies related to pathogenesis remain elusive, with the greatest advances to date relating to provision of care (including multidisciplinary management) and supportive care (nutrition and respiratory support).<br><br>The identification of C9orf72 hexanucleotide repeats as the most frequent genetic background to ALS, and the association with frontotemporal dementia, gives the potential of a genetic background against which to study other risk factors, triggers and pathogenic mechanisms, and to develop potential therapies.}, }
@article {pmid27445967, year = {2016}, author = {Lecarpentier, Y and Vallée, A}, title = {Opposite Interplay between PPAR Gamma and Canonical Wnt/Beta-Catenin Pathway in Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {7}, number = {}, pages = {100}, pmid = {27445967}, issn = {1664-2295}, abstract = {The opposite interplay between peroxisome proliferator-activated receptor gamma (PPAR gamma) and Wnt/beta-catenin signaling has led to the categorization of neurodegenerative diseases (NDs) as either NDs in which PPAR gamma is downregulated while the canonical Wnt/beta-catenin pathway is upregulated [amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, multiple sclerosis, Friedreich's ataxia] or NDs in which PPAR gamma is upregulated while the canonical Wnt/beta-catenin signaling is downregulated (bipolar disorder, schizophrenia, Alzheimer's disease). ALS, a common adult-onset debilitating ND, is characterized by a chronic and progressive degeneration of upper and lower motor neurons resulting in muscular atrophy, paralysis, and ultimately death. The intent of this review is to provide an analysis of the integration of these two opposed systems, i.e., canonical Wnt/beta-catenin and PPAR gamma, in ALS. Understanding this integration may aid in the development of novel ALS therapies. Although the canonical Wnt/beta-catenin pathway is upregulated in ALS, riluzole, an enhancer of the canonical Wnt signaling, is classically prescribed in this disease in humans. However, studies carried out on ALS transgenic mice have shown beneficial effects after treatment by PPAR gamma agonists partly due to their anti-inflammatory effects.}, }
@article {pmid27426933, year = {2016}, author = {Shakhbazau, A and Potapnev, M}, title = {Autologous mesenchymal stromal cells as a therapeutic in ALS and epilepsy patients: Treatment modalities and ex vivo neural differentiation.}, journal = {Cytotherapy}, volume = {18}, number = {10}, pages = {1245-1255}, doi = {10.1016/j.jcyt.2016.06.001}, pmid = {27426933}, issn = {1477-2566}, mesh = {Adult ; Adult Stem Cells/pathology/physiology/transplantation ; Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Animals ; Cells, Cultured ; Epilepsy/physiopathology/*therapy ; Humans ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology/*physiology ; Neural Stem Cells/*physiology/transplantation ; Neurogenesis/*physiology ; Transplantation, Autologous ; }, abstract = {Stem cell therapy for incurable central nervous system disorders has long been viewed as a promising therapeutic option. In this review, we discuss the existing data and approaches on cell transplantation in the context of the neural differentiation potential of adult autologous stem cells, focusing on those of mesenchymal origin as easily accessible and well studied. Mesenchymal stromal cells (MSCs) are a heterogeneous cell population with a remarkable therapeutic plasticity, demonstrated by their ability to dampen inflammation, inhibit pathogenic immune responses and secrete neuroprotective factors. To demonstrate and discuss the broad therapeutic potential of MSCs, this review focuses on two examples of neurological conditions: amyotrophic lateral sclerosis and epilepsy. We review the lessons from animal models and clinical trials, and consider encouraging newly published clinical data on therapeutic applications of neurally induced MSCs.}, }
@article {pmid27421971, year = {2016}, author = {Marini, C and Cistaro, A and Campi, C and Calvo, A and Caponnetto, C and Nobili, FM and Fania, P and Beltrametti, MC and Moglia, C and Novi, G and Buschiazzo, A and Perasso, A and Canosa, A and Scialò, C and Pomposelli, E and Massone, AM and Bagnara, MC and Cammarosano, S and Bruzzi, P and Morbelli, S and Sambuceti, G and Mancardi, G and Piana, M and Chiò, A}, title = {A PET/CT approach to spinal cord metabolism in amyotrophic lateral sclerosis.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {43}, number = {11}, pages = {2061-2071}, pmid = {27421971}, issn = {1619-7089}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*diagnostic imaging/*metabolism ; Female ; Fluorodeoxyglucose F18/*pharmacokinetics ; Humans ; Image Interpretation, Computer-Assisted/methods ; Male ; Metabolic Clearance Rate ; Middle Aged ; Neuroimaging/methods ; Organ Specificity ; Positron Emission Tomography Computed Tomography/*methods ; Radiopharmaceuticals/pharmacokinetics ; Reproducibility of Results ; Sensitivity and Specificity ; Spinal Cord/*diagnostic imaging/*metabolism ; Tissue Distribution ; }, abstract = {PURPOSE: In amyotrophic lateral sclerosis, functional alterations within the brain have been intensively assessed, while progression of lower motor neuron damage has scarcely been defined. The aim of the present study was to develop a computational method to systematically evaluate spinal cord metabolism as a tool to monitor disease mechanisms.<br><br>METHODS: A new computational three-dimensional method to extract the spinal cord from (18)F-FDG PET/CT images was evaluated in 30 patients with spinal onset amyotrophic lateral sclerosis and 30 controls. The algorithm identified the skeleton on the CT images by using an extension of the Hough transform and then extracted the spinal canal and the spinal cord. In these regions, (18)F-FDG standardized uptake values were measured to estimate the metabolic activity of the spinal canal and cord. Measurements were performed in the cervical and dorsal spine and normalized to the corresponding value in the liver.<br><br>RESULTS: Uptake of (18)F-FDG in the spinal cord was significantly higher in patients than in controls (p&#x2009;<&#x2009;0.05). By contrast, no significant differences were observed in spinal cord and spinal canal volumes between the two groups. (18)F-FDG uptake was completely independent of age, gender, degree of functional impairment, disease duration and riluzole treatment. Kaplan-Meier analysis showed a higher mortality rate in patients with standardized uptake values above the fifth decile at the 3-year follow-up evaluation (log-rank test, p&#x2009;<&#x2009;0.01). The independence of this value was confirmed by multivariate Cox analysis.<br><br>CONCLUSION: Our computational three-dimensional method enabled the evaluation of spinal cord metabolism and volume and might represent a potential new window onto the pathophysiology of amyotrophic lateral sclerosis.}, }
@article {pmid27400786, year = {2016}, author = {Trias, E and Ibarburu, S and Barreto-Núñez, R and Babdor, J and Maciel, TT and Guillo, M and Gros, L and Dubreuil, P and Díaz-Amarilla, P and Cassina, P and Martínez-Palma, L and Moura, IC and Beckman, JS and Hermine, O and Barbeito, L}, title = {Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {13}, number = {1}, pages = {177}, pmid = {27400786}, issn = {1742-2094}, support = {R01 NS058628/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*complications/genetics/mortality ; Animals ; Benzamides ; Cell Death ; Disease Models, Animal ; Disease Progression ; Encephalitis/*drug therapy/*etiology ; Humans ; Male ; Motor Neurons/drug effects/metabolism ; Mutation/genetics ; Neuroglia/drug effects/metabolism ; Paralysis/*drug therapy/*etiology ; Piperidines ; Protein Kinase Inhibitors/*therapeutic use ; Pyridines ; Rats ; Rats, Transgenic ; Spinal Cord/pathology ; Superoxide Dismutase/genetics ; Thiazoles/*therapeutic use ; }, abstract = {BACKGROUND: In the SOD1(G93A) mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS.<br><br>METHODS: The cellular effects of pharmacological inhibition of tyrosine kinases with masitinib were analyzed in cell cultures of microglia isolated from aged symptomatic SOD1(G93A) rats. To determine whether masitinib prevented the appearance of aberrant glial cells or modified post-paralysis survival, the drug was orally administered at 30&#xa0;mg/kg/day starting after paralysis onset.<br><br>RESULTS: We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations. In microglia cultures from symptomatic SOD1(G93A) spinal cords, masitinib prevented CSF-induced proliferation, cell migration, and the expression of inflammatory mediators. Oral administration of masitinib to SOD1(G93A) rats starting after paralysis onset decreased the number of aberrant glial cells, microgliosis, and motor neuron pathology in the degenerating spinal cord, relative to vehicle-treated rats. Masitinib treatment initiated 7&#xa0;days after paralysis onset prolonged post-paralysis survival by 40&#xa0;%.<br><br>CONCLUSIONS: These data show that masitinib is capable of controlling microgliosis and the emergence/expansion of aberrant glial cells, thus providing a strong biological rationale for its use to control neuroinflammation in ALS. Remarkably, masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS.}, }
@article {pmid27400686, year = {2016}, author = {Picher-Martel, V and Valdmanis, PN and Gould, PV and Julien, JP and Dupré, N}, title = {From animal models to human disease: a genetic approach for personalized medicine in ALS.}, journal = {Acta neuropathologica communications}, volume = {4}, number = {1}, pages = {70}, pmid = {27400686}, issn = {2051-5960}, support = {//CIHR/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/physiopathology/*therapy ; Animals ; Genetic Therapy ; Humans ; *Precision Medicine/methods ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.}, }
@article {pmid27400329, year = {2017}, author = {de Tommaso, M and Kunz, M and Valeriani, M}, title = {Therapeutic approach to pain in neurodegenerative diseases: current evidence and perspectives.}, journal = {Expert review of neurotherapeutics}, volume = {17}, number = {2}, pages = {143-153}, doi = {10.1080/14737175.2016.1210512}, pmid = {27400329}, issn = {1744-8360}, mesh = {Alzheimer Disease/physiopathology/therapy ; Humans ; Neurodegenerative Diseases/*physiopathology ; *Pain/physiopathology ; *Pain Management ; Parkinson Disease/physiopathology/therapy ; }, abstract = {Neurodegenerative diseases are increasing in parallel to the lengthening of survival. The management of Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD) and PD-related disorders, and motor neuron diseases (MND), is mainly targeted to motor and cognitive impairment, with special care for vital functions such as breathing and feeding. Areas covered: The present review focuses on chronic pain in main neurodegenerative diseases, addressing current evidence on pain therapeutic management, pain frequency and clinical features, and possible pathophysiological mechanisms. The search on PubMed had no time limits and was performed by searching for the following key issues: pain, dementia, Alzheimer disease, Parkinson's disease, extrapyramidal disorders, motoneuronal disease, Amyotrophic lateral sclerosis, FXTAS, frequency, pathophysiology, treatments, therapy, efficacy, opioids, side effects. No controlled therapeutic trials and guidelines are currently available. The effects of current therapies such as L-Dopa or riluzole on pain symptoms are not clear. Emerging evidences on the possible anti-nociceptive effects of cannabis or botulinum toxin might be available soon. Expert commentary: Pain needs to be better evaluated and fully considered in the global management of neurodegenerative disease because a more focused treatment may have a positive impact on the global burden of these devastating disorders.}, }
@article {pmid27389143, year = {2016}, author = {DeCoteau, W and Heckman, KL and Estevez, AY and Reed, KJ and Costanzo, W and Sandford, D and Studlack, P and Clauss, J and Nichols, E and Lipps, J and Parker, M and Hays-Erlichman, B and Leiter, JC and Erlichman, JS}, title = {Cerium oxide nanoparticles with antioxidant properties ameliorate strength and prolong life in mouse model of amyotrophic lateral sclerosis.}, journal = {Nanomedicine : nanotechnology, biology, and medicine}, volume = {12}, number = {8}, pages = {2311-2320}, doi = {10.1016/j.nano.2016.06.009}, pmid = {27389143}, issn = {1549-9642}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Catalase/metabolism ; Cerium/administration &amp; dosage/*pharmacology ; Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Mice, Transgenic ; *Nanoparticles ; Oxidative Stress ; Oxidoreductases/metabolism ; }, abstract = {Cerium oxide nanoparticles (CeNPs) neutralize reactive oxygen and nitrogen species. Since oxidative stress plays a role in amyotrophic lateral sclerosis (ALS) in humans and in the SOD1[G93A] mouse model of ALS, we tested whether administration of CeNPs would improve survival and reduce disease severity in SOD1[G93A] transgenic mice. Twice a week intravenous treatment of SOD1[G93A] mice with CeNPs started at the onset of muscle weakness preserved muscle function and increased longevity in males and females. Median survival after the onset of CeNP treatment was 33.0±3.7days (N=20), and only 22.0±2.5days in mice treated with vehicle, control injections (N=27; P=0.022). Since these citrate-EDTA stabilized CeNPs exhibited catalase and oxidase activity in cell-free systems and in in vitro models of ischemic oxidative stress, we hypothesize that antioxidant activity is the protective mechanism prolonging survival in the SOD1[G93A] mice.}, }
@article {pmid27383643, year = {2016}, author = {Vázquez-Costa, JF and Máñez, I and Alabajos, A and Guevara Salazar, M and Roda, C and Sevilla, T}, title = {Safety and efficacy of botulinum toxin A for the treatment of spasticity in amyotrophic lateral sclerosis: results of a pilot study.}, journal = {Journal of neurology}, volume = {263}, number = {10}, pages = {1954-1960}, pmid = {27383643}, issn = {1432-1459}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*complications/drug therapy ; Botulinum Toxins, Type A/*therapeutic use ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Muscle Spasticity/*drug therapy/*etiology ; Neuromuscular Agents/*therapeutic use ; Pilot Projects ; Retrospective Studies ; Severity of Illness Index ; *Treatment Outcome ; }, abstract = {Spasticity can be a very disabling problem in some amyotrophic lateral sclerosis (ALS) phenotypes, such as upper motor neuron-dominant ALS (UMN-D ALS) and primary lateral sclerosis (PLS). Our aim is to describe the safety and efficacy of botulinum toxin A (BoTox-A) for improving gait in those ALS phenotypes. UMN-D ALS and PLS outpatients experiencing gait disturbances, secondary to moderate-to-severe spasticity despite optimized oral medication, were offered BoTox-A treatment. Stretching exercises were indicated to complement BoTox-A effect, and ankle-foot orthotics were prescribed when appropriate. Tolerance (muscle strength, disease progression rate) and efficacy (10-m walk test) were measured at baseline and after treatment. Eight out of 122 ALS outpatients were offered BoTox-A treatment. One declined and the other seven were administered BoTox-A in the lower limbs, every 5-8 months. All of them experienced improvement in the clinical outcome and all but one referred subjective improvement. Moreover, after a median follow-up of 16 months and three injections, BoTox-A effect was maintained with no adverse events. This study provides class IV evidence that BoTox-A is safe , and could be beneficial in the short term and long term in a subset of ALS patients with moderate-to-severe spasticity.}, }
@article {pmid27383069, year = {2016}, author = {Iwai, Y and Shibuya, K and Misawa, S and Sekiguchi, Y and Watanabe, K and Amino, H and Kuwabara, S}, title = {Axonal Dysfunction Precedes Motor Neuronal Death in Amyotrophic Lateral Sclerosis.}, journal = {PloS one}, volume = {11}, number = {7}, pages = {e0158596}, pmid = {27383069}, issn = {1932-6203}, mesh = {Action Potentials/physiology ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*physiopathology ; Axons/*physiology ; Cell Death ; Electric Stimulation ; Female ; Humans ; Male ; Median Nerve/*physiopathology ; Middle Aged ; Motor Neurons/*physiology ; Muscles/innervation ; Potassium Channels/metabolism ; Sodium Channels/metabolism ; Time Factors ; Wrist/innervation ; }, abstract = {Wide-spread fasciculations are a characteristic feature in amyotrophic lateral sclerosis (ALS), suggesting motor axonal hyperexcitability. Previous excitability studies have shown increased nodal persistent sodium conductances and decreased potassium currents in motor axons of ALS patients, both of the changes inducing hyperexcitability. Altered axonal excitability potentially contributes to motor neuron death in ALS, but the relationship of the extent of motor neuronal death and abnormal excitability has not been fully elucidated. We performed multiple nerve excitability measurements in the median nerve at the wrist of 140 ALS patients and analyzed the relationship of compound muscle action potential (CMAP) amplitude (index of motor neuronal loss) and excitability indices, such as strength-duration time constant, threshold electrotonus, recovery cycle and current-threshold relationships. Compared to age-matched normal controls (n = 44), ALS patients (n = 140) had longer strength-duration time constant (SDTC: a measure of nodal persistent sodium current; p < 0.05), greater threshold changes in depolarizing threshold electrotonus (p < 0.05) and depolarizing current threshold relationship (i.e. less accommodation; (p < 0.05), greater superexcitability (a measure of fast potassium current; p < 0.05) and reduced late subexcitability (a measure of slow potassium current; p < 0.05), suggesting increased persistent sodium currents and decreased potassium currents. The reduced potassium currents were found even in the patient subgroups with normal CMAP (> 5mV). Regression analyses showed that SDTC (R = -0.22) and depolarizing threshold electrotonus (R = -0.22) increased with CMAP decline. These findings suggest that motor nerve hyperexcitability occurs in the early stage of the disease, and precedes motor neuronal loss in ALS. Modulation of altered ion channel function could be a treatment option for ALS.}, }
@article {pmid27374287, year = {2016}, author = {Nakatani, Y and Amano, T and Takeda, H}, title = {Corticosterone Inhibits the Proliferation of C6 Glioma Cells via the Translocation of Unphosphorylated Glucocorticoid Receptor.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {39}, number = {7}, pages = {1121-1129}, doi = {10.1248/bpb.b16-00017}, pmid = {27374287}, issn = {1347-5215}, mesh = {Animals ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Corticosterone/*pharmacology ; Glioma/metabolism ; Hormone Antagonists/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mifepristone/pharmacology ; Rats ; Receptors, Glucocorticoid/*metabolism ; Receptors, Mineralocorticoid/metabolism ; Spironolactone/pharmacology ; }, abstract = {Astroglial cells have been considered to have passive brain function by helping to maintain neurons. However, recent studies have revealed that the dysfunction of such passive functions may be associated with various neuropathological diseases, such as schizophrenia, Alzheimer's disease, amyotrophic lateral sclerosis and major depression. Corticosterone (CORT), which is often referred to as the stress hormone, is a well-known regulator of peripheral immune responses and also shows anti-inflammatory properties in the brain. However, it is still obscure how CORT affects astroglial cell function. In this study, we investigated the effects of CORT on the proliferation and survival of astroglial cells using C6 glioma cells. Under treatment with CORT for 24h, the proliferation of C6 glioma cells decreased in a dose-dependent manner. Moreover, this inhibition was diminised by treatment with mifepristone, a glucocorticoid receptor (GR) antagonist, but not by spironolactone, a mineralocorticoid receptor (MR) antagonist, and was independent of GR phosphorylation and other GR-related intracellular signaling cascades. Furthermore, it was observed that the translocation of GR from the cytosol to the nucleus was promoted by the treatment with CORT. These results indicate that CORT decreases the proliferation of C6 glioma cells by modifying the transcription of a particular gene related to cell proliferation independent of GR phosphorylation.}, }
@article {pmid27372362, year = {2016}, author = {Jani, MP and Gore, GB}, title = {Swallowing characteristics in Amyotrophic Lateral Sclerosis.}, journal = {NeuroRehabilitation}, volume = {39}, number = {2}, pages = {273-276}, doi = {10.3233/NRE-161357}, pmid = {27372362}, issn = {1878-6448}, mesh = {Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Cough/*etiology/physiopathology ; Deglutition/*physiology ; Deglutition Disorders/*etiology/physiopathology ; Electromyography ; Female ; Humans ; Male ; Middle Aged ; Muscle, Skeletal/physiopathology ; Neural Conduction/physiology ; Reflex/*physiology ; Symptom Assessment ; }, abstract = {BACKGROUND: Motor neurone disease also commonly known as Amyotrophic Lateral Sclerosis (ALS) is a neurological condition which affects various motor functions of the body. Dysphagia (disordered swallowing) is commonly seen in patients with ALS having bulbar symptoms.<br><br>OBJECTIVES: Research reveals presence of dysphagia in patients with ALS at various stages of swallowing using instrumental assessment. However, very few studies have been done focussing on clinical profiling of swallowing in these patients. Hence, a need was felt to profile the specific characteristics.<br><br>METHODOLOGY: Five patients diagnosed with ALS were assessed for presence of swallowing disorder using a swallowing checklist which focussed on assessing each stage of swallowing.<br><br>RESULTS: Results revealed that patients with ALS exhibit difficulties in oral preparatory, oral and pharyngeal stages of swallowing. Inability to hold bolus, reduced mastication, residue in the oral cavity and nasal regurgitation while swallow were observed due to the affected oromotor functions. Swallow reflex was delayed in all the patients. Cough before and during swallow was also observed.<br><br>CONCLUSION: Dysphagia is a common symptom in patients with ALS and occurs due to the affected oromotor functions. Specific information of the stages of swallowing helps in planning treatment in clinical practice.}, }
@article {pmid27368295, year = {2016}, author = {Lam, L and Chin, L and Halder, RC and Sagong, B and Famenini, S and Sayre, J and Montoya, D and Rubbi, L and Pellegrini, M and Fiala, M}, title = {Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {30}, number = {10}, pages = {3461-3473}, pmid = {27368295}, issn = {1530-6860}, support = {P50 AR063020/AR/NIAMS NIH HHS/United States ; T32 GM008553/GM/NIGMS NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Cytokines/*metabolism ; *Epigenesis, Genetic ; Female ; Humans ; Leukocytes, Mononuclear/*metabolism ; Macrophages/metabolism ; Male ; Middle Aged ; Monocytes/*metabolism ; Neurons/metabolism ; Rats ; Spinal Cord/metabolism ; T-Lymphocytes/*metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {We have investigated transcriptional and epigenetic differences in peripheral blood mononuclear cells (PBMCs) of monozygotic female twins discordant in the diagnosis of amyotrophic lateral sclerosis (ALS). Exploring DNA methylation differences by reduced representation bisulfite sequencing (RRBS), we determined that, over time, the ALS twin developed higher abundances of the CD14 macrophages and lower abundances of T cells compared to the non-ALS twin. Higher macrophage signature in the ALS twin was also shown by RNA sequencing (RNA-seq). Moreover, the twins differed in the methylome at loci near several genes, including EGFR and TNFRSF11A, and in the pathways related to the tretinoin and H3K27me3 markers. We also tested cytokine production by PBMCs. The ALS twin's PBMCs spontaneously produced IL-6 and TNF-α, whereas PBMCs of the healthy twin produced these cytokines only when stimulated by superoxide dismutase (SOD)-1. These results and flow cytometric detection of CD45 and CD127 suggest the presence of memory T cells in both twins, but effector T cells only in the ALS twin. The ALS twin's PBMC supernatants, but not the healthy twin's, were toxic to rat cortical neurons, and this toxicity was strongly inhibited by an IL-6 receptor antibody (tocilizumab) and less well by TNF-α and IL-1β antibodies. The putative neurotoxicity of IL-6 and TNF-α is in agreement with a high expression of these cytokines on infiltrating macrophages in the ALS spinal cord. We hypothesize that higher macrophage abundance and increased neurotoxic cytokines have a fundamental role in the phenotype and treatment of certain individuals with ALS.-Lam, L., Chin, L., Halder, R. C., Sagong, B., Famenini, S., Sayre, J., Montoya, D., Rubbi L., Pellegrini, M., Fiala, M. Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients.}, }
@article {pmid27362330, year = {2016}, author = {Garbuzova-Davis, S and Thomson, A and Kurien, C and Shytle, RD and Sanberg, PR}, title = {Potential new complication in drug therapy development for amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {16}, number = {12}, pages = {1397-1405}, pmid = {27362330}, issn = {1744-8360}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; *Disease Models, Animal ; Humans ; Pharmaceutical Preparations ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration in the brain and spinal cord. Treatment development for ALS is complicated by complex underlying disease factors. Areas covered: Numerous tested drug compounds have shown no benefits in ALS patients, although effective in animal models. Discrepant results of pre-clinical animal studies and clinical trials for ALS have primarily been attributed to limitations of ALS animal models for drug-screening studies and methodological inconsistencies in human trials. Current status of pre-clinical and clinical trials in ALS is summarized. Specific blood-CNS barrier damage in ALS patients, as a novel potential reason for the clinical failures in drug therapies, is discussed. Expert commentary: Pathological perivascular collagen IV accumulation, one unique characteristic of barrier damage in ALS patients, could be hindering transport of therapeutics to the CNS. Restoration of B-CNS-B integrity would foster delivery of therapeutics to the CNS.}, }
@article {pmid27358335, year = {2016}, author = {Glass, JD and Hertzberg, VS and Boulis, NM and Riley, J and Federici, T and Polak, M and Bordeau, J and Fournier, C and Johe, K and Hazel, T and Cudkowicz, M and Atassi, N and Borges, LF and Rutkove, SB and Duell, J and Patil, PG and Goutman, SA and Feldman, EL}, title = {Transplantation of spinal cord-derived neural stem cells for ALS: Analysis of phase 1 and 2 trials.}, journal = {Neurology}, volume = {87}, number = {4}, pages = {392-400}, pmid = {27358335}, issn = {1526-632X}, support = {R01 NS077982/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Age of Onset ; Amyotrophic Lateral Sclerosis/*therapy ; Cervical Vertebrae ; Female ; Humans ; Immunosuppressive Agents/adverse effects/therapeutic use ; Lumbosacral Region ; Male ; Middle Aged ; Neural Stem Cells/*transplantation ; Spinal Cord/*surgery ; Stem Cell Transplantation/adverse effects/*methods ; Treatment Outcome ; }, abstract = {OBJECTIVE: To test the safety of spinal cord transplantation of human stem cells in patients with amyotrophic lateral sclerosis (ALS) with escalating doses and expansion of the trial to multiple clinical centers.<br><br>METHODS: This open-label trial included 15 participants at 3 academic centers divided into 5 treatment groups receiving increasing doses of stem cells by increasing numbers of cells/injection and increasing numbers of injections. All participants received bilateral injections into the cervical spinal cord (C3-C5). The final group received injections into both the lumbar (L2-L4) and cervical cord through 2 separate surgical procedures. Participants were assessed for adverse events and progression of disease, as measured by the ALS Functional Rating Scale-Revised, forced vital capacity, and quantitative measures of strength. Statistical analysis focused on the slopes of decline of these phase 2 trial participants alone or in combination with the phase 1 participants (previously reported), comparing these groups to 3 separate historical control groups.<br><br>RESULTS: Adverse events were mostly related to transient pain associated with surgery and to side effects of immunosuppressant medications. There was one incident of acute postoperative deterioration in neurologic function and another incident of a central pain syndrome. We could not discern differences in surgical outcomes between surgeons. Comparisons of the slopes of decline with the 3 separate historical control groups showed no differences in mean rates of progression.<br><br>CONCLUSIONS: Intraspinal transplantation of human spinal cord-derived neural stem cells can be safely accomplished at high doses, including successive lumbar and cervical procedures. The procedure can be expanded safely to multiple surgical centers.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with ALS, spinal cord transplantation of human stem cells can be safely accomplished and does not accelerate the progression of the disease. This study lacks the precision to exclude important benefit or safety issues.}, }
@article {pmid27357213, year = {2016}, author = {Leman, P and Morley, P}, title = {Review article: Updated resuscitation guidelines for 2016: A summary of the Australian and New Zealand Committee on Resuscitation recommendations.}, journal = {Emergency medicine Australasia : EMA}, volume = {28}, number = {4}, pages = {379-382}, doi = {10.1111/1742-6723.12638}, pmid = {27357213}, issn = {1742-6723}, mesh = {Australia ; Evidence-Based Medicine ; Humans ; New Zealand ; Resuscitation/*standards ; }, abstract = {This review paper summarises the key changes made to the resuscitation guidelines used in Australia and New Zealand. They were released by the Australian and New Zealand Committee on Resuscitation in January 2016. These are local adaptations of the evidence previously published in October 2015 by the International Liaison Committee on Resuscitation (ILCOR). They are presented across the main working groups in ILCOR: ALS, BLS, paediatrics, neonates, acute coronary syndromes, first aid and 'Education, Implementation and Teams'.}, }
@article {pmid27356036, year = {2016}, author = {Blasco, H and Patin, F and Andres, CR and Corcia, P and Gordon, PH}, title = {Amyotrophic Lateral Sclerosis, 2016: existing therapies and the ongoing search for neuroprotection.}, journal = {Expert opinion on pharmacotherapy}, volume = {17}, number = {12}, pages = {1669-1682}, doi = {10.1080/14656566.2016.1202919}, pmid = {27356036}, issn = {1744-7666}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/genetics ; Biomarkers/metabolism ; Clinical Trials as Topic ; Frontotemporal Dementia/diagnosis/drug therapy/genetics ; Humans ; Hydroxylamines/therapeutic use ; Memantine/therapeutic use ; Neuroprotective Agents/*therapeutic use ; Riluzole/therapeutic use ; Superoxide Dismutase/genetics/metabolism ; Vitamin B 12/analogs &amp; derivatives/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS), one in a family of age-related neurodegenerative disorders, is marked by predominantly cryptogenic causes, partially elucidated pathophysiology, and elusive treatments. The challenges of ALS are illustrated by two decades of negative drug trials.<br><br>AREAS COVERED: In this article, we lay out the current understanding of disease genesis and physiology in relation to drug development in ALS, stressing important accomplishments and gaps in knowledge. We briefly consider clinical ALS, the ongoing search for biomarkers, and the latest in trial design, highlighting major recent and ongoing clinical trials; and we discuss, in a concluding section on future directions, the prion-protein hypothesis of neurodegeneration and what steps can be taken to end the drought that has characterized drug discovery in ALS.<br><br>EXPERT OPINION: Age-related neurodegenerative disorders are fast becoming major public health problems for the world's aging populations. Several agents offer promise in the near-term, but drug development is hampered by an interrelated cycle of obstacles surrounding etiological, physiological, and biomarkers discovery. It is time for the type of government-funded, public-supported offensive on neurodegenerative disease that has been effective in other fields.}, }
@article {pmid27353839, year = {2016}, author = {McDermott, CJ and Bradburn, MJ and Maguire, C and Cooper, CL and Baird, WO and Baxter, SK and Cohen, J and Cantrill, H and Dixon, S and Ackroyd, R and Baudouin, S and Bentley, A and Berrisford, R and Bianchi, S and Bourke, SC and Darlison, R and Ealing, J and Elliott, M and Fitzgerald, P and Galloway, S and Hamdalla, H and Hanemann, CO and Hughes, P and Imam, I and Karat, D and Leek, R and Maynard, N and Orrell, RW and Sarela, A and Stradling, J and Talbot, K and Taylor, L and Turner, M and Simonds, AK and Williams, T and Wedzicha, W and Young, C and Shaw, PJ}, title = {DiPALS: Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis - a randomised controlled trial.}, journal = {Health technology assessment (Winchester, England)}, volume = {20}, number = {45}, pages = {1-186}, doi = {10.3310/hta20450}, pmid = {27353839}, issn = {2046-4924}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; 09/55/33/DH_/Department of Health/United Kingdom ; SHAW/APR15/933-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L01629X/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*complications ; Cost-Benefit Analysis ; *Diaphragm ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Noninvasive Ventilation/*methods ; Quality of Life ; Respiratory Insufficiency/*etiology/*therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting in death, usually from respiratory failure, within 2-3 years of symptom onset. Non-invasive ventilation (NIV) is a treatment that when given to patients in respiratory failure leads to improved survival and quality of life. Diaphragm pacing (DP), using the NeuRx/4(®) diaphragm pacing system (DPS)™ (Synapse Biomedical, Oberlin, OH, USA), is a new technique that may offer additional or alternative benefits to patients with ALS who are in respiratory failure.<br><br>OBJECTIVE: The Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis (DiPALS) trial evaluated the effect of DP on survival over the study duration in patients with ALS with respiratory failure.<br><br>DESIGN: The DiPALS trial was a multicentre, parallel-group, open-label, randomised controlled trial incorporating health economic analyses and a qualitative longitudinal substudy.<br><br>PARTICIPANTS: Eligible participants had a diagnosis of ALS (ALS laboratory-supported probable, clinically probable or clinically definite according to the World Federation of Neurology revised El Escorial criteria), had been stabilised on riluzole for 30 days, were aged &#x2265;&#x2009;18 years and were in respiratory failure. We planned to recruit 108 patients from seven UK-based specialist ALS or respiratory centres. Allocation was performed using 1&#x2009;:&#x2009;1 non-deterministic minimisation.<br><br>INTERVENTIONS: Participants were randomised to either standard care (NIV alone) or standard care (NIV) plus DP using the NeuRX/4 DPS.<br><br>MAIN OUTCOME MEASURES: The primary outcome was overall survival, defined as the time from randomisation to death from any cause. Secondary outcomes were patient quality of life [assessed by European Quality of Life-5 Dimensions, three levels (EQ-5D-3L), Short Form questionnaire-36 items and Sleep Apnoea Quality of Life Index questionnaire]; carer quality of life (EQ-5D-3L and Caregiver Burden Inventory); cost-utility analysis and health-care resource use; tolerability and adverse events. Acceptability and attitudes to DP were assessed in a qualitative substudy.<br><br>RESULTS: In total, 74 participants were randomised into the trial and analysed, 37 participants to NIV plus pacing and 37 to standard care, before the Data Monitoring and Ethics Committee advised initial suspension of recruitment (December 2013) and subsequent discontinuation of pacing (on safety grounds) in all patients (June 2014). Follow-up assessments continued until the planned end of the study in December 2014. The median survival (interquartile range) was 22.5 months (lower quartile 11.8 months; upper quartile not reached) in the NIV arm and 11.0 months (6.7 to 17.0 months) in the NIV plus pacing arm, with an adjusted hazard ratio of 2.27 (95% confidence interval 1.22 to 4.25; p&#x2009;=&#x2009;0.01).<br><br>CONCLUSIONS: Diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure.<br><br>FUTURE WORK: It may be that certain population subgroups benefit from DP. We are unable to explain the mechanism behind the excess mortality in the pacing arm, something the small trial size cannot help address. Future research should investigate the mechanism by which harm or benefit occurs further.<br><br>TRIAL REGISTRATION: Current Controlled Trials ISRCTN53817913.<br><br>FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 45. See the HTA programme website for further project information. Additional funding was provided by the Motor Neurone Disease Association of England, Wales and Northern Ireland.}, }
@article {pmid27349438, year = {2017}, author = {Mis, MSC and Brajkovic, S and Tafuri, F and Bresolin, N and Comi, GP and Corti, S}, title = {Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders.}, journal = {Molecular neurobiology}, volume = {54}, number = {6}, pages = {4466-4476}, pmid = {27349438}, issn = {1559-1182}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; C9orf72 Protein/*genetics ; Frontotemporal Dementia/genetics/*therapy ; Genetic Therapy ; Humans ; Oligonucleotides, Antisense/therapeutic use ; RNA Interference ; }, abstract = {The identification of the hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in the non-coding region of the C9ORF72 gene as the most frequent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has opened the path for advances in the knowledge and treatment of these disorders, which remain incurable. Recent evidence suggests that HRE RNA can cause gain-of-function neurotoxicity, but haploinsufficiency has also been hypothesized. In this review, we describe the recent developments in therapeutic targeting of the pathological expansion of C9ORF72 for ALS, FTD, and other neurodegenerative disorders. Three approaches are prominent: (1) an antisense oligonucleotides/RNA interference strategy; (2) using small compounds to counteract the toxic effects directly exerted by RNA derived from the repeat transcription (foci), by the translation of dipeptide repeat proteins (DPRs) from the repeated sequence, or by the sequestration of RNA-binding proteins from the C9ORF72 expansion; and (3) gene therapy, not only for silencing the toxic RNA/protein, but also for rescuing haploinsufficiency caused by the reduced transcription of the C9ORF72 coding sequence or by the diminished availability of RNA-binding proteins that are sequestered by RNA foci. Finally, with the perspective of clinical therapy, we discuss the most promising progress that has been achieved to date in the field.}, }
@article {pmid27328427, year = {2016}, author = {Prosser, JM and Fieve, RR}, title = {Patients receiving lithium therapy have a reduced prevalence of neurological and cardiovascular disorders.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {71}, number = {}, pages = {39-44}, doi = {10.1016/j.pnpbp.2016.06.006}, pmid = {27328427}, issn = {1878-4216}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Cardiovascular Diseases/*epidemiology/*prevention &amp; control ; Female ; Humans ; Lithium Compounds/adverse effects/*therapeutic use ; Male ; Middle Aged ; Nervous System Diseases/*epidemiology/*prevention &amp; control ; New York City/epidemiology ; Odds Ratio ; Prevalence ; Retrospective Studies ; Young Adult ; }, abstract = {A variety of evidence from laboratory and animal studies suggests that lithium has neurotrophic and cytoprotective properties, and may ameliorate or prevent some disease states. We investigated whether such a protective effect can be observed in human psychiatric patients receiving lithium therapy. We carried out a retrospective chart review of 1028 adult psychiatric male and female outpatients attending four lithium clinics in metropolitan New York City. Patients were divided into two groups based on lithium usage, and the prevalence of neurological and cardiovascular disorders was compared. The main outcome measures were the occurrence in the two patient groups of a variety of neurological disorders and myocardial infarction. Odds ratios were calculated to assess the risk of having a disorder for patients receiving lithium compared to patients not receiving lithium: for seizures, the odds ratio was 0.097; for amyotrophic lateral sclerosis, the odds ratio was 0.112; for dementia not otherwise specified, the odds ratio was 0.112; and for myocardial infarction, the odds ratio was 0.30. Logistical regression analysis showed that lithium treatment is a significant negative predictive factor in the prevalence of each of these disease states, when age, duration of clinic attendance, and use of anti-psychotic medications are taken into account. Our results show that patients receiving regular lithium treatment have a reduced prevalence of some neurological disorders and myocardial infarctions. One possible explanation of these results is that a protective effect of lithium observed in laboratory and animal studies may also be present in human patients receiving regular lithium therapy.}, }
@article {pmid27323697, year = {2016}, author = {Crescimanno, G and Greco, F and Arrisicato, S and Morana, N and Marrone, O}, title = {Effects of positive end expiratory pressure administration during non-invasive ventilation in patients affected by amyotrophic lateral sclerosis: A randomized crossover study.}, journal = {Respirology (Carlton, Vic.)}, volume = {21}, number = {7}, pages = {1307-1313}, doi = {10.1111/resp.12836}, pmid = {27323697}, issn = {1440-1843}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/physiopathology/*therapy ; Cross-Over Studies ; Female ; Heart Rate ; Humans ; Male ; Middle Aged ; *Noninvasive Ventilation ; Polysomnography ; *Positive-Pressure Respiration ; Respiration ; Sleep/physiology ; }, abstract = {BACKGROUND AND OBJECTIVE: No studies have evaluated the impact of different settings of non-invasive ventilation (NIV) in patients affected by amyotrophic lateral sclerosis (ALS). We explored consequences of positive end-expiratory pressure (PEEP) application on effectiveness of ventilation, sleep architecture and heart rate variability (HRV) in patients with ALS naïve to ventilatory treatment.<br><br>METHODS: In two consecutive nights, 25 patients received in random order 0 or 4&#x2009;cm&#x2009;H2 0 of PEEP during nocturnal NIV administration (Idea Ultra ResMed) with the same level of total positive inspiratory pressure. Polysomnographies were performed to evaluate sleep and NIV quality, as well as HRV. HRV was analyzed on 4-h periods and on 5-min segments of stable NREM sleep.<br><br>RESULTS: We did not observe differences in gas exchanges during NIV with and without PEEP. Conversely, during PEEP application increases in leaks (41.4&#x2009;&#xb1;&#x2009;29.3% vs 31.0&#x2009;&#xb1;&#x2009;25.7%, P&#x2009;=&#x2009;0.0007) and in autotriggerings (4.2 (IQR 1.3-10.0) vs 0.9 (IQR 0.0-3.0) events/h, P&#x2009;<&#x2009;0.001, PEEP vs no PEEP, respectively) occurred. Besides, N3 sleep stage duration decreased (2.5% (IQR 0.0-18.0) vs 0.0% (IQR0.0-12.1), P&#x2009;=&#x2009;0.001) and arousal/awakening index increased (16.9&#x2009;&#xb1;&#x2009;7.4 vs 13.4&#x2009;&#xb1;&#x2009;5.0 events/h, P&#x2009;=&#x2009;0.01). Data on HRV were available in 15 patients. A higher low/high frequency ratio, either in the 4-h (3.8&#x2009;&#xb1;&#x2009;2.6 vs 2.9&#x2009;&#xb1;&#x2009;1.7, P&#x2009;=&#x2009;0.04, PEEP vs no PEEP, respectively) or in the 5-min segments (2.6&#x2009;&#xb1;&#x2009;1.8 vs 1.45&#x2009;&#xb1;&#x2009;0.9 P&#x2009;=&#x2009;0.01) was found during PEEP administration.<br><br>CONCLUSION: In ALS patients, PEEP application during NIV was associated with worse NIV and sleep quality and with higher sympathetic activity.}, }
@article {pmid27323612, year = {2016}, author = {Tang, ML and Du, BX and Chen, ZY and Chen, X and Liu, SR and Liu, YP and Huang, RH and Liu, B}, title = {[Correlation between Fractional Anisotropy and Amyotrophic Lateral Sclerosis, and Effect of Inte- grative Medical Treatment on ALS].}, journal = {Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine}, volume = {36}, number = {4}, pages = {421-424}, pmid = {27323612}, issn = {1003-5370}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Anisotropy ; *Diffusion Tensor Imaging ; Humans ; Integrative Medicine ; }, abstract = {OBJECTIVE: To explore whether fractional anisotropy (FA) value could be taken as a quantitative indicator for tracing and reexamining amyotrophic lateral sclerosis (ALS), and to analyze the correlation between FA value and integrative medical treatment.<br><br>METHODS: Totally 18 ALS patients were recruited in this study. All patients received diffusion tensor imaging (DTI) using 3. OT (Propeller HD) MRI twice. Six regions of interest (ROI) were selected to measure FA values. Survival analyses were performed in 11 cases of end point events.<br><br>RESULTS: (1) Three ROI (cerebral peduncle, posterior limb of internal capsule, and corona radiata) all indicated that FA value was the highest in patients with mild health status scale of amyotrophic lateral sclerosis (ALS/HSS). (2) There was statistical difference in the means of FA values in cerebral peduncle, posterior limb of internal capsule, and corona radiata of 18 cases between initial examination and reexamination (P < 0.01). (3) Kaplan-Meier survival curve showed the survival rate of ALS patients decreased as time went by, with the median survival time of 48 months.<br><br>CONCLUSIONS: FA value was inversely proportional to the severity of ALS, the more severe, the lower FA values. FA value was an objective indicator for assessing the severity of ALS. ALS is an incurable disease till now. Integrative medical treatment might become one direction for ALS patients.}, }
@article {pmid27315438, year = {2016}, author = {Stevic, Z and Kostic-Dedic, S and Peric, S and Dedic, V and Basta, I and Rakocevic-Stojanovic, V and Lavrnic, D}, title = {Prognostic factors and survival of ALS patients from Belgrade, Serbia.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {17}, number = {7-8}, pages = {508-514}, doi = {10.1080/21678421.2016.1195410}, pmid = {27315438}, issn = {2167-9223}, mesh = {Adult ; Age Distribution ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*diagnosis/epidemiology/*mortality ; Female ; Humans ; Kaplan-Meier Estimate ; Longitudinal Studies ; Male ; Middle Aged ; Predictive Value of Tests ; Retrospective Studies ; Serbia/epidemiology ; Sex Distribution ; Young Adult ; }, abstract = {Our aim was to assess the incidence, survival and its prognostic factors in ALS patients from the area of the City of Belgrade, Serbia. A retrospective analysis included 325 probable or definite ALS cases from all five Belgrade neurology departments in the period 1992-2009. Each patient was regularly followed up during the disease until death or until 31 December 2009. Results showed that the average annual ALS incidence rate was 1.11 per 100,000 inhabitants. Male predominance was registered, except for patients with ALS onset after the age of 80 years. Mean survival from the first symptoms was 4.4 ± 0.2 years. Cumulative probability of survival was 71% for two years, 24% for five years, and 17% for seven years. Patients with diagnostic delay longer than 1.6 years had a 1.4-times better chance for survival (p <0.01). Spinal-onset patients on riluzole therapy had 1.8-times better survival (p < 0.01). Patients with early-onset ALS and higher ALSFRS-R score at initial evaluation also had somewhat better survival (p < 0.05). In conclusion, the average annual ALS incidence rate was 1.11 per 100,000 inhabitants. Longer survival was observed in patients with early onset, longer diagnostic delay, less functional impairment at the time of diagnosis, and riluzole treatment.}, }
@article {pmid27311955, year = {2016}, author = {Marques, AS and Bedia, C and Lima, KMG and Tauler, R}, title = {Assessment of the effects of As(III) treatment on cyanobacteria lipidomic profiles by LC-MS and MCR-ALS.}, journal = {Analytical and bioanalytical chemistry}, volume = {408}, number = {21}, pages = {5829-5841}, doi = {10.1007/s00216-016-9695-5}, pmid = {27311955}, issn = {1618-2650}, mesh = {Anabaena/drug effects/metabolism/ultrastructure ; Arsenic/*metabolism ; Chlorophyll/*metabolism ; Chromatography, High Pressure Liquid/methods ; Cyanobacteria/*drug effects/metabolism/ultrastructure ; Environmental Pollutants/*metabolism ; Least-Squares Analysis ; Lipid Metabolism/*drug effects ; Mass Spectrometry/methods ; Multivariate Analysis ; }, abstract = {Cyanobacteria are a group of photosynthetic, nitrogen-fixing bacteria present in a wide variety of habitats such as freshwater, marine, and terrestrial ecosystems. In this work, the effects of As(III), a major toxic environmental pollutant, on the lipidomic profiles of two cyanobacteria species (Anabaena and Planktothrix agardhii) were assessed by means of a recently proposed method based on the concept of regions of interest (ROI) in liquid chromatography mass spectroscopy (LC-MS) together with multivariate curve resolution alternating least squares (MCR-ALS). Cyanobacteria were exposed to two concentrations of As(III) for a week, and lipid extracts were analyzed by ultrahigh-performance liquid chromatography/time-of-flight mass spectrometry in full scan mode. The data obtained were compressed by means of the ROI strategy, and the resulting LC-MS data sets were analyzed by the MCR-ALS method. Comparison of profile peak areas resolved by MCR-ALS in control and exposed samples allowed the discrimination of lipids whose concentrations were changed due to As(III) treatment. The tentative identification of these lipids revealed an important reduction of the levels of some galactolipids such as monogalactosyldiacylglycerol, the pigment chlorophyll a and its degradation product, pheophytin a, as well as carotene compounds such as 3-hydroxycarotene and carotene-3,3'-dione, all of these compounds being essential in the photosynthetic process. These results suggested that As(III) induced important changes in the composition of lipids of cyanobacteria, which were able to compromise their energy production processes. Graphical abstract Steps of the proposed LC-MS + MCR-ALS procedure.}, }
@article {pmid27302727, year = {2016}, author = {Huang, Z and Adachi, H}, title = {Natural Compounds Preventing Neurodegenerative Diseases Through Autophagic Activation.}, journal = {Journal of UOEH}, volume = {38}, number = {2}, pages = {139-148}, doi = {10.7888/juoeh.38.139}, pmid = {27302727}, issn = {0387-821X}, mesh = {Alzheimer Disease/pathology ; Amyotrophic Lateral Sclerosis ; Autophagy/*drug effects ; Humans ; Huntington Disease/pathology ; Machado-Joseph Disease/pathology ; Muscular Disorders, Atrophic/pathology ; Neurodegenerative Diseases/*therapy ; Parkinson Disease/pathology ; Plant Extracts/*pharmacology ; }, abstract = {Neurodegenerative diseases (NDDs) are a group of intractable diseases that significantly affect human health. To date, the pathogenesis of NDDs is still poorly understood and effective disease-modifying therapies for NDDs have not been established. NDDs share the common morphological characteristic of the deposition of abnormal proteins in the nervous system, including neurons. Autophagy is one of the major processes by which damaged organelles and abnormal proteins are removed from cells. Impairment of autophagy has been found to be involved in the pathogenesis of NDDs, and the regulation of autophagy may become a therapeutic strategy for NDDs. In recent years, some active compounds from plants have been found to regulate autophagy and exert neuroprotection against NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal and bulbar muscular atrophy, spinocerebellar ataxia 3, and amyotrophic lateral sclerosis, via activating autophagy. In this paper, we review recent advances in the use of active ingredients from plants for the regulation of autophagy and treatment of NDDs.}, }
@article {pmid27298447, year = {2016}, author = {Pulst, SM}, title = {Degenerative ataxias, from genes to therapies: The 2015 Cotzias Lecture.}, journal = {Neurology}, volume = {86}, number = {24}, pages = {2284-2290}, pmid = {27298447}, issn = {1526-632X}, mesh = {Animals ; Humans ; Spinocerebellar Ataxias/*genetics/physiopathology/*therapy ; }, abstract = {OBJECTIVE: To review progress in spinocerebellar ataxias (SCAs) and novel approaches to treatment.<br><br>RESULTS AND CONCLUSIONS: Autosomal dominant ataxias are now referred to as SCAs, with polyglutamine expansion mutations constituting the most common cause of SCAs. Phenotypic variation in patients with SCA is remarkable even in patients with identical mutations. In patients with SCA2, cerebellar ataxia is typically associated with slowed saccadic eye movements. In addition to classic cerebellar and brainstem signs, however, SCA2 can also present as a parkinsonian syndrome or as amyotrophic lateral sclerosis. After identifying the SCA2 gene (gene symbol ATXN2) in 1996, we generated several mouse models that recapitulated salient features of the human disease. In these models, behavioral and physiologic changes preceded cell death. Modified antisense oligonucleotides (ASOs) provide a unique tool to target mRNA transcripts in vivo with extended stability of ASOs and better activation of RNAse H. We generated methoxyethyl group-gapmer ASOs that reduced ATXN2 expression >80% in vitro and then progressed the lead ASO to in vivo testing in an SCA2 mouse model. Compared to intraventricular injection of saline, treatment with ASO resulted in significant knockdown of endogenous mouse and human transgenic ATXN2. In addition, progression of the motor phenotype was slowed and Purkinje cell firing in the acute cerebellar slice normalized. ASO-based therapies are underway in humans providing hope that this approach will also be applicable to patients with cerebellar degenerations.}, }
@article {pmid27287895, year = {2016}, author = {Simoncini, T and Russo, E and Mannella, P and Giannini, A}, title = {Robotic-assisted apical lateral suspension for advanced pelvic organ prolapse: surgical technique and perioperative outcomes.}, journal = {Surgical endoscopy}, volume = {30}, number = {12}, pages = {5647-5655}, pmid = {27287895}, issn = {1432-2218}, mesh = {Aged ; Female ; Humans ; Laparoscopy/*methods ; Middle Aged ; Operative Time ; Pelvic Organ Prolapse/*surgery ; Quality of Life ; *Robotic Surgical Procedures ; *Surgical Mesh ; Visual Analog Scale ; }, abstract = {BACKGROUND: Abdominal sacral hystero-cervicopexy (ASC) is the gold standard for the treatment of apical prolapse, but requires advanced laparoscopic skills and exposes to potentially life-threatening complications. Lateral apical suspension to the abdominal wall with mesh is a feasible alternative of ASC where robotic assistance may offer specific advantages. We here describe the surgical technique and the short-term outcomes of robotic-assisted lateral apical suspension (R-ALS) with the use of a titan-covered T-shaped mesh.<br><br>METHODS: Forty consecutive patients with stage III or IV symptomatic anterior and apical pelvic organ prolapse underwent R-ALS between September 2014 and September 2015.<br><br>RESULTS: R-ALS was completed without complications in all cases with a mean operative time of 117&#xa0;&#xb1;&#xa0;26&#xa0;min. From a technical standpoint, robotic assistance allowed for an extremely reproducible technique, with a swift learning curve and consistent length of the surgical steps. The procedure was extremely well tolerated and resulted in complete resolution of POP-associated symptoms and in improvements of POP- and incontinence-related quality-of-life scores (PQOL and IIQ7) at 1&#xa0;month from surgery.<br><br>CONCLUSIONS: R-ALS is feasible, safe, well-tolerated and effective at a short-term follow-up. R-ALS may represent an effective and simple alternative to abdominal sacral hystero-cervicopexy for the treatment of high-grade apical and anterior POP, avoiding the challenges of sacral mesh fixation. Robotic assistance helps achieving optimally tailored anatomic reconstruction, allowing seamless deep pelvic dissection and suturing.}, }
@article {pmid27284291, year = {2016}, author = {Chen, Y and Liu, XH and Wu, JJ and Ren, HM and Wang, J and Ding, ZT and Jiang, YP}, title = {Proteomic analysis of cerebrospinal fluid in amyotrophic lateral sclerosis.}, journal = {Experimental and therapeutic medicine}, volume = {11}, number = {6}, pages = {2095-2106}, pmid = {27284291}, issn = {1792-0981}, abstract = {The present study used comparative proteomic analysis of cerebrospinal fluid (CSF) in amyotrophic lateral sclerosis (ALS) patients in order to identify proteins that may act as diagnostic biomarkers and indicators of the pathogenesis of ALS. This analysis was performed using isobaric tags for relative and absolute quantitation (iTRAQ) technology, coupled with 2-dimensional liquid chromatography/mass spectrometry. Database for Annotation, Visualization and Integrated Discovery software was utilized for bioinformatic analysis of the data. Following this, western blotting was performed in order to examine the expression of 3 candidate proteins in ALS patients compared with healthy individuals [as a normal control (NC) group] or patients with other neurological disease (OND); these proteins were insulin-like growth factor II (IGF-2), glutamate receptor 4 (GRIA4) and leucine-rich α-2-glycoprotein 1 (LRG1). Clinical data, including gender, age, disease duration and ALS functional rating scale (ALSFRS-R) score, were also collected in the ALS patients. Multiple linear regression analysis was performed between the clinical data and the results of western blot analysis. A total of 248 distinct proteins were identified in the ALS and NC groups, amongst which a significant difference could be identified in 35 proteins; of these, 21 proteins were downregulated and 14 were upregulated. These differentially-expressed proteins were thus revealed to be associated with ALS. The western blot analysis confirmed a proportion of the data attained in the iTRAQ analysis, revealing the differential protein expression of IGF-2 and GRIA4 between the ALS and NC groups. IGF-2 was significantly downregulated in ALS patients (P=0.017) and GRIA4 was significantly upregulated (P=0.016). These results were subsequently validated in the 35-patient ALS and OND groups (P=0.002), but no significant difference was identified in LRG1 expression between these groups. GRIA4 protein expression was higher in male than female patients and was positively correlated with the ALSFRS-R score, meaning that GRIA4 expression was negatively correlated with the severity of ALS, while IGF-2 and LRG1 expression did not correlate with any clinical data. The present study thus demonstrated that GRIA4 expression levels, as a marker of severity, may be used as a reference for the timing of treatment, and that IGF-2 may serve as an effective biomarker of ALS progression.}, }
@article {pmid27276999, year = {2016}, author = {Hammond, FM and Alexander, DN and Cutler, AJ and D'Amico, S and Doody, RS and Sauve, W and Zorowitz, RD and Davis, CS and Shin, P and Ledon, F and Yonan, C and Formella, AE and Siffert, J}, title = {PRISM II: an open-label study to assess effectiveness of dextromethorphan/quinidine for pseudobulbar affect in patients with dementia, stroke or traumatic brain injury.}, journal = {BMC neurology}, volume = {16}, number = {}, pages = {89}, pmid = {27276999}, issn = {1471-2377}, mesh = {Aged ; Brain Injuries, Traumatic/complications ; Dementia/complications ; Dextromethorphan/administration &amp; dosage/*therapeutic use ; Drug Administration Schedule ; Drug Combinations ; Excitatory Amino Acid Antagonists/administration &amp; dosage/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Pseudobulbar Palsy/complications/*drug therapy ; Quinidine/administration &amp; dosage/*therapeutic use ; Severity of Illness Index ; Stroke/complications ; Treatment Outcome ; }, abstract = {BACKGROUND: Phase 3 trials supporting dextromethorphan/quinidine (DM/Q) use as a treatment for pseudobulbar affect (PBA) were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). The PRISM II study provides additional DM/Q experience with PBA secondary to dementia, stroke, or traumatic brain injury (TBI).<br><br>METHODS: Participants in this open-label, multicenter, 90-day trial received DM/Q 20/10&#xa0;mg twice daily. The primary outcome was the Center for Neurologic Study-Lability Scale (CNS-LS), assessing change in PBA episode frequency and severity. The CNS-LS final visit score was compared to baseline (primary analysis) and to the response in a previously conducted placebo-controlled trial with DM/Q in patients with ALS or MS. Secondary outcomes included change in PBA episode count and Clinical Global Impression of Change with respect to PBA as rated by a clinician (CGI-C) and by the patient or caregiver (PGI-C).<br><br>RESULTS: The study enrolled 367 participants with PBA secondary to dementia, stroke, or TBI. Mean (standard deviation [SD]) CNS-LS score improved significantly from 20.4 (4.4) at baseline to 12.8 (5.0) at Day 90/Final Visit (change, -7.7 [6.1]; P&#x2009;<&#x2009;.001, 95&#xa0;% CI: -8.4, -7.0). This magnitude of improvement was consistent with DM/Q improvement in the earlier phase-3, placebo-controlled trial (mean [95&#xa0;% CI] change from baseline, -8.2 [-9.4, -7.0]) and numerically exceeds the improvement seen with placebo in that study (-5.7 [-6.8, -4.7]). Reduction in PBA episode count was 72.3&#xa0;% at Day 90/Final Visit compared with baseline (P&#x2009;<&#x2009;.001). Scores on CGI-C and PGI-C showed that 76.6 and 72.4&#xa0;% of participants, respectively, were "much" or "very much" improved with respect to PBA. The most frequently occurring adverse events (AEs) were diarrhea (5.4&#xa0;%), headache (4.1&#xa0;%), urinary tract infection (2.7&#xa0;%), and dizziness (2.5&#xa0;%); 9.8&#xa0;% had AEs that led to discontinuation. Serious AEs were reported in 6.3&#xa0;%; however, none were considered treatment related.<br><br>CONCLUSIONS: DM/Q was shown to be an effective and well-tolerated treatment for PBA secondary to dementia, stroke, or TBI. The magnitude of PBA improvement was similar to that reported in patients with PBA secondary to ALS or MS, and the adverse event profile was consistent with the known safety profile of DM/Q.<br><br>TRIAL REGISTRATION: Clinicaltrials.gov, NCT01799941, registered on 25 February 2013.}, }
@article {pmid27275785, year = {2016}, author = {Blasco, H and Vourc'h, P and Pradat, PF and Gordon, PH and Andres, CR and Corcia, P}, title = {Further development of biomarkers in amyotrophic lateral sclerosis.}, journal = {Expert review of molecular diagnostics}, volume = {16}, number = {8}, pages = {853-868}, doi = {10.1080/14737159.2016.1199277}, pmid = {27275785}, issn = {1744-8352}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/*genetics/*metabolism ; *Biomarkers ; Biomedical Research ; Genome-Wide Association Study ; Genomics/methods ; Humans ; Metabolomics/methods ; Multimodal Imaging ; Neuroimaging/methods ; Proteomics/methods ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an idiopathic neurodegenerative disease usually fatal in less than three years. Even if standard guidelines are available to diagnose ALS, the mean diagnosis delay is more than one year. In this context, biomarker discovery is a priority. Research has to focus on new diagnostic tools, based on combined explorations.<br><br>AREAS COVERED: In this review, we specifically focus on biology and imaging markers. We detail the innovative field of 'omics' approach and imaging and explain their limits to be useful in routine practice. We describe the most relevant biomarkers and suggest some perspectives for biomarker research. Expert commentary: The successive failures of clinical trials in ALS underline the need for new strategy based on innovative tools to stratify patients and to evaluate their responses to treatment. Biomarker data may be useful to improve the designs of clinical trials. Biomarkers are also needed to better investigate disease pathophysiology, to identify new therapeutic targets, and to improve the performance of clinical assessments for diagnosis and prognosis in the clinical setting. A consensus on the best management of neuroimaging and 'omics' methods is necessary and a systematic independent validation of findings may add robustness to future studies.}, }
@article {pmid27261461, year = {2016}, author = {Álvarez-Zaldiernas, C and Lu, J and Zheng, Y and Yang, H and Blasi, J and Solsona, C and Holmgren, A}, title = {Cellular Redox Systems Impact the Aggregation of Cu,Zn Superoxide Dismutase Linked to Familial Amyotrophic Lateral Sclerosis.}, journal = {The Journal of biological chemistry}, volume = {291}, number = {33}, pages = {17197-17208}, pmid = {27261461}, issn = {1083-351X}, mesh = {Amino Acid Substitution ; *Amyotrophic Lateral Sclerosis/enzymology/genetics ; Animals ; Cell Line, Tumor ; Glutaredoxins/genetics/metabolism ; Humans ; Mutation, Missense ; Oxidation-Reduction ; *Oxidative Stress ; *Protein Aggregation, Pathological/enzymology/genetics ; *Protein Folding ; Rats ; *Superoxide Dismutase-1/genetics/metabolism ; Thioredoxins/genetics/metabolism ; }, abstract = {Protein misfolding is implicated in neurodegenerative diseases such as ALS, where mutations of superoxide dismutase 1 (SOD1) account for about 20% of the inherited mutations. Human SOD1 (hSOD1) contains four cysteines, including Cys(57) and Cys(146), which have been linked to protein stability and folding via forming a disulfide bond, and Cys(6) and Cys(111) as free thiols. But the roles of the cellular oxidation-reduction (redox) environment in SOD1 folding and aggregation are not well understood. Here we explore the effects of cellular redox systems on the aggregation of hSOD1 proteins. We found that the known hSOD1 mutations G93A and A4V increased the capability of the thioredoxin and glutaredoxin systems to reduce hSOD1 compared with wild-type hSOD1. Treatment with inhibitors of these redox systems resulted in an increase of hSOD1 aggregates in the cytoplasm of cells transfected with mutants but not in cells transfected with wild-type hSOD1 or those containing a secondary C111G mutation. This aggregation may be coupled to changes in the redox state of the G93A and A4V mutants upon mild oxidative stress. These results strongly suggest that the thioredoxin and glutaredoxin systems are the key regulators for hSOD1 aggregation and may play critical roles in the pathogenesis of ALS.}, }
@article {pmid27250836, year = {2016}, author = {Solomonov, Y and Hadad, N and Levy, R}, title = {Reduction of cytosolic phospholipase A2α upregulation delays the onset of symptoms in SOD1G93A mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {13}, number = {1}, pages = {134}, pmid = {27250836}, issn = {1742-2094}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology/*prevention &amp; control ; Animals ; Brain Stem/metabolism/pathology ; *Disease Models, Animal ; Group IV Phospholipases A2/antagonists &amp; inhibitors/*biosynthesis ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/*biosynthesis/genetics ; Up-Regulation/*physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by selective death of motor neurons in the cortex, brainstem, and spinal cord. Cytosolic phospholipase A2 alpha (cPLA2α) upregulation and activation in the spinal cord of patients with sporadic ALS and in the spinal cord of human mutant SOD1G93A (hmSOD1) transgenic mice were recently reported.<br><br>METHODS: cPLA2&#x3b1; upregulation in the brainstem and spinal cord was reduced by brain infusion of a specific antisense oligonucleotide against cPLA2&#x3b1; (AS), and the effect was evaluated on disease progression and brain cell activation.<br><br>RESULTS: We found that the elevation of cPLA2&#x3b1; protein expression in the spinal cord was first detected at 6-week-old hmSOD1 mice and remained elevated during their whole life span. Reduction of the elevated expression of cPLA2&#x3b1; in the spinal cord of hmSOD1 mice by brain infusion of an AS at week 15 (shortly before the appearance of the disease symptoms), for a duration of 6&#xa0;weeks, delayed the loss of motor neuron function in comparison with hmSOD1 mice and with sense brain-infused hmSOD1 mice. To characterize the effect of cPLA2&#x3b1; upregulation on different processes taking place at the appearance of the disease symptoms, mice were brain infused with AS or with sense at week 15 for 3-4&#xa0;weeks. The AS treatment that reduced cPLA2&#x3b1; upregulation in the spinal cord of AS-treated hmSOD1 mice (as analyzed at week 18-19) prevented the reduction in the number of the neurons (detected by NeuN) and inhibited astrocyte activation (detected by GFAP) and microglia activation (detected by Iba-1 and by CD40). In addition, AS treatment blunted the upregulation of the proinflammatory enzyme-inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) detected in hmSOD1 mice.<br><br>CONCLUSIONS: Since specific reduction of cPLA2&#x3b1; in the brainstem and spinal cord significantly attenuated the development of the disease, cPLA2&#x3b1; may offer an efficient target for treatment of ALS.}, }
@article {pmid27249331, year = {2016}, author = {Geevasinga, N and Menon, P and Ng, K and Van Den Bos, M and Byth, K and Kiernan, MC and Vucic, S}, title = {Riluzole exerts transient modulating effects on cortical and axonal hyperexcitability in ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {17}, number = {7-8}, pages = {580-588}, doi = {10.1080/21678421.2016.1188961}, pmid = {27249331}, issn = {2167-9223}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/*pathology ; Evoked Potentials, Motor/drug effects/*physiology ; Female ; Humans ; Male ; Middle Aged ; Motor Cortex/*physiopathology ; Neuroprotective Agents/*therapeutic use ; Prospective Studies ; Reaction Time/drug effects ; Riluzole/*therapeutic use ; Severity of Illness Index ; Transcranial Magnetic Stimulation ; }, abstract = {Riluzole is an established therapy for amyotrophic lateral sclerosis (ALS), although its effects are modest, prolonging survival by three months on average. While the neuroprotective effects of riluzole appear to be mediated by inhibition of glutaminergic transmission and antagonization of Na[+] channel function, the duration of these effects remains to be elucidated. Consequently, the present study combined assessment of cortical and peripheral function to determine the longitudinal effects of riluzole in ALS patients. Assessment of cortical function by threshold tracking transcranial magnetic stimulation (TMS) combined with peripheral nerve function excitability studies were longitudinally undertaken on 19 sporadic ALS patients, with assessment occurring at baseline, four, eight, and 12 weeks post riluzole initiation. Baseline results were compared to 31 healthy controls. Results showed that, at baseline, cortical hyperexcitability was a feature of ALS as indicated by a marked reduction in averaged short interval intracortical inhibition [SICI] (3.6 ± 6.9%, p < 0.0001) and cortical silent period duration (p < 0.05) as well as an increase in motor evoked potential amplitude (p < 0.05). Riluzole therapy resulted in individual patient increase in SICI of 4.3% (p < 0.01) and 5.2% (p < 0.01) at four and eight weeks, respectively. At a peripheral level, riluzole therapy lead to a transient increase at four weeks in the relative refractory period (p < 0.05), superexcitability (p < 0.05) and late subexcitability (p < 0.05), all of which returned to baseline levels eight weeks after initiation of riluzole. In conclusion, the present study has established that riluzole exerts transient effects on cortical and axonal hyperexcitability, potentially accounting for the modest clinical effectiveness in ALS.}, }
@article {pmid27245439, year = {2016}, author = {Wormser, U and Mandrioli, J and Vinceti, M and Fini, N and Sintov, A and Brodsky, B and Proskura, E and Finkelstein, Y}, title = {Reduced levels of alpha-1-antitrypsin in cerebrospinal fluid of amyotrophic lateral sclerosis patients: a novel approach for a potential treatment.}, journal = {Journal of neuroinflammation}, volume = {13}, number = {1}, pages = {131}, pmid = {27245439}, issn = {1742-2094}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*cerebrospinal fluid/diagnosis/*therapy ; Biomarkers/cerebrospinal fluid ; Female ; Humans ; Interleukin-23/*cerebrospinal fluid ; Male ; Middle Aged ; alpha 1-Antitrypsin/*cerebrospinal fluid ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative motor neuron disease that involves activation of the immune system and inflammatory response in the nervous system. Reduced level of the immuno-modulatory and anti-inflammatory protein alpha-1-antitrypsin (AAT) is associated with inflammation-related pathologies. The objective of the present is to determine AAT levels and IL-23 in the cerebrospinal fluid (CSF) of ALS patients and control group.<br><br>FINDINGS: CSF samples from newly diagnosed ALS patients and age-matched controls were analyzed for AAT and IL-23 by ELISA and magnetic luminex screening, respectively. A statistically significant reduction of 45&#xa0;% in mean AAT levels was observed in the CSF of ALS patients (21.4&#xa0;&#x3bc;g/ml) as compared to the control group (mean 38.8&#xa0;&#x3bc;g/ml, p&#x2009;=&#x2009;0.013). A statistically significant increase of 30.8&#xa0;% in CSF mean levels of the pro-inflammatory cytokine IL-23 was observed in ALS patients (1647&#xa0;pg/ml) in comparison to the controls (1259&#xa0;pg/ml, p&#x2009;=&#x2009;0.012). A negative correlation coefficient (r&#x2009;=&#x2009;-0.543) was obtained by linear regression analysis of the two measured parameters (p&#x2009;=&#x2009;0.036).<br><br>CONCLUSIONS: Reduced AAT and elevated IL-23 CSF levels support the notion of neuroinflammatory process occurring in ALS patients. Increasing AAT levels in the patients' nervous system should be further investigated as a new therapeutic approach and a novel potential tool for ALS treatment.}, }
@article {pmid27244217, year = {2016}, author = {Fogh, I and Lin, K and Tiloca, C and Rooney, J and Gellera, C and Diekstra, FP and Ratti, A and Shatunov, A and van Es, MA and Proitsi, P and Jones, A and Sproviero, W and Chiò, A and McLaughlin, RL and Sorarù, G and Corrado, L and Stahl, D and Del Bo, R and Cereda, C and Castellotti, B and Glass, JD and Newhouse, S and Dobson, R and Smith, BN and Topp, S and van Rheenen, W and Meininger, V and Melki, J and Morrison, KE and Shaw, PJ and Leigh, PN and Andersen, PM and Comi, GP and Ticozzi, N and Mazzini, L and D'Alfonso, S and Traynor, BJ and Van Damme, P and Robberecht, W and Brown, RH and Landers, JE and Hardiman, O and Lewis, CM and van den Berg, LH and Shaw, CE and Veldink, JH and Silani, V and Al-Chalabi, A and Powell, J}, title = {Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis.}, journal = {JAMA neurology}, volume = {73}, number = {7}, pages = {812-820}, pmid = {27244217}, issn = {2168-6157}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; RC2 NS070342/NS/NINDS NIH HHS/United States ; MRF_MRF-060-0003-RG-SMITH/MRF/MRF/United Kingdom ; R01 NS073873/NS/NINDS NIH HHS/United States ; JONES/OCT15/958-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MC_G1000733/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; R01 NS050557/NS/NINDS NIH HHS/United States ; G0900688/MRC_/Medical Research Council/United Kingdom ; SMITH/APR16/847-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; 070122/A/02/Z/WT_/Wellcome Trust/United Kingdom ; ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*genetics/*mortality ; Calcium-Binding Proteins/*genetics ; Cohort Studies ; Female ; Genetic Association Studies ; Genotype ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/*genetics ; Proportional Hazards Models ; Trans-Activators/*genetics ; }, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset.<br><br>OBJECTIVE: To identify gene variants influencing survival in ALS.<br><br>This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7&#x202f;174&#x202f;392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015.<br><br>MAIN OUTCOMES AND MEASURES: Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed by meta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis.<br><br>RESULTS: Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P&#x2009;=&#x2009;1.87&#x2009;&#xd7;&#x2009;10-9) and in the CAMTA1 gene at 1p36 (rs2412208, P&#x2009;=&#x2009;3.53&#x2009;&#xd7;&#x2009;10-8). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P&#x2009;=&#x2009;1.87&#x2009;&#xd7;&#x2009;10-9), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P&#x2009;=&#x2009;3.53&#x2009;&#xd7;&#x2009;10-8), corresponding to a 4-month reduction in survival compared with TT carriers.<br><br>CONCLUSIONS AND RELEVANCE: This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival.}, }
@article {pmid27242430, year = {2016}, author = {Juranek, JK and Daffu, GK and Geddis, MS and Li, H and Rosario, R and Kaplan, BJ and Kelly, L and Schmidt, AM}, title = {Soluble RAGE Treatment Delays Progression of Amyotrophic Lateral Sclerosis in SOD1 Mice.}, journal = {Frontiers in cellular neuroscience}, volume = {10}, number = {}, pages = {117}, pmid = {27242430}, issn = {1662-5102}, support = {P01 AG017490/AG/NIA NIH HHS/United States ; P30 CA016087/CA/NCI NIH HHS/United States ; }, abstract = {The etiology of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder characterized by progressive muscle weakness and spasticity, remains largely unknown. Approximately 5-10% of cases are familial, and of those, 15-20% are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Mutations of the SOD1 gene interrupt cellular homeostasis and contribute to cellular toxicity evoked by the presence of altered SOD1, along with other toxic species, such as advanced glycation end products (AGEs). AGEs trigger activation of their chief cell surface receptor, RAGE (receptor for advanced glycation end products), and induce RAGE-dependent cellular stress and inflammation in neurons, thereby affecting their function and leading to apoptosis. Here, we show for the first time that the expression of RAGE is higher in the SOD1 transgenic mouse model of ALS vs. wild-type mouse spinal cord. We tested whether pharmacological blockade of RAGE may delay the onset and progression of disease in this mouse model. Our findings reveal that treatment of SOD1 transgenic mice with soluble RAGE (sRAGE), a natural competitor of RAGE that sequesters RAGE ligands and blocks their interaction with cell surface RAGE, significantly delays the progression of ALS and prolongs life span compared to vehicle treatment. We demonstrate that in sRAGE-treated SOD1 transgenic animals at the final stage of the disease, a significantly higher number of neurons and lower number of astrocytes is detectable in the spinal cord. We conclude that RAGE antagonism may provide a novel therapeutic strategy for ALS intervention.}, }
@article {pmid27230771, year = {2016}, author = {Rabinovich-Nikitin, I and Ezra, A and Barbiro, B and Rabinovich-Toidman, P and Solomon, B}, title = {Chronic administration of AMD3100 increases survival and alleviates pathology in SOD1(G93A) mice model of ALS.}, journal = {Journal of neuroinflammation}, volume = {13}, number = {1}, pages = {123}, pmid = {27230771}, issn = {1742-2094}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*pathology ; Animals ; Benzylamines ; Calcium-Binding Proteins/metabolism ; Chemokine CCL2/metabolism ; Claudin-5/metabolism ; Cyclams ; Cytokines/metabolism ; Disease Models, Animal ; Gene Expression Regulation/drug effects/genetics ; Heterocyclic Compounds/*therapeutic use ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microfilament Proteins/metabolism ; Motor Neurons/pathology ; Muscle Strength/drug effects/genetics ; Psychomotor Disorders/drug therapy/etiology/genetics ; Receptors, CXCR4/*antagonists &amp; inhibitors ; Superoxide Dismutase/genetics/metabolism ; Zonula Occludens-1 Protein/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease, involving both upper and lower motor neurons. The disease is induced by multifactorial pathologies, and as such, it requires a multifaceted therapeutic approach. CXCR4, a chemokine receptor widely expressed in neurons and glial cells and its ligand, CXCL12, also known as stromal-cell-derived factor (SDF1), modulate both neuronal function and apoptosis by glutamate release signaling as well as hematopoietic stem and progenitor cells (HSPCs) migration into the blood and their homing towards injured sites. Inhibition approaches towards the CXCR4/CXCL12 signaling may result in preventing neuronal apoptosis and alter the HSPCs migration and homing. Such inhibition can be achieved by means of treatment with AMD3100, an antagonist of the chemokine receptor CXCR4.<br><br>METHODS: We chronically treated male and female transgenic mice model of ALS, SOD1(G93A) mice, with AMD3100. Mice body weight and motor function, evaluated by Rotarod test, were recorded once a week. The most effective treatment regimen was repeated for biochemical and histological analyses in female mice.<br><br>RESULTS: We found that chronic administration of AMD3100 to SOD1(G93A) mice led to significant extension in mice lifespan and improved motor function and weight loss. In addition, the treatment significantly improved microglial pathology and decreased proinflammatory cytokines in spinal cords of treated female mice. Furthermore, AMD3100 treatment decreased blood-spinal cord barrier (BSCB) permeability by increasing tight junction proteins levels and increased the motor neurons count in the lamina X area of the spinal cord, where adult stem cells are formed.<br><br>CONCLUSIONS: These data, relevant to the corresponding disease mechanism in human ALS, suggest that blocking CXCR4 by the small molecule, AMD3100, may provide a novel candidate for ALS therapy with an increased safety.}, }
@article {pmid27227717, year = {2016}, author = {Seibold, H and Zeileis, A and Hothorn, T}, title = {Model-Based Recursive Partitioning for Subgroup Analyses.}, journal = {The international journal of biostatistics}, volume = {12}, number = {1}, pages = {45-63}, doi = {10.1515/ijb-2015-0032}, pmid = {27227717}, issn = {1557-4679}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; *Data Interpretation, Statistical ; Humans ; Neuroprotective Agents/pharmacology ; Outcome Assessment, Health Care/*methods ; Precision Medicine/*methods ; Research Design/*standards ; Riluzole/pharmacology ; }, abstract = {The identification of patient subgroups with differential treatment effects is the first step towards individualised treatments. A current draft guideline by the EMA discusses potentials and problems in subgroup analyses and formulated challenges to the development of appropriate statistical procedures for the data-driven identification of patient subgroups. We introduce model-based recursive partitioning as a procedure for the automated detection of patient subgroups that are identifiable by predictive factors. The method starts with a model for the overall treatment effect as defined for the primary analysis in the study protocol and uses measures for detecting parameter instabilities in this treatment effect. The procedure produces a segmented model with differential treatment parameters corresponding to each patient subgroup. The subgroups are linked to predictive factors by means of a decision tree. The method is applied to the search for subgroups of patients suffering from amyotrophic lateral sclerosis that differ with respect to their Riluzole treatment effect, the only currently approved drug for this disease.}, }
@article {pmid27224441, year = {2016}, author = {Silvestri, NJ and Wolfe, GI and Bromberg, M and Lacomis, D}, title = {What's in the Literature?.}, journal = {Journal of clinical neuromuscular disease}, volume = {17}, number = {4}, pages = {227-238}, doi = {10.1097/CND.0000000000000134}, pmid = {27224441}, issn = {1537-1611}, abstract = {One of the first questions asked by patients and family members when a diagnosis of amyotrophic lateral sclerosis is made is "what about stem cells?" The term "stem cells" has attractiveness to it, with the assumption that stem cell treatment (stem nerve cells) can replace lost nerve cells. There are perhaps 2 types of stem cell trials, those that are vetted by the Food and Drug Administration and those that have no official oversight and whose results are infrequently published. The issue of the latter was discussed in the last edition of this column. The results of one of the formal stem cell trials now in the United States have been reported. Spinal muscular atrophy is a form of motor neuron disease affecting children and has a genetic cause, which has led to a feasibility study giving antisense oligonucleotides, and the results have also been reported. Biomarkers of amyotrophic lateral sclerosis are being sought, and the presence of neurofilaments is promising. Inflammatory neuropathies are an important group because they are treatable. Intravenous immune globulin is a commonly used agent, but a number of questions persist: one is efficacy among brands, another is the probability of a response, and a third is optimum dosing and taper schedules. A number of recent articles address these issues. The predictive value of single-fiber electromyography in determining which patients with ocular myasthenia will develop generalized disease, the risk of crisis after thymectomy, and 2 papers discussing new forms of congenital myasthenic syndrome are discussed. The risk of brain tumors, quality of life, and the assessment of trunk muscle strength in patients with type 1 myotonic dystrophy is reviewed. An article describing the discovery of mutations in SCN4A as a cause of congenital myopathy is discussed, as is one describing the occurrence of rhabdomyolysis in a group of patients subsequently discovered to have various forms of muscular dystrophy. Finally, articles describing the features of patients with inflammatory myopathies and Jo-1 and either 3-hydroxy-3-methylglutaryl-conezymea reductase or to signal recognition particle antibodies are reviewed.}, }
@article {pmid27213408, year = {2016}, author = {White, JA and Banerjee, R and Gunawardena, S}, title = {Axonal Transport and Neurodegeneration: How Marine Drugs Can Be Used for the Development of Therapeutics.}, journal = {Marine drugs}, volume = {14}, number = {5}, pages = {}, pmid = {27213408}, issn = {1660-3397}, support = {R03 NS084386/NS/NINDS NIH HHS/United States ; R03 NS092024/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Axonal Transport/drug effects/*physiology ; Humans ; Microtubules/drug effects/*physiology ; Neurodegenerative Diseases/drug therapy/*physiopathology ; Oceans and Seas ; Tubulin Modulators/pharmacology/*therapeutic use ; }, abstract = {Unlike virtually any other cells in the human body, neurons are tasked with the unique problem of transporting important factors from sites of synthesis at the cell bodies, across enormous distances, along narrow-caliber projections, to distally located nerve terminals in order to maintain cell viability. As a result, axonal transport is a highly regulated process whereby necessary cargoes of all types are packaged and shipped from one end of the neuron to the other. Interruptions in this finely tuned transport have been linked to many neurodegenerative disorders including Alzheimer's (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) suggesting that this pathway is likely perturbed early in disease progression. Therefore, developing therapeutics targeted at modifying transport defects could potentially avert disease progression. In this review, we examine a variety of potential compounds identified from marine aquatic species that affect the axonal transport pathway. These compounds have been shown to function in microtubule (MT) assembly and maintenance, motor protein control, and in the regulation of protein degradation pathways, such as the autophagy-lysosome processes, which are defective in many degenerative diseases. Therefore, marine compounds have great potential in developing effective treatment strategies aimed at early defects which, over time, will restore transport and prevent cell death.}, }
@article {pmid27212914, year = {2016}, author = {Ruiz-López, FJ and Blanquer, M}, title = {Autologous bone marrow mononuclear cells as neuroprotective treatment of amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {11}, number = {4}, pages = {568-569}, pmid = {27212914}, issn = {1673-5374}, }
@article {pmid27194130, year = {2017}, author = {Sasamori, T and Hida, K and Osanai, T and Yano, S and Seki, T and Houkin, K}, title = {Health-related quality of life in patients with spinal dural arteriovenous fistulae.}, journal = {Neurosurgical review}, volume = {40}, number = {1}, pages = {83-86}, pmid = {27194130}, issn = {1437-2320}, mesh = {Aged ; Aged, 80 and over ; Central Nervous System Vascular Malformations/*surgery ; Chronic Pain/*surgery ; Delivery of Health Care ; Humans ; Male ; Middle Aged ; Postoperative Period ; *Quality of Life ; Surveys and Questionnaires ; Treatment Outcome ; }, abstract = {Neurological improvement in patients with spinal dural arteriovenous fistulae (SDAVF) is often partial even after adequate treatment. While treatment outcomes have been evaluated primarily on the basis of the postoperative changes in neurological deficits, outcome measures should also reflect the patient-reported outcome (PRO). We conducted a health-related quality of life (HRQOL) survey in 52 SDAVF patients; 33 (63.5%) completed the short-form 36 Health Survey (SF-36) questionnaire. They were 25 males and 8 females ranging in age from 47 to 85 years (mean age 70.0 years). The mean follow-up period was 95.6 months. We analyzed the completed questionnaires and examined the clinical factors associated with their HRQOL. After treatment, gait- and micturition disturbances persisted in 31 (93.9%) and 31 (93.9%) of our patients; 26 (78.8%) reported chronic leg pain. The SF-36 scores of treated SDAVF patients were significantly lower than the national average of 50 for all 8 sub-items in the questionnaire. The scores for physical functioning (PF) and role-physical (RP) were particularly low. With the exception of bodily pain (BP), there was a significant negative correlation between the Aminoff-Logue scale (ALS) scores for gait- and micturition and the sub-item scores. The score for BP showed a significant positive correlation with the scores for the 7 other SF-36 sub-items. The HRQOL of treated SDAVF patients was lower than the national average with respect to both physical and mental aspects. Persistent post-treatment pain and gait- and micturition disturbances were responsible for their lower HRQOL.}, }
@article {pmid27193329, year = {2016}, author = {Dardis, A and Zampieri, S and Canterini, S and Newell, KL and Stuani, C and Murrell, JR and Ghetti, B and Fiorenza, MT and Bembi, B and Buratti, E}, title = {Altered localization and functionality of TAR DNA Binding Protein 43 (TDP-43) in niemann- pick disease type C.}, journal = {Acta neuropathologica communications}, volume = {4}, number = {1}, pages = {52}, pmid = {27193329}, issn = {2051-5960}, support = {GGP13183/TI_/Telethon/Italy ; P30 AG010133/AG/NIA NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Brain/metabolism/pathology ; Cell Nucleus/drug effects/metabolism/pathology ; Cells, Cultured ; DNA-Binding Proteins/*metabolism ; Disease Models, Animal ; Fibroblasts/drug effects/metabolism/pathology ; Humans ; Intracellular Signaling Peptides and Proteins ; Male ; Mice, Inbred BALB C ; Mice, Transgenic ; Middle Aged ; Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/pharmacology ; Niemann-Pick C1 Protein ; Niemann-Pick Disease, Type C/drug therapy/genetics/*metabolism/pathology ; Proteins/genetics/metabolism ; Spinal Cord/metabolism/pathology ; beta-Cyclodextrins/pharmacology ; }, abstract = {Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by the occurrence of visceral and neurological symptoms. At present, the molecular mechanisms causing neurodegeneration in this disease are unknown. Here we report the altered expression and/or mislocalization of the TAR-DNA binding protein 43 (TDP-43) in both NPC mouse and in a human neuronal model of the disease. We also report the neuropathologic study of a NPC patient's brain, showing that while TDP-43 is below immunohistochemical detection in nuclei of cerebellar Purkinje cells, it has a predominant localization in the cytoplasm of these cells. From a functional point of view, the TDP-43 mislocalization, that occurs in a human experimental neuronal model system, is associated with specific alterations in TDP-43 controlled genes. Most interestingly, treatment with N-Acetyl-cysteine (NAC) or beta-cyclodextrin (CD) can partially restore TDP-43 nuclear localization. Taken together, the results of these studies extend the role of TDP-43 beyond the Amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)/Alzheimer disease (AD) spectrum. These findings may open novel research/therapeutic avenues for a better understanding of both NPC disease and the TDP-43 proteinopathy disease mechanism.}, }
@article {pmid27183983, year = {2016}, author = {Catalano, A and Carocci, A}, title = {Antiarrhythmic Mexiletine: A Review on Synthetic Routes to Racemic and Homochiral Mexiletine and its Enantioseparation.}, journal = {Current medicinal chemistry}, volume = {23}, number = {29}, pages = {3227-3244}, doi = {10.2174/0929867323666160517120234}, pmid = {27183983}, issn = {1875-533X}, mesh = {Anti-Arrhythmia Agents/blood/*chemical synthesis/metabolism/therapeutic use ; Arrhythmias, Cardiac/drug therapy ; Chromatography, High Pressure Liquid ; Diabetic Nephropathies/drug therapy ; Humans ; Mexiletine/blood/*chemistry/metabolism/therapeutic use ; Stereoisomerism ; }, abstract = {Mexiletine is an oral class IB antiarrhythmic agent. Although it was primarily studied for the treatment of ventricular arrhythmias, it has been demonstrated to be useful also for the treatment of chronic painful diabetic neuropathy, neuropathic pain, skeletal muscle channelopathies, and recently amyotrophic lateral sclerosis. This review presents a detailed report on the different synthetic routes to racemic and homochiral mexiletine developed in the last decades, as well as analytical studies regarding enantioseparation methods and enantiomeric excess determination. Finally, some analogues of mexiletine reported in the literature, most of which along with pharmacological studies, have been mentioned.}, }
@article {pmid27181034, year = {2017}, author = {Bergþórsdóttir, &#xcd;&#xd6; and Ingham, RJ}, title = {Putting the cart before the horse: A cost effectiveness analysis of treatments for stuttering in young children requires evidence that the treatments analyzed were effective.}, journal = {Journal of communication disorders}, volume = {65}, number = {}, pages = {65-67}, doi = {10.1016/j.jcomdis.2016.04.006}, pmid = {27181034}, issn = {1873-7994}, mesh = {Child, Preschool ; *Cost-Benefit Analysis ; Humans ; Speech Production Measurement ; Speech Therapy/*methods ; Stuttering/*therapy ; Time Factors ; }, abstract = {PURPOSE: To investigate the validity of findings from a recent study reported in this journal by de Sonneville-Koedoot, Bouwmans, Franken, and Stolk (2015) on the cost effectiveness of two programs for treating young children who stutter.<br><br>METHODS: The de Sonneville-Koedoot, Bouwmans et al. study was based directly on the results obtained in an earlier study, known as the RESTART-study, which compared the outcomes from the Lidcombe Program and a Demands and Capacities Model program. The methodology of the RESTART-study was critically reviewed.<br><br>RESULTS: The absence of an untreated control group in the RESTART-study makes the results of that study uninterpretable. An inappropriate comparison made with the Yairi and Ambrose (2005) Illinois Study findings failed to resolve the control group problem. Furthermore, the criteria used to classify treated children as "non-stuttering" was also shown to be confounded. The foregoing problems meant that neither treatment program could be shown to be more effective than no treatment.<br><br>CONCLUSION: de Sonneville-Koedoot, Bouwmans et al's findings, which compared the cost effectiveness of two treatments for young children who stutter, have no value for clinical management because the treatments investigated were not shown to be more effective than no treatment.}, }
@article {pmid27174644, year = {2016}, author = {Martínez-Muriana, A and Mancuso, R and Francos-Quijorna, I and Olmos-Alonso, A and Osta, R and Perry, VH and Navarro, X and Gomez-Nicola, D and López-Vales, R}, title = {CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {25663}, pmid = {27174644}, issn = {2045-2322}, support = {MR/K022687/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Anisoles/pharmacology ; Cell Proliferation/drug effects/genetics ; Cell Survival/drug effects/genetics ; Disease Progression ; Gliosis/genetics/metabolism ; Inflammation/genetics/metabolism ; Macrophages/*metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/*metabolism/pathology ; Motor Neurons/metabolism ; Peripheral Nerves/*metabolism ; Pyrimidines/pharmacology ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists &amp; inhibitors/genetics/*metabolism ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Inflammation is a common neuropathological feature in several neurological disorders, including amyotrophic lateral sclerosis (ALS). We have studied the contribution of CSF1R signalling to inflammation in ALS, as a pathway previously reported to control the expansion and activation of microglial cells. We found that microglial cell proliferation in the spinal cord of SOD1(G93A) transgenic mice correlates with the expression of CSF1R and its ligand CSF1. Administration of GW2580, a selective CSF1R inhibitor, reduced microglial cell proliferation in SOD1(G93A) mice, indicating the importance of CSF1-CSF1R signalling in microgliosis in ALS. Moreover, GW2580 treatment slowed disease progression, attenuated motoneuron cell death and extended survival of SOD1(G93A) mice. Electrophysiological assessment revealed that GW2580 treatment protected skeletal muscle from denervation prior to its effects on microglial cells. We found that macrophages invaded the peripheral nerve of ALS mice before CSF1R-induced microgliosis occurred. Interestingly, treatment with GW2580 attenuated the influx of macrophages into the nerve, which was partly caused by the monocytopenia induced by CSF1R inhibition. Overall, our findings provide evidence that CSF1R signalling regulates inflammation in the central and peripheral nervous system in ALS, supporting therapeutic targeting of CSF1R in this disease.}, }
@article {pmid27174631, year = {2017}, author = {Andersen, T and Sandnes, A and Brekka, AK and Hilland, M and Clemm, H and Fondenes, O and Tysnes, OB and Heimdal, JH and Halvorsen, T and Vollsæter, M and Røksund, OD}, title = {Laryngeal response patterns influence the efficacy of mechanical assisted cough in amyotrophic lateral sclerosis.}, journal = {Thorax}, volume = {72}, number = {3}, pages = {221-229}, pmid = {27174631}, issn = {1468-3296}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*physiopathology ; *Cough ; Cross-Sectional Studies ; Female ; Humans ; Insufflation ; Laryngoscopy ; Male ; Norway ; Respiratory Function Tests ; Respiratory Therapy/*methods ; Video Recording ; }, abstract = {BACKGROUND: Most patients with amyotrophic lateral sclerosis (ALS) are treated with mechanical insufflation-exsufflation (MI-E) in order to improve cough. This method often fails in ALS with bulbar involvement, allegedly due to upper-airway malfunction. We have studied this phenomenon in detail with laryngoscopy to unravel information that could lead to better treatment.<br><br>METHODS: We conducted a cross-sectional study of 20 patients with ALS and 20 healthy age-matched and sex-matched volunteers. We used video-recorded flexible transnasal fibre-optic laryngoscopy during MI-E undertaken according to a standardised protocol, applying pressures of &#xb1;20 to &#xb1;50&#x2005;cm&#x2005;H2O. Laryngeal movements were assessed from video files. ALS type and characteristics of upper and lower motor neuron symptoms were determined.<br><br>RESULTS: At the supraglottic level, all patients with ALS and bulbar symptoms (n=14) adducted their laryngeal structures during insufflation. At the glottic level, initial abduction followed by subsequent adduction was observed in all patients with ALS during insufflation and exsufflation. Hypopharyngeal constriction during exsufflation was observed in all subjects, most prominently in patients with ALS and bulbar symptoms. Healthy subjects and patients with ALS and no bulbar symptoms (n=6) coordinated their cough well during MI-E.<br><br>CONCLUSIONS: Laryngoscopy during ongoing MI-E in patients with ALS and bulbar symptoms revealed laryngeal adduction especially during insufflation but also during exsufflation, thereby severely compromising the size of the laryngeal inlet in some patients. Individually customised settings can prevent this and thereby improve and extend the use of non-invasive MI-E.}, }
@article {pmid27173029, year = {2016}, author = {Golko-Perez, S and Amit, T and Youdim, MB and Weinreb, O}, title = {Beneficial Effects of Multitarget Iron Chelator on Central Nervous System and Gastrocnemius Muscle in SOD1(G93A) Transgenic ALS Mice.}, journal = {Journal of molecular neuroscience : MN}, volume = {59}, number = {4}, pages = {504-510}, pmid = {27173029}, issn = {1559-1166}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Apoptosis ; Female ; Frontal Lobe/drug effects/*metabolism ; Glycogen Synthase Kinase 3 beta/genetics/metabolism ; Glycolysis ; Hydroxyquinolines/*pharmacology ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; Iron Chelating Agents/*pharmacology ; Mice ; Muscle, Skeletal/drug effects/*metabolism ; Nerve Growth Factors/genetics/metabolism ; Neuroprotective Agents/*pharmacology ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Signal Transduction ; Superoxide Dismutase-1/genetics ; }, abstract = {Accumulation of evidence has demonstrated high levels of iron in the central nervous system of both sporadic and familial amyotrophic lateral sclerosis (ALS) patients and in ALS mouse models. In accordance, iron chelation therapy was found to exert beneficial effects on ALS mice. Our group has designed and synthesized series of multifunctional non-toxic, brain permeable iron-chelating compounds for neurodegenerative diseases. Recent study has shown that co-administration of one of these drugs, VAR10303 with high calorie/energy-supplemented diet (VAR-ced), initiated after the appearance of disease symptoms improved motor performance, extended survival, and attenuated iron accumulation and motoneuron loss in SOD1(G93A) mice. Since VAR was found to exert diverse pharmacological properties associated with mitochondrial biogenesis in the gastrocnemius (GNS) muscle, we further assessed in the current study the impact of VAR-ced on additional neurorescue-associated molecular targets in the GNS and frontal cortex in SOD1(G93A) mice. The results show that VAR-ced treatment upregulated the expression of various HIF-1α-target glycolytic genes and elevated the levels of Bcl-2, neurotrophic factors, and AKT/GSK3β signaling in the GNS and frontal cortex of SOD1(G93A) mice, suggesting that these protective regulatory parameters regulated by VAR-ced treatment may be associated with the beneficial effects of the drug observed on ALS mice.}, }
@article {pmid27164932, year = {2016}, author = {Blokhuis, AM and Koppers, M and Groen, EJN and van den Heuvel, DMA and Dini Modigliani, S and Anink, JJ and Fumoto, K and van Diggelen, F and Snelting, A and Sodaar, P and Verheijen, BM and Demmers, JAA and Veldink, JH and Aronica, E and Bozzoni, I and den Hertog, J and van den Berg, LH and Pasterkamp, RJ}, title = {Comparative interactomics analysis of different ALS-associated proteins identifies converging molecular pathways.}, journal = {Acta neuropathologica}, volume = {132}, number = {2}, pages = {175-196}, pmid = {27164932}, issn = {1432-0533}, mesh = {Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Vesicular Transport/genetics/*metabolism ; Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Ataxin-2/genetics/*metabolism ; Autophagy-Related Proteins ; C9orf72 Protein ; Cell Cycle Proteins ; DNA-Binding Proteins/genetics/*metabolism ; Disease Models, Animal ; Eye Proteins/genetics/*metabolism ; Fragile X Mental Retardation Protein/genetics/*metabolism ; Guanine Nucleotide Exchange Factors/genetics/*metabolism ; Membrane Transport Proteins ; Mice, Inbred C57BL ; Mitochondria/metabolism ; Motor Neurons/metabolism/pathology ; Mutant Proteins/genetics/metabolism ; Neurons/metabolism ; RNA-Binding Protein FUS/genetics/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment available. An increasing number of genetic causes of ALS are being identified, but how these genetic defects lead to motor neuron degeneration and to which extent they affect common cellular pathways remains incompletely understood. To address these questions, we performed an interactomic analysis to identify binding partners of wild-type (WT) and ALS-associated mutant versions of ATXN2, C9orf72, FUS, OPTN, TDP-43 and UBQLN2 in neuronal cells. This analysis identified several known but also many novel binding partners of these proteins. Interactomes of WT and mutant ALS proteins were very similar except for OPTN and UBQLN2, in which mutations caused loss or gain of protein interactions. Several of the identified interactomes showed a high degree of overlap: shared binding partners of ATXN2, FUS and TDP-43 had roles in RNA metabolism; OPTN- and UBQLN2-interacting proteins were related to protein degradation and protein transport, and C9orf72 interactors function in mitochondria. To confirm that this overlap is important for ALS pathogenesis, we studied fragile X mental retardation protein (FMRP), one of the common interactors of ATXN2, FUS and TDP-43, in more detail in in vitro and in vivo model systems for FUS ALS. FMRP localized to mutant FUS-containing aggregates in spinal motor neurons and bound endogenous FUS in a direct and RNA-sensitive manner. Furthermore, defects in synaptic FMRP mRNA target expression, neuromuscular junction integrity, and motor behavior caused by mutant FUS in zebrafish embryos, could be rescued by exogenous FMRP expression. Together, these results show that interactomics analysis can provide crucial insight into ALS disease mechanisms and they link FMRP to motor neuron dysfunction caused by FUS mutations.}, }
@article {pmid27139021, year = {2016}, author = {Chi, S and Jiang, T and Tan, L and Yu, JT}, title = {Distinct neurological disorders with C9orf72 mutations: genetics, pathogenesis, and therapy.}, journal = {Neuroscience and biobehavioral reviews}, volume = {66}, number = {}, pages = {127-142}, doi = {10.1016/j.neubiorev.2016.03.033}, pmid = {27139021}, issn = {1873-7528}, mesh = {Amyotrophic Lateral Sclerosis ; Animals ; C9orf72 Protein ; Frontotemporal Dementia ; Humans ; *Mutation ; Phenotype ; Proteins/*genetics ; }, abstract = {The G4C2 repeat expansion within C9orf72 has been recently identified as the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. This mutation has also been detected in a variety of other neurological diseases with distinct clinical manifestations. The exact mechanisms of how this mutation leads to the wide spectrum of clinical syndromes remain unknown. A series of molecular changes together with some potential modifiers may play a key role. Nucleolar stress, nucleocytoplasmic transport defect, oxidative damage, inhibited stress granules assembly, activated endoplasmic reticulum stress, and inhibited proteasome activity are mechanisms that contribute to the pathogenesis of these diseases. Additional mutations, epigenetic modifiers, and repeat size are potential modifiers that modulate specific phenotypes on the basis of the molecular changes. Here, we summarize distinct C9orf72-related neurological disorders and their corresponding neuropathological changes. Then, we elucidate the existing molecular knowledge and the potential modifiers. Finally, we detail the main target of treatment aiming at controlling expanded RNA transcripts.}, }
@article {pmid27138280, year = {2016}, author = {Evans, TM and Bhattacharya, A and Shi, Y and Qi, W and Block, TJ and Chaudhuri, A and Chaudhuri, AR and Hawker, K and Van Remmen, H}, title = {Moderate modulation of disease in the G93A model of ALS by the compound 2-(2-hydroxyphenyl)-benzoxazole (HBX).}, journal = {Neuroscience letters}, volume = {624}, number = {}, pages = {1-7}, doi = {10.1016/j.neulet.2016.04.035}, pmid = {27138280}, issn = {1872-7972}, support = {I01 BX002595/BX/BLRD VA/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*prevention &amp; control ; Animals ; Benzothiazoles/*administration &amp; dosage ; Body Composition/drug effects ; Chelating Agents/*administration &amp; dosage ; Copper/metabolism ; Cystatins/metabolism ; Disease Models, Animal ; Disease Progression ; Female ; Iron/metabolism ; Isoprostanes/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Phenols/*administration &amp; dosage ; Spinal Cord/metabolism ; Superoxide Dismutase-1/metabolism ; Survival Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disease characterized by degeneration and death of motor neurons. Aberrant protein aggregation and oxidative stress are implicated in the etiology of ALS; thus preventing propagation of early aggregation events and oxidative damage could be an effective therapy. We tested the effect of dietary supplementation (initiated 40 days of age) with 2-(2-hydroxyphenyl)-benzoxazole (HBX), a compound with metal chelator and anti-aggregation properties, on disease onset, progression and lifespan in the G93A mouse model of ALS. Tests were not sufficiently powerful to detect any change to survival distribution of mice treated with HBX. However, the disease onset was delayed and max lifespan was increased in the treatment group. Additionally, disease progression was moderated as shown by reduced neuromuscular denervation measured by repetitive nerve stimulation. F2-isoprostanes, a marker of oxidative damage, are elevated in skeletal muscle from G93A mice at onset and this increase is prevented in HBX fed G93A mice. Furthermore, HBX treatment reduced mutant SOD1 protein aggregation in whole spinal cord of G93A mice at disease onset. Overall, our data suggests that HBX may be able to improve the degenerative symptoms of ALS through the prevention of oxidative damage and protein aggregation. Further studies are needed to uncover the mechanistic effects of HBX in ameliorating ALS pathology.}, }
@article {pmid27136532, year = {2016}, author = {Tokuda, E and Furukawa, Y}, title = {Copper Homeostasis as a Therapeutic Target in Amyotrophic Lateral Sclerosis with SOD1 Mutations.}, journal = {International journal of molecular sciences}, volume = {17}, number = {5}, pages = {}, pmid = {27136532}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics/pathology ; Animals ; Chelating Agents/chemistry/metabolism/therapeutic use ; Copper/chemistry/*metabolism ; Disease Models, Animal ; Humans ; Polymorphism, Single Nucleotide ; Superoxide Dismutase-1/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease affecting both upper and lower motor neurons, and currently, there is no cure or effective treatment. Mutations in a gene encoding a ubiquitous antioxidant enzyme, Cu,Zn-superoxide dismutase (SOD1), have been first identified as a cause of familial forms of ALS. It is widely accepted that mutant SOD1 proteins cause the disease through a gain in toxicity but not through a loss of its physiological function. SOD1 is a major copper-binding protein and regulates copper homeostasis in the cell; therefore, a toxicity of mutant SOD1 could arise from the disruption of copper homeostasis. In this review, we will briefly review recent studies implying roles of copper homeostasis in the pathogenesis of SOD1-ALS and highlight the therapeutic interventions focusing on pharmacological as well as genetic regulations of copper homeostasis to modify the pathological process in SOD1-ALS.}, }
@article {pmid30512584, year = {2016}, author = {Soriani, MH}, title = {[Management of amyotrophic lateral sclerosis].}, journal = {La Revue du praticien}, volume = {66}, number = {5}, pages = {563-570}, pmid = {30512584}, issn = {2101-017X}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; *Home Care Services ; Humans ; *Nurse Practitioners ; Pain ; }, abstract = {Management Of amyotrophic lateral Sclerosis Management of amyotrophic lateral sclerosis starts with diagnosis announcement which is straightaway followed by initiating neuroprotective treatment (riluzole). A quarterly-based management is proposed, coordinated by an ALS center in close collaboration with the general practitioner, home care organization, and a dedicated health network. Key point for efficiency of global care is to develop a coordination with a multidisciplinary approach, including the involvement of neurologist and physicians from different medical specialties, nurse practitioners, physical and occupational therapists, speech language therapists, dietitians and psychologists. The assessments follow-up concern mainly motor impairments and physical disability, adaptations, nutritional and respiratory functions. Associated symptoms such as pain, spasticity, mood disorders have to be recognized and treated. Decisions about nutritional and respiratory assistive devices require a collaborative approach involving specialized practitioners and paramedical professionals. These decisions have to be anticipated (advanced directives) in agreement with the patient, the family and the trusted person. Along the disease's management, patients and their family may have support from a psychologist. Finally, home care organization requires the intervention of a social worker.}, }
@article {pmid27129027, year = {2016}, author = {Stelzer, AC and Hrobárik, P and Braun, T and Kaupp, M and Braun-Cula, B}, title = {Completing the Heterocubane Family [Cp*AlE]4 (E = O, S, Se, and Te) by Selective Oxygenation and Sulfuration of [Cp*Al]4: Density Functional Theory Calculations of [Cp*AlE]4 and Reactivity of [Cp*AlO]4 toward Hydrolysis.}, journal = {Inorganic chemistry}, volume = {55}, number = {10}, pages = {4915-4923}, doi = {10.1021/acs.inorgchem.6b00462}, pmid = {27129027}, issn = {1520-510X}, abstract = {The subvalent aluminum compound [Cp*Al]4 (1) reacts with dioxygen, N2O, or sulfur to yield the heterocubane complexes [Cp*AlX]4 [X = O (2) and S (3)]. Treatment of [Cp*AlO]4 (2) with (tBuO)3SiOH gave [(tBuO)3SiOAlO]4 (6) and Cp*H. The structures and spectroscopic data of the Al clusters are supported by density functional theory (DFT) calculations, which also demonstrate the importance of noncovalent interactions (NCI) in oligomeric Al(I) complexes as well as in [Cp*AlS]4 and the heavier homologues of Se and Te. The computed (27)Al NMR shifts indicate a deshielding at the Al centers with increasing electronegativity of the chalcogen atom as well as significant spin-orbit shielding effects within the heavier heterocubane [Al4E4] cores. Further hydrolysis of 6 with an additional amount of silanol in the presence of water resulted in the formation of [Al4(OH)6(OH2)2(OSiOtBu3)6] (7), which shows a structural motif found in boehmite and diaspore.}, }
@article {pmid27127712, year = {2016}, author = {Baum, GR and Turan, N and Buonanno, FS and Pradilla, G and Nogueira, RG}, title = {Intracranial dural arteriovenous fistula as a cause for symptomatic superficial siderosis: A report of two cases and review of the literature.}, journal = {Surgical neurology international}, volume = {7}, number = {Suppl 9}, pages = {S223-7}, pmid = {27127712}, issn = {2229-5097}, abstract = {BACKGROUND: Superficial siderosis (SS) is the occult deposition of hemosiderin within the cerebral cortex due to repeat microhemorrhages within the central nervous system. The collection of hemosiderin within the pia and superficial cortical surface can lead to injury to the nervous tissue. The most common presentation is occult sensorineural hearing loss although many patients have been misdiagnosed with diseases such as multiple sclerosis and amyotrophic lateral sclerosis before being diagnosed with SS. Only one case report exists in the literature describing an intracranial dural arteriovenous fistula (dAVF) as the putative cause for SS.<br><br>CASE DESCRIPTION: We describe two cases of SS caused by a dAVF. Both patients had a supratentorial, cortical lesion supplied by the middle meningeal artery with venous drainage into the superior sagittal sinus. In both patients, symptoms improved after endovascular embolization. The similar anatomic relationship of both dAVFs reported presents an interesting question about the pathogenesis of SS. Similar to the pathologic changes seen in the formation of intracranial arterial aneurysms; it would be possible that changes in the blood vessel lining and wall might predispose a patient to chronic, microhemorrhage resulting in SS.<br><br>CONCLUSIONS: We describe the second and third cases of a dAVF as the cause of SS, and the first cases of successful treatment of SS-associated dAVF with endovascular embolization. As noninvasive imaging techniques become more sensitive and easily obtained, one must consider their limitations in detecting occult intracranial vascular malformations such as dAVF as a possible etiology for SS.}, }
@article {pmid27126806, year = {2016}, author = {Moreno-Ortega, AJ and Al-Achbili, LM and Alonso, E and de Los Ríos, C and García, AG and Ruiz-Nuño, A and Cano-Abad, MF}, title = {Neuroprotective Effect of the Novel Compound ITH33/IQM9.21 Against Oxidative Stress and Na(+) and Ca(2+) Overload in Motor Neuron-like NSC-34 Cells.}, journal = {Neurotoxicity research}, volume = {30}, number = {3}, pages = {380-391}, pmid = {27126806}, issn = {1476-3524}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; Arsenicals ; Benzamides/*pharmacology ; Calbindin 1/metabolism ; Calcium/metabolism/toxicity ; Cell Survival/drug effects/physiology ; Drug Evaluation, Preclinical ; Glutamates/*pharmacology ; Mice ; Mitochondria/drug effects/metabolism/pathology ; Motor Neurons/*drug effects/pathology ; Neuroprotective Agents/*pharmacology ; Oligomycins/toxicity ; Oxidative Stress/*drug effects/physiology ; Parvalbumins/metabolism ; Riluzole/pharmacology ; Rotenone/toxicity ; Sodium/metabolism/toxicity ; Veratridine/toxicity ; }, abstract = {Alternatives for the treatment of amyotrophic lateral sclerosis (ALS) are scarce and controversial. The etiology of neuronal vulnerability in ALS is being studied in motor neuron-like NSC-34 cells to determine the underlying mechanisms leading to selective loss of motor neurons. One such mechanism is associated with mitochondrial oxidative stress, Ca(2+) overload, and low expression of Ca(2+)-buffering proteins. Therefore, in order to elicit neuronal death in ALS, NSC-34 cells were exposed to the following cytotoxic agents: (1) a mixture of oligomycin 10 µM and rotenone 30 µM (O/R), or (2) phenylarsine oxide 1 µM (PAO) (to mimic excess free radical production during mitochondrial dysfunction), and (3) veratridine 100 µM (VTD) (to induce overload of Na(+) and Ca(2+) and to alter distribution of Ca(2+)-buffering proteins [parvalbumin and calbindin-D28k]). Thus, the aim of the study was to test the novel neuroprotective compound ITH33/IQM9.21 (ITH33) and to compare it with riluzole on in vitro models of neurotoxicity. Cell viability measured with MTT showed that only ITH33 protected against O/R at 3 μM and PAO at 10 μM, but not riluzole. ITH33 and riluzole were neuroprotective against VTD, blocked the maximum peak and the number of [Ca(2+)]c oscillations per cell, and restored the effect on parvalbumin. However, only riluzole reversed the effect on calbindin-D28k levels. Therefore, ITH33 was neuroprotective against oxidative stress and Na(+)/Ca(2+) overload, both of which are involved in ALS.}, }
@article {pmid27117334, year = {2016}, author = {de Carvalho, M and Swash, M}, title = {Lower motor neuron dysfunction in ALS.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {127}, number = {7}, pages = {2670-2681}, doi = {10.1016/j.clinph.2016.03.024}, pmid = {27117334}, issn = {1872-8952}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Electromyography/methods ; Humans ; Motor Neurons/pathology/*physiology ; Muscle, Skeletal/pathology/physiopathology ; Neural Conduction ; }, abstract = {In the motor system there is a complex interplay between cortical structures and spinal cord lower motor neurons (LMN). In this system both inhibitory and excitatory neurons have relevant roles. LMN loss is a marker of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). Conventional needle electromyography (EMG) does not allow LMN loss to be quantified. Measurement of compound muscle action potential (CMAP) amplitude or area, and the neurophysiological index, provide a surrogate estimate of the number of functional motor units. Increased motor neuronal excitability is a neurophysiological marker of ALS in the context of a suspected clinical and electrophysiological diagnosis. In the LMN system, fasciculation potentials (FPs) are the earliest changes observed in affected muscles, a feature of LMN hyperexcitability. Reinnervation is best investigated by needle EMG although other methods can be explored. Moreover needle EMG give information about the temporal profile of the reinnervation process, important ancillary data. Quantitative motor unit potential analysis is a valuable method of evaluating reinnervation. The importance of FPs has been recognized in the Awaji criteria for the electrodiagnosis of ALS, criteria that are a sensitive adjunct to the revised El Escorial criteria. Finally, functionality of LMN's, and perhaps excitability studies in motor nerves, aids understanding of the disease process, allowing measurement of potential treatment effects in clinical trials. Other investigational techniques, such as electrical impedance myography, muscle and nerve ultrasound, and spinal cord imaging methods may prove useful in future.}, }
@article {pmid27114092, year = {2017}, author = {Tiigimäe-Saar, J and Taba, P and Tamme, T}, title = {Does Botulinum neurotoxin type A treatment for sialorrhea change oral health?.}, journal = {Clinical oral investigations}, volume = {21}, number = {3}, pages = {795-800}, pmid = {27114092}, issn = {1436-3771}, mesh = {Adolescent ; Adult ; Aged ; Botulinum Toxins, Type A/administration &amp; dosage/*therapeutic use ; Child ; Child, Preschool ; Female ; Humans ; Injections ; Male ; Middle Aged ; Neuromuscular Agents/administration &amp; dosage/*therapeutic use ; *Oral Health ; Sialorrhea/*drug therapy ; Treatment Outcome ; Ultrasonography, Interventional ; }, abstract = {OBJECTIVES: Botulinum neurotoxin type A (BNT-A) intrasalivary gland injections in patients with neurological disorders have been known to effectively treat hypersalivation. However, oral health can be compromised with increasing the dose. The aim of this study was to find out the therapeutic effect of low-dose, ultrasonography-controlled BNT-A injections into the bilateral parotid and submandibular glands on oral health in the treatment of sialorrhea.<br><br>MATERIAL AND METHODS: Twenty patients diagnosed with Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and other neurological disorders, including stroke or birth trauma, received BNT-A injections with salivary tests before and 1&#xa0;month after the injections. Drooling was evaluated using subjective scales and objective assessment of salivary flow rate and oral health (salivary composition and cariogenic bacterial counts).<br><br>RESULTS: A significant decrease was found in salivary flow rate at 1- and 3-month follow-up in the BNT-A treated group. There was no significant change in salivary composition or cariogenic bacterial counts.<br><br>CONCLUSION: BNT-A injections according to the current protocol can effectively manage sialorrhea while maintaining oral health.<br><br>CLINICAL RELEVANCE: Oral health can be considered the mirror of general human health, as the cause of many diseases. Saliva plays a crucial role in protecting the oral cavity. The present study is of high clinical relevance because, although earlier research has proved the effect of Botulinum neurotoxin type A injections on reduction in saliva flow, data about the risks of the treatment method to the oral condition through affecting saliva composition has so far been missing.}, }
@article {pmid27112318, year = {2016}, author = {Vandoorne, E and Vrijsen, B and Belge, C and Testelmans, D and Buyse, B}, title = {Noninvasive ventilation in amyotrophic lateral sclerosis: effects on sleep quality and quality of life.}, journal = {Acta clinica Belgica}, volume = {71}, number = {6}, pages = {389-394}, doi = {10.1080/17843286.2016.1173941}, pmid = {27112318}, issn = {2295-3337}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/physiopathology/*therapy ; Disease Progression ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Noninvasive Ventilation/*methods ; Polysomnography ; Prospective Studies ; *Quality of Life ; Severity of Illness Index ; Sleep/*physiology ; Sleep Wake Disorders/etiology/*physiopathology ; Surveys and Questionnaires ; Time Factors ; }, abstract = {OBJECTIVES: Little is known about the effects of noninvasive ventilation (NIV) on sleep quality in amyotrophic lateral sclerosis (ALS). We aim to evaluate the long-term effects of NIV on sleep quality and quality of life in patients with ALS.<br><br>METHODS: In this prospective observational study, 13 ALS patients were followed for one year after initiating NIV. We evaluated sleep quality, quality of life and functional status with several questionnaires: Epworth sleepiness Scale (ESS), Pittsburg sleep quality index (PSQI), Short Form 36 Health Questionnaire (SF-36), McGill Quality of Life questionnaire (McGillQoL) and revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores (ALSFRS-R).<br><br>RESULTS: Median and interquartile range (IQR) at the start of NIV was 59 (53-65) years. The ALSFRS-R at start was 30 (24-37) (median, IQR), with three patients having severe bulbar impairment (ALSFRS-R-bulbar&#xa0;&#x2264;&#xa0;9). The PaCO2 at start of NIV treatment was 48 (43-52) mmHg (median, IQR). During the one-year follow-up period, a significant decrease in the ALSFRS-R was observed. The impact of NIV in a short term (1&#xa0;month) revealed a statistically significant decrease in ESS, decrease in total PSQI and of four PSQI subscales and improvement of almost all subscales of the McGill questionnaire. Long-term analyses (9&#xa0;months to 1&#xa0;year) revealed that amelioration in ESS and total PSQI was sustained.<br><br>CONCLUSION: We conclude that accurately titrated NIV in ALS patients can stabilize sleep quality and quality of life for at least one year, despite significant disease progression.}, }
@article {pmid27111119, year = {2015}, author = {Althari, S and Gloyn, AL}, title = {When is it MODY? Challenges in the Interpretation of Sequence Variants in MODY Genes.}, journal = {The review of diabetic studies : RDS}, volume = {12}, number = {3-4}, pages = {330-348}, pmid = {27111119}, issn = {1614-0575}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Diabetes Mellitus, Type 2/*genetics ; Humans ; *Mutation ; *Phenotype ; }, abstract = {The genomics revolution has raised more questions than it has provided answers. Big data from large population-scale resequencing studies are increasingly deconstructing classic notions of Mendelian disease genetics, which support a simplistic correlation between mutational severity and phenotypic outcome. The boundaries are being blurred as the body of evidence showing monogenic disease-causing alleles in healthy genomes, and in the genomes of individu-als with increased common complex disease risk, continues to grow. In this review, we focus on the newly emerging challenges which pertain to the interpretation of sequence variants in genes implicated in the pathogenesis of maturity-onset diabetes of the young (MODY), a presumed mono-genic form of diabetes characterized by Mendelian inheritance. These challenges highlight the complexities surrounding the assignments of pathogenicity, in particular to rare protein-alerting variants, and bring to the forefront some profound clinical diagnostic implications. As MODY is both genetically and clinically heterogeneous, an accurate molecular diagnosis and cautious extrapolation of sequence data are critical to effective disease management and treatment. The biological and translational value of sequence information can only be attained by adopting a multitude of confirmatory analyses, which interrogate variant implication in disease from every possible angle. Indeed, studies which have effectively detected rare damaging variants in known MODY genes in normoglycemic individuals question the existence of a sin-gle gene mutation scenario: does monogenic diabetes exist when the genetic culprits of MODY have been systematical-ly identified in individuals without MODY?}, }
@article {pmid27110240, year = {2016}, author = {Bhandare, V and Ramaswamy, A}, title = {Structural Dynamics of Human Argonaute2 and Its Interaction with siRNAs Designed to Target Mutant tdp43.}, journal = {Advances in bioinformatics}, volume = {2016}, number = {}, pages = {8792814}, pmid = {27110240}, issn = {1687-8027}, abstract = {The human Argonaute2 protein (Ago2) is a key player in RNA interference pathway and small RNA recognition by Ago2 is the crucial step in siRNA mediated gene silencing mechanism. The present study highlights the structural and functional dynamics of human Ago2 and the interaction mechanism of Ago2 with a set of seven siRNAs for the first time. The human Ago2 protein adopts two conformations such as "open" and "close" during the simulation of 25 ns. One of the domains named as PAZ, which is responsible for anchoring the 3'-end of siRNA guide strand, is observed as a highly flexible region. The interaction between Ago2 and siRNA, analyzed using a set of siRNAs (targeting at positions 128, 251, 341, 383, 537, 1113, and 1115 of mRNA) designed to target tdp43 mutants causing Amyotrophic Lateral Sclerosis (ALS) disease, revealed the stable and strong recognition of siRNA by the Ago2 protein during dynamics. Among the studied siRNAs, the siRNA341 is identified as a potent siRNA to recognize Ago2 and hence could be used further as a possible siRNA candidate to target the mutant tdp43 protein for the treatment of ALS patients.}, }
@article {pmid27100517, year = {2016}, author = {Rudolf, R and Khan, MM and Wild, F and Hashemolhosseini, S}, title = {The impact of autophagy on peripheral synapses in health and disease.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {21}, number = {7}, pages = {1474-1487}, doi = {10.2741/4467}, pmid = {27100517}, issn = {2768-6698}, mesh = {Animals ; Autophagy/*physiology ; Charcot-Marie-Tooth Disease/physiopathology ; Humans ; Peripheral Nerves/*physiology ; Peripheral Nervous System Diseases/*physiopathology/therapy ; Protein Aggregation, Pathological/physiopathology ; Synapses/*physiology ; }, abstract = {Alterations of autophagy have been linked to several peripheral nervous system diseases, such as amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease. Modulation of autophagy by metabolic or pharmacological interventions has been increasingly recognized as a strategy to fight many of these disorders. Cellular processes that are aberrant in case of impaired autophagy and that might lead to these diseases belong to three different categories: (1) clearing of protein aggregates, (2) regulation of vesicle and cargo turnover, and (3) disposal of damaged mitochondria. This review summarizes the present literature that addresses both, the impact and mechanisms of autophagy on the health of the peripheral nervous system and treatment proposals for human disorders associated with impaired autophagy.}, }
@article {pmid27097283, year = {2016}, author = {Dafinca, R and Scaber, J and Ababneh, N and Lalic, T and Weir, G and Christian, H and Vowles, J and Douglas, AG and Fletcher-Jones, A and Browne, C and Nakanishi, M and Turner, MR and Wade-Martins, R and Cowley, SA and Talbot, K}, title = {C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell-Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Stem cells (Dayton, Ohio)}, volume = {34}, number = {8}, pages = {2063-2078}, pmid = {27097283}, issn = {1549-4918}, support = {TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L002167/1/MRC_/Medical Research Council/United Kingdom ; MR/L023784/1/MRC_/Medical Research Council/United Kingdom ; MC_EX_MR/N50192X/1/MRC_/Medical Research Council/United Kingdom ; MR/M024962/1/MRC_/Medical Research Council/United Kingdom ; TALBOT/OCT15/886-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; TALBOT-MUTIHAC/APR15/832-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; TALBOT/JULY13/820-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; SCABER/JULY13/945-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/P007023/1/MRC_/Medical Research Council/United Kingdom ; MR/L023784/2/MRC_/Medical Research Council/United Kingdom ; WADE-MARTINS/OCT13/867-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Apoptosis ; C9orf72 Protein/*genetics ; Calcium/*metabolism ; Caspase 3/metabolism ; Cell Differentiation ; Cellular Reprogramming ; Cerebral Cortex/pathology ; Cytoplasmic Granules/metabolism/ultrastructure ; DNA Repeat Expansion/*genetics ; Endoplasmic Reticulum/*metabolism/ultrastructure ; Fibroblasts/metabolism/pathology ; Frontotemporal Dementia/genetics/*pathology ; Homeostasis/genetics ; Humans ; Induced Pluripotent Stem Cells/*metabolism ; Mitochondria/metabolism/ultrastructure ; Motor Neurons/*metabolism ; Peptides/metabolism ; Protein Aggregates ; Proto-Oncogene Proteins c-bcl-2/metabolism ; RNA/genetics ; }, abstract = {An expanded hexanucleotide repeat in a noncoding region of the C9orf72 gene is a major cause of amyotrophic lateral sclerosis (ALS), accounting for up to 40% of familial cases and 7% of sporadic ALS in European populations. We have generated induced pluripotent stem cells (iPSCs) from fibroblasts of patients carrying C9orf72 hexanucleotide expansions, differentiated these to functional motor and cortical neurons, and performed an extensive phenotypic characterization. In C9orf72 iPSC-derived motor neurons, decreased cell survival is correlated with dysfunction in Ca(2+) homeostasis, reduced levels of the antiapoptotic protein Bcl-2, increased endoplasmic reticulum (ER) stress, and reduced mitochondrial membrane potential. Furthermore, C9orf72 motor neurons, and also cortical neurons, show evidence of abnormal protein aggregation and stress granule formation. This study is an extensive characterization of iPSC-derived motor neurons as cellular models of ALS carrying C9orf72 hexanucleotide repeats, which describes a novel pathogenic link between C9orf72 mutations, dysregulation of calcium signaling, and altered proteostasis and provides a potential pharmacological target for the treatment of ALS and the related neurodegenerative disease frontotemporal dementia. Stem Cells 2016;34:2063-2078.}, }
@article {pmid27093948, year = {2016}, author = {Shahrizaila, N and Sobue, G and Kuwabara, S and Kim, SH and Birks, C and Fan, DS and Bae, JS and Hu, CJ and Gourie-Devi, M and Noto, Y and Shibuya, K and Goh, KJ and Kaji, R and Tsai, CP and Cui, L and Talman, P and Henderson, RD and Vucic, S and Kiernan, MC}, title = {Amyotrophic lateral sclerosis and motor neuron syndromes in Asia.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {87}, number = {8}, pages = {821-830}, doi = {10.1136/jnnp-2015-312751}, pmid = {27093948}, issn = {1468-330X}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*epidemiology/genetics/mortality ; Asia/epidemiology ; Disease Progression ; Humans ; Motor Neuron Disease/*complications/*epidemiology/genetics/mortality ; Phenotype ; Syndrome ; }, abstract = {While the past 2 decades have witnessed an increasing understanding of amyotrophic lateral sclerosis (ALS) arising from East Asia, particularly Japan, South Korea, Taiwan and China, knowledge of ALS throughout the whole of Asia remains limited. Asia represents >50% of the world population, making it host to the largest patient cohort of ALS. Furthermore, Asia represents a diverse population in terms of ethnic, social and cultural backgrounds. In this review, an overview is presented that covers what is currently known of ALS in Asia from basic epidemiology and genetic influences, through to disease characteristics including atypical phenotypes which manifest a predilection for Asians. With the recent establishment of the Pan-Asian Consortium for Treatment and Research in ALS to facilitate collaborations between clinicians and researchers across the region, it is anticipated that Asia and the Pacific will contribute to unravelling the uncertainties in ALS.}, }
@article {pmid27090433, year = {2016}, author = {Georges, M and Attali, V and Golmard, JL and Morélot-Panzini, C and Crevier-Buchman, L and Collet, JM and Tintignac, A and Morawiec, E and Trosini-Desert, V and Salachas, F and Similowski, T and Gonzalez-Bermejo, J}, title = {Reduced survival in patients with ALS with upper airway obstructive events on non-invasive ventilation.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {87}, number = {10}, pages = {1045-1050}, doi = {10.1136/jnnp-2015-312606}, pmid = {27090433}, issn = {1468-330X}, mesh = {Aged ; Airway Obstruction/*mortality/*therapy ; Amyotrophic Lateral Sclerosis/*mortality/*therapy ; Combined Modality Therapy ; Comorbidity ; Female ; Hospitals, University ; Humans ; Male ; Middle Aged ; *Noninvasive Ventilation ; Oxygen/blood ; Polysomnography ; Prognosis ; Respiratory Insufficiency/mortality/therapy ; Retrospective Studies ; Riluzole/therapeutic use ; Survival Analysis ; }, abstract = {INTRODUCTION: Non-invasive ventilation (NIV) is part of standard care in amyotrophic lateral sclerosis (ALS). Intolerance or unavailability of NIV, as well as the quality of correction of nocturnal hypoventilation, has a direct impact on prognosis.<br><br>OBJECTIVES: We describe the importance of NIV failure due to upper airway obstructive events, the clinical characteristics, as well as their impact on the prognosis of ALS.<br><br>METHODS: Retrospective analysis of the data of 190 patients with ALS and NIV in a single centre for the period 2011-2014. 179 patients tolerating NIV for more than 4&#x2005;h per night without leaks were analysed.<br><br>RESULTS: Among the 179 patients, after correction of leaks, 73 remained inadequately ventilated at night (defined as more than 5% of the night spent at <90% of SpO2), as a result of obstructive events in 67% of cases (n=48). Patients who remained inadequately ventilated after optimal adjustment of ventilator settings presented with shorter survival than adequately ventilated patients. Unexpectedly, patients with upper airway obstructive events without nocturnal desaturation and in whom no adjustment of treatment was therefore performed also presented with shorter survival. On initiation of NIV, no difference was demonstrated between patients with and without upper airway obstructive events. In all patients, upper airway obstruction was concomitant with reduction of ventilatory drive.<br><br>CONCLUSIONS: This study shows that upper airway obstruction during NIV occurs in patients with ALS and is associated with poorer prognosis. Such events should be identified as they can be corrected by adjusting ventilator settings.}, }
@article {pmid27089615, year = {2016}, author = {Tienari, P and Kiviharju, A and Valori, M and Lindholm, D and Laaksovirta, H}, title = {[The pathogenesis of amyotrophic lateral sclerosis and frontal lobe dementia is unraveling: pathology of the nucleus and glutamate sensitivity].}, journal = {Duodecim; laaketieteellinen aikakauskirja}, volume = {132}, number = {5}, pages = {423-431}, pmid = {27089615}, issn = {0012-7183}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*genetics/metabolism/*pathology ; C9orf72 Protein ; DNA Repeat Expansion/genetics ; Frontotemporal Dementia/epidemiology/*genetics/metabolism/*pathology ; Glutamic Acid/metabolism ; Humans ; Mutation ; Proteins/*genetics ; }, abstract = {The mechanisms of neurodegenerative diseases have begun to become unraveled, thanks to the progress in stem cell research. The repeat expansion in the C90RF72 gene was identified in 2011 as the most common genetic cause of both ALS and frontal lobe dementia. Only over a couple of years the disease mechanisms of this mutation have been revealed and treatment trials have already been conducted in nerve cell cultures differentiated from patients' stem cells. We discuss the role of the repeat expansion in the C90RF72 gene in the epidemiology of the diseases and the resulting disturbances in nerve cell function.}, }
@article {pmid27080948, year = {2016}, author = {Cai, M and Yang, EJ}, title = {Ginsenoside Re Attenuates Neuroinflammation in a Symptomatic ALS Animal Model.}, journal = {The American journal of Chinese medicine}, volume = {44}, number = {2}, pages = {401-413}, doi = {10.1142/S0192415X16500233}, pmid = {27080948}, issn = {1793-6853}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Calcium-Binding Proteins/metabolism ; Disease Models, Animal ; Gene Expression/drug effects ; Ginsenosides/administration &amp; dosage/isolation &amp; purification/*pharmacology/*therapeutic use ; Humans ; Inflammation Mediators/metabolism ; Lipopolysaccharide Receptors/metabolism ; Male ; Mice, Transgenic ; Microfilament Proteins/metabolism ; Microglia/metabolism ; Motor Neurons/pathology ; Neuroprotective Agents/administration &amp; dosage/isolation &amp; purification/*pharmacology/*therapeutic use ; Panax/chemistry ; Signal Transduction/drug effects/genetics ; Spinal Cord/cytology/metabolism ; Toll-Like Receptor 4/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, which cause paralysis and respiratory dysfunction. There is currently no permanently effective drug for patients with ALS. Ginsenoside Re (G-Re), one of the most active ingredients of ginseng, has pharmacological activities that affect a number of targets. To investigate the effects of G-Re on neuroinflammation, we used G-Re (2.5[Formula: see text][Formula: see text]g/g) at the Joksamni acupressure point (ST36) once every other day for one week. To evaluate G-Re function in symptomatic human-superoxide dismutase 1 (hSOD1[Formula: see text] transgenic mice, immunohistochemistry and Western blot analysis were performed with the spinal cord of symptomatic hSOD1(G93A) transgenic mice. Here, we report that G-Re exhibits potent neuroprotective effects against neuroinflammation in a murine model of ALS. G-Re treatment reduced the loss of motor neurons and active-microglia-related expression of Iba-1 in the spinal cord of symptomatic hSOD1(G93A) transgenic mice. In addition, compared with age-matched hSOD1(G93A) mice, G-Re-treated hSOD1(G93A) mice showed a significant reduction in expression of pro-inflammatory proteins such as CD14 and TNF-[Formula: see text] protein related to TLR4 signaling pathway. G-Re administration also led to a decrease in cell death-related phospho-p38 protein levels, and had an antioxidative effect by reducing HO1 expression. Together, our data suggest that G-Re could have potent anti-neuroinflammatory effects on ALS by inhibiting the TLR4 pathway.}, }
@article {pmid27074163, year = {2016}, author = {Zeugswetter, FK and Pagitz, M and Friedrich, MS}, title = {Hypochloremia in cats - prevalence and associated diseases.}, journal = {Tierarztliche Praxis. Ausgabe K, Kleintiere/Heimtiere}, volume = {44}, number = {4}, pages = {237-244}, doi = {10.15654/TPK-150647}, pmid = {27074163}, issn = {2567-5842}, mesh = {Acid-Base Imbalance/blood/epidemiology/*veterinary ; Animals ; Blood Gas Analysis/veterinary ; Cat Diseases/blood/*epidemiology ; Cats ; Chlorides/blood ; Prevalence ; Retrospective Studies ; }, abstract = {OBJECTIVE: To describe the prevalence and possible causes of hypochloremia in the local hospital cat population.<br><br>MATERIAL AND METHODS: Retrospective study consisting of two parts. Data were collected from the local electronic medical records database using the search terms "chloride" and "cats" (part&#xa0;A), and "blood gas analysis" and "cats" (part&#xa0;B). The medical records of the hypochloremic cats were then reviewed to determine prior treatment or infusions and to identify major underlying disease processes. Part&#xa0;A included an age and gender matched non-hypochloremic control group, whereas in part&#xa0;B acid-base status was assessed.<br><br>RESULTS: Hypochloremia was detected in 367 (27%) of 1363 blood samples. The application of a correction formula to adjust for free water changes decreased the number of hypochloremic cats to 253 (19%). Only a minority had received glucocorticoids or loop diuretics and the prevalence of vomiting was 44%. Common associated disorders were gastrointestinal and respiratory diseases, as well as azotemia and diabetes mellitus. Polyuria/polydipsia, dehydration, prednisolone or furosemide pretreatment, azotemia and diabetes mellitus increased, whereas fluid therapy and the diagnosis of neoplasia decreased the prevalence of hypochloremia. An inverse correlation was found between corrected chloride and standardized base excess (rs&#xa0;=&#xa0;-0.597, p&#xa0;=&#xa0;0.001) as well as anion gap (rs&#xa0;= -0.4, p&#xa0;=&#xa0;0.026). 99% of the hypochloremic cats had derangements of acid-base balance.<br><br>CONCLUSION: Hypochloremia is a common electrolyte disorder in the local cat population. The correction formula is necessary to adjust for changes in plasma osmolality. Although associated with metabolic alkalosis, most of the hypochloremic cats have a normal or decreased pH. The inverse correlation of chloride and anion gap als well as the high proportion of azotemic or diabetic animals support the concept of compensatory acidosis induced hypochloremia.<br><br>CLINICAL RELEVANCE: Hypochloremia should prompt the clinician to performe blood-gas analysis. Diabetes mellitus (especially ketoacidosis) and renal disease should be included in current algorithms for the evaluation of hypochloremic patients.}, }
@article {pmid27063798, year = {2017}, author = {Bartus, RT and Johnson, EM}, title = {Clinical tests of neurotrophic factors for human neurodegenerative diseases, part 1: Where have we been and what have we learned?.}, journal = {Neurobiology of disease}, volume = {97}, number = {Pt B}, pages = {156-168}, doi = {10.1016/j.nbd.2016.03.027}, pmid = {27063798}, issn = {1095-953X}, mesh = {Animals ; Clinical Trials as Topic ; Humans ; Nerve Growth Factors/*administration &amp; dosage/genetics ; Neurodegenerative Diseases/*therapy ; Neuroprotective Agents/*administration &amp; dosage ; }, abstract = {Over the past 25years, about 3 dozen clinical reports have been published regarding the safety and possible efficacy of neurotrophic factors in patients with various neurodegenerative diseases. This effort involved a half dozen different neurotrophic factors, using at least 5 different general delivery approaches for ALS (amyolateral sclerosis), peripheral neuropathies, PD (Parkinson's disease) and AD (Alzheimer's disease). While none of these efforts have yet produced efficacy data sufficiently robust or reliable to establish neurotrophic factors as treatments for any human disease, the obstacles encountered and novel information reported, when viewed collectively, provide important insight to help future efforts. Three consistent themes emerge from these publications: (1) unexpected and undesirable side effects, at times serious, have plagued many efforts to deliver neurotrophic factors to humans; (2) the magnitude and consistency of clinical benefit has been disappointing; (3) by far that most consistently proposed reason for the side effects and poor efficacy has been inadequate dosing and delivery. This paper reviews and attempts to synthesize the available data derived from clinical tests of neurotrophic factors for neurodegenerative diseases. The obstacles encountered, the solutions attempted, and the lessons learned are discussed. The vast majority of solutions have involved changes in dosing paradigms and dose levels, which has primarily led to improved safety outcomes. However, lack of adequate efficacy remains a significant issue. While current efforts continue to focus exclusively on still-further changes in dosing parameters, a review of available data argues that it may now be the time to ask whether other, non-dose-related variables should be given more serious consideration as being responsible for the great divide that exists between the robust effects seen in animal models and the relatively weak effects seen in human neurodegenerative patients. Foremost among these appears to be the severe degeneration seen in the majority of patients enrolled in past and current trials testing neurotrophic factors in humans. A companion paper (Bartus and Johnson, 2016), reviews the contemporary data and concludes that compelling empirical evidence already exists for enrolling earlier-stage subjects as likely essential to achieving more robust and reliable benefit.}, }
@article {pmid27063797, year = {2017}, author = {Bartus, RT and Johnson, EM}, title = {Clinical tests of neurotrophic factors for human neurodegenerative diseases, part 2: Where do we stand and where must we go next?.}, journal = {Neurobiology of disease}, volume = {97}, number = {Pt B}, pages = {169-178}, doi = {10.1016/j.nbd.2016.03.026}, pmid = {27063797}, issn = {1095-953X}, mesh = {Animals ; Clinical Trials as Topic ; Humans ; Nerve Growth Factors/*administration &amp; dosage/genetics ; Neurodegenerative Diseases/*therapy ; Neuroprotective Agents/*administration &amp; dosage ; }, abstract = {The therapeutic potential of neurotrophic factors has been recognized for decades, with clinical trials in human neurodegenerative diseases extending back at least 25years. While improvements in clinical dosing paradigms have reduced the side effects commonly seen in the earlier trials, efficacy has remained a serious disappointment (reviewed in Bartus and Johnson, 2016). This lengthy clinical effort stands in contrast to robust effects consistently achieved from different neurotrophic factors in a variety of animal models of neurodegeneration. This review discusses the prevailing assumption and supporting data that the major reason for the disappointing efficacy of past clinical trials is related to suboptimal dosing methods. It is concluded that while further improvements in dosing parameters might be useful, a much greater problem centers around a number of specific morphologic and functional changes in neurons in human neurodegenerative disease that mitigate the ability of neurotrophic factors to exert their effects. Moreover, the biological substrate which neurotrophic factors depend upon to exert their effects continues to erode as time progresses, due to the progressive nature of these diseases. For this reason, most of the empirically-supported reasons contributing to the weak neurotrophic responses in human patients can be mitigated by enrolling less severely advanced cases. It is further concluded that recent clinical trials of neurotrophic factors have generated important evidence that shifts risk: benefit assessments to support enrolling earlier-stage patients. While the Alzheimer's field has begun to shift attention toward much earlier-stage (even prodromal) patients in trials intended to modify disease progression, other neurodegenerative diseases (e.g., Parkinson's, ALS and possibly HD) must now consider similar changes in approach.}, }
@article {pmid27059126, year = {2016}, author = {Hsueh, KW and Chiou, TW and Chiang, SF and Yamashita, T and Abe, K and Borlongan, CV and Sanberg, PR and Huang, AY and Lin, SZ and Harn, HJ}, title = {Autophagic down-regulation in motor neurons remarkably prolongs the survival of ALS mice.}, journal = {Neuropharmacology}, volume = {108}, number = {}, pages = {152-160}, doi = {10.1016/j.neuropharm.2016.03.035}, pmid = {27059126}, issn = {1873-7064}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*pathology ; Animals ; Autophagy/*physiology ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Down-Regulation/drug effects/*physiology ; Female ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/drug effects/*physiology ; Phthalic Anhydrides/*pharmacology/therapeutic use ; Random Allocation ; Superoxide Dismutase-1/genetics ; Survival Rate/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal degenerating disease, characterized by progressive muscular atrophy without any effective treatment. Here, we demonstrated the efficacy of abrograting autophagy in motor neurons (MN) by treatment with n-butylidenephthalide (n-BP) in ALS transgenic mice (SOD1(G93A)). Pre-symptomatic oral administration of 250 mg/kg/bid n-BP significantly prolonged the survival period (203.9 ± 18.3 days), improved motor function, and attenuated MN loss compared to vehicle control (126.4 ± 7.2 days). This prolonged survival of ALS mice is much more robust than that reported with riluzole (140 days), which is an approved clinical therapy for ALS. The therapeutic mechanism targeted by n-BP involved the autophagic pathway as evidenced by decreased LC3-II expression (a biomarker of autophagy), enhanced mTOR levels, and attenuated autophagic activity, altogether increasing MN survival in a dose-dependent manner. This result was also confirmed by double transgenic mice (SOD1(G93A):LC3-GFP) which showed that oral administration of n-BP reduced GFP density and decreased caspase-3 expression. In addition, electron microscopy revealed that n-BP administration not only decreased autophagosome number but also reduced morphological dysfunction of mitochondria. In summary, these results indicate that down-regulation of autophagy activation via n-BP may pose as a therapeutic regimen for ALS and relevant neurodegenerative diseases.}, }
@article {pmid27057909, year = {2016}, author = {Qiu, H and Li, JH and Yin, SB and Ke, JQ and Qiu, CL and Zheng, GQ}, title = {Dihuang Yinzi, a Classical Chinese Herbal Prescription, for Amyotrophic Lateral Sclerosis: A 12-Year Follow-up Case Report.}, journal = {Medicine}, volume = {95}, number = {14}, pages = {e3324}, pmid = {27057909}, issn = {1536-5964}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy ; Drugs, Chinese Herbal/*therapeutic use ; Female ; Follow-Up Studies ; Humans ; *Phytotherapy ; Survivors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease with no effective treatment and death within 2 to 5 years after symptom onset. Here, we reported a case of ALS patient using modified Dihuang Yinzi (DHYZ), a classical traditional Chinese medicine (TCM) prescription, who has survived 12 years with significant improvement in bulbar paralysis.A 41-year-old Chinese Han nationality woman was admitted to the hospital with complaints of weakened bilateral grip, slurred speech, stumbling, and muscle twitching for 3 years. The electromyography showed neurogenic injury in bilateral upper limbs and tongue. She was diagnosed with ALS according to the revised El escorial criteria. The patient was orally administrated with Riluzole 100 mg daily for 10 months and then stopped. Subsequently, she resorted to TCM. Based on the TCM theory, the patient was diagnosed with Yinfei syndrome because of kidney deficiency. DHYZ was chosen because it has the function of replenishing kidney essence to treat Yinfei syndrome. Up to now, she has been using modified DHYZ continuously for 12 years. The patient survived with ALS and did not require permanent continuous ventilator. In addition, the symptoms of choking on liquids are improved, and the utility of 30 mL water swallow test was improved with grade 2. The symptoms of muscle fibrillations of limbs are also reduced. However, muscle strength worsened slowly. The repeated electromyography showed motor conduction amplitude reducing gradually and velocity not changing more when compared with the initial electromyography.Our findings suggested that DHYZ can be potentially used in ALS patients because of its multi-targeted neuroprotection and general safety, although ALS does not have a cure. In addition, we identified the area that is worthy of further study and DHYZ as a promising candidate for further clinical application and ALS trials. Rigorous randomized controlled trials are needed in the future.}, }
@article {pmid27049459, year = {2016}, author = {Brennan, FH and Lee, JD and Ruitenberg, MJ and Woodruff, TM}, title = {Therapeutic targeting of complement to modify disease course and improve outcomes in neurological conditions.}, journal = {Seminars in immunology}, volume = {28}, number = {3}, pages = {292-308}, doi = {10.1016/j.smim.2016.03.015}, pmid = {27049459}, issn = {1096-3618}, mesh = {Brain/*pathology ; Clinical Trials as Topic ; Complement Activation ; Complement Inactivating Agents/*therapeutic use ; Complement System Proteins/*metabolism ; Disease Progression ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/immunology/*therapy ; Neuroprotection ; Treatment Outcome ; Wounds and Injuries/immunology/*therapy ; }, abstract = {The recognition that complement proteins are abundantly present and can have pathological roles in neurological conditions offers broad scope for therapeutic intervention. Accordingly, an increasing number of experimental investigations have explored the potential of harnessing the unique activation pathways, proteases, receptors, complexes, and natural inhibitors of complement, to mitigate pathology in acute neurotrauma and chronic neurodegenerative diseases. Here, we review mechanisms of complement activation in the central nervous system (CNS), and explore the effects of complement inhibition in cerebral ischemic-reperfusion injury, traumatic brain injury, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease. We consider the challenges and opportunities arising from these studies. As complement therapies approach clinical translation, we provide perspectives on how promising complement-targeted therapeutics could become part of novel and effective future treatment options to improve outcomes in the initiation and progression stages of these debilitating CNS disorders.}, }
@article {pmid27046344, year = {2016}, author = {Gonzalez Calzada, N and Prats Soro, E and Mateu Gomez, L and Giro Bulta, E and Cordoba Izquierdo, A and Povedano Panades, M and Dorca Sargatal, J and Farrero Muñoz, E}, title = {Factors predicting survival in amyotrophic lateral sclerosis patients on non-invasive ventilation.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {17}, number = {5-6}, pages = {337-342}, doi = {10.3109/21678421.2016.1165256}, pmid = {27046344}, issn = {2167-9223}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*mortality/psychology/*therapy ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Noninvasive Ventilation/*methods ; Predictive Value of Tests ; Prognosis ; Proportional Hazards Models ; Retrospective Studies ; Risk Factors ; Vital Capacity/physiology ; }, abstract = {OBJECTIVE: Non invasive ventilation (NIV) improves quality of life and extends survival in amyotrophic lateral sclerosis (ALS) patients. However, few data exist about the factors related to survival. We intended to assess the predictive factors that influence survival in patients after NIV initiation.<br><br>METHODS: Patients who started NIV from 2000 to 2014 and were tolerant (compliance&#x2009;&#x2265;&#x2009;4 hours) were included; demographic, disease related and respiratory variables at NIV initiation were analysed. Statistical analysis was performed using the Kaplan-Meier test and Cox proportional hazard models.<br><br>RESULTS: 213 patients were included with median survival from NIV initiation of 13.5 months. In univariate analysis, the identified risk factors for mortality were severity of bulbar involvement (HR 2), Forced Vital Capacity (FVC) % (HR 0.99) and ALSFRS-R (HR 0.97). Multivariate analysis showed that bulbar involvement (HR 1.92) and ALSFRS-R (HR 0.97) were independent predictive factors of survival in patients on NIV.<br><br>CONCLUSIONS: In our study, the two prognostic factors in ALS patients following NIV were the severity of bulbar involvement and ALSFRS-R at the time on NIV initiation. A better assessment of bulbar involvement, including evaluation of the upper airway, and a careful titration on NIV are necessary to optimize treatment efficacy.}, }
@article {pmid27045954, year = {2016}, author = {Tremolizzo, L and Pellegrini, A and Susani, E and Lunetta, C and Woolley, SC and Ferrarese, C and Appollonio, I}, title = {Behavioural But Not Cognitive Impairment Is a Determinant of Caregiver Burden in Amyotrophic Lateral Sclerosis.}, journal = {European neurology}, volume = {75}, number = {3-4}, pages = {191-194}, doi = {10.1159/000445110}, pmid = {27045954}, issn = {1421-9913}, mesh = {Adult ; Affect ; Aged ; Amyotrophic Lateral Sclerosis/*complications/*psychology ; Attention Deficit and Disruptive Behavior Disorders/etiology/psychology ; Caregivers/*psychology ; Cognition Disorders/etiology/psychology ; *Cost of Illness ; Female ; Humans ; Male ; Middle Aged ; Psychiatric Status Rating Scales ; Quality of Life/psychology ; }, abstract = {BACKGROUND: Caregivers of patients affected by amyotrophic lateral sclerosis (ALS) are involved with great determination in the treatment process since the earliest stages of the disease with an increasing burden to be of help to the ailing persons.<br><br>AIM: To test separately the impact of ALS patients' cognitive and behavioural impairments on caregiver burden and mood status in 84 outpatient/main caregiver couples.<br><br>DESIGN: Patients were tested with the ALS-Cognitive Behavioural Screen (ALSCBS-ci and -bi), Frontal Assessment Battery, Weigl's Sorting Test, Mini-Mental State Examination, Beck's Depression Inventory (BDI). Analogously, caregivers completed the BDI and Caregiver Burden Inventory (CBI).<br><br>RESULTS: CBI correlated with ALSCBS-bi, besides ALSFRS-R, disease progression index and caregiver BDI. Caregiver BDI also correlated with ALSCBS-bi scores. No correlations were found with cognitive tests. The correlation between CBI and the ALSCBS-bi score was specifically sustained by the social burden sub-domain of CBI.<br><br>CONCLUSIONS: As previously reported using other tools, behavioural impairment is a determinant of burden and mood in ALS caregivers. Conversely, cognitive impairment fails to emerge as a major target when aiming at easing the increasing burden or improving mood in ALS caregivers.}, }
@article {pmid27045653, year = {2016}, author = {Zhang, R and Zang, D}, title = {[Mechanism of neuroprotective effects of fibroblast growth factor 2 in the mouse model of ALS].}, journal = {Zhonghua yi xue za zhi}, volume = {96}, number = {11}, pages = {886-890}, doi = {10.3760/cma.j.issn.0376-2491.2016.11.013}, pmid = {27045653}, issn = {0376-2491}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Disease Models, Animal ; Fibroblast Growth Factor 2/*pharmacology ; Mice ; Mice, Transgenic ; Neural Stem Cells/*drug effects ; Neuroprotective Agents/*pharmacology ; Superoxide Dismutase/genetics ; }, abstract = {OBJECTIVE: To examine the neuroprotective effects of FGF-2 and explore the underlying mechanisms involved in its effects on neural precursor cells (NPCs) and S-IR boutons.<br><br>METHODS: The mice models were established, and the animals were randomly divided into 3 groups: non-transgenic wild type group (WT), superoxide dismutase (SOD)1 G93A G1H transgenic group (SOD1), and fibroblast growth factor (FGF)-2-treated group (FGF-2), each group 40 mice. Mice of FGF-2 group were treated with FGF-2 at postnatal day 60 (P60). These three groups were examined at postnatal day 90 (P90) and 120 (P120). The changes of NPCs and S-IR boutons were checked by means of immunohistochemical detection.<br><br>RESULTS: When mice were examined at P90 and P120, the number of Nestin(+) NPCs was (47&#xb1;24) and (147&#xb1;45) in the SOD1 group, (77&#xb1;27) and (285&#xb1;103) in the FGF-2 group. A marked increase was detected in the FGF-2 mice compared to the SOD1 mice at P120 (P<0.01). At P120 there was a clear decrease in the density of S-IR boutons in the SOD1 (0.5&#xb1;0.1) and FGF-2 (0.8&#xb1;0.1) mice compared to the WT (0.9&#xb1;0.1) mice, but a more significant decrease in the density of S-IR boutons was detected in the SOD1 mice compared to the FGF-2 mice (P<0.05).<br><br>CONCLUSION: FGF-2 may be a useful treatment to provide neuroprotection against neurodegeneration in amyotrophic lateral sclerosis (ALS) by encouraging the proliferation of NPCs and delaying the decrease in the density of S-IR boutons.}, }
@article {pmid27034475, year = {2016}, author = {Sechi, G and Sechi, E and Fois, C and Kumar, N}, title = {Advances in clinical determinants and neurological manifestations of B vitamin deficiency in adults.}, journal = {Nutrition reviews}, volume = {74}, number = {5}, pages = {281-300}, doi = {10.1093/nutrit/nuv107}, pmid = {27034475}, issn = {1753-4887}, mesh = {Adult ; Alzheimer Disease/etiology/metabolism ; Amyotrophic Lateral Sclerosis/etiology/metabolism ; Central Nervous System/metabolism/*pathology ; Humans ; Nervous System Diseases/*etiology/metabolism ; Parkinson Disease/etiology/metabolism ; Vitamin B Complex/*metabolism ; Vitamin B Deficiency/*complications/metabolism ; }, abstract = {B vitamin deficiency is a leading cause of neurological impairment and disability throughout the world. Multiple B vitamin deficiencies often coexist, and thus an understanding of the complex relationships between the different biochemical pathways regulated in the brain by these vitamins may facilitate prompter diagnosis and improved treatment. Particular populations at risk for multiple B vitamin deficiencies include the elderly, people with alcoholism, patients with heart failure, patients with recent obesity surgery, and vegetarians/vegans. Recently, new clinical settings that predispose individuals to B vitamin deficiency have been highlighted. Moreover, other data indicate a possible pathogenetic role of subclinical chronic B vitamin deficiency in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In light of these findings, this review examines the clinical manifestations of B vitamin deficiency and the effect of B vitamin deficiency on the adult nervous system. The interrelationships of multiple B vitamin deficiencies are emphasized, along with the clinical phenotypes related to B vitamin deficiencies. Recent advances in the clinical determinants and diagnostic clues of B vitamin deficiency, as well as the suggested therapies for B vitamin disorders, are described.}, }
@article {pmid27033194, year = {2017}, author = {Chong, CM and Ai, N and Lee, SM}, title = {ROCK in CNS: Different Roles of Isoforms and Therapeutic Target for Neurodegenerative Disorders.}, journal = {Current drug targets}, volume = {18}, number = {4}, pages = {455-462}, doi = {10.2174/1389450117666160401123825}, pmid = {27033194}, issn = {1873-5592}, mesh = {Animals ; Central Nervous System/metabolism ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/drug therapy/*metabolism ; Signal Transduction ; rho-Associated Kinases/*metabolism ; }, abstract = {Rho-associated protein kinase (ROCK) is a serine-threonine kinase originally identified as a crucial regulator of actin cytoskeleton. Recent studies have defined new functions of ROCK as a critical component of diverse signaling pathways in neurons. In addition, inhibition of ROCK causes several biological events such as increase of neurite outgrowth, axonal regeneration, and activation of prosurvival Akt. Thus, it has attracted scientist's strong attentions and considered ROCK as a promising therapeutic target for the treatment of neurodegenerative disorders including Alzheimer disease, Parkinson's disease, Huntington';s disease, multiple sclerosis, and amyotrophic lateral sclerosis. However, ROCK has two highly homologous isoforms, ROCK1 and ROCK2. Accumulated evidences indicate that ROCK1 and ROCK2 might involve in distinct cellular functions in central nervous system (CNS) and neurodegenerative processes. This review summarizes recent updates regarding ROCK isoformspecific functions in CNS and the progress of ROCK inhibitors in preclinical studies for neurodegenerative diseases.}, }
@article {pmid29377035, year = {2016}, author = {Walker, RH}, title = {The non-Huntington disease choreas: Five new things.}, journal = {Neurology. Clinical practice}, volume = {6}, number = {2}, pages = {150-156}, pmid = {29377035}, issn = {2163-0402}, abstract = {PURPOSE OF REVIEW: Chorea can be due to a wide variety of causes. In this review, I provide updates on several recently identified genetic and autoimmune causes of chorea, and review evidence supporting the use of deep brain stimulation in chorea.<br><br>RECENT FINDINGS: New genes that may cause chorea include ADCY5 (encoding for adenylate cyclase 5) C9ORF72 (in addition to amyotrophic lateral sclerosis and frontotemporal dementia), and those responsible for the neurodegeneration with brain iron accumulation disorders. Novel autoantibodies are increasingly being identified as associated with a variety of neurologic syndromes, including chorea, in both paraneoplastic and non-paraneoplastic settings. Deep brain stimulation can be a useful intervention in patients with chorea who do not respond to oral medications, whether due to neurodegenerative or nondegenerative causes.<br><br>SUMMARY: New causes of chorea continue to be identified. Correct diagnosis is essential for prognostication and treatment.}, }
@article {pmid27025224, year = {2016}, author = {Lin, CJ and Huang, HK and Wang, ST and Huang, YC and Liu, CL and Wang, JP}, title = {Open versus percutaneous release for trigger digits: Reversal between short-term and long-term outcomes.}, journal = {Journal of the Chinese Medical Association : JCMA}, volume = {79}, number = {6}, pages = {340-344}, doi = {10.1016/j.jcma.2016.01.009}, pmid = {27025224}, issn = {1728-7731}, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Patient Satisfaction ; Trigger Finger Disorder/*therapy ; }, abstract = {BACKGROUND: There have been excellent outcomes reported with both open and percutaneous release of trigger finger. However, a comparison of short- and long-term outcomes between these two techniques has not been performed. The purpose of this study is to compare the short-term (3 months) and long-term (2 years) outcomes between open surgical release and percutaneous needle release of trigger finger.<br><br>METHODS: Between 2009 and 2012, a total of 198 patients with trigger finger treated with either open (n&#xa0;=&#xa0;72) or percutaneous (n&#xa0;=&#xa0;126) release of the A1 pulley were enrolled in the study. Both short-term and long-term outcomes were evaluated, using the criteria established through Gilberts et&#xa0;al's questionnaire.<br><br>RESULTS: The short-term satisfaction of patients with their results was significantly better in the percutaneous release group, whereas the long-term satisfaction rates were better in the open-release group, although not at a statistically significant level.<br><br>CONCLUSION: The percutaneous release method to release trigger finger does not have a better long-term satisfaction rate than the open release approach, although percutaneous release has a significantly better short-term satisfaction rate.}, }
@article {pmid27012524, year = {2016}, author = {Browne, EC and Abbott, BM}, title = {Recent progress towards an effective treatment of amyotrophic lateral sclerosis using the SOD1 mouse model in a preclinical setting.}, journal = {European journal of medicinal chemistry}, volume = {121}, number = {}, pages = {918-925}, doi = {10.1016/j.ejmech.2016.02.048}, pmid = {27012524}, issn = {1768-3254}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Biological Products/therapeutic use ; Disease Models, Animal ; Drug Discovery ; Humans ; Mice ; Superoxide Dismutase-1/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, fatal and incurable neurodegenerative disorder. Motor neurone degeneration can be caused by genetic mutation but the exact etiology of the disease, particularly for sporadic illness, still remains unclear. Therapeutics which target known pathogenic mechanisms involved in ALS, such as protein aggregation, oxidative stress, apoptosis, inflammation, endoplasmic reticulum stress and mitochondria dysfunction, are currently being pursued in order to provide neuroprotection which may be able to slow down, or perhaps even halt, disease progression. This present review focuses on the compounds which have been recently evaluated using the SOD1 mouse model, the most widely used preclinical model for ALS research.}, }
@article {pmid27012417, year = {2016}, author = {Diaz-Amarilla, P and Miquel, E and Trostchansky, A and Trias, E and Ferreira, AM and Freeman, BA and Cassina, P and Barbeito, L and Vargas, MR and Rubbo, H}, title = {Electrophilic nitro-fatty acids prevent astrocyte-mediated toxicity to motor neurons in a cell model of familial amyotrophic lateral sclerosis via nuclear factor erythroid 2-related factor activation.}, journal = {Free radical biology &amp; medicine}, volume = {95}, number = {}, pages = {112-120}, pmid = {27012417}, issn = {1873-4596}, support = {R01 HL132550/HL/NHLBI NIH HHS/United States ; R01 NS089640/NS/NINDS NIH HHS/United States ; P01 HL103455/HL/NHLBI NIH HHS/United States ; R37 HL058115/HL/NHLBI NIH HHS/United States ; R01 HL058115/HL/NHLBI NIH HHS/United States ; P30 DK072506/DK/NIDDK NIH HHS/United States ; K99 ES019186/ES/NIEHS NIH HHS/United States ; R01 HL064937/HL/NHLBI NIH HHS/United States ; R00 ES019186/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Antioxidants/chemistry/*metabolism ; Arachidonic Acid/chemistry/metabolism ; Astrocytes/*metabolism/pathology ; Disease Models, Animal ; Fatty Acids/chemistry/metabolism ; Glutathione/biosynthesis ; Humans ; Mice ; Motor Neurons/*metabolism/pathology ; NF-E2-Related Factor 2/*genetics/metabolism ; Nitric Oxide/chemistry ; Oleic Acid/chemistry/metabolism ; Signal Transduction/genetics ; Superoxide Dismutase/metabolism ; Transcriptional Activation/genetics ; }, abstract = {Nitro-fatty acids (NO2-FA) are electrophilic signaling mediators formed in tissues during inflammation, which are able to induce pleiotropic cytoprotective and antioxidant pathways including up regulation of Nuclear factor erythroid 2-related factor 2 (Nrf2) responsive genes. Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons associated to an inflammatory process that usually aggravates the disease progression. In ALS animal models, the activation of the transcription factor Nrf2 in astrocytes confers protection to neighboring neurons. It is currently unknown whether NO2-FA can exert protective activity in ALS through Nrf2 activation. Herein we demonstrate that nitro-arachidonic acid (NO2-AA) or nitro-oleic acid (NO2-OA) administrated to astrocytes expressing the ALS-linked hSOD1(G93A) induce antioxidant phase II enzyme expression through Nrf2 activation concomitant with increasing intracellular glutathione levels. Furthermore, treatment of hSOD1(G93A)-expressing astrocytes with NO2-FA prevented their toxicity to motor neurons. Transfection of siRNA targeted to Nrf2 mRNA supported the involvement of Nrf2 activation in NO2-FA-mediated protective effects. Our results show for the first time that NO2-FA induce a potent Nrf2-dependent antioxidant response in astrocytes capable of preventing motor neurons death in a culture model of ALS.}, }
@article {pmid27010615, year = {2016}, author = {Prell, T and Ringer, TM and Wullenkord, K and Garrison, P and Gunkel, A and Stubendorff, B and Witte, OW and Grosskreutz, J}, title = {Assessment of pulmonary function in amyotrophic lateral sclerosis: when can polygraphy help evaluate the need for non-invasive ventilation?.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {87}, number = {9}, pages = {1022-1026}, pmid = {27010615}, issn = {1468-330X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/mortality/*physiopathology ; Dyspnea ; Female ; Humans ; Male ; Middle Aged ; Noninvasive Ventilation/*methods ; *Polysomnography ; Positive-Pressure Respiration/*methods ; Respiratory Insufficiency ; Retrospective Studies ; Vital Capacity ; }, abstract = {BACKGROUND: Non-invasive positive-pressure ventilation (NPPV) is an established, effective, long-term treatment for patients with amyotrophic lateral sclerosis (ALS), but the correct indicators for the establishment of NPPV have not been defined.<br><br>METHODS: In this retrospective study, records (spirometry, nocturnal polygraphy, nocturnal blood gases) of 131 patients with ALS were reviewed in order to evaluate the role of polygraphy for prediction of respiratory failure in ALS.<br><br>RESULTS: The patient group reporting with versus without dyspnoea had significantly lower values on the revised ALS-Functional Rating Scale (ALSFRS-R), vital capacity (VC), forced VC (FVC), arterial oxygen saturation and arterial oxygen tension readings, including a higher apnoea-hypopnoea index. 23 patients, who did not report about dyspnoea, had an FVC of <75%. Nocturnal hypoventilation was observed in 67% of the patients with ALS independent of their ALSFRS-R. The patient group with nocturnal hypoventilation was characterised by a significantly lower VC, FVC and maximal static inspiratory pressure compared with the group without nocturnal hypoventilation. However, also in the absence of nocturnal hypoventilation, 8 patients had a VC <50% as predicted.<br><br>DISCUSSION: Our study shows that in patients not reporting dyspnoea and having an FVC of >75%, nocturnal hypoventilation was observed in nearly every second patient. Therefore, for the question of whether NPPV should be initiated, polygraphy does not provide useful additional information if the FVC is already <75% as predicted. However, in patients with more or less normal lung function parameters or where lung spirometry cannot perform adequately (eg, bulbar ALS), it can provide sufficient evidence for the need of NPPV.}, }
@article {pmid26996632, year = {2016}, author = {Inan, SY and Soner, BC and Sahin, AS}, title = {Behavioural effects of basal ganglia rho-kinase inhibition in the unilateral 6-hydroxydopamine rat model of Parkinson's disease.}, journal = {Metabolic brain disease}, volume = {31}, number = {4}, pages = {849-857}, pmid = {26996632}, issn = {1573-7365}, mesh = {Amides/*pharmacology/therapeutic use ; Animals ; Antiparkinson Agents/*pharmacology/therapeutic use ; Basal Ganglia/*drug effects ; Behavior, Animal/*drug effects ; Disease Models, Animal ; Enzyme Inhibitors/*pharmacology/therapeutic use ; Male ; Motor Activity/drug effects ; Oxidopamine ; Parkinson Disease, Secondary/*drug therapy/metabolism ; Pyridines/*pharmacology/therapeutic use ; Rats ; rho-Associated Kinases/*antagonists &amp; inhibitors ; }, abstract = {Parkinson's disease (PD) is one of the most common neurodegenerative disorders, which affects more than six million people in the world. While current available pharmacological therapies for PD in the early stages of the disease usually improve motor symptoms, they cause side effects, such as fluctuations and dyskinesias in the later stages. In this later stage, high frequency deep brain stimulation of the subthalamic nucleus (STN-DBS) is a treatment option which is most successful to treat drug resistant advanced PD. It has previously been demonstrated that activation of Rho/Rho-kinase pathway is involved in the dopaminergic cell degeneration which is one of the main characteristics of PD pathology. In addition, the involvement of this pathway has been suggested in diverse cellular events in the central nervous system; such as epilepsy, anxiety-related behaviors, regulation of dendritic and axonal morphology, antinociception, subarachnoid haemorrhage, spinal cord injury and amyotrophic lateral sclerosis. However, up to date, to our knowledge there are no previous reports showing the beneficial effects of the potent Rho-kinase inhibitor Y-27632 in the 6-hydroxydopamine (6-OHDA) rat model of PD. Therefore, in the present study, we investigated the behavioural effects of basal ganglia Y-27632 microinjections in this PD model. Our results indicated that basal ganglia Y-27632 microinjections significantly decreased the number of contralateral rotations-induced by apomorphine, significantly increased line crossings in the open-field test, contralateral forelimb use in the limb-use asymmetry test and contralateral tape playing time in the somatosensory asymmetry test, which may suggest that Y-27632 could be a potentially active antiparkinsonian agent.}, }
@article {pmid26993125, year = {2016}, author = {Board, PG and Menon, D}, title = {Structure, function and disease relevance of Omega-class glutathione transferases.}, journal = {Archives of toxicology}, volume = {90}, number = {5}, pages = {1049-1067}, doi = {10.1007/s00204-016-1691-1}, pmid = {26993125}, issn = {1432-0738}, mesh = {Animals ; Anti-Inflammatory Agents/pharmacology ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation, Enzymologic ; Genetic Predisposition to Disease ; Glutathione/*metabolism ; Glutathione Transferase/antagonists &amp; inhibitors/chemistry/genetics/*metabolism ; Humans ; Inactivation, Metabolic ; Oxidation-Reduction ; Polymorphism, Genetic ; Protein Conformation ; Protein Processing, Post-Translational ; Structure-Activity Relationship ; Substrate Specificity ; }, abstract = {The Omega-class cytosolic glutathione transferases (GSTs) have distinct structural and functional attributes that allow them to perform novel roles unrelated to the functions of other GSTs. Mammalian GSTO1-1 has been found to play a previously unappreciated role in the glutathionylation cycle that is emerging as significant mechanism regulating protein function. GSTO1-1-catalyzed glutathionylation or deglutathionylation of a key signaling protein may explain the requirement for catalytically active GSTO1-1 in LPS-stimulated pro-inflammatory signaling through the TLR4 receptor. The observation that ML175 a specific GSTO1-1 inhibitor can block LPS-stimulated inflammatory signaling has opened a new avenue for the development of novel anti-inflammatory drugs that could be useful in the treatment of toxic shock and other inflammatory disorders. The role of GSTO2-2 remains unclear. As a dehydroascorbate reductase, it could contribute to the maintenance of cellular redox balance and it is interesting to note that the GSTO2 N142D polymorphism has been associated with multiple diseases including Alzheimer's disease, Parkinson's disease, familial amyotrophic lateral sclerosis, chronic obstructive pulmonary disease, age-related cataract and breast cancer.}, }
@article {pmid26991509, year = {2016}, author = {Jimenez, F and Rojano-Delgado, AM and Fernández, PT and Rodríguez-Suárez, C and Atienza, SG and De Prado, R}, title = {Physiological, biochemical and molecular characterization of an induced mutation conferring imidazolinone resistance in wheat.}, journal = {Physiologia plantarum}, volume = {158}, number = {1}, pages = {2-10}, doi = {10.1111/ppl.12445}, pmid = {26991509}, issn = {1399-3054}, mesh = {Acetolactate Synthase/*genetics ; Base Sequence ; Herbicide Resistance/*genetics ; Herbicides/pharmacology ; Imidazoles/*pharmacology ; Mutation ; Sequence Alignment ; Sequence Analysis, DNA ; Triticum/genetics/*physiology ; }, abstract = {The Clearfield(®) wheat cultivars possessing imidazolinone (IMI)-resistant traits provide an efficient option for controlling weeds. The imazamox-resistant cultivar Pantera (Clearfield(®)) was compared with a susceptible cultivar (Gazul). Target and non-target mechanisms of resistance were studied to characterize the resistance of Pantera and to identify the importance of each mechanism involved in this resistance. Pantera is resistant to imazamox as was determined in previous experiments. The molecular study confirmed that it carries a mutation Ser-Asn627 conferring resistance to imazamox in two out of three acetolactate synthase (ALS) genes (imi1 and imi2), located in wheat on chromosomes 6B and 6D, respectively. However, the last gene (imi3) located on chromosome 6A does not carry any mutation conferring resistance. As a result, photosynthetic activity and chlorophyll content were reduced after imazamox treatment. Detoxification was higher in the resistant biotype as shown by metabolomic study while imazamox translocation was higher in the susceptible cultivar. Interestingly, imazamox metabolism was higher at higher doses of herbicide, which suggests that the detoxification process is an inducible mechanism in which the upregulation of key gene coding for detoxification enzymes could play an important role. Thus, the identification of cultivars with a higher detoxification potential would allow the development of more resistant varieties.}, }
@article {pmid26988030, year = {2016}, author = {Ono, Y and Tsuruma, K and Takata, M and Shimazawa, M and Hara, H}, title = {Glycoprotein nonmetastatic melanoma protein B extracellular fragment shows neuroprotective effects and activates the PI3K/Akt and MEK/ERK pathways via the Na+/K+-ATPase.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {23241}, pmid = {26988030}, issn = {2045-2322}, mesh = {Animals ; Cell Line, Tumor ; Cell Membrane/metabolism ; Eye Proteins/chemistry/*metabolism ; MAP Kinase Signaling System ; Membrane Glycoproteins/chemistry/*metabolism ; Mice ; Neuroprotective Agents/chemistry/metabolism ; Phosphatidylinositol 3-Kinases/*metabolism ; Protein Binding ; Proto-Oncogene Proteins c-akt/*metabolism ; Sodium-Potassium-Exchanging ATPase/*metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Glycoprotein nonmetastatic melanoma protein B (GPNMB) plays important roles in various types of cancer and amyotrophic lateral sclerosis (ALS). The details of GPNMB function and its interacting protein have not been clarified. Therefore, to identify GPNMB binding partners on the cell membrane, we used membrane protein library/BLOTCHIP-MS technology, which enables us to analyze all cell membrane proteins as binding partners of the GPNMB extracellular fragment. As a result of a comprehensive search, we identified the alpha subunits of Na(+)/K(+)-ATPase (NKA) as a possible binding partner. We confirmed the interaction between the GPNMB extracellular fragment and NKA by immunoprecipitation and immunostaining in NSC-34 cells. Indeed, endogenous GPNMB extracellular fragment bound to and colocalized with NKA alpha subunits. Furthermore, exogenous GPNMB extracellular fragment, i.e., human recombinant GPNMB, also bound to and colocalized with NKA alpha subunits. Additionally, we found that the GPNMB extracellular fragment had neuroprotective effects and activated the phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathways via NKA. These findings indicated that NKA may act as a novel "receptor" for the GPNMB extracellular fragment, offering additional molecular targets for the treatment of GPNMB-related diseases, including various types of cancer and ALS.}, }
@article {pmid26985861, year = {2016}, author = {Albrecht, DS and Granziera, C and Hooker, JM and Loggia, ML}, title = {In Vivo Imaging of Human Neuroinflammation.}, journal = {ACS chemical neuroscience}, volume = {7}, number = {4}, pages = {470-483}, pmid = {26985861}, issn = {1948-7193}, support = {154508/SNSF_/Swiss National Science Foundation/Switzerland ; R21 NS087472/NS/NINDS NIH HHS/United States ; 5T32EB13180/EB/NIBIB NIH HHS/United States ; 1R21NS087472-01A1/NS/NINDS NIH HHS/United States ; T32 EB013180/EB/NIBIB NIH HHS/United States ; }, mesh = {*Brain Mapping ; Central Nervous System/*diagnostic imaging ; Humans ; Inflammation/diagnostic imaging/*pathology ; *Neuroimaging ; }, abstract = {Neuroinflammation is implicated in the pathophysiology of a growing number of human disorders, including multiple sclerosis, chronic pain, traumatic brain injury, and amyotrophic lateral sclerosis. As a result, interest in the development of novel methods to investigate neuroinflammatory processes, for the purpose of diagnosis, development of new therapies, and treatment monitoring, has surged over the past 15 years. Neuroimaging offers a wide array of non- or minimally invasive techniques to characterize neuroinflammatory processes. The intent of this Review is to provide brief descriptions of currently available neuroimaging methods to image neuroinflammation in the human central nervous system (CNS) in vivo. Specifically, because of the relatively widespread accessibility of equipment for nuclear imaging (positron emission tomography [PET]; single photon emission computed tomography [SPECT]) and magnetic resonance imaging (MRI), we will focus on strategies utilizing these technologies. We first provide a working definition of "neuroinflammation" and then discuss available neuroimaging methods to study human neuroinflammatory processes. Specifically, we will focus on neuroimaging methods that target (1) the activation of CNS immunocompetent cells (e.g. imaging of glial activation with TSPO tracer [(11)C]PBR28), (2) compromised BBB (e.g. identification of MS lesions with gadolinium-enhanced MRI), (3) CNS-infiltration of circulating immune cells (e.g. tracking monocyte infiltration into brain parenchyma with iron oxide nanoparticles and MRI), and (4) pathological consequences of neuroinflammation (e.g. imaging apoptosis with [(99m)Tc]Annexin V or iron accumulation with T2* relaxometry). This Review provides an overview of state-of-the-art techniques for imaging human neuroinflammation which have potential to impact patient care in the foreseeable future.}, }
@article {pmid26983673, year = {2016}, author = {Al-Ghawi, E and Al-Harbi, T and Al-Sarawi, A and Binfalah, M}, title = {Monomelic amyotrophy with proximal upper limb involvement: a case report.}, journal = {Journal of medical case reports}, volume = {10}, number = {}, pages = {54}, pmid = {26983673}, issn = {1752-1947}, mesh = {Adult ; Cervical Vertebrae/*pathology ; Deltoid Muscle/*pathology ; *Electromyography ; Humans ; Magnetic Resonance Imaging ; Male ; Muscle, Skeletal/*pathology ; *Physical Therapy Modalities ; Spinal Muscular Atrophies of Childhood/*diagnosis/physiopathology/therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: Monomelic amyotrophy is an uncommon, benign, unilateral disorder of the lower motor neurons, affecting predominantly the hand and forearm muscles. Proximal involvement of the arm and shoulder muscles is an unusual presentation that has been rarely reported in the literature.<br><br>CASE PRESENTATION: A 28-year-old white man presented with insidious-onset, slowly progressive, unilateral weakness and atrophy of his left shoulder girdle and deltoid muscles. A neurological examination revealed weakness and atrophy in his left deltoid, infraspinatus and supraspinatus muscles. Electromyography demonstrated an active and chronic neurogenic pattern affecting his left C5 and C6 myotomes; magnetic resonance imaging of his cervical spine was normal. He did well with conservative treatment.<br><br>CONCLUSIONS: Upper limb proximal form of monomelic amyotrophy is a rare clinical entity with a wide differential diagnosis. Physicians, especially neurologists, should be familiar with this benign condition to avoid inappropriately labeling patients as having amyotrophic lateral sclerosis and other disorders with less favorable outcomes.}, }
@article {pmid26982815, year = {2016}, author = {Shefner, JM and Wolff, AA and Meng, L and Bian, A and Lee, J and Barragan, D and Andrews, JA and , }, title = {A randomized, placebo-controlled, double-blind phase IIb trial evaluating the safety and efficacy of tirasemtiv in patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {17}, number = {5-6}, pages = {426-435}, doi = {10.3109/21678421.2016.1148169}, pmid = {26982815}, issn = {2167-9223}, mesh = {Adult ; Age Factors ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Double-Blind Method ; Female ; Follow-Up Studies ; Hand Strength ; Humans ; Imidazoles/*adverse effects/*therapeutic use ; International Cooperation ; Male ; Middle Aged ; Muscle Strength ; Pyrazines/*adverse effects/*therapeutic use ; Retrospective Studies ; Time Factors ; Treatment Outcome ; Vital Capacity/drug effects ; }, abstract = {Our objectives were to evaluate the safety and tolerability of tirasemtiv over 12 weeks and its effect on the revised ALS Functional Rating Scale (ALSFRS-R) and other secondary functional measures. This randomized, double-blind, placebo-controlled trial enrolled adults with ALS and slow vital capacity (SVC) > 50% from 73 centers in eight countries. Patients who tolerated open-label tirasemtiv 125 mg b.i.d. for one week were randomized to double-blind treatment either to placebo or tirasemtiv, escalating to a maximum tolerated dose up to 250 mg b.i.d. The primary endpoint was the change from baseline in ALSFRS-R; secondary endpoints included SVC, maximum voluntary ventilation, sniff nasal inspiratory pressure, isometric muscle strength, and sub-maximum handgrip fatigue. Of 711 patients enrolled, 596 were randomized and received at least one dose of double-blind treatment. The primary endpoint showed no treatment effect (tirasemtiv: -2.98 ± 0.28, placebo: -2.40 ± 0.25, p = 0.114); however, SVC and muscle strength declined significantly more slowly on tirasemtiv (95% CI p = 0.0006, p = 0.0158, respectively). Dropouts and serious adverse events occurred more frequently in the tirasemtiv group. In conclusion, this was a negative study with respect to the primary endpoint; however, the effects on SVC and muscle strength suggest a potentially important effect of tirasemtiv warranting further evaluation over a longer period in ALS.}, }
@article {pmid26982530, year = {2016}, author = {Bin-Dayel, AF and Abdel Baky, NA and Fadda, LM and Mohammad, RA and Al-Mohanna, F}, title = {Effect of aliskiren and carvedilol on expression of Ca(2+)/calmodulin-dependent protein kinase II δ-subunit isoforms in cardiac hypertrophy rat model.}, journal = {Toxicology mechanisms and methods}, volume = {26}, number = {2}, pages = {122-131}, doi = {10.3109/15376516.2015.1128035}, pmid = {26982530}, issn = {1537-6524}, mesh = {Amides/administration &amp; dosage/*therapeutic use ; Animals ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/*antagonists &amp; inhibitors/genetics ; Carbazoles/administration &amp; dosage/*therapeutic use ; Cardiomegaly/chemically induced/*drug therapy/enzymology ; Carvedilol ; Creatine Kinase, MB Form/blood ; Disease Models, Animal ; Drug Therapy, Combination ; Fumarates/administration &amp; dosage/*therapeutic use ; Heart/drug effects ; Isoproterenol/toxicity ; Male ; Myocardium/metabolism ; Organ Size/drug effects ; Propanolamines/administration &amp; dosage/*therapeutic use ; Protein Isoforms ; Rats, Wistar ; Real-Time Polymerase Chain Reaction ; Renin/blood ; Renin-Angiotensin System/*drug effects ; Troponin T/blood ; }, abstract = {CONTEXT: The critical role of CaMKIIδ isoforms in cardiac hypertrophy is well documented.<br><br>OBJECTIVE: This study was aimed to investigate the possible inhibitory effects of aliskiren (ALS) and/or carvedilol (CAV) on CaMKII&#x3b4; isoforms expression in experimental cardiac hypertrophy.<br><br>MATERIALS AND METHODS: Male Wistar albino rats were subcutaneously injected with isoproterenol (ISO) (5&#x2009;mg/kg/day) for 4 weeks to induce cardiac hypertrophy. Hypertrophied rats were daily treated with either ALS (10&#x2009;mg/kg) and/or CAV (10&#x2009;mg/kg). At the end of the treatment, rats were killed; blood and hearts were collected for assessing different biochemical parameters.<br><br>RESULTS: ISO treatment significantly increased heart weight to body weight (HW/BW) ratio, serum creatine kinase MB (CK-MB) and troponin T (Tn-T) levels, and plasma renin activity (PRA) as compared to control rats. Additionally, ISO treatment produced a significant increase in the expression of myocardial CaMKII&#x3b4;2 and CaMKII&#x3b4;3 that were associated with significant elevation in myocardial caspase-3 protein expression. Histopathological examination of rats exposed to ISO treatment showed severe myocardial cell degeneration. ALS and/or CAV treatment significantly reduced the altered HW/BW ratio, serum CK-MB and Tn-T levels, PRA, and caspase-3 protein expression in hypertrophied rats, with maximal improvement in the combination group. These biochemical findings were supported by the histopathological examination of the heart tissue. Additionally, treatment with ALS and CAV significantly inhibited ISO-induced increase in CaMKII&#x3b4;2 and CaMKII&#x3b4;3 expression levels.<br><br>DISCUSSION AND CONCLUSION: The present study indicated that ALS and CAV treatment ameliorated ISO-induced hypertrophy via inhibiting the expression and the activity of CaMKII&#x3b4; isoforms and the associated myocardial apoptosis.}, }
@article {pmid26979533, year = {2016}, author = {Gubert, F and Decotelli, AB and Bonacossa-Pereira, I and Figueiredo, FR and Zaverucha-do-Valle, C and Tovar-Moll, F and Hoffmann, L and Urmenyi, TP and Santiago, MF and Mendez-Otero, R}, title = {Intraspinal bone-marrow cell therapy at pre- and symptomatic phases in a mouse model of amyotrophic lateral sclerosis.}, journal = {Stem cell research &amp; therapy}, volume = {7}, number = {}, pages = {41}, pmid = {26979533}, issn = {1757-6512}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Animals ; Anterior Horn Cells/physiology ; Asymptomatic Diseases/*therapy ; *Bone Marrow Transplantation ; Cell Movement ; Cell Survival ; Cell Tracking ; Female ; Injections, Spinal ; Lumbosacral Region/pathology ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/physiology ; Motor Activity ; Mutation, Missense ; Recovery of Function ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease that selectively affects the motor neurons. The details of the mechanisms of selective motor-neuron death remain unknown and no effective therapy has been developed. We investigated the therapy with bone-marrow mononuclear cells (BMMC) in a mouse model of ALS (SOD1(G93A) mice).<br><br>METHODS: We injected 10(6) BMMC into the lumbar portion of the spinal cord of SOD1(G93A) mice in presymptomatic (9 weeks old) and symptomatic (14 weeks old) phases. In each condition, we analyzed the progression of disease and the lifespan of the animals.<br><br>RESULTS: We observed a mild transitory delay in the disease progression in the animals injected with BMMC in the presymptomatic phase. However, we observed no increase in the lifespan. When we injected BMMC in the symptomatic phase, we observed no difference in the animals' lifespan or in the disease progression. Immunohistochemistry for NeuN showed a decrease in the number of motor neurons during the course of the disease, and this decrease was not affected by either treatment. Using different strategies to track the BMMC, we noted that few cells remained in the spinal cord after transplantation. This observation could explain why the BMMC therapy had only a transitory effect.<br><br>CONCLUSION: This is the first report of intraspinal BMMC therapy in a mouse model of ALS. We conclude this cellular therapy has only a mild transitory effect when performed in the presymptomatic phase of the disease.}, }
@article {pmid26972033, year = {2016}, author = {Fermin, AM and Afzal, U and Culebras, A}, title = {Sleep in Neuromuscular Diseases.}, journal = {Sleep medicine clinics}, volume = {11}, number = {1}, pages = {53-64}, doi = {10.1016/j.jsmc.2015.10.005}, pmid = {26972033}, issn = {1556-4088}, mesh = {Humans ; Neuromuscular Diseases/*complications/diagnosis/physiopathology/therapy ; Sleep/physiology ; Sleep Wake Disorders/*complications/diagnosis/physiopathology/therapy ; }, abstract = {Sleep disorders in neuromuscular disorders are generally caused by respiratory dysfunction associated with these diseases. Hypoventilation in neuromuscular diseases results from both respiratory muscle weakness and reduced chemoreceptor sensitivity, which is required for ventilatory drive. This condition results in repeated arousals, sleep fragmentation, and nocturnal hypoxemia, manifesting most commonly as excessive daytime somnolence. Polysomnography can identify sleep disordered breathing in patients with neuromuscular disorders and treatment with noninvasive ventilation may improve quality of life.}, }
@article {pmid26971930, year = {2016}, author = {Wilke, C and Gillardon, F and Deuschle, C and Dubois, E and Hobert, MA and Müller vom Hagen, J and Krüger, S and Biskup, S and Blauwendraat, C and Hruscha, M and Kaeser, SA and Heutink, P and Maetzler, W and Synofzik, M}, title = {Serum Levels of Progranulin Do Not Reflect Cerebrospinal Fluid Levels in Neurodegenerative Disease.}, journal = {Current Alzheimer research}, volume = {13}, number = {6}, pages = {654-662}, doi = {10.2174/1567205013666160314151247}, pmid = {26971930}, issn = {1875-5828}, mesh = {Aged ; Alzheimer Disease/genetics/*metabolism ; Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Biomarkers/blood/cerebrospinal fluid ; Female ; Frontotemporal Dementia/genetics/*metabolism ; Humans ; Intercellular Signaling Peptides and Proteins/*blood/*cerebrospinal fluid/genetics ; Male ; Middle Aged ; Progranulins ; }, abstract = {Altered progranulin levels play a major role in neurodegenerative diseases, like Alzheimer's dementia (AD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), even in the absence of GRN mutations. Increasing progranulin levels could hereby provide a novel treatment strategy. However, knowledge on progranulin regulation in neurodegenerative diseases remains limited. We here demonstrate that cerebrospinal fluid progranulin levels do not correlate with its serum levels in AD, FTD and ALS, indicating a differential regulation of its central and peripheral levels in neurodegeneration. Blood progranulin levels thus do not reliably predict central nervous progranulin levels and their response to future progranulin-increasing therapeutics.}, }
@article {pmid26971480, year = {2016}, author = {Fathi, D and Mohammadi, B and Dengler, R and Böselt, S and Petri, S and Kollewe, K}, title = {Lower motor neuron involvement in ALS assessed by motor unit number index (MUNIX): Long-term changes and reproducibility.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {127}, number = {4}, pages = {1984-1988}, doi = {10.1016/j.clinph.2015.12.023}, pmid = {26971480}, issn = {1872-8952}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Electromyography/*standards ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; *Motor Neurons/physiology ; *Recruitment, Neurophysiological/physiology ; Reproducibility of Results ; Time Factors ; }, abstract = {OBJECTIVE: Motor unit number estimation (MUNE) techniques such as motor unit number index (MUNIX) have been used to quantify lower motor neuron loss and disease progression in amyotrophic lateral sclerosis (ALS). We investigated the consistency of reproducibility of MUNIX in 30 ALS-patients during the course of the disorder.<br><br>METHODS: MUNIX was recorded in abductor pollicis brevis and tibialis anterior muscles bilaterally in ALS-patients by two measurements at the first and at one follow-up visit and once in healthy controls. Intra-rater reproducibility was evaluated by three statistical methods: interclass correlation coefficient (ICC), correlation coefficient analysis (CCA), and coefficient of variation (CV).<br><br>RESULTS: We found significant correlation between the first and second measurement of MUNIX in all tested muscles and at the follow-up visit (r&#x2a7e;0.891, p<0.01) and good statistically significant reproducibility of MUNIX in all four measured muscles at the follow-up visit (ICC&#x2a7e;0.946, p<0.01). The CV of MUNIX at the follow-up visit ranged from 13.90% to 32.95%.<br><br>CONCLUSIONS: This study shows good consistency of reproducibility of MUNIX in the course of ALS.<br><br>SIGNIFICANCE: This study suggests that MUNIX can be used to track the progression of the disorder both in clinical routine and in treatment trials.}, }
@article {pmid26964569, year = {2016}, author = {Kim, SY and Wilson, R and De Vries, R and Ryan, KA and Holloway, RG and Kieburtz, K}, title = {Are patients with amyotrophic lateral sclerosis at risk of a therapeutic misconception?.}, journal = {Journal of medical ethics}, volume = {42}, number = {8}, pages = {514-518}, doi = {10.1136/medethics-2015-103319}, pmid = {26964569}, issn = {1473-4257}, support = {UL1 RR024160/RR/NCRR NIH HHS/United States ; R01 NS062770/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/psychology ; Clinical Trials as Topic/*ethics ; Comprehension ; Decision Support Techniques ; Ethics, Research ; Female ; Humans ; Informed Consent/*ethics ; Male ; Michigan ; Middle Aged ; Patient Participation/psychology ; *Therapeutic Misconception/ethics ; }, abstract = {OBJECTIVES: To assess whether persons with amyotrophic lateral sclerosis (ALS) are at risk of a therapeutic misconception (TM) in which they misconceive research as treatment or overestimate the likelihood of its benefit.<br><br>METHODS: 72 patients with ALS recruited via academic and patient organisations were surveyed using a hypothetical first-in-human intervention study scenario. We elicited their understanding of the purpose of the study ('purpose-of-research question') and then asked how they interpreted the question. We then asked for an estimate of the likelihood that their ALS would improve by participating and asked them to explain the meaning of their estimates.<br><br>RESULTS: Although 10 of 72 (14%) subjects incorrectly said that the intervention study was 'mostly intending to help [me]' in response to the purpose-of-research question, 7 of those 10 thought that the question was asking them about their own motivations for participating. Overall, only one of 72 respondents (1.4%) both understood the purpose-of-research question as intended and gave the incorrect response. Subjects' mean estimate of likelihood of benefit was 31% (SD 26). This was due to 29 of 72 of respondents providing high estimates (50%-54% likelihood), which they said were expressions of hope and need for a positive attitude; among those who said their estimates meant 'those are the facts' or 'there is a lot of uncertainty', the estimates were much lower (12.6% and 18.5%, respectively).<br><br>CONCLUSIONS: In this group of patients with ALS considering a hypothetical first-in-human intervention study, apparent TM responses have alternative explanations and the risk of true TM appears low.}, }
@article {pmid26959545, year = {2016}, author = {Darwish, HW and Bakheit, AH and Abdelhameed, AS}, title = {Simultaneous quantitative analysis of olmesartan, amlodipine and hydrochlorothiazide in their combined dosage form utilizing classical and alternating least squares based chemometric methods.}, journal = {Acta pharmaceutica (Zagreb, Croatia)}, volume = {66}, number = {1}, pages = {83-95}, doi = {10.1515/acph-2016-0004}, pmid = {26959545}, issn = {1846-9558}, mesh = {Amlodipine/*chemistry ; Calibration ; Dosage Forms ; Drug Combinations ; Hydrochlorothiazide/*chemistry ; Imidazoles/*chemistry ; Least-Squares Analysis ; Spectrophotometry/*methods ; Tetrazoles/*chemistry ; }, abstract = {Simultaneous spectrophotometric analysis of a multi-component dosage form of olmesartan, amlodipine and hydrochlorothiazide used for the treatment of hypertension has been carried out using various chemometric methods. Multivariate calibration methods include classical least squares (CLS) executed by net analyte processing (NAP-CLS), orthogonal signal correction (OSC-CLS) and direct orthogonal signal correction (DOSC-CLS) in addition to multivariate curve resolution-alternating least squares (MCR-ALS). Results demonstrated the efficiency of the proposed methods as quantitative tools of analysis as well as their qualitative capability. The three analytes were determined precisely using the aforementioned methods in an external data set and in a dosage form after optimization of experimental conditions. Finally, the efficiency of the models was validated via comparison with the partial least squares (PLS) method in terms of accuracy and precision.}, }
@article {pmid26956112, year = {2016}, author = {Ferrara, P}, title = {The Unbiased Search of Biomarkers in Neurodegenerative Diseases.}, journal = {Current pharmaceutical biotechnology}, volume = {17}, number = {5}, pages = {471-479}, doi = {10.2174/138920101705160303165719}, pmid = {26956112}, issn = {1873-4316}, mesh = {Biomarkers/analysis/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism ; Proteomics ; }, abstract = {A clear link exists between the extension of life expectancy throughout the world and the increased incidence of age-related neurodegenerative disorders. Diseases like Alzheimer's and Parkinson's are chronic diseases with devastating consequences for patients and their families. They also represent a major economic cost for society. Therapeutic progress has been made mainly by alleviating some of the symptoms of these diseases, but currently no cure is available. Attempts to develop new therapies have been hampered mainly because of gaps in our current knowledge about the pathogenic mechanism underlying neurodegeneration, making difficult the identification of targets for new drug development, and also because of the lack of biomarkers essential for early diagnosis, patient stratification and follow up of treatment. Taking advantage of the latest technical developments, proteomics and peptidomics based approaches are being used to identify new cellular pathophysiological pathways as well as biomarkers in biological fluids. Here we will review the results, mainly published in the last five years, of unbiased proteomics and peptidomics approaches for biomarker research using biological fluids of Alzheimer's, Parkinson's and Amyotrophic Lateral Sclerosis patients.}, }
@article {pmid26946488, year = {2016}, author = {Naujock, M and Stanslowsky, N and Bufler, S and Naumann, M and Reinhardt, P and Sterneckert, J and Kefalakes, E and Kassebaum, C and Bursch, F and Lojewski, X and Storch, A and Frickenhaus, M and Boeckers, TM and Putz, S and Demestre, M and Liebau, S and Klingenstein, M and Ludolph, AC and Dengler, R and Kim, KS and Hermann, A and Wegner, F and Petri, S}, title = {4-Aminopyridine Induced Activity Rescues Hypoexcitable Motor Neurons from Amyotrophic Lateral Sclerosis Patient-Derived Induced Pluripotent Stem Cells.}, journal = {Stem cells (Dayton, Ohio)}, volume = {34}, number = {6}, pages = {1563-1575}, doi = {10.1002/stem.2354}, pmid = {26946488}, issn = {1549-4918}, mesh = {4-Aminopyridine/*pharmacology ; Amyotrophic Lateral Sclerosis/genetics/*pathology ; Caspases/metabolism ; Cell Differentiation/drug effects ; Endoplasmic Reticulum Stress/drug effects ; Enzyme Activation/drug effects ; Female ; Humans ; Induced Pluripotent Stem Cells/*pathology ; Ion Channels/metabolism ; Male ; Middle Aged ; Motor Neurons/*pathology ; Mutation/genetics ; Neuroprotection/drug effects ; Phenotype ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase/genetics ; Synapses/drug effects/metabolism ; }, abstract = {Despite decades of research on amyotrophic lateral sclerosis (ALS), there is only one approved drug, which minimally extends patient survival. Here, we investigated pathophysiological mechanisms underlying ALS using motor neurons (MNs) differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying mutations in FUS or SOD1. Patient-derived MNs were less active and excitable compared to healthy controls, due to reduced Na(+) /K(+) ratios in both ALS groups accompanied by elevated potassium channel (FUS) and attenuated sodium channel expression levels (FUS, SOD1). ALS iPSC-derived MNs showed elevated endoplasmic reticulum stress (ER) levels and increased caspase activation. Treatment with the FDA approved drug 4-Aminopyridine (4AP) restored ion-channel imbalances, increased neuronal activity levels and decreased ER stress and caspase activation. This study provides novel pathophysiological data, including a mechanistic explanation for the observed hypoexcitability in patient-derived MNs and a new therapeutic strategy to provide neuroprotection in MNs affected by ALS. Stem Cells 2016;34:1563-1575.}, }
@article {pmid26944603, year = {2016}, author = {Sharma, DR and Wani, WY and Sunkaria, A and Kandimalla, RJ and Sharma, RK and Verma, D and Bal, A and Gill, KD}, title = {Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus.}, journal = {Neuroscience}, volume = {324}, number = {}, pages = {163-176}, doi = {10.1016/j.neuroscience.2016.02.055}, pmid = {26944603}, issn = {1873-7544}, mesh = {Aluminum/blood/*toxicity ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects/physiology ; Caspase 3/metabolism ; Cell Nucleus/drug effects/pathology/physiology ; Chromatin/drug effects/metabolism/pathology ; Cytochromes c/metabolism ; DNA Fragmentation/drug effects ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Hippocampus/*drug effects/pathology/physiopathology ; Male ; Mitochondria/drug effects/pathology/physiology ; Neurodegenerative Diseases/*drug therapy/pathology/physiopathology ; Neurons/*drug effects/pathology/physiology ; Neuroprotective Agents/*pharmacology ; Quercetin/*pharmacology ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Aluminum is a light weight and toxic metal present ubiquitously on earth, which has gained considerable attention due to its neurotoxic effects. It also has been linked ecologically and epidemiologically to several neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Guamanian-Parkinsonian complex and Amyotrophic lateral sclerosis (ALS). The mechanism of aluminum neurotoxicity is poorly understood, but it is well documented that aluminum generates reactive oxygen species (ROS). Enhanced ROS production leads to disruption of cellular antioxidant defense systems and release of cytochrome c (cyt-c) from mitochondria to cytosol resulting in apoptotic cell death. Quercetin (a natural flavonoid) protects it from oxidative damage and has been shown to decrease mitochondrial damage in various animal models of oxidative stress. We hypothesized that if oxidative damage to mitochondria does play a significant role in aluminum-induced neurodegeneration, and then quercetin should ameliorate neuronal apoptosis. Administration of quercetin (10 mg/kg body wt/day) reduced aluminum (10 mg/kg body wt/day)-induced oxidative stress (decreased ROS production, increased mitochondrial superoxide dismutase (MnSOD) activity). In addition, quercetin also prevents aluminum-induced translocation of cyt-c, and up-regulates Bcl-2, down-regulates Bax, p53, caspase-3 activation and reduces DNA fragmentation. Quercetin also obstructs aluminum-induced neurodegenerative changes in aluminum-treated rats as seen by Hematoxylin and Eosin (H&amp;E) staining. Further electron microscopic studies revealed that quercetin attenuates aluminum-induced mitochondrial swelling, loss of cristae and chromatin condensation. These results indicate that treatment with quercetin may represent a therapeutic strategy to attenuate the neuronal death against aluminum-induced neurodegeneration.}, }
@article {pmid26931465, year = {2016}, author = {Kanekura, K and Yagi, T and Cammack, AJ and Mahadevan, J and Kuroda, M and Harms, MB and Miller, TM and Urano, F}, title = {Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation.}, journal = {Human molecular genetics}, volume = {25}, number = {9}, pages = {1803-1813}, pmid = {26931465}, issn = {1460-2083}, support = {P30 DK020579/DK/NIDDK NIH HHS/United States ; P60 DK020579/DK/NIDDK NIH HHS/United States ; T32 GM008151/GM/NIGMS NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Brain/drug effects/metabolism/*pathology ; C9orf72 Protein ; Case-Control Studies ; Cells, Cultured ; DNA Repeat Expansion/drug effects/genetics ; Dipeptides/*pharmacology ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism ; Humans ; Mice ; Motor Neurons/drug effects/metabolism/*pathology ; Protein Biosynthesis/*drug effects ; Proteins/*genetics ; }, abstract = {The expansion of the GGGGCC hexanucleotide repeat in the non-coding region of the Chromosome 9 open-reading frame 72 (C9orf72) gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This genetic alteration leads to the accumulation of five types of poly-dipeptides translated from the GGGGCC hexanucleotide repeat. Among these, poly-proline-arginine (poly-PR) and poly-glycine-arginine (poly-GR) peptides are known to be neurotoxic. However, the mechanisms of neurotoxicity associated with these poly-dipeptides are not clear. A proteomics approach identified a number of interacting proteins with poly-PR peptide, including mRNA-binding proteins, ribosomal proteins, translation initiation factors and translation elongation factors. Immunostaining of brain sections from patients with C9orf72 ALS showed that poly-GR was colocalized with a mRNA-binding protein, hnRNPA1. In vitro translation assays showed that poly-PR and poly-GR peptides made insoluble complexes with mRNA, restrained the access of translation factors to mRNA, and blocked protein translation. Our results demonstrate that impaired protein translation mediated by poly-PR and poly-GR peptides plays a role in neurotoxicity and reveal that the pathways altered by the poly-dipeptides-mRNA complexes are potential therapeutic targets for treatment of C9orf72 FTD/ALS.}, }
@article {pmid26927092, year = {2016}, author = {Kai, M}, title = {Roles of RNA-Binding Proteins in DNA Damage Response.}, journal = {International journal of molecular sciences}, volume = {17}, number = {3}, pages = {310}, pmid = {26927092}, issn = {1422-0067}, mesh = {Animals ; *DNA Damage ; *DNA Repair ; DNA-Binding Proteins/*genetics/metabolism ; Humans ; Signal Transduction ; }, abstract = {Living cells experience DNA damage as a result of replication errors and oxidative metabolism, exposure to environmental agents (e.g., ultraviolet light, ionizing radiation (IR)), and radiation therapies and chemotherapies for cancer treatments. Accumulation of DNA damage can lead to multiple diseases such as neurodegenerative disorders, cancers, immune deficiencies, infertility, and also aging. Cells have evolved elaborate mechanisms to deal with DNA damage. Networks of DNA damage response (DDR) pathways are coordinated to detect and repair DNA damage, regulate cell cycle and transcription, and determine the cell fate. Upstream factors of DNA damage checkpoints and repair, "sensor" proteins, detect DNA damage and send the signals to downstream factors in order to maintain genomic integrity. Unexpectedly, we have discovered that an RNA-processing factor is involved in DNA repair processes. We have identified a gene that contributes to glioblastoma multiforme (GBM)'s treatment resistance and recurrence. This gene, RBM14, is known to function in transcription and RNA splicing. RBM14 is also required for maintaining the stem-like state of GBM spheres, and it controls the DNA-PK-dependent non-homologous end-joining (NHEJ) pathway by interacting with KU80. RBM14 is a RNA-binding protein (RBP) with low complexity domains, called intrinsically disordered proteins (IDPs), and it also physically interacts with PARP1. Furthermore, RBM14 is recruited to DNA double-strand breaks (DSBs) in a poly(ADP-ribose) (PAR)-dependent manner (unpublished data). DNA-dependent PARP1 (poly-(ADP) ribose polymerase 1) makes key contributions in the DNA damage response (DDR) network. RBM14 therefore plays an important role in a PARP-dependent DSB repair process. Most recently, it was shown that the other RBPs with intrinsically disordered domains are recruited to DNA damage sites in a PAR-dependent manner, and that these RBPs form liquid compartments (also known as "liquid-demixing"). Among the PAR-associated IDPs are FUS/TLS (fused in sarcoma/translocated in sarcoma), EWS (Ewing sarcoma), TARF15 (TATA box-binding protein-associated factor 68 kDa) (also called FET proteins), a number of heterogeneous nuclear ribonucleoproteins (hnRNPs), and RBM14. Importantly, various point mutations within the FET genes have been implicated in pathological protein aggregation in neurodegenerative diseases, specifically with amyotrophic lateral sclerosis (ALS), and frontotemporal lobe degeneration (FTLD). The FET proteins also frequently exhibit gene translocation in human cancers, and emerging evidence shows their physical interactions with DDR proteins and thus implies their involvement in the maintenance of genome stability.}, }
@article {pmid26926633, year = {2016}, author = {Hogan, S and Zapotoczna, M and Stevens, NT and Humphreys, H and O'Gara, JP and O'Neill, E}, title = {In Vitro Approach for Identification of the Most Effective Agents for Antimicrobial Lock Therapy in the Treatment of Intravascular Catheter-Related Infections Caused by Staphylococcus aureus.}, journal = {Antimicrobial agents and chemotherapy}, volume = {60}, number = {5}, pages = {2923-2931}, pmid = {26926633}, issn = {1098-6596}, mesh = {Anti-Infective Agents/*pharmacology ; Biofilms/drug effects ; Catheter-Related Infections/*microbiology ; Daptomycin/pharmacology ; Ethanol/pharmacology ; Microbial Sensitivity Tests ; Minocycline/analogs &amp; derivatives/pharmacology ; Rifampin/pharmacology ; Staphylococcus aureus ; Tigecycline ; }, abstract = {Infection of intravascular catheters by Staphylococcus aureus is a significant risk factor within the health care setting. To treat these infections and attempt salvage of an intravascular catheter, antimicrobial lock solutions (ALSs) are being increasingly used. However, the most effective ALSs against these biofilm-mediated infections have yet to be determined, and clinical practice varies greatly. The purpose of this study was to evaluate and compare the efficacies of antibiotics and antiseptics in current clinical use against biofilms produced by reference and clinical isolates of S. aureus Static and flow biofilm assays were developed using newly described in vivo-relevant conditions to examine the effect of each agent on S. aureus within the biofilm matrix. The antibiotics daptomycin, tigecycline, and rifampin and the antiseptics ethanol and Taurolock inactivated established S. aureus biofilms, while other commonly used antistaphylococcal antibiotics and antiseptic agents were less effective. These findings were confirmed by live/dead staining of S. aureus biofilms formed and treated within a flow cell model. The results from this study demonstrate the most effective clinically used agents and their concentrations which should be used within an ALS to treat S. aureus-mediated intravascular catheter-related infections.}, }
@article {pmid26914920, year = {2016}, author = {Amador, Mdel M and Assouline, A and Gonzalez-Bermejo, J and Pradat, PF}, title = {Response to the Letter to the Editor: "Radiotherapy of salivary glands as treatment of sialorrhea in patients with amyotrophic lateral sclerosis requiring non-invasive ventilation: what are we doing?".}, journal = {Journal of neurology}, volume = {263}, number = {3}, pages = {585}, pmid = {26914920}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Female ; Humans ; Male ; *Noninvasive Ventilation ; Sialorrhea/*radiotherapy ; }, }
@article {pmid26914813, year = {2016}, author = {Lind, AL and Wu, D and Freyhult, E and Bodolea, C and Ekegren, T and Larsson, A and Gustafsson, MG and Katila, L and Bergquist, J and Gordh, T and Landegren, U and Kamali-Moghaddam, M}, title = {A Multiplex Protein Panel Applied to Cerebrospinal Fluid Reveals Three New Biomarker Candidates in ALS but None in Neuropathic Pain Patients.}, journal = {PloS one}, volume = {11}, number = {2}, pages = {e0149821}, pmid = {26914813}, issn = {1932-6203}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Case-Control Studies ; Cerebrospinal Fluid Proteins/*cerebrospinal fluid ; Female ; Humans ; Male ; Middle Aged ; Neuralgia/*cerebrospinal fluid ; Young Adult ; }, abstract = {The objective of this study was to develop and apply a novel multiplex panel of solid-phase proximity ligation assays (SP-PLA) requiring only 20 μL of samples, as a tool for discovering protein biomarkers for neurological disease and treatment thereof in cerebrospinal fluid (CSF). We applied the SP-PLA to samples from two sets of patients with poorly understood nervous system pathologies amyotrophic lateral sclerosis (ALS) and neuropathic pain, where patients were treated with spinal cord stimulation (SCS). Forty-seven inflammatory and neurotrophic proteins were measured in samples from 20 ALS patients and 15 neuropathic pain patients, and compared to normal concentrations in CSF from control individuals. Nineteen of the 47 proteins were detectable in more than 95% of the 72 controls. None of the 21 proteins detectable in CSF from neuropathic pain patients were significantly altered by SCS. The levels of the three proteins, follistatin, interleukin-1 alpha, and kallikrein-5 were all significantly reduced in the ALS group compared to age-matched controls. These results demonstrate the utility of purpose designed multiplex SP-PLA panels in CSF biomarker research for understanding neuropathological and neurotherapeutic mechanisms. The protein changes found in the CSF of ALS patients may be of diagnostic interest.}, }
@article {pmid26911633, year = {2016}, author = {Weiss, MD and Macklin, EA and Simmons, Z and Knox, AS and Greenblatt, DJ and Atassi, N and Graves, M and Parziale, N and Salameh, JS and Quinn, C and Brown, RH and Distad, JB and Trivedi, J and Shefner, JM and Barohn, RJ and Pestronk, A and Swenson, A and Cudkowicz, ME and , }, title = {A randomized trial of mexiletine in ALS: Safety and effects on muscle cramps and progression.}, journal = {Neurology}, volume = {86}, number = {16}, pages = {1474-1481}, pmid = {26911633}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Disease Progression ; Dose-Response Relationship, Drug ; Female ; Follow-Up Studies ; Humans ; Male ; Mexiletine/adverse effects/pharmacokinetics/*therapeutic use ; Middle Aged ; Muscle Cramp/drug therapy/physiopathology ; Postural Balance/drug effects ; Treatment Outcome ; Voltage-Gated Sodium Channel Blockers/adverse effects/pharmacokinetics/*therapeutic use ; }, abstract = {OBJECTIVE: To determine the safety and tolerability of mexiletine in a phase II double-blind randomized controlled trial of sporadic amyotrophic lateral sclerosis (SALS).<br><br>METHODS: Sixty participants with SALS from 10 centers were randomized 1:1:1 to placebo, mexiletine 300 mg/d, or mexiletine 900 mg/d and followed for 12 weeks. The primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetic study from plasma and CSF, ALS Functional Rating Scale-Revised (ALSFRS-R) score, slow vital capacity (SVC), and muscle cramp frequency and severity.<br><br>RESULTS: The only serious adverse event among active arm participants was one episode of imbalance. Thirty-two percent of participants receiving 900 mg of mexiletine discontinued study drug vs 5% on placebo (p = 0.026). Pharmacokinetic study demonstrated a peak plasma concentration 2 hours postdose and strong correlation between plasma and CSF (p < 0.001). Rates of decline of ALSFRS-R and SVC did not differ from placebo. Analysis of all randomized patients demonstrated significant reductions of muscle cramp frequency (300 mg: rate = 31% of placebo, p = 0.047; 900 mg: 16% of placebo, p = 0.002) and cramp intensity (300 mg: mean = 45% of placebo, p = 0.08; 900 mg: 25% of placebo, p = 0.005).<br><br>CONCLUSIONS: Mexiletine was safe at both doses and well-tolerated at 300 mg/d but adverse effects at 900 mg/d led to a high rate of discontinuation. Mexiletine treatment resulted in large dose-dependent reductions in muscle cramp frequency and severity. No effect on rate of progression was detected, but clinically important differences could not be excluded in this small and short-duration study.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that mexiletine is safe when given daily to patients with amyotrophic lateral sclerosis at 300 and 900 mg and well-tolerated at the lower dose.}, }
@article {pmid26910108, year = {2016}, author = {Nagata, E and Ogino, M and Iwamoto, K and Kitagawa, Y and Iwasaki, Y and Yoshii, F and Ikeda, JE and , }, title = {Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients.}, journal = {PloS one}, volume = {11}, number = {2}, pages = {e0149509}, pmid = {26910108}, issn = {1932-6203}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Bromocriptine/adverse effects/*therapeutic use ; Double-Blind Method ; Female ; Humans ; Leukocyte Count ; Male ; Middle Aged ; Riluzole/therapeutic use ; Treatment Outcome ; }, abstract = {OBJECTIVE: Bromocriptine mesylate (BRC), a dopamine D2 receptor agonist has been shown to confer neuroprotection, sustained motor function and slowed disease progression in mouse models of amyotrophic lateral sclerosis (ALS) Here we report a first in human trial in ALS.<br><br>DESIGN: A multicenter, Riluzole add-on, randomized, double-blind, placebo controlled 102-week extension BRC clinical trial.<br><br>METHODS: The trial was conducted between January 2009 and March 2012 on 36 Japanese ALS patients. A 12-week treatment with Riluzole observational period was followed by combined treatment (Riluzole + BRC; n = 29 or Riluzole + placebo; n = 7). The dosing commenced at 1.25 mg/day increasing in steps at two weeks intervals to a maximum of 15 mg/day. The efficacy of BRC was evaluated by comparing BRC and placebo groups upon completion of stepwise dosing at 14 weeks 2 points (1st endpoint) and upon completion or discontinuation of the study (2nd endpoint) of the dosing.<br><br>RESULTS: Statistics analyses revealed a marginal BRC treatment efficacy with P&#x2266;20%to placebo by 1st and 2nd endpoint analysis. In the 1st endpoint analysis, BRC group was significantly effective on the scores of ALSAQ40-communicaton (P = 1.2%), eating and drinking (P = 2.2%), ALSFRS-R total (P = 17.6%), grip strength (P = 19.8%) compared to the placebo group. In the 2nd endpoint analysis, differences between the scores of Limb Norris Scale (P = 18.3%), ALSAQ40-communication (P = 11.9%), eating and drinking (P = 13.6%), and neck forward-bent test (P = 15.4%) of BRC group were detected between the two groups. There was no significant difference between the treatment groups for adverse events or serious drug reactions incidence.<br><br>CONCLUSIONS: BRC sustains motoneuronal function at least in part through BRC treatment. Further analysis involving a Phase 2b or 3 clinical trial is required but BRC currently shows promise for ALS treatment.<br><br>TRIAL REGISTRATION: UMIN Clinical Trials UMIN000008527.}, }
@article {pmid26905828, year = {2016}, author = {Forostyak, O and Forostyak, S and Kortus, S and Sykova, E and Verkhratsky, A and Dayanithi, G}, title = {Physiology of Ca(2+) signalling in stem cells of different origins and differentiation stages.}, journal = {Cell calcium}, volume = {59}, number = {2-3}, pages = {57-66}, doi = {10.1016/j.ceca.2016.02.001}, pmid = {26905828}, issn = {1532-1991}, mesh = {Animals ; Calcium/*metabolism ; *Calcium Signaling ; *Cell Differentiation ; Humans ; Stem Cells/*cytology/*metabolism ; }, abstract = {Stem cells (SCs) of different origins have brought hope as potential tools for the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis. Calcium signalling plays a key role in SC differentiation and proliferation, and dysregulation of Ca(2+) homeostasis may instigate pathological scenarios. Currently, the role of ion channels and receptors in SCs is not fully understood. In the recent years, we found that (i) the pre-differentiation of human embryonic SCs (hESCs) led to the activation of Ca(2+) signalling cascades and enhanced the functional activities of these cells, (ii) the Ca(2+) homeostasis and the physiological properties of hESC-derived neural precursors (NPs) changed during long term propagation in vitro, (iii) differentiation of NPs derived from human induced pluripotent SCs affects the expression of ion channels and receptors, (iv) these neuronal precursors exhibited spontaneous activity, indicating that their electrophysiological and Ca(2+) handling properties are similar to those of mature neurones, and (v) in mesenchymal SCs isolated from the adipose tissue and bone marrow of rats the expression profile of ion channels and receptors depends not only on the differentiation conditions but also on the source from which the cells were isolated, indicating that the fate and functional properties of the differentiated cells are driven by intrinsic mechanisms. Together, identification and assignment of a unique ion channel and a Ca(2+) handling footprint for each cell type would be necessary to qualify them as physiologically suitable for medical research, drug screening, and cell therapy.}, }
@article {pmid26899126, year = {2016}, author = {Watzlawik, JO and Wootla, B and Rodriguez, M}, title = {Tryptophan Catabolites and Their Impact on Multiple Sclerosis Progression.}, journal = {Current pharmaceutical design}, volume = {22}, number = {8}, pages = {1049-1059}, pmid = {26899126}, issn = {1873-4286}, support = {R01 GM092993/GM/NIGMS NIH HHS/United States ; R01 NS048357/NS/NINDS NIH HHS/United States ; R21 NS073684/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Disease Progression ; Humans ; Multiple Sclerosis/*physiopathology ; Tryptophan/*metabolism ; }, abstract = {Accumulating evidence demonstrates involvement of tryptophan metabolites and in particular activation of the kynurenine pathway (KP) in neurocognitive disorders under CNS inflammatory conditions. The KP is involved in several brain-associated disorders including Parkinson's disease, AIDS dementia, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, schizophrenia, and brain tumors. Our review is an attempt to address any relevant association between dysregulation of KP and multiple sclerosis (MS), an inflammatory CNS disorder that ultimately leads to demyelinated brain areas and severe neurological deficits. Modulation of KP is a new topic for the field of MS and warrants further research. The availability of potential KP modulators approved for MS may shed some light into the therapeutic potential of KP antagonists for the treatment of MS patients.}, }
@article {pmid26892289, year = {2016}, author = {Forlenza, OV and Aprahamian, I and de Paula, VJ and Hajek, T}, title = {Lithium, a Therapy for AD: Current Evidence from Clinical Trials of Neurodegenerative Disorders.}, journal = {Current Alzheimer research}, volume = {13}, number = {8}, pages = {879-886}, doi = {10.2174/1567205013666160219112854}, pmid = {26892289}, issn = {1875-5828}, mesh = {Alzheimer Disease/drug therapy ; Animals ; Clinical Trials as Topic ; Humans ; Lithium Compounds/*therapeutic use ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/*therapeutic use ; }, abstract = {BACKGROUND: Preclinical studies have shown that lithium modifies pathological cascades implicated in certain neurodegenerative disorders, such as Alzheimer's disease (AD), Huntigton`s disease (HD), multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS). A critical question is whether these pharmacodynamic properties of lithium translate into neurodegenerative diseases modifying effects in human subjects.<br><br>METHODS: We reviewed all English controlled clinical trials published in PubMed, PsycINFO, Embase, SCOPUS, ISI-Web with the use of lithium for the treatment of neurodegenerative disorders between July 2004 and July 2014.<br><br>RESULTS: Lithium showed evidence for positive effects on cognitive functions and biomarkers in amnestic mild cognitive impairment (aMCI, 1 study) and AD (2 studies), even with doses lower than those used for mood stabilisation. Studies of Li in HD, MSA and CSI did not show benefits of lithium. However, due to methodological limitations and small sample size, these studies may be inconclusive. Studies in ALS showed consistently negative results and presented evidence against the use of lithium for the treatment of this disease.<br><br>CONCLUSION: In absence of disease modifying treatments for any neurodegenerative disorders, the fact that at least 3 studies supported the effect of lithium in aMCI/AD is noteworthy. Future studies should focus on defining the dose range necessary for neuroprotective effects to occur.}, }
@article {pmid26888995, year = {2016}, author = {Thakore, NJ and Pioro, EP}, title = {Depression in ALS in a large self-reporting cohort.}, journal = {Neurology}, volume = {86}, number = {11}, pages = {1031-1038}, doi = {10.1212/WNL.0000000000002465}, pmid = {26888995}, issn = {1526-632X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/*epidemiology/*psychology ; Cohort Studies ; Depression/diagnosis/*epidemiology/*psychology ; Female ; Humans ; Male ; Middle Aged ; Quality of Life/*psychology ; *Self Report ; Survival Rate/trends ; }, abstract = {OBJECTIVE: To report an observational study of depression in a large cohort of patients with amyotrophic lateral sclerosis (ALS), including its prevalence, associations, longitudinal course, and effect on survival.<br><br>METHODS: The Patient Health Questionnaire-9 (PHQ-9) (a validated depression instrument) and other self-reported measures were obtained from patients with ALS as part of routine clinical care via tablet devices using a software system (Knowledge Program). Cox proportional hazard models, linear models, mixed effects models, and logistic regression were used for statistical analyses.<br><br>RESULTS: Of 1,067 patients seen over an 8-year period, 964 had at least one PHQ-9 recorded. Initially, at least moderate (PHQ-9 &#x2265; 10), moderately severe (PHQ-9 &#x2265; 15), and severe depression (PHQ-9 &#x2265; 20) were found in about 33%, 14%, and 5% of patients, respectively. Higher initial PHQ-9 was significantly predictive of mortality (hazard ratio 1.041 per increasing point, 95% confidence interval 1.018-1.065) after controlling for covariates. PHQ-9 was also associated with poorer quality of life. More advanced disease initially and pseudobulbar affect were associated with depression. In 587 patients with repeated PHQ-9 measures, worsening depression was not observed.<br><br>CONCLUSION: Depression is prevalent in ALS and is associated with disease severity at initial assessment. Paradoxically, however, worsening depression is not observed during follow-up despite motor progression. Most importantly, depression has detrimental effects on survival and quality of life. Treatment of depression is recommended in ALS, although it is unknown if this would improve survival.}, }
@article {pmid26888146, year = {2017}, author = {Holt, RI and Guha, N and Böhning, W and Bartlett, C and Cowan, DA and Sönksen, PH and Böhning, D}, title = {Novel markers to detect recombinant human insulin-like growth factor-I (rhIGF-I)/rhIGF binding protein-3 (rhIGFBP-3) misuse in athletes.}, journal = {Drug testing and analysis}, volume = {9}, number = {1}, pages = {30-37}, doi = {10.1002/dta.1941}, pmid = {26888146}, issn = {1942-7611}, mesh = {Adolescent ; Adult ; Double-Blind Method ; Female ; Humans ; Insulin-Like Growth Factor Binding Protein 3/administration &amp; dosage/*blood ; Insulin-Like Growth Factor I/administration &amp; dosage ; Male ; Placebo Effect ; Recombinant Proteins/administration &amp; dosage/blood ; Substance Abuse Detection/*methods ; Young Adult ; }, abstract = {Insulin-like growth factor-I (IGF-I) is abused by elite athletes for its metabolic and anabolic effects. We have previously shown that it is possible to detect IGF-I misuse by measuring serum IGF-I and procollagen type III amino-terminal propeptide (P-III-NP) but a pilot study suggested measuring IGF-II, IGF binding protein-2 (IGFBP-2) and acid-labile subunit (ALS) may improve the detection of IGF-I administration. The aim of the study was to assess this in a randomized controlled trial. Twenty-six female and 30 male recreational athletes were randomized to 28 days' treatment with placebo or recombinant human (rh)IGF-I/rhIGF binding protein-3 (IGFBP-3) complex (30 mg/day or 60 mg/day), followed by 56 days' washout. IGF-II, IGFBP-2 and ALS (women only) were measured using commercial immunoassays. IGFBP-2 increased and IGF-II decreased in response to both low and high dose rhIGF-I/rhIGFBP-3 in both women and men while ALS decreased in women in response to high dose rhIGF-I/rhIGFBP-3. Two days after discontinuing treatment, significant differences remained between the three treatment groups in IGFBP-2 and IGF-II, but not ALS. Thereafter there were no significant differences between the three treatment groups in any of the markers. Combining IGF-I with IGF-II and/or IGFBP-2 improved the performance of the test to detect rhIGF-I/rhIGFBP-3 administration in both women and men. Copyright © 2016 John Wiley &amp; Sons, Ltd.}, }
@article {pmid26883171, year = {2016}, author = {Chiang, CH and Grauffel, C and Wu, LS and Kuo, PH and Doudeva, LG and Lim, C and Shen, CK and Yuan, HS}, title = {Structural analysis of disease-related TDP-43 D169G mutation: linking enhanced stability and caspase cleavage efficiency to protein accumulation.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {21581}, pmid = {26883171}, issn = {2045-2322}, mesh = {Amino Acid Substitution ; Caspases/metabolism ; Codon ; DNA/chemistry/metabolism ; DNA-Binding Proteins/*chemistry/*genetics/metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; *Models, Molecular ; Molecular Dynamics Simulation ; *Mutation ; *Protein Conformation ; Protein Denaturation ; Protein Stability ; Proteolysis ; Thermodynamics ; }, abstract = {The RNA-binding protein TDP-43 forms intracellular inclusions in amyotrophic lateral sclerosis (ALS). While TDP-43 mutations have been identified in ALS patients, how these mutations are linked to ALS remains unclear. Here we examined the biophysical properties of six ALS-linked TDP-43 mutants and found that one of the mutants, D169G, had higher thermal stability than wild-type TDP-43 and that it was cleaved by caspase 3 more efficiently, producing increased levels of the C-terminal 35 kD fragments (TDP-35) in vitro and in neuroblastoma cells. The crystal structure of the TDP-43 RRM1 domain containing the D169G mutation in complex with DNA along with molecular dynamics simulations reveal that the D169G mutation induces a local conformational change in a β turn and increases the hydrophobic interactions in the RRM1 core, thus enhancing the thermal stability of the RRM1 domain. Our results provide the first crystal structure of TDP-43 containing a disease-linked D169G mutation and a disease-related mechanism showing that D169G mutant is more susceptible to proteolytic cleavage by caspase 3 into the pathogenic C-terminal 35-kD fragments due to its increased stability in the RRM1 domain. Modulation of TDP-43 stability and caspase cleavage efficiency could present an avenue for prevention and treatment of TDP-43-linked neurodegeneration.}, }
@article {pmid26878392, year = {2016}, author = {Stephens, HE and Lehman, E and Raheja, D and Yang, C and Walsh, S and Simmons, Z}, title = {The role of mental health and self-efficacy in the pain experience of patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {17}, number = {3-4}, pages = {206-212}, doi = {10.3109/21678421.2015.1131832}, pmid = {26878392}, issn = {2167-9223}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*complications/*psychology ; Female ; Humans ; Male ; Middle Aged ; Pain/*etiology/psychology ; Pain Management ; Pain Measurement ; Psychiatric Status Rating Scales ; Psychotic Disorders/diagnosis/*etiology ; Regression Analysis ; *Self Efficacy ; }, abstract = {Complex interactions between pain, depression, and anxiety impact quality of life in patients with ALS. Psychological approaches to pain control may be useful. This study explored the role of self-efficacy in mitigating pain. Individuals registered with the Agency for Toxic Substances and Disease Registry National ALS Registry and who experienced pain were invited to participate in an online survey. Subjects completed the Brief Pain Inventory-Short Form, Hospital Anxiety and Depression Scale, and Chronic Pain Self-Efficacy Scale. Correlations between variables were determined. Multiple linear regression models assessed relationships between depression, anxiety and self-efficacy predictions, and pain severity, interference, and relief. Results recorded that there were 197 participants (58% males, mean age 59 ± 10 years). Cases or borderline cases of depression or anxiety were common. Mean levels of pain were moderate. Higher pain self-efficacy scores predicted lower pain severity, lower pain interference, and higher pain relief with treatment. As depression scores increased, pain interference with daily life was higher. In conclusion, anxiety and depression are common in patients with ALS and pain. Self-efficacy appears to mitigate pain. A multifactorial approach to pain management should be considered in these patients, addressing mental health and self-efficacy to augment pharmacologic pain treatments.}, }
@article {pmid26877221, year = {2016}, author = {Pardillo-Díaz, R and Carrascal, L and Muñoz, MF and Ayala, A and Nunez-Abades, P}, title = {Time and dose dependent effects of oxidative stress induced by cumene hydroperoxide in neuronal excitability of rat motor cortex neurons.}, journal = {Neurotoxicology}, volume = {53}, number = {}, pages = {201-214}, doi = {10.1016/j.neuro.2016.02.005}, pmid = {26877221}, issn = {1872-9711}, mesh = {Analysis of Variance ; Animals ; Animals, Newborn ; Benzene Derivatives/*pharmacology ; Biophysical Phenomena/drug effects ; Biophysics ; Dose-Response Relationship, Drug ; Electric Stimulation ; In Vitro Techniques ; Membrane Potentials/drug effects ; Motor Cortex/*cytology ; Neurons/*drug effects ; Oxidants/*pharmacology ; Oxidative Stress/*drug effects ; Patch-Clamp Techniques ; Rats ; Rats, Wistar ; Time Factors ; }, abstract = {It has been claimed that oxidative stress and the production of reactive oxygen radicals can contribute to neuron degeneration and might be one factor in the development of different neurological diseases. In our study, we have attempted to clarify how oxidative damage induces dose dependent changes in functional membrane properties of neurons by means of whole cell patch clamp techniques in brain slices from young adult rats. Our research demonstrates physiological changes in membrane properties of pyramidal motor cortex neurons exposed to 3 concentrations of cumene hydroperoxide (CH; 1, 10 and 100μM) during 30min. Results show that oxidative stress induced by CH evokes important changes, in a concentration and time dependent manner, in the neuronal excitability of motor cortex neurons of the rat: (i) Low concentration of the drug (1μM) already blocks inward rectifications (sag) and decreases action potential amplitude and gain, a drug concentration which has no effects on other neuronal populations, (ii) 10μM of CH depresses the excitability of pyramidal motor cortex neurons by decreasing input resistance, amplitude of the action potential, and gain and maximum frequency of the repetitive firing discharge, and (iii) 100μM completely blocks the capability to produce repetitive discharge of action potentials in all cells. Both larger drug concentrations and/or longer times of exposure to CH narrow the current working range. This happens because of the increase in the rheobase, and the reduction of the cancelation current. The effects caused by oxidative stress, including those produced by the level of lipid peroxidation, are practically irreversible and, this, therefore, indicates that neuroprotective agents should be administered at the first symptoms of alterations to membrane properties. In fact, the pre-treatment with melatonin, acting as an antioxidant, prevented the lipid peroxidation and the physiological changes induced by CH. Larger cells (as estimated by their cell capacitance) were also more susceptible to oxidative stress. Our results provide previously unavailable observations that large size and high sensitivity to oxidative stress (even at low concentrations) make pyramidal neurons of the motor cortex, in particular corticofugal neurons, more susceptible to cell death when compared with other neuronal populations. These results could also shed some light on explaining the causes behind diseases such as Amyotrophic Lateral Sclerosis.}, }
@article {pmid26870889, year = {2016}, author = {Rudolf, R and Deschenes, MR and Sandri, M}, title = {Neuromuscular junction degeneration in muscle wasting.}, journal = {Current opinion in clinical nutrition and metabolic care}, volume = {19}, number = {3}, pages = {177-181}, pmid = {26870889}, issn = {1473-6519}, support = {R15 AR060637/AR/NIAMS NIH HHS/United States ; R15 060 637//PHS HHS/United States ; }, mesh = {Animals ; Autophagy ; Gene Expression Regulation ; Humans ; *Models, Biological ; Muscle Proteins/agonists/genetics/metabolism ; Muscular Atrophy/*etiology ; Nerve Degeneration/*etiology ; Nerve Tissue Proteins/genetics/metabolism ; Neuromuscular Junction/metabolism/pathology/*physiopathology ; Neuromuscular Junction Diseases/*etiology ; Wasting Syndrome/metabolism/pathology/*physiopathology ; Wnt Signaling Pathway ; }, abstract = {PURPOSE OF REVIEW: Denervation is a hallmark of age-related and other types of muscle wasting. This review focuses on recent insights and current viewpoints regarding the mechanisms and clinical relevance of maintaining the neuromuscular junction to counteract muscle wasting resulting from aging or neural disease/damage.<br><br>RECENT FINDINGS: Activity-dependent regulation of autophagy, the agrin-muscle specific kinase-Lrp4 signaling axis, and sympathetic modulation are principal mechanisms involved in stabilizing the neuromuscular junction. These findings are derived from several animal models and were largely confirmed by human gene expression analysis as well as insights from rare neuromuscular diseases such as amyotrophic lateral sclerosis and congenital myasthenic syndromes. Based on these insights, agrin-derived fragments are currently being evaluated as biomarkers for age-related muscle wasting. Tuning of autophagy, of the agrin pathway, and of sympathetic input are being studied as clinical treatment of muscle wasting disorders.<br><br>SUMMARY: Basic research has revealed that maintenance of neuromuscular junctions and a few signaling pathways are important in the context of age-dependent and other forms of muscle wasting. These findings have recently started to enter clinical practice, but further research needs to substantiate and refine our knowledge.}, }
@article {pmid26866492, year = {2016}, author = {Hosp, C and Naumann, MK and Hamm, H}, title = {Botulinum Toxin Treatment of Autonomic Disorders: Focal Hyperhidrosis and Sialorrhea.}, journal = {Seminars in neurology}, volume = {36}, number = {1}, pages = {20-28}, doi = {10.1055/s-0035-1571214}, pmid = {26866492}, issn = {1098-9021}, mesh = {Acetylcholine Release Inhibitors/therapeutic use ; Animals ; Autonomic Nervous System Diseases/diagnosis/*drug therapy/physiopathology ; Botulinum Toxins/*therapeutic use ; Humans ; Hyperhidrosis/diagnosis/*drug therapy/physiopathology ; Multicenter Studies as Topic ; Prospective Studies ; Sialorrhea/diagnosis/*drug therapy/physiopathology ; Treatment Outcome ; }, abstract = {Primary focal hyperhidrosis is a common autonomic disorder that significantly impacts quality of life. It is characterized by excessive sweating confined to circumscribed areas, such as the axillae, palms, soles, and face. Less frequent types of focal hyperhidrosis secondary to underlying causes include gustatory sweating in Frey's syndrome and compensatory sweating in Ross' syndrome and after sympathectomy. Approval of onabotulinumtoxinA for severe primary axillary hyperhidrosis in 2004 has revolutionized the treatment of this indication. Meanwhile further type A botulinum neurotoxins like abobotulinumtoxinA and incobotulinumtoxinA, as well as the type B botulinum neurotoxin rimabotulinumtoxinB are successfully used off-label for axillary and various other types of focal hyperhidrosis. For unexplained reasons, the duration of effect differs considerably at different sites. Beside hyperhidrosis, botulinum neurotoxin is also highly valued for the treatment of sialorrhea affecting patients with Parkinson's disease, cerebral palsy, amyotrophic lateral sclerosis, motor neuron disease, and other neurologic conditions. With correct dosing and application, side effects are manageable and transient.}, }
@article {pmid26861067, year = {2016}, author = {Clerc, P and Lipnick, S and Willett, C}, title = {A look into the future of ALS research.}, journal = {Drug discovery today}, volume = {21}, number = {6}, pages = {939-949}, doi = {10.1016/j.drudis.2016.02.002}, pmid = {26861067}, issn = {1878-5832}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Biomedical Research ; Disease Models, Animal ; Humans ; }, abstract = {Although amyotrophic lateral sclerosis (ALS), also referred as 'Lou Gehrig's Disease,' was first described in 1869 and the first disease-associated gene was discovered almost 20 years ago, the disease etiology is still not fully understood and treatment options are limited to one drug approved by the US Food and Drug Administration (FDA). The slow translational progress suggests that current research models are not ideal to study such a complicated disease and need to be re-examined. Progress will require greater insight into human genes and biology involved in ALS susceptibility, as well as a deeper understanding of disease phenotype at the histological and molecular levels. Improving human disease outcome will require directing focus toward improved assessment technologies and innovative approaches.}, }
@article {pmid26860749, year = {2016}, author = {van Es, MA and Kruitwagen-van Reenen, ET and Schröder, CD and Pasterkamp, RJ and Veldink, JH and van den Berg, LH}, title = {[Amyotrophic lateral sclerosis, a heterogeneous disorder].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {160}, number = {}, pages = {A9658}, pmid = {26860749}, issn = {1876-8784}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*genetics/therapy ; Diagnosis, Differential ; Frontotemporal Dementia/diagnosis/genetics/therapy ; Humans ; Quality of Life ; }, abstract = {ALS is a disease characterized by the progressive loss of upper and lower motor neurons leading to weakness and spasticity. Diagnosis of ALS is based on exclusion. ALS and frontotemporal dementia (FTD) constitute the extremes of the spectrum of one disease. Many patients show signs of both ALS and FTD. ALS is a heterogeneous disease in which multiple genetic factors contribute. More than 20 genes are known to play a role in ALS pathogenesis. In approximately 5-10% of cases the disease is familial with autosomal dominant inheritance. There is no curative treatment for ALS. The treatment of ALS patients is symptomatic and is focused on achieving a high level of quality of life. New insights into the genetic fundamentals of ALS offer hope for new therapies. Gene-targeted treatment strategies using antisense oligonucleotides are a promising development.}, }
@article {pmid26858201, year = {2016}, author = {Cornaglia, M and Krishnamani, G and Mouchiroud, L and Sorrentino, V and Lehnert, T and Auwerx, J and Gijs, MA}, title = {Automated longitudinal monitoring of in vivo protein aggregation in neurodegenerative disease C. elegans models.}, journal = {Molecular neurodegeneration}, volume = {11}, number = {}, pages = {17}, pmid = {26858201}, issn = {1750-1326}, support = {320404/ERC_/European Research Council/International ; R01 AG043930/AG/NIA NIH HHS/United States ; R01AG043930/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Caenorhabditis elegans/*metabolism ; Disease Models, Animal ; Doxycycline/pharmacology ; Superoxide Dismutase/*metabolism ; Temperature ; }, abstract = {BACKGROUND: While many biological studies can be performed on cell-based systems, the investigation of molecular pathways related to complex human dysfunctions - e.g. neurodegenerative diseases - often requires long-term studies in animal models. The nematode Caenorhabditis elegans represents one of the best model organisms for many of these tests and, therefore, versatile and automated systems for accurate time-resolved analyses on C. elegans are becoming highly desirable tools in the field.<br><br>RESULTS: We describe a new multi-functional platform for C. elegans analytical research, enabling automated worm isolation and culture, reversible worm immobilization and long-term high-resolution imaging, and this under active control of the main culture parameters, including temperature. We employ our platform for in vivo observation of biomolecules and automated analysis of protein aggregation in a C. elegans model for amyotrophic lateral sclerosis (ALS). Our device allows monitoring the growth rate and development of each worm, at single animal resolution, within a matrix of microfluidic chambers. We demonstrate the progression of individual protein aggregates, i.e. mutated human superoxide dismutase 1 - Yellow Fluorescent Protein (SOD1-YFP) fusion proteins in the body wall muscles, for each worm and over several days. Moreover, by combining reversible worm immobilization and on-chip high-resolution imaging, our method allows precisely localizing the expression of biomolecules within the worms' tissues, as well as monitoring the evolution of single aggregates over consecutive days at the sub-cellular level. We also show the suitability of our system for protein aggregation monitoring in a C. elegans Huntington disease (HD) model, and demonstrate the system's ability to study long-term doxycycline treatment-linked modification of protein aggregation profiles in the ALS model.<br><br>CONCLUSION: Our microfluidic-based method allows analyzing in vivo the long-term dynamics of protein aggregation phenomena in C. elegans at unprecedented resolution. Pharmacological screenings on neurodegenerative disease C. elegans models may strongly benefit from this method in the near future, because of its full automation and high-throughput potential.}, }
@article {pmid26854247, year = {2016}, author = {Bautista, E and Vergara, P and Segovia, J}, title = {Iron-induced oxidative stress activates AKT and ERK1/2 and decreases Dyrk1B and PRMT1 in neuroblastoma SH-SY5Y cells.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {34}, number = {}, pages = {62-69}, doi = {10.1016/j.jtemb.2015.11.005}, pmid = {26854247}, issn = {1878-3252}, mesh = {Cell Death/drug effects ; Cell Line, Tumor ; Humans ; Iron/*pharmacology ; MAP Kinase Signaling System/*drug effects ; Oxidative Stress/*drug effects ; Protein Serine-Threonine Kinases/*metabolism ; Protein-Arginine N-Methyltransferases/*metabolism ; Protein-Tyrosine Kinases/*metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Repressor Proteins/*metabolism ; Dyrk Kinases ; }, abstract = {Iron is essential for proper neuronal functioning; however, excessive accumulation of brain iron is reported in Parkinson's, Alzheimer's, Huntington's diseases and amyotrophic lateral sclerosis. This indicates that dysregulated iron homeostasis is involved in the pathogenesis of these diseases. To determinate the effect of iron on oxidative stress and on cell survival pathways, such as AKT, ERK1/2 and DyrK1B, neuroblastoma SH-SY5Y cells were exposed to different concentration of FeCl2 (iron). We found that iron induced cell death in SH-SY5Y cells in a concentration-dependent manner. Detection of iNOS and 3-nitrotyrosine confirms the presence of increased nitrogen species. Furthermore, we found a decrease of catalase and protein arginine methyl-transferase 1 (PRMT1). Interestingly, iron increased the activity of ERK and AKT and reduced DyrK1B. Moreover, after FeCl2 treatment, the transcription factors c-Jun and pSmad1/5 were activated. These results indicate that the presence of high levels of iron increase the vulnerability of neurons to oxidative stress.}, }
@article {pmid26844759, year = {2017}, author = {Smith, DK and He, M and Zhang, CL and Zheng, JC}, title = {The therapeutic potential of cell identity reprogramming for the treatment of aging-related neurodegenerative disorders.}, journal = {Progress in neurobiology}, volume = {157}, number = {}, pages = {212-229}, pmid = {26844759}, issn = {1873-5118}, support = {R01 NS097195/NS/NINDS NIH HHS/United States ; R01 NS070981/NS/NINDS NIH HHS/United States ; R01 NS088095/NS/NINDS NIH HHS/United States ; R01 NS061642/NS/NINDS NIH HHS/United States ; R01 NS041858/NS/NINDS NIH HHS/United States ; R56 NS041858/NS/NINDS NIH HHS/United States ; P30 GM103509/GM/NIGMS NIH HHS/United States ; }, mesh = {*Aging/physiology ; Animals ; *Cellular Reprogramming/drug effects/physiology ; Humans ; Induced Pluripotent Stem Cells/drug effects/physiology/*transplantation ; Neurodegenerative Diseases/physiopathology/*therapy ; }, abstract = {Neural cell identity reprogramming strategies aim to treat age-related neurodegenerative disorders with newly induced neurons that regenerate neural architecture and functional circuits in vivo. The isolation and neural differentiation of pluripotent embryonic stem cells provided the first in vitro models of human neurodegenerative disease. Investigation into the molecular mechanisms underlying stem cell pluripotency revealed that somatic cells could be reprogrammed to induced pluripotent stem cells (iPSCs) and these cells could be used to model Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease. Additional neural precursor and direct transdifferentiation strategies further enabled the induction of diverse neural linages and neuron subtypes both in vitro and in vivo. In this review, we highlight neural induction strategies that utilize stem cells, iPSCs, and lineage reprogramming to model or treat age-related neurodegenerative diseases, as well as, the clinical challenges related to neural transplantation and in vivo reprogramming strategies.}, }
@article {pmid26844270, year = {2015}, author = {Park, SB and Vucic, S and Cheah, BC and Lin, CS and Kirby, A and Mann, KP and Zoing, MC and Winhammar, J and Kiernan, MC}, title = {Flecainide in Amyotrophic Lateral Sclerosis as a Neuroprotective Strategy (FANS): A Randomized Placebo-Controlled Trial.}, journal = {EBioMedicine}, volume = {2}, number = {12}, pages = {1916-1922}, pmid = {26844270}, issn = {2352-3964}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/physiopathology ; Female ; Flecainide/administration &amp; dosage/adverse effects/*therapeutic use ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/administration &amp; dosage/adverse effects/*therapeutic use ; Quality of Life ; Treatment Outcome ; Voltage-Gated Sodium Channel Blockers/administration &amp; dosage/adverse effects/therapeutic use ; }, abstract = {BACKGROUND: Abnormalities in membrane excitability and Na(+) channel function are characteristic of amyotrophic lateral sclerosis (ALS). We aimed to examine the neuroprotective potential, safety and tolerability of the Na(+) channel blocker and membrane stabiliser flecainide in ALS.<br><br>METHODS: A double-blind, placebo-controlled, randomised clinical trial of flecainide (200 mg/day) for 32-weeks with a 12-week lead-in phase was conducted in participants with probable or definite ALS recruited from multiple Australian centres (ANZCT Registry number ACTRN12608000338369). Patients were reviewed by a cardiologist to rule out cardiac contraindications. Participants were randomly assigned (1:1) to flecainide or placebo using stratified permuted blocks by a central pharmacy. The primary outcome measure was the slope of decline of the ALS Functional Rating Scale-revised (ALS FRS-r) during the treatment period.<br><br>FINDINGS: Between March 11, 2008 and July 1, 2010, 67 patients were screened, 54 of whom were randomly assigned to receive flecainide (26 patients) or placebo (28 patients). Four patients in the flecainide group and three patients in the placebo group withdrew from the study. One patient in the flecainide group died during the study, attributed to disease progression. Flecainide was generally well tolerated, with no serious adverse events reported in either group. There was no significant difference in the rate of decline in the primary outcome measure ALS-FRS-r between placebo and flecainide treated patients (Flecainide 0.65 [95% CI 0.49 to 0.98]; Placebo 0.81 [0.49 to 2.12] P = 0.50). However, the rate of decline of the neurophysiological index was significantly reduced in the flecainide group (Flecainide 0.06 [0.01 to 0.11]; Placebo 0.14 [0.09 to 0.19], P = 0.02). Placebo-treated patients demonstrated greater CMAP amplitude reduction during the course of the study in the subset of patients with a reduced baseline CMAP amplitude (Flecainide: - 15 &#xb1; 12%; Placebo - 59 &#xb1; 12%; P = 0.03). Flecainide-treated patients maintained stabilized peripheral axonal excitability over the study compared to placebo.<br><br>INTERPRETATION: This pilot study indicated that flecainide was safe and potentially biologically effective in ALS. There was evidence that flecainide stabilized peripheral axonal membrane function in ALS. While the study was not powered to detect evidence of benefit of flecainide on ALS-FRS-r decline, further studies may demonstrate clinical efficacy of flecainide in ALS.}, }
@article {pmid26840391, year = {2016}, author = {Schreiber, S and Dannhardt-Stieger, V and Henkel, D and Debska-Vielhaber, G and Machts, J and Abdulla, S and Kropf, S and Kollewe, K and Petri, S and Heinze, HJ and Dengler, R and Nestor, PJ and Vielhaber, S}, title = {Quantifying disease progression in amyotrophic lateral sclerosis using peripheral nerve sonography.}, journal = {Muscle &amp; nerve}, volume = {54}, number = {3}, pages = {391-397}, doi = {10.1002/mus.25066}, pmid = {26840391}, issn = {1097-4598}, mesh = {Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/physiopathology ; Disease Progression ; Female ; Follow-Up Studies ; Forearm/innervation ; Humans ; Male ; Middle Aged ; Neural Conduction/physiology ; Peripheral Nerves/*diagnostic imaging/*physiopathology ; Ultrasonography/*methods ; Wrist/innervation ; }, abstract = {INTRODUCTION: In this study we investigated whether peripheral nerve sonography could be used as a biomarker to monitor disease progression in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: In 37 patients, ulnar and median nerve cross-sectional area (CSA) was determined in at least 2 ultrasound sessions; mean follow-up was 14.5 months. Linear mixed-effects models were conducted to analyze time effects on CSA.<br><br>RESULTS: Ulnar nerve CSA declined significantly at a monthly rate of -0.04 mm(2) (forearm) and -0.05 mm(2) (wrist); the decrease was more pronounced when baseline CSA was greater. To detect a 50% treatment effect on ulnar nerve CSA, 332 patients would need to be entered in a hypothetical randomized, controlled clinical trial. Time had no significant impact on median nerve CSA.<br><br>CONCLUSIONS: Distal ulnar nerve ultrasound may be a useful biomarker to monitor disease progression in ALS, especially as hypothetical treatment effects on CSA seem to be detectable in manageable cohort sizes. Muscle Nerve 54: 391-397, 2016.}, }
@article {pmid26839121, year = {2019}, author = {Seeber, AA and Pols, AJ and Hijdra, A and Grupstra, HF and Willems, DL and de Visser, M}, title = {Experiences and reflections of patients with motor neuron disease on breaking the news in a two-tiered appointment: a qualitative study.}, journal = {BMJ supportive &amp; palliative care}, volume = {9}, number = {1}, pages = {e8}, doi = {10.1136/bmjspcare-2015-000977}, pmid = {26839121}, issn = {2045-4368}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/psychology ; *Appointments and Schedules ; Attitude to Health ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*psychology ; Netherlands ; Patient Care Planning ; Qualitative Research ; Time Factors ; *Truth Disclosure ; }, abstract = {BACKGROUND: Breaking bad news should be fine-tuned to the individual patient, contain intelligible information, include emotional support and offer a tailor-made treatment plan. To achieve this goal in motor neuron disease (MND), neurologists of the amyotrophic lateral sclerosis (ALS) centre Amsterdam deliver the message on 2 separate visits within 14 days.<br><br>AIM: To evaluate how patients with MND react to and view disclosure of the diagnosis, in this 2-tiered approach.<br><br>METHODS: Non-participating observations and in-depth interviews with patients were conducted in 1 tertiary ALS referral centre. Qualitative analysis consisted of inductive analysis of observation reports and verbatim typed out interviews.<br><br>RESULTS: 10 2-tiered appointments were observed and 21 Dutch patients with MND interviewed. They experienced the straightforward message to be suffering from a fatal disease as devastating, yet unavoidable. The prospect of a short-term second appointment offered structure for the period immediately following the diagnosis. The time between appointments provided the opportunity for a first reorientation on their changed perspective on their life. The second appointment allowed for detailed discussions about various aspects of MND and a tailor-made treatment plan.<br><br>CONCLUSIONS: The 2-tiered approach fits well with the way in which Dutch patients with MND process the disclosure of their diagnosis, gather information and handle the changed perspective on their life. It may serve as a model for other life-limiting diseases.}, }
@article {pmid26826269, year = {2016}, author = {Williams, JR and Trias, E and Beilby, PR and Lopez, NI and Labut, EM and Bradford, CS and Roberts, BR and McAllum, EJ and Crouch, PJ and Rhoads, TW and Pereira, C and Son, M and Elliott, JL and Franco, MC and Estévez, AG and Barbeito, L and Beckman, JS}, title = {Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SOD(G93A) mice co-expressing the Copper-Chaperone-for-SOD.}, journal = {Neurobiology of disease}, volume = {89}, number = {}, pages = {1-9}, pmid = {26826269}, issn = {1095-953X}, support = {R01 NS058628/NS/NINDS NIH HHS/United States ; NS036761/NS/NINDS NIH HHS/United States ; NS058628/NS/NINDS NIH HHS/United States ; AT002034/AT/NCCIH NIH HHS/United States ; R01 NS036761/NS/NINDS NIH HHS/United States ; P01 AT002034/AT/NCCIH NIH HHS/United States ; P30 ES000210/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/metabolism ; Animals ; Copper/*administration &amp; dosage/*metabolism ; Disease Models, Animal ; Electron Transport Complex IV/metabolism ; Kaplan-Meier Estimate ; Mice ; Mice, Transgenic ; Molecular Chaperones/genetics/*metabolism ; Spinal Cord/*metabolism ; Superoxide Dismutase/genetics/*metabolism ; }, abstract = {Over-expression of mutant copper, zinc superoxide dismutase (SOD) in mice induces ALS and has become the most widely used model of neurodegeneration. However, no pharmaceutical agent in 20 years has extended lifespan by more than a few weeks. The Copper-Chaperone-for-SOD (CCS) protein completes the maturation of SOD by inserting copper, but paradoxically human CCS causes mice co-expressing mutant SOD to die within two weeks of birth. Hypothesizing that co-expression of CCS created copper deficiency in spinal cord, we treated these pups with the PET-imaging agent CuATSM, which is known to deliver copper into the CNS within minutes. CuATSM prevented the early mortality of CCSxSOD mice, while markedly increasing Cu, Zn SOD protein in their ventral spinal cord. Remarkably, continued treatment with CuATSM extended the survival of these mice by an average of 18 months. When CuATSM treatment was stopped, these mice developed ALS-related symptoms and died within 3 months. Restoring CuATSM treatment could rescue these mice after they became symptomatic, providing a means to start and stop disease progression. All ALS patients also express human CCS, raising the hope that familial SOD ALS patients could respond to CuATSM treatment similarly to the CCSxSOD mice.}, }
@article {pmid26824413, year = {2016}, author = {Raheja, D and Stephens, HE and Lehman, E and Walsh, S and Yang, C and Simmons, Z}, title = {Patient-reported problematic symptoms in an ALS treatment trial.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {17}, number = {3-4}, pages = {198-205}, pmid = {26824413}, issn = {2167-9223}, support = {U01 NS049640/NS/NINDS NIH HHS/United States ; 5U01NS049640-08/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology/therapy ; Bulbar Palsy, Progressive/*etiology ; *Disease Management ; Double-Blind Method ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Quality of Life ; Retrospective Studies ; Severity of Illness Index ; Statistics, Nonparametric ; }, abstract = {This study was undertaken to determine which symptoms are perceived to be most problematic for patients with ALS and how their severity changes over time. A retrospective study was performed of data from a randomized, double-blind, placebo-controlled trial of ceftriaxone in ALS. Participants completed the ALS Specific Quality of Life Instrument (ALSSQoL) at baseline and at intervals up to 96 weeks. Ten ALSSQoL items ask participants to rate how problematic symptoms are (the subjective feeling of burden of these symptoms), ranging from 0 (no problem) to 10 (tremendous problem). Six are non-bulbar (pain, fatigue, breathing, strength and ability to move, sleep, and bowel and bladder) and four are bulbar (eating, speaking, excessive saliva, and mucus). Results revealed that there were 82 subjects (56% males, mean age 53 ± 10.3 years) with ALSSQoL data for weeks 0 and 96. All 10 symptoms became more problematic over time. For non-bulbar symptoms, strength/ability to move and fatigue were the most problematic. Speaking was the most problematic bulbar symptom. In conclusion, although all the symptoms in the ALSSQoL were acknowledged as problematic, some had greater impact than others. All became more problematic over time. This should help prioritize research into symptom management, and assist individual clinicians in their approach to patient care.}, }
@article {pmid26821783, year = {2016}, author = {Shaby, BA and Skibinski, G and Ando, M and LaDow, ES and Finkbeiner, S}, title = {A three-groups model for high-throughput survival screens.}, journal = {Biometrics}, volume = {72}, number = {3}, pages = {936-944}, pmid = {26821783}, issn = {1541-0420}, support = {R01 NS039074/NS/NINDS NIH HHS/United States ; R01 NS083390/NS/NINDS NIH HHS/United States ; T32 GM008568/GM/NIGMS NIH HHS/United States ; U01 MH105035/MH/NIMH NIH HHS/United States ; U54 NS091046/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/mortality ; Computer Simulation ; High-Throughput Screening Assays/*methods ; Humans ; *Models, Statistical ; Motor Neurons/drug effects ; *Survival Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by the progressive deterioration of motor neurons in the cortex and spinal cord. Using an automated robotic microscope platform that enables the longitudinal tracking of thousands of single neurons, we examine the effects a large library of compounds on modulating the survival of primary neurons expressing a mutation known to cause ALS. The goal of our analysis is to identify the few potentially beneficial compounds among the many assayed, the vast majority of which do not extend neuronal survival. This resembles the large-scale simultaneous inference scenario familiar from microarray analysis, but transferred to the survival analysis setting due to the novel experimental setup. We apply a three-component mixture model to censored survival times of thousands of individual neurons subjected to hundreds of different compounds. The shrinkage induced by our model significantly improves performance in simulations relative to performing treatment-wise survival analysis and subsequent multiple testing adjustment. Our analysis identified compounds that provide insight into potential novel therapeutic strategies for ALS.}, }
@article {pmid26818266, year = {2016}, author = {Christensen, T}, title = {Human endogenous retroviruses in neurologic disease.}, journal = {APMIS : acta pathologica, microbiologica, et immunologica Scandinavica}, volume = {124}, number = {1-2}, pages = {116-126}, doi = {10.1111/apm.12486}, pmid = {26818266}, issn = {1600-0463}, mesh = {Anti-Retroviral Agents/therapeutic use ; Endogenous Retroviruses/*genetics/pathogenicity/physiology ; Epigenomics ; *Gene Expression Regulation, Viral ; HIV Infections/therapy ; Humans ; Multiple Sclerosis/etiology/*physiopathology/therapy/*virology ; Nervous System Diseases/physiopathology/therapy/*virology ; Schizophrenia/etiology/physiopathology/therapy/virology ; *Viral Envelope Proteins/genetics ; Virus Activation ; }, abstract = {Endogenous retroviruses are pathogenic - in other species than the human. Disease associations for Human Endogenous RetroViruses (HERVs) are emerging, but so far an unequivocal pathogenetic cause-effect relationship has not been established. A role for HERVs has been proposed in neurological and neuropsychiatric diseases as diverse as multiple sclerosis (MS) and schizophrenia (SCZ). Particularly for MS, many aspects of the activation and involvement of specific HERV families (HERV-H/F and HERV-W/MSRV) have been reported, both for cells in the circulation and in the central nervous system. Notably envelope genes and their gene products (Envs) appear strongly associated with the disease. For SCZ, for ALS, and for HIV-associated dementia (HAD), indications are accumulating for involvement of the HERV-K family, and also HERV-H/F and/or HERV-W. Activation is reasonably a prerequisite for causality as most HERV sequences remain quiescent in non-pathological conditions, so the importance of regulatory pathways and epigenetics involved in regulating HERV activation, derepression, and also involvement of retroviral restriction factors, is emerging. HERV-directed antiretrovirals have potential as novel therapeutic paradigms in neurologic disease, particularly in MS. The possible protective or ameliorative effects of antiretroviral therapy in MS are substantiated by reports that treatment of HIV infection may be associated with a significantly decreased risk of MS. Further studies of HERVs, their role in neurologic diseases, and their potential as therapeutic targets are essential.}, }
@article {pmid26812787, year = {2016}, author = {Esteras, N and Dinkova-Kostova, AT and Abramov, AY}, title = {Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function.}, journal = {Biological chemistry}, volume = {397}, number = {5}, pages = {383-400}, doi = {10.1515/hsz-2015-0295}, pmid = {26812787}, issn = {1437-4315}, support = {18644/CRUK_/Cancer Research UK/United Kingdom ; BB/L01923X/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; C20953/A18644/CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Animals ; Brain/metabolism ; *Energy Metabolism ; Glycogen Synthase Kinase 3/antagonists &amp; inhibitors ; Humans ; Lipid Metabolism ; Membrane Transport Proteins/metabolism ; Mitochondria/*metabolism ; NF-E2-Related Factor 2/*metabolism ; Neurodegenerative Diseases/*metabolism ; }, abstract = {The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor well-known for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich's ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.}, }
@article {pmid26812695, year = {2016}, author = {Ramchandani, R and Schoenfeld, DA and Finkelstein, DM}, title = {Global rank tests for multiple, possibly censored, outcomes.}, journal = {Biometrics}, volume = {72}, number = {3}, pages = {926-935}, pmid = {26812695}, issn = {1541-0420}, support = {T32 NS048005/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/mortality/physiopathology ; Clinical Trials as Topic ; Computer Simulation ; *Data Interpretation, Statistical ; Humans ; Nervous System/physiopathology ; *Statistics, Nonparametric ; Survival Analysis ; *Treatment Outcome ; }, abstract = {Clinical trials often collect multiple outcomes on each patient, as the treatment may be expected to affect the patient on many dimensions. For example, a treatment for a neurological disease such as ALS is intended to impact several dimensions of neurological function as well as survival. The assessment of treatment on the basis of multiple outcomes is challenging, both in terms of selecting a test and interpreting the results. Several global tests have been proposed, and we provide a general approach to selecting and executing a global test. The tests require minimal parametric assumptions, are flexible about weighting of the various outcomes, and are appropriate even when some or all of the outcomes are censored. The test we propose is based on a simple scoring mechanism applied to each pair of subjects for each endpoint. The pairwise scores are then reduced to a summary score, and a rank-sum test is applied to the summary scores. This can be seen as a generalization of previously proposed nonparametric global tests (e.g., O'Brien, 1984). We discuss the choice of optimal weighting schemes based on power and relative importance of the outcomes. As the optimal weights are generally unknown in practice, we also propose an adaptive weighting scheme and evaluate its performance in simulations. We apply the methods to analyze the impact of a treatment on neurological function and death in an ALS trial.}, }
@article {pmid29461733, year = {2016}, author = {de Schoutheete, JC and Hachimi Idrissi, S and Watelet, JB}, title = {Pre-hospital interventions: introduction to life support systems.}, journal = {B-ENT}, volume = {Suppl 26}, number = {1}, pages = {41-54}, pmid = {29461733}, issn = {1781-782X}, mesh = {*Emergency Medical Services ; Humans ; *Life Support Care ; *Life Support Systems ; Mass Casualty Incidents ; Military Medicine ; Otolaryngology ; Patient Care Team ; Triage ; War-Related Injuries/diagnosis/*therapy ; }, abstract = {Pre-hospital interventions: introduction to life support systems. Crucial decisions in pre-hospital emergency care are often made; therefore, a tactical emergency medical support team (TEMS) should maintain the capacity to capture the situation instantaneously and in all circumstances. However, low exposure to severe trauma cases can be a weakness for emergency specialists, which makes pre-hospital assessment more difficult. Pre-hospital interventions (PHI) are usually classified in Western countries into BLS (basic life support) and ALS (ad- vanced life support) levels, according to the methods used. This review introduces tactical combat casualty care for medical personnel (TCCC) guidelines, designed for basic care management under fire or in a hostile environment. The phases of TCCC are: (1) care under fire (or in an unstable environment); (2) tactical field care; and (3) tactical evacuation care, and are mainly dependent on the different hazard zones (hot, warm or cold). In a mass casualty situation due to disaster or cataclysm, standardized protocol and triage are unquestionably required for identifying the environmental risks, for categorizing the casualties in accordance with medical care priorities, and for the initial management of casualty care. When considering conflict situations, or chemical, biological, radiological, or nuclear (CBRN) events, processes always start at the local level. Even before the detection and analysis of agents can be undertaken, zoning, triage, decontamination, and treatment should be initiated promptly. Otorhinolaryngologists should be aware of PHI procedures for completing preliminary assessment and management together with emergency specialists or TEMS.}, }
@article {pmid28296861, year = {2016}, author = {Bansal, H and Singh, L and Agrawal, A and Leon, J and Sundell, IB and Koka, PS}, title = {Therapy with Bone Marrow-Derived Autologous Adult Stem Cells in Quadriparesis due to Motor Neuron Disease.}, journal = {Journal of stem cells}, volume = {11}, number = {1}, pages = {15-23}, pmid = {28296861}, issn = {1556-8539}, mesh = {Adult ; Adult Stem Cells/*cytology ; Amyotrophic Lateral Sclerosis/pathology ; Bone Marrow Cells/*cytology ; Electromyography ; Humans ; Male ; Motor Neuron Disease/*complications ; Quadriplegia/*etiology/*therapy ; *Stem Cell Transplantation/adverse effects ; Transplantation, Autologous ; }, abstract = {OBJECTIVE: To report the safety and therapeutic effectiveness of application of concentrated bone marrow aspirate in three bedridden patients with weakness in both legs, and monitor potential improvement in neurological outcomes.<br><br>DESIGN: Case report. Intervention: Five infusions of 3x10[8] mononuclear cells were administrated with 12 week intervals. Bone marrow (240ML) were obtained from the posterior superior iliac spine and Bone marrow mononuclear cells were enriched by standard manual close method under aseptic condition.<br><br>RESULTS: During the follow-up study of one year after stem cell implantation, the conditions of all three patients were improved and were confirmed by physical assessment, muscle charting and Electromyography (EMG). One year after stem cell implantation patients who were bedridden before treatment could sit without support and walk with support up to 200 feet at a stretch.<br><br>CONCLUSION: The local application of a cocktail of regenerative cell population found in an MNC fraction of bone marrow was safe and effective in improving quality of life and muscle strength in ALS patients. This case opens the need for further investigations on Autogenic stem cell transplant therapies for MND disease.}, }
@article {pmid27145589, year = {2015}, author = {S, C and B, de C}, title = {RESISTANCE TO ALS-INHIBITING HERBICIDES IN WEED POPULATIONS FROM BELGIAN WHEAT FIELDS.}, journal = {Communications in agricultural and applied biological sciences}, volume = {80}, number = {2}, pages = {251-259}, pmid = {27145589}, issn = {1379-1176}, mesh = {Acetolactate Synthase/*antagonists &amp; inhibitors ; Belgium ; Crops, Agricultural/growth &amp; development ; *Herbicide Resistance ; Herbicides/*pharmacology ; Plant Proteins/*antagonists &amp; inhibitors ; Plant Weeds/*drug effects ; Sulfur Compounds/*pharmacology ; Triticum/growth &amp; development ; *Weed Control ; }, abstract = {In modern agriculture, most farmers rely on herbicides for weed control. The intensive use of herbicides in crops has led to the development of herbicide resistance in numerous weeds worldwide. In Belgium, farmers have encountered problems with controlling populations of Alopecurus myosuroides, Matricaria recutita, Stellaria media and Popover rhoeas in some wheat fields with the conventionally used acetolactate synthase (ALS)-inhibiting herbicides. Dose response assays were conducted in the greenhouse to test the sensitivity of these populations to the key ALS-inhibiting herbicides mesosulfuron-methyl + iodosulfuron-methyl for A. myosuroides and metsulfuron-methyl and florasulam for M. recutita, S. media and P. rhoeas. The ED90- and ED50-values (effective dose for resp. 90% and 50% biomass reduction) were compared with those of sensitive reference populations and the resistance index (RI) was calculated. High levels of resistance were detected forA. myosuroides (RI: 24.3) after treatment with mesosulfuron-methyl and for M. recutita (RI: 36.4 to 49.5), S. media (RI > 20) and P. rhoeas (RI: 23.6) after treatment with metsulfuron-methyl. However, the metsulfuron-methyl resistant populations of M. recutita and S. media were sufficiently controlled with florasulam at the maximum authorised field dose. This was not the case for P. rhoeas. The metsulfuron-methyl resistant P. rhoeas population were also high-level resistant against florasulam (RI: 29.5). Integrated weed management practices (crop rotation, herbicide mixing, ...) should be applied to reduce the selection pressure for resistant weeds.}, }
@article {pmid28548072, year = {2014}, author = {Matsumoto, K and Funakoshi, H and Takahashi, H and Sakai, K}, title = {HGF-Met Pathway in Regeneration and Drug Discovery.}, journal = {Biomedicines}, volume = {2}, number = {4}, pages = {275-300}, pmid = {28548072}, issn = {2227-9059}, abstract = {Hepatocyte growth factor (HGF) is composed of an α-chain and a β-chain, and these chains contain four kringle domains and a serine protease-like structure, respectively. Activation of the HGF-Met pathway evokes dynamic biological responses that support morphogenesis (e.g., epithelial tubulogenesis), regeneration, and the survival of cells and tissues. Characterizations of conditional Met knockout mice have indicated that the HGF-Met pathway plays important roles in regeneration, protection, and homeostasis in various cells and tissues, which includes hepatocytes, renal tubular cells, and neurons. Preclinical studies designed to address the therapeutic significance of HGF have been performed on injury/disease models, including acute tissue injury, chronic fibrosis, and cardiovascular and neurodegenerative diseases. The promotion of cell growth, survival, migration, and morphogenesis that is associated with extracellular matrix proteolysis are the biological activities that underlie the therapeutic actions of HGF. Recombinant HGF protein and the expression vectors for HGF are biological drug candidates for the treatment of patients with diseases and injuries that are associated with impaired tissue function. The intravenous/systemic administration of recombinant HGF protein has been well tolerated in phase I/II clinical trials. The phase-I and phase-I/II clinical trials of the intrathecal administration of HGF protein for the treatment of patients with amyotrophic lateral sclerosis and spinal cord injury, respectively, are ongoing.}, }
@article {pmid30049125, year = {2014}, author = {Brah, S and Assogba, K and Adehossi, E and Kevi, S and Apetse, K and Kombate, D and Barque, B and Ballougou, AK and Grunitzky, EK}, title = {[Amyotrophic Lateral Sclerosis (ALS) in the 10 last years in CHU Campus of Lomé (TOGO)].}, journal = {Le Mali medical}, volume = {29}, number = {2}, pages = {33-37}, pmid = {30049125}, issn = {1993-0836}, abstract = {UNLABELLED: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes damage of upper motor neuron and lower motor neuron. Our objective was to describe the incidence and demographic characteristics of ALS and to analyze its diagnosis and management in Togo.<br><br>MATERIALS AND METHODS: A retrospective and descriptive study of patient's observations was conducted in the department of neurology of the teaching hospital in Lom&#xe9; during a 10 years period (2000 to 2009). The diagnosis of ALS was made according to the clinical classification of El Escorial.<br><br>RESULTS: 5 cases of ALS were diagnosed, representing 0.049% of the hospitalizations in the department of neurology. The average age of patients was 49 years [range: 24 - 67 years] and the average evolution of the disease was 17.6 months [range: 6 - 36 months]. All the patients were men. The treatment was symptomatic in every case. Treatment with Riluzole was not delivered. During the follow-up, one patient died from respiratory complications.<br><br>CONCLUSION: The El Escorial criteria should be made more accessible for a larger audience, as the availability and classification of care management relies heavily on diagnosed cases, namely early diagnosis.}, }
@article {pmid29473612, year = {2013}, author = {Ruzhansky, K and Brannagan, TH}, title = {Intravenous immunoglobulin for treatment of neuromuscular disease.}, journal = {Neurology. Clinical practice}, volume = {3}, number = {5}, pages = {440-445}, pmid = {29473612}, issn = {2163-0402}, abstract = {Intravenous immunoglobulin (IVIg) has been widely used in the treatment of autoimmune neuromuscular diseases. Compared to other treatment modalities, such as corticosteroids and chemotherapy for autoimmune disorders, IVIg has relatively few side effects and favorable therapeutic outcomes in certain neuromuscular diseases. There is Class I evidence for IVIg as an initial treatment for patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and multifocal motor neuropathy. It is as effective as plasma exchange in GBS and CIDP. In myasthenia gravis, IVIg is used for myasthenic crisis and exacerbations, though it is also helpful as maintenance therapy, particularly in patients with a suboptimal response or contraindications to prednisone or other immunosuppressive agents. IVIg has been demonstrated to be beneficial in placebo-controlled, double-blind, randomized studies in dermatomyositis and Lambert-Eaton syndrome. IVIg has also been beneficial in select patients with polymyositis and other autoimmune peripheral neuropathies. Clinical trials in amyotrophic lateral sclerosis, inclusion body myositis, and anti-myelin-associated glycoprotein neuropathy have been negative.}, }
@article {pmid29095080, year = {2013}, author = {}, title = {Prion and Prion-like Diseases in Humans: Poster Abstracts.}, journal = {Prion}, volume = {7}, number = {sup1}, pages = {54-80}, pmid = {29095080}, issn = {1933-690X}, }
@article {pmid29768799, year = {2012}, author = {Riley, J and Hurtig, CV and Boulis, N}, title = {Translating cellular therapies from bench to bedside for amyotrophic lateral sclerosis.}, journal = {Personalized medicine}, volume = {9}, number = {6}, pages = {645-655}, doi = {10.2217/pme.12.74}, pmid = {29768799}, issn = {1744-828X}, abstract = {The last decade has witnessed an increasing number of biologic (e.g., cell- or viral vector-based) therapeutics supported by preclinical efficacy data for the treatment of afflictions to the CNS. While some international investigators have undertaken preliminary clinical safety studies, published literature indicate varying degrees of rigor with respect to study design and technical approach. To our knowledge, ours is the first group to have systematically generated preclinical validation data for a delivery approach and translated this into a Phase I trial attempting to covalidate the safety of a direct, targeted delivery approach, as well as a cell-based therapeutic. This article discusses the rationale for cell-based therapy in amyotrophic lateral sclerosis and several of the unique considerations encountered during this process.}, }
@article {pmid26998403, year = {2011}, author = {Ohta, Y and Nagai, M and Miyazaki, K and Tanaka, N and Kawai, H and Mimoto, T and Morimoto, N and Kurata, T and Ikeda, Y and Matsuura, T and Abe, K}, title = {Neuroprotective and Angiogenic Effects of Bone Marrow Transplantation Combined With Granulocyte Colony-Stimulating Factor in a Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Cell medicine}, volume = {2}, number = {2}, pages = {69-83}, pmid = {26998403}, issn = {2155-1790}, abstract = {Bone marrow (BM) cells from amyotrophic lateral sclerosis (ALS) patients show significantly reduced expression of several neurotrophic factors. Monotherapy with either wild-type (WT) BM transplantation (BMT) or granulocyte colony-stimulating factor (GCSF) has only a small clinical therapeutic effect in an ALS mouse model, due to the phenomenon of neuroprotection. In this study, we investigated the clinical benefits of combination therapy using BMT with WT BM cells, plus GCSF after disease onset in ALS mice [transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) bearing a G93A mutation]. Combined treatment with BMT and GCSF delayed disease progression and prolonged the survival of G93A mice, whereas BMT or GCSF treatment alone did not. Histological study of the ventral horns of lumbar cords from G93A mice treated with BMT and GCSF showed a reduction in motor neuron loss coupled with induced neuronal precursor cell proliferation, increased expression of neurotrophic factors (glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor and angiogenin), and neovascularization compared with controls (vehicle only). Compared with G93A microglial cells, most BM-derived WT cells differentiated into microglial cells and strongly expressed neurotrophic factors, combined BMT and GCSF treatment led to the replacement of G93A microglial cells with BM-derived WT cells. These results indicate combined treatment with BMT and GCSF has potential neuroprotective and angiogenic effects in ALS mice, induced by the replacement of G93A microglial cells with BM-derived WT cells. Furthermore, this is the first report showing the effects of combined BMT and GCSF treatment on blood vessels in ALS.}, }
@article {pmid27713230, year = {2009}, author = {Mancuso, M and Orsucci, D and Calsolaro, V and Choub, A and Siciliano, G}, title = {Coenzyme Q10 and Neurological Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {2}, number = {3}, pages = {134-149}, pmid = {27713230}, issn = {1424-8247}, abstract = {Coenzyme Q10 (CoQ10, or ubiquinone) is a small electron carrier of the mitochondrial respiratory chain with antioxidant properties. CoQ10 supplementation has been widely used for mitochondrial disorders. The rationale for using CoQ10 is very powerful when this compound is primary decreased because of defective synthesis. Primary CoQ10 deficiency is a treatable condition, so heightened "clinical awareness" about this diagnosis is essential. CoQ10 and its analogue, idebenone, have also been widely used in the treatment of other neurodegenerative disorders. These compounds could potentially play a therapeutic role in Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological diseases, from primary CoQ10 deficiency to neurodegenerative disorders.}, }
@article {pmid30818473, year = {2002}, author = {Abbasi, PA and Soltani, N and Cuppels, DA and Lazarovits, G}, title = {Reduction of Bacterial Spot Disease Severity on Tomato and Pepper Plants with Foliar Applications of Ammonium Lignosulfonate and Potassium Phosphate.}, journal = {Plant disease}, volume = {86}, number = {11}, pages = {1232-1236}, doi = {10.1094/PDIS.2002.86.11.1232}, pmid = {30818473}, issn = {0191-2917}, abstract = {Bacterial spot is a serious and persistent disease problem of tomato and bell pepper in both the United States and Canada. Current disease management practices, based primarily on fixed copper bactericides, do not give consistent, effective protection. Foliar applications of ammonium lignosulfonate (ALS), derived from the wood pulping process, and the fertilizer potassium phosphate (KP) were tested for their ability to control this disease under both greenhouse and field conditions. Acibenzolar-S-methyl was included as a control. Greenhouse-grown tomato transplants treated with acibenzolar-S-methyl, 2 or 4% (vol/vol) ALS, 25 mM KP, or 2% ALS plus 10 mM KP and then inoculated with Xanthomonas campestris pv. vesicatoria had significantly less disease than the unprotected controls. Weekly foliar applications of acibenzolar-S-methyl, ALS, or KP significantly reduced disease severity on the foliage of inoculated field-grown tomato and pepper plants; although less disease appeared on the fruit of these plants, the effect was not always statistically significant except for the acibenzolar-S-methyl treatment. Acibenzolar-S-methyl increased the yield of marketable tomato fruit in 2 of 3 years of the study and that of pepper fruit in 1 of 2 years. There was a marked increase in the yield of marketable fruit on all ALS-treated pepper plants in 2001. None of the treatments significantly increased total tomato or pepper yield. ALS and KP had no observable phytotoxic effect on tomato or pepper foliage. Our results indicate that future integrated disease management programs for bacterial spot may be enhanced by including foliar sprays of these two products.}, }
@article {pmid27517546, year = {2001}, author = {Mauri, MC and Laini, V and Scalvini, ME and Omboni, A and Ferrari, VM and Clemente, A and Salvi, V and Cerveri, G}, title = {Gabapentin and the Prophylaxis of Bipolar Disorders in Patients Intolerant to Lithium.}, journal = {Clinical drug investigation}, volume = {21}, number = {3}, pages = {169-174}, pmid = {27517546}, issn = {1173-2563}, abstract = {OBJECTIVE: Gabapentin (GBP) is a new anticonvulsant drug that has shown efficacy in the treatment of epilepsy, several neurological disorders (pain syndromes, acquired nystagmus, Huntington's chorea, amyotrophic lateral sclerosis), and more recently in the treatment of bipolar disorders. The aim of this preliminary study was to assess the efficacy of GBP as a mood stabiliser in bipolar disorders. The adverse events of GBP were also evaluated.<br><br>PATIENTS AND METHODS: 21 outpatients, 13 females and 8 males (mean age &#xb1; SD: 51.90 &#xb1; 11.51 years) affected by bipolar disorder (BD), in partial remission (DSM IV) and intolerant to lithium, were treated with GBP at a dose ranging from 300 to 2400 mg/day (mean &#xb1; SD: 1010.86 &#xb1; 268.55mg; 13.81 &#xb1; 4.21 mg/kg) for 1 year. Clinical assessments were performed with the Brief Psychiatric Rating Scale (BPRS), the Hamilton Rating Scale for Depression (HRS-D), the Hamilton Rating Scale for Anxiety (HRS-A) and the Manic Rating Scale (MRS) at baseline (T0), after 15 days (T0.5), after 30 days (T1), and then every month for 12 months.<br><br>RESULTS: Mean HRS-D, HRS-A and MRS scores did not show any significant variation during the study. Only one patient showed a clinical relapse. The most frequent adverse events reported by patients were dizziness (1%), dry mouth (1%) and sedation (0.5%). There was a significant negative correlation between GBP dosage (mg/kg) and HRS-A score. Mean leucocyte and neutrophil counts showed a significant increase during the study.<br><br>CONCLUSIONS: These preliminary data show potential efficacy and good tolerability of GBP in the prophylaxis of BD, but double-blind studies are required.}, }
@article {pmid28140070, year = {1999}, author = {Nichol, G and Stiell, IG and Laupacis, A and Pham, B and Maio, VJ and Wells, GA}, title = {A cumulative meta-analysis of the effectiveness of defibrillator-capable emergency medical services for victims of out-of-hospital cardiac arrest.}, journal = {Annals of emergency medicine}, volume = {34}, number = {4 Pt 1}, pages = {517-525}, pmid = {28140070}, issn = {1097-6760}, abstract = {STUDY OBJECTIVE: More than 1,000 patients experience sudden cardiac arrest each day. Treatment for this includes cardiopulmonary resuscitation (CPR_ and emergency medical services (EMS) that provide CPR-basic life support (BLS), BLS with defibrillation (BLS-D), or advanced life support (ALS). Our previous systematic review of treatments for sudden cardiac arrest was limited by suboptimal data. Since then, debate has increased about whether bystander CPR is effective or whether attention should focus instead on rapid defibrillation. Therefore a cumulative meta-analysis was conducted to determine the relative effectiveness of differences in the defibrillation response time interval, proportion of bystander CPR, and type of EMS system on survival after out-of-hospital cardiac arrest.<br><br>METHODS: A comprehensive literature search was performed by using a priori exclusion criteria. We considered EMS systems that provided BLS-D, ALS, BLS plus ALS, or BLS-D plus ALS care. A generalized linear model was used with dispersion estimation for random effects.<br><br>RESULTS: Thirty-seven eligible articles described 39 EMS systems and included 33, 124 patients. Median survival for all rhythm groups to hospital discharge was 6.4% (interquartile range, 3.7 to 10.3). Odds of survival were 1.06 (95% confidence interval [Cl], 1.03 to 1.09; P<.01) per 5% increase in bystander CPR. Survival was constant if the defibrillation response time interval was less than 6 minutes, decreased as the interval increased from 6 to 11 minutes, and leveled of after 11 minutes (P<.01). Compared with BLS-D, odds of survival were as follows: ALS, 1.71 (95% Cl, 1.09 to 2.70; P=.01); BLS plus ALS, 1.47 (95% Cl, 0.89 to 2.42; P=.07); and BLS with defibrillation plus ALS, 2.31 (95% Cl, 1.47 to 3.62; P<.01.) Conclusion: We confirm that greater survival after sudden cardiac arrest is associated with provision of bystander CPR, early defibrillation, or ALS. More research is required to evaluate the relative benefit of early defibrillation versus early ALS.}, }
@article {pmid26563499, year = {2016}, author = {Yung, C and Sha, D and Li, L and Chin, LS}, title = {Parkin Protects Against Misfolded SOD1 Toxicity by Promoting Its Aggresome Formation and Autophagic Clearance.}, journal = {Molecular neurobiology}, volume = {53}, number = {9}, pages = {6270-6287}, pmid = {26563499}, issn = {1559-1182}, support = {R01 AG034126/AG/NIA NIH HHS/United States ; F31 NS074620/NS/NINDS NIH HHS/United States ; T32 GM008602/GM/NIGMS NIH HHS/United States ; R01 GM103613/GM/NIGMS NIH HHS/United States ; P50 NS071669/NS/NINDS NIH HHS/United States ; R21 NS093550/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Autophagy/*drug effects ; Cell Line, Tumor ; Cytoprotection/drug effects ; Gene Deletion ; Humans ; Lysine/metabolism ; Lysosomes/drug effects/metabolism ; Mice, Knockout ; Mutant Proteins/toxicity ; Neuroprotection/drug effects ; Polyubiquitin/metabolism ; Proteasome Endopeptidase Complex/metabolism ; *Protein Aggregates/drug effects ; *Protein Folding/drug effects ; Proteolysis/drug effects ; Superoxide Dismutase/*toxicity ; Ubiquitin-Protein Ligases/*metabolism ; Ubiquitination/drug effects ; }, abstract = {Mutations in Cu/Zn superoxide dismutase (SOD1) cause autosomal dominant amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease with no effective treatment. Despite ample evidence indicating involvement of mutation-induced SOD1 protein misfolding and aggregation in ALS pathogenesis, the molecular mechanisms that control cellular management of misfolded, aggregation-prone SOD1 mutant proteins remain unclear. Here, we report that parkin, an E3 ubiquitin-protein ligase which is linked to Parkinson's disease, is a novel regulator of cellular defense against toxicity induced by ALS-associated SOD1 mutant proteins. We find that parkin mediates K63-linked polyubiquitination of SOD1 mutants in cooperation with the UbcH13/Uev1a E2 enzyme and promotes degradation of these misfolded SOD1 proteins by the autophagy-lysosome system. In response to strong proteotoxic stress associated with proteasome impairment, parkin promotes sequestration of misfolded and aggregated SOD1 proteins to form perinuclear aggresomes, regulates positioning of lysosomes around misfolded SOD1 aggresomes, and facilitates aggresome clearance by autophagy. Our findings reveal parkin-mediated cytoprotective mechanisms against misfolded SOD1 toxicity and suggest that enhancing parkin-mediated cytoprotection may provide a novel therapeutic strategy for treating ALS.}, }
@article {pmid26807587, year = {2016}, author = {Herrando-Grabulosa, M and Mulet, R and Pujol, A and Mas, JM and Navarro, X and Aloy, P and Coma, M and Casas, C}, title = {Novel Neuroprotective Multicomponent Therapy for Amyotrophic Lateral Sclerosis Designed by Networked Systems.}, journal = {PloS one}, volume = {11}, number = {1}, pages = {e0147626}, pmid = {26807587}, issn = {1932-6203}, mesh = {Algorithms ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Chromones/pharmacology/*therapeutic use ; Computer Simulation ; Drug Therapy, Combination ; Humans ; Mefloquine/pharmacology/*therapeutic use ; Models, Theoretical ; Neuroprotective Agents/pharmacology/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/drug effects ; }, abstract = {Amyotrophic Lateral Sclerosis is a fatal, progressive neurodegenerative disease characterized by loss of motor neuron function for which there is no effective treatment. One of the main difficulties in developing new therapies lies on the multiple events that contribute to motor neuron death in amyotrophic lateral sclerosis. Several pathological mechanisms have been identified as underlying events of the disease process, including excitotoxicity, mitochondrial dysfunction, oxidative stress, altered axonal transport, proteasome dysfunction, synaptic deficits, glial cell contribution, and disrupted clearance of misfolded proteins. Our approach in this study was based on a holistic vision of these mechanisms and the use of computational tools to identify polypharmacology for targeting multiple etiopathogenic pathways. By using a repositioning analysis based on systems biology approach (TPMS technology), we identified and validated the neuroprotective potential of two new drug combinations: Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine. In addition, we estimated their molecular mechanisms of action in silico and validated some of these results in a well-established in vitro model of amyotrophic lateral sclerosis based on cultured spinal cord slices. The results verified that Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine promote neuroprotection of motor neurons and reduce microgliosis.}, }
@article {pmid26807190, year = {2015}, author = {Shu, LP and Zhou, ZW and Zi, D and He, ZX and Zhou, SF}, title = {A SILAC-based proteomics elicits the molecular interactome of alisertib (MLN8237) in human erythroleukemia K562 cells.}, journal = {American journal of translational research}, volume = {7}, number = {11}, pages = {2442-2461}, pmid = {26807190}, issn = {1943-8141}, abstract = {Alisertib (MLN8237, ALS), an Aurora kinase A (AURKA) inhibitor, exerts potent anti-tumor effects in the treatment of solid tumor and hematologic malignancies in preclinical and clinical studies. However, the fully spectrum of molecular targets of ALS and its anticancer effect in the treatment of chronic myeloid leukemia (CML) are not clear. This study aimed to examine the proteomic responses to ALS treatment and unveil the molecular interactome and possible mechanisms for its anticancer effect in K562 cells using stable-isotope labeling by amino acids in cell culture (SILAC) approach. The proteomic data identified that ALS treatment modulated the expression of 1541 protein molecules (570 up; 971 down). The pathway analysis showed that 299 signaling pathways and 459 cellular functional proteins directly responded to ALS treatment in K562 cells. These targeted molecules and signaling pathways were mainly involved in cell growth and proliferation, cell metabolism, and cell survival and death. Subsequently, the effects of ALS on cell cycle distribution, apoptosis, and autophagy were verified. The flow cytometric analysis showed that ALS significantly induced G2/M phase arrest and the Western blotting assays showed that ALS induced apoptosis via mitochondria-dependent pathway and promoted autophagy with the involvement of PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways in K562 cells. Collectively, this study provides a clue to quantitatively evaluate the proteomic responses to ALS and assists in globally identifying the potential molecular targets and elucidating the underlying mechanisms of ALS for CML treatment, which may help develop new efficacious and safe therapies for CML treatment.}, }
@article {pmid26803950, year = {2016}, author = {Weikamp, JG and Schinagl, DA and Verstappen, CC and Schelhaas, HJ and de Swart, BJ and Kalf, JG}, title = {Botulinum toxin-A injections vs radiotherapy for drooling in ALS.}, journal = {Acta neurologica Scandinavica}, volume = {134}, number = {3}, pages = {224-231}, doi = {10.1111/ane.12559}, pmid = {26803950}, issn = {1600-0404}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications ; Botulinum Toxins, Type A/administration &amp; dosage/*pharmacology ; Female ; Humans ; Injections ; Male ; Middle Aged ; Neuromuscular Agents/administration &amp; dosage/*pharmacology ; *Parotid Gland/drug effects ; Pilot Projects ; Prospective Studies ; Sialorrhea/*drug therapy/etiology/*radiotherapy ; *Submandibular Gland ; Treatment Outcome ; }, abstract = {OBJECTIVES: Botulinum neurotoxin (BoNT) injections in the salivary glands and radiotherapy (RT) on these glands are commonly used to alleviate severe drooling in patients with amyotrophic lateral sclerosis (ALS). This study compares BoNT type A with RT based on patient-rated evaluations.<br><br>MATERIALS &amp; METHODS: A prospective randomized controlled pilot study to compare RT (n = 10; on the parotid and the posterior part of the submandibular glands) with BoNT-A treatment (n = 10; in the parotid glands only, because of the risk of increasing oropharyngeal weakness) in patients with ALS. The primary outcome was the drooling status (burden of drooling), and our secondary interests were the degree of salivation, global change of drooling after treatment, and level of satisfaction with the treatment and negative experiences.<br><br>RESULTS: There were no statistically significant between-treatment differences for the drooling status after treatment. Only at twelve weeks more saliva reduction was achieved by RT (P = 0.02). Patients treated with RT also described more transient negative experiences (like pain in mandible) directly after treatment. Subgroup analysis showed that patients with very severe dysphagia (no oral intake) were less satisfied and experienced a lower global change of drooling after treatment.<br><br>CONCLUSIONS: This pilot study showed no significant difference in the burden of drooling between the treatments. However, with RT more saliva reduction was achieved, including negative experiences directly after treatment, but without the risk of decreasing oropharyngeal function. In addition, patients with very severe dysphagia do not seem to benefit from either treatment.}, }
@article {pmid26795196, year = {2016}, author = {Miyazaki, I and Asanuma, M}, title = {Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson's Disease.}, journal = {Current medicinal chemistry}, volume = {23}, number = {7}, pages = {686-700}, pmid = {26795196}, issn = {1875-533X}, mesh = {Animals ; Astrocytes/*drug effects/*metabolism/pathology ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Humans ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/drug effects ; Parkinson Disease/*drug therapy/metabolism/pathology ; Receptor, Serotonin, 5-HT1A/*metabolism ; }, abstract = {Astrocytes are the most abundant neuron-supporting glial cells in the central nervous system. The neuroprotective role of astrocytes has been demonstrated in various neurological disorders such as amyotrophic lateral sclerosis, spinal cord injury, stroke and Parkinson's disease (PD). Astrocyte dysfunction or loss-of-astrocytes increases the susceptibility of neurons to cell death, while astrocyte transplantation in animal studies has therapeutic advantage. We reported recently that stimulation of serotonin 1A (5-HT1A) receptors on astrocytes promoted astrocyte proliferation and upregulated antioxidative molecules to act as a neuroprotectant in parkinsonian mice. PD is a progressive neurodegenerative disease with motor symptoms such as tremor, bradykinesia, rigidity and postural instability, that are based on selective loss of nigrostriatal dopaminergic neurons, and with non-motor symptoms such as orthostatic hypotension and constipation based on peripheral neurodegeneration. Although dopaminergic therapy for managing the motor disability associated with PD is being assessed at present, the main challenge remains the development of neuroprotective or disease- modifying treatments. Therefore, it is desirable to find treatments that can reduce the progression of dopaminergic cell death. In this article, we summarize first the neuroprotective properties of astrocytes targeting certain molecules related to PD. Next, we review neuroprotective effects induced by stimulation of 5-HT1A receptors on astrocytes. The review discusses new promising therapeutic strategies based on neuroprotection against oxidative stress and prevention of dopaminergic neurodegeneration.}, }
@article {pmid26786249, year = {2016}, author = {Lu, H and Le, WD and Xie, YY and Wang, XP}, title = {Current Therapy of Drugs in Amyotrophic Lateral Sclerosis.}, journal = {Current neuropharmacology}, volume = {14}, number = {4}, pages = {314-321}, pmid = {26786249}, issn = {1875-6190}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Anti-Inflammatory Agents/therapeutic use ; Antioxidants/therapeutic use ; Apoptosis/drug effects ; Cholestenones/therapeutic use ; Dasatinib/therapeutic use ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Mice ; Mitochondria/drug effects ; Nerve Growth Factors/therapeutic use ; Neuroprotective Agents/*therapeutic use ; Riluzole/therapeutic use ; Superoxide Dismutase-1/genetics ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS), commonly termed as motor neuron disease (MND) in UK, is a chronically lethal disorder among the neurodegenerative diseases, meanwhile. ALS is basically irreversible and progressive deterioration of upper and lower motor neurons in the motor cortex, brain stem and medulla spinalis. Riluzole, used for the treatment of ALS, was demonstrated to slightly delay the initiation of respiratory dysfunction and extend the median survival of patients by a few months. In this study, the key biochemical defects were discussed, such as: mutant Cu/Zn superoxide dismutase, mitochondrial protectants, and anti-excitotoxic/ anti-oxidative / antiinflammatory/ anti-apoptotic agents, so the related drug candidates that have been studied in ALS models would possibly be further used in ALS patients.}, }
@article {pmid26785365, year = {2015}, author = {Nagańska, E and Matyja, E and Taraszewska, A and Rafałowska, J}, title = {Protective effect of valproic acid on cultured motor neurons under glutamate excitotoxic conditions. Ultrastructural study.}, journal = {Folia neuropathologica}, volume = {53}, number = {4}, pages = {309-316}, doi = {10.5114/fn.2015.56545}, pmid = {26785365}, issn = {1509-572X}, mesh = {Animals ; Animals, Newborn ; Cells, Cultured ; Excitatory Amino Acid Agonists/*pharmacology ; Glutamic Acid/*toxicity ; Motor Neurons/*drug effects/pathology/*ultrastructure ; Neuroprotective Agents/*pharmacology ; Organ Culture Techniques ; Rats ; Spinal Cord/drug effects/pathology/ultrastructure ; Valproic Acid/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that involves the upper and lower motor neurons and leads to the patient's death within 5 years after diagnosis. Approximately 2 per 100,000 people worldwide are affected every year. The only FDA-approved drug available for medical treatment is riluzole. It slows the disease progression and improves limb function and muscle strength for 3-4 months. Thus, looking for new therapeutic agents is a pressing challenge. Valproic acid (VPA) is a short-chain fatty acid, widely used for the treatment of seizures and bipolar mood disorder. The beneficial effect of VPA has been documented in different neurodegenerative experimental models, including amyotrophic lateral sclerosis (ALS). The real mechanisms underlying numerous beneficial effects of VPA are complex, but recently it has been postulated that the neuroprotective properties might be related to direct inhibition of histone deacetylase (HDAC). The aim of this ultrastructural study was to evaluate the beneficial effect of VPA on the spinal cord motor neurons (MNs) in a glutamate (GLU)-induced excitotoxic ALS model in vitro. It had been previously documented that chronic GLU excitotoxicity resulted in various MN injuries, including necrotic, apoptotic and autophagic modes of cell death. The present results demonstrated the neuroprotective properties of VPA associated with inhibition of apoptotic and autophagic changes of spinal MNs in a model of neurodegeneration in vitro.}, }
@article {pmid26781007, year = {2016}, author = {Ishii, T and Bandoh, S and Kanaji, N and Tadokoro, A and Watanabe, N and Imataki, O and Dobashi, H and Kushida, Y and Haba, R and Yokomise, H}, title = {Air-leak Syndrome by Pleuroparenchymal Fibroelastosis after Bone Marrow Transplantation.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {55}, number = {2}, pages = {105-111}, doi = {10.2169/internalmedicine.55.4539}, pmid = {26781007}, issn = {1349-7235}, mesh = {Adult ; Bone Marrow Transplantation/*adverse effects ; Female ; Graft vs Host Disease/etiology ; Humans ; Immunosuppressive Agents/therapeutic use ; Lung Diseases/*etiology/mortality/*physiopathology/therapy ; Lung Transplantation ; Male ; Middle Aged ; Retrospective Studies ; Syndrome ; }, abstract = {Objective Air-leak syndrome (ALS) is a life-threatening pulmonary complication following allogeneic bone marrow transplantation (allo-BMT) which is thought to be associated with graft-versus-host disease (GVHD). Recently, it has been reported that pleuroparenchymal fibroelastosis (PPFE) also occurs after allo-BMT and often causes ALS. We sought to extract common features of ALS caused by PPFE after allo-BMT. Methods The clinical data of patients who developed ALS caused by PPFE after undergoing allo-BMT (ALS-PPFE) between April 1996 and December 2007 at our institution were collected and reviewed retrospectively. The clinical findings, radiological and pathological features and treatment outcomes of ALS-PPFE were assessed. Results Five patients who developed ALS had histologically proven PPFE (four men, one woman: median age, 37 years). The age of onset of ALS-PPFE was 13 to 109 months (median, 68.8 months) after BMT. Alkylating agents were used as conditioning chemotherapy for BMT in all patients. Only one patient developed chronic GVHD (limited type). The common radiological findings were subpleural thickening and traction bronchiectasis predominantly in the bilateral upper lung fields. The histological pulmonary specimens showed no findings of bronchiolitis obliterans or GVHD. Immunosuppressive therapy was not effective in any of the cases, and all patients died of respiratory failure with or without lung transplantation. Conclusion ALS-PPFE is an extremely late-onset noninfectious pulmonary complication of allo-BMT. This complication is progressive, resistant to immunosuppressive treatment and has a poor prognosis. No association was found between PPFE and GVHD.}, }
@article {pmid26779612, year = {2016}, author = {Rossi, S and Cozzolino, M and Carrì, MT}, title = {Old versus New Mechanisms in the Pathogenesis of ALS.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {26}, number = {2}, pages = {276-286}, pmid = {26779612}, issn = {1750-3639}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*physiopathology/therapy ; Animals ; Humans ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is recognized as a very complex disease. As we have learned in the past 20 years from studies in patients and in models based on the expression of mutant SOD1, ALS is not a purely motor neuron disease as previously thought. While undoubtedly motor neurons are lost in patients, a number of alterations in those cell-types that interact functionally with motor neurons (astrocytes, microglia, muscle fibers, oligodendrocytes) take place even long before onset of symptoms. At the same time, disturbance of several, only partly inter-related physiological functions play some role in the onset and progression of the disease. Traditionally, mitochondrial damage and oxidative stress, excitotoxicity, neuroinflammation, altered axonal transport, ER stress, protein aggregation and defective removal of toxic proteins have been considered as key factors in the pathogenesis of ALS, with the relatively recent addition of disturbances in RNA metabolism. This complexity makes the search for an effective treatment extremely difficult and prompts further studies to reveal other possible, previously unappreciated aspects of the pathogenesis of ALS. In this review, we focus on previous knowledge on ALS mechanisms as well as new facets emerging from studies on genetic ALS patients and models that may both provide precious information for a novel therapeutic approach.}, }
@article {pmid26775178, year = {2016}, author = {Van Dyke, JM and Smit-Oistad, IM and Macrander, C and Krakora, D and Meyer, MG and Suzuki, M}, title = {Macrophage-mediated inflammation and glial response in the skeletal muscle of a rat model of familial amyotrophic lateral sclerosis (ALS).}, journal = {Experimental neurology}, volume = {277}, number = {}, pages = {275-282}, pmid = {26775178}, issn = {1090-2430}, support = {R01 NS091540/NS/NINDS NIH HHS/United States ; R21 NS061049/NS/NINDS NIH HHS/United States ; R01NS091540/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*complications/genetics/*pathology ; Animals ; Antigens, CD/metabolism ; Disease Models, Animal ; Glial Cell Line-Derived Neurotrophic Factor/administration &amp; dosage ; Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism ; Inflammation/*etiology/genetics ; Interleukin-1beta/metabolism ; Macrophages/drug effects/*physiology ; Muscle, Skeletal/*pathology ; Nerve Tissue Proteins/metabolism ; Neuroglia/*physiology ; Neuromuscular Junction/pathology ; Rats ; Rats, Transgenic ; Receptors, Cholinergic/metabolism ; S100 Calcium Binding Protein beta Subunit/metabolism ; Schwann Cells/metabolism/pathology ; Superoxide Dismutase/genetics ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor dysfunction and loss of large motor neurons in the spinal cord and brain stem. While much research has focused on mechanisms of motor neuron cell death in the spinal cord, degenerative processes in skeletal muscle and neuromuscular junctions (NMJs) are also observed early in disease development. Although recent studies support the potential therapeutic benefits of targeting the skeletal muscle in ALS, relatively little is known about inflammation and glial responses in skeletal muscle and near NMJs, or how these responses contribute to motor neuron survival, neuromuscular innervation, or motor dysfunction in ALS. We recently showed that human mesenchymal stem cells modified to release glial cell line-derived neurotrophic factor (hMSC-GDNF) extend survival and protect NMJs and motor neurons in SOD1(G93A) rats when delivered to limb muscles. In this study, we evaluate inflammatory and glial responses near NMJs in the limb muscle collected from a rat model of familial ALS (SOD1(G93A) transgenic rats) during disease progression and following hMSC-GDNF transplantation. Muscle samples were collected from pre-symptomatic, symptomatic, and end-stage animals. A significant increase in the expression of microglial inflammatory markers (CD11b and CD68) occurred in the skeletal muscle of symptomatic and end-stage SOD1(G93A) rats. Inflammation was confirmed by ELISA for inflammatory cytokines interleukin-1 β (IL-1β) and tumor necrosis factor-α (TNF-α) in muscle homogenates of SOD1(G93A) rats. Next, we observed active glial responses in the muscle of SOD1(G93A) rats, specifically near intramuscular axons and NMJs. Interestingly, strong expression of activated glial markers, glial fibrillary acidic protein (GFAP) and nestin, was observed in the areas adjacent to NMJs. Finally, we determined whether ex vivo trophic factor delivery influences inflammation and terminal Schwann cell (TSC) response during ALS. We found that intramuscular transplantation of hMSC-GDNF tended to exhibit less inflammation and significantly maintained TSC association with NMJs. Understanding cellular responses near NMJs is important to identify suitable cellular and molecular targets for novel treatment of ALS and other neuromuscular diseases.}, }
@article {pmid26774696, year = {2016}, author = {Costa, J and de Carvalho, M}, title = {Emerging molecular biomarker targets for amyotrophic lateral sclerosis.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {455}, number = {}, pages = {7-14}, doi = {10.1016/j.cca.2016.01.011}, pmid = {26774696}, issn = {1873-3492}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/diagnosis/genetics/*metabolism ; Biomarkers/*metabolism ; Child ; Humans ; }, abstract = {Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects upper (UMN) and lower motor (LMN) neurons. It is associated with a short survival and there is no effective treatment, in spite of a large number of clinical trials. Strong efforts have been made to identify novel disease biomarkers to support diagnosis, provide information on prognosis, to measure disease progression in trials and increase our knowledge on disease pathogenesis. Electromyography by testing the function of the LMN can be used as a biomarker of its dysfunction. A number of electrophysiological and neuroimaging methods have been explored to identify a reliable marker of UMN degeneration. Recently, strong evidence from independent groups, large cohorts of patients and multicenter studies indicate that neurofilaments are very promising diagnostic biomarkers, in particular cerebrospinal fluid and blood levels of phosphoneurofilament heavy chain and neurofilament light chain. Furthermore, their increased levels are associated with poor prognosis. Additional studies have been performed aiming to identify other biomarkers, which alone or in combination with neurofilaments could increase the sensitivity and the specificity of the assays. Emerging molecular marker targets are being discovered, but more studies with standardized methods are required in larger cohorts of ALS patients.}, }
@article {pmid26770824, year = {2015}, author = {Flanagan, MF}, title = {The Role of the Craniocervical Junction in Craniospinal Hydrodynamics and Neurodegenerative Conditions.}, journal = {Neurology research international}, volume = {2015}, number = {}, pages = {794829}, pmid = {26770824}, issn = {2090-1852}, abstract = {The craniocervical junction (CCJ) is a potential choke point for craniospinal hydrodynamics and may play a causative or contributory role in the pathogenesis and progression of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, MS, and ALS, as well as many other neurological conditions including hydrocephalus, idiopathic intracranial hypertension, migraines, seizures, silent-strokes, affective disorders, schizophrenia, and psychosis. The purpose of this paper is to provide an overview of the critical role of the CCJ in craniospinal hydrodynamics and to stimulate further research that may lead to new approaches for the prevention and treatment of the above neurodegenerative and neurological conditions.}, }
@article {pmid26765769, year = {2016}, author = {Pollock, K and Dahlenburg, H and Nelson, H and Fink, KD and Cary, W and Hendrix, K and Annett, G and Torrest, A and Deng, P and Gutierrez, J and Nacey, C and Pepper, K and Kalomoiris, S and D Anderson, J and McGee, J and Gruenloh, W and Fury, B and Bauer, G and Duffy, A and Tempkin, T and Wheelock, V and Nolta, JA}, title = {Human Mesenchymal Stem Cells Genetically Engineered to Overexpress Brain-derived Neurotrophic Factor Improve Outcomes in Huntington's Disease Mouse Models.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {24}, number = {5}, pages = {965-977}, pmid = {26765769}, issn = {1525-0024}, support = {T32 HL086350/HL/NHLBI NIH HHS/United States ; S10 RR026825/RR/NCRR NIH HHS/United States ; F32 NS090722/NS/NINDS NIH HHS/United States ; P51 RR000169/RR/NCRR NIH HHS/United States ; T32 GM008799/GM/NIGMS NIH HHS/United States ; R01 GM099688/GM/NIGMS NIH HHS/United States ; T32 GM099608/GM/NIGMS NIH HHS/United States ; }, abstract = {Huntington's disease (HD) is a fatal degenerative autosomal dominant neuropsychiatric disease that causes neuronal death and is characterized by progressive striatal and then widespread brain atrophy. Brain-derived neurotrophic factor (BDNF) is a lead candidate for the treatment of HD, as it has been shown to prevent cell death and to stimulate the growth and migration of new neurons in the brain in transgenic mouse models. BDNF levels are reduced in HD postmortem human brain. Previous studies have shown efficacy of mesenchymal stem/stromal cells (MSC)/BDNF using murine MSCs, and the present study used human MSCs to advance the therapeutic potential of the MSC/BDNF platform for clinical application. Double-blinded studies were performed to examine the effects of intrastriatally transplanted human MSC/BDNF on disease progression in two strains of immune-suppressed HD transgenic mice: YAC128 and R6/2. MSC/BDNF treatment decreased striatal atrophy in YAC128 mice. MSC/BDNF treatment also significantly reduced anxiety as measured in the open-field assay. Both MSC and MSC/BDNF treatments induced a significant increase in neurogenesis-like activity in R6/2 mice. MSC/BDNF treatment also increased the mean lifespan of the R6/2 mice. Our genetically modified MSC/BDNF cells set a precedent for stem cell-based neurotherapeutics and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis, Alzheimer's disease, and some forms of Parkinson's disease. These cells provide a platform delivery system for future studies involving corrective gene-editing strategies.}, }
@article {pmid26756888, year = {2016}, author = {Rao, MV and Campbell, J and Palaniappan, A and Kumar, A and Nixon, RA}, title = {Calpastatin inhibits motor neuron death and increases survival of hSOD1(G93A) mice.}, journal = {Journal of neurochemistry}, volume = {137}, number = {2}, pages = {253-265}, pmid = {26756888}, issn = {1471-4159}, support = {5R21NS61190-2/NS/NINDS NIH HHS/United States ; R01 AG005604/AG/NIA NIH HHS/United States ; P01AG017617/AG/NIA NIH HHS/United States ; R21 NS061190/NS/NINDS NIH HHS/United States ; R01AG005604/AG/NIA NIH HHS/United States ; P01 AG017617/AG/NIA NIH HHS/United States ; }, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Animals ; Axons/pathology ; Calcium-Binding Proteins/*pharmacology ; Calpain/metabolism ; Cell Death/drug effects/genetics ; Cyclin-Dependent Kinase 5/metabolism ; Cysteine Proteinase Inhibitors/*pharmacology ; Cytoskeletal Proteins/metabolism ; Disease Models, Animal ; Disease Progression ; Gene Expression Regulation ; Humans ; Mice ; Mice, Transgenic ; Motor Activity/drug effects/genetics ; Motor Neurons/cytology/*drug effects/metabolism ; Nerve Degeneration/drug therapy/genetics/pathology ; Spinal Cord/cytology ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with a poorly understood cause and no effective treatment. Given that calpains mediate neurodegeneration in other pathological states and are abnormally activated in ALS, we investigated the possible ameliorative effects of inhibiting calpain over-activation in hSOD1(G93A) transgenic (Tg) mice in vivo by neuron-specific over-expression of calpastatin (CAST), the highly selective endogenous inhibitor of calpains. Our data indicate that over-expression of CAST in hSOD1(G93A) mice, which lowered calpain activation to levels comparable to wild-type mice, inhibited the abnormal breakdown of cytoskeletal proteins (spectrin, MAP2 and neurofilaments), and ameliorated motor axon loss. Disease onset in hSOD1(G93A) /CAST mice compared to littermate hSOD1(G93A) mice is delayed, which accounts for their longer time of survival. We also find that neuronal over-expression of CAST in hSOD1(G93A) transgenic mice inhibited production of putative neurotoxic caspase-cleaved tau and activation of Cdk5, which have been implicated in neurodegeneration in ALS models, and also reduced the formation of SOD1 oligomers. Our data indicate that inhibition of calpain with CAST is neuroprotective in an ALS mouse model. CAST (encoding calpastatin) inhibits hyperactivated calpain to prevent motor neuron disease operating through a cascade of events as indicated in the schematic, with relevance to amyotrophic lateral sclerosis (ALS). We propose that over-expression of CAST in motor neurons of hSOD1(G93A) mice inhibits activation of CDK5, breakdown of cytoskeletal proteins (NFs, MAP2 and Tau) and regulatory molecules (Cam Kinase IV, Calcineurin A), and disease-causing proteins (TDP-43, α-Synuclein and Huntingtin) to prevent neuronal loss and delay neurological deficits. In our experiments, CAST could also inhibit cleavage of Bid, Bax, AIF to prevent mitochondrial, ER and lysosome-mediated cell death mechanisms. Similarly, CAST over-expression in neurons attenuated pathological effects of TDP-43, α-synuclein and Huntingtin. These results suggest a potential value of specific small molecule inhibitors of calpains in delaying the development of ALS. Read the Editorial Highlight for this article on page 140.}, }
@article {pmid26751860, year = {2015}, author = {Liščić, RM}, title = {Molecular basis of ALS and FTD: implications for translational studies.}, journal = {Arhiv za higijenu rada i toksikologiju}, volume = {66}, number = {4}, pages = {285-290}, doi = {10.1515/aiht-2015-66-2679}, pmid = {26751860}, issn = {1848-6312}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics ; DNA-Binding Proteins/*genetics ; Frontotemporal Dementia/*genetics ; Humans ; Hydroxylamines/*therapeutic use ; Mutation/*genetics ; Riluzole/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The cause is unknown and no effective treatment currently exists. For ALS, there is only a drug Riluzole and a promising substance arimoclomol. The overlap between ALS and FTD occurs at clinical, genetic, and pathological levels. The majority of ALS cases are sporadic (SALS) and a subset of patients has an inherited form of the disease, familial ALS (FALS), with a common SOD1 mutation, also present in SALS. A few of the mutant genes identified in FALS have also been found in SALS. Recently, hexanucleotide repeat expansions in C9ORF72 gene were found to comprise the largest fraction of ALS- and FTD-causing mutations known to date. TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the pathological protein of FALS, SALS and, less frequently, FTD. The less frequent TDP-43 pathology in other forms of familial FTD has been linked to a range of mutations in GRN, FUS/TLS, rarely VCP, and other genes. TDP-43 and FUS/TLS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis. The clinical overlap of the symptoms of FTD and ALS is complemented by overlapping neuropathology, with intracellular inclusions composed of microtubule-associated protein tau, TDP-43 and less frequently FUS, or unknown ubiquitinated proteins. Furthermore, new therapeutic approaches continue to emerge, by targeting SOD1, TDP-43 or GRN proteins. This review addresses new advances that are being made in our understanding of the molecular mechanisms of both diseases, which may eventually translate into new treatment options.}, }
@article {pmid26751635, year = {2016}, author = {Petrou, P and Gothelf, Y and Argov, Z and Gotkine, M and Levy, YS and Kassis, I and Vaknin-Dembinsky, A and Ben-Hur, T and Offen, D and Abramsky, O and Melamed, E and Karussis, D}, title = {Safety and Clinical Effects of Mesenchymal Stem Cells Secreting Neurotrophic Factor Transplantation in Patients With Amyotrophic Lateral Sclerosis: Results of Phase 1/2 and 2a Clinical Trials.}, journal = {JAMA neurology}, volume = {73}, number = {3}, pages = {337-344}, doi = {10.1001/jamaneurol.2015.4321}, pmid = {26751635}, issn = {2168-6157}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*therapy ; Female ; Follow-Up Studies ; Humans ; Male ; Mesenchymal Stem Cell Transplantation/adverse effects/*methods ; Mesenchymal Stem Cells/*metabolism ; Middle Aged ; Nerve Growth Factors/*metabolism ; *Outcome Assessment, Health Care ; Transplantation, Autologous ; Young Adult ; }, abstract = {IMPORTANCE: Preclinical studies have shown that neurotrophic growth factors (NTFs) extend the survival of motor neurons in amyotrophic lateral sclerosis (ALS) and that the combined delivery of these neurotrophic factors has a strong synergistic effect. We have developed a culture-based method for inducing mesenchymal stem cells (MSCs) to secrete neurotrophic factors. These MSC-NTF cells have been shown to be protective in several animal models of neurodegenerative diseases.<br><br>OBJECTIVE: To determine the safety and possible clinical efficacy of autologous MSC-NTF cells transplantation in patients with ALS.<br><br>In these open-label proof-of-concept studies, patients with ALS were enrolled between June 2011 and October 2014 at the Hadassah Medical Center in Jerusalem, Israel. All patients were followed up for 3 months before transplantation and 6 months after transplantation. In the phase 1/2 part of the trial, 6 patients with early-stage ALS were injected intramuscularly (IM) and 6 patients with more advanced disease were transplanted intrathecally (IT). In the second stage, a phase 2a dose-escalating study, 14 patients with early-stage ALS received a combined IM and IT transplantation of autologous MSC-NTF cells.<br><br>INTERVENTIONS: Patients were administered a single dose of MSC-NTF cells.<br><br>MAIN OUTCOMES AND MEASURES: The primary end points of the studies were safety and tolerability of this cell therapy. Secondary end points included the effects of the treatment on various clinical parameters, such as the ALS Functional Rating Scale-Revised score and the respiratory function.<br><br>RESULTS: Among the 12 patients in the phase 1/2 trial and the 14 patients in the phase 2a trial aged 20 and 75 years, the treatment was found to be safe and well tolerated over the study follow-up period. Most of the adverse effects were mild and transient, not including any treatment-related serious adverse event. The rate of progression of the forced vital capacity and of the ALS Functional Rating Scale-Revised score in the IT (or IT+IM)-treated patients was reduced (from -5.1% to -1.2%/month percentage predicted forced vital capacity, P < .04 and from -1.2 to 0.6 ALS Functional Rating Scale-Revised points/month, P = .052) during the 6 months following MSC-NTF cell transplantation vs the pretreatment period. Of these patients, 13 (87%) were defined as responders to either ALS Functional Rating Scale-Revised or forced vital capacity, having at least 25% improvement at 6 months after treatment in the slope of progression.<br><br>CONCLUSIONS AND RELEVANCE: The results suggest that IT and IM administration of MSC-NTF cells in patients with ALS is safe and provide indications of possible clinical benefits, to be confirmed in upcoming clinical trials.<br><br>TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT01051882 and NCT01777646.}, }
@article {pmid26744412, year = {2016}, author = {McGinley, LM and Sims, E and Lunn, JS and Kashlan, ON and Chen, KS and Bruno, ES and Pacut, CM and Hazel, T and Johe, K and Sakowski, SA and Feldman, EL}, title = {Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer's Disease.}, journal = {Stem cells translational medicine}, volume = {5}, number = {3}, pages = {379-391}, pmid = {26744412}, issn = {2157-6564}, support = {R25 NS089450/NS/NINDS NIH HHS/United States ; T32 NS007222/NS/NINDS NIH HHS/United States ; R25NS089450/NS/NINDS NIH HHS/United States ; T32NS07222/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/pathology/*therapy ; Animals ; Cell Differentiation/genetics ; Cell- and Tissue-Based Therapy ; Disease Models, Animal ; Gene Expression Regulation, Developmental ; Humans ; Insulin-Like Growth Factor I/*biosynthesis/genetics ; Mice ; Neural Stem Cells/cytology/*transplantation ; *Neurogenesis ; Neurons/pathology/transplantation ; Synapses/physiology ; }, abstract = {Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder and a leading cause of dementia. Current treatment fails to modify underlying disease pathologies and very little progress has been made to develop effective drug treatments. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional single-target approaches. In amyotrophic lateral sclerosis, we have shown that transplanted spinal neural stem cells (NSCs) integrate into the spinal cord, form synapses with the host, improve inflammation, and reduce disease-associated pathologies. Our current goal is to develop a similar "best in class" cellular therapy for AD. Here, we characterize a novel human cortex-derived NSC line modified to express insulin-like growth factor-I (IGF-I), HK532-IGF-I. Because IGF-I promotes neurogenesis and synaptogenesis in vivo, this enhanced NSC line offers additional environmental enrichment, enhanced neuroprotection, and a multifaceted approach to treating complex AD pathologies. We show that autocrine IGF-I production does not impact the cell secretome or normal cellular functions, including proliferation, migration, or maintenance of progenitor status. However, HK532-IGF-I cells preferentially differentiate into gamma-aminobutyric acid-ergic neurons, a subtype dysregulated in AD; produce increased vascular endothelial growth factor levels; and display an increased neuroprotective capacity in vitro. We also demonstrate that HK532-IGF-I cells survive peri-hippocampal transplantation in a murine AD model and exhibit long-term persistence in targeted brain areas. In conclusion, we believe that harnessing the benefits of cellular and IGF-I therapies together will provide the optimal therapeutic benefit to patients, and our findings support further preclinical development of HK532-IGF-I cells into a disease-modifying intervention for AD.}, }
@article {pmid26740062, year = {2016}, author = {Kozlowski, AJ and Cella, D and Nitsch, KP and Heinemann, AW}, title = {Evaluating Individual Change With the Quality of Life in Neurological Disorders (Neuro-QoL) Short Forms.}, journal = {Archives of physical medicine and rehabilitation}, volume = {97}, number = {4}, pages = {650-654.e8}, pmid = {26740062}, issn = {1532-821X}, support = {HHSN265200423601C/NS/NINDS NIH HHS/United States ; P30 CA060553/CA/NCI NIH HHS/United States ; U2C CA186878/CA/NCI NIH HHS/United States ; HHSN265200423601C//PHS HHS/United States ; }, mesh = {Activities of Daily Living/psychology ; Adult ; Anxiety/diagnosis/psychology ; Cognition ; Depression/diagnosis/psychology ; *Disability Evaluation ; Humans ; Nervous System Diseases/*psychology ; *Psychological Tests ; *Quality of Life ; }, abstract = {OBJECTIVE: To provide a clinically useful means of interpreting change for individual patients on the Quality of Life in Neurological Disorders (Neuro-QoL) adult short forms (SFs) by applying a classical test theory concept for interpreting individual change.<br><br>DESIGN: Secondary analysis of existing data.<br><br>SETTING: Community.<br><br>PARTICIPANTS: Persons with neurologic conditions including stroke, epilepsy, amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson disease residing in community settings.<br><br>INTERVENTIONS: Not applicable.<br><br>MAIN OUTCOME MEASURES: Neuro-QoL SFs for Applied Cognition-General Concerns, Applied Cognition-Executive Function, Applied Cognition-Combined, Ability to Participate in Social Roles and Activities, Satisfaction With Social Roles and Activities, Positive Affect and Well-Being, Depression, Stigma, Upper Extremity Function (Fine Motor, Activities of Daily Living), Lower Extremity Function (Mobility), Anxiety, Sleep Disturbance, Fatigue, and Emotional and Behavioral Dyscontrol. We estimated conditional minimal detectable change (cMDC) indices from the pooled SEs adjusted for a 95% confidence interval using the average of the SEs for any given pair of scores multiplied by the z score, or ([SE(Score1) + SE(Score2)]/2) * (1.96) * (SQRT(2)).<br><br>RESULTS: The cMDC indices are generally smallest in the midrange of all scales, ranging from 3.6 to 11.2 T-score points, and higher on the outer quartiles ranging from 3.7 to 21.6 T-score points. The lowest midrange cMDCs were for Satisfaction With Social Roles and Activities (3.6-4.7 T-score points), and the largest were for Sleep Disturbance (9.4-11.2 T-score points).<br><br>CONCLUSIONS: Change indices can help clinicians and investigators identify differences for individual patients or subjects that are large enough to motivate treatment change. cMDCs can reduce misclassification of magnitudes of change that are near the margins of error across the range of the Neuro-QoL SFs.}, }
@article {pmid26735587, year = {2016}, author = {Kim, S and Chung, SE and Lee, S and Park, J and Choi, S and Kim, S}, title = {Experience of complementary and alternative medicine in patients with amyotrophic lateral sclerosis and their families: A qualitative study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {17}, number = {3-4}, pages = {191-197}, doi = {10.3109/21678421.2015.1125504}, pmid = {26735587}, issn = {2167-9223}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*psychology/*therapy ; Complementary Therapies/*methods ; *Family Health ; Female ; Humans ; Interview, Psychological ; Male ; Middle Aged ; Qualitative Research ; Surveys and Questionnaires ; Tape Recording ; }, abstract = {The purpose of this study was to explore the life experience related to complementary and alternative medicine (CAM) use among patients with amyotrophic lateral sclerosis (ALS). Data were collected though semi-structured interviews of nine patients with ALS and seven family members, who have used CAM. Audio recordings of the interviews were transcribed verbatim and checked for accuracy. The Giorgi's method of phenomenology was used for data analysis. Five constituents forming the units of meaning were: facing the limits of conventional medicine; getting to know CAM; recognizing the ineffectiveness of CAM; using CAM for symptomatic treatment; and seeking new CAM endlessly for complete cure. The study results provide an in-depth understanding of experience with CAM among patients with ALS and their family members. Healthcare providers must give accurate information about the efficacy of CAM as well as its safety and possible adverse effects and should offer patient-centred treatment through active communication throughout the process of diagnosis and treatment.}, }
@article {pmid26725093, year = {2016}, author = {Garuti, G and Mandrioli, J and Esquinas, AM}, title = {Radiotherapy treatment of the salivary glands, sialorrhea, and non-invasive mechanical ventilation in amyotrophic lateral sclerosis: what are we doing?.}, journal = {Journal of neurology}, volume = {263}, number = {3}, pages = {583-584}, pmid = {26725093}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Female ; Humans ; Male ; *Noninvasive Ventilation ; Sialorrhea/*radiotherapy ; }, }
@article {pmid26723986, year = {2016}, author = {Riancho, J and Berciano, MT and Ruiz-Soto, M and Berciano, J and Landreth, G and Lafarga, M}, title = {Retinoids and motor neuron disease: Potential role in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {360}, number = {}, pages = {115-120}, pmid = {26723986}, issn = {1878-5883}, support = {R01 AG043522/AG/NIA NIH HHS/United States ; RF1 AG050597/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Humans ; Motor Neurons/*metabolism/pathology ; Retinoids/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MN). This fatal disease is characterized by progressive muscular atrophy and unfortunately it does not have an effective treatment. Although a small proportion of ALS cases have a familiar origin, the vast majority of them are thought to have a sporadic origin. Although the pathogenesis of ALS has not been fully elucidated, various disorders in different cellular functions such as gene expression, protein metabolism, axonal transport and glial cell disorders have been linked to MN degeneration. Among them, proteostasis is one of the best studied. Retinoids are vitamin A-derived substances that play a crucial role in embryogenesis, development, programmed cell death and other cellular functions. Retinoid agonists behave as transcription factors throughout the activation of the nuclear retinoid receptors. Several reports in the literature suggest that retinoids are involved in proteostasis regulation, by modulating its two major pathways, the ubiquitin-proteasome system and the autophagy-lysosome response. Additionally, there are some evidences for a role of retinoids themselves, in ALS pathogenesis. In this review, we discuss the importance of proteostasis disruption as a trigger for MN degeneration and the capability of retinoids to modulate it, as well as the potential therapeutic role of retinoids as a new therapy in ALS.}, }
@article {pmid26713267, year = {2015}, author = {Siklos, M and BenAissa, M and Thatcher, GR}, title = {Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors.}, journal = {Acta pharmaceutica Sinica. B}, volume = {5}, number = {6}, pages = {506-519}, pmid = {26713267}, issn = {2211-3835}, abstract = {Cysteine proteases continue to provide validated targets for treatment of human diseases. In neurodegenerative disorders, multiple cysteine proteases provide targets for enzyme inhibitors, notably caspases, calpains, and cathepsins. The reactive, active-site cysteine provides specificity for many inhibitor designs over other families of proteases, such as aspartate and serine; however, a) inhibitor strategies often use covalent enzyme modification, and b) obtaining selectivity within families of cysteine proteases and their isozymes is problematic. This review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders; the latter focus providing an interesting query for the contemporary assumptions that irreversible, covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.}, }
@article {pmid26713266, year = {2015}, author = {Niu, L}, title = {Mechanism-based design of 2,3-benzodiazepine inhibitors for AMPA receptors.}, journal = {Acta pharmaceutica Sinica. B}, volume = {5}, number = {6}, pages = {500-505}, pmid = {26713266}, issn = {2211-3835}, support = {R01 NS060812/NS/NINDS NIH HHS/United States ; }, abstract = {2,3-Benzodiazepine (2,3-BDZ) compounds represent a group of structurally diverse, small-molecule antagonists of (R, S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors. Antagonists of AMPA receptors are drug candidates for potential treatment of a number of neurological disorders such as epilepsy, stroke and amyotrophic lateral sclerosis (ALS). How to make better inhibitors, such as 2,3-BDZs, has been an enduring quest in drug discovery. Among a few available tools to address this specific question for making better 2,3-BDZs, perhaps the best one is to use mechanistic clues from studies of the existing antagonists to design and discover more selective and more potent antagonists. Here I review recent work in this area, and propose some ideas in the continuing effort of developing newer 2,3-BDZs for tighter control of AMPA receptor activities in vivo.}, }
@article {pmid26713081, year = {2015}, author = {Seo, JS and Choi, J and Leem, YH and Han, PL}, title = {Rosmarinic Acid Alleviates Neurological Symptoms in the G93A-SOD1 Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Experimental neurobiology}, volume = {24}, number = {4}, pages = {341-350}, pmid = {26713081}, issn = {1226-2560}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons in the brain and spinal cord, resulting in paralysis of voluntary skeletal muscles and eventually death, usually within 2~3 years of symptom onset. The pathophysiology mechanism underlying ALS is not yet clearly understood. Moreover the available medication for treating ALS, riluzole, only modestly improves neurological symptoms and increases survival by a few months. Therefore, improved therapeutic strategies are urgently needed. In the present study, we investigated whether rosmarinic acid has a therapeutic potential to alleviate neurological deterioration in the G93A-SOD1 transgenic mouse model of ALS. Treatment of G93A-SOD1 transgenic mice with rosmarinic acid from 7 weeks of age at the dose of 400 mg/kg/day significantly extended survival, and relieved motor function deficits. Specifically, disease onset and symptom progression were delayed by more than one month. These symptomatic improvements were correlated with decreased oxidative stress and reduced neuronal loss in the ventral horns of G93A-SOD1 mice. These results support that rosmarinic acid is a potentially useful supplement for relieving ALS symptoms.}, }
@article {pmid26713006, year = {2015}, author = {Ambesh, P and Angeli, DG}, title = {Nanotechnology in neurology: Genesis, current status, and future prospects.}, journal = {Annals of Indian Academy of Neurology}, volume = {18}, number = {4}, pages = {382-386}, pmid = {26713006}, issn = {0972-2327}, abstract = {Nanotechnology is a promising, novel field of technological development. There is great potential in research and clinical applications for neurological diseases. Here we chronicle the inception of nanotechnology, discuss its integration with neurology, and highlight the challenges in current application. Some of the problems involving practical use of neuronanotechnology are direct biological toxicity, visualization of the nanodevice, and the short life expectancy of nanomachinery. Neuron cell therapy is an upcoming field for the treatment of challenging problems in neurology. Peptide nanofibers based on amphiphilic molecules have been developed that can autoregulate their structure depending on the conditions of the surrounding milieu. Such frameworks are promising for serving as drug delivery systems or communication bridges between damaged neurons. For common disabling diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), recent developments have seen revolutionary nanotech-based novelties, which are discussed here in detail. Bioimaging integrated with nanoneuromedicine has opened up new doors for cancer and infection therapeutics.}, }
@article {pmid26712036, year = {2016}, author = {Fidèle, NJ and Amanuel, A}, title = {Spectrum of nontraumatic myelopathies in Ethiopian patients: hospital-based retrospective study.}, journal = {Spinal cord}, volume = {54}, number = {8}, pages = {604-608}, pmid = {26712036}, issn = {1476-5624}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Back Pain/etiology ; Ethiopia/epidemiology ; Female ; Hospitals/statistics &amp; numerical data ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Multiple Sclerosis ; Myelitis, Transverse ; Neuromyelitis Optica ; Retrospective Studies ; Sex Distribution ; Spinal Cord Diseases/complications/diagnostic imaging/*epidemiology/*etiology ; Young Adult ; }, abstract = {STUDY DESIGN: This is a retrospective hospital-based study.<br><br>OBJECTIVES: The study aimed at a better understanding of the etiology, clinical presentation and treatment outcome of nontraumatic myelopathies in Ethiopian patients.<br><br>SETTING: Etiologies of nontraumatic myelopathies have not been evaluated extensively in most sub-Saharan African countries. The available studies in this region were conducted before the widespread clinical use of modern neuroimaging modalities. This study was conducted in Addis Abba, Ethiopia.<br><br>METHODS: We retrospectively analyzed medical files of patients with a diagnosis of myelopathy (age &#x2a7e;13 years) admitted or followed up at Tikur Anbesa Hospital between 1 January 2010 and 30 June 2013.<br><br>RESULTS: Records of 105 patients were analyzed. The male to female ratio was 1.7. The mean age was 38.5 years. Weakness, sensory symptoms (including sensory level), back pain and sphincter dysfunction were the dominant features. Etiologies were dominated by spinal tuberculosis (23.8%) followed by spinal cord neoplastic lesions (primary (10.5%) and secondary neoplasms 8.6%). Other important etiological causes were transverse myelitis (16.2%), degenerative cervical spondylotic myelopathy (15.2%), amyotrophic lateral sclerosis (4.8%) and neuromyelitis optica/multiple sclerosis (3.8%). The mortality rate was 9.5%. Among the patients who died, 40% had chest infection as a complication and 70% presented with complete weakness.<br><br>CONCLUSION: Infections remain a major cause of spinal cord disease, and tuberculosis constitutes public health target for reducing the incidence of myelopathies. Early detection and treatment of complications may reduce the high rate of mortality and morbidity observed.}, }
@article {pmid26710998, year = {2016}, author = {Borel, F and Gernoux, G and Cardozo, B and Metterville, JP and Toro Cabrera, GC and Song, L and Su, Q and Gao, GP and Elmallah, MK and Brown, RH and Mueller, C}, title = {Therapeutic rAAVrh10 Mediated SOD1 Silencing in Adult SOD1(G93A) Mice and Nonhuman Primates.}, journal = {Human gene therapy}, volume = {27}, number = {1}, pages = {19-31}, pmid = {26710998}, issn = {1557-7422}, support = {K08 HD077040/HD/NICHD NIH HHS/United States ; NS079836/NS/NINDS NIH HHS/United States ; NS088689/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/*therapy ; Animals ; Dependovirus/genetics ; Disease Models, Animal ; Gene Expression Regulation, Developmental ; Gene Silencing ; Humans ; Mice ; Mutation ; Superoxide Dismutase/antagonists &amp; inhibitors/*genetics/therapeutic use ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; survival in ALS is typically 3-5 years. No treatment extends patient survival by more than three months. Approximately 20% of familial ALS and 1-3% of sporadic ALS patients carry a mutation in the gene encoding superoxide dismutase 1 (SOD1). In a transgenic ALS mouse model expressing the mutant SOD1(G93A) protein, silencing the SOD1 gene prolongs survival. One study reports a therapeutic effect of silencing the SOD1 gene in systemically treated adult ALS mice; this was achieved with a short hairpin RNA, a silencing molecule that has raised multiple safety concerns, and recombinant adeno-associated virus (rAAV) 9. We report here a silencing method based on an artificial microRNA termed miR-SOD1 systemically delivered using adeno-associated virus rAAVrh10, a serotype with a demonstrated safety profile in CNS clinical trials. Silencing of SOD1 in adult SOD1(G93A) transgenic mice with this construct profoundly delayed both disease onset and death in the SOD1(G93A) mice, and significantly preserved muscle strength and motor and respiratory functions. We also document that intrathecal delivery of the same rAAVrh10-miR-SOD1 in nonhuman primates significantly and safely silences SOD1 in lower motor neurons. This study supports the view that rAAVrh10-miR-SOD1 merits further development for the treatment of SOD1-linked ALS in humans.}, }
@article {pmid26708289, year = {2016}, author = {Bonafede, R and Scambi, I and Peroni, D and Potrich, V and Boschi, F and Benati, D and Bonetti, B and Mariotti, R}, title = {Exosome derived from murine adipose-derived stromal cells: Neuroprotective effect on in vitro model of amyotrophic lateral sclerosis.}, journal = {Experimental cell research}, volume = {340}, number = {1}, pages = {150-158}, doi = {10.1016/j.yexcr.2015.12.009}, pmid = {26708289}, issn = {1090-2422}, mesh = {Adipose Tissue/*cytology ; Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology ; Animals ; Apoptosis/drug effects ; Cell Survival ; Cells, Cultured ; Exosomes/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Mice ; Mice, Inbred C57BL ; *Models, Biological ; Mutation ; *Neuroprotective Agents ; Oxidative Stress/genetics ; Stem Cells/*cytology ; Stromal Cells/*cytology ; }, abstract = {Therapeutic strategies for the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) have not yet provided satisfactory results. Interest in stem cells for the treatment of neurodegenerative diseases is increasing and their beneficial action seems to be due to a paracrine effect via the release of exosomes, main mediators of cell-cell communication. Here we wished to assess, in vitro, the efficacy of a novel non-cell therapeutic approach based on the use of exosomes derived from murine adipose-derived stromal cells on motoneuron-like NSC-34 cells expressing ALS mutations, and used as in vitro models of disease. In particular, we set out to investigate the effect of exosomes on NSC-34 naïve cells and NSC-34 cells overexpressing human SOD1(G93A) or SOD1(G37R) or SOD1(A4V) mutants, exposed to oxidative stress. The data presented here indicate for the first time that exosomes (0.2 µg/ml) are able to protect NSC-34 cells from oxidative damage, which is one of the main mechanism of damage in ALS, increasing cell viability. These data highlight a promising role of exosomes derived from stem cells for potential therapeutic applications in motoneuron disease.}, }
@article {pmid26705515, year = {2015}, author = {Ratti, E and Berry, JD and Greenblatt, DJ and Loci, L and Ellrodt, AS and Shefner, JM and Cudkowicz, ME}, title = {Preclinical Rodent Toxicity Studies for Long Term Use of Ceftriaxone.}, journal = {Toxicology reports}, volume = {2}, number = {}, pages = {1396-1403}, pmid = {26705515}, issn = {2214-7500}, support = {R25 NS065743/NS/NINDS NIH HHS/United States ; U01 NS049640/NS/NINDS NIH HHS/United States ; }, abstract = {A 6-month rodent toxicology and pharmacokinetic (PK) study was performed to provide supportive safety data for long-term use of intravenous ceftriaxone in a clinical trial in patients with amyotrophic lateral sclerosis (ALS). Ceftriaxone was administered by subcutaneous injection at up to 2 g/kg/day to Sprague-Dawley Crl:CD (SD) rats. Ceftriaxone was found to be safe and well tolerated. Specifically, no significant differences in body weight and food consumption were observed between the treatment and control groups. With the exception of in red cell parameters decrease, there were no ceftriaxone-related changes in hematology, coagulation, clinical chemistry and urinalysis parameters. Injection site trauma and associated reversible anemia, likely due to chronic blood loss at the injection site, were all attributable to subcutaneous route of administration. Cecum dilatation and some skin changes were reversible after recovery period, while bile duct dilatation, observed only in a few animals, persisted. Changes in the non-glandular stomach do not have a human correlate. The no-observed-adverse-effect dose level (NOAEL) was 0.5 g/kg/day ceftriaxone in both sexes. Ceftriaxone showed rapid absorption with half-life values ranging between 1 and 1.5 hours. Additionally, there was no evidence of accumulation and a virtually complete elimination by 16 hours after the last dose. Overall there were no toxicologically meaningful drug-related animal findings associated with the long-term administration (6 months) of ceftriaxone. These results support safety of long-term use of ceftriaxone in human clinical trials.}, }
@article {pmid26705123, year = {2016}, author = {Hübers, A and Hildebrandt, V and Petri, S and Kollewe, K and Hermann, A and Storch, A and Hanisch, F and Zierz, S and Rosenbohm, A and Ludolph, AC and Dorst, J}, title = {Clinical features and differential diagnosis of flail arm syndrome.}, journal = {Journal of neurology}, volume = {263}, number = {2}, pages = {390-395}, pmid = {26705123}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Arm ; Diagnosis, Differential ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*diagnosis ; Retrospective Studies ; Syndrome ; }, abstract = {Flail arm syndrome (FAS) is a variant of motor neuron disease which is characterized by progressive, predominantly proximal weakness and atrophy of the upper limbs (UL). Because of its heterogeneous presentation and its relatively slow progression, differential diagnosis may be difficult particularly in the early stages of the disease. The aim of this study was to investigate typical clinical features of FAS with special regard to initial symptoms and differences to classical Charcot type amyotrophic lateral sclerosis (ALS). We retrospectively evaluated the clinical features of 42 FAS patients who were seen in the outpatient clinics of 4 German centers between 2000 and 2010 and compared them to 146 sex-matched control patients with classical spinal-onset ALS. FAS patients were younger (54.7 ± 9.3 versus 59.4 ± 12.2 years), male patients were predominantly affected (3.8:1 versus 1.9:1), and FAS patients showed a prolonged survival (53 versus 33 months) compared to classical ALS patients. The share of patients with initial misdiagnoses was 54.8% and led to ineffective therapy with immunoglobulins in 26%. Initial symptoms were most frequently present either in distal muscles only or in both proximal and distal muscle groups combined (76%) and showed an asymmetric distribution pattern in the majority of cases (76%). Although all patients developed symmetric and predominantly proximal UL weakness and atrophy during the course of their disease, we found that most patients initially showed asymmetric and predominantly distal distribution of symptoms. This may contribute to difficulties in differential diagnosis and to ineffective treatment regimes.}, }
@article {pmid26704722, year = {2016}, author = {Jara, JH and Stanford, MJ and Zhu, Y and Tu, M and Hauswirth, WW and Bohn, MC and DeVries, SH and Özdinler, PH}, title = {Healthy and diseased corticospinal motor neurons are selectively transduced upon direct AAV2-2 injection into the motor cortex.}, journal = {Gene therapy}, volume = {23}, number = {3}, pages = {272-282}, pmid = {26704722}, issn = {1476-5462}, support = {R01 EY018204/EY/NEI NIH HHS/United States ; R21 NS085750/NS/NINDS NIH HHS/United States ; 1R01NS085161-01/NS/NINDS NIH HHS/United States ; UL1 TR001422/TR/NCATS NIH HHS/United States ; R01 NS085161/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Animals, Genetically Modified ; Dependovirus/*genetics ; Genetic Therapy ; Genetic Vectors/*therapeutic use ; Mice ; Motor Cortex/*metabolism ; Motor Neuron Disease/*genetics/*therapy ; Motor Neurons/metabolism ; *Transduction, Genetic ; }, abstract = {Direct gene delivery to the neurons of interest, without affecting other neuron populations in the cerebral cortex, represent a challenge owing to the heterogeneity and cellular complexity of the brain. Genetic modulation of corticospinal motor neurons (CSMN) is required for developing effective and long-term treatment strategies for motor neuron diseases, in which voluntary movement is impaired. Adeno-associated viruses (AAV) have been widely used for neuronal transduction studies owing to long-term and stable gene expression as well as low immunoreactivity in humans. Here we report that AAV2-2 transduces CSMN with high efficiency upon direct cortex injection and that transduction efficiencies are similar during presymptomatic and symptomatic stages in hSOD1(G93A) transgenic amyotrophic lateral sclerosis (ALS) mice. Our findings reveal that choice of promoter improves selectivity as AAV2-2 chicken β-actin promoter injection results in about 70% CSMN transduction, the highest percentage reported to date. CSMN transduction in both wild-type and transgenic ALS mice allows detailed analysis of single axon fibers within the corticospinal tract in both cervical and lumbar spinal cord and reveals circuitry defects, which mainly occur between CSMN and spinal motor neurons in hSOD1(G93A) transgenic ALS mice. Our findings set the stage for CSMN gene therapy in ALS and related motor neuron diseases.}, }
@article {pmid26703254, year = {2016}, author = {Pinto, L and Díaz Nieto, CH and Zón, MA and Fernández, H and de Araujo, MCU}, title = {Handling time misalignment and rank deficiency in liquid chromatography by multivariate curve resolution: Quantitation of five biogenic amines in fish.}, journal = {Analytica chimica acta}, volume = {902}, number = {}, pages = {59-69}, doi = {10.1016/j.aca.2015.10.043}, pmid = {26703254}, issn = {1873-4324}, mesh = {Animals ; Biogenic Amines/*analysis ; Chromatography, Liquid/*methods ; Fishes/*metabolism ; *Time and Motion Studies ; }, abstract = {Biogenic amines (BAs) are used for identifying spoilage in food. The most common are tryptamine (TRY), 2-phenylethylamine (PHE), putrescine (PUT), cadaverine (CAD) and histamine (HIS). Due to lack of chromophores, chemical derivatization with dansyl was employed to analyze these BAs using high performance liquid chromatography with a diode array detector (HPLC-DAD). However, the derivatization reaction occurs with any primary or secondary amine, leading to co-elution of analytes and interferents with identical spectral profiles, and thus causing rank deficiency. When the spectral profile is the same and peak misalignment is present on the chromatographic runs, it is not possible to handle the data only with Multivariate Curve Resolution and Alternative Least Square (MCR-ALS), by augmenting the time, or the spectral mode. A way to circumvent this drawback is to receive information from another detector that leads to a selective profile for the analyte. To overcome both problems, (tri-linearity break in time, and spectral mode), this paper proposes a new analytical methodology for fast quantitation of these BAs in fish with HPLC-DAD by using the icoshift algorithm for temporal misalignment correction before MCR-ALS spectral mode augmented treatment. Limits of detection, relative errors of prediction (REP) and average recoveries, ranging from 0.14 to 0.50 µg mL(-1), 3.5-8.8% and 88.08%-99.68%, respectively. These are outstanding results obtained, reaching quantification limits for the five BAs much lower than those established by the Food and Agriculture Organization of the United Nations and World Health Organization (FAO/WHO), and the European Food Safety Authority (EFSA), all without any pre-concentration steps. The concentrations of BAs in fish samples ranged from 7.82 to 29.41 µg g(-1), 8.68-25.95 µg g(-1), 4.76-28.54 µg g(-1), 5.18-39.95 µg g(-1) and 1.45-52.62 µg g(-1) for TRY, PHE, PUT, CAD, and HIS, respectively. In addition, the proposed method spends less than 4 min in an isocratic run, consuming less solvent in accordance with the principles of green analytical chemistry.}, }
@article {pmid26702505, year = {2016}, author = {Woo, S and Yoon, M and Kim, J and Hong, Y and Kim, MY and Shin, SS and Yoon, M}, title = {The anti-angiogenic herbal extract from Melissa officinalis inhibits adipogenesis in 3T3-L1 adipocytes and suppresses adipocyte hypertrophy in high fat diet-induced obese C57BL/6J mice.}, journal = {Journal of ethnopharmacology}, volume = {178}, number = {}, pages = {238-250}, doi = {10.1016/j.jep.2015.12.015}, pmid = {26702505}, issn = {1872-7573}, mesh = {3T3-L1 Cells ; Adipocytes/*drug effects/metabolism ; Adipogenesis/*drug effects ; Adipose Tissue/*drug effects/metabolism ; Angiogenesis Inducing Agents/metabolism ; Animals ; Cell Line ; Diet, High-Fat/*adverse effects ; Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; Humans ; Hypertrophy/*drug therapy/metabolism ; Male ; Melissa/*chemistry ; Mice ; Mice, Inbred C57BL ; Obesity/chemically induced/drug therapy/metabolism ; Plant Extracts/chemistry/*pharmacology ; RNA, Messenger/metabolism ; }, abstract = {Melissa officinalis L. (Labiatae; lemon balm) has been used traditionally and contemporarily as an anti-stress herb. Current hypotheses suggest that not only chronic stress promotes angiogenesis, but angiogenesis also modulates adipogenesis and obesity. Because the herbal extract ALS-L1023 from M. officinalis L. (Labiatae; lemon balm) has an anti-angiogenic activity, we hypothesized that ALS-L1023 could inhibit adipogenesis and adipocyte hypertrophy.<br><br>MATERIALS AND METHODS: ALS-L1023 was prepared by a two-step organic solvent fractionation from M. officinalis. The effects of ALS-L1023 on adipogenesis in 3T3-L1 adipocytes and adipocyte hypertrophy in high fat diet (HFD)-fed obese mice were measured using in vivo and in vitro approaches.<br><br>RESULTS: ALS-L1023 inhibited angiogenesis in a dose-dependent manner in the HUVEC tube formation assay in vitro. Treatment of cells with ALS-L1023 inhibited lipid accumulation and adipocyte-specific gene expression caused by troglitazone or MDI differentiation mix. ALS-L1023 reduced mRNA expression of angiogenic factors (VEGF-A and FGF-2) and MMPs (MMP-2 and MMP-9) in differentiated cells. In contrast, mRNA levels of angiogenic inhibitors (TSP-1, TIMP-1, and TIMP-2) increased. Protease activity, as measured by zymography, showed that activity of MMP-2 and MMP-9 decreased in ALS-L1023-treated cells. ALS-L1023 also inhibited MMP-2 and MMP-9 reporter gene expression in the presence of the MMP inducer phorbol 12-myristate 13-acetate. An in vivo study showed that ALS-L1023 not only decreased adipose tissue mass and adipocyte size, but also reduced mRNA levels of adipose tissue angiogenic factors and MMPs in HFD-fed obese mice.<br><br>CONCLUSIONS: These results suggest that the anti-angiogenic herbal extract ALS-L1023 suppresses adipogenesis and adipocyte hypertrophy, and this effect may be mediated by inhibiting angiogenesis and MMP activities. Thus, by curbing adipogenesis, anti-angiogenic ALS-L1023 yields a possible therapeutic choice for the prevention and treatment of human obesity and its associated conditions.}, }
@article {pmid26702336, year = {2015}, author = {Radick, L and Mehr, SR}, title = {The Latest Innovations in the Drug Pipeline for Multiple Sclerosis.}, journal = {American health &amp; drug benefits}, volume = {8}, number = {8}, pages = {448-453}, pmid = {26702336}, issn = {1942-2962}, abstract = {Several new medications are being investigated in late-phase studies for the treatment of patients with relapsing or progressive multiple sclerosis (MS). These agents represent a variety of mechanisms of action and provide not only lower relapse rates but also improvement in disabilities. The majority of investigational trials involve selective sphingosine-1-phosphate receptor 1 immunomodulators, such as laquinimod, ozanimod, ponesimod, and siponimod, in an effort to build on the success of fingolimod. Ocrelizumab is a CD20-positive B-cell-targeting monoclonal antibody with a promising new mechanism of action. Ofatumumab is also a CD20 inhibitor. Daclizumab, an interleukin-2 inhibitor, has evidence of good efficacy but is associated with unfavorable side effects. Masitinib is a mast-cell inhibitor that also has shown efficacy in Alzheimer's disease and amyotrophic lateral sclerosis. Phase 3 trials for some of these agents will conclude in the next 12 months, and their manufacturers are expected to apply for US Food and Drug Administration approval soon thereafter. This review article summarizes data for newly approved and late-phase investigational agents for the treatment of patients with MS.}, }
@article {pmid26702100, year = {2016}, author = {Xia, Q and Wang, H and Hao, Z and Fu, C and Hu, Q and Gao, F and Ren, H and Chen, D and Han, J and Ying, Z and Wang, G}, title = {TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion.}, journal = {The EMBO journal}, volume = {35}, number = {2}, pages = {121-142}, pmid = {26702100}, issn = {1460-2075}, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Autophagy/*physiology ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/*metabolism ; Cell Line ; Cell Line, Tumor ; DNA-Binding Proteins/genetics/*metabolism ; Drosophila ; Frontotemporal Lobar Degeneration/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Lysosomes/*metabolism ; Mechanistic Target of Rapamycin Complex 1 ; Mice ; Models, Biological ; Multiprotein Complexes/genetics/metabolism ; Rats ; TOR Serine-Threonine Kinases/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by selective loss of motor neurons in brain and spinal cord. TAR DNA-binding protein 43 (TDP-43) was identified as a major component of disease pathogenesis in ALS, frontotemporal lobar degeneration (FTLD), and other neurodegenerative disease. Despite the fact that TDP-43 is a multi-functional protein involved in RNA processing and a large number of TDP-43 RNA targets have been discovered, the initial toxic effect and the pathogenic mechanism underlying TDP-43-linked neurodegeneration remain elusive. In this study, we found that loss of TDP-43 strongly induced a nuclear translocation of TFEB, the master regulator of lysosomal biogenesis and autophagy, through targeting the mTORC1 key component raptor. This regulation in turn enhanced global gene expressions in the autophagy-lysosome pathway (ALP) and increased autophagosomal and lysosomal biogenesis. However, loss of TDP-43 also impaired the fusion of autophagosomes with lysosomes through dynactin 1 downregulation, leading to accumulation of immature autophagic vesicles and overwhelmed ALP function. Importantly, inhibition of mTORC1 signaling by rapamycin treatment aggravated the neurodegenerative phenotype in a TDP-43-depleted Drosophila model, whereas activation of mTORC1 signaling by PA treatment ameliorated the neurodegenerative phenotype. Taken together, our data indicate that impaired mTORC1 signaling and influenced ALP may contribute to TDP-43-mediated neurodegeneration.}, }
@article {pmid26691640, year = {2015}, author = {Xu, X and Xie, S and Shi, X and Lv, J and Tang, X and Wang, X and Lu, S and Wang, M and Zhang, X and Sun, J and Yao, H}, title = {Hexanucleotide Repeat Expansion in C9ORF72 Is Not Detected in the Treatment-Resistant Schizophrenia Patients of Chinese Han.}, journal = {PloS one}, volume = {10}, number = {12}, pages = {e0145347}, pmid = {26691640}, issn = {1932-6203}, mesh = {Adult ; Aged ; Aged, 80 and over ; Antipsychotic Agents/therapeutic use ; Asian People/genetics ; C9orf72 Protein ; Case-Control Studies ; *DNA Repeat Expansion ; Female ; Humans ; Male ; Middle Aged ; Proteins/*genetics ; Schizophrenia/drug therapy/*genetics ; Young Adult ; }, abstract = {Hexanucleotide (GGGGCC) repeat expansion in C9ORF72 (HRE) causes frontotemporal lobar degeneration, frontotemporal dementia-amyotrophic lateral sclerosis, and amyotrophic lateral sclerosis. HRE was also seen in the genomes of patients suffering from several other degenerative diseases. However, whether it is present in the treatment-resistant schizophrenia patients remains unknown. Genotyping 386 patients suffering from treatment-resistant schizophrenia using the method of Repeat-Primed PCR, we reported here that no HRE was detected in the patients of Chinese Han.}, }
@article {pmid26691332, year = {2016}, author = {Benkler, C and Barhum, Y and Ben-Zur, T and Offen, D}, title = {Multifactorial Gene Therapy Enhancing the Glutamate Uptake System and Reducing Oxidative Stress Delays Symptom Onset and Prolongs Survival in the SOD1-G93A ALS Mouse Model.}, journal = {Journal of molecular neuroscience : MN}, volume = {58}, number = {1}, pages = {46-58}, pmid = {26691332}, issn = {1559-1166}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*therapy ; Animals ; Cells, Cultured ; *Genetic Therapy ; Glutamate Plasma Membrane Transport Proteins/*genetics/metabolism ; Glutamic Acid/*metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Mutation, Missense ; NF-E2-Related Factor 2/genetics/metabolism ; *Oxidative Stress ; Sugar Alcohol Dehydrogenases/genetics/metabolism ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {The 150-year-long search for treatments of amyotrophic lateral sclerosis (ALS) is still fueled by frustration over the shortcomings of available therapeutics. Contributing to the therapeutic limitations might be the targeting of a single aspect of this multifactorial-multisystemic disease. In an attempt to overcome this, we devised a novel multifactorial-cocktail treatment, using lentiviruses encoding: EAAT2, GDH2, and NRF2, that act synergistically to address the band and width of the effected excito-oxidative axis, reducing extracellular-glutamate and glutamate availability while improving the metabolic state and the anti-oxidant response. This strategy yielded particularly impressive results, as all three genes together but not separately prolonged survival in ALS mice by an average of 19-22 days. This was accompanied by improvement in every parameter evaluated, including body-weight loss, reflex score, neurologic score, and motor performance. We hope to provide a novel strategy to slow down disease progression and alleviate symptoms of patients suffering from ALS.}, }
@article {pmid26691296, year = {2016}, author = {Caballero-Hernandez, D and Toscano, MG and Cejudo-Guillen, M and Garcia-Martin, ML and Lopez, S and Franco, JM and Quintana, FJ and Roodveldt, C and Pozo, D}, title = {The 'Omics' of Amyotrophic Lateral Sclerosis.}, journal = {Trends in molecular medicine}, volume = {22}, number = {1}, pages = {53-67}, doi = {10.1016/j.molmed.2015.11.001}, pmid = {26691296}, issn = {1471-499X}, support = {AI075285/AI/NIAID NIH HHS/United States ; AI093903/AI/NIAID NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/therapy ; Female ; Genomics ; Humans ; Male ; Precision Medicine ; Proteomics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that primarily affects motor neurons and is accompanied by sustained unregulated immune responses, but without clear indications of the ultimate causative mechanisms. The identification of a diverse array of ALS phenotypes, a series of recently discovered mutations, and the links between ALS and frontotemporal degeneration have significantly increased our knowledge of the disease. In this review we discuss the main features involved in ALS pathophysiology in the context of recent advances in 'omics' approaches, including genomics, proteomics, and others. We emphasize the pressing need to combine clinical imaging with various different parameters taken from omics fields to facilitate early, accurate diagnosis and rational drug design in the treatment of ALS.}, }
@article {pmid26677802, year = {2016}, author = {Slowicka, K and Vereecke, L and Mc Guire, C and Sze, M and Maelfait, J and Kolpe, A and Saelens, X and Beyaert, R and van Loo, G}, title = {Optineurin deficiency in mice is associated with increased sensitivity to Salmonella but does not affect proinflammatory NF-κB signaling.}, journal = {European journal of immunology}, volume = {46}, number = {4}, pages = {971-980}, doi = {10.1002/eji.201545863}, pmid = {26677802}, issn = {1521-4141}, mesh = {Animals ; Cell Cycle Proteins ; Eye Proteins/*genetics ; Fibroblasts/immunology ; Influenza A Virus, H3N2 Subtype/immunology ; Interferon Regulatory Factor-3/metabolism ; Interferon Type I/biosynthesis ; Lipopolysaccharides/pharmacology ; Macrophages/immunology ; Membrane Transport Proteins ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NF-kappa B/*immunology ; Orthomyxoviridae Infections/immunology/virology ; Poly I-C/pharmacology ; Salmonella Infections/*immunology/microbiology ; Salmonella typhimurium/*immunology ; Signal Transduction/immunology ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {Optineurin (OPTN) is an evolutionary conserved and ubiquitously expressed ubiquitin-binding protein that has been implicated in glaucoma, Paget bone disease, amyotrophic lateral sclerosis, and other neurodegenerative diseases. From in vitro studies, OPTN was shown to suppress TNF-induced NF-κB signaling and virus-induced IRF signaling, and was identified as an autophagy receptor required for the clearance of cytosolic Salmonella upon infection. To assess the in vivo functions of OPTN in inflammation and infection, we generated OPTN-deficient mice. OPTN knockout mice are born with normal Mendelian distribution and develop normally without any signs of spontaneous organ abnormality or inflammation. However, no differences in NF-κB activation could be observed in OPTN knockout mice or fibroblasts derived from these mice upon TNF or LPS treatment. Primary bone marrow-derived macrophages from OPTN-deficient mice had slightly impaired IRF signaling and reduced IFN type I production in response to LPS or poly(I,C). Finally, OPTN-deficient mice were more susceptible to infection with Salmonella, confirming in vivo the importance of OPTN in bacterial clearance.}, }
@article {pmid26674790, year = {2015}, author = {Zhang, H and Tang, L and Zhang, N and Fan, D}, title = {[Ventilation function disorder of flail arm syndrome].}, journal = {Zhonghua nei ke za zhi}, volume = {54}, number = {9}, pages = {749-752}, pmid = {26674790}, issn = {0578-1426}, mesh = {Amyotrophic Lateral Sclerosis/complications/*physiopathology/therapy ; Arm/*physiopathology ; Forced Expiratory Volume/physiology ; Humans ; Prognosis ; Respiration, Artificial/methods ; Respiratory Function Tests/methods ; Respiratory Insufficiency/*etiology ; Respiratory System Abnormalities/*etiology ; Retrospective Studies ; Tidal Volume ; Vital Capacity/physiology ; }, abstract = {OBJECTIVE: To study the features of ventilation function in patients with flail arm syndrome (FAS).<br><br>METHODS: The clinical data of 351 patients with sporadic amyotrophic lateral sclerosis (ALS) from 2009 to 2013 were retrospectively reviewed. Among them, 329 were classical ALS and 22 were FAS. The differences of forced vital capacity (FVC) between FAS and classical ALS were analyzed.<br><br>RESULTS: The percent predicted FVC (FVC% pred) values were (88.0 &#xb1; 9.5)% in FAS and (84.3 &#xb1; 16.8)% in classical ALS including 4 and 128 patients with abnormal FVC% pred (< 80%) in FAS and classical ALS, respectively. The FVC% pred levels were significantly higher in FAS subjects [(88.0 &#xb1; 9.5)%] than in classical ALS subjects of bulb [(80.0 &#xb1; 14.8)%] or those of upper limb [(80.8 &#xb1; 16.0)%] onset with duration over 12 months (All P < 0.05). The proportion of subjects with FVC% pred < 80% was statistically lower in FAS [18.2% (4/22)] than in both classical ALS of upper limb onset [42.8% (80/187); P = 0.037] and classical ALS with duration over one year [48.5% (48/99); P = 0.009].<br><br>CONCLUSIONS: Impaired ventilation function occurs less and later in FAS than that in classical ALS of upper limb onset with duration over one year, suggesting later and less requirement for non-invasive positive pressure ventilation treatment for FAS patients. Differentiation of FAS subjects from ALS helps assess prognosis and make treatment plan for these patients.}, }
@article {pmid26668778, year = {2015}, author = {Sato, Y and Nakatani, E and Watanabe, Y and Fukushima, M and Nakashima, K and Kannagi, M and Kanatani, Y and Mizushima, H}, title = {Prediction of prognosis of ALS: Importance of active denervation findings of the cervical-upper limb area and trunk area.}, journal = {Intractable &amp; rare diseases research}, volume = {4}, number = {4}, pages = {181-189}, pmid = {26668778}, issn = {2186-3644}, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by serious muscle atrophy and weakness. The purpose of this study was to find prognostic factors in patients with mild ALS using application forms for the Specified Disease Treatment Research Program in Japan. We classified ALS as mild, moderate and severe. The subjects consisted of 363 patients with mild ALS who underwent needle electromyography at registration and were followed for more than one year. Time to progression to severe ALS and time to deterioration of activities of daily living such as speech dysfunction, upper limb dysfunction, and walking disability were used as outcomes. Cox proportional hazards model analysis was performed to identify prognostic factors. Of the patients with initially mild ALS, 38.3% (139/363) had progressed severe ALS at the last follow-up. In multivariate analysis of time to progression to severe ALS, bulbar onset (hazard ratio [95% confidence interval]: 1.68 [1.13-2.49], p = 0.010), tongue atrophy (1.69 [1.14-2.51], p = 0.009), dyspnea (1.57 [1.02-2.41], p = 0.042) and active denervation findings (ADFs) of the cervical-upper limb area (1.81 [1.25-2.63], p = 0.002) emerged as prognostic factors. Furthermore ADFs in the trunk area were prognostic factors for upper limb dysfunction and walking disability (1.72 [1.05-2.81], p = 0.031, and 1.97 [1.09-3.59], p = 0.026). In conclusion ADFs of the cervical-upper limb area and trunk area were prognostic factors in ALS patients.}, }
@article {pmid26668144, year = {2015}, author = {Ju, XD and Liu, T and Chen, J and Li, XG and Liu, XX and Liu, WC and Wang, K and Deng, M}, title = {Single-nucleotide Polymorphism rs2275294 in ZNF512B is not Associated with Susceptibility to Amyotrophic Lateral Sclerosis in a Large Chinese Cohort.}, journal = {Chinese medical journal}, volume = {128}, number = {24}, pages = {3305-3309}, pmid = {26668144}, issn = {2542-5641}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*epidemiology/*genetics ; Asian People/genetics ; Carrier Proteins/*genetics ; Case-Control Studies ; China/epidemiology ; Female ; Genetic Predisposition to Disease/genetics ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/*genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons and has no effective treatment. Recently, Iida et al. identified a single-nucleotide polymorphism (SNP) rs2275294 in the ZNF512B gene that is significantly associated with susceptibility to ALS in the Japanese population. Here, we performed a case-control study examining the possible association of rs2275294 with risk of sporadic ALS (SALS) in a large Chinese cohort.<br><br>METHODS: To assess this association, we performed a replication study in 953 SALS patients and 1039 age- and gender-matched healthy control subjects, who were recruited from Peking University Third Hospital and the First Affiliated Hospital of Anhui Medical University from January 2004 to December 2013 throughout China. We genotyped the rs2275294 SNP using polymerase chain reaction and direct sequencing.<br><br>RESULTS: The allele frequency of rs2275294 in ZNF512B was different between Japanese and Chinese. The association in Chinese between ALS patients and controls did not reach statistical significance (P = 0.54; odds ratio = 0.94; 95% confidence interval = 0.76-1.15).<br><br>CONCLUSIONS: The SNP rs2275294 in ZNF512B is not considered to be associated with ALS susceptibility in the Chinese population. Our study highlights genetic heterogeneity in ALS susceptibility in different population. Given our negative results, further replication study involving larger and more homogeneous samples in different ethnicities should be performed in the future.}, }
@article {pmid26667001, year = {2015}, author = {Watzlawik, JO and Wootla, B and Rodriguez, M}, title = {Tryptophan Metabolites and Their Impact on Multiple Sclerosis Progression.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, pmid = {26667001}, issn = {1873-4286}, abstract = {Accumulating evidence demonstrates involvement of tryptophan metabolites and in particular activation of the kynurenine pathway (KP) in neurocognitive disorders under CNS inflammatory conditions. The KP is involved in several brain-associated disorders including Parkinson's disease, AIDS dementia, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, schizophrenia, and brain tumors. Our review is an attempt to address any relevant association between dysregulation of KP and multiple sclerosis (MS), an inflammatory CNS disorder that ultimately leads to demyelinated brain areas and severe neurological deficits. Modulation of KP is a new topic for the field of MS and warrants further research. The availability of potential KP modulators approved for MS may shed some light into the therapeutic potential of KP antagonists for the treatment of MS patients.}, }
@article {pmid26659872, year = {2016}, author = {Xu, L and He, D and Bai, Y}, title = {Microglia-Mediated Inflammation and Neurodegenerative Disease.}, journal = {Molecular neurobiology}, volume = {53}, number = {10}, pages = {6709-6715}, pmid = {26659872}, issn = {1559-1182}, mesh = {Animals ; Humans ; Inflammation/*pathology ; Microglia/*pathology ; Neurodegenerative Diseases/*pathology ; }, abstract = {Microglia are the main effectors in the inflammatory process of the central nervous system. As the first line of defense, microglia play an important role in the inflammatory reaction. When there is pathogen invasion or cell debris, microglia will be activated rapidly and remove it, while releasing the inflammatory cytokines to mediate inflammatory reaction. Activated microglia were found surrounding lesions of various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, muscular amyotrophic lateral sclerosis, and multiple sclerosis. Microglia, the effectors of neuronal degeneration and necrosis, are involved in the removal of necrotic neurons. But over activated microglia may accelerate the process of some neurodegenerative diseases. Activated microglia can release cytotoxic factor and cytokines. Some of them may cause further damage to neuron, and some of them can regulate inflammatory cells to gather to the lesion. Microglia-mediated inflammation was considered to be the possible mechanism for the occurrence or deterioration of neurodegenerative diseases. Therefore, inhibiting the activity of microglia appropriately may be an effective way for the treatment of neurodegenerative diseases.}, }
@article {pmid26658909, year = {2016}, author = {Bedlack, RS and Vaughan, T and Wicks, P and Heywood, J and Sinani, E and Selsov, R and Macklin, EA and Schoenfeld, D and Cudkowicz, M and Sherman, A}, title = {How common are ALS plateaus and reversals?.}, journal = {Neurology}, volume = {86}, number = {9}, pages = {808-812}, pmid = {26658909}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*epidemiology/therapy ; Clinical Trials as Topic/*statistics &amp; numerical data ; Disease Progression ; Evidence-Based Medicine ; Humans ; Incidence ; Longitudinal Studies ; Middle Aged ; *Registries ; *Remission, Spontaneous ; Reproducibility of Results ; Sensitivity and Specificity ; Treatment Outcome ; United States/epidemiology ; }, abstract = {OBJECTIVE: To determine the frequency of amyotrophic lateral sclerosis (ALS) plateaus and reversals in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.<br><br>METHODS: We analyzed Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) and ALSFRS-revised (ALSFRS-R) data from PRO-ACT participants. The frequencies of participants experiencing plateaus (periods where scores did not change) were calculated over 6-, 12-, and 18-month epochs. The percentage of participants ever experiencing reversals (periods where scores improved) of different lengths were also calculated and plotted.<br><br>RESULTS: Over 6 months, 25% of 3,132 participants did not decline. Over 12 months, 16% of 2,105 participants did not decline. Over 18 months, 7% of 1,218 participants did not decline. Small ALS reversals were also common, especially over shorter follow-up intervals; 14% of 1,343 participants had a 180-day interval where their ALSFRS-R slope was greater than zero. Fewer than 1% of participants ever experienced improvements of 4 or more ALSFRS-R points lasting at least 12 months.<br><br>CONCLUSION: ALS plateaus and small reversals are common, especially over brief intervals. In light of these data, stable disease, especially for a short period of time, should not be interpreted as an ALS treatment effect. Large sustained ALS reversals, on the other hand, are rare, potentially important, and warrant further study.}, }
@article {pmid26657039, year = {2016}, author = {Kaur, SJ and McKeown, SR and Rashid, S}, title = {Mutant SOD1 mediated pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Gene}, volume = {577}, number = {2}, pages = {109-118}, doi = {10.1016/j.gene.2015.11.049}, pmid = {26657039}, issn = {1879-0038}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/therapy ; Animals ; Genetic Therapy ; Humans ; Molecular Sequence Data ; *Mutation ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/chemistry/*genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neural disorder that causes death of the motor neurons in the brain and spinal cord; this affects the voluntary muscles and gradually leads to paralysis of the whole body. Most ALS cases are sporadic, though about 5-10% are familial. ALS is caused by multiple factors including mutation in any one of a number of specific genes, one of the most frequently affected is superoxide dismutase (SOD) 1. Alterations in SOD 1 have been linked with several variants of familial ALS. SOD 1 is a powerful antioxidant enzyme that protects cells from the damaging effects of superoxide radicals. The enzyme binds both copper and zinc ions that are directly involved in the deactivation of toxic superoxide radicals. Mutated SOD1 gene can acquire both gain and loss of function mutations. The most commonly identified mutations in SOD1 that affect protein activity are D90A, A4V and G93A. Deleterious mutations have been shown to modify SOD1 activity, which leads to the accumulation of highly toxic hydroxyl radicals. Accumulation of these free radicals causes degradation of both nuclear and mitochondrial DNA and protein misfolding, features which can be used as pathological indicators associated with ALS. Numerous clinical trials have been carried out over last few years with limited success. In some patients advanced techniques like gene and stem cell therapy have been trialed. However no definitive treatment option can provide a cure and currently ALS is managed by drugs and other supportive therapies. Consequently there is a need to identify new approaches for treatment of this ultimately fatal disease.}, }
@article {pmid26653545, year = {2015}, author = {Shu, YH and Lu, XM and Wei, JX and Xiao, L and Wang, YT}, title = {Update on the role of p75NTR in neurological disorders: A novel therapeutic target.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {76}, number = {}, pages = {17-23}, doi = {10.1016/j.biopha.2015.10.010}, pmid = {26653545}, issn = {1950-6007}, mesh = {Animals ; Apoptosis/physiology ; Cell Cycle Checkpoints/physiology ; Cell Movement/physiology ; Cell Survival/physiology ; Humans ; Mental Disorders/*physiopathology ; Nervous System Diseases/*physiopathology ; Receptor, Nerve Growth Factor/*metabolism ; }, abstract = {As a low-affinity neurotrophins receptor, p75 neurotrophin receptor (p75NTR) is a transmembrane receptor involved in a diverse array of cellular responses, including apoptosis, survival, neurite outgrowth, migration, and cell cycle arrest, which may be related to some neurological disorders, such as Alzheimer's disease (AD), schizophrenia, major depressive disorder (MDD), posttraumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Indeed, a series of studies during the last decade has demonstrated that the p75NTR signaling plays key roles in most aspects of the neurological disorder diseases. In spite of the limited information available, this review still tried to summary the relationship between p75NTR and diverse neurological disorder diseases, and tried to further clarify the possible mechanism, which may provide a novel therapeutic target for the treatment of neurological disorders.}, }
@article {pmid26648846, year = {2015}, author = {Jeyachandran, A and Mertens, B and McKissick, EA and Mitchell, CS}, title = {Type I Vs. Type II Cytokine Levels as a Function of SOD1 G93A Mouse Amyotrophic Lateral Sclerosis Disease Progression.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {462}, pmid = {26648846}, issn = {1662-5102}, support = {K01 NS069616/NS/NINDS NIH HHS/United States ; R21 NS081426/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal motoneuron disease that is characterized by the degradation of neurons throughout the central nervous system. Inflammation have been cited a key contributor to ALS neurodegeneration, but the timeline of cytokine upregulation remains unresolved. The goal of this study was to temporally examine the correlation between the varying levels of pro-inflammatory type I cytokines (IL-1β, IL-1α, IL-12, TNF-α, and GFAP) and anti-inflammatory type II cytokines (IL-4, IL-6, IL-10) throughout the progression of ALS in the SOD1 G93A mouse model. Cytokine level data from high copy SOD1 G93A transgenic mice was collected from 66 peer-reviewed studies. For each corresponding experimental time point, the ratio of transgenic to wild type (TG/WT) cytokine was calculated. One-way ANOVA and t-tests with Bonferonni correction were used to analyze the data. Meta-analysis was performed for four discrete stages: early, pre-onset, post-onset, and end stage. A significant increase in TG cytokine levels was found when compared to WT cytokine levels across the entire SOD1 G93A lifespan for majority of the cytokines. The rates of change of the individual cytokines, and type I and type II were not significantly different; however, the mean fold change of type I was expressed at significantly higher levels than type II levels across all stages with the difference between the means becoming more pronounced at the end stage. An overexpression of cytokines occurred both before and after the onset of ALS symptoms. The trend between pro-inflammatory type I and type II cytokine mean levels indicate a progressive instability of the dynamic balance between pro- and anti-inflammatory cytokines as anti-inflammatory cytokines fail to mediate the pronounced increase in pro-inflammatory cytokines. Very early immunoregulatory treatment is necessary to successfully interrupt ALS-induced neuroinflammation.}, }
@article {pmid26646002, year = {2016}, author = {Jeon, GS and Im, W and Shim, YM and Lee, M and Kim, MJ and Hong, YH and Seong, SY and Kim, M and Sung, JJ}, title = {Neuroprotective Effect of Human Adipose Stem Cell-Derived Extract in Amyotrophic Lateral Sclerosis.}, journal = {Neurochemical research}, volume = {41}, number = {4}, pages = {913-923}, pmid = {26646002}, issn = {1573-6903}, mesh = {Adipose Tissue/cytology/*metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology/physiopathology ; Animals ; Apoptosis Regulatory Proteins/metabolism ; Cell Extracts/*pharmacology/therapeutic use ; Cell Survival ; Cyclic AMP Response Element-Binding Protein/metabolism ; Female ; Humans ; Male ; Mice, Transgenic ; Mitochondria/metabolism ; Motor Neurons/drug effects/pathology ; Neuroprotective Agents/*pharmacology/therapeutic use ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Phosphorylation ; Stem Cells/*metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Transcription Factors/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating human neurodegenerative disease. The precise pathogenic mechanisms of the disease remain uncertain, and as of yet, there is no effective cure. Human adipose stem cells (hASC) can be easily obtained during operative procedures. hASC have a clinically feasible potential to treat neurodegenerative disorders, since cytosolic extract of hASC contain a number of essential neurotrophic factors. In this study, we investigated effects of hASC extract on the SOD1 G93A mouse model of ALS and in vitro test. Administration of hASC extract improved motor function and prolonged the time until symptom onset, rotarod failure, and death in ALS mice. In the hASC extracts group, choline acetyltransferase immunostaining in the ventral horn of the lumbar spinal cord showed a large number of motor neurons, suggesting normal morphology. The neuroprotective effect of hASC extract in ALS mice was also suggested by western blot analysis of spinal cord extract from ALS mice and in vitro test. hASC extract treatment significantly increased expression of p-Akt, p-CREB, and PGC-1α in SOD1 G93A mouse model and in vitro test. Our results indicated that hASC extract reduced apoptotic cell death and recovered mutant SOD1-induced mitochondrial dysfunction. Moreover, hASC extract reduced mitochondrial membrane potential. In conclusion, we have demonstrated, for the first time, that hASC extract exert a potential therapeutic action in the SOD1 G93A mouse model of ALS and in vitro test. These findings suggest that hASC hold promise as a novel therapeutic strategy for treating ALS.}, }
@article {pmid26642082, year = {2016}, author = {Choong, CJ and Baba, K and Mochizuki, H}, title = {Gene therapy for neurological disorders.}, journal = {Expert opinion on biological therapy}, volume = {16}, number = {2}, pages = {143-159}, doi = {10.1517/14712598.2016.1114096}, pmid = {26642082}, issn = {1744-7682}, mesh = {Alzheimer Disease/genetics/therapy ; Animals ; Clinical Trials as Topic/methods ; Gene Silencing/physiology ; Genetic Therapy/*methods/trends ; Genetic Vectors ; Humans ; Nervous System Diseases/*genetics/*therapy ; Parkinson Disease/genetics/therapy ; RNA Interference/physiology ; }, abstract = {INTRODUCTION: Many nervous system disorders are minimally responsive to existing treatments but they are potential candidates for gene therapy, an approach that can correct the genetic abnormalities contributing to its pathogenesis at molecular level. Gene therapy involves either the introduction of a replacement allele into cells to compensate for loss of gene function or the silencing of dominant mutant allele that is pathologic to cells.<br><br>AREAS COVERED: This review discusses the currently available gene therapy techniques, potential problems derived from gene therapy strategies and the recent development of gene therapy to treat neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and strokes.<br><br>EXPERT OPINION: Gene therapy may revolutionize the treatment of neurological disorders in the coming decades but there are still great challenges ahead. The strength of gene therapy has been emphasized in the overexpression of therapeutic genes. However, in a number of dominantly inherited nervous system diseases, the ideal therapeutic goal would be to inhibit the expression of disease-causing allele. Gene silencing strategies by single-stranded antisense oligonucleotides and RNA interference represent a major breakthrough. Clinical trials using these approaches for dominant diseases are likely to be implemented in the near future.}, }
@article {pmid26640075, year = {2016}, author = {De Paola, M and Sestito, SE and Mariani, A and Memo, C and Fanelli, R and Freschi, M and Bendotti, C and Calabrese, V and Peri, F}, title = {Synthetic and natural small molecule TLR4 antagonists inhibit motoneuron death in cultures from ALS mouse model.}, journal = {Pharmacological research}, volume = {103}, number = {}, pages = {180-187}, doi = {10.1016/j.phrs.2015.11.020}, pmid = {26640075}, issn = {1096-1186}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Cell Death/drug effects ; Coculture Techniques ; Disease Models, Animal ; HEK293 Cells ; Humans ; Lipopolysaccharides/pharmacology ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/metabolism ; Motor Neurons/*drug effects/metabolism ; Nitric Oxide/metabolism ; Olive Oil/*pharmacology ; Phenols/*pharmacology ; Spinal Cord/metabolism ; Superoxide Dismutase/genetics ; Toll-Like Receptor 4/*antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {Increasing evidence indicates that inflammatory responses could play a critical role in the pathogenesis of motor neuron injury in amyotrophic lateral sclerosis (ALS). Recent findings have underlined the role of Toll-like receptors (TLRs) and the involvement of both the innate and adaptive immune responses in ALS pathogenesis. In particular, abnormal TLR4 signaling in pro-inflammatory microglia cells has been related to motoneuron degeneration leading to ALS. In this study the effect of small molecule TLR4 antagonists on in vitro ALS models has been investigated. Two different types of synthetic glycolipids and the phenol fraction extracted from commercial extra-virgin olive oil (EVOO) were selected since they efficiently inhibit TLR4 stimulus in HEK cells by interacting with the TLR4·MD-2 complex and CD14 co-receptor. Here, TLR4 antagonists efficiently protected motoneurons from LPS-induced lethality in spinal cord cultures, and inhibited the interleukine-1β production by LPS-stimulated microglia. In motoneurons/glia cocultures obtained from wild type or SOD1 G93A mice, motoneuron death induced by SOD1mut glia was counteracted by TLR4 antagonists. The release of nitric oxide by LPS treatment or SOD1mut glia was also inhibited by EVOO, suggesting that the action of this natural extract could be mainly related to the modulation of this inflammatory mediator.}, }
@article {pmid26639457, year = {2016}, author = {Catorce, MN and Gevorkian, G}, title = {LPS-induced Murine Neuroinflammation Model: Main Features and Suitability for Pre-clinical Assessment of Nutraceuticals.}, journal = {Current neuropharmacology}, volume = {14}, number = {2}, pages = {155-164}, pmid = {26639457}, issn = {1875-6190}, mesh = {Animals ; Anti-Inflammatory Agents/*therapeutic use ; Astrocytes/metabolism ; Brain/drug effects/metabolism ; *Dietary Supplements ; *Disease Models, Animal ; Encephalitis/chemically induced/etiology/*metabolism/*prevention &amp; control ; Lipopolysaccharides/*administration &amp; dosage ; Mice ; Microglia/metabolism ; Neurodegenerative Diseases/*complications ; Reproducibility of Results ; }, abstract = {Neuroinflammation is an important feature in the pathogenesis and progression of neurodegenerative diseases such as Alzheimer´s disease (AD), Parkinson´s disease (PD), frontotemporal dementia and amyotrophic lateral sclerosis. Based on current knowledge in the field, suggesting that targeting peripheral inflammation could be a promising additional treatment/prevention approach for neurodegenerative diseases, drugs and natural products with anti-inflammatory properties have been evaluated in animal models of neuroinflammation and neurodegeneration. In this review, we provide an extensive analysis of one of the most important and widely-used animal models of peripherally induced neuroinflammation and neurodegeneration - lipopolysaccharide (LPS)-treated mice, and address the data reproducibility in published research. We also summarize briefly basic features of various natural products, nutraceuticals, with known anti-inflammatory effects and present an overview of data on their therapeutic potential for reducing neuroinflammation in LPS-treated mice.}, }
@article {pmid26638977, year = {2016}, author = {Parikh, RH and Patel, RJ}, title = {Nanoemulsions for Intranasal Delivery of Riluzole to Improve Brain Bioavailability: Formulation Development and Pharmacokinetic Studies.}, journal = {Current drug delivery}, volume = {13}, number = {7}, pages = {1130-1143}, doi = {10.2174/1567201813666151202195729}, pmid = {26638977}, issn = {1875-5704}, mesh = {Administration, Intranasal ; Animals ; Biological Availability ; Brain/*metabolism ; Chemistry, Pharmaceutical ; Drug Stability ; Emulsions ; Lipids/chemistry ; *Nanoparticles/administration &amp; dosage/chemistry/toxicity ; Nasal Mucosa/drug effects/pathology ; *Neuroprotective Agents/administration &amp; dosage/chemistry/pharmacokinetics/toxicity ; Polymers/chemistry ; Rats, Wistar ; *Riluzole/administration &amp; dosage/chemistry/pharmacokinetics/toxicity ; Solubility ; Surface-Active Agents/chemistry ; Viscosity ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS), a motor neuron disease (MND), is a progressive neurodegenerative disorder characterized by the deterioration of both upper and lower motor neurons. Only one drug (riluzole) has been approved for the treatment of ALS. Riluzole is a BCS class II drug having 60% absolute bioavailability. It is a substrate of P-glycoprotein and BBB restricts its entry in brain.<br><br>OBJECTIVE: This investigation was aimed to develop O/W nanoemulsion system of riluzole to improve its brain bioavailability.<br><br>METHODS: Riluzole loaded nanoemulsion was prepared by phase titration method. It was consisting of 3% w/w Sefsol 218, 28.3% w/w Tween 80:Carbitol (1:1) and 68.7% w/w water. It was characterized for drop size, drop size distribution, transmittance, viscosity, pH, zeta potential, conductivity and nasal ciliotoxicity study. Thermodynamic stability and room temperature stability of prepared nanoemulsion formulation were evaluated. Pharmacokinetic and brain uptake study was carried out using albino rats (wistar) post intranasal and oral administration.<br><br>RESULTS: Riluzole loaded nanoemulsion was having a drop size of 23.92&#xb1;0.52 nm. It was free from nasal ciliotoxicity and stable for three months. Brain uptake of riluzole post intranasal administration of riluzole loaded nanoemulsion was significantly (P <4.10 &#xd7; 10-6) higher when it was compared with oral administration of riluzole loaded nanoemulsion.<br><br>CONCLUSION: This study indicates that nanoemulsion of riluzole for intranasal administration could be a promising approach for the treatment of ALS to minimize the dose of riluzole in order to avoid dose related adverse events.}, }
@article {pmid26636518, year = {2015}, author = {Terzano, C and Romani, S}, title = {Early use of non invasive ventilation in patients with amyotrophic lateral sclerosis: what benefits?.}, journal = {European review for medical and pharmacological sciences}, volume = {19}, number = {22}, pages = {4304-4313}, pmid = {26636518}, issn = {2284-0729}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology/*therapy ; Blood Gas Analysis/methods ; Female ; Forced Expiratory Volume/physiology ; Humans ; Male ; Middle Aged ; Muscle Strength/physiology ; Noninvasive Ventilation/*statistics &amp; numerical data ; Respiratory Function Tests/methods ; Respiratory Muscles/physiology ; Risk Assessment ; Time Factors ; Vital Capacity/physiology ; }, abstract = {OBJECTIVE: The aim of this study was to analyze the efficacy of an early start of NIV in ALS patients, evaluating respiratory and ventilatory parameters.<br><br>PATIENTS AND METHODS: Functional respiratory parameters and arterial blood gas analysis were evaluated in forty-six patients. All patients were informed about the benefits and possible adverse effects of therapeutic support with NIV and divided in two groups based on the compliance to early start therapy with NIV (Group A) or not (Group B).<br><br>RESULTS: Among 46 ALS patients consecutively visited in our Unit, we included 20 patients in the Group A and 16 in the Group B. We have emphasized the importance of the early use of NIV stressing the difference between two groups analyzed, particularly in terms of pulmonary function tests and arterial blood gas analysis. Significant correlation was observed between Vital Capacity (VC), Forced Expiratory volume in one second (FEV1), and maximal inspiratory pressures (PImax).<br><br>CONCLUSIONS: Our study highlights the importance of noninvasive mechanical ventilation as a treatment for ALS patients and also shows the early start of NIV as an important approach in order to postpone the functional decline and the decrease of respiratory muscle strength.}, }
@article {pmid26630810, year = {2015}, author = {Morris, J}, title = {Amyotrophic Lateral Sclerosis (ALS) and Related Motor Neuron Diseases: An Overview.}, journal = {The Neurodiagnostic journal}, volume = {55}, number = {3}, pages = {180-194}, doi = {10.1080/21646821.2015.1075181}, pmid = {26630810}, issn = {2164-6821}, mesh = {Adult ; Aged ; *Amyotrophic Lateral Sclerosis ; Electromyography ; Female ; Humans ; Male ; Middle Aged ; *Motor Neuron Disease ; Motor Neurons ; Neural Conduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative motor neuron disease, resulting in the destruction and ultimate death of neurons that control muscles. ALS affects motor neurons in the brain, brainstem, and spinal cord (upper motor neurons, bulbar region of the brain, and lower motor neurons). ALS patients have an average life expectancy of 3-5 years, therefore, proper diagnosis, care, and treatment is essential in order to provide the best quality of life for these patients. A thorough understanding of the symptomatology, potential cause(s), progression, and treatment of ALS is essential to provide timely and high-quality patient care. Electrodiagnostic examination, specifically electromyography (EMG) and nerve conduction studies (NCS), is one of the key diagnostics of ALS.}, }
@article {pmid26629397, year = {2015}, author = {Zarei, S and Carr, K and Reiley, L and Diaz, K and Guerra, O and Altamirano, PF and Pagani, W and Lodin, D and Orozco, G and Chinea, A}, title = {A comprehensive review of amyotrophic lateral sclerosis.}, journal = {Surgical neurology international}, volume = {6}, number = {}, pages = {171}, pmid = {26629397}, issn = {2229-5097}, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease affecting motor neurons with an incidence of about 1/100,000. Most ALS cases are sporadic, but 5-10% of the cases are familial ALS. Both sporadic and familial ALS (FALS) are associated with degeneration of cortical and spinal motor neurons. The etiology of ALS remains unknown. However, mutations of superoxide dismutase 1 have been known as the most common cause of FALS. In this study, we provide a comprehensive review of ALS. We cover all aspects of the disease including epidemiology, comorbidities, environmental risk factor, molecular mechanism, genetic factors, symptoms, diagnostic, treatment, and even the available supplement and management of ALS. This will provide the reader with an advantage of receiving a broad range of information about the disease.}, }
@article {pmid26626189, year = {2016}, author = {Denzer, I and Münch, G and Friedland, K}, title = {Modulation of mitochondrial dysfunction in neurodegenerative diseases via activation of nuclear factor erythroid-2-related factor 2 by food-derived compounds.}, journal = {Pharmacological research}, volume = {103}, number = {}, pages = {80-94}, doi = {10.1016/j.phrs.2015.11.019}, pmid = {26626189}, issn = {1096-1186}, mesh = {Animals ; *Food ; Humans ; Mitochondria/*metabolism ; NF-E2-Related Factor 2/*metabolism ; Neurodegenerative Diseases/*metabolism ; Oxidative Stress ; }, abstract = {Oxidative stress and mitochondrial dysfunction are early events in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Mitochondria are important key players in cellular function based on mitochondrial energy production and their major role in cell physiology. Since neurons are highly depending on mitochondrial energy production due to their high energy demand and their reduced glycolytic capacity mitochondrial dysfunction has fatal consequences for neuronal function and survival. The transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2) is the major regulator of cellular response to oxidative stress. Activation of Nrf2 induces the transcriptional regulation of antioxidant response element (ARE)-dependent expression of a battery of cytoprotective and antioxidant enzymes and proteins. Moreover, activation of Nrf2 protects mitochondria from dysfunction and promotes mitochondrial biogenesis. Therefore, the Nrf2/ARE pathway has become an attractive target for the prevention and treatment of oxidative stress-related neurodegenerative diseases. Small food-derived inducers of the Nrf2/ARE pathway including l-sulforaphane from broccoli and isoliquiritigenin from licorice displayed promising protection of mitochondrial function in models of oxidative stress and neurodegenerative diseases and represent a novel approach to prevent and treat aging-associated neurodegenerative diseases.}, }
@article {pmid26619801, year = {2016}, author = {Dell'Orco, M and Milani, P and Arrigoni, L and Pansarasa, O and Sardone, V and Maffioli, E and Polveraccio, F and Bordoni, M and Diamanti, L and Ceroni, M and Peverali, FA and Tedeschi, G and Cereda, C}, title = {Hydrogen peroxide-mediated induction of SOD1 gene transcription is independent from Nrf2 in a cellular model of neurodegeneration.}, journal = {Biochimica et biophysica acta}, volume = {1859}, number = {2}, pages = {315-323}, doi = {10.1016/j.bbagrm.2015.11.009}, pmid = {26619801}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Cell Line ; Gene Expression Regulation/genetics ; Humans ; Hydrogen Peroxide/toxicity ; Intracellular Signaling Peptides and Proteins/biosynthesis/*genetics ; Kelch-Like ECH-Associated Protein 1 ; NF-E2-Related Factor 2/*biosynthesis/genetics ; Nerve Degeneration/chemically induced/*genetics/pathology ; Oxidative Stress/genetics ; Promoter Regions, Genetic/drug effects ; RNA, Messenger/biosynthesis ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/*biosynthesis/genetics ; Superoxide Dismutase-1 ; *Transcription, Genetic ; }, abstract = {BACKGROUND: It is still unclear whether oxidative stress (OS) is a disease consequence or is directly involved in the etiology of neurodegenerative disorders (NDs) onset and/or progression; however, many of these conditions are associated with increased levels of oxidation markers and damaged cell components. Previously we demonstrated the accumulation of reactive oxygen species (ROS) and increased SOD1 gene expression in H2O2-treated SH-SY5Y cells, recapitulating pathological features of Amyotrophic Lateral Sclerosis (ALS). Since we observed a post-transcriptional regulation of SOD1 gene in this cellular model, we investigated the transcriptional regulation of SOD1 mRNA under oxidative stress (OS).<br><br>RESULTS: In response to H2O2 treatment, PolII increased its association to SOD1 promoter. Electrophoretic mobility shift assays and mass spectrometry analyses on SOD1 promoter highlighted the formation of a transcriptional complex bound to the ARE sequences. Western Blotting experiments showed that in our in vitro model, H2O2 exposure increases Nrf2 expression in the nuclear fraction while immunoprecipitation confirmed its phosphorylation and release from Keap1 inhibition. However, H2O2 treatment did not modify Nrf2 binding on SOD1 promoter, which seems to be regulated by different transcription factors (TFs).<br><br>CONCLUSIONS: Although our data suggest that SOD1 is transcriptionally regulated in response to OS, Nrf2 does not appear to associate with SOD1 promoter in this cellular model of neurodegeneration. Our results open new perspectives in the comprehension of two key antioxidant pathways involved in neurodegenerative disorders.}, }
@article {pmid26611602, year = {2016}, author = {McEachin, ZT and Donsante, A and Boulis, N}, title = {Gene Therapy for the Treatment of Neurological Disorders: Amyotrophic Lateral Sclerosis.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {1382}, number = {}, pages = {399-408}, doi = {10.1007/978-1-4939-3271-9_28}, pmid = {26611602}, issn = {1940-6029}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Genetic Therapy/*methods ; Genetic Vectors/administration &amp; dosage ; Humans ; Mice ; Transgenes ; }, abstract = {Gene therapy is a powerful tool for treating diseases, including neurological disorder such at amyotrophic lateral sclerosis. When delivered to the CNS, gene therapy vectors can provide prosurvival signals to neurons, knock down the expression of toxic proteins, or restore lost function. How to best deliver this type of therapeutic depends on the nature of the disease and the expected function of the transgene. Here we describe a method for parenchymal injection into rodent models, allowing for localized delivery of gene therapy vectors and other therapeutic molecules. This technique has been a robust mechanism for proof-of-principle experiments.}, }
@article {pmid26608203, year = {2015}, author = {Grasso, M and Piscopo, P and Crestini, A and Confaloni, A and Denti, MA}, title = {Circulating microRNAs in Neurodegenerative Diseases.}, journal = {Experientia supplementum (2012)}, volume = {106}, number = {}, pages = {151-169}, doi = {10.1007/978-3-0348-0955-9_7}, pmid = {26608203}, issn = {1664-431X}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are caused by a combination of events that impair normal neuronal function. Although they are considered different disorders, there are overlapping features among them from the clinical, pathological, and genetic points of view. Synaptic dysfunction and loss, neurite retraction, and the appearance of other abnormalities such as axonal transport defects normally precede the neuronal loss that is a relatively late event. The diagnosis of many neurodegenerative diseases is mainly based on patient's cognitive function analysis, and the development of diagnostic methods is complicated by the brain's capacity to compensate for neuronal loss over a long period of time. This results in the late clinical manifestation of symptoms, a time when successful treatment is no longer feasible. Thus, a noninvasive diagnostic method based on early events detection is particularly important. In the last years, some biomarkers expressed in human body fluids have been proposed. microRNAs (miRNAs), with their high stability, tissue- or cell type-specific expression, lower cost, and shorter time in the assay development, could constitute a good tool to obtain an early disease diagnosis for a wide number of human pathologies, including neurodegenerative diseases. The possibilities and challenges of using these small RNA molecules as a signature for neurodegenerative disorders is a highly promising approach for developing minimally invasive screening tests and to identify new therapeutic targets.}, }
@article {pmid26604922, year = {2015}, author = {Al-Sammak, MA and Rogers, DG and Hoagland, KD}, title = {Acute β-N-Methylamino-L-alanine Toxicity in a Mouse Model.}, journal = {Journal of toxicology}, volume = {2015}, number = {}, pages = {739746}, pmid = {26604922}, issn = {1687-8191}, abstract = {The cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) is considered to be an "excitotoxin," and its suggested mechanism of action is killing neurons. Long-term exposure to L-BMAA is believed to lead to neurodegenerative diseases including Parkinson's and Alzheimer's diseases and amyotrophic lateral sclerosis (Lou Gehrig's disease). Objectives of this study were to determine the presumptive median lethal dose (LD50), the Lowest-Observed-Adverse-Effect Level (LOAEL), and histopathologic lesions caused by the naturally occurring BMAA isomer, L-BMAA, in mice. Seventy NIH Swiss Outbred mice (35 male and 35 female) were used. Treatment group mice were injected intraperitoneally with 0.03, 0.3, 1, 2, and 3 mg/g body weight L-BMAA, respectively, and control mice were sham-injected. The presumptive LD50 of L-BMAA was 3 mg/g BW and the LOAEL was 2 mg/g BW. There were no histopathologic lesions in brain, liver, heart, kidney, lung, or spleen in any of the mice during the 14-day study. L-BMAA was detected in brains and livers in all of treated mice but not in control mice. Males injected with 0.03 mg/g BW, 0.3 mg/g BW, and 3.0 mg/g BW L-BMAA showed consistently higher concentrations (P < 0.01) in brain and liver samples as compared to females in those respective groups.}, }
@article {pmid26604152, year = {2016}, author = {Fujisawa, T and Takahashi, M and Tsukamoto, Y and Yamaguchi, N and Nakoji, M and Endo, M and Kodaira, H and Hayashi, Y and Nishitoh, H and Naguro, I and Homma, K and Ichijo, H}, title = {The ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosis.}, journal = {Human molecular genetics}, volume = {25}, number = {2}, pages = {245-253}, doi = {10.1093/hmg/ddv467}, pmid = {26604152}, issn = {1460-2083}, mesh = {Administration, Oral ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Antineoplastic Agents/administration &amp; dosage/*therapeutic use ; Disease Models, Animal ; Heterocyclic Compounds, 4 or More Rings/administration &amp; dosage/*therapeutic use ; MAP Kinase Kinase Kinase 5/*antagonists &amp; inhibitors ; Male ; Mice ; Mice, Transgenic ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure. To develop effective treatments for this devastating disease, an appropriate strategy for targeting the molecule responsible for the pathogenesis of ALS is needed. We previously reported that mutant SOD1 protein causes motor neuron death through activation of ASK1, a mitogen-activated protein kinase kinase kinase. Additionally, we recently developed K811 and K812, which are selective inhibitors for ASK1. Here, we report the effect of K811 and K812 in a mouse model of ALS (SOD1(G93A) transgenic mice). Oral administration of K811 or K812 significantly extended the life span of SOD1(G93A) transgenic mice (1.06 and 1.08% improvement in survival). Moreover, ASK1 activation observed in the lumbar spinal cord of mice at the disease progression stage was markedly decreased in the K811- and K812-treated groups. In parallel, immunohistochemical analysis revealed that K811 and K812 treatment inhibited glial activation in the lumbar spinal cord of SOD1(G93A) transgenic mice. These results reinforce the importance of ASK1 as a therapeutic target for ALS treatment.}, }
@article {pmid26604027, year = {2015}, author = {Cavaleri, F}, title = {Review of Amyotrophic Lateral Sclerosis, Parkinson's and Alzheimer's diseases helps further define pathology of the novel paradigm for Alzheimer's with heavy metals as primary disease cause.}, journal = {Medical hypotheses}, volume = {85}, number = {6}, pages = {779-790}, doi = {10.1016/j.mehy.2015.10.009}, pmid = {26604027}, issn = {1532-2777}, mesh = {Brain/*drug effects/*physiopathology ; Disease Progression ; Evidence-Based Medicine ; Heavy Metal Poisoning, Nervous System/complications/*physiopathology ; Humans ; Metals/*poisoning ; *Models, Neurological ; Neurodegenerative Diseases/etiology/*physiopathology ; }, abstract = {Pathologies of neurological diseases are increasingly recognized to have common structural and molecular events that can fit, sometimes loosely, into a central pathological theme. A better understanding of the genetic, proteomic and metabolic similarities between three common neurodegenerative diseases - Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD) - and how these similarities relate to their unique pathological features may shed more light on the underlying pathology of each. These are complex multigenic neuroinflammatory diseases caused by a combined action by multiple genetic mutations, lifestyle factors and environmental elements including a proposed contribution by transition metals. This comprehensive dynamic makes disease decoding and treatment difficult. One case of ALS, for example, can manifest from a very different pool of genetic mutations than another. In the case of ALS multiple genes in addition to SOD1 are implicated in the pathogenesis of both sporadic and familial variants of the disease. These genes play different roles in the processing and trafficking of signalling, metabolic and structural proteins. However, many of these genetic mutations or the cellular machinery they regulate can play a role in one form or another in PD and AD as well. In addition, the more recent understanding of how TREM-2 mutations factor into inflammatory response has shed new light on how chronic inflammatory activity can escalate to uncontrolled systemic levels in a variety of inflammatory diseases from neurodegenerative, auto-inflammatory and autoimmune diseases. TREM-2 mutations represent yet another complicating element in these multigenic disease pathologies. This review takes us one step back to discuss basic pathological features of these neurodegenerative diseases known to us for some time. However, the objective is to discuss the possibility of related or linked mechanisms that may exist through these basic disease hallmarks that we often classify as absolute signatures of one disease. These new perspectives will be discussed in the context of a new paradigm for Alzheimer's disease that implicates heavy metals as a primary cause. Plausible links between these distinctly different pathologies are presented showing intersections of their distinct pathologies that hinge on metal interactions.}, }
@article {pmid26603295, year = {2016}, author = {Fujii, S and Takanashi, K and Kitajo, K and Yamaguchi, A}, title = {Treatment with a Global Methyltransferase Inhibitor Induces the Intranuclear Aggregation of ALS-Linked FUS Mutant In Vitro.}, journal = {Neurochemical research}, volume = {41}, number = {4}, pages = {826-835}, pmid = {26603295}, issn = {1573-6903}, mesh = {Adenosine/*analogs &amp; derivatives/pharmacology ; Amyotrophic Lateral Sclerosis/*genetics ; Cell Line, Tumor ; Cell Nucleus/*metabolism ; HEK293 Cells ; Humans ; Methylation ; Methyltransferases/*antagonists &amp; inhibitors ; Mutation ; Protein Aggregates ; RNA-Binding Protein FUS/genetics/*metabolism ; Subcellular Fractions/metabolism ; Time Factors ; }, abstract = {FUS/TLS (fused in sarcoma/translocated in liposarcoma) encodes a multifunctional DNA/RNA binding protein with non-classical carboxy (C)-terminal nuclear localization signal (NLS). A variety of ALS-linked mutations are clustered in the C-terminal NLS, resulting in the cytoplasmic mislocalization and aggregation. Since the arginine methylations are implicated in the nuclear-cytoplasmic shuttling of FUS, a methylation inhibitor could be one of therapeutic targets for FUS-linked ALS. We here examined effects of methylation inhibitors on the cytoplasmic mislocalization and aggregates of ALS-linked C-terminal FUS mutant in a cell culture system. Treatment with adenosine dialdehyde (AdOx), a representative global methyltransferase inhibitor, remarkably mitigated the cytoplasmic mislocalization and aggregation of FUS mutant, which is consistent with previous reports. However, AdOx treatment of higher concentration and longer time period evoked the intranuclear aggregation of the ectopic expressed FUS protein. The pull down assay and the morphological analysis indicated the binding between FUS and Transportin could be potentiated by AdOx treatment through modulating methylation status in RGG domains of FUS. These findings indicated the treatment with a methylation inhibitor at the appropriate levels could alleviate the cytoplasmic mislocalization but in excess this could cause the intranuclear aggregation of FUS C-terminal mutant.}, }
@article {pmid26600047, year = {2015}, author = {Rabinovich-Toidman, P and Rabinovich-Nikitin, I and Ezra, A and Barbiro, B and Fogel, H and Slutsky, I and Solomon, B}, title = {Mutant SOD1 Increases APP Expression and Phosphorylation in Cellular and Animal Models of ALS.}, journal = {PloS one}, volume = {10}, number = {11}, pages = {e0143420}, pmid = {26600047}, issn = {1932-6203}, mesh = {Amyloid beta-Peptides/genetics/metabolism ; Amyloid beta-Protein Precursor/*genetics/*metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/*genetics/*metabolism/mortality ; Animals ; Cell Line ; Disease Models, Animal ; *Gene Expression Regulation/drug effects ; Hippocampus/metabolism ; Humans ; Male ; Mice ; Mice, Transgenic ; *Mutation ; Phosphorylation ; Protein Binding ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Synapses/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease and it is the most common adult onset neurodegenerative disorder affecting motor neurons. There is currently no effective treatment for ALS and our understanding of the pathological mechanism is still far away from prevention and/or treatment of this devastating disease. Amyloid precursor protein (APP) is a transmembrane protein that undergoes processing either by β-secretase or α-secretase, followed by γ-secretase. In the present study, we show that APP levels, and aberrant phosphorylation, which is associated with enhanced β-secretase cleavage, are increased in SOD1G93A ALS mouse model. Fluorescence resonance energy transfer (FRET) analysis suggests a close interaction between SOD1 and APP at hippocampal synapses. Notably, SOD1G93A mutation induces APP-SOD1 conformational changes, indicating a crosstalk between these two signaling proteins. Inhibition of APP processing via monoclonal antibody called BBS that blocks APP β-secretase cleavage site, resulted in reduction of mutant SOD1G93A levels in animal and cellular models of ALS, significantly prolonged life span of SOD1G93A mice and diminished inflammation. Beyond its effect on toxic mutant SOD1G93A, BBS treatment resulted in a reduction in the levels of APP, its processing product soluble APPβ and pro-apoptotic p53. This study demonstrates that APP and its processing products contribute to ALS pathology through several different pathways; thus BBS antibody could be a promising neuroprotective strategy for treatment of this disease.}, }
@article {pmid26599360, year = {2015}, author = {Park, BY and Lee, H and Woo, S and Yoon, M and Kim, J and Hong, Y and Lee, HS and Park, EK and Hahm, JC and Kim, JW and Shin, SS and Kim, MY and Yoon, M}, title = {Reduction of Adipose Tissue Mass by the Angiogenesis Inhibitor ALS-L1023 from Melissa officinalis.}, journal = {PloS one}, volume = {10}, number = {11}, pages = {e0141612}, pmid = {26599360}, issn = {1932-6203}, mesh = {Adipocytes/drug effects ; Adipose Tissue/blood supply/drug effects/enzymology/*pathology ; Angiogenesis Inhibitors/*pharmacology ; Animals ; Body Weight/drug effects ; Cell Size/drug effects ; Diet, High-Fat ; Human Umbilical Vein Endothelial Cells ; Lipids/blood ; Liver/drug effects/metabolism ; Male ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Matrix Metalloproteinase Inhibitors/pharmacology ; Melissa/*chemistry ; Mice, Inbred C57BL ; Mice, Obese ; Organ Size/drug effects ; Oxidation-Reduction/drug effects ; PPAR alpha/genetics/metabolism ; Plant Extracts/*pharmacology ; RNA, Messenger/genetics/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Weight Gain/drug effects ; }, abstract = {It has been suggested that angiogenesis modulates adipogenesis and obesity. This study was undertaken to determine whether ALS-L1023 (ALS) prepared by a two-step organic solvent fractionation from Melissa leaves, which exhibits antiangiogenic activity, can regulate adipose tissue growth. The effects of ALS on angiogenesis and extracellular matrix remodeling were measured using in vitro assays. The effects of ALS on adipose tissue growth were investigated in high fat diet-induced obese mice. ALS inhibited VEGF- and bFGF-induced endothelial cell proliferation and suppressed matrix metalloproteinase (MMP) activity in vitro. Compared to obese control mice, administration of ALS to obese mice reduced body weight gain, adipose tissue mass and adipocyte size without affecting appetite. ALS treatment decreased blood vessel density and MMP activity in adipose tissues. ALS reduced the mRNA levels of angiogenic factors (VEGF-A and FGF-2) and MMPs (MMP-2 and MMP-9), whereas ALS increased the mRNA levels of angiogenic inhibitors (TSP-1, TIMP-1, and TIMP-2) in adipose tissues. The protein levels of VEGF, MMP-2 and MMP-9 were also decreased by ALS in adipose tissue. Metabolic changes in plasma lipids, liver triglycerides, and hepatic expression of fatty acid oxidation genes occurred during ALS-induced weight loss. These results suggest that ALS, which has antiangiogenic and MMP inhibitory activities, reduces adipose tissue mass in nutritionally obese mice, demonstrating that adipose tissue growth can be regulated by angiogenesis inhibitors.}, }
@article {pmid26597538, year = {2015}, author = {Dahlke, C and Saberi, D and Ott, B and Brand-Saberi, B and Schmitt-John, T and Theiss, C}, title = {Inflammation and neuronal death in the motor cortex of the wobbler mouse, an ALS animal model.}, journal = {Journal of neuroinflammation}, volume = {12}, number = {}, pages = {215}, pmid = {26597538}, issn = {1742-2094}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Cell Death/physiology ; *Disease Models, Animal ; Inflammation/metabolism/pathology ; *Inflammation Mediators/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/metabolism/pathology ; Motor Cortex/metabolism/*pathology ; Neurons/metabolism/*pathology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder of the upper and lower motor neurons, characterized by rapid progressive weakness, muscle atrophy, dysarthria, dysphagia, and dyspnea. Whereas the exact cause of ALS remains uncertain, the wobbler mouse (phenotype WR; genotype wr/wr) equally develops a progressive degeneration of motor neurons in the spinal cord and motor cortex with striking similarities to sporadic human ALS, suggesting the possibility of a common pathway to cell death.<br><br>METHODS: With the aid of immunohistochemistry, confocal laser scanning microscopy, and transmission electron microscopy techniques, we analyze the proliferation behavior of microglial cells and astrocytes. We also investigate possible motor neuron death in the mouse motor cortex at different stages of the wobbler disease, which so far has not received much attention.<br><br>RESULTS: An abnormal density of Iba-1-positive microglial cells expressing pro-inflammatory tumor necrosis factor (TNF) alpha- and glial fibrillary acidic protein (GFAP)-positive activated astroglial cells was detected in the motor cortex region of the WR mouse 40&#xa0;days postnatal (d.p.n.). Motor neurons in the same area show caspase 3 activation indicating neurodegenerative processes, which may cause progressive paralysis of the WR mice. It could also cause cell degeneration, such as vacuolization, dilation of the ER, and swollen mitochondria at the same time, and support the assumption that inflammation might be an important contributing factor of motor neuron degeneration. This would appear to be confirmed by the fact that there was no conspicuous increase of microglial cells and astrocytes in the motor cortex of control mice at any time.<br><br>CONCLUSIONS: Activated microglial cells secrete a variety of pro-inflammatory and neurotoxic factors, such as TNF alpha, which could initiate apoptotic processes in the affected wobbler motor neurons, as reflected by caspase 3 activation, and thus, the neuroinflammatory processes might influence or exacerbate the neurodegeneration. Although it remains to be clarified whether the immune response is primary or secondary and how harmful or beneficial it is in the WR motor neuron disease, anti-inflammatory treatment might be considered.}, }
@article {pmid26594318, year = {2015}, author = {Mao, Z and Zhang, S and Chen, H}, title = {Stem cell therapy for amyotrophic lateral sclerosis.}, journal = {Cell regeneration (London, England)}, volume = {4}, number = {}, pages = {11}, pmid = {26594318}, issn = {2045-9769}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of motor neurons. Currently, no effective therapy is available to treat ALS, except for Riluzole, which has only limited clinical benefits. Stem-cell-based therapy has been intensively and extensively studied as a potential novel treatment strategy for ALS and has been shown to be effective, at least to some extent. In this article, we will review the current state of research on the use of stem cell therapy in the treatment of ALS and discuss the most promising stem cells for the treatment of ALS.}, }
@article {pmid26586020, year = {2015}, author = {Fontanilla, CV and Gu, H and Liu, Q and Zhu, TZ and Zhou, C and Johnstone, BH and March, KL and Pascuzzi, RM and Farlow, MR and Du, Y}, title = {Adipose-derived Stem Cell Conditioned Media Extends Survival time of a mouse model of Amyotrophic Lateral Sclerosis.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {16953}, pmid = {26586020}, issn = {2045-2322}, support = {UL1 TR001108/TR/NCATS NIH HHS/United States ; }, mesh = {Adipose Tissue/*cytology ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/pathology ; Animals ; Astrocytes/metabolism/pathology ; Blotting, Western ; CD11b Antigen/metabolism ; Culture Media, Conditioned/*pharmacology ; *Disease Models, Animal ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Immunohistochemistry ; Mice, Transgenic ; Microglia/metabolism/pathology ; Motor Neurons/metabolism/pathology ; Phosphorylation/drug effects ; Point Mutation ; Spectrin/metabolism ; Spinal Cord/drug effects/metabolism/pathology ; Stem Cells/*physiology ; Superoxide Dismutase/genetics/metabolism ; Survival Analysis ; Time Factors ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Adipose stromal cells (ASC) secrete various trophic factors that assist in the protection of neurons in a variety of neuronal death models. In this study, we tested the effects of human ASC conditional medium (ASC-CM) in human amyotrophic lateral sclerosis (ALS) transgenic mouse model expressing mutant superoxide dismutase (SOD1(G93A)). Treating symptomatic SOD1(G93A) mice with ASC-CM significantly increased post-onset survival time and lifespan. Moreover, SOD1(G93A) mice given ASC-CM treatment showed high motor neuron counts, less activation of microglia and astrocytes at an early symptomatic stage in the spinal cords under immunohistochemical analysis. SOD1(G93A) mice treated with ASC-CM for 7 days showed reduced levels of phosphorylated p38 (pp38) in the spinal cord, a mitogen-activated protein kinase that is involved in both inflammation and neuronal death. Additionally, the levels of α-II spectrin in spinal cords were also inhibited in SOD1(G93A) mice treated with ASC-CM for 3 days. Interestingly, nerve growth factor (NGF), a neurotrophic factor found in ASC-CM, played a significant role in the protection of neurodegeneration inSOD1(G93A) mouse. These results indicate that ASC-CM has the potential to develop into a novel and effective therapeutic treatment for ALS.}, }
@article {pmid26581376, year = {2016}, author = {Golko-Perez, S and Mandel, S and Amit, T and Kupershmidt, L and Youdim, MB and Weinreb, O}, title = {Additive Neuroprotective Effects of the Multifunctional Iron Chelator M30 with Enriched Diet in a Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Neurotoxicity research}, volume = {29}, number = {2}, pages = {208-217}, pmid = {26581376}, issn = {1476-3524}, mesh = {3,4-Dihydroxyphenylacetic Acid/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology/*prevention &amp; control ; Animals ; Biogenic Monoamines/metabolism ; Corpus Striatum/drug effects/metabolism ; *Diet ; Disease Models, Animal ; Hydroxyquinolines/*administration &amp; dosage ; Iron Chelating Agents/*administration &amp; dosage ; Male ; Mice ; Mice, Transgenic ; Monoamine Oxidase/metabolism ; Monoamine Oxidase Inhibitors/*administration &amp; dosage ; Motor Activity/drug effects ; Neuroprotective Agents/*administration &amp; dosage ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Phenylacetates/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Survival Analysis ; Transcription Factors/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motoneuron system, involving various abnormalities, such as mitochondrial dysfunction, oxidative stress, transitional metal accumulation, neuroinflammation, glutamate excitotoxicity, apoptosis, decreased supply of trophic factors, cytoskeletal abnormalities, and extracellular superoxide dismutase (SOD)-1 toxicity. These multiple disease etiologies implicated in ALS gave rise to the perception that future therapeutic approaches for the disease should be aimed at targeting multiple pathological pathways. In line with this view, we have evaluated in the current study the therapeutic effects of low doses of the novel multifunctional monoamine oxidase (MAO) inhibitor/iron-chelating compound, M30 in combination with high Calorie Energy supplemented Diet (CED) in the SOD1-G93A transgenic mouse model of ALS. Our results demonstrated that the combined administration of M30 with CED produced additive neuroprotective effects on motor performance and increased survival of SOD1-G93A mice. We also found that both M30 and M30/CED regimens caused a significant inhibition of MAO-A and -B activities and decreased the turnover of dopamine in the brain of SOD1-G93A mice. In addition, M30/CED combined treatment resulted in a significant increase in mRNA expression levels of various mitochondrial biogenesis and metabolism regulators, such as peroxisome proliferator-activated receptor-γ (PPARγ)-co activator 1 alpha (PGC-1α), PPARγ, uncoupling protein 1, and insulin receptor in the gastrocnemius muscle of SOD1-G93A mice. These results suggest that a combination of drug/agents with different, but complementary mechanisms may be beneficial in the treatment of ALS.}, }
@article {pmid26580997, year = {2015}, author = {DeVincenzo, JP and McClure, MW and Symons, JA and Fathi, H and Westland, C and Chanda, S and Lambkin-Williams, R and Smith, P and Zhang, Q and Beigelman, L and Blatt, LM and Fry, J}, title = {Activity of Oral ALS-008176 in a Respiratory Syncytial Virus Challenge Study.}, journal = {The New England journal of medicine}, volume = {373}, number = {21}, pages = {2048-2058}, doi = {10.1056/NEJMoa1413275}, pmid = {26580997}, issn = {1533-4406}, mesh = {Administration, Oral ; Adolescent ; Adult ; Antiviral Agents/*administration &amp; dosage/adverse effects/pharmacokinetics ; Area Under Curve ; Deoxycytidine/administration &amp; dosage/adverse effects/*analogs &amp; derivatives/pharmacokinetics ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Mucus ; Respiratory Syncytial Virus Infections/*drug therapy/virology ; *Respiratory Syncytial Viruses/isolation &amp; purification/physiology ; Viral Load/drug effects ; Virus Replication/drug effects ; Young Adult ; }, abstract = {BACKGROUND Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality. There is no known effective therapy. METHODS We conducted a randomized, double-blind, clinical trial in healthy adults inoculated with RSV. Participants received the oral nucleoside analogue ALS-008176 or placebo 12 hours after confirmation of RSV infection or 6 days after inoculation. Treatment was administered every 12 hours for 5 days. Viral load, disease severity, resistance, and safety were measured throughout the 28-day study period, with measurement beginning before inoculation. The primary end point was the area under the curve (AUC) for viral load, which was assessed immediately before administration of the first dose through the 12th day after inoculation in participants infected with RSV. RESULTS A total of 62 participants received placebo or one of three ALS-008176 dosing regimens: 1 loading dose of 750 mg followed by 9 maintenance doses of 500 mg (group 1), 1 loading dose of 750 mg followed by 9 maintenance doses of 150 mg (group 2), or 10 doses of 375 mg (group 3). In the 35 infected participants (23 of whom were treated with ALS-008176), the AUCs for viral load for groups 1, 2, and 3 and the placebo group were 59.9, 73.7, 133.4, and 500.9 log10 plaque-forming-unit equivalents × hours per milliliter, respectively (P≤0.001). The time to nondetectability on polymerase-chain-reaction assay (P<0.001), the peak viral load (P≤0.001), the AUC for symptom score (P<0.05), and the AUC for mucus weight were lower in all groups receiving ALS-008176 than in the placebo group. Antiviral activity was greatest in the two groups that received a loading dose--viral clearance was accelerated (P≤0.05), and the AUC for viral load decreased by 85 to 88% as compared with the placebo group. Within this small trial, no viral rebound or resistance was identified. There were no serious adverse events, and there was no need for premature discontinuation of the study drug. CONCLUSIONS In this RSV challenge study, more rapid RSV clearance and a greater reduction of viral load, with accompanying improvements in the severity of clinical disease, were observed in the groups treated with ALS-008176 than in the placebo group. (Funded by Alios BioPharma; ClinicalTrials.gov number, NCT02094365.).}, }
@article {pmid26579223, year = {2015}, author = {Ni, Z and Chen, R}, title = {Transcranial magnetic stimulation to understand pathophysiology and as potential treatment for neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {4}, number = {}, pages = {22}, pmid = {26579223}, issn = {2047-9158}, abstract = {Common neurodegenerative diseases include Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Transcranial magnetic stimulation (TMS) is a noninvasive and painless method to stimulate the human brain. Single- and paired-pulse TMS paradigms are powerful ways to study the pathophysiological mechanisms of neurodegenerative diseases. Motor evoked potential studied with single-pulse TMS is increased in PD, AD and ALS, but is decreased in HD. Changes in motor cortical excitability in neurodegenerative diseases may be related to functional deficits in cortical circuits or to compensatory mechanisms. Reduction or even absence of short interval intracortical inhibition induced by paired-pulse TMS is common in neurodegenerative diseases, suggesting that there are functional impairments of inhibitory cortical circuits. Decreased short latency afferent inhibition in AD, PD and HD may be related to the cortical cholinergic deficits in these conditions. Cortical plasticity tested by paired associative stimulation or theta burst stimulation is impaired in PD, AD and HD. Repetitive TMS (rTMS) refers to the application of trains of regularly repeating TMS pulses. High-frequency facilitatory rTMS may improve motor symptoms in PD patients whereas low-frequency inhibitory stimulation is a potential treatment for levodopa induced dyskinesia. rTMS delivered both to the left and right dorsolateral prefrontal cortex improves memory in AD patients. Supplementary motor cortical stimulation in low frequency may be useful for HD patients. However, the effects of treatment with multiple sessions of rTMS for neurodegenerative diseases need to be tested in large, sham-controlled studies in the future before they can be adopted for routine clinical practice.}, }
@article {pmid26578880, year = {2015}, author = {Radford, RA and Morsch, M and Rayner, SL and Cole, NJ and Pountney, DL and Chung, RS}, title = {The established and emerging roles of astrocytes and microglia in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {414}, pmid = {26578880}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two progressive, fatal neurodegenerative syndromes with considerable clinical, genetic and pathological overlap. Clinical symptoms of FTD can be seen in ALS patients and vice versa. Recent genetic discoveries conclusively link the two diseases, and several common molecular players have been identified (TDP-43, FUS, C9ORF72). The definitive etiologies of ALS and FTD are currently unknown and both disorders lack a cure. Glia, specifically astrocytes and microglia are heavily implicated in the onset and progression of neurodegeneration witnessed in ALS and FTD. In this review, we summarize the current understanding of the role of microglia and astrocytes involved in ALS and FTD, highlighting their recent implications in neuroinflammation, alterations in waste clearance involving phagocytosis and the newly described glymphatic system, and vascular abnormalities. Elucidating the precise mechanisms of how astrocytes and microglia are involved in ALS and FTD will be crucial in characterizing these two disorders and may represent more effective interventions for disease progression and treatment options in the future.}, }
@article {pmid26559613, year = {2016}, author = {Main, BJ and Dunlop, RA and Rodgers, KJ}, title = {The use of L-serine to prevent β-methylamino-L-alanine (BMAA)-induced proteotoxic stress in vitro.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {109}, number = {}, pages = {7-12}, doi = {10.1016/j.toxicon.2015.11.003}, pmid = {26559613}, issn = {1879-3150}, mesh = {Amino Acids, Diamino/*toxicity ; Cathepsin B/metabolism ; Cell Line, Tumor ; Cyanobacteria Toxins ; Humans ; In Vitro Techniques ; Serine/*pharmacology ; }, abstract = {β-methylamino-L-alanine (BMAA), a non-protein amino acid synthesised by cyanobacteria, has been linked to a complex neurological disorder on Guam and more recently to other cases of sporadic ALS (sALS), however the mechanisms of BMAA toxicity are not completely understood. We have previously demonstrated that BMAA is misincorporated into newly synthesised proteins by human neuroblastoma cells and fibroblasts, resulting in the formation of autofluorescent material and the induction of apoptotic cell death. In the present study we show that BMAA at low levels does not cause an acute toxicity in neuroblastoma cells but increases the expression of the ER stress marker, C/EBP homologous protein (CHOP) and increases the activity of the pro-apoptotic enzyme caspase-3. We also observed an increase in the activity of the lysosomal cysteine proteases cathepsin B and L, characteristic of the accumulation of proteins in the lysosomal system. We were able to prevent these proteotoxic effects in neuroblastoma cells through co-treatment with l-serine suggesting that they resulted from incorporation of BMAA into proteins. Misincorporation provides a possible mechanism whereby BMAA could initiate misfolding, and the accumulation of aggregate-prone proteins in neurons. This build-up of misfolded proteins could explain the long latency period of the disease previously reported on Guam.}, }
@article {pmid26558293, year = {2016}, author = {Mazzini, L and Vescovi, A and Cantello, R and Gelati, M and Vercelli, A}, title = {Stem cells therapy for ALS.}, journal = {Expert opinion on biological therapy}, volume = {16}, number = {2}, pages = {187-199}, doi = {10.1517/14712598.2016.1116516}, pmid = {26558293}, issn = {1744-7682}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*metabolism/*therapy ; Animals ; Clinical Trials as Topic/methods ; Genetic Therapy/methods/trends ; Humans ; Inflammation Mediators/antagonists &amp; inhibitors/metabolism ; Neural Stem Cells/transplantation ; Quality of Life ; Stem Cell Transplantation/*methods/trends ; }, abstract = {INTRODUCTION: Despite knowledge on the molecular basis of amyotrophic lateral sclerosis (ALS) having quickly progressed over the last few years, such discoveries have not yet translated into new therapeutics. With the advancement of stem cell technologies there is hope for stem cell therapeutics as novel treatments for ALS.<br><br>AREAS COVERED: We discuss in detail the therapeutic potential of different types of stem cells in preclinical and clinical works. Moreover, we address many open questions in clinical translation.<br><br>EXPERT OPINION: SC therapy is a potentially promising new treatment for ALS and the need to better understand how to develop cell-based experimental treatments, and how to implement them in clinical trials, becomes more pressing. Mesenchymal stem cells and neural fetal stem cells have emerged as safe and potentially effective cell types, but there is a need to carry out appropriately designed experimental studies to verify their long-term safety and possibly efficacy. Moreover, the cost-benefit analysis of the results must take into account the quality of life of the patients as a major end point. It is our opinion that a multicenter international clinical program aime d at fine-tuning and coordinating transplantation procedures and protocols is mandatory.}, }
@article {pmid26547696, year = {2016}, author = {Pols, J and Limburg, S}, title = {A Matter of Taste? Quality of Life in Day-to-Day Living with ALS and a Feeding Tube.}, journal = {Culture, medicine and psychiatry}, volume = {40}, number = {3}, pages = {361-382}, pmid = {26547696}, issn = {1573-076X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*psychology/therapy ; Enteral Nutrition/*psychology ; Humans ; Netherlands ; Quality of Life/*psychology ; }, abstract = {Although people often refer to quality of life and there is a respectable research tradition to establish it, the meaning of the term is unclear. In this article we qualitatively study an intervention of which the quantitative effects are documented as indecisive. We do this in order to learn more about what the meaning of the term quality of life means when it is studied in daily life. With the help of these findings we reflect on the intricacies of objectifying and measuring quality of life using quantitative research designs. Our case is the feeding tube for patients suffering from ALS, a severe motor neuron disease that rapidly and progressively incapacitates patients. We studied how these patients, who lived in the Netherlands, anticipated and lived with a feeding tube in the course of their physical deterioration. Our analysis shows that the quality of life related to the feeding tube has to be understood as a process rather than as an outcome. The feeding tube becomes a different thing as patients move through the various phases of their illness, due to changes in their condition, living circumstances, and concerns and values. There are very different appreciations of the way the feeding tube changes the body's appearance and feel. Some patients refuse it because they feel it disfigures their body, whereas others are indifferent to its appearance. Our conclusion is that these differences are difficult to grasp with a quantitative study designs because 'matters of taste' and values are not distributed in a population in the same ways as physiological responses to medication. Effect studies assume physiological responses to be more or less the same for everyone, with only gradual differences. Our analysis of quality in daily life, however, shows that what a treatment comes to be and how it is valued shows shows generalities for subgroups rather than populations.}, }
@article {pmid26537817, year = {2016}, author = {Zhang, Y and Li, H and Yang, C and Fan, DF and Guo, DZ and Hu, HJ and Meng, XE and Pan, SY}, title = {Treatment with Hydrogen-Rich Saline Delays Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Neurochemical research}, volume = {41}, number = {4}, pages = {770-778}, pmid = {26537817}, issn = {1573-6903}, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology/*prevention &amp; control ; Animals ; Apoptosis ; Humans ; Hydrogen/*therapeutic use ; Mice, Transgenic ; Mitochondria/physiology ; Motor Neurons/pathology ; Neuroglia/pathology ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress ; Sodium Chloride/*therapeutic use ; Spinal Cord/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease, and accumulating evidence indicates that oxidative mechanisms contribute to ALS pathology, but classical antioxidants have not performed well in clinical trials. The aim of this work was to investigate the effect of treatment with hydrogen molecule on the development of disease in mutant SOD1 G93A transgenic mouse model of ALS. Treatment of mutant SOD1 G93A mice with hydrogen-rich saline (HRS, i.p.) significantly delayed disease onset and prolonged survival, and attenuated loss of motor neurons and suppressed microglial and glial activation. Treatment of mutant SOD1 G93A mice with HRS inhibited the release of mitochondrial apoptogenic factors and the subsequent activation of downstream caspase-3. Furthermore, treatment of mutant SOD1 G93A mice with HRS reduced levels of protein carbonyl and 3-nitrotyrosine, and suppressed formation of reactive oxygen species (ROS), peroxynitrite, and malondialdehyde. Treatment of mutant SOD1 G93A mice with HRS preserved mitochondrial function, marked by restored activities of Complex I and IV, reduced mitochondrial ROS formation and enhanced mitochondrial adenosine triphosphate synthesis. In conclusion, hydrogen molecule may be neuroprotective against ALS, possibly through abating oxidative and nitrosative stress and preserving mitochondrial function.}, }
@article {pmid26521126, year = {2015}, author = {Picher-Martel, V and Dutta, K and Phaneuf, D and Sobue, G and Julien, JP}, title = {Ubiquilin-2 drives NF-κB activity and cytosolic TDP-43 aggregation in neuronal cells.}, journal = {Molecular brain}, volume = {8}, number = {1}, pages = {71}, pmid = {26521126}, issn = {1756-6606}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Adaptor Proteins, Signal Transducing ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Autophagy-Related Proteins ; Cell Cycle Proteins/*metabolism ; Cell Death ; Cytosol/*metabolism ; DNA-Binding Proteins/chemistry/*metabolism ; Endoplasmic Reticulum Stress ; Humans ; I-kappa B Proteins/metabolism ; Inclusion Bodies/metabolism ; MAP Kinase Signaling System ; Mice ; NF-KappaB Inhibitor alpha ; NF-kappa B/*metabolism ; Neurons/*metabolism ; *Protein Aggregates ; RNA, Small Interfering/metabolism ; Stress, Physiological ; Transcription Factor RelA/metabolism ; Ubiquitins/*metabolism ; Up-Regulation ; }, abstract = {BACKGROUND: Mutations in the gene encoding Ubiquilin-2 (UBQLN2) are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). UBQLN2 plays a central role in ubiquitin proteasome system (UPS) and UBQLN2 mutants can form cytoplasmic aggregates in vitro and in vivo.<br><br>RESULTS: Here, we report that overexpression of WT or mutant UBQLN2 species enhanced nuclear factor &#x3ba;B (NF-&#x3ba;B) activation in Neuro2A cells. The inhibition of NF-&#x3ba;B stress-mediated activation with SB203580, a p38 MAPK inhibitor, demonstrated a role for MAPK in NF-&#x3ba;B activation by UBQLN2 species. Live cell imaging and microscopy showed that UBQLN2 aggregates are dynamic structures that promote cytoplasmic accumulation of TAR DNA-binding protein (TDP-43), a major component of ALS inclusion bodies. Furthermore, up-regulation of UBQLN2 species in neurons caused an ER-stress response and increased their vulnerability to death by toxic mediator TNF-&#x3b1;. Withaferin A, a known NF-&#x3ba;B inhibitor, reduced mortality of Neuro2A cells overexpressing UBQLN2 species.<br><br>CONCLUSIONS: These results suggest that UBQLN2 dysregulation in neurons can drive NF-&#x3ba;B activation and cytosolic TDP-43 aggregation, supporting the concept of pathway convergence in ALS pathogenesis. These Ubiquilin-2 pathogenic pathways might represent suitable therapeutic targets for future ALS treatment.}, }
@article {pmid26515630, year = {2015}, author = {Katz, JS and Barohn, RJ and Dimachkie, MM and Mitsumoto, H}, title = {The Dilemma of the Clinical Trialist in Amyotrophic Lateral Sclerosis: The Hurdles to Finding a Cure.}, journal = {Neurologic clinics}, volume = {33}, number = {4}, pages = {937-947}, doi = {10.1016/j.ncl.2015.07.014}, pmid = {26515630}, issn = {1557-9875}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; *Clinical Trials as Topic/methods ; Humans ; Research Personnel/*psychology ; }, abstract = {Amyotrophic lateral sclerosis can be described as a disease with a poorly understood pathophysiologic mechanism and no treatment that dramatically impacts the course of the disease. Clinical trialists are faced with finding small treatment effects against a background of multiple potential treatments, a past history of failed trials, and heterogenous clinical outcomes. This article summarizes this environment and provides a rationale for drug development going forward.}, }
@article {pmid26515628, year = {2015}, author = {Jackson, CE and McVey, AL and Rudnicki, S and Dimachkie, MM and Barohn, RJ}, title = {Symptom Management and End-of-Life Care in Amyotrophic Lateral Sclerosis.}, journal = {Neurologic clinics}, volume = {33}, number = {4}, pages = {889-908}, pmid = {26515628}, issn = {1557-9875}, support = {UL1 TR000001/TR/NCATS NIH HHS/United States ; UL1TR000001/TR/NCATS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/complications/*nursing/*therapy ; *Disease Management ; Humans ; Terminal Care ; }, abstract = {The number of available symptomatic treatments has markedly enhanced the care of patients with amyotrophic lateral sclerosis (ALS). Once thought to be untreatable, patients with ALS today clearly benefit from multidisciplinary care. The impact of such care on the disease course, including rate of progression and mortality, has surpassed the treatment effects commonly sought in clinical drug trials. Unfortunately, there are few randomized controlled trials of medications or interventions addressing symptom management. In this review, the authors provide the level of evidence, when available, for each intervention that is currently considered standard of care by consensus opinion.}, }
@article {pmid26503157, year = {2016}, author = {Matusica, D and Alfonsi, F and Turner, BJ and Butler, TJ and Shepheard, SR and Rogers, ML and Skeldal, S and Underwood, CK and Mangelsdorf, M and Coulson, EJ}, title = {Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment.}, journal = {Journal of cell science}, volume = {129}, number = {3}, pages = {517-530}, doi = {10.1242/jcs.173864}, pmid = {26503157}, issn = {1477-9137}, mesh = {Animals ; Apoptosis/physiology ; Brain-Derived Neurotrophic Factor/metabolism ; Cell Death/*physiology ; Cell Survival/physiology ; Cell-Penetrating Peptides/*metabolism ; Cells, Cultured ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/*metabolism ; Receptor, Nerve Growth Factor/*metabolism ; Signal Transduction/physiology ; Spinal Cord/metabolism/physiology ; Superoxide Dismutase/metabolism ; }, abstract = {The p75 neurotrophin receptor (p75(NTR); also known as NGFR) can mediate neuronal apoptosis in disease or following trauma, and facilitate survival through interactions with Trk receptors. Here we tested the ability of a p75(NTR)-derived trophic cell-permeable peptide, c29, to inhibit p75(NTR)-mediated motor neuron death. Acute c29 application to axotomized motor neuron axons decreased cell death, and systemic c29 treatment of SOD1(G93A) mice, a common model of amyotrophic lateral sclerosis, resulted in increased spinal motor neuron survival mid-disease as well as delayed disease onset. Coincident with this, c29 treatment of these mice reduced the production of p75(NTR) cleavage products. Although c29 treatment inhibited mature- and pro-nerve-growth-factor-induced death of cultured motor neurons, and these ligands induced the cleavage of p75(NTR) in motor-neuron-like NSC-34 cells, there was no direct effect of c29 on p75(NTR) cleavage. Rather, c29 promoted motor neuron survival in vitro by enhancing the activation of TrkB-dependent signaling pathways, provided that low levels of brain-derived neurotrophic factor (BDNF) were present, an effect that was replicated in vivo in SOD1(G93A) mice. We conclude that the c29 peptide facilitates BDNF-dependent survival of motor neurons in vitro and in vivo.}, }
@article {pmid26503070, year = {2015}, author = {Ritz, L and Lannuzel, C and Boudehent, C and Vabret, F and Bordas, N and Segobin, S and Eustache, F and Pitel, AL and Beaunieux, H}, title = {Validation of a brief screening tool for alcohol-related neuropsychological impairments.}, journal = {Alcoholism, clinical and experimental research}, volume = {39}, number = {11}, pages = {2249-2260}, doi = {10.1111/acer.12888}, pmid = {26503070}, issn = {1530-0277}, mesh = {Adult ; Alcoholism/*diagnosis/epidemiology/*psychology ; Cognition Disorders/*diagnosis/epidemiology/*psychology ; Female ; Humans ; Male ; Middle Aged ; Neuropsychological Tests/*standards ; }, abstract = {BACKGROUND: Alcohol-related neuropsychological impairments mainly affect episodic memory, working memory, and visuospatial abilities, as well as executive and motor functioning. These impairments can prevent alcoholic patients (ALs) early in abstinence from benefiting fully from treatment and reduce their ability to remain abstinent. A neuropsychological assessment seems essential for making the relevant clinical decisions. However, very few alcohol treatment departments have the financial and human resources needed to conduct an extensive neuropsychological examination of each AL. The goal of this study was therefore to assess the validity and the psychometric properties of the Brief Evaluation of Alcohol-Related Neuropsychological Impairments (BEARNI), a new screening tool especially designed to assess alcohol-related neuropsychological impairments.<br><br>METHODS: A total of 254 healthy controls (HCs) completed the BEARNI, and 58 of them also performed an extensive neuropsychological battery. Seventy-three ALs underwent both the BEARNI and the neuropsychological battery. This extensive neuropsychological battery of proven classification accuracy served as the reference (i.e., gold standard) for determining the ALs' cognitive status.<br><br>RESULTS: An exploratory factor analysis validated the BEARNI's underlying structure, highlighting 5 factors that reflected visuospatial abilities, executive functions, ataxia, verbal episodic memory, and verbal working memory. The standardization of each BEARNI subtest and the 2 total scores revealed that this test has sufficient diagnostic accuracy for the detection of ALs with cognitive and motor impairments.<br><br>CONCLUSIONS: This study indicates that the BEARNI is a useful screening tool in clinical settings for detecting ALs' motor and cognitive impairments.}, }
@article {pmid26503013, year = {2016}, author = {Kotelis, D and Bischoff, MS and Rengier, F and Ruhparwar, A and Gorenflo, M and Böckler, D}, title = {Endovascular repair of pseudoaneurysms after open surgery for aortic coarctation.}, journal = {Interactive cardiovascular and thoracic surgery}, volume = {22}, number = {1}, pages = {26-31}, doi = {10.1093/icvts/ivv297}, pmid = {26503013}, issn = {1569-9285}, mesh = {Adolescent ; Adult ; Aged ; Aneurysm, False/diagnosis/etiology/*surgery ; Aortic Aneurysm, Thoracic/diagnosis/etiology/*surgery ; Aortic Coarctation/*surgery ; Blood Vessel Prosthesis Implantation/*adverse effects ; Child ; Child, Preschool ; Endovascular Procedures/*methods ; Female ; Humans ; Male ; Middle Aged ; Postoperative Complications/diagnosis/etiology/*surgery ; Reoperation ; Retrospective Studies ; Time Factors ; Treatment Outcome ; Young Adult ; }, abstract = {OBJECTIVES: To analyse early and long-term results of thoracic endovascular aortic repair (TEVAR) in patients with pseudoaneurysms after open aortic coarctation (CoA) repair.<br><br>METHODS: A total of 11 patients of 418 patients who had been treated with TEVAR during the period from January 1998 to April 2015 (8 males; median age 53 years) were retrospectively analysed. Dacron patch aortoplasty was primarily performed in 9 patients and subclavian flap aortoplasty in 2 patients. Seven of the 11 patients had asymptomatic pseudoaneurysms (median diameter 56 mm, range 20-65 mm) diagnosed by routine screening. Symptomatic patients presented with haemoptysis, lower limb ischaemia, haemodynamic collapse and back pain and underwent emergency repair (4/11). Adjunctive procedures at the proximal landing zone were required in 7/11 patients. The median number of implanted endoprostheses per patient was 1 (range: 1-5). The median follow-up was 60 months (range 6-161 months).<br><br>RESULTS: Technical success was achieved in 91% (10/11; 1 secondary elective open conversion). The 30-day mortality was 0%. The stroke rate was 18% (2 non-disabling strokes). In 2 patients (20%), stent-graft displacement during deployment was observed. The reintervention rate was 33% (Type Ib endoleak, left arm claudication, partial coverage of the left common carotid artery). Clinical success during follow-up was achieved in 10/11 patients. In 9/10 patients, aneurysm sac shrinkage was observed. The Type II endoleak rate was 10% (1/10; intercostal artery). The overall mortality rate was 9% (1 patient died of amyotrophic lateral sclerosis).<br><br>CONCLUSIONS: Endovascular treatment of post-coarctation pseudoaneurysms is feasible in elective and emergency cases, yielding durable results in the long term. Due to anatomical specifics, implantation may be challenging and requires careful procedural planning. On-site cardiothoracic surgery backup is essential in case open conversion is required.}, }
@article {pmid26500495, year = {2015}, author = {Bukharaeva, E and Shakirzyanova, A and Khuzakhmetova, V and Sitdikova, G and Giniatullin, R}, title = {Homocysteine aggravates ROS-induced depression of transmitter release from motor nerve terminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {391}, pmid = {26500495}, issn = {1662-5102}, abstract = {Homocysteine (HCY) is a pro-inflammatory sulphur-containing redox active endogenous amino acid, which concentration increases in neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). A widely held view suggests that HCY could contribute to neurodegeneration via promotion of oxidative stress. However, the action of HCY on motor nerve terminals has not been investigated so far. We previously reported that oxidative stress inhibited synaptic transmission at the neuromuscular junction, targeting primarily the motor nerve terminals. In the current study, we investigated the effect of HCY on oxidative stress-induced impairment of transmitter release at the mouse diaphragm muscle. The mild oxidant H2O2 decreased the intensity of spontaneous quantum release from nerve terminals (measured as the frequency of miniature endplate potentials, MEPPs) without changes in the amplitude of MEPPs, indicating a presynaptic effect. Pre-treatment with HCY for 2 h only slightly affected both amplitude and frequency of MEPPs but increased the inhibitory potency of H2O2 almost two fold. As HCY can activate certain subtypes of glutamate N-methyl D-aspartate (NMDA) receptors we tested the role of NMDA receptors in the sensitizing action of HCY. Remarkably, the selective blocker of NMDA receptors, AP-5 completely removed the sensitizing effect of HCY on the H2O2-induced presynaptic depressant effect. Thus, at the mammalian neuromuscular junction HCY largely increases the inhibitory effect of oxidative stress on transmitter release, via NMDA receptors activation. This combined effect of HCY and local oxidative stress can specifically contribute to the damage of presynaptic terminals in neurodegenerative motoneuron diseases, including ALS.}, }
@article {pmid26487927, year = {2015}, author = {Orsini, M and Oliveira, AB and Nascimento, OJ and Reis, CH and Leite, MA and de Souza, JA and Pupe, C and de Souza, OG and Bastos, VH and de Freitas, MR and Teixeira, S and Bruno, C and Davidovich, E and Smidt, B}, title = {Amyotrophic Lateral Sclerosis: New Perpectives and Update.}, journal = {Neurology international}, volume = {7}, number = {2}, pages = {5885}, pmid = {26487927}, issn = {2035-8385}, abstract = {Amyotrophic lateral sclerosis (ALS), Charcot's disease or Lou Gehrig's disease, is a term used to cover the spetrum of syndromes caracterized by progressive degeneration of motor neurons, a paralytic disorder caused by motor neuron degeneration. Currently, there are approximately 25,000 patients with ALS in the USA, with an average age of onset of 55 years. The incidence and prevalence of ALS are 1-2 and 4-6 per 100,000 each year, respectively, with a lifetime ALS risk of 1/600 to 1/1000. It causes progressive and cumulative physical disabilities, and leads to eventual death due to respiratory muscle failure. ALS is diverse in its presentation, course, and progression. We do not yet fully understand the causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. In this chapter, we will discuss the diagnosis, treatment, and how to cope with impaired function and end of life based on of our experience, guidelines, and clinical trials. Nowadays ALS seems to be a more complex disease than it did two decades - or even one decade - ago, but new insights have been plentiful. Clinical trials should be seen more as experiments on pathogenic mechanisms. A medication or combination of medications that targets more than one pathogenic pathway may slow disease progression in an additive or synergistic fashion.}, }
@article {pmid26487835, year = {2015}, author = {Chung, JY and Sunwoo, JS and Kim, MW and Kim, M}, title = {The neuroprotective effects of human growth hormone as a potential treatment for amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {10}, number = {8}, pages = {1201-1203}, pmid = {26487835}, issn = {1673-5374}, }
@article {pmid26477027, year = {2016}, author = {Lunetta, C and Lizio, A and Sansone, VA and Cellotto, NM and Maestri, E and Bettinelli, M and Gatti, V and Melazzini, MG and Meola, G and Corbo, M}, title = {Strictly monitored exercise programs reduce motor deterioration in ALS: preliminary results of a randomized controlled trial.}, journal = {Journal of neurology}, volume = {263}, number = {1}, pages = {52-60}, pmid = {26477027}, issn = {1432-1459}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*rehabilitation ; *Disease Progression ; Exercise Therapy/*methods ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; *Outcome Assessment, Health Care ; *Severity of Illness Index ; Single-Blind Method ; }, abstract = {The objective of our study was to perform a randomized controlled trial (RCT) aimed to evaluate the effects of three strictly monitored exercise programs(SMEP) compared to "usual care" (UCP) in a cohort of ALS patients. We included patients with definite and probable ALS and disease duration ≤24 months. Patients were randomized to receive a SMEPs or a UCP. SMEPs included three subgroups of treatment: active exercises associated with cycloergometer activity (1A), only active (1B) and passive (1C) exercises, respectively. Moreover, SMEP patients and their caregivers were trained to a daily home-based passive exercise program. The UCP group was treated with passive and stretching exercises twice weekly. The treatment period for both groups was 6 months (T180), and patients were assessed by revised ALS Functional Rating Scale (ALSFRS-R), % Forced Vital Capacity (FVC %), and McGill Quality of Life (MGQoL) questionnaire. ALSFRS-R score was also evaluated at 6 months after the treatment period (T360). Sixty ALS patients were randomly assigned to one of two arms: SMEP Group included 30 patients, ten subjects for each subgroup (1A, 1B, and 1C); 30 patients were included in the UCP Group.At T180 and T360, SMEPs group had significantly higher ALSFRS-R score compared to the UCP group (32.8 ± 6.5 vs 28.7 ± 7.5, p = 0.0298; 27.5 ± 7.6 vs 23.3 ± 7.6, p = 0.0338, respectively). No effects of SMEPs on survival, respiratory decline and MGQol were found. In conclusion, although no effect on survival was demonstrated,our data suggest that a strictly monitored exercise program may significantly reduce motor deterioration in ALS patients.}, }
@article {pmid26476198, year = {2015}, author = {Kudenchuk, PJ and Stuart, R and Husain, S and Fahrenbruch, C and Eisenberg, M}, title = {Treatment and outcome of out-of-hospital cardiac arrest in outpatient health care facilities.}, journal = {Resuscitation}, volume = {97}, number = {}, pages = {97-102}, doi = {10.1016/j.resuscitation.2015.08.025}, pmid = {26476198}, issn = {1873-1570}, mesh = {Aged ; Ambulatory Care Facilities ; *Cardiopulmonary Resuscitation ; Female ; Humans ; Male ; Middle Aged ; Out-of-Hospital Cardiac Arrest/*therapy ; Retrospective Studies ; Treatment Outcome ; }, abstract = {AIM: We evaluated the frequency and effectiveness of basic and advanced life support (ALS) interventions by medical professionals when out-of-hospital cardiac arrest (OHCA) occurred in ambulatory healthcare clinics before emergency medical services (EMS) arrival.<br><br>METHODS: Non-traumatic OHCAs in adults were systematically characterized over a 15 year period by their occurrence in clinics, at home, or in non-medical public locations, and outcomes compared between matched cohorts from each group.<br><br>RESULTS: Among 7784 patients, 6098 OHCA occurred at home, 1612 in non-medical public locations and 74 in clinics. Compared to non-medical public locations, clinic patients with OHCA were older, more often women and more frequently shocked; clinic arrests were more often witnessed, less likely to be of cardiac cause and to occur before EMS arrival. Compared to home, more clinic arrests were witnessed, occurred after EMS arrival, had bystander CPR, shockable rhythms and were defibrillated. When OHCA occurred before EMS arrival, 51 of 56 clinic patients (91%) received CPR, a defibrillator applied to 23 (41%), 17 (30%) were shocked, 4 (7%) intubated, and 7 (13%) received intravenous medications from facility personnel. Of these, only pre-EMS defibrillator use was associated with improved outcome. Among matched patients, OHCA survival was higher in clinics than at home (42% vs 26%, p=0.029), but comparable to other public locations.<br><br>CONCLUSIONS: Survival from OHCA in clinics was comparable to non-medical public locations, and higher than at home. Alongside CPR, use of defibrillators was associated with improved survival and worth prioritizing over other interventions before EMS arrival regardless of OHCA location.}, }
@article {pmid26473473, year = {2016}, author = {Bacci, ED and Staniewska, D and Coyne, KS and Boyer, S and White, LA and Zach, N and Cedarbaum, JM and , }, title = {Item response theory analysis of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised in the Pooled Resource Open-Access ALS Clinical Trials Database.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {17}, number = {3-4}, pages = {157-167}, doi = {10.3109/21678421.2015.1095930}, pmid = {26473473}, issn = {2167-9223}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; *Clinical Trials as Topic ; Databases, Factual/statistics &amp; numerical data ; Female ; Health Resources/statistics &amp; numerical data ; Humans ; Male ; Middle Aged ; Models, Statistical ; Young Adult ; }, abstract = {Our objective was to examine dimensionality and item-level performance of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) across time using classical and modern test theory approaches. Confirmatory factor analysis (CFA) and Item Response Theory (IRT) analyses were conducted using data from patients with amyotrophic lateral sclerosis (ALS) Pooled Resources Open-Access ALS Clinical Trials (PRO-ACT) database with complete ALSFRS-R data (n = 888) at three time-points (Time 0, Time 1 (6-months), Time 2 (1-year)). Results demonstrated that in this population of 888 patients, mean age was 54.6 years, 64.4% were male, and 93.7% were Caucasian. The CFA supported a 4* individual-domain structure (bulbar, gross motor, fine motor, and respiratory domains). IRT analysis within each domain revealed misfitting items and overlapping item response category thresholds at all time-points, particularly in the gross motor and respiratory domain items. Results indicate that many of the items of the ALSFRS-R may sub-optimally distinguish among varying levels of disability assessed by each domain, particularly in patients with less severe disability. Measure performance improved across time as patient disability severity increased. In conclusion, modifications to select ALSFRS-R items may improve the instrument's specificity to disability level and sensitivity to treatment effects.}, }
@article {pmid26471212, year = {2016}, author = {Doody, RS and D'Amico, S and Cutler, AJ and Davis, CS and Shin, P and Ledon, F and Yonan, C and Siffert, J}, title = {An open-label study to assess safety, tolerability, and effectiveness of dextromethorphan/quinidine for pseudobulbar affect in dementia: PRISM II results.}, journal = {CNS spectrums}, volume = {21}, number = {6}, pages = {450-459}, doi = {10.1017/S1092852915000620}, pmid = {26471212}, issn = {1092-8529}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/complications ; Dementia/*complications ; Dementia, Vascular/complications ; Dextromethorphan/*therapeutic use ; Diarrhea/chemically induced ; Drug Combinations ; Excitatory Amino Acid Antagonists/*therapeutic use ; Female ; Frontotemporal Dementia/complications ; Headache/chemically induced ; Humans ; Lewy Body Disease/complications ; Male ; Middle Aged ; Pseudobulbar Palsy/*drug therapy/etiology ; Quinidine/*therapeutic use ; Urinary Tract Infections/chemically induced ; }, abstract = {BACKGROUND: Dextromethorphan (DM)/quinidine (Q) is an approved treatment for pseudobulbar affect (PBA) based on trials in amyotrophic lateral sclerosis or multiple sclerosis. PRISM II evaluated DM/Q effectiveness and tolerability for PBA secondary to dementia, stroke, or traumatic brain injury; dementia cohort results are reported.<br><br>METHODS: This was an open-label, multicenter, 90 day trial; patients received DM/Q 20/10 mg twice daily. Primary outcome was change in Center for Neurologic Study-Lability Scale (CNS-LS) score. Secondary outcomes included PBA episode count and Clinical and Patient/Caregiver Global Impression of Change scores with respect to PBA (CGI-C/PGI-C).<br><br>RESULTS: 134 patients were treated. CNS-LS improved by a mean (SD) of 7.2 (6.0) points at Day 90/Endpoint (P<.001) vs. baseline. PBA episodes were reduced 67.7% (P<.001) vs. baseline; global measures showed 77.5% CGI-C and 76.5% PGI-C "much"/"very much" improved. Adverse events included headache (7.5%), urinary tract infection (4.5%), and diarrhea (3.7%); few patients dropped out for adverse events (10.4%).<br><br>CONCLUSIONS: DM/Q significantly reduced PBA symptoms in patients with dementia; reported adverse events were consistent with the known safety profile of DM/Q. Trial Registration clinicaltrials.gov identifier: NCT01799941.}, }
@article {pmid26469273, year = {2015}, author = {Ikeda, K and Iwasaki, Y}, title = {Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse.}, journal = {PloS one}, volume = {10}, number = {10}, pages = {e0140316}, pmid = {26469273}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*pathology ; Animals ; Antipyrine/administration &amp; dosage/*analogs &amp; derivatives/pharmacology ; Astrocytes/drug effects ; *Disease Models, Animal ; Disease Progression ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Edaravone ; Free Radical Scavengers/*administration &amp; dosage/pharmacology ; Injections, Intraperitoneal ; Mice ; Muscle Contraction/drug effects ; Muscle Strength/drug effects ; Random Allocation ; }, abstract = {Edaravone, a free radical scavenger is used widely in Japanese patients with acute cerebral infarction. This antioxidant could have therapeutic potentials for other neurological diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the upper and the lower motor neuron, leading to death within 3-5 years after onset. A phase III clinical trial of edaravone suggested no significant effects in ALS patients. However, recent 2nd double-blind trial has demonstrated therapeutic benefits of edaravone in definite patients diagnosed by revised El Escorial diagnostic criteria of ALS. Two previous studies showed that edaravone attenuated motor symptoms or motor neuron degeneration in mutant superoxide dismutase 1-transgenic mice or rats, animal models of familial ALS. Herein we examined whether this radical scavenger can retard progression of motor dysfunction and neuropathological changes in wobbler mice, sporadic ALS-like model. After diagnosis of the disease onset at the postnatal age of 3-4 weeks, wobbler mice received edaravone (1 or 10 mg/kg, n = 10/group) or vehicle (n = 10), daily for 4 weeks by intraperitoneal administration. Motor symptoms and neuropathological changes were compared among three groups. Higher dose (10 mg/kg) of edaravone treatment significantly attenuated muscle weakness and contracture in the forelimbs, and suppressed denervation atrophy in the biceps muscle and degeneration in the cervical motor neurons compared to vehicle. Previous and the present studies indicated neuroprotective effects of edaravone in three rodent ALS-like models. This drug seems to be worth performing the clinical trial in ALS patients in the United States of American and Europe, in addition to Japan.}, }
@article {pmid26461404, year = {2014}, author = {Svetoni, F and Caporossi, D and Paronetto, MP}, title = {Oxidative stress affects FET proteins localization and alternative pre-mRNA processing in cellular models of ALS.}, journal = {Free radical biology &amp; medicine}, volume = {75 Suppl 1}, number = {}, pages = {S51}, doi = {10.1016/j.freeradbiomed.2014.10.820}, pmid = {26461404}, issn = {1873-4596}, abstract = {FUS/TLS, EWS and TAF15 are members of the FET family of DNA and RNA binding proteins, involved in multiple steps of DNA and RNA processing and implicated in the regulation of gene expression and cell-signaling. All members of the FET family contribute to human pathologies, as they are involved in sarcoma translocations and neurodegenerative diseases. Mutations in FUS/TLS, in EWSR1 and in TAF15 genescause Amyotrophic Lateral Sclerosis (ALS), a fatal human neurodegenerative disease that affects primarily motor neurons and is characterized by the progressive loss of motor neurons and degradation of the neuromuscular junctions.ALS-associated FET mutations cause FET protein relocalization into cytoplasmic aggregates, thus impairing their normal function. Protein aggregation has been suggested as a co-opting factor during the disease pathogenesis. Cytoplasmic mislocalization of FET proteins contributes to the formation of cytoplasmic aggregates that may alter RNA processing and initiate motor neuron degeneration. Interestingly, oxidative stress, which is implicated in the pathogenesis of ALS, triggers the accumulation of mutant FUS in cytoplasmic stress granules where it binds and sequester wild-type FUS.In order to evaluate the role of FET proteins in ALS and their involvement in the response to oxidative stress, we have developed cellular models of ALS expressing ALS-related FET mutants in neuroblastoma cell lines. Upon treatment with sodium arsenite, cells were analysed by immunofluorescence to monitor the localization of wild-type and mutated FET proteins. Furthermore, we have characterized signal transduction pathways and cell survival upon oxidative stress in our cellular models of ALS. Interestingly, we found that EWS mutant proteins display a different localization from FUS mutants and neither wild-type nor mutated EWS protein translocate into stress granules upon oxidative stress treatment. Collectively, our data provide a new link between the oxidative stress response and RNA metabolism in ALS disease.}, }
@article {pmid26459114, year = {2016}, author = {Bartus, RT and Bétourné, A and Basile, A and Peterson, BL and Glass, J and Boulis, NM}, title = {β2-Adrenoceptor agonists as novel, safe and potentially effective therapies for Amyotrophic lateral sclerosis (ALS).}, journal = {Neurobiology of disease}, volume = {85}, number = {}, pages = {11-24}, doi = {10.1016/j.nbd.2015.10.006}, pmid = {26459114}, issn = {1095-953X}, mesh = {Administration, Oral ; Adrenergic beta-2 Receptor Agonists/*administration &amp; dosage/adverse effects ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Humans ; Neuroprotective Agents/*administration &amp; dosage/adverse effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic and progressive neuromuscular disease for which no cure exists and better treatment options are desperately needed. We hypothesize that currently approved β2-adrenoceptor agonists may effectively treat the symptoms and possibly slow the progression of ALS. Although β2-agonists are primarily used to treat asthma, pharmacologic data from animal models of neuromuscular diseases suggest that these agents may have pharmacologic effects of benefit in treating ALS. These include inhibiting protein degradation, stimulating protein synthesis, inducing neurotrophic factor synthesis and release, positively modulating microglial and systemic immune function, maintaining the structural and functional integrity of motor endplates, and improving energy metabolism. Moreover, stimulation of β2-adrenoceptors can activate a range of downstream signaling events in many different cell types that could account for the diverse array of effects of these agents. The evidence supporting the possible therapeutic benefits of β2-agonists is briefly reviewed, followed by a more detailed review of clinical trials testing the efficacy of β-agonists in a variety of human neuromuscular maladies. The weight of evidence of the potential benefits from treating these diseases supports the hypothesis that β2-agonists may be efficacious in ALS. Finally, ways to monitor and manage the side effects that may arise with chronic administration of β2-agonists are evaluated. In sum, effective, safe and orally-active β2-agonists may provide a novel and convenient means to reduce the symptoms of ALS and possibly delay disease progression, affording a unique opportunity to repurpose these approved drugs for treating ALS, and rapidly transforming the management of this serious, unmet medical need.}, }
@article {pmid26455662, year = {2016}, author = {de Pedro, N and Cantizani, J and Ortiz-López, FJ and González-Menéndez, V and Cautain, B and Rodríguez, L and Bills, GF and Reyes, F and Genilloud, O and Vicente, F}, title = {Protective effects of isolecanoric acid on neurodegenerative in vitro models.}, journal = {Neuropharmacology}, volume = {101}, number = {}, pages = {538-548}, doi = {10.1016/j.neuropharm.2015.09.029}, pmid = {26455662}, issn = {1873-7064}, mesh = {Amino Acids, Diamino/pharmacology ; Apoptosis/drug effects/genetics ; Cell Line, Transformed ; Cell Survival ; Cyanobacteria Toxins ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Agonists/pharmacology ; Flow Cytometry ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Neuroblastoma/pathology ; Neuroprotective Agents/*pharmacology ; Reactive Oxygen Species/metabolism ; Salicylates/*pharmacology ; }, abstract = {Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS), are neurodegenerative disorders characterized by loss of dopaminergic or motor neurons, respectively. Although understanding of the PD and ALS pathogenesis remains incomplete, increasing evidence from human and animal studies has suggested that aberrant GSK3β, oxidative stress and mitochondrial damage are involved in their pathogenesis. Using two different molecular models, treatment with L-BMAA for ALS and rotenone for PD the effect of isolecanoric acid, a natural product isolated from a fungal culture, was evaluated. Pre-treatment with this molecule caused inhibition of GSK3β and CK1, and a decrease in oxidative stress, mitochondrial damage, apoptosis and cell death. Taken together, these results indicated that isolecanoric acid might have a protective effect against the development of these neurodegenerative disorders.}, }
@article {pmid26454200, year = {2016}, author = {Kramerov, AA and Ljubimov, AV}, title = {Stem cell therapies in the treatment of diabetic retinopathy and keratopathy.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {241}, number = {6}, pages = {559-568}, pmid = {26454200}, issn = {1535-3699}, support = {R01 EY013431/EY/NEI NIH HHS/United States ; R01 EY023429/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Biomedical Research/trends ; Corneal Diseases/*therapy ; Diabetic Retinopathy/*therapy ; Disease Models, Animal ; Humans ; Stem Cell Transplantation/*methods ; }, abstract = {Nonproliferative diabetic retinopathy (DR) is characterized by multiple degenerative changes that could be potentially corrected by stem cell therapies. Most studies so far have attempted to alleviate typical abnormalities of early retinopathy, including vascular hyperpermeability, capillary closure and pericyte dropout. Success was reported with adult stem cells (vascular progenitors or adipose stem cells), as well as induced pluripotent stem cells from cord blood. The cells were able to associate with damaged vessels in both pericyte and endothelial lining positions in models of DR and ischemia-reperfusion. In some diabetic models, functional amelioration of vasculature and electroretinograms was noted. Another approach for endogenous progenitor cell therapy is to normalize dysfunctional diabetic bone marrow and residing endothelial progenitors using NO donors, PPAR-δ and -γ agonists, or inhibition of TGF-β. A potentially important strategy would be to reduce neuropathy by stem cell inoculations, either naïve (e.g., paracrine-acting adipose stem cells) or secreting specific neuroprotectants, such as ciliary neurotrophic factor or brain-derived neurotrophic factor that showed benefit in amyotrophic lateral sclerosis and Parkinson's disease. Recent advances in stem cell therapies for diabetic retinal microangiopathy may form the basis of first clinical trials in the near future. Additionally, stem cell therapies may prove beneficial for diabetic corneal disease (diabetic keratopathy) with pronounced epithelial stem cell dysfunction.}, }
@article {pmid26450877, year = {2017}, author = {Tiirola, A and Korhonen, T and Surakka, T and Lehto, JT}, title = {End-of-Life Care of Patients With Amyotrophic Lateral Sclerosis and Other Nonmalignant Diseases.}, journal = {The American journal of hospice &amp; palliative care}, volume = {34}, number = {2}, pages = {154-159}, doi = {10.1177/1049909115610078}, pmid = {26450877}, issn = {1938-2715}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/pathology/*therapy ; Dyspnea/therapy ; Fatigue/therapy ; Female ; Hospice Care/methods ; Humans ; Male ; Middle Aged ; Noninvasive Ventilation ; Pain Management/methods ; Retrospective Studies ; Terminal Care/*methods ; }, abstract = {BACKGROUND: Palliative care services extend to meet the needs of patients with nonmalignant diseases.<br><br>AIM: To explore the diagnoses, symptoms, and treatment of patients dying in hospice due to nonmalignant diseases, with special emphasis on amyotrophic lateral sclerosis (ALS).<br><br>DESIGN: A retrospective study based on a detailed analysis of patient records.<br><br>SETTING/PARTICIPANTS: All patients with nonmalignant diseases who died in Pirkanmaa Hospice during the period 2004 to 2013 were included.<br><br>RESULTS: Of the 67 patients studied, 48% had ALS, and the remaining had pulmonary (18%), cardiovascular (13%), neurologic (10%), and other (10%) diseases. Dyspnea, followed by pain and fatigue, was the most common symptom reported, increasing in frequency from admission to the last day of life (31% vs 48%; P < .05). Compared with ALS, patients with other diseases had more comorbidities (3.8% vs 1.4%, P < .001) and were more likely to have very short (&#x2264;3 days) final care periods (31% vs 9%; P < .05). During the last day of life, patients with ALS were more frequently unable to swallow (87% vs 31%, P < .001) and received significantly more antidepressants, antibiotics, and laxatives but less corticosteroids and oxygen compared to other patients. Noninvasive ventilation was used in 31% of all patients.<br><br>CONCLUSION: Respiratory symptoms are important in the management of nonmalignant diseases in hospice. Especially, units taking care of ALS should be prepared to meet the special needs involved in ventilation support. In contrast to ALS, late referrals to hospice are common in patients with other nonmalignant diseases.}, }
@article {pmid26446984, year = {2016}, author = {Holm, IE and Alstrup, AK and Luo, Y}, title = {Genetically modified pig models for neurodegenerative disorders.}, journal = {The Journal of pathology}, volume = {238}, number = {2}, pages = {267-287}, doi = {10.1002/path.4654}, pmid = {26446984}, issn = {1096-9896}, mesh = {Animals ; Animals, Genetically Modified/*genetics ; Behavior, Animal ; Brain/anatomy &amp; histology ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; *Disease Models, Animal ; Forecasting ; Humans ; Magnetic Resonance Imaging ; Neurodegenerative Diseases/*genetics ; Nuclear Transfer Techniques ; Positron-Emission Tomography ; Swine/anatomy &amp; histology/*genetics ; Tomography, X-Ray Computed ; }, abstract = {Increasing incidence of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease has become one of the most challenging health issues in ageing humans. One approach to combat this is to generate genetically modified animal models of neurodegenerative disorders for studying pathogenesis, prognosis, diagnosis, treatment, and prevention. Owing to the genetic, anatomic, physiologic, pathologic, and neurologic similarities between pigs and humans, genetically modified pig models of neurodegenerative disorders have been attractive large animal models to bridge the gap of preclinical investigations between rodents and humans. In this review, we provide a neuroanatomical overview in pigs and summarize and discuss the generation of genetically modified pig models of neurodegenerative disorders including Alzheimer's diseases, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, and ataxia-telangiectasia. We also highlight how non-invasive bioimaging technologies such as positron emission tomography (PET), computer tomography (CT), and magnetic resonance imaging (MRI), and behavioural testing have been applied to characterize neurodegenerative pig models. We further propose a multiplex genome editing and preterm recloning (MAP) approach by using the rapid growth of the ground-breaking precision genome editing technology CRISPR/Cas9 and somatic cell nuclear transfer (SCNT). With this approach, we hope to shorten the temporal requirement in generating multiple transgenic pigs, increase the survival rate of founder pigs, and generate genetically modified pigs that will more closely resemble the disease-causing mutations and recapitulate pathological features of human conditions.}, }
@article {pmid26444430, year = {2015}, author = {Correia, AS and Patel, P and Dutta, K and Julien, JP}, title = {Inflammation Induces TDP-43 Mislocalization and Aggregation.}, journal = {PloS one}, volume = {10}, number = {10}, pages = {e0140248}, pmid = {26444430}, issn = {1932-6203}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Astrocytes/immunology/metabolism ; Cells, Cultured ; DNA-Binding Proteins/*analysis/genetics/*immunology ; Gene Expression Regulation ; Humans ; Inflammation/genetics/*immunology ; Lipopolysaccharides/immunology ; Mice ; Mice, Transgenic ; Microglia/immunology/metabolism ; Point Mutation ; *Protein Aggregates ; RNA, Messenger/genetics/immunology ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a major component in aggregates of ubiquitinated proteins in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we report that lipopolysaccharide (LPS)-induced inflammation can promote TDP-43 mislocalization and aggregation. In culture, microglia and astrocytes exhibited TDP-43 mislocalization after exposure to LPS. Likewise, treatment of the motoneuron-like NSC-34 cells with TNF-alpha (TNF-α) increased the cytoplasmic levels of TDP-43. In addition, the chronic intraperitoneal injection of LPS at a dose of 1mg/kg in TDP-43(A315T) transgenic mice exacerbated the pathological TDP-43 accumulation in the cytoplasm of spinal motor neurons and it enhanced the levels of TDP-43 aggregation. These results suggest that inflammation may contribute to development or exacerbation of TDP-43 proteinopathies in neurodegenerative disorders.}, }
@article {pmid26444282, year = {2015}, author = {Maier, A and Deigendesch, N and Müller, K and Weishaupt, JH and Krannich, A and Röhle, R and Meissner, F and Molawi, K and Münch, C and Holm, T and Meyer, R and Meyer, T and Zychlinsky, A}, title = {Interleukin-1 Antagonist Anakinra in Amyotrophic Lateral Sclerosis--A Pilot Study.}, journal = {PloS one}, volume = {10}, number = {10}, pages = {e0139684}, pmid = {26444282}, issn = {1932-6203}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Disease Progression ; Female ; Humans ; Interleukin 1 Receptor Antagonist Protein/*therapeutic use ; Interleukin-1/*antagonists &amp; inhibitors ; Male ; Middle Aged ; Motor Neuron Disease/drug therapy/metabolism ; Musculoskeletal Physiological Phenomena/drug effects ; Pilot Projects ; }, abstract = {UNLABELLED: Preclinical studies show that blocking Interleukin-1 (IL-1) retards the progression of Amyotrophic Lateral Sclerosis (ALS). We assessed the safety of Anakinra (ANA), an IL-1 receptor antagonist, in ALS patients. In a single arm pilot study we treated 17 ALS patients with ANA (100 mg) daily for one year. We selected patients with dominant or exclusive lower motor neuron degeneration (LMND) presentation, as peripheral nerves may be more accessible to the drug. Our primary endpoint was safety and tolerability. Secondary endpoints included measuring disease progression with the revised ALS functional rating scale (ALSFRSr). We also quantified serum inflammatory markers. For comparison, we generated a historical cohort of 47 patients that fit the criteria for enrollment, disease characteristics and rate of progression of the study group. Only mild adverse events occurred in ALS patients treated with ANA. Notably, we observed lower levels of cytokines and the inflammatory marker fibrinogen during the first 24 weeks of treatment. Despite of this, we could not detect a significant reduction in disease progression during the same period in patients treated with ANA compared to controls as measured by the ALSFRSr. In the second part of the treatment period we observed an increase in serum inflammatory markers. Sixteen out of the 17 patients (94%) developed antibodies against ANA. This study showed that blocking IL-1 is safe in patients with ALS. Further trials should test whether targeting IL-1 more efficiently can help treating this devastating disease.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT01277315.}, }
@article {pmid26440825, year = {2015}, author = {Lautenschläger, J and Lautenschläger, C and Tadic, V and Süße, H and Ortmann, W and Denzler, J and Stallmach, A and Witte, OW and Grosskreutz, J}, title = {Novel computer vision algorithm for the reliable analysis of organelle morphology in whole cell 3D images--A pilot study for the quantitative evaluation of mitochondrial fragmentation in amyotrophic lateral sclerosis.}, journal = {Mitochondrion}, volume = {25}, number = {}, pages = {49-59}, doi = {10.1016/j.mito.2015.10.003}, pmid = {26440825}, issn = {1872-8278}, mesh = {*Algorithms ; Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Biometry/*methods ; Disease Models, Animal ; Evaluation Studies as Topic ; Image Processing, Computer-Assisted/*methods ; Imaging, Three-Dimensional/*methods ; Mice, Transgenic ; Mitochondria/*pathology ; Neurons/pathology ; Pilot Projects ; }, abstract = {The function of intact organelles, whether mitochondria, Golgi apparatus or endoplasmic reticulum (ER), relies on their proper morphological organization. It is recognized that disturbances of organelle morphology are early events in disease manifestation, but reliable and quantitative detection of organelle morphology is difficult and time-consuming. Here we present a novel computer vision algorithm for the assessment of organelle morphology in whole cell 3D images. The algorithm allows the numerical and quantitative description of organelle structures, including total number and length of segments, cell and nucleus area/volume as well as novel texture parameters like lacunarity and fractal dimension. Applying the algorithm we performed a pilot study in cultured motor neurons from transgenic G93A hSOD1 mice, a model of human familial amyotrophic lateral sclerosis. In the presence of the mutated SOD1 and upon excitotoxic treatment with kainate we demonstrate a clear fragmentation of the mitochondrial network, with an increase in the number of mitochondrial segments and a reduction in the length of mitochondria. Histogram analyses show a reduced number of tubular mitochondria and an increased number of small mitochondrial segments. The computer vision algorithm for the evaluation of organelle morphology allows an objective assessment of disease-related organelle phenotypes with greatly reduced examiner bias and will aid the evaluation of novel therapeutic strategies on a cellular level.}, }
@article {pmid26440597, year = {2015}, author = {Watanabe, Y and Kazuki, Y and Kazuki, K and Ebiki, M and Nakanishi, M and Nakamura, K and Yoshida Yamakawa, M and Hosokawa, H and Ohbayashi, T and Oshimura, M and Nakashima, K}, title = {Use of a Human Artificial Chromosome for Delivering Trophic Factors in a Rodent Model of Amyotrophic Lateral Sclerosis.}, journal = {Molecular therapy. Nucleic acids}, volume = {4}, number = {10}, pages = {e253}, pmid = {26440597}, issn = {2162-2531}, abstract = {A human artificial chromosome (HAC) is maintained as an episome within a cell and avoids random integration into the host genome. It can transfer multiple and/or large transgenes along with their regulatory elements thereby resembling native chromosomes. Using this HAC system, we established mesenchymal stem cells (MSCs) that simultaneously expressed hepatocyte growth factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor 1, termed HAC-MSCs. This cell line provides an opportunity for stable transplantation and thorough analyses. We then introduced the cells for the treatment of a neurodegenerative disorder, amyotrophic lateral sclerosis. The HAC-MSCs were transplanted via the fourth cerebral ventricle (CV) or intravenous (i.v.) infusion at various ages of recipient mice. Littermate- and sex-matched mice underwent a sham procedure. Compared to the controls, there was an encouraging trend of increased life span via CV transplantation and delayed onset in i.v. infusion 60 days after transplantation. Further, we confirmed a statistically significant increase in life span via CV transplantation at 100 days. This effect was not seen in mice transplanted with MSCs lacking the HAC. We successfully enhanced the trophic potential of the MSCs using the HAC. This strategy could be a promising direction for the treatment of neurodegenerative disorders.}, }
@article {pmid26437251, year = {2015}, author = {Callaghan, BC and Price, RS and Chen, KS and Feldman, EL}, title = {The Importance of Rare Subtypes in Diagnosis and Treatment of Peripheral Neuropathy: A Review.}, journal = {JAMA neurology}, volume = {72}, number = {12}, pages = {1510-1518}, pmid = {26437251}, issn = {2168-6157}, support = {K23 NS079417/NS/NINDS NIH HHS/United States ; DP3 DK094292/DK/NIDDK NIH HHS/United States ; R25 NS089450/NS/NINDS NIH HHS/United States ; R24 DK082841/DK/NIDDK NIH HHS/United States ; K23 NS079417-01/NS/NINDS NIH HHS/United States ; }, mesh = {*Disease Management ; Humans ; Peripheral Nervous System Diseases/*classification/*diagnosis ; *Treatment Outcome ; }, abstract = {IMPORTANCE: Peripheral neuropathy is a prevalent condition that usually warrants a thorough history and examination but has limited diagnostic evaluation. However, rare localizations of peripheral neuropathy often require more extensive diagnostic testing and different treatments.<br><br>OBJECTIVE: To describe rare localizations of peripheral neuropathy, including the appropriate diagnostic evaluation and available treatments.<br><br>EVIDENCE REVIEW: References were identified from PubMed searches conducted on May 29, 2015, with an emphasis on systematic reviews and randomized clinical trials. Articles were also identified through the use of the authors' own files. Search terms included common rare neuropathy localizations and their causes, as well as epidemiology, pathophysiology, diagnosis, and treatment.<br><br>FINDINGS: Diffuse, nonlength-dependent neuropathies, multiple mononeuropathies, polyradiculopathies, plexopathies, and radiculoplexus neuropathies are rare peripheral neuropathy localizations that often require extensive diagnostic testing. Atypical neuropathy features, such as acute/subacute onset, asymmetry, and/or motor predominant signs, are frequently present. The most common diffuse, nonlength-dependent neuropathies are Guillain-Barr&#xe9; syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and amyotrophic lateral sclerosis. Effective disease-modifying therapies exist for many diffuse, nonlength-dependent neuropathies including Guillain-Barr&#xe9; syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and some paraprotein-associated demyelinating neuropathies. Vasculitic neuropathy (multiple mononeuropathy) also has efficacious treatment options, but definitive evidence of a treatment effect for IgM anti-MAG neuropathy and diabetic amyotrophy (radiculoplexus neuropathy) is lacking.<br><br>CONCLUSIONS AND RELEVANCE: Recognition of rare localizations of peripheral neuropathy is essential given the implications for diagnostic testing and treatment. Electrodiagnostic studies are an important early step in the diagnostic evaluation and provide information on the localization and pathophysiology of nerve injury.}, }
@article {pmid26429216, year = {2015}, author = {Simon, NG and Huynh, W and Vucic, S and Talbot, K and Kiernan, MC}, title = {Motor neuron disease: current management and future prospects.}, journal = {Internal medicine journal}, volume = {45}, number = {10}, pages = {1005-1013}, doi = {10.1111/imj.12874}, pmid = {26429216}, issn = {1445-5994}, mesh = {Biomarkers ; C9orf72 Protein ; Clinical Trials as Topic ; Disease Progression ; Exercise ; Humans ; Motor Neuron Disease/*diagnosis/*genetics/*therapy ; Nutritional Support ; Proteins/*genetics ; }, abstract = {Motor neuron disease (MND) is characterised by progressive neurological deterioration and coexistence of upper and lower motor neuron signs. Over the past decade, evidence has emerged of unique pathophysiological processes, including glutamate-mediated excitotoxicity, which has resulted in the development of novel diagnostic investigations and uncovered potential therapeutic targets. Advances in genetics, including the recently discovered C9orf72 gene, have radically changed the pathological mindset, from MND being classified as a neuromuscular disease to one that MND forms a continuum with other primary neurodegenerative disorders, including frontotemporal dementia. The present review will highlight the improvements that have occurred in clinical care, in conjunction with recent scientific developments.}, }
@article {pmid26424237, year = {2015}, author = {Oh, SI and Baek, S and Park, JS and Piao, L and Oh, KW and Kim, SH}, title = {Prognostic Role of Serum Levels of Uric Acid in Amyotrophic Lateral Sclerosis.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {11}, number = {4}, pages = {376-382}, pmid = {26424237}, issn = {1738-6586}, abstract = {BACKGROUND AND PURPOSE: It has been suggested that oxidative stress is one of the pathomechanisms underlying amyotrophic lateral sclerosis (ALS), and thus antioxidants such as uric acid (UA) that could reduce oxidative stress might be beneficial in the prevention or treatment of this disease. The objective of this study was to prospectively investigate serum UA levels in Korean ALS patients and to relate them to disease progression.<br><br>METHODS: ALS patients and healthy controls who were individually well-matched for sex, age, and body mass index (BMI) underwent blood testing for serum UA levels, and analyzed whether UA levels were correlated with the disease status of the patients, as defined by the ALS Functional Rating Scale-Revised (ALSFRS-R).<br><br>RESULTS: The study included 136 ALS patients and 136 matched controls. The UA level was lower in the ALS patients (4.50&#xb1;1.17 mg/dL, mean&#xb1;SD) than in the controls (5.51&#xb1;1.22 mg/dL; p<0.001). Among the ALS patients, the level of UA acid was inversely correlated with the rate of disease progression (decrease in ALSFRS-R score). Kaplan-Meier analysis revealed that a better survival rate was more strongly correlated with top-tertile levels of serum UA than with bottom-tertile levels (log-rank test: p=0.035).<br><br>CONCLUSIONS: ALS patients had lower serum UA levels than did healthy individuals. UA levels in ALS were negatively correlated with the rate of disease progression and positively associated with survival, suggesting that UA levels contribute to the progression of ALS. UA levels could be considered a biomarker of disease progression in the early phase in ALS patients.}, }
@article {pmid26421849, year = {2015}, author = {Martić-Kehl, MI and Wernery, J and Folkers, G and Schubiger, PA}, title = {Quality of Animal Experiments in Anti-Angiogenic Cancer Drug Development--A Systematic Review.}, journal = {PloS one}, volume = {10}, number = {9}, pages = {e0137235}, pmid = {26421849}, issn = {1932-6203}, mesh = {Angiogenesis Inhibitors/*pharmacology/therapeutic use ; Animal Experimentation/*standards ; Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Cluster Analysis ; *Drug Discovery ; Drug Evaluation, Preclinical ; Humans ; Neoplasms/drug therapy/pathology ; Neovascularization, Pathologic/drug therapy ; }, abstract = {Translation from preclinical animal research to clinical bedside has proven to be difficult to impossible in many fields of research (e.g. acute stroke, ALS and HIV vaccination development) with oncology showing particularly low translation rates (5% vs. 20% for cardiovascular diseases). Several investigations on published preclinical animal research have revealed that apart from plain species differences, translational problems can arise from low study quality (e.g. study design) or non-representative experimental conditions (e.g. treatment schedule). This review assessed the published experimental circumstances and quality of anti-angiogenic cancer drug development in 232 in vivo studies. The quality of study design was often insufficient; at least the information published about the experiments was not satisfactory in most cases. There was no quality improvement over time, with the exception of conflict of interest statements. This increase presumably arose mainly because journal guidelines request such statements more often recently. Visual inspection of data and a cluster analysis confirmed a trend described in literature that low study quality tends to overestimate study outcome. It was also found that experimental outcome was more favorable when a potential drug was investigated as the main focus of a study, compared to drugs that were used as comparison interventions. We assume that this effect arises from the frequent neglect of blinding investigators towards treatment arms and refer to it as hypothesis bias. In conclusion, the reporting and presumably also the experimental performance of animal studies in drug development for oncology suffer from similar shortcomings as other fields of research (such as stroke or ALS). We consider it necessary to enforce experimental quality and reporting that corresponds to the level of clinical studies. It seems that only clear journal guidelines or guidelines from licensing authorities, where failure to fulfill prevents publication or experimental license, can help to improve this situation.}, }
@article {pmid26415311, year = {2015}, author = {Vidović, V and Rovazdi, M&#x10c; and Kraml, O and Kes, VB}, title = {PSEUDOBULBAR AFFECT IN MULTIPLE SCLEROSIS PATIENTS.}, journal = {Acta clinica Croatica}, volume = {54}, number = {2}, pages = {159-163}, pmid = {26415311}, issn = {0353-9466}, mesh = {Adult ; Aged ; Antipsychotic Agents/*therapeutic use ; Croatia/epidemiology ; *Disability Evaluation ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Multiple Sclerosis/*complications/rehabilitation ; Prevalence ; Prognosis ; Pseudobulbar Palsy/epidemiology/*etiology/rehabilitation ; Retrospective Studies ; Young Adult ; }, abstract = {The aim of the study was to determine the prevalence of pseudobulbar affect (PBA) in patients with multiple sclerosis (MS) and to analyze the link between PBA and patient age, sex, clinical course of MS, disease duration and degree of disability. The study was conducted on 79 MS patients that underwent inpatient rehabilitation at the Lipik Special Hospital for Medical Rehabilitation in the period from August 15, 2014 to February 15, 2015. PBA is a term used for an emotional disinhibition syndrome characterized by sudden and involuntary episodes of crying or laughing which are not in proportion to the stimulus applied or occur without stimulus. The condition can be present in patients with various neurological disorders, such as amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, patients having recovered from stroke, or following traumatic brain injury. The estimated prevalence in patients with MS ranges from 10% to 46.2%. As a measuring instrument in the study, we used the Center for Neurologic Study-Lability Scale (CNS-LS), where a sum 17 denoted positive finding. The total number of respondents was 79, of which 33 (41.8%) met the CNS-LS criteria for the diagnosis of PBA. There was no statistically significant correlation between PBA, age and degree of disability, although PBA was more common in women and in patients with a secondary progressive form of the disease. We found that 42.4% of respondents with positive CNS-LS criteria for PBA did not inform their neurologist on the presence of sudden mood changes. The high frequency of PBA and the fact that a significant proportion of patients did not inform the neurologist on their affective disturbances call for an active approach to diagnosis and treatment.}, }
@article {pmid26414627, year = {2016}, author = {Ehrhart, J and Darlington, D and Kuzmin-Nichols, N and Sanberg, CD and Sawmiller, DR and Sanberg, PR and Tan, J}, title = {Biodistribution of Infused Human Umbilical Cord Blood Cells in Alzheimer's Disease-Like Murine Model.}, journal = {Cell transplantation}, volume = {25}, number = {1}, pages = {195-199}, pmid = {26414627}, issn = {1555-3892}, support = {R01 AG032432/AG/NIA NIH HHS/United States ; R42 AG031586/AG/NIA NIH HHS/United States ; 5R42 AG031586-03/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/*pathology/*therapy ; Animals ; *Cord Blood Stem Cell Transplantation ; Disease Models, Animal ; Glycerolphosphate Dehydrogenase/metabolism ; Humans ; Mice, Transgenic ; Rats, Sprague-Dawley ; Tissue Distribution ; Umbilical Cord/*cytology ; }, abstract = {Human umbilical cord blood cells (HUCBCs), a prolific source of non-embryonic or adult stem cells, have emerged as effective and relatively safe immunomodulators and neuroprotectors, reducing behavioral impairment in animal models of Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, and stroke. In this report, we followed the bioavailability of HUCBCs in AD-like transgenic PSAPP mice and nontransgenic Sprague-Dawley rats. HUCBCs were injected into tail veins of mice or rats at a single dose of 1 × 10(6) or 2.2 × 10(6) cells, respectively, prior to harvesting of tissues at 24 h, 7 days, and 30 days after injection. For determination of HUCBC distribution, tissues from both species were subjected to total DNA isolation and polymerase chain reaction (PCR) amplification of the gene for human glycerol-3-phosphate dehydrogenase. Our results show a relatively similar biodistribution and retention of HUCBCs in both mouse and rat organs. HUCBCs were broadly detected both in the brain and several peripheral organs, including the liver, kidney, and bone marrow, of both species, starting within 7 days and continuing up to 30 days posttransplantation. No HUCBCs were recovered in the peripheral circulation, even at 24 h posttransplantation. Therefore, HUCBCs reach several tissues including the brain following a single intravenous treatment, suggesting that this route can be a viable method of administration of these cells for the treatment of neurodegenerative diseases.}, }
@article {pmid26413785, year = {2015}, author = {Isobe, T and Tooi, N and Nakatsuji, N and Aiba, K}, title = {Amyotrophic lateral sclerosis models derived from human embryonic stem cells with different superoxide dismutase 1 mutations exhibit differential drug responses.}, journal = {Stem cell research}, volume = {15}, number = {3}, pages = {459-468}, doi = {10.1016/j.scr.2015.09.006}, pmid = {26413785}, issn = {1876-7753}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Human Embryonic Stem Cells ; Humans ; Motor Neurons/*drug effects ; Mutation ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron (MN) disease. The gene encoding superoxide dismutase 1 (SOD1) is a causative element of familial ALS. Animal ALS models involving SOD1 gene mutations are widely used to study the underlying mechanisms of disease and facilitate drug discovery. Unfortunately, most drug candidates have failed in clinical trials, potentially due to species differences among rodents and humans. It is unclear, however, whether there are different responses to drugs among the causative genes of ALS or their associated mutations. In this study, to evaluate different SOD1 mutations, we generated SOD1-ALS models derived from human embryonic stem cells with identical genetic backgrounds, except for the overexpression of mutant variants of SOD1. The overexpression of mutant SOD1 did not affect pluripotency or MN differentiation. However, mutation-dependent reductions in neurite length were observed in MNs. Moreover, experiments investigating the effects of specific compounds revealed that each ALS model displayed different responses with respect to MN neurite length. These results suggest that SOD1 mutations could be classified based the response of MNs to drug treatment. This classification could be useful for the development of mutant-specific strategies for drug discovery and clinical trials.}, }
@article {pmid26409694, year = {2015}, author = {Fried-Oken, M and Mooney, A and Peters, B}, title = {Supporting communication for patients with neurodegenerative disease.}, journal = {NeuroRehabilitation}, volume = {37}, number = {1}, pages = {69-87}, pmid = {26409694}, issn = {1878-6448}, support = {R01 DC009834/DC/NIDCD NIH HHS/United States ; R21 DC014099/DC/NIDCD NIH HHS/United States ; }, mesh = {*Communication Devices for People with Disabilities ; Humans ; Neurodegenerative Diseases/psychology/*rehabilitation ; Speech Therapy/instrumentation/*methods ; }, abstract = {BACKGROUND: Communication supports, referred to as augmentative and alternative communication (AAC), are an integral part of medical speech-language pathology practice, yet many providers remain unfamiliar with assessment and intervention principles. For patients with complex communication impairments secondary to neurodegenerative disease, AAC services differ depending on whether their condition primarily affects speech and motor skills (ALS), language (primary progressive aphasia) or cognition (Alzheimer's disease). This review discusses symptom management for these three conditions, identifying behavioral strategies, low- and high-tech solutions for implementation during the natural course of disease. These AAC principles apply to all neurodegenerative diseases in which common symptoms appear.<br><br>OBJECTIVES: To present AAC interventions for patients with neurodegenerative diseases affecting speech, motor, language and cognitive domains. Three themes emerge: (1) timing of intervention: early referral, regular re-evaluations and continual treatment are essential; (2) communication partners must be included from the onset to establish AAC acceptance and use; and (3) strategies will change over time and use multiple modalities to capitalize on patients' strengths.<br><br>CONCLUSIONS: AAC should be standard practice for adults with neurodegenerative disease. Patients can maintain effective, functional communication with AAC supports. Individualized communication systems can be implemented ensuring patients remain active participants in daily activities.}, }
@article {pmid26403240, year = {2015}, author = {Navarro-Reig, M and Jaumot, J and García-Reiriz, A and Tauler, R}, title = {Evaluation of changes induced in rice metabolome by Cd and Cu exposure using LC-MS with XCMS and MCR-ALS data analysis strategies.}, journal = {Analytical and bioanalytical chemistry}, volume = {407}, number = {29}, pages = {8835-8847}, doi = {10.1007/s00216-015-9042-2}, pmid = {26403240}, issn = {1618-2650}, mesh = {Cadmium/*metabolism ; Chromatography, High Pressure Liquid ; Copper/*metabolism ; Least-Squares Analysis ; Mass Spectrometry ; *Metabolome ; Multivariate Analysis ; Oryza/chemistry/growth &amp; development/*metabolism ; }, abstract = {The comprehensive analysis of untargeted metabolomics data acquired using LC-MS is still a major challenge. Different data analysis tools have been developed in recent years such as XCMS (various forms (X) of chromatography mass spectrometry) and multivariate curve resolution alternating least squares (MCR-ALS)-based strategies. In this work, metabolites extracted from rice tissues cultivated in an environmental test chamber were subjected to untargeted full-scan LC-MS analysis, and the obtained data sets were analyzed using XCMS and MCR-ALS. These approaches were compared in the investigation of the effects of copper and cadmium exposure on rice tissue (roots and aerial parts) samples. Both methods give, as a result of their application, the whole set of resolved elution and spectra profiles of the extracted metabolites in control and metal-treated samples, as well as the values of their corresponding chromatographic peak areas. The effects caused by the two considered metals on rice samples were assessed by further chemometric analysis and statistical evaluation of these peak area values. Results showed that there was a statistically significant interaction between the considered factors (type of metal of treatment and tissue). Also, the discrimination of the samples according to both factors was possible. A tentative identification of the most discriminant metabolites (biomarkers) was assessed. It is finally concluded that both XCMS- and MCR-ALS-based strategies provided similar results in all the considered cases despite the completely different approaches used by these two methods in the chromatographic peak resolution and detection strategies. Finally, advantages and disadvantages of using these two methods are discussed. Graphical Abstract Summary of the workflow for untargeted metabolomics using the compared approaches.}, }
@article {pmid26395626, year = {2015}, author = {Rushkevich, YN and Kosmacheva, SM and Zabrodets, GV and Ignatenko, SI and Goncharova, NV and Severin, IN and Likhachev, SA and Potapnev, MP}, title = {The Use of Autologous Mesenchymal Stem Cells for Cell Therapy of Patients with Amyotrophic Lateral Sclerosis in Belarus.}, journal = {Bulletin of experimental biology and medicine}, volume = {159}, number = {4}, pages = {576-581}, doi = {10.1007/s10517-015-3017-3}, pmid = {26395626}, issn = {1573-8221}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/metabolism/pathology/*therapy ; Cell Differentiation ; Cells, Cultured ; Female ; Humans ; Male ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/enzymology ; Middle Aged ; Nestin/metabolism ; Phosphopyruvate Hydratase/metabolism ; Republic of Belarus ; Transplantation, Autologous ; Treatment Outcome ; }, abstract = {We studied a new method of treatment of amyotrophic lateral sclerosis with autologous mesenchymal stem cells. Autologous mesenchymal stem cells were injected intravenously (intact cells) or via lumbar puncture (cells committed to neuronal differentiation). Evaluation of the results of cell therapy after 12-month follow-up revealed slowing down of the disease progression in 10 patients in comparison with the control group consisting of 15 patients. The cell therapy was safe for the patients.}, }
@article {pmid26389734, year = {2015}, author = {Wootla, B and Watzlawik, JO and Warrington, AE and Wittenberg, NJ and Denic, A and Xu, X and Jordan, LR and Papke, LM and Zoecklein, LJ and Pierce, ML and Oh, SH and Kantarci, OH and Rodriguez, M}, title = {Naturally Occurring Monoclonal Antibodies and Their Therapeutic Potential for Neurologic Diseases.}, journal = {JAMA neurology}, volume = {72}, number = {11}, pages = {1346-1353}, doi = {10.1001/jamaneurol.2015.2188}, pmid = {26389734}, issn = {2168-6157}, support = {R01 GM092993/GM/NIGMS NIH HHS/United States ; R01 NS048357/NS/NINDS NIH HHS/United States ; R21 NS073684/NS/NINDS NIH HHS/United States ; UL1 TR000135/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; Antibodies, Monoclonal/*therapeutic use ; Humans ; Immunoglobulin Isotypes/*immunology ; Nervous System Diseases/*drug therapy/immunology ; Recombinant Proteins/*therapeutic use ; }, abstract = {IMPORTANCE: Modulating the immune system does not reverse long-term disability in neurologic disorders. Better neuroregenerative and neuroprotective treatment strategies are needed for neuroinflammatory and neurodegenerative diseases.<br><br>OBJECTIVE: To review the role of monoclonal, naturally occurring antibodies (NAbs) as novel therapeutic molecules for treatment of neurologic disorders.<br><br>EVIDENCE REVIEW: Peer-reviewed articles, including case reports, case series, retrospective reviews, prospective randomized clinical trials, and basic science reports, were identified in a PubMed search for articles about NAbs and neurologic disorders that were published from January 1, 1964, through June 30, 2015. We concentrated our review on multiple sclerosis, Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis.<br><br>FINDINGS: Many insults, including trauma, ischemia, infection, inflammation, and neurodegeneration, result in irreversible damage to the central nervous system. Central nervous system injury often results in a pervasive inhibitory microenvironment that hinders regeneration. A common targeted drug development strategy is to identify molecules with high potency in animal models. Many approaches often fail in the clinical setting owing to a lack of efficacy in human diseases (eg, less than the response demonstrated in animal models) or a high incidence of toxic effects. An alternative approach is to identify NAbs in humans because these therapeutic molecules have potential physiologic function without toxic effects. NAbs of the IgG, IgA, or IgM isotype contain germline or close to germline sequences and are reactive to self-components, altered self-components, or foreign antigens. Our investigative group developed recombinant, autoreactive, natural human IgM antibodies directed against oligodendrocytes or neurons with therapeutic potential for central nervous system repair. One such molecule, recombinant HIgM22, directed against myelin and oligodendrocytes completed a successful phase 1 clinical trial without toxic effects with the goal of promoting remyelination in multiple sclerosis.<br><br>CONCLUSIONS AND RELEVANCE: Animal studies demonstrate that certain monoclonal NAbs are beneficial as therapeutic agents for neurologic diseases. This class of antibodies represents a unique source from which to develop a new class of disease-modifying therapies.}, }
@article {pmid26384962, year = {2015}, author = {Sábado, J and Casanovas, A and Rodrigo, H and Arqué, G and Esquerda, JE}, title = {Adverse effects of a SOD1-peptide immunotherapy on SOD1 G93A mouse slow model of amyotrophic lateral sclerosis.}, journal = {Neuroscience}, volume = {310}, number = {}, pages = {38-50}, doi = {10.1016/j.neuroscience.2015.09.027}, pmid = {26384962}, issn = {1873-7544}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/immunology/pathology/*therapy ; Animals ; Calcium-Binding Proteins/metabolism ; Cytokines/genetics/metabolism ; Disease Models, Animal ; Exploratory Behavior/physiology ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Immunoglobulin G/metabolism ; Immunotherapy/*adverse effects ; Inflammation/*chemically induced ; Mice ; Mice, Transgenic ; Microfilament Proteins/metabolism ; Neurons/metabolism/pathology ; Peptides/*adverse effects/immunology ; Receptors, Purinergic P2X4/chemistry/immunology ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/adverse effects/*chemistry/genetics/immunology ; Superoxide Dismutase-1 ; }, abstract = {Previous reports from our lab had shown that some anti-purinergic receptor P2X4 antibodies cross-reacted with misfolded forms of mutant Cu/Zn superoxide dismutase 1 (SOD1), linked to amyotrophic lateral sclerosis (ALS). Cross-reactivity could be caused by the abnormal exposure of an epitope located in the inner hydrophobic region of SOD1 that shared structural homology with the P2X4-immunizing peptide. We had previously raised antibodies against human SOD1 epitope mimicked by the P2X4 immunizing peptide. One of these antibodies, called AJ10, was able to recognize mutant/misfolded forms of ALS-linked mutant SOD1. Here, we used the AJ10 antigen as a vaccine to target neurotoxic species of mutant SOD1 in a slow mouse model of ALS. However, the obtained results showed no improvement in life span, disease onset or weight loss in treated animals; we observed an increased microglial neuroinflammatory response and high amounts of misfolded SOD1 accumulated within spinal cord neurons after AJ10 immunization. An increase of immunoglobulin G deposits was also found due to the treatment. Finally, a significantly worse clinical evolution was displayed by an impairment on motor function as a consequence of AJ10 peptide immunization.}, }
@article {pmid26375661, year = {2015}, author = {von Vopelius-Feldt, J and Coulter, A and Benger, J}, title = {The impact of a pre-hospital critical care team on survival from out-of-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {96}, number = {}, pages = {290-295}, doi = {10.1016/j.resuscitation.2015.08.020}, pmid = {26375661}, issn = {1873-1570}, mesh = {Aged ; Cardiopulmonary Resuscitation/*methods/standards ; *Emergency Medical Services ; England/epidemiology ; Female ; Follow-Up Studies ; *Health Knowledge, Attitudes, Practice ; Humans ; Male ; Out-of-Hospital Cardiac Arrest/mortality/*therapy ; Patient Care Team/*standards ; Retrospective Studies ; Survival Rate/trends ; United Kingdom/epidemiology ; Workforce ; }, abstract = {AIM: To assess the impact of a pre-hospital critical care team (CCT) on survival from out-of-hospital cardiac arrest (OHCA).<br><br>METHODS: We undertook a retrospective observational study, comparing OHCA patients attended by advanced life support (ALS) paramedics with OHCA patients attended by ALS paramedics and a CCT between April 2011 and April 2013 in a single ambulance service in Southwest England. We used multiple logistic regression to control for an anticipated imbalance of prognostic factors between the groups. The primary outcome was survival to hospital discharge. All data were collected independently of the research.<br><br>RESULTS: 1851 cases of OHCA were included in the analysis, of which 1686 received ALS paramedic treatment and 165 were attended by both ALS paramedics and a CCT. Unadjusted rates of survival to hospital discharge were significantly higher in the CCT group, compared to the ALS paramedic group (15.8% and 6.5%, respectively, p<0.001). After adjustment using multiple logistic regression, the effect of CCT treatment was no longer statistically significant (OR 1.54, 95% CI 0.89-2.67, p=0.13). Subgroup analysis of OHCA with first monitored rhythm of ventricular fibrillation or pulseless ventricular tachycardia showed similar results.<br><br>CONCLUSION: Pre-hospital critical care for OHCA was not associated with significantly improved rates of survival to hospital discharge. These results are in keeping with previously published studies. Further research with a larger sample size is required to determine whether CCTs can improve outcome in OHCA.}, }
@article {pmid26365142, year = {2015}, author = {Gazulla, J and Ruiz-Gazulla, C and Tintore, M}, title = {GABAergic Pharmacotherapy in the Treatment of Motor Disorders of the Central Nervous System.}, journal = {Current pharmaceutical design}, volume = {21}, number = {34}, pages = {4989-4995}, doi = {10.2174/1381612821666150914120923}, pmid = {26365142}, issn = {1873-4286}, mesh = {Adult ; Animals ; Central Nervous System Diseases/*drug therapy/physiopathology ; Cerebellar Ataxia/drug therapy/physiopathology ; GABA Agents/pharmacology/therapeutic use ; Humans ; Motor Disorders/*drug therapy/physiopathology ; Neurotransmitter Agents/metabolism ; Purkinje Cells/metabolism ; gamma-Aminobutyric Acid/*metabolism ; }, abstract = {Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system, and diseases that associate a deficiency in GABA might benefit from GABAergic drugs. Cerebellar Purkinje cells employ GABA as a neurotransmitter. Cortical cerebellar atrophy (CCA) shows Purkinje cell loss, and ataxia caused by it was alleviated by gabapentin and pregabalin. Thus, CCA is proposed as a model of selective deficiency in GABA in the cerebellum, which benefits clinically from administration of GABAergic drugs, in a manner similar in which levodopa improves motor manifestations in Parkinson's disease. Other ataxias also benefited clinically from GABAergic drugs, as adult-onset GM2 gangliosidosis, olivopontocerebellar atrophy, cerebellar ataxia with hypogonadism, spinocerebellar ataxias 1, 2 and 6, and adult-onset ataxia-telangiectasia. Complex neurochemical diseases, as multiple-system atrophy, had ataxia worsened by GABAergic drugs. Various disorders with a deficiency in GABA content had their manifestations relieved by admistration of GABAergic drugs, as one patient with progressive encephalomyelitis with rigidity, whose muscular spasms were suppressed by a combination of gabapentin and tiagabine, and another with diaphragmatic myoclonus, who required gabapentin and tiagabine for symptomatic control. On the contrary, GABAergic drugs were not effective in cervical dystonia, amyotrophic lateral sclerosis, Parkinson's disease and progressive supranuclear palsy, presumably because a deficiency in GABA is not an essential neurochemical abnormality in these diseases. Research aimed at identifying effective therapies to treat cerebellar ataxias and other motor disorders of the central nervous system is warranted. Meanwhile, therapeutic tests with GABAergic drugs might yield clinical improvement in these diseases.}, }
@article {pmid26362794, year = {2017}, author = {Phelps, K and Regen, E and Oliver, D and McDermott, C and Faull, C}, title = {Withdrawal of ventilation at the patient's request in MND: a retrospective exploration of the ethical and legal issues that have arisen for doctors in the UK.}, journal = {BMJ supportive &amp; palliative care}, volume = {7}, number = {2}, pages = {189-196}, pmid = {26362794}, issn = {2045-4368}, support = {SHAW/APR15/933-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; FAULL/APR12/6389/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Attitude to Death ; Humans ; Interviews as Topic ; Neoplasms/*therapy ; Practice Patterns, Physicians'/ethics/legislation &amp; jurisprudence ; Respiration, Artificial ; Retrospective Studies ; State Medicine ; Terminal Care ; United Kingdom ; Withholding Treatment/*ethics/legislation &amp; jurisprudence ; }, abstract = {BACKGROUND: Ventilatory support has benefits including prolonging survival for respiratory failure in motor neurone disease (MND). At some point some patients may wish to stop the intervention. The National Institute of Health and Care Excellence (NICE) guidance recommends research is needed on ventilation withdrawal. There is little literature focusing on the issues doctors encounter when withdrawing ventilation at the request of a patient.<br><br>AIM: To identify and explore with doctors the ethical and legal issues that they had encountered in the withdrawal of ventilation at the request of a patient with MND.<br><br>METHOD: A retrospective thematic analysis of interviews of 24 doctors (including palliative care, respiratory, neurology and general practice) regarding their experiences with withdrawal of ventilation support from patients with MND.<br><br>RESULTS: Respondents found withdrawal of ventilation at the request of patients with MND to pose legal, ethical and moral challenges in five themes: ethical and legal rights to withdrawal from treatment; discussions with family; discussions with colleagues; experiences of legal advice; issues contributing to ethical complexity. Though clear about the legality of withdrawal of treatment in theory, the practice led to ethical and moral uncertainty and mixed feelings. Many respondents had experienced negative reactions from other healthcare professionals when these colleagues were unclear of the distinction between palliation of symptoms, withdrawal of treatment and assisted death.<br><br>CONCLUSIONS: Legal, ethical and practical guidance is needed for professionals who support a patient with MND who wishes to withdraw from ventilation. Open discussion of the ethical challenges is needed as well as education and support for professionals.}, }
@article {pmid26347879, year = {2015}, author = {Quansah, E and Karikari, TK}, title = {Motor Neuron Diseases in Sub-Saharan Africa: The Need for More Population-Based Studies.}, journal = {BioMed research international}, volume = {2015}, number = {}, pages = {298409}, pmid = {26347879}, issn = {2314-6141}, mesh = {Animals ; *Disease Models, Animal ; Glaucoma/*metabolism/*pathology ; Humans ; }, abstract = {Motor neuron diseases (MNDs) are devastating neurological diseases that are characterised by gradual degeneration and death of motor neurons. Major types of MNDs include amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). These diseases are incurable, with limited disease-modifying treatment options. In order to improve MND-based biomedical research, drug development, and clinical care, population-based studies will be important. These studies, especially among less-studied populations, might identify novel factors controlling disease susceptibility and resistance. To evaluate progress in MND research in Africa, we examined the published literature on MNDs in Sub-Saharan Africa to identify disease prevalence, genetic factors, and other risk factors. Our findings indicate that the amount of research evidence on MNDs in Sub-Saharan Africa is scanty; molecular and genetics-based studies are particularly lacking. While only a few genetic studies were identified, these studies strongly suggest that there appear to be population-specific causes of MNDs among Africans. MND genetic underpinnings vary among different African populations and also between African and non-African populations. Further studies, especially molecular, genetic and genomic studies, will be required to advance our understanding of MND biology among African populations. Insights from these studies would help to improve the timeliness and accuracy of clinical diagnosis and treatment.}, }
@article {pmid26339260, year = {2014}, author = {Jafari, S and Babaeipour, V and Seyedi, HA and Rahaie, M and Mofid, MR and Haddad, L and Namvaran, MM and Fallah, J}, title = {Recombinant production of mecasermin in E. coli expression system.}, journal = {Research in pharmaceutical sciences}, volume = {9}, number = {6}, pages = {453-461}, pmid = {26339260}, issn = {1735-5362}, abstract = {Human Insulin-like growth factor 1 (hIGF-1) consists of 70 amino acids in a single chain with three intermolecular disulfide bridges possessing valuable therapeutic effects. To date, numerous variants of specifically engineered hIGF-1 have been produced so as to improve hIGF-1 biological activity, stability and stronger binding to IGF-1 receptor. Mecasermin is one of the modified variants with one amino acid substitution near the N-terminal (T4I) approved for the treatment of growth failure diabetes, wound healing, amyotrophic lateral sclerosis and severe primary IGF-1 deficiency. No scientific report for recombinant production of mecasermin in Escherichia coli (E. coli) expression system has been sofar reported. In the present study, we therefore investigated the overexpression of mecasermin in two different E. coli strains in order to obtain higher yield of recombinant protein. To achieve this goal, mecasermin DNA encoding sequence was designed based on polypeptide sequence, optimized according to E. coli codon preference, and cloned in pET15b. Recombinant vector, pET15-mecasermin, transferred into two E. coli strains rigami B (DE3) and BL21 (DE3) and induced for expression in a small scale. Results revealed the E. coli Origami B (DE3) expression system was a preferable host for mecasermin production due to its high expression level being around twice as much as BL21 (DE3). Large scale mecasermin production was performed in batch culture and produced recombinant protein specifically confirmed by western blotting and mass spectroscopy. Since major part of recombinant mecasermin was expressed as inclusion body, isolation and refolding was accomplished through developed purification procedure, and finally recombinant protein was successfully purified by gel filtration chromatography.}, }
@article {pmid26332705, year = {2016}, author = {Caress, JB and Ciarlone, SL and Sullivan, EA and Griffin, LP and Cartwright, MS}, title = {Natural history of muscle cramps in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {53}, number = {4}, pages = {513-517}, pmid = {26332705}, issn = {1097-4598}, support = {K23 NS062892/NS/NINDS NIH HHS/United States ; NIH K23NS06289223/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*diagnosis/*epidemiology/physiopathology ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Muscle Cramp/*diagnosis/*epidemiology/physiopathology ; *Surveys and Questionnaires ; }, abstract = {INTRODUCTION: Muscle cramping is a common symptom in amyotrophic lateral sclerosis (ALS) that lacks efficacious treatment. The natural history of this symptom is unknown, which hampers efforts to design optimal clinical trials.<br><br>METHODS: We surveyed early stage ALS patients about their experience with cramps each month by phone for up to 21 months.<br><br>RESULTS: Cramps developed in 95% of patients over the course of their disease. The number of cramps experienced by an individual varied widely from month-to-month and trended lower after the first year of illness (P = 0.26). Those with limb-onset and age >60 years had more cramps than bulbar-onset (P < 0.0001) and younger patients (P < 0.0001).<br><br>CONCLUSIONS: The high variability of the number of cramps experienced suggests that clinical trials will need to use crossover designs or large numbers of participants, even when the treatment effect is substantial.}, }
@article {pmid26329483, year = {2016}, author = {Hajivalili, M and Pourgholi, F and Kafil, HS and Jadidi-Niaragh, F and Yousefi, M}, title = {Mesenchymal Stem Cells in the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Current stem cell research &amp; therapy}, volume = {11}, number = {1}, pages = {41-50}, doi = {10.2174/1574888x10666150902095031}, pmid = {26329483}, issn = {2212-3946}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Humans ; Mesenchymal Stem Cell Transplantation/*methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS is a neurodegenerative disorder which is characterized by motor neuron (MN dysfunction, progressive paralysis, and death. Although several therapeutic approaches have been used for treatment of ALS, little success has been achieved. Natural vectors such as mesenchymal stem cells (MSCs can be a promising tool for overcoming therapeutic problems. MSCs have multipotential characteristics such as the ability to differentiate into variety of cell types, easy access, immunomodulation, tissue repair, exertion of trophic factors, exosome secretion and efficient homing. In this review, we will discuss the characteristics of MSCs and their possible therapeutic mechanisms in ALS patients.}, }
@article {pmid26327120, year = {2015}, author = {Petracca, M and Guidubaldi, A and Ricciardi, L and Ialongo, T and Del Grande, A and Mulas, D and Di Stasio, E and Bentivoglio, AR}, title = {Botulinum Toxin A and B in sialorrhea: Long-term data and literature overview.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {107}, number = {Pt A}, pages = {129-140}, doi = {10.1016/j.toxicon.2015.08.014}, pmid = {26327120}, issn = {1879-3150}, mesh = {Botulinum Toxins, Type A/administration &amp; dosage/adverse effects/*therapeutic use ; Humans ; Injections ; Salivary Glands/drug effects ; Sialorrhea/*drug therapy ; Treatment Outcome ; }, abstract = {INTRODUCTION AND OBJECTIVES: In recent years, Botulinum Toxin has been shown to be efficacious and safe in the treatment of sialorrhea, but scanty data are available on its long term use. The aim of this study was to investigate adverse events, discriminate differences in safety, and evaluate the efficacy of long-term use of both abobotulinumtoxinA and rimabotulinumtoxinB ultrasound-guided injections for sialorrhea in a retrospective trial. Moreover we review the literature on this topic.<br><br>PATIENTS AND METHODS: Consecutive patients with severe sialorrhea and receiving at least two ultrasound-guided intrasalivary glands abobotulinumtoxinA 250 U or rimabotulinumtoxinB 2500 U injections were included. Clinical and demographic data were collected. Safety and tolerability were assessed on the basis of patients' self-reports. Efficacy was assessed by recording the duration of benefit and by the Drooling Severity Scale and Drooling Frequency Scale 4 weeks after intervention. A review of literature was performed using 'Botulinum Toxin' and/or 'drooling' and/or 'sialorrhea' and/or 'hypersalivation' as keywords.<br><br>RESULTS: Sixty-five patients (32 Amyotrophic Lateral Sclerosis and 33 Parkinson's Disease) were treated in a total of 317 sessions (181 rimabotulinumtoxinB and 136 abobotulinumtoxinA). Both serotypes induced a clear-cut benefit in 89% of injections. Mean benefit duration was 87 days (range 30-240), similar for abobotulinumtoxinA and rimabotulinumtoxinB but significantly shorter in Amyotrophic Lateral Sclerosis group compared to Parkinson's Disease (p < 0.001). Older age was positively correlated to benefit duration (p = 0.003). Botulinum Toxin-related and injection-related side effects complicated respectively 8,2% and 1,5% of treatments. The only Botulinum Toxin-related adverse event was a change of saliva thickness, mostly rated mild to moderate and more frequent in Amyotrophic Lateral Sclerosis patients (p = NS).<br><br>CONCLUSIONS: Both 250 U abobotulinumtoxinA and 2500 U rimabotulinumtoxinB administered by ultrasound-guided intrasalivary gland injection are safe and effective in treating sialorrhea, even in long-term follow-up. Older age is significantly associated with longer benefit duration. Parkinson's Disease patients showed a more favorable safety-efficacy ratio than did Amyotrophic Lateral Sclerosis patients, due to lower adverse events (p = NS) and longer benefit duration (p < 0.001).}, }
@article {pmid26315761, year = {2015}, author = {Pal, R and Larsen, JP and Moller, SG}, title = {The Potential of Proteomics in Understanding Neurodegeneration.}, journal = {International review of neurobiology}, volume = {121}, number = {}, pages = {25-58}, doi = {10.1016/bs.irn.2015.05.002}, pmid = {26315761}, issn = {2162-5514}, mesh = {Animal Diseases ; Animals ; Humans ; Neurodegenerative Diseases/*diagnosis/*metabolism ; Protein Processing, Post-Translational/*physiology ; Proteomics/*methods ; }, abstract = {Neurodegenerative diseases are a major health concern worldwide. Diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, as well as many other diseases affecting the neuromuscular system, are a leading cause of disability in the aging population. Presymptomatic diagnosis of neurodegenerative disorders is challenging due to the lack of robust biomarkers. Likewise, the design of effective intervention strategies is limited because most neurodegenerative disorders are heterogeneous in nature. Reliable noninvasive biomarkers are therefore urgently needed to allow presymptomatic and accurate diagnosis, to track disease progression, to evaluate the effectiveness of new treatment regimens, and to ultimately design new therapeutic intervention strategies. Recent biological and technological advances within the field of proteomic promises to provide insight into global proteome changes in neurodegeneration, thus allowing increased understanding of molecular pathways leading to neuronal cell death and the identification of biomarkers. The combination of gel-based techniques and mass spectrometry permits large-scale identification of peptide sequences in biological samples as well as the characterization of posttranslational protein modifications. The application of comparative high-throughput proteomic analyses in animal models and human tissues will aid in the identification of both diagnostic and prognostic biomarkers and will provide a platform for a future personalized medicine approach in neurodegeneration.}, }
@article {pmid26311432, year = {2015}, author = {Thompson, JM and Ji, G and Neugebauer, V}, title = {Small-conductance calcium-activated potassium (SK) channels in the amygdala mediate pain-inhibiting effects of clinically available riluzole in a rat model of arthritis pain.}, journal = {Molecular pain}, volume = {11}, number = {}, pages = {51}, pmid = {26311432}, issn = {1744-8069}, support = {R01 NS038261/NS/NINDS NIH HHS/United States ; R01 NS081121/NS/NINDS NIH HHS/United States ; NS038261/NS/NINDS NIH HHS/United States ; NS081121/NS/NINDS NIH HHS/United States ; }, mesh = {Amygdala/drug effects/*metabolism ; Animals ; Arthritis/complications/*drug therapy/metabolism/pathology ; Disease Models, Animal ; Hindlimb/drug effects ; Male ; Microdialysis ; Pain/complications/*drug therapy/metabolism/pathology ; Rats, Sprague-Dawley ; Riluzole/administration &amp; dosage/pharmacology/*therapeutic use ; Small-Conductance Calcium-Activated Potassium Channels/*metabolism ; Stereotaxic Techniques ; Vocalization, Animal/drug effects ; }, abstract = {BACKGROUND: Arthritis pain is an important healthcare issue with significant emotional and affective consequences. Here we focus on potentially beneficial effects of activating small-conductance calcium-activated potassium (SK) channels in the amygdala, a brain center of emotions that plays an important role in central pain modulation and processing. SK channels have been reported to regulate neuronal activity in the central amygdala (CeA, output nucleus). We tested the effects of riluzole, a clinically available drug for the treatment of amyotrophic lateral sclerosis, for the following reasons. Actions of riluzole include activation of SK channels. Evidence in the literature suggests that riluzole may have antinociceptive effects through an action in the brain but not the spinal cord. Mechanism and site of action of riluzole remain to be determined. Here we tested the hypothesis that riluzole inhibits pain behaviors by acting on SK channels in the CeA in an arthritis pain model.<br><br>RESULTS: Systemic (intraperitoneal) application of riluzole (8&#xa0;mg/kg) inhibited audible (nocifensive response) and ultrasonic (averse affective response) vocalizations of adult rats with arthritis (5&#xa0;h postinduction of a kaolin-carrageenan monoarthritis in the knee) but did not affect spinal withdrawal thresholds, which is consistent with a supraspinal action. Stereotaxic administration of riluzole into the CeA by microdialysis (1&#xa0;mM, concentration in the microdialysis fiber, 15&#xa0;min) also inhibited vocalizations, confirming the CeA as a site of action of riluzole. Stereotaxic administration of a selective SK channel blocker (apamin, 1&#xa0;&#xb5;M, concentration in the microdialysis fiber, 15&#xa0;min) into the CeA had no effect by itself but inhibited the effect of systemic riluzole on vocalizations. Off-site administration of apamin into the basolateral amygdala (BLA) as a placement control or stereotaxic application of a selective blocker of large-conductance calcium-activated potassium (BK) channels (charybdotoxin, 1&#xa0;&#xb5;M, concentration in the microdialysis fiber, 15&#xa0;min) into the CeA did not affect the inhibitory effects of systemically applied riluzole.<br><br>CONCLUSIONS: The results suggest that riluzole can inhibit supraspinally organized pain behaviors in an arthritis model by activating SK, but not BK, channels in the amygdala (CeA but not BLA).}, }
@article {pmid26295717, year = {2015}, author = {Liddell, JR}, title = {Targeting mitochondrial metal dyshomeostasis for the treatment of neurodegeneration.}, journal = {Neurodegenerative disease management}, volume = {5}, number = {4}, pages = {345-364}, doi = {10.2217/nmt.15.19}, pmid = {26295717}, issn = {1758-2032}, mesh = {Brain/*metabolism ; *Brain Chemistry ; Clinical Trials as Topic ; *Homeostasis ; Humans ; Iron/metabolism ; Metalloproteins/*metabolism ; Mitochondrial Diseases/*metabolism ; Neurodegenerative Diseases/*metabolism/*therapy ; Oxyquinoline/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Mitochondrial impairment and metal dyshomeostasis are suggested to be associated with many neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and Friedreich's ataxia. Treatments aimed at restoring metal homeostasis are highly effective in models of these diseases, and clinical trials hold promise. However, in general, the effect of these treatments on mitochondrial metal homeostasis is unclear, and the contribution of mitochondrial metal dyshomeostasis to disease pathogenesis requires further investigation. This review describes the role of metals in mitochondria in health, how mitochondrial metals are disrupted in neurodegenerative diseases, and potential therapeutics aimed at restoring mitochondrial metal homeostasis and function.}, }
@article {pmid26295258, year = {2015}, author = {Silva, J and Monge-Fuentes, V and Gomes, F and Lopes, K and dos Anjos, L and Campos, G and Arenas, C and Biolchi, A and Gonçalves, J and Galante, P and Campos, L and Mortari, M}, title = {Pharmacological Alternatives for the Treatment of Neurodegenerative Disorders: Wasp and Bee Venoms and Their Components as New Neuroactive Tools.}, journal = {Toxins}, volume = {7}, number = {8}, pages = {3179-3209}, pmid = {26295258}, issn = {2072-6651}, mesh = {Animals ; Bee Venoms/pharmacology/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/pharmacology/*therapeutic use ; Wasp Venoms/pharmacology/*therapeutic use ; }, abstract = {Neurodegenerative diseases are relentlessly progressive, severely impacting affected patients, families and society as a whole. Increased life expectancy has made these diseases more common worldwide. Unfortunately, available drugs have insufficient therapeutic effects on many subtypes of these intractable diseases, and adverse effects hamper continued treatment. Wasp and bee venoms and their components are potential means of managing or reducing these effects and provide new alternatives for the control of neurodegenerative diseases. These venoms and their components are well-known and irrefutable sources of neuroprotectors or neuromodulators. In this respect, the present study reviews our current understanding of the mechanisms of action and future prospects regarding the use of new drugs derived from wasp and bee venom in the treatment of major neurodegenerative disorders, including Alzheimer's Disease, Parkinson's Disease, Epilepsy, Multiple Sclerosis and Amyotrophic Lateral Sclerosis.}, }
@article {pmid26288094, year = {2015}, author = {Vieira, FG and Ping, Q and Moreno, AJ and Kidd, JD and Thompson, K and Jiang, B and Lincecum, JM and Wang, MZ and De Zutter, GS and Tassinari, VR and Levine, B and Hatzipetros, T and Gill, A and Perrin, S}, title = {Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS.}, journal = {PloS one}, volume = {10}, number = {8}, pages = {e0135570}, pmid = {26288094}, issn = {1932-6203}, mesh = {Adrenergic alpha-2 Receptor Agonists/*pharmacology ; Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; Antihypertensive Agents/pharmacology ; Disease Models, Animal ; Disease Progression ; Endoplasmic Reticulum Stress/*drug effects ; Eukaryotic Initiation Factor-2/metabolism ; Fibroblasts/drug effects ; Guanabenz/*pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Nerve Degeneration/pathology ; Phosphorylation ; Protein Phosphatase 1/metabolism ; Superoxide Dismutase/*drug effects/genetics ; Tunicamycin ; Unfolded Protein Response ; eIF-2 Kinase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons. The mechanisms leading to motor neuron degeneration in ALS are unclear. However, there is evidence for involvement of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in ALS, notably in mutant SOD1 mediated models of ALS. Stress induced phosphorylation of the eIF2 alpha subunit by eukaryotic translation initiation factor 2-alpha kinase 3 Perk activates the UPR. Guanabenz is a centrally acting alpha2 adrenergic receptor agonist shown to interact with a regulatory subunit of the protein phosphatase, Pp1/Gadd34, and selectively disrupt the dephosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eif2alpha). Here we demonstrate that guanabenz is protective in fibroblasts expressing G93A mutant SOD1 when they are exposed to tunicamycin mediated ER stress. However, in contrast to other reports, guanabenz treatment accelerated ALS-like disease progression in a strain of mutant SOD1 transgenic ALS mice. This study highlights challenges of pharmacological interventions of cellular stress responses in whole animal models of ALS.}, }
@article {pmid26287750, year = {2015}, author = {Nichols, NL and Satriotomo, I and Harrigan, DJ and Mitchell, GS}, title = {Acute intermittent hypoxia induced phrenic long-term facilitation despite increased SOD1 expression in a rat model of ALS.}, journal = {Experimental neurology}, volume = {273}, number = {}, pages = {138-150}, pmid = {26287750}, issn = {1090-2430}, support = {R00 HL119606/HL/NHLBI NIH HHS/United States ; R01 HL080209/HL/NHLBI NIH HHS/United States ; R01 HL69064/HL/NHLBI NIH HHS/United States ; T32 HL007654/HL/NHLBI NIH HHS/United States ; K99 HL119606/HL/NHLBI NIH HHS/United States ; R01 HL069064/HL/NHLBI NIH HHS/United States ; K99/R00 HL119606/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetophenones/pharmacology ; Age Factors ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/*pathology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Blood Gas Analysis ; Body Temperature/drug effects ; Disease Models, Animal ; Female ; Hypoxia/*physiopathology ; Long-Term Potentiation/genetics/*physiology ; Male ; Motor Neurons/pathology ; Phrenic Nerve/*physiopathology ; Rats ; Rats, Transgenic ; Reactive Oxygen Species/metabolism ; Respiratory Insufficiency/etiology ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/genetics/metabolism ; Vagotomy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by motor neuron death. Since most ALS patients succumb to ventilatory failure from loss of respiratory motor neurons, any effective ALS treatment must preserve and/or restore breathing capacity. In rats over-expressing mutated super-oxide dismutase-1 (SOD1(G93A)), the capacity to increase phrenic motor output is decreased at disease end-stage, suggesting imminent ventilatory failure. Acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF), a form of spinal respiratory motor plasticity with potential to restore phrenic motor output in clinical disorders that compromise breathing. Since pLTF requires NADPH oxidase activity and reactive oxygen species (ROS) formation, it is blocked by NADPH oxidase inhibition and SOD mimetics in normal rats. Thus, we hypothesized that SOD1(G93A) (mutant; MT) rats do not express AIH-induced pLTF due to over-expression of active mutant superoxide dismutase-1. AIH-induced pLTF and hypoglossal (XII) LTF were assessed in young, pre-symptomatic and end-stage anesthetized MT rats and age-matched wild-type littermates. Contrary to predictions, pLTF and XII LTF were observed in MT rats at all ages; at end-stage, pLTF was actually enhanced. SOD1 levels were elevated in young and pre-symptomatic MT rats, yet superoxide accumulation in putative phrenic motor neurons (assessed with dihydroethidium) was unchanged; however, superoxide accumulation significantly decreased at end-stage. Thus, compensatory mechanisms appear to maintain ROS homoeostasis until late in disease progression, preserving AIH-induced respiratory plasticity. Following intrathecal injections of an NADPH oxidase inhibitor (apocynin; 600 μM; 12 μL), pLTF was abolished in pre-symptomatic, but not end-stage MT rats, demonstrating that pLTF is NADPH oxidase dependent in pre-symptomatic, but NADPH oxidase independent in end-stage MT rats. Mechanisms preserving/enhancing the capacity for pLTF in MT rats are not known.}, }
@article {pmid26281945, year = {2015}, author = {Johnson, DA and Johnson, JA}, title = {Nrf2--a therapeutic target for the treatment of neurodegenerative diseases.}, journal = {Free radical biology &amp; medicine}, volume = {88}, number = {Pt B}, pages = {253-267}, pmid = {26281945}, issn = {1873-4596}, support = {P50AG033514/AG/NIA NIH HHS/United States ; R01 ES10042/ES/NIEHS NIH HHS/United States ; R01 ES008089/ES/NIEHS NIH HHS/United States ; R01 AG033493/AG/NIA NIH HHS/United States ; R01 ES08089/ES/NIEHS NIH HHS/United States ; R01 ES010042/ES/NIEHS NIH HHS/United States ; P50 AG033514/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Brain/metabolism ; Humans ; NF-E2-Related Factor 2/*metabolism ; Neurodegenerative Diseases/*metabolism ; Oxidation-Reduction ; Oxidative Stress/*physiology ; Signal Transduction/*physiology ; }, abstract = {The brain is very sensitive to changes in redox status; thus maintaining redox homeostasis in the brain is critical for the prevention of accumulating oxidative damage. Aging is the primary risk factor for developing neurodegenerative diseases. In addition to age, genetic and environmental risk factors have also been associated with disease development. The primary reactive insults associated with the aging process are a result of oxidative stress (OS) and nitrosative stress (NS). Markers of increased oxidative stress, protein and DNA modification, inflammation, and dysfunctional proteostasis have all been implicated in contributing to the progression of neurodegeneration. The ability of the cell to combat OS/NS and maintain a clearance mechanism for misfolded aggregating proteins determines whether or not it will survive. A critical pathway in this regard is the Nrf2 (nuclear factor erythroid 2-related factor 2)- antioxidant response element (ARE) pathway. Nrf2 activation has been shown to mitigate a number of pathologic mechanisms associated with Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. This review will focus on the role of Nrf2 in these diseases and the potential for Nrf2 activation to attenuate disease progression.}, }
@article {pmid26278107, year = {2015}, author = {Michaud, M and Gauchet, C and Dray, C}, title = {Response to Elia et al. 'Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis'.}, journal = {European journal of neurology}, volume = {22}, number = {9}, pages = {e77}, doi = {10.1111/ene.12729}, pmid = {26278107}, issn = {1468-1331}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Cholagogues and Choleretics/*pharmacology ; Endoplasmic Reticulum/*physiology ; Humans ; Taurochenodeoxycholic Acid/*pharmacology ; Unfolded Protein Response/*physiology ; }, }
@article {pmid26268132, year = {2015}, author = {de Luis, DA and Izaola, O and de la Fuente, B and Muñoz-Calero, P and Franco-Lopez, A}, title = {[NEURODEGENERATIVE DISEASES; NUTRITIONAL ASPECTS].}, journal = {Nutricion hospitalaria}, volume = {32}, number = {2}, pages = {946-951}, doi = {10.3305/nh.2015.32.2.9252}, pmid = {26268132}, issn = {1699-5198}, mesh = {Disease Progression ; Humans ; Neurodegenerative Diseases/diagnosis/*epidemiology/therapy ; Nutrition Assessment ; Nutritional Status ; Nutritional Support ; Patient Outcome Assessment ; Prognosis ; }, abstract = {INTRODUCTION: neurodegenerative diseases cause changes in the level of consciousness or swallowing mechanisms that often necessitate a specialized nutritional support.<br><br>OBJECTIVE: review the risk of malnutrition and its treatment in patients with cerebral vascular disease, Parkinson's disease, dementia and amyotrophic lateral sclerosis.<br><br>DEVELOPMENT: degenerative neurological diseases are one of the main indications for nutritional support in our country. In acute processes (cerebral vascular disease), proper nutritional management is related to better outcomes and reduced complications. In chronic neurodegenerative processes (amyotrophic lateral sclerosis and dementia), malnutrition is a major problem that worsens the prognosis of these patients, the proper management of dysphagia and its complications, as well as the use of different stages of support being necessary nutritional. A correct nutritional evaluation of these patients and a right nutrition intervention is essential in monitoring their disease. Finally, in advanced Parkinson's disease, nutritional support, as in previous neurodegenerative diseases, is of huge importance. Protein dietary load and its distribution in the diet of these patients are important, too. Finally, American Society for Parenteral and Enteral Nutrition ASPEN recommend, with a degree of evidence B, performing a screening of malnutrition in patients with neurological diseases.<br><br>CONCLUSIONS: a correct nutritional evaluation and adequate nutritional support should be part of diagnostic and therapeutic process of these diseases.}, }
@article {pmid26263977, year = {2015}, author = {Abdelhak, A and Junker, A and Brettschneider, J and Kassubek, J and Ludolph, AC and Otto, M and Tumani, H}, title = {Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis?.}, journal = {International journal of molecular sciences}, volume = {16}, number = {8}, pages = {17565-17588}, pmid = {26263977}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/*cerebrospinal fluid/physiopathology ; Biomarkers/*cerebrospinal fluid ; Brain/pathology ; Brain Injuries/*genetics/pathology ; Cytoskeleton/pathology ; Humans ; Motor Neurons/metabolism/pathology ; Multiple Sclerosis, Chronic Progressive/*cerebrospinal fluid/physiopathology ; Tubulin/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; }, abstract = {Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and its severity during disease course. In this article, we review the published literature regarding brain-specific CSF markers for cytoskeletal damage in primary progressive multiple sclerosis and amyotrophic lateral sclerosis in order to evaluate their utility as a biomarker for disease progression in conjunction with imaging and histological markers which might also be useful in other neurodegenerative diseases associated with affection of the upper motor neurons. A long-term benefit of such an approach could be facilitating early diagnostic and prognostic tools and assessment of treatment efficacy of disease modifying drugs.}, }
@article {pmid26263830, year = {2015}, author = {Cortez, E and Panchal, AR and Davis, J and Zeeb, P and Keseg, DP}, title = {Clinical Outcomes in Cardiac Arrest Patients Following Prehospital Treatment with Therapeutic Hypothermia.}, journal = {Prehospital and disaster medicine}, volume = {30}, number = {5}, pages = {452-456}, doi = {10.1017/S1049023X15004987}, pmid = {26263830}, issn = {1945-1938}, mesh = {Aged ; Cardiopulmonary Resuscitation ; Emergency Medical Services ; Female ; Humans ; Hypothermia, Induced/adverse effects/*methods ; Male ; Middle Aged ; Out-of-Hospital Cardiac Arrest/mortality/*therapy ; Retrospective Studies ; Survival Rate ; Treatment Outcome ; }, abstract = {INTRODUCTION: Recent studies have brought to question the efficacy of the use of prehospital therapeutic hypothermia for victims of out-of-hospital cardiac arrest (OHCA). Though guidelines recommend therapeutic hypothermia as a critical link in the chain of survival, the safety of this intervention, with the possibility of minimal treatment benefit, becomes important. Hypothesis/Problem This study examined prehospital therapeutic hypothermia for OHCA, its association with survival, and its complication profile in a large, metropolitan, fire-based Emergency Medical Services (EMS) system, where bystander cardiopulmonary resuscitation (CPR) and post-arrest care are in the process of being optimized.<br><br>METHODS: This evaluation was a retrospective chart review of all OHCA patients with return of spontaneous circulation (ROSC) treated with therapeutic hypothermia, from January 1, 2013 through November 30, 2013. The primary outcomes were the proportion of patients with initiation of prehospital therapeutic hypothermia with survival to hospital admission, the proportion of patients with initiation of prehospital therapeutic hypothermia with survival to hospital discharge, and the complication profile of therapeutic hypothermia in this population. The complication profile included several clinical, radiographic, and laboratory parameters. Exclusion criteria included: no prehospital therapeutic hypothermia initiation; no ROSC; and age of 17 year old or younger.<br><br>RESULTS: Fifty-one post-cardiac arrest patients were identified that met inclusion criteria. The mean age was 61 years (SD=14.7 years), and 33 (72%) were male. The initial rhythm was ventricular fibrillation or pulseless ventricular tachycardia in 17 (37%) patients, and bystander CPR was performed in 28 (61%) patients with ROSC. Thirty-nine (85%) patients survived to hospital admission. Twenty-one patients (48%; 95% CI, 33-64) were administered vasopressors, 10 patients (24%; 95% CI, 10-37) were administered diuretics, and 19 patients (44%; 95% CI, 29-60) were administered antibiotics. Initial chest radiograph (CXR) findings were normal in 12 (29%) patients. Overall, 13 (28%; 95% CI, 15-42) study patients survived to hospital discharge.<br><br>CONCLUSION: Recent reports have questioned the efficacy and safety of prehospital therapeutic hypothermia. In this evaluation, in the setting of unstandardized post-arrest care, 85% of the patients survived to hospital admission and 28% survived to hospital discharge, with a complication profile which was similar to that noted in other studies. This suggests that further evidence may be needed before EMS systems stop administering therapeutic hypothermia to appropriately selected patients. In less-optimized systems, therapeutic hypothermia may still be an essential link in the chain of survival.}, }
@article {pmid26260390, year = {2015}, author = {Fernández-Ruiz, J and Moro, MA and Martínez-Orgado, J}, title = {Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {4}, pages = {793-806}, pmid = {26260390}, issn = {1878-7479}, mesh = {Animals ; Brain Injuries/*drug therapy ; Cannabinoids/*therapeutic use ; Disease Models, Animal ; *Drug Evaluation, Preclinical ; Humans ; Neurodegenerative Diseases/*drug therapy ; Stroke/*drug therapy ; }, abstract = {Cannabinoids form a singular family of plant-derived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects.}, }
@article {pmid26257025, year = {2015}, author = {Odackal, J and Sherpa, AD and Patel, N and Colbourn, R and Hrabetova, S}, title = {T-type calcium channels contribute to calcium disturbances in brain during hyponatremia.}, journal = {Experimental neurology}, volume = {273}, number = {}, pages = {105-113}, pmid = {26257025}, issn = {1090-2430}, support = {R01 NS028642/NS/NINDS NIH HHS/United States ; R01 NS047557/NS/NINDS NIH HHS/United States ; R01NS028642/NS/NINDS NIH HHS/United States ; R01NS047557/NS/NINDS NIH HHS/United States ; }, mesh = {Analysis of Variance ; Animals ; Brain/drug effects/*metabolism ; Calcium/*metabolism ; Calcium Channel Blockers/pharmacology ; Calcium Channels, T-Type/*metabolism ; Chondroitin ABC Lyase/pharmacology ; Disease Models, Animal ; Extracellular Space/metabolism ; Hyponatremia/*pathology ; In Vitro Techniques ; Ion-Selective Electrodes ; Mice ; Mice, Inbred C57BL ; Osmolar Concentration ; }, abstract = {Disturbance of calcium homeostasis is implicated in the normal process of aging and brain pathology prevalent in the elderly such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Previous studies demonstrated that applying a hyponatremic iso-osmotic (low-NaCl) artificial cerebrospinal fluid (ACSF) to rodent hippocampus causes extracellular calcium to rapidly decrease. Restoring normonatremia after low-NaCl treatment causes a rapid increase in extracellular calcium that overshoots baseline. This study examined the amplitude, timing, and mechanism of these surprising calcium changes. We also tested whether hyponatremia increased calcium entry into brain cells or calcium binding to chondroitin sulfate (CS), a negatively charged constituent of the extracellular matrix (ECM) that may be occupied by sodium during normonatremia. We report three major findings. First we show that CS does not contribute to extracellular calcium changes during low-NaCl treatments. Second, we show that the time to minimum extracellular calcium during low-NaCl treatment is significantly shorter than the time to maximum extracellular calcium in recovery from low-NaCl treatment. Third, we show that the decrease in extracellular calcium observed during hyponatremia is attenuated by ML 218, a highly selective T-type calcium channel blocker. Together these data suggest that calcium rapidly enters cells at the onset of low-NaCl treatment and is extruded from cells when normonatremia is restored. Calcium binding to CS does not significantly contribute to calcium changes in brain during hyponatremia. Differences in timing suggest that extracellular calcium changes during and in recovery from hyponatremia occur by distinct mechanisms or by a multistep process. Finally, partial block of extracellular calcium influx by ML 218 suggests that T-type channels are involved in calcium entering cells during hyponatremia. Given the high prevalence of hyponatremia among elderly patients and the growing understanding of calcium's role in multiple neurologic pathologies, this study promotes a novel approach for studying and potentially preventing the effects of hyponatremia on calcium dysregulation in brain tissue.}, }
@article {pmid26240626, year = {2015}, author = {Huang, J and Hao, S and Yang, F and Di, Y and Yao, L and Li, J and Jiang, Y and Zhong, L and Fu, D and Jin, C}, title = {Endoscopic metal enteral stent placement for malignant afferent loop syndrome after pancreaticoduodenectomy.}, journal = {Wideochirurgia i inne techniki maloinwazyjne = Videosurgery and other miniinvasive techniques}, volume = {10}, number = {2}, pages = {257-265}, pmid = {26240626}, issn = {1895-4588}, abstract = {INTRODUCTION: Afferent loop syndrome (ALS) is a rare and dreaded complication after pancreaticoduodenectomy (PD). Malignant ALS after PD is usually difficult to manage due to patients' poor condition. Effective and safe therapeutic strategies for these patients are reported scarcely at present.<br><br>AIM: To analyze and evaluate the clinical characteristics and treatment of these patients.<br><br>MATERIAL AND METHODS: We analyzed 3 patients with malignant ALS after PD. They were treated by endoscopic enteral metal stent placement in our hospital. Meanwhile we retrospectively reviewed 49 cases with ALS after PD through available English literature. All these patients' clinical features, laboratory study, treatment and outcome were evaluated.<br><br>RESULTS: A total of 52 cases were analyzed in the study. The most common presenting symptoms of ALS after PD were jaundice (56.5%), upper abdominal pain (45.7%), fever (26.1%), and vomiting (23.9%). Sixty percent of ALS cases were caused by tumor recurrence. The mean time from prior surgery to diagnosis of ALS was 13.3 months. The rates of treatment with the endoscopic approach, percutaneous stenting or drainage, surgery, and the conservative method were 40.4%, 32.7%, 11.5%, and 15.4%, respectively. Endoscopic enteral metal stent placement proved more effective and less invasive in the treatment of malignant ALS after PD.<br><br>CONCLUSIONS: Cholangitis and cholangiectasis are the major manifestations of malignant ALS after PD. Invasive interventions are enjoying more and more acceptance for treatment. Endoscopic enteral metal stent placement appears to be a promising technique with effective palliation in these patients.}, }
@article {pmid26237914, year = {2015}, author = {Siirala, W and Korpela, J and Vuori, A and Saaresranta, T and Olkkola, KT and Aantaa, R}, title = {[Amyotrophic lateral sclerosis and respiratory insufficiency].}, journal = {Duodecim; laaketieteellinen aikakauskirja}, volume = {131}, number = {2}, pages = {127-135}, pmid = {26237914}, issn = {0012-7183}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; *Noninvasive Ventilation ; Respiratory Insufficiency/*diagnosis/*etiology/*therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease causing degeneration of motor neurons, without any curative treatment. The most common cause of death is respiratory arrest due to atrophy of the respiratory musculature. ALS-associated respiratory insufficiency differs in mechanism from the more common causes of dyspnea, such as diseases of pulmonary or cardiac origin. Recognizing the respiratory insufficiency can be challenging for a clinician. It should be possible to predict the development of respiratory insufficiency in order to avoid leaving the treatment decisions concerning respiratory insufficiency to emergency services. Noninvasive ventilatory support can be used to alleviate the patient's dyspnea. It is actually recommended as the first-line treatment of ALS-associated respiratory insufficiency.}, }
@article {pmid26234554, year = {2015}, author = {,  and , }, title = {Safety and efficacy of diaphragm pacing in patients with respiratory insufficiency due to amyotrophic lateral sclerosis (DiPALS): a multicentre, open-label, randomised controlled trial.}, journal = {The Lancet. Neurology}, volume = {14}, number = {9}, pages = {883-892}, doi = {10.1016/S1474-4422(15)00152-0}, pmid = {26234554}, issn = {1474-4465}, support = {MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*complications/diagnosis/*therapy ; *Diaphragm/physiology ; Female ; Humans ; Male ; Middle Aged ; Respiratory Insufficiency/diagnosis/*etiology/*therapy ; Respiratory Therapy/adverse effects/*methods ; Treatment Outcome ; }, abstract = {BACKGROUND: Non-invasive ventilation is part of the standard of care for treatment of respiratory failure in patients with amyotrophic lateral sclerosis (ALS). The NeuRx RA/4 Diaphragm Pacing System has received Humanitarian Device Exemption approval from the US Food and Drug Administration for treatment of respiratory failure in patients with ALS. We aimed to establish the safety and efficacy of diaphragm pacing with this system in patients with respiratory muscle weakness due to ALS.<br><br>METHODS: We undertook a multicentre, open-label, randomised controlled trial at seven specialist ALS and respiratory centres in the UK. Eligible participants were aged 18 years or older with laboratory supported probable, clinically probable, or clinically definite ALS; stable riluzole treatment for at least 30 days; and respiratory insufficiency. We randomly assigned participants (1:1), via a centralised web-based randomisation system with minimisation that balanced patients for age, sex, forced vital capacity, and bulbar function, to receive either non-invasive ventilation plus pacing with the NeuRx RA/4 Diaphragm Pacing System or non-invasive ventilation alone. Patients, carers, and outcome assessors were not masked to treatment allocation. The primary outcome was overall survival, defined as the time from randomisation to death from any cause. Analysis was by intention to treat. This trial is registered, ISRCTN number 53817913.<br><br>FINDINGS: Between Dec 5, 2011, and Dec 18, 2013, we randomly assigned 74 participants to receive either non-invasive ventilation alone (n=37) or non-invasive ventilation plus diaphragm pacing (n=37). On Dec 18, 2013, the Data Monitoring and Ethics Committee (DMEC) recommended suspension of recruitment on the basis of overall survival figures. Randomly assigned participants continued as per the study protocol until June 23, 2014, when the DMEC advised discontinuation of pacing in all patients. Follow-up assessments continued until the planned end of the study in December, 2014. Survival was shorter in the non-invasive ventilation plus pacing group than in the non-invasive ventilation alone group (median 11&#xb7;0 months [95% CI 8&#xb7;3-13&#xb7;6] vs 22&#xb7;5 months [13&#xb7;6-not reached]; adjusted hazard ratio 2&#xb7;27, 95% CI 1&#xb7;22-4&#xb7;25; p=0&#xb7;009). 28 (76%) patients died in the pacing group and 19 (51%) patients died in the non-invasive ventilation alone group. We recorded 162 adverse events (5&#xb7;9 events per person-year) in the pacing group, of which 46 events were serious, compared with 81 events (2&#xb7;5 events per person-year) in the non-invasive ventilation alone group, of which 31 events were serious.<br><br>INTERPRETATION: Addition of diaphragm pacing to standard care with non-invasive ventilation was associated with decreased survival in patients with ALS. Our results suggest that diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure.<br><br>FUNDING: The National Institute for Health Research Health Technology Assessment Programme; the Motor Neurone Disease Association of England, Wales, and Northern Ireland.}, }
@article {pmid26230709, year = {2015}, author = {Lee, SH and Choi, SM and Yang, EJ}, title = {Bee Venom Acupuncture Augments Anti-Inflammation in the Peripheral Organs of hSOD1G93A Transgenic Mice.}, journal = {Toxins}, volume = {7}, number = {8}, pages = {2835-2844}, pmid = {26230709}, issn = {2072-6651}, mesh = {*Acupuncture Therapy ; Amyotrophic Lateral Sclerosis/metabolism/*therapy ; Animals ; Anti-Inflammatory Agents/*administration &amp; dosage/therapeutic use ; Bee Venoms/*administration &amp; dosage/therapeutic use ; Calcium-Binding Proteins/metabolism ; Cyclooxygenase 2/metabolism ; Disease Models, Animal ; Kidney/drug effects/metabolism ; Liver/drug effects/metabolism ; Mice, Transgenic ; Microfilament Proteins/metabolism ; Spleen/drug effects/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) includes progressively degenerated motor neurons in the brainstem, motor cortex, and spinal cord. Recent reports demonstrate the dysfunction of multiple organs, including the lungs, spleen, and liver, in ALS animals and patients. Bee venom acupuncture (BVA) has been used for treating inflammatory diseases in Oriental Medicine. In a previous study, we demonstrated that BV prevented motor neuron death and increased anti-inflammation in the spinal cord of symptomatic hSOD1G93A transgenic mice. In this study, we examined whether BVA's effects depend on acupuncture point (ST36) in the organs, including the liver, spleen and kidney, of hSOD1G93A transgenic mice. We found that BV treatment at ST36 reduces inflammation in the liver, spleen, and kidney compared with saline-treatment at ST36 and BV injected intraperitoneally in symptomatic hSOD1G93A transgenic mice. Those findings suggest that BV treatment combined with acupuncture stimulation is more effective at reducing inflammation and increasing immune responses compared with only BV treatment, at least in an ALS animal model.}, }
@article {pmid26225210, year = {2015}, author = {Jiang, Z and Wang, W and Perry, G and Zhu, X and Wang, X}, title = {Mitochondrial dynamic abnormalities in amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {4}, number = {}, pages = {14}, pmid = {26225210}, issn = {2047-9158}, support = {G12 MD007591/MD/NIMHD NIH HHS/United States ; R01 NS089604/NS/NINDS NIH HHS/United States ; R03 AG044680/AG/NIA NIH HHS/United States ; R21 NS085747/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease characterized by progressive loss of motor neurons in the brainstem and spinal cord. Currently, there is no cure or effective treatment for ALS and the cause of disease is unknown in the majority of ALS cases. Neuronal mitochondria dysfunction is one of the earliest features of ALS. Mitochondria are highly dynamic organelles that undergo continuous fission, fusion, trafficking and turnover, all of which contribute to the maintenance of mitochondrial function. Abnormal mitochondrial dynamics have been repeatedly reported in ALS and increasing evidence suggests altered mitochondrial dynamics as possible pathomechanisms underlying mitochondrial dysfunction in ALS. Here, we provide an overview of mitochondrial dysfunction and dynamic abnormalities observed in ALS, and discuss the possibility of targeting mitochondrial dynamics as a novel therapeutic approach for ALS.}, }
@article {pmid26221970, year = {2016}, author = {Roh, YJ and Jee, D and Rho, CR and Cho, WK and Kang, S}, title = {Anti-angiogenic effect of ALS-L1023, an extract of Melissa officinalis L., on experimental choroidal neovascularization in mice.}, journal = {Clinical &amp; experimental ophthalmology}, volume = {44}, number = {1}, pages = {43-51}, doi = {10.1111/ceo.12583}, pmid = {26221970}, issn = {1442-9071}, mesh = {Administration, Oral ; Angiogenesis Inhibitors/*pharmacology ; Animals ; Blotting, Western ; Choroid/blood supply ; Choroidal Neovascularization/*drug therapy/metabolism/physiopathology ; Chromatography, High Pressure Liquid ; *Disease Models, Animal ; Endothelium, Vascular/drug effects/metabolism ; Fluorescein Angiography ; Human Umbilical Vein Endothelial Cells ; Male ; Melissa/*chemistry ; Mice ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Phosphorylation ; Plant Extracts/*pharmacology ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {BACKGROUND: The effect of ALS-L1023, an extract of Melissa officinalis L. (Labiatae; lemon balm) leaves, on experimental choroidal neovascularization (CNV) in mice was evaluated.<br><br>METHODS: C57BL/6 mice were given either vehicle or ALS-L1023 daily via oral gavage for 3&#x2009;weeks (days 0-21). CNV was induced by rupturing Bruch's membrane using laser photocoagulation (day 7). Two weeks after laser injury (day 21), the CNV lesions were evaluated by an examination of choroidal flat mounts using fluorescein-labelled dextran, immunofluorescence staining with isolectin B4 and fluorescence angiography. The effects of ALS-L1023 on endothelial cell tube formation and the expression of phosphorylated extracellular signal-regulated kinase 1/2 were evaluated using human umbilical vein endothelial cells.<br><br>RESULTS: The extent of CNV was reduced by ALS-L1023. Mice treated with 100 and 200&#x2009;mg/kg/day of the material exhibited 44.3 and 68.1% reductions in the extent of CNV lesions, respectively, compared to the vehicle group (P&#x2009;<&#x2009;0.001). The size of the isolectin B4-labelled area was also significantly decreased in the ALS-L1023-treated groups (P&#x2009;<&#x2009;0.001). On fluorescein angiography, ALS-L1023-treated mice exhibited significantly less leakage of fluorescent material than did vehicle-treated mice. ALS-L1023 decreased vascular endothelial growth factor-induced human umbilical vein endothelial cell tube formation in a dose-dependent manner. The expression of phosphorylated extracellular signal-regulated kinase 1/2 was suppressed by ALS-L1023.<br><br>CONCLUSIONS: The laser-induced CNV in mice can be inhibited by ALS-L1023. Therefore, it may have therapeutic potential for the treatment of diseases involving CNV.}, }
@article {pmid26221742, year = {2015}, author = {Opattova, A and Cente, M and Novak, M and Filipcik, P}, title = {The ubiquitin proteasome system as a potential therapeutic target for treatment of neurodegenerative diseases.}, journal = {General physiology and biophysics}, volume = {34}, number = {4}, pages = {337-352}, doi = {10.4149/gpb_2015024}, pmid = {26221742}, issn = {0231-5882}, mesh = {Animals ; Brain/*metabolism ; Humans ; Models, Neurological ; Molecular Targeted Therapy/methods ; Nerve Tissue Proteins/*metabolism ; Neurodegenerative Diseases/*metabolism/therapy ; Neuroprotective Agents/therapeutic use ; Proteasome Endopeptidase Complex/*metabolism ; Ubiquitin-Protein Ligase Complexes/*metabolism ; Ubiquitins/*metabolism ; }, abstract = {Impairment of "protein quality control" in neurons is associated with etiopathogenesis of neurodegenerative diseases. The worn-out products of cell metabolism should be safely eliminated via the proteasome, autophago-lysosome and exocytosis. Insufficient activity of these degradation mechanisms within neurons leads to the accumulation of toxic protein oligomers, which represent a starting material for development of neurodegenerative proteinopathy. The spectrum of CNS linked proteinopathies is particularly broad and includes Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia, Pick disease, Frontotemporal dementia, Huntington disease, Amyotrophic lateral sclerosis and many others. Although the primary events in etiopathogenesis of sporadic forms of these diseases are still unknown, it is clear that aging, in connection with decreased activity of ubiquitin proteasome system, is the most significant risk factor. In this review we discuss the pathogenic role and intracellular fate of the candidate molecules associated with onset and progression of AD and PD, the protein tau and α-synuclein in context with the function of ubiquitin proteasome system. We also discuss the possibility whether or not the strategies focused to re-establishment of neuroproteostasis via accelerated clearance of damaged proteins in proteasome could be a promising therapeutic approach for treatment of major neurodegenerative diseases.}, }
@article {pmid26220007, year = {2015}, author = {Funke, A and Grehl, T and Großkreutz, J and Münch, C and Walter, B and Kettemann, D and Karnapp, C and Gajewski, N and Meyer, R and Maier, A and Gruhn, KM and Prell, T and Kollewe, K and Abdulla, S and Kobeleva, X and Körner, S and Petri, S and Meyer, T}, title = {[Provision of assistive devices in amyotrophic lateral sclerosis. Analysis of 3 years case management in an internet-based supply network].}, journal = {Der Nervenarzt}, volume = {86}, number = {8}, pages = {1007-1017}, pmid = {26220007}, issn = {1433-0407}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*rehabilitation ; Case Management/*statistics &amp; numerical data ; Germany/epidemiology ; Health Care Rationing/statistics &amp; numerical data ; Health Services Accessibility/statistics &amp; numerical data ; Humans ; Internet/*statistics &amp; numerical data/supply &amp; distribution ; Longitudinal Studies ; Patient Acceptance of Health Care/*statistics &amp; numerical data ; Prevalence ; Self-Help Devices/*statistics &amp; numerical data/*supply &amp; distribution ; Utilization Review ; }, abstract = {BACKGROUND: The provision of assistive devices (PAD) is a key element of care in amyotrophic lateral sclerosis (ALS). Since 2011, assistive devices (AD) have been coordinated in an internet-supported care network at university-based ALS centers in Berlin, Bochum, Hannover and Jena. The digitization of PAD processes has facilitated the evaluation of real-life ALS care.<br><br>OBJECTIVES: Orthotics (OT), augmentative and alternative communication (AAC), supported treadmill (ST) and powered wheelchair (PW) were the PAD groups analyzed for delivery rates (proportion of delivered AD vs. medically indicated AD), rejection by patients and payers and latency of provision of care.<br><br>RESULTS: Between June 2011 and October 2014 a total of 1479 patients and 12,478 AD were coordinated, among which 3313 PAD were related to OT, AAC, ST or EM. The median delivery rate was 64.3&#x2009;%. The mean rejection rate by patients was 9.8&#x2009;% (OT 5.4&#x2009;%, AAC 9.8&#x2009;%, ST 10.2&#x2009;% and PW 15.6&#x2009;%). Marked differences were noted in the rejection rate by payers and in care provision latency: OT (16.2&#x2009;%, 68 days, n&#x2009;=&#x2009;734), AAC (30.4&#x2009;%, 96 days, n&#x2009;=&#x2009;392), ST (34.8&#x2009;%, 113 days, n&#x2009;=&#x2009;164) and PW (35.6&#x2009;%, 129 days, n&#x2009;=&#x2009;259). Analysis of rejection rates showed significant differences among insurers.<br><br>CONCLUSION: Only two thirds of the medically indicated AD reached the patients. Rejection rates by patients and payers and latency of provision of care were high. The PAD can substantially vary among health insurance companies. The establishment of consented criteria for PAD and their integration into treatment regimens and guidelines are crucial tasks for the future.}, }
@article {pmid26210990, year = {2015}, author = {Scheper, W and Hoozemans, JJ}, title = {The unfolded protein response in neurodegenerative diseases: a neuropathological perspective.}, journal = {Acta neuropathologica}, volume = {130}, number = {3}, pages = {315-331}, pmid = {26210990}, issn = {1432-0533}, mesh = {Animals ; Brain/*pathology/*physiopathology ; Humans ; Neurodegenerative Diseases/*pathology/*physiopathology ; Unfolded Protein Response/*physiology ; }, abstract = {The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER) to a disturbance in protein folding. The so-called ER stress sensors PERK, IRE1 and ATF6 play a central role in the initiation and regulation of the UPR. The accumulation of misfolded and aggregated proteins is a common characteristic of neurodegenerative diseases. With the discovery of the basic machinery of the UPR, the idea was born that the UPR or part of its machinery could be involved in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and prion disease. Over the last decade, the UPR has been addressed in an increasing number of studies on neurodegeneration. The involvement of the UPR has been investigated in human neuropathology across different neurological diseases, as well as in cell and mouse models for neurodegeneration. Studies using different disease models display discrepancies on the role and function of the UPR during neurodegeneration, which can often be attributed to differences in methodology. In this review, we will address the importance of investigation of human brain material for the interpretation of the role of the UPR in neurological diseases. We will discuss evidence for UPR activation in neurodegenerative diseases, and the methodology to study UPR activation and its connection to brain pathology will be addressed. More recently, the UPR is recognized as a target for drug therapy for treatment and prevention of neurodegeneration, by inhibiting the function of specific mediators of the UPR. Several preclinical studies have shown a proof-of-concept for this approach targeting the machinery of UPR, in particular the PERK pathway, in different models for neurodegeneration and have yielded paradoxical results. The promises held by these observations will need further support by clarification of the observed differences between disease models, as well as increased insight obtained from human neuropathology.}, }
@article {pmid26210454, year = {2015}, author = {Kim, HJ and Nagano, Y and Choi, SJ and Park, SY and Kim, H and Yao, TP and Lee, JY}, title = {HDAC6 maintains mitochondrial connectivity under hypoxic stress by suppressing MARCH5/MITOL dependent MFN2 degradation.}, journal = {Biochemical and biophysical research communications}, volume = {464}, number = {4}, pages = {1235-1240}, doi = {10.1016/j.bbrc.2015.07.111}, pmid = {26210454}, issn = {1090-2104}, mesh = {Animals ; Cell Hypoxia/physiology ; Down-Regulation ; Female ; GTP Phosphohydrolases/*metabolism ; Histone Deacetylase 6 ; Histone Deacetylases/*metabolism ; Humans ; Membrane Proteins ; Mice ; Mitochondria/*metabolism/ultrastructure ; Mitochondrial Proteins/*metabolism ; Oxygen/metabolism ; Stress, Physiological/*physiology ; Ubiquitin-Protein Ligases/*metabolism ; }, abstract = {Mitochondria undergo fusion and fission in response to various metabolic stresses. Growing evidences have suggested that the morphological change of mitochondria by fusion and fission plays a critical role in protecting mitochondria from metabolic stresses. Here, we showed that hypoxia treatment could induce interaction between HDAC6 and MFN2, thus protecting mitochondrial connectivity. Mechanistically, we demonstrated that a mitochondrial ubiquitin ligase MARCH5/MITOL was responsible for hypoxia-induced MFN2 degradation in HDAC6 deficient cells. Notably, genetic abolition of HDAC6 in amyotrophic lateral sclerosis model mice showed MFN2 degradation with MARCH5 induction. Our results indicate that HDAC6 is a critical regulator of MFN2 degradation by MARCH5, thus protecting mitochondrial connectivity from hypoxic stress.}, }
@article {pmid26203659, year = {2015}, author = {Wei, Q and Chen, X and Zheng, Z and Huang, R and Guo, X and Cao, B and Zhao, B and Shang, H}, title = {Clinical features of amyotrophic lateral sclerosis in south-west China.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {16}, number = {7-8}, pages = {512-519}, doi = {10.3109/21678421.2015.1069849}, pmid = {26203659}, issn = {2167-9223}, mesh = {Adult ; Age of Onset ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/complications/drug therapy/epidemiology/*physiopathology ; Bulbar Palsy, Progressive/etiology/*physiopathology ; China/epidemiology ; Cross-Sectional Studies ; Educational Status ; Female ; Humans ; Male ; Middle Aged ; Muscle Weakness/etiology/*physiopathology ; Neuroprotective Agents/therapeutic use ; *Registries ; Riluzole/therapeutic use ; Rural Population ; Sex Distribution ; Tertiary Care Centers ; Urban Population ; }, abstract = {Our objective was to profile clinical features of amyotrophic lateral sclerosis (ALS); we performed a large sample, cross-sectional study based on a hospital registry of ALS in south-west China. Patients were coded in our tertiary referral centre from May 2006 to September 2014. Demographic data and disease-related parameters were collected. A total of 1131 patients were included. Mean age of onset was 54.3 ± 11.6 years and the highest proportion of onset age (30.6%) was between 51 and 60 years. Male:female ratio was 1.45:1. Nearly 30% of the patients were young onset, and 20.3% of the patients were bulbar onset; only 35% received riluzole treatment. The young-onset patients had a higher educational level with a higher proportion performing manual labour and living in rural areas, and a lower proportion with bulbar onset than those who were older at onset. The bulbar-onset patients were older at age of onset, with a lower proportion of males than spinal-onset patients. In conclusion, Chinese ALS patients may be younger at age of onset than Caucasian patients. Environmental and geographical factors are related to the occurrence of ALS. The large treatment gap indicated a pressing need for medical and financial support for Chinese ALS patients.}, }
@article {pmid26202426, year = {2016}, author = {Perera, ND and Turner, BJ}, title = {AMPK Signalling and Defective Energy Metabolism in Amyotrophic Lateral Sclerosis.}, journal = {Neurochemical research}, volume = {41}, number = {3}, pages = {544-553}, pmid = {26202426}, issn = {1573-6903}, support = {G1002117//Medical Research Council/United Kingdom ; }, mesh = {AMP-Activated Protein Kinases/*metabolism ; Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Brain/metabolism ; *Energy Metabolism ; Glycolysis ; Humans ; Lipid Metabolism ; Mitochondria/metabolism ; Motor Neurons/metabolism ; Oxidative Phosphorylation ; Signal Transduction ; Spinal Cord/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is caused by selective loss of upper and lower motor neurons by complex mechanisms that are incompletely understood. Motor neurons are large, highly polarised and excitable cells with unusually high energetic demands to maintain resting membrane potential and propagate action potentials. This leads to higher ATP consumption and mitochondrial metabolism in motor neurons relative to other cells. Here, we review increasing evidence that defective energy metabolism and homeostasis contributes to selective vulnerability and degeneration of motor neurons in ALS. Firstly, we provide a brief overview of major energetic pathways in the CNS, including glycolysis, oxidative phosphorylation and the AMP-activated protein kinase (AMPK) signalling pathway, while highlighting critical metabolic interactions between neurons and astrocytes. Next, we review evidence from ALS patients and transgenic mutant SOD1 mice for weight loss, hypermetabolism, hyperlipidemia and mitochondrial dysfunction in disease onset and progression. Genetic and therapeutic modifiers of energy metabolism in mutant SOD1 mice will also be summarised. We also present evidence that additional ALS-linked proteins, TDP-43 and FUS, lead to energy disruption and mitochondrial defects in motor neurons. Lastly, we review emerging evidence including our own that dysregulation of the AMPK signalling cascade in motor neurons is an early and common event in ALS pathogenesis. We suggest that an imbalance in energy metabolism should be considered an important factor in both progression and potential treatment of ALS.}, }
@article {pmid26196041, year = {2016}, author = {Fujisawa, A and Yamamoto, Y}, title = {Edaravone, a potent free radical scavenger, reacts with peroxynitrite to produce predominantly 4-NO-edaravone.}, journal = {Redox report : communications in free radical research}, volume = {21}, number = {3}, pages = {98-103}, pmid = {26196041}, issn = {1743-2928}, mesh = {Antipyrine/*analogs &amp; derivatives/chemistry ; Edaravone ; Free Radical Scavengers/*chemistry ; Lipid Peroxidation ; Neuroprotective Agents/chemistry ; Oxidation-Reduction ; Peroxynitrous Acid/*chemistry ; Uric Acid/chemistry ; }, abstract = {OBJECTIVES: 3-Methyl-1-phenyl-2-pyrazolin-5-one (edaravone) is used in clinical treatment of acute brain infarction to rescue the penumbra, based on its ability to prevent lipid peroxidation by scavenging lipid peroxyl radicals. Here, we show that edaravone also reacts with peroxynitrite to yield 4-NO-edaravone as the major product and 4-NO2-edaravone as a minor product.<br><br>RESULTS: We observed little formation of 3-methyl-1-phenyl-2-pyrazolin-4,5-dione (4-oxoedaravone) and its hydrate, 2-oxo-3-(phenylhydrazono)butanoic acid, which are the major free radical-induced oxidation products of edaravone, suggesting that free radicals are not involved in the reaction with peroxynitrite. The reaction of peroxynitrite with edaravone is approximately 30-fold greater than with uric acid, a physiological peroxynitrite scavenger (reaction rate k&#x2009;=&#x2009;1.5&#x2009;&#xd7;&#x2009;10 (4) &#x2005;M(-1)&#x2005;s(-1) vs. 480&#x2005;M(-1)&#x2005;s(-1)).<br><br>DISCUSSION: These results suggest that edaravone functions therapeutically as a scavenger of peroxynitrite as well as lipid peroxyl radicals, which is consistent with a report that edaravone treatment reduced levels of 3-nitrotyrosine in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis.}, }
@article {pmid26194201, year = {2015}, author = {Hellmann, MA and Kakhlon, O and Landau, EH and Sadeh, M and Giladi, N and Schlesinger, I and Kidron, D and Abramsky, O and Reches, A and Argov, Z and Rabey, JM and Chapman, J and Rosenmann, H and Gal, A and Moshe Gomori, J and Meiner, V and Lossos, A}, title = {Frequent misdiagnosis of adult polyglucosan body disease.}, journal = {Journal of neurology}, volume = {262}, number = {10}, pages = {2346-2351}, pmid = {26194201}, issn = {1432-1459}, mesh = {Adult ; Aged ; *Delayed Diagnosis ; *Diagnostic Errors ; Female ; Glycogen Storage Disease/*diagnosis/therapy ; Humans ; Male ; Middle Aged ; Nervous System Diseases/*diagnosis/therapy ; Retrospective Studies ; }, abstract = {Adult polyglucosan body disease (APBD) is a rare glycogenosis manifesting progressive spastic paraparesis, sensorimotor polyneuropathy and neurogenic bladder. Misdiagnosis of APBD may lead to unnecessary investigations and to potentially harmful therapeutic interventions. To examine the frequency of misdiagnosis of APBD, we retrospectively reviewed the clinical data of 30 patients diagnosed between 1991 and 2013. Diagnosis was based on the combination of typical clinical and imaging findings, reduced glycogen branching enzyme activity, and the presence of p.Y326S GBE1 mutation. Initial symptoms started in the 5th-6th decade with bladder dysfunction (47 %), gait problems (33 %) or both. Diagnosis of APBD was delayed by 6.8 (±4.8) years. Consistent signs at diagnosis were spasticity in the legs (93 %), decreased or absent ankle reflexes (100 %), bilateral extensor plantar response (100 %) and distal sensory deficit (80 %). Nerve conduction study showed invariable sensorimotor polyneuropathy, and MRI demonstrated cervical spinal cord atrophy (100 %) and leukoencephalopathy (97 %). All 30 patients were initially misdiagnosed. Common misdiagnoses included cerebral small vessel disease (27 %), multiple sclerosis (17 %), amyotrophic lateral sclerosis (17 %) and peripheral neuropathies (20 %). Consequently, 27 % received inappropriate therapy. In addition, lower urinary tract symptoms in 60 % of men were attributed solely to prostatic disorders but did not respond to medical treatment or prostatectomy. These findings suggest that despite limited clinical variability, APBD is invariably misdiagnosed and patients are often mistreated. Physicians' unfamiliarity with the typical clinical and imaging features of APBD appears as the main reason for misdiagnosis.}, }
@article {pmid26191780, year = {2016}, author = {Nagase, M and Yamamoto, Y and Miyazaki, Y and Yoshino, H}, title = {Increased oxidative stress in patients with amyotrophic lateral sclerosis and the effect of edaravone administration.}, journal = {Redox report : communications in free radical research}, volume = {21}, number = {3}, pages = {104-112}, pmid = {26191780}, issn = {1743-2928}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism ; Antipyrine/*analogs &amp; derivatives/therapeutic use ; Biomarkers/blood ; Edaravone ; Fatty Acids, Nonesterified/blood ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Middle Aged ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Peroxynitrous Acid/blood ; Ubiquinone/analogs &amp; derivatives/blood ; Uric Acid/blood ; }, abstract = {OBJECTIVES AND METHODS: Compared to age-matched healthy controls (n = 55), patients with amyotrophic lateral sclerosis (ALS) (n = 26) showed increased oxidative stress as indicated by a significantly increased percentage of oxidized coenzyme Q10 (%CoQ10) in total plasma coenzyme Q10, a significantly decreased level of plasma uric acid, and a significantly decreased percentage of polyunsaturated fatty acids in total plasma free fatty acids (FFA). Therefore, the efficacy of edaravone, a radical scavenger, in these ALS patients was examined.<br><br>RESULTS AND DISCUSSION: Among 26 ALS patients, 17 received edaravone (30&#x2005;mg/day, one to four times a week) for at least 3 months, and 13 continued for 6 months. Changes in revised ALS functional rating scale (ALSFRS-R) were significantly smaller in these patients than in edaravone-untreated ALS patients (n&#x2009;=&#x2009;19). Edaravone administration significantly reduced excursions of more than one standard deviation from the mean for plasma FFA levels and the contents of palmitoleic and oleic acids, plasma markers of tissue oxidative damage, in the satisfactory progress group (&#x394;ALSFRS-R&#x2009;&#x2265;&#x2009;0) as compared to the ingravescent group (&#x394;ALSFRS-R&#x2009;<&#x2009;-5). Edaravone treatment increased plasma uric acid, suggesting that it is an effective scavenger of peroxynitrite. However, edaravone administration did not decrease %CoQ10. Therefore, combined treatment with agents such as coenzyme Q10 may further reduce oxidative stress in ALS patients.}, }
@article {pmid26190974, year = {2015}, author = {Riancho, J and Ruiz-Soto, M and Berciano, MT and Berciano, J and Lafarga, M}, title = {Neuroprotective Effect of Bexarotene in the SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {250}, pmid = {26190974}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive weakness and muscle atrophy related to the loss of upper and lower motor neurons (MNs) without a curative treatment. There is experimental evidence suggesting that retinoids may be involved in ALS pathogenesis. Bexarotene (Bxt) is a retinoid-X receptor agonist used in the treatment of cutaneous lymphoma with a favorable safety profile whose effects have been recently investigated in other neurodegenerative diseases. In this study, we analyze the potential therapeutic effect of Bxt in the SOD1(G93A) mouse model of ALS. Mice were treated with Bxt or vehicle five times per week from day 60 onward. Survival, weight, and neuromuscular function studies together with histological and biochemical analyses were performed. Bxt significantly delayed motor function deterioration, ameliorated the loss of body weight, and extended mice survival up to 30% of the symptomatic period. Histological analyses of the lumbosacral spinal cord revealed that Bxt markedly delayed the early motor-neuron degeneration occurring at presymptomatic stages in ALS-transgenic mice. Bxt treatment contributed to preserve the MN homeostasis in the SOD1(G93A) mice. Particularly, it reduced the neuronal loss and the chromatolytic response, induced nucleolar hypertrophy, decreased the formation of ubiquitylated inclusions, and modulated the lysosomal response. As an agonist of the retinoic-X receptor (RXR) pathway, Bxt notably increased the nuclear expression of the RXRα throughout transcriptionally active euchromatin domains. Bxt also contributed to protect the MN environment by reducing reactive astrogliosis and preserving perisomatic synapsis. Overall, these neuroprotective effects suggest that treatment with Bxt could be useful in ALS, particularly in those cases related to SOD1 mutations.}, }
@article {pmid26190973, year = {2015}, author = {Irvin, CW and Kim, RB and Mitchell, CS}, title = {Seeking homeostasis: temporal trends in respiration, oxidation, and calcium in SOD1 G93A Amyotrophic Lateral Sclerosis mice.}, journal = {Frontiers in cellular neuroscience}, volume = {9}, number = {}, pages = {248}, pmid = {26190973}, issn = {1662-5102}, support = {K01 NS069616/NS/NINDS NIH HHS/United States ; R01 NS061696/NS/NINDS NIH HHS/United States ; R21 NS081426/NS/NINDS NIH HHS/United States ; }, abstract = {Impairments in mitochondria, oxidative regulation, and calcium homeostasis have been well documented in numerous Amyotrophic Lateral Sclerosis (ALS) experimental models, especially in the superoxide dismutase 1 glycine 93 to alanine (SOD1 G93A) transgenic mouse. However, the timing of these deficiencies has been debatable. In a systematic review of 45 articles, we examine experimental measurements of cellular respiration, mitochondrial mechanisms, oxidative markers, and calcium regulation. We evaluate the quantitative magnitude and statistical temporal trend of these aggregated assessments in high transgene copy SOD1 G93A mice compared to wild type mice. Analysis of overall trends reveals cellular respiration, intracellular adenosine triphosphate, and corresponding mitochondrial elements (Cox, cytochrome c, complex I, enzyme activity) are depressed for the entire lifespan of the SOD1 G93A mouse. Oxidant markers (H2O2, 8OH2'dG, MDA) are initially similar to wild type but are double that of wild type by the time of symptom onset despite early post-natal elevation of protective heat shock proteins. All aspects of calcium regulation show early disturbances, although a notable and likely compensatory convergence to near wild type levels appears to occur between 40 and 80 days (pre-onset), followed by a post-onset elevation in intracellular calcium. The identified temporal trends and compensatory fluctuations provide evidence that the "cause" of ALS may lay within failed homeostatic regulation, itself, rather than any one particular perturbing event or cellular mechanism. We discuss the vulnerabilities of motoneurons to regulatory instability and possible hypotheses regarding failed regulation and its potential treatment in ALS.}, }
@article {pmid26188162, year = {2015}, author = {Trivedi, RB and Humphreys, K}, title = {Participant exclusion criteria in treatment research on neurological disorders: Are unrepresentative study samples problematic?.}, journal = {Contemporary clinical trials}, volume = {44}, number = {}, pages = {20-25}, doi = {10.1016/j.cct.2015.07.009}, pmid = {26188162}, issn = {1559-2030}, abstract = {OBJECTIVE: Exclusion criteria are an important determinant of the external validity of treatment research findings, yet the prevalence and impact of exclusion criteria have not been studied systematically. Our objective was to describe prevalent exclusion criteria in treatment research on neurological disorders and to analyze their impact on sample representativeness and generalizability of findings.<br><br>DESIGN: Narrative literature review of studies focusing on treatment for neurological disorders. Studies were identified from PubMed and bibliographies.<br><br>RESULTS: Eight studies were included in the narrative review: 3 studies focused on Alzheimer's disease/dementia, 2 each focused on traumatic brain injury (TBI) and epilepsy, and 1 focused on amyotrophic lateral sclerosis (ALS). The total number of patients screened across all studies was 20,018, of which 14,721 (73.5%) were excluded. An average of 6 exclusion criteria was applied. The criteria that contributed most to exclusion were the presence of comorbid psychiatric conditions, a history of alcohol or other substance misuse, and cognitive impairments. Women and the elderly were underrepresented among included samples. Race/ethnicity proportions were seldom reported.<br><br>CONCLUSION: Exclusion criteria are used extensively in neurological treatment research and prevent about 3 in 4 patients from participating in research. This limits the generalizability of current findings. Further, because excluded individuals are disproportionately from vulnerable populations, extensive exclusion also raises ethical concerns. Exclusion criteria should be used only in cases where there is a strong rationale so that neurological treatment research can make a greater impact on clinical care.}, }
@article {pmid26186011, year = {2015}, author = {Zhang, Y and Zhao, KT and Fox, SG and Kim, J and Kirsch, DR and Ferrante, RJ and Morimoto, RI and Silverman, RB}, title = {Tertiary Amine Pyrazolones and Their Salts as Inhibitors of Mutant Superoxide Dismutase 1-Dependent Protein Aggregation for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Journal of medicinal chemistry}, volume = {58}, number = {15}, pages = {5942-5949}, pmid = {26186011}, issn = {1520-4804}, support = {R43 NS057849/NS/NINDS NIH HHS/United States ; 1R43 NS057849/NS/NINDS NIH HHS/United States ; }, mesh = {Amines/chemistry ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Female ; Humans ; In Vitro Techniques ; Male ; Mice ; Pyrazolones/chemistry/*pharmacology/therapeutic use ; Salts ; Structure-Activity Relationship ; Superoxide Dismutase/*antagonists &amp; inhibitors ; }, abstract = {Pyrazolone derivatives have previously been found to be inhibitors of Cu/Zn superoxide dismutase 1 (SOD1)-dependent protein aggregation, which extended survival of an amyotrophic lateral sclerosis (ALS) mouse model. On the basis of ADME analysis, we describe herein a new series of tertiary amine-containing pyrazolones and their structure-activity relationships. Further conversion to the conjugate salts greatly improved their solubility. Phosphate compound 17 exhibited numerous benefits both to cellular activity and to CNS-related drug-like properties in vitro and in vivo, including microsomal stability, tolerated toxicity, and blood-brain barrier permeation. These results indicate that tertiary amine pyrazolones comprise a valuable class of ALS drug candidates.}, }
@article {pmid26183171, year = {2015}, author = {Coan, G and Mitchell, CS}, title = {An Assessment of Possible Neuropathology and Clinical Relationships in 46 Sporadic Amyotrophic Lateral Sclerosis Patient Autopsies.}, journal = {Neuro-degenerative diseases}, volume = {15}, number = {5}, pages = {301-312}, pmid = {26183171}, issn = {1660-2862}, support = {K01 NS069616/NS/NINDS NIH HHS/United States ; R21 NS081426/NS/NINDS NIH HHS/United States ; NS069616/NS/NINDS NIH HHS/United States ; NS081426/NS/NINDS NIH HHS/United States ; }, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/drug therapy/*epidemiology/metabolism/*pathology ; Brain/metabolism/*pathology ; DNA-Binding Proteins/metabolism ; Female ; Humans ; Male ; Middle Aged ; Riluzole/therapeutic use ; Severity of Illness Index ; Sex Factors ; }, abstract = {BACKGROUND: Recent studies have suggested overlapping pathological features among motor neuron, cognitive and neurodegenerative diseases.<br><br>AIMS/METHODS: Secondary analysis of 46 amyotrophic lateral sclerosis (ALS) patient autopsies was performed to independently assess pathological feature prevalence (e.g. percent of patients with any positive finding), degree of severity (e.g. mild, moderate, severe), and 2,200+ potential clinical/neuropathological correlations. The possible impact of gender, onset age, onset type (limb vs. bulbar), riluzole treatment, and severe TDP-43 pathology was assessed within patient subgroups.<br><br>RESULTS: Assessed features (prevalence, severity) include: lateral corticospinal tract degeneration (89%, moderate); Purkinje cell loss (85%, mild); localized neuronal loss (83%, mild to moderate); TDP-43 inclusions (80%, moderate); Betz cell loss (76%, mild); neurofibrillary tangles (78%, severe); anterior corticospinal tract degeneration (72%, moderate); spinal ventral root atrophy (65%, moderate); atherosclerosis (35%, mild); &#x3b2;-amyloid (35%, mild); tauopathy/tau inclusions (17%, mild); ventricular dilation (13%, mild); Lewy body formation (11%, mild); microinfarcts (7%, mild); and &#x3b1;-synuclein (4%, mild). Twenty-two percent of patients met criteria for Alzheimer's disease (AD) and 26% for frontotemporal lobar degeneration. Substantial differences were identified in the AD group and in the different onset age groups.<br><br>CONCLUSION: Our findings support the hypothesis that ALS and its variants could comprise a larger neuropathological continuum.}, }
@article {pmid26174654, year = {2015}, author = {Amador, Mdel M and Assouline, A and Gonzalez-Bermejo, J and Pradat, PF}, title = {Radiotherapy treatment of sialorrhea in patients with amyotrophic lateral sclerosis requiring non-invasive ventilation.}, journal = {Journal of neurology}, volume = {262}, number = {8}, pages = {1981-1983}, pmid = {26174654}, issn = {1432-1459}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*therapy ; Clinical Protocols ; Female ; Humans ; Male ; Middle Aged ; *Noninvasive Ventilation ; Pilot Projects ; Sialorrhea/etiology/*radiotherapy ; Treatment Outcome ; }, }
@article {pmid26171319, year = {2015}, author = {Maiese, K}, title = {FoxO proteins in the nervous system.}, journal = {Analytical cellular pathology (Amsterdam)}, volume = {2015}, number = {}, pages = {569392}, pmid = {26171319}, issn = {2210-7185}, mesh = {Animals ; Epigenesis, Genetic ; Forkhead Transcription Factors/genetics/*metabolism ; Humans ; Nervous System/*metabolism ; Nervous System Diseases/metabolism/pathology ; Oxidative Stress ; Protein Processing, Post-Translational ; }, abstract = {Acute as well as chronic disorders of the nervous system lead to significant morbidity and mortality for millions of individuals globally. Given the ability to govern stem cell proliferation and differentiated cell survival, mammalian forkhead transcription factors of the forkhead box class O (FoxO) are increasingly being identified as potential targets for disorders of the nervous system, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and auditory neuronal disease. FoxO proteins are present throughout the body, but they are selectively expressed in the nervous system and have diverse biological functions. The forkhead O class transcription factors interface with an array of signal transduction pathways that include protein kinase B (Akt), serum- and glucocorticoid-inducible protein kinase (SgK), IκB kinase (IKK), silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), growth factors, and Wnt signaling that can determine the activity and integrity of FoxO proteins. Ultimately, there exists a complex interplay between FoxO proteins and their signal transduction pathways that can significantly impact programmed cell death pathways of apoptosis and autophagy as well as the development of clinical strategies for the treatment of neurodegenerative disorders.}, }
@article {pmid26169755, year = {2015}, author = {Lahr, J and Schwartz, C and Heimbach, B and Aertsen, A and Rickert, J and Ball, T}, title = {Invasive brain-machine interfaces: a survey of paralyzed patients' attitudes, knowledge and methods of information retrieval.}, journal = {Journal of neural engineering}, volume = {12}, number = {4}, pages = {043001}, doi = {10.1088/1741-2560/12/4/043001}, pmid = {26169755}, issn = {1741-2552}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Attitude to Health ; Brain-Computer Interfaces/*statistics &amp; numerical data ; Electrodes, Implanted ; Female ; Germany/epidemiology ; Health Care Surveys ; Health Knowledge, Attitudes, Practice ; Humans ; Male ; Middle Aged ; Paralysis/epidemiology/*rehabilitation ; Patient Education as Topic/*statistics &amp; numerical data ; Patient Satisfaction/*statistics &amp; numerical data ; Self-Help Devices/*statistics &amp; numerical data ; Young Adult ; }, abstract = {OBJECTIVE: Brain-machine interfaces (BMI) are an emerging therapeutic option that can allow paralyzed patients to gain control over assistive technology devices (ATDs). BMI approaches can be broadly classified into invasive (based on intracranially implanted electrodes) and noninvasive (based on skin electrodes or extracorporeal sensors). Invasive BMIs have a favorable signal-to-noise ratio, and thus allow for the extraction of more information than noninvasive BMIs, but they are also associated with the risks related to neurosurgical device implantation. Current noninvasive BMI approaches are typically concerned, among other issues, with long setup times and/or intensive training. Recent studies have investigated the attitudes of paralyzed patients eligible for BMIs, particularly patients affected by amyotrophic lateral sclerosis (ALS). These studies indicate that paralyzed patients are indeed interested in BMIs. Little is known, however, about the degree of knowledge among paralyzed patients concerning BMI approaches or about how patients retrieve information on ATDs. Furthermore, it is not yet clear if paralyzed patients would accept intracranial implantation of BMI electrodes with the premise of decoding improvements, and what the attitudes of a broader range of patients with diseases such as stroke or spinal cord injury are towards this new kind of treatment.<br><br>APPROACH: Using a questionnaire, we surveyed 131 paralyzed patients for their opinions on invasive BMIs and their attitude toward invasive BMI treatment options.<br><br>MAIN RESULTS: The majority of the patients knew about and had a positive attitude toward invasive BMI approaches. The group of ALS patients was especially open to the concept of BMIs. The acceptance of invasive BMI technology depended on the improvements expected from the technology. Furthermore, the survey revealed that for paralyzed patients, the Internet is an important source of information on ATDs.<br><br>SIGNIFICANCE: Websites tailored to prospective BMI users should be further developed to provide reliable information to patients, and also to help to link prospective BMI users with researchers involved in the development of BMI technology.}, }
@article {pmid26166612, year = {2015}, author = {Finsterwald, C and Magistretti, PJ and Lengacher, S}, title = {Astrocytes: New Targets for the Treatment of Neurodegenerative Diseases.}, journal = {Current pharmaceutical design}, volume = {21}, number = {25}, pages = {3570-3581}, doi = {10.2174/1381612821666150710144502}, pmid = {26166612}, issn = {1873-4286}, mesh = {Animals ; Astrocytes/drug effects/*metabolism ; Cerebral Cortex/drug effects/*metabolism ; Drug Discovery/*methods ; Energy Metabolism/*drug effects ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neurons/drug effects/metabolism ; }, abstract = {The causes of neurodegenerative disorders are multiple, and for most of them a mechanistic understanding is still lacking. However, neurodegenerative diseases such as Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD) all share common features that include elevated oxidative stress levels and impaired energy metabolism in the nervous system. Most of the current treatments are only successful at alleviating some of the pathological symptoms, but fail at preventing neurodegeneration. There is therefore an urgent need for innovative and more efficient treatments for neurodegenerative disorders. We review here the central role played by astrocytes in the regulation of brain homeostasis, protection and function by supporting neuronal health and activity. In particular, astrocytes are key partners of neuronal metabolism, notably through activation of the astrocyteneuron lactate shuttle (ANLS). They also control the levels of extracellular glutamate, production of antioxidant molecules, disposal of neuronal waste products, storage of energy in the form of glycogen, and expression of neurotrophic factors. These mechanisms, which are key for brain activity and cognition, also largely contribute to neuronal degeneration in pathological situations. Thus, as astrocytes appear to play a key role in the etiology of neurodegenerative disorders, a growing interest has arisen for astrocytemediated pathways as targets for drugs that aim at treating the root causes of the pathology. We present here the most recent and promising astrocyte-based therapeutic approaches - from fundamental discoveries to clinical trials - that intent to sustain neuronal health and function in neurodegenerative disorders.}, }
@article {pmid26159164, year = {2016}, author = {Eve, DJ and Ehrhart, J and Zesiewicz, T and Jahan, I and Kuzmin-Nichols, N and Sanberg, CD and Gooch, C and Sanberg, PR and Garbuzova-Davis, S}, title = {Plasma Derived From Human Umbilical Cord Blood Modulates Mitogen-Induced Proliferation of Mononuclear Cells Isolated From the Peripheral Blood of ALS Patients.}, journal = {Cell transplantation}, volume = {25}, number = {5}, pages = {963-971}, doi = {10.3727/096368915X688579}, pmid = {26159164}, issn = {1555-3892}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*blood ; Apoptosis/physiology ; Caspase 3/*biosynthesis ; Caspase 7/*biosynthesis ; Cells, Cultured ; Cytokines/metabolism ; Female ; Fetal Blood/*cytology ; Humans ; Leukocytes/*metabolism ; Male ; Middle Aged ; Mitogens/*pharmacology ; Phytohemagglutinins/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by degeneration of motor neurons in the spinal cord and brain. This disease clinically manifests as gradual muscular weakness and atrophy leading to paralysis and death by respiratory failure. While multiple interdependent factors may contribute to the pathogenesis of ALS, increasing evidence shows the possible presence of autoimmune mechanisms that promote disease progression. The potential use of plasma derived from human umbilical cord blood (hUCB) as a therapeutic tool is currently in its infancy. The hUCB plasma is rich in cytokines and growth factors that are required for growth and survival of cells during hematopoiesis. In this study, we investigated the effects of hUCB plasma on the mitogen-induced proliferation of mononuclear cells (MNCs) isolated from the peripheral blood of ALS patients and apoptotic activity by detection of caspase 3/7 expression of the isolated MNCs in vitro. Three distinct responses to phytohemagglutinin (PHA)-induced proliferation of MNCs were observed, which were independent of age, disease duration, and the ALS rating scale: Group I responded normally to PHA, Group II showed no response to PHA, while Group III showed a hyperactive response to PHA. hUCB plasma attenuated the hyperactive response (Group III) and potentiated the normal response in Group I ALS patients, but did not alter that of the nonresponders to PHA (Group II). The elevated activity of caspase 3/7 observed in the MNCs from ALS patients was significantly reduced by hUCB plasma treatment. Thus, study results showing different cell responses to mitogen suggest alteration in lymphocyte functionality in ALS patients that may be a sign of immune deficiency in the nonresponders and autoimmunity alterations in the hyperactive responders. The ability of hUCB plasma to modulate the mitogen cell response and reduce caspase activity suggests that the use of hUCB plasma alone, or with stem cells, may prove useful as a therapeutic in ALS patients.}, }
@article {pmid26153204, year = {2015}, author = {Khalkhali Rad, T and Sayad, S and Baghaei, M and Mola Hossini, S and Salahshorian, A and Zare, M}, title = {A Study of Patients and Nurses' Perception of the Quality of Pain Management in the Patients Undergoing Surgery in the Departments of Surgery of Rasht Hospitals in 2013.}, journal = {Global journal of health science}, volume = {7}, number = {7 Spec No}, pages = {55-61}, pmid = {26153204}, issn = {1916-9736}, mesh = {Adult ; Attitude of Health Personnel ; Female ; Humans ; Inpatients/*psychology ; Male ; Middle Aged ; Nursing Staff, Hospital/*psychology ; Pain Management/*methods/psychology ; Pain Measurement ; Pain, Postoperative/psychology/*therapy ; *Patient Satisfaction ; Perception ; Socioeconomic Factors ; }, abstract = {PURPOSE &amp; FIELD: More than one hundred million people around the world undergo a surgery annually. Although, the surgery itself is a treatment method to relieve pain and discomfort, it can be considered as one of the important factors to make a pain too. Perception and diagnosis of the pain is the most important duty of nurses. Effective pain management after surgery facilitates the patient's recovery, decreases the length of hospitalization and increases the patient satisfaction. This study aims to investigate the patients and nurses' perception of the quality of pain management in the patients undergoing an abdominal surgery.<br><br>MATERIALS &amp; METHODS: The current study is a descriptive research that has been conducted on 204 candidate patients for the abdominal surgery and the nurses who care them in the departments of surgery of Rasht hospitals by using the Simple Random Sampling method. The necessary tools in gathering data for the questionnaire consist of demographic characteristics. Idval,E et al's Questionnaire for evaluation and pain perception, numerical and visual evaluation tools for the patient and nurse satisfaction with pain relief. Statistical analysis has been made through the 16 version of SPSS software by using descriptive statistics, average and standard deviation.<br><br>FINDINGS: The results show that the level of patient satisfaction with providing necessary care to relieve pain was 29.1% (maximum), 20.8% (minimum) and 78.7% to the confidence, environment and all areas, respectively. For the nurses, this level was 32.4% (maximum), 16.4% (minimum) and 77.1% to the performance, environment and all areas, respectively. The maximum level of patient perception of satisfaction with pain relief was 49.1% and for the nurses, it was 37.7% (good level).<br><br>CONCLUSIONS: The results indicated that the patients' perception of providing necessary cares to relieve pain and their satisfaction with the pain relief are more than the nurses and in a good level.}, }
@article {pmid26152655, year = {2016}, author = {Hawkey, NM and Zaorsky, NG and Galloway, TJ}, title = {The role of radiation therapy in the management of sialorrhea: A systematic review.}, journal = {The Laryngoscope}, volume = {126}, number = {1}, pages = {80-85}, doi = {10.1002/lary.25444}, pmid = {26152655}, issn = {1531-4995}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Parkinson Disease/*complications ; Salivary Glands/*radiation effects ; Sialorrhea/etiology/*radiotherapy ; }, abstract = {PURPOSE: Up to 80% of patients with Parkinson disease and 30% of patients with amyotrophic lateral sclerosis (ALS) suffer from sialorrhea. Patients who fail medical and surgical therapy should be considered for external beam radiation therapy (EBRT). In this study, we conduct a systematic review to determine the dose and techniques used that result in greatest efficacy and lowest toxicity for the administration of EBRT in patients with Parkinson disease or ALS-associated sialorrhea.<br><br>METHODS AND MATERIALS: This review included 216 patients from four prospective and six retrospective studies published from 1998 to 2014, with ALS or Parkinson disease who were treated with electron or photon EBRT for sialorrhea.<br><br>RESULTS: A total of 216 patients were treated with EBRT from 10 studies. The indication for EBRT was failure of alternative medical treatment in all ALS patients. For patients with Parkinson disease, EBRT was the primary mode of treatment in 68% of cases. Overall, 176 (81%) of 216 patients treated with EBRT for sialorrhea reported symptomatic improvement from baseline. The most common target was the inferior two-thirds of the bilateral parotid glands and the entire bilateral submandibular glands. The total number of patients who experienced short-term toxicity was 86 of 216 patients (40%). The total number of patients who experienced long-term toxicity was 24 of 207 (12%).<br><br>CONCLUSIONS: EBRT is an effective treatment for sialorrhea in patients suffering from ALS or Parkinson disease. Treatment to the bilateral submandibular glands and caudal parotid glands is the most common field arrangement.}, }
@article {pmid26150098, year = {2015}, author = {Maizels, N}, title = {G4-associated human diseases.}, journal = {EMBO reports}, volume = {16}, number = {8}, pages = {910-922}, pmid = {26150098}, issn = {1469-3178}, support = {P01 CA077852/CA/NCI NIH HHS/United States ; R01 GM065988/GM/NIGMS NIH HHS/United States ; P01 CA77852/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; DNA/genetics ; Disease/*genetics ; *G-Quadruplexes ; *Genome, Human ; Genomic Instability ; Humans ; Neoplasms/genetics ; Nervous System Diseases/*genetics ; }, abstract = {Recent research has established clear connections between G-quadruplexes and human disease. Features of quadruplex structures that promote genomic instability have been determined. Quadruplexes have been identified as transcriptional, translational and epigenetic regulatory targets of factors associated with human genetic disease. An expandable GGGGCC motif that can adopt a G4 structure, located in the previously obscure C9ORF72 locus, has been shown to contribute to two well-recognized neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This review focuses on these advances, which further dispel the view that genomic biology is limited to the confines of the canonical B-form DNA duplex, and show how quadruplexes contribute spatial and temporal dimensionalities to linear sequence information. This recent progress also has clear practical ramifications, as prevention, diagnosis, and treatment of disease depend on understanding the underlying mechanisms.}, }
@article {pmid26148561, year = {2015}, author = {Jones, KJ and Lovett-Racke, AE and Walker, CL and Sanders, VM}, title = {CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {10}, number = {4}, pages = {587-594}, pmid = {26148561}, issn = {1557-1904}, support = {R01 NS040433/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Animals ; CD4-Positive T-Lymphocytes/*immunology ; Humans ; Motor Neurons/*immunology ; Nerve Regeneration/*immunology ; Neuroprotection/*immunology ; }, abstract = {We have established a physiologically relevant mechanism of CD4+ T cell-mediated neuroprotection involving axotomized wildtype (WT) mouse facial motoneurons (FMN) with significance in the treatment of amyotrophic lateral sclerosis (ALS), a fatal MN disease. Use of the transgenic mouse model of ALS involving expression of human mutant superoxide dismutase genes (SOD1(G93A); abbreviated here as mSOD1) has accelerated basic ALS research. Superimposition of facial nerve axotomy (FNA) on the mSOD1 mouse during pre-symptomatic stages indicates that they behave like immunodeficient mice in terms of increased FMN loss and decreased functional recovery, through a mechanism that, paradoxically, is not inherent within the MN itself, but, instead, involves a defect in peripheral immune: CNS glial cell interactions. Our goal is to utilize our WT mouse model of immune-mediated neuroprotection after FNA as a template to elucidate how a malfunctioning peripheral immune system contributes to motoneuron cell loss in the mSOD1 mouse. This review will discuss potential immune defects in ALS, as well as provide an up-to-date understanding of how the CD4+ effector T cells provide neuroprotection to motoneurons through regulation of the central microglial and astrocytic response to injury. We will discuss an IL-10 cascade within the facial nucleus that requires a functional CD4+ T cell trigger for activation. The review will discuss the role of T cells in ALS, and our recent reconstitution experiments utilizing our model of T cell-mediated neuroprotection in WT vs mSOD1 mice after FNA. Identification of defects in neural:immune interactions could provide targets for therapeutic intervention in ALS.}, }
@article {pmid26146790, year = {2015}, author = {Hunsberger, HC and Weitzner, DS and Rudy, CC and Hickman, JE and Libell, EM and Speer, RR and Gerhardt, GA and Reed, MN}, title = {Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression.}, journal = {Journal of neurochemistry}, volume = {135}, number = {2}, pages = {381-394}, pmid = {26146790}, issn = {1471-4159}, support = {R15 AG045812/AG/NIA NIH HHS/United States ; U54 GM104942/GM/NIGMS NIH HHS/United States ; R15AG045812/AG/NIA NIH HHS/United States ; U54GM104942/GM/NIGMS NIH HHS/United States ; }, mesh = {Alzheimer Disease/prevention &amp; control/psychology ; Animals ; Brain Chemistry/drug effects ; Cognition Disorders/*prevention &amp; control/*psychology ; Excitatory Amino Acid Antagonists/*pharmacology ; Glutamic Acid/*metabolism ; Humans ; Maze Learning/drug effects ; Mice ; Mice, Transgenic ; Neuroprotective Agents/*pharmacology ; Riluzole/*pharmacology ; Synapses/drug effects/pathology ; Tauopathies/*prevention &amp; control/*psychology ; Vesicular Glutamate Transport Protein 1/metabolism ; tau Proteins/*biosynthesis ; }, abstract = {Hyperexcitability of the hippocampus is a commonly observed phenomenon in the years preceding a diagnosis of Alzheimer's disease (AD). Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for amyotrophic lateral sclerosis that lowers extracellular glutamate levels. Riluzole-treated TauP301L mice exhibited improved performance in the water radial arm maze and the Morris water maze, associated with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus, cornu ammonis 3 (CA3), and cornu ammonis 1 (CA1) regions of the hippocampus. Riluzole also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter 1, which packages glutamate into vesicles and influences glutamate release; and the TauP301L-mediated decrease in hippocampal glutamate transporter 1, the major transporter responsible for removing glutamate from the extracellular space. The TauP301L-mediated reduction in PSD-95 expression, a marker of excitatory synapses in the hippocampus, was also rescued by riluzole. Riluzole treatment reduced total levels of tau, as well as the pathological phosphorylation and conformational changes in tau associated with the P301L mutation. These findings open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD.}, }
@article {pmid26136710, year = {2015}, author = {Kleinbub, JR and Palmieri, A and Broggio, A and Pagnini, F and Benelli, E and Sambin, M and Sorarù, G}, title = {Hypnosis-based psychodynamic treatment in ALS: a longitudinal study on patients and their caregivers.}, journal = {Frontiers in psychology}, volume = {6}, number = {}, pages = {822}, pmid = {26136710}, issn = {1664-1078}, abstract = {BACKGROUND: Evidence of psychological treatment efficacy is strongly needed in ALS, particularly regarding long-term effects.<br><br>METHODS: Fifteen patients participated in a hypnosis treatment and self-hypnosis training protocol after an in-depth psychological and neurological evaluation. Patients' primary caregivers and 15 one-by-one matched control patients were considered in the study. Measurements of anxiety, depression and quality of life (QoL) were collected at the baseline, post-treatment, and after 3 and 6 months from the intervention. Bayesian linear mixed-models were used to evaluate the impact of treatment and defense style on patients' anxiety, depression, QoL, and functional impairment (ALSFRS-r), as well as on caregivers' anxiety and depression.<br><br>RESULTS: The statistical analyses revealed an improvement in psychological variables' scores immediately after the treatment. Amelioration in patients' and caregivers' anxiety as well as caregivers' depression, were found to persist at 3 and 6 months follow-ups. The observed massive use of primitive defense mechanisms was found to have a reliable and constant buffer effect on psychopathological symptoms in both patients and caregivers. Notably, treated patients decline in ALSFRS-r score was observed to be slower than that of control group's patients.<br><br>DISCUSSION: Our brief psychodynamic hypnosis-based treatment showed efficacy both at psychological and physical levels in patients with ALS, and was indirectly associated to long-lasting benefits in caregivers. The implications of peculiar psychodynamic factors and mind-body techniques are discussed. Future directions should be oriented toward a convergence of our results and further psychological interventions, in order to delineate clinical best practices for ALS.}, }
@article {pmid26130816, year = {2015}, author = {Vrijsen, B and Chatwin, M and Contal, O and Derom, E and Janssens, JP and Kampelmacher, MJ and Muir, JF and Pinto, S and Rabec, C and Ramsay, M and Randerath, WJ and Storre, JH and Wijkstra, PJ and Windisch, W and Testelmans, D}, title = {Hot Topics in Noninvasive Ventilation: Report of a Working Group at the International Symposium on Sleep-Disordered Breathing in Leuven, Belgium.}, journal = {Respiratory care}, volume = {60}, number = {9}, pages = {1337-1362}, doi = {10.4187/respcare.03796}, pmid = {26130816}, issn = {1943-3654}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Belgium ; Europe ; Humans ; Noninvasive Ventilation/methods/*trends ; Pulmonary Disease, Chronic Obstructive/*therapy ; Respiratory Insufficiency/*therapy ; Sleep Apnea Syndromes/*therapy ; }, abstract = {During the last few decades, attention has increasingly focused on noninvasive ventilation (NIV) in the treatment of chronic respiratory failure. The University of Leuven and the University Hospitals Leuven therefore chose this topic for a 2-day working group session during their International Symposium on Sleep-Disordered Breathing. Numerous European experts took part in this session and discussed (1) NIV in amyotrophic lateral sclerosis (when to start NIV, NIV and sleep, secretion management, and what to do when NIV fails), (2) recent insights in NIV and COPD (high-intensity NIV, NIV in addition to exercise training, and NIV during exercise training), (3) monitoring of NIV (monitoring devices, built-in ventilator software, leaks, and asynchronies) and identifying events during NIV; and (4) recent and future developments in NIV (target-volume NIV, electromyography-triggered NIV, and autoregulating algorithms).}, }
@article {pmid26129625, year = {2015}, author = {Nakagawa, Y and Chiba, K}, title = {Diversity and plasticity of microglial cells in psychiatric and neurological disorders.}, journal = {Pharmacology &amp; therapeutics}, volume = {154}, number = {}, pages = {21-35}, doi = {10.1016/j.pharmthera.2015.06.010}, pmid = {26129625}, issn = {1879-016X}, mesh = {Adiponectin/immunology ; Bipolar Disorder/*immunology ; Brain/immunology ; Cytokines/immunology ; Endocannabinoids/immunology ; Feeding Behavior/physiology ; Ghrelin/immunology ; Humans ; Inflammation Mediators/immunology ; Lysophospholipids/immunology ; Macrophages/*immunology ; Mental Disorders/immunology ; Microglia/*immunology ; Nerve Net/immunology ; Nervous System Diseases/*immunology ; Obesity/*immunology ; Social Behavior ; Sphingosine/analogs &amp; derivatives/immunology ; }, abstract = {Recent advanced immunological analyses have revealed that the diversity and plasticity of macrophages lead to the identification of functional polarization states (classically activated M1 type and alternatively activated M2 type) which are dependent on the extracellular environment. M1 and M2 polarization states of macrophages play an important role in controlling the balance between pro-inflammatory and anti-inflammatory conditions. Microglial cells are resident mononuclear phagocytes in the central nervous system (CNS), express several macrophage-associated markers, and appear to display functional polarization states similar to macrophages. Like M1 macrophages, M1 polarized microglia can produce pro-inflammatory cytokines and mediators such as interleukin (IL) 1β, IL-6, tumor necrosis factor-α, CC-chemokine ligand 2, nitric oxide, and reactive oxygen species, suggesting that these molecules contribute to dysfunction of neural network in the CNS. On the other hand, M2 polarized microglia can produce anti-inflammatory cytokine, IL-10 and express several receptors that are implicated in inhibiting inflammation and restoring homeostasis. In this review, we summarize the diversity, plasticity, and immunoregulatory functions of M1 and M2 microglia in psychiatric and neurological disorders. Based on these aspects, we propose a contribution of imbalance between M1 and M2 polarization of microglia in bipolar disorder, obesity, amyotrophic lateral sclerosis, and Rett syndrome. Consequently, molecules that normalize the imbalance between M1 and M2 microglial polarization states may provide a beneficial therapeutic target for the treatment of these disorders.}, }
@article {pmid26126965, year = {2015}, author = {Ehrhart, J and Smith, AJ and Kuzmin-Nichols, N and Zesiewicz, TA and Jahan, I and Shytle, RD and Kim, SH and Sanberg, CD and Vu, TH and Gooch, CL and Sanberg, PR and Garbuzova-Davis, S}, title = {Humoral factors in ALS patients during disease progression.}, journal = {Journal of neuroinflammation}, volume = {12}, number = {}, pages = {127}, pmid = {26126965}, issn = {1742-2094}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; R01 NS090962-01/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*blood/*diagnosis ; Biomarkers/blood ; Case-Control Studies ; *Disease Progression ; Female ; Glutathione/blood ; Humans ; Interleukin-2/*blood ; Interleukin-5/*blood ; Interleukin-6/*blood ; Interleukin-8/blood ; Male ; Middle Aged ; Nitrites/blood ; Prognosis ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons in the CNS and leading to paralysis and death. There are currently no effective treatments for ALS due to the complexity and heterogeneity of factors involved in motor neuron degeneration. A complex of interrelated effectors have been identified in ALS, yet systemic factors indicating and/or reflecting pathological disease developments are uncertain. The purpose of the study was to identify humoral effectors as potential biomarkers during disease progression.<br><br>METHODS: Thirteen clinically definite ALS patients and seven non-neurological controls enrolled in the study. Peripheral blood samples were obtained from each ALS patient and control at two visits separated by 6 months. The Revised ALS Functional Rating Scale (ALSFRS-R) was used to evaluate overall ALS-patient functional status at each visit. Eleven humoral factors were analyzed in sera. Cytokine levels (GM-CSF, IL-1&#x3b2;, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNF-&#x3b1;) were determined using the Bio-Rad Bio-Plex&#xae; Luminex 200 multiplex assay system. Nitrite, a breakdown product of NO, was quantified using a Griess Reagent System. Glutathione (GSH) concentrations were measured using a Glutathione Fluorometric Assay Kit.<br><br>RESULTS: ALS patients had ALSFRS-R scores of 30.5 &#xb1; 1.9 on their first visit and 27.3 &#xb1; 2.7 on the second visit, indicating slight disease progression. Serum multiplex cytokine panels revealed statistically significant changes in IL-2, IL-5, IL-6, and IL-8 levels in ALS patients depending on disease status at each visit. Nitrite serum levels trended upwards in ALS patients while serum GSH concentrations were drastically decreased in sera from ALS patients versus controls at both visits.<br><br>CONCLUSIONS: Our results demonstrated a systemic pro-inflammatory state and impaired antioxidant system in ALS patients during disease progression. Increased levels of pro-inflammatory IL-6, IL-8, and nitrite and significantly decreased endogenous antioxidant GSH levels could identify these humoral constituents as systemic biomarkers for ALS. However, systemic changes in IL-2, IL-5, and IL-6 levels determined between visits in ALS patients might indicate adaptive immune system responses dependent on current disease stage. These novel findings, showing dynamic changes in humoral effectors during disease progression, could be important for development of an effective treatment for ALS.}, }
@article {pmid26113413, year = {2015}, author = {Ruban, A and Malina, KC and Cooper, I and Graubardt, N and Babakin, L and Jona, G and Teichberg, VI}, title = {Combined Treatment of an Amyotrophic Lateral Sclerosis Rat Model with Recombinant GOT1 and Oxaloacetic Acid: A Novel Neuroprotective Treatment.}, journal = {Neuro-degenerative diseases}, volume = {15}, number = {4}, pages = {233-242}, doi = {10.1159/000382034}, pmid = {26113413}, issn = {1660-2862}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Aspartate Aminotransferases/*administration &amp; dosage/pharmacokinetics ; Disease Models, Animal ; Drug Therapy, Combination ; Kaplan-Meier Estimate ; Male ; Motor Activity/drug effects ; Motor Neurons/drug effects/pathology ; Neuroprotective Agents/*administration &amp; dosage/pharmacokinetics ; Oxaloacetic Acid/*administration &amp; dosage/pharmacokinetics ; Rats ; Rats, Wistar ; Recombinant Proteins/administration &amp; dosage/pharmacokinetics ; Rotarod Performance Test ; Spinal Cord/drug effects/pathology ; }, abstract = {BACKGROUND/AIM: The sporadic form of the disease affects the majority of amyotrophic lateral sclerosis (ALS) patients. The role of glutamate (Glu) excitotoxicity in ALS has been extensively documented and remains one of the prominent hypotheses of ALS pathogenesis. In light of this evidence, the availability of a method to remove excess Glu from brain and spinal cord extracellular fluids without the need to deliver drugs across the blood-brain barrier and with minimal or no adverse effects may provide a major therapeutic asset, which is the primary aim of this study.<br><br>METHODS: The therapeutic efficacy of the combined treatment with recombinant Glu-oxaloacetate-transaminase (rGOT) and its co-factor oxaloacetic acid (OxAc) has been tested in an animal model of sporadic ALS.<br><br>RESULTS: We found that OxAc/rGOT treatment provides significant neuroprotection to spinal cord motor neurons. It also slows down the development of motor weakness and prolongs survival.<br><br>CONCLUSION: In this study we bring evidence that the administration of Glu scavengers to rats with sporadic ALS inhibited the massive death of spinal cord motor neurons, slowed the onset of motor weakness and prolonged survival. This treatment may be of high clinical significance for the future treatment of chronic neurodegenerative diseases.}, }
@article {pmid26107316, year = {2015}, author = {Bennett, JP and Boulicault, D}, title = {A spotlight on microneurotrophins: the future of amyotrophic lateral sclerosis treatment?.}, journal = {Neurodegenerative disease management}, volume = {5}, number = {3}, pages = {181-185}, doi = {10.2217/nmt.15.13}, pmid = {26107316}, issn = {1758-2032}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/history ; History, 20th Century ; History, 21st Century ; Humans ; Nerve Growth Factors/*therapeutic use ; Neuroprotective Agents/*therapeutic use ; United States ; }, }
@article {pmid26101799, year = {2015}, author = {Yin, X and Qi, Y and Ren, M and Wang, S and Jiang, H and Feng, H and Cui, S}, title = {Roscovitine treatment caused impairment of fertilizing ability in mice.}, journal = {Toxicology letters}, volume = {237}, number = {3}, pages = {200-209}, doi = {10.1016/j.toxlet.2015.06.014}, pmid = {26101799}, issn = {1879-3169}, mesh = {Animals ; Fertility/*drug effects ; Hormones/blood ; Male ; Malondialdehyde/blood ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Purines/*adverse effects ; Reactive Oxygen Species/metabolism ; Reproduction/*drug effects ; Roscovitine ; Seminiferous Tubules/drug effects ; Sperm Motility/drug effects ; Spermatozoa/abnormalities/*drug effects ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Testis/drug effects/metabolism ; }, abstract = {OBJECTIVE: To explore the adverse effect of roscovitine on reproductive system of male mice.<br><br>MATERIALS AND METHODS: Male hSOD1(G93A) transgenetic mice received roscovitine 72 nmol/day (d) for 4 weeks (w), with normal control and dimethyl sulfoxide (DMSO)-treated animals served as controls (n=4). Male C57BL/6 mice were treated with roscovitine at either 72 nmol/d or 144 nmol/d for 4 w or 8 w, and normal control and DMSO treated mice served as controls. Fertility of male mice, sperm quality parameters, histological and related pathological changes of seminiferous tubules associated with roscovitine treatment were evaluated.<br><br>RESULTS: In male hSOD1(G93A) transgenetic mice treated with 72 nmol/d roscovitine for 4 w and C57BL/6 male mice treated with 72 nmol/d roscovitine for 8w and 144 nmol/d roscovitine for 4 w and 8 w, sperm counts and sperm motility rates decreased and sperm abnormality rates increased, and damage of seminiferous tubules were detected. Roscovitine treatment induced inhibition of CDK5 activities and decrease of BrdU-positive tubuler cells.<br><br>CONCLUSION: These results demonstrated that roscovitine treatment induced interference of male reproductive system and caused impairment of fertilizing ability. Reproductive system of ALS male mice was more susceptible to roscovitine induced impaired fertilizing ability.}, }
@article {pmid26091205, year = {2015}, author = {Plowman, EK}, title = {Is There a Role for Exercise in the Management of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis?.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {58}, number = {4}, pages = {1151-1166}, doi = {10.1044/2015_JSLHR-S-14-0270}, pmid = {26091205}, issn = {1558-9102}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Animals ; Exercise Therapy/*methods ; Extremities/physiopathology ; Humans ; Respiration ; Speech/physiology ; }, abstract = {PURPOSE: The role of exercise in the management of people with amyotrophic lateral sclerosis (PALS) is controversial and currently unclear. The purpose of this review article is to review literature examining the impact of limb, respiratory, and oral motor exercise on function, disease progression, and survival in PALS and the transgenic ALS animal model.<br><br>METHOD: A literature review was conducted to examine relevant studies published in peer-reviewed journals between 1960 and 2014. All studies were appraised for quality of research and were assigned a level of evidence, and treatment outcomes were classified as either positive, negative, or neutral.<br><br>RESULTS: A total of 18 exercise-based intervention studies on limb (13), respiratory (3), or speech (2) function were identified. Of the human clinical trials, 6 were experimental and 4 were exploratory. No experimental studies were identified examining the impact of targeted exercise on speech or swallowing function. Mild to moderate intensity limb or respiratory exercise, applied early in the disease, was noted to have a beneficial impact on motor function and survival.<br><br>CONCLUSION: Insufficient data exist to support or refute the role of exercise in the management of bulbar dysfunction in PALS. This represents a critical area of future investigation.}, }
@article {pmid26088116, year = {2015}, author = {Hulse, G and Kelty, E and Hood, S and Norman, A and Basso, MR and Reece, AS}, title = {Novel Indications for Benzodiazepine Antagonist Flumazenil in GABA Mediated Pathological Conditions of the Central Nervous System.}, journal = {Current pharmaceutical design}, volume = {21}, number = {23}, pages = {3325-3342}, doi = {10.2174/1381612821666150619092720}, pmid = {26088116}, issn = {1873-4286}, mesh = {Animals ; Central Nervous System/*drug effects/metabolism/physiopathology ; Central Nervous System Diseases/diagnosis/*drug therapy/metabolism/physiopathology ; Flumazenil/adverse effects/*therapeutic use ; GABA Antagonists/adverse effects/*therapeutic use ; Humans ; Inappropriate Prescribing ; *Off-Label Use ; Patient Safety ; Practice Patterns, Physicians' ; Risk Assessment ; Risk Factors ; Treatment Outcome ; gamma-Aminobutyric Acid/*metabolism ; }, abstract = {This review paper discusses the central role of gamma-aminobutyric acid (GABA) in diverse physiological systems and functions and the therapeutic potential of the benzodiazepine antagonist flumazenil (Ro 15- 1788) for a wide range of disorders of the central nervous system (CNS). Our group and others have studied the potential of flumazenil as a treatment for benzodiazepine dependence. A small but growing body of research has indicated that flumazenil may also have clinical application in CNS disorders such as Parkinson's disease, idiopathic hypersomnia and amyotrophic lateral sclerosis. Despite this body of research the therapeutic potential of flumazenil remains poorly understood and largely unrealized. The purpose of this paper is not to provide an exhaustive review of all possible therapeutic applications for flumazenil but rather to stimulate research interest, and discussion of the exciting therapeutic potential of this drug for a range of chronic debilitating conditions.}, }
@article {pmid26087000, year = {2016}, author = {Ganie, SA and Dar, TA and Bhat, AH and Dar, KB and Anees, S and Zargar, MA and Masood, A}, title = {Melatonin: A Potential Anti-Oxidant Therapeutic Agent for Mitochondrial Dysfunctions and Related Disorders.}, journal = {Rejuvenation research}, volume = {19}, number = {1}, pages = {21-40}, doi = {10.1089/rej.2015.1704}, pmid = {26087000}, issn = {1557-8577}, mesh = {Aging/drug effects/pathology ; Antioxidants/pharmacology/*therapeutic use ; Humans ; Melatonin/pharmacology/*therapeutic use ; Metabolome/drug effects ; Mitochondrial Diseases/*drug therapy/pathology ; Oxidative Stress/drug effects ; }, abstract = {Mitochondria play a central role in cellular physiology. Besides their classic function of energy metabolism, mitochondria are involved in multiple cell functions, including energy distribution through the cell, energy/heat modulation, regulation of reactive oxygen species (ROS), calcium homeostasis, and control of apoptosis. Simultaneously, mitochondria are the main producer and target of ROS with the result that multiple mitochondrial diseases are related to ROS-induced mitochondrial injuries. Increased free radical generation, enhanced mitochondrial inducible nitric oxide synthase (iNOS) activity, enhanced nitric oxide (NO) production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pores have all been suggested as factors responsible for impaired mitochondrial function. Because of these, neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and aging, are caused by ROS-induced mitochondrial dysfunctions. Melatonin, the major hormone of the pineal gland, also acts as an anti-oxidant and as a regulator of mitochondrial bioenergetic function. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other anti-oxidants, and thus has emerged as a major potential therapeutic tool for treating neurodegenerative disorders. Multiple in vitro and in vivo experiments have shown the protective role of melatonin for preventing oxidative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. With these functions in mind, this article reviews the protective role of melatonin with mechanistic insights against mitochondrial diseases and suggests new avenues for safe and effective treatment modalities against these devastating neurodegenerative diseases. Future insights are also discussed.}, }
@article {pmid26085633, year = {2015}, author = {Zhai, J and Zhang, L and Mojsilovic-Petrovic, J and Jian, X and Thomas, J and Homma, K and Schmitz, A and Famulok, M and Ichijo, H and Argon, Y and Randazzo, PA and Kalb, RG}, title = {Inhibition of Cytohesins Protects against Genetic Models of Motor Neuron Disease.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {35}, number = {24}, pages = {9088-9105}, pmid = {26085633}, issn = {1529-2401}, support = {Z01 BC007365//Intramural NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; R01 AG018001/AG/NIA NIH HHS/United States ; T32 CA009140/CA/NCI NIH HHS/United States ; NS052325/NS/NINDS NIH HHS/United States ; R21 NS077909/NS/NINDS NIH HHS/United States ; CA-009140/CA/NCI NIH HHS/United States ; NS077909/NS/NINDS NIH HHS/United States ; AG042179/AG/NIA NIH HHS/United States ; R01 NS052325/NS/NINDS NIH HHS/United States ; AG-18001/AG/NIA NIH HHS/United States ; R21 AG042179/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Caenorhabditis elegans ; Caenorhabditis elegans Proteins/*antagonists &amp; inhibitors/biosynthesis/*genetics ; Cells, Cultured ; *Disease Models, Animal ; GTPase-Activating Proteins/antagonists &amp; inhibitors/biosynthesis/genetics ; Guanine Nucleotide Exchange Factors/*antagonists &amp; inhibitors/biosynthesis/*genetics ; HeLa Cells ; Humans ; Mice ; Models, Genetic ; Motor Neuron Disease/*genetics ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/biosynthesis/genetics ; }, abstract = {Mutant genes that underlie Mendelian forms of amyotrophic lateral sclerosis (ALS) and biochemical investigations of genetic disease models point to potential driver pathophysiological events involving endoplasmic reticulum (ER) stress and autophagy. Several steps in these cell biological processes are known to be controlled physiologically by small ADP-ribosylation factor (ARF) signaling. Here, we investigated the role of ARF guanine nucleotide exchange factors (GEFs), cytohesins, in models of ALS. Genetic or pharmacological inhibition of cytohesins protects motor neurons in vitro from proteotoxic insults and rescues locomotor defects in a Caenorhabditis elegans model of disease. Cytohesins form a complex with mutant superoxide dismutase 1 (SOD1), a known cause of familial ALS, but this is not associated with a change in GEF activity or ARF activation. ER stress evoked by mutant SOD1 expression is alleviated by antagonism of cytohesin activity. In the setting of mutant SOD1 toxicity, inhibition of cytohesin activity enhances autophagic flux and reduces the burden of misfolded SOD1. These observations suggest that targeting cytohesins may have potential benefits for the treatment of ALS.}, }
@article {pmid26082680, year = {2015}, author = {Hensel, N and Rademacher, S and Claus, P}, title = {Chatting with the neighbors: crosstalk between Rho-kinase (ROCK) and other signaling pathways for treatment of neurological disorders.}, journal = {Frontiers in neuroscience}, volume = {9}, number = {}, pages = {198}, pmid = {26082680}, issn = {1662-4548}, abstract = {ROCK inhibition has been largely applied as a strategy to treat neurodegenerative diseases (NDDs) and promising results have been obtained in the recent years. However, the underlying molecular and cellular mechanisms are not fully understood and different models have been proposed for neurodegenerative disorders. Here, we aim to review the current knowledge obtained for NDDs identifying common mechanisms as well as disease-specific models. In addition to the role of ROCK in different cell types such as neurons and microglia, we focus on the molecular signaling-pathways which mediate the beneficial effects of ROCK. Besides canonical ROCK signaling, modulation of neighboring pathways by non-canonical ROCK-crosstalk is a recurrent pattern in many NDD-model systems and has been suggested to mediate beneficial effects of ROCK-inhibition.}, }
@article {pmid26080415, year = {2015}, author = {Sekiya, T and Holley, MC and Hashido, K and Ono, K and Shimomura, K and Horie, RT and Hamaguchi, K and Yoshida, A and Sakamoto, T and Ito, J}, title = {Cells transplanted onto the surface of the glial scar reveal hidden potential for functional neural regeneration.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {112}, number = {26}, pages = {E3431-40}, pmid = {26080415}, issn = {1091-6490}, mesh = {Animals ; *Cell Proliferation ; Chondroitin ABC Lyase/administration &amp; dosage ; Cochlear Nerve/*pathology ; Disease Models, Animal ; Humans ; Male ; *Nerve Regeneration ; Neurodegenerative Diseases/pathology/therapy ; Neuroglia/*pathology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Cell transplantation therapy has long been investigated as a therapeutic intervention for neurodegenerative disorders, including spinal cord injury, Parkinson's disease, and amyotrophic lateral sclerosis. Indeed, patients have high hopes for a cell-based therapy. However, there are numerous practical challenges for clinical translation. One major problem is that only very low numbers of donor cells survive and achieve functional integration into the host. Glial scar tissue in chronic neurodegenerative disorders strongly inhibits regeneration, and this inhibition must be overcome to accomplish successful cell transplantation. Intraneural cell transplantation is considered to be the best way to deliver cells to the host. We questioned this view with experiments in vivo on a rat glial scar model of the auditory system. Our results show that intraneural transplantation to the auditory nerve, preceded by chondroitinase ABC (ChABC)-treatment, is ineffective. There is no functional recovery, and almost all transplanted cells die within a few weeks. However, when donor cells are placed on the surface of a ChABC-treated gliotic auditory nerve, they autonomously migrate into it and recapitulate glia- and neuron-guided cell migration modes to repair the auditory pathway and recover auditory function. Surface transplantation may thus pave the way for improved functional integration of donor cells into host tissue, providing a less invasive approach to rescue clinically important neural tracts.}, }
@article {pmid26078717, year = {2015}, author = {Wang, X and Ma, M and Teng, J and Che, X and Zhang, W and Feng, S and Zhou, S and Zhang, Y and Wu, E and Ding, X}, title = {Valproate Attenuates 25-kDa C-Terminal Fragment of TDP-43-Induced Neuronal Toxicity via Suppressing Endoplasmic Reticulum Stress and Activating Autophagy.}, journal = {International journal of biological sciences}, volume = {11}, number = {7}, pages = {752-761}, pmid = {26078717}, issn = {1449-2288}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Autophagy/*drug effects ; Cell Line ; DNA-Binding Proteins/genetics/*metabolism ; Endoplasmic Reticulum Stress/*drug effects ; Flow Cytometry ; Immunoblotting ; Mice ; Neurons/*drug effects ; Peptide Fragments/metabolism/*toxicity ; Tetrazolium Salts ; Thiazoles ; Valproic Acid/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease. To date, there is no any effective pharmacological treatment for improving patients' symptoms and quality of life. Rapidly emerging evidence suggests that C-terminal fragments (CTFs) of TAR DNA-binding protein of 43 kDa (TDP-43), including TDP-35 and TDP-25, may play an important role in ALS pathogenesis. Valproate (VPA), a widely used antiepileptic drug, has neuroprotective effects on neurodegenerative disorders. As for ALS, preclinical studies also provide encouraging evidence for multiple beneficial effects in ALS mouse models. However, the potential molecular mechanisms have not been explored. Here, we show protective effects of VPA against TDP-43 CTFs-mediated neuronal toxicity and its underlying mechanisms in vitro. Remarkably, TDP-43 CTFs induced neuronal damage via endoplastic reticulum (ER) stress-mediated apoptosis. Furthermore, autophagic self-defense system was activated to reduce TDP-43 CTFs-induced neuronal death. Finally, VPA attenuated TDP-25-induced neuronal toxicity via suppressing ER stress-mediated apoptosis and enhancing autophagy. Taken together, these results demonstrate that VPA exerts neuroprotective effects against TDP-43 CTFs-induced neuronal damage. Thus, we provide new molecular evidence for VPA treatment in patients with ALS and other TDP-43 proteinopathies.}, }
@article {pmid26076745, year = {2015}, author = {Boentert, M and Brenscheidt, I and Glatz, C and Young, P}, title = {Effects of non-invasive ventilation on objective sleep and nocturnal respiration in patients with amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {262}, number = {9}, pages = {2073-2082}, pmid = {26076745}, issn = {1432-1459}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*physiopathology ; Female ; Humans ; Male ; Middle Aged ; *Noninvasive Ventilation ; Polysomnography ; Respiration ; Sleep/*physiology ; Sleep Apnea Syndromes/complications/physiopathology/*therapy ; Treatment Outcome ; }, abstract = {In amyotrophic lateral sclerosis (ALS), non-invasive ventilation (NIV) is indicated if sleep-disordered breathing (SDB), daytime hypercapnia, or significant diaphragmatic weakness is present. We investigated both short-term and long-term effects of NIV on objective measures of sleep and nocturnal respiration in patients with ALS. Polysomnography (PSG) and transcutaneous capnography were conducted for diagnosis of SDB (T0), for treatment initiation (T1), and follow-up 3, 9, and 15 months later (T2, T3, and T4, respectively). Records from 65 patients were retrospectively analyzed at T0 and T1. At subsequent timepoints, the number of full data sets decreased since follow-up sleep studies frequently included polygraphy rather than PSG (T2, 38 patients, T3, 17 patients, T4, 11 patients). At T0, mean age was 63.2 years, 29 patients were female, and 22 patients had bulbar ALS. Immediate sequelae of NIV initiation included significant increases of slow wave sleep, rapid eye movement sleep, and oxygen saturation. Mean apnea-hypopnea index, respiratory rate, and the maximum transcutaneous carbon dioxide tension were reduced. At T2-T4, normoxia and normocapnia were preserved. Sleep quality measures showed no alteration as diurnal use of NIV gradually increased reflecting disease progression. In contrast to previous reports, improvement of sleep and respiratory outcomes was found in both non-bulbar and bulbar patients. NIV significantly improves objective sleep quality and SDB in the first night of treatment in patients with bulbar and non-bulbar ALS. NIV warrants nocturnal normoventilation without deterioration of sleep quality in the long run with only minor changes to ventilator settings.}, }
@article {pmid26075221, year = {2015}, author = {Galuppo, M and Giacoppo, S and Iori, R and De Nicola, GR and Bramanti, P and Mazzon, E}, title = {Administration of 4-(α-L-rhamnosyloxy)-benzyl isothiocyanate delays disease phenotype in SOD1(G93A) rats: a transgenic model of amyotrophic lateral sclerosis.}, journal = {BioMed research international}, volume = {2015}, number = {}, pages = {259417}, pmid = {26075221}, issn = {2314-6141}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/physiopathology ; Animals ; Biotransformation ; Brain/drug effects/metabolism/pathology ; Disease Models, Animal ; Glycoside Hydrolases/metabolism ; Humans ; Isothiocyanates/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Male ; Mutant Proteins/genetics ; Phenotype ; Rats ; Rats, Sprague-Dawley ; Rats, Transgenic ; Rhamnose/administration &amp; dosage/*analogs &amp; derivatives/pharmacokinetics/therapeutic use ; Superoxide Dismutase/*genetics ; }, abstract = {4-(α-L-Rhamnosyloxy)-benzyl glucosinolate (glucomoringin, GMG) is a compound found in Moringa oleifera seeds. Myrosinase-catalyzed hydrolysis at neutral pH of GMG releases the biologically active compound 4-(α-L-rhamnosyloxy)-benzyl isothiocyanate (GMG-ITC). The present study was designed to test the potential therapeutic effectiveness of GMG-ITC to counteract the amyotrophic lateral sclerosis (ALS) using SOD1tg rats, which physiologically develops SOD1(G93A) at about 16 weeks of life, and can be considered a genetic model of disease. Rats were treated once a day with GMG (10 mg/Kg) bioactivated with myrosinase (20 µL/rat) via intraperitoneal (i.p.) injection for two weeks before disease onset and the treatment was prolonged for further two weeks before the sacrifice. Immune-inflammatory markers as well as apoptotic pathway were investigated to establish whether GMG-ITC could represent a new promising tool in clinical practice to prevent ALS. Achieved data display clear differences in molecular and biological profiles between treated and untreated SOD1tg rats leading to guessing that GMG-ITC can interfere with the pathophysiological mechanisms at the basis of ALS development. Therefore, GMG-ITC produced from myrosinase-catalyzed hydrolysis of pure GMG could be a candidate for further studies aimed to assess its possible use in clinical practice for the prevention or to slow down this disease.}, }
@article {pmid26073601, year = {2015}, author = {Bortz, H and Coutsouvelis, J and Corallo, CE and Spencer, A and Patil, S}, title = {Modifying chemotherapeutic management of a patient with Burkitt's lymphoma and pre-existing motor neurone disease.}, journal = {Journal of clinical pharmacy and therapeutics}, volume = {40}, number = {4}, pages = {483-485}, doi = {10.1111/jcpt.12293}, pmid = {26073601}, issn = {1365-2710}, mesh = {Aged ; Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use ; Burkitt Lymphoma/*drug therapy/pathology ; Female ; Fluorodeoxyglucose F18/administration &amp; dosage ; Humans ; Motor Neuron Disease/*complications ; Neurotoxicity Syndromes/*prevention &amp; control ; Positron-Emission Tomography/methods ; Radiopharmaceuticals/administration &amp; dosage ; Remission Induction/methods ; }, abstract = {WHAT IS KNOWN AND OBJECTIVE: Intensive chemotherapy for treatment of Burkitt's lymphoma (BL) - a high-grade lymphoproliferative disorder (LPD) - can cause neurotoxicity. An association between motor neurone disease (MND) and LPDs has previously been described, but there is a lack of recommendations available to guide management of such patients. This report aims to describe suitable management of BL in a patient with MND.<br><br>CASE DESCRIPTION: A 66-year-old woman with a history of MND affecting her limbs was diagnosed with bulky, extranodal, high-risk gastric BL. Standard chemotherapy is with multiple non-cross-resistant cytotoxic agents. To avoid exacerbation of neuropathy, six cycles of a modified regimen was planned, aiming to minimize exposure to the most neurotoxic agents. A PET-FDG-negative remission was obtained at 12&#xa0;months, without the signs of central neurotoxicity, peripheral neuropathy or muscle weakness.<br><br>WHAT IS NEW AND CONCLUSION: High-intensity chemotherapy, minimizing known neurotoxic agents, was delivered safely and effectively in a patient with BL and pre-existing MND. More case descriptions are required to guide management decisions.}, }
@article {pmid26071511, year = {2015}, author = {Khin Khin, E and Minor, D and Holloway, A and Pelleg, A}, title = {Decisional Capacity in Amyotrophic Lateral Sclerosis.}, journal = {The journal of the American Academy of Psychiatry and the Law}, volume = {43}, number = {2}, pages = {210-217}, pmid = {26071511}, issn = {1943-3662}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*psychology ; Behavior Observation Techniques ; Cognition Disorders/diagnosis/psychology ; *Decision Making ; Humans ; Mental Competency/*legislation &amp; jurisprudence ; Mental Disorders/diagnosis/psychology ; Patient Self-Determination Act ; United States ; }, abstract = {The cognitive and behavioral changes that can be observed in the neurodegenerative terminal disease amyotrophic lateral sclerosis (ALS), once characterized as purely a motor neuron disease, have become increasingly recognized over the past century. Detecting cognitive deficits earlier and identifying continued changes at regular intervals can lead to improved care, proactive treatments, and earlier discussions about end-of-life wishes. Although medical decisional capacity is required for every treatment decision made, its importance becomes paramount when making decisions on complex medical treatments that will invariably and significantly affect quality of life or life itself. In this review, we conducted a critical analysis of the evidence-based literature on the cognitive and behavioral impairments in ALS that can compromise medical decisional capacity. We review specific ALS-related clinical scenarios in which decisional capacity is of utmost importance and discuss a practical framework for cognitive and behavioral assessment that can be routinely and efficiently used, while being mindful of the confounding factors associated with ALS. Finally, we review models for preserving patient choices that can be used in patients with ALS to help safeguard autonomy and retain dignity toward the end of life.}, }
@article {pmid26071088, year = {2015}, author = {Dennys, CN and Armstrong, J and Levy, M and Byun, YJ and Ramdial, KR and Bott, M and Rossi, FH and Fernández-Valle, C and Franco, MC and Estevez, AG}, title = {Chronic inhibitory effect of riluzole on trophic factor production.}, journal = {Experimental neurology}, volume = {271}, number = {}, pages = {301-307}, pmid = {26071088}, issn = {1090-2430}, support = {R01 NS036761/NS/NINDS NIH HHS/United States ; NS36761/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Animals, Newborn ; Cells, Cultured ; Culture Media, Conditioned/chemistry/pharmacology ; Embryo, Mammalian ; Gene Expression Regulation/drug effects ; Intercellular Signaling Peptides and Proteins/genetics/*metabolism/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Nervous System/*growth &amp; development/metabolism ; Neuroglia/*drug effects/metabolism ; Neurons/*drug effects ; Neuroprotective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Riluzole/*pharmacology ; Schwann Cells/chemistry/drug effects ; Time Factors ; }, abstract = {Riluzole is the only FDA approved drug for the treatment of amyotrophic lateral sclerosis (ALS). However, the drug affords moderate protection to ALS patients, extending life for a few months by a mechanism that remains controversial. In the presence of riluzole, astrocytes increase the production of factors protective to motor neurons. The stimulation of trophic factor production by motor neuron associated cells may contribute to riluzole's protective effect in ALS. Here, we investigated the effects of media conditioned by astrocytes and Schwann cells acutely or chronically incubated with riluzole on trophic factor-deprived motor neuron survival. While acute riluzole incubation induced CT-1 secretion by astrocytes and Schwann cells, chronic treatment stimulated a significant decrease in trophic factor production compared to untreated cultures. Accordingly, conditioned media from astrocytes and Schwann cells acutely treated with riluzole protected motor neurons from trophic factor deprivation-induced cell death. Motor neuron protection was prevented by incubation with CT-1 neutralizing antibodies. In contrast, conditioned media from astrocytes and Schwann cells chronically treated with riluzole was not protective. Acute and chronic treatment of mice with riluzole showed opposite effects on trophic factor production in spinal cord, sciatic nerve and brain. There was an increase in the production of CT-1 and GDNF in the spinal cord and CT-1 in the sciatic nerve during the first days of treatment with riluzole, but the levels dropped significantly after chronic treatment with the drug. Similar results were observed in brain for CT-1 and BDNF while there was no change in GDNF levels after riluzole treatment. Our results reveal that riluzole regulates long-lasting processes involving protein synthesis, which may be relevant for riluzole therapeutic effects. Changing the regimen of riluzole administration to favor the acute effect of the drug on trophic factor production by discontinuous long-term treatment may improve the outcome of ALS patient therapy.}, }
@article {pmid26067594, year = {2015}, author = {Wang, SY and Ren, M and Jiang, HZ and Wang, J and Jiang, HQ and Yin, X and Qi, Y and Wang, XD and Dong, GT and Wang, TH and Yang, YQ and Feng, HL}, title = {Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate.}, journal = {Neuroscience}, volume = {301}, number = {}, pages = {276-288}, doi = {10.1016/j.neuroscience.2015.06.002}, pmid = {26067594}, issn = {1873-7544}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Cells, Cultured ; Disease Models, Animal ; Embryo, Mammalian ; Gene Expression Regulation/drug effects/genetics ; Humans ; Lithium Chloride/*therapeutic use ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/metabolism ; Neuroprotective Agents/*therapeutic use ; RNA, Small Interfering/genetics/metabolism ; Receptors, Notch/*metabolism ; Signal Transduction/*drug effects ; Spinal Cord/cytology ; Superoxide Dismutase/genetics ; Transfection ; Valproic Acid/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an idiopathic and lethal neurodegenerative disease that currently has no effective treatment. A recent study found that the Notch signaling pathway was up-regulated in a TAR DNA-binding protein-43 (TDP-43) Drosophila model of ALS. Notch signaling acts as a master regulator in the central nervous system. However, the mechanisms by which Notch participates in the pathogenesis of ALS have not been completely elucidated. Recent studies have shown that the mood stabilizers lithium and valproic acid (VPA) are able to regulate Notch signaling. Our study sought to confirm the relationship between the Notch pathway and ALS and whether the Notch pathway contributes to the neuroprotective effects of lithium and VPA in ALS. We found that the Notch pathway was activated in in vitro and in vivo models of ALS, and suppression of Notch activation with a Notch signaling inhibitor, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) and Notch1 siRNA significantly reduced neuronal apoptotic signaling, as evidenced by the up-regulation of Bcl-2 as well as the down-regulation of Bax and cytochrome c. We also found that lithium and VPA suppressed the Notch activation associated with the superoxide dismutase-1 (SOD1) mutation, and the combination of lithium and VPA produced a more robust effect than either agent alone. Our findings indicate that the Notch pathway plays a critical role in ALS, and the neuroprotective effects of lithium and VPA against mutant SOD1-mediated neuronal damage are at least partially dependent on their suppression of Notch activation.}, }
@article {pmid26055774, year = {2015}, author = {Galik, E and Resnick, B and Lerner, N and Hammersla, M and Gruber-Baldini, AL}, title = {Function Focused Care for Assisted Living Residents With Dementia.}, journal = {The Gerontologist}, volume = {55 Suppl 1}, number = {Suppl 1}, pages = {S13-26}, pmid = {26055774}, issn = {1758-5341}, support = {R01 AG046217/AG/NIA NIH HHS/United States ; }, mesh = {*Activities of Daily Living ; Adult ; Aged, 80 and over ; *Assisted Living Facilities ; Dementia ; Female ; *Geriatric Nursing/methods ; Health Personnel/*education/psychology ; Humans ; Job Satisfaction ; Male ; *Motor Activity ; Outcome Assessment, Health Care ; Patient-Centered Care/*methods ; }, abstract = {PURPOSE OF THE STUDY: Assisted living (AL) residents with dementia require assistance with activities of daily living, encounter limited opportunities to engage in physical activity, and often exhibit challenging behavioral symptoms. The Function Focused Care Intervention for the Cognitively Impaired (FFC-CI) teaches and motivates direct care workers (DCWs) to engage residents with dementia in activities that optimize function and activity while minimizing behavioral symptoms. The purpose of this study was to test the impact of FFC-CI on function, physical activity, behavior, and falls.<br><br>DESIGN AND METHODS: A cluster-randomized trial included 96 residents with dementia and 76 DCWs from 4 ALs. Generalized estimating equations were used to evaluate outcomes at 3 and 6 months.<br><br>RESULTS: There were no treatment by time differences with regard to resident behavior, mood, counts of physical activity based on actigraphy, falls, and function. There were significant increases in physical activity based on kilocalories burned (p = .001), time spent in physical activity based on survey results (p = .001), and time spent in repetitive behaviors, such as wandering (p = .01) among the control group over time. There were no treatment by time differences with regard to DCW beliefs, knowledge, or performance of FFC, except for less decline in job satisfaction among the treatment group (p = .002). Treatment fidelity with regard to delivery and receipt were poor due to high staff attrition in the treatment group (46% vs. 16%) and limited site support.<br><br>IMPLICATIONS: The findings from this study can be used to adapt future FFC intervention studies to improve treatment fidelity and optimize intervention efficacy.}, }
@article {pmid26050838, year = {2015}, author = {Nordentoft, T}, title = {Sealing of gastrointestinal anastomoses with fibrin glue coated collagen patch.}, journal = {Danish medical journal}, volume = {62}, number = {5}, pages = {}, pmid = {26050838}, issn = {2245-1919}, mesh = {Anastomosis, Surgical/instrumentation/methods ; Anastomotic Leak/*prevention &amp; control ; Animals ; Collagen ; Colon/*surgery ; Denmark ; Disease Models, Animal ; Drug Combinations ; Fibrin Tissue Adhesive/*therapeutic use ; Fibrinogen/*therapeutic use ; Peritonitis/etiology ; Random Allocation ; Swine ; Thrombin/*therapeutic use ; Tissue Adhesives/*therapeutic use ; }, abstract = {BACKGROUND: Colorectal cancer (CRC) is the most common cancer of the gastrointestinal tract. In Denmark is CRC the 3. most frequent form of cancer and the 3. leading cause of cancer-related death. Anastomoses: Surgical resection is the only curative treatment of CRC and in Denmark about 85% of patients with CRC are therefore operated. An anastomosis will be established in most cases. Colorectal anastomoses are established in the treatment of benign diseases too, i.e. as part of the surgical treatment of inflammatory bowel disease and in acute surgery. Furthermore anastomoses are conducted in other parts of the gastrointestinal tract i.e. esophagus, stomach, small bowel and bile system. Anastomotic leakage (AL): AL is the most serious complication of gastrointestinal surgery with a 30-day mortality of 13-27%. The reported AL rate ranges from 1 to 39%. In addition to immediate clinical consequences AL is an independent predictor of reduced general and cancer-specific survival. Leakage can manifest as generalized peritonitis, requiring acute resurgery or as a more localized accumulation/abscess or as a subclinical leakage. Sealing of anastomoses: Numerous studies on anastomotic sealing have been conducted with the aim of reducing the number of AL's. The results of these are conflicting and predominantly disappointing. The drug Tacho-Sil (TS) consists of a collagen patch, which on the one side is coated with fibrin glue (FG), which gives it an adhesive property. TS is registered for use in surgical hemostasis. Animal models: Spontaneous AL in animals is infrequent. It is therefore necessary to use a model of AL. No such model exists and must be developed.<br><br>OBJECTIVE: To clarify if the sealing of anastomoses with TS is feasible and safe in an experimental design. To develop a standardized model of AL in pigs. To clarify if sealing of colon-anastomoses with TS can reduce the number of clinical ALs in an experimental design. To clarify whether there is evidence that FG influences healing of gastrointestinal anastomosis.<br><br>STUDIES: Safety study, that examines whether it is safe to seal anastomoses with a TS. Experimental study on pigs. Two anastomoses on each pig, one sealed with TS. After 1-6 weeks of observation the anastomosis were examined for AL, stenoses, strength and compared microscopic.<br><br>RESULTS: No difference between sealed and unsealed anastomosis. This study is completed and published. Model study, to develop model of AL on pigs. A total of 22 pigs had an anastomosis of colon. All anastomoses were left with a standardized defect on 5-21 mm. The pigs were observed in order to assess how big the defect should be before the pigs developed visible leakage and/or fecal peritonitis.<br><br>RESULTS: Model developed. 21 mm defect significant. This study is completed and published. Efficacy study, testing if TachoSil can seal an AL and thus prevent that this becomes clinically significant. A total of 20 pigs had a colon-anastomoses with a standardized defect of 21 mm. The pigs were randomized to sealing with TS or no sealing. Re-laparotomy after 7 days examining for visible leakage and/or fecal peritonitis.<br><br>RESULTS: TachoSil&#xae; able to seal the defect (p=0.0055). This study is completed and published. Systematic review, with the purpose to study whether there is evidence that FG influence the healing of gastrointestinal anastomosis.<br><br>RESULTS: Conflicting. FG does not seem to have an effect. This study completed and published.<br><br>CONCLUSIONS: Sealing of GI-anastomosis with TachoSil is safe and feasible. A defect of at least 21mm must be left in colon anastomosis to induce clinical peritonitis. Sealing of defect colon-anastomosis in pigs with TachoSil can prevent clinical leakage and peritonitis. FG has no positive effect on microscopically healing of GI-anastomosis.}, }
@article {pmid26050733, year = {2015}, author = {Bakker, NE and van Doorn, J and Renes, JS and Donker, GH and Hokken-Koelega, AC}, title = {IGF-1 Levels, Complex Formation, and IGF Bioactivity in Growth Hormone-Treated Children With Prader-Willi Syndrome.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {100}, number = {8}, pages = {3041-3049}, doi = {10.1210/jc.2015-1410}, pmid = {26050733}, issn = {1945-7197}, mesh = {Adolescent ; Carrier Proteins/metabolism ; Case-Control Studies ; Child ; Child, Preschool ; Cross-Sectional Studies ; Female ; Glycoproteins/metabolism ; Human Growth Hormone/*therapeutic use ; Humans ; Infant ; Insulin-Like Growth Factor I/*metabolism ; Male ; Multiprotein Complexes/metabolism ; Netherlands ; Prader-Willi Syndrome/*drug therapy/metabolism ; }, abstract = {CONTEXT: Children with Prader-Willi syndrome (PWS) attain high-serum immunoreactive IGF-1 levels during a standard-dose GH treatment, which leads to concern, but lowering the dose deteriorates their body composition.<br><br>OBJECTIVE: The objective of the study was to evaluate serum IGF-1, IGF binding protein (IGFBP)-3, and acid-labile subunit (ALS) levels, complex formation, and IGF bioactivity in GH-treated PWS children.<br><br>DESIGN: This was a cross-sectional study.<br><br>SETTING: The setting of the study was a Dutch PWS cohort.<br><br>PARTICIPANTS: Forty GH-treated PWS children compared with 41 age- and sex-matched healthy controls participated in the study.<br><br>INTERVENTIONS: Interventions included GH treatment (1.0 mg/m(2) &#xb7; d = &#x223c;0.035 mg/kg &#xb7; d).<br><br>MAIN OUTCOME MEASURES: Serum IGF-1, IGFBP-3, and ALS levels, complex formation, and IGF bioactivity by IGF-1 receptor kinase activation assay were measured.<br><br>RESULTS: Serum IGF-1, IGFBP-3, and ALS levels and IGF-1 to IGFBP-3 ratio were significantly higher in GH-treated PWS children than in healthy controls. The 150-kDa ternary complex formation was, however, also significantly higher than in controls, indicating that most of serum IGF-1 is sequestered in the ternary 150-kDa complex with ALS and IGFBP-3. Young GH-treated PWS children [median (interquartile range) aged 5.2 (4.3-7.2) y] exhibited higher serum IGF bioactivity than controls, but no difference was observed in IGF bioactivity between older GH-treated PWS children, aged 14.9 (13.8-16.2) years, and controls. The proportion of IGF bioactivity of total serum IGF-1 was, however, lower in GH-treated PWS children than in controls. Serum immunoreactive IGF-1 levels did not correlate with IGF bioactivity in GH-treated children with PWS, in contrast to a strong positive correlation in healthy controls.<br><br>CONCLUSIONS: In GH-treated PWS children, most serum IGF-1 is sequestered in the 150-kDa complex. Higher IGF bioactivity was found only in young GH-treated PWS children and not in the older ones. IGF bioactivity during GH showed a wide variation, and there was a disrupted correlation with immunoreactive IGF-1 levels, which makes immunoreactive IGF-1 levels an inappropriate indicator for GH dosing in PWS children.}, }
@article {pmid26047147, year = {2015}, author = {Ardila, JA and Funari, CS and Andrade, AM and Cavalheiro, AJ and Carneiro, RL}, title = {Cluster analysis of commercial samples of Bauhinia spp. using HPLC-UV/PDA and MCR-ALS/PCA without peak alignment procedure.}, journal = {Phytochemical analysis : PCA}, volume = {26}, number = {5}, pages = {367-373}, doi = {10.1002/pca.2571}, pmid = {26047147}, issn = {1099-1565}, mesh = {Bauhinia/*chemistry ; Chromatography, High Pressure Liquid/*methods ; Cluster Analysis ; Least-Squares Analysis ; Multivariate Analysis ; Plant Leaves/chemistry ; Plant Preparations/*analysis/classification/standards ; Principal Component Analysis/*methods ; Product Surveillance, Postmarketing/methods/standards ; Reference Standards ; Reproducibility of Results ; Spectrophotometry, Ultraviolet/*methods ; }, abstract = {INTRODUCTION: Bauhinia forficata Link. is recognised by the Brazilian Health Ministry as a treatment of hypoglycemia and diabetes. Analytical methods are useful to assess the plant identity due the similarities found in plants from Bauhinia spp. HPLC-UV/PDA in combination with chemometric tools is an alternative widely used and suitable for authentication of plant material, however, the shifts of retention times for similar compounds in different samples is a problem.<br><br>OBJECTIVE: To perform comparisons between the authentic medicinal plant (Bauhinia forficata Link.) and samples commercially available in drugstores claiming to be "Bauhinia spp. to treat diabetes" and to evaluate the performance of multivariate curve resolution - alternating least squares (MCR-ALS) associated to principal component analysis (PCA) when compared to pure PCA.<br><br>METHODOLOGY: HPLC-UV/PDA data obtained from extracts of leaves were evaluated employing a combination of MCR-ALS and PCA, which allowed the use of the full chromatographic and spectrometric information without the need of peak alignment procedures.<br><br>RESULTS: The use of MCR-ALS/PCA showed better results than the conventional PCA using only one wavelength. Only two of nine commercial samples presented characteristics similar to the authentic Bauhinia forficata spp., considering the full HPLC-UV/PDA data.<br><br>CONCLUSION: The combination of MCR-ALS and PCA is very useful when applied to a group of samples where a general alignment procedure could not be applied due to the different chromatographic profiles. This work also demonstrates the need of more strict control from the health authorities regarding herbal products available on the market.}, }
@article {pmid26037479, year = {2015}, author = {Busch, CW and Qalanawi, M and Kersten, JF and Kalwa, TJ and Scotti, NA and Reip, W and Doehn, C and Maisch, S and Nitzschke, R}, title = {Providers with Limited Experience Perform Better in Advanced Life Support with Assistance Using an Interactive Device with an Automated External Defibrillator Linked to a Ventilator.}, journal = {The Journal of emergency medicine}, volume = {49}, number = {4}, pages = {455-463}, doi = {10.1016/j.jemermed.2015.03.020}, pmid = {26037479}, issn = {0736-4679}, mesh = {Adult ; Advanced Cardiac Life Support/instrumentation/*methods/standards ; Analysis of Variance ; Cross-Over Studies ; *Defibrillators ; Emergency Medical Services/*standards ; Female ; Heart Arrest/*therapy ; Humans ; Male ; Manikins ; *Pulmonary Ventilation ; Quality of Health Care/*standards ; Time Factors ; }, abstract = {BACKGROUND: Medical teams with limited experience in performing advanced life support (ALS) or with a low frequency of cardiopulmonary resuscitation (CPR) while on duty, often have difficulty complying with CPR guidelines.<br><br>OBJECTIVE: This study evaluated whether the quality of CPR of trained medical students, who served as an example of teams with limited experience in ALS, could be improved with device assistance. The primary outcome was the hands-off time (i.e., the percentage of the entire CPR time without chest compressions). The secondary outcome was seven time intervals, which should be as short as possible, and the quality of ventilations and chest compressions on the mannequin.<br><br>METHODS: We compared standard CPR equipment to an interactive device with visual and acoustic instructions for ALS workflow measures to guide briefly trained medical students through the ALS algorithm in a full-scale mannequin simulation study with a randomized crossover study design. The study equipment consisted of an automatic external defibrillator and ventilator that were electronically linked and communicating as a single system. Included were regular medical students in the third to sixth years of medical school of one class who provided written informed consent for voluntary participation and for the analysis of their CPR performance data. No exclusion criteria were applied. For statistical measures of evaluation we used an analysis of variance for crossover trials accounting for treatment effect, sequence effect, and carry-over effect, with adjustment for prior practical experience of the participants.<br><br>RESULTS: Forty-two medical students participated in 21 CPR sessions, each using the standard and study equipment. Regarding the primary end point, the study equipment reduced the hands-off time from 40.1% (95% confidence interval [CI] 36.9-43.4%) to 35.6% (95% CI 32.4-38.9%, p = 0.031) compared with the standard equipment. Within the prespecified secondary end points, study equipment reduced the time interval until the first rescuer changeover from 273 s (95% CI 244-302 s) to 223 s (95% CI 194-253 s, p = 0.001) and increased the percentage of ventilations with a correct tidal volume of 400-600 mL from 34.3% (95% CI 19.0-49.6%) to 60.9% (95% CI 45.6-76.2%, p = 0.018).<br><br>CONCLUSIONS: The assist device increased the rescuers' CPR quality. CPR providers with limited experience or a limited frequency of CPR performance (i.e., rural Emergency Medical Services crew) may potentially benefit from this assist device.}, }
@article {pmid26035393, year = {2015}, author = {Xu, X and Denic, A and Jordan, LR and Wittenberg, NJ and Warrington, AE and Wootla, B and Papke, LM and Zoecklein, LJ and Yoo, D and Shaver, J and Oh, SH and Pease, LR and Rodriguez, M}, title = {A natural human IgM that binds to gangliosides is therapeutic in murine models of amyotrophic lateral sclerosis.}, journal = {Disease models &amp; mechanisms}, volume = {8}, number = {8}, pages = {831-842}, pmid = {26035393}, issn = {1754-8411}, support = {R01 GM092993/GM/NIGMS NIH HHS/United States ; R01 NS048357/NS/NINDS NIH HHS/United States ; R21 NS073684/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/immunology/pathology ; Animals ; Cell Line ; Disease Models, Animal ; Disease Progression ; Dose-Response Relationship, Immunologic ; Epitopes/chemistry ; Gangliosides/chemistry/*metabolism ; Humans ; Immunoglobulin M/*therapeutic use ; Lipid Bilayers/metabolism ; Mice ; Mice, Transgenic ; Microtubules/metabolism ; Models, Molecular ; Neurites/metabolism/pathology ; Protein Binding ; Recombinant Proteins/therapeutic use ; Solubility ; Spinal Cord/pathology ; Superoxide Dismutase/metabolism ; Surface Plasmon Resonance ; Survival Analysis ; Tubulin/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating, fatal neurological disease that primarily affects spinal cord anterior horn cells and their axons for which there is no treatment. Here we report the use of a recombinant natural human IgM that binds to the surface of neurons and supports neurite extension, rHIgM12, as a therapeutic strategy in murine models of human ALS. A single 200 µg intraperitoneal dose of rHIgM12 increases survival in two independent genetic-based mutant SOD1 mouse strains (SOD1G86R and SOD1G93A) by 8 and 10 days, delays the onset of neurological deficits by 16 days, delays the onset of weight loss by 5 days, and preserves spinal cord axons and anterior horn neurons. Immuno-overlay of thin layer chromatography and surface plasmon resonance show that rHIgM12 binds with high affinity to the complex gangliosides GD1a and GT1b. Addition of rHIgM12 to neurons in culture increases α-tubulin tyrosination levels, suggesting an alteration of microtubule dynamics. We previously reported that a single peripheral dose of rHIgM12 preserved neurological function in a murine model of demyelination with axon loss. Because rHIgM12 improves three different models of neurological disease, we propose that the IgM might act late in the cascade of neuronal stress and/or death by a broad mechanism.}, }
@article {pmid26025385, year = {2016}, author = {López-Tarjuelo, J and Morillo-Macías, V and Bouché-Babiloni, A and Ferrer-Albiach, C and Santos-Serra, A}, title = {Defining Action Levels for In Vivo Dosimetry in Intraoperative Electron Radiotherapy.}, journal = {Technology in cancer research &amp; treatment}, volume = {15}, number = {3}, pages = {453-459}, doi = {10.1177/1533034615588196}, pmid = {26025385}, issn = {1533-0338}, mesh = {Electrons/*therapeutic use ; Humans ; In Vivo Dosimetry/*methods ; Neoplasms/*radiotherapy ; Radiotherapy/*methods ; Radiotherapy Planning, Computer-Assisted/methods ; }, abstract = {In vivo dosimetry is recommended in intraoperative electron radiotherapy (IOERT). To perform real-time treatment monitoring, action levels (ALs) have to be calculated. Empirical approaches based on observation of samples have been reported previously, however, our aim is to present a predictive model for calculating ALs and to verify their validity with our experimental data. We considered the range of absorbed doses delivered to our detector by means of the percentage depth dose for the electron beams used. Then, we calculated the absorbed dose histograms and convoluted them with detector responses to obtain probability density functions in order to find ALs as certain probability levels. Our in vivo dosimeters were reinforced TN-502RDM-H mobile metal-oxide-semiconductor field-effect transistors (MOSFETs). Our experimental data came from 30 measurements carried out in patients undergoing IOERT for rectal, breast, sarcoma, and pancreas cancers, among others. The prescribed dose to the tumor bed was 90%, and the maximum absorbed dose was 100%. The theoretical mean absorbed dose was 90.3% and the measured mean was 93.9%. Associated confidence intervals at P = .05 were 89.2% and 91.4% and 91.6% and 96.4%, respectively. With regard to individual comparisons between the model and the experiment, 37% of MOSFET measurements lay outside particular ranges defined by the derived ALs. Calculated confidence intervals at P = .05 ranged from 8.6% to 14.7%. The model can describe global results successfully but cannot match all the experimental data reported. In terms of accuracy, this suggests an eventual underestimation of tumor bed bleeding or detector alignment. In terms of precision, it will be necessary to reduce positioning uncertainties for a wide set of location and treatment postures, and more precise detectors will be required. Planning and imaging tools currently under development will play a fundamental role.}, }
@article {pmid26024411, year = {2015}, author = {Kim, KH and Lee, HB and Kim, SH and Kim, MC and Jung, GJ}, title = {Role of percutaneous transhepatic biliary drainage in patients with complications after gastrectomy.}, journal = {International surgery}, volume = {}, number = {}, pages = {}, doi = {10.9738/INTSURG-D-15-00117.1}, pmid = {26024411}, issn = {2520-2456}, abstract = {OBJECTIVE: The aim of this study was to elucidate the role of PTBD in patients with DSL and ALS post-gastrectomy for malignancy or benign ulcer perforation.<br><br>SUMMARY OF BACKGROUND DATA: Percutaneous transhepatic biliary drainage (PTBD) is an interventional radiologic procedure used to promote bile drainage. Duodenal stump leakage (DSL) and afferent loop syndrome (ALS) can be serious complications after gastrectomy.<br><br>METHODS: From January 2002 through December 2014, we retrospectively reviewed 19 patients who underwent PTBD secondary to DSL and ALS post-gastrectomy. In this study, a PTBD tube was placed in the proximal duodenum near the stump or distal duodenum in order to decompress and drain bile and pancreatic fluids.<br><br>RESULTS: Nine patients with DSL and 10 patients with ALS underwent PTBD. The mean hospital stay was 34.3 days (range, 12-71) in DSL group and 16.4 days (range, 6-48) in ALS group after PTBD. A liquid or soft diet was started within 2.6 days (range, 1-7) in the ALS group and within 3.4 days (range, 0-15) in the DSL group after PTBD. One patient with DSL had PTBD changed, and 2 patients with ALS underwent additional surgical interventions after PTBD.<br><br>CONCLUSIONS: The PTBD procedure, during which the tube was inserted into the duodenum, was well-suited for decompression of the duodenum as well as for drainage of bile and pancreatic fluids. This procedure can be an alternative treatment for cases of DSL and ALS post-gastrectomy.}, }
@article {pmid26018749, year = {2016}, author = {Breuer, G and Knipfer, C and Huber, T and Huettl, S and Shams, N and Knipfer, K and Neukam, FW and Schuettler, J and Stelzle, F}, title = {Competency in managing cardiac arrest: A scenario-based evaluation of dental students.}, journal = {Acta odontologica Scandinavica}, volume = {74}, number = {4}, pages = {241-249}, doi = {10.3109/00016357.2015.1042782}, pmid = {26018749}, issn = {1502-3850}, mesh = {Adult ; Advanced Cardiac Life Support/education/*methods ; Blood Circulation/physiology ; Cardiopulmonary Resuscitation/methods ; *Clinical Competence ; Cohort Studies ; Consciousness ; Curriculum ; Defibrillators ; Education, Dental ; Educational Measurement/methods ; Emergency Medicine/education ; Female ; Heart Arrest/*therapy ; Humans ; Male ; Masks ; Respiration ; Respiration, Artificial/instrumentation ; Simulation Training/methods ; *Students, Dental ; Young Adult ; }, abstract = {OBJECTIVE: Advanced Cardiovascular Life Support (ACLS) in life-threatening situations is perceived as a basic skill for dental professionals. However, medical emergency training in dental schools is often not standardized. The dental students' knowledge transfer to an ACLS setting thus remains questionable. The aim of the study was to evaluate dental pre-doctorate students' practical competence in ACLS in a standardized manner to enable the curriculum to be adapted to meet their particular needs.<br><br>MATERIALS AND METHODS: Thirty dental students (age 25.47 &#xb1; 1.81; 16 male/14 female) in their last year of dental studies were randomly assigned to 15 teams. Students' ability to successfully manage ACLS was assessed by a scenario-based approach (training module: Laerdal&#xae; ALS Skillmaster). Competence was assessed by means of (a) an observation chart, (b) video analysis and (c) training module analysis (Laerdal HeartSim&#xae;4000; Version 1.4). The evaluation was conducted by a trained anesthesiologist with regard to the 2010 guidelines of the European Resuscitation Council (ERC).<br><br>RESULTS: Only five teams (33.3%) checked for all three vital functions (response, breathing and circulation). All teams initiated cardiopulmonary resuscitation (CPR). Only 54.12% of the compressions performed during CPR were sufficient. Four teams stopped the CPR after initiation. In total, 93% of the teams used the equipment for bag-valve-mask ventilation and 53.3% used the AED (Automated external defibrillator).<br><br>CONCLUSIONS: ACLS training on a regular basis is necessary and, consistent with a close link between dentistry and medicine, should be a standardized part of the medical emergency curriculum for dental students with a specific focus on the deficiencies revealed in this study.}, }
@article {pmid26018231, year = {2016}, author = {Bohl, D and Pochet, R and Mitrecic, D and Nicaise, C}, title = {Modelling and treating amyotrophic lateral sclerosis through induced-pluripotent stem cells technology.}, journal = {Current stem cell research &amp; therapy}, volume = {11}, number = {4}, pages = {301-312}, doi = {10.2174/1574888x10666150528144303}, pmid = {26018231}, issn = {2212-3946}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Animals ; Cell Differentiation/genetics ; *Cellular Reprogramming ; Disease Models, Animal ; Humans ; Induced Pluripotent Stem Cells/*transplantation ; Motor Neurons/transplantation ; *Stem Cell Transplantation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease affecting primarily the population of motor neurons, even though a non-cell autonomous component, involving neighbouring non-neuronal cells, is more and more described. Despite 140 years of disease experience, still no efficient treatment exists against ALS. The inability to readily obtain the faulty cell types relevant to ALS has impeded progress in drug discovery for decades. However, the pioneer work of Shinya Yamanaka in 2007 in the stem cell field was a real breakthrough. Recent advances in cell reprogramming now grant access to significant quantities of CNS disease-affected cells. Induced pluripotent stem cells (iPSc) have been recently derived from patients carrying mutations linked to familial forms of ALS as well as from sporadic patients. Precise and mature protocols allow now their differentiation into ALS-relevant cell subtypes; sustainable and renewable sources of human motor neurons or glia are being available for ALS disease modelling, drug screening or for the development of cell therapies. In few years, the proof-of-concept was made that ALS disease-related phenotypes can be reproduced with iPSc and despite some remaining challenges, we are now not so far to provide platforms for the investigation of ALS therapeutics. This paper also reviews the pioneering studies regarding the applicability of iPSc technology in ALS animal models. From modest slowing down of ALS progression to no severe adverse effects, iPSc-based cell therapy resulted in promising premises in ALS preclinical paradigms, although long-term surveys are highly recommended.}, }
@article {pmid26005122, year = {2015}, author = {Sibon, I and de Toffol, B and Azulay, JP and Sellal, F and Thomas-Antérion, C and Léger, JM and Pierrot-Deseilligny, C}, title = {[American Academy of Neurology, Washington, 18-25 April 2015].}, journal = {Revue neurologique}, volume = {171}, number = {6-7}, pages = {581-601}, doi = {10.1016/j.neurol.2015.04.005}, pmid = {26005122}, issn = {0035-3787}, mesh = {Cerebrovascular Disorders/genetics ; Humans ; Movement Disorders/genetics ; Multiple Sclerosis/genetics ; Neurology/*trends ; Peripheral Nervous System Diseases/genetics ; }, abstract = {CEREBROVASCULAR DISEASES: The benefit of the thrombectomy using stents retrievers in the acute stroke phase is now demonstrated when there is a proximal occlusion of an intracranial artery, whatever its mechanism. The place of the anticoagulants in the management of cervical artery dissections remains uncertain, while the benefit of the blood pressure control in the secondary prevention of deep and lobar intracerebral hemorrhages is critical. The development of cardiac MRI, prolonged cardiac monitoring and transcranial doppler seems to improve the diagnosis of cardio-embolic sources of stroke.<br><br>EPILEPSY: A specialized urgent-access single seizure clinic represents a model which reduces wait-times and improves patient access after a first fit. Co-locating a psychiatrist within outpatient epilepsy center leads to a reduction in psychiatric symptoms and people with psychogenic non-epileptic seizures. When neurologists around the world assess identical case scenarios for the diagnosis of epilepsy, concordance is between moderate and poor, showing that epilepsy diagnosis remains difficult. More than one third of elderly with new-onset epilepsy of unknown etiology exhibit temporal lobe atrophy on brain imaging.<br><br>MOVEMENT DISORDERS: There is no major progress in the therapeutic approach of Parkinson's disease but the discovery of new genetic markers such as glucocerebrosidase mutations may greatly change our knowledge of the disease process and may induce new therapeutic strategies in the future. The natural history of the disease is also better understood from the prodromal phase to the post-mortem analysis of the brain and the classification of the processes based on abnormal protein deposits.<br><br>DEMENTIA: The respective value of biomarkers (amyloid imaging versus CSF biomarkers) for in vivo diagnosis of Alzheimer's disease (AD) has been detailed. Therapeutic expectations mainly rely on anti-A&#x3b2; immunization trials performed in preclinical (and no longer prodromal) stages of AD, with the aim of slowing the evolution of neuronal loss. Besides a lot of communications on dementia genetics or physiopathogeny, fascinating and promising results were presented on deep brain stimulation for depression resistant to medical treatment.<br><br>PERIPHERAL NEUROPATHY: Ibudilast, administered with riluzole, is safe and tolerable in patients with amyotrophic lateral sclerosis (ALS), improves ALS function and delays progression. Patients with painful small fiber neuropathy have a high rate of mutations in the SCN9A gene, coding for Nav1.7&#xa0;voltage-gated sodium-channels. Peripheral nerve lymphoma (NL) is a multifocal painful neuropathy that causes endoneurial inflammatory demyelination: primary NL is less severe than secondary NL, which occurs after remission, suggesting that nerve may be considered a "safe lymphoma haven".<br><br>MULTIPLE SCLEROSIS (MS): Biotin in progressive forms of MS and daclizumab in relapsing-remitting forms appear to be promising treatments. In case of failure of current first-line and/or second-line therapeutics, alemtuzumab may be an interesting alternative treatment. Teriflunomide, dimethyl fumarate and fingolimod are oral treatments with confirmed efficacy and acceptable safety. Besides vitamin&#xa0;D insufficiency and smoking, which are confirmed risk factors for the disease, testosterone insufficiency (in males) and obesity are emerging risk factors, which could also be corrected.}, }
@article {pmid26000221, year = {2014}, author = {Pioro, EP}, title = {Review of Dextromethorphan 20 mg/Quinidine 10 mg (NUEDEXTA(®)) for Pseudobulbar Affect.}, journal = {Neurology and therapy}, volume = {3}, number = {1}, pages = {15-28}, pmid = {26000221}, issn = {2193-8253}, abstract = {Pseudobulbar affect (PBA) is a dysfunction of emotional expression characterized by involuntary outbursts of crying or laughing disproportionate or unrelated to mood, occurring in patients with various underlying neurologic disorders. This review describes the clinical data supporting dextromethorphan (DM) hydrobromide combined with quinidine sulfate (Q) as treatment of PBA and briefly surveys the ongoing debates concerning the terminology for dysfunction of emotional expression, as well as the ongoing searches for its brain substrates. Until recently, pharmacologic intervention consisted chiefly of off-label antidepressants. In October 2010, however, DM/Q at 20/10 mg twice daily received approval from the United States Food and Drug Administration for PBA in any setting, and in June 2013, dosages of 20/10 and 30/10 mg twice daily (labeled as 15/9 and 23/9 mg, respectively, DM/Q base) received approval from the European Medicines Agency. DM is an uncompetitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist, a sigma-1 receptor agonist, and a serotonin and norepinephrine reuptake inhibitor. To block DM hepatic metabolism, thereby increasing DM bioavailability, Quinidine, a cytochrome P450 2D6 inhibitor, is coadministered at a dosage well below those for treating cardiac arrhythmia. Three large-scale DM/Q trials have utilized PBA-episode counts and the Center for Neurologic Study-Lability Scale (CNS-LS), a validated PBA rating scale, to measure efficacy. In a 4-week study of patients with PBA in amyotrophic lateral sclerosis (ALS), DM/Q 30/30 mg was superior to its component drugs. A 12-week, double-blind, placebo-controlled study of DM/Q 30/30 mg showed similar efficacy in patients with PBA in multiple sclerosis (MS). A subsequent 12-week study of patients with PBA and ALS or MS showed superiority to placebo for the 20/10 and 30/10 mg doses. Efficacy was maintained during a 12-week, open-label extension (30/10 mg dose), with further improvement of mean CNS-LS scores. Across these studies, DM/Q was generally safe and well tolerated, with no evidence of clinically relevant cardiac or respiratory effects. DM/Q is being studied (currently unapproved) for conditions including agitation in autism and in dementia.}, }
@article {pmid25998392, year = {2015}, author = {Kabuta, C and Kono, K and Wada, K and Kabuta, T}, title = {4-Hydroxynonenal induces persistent insolubilization of TDP-43 and alters its intracellular localization.}, journal = {Biochemical and biophysical research communications}, volume = {463}, number = {1-2}, pages = {82-87}, doi = {10.1016/j.bbrc.2015.05.027}, pmid = {25998392}, issn = {1090-2104}, mesh = {Aldehydes/*metabolism/pharmacology ; Amyotrophic Lateral Sclerosis/etiology/metabolism ; Animals ; Biomarkers/metabolism ; COS Cells ; Cell Nucleus/metabolism ; Chlorocebus aethiops ; Cytosol/metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Humans ; Oxidative Stress ; Phosphorylation ; Recombinant Proteins/chemistry/genetics/metabolism ; Risk Factors ; Solubility ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive degeneration of motor neurons. TDP-43 has been found to be a major component of ubiquitin-positive inclusions in ALS. Aberrant TDP-43, which is found in inclusions, is phosphorylated and is re-distributed from the nucleus to the cytoplasm. Alterations of TDP-43 protein, particularly insolubilization/aggregation and cytosolic distribution are thought to be involved in the pathogenesis of ALS. Levels of 4-hydroxynonenal (HNE), a marker of oxidative stress, have been reported to be elevated in sporadic ALS patients. However, the effects of HNE on TDP-43 are unclear. In this study, we found that HNE treatment of cells causes insolubilization, phosphorylation, and partial cytosolic localization of TDP-43. HNE-induced cytosolic TDP-43 was diffusely localized and only a small proportion of TDP-43 localized to stress granules, which are transient structures. HNE-induced TDP-43 insolubilization and phosphorylation were even observed 24 h after washout of HNE. We also showed that the cysteine residues of TDP-43 are responsible for HNE-induced insolubilization of TDP-43. Our results indicate that HNE can cause biochemical changes of TDP-43, which resemble the aberrant alterations of this protein in ALS, and suggest that upregulation of HNE could be a risk factor for ALS.}, }
@article {pmid25987361, year = {2015}, author = {Narayan, M and Peralta, DA and Gibson, C and Zitnyar, A and Jinwal, UK}, title = {An optimized InCell Western screening technique identifies hexachlorophene as a novel potent TDP43 targeting drug.}, journal = {Journal of biotechnology}, volume = {207}, number = {}, pages = {34-38}, doi = {10.1016/j.jbiotec.2015.04.012}, pmid = {25987361}, issn = {1873-4863}, mesh = {Animals ; Cell Line ; DNA-Binding Proteins/*antagonists &amp; inhibitors/metabolism ; Drug Discovery/*methods ; HEK293 Cells ; HeLa Cells ; Hexachlorophene/chemistry/*pharmacology ; Humans ; Mice ; Molecular Targeted Therapy ; TDP-43 Proteinopathies/drug therapy ; }, abstract = {TAR DNA binding protein (TDP43) is a DNA- and RNA-binding protein that is implicated in several neurodegenerative disorders termed as "TDP43 proteinopathies" including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and fronto-temporal lobe dementia (FTLD). We have developed an InCell Western (ICW) technique for screening TDP targeting drugs in 96 well plates. We tested 281 compounds and identified a novel compound hexachlorophene (referred to as B10) that showed potent reduction in TDP43 levels. The effect of B10 on TDP protein level was validated in two different cellular models: endogenous TDP43 expressing N9 microglial cells and TDP43-over-expressing HEK293 and HeLa cells. We also analyzed effect of B10 on various pathological forms of TDP such as the C25 cleaved fragment that localizes to the cytosol, insoluble high molecular weight species, and ALS-linked mutants. Our data suggest that B10 effectively reduces all forms of TDP. Overall, our data suggest that B10 could serve as a potential drug molecule for the treatment of AD, ALS and other TDP43 proteinopathies.}, }
@article {pmid25986728, year = {2015}, author = {Li, W and Fotinos, A and Wu, Q and Chen, Y and Zhu, Y and Baranov, S and Tu, Y and Zhou, EW and Sinha, B and Kristal, BS and Wang, X}, title = {N-acetyl-L-tryptophan delays disease onset and extends survival in an amyotrophic lateral sclerosis transgenic mouse model.}, journal = {Neurobiology of disease}, volume = {80}, number = {}, pages = {93-103}, doi = {10.1016/j.nbd.2015.05.002}, pmid = {25986728}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/mortality/pathology/*prevention &amp; control ; Animals ; Apoptosis/drug effects ; Male ; Mice ; Mice, Transgenic ; Mitochondria/drug effects/metabolism ; Motor Neurons/drug effects/pathology ; Neuroglia/drug effects ; Receptors, Neurokinin-1/metabolism ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase/genetics ; Survival Analysis ; Tryptophan/administration &amp; dosage/*analogs &amp; derivatives ; }, abstract = {BACKGROUND: Whether L-NAT, a cytochrome c release inhibitor and an antagonist of NK-1R, provides protection in ALS is not known.<br><br>RESULTS: L-NAT delays disease onset and mortality in mSOD1(G93A) ALS mice by inhibiting mitochondrial cell death pathways, inflammation, and NK-1R downregulation.<br><br>CONCLUSION: L-NAT offers protection in a mouse model of ALS.<br><br>SIGNIFICANCE: Data suggest the potential of L-NAT as a novel therapeutic strategy for ALS and provide insight into its action mechanisms. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, while inflammation has been implicated in its pathogenesis. Both inhibitors of cytochrome c release and antagonists of the neurokinin 1 receptor (NK-1R) have been reported to provide neuroprotection in ALS and/or other neurodegenerative diseases by us and other researchers. However, whether N-acetyl-L-tryptophan (L-NAT), an inhibitor of cytochrome c release and an antagonist of NK-1R, provides neuroprotection in ALS remains unknown. Here we demonstrate that the administration of L-NAT delayed disease onset, extended survival, and ameliorated deteriorations in motor performance in mSOD1(G93A) ALS transgenic mice. Our data showed that L-NAT reached the spinal cord, skeletal muscle, and brain. In addition, we demonstrate that L-NAT reduced the release of cytochrome c/smac/AIF, increased Bcl-xL levels, and inhibited the activation of caspase-3. L-NAT also ameliorated motor neuron loss and gross atrophy, and suppressed inflammation, as shown by decreased GFAP and Iba1 levels. Furthermore, we found gradually reduced NK-1R levels in the spinal cords of mSOD1(G93A) mice, while L-NAT treatment restored NK-1R levels. We propose the use of L-NAT as a potential therapeutic invention against ALS.}, }
@article {pmid25982504, year = {2015}, author = {Ikeda, K and Iwasaki, Y and Kaji, R}, title = {Neuroprotective effect of ultra-high dose methylcobalamin in wobbler mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {354}, number = {1-2}, pages = {70-74}, doi = {10.1016/j.jns.2015.04.052}, pmid = {25982504}, issn = {1878-5883}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*pathology ; Animals ; *Disease Models, Animal ; Dose-Response Relationship, Drug ; Mice ; Mice, Inbred C57BL ; Mice, Neurologic Mutants ; Muscle Strength/drug effects/genetics ; Neuroprotective Agents/*administration &amp; dosage ; Vitamin B 12/administration &amp; dosage/*analogs &amp; derivatives ; }, abstract = {BACKGROUND: High-dose of methylcobalamin promotes nerve regeneration in rats with acrylamide neuropathy. A double-blind controlled trial suggested that high-dose methylcobalamin could increase compound muscle action potentials in patients with amyotrophic lateral sclerosis (ALS). A large-scale extended period human trial is now on-going in ALS (Clinicaltrial.govNCT00444613). We attempted to study whether high-dose methylcobalamin can improve symptoms or retard progression of motor dysfunction in the wobbler mouse model of ALS.<br><br>METHODS: After initial diagnosis of the disease at the postnatal age of 3-4 weeks, wobbler mice received methylcobalamin (3 or 30 mg/kg, n=10/group) or vehicle (n=10), daily for 4 weeks by intraperitoneal administration in a blinded fashion. We compared clinical symptoms and pathological changes among all groups. Vitamin B12 concentrations were measured in the serum, the skeletal muscle and the spinal cord of three groups (n=5/group).<br><br>RESULTS: In comparison with vehicle, mice treated with ultra-high dose (30 mg/kg) of methylcobalamin significantly inhibited muscle weakness and contracture in the forelimb, and increased the weight of the bicep muscles and the number of musculocutaneous nerves. Methylcobalamin-treated mice significantly elevated vitamin B12 concentrations of the serum, the bicep muscle and the spinal cord compared to vehicle.<br><br>CONCLUSION: Our results suggest that treatment with methylcobalamin could delay progression of motor symptoms and neuropathological changes in wobbler mouse motor neuron disease if very high doses are used.}, }
@article {pmid25982050, year = {2015}, author = {Körner, S and Kollewe, K and Abdulla, S and Zapf, A and Dengler, R and Petri, S}, title = {Interaction of physical function, quality of life and depression in Amyotrophic lateral sclerosis: characterization of a large patient cohort.}, journal = {BMC neurology}, volume = {15}, number = {}, pages = {84}, pmid = {25982050}, issn = {1471-2377}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*physiopathology/*psychology ; Cohort Studies ; Depression/*psychology ; Female ; Humans ; Male ; Middle Aged ; Quality of Life/*psychology ; }, abstract = {BACKGROUND: Due to lack of any curative therapy for ALS, symptomatic treatment and maintenance of quality of life (QoL) is very important. We aimed to characterize the affected domains of QoL in ALS patients and to identify factors which are associated with reduced QoL and increased depression.<br><br>METHODS: 159 ALS patients answered standardized questionnaires (Beck Depression Inventory-II, SF-36 Health Survey questionnaire, revised ALS functional rating scale). Multiple regression analysis was used to identify correlations between clinical features of ALS patients and depression/QoL scores. In addition, QoL data from ALS patients were compared to age-matched reference values representing the German normal population.<br><br>RESULTS: QoL of ALS patients was reduced in nearly all SF-36-categories. Progression of physical impairment was positively correlated with depression but reduced QoL scores only in items directly related to physical function. However, QoL was considerably influenced by depression, independently from physical impairment. Regarding distinct patient characteristics one of the most interesting findings was that increasing age was correlated with significantly worse QoL results regarding social functioning.<br><br>CONCLUSIONS: Depressive symptoms had a strong influence on QoL, hence their detection and treatment is of particular importance. Different domains of QoL are differently affected in subgroups of ALS patients. Being aware of these differences can be valuable for both ALS professional and family caregivers and physicians.}, }
@article {pmid25979579, year = {2015}, author = {Valadi, N}, title = {Evaluation and management of amyotrophic lateral sclerosis.}, journal = {Primary care}, volume = {42}, number = {2}, pages = {177-187}, doi = {10.1016/j.pop.2015.01.009}, pmid = {25979579}, issn = {1558-299X}, mesh = {Adaptation, Psychological ; Amyotrophic Lateral Sclerosis/*diagnosis/epidemiology/*therapy ; Diagnosis, Differential ; Electromyography ; Genetic Predisposition to Disease ; Humans ; Magnetic Resonance Imaging ; Primary Health Care/*methods ; Quality of Life ; Risk Factors ; }, abstract = {Motor neuron diseases can cause progressive impairment of voluntary muscles of movement, respiration, speech, and swallowing. This review discusses the most common motor neuron disease, amyotrophic lateral sclerosis (ALS). It reviews the evaluation, diagnosis, and management of ALS, and its epidemiology, pathophysiology, and management. A coordinated approach by the primary care physician and neurologist is necessary with a focus on treatment options, durable medical equipment needs, and end-of-life discussions.}, }
@article {pmid25979489, year = {2015}, author = {Boison, D and Aronica, E}, title = {Comorbidities in Neurology: Is adenosine the common link?.}, journal = {Neuropharmacology}, volume = {97}, number = {}, pages = {18-34}, pmid = {25979489}, issn = {1873-7064}, support = {R01 MH083973/MH/NIMH NIH HHS/United States ; R01 NS084920/NS/NINDS NIH HHS/United States ; R21 NS088024/NS/NINDS NIH HHS/United States ; R01MH83973/MH/NIMH NIH HHS/United States ; }, mesh = {Adenosine/*metabolism ; Animals ; Comorbidity ; Humans ; Nervous System Diseases/complications/epidemiology/*metabolism/therapy ; Neuroglia/metabolism ; Signal Transduction ; }, abstract = {Comorbidities in Neurology represent a major conceptual and therapeutic challenge. For example, temporal lobe epilepsy (TLE) is a syndrome comprised of epileptic seizures and comorbid symptoms including memory and psychiatric impairment, depression, and sleep dysfunction. Similarly, Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are accompanied by various degrees of memory dysfunction. Patients with AD have an increased likelihood for seizures, whereas all four conditions share certain aspects of psychosis, depression, and sleep dysfunction. This remarkable overlap suggests common pathophysiological mechanisms, which include synaptic dysfunction and synaptotoxicity, as well as glial activation and astrogliosis. Astrogliosis is linked to synapse function via the tripartite synapse, but astrocytes also control the availability of gliotransmitters and adenosine. Here we will specifically focus on the 'adenosine hypothesis of comorbidities' implying that astrocyte activation, via overexpression of adenosine kinase (ADK), induces a deficiency in the homeostatic tone of adenosine. We present evidence from patient-derived samples showing astrogliosis and overexpression of ADK as common pathological hallmark of epilepsy, AD, PD, and ALS. We discuss a transgenic 'comorbidity model', in which brain-wide overexpression of ADK and resulting adenosine deficiency produces a comorbid spectrum of seizures, altered dopaminergic function, attentional impairment, and deficits in cognitive domains and sleep regulation. We conclude that dysfunction of adenosine signaling is common in neurological conditions, that adenosine dysfunction can explain co-morbid phenotypes, and that therapeutic adenosine augmentation might be effective for the treatment of comorbid symptoms in multiple neurological conditions.}, }
@article {pmid25976755, year = {2015}, author = {Bakhtiari, N and Hosseinkhani, S and Tashakor, A and Hemmati, R}, title = {Ursolic acid ameliorates aging-metabolic phenotype through promoting of skeletal muscle rejuvenation.}, journal = {Medical hypotheses}, volume = {85}, number = {1}, pages = {1-6}, doi = {10.1016/j.mehy.2015.02.014}, pmid = {25976755}, issn = {1532-2777}, mesh = {Aging/*metabolism ; Animals ; Male ; Mice ; Mice, Inbred C57BL ; Muscle, Skeletal/metabolism/*physiology ; Phenotype ; Triterpenes/*pharmacology ; Ursolic Acid ; }, abstract = {Ursolic acid (UA) is a lipophilic compound, which highly found in apple peels. UA has some certain features, of the most important is its anabolic effects on skeletal muscles, which in turn plays a prominent role in the aging process, encouraged us to evaluate skeletal muscle rejuvenation. This study seeks to address the two following questions: primarily, we wonder to know if UA increases anti-aging biomarkers (SIRT1 and PGC-1α) in the isolated satellite cells, to pave the way for satellite cells proliferation. The results revealed that UA elevated the expression of SIRT1 (∼ 35 folds) and PGC-1α (∼ 175 folds) genes. The other question that needs to be asked, however, is to understand whether it is possible to generalize the in vitro findings to in vivo. For this, a study was designed to investigate the effects of UA on the cellular energy status in the animal models (C57BL/6 mice). We found that UA decreased cellular energy charges such as ATP (∼ 3 times) and ADP (∼ 18 times). With respect to the role of UA in energy expenditure and as an anti-aging biomarker, one might wonder to elucidate skeletal muscle rejuvenation as well as satellite cells proliferation and neomyogenesis. The results illustrated that UA boosted neomyogenesis through enhancing the number of satellite cells. In addition, rejuvenation effects of UA on the skeletal muscle promptly encouraged us to reexamine the performance of skeletal muscles. The results indicated that UA through increasing myoglobin expression (∼ 2 folds) accompanied with transforming of glycolytic to fast oxidative status chiefly and slow-twitch muscle fibers. To the best of our knowledge, it seems that UA might be considered as a potential candidate for treatment of pathological conditions associated with muscular atrophy and dysfunction, including skeletal muscle atrophy, amyotrophic lateral sclerosis (ALS), sarcopenia and metabolic diseases of the muscles.}, }
@article {pmid25973331, year = {2015}, author = {Sharma, AK and Sane, HM and Paranjape, AA and Gokulchandran, N and Nagrajan, A and D'sa, M and Badhe, PB}, title = {The effect of autologous bone marrow mononuclear cell transplantation on the survival duration in Amyotrophic Lateral Sclerosis - a retrospective controlled study.}, journal = {American journal of stem cells}, volume = {4}, number = {1}, pages = {50-65}, pmid = {25973331}, issn = {2160-4150}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disorder with fatal prognosis. Cellular therapy has been studied for ALS in various animal models and these advances have highlighted its potential to be a treatment modality. This is a retrospective controlled cohort study of total 57 patients. Out of these, 37 patients underwent autologous bone marrow mononuclear cell transplantation in addition to standard rehabilitation and Riluzole. Control group consisted of 20 patients who did not receive cell transplantation. The survival duration since the onset of the disease for both the groups was computed using a Kaplan-Meier Survival analysis and compared using log-rank test. Effect of age at onset, type of onset and lithium on survival duration in the intervention group was analyzed. Mean survival duration of patients in intervention group was 87.76 months which was higher than the control group mean survival duration of 57.38 months. Survival duration was significantly (p = 0.039) higher in people with the onset of the disease below 50 years of age. Limb onset and lithium also showed positive influence on the survival duration. Mean survival duration of the intervention group was also higher than the survival duration of ALS patients in previous epidemiological studies. In addition to the standard treatment with Riluzole, early intervention with combination of BMMNCs transplantation and Lithium may have a positive effect on the survival duration in ALS. Prospective randomized controlled studies with a larger sample size and rigorous methodology are required for conclusive findings.}, }
@article {pmid25972546, year = {2015}, author = {Cortez, LM and Campeau, J and Norman, G and Kalayil, M and Van der Merwe, J and McKenzie, D and Sim, VL}, title = {Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease.}, journal = {Journal of virology}, volume = {89}, number = {15}, pages = {7660-7672}, pmid = {25972546}, issn = {1098-5514}, mesh = {Animals ; Bile Acids and Salts/metabolism ; Cell Death ; Cell Survival ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Neurons/cytology/*metabolism ; PrPC Proteins/*metabolism ; PrPSc Proteins/*metabolism ; Prion Diseases/*metabolism/*physiopathology ; Species Specificity ; Taurochenodeoxycholic Acid/*metabolism ; Ursodeoxycholic Acid/*metabolism ; }, abstract = {UNLABELLED: Prion diseases are fatal neurodegenerative disorders associated with the conversion of cellular prion protein (PrPC) into its aberrant infectious form (PrPSc). There is no treatment available for these diseases. The bile acids tauroursodeoxycholic acid(TUDCA) and ursodeoxycholic acid (UDCA) have been recently shown to be neuroprotective in other protein misfolding disease models, including Parkinson’s, Huntington’s and Alzheimer’s diseases, and also in humans with amyotrophic lateral sclerosis.Here, we studied the therapeutic efficacy of these compounds in prion disease. We demonstrated that TUDCA and UDCA substantially reduced PrP conversion in cell-free aggregation assays, as well as in chronically and acutely infected cell cultures. This effect was mediated through reduction of PrPSc seeding ability, rather than an effect on PrPC. We also demonstrated the ability of TUDCA and UDCA to reduce neuronal loss in prion-infected cerebellar slice cultures. UDCA treatment reduced astrocytosis and prolonged survival in RML prion-infected mice. Interestingly, these effects were limited to the males, implying a gender-specific difference in drug metabolism. Beyond effects on PrPSc, we found that levels of phosphorylated eIF2 were increased at early time points, with correlated reductions in postsynaptic density protein 95. As demonstrated for other neurodegenerative diseases, we now show that TUDCA and UDCA may have a therapeutic role in prion diseases, with effects on both prion conversion and neuroprotection. Our findings, together with the fact that these natural compounds are orally bioavailable, permeable to the blood-brain barrier, and U.S. Food and Drug Administration-approved for use in humans, make these compounds promising alternatives for the treatment of prion diseases.<br><br>IMPORTANCE: Prion diseases are fatal neurodegenerative diseases that are transmissible to humans and other mammals. There are no disease-modifying therapies available, despite decades of research. Treatment targets have included inhibition of protein accumulation,clearance of toxic aggregates, and prevention of downstream neurodegeneration. No one target may be sufficient; rather, compounds which have a multimodal mechanism, acting on different targets, would be ideal. TUDCA and UDCA are bile acids that may fulfill this dual role. Previous studies have demonstrated their neuroprotective effects in several neurodegenerative disease models, and we now demonstrate that this effect occurs in prion disease, with an added mechanistic target of upstream prion seeding. Importantly, these are natural compounds which are orally bioavailable, permeable to the blood-brain barrier, and U.S.Food and Drug Administration-approved for use in humans with primary biliary cirrhosis. They have recently been proven efficacious in human amyotrophic lateral sclerosis. Therefore, these compounds are promising options for the treatment of prion diseases.}, }
@article {pmid25960085, year = {2015}, author = {Shibuya, K and Misawa, S and Kimura, H and Noto, Y and Sato, Y and Sekiguchi, Y and Iwai, Y and Mitsuma, S and Beppu, M and Watanabe, K and Fujimaki, Y and Tsuji, Y and Shimizu, T and Mizuno, T and Nakagawa, M and Sawaguchi, K and Hanaoka, H and Kuwabara, S}, title = {A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis: Efficacy and safety of sodium channel blocker phase II trial.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {16}, number = {5-6}, pages = {353-358}, doi = {10.3109/21678421.2015.1038277}, pmid = {25960085}, issn = {2167-9223}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Dose-Response Relationship, Drug ; Evoked Potentials, Motor/drug effects ; Female ; Follow-Up Studies ; Humans ; Male ; Mexiletine/*therapeutic use ; Middle Aged ; Neural Conduction/drug effects/physiology ; Severity of Illness Index ; Single-Blind Method ; *Treatment Outcome ; Voltage-Gated Sodium Channel Blockers/*therapeutic use ; }, abstract = {Fasciculations are characteristic features of amyotrophic lateral sclerosis (ALS), and suggest motor nerve hyperexcitability. Recent reports have shown that an increase in persistent nodal sodium current is associated with shorter survival in ALS patients. This objective of this trial is to study the efficacy and safety of mexiletine, a sodium channel blocker, for ALS. Sixty eligible participants were randomly allocated (1:1) to riluzole 100 mg or riluzole plus mexiletine 300 mg. The primary endpoint was change in the revised ALS functional rating scale (ALSFRS-R) scores during six months. We also monitored strength-duration time constant (SDTC, a measure of persistent sodium current) in median motor axons. Results showed that during six months of treatment, changes in the ALSFRS-R score and SDTC were -7.0 ± 7.1 and -0.04 ± 0.1, respectively, in the riluzole group and -6.9 ± 6.4 and 0.04 ± 0.1, respectively, in the mexiletine group (p = 0.96 and 0.049). Adverse events amounted 20% in the riluzole and 33% in the mexiletine groups. In conclusion, the results suggest that daily 300 mg mexiletine has no effects on axonal sodium current and ALSFRS-R deterioration in ALS. We have to attempt another trial using a higher dose of mexiletine or other agents to suppress sodium currents and ALS progression in the future.}, }
@article {pmid25959569, year = {2015}, author = {Scarrott, JM and Herranz-Martín, S and Alrafiah, AR and Shaw, PJ and Azzouz, M}, title = {Current developments in gene therapy for amyotrophic lateral sclerosis.}, journal = {Expert opinion on biological therapy}, volume = {15}, number = {7}, pages = {935-947}, doi = {10.1517/14712598.2015.1044894}, pmid = {25959569}, issn = {1744-7682}, support = {G1001492/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/physiopathology/*therapy ; Animals ; C9orf72 Protein ; Dependovirus/genetics ; Disease Models, Animal ; *Genetic Therapy ; Humans ; Motor Neurons/metabolism/pathology ; Nerve Degeneration ; Nerve Growth Factors/genetics/metabolism ; Proteins/genetics/metabolism ; RNA Interference ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating adult neurodegenerative disorder characterized by motor neuron degeneration and death around 3 years from onset. So far, riluzole is the only treatment available, although it only offers a slight increase in survival. The complex etiology of ALS, with several genes able to trigger the disease, makes its study difficult.<br><br>AREAS COVERED: RNA-mediated or protein-mediated toxic gain-of-function leading to motor neuron degeneration appears to be likely common pathogenic mechanisms in ALS. Consequently, gene therapy technologies to reduce toxic RNA and/or proteins and to protect motor neurons by modulating gene expression are at the forefront of the field. Here, we review the most promising scientific advances, paying special attention to the successful treatments tested in animal models as well as analyzing relevant gene therapy clinical trials.<br><br>EXPERT OPINION: Despite broad advances in target gene identification in ALS and advances in gene therapy technologies, a successful gene therapy for ALS continues to elude researchers. Multiple hurdles encompassing technical, biological, economical and clinical challenges must be overcome before a therapy for patients becomes available. Optimism remains due to positive results obtained in several in vivo studies demonstrating significant disease amelioration in animal models of ALS.}, }
@article {pmid25957927, year = {2015}, author = {Deepmala,  and Slattery, J and Kumar, N and Delhey, L and Berk, M and Dean, O and Spielholz, C and Frye, R}, title = {Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review.}, journal = {Neuroscience and biobehavioral reviews}, volume = {55}, number = {}, pages = {294-321}, doi = {10.1016/j.neubiorev.2015.04.015}, pmid = {25957927}, issn = {1873-7528}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adolescent ; Adult ; Clinical Trials as Topic ; Female ; Humans ; Male ; Mental Disorders/*drug therapy ; Nervous System Diseases/*drug therapy ; Neurology ; Psychiatry ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Young Adult ; }, abstract = {N-acetylcysteine (NAC) is recognized for its role in acetaminophen overdose and as a mucolytic. Over the past decade, there has been growing evidence for the use of NAC in treating psychiatric and neurological disorders, considering its role in attenuating pathophysiological processes associated with these disorders, including oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation and glutamate and dopamine dysregulation. In this systematic review we find favorable evidence for the use of NAC in several psychiatric and neurological disorders, particularly autism, Alzheimer's disease, cocaine and cannabis addiction, bipolar disorder, depression, trichotillomania, nail biting, skin picking, obsessive-compulsive disorder, schizophrenia, drug-induced neuropathy and progressive myoclonic epilepsy. Disorders such as anxiety, attention deficit hyperactivity disorder and mild traumatic brain injury have preliminary evidence and require larger confirmatory studies while current evidence does not support the use of NAC in gambling, methamphetamine and nicotine addictions and amyotrophic lateral sclerosis. Overall, NAC treatment appears to be safe and tolerable. Further well designed, larger controlled trials are needed for specific psychiatric and neurological disorders where the evidence is favorable.}, }
@article {pmid25943884, year = {2015}, author = {Ying, H and Turturro, S and Nguyen, T and Shen, X and Zelkha, R and Johnson, EC and Morrison, JC and Yue, BY}, title = {Induction of autophagy in rats upon overexpression of wild-type and mutant optineurin gene.}, journal = {BMC cell biology}, volume = {16}, number = {}, pages = {14}, pmid = {25943884}, issn = {1471-2121}, support = {P30 EY001792/EY/NEI NIH HHS/United States ; EY001792/EY/NEI NIH HHS/United States ; P30 EY010572/EY/NEI NIH HHS/United States ; R01 EY018828/EY/NEI NIH HHS/United States ; EY018828/EY/NEI NIH HHS/United States ; }, mesh = {Amino Acid Substitution ; Animals ; *Autophagy ; Cell Line ; Green Fluorescent Proteins/genetics/metabolism ; Intraocular Pressure/drug effects ; Male ; Microtubule-Associated Proteins/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Rats ; Recombinant Fusion Proteins/biosynthesis/genetics ; Retinal Ganglion Cells/cytology/drug effects/metabolism ; Sirolimus/pharmacology ; Transcription Factor TFIIIA/genetics/*metabolism ; }, abstract = {BACKGROUND: Optineurin is a gene associated with normal tension glaucoma and amyotrophic lateral sclerosis. It has been reported previously that in cultured RGC5 cells, the turnover of endogenous optineurin involves mainly the ubiquitin-proteasome pathway (UPP). When optineurin is upregulated or mutated, the UPP function is compromised as evidenced by a decreased proteasome β5 subunit (PSMB5) level and autophagy is induced for clearance of the optineurin protein.<br><br>RESULTS: Adeno-associated type 2 viral (AAV2) vectors for green fluorescence protein (GFP) only, GFP-tagged wild-type and Glu50Lys (E50K) mutated optineurin were intravitreally injected into rats for expression in retinal ganglion cells (RGCs). Following intravitreal injections, eyes that received optineurin vectors exhibited retinal thinning, as well as RGC and axonal loss compared to GFP controls. By immunostaining and Western blotting, the level of PSMB5 and autophagic substrate degradation marker p62 was reduced, and the level of autophagic marker microtubule associated protein 1 light chain 3 (LC3) was enhanced. The UPP impairment and autophagy induction evidently occurred in vivo as in vitro. The optineurin level, RGC and axonal counts, and apoptosis in AAV2-E50K-GFP-injected rat eyes were averted to closer to normal limits after treatment with rapamycin, an autophagic enhancer.<br><br>CONCLUSIONS: The UPP function was reduced and autophagy was induced when wild-type and E50K optineurin was overexpressed in rat eyes. This study validates the in vitro findings, confirming that UPP impairment and autophagy induction also occur in vivo. In addition, rapamycin is demonstrated to clear the accumulated mutant optineurin. This agent may potentially be useful for rescuing of the adverse optineurin phenotypes in vivo.}, }
@article {pmid25939067, year = {2015}, author = {Nagoshi, N and Nakashima, H and Fehlings, MG}, title = {Riluzole as a neuroprotective drug for spinal cord injury: from bench to bedside.}, journal = {Molecules (Basel, Switzerland)}, volume = {20}, number = {5}, pages = {7775-7789}, pmid = {25939067}, issn = {1420-3049}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Clinical Trials as Topic ; Humans ; Neuroprotective Agents/pharmacology/*therapeutic use ; Rats ; Riluzole/pharmacology/*therapeutic use ; Sodium Channel Blockers/*therapeutic use ; Spinal Cord Injuries/*drug therapy ; Synaptic Transmission/*drug effects ; }, abstract = {Spinal cord injury (SCI) is a devastating event resulting in permanent loss of neurological function. To date, effective therapies for SCI have not been established. With recent progress in neurobiology, however, there is hope that drug administration could improve outcomes after SCI. Riluzole is a benzothiazole anticonvulsant with neuroprotective effects. It has been approved by the U.S. Food and Drug Administration as a safe and well-tolerated treatment for patients with amyotrophic lateral sclerosis. The mechanism of action of riluzole involves the inhibition of pathologic glutamatergic transmission in synapses of neurons via sodium channel blockade. There is convincing evidence that riluzole diminishes neurological tissue destruction and promotes functional recovery in animal SCI models. Based on these results, a phase I/IIa clinical trial with riluzole was conducted for patients with SCI between 2010 and 2011. This trial demonstrated significant improvement in neurological outcomes and showed it to be a safe drug with no serious adverse effects. Currently, an international, multi-center clinical trial (Riluzole in Acute Spinal Cord Injury Study: RISCIS) in phase II/III is in progress with riluzole for patients with SCI (clinicaltrials.gov, registration number NCT01597518). This article reviews the pharmacology and neuroprotective mechanisms of riluzole, and focuses on existing preclinical evidence, and emerging clinical data in the treatment of SCI.}, }
@article {pmid25938606, year = {2015}, author = {Jiménez García, I and Sala Moya, N and Riera Munt, M and Herrera Rodríguez, MV and Povedano Panadés, M and Virgili Casas, MN}, title = {[The patient's opinion matters: experience in the nutritional care in an ALS multidisciplinary team].}, journal = {Nutricion hospitalaria}, volume = {31 Suppl 5}, number = {}, pages = {56-66}, doi = {10.3305/nh.2015.31.sup5.9132}, pmid = {25938606}, issn = {1699-5198}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Family ; Humans ; Nutrition Therapy/*methods ; Patient Care Team/*organization &amp; administration ; Patient Satisfaction ; }, abstract = {UNLABELLED: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease which has no cure, so the treatment will be symptomatic in a Multidisciplinary Unit. It is composed of professionals, experts in patient care, with an interdisciplinary vision in order to act in a coordinated manner depending on the different situations which may arise over the course of the disease. There are several studies showing improved survival in patients treated within the framework of a multidisciplinary team compared to treatment by isolated specialties. An ALS Multidisciplinary Unit was created in 2004 in the University Hospital of Bellvitge (HUB). It is composed of a neurologist, pulmonologist, nutritionist, endocrinologist, rehabilitation, physical therapist, psychologist, social worker, nurse manager, speech therapist and an administrative worker. To assess the impact of the multidisciplinary care of our program 418 patients diagnosed with ALS were evaluated, 84 patients who had been treated by general neurology and 334 who had been treated under a model of multidisciplinary care. Patients who were treated in the unit of multidisciplinary care had a median survival of 1246 days (IC 1109-1382), 104 days above the median 1148 days of those followed by a general neurology consultation (CI 998-1297). This difference was statistically significant (log-rank 10,8; p= 0.008). This benefit was independent of having received treatment with riluzole, non-invasive mechanical ventilation or percutaneous gastrostomy. Nutritional assessment was performed on the first visit and all subsequent controls. It is important to do anthropometric measurements and detect unintentional weight loss and its possible precipitating causes in order to establish the appropriate nutritional treatment. The exploration of dysphagia allows a determination of the appropriate dietary advice, the introduction of thickeners to adjust the texture of food or nutritional supplementation with high-calorie formulas to prevent or correct weight loss. If these measures are not sufficient or there is the risk of failure of respiratory function, early gastrostomy placement will be indicated. The analysis of 140 ALS patients (92 controls and 48 with radiologic percutaneous gastrostomy) showed no difference in mean survival time between groups (32 vs 33.9 months, log Rank 1.86 p=0.39). Any patient had major complications. Despite not find changes in survival, the use of gastrostomy should be understood as a treatment to improve the quality of life and well-being of the patient. Psychosocial support of the person and the family environment is essential to integrate all the changes and situations that arise in the course of the disease. This should start from diagnosis as early intervention contributes to improved training, preventing situations of deterioration and helping coping with the dependency process. It is also possible to use technology and social media to complement the classic care model. In the case of the HUB ALS Multidisciplinary Unit, affected individuals and their families have the resources of the Aula Paciente and ALS blog, created with the objective of providing opportunities for dialogue between patients, families and caregivers. The satisfaction degree of the patients with the care provided by the ALS Multidisciplinary Unit on service accessibility, information received and the quality of care was assessed globally as good in 52.8% or very good in 29, 2% of patients.<br><br>CONCLUSION: Attention for the ALS affected person must be considered within the framework of a multidisciplinary team made up of all the professionals who go to intervene throughout the disease process in order to provide increased survival with the best care and quality of life.}, }
@article {pmid25936269, year = {2015}, author = {Lu, K and Zhang, C and Wu, W and Zhou, M and Tang, Y and Peng, Y}, title = {Rhubarb extract has a protective role against radiation-induced brain injury and neuronal cell apoptosis.}, journal = {Molecular medicine reports}, volume = {12}, number = {2}, pages = {2689-2694}, doi = {10.3892/mmr.2015.3693}, pmid = {25936269}, issn = {1791-3004}, mesh = {Animals ; Apoptosis/drug effects ; Brain Injuries/*drug therapy/etiology/metabolism/pathology ; Cells, Cultured ; DNA Fragmentation/drug effects ; Female ; Gamma Rays/adverse effects ; Neurons/drug effects/metabolism/pathology/radiation effects ; Neuroprotective Agents/chemistry/*pharmacology ; Oxidative Stress/drug effects ; Plant Extracts/chemistry/*pharmacology ; Radiation Injuries/*drug therapy/metabolism/pathology ; Radiation-Protective Agents/chemistry/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Rheum/*chemistry ; }, abstract = {Oxidative stress caused by ionizing radiation is involved in neuronal damage in a number of disorders, including trauma, stroke, Alzheimer's disease and amyotrophic lateral sclerosis. Ionizing radiation can lead to the formation of free radicals, which cause neuronal apoptosis and have important roles in the development of some types of chronic brain disease. The present study evaluated the effects of varying concentrations (2, 5 and 10 µg/ml) of ethanolic rhubarb extract on the neuronal damage caused by irradiation in primary neuronal cultures obtained from the cortices of rat embryos aged 20 days. Brain damage was induced with a single dose of γ-irradiation that induced DNA fragmentation, increased lactate dehydrogenase release in neuronal cells and acted as a trigger for microglial cell proliferation. Treatment with rhubarb extract significantly decreased radiation-induced lactate dehydrogenase release and DNA fragmentation, which are important in the process of cell apoptosis. The rhubarb extract exhibited dose-dependent inhibition of lactate dehydrogenase release and neuronal cell apoptosis that were induced by the administration of ionizing radiation. The effect of a 10 µg/ml dose of rhubarb extract on the generation of reactive oxygen species (ROS) induced by radiation was also investigated. This dose led to significant inhibition of ROS generation. In conclusion, the present study showed a protective role of rhubarb extract against irradiation-induced apoptotic neuronal cell death and ROS generation.}, }
@article {pmid25934946, year = {2015}, author = {Oh, KW and Moon, C and Kim, HY and Oh, SI and Park, J and Lee, JH and Chang, IY and Kim, KS and Kim, SH}, title = {Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis.}, journal = {Stem cells translational medicine}, volume = {4}, number = {6}, pages = {590-597}, pmid = {25934946}, issn = {2157-6564}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Autografts ; *Bone Marrow Cells ; Female ; Follow-Up Studies ; Humans ; Male ; *Mesenchymal Stem Cell Transplantation ; *Mesenchymal Stem Cells ; Middle Aged ; }, abstract = {UNLABELLED: Stem cell therapy is an emerging alternative therapeutic or disease-modifying strategy for amyotrophic lateral sclerosis (ALS). The aim of this open-label phase I clinical trial was to evaluate the safety of two repeated intrathecal injections of autologous bone marrow (BM)-derived mesenchymal stromal cells (MSCs) in ALS patients. Eight patients with definite or probable ALS were enrolled. After a 3-month lead-in period, autologous MSCs were isolated two times from the BM at an interval of 26 days and were then expanded in vitro for 28 days and suspended in autologous cerebrospinal fluid. Of the 8 patients, 7 received 2 intrathecal injections of autologous MSCs (1 × 10(6) cells per kg) 26 days apart. Clinical or laboratory measurements were recorded to evaluate the safety 12 months after the first MSC injection. The ALS Functional Rating Scale-Revised (ALSFRS-R), the Appel ALS score, and forced vital capacity were used to evaluate the patients' disease status. One patient died before treatment and was withdrawn from the study. With the exception of that patient, no serious adverse events were observed during the 12-month follow-up period. Most of the adverse events were self-limited or subsided after supportive treatment within 4 days. Decline in the ALSFRS-R score was not accelerated during the 6-month follow-up period. Two repeated intrathecal injections of autologous MSCs were safe and feasible throughout the duration of the 12-month follow-up period.<br><br>SIGNIFICANCE: Stem cell therapy is an emerging alternative therapeutic or disease-modifying strategy for amyotrophic lateral sclerosis (ALS). To the authors' best knowledge, there are no clinical trials to evaluate the safety of repeated intrathecal injections of autologous bone marrow mesenchymal stromal cells in ALS. After the clinical trial (phase I/II) was conducted, the stem cell (HYNR-CS, NEURONATA-R) was included in the revision of the regulations on orphan drug designation (number 160; December 31, 2013) and approved as a New Drug Application (Department of Cell and Gene Therapy 233; July 30, 2014) by the Korean Food and Drug Administration. The phase II trial is expected to be reported later.}, }
@article {pmid25928051, year = {2015}, author = {Hasegawa, M and Abe, T and Nagata, T and Onozuka, D and Hagihara, A}, title = {The number of prehospital defibrillation shocks and 1-month survival in patients with out-of-hospital cardiac arrest.}, journal = {Scandinavian journal of trauma, resuscitation and emergency medicine}, volume = {23}, number = {}, pages = {34}, pmid = {25928051}, issn = {1757-7241}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Electric Countershock ; Emergency Medical Services/*organization &amp; administration ; Female ; Humans ; Male ; Middle Aged ; Out-of-Hospital Cardiac Arrest/*mortality/*therapy ; Prospective Studies ; Registries ; Survival Rate ; }, abstract = {BACKGROUND: The relationship between the number of pre-hospital defibrillation shocks and treatment outcome in patients with out-of-hospital cardiac arrest (OHCA) presenting with ventricular fibrillation (VF) is unknown currently. We examined the association between the number of pre-hospitalization defibrillation shocks and 1-month survival in OHCA patients.<br><br>METHODS: We conducted a prospective observational study using national registry data obtained from patients with OHCA between January 1, 2009 and December 31, 2012 in Japan. The study subjects were &#x2265; 18-110 years of age, had suffered from an OHCA before arrival of EMS personnel, had a witnessed collapse, had an initial rhythm that was shockable [VF/ventricular tachycardia (pulseless VT)], were not delivered a shock using a public automated external defibrillator (AED), received one or more shocks using a biphasic defibrillator by EMS personnel, and were transported to a medical institution between January 1, 2009 and December 31, 2012. There were 20,851 OHCA cases which met the inclusion criteria during the study period. Signal detection analysis was used to identify the cutoff point in the number of prehospital defibrillation shocks most closely related to one-month survival. Variables related to the number of defibrillations or one-month survival in OHCA were identified using multiple logistic regression analysis.<br><br>RESULTS: A cutoff point in the number of pre-hospital defibrillation shocks most closely associated with 1-month OHCA survival was between two and three (&#x3c7;(2) = 209.61, p < 0.0001). Among those patients who received two shocks or less, 34.48% survived for at least 1 month, compared with 24.75% of those who received three shocks or more. The number of defibrillations (odds ratio [OR] = 1.19, 95% CI: 1.03, 1.38), OHCA origin (OR = 2.81, 95% CI: 2.26, 3.49), use of ALS devices (OR = 0.68, 95% CI: 0.59, 0.79), use of epinephrine (OR = 0.33, 95% C: 0.28, 0.39), interval between first defibrillation and first ROSC (OR = 1.45, 95% CI: 1.18, 1.78), and chest compression (OR = 1.21, 95% CI: 1.06, 1.38) were associated significantly with 1-month OCHA survival.<br><br>CONCLUSIONS: The cutoff point in the number of defibrillations of patients with OHCA most closely related to one-month survival was between 2 and 3, and the likelihood of non-survival 1 month after an OHCA was increased when &#x2265;3 shocks were needed. Further studies are needed to verify this finding.}, }
@article {pmid25921543, year = {2015}, author = {Smith, GB and Welch, J and DeVita, MA and Hillman, KM and Jones, D}, title = {Education for cardiac arrest--Treatment or prevention?.}, journal = {Resuscitation}, volume = {92}, number = {}, pages = {59-62}, doi = {10.1016/j.resuscitation.2015.04.018}, pmid = {25921543}, issn = {1873-1570}, mesh = {Advanced Cardiac Life Support/*education ; Cardiopulmonary Resuscitation/*education ; *Emergency Medical Services ; Heart Arrest/*prevention &amp; control ; Humans ; Medical Staff, Hospital/*education ; }, abstract = {In-hospital cardiac arrests (IHCA) occur infrequently and individual staff members working on general wards may only rarely encounter one. Mortality following IHCA is high and the evidence for the benefits of many advanced life support (ALS) interventions is scarce. Nevertheless, regular, often frequent, ALS training is mandatory for many hospital medical staff and nurses. The incidence of pre-cardiac arrest deterioration is much higher than that of cardiac arrests, and there is evidence that intervention prior to cardiac arrest can reduce the incidence of IHCA. This article discusses a proposal to reduce the emphasis on widespread ALS training and to increase education in the recognition and response to pre-arrest clinical deterioration.}, }
@article {pmid25917321, year = {2015}, author = {Rabie, EM and Heeba, GH and Abouzied, MM and Khalifa, MM}, title = {Comparative effects of Aliskiren and Telmisartan in high fructose diet-induced metabolic syndrome in rats.}, journal = {European journal of pharmacology}, volume = {760}, number = {}, pages = {145-153}, doi = {10.1016/j.ejphar.2015.04.019}, pmid = {25917321}, issn = {1879-0712}, mesh = {Amides/pharmacology/*therapeutic use ; Animals ; Antihypertensive Agents/pharmacology/*therapeutic use ; Benzimidazoles/pharmacology/*therapeutic use ; Benzoates/pharmacology/*therapeutic use ; Blood Glucose/drug effects/metabolism ; Fructose/administration &amp; dosage/*toxicity ; Fumarates/pharmacology/*therapeutic use ; Insulin Resistance/physiology ; Male ; Metabolic Syndrome/blood/chemically induced/*drug therapy ; Rats ; Rats, Wistar ; Telmisartan ; Treatment Outcome ; }, abstract = {Fructose is a commonly used sweetener associated with diets that increase the prevalence of metabolic syndrome (MS). Inhibition of the renin-angiotensin system (RAS) has been consistently demonstrated to reduce MS. However, there has been no direct comparison among different pharmacological modes of inhibiting the RAS concerning their effects on MS. This study investigated the effect of aliskiren, a direct renin inhibitor, versus telmisartan, an angiotensin II-receptor blocker, in the treatment of fructose-induced MS in rats. MS was induced by high fructose (FRC) diet feeding for 12 weeks. Oral administrations of telmisartan (TEL, 5 mg/kg), aliskiren (ALS, 30 mg/kg) or vehicle were started in the last 4 weeks. Results showed that administration of either TEL or ALS with FRC diet equally ameliorated the metabolic parameters (glucose level, oral glucose tolerance test, insulin resistance and serum lipids profile), systolic blood pressure and oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione levels and catalase activity). Additionally, the effects of TEL and ALS were associated with a decrease in body composition index and attenuation of liver index, serum liver enzyme activities and hepatic expressions of inflammatory and fibrotic markers (tumor necrosis factor-α, nuclear factor kappa-B and transforming growth factor-β) with a significant increase in hepatic glucose transporter-2 and peroxisome proliferator-activated receptors-alpha and gamma expressions. The results suggested that, at indicated dosage, ALS has ameliorative effect equal to that of TEL against FRC-induced metabolic and hepatic disorders; implying that drugs which inhibit the RAS, by different mode of inhibition, profoundly affect fructose-induced MS in rats.}, }
@article {pmid25914026, year = {2015}, author = {Tong, H and Yu, X and Lu, X and Wang, P}, title = {Downregulation of solute carriers of glutamate in gliosomes and synaptosomes may explain local brain metastasis in anaplastic glioblastoma.}, journal = {IUBMB life}, volume = {67}, number = {4}, pages = {306-311}, doi = {10.1002/iub.1372}, pmid = {25914026}, issn = {1521-6551}, mesh = {Aged ; Brain Neoplasms/*metabolism/pathology ; Case-Control Studies ; *Down-Regulation ; Excitatory Amino Acid Transporter 1/*metabolism ; Glioblastoma/*metabolism/pathology ; Glutamates/*metabolism ; Humans ; Lipoylation ; Male ; Middle Aged ; *Neoplasm Metastasis ; Synaptosomes/*metabolism/pathology ; }, abstract = {Advanced grades of glioblastoma are highly aggressive, especially in terms of multisite spread within the brain or even to distant sites at the spinal cord. In advanced grades of glioblastoma, glutamate and glutamine are reported to be increased in concentration in the extracellular fluid. It has been reported that glutamate acts as an extracellular signaling molecule for facilitating local spread of advanced grades of glioblastoma. In the present study, we aimed to examine whether glutamate uptake mechanisms is impaired in advanced glioblastoma. The possible downregulated mechanisms of glutamate uptake would facilitate persistence of glutamate in the extracellular environment, rather than intracellular uptake. We obtained biobanked human specimens of glioblastoma and tested expression of proteins belonging to the solute carrier families of proteins that are known to function as membrane-located excitatory amino acid like glutamate transporters. The present study provides preliminary evidence of the downregulation of membrane expression of excitatory amino acid transporters solute carrier family 1 member 3 (SLC1A3) and its palmitoylated form in gliosomes, as well as SLC1A2 in the glio-synaptosomes. Compounds like riluzole used in the treatment of amyotrophic lateral sclerosis and the antibiotic ceftriaxone have the potential to facilitate glutamate uptake. These medications may be examined as adjunct chemotherapy in the massively aggressive tumor glioblastoma multiforme.}, }
@article {pmid25913322, year = {2015}, author = {Serrano, T and Dupas, R and Upegui, E and Buscail, C and Grimaldi, C and Viel, JF}, title = {Geographical modeling of exposure risk to cyanobacteria for epidemiological purposes.}, journal = {Environment international}, volume = {81}, number = {}, pages = {18-25}, doi = {10.1016/j.envint.2015.04.007}, pmid = {25913322}, issn = {1873-6750}, mesh = {Amino Acids, Diamino ; Amyotrophic Lateral Sclerosis/epidemiology ; *Cyanobacteria ; Cyanobacteria Toxins ; *Environmental Exposure ; Environmental Monitoring ; Epidemiologic Studies ; Eutrophication ; France ; Geographic Information Systems ; Humans ; *Models, Theoretical ; Phosphorus/*analysis ; Risk Factors ; }, abstract = {The cyanobacteria-derived neurotoxin β-methylamino-L-alanine (BMAA) represents a plausible environmental trigger for amyotrophic lateral sclerosis (ALS), a debilitating and fatal neuromuscular disease. With the eutrophication of water bodies, cyanobacterial blooms and their toxins are becoming increasingly prevalent in France, especially in the Brittany region. Cyanobacteria are monitored at only a few recreational sites, preventing an estimation of exposure of the human population. By contrast, phosphorus, a limiting nutrient for cyanobacterial growth and thus considered a good proxy for cyanobacteria exposure, is monitored in many but not all surface water bodies. Our goal was to develop a geographic exposure indicator that could be used in epidemiological research. We considered the total phosphorus (TP) concentration (mg/L) of samples collected between October 2007 and September 2012 at 179 monitoring stations distributed throughout the Brittany region. Using readily available spatial data, we computed environmental descriptors at the watershed level with a Geographic Information System. Then, these descriptors were introduced into a backward stepwise linear regression model to predict the median TP concentration in unmonitored surface water bodies. TP concentrations in surface water follow an increasing gradient from West to East and inland to coast. The empirical concentration model included five predictor variables with a fair coefficient of determination (R(2) = 0.51). The specific total runoff and the watershed slope correlated negatively with the TP concentrations (p = 0.01 and p< 10(-9), respectively), whereas positive associations were found for the proportion of built-up area, the upstream presence of sewage treatment plants, and the algae volume as indicated by the Landsat red/green reflectance ratio (p < 0.01, p < 10(-6) and p < 0.01, respectively). Complementing the monitoring networks, this geographical modeling can help estimate TP concentrations at the watershed level, delivering a proxy for cyanobacteria exposure that can be used along with other risk factors in further ALS epidemiologic case-control studies.}, }
@article {pmid25912081, year = {2015}, author = {Liu, X and Chen, J and Liu, W and Li, X and Chen, Q and Liu, T and Gao, S and Deng, M}, title = {The fused in sarcoma protein forms cytoplasmic aggregates in motor neurons derived from integration-free induced pluripotent stem cells generated from a patient with familial amyotrophic lateral sclerosis carrying the FUS-P525L mutation.}, journal = {Neurogenetics}, volume = {16}, number = {3}, pages = {223-231}, pmid = {25912081}, issn = {1364-6753}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Cell Differentiation ; Cell Line ; Cytoplasm/metabolism ; Genetic Vectors ; Humans ; Induced Pluripotent Stem Cells/cytology/*physiology ; Male ; Motor Neurons/cytology/*physiology ; Mutation ; Protein Aggregates/genetics ; RNA-Binding Protein FUS/*genetics ; Young Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons (MNs) and has no effective treatment. Mutations in the fused in sarcoma (FUS) gene and abnormal aggregation of FUS protein have been reported in ALS. However, the mechanisms involved in ALS are poorly understood. Clinical drug trails have failed due to a lack of appropriate disease models, including a lack of access to MNs from ALS patients. Induced pluripotent stem (iPS) cells derived from patients with ALS provide an indispensable resource for in vitro mechanistic studies and for future patient-specific cell-based therapies. Previous reports demonstrated that viral-based ALS-iPS cells generated from fibroblasts harvested from Caucasian populations are ideal for basic research; however, ALS-iPS cells are precluded from cell-based therapeutic applications because of the risks associated with the integration of viral sequences into the genome and inconvenience associated with dermal biopsies. To establish a model for use in clinical applications, using episomal vectors, we generated an integration-free iPS cell line from peripheral blood mononuclear cells (PBMCs) harvested from a familial ALS (FALS) patient carrying the FUS-P525L mutation and a healthy control. Furthermore, we successfully differentiated ALS patient-specific iPS cells into MNs and subsequently detected cytoplasmic mislocalization and formation of FUS protein aggregates in MNs due to the FUS-P525L mutation. Our findings offer a cell-based disease model for use in further elucidating ALS pathogenesis and provide a tool for exploring gene repair coupled with cell replacement therapy.}, }
@article {pmid25904790, year = {2015}, author = {Kunis, G and Baruch, K and Miller, O and Schwartz, M}, title = {Immunization with a Myelin-Derived Antigen Activates the Brain's Choroid Plexus for Recruitment of Immunoregulatory Cells to the CNS and Attenuates Disease Progression in a Mouse Model of ALS.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {35}, number = {16}, pages = {6381-6393}, pmid = {25904790}, issn = {1529-2401}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/pathology ; Animals ; Cell Movement/immunology ; Choroid Plexus/*cytology/*immunology ; Disease Models, Animal ; *Disease Progression ; Female ; Glial Cell Line-Derived Neurotrophic Factor/metabolism ; *Immunization ; Insulin-Like Growth Factor I/metabolism ; Macrophages/cytology/immunology ; Male ; Mice ; Mice, Transgenic ; Mutation ; Myelin-Oligodendrocyte Glycoprotein/*immunology ; Primary Cell Culture ; Spinal Cord/immunology/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; T-Lymphocytes/*immunology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating fatal motor neuron disease, for which there is currently no cure or effective treatment. In this disease, local neuroinflammation develops along the disease course and contributes to its rapid progression. In several models of CNS pathologies, circulating immune cells were shown to display an indispensable role in the resolution of the neuroinflammatory response. The recruitment of such cells to the CNS involves activation of the choroid plexus (CP) of the brain for leukocyte trafficking, through a mechanism that requires IFN-γ signaling. Here, we found that in the mutant SOD1(G93A) (mSOD1) mouse model of ALS, the CP does not support leukocyte trafficking during disease progression, due to a local reduction in IFN-γ levels. Therapeutic immunization of mSOD1 mice with a myelin-derived peptide led to CP activation, and was followed by the accumulation of immunoregulatory cells, including IL-10-producing monocyte-derived macrophages and Foxp3(+) regulatory T cells, and elevation of the neurotrophic factors IGF-1 and GDNF in the diseased spinal cord parenchyma. The immunization resulted in the attenuation of disease progression and an increased life expectancy of the mSOD1 mice. Collectively, our results demonstrate that recruitment of immunoregulatory cells to the diseased spinal cord in ALS, needed for fighting off the pathology, can be enhanced by transiently boosting peripheral immunity to myelin antigens.}, }
@article {pmid25896576, year = {2015}, author = {Belendiuk, KA and Baldini, LL and Bonn-Miller, MO}, title = {Narrative review of the safety and efficacy of marijuana for the treatment of commonly state-approved medical and psychiatric disorders.}, journal = {Addiction science &amp; clinical practice}, volume = {10}, number = {}, pages = {10}, pmid = {25896576}, issn = {1940-0640}, support = {R01 MH40564/MH/NIMH NIH HHS/United States ; }, mesh = {Cachexia/drug therapy ; *Cannabis ; Central Nervous System Diseases/drug therapy ; Chronic Disease/*drug therapy ; Crohn Disease/drug therapy ; Glaucoma/drug therapy ; HIV Infections/drug therapy ; Humans ; Medical Marijuana/administration &amp; dosage/adverse effects/*therapeutic use ; Mental Disorders/*drug therapy ; Neoplasms/drug therapy ; }, abstract = {The present investigation aimed to provide an objective narrative review of the existing literature pertaining to the benefits and harms of marijuana use for the treatment of the most common medical and psychological conditions for which it has been allowed at the state level. Common medical conditions for which marijuana is allowed (i.e., those conditions shared by at least 80 percent of medical marijuana states) were identified as: Alzheimer's disease, amyotrophic lateral sclerosis, cachexia/wasting syndrome, cancer, Crohn's disease, epilepsy and seizures, glaucoma, hepatitis C virus, human immunodeficiency virus/acquired immunodeficiency syndrome, multiple sclerosis and muscle spasticity, severe and chronic pain, and severe nausea. Post-traumatic stress disorder was also included in the review, as it is the sole psychological disorder for which medical marijuana has been allowed. Studies for this narrative review were included based on a literature search in PsycINFO, MEDLINE, and Google Scholar. Findings indicate that, for the majority of these conditions, there is insufficient evidence to support the recommendation of medical marijuana at this time. A significant amount of rigorous research is needed to definitively ascertain the potential implications of marijuana for these conditions. It is important for such work to not only examine the effects of smoked marijuana preparations, but also to compare its safety, tolerability, and efficacy in relation to existing pharmacological treatments.}, }
@article {pmid25894871, year = {2015}, author = {Aoki, Y and Douglas, AG and Wood, MJ}, title = {Oligonucleotide therapies: the future of amyotrophic lateral sclerosis treatment?.}, journal = {Neurodegenerative disease management}, volume = {5}, number = {2}, pages = {93-95}, doi = {10.2217/nmt.15.4}, pmid = {25894871}, issn = {1758-2032}, support = {G0900887/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; C9orf72 Protein ; Genetic Therapy/methods ; Humans ; Oligonucleotides/*therapeutic use ; Proteins/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, }
@article {pmid25889343, year = {2015}, author = {Mazzini, L and Gelati, M and Profico, DC and Sgaravizzi, G and Projetti Pensi, M and Muzi, G and Ricciolini, C and Rota Nodari, L and Carletti, S and Giorgi, C and Spera, C and Domenico, F and Bersano, E and Petruzzelli, F and Cisari, C and Maglione, A and Sarnelli, MF and Stecco, A and Querin, G and Masiero, S and Cantello, R and Ferrari, D and Zalfa, C and Binda, E and Visioli, A and Trombetta, D and Novelli, A and Torres, B and Bernardini, L and Carriero, A and Prandi, P and Servo, S and Cerino, A and Cima, V and Gaiani, A and Nasuelli, N and Massara, M and Glass, J and Sorarù, G and Boulis, NM and Vescovi, AL}, title = {Human neural stem cell transplantation in ALS: initial results from a phase I trial.}, journal = {Journal of translational medicine}, volume = {13}, number = {}, pages = {17}, pmid = {25889343}, issn = {1479-5876}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Cell Culture Techniques ; Central Nervous System/pathology ; Chromosome Banding ; Disease Progression ; Female ; Humans ; Immunosuppression Therapy ; Intercellular Signaling Peptides and Proteins ; Italy ; Karyotyping ; Male ; Mice ; Mice, Nude ; Middle Aged ; Neural Stem Cells/*cytology ; Pilot Projects ; Prospective Studies ; Spinal Cord/cytology ; *Stem Cell Transplantation ; }, abstract = {BACKGROUND: We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità and the competent Ethics Committees and was monitored by an external Safety Board.<br><br>METHODS: Six non-ambulatory patients were treated. Three of them received 3 unilateral hNSCs microinjections into the lumbar cord tract, while the remaining ones received bilateral (n&#x2009;=&#x2009;3&#x2009;+&#x2009;3) microinjections. None manifested severe adverse events related to the treatment, even though nearly 5 times more cells were injected in the patients receiving bilateral implants and a much milder immune-suppression regimen was used as compared to previous trials.<br><br>RESULTS: No increase of disease progression due to the treatment was observed for up to18 months after surgery. Rather, two patients showed a transitory improvement of the subscore ambulation on the ALS-FRS-R scale (from 1 to 2). A third patient showed improvement of the MRC score for tibialis anterior, which persisted for as long as 7&#xa0;months. The latter and two additional patients refused PEG and invasive ventilation and died 8&#xa0;months after surgery due to the progression of respiratory failure. The autopsies confirmed that this was related to the evolution of the disease.<br><br>CONCLUSIONS: We describe a safe cell therapy approach that will allow for the treatment of larger pools of patients for later-phase ALS clinical trials, while warranting good reproducibility. These can now be carried out under more standardized conditions, based on a more homogenous repertoire of clinical grade hNSCs. The use of brain tissue from natural miscarriages eliminates the ethical concerns that may arise from the use of fetal material.<br><br>TRIAL REGISTRATION: EudraCT:2009-014484-39 .}, }
@article {pmid25884010, year = {2015}, author = {Miller, RG and Block, G and Katz, JS and Barohn, RJ and Gopalakrishnan, V and Cudkowicz, M and Zhang, JR and McGrath, MS and Ludington, E and Appel, SH and Azhir, A and , }, title = {Randomized phase 2 trial of NP001-a novel immune regulator: Safety and early efficacy in ALS.}, journal = {Neurology(R) neuroimmunology &amp; neuroinflammation}, volume = {2}, number = {3}, pages = {e100}, pmid = {25884010}, issn = {2332-7812}, support = {UL1 RR025758/RR/NCRR NIH HHS/United States ; UL1 TR000439/TR/NCATS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; }, abstract = {OBJECTIVE: To assess the safety, tolerability, and preliminary efficacy of NP001, a novel immune regulator of inflammatory monocytes/macrophages, for slowing progression of amyotrophic lateral sclerosis (ALS).<br><br>METHODS: This was a phase 2 randomized, double-blind, placebo-controlled trial of NP001 in 136 patients with ALS of <3 years' duration and forced vital capacity &#x2265;70%. Participants received NP001 2 mg/kg, NP001 1 mg/kg, or placebo for 6 months. Safety, tolerability, and inflammatory biomarkers were assessed throughout the study. Preliminary efficacy was evaluated using the ALS Functional Rating Scale-Revised (ALSFRS-R) slope and change from baseline, with and without matched historical placebo controls, after 6 months of treatment. A post hoc analysis of the percentage of patients ("responders") whose ALSFRS-R did not change from baseline was also conducted.<br><br>RESULTS: NP001 was generally safe and well-tolerated, except for infusion site pain and dizziness. No significant slowing of decline in the primary or secondary measures was observed. However, slowing of progression was observed in the high-dose group in patients with greater inflammation (wide range C-reactive protein). Moreover, NP001 may have dose dependently halted symptom progression in a subset of patients. More than 2 times as many patients on high-dose NP001 (25%) did not progress during 6 months of treatment compared with those on placebo (11%). Most "responders" had an elevated biomarker of inflammation, interleukin-18, and were positive for lipopolysaccharide at baseline, which decreased after treatment with NP001.<br><br>CONCLUSION: The arresting of progression of ALS symptoms by NP001 in a subset of patients with marked neuroinflammation, as observed here, will represent a novel therapeutic approach for patients with ALS, if confirmed.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with ALS, NP001 is safe and did not significantly slow progression of the disease (difference in slope of the ALSFRS-R/month 0.12 favoring NP001, p = 0.55). The study lacks the precision to exclude an important effect of NP001.}, }
@article {pmid25881952, year = {2015}, author = {Slade, A and Stanic, S}, title = {Managing excessive saliva with salivary gland irradiation in patients with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {352}, number = {1-2}, pages = {34-36}, doi = {10.1016/j.jns.2015.02.008}, pmid = {25881952}, issn = {1878-5883}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications/physiopathology/*radiotherapy ; Female ; Humans ; Male ; Middle Aged ; Parotid Gland/radiation effects ; Salivary Glands/*radiation effects ; Salivation/*radiation effects ; Sialorrhea/etiology/*radiotherapy ; Treatment Outcome ; }, abstract = {OBJECTIVE: A significant fraction of patients with amyotrophic lateral sclerosis (ALS) are unable to swallow saliva, which may result in the spillage of saliva outside of the oral cavity. Although anticholinergic agents and botulin toxin injections are considered the first line of treatment, they have not been effective for all patients. We performed a literature search on therapeutic salivary gland irradiation in patients with ALS.<br><br>METHODS: We searched the PubMed for English language publications up to December 2014 on therapeutic salivary gland irradiation in patients with ALS. The search was performed using the following key words: amyotrophic lateral sclerosis, excessive salivation, sialorrhea, and radiation therapy.<br><br>RESULTS: The majority of ALS patients with excessive salivation respond well to salivary gland irradiation. The whole bilateral submandibular, and whole or partial bilateral parotid glands have been the target tissue for radiation therapy in most of the published studies. Various radiation therapy regimens have been utilized. The response to radiation therapy lasts for several months.<br><br>CONCLUSIONS: The majority of ALS patients with excessive salivation respond well to salivary gland irradiation. Neurologists should consider this treatment option for select patients with ALS and excessive salivation.}, }
@article {pmid25880309, year = {2015}, author = {Li, Z and Cheng, Y and Cui, J and Zhang, P and Zhao, H and Hu, S}, title = {Comparative transcriptome analysis reveals carbohydrate and lipid metabolism blocks in Brassica napus L. male sterility induced by the chemical hybridization agent monosulfuron ester sodium.}, journal = {BMC genomics}, volume = {16}, number = {1}, pages = {206}, pmid = {25880309}, issn = {1471-2164}, mesh = {Brassica napus/*genetics/metabolism ; Carbohydrate Metabolism/*drug effects ; Cell Wall/genetics/metabolism ; Down-Regulation/drug effects ; Flowers/genetics/metabolism ; Gene Expression Profiling ; Lipid Metabolism/*drug effects ; Microscopy, Electron, Transmission ; Molecular Sequence Annotation ; Oligonucleotide Array Sequence Analysis ; Plant Infertility/drug effects ; Plant Leaves/genetics/metabolism ; Plastids/drug effects/metabolism/ultrastructure ; Pyrimidines/*pharmacology ; Sulfonylurea Compounds/*pharmacology ; Transcriptome/*drug effects ; Up-Regulation/drug effects ; }, abstract = {BACKGROUND: Chemical hybridization agents (CHAs) are often used to induce male sterility for the production of hybrid seeds. We previously discovered that monosulfuron ester sodium (MES), an acetolactate synthase (ALS) inhibitor of the herbicide sulfonylurea family, can induce rapeseed (Brassica napus L.) male sterility at approximately 1% concentration required for its herbicidal activity. To find some clues to the mechanism of MES inducing male sterility, the ultrastructural cytology observations, comparative transcriptome analysis, and physiological analysis on carbohydrate content were carried out in leaves and anthers at different developmental stages between the MES-treated and mock-treated rapeseed plants.<br><br>RESULTS: Cytological analysis revealed that the plastid ultrastructure was abnormal in pollen mother cells and tapetal cells in male sterility anthers induced by MES treatment, with less material accumulation in it. However, starch granules were observed in chloroplastids of the epidermis cells in male sterility anthers. Comparative transcriptome analysis identified 1501 differentially expressed transcripts (DETs) in leaves and anthers at different developmental stages, most of these DETs being localized in plastid and mitochondrion. Transcripts involved in metabolism, especially in carbohydrate and lipid metabolism, and cellular transport were differentially expressed. Pathway visualization showed that the tightly regulated gene network for metabolism was reprogrammed to respond to MES treatment. The results of cytological observation and transcriptome analysis in the MES-treated rapeseed plants were mirrored by carbohydrate content analysis. MES treatment led to decrease in soluble sugars content in leaves and early stage buds, but increase in soluble sugars content and decrease in starch content in middle stage buds.<br><br>CONCLUSIONS: Our integrative results suggested that carbohydrate and lipid metabolism were influenced by CHA-MES treatment during rapeseed anther development, which might responsible for low concentration MES specifically inducing male sterility. A simple action model of CHA-MES inducing male sterility in B. napus was proposed. These results will help us to understand the mechanism of MES inducing male sterility at low concentration, and might provide some potential targets for developing new male sterility inducing CHAs and for genetic manipulation in rapeseed breeding.}, }
@article {pmid25864739, year = {2015}, author = {Wong, SC and Dalzell, AM and Mcgrogan, P and Didi, M and Laing, P and Ahmed, SF}, title = {The inflammatory milieu and the insulin like growth factor axis in children with inflammatory bowel disease following recombinant human growth hormone treatment.}, journal = {Journal of biological regulators and homeostatic agents}, volume = {29}, number = {1}, pages = {27-37}, pmid = {25864739}, issn = {0393-974X}, mesh = {Adolescent ; Biomarkers/blood ; Child ; Cytokines/*blood ; Female ; Human Growth Hormone/*therapeutic use ; Humans ; Inflammatory Bowel Diseases/*drug therapy/metabolism ; Insulin-Like Growth Factor Binding Protein 2/blood ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/*metabolism ; Male ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {It is unclear whether recombinant human growth hormone (rhGH) in inflammatory bowel disease (IBD) alters cytokine profile. The objective of this study is to evaluate changes in cytokines and systemic markers of the insulin growth factor axis following 6 months of rhGH treatment in children with IBD. In a six-month randomised control trial in children with IBD treated with rhGH at 0.067 mg/kg/day and controls (11 in each group), we measured pro-, anti-inflammatory cytokines and systemic markers of the IGF axis (total IGF-1, free IGF-1, total IGFBP-3, ALS, IGFBP-2) at baseline (T+0), and six months (T+6). Results expressed as median (range). In the rhGH group, TNFα was 3.1pg/ml (2.9, 100.6) and 3.6pg/ml (3.1, 5.3) at T+0 and T+6, respectively (p=0.85), whereas in the controls this was 3.3pg/ ml (2.7, 4.0) and 3.1pg/m l (2.7, 4.7), respectively (p=0.79). In the rhGH group, IL1β was 18.0pg/ml (5.0,716.7) and 18.0pg/ml (1.7, 52.2) at T+0 and T+6 respectively(p=0.90), whereas in the controls this was 19.8pg/ml (4.1, 27.1) and 19.1pg/ml (2.4,77.3), respectively (p=0.65). None of the twenty-eight other cytokines analysed was different at T+6 in either group. Despite increase in total IGF1 in the rhGH group (p=0.03), free IGF1, IGFBP3, ALS and IGFBP2 did not change in either group at T+6. Percentage change in IGFBP3, was significantly associated with percentage change in IL2 (r=0.77, p=0.009) and IL4 (r=0.58, p=0.01). Percentage change in ALS was significantly associated with percentage change in IL2 (r=0.90, p less than 0.0001) and IL4 (r=0.63, p=0.04). Although changes in markers of the GH/IGF-1 axis do show an association with cytokines (IL-2, IL-4) in pediatric IBD, six months of rhGH treatment was not associated with any significant changes in levels of a range of pro and anti-inflammatory cytokine. Careful evaluation of disease process is required in future trials of rhGH in paediatric IBD.}, }
@article {pmid25858436, year = {2015}, author = {Tsai, SJ}, title = {Is riluzole a potential therapy for Rett syndrome?.}, journal = {Medical hypotheses}, volume = {85}, number = {1}, pages = {76-78}, doi = {10.1016/j.mehy.2015.03.025}, pmid = {25858436}, issn = {1532-2777}, mesh = {Humans ; Models, Theoretical ; Neuroprotective Agents/*therapeutic use ; Rett Syndrome/*drug therapy ; Riluzole/*therapeutic use ; }, abstract = {Rett syndrome (RTT) is a severe neurodevelopmental disorder with autistic features and is caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2) in the majority of cases. Besides symptomatic treatment, no therapeutic trials have shown effectiveness for RTT. Some perspectives in the treatment of RTT have been provided by recent works showing a phenotypic reversal by increasing brain-derived neurotrophic factor (BDNF) expression in a RTT mouse model. Glutamate may also play an important role in the primary pathogenesis in Rett syndrome through the excitotoxic neuronal injury in experimental models. Riluzole, an agent currently approved for the treatment of amyotrophic lateral sclerosis, is a glutamatergic modulator and BDNF enhancer with neuroprotective properties. For these reasons, riluzole could potentially play an important role in the treatment of RTT symptoms. Several points regarding the use of riluzole in RTT are discussed. Further evaluation of the therapeutic effects of this agent in RTT animal models is needed before clinical trials can begin.}, }
@article {pmid25851895, year = {2015}, author = {Amirzagar, N and Nafissi, S and Tafakhori, A and Modabbernia, A and Amirzargar, A and Ghaffarpour, M and Siroos, B and Harirchian, MH}, title = {Granulocyte colony-stimulating factor for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled study of Iranian patients.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {11}, number = {2}, pages = {164-171}, pmid = {25851895}, issn = {1738-6586}, abstract = {BACKGROUND AND PURPOSE: The aim of this study was to determine the efficacy and tolerability of granulocyte colony-stimulating factor (G-CSF) in subjects with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Forty subjects with ALS were randomly assigned to two groups, which received either subcutaneous G-CSF (5 &#x3bc;g/kg/q12h) or placebo for 5 days. The subjects were then followed up for 3 months using the ALS Functional Rating Scale-Revised (ALSFRS-R), manual muscle testing, ALS Assessment Questionnaire-40, and nerve conduction studies. CD34+/CD133+ cell count and monocyte chemoattractant protein-1 (MCP-1) levels were evaluated at baseline.<br><br>RESULTS: The rate of disease progression did not differ significantly between the two groups. The reduction in ALSFRS-R scores was greater in female subjects in the G-CSF group than in their counterparts in the placebo group. There was a trend toward a positive correlation between baseline CSF MCP-1 levels and the change in ALSFRS-R scores in both groups (Spearman's &#x3c1;=0.370, p=0.070).<br><br>CONCLUSIONS: With the protocol implemented in this study, G-CSF is not a promising option for the treatment of ALS. Furthermore, it may accelerate disease progression in females.}, }
@article {pmid25847918, year = {2015}, author = {Wu, S and Yi, J and Zhang, YG and Zhou, J and Sun, J}, title = {Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model.}, journal = {Physiological reports}, volume = {3}, number = {4}, pages = {}, pmid = {25847918}, issn = {2051-817X}, support = {R01 AR057404/AR/NIAMS NIH HHS/United States ; R03 DK089010/DK/NIDDK NIH HHS/United States ; }, abstract = {Emerging evidence has demonstrated that intestinal homeostasis and the microbiome play essential roles in neurological diseases, such as Parkinson's disease. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and muscle atrophy. Currently, there is no effective treatment. Most patients die within 3-5 years due to respiratory paralysis. Although the death of motor neurons is a hallmark of ALS, other organs may also contribute to the disease progression. We examined the gut of an ALS mouse model, G93A, which expresses mutant superoxide dismutase (SOD1(G93A)), and discovered a damaged tight junction structure and increased permeability with a significant reduction in the expression levels of tight junction protein ZO-1 and the adherens junction protein E-cadherin. Furthermore, our data demonstrated increased numbers of abnormal Paneth cells in the intestine of G93A mice. Paneth cells are specialized intestinal epithelial cells that can sense microbes and secrete antimicrobial peptides, thus playing key roles in host innate immune responses and shaping the gut microbiome. A decreased level of the antimicrobial peptides defensin 5 alpha was indeed found in the ALS intestine. These changes were associated with a shifted profile of the intestinal microbiome, including reduced levels of Butyrivibrio Fibrisolvens, Escherichia coli, and Fermicus, in G93A mice. The relative abundance of bacteria was shifted in G93A mice compared to wild-type mice. Principal coordinate analysis indicated a difference in fecal microbial communities between ALS and wild-type mice. Taken together, our study suggests a potential novel role of the intestinal epithelium and microbiome in the progression of ALS.}, }
@article {pmid25845857, year = {2015}, author = {Kaminska, M and Browman, F and Trojan, DA and Genge, A and Benedetti, A and Petrof, BJ}, title = {Feasibility of Lung Volume Recruitment in Early Neuromuscular Weakness: A Comparison Between Amyotrophic Lateral Sclerosis, Myotonic Dystrophy, and Postpolio Syndrome.}, journal = {PM &amp; R : the journal of injury, function, and rehabilitation}, volume = {7}, number = {7}, pages = {677-684}, doi = {10.1016/j.pmrj.2015.04.001}, pmid = {25845857}, issn = {1934-1563}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications/physiopathology/*rehabilitation ; Feasibility Studies ; Female ; Follow-Up Studies ; Humans ; Lung/physiopathology ; Lung Volume Measurements/methods ; Male ; Middle Aged ; Myotonic Dystrophy/complications/physiopathology/*rehabilitation ; Organ Size ; Postpoliomyelitis Syndrome/complications/physiopathology/*rehabilitation ; *Quality of Life ; Respiratory Insufficiency/etiology/physiopathology/*rehabilitation ; Respiratory Therapy/*methods ; Retrospective Studies ; Tidal Volume/*physiology ; Time Factors ; }, abstract = {BACKGROUND: Lung volume recruitment (LVR) is a cough assistance technique used in persons with neuromuscular disorders (NMDs), most typically in those requiring noninvasive ventilation (NIV). Whether it may be useful in persons with NMDs who have milder respiratory impairment is unknown.<br><br>OBJECTIVE: To assess the feasibility, impact on quality of life (QOL), and preliminary physiological effects of daily LVR in different categories of persons with NMDs who have an early stage of respiratory impairment.<br><br>DESIGN: Feasibility study.<br><br>SETTING: Academic tertiary care center.<br><br>PARTICIPANTS: Outpatients diagnosed with amyotrophic lateral sclerosis (n = 8), postpolio syndrome (n = 10), and myotonic dystrophy (n = 6) who had restrictive respiratory defects but were not yet using NIV.<br><br>METHODS: Participants were asked to perform LVR up to 4 times daily and log their LVR use in a diary. Physiological measurements and questionnaires were completed at baseline and after 3 months.<br><br>MAIN OUTCOME MEASUREMENTS: Compliance with LVR use was assessed, along with QOL and willingness to continue the treatment. Physiological measurements included forced vital capacity (FVC), lung insufflation capacity (LIC), and the LIC minus FVC difference.<br><br>RESULTS: Of the 24 recruited subjects, 7 with amyotrophic lateral sclerosis, 7 with postpolio syndrome, and 5 with myotonic dystrophy completed the study (n = 19). At baseline, mean values for FVC and spontaneous peak cough flow were 59.9% predicted and 373.1 L/min, respectively. For subjects completing the study, 74% were willing to continue long-term LVR use, and QOL scores were not adversely affected by LVR in any NMD subgroup. The LIC-FVC difference increased from baseline to follow-up by a mean of 0.243 L (P = .006) in all subjects (n = 19), suggesting a possible improvement in respiratory system mechanics.<br><br>CONCLUSIONS: In patients with NMDs who have early restrictive respiratory defects but do not yet require NIV, regular use of LVR is feasible with no negative impact on QOL over a 3-month period and may have physiological benefits. Further work is needed to determine whether early institution of LVR can improve respiratory system mechanics and help delay ventilatory failure in persons with NMDs.}, }
@article {pmid25845840, year = {2015}, author = {Volpe, CM and Nogueira-Machado, JA}, title = {Is Innate Immunity and Inflammasomes Involved in Pathogenesis of Amyotrophic Lateral Sclerosis (ALS)?.}, journal = {Recent patents on endocrine, metabolic &amp; immune drug discovery}, volume = {9}, number = {1}, pages = {40-45}, doi = {10.2174/1872214809666150407111420}, pmid = {25845840}, issn = {2212-3334}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/*immunology/metabolism ; Animals ; Anti-Inflammatory Agents/therapeutic use ; Drug Design ; Genetic Predisposition to Disease ; Humans ; *Immunity, Innate/drug effects ; Inflammasomes/drug effects/*immunology/metabolism ; Mutation ; Neuroprotective Agents/therapeutic use ; Patents as Topic ; Phenotype ; Signal Transduction ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's disease is an axonopathy with adultonset, progressive and irreversible degeneration of upper and lower motor neurons. Around 90% of ALS is considered as sporadic ALS (sALS) without apparent genetic cause while in the familial type of ALS (fALS) at least one affected blood relative needs to be identified. Both sALS and fALS show similar progression and pathological profile. Biochemical and immunological roles have been reported for both types of ALS. It has been suggested that mutation in SOD1 gene would be responsible for the oxidative stress and neurotoxicity. Besides, oxidative stress, protein aggregation, altered cholinergic synapse, neuro-inflammation and production of pro-inflammatory cytokines have also been reported. Thus, the focus of the present review was on biochemical and immunological biomarkers and pathogenic mechanism. Regulatory T cells, pro-inflammatory cytokines and activation of pro-inflammatory signaling pathway are discussed. The activation of NRL inflammasomes in ALS and the involvement of IL-18, IL-1β and caspases-1 are also suggested. The presence and importance of HMGB-1 (DAMP) and activation of Tolllike receptors and/or RAGE also are envisaged. The patents US20140212508, WO2014145776, WO2014145118, US20140255371, US20140194427, US20140243400, WO2014128254, WO2014076702, WO2014071449, WO2014043696, WO2014001742, and WO2013082299 are summarized. This review intends to evaluate the biochemical and immunological responses and the involvement of inflammasomes in the pathogenesis of ALS. In the present review, we suggest hypothetical model for ALS pathogenesis and we discuss some patents that suggest new treatment and/or therapeutic targets. Due to a large number of patents covering therapy and control of neurodegenerative diseases, our focus was restricted only to discuss the latest registered patents in 2014.}, }
@article {pmid25841320, year = {2015}, author = {Li, Y and Guo, Y and Wang, X and Yu, X and Duan, W and Hong, K and Wang, J and Han, H and Li, C}, title = {Trehalose decreases mutant SOD1 expression and alleviates motor deficiency in early but not end-stage amyotrophic lateral sclerosis in a SOD1-G93A mouse model.}, journal = {Neuroscience}, volume = {298}, number = {}, pages = {12-25}, doi = {10.1016/j.neuroscience.2015.03.061}, pmid = {25841320}, issn = {1873-7544}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*complications/genetics/pathology ; Animals ; Autophagy/drug effects ; Body Weight/drug effects/genetics ; Cells, Cultured ; Disease Models, Animal ; Gene Expression Regulation/*drug effects ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/pathology ; Movement Disorders/*drug therapy/*etiology ; Neurologic Examination ; Statistics, Nonparametric ; Superoxide Dismutase/genetics/*metabolism ; Survival Analysis ; Trehalose/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder for which there is currently no effective treatment. Studies indicate that enhancing autophagy in mouse models of neurodegenerative disease can ameliorate the behavioral symptoms and pathological damage associated with the accumulation of pathological mutant proteins such as mutant superoxide dismutase (SOD1). This study investigated the effects of trehalose treatment on both early and end-stage disease in a transgenic mouse model of ALS via short-term (30 days after administration) and long-term (from 60 days after administration to death) trehalose treatment experiments. Sixty-day-old female SOD1-G93A transgenic mice were treated daily with 2% (w/v) trehalose in their drinking water for 30 days and monitored until they reached a neurological score of four, whereupon they were euthanized by cervical dislocation. Neurological, rotarod performance test and hanging wire test scores were recorded and body weight monitored. After death, the spinal cord was removed to assess the number of motor neurons and to measure the expression of mutant SOD1, LC3-II and p62. Trehalose significantly reduced the levels of mutant SOD1 and p62 and increased LC3-II in the spinal cords of 90-day-old SOD1-G93A transgenic mice. Furthermore, trehalose treatment significantly postponed disease onset, lengthened the time it took to reach a neurological score of 2 and preserved motor function; however, trehalose became less effective at delaying further disease progression as the disease progressed beyond a neurological score of 2 and it failed to extend the survival of SOD1-G93A transgenic mice. Additionally, independent of autophagy, trehalose consistently inhibited microgliosis and astrogliosis throughout the entire duration of the study. In conclusion, trehalose may be a useful add-on therapy in conjunction with other ALS treatment options to alleviate symptoms in early-stage ALS.}, }
@article {pmid25834401, year = {2015}, author = {Li, JP and Yang, YX and Liu, QL and Pan, ST and He, ZX and Zhang, X and Yang, T and Chen, XW and Wang, D and Qiu, JX and Zhou, SF}, title = {The investigational Aurora kinase A inhibitor alisertib (MLN8237) induces cell cycle G2/M arrest, apoptosis, and autophagy via p38 MAPK and Akt/mTOR signaling pathways in human breast cancer cells.}, journal = {Drug design, development and therapy}, volume = {9}, number = {}, pages = {1627-1652}, pmid = {25834401}, issn = {1177-8881}, mesh = {Apoptosis/*drug effects ; Aurora Kinase A/antagonists &amp; inhibitors/metabolism ; Autophagy/*drug effects ; Azepines/chemical synthesis/chemistry/*pharmacology ; Breast Neoplasms/*drug therapy/metabolism/pathology ; Cell Cycle/*drug effects ; Cell Division/drug effects ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Female ; G2 Phase Cell Cycle Checkpoints/drug effects ; Humans ; M Phase Cell Cycle Checkpoints/drug effects ; MAP Kinase Signaling System/*drug effects ; MCF-7 Cells ; Protein Kinase Inhibitors/chemical synthesis/chemistry/pharmacology ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/*metabolism ; Pyrimidines/chemical synthesis/chemistry/*pharmacology ; Structure-Activity Relationship ; TOR Serine-Threonine Kinases/antagonists &amp; inhibitors/*metabolism ; Tumor Cells, Cultured ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Alisertib (ALS) is an investigational potent Aurora A kinase inhibitor currently undergoing clinical trials for the treatment of hematological and non-hematological malignancies. However, its antitumor activity has not been tested in human breast cancer. This study aimed to investigate the effect of ALS on the growth, apoptosis, and autophagy, and the underlying mechanisms in human breast cancer MCF7 and MDA-MB-231 cells. In the current study, we identified that ALS had potent growth-inhibitory, pro-apoptotic, and pro-autophagic effects in MCF7 and MDA-MB-231 cells. ALS arrested the cells in G2/M phase in MCF7 and MDA-MB-231 cells which was accompanied by the downregulation of cyclin-dependent kinase (CDK)1/cell division cycle (CDC) 2, CDK2, and cyclin B1 and upregulation of p21 Waf1/Cip1, p27 Kip1, and p53, suggesting that ALS induces G2/M arrest through modulation of p53/p21/CDC2/cyclin B1 pathways. ALS induced mitochondria-mediated apoptosis in MCF7 and MDA-MB-231 cells; ALS significantly decreased the expression of B-cell lymphoma 2 (Bcl-2), but increased the expression of B-cell lymphoma 2-associated X protein (Bax) and p53-upregulated modulator of apoptosis (PUMA), and increased the expression of cleaved caspases 3 and 9. ALS significantly increased the expression level of membrane-bound microtubule-associated protein 1 light chain 3 (LC3)-II and beclin 1 and induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) pathways in MCF7 and MDA-MB-231 cells as indicated by their altered phosphorylation, contributing to the pro-autophagic activities of ALS. Furthermore, treatment with wortmannin markedly downregulated ALS-induced p38 MAPK activation and LC3 conversion. In addition, knockdown of the p38 MAPK gene by ribonucleic acid interference upregulated Akt activation and resulted in LC3-II accumulation. These findings indicate that ALS promotes cellular apoptosis and autophagy in breast cancer cells via modulation of p38 MAPK/Akt/mTOR pathways. Further studies are warranted to further explore the molecular targets of ALS in the treatment of breast cancer.}, }
@article {pmid25832720, year = {2015}, author = {Farber, NM and Perez-Lloret, S and Gamzu, ER}, title = {Design and development of a novel supportive care product for the treatment of sialorrhea in Parkinson's disease.}, journal = {Current topics in medicinal chemistry}, volume = {15}, number = {10}, pages = {939-954}, doi = {10.2174/156802661510150328224130}, pmid = {25832720}, issn = {1873-4294}, mesh = {Animals ; *Drug Design ; *Drug Discovery ; Humans ; Muscarinic Antagonists/*therapeutic use ; Parkinson Disease/*complications ; Sialorrhea/*drug therapy/*etiology ; Tropicamide/*therapeutic use ; }, abstract = {Sialorrhea or excessive drooling is a significant medical issue in Parkinson's disease (PD) and neurodegenerative disorders, although it is often underreported by patients. Sialorrhea affects a large proportion of PD patients, ranging up to 78% in advanced stages, with many PD patients considering drooling as their worst non-motor symptom. Sialorrhea affects up to a million patients with diverse neurological impairments, including cerebral palsy, amyotrophic lateral sclerosis (ALS), Huntington's, survivors of stroke and severe traumatic brain injury. Numerous approaches have been attempted to treat sialorrhea in PD patients, including surgical procedures, prosthetic devices, botulinum injections, systemic anticholinergic drugs, and speech and behavioral therapy. A novel drug treatment (NH004) to control the symptoms of sialorrhea is under development. The active ingredient is the anticholinergic drug tropicamide. Anticholinergic drugs work by blocking acetylcholine muscarinic receptors and ultimately decreasing saliva secretion via the reduction of parasympathetic autonomic nervous system activity. The tropicamide is delivered in a thin film designed to adhere to the buccal mucosa and to slowly dissolve within the oral cavity, allowing the drug to reach the underlying salivary gland. A pilot study testing NH004 in PD patients has suggested a potentially useful sialorrhea-reducing effect with NH004 compared to placebo. The advantages of NH004 include local bioavailability with low systemic exposure, rapid onset of action and, importantly, convenience of use for patients. This review summarizes the current knowledge and impact of sialorrhea as a common non-motor symptom in PD, treatment options, the anticholinergic drug tropicamide, the design and development of the thin film drug delivery system, and NH004 for the treatment of sialorrhea.}, }
@article {pmid25832510, year = {2015}, author = {Grassi, L and Caruso, R and Costantini, A}, title = {Communication with patients suffering from serious physical illness.}, journal = {Advances in psychosomatic medicine}, volume = {34}, number = {}, pages = {10-23}, doi = {10.1159/000369050}, pmid = {25832510}, issn = {0065-3268}, mesh = {Chronic Disease/*psychology ; *Communication ; Education, Medical/*standards ; Humans ; Patients/*psychology ; *Physician-Patient Relations ; }, abstract = {Communication is the corner stone of the relationship with the patient in all medical settings with the main aims of creating a good inter-personal relationship, exchanging information, and making treatment-related decisions. In a rapidly changing cultural and social context, the paternalistic approach of doctors knowing the best and deciding what should be done for a patient has been replaced by a shared decision-making approach, with patients being advised to educate themselves, ask questions and influence the course of the discussion with their doctors. Thus, a need for an improvement in the communication skills of physicians is extremely important for patients affected by serious physical illness (e.g. cancer, HIV infection, multiple sclerosis, amyotrophic lateral sclerosis). Certain attitudes, behaviour and skills (e.g. capacity to impart confidence, being empathetic, providing a 'human touch', relating on a personal level, being forthright, being respectful, and being thorough) are part of effective communication. However, some specific aspects influencing doctor-patient communication and relationships, such as personality variables, coping and attachment styles, as well as cultural factors, should also be taken in to account. The development of training curricula to help doctors acquire proper skills in communication is mandatory, since research has shown that training in communication may facilitate the effectiveness of a doctor-patient relationship and the patient's satisfaction with care and give a general sense of humanity, which is easily lost in a biotechnologically oriented medicine.}, }
@article {pmid25832828, year = {2015}, author = {Macchi, Z and Wang, Y and Moore, D and Katz, J and Saperstein, D and Walk, D and Simpson, E and Genge, A and Bertorini, T and Fernandes, JA and Swenson, A and Elman, L and Dimachkie, M and Herbelin, L and Miller, J and Lu, J and Wilkins, H and Swerdlow, RH and Statland, J and Barohn, R and , }, title = {A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {16}, number = {5-6}, pages = {345-352}, pmid = {25832828}, issn = {2167-9223}, support = {UL1TR000001/TR/NCATS NIH HHS/United States ; TL1 TR000120/TR/NCATS NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; P30 GM103326/GM/NIGMS NIH HHS/United States ; KL2TR000119/TR/NCATS NIH HHS/United States ; UL1 TR000001/TR/NCATS NIH HHS/United States ; P30AG035982/AG/NIA NIH HHS/United States ; KL2 TR000119/TR/NCATS NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Apoptosis/drug effects ; Female ; Humans ; Indans/*therapeutic use ; Male ; Membrane Potential, Mitochondrial/*drug effects ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Retrospective Studies ; Statistics, Nonparametric ; Time Factors ; Treatment Outcome ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Rasagiline, a monoamine oxidase B inhibitor, slowed disease progression in the SOD1 mouse, and in a case series of patients with amyotrophic lateral sclerosis (ALS). Here we determine whether rasagiline is safe and effective in ALS compared to historical placebo controls, and whether it alters mitochondrial biomarkers. We performed a prospective open-label, multicenter screening trial of 36 ALS patients treated with 2 mg oral rasagiline daily for 12 months. Outcomes included the slope of deterioration of the revised ALS Functional Rating Scale (ALSFRS-R), adverse event monitoring, time to treatment failure, and exploratory biomarkers. Participants experienced no serious drug-related adverse events, and the most common adverse event was nausea (11.1%). Rasagiline did not improve the rate of decline in the ALSFRS-R; however, differences in symptom duration compared to historical placebo controls differentially affected ALSFRS-R slope estimates. Rasagiline changed biomarkers over 12 months, such that the mitochondrial membrane potential increased (JC-1 red/green fluorescent ratio 1.92, p = 0.0001) and apoptosis markers decreased (Bcl-2/Bax ratio 0.24, p < 0.0001). In conclusion, engagement of exploratory biomarkers and questions about comparability of baseline characteristics lead us to recommend a further placebo-controlled trial.}, }
@article {pmid25822003, year = {2015}, author = {Valle, J and Roberts, E and Paulukonis, S and Collins, N and English, P and Kaye, W}, title = {Epidemiology and surveillance of amyotrophic lateral sclerosis in two large metropolitan areas in California.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {16}, number = {3-4}, pages = {209-215}, pmid = {25822003}, issn = {2167-9223}, support = {CC999999//Intramural CDC HHS/United States ; }, mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*epidemiology ; Female ; Humans ; Incidence ; Los Angeles/epidemiology ; Male ; Middle Aged ; *Population Surveillance ; Retrospective Studies ; San Francisco/epidemiology ; Urban Health Services ; Young Adult ; }, abstract = {Our objective was to provide demographic profiles and incidence estimates of amyotrophic lateral sclerosis (ALS) in two diverse California metropolitan areas: Los Angeles County (LA) and the San Francisco Bay Area (SFBA). Data were retrospectively collected from multiple sources. Case eligibility criteria included residency in SFBA or LA, and treatment for or diagnosis of ALS between 1 January 2009 and 31 December 2011. Overall incidence rates as well as age-, gender-, race- and ethnicity-specific rates were calculated. We identified 539 ALS cases in SFBA and 545 in LA; 618 were incident cases. Cases were more likely to be male and white. There were considerably more cases (p < 0.05) in LA who were foreign-born (LA, 22%; SFBA, 15%), black (LA, 10%; SFBA, 6%) or Hispanic (LA, 19%; SFBA, 10%). Conversely, the age adjusted incidence rates (per 100,000) were higher in SFBA for whites (LA, 1.40; SFBA, 2.49) and Hispanics (LA, 0.66; SFBA, 1.57) compared with LA. General case demographics and incidence rates in these two areas were similar to published studies. However, the differences between the two areas raise questions about how factors such as geography, access to care, and referral patterns may affect case ascertainment and diagnosis.}, }
@article {pmid25815256, year = {2015}, author = {Raglio, A and Attardo, L and Gontero, G and Rollino, S and Groppo, E and Granieri, E}, title = {Effects of music and music therapy on mood in neurological patients.}, journal = {World journal of psychiatry}, volume = {5}, number = {1}, pages = {68-78}, pmid = {25815256}, issn = {2220-3206}, abstract = {Mood disorder and depressive syndromes represent a common comorbid condition in neurological disorders with a prevalence rate that ranges between 20% and 50% of patients with stroke, epilepsy, multiple sclerosis, and Parkinson's disease. Notwithstanding, these conditions are often under-diagnosed and under-treated in the clinical practice and negatively affect the functional recovery, the adherence to treatment, the quality of life, and even the mortality risk. In addition, a bidirectional association between depression and neurological disorders may be possible being that depressive syndromes may be considered as a risk factor for certain neurological diseases. Despite the large amount of evidence regarding the effects of music therapy (MT) and other musical interventions on different aspects of neurological disorders, no updated article reviewing outcomes such as mood, emotions, depression, activity of daily living and so on is actually available; for this reason, little is known about the effectiveness of music and MT on these important outcomes in neurological patients. The aim of this article is to provide a narrative review of the current literature on musical interventions and their effects on mood and depression in patients with neurological disorders. Searching on PubMed and PsycInfo databases, 25 studies corresponding to the inclusion criteria have been selected; 11 of them assess the effects of music or MT in Dementia, 9 explore the efficacy on patients with Stroke, and 5 regard other neurological diseases like Multiple Sclerosis, Amyotrophic Lateral Sclerosis/motor neuron disease, Chronic quadriplegia, Parkinson's Disease, and Acquired Brain dysfunctions. Selected studies are based on relational and rehabilitative music therapy approaches or concern music listening interventions. Most of the studies support the efficacy of MT and other musical interventions on mood, depressive syndromes, and quality of life on neurological patients.}, }
@article {pmid25815122, year = {2015}, author = {Nicaise, C and Mitrecic, D and Falnikar, A and Lepore, AC}, title = {Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury.}, journal = {World journal of stem cells}, volume = {7}, number = {2}, pages = {380-398}, pmid = {25815122}, issn = {1948-0210}, support = {R01 NS079702/NS/NINDS NIH HHS/United States ; }, abstract = {Neglected for years, astrocytes are now recognized to fulfill and support many, if not all, homeostatic functions of the healthy central nervous system (CNS). During neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI), astrocytes in the vicinity of degenerating areas undergo both morphological and functional changes that might compromise their intrinsic properties. Evidence from human and animal studies show that deficient astrocyte functions or loss-of-astrocytes largely contribute to increased susceptibility to cell death for neurons, oligodendrocytes and axons during ALS and SCI disease progression. Despite exciting advances in experimental CNS repair, most of current approaches that are translated into clinical trials focus on the replacement or support of spinal neurons through stem cell transplantation, while none focus on the specific replacement of astroglial populations. Knowing the important functions carried out by astrocytes in the CNS, astrocyte replacement-based therapies might be a promising approach to alleviate overall astrocyte dysfunction, deliver neurotrophic support to degenerating spinal tissue and stimulate endogenous CNS repair abilities. Enclosed in this review, we gathered experimental evidence that argue in favor of astrocyte transplantation during ALS and SCI. Based on their intrinsic properties and according to the cell type transplanted, astrocyte precursors or stem cell-derived astrocytes promote axonal growth, support mechanisms and cells involved in myelination, are able to modulate the host immune response, deliver neurotrophic factors and provide protective molecules against oxidative or excitotoxic insults, amongst many possible benefits. Embryonic or adult stem cells can even be genetically engineered in order to deliver missing gene products and therefore maximize the chance of neuroprotection and functional recovery. However, before broad clinical translation, further preclinical data on safety, reliability and therapeutic efficiency should be collected. Although several technical challenges need to be overcome, we discuss the major hurdles that have already been met or solved by targeting the astrocyte population in experimental ALS and SCI models and we discuss avenues for future directions based on latest molecular findings regarding astrocyte biology.}, }
@article {pmid25814048, year = {2015}, author = {Zhou, N and Li, J and Zhang, Y and Lu, J and Chen, E and Du, W and Wang, J and Pan, X and Zhu, D and Yang, Y and Chen, Y and Cao, H and Li, L}, title = {Efficacy of coupled low-volume plasma exchange with plasma filtration adsorption in treating pigs with acute liver failure: A randomised study.}, journal = {Journal of hepatology}, volume = {63}, number = {2}, pages = {378-387}, doi = {10.1016/j.jhep.2015.03.018}, pmid = {25814048}, issn = {1600-0641}, mesh = {Animals ; Disease Models, Animal ; Equipment Design ; Extracorporeal Circulation/*instrumentation ; Filtration/methods ; Liver Failure, Acute/metabolism/*therapy ; Liver Regeneration/*physiology ; *Liver, Artificial ; Male ; Plasma Exchange/*methods ; Swine ; Swine, Miniature ; }, abstract = {BACKGROUND &amp; AIMS: Extracorporeal blood purification systems for supportive therapy of liver failure are widely used. We developed a novel blood purification system, named Li's artificial liver system (Li-ALS), which couples low-volume plasma exchange (low-volume PE) with plasma filtration adsorption (PFA). This study aims to evaluate the efficacy of our novel system in pigs with acute liver failure (ALF).<br><br>METHODS: Thirty-two pigs were infused with D-galactosamine (1.3g/kg) to induce ALF. All animals were equally and randomly divided into four groups: the ALF control group received intensive care, the PFA group underwent five hour plasma recycling filtration and adsorption purification, the low-volume PE group received one hour low-volume PE, and the Li-ALS group underwent one hour low-volume PE, followed by five hour PFA. Intervention was initiated 36hours after drug administration. The efficacy of each treatment was assessed by survival time and improvement in hematological, biochemical, and immunohistological parameters.<br><br>RESULTS: Pigs in the Li-ALS group survived longer than those in the other groups (p<0.001, ALF control: 60&#xb1;2h; PFA group: 74&#xb1;2h; low-volume PE group: 75&#xb1;2h; and Li-ALS group: 90&#xb1;3h). Liver enzyme, bilirubin, bile acid and blood ammonia levels were decreased significantly after Li-ALS treatment, and increases in inflammatory cytokines were ameliorated. A higher hepatocyte regeneration index was also observed in the Li-ALS group.<br><br>CONCLUSION: Our novel Li-ALS could expedite liver regeneration and improve survival time; hence, it could be promising for treating ALF.}, }
@article {pmid25807946, year = {2015}, author = {Milenkovic, VM and Rupprecht, R and Wetzel, CH}, title = {The Translocator Protein 18 kDa (TSPO) and Its Role in Mitochondrial Biology and Psychiatric Disorders.}, journal = {Mini reviews in medicinal chemistry}, volume = {15}, number = {5}, pages = {366-372}, doi = {10.2174/1389557515666150324122642}, pmid = {25807946}, issn = {1875-5607}, mesh = {Antipsychotic Agents/therapeutic use ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Humans ; Isoquinolines/therapeutic use ; Ligands ; Mental Disorders/drug therapy/metabolism/*pathology ; Mitochondria/*metabolism ; Neurodegenerative Diseases/metabolism/pathology ; Receptors, GABA/chemistry/genetics/*metabolism ; }, abstract = {The translocator protein 18 kDa (TSPO) is localized in the outer mitochondrial membrane of many cell types and its expression is found to be up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions, and neurological diseases, e.g. amyotrophic lateral sclerosis (ALS). Its primary function is to mediate the transport of cholesterol into the inner compartments of mitochondria. Moreover, TSPO is interacting and building up functional complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC), the adenine nucleotide transporter (ANT), hexokinase I and II and Glycogen synthase kinase 3 beta (GSK3β). This mini review will focus on the role of TSPO as a central regulator of mitochondrial function with regard to pathologic states and as a target for new therapeutic strategies for the treatment of psychiatric disorders.}, }
@article {pmid25798606, year = {2015}, author = {Kepp, KP}, title = {Genotype-property patient-phenotype relations suggest that proteome exhaustion can cause amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {10}, number = {3}, pages = {e0118649}, pmid = {25798606}, issn = {1932-6203}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/*pathology ; Genotype ; Humans ; Middle Aged ; Motor Neurons/metabolism ; Mutation ; Neurodegenerative Diseases/metabolism ; Phenotype ; Protein Folding ; Protein Isoforms/genetics/metabolism ; Proteome/*metabolism ; RNA, Messenger/*metabolism ; Superoxide Dismutase/chemistry/genetics/*metabolism ; Superoxide Dismutase-1 ; Survival Analysis ; }, abstract = {Late-onset neurodegenerative diseases remain poorly understood as search continues for the perceived pathogenic protein species. Previously, variants in Superoxide Dismutase 1 (SOD1) causing Amyotrophic Lateral Sclerosis (ALS) were found to destabilize and reduce net charge, suggesting a pathogenic aggregation mechanism. This paper reports analysis of compiled patient data and experimental and computed protein properties for variants of human SOD1, a major risk factor of ALS. Both stability and reduced net charge correlate significantly with disease, with larger significance than previously observed. Using two independent methods and two data sets, a probability < 3% (t-statistical test) is found that ALS-causing mutations share average stability with all possible 2907 SOD1 mutations. Most importantly, un-weighted patient survival times correlate strongly with the misfolded/unfolded protein copy number, expressed as an exponential function of the experimental stabilities (R2 = 0.31, p = 0.002), and this phenotype is further aggravated by charge (R2 = 0.51, p = 1.8 x 10-5). This finding suggests that disease relates to the copy number of misfolded proteins. Exhaustion of motor neurons due to expensive protein turnover of misfolded protein copies is consistent with the data but can further explain e.g. the expression-dependence of SOD1 pathogenicity, the lack of identification of a molecular toxic mode, elevated SOD1 mRNA levels in sporadic ALS, bioenergetic effects and increased resting energy expenditure in ALS patients, genetic risk factors affecting RNA metabolism, and recent findings that a SOD1 mutant becomes toxic when proteasome activity is recovered after washout of a proteasome inhibitor. Proteome exhaustion is also consistent with energy-producing mitochondria accumulating at the neuromuscular junctions where ALS often initiates. If true, this exhaustion mechanism implies a complete change of focus in treatment of ALS towards actively nursing the energy state and protein turnover of the motor neurons.}, }
@article {pmid25793201, year = {2015}, author = {Gotkine, M and Rozenstein, L and Einstein, O and Abramsky, O and Argov, Z and Rosenmann, H}, title = {Corrigendum to "Presymptomatic treatment with acetylcholinesterase antisense oligonucleotides prolongs survival in ALS (G93A-SOD1) mice".}, journal = {BioMed research international}, volume = {2015}, number = {}, pages = {651934}, doi = {10.1155/2015/651934}, pmid = {25793201}, issn = {2314-6141}, abstract = {[This corrects the article DOI: 10.1155/2013/845345.].}, }
@article {pmid25792811, year = {2015}, author = {Niu, NK and Wang, ZL and Pan, ST and Ding, HQ and Au, GH and He, ZX and Zhou, ZW and Xiao, G and Yang, YX and Zhang, X and Yang, T and Chen, XW and Qiu, JX and Zhou, SF}, title = {Pro-apoptotic and pro-autophagic effects of the Aurora kinase A inhibitor alisertib (MLN8237) on human osteosarcoma U-2 OS and MG-63 cells through the activation of mitochondria-mediated pathway and inhibition of p38 MAPK/PI3K/Akt/mTOR signaling pathway.}, journal = {Drug design, development and therapy}, volume = {9}, number = {}, pages = {1555-1584}, pmid = {25792811}, issn = {1177-8881}, mesh = {Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Azepines/chemistry/*pharmacology ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Humans ; MAP Kinase Signaling System/*drug effects ; Mitochondria/*drug effects/metabolism ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Molecular Structure ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Protein Kinase Inhibitors/chemistry/*pharmacology ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/metabolism ; Pyrimidines/chemistry/*pharmacology ; Reactive Oxygen Species/metabolism ; Structure-Activity Relationship ; TOR Serine-Threonine Kinases/antagonists &amp; inhibitors/metabolism ; Tumor Cells, Cultured ; }, abstract = {Osteosarcoma (OS) is the most common malignant bone tumor occurring mostly in children and adolescents between 10 and 20 years of age with poor response to current therapeutics. Alisertib (ALS, MLN8237) is a selective Aurora kinase A inhibitor that displays anticancer effects on several types of cancer. However, the role of ALS in the treatment of OS remains unknown. This study aimed to investigate the effects of ALS on the cell growth, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT) and the underlying mechanisms in two human OS cell lines U-2 OS and MG-63. The results showed that ALS had potent growth inhibitory, pro-apoptotic, pro-autophagic, and EMT inhibitory effects on U-2 OS and MG-63 cells. ALS remarkably induced G2/M arrest and down-regulated the expression levels of cyclin-dependent kinases 1 and 2 and cyclin B1 in both U-2 OS and MG-63 cells. ALS markedly induced mitochondria-mediated apoptosis with a significant increase in the expression of key pro-apoptotic proteins and a decrease in main anti-apoptotic proteins. Furthermore, ALS promoted autophagic cell death via the inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways, and activation of 5'-AMP-dependent kinase (AMPK) signaling pathway. Inducers or inhibitors of apoptosis or autophagy simultaneously altered ALS-induced apoptotic and autophagic death in both U-2 OS and MG-63 cells, suggesting a crosstalk between these two primary modes of programmed cell death. Moreover, ALS suppressed EMT-like phenotypes with a marked increase in the expression of E-cadherin but a decrease in N-cadherin in U-2 OS and MG-63 cells. ALS treatment also induced reactive oxygen species (ROS) generation but inhibited the expression levels of sirtuin 1 and nuclear factor-erythroid-2-related factor 2 (Nrf2) in both cell lines. Taken together, these findings show that ALS promotes apoptosis and autophagy but inhibits EMT via PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways with involvement of ROS- and sirtuin 1-associated pathways in U-2 OS and MG-63 cells. ALS is a promising anticancer agent in OS treatment and further studies are needed to confirm its efficacy and safety in OS chemotherapy.}, }
@article {pmid25792726, year = {2015}, author = {Finelli, MJ and Liu, KX and Wu, Y and Oliver, PL and Davies, KE}, title = {Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations.}, journal = {Human molecular genetics}, volume = {24}, number = {12}, pages = {3529-3544}, pmid = {25792726}, issn = {1460-2083}, support = {MC_UU_12021/2/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism ; Animals ; Arginine/metabolism ; Autophagy/genetics ; Cytoplasm/metabolism ; DNA-Binding Proteins/*genetics ; Humans ; Methylation ; Mice ; Mitochondrial Proteins/genetics/metabolism ; *Mutation ; Oxidative Stress ; Proteasome Endopeptidase Complex/metabolism ; Protein Aggregation, Pathological ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Isoforms ; Proteins/chemistry/*genetics/*metabolism ; Proteolysis ; RNA Splicing ; RNA-Binding Protein FUS/*genetics ; Transcription, Genetic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neuron-like cells. Mutations in the RNA- and DNA-binding proteins, fused in sarcoma (FUS) and transactive response DNA-binding protein 43 kDa (TDP-43), are responsible for 5-10% of familial and 1% of sporadic ALS cases. Importantly, aggregation of misfolded FUS or TDP-43 is also characteristic of several neurodegenerative disorders in addition to ALS, including frontotemporal lobar degeneration. Moreover, splicing deregulation of FUS and TDP-43 target genes as well as mitochondrial abnormalities are associated with disease-causing FUS and TDP-43 mutants. While progress has been made to understand the functions of these proteins, the exact mechanisms by which FUS and TDP-43 cause ALS remain unknown. Recently, we discovered that, in addition to being up-regulated in spinal cords of ALS patients, the novel protein oxidative resistance 1 (Oxr1) protects neurons from oxidative stress-induced apoptosis. To further understand the function of Oxr1, we present here the first interaction study of the protein. We show that Oxr1 binds to Fus and Tdp-43 and that certain ALS-associated mutations in Fus and Tdp-43 affect their Oxr1-binding properties. We further demonstrate that increasing Oxr1 levels in cells expressing specific Fus and Tdp-43 mutants improves the three main cellular features associated with ALS: cytoplasmic mis-localization and aggregation, splicing changes of a mitochondrial gene and mitochondrial defects. Taken together, these findings suggest that OXR1 may have therapeutic benefits for the treatment of ALS and related neurodegenerative disorders with TDP-43 pathology.}, }
@article {pmid25781653, year = {2015}, author = {Cai, M and Choi, SM and Yang, EJ}, title = {The effects of bee venom acupuncture on the central nervous system and muscle in an animal hSOD1G93A mutant.}, journal = {Toxins}, volume = {7}, number = {3}, pages = {846-858}, pmid = {25781653}, issn = {2072-6651}, mesh = {*Acupuncture Therapy ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Bee Venoms/*pharmacology ; Central Nervous System/*drug effects/physiology ; Disease Models, Animal ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/physiology ; Muscle, Skeletal/*drug effects/physiology ; Signal Transduction ; Spinal Cord/drug effects/physiology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Toll-Like Receptor 4/genetics/metabolism ; Tumor Necrosis Factor-alpha/genetics/metabolism ; bcl-2-Associated X Protein/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is caused by the degeneration of lower and upper motor neurons, leading to muscle paralysis and respiratory failure. However, there is no effective drug or therapy to treat ALS. Complementary and alternative medicine (CAM), including acupuncture, pharmacopuncture, herbal medicine, and massage is popular due to the significant limitations of conventional therapy. Bee venom acupuncture (BVA), also known as one of pharmacopunctures, has been used in Oriental medicine to treat inflammatory diseases. The purpose of this study is to investigate the effect of BVA on the central nervous system (CNS) and muscle in symptomatic hSOD1G93A transgenic mice, an animal model of ALS. Our findings show that BVA at ST36 enhanced motor function and decreased motor neuron death in the spinal cord compared to that observed in hSOD1G93A transgenic mice injected intraperitoneally (i.p.) with BV. Furthermore, BV treatment at ST36 eliminated signaling downstream of inflammatory proteins such as TLR4 in the spinal cords of symptomatic hSOD1G93A transgenic mice. However, i.p. treatment with BV reduced the levels of TNF-α and Bcl-2 expression in the muscle hSOD1G93A transgenic mice. Taken together, our findings suggest that BV pharmacopuncture into certain acupoints may act as a chemical stimulant to activate those acupoints and subsequently engage the endogenous immune modulatory system in the CNS in an animal model of ALS.}, }
@article {pmid25779930, year = {2015}, author = {Ng, SK and Higashimori, H and Tolman, M and Yang, Y}, title = {Suppression of adenosine 2a receptor (A2aR)-mediated adenosine signaling improves disease phenotypes in a mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {267}, number = {}, pages = {115-122}, pmid = {25779930}, issn = {1090-2430}, support = {T32 NS061764/NS/NINDS NIH HHS/United States ; }, mesh = {Adenosine/*metabolism/therapeutic use ; Adenosine A2 Receptor Antagonists/pharmacology/therapeutic use ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/drug therapy/genetics/*metabolism ; Animals ; Astrocytes/drug effects ; Cell Differentiation/drug effects ; Cells, Cultured ; Cerebral Cortex/cytology ; Disease Models, Animal ; Female ; Humans ; Male ; Mediator Complex/genetics/metabolism ; Mice ; Mice, Transgenic ; Middle Aged ; Motor Neurons/drug effects/metabolism ; Muscle Strength/drug effects/genetics ; Purines/pharmacology/therapeutic use ; Receptor, Adenosine A2A/*deficiency/genetics ; Signal Transduction/drug effects/genetics/*physiology ; Spinal Cord/pathology ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease in which the majority of upper and lower motor neurons are degenerated. Despite intensive efforts to identify drug targets and develop neuroprotective strategies, effective therapeutics for ALS remains unavailable. The identification and characterization of novel targets and pathways remain crucial in the development of ALS therapeutics. Adenosine is a major neuromodulator that actively regulates synaptic transmission. Interestingly, adenosine levels are significantly elevated in the cerebrospinal fluid (CSF) of progressing human ALS patients. In the current study, we showed that adenosine 2a receptor (A2aR), but not adenosine 1 receptor (A1R), is highly enriched in spinal (motor) neurons. A2aR expression is also selectively increased at the symptomatic onset in the spinal cords of SOD1G93A mice and end-stage human ALS spinal cords. Interestingly, we found that direct adenosine treatment is sufficient to induce embryonic stem cell-derived motor neuron (ESMN) cell death in cultures. Subsequent pharmacological inhibition and partial genetic ablation of A2aR (A2aR(+/-)) significantly protect ESMN from SOD1G93A(+) astrocyte-induced cell death and delay disease progression of SOD1G93A mice. Taken together, our results provide compelling novel evidence that A2aR-mediated adenosine signaling contributes to the selective spinal motor neuron degeneration observed in the SOD1G93A mouse model of ALS.}, }
@article {pmid25776222, year = {2015}, author = {Goutman, SA and Chen, KS and Feldman, EL}, title = {Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {428-448}, pmid = {25776222}, issn = {1878-7479}, support = {R25 NS089450/NS/NINDS NIH HHS/United States ; R25NS089450/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*surgery ; Animals ; Humans ; Pluripotent Stem Cells/*physiology ; Stem Cell Transplantation/*methods/*trends ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of the motor neurons without a known cure. Based on the possibility of cellular neuroprotection and early preclinical results, stem cells have gained widespread enthusiasm as a potential treatment strategy. Preclinical models demonstrate a protective role of engrafted stem cells and provided the basis for human trials carried out using various types of stem cells, as well as a range of cell delivery methods. To date, no trial has demonstrated a clear therapeutic benefit; however, results remain encouraging and are the basis for ongoing studies. In addition, stem cell technology continues to improve, and induced pluripotent stem cells may offer additional therapeutic options in the future. Improved disease models and clinical trials will be essential in order to validate stem cells as a beneficial therapy.}, }
@article {pmid25772516, year = {2015}, author = {Larsson, BJ and Fröjd, C and Nordin, K and Nygren, I}, title = {Relatives of patients with amyotrophic lateral sclerosis: Their experience of care and support.}, journal = {Palliative &amp; supportive care}, volume = {13}, number = {6}, pages = {1569-1577}, doi = {10.1017/S1478951515000188}, pmid = {25772516}, issn = {1478-9523}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*complications/*psychology ; Attitude to Health ; Caregivers/*psychology ; Family/*psychology ; Female ; Humans ; Male ; Middle Aged ; Qualitative Research ; Surveys and Questionnaires ; Sweden ; }, abstract = {OBJECTIVE: The purpose of this study was to describe relatives' experience of patient care and the support they themselves received during the course of disease progression.<br><br>METHOD: A total of 15 relatives were included from two neurology clinics in Sweden: 7 wives, 4 husbands, and 4 daughters. Data were collected through qualitative interviews 6 to 12 months after the patient had died. Content analysis was performed to analyze the interviews.<br><br>RESULT: The results showed that patient care was experienced as positive and as being based on the patient's needs and desires. Treatment from the staff, support and help, knowledge, availability, and continuity among the team were important reasons for the relations to feel secure. In addition, support for relatives was available, but different factors influenced its use. Most relatives did not think about their own needs but focused on the patient.<br><br>SIGNIFICANCE OF RESULTS: It is important that care and support for both patients and relatives be based on individual needs. The staff members responsible for providing this care and support must have knowledge and experience of the disease and its specific care. If they do not belong to an ALS (amyotrophic lateral sclerosis) team, they may require further education and support. The relatives focus on the patient's situation and do not think of their own needs. It is therefore important that health professionals be observant of the relatives and offer them help and support to better manage their situation.}, }
@article {pmid25770121, year = {2015}, author = {Sakai, K and Aoki, S and Matsumoto, K}, title = {Hepatocyte growth factor and Met in drug discovery.}, journal = {Journal of biochemistry}, volume = {157}, number = {5}, pages = {271-284}, doi = {10.1093/jb/mvv027}, pmid = {25770121}, issn = {1756-2651}, mesh = {Animals ; *Drug Discovery ; Hepatocyte Growth Factor/*metabolism ; Homeostasis ; Humans ; Mice ; Mice, Knockout ; Models, Molecular ; Protein Binding ; Proto-Oncogene Proteins c-met/genetics/*metabolism ; }, abstract = {Activation of the hepatocyte growth factor (HGF)-Met pathway evokes dynamic biological responses that support the morphogenesis, regeneration and survival of cells and tissues. A characterization of conditional Met knockout mice indicates that the HGF-Met pathway plays important roles in the regeneration, protection and homeostasis of cells such as hepatocytes, renal tubular cells and neurons. Preclinical studies in disease models have indicated that recombinant HGF protein and expression plasmid for HGF are biological drug candidates for the treatment of patients with diseases or injuries that involve impaired tissue function. The phase-I and phase-I/II clinical trials of the intrathecal administration of HGF protein for the treatment of patients with amyotrophic lateral sclerosis and spinal cord injury, respectively, are ongoing. Biological actions of HGF that promote the dynamic movement, morphogenesis and survival of cells also closely participate in invasion-metastasis and resistance to the molecular-targeted drugs in tumour cells. Different types of HGF-Met pathway inhibitors are now in clinical trials for treatment of malignant tumours. Basic research on HGF and Met has lead to drug discoveries in regenerative medicine and tumour biology.}, }
@article {pmid25766674, year = {2015}, author = {McAllum, EJ and Roberts, BR and Hickey, JL and Dang, TN and Grubman, A and Donnelly, PS and Liddell, JR and White, AR and Crouch, PJ}, title = {Zn II(atsm) is protective in amyotrophic lateral sclerosis model mice via a copper delivery mechanism.}, journal = {Neurobiology of disease}, volume = {81}, number = {}, pages = {20-24}, doi = {10.1016/j.nbd.2015.02.023}, pmid = {25766674}, issn = {1095-953X}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Analysis of Variance ; Animals ; Coordination Complexes/*therapeutic use ; Copper/*metabolism ; Disease Models, Animal ; Locomotion/drug effects ; Mass Spectrometry ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Organometallic Compounds/pharmacology/therapeutic use ; Superoxide Dismutase/genetics ; Thiosemicarbazones/pharmacology/therapeutic use ; Zinc/metabolism ; }, abstract = {Mutations in the metalloprotein Cu,Zn-superoxide dismutase (SOD1) cause approximately 20% of familial cases of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease for which effective therapeutics do not yet exist. Transgenic rodent models based on over-expression of mutant SOD1 have been developed and these have provided opportunity to test new therapeutic strategies and to study the mechanisms of mutant SOD1 toxicity. Although the mechanisms of mutant SOD1 toxicity are yet to be fully elucidated, incorrect or incomplete metallation of SOD1 confers abnormal folding, aggregation and biochemical properties, and improving the metallation state of SOD1 provides a viable therapeutic option. The therapeutic effects of delivering copper (Cu) to mutant SOD1 have been demonstrated recently. The aim of the current study was to determine if delivery of zinc (Zn) to SOD1 was also therapeutic. To investigate this, SOD1G37R mice were treated with the metal complex diacetyl-bis(4-methylthiosemicarbazonato)zinc(II) [Zn(II)(atsm)]. Treatment resulted in an improvement in locomotor function and survival of the mice. However, biochemical analysis of spinal cord tissue collected from the mice revealed that the treatment did not increase overall Zn levels in the spinal cord nor the Zn content of SOD1. In contrast, overall levels of Cu in the spinal cord were elevated in the Zn(II)(atsm)-treated SOD1G37R mice and the Cu content of SOD1 was also elevated. Further experiments demonstrated transmetallation of Zn(II)(atsm) in the presence of Cu to form the Cu-analogue Cu(II)(atsm), indicating that the observed therapeutic effects for Zn(II)(atsm) in SOD1G37R mice may in fact be due to in vivo transmetallation and subsequent delivery of Cu.}, }
@article {pmid25762155, year = {2015}, author = {Nagano, S and Takahashi, Y and Yamamoto, K and Masutani, H and Fujiwara, N and Urushitani, M and Araki, T}, title = {A cysteine residue affects the conformational state and neuronal toxicity of mutant SOD1 in mice: relevance to the pathogenesis of ALS.}, journal = {Human molecular genetics}, volume = {24}, number = {12}, pages = {3427-3439}, doi = {10.1093/hmg/ddv093}, pmid = {25762155}, issn = {1460-2083}, mesh = {Amino Acid Substitution ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/mortality ; Animals ; *Cysteine ; Disease Models, Animal ; Gene Dosage ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/*metabolism/pathology ; *Mutation ; Oxidation-Reduction ; Phenotype ; Physical Exertion ; Protein Aggregation, Pathological ; *Protein Conformation ; Protein Folding ; Spinal Cord/metabolism ; Superoxide Dismutase/*chemistry/*genetics/metabolism ; Superoxide Dismutase-1 ; Transgenes ; }, abstract = {We previously showed by in vitro experiments that the cysteine residue (Cys111) near the dimer interface is critical for monomerization and resultant aggregate formation of mutant Cu, Zn-superoxide dismutase (SOD1) protein, which is toxic to motor neurons in familial amyotrophic lateral sclerosis (ALS). To verify the importance of Cys111 in the mutant SOD1-associated ALS pathogenesis in vivo, we analyzed the disease phenotype of SOD1 transgenic mice harboring H46R mutation alone (H46R mice) or H46R/C111S double mutations (H46R/C111S mice). Behavioral, histological and biochemical analyses of the spinal cord showed that the onset and progression of the disease phenotype were delayed in H46R/C111S mice compared with H46R mice. We found that peroxidized Cys111 of H46R SOD1 plays a role in promoting formation of high molecular weight insoluble SOD1 species that is correlated with the progression of the motor neuron disease phenotype. These results support that Cys111 is a critical residue for the neuronal toxicity of mutant SOD1 in vivo, and the blockage of peroxidation of this residue in mutant SOD1 may constitute a future target for developing ALS treatment.}, }
@article {pmid25761970, year = {2015}, author = {Tokuda, E and Watanabe, S and Okawa, E and Ono, S}, title = {Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {461-476}, pmid = {25761970}, issn = {1878-7479}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*pathology ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; CD11b Antigen/metabolism ; Copper/*metabolism ; Dexamethasone/*therapeutic use ; Disease Models, Animal ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Lipid Peroxides/metabolism ; Metallothionein/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Phosphopyruvate Hydratase/metabolism ; Protein Isoforms/genetics/metabolism ; Spinal Cord/pathology ; Superoxide Dismutase/genetics/metabolism ; Time Factors ; Up-Regulation/*drug effects/genetics ; }, abstract = {Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), an incurable motor neuron disease. The pathogenesis of the disease is poorly understood, but intracellular copper dyshomeostasis has been implicated as a key process in the disease. We recently observed that metallothioneins (MTs) are an excellent target for the modification of copper dyshomeostasis in a mouse model of ALS (SOD1(G93A)). Here, we offer a therapeutic strategy designed to increase the level of endogenous MTs. The upregulation of endogenous MTs by dexamethasone, a synthetic glucocorticoid, significantly improved the disease course and rescued motor neurons in SOD1(G93A) mice, even if the induction was initiated when peak body weight had decreased by 10%. Neuroprotection was associated with the normalization of copper dyshomeostasis, as well as with decreased levels of SOD1(G93A) aggregates. Importantly, these benefits were clearly mediated in a MT-dependent manner, as dexamethasone did not provide any protection when endogenous MTs were abolished from SOD1(G93A) mice. In conclusion, the upregulation of endogenous MTs represents a promising strategy for the treatment of ALS linked to mutant SOD1.}, }
@article {pmid25749171, year = {2015}, author = {Rosenberg, SA and Niglio, SA and Salehomoum, N and Chan, JL and Jeong, BS and Wen, Y and Li, J and Fukui, J and Chen, S and Shin, SS and Goydos, JS}, title = {Targeting Glutamatergic Signaling and the PI3 Kinase Pathway to Halt Melanoma Progression.}, journal = {Translational oncology}, volume = {8}, number = {1}, pages = {1-9}, pmid = {25749171}, issn = {1936-5233}, support = {K24 CA138709/CA/NCI NIH HHS/United States ; R01 CA124975/CA/NCI NIH HHS/United States ; R01 CA149627/CA/NCI NIH HHS/United States ; }, abstract = {Our group has previously reported that the majority of human melanomas (>60%) express the metabotropic glutamate receptor 1 (GRM1) and that the glutamate release inhibitor riluzole, a drug currently used to treat amyotrophic lateral sclerosis, can induce apoptosis in GRM1-expressing melanoma cells. Our group previously reported that in vitro riluzole treatment reduces cell growth in three-dimensional (3D) soft agar colony assays by 80% in cells with wildtype phosphoinositide 3-kinase (PI3K) pathway activation. However, melanoma cell lines harboring constitutive activating mutations of the PI3K pathway (PTEN and NRAS mutations) showed only a 35% to 40% decrease in colony formation in soft agar in the presence of riluzole. In this study, we have continued our preclinical studies of riluzole and its effect on melanoma cells alone and in combination with inhibitors of the PI3 kinase pathway: the AKT inhibitor, API-2, and the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. We modeled these combinatorial therapies on various melanoma cell lines in 3D and 2D systems and in vivo. Riluzole combined with mTOR inhibition is more effective at halting melanoma anchorage-independent growth and xenograft tumor progression than either agent alone. PI3K signaling changes associated with this combinatorial treatment shows that 3D (nanoculture) modeling of cell signaling more closely resembles in vivo signaling than monolayer models. Riluzole combined with mTOR inhibition is effective at halting tumor cell progression independent of BRAF mutational status. This makes this combinatorial therapy a potentially viable alternative for metastatic melanoma patients who are BRAF WT and are therefore ineligible for vemurafenib therapy.}, }
@article {pmid25747736, year = {2015}, author = {Frausin, S and Viventi, S and Verga Falzacappa, L and Quattromani, MJ and Leanza, G and Tommasini, A and Valencic, E}, title = {Wharton's jelly derived mesenchymal stromal cells: Biological properties, induction of neuronal phenotype and current applications in neurodegeneration research.}, journal = {Acta histochemica}, volume = {117}, number = {4-5}, pages = {329-338}, doi = {10.1016/j.acthis.2015.02.005}, pmid = {25747736}, issn = {1618-0372}, mesh = {Adult ; Adult Stem Cells/*metabolism ; *Cell Differentiation ; Humans ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*metabolism ; Neurodegenerative Diseases/metabolism/pathology/*therapy ; Neurons/*metabolism ; }, abstract = {Multipotent mesenchymal stromal cells, also known as mesenchymal stem cells (MSC), can be isolated from bone marrow or other tissues, including fat, muscle and umbilical cord. It has been shown that MSC behave in vitro as stem cells: they self-renew and are able to differentiate into mature cells typical of several mesenchymal tissues. Moreover, the differentiation toward non-mesenchymal cell lineages (e.g. neurons) has been reported as well. The clinical relevance of these cells is mainly related to their ability to spontaneously migrate to the site of inflammation/damage, to their safety profile thanks to their low immunogenicity and to their immunomodulation capacities. To date, MSCs isolated from the post-natal bone marrow have represented the most extensively studied population of adult MSCs, in view of their possible use in various therapeutical applications. However, the bone marrow-derived MSCs exhibit a series of limitations, mainly related to their problematic isolation, culturing and use. In recent years, umbilical cord (UC) matrix (i.e. Wharton's jelly, WJ) stromal cells have therefore emerged as a more suitable alternative source of MSCs, thanks to their primitive nature and the easy isolation without relevant ethical concerns. This review seeks to provide an overview of the main biological properties of WJ-derived MSCs. Moreover, the potential application of these cells for the treatment of some known dysfunctions in the central and peripheral nervous system will also be discussed.}, }
@article {pmid25731823, year = {2015}, author = {Cooper-Knock, J and Kirby, J and Highley, R and Shaw, PJ}, title = {The Spectrum of C9orf72-mediated Neurodegeneration and Amyotrophic Lateral Sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {326-339}, pmid = {25731823}, issn = {1878-7479}, support = {MR/K000039/1/MRC_/Medical Research Council/United Kingdom ; MR/K003771/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/therapy ; Animals ; C9orf72 Protein ; DNA Repeat Expansion/*genetics ; Humans ; Nerve Degeneration/*genetics/metabolism ; Proteins/*genetics ; }, abstract = {The discovery that a hexanucleotide repeat expansion in C9orf72 is the most numerous genetic variant of both amyotrophic lateral sclerosis and frontotemporal dementia has opened a rapidly growing field, which may provide long hoped for advances in the understanding and treatment of these devastating diseases. In this review we describe the various phenotypes, clinical and pathological, associated with expansion of C9orf72, which go beyond amyotrophic lateral sclerosis and frontotemporal dementia to include neurodegeneration more broadly. Next we take a step back and summarize the current understanding of the C9orf72 expansion and its protein products at a molecular level. Three mechanisms are prominent: toxicity mediated directly by RNA transcribed from the repeat; toxicity mediated by dipeptide repeat proteins translated from the repeat sequence; and haploinsufficiency resulting from reduced transcription of the C9orf72 exonic sequence. A series of exciting advances have recently described how dipeptide repeat proteins might interfere with the normal role of the nucleolus in maturation of RNA binding proteins and in production of ribosomes. Importantly, these mechanisms are unlikely to be mutually exclusive. We draw attention to the fact that clinical and pathological similarities to other genetic variants without a repeat expansion must not be overlooked in ascribing a pathogenic mechanism to C9orf72-disease. Finally, with a view to impact on patient care, we discuss current practice with respect to genetic screening in patients with and without a family history of disease, and the most promising developments towards therapy that have been reported to date.}, }
@article {pmid25730223, year = {2015}, author = {Hermans, AJ and Kluivers, KB and Wijnen, MH and Bulten, J and Massuger, LF and Coppus, SF}, title = {Diagnosis and treatment of adnexal masses in children and adolescents.}, journal = {Obstetrics and gynecology}, volume = {125}, number = {3}, pages = {611-615}, doi = {10.1097/AOG.0000000000000665}, pmid = {25730223}, issn = {1873-233X}, mesh = {Adolescent ; Child ; Child, Preschool ; Female ; Genital Neoplasms, Female/diagnosis/epidemiology/*surgery ; Humans ; Infant ; Infant, Newborn ; Netherlands/epidemiology ; Organ Sparing Treatments/*statistics &amp; numerical data ; Retrospective Studies ; }, abstract = {OBJECTIVE: To evaluate the diagnosis and treatment decisions made in children and adolescents with an adnexal mass.<br><br>METHODS: This was a retrospective cohort study among patients younger than age 18 years who were diagnosed with or treated for an adnexal mass at the Radboud University Medical Center, Nijmegen, the Netherlands, between January 1999 and October 2013. Age, signs and symptoms, laboratory results, imaging data, type of surgery including surgeon specialty, and histologic diagnosis were analyzed. Published criteria for characterizing a mass as benign (Papic et al) were applied to the present data set.<br><br>RESULTS: One hundred eleven patients were included. The mean age of the patients was 10.2&#xb1;5.6 years, ranging between 0 and 17 years. Ovarian masses were malignant in 28 patients (25.2%). Surgical therapy was applied in 83.1% of the benign masses and in 100% of the malignant masses. Oophorectomy was performed in 46.4% of the benign masses. The presence of a gynecologist was the only factor that significantly lowered the chance of oophorectomy in benign masses (odds ratio 0.14, 95% confidence interval 0.04-0.47). Papic et al's model had a sensitivity of 40.91% and a specificity of 100%.<br><br>CONCLUSION: The malignancy rate among patients with adnexal masses in our cohort was one in four patients. Most patients with an adnexal mass were treated surgically, and oophorectomy was performed in almost half of the benign masses. The presence of a gynecologic surgeon protected against oophorectomy in benign cases.<br><br>LEVEL OF EVIDENCE: II.}, }
@article {pmid25715475, year = {2014}, author = {Ismailov, ShM and Barykova, IuA and Shmarov, MM and Tarantul, VZ and Barskov, IV and Kucherianu, VG and Brylev, LV and Logunov, DIu and Tutykhina, IL and Bocharov, EV and Zakharova, MN and Naroditskiĭ, BS and Illarioshkin, SN}, title = {[Experimental approach to the gene therapy of motor neuron disease with the use of genes hypoxia-inducible factors].}, journal = {Genetika}, volume = {50}, number = {5}, pages = {591-601}, pmid = {25715475}, issn = {0016-6758}, mesh = {Adenoviridae ; Animals ; Disease Models, Animal ; Gene Transfer Techniques ; *Genetic Therapy ; Genetic Vectors ; Humans ; Mice ; Mice, Transgenic ; Motor Neuron Disease/*genetics/pathology/*therapy ; Motor Neurons/*pathology ; Ribonuclease, Pancreatic/biosynthesis/genetics ; Somatomedins/genetics ; Spinal Cord/pathology/surgery ; Vascular Endothelial Growth Factor A/biosynthesis/genetics ; }, abstract = {Motor neuron disease (MND), or amyotrophic lateral sclerosis, is a fatal neurodegenerative disorder characterized by a progressive loss of motor neurons in the spinal cord and the brain. Several angiogenic and neurogenic growth factors, such as the vascular endothelial growth factor (VEGF), angiogenin (ANG), insulin-like growth factor (IGF) and others, have been shown to promote survival of the spinal motor neurons during ischemia. We constructed recombinant vectors using human adenovirus 5 (Ad5) carrying the VEGF, ANG or IGF genes under the control of the cytomegalovirus promoter. As a model for MND, we employed a transgenic mice strain, B6SJL-Tg (SOD1*G93A)d11 Gur/J that develops a progressive degeneration of the spinal motor neurons caused by the expression of a mutated Cu/Zn superoxide dismutase gene SOD1. Delivery of the therapeutic genes to the spinal motor neurons was done using the effect of the retrograde axonal transport after multiple injections of the Ad5-VEGF, Ad5-ANG and Ad5-IGF vectors and their combinations into the limbs and back muscles of the SOD1(G93A) mice. Viral transgene expression in the spinal cord motor neurons was confirmed by immunocytochemistry and RT-RCR. We assessed the neurological status, motor activity and lifespan of experimental and control animal groups. We discovered that SOD1(G93A) mice injected with the Ad5-VEGF + Ad5-ANG combination showed a 2-3 week delay in manifestation of the disease, higher motor activity at the advanced stages of the disease, and at least a 10% increase in the lifespan compared to the control and other experimental groups. These results support the safety and therapeutic efficacy of the tested recombinant treatment. We propose that the developed experimental MND treatment based on viral delivery of VEGF + ANG can be used as a basis for gene therapy drug development and testing in the preclinical and clinical trials of the MND.}, }
@article {pmid25708791, year = {2015}, author = {Bourke, C}, title = {Molybdenum deprivation, purine ingestion and an astrocyte-associated motor neurone syndrome in sheep: assumed clinical effects of inosine.}, journal = {Australian veterinary journal}, volume = {93}, number = {3}, pages = {79-83}, doi = {10.1111/avj.12286}, pmid = {25708791}, issn = {1751-0813}, mesh = {Animals ; Astrocytes/*drug effects ; Inosine/*toxicity ; Molybdenum/*deficiency ; Motor Neuron Disease/chemically induced/*veterinary ; Muscle Weakness/chemically induced/veterinary ; Sheep ; Sheep Diseases/*etiology ; Syndrome ; }, abstract = {BACKGROUND: An astrocyte-associated motor neurone syndrome was produced in molybdenum-deprived sheep fed xanthosine. Mo-deprived sheep fed inosine, adenosine or guanosine would be also expected to develop astrocyte-associated motor neurone syndromes, because all these purine nucleosides can act as neuromodulators and all depend on the Mo-associated enzyme xanthine oxidase-dehydrogenase for their catabolism.<br><br>DESIGN: To investigate the relationship between inosine ingestion and low Mo concentration, eight sheep were fed lucerne chaff with a Mo value <0.10&#x2009;ppm and the Mo antagonist, sodium tungstate, for 21 weeks, with inosine (35&#x2009;mg/kg/day) fed for the last 18 of these weeks. This clinical study was uncontrolled.<br><br>RESULTS: An astrocyte-associated motor neurone syndrome was produced in three sheep 18-27 months later. It was characterised by diaphragmatic, laryngeal, lingual and pharyngeal muscle weakness. The diaphragmatic muscle weakness was the most severe and potentially lethal.<br><br>CONCLUSION: These findings suggest that purinergic neuromodulation of respiration, vocalisation and swallowing is different to that of limb movement. The syndrome produced, and assumed to be caused by the treatment given, has not been reported in livestock. A similar syndrome is seen in human motor neurone disease, but not in equine motor neurone disease, and this is consistent with it being an upper, not a lower, motor neurone effect.}, }
@article {pmid25706882, year = {2015}, author = {Berges, A and Bullman, J and Bates, S and Krull, D and Williams, N and Chen, C}, title = {Ozanezumab dose selection for amyotrophic lateral sclerosis by pharmacokinetic-pharmacodynamic modelling of immunohistochemistry data from patient muscle biopsies.}, journal = {PloS one}, volume = {10}, number = {2}, pages = {e0117355}, pmid = {25706882}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Antibodies, Monoclonal, Humanized/*administration &amp; dosage/therapeutic use ; Biopsy ; Computer Simulation ; Dose-Response Relationship, Drug ; Double-Blind Method ; Humans ; Immunohistochemistry ; *Models, Biological ; Muscle, Skeletal/*metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rare and fatal neurodegenerative disease with a high unmet medical need. In this context, a potential therapy should be brought to patients in the most expeditious way and early exploration of pharmacology is highly beneficial. Ozanezumab, a humanised IgG monoclonal antibody against Nogo-A protein which is an inhibitor of neurite outgrowth, is currently under development for the treatment of ALS and has been recently assessed in 76 patients in a first-in-human study. Inadequate target engagement has been recognised as a major contributing reason for drug trial failures. In this work, we describe the development of a pharmacokinetic-pharmacodynamic (PKPD) model using immunohistochemistry (IHC) data of co-localization of ozanezumab with Nogo-A in skeletal muscle as a surrogate measure of target engagement. The rich plasma concentration data and the sparse IHC data after one or two intravenous doses of ozanezumab were modelled simultaneously using a non-linear mixed-effect approach. The final PKPD model was a two-compartment PK model combined with an effect compartment PD model that accounted for the delay in ozanezumab concentrations to reach the site of action which is skeletal muscle. Diagnostic plots showed a satisfactory fit of both PK and IHC data. The model was used as a simulation tool to design a dose regimen for sustained drug-target co-localization in a phase II study.}, }
@article {pmid25703524, year = {2015}, author = {McDermott, FD and Heeney, A and Kelly, ME and Steele, RJ and Carlson, GL and Winter, DC}, title = {Systematic review of preoperative, intraoperative and postoperative risk factors for colorectal anastomotic leaks.}, journal = {The British journal of surgery}, volume = {102}, number = {5}, pages = {462-479}, doi = {10.1002/bjs.9697}, pmid = {25703524}, issn = {1365-2168}, mesh = {Age Factors ; Aged ; Anastomotic Leak/*etiology ; Biomarkers/metabolism ; C-Reactive Protein/metabolism ; Colon/*surgery ; Colorectal Neoplasms/surgery ; Emergency Treatment/adverse effects ; Female ; Humans ; Male ; Middle Aged ; Operative Time ; Perioperative Care/*statistics &amp; numerical data ; Rectum/*surgery ; Risk Factors ; Sex Factors ; }, abstract = {BACKGROUND: Anastomotic leak (AL) represents a dreaded complication following colorectal surgery, with a prevalence of 1-19 per cent. There remains a lack of consensus regarding factors that may predispose to AL and the relative risks associated with them. The objective was to perform a systematic review of the literature, focusing on the role of preoperative, intraoperative and postoperative factors in the development of colorectal ALs.<br><br>METHODS: A systematic review was performed to identify adjustable and non-adjustable preoperative, intraoperative and postoperative factors in the pathogenesis of AL. Additionally, a severity grading system was proposed to guide treatment.<br><br>RESULTS: Of 1707 papers screened, 451 fulfilled the criteria for inclusion in the review. Significant preoperative risk factors were: male sex, American Society of Anesthesiologists fitness grade above II, renal disease, co-morbidity and history of radiotherapy. Tumour-related factors were: distal site, size larger than 3&#x2009;cm, advanced stage, emergency surgery and metastatic disease. Adjustable risk factors were: smoking, obesity, poor nutrition, alcohol excess, immunosuppressants and bevacizumab. Intraoperative risk factors were: blood loss/transfusion and duration of surgery more than 4&#x2009;h. Stomas lessen the consequences but not the prevalence of AL. In the postoperative period, CT is the most commonly used imaging tool, with or without rectal contrast, and a C-reactive protein level exceeding 150&#x2009;mg/l on day 3-5 is the most sensitive biochemical marker. A five-level classification system for AL severity and appropriate management is presented.<br><br>CONCLUSION: Specific risk factors and their potential correction or indications for stoma were identified. An AL severity score is proposed to aid clinical decision-making.}, }
@article {pmid25700216, year = {2015}, author = {Walter, TR}, title = {Benign fasciculation syndrome.}, journal = {Journal of pain &amp; palliative care pharmacotherapy}, volume = {29}, number = {1}, pages = {54-55}, doi = {10.3109/15360288.2014.997856}, pmid = {25700216}, issn = {1536-0539}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*etiology ; Fasciculation/complications/*epidemiology ; Humans ; Syndrome ; }, abstract = {Questions from patients about pain conditions, analgesic pharmacotherapy, and responses from authors are presented to help educate patients and make them more effective self-advocates. In reply to a question about benign fasciculation syndrome, the presentation, causes, treatment, and chances of developing amyotrophic lateral sclerosis will be discussed.}, }
@article {pmid25700176, year = {2015}, author = {Cirulli, ET and Lasseigne, BN and Petrovski, S and Sapp, PC and Dion, PA and Leblond, CS and Couthouis, J and Lu, YF and Wang, Q and Krueger, BJ and Ren, Z and Keebler, J and Han, Y and Levy, SE and Boone, BE and Wimbish, JR and Waite, LL and Jones, AL and Carulli, JP and Day-Williams, AG and Staropoli, JF and Xin, WW and Chesi, A and Raphael, AR and McKenna-Yasek, D and Cady, J and Vianney de Jong, JM and Kenna, KP and Smith, BN and Topp, S and Miller, J and Gkazi, A and ,  and Al-Chalabi, A and van den Berg, LH and Veldink, J and Silani, V and Ticozzi, N and Shaw, CE and Baloh, RH and Appel, S and Simpson, E and Lagier-Tourenne, C and Pulst, SM and Gibson, S and Trojanowski, JQ and Elman, L and McCluskey, L and Grossman, M and Shneider, NA and Chung, WK and Ravits, JM and Glass, JD and Sims, KB and Van Deerlin, VM and Maniatis, T and Hayes, SD and Ordureau, A and Swarup, S and Landers, J and Baas, F and Allen, AS and Bedlack, RS and Harper, JW and Gitler, AD and Rouleau, GA and Brown, R and Harms, MB and Cooper, GM and Harris, T and Myers, RM and Goldstein, DB}, title = {Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.}, journal = {Science (New York, N.Y.)}, volume = {347}, number = {6229}, pages = {1436-1441}, pmid = {25700176}, issn = {1095-9203}, support = {P01 AG032953/AG/NIA NIH HHS/United States ; 089701//Wellcome Trust/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; T32 GM007754/GM/NIGMS NIH HHS/United States ; MR/L021803/1/MRC_/Medical Research Council/United Kingdom ; P01 AG017586/AG/NIA NIH HHS/United States ; R37 NS033123/NS/NINDS NIH HHS/United States ; R37 NS083524/NS/NINDS NIH HHS/United States ; R01 NS073873/NS/NINDS NIH HHS/United States ; TL1 TR001066/TR/NCATS NIH HHS/United States ; G9318379/MRC_/Medical Research Council/United Kingdom ; MC_G1000733/MRC_/Medical Research Council/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; UL1 TR001067/TR/NCATS NIH HHS/United States ; K08 NS075094/NS/NINDS NIH HHS/United States ; MR/L016397/1/MRC_/Medical Research Council/United Kingdom ; P50 AG025688/AG/NIA NIH HHS/United States ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; G1100695/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Adaptor Proteins, Signal Transducing/genetics/metabolism ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*genetics ; Autophagy/*genetics ; Cell Cycle Proteins ; Exome/*genetics ; Female ; Genes ; Genetic Association Studies ; *Genetic Predisposition to Disease ; Humans ; Male ; Membrane Transport Proteins ; Middle Aged ; Protein Binding ; Protein Serine-Threonine Kinases/*genetics/metabolism ; Risk ; Sequence Analysis, DNA ; Sequestosome-1 Protein ; Transcription Factor TFIIIA/genetics/metabolism ; Young Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.}, }
@article {pmid25689221, year = {2015}, author = {Kupas, DF and Schenk, E and Sholl, JM and Kamin, R}, title = {Characteristics of statewide protocols for emergency medical services in the United States.}, journal = {Prehospital emergency care}, volume = {19}, number = {2}, pages = {292-301}, doi = {10.3109/10903127.2014.964891}, pmid = {25689221}, issn = {1545-0066}, mesh = {Adolescent ; Child ; *Clinical Protocols ; *Emergencies ; Emergency Medical Services/*standards ; Female ; Humans ; Male ; Surveys and Questionnaires ; United States ; }, abstract = {OBJECTIVE: We sought to categorize and characterize the utilization of statewide emergency medical services (EMS) protocols as well as state recognition of specialty receiving facilities for trauma and time-sensitive conditions in the United States.<br><br>METHODS: A survey of all state EMS offices was conducted to determine which states use mandatory or model statewide EMS protocols and to characterize these protocols based on the process for authorizing such protocols. The survey also inquired as to which states formally recognize specialty receiving facilities for trauma, STEMI, stroke, cardiac arrest, and burn as well as whether or not states have mandatory or model statewide destination protocols for these specialty centers.<br><br>RESULTS: Thirty-eight states were found to have either mandatory or model statewide EMS protocols. Twenty-one states had mandatory statewide EMS protocols at either the basic life support (BLS) or advanced life support (ALS) level, and in 16 of these states, mandatory protocols covered both BLS and ALS levels of care. Seventeen states had model statewide protocols at either the BLS or ALS level, and in 14 of these states, the model protocols covered both BLS and ALS levels of care. Twenty states had separate protocols for the care of pediatric patients, while 18 states combined pediatric and adult care within the same protocols. When identified, the median age used to consider a patient for pediatric care was &#x2264;14&#xa0;years (range &#x2264;8 to &#x2264;17&#xa0;years). Three states' protocols used a child's height based on a length-based dosage tool as the threshold for identifying a pediatric patient for care using their pediatric protocols. States varied in recognition of receiving centers for EMS patients with special medical needs: 46 recognized trauma centers, 25 recognized burn centers, 22 recognized stroke centers, 11 recognized centers capable of percutaneous coronary intervention for ST-elevation myocardial infarction, and 3 recognized centers for patients surviving cardiac arrest.<br><br>CONCLUSION: Statewide mandated EMS treatment protocols exist in 21 states, and optional model protocol guidelines are provided by 17 states. There is wide variation in the format and characteristics of these protocols and the recognition of specialty receiving centers for patients with time-sensitive illnesses.}, }
@article {pmid25683987, year = {2015}, author = {Shin, DA and Park, KY and Ji, GY and Yi, S and Ha, Y and Park, SW and Yoon, DH and Kim, KN}, title = {The use of magnetic resonance imaging in predicting the clinical outcome of spinal arteriovenous fistula.}, journal = {Yonsei medical journal}, volume = {56}, number = {2}, pages = {397-402}, pmid = {25683987}, issn = {1976-2437}, mesh = {Adult ; Aged ; Angiography ; Arteriovenous Fistula/diagnostic imaging/*pathology/*surgery ; Central Nervous System Vascular Malformations/diagnostic imaging/*pathology/*surgery ; Embolization, Therapeutic/*methods ; Female ; Humans ; *Magnetic Resonance Imaging ; Male ; Middle Aged ; Postoperative Period ; Predictive Value of Tests ; Prognosis ; Retrospective Studies ; Severity of Illness Index ; Spinal Cord/abnormalities/*blood supply/pathology/surgery ; Treatment Outcome ; }, abstract = {PURPOSE: Magnetic resonance imaging (MRI) has been used to screen and follow-up spinal dural arteriovenous fistulae (SDAVF). The purpose of this study was to evaluate the association between MRI findings and neurologic function in SDAVF. This study also investigated clinical features and treatment results of SDAVF.<br><br>MATERIALS AND METHODS: A total of 15 consecutive patients who underwent embolization or surgery for SDAVF were included. We treated seven (60%) patients with embolization and six (40%) with surgery. We analysed clinical features, MRI findings, treatment results, and neurologic function. Neurologic function was measured by the Aminoff-Logue disability scale (ALS).<br><br>RESULTS: Patients with longer levels of intramedullary high signal intensity in preoperative T2-weighted images (T2WI) exhibited worse pre- and postoperative ALS scores (r=0.557, p=0.031; r=0.530, p=0.042, Pearson correlation). Preoperative ALS score was significantly correlated with postoperative ALS score (r=0.908, p=0.000, Pearson correlation). The number of levels showing intramedullary high signal intensity in T2WI decreased significantly postoperatively (5.2&#xb1;3.1 vs. 1.0&#xb1;1.4, p=0.001, Wilcoxon ranked test).<br><br>CONCLUSION: The number of involved levels of high signal intensity in preoperative T2WI is useful for predicting pre- and postoperative neurologic function in SDAVF.}, }
@article {pmid25683764, year = {2015}, author = {Truini, A and Biasiotta, A and Onesti, E and Di Stefano, G and Ceccanti, M and La Cesa, S and Pepe, A and Giordano, C and Cruccu, G and Inghilleri, M}, title = {Small-fibre neuropathy related to bulbar and spinal-onset in patients with ALS.}, journal = {Journal of neurology}, volume = {262}, number = {4}, pages = {1014-1018}, pmid = {25683764}, issn = {1432-1459}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications ; Biopsy ; Erythromelalgia/*etiology ; Female ; Humans ; Male ; Middle Aged ; Neural Conduction/*physiology ; Normal Distribution ; Pain Threshold/*physiology ; Skin/innervation/pathology ; }, abstract = {We aimed at seeking more precise diagnostic information on the sensory nervous system involvement described in patients with amyotrophic lateral sclerosis (ALS). We investigated large myelinated nerve fibres with nerve conduction study and small-nerve fibres with Quantitative Sensory Testing (QST) (assessing thermal-pain perceptive thresholds) and skin biopsy (assessing intraepidermal nerve fibre density) in 24 consecutive patients with ALS, 11 with bulbar-onset and 13 with spinal-onset. In 23 of the 24 patients, regardless of ALS onset, nerve conduction study invariably showed large myelinated fibre sparing. In patients with bulbar-onset ALS, QST found normal thermal-pain perceptive thresholds and skin biopsy disclosed normal intraepidermal nerve fibre density. Conversely, in patients with spinal-onset, thermal-pain thresholds were abnormal and distal intraepidermal nerve fibre density was reduced. Sensory nervous system involvement in ALS differs according to disease onset. Patients with spinal-onset but not those with bulbar-onset ALS have concomitant distal small-fibre neuropathy. Neurologists should therefore seek this ALS-related non-motor feature to improve its diagnosis and treatment.}, }
@article {pmid25680510, year = {2015}, author = {Reith, S and Burgmaier, M}, title = {[Resuscitation].}, journal = {Medizinische Klinik, Intensivmedizin und Notfallmedizin}, volume = {110}, number = {1}, pages = {81-93; quiz 94-5}, doi = {10.1007/s00063-014-0460-2}, pmid = {25680510}, issn = {2193-6226}, mesh = {Advanced Cardiac Life Support/methods ; Cardiac Catheterization/methods ; Cardiopulmonary Resuscitation/*methods ; Electric Countershock/methods ; Guideline Adherence ; Humans ; Hypothermia, Induced/methods ; }, abstract = {The primary aim of cardiopulmonary resuscitation after cardiac arrest is to achieve the return of spontaneous circulation (ROSC). However, following ROSC the clinical and neurologic outcome is mainly influenced by adequate treatment in the postresuscitation period. There are several novel recommendations in the current 2010 guidelines of the European Resuscitation Council (ERC) concerning advanced life support (ALS). In addition to established standards for mechanical, electrical (defibrillation), and pharmacological resuscitation during the initial phase, the guidelines moreover deal with recommendations for standardized therapy in the postresuscitation period. Major aspects concerning the therapy of the postcardiac arrest syndrome include temperature management with therapeutic hypothermia, mechanical ventilation and the extent of oxygenation and blood glucose control. Thus, the initial cardiopulmonary resuscitation and the following postresuscitation treatment have to be considered as merging therapy concepts. Only a standardized therapeutic approach in these different phases of treatment will result in successful resuscitation with high rates of survival and good neurologic outcome.}, }
@article {pmid25676865, year = {2015}, author = {Jindal, R and Unadkat, J and Zhang, W and Zhang, D and Ng, TW and Wang, Y and Jiang, J and Lakkis, F and Rubin, P and Lee, WP and Gorantla, VS and Zheng, XX}, title = {Spontaneous resolution of acute rejection and tolerance induction with IL-2 fusion protein in vascularized composite allotransplantation.}, journal = {American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons}, volume = {15}, number = {5}, pages = {1231-1240}, doi = {10.1111/ajt.13118}, pmid = {25676865}, issn = {1600-6143}, mesh = {Animals ; Cell Proliferation ; Cyclosporine/chemistry ; Forkhead Transcription Factors/metabolism ; Gene Expression Regulation ; Graft Rejection ; Graft Survival ; Granzymes/metabolism ; Hindlimb/*transplantation ; Humans ; Immune System ; Immune Tolerance ; Interleukin-2/*chemistry ; Male ; Pore Forming Cytotoxic Proteins/metabolism ; Rats ; Rats, Inbred Lew ; Rats, Wistar ; Recombinant Fusion Proteins/*chemistry ; Transplantation Tolerance/*drug effects ; Transplantation, Homologous ; Vascularized Composite Allotransplantation/*methods ; }, abstract = {Vascularized composite allotransplantation (VCA) has emerged as a treatment option for treating nonlife-threatening conditions. Therefore, in order to make VCA a safe reconstruction option, there is a need to minimize immunosuppression, develop tolerance-inducing strategies and elucidate the mechanisms of VCA rejection and tolerance. In this study we explored the effects of hIL-2/Fc (a long-lasting human IL-2 fusion protein), in combination with antilymphocyte serum (ALS) and short-term cyclosporine A (CsA), on graft survival, regulatory T cell (Treg) proliferation and tolerance induction in a rat hind-limb transplant model. We demonstrate that hIL-2/Fc therapy tips the immune balance, increasing Treg proliferation and suppressing effector T cells, and permits VCA tolerance as demonstrated by long-term allograft survival and donor-antigen acceptance. Moreover, we observe two distinct types of acute rejection (AR), progressive and reversible, within hIL-2/Fc plus ALS and CsA treated recipients. Our study shows differential gene expression profiles of FoxP3 versus GzmB, Prf1 or interferon-γ in these two types of AR, with reversible rejection demonstrating higher Treg to Teff gene expression. This correlation of gene expression profile at the first clinical sign of AR with VCA outcomes can provide the basis for further inquiry into the mechanistic aspects of VCA rejection and future drug targets.}, }
@article {pmid25674312, year = {2014}, author = {Brizuela, A and Martín, N and Fernández-Gonzalez, FJ and Larrazábal, C and Anta, A}, title = {Osteotome sinus floor elevation without grafting material: Results of a 2-year prospective study.}, journal = {Journal of clinical and experimental dentistry}, volume = {6}, number = {5}, pages = {e479-84}, pmid = {25674312}, issn = {1989-5488}, abstract = {OBJECTIVES: The aim of this prospective clinical trial was to evaluate the success implant rates during 24 months using OSFE procedure without grafting materials.<br><br>STUDY DESIGN: 42 adult patients (22 female, 15 male) were selected according to Nedir et al&#xb4;s inclusion criteria of which 5 patients were excluded, due to periapical pathology in adjacent teeth (n=3) and treatment with bisphosphonates (n=2). 37 patients aged 31-68 years were selected. Smokers were divided in two groups depending on the number of cigarettes consumed per day (a) 0-10, (b) 11-20. One patient was excluded because he was lost to follow-up at 24 months A total of 36 threaded implants were placed, &#x2205;4,1mm Straumann&#xae; (Straumann AG, Waldenburg, Switzerland) and &#x2205;3,5mm Klockner&#xae; (Klockner Implant System, Barcelona, Spain). The most used implant diameter was 4,1 mm (n=29), followed by 3,5 mm (n=7), and length used was 10 mm (n=32) and 8 mm (n=4). Initial RBH ranged from 4 mm to 9 mm. All statistical data were processed using the program R 3.0.2 for windows.<br><br>RESULTS: A total of 36 threaded implants were placed. Residual bone height (RBH) at implant placement averaged 7,4 &#xb1; 0,4 mm. Mean bone gain was 1,8 &#xb1; 0,3 mm. Four implants showed a bone gain exceeding 3 mm. Mean implant protrusion length into the sinus amounted to 2.1 &#xb1; 0,3 mm. Regarding the relationship between smoking and periodontal probes, no statistically significant differences were found (P=0,25), neither in relation to the number of threads that the implants showed (P=0,29) or bone gain (P=0,79). After 24 months the implant success rate was 91,6%.<br><br>CONCLUSIONS: Implant rehabilitation of edentulous atrophied posterior maxilla can be safely performed and simplified using the OSFE technique without grafting with reliable long-term results. Key words:Crestal bone loss, dental implants, internal sinus lift, no grafting, osteotome sinus elevation, grafting, sinus floor elevation.}, }
@article {pmid25672715, year = {2014}, author = {Shibuya, K and Misawa, S and Kuwabara, S}, title = {[Motor nerve hyperexcitability in ALS: its pathophysiology and treatment].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {54}, number = {12}, pages = {1086-1088}, doi = {10.5692/clinicalneurol.54.1086}, pmid = {25672715}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*physiopathology ; Cell Death/physiology ; Humans ; Mexiletine/therapeutic use ; Motor Neurons/*physiology ; Voltage-Gated Sodium Channel Blockers/therapeutic use ; }, abstract = {Wide-spread fasciculations are prominent clinical features in patients with amyotrophic lateral sclerosis (ALS), specifically seen in ALS among disorders with neurogenic muscle atrophy. Fasciculations frequently arise from the motor nerve terminals, and the hyperexcitability of motor axons appears to constitute the pathophysiology of the disease. Neurophysiologic investigations of the upper and lower motor neurons/axons have shown increased excitability. The altered excitability is supposed to relate to motor neuron death. Based on these findings, a clinical trial of mexiletine (non-selective sodium channel blocker) is ongoing.}, }
@article {pmid25667954, year = {2015}, author = {Wang, G and Deval, J and Hong, J and Dyatkina, N and Prhavc, M and Taylor, J and Fung, A and Jin, Z and Stevens, SK and Serebryany, V and Liu, J and Zhang, Q and Tam, Y and Chanda, SM and Smith, DB and Symons, JA and Blatt, LM and Beigelman, L}, title = {Discovery of 4'-chloromethyl-2'-deoxy-3',5'-di-O-isobutyryl-2'-fluorocytidine (ALS-8176), a first-in-class RSV polymerase inhibitor for treatment of human respiratory syncytial virus infection.}, journal = {Journal of medicinal chemistry}, volume = {58}, number = {4}, pages = {1862-1878}, doi = {10.1021/jm5017279}, pmid = {25667954}, issn = {1520-4804}, mesh = {Animals ; Antiviral Agents/administration &amp; dosage/chemistry/*pharmacology ; Cricetinae ; DNA-Directed DNA Polymerase/metabolism ; DNA-Directed RNA Polymerases/antagonists &amp; inhibitors/metabolism ; Deoxycytidine/*analogs &amp; derivatives/chemical synthesis/chemistry/pharmacology ; Dose-Response Relationship, Drug ; Drug Discovery ; Enzyme Inhibitors/administration &amp; dosage/chemistry/*pharmacology ; Haplorhini ; Humans ; Male ; Molecular Conformation ; *Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/metabolism ; Prodrugs/administration &amp; dosage/chemistry/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Respiratory Syncytial Virus Infections/*drug therapy/virology ; Respiratory Syncytial Viruses/*drug effects/*enzymology ; Structure-Activity Relationship ; Virus Replication/drug effects ; }, abstract = {Respiratory syncytial virus (RSV) is a leading pathogen of childhood and is associated with significant morbidity and mortality. To date, ribavirin is the only approved small molecule drug, which has limited use. The only other RSV drug is palivizumab, a monoclonal antibody, which is used for RSV prophylaxis. Clearly, there is an urgent need for small molecule RSV drugs. This article reports the design, synthesis, anti-RSV activity, metabolism, and pharmacokinetics of a series of 4'-substituted cytidine nucleosides. Among tested compounds 4'-chloromethyl-2'-deoxy-2'-fluorocytidine (2c) exhibited the most promising activity in the RSV replicon assay with an EC50 of 0.15 μM. The 5'-triphosphate of 2c (2c-TP) inhibited RSV polymerase with an IC50 of 0.02 μM without appreciable inhibition of human DNA and RNA polymerases at 100 μM. ALS-8176 (71), the 3',5'-di-O-isobutyryl prodrug of 2c, demonstrated good oral bioavailability and a high level of 2c-TP in vivo. Compound 71 is a first-in-class nucleoside RSV polymerase inhibitor that demonstrated excellent anti-RSV efficacy and safety in a phase 2 clinical RSV challenge study.}, }
@article {pmid25666897, year = {2015}, author = {Bhatia, NK and Srivastava, A and Katyal, N and Jain, N and Khan, MA and Kundu, B and Deep, S}, title = {Curcumin binds to the pre-fibrillar aggregates of Cu/Zn superoxide dismutase (SOD1) and alters its amyloidogenic pathway resulting in reduced cytotoxicity.}, journal = {Biochimica et biophysica acta}, volume = {1854}, number = {5}, pages = {426-436}, doi = {10.1016/j.bbapap.2015.01.014}, pmid = {25666897}, issn = {0006-3002}, mesh = {Amyloid/chemistry/*drug effects/metabolism/*toxicity ; Cells, Cultured ; Curcumin/chemistry/*pharmacokinetics ; Cytoprotection/drug effects ; Humans ; Metabolic Networks and Pathways/drug effects ; Models, Molecular ; Molecular Docking Simulation ; Protein Aggregates/*drug effects ; Protein Binding ; Protein Multimerization/drug effects ; Superoxide Dismutase/chemistry/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons. Unfortunately, effective therapeutics against this disease is still not available. Almost 20% of familial ALS (fALS) is suggested to be associated with pathological deposition of superoxide dismutase (SOD1). Evidences suggest that SOD1-containing pathological inclusions in ALS exhibit amyloid like properties. An effective strategy to combat ALS may be to inhibit amyloid formation of SOD1 using small molecules. In the present study, we observed the fibrillation of one of the premature forms of SOD1 (SOD1 with reduced disulfide) in the presence of curcumin. Using ThT binding assay, AFM, TEM images and FTIR, we demonstrate that curcumin inhibits the DTT-induced fibrillation of SOD1 and favors the formation of smaller and disordered aggregates of SOD1. The enhancement in curcumin fluorescence on the addition of oligomers and pre-fibrillar aggregates of SOD1 suggests binding of these species to curcumin. Docking studies indicate that putative binding site of curcumin may be the amyloidogenic regions of SOD1. Further, there is a significant increase in SOD1 mediated toxicity in the regime of pre-fibrillar and fibrillar aggregates which is not evident in curcumin containing samples. All these data suggest that curcumin reduces toxicity by binding to the amyloidogenic regions of the species on the aggregation pathway and blocking the formation of the toxic species. Nanoparticles of curcumin with higher aqueous solubility show similar aggregation control as that of curcumin bulk. This suggests a potential role for curcumin in the treatment of ALS.}, }
@article {pmid25666449, year = {2015}, author = {Bucchia, M and Ramirez, A and Parente, V and Simone, C and Nizzardo, M and Magri, F and Dametti, S and Corti, S}, title = {Therapeutic development in amyotrophic lateral sclerosis.}, journal = {Clinical therapeutics}, volume = {37}, number = {3}, pages = {668-680}, doi = {10.1016/j.clinthera.2014.12.020}, pmid = {25666449}, issn = {1879-114X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Disease Progression ; Humans ; Riluzole/*therapeutic use ; Treatment Outcome ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. It is almost invariably lethal within a few years after the onset of symptoms. No effective treatment is currently available beyond supportive care and riluzole, a putative glutamate release blocker linked to modestly prolonged survival. This review provides a general overview of preclinical and clinical advances during recent years and summarizes the literature regarding emerging therapeutic approaches, focusing on their molecular targets.<br><br>METHODS: A systematic literature review of PubMed was performed, identifying key clinical trials involving molecular therapies for ALS. In addition, the ALS Therapy Development Institute website was carefully analyzed, and a selection of ALS clinical trials registered at ClinicalTrials.gov has been included.<br><br>FINDINGS: In the last several years, strategies have been developed to understand both the genetic and molecular mechanisms of ALS. Several therapeutic targets have been actively pursued, including kinases, inflammation inhibitors, silencing of key genes, and modulation or replacement of specific cell populations. The majority of ongoing clinical trials are investigating the safety profiles and tolerability of pharmacologic, gene, and cellular therapies, and have begun to assess their effects on ALS progression.<br><br>IMPLICATIONS: Currently, no therapeutic effort seems to be efficient, but recent findings in ALS could help accelerate the discovery of an effective treatment for this disease.}, }
@article {pmid25664595, year = {2016}, author = {Elia, AE and Lalli, S and Monsurrò, MR and Sagnelli, A and Taiello, AC and Reggiori, B and La Bella, V and Tedeschi, G and Albanese, A}, title = {Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {23}, number = {1}, pages = {45-52}, pmid = {25664595}, issn = {1468-1331}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/administration &amp; dosage/adverse effects/*pharmacology ; *Outcome Assessment, Health Care ; Pilot Projects ; Riluzole/*therapeutic use ; Taurochenodeoxycholic Acid/administration &amp; dosage/adverse effects/*pharmacology ; }, abstract = {BACKGROUND AND PURPOSE: Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is produced in the liver and used for treatment of chronic cholestatic liver diseases. Experimental studies suggest that TUDCA may have cytoprotective and anti-apoptotic action, with potential neuroprotective activity. A proof of principle approach was adopted to provide preliminary data regarding the efficacy and tolerability of TUDCA in a series of patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: As a proof of principle, using a double-blind placebo controlled design, 34 ALS patients under treatment with riluzole who were randomized to placebo or TUDCA (1 g twice daily for 54 weeks) were evaluated after a lead-in period of 3 months. The patients were examined every 6 weeks. The primary outcome was the proportion of responders [those subjects with improvement of at least 15% in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) slope during the treatment period compared to the lead-in phase]. Secondary outcomes included between-treatment comparison of ALSFRS-R at study end, comparison of the linear regression slopes for ALSFFRS-R mean scores and the occurrence of adverse events.<br><br>RESULTS: Tauroursodeoxycholic acid was well tolerated; there were no between-group differences for adverse events. The proportion of responders was higher under TUDCA (87%) than under placebo (P = 0.021; 43%). At study end baseline-adjusted ALSFRS-R was significantly higher (P = 0.007) in TUDCA than in placebo groups. Comparison of the slopes of regression analysis showed slower progression in the TUDCA than in the placebo group (P < 0.01).<br><br>CONCLUSIONS: This pilot study provides preliminary clinical data indicating that TUDCA is safe and may be effective in ALS.}, }
@article {pmid25661004, year = {2015}, author = {Baratin, E and Sugavaneswaran, L and Umapathy, K and Ioana, C and Krishnan, S}, title = {Wavelet-based characterization of gait signal for neurological abnormalities.}, journal = {Gait &amp; posture}, volume = {41}, number = {2}, pages = {634-639}, doi = {10.1016/j.gaitpost.2015.01.012}, pmid = {25661004}, issn = {1879-2219}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/*physiopathology ; Databases, Factual ; Diagnosis, Computer-Assisted/*methods ; Female ; Gait/*physiology ; Humans ; Huntington Disease/diagnosis/*physiopathology ; Male ; Middle Aged ; Parkinson Disease/diagnosis/*physiopathology ; *Wavelet Analysis ; Young Adult ; }, abstract = {Studies conducted by the World Health Organization (WHO) indicate that over one billion suffer from neurological disorders worldwide, and lack of efficient diagnosis procedures affects their therapeutic interventions. Characterizing certain pathologies of motor control for facilitating their diagnosis can be useful in quantitatively monitoring disease progression and efficient treatment planning. As a suitable directive, we introduce a wavelet-based scheme for effective characterization of gait associated with certain neurological disorders. In addition, since the data were recorded from a dynamic process, this work also investigates the need for gait signal re-sampling prior to identification of signal markers in the presence of pathologies. To benefit automated discrimination of gait data, certain characteristic features are extracted from the wavelet-transformed signals. The performance of the proposed approach was evaluated using a database consisting of 15 Parkinson's disease (PD), 20 Huntington's disease (HD), 13 Amyotrophic lateral sclerosis (ALS) and 16 healthy control subjects, and an average classification accuracy of 85% is achieved using an unbiased cross-validation strategy. The obtained results demonstrate the potential of the proposed methodology for computer-aided diagnosis and automatic characterization of certain neurological disorders.}, }
@article {pmid25659970, year = {2015}, author = {Prakash, A and Bharti, K and Majeed, AB}, title = {Zinc: indications in brain disorders.}, journal = {Fundamental &amp; clinical pharmacology}, volume = {29}, number = {2}, pages = {131-149}, doi = {10.1111/fcp.12110}, pmid = {25659970}, issn = {1472-8206}, mesh = {Animals ; Biological Transport/physiology ; Brain/*metabolism/pathology ; Brain Diseases/diagnosis/*metabolism ; Brain Injuries/diagnosis/metabolism ; Cation Transport Proteins/metabolism ; Homeostasis/physiology ; Humans ; Neurodegenerative Diseases/diagnosis/metabolism ; Stroke/diagnosis/metabolism ; Zinc/*metabolism ; }, abstract = {Zinc is the authoritative metal which is present in our body, and reactive zinc metal is crucial for neuronal signaling and is largely distributed within presynaptic vesicles. Zinc also plays an important role in synaptic function. At cellular level, zinc is a modulator of synaptic activity and neuronal plasticity in both development and adulthood. Different importers and transporters are involved in zinc homeostasis. ZnT-3 is a main transporter involved in zinc homeostasis in the brain. It has been found that alterations in brain zinc status have been implicated in a wide range of neurological disorders including impaired brain development and many neurodegenerative disorders such as Alzheimer's disease, and mood disorders including depression, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. Furthermore, zinc has also been implicated in neuronal damage associated with traumatic brain injury, stroke, and seizure. Understanding the mechanisms that control brain zinc homeostasis is thus critical to the development of preventive and treatment strategies for these and other neurological disorders.}, }
@article {pmid25653590, year = {2014}, author = {Henriques, A and Kastner, S and Chatzikonstantinou, E and Pitzer, C and Plaas, C and Kirsch, F and Wafzig, O and Krüger, C and Spoelgen, R and Gonzalez De Aguilar, JL and Gretz, N and Schneider, A}, title = {Gene expression changes in spinal motoneurons of the SOD1(G93A) transgenic model for ALS after treatment with G-CSF.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {464}, pmid = {25653590}, issn = {1662-5102}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable fatal motoneuron disease with a lifetime risk of approximately 1:400. It is characterized by progressive weakness, muscle wasting, and death ensuing 3-5 years after diagnosis. Granulocyte-colony stimulating factor (G-CSF) is a drug candidate for ALS, with evidence for efficacy from animal studies and interesting data from pilot clinical trials. To gain insight into the disease mechanisms and mode of action of G-CSF, we performed gene expression profiling on isolated lumbar motoneurons from SOD1(G93A) mice, the most frequently studied animal model for ALS, with and without G-CSF treatment.<br><br>RESULTS: Motoneurons from SOD1(G93A) mice present a distinct gene expression profile in comparison to controls already at an early disease stage (11 weeks of age), when treatment was initiated. The degree of deregulation increases at a time where motor symptoms are obvious (15 weeks of age). Upon G-CSF treatment, transcriptomic deregulations of SOD1(G93A) motoneurons were notably restored. Discriminant analysis revealed that SOD1 mice treated with G-CSF has a transcriptom close to presymptomatic SOD1 mice or wild type mice. Some interesting genes modulated by G-CSF treatment relate to neuromuscular function such as CCR4-NOT or Prss12.<br><br>CONCLUSIONS: Our data suggest that G-CSF is able to re-adjust gene expression in symptomatic SOD1(G93A) motoneurons. This provides further arguments for G-CSF as a promising drug candidate for ALS.}, }
@article {pmid25642388, year = {2015}, author = {Hanisch, F and Skudlarek, A and Berndt, J and Kornhuber, ME}, title = {Characteristics of pain in amyotrophic lateral sclerosis.}, journal = {Brain and behavior}, volume = {5}, number = {3}, pages = {e00296}, pmid = {25642388}, issn = {2162-3279}, mesh = {Activities of Daily Living ; Adult ; Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; Cross-Sectional Studies ; Female ; Germany/epidemiology ; Humans ; Male ; Middle Aged ; *Muscle Cramp/epidemiology/etiology/physiopathology/therapy ; *Musculoskeletal Pain/diagnosis/epidemiology/etiology/physiopathology/psychology/therapy ; *Myotonic Dystrophy/complications/diagnosis/epidemiology ; Pain Management/methods ; Pain Measurement/methods ; Prevalence ; Quality of Life/*psychology ; Research Design ; Severity of Illness Index ; }, abstract = {BACKGROUND: Pain is an often underestimated and neglected symptom in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: In a cross-sectional survey, 46 patients with ALS, 46 age- and gender matched population-based controls, and 23 diseased controls with myotonic dystrophy type 2 (DM2) were screened for occurrence, type, distribution, and treatment of pain and cramps. Data were collected with the use of the short form brief pain inventory (BPI).<br><br>RESULTS: Pain was reported in 78% of ALS patients,79% of DM2 patients, and 54% of controls (P<0.05). More ALS patients than controls reported moderate to severe pain (42% vs. 20%). Pain in ALS patients interfered significantly more with daily activities than in controls (median pain interference score: 3.0 vs. 1.2, P<0.05), especially enjoyment of life (5.0 vs. 1.0) and mood (3.0 vs. 1.0). There was no correlation between the duration of the disease and the severity of pain. Movement-induced cramps were reported in 63% of ALS patients, mostly in the distal extremities. There was no difference in the duration of ALS disease between patients reporting cramps and those who did not.<br><br>DISCUSSION: Our study showed that pain was a relatively frequent symptom which had an important impact on the quality of life. Pain that requires treatment can occur at every stage of ALS.}, }
@article {pmid25641599, year = {2017}, author = {Knippenberg, S and Rath, KJ and Böselt, S and Thau-Habermann, N and Schwarz, SC and Dengler, R and Wegner, F and Petri, S}, title = {Intraspinal administration of human spinal cord-derived neural progenitor cells in the G93A-SOD1 mouse model of ALS delays symptom progression, prolongs survival and increases expression of endogenous neurotrophic factors.}, journal = {Journal of tissue engineering and regenerative medicine}, volume = {11}, number = {3}, pages = {751-764}, doi = {10.1002/term.1972}, pmid = {25641599}, issn = {1932-7005}, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology/*therapy ; Animals ; Cell Lineage ; Disease Models, Animal ; Disease Progression ; Humans ; Injections, Spinal ; Mice, Transgenic ; Motor Activity ; Nerve Growth Factors/*metabolism ; Neural Stem Cells/cytology/*transplantation ; RNA, Messenger/genetics/metabolism ; Spinal Cord/*cytology ; Stem Cell Transplantation ; Superoxide Dismutase/*genetics ; Survival Analysis ; }, abstract = {Neural stem or progenitor cells are considered to be a novel therapeutic strategy for amyotrophic lateral sclerosis (ALS), based on their potential to generate a protective environment rather than to replace degenerating motor neurons. Following local injection to the spinal cord, neural progenitor cells may generate glial cells and release neurotrophic factors. In the present study, human spinal cord-derived neural progenitor cells (hscNPCs) were injected into the lumbar spinal cord of G93A-SOD1 ALS transgenic mice. We evaluated the potential effect of hscNPC treatment by survival analysis and behavioural/phenotypic assessments. Immunohistological and real-time PCR experiments were performed at a defined time point to study the underlying mechanisms. Symptom progression in hscNPC-injected mice was significantly delayed at the late stage of disease. On average, survival was only prolonged for 5 days. Animals treated with hscNPCs performed significantly better in motor function tests between weeks 18 and 19. Increased production of GDNF and IGF-1 mRNA was detectable in spinal cord tissue of hscNPC-treated mice. In summary, treatment with hscNPCs led to increased endogenous production of several growth factors and increased the preservation of innervated motor neurons but had only a small effect on overall survival. Copyright © 2015 John Wiley &amp; Sons, Ltd.}, }
@article {pmid25640119, year = {2015}, author = {Vosough, M and Rashvand, M and Esfahani, HM and Kargosha, K and Salemi, A}, title = {Direct analysis of six antibiotics in wastewater samples using rapid high-performance liquid chromatography coupled with diode array detector: a chemometric study towards green analytical chemistry.}, journal = {Talanta}, volume = {135}, number = {}, pages = {7-17}, doi = {10.1016/j.talanta.2014.12.036}, pmid = {25640119}, issn = {1873-3573}, mesh = {Amoxicillin/analysis ; Anti-Bacterial Agents/*analysis ; Chromatography, High Pressure Liquid/methods ; Green Chemistry Technology ; Metronidazole/analysis ; Ofloxacin/analysis ; Sulfadiazine/analysis ; Sulfamerazine/analysis ; Sulfamethoxazole/analysis ; Wastewater/*analysis ; Water Pollutants, Chemical/*analysis ; }, abstract = {In this work, a rapid HPLC-DAD method has been developed for the analysis of six antibiotics (amoxicillin, metronidazole, sulfamethoxazole, ofloxacine, sulfadiazine and sulfamerazine) in the sewage treatment plant influent and effluent samples. Decreasing the chromatographic run time to less than 4 min as well as lowering the cost per analysis, were achieved through direct injection of the samples into the HPLC system followed by chemometric analysis. The problem of the complete separation of the analytes from each other and/or from the matrix ingredients was resolved as a posteriori. The performance of MCR/ALS and U-PLS/RBL, as second-order algorithms, was studied and comparable results were obtained from implication of these modeling methods. It was demonstrated that the proposed methods could be used promisingly as green analytical strategies for detection and quantification of the targeted pollutants in wastewater samples while avoiding the more complicated high cost instrumentations.}, }
@article {pmid25635128, year = {2015}, author = {Chae, JH and Vasta, V and Cho, A and Lim, BC and Zhang, Q and Eun, SH and Hahn, SH}, title = {Utility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders.}, journal = {Journal of medical genetics}, volume = {52}, number = {3}, pages = {208-216}, doi = {10.1136/jmedgenet-2014-102819}, pmid = {25635128}, issn = {1468-6244}, mesh = {Adolescent ; Age of Onset ; Child ; Child, Preschool ; Collagen Type VI/*genetics ; Extracellular Matrix Proteins/*genetics ; Female ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Muscular Diseases/congenital/*genetics/pathology ; Mutation ; Polymorphism, Single Nucleotide/*genetics ; Young Adult ; }, abstract = {BACKGROUND: Neuromuscular disorders are a clinically, pathologically, and genetically heterogeneous group. Even for the experienced clinician, an accurate diagnosis is often challenging due to the complexity of these disorders. Here, we investigated the utility of next generation sequencing (NGS) in early diagnostic algorithms to improve the diagnosis for patients currently lacking precise molecular characterisation, particularly for hereditary myopathies.<br><br>METHODS: 43 patients presenting with early onset neuromuscular disorders from unknown genetic origin were tested by NGS for 579 nuclear genes associated with myopathy.<br><br>RESULTS: In 21 of the 43 patients, we identified the definite genetic causes (48.8%). Additionally, likely pathogenic variants were identified in seven cases and variants of uncertain significance (VUS) were suspected in four cases. In total, 19 novel and 15 known pathogenic variants in 17 genes were identified in 32 patients. Collagen VI related myopathy was the most prevalent type in our cohort. The utility of NGS was highlighted in three cases with congenital myasthenia syndrome, as early diagnosis is important for effective treatment.<br><br>CONCLUSIONS: A targeted NGS can offer cost effective, safe and fairly rapid turnaround time, which can improve quality of care for patients with early onset myopathies and muscular dystrophies; in particular, collagen VI related myopathy and congenital myasthenia syndromes. Nevertheless, a substantial number of patients remained without molecular diagnosis in our cohort. This may be due to the intrinsic limitation of detection for some types of mutations by NGS or to the fact that other causative genes for neuromuscular disorders are yet to be identified.}, }
@article {pmid25632606, year = {2014}, author = {Hübers, A and Weishaupt, JH and Ludolph, AC}, title = {[Amyotrophic lateral sclerosis].}, journal = {Medizinische Monatsschrift fur Pharmazeuten}, volume = {37}, number = {10}, pages = {356-64; quiz 365-6}, pmid = {25632606}, issn = {0342-9601}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Humans ; Motor Neurons/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an aggressive degeneration of upper and lower motor neurons and thus affects both the central and the peripheral nervous system. Clinically, the disease is characterized by rapidly progressing atrophy and paresis of all muscle groups with a letal outcome after three to six years due to paresis of the respiratory muscles. So far, no causal treatment is known.}, }
@article {pmid25632225, year = {2015}, author = {Wang, F and Li, H and Yan, XG and Zhou, ZW and Yi, ZG and He, ZX and Pan, ST and Yang, YX and Wang, ZZ and Zhang, X and Yang, T and Qiu, JX and Zhou, SF}, title = {Alisertib induces cell cycle arrest and autophagy and suppresses epithelial-to-mesenchymal transition involving PI3K/Akt/mTOR and sirtuin 1-mediated signaling pathways in human pancreatic cancer cells.}, journal = {Drug design, development and therapy}, volume = {9}, number = {}, pages = {575-601}, pmid = {25632225}, issn = {1177-8881}, mesh = {Antineoplastic Agents/*pharmacology ; Aurora Kinase A/antagonists &amp; inhibitors/metabolism ; Autophagy/*drug effects ; Azepines/*pharmacology ; Cell Cycle Checkpoints/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Epithelial-Mesenchymal Transition/*drug effects ; Humans ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Pancreatic Neoplasms/*enzymology/pathology ; Phosphatidylinositol 3-Kinase/*metabolism ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-akt/*metabolism ; Pyrimidines/*pharmacology ; Signal Transduction/drug effects ; Sirtuin 1/*metabolism ; TOR Serine-Threonine Kinases/*metabolism ; Time Factors ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Pancreatic cancer is the most aggressive cancer worldwide with poor response to current therapeutics. Alisertib (ALS), a potent and selective Aurora kinase A inhibitor, exhibits potent anticancer effects in preclinical and clinical studies; however, the effect and underlying mechanism of ALS in the pancreatic cancer treatment remain elusive. This study aimed to examine the effects of ALS on cell growth, autophagy, and epithelial-to-mesenchymal transition (EMT) and to delineate the possible molecular mechanisms in human pancreatic cancer PANC-1 and BxPC-3 cells. The results showed that ALS exerted potent cell growth inhibitory, pro-autophagic, and EMT-suppressing effects in PANC-1 and BxPC-3 cells. ALS remarkably arrested PANC-1 and BxPC-3 cells in G2/M phase via regulating the expression of cyclin-dependent kinases 1 and 2, cyclin B1, cyclin D1, p21 Waf1/Cip1, p27 Kip1, and p53. ALS concentration-dependently induced autophagy in PANC-1 and BxPC-3 cells, which may be attributed to the inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), p38 mitogen-activated protein kinase (p38 MAPK), and extracellular signal-regulated kinases 1 and 2 (Erk1/2) but activation of 5'-AMP-dependent kinase signaling pathways. ALS significantly inhibited EMT in PANC-1 and BxPC-3 cells with an increase in the expression of E-cadherin and a decrease in N-cadherin. In addition, ALS suppressed the expression of sirtuin 1 (Sirt1) and pre-B cell colony-enhancing factor/visfatin in both cell lines with a rise in the level of acetylated p53. These findings show that ALS induces cell cycle arrest and promotes autophagic cell death but inhibits EMT in pancreatic cancer cells with the involvement of PI3K/Akt/mTOR, p38 MAPK, Erk1/2, and Sirt1-mediated signaling pathways. Taken together, ALS may represent a promising anticancer drug for pancreatic cancer treatment. More studies are warranted to investigate other molecular targets and mechanisms and verify the efficacy and safety of ALS in the treatment of pancreatic cancer.}, }
@article {pmid25631784, year = {2015}, author = {Bloch, S and Saldert, C and Ferm, U}, title = {Problematic topic transitions in dysarthric conversation.}, journal = {International journal of speech-language pathology}, volume = {17}, number = {4}, pages = {373-383}, doi = {10.3109/17549507.2014.979879}, pmid = {25631784}, issn = {1754-9515}, mesh = {Adult ; Aged ; Dysarthria/etiology/*physiopathology ; Female ; Humans ; Male ; Motor Neuron Disease/complications ; Speech Intelligibility/*physiology ; }, abstract = {PURPOSE: This study examined the nature of topic transition problems associated with acquired progressive dysarthric speech in the everyday conversation of people with motor neurone disease.<br><br>METHOD: Using conversation analytic methods, a video collection of five naturally occurring problematic topic transitions was identified, transcribed and analysed. These were extracted from a main collection of over 200 other-initiated repair sequences and a sub-set of 15 problematic topic transition sequences. The sequences were analysed with reference to how the participants both identified and resolved the problems.<br><br>RESULT: Analysis revealed that topic transition by people with dysarthria can prove problematic. Conversation partners may find transitions problematic not only because of speech intelligibility but also because of a sequential disjuncture between the dysarthric speech turn and whatever topic has come prior. In addition the treatment of problematic topic transition as a complaint reveals the potential vulnerability of people with dysarthria to judgements of competence.<br><br>CONCLUSION: These findings have implications for how dysarthria is conceptualized and how specific actions in conversation, such as topic transition, might be suitable targets for clinical intervention.}, }
@article {pmid25624750, year = {2015}, author = {Ding, YH and Zhou, ZW and Ha, CF and Zhang, XY and Pan, ST and He, ZX and Edelman, JL and Wang, D and Yang, YX and Zhang, X and Duan, W and Yang, T and Qiu, JX and Zhou, SF}, title = {Alisertib, an Aurora kinase A inhibitor, induces apoptosis and autophagy but inhibits epithelial to mesenchymal transition in human epithelial ovarian cancer cells.}, journal = {Drug design, development and therapy}, volume = {9}, number = {}, pages = {425-464}, pmid = {25624750}, issn = {1177-8881}, mesh = {Antineoplastic Agents/chemistry/metabolism/*pharmacology ; Apoptosis/*drug effects ; Aurora Kinase A/*antagonists &amp; inhibitors/chemistry/metabolism ; Autophagy/*drug effects ; Azepines/chemistry/metabolism/*pharmacology ; Binding Sites ; Carcinoma, Ovarian Epithelial ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Epithelial-Mesenchymal Transition/*drug effects ; Female ; G2 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Hydrogen Bonding ; Molecular Docking Simulation ; Molecular Structure ; Molecular Targeted Therapy ; Neoplasms, Glandular and Epithelial/*enzymology/pathology ; Ovarian Neoplasms/*enzymology/pathology ; Phosphatidylinositol 3-Kinase/metabolism ; Protein Binding ; Protein Conformation ; Protein Kinase Inhibitors/chemistry/metabolism/*pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Pyrimidines/chemistry/metabolism/*pharmacology ; Signal Transduction/drug effects ; Sirtuin 1/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Time Factors ; }, abstract = {Ovarian cancer is a leading killer of women, and no cure for advanced ovarian cancer is available. Alisertib (ALS), a selective Aurora kinase A (AURKA) inhibitor, has shown potent anticancer effects, and is under clinical investigation for the treatment of advanced solid tumor and hematologic malignancies. However, the role of ALS in the treatment of ovarian cancer remains unclear. This study investigated the effects of ALS on cell growth, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT), and the underlying mechanisms in human epithelial ovarian cancer SKOV3 and OVCAR4 cells. Our docking study showed that ALS, MLN8054, and VX-680 preferentially bound to AURKA over AURKB via hydrogen bond formation, charge interaction, and π-π stacking. ALS had potent growth-inhibitory, proapoptotic, proautophagic, and EMT-inhibitory effects on SKOV3 and OVCAR4 cells. ALS arrested SKOV3 and OVCAR4 cells in G2/M phase and induced mitochondria-mediated apoptosis and autophagy in both SKOV3 and OVCAR4 cell lines in a concentration-dependent manner. ALS suppressed phosphatidylinositol 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase pathways but activated 5'-AMP-dependent kinase, as indicated by their altered phosphorylation, contributing to the proautophagic activity of ALS. Modulation of autophagy altered basal and ALS-induced apoptosis in SKOV3 and OVCAR4 cells. Further, ALS suppressed the EMT-like phenotype in both cell lines by restoring the balance between E-cadherin and N-cadherin. ALS downregulated sirtuin 1 and pre-B cell colony enhancing factor (PBEF/visfatin) expression levels and inhibited phosphorylation of AURKA in both cell lines. These findings indicate that ALS blocks the cell cycle by G2/M phase arrest and promotes cellular apoptosis and autophagy, but inhibits EMT via phosphatidylinositol 3-kinase/Akt/mTOR-mediated and sirtuin 1-mediated pathways in human epithelial ovarian cancer cells. Further studies are warranted to validate the efficacy and safety of ALS in the treatment of ovarian cancer.}, }
@article {pmid25623782, year = {2015}, author = {Dohrn, MF and Othman, A and Hirshman, SK and Bode, H and Alecu, I and Fähndrich, E and Karges, W and Weis, J and Schulz, JB and Hornemann, T and Claeys, KG}, title = {Elevation of plasma 1-deoxy-sphingolipids in type 2 diabetes mellitus: a susceptibility to neuropathy?.}, journal = {European journal of neurology}, volume = {22}, number = {5}, pages = {806-14, e55}, doi = {10.1111/ene.12663}, pmid = {25623782}, issn = {1468-1331}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*blood ; Diabetes Mellitus, Type 2/*blood ; Diabetic Neuropathies/*blood ; Disease Susceptibility ; Erythromelalgia/*blood ; Female ; Humans ; Male ; Middle Aged ; Polyneuropathies/*blood ; Sphingolipids/*blood ; }, abstract = {BACKGROUND AND PURPOSE: Diabetic distal sensorimotor polyneuropathy (DSPN) is a frequent, disabling complication of diabetes mellitus. There is increasing evidence that sphingolipids play a role in insulin resistance and type 2 diabetes (T2DM). Whether neurotoxic 1-deoxy-sphingolipids are elevated in DSPN patients' plasma and whether levels correlate to the DSPN stage were examined.<br><br>METHODS: The plasma profile of 12 sphingoid bases in patients with DSPN and T2DM(n = 39) were cross-sectionally compared to other nerve disorders including chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 13), transthyretin-related familial amyloid polyneuropathy (FAP) (n = 10), amyotrophic lateral sclerosis (ALS) (n = 13) and small fibre neuropathy (n = 12) by liquid chromatography mass spectrometry. Correlations to the DSPN stage were additionally performed. Furthermore, the sphingoid base distribution in sural nerve specimens was measured in patients with DSPN (n = 6) compared to CIDP (n = 3).<br><br>RESULTS: A significantly increased amount of 1-deoxy-sphingolipids [1-deoxy-sphinganine (0.11 &#xb1; 0.06 &#x3bc;mol/l), 1-deoxy-sphingosine (0.24 &#xb1; 0.16 &#x3bc;mol/l)] in patients with DSPN was observed compared to age-matched healthy controls (0.06 &#xb1; 0.03 &#x3bc;mol/l; 0.12 &#xb1; 0.05 &#x3bc;mol/l) and to the other groups. (Para)clinical parameters including sensory loss, neuropathic pain, weakness, vibration perception, nerve conduction velocity, sensory nerve action potentials (sural nerve) and duration of T2DM did not correlate with plasma 1-deoxy-sphingolipid levels, neither did the clinical stage according to the Dyck classification for DSPN. Sphingolipid levels in sural nerve biopsies showed no differences between DSPN and CIDP. Contrarily, patients with a small fibre neuropathy had decreased C&#x2082;&#x2080;-sphingosine plasma levels.<br><br>CONCLUSION: 1-deoxy-sphingolipid plasma levels are significantly elevated in DSPN. They are already detectable in early disease stages but do not correlate with the clinical course. Further knowledge on 1-deoxy-sphingolipids might lead to a better pathophysiological understanding and future treatment options in DSPN.}, }
@article {pmid25622610, year = {2015}, author = {Cook, DW and Rutan, SC and Stoll, DR and Carr, PW}, title = {Two dimensional assisted liquid chromatography - a chemometric approach to improve accuracy and precision of quantitation in liquid chromatography using 2D separation, dual detectors, and multivariate curve resolution.}, journal = {Analytica chimica acta}, volume = {859}, number = {}, pages = {87-95}, doi = {10.1016/j.aca.2014.12.009}, pmid = {25622610}, issn = {1873-4324}, abstract = {Comprehensive two-dimensional liquid chromatography (LC×LC) is rapidly evolving as the preferred method for the analysis of complex biological samples owing to its much greater resolving power compared to conventional one-dimensional (1D-LC). While its enhanced resolving power makes this method appealing, it has been shown that the precision of quantitation in LC×LC is generally not as good as that obtained with 1D-LC. The poorer quantitative performance of LC×LC is due to several factors including but not limited to the undersampling of the first dimension and the dilution of analytes during transit from the first dimension ((1)D) column to the second dimension ((2)D) column, and the larger relative background signals. A new strategy, 2D assisted liquid chromatography (2DALC), is presented here. 2DALC makes use of a diode array detector placed at the end of each column, producing both multivariate (1)D and two-dimensional (2D) chromatograms. The increased resolution of the analytes provided by the addition of a second dimension of separation enables the determination of analyte absorbance spectra from the (2)D detector signal that are relatively pure and can be used to initiate the treatment of data from the first dimension detector using multivariate curve resolution-alternating least squares (MCR-ALS). In this way, the approach leverages the strengths of both separation methods in a single analysis: the (2)D detector data is used to provide relatively pure analyte spectra to the MCR-ALS algorithm, and the final quantitative results are obtained from the resolved (1)D chromatograms, which has a much higher sampling rate and lower background signal than obtained in conventional single detector LC×LC, to obtain accurate and precise quantitative results. It is shown that 2DALC is superior to both single detector selective or comprehensive LC×LC and 1D-LC for quantitation of compounds that appear as severely overlapped peaks in the (1)D chromatogram - this is especially true in the case of untargeted analyses. We also anticipate that 2DALC will provide superior quantitation in targeted analyses in which unknown interfering compounds overlap with the targeted compound(s). When peaks are significantly overlapped in the first dimension, 2DALC can decrease the error of quantitation (i.e., improve the accuracy by up to 14-fold compared to 1D-LC and up to 3.8-fold compared to LC×LC with a single multivariate detector). The degree of improvement in performance varies depending upon the degree of peak overlap in each dimension and the selectivities of the spectra with respect to one another and the background, as well as the extent of analyte dilution prior to the (2)D column.}, }
@article {pmid25618254, year = {2015}, author = {Dorst, J and Dupuis, L and Petri, S and Kollewe, K and Abdulla, S and Wolf, J and Weber, M and Czell, D and Burkhardt, C and Hanisch, F and Vielhaber, S and Meyer, T and Frisch, G and Kettemann, D and Grehl, T and Schrank, B and Ludolph, AC}, title = {Percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis: a prospective observational study.}, journal = {Journal of neurology}, volume = {262}, number = {4}, pages = {849-858}, pmid = {25618254}, issn = {1432-1459}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*therapy ; Enteral Nutrition/adverse effects/*methods ; Female ; Gastroscopy/adverse effects/*methods ; Gastrostomy/adverse effects/*methods ; Humans ; Male ; Middle Aged ; Prospective Studies ; Treatment Outcome ; }, abstract = {Weight loss is increasingly considered as a negative prognostic marker in amyotrophic lateral sclerosis (ALS). Despite the critical importance of nutritional issues in ALS, and the common use of percutaneous endoscopic gastrostomy (PEG), there is a general lack of knowledge on peri-interventional treatment, optimal parameters of enteral nutrition, its timing during disease progression and its potential disease-modifying effects in ALS patients. Here we report the results of a multi-center prospective study of percutaneous endoscopic gastrostomy (PEG) in ALS. In this observational clinical trial, 89 ALS patients were prospectively enrolled over a 3-year period and longitudinal data were collected over 18 months. PEG was a safe procedure even in patients with low forced vital capacity, and prophylactic single-shot antibiosis as well as slow increase of caloric nutrition via PEG was beneficial to avoid complications. No signs of refeeding syndrome were observed. High-caloric intake (>1,500 kcal/d) via PEG in patients that lived at least 12 months after PEG insertion was correlated with prolonged survival. Additional oral food intake was not associated with a worse prognosis. Our results suggest that peri-interventional PEG management should include prophylactic single-shot antibiosis, slow increase of caloric intake, and long-term high-caloric nutrition. Although our results indicate that PEG might be more beneficial when applied early, we believe that it can also be performed safely in patients with far advanced disease. Because of its explorative and observational character, most of our results have to be confirmed by a randomized interventional trial.}, }
@article {pmid25613506, year = {2015}, author = {Volonte, C and Apolloni, S and Parisi, C}, title = {MicroRNAs: newcomers into the ALS picture.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {14}, number = {2}, pages = {194-207}, doi = {10.2174/1871527314666150116125506}, pmid = {25613506}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*genetics ; Genetic Predisposition to Disease/*genetics ; Humans ; MicroRNAs/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) causes neurodegeneration of both upper and lower motor neurons and progressive muscle impairment, atrophy and death within approximately five years from diagnosis. The aetiology is still not clear but evidence obtained in animal models of the disease indicates a non-cell-autonomous mechanism with the active contribution of non-neuronal cells such as microglia, astrocytes, muscle and T cells, which differently participate to the diverse phases of the disease. Clinically indistinguishable forms of ALS occur as sporadic disease in the absence of known mutation, or can be initiated by genetic mutations. About two-third of familial cases are triggered by mutations of four genes that are chromosome 9 open reading frame 72 (C9ORF72), Cu/Zn superoxide dismutase (SOD1), fused in sarcoma/translocated in liposarcoma (FUS/TLS), TAR-DNA binding protein 43 (TDP43). There is at present no succesfull treatment against ALS and the identification of novel signalling pathways, molecular mechanisms and cellular mediators are still a major task in the search for effective therapies. MiRNAs are conserved, endogenous, non-coding RNAs that post-transcriptionally regulate protein expression. Produced as long primary transcripts, they are exported to the cytoplasm and further modified to obtain the mature miRNAs, with each step of their biogenesis being a potential step of regulation. There are more than 1000 different known human miRNA sequences, and more than 20-30% of all human protein-coding genes are likely controlled by miRNAs. This earns to miRNAs the definition of fine regulators of genetic networks. The discovery of the involvement of ALS mutated proteins TDP43 and FUS/TLS in miRNAs biogenesis strongly suggests a role of miRNA dysregulation also in ALS and many efforts are thus directed toward understanding the role of these small RNA molecules in the pathogenesis of ALS. The overall objective of this review is thus to highlight the emerging involvement of miRNAs in ALS. After a brief description of miRNA biogenesis and function, we discuss the effects of miRNA dysregulation in cellular and molecular pathways that lead to ALS neuroinflammation and neurodegeneration. In the last part, we focus on the mechanistic insights of miRNAs that might have implications for the development of novel neuroprotective agents against ALS, and on recent attempts to establish new molecular miRNA-based therapies. Paving the way for more comparative studies on neuroinflammatory and neurodegenerative mechanisms, this strategy indeed promises a broader impact on ALS.}, }
@article {pmid25609923, year = {2015}, author = {Yuan, CX and Zhou, ZW and Yang, YX and He, ZX and Zhang, X and Wang, D and Yang, T and Wang, NJ and Zhao, RJ and Zhou, SF}, title = {Inhibition of mitotic Aurora kinase A by alisertib induces apoptosis and autophagy of human gastric cancer AGS and NCI-N78 cells.}, journal = {Drug design, development and therapy}, volume = {9}, number = {}, pages = {487-508}, pmid = {25609923}, issn = {1177-8881}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Aurora Kinase A/*antagonists &amp; inhibitors/metabolism ; Autophagy/*drug effects ; Azepines/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; G2 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Mitosis/*drug effects ; Phosphatidylinositol 3-Kinase/metabolism ; Phosphorylation ; Protein Kinase Inhibitors/*pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Pyrimidines/*pharmacology ; Signal Transduction/drug effects ; Stomach Neoplasms/*enzymology/pathology ; TOR Serine-Threonine Kinases/metabolism ; Time Factors ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Gastric cancer is one of the most common cancers and responds poorly to current chemotherapy. Alisertib (ALS) is a second-generation, orally bioavailable, highly selective small-molecule inhibitor of the serine/threonine protein kinase Aurora kinase A (AURKA). ALS has been shown to have potent anticancer effects in preclinical and clinical studies, but its role in gastric cancer treatment is unclear. This study aimed to investigate the cancer cell-killing effect of ALS on gastric cancer cell lines AGS and NCI-N78, with a focus on cell proliferation, cell-cycle distribution, apoptosis, and autophagy and the mechanism of action. The results showed that ALS exhibited potent growth-inhibitory, proapoptotic, and proautophagic effects on AGS and NCI-N78 cells. ALS concentration-dependently inhibited cell proliferation and induced cell-cycle arrest at G2/M phase in both cell lines, with a downregulation of cyclin-dependent kinase 1 and cyclin B1 expression but upregulation of p21 Waf1/Cip1, p27 Kip1, and p53 expression. ALS induced mitochondria-mediated apoptosis and autophagy in both AGS and NCI-N78 cells. ALS induced the expression of proapoptotic proteins but inhibited the expression of antiapoptotic proteins, with a significant increase in the release of cytochrome c and the activation of caspase 9 and caspase 3 in both cell lines. ALS induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) signaling pathways while activating the 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway as indicated by their altered phosphorylation, contributing to the proautophagic effects of ALS. SB202191 and wortmannin enhanced the autophagy-inducing effect of ALS in AGS and NCI-N78 cells. Notably, ALS treatment significantly decreased the ratio of phosphorylated AURKA over AURKA, which may contribute, at least in part, to the inducing effects of ALS on cell-cycle arrest and autophagy in AGS and NCI-N78 cells. Taken together, these results indicate that ALS exerts a potent inhibitory effect on cell proliferation but inducing effects on cell-cycle arrest, mitochondria-dependent apoptosis, and autophagy with the involvement of PI3K/Akt/mTOR, p38 MAPK, and AURKA-mediated signaling pathways in AGS and NCI-N78 cells.}, }
@article {pmid25609642, year = {2015}, author = {Toma, JS and Shettar, BC and Chipman, PH and Pinto, DM and Borowska, JP and Ichida, JK and Fawcett, JP and Zhang, Y and Eggan, K and Rafuse, VF}, title = {Motoneurons derived from induced pluripotent stem cells develop mature phenotypes typical of endogenous spinal motoneurons.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {35}, number = {3}, pages = {1291-1306}, pmid = {25609642}, issn = {1529-2401}, support = {R00 NS077435/NS/NINDS NIH HHS/United States ; //Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Axons/physiology ; Chick Embryo ; Induced Pluripotent Stem Cells/*cytology ; LIM-Homeodomain Proteins/metabolism ; Mice ; Motor Neurons/*cytology ; Muscle, Skeletal/*cytology/physiology ; Neurogenesis/*physiology ; Neuromuscular Junction/*cytology/physiology ; Phenotype ; Proteomics ; Transcription Factors/metabolism ; }, abstract = {Induced pluripotent cell-derived motoneurons (iPSCMNs) are sought for use in cell replacement therapies and treatment strategies for motoneuron diseases such as amyotrophic lateral sclerosis (ALS). However, much remains unknown about the physiological properties of iPSCMNs and how they compare with endogenous spinal motoneurons or embryonic stem cell-derived motoneurons (ESCMNs). In the present study, we first used a proteomic approach and compared protein expression profiles between iPSCMNs and ESCMNs to show that <4% of the proteins identified were differentially regulated. Like ESCs, we found that mouse iPSCs treated with retinoic acid and a smoothened agonist differentiated into motoneurons expressing the LIM homeodomain protein Lhx3. When transplanted into the neural tube of developing chick embryos, iPSCMNs selectively targeted muscles normally innervated by Lhx3 motoneurons. In vitro studies showed that iPSCMNs form anatomically mature and functional neuromuscular junctions (NMJs) when cocultured with chick myofibers for several weeks. Electrophysiologically, iPSCMNs developed passive membrane and firing characteristic typical of postnatal motoneurons after several weeks in culture. Finally, iPSCMNs grafted into transected mouse tibial nerve projected axons to denervated gastrocnemius muscle fibers, where they formed functional NMJs, restored contractile force. and attenuated denervation atrophy. Together, iPSCMNs possess many of the same cellular and physiological characteristics as ESCMNs and endogenous spinal motoneurons. These results further justify using iPSCMNs as a source of motoneurons for cell replacement therapies and to study motoneuron diseases such as ALS.}, }
@article {pmid25602021, year = {2015}, author = {Xiao, Y and Ma, C and Yi, J and Wu, S and Luo, G and Xu, X and Lin, PH and Sun, J and Zhou, J}, title = {Suppressed autophagy flux in skeletal muscle of an amyotrophic lateral sclerosis mouse model during disease progression.}, journal = {Physiological reports}, volume = {3}, number = {1}, pages = {}, pmid = {25602021}, issn = {2051-817X}, support = {R01 AR057404/AR/NIAMS NIH HHS/United States ; R03 DK089010/DK/NIDDK NIH HHS/United States ; }, abstract = {Accumulation of abnormal protein inclusions is implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Autophagy, an intracellular process targeting misfolded proteins and damaged organelles for lysosomal degradation, plays crucial roles in survival and diseased conditions. Efforts were made to understand the role of autophagy in motor neuron degeneration and to target autophagy in motor neuron for ALS treatment. However, results were quite contradictory. Possible autophagy defects in other cell types may also complicate the results. Here, we examined autophagy activity in skeletal muscle of an ALS mouse model G93A. Through overexpression of a fluorescent protein LC3-RFP, we found a basal increase in autophagosome formation in G93A muscle during disease progression when the mice were on a regular diet. As expected, an autophagy induction procedure (starvation plus colchicine) enhanced autophagy flux in skeletal muscle of normal mice. However, in response to the same autophagy induction procedure, G93A muscle showed significant reduction in the autophagy flux. Immunoblot analysis revealed that increased cleaved caspase-3 associated with apoptosis was linked to the cleavage of several key proteins involved in autophagy, including Beclin-1, which is an essential molecule connecting autophagy and apoptosis pathways. Taking together, we provide the evidence that the cytoprotective autophagy pathway is suppressed in G93A skeletal muscle and this suppression may link to the enhanced apoptosis during ALS progression. The abnormal autophagy activity in skeletal muscle likely contributes muscle degeneration and disease progression in ALS.}, }
@article {pmid25601606, year = {2015}, author = {Nabavi, SF and Daglia, M and D'Antona, G and Sobarzo-Sánchez, E and Talas, ZS and Nabavi, SM}, title = {Natural compounds used as therapies targeting to amyotrophic lateral sclerosis.}, journal = {Current pharmaceutical biotechnology}, volume = {16}, number = {3}, pages = {211-218}, doi = {10.2174/1389201016666150118132224}, pmid = {25601606}, issn = {1873-4316}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/*metabolism ; Animals ; Biological Products/*administration &amp; dosage ; Humans ; Neuroprotective Agents/administration &amp; dosage ; Oxidative Stress/drug effects/physiology ; Plant Extracts/*administration &amp; dosage ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease that occurs throughout the world with no racial, ethnic or socioeconomic boundaries. Despite its high morbidity and mortality, there are limited medications available for ALS that may increase survival in patients with amyotrophic lateral sclerosis by approximately 2-3 months. Inasmuch as negative effects of riluzole on muscle atrophy and wasting, weakness, muscle spasticity, dysarthria, dysphagia, and overall patient quality of life and its different adverse effects, much attention has been paid to natural products and herbal medicines. Overall scientific reports indicate that natural products have beneficial effects on patients with ALS low side effects and multiple targets. In the present paper, we review the scientific reports on beneficial role of natural polyphenolic compounds in treatment of ALS.}, }
@article {pmid25600110, year = {2015}, author = {Bethea, CL and Reddy, AP}, title = {Ovarian steroids regulate gene expression related to DNA repair and neurodegenerative diseases in serotonin neurons of macaques.}, journal = {Molecular psychiatry}, volume = {20}, number = {12}, pages = {1565-1578}, pmid = {25600110}, issn = {1476-5578}, support = {P51 OD011092/OD/NIH HHS/United States ; R01 MH062677/MH/NIMH NIH HHS/United States ; R24 OD011895/OD/NIH HHS/United States ; U54 HD 18185/HD/NICHD NIH HHS/United States ; MH62677/MH/NIMH NIH HHS/United States ; P30 HD018185/HD/NICHD NIH HHS/United States ; P51 OD 011092/OD/NIH HHS/United States ; U54 HD018185/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; DNA Repair/*genetics ; Estradiol/*physiology ; Female ; *Gene Expression Regulation ; Macaca mulatta ; Neurodegenerative Diseases/*genetics ; Ovariectomy ; Progesterone/*physiology ; Serotonergic Neurons/*metabolism ; }, abstract = {Depression often accompanies the perimenopausal transition and it often precedes overt symptomology in common neurodegenerative diseases (NDDs, such as Alzheimer's, Parkinson's, Huntington, amyotrophic lateral sclerosis). Serotonin dysfunction is frequently found in the different etiologies of depression. We have shown that ovariectomized (Ovx) monkeys treated with estradiol (E) for 28 days supplemented with placebo or progesterone (P) on days 14-28 had reduced DNA fragmentation in serotonin neurons of the dorsal raphe nucleus, and long-term Ovx monkeys had fewer serotonin neurons than intact controls. We questioned the effect of E alone or E+P (estradiol supplemented with progesterone) on gene expression related to DNA repair, protein folding (chaperones), the ubiquitin-proteosome, axon transport and NDD-specific genes in serotonin neurons. Ovx macaques were treated with placebo, E or E+P (n=3 per group) for 1 month. Serotonin neurons were laser captured and subjected to microarray analysis and quantitative real-time PCR (qRT-PCR). Increases were confirmed with qRT-PCR in five genes that code for proteins involved in repair of strand breaks and nucleotide excision. NBN1, PCNA (proliferating nuclear antigen), GADD45A (DNA damage-inducible), RAD23A (DNA damage recognition) and GTF2H5 (gene transcription factor 2H5) significantly increased with E or E+P treatment (all analysis of variance (ANOVA), P<0.01). Chaperone genes HSP70 (heat-shock protein 70), HSP60 and HSP27 significantly increased with E or E+P treatment (all ANOVA, P<0.05). HSP90 showed a similar trend. Ubiquinase coding genes UBEA5, UBE2D3 and UBE3A (Parkin) increased with E or E+P (all ANOVA, P<0.003). Transport-related genes coding kinesin, dynein and dynactin increased with E or E+P treatment (all ANOVA, P<0.03). SCNA (α-synuclein) and ADAM10 (α-secretase) increased (both ANOVA, P<0.02) but PSEN1 (presenilin1) decreased (ANOVA, P<0.02) with treatment. APP decreased 10-fold with E or E+P administration. Newman-Keuls post hoc comparisons indicated variation in the response to E alone versus E+P across the different genes. In summary, E or E+P increased gene expression for DNA repair mechanisms in serotonin neurons, thereby rendering them less vulnerable to stress-induced DNA fragmentation. In addition, E or E+P regulated four genes encoding proteins that are often misfolded or malfunctioning in neuronal populations subserving overt NDD symptomology. The expression and regulation of these genes in serotonergic neurons invites speculation that they may mediate an underlying disease process in NDDs, which in turn may be ameliorated or delayed with timely hormone therapy in women.}, }
@article {pmid25595151, year = {2015}, author = {Lauria, G and Dalla Bella, E and Antonini, G and Borghero, G and Capasso, M and Caponnetto, C and Chiò, A and Corbo, M and Eleopra, R and Fazio, R and Filosto, M and Giannini, F and Granieri, E and La Bella, V and Logroscino, G and Mandrioli, J and Mazzini, L and Monsurrò, MR and Mora, G and Pietrini, V and Quatrale, R and Rizzi, R and Salvi, F and Siciliano, G and Sorarù, G and Volanti, P and Tramacere, I and Filippini, G and , }, title = {Erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomised, double blind, placebo controlled, phase III study.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {86}, number = {8}, pages = {879-886}, pmid = {25595151}, issn = {1468-330X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Double-Blind Method ; Epoetin Alfa ; Erythropoietin/adverse effects/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Recombinant Proteins/adverse effects/therapeutic use ; Treatment Outcome ; }, abstract = {OBJECTIVE: To assess the efficacy of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Patients with probable laboratory-supported, probable or definite ALS were enrolled by 25 Italian centres and randomly assigned (1:1) to receive intravenous rhEPO 40,000&#x2005;IU or placebo fortnightly as add-on treatment to riluzole 100&#x2005;mg daily for 12&#x2005;months. The primary composite outcome was survival, tracheotomy or >23&#x2005;h non-invasive ventilation (NIV). Secondary outcomes were ALSFRS-R, slow vital capacity (sVC) and quality of life (ALSAQ-40) decline. Tolerability was evaluated analysing adverse events (AEs) causing withdrawal. The randomisation sequence was computer-generated by blocks, stratified by centre, disease severity (ALSFRS-R cut-off score of 33) and onset (spinal or bulbar). The main outcome analysis was performed in all randomised patients and by intention-to-treat for the entire population and patients stratified by severity and onset. The study is registered, EudraCT 2009-016066-91.<br><br>RESULTS: We randomly assigned 208 patients, of whom 5 (1 rhEPO and 4 placebo) withdrew consent and 3 (placebo) became ineligible (retinal thrombosis, respiratory insufficiency, SOD1 mutation) before receiving treatment; 103 receiving rhEPO and 97 placebo were eligible for analysis. At 12&#x2005;months, the annualised rate of death (rhEPO 0.11, 95% CI 0.06 to 0.20; placebo: 0.08, CI 0.04 to 0.17), tracheotomy or >23&#x2005;h NIV (rhEPO 0.16, CI 0.10 to 0.27; placebo 0.18, CI 0.11 to 0.30) did not differ between groups, also after stratification by onset and ALSFRS-R at baseline. Withdrawal due to AE was 16.5% in rhEPO and 8.3% in placebo. No differences were found for secondary outcomes.<br><br>CONCLUSIONS: RhEPO 40,000&#x2005;IU fortnightly did not change the course of ALS.}, }
@article {pmid25587161, year = {2015}, author = {Fregonezi, G and Azevedo, IG and Resqueti, VR and De Andrade, AD and Gualdi, LP and Aliverti, A and Dourado-Junior, ME and Parreira, VF}, title = {Muscle impairment in neuromuscular disease using an expiratory/inspiratory pressure ratio.}, journal = {Respiratory care}, volume = {60}, number = {4}, pages = {533-539}, doi = {10.4187/respcare.03367}, pmid = {25587161}, issn = {1943-3654}, mesh = {Adult ; Aged ; Aged, 80 and over ; Anthropometry ; Exhalation/*physiology ; Female ; Humans ; Inhalation/*physiology ; Male ; Middle Aged ; Muscle Strength/physiology ; Muscle Weakness/physiopathology ; Neuromuscular Diseases/complications/*physiopathology ; Pressure ; Respiratory Function Tests ; Respiratory Insufficiency/etiology/*physiopathology ; Respiratory Muscles/*physiopathology ; Young Adult ; }, abstract = {BACKGROUND: Neuromuscular diseases (NMDs) lead to different weakness patterns, and most patients with NMDs develop respiratory failure. Inspiratory and expiratory muscle strength can be measured by maximum static inspiratory pressure (PImax) and maximum static expiratory pressure (PEmax), and the relationship between them has not been well described in healthy subjects and subjects with NMDs. Our aim was to assess expiratory/inspiratory muscle strength in NMDs and healthy subjects and calculate PEmax/PImax ratio for these groups.<br><br>METHODS: Seventy (35 males) subjects with NMDs (amyotrophic lateral sclerosis, myasthenia gravis, and myotonic dystrophy), and 93 (47 males) healthy individuals 20-80 y of age were evaluated for anthropometry, pulmonary function, PImax, and PEmax, respectively.<br><br>RESULTS: Healthy individuals showed greater values for PImax and PEmax when compared with subjects with NMDs. PEmax/PImax ratio for healthy subjects was 1.31 &#xb1; 0.26, and PEmax%/PImax% was 1.04 &#xb1; 0.05; for subjects with NMDs, PEmax/PImax ratio was 1.45 &#xb1; 0.65, and PEmax%/PImax% ratio was 1.42 &#xb1; 0.67. We found that PEmax%/PImax% for myotonic dystrophy was 0.93 &#xb1; 0.24, for myasthenia gravis 1.94 &#xb1; 0.6, and for amyotrophic lateral sclerosis 1.33 &#xb1; 0.62 when we analyzed them separately. All healthy individuals showed higher PEmax compared with PImax. For subjects with NMDs, the impairment of PEmax and PImax is different among the 3 pathologies studied (P < .001).<br><br>CONCLUSIONS: Healthy individuals and subjects with NMDs showed higher PEmax in comparison to PImax regarding the PEmax/PImax ratio. Based on the ratio, it is possible to state that NMDs show different patterns of respiratory muscle strength loss. PEmax/PImax ratio is a useful parameter to assess the impairment of respiratory muscles in a patient and to customize rehabilitation and treatment.}, }
@article {pmid25581512, year = {2015}, author = {Wei, Q and Chen, X and Zheng, Z and Guo, X and Huang, R and Cao, B and Zeng, Y and Shang, H}, title = {The predictors of survival in Chinese amyotrophic lateral sclerosis patients.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {16}, number = {3-4}, pages = {237-244}, doi = {10.3109/21678421.2014.993650}, pmid = {25581512}, issn = {2167-9223}, mesh = {Adult ; Age of Onset ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/diagnosis/*epidemiology/*mortality ; China/epidemiology ; Cohort Studies ; Disease Progression ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Predictive Value of Tests ; Probability ; Proportional Hazards Models ; Time Factors ; Young Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease, so it is important to explore the survival factors for ALS. Our aim was to evaluate the predictors of survival in Chinese ALS patients. A total of 1049 sporadic ALS patients were enrolled. Kaplan-Meier curves were used to compare survival time. Cox proportional hazards function and the hazard ratio were used to identify adjusted prognostic predictors. Results showed that the mean age of onset was 52.6 ± 12.0 years. During follow-up, 155 patients (14.8%) were lost and 378 patients were deceased. Median survival was 33 months for the deceased patients. In the adjusted Cox proportional hazard model, age of onset, diagnosis delay, rate of disease progression, and non-invasive positive pressure ventilation (NIPPV) treatment had an effect on survival in ALS. In conclusion, our study provides information on survival factors for Chinese ALS patients. Although the onset age of Chinese ALS patients is earlier than that of Caucasian patients, survival factors, including the age of onset, diagnostic delay, rate of disease progression, and NIPPV treatment, are similar.}, }
@article {pmid25580472, year = {2014}, author = {Ko, KD and El-Ghazawi, T and Kim, D and Morizono, H and , }, title = {Predicting the severity of motor neuron disease progression using electronic health record data with a cloud computing Big Data approach.}, journal = {IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology proceedings. IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology}, volume = {2014}, number = {}, pages = {}, pmid = {25580472}, support = {UL1 TR000075/TR/NCATS NIH HHS/United States ; }, abstract = {Motor neuron diseases (MNDs) are a class of progressive neurological diseases that damage the motor neurons. An accurate diagnosis is important for the treatment of patients with MNDs because there is no standard cure for the MNDs. However, the rates of false positive and false negative diagnoses are still very high in this class of diseases. In the case of Amyotrophic Lateral Sclerosis (ALS), current estimates indicate 10% of diagnoses are false-positives, while 44% appear to be false negatives. In this study, we developed a new methodology to profile specific medical information from patient medical records for predicting the progression of motor neuron diseases. We implemented a system using Hbase and the Random forest classifier of Apache Mahout to profile medical records provided by the Pooled Resource Open-Access ALS Clinical Trials Database (PRO-ACT) site, and we achieved 66% accuracy in the prediction of ALS progress.}, }
@article {pmid25577170, year = {2016}, author = {Lee, SH and Choi, NY and Yu, HJ and Park, J and Choi, H and Lee, KY and Huh, YM and Lee, YJ and Koh, SH}, title = {Atorvastatin Protects NSC-34 Motor Neurons Against Oxidative Stress by Activating PI3K, ERK and Free Radical Scavenging.}, journal = {Molecular neurobiology}, volume = {53}, number = {1}, pages = {695-705}, pmid = {25577170}, issn = {1559-1182}, mesh = {Animals ; Antioxidants/pharmacology ; Atorvastatin/*pharmacology ; Cell Line ; Cell Survival/drug effects/physiology ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects/physiology ; Free Radical Scavengers/*metabolism ; Free Radicals/antagonists &amp; inhibitors/metabolism ; MAP Kinase Signaling System/drug effects/*physiology ; Mice ; Motor Neurons/drug effects/*metabolism ; Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects/*physiology ; Phosphatidylinositol 3-Kinases/*metabolism ; }, abstract = {Although statins, or hydroxymethylglutaryl coenzyme A (HMG-Co A) reductase inhibitors, are generally used to decrease levels of circulating cholesterol, they have also been reported to have neuroprotective effects through various mechanisms. However, recent results have indicated that they may be harmful in patients with amyotrophic lateral sclerosis (ALS). In this study, we investigate whether atorvastatin protects motor neuron-like cells (NSC-34D) from oxidative stress. To evaluate the effects of atorvastatin or hydrogen peroxide or both on NSC-34D cells, the cells were treated with various combinations of these agents. To evaluate the viability of the cells, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and trypan blue staining were performed. Levels of free radicals and intracellular signaling proteins were evaluated using the fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and Western blotting, respectively. Atorvastatin protected NSC-34D cells against oxidative stress in a concentration-dependent manner. This neuroprotective effect of atorvastatin was blocked by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor and by FR180204, a selective extracellular signal-related kinase (ERK) inhibitor. Atorvastatin treatment increased the expression levels of p85αPI3K, phosphorylated Akt, phosphorylated glycogen synthase kinase-3β, phosphorylated ERK, and Bcl-2, which are proteins related to survival. Furthermore, atorvastatin decreased the levels of cytosolic cytochrome C, Bax, cleaved caspase-9, and cleaved caspase-3, which are associated with death in oxidative stress-injured NSC-34D cells. We conclude that atorvastatin has a protective effect against oxidative stress in motor neurons by activating the PI3K and ERK pathways as well as by scavenging free radicals. These findings indicate that statins could help protect motor neurons from oxidative stress.}, }
@article {pmid25574882, year = {2015}, author = {Lisle, S and Tennison, M}, title = {Amyotrophic lateral sclerosis: the role of exercise.}, journal = {Current sports medicine reports}, volume = {14}, number = {1}, pages = {45-46}, doi = {10.1249/JSR.0000000000000122}, pmid = {25574882}, issn = {1537-8918}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/*therapy ; *Exercise/physiology ; Exercise Therapy/*methods ; Humans ; Resistance Training/*methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic progressive neurodegenerative disease affecting both the upper and lower motor neurons. Given the deterioration of skeletal muscle function, historically there has been concern regarding exercise and its affect on ALS. This article reviews and explains current research, helping patients, caregivers, and providers be equipped better to make decisions regarding the treatment of ALS with exercise.}, }
@article {pmid25574474, year = {2014}, author = {Jablonski, MR and Markandaiah, SS and Jacob, D and Meng, NJ and Li, K and Gennaro, V and Lepore, AC and Trotti, D and Pasinelli, P}, title = {Inhibiting drug efflux transporters improves efficacy of ALS therapeutics.}, journal = {Annals of clinical and translational neurology}, volume = {1}, number = {12}, pages = {996-1005}, pmid = {25574474}, issn = {2328-9503}, support = {F31 NS080539/NS/NINDS NIH HHS/United States ; R01 NS074886/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVE: Research identified promising therapeutics in cell models of Amyotrophic Lateral Sclerosis (ALS), but there is limited progress translating effective treatments to animal models and patients, and ALS remains a disease with no effective treatment. One explanation stems from an acquired pharmacoresistance driven by the drug efflux transporters P-glycoprotein (P-gp) and breast cancer-resistant protein (BCRP), which we have shown are selectively upregulated at the blood-brain and spinal cord barrier (BBB/BSCB) in ALS mice and patients. Pharmacoresistance is well appreciated in other brain diseases, but overlooked in ALS despite many failures in clinical trials.<br><br>METHODS: Here, we prove that a P-gp/BCRP-driven pharmacoresistance limits the bioavailability of ALS therapeutics using riluzole, the only FDA-approved drug for ALS and a substrate of P-gp and BCRP. ALS mice (SOD1-G93A) were treated with riluzole and elacridar, to block P-gp and BCRP, and monitored for survival as well as behavioral and physiological parameters.<br><br>RESULTS: We show that riluzole, which normally is not effective when given at onset of symptoms, is now effective in the ALS mice when administered in combination with the P-gp/BCRP inhibitor elacridar. Chronic elacridar treatment increases riluzole Central nervous system (CNS) penetration, improves behavioral measures, including muscle function, slowing down disease progression, and significantly extending survival.<br><br>INTERPRETATION: Our approach improves riluzole efficacy with treatment beginning at symptom onset. Riluzole will not provide a cure, but enhancing its efficacy postsymptoms by addressing pharmacoresistance demonstrates a proof-of-principle concept to consider when developing new ALS therapeutic strategies. We highlight a novel improved therapeutic approach for ALS and demonstrate that pharmacoresistance can no longer be ignored in ALS.}, }
@article {pmid25573097, year = {2015}, author = {Moszczynski, AJ and Gohar, M and Volkening, K and Leystra-Lantz, C and Strong, W and Strong, MJ}, title = {Thr175-phosphorylated tau induces pathologic fibril formation via GSK3β-mediated phosphorylation of Thr231 in vitro.}, journal = {Neurobiology of aging}, volume = {36}, number = {3}, pages = {1590-1599}, doi = {10.1016/j.neurobiolaging.2014.12.001}, pmid = {25573097}, issn = {1558-1497}, mesh = {Amino Acid Motifs ; Amyotrophic Lateral Sclerosis/genetics/pathology/therapy ; Cell Death/genetics ; Cells, Cultured ; Computational Biology ; Gene Knockdown Techniques ; Glycogen Synthase Kinase 3/antagonists &amp; inhibitors/*metabolism ; Glycogen Synthase Kinase 3 beta ; HEK293 Cells ; Humans ; Neurofibrils/*pathology ; Phosphorylation ; RNA, Small Interfering/genetics ; Tauopathies/genetics/pathology/therapy ; Threonine/metabolism ; tau Proteins/chemistry/*metabolism ; }, abstract = {We have previously shown that amyotrophic lateral sclerosis with cognitive impairment can be characterized by pathologic inclusions of microtubule-associated protein tau (tau) phosphorylated at Thr(175) (pThr(175)) in association with GSK3β activation. We have now examined whether pThr(175) induces GSK3β activation and whether this leads to pathologic fibril formation through Thr(231) phosphorylation. Seventy-two hours after transfection of Neuro2A cells with pseudophosphorylated green fluorescent protein-tagged 2N4R tau (Thr(175)Asp), phosphorylated kinase glycogen synthase kinase 3 beta (active GSK3β) levels were significantly increased as was pathologic fibril formation and cell death. Treatment with each of 4 GSK3β inhibitors or small hairpin RNA knockdown of GSK3β abolished fibril formation and prevented cell death. Inhibition of Thr(231) phosphorylation (Thr(231)Ala) prevented pathologic tau fibril formation, regardless of Thr(175) state, whereas Thr(231)Asp (pseudophosphorylated at Thr(231)) developed pathologic tau fibrils. Ser(235) mutations did not affect fibril formation, indicating an unprimed mechanism of Thr(231) phosphorylation. These findings suggest a mechanism of tau pathology by which pThr(175) induces GSK3β phosphorylation of Thr(231) leading to fibril formation, indicating a potential therapeutic avenue for amyotrophic lateral sclerosis with cognitive impairment.}, }
@article {pmid25572957, year = {2015}, author = {Rosenfeld, J and Strong, MJ}, title = {Challenges in the Understanding and Treatment of Amyotrophic Lateral Sclerosis/Motor Neuron Disease.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {2}, pages = {317-325}, pmid = {25572957}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/genetics/*therapy ; Animals ; Biomarkers/metabolism ; Humans ; }, abstract = {With the acceleration in our understanding of ALS and the related motor neuron disease has come even greater challenges in reconciling all of the proposed pathogenic mechanisms and how this will translate into impactful treatments. Fundamental issues such as diagnostic definition(s) of the disease spectrum, relevant biomarkers, the impact of multiple novel genetic mutations and the significant effect of symptomatic treatments on disease progression are all areas of active investigation. In this review, we will focus on these key issues and highlight the challenges that confront both clinicians and basic science researchers.}, }
@article {pmid25571962, year = {2015}, author = {Cetin, H and Rath, J and Füzi, J and Reichardt, B and Fülöp, G and Koppi, S and Erdler, M and Ransmayr, G and Weber, J and Neumann, K and Hagmann, M and Löscher, WN and Auff, E and Zimprich, F}, title = {Epidemiology of amyotrophic lateral sclerosis and effect of riluzole on disease course.}, journal = {Neuroepidemiology}, volume = {44}, number = {1}, pages = {6-15}, doi = {10.1159/000369813}, pmid = {25571962}, issn = {1423-0208}, mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/drug therapy/*epidemiology/mortality ; Austria/epidemiology ; Databases, Factual ; Disease Progression ; Female ; Humans ; Incidence ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Prevalence ; Prognosis ; Riluzole/*therapeutic use ; Sex Factors ; Treatment Outcome ; Young Adult ; }, abstract = {OBJECTIVES: To assess the epidemiology of ALS in Austria and to evaluate the long-term effect of riluzole treatment on survival.<br><br>METHODS: Hospital discharge and riluzole prescription databases were used to identify ALS cases from January 2008 to June 2012. Using the capture-recapture method we evaluated the incidence and prevalence of ALS and patients' survival in dependence of age, gender and riluzole treatment.<br><br>RESULTS: The corrected incidence and prevalence of ALS were 3.13/100,000 person-years (95% CI, 2.77 to 3.50) and 9.14/100,000 persons (95% CI, 8.53 to 9.79), respectively. Median survival from diagnosis was 676 days (95% CI, 591 to 761). A younger age at diagnosis was associated with a longer survival. Gender did not appear to affect survival time. Riluzole therapy was associated with a survival advantage only for the initial treatment period. The adjusted hazard ratio of mortality for using riluzole increased continually over time resulting in an apparent reversal of its beneficial effect after 6 months of therapy.<br><br>CONCLUSIONS: We report incidence and prevalence estimates that are on the upper end of the wide range discussed in literature. Riluzole seems to exert a beneficial effect only in the first 6 months of therapy.}, }
@article {pmid25565966, year = {2014}, author = {Martin, LJ and Fancelli, D and Wong, M and Niedzwiecki, M and Ballarini, M and Plyte, S and Chang, Q}, title = {GNX-4728, a novel small molecule drug inhibitor of mitochondrial permeability transition, is therapeutic in a mouse model of amyotrophic lateral sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {433}, pmid = {25565966}, issn = {1662-5102}, support = {R01 NS034100/NS/NINDS NIH HHS/United States ; R01 NS065895/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder in humans characterized by progressive degeneration of skeletal muscle and motor neurons in spinal cord, brainstem, and cerebral cortex causing skeletal muscle paralysis, respiratory insufficiency, and death. There are no cures or effective treatments for ALS. ALS can be inherited, but most cases are not associated with a family history of the disease. Mitochondria have been implicated in the pathogenesis but definitive proof of causal mechanisms is lacking. Identification of new clinically translatable disease mechanism-based molecular targets and small molecule drug candidates are needed for ALS patients. We tested the hypothesis in an animal model that drug modulation of the mitochondrial permeability transition pore (mPTP) is therapeutic in ALS. A prospective randomized placebo-controlled drug trial was done in a transgenic (tg) mouse model of ALS. We explored GNX-4728 as a therapeutic drug. GNX-4728 inhibits mPTP opening as evidenced by increased mitochondrial calcium retention capacity (CRC) both in vitro and in vivo. Chronic systemic treatment of G37R-human mutant superoxide dismutase-1 (hSOD1) tg mice with GNX-4728 resulted in major therapeutic benefits. GNX-4728 slowed disease progression and significantly improved motor function. The survival of ALS mice was increased significantly by GNX-4728 treatment as evidence by a nearly 2-fold extension of lifespan (360 days-750 days). GNX-4728 protected against motor neuron degeneration and mitochondrial degeneration, attenuated spinal cord inflammation, and preserved neuromuscular junction (NMJ) innervation in the diaphragm in ALS mice. This work demonstrates that a mPTP-acting drug has major disease-modifying efficacy in a preclinical mouse model of ALS and establishes mitochondrial calcium retention, and indirectly the mPTP, as targets for ALS drug development.}, }
@article {pmid25557448, year = {2015}, author = {Hansen, RL and Jessen, PT}, title = {[Chronic exertional compartment syndrome in the lower leg].}, journal = {Ugeskrift for laeger}, volume = {177}, number = {2}, pages = {}, pmid = {25557448}, issn = {1603-6824}, mesh = {Athletes ; Botulinum Toxins, Type A/therapeutic use ; Chronic Disease ; *Compartment Syndromes/diagnosis/drug therapy/physiopathology/surgery ; Diagnosis, Differential ; Humans ; *Leg/blood supply/physiopathology ; Needles ; Neurotoxins/therapeutic use ; Physical Exertion ; Pressure ; Running ; Young Adult ; }, abstract = {Chronic exertional compartment syndrome (CECS) commonly occurs in young adult runners. The mechanism of pain is unknown. CECS is a clinical diagnosis and is confirmed by intracompartmental pressure testing (IPT). The evidence-based guidance for IPT is sparse. Instead of Pedowitz et al's criteria we recommend one minute after pain triggered exercise IPT ≥ 36 mmHg as diagnostic value. At the moment fasciotomy is the treatment of choice for athletes who would like to maintain the same level of activity, but injection with botulinum toxin type A could be a new useful alternative.}, }
@article {pmid25549972, year = {2015}, author = {Vlam, L and Piepers, S and Sutedja, NA and Jacobs, BC and Tio-Gillen, AP and Stam, M and Franssen, H and Veldink, JH and Cats, EA and Notermans, NC and Bloem, AC and Wadman, RI and van der Pol, WL and van den Berg, LH}, title = {Association of IgM monoclonal gammopathy with progressive muscular atrophy and multifocal motor neuropathy: a case-control study.}, journal = {Journal of neurology}, volume = {262}, number = {3}, pages = {666-673}, pmid = {25549972}, issn = {1432-1459}, mesh = {Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; Databases, Bibliographic/statistics &amp; numerical data ; Female ; Humans ; Immunoglobulin M/*blood ; Male ; Middle Aged ; Muscular Atrophy, Spinal/*complications/*immunology ; Paraproteinemias/*complications ; Young Adult ; }, abstract = {Monoclonal gammopathy in patients with amyotrophic lateral sclerosis (ALS) and related disorders has been reported in small studies but the validity of the reported associations remains uncertain. Presence of monoclonal gammopathy may indicate specific pathogenic pathways and may facilitate the development of novel treatment strategies. The objective of this large case-control study was to determine the prevalence of monoclonal gammopathy in motor neuron diseases (MND) and multifocal motor neuropathy (MMN). Monoclonal gammopathy was determined by immunoelectrophoresis and immunofixation in serum from 445 patients with ALS, 158 patients with progressive muscular atrophy (PMA), 60 patients with primary lateral sclerosis (PLS), 88 patients with MMN and in 430 matched healthy controls. Anti-ganglioside antibody titers were determined in sera from patients with MMN and PMA, and in ALS and PLS patients with monoclonal gammopathy. Logistic regression analysis was used to investigate associations of monoclonal gammopathy with motor neuron diseases and clinical characteristics. Neither ALS nor PLS was associated with monoclonal gammopathy. IgM monoclonal gammopathy was more frequent in patients with PMA (8 %) (OR = 4.2; p = 0.001) and MMN (7 %) (OR = 5.8; p = 0.002) than in controls (2 %). High titers of anti-GM1 IgM antibodies were present in 43 % of MMN patients and 7 % of PMA patients. Patients with PMA and IgM monoclonal gammopathy or anti-GM1 antibodies had a higher age at onset, more often weakness of upper legs and more severe outcome than patients with MMN. PMA and MMN, but not ALS and PLS, are significantly associated with IgM monoclonal gammopathy and anti-GM1 antibodies. These results may indicate that a subset of patients presenting with PMA share pathogenic mechanisms with MMN.}, }
@article {pmid25548669, year = {2014}, author = {Deflorio, C and Onesti, E and Lauro, C and Tartaglia, G and Giovannelli, A and Limatola, C and Inghilleri, M and Grassi, F}, title = {Partial block by riluzole of muscle sodium channels in myotubes from amyotrophic lateral sclerosis patients.}, journal = {Neurology research international}, volume = {2014}, number = {}, pages = {946073}, pmid = {25548669}, issn = {2090-1852}, abstract = {Denervated muscles undergo fibrillations due to spontaneous activation of voltage-gated sodium (Na(+)) channels generating action potentials. Fibrillations also occur in patients with amyotrophic lateral sclerosis (ALS). Riluzole, the only approved drug for ALS treatment, blocks voltage-gated Na(+) channels, but its effects on muscle Na(+) channels and fibrillations are yet poorly characterized. Using patch-clamp technique, we studied riluzole effect on Na(+) channels in cultured myotubes from ALS patients. Needle electromyography was used to study fibrillation potentials (Fibs) in ALS patients during riluzole treatment and after one week of suspension. Patients were clinically characterized in all recording sessions. In myotubes, riluzole (1 μM, a therapeutic concentration) reduced Na(+) current by 20%. The rate of rise and amplitude of spikes evoked by depolarizing stimuli were also reduced. Fibs were detected in all patients tested during riluzole treatment and riluzole washout had no univocal effect. Our study indicates that, in human myotubes, riluzole partially blocks Na(+) currents and affects action potentials but does not prevent firing. In line with this in vitro finding, muscle Fibs in ALS patients appear to be largely unaffected by riluzole.}, }
@article {pmid25526593, year = {2014}, author = {Vieira, FG and LaDow, E and Moreno, A and Kidd, JD and Levine, B and Thompson, K and Gill, A and Finkbeiner, S and Perrin, S}, title = {Dexpramipexole is ineffective in two models of ALS related neurodegeneration.}, journal = {PloS one}, volume = {9}, number = {12}, pages = {e91608}, pmid = {25526593}, issn = {1932-6203}, support = {R01 NS039074/NS/NINDS NIH HHS/United States ; R01 NS083390/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Benzothiazoles/pharmacology/*therapeutic use ; Cells, Cultured ; DNA-Binding Proteins/genetics/metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Neurons/*drug effects/metabolism ; Neuroprotective Agents/pharmacology/*therapeutic use ; Pramipexole ; Rats ; Rats, Long-Evans ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Treatment options for people living with amyotrophic lateral sclerosis (ALS) are limited and ineffective. Recently, dexpramipexole (RPPX) was advanced into human ALS clinical trials. In the current studies, we investigated RPPX in two parallel screening systems: 1) appropriately powered, sibling-matched, gender-balanced survival efficacy screening in high-copy B6-SJL-SOD1G93A/Gur1 mice, and 2) high-content neuronal survival screening in primary rat cortical neurons transfected with wild-type human TDP43 or mutant human TDP43. In both cases, we exposed the test systems to RPPX levels approximating those achieved in human Phase II clinical investigations. In SOD1G93A mice, no effect was observed on neuromotor disease progression or survival. In primary cortical neurons transfected with either mutant or wild-type human TDP43, a marginally significant improvement in a single indicator of neuronal survival was observed, and only at the 10 µM RPPX treatment. These systems reflect both mutant SOD1- and TDP43-mediated forms of neurodegeneration. The systems also reflect both complex non-cell autonomous and neuronal cell autonomous disease mechanisms. The results of these experiments, taken in context with results produced by other molecules tested in both screening systems, do not argue positively for further study of RPPX in ALS.}, }
@article {pmid25524221, year = {2015}, author = {Tripodo, G and Chlapanidas, T and Perteghella, S and Vigani, B and Mandracchia, D and Trapani, A and Galuzzi, M and Tosca, MC and Antonioli, B and Gaetani, P and Marazzi, M and Torre, ML}, title = {Mesenchymal stromal cells loading curcumin-INVITE-micelles: a drug delivery system for neurodegenerative diseases.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {125}, number = {}, pages = {300-308}, doi = {10.1016/j.colsurfb.2014.11.034}, pmid = {25524221}, issn = {1873-4367}, mesh = {Adipose Tissue/cytology/surgery ; Anti-Inflammatory Agents, Non-Steroidal/chemistry/*pharmacology ; Cell Survival/drug effects ; Curcumin/chemistry/*pharmacology ; *Drug Carriers ; Drug Liberation ; Humans ; Hydrophobic and Hydrophilic Interactions ; Inulin/chemistry ; Kinetics ; Mesenchymal Stem Cells/cytology/*drug effects/metabolism ; *Micelles ; Neuroprotective Agents/chemistry/*pharmacology ; Primary Cell Culture ; Vitamin E/chemistry ; alpha-Tocopherol/chemistry ; }, abstract = {This work reports on the formation of a carrier-in-carrier device for the systemic delivery and targeting of hydrophobic drugs mediated by micelle-loaded mesenchymal stromal cells (MSCs) (carrier-in-carrier) to be administered by intravenous injection. The innate ability of MSCs to reach injured tissues such as the central nervous system or other damaged tissues, is the key for the second order delivery and first order targeting. Inulin-D-alfa-tocopherol succinate micelles (INVITE M) are able to incorporate highly hydrophobic drugs and, due to their dimensions (≈7 nm diameter), to penetrate the cell membrane easily and quickly. This study demonstrates that the curcumin loaded micelles (INVITE MC), sterilized by filtration, reached the maximum loading in MSCs in few minutes and that the loading was concentration-dependent. When "naked" curcumin was used, an evident cytotoxicity on MSCs was detected, while INVITE micelles protected them from this effect. Moreover, MSCs loaded with INVITE MC are able to release the entrapped drug. This study strongly supports the feasibility of the carrier-in-carrier approach for the therapy of selected diseases, i.e., this innovative drug delivery system will be proposed for the treatment of the amyotrophic lateral sclerosis (ALS).}, }
@article {pmid25520673, year = {2014}, author = {Pettorruso, M and De Risio, L and Di Nicola, M and Martinotti, G and Conte, G and Janiri, L}, title = {Allostasis as a conceptual framework linking bipolar disorder and addiction.}, journal = {Frontiers in psychiatry}, volume = {5}, number = {}, pages = {173}, pmid = {25520673}, issn = {1664-0640}, abstract = {Bipolar disorders (BDs) and addictions constitute reciprocal risk factors and are best considered under a unitary perspective. The concepts of allostasis and allostatic load (AL) may contribute to the understanding of the complex relationships between BD and addictive behaviors. Allostasis entails the safeguarding of reward function stability by recruitment of changes in the reward and stress system neurocircuitry and it may help to elucidate neurobiological underpinnings of vulnerability to addiction in BD patients. Conceptualizing BD as an illness involving the cumulative build-up of allostatic states, we hypothesize a progressive dysregulation of reward circuits clinically expressed as negative affective states (i.e., anhedonia). Such negative affective states may render BD patients more vulnerable to drug addiction, fostering a very rapid transition from occasional drug use to addiction, through mechanisms of negative reinforcement. The resulting addictive behavior-related ALs, in turn, may contribute to illness progression. This framework could have a heuristic value to enhance research on pathophysiology and treatment of BD and addiction comorbidity.}, }
@article {pmid25515509, year = {2015}, author = {Hroch, L and Aitken, L and Benek, O and Dolezal, M and Kuca, K and Gunn-Moore, F and Musilek, K}, title = {Benzothiazoles - scaffold of interest for CNS targeted drugs.}, journal = {Current medicinal chemistry}, volume = {22}, number = {6}, pages = {730-747}, doi = {10.2174/0929867322666141212120631}, pmid = {25515509}, issn = {1875-533X}, support = {188/ALZS_/Alzheimer's Society/United Kingdom ; }, mesh = {Alzheimer Disease/diagnostic imaging/drug therapy ; Animals ; Anticonvulsants/*chemistry/therapeutic use ; Benzothiazoles/*chemistry/therapeutic use ; Humans ; Neuroprotective Agents/*chemistry/therapeutic use ; Quantitative Structure-Activity Relationship ; Radionuclide Imaging ; }, abstract = {Benzothiazole compounds represent heterocyclic systems comprising a benzene ring fused with a thiazole ring containing nitrogen and sulphur in its structure. Besides the presence of a benzothiazole core in naturally occurring molecules, synthesized compounds containing a benzothiazole moiety in their structure proved to be a significant class of potential therapeutics, as they exhibit biological effects such as antitumor, antibacterial, antitubercular, antiviral, anthelmintic, antidiabetic and many others. Apart from the aforementioned peripheral or microbial active sites, benzothiazole analogues are also biologically active compounds in the central nervous system, where some approved drugs containing a benzothiazole moiety have already been identified and are used in the treatment of various neurological disorders. New benzothiazole molecules are currently under development and are being evaluated for several uses including diagnostics and as therapeutic drug candidates for the treatment of epilepsy and neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis amongst others.}, }
@article {pmid25505901, year = {2014}, author = {Cortés-Gutiérrez, EI and López-Fernández, C and Fernández, JL and Dávila-Rodríguez, MI and Johnston, SD and Gosálvez, J}, title = {Interpreting sperm DNA damage in a diverse range of mammalian sperm by means of the two-tailed comet assay.}, journal = {Frontiers in genetics}, volume = {5}, number = {}, pages = {404}, pmid = {25505901}, issn = {1664-8021}, abstract = {Key ConceptsThe two-dimensional Two-Tailed Comet assay (TT-comet) protocol is a valuable technique to differentiate between single-stranded (SSBs) and double-stranded DNA breaks (DSBs) on the same sperm cell.Protein lysis inherent with the TT-comet protocol accounts for differences in sperm protamine composition at a species-specific level to produce reliable visualization of sperm DNA damage.Alkaline treatment may break the sugar-phosphate backbone in abasic sites or at sites with deoxyribose damage, transforming these lesions into DNA breaks that are also converted into ssDNA. These lesions are known as Alkali Labile Sites "ALSs."DBD-FISH permits the in situ visualization of DNA breaks, abasic sites or alkaline-sensitive DNA regions.The alkaline comet single assay reveals that all mammalian species display constitutive ALS related with the requirement of the sperm to undergo transient changes in DNA structure linked with chromatin packing.Sperm DNA damage is associated with fertilization failure, impaired pre-and post- embryo implantation and poor pregnancy outcome.The TT is a valuable tool for identifying SSBs or DSBs in sperm cells with DNA fragmentation and can be therefore used for the purposes of fertility assessment. Sperm DNA damage is associated with fertilization failure, impaired pre-and post- embryo implantation and poor pregnancy outcome. A series of methodologies to assess DNA damage in spermatozoa have been developed but most are unable to differentiate between single-stranded DNA breaks (SSBs) and double-stranded DNA breaks (DSBs) on the same sperm cell. The two-dimensional Two-Tailed Comet assay (TT-comet) protocol highlighted in this review overcomes this limitation and emphasizes the importance in accounting for the difference in sperm protamine composition at a species-specific level for the appropriate preparation of the assay. The TT-comet is a modification of the original comet assay that uses a two dimensional electrophoresis to allow for the simultaneous evaluation of DSBs and SSBs in mammalian spermatozoa. Here we have compiled a retrospective overview of how the TT-comet assay has been used to investigate the structure and function of sperm DNA across a diverse range of mammalian species (eutheria, metatheria, and prototheria). When conducted as part of the TT-comet assay, we illustrate (a) how the alkaline comet single assay has been used to help understand the constitutive and transient changes in DNA structure associated with chromatin packing, (b) the capacity of the TT-comet to differentiate between the presence of SSBs and DSBs (c) and the possible implications of SSBs or DSBs for the assessment of infertility.}, }
@article {pmid25501828, year = {2014}, author = {Feng, Y and Zhu, M and Dangelmajer, S and Lee, YM and Wijesekera, O and Castellanos, CX and Denduluri, A and Chaichana, KL and Li, Q and Zhang, H and Levchenko, A and Guerrero-Cazares, H and Quiñones-Hinojosa, A}, title = {Hypoxia-cultured human adipose-derived mesenchymal stem cells are non-oncogenic and have enhanced viability, motility, and tropism to brain cancer.}, journal = {Cell death &amp; disease}, volume = {5}, number = {12}, pages = {e1567}, pmid = {25501828}, issn = {2041-4889}, support = {R01 CA183827/CA/NCI NIH HHS/United States ; R01 NS070024/NS/NINDS NIH HHS/United States ; T32 R01 NS070024/NS/NINDS NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; }, mesh = {Adipose Tissue/*cytology/metabolism ; Adult ; Aged ; Brain Neoplasms/metabolism/*physiopathology ; Cell Differentiation ; Cell Hypoxia ; Cell Line ; *Cell Movement ; Cell Survival ; Cells, Cultured ; Female ; Humans ; Male ; Mesenchymal Stem Cells/*cytology/metabolism ; Middle Aged ; Oxygen/analysis/*metabolism ; *Tropism ; }, abstract = {Adult human adipose-derived mesenchymal stem cells (hAMSCs) are multipotent cells, which are abundant, easily collected, and bypass the ethical concerns that plague embryonic stem cells. Their utility and accessibility have led to the rapid development of clinical investigations to explore their autologous and allogeneic cellular-based regenerative potential, tissue preservation capabilities, anti-inflammatory properties, and anticancer properties, among others. hAMSCs are typically cultured under ambient conditions with 21% oxygen. However, physiologically, hAMSCs exist in an environment of much lower oxygen tension. Furthermore, hAMSCs cultured in standard conditions have shown limited proliferative and migratory capabilities, as well as limited viability. This study investigated the effects hypoxic culture conditions have on primary intraoperatively derived hAMSCs. hAMSCs cultured under hypoxia (hAMSCs-H) remained multipotent, capable of differentiation into osteogenic, chondrogenic, and adipogenic lineages. In addition, hAMSCs-H grew faster and exhibited less cell death. Furthermore, hAMSCs-H had greater motility than normoxia-cultured hAMSCs and exhibited greater homing ability to glioblastoma (GBM) derived from brain tumor-initiating cells from our patients in vitro and in vivo. Importantly, hAMSCs-H did not transform into tumor-associated fibroblasts in vitro and were not tumorigenic in vivo. Rather, hAMSCs-H promoted the differentiation of brain cancer cells in vitro and in vivo. These findings suggest an alternative culturing technique that can enhance the function of hAMSCs, which may be necessary for their use in the treatment of various pathologies including stroke, myocardial infarction, amyotrophic lateral sclerosis, and GBM.}, }
@article {pmid25492460, year = {2014}, author = {Razuc, MF and Grünhut, M and Garrido, M and Fernández Band, BS}, title = {Second order advantage applied to the spectrophotometric analysis of ciprofloxacin and dexamethasone in ophthalmic drops; automatic green method using on-line photodegradation.}, journal = {Analytical sciences : the international journal of the Japan Society for Analytical Chemistry}, volume = {30}, number = {12}, pages = {1121-1127}, doi = {10.2116/analsci.30.1121}, pmid = {25492460}, issn = {1348-2246}, mesh = {Ciprofloxacin/*analysis ; Dexamethasone/*analysis ; Ophthalmic Solutions/*chemistry ; Photolysis ; Spectrophotometry, Ultraviolet/instrumentation ; }, abstract = {On-line photodegradation and spectrophotometric analysis assisted by multivariate curve resolution-alternating least squares (MCR-ALS) was developed the simultaneous determination of ciprofloxacin (CIP) and dexamethasone (DEX) in ophthalmic suspensions using an automated flow-batch analysis (FBA) system. CIP and DEX have strongly overlapped UV spectra. Overcoming this lack of selectivity involves augmenting data dimensionality. This could be performed by adding information about the sample photodegradation to obtain the so-called second order advantage. Commercial sample analysis was successfully performed and no statistical differences (α = 0.05) with respect to pharmacopeia methods were obtained. The proposed method offers several advantages over the methods developed to date. In agreement with the principles of green chemistry, only water was used as solvent, low amounts of waste were generated and on-line waste treatment was included in the system. Moreover, the cost per analysis was significantly reduced compared to methods that employ separative techniques.}, }
@article {pmid25482048, year = {2016}, author = {Apolloni, S and Fabbrizio, P and Parisi, C and Amadio, S and Volonté, C}, title = {Clemastine Confers Neuroprotection and Induces an Anti-Inflammatory Phenotype in SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {53}, number = {1}, pages = {518-531}, pmid = {25482048}, issn = {1559-1182}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/*genetics ; Animals ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; Cells, Cultured ; Clemastine/pharmacology/*therapeutic use ; *Disease Models, Animal ; Female ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/drug effects/enzymology ; Neuroprotection/*drug effects/physiology ; Phenotype ; Superoxide Dismutase/*genetics ; }, abstract = {Mutations in the Cu(2+)/Zn(2+) superoxide dismutase 1 (SOD1) gene underlie 14-23 % of familial and 1-7 % of sporadic cases of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by a specific loss of motor neurons in the brain and spinal cord. Neuroinflammation and oxidative stress are emerging as key players in the pathogenesis of ALS, thus justifying the interest in glial cells and particularly microglia, in addition to motor neurons, as novel therapeutic approaches against ALS. Recently, histamine was proven to participate in the pathogenesis of neuroinflammatory and neurodegenerative diseases, and particularly, microglia was shown to be sensitive to the histamine challenge mainly through histamine H1 receptors. Clemastine is a first-generation and CNS-penetrant H1 receptor antagonist considered as a safe antihistamine compound that was shown to possess immune suppressive properties. In order to investigate if clemastine might find promising application in the treatment of ALS, in this work, we tested its action in the SOD1(G93A) mouse model which is extensively used in ALS preclinical studies. We demonstrated that chronic clemastine administration in SOD1(G93A) mice reduces microgliosis, modulates microglia-related inflammatory genes, and enhances motor neuron survival. Moreover, in vitro, clemastine is able to modify several activation parameters of SOD1(G93A) microglia, and particularly CD68 and arginase-1 expression, as well as phospho-ERK1/2 and NADPH oxidase 2 levels. Being clemastine a drug already employed in clinical practice, our results strongly encourage its further exploitation as a candidate for preclinical trials and a new modulator of neuroinflammation in ALS.}, }
@article {pmid25460198, year = {2015}, author = {Engel, WK}, title = {Diagnostic histochemistry and clinical-pathological testings as molecular pathways to pathogenesis and treatment of the ageing neuromuscular system: a personal view.}, journal = {Biochimica et biophysica acta}, volume = {1852}, number = {4}, pages = {563-584}, doi = {10.1016/j.bbadis.2014.11.015}, pmid = {25460198}, issn = {0006-3002}, mesh = {*Aging/genetics/metabolism/pathology ; Humans ; *Neuromuscular Diseases/diagnosis/genetics/metabolism/pathology/therapy ; }, abstract = {Ageing of the neuromuscular system in elderhood ingravescently contributes to slowness, weakness, falling and death, often accompanied by numbness and pain. This article is to put in perspective examples from a half-century of personal and team neuromuscular histochemical-pathological and clinical-pathological research, including a number of lucky and instructive accomplishments identifying new treatments and new diseases. A major focus currently is on some important, still enigmatic, aspects of the ageing neuromuscular system. It is also includes some of the newest references of others on various closely-related aspects of this ageing system. The article may help guide others in their molecular-based endeavors to identify paths leading to discovering new treatments and new pathogenic aspects. These are certainly needed - our ageing and unsteady constituents are steadily increasing. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.}, }
@article {pmid25457026, year = {2015}, author = {Lu, HP and Gan, SR and Chen, S and Li, HF and Liu, ZJ and Ni, W and Wang, N and Wu, ZY}, title = {Intermediate-length polyglutamine in ATXN2 is a possible risk factor among Eastern Chinese patients with amyotrophic lateral sclerosis.}, journal = {Neurobiology of aging}, volume = {36}, number = {3}, pages = {1603.e11-4}, doi = {10.1016/j.neurobiolaging.2014.10.015}, pmid = {25457026}, issn = {1558-1497}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*genetics ; Asian People/genetics ; Ataxin-2/chemistry/*genetics ; Female ; *Genetic Association Studies ; Genetic Predisposition to Disease/*genetics ; Humans ; Male ; Middle Aged ; Peptides/*genetics ; Risk Factors ; *Trinucleotide Repeat Expansion ; Young Adult ; }, abstract = {An effective treatment for amyotrophic lateral sclerosis (ALS) has not yet been found because the pathogenesis of this fatal disease is not well understood. A number of previous studies demonstrated that intermediate-length polyglutamine repeats within the ataxin-2 gene (ATXN2) might be a risk factor among patients with ALS in Western countries. Here, we aim to determine whether this sequence is a risk factor in Eastern Chinese ALS patients. Therefore, 379 unrelated sporadic ALS patients, 15 unrelated familial ALS patients, and 900 neurologically normal controls were studied. The ATXN2 CAG repeats were amplified using polymerase chain reaction. The products were separated on an 8% polyacrylamide gel and confirmed using Sanger sequencing. The results were evaluated using SPSS 17.0. We found that ATXN2 intermediate-length polyglutamine expansions greater than 24 and 27 repeats were associated with sporadic ALS. Our finding supports the hypothesis that ATXN2 plays an important role in the pathogenesis of ALS.}, }
@article {pmid25446478, year = {2015}, author = {Nachiappan, S and Askari, A and Malietzis, G and Giacometti, M and White, I and Jenkins, JT and Kennedy, RH and Faiz, O}, title = {The impact of anastomotic leak and its treatment on cancer recurrence and survival following elective colorectal cancer resection.}, journal = {World journal of surgery}, volume = {39}, number = {4}, pages = {1052-1058}, pmid = {25446478}, issn = {1432-2323}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anastomosis, Surgical/adverse effects ; Anastomotic Leak/*mortality/*therapy ; Anti-Bacterial Agents/therapeutic use ; Colectomy/adverse effects ; Colon/*surgery ; Colorectal Neoplasms/*surgery ; Disease-Free Survival ; Drainage ; Elective Surgical Procedures/adverse effects ; Female ; Humans ; Ileum/*surgery ; Male ; Middle Aged ; Rectum/*surgery ; Reoperation/mortality ; Retrospective Studies ; Survival Analysis ; Survival Rate ; Young Adult ; }, abstract = {AIM: Anastomotic leakage is a serious complication in restorative colorectal surgery. Anastomotic leakage and its subsequent management may have long-term impact on survival. This study aims to assess the impact of colorectal anastomotic leak (AL) on overall survival (OS) and disease-free survival (DFS).<br><br>METHODS: A prospective database of 1,048 patients undergoing restorative colorectal cancer resections at St Mark's hospital between October 2004 and October 2013 was examined.<br><br>RESULTS: The overall leak rate was 99/1,048 (9.4%). 43 ALs were managed conservatively with antibiotics or radiological drainage and 56 with reoperations. OS was significantly reduced in the AL group treated with a reoperation (HR 2.74, 95% CI 1.67-4.52, p < 0.001). AL was not significantly associated with worse DFS [conservatively managed AL's vs. no AL-HR 2.07 (95% CI 1.05-4.10); reoperated AL's vs. no AL-HR 1.56 (95% CI 0.81-2.99), overall p value = 0.058].<br><br>CONCLUSION: Patients who suffer anastomotic leaks requiring reoperations have worse OS compared to patients who do not leak, but there were no significant differences in DFS between patients who leaked and those who did not.}, }
@article {pmid25445474, year = {2015}, author = {Inan, SY and Soner, BC and Sahin, AS}, title = {Infralimbic cortex Rho-kinase inhibition causes antidepressant-like activity in rats.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {57}, number = {}, pages = {36-43}, doi = {10.1016/j.pnpbp.2014.10.008}, pmid = {25445474}, issn = {1878-4216}, mesh = {Amides/administration &amp; dosage/*pharmacology ; Animals ; Antidepressive Agents/*pharmacology ; Behavior, Animal/*drug effects ; Gyrus Cinguli/*drug effects/enzymology ; Male ; Microinjections ; Protein Kinase Inhibitors/administration &amp; dosage/*pharmacology ; Pyridines/administration &amp; dosage/*pharmacology ; Rats ; rho-Associated Kinases/*antagonists &amp; inhibitors ; }, abstract = {Depression is one of the most common psychiatric disorders in the world; however, its mechanisms remain unclear. Recently, a new signal-transduction pathway, namely Rho/Rho-kinase signalling, has been suggested to be involved in diverse cellular events in the central nervous system; such as epilepsy, anxiety-related behaviors, regulation of dendritic and axonal morphology, antinociception, subarachnoid haemorrhage, spinal cord injury and amyotrophic lateral sclerosis. However there is no evidence showing the involvement of Rho-kinase pathway in depression. In addition, the infralimbic cortex, rodent equivalent to subgenual cingulate cortex has been shown to be responsible for emotional responses. Thus, in the present study, intracranial guide cannulae were stereotaxically implanted bilaterally into the infralimbic cortex, and the effects of repeated microinjections of a Rho-kinase (ROCK) inhibitor Y-27632 (10 nmol) were investigated in rats. Y-27632 significantly decreased immobility time and increased swimming and climbing behaviors when compared to fluoxetine (10 μg) and saline groups in the forced swim test. In addition, Y-27632 treatment did not affect spontaneous locomotor activity and forelimb use in the open-field and cylinder tests respectively; but it enhanced limb placing accuracy in the ladder rung walking test. Our results suggest that Y-27632 could be a potentially active antidepressant agent.}, }
@article {pmid25443832, year = {2014}, author = {Matzrafi, M and Gadri, Y and Frenkel, E and Rubin, B and Peleg, Z}, title = {Evolution of herbicide resistance mechanisms in grass weeds.}, journal = {Plant science : an international journal of experimental plant biology}, volume = {229}, number = {}, pages = {43-52}, doi = {10.1016/j.plantsci.2014.08.013}, pmid = {25443832}, issn = {1873-2259}, mesh = {Acetyl-CoA Carboxylase/antagonists &amp; inhibitors/metabolism ; Amino Acid Sequence ; Arabidopsis/metabolism ; Brachypodium/drug effects/*genetics ; Ecosystem ; *Evolution, Molecular ; Halogenated Diphenyl Ethers/toxicity ; Herbicide Resistance/*genetics ; Heterocyclic Compounds, 2-Ring/toxicity ; Israel ; Molecular Sequence Data ; Photosystem II Protein Complex/metabolism ; Plant Proteins/chemistry ; Plant Weeds/drug effects/*genetics ; }, abstract = {Herbicide resistant weeds are becoming increasingly common, threatening global food security. Here, we present BrIFAR: a new model system for the functional study of mechanisms of herbicide resistance in grass weeds. We have developed a large collection of Brachypodium accessions, the BrI collection, representing a wide range of habitats. Wide screening of the responses of the accessions to four major herbicide groups (PSII, ACCase, ALS/AHAS and EPSPS inhibitors) identified 28 herbicide-resistance candidate accessions. Target-site resistance to PSII inhibitors was found in accessions collected from habitats with a known history of herbicide applications. An amino acid substitution in the psbA gene (serine264 to glycine) conferred resistance and also significantly affected the flowering and shoot dry weight of the resistant accession, as compared to the sensitive accession. Non-target site resistance to ACCase inhibitors was found in accessions collected from habitats with a history of herbicide application and from a nature reserve. In-vitro enzyme activity tests and responses following pre-treatment with malathion (a cytochrome-P450 inhibitor) indicated sensitivity at the enzyme level, and give strong support to diclofop-methyl and pinoxaden enhanced detoxification as NTS resistance mechanism. BrIFAR can promote better understanding of the evolution of mechanisms of herbicide resistance and aid the implementation of integrative management approaches for sustainable agriculture.}, }
@article {pmid25443289, year = {2015}, author = {Coughlan, KS and Mitchem, MR and Hogg, MC and Prehn, JH}, title = {"Preconditioning" with latrepirdine, an adenosine 5'-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1(G93A) mice.}, journal = {Neurobiology of aging}, volume = {36}, number = {2}, pages = {1140-1150}, doi = {10.1016/j.neurobiolaging.2014.09.022}, pmid = {25443289}, issn = {1558-1497}, support = {R01 HL093149/HL/NHLBI NIH HHS/United States ; }, mesh = {AMP-Activated Protein Kinases/*metabolism/physiology ; Amyotrophic Lateral Sclerosis/enzymology/*genetics/*prevention &amp; control ; Animals ; Cell Survival/drug effects ; Cells, Cultured ; Disease Progression ; Energy Metabolism ; Enzyme Activation/drug effects ; Female ; Indoles/*administration &amp; dosage ; Injections, Intraperitoneal ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/enzymology/pathology ; Mutation ; Risk ; Spinal Cord/enzymology ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a master regulator of energy balance. As energy imbalance is documented as a key pathologic feature of amyotrophic lateral sclerosis (ALS), we investigated AMPK as a pharmacologic target in SOD1(G93A) mice. We noted a strong activation of AMPK in lumbar spinal cords of SOD1(G93A) mice. Pharmacologic activation of AMPK has shown protective effects in neuronal "preconditioning" models. We tested the hypothesis that "preconditioning" with a small molecule activator of AMPK, latrepirdine, exerts beneficial effects on disease progression. SOD1(G93A) mice (n = 24 animals per group; sex and litter matched) were treated with latrepirdine (1 μg/kg, intraperitoneal) or vehicle from postnatal day 70 to 120. Treatment with latrepirdine increased AMPK activity in primary mouse motor neuron cultures and in SOD1(G93A) lumbar spinal cords. Mice "preconditioned" with latrepirdine showed a delayed symptom onset and a significant increase in life span (p < 0.01). Our study suggests that "preconditioning" with latrepirdine may represent a possible therapeutic strategy for individuals harboring ALS-associated gene mutations who are at risk for developing ALS.}, }
@article {pmid25434487, year = {2015}, author = {Battaglia, G and Riozzi, B and Bucci, D and Di Menna, L and Molinaro, G and Pallottino, S and Nicoletti, F and Bruno, V}, title = {Activation of mGlu3 metabotropic glutamate receptors enhances GDNF and GLT-1 formation in the spinal cord and rescues motor neurons in the SOD-1 mouse model of amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {74}, number = {}, pages = {126-136}, doi = {10.1016/j.nbd.2014.11.012}, pmid = {25434487}, issn = {1095-953X}, mesh = {Amino Acids/*pharmacology ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology/physiopathology ; Animals ; Astrocytes/drug effects/pathology/physiology ; Bridged Bicyclo Compounds, Heterocyclic/*pharmacology ; Cells, Cultured ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Agonists/*pharmacology ; Excitatory Amino Acid Transporter 2/*metabolism ; Glial Cell Line-Derived Neurotrophic Factor/*metabolism ; Humans ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Motor Neurons/*drug effects/pathology/physiology ; Receptors, Metabotropic Glutamate/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Enhancement of glial-derived neurotrophic factor (GDNF) is an established therapeutic target for amyotrophic lateral sclerosis (ALS). Activation of group II metabotropic glutamate (mGlu) receptors with the orthosteric agonist, LY379268, enhanced GDNF levels in cultured spinal cord astrocytes from wild-type mice and mGlu2(-/-) mice, but not in astrocytes from mGlu3(-/-) mice. LY379268 protected Sternberger monoclonal incorporated antibody-32 (SMI-32)(+) motor neurons against excitotoxic death in mixed cultures of spinal cord cells, and its action was abrogated by anti-GDNF antibodies. Acute systemic injection of LY379268 (0.5, 1 or 5mg/kg, i.p.) enhanced spinal cord GDNF levels in wild-type and mGlu2(-/-) mice, but not in mGlu3(-/-) mice. No tolerance developed to the GDNF-enhancing effect of LY379268 when the drug was continuously delivered for 28days by means of s.c. osmotic minipumps (0.5-5mg/day). Double fluorescent immunostaining showed a co-localization of GDNF with the astrocyte marker, GFAP, but not with the neuronal marker, Neuronal Nuclear Antigen (NeuN), or with SMI-32. Continuous infusion of LY379268 also enhanced the expression of the glutamate transporter GLT-1, in the spinal cord. These data laid the groundwork for the study of LY379268 in ALS mice. Continuous treatment with 1 or 5mg/kg/day with LY379268 had a beneficial effect on neurological disability in SOD1G93A mice. At day 40 of treatment, LY379268 enhanced spinal cord levels of GDNF and GLT-1, and rescued spinal cord motor neurons, as assessed by stereologic counting of SMI-32(+) cells. LY379268 had no significant effect on the mortality rate of SODG93A. These findings encourage the development of selective mGlu3 receptor agonists/enhancers as neuroprotective agents in ALS.}, }
@article {pmid25420446, year = {2015}, author = {Yang, LP and Deeks, ED}, title = {Dextromethorphan/quinidine: a review of its use in adults with pseudobulbar affect.}, journal = {Drugs}, volume = {75}, number = {1}, pages = {83-90}, pmid = {25420446}, issn = {1179-1950}, mesh = {Adult ; Dextromethorphan/*therapeutic use ; Drug Combinations ; Humans ; Mood Disorders/*drug therapy/etiology ; Nervous System Diseases/*complications ; Quinidine/*therapeutic use ; }, abstract = {Fixed-dose dextromethorphan/quinidine capsules (Nuedexta(®)) utilize quinidine to inhibit the metabolism of dextromethorphan, enabling high plasma dextromethorphan concentrations to be reached without using a larger dose of the drug. The drug combination is the first treatment to be approved for pseudobulbar affect (PBA), a condition of contextually inappropriate/exaggerated emotional expression that often occurs in adults with neurological damage conditions, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, traumatic brain injury, Alzheimer's disease or Parkinson's disease. Dextromethorphan/quinidine at the recommended dosages of 20/10 or 30/10 mg twice daily reduced the rate of PBA episodes and improved PBA severity in a 12-week, double-blind, placebo-controlled trial in adults with ALS or MS (STAR), with further improvements in the severity of the condition observed in a 12-week open-label extension phase. Dextromethorphan/quinidine 20/10 mg twice daily also improved PBA secondary to dementia in a cohort of a 12-week noncomparative trial (PRISM II). The drug combination was generally well tolerated in these studies, with no particular safety or tolerability concerns. Although longer-term efficacy and tolerability data for dextromethorphan/quinidine 20/10 or 30/10 mg twice daily would be beneficial, current evidence indicates that it is a useful option in the treatment of adults with PBA.}, }
@article {pmid25414544, year = {2015}, author = {Kim, J and Kumar, N and Tsiartas, A and Li, M and Narayanan, SS}, title = {Automatic intelligibility classification of sentence-level pathological speech.}, journal = {Computer speech &amp; language}, volume = {29}, number = {1}, pages = {132-144}, pmid = {25414544}, issn = {0885-2308}, support = {R01 DC007124/DC/NIDCD NIH HHS/United States ; }, abstract = {Pathological speech usually refers to the condition of speech distortion resulting from atypicalities in voice and/or in the articulatory mechanisms owing to disease, illness or other physical or biological insult to the production system. Although automatic evaluation of speech intelligibility and quality could come in handy in these scenarios to assist experts in diagnosis and treatment design, the many sources and types of variability often make it a very challenging computational processing problem. In this work we propose novel sentence-level features to capture abnormal variation in the prosodic, voice quality and pronunciation aspects in pathological speech. In addition, we propose a post-classification posterior smoothing scheme which refines the posterior of a test sample based on the posteriors of other test samples. Finally, we perform feature-level fusions and subsystem decision fusion for arriving at a final intelligibility decision. The performances are tested on two pathological speech datasets, the NKI CCRT Speech Corpus (advanced head and neck cancer) and the TORGO database (cerebral palsy or amyotrophic lateral sclerosis), by evaluating classification accuracy without overlapping subjects' data among training and test partitions. Results show that the feature sets of each of the voice quality subsystem, prosodic subsystem, and pronunciation subsystem, offer significant discriminating power for binary intelligibility classification. We observe that the proposed posterior smoothing in the acoustic space can further reduce classification errors. The smoothed posterior score fusion of subsystems shows the best classification performance (73.5% for unweighted, and 72.8% for weighted, average recalls of the binary classes).}, }
@article {pmid25413276, year = {2015}, author = {Chen, BK and Staff, NP and Knight, AM and Nesbitt, JJ and Butler, GW and Padley, DJ and Parisi, JE and Dietz, AB and Windebank, AJ}, title = {A safety study on intrathecal delivery of autologous mesenchymal stromal cells in rabbits directly supporting Phase I human trials.}, journal = {Transfusion}, volume = {55}, number = {5}, pages = {1013-1020}, pmid = {25413276}, issn = {1537-2995}, support = {K08 CA169443/CA/NCI NIH HHS/United States ; UL1 TR000135/TR/NCATS NIH HHS/United States ; K08 169443//PHS HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/therapy ; Animals ; Cells, Cultured ; Clinical Trials, Phase I as Topic ; Disease Models, Animal ; Female ; Humans ; Injections, Spinal ; Interleukin-6/blood/metabolism ; Male ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*physiology ; Multiple System Atrophy/metabolism/therapy ; Organ Size ; Rabbits ; }, abstract = {BACKGROUND: There are no effective treatments that slow the progression of neurodegenerative diseases. A major challenge of treatment in neurodegenerative diseases is appropriate delivery of pharmaceuticals into the cerebrospinal fluid (CSF) of affected individuals. Mesenchymal stromal cells (MSCs-either naïve or modified) are a promising therapy in neurodegenerative diseases and may be delivered directly into the CSF where they can reside for months. In this preclinical study, we evaluated the safety of intrathecal autologous MSCs in a rabbit model.<br><br>STUDY DESIGN AND METHODS: Autologous adipose-derived MSCs (or artificial CSF) were delivered intrathecally, either with single or with repeated injections into the foramen magnum of healthy rabbits and monitored for 4 and 12 weeks, respectively.<br><br>RESULTS: Rabbits tolerated injections well and no definitive MSC-related side effects were observed apart from three rabbits that had delayed death secondary to traumatic foramen magnum puncture. Functional assessments and body weights were equivalent between groups. Gross pathology and histology did not reveal any abnormalities or tumor growth. Complete blood count data were normal and there were no differences in CSF interleukin-6 levels in all groups tested.<br><br>CONCLUSION: Our data suggest that intrathecal delivery of autologous MSCs is safe in a rabbit model. Data from this study have supported two successful investigational new drug applications to the Food and Drug Administration, resulting in the initiation of two clinical trials using autologous MSCs in amyotrophic lateral sclerosis and multiple system atrophy.}, }
@article {pmid25410659, year = {2015}, author = {Lattante, S and de Calbiac, H and Le Ber, I and Brice, A and Ciura, S and Kabashi, E}, title = {Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD.}, journal = {Human molecular genetics}, volume = {24}, number = {6}, pages = {1682-1690}, doi = {10.1093/hmg/ddu580}, pmid = {25410659}, issn = {1460-2083}, mesh = {Adaptor Proteins, Signal Transducing/*genetics ; Amyotrophic Lateral Sclerosis/drug therapy/*genetics ; Animals ; Disease Models, Animal ; Frontotemporal Lobar Degeneration/drug therapy/*genetics ; Gene Knockdown Techniques ; Locomotion/drug effects/*genetics ; Phenotype ; Sequestosome-1 Protein ; Sirolimus/*pharmacology ; TOR Serine-Threonine Kinases/metabolism ; Zebrafish/genetics ; Zebrafish Proteins/*genetics/metabolism ; }, abstract = {Mutations in SQSTM1, encoding for the protein SQSTM1/p62, have been recently reported in 1-3.5% of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS/FTLD). Inclusions positive for SQSTM1/p62 have been detected in patients with neurodegenerative disorders, including ALS/FTLD. In order to investigate the pathogenic mechanisms induced by SQSTM1 mutations in ALS/FTLD, we developed a zebrafish model. Knock-down of the sqstm1 zebrafish ortholog, as well as impairment of its splicing, led to a specific phenotype, consisting of behavioral and axonal anomalies. Here, we report swimming deficits associated with shorter motor neuronal axons that could be rescued by the overexpression of wild-type human SQSTM1. Interestingly, no rescue of the loss-of-function phenotype was observed when overexpressing human SQSTM1 constructs carrying ALS/FTLD-related mutations. Consistent with its role in autophagy regulation, we found increased mTOR levels upon knock-down of sqstm1. Furthermore, treatment of zebrafish embryos with rapamycin, a known inhibitor of the mTOR pathway, yielded an amelioration of the locomotor phenotype in the sqstm1 knock-down model. Our results suggest that loss-of-function of SQSTM1 causes phenotypic features characterized by locomotor deficits and motor neuron axonal defects that are associated with a misregulation of autophagic processes.}, }
@article {pmid25409785, year = {2014}, author = {Chang, KA and Lee, JH and Suh, YH}, title = {Therapeutic potential of human adipose-derived stem cells in neurological disorders.}, journal = {Journal of pharmacological sciences}, volume = {126}, number = {4}, pages = {293-301}, doi = {10.1254/jphs.14R10CP}, pmid = {25409785}, issn = {1347-8648}, mesh = {Adipose Tissue/*cytology ; Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Animals ; Cell Differentiation ; Cell- and Tissue-Based Therapy/*methods/*trends ; Humans ; Huntington Disease/therapy ; Mice ; Nervous System Diseases/*therapy ; Parkinson Disease/therapy ; Pluripotent Stem Cells/cytology/*transplantation ; Regenerative Medicine/*methods/*trends ; Stem Cell Transplantation/*methods/*trends ; }, abstract = {Stem cell therapy has been noted as a novel strategy to various diseases including neurological disorders such as Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and Huntington's disease that have no effective treatment available to date. The adipose-derived stem cells (ASCs), mesenchymal stem cells (MSCs) isolated from adipose tissue, are well known for their pluripotency with the ability to differentiate into various types of cells and immuno-modulatory property. These biological features make ASCs a promising source for regenerative cell therapy in neurological disorders. Here we discuss the recent progress of regenerative therapies in various neurological disorders utilizing ASCs.}, }
@article {pmid25408825, year = {2014}, author = {Ozdinler, PH and Silverman, RB}, title = {Treatment of amyotrophic lateral sclerosis: lessons learned from many failures.}, journal = {ACS medicinal chemistry letters}, volume = {5}, number = {11}, pages = {1179-1181}, pmid = {25408825}, issn = {1948-5875}, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most complex neurodegenerative diseases, involving both cortical and spinal components of motor neuron circuitry and non-neuronal cells that support the motor neurons. There is no effective therapeutic for ALS, and compounds that have extended the lifespan of ALS mouse models have failed in clinical trials. This viewpoint discusses current information regarding the changing views about ALS and what the failures in clinical trials can teach us in the search for an effective treatment. Previous challenges and roadblocks in drug discovery for ALS are noted, and solutions to current limitations are discussed. Learning from the past and moving forward with a new mindset can translate into successful and effective treatment strategies in ALS and other related diseases.}, }
@article {pmid25404049, year = {2015}, author = {Patel, P and Julien, JP and Kriz, J}, title = {Early-stage treatment with Withaferin A reduces levels of misfolded superoxide dismutase 1 and extends lifespan in a mouse model of amyotrophic lateral sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {12}, number = {1}, pages = {217-233}, pmid = {25404049}, issn = {1878-7479}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Blotting, Western ; Disease Models, Animal ; Fluorescent Antibody Technique ; Immunoprecipitation ; Longevity/*drug effects ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/pathology ; Neuroprotective Agents/*pharmacology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Withanolides/*pharmacology ; }, abstract = {Approximately 20% of cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Recent studies have shown that Withaferin A (WA), an inhibitor of nuclear factor-kappa B activity, was efficient in reducing disease phenotype in a TAR DNA binding protein 43 transgenic mouse model of ALS. These findings led us to test WA in mice from 2 transgenic lines expressing different ALS-linked SOD1 mutations, SOD1(G93A) and SOD1(G37R). Intraperitoneal administration of WA at a dosage of 4 mg/kg of body weight was initiated from postnatal day 40 until end stage in SOD1(G93A) mice, and from 9 months until end stage in SOD1(G37R) mice. The beneficial effects of WA in the SOD1(G93A) mice model were accompanied by an alleviation of neuroinflammation, a decrease in levels of misfolded SOD1 species in the spinal cord, and a reduction in loss of motor neurons resulting in delayed disease progression and mortality. Interestingly, WA treatment triggered robust induction of heat shock protein 25 (a mouse ortholog of heat shock protein 27), which may explain the reduced level of misfolded SOD1 species in the spinal cord of SOD1(G93A) mice and the decrease of neuronal injury responses, as revealed by real-time imaging of biophotonic SOD1(G93A) mice expressing a luciferase transgene under the control of the growth-associated protein 43 promoter. These results suggest that WA may represent a potential lead compound for drug development aiming to treat ALS.}, }
@article {pmid25384989, year = {2015}, author = {Gentile, I and Buonomo, AR and Zappulo, E and Borgia, G}, title = {Discontinued drugs in 2012 - 2013: hepatitis C virus infection.}, journal = {Expert opinion on investigational drugs}, volume = {24}, number = {2}, pages = {239-251}, doi = {10.1517/13543784.2015.982274}, pmid = {25384989}, issn = {1744-7658}, mesh = {Antiviral Agents/*therapeutic use ; Clinical Trials as Topic/statistics &amp; numerical data ; Drug Design ; Drug Evaluation, Preclinical/statistics &amp; numerical data ; *Drugs, Investigational ; Hepatitis C/*drug therapy ; Humans ; Treatment Failure ; }, abstract = {INTRODUCTION: Hepatitis C virus (HCV) chronically infects about 150 million people worldwide. Antiviral treatment can stop and even reverse the progression of the disease. Several antivirals have been developed. However, about 10,000 compounds are tested for each drug that eventually reaches the market. It would be useful to learn from these failures, for example, by reporting the candidate drugs that were discontinued and the reason for discontinuation.<br><br>AREAS COVERED: This article focuses on the anti-HCV drug candidates discontinued between 1 January 2012 and 1 January 2014.<br><br>EXPERT OPINION: In detail, 17 drugs were discontinued. Of these: 10 were NS5B inhibitors, 3 were NS5A inhibitors, 2 were immunostimulants, 1 was a therapeutic and prophylactic vaccine and 1 an NS3 inhibitor. Only 3 candidates were discontinued in the preclinical phase, and 14 were discontinued during clinical development (8 in Phase II and 6 in Phase I). Most discontinuations were attributed to corporate strategic decisions. The authors believe that learning from HCV drug development failures will help pharmaceutical companies and researchers to develop better strategies for the future. It is therefore important that this information is made available.}, }
@article {pmid25381879, year = {2015}, author = {Butovsky, O and Jedrychowski, MP and Cialic, R and Krasemann, S and Murugaiyan, G and Fanek, Z and Greco, DJ and Wu, PM and Doykan, CE and Kiner, O and Lawson, RJ and Frosch, MP and Pochet, N and Fatimy, RE and Krichevsky, AM and Gygi, SP and Lassmann, H and Berry, J and Cudkowicz, ME and Weiner, HL}, title = {Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice.}, journal = {Annals of neurology}, volume = {77}, number = {1}, pages = {75-99}, pmid = {25381879}, issn = {1531-8249}, support = {R01 AG043975/AG/NIA NIH HHS/United States ; R01 NS088137/NS/NINDS NIH HHS/United States ; 1R01NS088137/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/drug therapy/*genetics/metabolism/*pathology ; Animals ; Apolipoproteins E/pharmacology/therapeutic use ; Cells, Cultured ; Disease Models, Animal ; Female ; Gene Expression Regulation/drug effects/*genetics ; Hippocampus/cytology ; Humans ; Male ; Mice ; Mice, Transgenic ; MicroRNAs/chemistry/genetics/*metabolism ; Microglia/drug effects/metabolism ; Middle Aged ; Monocytes/drug effects/metabolism ; Neurons/drug effects/metabolism ; Oligoribonucleotides, Antisense/therapeutic use ; Phagocytosis/drug effects/genetics ; Spinal Cord/*pathology ; Superoxide Dismutase/*genetics ; Transforming Growth Factor beta/genetics/metabolism ; }, abstract = {OBJECTIVE: To investigate miR-155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS).<br><br>METHODS: NanoString microRNA, microglia and immune gene profiles, protein mass spectrometry, and RNA-seq analyses were measured in spinal cord microglia, splenic monocytes, and spinal cord tissue from SOD1 mice and in spinal cord tissue of familial and sporadic ALS. miR-155 was targeted by genetic ablation or by peripheral or centrally administered anti-miR-155 inhibitor in SOD1 mice.<br><br>RESULTS: In SOD1 mice, we found loss of the molecular signature that characterizes homeostatic microglia and increased expression of miR-155. There was loss of the microglial molecules P2ry12, Tmem119, Olfml3, transcription factors Egr1, Atf3, Jun, Fos, and Mafb, and the upstream regulators Csf1r, Tgfb1, and Tgfbr1, which are essential for microglial survival. Microglia biological functions were suppressed including phagocytosis. Genetic ablation of miR-155 increased survival in SOD1 mice by 51 days in females and 27 days in males and restored the abnormal microglia and monocyte molecular signatures. Disease severity in SOD1 males was associated with early upregulation of inflammatory genes, including Apoe in microglia. Treatment of adult microglia with apolipoprotein E suppressed the M0-homeostatic unique microglia signature and induced an M1-like phenotype. miR-155 expression was increased in the spinal cord of both familial and sporadic ALS. Dysregulated proteins that we identified in human ALS spinal cord were restored in SOD1(G93A) /miR-155(-/-) mice. Intraventricular anti-miR-155 treatment derepressed microglial miR-155 targeted genes, and peripheral anti-miR-155 treatment prolonged survival.<br><br>INTERPRETATION: We found overexpression of miR-155 in the SOD1 mouse and in both sporadic and familial human ALS. Targeting miR-155 in SOD1 mice restores dysfunctional microglia and ameliorates disease. These findings identify miR-155 as a therapeutic target for the treatment of ALS.}, }
@article {pmid25372079, year = {2014}, author = {Allers, C and Jones, JA and Lasala, GP and Minguell, JJ}, title = {Mesenchymal stem cell therapy for the treatment of amyotrophic lateral sclerosis: signals for hope?.}, journal = {Regenerative medicine}, volume = {9}, number = {5}, pages = {637-647}, doi = {10.2217/rme.14.30}, pmid = {25372079}, issn = {1746-076X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Cell Differentiation ; Cell- and Tissue-Based Therapy/*trends ; Clinical Trials as Topic ; Humans ; Mesenchymal Stem Cell Transplantation/*trends ; Mesenchymal Stem Cells/*cytology ; }, abstract = {Based on the distinctive cellular, molecular and immunomodulatory traits of mesenchymal stem cells (MSC), it has been postulated that these cells may play a critical role in regenerative medicine. In addition to the participation of MSC in the repair of mesodermal-derived tissues (bone, cartilage), robust data have suggested that MSC may also play a reparative role in conditions involving damage of cells of ectodermal origin. The above content has been supported by the capability of MSC to differentiate into neuron-like cells as well as by a competence to generate a 'neuroprotective' environment. In turn, several preclinical studies have put forward the concept that MSC therapy may represent an option for the treatment of several neurological disorders and injuries, including amyotrophic lateral sclerosis. We expect that the above foundations, which have inspired this review, may result in the founding of an effective and/or palliative therapy for amyotrophic lateral sclerosis.}, }
@article {pmid25364724, year = {2014}, author = {Adami, R and Scesa, G and Bottai, D}, title = {Stem cell transplantation in neurological diseases: improving effectiveness in animal models.}, journal = {Frontiers in cell and developmental biology}, volume = {2}, number = {}, pages = {17}, pmid = {25364724}, issn = {2296-634X}, abstract = {Neurological diseases afflict a growing proportion of the human population. There are two reasons for this: first, the average age of the population (especially in the industrialized world) is increasing, and second, the diagnostic tools to detect these pathologies are now more sophisticated and can be used on a higher percentage of the population. In many cases, neurological disease has a pharmacological treatment which, as in the case of Alzheimer's disease, Parkinson's disease, Epilepsy, and Multiple Sclerosis can reduce the symptoms and slow down the course of the disease but cannot reverse its effects or heal the patient. In the last two decades the transplantation approach, by means of stem cells of different origin, has been suggested for the treatment of neurological diseases. The choice of slightly different animal models and the differences in methods of stem cell preparation make it difficult to compare the results of transplantation experiments. Moreover, the translation of these results into clinical trials with human subjects is difficult and has so far met with little success. This review seeks to discuss the reasons for these difficulties by considering the differences between human and animal cells (including isolation, handling and transplantation) and between the human disease model and the animal disease model.}, }
@article {pmid25362243, year = {2015}, author = {Küffner, R and Zach, N and Norel, R and Hawe, J and Schoenfeld, D and Wang, L and Li, G and Fang, L and Mackey, L and Hardiman, O and Cudkowicz, M and Sherman, A and Ertaylan, G and Grosse-Wentrup, M and Hothorn, T and van Ligtenberg, J and Macke, JH and Meyer, T and Schölkopf, B and Tran, L and Vaughan, R and Stolovitzky, G and Leitner, ML}, title = {Crowdsourced analysis of clinical trial data to predict amyotrophic lateral sclerosis progression.}, journal = {Nature biotechnology}, volume = {33}, number = {1}, pages = {51-57}, pmid = {25362243}, issn = {1546-1696}, mesh = {Algorithms ; Amyotrophic Lateral Sclerosis/*pathology ; *Clinical Trials as Topic ; *Crowdsourcing ; Disease Progression ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with substantial heterogeneity in its clinical presentation. This makes diagnosis and effective treatment difficult, so better tools for estimating disease progression are needed. Here, we report results from the DREAM-Phil Bowen ALS Prediction Prize4Life challenge. In this crowdsourcing competition, competitors developed algorithms for the prediction of disease progression of 1,822 ALS patients from standardized, anonymized phase 2/3 clinical trials. The two best algorithms outperformed a method designed by the challenge organizers as well as predictions by ALS clinicians. We estimate that using both winning algorithms in future trial designs could reduce the required number of patients by at least 20%. The DREAM-Phil Bowen ALS Prediction Prize4Life challenge also identified several potential nonstandard predictors of disease progression including uric acid, creatinine and surprisingly, blood pressure, shedding light on ALS pathobiology. This analysis reveals the potential of a crowdsourcing competition that uses clinical trial data for accelerating ALS research and development.}, }
@article {pmid25339858, year = {2014}, author = {Günther, R and Saal, KA and Suhr, M and Scheer, D and Koch, JC and Bähr, M and Lingor, P and Tönges, L}, title = {The rho kinase inhibitor Y-27632 improves motor performance in male SOD1(G93A) mice.}, journal = {Frontiers in neuroscience}, volume = {8}, number = {}, pages = {304}, pmid = {25339858}, issn = {1662-4548}, abstract = {Disease progression in amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motoneurons and their axons which results in a progressive muscle weakness and ultimately death from respiratory failure. The only approved drug, riluzole, lacks clinical efficacy so that more potent treatment options are needed. We have identified rho kinase (ROCK) as a target, which can be manipulated to beneficially influence disease progression in models of ALS. Here, we examined the therapeutic potential of the ROCK inhibitor Y-27632 in both an in vitro and in an in vivo paradigm of motoneuron disease. Application of Y-27632 to primary motoneurons in vitro increased survival and promoted neurite outgrowth. In vivo, SOD1(G93A) mice were orally treated with 2 or 30 mg/kg body weight of Y-27632. The 2 mg/kg group did not benefit from Y-27632 treatment, whereas treatment with 30 mg/kg resulted in improved motor function in male mice. Female mice showed only limited improvement and overall survival was not modified in both 2 and 30 mg/kg Y-27632 groups. In conclusion, we provide evidence that inhibition of ROCK by Y-27632 is neuroprotective in vitro but has limited beneficial effects in vivo being restricted to male mice. Therefore, the evaluation of ROCK inhibitors in preclinical models of ALS should always take gender differences into account.}, }
@article {pmid25336094, year = {2015}, author = {Canosa, A and Calvo, A and Barberis, M and Brunetti, M and Restagno, G and Cammarosano, S and Ilardi, A and Vigliani, MC and Chiò, A and Moglia, C}, title = {Amyotrophic lateral sclerosis onset after prolonged treatment with a VEGF receptors inhibitor.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {16}, number = {1-2}, pages = {129-130}, doi = {10.3109/21678421.2014.969274}, pmid = {25336094}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Vascular Endothelial Growth Factor A/genetics/*therapeutic use ; }, }
@article {pmid25326688, year = {2014}, author = {Tada, S and Okuno, T and Hitoshi, Y and Yasui, T and Honorat, JA and Takata, K and Koda, T and Shimagami, H and Chi-Jing, C and Namba, A and Sugimoto, T and Sakoda, S and Mochizuki, H and Kikutani, H and Nakatsuji, Y}, title = {Partial suppression of M1 microglia by Janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {11}, number = {}, pages = {179}, pmid = {25326688}, issn = {1742-2094}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Disease Models, Animal ; Enzyme Inhibitors/*pharmacology ; Flow Cytometry ; Immunohistochemistry ; Janus Kinase 2/*antagonists &amp; inhibitors ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/*drug effects ; Nerve Degeneration/enzymology/immunology/*prevention &amp; control ; Spinal Cord/drug effects/immunology/pathology ; }, abstract = {BACKGROUND: Accumulating evidence has shown that the inflammatory process participates in the pathogenesis of amyotrophic lateral sclerosis (ALS), suggesting a therapeutic potential of anti-inflammatory agents. Janus kinase 2 (JAK2), one of the key molecules in inflammation, transduces signals downstream of various inflammatory cytokines, and some Janus kinase inhibitors have already been clinically applied to the treatment of inflammatory diseases. However, the efficacy of JAK2 inhibitors in treatment of ALS remains to be demonstrated. In this study, we examined the role of JAK2 in ALS by administering a selective JAK2 inhibitor, R723, to an animal model of ALS (mSOD1G93A mice).<br><br>FINDINGS: Orally administered R723 had sufficient access to spinal cord tissue of mSOD1G93A mice and significantly reduced the number of Ly6c positive blood monocytes, as well as the expression levels of IFN-&#x3b3; and nitric oxide synthase 2, inducible (iNOS) in the spinal cord tissue. R723 treatment did not alter the expression levels of Il-1&#x3b2;, Il-6, TNF, and NADPH oxidase 2 (NOX2), and suppressed the expression of Retnla, which is one of the markers of neuroprotective M2 microglia. As a result, R723 did not alter disease progression or survival of mSOD1G93A mice.<br><br>CONCLUSIONS: JAK2 inhibitor was not effective against ALS symptoms in mSOD1G93A mice, irrespective of suppression in several inflammatory molecules. Simultaneous suppression of anti-inflammatory microglia with a failure to inhibit critical other inflammatory molecules might explain this result.}, }
@article {pmid25324884, year = {2014}, author = {Kim, HY and Moon, C and Kim, KS and Oh, KW and Oh, SI and Kim, J and Kim, SH}, title = {Recombinant human erythropoietin in amyotrophic lateral sclerosis: a pilot study of safety and feasibility.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {10}, number = {4}, pages = {342-347}, pmid = {25324884}, issn = {1738-6586}, abstract = {BACKGROUND AND PURPOSE: It has been shown that erythropoietin is neuroprotective in animal models of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). The aim of this study was to determine the safety and feasibility of repetitive high-dose recombinant human erythropoietin (rhEPO) therapy in ALS patients.<br><br>METHODS: Two consecutive studies were conducted. We first recruited 26 subjects for an initial single-arm safety study. After a lead-in period of 3 months to assess the disease progression, rhEPO was infused intravenously (35,000 IU) once per month for 3 months, and the subjects were followed for an additional 3 months. The ALS Functional Rating Scale-Revised (ALSFRS-R) was used for clinical assessment. After confirming the safety of rhEPO, 60 subjects were recruited for the second controlled study (rhEPO and control groups), which involved a total of 6 infusions at a rate of 1/month.<br><br>RESULTS: There were no serious adverse events in the first study. The mean rate of decline in the ALSFRS-R score was lower during the treatment period than during the lead-in period (mean&#xb1;SD: 2.6&#xb1;1.8 and 3.7&#xb1;2.6, respectively; p=0.02). However, the rate of decline during the subsequent 3 months returned to that observed in the lead-in period. In the second study, the mean rate of decline in ALSFRS-R score was significantly lower in the rhEPO group than in the control group (during months 0-3, 1.8&#xb1;1.7 vs. 3.1&#xb1;2.3, p=0.03; during months 4-6, 2.1&#xb1;2.2 vs. 3.5&#xb1;2.3, p=0.02).<br><br>CONCLUSIONS: Intravenous high-dose rhEPO is both safe and feasible for the treatment of ALS. Further investigation using different intervals and doses should be considered.}, }
@article {pmid25316599, year = {2015}, author = {Joshi, G and Gan, KA and Johnson, DA and Johnson, JA}, title = {Increased Alzheimer's disease-like pathology in the APP/ PS1ΔE9 mouse model lacking Nrf2 through modulation of autophagy.}, journal = {Neurobiology of aging}, volume = {36}, number = {2}, pages = {664-679}, pmid = {25316599}, issn = {1558-1497}, support = {P50 AG033514/AG/NIA NIH HHS/United States ; R01 ES008089/ES/NIEHS NIH HHS/United States ; R01 ES08089/ES/NIEHS NIH HHS/United States ; P50AG033514/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/*genetics/*pathology/therapy ; Amyloid beta-Peptides/*metabolism ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Autophagy/*genetics ; Disease Models, Animal ; Endosomes/metabolism ; Gene Deletion ; Lysosomes/metabolism ; Mice, Transgenic ; Molecular Targeted Therapy ; NF-E2-Related Factor 2/*genetics/*physiology ; }, abstract = {The presence of senile plaques is one of the major pathologic hallmarks of the brain with Alzheimer's disease (AD). The plaques predominantly contain insoluble amyloid β-peptide, a cleavage product of the larger amyloid precursor protein (APP). Two enzymes, named β and γ secretase, generate the neurotoxic amyloid-β peptide from APP. Mature APP is also turned over endogenously by autophagy, more specifically by the endosomal-lysosomal pathway. A defective lysosomal system is known to be pathogenic in AD. Modulation of NF-E2 related factor 2 (Nrf2) has been shown in several neurodegenerative disorders, and Nrf2 has become a potential therapeutic target for various neurodegenerative disorders, including AD, Parkinson's disease, and amyotrophic lateral sclerosis. In the current study, we explored the effect of genetic ablation of Nrf2 on APP/Aβ processing and/or aggregation as well as changes in autophagic dysfunction in APP/PS1 mice. There was a significant increase in inflammatory response in APP/PS1 mice lacking Nrf2. This was accompanied by increased intracellular levels of APP, Aβ (1-42), and Aβ (1-40), without a change total full-length APP. There was a shift of APP and Aβ into the insoluble fraction, as well as increased poly-ubiquitin conjugated proteins in mice lacking Nrf2. APP/PS1-mediated autophagic dysfunction is also enhanced in Nrf2-deficient mice. Finally, neurons in the APP/PS1/Nrf2-/- mice had increased accumulation of multivesicular bodies, endosomes, and lysosomes. These outcomes provide a better understanding of the role of Nrf2 in modulating autophagy in an AD mouse model and may help design better Nrf2 targeted therapeutics that could be efficacious in the treatment of AD.}, }
@article {pmid25316381, year = {2015}, author = {Hu, Z and Yang, B and Mo, X and Xiao, H}, title = {Mechanism and Regulation of Autophagy and Its Role in Neuronal Diseases.}, journal = {Molecular neurobiology}, volume = {52}, number = {3}, pages = {1190-1209}, pmid = {25316381}, issn = {1559-1182}, mesh = {Animals ; Autophagy/*physiology ; Brain Ischemia/metabolism/pathology/*physiopathology ; Disease Models, Animal ; Humans ; Intracellular Membranes/metabolism ; Lysosomes/physiology ; Mechanistic Target of Rapamycin Complex 1 ; Mechanistic Target of Rapamycin Complex 2 ; Mice ; Multiprotein Complexes/metabolism ; Nerve Tissue Proteins/metabolism ; Neurodegenerative Diseases/metabolism/pathology/*physiopathology ; Neurons/metabolism ; Phagosomes/physiology/ultrastructure ; Proteasome Endopeptidase Complex/metabolism ; Protein Processing, Post-Translational ; TOR Serine-Threonine Kinases/metabolism ; Ubiquitination ; ras Proteins/metabolism ; }, abstract = {Autophagy is a constitutive lysosomal catabolic pathway that degrades damaged organelles and protein aggregates. Neuronal survival is highly dependent on autophagy due to its post-mitotic nature, polarized morphology, and active protein trafficking. Autophagic dysfunction has been linked to several neuronal diseases. Our understanding is still incomplete but may highlight up-to-date findings on how autophagy is executed and regulated at the molecular level and its role in neurodegenerative diseases (including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS)), brain ischemia, and myelin diseases, hence providing attractive new avenues for the development of treatment strategies to combat neuronal diseases.}, }
@article {pmid25316019, year = {2014}, author = {Mitsumoto, H and Brooks, BR and Silani, V}, title = {Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved?.}, journal = {The Lancet. Neurology}, volume = {13}, number = {11}, pages = {1127-1138}, doi = {10.1016/S1474-4422(14)70129-2}, pmid = {25316019}, issn = {1474-4465}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*therapy ; Humans ; Neuroprotective Agents/*therapeutic use ; Randomized Controlled Trials as Topic/*standards/trends ; Riluzole/*therapeutic use ; Stem Cell Transplantation/*standards/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most rapidly progressive neurodegenerative diseases of unknown cause. Riluzole is the only drug that slows disease progression. More than 50 randomised controlled trials (RCTs) of proposed disease-modifying drugs have failed to show positive results in the past half-century. In the past decade, at least 18 drugs have been tested in large phase 2 or 3 RCTs, including lithium, which was tested in several RCTs. Potential reasons for the negative results can be classified into three categories: first, issues regarding trial rationale and preclinical study results; second, pharmacological issues; and third, clinical trial design and methodology issues. Clinical trials for stem cell therapy and RCTs targeting pharmacological or non-pharmacological symptomatic treatment in ALS are examples of areas that need novel design strategies. Only through critical analyses of the failed trials can new and important suggestions be identified for the future success of clinical trials in ALS.}, }
@article {pmid25312503, year = {2014}, author = {Soni, N and Reddy, BV and Kumar, P}, title = {GLT-1 transporter: an effective pharmacological target for various neurological disorders.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {127}, number = {}, pages = {70-81}, doi = {10.1016/j.pbb.2014.10.001}, pmid = {25312503}, issn = {1873-5177}, mesh = {Animals ; Drug Delivery Systems/*methods ; Excitatory Amino Acid Agonists/administration &amp; dosage ; Excitatory Amino Acid Antagonists/administration &amp; dosage ; Excitatory Amino Acid Transporter 2 ; Glutamate Plasma Membrane Transport Proteins/agonists/antagonists &amp; inhibitors/*metabolism ; Glutamic Acid/metabolism ; Humans ; Nervous System Diseases/*drug therapy/*metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {L-Glutamate is the predominant excitatory neurotransmitter in the central nervous system (CNS) and is directly and indirectly involved in a variety of brain functions. Glutamate is released in the synaptic cleft at a particular concentration that further activates the various glutaminergic receptors. This concentration of glutamate in the synapse is maintained by either glutamine synthetase or excitatory amino acid proteins which reuptake the excessive glutamate from the synapse and named as excitatory amino acid transporters (EAATs). Out of all the subtypes GLT-1 (glutamate transporter 1) is abundantly distributed in the CNS. Down-regulation of GLT-1 is reported in various neurological diseases such as, epilepsy, stroke, Alzheimer's disease and movement disorders. Therefore, positive modulators of GLT-1 which up-regulate the GLT-1 expression can serve as a potential target for the treatment of neurological disorders. GLT-1 translational activators such as ceftriaxone are found to have significant protective effects in ALS and epilepsy animal models, suggesting that this translational activation approach works well in rodents and that these compounds are worth further pursuit for various neurological disorders. This drug is currently in human clinical trials for ALS. In addition, a thorough understanding of the mechanisms underlying translational regulation of GLT-1, such as identifying the molecular targets of the compounds, signaling pathways involved in the regulation, and translational activation processes, is very important for this novel drug-development effort. This review mainly emphasizes the role of glutamate and its transporter, GLT-1 subtype in excitotoxicity. Further, recent reports on GLT-1 transporters for the treatment of various neurological diseases, including a summary of the presumed physiologic mechanisms behind the pharmacology of these disorders are also explained.}, }
@article {pmid25311268, year = {2015}, author = {Goursaud, S and Schäfer, S and Dumont, AO and Vergouts, M and Gallo, A and Desmet, N and Deumens, R and Hermans, E}, title = {The anti-inflammatory peptide stearyl-norleucine-VIP delays disease onset and extends survival in a rat model of inherited amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {263}, number = {}, pages = {91-101}, doi = {10.1016/j.expneurol.2014.09.022}, pmid = {25311268}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Blotting, Western ; Disease Models, Animal ; Humans ; Immunohistochemistry ; Neuroprotective Agents/pharmacology ; Rats ; Rats, Sprague-Dawley ; Rats, Transgenic ; Reverse Transcriptase Polymerase Chain Reaction ; Spinal Cord/*drug effects/metabolism/pathology ; Superoxide Dismutase/biosynthesis/*drug effects/genetics ; Superoxide Dismutase-1 ; Vasoactive Intestinal Peptide/*pharmacology ; }, abstract = {Vasoactive intestinal peptide (VIP) has potent immune modulatory actions that may influence the course of neurodegenerative disorders associated with chronic inflammation. Here, we show the therapeutic benefits of a modified peptide agonist stearyl-norleucine-VIP (SNV) in a transgenic rat model of amyotrophic lateral sclerosis (mutated superoxide dismutase 1, hSOD1(G93A)). When administered by systemic every-other-day intraperitoneal injections during a period of 80 days before disease, SNV delayed the onset of motor dysfunction by no less than three weeks, while survival was extended by nearly two months. SNV-treated rats showed reduced astro- and microgliosis in the lumbar ventral spinal cord and a significant degree of motor neuron preservation. Throughout the treatment, SNV promoted the expression of the anti-inflammatory cytokine interleukin-10 as well as neurotrophic factors commonly considered as beneficial in amyotrophic lateral sclerosis management (glial derived neuroptrophic factor, insulin like growth factor, brain derived neurotrophic factor). The peptide nearly totally suppressed the expression of tumor necrosis factor-α and repressed the production of the pro-inflammatory mediators interleukin-1β, nitric oxide and of the transcription factor nuclear factor kappa B. Inhibition of tumor necrosis factor-α likely accounted for the observed down-regulation of nuclear factor kappa B that modulates the transcription of genes specifically involved in amyotrophic lateral sclerosis (sod1 and the glutamate transporter slc1a2). In line with this, levels of human superoxide dismutase 1 mRNA and protein were decreased by SNV treatment, while the expression and activity of the glutamate transporter-1 was promoted. Considering the large diversity of influences of this peptide on both clinical features of the disease and associated biochemical markers, we propose that SNV or related peptides may constitute promising candidates for amyotrophic lateral sclerosis treatment.}, }
@article {pmid25309711, year = {2014}, author = {Leite, MA and Orsini, M and de Freitas, MR and Pereira, JS and Gobbi, FH and Bastos, VH and de Castro Machado, D and Machado, S and Arrias-Carrion, O and de Souza, JA and Oliveira, AB}, title = {Another Perspective on Fasciculations: When is it not Caused by the Classic form of Amyotrophic Lateral Sclerosis or Progressive Spinal Atrophy?.}, journal = {Neurology international}, volume = {6}, number = {3}, pages = {5208}, pmid = {25309711}, issn = {2035-8385}, abstract = {Fasciculations are visible, fine and fast, sometimes vermicular contractions of fine muscle fibers that occur spontaneously and intermittently. The aim of this article is to discuss the main causes for fasciculations and their pathophysiology in different sites of the central/peripheral injury and in particular to disprove that the presence of this finding in the neurological examination is indicative of amyotrophic lateral sclerosis. Undoubtedly, most fasciculations have a distal origin in the motor nerve both in normal subjects and in patients with motor neuron disease. Most of them spread to other dendritic spines often producing an antidromic impulse in the main axon. The clinical and neurophysiological diagnosis must be thorough. It may often take long to record fasciculations with electroneuromyography. In other cases, temporal monitoring is necessary before the diagnosis. The treatment, which may be adequate in some cases, is not always necessary.}, }
@article {pmid25309365, year = {2014}, author = {Abrieux, A and Duportets, L and Debernard, S and Gadenne, C and Anton, S}, title = {The GPCR membrane receptor, DopEcR, mediates the actions of both dopamine and ecdysone to control sex pheromone perception in an insect.}, journal = {Frontiers in behavioral neuroscience}, volume = {8}, number = {}, pages = {312}, pmid = {25309365}, issn = {1662-5153}, abstract = {Olfactory information mediating sexual behavior is crucial for reproduction in many animals, including insects. In male moths, the macroglomerular complex (MGC) of the primary olfactory center, the antennal lobe (AL) is specialized in the treatment of information on the female-emitted sex pheromone. Evidence is accumulating that modulation of behavioral pheromone responses occurs through neuronal plasticity via the action of hormones and/or catecholamines. We recently showed that a G-protein-coupled receptor (GPCR), AipsDopEcR, with its homologue known in Drosophila for its double affinity to the main insect steroid hormone 20-hydroxyecdysone (20E), and dopamine (DA), present in the ALs, is involved in the behavioral response to pheromone in the moth, Agrotis ipsilon. Here we tested the role of AipsDopEcR as compared to nuclear 20E receptors in central pheromone processing combining receptor inhibition with intracellular recordings of AL neurons. We show that the sensitivity of AL neurons for the pheromone in males decreases strongly after AipsDopEcR-dsRNA injection but also after inhibition of nuclear 20E receptors. Moreover we tested the involvement of 20E and DA in the receptor-mediated behavioral modulation in wind tunnel experiments, using ligand applications and receptor inhibition treatments. We show that both ligands are necessary and act on AipsDopEcR-mediated behavior. Altogether these results indicate that the GPCR membrane receptor, AipsDopEcR, controls sex pheromone perception through the action of both 20E and DA in the central nervous system, probably in concert with 20E action through nuclear receptors.}, }
@article {pmid25297012, year = {2014}, author = {Cudkowicz, ME and Titus, S and Kearney, M and Yu, H and Sherman, A and Schoenfeld, D and Hayden, D and Shui, A and Brooks, B and Conwit, R and Felsenstein, D and Greenblatt, DJ and Keroack, M and Kissel, JT and Miller, R and Rosenfeld, J and Rothstein, JD and Simpson, E and Tolkoff-Rubin, N and Zinman, L and Shefner, JM and , }, title = {Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial.}, journal = {The Lancet. Neurology}, volume = {13}, number = {11}, pages = {1083-1091}, pmid = {25297012}, issn = {1474-4465}, support = {R01 NS085207/NS/NINDS NIH HHS/United States ; U01 NS049640/NS/NINDS NIH HHS/United States ; 5 U01-NS-049640/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Ceftriaxone/*adverse effects/therapeutic use ; Double-Blind Method ; Dyspnea/chemically induced/diagnosis ; Female ; Humans ; Male ; Middle Aged ; Treatment Outcome ; }, abstract = {BACKGROUND: Glutamate excitotoxicity might contribute to the pathophysiology of amyotrophic lateral sclerosis. In animal models, decreased excitatory aminoacid transporter 2 (EAAT2) overexpression delays disease onset and prolongs survival, and ceftriaxone increases EAAT2 activity. We aimed to assess the safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis in a combined phase 1, 2, and 3 clinical trial.<br><br>METHODS: This three-stage randomised, double-blind, placebo-controlled study was done at 59 clinical sites in the USA and Canada between Sept 4, 2006, and July 30, 2012. Eligible adult patients had amyotrophic lateral sclerosis, a vital capacity of more than 60% of that predicted for age and height, and symptom duration of less than 3 years. In stages 1 (pharmacokinetics) and 2 (safety), participants were randomly allocated (2:1) to ceftriaxone (2 g or 4 g per day) or placebo. In stage 3 (efficacy), participants assigned to ceftriaxone in stage 2 received 4 g ceftriaxone, participants assigned to placebo in stage 2 received placebo, and new participants were randomly assigned (2:1) to 4 g ceftriaxone or placebo. Participants, family members, and site staff were masked to treatment assignment. Randomisation was done by a computerised randomisation sequence with permuted blocks of 3. Participants received 2 g ceftriaxone or placebo twice daily through a central venous catheter administered at home by a trained caregiver. To minimise biliary side-effects, participants assigned to ceftriaxone also received 300 mg ursodeoxycholic acid twice daily and those assigned to placebo received matched placebo capsules. The coprimary efficacy outcomes were survival and functional decline, measured as the slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00349622.<br><br>FINDINGS: Stage 3 included 66 participants from stages 1 and 2 and 448 new participants. In total, 340 participants were randomly allocated to ceftriaxone and 173 to placebo. During stages 1 and 2, mean ALSFRS-R declined more slowly in participants who received 4 g ceftriaxone than in those on placebo (difference 0&#xb7;51 units per month, 95% CI 0&#xb7;02 to 1&#xb7;00; p=0&#xb7;0416), but in stage 3 functional decline between the treatment groups did not differ (0&#xb7;09, -0&#xb7;06 to 0&#xb7;24; p=0&#xb7;2370). No significant differences in survival between the groups were recorded in stage 3 (HR 0&#xb7;90, 95% CI 0&#xb7;71 to 1&#xb7;15; p=0&#xb7;4146). Gastrointestinal adverse events and hepatobiliary adverse events were more common in the ceftriaxone group than in the placebo group (gastrointestinal, 245 of 340 [72%] ceftriaxone vs 97 of 173 [56%] placebo, p=0&#xb7;0004; hepatobiliary, 211 [62%] vs 19 [11%], p<0&#xb7;0001). Significantly more participants who received ceftriaxone had serious hepatobiliary serious adverse events (41 participants [12%]) than did those who received placebo (0 participants).<br><br>INTERPRETATION: Despite promising stage 2 data, stage 3 of this trial of ceftriaxone in amyotrophic lateral sclerosis did not show clinical efficacy. The adaptive design allowed for seamless transition from one phase to another, and central venous catheter use in the home setting was shown to be feasible.<br><br>FUNDING: National Institute of Neurological Disorders and Stroke.}, }
@article {pmid25289790, year = {2014}, author = {Wei, D and Wu, C and He, P and Kerr, D and Stecher, S and Yang, L}, title = {Chiral liquid chromatography-tandem mass spectrometry assay to determine that dexpramipexole is not converted to pramipexole in vivo after administered in humans.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {971}, number = {}, pages = {133-140}, doi = {10.1016/j.jchromb.2014.09.029}, pmid = {25289790}, issn = {1873-376X}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; Benzothiazoles/*administration &amp; dosage/*blood/chemistry/pharmacokinetics ; Chromatography, Liquid/*methods ; Drug Stability ; Humans ; Placebos ; Pramipexole ; Quality Control ; Sensitivity and Specificity ; Stereoisomerism ; Tandem Mass Spectrometry/*methods ; }, abstract = {Dexpramipexole (DEX) was being investigated in clinical studies for the treatment of amyotrophic lateral sclerosis (ALS). To monitor the potential chiral interconversion of dexpramipexole to pramipexole (PPX) in vivo, a highly sensitive and selective chiral LC-MS/MS assay was developed and qualified for the detection of pramipexole in the presence of dexpramipexole in human plasma. In this assay, plasma samples were extracted by protein precipitation coupled with solid phase extraction (SPE). The analyte PPX was separated from its enantiomer DEX using a chiral HPLC method. The assay was qualified with a dynamic range of 0.150-1.00ng/mL. The lower limit of quantitation (LLOQ) for PPX was 0.150ng/mL in the presence of up to 1000ng/mL of DEX. The qualified method was used to analyze plasma samples from a DEX clinical study. No PPX was detected in humans at pharmacologically significant levels after administration of dexpramipexole at single doses up to 600mg per day.}, }
@article {pmid25288160, year = {2015}, author = {Katsavarou, O and Ntampos, S and Sarmas, I and Triantafyllou, N and Giannopoulos, S and Kyritsis, AP}, title = {Embolization treatment of cerebral arteriovenous malformations and amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {36}, number = {3}, pages = {483-484}, pmid = {25288160}, issn = {1590-3478}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*etiology ; Embolization, Therapeutic/*adverse effects ; Female ; Humans ; Intracranial Arteriovenous Malformations/*complications/pathology/*therapy ; Middle Aged ; }, }
@article {pmid25287877, year = {2013}, author = {Prokšelj, T and Jerin, A and Kogoj, A}, title = {Memantine may affect pseudobulbar affect in patients with Alzheimer's disease.}, journal = {Acta neuropsychiatrica}, volume = {25}, number = {6}, pages = {361-366}, doi = {10.1017/neu.2013.14}, pmid = {25287877}, issn = {1601-5215}, abstract = {OBJECTIVE: Behavioural symptoms are common in moderate to severe Alzheimer's disease (AD) and are improved by memantine with the most pronounced effect on agitation/aggression. Dextromethorphan in combination with quinidine is the only drug approved by US Food and Drug Administration for the treatment of pseudobulbar affect (PBA) on the basis of efficacy in patients with multiple sclerosis or amyotrophic lateral sclerosis. The aim of our study was to evaluate the efficacy of memantine on PBA in patients with AD.<br><br>METHODS: In a prospective, double-blind, case-control study to assess PBA with pathological laughter and crying scale patients were administered memantine (final dose of 20 mg daily) or citalopram (20 mg once daily), each for 10 weeks. The number of episodes of involuntary emotional expression, Neuropsychiatric Inventory (NPI) and Overt Aggression Scale-Modified (OAS-M) total scores were also recorded. Furthermore, the platelet serotonin (5-HT) concentration was measured.<br><br>RESULTS: Although memantine had beneficial effects on PBA, it also had a crucial impact on behavioural symptoms, especially aggression and agitation (to an average of 3.5 times higher end-point scores on OAS-M and increase of NPI total scores for an average of 114% of initial value). Therefore, the study was prematurely stopped. In addition, we had evidenced a drop of platelet 5-HT concentration (to an average of 73% of initial value).<br><br>CONCLUSION: Surprisingly, our research showed the opposite action of memantine on neuropsychiatric symptoms as expected. In a limited number of AD patients with PBA, memantine had a beneficial effect on involuntary emotional expression, but it potentiated agitation/aggression, irritability and caused a crucial drop of the platelet 5-HT concentration.}, }
@article {pmid25286015, year = {2014}, author = {Abe, K and Itoyama, Y and Sobue, G and Tsuji, S and Aoki, M and Doyu, M and Hamada, C and Kondo, K and Yoneoka, T and Akimoto, M and Yoshino, H and , }, title = {Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {15}, number = {7-8}, pages = {610-617}, pmid = {25286015}, issn = {2167-9223}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Analysis of Variance ; Antipyrine/*analogs &amp; derivatives/therapeutic use ; Double-Blind Method ; Edaravone ; Female ; Follow-Up Studies ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Severity of Illness Index ; Time Factors ; Young Adult ; }, abstract = {Our objective was to confirm the efficacy and safety of edaravone in amyotrophic lateral sclerosis (ALS) patients. We conducted a 36-week confirmatory study, consisting of 12-week pre-observation period followed by 24-week treatment period. Patients received placebo or edaravone i.v. infusion over 60 min for the first 14 days in cycle 1, and for 10 of the first 14 days during cycles 2 to 6. The efficacy primary endpoint was changed in the revised ALS functional rating scale (ALSFRS-R) scores during the 24-week treatment. Patients were treated with placebo (n = 104) and edaravone (n = 102). Changes in ALSFRS-R during the 24-week treatment were -6.35 ± 0.84 in the placebo group (n = 99) and -5.70 ± 0.85 in the edaravone group (n = 100), with a difference of 0.65 ± 0.78 (p = 0.411). Adverse events amounted to 88.5% (92/104) in the placebo group and 89.2% (91/102) in the edaravone group. In conclusion, the reduction of ALSFRS-R was smaller in the edaravone group than in the placebo group, but efficacy of edaravone for treatment of ALS was not demonstrated. Levels and frequencies of reported adverse events were similar in the two groups.}, }
@article {pmid25264355, year = {2015}, author = {Osborne, A and Taylor, L and Reuber, M and Grünewald, RA and Parkinson, M and Dickson, JM}, title = {Pre-hospital care after a seizure: Evidence base and United Kingdom management guidelines.}, journal = {Seizure}, volume = {24}, number = {}, pages = {82-87}, doi = {10.1016/j.seizure.2014.09.002}, pmid = {25264355}, issn = {1532-2688}, support = {2004/DH_/Department of Health/United Kingdom ; }, mesh = {Anticonvulsants/therapeutic use ; Benzodiazepines/therapeutic use ; *Disease Management ; Emergency Medical Services/*methods/*standards ; Female ; Guideline Adherence/*standards ; Humans ; Male ; Seizures/*therapy ; United Kingdom ; }, abstract = {PURPOSE: Seizures are a common presentation to pre-hospital emergency services and they generate significant healthcare costs. This article summarises the United Kingdom (UK) Ambulance Service guidelines for the management of seizures and explores the extent to which these guidelines are evidence-based.<br><br>METHODS: Summary of the Clinical Practice Guidelines of the UK Joint Royal Colleges Ambulance Liaison Committee relating to the management of seizures. Review of the literature relating to pre-hospital management of seizure emergencies.<br><br>RESULTS: Much standard practice relating to the emergency out of hospital management of patients with seizures is drawn from generic Advanced Life Support (ALS) guidelines although many patients do not need ALS during or after a seizure and the benefit of many ALS interventions in seizure patients remains to be established. The majority of studies identified pertain to medical treatment of status epilepticus. These papers show that benzodiazepines are safe and effective but it is not possible to draw definitive conclusions about the best medication or the optimal route of administration.<br><br>CONCLUSION: The evidence base for current pre-hospital guidelines for seizure emergencies is incomplete. A large proportion of patients are transported to hospital after a seizure but many of these may be suitable for home management. However, there is very little research into alternative care pathways or criteria that could be used to help paramedics avoid transport to hospital. More research is needed to improve care for people after a seizure and to improve the cost-effectiveness of the healthcare systems within which they are treated.}, }
@article {pmid25261695, year = {2015}, author = {Mendez, EF and Sattler, R}, title = {Biomarker development for C9orf72 repeat expansion in ALS.}, journal = {Brain research}, volume = {1607}, number = {}, pages = {26-35}, doi = {10.1016/j.brainres.2014.09.041}, pmid = {25261695}, issn = {1872-6240}, support = {R01 NS085207/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism/pathology ; Animals ; Biomarkers/blood/cerebrospinal fluid ; C9orf72 Protein ; *DNA Repeat Expansion ; Epigenesis, Genetic ; Humans ; Proteins/*genetics/*metabolism ; }, abstract = {The expanded GGGGCC hexanucleotide repeat in the non-coding region of the C9orf72 gene on chromosome 9p21 has been discovered as the cause of approximately 20-50% of familial and up to 5-20% of sporadic amyotrophic lateral sclerosis (ALS) cases, making this the most common known genetic mutation of ALS to date. At the same time, it represents the most common genetic mutation in frontotemporal dementia (FTD; 10-30%). Because of the high prevalence of mutant C9orf72, pre-clinical efforts in identifying therapeutic targets and developing novel therapeutics for this mutation are highly pursued in the hope of providing a desperately needed disease-modifying treatment for ALS patients, as well as other patient populations affected by the C9orf72 mutation. The current lack of effective treatments for ALS is partially due to the lack of appropriate biomarkers that aide in assessing drug efficacy during clinical trials independent of clinical outcome measures, such as increased survival. In this review we will summarize the opportunities for biomarker development specifically targeted to the newly discovered C9orf72 repeat expansion. While drugs are being developed for this mutation, it will be crucial to provide a reliable biomarker to accompany the clinical development of these novel therapeutic interventions to maximize the chances of a successful clinical trial. This article is part of a Special Issue entitled ALS complex pathogenesis.}, }
@article {pmid25261035, year = {2014}, author = {Nguyen, L and Kaushal, N and Robson, MJ and Matsumoto, RR}, title = {Sigma receptors as potential therapeutic targets for neuroprotection.}, journal = {European journal of pharmacology}, volume = {743}, number = {}, pages = {42-47}, pmid = {25261035}, issn = {1879-0712}, support = {R01 DA023205/DA/NIDA NIH HHS/United States ; T32 NS007491/NS/NINDS NIH HHS/United States ; R01DA023205/DA/NIDA NIH HHS/United States ; R01DA011979/DA/NIDA NIH HHS/United States ; T32NS007491/NS/NINDS NIH HHS/United States ; R01 DA013978/DA/NIDA NIH HHS/United States ; R01 DA011979/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Ligands ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/*pharmacology/*therapeutic use ; Receptors, sigma/*metabolism ; }, abstract = {Sigma receptors comprise a unique family of proteins that have been implicated in the pathophysiology and treatment of many central nervous system disorders, consistent with their high level of expression in the brain and spinal cord. Mounting evidence indicate that targeting sigma receptors may be particularly beneficial in a number of neurodegenerative conditions including Alzheimer׳s disease, Parkinson׳s disease, stroke, methamphetamine neurotoxicity, Huntington׳s disease, amyotrophic lateral sclerosis, and retinal degeneration. In this perspective, a brief overview is given on sigma receptors, followed by a focus on common mechanisms of neurodegeneration that appear amenable to modulation by sigma receptor ligands to convey neuroprotective effects and/or restorative functions. Within each of the major mechanisms discussed herein, the neuroprotective effects of sigma ligands are summarized, and when known, the specific sigma receptor subtype(s) involved are identified. Together, the literature suggests sigma receptors may provide a novel target for combatting neurodegenerative diseases through both neuronal and glial mechanisms.}, }
@article {pmid25258567, year = {2014}, author = {Kim, C and Lee, HC and Sung, JJ}, title = {Amyotrophic lateral sclerosis - cell based therapy and novel therapeutic development.}, journal = {Experimental neurobiology}, volume = {23}, number = {3}, pages = {207-214}, pmid = {25258567}, issn = {1226-2560}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterized by the predominant loss of motor neurons (MNs) in primary motor cortex, the brainstem, and the spinal cord, causing premature death in most cases. Minimal delay of pathological development by available medicine has prompted the search for novel therapeutic treatments to cure ALS. Cell-based therapy has been proposed as an ultimate source for regeneration of MNs. Recent completion of non-autologous fetal spinal stem cell transplant to ALS patients brought renewed hope for further human trials to cure the disease. Autologous somatic stem cell-based human trials are now in track to reveal the outcome of the ongoing trials. Furthermore, induced pluripotent stem cell (iPSC)-based ALS disease drug screen and autologous cell transplant options will broaden therapeutic options. In this review paper, we discuss recent accomplishments in cell transplant treatment for ALS and future options with iPSC technology.}, }
@article {pmid25251499, year = {2015}, author = {Mikamo, S and Kodama, N and Pan, Q and Maeda, N and Minagi, S}, title = {Effect of nasal speaking valve on speech intelligibility under velopharyngeal incompetence: a questionnaire survey.}, journal = {Journal of oral rehabilitation}, volume = {42}, number = {2}, pages = {136-143}, doi = {10.1111/joor.12237}, pmid = {25251499}, issn = {1365-2842}, mesh = {Female ; Humans ; Male ; Nasal Cavity/*physiopathology ; Palate, Soft/*physiopathology ; Speech Articulation Tests ; Speech Disorders/*etiology/*physiopathology/rehabilitation ; Speech Intelligibility ; Surveys and Questionnaires ; Treatment Outcome ; Velopharyngeal Insufficiency/complications/*physiopathology/rehabilitation ; }, abstract = {Velopharyngeal incompetence is known as a contributing factor to speech disorders. Suwaki et al. reported that nasal speaking valve (NSV) could improve dysarthria by regulating nasal emission utilising one-way valve. However, disease or condition which would be susceptible to treatment by NSV has not been clarified yet. This study aimed to evaluate the effect of NSV by questionnaire survey using ready-made NSV. Subjects were recruited through the internet bulletin, and NSV survey set was sent to the applicant. Sixty-six participants, who agreed to participate in this study, used NSV and mailed back the questionnaire which included self-evaluation and third-party evaluation of speech intelligibility. Statistical analysis revealed that the use of NSV resulted in significant speech intelligibility improvement in both self-evaluation and third-party evaluation (P < 0·01). Regarding the type of underlying disease of dysarthria, significant effect of NSV on self-evaluation of speech intelligibility could be observed in cerebrovascular disease and neurodegenerative disease (P < 0·01) and that on third-party evaluation in neurodegenerative disease (P < 0·01). Eighty-six percent of subjects showed improvement of speech intelligibility by shutting up nostrils by fingers, and the significant effect of NSV on both self-evaluation and third-party evaluation of speech intelligibility was observed (P < 0·001). From the results of this study, it was suggested that NSV would be effective in cerebrovascular disease and neurodegenerative disease, as well as in subjects whose speech intelligibility was improved by closing nostrils.}, }
@article {pmid25248677, year = {2014}, author = {Tanna, T and Sachan, V}, title = {Mesenchymal stem cells: potential in treatment of neurodegenerative diseases.}, journal = {Current stem cell research &amp; therapy}, volume = {9}, number = {6}, pages = {513-521}, doi = {10.2174/1574888x09666140923101110}, pmid = {25248677}, issn = {2212-3946}, mesh = {Animals ; Humans ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*physiology ; Neurodegenerative Diseases/pathology/*therapy ; Regenerative Medicine ; }, abstract = {Mesenchymal Stem Cells or Marrow Stromal Cells (MSCs) have long been viewed as a potent tool for regenerative cell therapy. MSCs are easily accessible from both healthy donor and patient tissue and expandable in vitro on a therapeutic scale without posing significant ethical or procedural problems. MSC based therapies have proven to be effective in preclinical studies for graft versus host disease, stroke, myocardial infarction, pulmonary fibrosis, autoimmune disorders and many other conditions and are currently undergoing clinical trials at a number of centers all over the world. MSCs are also being extensively researched as a therapeutic tool against neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD) and Multiple Sclerosis (MS). MSCs have been discussed with regard to two aspects in the context of neurodegenerative diseases: their ability to transdifferentiate into neural cells under specific conditions and their neuroprotective and immunomodulatory effects. When transplanted into the brain, MSCs produce neurotrophic and growth factors that protect and induce regeneration of damaged tissue. Additionally, MSCs have also been explored as gene delivery vehicles, for example being genetically engineered to over express glial-derived or brain-derived neurotrophic factor in the brain. Clinical trials involving MSCs are currently underway for MS, ALS, traumatic brain injuries, spinal cord injuries and stroke. In the present review, we explore the potential that MSCs hold with regard to the aforementioned neurodegenerative diseases and the current scenario with reference to the same.}, }
@article {pmid25245119, year = {2015}, author = {Obermann, M and Lyon, M}, title = {Financial cost of amyotrophic lateral sclerosis: a case study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {16}, number = {1-2}, pages = {54-57}, doi = {10.3109/21678421.2014.951946}, pmid = {25245119}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*economics/therapy ; *Cost of Illness ; Humans ; Longitudinal Studies ; Male ; Retrospective Studies ; Young Adult ; }, abstract = {There are only a few recently published reports of the cost of amyotrophic lateral sclerosis (ALS) care in the United States. Our objectives were to: 1) report annual and disease-duration costs; 2) provide costs related to specific care and services; 3) present costs by payor; and 4) identify strategies and resources that can be offered to patients to assist with the financial burden of ALS. Over a 10-year period (2001-2010), all expenses related to the cost of care for an individual patient were collected concurrently and then analyzed in 2012. Results showed that total disease-duration costs were $1,433,992 (85% paid by insurance, 9% paid by family, 6% paid by charities). The highest costs were for in-home caregivers ($669,150), ventilation ($212,430) and hospital care ($114,558). In conclusion, this case study illustrates costs of care for ALS as a burden for patients that may impact treatment decisions. Charity organizations and insurance case-managers provide services to patients that can help reduce this burden. Costs for specific services as well as resources identified by this study offer physicians and other healthcare providers data-based cost of care information and strategies to share with their patients.}, }
@article {pmid25240501, year = {2014}, author = {Kim, H and Kim, HI and Kim, YH and Kim, SY and Shin, YI}, title = {An animal study to examine the effects of the bilateral, epidural cortical stimulation on the progression of amyotrophic lateral sclerosis.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {11}, number = {}, pages = {139}, pmid = {25240501}, issn = {1743-0003}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Disease Models, Animal ; Disease Progression ; *Dura Mater ; Electric Stimulation Therapy/*methods ; Male ; Mice ; Mice, Transgenic ; *Motor Cortex ; }, abstract = {BACKGROUND: We examined the effects of the unilateral cortical stimulation on the survival of neurons showing degenerative changes and compared those in delaying the progression of amyotrophic lateral sclerosis (ALS) between the unilateral cortical stimulation and the bilateral one in an animal experimental model using mice.<br><br>METHODS: We used 19 G93A transgenic mice and randomly divided into three groups: the control group (n=6) (the implantation of electrodes in the bilateral motor cortex without electrical stimulation), the unilateral stimulation group (n=7) (the implantation of electrodes in the unilateral motor cortex with a 24-hour cortical stimulation) and the bilateral stimulation group (n=6) (the implantation of electrodes in the bilateral motor cortex with a 24-hour cortical stimulation).<br><br>RESULTS: The mean survival period was significantly longer in the bilateral stimulation group as compared with the control group (124.33 &#xb1; 11.00 days vs. 109.50 &#xb1; 10.41 days) (P<0.05). In addition, on postoperative weeks 11, 12, 13, 14 and 15, the mean Rota-rod score was significantly higher in the unilateral stimulation group as compared with the control group (P<0.05). Furthermore, despite a lack of statistical significance, it was the lowest in the bilateral stimulation group on postoperative weeks 13, 14, 15 and 17. On postoperative weeks 11, 12, 13, 14 and 16, the mean score of paw-grip endurance was significantly higher in the unilateral stimulation group as compared with the control group (P<0.05). Furthermore, despite a lack of statistical significance, it was the lowest in the bilateral stimulation group on postoperative weeks 13, 14, 15 and 17.<br><br>CONCLUSIONS: In conclusion, our results indicate that the bilateral epidural cortical stimulation might have a treatment effect in a murine model of ALS. But it is the limitation that we examined a small number of experimental animals. Further studies are therefore warranted to establish our results and to identify the optimal parameters of the epidural cortical stimulation in a larger number of experimental animals.}, }
@article {pmid25238961, year = {2014}, author = {Sun, P and Zhang, S and Li, Y and Wang, L}, title = {Harmine mediated neuroprotection via evaluation of glutamate transporter 1 in a rat model of global cerebral ischemia.}, journal = {Neuroscience letters}, volume = {583}, number = {}, pages = {32-36}, doi = {10.1016/j.neulet.2014.09.023}, pmid = {25238961}, issn = {1872-7972}, mesh = {Animals ; Astrocytes/drug effects/pathology ; Brain Infarction/drug therapy/pathology ; Brain Ischemia/*metabolism/pathology/physiopathology ; Cell Survival/drug effects ; Cerebral Cortex/drug effects/metabolism/pathology ; Excitatory Amino Acid Transporter 2/antagonists &amp; inhibitors/genetics/*metabolism ; Female ; Harmine/*pharmacology/therapeutic use ; Injections, Intraperitoneal ; Kainic Acid/analogs &amp; derivatives/pharmacology ; Neurons/drug effects/pathology ; Neuroprotective Agents/*pharmacology/therapeutic use ; RNA, Messenger/metabolism ; Rats, Sprague-Dawley ; }, abstract = {Global cerebral ischemia (GCI) causes energy deficiency results in excessive release of glutamate from neurons. Astrocytic glutamate transporters play a predominant role in keeping extracellular glutamate concentrations below excitotoxic levels. Glutamate transporter 1 (GLT-1) may account for more than 90% of glutamate uptake in adult forebrain. Preclinical findings implicate that Harmine present neuroprotection effects in a rat model of amyotrophic lateral sclerosis disease, and the beneficial effects were specifically due to up-regulation of GLT-1. However, no experiments have explored the potential of Harmine to provide neuroprotection in the setting of GCI. The current study was designed to determine whether Harmine could attenuate cerebral infarction as well as improve neuronal survival after GCI. Furthermore, to test whether the mechanisms were associated with up-regulating of GLT-1, we used a GLT-1 specific inhibitor dihydrokainate (DHK) and analysis the expression of GLT-1 mRNA and protein in cortex of brain. We also examined whether Harmine treatment affected astrocytes activation via immunofluorescence. Our results showed that post-GCI administration of Harmine could attenuate cerebral infarct volume and decrease neurons death. It also caused significantly elevation of GLT-1 mRNA and protein and remarkably attenuation of astrocyte activation. We provide novel clues in understanding the mechanisms of which Harmine exerts its neuroprotective activity in neurological disorders.}, }
@article {pmid25238733, year = {2014}, author = {Tsai, RM and Boxer, AL}, title = {Treatment of frontotemporal dementia.}, journal = {Current treatment options in neurology}, volume = {16}, number = {11}, pages = {319}, pmid = {25238733}, issn = {1092-8480}, support = {R01 AG038791/AG/NIA NIH HHS/United States ; T32 AG023481/AG/NIA NIH HHS/United States ; }, abstract = {Frontotemporal dementia (FTD) encompasses a spectrum of neurodegenerative diseases with heterogeneous clinical presentations and two predominant types of underlying neuropathology. FTD typically comprises three distinct clinical syndromes: behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), and nonfluent variant primary progressive aphasia (nfvPPA). FTD also frequently overlaps both clinically and neuropathologically with three other neurodegenerative syndromes: corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). Each syndrome can be associated with one or more underlying neuropathological diagnoses and are referred to as frontotemporal lobar degeneration (FTLD). Although the various FTD syndromes can substantially differ in terms of clinical symptoms and underlying pathology, the symptoms can be broadly categorized into behavioral, cognitive and motor domains. Currently there are no Food and Drug Administration (FDA) approved therapies for the above syndromes except riluzole for ALS. FTD treatment strategies generally rely on off-label use of medications for symptomatic management, and most therapies lack quality evidence from randomized, placebo-controlled clinical trials. For behavioral symptoms, selective serotonin reuptake inhibitors may be effective, while case reports hint at possible efficacy with antipsychotics or anti-epileptics, but use of these latter agents is limited due to concerns regarding side effects. There are no effective therapies for cognitive complaints in FTD, which frequently involve executive function, memory, and language. Motor difficulties associated with FTD may present with parkinsonian symptoms or motor neuron disease, for which riluzole is indicated as therapy. Compared to idiopathic Parkinson's disease, FTD-related atypical parkinsonism is generally not responsive to dopamine replacement therapies, but a small percentage of patients may experience improvement with a trial of carbidopa-levodopa. Physical and occupational therapy remain an important corner stone of motor symptom management in FTD. Speech therapy may also help patients manage symptoms associated with aphasia, apraxia, and dysarthria. Recent advances in the understanding of FTLD pathophysiology and genetics have led to development of potentially disease-modifying therapies as well as symptomatic therapies aimed at ameliorating social and behavioral deficits.}, }
@article {pmid25231843, year = {2014}, author = {Kruminis-Kaszkiel, E and Wojtkiewicz, J and Maksymowicz, W}, title = {Glial-restricted precursors as potential candidates for ALS cell-replacement therapy.}, journal = {Acta neurobiologiae experimentalis}, volume = {74}, number = {3}, pages = {233-241}, doi = {10.55782/ane-2014-1989}, pmid = {25231843}, issn = {1689-0035}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Astrocytes/pathology ; Cell Differentiation/*physiology ; *Cell- and Tissue-Based Therapy ; Humans ; Neuroglia/*pathology ; Spinal Cord Injuries/therapy ; }, abstract = {Amyotrophic lateral sclerosis is a multifactorial progressive neurodegenerative disorder leading to severe disability and death within 3-5 years after diagnosis. The main mechanisms underlying the disease progression are poorly known but according to the current knowledge, neuroinflammation is a key player in motor neurons damage. Astrocytes constitute an important cell population involved in neuroinflammatory reaction. Many studies confirmed their striking connection with motor neuron pathology and therefore they might be a target for the treatment of ALS. Cell-based therapy appears to be a promising strategy. Since direct replacement or restoring of motor neurons using various stem cells is challenging, enrichment of healthy donor-derived astrocytes appears to be a more realistic and beneficial approach. The effects of astrocytes have been examined using transplantation of glial-restricted precursors (GRPs) that represent one of the earliest precursors within the oligodendrocytic and astrocytic cell lineage. In this review, we focused on evidence-based data on astrocyte replacement transplantation therapy using GRPs in animal models of motor neuron diseases. The efficacy of GRPs engrafting is very encouraging. Furthermore, the lesson learned from application of lineage-restricted precursors in spinal cord injury (SCI) indicates that differentiation of GRPs into astrocytes before transplantation might be more advantageous in the context of axon regeneration. To sum up, the studies of glial-restricted precursors have made a step forward to ALS research and might bring breakthroughs to the field of ALS therapy in the future.}, }
@article {pmid25230220, year = {2014}, author = {Karim, S and Mirza, Z and Kamal, MA and Abuzenadah, AM and Azhar, EI and Al-Qahtani, MH and Damanhouri, GA and Ahmad, F and Gan, SH and Sohrab, SS}, title = {The role of viruses in neurodegenerative and neurobehavioral diseases.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {13}, number = {7}, pages = {1213-1223}, doi = {10.2174/187152731307141015122638}, pmid = {25230220}, issn = {1996-3181}, mesh = {Animals ; Humans ; Mental Disorders/physiopathology/*virology ; Neurodegenerative Diseases/physiopathology/*virology ; }, abstract = {Neurodegenerative and neurobehavioral diseases may be caused by chronic and neuropathic viral infections and may result in a loss of neurons and axons in the central nervous system that increases with age. To date, there is evidence of systemic viral infections that occur with some neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, autism spectrum disorders, and HIV-associated neurocognitive disorders. With increasing lifespan, the incidence of neurodegenerative diseases increases consistently. Neurodegenerative diseases affect approximately 37 million people worldwide and are an important cause of mortality. In addition to established non-viral-induced reasons for neurodegenerative diseases, neuropathic infections and viruses associated with neurodegenerative diseases have been proposed. Neuronal degeneration can be either directly or indirectly affected by viral infection. Viruses that attack the human immune system can also affect the nervous system and interfere with classical pathways of neurodegenerative diseases. Viruses can enter the central nervous system, but the exact mechanism cannot be understood well. Various studies have supported viral- and non-viral-mediated neurodegeneration at the cellular, molecular, genomic and proteomic levels. The main focus of this review is to illustrate the association between viral infections and both neurodegenerative and neurobehavioral diseases, so that the possible mechanism and pathway of neurodegenerative diseases can be better explained. This information will strengthen new concepts and ideas for neurodegenerative and neurobehavioral disease treatment.}, }
@article {pmid25228854, year = {2014}, author = {Agam, G and Israelson, A}, title = {Why lithium studies for ALS treatment should not be halted prematurely.}, journal = {Frontiers in neuroscience}, volume = {8}, number = {}, pages = {267}, pmid = {25228854}, issn = {1662-4548}, }
@article {pmid25228780, year = {2015}, author = {Banfi, P and Ticozzi, N and Lax, A and Guidugli, GA and Nicolini, A and Silani, V}, title = {A review of options for treating sialorrhea in amyotrophic lateral sclerosis.}, journal = {Respiratory care}, volume = {60}, number = {3}, pages = {446-454}, doi = {10.4187/respcare.02856}, pmid = {25228780}, issn = {1943-3654}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; *Disease Management ; Humans ; Sialorrhea/etiology/*therapy ; Treatment Outcome ; }, abstract = {Sialorrhea or drooling represents quite a common problem in patients with amyotrophic lateral sclerosis (ALS). In this review, we describe the possible treatments for this issue. Current medical management is not always effective: anticholinergic drugs (atropine, glycopyrrolate, amitriptyline, hyoscyamine, and transdermal scopolamine) are often used, but there is very little evidence of their effectiveness in patients with ALS. More invasive treatments, such as botulinum toxin injections and/or radiation therapy in the salivary glands, can be considered when anticholinergic drugs are not effective. In this review, we also explore the possible surgical options for treatment of sialorrhea. Although no specific studies have been conducted on patients with ALS, surgical therapies might represent a valid option for treatment of sialorrhea since there is no tachyphylaxis or need for repeated therapeutic sessions.}, }
@article {pmid25218556, year = {2015}, author = {Doty, KR and Guillot-Sestier, MV and Town, T}, title = {The role of the immune system in neurodegenerative disorders: Adaptive or maladaptive?.}, journal = {Brain research}, volume = {1617}, number = {}, pages = {155-173}, pmid = {25218556}, issn = {1872-6240}, support = {1R01NS076794-01/NS/NINDS NIH HHS/United States ; 3R00AG029726-04S1/AG/NIA NIH HHS/United States ; R01 NS076794/NS/NINDS NIH HHS/United States ; R00 AG029726/AG/NIA NIH HHS/United States ; 5R00AG029726-04/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Astrocytes/immunology/metabolism ; Brain/*immunology/metabolism ; Encephalitis/genetics/immunology ; Humans ; Inflammation Mediators/metabolism ; Microglia/*immunology/metabolism ; Neurodegenerative Diseases/genetics/*immunology/metabolism ; Neurons/*immunology/metabolism ; Parkinson Disease/genetics/metabolism ; Risk Factors ; }, abstract = {Neurodegenerative diseases share common features, including catastrophic neuronal loss that leads to cognitive or motor dysfunction. Neuronal injury occurs in an inflammatory milieu that is populated by resident and sometimes, infiltrating, immune cells - all of which participate in a complex interplay between secreted inflammatory modulators and activated immune cell surface receptors. The importance of these immunomodulators is highlighted by the number of immune factors that have been associated with increased risk of neurodegeneration in recent genome-wide association studies. One of the more difficult tasks for designing therapeutic strategies for immune modulation against neurodegenerative diseases is teasing apart beneficial from harmful signals. In this regard, learning more about the immune components of these diseases has yielded common themes. These unifying concepts should eventually enable immune-based therapeutics for treatment of Alzheimer׳s and Parkinson׳s diseases and amyotrophic lateral sclerosis. Targeted immune modulation should be possible to temper maladaptive factors, enabling beneficial immune responses in the context of neurodegenerative diseases. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.}, }
@article {pmid25216370, year = {2014}, author = {Philips, T and Rothstein, JD and Pouladi, MA}, title = {Preclinical models: needed in translation? A Pro/Con debate.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {29}, number = {11}, pages = {1391-1396}, doi = {10.1002/mds.26010}, pmid = {25216370}, issn = {1531-8257}, mesh = {Animals ; *Disease Models, Animal ; Drug Evaluation, Preclinical ; Humans ; Huntington Disease/genetics/*therapy ; Translational Research, Biomedical/*methods ; }, abstract = {The discovery of the causative mutations and many of the predisposing risk factors for neurodegenerative disorders such as Amyotrophic Lateral Sclerosis, Alzheimer's, Parkinson's, and Huntington's disease (HD), has led to the development of a large number of genetic animal models of disease. In the case of HD, for example, over 20 different transgenic rodent models have been generated. These models have been of immense value in providing novel insights into mechanisms of disease, with the promise of accelerating the development of therapies that can delay the onset or slow the progression of the disease. Yet, despite extensive use of such models, no effective treatment for HD has been developed. Here, we discuss the value of animal models, highlighting their strengths and shortcomings in the context of translational research for HD.}, }
@article {pmid25213598, year = {2015}, author = {Cai, M and Lee, KW and Choi, SM and Yang, EJ}, title = {TDP-43 modification in the hSOD1(G93A) amyotrophic lateral sclerosis mouse model.}, journal = {Neurological research}, volume = {37}, number = {3}, pages = {253-262}, doi = {10.1179/1743132814Y.0000000443}, pmid = {25213598}, issn = {1743-1328}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Astrocytes/metabolism ; Brain Stem/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Disease Models, Animal ; Heme Oxygenase-1/metabolism ; Humans ; Iron/blood ; Male ; Membrane Proteins/metabolism ; Mice, Transgenic ; Microglia/metabolism ; Oxidative Stress ; Phosphorylation ; Spinal Cord/metabolism ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; Transferrin/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult onset disease that produces gradual motor neuron cell death in the spinal cord (SP). Recently, transactive response DNA-binding protein 43 kDa (TDP-43), a critical component of insoluble ubiquitinated inclusions, has received attention in the treatment of neurodegenerative disorders, including frontotemporal lobar degeneration (FTLD) and ALS. TDP-43 modifications, including hyperphosphorylation, truncation, and ubiquitination, have been reported in the pathogenesis of neurodegenerative diseases (NDs). However, the pathogenic mechanism of TDP-43 in ALS is unclear. To determine the association between TDP-43 and neurotoxicity in an ALS model, we characterized TDP-43 expression in hSOD1(G93A) transgenic mice (Tg) as an ALS animal model. TDP-43 was expressed by astrocytes and microglial cells in the SP of hSOD1(G93A) transgenic mice. In addition, the expression of phosphorylated and truncated TDP-43 increased in the SP of ALS mice compared with age-matched non-Tg. Furthermore, the serum iron concentration and expression of transferrin, a homeostasis-related iron protein, in the SP were increased relative to non-Tg. The protein expression level of HO-1 related to oxidative stress was increased in the SP of hSOD1(G93A) Tg relative to non-Tg. We show that an increase of TDP-43 modification, including phosphorylation or truncation, associates with dysfunctional iron homeostasis and an increase in oxidative stress in the SP of symptomatic hSOD1(G93A) Tg. These findings suggest that modified TDP-43 may be involved in motor neuron death in the SP of a SOD1(G93A)-expressing familial ALS (fALS) animal model.}, }
@article {pmid25212999, year = {2014}, author = {Jiang, Y and Choi, WH and Lee, JH and Han, DH and Kim, JH and Chung, YS and Kim, SH and Lee, MJ}, title = {A neurostimulant para-chloroamphetamine inhibits the arginylation branch of the N-end rule pathway.}, journal = {Scientific reports}, volume = {4}, number = {}, pages = {6344}, pmid = {25212999}, issn = {2045-2322}, mesh = {Animals ; Arginine/*metabolism ; Cell Line, Tumor ; Frontal Lobe/drug effects/metabolism ; GTP-Binding Proteins/metabolism ; HeLa Cells ; Hippocampus/drug effects/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Proteolysis/*drug effects ; RGS Proteins/metabolism ; Signal Transduction/*drug effects ; p-Chloroamphetamine/*pharmacology ; }, abstract = {In the arginylation branch of the N-end rule pathway, unacetylated N-terminal destabilizing residues function as essential determinants of protein degradation signals (N-degron). Here, we show that a neurostimulant, para-chloroamphetamine (PCA), specifically inhibits the Arg/N-end rule pathway, delaying the degradation of its artificial and physiological substrates, including regulators of G protein signaling 4 (RGS4), in vitro and in cultured cells. In silico computational analysis indicated that PCA strongly interacts with both UBR box and ClpS box, which bind to type 1 and type 2 N-degrons, respectively. Moreover, intraperitoneal injection of PCA significantly stabilized endogenous RGS4 proteins in the whole mouse brain and, particularly, in the frontal cortex and hippocampus. Consistent with the role of RGS4 in G protein signaling, treatment with PCA impaired the activations of GPCR downstream effectors in N2A cells, phenocopying ATE1-null mutants. In addition, levels of pathological C-terminal fragments of TDP43 bearing N-degrons (Arg208-TDP25) were significantly elevated in the presence of PCA. Thus, our study identifies PCA as a potential tool to understand and modulate various pathological processes regulated by the Arg/N-end rule pathway, including neurodegenerative processes in FTLD-U and ALS.}, }
@article {pmid25206650, year = {2013}, author = {Zheng, M and Shi, Y and Fan, D}, title = {Nuclear TAR DNA-binding protein 43: A new target for amyotrophic lateral sclerosis treatment.}, journal = {Neural regeneration research}, volume = {8}, number = {35}, pages = {3284-3295}, pmid = {25206650}, issn = {1673-5374}, abstract = {Abnormal TAR DNA-binding protein 43 (TDP-43) inclusion bodies can be detected in the degenerative neurons of amyotrophic lateral sclerosis. In this study, we induced chronic oxidative stress injury by applying malonate to cultured mouse cortical motor neurons. In the later stages of the malonate insult, TDP-43 expression reduced in the nuclei and transferred to the cytoplasm. This was accompanied by neuronal death, mimicking the pathological changes in TDP-43 that are seen in patients with amyotrophic lateral sclerosis. Interestingly, in the early stages of the response to malonate treatment, nuclear TDP-43 expression increased, and neurons remained relatively intact, without inclusion bodies or fragmentation. Therefore, we hypothesized that the increase of nuclear TDP-43 expression might be a pro-survival factor against oxidative stress injury. This hypothesis was confirmed by an in vitro transgenic experiment, in which overexpression of wild type mouse TDP-43 in cultured cortical motor neurons significantly reduced malonate-induced neuronal death. Our findings suggest that the loss of function of TDP-43 is an important cause of neuronal degeneration, and upregulation of nuclear TDP-43 expression might be neuroprotective in amyotrophic lateral sclerosis.}, }
@article {pmid25196144, year = {2014}, author = {Shih, J and Liu, L and Mason, A and Higashimori, H and Donmez, G}, title = {Loss of SIRT4 decreases GLT-1-dependent glutamate uptake and increases sensitivity to kainic acid.}, journal = {Journal of neurochemistry}, volume = {131}, number = {5}, pages = {573-581}, doi = {10.1111/jnc.12942}, pmid = {25196144}, issn = {1471-4159}, mesh = {Animals ; Biotinylation ; Brain/cytology/drug effects ; Cells, Cultured ; Disease Models, Animal ; Embryo, Mammalian ; Excitatory Amino Acid Agonists/*pharmacology ; Excitatory Amino Acid Transporter 2/*metabolism ; Female ; Gene Expression Regulation/*drug effects ; Glutamic Acid/*metabolism ; Kainic Acid/*pharmacology ; Male ; Mice ; Mice, Knockout ; Mitochondrial Proteins/*deficiency ; Neurons/drug effects/ultrastructure ; Seizures/chemically induced/pathology ; Sirtuins/*deficiency ; Synaptosomes/drug effects/metabolism ; }, abstract = {Glutamate transport is a critical process in the brain that maintains low extracellular levels of glutamate to allow for efficient neurotransmission and prevent excitotoxicity. Loss of glutamate transport function is implicated in epilepsy, traumatic brain injury, and amyotrophic lateral sclerosis. It remains unclear whether or not glutamate transport can be modulated in these disease conditions to improve outcome. Here, we show that sirtuin (SIRT)4, a mitochondrial sirtuin, is up-regulated in response to treatment with the potent excitotoxin kainic acid. Loss of SIRT4 leads to a more severe reaction to kainic acid and decreased glutamate transporter expression and function in the brain. Together, these results indicate a critical and novel stress response role for SIRT4 in promoting proper glutamate transport capacity and protecting against excitotoxicity.}, }
@article {pmid25193423, year = {2014}, author = {Cleeland, CS and Mayer, M and Dreyer, NA and Yim, YM and Yu, E and Su, Z and Mun, Y and Sloan, JA and Kaufman, PA}, title = {Impact of symptom burden on work-related abilities in patients with locally recurrent or metastatic breast cancer: Results from a substudy of the VIRGO observational cohort study.}, journal = {Breast (Edinburgh, Scotland)}, volume = {23}, number = {6}, pages = {763-769}, doi = {10.1016/j.breast.2014.08.004}, pmid = {25193423}, issn = {1532-3080}, mesh = {*Activities of Daily Living ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/therapeutic use ; Antineoplastic Agents, Hormonal/therapeutic use ; Breast Neoplasms/*complications/drug therapy/pathology ; Cohort Studies ; Cost of Illness ; Cross-Sectional Studies ; Fatigue/*etiology ; Female ; Humans ; Middle Aged ; Neoplasm Metastasis ; Neoplasm Recurrence, Local/*complications/drug therapy/pathology ; Patient Outcome Assessment ; Prospective Studies ; Severity of Illness Index ; Sleep Wake Disorders/*etiology ; Stress, Psychological/*etiology ; *Work ; }, abstract = {Limited data exist on the association of symptom burden, daily activity impairment, and work productivity (WP) in patients with advanced breast cancer. This cross-sectional analysis evaluated baseline patient-reported outcomes (PROs) in patients with locally recurrent or metastatic breast cancer (MBC) receiving first-line hormonal therapy or chemotherapy and/or targeted therapy in the VIRGO observational study. The primary PRO study endpoint, symptom severity and interference score, was measured using the MD Anderson Symptom Inventory (MDASI). Secondary endpoints included Activity Level Scale (ALS), health-related quality of life (HRQOL), and Work Productivity and Activity Impairment Questionnaire (WPAI:SHP) scores. Overall, 152 patients (chemotherapy cohort, 104; hormonal therapy cohort, 48) answered questionnaires. Fatigue, decreased sexual interest, disturbed sleep, emotional distress, and drowsiness were the most common severe symptoms, and were of moderate-to-severe intensity in 38.8%-52.0% of patients. Mean percent daily activity impairment was 30% for study patients, and WP impairment ranged from 20% to 40% across indices in employed patients (n, 58). Significant positive correlations existed for MDASI severity and interference scores with activity impairment and WP indices (Pearson correlation coefficients [R] = 0.47-0.82; p < 0.0001). ALS and overall HRQOL correlated negatively with these indices (R = -0.41 to -0.60; p ≤ 0.001). After adjustment for potential confounders, MDASI symptom interference and ALS were significant predictors of activity and WP impairment. Our results indicate patients receiving treatment for MBC are symptomatic with significant daily activity and/or WP impairment. Symptom severity and interference, functional status, and overall HRQOL were moderately correlated with perceived work-related ability.}, }
@article {pmid25193343, year = {2014}, author = {Burns, A and Adeli, H and Buford, JA}, title = {Brain-computer interface after nervous system injury.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {20}, number = {6}, pages = {639-651}, doi = {10.1177/1073858414549015}, pmid = {25193343}, issn = {1089-4098}, mesh = {Amyotrophic Lateral Sclerosis/rehabilitation ; Brain/*physiopathology ; *Brain-Computer Interfaces/trends ; Consciousness Disorders/rehabilitation ; Humans ; Parkinson Disease/rehabilitation ; Signal Processing, Computer-Assisted ; Spinal Cord Injuries/rehabilitation ; Stroke Rehabilitation ; Trauma, Nervous System/*rehabilitation ; }, abstract = {Brain-computer interface (BCI) has proven to be a useful tool for providing alternative communication and mobility to patients suffering from nervous system injury. BCI has been and will continue to be implemented into rehabilitation practices for more interactive and speedy neurological recovery. The most exciting BCI technology is evolving to provide therapeutic benefits by inducing cortical reorganization via neuronal plasticity. This article presents a state-of-the-art review of BCI technology used after nervous system injuries, specifically: amyotrophic lateral sclerosis, Parkinson's disease, spinal cord injury, stroke, and disorders of consciousness. Also presented is transcending, innovative research involving new treatment of neurological disorders.}, }
@article {pmid25193138, year = {2014}, author = {Freischmidt, A and Müller, K and Zondler, L and Weydt, P and Volk, AE and Božič, AL and Walter, M and Bonin, M and Mayer, B and von Arnim, CA and Otto, M and Dieterich, C and Holzmann, K and Andersen, PM and Ludolph, AC and Danzer, KM and Weishaupt, JH}, title = {Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers.}, journal = {Brain : a journal of neurology}, volume = {137}, number = {Pt 11}, pages = {2938-2950}, doi = {10.1093/brain/awu249}, pmid = {25193138}, issn = {1460-2156}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/blood/*genetics ; C9orf72 Protein ; Down-Regulation ; Heterozygote ; Humans ; MicroRNAs/blood/*genetics ; Microarray Analysis ; Mutation/genetics ; *Prodromal Symptoms ; Proteins/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Knowledge about the nature of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis is largely lacking. It could not only pave the way for the discovery of valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained comprehensive expression profiles of microRNAs in the serum of patients with familial amyotrophic lateral sclerosis, asymptomatic mutation carriers and healthy control subjects. We observed a strikingly homogenous microRNA profile in patients with familial amyotrophic lateral sclerosis that was largely independent from the underlying disease gene. Moreover, we identified 24 significantly downregulated microRNAs in pre-manifest amyotrophic lateral sclerosis mutation carriers up to two decades or more before the estimated time window of disease onset; 91.7% of the downregulated microRNAs in mutation carriers overlapped with the patients with familial amyotrophic lateral sclerosis. Bioinformatic analysis revealed a consensus sequence motif present in the vast majority of downregulated microRNAs identified in this study. Our data thus suggest specific common denominators regarding molecular pathogenesis of different amyotrophic lateral sclerosis genes. We describe the earliest pathomolecular alterations in amyotrophic lateral sclerosis mutation carriers known to date, which provide a basis for the discovery of novel therapeutic targets and strongly argue for studies evaluating presymptomatic disease-modifying treatment in amyotrophic lateral sclerosis.}, }
@article {pmid25175561, year = {2014}, author = {Tagashira, H and Shinoda, Y and Shioda, N and Fukunaga, K}, title = {Methyl pyruvate rescues mitochondrial damage caused by SIGMAR1 mutation related to amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta}, volume = {1840}, number = {12}, pages = {3320-3334}, doi = {10.1016/j.bbagen.2014.08.012}, pmid = {25175561}, issn = {0006-3002}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease caused by motor neuron degeneration. Recently, a novel SIGMAR1 gene variant (p.E102Q) was discovered in some familial ALS patients.<br><br>METHODS: We address mechanisms underlying neurodegeneration caused by the mutation using Neuro2A cells overexpressing &#x3c3;1R(E102Q), a protein of a SIGMAR1 gene variant (p.E102Q) and evaluate potential amelioration by ATP production via methyl pyruvate (MP) treatment.<br><br>RESULTS: &#x3c3;1R(E102Q) overexpression promoted dissociation of the protein from the endoplasmic reticulum (ER) membrane and cytoplasmic aggregation, which in turn impaired mitochondrial ATP production and proteasome activity. Under ER stress conditions, overexpression of wild-type &#x3c3;1R suppressed ER stress-induced mitochondrial injury, whereas &#x3c3;1R(E102Q) overexpression aggravated mitochondrial damage and induced autophagic cell death. Moreover, &#x3c3;1R(E102Q)-overexpressing cells showed aberrant extra-nuclear localization of the TAR DNA-binding protein (TDP-43), a condition exacerbated by ER stress. Treatment of cells with the mitochondrial Ca(2+) transporter inhibitor Ru360 mimicked the effects of &#x3c3;1R(E102Q) overexpression, indicating that aberrant &#x3c3;1R-mediated mitochondrial Ca(2+) transport likely underlies TDP-43 extra-nuclear localization, segregation in inclusion bodies, and ubiquitination. Finally, enhanced ATP production promoted by methyl pyruvate (MP) treatment rescued proteasome impairment and TDP-43 extra-nuclear localization caused by &#x3c3;1R(E102Q) overexpression.<br><br>CONCLUSIONS: Our observations suggest that neurodegeneration seen in some forms of ALS are due in part to aberrant mitochondrial ATP production and proteasome activity as well as TDP-43 mislocalization resulting from the SIGMAR1 mutation.<br><br>GENERAL SIGNIFICANCE: ATP supplementation by MP represents a potential therapeutic strategy to treat ALS caused by SIGMAR1 mutation.}, }
@article {pmid25157751, year = {2014}, author = {Lewis, CM and Suzuki, M}, title = {Therapeutic applications of mesenchymal stem cells for amyotrophic lateral sclerosis.}, journal = {Stem cell research &amp; therapy}, volume = {5}, number = {2}, pages = {32}, pmid = {25157751}, issn = {1757-6512}, support = {R21NS06104/NS/NINDS NIH HHS/United States ; UL1 TR000427/TR/NCATS NIH HHS/United States ; UL1 RR025011/RR/NCRR NIH HHS/United States ; T32 GM008349/GM/NIGMS NIH HHS/United States ; 9U54TR000021/TR/NCATS NIH HHS/United States ; T32GM08349/GM/NIGMS NIH HHS/United States ; R21 NS061049/NS/NINDS NIH HHS/United States ; 1UL1RR025011/RR/NCRR NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Humans ; Mesenchymal Stem Cell Transplantation/*methods ; Mesenchymal Stem Cells/*cytology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the neuromuscular system and does not have a known singular cause. Genetic mutations, extracellular factors, non-neuronal support cells, and the immune system have all been shown to play varied roles in clinical and pathological disease progression. The therapeutic plasticity of mesenchymal stem cells (MSCs) may be well matched to this complex disease pathology, making MSCs strong candidates for cellular therapy in ALS. In this review, we summarize a variety of explored mechanisms by which MSCs play a role in ALS progression, including neuronal and non-neuronal cell replacement, trophic factor delivery, and modulation of the immune system. Currently relevant techniques for applying MSC therapy in ALS are discussed, focusing in particular on delivery route and cell source. We include examples from in vitro, preclinical, and clinical investigations to elucidate the remaining progress that must be made to understand and apply MSCs as a treatment for ALS.}, }
@article {pmid25157374, year = {2014}, author = {Calvo, AC and Manzano, R and Mendonça, DM and Muñoz, MJ and Zaragoza, P and Osta, R}, title = {Amyotrophic lateral sclerosis: a focus on disease progression.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {925101}, pmid = {25157374}, issn = {2314-6141}, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*pathology/physiopathology/therapy ; Animals ; Biomarkers/metabolism ; *Disease Progression ; Humans ; Practice Guidelines as Topic ; }, abstract = {Since amyotrophic lateral sclerosis (ALS) was discovered and described in 1869 as a neurodegenerative disease in which motor neuron death is induced, a wide range of biomarkers have been selected to identify therapeutic targets. ALS shares altered molecular pathways with other neurodegenerative diseases, such as Alzheimer's, Huntington's, and Parkinson's diseases. However, the molecular targets that directly influence its aggressive nature remain unknown. What is the first link in the neurodegenerative chain of ALS that makes this disease so peculiar? In this review, we will discuss the progression of the disease from the viewpoint of the potential biomarkers described to date in human and animal model samples. Finally, we will consider potential therapeutic strategies for ALS treatment and future, innovative perspectives.}, }
@article {pmid25147206, year = {2014}, author = {Reddy, K and Schmidt, MH and Geist, JM and Thakkar, NP and Panigrahi, GB and Wang, YH and Pearson, CE}, title = {Processing of double-R-loops in (CAG)·(CTG) and C9orf72 (GGGGCC)·(GGCCCC) repeats causes instability.}, journal = {Nucleic acids research}, volume = {42}, number = {16}, pages = {10473-10487}, pmid = {25147206}, issn = {1362-4962}, support = {R01 GM101192/GM/NIGMS NIH HHS/United States ; MOP-97896/CAPMC/CIHR/Canada ; R01GM101192/GM/NIGMS NIH HHS/United States ; }, mesh = {C9orf72 Protein ; Cell Line, Tumor ; DNA/chemistry/metabolism ; *DNA Repeat Expansion ; *Genomic Instability ; HeLa Cells ; Humans ; Neurons/metabolism ; Proteins/*genetics ; RNA/chemistry/metabolism ; Ribonuclease H/metabolism ; *Trinucleotide Repeat Expansion ; }, abstract = {R-loops, transcriptionally-induced RNA:DNA hybrids, occurring at repeat tracts (CTG)n, (CAG)n, (CGG)n, (CCG)n and (GAA)n, are associated with diseases including myotonic dystrophy, Huntington's disease, fragile X and Friedreich's ataxia. Many of these repeats are bidirectionally transcribed, allowing for single- and double-R-loop configurations, where either or both DNA strands may be RNA-bound. R-loops can trigger repeat instability at (CTG)·(CAG) repeats, but the mechanism of this is unclear. We demonstrate R-loop-mediated instability through processing of R-loops by HeLa and human neuron-like cell extracts. Double-R-loops induced greater instability than single-R-loops. Pre-treatment with RNase H only partially suppressed instability, supporting a model in which R-loops directly generate instability by aberrant processing, or via slipped-DNA formation upon RNA removal and its subsequent aberrant processing. Slipped-DNAs were observed to form following removal of the RNA from R-loops. Since transcriptionally-induced R-loops can occur in the absence of DNA replication, R-loop processing may be a source of repeat instability in the brain. Double-R-loop formation and processing to instability was extended to the expanded C9orf72 (GGGGCC)·(GGCCCC) repeats, known to cause amyotrophic lateral sclerosis and frontotemporal dementia, providing the first suggestion through which these repeats may become unstable. These findings provide a mechanistic basis for R-loop-mediated instability at disease-associated repeats.}, }
@article {pmid25146848, year = {2015}, author = {Cao, L and Tan, L and Jiang, T and Zhu, XC and Yu, JT}, title = {Induced Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {52}, number = {1}, pages = {244-255}, pmid = {25146848}, issn = {1559-1182}, mesh = {Animals ; Disease Models, Animal ; *Drug Discovery ; Genomics ; Humans ; Induced Pluripotent Stem Cells/*cytology ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*therapy ; }, abstract = {Although most neurodegenerative diseases have been closely related to aberrant accumulation of aggregation-prone proteins in neurons, understanding their pathogenesis remains incomplete, and there is no treatment to delay the onset or slow the progression of many neurodegenerative diseases. The availability of induced pluripotent stem cells (iPSCs) in recapitulating the phenotypes of several late-onset neurodegenerative diseases marks the new era in in vitro modeling. The iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in these diseases and provides a novel human stem cell platform for screening new candidate therapeutics. Modeling human diseases using iPSCs has created novel opportunities for both mechanistic studies as well as for the discovery of new disease therapies. In this review, we introduce iPSC-based disease modeling in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In addition, we discuss the implementation of iPSCs in drug discovery associated with some new techniques.}, }
@article {pmid25146247, year = {2014}, author = {Baig, AM}, title = {Designer's microglia with novel delivery system in neurodegenerative diseases.}, journal = {Medical hypotheses}, volume = {83}, number = {4}, pages = {510-512}, doi = {10.1016/j.mehy.2014.08.003}, pmid = {25146247}, issn = {1532-2777}, mesh = {Cell Line ; *Drug Delivery Systems ; Humans ; Microglia/*drug effects ; Models, Theoretical ; Neurodegenerative Diseases/*drug therapy ; }, abstract = {Neurodegenerative diseases are a group of central nervous system diseases that have a high rate of morbidity and mortality. More disabling than lethal, the pathogenesis of many of these diseases, like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and Multiple sclerosis, (MS) remains to be established. Even after passage of several decades subsequent to their first recognition, these diseases have proven to be notoriously refractory towards drug treatment. Stem cell therapy itself has faced problems like ethical issues with such transplants, difficult and risky implantation routes and immune rejections of the implanted stem cells. Somatic cell nuclear transfer (SCNT) offers a hope to the aforesaid diseases if the cells selected for nuclear donation itself has inherent regenerative and scavenging properties. Here we propose olfactory ensheathing cells (OEC's) as the donor somatic cell that conceivably would attempt regeneration in above mentioned diseases by differentiating into glia, which would have healthy mitochondria and without any fear of immune rejection. Also proposed is a method of delivering these cells after SCNT to the brain by a novel "transcribrial route" through a device that can deliver cells to the brain across the cribriform plate of ethmoid bone.}, }
@article {pmid25143843, year = {2014}, author = {Tremolizzo, L and Sala, G and Conti, E and Rodriguez-Menendez, V and Fogli, A and Michelucci, A and Simi, P and Penco, S and Lunetta, C and Corbo, M and Ferrarese, C}, title = {Valproate Treatment in an ALS Patient Carrying a c.194G&gt;A Spastin Mutation and SMN2 Homozygous Deletion.}, journal = {Case reports in neurological medicine}, volume = {2014}, number = {}, pages = {216094}, pmid = {25143843}, issn = {2090-6668}, abstract = {Here we report the case of an ALS patient found to carry both a novel heterozygous change (c.194G>A) within the spastin gene and a homozygous deletion of the SMN2 gene. The patient was started on valproic acid (VPA, 600 mg/die per os) considering the capacity of this drug of increasing survival motor neuron through an epigenetic mechanism. Patient clinical course and molecular effects of VPA on skin fibroblasts obtained from the proband are described. This c.194G>A spastin mutation might expand the previously known borders of type 4 spastic paraplegia (SPG4) and we suggest the intriguing possibility that the absence of SMN2 might have acted as a contributory risk factor for starting lower motor neuron damage. Exploring the relationship genocopy-phenocopy in selected ALS patients might represent an interesting strategy for understanding its clinical variability.}, }
@article {pmid25142597, year = {2014}, author = {Finnen, RL and Hay, TJ and Dauber, B and Smiley, JR and Banfield, BW}, title = {The herpes simplex virus 2 virion-associated ribonuclease vhs interferes with stress granule formation.}, journal = {Journal of virology}, volume = {88}, number = {21}, pages = {12727-12739}, pmid = {25142597}, issn = {1098-5514}, support = {37955//Canadian Institutes of Health Research/Canada ; 93804//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Arsenic/*toxicity ; Cell Line ; Cytoplasmic Granules/*metabolism ; Herpesvirus 2, Human/*enzymology ; *Host-Pathogen Interactions ; Humans ; *Oxidative Stress ; Ribonucleases/*metabolism ; Viral Proteins/*metabolism ; Virion/*enzymology ; }, abstract = {UNLABELLED: In a previous study, it was observed that cells infected with herpes simplex virus 2 (HSV-2) failed to accumulate stress granules (SGs) in response to oxidative stress induced by arsenite treatment. As a follow-up to this observation, we demonstrate here that disruption of arsenite-induced SG formation by HSV-2 is mediated by a virion component. Through studies on SG formation in cells infected with HSV-2 strains carrying defective forms of UL41, the gene that encodes vhs, we identify vhs as a virion component required for this disruption. Cells infected with HSV-2 strains producing defective forms of vhs form SGs spontaneously late in infection. In addition to core SG components, these spontaneous SGs contain the viral immediate early protein ICP27 as well as the viral serine/threonine kinase Us3. As part of these studies, we reexamined the frameshift mutation known to reside within the UL41 gene of HSV-2 strain HG52. We demonstrate that this mutation is unstable and can rapidly revert to restore wild-type UL41 following low-multiplicity passaging. Identification of the involvement of virion-associated vhs in the disruption of SG formation will enable mechanistic studies on how HSV-2 is able to counteract antiviral stress responses early in infection. In addition, the ability of Us3 to localize to stress granules may indicate novel roles for this viral kinase in the regulation of translation.<br><br>IMPORTANCE: Eukaryotic cells respond to stress by rapidly shutting down protein synthesis and storing mRNAs in cytoplasmic stress granules (SGs). Stoppages in protein synthesis are problematic for all viruses as they rely on host cell machinery to synthesize viral proteins. Thus, many viruses target SGs for disruption or modification. Infection by herpes simplex virus 2 (HSV-2) was previously observed to disrupt SG formation induced by oxidative stress. In this follow-up study, we identify virion host shutoff protein (vhs) as a viral protein involved in this disruption. The identification of a specific viral protein involved in disrupting SG formation is a key step toward understanding how HSV-2 interacts with these antiviral structures. Additionally, this understanding may provide insights into the biology of SGs that may find application in studies on human motor neuron degenerative diseases, like amyotrophic lateral sclerosis (ALS), which may arise as a result of dysregulation of SG formation.}, }
@article {pmid25138758, year = {2015}, author = {Mukhopadhyay, S and Sen, S and Datta, H}, title = {Comparative role of 20% cord blood serum and 20% autologous serum in dry eye associated with Hansen's disease: a tear proteomic study.}, journal = {The British journal of ophthalmology}, volume = {99}, number = {1}, pages = {108-112}, doi = {10.1136/bjophthalmol-2013-304801}, pmid = {25138758}, issn = {1468-2079}, mesh = {Administration, Topical ; Adult ; Aged ; Conjunctiva/pathology ; Double-Blind Method ; Dry Eye Syndromes/metabolism/microbiology/*therapy ; Electrophoresis, Polyacrylamide Gel ; Eye Infections, Bacterial/metabolism/microbiology/*therapy ; Eye Proteins/*metabolism ; Female ; *Fetal Blood ; Humans ; Lactoferrin/metabolism ; Leprosy/metabolism/microbiology/*therapy ; Male ; Middle Aged ; Muramidase/metabolism ; Prospective Studies ; Proteomics ; *Serum ; Tears/chemistry ; }, abstract = {BACKGROUND: To compare the role of topically applied serum therapy with preservative-free artificial tear (AT) drops in patients with moderate to severe dry eye in Hansen's disease along with change in tear protein profile.<br><br>METHODS: 144 consecutive patients were randomly divided into three groups. After a baseline examination of clinical parameters, each of the patients received designated modality of topical therapy six times a day for 6&#x2005;weeks. Post-treatment documentation of clinical parameters was done at 6&#x2005;weeks, and then at 12&#x2005;weeks after discontinuation of topical therapy. Analysis of three tear proteins using gel electrophoresis (sodium dodecyl sulfate polyacrylamide gel electrophoresis) was done at baseline, at the first and second post-treatment visits.<br><br>RESULTS: In the cord blood serum (CBS) group, except for McMonnies score and staining score, all other clinical parameters showed continued improvement in the first and second post-treatment analyses. In the autologous serum (ALS) group, all the clinical parameters except Schirmer's I showed significant improvement in the first post-treatment analysis .This was sustained at a significant level in the second analysis except for tear film break-up time (TBUT) and conjunctival impression cytology grading. In the AT group, all the parameters improved at a non-significant level except for TBUT in the first analysis. In the next analysis, apart from McMonnies score and TBUT, other clinical parameters did not improve. In the ALS and CBS groups, tear lysozyme, lactoferrin levels improved in both post-treatment measurements (statistically insignificant).Total tear protein continued to increase at statistically significant levels in the first and second post-treatment analyses in the CBS group and at a statistically insignificant level in the ALS group. In the AT group, the three tear proteins continued to decrease in both the analyses.<br><br>CONCLUSIONS: In moderate to severe dry eye in Hansen's disease, serum therapy in comparison with AT drops, improves clinical parameters and causes betterment in tear protein profile.<br><br>TRIAL REGISTRATION NUMBER: CTRI/2013/07/003802.}, }
@article {pmid25137152, year = {2015}, author = {Caga, J and Ramsey, E and Hogden, A and Mioshi, E and Kiernan, MC}, title = {A longer diagnostic interval is a risk for depression in amyotrophic lateral sclerosis.}, journal = {Palliative &amp; supportive care}, volume = {13}, number = {4}, pages = {1019-1024}, doi = {10.1017/S1478951514000881}, pmid = {25137152}, issn = {1478-9523}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*diagnosis/psychology ; Depression/*etiology ; Female ; Humans ; Male ; Middle Aged ; Psychiatric Status Rating Scales ; Risk Factors ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: Recognizing depressive symptoms in patients with amyotrophic lateral sclerosis (ALS) remains problematic given the potential overlap with the normal psychological responses to a terminal illness. Understanding mental health and disease-related risk factors for depression is key to identifying psychological morbidity. The present study aimed to determine the prevalence of depressive symptoms in ALS and to explore mental health and disease-related risk factors for depression.<br><br>METHOD: Structured medical and psychiatric history questionnaires and a validated depression scale (Depression, Anxiety, Stress Scale-21) were completed by 27 ALS patients (60% female; 59% limb onset; age 65.11 &#xb1; SE 2.21) prior to their initial review at a multidisciplinary clinic. Physical function was assessed with the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).<br><br>RESULTS: At the time of initial assessment, 44% of patients had a previous psychiatric history, although the majority (62%) reported no symptoms of depression. The mean ALSFRS-R score was 37.78 &#xb1; SE 1.22, with an average diagnostic interval of 16.04 &#xb1; SE 2.39 months. Logistic regression analysis revealed that the length of the diagnostic interval alone predicted depressive symptoms (&#x3c7;&#xb2;(3, n = 26) = 9.21, Odds Ratio (OR) = 1.12, p < 0.05.<br><br>SIGNIFICANCE OF RESULTS: The illness experiences of ALS patients rather than established mental health risk factors influence the manifestation of depressive symptoms in the early stages of the disease, with clinical implications for the assessment and treatment of psychological morbidity. Patients with lengthy diagnostic intervals may be prime targets for psychological assessment and intervention, especially in the absence of ALS-specific tests and biomarkers.}, }
@article {pmid25134731, year = {2014}, author = {Wang, L and Popko, B and Tixier, E and Roos, RP}, title = {Guanabenz, which enhances the unfolded protein response, ameliorates mutant SOD1-induced amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {71}, number = {}, pages = {317-324}, pmid = {25134731}, issn = {1095-953X}, support = {UL1 TR000430/TR/NCATS NIH HHS/United States ; R21 NS078142/NS/NINDS NIH HHS/United States ; R01 NS034939/NS/NINDS NIH HHS/United States ; NS078142-01/NS/NINDS NIH HHS/United States ; NS34939/NS/NINDS NIH HHS/United States ; }, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/mortality ; Animals ; Calcium-Binding Proteins/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Gene Expression Regulation/drug effects/genetics ; Glial Fibrillary Acidic Protein/metabolism ; Guanabenz/pharmacology/*therapeutic use ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microfilament Proteins/metabolism ; Protein Unfolding/*drug effects ; Superoxide Dismutase/*genetics ; Survival Analysis ; }, abstract = {Approximately 20% of familial amyotrophic lateral sclerosis (FALS) cases are caused by mutant superoxide dismutase type 1 (mtSOD1). Although the mechanisms of mtSOD1-induced toxicity remain poorly understood, evidence suggests that accumulation of misfolded SOD1 is fundamental to its toxicity and the death of motor neurons. Misfolded mtSOD1 can accumulate inside the endoplasmic reticulum (ER), leading to ER stress, with activation of the unfolded protein response (UPR). We have previously carried out genetic studies focused on PERK (which is an eIF2α kinase that is rapidly activated in response to ER stress and leads to a repression in translation) and GADD34 (which participates in the dephosphorylation of eIF2α). We reported that mtSOD1 transgenic mice that are haploinsufficient for PERK have a significantly accelerated ALS disease, while mtSOD1 mice that are mutated for GADD34 have a remarkably ameliorated disease. Guanabenz, a centrally acting oral drug approved for the treatment of hypertension, enhances the PERK pathway by selectively inhibiting GADD34-mediated dephosphorylation of eIF2α. We have now treated G93A mtSOD1 transgenic mice with guanabenz and found a significant amelioration of disease with a delay in the onset and prolongation of the early phase of disease and survival. Guanabenz-treated G93A mice have less accumulation of mtSOD1 and an enhanced phosphorylation of eIF2α at endstage. This study further emphasizes the importance of the PERK pathway in the pathogenesis of FALS and as a therapeutic target in ALS, and identifies guanabenz as a candidate drug for the treatment of ALS patients.}, }
@article {pmid25129998, year = {2014}, author = {Iwase, S and Kaneko, H and Fujioka, C and Sugimoto, K and Kondo, M and Takai, Y and Kachi, S and Terasaki, H}, title = {A long-term follow-up of patients with retinopathy of prematurity treated with photocoagulation and cryotherapy.}, journal = {Nagoya journal of medical science}, volume = {76}, number = {1-2}, pages = {121-128}, pmid = {25129998}, issn = {0027-7622}, mesh = {Adolescent ; Adult ; Axial Length, Eye ; *Cryosurgery/adverse effects ; Female ; Follow-Up Studies ; Humans ; Lens, Crystalline/pathology/physiopathology ; *Light Coagulation/adverse effects ; Male ; Myopia/diagnosis/etiology/physiopathology ; Refraction, Ocular ; Retina/pathology/physiopathology/*surgery ; Retinopathy of Prematurity/complications/diagnosis/physiopathology/*surgery ; Time Factors ; Treatment Outcome ; Visual Acuity ; Young Adult ; }, abstract = {To evaluate the refractive characteristics of adults diagnosed with retinopathy of prematurity (ROP) treated with ablation treatment as children, we measured best corrected visual acuity (BCVA, logMAR), spherical equivalent refraction (SER), axial length (AL), lens thickness (LT), anterior chamber depth (ACD) and the corneal curvature radius (CCR) from 46 eyes, 24 patients (15-30 years old) that were diagnosed with ROP. Patients were divided into two groups dependent on the size of the treated retina at the time of ablation treatment; i.e., 360 degrees group (treatment over the whole circumference of the retina; n = 18) and partial group (treatment over part of the retina; n = 28). The study showed that LT was significantly larger (P < 1x10(-4)) and ACD was significantly shorter (P < 1 x 10(-3)) in 360 degrees group (4.26 +/- 0.40 mm and 2.92 +/- 0.48 mm, respectively) than those in partial group (3.71 +/- 0.34 mm and 3.42 +/- 0.26 mm, respectively). However, there were no differences in SER (-6.52 +/- 3.54 diopter vs. -5.95 +/- 4.12 diopter, P = 0.31), AL (23.9 +/- 1.42 mm vs. 25.0 +/- 21.48 mm, P = 0.08) and CCR (7.59 +/- 0.37 mm vs. 7.59 +/- 0.19 mm, P = 0.86). These results indicated that the eyes in the 360 degrees group had larger LTs but did not have extended ALs compared with the partial group.}, }
@article {pmid25120635, year = {2014}, author = {Xie, L and Zhou, F}, title = {Autologous stem cell transplantation for a monoclonal gammopathy of undetermined significance mimicking amyotrophic lateral sclerosis: A case report.}, journal = {Experimental and therapeutic medicine}, volume = {8}, number = {3}, pages = {988-990}, pmid = {25120635}, issn = {1792-0981}, abstract = {It is rare for patients with monoclonal gammopathy of undetermined significance (MGUS) to present with clinical features of fatal motor neuron disease, for example amyotrophic lateral sclerosis (ALS). There is no standard and effective therapy for either MGUS or ALS. In addition, stem cell transplantation appears to be ineffective for the treatment of this disease. In the present study, a 47-year old female with MGUS that mimicked ALS is presented. The M-protein levels of the patient were normalized following two cycles of chemotherapy and autologous stem cell transplantation treatment. MGUS was found to be alleviated and the symptoms of ALS did not deteriorate. The results showed a positive therapeutic effect of autologous stem cell transplantation for MGUS.}, }
@article {pmid25113670, year = {2014}, author = {Forostyak, S and Homola, A and Turnovcova, K and Svitil, P and Jendelova, P and Sykova, E}, title = {Intrathecal delivery of mesenchymal stromal cells protects the structure of altered perineuronal nets in SOD1 rats and amends the course of ALS.}, journal = {Stem cells (Dayton, Ohio)}, volume = {32}, number = {12}, pages = {3163-3172}, pmid = {25113670}, issn = {1549-4918}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Cell Differentiation/physiology ; Chondroitin Sulfate Proteoglycans/metabolism ; Extracellular Matrix/metabolism ; Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; Male ; Mesenchymal Stem Cells/*cytology ; Nerve Net/cytology ; Neurons/*cytology ; Rats ; Spinal Cord/*metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder resulting in a lethal outcome. We studied changes in ventral horn perineuronal nets (PNNs) of superoxide dismutase 1 (SOD1) rats during the normal disease course and after the intrathecal application (5 × 10(5) cells) of human bone marrow mesenchymal stromal cells (MSCs) postsymptom manifestation. We found that MSCs ameliorated disease progression, significantly improved motor activity, and prolonged survival. For the first time, we report that SOD1 rats have an abnormal disorganized PNN structure around the spinal motoneurons and give different expression profiles of chondroitin sulfate proteoglycans (CSPGs), such as versican, aggrecan, and phosphacan, but not link protein-1. Additionally, SOD1 rats had different profiles for CSPG gene expression (Versican, Hapln1, Neurocan, and Tenascin-R), whereas Aggrecan and Brevican profiles remained unchanged. The application of MSCs preserved PNN structure, accompanied by better survival of motorneurons. We measured the concentration of cytokines (IL-1α, MCP-1, TNF-α, GM-CSF, IL-4, and IFN-γ) in the rats' cerebrospinal fluid and found significantly higher concentrations of IL-1α and MCP-1. Our results show that PNN and cytokine homeostasis are altered in the SOD1 rat model of ALS. These changes could potentially serve as biological markers for the diagnosis, assessment of treatment efficacy, and prognosis of ALS. We also show that the administration of human MSCs is a safe procedure that delays the loss of motor function and increases the overall survival of symptomatic ALS animals, by remodeling the recipients' pattern of gene expression and having neuroprotective and immunomodulatory effects.}, }
@article {pmid25111654, year = {2014}, author = {Malek, AM and Stickler, DE and Antao, VC and Horton, DK}, title = {The National ALS Registry: a recruitment tool for research.}, journal = {Muscle &amp; nerve}, volume = {50}, number = {5}, pages = {830-834}, pmid = {25111654}, issn = {1097-4598}, support = {CC999999//Intramural CDC HHS/United States ; UL1 TR000062/TR/NCATS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*epidemiology ; *Biomedical Research ; Community Health Planning ; Female ; Humans ; Internet/statistics &amp; numerical data ; Male ; Middle Aged ; *Patient Selection ; *Registries ; United States/epidemiology ; Young Adult ; }, abstract = {INTRODUCTION: Subject recruitment is critical for understanding fatal diseases like ALS, however linking patients with researchers can be challenging. The U.S. population-based National ALS Registry allows recruitment of persons with ALS (PALS) for research opportunities.<br><br>METHODS: The Registry's Research Notification Mechanism was used to recruit PALS aged &#x2265;21 years; participants completed a Web-based epidemiologic survey. PALS (n&#x2009;=&#x2009;2,232) were sent an email describing the study, and 268 surveys were completed.<br><br>RESULTS: The mean age (&#xb1; SD) of eligible participants was 57.7&#x2009;&#xb1;&#x2009;9.3 years for men and 61.5&#x2009;&#xb1;&#x2009;8.9 for women. Most were men (63%) and Caucasian (92%). Of 256 potentially eligible participants, 37.5% (n&#x2009;=&#x2009;96) returned an authorization to disclose protected health information. ALS was confirmed for 94% (83/88) from physician responses.<br><br>CONCLUSIONS: This analysis demonstrates the National ALS Registry's usefulness in recruiting PALS for research. This recruitment source can potentially foster the discovery of better treatment options and therapies, and of prevention strategies.}, }
@article {pmid25111569, year = {2014}, author = {Rezania, K and Gottlieb, O and Guralnick, A and Prachand, V and Sweitzer, BJ and Vigneswaran, W and White, SR and Roos, RP}, title = {Venous thromboembolism after diaphragm pacing in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {50}, number = {5}, pages = {863-865}, doi = {10.1002/mus.24420}, pmid = {25111569}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*pathology ; Diaphragm/*physiopathology/transplantation ; Female ; Humans ; Male ; Middle Aged ; Respiration Disorders/*etiology/surgery ; Venous Thrombosis/*etiology/surgery ; }, abstract = {INTRODUCTION: Patients with amyotrophic lateral sclerosis (ALS) are prone to venous thromboembolism (VTE) and secondary complications. Because there is an increased incidence of VTE after surgical procedures, placement of a Diaphragm Pacing System (DPS) in ALS patients as treatment for respiratory muscle weakness could potentially increase the incidence of VTE, especially in patients with limited mobility.<br><br>METHODS: We implanted a DPS in 10 ALS patients who met the criteria for this procedure. They underwent a preoperative evaluation as recommended by the guidelines.<br><br>RESULTS: We report 2 patients with no symptoms of deep vein thrombosis (DVT) before the surgical procedure who then developed perioperative VTE.<br><br>CONCLUSIONS: These patients highlight the need to consider preoperative screening for DVT and postoperative thromboprophylaxis in high-risk ALS patients who undergo DPS placement.}, }
@article {pmid25110934, year = {2014}, author = {Jenkins, TM and Hollinger, H and McDermott, CJ}, title = {The evidence for symptomatic treatments in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {27}, number = {5}, pages = {524-531}, doi = {10.1097/WCO.0000000000000135}, pmid = {25110934}, issn = {1473-6551}, support = {09/55/33/DH_/Department of Health/United Kingdom ; II-ES-0511-21003/DH_/Department of Health/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/psychology/therapy ; *Disease Management ; Humans ; *Quality of Life ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a progressive, incurable and fatal neurodegenerative disease. Few interventions significantly alter the disease course, but many symptomatic treatments exist to improve patients' quality of life. In this review, we describe our approach to symptomatic management of ALS and discuss the underlying evidence base.<br><br>RECENT FINDINGS: Discussion focuses predominantly on recently published articles. We cover management settings, disease-modifying treatment, vitamin D, respiratory management including noninvasive ventilation and diaphragmatic pacing, secretions, nutrition, dysphagia and gastrostomy, communication problems, mobility, spasticity, pain, cognition, depression and emotional lability, fatigue, sleep disturbance, head drop, prevention of deep venous thrombosis and end-of-life issues.<br><br>SUMMARY: Multidisciplinary specialist care appears to improve quality of life and survival. Riluzole remains the only available disease-modifying medication and confers a survival advantage of 2-3 months. Noninvasive ventilation improves quality of life and extends survival by approximately 7 months, at least in patients without severe bulbar problems. Nutrition is an independent prognostic factor; whether gastrostomy improves survival and quality of life remains unclear and further studies are underway. Many other symptomatic treatments appear helpful to individuals in clinic, but further randomized clinical trials are required to provide a more robust evidence base.}, }
@article {pmid25101284, year = {2014}, author = {Paoli, A and Bianco, A and Damiani, E and Bosco, G}, title = {Ketogenic diet in neuromuscular and neurodegenerative diseases.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {474296}, pmid = {25101284}, issn = {2314-6141}, mesh = {3-Hydroxybutyric Acid/*metabolism ; Alzheimer Disease/diet therapy/metabolism ; Amyotrophic Lateral Sclerosis/diet therapy/metabolism ; Brain/metabolism ; *Diet, Ketogenic ; Glucose/*metabolism ; Glycogen Storage Disease/diet therapy/metabolism ; Humans ; Mitochondrial Diseases/*diet therapy/metabolism ; Parkinson Disease/diet therapy/metabolism ; }, abstract = {An increasing number of data demonstrate the utility of ketogenic diets in a variety of metabolic diseases as obesity, metabolic syndrome, and diabetes. In regard to neurological disorders, ketogenic diet is recognized as an effective treatment for pharmacoresistant epilepsy but emerging data suggests that ketogenic diet could be also useful in amyotrophic lateral sclerosis, Alzheimer, Parkinson's disease, and some mitochondriopathies. Although these diseases have different pathogenesis and features, there are some common mechanisms that could explain the effects of ketogenic diets. These mechanisms are to provide an efficient source of energy for the treatment of certain types of neurodegenerative diseases characterized by focal brain hypometabolism; to decrease the oxidative damage associated with various kinds of metabolic stress; to increase the mitochondrial biogenesis pathways; and to take advantage of the capacity of ketones to bypass the defect in complex I activity implicated in some neurological diseases. These mechanisms will be discussed in this review.}, }
@article {pmid25100994, year = {2014}, author = {Lovejoy, DB and Guillemin, GJ}, title = {The potential for transition metal-mediated neurodegeneration in amyotrophic lateral sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {6}, number = {}, pages = {173}, pmid = {25100994}, issn = {1663-4365}, abstract = {Modulations of the potentially toxic transition metals iron (Fe) and copper (Cu) are implicated in the neurodegenerative process in a variety of human disease states including amyotrophic lateral sclerosis (ALS). However, the precise role played by these metals is still very much unclear, despite considerable clinical and experimental data suggestive of a role for these elements in the neurodegenerative process. The discovery of mutations in the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD-1) in ALS patients established the first known cause of ALS. Recent data suggest that various mutations in SOD-1 affect metal-binding of Cu and Zn, in turn promoting toxic protein aggregation. Copper homeostasis is also disturbed in ALS, and may be relevant to ALS pathogenesis. Another set of interesting observations in ALS patients involves the key nutrient Fe. In ALS patients, Fe loading can be inferred by studies showing increased expression of serum ferritin, an Fe-storage protein, with high serum ferritin levels correlating to poor prognosis. Magnetic resonance imaging of ALS patients shows a characteristic T2 shortening that is attributed to the presence of Fe in the motor cortex. In mutant SOD-1 mouse models, increased Fe is also detected in the spinal cord and treatment with Fe-chelating drugs lowers spinal cord Fe, preserves motor neurons, and extends lifespan. Inflammation may play a key causative role in Fe accumulation, but this is not yet conclusive. Excess transition metals may enhance induction of endoplasmic reticulum (ER) stress, a system that is already under strain in ALS. Taken together, the evidence suggests a role for transition metals in ALS progression and the potential use of metal-chelating drugs as a component of future ALS therapy.}, }
@article {pmid25096786, year = {2014}, author = {Arkema, EV and Feltelius, N and Olsson, T and Askling, J and , }, title = {No association between rheumatoid arthritis, amyotrophic lateral sclerosis, and tumour necrosis factor inhibitor treatment.}, journal = {Annals of the rheumatic diseases}, volume = {73}, number = {11}, pages = {2061-2062}, doi = {10.1136/annrheumdis-2014-205622}, pmid = {25096786}, issn = {1468-2060}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*chemically induced ; Arthritis, Rheumatoid/*drug therapy ; Biological Products/*adverse effects ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; Registries ; Tumor Necrosis Factor-alpha/*antagonists &amp; inhibitors ; }, }
@article {pmid25096716, year = {2014}, author = {Sippl, C and Zeilbeck, LF and Fuchshofer, R and Tamm, ER}, title = {Optineurin associates with the podocyte Golgi complex to maintain its structure.}, journal = {Cell and tissue research}, volume = {358}, number = {2}, pages = {567-583}, doi = {10.1007/s00441-014-1968-8}, pmid = {25096716}, issn = {1432-0878}, mesh = {Actin Cytoskeleton/metabolism ; Animals ; Apoptosis ; Cell Cycle Proteins ; Cell Line ; Cell Survival ; Focal Adhesions/metabolism ; Golgi Apparatus/*metabolism/ultrastructure ; Humans ; Lysosomes/metabolism ; Male ; Membrane Transport Proteins ; Microtubules/metabolism ; Nephrosis/metabolism/pathology ; Podocytes/*metabolism/pathology/*ultrastructure ; Protein Binding ; Protein Transport ; Puromycin Aminonucleoside ; RNA Interference ; RNA, Messenger/genetics/metabolism ; Rats, Sprague-Dawley ; Subcellular Fractions/metabolism ; Transcription Factor TFIIIA/deficiency/genetics/*metabolism ; Up-Regulation ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {Optineurin, a cytosolic protein associated with the actin cytoskeleton, microtubules, and the Golgi complex, appears to have an important function in neurons, as mutations in its gene are causative for neurodegenerative diseases such as primary open-angle glaucoma and amyotrophic lateral sclerosis. Here, we report that optineurin is localized in podocytes of the kidney and induced upon injury following treatment with puromycin aminonucleoside. In cultured human podocytes, optineurin localizes to the Golgi complex. Optineurin depletion by RNA interference causes Golgi fragmentation. Moreover, if the Golgi complex is fragmented following microtubule destabilization induced by nocodazole treatment, optineurin dissociates from Golgi vesicles. Furthermore, optineurin colocalizes with vinculin-labeled focal contacts of cultured podocytes and with lysosome-like structures. Optineurin is essential for the survival of cultured podocytes, as optineurin depletion causes cell death. Thus, optineurin appears to play an important role in the maintenance of the podocyte Golgi complex and in the trafficking of vesicles to focal contacts and lysosomes.}, }
@article {pmid25077336, year = {2014}, author = {Planas Vilà, M}, title = {[Nutritional and metabolic aspects of neurological diseases].}, journal = {Nutricion hospitalaria}, volume = {29 Suppl 2}, number = {}, pages = {3-12}, pmid = {25077336}, issn = {1699-5198}, mesh = {Brain Injuries/therapy ; Humans ; Nervous System Diseases/*metabolism/*physiopathology/therapy ; *Nutritional Physiological Phenomena ; Nutritional Support ; }, abstract = {The central nervous system regulates food intake, homoeostasis of glucose and electrolytes, and starts the sensations of hunger and satiety. Different nutritional factors are involved in the pathogenesis of several neurological diseases. Patients with acute neurological diseases (traumatic brain injury, cerebral vascular accident hemorrhagic or ischemic, spinal cord injuries, and cancer) and chronic neurological diseases (Alzheimer's Disease and other dementias, amyotrophic lateral sclerosis, Parkinson's Disease) increase the risk of malnutrition by multiple factors related to nutrient ingestion, abnormalities in the energy expenditure, changes in eating behavior, gastrointestinal changes, and by side effects of drugs administered. Patients with acute neurological diseases have in common the presence of hyper metabolism and hyper catabolism both associated to a period of prolonged fasting mainly for the frequent gastrointestinal complications, many times as a side effect of drugs administered. During the acute phase, spinal cord injuries presented a reduction in the energy expenditure but an increase in the nitrogen elimination. In order to correct the negative nitrogen balance increase intakes is performed with the result of a hyper alimentation that should be avoided due to the complications resulting. In patients with chronic neurological diseases and in the acute phase of cerebrovascular accident, dysphagia could be present which also affects intakes. Several chronic neurological diseases have also dementia, which lead to alterations in the eating behavior. The presence of malnutrition complicates the clinical evolution, increases muscular atrophy with higher incidence of respiratory failure and less capacity to disphagia recuperation, alters the immune response with higher rate of infections, increases the likelihood of fractures and of pressure ulcers, increases the incapacity degree and is an independent factor to increase mortality. The periodic nutritional evaluation due to the evolutionary changes should be part of the treatment. At the same time to know the metabolic and nutritional characteristics is important to be able to prevent and treat early the possible side effects. If nutritional support is indicated, the enteral route is the route of choice although some times, mainly in critical patients, parentral nutrition is necessary to ensure the administration of the required nutrients.}, }
@article {pmid25062507, year = {2014}, author = {Pattee, GL and Wymer, JP and Lomen-Hoerth, C and Appel, SH and Formella, AE and Pope, LE}, title = {An open-label multicenter study to assess the safety of dextromethorphan/quinidine in patients with pseudobulbar affect associated with a range of underlying neurological conditions.}, journal = {Current medical research and opinion}, volume = {30}, number = {11}, pages = {2255-2265}, pmid = {25062507}, issn = {1473-4877}, mesh = {Adolescent ; Adult ; Affective Symptoms/*drug therapy/etiology ; Aged ; Aged, 80 and over ; Cohort Studies ; Crying ; Cytochrome P-450 CYP2D6 Inhibitors/*therapeutic use ; Dextromethorphan/*therapeutic use ; Drug Combinations ; Excitatory Amino Acid Antagonists/*therapeutic use ; Female ; Humans ; Laughter ; Male ; Middle Aged ; Pseudobulbar Palsy/*drug therapy/etiology/*psychology ; Quinidine/*therapeutic use ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Pseudobulbar affect (PBA) is associated with neurological disorders or injury affecting the brain, and characterized by frequent, uncontrollable episodes of crying and/or laughing that are exaggerated or unrelated to the patient's emotional state. Clinical trials establishing dextromethorphan and quinidine (DM/Q) as PBA treatment were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). This trial evaluated DM/Q safety in patients with PBA secondary to any neurological condition affecting the brain.<br><br>OBJECTIVE: To evaluate the safety and tolerability of DM/Q during long-term administration to patients with PBA associated with multiple neurological conditions.<br><br>METHODS: Fifty-two-week open-label study of DM/Q 30/30&#x2009;mg twice daily. Safety measures included adverse events (AEs), laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations.<br><br>CLINICAL TRIAL REGISTRATION: #NCT00056524.<br><br>RESULTS: A total of 553 PBA patients with >30 different neurological conditions enrolled; 296 (53.5%) completed. The most frequently reported treatment-related AEs (TRAEs) were nausea (11.8%), dizziness (10.5%), headache (9.9%), somnolence (7.2%), fatigue (7.1%), diarrhea (6.5%), and dry mouth (5.1%). TRAEs were mostly mild/moderate, generally transient, and consistent with previous controlled trials. Serious AEs (SAEs) were reported in 126 patients (22.8%), including 47 deaths, mostly due to ALS progression and respiratory failure. No SAEs were deemed related to DM/Q treatment by investigators. ECG results suggested no clinically meaningful effect of DM/Q on myocardial repolarization. Differences in AEs across neurological disease groups appeared consistent with the known morbidity of the primary neurological conditions. Study interpretation is limited by the small size of some disease groups, the lack of a specific efficacy measure and the use of a DM/Q dose higher than the eventually approved dose.<br><br>CONCLUSIONS: DM/Q was generally well tolerated over this 52 week trial in patients with PBA associated with a wide range of neurological conditions.}, }
@article {pmid25061944, year = {2014}, author = {Ari, C and Poff, AM and Held, HE and Landon, CS and Goldhagen, CR and Mavromates, N and D'Agostino, DP}, title = {Metabolic therapy with Deanna Protocol supplementation delays disease progression and extends survival in amyotrophic lateral sclerosis (ALS) mouse model.}, journal = {PloS one}, volume = {9}, number = {7}, pages = {e103526}, pmid = {25061944}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Arginine/administration &amp; dosage/*analogs &amp; derivatives/therapeutic use ; Caprylates/administration &amp; dosage/*therapeutic use ; Dietary Supplements ; Ketoglutaric Acids/administration &amp; dosage/*therapeutic use ; Male ; Mice ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Ubiquinone/administration &amp; dosage/*analogs &amp; derivatives/therapeutic use ; gamma-Aminobutyric Acid/administration &amp; dosage/*therapeutic use ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and eventual death from respiratory failure. There is currently no cure or effective treatment for ALS. Besides motor neuron degeneration, ALS is associated with impaired energy metabolism, which is pathophysiologically linked to mitochondrial dysfunction and glutamate excitotoxicity. The Deanna Protocol (DP) is a metabolic therapy that has been reported to alleviate symptoms in patients with ALS. In this study we hypothesized that alternative fuels in the form of TCA cycle intermediates, specifically arginine-alpha-ketoglutarate (AAKG), the main ingredient of the DP, and the ketogenic diet (KD), would increase motor function and survival in a mouse model of ALS (SOD1-G93A). ALS mice were fed standard rodent diet (SD), KD, or either diets containing a metabolic therapy of the primary ingredients of the DP consisting of AAKG, gamma-aminobutyric acid, Coenzyme Q10, and medium chain triglyceride high in caprylic triglyceride. Assessment of ALS-like pathology was performed using a pre-defined criteria for neurological score, accelerated rotarod test, paw grip endurance test, and grip strength test. Blood glucose, blood beta-hydroxybutyrate, and body weight were also monitored. SD+DP-fed mice exhibited improved neurological score from age 116 to 136 days compared to control mice. KD-fed mice exhibited better motor performance on all motor function tests at 15 and 16 weeks of age compared to controls. SD+DP and KD+DP therapies significantly extended survival time of SOD1-G93A mice by 7.5% (p = 0.001) and 4.2% (p = 0.006), respectively. Sixty-three percent of mice in the KD+DP and 72.7% of the SD+DP group lived past 125 days, while only 9% of the control animals survived past that point. Targeting energy metabolism with metabolic therapy produces a therapeutic effect in ALS mice which may prolong survival and quality of life in ALS patients.}, }
@article {pmid25061302, year = {2014}, author = {Schoedel, KA and Morrow, SA and Sellers, EM}, title = {Evaluating the safety and efficacy of dextromethorphan/quinidine in the treatment of pseudobulbar affect.}, journal = {Neuropsychiatric disease and treatment}, volume = {10}, number = {}, pages = {1161-1174}, pmid = {25061302}, issn = {1176-6328}, abstract = {Pseudobulbar affect (PBA) is a common manifestation of brain pathology associated with many neurological diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, stroke, multiple sclerosis, Parkinson's disease, and traumatic brain injury. PBA is defined by involuntary and uncontrollable expressed emotion that is exaggerated and inappropriate, and also incongruent with the underlying emotional state. Dextromethorphan/quinidine (DM/Q) is a combination product indicated for the treatment of PBA. The quinidine component of DM/Q inhibits the cytochrome P450 2D6-mediated metabolic conversion of dextromethorphan to its active metabolite dextrorphan, thereby increasing dextromethorphan systemic bioavailability and driving the pharmacology toward that of the parent drug and away from adverse effects of the dextrorphan metabolite. Three published efficacy and safety studies support the use of DM/Q in the treatment of PBA; significant effects were seen on the primary end point, the Center for Neurologic Study-Lability Scale, as well as secondary efficacy end points and quality of life. While concentration-effect relationships appear relatively weak for efficacy parameters, concentrations of DM/Q may have an impact on safety. Some special safety concerns exist with DM/Q, primarily because of the drug interaction and QT prolongation potential of the quinidine component. However, because concentrations of dextrorphan (which is responsible for many of the parent drug's side effects) and quinidine are lower than those observed in clinical practice with these drugs administered alone, some of the perceived safety issues may not be as relevant with this low dose combination product. However, since patients with PBA have a variety of other medical problems and are on numerous other medications, they may not tolerate DM/Q adverse effects, or may be at risk for drug interactions. Some caution is warranted when initiating DM/Q treatment, particularly in patients with underlying risk factors for torsade de pointes and in those receiving medications that may interact with DM/Q.}, }
@article {pmid25057490, year = {2014}, author = {Song, L and Chen, L and Zhang, X and Li, J and Le, W}, title = {Resveratrol ameliorates motor neuron degeneration and improves survival in SOD1(G93A) mouse model of amyotrophic lateral sclerosis.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {483501}, pmid = {25057490}, issn = {2314-6141}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Antioxidants/chemistry ; Apoptosis ; Behavior, Animal ; Disease Models, Animal ; Female ; Lipid Peroxidation ; Lumbar Vertebrae/pathology ; Male ; Mice ; Mice, Transgenic ; Microscopy, Fluorescence ; Motor Neurons/*drug effects/pathology ; Muscle, Skeletal/pathology ; Neurodegenerative Diseases/*drug therapy ; Oxidative Stress ; Resveratrol ; Spinal Cord/pathology ; Stilbenes/chemistry/*therapeutic use ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Resveratrol has recently been used as a supplemental treatment for several neurological and nonneurological diseases. It is not known whether resveratrol has neuroprotective effect on amyotrophic lateral sclerosis (ALS). To assess the effect of resveratrol on the disease, we tested this agent on an ALS model of SOD1(G93A) transgenic mouse. Rotarod measurement was performed to measure the motor function of the ALS mice. Nissl staining and SMI-32 immunofluorescent staining were used to determine motor neurons survival in the spinal cord of the ALS mice. Hematoxylin-eosin (H&amp;E), succinic dehydrogenase (SDH), and cytochrome oxidase (COX) staining were applied to pathologically analyze the skeletal muscles of the ALS mice. We found that resveratrol treatment significantly delayed the disease onset and prolonged the lifespan of the ALS mice. Furthermore, resveratrol treatment attenuated motor neuron loss, relieved muscle atrophy, and improved mitochondrial function of muscle fibers in the ALS mice. In addition, we demonstrated that resveratrol exerted these neuroprotective effects mainly through increasing the expression of Sirt1, consequently suppressing oxidative stress and downregulating p53 and its related apoptotic pathway. Collectively, our findings suggest that resveratrol might provide a promising therapeutic intervention for ALS.}, }
@article {pmid25048984, year = {2015}, author = {Zhang, HY and Wang, ZG and Lu, XH and Kong, XX and Wu, FZ and Lin, L and Tan, X and Ye, LB and Xiao, J}, title = {Endoplasmic reticulum stress: relevance and therapeutics in central nervous system diseases.}, journal = {Molecular neurobiology}, volume = {51}, number = {3}, pages = {1343-1352}, pmid = {25048984}, issn = {1559-1182}, mesh = {Animals ; Central Nervous System Diseases/*metabolism/pathology/*therapy ; Endoplasmic Reticulum/*metabolism/pathology ; Endoplasmic Reticulum Stress/*physiology ; Humans ; Neurons/*metabolism ; Signal Transduction/*physiology ; Unfolded Protein Response/physiology ; }, abstract = {Endoplasmic reticulum (ER) stress plays an important role in a range of neurological disorders, such as neurodegenation diseases, cerebral ischemia, spinal cord injury, sclerosis, and diabetic neuropathy. Protein misfolding and accumulation in the ER lumen initiate unfolded protein response in energy-starved neurons which are relevant to toxic effects. In neurological disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, ER dysfunction is well recognized, but the mechanisms remain unclear. In stroke and ischemia, spinal cord injury, and amyotrophic lateral sclerosis, chronic activation of ER stress is considered as main pathogeny which causes neuronal disorders. By targeting components of these ER signaling responses, to explore clinical treatment strategies or new drugs in CNS neurological diseases might become possible and valuable in the future.}, }
@article {pmid25047909, year = {2014}, author = {Łukaszewicz-Zając, M and Mroczko, B and Słowik, A}, title = {Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in amyotrophic lateral sclerosis (ALS).}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {121}, number = {11}, pages = {1387-1397}, pmid = {25047909}, issn = {1435-1463}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Humans ; Matrix Metalloproteinases/*metabolism ; Tissue Inhibitor of Metalloproteinases/*metabolism ; }, abstract = {Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases, responsible for the integrity of the basement membrane (BM) via degradation of extracellular matrix and BM components. These enzymes are presented in central and peripheral nervous system. They are considered to be involved in the pathogenesis of several neurological diseases, including amyotrophic lateral sclerosis (ALS). ALS is a motor neuron disease, leading to muscle atrophy, paralysis and death within 3-5 years from diagnosis. Currently, there is no treatment that can substantially prolong life of ALS patients. Despite the fact that MMPs are not specific for ALS, there is also strong evidence that these enzymes are involved in the pathology of ALS. MMPs are able to exert direct neurotoxic effects, or may cause cell death by degrading matrix proteins. The objective of this paper is to provide an updated and comprehensive review concerning the role of MMPs and their tissue inhibitors (TIMPs) in the pathology of ALS with an emphasis on the significance of MMP-2 and MMP-9 as well as their tissue inhibitors as potential biomarkers of ALS. Numerous hypotheses have been proposed regarding the role of selected MMPs and TIMPs in ALS pathogenesis. Moreover, selective MMPs' inhibitors might be potential targets for therapeutic strategies for patients with ALS. However, future investigations are necessary before some of those non-specific for ALS enzymes could finally be used as biomarkers of this disease.}, }
@article {pmid25036750, year = {2015}, author = {Lu, D and Chen, EY and Lee, P and Wang, YC and Ching, W and Markey, C and Gulstrom, C and Chen, LC and Nguyen, T and Chin, WC}, title = {Accelerated neuronal differentiation toward motor neuron lineage from human embryonic stem cell line (H9).}, journal = {Tissue engineering. Part C, Methods}, volume = {21}, number = {3}, pages = {242-252}, pmid = {25036750}, issn = {1937-3392}, mesh = {Animals ; *Cell Differentiation/drug effects ; Cell Line ; *Cell Lineage/drug effects ; Embryonic Stem Cells/*cytology/drug effects/metabolism ; Fluorescent Antibody Technique ; Humans ; Iron/pharmacology ; Mice ; Motor Neurons/*cytology/drug effects ; Neural Stem Cells/cytology/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Transferrin/antagonists &amp; inhibitors/metabolism ; }, abstract = {Motor neurons loss plays a pivotal role in the pathoetiology of various debilitating diseases such as, but not limited to, amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, and spinal muscular atrophy. However, advancement in motor neuron replacement therapy has been significantly constrained by the difficulties in large-scale production at a cost-effective manner. Current methods to derive motor neuron heavily rely on biochemical stimulation, chemical biological screening, and complex physical cues. These existing methods are seriously challenged by extensive time requirements and poor yields. An innovative approach that overcomes prior hurdles and enhances the rate of successful motor neuron transplantation in patients is of critical demand. Iron, a trace element, is indispensable for the normal development and function of the central nervous system. Whether ferric ions promote neuronal differentiation and subsequently promote motor neuron lineage has never been considered. Here, we demonstrate that elevated iron concentration can drastically accelerate the differentiation of human embryonic stem cells (hESCs) toward motor neuron lineage potentially via a transferrin mediated pathway. HB9 expression in 500 nM iron-treated hESCs is approximately twofold higher than the control. Moreover, iron treatment generated more matured and functional motor neuron-like cells that are ∼1.5 times more sensitive to depolarization when compared to the control. Our methodology renders an expedited approach to harvest motor neuron-like cells for disease, traumatic injury regeneration, and drug screening.}, }
@article {pmid25034472, year = {2014}, author = {Lefaucheur, JP and André-Obadia, N and Antal, A and Ayache, SS and Baeken, C and Benninger, DH and Cantello, RM and Cincotta, M and de Carvalho, M and De Ridder, D and Devanne, H and Di Lazzaro, V and Filipović, SR and Hummel, FC and Jääskeläinen, SK and Kimiskidis, VK and Koch, G and Langguth, B and Nyffeler, T and Oliviero, A and Padberg, F and Poulet, E and Rossi, S and Rossini, PM and Rothwell, JC and Schönfeldt-Lecuona, C and Siebner, HR and Slotema, CW and Stagg, CJ and Valls-Sole, J and Ziemann, U and Paulus, W and Garcia-Larrea, L}, title = {Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS).}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {125}, number = {11}, pages = {2150-2206}, doi = {10.1016/j.clinph.2014.05.021}, pmid = {25034472}, issn = {1872-8952}, support = {102584//Wellcome Trust/United Kingdom ; }, mesh = {Cerebral Cortex/*physiopathology ; Epilepsy/physiopathology/*therapy ; Evidence-Based Medicine ; Humans ; Mental Disorders/physiopathology/*therapy ; Movement Disorders/physiopathology/*therapy ; Multiple Sclerosis/physiopathology/*therapy ; Stroke/physiopathology/*therapy ; Transcranial Magnetic Stimulation/*methods ; }, abstract = {A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.}, }
@article {pmid25033844, year = {2014}, author = {Srivastava, AK}, title = {Clinical relevance of stem cell therapies in amyotrophic lateral sclerosis.}, journal = {Neurology India}, volume = {62}, number = {3}, pages = {239-248}, doi = {10.4103/0028-3886.136895}, pmid = {25033844}, issn = {0028-3886}, mesh = {Amyotrophic Lateral Sclerosis/surgery/*therapy ; *Clinical Trials as Topic ; Humans ; Stem Cell Transplantation/*methods/standards ; }, abstract = {Amyotrophic lateral sclerosis (ALS), characterized by the progressive loss of both upper and lower motor neurons, is a fatal neurodegenerative disorder. This disease is often accompanied by a tremendous physical and emotional burden not only for the patients, but also for their families and friends as well. There is no clinically relevant treatment available for ALS. To date, only one Food and Drug Administration (FDA)-approved drug, Riluzole, licensed 18 years ago, has been proven to marginally prolong patients' survival without improving the quality of their lives. Because of the lack of an effective drug treatment and the promising outcomes from several preclinical studies, researchers have highlighted this disease as a suitable candidate for stem cell therapy. This review article highlights the finding of key preclinical studies that present a rationale for the use of different types of stem cells for the treatment of ALS, and the most recent updates on the stem cell-based ALS clinical trials around the world.}, }
@article {pmid25017368, year = {2014}, author = {Poppe, L and Rué, L and Robberecht, W and Van Den Bosch, L}, title = {Translating biological findings into new treatment strategies for amyotrophic lateral sclerosis (ALS).}, journal = {Experimental neurology}, volume = {262 Pt B}, number = {}, pages = {138-151}, doi = {10.1016/j.expneurol.2014.07.001}, pmid = {25017368}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Disease Models, Animal ; Humans ; Translational Research, Biomedical/*methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the selective death of motor neurons in the motor cortex, brainstem and spinal cord. It is a neurodegenerative disorder with high genetic and phenotypic variability. In most patients, the cause of the disease is unknown. Until now, no treatment strategy has been discovered with the exception of riluzole which has a moderate effect on the disease process. While developing a new causal therapy targeting a specific disease-causing gene can have a huge effect on the disease process, only a limited number of ALS patients will benefit from such a therapy. Alternatively, pathogenic processes that are common in ALS patients with different etiology can also be targeted. The effect of such a modifying treatment will be smaller, but the target population will be larger as more ALS patients could benefit. In this review, we summarize the evidence for the involvement of different biological processes in the pathogenesis of ALS and will discuss how strategies influencing these processes can be translated into new therapeutic approaches. In order to further improve this translational step, there is an urgent need for a better understanding of the underlying mechanism(s), for new ALS animal models and for rigorous protocols to perform preclinical studies.}, }
@article {pmid25007880, year = {2015}, author = {Corona, JC and Duchen, MR}, title = {PPARγ and PGC-1α as therapeutic targets in Parkinson's.}, journal = {Neurochemical research}, volume = {40}, number = {2}, pages = {308-316}, pmid = {25007880}, issn = {1573-6903}, support = {G-1101/PUK_/Parkinson's UK/United Kingdom ; MR/M02492X/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Humans ; PPAR gamma/*agonists ; Parkinson Disease/*drug therapy ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Transcription Factors/*drug effects ; }, abstract = {The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcriptional factor that belongs to the nuclear hormone receptor superfamily. PPARγ was initially identified through its role in the regulation of glucose and lipid metabolism and cell differentiation. It also influences the expression or activity of a number of genes in a variety of signalling networks. These include regulation of redox balance, fatty acid oxidation, immune responses and mitochondrial function. Recent studies suggest that the PPARγ agonists may serve as good candidates for the treatment of several neurodegenerative disorders including Parkinson's disease (PD), Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis, even though multiple etiological factors contribute to the development of these disorders. Recent reports have also signposted a role for PPARγ coactivator-1α (PGC-1α) in several neurodegenerative disorders including PD. In this review, we explore the current knowledge of mechanisms underlying the beneficial effects of PPARγ agonists and PGC-1α in models of PD.}, }
@article {pmid25005187, year = {2014}, author = {Lee, J and Ryu, H and Keum, G and Yoon, YJ and Kowall, NW and Ryu, H}, title = {Therapeutic targeting of epigenetic components in amyotrophic lateral sclerosis (ALS).}, journal = {Current medicinal chemistry}, volume = {21}, number = {31}, pages = {3576-3582}, doi = {10.2174/0929867321666140706131825}, pmid = {25005187}, issn = {1875-533X}, support = {I01 BX000856/BX/BLRD VA/United States ; NS067283/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology/therapy ; Animals ; *Epigenesis, Genetic ; Histone Deacetylase Inhibitors/therapeutic use ; Histone Deacetylases/chemistry/genetics/metabolism ; Humans ; Hydroxamic Acids/therapeutic use ; Motor Neurons/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Valproic Acid/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease characterized by degeneration of motor neuron and glial activation followed by the progressive muscle loss and paralysis. Numerous distinct therapeutic interventions have been examined but currently ALS does not have a cure or an efficacious treatment for the disorder. Glutamate- induced excitotoxicity, inflammation, mitochondrial dysfunction, oxidative stress, protein aggregation, transcription deregulation, and epigenetic modifications are associated with the pathogenesis of ALS and known to be therapeutic targets in ALS. In this review, we discuss translational pharmacological studies targeting epigenetic components to ameliorate ALS. Understanding of the epigenetic mechanisms will provide novel insights that will further identify potential biological markers and therapeutic approaches for treating ALS. A combination of treatments that modulate epigenetic components and multiple targets may prove to be the most effective therapy for ALS.}, }
@article {pmid25004804, year = {2014}, author = {Dini Modigliani, S and Morlando, M and Errichelli, L and Sabatelli, M and Bozzoni, I}, title = {An ALS-associated mutation in the FUS 3'-UTR disrupts a microRNA-FUS regulatory circuitry.}, journal = {Nature communications}, volume = {5}, number = {}, pages = {4335}, doi = {10.1038/ncomms5335}, pmid = {25004804}, issn = {2041-1723}, support = {GGP11149/TI_/Telethon/Italy ; }, mesh = {3' Untranslated Regions ; Amyotrophic Lateral Sclerosis/*genetics/metabolism ; *Gene Expression Regulation ; Homeodomain Proteins/genetics/metabolism ; Humans ; MicroRNAs/*genetics/metabolism ; Mutation ; RNA-Binding Protein FUS/*genetics/metabolism ; Transcription Factors/genetics/metabolism ; Zinc Finger E-box-Binding Homeobox 1 ; }, abstract = {While the physiologic functions of the RNA-binding protein FUS still await thorough characterization, the pathonegetic role of FUS mutations in amyotrophic lateral sclerosis (ALS) is clearly established. Here we find that a human FUS mutation that leads to increased protein expression, and was identified in two ALS patients with severe outcome, maps to the seed sequence recognized by miR-141 and miR-200a in the 3'-UTR of FUS. We demonstrate that FUS and these microRNAs are linked by a feed-forward regulatory loop where FUS upregulates miR-141/200a, which in turn impact FUS protein synthesis. We also show that Zeb1, a target of miR-141/200a and transcriptional repressor of these two microRNAs, is part of the circuitry and reinforces it. Our results reveal a possible correlation between deregulation of this regulatory circuit and ALS pathogenesis, and open interesting perspectives in the treatment of these mutations through ad hoc-modified microRNAs.}, }
@article {pmid24995608, year = {2014}, author = {Kwon, MS and Noh, MY and Oh, KW and Cho, KA and Kang, BY and Kim, KS and Kim, YS and Kim, SH}, title = {The immunomodulatory effects of human mesenchymal stem cells on peripheral blood mononuclear cells in ALS patients.}, journal = {Journal of neurochemistry}, volume = {131}, number = {2}, pages = {206-218}, doi = {10.1111/jnc.12814}, pmid = {24995608}, issn = {1471-4159}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*immunology/*therapy ; Animals ; Coculture Techniques ; Female ; Humans ; Immunomodulation/*immunology ; Injections, Spinal ; Leukocytes, Mononuclear/*immunology ; Male ; Mesenchymal Stem Cell Transplantation/*methods ; Mesenchymal Stem Cells/*immunology ; Mice ; Mice, Transgenic ; Middle Aged ; T-Lymphocytes, Regulatory/immunology ; Young Adult ; }, abstract = {In a previous study, we reported that intrathecal injection of mesenchymal stem cells (MSCs) slowed disease progression in G93A mutant superoxide dismutase1 transgenic mice. In this study, we found that intrathecal MSC administration vastly increased the infiltration of peripheral immune cells into the spinal cord of Amyotrophic lateral sclerosis (ALS) mice (G93A mutant superoxide dismutase1 transgenic). Thus, we investigated the immunomodulatory effect of MSCs on peripheral blood mononuclear cells (PBMCs) in ALS patients, focusing on regulatory T lymphocytes (Treg ; CD4(+) /CD25(high) /FoxP3(+)) and the mRNA expression of several cytokines (IFN-γ, TNF-α, IL-17, IL-4, IL-10, IL-13, and TGF-β). Peripheral blood samples were obtained from nine healthy controls (HC) and sixteen patients who were diagnosed with definite or probable ALS. Isolated PBMCs from the blood samples of all subjects were co-cultured with MSCs for 24 or 72 h. Based on a fluorescence-activated cell sorting analysis, we found that co-culture with MSCs increased the Treg /total T-lymphocyte ratio in the PBMCs from both groups according to the co-culture duration. Co-culture of PBMCs with MSCs for 24 h led to elevated mRNA levels of IFN-γ and IL-10 in the PBMCs from both groups. However, after co-culturing for 72 h, although the IFN-γ mRNA level had returned to the basal level in co-cultured HC PBMCs, the IFN-γ mRNA level in co-cultured ALS PBMCs remained elevated. Additionally, the levels of IL-4 and TGF-β were markedly elevated, along with Gata3 mRNA, a Th2 transcription factor mRNA, in both HC and ALS PBMCs co-cultured for 72 h. The elevated expression of these cytokines in the co-culture supernatant was confirmed via ELISA. Furthermore, we found that the increased mRNA level of indoleamine 2,3-dioxygenase (IDO) in the co-cultured MSCs was correlated with the increase in Treg induction. These findings of Treg induction and increased anti-inflammatory cytokine expression in co-cultured ALS PBMCs provide indirect evidence that MSCs may play a role in the immunomodulation of inflammatory responses when MSC therapy is targeted to ALS patients. We propose the following mechanism for the effect of mesenchymal stem cells (MSCs) administered intrathecally in amyotrophic lateral sclerosis (ALS): MSCs increase infiltration of peripheral immune cells into CNS and skew the infiltrated immune cells toward regulatory T lymphocytes (Treg) and Th2 lymphocytes. Treg and Th2 secret anti-inflammatory cytokines such as IL-4, IL-10, and TGF-β. A series of immunomodulatory mechanism provides a new strategy for ALS treatment.}, }
@article {pmid24991537, year = {2014}, author = {Manzano, S and Gaffney, EA and Doblaré, M and Hamdy Doweidar, M}, title = {Cartilage dysfunction in ALS patients as side effect of motion loss: 3D mechano-electrochemical computational model.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {179070}, pmid = {24991537}, issn = {2314-6141}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Biomechanical Phenomena ; Cartilage, Articular/metabolism/pathology/*ultrastructure ; Chondrocytes/pathology/ultrastructure ; *Computer Simulation ; Humans ; Motor Neurons/pathology/*ultrastructure ; Osmotic Pressure ; Permeability ; Proteoglycans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease characterized by progressive weakness, muscle atrophy, and fasciculation. This fact results in a continuous degeneration and dysfunction of articular soft tissues. Specifically, cartilage is an avascular and nonneural connective tissue that allows smooth motion in diarthrodial joints. Due to the avascular nature of cartilage tissue, cells nutrition and by-product exchange are intermittently occurring during joint motions. Reduced mobility results in a change of proteoglycan density, osmotic pressure, and permeability of the tissue. This work aims to demonstrate the abnormal cartilage deformation in progressive immobilized articular cartilage for ALS patients. For this aim a novel 3D mechano-electrochemical model based on the triphasic theory for charged hydrated soft tissues is developed. ALS patient parameters such as tissue porosity, osmotic coefficient, and fixed anions were incorporated. Considering different mobility reduction of each phase of the disease, results predicted the degree of tissue degeneration and the reduction of its capacity for deformation. The present model can be a useful tool to predict the evolution of joints in ALS patients and the necessity of including specific cartilage protectors, drugs, or maintenance physical activities as part of the symptomatic treatment in amyotrophic lateral sclerosis.}, }
@article {pmid24984404, year = {2014}, author = {Whiteman, C and Shaver, E and Doerr, R and Davis, SM and Blum, F and Davidov, D and Lander, O}, title = {Trauma patient access: the role of the emergency medical services system in North-Central West Virginia.}, journal = {The West Virginia medical journal}, volume = {110}, number = {3}, pages = {30-35}, pmid = {24984404}, issn = {0043-3284}, mesh = {Emergency Service, Hospital/*statistics &amp; numerical data ; Health Services Accessibility/*statistics &amp; numerical data ; Humans ; Retrospective Studies ; Rural Health Services/*statistics &amp; numerical data ; Time Factors ; Transportation of Patients/*statistics &amp; numerical data ; Trauma Centers/standards/*statistics &amp; numerical data ; West Virginia ; Wounds and Injuries/*therapy ; }, abstract = {UNLABELLED: Trauma patients face many obstacles as they access the healthcare system in North-Central West Virginia. This study highlights some of these barriers and discusses administrative and legislative initiatives that could help mitigate the disparities that rural trauma patients face.<br><br>METHODS: This is a retrospective, observational study utilizing information from the West Virginia University (WVU) MedCom Database. Trauma related Emergency Medical Services (EMS) calls from 2002 to 2011 were reviewed to determine many of the parameters of the care provided by EMS in the WVU MedCom catchment area. These 54,952 trauma related EMS contacts were reviewed to determine estimated time of arrival (ETA) at the receiving facility, level of EMS response, trauma activation criteria, time of day, and day of week of the transport.<br><br>RESULTS: The mean ETA for all transports was 11.7 minutes with mean transport ETA from the most rural county, Pendleton County, being 28.4 minutes. Emergency Medical Technician-B (BLS) providers covered 23% of the calls. Emergency Medical Technician-P (ALS) providers covered 76% of the calls. West Virginia State Trauma activation criteria were met for 30% of the transports. BLS providers transported 19% of these trauma activation criteria patients and ALS providers transported 78% of these transports.<br><br>CONCLUSIONS: In north-central West Virginia, there are many barriers facing the trauma patient as they access the healthcare system. Among these are extended transport times, the capabilities of the EMS provider responding, and the limitation that approximately 50% of counties have either no hospital at all or only a hospital with limited treatment capability for the trauma patient transported by EMS.}, }
@article {pmid24973750, year = {2014}, author = {Patten, SA and Armstrong, GA and Lissouba, A and Kabashi, E and Parker, JA and Drapeau, P}, title = {Fishing for causes and cures of motor neuron disorders.}, journal = {Disease models &amp; mechanisms}, volume = {7}, number = {7}, pages = {799-809}, pmid = {24973750}, issn = {1754-8411}, mesh = {Animals ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Humans ; Motor Neuron Disease/*drug therapy/*etiology/pathology ; Signal Transduction ; Zebrafish/*metabolism ; }, abstract = {Motor neuron disorders (MNDs) are a clinically heterogeneous group of neurological diseases characterized by progressive degeneration of motor neurons, and share some common pathological pathways. Despite remarkable advances in our understanding of these diseases, no curative treatment for MNDs exists. To better understand the pathogenesis of MNDs and to help develop new treatments, the establishment of animal models that can be studied efficiently and thoroughly is paramount. The zebrafish (Danio rerio) is increasingly becoming a valuable model for studying human diseases and in screening for potential therapeutics. In this Review, we highlight recent progress in using zebrafish to study the pathology of the most common MNDs: spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). These studies indicate the power of zebrafish as a model to study the consequences of disease-related genes, because zebrafish homologues of human genes have conserved functions with respect to the aetiology of MNDs. Zebrafish also complement other animal models for the study of pathological mechanisms of MNDs and are particularly advantageous for the screening of compounds with therapeutic potential. We present an overview of their potential usefulness in MND drug discovery, which is just beginning and holds much promise for future therapeutic development.}, }
@article {pmid24966876, year = {2014}, author = {Lai, YC and Li, HY and Wu, TJ and Jeng, CY and Chuang, LM}, title = {Correlation of Circulating Acid-Labile Subunit Levels with Insulin Sensitivity and Serum LDL Cholesterol in Patients with Type 2 Diabetes: Findings from a Prospective Study with Rosiglitazone.}, journal = {PPAR research}, volume = {2014}, number = {}, pages = {917823}, pmid = {24966876}, issn = {1687-4757}, abstract = {Silencing of acid-labile subunit (ALS) improved glucose metabolism in animal models. The aim of this study is to evaluate the effects of rosiglitazone (RSG) on ALS levels in individuals with type 2 diabetes. A randomized, double-blind, placebo-controlled trial was conducted. Subjects with type 2 diabetes mellitus were randomly distributed to an RSG-treated (n = 30) or a placebo (n = 31) group. Patients were evaluated prior to treatment at baseline and at 12 and 24 weeks after treatment. At baseline, ALS levels were negatively associated with low-density lipoprotein cholesterol (LDLc) levels and homeostatic model assessment version 2 insulin sensitivity (HOMA2-%S). Over 24 weeks, there was a significantly greater reduction in ALS levels in the nonobese RSG-treated individuals than placebo-treated group. The effect of RSG on ALS was not significant in obese individuals. Fasting plasma glucose and hemoglobin A1c were reduced, but total cholesterol and LDLc were increased, in patients on RSG. Change in ALS levels predicted changes in total cholesterol and HOMA2-%S over time. This study suggested a BMI-dependent effect of RSG treatment on ALS levels. Reduction of ALS by RSG increases the risk of atherosclerosis in individuals with type 2 diabetes.}, }
@article {pmid24966156, year = {2014}, author = {Kim, HY and Kim, H and Oh, KW and Oh, SI and Koh, SH and Baik, W and Noh, MY and Kim, KS and Kim, SH}, title = {Biological markers of mesenchymal stromal cells as predictors of response to autologous stem cell transplantation in patients with amyotrophic lateral sclerosis: an investigator-initiated trial and in vivo study.}, journal = {Stem cells (Dayton, Ohio)}, volume = {32}, number = {10}, pages = {2724-2731}, doi = {10.1002/stem.1770}, pmid = {24966156}, issn = {1549-4918}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/pathology/*therapy ; Animals ; Biomarkers/*metabolism ; Cell Count ; Female ; Humans ; Male ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*cytology ; Mice ; Middle Aged ; Motor Neurons/pathology ; Transplantation, Autologous ; }, abstract = {Bone marrow mesenchymal stromal cells (MSCs) can modify disease progression in amyotrophic lateral sclerosis (ALS) model. However, there are currently no accurate biological markers for predicting the efficacy of autologous MSC transplants in ALS patients. This open-label, single-arm, investigator-initiated clinical study was designed to identify markers of MSCs that could be used as potential predictors of response to autologous MSC therapy in patients with ALS. We enrolled 37 patients with ALS who received autologous MSCs via intrathecal injection in two monthly doses. After a 6-month follow-up period, the patients were categorized as responders and non-responders based on their scores on the revised ALS Functional Rating Scale (ALSFRS-R). Biological markers including β-fibroblast growth factor-2, stromal cell-derived factor-1α, vascular endothelial growth factor (VEGF), insulin-like growth factor-1, brain-derived neurotrophic factor, angiogenin (ANG), interleukin (IL)-4, IL-10, and transforming growth factor-β (TGF-β) were measured in the MSC cultures and their levels were compared between the responders and nonresponders. To confirm the markers' predictive ability, MSCs isolated from one patient in each group were transplanted into the cisterna magna of mutant SOD1(G93A) transgenic mice to measure their lifespans, locomotor activity, and motor neuron numbers. The levels of VEGF, ANG, and TGF-β were significantly higher in responders than in nonresponders. In the mouse model, the recipients of responder MSCs had a significantly slower onset of symptoms and a significantly longer lifespan than the recipients of nonresponders or controls. Our data suggest that VEGF, ANG, and TGF-β levels in MSCs could be used as potential biological markers to predict the effectiveness of autologous MSC therapy and to identify those patients who could optimally benefit from MSC treatment.}, }
@article {pmid24964114, year = {2014}, author = {Batista, CE and Mariano, ED and Marie, SK and Teixeira, MJ and Morgalla, M and Tatagiba, M and Li, J and Lepski, G}, title = {Stem cells in neurology--current perspectives.}, journal = {Arquivos de neuro-psiquiatria}, volume = {72}, number = {6}, pages = {457-465}, doi = {10.1590/0004-282x20140045}, pmid = {24964114}, issn = {1678-4227}, mesh = {Central Nervous System/physiopathology ; Central Nervous System Diseases/*therapy ; Humans ; Nerve Regeneration ; Stem Cell Transplantation/methods/*standards ; Stem Cells/*cytology ; }, abstract = {UNLABELLED: Central nervous system (CNS) restoration is an important clinical challenge and stem cell transplantation has been considered a promising therapeutic option for many neurological diseases.<br><br>OBJECTIVE: The present review aims to briefly describe stem cell biology, as well as to outline the clinical application of stem cells in the treatment of diseases of the CNS.<br><br>METHOD: Literature review of animal and human clinical experimental trials, using the following key words: "stem cell", "neurogenesis", "Parkinson", "Huntington", "amyotrophic lateral sclerosis", "traumatic brain injury", "spinal cord injury", "ischemic stroke", and "demyelinating diseases".<br><br>CONCLUSION: Major recent advances in stem cell research have brought us several steps closer to their effective clinical application, which aims to develop efficient ways of regenerating the damaged CNS.}, }
@article {pmid24961916, year = {2014}, author = {Shemisa, K and Kaelber, D and Parikh, SA and Mackall, JA}, title = {Autonomic etiology of heart block in amyotrophic lateral sclerosis: a case report.}, journal = {Journal of medical case reports}, volume = {8}, number = {}, pages = {224}, pmid = {24961916}, issn = {1752-1947}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Atrioventricular Block/diagnosis/*etiology/physiopathology ; Autonomic Nervous System Diseases/*complications/physiopathology ; Dyspnea/*etiology/physiopathology ; Electrocardiography ; Humans ; Male ; }, abstract = {INTRODUCTION: The cardiovascular consequences related to amyotrophic lateral sclerosis are relatively underappreciated. The disease invokes a systematic degeneration of autonomic neurons leading to autonomic dysfunction. We therefore hypothesized that patients with amyotrophic lateral sclerosis may have a predilection to the development of cardiac conduction disorders.<br><br>CASE PRESENTATION: A 65-year-old Caucasian man with advanced amyotrophic lateral sclerosis presented with progressive dyspnea and palpitations. A previous evaluation attributed his dyspnea to neuromuscular weakness and he underwent a pulmonary evaluation. Pulmonary function tests did not indicate a worsening from baseline. An electrocardiogram was obtained which demonstrated new third degree atrioventricular block. A previously obtained electrocardiogram indicated normal sinus rhythm. On echocardiogram, a structurally normal heart was observed without significant valvular disease. He was offered a permanent dual chamber pacemaker for definitive treatment, however, he declined.<br><br>CONCLUSIONS: We believe that his symptoms were probably attributable to atrioventricular block. Patients with advanced amyotrophic lateral sclerosis experience loss of heart rate variability and enhanced vasomotor responses. As patients progress later in the disease, sympathetic denervation and vagal predominance contribute to the development of atrioventricular block. We conducted a query using the Explorys database of patients with amyotrophic lateral sclerosis and heart block. The prevalence of heart block was estimated to be 25% higher in patients with the disease as compared to the general population. This is the first reported case that attempts to describe the relationship of atrioventricular block with amyotrophic lateral sclerosis.}, }
@article {pmid24946089, year = {2014}, author = {Valle, C and Salvatori, I and Gerbino, V and Rossi, S and Palamiuc, L and René, F and Carrì, MT}, title = {Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models: pharmacological characterization of SIRT1 and SIRT2 pathways.}, journal = {Cell death &amp; disease}, volume = {5}, number = {6}, pages = {e1296}, pmid = {24946089}, issn = {2041-4889}, mesh = {Amino Acid Substitution ; Amyotrophic Lateral Sclerosis/*enzymology/genetics/pathology ; Animals ; Disease Models, Animal ; Enzyme Inhibitors/pharmacology ; Histone Deacetylases/genetics/*metabolism ; Humans ; Mice ; Mice, Transgenic ; Mutation, Missense ; Sirtuin 1/antagonists &amp; inhibitors/genetics/*metabolism ; Sirtuin 2/antagonists &amp; inhibitors/genetics/*metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Acetylation homeostasis is thought to play a role in amyotrophic lateral sclerosis, and treatment with inhibitors of histone deacetylases has been considered a potential and attractive therapeutic approach, despite the lack of a thorough study of this class of proteins. In this study, we have considerably extended previous knowledge on the expression of 13 histone deacetylases in tissues (spinal cord and muscle) from mice carrying two different ALS-linked SOD1 mutations (G93A-SOD1 and G86R-SOD1). We have then focused on class III histone deacetylases SIRT1 and SIRT2 that are considered relevant in neurodegenerative diseases. SIRT1 decreases in the spinal cord, but increases in muscle during the progression of the disease, and a similar expression pattern is observed in the corresponding cell models (neuroblastoma and myoblasts). SIRT2 mRNA expression increases in the spinal cord in both G93A-SOD1 and G86R-SOD1 mice but protein expression is substantially unchanged in all the models examined. At variance with other sirtuin modulators (sirtinol, AGK2 and SRT1720), the well-known SIRT1 inhibitor Ex527 has positive effects on survival of neuronal cells expressing mutant SOD1, but this effect is neither mediated by SIRT1 inhibition nor by SIRT2 inhibition. These data call for caution in proposing sirtuin modulation as a target for treatment.}, }
@article {pmid24945434, year = {2014}, author = {Natarajan, R and Singal, V and Benes, R and Gao, J and Chan, H and Chen, H and Yu, Y and Zhou, J and Wu, P}, title = {STAT3 modulation to enhance motor neuron differentiation in human neural stem cells.}, journal = {PloS one}, volume = {9}, number = {6}, pages = {e100405}, pmid = {24945434}, issn = {1932-6203}, mesh = {Astrocytes/drug effects/metabolism ; *Cell Differentiation/drug effects ; Cell Line ; Cell Nucleus/drug effects/metabolism ; Cell Survival/drug effects ; Cyclic S-Oxides/pharmacology ; Fibroblast Growth Factor 2/pharmacology ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Motor Neurons/*cytology/drug effects/metabolism ; Neural Stem Cells/*cytology/drug effects/*metabolism ; Niclosamide/pharmacology ; Phosphorylation/drug effects ; Phosphotyrosine/metabolism ; Protein Transport/drug effects ; STAT3 Transcription Factor/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Spinal cord injury or amyotrophic lateral sclerosis damages spinal motor neurons and forms a glial scar, which prevents neural regeneration. Signal transducer and activator of transcription 3 (STAT3) plays a critical role in astrogliogenesis and scar formation, and thus a fine modulation of STAT3 signaling may help to control the excessive gliogenic environment and enhance neural repair. The objective of this study was to determine the effect of STAT3 inhibition on human neural stem cells (hNSCs). In vitro hNSCs primed with fibroblast growth factor 2 (FGF2) exhibited a lower level of phosphorylated STAT3 than cells primed by epidermal growth factor (EGF), which correlated with a higher number of motor neurons differentiated from FGF2-primed hNSCs. Treatment with STAT3 inhibitors, Stattic and Niclosamide, enhanced motor neuron differentiation only in FGF2-primed hNSCs, as shown by increased homeobox gene Hb9 mRNA levels as well as HB9+ and microtubule-associated protein 2 (MAP2)+ co-labeled cells. The increased motor neuron differentiation was accompanied by a decrease in the number of glial fibrillary acidic protein (GFAP)-positive astrocytes. Interestingly, Stattic and Niclosamide did not affect the level of STAT3 phosphorylation; rather, they perturbed the nuclear translocation of phosphorylated STAT3. In summary, we demonstrate that FGF2 is required for motor neuron differentiation from hNSCs and that inhibition of STAT3 further increases motor neuron differentiation at the expense of astrogliogenesis. Our study thus suggests a potential benefit of targeting the STAT3 pathway for neurotrauma or neurodegenerative diseases.}, }
@article {pmid24936617, year = {2014}, author = {Terashima, T and Kojima, H and Urabe, H and Yamakawa, I and Ogawa, N and Kawai, H and Chan, L and Maegawa, H}, title = {Stem cell factor-activated bone marrow ameliorates amyotrophic lateral sclerosis by promoting protective microglial migration.}, journal = {Journal of neuroscience research}, volume = {92}, number = {7}, pages = {856-869}, pmid = {24936617}, issn = {1097-4547}, support = {P30 DK079638/DK/NIDDK NIH HHS/United States ; R01 HL051586/HL/NHLBI NIH HHS/United States ; P30-DK079638/DK/NIDDK NIH HHS/United States ; R01-HL51586/HL/NHLBI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/*surgery ; Animals ; Antigens, CD/metabolism ; Antigens, Differentiation, Myelomonocytic/metabolism ; Bone Marrow Transplantation/*methods ; Calcium-Binding Proteins/metabolism ; Cell Movement/drug effects/*physiology ; Disease Models, Animal ; Female ; Glial Fibrillary Acidic Protein/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microfilament Proteins/metabolism ; Microglia/*physiology ; Microtubule-Associated Proteins/metabolism ; Motor Neurons/physiology ; Rotarod Performance Test ; Spinal Cord/metabolism/pathology ; Stem Cell Factor/*therapeutic use ; Superoxide Dismutase/genetics ; fms-Like Tyrosine Kinase 3/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with motor neuron death. Several experimental treatments, including cell therapy using hematopoietic or neuronal stem cells, have been tested in ALS animal models, but therapeutic benefits have been modest. Here we used a new therapeutic strategy, bone marrow transplantation (BMT) with stem cell factor (SCF)- or FMS-like tyrosine kinase 3 (flt3)-activated bone marrow (BM) cells for the treatment of hSOD1(G93A) transgenic mice. Motor function and survival showed greater improvement in the SCF group than in the group receiving BM cells that had not been activated (BMT alone group), although no improvement was shown in the flt3 group. In addition, larger numbers of BM-derived cells that expressed the microglia marker Iba1 migrated to the spinal cords of recipient mice compared with the BMT alone group. Moreover, after SCF activation, but not flt3 activation or no activation, the migrating microglia expressed glutamate transporter-1 (GLT-1). In spinal cords in the SCF group, inflammatory cytokines tumor necrosis factor-α and interleukin-1β were suppressed and the neuroprotective molecule insulin-like growth factor-1 increased relative to nontreatment hSOD1(G93A) transgenic mice. Therefore, SCF activation changed the character of the migrating donor BM cells, which resulted in neuroprotective effects. These studies have identified SCF-activated BM cells as a potential new therapeutic agent for the treatment of ALS.}, }
@article {pmid24934359, year = {2014}, author = {Menon, P and Kiernan, MC and Vucic, S}, title = {Biomarkers and future targets for development in amyotrophic lateral sclerosis.}, journal = {Current medicinal chemistry}, volume = {21}, number = {31}, pages = {3535-3550}, doi = {10.2174/0929867321666140601161148}, pmid = {24934359}, issn = {1875-533X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology/therapy ; Animals ; Biomarkers/*metabolism ; DNA-Binding Proteins/genetics/metabolism ; Disease Models, Animal ; Glutamic Acid/toxicity ; Humans ; Neuroprotective Agents/therapeutic use ; Oligonucleotides, Antisense/therapeutic use ; Receptors, AMPA/metabolism ; Sodium Channels/chemistry/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Although the pathophysiological mechanisms underlying the development of amyotrophic lateral sclerosis (ALS) remain to be fully elucidated, there have been significant advances in the understanding of ALS pathogenesis, with evidence emerging of a complex interaction between genetic factors and dysfunction of vital molecular pathways. Glutamate- mediated excitoxicity is an important pathophysiological pathway in ALS, and was identified as an important therapeutic biomarker leading to development of the only pharmacologically based disease-modifying treatment currently available for ALS. More recently, a putative role of voltage-gated persistent Na(+) channels in ALS pathogenesis has been suggested and underscored by neuroprotective effects of Na(+) channel blocking agents in animal models. In addition, advances in ALS genetics have lead to identification of novel pathophysiological processes that could potentially serve as therapeutic targets in ALS. Genetic therapies, including antisense oligonucleotide approaches have been shown to exert neuroprotective effects in animal models of ALS, and Phase I human trial have been completed demonstrating the feasibility of such a therapeutic approach. The present review summarises the advances in ALS pathogenesis, emphasising the importance of these processes as potential targets for drug development in ALS.}, }
@article {pmid24934355, year = {2014}, author = {Yacila, G and Sari, Y}, title = {Potential therapeutic drugs and methods for the treatment of amyotrophic lateral sclerosis.}, journal = {Current medicinal chemistry}, volume = {21}, number = {31}, pages = {3583-3593}, pmid = {24934355}, issn = {1875-533X}, support = {R01 AA019458/AA/NIAAA NIH HHS/United States ; R01AA019458/AA/NIAAA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*therapy ; Animals ; Anticonvulsants/therapeutic use ; Biomarkers/metabolism ; Cell- and Tissue-Based Therapy ; Disease Models, Animal ; Genetic Therapy ; Humans ; Immunotherapy ; Nerve Growth Factors/therapeutic use ; Riluzole/therapeutic use ; Stem Cell Transplantation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder caused by damage of motoneurons leading to paralysis state and long term disability. Riluzole is currently the only FDA-approved drug for the treatment of ALS. The proposed mechanisms of ALS include glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, protein aggregation, SOD1 accumulations, and neuronal death. In this review, we discuss potential biomarkers for the identification of patients with ALS. We further emphasize potential therapy involving the uses of neurotrophic factors such as IGFI, GDNF, VEGF, ADNF-9, colivelin and angiogenin in the treatment of ALS. Moreover, we described several existing drugs such as talampanel, ceftriaxone, pramipexole, dexpramipexole and arimoclomol potential compounds for the treatment of ALS. Interestingly, the uses of stem cell therapy and immunotherapy are promising for the treatment of ALS.}, }
@article {pmid24931271, year = {2014}, author = {Sanjuán-López, P and Valiño-López, P and Ricoy-Gabaldón, J and Verea-Hernando, H}, title = {Amyotrophic lateral sclerosis: impact of pulmonary follow-up and mechanical ventilation on survival. A study of 114 cases.}, journal = {Archivos de bronconeumologia}, volume = {50}, number = {12}, pages = {509-513}, doi = {10.1016/j.arbres.2014.04.010}, pmid = {24931271}, issn = {1579-2129}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/mortality/physiopathology/*therapy ; Animals ; Disease Progression ; Dogs ; Female ; Follow-Up Studies ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; *Noninvasive Ventilation ; Respiration, Artificial ; Respiratory Center/physiopathology ; Respiratory Insufficiency/etiology/therapy ; Retrospective Studies ; Survival Analysis ; Tracheostomy ; }, abstract = {OBJECTIVE: To study the impact of ventilatory management and treatment on the survival of patients with amyotrophic lateral sclerosis (ALS).<br><br>METHOD: Retrospective analysis of 114 consecutive patients admitted to a general hospital, evaluating demographic data, type of presentation, clinical management, treatment with mechanical ventilation and survival.<br><br>STATISTICS: descriptive and Kaplan-Meier estimator.<br><br>RESULTS: Sixty four patients presented initial bulbar involvement. Overall mean survival after diagnosis was 28.0 months (95%CI, 21.1-34.8). Seventy patients were referred to the pulmonary specialist (61.4%) and 43 received non-invasive ventilation (NIV) at 12.7 months (median) after diagnosis. Thirty seven patients continued to receive NIV with no subsequent invasive ventilation. The mean survival of these patients was 23.3 months (95%CI, 16.7-28.8), higher in those without bulbar involvement, although below the range of significance. Survival in the 26 patients receiving programmed NIV was higher than in the 11 patients in whom this was indicated without prior pulmonary assessment (considered following diagnosis, P<.012, and in accordance with the start of ventilation, P<.004). A total of 7 patients were treated invasively; mean survival in this group was 72 months (95%CI, 14.36-129.6), median 49.6&#xb1;17.5 (95%CI, 15.3-83.8), and despite the difficulties involved in home care, acceptance and tolerance was acceptable.<br><br>CONCLUSIONS: Long-term mechanical ventilation prolongs survival in ALS. Programmed pulmonary assessment has a positive impact on survival of ALS patients and is key to the multidisciplinary management of this disease.}, }
@article {pmid24927875, year = {2014}, author = {Vucic, S and Rothstein, JD and Kiernan, MC}, title = {Advances in treating amyotrophic lateral sclerosis: insights from pathophysiological studies.}, journal = {Trends in neurosciences}, volume = {37}, number = {8}, pages = {433-442}, doi = {10.1016/j.tins.2014.05.006}, pmid = {24927875}, issn = {1878-108X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/*physiopathology/*therapy ; C9orf72 Protein ; Causality ; DNA-Binding Proteins/genetics ; Humans ; Neuroprotective Agents/therapeutic use ; Proteins/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequently occurring of the neuromuscular degenerative disorders, with a median survival time of 3-5 years. The pathophysiological mechanisms underlying ALS are multifactorial, with a complex interaction between genetic factors and molecular pathways. To date 16 genes and loci have been associated with ALS, with mutations in DNA/RNA-regulating genes including the recently described c9orf72 (chromosome 9 open reading frame 72) gene, suggesting an important role for dysregulation of RNA metabolism in ALS pathogenesis. Further, dysfunction of molecular pathways, including glutamate-mediated excitotoxicity, has been identified in sporadic and familial ALS, indicating the existence of a common pathogenic pathway. These pathophysiological insights have suggested novel therapeutic approaches, including stem cell and genetics-based strategies, providing hope for feasible treatment of ALS.}, }
@article {pmid24926935, year = {2014}, author = {Tauchi, R and Imagama, S and Inoh, H and Yukawa, Y and Kanemura, T and Sato, K and Sakai, Y and Kamiya, M and Yoshihara, H and Ito, Z and Ando, K and Muramoto, A and Matsui, H and Matsumoto, T and Ukai, J and Kobayashi, K and Shinjo, R and Nakashima, H and Morozumi, M and Ishiguro, N}, title = {Characteristics and surgical results of the distal type of cervical spondylotic amyotrophy.}, journal = {Journal of neurosurgery. Spine}, volume = {21}, number = {3}, pages = {411-416}, doi = {10.3171/2014.4.SPINE13681}, pmid = {24926935}, issn = {1547-5646}, mesh = {Adult ; Aged ; Cervical Vertebrae/*surgery ; Diagnostic Imaging ; Female ; Humans ; Male ; Middle Aged ; Muscle Weakness/etiology ; Muscular Atrophy, Spinal/etiology/*surgery ; Recovery of Function ; Retrospective Studies ; Spondylosis/diagnosis/*surgery ; Treatment Outcome ; Upper Extremity ; }, abstract = {OBJECT: Cervical spondylosis that causes upper-extremity muscle atrophy without gait disturbance is called cervical spondylotic amyotrophy (CSA). The distal type of CSA is characterized by weakness of the hand muscles. In this retrospective analysis, the authors describe the clinical features of the distal type of CSA and evaluate the results of surgical treatment.<br><br>METHODS: The authors performed a retrospective review of 17 consecutive cases involving 16 men and 1 woman (mean age 56.3 years) who underwent surgical treatment for the distal type of CSA. The condition was diagnosed on the basis of cervical spondylosis in the presence of muscle impairment of the upper extremity (intrinsic muscle and/or finger extension muscles) without gait disturbance, and the presence of a compressive lesion involving the anterior horn of the spinal cord, the nerve root at the foramen, or both sites as seen on axial and sagittal views of MRI or CT myelography. The authors assessed spinal cord or nerve root impingement by MRI or CT myelography and evaluated surgical outcomes.<br><br>RESULTS: The preoperative duration of symptoms averaged 11.8 months. There were 14 patients with impingement of the anterior horn of the spinal cord and 3 patients with both anterior horn and nerve root impingement. Twelve patients were treated with laminoplasty (plus foraminotomy in 1 case), 3 patients were treated with anterior cervical discectomy and fusion, and 2 patients were treated with posterior spinal fixation. The mean manual muscle testing grade was 2.4 (range 1-4) preoperatively and 3.4 (range 1-5) postoperatively. The surgical results were excellent in 7 patients, good in 2, and fair in 8.<br><br>CONCLUSIONS: Most of the patients in this series of cases of the distal type of CSA suffered from impingement of the anterior horn of the spinal cord, and surgical outcome was fair in about half of the cases.}, }
@article {pmid24923195, year = {2014}, author = {Evans, MC and Gaillard, PJ and de Boer, M and Appeldoorn, C and Dorland, R and Sibson, NR and Turner, MR and Anthony, DC and Stolp, HB}, title = {CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {2}, number = {}, pages = {66}, pmid = {24923195}, issn = {2051-5960}, support = {16945/CRUK_/Cancer Research UK/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0701923/MRC_/Medical Research Council/United Kingdom ; C5255/A12678/CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Area Under Curve ; Body Weight/drug effects ; Cell Survival/drug effects ; Central Nervous System/*drug effects/physiology ; Disease Models, Animal ; Drug Delivery Systems ; Glucocorticoids/administration &amp; dosage/pharmacology ; Glutathione/administration &amp; dosage/pharmacology ; Humans ; Methylprednisolone/*administration &amp; dosage/*pharmacology ; Mice ; Mice, Transgenic ; Motor Activity/drug effects ; Motor Neurons/drug effects/pathology ; Neuroglia/drug effects/physiology ; Polyethylene Glycols/administration &amp; dosage/pharmacology ; Superoxide Dismutase/genetics ; Time Factors ; Vacuoles/drug effects/pathology ; }, abstract = {BACKGROUND: Hallmarks of CNS inflammation, including microglial and astrocyte activation, are prominent features in post-mortem tissue from amyotrophic lateral sclerosis (ALS) patients and in mice overexpressing mutant superoxide dismutase-1 (SOD1G93A). Administration of non-targeted glucocorticoids does not significantly alter disease progression, but this may reflect poor CNS delivery. Here, we sought to discover whether CNS-targeted, liposomal encapsulated glucocorticoid would inhibit the CNS inflammatory response and reduce motor neuron loss. SOD1G93A mice were treated with saline, free methylprednisolone (MP, 10 mg/kg/week) or glutathione PEGylated liposomal MP (2B3-201, 10 mg/kg/week) and compared to saline treated wild-type animals. Animals were treated weekly with intravenous injections for 9 weeks from 60 days of age. Weights and motor performance were monitored during this period. At the end of the experimental period (116 days) mice were imaged using T2-weighted MRI for brainstem pathology; brain and spinal cord tissue were then collected for histological analysis.<br><br>RESULTS: All SOD1G93A groups showed a significant decrease in motor performance, compared to baseline, from ~100&#xa0;days. SOD1G93A animals showed a significant increase in signal intensity on T2 weighted MR images, which may reflect the combination of neuronal vacuolation and glial activation in these motor nuclei. Treatment with 2B3-201, but not free MP, significantly reduced T2 hyperintensity observed in SOD1G93A mice. Compared to saline-treated and free-MP-treated SOD1G93A mice, those animals given 2B3-201 displayed significantly improved histopathological outcomes in brainstem motor nuclei, which included reduced gliosis and neuronal loss.<br><br>CONCLUSIONS: In contrast to previous reports that employed free steroid preparations, CNS-targeted anti-inflammatory agent 2B3-201 (liposomal methylprednisolone) has therapeutic potential, reducing brainstem pathology in the SOD1G93A mouse model of ALS. 2B3-201 reduced neuronal loss and vacuolation in brainstem nuclei, and reduced activation preferentially in astrocytes compared with microglia. These data also suggest that other previously ineffective therapies could be of therapeutic value if delivered specifically to the CNS.}, }
@article {pmid24918689, year = {2014}, author = {Shefner, JM and Mihaila, D}, title = {Assessment of disease progression and functional benefit in neurodegenerative disease: can we tell the difference?.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {15}, number = {5-6}, pages = {337-343}, doi = {10.3109/21678421.2014.918150}, pmid = {24918689}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis ; *Clinical Trials as Topic ; Disease Progression ; Humans ; Neurodegenerative Diseases/*diagnosis/*drug therapy ; Parkinson Disease ; *Treatment Outcome ; }, abstract = {Therapeutic strategies for neurodegenerative diseases include modalities intended to modulate disease progression as well as those whose intent is to improve or maintain functional capacity. As the search for pharmacodynamic markers has proved elusive, treatment outcomes most commonly reflect patient function. As a result, even when clinical trials show a beneficial effect, the underlying etiology of that benefit can be difficult to determine. This review summarizes recent trials in ALS and Parkinson's disease, with the goal of increasing understanding of how the choice of outcome measures influences what can be concluded from the results. Although most ALS trials have been negative in recent years, outcomes are reviewed in terms of potential conclusions that could have been drawn. Functional benefit has been established in a number of recent trials; however, the outcomes used have lead to uncertainty as to whether specific agents modify disease or alter function. In the absence of specific markers sensitive to alteration of disease specific pathways, the distinction between agents that alter underlying disease versus those that affect function may depend on underlying hypotheses rather than clinical trial results.}, }
@article {pmid24918638, year = {2014}, author = {Venkova, K and Christov, A and Kamaluddin, Z and Kobalka, P and Siddiqui, S and Hensley, K}, title = {Semaphorin 3A signaling through neuropilin-1 is an early trigger for distal axonopathy in the SOD1G93A mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {73}, number = {7}, pages = {702-713}, pmid = {24918638}, issn = {1554-6578}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; Antibodies, Blocking/pharmacology ; Axons/*pathology ; Cells, Cultured ; Data Interpretation, Statistical ; Female ; Immunohistochemistry ; Mice ; Motor Neurons/metabolism ; Neuromuscular Junction/pathology ; Neuropilin-1/genetics/immunology/*physiology ; Postural Balance/physiology ; Semaphorin-3A/genetics/immunology/*physiology ; Signal Transduction/genetics/physiology ; Spinal Nerve Roots/pathology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Survival Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive distal axonopathy that precedes actual motor neuron death. Triggers for neuromuscular junction degeneration remain to be determined, but the axon repulsion factor semaphorin 3A (Sema3A), which is derived from terminal Schwann cells, is a plausible candidate. This study examines the hypothesis that Sema3A signaling through its motor neuron neuropilin-1 (NRP1) receptor triggers distal axonopathy and muscle denervation in the SOD1 mouse model of ALS. Neuropilin-1 was found to be expressed in axonal terminals at the mouse neuromuscular junction in vivo and in NSC-34 motor neuron-like cells in vitro. In differentiated NSC-34 cells, an anti-NRP1 antibody that selectively blocks Sema3A binding to NRP1 prevented Sema3A-induced growth cone collapse. Furthermore, intraperitoneal injections of anti-NRP1 antibody administered twice weekly from age 40 days significantly delayed and even temporarily reversed motor functional decline while prolonging the life span of SOD1 mice. Histologic evaluation at 90 and 125 days revealed that anti-NRP1 antibody reduced neuromuscular junction denervation and attenuated pathologic alterations in ventral roots at late-stage disease. These data suggest that peripheral NRP1 signaling is involved in the pathobiology of this ALS model and that antagonizing Sema3A/NRP1 binding or downstream signals could have implications for the treatment of ALS.}, }
@article {pmid24917047, year = {2014}, author = {Oliván, S and Martínez-Beamonte, R and Calvo, AC and Surra, JC and Manzano, R and Arnal, C and Osta, R and Osada, J}, title = {Extra virgin olive oil intake delays the development of amyotrophic lateral sclerosis associated with reduced reticulum stress and autophagy in muscle of SOD1G93A mice.}, journal = {The Journal of nutritional biochemistry}, volume = {25}, number = {8}, pages = {885-892}, doi = {10.1016/j.jnutbio.2014.04.005}, pmid = {24917047}, issn = {1873-4847}, mesh = {Activating Transcription Factor 6/metabolism ; Amyotrophic Lateral Sclerosis/etiology/physiopathology/*prevention &amp; control ; Animals ; Autophagy/*drug effects ; Cholesterol/metabolism ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/drug effects ; Female ; Heat-Shock Proteins/metabolism ; Longevity/drug effects ; Male ; Mice, Transgenic ; Motor Activity/drug effects ; Muscle Fibers, Skeletal/drug effects ; Olive Oil ; Palm Oil ; Plant Oils/*pharmacology ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease associated with mutations in antioxidant enzyme Cu/Zn-superoxide dismutase 1. Albeit there is no treatment for this disease, new insights related to an exacerbated lipid metabolism have been reported. In connection with the hypermetabolic lipid status, the hypothesis whether nature of dietary fat might delay the progression of the disease was tested by using a transgenic mouse that overexpresses the human SOD1G93A variant. For this purpose, SOD1G93A mice were assigned randomly to one of the following three experimental groups: (1) a standard chow diet (control, n=21), (2) a chow diet enriched with 20% (w/w) extra virgin olive oil (EVOO, n=22) and (3) a chow diet containing 20% palm oil (palm, n=20). They received the diets for 8 weeks and the progression of the disease was assessed. On the standard chow diet, average plasma cholesterol levels were lower than those mice receiving the high-fat diets. Mice fed an EVOO diet showed a significant higher survival and better motor performance than control mice. EVOO group mice survived longer and showed better motor performance and larger muscle fiber area than animals receiving palm. Moreover, the EVOO-enriched diet improved the muscle status as shown by expression of myogenic factors (Myod1 and Myog) and autophagy markers (LC3 and Beclin1), as well as diminished endoplasmic reticulum (ER) stress through decreasing Atf6 and Grp78. Our results demonstrate that EVOO may be effective in increasing survival rate, improving motor coordination together with a potential amelioration of ER stress, autophagy and muscle damage.}, }
@article {pmid24910594, year = {2014}, author = {Tadic, V and Prell, T and Lautenschlaeger, J and Grosskreutz, J}, title = {The ER mitochondria calcium cycle and ER stress response as therapeutic targets in amyotrophic lateral sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {147}, pmid = {24910594}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Although the etiology remains unclear, disturbances in calcium homoeostasis and protein folding are essential features of neurodegeneration in this disorder. Here, we review recent research findings on the interaction between endoplasmic reticulum (ER) and mitochondria, and its effect on calcium signaling and oxidative stress. We further provide insights into studies, providing evidence that structures of the ER mitochondria calcium cycle serve as a promising targets for therapeutic approaches for treatment of ALS.}, }
@article {pmid24906288, year = {2014}, author = {Sun, H and Hou, Z and Yang, H and Meng, M and Li, P and Zou, Q and Yang, L and Chen, Y and Chai, H and Zhong, H and Yang, ZZ and Zhao, J and Lai, L and Jiang, X and Xiao, Z}, title = {Multiple systemic transplantations of human amniotic mesenchymal stem cells exert therapeutic effects in an ALS mouse model.}, journal = {Cell and tissue research}, volume = {357}, number = {3}, pages = {571-582}, doi = {10.1007/s00441-014-1903-z}, pmid = {24906288}, issn = {1432-0878}, mesh = {Amnion/*cytology ; Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Animals ; Behavior, Animal ; Cell Movement ; Cell Survival ; Disease Models, Animal ; Disease Progression ; Female ; Green Fluorescent Proteins/metabolism ; Humans ; Inflammation/pathology ; Injections, Intravenous ; Male ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*cytology ; Mice ; Motor Activity ; Motor Neurons/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease involving degeneration of motor neurons in the central nervous system. Stem cell treatment is a potential therapy for this fatal disorder. The human amniotic membrane (HAM), an extremely rich and easily accessible tissue, has been proposed as an attractive material in cellular therapy and regenerative medicine because of its advantageous characteristics. In the present study, we evaluate the long-term effects of a cellular treatment by intravenous administration of human amniotic mesenchymal stem cells (hAMSCs) derived from HAM into a hSOD1(G93A) mouse model. The mice received systemic administration of hAMSCs or phosphate-buffered saline (PBS) at the onset, progression and symptomatic stages of the disease. hAMSCs were detected in the spinal cord at the final stage of the disease, in the form of isolates or clusters and were negative for β-tubulin III and GFAP. Compared with the treatment with PBS, multiple hAMSC transplantations significantly retarded disease progression, extended survival, improved motor function, prevented motor neuron loss and decreased neuroinflammation in mice. These findings demonstrate that hAMSC transplantation is a promising cellular treatment for ALS.}, }
@article {pmid24903509, year = {2014}, author = {Ariga, T}, title = {Pathogenic role of ganglioside metabolism in neurodegenerative diseases.}, journal = {Journal of neuroscience research}, volume = {92}, number = {10}, pages = {1227-1242}, doi = {10.1002/jnr.23411}, pmid = {24903509}, issn = {1097-4547}, mesh = {Animals ; Blood-Brain Barrier ; Central Nervous System/*metabolism ; Gangliosides/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/*pathology ; Protein Folding ; }, abstract = {Ganglioside metabolism is altered in several neurodegenerative diseases, and this may participate in several events related to the pathogenesis of these diseases. Most changes occur in specific areas of the brain and their distinct membrane microdomains or lipid rafts. Antiganglioside antibodies may be involved in dysfunction of the blood-brain barrier and disease progression in these diseases. In lipid rafts, interactions of glycosphingolipids, including ganglioside, with proteins may be responsible for the misfolding events that cause the fibril and/or aggregate processing of disease-specific proteins, such as α-synuclein, in Parkinson's disease, huntingtin protein in Huntington's disease, and copper-zinc superoxide dismutase in amyotrophic lateral sclerosis. Targeting ganglioside metabolism may represent an underexploited opportunity to design novel therapeutic strategies for neurodegeneration in these diseases.}, }
@article {pmid24899723, year = {2014}, author = {Roberts, BR and Lim, NK and McAllum, EJ and Donnelly, PS and Hare, DJ and Doble, PA and Turner, BJ and Price, KA and Lim, SC and Paterson, BM and Hickey, JL and Rhoads, TW and Williams, JR and Kanninen, KM and Hung, LW and Liddell, JR and Grubman, A and Monty, JF and Llanos, RM and Kramer, DR and Mercer, JF and Bush, AI and Masters, CL and Duce, JA and Li, QX and Beckman, JS and Barnham, KJ and White, AR and Crouch, PJ}, title = {Oral treatment with Cu(II)(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {34}, number = {23}, pages = {8021-8031}, pmid = {24899723}, issn = {1529-2401}, mesh = {Administration, Oral ; Age Factors ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/mortality/pathology ; Animals ; Cation Transport Proteins/genetics ; Chromatography, Gel ; Coordination Complexes ; Copper Transporter 1 ; Disease Models, Animal ; Humans ; Locomotion/drug effects/genetics ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects ; Mutation/*genetics ; Organometallic Compounds/*administration &amp; dosage ; Phenotype ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; Thiosemicarbazones/*administration &amp; dosage ; }, abstract = {Mutations in the metallo-protein Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) in humans and an expression level-dependent phenotype in transgenic rodents. We show that oral treatment with the therapeutic agent diacetyl-bis(4-methylthiosemicarbazonato)copper(II) [Cu(II)(atsm)] increased the concentration of mutant SOD1 (SOD1G37R) in ALS model mice, but paradoxically improved locomotor function and survival of the mice. To determine why the mice with increased levels of mutant SOD1 had an improved phenotype, we analyzed tissues by mass spectrometry. These analyses revealed most SOD1 in the spinal cord tissue of the SOD1G37R mice was Cu deficient. Treating with Cu(II)(atsm) decreased the pool of Cu-deficient SOD1 and increased the pool of fully metallated (holo) SOD1. Tracking isotopically enriched (65)Cu(II)(atsm) confirmed the increase in holo-SOD1 involved transfer of Cu from Cu(II)(atsm) to SOD1, suggesting the improved locomotor function and survival of the Cu(II)(atsm)-treated SOD1G37R mice involved, at least in part, the ability of the compound to improve the Cu content of the mutant SOD1. This was supported by improved survival of SOD1G37R mice that expressed the human gene for the Cu uptake protein CTR1. Improving the metal content of mutant SOD1 in vivo with Cu(II)(atsm) did not decrease levels of misfolded SOD1. These outcomes indicate the metal content of SOD1 may be a greater determinant of the toxicity of the protein in mutant SOD1-associated forms of ALS than the mutations themselves. Improving the metal content of SOD1 therefore represents a valid therapeutic strategy for treating ALS caused by SOD1.}, }
@article {pmid24899704, year = {2014}, author = {Deng, Q and Holler, CJ and Taylor, G and Hudson, KF and Watkins, W and Gearing, M and Ito, D and Murray, ME and Dickson, DW and Seyfried, NT and Kukar, T}, title = {FUS is phosphorylated by DNA-PK and accumulates in the cytoplasm after DNA damage.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {34}, number = {23}, pages = {7802-7813}, pmid = {24899704}, issn = {1529-2401}, support = {K99 AG032362/AG/NIA NIH HHS/United States ; P50AG032362/AG/NIA NIH HHS/United States ; P30 NS069289/NS/NINDS NIH HHS/United States ; P30NS069289/NS/NINDS NIH HHS/United States ; R00AG032362/AG/NIA NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; 2T32 NS 007480/NS/NINDS NIH HHS/United States ; T32 NS007480/NS/NINDS NIH HHS/United States ; R00 AG032362/AG/NIA NIH HHS/United States ; }, mesh = {Aminoglycosides/pharmacology ; Antibiotics, Antineoplastic/pharmacology ; Astrocytes/drug effects/metabolism ; Cells, Cultured ; Cytoplasm/drug effects/*metabolism ; DNA Damage/drug effects/*physiology ; DNA-Activated Protein Kinase/*metabolism ; Enediynes/pharmacology ; Frontotemporal Lobar Degeneration/metabolism/*pathology ; Humans ; Immunoprecipitation ; Mutagens/pharmacology ; Mutation/genetics ; Neurons ; Nuclear Proteins/metabolism ; Phosphorylation/drug effects ; RNA-Binding Protein EWS/metabolism ; RNA-Binding Protein FUS/*metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; TATA-Binding Protein Associated Factors/metabolism ; }, abstract = {Abnormal cytoplasmic accumulation of Fused in Sarcoma (FUS) in neurons defines subtypes of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). FUS is a member of the FET protein family that includes Ewing's sarcoma (EWS) and TATA-binding protein-associated factor 2N (TAF15). FET proteins are predominantly localized to the nucleus, where they bind RNA and DNA to modulate transcription, mRNA splicing, and DNA repair. In ALS cases with FUS inclusions (ALS-FUS), mutations in the FUS gene cause disease, whereas FTLD cases with FUS inclusions (FTLD-FUS) do not harbor FUS mutations. Notably, in FTLD-FUS, all FET proteins accumulate with their nuclear import receptor Transportin 1 (TRN1), in contrast ALS-FUS inclusions are exclusively positive for FUS. In the present study, we show that induction of DNA damage replicates several pathologic hallmarks of FTLD-FUS in immortalized human cells and primary human neurons and astrocytes. Treatment with the antibiotic calicheamicin γ1, which causes DNA double-strand breaks, leads to the cytoplasmic accumulation of FUS, TAF15, EWS, and TRN1. Moreover, cytoplasmic translocation of FUS is mediated by phosphorylation of its N terminus by the DNA-dependent protein kinase. Finally, we observed elevated levels of phospho-H2AX in FTLD-FUS brains, indicating that DNA damage occurs in patients. Together, our data reveal a novel regulatory mechanism for FUS localization in cells and suggest that DNA damage may contribute to the accumulation of FET proteins observed in human FTLD-FUS cases, but not in ALS-FUS.}, }
@article {pmid24894177, year = {2014}, author = {Orsucci, D and Rocchi, A and Caldarazzo Ienco, E and Alì, G and LoGerfo, A and Petrozzi, L and Scarpelli, M and Filosto, M and Carlesi, C and Siciliano, G and Bonuccelli, U and Mancuso, M}, title = {Myopathic involvement and mitochondrial pathology in Kennedy disease and in other motor neuron diseases.}, journal = {Current molecular medicine}, volume = {14}, number = {5}, pages = {598-602}, doi = {10.2174/1566524014666140603100131}, pmid = {24894177}, issn = {1875-5666}, mesh = {Animals ; Bulbo-Spinal Atrophy, X-Linked/genetics/*metabolism/*physiopathology ; DNA, Mitochondrial/genetics ; Humans ; Mitochondria/metabolism/pathology ; Motor Neuron Disease/genetics/*metabolism/*physiopathology ; Receptors, Androgen/genetics ; }, abstract = {Kennedy disease (spinal and bulbar muscular atrophy, or SBMA) is a motor neuron disease caused by a CAG expansion in the androgen-receptor (AR) gene. Increasing evidence shows that SBMA may have a primary myopathic component and that mitochondrial dysfunction may have some role in the pathogenesis of this disease. In this article, we review the role of mitochondrial dysfunction and of the mitochondrial genome (mtDNA) in SBMA, and we present the illustrative case of a patient who presented with increased CK levels and exercise intolerance. Molecular analysis led to definitive diagnosis of SBMA, whereas muscle biopsy showed a mixed myopathic and neurogenic process with "mitochondrial features" and multiple mtDNA deletions, supporting some role of mitochondria in the pathogenesis of the myopathic component of Kennedy disease. Furthermore, we briefly review the role of mitochondrial dysfunction in two other motor neuron diseases (namely spinal muscular atrophy and amyotrophic lateral sclerosis). Most likely, in most cases mtDNA does not play a primary role and it is involved subsequently. MtDNA deletions may contribute to the neurodegenerative process, but the exact mechanisms are still unclear. It will be important to develop a better understanding of the role of mitochondrial dysfunction in motoneuron diseases, since it may lead to the development of more effective strategies for the treatment of this devastating disorder.}, }
@article {pmid24891994, year = {2014}, author = {Vang, S and Longley, K and Steer, CJ and Low, WC}, title = {The Unexpected Uses of Urso- and Tauroursodeoxycholic Acid in the Treatment of Non-liver Diseases.}, journal = {Global advances in health and medicine}, volume = {3}, number = {3}, pages = {58-69}, pmid = {24891994}, issn = {2164-957X}, abstract = {Tauroursodeoxycholic acid (TUDCA) is the taurine conjugate of ursodeoxycholic acid (UDCA), a US Food and Drug Administration-approved hydrophilic bile acid for the treatment of certain cholestatic liver diseases. There is a growing body of research on the mechanism(s) of TUDCA and its potential therapeutic effect on a wide variety of non-liver diseases. Both UDCA and TUDCA are potent inhibitors of apoptosis, in part by interfering with the upstream mitochondrial pathway of cell death, inhibiting oxygen-radical production, reducing endoplasmic reticulum (ER) stress, and stabilizing the unfolded protein response (UPR). Several studies have demonstrated that TUDCA serves as an anti-apoptotic agent for a number of neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease. In addition, TUDCA plays an important role in protecting against cell death in certain retinal disorders, such as retinitis pigmentosa. It has been shown to reduce ER stress associated with elevated glucose levels in diabetes by inhibiting caspase activation, up-regulating the UPR, and inhibiting reactive oxygen species. Obesity, stroke, acute myocardial infarction, spinal cord injury, and a long list of acute and chronic non-liver diseases associated with apoptosis are all potential therapeutic targets for T/UDCA. A growing number of pre-clinical and clinical studies underscore the potential benefit of this simple, naturally occurring bile acid, which has been used in Chinese medicine for more than 3000 years.}, }
@article {pmid24885036, year = {2014}, author = {Mancuso, R and Del Valle, J and Morell, M and Pallás, M and Osta, R and Navarro, X}, title = {Lack of synergistic effect of resveratrol and sigma-1 receptor agonist (PRE-084) in SOD1G[93]A ALS mice: overlapping effects or limited therapeutic opportunity?.}, journal = {Orphanet journal of rare diseases}, volume = {9}, number = {}, pages = {78}, pmid = {24885036}, issn = {1750-1172}, mesh = {Adenylate Kinase/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/*genetics/physiopathology ; Animals ; Drug Synergism ; Mice ; Mice, Transgenic ; Morpholines/pharmacology/*therapeutic use ; Neural Conduction ; Phosphorylation ; Protein Kinase C/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism ; Receptors, sigma/*agonists ; Resveratrol ; Rotarod Performance Test ; Sirtuin 1/metabolism ; Stilbenes/pharmacology/*therapeutic use ; Superoxide Dismutase/*genetics ; Sigma-1 Receptor ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by the loss of motoneurons (MNs) in the spinal cord, brainstem and motor cortex, causing progressive paralysis and death. Nowadays, there is no effective therapy and most patients die 2-5 years after diagnosis. Sigma-1R is a transmembrane protein highly expressed in the CNS and specially enriched in MNs. Mutations on the Sigma-1R leading to frontotemporal lobar degeneration-ALS were recently described in human patients. We previously reported the therapeutic role of the selective sigma-1R agonist 2-(4-morpholi-nethyl)1-phenylcyclohexanecarboxylate (PRE-084) in SOD1G93A ALS mice, that promoted spinal MN preservation and extended animal survival by controlling NMDA receptor calcium influx. Resveratrol (RSV, trans-3,4',5-trihydroxystilbene) is a natural polyphenol with promising neuroprotective effects. We recently found that RSV administration to SOD1G93A mice preserves spinal MN function and increases mice survival. These beneficial effects were associated to activation of Sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK) pathways, leading to the modulation of autophagy and an increase of mitochondrial biogenesis. The main goal of this work was to assess the effect of combined RSV and PRE-084 administration in SOD1G93A ALS mice.<br><br>METHODS: We determined the locomotor performance of the animals by rotarod test and evaluated spinal motoneuron function using electrophysiological tests.<br><br>RESULTS: RSV plus PRE-084 treatment from 8 weeks of age significantly improved locomotor performance and spinal MN function, accompanied by a significant reduction of MN degeneration and an extension of mice lifespan. In agreement with our previous findings, there was an induction of PKC-specific phosphorylation of the NMDA-NR1 subunit and an increased expression and activation of Sirt1 and AMPK in the ventral spinal cord of treated SOD1G93A animals.<br><br>CONCLUSIONS: Although combined PRE and RSV treatment significantly ameliorated SOD1G93A mice, it did not show a synergistic effect compared to RSV-only and PRE-084-only treated groups.}, }
@article {pmid24874548, year = {2014}, author = {Skerrett, R and Malm, T and Landreth, G}, title = {Nuclear receptors in neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {72 Pt A}, number = {}, pages = {104-116}, pmid = {24874548}, issn = {1095-953X}, support = {R01 AG043522/AG/NIA NIH HHS/United States ; R56 NS084856/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/metabolism ; Animals ; Disease Models, Animal ; Humans ; Huntington Disease/metabolism ; Liver X Receptors ; Mice ; Microglia/metabolism ; Neurodegenerative Diseases/*metabolism ; Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism ; Orphan Nuclear Receptors/metabolism ; Parkinson Disease/metabolism ; Peroxisome Proliferator-Activated Receptors/metabolism ; Rats ; Receptors, Cytoplasmic and Nuclear/*metabolism ; Retinoid X Receptors/metabolism ; Signal Transduction ; }, abstract = {Nuclear receptors have generated substantial interest in the past decade as potential therapeutic targets for the treatment of neurodegenerative disorders. Despite years of effort, effective treatments for progressive neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and ALS remain elusive, making non-classical drug targets such as nuclear receptors an attractive alternative. A substantial literature in mouse models of disease and several clinical trials have investigated the role of nuclear receptors in various neurodegenerative disorders, most prominently AD. These studies have met with mixed results, yet the majority of studies in mouse models report positive outcomes. The mechanisms by which nuclear receptor agonists affect disease pathology remain unclear. Deciphering the complex signaling underlying nuclear receptor action in neurodegenerative diseases is essential for understanding this variability in preclinical studies, and for the successful translation of nuclear receptor agonists into clinical therapies.}, }
@article {pmid24866055, year = {2014}, author = {Cooper-Knock, J and Walsh, MJ and Higginbottom, A and Robin Highley, J and Dickman, MJ and Edbauer, D and Ince, PG and Wharton, SB and Wilson, SA and Kirby, J and Hautbergue, GM and Shaw, PJ}, title = {Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions.}, journal = {Brain : a journal of neurology}, volume = {137}, number = {Pt 7}, pages = {2040-2051}, pmid = {24866055}, issn = {1460-2156}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/L016451/1/MRC_/Medical Research Council/United Kingdom ; G0900652/MRC_/Medical Research Council/United Kingdom ; MR/K003771/1/MRC_/Medical Research Council/United Kingdom ; MR/K000039/1/MRC_/Medical Research Council/United Kingdom ; COOPER-KNOCK/FEB12/942-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0400074/MRC_/Medical Research Council/United Kingdom ; G0502157/MRC_/Medical Research Council/United Kingdom ; BB/D011795/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; G1100540/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Adenosine Triphosphate/pharmacokinetics ; Amyotrophic Lateral Sclerosis/*genetics/pathology ; Biotinylation ; Brain/pathology ; C9orf72 Protein ; DNA Repeat Expansion/*genetics ; Female ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism ; Humans ; Male ; Mass Spectrometry ; Neurons/pathology ; Nuclear Proteins/metabolism ; Phosphorus Isotopes/pharmacokinetics ; Protein Binding/drug effects ; Proteins/*genetics ; RNA-Binding Proteins/genetics/*metabolism ; Ribonucleoproteins/metabolism ; Serine-Arginine Splicing Factors ; Transcription Factors/metabolism ; }, abstract = {GGGGCC repeat expansions of C9orf72 represent the most common genetic variant of amyotrophic lateral sclerosis and frontotemporal degeneration, but the mechanism of pathogenesis is unclear. Recent reports have suggested that the transcribed repeat might form toxic RNA foci that sequester various RNA processing proteins. Consensus as to the identity of the binding partners is missing and whole neuronal proteome investigation is needed. Using RNA fluorescence in situ hybridization we first identified nuclear and cytoplasmic RNA foci in peripheral and central nervous system biosamples from patients with amyotrophic lateral sclerosis with a repeat expansion of C9orf72 (C9orf72+), but not from those patients without a repeat expansion of C9orf72 (C9orf72-) or control subjects. Moreover, in the cases examined, the distribution of foci-positive neurons correlated with the clinical phenotype (t-test P < 0.05). As expected, RNA foci are ablated by RNase treatment. Interestingly, we identified foci in fibroblasts from an asymptomatic C9orf72+ carrier. We next performed pulldown assays, with GGGGCC5, in conjunction with mass spectrometry analysis, to identify candidate binding partners of the GGGGCC repeat expansion. Proteins containing RNA recognition motifs and involved in splicing, messenger RNA nuclear export and/or translation were significantly enriched. Immunohistochemistry in central nervous system tissue from C9orf72+ patients with amyotrophic lateral sclerosis demonstrated co-localization of RNA foci with SRSF2, hnRNP H1/F, ALYREF and hnRNP A1 in cerebellar granule cells and with SRSF2, hnRNP H1/F and ALYREF in motor neurons, the primary target of pathology in amyotrophic lateral sclerosis. Direct binding of proteins to GGGGCC repeat RNA was confirmed in vitro by ultraviolet-crosslinking assays. Co-localization was only detected in a small proportion of RNA foci, suggesting dynamic sequestration rather than irreversible binding. Additional immunohistochemistry demonstrated that neurons with and without RNA foci were equally likely to show nuclear depletion of TDP-43 (χ(2) P = 0.75) or poly-GA dipeptide repeat protein inclusions (χ(2) P = 0.46). Our findings suggest two non-exclusive pathogenic mechanisms: (i) functional depletion of RNA-processing proteins resulting in disruption of messenger RNA splicing; and (ii) licensing of expanded C9orf72 pre-messenger RNA for nuclear export by inappropriate association with messenger RNA export adaptor protein(s) leading to cytoplasmic repeat associated non-ATG translation and formation of potentially toxic dipeptide repeat protein.}, }
@article {pmid24863134, year = {2014}, author = {Alanazy, MH and White, C and Korngut, L}, title = {Diagnostic yield and cost-effectiveness of investigations in patients presenting with isolated lower motor neuron signs.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {15}, number = {5-6}, pages = {414-419}, doi = {10.3109/21678421.2014.913635}, pmid = {24863134}, issn = {2167-9223}, mesh = {Adult ; Aged ; Aged, 80 and over ; Cost-Benefit Analysis/*methods ; Creatine Kinase/metabolism ; Disease Progression ; Female ; Follow-Up Studies ; Humans ; Immunoglobulins, Intravenous/*economics/therapeutic use ; Immunologic Factors/economics/therapeutic use ; Male ; Middle Aged ; Motor Neuron Disease/complications/*diagnosis/drug therapy/*economics ; Muscular Atrophy/drug therapy/etiology ; Retrospective Studies ; }, abstract = {Our objective was to investigate the yield and cost-effectiveness of investigations and therapeutic trials of intravenous immunoglobulin (IVIg) in patients presenting with isolated lower motor neuron (LMN) signs. We performed a retrospective chart review of cases diagnosed between January 2007 and September 2013. Investigation results and their impact on outcome, and outcome of IVIg treatment trials were abstracted. Cost was calculated in Canadian dollars (C$). Fifty-nine of 333 patients presented with isolated LMN signs. The majority of patients (61%) evolved to amyotrophic lateral sclerosis (ALS) within 36 months of presentation, while 37.3% remained with progressive muscular atrophy (PMA) with mean follow-up 29.6 months. Of the 1210 tests performed, 4.9% were abnormal. The diagnosis was changed in only one patient where a muscle biopsy revealed a distal myopathy. Fourteen patients received therapeutic trials of IVIg to rule out an IVIg-responsive inflammatory motor neuropathy with no objective clinical benefit. Total group cost was C$630,484.72 (C$10,686.18/patient). IVIg represented 58.7% of total costs. In conclusion, extensive investigations and treatment trials of IVIg have low yield in the work-up of patients with isolated LMN signs and are not cost-effective when clinical features do not suggest an alternative diagnosis to PMA.}, }
@article {pmid24862096, year = {2014}, author = {Tay, CM and Howe, J and Borromeo, GI}, title = {Oral health and dental treatment needs of people with motor neurone disease.}, journal = {Australian dental journal}, volume = {59}, number = {3}, pages = {309-313}, doi = {10.1111/adj.12195}, pmid = {24862096}, issn = {1834-7819}, mesh = {Aged ; *Dental Care for Chronically Ill ; Dental Caries/diagnosis ; Dental Plaque/diagnosis ; Feeding Behavior ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*complications ; *Oral Health ; *Oral Hygiene ; Periodontal Index ; Surveys and Questionnaires ; Victoria ; }, abstract = {BACKGROUND: People with motor neurone disease (MND) may present with physical limitations impacting on oral health and access to oral health care. This study aimed to assess the oral health status and treatment needs of people with MND in Victoria, Australia.<br><br>METHODS: Patients with advanced MND attending a multidisciplinary MND clinic in Melbourne were recruited. Data collection included self-reporting questionnaires on previous dental experience, current oral hygiene practices and current dietary habits, a medical questionnaire, and a clinical examination charting participants' dentition, restorations, caries and periodontal status, plaque and gingival indices, and assessment of oral health.<br><br>RESULTS: Thirty-three participants took part in the study with eight self-reporting regular dental visits. No participant exhibited probing depths of more than 3 mm. Ten out of 27 dentate participants required extractions and restorations for retained roots and caries, while three presented with non-carious cavities, lost restorations and fractured cusps. Oral health status was not affected by MND presentation in these participants.<br><br>CONCLUSIONS: The study found that oral health was not affected by advanced MND. Participants' and clinical teams' motivation towards oral health care may have contributed to oral health. The dental profession should be involved as part of the multidisciplinary effort towards ongoing care.}, }
@article {pmid24848437, year = {2014}, author = {Gentile, I and Coppola, N and Buonomo, AR and Zappulo, E and Borgia, G}, title = {Investigational nucleoside and nucleotide polymerase inhibitors and their use in treating hepatitis C virus.}, journal = {Expert opinion on investigational drugs}, volume = {23}, number = {9}, pages = {1211-1223}, doi = {10.1517/13543784.2014.921680}, pmid = {24848437}, issn = {1744-7658}, mesh = {Animals ; Antiviral Agents/pharmacology/*therapeutic use ; Disease Progression ; Drug Design ; Drug Therapy, Combination ; Enzyme Inhibitors/pharmacology/*therapeutic use ; Hepacivirus/drug effects/enzymology/genetics ; Hepatitis C, Chronic/*drug therapy/enzymology/virology ; Humans ; Ribavirin/administration &amp; dosage/therapeutic use ; Sofosbuvir ; Uridine Monophosphate/administration &amp; dosage/analogs &amp; derivatives/therapeutic use ; }, abstract = {INTRODUCTION: About 150 million people worldwide are estimated to be chronically infected with the hepatitis C virus (HCV). Successful antiviral treatment can stop the progression of the disease toward liver cirrhosis, hepatocellular carcinoma and death. IFN has been the drug of choice and the backbone of all combinations in the past two decades. However, an IFN-free combination (sofosbuvir and ribavirin) has been recently approved for genotypes 2 and 3 patients with many other drugs in preclinical and clinical development.<br><br>AREAS COVERED: This review focuses on investigational nucleoside or nucleotide inhibitors of viral polymerase that are potential treatments of HCV. The article reviews drugs that are currently under investigational status.<br><br>EXPERT OPINION: Currently, mericitabine has the most robust data but its efficacy appears to be less than optimal. Other drugs such as ALS-2200 (and its diastereomer VX-135) and BMS-986094 are promising but the data in humans are too scanty to draw conclusions about their future role at this current point in time. Other promising molecules are LG-7501, ACH-3422 and EP-NI266, although no clinical studies have been performed thus far, so this must be rectified. Another drug of promise GS-6620 has displayed a high degree of pharmacokinetic and pharmacodynamic variability, which makes further development unlikely.}, }
@article {pmid24847964, year = {2014}, author = {Squires, N and Humberstone, M and Wills, A and Arthur, A}, title = {The use of botulinum toxin injections to manage drooling in amyotrophic lateral sclerosis/motor neurone disease: a systematic review.}, journal = {Dysphagia}, volume = {29}, number = {4}, pages = {500-508}, pmid = {24847964}, issn = {1432-0460}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Botulinum Toxins, Type A/*administration &amp; dosage ; Humans ; Injections ; Neurotoxins/administration &amp; dosage ; Sialorrhea/*drug therapy/etiology ; Treatment Outcome ; }, abstract = {Difficulty in managing oral secretions is commonly experienced by patients with amyotrophic lateral sclerosis (ALS)/motor neurone disease (MND) and associated bulbar weakness including dysphagia. There are no definitive evidence-based treatment guidelines to manage the distressing symptom of drooling. We reviewed the evidence for the effectiveness of botulinum toxin injections to reduce saliva in ALS/MND. The search strategy was conducted in four stages: (1) electronic search of relevant databases, (2) hand searches of all international ALS/MND symposium journals, (3) email request to MND care centres in the UK and Ireland, and (4) hand searching of reference lists. All studies were critically appraised and relevant data extracted. Botulinum toxin type A and type B were analysed separately. Due to heterogeneity, it was not possible to calculate a pooled estimate of effect. Twelve studies met the inclusion criteria (9 for type A and 3 for type B). Only two randomised controlled trials were identified. Study sample sizes were small with a mean of 12.5 subjects. The most frequently reported outcomes were weight of cotton rolls and number of tissues used. All studies claimed the intervention tested was effective, but only seven studies (4 for type A and 3 for type B) reported statistically significant differences. Although there is evidence to suggest that botulinum toxin B can reduce drooling, the evidence base is limited by a lack of randomized controlled trials. Evidence to support the use of botulinum toxin A is weaker. Larger trials will help remove the uncertainty practitioners face in treating this disabling symptom.}, }
@article {pmid24845847, year = {2014}, author = {Mulcahy, PJ and Iremonger, K and Karyka, E and Herranz-Martín, S and Shum, KT and Tam, JK and Azzouz, M}, title = {Gene therapy: a promising approach to treating spinal muscular atrophy.}, journal = {Human gene therapy}, volume = {25}, number = {7}, pages = {575-586}, doi = {10.1089/hum.2013.186}, pmid = {24845847}, issn = {1557-7422}, mesh = {Animals ; Genetic Diseases, Inborn/genetics/pathology/physiopathology/*therapy ; Genetic Therapy/*methods/trends ; Humans ; Muscular Atrophy, Spinal/genetics/pathology/physiopathology/*therapy ; *Mutation ; Survival of Motor Neuron 1 Protein/*genetics ; }, abstract = {Spinal muscular atrophy (SMA) is a severe autosomal recessive disease caused by a genetic defect in the survival motor neuron 1 (SMN1) gene, which encodes SMN, a protein widely expressed in all eukaryotic cells. Depletion of the SMN protein causes muscle weakness and progressive loss of movement in SMA patients. The field of gene therapy has made major advances over the past decade, and gene delivery to the central nervous system (CNS) by in vivo or ex vivo techniques is a rapidly emerging field in neuroscience. Despite Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis being among the most common neurodegenerative diseases in humans and attractive targets for treatment development, their multifactorial origin and complicated genetics make them less amenable to gene therapy. Monogenic disorders resulting from modifications in a single gene, such as SMA, prove more favorable and have been at the fore of this evolution of potential gene therapies, and results to date have been promising at least. With the estimated number of monogenic diseases standing in the thousands, elucidating a therapeutic target for one could have major implications for many more. Recent progress has brought about the commercialization of the first gene therapies for diseases, such as pancreatitis in the form of Glybera, with the potential for other monogenic disease therapies to follow suit. While much research has been carried out, there are many limiting factors that can halt or impede translation of therapies from the bench to the clinic. This review will look at both recent advances and encountered impediments in terms of SMA and endeavor to highlight the promising results that may be applicable to various associated diseases and also discuss the potential to overcome present limitations.}, }
@article {pmid24844281, year = {2014}, author = {Lee, HJ and Kim, KS and Ahn, J and Bae, HM and Lim, I and Kim, SU}, title = {Human motor neurons generated from neural stem cells delay clinical onset and prolong life in ALS mouse model.}, journal = {PloS one}, volume = {9}, number = {5}, pages = {e97518}, pmid = {24844281}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology/*therapy ; Animals ; Antigens, Differentiation/metabolism ; *Cell Differentiation ; Cell Line, Transformed ; Female ; Heterografts ; Humans ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/*metabolism/pathology/*transplantation ; Neural Stem Cells/*metabolism/pathology ; Time Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult onset motor neuron disease. The etiology and pathogenic mechanisms of the disease remain unknown, and there is no effective treatment. Here we show that intrathecal transplantation of human motor neurons derived from neural stem cells (NSCs) in spinal cord of the SOD1G93A mouse ALS model delayed disease onset and extended life span of the animals. When HB1.F3.Olig2 (F3.Olig2) cells, stable immortalized human NSCs encoding the human Olig2 gene, were treated with sonic hedgehog (Shh) protein for 5-7 days, the cells expressed motor neuron cell type-specific phenotypes Hb9, Isl-1 and choline acetyltransferase (ChAT). These F3.Olig2-Shh human motor neurons were transplanted intrathecally in L5-L6 spinal cord of SOD1G93A mice, and at 4 weeks post-transplantation, transplanted F3.Olig2-Shh motor neurons expressing the neuronal phenotype markers NF, MAP2, Hb9, and ChAT were found in the ventral horn of the spinal cord. Onset of clinical signs in ALS mice with F3.Olig2-Shh motor neuron implants was delayed for 7 days and life span of animals was significantly extended by 20 days. Our results indicate that this treatment modality of intrathecal transplantation of human motor neurons derived from NSCs might be of value in the treatment of ALS patients without significant adverse effects.}, }
@article {pmid24841795, year = {2014}, author = {Meininger, V and Pradat, PF and Corse, A and Al-Sarraj, S and Rix Brooks, B and Caress, JB and Cudkowicz, M and Kolb, SJ and Lange, D and Leigh, PN and Meyer, T and Milleri, S and Morrison, KE and Orrell, RW and Peters, G and Rothstein, JD and Shefner, J and Lavrov, A and Williams, N and Overend, P and Price, J and Bates, S and Bullman, J and Krull, D and Berges, A and Abila, B and Meno-Tetang, G and Wurthner, J}, title = {Safety, pharmacokinetic, and functional effects of the nogo-a monoclonal antibody in amyotrophic lateral sclerosis: a randomized, first-in-human clinical trial.}, journal = {PloS one}, volume = {9}, number = {5}, pages = {e97803}, pmid = {24841795}, issn = {1932-6203}, mesh = {Administration, Intravenous ; Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism ; Antibodies, Monoclonal/administration &amp; dosage/adverse effects/*pharmacokinetics/*pharmacology ; Antibodies, Monoclonal, Humanized/administration &amp; dosage/adverse effects/*pharmacokinetics/*pharmacology ; Biomarkers/metabolism ; Dose-Response Relationship, Drug ; Female ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Myelin Proteins/*metabolism ; Nogo Proteins ; }, abstract = {UNLABELLED: The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab treatment (0.01-15 mg/kg) was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab) showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated co-localization at the site of action. These findings support future studies with ozanezumab in ALS.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT00875446 GSK-ClinicalStudyRegister.com GSK ID 111330.}, }
@article {pmid24841627, year = {2014}, author = {Yuki, N and Yanaka, C and Sudo, M and Funakoshi, M and Ishida, H and Mori, M and Kanda, F and Hirata, K}, title = {Lower motor neuron syndrome associated with IgG anti-GM1 antibodies revisited.}, journal = {Journal of neuroimmunology}, volume = {272}, number = {1-2}, pages = {62-66}, doi = {10.1016/j.jneuroim.2014.04.014}, pmid = {24841627}, issn = {1872-8421}, mesh = {Amyotrophic Lateral Sclerosis/blood/*immunology ; Complement C3/metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; G(M1) Ganglioside/*immunology ; Humans ; Immunoglobulin G/*blood/immunology ; Immunoglobulin M/blood/immunology ; Male ; Retrospective Studies ; }, abstract = {A patient, who developed an amyotrophic lateral sclerosis-like disorder subsequent to ganglioside treatment, had IgM antibodies to GM2 as well as to minor gangliosides X1 and X2 containing GM2 epitope. These gangliosides as well as GM1 were tested in 655 sera obtained from patients who were suspected of having amyotrophic lateral sclerosis or motor neuron disease to find a treatable condition. Three patients had high titers of IgG anti-GM1 antibodies, but no IgM anti-GM1 antibodies. One of the patients also had IgG anti-X2 antibodies. The patients, being diagnosed with having lower motor neuron syndrome, had neither upper motor neuron signs nor multifocal conduction block. Both IgM and IgG anti-GM1 antibodies should be tested in patients who have lower motor neuron syndrome.}, }
@article {pmid24840975, year = {2014}, author = {Deng, H and Gao, K and Jankovic, J}, title = {The role of FUS gene variants in neurodegenerative diseases.}, journal = {Nature reviews. Neurology}, volume = {10}, number = {6}, pages = {337-348}, pmid = {24840975}, issn = {1759-4766}, mesh = {Humans ; Neurodegenerative Diseases/*genetics ; RNA-Binding Protein FUS/genetics/*physiology ; }, abstract = {The neurodegenerative diseases are a diverse group of disorders characterized by progressive loss of specific groups of neurons. These diseases affect different populations, and have a variable age of onset, clinical symptoms, and pathological findings. Variants in the FUS gene, which encodes an RNA-binding protein, have been identified as causative or risk factors for amyotrophic lateral sclerosis (ALS), essential tremor and rare forms of frontotemporal lobar degeneration (FTLD). Additionally, abnormal aggregation of FUS protein has been reported in multiple neurodegenerative diseases, including ALS, FTLD and the polyglutamine diseases, suggesting a role for FUS in the pathogenesis of these neurodegenerative diseases. This Review summarizes current understanding of the normal function of FUS, and describes its role in the pathology of ALS, FTLD, essential tremor and other neurodegenerative diseases. Comments on the underlying pathogenetic mechanisms of these FUS-related disorders are included. Finally, the clinical implications of recent advances in FUS research are discussed. Further understanding of the role of FUS in neurodegenerative diseases might lead to improvements in the treatment and prevention of these disorders.}, }
@article {pmid24839771, year = {2014}, author = {Trpković, S and Pavlović, A and Bumbasirević, V and Sekulić, A and Milicić, B}, title = {[Outcome among patients suffering from in-hospital cardiac arrest].}, journal = {Srpski arhiv za celokupno lekarstvo}, volume = {142}, number = {3-4}, pages = {170-177}, doi = {10.2298/sarh1404170t}, pmid = {24839771}, issn = {0370-8179}, mesh = {Adult ; Advanced Cardiac Life Support/statistics &amp; numerical data ; Aged ; Aged, 80 and over ; Cardiopulmonary Resuscitation/statistics &amp; numerical data ; Female ; Heart Arrest/*diagnosis/*epidemiology/etiology/therapy ; Hospital Mortality ; Hospitalization/*statistics &amp; numerical data ; Hospitals/statistics &amp; numerical data ; Humans ; Male ; Middle Aged ; Prognosis ; Prospective Studies ; Young Adult ; }, abstract = {INTRODUCTION: In relation to pre-hospital treatment of patients with cardiac arrest (CA) in the field where resuscitation is often started by nonprofessionals, resuscitation in hospital is most commonly performed by well-trained personnel.<br><br>OBJECTIVE: The aim was to define the factors associated with an improved outcome among patients suffering from the in-hospital CA (IHCA).<br><br>METHODS: The prospective study included a total of 100 patients in the Emergency Center over two-year period.The patterns by the Utstein-Style guidelines recorded the following: age, sex, reason for hospital admission, comorbidity, cause and origin of CA, continuous monitoring, time of arrival of the medical emergency team and time of delivery of the first defibrillation shock (DC).<br><br>RESULTS: Most patients (61%) had cardiac etiology. Return of spontaneous circulation (ROSC) was achieved in 58% of patients. ROSC was more frequently achieved in younger patients (57.69 +/- 11.37), (p < 0.05), non-surgical patients (76.1%), (p < 0.01) and in patients who were in continuous monitoring (66.7%) (p < 0.05). The outcome of CPR was significantly better in patients who received advanced life support (ALS) (76.6%) (p < 0.01). Time until the delivery of the first DC shock was significantly shorter in patients who achieved ROSC (1.67 +/- 1.13 min), (p < 0.01). A total of 5% of IHCA patients survived to hospital discharge.<br><br>CONCLUSION: In our study, the outcome of CPR was better in patients who were younger and with non-surgical diseases, which are prognostic factors that we cannot control. Factors associated with better outcome of IHCA patients were: continuous monitoring, shorter time until the delivery of the first DC and ALS. This means that better education of medical staff, better organization and up-to-dated technical equipment are needed.}, }
@article {pmid24836816, year = {2014}, author = {Dumont, AO and Goursaud, S and Desmet, N and Hermans, E}, title = {Differential regulation of glutamate transporter subtypes by pro-inflammatory cytokine TNF-α in cortical astrocytes from a rat model of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {9}, number = {5}, pages = {e97649}, pmid = {24836816}, issn = {1932-6203}, mesh = {Amino Acid Transport System X-AG/*genetics/*metabolism ; Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Astrocytes/*metabolism ; Cells, Cultured ; Cerebellar Cortex/cytology ; Cycloheximide/pharmacology ; Cytokines/metabolism ; Disease Models, Animal ; *Gene Expression Regulation ; Inflammation/*metabolism ; Male ; Protein Biosynthesis/drug effects ; Protein Isoforms/metabolism ; Rats, Sprague-Dawley ; Recombinant Proteins/metabolism ; Spinal Cord/cytology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {Dysregulation of the astroglial glutamate transporters GLAST and GLT-1 has been implicated in several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) where a loss of GLT-1 protein expression and activity is reported. Furthermore, the two principal C-terminal splice variants of GLT-1 (namely GLT-1a and GLT-1b) show altered expression ratio in animal models of this disease. Considering the putative link between inflammation and excitotoxicity, we have here characterized the influence of TNF-α on glutamate transporters in cerebral cortical astrocyte cultures from wild-type rats and from a rat model of ALS (hSOD1G93A). Contrasting with the down-regulation of GLAST, a 72 h treatment with TNF-α substantially increased the expression of GLT-1a and GLT-1b in both astrocyte cultures. However, as the basal level of GLT-1a appeared considerably lower in hSOD1G93A astrocytes, its up-regulation by TNF-α was insufficient to recapitulate the expression observed in wild-type astrocytes. Also the glutamate uptake activity after TNF-α treatment was lower for hSOD1G93A astrocytes as compared to wild-type astrocytes. In the presence of the protein synthesis inhibitor cycloheximide, TNF-α did not influence GLT-1 isoform expression, suggesting an active role of dynamically regulated protein partners in the adaptation of astrocytes to the inflammatory environment. Confirming the influence of inflammation on the control of glutamate transmission by astrocytes, these results shed light on the regulation of glutamate transporter isoforms in neurodegenerative disorders.}, }
@article {pmid24820540, year = {2014}, author = {Noh, MY and Cho, KA and Kim, H and Kim, SM and Kim, SH}, title = {Erythropoietin modulates the immune-inflammatory response of a SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS).}, journal = {Neuroscience letters}, volume = {574}, number = {}, pages = {53-58}, doi = {10.1016/j.neulet.2014.05.001}, pmid = {24820540}, issn = {1872-7972}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/immunology ; Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Cell Death ; Cytokines/metabolism ; Erythropoietin/pharmacology/*therapeutic use ; Humans ; Mice, Transgenic ; Neurons/drug effects/pathology ; Spinal Cord/drug effects/pathology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Up-Regulation ; }, abstract = {Temporal patterns of inflammatory cytokine levels reflect the immune-inflammatory role in pathogenic mechanisms of SOD1 animal model of Amyotrophic Lateral Sclerosis (ALS) and these cytokines have important roles in both toxic and protective functions depending on the stage of disease progression in ALS patients. Erythropoietin (EPO) has various neuroprotective effects, including the reduction of inflammation, the enhancement of survival signals, and the prevention of neuronal cell death. This study was undertaken to evaluate the temporal pattern of inflammatory cytokine levels induced by EPO treatment in the SOD1(G93A) mice model of ALS. We treated mice with 5 IU of EPO per gram of animal weight once every other week after the mice were 60 days old, and pro/anti-inflammatory cytokines were analyzed at 30, 60, 90, and 120 days of age. In untreated controls, pro-inflammatory cytokines (IFN-γ, TNF-α, IL-1β, CCL2 (MCP-1), CCL5 (RANTES), CXCL10 (IP-10), and IL-17A) were gradually increased with aging. In contrast, increment of anti-inflammatory cytokines (IL-4, IL-10, and TGF-β) showed the highest level at 90 days of age and their levels were remarkably faded until 120 days of age. EPO treatment, however, showed significantly decreased level of pro-inflammatory cytokines. And, up-regulated levels of anti-inflammatory cytokines with EPO were highly maintained until 120 days. In addition, the treatment of EPO delayed symptom onset, prolonged time of rotarod failure, and showed more preserved number of motoneurons. These findings suggest that EPO may be a potential therapeutic candidate having ability to modulate immune-inflammation in ALS.}, }
@article {pmid24816450, year = {2014}, author = {Chan, TM and Chen, JY and Ho, LI and Lin, HP and Hsueh, KW and Liu, DD and Chen, YH and Hsieh, AC and Tsai, NM and Hueng, DY and Tsai, ST and Chou, PW and Lin, SZ and Harn, HJ}, title = {ADSC therapy in neurodegenerative disorders.}, journal = {Cell transplantation}, volume = {23}, number = {4-5}, pages = {549-557}, doi = {10.3727/096368914X678445}, pmid = {24816450}, issn = {1555-3892}, mesh = {Adipose Tissue/*cytology ; Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Animals ; Cell Differentiation ; Cell Lineage ; Humans ; Huntington Disease/therapy ; Neurodegenerative Diseases/*therapy ; Parkinson Disease/therapy ; *Stem Cell Transplantation ; Stem Cells/*cytology ; }, abstract = {Neurodegenerative disorders, chronic diseases that can severely affect the patient's daily life, include amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's diseases. However, these diseases all have the common characteristic that they are due to degenerative irreversibility, and thus no efficient drugs or therapy methods can mitigate symptoms completely. Stem cell therapy, such as adipose tissue-derived stem cells (ADSCs), is a promising treatment for incurable disorders. In this review, we summarized the previous studies using ADSCs to treat neurodegenerative disorders, as well as their therapeutic mechanisms. We also suggested possible expectations for future human clinical trials involving minimized intracerebroventricular combined with intravenous administration, using different cell lineages to finish complementary therapy as well as change the extracellular matrix to create a homing niche. Depending on successful experiments in relevant neurodegenerative disorders models, this could form the theoretical basis for future human clinical trials.}, }
@article {pmid24816247, year = {2014}, author = {Van Damme, P and Robberecht, W}, title = {Developments in treatments for amyotrophic lateral sclerosis via intracerebroventricular or intrathecal delivery.}, journal = {Expert opinion on investigational drugs}, volume = {23}, number = {7}, pages = {955-963}, doi = {10.1517/13543784.2014.912275}, pmid = {24816247}, issn = {1744-7658}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Blood-Brain Barrier/metabolism ; Humans ; Injections, Intraventricular ; Injections, Spinal ; }, abstract = {INTRODUCTION: Amyotrophic lateral scleroses (ALS) are neurodegenerative disorders primarily affecting the motor system. These incurable disorders are relentlessly progressive and typically limit survival to 2 - 5 years after disease onset. An improved knowledge about disease-causing genes, disease proteins and pathways has revealed considerable heterogeneity in ALS. Novel targeted therapies are being developed, but getting these beyond the BBB remains a challenge.<br><br>AREAS COVERED: The authors review the intracerebroventricular and intrathecal delivery of drugs for the treatment of ALS in preclinical and clinical studies.<br><br>EXPERT OPINION: Lack of BBB permeability should not hold back the development of promising treatments for ALS, as the available evidence suggest that direct intrathecal or intracerebroventricular administration of drug is a feasible delivery route in patients with ALS.}, }
@article {pmid24809691, year = {2014}, author = {Riboldi, G and Zanetta, C and Ranieri, M and Nizzardo, M and Simone, C and Magri, F and Bresolin, N and Comi, GP and Corti, S}, title = {Antisense oligonucleotide therapy for the treatment of C9ORF72 ALS/FTD diseases.}, journal = {Molecular neurobiology}, volume = {50}, number = {3}, pages = {721-732}, pmid = {24809691}, issn = {1559-1182}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; C9orf72 Protein ; DNA Repeat Expansion ; Frontotemporal Dementia/*drug therapy/genetics ; Humans ; Motor Neurons ; Oligonucleotides, Antisense/*therapeutic use ; Proteins/*genetics ; }, abstract = {Motor neuron disorders, and particularly amyotrophic lateral sclerosis (ALS), are fatal diseases that are due to the loss of motor neurons in the brain and spinal cord, with progressive paralysis and premature death. It has been recently shown that the most frequent genetic cause of ALS, frontotemporal dementia (FTD), and other neurological diseases is the expansion of a hexanucleotide repeat (GGGGCC) in the non-coding region of the C9ORF72 gene. The pathogenic mechanisms that produce cell death in the presence of this expansion are still unclear. One of the most likely hypotheses seems to be the gain-of-function that is achieved through the production of toxic RNA (able to sequester RNA-binding protein) and/or toxic proteins. In recent works, different authors have reported that antisense oligonucleotides complementary to the C9ORF72 RNA transcript sequence were able to significantly reduce RNA foci generated by the expanded RNA, in affected cells. Here, we summarize the recent findings that support the idea that the buildup of "toxic" RNA containing the GGGGCC repeat contributes to the death of motor neurons in ALS and also suggest that the use of antisense oligonucleotides targeting this transcript is a promising strategy for treating ALS/frontotemporal lobe dementia (FTLD) patients with the C9ORF72 repeat expansion. These data are particularly important, given the state of the art antisense technology, and they allow researchers to believe that a clinical application of these discoveries will be possible soon.}, }
@article {pmid24796478, year = {2014}, author = {Oh, H and Schepp, KG and McGrath, BB}, title = {A journey of suffering: living with amyotrophic lateral sclerosis in South Korea.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {46}, number = {3}, pages = {E3-11}, doi = {10.1097/JNN.0000000000000054}, pmid = {24796478}, issn = {1945-2810}, mesh = {Adaptation, Psychological ; Adult ; Amyotrophic Lateral Sclerosis/ethnology/nursing/*psychology ; Anthropology, Cultural/methods ; Asian People/psychology ; Cultural Characteristics ; Disease Progression ; Emotions ; Female ; Humans ; Interviews as Topic ; Male ; Middle Aged ; Neuroscience Nursing/*methods ; Pain/ethnology/nursing/*psychology ; Republic of Korea ; Social Behavior ; Stress, Psychological/ethnology/nursing/*psychology ; }, abstract = {Amyotrophic lateral sclerosis presents significant challenges for patients because of the devastating disease characteristics and the fact that there is no treatment available. In this article, we explored the illness experiences from the perspectives of patients with amyotrophic lateral sclerosis in the sociocultural context of South Korea. Fifteen patients were observed and interviewed between September 2009 and July 2010 in the metropolitan area of South Korea. We used an ethnographic approach for data collection and analysis. The meta-theme generated was "a journey of suffering," and three themes emerged: (a) off the course, (b) drifting, and (c) on a new boat. Participants experienced multidimensional suffering as the disease progressed. Healthcare professionals should understand that, for many patients, this disease is a process or a series of experiences rather than a single diagnosis. This knowledge would allow healthcare providers to help patients prepare for those needs that arise as the disease worsens.}, }
@article {pmid24796270, year = {2015}, author = {Ando, H and Williams, C and Angus, RM and Thornton, EW and Chakrabarti, B and Cousins, R and Piggin, LH and Young, CA}, title = {Why don't they accept non-invasive ventilation?: insight into the interpersonal perspectives of patients with motor neurone disease.}, journal = {British journal of health psychology}, volume = {20}, number = {2}, pages = {341-359}, doi = {10.1111/bjhp.12104}, pmid = {24796270}, issn = {2044-8287}, support = {YOUNG/MAR07/6026/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Adult ; Aged ; *Attitude to Health ; Decision Making ; Female ; Humans ; Interviews as Topic ; Male ; Middle Aged ; Motor Neuron Disease/*therapy ; Noninvasive Ventilation/*psychology/statistics &amp; numerical data ; Patient Acceptance of Health Care/*psychology/statistics &amp; numerical data ; Patient Participation/psychology/statistics &amp; numerical data ; Quality of Life/psychology ; Surveys and Questionnaires ; }, abstract = {OBJECTIVES: Although non-invasive ventilation (NIV) can benefit survival and quality of life, it is rejected by a substantial proportion of people with motor neurone disease (MND). The aim of this study was to understand why some MND patients decline or withdraw from NIV.<br><br>METHOD: Nine patients with MND (male&#xa0;=&#xa0;7, mean age&#xa0;=&#xa0;67&#xa0;years) participated in this study. These patients, from a cohort of 35 patients who were offered NIV treatment to support respiratory muscle weakness, did not participate in NIV treatment when it was clinically appropriate. Semi-structured interviews and interpretative phenomenological analysis (IPA) were employed to explore these patient's experience of MND and their thoughts and understanding of NIV treatment.<br><br>RESULTS: Using IPA, four themes were identified: preservation of the self, negative perceptions of NIV, negative experience with health care services, and not needing NIV. Further analysis identified the fundamental issue to be the maintenance of perceived self, which was interpreted to consist of the sense of autonomy, dignity, and quality of life.<br><br>CONCLUSIONS: The findings indicate psychological reasons for disengagement with NIV. The threat to the self, the sense of loss of control, and negative views of NIV resulting from anxiety were more important to these patients than prolonging life in its current form. These findings suggest the importance of understanding the psychological dimension involved in decision-making regarding uptake of NIV and a need for sensitive holistic evaluation if NIV is declined. Statement of contribution What is already known on this subject? Non-invasive ventilation is widely used as an effective symptomatic therapy in MND, yet about a third of patients decline the treatment. Psychological disturbance generated by NIV use leads to negative experiences of the treatment. Decision-making about treatment potentials is complex and unique to each individual affected by perceived impact of disease. What does this study add? A decision concerning NIV uptake was influenced by perceived impact on individuals' sense of self. Sense of self was influenced by the maintenance of autonomy, dignity, and quality of life. Individuals' sense of self was identified to have been challenged by the disease, NIV, and their experience of health care service.}, }
@article {pmid24785142, year = {2014}, author = {Camdessanché, JP and Lenglet, T}, title = {[Neurophysiological investigations in amyotrophic lateral sclerosis].}, journal = {Presse medicale (Paris, France : 1983)}, volume = {43}, number = {5}, pages = {563-568}, doi = {10.1016/j.lpm.2014.03.003}, pmid = {24785142}, issn = {2213-0276}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Diagnostic Techniques, Neurological ; Evoked Potentials, Motor ; Humans ; Transcranial Magnetic Stimulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative disease which prognosis is poor. Early diagnosis permits to set up immediately adapted treatment and cares. Available diagnostic criteria are based on the detection of both the central and peripheral motor neuron injury in bulbar, cervical, thoracic and lumbar regions. Electromyographic study is the key tool to identify peripheral motor neuron involvement. Conduction velocities are systematically performed to rule out differential diagnosis. Needle examination records abnormal activities at rest and looks for neurogenic pattern during muscle contraction. Motor unit potentials morphology is modified primary to recruitment. Motor evoked potentials remain the test of choice to identify impairment of central motor neurons. For the monitoring of ALS patients, the MUNE technique (motor unit number estimation) seems the most interesting.}, }
@article {pmid24771634, year = {2014}, author = {Zhao, Y and Cudkowicz, ME and Shefner, JM and Krivickas, L and David, WS and Vriesendorp, F and Pestronk, A and Caress, JB and Katz, J and Simpson, E and Rosenfeld, J and Pascuzzi, R and Glass, J and Rezania, K and Harmatz, JS and Schoenfeld, D and Greenblatt, DJ}, title = {Systemic pharmacokinetics and cerebrospinal fluid uptake of intravenous ceftriaxone in patients with amyotrophic lateral sclerosis.}, journal = {Journal of clinical pharmacology}, volume = {54}, number = {10}, pages = {1180-1187}, pmid = {24771634}, issn = {1552-4604}, support = {U01 NS049640/NS/NINDS NIH HHS/United States ; UL1 TR001108/TR/NCATS NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; U01 NS049640-05/NS/NINDS NIH HHS/United States ; R01 NS049640/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Anti-Bacterial Agents/administration &amp; dosage/*pharmacokinetics/therapeutic use ; Ceftriaxone/administration &amp; dosage/*pharmacokinetics/therapeutic use ; Female ; Half-Life ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Tissue Distribution ; }, abstract = {The cephalosporin antibiotic ceftriaxone was evaluated as a potential therapeutic agent for the treatment of amyotrophic lateral sclerosis (ALS). The pharmacokinetics (PK) of ceftriaxone in plasma and cerebrospinal fluid (CSF) were investigated in 66 participants in a previously reported clinical trial. Their mean age was 51 years, and 65% were male. Participants were randomly assigned to 1 of 3 treatment groups receiving intravenous infusions (mean duration: 25 minutes) every 12 hours of either: placebo and placebo; 2 g ceftriaxone and placebo; or 2 g ceftriaxone twice. Mean steady-state plasma PK variables were: volume of distribution, 14 L (0.17 L/kg); elimination half-life, 8-9 h; total clearance, 17-21 mL/min (0.22-0.25 mL/min/kg). Values were not different between dosage groups. CSF PK analysis, determined through sparse CSF sampling, indicated apparent entry and elimination half-life values of 1.0 and 34 hours, respectively. With both dosage regimens, CSF concentrations were maintained above the target threshold of 1.0 µM (0.55 µg/mL) as determined from in vitro models. The plasma and CSF PK profiles of ceftriaxone were used as a basis for planning the Phase 3 clinical trial of ceftriaxone in ALS.}, }
@article {pmid24766396, year = {2014}, author = {Forlenza, OV and De-Paula, VJ and Diniz, BS}, title = {Neuroprotective effects of lithium: implications for the treatment of Alzheimer's disease and related neurodegenerative disorders.}, journal = {ACS chemical neuroscience}, volume = {5}, number = {6}, pages = {443-450}, pmid = {24766396}, issn = {1948-7193}, mesh = {Alzheimer Disease/*drug therapy/physiopathology ; Animals ; Humans ; Lithium Compounds/*pharmacology/therapeutic use ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neuroprotective Agents/*pharmacology/therapeutic use ; }, abstract = {Lithium is a well-established therapeutic option for the acute and long-term management of bipolar disorder and major depression. More recently, based on findings from translational research, lithium has also been regarded as a neuroprotective agent and a candidate drug for disease-modification in certain neurodegenerative disorders, namely, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and, more recently, Parkinson's disease (PD). The putative neuroprotective effects of lithium rely on the fact that it modulates several homeostatic mechanisms involved in neurotrophic response, autophagy, oxidative stress, inflammation, and mitochondrial function. Such a wide range of intracellular responses may be secondary to two key effects, that is, the inhibition of glycogen synthase kinase-3 beta (GSK-3β) and inositol monophosphatase (IMP) by lithium. In the present review, we revisit the neurobiological properties of lithium in light of the available evidence of its neurotrophic and neuroprotective properties, and discuss the rationale for its use in the treatment and prevention of neurodegenerative diseases.}, }
@article {pmid24742612, year = {2014}, author = {Pradat, PF and Dupuis, L}, title = {[ALS treatment: state of the art in 2014 and perspectives].}, journal = {Presse medicale (Paris, France : 1983)}, volume = {43}, number = {5}, pages = {595-602}, doi = {10.1016/j.lpm.2014.01.013}, pmid = {24742612}, issn = {2213-0276}, mesh = {Amyotrophic Lateral Sclerosis/complications/diagnosis/*therapy ; Humans ; }, abstract = {Progresses in the multidisciplinary care, particularly in the nutritional and respiratory management, allowed improving the quality of life and survival of ALS patients. Non-invasive ventilation is initially performed overnight but with the progression of diaphragmatic weakness, a continuous ventilatory support is often needed. Advances directives regarding end-of-life issues are important to respect patient's wishes regarding the choice of invasive ventilation with tracheostomy. Riluzole is the only neuroprotective drug that has demonstrated a significant but modest effect on survival and is well tolerated The failure of therapeutic trials may be partly related to the heterogeneity of the disease. Recent progress in the genetic of ALS may lead to new therapeutic strategies. Results of therapeutic trials with drugs or nutritional intervention are expected in 2014.}, }
@article {pmid24737943, year = {2014}, author = {Lee, SH and Choi, SM and Yang, EJ}, title = {Melittin ameliorates the inflammation of organs in an amyotrophic lateral sclerosis animal model.}, journal = {Experimental neurobiology}, volume = {23}, number = {1}, pages = {86-92}, pmid = {24737943}, issn = {1226-2560}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder characterized by a selective loss of motor neurons in the spinal cord, brainstem, and motor cortex, leading to weakness of the limb and bulbar muscles. Although the immediate cause of death in ALS is the destruction of motor neurons, ALS is a multi-organ disease that also affects the lungs, spleen, and liver. Melittin is one of components of bee venom and has anti-neuroinflammatory effects in the spinal cord, as shown in an ALS animal model. To investigate the effects of melittin on inflammation in the lungs and spleen, we used hSOD1(G93A) transgenic mice that are mimic for ALS. Melittin treatment reduced the expression of inflammatory proteins, including Iba-1 and CD14 by 1.9- and 1.3-fold (p<0.05), respectively, in the lungs of symptomatic hSOD1(G93A) transgenic mice. In the spleen, the expression of CD14 and COX2 that are related to inflammation were decreased by 1.4 fold (p<0.05) and cell survival proteins such as pERK and Bcl2 were increased by 1.3- and 1.5-fold (p<0.05) in the melittin-treated hSOD1G93A transgenic mice. These findings suggest that melittin could be a candidate to regulate the immune system in organs affected by ALS.}, }
@article {pmid24735613, year = {2014}, author = {De Clercq, E}, title = {Current race in the development of DAAs (direct-acting antivirals) against HCV.}, journal = {Biochemical pharmacology}, volume = {89}, number = {4}, pages = {441-452}, doi = {10.1016/j.bcp.2014.04.005}, pmid = {24735613}, issn = {1873-2968}, mesh = {Animals ; Antiviral Agents/adverse effects/chemistry/*pharmacology/therapeutic use ; *Drug Discovery ; Drug Resistance, Viral ; Drug Therapy, Combination ; Enzyme Inhibitors/adverse effects/chemistry/pharmacology/therapeutic use ; Hepacivirus/*drug effects/enzymology ; Hepatitis C/drug therapy/virology ; Humans ; Molecular Targeted Therapy ; Viral Nonstructural Proteins/*antagonists &amp; inhibitors ; }, abstract = {The direct-acting antivirals (DAAs) currently in development for treatment of hepatitis C fall into four categories: (i) NS3/4A protease inhibitors: ABT-450/r, faldaprevir, asunaprevir, GS-9256, vedroprevir (GS-9451), danoprevir, MK-5172, vaniprevir, sovaprevir, ACH-2684, narlaprevir and simeprevir, in addition to those that are already developed [telaprevir (Incivek®) and boceprevir (Victrelis®)], (ii) NS5A protein inhibitors: ABT-267, daclatasvir, ledipasvir, ACH-2928, ACH-3102, PPI-668, AZD-7295, MK-8742, and GSK 2336805; (iii) NS5B (nucleoside-type) polymerase inhibitors: sofosbuvir (now approved by the FDA since 6 December 2013), GS-0938, mericitabine, VX-135, ALS 2158 and TMC 649128; (iv) NS5B (non-nucleoside-type) polymerase inhibitors: VX-222, ABT-072, ABT-333, deleobuvir, tegobuvir, setrobuvir, VCH-916, VCH-759, BMS-791325 and TMC-647055. Future drug combinations will likely exist of two or more DAAs belonging to any of the 4 categories, with the aim to achieve (i) pan-genotypic hepatitis C virus (HCV) activity, (ii) little or no risk for resistance; (iii) short duration (i.e. 12 weeks) of treatment, and (iv) a sustained viral response (SVR) and definite cure of the disease.}, }
@article {pmid24731566, year = {2014}, author = {Chen, YY and Liu, XW and Gong, TX and Zhang, ZY and Liu, YE and Zhang, YB and Xiang, LB and Xia, H}, title = {Role of platelet derived growth factor (PDGF) in reverting neuronal nuclear and soma size alterations in NSC-34 cells exposed to cerebrospinal fluid from amyotrophic lateral sclerosis patients.}, journal = {Clinical neurology and neurosurgery}, volume = {120}, number = {}, pages = {1-5}, doi = {10.1016/j.clineuro.2014.02.004}, pmid = {24731566}, issn = {1872-6968}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*cerebrospinal fluid ; Cell Line ; *Cerebrospinal Fluid ; Female ; Humans ; Male ; Middle Aged ; Motor Neurons/*drug effects/pathology ; Neuroprotective Agents/*pharmacology ; Platelet-Derived Growth Factor/*pharmacology/physiology ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) or motor neuron disease is an adult-onset progressive neurodegenerative disorder. ALS-CSF has been shown to produce toxic effects on motor neuron cells like aberrant neurofilament phosphorylation and morphological alterations of nuclear and soma size. Our current study was designed to investigate the neuroprotective role of platelet derived growth factor (PDGF) in reverting the adverse effects produced by ALS-CSF.<br><br>METHODS: Our present study was carried out to determine the restorative potential of PDGF on the toxic effects of ALS-CSF on NSC motor neuron cells from patients. Therefore the cells were divided in to three groups: (a) normal control (NC) - the cells were not exposed to ALS-CSF; (b) ALS group - the cells were exposed to ALS-CSF; (c) NALS group - the cells were exposed to non ALS CSF. Further each of these groups was supplemented with PDGF.<br><br>RESULTS AND CONCLUSIONS: We observed that the mean area of nucleus and cell soma of the differentiated NSC motor neuron cells was significantly reduced in the cells exposed to ALS-CSF. We also observed that subsequent treatment with PDGF restored the soma area and nucleus of the ALS-CSF exposed cells significantly. Taken together, we show that supplementation with PDGF restores the morphological changes induced by ALS-CSF and PDGF may play a significant role in protecting motor neurons from apoptosis in ALS and thereby it promoting the cell survival.}, }
@article {pmid24730717, year = {2014}, author = {Forlenza, OV and Coutinho, AM and Aprahamian, I and Prando, S and Mendes, LL and Diniz, BS and Gattaz, WF and Buchpiguel, CA}, title = {Long-term lithium treatment reduces glucose metabolism in the cerebellum and hippocampus of nondemented older adults: an [[18]F]FDG-PET study.}, journal = {ACS chemical neuroscience}, volume = {5}, number = {6}, pages = {484-489}, pmid = {24730717}, issn = {1948-7193}, mesh = {Aged ; Brain Mapping ; Cerebellum/diagnostic imaging/*drug effects/metabolism ; Cognitive Dysfunction/*drug therapy/metabolism ; Female ; Fluorodeoxyglucose F18 ; Glucose/*metabolism ; Hippocampus/diagnostic imaging/*drug effects/metabolism ; Humans ; Lithium Carbonate/*therapeutic use ; Male ; Positron-Emission Tomography ; Psychotropic Drugs/*therapeutic use ; Radiopharmaceuticals ; }, abstract = {Lithium modulates several intracellular pathways related to neuroplasticity and resilience against neuronal injury. These properties have been consistently reported in experimental models, and involve the up-regulation of neurotrophic response and autophagy, and down-regulation of apoptosis, oxidative stress, and inflammation. Clinical and epidemiological studies in bipolar disorder show that acute treatment with lithium increases plasma concentrations of brain-derived neurotrophic factor, and long-term treatment lowers the risk of dementia. Neuroimaging studies indicate that lithium use is further associated with increased cortical thickness and larger hippocampal volumes. The objective of the present study was to evaluate whether these neurobiological properties of lithium reflect in increased regional brain glucose metabolism, as shown by [(18)F]FDG-PET. Participants (n = 19) were nondemented older adults recruited at the end point of a controlled trial addressing clinical and biological effects of lithium in a sample of patients with amnestic mild cognitive impairment. Twelve patients who had received low-dose lithium carbonate for 4 years were compared to seven matched controls. Chronic lithium treatment was not associated with any significant increase in brain glucose metabolism in the studied areas. Conversely, we found a significant reduction in glucose uptake in several clusters of the cerebellum and in both hippocampi. These findings were not associated with any clinical evidence of toxicity. The clinical implications of the present findings need to be clarified by future controlled studies, particularly in the light of the potential use of lithium as a disease-modifying treatment approach for certain neurodegenerative disorders, namely, Alzheimer's disease and amyotrophic lateral sclerosis.}, }
@article {pmid24723858, year = {2014}, author = {Jara, JH and Genç, B and Klessner, JL and Ozdinler, PH}, title = {Retrograde labeling, transduction, and genetic targeting allow cellular analysis of corticospinal motor neurons: implications in health and disease.}, journal = {Frontiers in neuroanatomy}, volume = {8}, number = {}, pages = {16}, pmid = {24723858}, issn = {1662-5129}, support = {P30 CA060553/CA/NCI NIH HHS/United States ; R01 NS085161/NS/NINDS NIH HHS/United States ; }, abstract = {Corticospinal motor neurons (CSMN) have a unique ability to receive, integrate, translate, and transmit the cerebral cortex's input toward spinal cord targets and therefore act as a "spokesperson" for the initiation and modulation of voluntary movements that require cortical input. CSMN degeneration has an immense impact on motor neuron circuitry and is one of the underlying causes of numerous neurodegenerative diseases, such as primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), and amyotrophic lateral sclerosis (ALS). In addition, CSMN death results in long-term paralysis in spinal cord injury patients. Detailed cellular analyses are crucial to gain a better understanding of the pathologies underlying CSMN degeneration. However, visualizing and identifying these vulnerable neuron populations in the complex and heterogeneous environment of the cerebral cortex have proved challenging. Here, we will review recent developments and current applications of novel strategies that reveal the cellular and molecular basis of CSMN health and vulnerability. Such studies hold promise for building long-term effective treatment solutions in the near future.}, }
@article {pmid24715356, year = {2015}, author = {Jiang, H and Wang, C and Ren, M and Yin, X and Chi, C and Guo, L and Ke, C and Feng, H and Li, E}, title = {Blood volatile organic compounds as potential biomarkers for amyotrophic lateral sclerosis: an animal study in the SOD1 G93A mouse.}, journal = {Journal of molecular neuroscience : MN}, volume = {55}, number = {1}, pages = {167-173}, pmid = {24715356}, issn = {1559-1166}, mesh = {Amyotrophic Lateral Sclerosis/*blood/genetics ; Animals ; Biomarkers/blood ; Mice ; *Mutation, Missense ; Superoxide Dismutase/*metabolism ; Superoxide Dismutase-1 ; Volatile Organic Compounds/*blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapid progressive motor neuron disease. Currently, there are no specific or reliable biomarkers for the diagnosis of this disease, and there are no effective medical treatments. The early diagnosis and treatment of this disease has the potential to prolong the survival of ALS patients, but typically, approximately 1 year passes between the onset of symptoms and the diagnosis of this disease. Therefore, there is an urgent need to find specific biomarkers to enable early diagnosis and therapeutic intervention in this disease. Analyzing the volatile organic compounds (VOCs) present in the blood and exhaled breath is a useful and convenient approach for investigating potential biomarkers. In this study, we examined the VOCs present in blood samples from copper zinc superoxide dismutase 1 (SOD1) glycine to alanine mutation at position 93 (G93A) mice to determine whether a specific biomarker pattern exists in these transgenic mice. Blood samples from ALS mice and their age-matched littermates were analyzed using gas chromatography-mass spectrometry. A total of 12 independent compounds associated with oxidative stress were identified at the early stage of disease. The data show that there is a specific pattern of blood VOCs in ALS mice that could potentially be used as biomarkers that could improve the diagnosis of this disease. Furthermore, these compounds could also potentially be used to monitor the response to neuroprotective agents and to help us better understand the underlying mechanisms of ALS.}, }
@article {pmid24705136, year = {2014}, author = {Babin, PJ and Goizet, C and Raldúa, D}, title = {Zebrafish models of human motor neuron diseases: advantages and limitations.}, journal = {Progress in neurobiology}, volume = {118}, number = {}, pages = {36-58}, doi = {10.1016/j.pneurobio.2014.03.001}, pmid = {24705136}, issn = {1873-5118}, mesh = {Animals ; Brain/anatomy &amp; histology/physiopathology ; *Disease Models, Animal ; Humans ; *Motor Neuron Disease/genetics/physiopathology ; Nerve Degeneration/genetics/physiopathology ; Spinal Cord/anatomy &amp; histology/physiopathology ; *Zebrafish/anatomy &amp; histology/genetics/physiology ; }, abstract = {Motor neuron diseases (MNDs) are an etiologically heterogeneous group of disorders of neurodegenerative origin, which result in degeneration of lower (LMNs) and/or upper motor neurons (UMNs). Neurodegenerative MNDs include pure hereditary spastic paraplegia (HSP), which involves specific degeneration of UMNs, leading to progressive spasticity of the lower limbs. In contrast, spinal muscular atrophy (SMA) involves the specific degeneration of LMNs, with symmetrical muscle weakness and atrophy. Amyotrophic lateral sclerosis (ALS), the most common adult-onset MND, is characterized by the degeneration of both UMNs and LMNs, leading to progressive muscle weakness, atrophy, and spasticity. A review of the comparative neuroanatomy of the human and zebrafish motor systems showed that, while the zebrafish was a homologous model for LMN disorders, such as SMA, it was only partially relevant in the case of UMN disorders, due to the absence of corticospinal and rubrospinal tracts in its central nervous system. Even considering the limitation of this model to fully reproduce the human UMN disorders, zebrafish offer an excellent alternative vertebrate model for the molecular and genetic dissection of MND mechanisms. Its advantages include the conservation of genome and physiological processes and applicable in vivo tools, including easy imaging, loss or gain of function methods, behavioral tests to examine changes in motor activity, and the ease of simultaneous chemical/drug testing on large numbers of animals. This facilitates the assessment of the environmental origin of MNDs, alone or in combination with genetic traits and putative modifier genes. Positive hits obtained by phenotype-based small-molecule screening using zebrafish may potentially be effective drugs for treatment of human MNDs.}, }
@article {pmid24704895, year = {2014}, author = {Patatanian, E and Casselman, J}, title = {Dextromethorphan/quinidine for the treatment of pseudobulbar affect.}, journal = {The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists}, volume = {29}, number = {4}, pages = {264-269}, doi = {10.4140/TCP.n.2014.264}, pmid = {24704895}, issn = {2331-0936}, mesh = {Clinical Trials as Topic ; Crying/psychology ; Dextromethorphan/administration &amp; dosage/adverse effects/pharmacology/*therapeutic use ; Drug Combinations ; Excitatory Amino Acid Antagonists/administration &amp; dosage/adverse effects/*therapeutic use ; Humans ; Laughter/psychology ; Pseudobulbar Palsy/*drug therapy/metabolism/psychology ; Quinidine/administration &amp; dosage/adverse effects/pharmacology/*therapeutic use ; Receptors, sigma/*agonists ; Treatment Outcome ; Sigma-1 Receptor ; }, abstract = {OBJECTIVE: To evaluate the role of dextromethorphan/quinidine (DM/Q; Nuedexta™) in the treatment of pseudobulbar affect (PBA).<br><br>DATA SOURCES: A literature search of MEDLINE/PubMed (January 1966-June 2013) was conducted using search terms pseudobulbar affect, pathological laughing and/or crying, emotional lability, dextromethorphan, and quinidine.<br><br>English language clinical trials and case reports evaluating the safety and efficacy of DM/Q in PBA were included for review. Bibliographies of all relevant articles were reviewed for additional citations.<br><br>DATA SYNTHESIS: PBA, a poorly understood disorder, is characterized by involuntary crying and/or laughing. In the past, antidepressants and antiepileptics have been used off-label with mixed results. Four clinical trials have evaluated the use of DM/Q for the treatment of PBA. Although the therapeutic outcomes with DM/Q have been positive, interpretation of the published evidence is limited by small sample size and short treatment duration.<br><br>CONCLUSIONS: Based on the data available, DM/Q may be a viable, short-term treatment alternative for PBA. Long-term safety and efficacy data are lacking.}, }
@article {pmid24703394, year = {2014}, author = {Moreno-Martet, M and Espejo-Porras, F and Fernández-Ruiz, J and de Lago, E}, title = {Changes in endocannabinoid receptors and enzymes in the spinal cord of SOD1(G93A) transgenic mice and evaluation of a Sativex(®) -like combination of phytocannabinoids: interest for future therapies in amyotrophic lateral sclerosis.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {20}, number = {9}, pages = {809-815}, pmid = {24703394}, issn = {1755-5949}, mesh = {Age Factors ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Analysis of Variance ; Animals ; Cannabidiol ; Dronabinol ; Drug Combinations ; Endocannabinoids/genetics/*metabolism ; Female ; Gene Expression Regulation/*drug effects/genetics ; Humans ; Male ; Mice, Transgenic ; Phospholipase D/*metabolism ; Plant Extracts/*therapeutic use ; Receptors, Cannabinoid/genetics/*metabolism ; Sex Factors ; Spinal Cord/*metabolism ; Superoxide Dismutase/genetics ; }, abstract = {AIMS: Cannabinoids afford neuroprotection in SOD1(G93A) mutant mice, an experimental model of amyotrophic lateral sclerosis (ALS). However, these mice have been poorly studied to identify alterations in those elements of the endocannabinoid system targeted by these treatments. Moreover, we studied the neuroprotective effect of the phytocannabinoid-based medicine Sativex(®) in these mice.<br><br>METHODS: First, we analyzed the endocannabinoid receptors and enzymes in the spinal cord of SOD1(G93A) transgenic mice at a late stage of the disease. Second, 10-week-old transgenic mice were daily treated with an equimolecular combination of &#x394;(9) -tetrahydrocannabinol- and cannabidiol-enriched botanical extracts (20&#xa0;mg/kg for each phytocannabinoid).<br><br>RESULTS: We found a significant increase of CB2 receptors and NAPE-PLD enzyme in SOD1(G93A) transgenic males and only CB2 receptors in females. Pharmacological experiments demonstrated that the treatment of these mice with the Sativex(&#xae;) -like combination of phytocannabinoids only produced weak improvements in the progression of neurological deficits and in the animal survival, particularly in females.<br><br>CONCLUSIONS: Our results demonstrated changes in endocannabinoid signaling, in particular a marked up-regulation of CB2 receptors, in SOD1(G93A) transgenic mice, and provide support that Sativex(&#xae;) may serve as a novel disease-modifying therapy in ALS.}, }
@article {pmid24699224, year = {2014}, author = {Jiang, HQ and Ren, M and Jiang, HZ and Wang, J and Zhang, J and Yin, X and Wang, SY and Qi, Y and Wang, XD and Feng, HL}, title = {Guanabenz delays the onset of disease symptoms, extends lifespan, improves motor performance and attenuates motor neuron loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis.}, journal = {Neuroscience}, volume = {277}, number = {}, pages = {132-138}, doi = {10.1016/j.neuroscience.2014.03.047}, pmid = {24699224}, issn = {1873-7544}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology/physiopathology ; Animals ; Cell Death/drug effects/physiology ; Disease Models, Animal ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/drug effects/physiology ; Female ; Guanabenz/*pharmacology ; Mice, Transgenic ; Mitochondria/drug effects/pathology/physiology ; Motor Activity/drug effects/physiology ; Motor Neurons/drug effects/pathology/physiology ; Nerve Degeneration/drug therapy/pathology/physiopathology ; Neuroprotective Agents/*pharmacology ; Random Allocation ; Superoxide Dismutase/genetics/metabolism ; Survival Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease characterized by the loss of motor neurons in the motor cortex, brain stem and spinal cord. Currently, there is no cure for this lethal disease. Although the mechanism underlying neuronal cell death in ALS remains elusive, growing evidence supports a crucial role of endoplasmic reticulum (ER) stress in the pathogenesis of ALS. Recent reports show that guanabenz, a novel inhibitor of eukaryotic initiation factor 2α (eIF2α) dephosphorylation, possesses anti-prion properties, attenuates ER stress and reduces paralysis and neurodegeneration in mTDP-43 Caenorhabditis elegans and Danio rerio models of ALS. However, the therapeutic potential of guanabenz for the treatment of ALS has not yet been assessed in a mouse model of ALS. In the present study, guanabenz was administered to a widely used mouse model of ALS expressing copper zinc superoxide dismutase-1 (SOD1) with a glycine to alanine mutation at position 93 (G93A). The results showed that the administration of guanabenz significantly extended the lifespan, delayed the onset of disease symptoms, improved motor performance and attenuated motor neuron loss in female SOD1 G93A mice. Moreover, western blotting results revealed that guanabenz dramatically increased the levels of phosphorylated-eIF2α (P-eIF2α) protein, without affecting total eIF2α protein levels. The results also revealed a significant decrease in the levels of the ER chaperone glucose-regulated protein 78 (BiP/Grp78) and markers of another two ER stress pathways, activating transcription factor 6α (ATF6α) and inositol-requiring enzyme 1 (IRE1). In addition, guanabenz increased the protein levels of anti-apoptotic B cell lymphoma/lewkmia-2 (Bcl-2), and down-regulated the pro-apoptotic protein levels of C/EBP homologous protein (CHOP), Bcl-2-associated X protein (BAX) and cytochrome C in SOD1 G93A mice. Our findings indicate that guanabenz may represent a novel therapeutic candidate for the treatment of ALS, a lethal human disease with an underlying mechanism involving the attenuation of ER stress and mitochondrial stress via prolonging eIF2α phosphorylation.}, }
@article {pmid24690380, year = {2014}, author = {Ohta, Y and Tremblay, C and Schneider, JA and Bennett, DA and Calon, F and Julien, JP}, title = {Interaction of transactive response DNA binding protein 43 with nuclear factor κB in mild cognitive impairment with episodic memory deficits.}, journal = {Acta neuropathologica communications}, volume = {2}, number = {}, pages = {37}, pmid = {24690380}, issn = {2051-5960}, support = {R01AG42210/AG/NIA NIH HHS/United States ; P30AG101/AG/NIA NIH HHS/United States ; /CAPMC/CIHR/Canada ; P30 AG010161/AG/NIA NIH HHS/United States ; R01AG15819/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; R01 AG042210/AG/NIA NIH HHS/United States ; RF1 AG015819/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Cognitive Dysfunction/complications/*pathology ; DNA-Binding Proteins/*metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Immunoprecipitation ; Longitudinal Studies ; Male ; Memory Disorders/complications/*pathology ; Peptide Fragments/metabolism ; Statistics, Nonparametric ; Temporal Lobe/*metabolism ; Transcription Factor RelA/*metabolism ; tau Proteins/metabolism ; }, abstract = {INTRODUCTION: Transactive response DNA binding protein 43 (TDP-43) is detected in pathological inclusions in many cases of Alzheimer's disease (AD) and mild cognitive impairment (MCI), but its pathological role in AD and MCI remains unknown. Recently, TDP-43 was reported to contribute to pathogenesis in amyotrophic lateral sclerosis through its interaction with p65 nuclear factor κB (NF-κB) resulting in abnormal hyperactivation of this signaling pathway in motor neurons. Hence, we investigated the interaction of TDP-43 with p65 in the temporal cortex of subjects with a clinical diagnosis of MCI (n = 12) or AD (n = 12) as well as of age-matched controls with no cognitive impairment (NCI, n = 12).<br><br>RESULTS: Immunoprecipitation and immunofluorescence approaches revealed a robust interaction of TDP-43 with p65 in the nucleus of temporal lobe neurons in four individuals with MCI (named MCI-p). These MCI-p cases exhibited high expression levels of soluble TDP-43, p65, phosphorylated p65 and low expression levels of &#x3b2;-amyloid 40 when compared to AD or NCI cases. The analysis of cognitive performance tests showed that MCI-p individuals presented intermediate deficits of global cognition and episodic memory between those of AD cases and of NCI cases and MCI cases with no interaction of TDP-43 with p65.<br><br>CONCLUSIONS: From these results, we propose that enhanced NF-&#x3ba;B activation due to TDP-43 and p65 interaction may contribute to neuronal dysfunction in MCI individuals with episodic memory deficits. Accordingly, treatment with inhibitors of NF-&#x3ba;B activation may be considered for MCI individuals with episodic memory deficits.}, }
@article {pmid24689740, year = {2014}, author = {Cui, F and Liu, M and Chen, Y and Huang, X and Cui, L and Fan, D and Pu, C and Lu, J and Zhou, D and Zhang, C and Yan, C and Li, C and Ding, X and Liu, Y and Li, X and Jiang, Y and Zhang, J and Shang, H and Yao, X and Ding, Y and Niu, Q and Wang, L}, title = {Epidemiological characteristics of motor neuron disease in Chinese patients.}, journal = {Acta neurologica Scandinavica}, volume = {130}, number = {2}, pages = {111-117}, doi = {10.1111/ane.12240}, pmid = {24689740}, issn = {1600-0404}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/therapy ; China/epidemiology ; Female ; Humans ; Incidence ; Male ; Middle Aged ; Motor Neuron Disease/diagnosis/*epidemiology/therapy ; Sex Factors ; }, abstract = {BACKGROUND: The epidemiology, diagnosis, and treatment of motor neuron disease (MND) in Chinese patients are ill known.<br><br>METHODS: A registered study of 461 MND patients was conducted across 10 facilities in 7 Chinese cities from February 2009 to March 2010.<br><br>RESULTS: Patients were classified as amyotrophic lateral sclerosis (ALS) (84.4%), progressive bulbar palsy (PBP) (4.1%), progressive muscular atrophy (PMA) (10.4%), or primary lateral sclerosis (PLS) (0.9%). MND was predominant in men (men/women; 1.6:1.0). Mean onset age was 52.6&#xa0;years, with the highest incidence being observed between 51 and 60&#xa0;years. Notably, 26.0% of MND patients were employed in forestry, fishery, or animal husbandry industries. Ten cases (2.7%) reported family history of MND, and 54.2% exhibited cervical onset. MND was also associated with head/neck trauma. Non-invasive positive pressure ventilation was the most common supportive therapy.<br><br>CONCLUSION: As a novel comprehensive report of a Chinese population, this study reveals that epidemiological characteristics of MND patients were similar to those observed in international populations. MND is age-related, male gender predominant, and may be associated with both environmental and genetic risk factors.}, }
@article {pmid24683506, year = {2014}, author = {Bavarsad Shahripour, R and Harrigan, MR and Alexandrov, AV}, title = {N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities.}, journal = {Brain and behavior}, volume = {4}, number = {2}, pages = {108-122}, pmid = {24683506}, issn = {2162-3279}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Free Radical Scavengers/*pharmacology ; Humans ; Nervous System Diseases/*drug therapy ; }, abstract = {BACKGROUND: There is an expanding field of research investigating the benefits of medicines with multiple mechanisms of action across neurological disorders. N-acetylcysteine (NAC), widely known as an antidote to acetaminophen overdose, is now emerging as treatment of vascular and nonvascular neurological disorders. NAC as a precursor to the antioxidant glutathione modulates glutamatergic, neurotrophic, and inflammatory pathways.<br><br>AIM AND DISCUSSION: Most NAC studies up to date have been carried out in animal models of various neurological disorders with only a few studies completed in humans. In psychiatry, NAC has been tested in over 20 clinical trials as an adjunctive treatment; however, this topic is beyond the scope of this review. Herein, we discuss NAC molecular, intracellular, and systemic effects, focusing on its potential applications in neurodegenerative diseases including spinocerebellar ataxia, Parkinson's disease, tardive dyskinesia, myoclonus epilepsy of the Unverricht-Lundbor type as well as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease.<br><br>CONCLUSION: Finally, we review the potential applications of NAC to facilitate recovery after traumatic brain injury, cerebral ischemia, and in treatment of cerebrovascular vasospasm after subarachnoid hemorrhage.}, }
@article {pmid24681328, year = {2014}, author = {Nichols, NL and Johnson, RA and Satriotomo, I and Mitchell, GS}, title = {Neither serotonin nor adenosine-dependent mechanisms preserve ventilatory capacity in ALS rats.}, journal = {Respiratory physiology &amp; neurobiology}, volume = {197}, number = {}, pages = {19-28}, pmid = {24681328}, issn = {1878-1519}, support = {UL1 TR000427/TR/NCATS NIH HHS/United States ; T32 HL007654/HL/NHLBI NIH HHS/United States ; UL1TR000427/TR/NCATS NIH HHS/United States ; R01 NS057778/NS/NINDS NIH HHS/United States ; P01 NS057778/NS/NINDS NIH HHS/United States ; K99 HL119606/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetophenones/pharmacology ; Adenosine/*physiology ; Adenosine A2 Receptor Antagonists/pharmacology ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology/*physiopathology ; Animals ; Enzyme Inhibitors/pharmacology ; Humans ; Male ; Methysergide/pharmacology ; Motor Neurons/drug effects/pathology/physiology ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; Phrenic Nerve/drug effects/pathology/physiopathology ; Plethysmography ; Pulmonary Ventilation/*drug effects/*physiology ; Rats, Sprague-Dawley ; Rats, Transgenic ; *Respiration/drug effects ; Serotonin/*physiology ; Serotonin Antagonists/pharmacology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Tidal Volume/drug effects/physiology ; Xanthines/pharmacology ; }, abstract = {In rats over-expressing SOD1G93A, ventilation is preserved despite significant loss of respiratory motor neurons. Thus, unknown forms of compensatory respiratory plasticity may offset respiratory motor neuron cell death. Although mechanisms of such compensation are unknown, other models of respiratory motor plasticity may provide a conceptual guide. Multiple cellular mechanisms give rise to phrenic motor facilitation; one mechanism requires spinal serotonin receptor and NADPH oxidase activity whereas another requires spinal adenosine receptor activation. Here, we studied whether these mechanisms contribute to compensatory respiratory plasticity in SOD1G93A rats. Using plethysmography, we assessed ventilation in end-stage SOD1G93A rats after: (1) serotonin depletion with parachlorophenylalanine (PCPA), (2) serotonin (methysergide) and A2A (MSX-3) receptor inhibition, (3) NADPH oxidase inhibition (apocynin), and (4) combined treatments. The ability to increase ventilation was not decreased by individual or combined treatments; thus, these mechanisms do not maintain breathing capacity at end-stage motor neuron disease. Possible mechanisms giving rise to enhanced breathing capacity with combined treatment in end-stage SOD1G93A rats are discussed.}, }
@article {pmid24681158, year = {2014}, author = {Bourassa, MW and Ratan, RR}, title = {The interplay between microRNAs and histone deacetylases in neurological diseases.}, journal = {Neurochemistry international}, volume = {77}, number = {}, pages = {33-39}, pmid = {24681158}, issn = {1872-9754}, support = {P01 AG014930/AG/NIA NIH HHS/United States ; }, mesh = {Histone Deacetylases/*genetics/*metabolism ; Humans ; MicroRNAs/*genetics/*metabolism ; Nervous System Diseases/enzymology/*genetics/*metabolism ; }, abstract = {Neurological conditions, such as Alzheimer's disease and stroke, represent a prevalent group of devastating illnesses with few treatments. Each of these diseases or conditions is in part characterized by the dysregulation of many genes, including those that code for microRNAs (miRNAs) and histone deacetylases (HDACs). Recently, a complex relationship has been uncovered linking miRNAs and HDACs and their ability to regulate one another. This provides a new avenue for potential therapeutics as the ability to reinstate a careful balance between miRNA and HDACs has lead to improved outcomes in a number of in vitro and in vivo models of neurological conditions. In this review, we will discuss recent findings on the interplay between miRNAs and HDACs and its implications for pathogenesis and treatment of neurological conditions, including amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease and stroke.}, }
@article {pmid24680478, year = {2014}, author = {Grassinger, J and Khomenko, A and Hart, C and Baldaranov, D and Johannesen, SW and Mueller, G and Schelker, R and Schulte-Mattler, W and Andreesen, R and Bogdahn, U}, title = {Safety and feasibility of long term administration of recombinant human granulocyte-colony stimulating factor in patients with amyotrophic lateral sclerosis.}, journal = {Cytokine}, volume = {67}, number = {1}, pages = {21-28}, doi = {10.1016/j.cyto.2014.02.003}, pmid = {24680478}, issn = {1096-0023}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy ; Disease Progression ; Erythrocytes/drug effects ; Female ; Granulocyte Colony-Stimulating Factor/*adverse effects/*therapeutic use ; Granulocytes/drug effects ; Humans ; Leukocyte Count ; Macrophages/drug effects ; Male ; Middle Aged ; Neuroprotective Agents/adverse effects/therapeutic use ; Platelet Count ; Recombinant Proteins/adverse effects/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neuronal disease resulting in a loss of the upper and lower motor neurons and subsequent death within three to four years after diagnosis. Mouse models and preliminary human exposure data suggest that the treatment with granulocyte-colony stimulating factor (G-CSF) has neuro-protective effects and may delay ALS progression. As data on long-term administration of G-CSF in patients with normal bone marrow (BM) function are scarce, we initiated a compassionate use program including 6 ALS patients with monthly G-CSF treatment cycles. Here we demonstrate that G-CSF injection was safe and feasible throughout our observation period up to three years. Significant decrease of mobilization efficiency occurred in one patient and a loss of immature erythroid progenitors was observed in all six patients. These data imply that follow-up studies analyzing BM function during long-term G-CSF stimulation are required.}, }
@article {pmid24667415, year = {2014}, author = {Bros-Facer, V and Krull, D and Taylor, A and Dick, JR and Bates, SA and Cleveland, MS and Prinjha, RK and Greensmith, L}, title = {Treatment with an antibody directed against Nogo-A delays disease progression in the SOD1G93A mouse model of Amyotrophic lateral sclerosis.}, journal = {Human molecular genetics}, volume = {23}, number = {16}, pages = {4187-4200}, doi = {10.1093/hmg/ddu136}, pmid = {24667415}, issn = {1460-2083}, support = {MR/K000608/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Antibodies/immunology/*therapeutic use ; Disease Models, Animal ; Disease Progression ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/pathology ; Muscle Fibers, Slow-Twitch/metabolism ; Myelin Proteins/*immunology/metabolism ; Nogo Proteins ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disorder in which motor neurons in the spinal cord and motor cortex degenerate. Although the majority of ALS cases are sporadic, mutations in Cu-Zn superoxide dismutase-1 (SOD1) are causative for 10-20% of familial ALS (fALS), and recent findings show that a hexanucleotide repeat expansion in the C9ORF72 gene may account for >30% of fALS cases in Europe. SOD1(G93A) transgenic mice have a phenotype and pathology similar to human ALS. In both ALS patients and SOD1(G93A) mice, the first pathological features of disease manifest at the neuromuscular junction, where significant denervation occurs prior to motor neuron degeneration. Strategies aimed at preventing or delaying denervation may therefore be of benefit in ALS. In this study, we show that Nogo-A levels increase in muscle fibres of SOD1(G93A) mice along with the elevation of markers of neuromuscular dysfunction (CHRNA1/MUSK). Symptomatic treatment of SOD1(G93A) mice from 70 days of age with an anti-Nogo-A antibody (GSK577548) significantly improves hindlimb muscle innervation at 90 days, a late symptomatic stage of disease, resulting in increased muscle force and motor unit survival and a significant increase in motor neuron survival. However, not all aspects of this improvement in anti-Nogo-A antibody-treated SOD1(G93A) mice were maintained at end-stage disease. These results show that treatment with anti-Nogo-A antibody significantly improves neuromuscular function in the SOD1(G93A) mouse model of ALS, at least during the earlier stages of disease and suggest that pharmacological inhibition of Nogo-A may be a disease-modifying approach in ALS.}, }
@article {pmid24667005, year = {2014}, author = {Boll, MC and Bayliss, L and Vargas-Cañas, S and Burgos, J and Montes, S and Peñaloza-Solano, G and Rios, C and Alcaraz-Zubeldia, M}, title = {Clinical and biological changes under treatment with lithium carbonate and valproic acid in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {340}, number = {1-2}, pages = {103-108}, doi = {10.1016/j.jns.2014.03.005}, pmid = {24667005}, issn = {1878-5883}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism/mortality ; Cadmium/blood/urine ; Cause of Death ; Disability Evaluation ; Enzyme Inhibitors/*therapeutic use ; Female ; Follow-Up Studies ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Humans ; Kaplan-Meier Estimate ; Lithium Carbonate/*therapeutic use ; Male ; Middle Aged ; Statistics, Nonparametric ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; Valproic Acid/*therapeutic use ; }, abstract = {The aim of this study was to evaluate the ability of lithium carbonate and valproate cotreatment to modify the survival rate and functional score of patients with definite sporadic amyotrophic lateral sclerosis (ALS). The clinical response of 18 enrolled patients was compared to the evolution of 31 ALS out-patients, carefully paired by age, gender, evolution rate and time of the disease, who never received treatment with lithium and/or valproate. The ALS functional rating scale, revised version (ALSFRS-R), was applied at baseline, 1 month, and every 4 months until the outcome (death or an adverse event). Biochemical markers, such as Cu/Zn superoxide dismutase and glutathione peroxidase activity, and reduced glutathione were assayed in plasma samples obtained at the baseline visit and after 5 and 9 months of treatment. Our results showed that lithium and valproate cotreatment significantly increased survival (p=0.016), and this treatment also exerted neuroprotection in our patients because all three markers reached levels that were not significantly different from the matched samples of healthy donors. The trial stopped after 21 months, when the sample was reduced to under two-thirds, due to the late adverse events of the treatment. The results call for large randomized clinical trials with the dual association, but at low doses to avoid adverse events.}, }
@article {pmid24655385, year = {2014}, author = {Bhoomika, K and Pyngrope, S and Dubey, RS}, title = {Effect of aluminum on protein oxidation, non-protein thiols and protease activity in seedlings of rice cultivars differing in aluminum tolerance.}, journal = {Journal of plant physiology}, volume = {171}, number = {7}, pages = {497-508}, doi = {10.1016/j.jplph.2013.12.009}, pmid = {24655385}, issn = {1618-1328}, mesh = {Aluminum/*toxicity ; Environmental Pollutants/toxicity ; Oryza/*drug effects/*enzymology/genetics/metabolism ; Plant Proteins/genetics/*metabolism ; Plant Roots/drug effects/metabolism ; Protein Carbonylation/drug effects ; Proteolysis/drug effects ; Seedlings/*drug effects/*enzymology ; Sulfhydryl Compounds/metabolism ; }, abstract = {The effect of toxic concentrations of aluminum (Al) was investigated on contents of protein-thiols, non-protein and total thiols, protein carbonylation and protease activity in the seedlings of Al-sensitive (Al-S) Indica rice cv. HUR-105 and Al-tolerant (Al-T) cv. Vandana grown in sand cultures. Al treatment of 178 μM and 421 μM for 3-12 days caused a significant decline in the level of protein thiols, rise in non-protein thiols (NPTs) as well as protein carbonyl content and an insignificant alteration in the level of total thiols in cv. HUR-105 seedlings. However, in the seedlings of Al-T cv. Vandana, no significant alteration could be observed on any of these parameters with Al treatment. Al treatment inhibited protease activity in roots, whereas the opposite trend was seen in shoots. New isozymes of protease appeared in shoots of cv. Vandana with increased level of Al treatment. Our results show a link between protein thiols and NPTs and suggest the role of NPTs in the repair and protection of protein thiols. Inhibitory effect of Al on protease activity in roots could be a major reason for Al rhizotoxic effects. Al tolerance in rice appears to be associated with lesser content of protein thiols in roots, smaller amount of carbonylated proteins in roots as well as shoots and higher protease activity in shoots.}, }
@article {pmid24641613, year = {2014}, author = {Jones, AR and Jivraj, N and Balendra, R and Murphy, C and Kelly, J and Thornhill, M and Young, C and Shaw, PJ and Leigh, PN and Turner, MR and Steen, IN and McCrone, P and Al-Chalabi, A}, title = {Health utility decreases with increasing clinical stage in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {15}, number = {3-4}, pages = {285-291}, doi = {10.3109/21678421.2013.872149}, pmid = {24641613}, issn = {2167-9223}, support = {G0600974/MRC_/Medical Research Council/United Kingdom ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/economics/*psychology/*therapy ; Anxiety/diagnosis/etiology ; Cost-Benefit Analysis ; Depression/diagnosis/etiology ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Predictive Value of Tests ; Quality of Life/*psychology ; Randomized Controlled Trials as Topic ; Severity of Illness Index ; Surveys and Questionnaires ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease typically causing death within three years. Understanding the impact of disease on patients using health utility at different stages of ALS would allow meaningful cost-benefit analysis of new potential therapies. A common health-related quality of life measurement, developed and validated for the UK, is the EQ-5D. Using clinical trial data from the LiCALS study, we calculated health utility using the EQ-5D for each King's ALS clinical stage from 214 patients. We analysed whether health utility, and other health-related measures, significantly changed between each of the clinical stages. Results showed that mean health utility decreased by 0.487 (the scale runs from 1 to - 0.594) between clinical stages 2A and 4. Emotional states, measured using the Hospital Anxiety and Depression Scale (HADS), showed worsening depression and anxiety scores as ALS progressed. Age of onset, disease onset, gender and treatment group were not predictors of EQ-5D, depression or anxiety. In conclusion, increasing severity of King's ALS Clinical Stage is associated with a progressive decrease in EQ-5D health utility. This is useful for cost-benefit analysis of new therapies and validates this ALS clinical staging system.}, }
@article {pmid24640982, year = {2014}, author = {Pinto, S and Carvalho, Md}, title = {Breathing new life into treatment advances for respiratory failure in amyotrophic lateral sclerosis patients.}, journal = {Neurodegenerative disease management}, volume = {4}, number = {1}, pages = {83-102}, doi = {10.2217/nmt.13.74}, pmid = {24640982}, issn = {1758-2032}, mesh = {Amyotrophic Lateral Sclerosis/*complications/epidemiology/physiopathology ; Animals ; Humans ; Respiratory Insufficiency/epidemiology/*etiology/physiopathology/*therapy ; Respiratory Therapy/economics/*methods ; }, abstract = {In the last three decades, improvements in respiratory management are responsible for increasing survival and improving quality of life for amyotrophic lateral sclerosis (ALS) patients. Nowadays, ALS patients with respiratory involvement are offered a support treatment other than the traditional respiratory palliative care. Knowledge about available respiratory support potentialities is essential for appropriate, customized and effective treatment of ALS, which should probably be started sooner than the conventional approach. There is evidence supporting that respiratory support has a larger impact than riluzole on survival. Noninvasive ventilation is essential in the treatment of ALS patients with respiratory involvement. In this article methods to determine respiratory failure in ALS, mechanical invasive and noninvasive ventilation, telemetry, diaphragm pacing, cough aids and respiratory exercise are reviewed, after a brief overlook of respiratory insufficiency in ALS.}, }
@article {pmid24637017, year = {2014}, author = {Korkmaz, OT and Aytan, N and Carreras, I and Choi, JK and Kowall, NW and Jenkins, BG and Dedeoglu, A}, title = {7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis.}, journal = {Neuroscience letters}, volume = {566}, number = {}, pages = {286-291}, pmid = {24637017}, issn = {1872-7972}, support = {R01AG031896/AG/NIA NIH HHS/United States ; I21 BX001624/BX/BLRD VA/United States ; P30AG013846/AG/NIA NIH HHS/United States ; P30 AG013846/AG/NIA NIH HHS/United States ; R01 AG031896/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology/physiopathology ; Animals ; Cell Count ; Cell Survival/drug effects ; Dendritic Cells/drug effects/pathology ; Flavanones/*pharmacology/therapeutic use ; Humans ; Mice, Transgenic ; Motor Neurons/*drug effects/pathology ; Motor Skills/drug effects ; Neuroprotective Agents/*pharmacology/therapeutic use ; Receptor, trkB/*agonists ; Spinal Cord/drug effects/pathology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an enigmatic neurodegenerative disorder without any effective treatment characterized by loss of motor neurons (MNs) that results in rapidly progressive motor weakness and early death due to respiratory failure. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family known to play a prominent role in the differentiation and survival of MNs. The flavonoid 7,8-dihydroxyflavone (7,8-DHF) is a potent and selective small molecule tyrosine kinase receptor B (TrkB) agonist that mimics the effects of BDNF. In the present study, we evaluated the neuroprotective effects of 7,8-DHF in a transgenic ALS mouse model (SOD1(G93A)). We found that chronic administration of 7,8-DHF significantly improved motor deficits, and preserved spinal MNs count and dendritic spines in SOD1(G93A) mice. These data suggest that 7,8-DHF should be considered as a potential therapy for ALS and the other motor neuron diseases.}, }
@article {pmid24630363, year = {2014}, author = {Aggarwal, T and Polanco, MJ and Scaramuzzino, C and Rocchi, A and Milioto, C and Emionite, L and Ognio, E and Sambataro, F and Galbiati, M and Poletti, A and Pennuto, M}, title = {Androgens affect muscle, motor neuron, and survival in a mouse model of SOD1-related amyotrophic lateral sclerosis.}, journal = {Neurobiology of aging}, volume = {35}, number = {8}, pages = {1929-1938}, doi = {10.1016/j.neurobiolaging.2014.02.004}, pmid = {24630363}, issn = {1558-1497}, support = {TCP12013/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*genetics/metabolism/pathology ; Anabolic Agents/adverse effects ; Androgens/*physiology ; Animals ; Cell Death/drug effects ; Disease Models, Animal ; Humans ; Hypertrophy ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects/*pathology ; Muscle, Skeletal/drug effects/*metabolism/pathology ; Nandrolone/adverse effects/analogs &amp; derivatives ; Nandrolone Decanoate ; Orchiectomy ; Receptors, Androgen/*metabolism ; Spinal Cord/metabolism ; *Superoxide Dismutase ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of upper and lower motor neurons and skeletal muscle atrophy. Epidemiologic and experimental evidence suggest the involvement of androgens in ALS pathogenesis, but the mechanism through which androgens modify the ALS phenotype is unknown. Here, we show that androgen ablation by surgical castration extends survival and disease duration of a transgenic mouse model of ALS expressing mutant human SOD1 (hSOD1-G93A). Furthermore, long-term treatment of orchiectomized hSOD1-G93A mice with nandrolone decanoate (ND), an anabolic androgenic steroid, worsened disease manifestations. ND treatment induced muscle fiber hypertrophy but caused motor neuron death. ND negatively affected survival, thereby dissociating skeletal muscle pathology from life span in this ALS mouse model. Interestingly, orchiectomy decreased androgen receptor levels in the spinal cord and muscle, whereas ND treatment had the opposite effect. Notably, stimulation with ND promoted the recruitment of endogenous androgen receptor into biochemical complexes that were insoluble in sodium dodecyl sulfate, a finding consistent with protein aggregation. Overall, our results shed light on the role of androgens as modifiers of ALS pathogenesis via dysregulation of androgen receptor homeostasis.}, }
@article {pmid24613827, year = {2014}, author = {Thomsen, GM and Gowing, G and Svendsen, S and Svendsen, CN}, title = {The past, present and future of stem cell clinical trials for ALS.}, journal = {Experimental neurology}, volume = {262 Pt B}, number = {}, pages = {127-137}, doi = {10.1016/j.expneurol.2014.02.021}, pmid = {24613827}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; *Clinical Trials as Topic/history/methods/trends ; History, 20th Century ; History, 21st Century ; Humans ; Stem Cell Transplantation/*methods/*trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that is characterized by progressive degeneration of motor neurons in the cortex, brainstem and spinal cord. This leads to paralysis, respiratory insufficiency and death within an average of 3 to 5 years from disease onset. While the genetics of ALS are becoming more understood in familial cases, the mechanisms underlying disease pathology remain unclear and there are no effective treatment options. Without understanding what causes ALS it is difficult to design treatments. However, in recent years stem cell transplantation has emerged as a potential new therapy for ALS patients. While motor neuron replacement remains a focus of some studies trying to treat ALS with stem cells, there is more rationale for using stem cells as support cells for dying motor neurons as they are already connected to the muscle. This could be through reducing inflammation, releasing growth factors, and other potential less understood mechanisms. Prior to moving into patients, stringent pre-clinical studies are required that have at least some rationale and efficacy in animal models and good safety profiles. However, given our poor understanding of what causes ALS and whether stem cells may ameliorate symptoms, there should be a push to determine cell safety in pre-clinical models and then a quick translation to the clinic where patient trials will show if there is any efficacy. Here, we provide a critical review of current clinical trials using either mesenchymal or neural stem cells to treat ALS patients. Pre-clinical data leading to these trials, as well as those in development are also evaluated in terms of mechanisms of action, validity of conclusions and rationale for advancing stem cell treatment strategies for this devastating disorder.}, }
@article {pmid24613662, year = {2014}, author = {Diskin, FJ and Camp-Rogers, T and Peberdy, MA and Ornato, JP and Kurz, MC}, title = {External validation of termination of resuscitation guidelines in the setting of intra-arrest cold saline, mechanical CPR, and comprehensive post resuscitation care.}, journal = {Resuscitation}, volume = {85}, number = {7}, pages = {910-914}, doi = {10.1016/j.resuscitation.2014.02.028}, pmid = {24613662}, issn = {1873-1570}, mesh = {Adult ; Aged ; Cardiopulmonary Resuscitation/*standards ; Emergency Medical Services ; Female ; Humans ; Male ; Middle Aged ; Out-of-Hospital Cardiac Arrest/mortality/*therapy ; Practice Guidelines as Topic ; Retrospective Studies ; Sensitivity and Specificity ; Sodium Chloride/*therapeutic use ; Survival Rate ; Virginia ; }, abstract = {BACKGROUND: The development of advanced life support (ALS) termination of resuscitation (TOR) guidelines for out-of-hospital cardiac arrest (OHCA) seeks to improve the efficiency of scarce pre-hospital resources. However, as pre-hospital treatment for OHCA evolves and survival improves, these TOR guidelines must be reevaluated in the contemporary context of emergency medical services (EMS) providing access to advanced resuscitation care.<br><br>METHODS: Retrospective review of all adult (>18 years old), non-traumatic, OHCA patients (defined as patients with absence of pulse who received either CPR and/or defibrillation) treated by EMS in Richmond, VA, from January 1, 2009 to December 31, 2010. In addition to standard ALS, intra-arrest cold saline, mechanical CPR, and transportation to a comprehensive post-resuscitation center (CPRC) was provided. Patient treatment and outcomes were recorded via prehospital patient care reports and data were evaluated against previously established criteria for termination of resuscitation in an ALS EMS system. According to the aforementioned previously described criteria for TOR, patients meeting a single criterion for transport are recommended to be transported emergently to a comprehensive post-resuscitation care facility. Conversely, patients failing to meet any of the TOR criteria can be presumed to be expired without exception. Survival at 180 days was presumed when death could not be verified from publically reportable sources.<br><br>RESULTS: Of the 322 OHCA patients enrolled, the majority were male (59%), unwitnessed (52%), received no bystander CPR (67%), and presented in a non-shockable initial rhythm (79%), with an average age of 62.5 years. Overall survival was 17%, 14%, 12%, and 11% at 7, 14, 30, and 180 days, respectively. Of the 75 patients for which TOR guidelines recommended termination, none survived yielding both 100% specificity (95% CI 100-92.8%) and positive predictive value (95% CI 100-94.1%). However, TOR guidelines recommended transport of 208 of the 283 patients who died within 30 days, resulting in a sensitivity of 26.5% (95% CI 34.5-23.4%).<br><br>CONCLUSION: The TOR guidelines continue to have a reliable positive predictive value for death even in the setting of advanced EMS resuscitation methods and access to a CPRC. However, as the potential for survival from OHCA improves, the efficiency gained from their use is impacted greatly.}, }
@article {pmid24604371, year = {2014}, author = {Salvioni, CC and Stanich, P and Almeida, CS and Oliveira, AS}, title = {Nutritional care in motor neurone disease/ amyotrophic lateral sclerosis.}, journal = {Arquivos de neuro-psiquiatria}, volume = {72}, number = {2}, pages = {157-163}, doi = {10.1590/0004-282X20130185}, pmid = {24604371}, issn = {1678-4227}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications/*diet therapy ; Female ; Humans ; Nutrition Assessment ; Nutrition Disorders/etiology/*prevention &amp; control ; Nutrition Therapy/*methods ; Nutritional Requirements ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) often present changes in nutritional status. Based on weight loss and on difficulty in nutritional management, this study aims to review the different possibilities and to present guidelines concerning nutritional treatment to such patients. Diet characteristics, types of treatment and nutritional therapy indicating administration routes and discussing the details of the disease are described herein. Nutritional therapy has been a substantial therapeutic resource for ALS development.}, }
@article {pmid24598527, year = {2014}, author = {Koschnitzky, JE and Quinlan, KA and Lukas, TJ and Kajtaz, E and Kocevar, EJ and Mayers, WF and Siddique, T and Heckman, CJ}, title = {Effect of fluoxetine on disease progression in a mouse model of ALS.}, journal = {Journal of neurophysiology}, volume = {111}, number = {11}, pages = {2164-2176}, pmid = {24598527}, issn = {1522-1598}, support = {NS-077863/NS/NINDS NIH HHS/United States ; F31 NS-060532/NS/NINDS NIH HHS/United States ; NS-046535/NS/NINDS NIH HHS/United States ; NS-050162/NS/NINDS NIH HHS/United States ; R01 NS077863/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/*physiopathology ; Animals ; Antidepressive Agents, Second-Generation/administration &amp; dosage ; Behavior, Animal/*drug effects ; *Disease Models, Animal ; Disease Progression ; Dose-Response Relationship, Drug ; Fluoxetine/*administration &amp; dosage ; Longitudinal Studies ; Mice ; Mice, Transgenic ; Rotarod Performance Test ; Selective Serotonin Reuptake Inhibitors/administration &amp; dosage ; Treatment Outcome ; Tremor/diagnosis/*physiopathology/*prevention &amp; control ; }, abstract = {Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5-11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1(G93A) and control: nontransgenic and SOD1(WT)) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1(G93A) mice reached end stage ∼8 days (∼6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models.}, }
@article {pmid24597488, year = {2014}, author = {Martin, NH and Landau, S and Janssen, A and Lyall, R and Higginson, I and Burman, R and McCrone, P and Sakel, M and Ellis, CM and Shaw, CE and Al-Chalabi, A and Leigh, PN and Goldstein, LH}, title = {Psychological as well as illness factors influence acceptance of non-invasive ventilation (NIV) and gastrostomy in amyotrophic lateral sclerosis (ALS): a prospective population study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {15}, number = {5-6}, pages = {376-387}, doi = {10.3109/21678421.2014.886700}, pmid = {24597488}, issn = {2167-9223}, support = {089701/WT_/Wellcome Trust/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*psychology/*therapy ; Caregivers/psychology ; Community Health Planning ; Decision Making ; Female ; Follow-Up Studies ; Gastrostomy/*methods ; Humans ; Male ; Middle Aged ; Noninvasive Ventilation/*methods ; Odds Ratio ; Patient Acceptance of Health Care/*psychology ; Quality of Life ; Retrospective Studies ; Surveys and Questionnaires ; }, abstract = {Our objective was to identify factors associated with acceptance of non-invasive ventilation (NIV) and gastrostomy in an exploratory population-based study. Seventy-eight people with ALS at least six months post-diagnosis, and 50 caregivers, were recruited from the South-East ALS Register. Baseline physical, cognitive and psychological measures were obtained. Three-monthly follow-ups monitored whether patients had accepted or refused NIV or gastrostomy. Following an intervention decision, post-decision interviews repeated baseline measures and included further intervention-specific questionnaires. Results showed that 32 people with ALS made at least one intervention decision and of these 10 decided about both NIV and gastrostomy. While illness factors predicted those needing to make an intervention decision, cognitive and education status, and level of executive dysfunction were associated with decision-making and acceptance or refusal of interventions. Patients' understanding of their illness, their early approach to considering interventions and carer-related factors were also associated with treatment decisions. In conclusion, our findings highlight the complexity of decision-making and provide a platform for designing further studies. Cognitive and psychosocial factors may assume a greater role in palliative care decisions for people with ALS than has been explicitly recognized. Future work must clarify how to ensure patients are not inadvertently being denied suitable interventions.}, }
@article {pmid24591593, year = {2014}, author = {Winkler, EA and Sengillo, JD and Sagare, AP and Zhao, Z and Ma, Q and Zuniga, E and Wang, Y and Zhong, Z and Sullivan, JS and Griffin, JH and Cleveland, DW and Zlokovic, BV}, title = {Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {111}, number = {11}, pages = {E1035-42}, pmid = {24591593}, issn = {1091-6490}, support = {R37 NS034467/NS/NINDS NIH HHS/United States ; R37 HL052246/HL/NHLBI NIH HHS/United States ; NS27036/NS/NINDS NIH HHS/United States ; NS34467/NS/NINDS NIH HHS/United States ; AG039452/AG/NIA NIH HHS/United States ; R01 HL052246/HL/NHLBI NIH HHS/United States ; AG23084/AG/NIA NIH HHS/United States ; R01 HL021544/HL/NHLBI NIH HHS/United States ; P01 HL031950/HL/NHLBI NIH HHS/United States ; HL052246/HL/NHLBI NIH HHS/United States ; 089701//Wellcome Trust/United Kingdom ; R01 AG023084/AG/NIA NIH HHS/United States ; R37 NS027036/NS/NINDS NIH HHS/United States ; P50 AG005142/AG/NIA NIH HHS/United States ; R01 AG039452/AG/NIA NIH HHS/United States ; R37 AG023084/AG/NIA NIH HHS/United States ; HL031950/HL/NHLBI NIH HHS/United States ; R01 NS027036/NS/NINDS NIH HHS/United States ; R01 NS034467/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Blood-Nerve Barrier/*pathology/physiology ; Ferrocyanides ; Humans ; Immunoblotting ; In Situ Nick-End Labeling ; Male ; Mice ; Mice, Transgenic ; Microscopy, Confocal ; Motor Neurons/*pathology/physiology ; Nerve Degeneration/*physiopathology ; Point Mutation/genetics ; Protein C/metabolism ; Real-Time Polymerase Chain Reaction ; Rotarod Performance Test ; Spinal Cord/*pathology/physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Tight Junction Proteins/genetics/metabolism ; Warfarin ; }, abstract = {Humans with ALS and transgenic rodents expressing ALS-associated superoxide dismutase (SOD1) mutations develop spontaneous blood-spinal cord barrier (BSCB) breakdown, causing microvascular spinal-cord lesions. The role of BSCB breakdown in ALS disease pathogenesis in humans and mice remains, however, unclear, although chronic blood-brain barrier opening has been shown to facilitate accumulation of toxic blood-derived products in the central nervous system, resulting in secondary neurodegenerative changes. By repairing the BSCB and/or removing the BSCB-derived injurious stimuli, we now identify that accumulation of blood-derived neurotoxic hemoglobin and iron in the spinal cord leads to early motor-neuron degeneration in SOD1(G93A) mice at least in part through iron-dependent oxidant stress. Using spontaneous or warfarin-accelerated microvascular lesions, motor-neuron dysfunction and injury were found to be proportional to the degree of BSCB disruption at early disease stages in SOD1(G93A) mice. Early treatment with an activated protein C analog restored BSCB integrity that developed from spontaneous or warfarin-accelerated microvascular lesions in SOD1(G93A) mice and eliminated neurotoxic hemoglobin and iron deposits. Restoration of BSCB integrity delayed onset of motor-neuron impairment and degeneration. Early chelation of blood-derived iron and antioxidant treatment mitigated early motor-neuronal injury. Our data suggest that BSCB breakdown contributes to early motor-neuron degeneration in ALS mice and that restoring BSCB integrity during an early disease phase retards the disease process.}, }
@article {pmid24588281, year = {2014}, author = {Umebayashi, D and Natsume, A and Takeuchi, H and Hara, M and Nishimura, Y and Fukuyama, R and Sumiyoshi, N and Wakabayashi, T}, title = {Blockade of gap junction hemichannel protects secondary spinal cord injury from activated microglia-mediated glutamate exitoneurotoxicity.}, journal = {Journal of neurotrauma}, volume = {31}, number = {24}, pages = {1967-1974}, pmid = {24588281}, issn = {1557-9042}, mesh = {Animals ; Excitatory Amino Acid Antagonists/pharmacology ; Excitatory Amino Acids/*toxicity ; Female ; Gap Junctions/*drug effects/metabolism ; Glutamic Acid/*toxicity ; Heterocyclic Compounds, 4 or More Rings/*pharmacology ; Immunohistochemistry ; Mice ; Mice, Inbred C57BL ; Microglia/*metabolism ; Neuroprotective Agents/*pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Spinal Cord Injuries/*metabolism ; }, abstract = {We previously demonstrated that activated microglia release excessive glutamate through gap junction hemichannels and identified a novel gap junction hemichannel blocker, INI-0602, that was proven to penetrate the blood-brain barrier and be an effective treatment in mouse models of amyotrophic lateral sclerosis and Alzheimer disease. Spinal cord injury causes tissue damage in two successive waves. The initial injury is mechanical and directly causes primary tissue damage, which induces subsequent ischemia, inflammation, and neurotoxic factor release resulting in the secondary tissue damage. These lead to activation of glial cells. Activated glial cells such as microglia and astrocytes are common pathological observations in the damaged lesion. Activated microglia release glutamate, the major neurotoxic factor released into the extracellular space after neural injury, which causes neuronal death at high concentration. In the present study, we demonstrate that reduction of glutamate-mediated exitotoxicity via intraperitoneal administration of INI-0602 in the microenvironment of the injured spinal cord elicited neurobehavioral recovery and extensive suppression of glial scar formation by reducing secondary tissue damage. Further, this intervention stimulated anti-inflammatory cytokines, and subsequently elevated brain-derived neurotrophic factor. Thus, preventing microglial activation by a gap junction hemichannel blocker, INI-0602, may be a promising therapeutic strategy in spinal cord injury.}, }
@article {pmid24582549, year = {2014}, author = {Miquel, E and Cassina, A and Martínez-Palma, L and Souza, JM and Bolatto, C and Rodríguez-Bottero, S and Logan, A and Smith, RA and Murphy, MP and Barbeito, L and Radi, R and Cassina, P}, title = {Neuroprotective effects of the mitochondria-targeted antioxidant MitoQ in a model of inherited amyotrophic lateral sclerosis.}, journal = {Free radical biology &amp; medicine}, volume = {70}, number = {}, pages = {204-213}, doi = {10.1016/j.freeradbiomed.2014.02.019}, pmid = {24582549}, issn = {1873-4596}, support = {MC_U105663142/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Antioxidants/*administration &amp; dosage ; Disease Models, Animal ; Humans ; Mice ; Mitochondria/drug effects ; Neuroprotective Agents/*administration &amp; dosage ; Organophosphorus Compounds/*administration &amp; dosage ; Oxidative Stress/drug effects ; Ubiquinone/administration &amp; dosage/*analogs &amp; derivatives ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron degeneration that ultimately results in progressive paralysis and death. Growing evidence indicates that mitochondrial dysfunction and oxidative stress contribute to motor neuron degeneration in ALS. To further explore the hypothesis that mitochondrial dysfunction and nitroxidative stress contribute to disease pathogenesis at the in vivo level, we assessed whether the mitochondria-targeted antioxidant [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl]triphenylphosphonium methane sulfonate (MitoQ) can modify disease progression in the SOD1(G93A) mouse model of ALS. To do this, we administered MitoQ (500 µM) in the drinking water of SOD1(G93A) mice from a time when early symptoms of neurodegeneration become evident at 90 days of age until death. This regime is a clinically plausible scenario and could be more easily translated to patients as this corresponds to initiating treatment of patients after they are first diagnosed with ALS. MitoQ was detected in all tested tissues by liquid chromatography/mass spectrometry after 20 days of administration. MitoQ treatment slowed the decline of mitochondrial function, in both the spinal cord and the quadriceps muscle, as measured by high-resolution respirometry. Importantly, nitroxidative markers and pathological signs in the spinal cord of MitoQ-treated animals were markedly reduced and neuromuscular junctions were recovered associated with a significant increase in hindlimb strength. Finally, MitoQ treatment significantly prolonged the life span of SOD1(G93A) mice. Our results support a role for mitochondrial nitroxidative damage and dysfunction in the pathogenesis of ALS and suggest that mitochondria-targeted antioxidants may be of pharmacological use for ALS treatment.}, }
@article {pmid24576285, year = {2015}, author = {Cortés-Gutiérrez, EI and Dávila-Rodríguez, MI and Cerda-Flores, RM and Fernández, JL and López-Fernández, C and Aragón Tovar, AR and Gosálvez, J}, title = {Localisation and quantification of alkali-labile sites in human spermatozoa by DNA breakage detection-fluorescence in situ hybridisation.}, journal = {Andrologia}, volume = {47}, number = {2}, pages = {221-227}, doi = {10.1111/and.12250}, pmid = {24576285}, issn = {1439-0272}, mesh = {Adolescent ; Adult ; Alkalies/*analysis ; Chromatin/chemistry/genetics ; Comet Assay/methods ; DNA/*chemistry/genetics ; *DNA Breaks ; Fertility/genetics ; Fluorescence ; Humans ; In Situ Hybridization, Fluorescence/*methods ; Infertility, Male/genetics ; Male ; Sperm Head/*chemistry ; Spermatozoa/*chemistry ; Young Adult ; }, abstract = {The localisation and quantification of constitutive alkali-labile sites (ALSs) were investigated using a protocol of DNA breakage detection plus fluorescence in situ hybridisation (DBD-FISH) and alkaline single-cell gel electrophoresis (SCGE or comet assay), in spermatozoa of infertile and fertile men. Semen samples from 10 normozoospermic patients undergoing infertility treatment and 10 fertile men were included in this study. ALSs were localised and quantified by DBD-FISH. The region most sensitive to alkali treatment in human spermatozoa was located in the basal region of the head. ALSs were more frequent in spermatozoa of infertile men than in those of fertile men. These results were confirmed by SCGE comet assays. In conclusion, the most intense localisation of hybridisation signals in human spermatozoa, representing the highest density of constitutive ALSs, was not randomly distributed and was predominantly located in the base of the head. Moreover, infertile men presented with an increase in ALS frequency. Further studies are necessary to determine the association between ALS, sperm chromatin organisation and infertility.}, }
@article {pmid24575322, year = {2014}, author = {Gokhale, S and Khan, SA and McDonagh, DL and Britz, G}, title = {Comparison of surgical and endovascular approach in management of spinal dural arteriovenous fistulas: A single center experience of 27 patients.}, journal = {Surgical neurology international}, volume = {5}, number = {}, pages = {7}, pmid = {24575322}, issn = {2229-5097}, abstract = {BACKGROUND: Spinal dural arteriovenous fistula (SDAVF) is a rare spinal vascular malformation with an annual incidence of 5-10 cases per million. The data on efficacy, recurrence rates and complications of endovascular versus surgical treatment of SDAVF is limited.<br><br>METHODS: We conducted a retrospective chart review of 27 adult patients with a diagnosis of SDAVF and who underwent treatment at Duke University Hospital between January 1, 1993 and December 31, 2012. We compared the outcome measures by Aminoff-Logue score (ALS) in patients who underwent treatment with endovascular embolization versus surgical ligation of fistula. We compared complication rates, recurrence rates as well as data on long-term follow up in these patients.<br><br>RESULTS: Out of 27 patients in the study, 10 patients underwent endovascular embolization (Onyx was used in 5 patients and NBCA in 5 patients) as the first line therapy. Seventeen patients underwent surgical ligation as initial therapeutic modality. Patients in both groups showed significant improvement in clinical status (ALS) after treatment. One patient in endovascular group developed spinal infarction due to accidental embolization of medullary artery. Three patients in embolization group had recurrence of fistula during the course of follow up requiring surgical ligation. Two patients in surgical group developed local wound infection. None of the patients in surgical group had recurrence of fistula during the course of follow up.<br><br>CONCLUSIONS: Endovascular embolization and surgical ligation are effective treatment strategies for SDAVF. Our observations show that surgical ligation may offer permanent cure without any recurrence. Endovascular approach is associated with higher incidence of recurrence, especially with use of onyx.}, }
@article {pmid24574452, year = {2014}, author = {Flécher, E and Anselmi, A and Corbineau, H and Langanay, T and Verhoye, JP and Félix, C and Leurent, G and Le Tulzo, Y and Malledant, Y and Leguerrier, A}, title = {Current aspects of extracorporeal membrane oxygenation in a tertiary referral centre: determinants of survival at follow-up.}, journal = {European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery}, volume = {46}, number = {4}, pages = {665-71; discussion 671}, doi = {10.1093/ejcts/ezu029}, pmid = {24574452}, issn = {1873-734X}, mesh = {Adult ; Aged ; Extracorporeal Membrane Oxygenation/*methods ; Female ; Follow-Up Studies ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Tertiary Care Centers/statistics &amp; numerical data ; }, abstract = {OBJECTIVES: To describe the clinical results (both early and at follow-up) of patients currently receiving extracorporeal membrane oxygenation (ECMO) therapy for cardiac and/or pulmonary failure. To assess the effect of indications, clinical presentations and ECMO modalities on early/late clinical outcomes. To identify baseline factors associated with worse survival at follow-up.<br><br>METHODS: We reviewed the prospectively collected data of 325 patients receiving ECMO therapy at a tertiary referral centre during the 2005-2013 period. Follow-up was prospectively conducted by dedicated personnel (average: 84 &#xb1; 86 days, 100% complete). Survival was analysed by stratified Kaplan-Meier curves.<br><br>RESULTS: Veno-arterial (VA) ECMO was employed in 80% of cases (due to early graft failure (EGF) in 13% of cases, post-cardiotomy in 29%, primary cardiogenic shock in 42% for miscellaneous aetiologies, other indications in 15.4%) and veno-venous (VV) ECMO in the remainders (adult respiratory distress syndrome). In the VA and VV groups, weaning rates were 59 and 53%, survival at 30th postimplantation day was 44 and 45% and survival at the end of the follow-up was 41 and 45%, respectively. Implantation under advanced life support (ALS) occurred in 15% of cases (26% survival at 30 days). VA patients had a higher rate of thrombotic/haemorrhagic complications and of transfusion of blood products and shorter ventilation time. Worse early and follow-up survival were observed among patients aged &#x2265;65 years, having pH &#x2264; 7, lactates >12 mmol/l, creatinine >200 &#x3bc;mol/l at implantation or receiving ECMO under ALS. No difference in survival was noted among VA vs VV patients. Patients receiving ECMO for EGF displayed better early and late survival (64% at 30 days and 53% at 6 months) than post-cardiotomy (36 and 34%, respectively), post-acute myocardial infarction (48 and 40%) and the remaining patients (46 and 45%).<br><br>CONCLUSIONS: Despite most critical baseline conditions, ECMO therapy is confirmed useful for the treatment of patients with acute cardiopulmonary failure refractory to conventional treatments. The ECMO modality (VA vs VV), as well as indications to support, identifies different patient profiles and dissimilar outcomes. Preimplantation markers of gravity and end-organ damage are useful in the stratification of expected survival. These may facilitate clinical decision-making and appropriate allocation of hospital resources.}, }
@article {pmid24569372, year = {2014}, author = {Kong, Q and Chang, LC and Takahashi, K and Liu, Q and Schulte, DA and Lai, L and Ibabao, B and Lin, Y and Stouffer, N and Das Mukhopadhyay, C and Xing, X and Seyb, KI and Cuny, GD and Glicksman, MA and Lin, CL}, title = {Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection.}, journal = {The Journal of clinical investigation}, volume = {124}, number = {3}, pages = {1255-1267}, pmid = {24569372}, issn = {1558-8238}, support = {R01 NS064275/NS/NINDS NIH HHS/United States ; U01 NS074601/NS/NINDS NIH HHS/United States ; R01NS064275/NS/NINDS NIH HHS/United States ; U01NS074601/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/enzymology/pathology ; Animals ; Anterior Horn Cells/drug effects ; Astrocytes/drug effects/metabolism ; Cell Line ; Coculture Techniques ; Enzyme Activation/drug effects ; Excitatory Amino Acid Transporter 2/*genetics/metabolism ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Activity/drug effects ; Mutation, Missense ; Neuroprotective Agents/pharmacokinetics/*pharmacology ; Pilocarpine ; Protein Biosynthesis/*drug effects ; Protein Kinase C/metabolism ; Pyridazines/pharmacokinetics/*pharmacology ; Pyridines/pharmacokinetics/*pharmacology ; Rats ; Status Epilepticus/chemically induced/drug therapy/pathology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Tissue Distribution ; Transcription Factors/metabolism ; }, abstract = {Glial glutamate transporter EAAT2 plays a major role in glutamate clearance in synaptic clefts. Several lines of evidence indicate that strategies designed to increase EAAT2 expression have potential for preventing excitotoxicity, which contributes to neuronal injury and death in neurodegenerative diseases. We previously discovered several classes of compounds that can increase EAAT2 expression through translational activation. Here, we present efficacy studies of the compound LDN/OSU-0212320, which is a pyridazine derivative from one of our lead series. In a murine model, LDN/OSU-0212320 had good potency, adequate pharmacokinetic properties, no observed toxicity at the doses examined, and low side effect/toxicity potential. Additionally, LDN/OSU-0212320 protected cultured neurons from glutamate-mediated excitotoxic injury and death via EAAT2 activation. Importantly, LDN/OSU-0212320 markedly delayed motor function decline and extended lifespan in an animal model of amyotrophic lateral sclerosis (ALS). We also found that LDN/OSU-0212320 substantially reduced mortality, neuronal death, and spontaneous recurrent seizures in a pilocarpine-induced temporal lobe epilepsy model. Moreover, our study demonstrated that LDN/OSU-0212320 treatment results in activation of PKC and subsequent Y-box-binding protein 1 (YB-1) activation, which regulates activation of EAAT2 translation. Our data indicate that the use of small molecules to enhance EAAT2 translation may be a therapeutic strategy for the treatment of neurodegenerative diseases.}, }
@article {pmid24566026, year = {2014}, author = {Le Pimpec-Barthes, F and Pricopi, C and Mordant, P and Arame, A and Badia, A and Grand, B and Bagan, P and Hernigou, A and Riquet, M}, title = {[Diaphragmatic palsy and dysfunction: from physiology to surgery].}, journal = {Revue de pneumologie clinique}, volume = {70}, number = {1-2}, pages = {95-107}, doi = {10.1016/j.pneumo.2013.11.002}, pmid = {24566026}, issn = {1776-2561}, mesh = {Diaphragm/anatomy &amp; histology/physiology ; Diaphragmatic Eventration/*physiopathology/*surgery ; Humans ; Respiratory Paralysis/*physiopathology/*surgery ; }, abstract = {The clinical presentations of diaphragm dysfunctions vary according to etiologies and unilateral or bilateral diseases. Elevation of the hemidiaphragm from peripheral origins, the most frequent situation, requires a surgical treatment only in case of major functional impact. Complete morphological and functional analyses of the neuromuscular chain and respiratory tests allow the best selection of patients to be operated. The surgical procedure may be proposed only when the diaphragm dysfunction is permanent and irreversible. Diaphragm plication for eventration through a short lateral thoracotomy, or sometimes by videothoracoscopy, is the only procedure for retensioning the hemidiaphragm. This leads to a decompression of intrathoracic organs and a repositioning of abdominal organs without effect on the hemidiaphragm active contraction. Morbidity and mortality rates after diaphragm plication are very low, more due to the patient's general condition than to surgery itself. Functional improvements after retensioning for most patients with excellent long-term results validate this procedure for symptomatic patients. In case of bilateral diseases, very few bilateral diaphragm plications have been reported. Some patients with diaphragm paralyses from central origins become permanently dependent on mechanical ventilation whereas their lungs, muscles and nerves are intact. In patients selected by rigorous neuromuscular tests, a phrenic pacing may be proposed to wean them from respirator. Two main indications have been validated: high-level tetraplegia above C3 and congenital alveolar hypoventilation from central origin. After progressive reconditioning of the diaphragm muscles following phrenic pacing at thoracic level, more than 90% of patients can be weaned from respirator within a few weeks. This weaning improves the quality of life with more physiological breathing, restored olfaction, better sleep and better speech. The positive impact of diaphragm stimulation has also been evaluated in other degenerative neurological diseases, particularly the amyotrophic lateral sclerosis. For either central or peripheral diaphragm dysfunctions, a successful surgical treatment lies on a strict preoperative selection of patients.}, }
@article {pmid24565565, year = {2014}, author = {Meyer, M and Gonzalez Deniselle, MC and Hunt, H and de Kloet, ER and De Nicola, AF}, title = {The selective glucocorticoid receptor modulator CORT108297 restores faulty hippocampal parameters in Wobbler and corticosterone-treated mice.}, journal = {The Journal of steroid biochemistry and molecular biology}, volume = {143}, number = {}, pages = {40-48}, doi = {10.1016/j.jsbmb.2014.02.007}, pmid = {24565565}, issn = {1879-1220}, mesh = {Animals ; Anti-Inflammatory Agents/*pharmacology ; Astrocytes/cytology/drug effects/metabolism ; Aza Compounds/*pharmacology ; Blotting, Western ; Cells, Cultured ; Corticosterone/*pharmacology ; DNA-Binding Proteins ; Disease Models, Animal ; Doublecortin Domain Proteins ; Doublecortin Protein ; Female ; Fluorescent Antibody Technique ; Glial Fibrillary Acidic Protein/metabolism ; Heterocyclic Compounds, 4 or More Rings/*pharmacology ; Hippocampus/abnormalities/*drug effects/metabolism ; Humans ; Immunoenzyme Techniques ; Mice ; Mice, Neurologic Mutants ; Microglia/cytology/drug effects/metabolism ; Microtubule-Associated Proteins/*physiology ; Nerve Tissue Proteins/metabolism ; Neurons/cytology/drug effects/metabolism ; Neuropeptides/*physiology ; Nuclear Proteins/metabolism ; Receptors, Glucocorticoid/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Mutant Wobbler mice are models for human amyotrophic lateral sclerosis (ALS). In addition to spinal cord degeneration, Wobbler mice show high levels of blood corticosterone, hyperactivity of the hypothalamic-pituitary-adrenal axis and abnormalities of the hippocampus. Hypersecretion of glucocorticoids increase hippocampus vulnerability, a process linked to an enriched content of glucocorticoid receptors (GR). Hence, we studied if a selective GR antagonist (CORT108297) with null affinity for other steroid receptors restored faulty hippocampus parameters of Wobbler mice. Three months old genotyped Wobbler mice received s.c. vehicle or CORT108297 during 4 days. We compared the response of doublecortin (DCX)+ neuroblasts in the subgranular layer of the dentate gyrus (DG), NeuN+ cells in the hilus of the DG, glial fibrillary acidic protein (GFAP)+ astrocytes and the phenotype of Iba1+ microglia in CORT108297-treated and vehicle-treated Wobblers. The number of DCX+ cells in Wobblers was lower than in control mice, whereas CORT108297 restored this parameter. After CORT108297 treatment, Wobblers showed diminished astrogliosis, and changed the phenotype of Iba1+ microglia from an activated to a quiescent form. These changes occurred without alterations in the hypercorticosteronemia or the number of NeuN+ cells of the Wobblers. In a separate experiment employing control NFR/NFR mice, treatment with corticosterone for 5 days reduced DCX+ neuroblasts and induced astrocyte hypertrophy, whereas treatment with CORT108297 antagonized these effects. Normalization of neuronal progenitors, astrogliosis and microglial phenotype by CORT108297 indicates the usefulness of this antagonist to normalize hippocampus parameters of Wobbler mice. Thus, CORT108297 opens new therapeutic options for the brain abnormalities of ALS patients and hyperadrenocorticisms.}, }
@article {pmid24560539, year = {2014}, author = {Lukas, TJ and Schiltz, GE and Arrat, H and Scheidt, K and Siddique, T}, title = {Discovery of 1,3,4-oxidiazole scaffold compounds as inhibitors of superoxide dismutase expression.}, journal = {Bioorganic &amp; medicinal chemistry letters}, volume = {24}, number = {6}, pages = {1532-1537}, doi = {10.1016/j.bmcl.2014.01.078}, pmid = {24560539}, issn = {1464-3405}, mesh = {Animals ; Cell Line ; Drug Evaluation, Preclinical ; Gene Expression Regulation/*drug effects ; Mice ; Oxadiazoles/chemical synthesis/*chemistry/*pharmacology ; Small Molecule Libraries/chemical synthesis/chemistry/*pharmacology ; Structure-Activity Relationship ; Superoxide Dismutase/antagonists &amp; inhibitors/*metabolism ; }, abstract = {The treatment of neurodegenerative diseases is difficult because of multiple etiologies and the interplay of genetics and environment as precipitating factors. In the case of amyotrophic lateral sclerosis (ALS), we have knowledge of a handful of genes that cause disease when mutated. However, drugs to counteract the effect of genetic mutations have not yet been found. One of the causative genes, Cu, Zn-superoxide dismutase (SOD1) is responsible for about 10-15% of the genetically linked autosomal dominant disease. Our rationale was that compounds that reduce expression of the mutant protein would be beneficial to slow onset and/or disease progression. We screened candidate compounds using a cell-based in vitro assay for those that reduce mutant SOD1 (G93A) protein expression. This led to the discovery of 2-[3-iodophenyl)methylsulfanyl]-5pyridin-4-yl-1,3,4-oxadiazole, a known protein kinase inhibitor that decreases G93A-SOD1 expression in vitro and in the brain and spinal cord in vivo. However, this compound has a biphasic dose response curve and a likely toxophore which limit its therapeutic window for chronic disease such as ALS. Therefore, we designed and tested a focused library of analogs for their ability to decrease SOD1 expression in vitro. This exercise resulted in the identification of a lead compound with improved drug-like characteristics and activity. Development of small molecules that reduce the expression of etiologically relevant toxic proteins is a strategy that may also be extended to familial ALS linked to gain of function mutations in other genes.}, }
@article {pmid24550511, year = {2014}, author = {Grad, LI and Yerbury, JJ and Turner, BJ and Guest, WC and Pokrishevsky, E and O'Neill, MA and Yanai, A and Silverman, JM and Zeineddine, R and Corcoran, L and Kumita, JR and Luheshi, LM and Yousefi, M and Coleman, BM and Hill, AF and Plotkin, SS and Mackenzie, IR and Cashman, NR}, title = {Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {111}, number = {9}, pages = {3620-3625}, pmid = {24550511}, issn = {1091-6490}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*physiopathology ; Animals ; Cell Line ; Electrophoresis, Polyacrylamide Gel ; Exosomes/*metabolism ; Humans ; Mice ; Microscopy, Electron ; Pinocytosis/physiology ; *Protein Folding ; RNA Interference ; RNA, Small Interfering/genetics ; Superoxide Dismutase/*chemistry/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is predominantly sporadic, but associated with heritable genetic mutations in 5-10% of cases, including those in Cu/Zn superoxide dismutase (SOD1). We previously showed that misfolding of SOD1 can be transmitted to endogenous human wild-type SOD1 (HuWtSOD1) in an intracellular compartment. Using NSC-34 motor neuron-like cells, we now demonstrate that misfolded mutant and HuWtSOD1 can traverse between cells via two nonexclusive mechanisms: protein aggregates released from dying cells and taken up by macropinocytosis, and exosomes secreted from living cells. Furthermore, once HuWtSOD1 propagation has been established, misfolding of HuWtSOD1 can be efficiently and repeatedly propagated between HEK293 cell cultures via conditioned media over multiple passages, and to cultured mouse primary spinal cord cells transgenically expressing HuWtSOD1, but not to cells derived from nontransgenic littermates. Conditioned media transmission of HuWtSOD1 misfolding in HEK293 cells is blocked by HuWtSOD1 siRNA knockdown, consistent with human SOD1 being a substrate for conversion, and attenuated by ultracentrifugation or incubation with SOD1 misfolding-specific antibodies, indicating a relatively massive transmission particle which possesses antibody-accessible SOD1. Finally, misfolded and protease-sensitive HuWtSOD1 comprises up to 4% of total SOD1 in spinal cords of patients with sporadic ALS (SALS). Propagation of HuWtSOD1 misfolding, and its subsequent cell-to-cell transmission, is thus a candidate process for the molecular pathogenesis of SALS, which may provide novel treatment and biomarker targets for this devastating disease.}, }
@article {pmid24549040, year = {2014}, author = {Farg, MA and Sundaramoorthy, V and Sultana, JM and Yang, S and Atkinson, RA and Levina, V and Halloran, MA and Gleeson, PA and Blair, IP and Soo, KY and King, AE and Atkin, JD}, title = {C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking.}, journal = {Human molecular genetics}, volume = {23}, number = {13}, pages = {3579-3595}, pmid = {24549040}, issn = {1460-2083}, mesh = {Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Vesicular Transport/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Autophagy-Related Proteins ; Biological Transport ; C9orf72 Protein ; Endosomes/*metabolism ; Frontotemporal Dementia/genetics/*metabolism ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/metabolism ; Humans ; Mass Spectrometry ; Mice ; Proteins/genetics/metabolism ; rab GTP-Binding Proteins/genetics/metabolism ; rab7 GTP-Binding Proteins ; }, abstract = {Intronic expansion of a hexanucleotide GGGGCC repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene is the major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. However, the cellular function of the C9ORF72 protein remains unknown. Here, we demonstrate that C9ORF72 regulates endosomal trafficking. C9ORF72 colocalized with Rab proteins implicated in autophagy and endocytic transport: Rab1, Rab5, Rab7 and Rab11 in neuronal cell lines, primary cortical neurons and human spinal cord motor neurons, consistent with previous predictions that C9ORF72 bears Rab guanine exchange factor activity. Consistent with this notion, C9ORF72 was present in the extracellular space and as cytoplasmic vesicles. Depletion of C9ORF72 using siRNA inhibited transport of Shiga toxin from the plasma membrane to Golgi apparatus, internalization of TrkB receptor and altered the ratio of autophagosome marker light chain 3 (LC3) II:LC3I, indicating that C9ORF72 regulates endocytosis and autophagy. C9ORF72 also colocalized with ubiquilin-2 and LC3-positive vesicles, and co-migrated with lysosome-stained vesicles in neuronal cell lines, providing further evidence that C9ORF72 regulates autophagy. Investigation of proteins interacting with C9ORF72 using mass spectrometry identified other proteins implicated in ALS; ubiquilin-2 and heterogeneous nuclear ribonucleoproteins, hnRNPA2/B1 and hnRNPA1, and actin. Treatment of cells overexpressing C9ORF72 with proteasome inhibitors induced the formation of stress granules positive for hnRNPA1 and hnRNPA2/B1. Immunohistochemistry of C9ORF72 ALS patient motor neurons revealed increased colocalization between C9ORF72 and Rab7 and Rab11 compared with controls, suggesting possible dysregulation of trafficking in patients bearing the C9ORF72 repeat expansion. Hence, this study identifies a role for C9ORF72 in Rab-mediated cellular trafficking.}, }
@article {pmid24534024, year = {2014}, author = {Turnbull, J}, title = {Why is ALS so Difficult to Treat?.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {41}, number = {2}, pages = {144-155}, doi = {10.1017/s0317167100016516}, pmid = {24534024}, issn = {0317-1671}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*therapy ; Genotype ; Homeostasis ; Humans ; Phenotype ; Proteins/*metabolism ; Proteostasis Deficiencies/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is proving intractable. Difficulties in pre-clinical studies contribute in small measure to this futility, but the chief reason for failure is an inadequate understanding of disease pathogenesis. Many acquired and inherited processes have been advanced as potential causes of ALS but, while they may predispose to disease, it seems increasingly likely that none leads directly to ALS. Rather, two recent overlapping considerations, both involving aberrant protein homeostasis, may provide a better explanation for a common disease phenotype and a common terminal pathogenesis. If so, therapeutic approaches will need to be altered and carefully nuanced, since protein homeostasis is essential and highly conserved. Nonetheless, these considerations provide new optimism in a difficult disease which has hitherto defied treatment.}, }
@article {pmid24532698, year = {2014}, author = {Gadd, RJ and Barwick, TW and Paling, E and Davies, MB and Blundell, CM}, title = {Assessment of a three-grade classification of complications in total ankle replacement.}, journal = {Foot &amp; ankle international}, volume = {35}, number = {5}, pages = {434-437}, doi = {10.1177/1071100714524549}, pmid = {24532698}, issn = {1944-7876}, mesh = {Ankle Joint/*surgery ; Arthroplasty, Replacement, Ankle/*adverse effects ; Female ; Follow-Up Studies ; Humans ; Male ; Postoperative Complications/*classification ; Prosthesis Failure ; Retrospective Studies ; United Kingdom ; }, abstract = {BACKGROUND: Prompted by the success of hip and knee arthroplasty, total ankle replacement (TAR) has become increasingly popular as a treatment for end stage arthritis of the ankle. A 3-grade classification of complications to assist in prediction of early implant failure has been proposed. We have compared the experience of a tertiary referral center in the United Kingdom to the proposed system.<br><br>METHODS: A retrospective review of the Sheffield Foot and Ankle Unit TAR database was performed from 1995 to 2010. All complications were recorded and categorized using Glazebrook et al's proposed system of increasing severity. Low-grade complications including postoperative bone fracture, intraoperative bone fracture, and wound healing problems rarely lead to revision. Medium-grade complications, technical error and subsidence, lead to failure <50% of the time. High-grade complications--deep infection, aseptic loosening, and implant failure--lead to revision >50% of the time. In our center, 217 TAR were implanted in 198 patients with a minimum follow-up of 30 months.<br><br>RESULTS: The complication rate was 23%, with a revision rate of 17%. All complications recorded in our study except intraoperative bone fracture and wound healing had a failure rate of at least 50%.<br><br>CONCLUSION: Unfortunately most complications associated with TAR have a significant impact on the life span of a TAR. Glazebrook et al's proposed 3-tier system did not reliably reflect our experience. Hence, we would categorize complications as either high or low risk for early failure of TAR.<br><br>LEVEL OF EVIDENCE: Level IV, case series.}, }
@article {pmid24526455, year = {2014}, author = {Lisak, RP and Nedelkoska, L and Benjamins, JA}, title = {Effects of dextromethorphan on glial cell function: proliferation, maturation, and protection from cytotoxic molecules.}, journal = {Glia}, volume = {62}, number = {5}, pages = {751-762}, doi = {10.1002/glia.22639}, pmid = {24526455}, issn = {1098-1136}, mesh = {Animals ; Cell Differentiation/drug effects/physiology ; Cell Enlargement/*drug effects ; Cell Proliferation/*drug effects ; Cells, Cultured ; Cytotoxins/*pharmacology/toxicity ; Dextromethorphan/*pharmacology/toxicity ; Dose-Response Relationship, Drug ; Neuroglia/*drug effects/physiology ; Rats ; }, abstract = {Dextromethorphan (DM), a sigma receptor agonist and NMDA receptor antagonist, protects neurons from glutamate excitotoxicity, hypoxia and ischemia, and inhibits microglial activation, but its effects on differentiation and protection of cells in the oligodendroglial lineage are unknown. It is important to protect oligodendroglia (OL) to prevent demyelination and preserve axons, and to protect oligodendroglial progenitors (OPC) to optimize myelination during development and remyelination following damage. Enriched glial cultures from newborn rat brain were used 1-2 days or 6-8 days after shakeoff for OPC or mature OL. DM had large effects on glial proliferation in less mature cultures in contrast to small variable effects in mature cultures; 1 μM DM stimulated proliferation of OPC by 4-fold, microglia (MG) by 2.5-fold and astroglia (AS) by 2-fold. In agreement with increased OPC proliferation, treatment of OPC with DM for 3 days increased the % of OPC relative to OL, with a smaller difference by 5 days, suggesting that maturation of OPC to OL was "catching up" by 5 days. DM at 2 and 20 μM protected both OL and OPC from killing by glutamate as well as NMDA, AMPA, quinolinic acid, staurosporine, and reactive oxygen species (ROS). DM did not protect against kynurenic acid, and only modestly against NO. These agents and DM were not toxic to AS or MG at the concentrations used. Thus, DM stimulates proliferation of OPC, and protects both OL and OPC against excitotoxic and inflammatory insults.}, }
@article {pmid24510776, year = {2014}, author = {Feldman, EL and Boulis, NM and Hur, J and Johe, K and Rutkove, SB and Federici, T and Polak, M and Bordeau, J and Sakowski, SA and Glass, JD}, title = {Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: phase 1 trial outcomes.}, journal = {Annals of neurology}, volume = {75}, number = {3}, pages = {363-373}, pmid = {24510776}, issn = {1531-8249}, support = {P50 AG025688/AG/NIA NIH HHS/United States ; R01 NS077982/NS/NINDS NIH HHS/United States ; 5P50AG025688/AG/NIA NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*therapy ; Cervical Vertebrae/surgery ; Female ; Humans ; Lumbar Vertebrae/surgery ; Male ; Middle Aged ; Neural Stem Cells/*transplantation ; Recovery of Function ; Spinal Cord/*surgery ; Stem Cell Transplantation/adverse effects/methods ; Treatment Outcome ; }, abstract = {OBJECTIVE: The US Food and Drug Administration-approved trial, "A Phase 1, Open-Label, First-in-Human, Feasibility and Safety Study of Human Spinal Cord-Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis, Protocol Number: NS2008-1," is complete. Our overall objective was to assess the safety and feasibility of stem cell transplantation into lumbar and/or cervical spinal cord regions in amyotrophic lateral sclerosis (ALS) subjects.<br><br>METHODS: Preliminary results have been reported on the initial trial cohort of 12 ALS subjects. Here, we describe the safety and functional outcome monitoring results for the final trial cohort, consisting of 6 ALS subjects receiving 5 unilateral cervical intraspinal neural stem cell injections. Three of these subjects previously received 10 total bilateral lumbar injections as part of the earlier trial cohort. All injections utilized a novel spinal-mounted stabilization and injection device to deliver 100,000 neural stem cells per injection, for a dosing range up to 1.5 million cells. Subject assessments included detailed pre- and postsurgical neurological outcome measures.<br><br>RESULTS: The cervical injection procedure was well tolerated and disease progression did not accelerate in any subject, verifying the safety and feasibility of cervical and dual-targeting approaches. Analyses on outcome data revealed preliminary insight into potential windows of stem cell biological activity and identified clinical assessment measures that closely correlate with ALS Functional Rating Scale-Revised scores, a standard assessment for ALS clinical trials.<br><br>INTERPRETATION: This is the first report of cervical and dual-targeted intraspinal transplantation of neural stem cells in ALS subjects. This approach is feasible and well-tolerated, supporting future trial phases examining therapeutic dosing and efficacy.}, }
@article {pmid24504619, year = {2014}, author = {Zheng, Z and Guo, X and Huang, R and Chen, X and Shang, H}, title = {An exploratory study of the association between thyroid hormone and survival of amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {35}, number = {7}, pages = {1103-1108}, pmid = {24504619}, issn = {1590-3478}, mesh = {Adult ; Age of Onset ; Aged ; Amyotrophic Lateral Sclerosis/*blood/*mortality/physiopathology ; China ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Severity of Illness Index ; Statistics, Nonparametric ; Survival Analysis ; Thyroid Hormones/*blood ; Thyrotropin/blood ; Thyroxine/blood ; Triiodothyronine/blood ; Vital Capacity/physiology ; Young Adult ; }, abstract = {The objective of the study was to determine the correlation of thyroid hormones (THs) and survival in patients with amyotrophic lateral sclerosis (ALS). A total of 278 patients with ALS were enrolled and followed up prospectively every 3 months by face-to-face interviews or phone calls. Level of fasting serum TH was determined at the time of enrollment. Clinical data including age, onset age, onset body region, ALS Functional Rating Scale- Revised (ALS-FRS-R), and survival were collected. Patients were separated into four subgroups according to the quartile distribution of TH, and survival was compared among them. There was no significant difference in baseline characteristics, including onset age, gender, onset form as well as treatment with riluzole among different levels of TH subgroups. Chi-square test indicated that the lowest quartile of FT3 (<4.26 mg/L) might correlate with higher incidences of death (OR 0.374, 95 % CI 0.173-0.813), while second and third quartiles of FT4 (range 14.25-18.0 mg/L) with lower incidences of death in ALS. However, after correction for onset age and onset form using logistic regression analysis, no statistical difference was revealed in survival among patients with different TH levels. TH does not correlate with survival and is not a prognostic factor for ALS.}, }
@article {pmid24497973, year = {2014}, author = {Capitini, C and Conti, S and Perni, M and Guidi, F and Cascella, R and De Poli, A and Penco, A and Relini, A and Cecchi, C and Chiti, F}, title = {TDP-43 inclusion bodies formed in bacteria are structurally amorphous, non-amyloid and inherently toxic to neuroblastoma cells.}, journal = {PloS one}, volume = {9}, number = {1}, pages = {e86720}, pmid = {24497973}, issn = {1932-6203}, mesh = {Amyloid/chemistry ; Cell Line, Tumor ; Cell Survival ; DNA-Binding Proteins/*chemistry/physiology/ultrastructure ; Endopeptidase K/chemistry ; Escherichia coli ; Humans ; Inclusion Bodies/ultrastructure ; Microscopy, Atomic Force ; Neuroblastoma ; Phosphorylation ; Protein Binding ; Protein Structure, Secondary ; Proteolysis ; Transfection ; Ubiquitination ; }, abstract = {Accumulation of ubiquitin-positive, tau- and α-synuclein-negative intracellular inclusions of TDP-43 in the central nervous system represents the major hallmark correlated to amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions. Such inclusions have variably been described as amorphous aggregates or more structured deposits having an amyloid structure. Following the observations that bacterial inclusion bodies generally consist of amyloid aggregates, we have overexpressed full-length TDP-43 and C-terminal TDP-43 in E. coli, purified the resulting full-length and C-terminal TDP-43 containing inclusion bodies (FL and Ct TDP-43 IBs) and subjected them to biophysical analyses to assess their structure/morphology. We show that both FL and Ct TDP-43 aggregates contained in the bacterial IBs do not bind amyloid dyes such as thioflavin T and Congo red, possess a disordered secondary structure, as inferred using circular dichroism and infrared spectroscopies, and are susceptible to proteinase K digestion, thus possessing none of the hallmarks for amyloid. Moreover, atomic force microscopy revealed an irregular structure for both types of TDP-43 IBs and confirmed the absence of amyloid-like species after proteinase K treatment. Cell biology experiments showed that FL TDP-43 IBs were able to impair the viability of cultured neuroblastoma cells when added to their extracellular medium and, more markedly, when transfected into their cytosol, where they are at least in part ubiquitinated and phosphorylated. These data reveal an inherently high propensity of TDP-43 to form amorphous aggregates, which possess, however, an inherently high ability to cause cell dysfunction. This indicates that a gain of toxic function caused by TDP-43 deposits is effective in TDP-43 pathologies, in addition to possible loss of function mechanisms originating from the cellular mistrafficking of the protein.}, }
@article {pmid24496499, year = {2014}, author = {Pliner, HA and Mann, DM and Traynor, BJ}, title = {Searching for Grendel: origin and global spread of the C9ORF72 repeat expansion.}, journal = {Acta neuropathologica}, volume = {127}, number = {3}, pages = {391-396}, pmid = {24496499}, issn = {1432-0533}, support = {089701//Wellcome Trust/United Kingdom ; Z01 AG000949//Intramural NIH HHS/United States ; ZIA AG000933-02//Intramural NIH HHS/United States ; Z01-AG000949-02/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein ; *DNA Repeat Expansion ; *Evolution, Molecular ; Human Migration ; Humans ; Internationality ; Proteins/*genetics ; Time Factors ; White People/genetics ; }, abstract = {Recent advances are uncovering more and more of the genetic architecture underlying amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative condition that affects ~6,000 Americans annually. Chief among these was the discovery that a large repeat expansion in the C9ORF72 gene is responsible for an unprecedented portion of familial and sporadic ALS cases. Much has been published on how this expansion disrupts neuronal homeostasis and how gene-based therapy might be an effective treatment in the future. Nevertheless, it is instructive to look back at the origins of this important mutation. In this opinion piece, we attempt to answer three key questions concerning C9ORF72. First, how many times did the expansion occur throughout human history? Second, how old is the expansion? And finally and perhaps most importantly, how did the expansion spread throughout Europe? We speculate that the expansion occurred only once in the past, that this event took place in the Finnish population and that the Vikings and their descendants were responsible for disseminating this mutation throughout the rest of the continent.}, }
@article {pmid24488689, year = {2014}, author = {Su, XW and Broach, JR and Connor, JR and Gerhard, GS and Simmons, Z}, title = {Genetic heterogeneity of amyotrophic lateral sclerosis: implications for clinical practice and research.}, journal = {Muscle &amp; nerve}, volume = {49}, number = {6}, pages = {786-803}, doi = {10.1002/mus.24198}, pmid = {24488689}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/physiopathology ; Biomedical Research/*trends ; Drug Therapy ; Epigenomics ; *Genetic Heterogeneity ; Humans ; Mutation/genetics ; Practice Patterns, Physicians'/*trends ; Prognosis ; }, abstract = {Genetic insights into the pathophysiology of amyotrophic lateral sclerosis (ALS) are untangling the clinical heterogeneity that may contribute to poor clinical trial outcomes and thus to a lack of effective treatments. Mutations in a large number of genes, including SOD1, C9ORF72, TARDBP, FUS, VAPB, VCP, UBQLN2, ALS2, SETX, OPTN, ANG, and SPG11, are thought to cause ALS, whereas others, including ATAXN2, GRN, HFE, NEFH, UNC13A, and VEGF, appear to be disease-modifying genes. Epigenetic influences may also play important roles. An improved understanding of ALS genetics should lead to better trial designs, insights into common molecular pathways, and better characterization of preclinical models. New genetic sequencing techniques, which use high-throughput methods to assess variants across the genome or exome, may facilitate rational patient stratification for clinical trials and permit more individualized prognostic information and treatment decisions in clinical care. Muscle Nerve 49: 786-803, 2014.}, }
@article {pmid24481285, year = {2014}, author = {Renes, JS and van Doorn, J and Breukhoven, PE and Lem, AJ and de Ridder, MA and Hokken-Koelega, AC}, title = {Acid-labile subunit levels and the association with response to growth hormone treatment in short children born small for gestational age.}, journal = {Hormone research in paediatrics}, volume = {81}, number = {2}, pages = {126-132}, doi = {10.1159/000356926}, pmid = {24481285}, issn = {1663-2826}, mesh = {Adolescent ; Blood Glucose/metabolism ; Body Height/drug effects ; Carrier Proteins/*blood ; Case-Control Studies ; Child ; Child, Preschool ; Cohort Studies ; Female ; Glycoproteins/*blood ; Growth Disorders/*blood/*drug therapy ; Growth Hormone/pharmacology/*therapeutic use ; Homeostasis/physiology ; Humans ; Infant ; *Infant, Small for Gestational Age ; Insulin-Like Growth Factor Binding Protein 3/blood ; Male ; Models, Biological ; Predictive Value of Tests ; }, abstract = {AIMS: To determine acid-labile subunit (ALS) levels in short small for gestational age (SGA) children and to assess the relationship between ALS levels and several clinical and laboratory characteristics. Also, to assess whether adding ALS levels to a growth prediction model might improve the long-term growth prediction.<br><br>DESIGN/METHODS: ALS levels were measured in 312 short SGA children at the start of growth hormone (GH) treatment.<br><br>RESULTS: Median (interquartile range) ALS of all subjects was -0.5 SDS, significantly below the 0 SDS (p < 0.001). In 34 children (11%), ALS levels were &#x2264;-2 SDS. ALS SDS correlated significantly with height SDS (r = 0.24, p < 0.001), weight SDS (r = 0.30, p < 0.001), BMI SDS (r = 0.20, p = 0.001), IGF-I SDS (r = 0.56, p < 0.001) and IGFBP-3 SDS (r = 0.67, p < 0.001). ALS SDS was also positively correlated with fasting insulin (r = 0.41, p < 0.001) and glucose levels (r = 0.33, p < 0.001), and HOMA-IR (r = 0.35, p < 0.001). Baseline ALS levels contributed to the long-term growth prediction of GH treatment (5%, p < 0.001).<br><br>CONCLUSION: Short SGA children tend to have lower ALS levels compared to controls, albeit less reduced than IGF-I and IGFBP-3 levels. Our data suggest that ALS may be involved in glucose homeostasis. Determination of ALS levels before the start of GH treatment in short SGA children contributes moderately to a more accurate prediction of the growth response to GH treatment.}, }
@article {pmid24477737, year = {2014}, author = {Araki, W and Minegishi, S and Motoki, K and Kume, H and Hohjoh, H and Araki, YM and Tamaoka, A}, title = {Disease-associated mutations of TDP-43 promote turnover of the protein through the proteasomal pathway.}, journal = {Molecular neurobiology}, volume = {50}, number = {3}, pages = {1049-1058}, pmid = {24477737}, issn = {1559-1182}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Brain/metabolism/pathology ; Cell Line, Tumor ; DNA-Binding Proteins/genetics/*metabolism ; Frontotemporal Lobar Degeneration/genetics/*metabolism/pathology ; Humans ; Inclusion Bodies/metabolism ; *Mutation ; Phosphorylation ; Proteasome Endopeptidase Complex/*metabolism ; }, abstract = {TAR DNA-binding protein (TDP-43) is a major component of most ubiquitin-positive neuronal and glial inclusions of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A number of missense mutations in the TARDBP gene have been identified in patients with familial and sporadic ALS, as well as familial FTLD with ALS. In the diseased states, TDP-43 proteins exhibit characteristic alterations, including truncation, abnormal phosphorylation, and altered subcellular distribution. However, the mechanisms by which TDP-43 mutations induce neurodegeneration remain unclear at present. In the current study, we analyzed protein turnover and subcellular distribution of wild-type TDP-43 and two disease-associated mutants (G298S and A382T) in human neuroblastoma SH-SY5Y cells stably expressing TDP-43 with a C-terminal tag. Cycloheximide chase experiments revealed more rapid turnover of TDP-43 mutant proteins than their wild-type counterpart. The decrease in the TDP-43 level after cycloheximide treatment was partially recovered upon co-treatment with the proteasome inhibitor, epoxomicin, but not the lysosomotropic agent, chloroquine, suggesting involvement of the proteasomal pathway in TDP-43 degradation. Analysis of the subcellular distribution of TDP-43 revealed predominant localization in the nuclear fraction, whereas the relative level in the cytoplasm remained unaltered in cells expressing either mutant protein, compared with wild-type protein. Our results suggest that higher turnover of disease-associated mutant TDP-43 proteins through the ubiquitin proteasome system is pathogenetically relevant and highlight the significance of proteolysis in the pathogenetic mechanism of TDP-43 proteinopathy.}, }
@article {pmid24472060, year = {2014}, author = {Bruijn, L and Cudkowicz, M and , }, title = {Opportunities for improving therapy development in ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {15}, number = {3-4}, pages = {169-173}, doi = {10.3109/21678421.2013.872662}, pmid = {24472060}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/classification/*therapy ; Clinical Trials, Phase II as Topic/*methods ; Humans ; Research Design ; }, abstract = {In May 2013, The ALS Association and The Northeast ALS Consortium (NEALS) convened a meeting of stakeholders for a round-table discussion of ways to improve therapy development in ALS. The following overview summarizes issues raised and potential new directions discussed at the meeting. We recommend that future phase II clinical trials in ALS proceed when the proposed treatment is directed at targets that are likely to be involved in ALS pathogenesis in a defined subgroup of patients, and be accompanied by one or more biomarkers to track both clinical progression and pharmacodynamic engagement of the target. Innovations in trial structure and design, and greater involvement of patient advocates, may also improve trials.}, }
@article {pmid24462361, year = {2014}, author = {Jiang, WC and Cheng, YH and Yen, MH and Chang, Y and Yang, VW and Lee, OK}, title = {Cryo-chemical decellularization of the whole liver for mesenchymal stem cells-based functional hepatic tissue engineering.}, journal = {Biomaterials}, volume = {35}, number = {11}, pages = {3607-3617}, pmid = {24462361}, issn = {1878-5905}, support = {R01 CA084197/CA/NCI NIH HHS/United States ; R01 DK052230/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Biomarkers/metabolism ; Cell Differentiation/genetics ; *Cold Temperature ; Gene Expression Regulation ; Liver/metabolism/*pathology/physiopathology/ultrastructure ; Liver Transplantation ; Mesenchymal Stem Cells/*cytology/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, SCID ; Real-Time Polymerase Chain Reaction ; Tissue Engineering/*methods ; Tissue Scaffolds ; }, abstract = {Liver transplantation is the ultimate treatment for severe hepatic failure to date. However, the limited supply of donor organs has severely hampered this treatment. So far, great potentials of using mesenchymal stem cells (MSCs) to replenish the hepatic cell population have been shown; nevertheless, there still is a lack of an optimal three-dimensional scaffold for generation of well-transplantable hepatic tissues. In this study, we utilized a cryo-chemical decellularization method which combines physical and chemical approach to generate acellular liver scaffolds (ALS) from the whole liver. The produced ALS provides a biomimetic three-dimensional environment to support hepatic differentiation of MSCs, evidenced by expression of hepatic-associated genes and marker protein, glycogen storage, albumin secretion, and urea production. It is also found that hepatic differentiation of MSCs within the ALS is much more efficient than two-dimensional culture in vitro. Importantly, the hepatic-like tissues (HLT) generated by repopulating ALS with MSCs are able to act as functional grafts and rescue lethal hepatic failure after transplantation in vivo. In summary, the cryo-chemical method used in this study is suitable for decellularization of liver and create acellular scaffolds that can support hepatic differentiation of MSCs and be used to fabricate functional tissue-engineered liver constructs.}, }
@article {pmid24459993, year = {2014}, author = {Beskind, DL and Rhodes, SM and Stolz, U and Birrer, B and Mayfield, TR and Bourn, S and Denninghoff, K}, title = {When should you test for and treat hypoglycemia in prehospital seizure patients?.}, journal = {Prehospital emergency care}, volume = {18}, number = {3}, pages = {433-441}, doi = {10.3109/10903127.2013.864358}, pmid = {24459993}, issn = {1545-0066}, mesh = {Adult ; Aged ; Benzodiazepines/*administration &amp; dosage ; Blood Glucose/analysis/drug effects ; Confidence Intervals ; Databases, Factual ; Emergency Medical Services/*methods ; Female ; Humans ; Hypoglycemia/complications/*diagnosis/*drug therapy ; Male ; Middle Aged ; Patient Safety ; Retrospective Studies ; Risk Assessment ; Seizures/complications/diagnosis/*drug therapy ; Severity of Illness Index ; Time Factors ; Treatment Outcome ; }, abstract = {OBJECTIVES: Seizure is a frequent reason for activating the Emergency Medical System (EMS). Little is known about the frequency of seizure caused by hypoglycemia, yet many EMS protocols require glucose testing prior to treatment. We hypothesized that hypoglycemia is rare among EMS seizure patients and glucose testing results in delayed administration of benzodiazepines.<br><br>METHODS: This was a retrospective study of a national ambulance service database encompassing 140 ALS capable EMS systems spanning 40 states and Washington DC. All prehospital calls from August 1, 2010 through December 31, 2012 with a primary or secondary impression of seizure that resulted in patient treatment or transport were included. Median regression with robust and cluster (EMS agency) adjusted standard errors was used to determine if time to benzodiazepine administration was significantly related to blood glucose testing.<br><br>RESULTS: Of 2,052,534 total calls, 76,584 (3.7%) were for seizure with 53,505 (69.9%) of these having a glucose measurement recorded. Hypoglycemia (blood glucose <60 mg/dL) was present in 638 (1.2%; CI: 1.1, 1.3) patients and 478 (0.9%; CI: 0.8, 1.0) were treated with a glucose product. A benzodiazepine was administered to 73 (11.4%; CI: 9.0, 13.9) of the 638 hypoglycemic patients. Treatment of seizure patients with a benzodiazepine occurred in 6,389 (8.3%; CI: 8.1, 8.5) cases and treatment with a glucose product occurred in 975 (1.3%; CI: 1.2, 1.4) cases. Multivariable median regression showed that obtaining a blood glucose measurement prior to benzodiazepine administration compared to no glucose measurement or glucose measurement after benzodiazepine administration was independently associated with a 2.1 minute (CI: 1.5, 2.8) and 5.9 minute (CI: 5.3, 6.6) delay to benzodiazepine administration by EMS, respectively.<br><br>CONCLUSIONS: Rates of hypoglycemia were very low in patients treated by EMS for seizure. Glucose testing prior to benzodiazepine administration significantly increased the median time to benzodiazepine administration. Given the importance of rapid treatment of seizure in actively seizing patients, measurement of blood glucose prior to treating a seizure with a benzodiazepine is not supported by our study. EMS seizure protocols should be revisited.}, }
@article {pmid24455732, year = {2013}, author = {Gotkine, M and Rozenstein, L and Einstein, O and Abramsky, O and Argov, Z and Rosenmann, H}, title = {Presymptomatic treatment with acetylcholinesterase antisense oligonucleotides prolongs survival in ALS (G93A-SOD1) mice.}, journal = {BioMed research international}, volume = {2013}, number = {}, pages = {845345}, pmid = {24455732}, issn = {2314-6141}, mesh = {Acetylcholinesterase/genetics ; Amyotrophic Lateral Sclerosis/*genetics/pathology/*therapy ; Animals ; Disease Models, Animal ; Disease Progression ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/pathology ; Neostigmine/administration &amp; dosage ; Oligonucleotides, Antisense/*administration &amp; dosage/genetics ; Superoxide Dismutase ; }, abstract = {OBJECTIVE: Previous research suggests that acetylcholinesterase (AChE) may be involved in ALS pathogenesis. AChE enzyme inhibitors can upregulate AChE transcription which in certain contexts can have deleterious (noncatalytic) effects, making them theoretically harmful in ALS, whilst AChE antisense-oligonucleotides (mEN101), which downregulate AChE may be beneficial. Our aim was to investigate whether downregulation of AChE using mEN101 is beneficial in an ALS mouse model.<br><br>METHODS: ALS (G93A-SOD1) mice received saline, mEN101, inverse-EN101, or neostigmine. Treatments were administered from 5 weeks. Disease-onset and survival were recorded. Additional mice were sacrificed for pathological analysis at 15 weeks of age. In a follow-up experiment treatment was started at the symptomatic stage at a higher dose.<br><br>RESULTS: mEN101 given at the presymptomatic (but not symptomatic) stage prolonged survival and attenuated motor-neuron loss in ALS mice. In contrast, neostigmine exacerbated the clinical parameters.<br><br>CONCLUSIONS: These results suggest that AChE may be involved in ALS pathogenesis. The accelerated disease course with neostigmine suggests that any beneficial effects of mEN101 occur through a non-catalytic rather than cholinergic mechanism.}, }
@article {pmid24448926, year = {2014}, author = {Lunn, JS and Sakowski, SA and Feldman, EL}, title = {Concise review: Stem cell therapies for amyotrophic lateral sclerosis: recent advances and prospects for the future.}, journal = {Stem cells (Dayton, Ohio)}, volume = {32}, number = {5}, pages = {1099-1109}, pmid = {24448926}, issn = {1549-4918}, support = {R01 NS077982/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Biomedical Research/*methods/trends ; Cell Differentiation ; Forecasting ; Humans ; Models, Neurological ; Motor Neurons/cytology ; Stem Cell Transplantation/*methods/trends ; Stem Cells/*cytology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal disease involving the loss of motor neurons. Although the mechanisms responsible for motor neuron degeneration in ALS remain elusive, the development of stem cell-based therapies for the treatment of ALS has gained widespread support. Here, we review the types of stem cells being considered for therapeutic applications in ALS, and emphasize recent preclinical advances that provide supportive rationale for clinical translation. We also discuss early trials from around the world translating cellular therapies to ALS patients, and offer important considerations for future clinical trial design. Although clinical translation is still in its infancy, and additional insight into the mechanisms underlying therapeutic efficacy and the establishment of long-term safety are required, these studies represent an important first step toward the development of effective cellular therapies for the treatment of ALS.}, }
@article {pmid24447620, year = {2014}, author = {Lenglet, T and Lacomblez, L and Abitbol, JL and Ludolph, A and Mora, JS and Robberecht, W and Shaw, PJ and Pruss, RM and Cuvier, V and Meininger, V and , }, title = {A phase II-III trial of olesoxime in subjects with amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {21}, number = {3}, pages = {529-536}, doi = {10.1111/ene.12344}, pmid = {24447620}, issn = {1468-1331}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Case-Control Studies ; Cholestenones/*therapeutic use ; Double-Blind Method ; Europe ; Female ; Humans ; International Cooperation ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Treatment Outcome ; }, abstract = {BACKGROUND AND PURPOSE: To assess the efficacy and safety of olesoxime, a molecule with neuroprotective properties, in patients with amyotrophic lateral sclerosis (ALS) treated with riluzole.<br><br>METHODS: A double-blind, randomized, placebo-controlled, multicenter trial of 18 months' duration was conducted in 512 subjects, with probable or definite ALS and a slow vital capacity (SVC) &#x2265;70%, receiving 330 mg olesoxime daily or matching placebo and 50 mg riluzole twice a day in all. The primary intention-to-treat (ITT) outcome analysis was 18 months' survival. Secondary outcomes were rates of deterioration of the revised ALS functional rating scale (ALSFRS-R), focusing on the 9-month assessment, SVC and manual muscle testing. Blood levels, safety and tolerability of olesoxime were also assessed.<br><br>RESULTS: At 18 months, 154 of the 512 ITT patients had died (79 of 253 placebo, 75 of 259 olesoxime). Estimated overall survival according to Kaplan-Meier analysis was 67.5% (95% CI 61.0%-73.1%) in the placebo group and 69.4% (95% CI 63.0%-74.9%) in the olesoxime group; hence survival was not significantly different between treatment arms (P = 0.71, stratified bulbar/spinal log-rank). The other efficacy end-points evaluated were also negative, with the exception of a small difference in ALSFRS-R global score at 9 months in favor of olesoxime but not sustained after 18 months' treatment nor evident in either the stratified bulbar or spinal subpopulations. Treatment did not raise any safety concerns.<br><br>CONCLUSIONS: Olesoxime, although well tolerated, did not show a significant beneficial effect in ALS patients treated with riluzole.}, }
@article {pmid24441414, year = {2014}, author = {Zhang, X and Chen, S and Song, L and Tang, Y and Shen, Y and Jia, L and Le, W}, title = {MTOR-independent, autophagic enhancer trehalose prolongs motor neuron survival and ameliorates the autophagic flux defect in a mouse model of amyotrophic lateral sclerosis.}, journal = {Autophagy}, volume = {10}, number = {4}, pages = {588-602}, pmid = {24441414}, issn = {1554-8635}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Autophagy/*drug effects ; Cell Survival ; Disease Models, Animal ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects/pathology ; Spinal Cord/*metabolism ; Superoxide Dismutase/genetics/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Trehalose/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by selective motor neuron degeneration. Abnormal protein aggregation and impaired protein degradation pathways may contribute to the disease pathogenesis. Although it has been reported that autophagy is altered in patients and animal model of ALS, little is known about the role of autophagy in motor neuron degeneration in this disease. Our previous study shows that rapamycin, an MTOR-dependent autophagic activator, accelerates disease progression in the SOD1(G93A) mouse model of ALS. In the present report, we have assessed the role of the MTOR-independent autophagic pathway in ALS by determining the effect of the MTOR-independent autophagic inducer trehalose on disease onset and progression, and on motor neuron degeneration in SOD1(G93A) mice. We have found that trehalose significantly delays disease onset prolongs life span, and reduces motor neuron loss in the spinal cord of SOD1(G93A) mice. Most importantly, we have documented that trehalose decreases SOD1 and SQSTM1/p62 aggregation, reduces ubiquitinated protein accumulation, and improves autophagic flux in the motor neurons of SOD1(G93A) mice. Moreover, we have demonstrated that trehalose can reduce skeletal muscle denervation, protect mitochondria, and inhibit the proapoptotic pathway in SOD1(G93A) mice. Collectively, our study indicated that the MTOR-independent autophagic inducer trehalose is neuroprotective in the ALS model and autophagosome-lysosome fusion is a possible therapeutic target for the treatment of ALS.}, }
@article {pmid24440210, year = {2014}, author = {Bhuiyan, TR and Choudhury, FK and Khanam, F and Saha, A and Sayeed, MA and Salma, U and Lundgren, A and Sack, DA and Svennerholm, AM and Qadri, F}, title = {Evaluation of immune responses to an oral typhoid vaccine, Ty21a, in children from 2 to 5 years of age in Bangladesh.}, journal = {Vaccine}, volume = {32}, number = {9}, pages = {1055-1060}, doi = {10.1016/j.vaccine.2014.01.001}, pmid = {24440210}, issn = {1873-2518}, mesh = {Administration, Oral ; Albendazole/administration &amp; dosage ; Anthelmintics/administration &amp; dosage ; Antibodies, Bacterial ; Bangladesh ; Child, Preschool ; Double-Blind Method ; Female ; Humans ; Male ; Metronidazole/administration &amp; dosage/analogs &amp; derivatives ; Pilot Projects ; Polysaccharides, Bacterial/*administration &amp; dosage/*immunology ; T-Lymphocytes/immunology ; Typhoid Fever/*prevention &amp; control ; Typhoid-Paratyphoid Vaccines/*administration &amp; dosage/*immunology ; }, abstract = {Young children are very susceptible to typhoid fever, emphasizing the need for vaccination in under five age groups. The parenteral Vi polysaccharide vaccine is not immunogenic in children under 2 years and the oral Ty21a vaccine (Vivotif) available in capsular formulation is only recommended for those over 5 years. We studied immune responses to a liquid formulation of Ty21a in children 2-5 years of age. Since children in developing countries are in general hypo responsive to oral vaccines, the study was designed to determine if anti-helminthic treatment prior to vaccination, improves responses. In a pilot study in 20 children aged 4-5 years, the immune responses in plasma and in antibody in lymphocyte secretions (ALS) to the enteric coated capsule formulation of Ty21a was found to be comparable to a liquid formulation (P>0.05). Based on this, children (n=252) aged ≥ 2-<3 years and ≥3-<5 years were randomized to receive a liquid formulation of Ty21a with and without previous anti-helminthic treatment. The vaccine was well tolerated with only a few mild adverse events recorded in <1% of the children. De-worming did not improve immune responses and both age groups developed 32-71% IgA, IgG, and IgM responses in plasma and 63-86% IgA responses in ALS and stool specimens to a membrane preparation (MP) of Ty21a. An early MP specific proliferative T cell response was also seen. We recommend that safety and efficacy studies with a liquid formulation of the vaccine are carried out in children under five, including those less than two years of age to determine if Ty21a is protective in these age groups and applicable as a public health tool for controlling typhoid fever in high prevalence areas of typhoid fever including Bangladesh.}, }
@article {pmid24434522, year = {2014}, author = {Dolga, AM and de Andrade, A and Meissner, L and Knaus, HG and Höllerhage, M and Christophersen, P and Zischka, H and Plesnila, N and Höglinger, GU and Culmsee, C}, title = {Subcellular expression and neuroprotective effects of SK channels in human dopaminergic neurons.}, journal = {Cell death &amp; disease}, volume = {5}, number = {1}, pages = {e999}, pmid = {24434522}, issn = {2041-4889}, mesh = {Calcium/metabolism ; Cell Differentiation ; Dopaminergic Neurons/cytology/*metabolism ; Humans ; Membrane Potential, Mitochondrial ; Mitochondrial Membranes/metabolism ; Neuroprotective Agents/*metabolism ; Parkinson Disease/genetics/*metabolism/physiopathology ; Protein Transport ; Small-Conductance Calcium-Activated Potassium Channels/genetics/*metabolism ; }, abstract = {Small-conductance Ca(2+)-activated K(+) channel activation is an emerging therapeutic approach for treatment of neurological diseases, including stroke, amyotrophic lateral sclerosis and schizophrenia. Our previous studies showed that activation of SK channels exerted neuroprotective effects through inhibition of NMDAR-mediated excitotoxicity. In this study, we tested the therapeutic potential of SK channel activation of NS309 (25 μM) in cultured human postmitotic dopaminergic neurons in vitro conditionally immortalized and differentiated from human fetal mesencephalic cells. Quantitative RT-PCR and western blotting analysis showed that differentiated dopaminergic neurons expressed low levels of SK2 channels and high levels of SK1 and SK3 channels. Further, protein analysis of subcellular fractions revealed expression of SK2 channel subtype in mitochondrial-enriched fraction. Mitochondrial complex I inhibitor rotenone (0.5 μM) disrupted the dendritic network of human dopaminergic neurons and induced neuronal death. SK channel activation reduced mitochondrial membrane potential, while it preserved the dendritic network, cell viability and ATP levels after rotenone challenge. Mitochondrial dysfunction and delayed dopaminergic cell death were prevented by increasing and/or stabilizing SK channel activity. Overall, our findings show that activation of SK channels provides protective effects in human dopaminergic neurons, likely via activation of both membrane and mitochondrial SK channels. Thus, SK channels are promising therapeutic targets for neurodegenerative disorders such as Parkinson's disease, where dopaminergic cell loss is associated with progression of the disease.}, }
@article {pmid24433963, year = {2014}, author = {Brunden, KR and Trojanowski, JQ and Smith, AB and Lee, VM and Ballatore, C}, title = {Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {22}, number = {18}, pages = {5040-5049}, pmid = {24433963}, issn = {1464-3391}, support = {R01 AG044332/AG/NIA NIH HHS/United States ; U01 AG029213/AG/NIA NIH HHS/United States ; AG029213/AG/NIA NIH HHS/United States ; AG044332/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Microtubules/*drug effects/metabolism ; Molecular Structure ; Neurodegenerative Diseases/*drug therapy/metabolism ; Structure-Activity Relationship ; Tubulin Modulators/chemistry/*pharmacology/*therapeutic use ; }, abstract = {Microtubules (MTs), cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in the proper functioning of post-mitotic central nervous system neurons, where MTs serve as the structures on which key cellular constituents are trafficked in axonal projections. MTs are stabilized in axons by the MT-associated protein tau, and in several neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease, tau function appears to be compromised due to the protein dissociating from MTs and depositing into insoluble inclusions referred to as neurofibrillary tangles. This loss of tau function is believed to result in alterations of MT structure and function, resulting in aberrant axonal transport that likely contributes to the neurodegenerative process. There is also evidence of axonal transport deficiencies in other neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington's disease, which may result, at least in part, from MT alterations. Accordingly, a possible therapeutic strategy for such neurodegenerative conditions is to treat with MT-stabilizing agents, such as those that have been used in the treatment of cancer. Here, we review evidence of axonal transport and MT deficiencies in a number of neurodegenerative diseases, and summarize the various classes of known MT-stabilizing agents. Finally, we highlight the growing evidence that small molecule MT-stabilizing agents provide benefit in animal models of neurodegenerative disease and discuss the desired features of such molecules for the treatment of these central nervous system disorders.}, }
@article {pmid24428861, year = {2014}, author = {Gianforcaro, A and Hamadeh, MJ}, title = {Vitamin D as a potential therapy in amyotrophic lateral sclerosis.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {20}, number = {2}, pages = {101-111}, pmid = {24428861}, issn = {1755-5949}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; *Dietary Supplements ; Humans ; Vitamin D/*therapeutic use ; Vitamins/*therapeutic use ; }, abstract = {Vitamin D has been demonstrated to influence multiple aspects of amyotrophic lateral sclerosis (ALS) pathology. Both human and rodent central nervous systems express the vitamin D receptor (VDR) and/or its enzymatic machinery needed to fully activate the hormone. Clinical research suggests that vitamin D treatment can improve compromised human muscular ability and increase muscle size, supported by loss of motor function and muscle mass in animals following VDR knockout, as well as increased muscle protein synthesis and ATP production following vitamin D supplementation. Vitamin D has also been shown to reduce the expression of biomarkers associated with oxidative stress and inflammation in patients with multiple sclerosis, rheumatoid arthritis, congestive heart failure, Parkinson's disease and Alzheimer's disease; diseases that share common pathophysiologies with ALS. Furthermore, vitamin D treatment greatly attenuates hypoxic brain damage in vivo and reduces neuronal lethality of glutamate insult in vitro; a hallmark trait of ALS glutamate excitotoxicity. We have recently shown that high-dose vitamin D3 supplementation improved, whereas vitamin D3 restriction worsened, functional capacity in the G93A mouse model of ALS. In sum, evidence demonstrates that vitamin D, unlike the antiglutamatergic agent Riluzole, affects multiple aspects of ALS pathophysiology and could provide a greater cumulative effect.}, }
@article {pmid24424061, year = {2014}, author = {Kennedy, OD and Sun, H and Wu, Y and Courtland, HW and Williams, GA and Cardoso, L and Basta-Pljakic, J and Schaffler, MB and Yakar, S}, title = {Skeletal response of male mice to anabolic hormone therapy in the absence of the Igfals gene.}, journal = {Endocrinology}, volume = {155}, number = {3}, pages = {987-999}, pmid = {24424061}, issn = {1945-7170}, support = {AR054919/AR/NIAMS NIH HHS/United States ; R01 AR054919/AR/NIAMS NIH HHS/United States ; AR055141/AR/NIAMS NIH HHS/United States ; R01 AR055141/AR/NIAMS NIH HHS/United States ; AR057139/AR/NIAMS NIH HHS/United States ; AR041210/AR/NIAMS NIH HHS/United States ; R01 AR057139/AR/NIAMS NIH HHS/United States ; R01 AR041210/AR/NIAMS NIH HHS/United States ; }, mesh = {Anabolic Agents/*metabolism ; Animals ; Body Weight ; Bone Density/drug effects ; Bone Development/drug effects/physiology ; Bone and Bones/*drug effects/*metabolism ; Carrier Proteins/*genetics/*physiology ; Crosses, Genetic ; Glucose Tolerance Test ; Glycoproteins/*genetics/*physiology ; Hormones/*metabolism ; Insulin/metabolism ; Insulin-Like Growth Factor Binding Protein 3/metabolism ; Insulin-Like Growth Factor I/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Organ Size ; Phenotype ; Protein Binding ; Time Factors ; X-Ray Microtomography ; }, abstract = {IGF-I is a critical regulator of skeletal acquisition, which acts in endocrine and autocrine/paracrine modes. In serum, IGF-I is carried by the IGF-binding proteins in binary complexes. Further stabilization of these complexes is achieved by binding to the acid labile subunit (ALS) in a ternary complex (of IGF-I-IGF-binding protein 3/5-ALS). Ablation of the Igfals gene in humans (ALS deficiency) and mice (ALS knockout [ALSKO]) leads to markedly decreased serum IGF-I levels, growth retardation, and impaired skeletal acquisition. To investigate whether hormonal replacement therapy would improve the skeletal phenotype in cases of Igfals gene ablation, we treated male ALSKO mice with GH, IGF-I, or a combination of both. Treatments were administered to animals between 4 and 16 weeks of age or from 8 to 16 weeks of age. Although all treatment groups showed an increase (20%) in serum IGF-I levels, there was no increase in body weight, weight gain, or bone length in either age group. Despite the blunted linear growth in response to hormone therapy, ALSKO mice treated with GH showed radial bone growth, which contributed to bone strength tested by 4-point bending. We found that ALSKO mice treated with GH showed increased total cross-sectional area, cortical bone area, and cortical thickness by microtomography. Dynamic histomorphometry showed that although GH and double treatment groups resulted in trends towards increased bone formation parameters, these did not reach significance. However, bone resorption parameters were significantly increased in all treatment groups. ALSKO mice treated between 4 and 16 weeks of age showed minor differences in bone traits compared with vehicle-treated mice. In conclusion, treatment with GH and IGF-I do not work synergistically to rescue the stunted growth found in mice lacking the Igfals gene. Although GH alone appears to increase bone parameters slightly, it does not affect body weight or linear growth.}, }
@article {pmid24423643, year = {2014}, author = {Ranno, E and D'Antoni, S and Spatuzza, M and Berretta, A and Laureanti, F and Bonaccorso, CM and Pellitteri, R and Longone, P and Spalloni, A and Iyer, AM and Aronica, E and Catania, MV}, title = {Endothelin-1 is over-expressed in amyotrophic lateral sclerosis and induces motor neuron cell death.}, journal = {Neurobiology of disease}, volume = {65}, number = {}, pages = {160-171}, doi = {10.1016/j.nbd.2014.01.002}, pmid = {24423643}, issn = {1095-953X}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; Astrocytes/drug effects/metabolism ; Cell Death/drug effects ; Cells, Cultured ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Embryo, Mammalian ; Endothelin-1/*pharmacology ; Female ; Humans ; Male ; Mice ; Mice, Transgenic ; Middle Aged ; Motor Neurons/*drug effects ; Pregnancy ; Rats ; Rats, Wistar ; Spinal Cord/cytology ; Superoxide Dismutase/genetics ; Time Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor neurons (MNs) and astrogliosis. Recent evidence suggests that factors secreted by activated astrocytes might contribute to degeneration of MNs. We focused on endothelin-1 (ET-1), a peptide which is strongly up-regulated in reactive astrocytes under different pathological conditions. We show that ET-1 is abundantly expressed by reactive astrocytes in the spinal cord of the SOD1-G93A mouse model and sporadic ALS patients. To test if ET-1 might play a role in degeneration of MNs, we investigated its effect on MN survival in an in vitro model of mixed rat spinal cord cultures (MSCs) enriched of astrocytes exhibiting a reactive phenotype. ET-1 exerted a toxic effect on MNs in a time- and concentration-dependent manner, with an exposure to 100-200nM ET-1 for 48h resulting in 40-50% MN cell death. Importantly, ET-1 did not induce MN degeneration when administered on cultures treated with AraC (5μM) or grown in a serum-free medium that did not favor astrocyte proliferation and reactivity. We found that both ETA and ETB receptors are enriched in astrocytes in MSCs. The ET-1 toxic effect was mimicked by ET-3 (100nM) and sarafotoxin S6c (10nM), two selective agonists of endothelin-B receptors, and was not additive with that of ET-3 suggesting the involvement of ETB receptors. Surprisingly, however, the ET-1 effect persisted in the presence of the ETB receptor antagonist BQ-788 (200nM-2μM) and was slightly reversed by the ETA receptor antagonist BQ-123 (2μM), suggesting an atypical pharmacological profile of the astrocytic receptors responsible for ET-1 toxicity. The ET-1 effect was not undone by the ionotropic glutamate receptor AMPA antagonist GYKI 52466 (20μM), indicating that it is not caused by an increased glutamate release. Conversely, a 48-hour ET-1 treatment increased MN cell death induced by acute exposure to AMPA (50μM), which is indicative of two distinct pathways leading to neuronal death. Altogether these results indicate that ET-1 exerts a toxic effect on cultured MNs through mechanisms mediated by reactive astrocytes and suggest that ET-1 may contribute to MN degeneration in ALS. Thus, a treatment aimed at lowering ET-1 levels or antagonizing its effect might be envisaged as a potential therapeutic strategy to slow down MN degeneration in this devastating disease.}, }
@article {pmid24419304, year = {2013}, author = {Kilickap, S and Hayran, M and Cakir, B and Cilingiroglu, N and Erman, M and Buyukdamgaci, G and Ozisik, Y}, title = {Effect of endocrine therapy on quality of life and cognitive functions in patients with breast cancer.}, journal = {Breast care (Basel, Switzerland)}, volume = {8}, number = {2}, pages = {128-132}, pmid = {24419304}, issn = {1661-3791}, abstract = {BACKGROUND: The use of endocrine therapy (ET) in postmenopausal breast cancer patients may affect their cognitive status. This study aims to assess the effects of tamoxifen and aromatase inhibitors (Als) on quality of life (QoL) and cognitive functions in breast cancer patients.<br><br>PATIENTS AND METHODS: The study included 101 patients receiving tamoxifen, 97 patients receiving Als, and 95 patients without any ET. All patients completed both the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the Short Form-12 (SF-12) questionnaires.<br><br>RESULTS: The patients' characteristics were similar between the groups. The mean duration of ET was 2.6 years for tamoxifen and 2.5 years for Als. EORTC QLQ-C30 global scores and cognitive functioning scores as well as SF-12 mental scorings (mcs) were found not significantly different between patients without any ET and those receiving tamoxifen or Als (p = 0.529, p = 0.333, and p = 0.452, respectively). SF-12 mcs correlated moderately with EORTC QLQ-C30 global scores for the 3 treatment groups (all p values < 0.001).<br><br>CONCLUSION: Our study suggests that QoL and cognitive functions are similar in patients receiving Als or tamoxifen. Moreover, it appears that these parameters also do not differ in patients with respect to the use of ET.}, }
@article {pmid24414863, year = {2014}, author = {Mancuso, R and del Valle, J and Modol, L and Martinez, A and Granado-Serrano, AB and Ramirez-Núñez, O and Pallás, M and Portero-Otin, M and Osta, R and Navarro, X}, title = {Resveratrol improves motoneuron function and extends survival in SOD1(G93A) ALS mice.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {11}, number = {2}, pages = {419-432}, pmid = {24414863}, issn = {1878-7479}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Disease Models, Animal ; Female ; Male ; Mice ; Mice, Transgenic ; Microglia/drug effects ; Mitochondria/drug effects ; Motor Activity/*drug effects ; Motor Neurons/*drug effects ; Neuroprotective Agents/*pharmacology/therapeutic use ; Resveratrol ; Sirtuins/metabolism ; Stilbenes/*pharmacology/therapeutic use ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that causes progressive paralysis and death due to degeneration of motoneurons in spinal cord, brainstem and motor cortex. Nowadays, there is no effective therapy and patients die 2-5 years after diagnosis. Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural polyphenol found in grapes, with promising neuroprotective effects since it induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of resveratrol administration on SOD1(G93A) ALS mice. We determined the onset of symptoms by rotarod test and evaluated upper and lower motoneuron function using electrophysiological tests. We assessed the survival of the animals and determined the number of spinal motoneurons. Finally, we further investigated resveratrol mechanism of action by means of western blot and immunohistochemical analysis. Resveratrol treatment from 8 weeks of age significantly delayed disease onset and preserved lower and upper motoneuron function in female and male animals. Moreover, resveratrol significantly extended SOD1(G93A) mice lifespan and promoted survival of spinal motoneurons. Delayed resveratrol administration from 12 weeks of age also improved spinal motoneuron function preservation and survival. Further experiments revealed that resveratrol protective effects were associated with increased expression and activation of Sirtuin 1 and AMPK in the ventral spinal cord. Both mediators promoted normalization of the autophagic flux and, more importantly, increased mitochondrial biogenesis in the SOD1(G93A) spinal cord. Taken together, our findings suggest that resveratrol may represent a promising therapy for ALS.}, }
@article {pmid24411632, year = {2014}, author = {Assouline, A and Levy, A and Abdelnour-Mallet, M and Gonzalez-Bermejo, J and Lenglet, T and Le Forestier, N and Salachas, F and Bruneteau, G and Meininger, V and Delanian, S and Pradat, PF}, title = {Radiation therapy for hypersalivation: a prospective study in 50 amyotrophic lateral sclerosis patients.}, journal = {International journal of radiation oncology, biology, physics}, volume = {88}, number = {3}, pages = {589-595}, doi = {10.1016/j.ijrobp.2013.11.230}, pmid = {24411632}, issn = {1879-355X}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*complications ; Female ; Humans ; Male ; Middle Aged ; Parotid Gland/radiation effects ; Photons/therapeutic use ; Prospective Studies ; Radiotherapy Dosage ; Remission Induction/methods ; Sialorrhea/etiology/*radiotherapy ; Statistics, Nonparametric ; Submandibular Gland ; }, abstract = {PURPOSE: This study aimed to evaluate the efficiency and the tolerance of radiation therapy (RT) on salivary glands in a large series of amyotrophic lateral sclerosis (ALS) patients with hypersalivation.<br><br>METHODS AND MATERIALS: Fifty ALS patients that had medically failure pretreatment were included in this prospective study. RT was delivered through a conventional linear accelerator with 6-MV photons and 2 opposed beams fields including both submandibular glands and two-thirds of both parotid glands. Total RT dose was 10 Gy in 2 fractions (n=30) or 20 Gy in 4 fractions (n=20). RT efficacy was assessed with the 9-grade Sialorrhea Scoring Scale (SSS), recently prospectively validated as the most effective and sensitive tool to measure sialorrhea in ALS patients.<br><br>RESULTS: At the end of RT, all patients had improved: 46 had a complete response (92% CR, SSS 1-3) and 4 had a partial response (8% PR, SSS 4-5). A significant lasting salivary reduction was observed 6 months after RT completion: there was 71% CR and 26% PR, and there was a significant SSS reduction versus baseline (P<10(-6)). There was no grade 3 to 4 toxicity, and most side effects (34%) occurred during RT. Nine patients (18%) underwent a second salivary gland RT course, with a 3-months mean delay from the first RT, resulting in a SSS decrease (-77%). Both RT dose regimens induced a significant SSS decrease with no significant toxicity. There were, however, more patients with CR/PR in the 20-Gy protocol (P=.02), and 8 of 9 patients (89%) receiving a second RT course had previously been treated within the 10-Gy protocol.<br><br>CONCLUSION: Radiation therapy of 20 Gy in 4 fractions is an efficient and safe treatment for ALS patients with sialorrhea. A shorter RT course (10 Gy in 2 fractions) may be proposed in patients in poor medical condition.}, }
@article {pmid24409117, year = {2013}, author = {Gerber, YN and Privat, A and Perrin, FE}, title = {Gacyclidine improves the survival and reduces motor deficits in a mouse model of amyotrophic lateral sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {7}, number = {}, pages = {280}, pmid = {24409117}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder typified by a massive loss of motor neurons with few therapeutic options. The exact cause of neuronal degeneration is unknown but it is now admitted that ALS is a multifactorial disease with several mechanisms involved including glutamate excitotoxicity. More specifically, N-methyl-D-aspartate (NMDA)-mediated cell death and impairment of the glutamate-transport has been suggested to play a key role in ALS pathophysiology. Thus, evaluating NMDAR antagonists is of high therapeutic interest. Gacyclidine, also named GK11, is a high affinity non-competitive NMDAR antagonist that may protect against motor neuron death in an ALS context. Moreover, GK11 presents a low intrinsic neurotoxicity and has already been used in two clinical trials for CNS lesions. In the present study, we investigated the influence of chronic administration of two doses of GK11 (0.1 and 1 mg/kg) on the survival and the functional motor activity of hSOD1(G93A) mice, an animal model of ALS. Treatment started at early symptomatic age (60 days) and was applied bi-weekly until the end stage of the disease. We first confirmed that functional alteration of locomotor activity was evident in the hSOD1(G93A) transgenic female mice by 60 days of age. A low dose of GK11 improved the survival of the mice by 4.3% and partially preserved body weight. Improved life span was associated with a delay in locomotor function impairment. Conversely, the high dose treatment worsened motor functions. These findings suggest that chronic administration of GK11 beginning at early symptomatic stage may be beneficial for patients with ALS.}, }
@article {pmid24400881, year = {2014}, author = {Nagurka, R and Bechmann, S and Gluckman, W and Scott, SR and Compton, S and Lamba, S}, title = {Utility of initial prehospital end-tidal carbon dioxide measurements to predict poor outcomes in adult asthmatic patients.}, journal = {Prehospital emergency care}, volume = {18}, number = {2}, pages = {180-184}, doi = {10.3109/10903127.2013.851306}, pmid = {24400881}, issn = {1545-0066}, mesh = {Adult ; Asthma/classification/*diagnosis ; Blood Gas Analysis/instrumentation/*methods ; Carbon Dioxide/*analysis ; Emergency Medical Services/methods/*standards/statistics &amp; numerical data ; Female ; Hospitals, Urban/statistics &amp; numerical data ; Humans ; Male ; Predictive Value of Tests ; Prognosis ; Retrospective Studies ; *Severity of Illness Index ; Tidal Volume ; }, abstract = {STUDY OBJECTIVE: To determine if an initial (before treatment) prehospital end-tidal carbon dioxide (EtCO2) measurement in adult, non-chronic obstructive pulmonary disease (COPD), asthmatic patients predicts patient outcomes.<br><br>METHODS: This is a retrospective chart review of EtCO2 assessment data in a convenience sample of adult, asthmatic patients transported via advanced life support (ALS) units to a large, urban, academic hospital. Initial EtCO2 measurements were obtained routinely on all respiratory distress patients in the field, and emergency department physicians were unaware of the results. Data were analyzed using descriptive statistics, including percentages, means, and 95% confidence intervals (CI).<br><br>RESULTS: We reviewed data for prehospital initial EtCO2 measurements on 299 unique asthma patients (repeat visits by same patient were not included). Mean (SD) age was 43.1 years (12.5) and 142 (47.5%) were male. The mean EtCO2 measurement was 38.8 mmHg (SD &#xb1; 9.5; CI: 37.7-39.9; range: 14-82). Examination of initial EtCO2 measurements by deciles revealed that extreme values, in the lowest (14-28 mmHg) and highest (50-82 mmHg) deciles, experienced more markers of poor outcome than less extreme measurements. Patients were thus dichotomized by extreme (n = 59) or nonextreme (n = 240) EtCO2 measurements. More extreme patients were ultimately intubated (30.5 vs. 5.8%; p < 0.001; positive predictive value (ppv) = 30.5%), and/or admitted to the intensive care unit (ICU) (28.8 vs. 6.7%; p <0.001; ppv = 28.8%), and/or died (5.1 vs. 0%; p = 0.007 [Fisher's exact test]; ppv = 5.1%), than nonextreme patients, respectively.<br><br>CONCLUSION: Extreme (both low and high) prehospital initial EtCO2 measurements may be associated with markers of poor patient outcomes. Future work will prospectively determine whether the addition of this information improves early recognition of severe asthma episodes beyond clinical assessment.}, }
@article {pmid24398467, year = {2014}, author = {Wang, Y and Zhu, R and Ni, Y and Kokot, S}, title = {Competitive interactions of anti-carcinogens with serum albumin: a spectroscopic study of bendamustine and dexamethasone with the aid of chemometrics.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {123}, number = {}, pages = {241-248}, doi = {10.1016/j.saa.2013.12.063}, pmid = {24398467}, issn = {1873-3557}, mesh = {Animals ; Anticarcinogenic Agents/chemistry/*metabolism ; Bendamustine Hydrochloride ; Cattle ; Dexamethasone/chemistry/*metabolism ; Least-Squares Analysis ; Multivariate Analysis ; Nitrogen Mustard Compounds/chemistry/*metabolism ; Protein Binding ; Serum Albumin, Bovine/chemistry/*metabolism ; Spectrometry, Fluorescence ; Thermodynamics ; }, abstract = {Interactions between the anti-carcinogens, bendamustine (BDM) and dexamethasone (DXM), with bovine serum albumin (BSA) were investigated with the use of fluorescence and UV-vis spectroscopies under pseudo-physiological conditions (Tris-HCl buffer, pH 7.4). The static mechanism was responsible for the fluorescence quenching during the interactions; the binding formation constant of the BSA-BDM complex and the binding number were 5.14×10(5)Lmol(-1) and 1.0, respectively. Spectroscopic studies for the formation of BDM-BSA complex were interpreted with the use of multivariate curve resolution - alternating least squares (MCR-ALS), which supported the complex formation. The BSA samples treated with site markers (warfarin - site I and ibuprofen - site II) were reacted separately with BDM and DXM; while both anti-carcinogens bound to site I, the binding constants suggested that DXM formed a more stable complex. Relative concentration profiles and the fluorescence spectra associated with BDM, DXM and BSA, were recovered simultaneously from the full fluorescence excitation-emission data with the use of the parallel factor analysis (PARAFAC) method. The results confirmed that on addition of DXM to the BDM-BSA complex, the BDM was replaced and the DXM-BSA complex formed; free BDM was released. This finding may have consequences for the transport of these drugs during any anti-cancer treatment.}, }
@article {pmid24397499, year = {2014}, author = {Burakgazi, AZ}, title = {Lyme disease -induced polyradiculopathy mimicking amyotrophic lateral sclerosis.}, journal = {The International journal of neuroscience}, volume = {124}, number = {11}, pages = {859-862}, doi = {10.3109/00207454.2013.879582}, pmid = {24397499}, issn = {1563-5279}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Diagnosis, Differential ; Guillain-Barre Syndrome/diagnosis ; Humans ; Lyme Disease/complications/*diagnosis ; Male ; Middle Aged ; Polyradiculopathy/complications/*diagnosis ; }, abstract = {IMPORTANCE: To describe a case of predominantly motor polyradiculopathy secondary to Lyme disease that can mimic motor neuron disease and has been rarely reported.<br><br>OBSERVATIONS: A 64-year-old man presented with a 1-month history of rapidly progressive weakness involving bulbar, upper limb and lower limb muscles. The physical examination showed widespread weakness, atrophy, fasciculation, and brisk reflexes. The initial electrodiagnostic test showed widespread active and chronic denervation findings. The initial physical and electrodiagnostic findings were suggestive of Amyotrophic Lateral Sclerosis (ALS). However, blood serology indicated possible Lyme disease. Thus, the patient was treated with doxycycline. The clinical and electrodiagnostic findings were resolved with the treatment.<br><br>CONCLUSION AND RELEVANCE: The diagnosis of Lyme disease can be very challenging and it can mimic other neurological disorders such as ALS or Guillain-Barre syndrome (GBS). Careful and detailed examination and investigation are required to confirm the diagnosis and to prevent misleading inaccurate diagnoses.}, }
@article {pmid24395787, year = {2014}, author = {Arif, M and Kazim, SF and Grundke-Iqbal, I and Garruto, RM and Iqbal, K}, title = {Tau pathology involves protein phosphatase 2A in parkinsonism-dementia of Guam.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {111}, number = {3}, pages = {1144-1149}, pmid = {24395787}, issn = {1091-6490}, support = {R01 AG019158/AG/NIA NIH HHS/United States ; AG019158/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Brain/enzymology ; Female ; *Gene Expression Regulation, Enzymologic ; Hippocampus/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Neurons/metabolism ; Neurotoxins/metabolism ; Phosphorylation ; Protein Phosphatase 2/*metabolism ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Receptor, Metabotropic Glutamate 5/metabolism ; Time Factors ; Tyrosine/chemistry ; src-Family Kinases/metabolism ; tau Proteins/*metabolism ; }, abstract = {Parkinsonism-dementia (PD) of Guam is a neurodegenerative disease with parkinsonism and early-onset Alzheimer-like dementia associated with neurofibrillary tangles composed of hyperphosphorylated microtubule-associated protein, tau. β-N-methylamino-l-alanine (BMAA) has been suspected of being involved in the etiology of PD, but the mechanism by which BMAA leads to tau hyperphosphorylation is not known. We found a decrease in protein phosphatase 2A (PP2A) activity associated with an increase in inhibitory phosphorylation of its catalytic subunit PP2Ac at Tyr(307) and abnormal hyperphosphorylation of tau in brains of patients who had Guam PD. To test the possible involvement of BMAA in the etiopathogenesis of PD, we studied the effect of this environmental neurotoxin on PP2A activity and tau hyperphosphorylation in mouse primary neuronal cultures and metabolically active rat brain slices. BMAA treatment significantly decreased PP2A activity, with a concomitant increase in tau kinase activity resulting in elevated tau hyperphosphorylation at PP2A favorable sites. Moreover, we found an increase in the phosphorylation of PP2Ac at Tyr(307) in BMAA-treated rat brains. Pretreatment with metabotropic glutamate receptor 5 (mGluR5) and Src antagonists blocked the BMAA-induced inhibition of PP2A and the abnormal hyperphosphorylation of tau, indicating the involvement of an Src-dependent PP2A pathway. Coimmunoprecipitation experiments showed that BMAA treatment dissociated PP2Ac from mGluR5, making it available for phosphorylation at Tyr(307). These findings suggest a scenario in which BMAA can lead to tau pathology by inhibiting PP2A through the activation of mGluR5, the consequent release of PP2Ac from the mGluR5-PP2A complex, and its phosphorylation at Tyr(307) by Src.}, }
@article {pmid24394188, year = {2014}, author = {Patel, P and Kriz, J and Gravel, M and Soucy, G and Bareil, C and Gravel, C and Julien, JP}, title = {Adeno-associated virus-mediated delivery of a recombinant single-chain antibody against misfolded superoxide dismutase for treatment of amyotrophic lateral sclerosis.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {22}, number = {3}, pages = {498-510}, pmid = {24394188}, issn = {1525-0024}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/immunology/*therapy ; Animals ; Dependovirus/*genetics ; Disease Models, Animal ; Disease Progression ; Genetic Therapy ; Genetic Vectors/administration &amp; dosage ; Gliosis/pathology/therapy ; HEK293 Cells ; Humans ; Immunotherapy ; Injections, Spinal ; Mice ; Protein Folding ; Recombinant Proteins/genetics/immunology ; Single-Chain Antibodies/*immunology/pharmacology ; Spinal Cord/*immunology ; Superoxide Dismutase/*immunology/metabolism ; Superoxide Dismutase-1 ; }, abstract = {There is emerging evidence that the misfolding of superoxide dismutase 1 (SOD1) may represent a common pathogenic event in both familial and sporadic amyotrophic lateral sclerosis (ALS). To reduce the burden of misfolded SOD1 species in the nervous system, we have tested a novel therapeutic approach based on adeno-associated virus (AAV)-mediated tonic expression of a DNA construct encoding a secretable single-chain fragment variable (scFv) antibody composed of the variable heavy and light chain regions of a monoclonal antibody (D3H5) binding specifically to misfolded SOD1. A single intrathecal injection of the AAV encoding the single-chain antibody in SOD1(G93A) mice at 45 days of age resulted in sustained expression of single-chain antibodies in the spinal cord, and it delayed disease onset and extension of life span by up to 28%, in direct correlation with scFv titers in the spinal cord. The treatment caused attenuation of neuronal stress signals and reduction in levels of misfolded SOD1 in the spinal cord of SOD1(G93A) mice. From these results, we propose that an immunotherapy based on intrathecal inoculation of AAV encoding a secretable scFv against misfolded SOD1 should be considered as potential treatment for ALS, especially for individuals carrying SOD1 mutations.}, }
@article {pmid24391590, year = {2013}, author = {Boyer, JG and Ferrier, A and Kothary, R}, title = {More than a bystander: the contributions of intrinsic skeletal muscle defects in motor neuron diseases.}, journal = {Frontiers in physiology}, volume = {4}, number = {}, pages = {356}, pmid = {24391590}, issn = {1664-042X}, abstract = {Spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and spinal-bulbar muscular atrophy (SBMA) are devastating diseases characterized by the degeneration of motor neurons. Although the molecular causes underlying these diseases differ, recent findings have highlighted the contribution of intrinsic skeletal muscle defects in motor neuron diseases. The use of cell culture and animal models has led to the important finding that muscle defects occur prior to and independently of motor neuron degeneration in motor neuron diseases. In SMA for instance, the muscle specific requirements of the SMA disease-causing gene have been demonstrated by a series of genetic rescue experiments in SMA models. Conditional ALS mouse models expressing a muscle specific mutant SOD1 gene develop atrophy and muscle degeneration in the absence of motor neuron pathology. Treating SBMA mice by over-expressing IGF-1 in a skeletal muscle-specific manner attenuates disease severity and improves motor neuron pathology. In the present review, we provide an in depth description of muscle intrinsic defects, and discuss how they impact muscle function in these diseases. Furthermore, we discuss muscle-specific therapeutic strategies used to treat animal models of SMA, ALS, and SBMA. The study of intrinsic skeletal muscle defects is crucial for the understanding of the pathophysiology of these diseases and will open new therapeutic options for the treatment of motor neuron diseases.}, }
@article {pmid24390801, year = {2014}, author = {Goyal, NA and Mozaffar, T}, title = {Respiratory and nutritional support in amyotrophic lateral sclerosis.}, journal = {Current treatment options in neurology}, volume = {16}, number = {2}, pages = {270}, pmid = {24390801}, issn = {1092-8480}, abstract = {Amyotrophic lateral sclerosis (ALS) is an uncommon and almost invariably fatal neurodegenerative disease. There is no known cure for ALS, and only one disease-modifying therapy is currently approved. In the absence of robust pharmacologic treatment options, the value of nutritional and respiratory support in the management of the disease should not be underestimated. The primary causes of morbidity and mortality in ALS are complications from dysphagia, leading to malnutrition and respiratory insufficiency, and these require focused therapeutic attention. This article reviews the current evidence for nutritional and respiratory support in the management of ALS patients.}, }
@article {pmid24390568, year = {2014}, author = {Abdanipour, A and Tiraihi, T and Noori-Zadeh, A and Majdi, A and Gosaili, R}, title = {Evaluation of lovastatin effects on expression of anti-apoptotic Nrf2 and PGC-1α genes in neural stem cells treated with hydrogen peroxide.}, journal = {Molecular neurobiology}, volume = {49}, number = {3}, pages = {1364-1372}, pmid = {24390568}, issn = {1559-1182}, mesh = {Animals ; Apoptosis/drug effects/physiology ; Cells, Cultured ; Drug Evaluation, Preclinical/methods ; Gene Expression Regulation ; Hydrogen Peroxide/*toxicity ; Lovastatin/*pharmacology ; NF-E2-Related Factor 2/*biosynthesis/genetics ; Neural Stem Cells/drug effects/*metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Rats ; Rats, Wistar ; Transcription Factors/*biosynthesis/genetics ; }, abstract = {Reactive oxygen species and oxidative stress are associated with various cell processes, including cell survival and apoptosis. Oxidative stress has been implicated in the pathogenesis of several neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and multiple sclerosis (MS). In the present study, we evaluated the effects of lovastatin chemoprotection against hydrogen peroxide-induced oxidative stress in bone marrow stromal cell-derived neural stem cells (BMSC-derived NSCs) and whether it has protective effects. BMSC-derived NSCs were pretreated with different doses of lovastatin for 48 h and then exposed to 125 μM H2O2 for 30 min. Using MTT, TUNEL assay, and real-time RT-PCR, we evaluated the effects of lovastatin on cell survival, apoptosis, and PGC-1α and Nrf2 expression rates in pretreated BMSC-derived NSCs compared to control groups. Results showed that apoptosis rate in the lovastatin-pretreated BMSC-derived NSCs was significantly decreased compared to the control group. Our findings suggest that lovastatin protects NSCs against oxidative stress-induced cell death, and therefore, it may be used to promote the survival rate of NSCs and can be a candidate for treatment of oxidative stress-mediated neurological diseases.}, }
@article {pmid24389194, year = {2014}, author = {Polimeni, G and Esposito, E and Bevelacqua, V and Guarneri, C and Cuzzocrea, S}, title = {Role of melatonin supplementation in neurodegenerative disorders.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {19}, number = {3}, pages = {429-446}, doi = {10.2741/4217}, pmid = {24389194}, issn = {2768-6698}, mesh = {*Dietary Supplements ; Humans ; Melatonin/*administration &amp; dosage/therapeutic use ; Neurodegenerative Diseases/*drug therapy ; }, abstract = {Neurodegenerative diseases are chronic and progressive disorders characterized by selective destruction of neurons in motor, sensory and cognitive systems. Despite their different origin, free radicals accumulation and consequent tissue damage are importantly concerned for the majority of them. In recent years, research on melatonin revealed a potent activity of this hormone against oxidative and nitrosative stress-induced damage within the nervous system. Indeed, melatonin turned out to be more effective than other naturally occurring antioxidants, suggesting its beneficial effects in a number of diseases where oxygen radical-mediated tissue damage is involved. With specific reference to the brain, the considerable amount of evidence accumulated from studies on various neurodegeneration models and recent clinical reports support the use of melatonin for the preventive treatment of major neurodegenerative disorders. This review summarizes the literature on the protective effects of melatonin on Alzheimer disease, Parkinson disease, Huntington's disease and Amyotrophic Lateral Sclerosis. Additional studies are required to test the clinical efficacy of melatonin supplementation in such disorders, and to identify the specific therapeutic concentrations needed.}, }
@article {pmid24381807, year = {2013}, author = {Vinsant, S and Mansfield, C and Jimenez-Moreno, R and Del Gaizo Moore, V and Yoshikawa, M and Hampton, TG and Prevette, D and Caress, J and Oppenheim, RW and Milligan, C}, title = {Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part I, background and methods.}, journal = {Brain and behavior}, volume = {3}, number = {4}, pages = {335-350}, pmid = {24381807}, issn = {2162-3279}, support = {R01 NS069212/NS/NINDS NIH HHS/United States ; }, abstract = {Charcot first described amyotrophic lateral sclerosis (ALS) in 1869; however, its causes remain largely unknown and effective, long-term treatment strategies are not available. The first mouse model of ALS was developed after the identification of mutations in the superoxide dismutase 1 (SOD1) gene in 1993, and accordingly most of our knowledge of the etiology and pathogenesis of the disease comes from studies carried out using this animal model. Although numerous preclinical trials have been conducted in the mutant SOD1 mouse models, the results have been disappointing because they did not positively translate to clinical trials. One explanation may be that current understanding of when and where pathogenesis begins is insufficient to accurately guide preclinical trials. Further characterization of these early events may provide insight into disease onset, help in the discovery of presymptomatic diagnostic disease markers, and identify novel therapeutic targets. Here, we describe the rationale, approach, and methods for our extensive analysis of early changes that included an ultrastructural examination of central and peripheral components of the neuromuscular system in the SOD1(G93A) mouse and correlated these alterations with early muscle denervation, motor dysfunction, and motoneuron death. We also provide a discussion of published work to review what is known regarding early pathology in the SOD1 mouse model of ALS. The significance of this work is that we have examined early pathology simultaneously in both the spinal cord and peripheral neuromuscular system, and the results are presented in the companion paper (Part II, Results and Discussion). Our results provide evidence as to why a thorough characterization of animal models throughout the life span is critical for a strong foundation to design preclinical trials that may produce meaningful results.}, }
@article {pmid26785244, year = {2014}, author = {Ross, EK and Winter, AN and Wilkins, HM and Sumner, WA and Duval, N and Patterson, D and Linseman, DA}, title = {A Cystine-Rich Whey Supplement (Immunocal(®)) Delays Disease Onset and Prevents Spinal Cord Glutathione Depletion in the hSOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {3}, number = {4}, pages = {843-865}, pmid = {26785244}, issn = {2076-3921}, abstract = {Depletion of the endogenous antioxidant, glutathione (GSH), underlies progression of the devastating neurodegenerative disease, amyotrophic lateral sclerosis (ALS). Thus, strategies aimed at elevating GSH may yield new therapeutics for ALS. Here, we investigated the effects of a unique non-denatured whey protein supplement, Immunocal(®), in the transgenic Gly position 93 to Ala (G93A) mutant hSOD1 (hSOD1(G93A)) mouse model of ALS. Immunocal(®) is rich in the GSH precursor, cystine, and is therefore capable of bolstering GSH content. Transgenic hSOD1(G93A) mice receiving Immunocal(®) displayed a significant delay in disease onset compared to untreated hSOD1(G93A) controls. Additionally, Immunocal(®) treatment significantly decreased the rate of decline in grip strength and prevented disease-associated reductions in whole blood and spinal cord tissue GSH levels in end-stage hSOD1(G93A) mice. However, Immunocal(®) did not extend survival, likely due to its inability to preserve the mitochondrial GSH pool in spinal cord. Combination treatment with Immunocal(®) and the anti-glutamatergic compound, riluzole, delayed disease onset and extended survival in hSOD1(G93A) mice. These findings demonstrate that sustaining tissue GSH with Immunocal(®) only modestly delays disease onset and slows the loss of skeletal muscle strength in hSOD1(G93A) mice. Moreover, the inability of Immunocal(®) to rescue mitochondrial GSH in spinal cord provides a possible mechanism for its lack of effect on survival and is a limiting factor in the potential utility of this supplement as a therapeutic for ALS.}, }
@article {pmid26237595, year = {2014}, author = {Faravelli, I and Frattini, E and Ramirez, A and Stuppia, G and Nizzardo, M and Corti, S}, title = {iPSC-Based Models to Unravel Key Pathogenetic Processes Underlying Motor Neuron Disease Development.}, journal = {Journal of clinical medicine}, volume = {3}, number = {4}, pages = {1124-1145}, pmid = {26237595}, issn = {2077-0383}, abstract = {Motor neuron diseases (MNDs) are neuromuscular disorders affecting rather exclusively upper motor neurons (UMNs) and/or lower motor neurons (LMNs). The clinical phenotype is characterized by muscular weakness and atrophy leading to paralysis and almost invariably death due to respiratory failure. Adult MNDs include sporadic and familial amyotrophic lateral sclerosis (sALS-fALS), while the most common infantile MND is represented by spinal muscular atrophy (SMA). No effective treatment is ccurrently available for MNDs, as for the vast majority of neurodegenerative disorders, and cures are limited to supportive care and symptom relief. The lack of a deep understanding of MND pathogenesis accounts for the difficulties in finding a cure, together with the scarcity of reliable in vitro models. Recent progresses in stem cell field, in particular in the generation of induced Pluripotent Stem Cells (iPSCs) has made possible for the first time obtaining substantial amounts of human cells to recapitulate in vitro some of the key pathogenetic processes underlying MNDs. In the present review, recently published studies involving the use of iPSCs to unravel aspects of ALS and SMA pathogenesis are discussed with an overview of their implications in the process of finding a cure for these still orphan disorders.}, }
@article {pmid26084085, year = {2014}, author = {Claerhout, S and De Cauwer, B and Reheul, D}, title = {HERBICIDE SENSITIVITY OF ECHINOCHLOA CRUS-GALLI POPULATIONS: A COMPARISON BETWEEN CROPPING SYSTEMS.}, journal = {Communications in agricultural and applied biological sciences}, volume = {79}, number = {2}, pages = {81-88}, pmid = {26084085}, issn = {1379-1176}, mesh = {Agriculture/*methods ; Crops, Agricultural/*growth &amp; development ; Echinochloa/*drug effects/growth &amp; development ; Herbicides/*pharmacology ; Weed Control ; }, abstract = {Echinochloa crus-galli populations exhibit high morphological variability and their response to herbicides varies from field to field. Differential response to herbicides could reflect differences in selection pressure, caused by years of cropping system related herbicide usage. This study investigates the relation between herbicide sensitivity of Echinochloa crus-galli populations and the cropping system to which they were subjected. The herbicide sensitivity of Echinochloa crus-galli was evaluated for populations collected on 18 fields, representing three cropping systems, namely (1) a long-term organic cropping system, (2) a conventional cropping system with corn in crop rotation or (3) a conventional cropping system with long-term monoculture of corn. Each cropping system was represented by 6 E. crus-galli populations. All fields were located on sandy soils. Dose-response pot experiments were conducted in the greenhouse to assess the effectiveness of three foliar-applied corn herbicides: nicosulfuron (ALS-inhibitor), cycloxydim (ACCase-inhibitor) and topramezone (HPPD-inhibitor), and two soil-applied corn herbicides: S-metolachlor and dimethenamid-P (both VLCFA-inhibitors). Foliar-applied herbicides were tested at a quarter, half and full recommended doses. Soil-applied herbicides were tested within a dose range of 0-22.5 g a.i. ha(-1) for S-metolachlor and 0-45 g a.i. ha(-1) for dimethenamid-P. Foliar-applied herbicides were applied at the three true leaves stage. Soil-applied herbicides were treated immediately after sowing the radicle-emerged seeds. All experiments were performed twice. The foliage dry weight per pot was determined four weeks after treatment. Plant responses to herbicides were expressed as biomass reduction (%, relative to the untreated control). Sensitivity to foliar-applied herbicides varied among cropping systems. Compared to populations from monoculture corn fields, populations originating from organic fields were significantly more sensitive to cycloxydim, topramezone and nicosulfuron (resp. 5.3%, 5.9% and 12.3%). Populations from the conventional crop rotation system showed intermediate sensitivity levels. Contrary to foliar-applied herbicides, the effectiveness of soil-applied herbicides was not affected by cropping system. Integrated weed management may be necessary to preserve herbicide efficacy on the long term.}, }
@article {pmid24368417, year = {2014}, author = {Wang, L and Popko, B and Roos, RP}, title = {An enhanced integrated stress response ameliorates mutant SOD1-induced ALS.}, journal = {Human molecular genetics}, volume = {23}, number = {10}, pages = {2629-2638}, pmid = {24368417}, issn = {1460-2083}, support = {NS34939/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Biomarkers/metabolism ; Cells, Cultured ; Endoplasmic Reticulum Stress ; Eukaryotic Initiation Factor-2/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation, Missense ; Protein Phosphatase 1/genetics/metabolism ; Protein Processing, Post-Translational ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Varied stresses to cells can lead to a repression in translation by triggering phosphorylation of eukaryotic translation initiator factor 2α (eIF2α), which is central to a process known as the integrated stress response (ISR). PKR-like ER-localized eIF2 kinase (PERK), one of the kinases that phosphorylates eIF2α and coordinates the ISR, is activated by stress occurring from the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum (ER). Mutant Cu/Zn superoxide dismutase (mtSOD1) is thought to cause familial amyotrophic lateral sclerosis (FALS) because it misfolds and aggregates. Published studies have suggested that ER stress is involved in FALS pathogenesis since mtSOD1 accumulates inside the ER and activates PERK leading to phosphorylated eIF2α (p-eIF2α). We previously used a genetic approach to show that haploinsufficiency of PERK significantly accelerates disease onset and shortens survival of G85R mtSOD1 FALS transgenic mice. We now show that G85R mice that express reduced levels of active GADD34, which normally dephosphorylates p-eIF2α and allows recovery from the global suppression of protein synthesis, markedly ameliorates disease. These studies emphasize the importance of the ISR, and specifically the PERK pathway, in the pathogenesis of mtSOD1-induced FALS and as a target for treatment. Furthermore, the ISR may be an appropriate therapeutic target for sporadic ALS and other neurodegenerative diseases since misfolded proteins have been implicated in these disorders.}, }
@article {pmid24367722, year = {2013}, author = {Anand, A and Thakur, K and Gupta, PK}, title = {ALS and oxidative stress: the neurovascular scenario.}, journal = {Oxidative medicine and cellular longevity}, volume = {2013}, number = {}, pages = {635831}, pmid = {24367722}, issn = {1942-0994}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Blood-Brain Barrier/metabolism/pathology ; Humans ; Motor Neurons/metabolism/pathology ; Nervous System/*blood supply/*pathology ; *Oxidative Stress ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {Oxidative stress and angiogenic factors have been placed as the prime focus of scientific investigations after an establishment of link between vascular endothelial growth factor promoter (VEGF), hypoxia, and amyotrophic lateral sclerosis (ALS) pathogenesis. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter and mutant superoxide dismutase 1 (SOD1) which are characterised by atrophy and muscle weakness resulted in phenotype resembling human ALS in mice. This results in lower motor neurodegeneration thus establishing an important link between motor neuron degeneration, vasculature, and angiogenic molecules. In this review, we have presented human, animal, and in vitro studies which suggest that molecules like VEGF have a therapeutic, diagnostic, and prognostic potential in ALS. Involvement of vascular growth factors and hypoxia response elements also highlights the converging role of oxidative stress and neurovascular network for understanding and treatment of various neurodegenerative disorders like ALS.}, }
@article {pmid24363770, year = {2013}, author = {Pan, W and Chen, X and Bao, J and Bai, Y and Lu, H and Wang, Q and Liu, Y and Yuan, C and Li, W and Liu, Z and Liu, J and Zhu, X and Qin, B and Cai, D and Zhou, H}, title = {The use of integrative therapies in patients with amyotrophic lateral sclerosis in shanghai, china.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2013}, number = {}, pages = {613596}, pmid = {24363770}, issn = {1741-427X}, abstract = {Objective. To investigate the current use of integrative therapies (IT) in the treatment of patients with amyotrophic lateral sclerosis (ALS). Methods. A cross-sectional, multicenter clinical epidemiological survey was conducted in 12 hospitals in Shanghai. We investigated the type and frequency of IT use and determined whether the use of IT correlated with demographic, social, or disease-specific characteristics in our patient population. Results. A total of 231 (89.5%) of 258 patients with ALS were eligible for the study and 229 (99% of all) of 231 reported the use of at least one IT for the treatment of ALS. Vitamins and Chinese herb decoctions, Chinese herb compounds, massage therapy, and acupuncture were the 5 most commonly used therapies. There was a strong association between education level, income, and use of IT. A household income of more than 75,000 RMB ($49,995) correlated with multiple IT use, and married patients used IT more often than single individuals. The main reasons for using IT were to treat weakness and fatigue, muscle atrophy, the development of ALS, depression, insomnia, limb pain or numbness, and side effects associated with Riluzole. Conclusion. The use of IT is common in patients with ALS in Shanghai. Vitamins and TCM are the most used additional therapies and the widespread and largely unexamined use of IT for ALS requires more attention.}, }
@article {pmid24356417, year = {2014}, author = {Yáñez, M and Matías-Guiu, J and Arranz-Tagarro, JA and Galán, L and Viña, D and Gómez-Pinedo, U and Vela, A and Guerrero, A and Martínez-Vila, E and García, AG}, title = {The neuroprotection exerted by memantine, minocycline and lithium, against neurotoxicity of CSF from patients with amyotrophic lateral sclerosis, is antagonized by riluzole.}, journal = {Neuro-degenerative diseases}, volume = {13}, number = {2-3}, pages = {171-179}, doi = {10.1159/000357281}, pmid = {24356417}, issn = {1660-2862}, mesh = {Amyotrophic Lateral Sclerosis/*cerebrospinal fluid ; Animals ; Cell Survival/drug effects ; Excitatory Amino Acid Antagonists/toxicity ; Humans ; Lithium/pharmacology ; Memantine/pharmacology ; Minocycline/pharmacology ; Neurons/*drug effects ; Neuroprotective Agents/*pharmacology ; Rats ; Riluzole/*toxicity ; }, abstract = {In a recent study we found that cerebrospinal fluids (CSFs) from amyotrophic lateral sclerosis (ALS) patients caused 20-30% loss of cell viability in primary cultures of rat embryo motor cortex neurons. We also found that the antioxidant resveratrol protected against such damaging effects and that, surprisingly, riluzole antagonized its protecting effects. Here we have extended this study to the interactions of riluzole with 3 other recognized neuroprotective agents, namely memantine, minocycline and lithium. We found: (1) by itself riluzole exerted neurotoxic effects at concentrations of 3-30 µM; this cell damage was similar to that elicited by 30 µM glutamate and a 10% dilution of ALS/CSF; (2) memantine (0.1-30 µM), minocycline (0.03-1 µM) and lithium (1-80 µg/ml) afforded 10-30% protection against ALS/CSF-elicited neurotoxicity, and (3) at 1-10 µM, riluzole antagonized the protection afforded by the 3 agents. These results strongly support the view that at the riluzole concentrations reached in the brain of patients, the neurotoxic effects of this drug could be masking the potential neuroprotective actions of new compounds being tested in clinical trials. Therefore, in the light of the present results, the inclusion of a group of patients free of riluzole treatment may be mandatory in future clinical trials performed in ALS patients with novel neuroprotective compounds.}, }
@article {pmid24355453, year = {2013}, author = {Elkjær, MC and Borre, M}, title = {Only carefully selected patients may have a beneficial effect of salvage cryoablation in recurrent prostate cancer after radiotherapy.}, journal = {Danish medical journal}, volume = {60}, number = {12}, pages = {A4756}, pmid = {24355453}, issn = {2245-1919}, mesh = {Aged ; *Cryosurgery/adverse effects ; Denmark ; Disease-Free Survival ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Neoplasm Recurrence, Local/blood/classification/*surgery ; *Patient Selection ; Prostate-Specific Antigen/blood ; Prostatic Neoplasms/blood/radiotherapy/*surgery ; Rectal Fistula/*etiology ; Retrospective Studies ; Risk Assessment ; *Salvage Therapy/adverse effects ; Urethral Diseases/*etiology ; Urinary Fistula/*etiology ; Urinary Incontinence/etiology ; Urinary Retention/etiology ; }, abstract = {INTRODUCTION: In Denmark, salvage cryoablation of locally recurrent prostate cancer (sCAP) after curatively intended radiation therapy (RT) is the only potentially curable option, and this experimental treatment has only been offered at Aarhus University Hospital. This study presents our experiences with the treatment.<br><br>MATERIAL AND METHODS: sCAP procedures were performed from 2006 to 2012. Cases were registered prospectively. Recurrent disease was defined by the Phoenix criterion (prostate-specific antigen (PSA) level > PSA nadir + 2 ng/ml).<br><br>RESULTS: A total of 39 sCAP treatments were performed in 37 patients. Four patients had previously been treated with brachytherapy and 33 with external radiation. There were two cases of hemiablations; the remaining cases were total ablations. The median follow-up period was 42 (0-69) months and the age at the time of treatment was 66 (53-78) years. Stratified according to D'Amico et al's 2003 risk definition, five patients had pre-RT intermediate-risk disease, and 31 had high-risk disease. Three cases could not be classified. Biochemical recurrence was found in 27 cases, and the 12-month disease-free survival was 18.2% overall. No patient in the intermediate group had recurrence. In high-risk patients, there were 25 cases of recurrence and the 12-month disease-free survival was 10.7%. There were five (13%) cases of fistula formation and seven (19%) cases of severe post-operative incontinence, all in previous high-risk patients. Information on potency was deficient.<br><br>CONCLUSION: In this limited study, sCAP was very infrequently a curable treatment in high-risk patients, and the treatment carried a high risk of severe morbidity. It seems, however, that sCAP could be beneficial to patients, primarily in the intermediate-risk group.<br><br>FUNDING: The Central Denmark Region's Health Research Foundation and the Danish Cancer Society financed the salary of the primary investigator.<br><br>TRIAL REGISTRATION: not relevant.}, }
@article {pmid24349764, year = {2013}, author = {Fernandes, SA and Douglas, AG and Varela, MA and Wood, MJ and Aoki, Y}, title = {Oligonucleotide-Based Therapy for FTD/ALS Caused by the C9orf72 Repeat Expansion: A Perspective.}, journal = {Journal of nucleic acids}, volume = {2013}, number = {}, pages = {208245}, pmid = {24349764}, issn = {2090-0201}, support = {G0900887/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and lethal disease of motor neuron degeneration, leading to paralysis of voluntary muscles and death by respiratory failure within five years of onset. Frontotemporal dementia (FTD) is characterised by degeneration of frontal and temporal lobes, leading to changes in personality, behaviour, and language, culminating in death within 5-10 years. Both of these diseases form a clinical, pathological, and genetic continuum of diseases, and this link has become clearer recently with the discovery of a hexanucleotide repeat expansion in the C9orf72 gene that causes the FTD/ALS spectrum, that is, c9FTD/ALS. Two basic mechanisms have been proposed as being potentially responsible for c9FTD/ALS: loss-of-function of the protein encoded by this gene (associated with aberrant DNA methylation) and gain of function through the formation of RNA foci or protein aggregates. These diseases currently lack any cure or effective treatment. Antisense oligonucleotides (ASOs) are modified nucleic acids that are able to silence targeted mRNAs or perform splice modulation, and the fact that they have proved efficient in repeat expansion diseases including myotonic dystrophy type 1 makes them ideal candidates for c9FTD/ALS therapy. Here, we discuss potential mechanisms and challenges for developing oligonucleotide-based therapy for c9FTD/ALS.}, }
@article {pmid24349357, year = {2013}, author = {Thielsen, KD and Moser, JM and Schmitt-John, T and Jensen, MS and Jensen, K and Holm, MM}, title = {The Wobbler mouse model of amyotrophic lateral sclerosis (ALS) displays hippocampal hyperexcitability, and reduced number of interneurons, but no presynaptic vesicle release impairments.}, journal = {PloS one}, volume = {8}, number = {12}, pages = {e82767}, pmid = {24349357}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*physiopathology ; Animals ; Disease Models, Animal ; Hippocampus/*pathology/*physiopathology ; Interneurons/*pathology ; Mice ; Presynaptic Terminals/*metabolism ; Pyramidal Cells/metabolism/physiopathology ; Synaptic Potentials ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. It is a fatal degenerative disease, best recognized for its debilitating neuromuscular effects. ALS however also induces cognitive impairments in as many as 50% of affected individuals. Moreover, many ALS patients demonstrate cortical hyperexcitability, which has been shown to precede the onset of clinical symptoms. The wobbler mouse is a model of ALS, and like ALS patients the wobbler mouse displays cortical hyperexcitability. Here we investigated if the neocortical aberrations of the wobbler mouse also occur in the hippocampus. Consequently, we performed extracellular field excitatory postsynaptic potential recordings in the CA1 region of the hippocampus on acute brain slices from symptomatic (P45-P60) and presymptomatic (P17-P21) wobbler mice. Significant increased excitation of hippocampal synapses was revealed by leftward shifted input/output-curves in both symptomatic and presymptomatic wobbler mice, and substantiated by population spike occurrence analyses, demonstrating that the increased synaptic excitation precedes the onset of visible phenotypic symptoms in the mouse. Synaptic facilitation tested by paired-pulse facilitation and trains in wobbler and control mice showed no differences, suggesting the absence of presynaptic defects. Immunohistochemical staining revealed that symptomatic wobbler mice have a lower number of parvalbumin positive interneurons when compared to controls and presymptomatic mice. This study reveals that the wobbler mouse model of ALS exhibits hippocampal hyperexcitability. We suggest that the hyperexcitability could be caused by increased excitatory synaptic transmission and a concomitant reduced inhibition due to a decreased number of parvalbumin positive interneurons. Thus we substantiate that wobbler brain impairments are not confined to the motor cortex, but extend to the hippocampus. Importantly, we have revealed more details of the early pathophysiology in asymptomatic animals, and studies like the present may facilitate the development of novel treatment strategies for earlier intervention in ALS patients in the future.}, }
@article {pmid24348042, year = {2013}, author = {Ahmed, A and Simmons, Z}, title = {Pseudobulbar affect: prevalence and management.}, journal = {Therapeutics and clinical risk management}, volume = {9}, number = {}, pages = {483-489}, pmid = {24348042}, issn = {1176-6336}, abstract = {Pseudobulbar affect (PBA) may occur in association with a variety of neurological diseases, and so may be encountered in the setting of amyotrophic lateral sclerosis, extrapyramidal and cerebellar disorders, multiple sclerosis, traumatic brain injury, Alzheimer's disease, stroke, and brain tumors. The psychological consequences and the impact on social interactions may be substantial. Although it is most commonly misidentified as a mood disorder, particularly depression or a bipolar disorder, there are characteristic features that can be recognized clinically or assessed by validated scales, resulting in accurate identification of PBA, and thus permitting proper management and treatment. Mechanistically, PBA is a disinhibition syndrome in which pathways involving serotonin and glutamate are disrupted. This knowledge has permitted effective treatment for many years with antidepressants, particularly tricyclic antidepressants and selective serotonin reuptake inhibitors. A recent therapeutic breakthrough occurred with the approval by the Food and Drug Administration of a dextromethorphan/quinidine combination as being safe and effective for treatment of PBA. Side effect profiles and contraindications differ for the various treatment options, and the clinician must be familiar with these when choosing the best therapy for an individual, particularly elderly patients and those with multiple comorbidities and concomitant medications.}, }
@article {pmid24338148, year = {2013}, author = {Mehrpour, M and Mohebi, N and Motamed, MR and Zamani, F}, title = {Amyotrophic lateral sclerosis as a paraneoplastic manifestation in the neuroendocrine tumor of stomach: a case report.}, journal = {Acta medica Iranica}, volume = {51}, number = {10}, pages = {724-726}, pmid = {24338148}, issn = {1735-9694}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Female ; Humans ; Neuroendocrine Tumors/*complications ; Stomach Neoplasms/*complications ; }, abstract = {Motor neuron diseases have been reported as a rare paraneoplastic syndrome (PNS) of a systemic neoplasm. We present a patient with amyotrophic lateral sclerosis (ALS) in association with neuroendocrine tumor (NET) of stomach, which is the first case of motor neuronopathy with underlying neuroendocrine tumor. A 79-year old woman presented with a two months history of progressive dysphagia, spastic dysarthria and marked fasciculation in her atrophic tongue. Gag reflexes were diminished bilaterally. Other cranial nerves were intact. In muscle testing there was significant atrophy in thenar and hypothenar areas of both hands compatible with diffuse motor neuronopathy with active denervation. Upper GI endoscopic study showed patchy erythematous mucosa with congestion in body of stomach, Histological biopsy of stomach confirmed the neuroendocrine tumor (NET). The importance of considering a paraneoplastic syndrome in a patient with presentation of ALS, which can leads to searching for underlying neoplasm before its apparent signs and symptoms, to initiate tumor treatment so much sooner. In addition even though paraneoplastic motor neuron disease is rare, treating the underlying neoplasm may resolve neurologic signs and symptoms.}, }
@article {pmid24336168, year = {2014}, author = {Kim, HJ and Raphael, AR and LaDow, ES and McGurk, L and Weber, RA and Trojanowski, JQ and Lee, VM and Finkbeiner, S and Gitler, AD and Bonini, NM}, title = {Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models.}, journal = {Nature genetics}, volume = {46}, number = {2}, pages = {152-160}, pmid = {24336168}, issn = {1546-1718}, support = {AG10124/AG/NIA NIH HHS/United States ; P01 AG017586/AG/NIA NIH HHS/United States ; R01 NS039074/NS/NINDS NIH HHS/United States ; P50 NS053488/NS/NINDS NIH HHS/United States ; AG17586/AG/NIA NIH HHS/United States ; NS53488/NS/NINDS NIH HHS/United States ; DP2OD004417/OD/NIH HHS/United States ; R01 NS073660/NS/NINDS NIH HHS/United States ; R01NS073660/NS/NINDS NIH HHS/United States ; P01 AG032953/AG/NIA NIH HHS/United States ; DP2 OD004417/OD/NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; AG32953/AG/NIA NIH HHS/United States ; R01NS065317/NS/NINDS NIH HHS/United States ; R01 NS065317/NS/NINDS NIH HHS/United States ; }, mesh = {Adenine/*analogs &amp; derivatives/pharmacology ; Amyotrophic Lateral Sclerosis/*genetics ; Analysis of Variance ; Animals ; Ataxins ; DNA-Binding Proteins/genetics/*metabolism ; Drosophila melanogaster ; Eukaryotic Initiation Factor-2/*metabolism ; Gene Ontology ; High-Throughput Screening Assays ; Humans ; Immunoblotting ; Immunohistochemistry ; Indoles/*pharmacology ; Luminescent Proteins ; Motor Neurons/metabolism ; Nerve Tissue Proteins/metabolism ; Phosphorylation/drug effects ; Poly(A)-Binding Proteins/metabolism ; RNA Interference ; Retina/metabolism/ultrastructure ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/metabolism ; Small Molecule Libraries ; Spinal Cord/cytology/metabolism ; Red Fluorescent Protein ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, late-onset neurodegenerative disease primarily affecting motor neurons. A unifying feature of many proteins associated with ALS, including TDP-43 and ataxin-2, is that they localize to stress granules. Unexpectedly, we found that genes that modulate stress granules are strong modifiers of TDP-43 toxicity in Saccharomyces cerevisiae and Drosophila melanogaster. eIF2α phosphorylation is upregulated by TDP-43 toxicity in flies, and TDP-43 interacts with a central stress granule component, polyA-binding protein (PABP). In human ALS spinal cord neurons, PABP accumulates abnormally, suggesting that prolonged stress granule dysfunction may contribute to pathogenesis. We investigated the efficacy of a small molecule inhibitor of eIF2α phosphorylation in ALS models. Treatment with this inhibitor mitigated TDP-43 toxicity in flies and mammalian neurons. These findings indicate that the dysfunction induced by prolonged stress granule formation might contribute directly to ALS and that compounds that mitigate this process may represent a novel therapeutic approach.}, }
@article {pmid24323921, year = {2014}, author = {McCartney, AJ and Zhang, Y and Weisman, LS}, title = {Phosphatidylinositol 3,5-bisphosphate: low abundance, high significance.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {36}, number = {1}, pages = {52-64}, pmid = {24323921}, issn = {1521-1878}, support = {F31NS074740/NS/NINDS NIH HHS/United States ; R01 NS064015/NS/NINDS NIH HHS/United States ; F31 NS074740/NS/NINDS NIH HHS/United States ; R01 GM050403/GM/NIGMS NIH HHS/United States ; R01-GM50403/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mutation/genetics ; Neurodegenerative Diseases/genetics/metabolism ; Phosphatidylinositol Phosphates/*genetics/*metabolism ; Signal Transduction/*genetics ; }, abstract = {Recent studies of the low abundant signaling lipid, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), reveal an intriguingly diverse list of downstream pathways, the intertwined relationship between PI(3,5)P2 and PI5P, as well as links to neurodegenerative diseases. Derived from the structural lipid phosphatidylinositol, PI(3,5)P2 is dynamically generated on multiple cellular compartments where interactions with an increasing list of effectors regulate many cellular pathways. A complex of proteins that includes Fab1/PIKfyve, Vac14, and Fig4/Sac3 mediates the biosynthesis of PI(3,5)P2 , and mutations that disrupt complex function and/or formation cause profound consequences in cells. Surprisingly, mutations in this pathway are linked with neurological diseases, including Charcot-Marie-Tooth syndrome and amyotrophic lateral sclerosis. Future studies of PI(3,5)P2 and PI5P are likely to expand the roles of these lipids in regulation of cellular functions, as well as provide new approaches for treatment of some neurological diseases.}, }
@article {pmid24323712, year = {2014}, author = {Wu, LJ}, title = {Microglial voltage-gated proton channel Hv1 in ischemic stroke.}, journal = {Translational stroke research}, volume = {5}, number = {1}, pages = {99-108}, pmid = {24323712}, issn = {1868-601X}, mesh = {Animals ; Brain Ischemia/*metabolism ; Disease Models, Animal ; Humans ; Hydrogen-Ion Concentration ; Ion Channels/*metabolism ; Mice ; Microglia/*metabolism ; Reactive Oxygen Species/metabolism ; Stroke/*metabolism ; }, abstract = {Microglia, resident immune cells in the brain, contribute both to the damage and resolution of ischemic stroke. However, the mechanisms of microglia's detrimental or beneficial role in the disease are poorly understood. The voltage-gated proton channel, Hv1, rapidly removes protons from depolarized cytoplasm, and is highly expressed in the immune system. In the brain, Hv1 is selectively and functionally expressed in microglia but not neurons. Although the physiological function of microglial Hv1 is still not clear, Hv1 is one of major ion channels expressed in resting microglia. Under pathological conditions, microglial Hv1 is required for NADPH oxidase (NOX)-dependent generation of reactive oxygen species (ROS) by providing charge compensation for exported electrons and relieving intracellular acidosis. In a mouse model of cerebral middle artery occlusion, Hv1 knockout mice are protected from ischemic damage, showing reduced NOX-dependent ROS production, microglial activation and neuronal cell death. Therefore, microglial Hv1 aids in NOX-dependent ROS generation, which subsequently induces neuronal cell death and a significant fraction of brain damage after ischemic stroke. These studies illuminate a critical role of microglial Hv1 in ischemic brain injury, providing a rationale for Hv1 as a potential therapeutic target for the treatment of ischemic stroke. The current understanding of Hv1 in ischemic injury through NOX-dependent ROS production may serve as a common model to reveal the deleterious role of microglia in neurological diseases other than ischemic stroke, such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, and neuropathic pain.}, }
@article {pmid24323427, year = {2014}, author = {Pal, R and Alves, G and Larsen, JP and Møller, SG}, title = {New insight into neurodegeneration: the role of proteomics.}, journal = {Molecular neurobiology}, volume = {49}, number = {3}, pages = {1181-1199}, pmid = {24323427}, issn = {1559-1182}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*diagnosis/*genetics/metabolism ; Proteomics/methods/*trends ; }, abstract = {Recent advances within the field of proteomics, including both upstream and downstream protocols, have fuelled a transition from simple protein identification to functional analysis. A battery of proteomics approaches is now being employed for the analysis of protein expression levels, the monitoring of cellular activities and for gaining an increased understanding into biochemical pathways. Combined, these approaches are changing the way we study disease by allowing accurate and targeted, large scale protein analysis, which will provide invaluable insight into disease pathogenesis. Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), prion disease, and other diseases that affect the neuromuscular system, are a leading cause of disability in the aging population. There are no effective intervention strategies for these disorders and diagnosis is challenging as it relies primarily on clinical symptomatic features, which often overlap at early stages of disease. There is, therefore, an urgent need to develop reliable biomarkers to improve early and specific diagnosis, to track disease progression, to measure molecular responses towards treatment regimes and ultimately devise new therapeutic strategies. To accomplish this, a better understanding of disease mechanisms is needed. In this review we summarize recent advances in the field of proteomics applicable to neurodegenerative disorders, and how these advances are fueling our understanding, diagnosis, and treatment of these complex disorders.}, }
@article {pmid24312501, year = {2013}, author = {Liu, D and Liu, C and Li, J and Azadzoi, K and Yang, Y and Fei, Z and Dou, K and Kowall, NW and Choi, HP and Vieira, F and Yang, JH}, title = {Proteomic analysis reveals differentially regulated protein acetylation in human amyotrophic lateral sclerosis spinal cord.}, journal = {PloS one}, volume = {8}, number = {12}, pages = {e80779}, pmid = {24312501}, issn = {1932-6203}, support = {AG013846/AG/NIA NIH HHS/United States ; K02-AI-060701/AI/NIAID NIH HHS/United States ; I01 BX001428/BX/BLRD VA/United States ; K02 AI060701/AI/NIAID NIH HHS/United States ; P30 AG013846/AG/NIA NIH HHS/United States ; }, mesh = {Acetylation ; Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Female ; Humans ; Male ; Nerve Tissue Proteins/*metabolism ; *Proteomics ; Spinal Cord/*metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease that primarily affects motor neurons in the brain and spinal cord. Histone deacetylase (HDAC) inhibitors have neuroprotective effects potentially useful for the treatment of neurodegenerative diseases including ALS; however, the molecular mechanisms underlying their potential efficacy is not well understood. Here we report that protein acetylation in urea-soluble proteins is differently regulated in post-mortem ALS spinal cord. Two-dimensional electrophoresis (2-DE) analysis reveals several protein clusters with similar molecular weight but different charge status. Liquid chromatography and tandem mass spectrometry (LC-MS/MS) identifies glial fibrillary acidic protein (GFAP) as the dominant component in the protein clusters. Further analysis indicates six heavily acetylated lysine residues at positions 89, 153, 189, 218, 259 and 331 of GFAP. Immunoprecipitation followed by Western blotting confirms that the larger form of GFAP fragments are acetylated and upregulated in ALS spinal cord. Further studies demonstrate that acetylation of the proteins additional to GFAP is differently regulated, suggesting that acetylation and/or deacetylation play an important role in pathogenesis of ALS.}, }
@article {pmid24312274, year = {2013}, author = {Walker, AK and Soo, KY and Sundaramoorthy, V and Parakh, S and Ma, Y and Farg, MA and Wallace, RH and Crouch, PJ and Turner, BJ and Horne, MK and Atkin, JD}, title = {ALS-associated TDP-43 induces endoplasmic reticulum stress, which drives cytoplasmic TDP-43 accumulation and stress granule formation.}, journal = {PloS one}, volume = {8}, number = {11}, pages = {e81170}, pmid = {24312274}, issn = {1932-6203}, support = {//Medical Research Council/United Kingdom ; }, mesh = {Active Transport, Cell Nucleus/drug effects ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/*pathology ; Animals ; Cell Line ; Cell Nucleus/drug effects/metabolism ; Cinnamates/pharmacology ; Cytoplasm/drug effects/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; *Endoplasmic Reticulum Stress/drug effects ; Golgi Apparatus/drug effects/metabolism ; Humans ; Mice ; Mutation ; Protein Disulfide-Isomerases/metabolism ; Spinal Cord/metabolism ; Thiourea/analogs &amp; derivatives/pharmacology ; }, abstract = {In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, TAR DNA binding protein 43 (TDP-43) accumulates in the cytoplasm of affected neurons and glia, where it associates with stress granules (SGs) and forms large inclusions. SGs form in response to cellular stress, including endoplasmic reticulum (ER) stress, which is induced in both familial and sporadic forms of ALS. Here we demonstrate that pharmacological induction of ER stress causes TDP-43 to accumulate in the cytoplasm, where TDP-43 also associates with SGs. Furthermore, treatment with salubrinal, an inhibitor of dephosphorylation of eukaryotic initiation factor 2-α, a key modulator of ER stress, potentiates ER stress-mediated SG formation. Inclusions of C-terminal fragment TDP-43, reminiscent of disease-pathology, form in close association with ER and Golgi compartments, further indicating the involvement of ER dysfunction in TDP-43-associated disease. Consistent with this notion, over-expression of ALS-linked mutant TDP-43, and to a lesser extent wildtype TDP-43, triggers several ER stress pathways in neuroblastoma cells. Similarly, we found an interaction between the ER chaperone protein disulphide isomerase and TDP-43 in transfected cell lysates and in the spinal cords of mutant A315T TDP-43 transgenic mice. This study provides evidence for ER stress as a pathogenic pathway in TDP-43-mediated disease.}, }
@article {pmid24311453, year = {2014}, author = {Tönges, L and Günther, R and Suhr, M and Jansen, J and Balck, A and Saal, KA and Barski, E and Nientied, T and Götz, AA and Koch, JC and Mueller, BK and Weishaupt, JH and Sereda, MW and Hanisch, UK and Bähr, M and Lingor, P}, title = {Rho kinase inhibition modulates microglia activation and improves survival in a model of amyotrophic lateral sclerosis.}, journal = {Glia}, volume = {62}, number = {2}, pages = {217-232}, doi = {10.1002/glia.22601}, pmid = {24311453}, issn = {1098-1136}, mesh = {1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/*analogs &amp; derivatives/pharmacology ; Amyotrophic Lateral Sclerosis/*enzymology/genetics/pathology ; Animals ; Astrocytes/cytology/drug effects ; Axons/drug effects/pathology ; Cell Survival/drug effects ; Cells, Cultured ; Disease Models, Animal ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/*drug effects/pathology ; Protein Kinase Inhibitors/*pharmacology ; Spinal Cord/drug effects ; rho-Associated Kinases/*antagonists &amp; inhibitors ; }, abstract = {Disease progression in amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motoneurons (MN) and their axons, but is also influenced by neighboring cells such as astrocytes and microglial cells. The role of microglia in ALS is complex as it switches from an anti-inflammatory and neuroprotective phenotype in early disease to a proinflammatory and neurotoxic phenotype in later stages. Our previous studies in models of neurodegeneration identified rho kinase (ROCK) as a target, which can be manipulated to beneficially influence disease progression. Here, we examined the neuroprotective potential of the ROCK inhibitor Fasudil to target the central pathogenic features of ALS. Application of Fasudil to kainic acid-lesioned primary MN in vitro resulted in a strong prosurvival effect. In vivo, SOD1(G93A) mice benefited from oral treatment with Fasudil showing prolonged survival and improved motor function. These findings were correlated to an improved survival of motor neurons and a pronounced alteration of astroglial and microglial cell infiltration of the spinal cord under Fasudil treatment. Modeling a proinflammatory microglial phenotype by stimulation with LPS in vitro, Fasudil decreased the release of proinflammatory cytokines and chemokines TNFα, Il6, CCL2, CCL3, and CCL5 while CXCL1 release was only transiently suppressed. In sciatic nerve motor axons, neuromuscular junction remodeling processes were increased. In conclusion, we provide preclinical and neurobiological evidence that inhibition of ROCK by the clinically approved small molecule inhibitor Fasudil may be a novel therapeutic approach in ALS combining both neuroprotection and immunomodulation for the cure of this devastating disease.}, }
@article {pmid24307082, year = {2014}, author = {Liu, M and Hulting, AG and Mallory-Smith, CA}, title = {Characterization of multiple-herbicide-resistant Italian ryegrass (Lolium perenne spp. multiflorum).}, journal = {Pest management science}, volume = {70}, number = {7}, pages = {1145-1150}, doi = {10.1002/ps.3665}, pmid = {24307082}, issn = {1526-4998}, mesh = {3-Phosphoshikimate 1-Carboxyvinyltransferase/genetics/metabolism ; Acetolactate Synthase/genetics/metabolism ; Gene Expression Regulation ; *Herbicide Resistance ; Herbicides/*pharmacology ; Lolium/*drug effects/enzymology/*genetics ; Molecular Sequence Data ; Mutation ; Oregon ; Photosystem II Protein Complex/genetics/metabolism ; Plant Proteins/genetics/metabolism ; Sequence Analysis, DNA ; Weed Control ; }, abstract = {BACKGROUND: Multiple-herbicide resistance in Lolium perenne spp. multiflorum has evolved in many areas in Oregon. To manage the resistant populations, the resistance patterns must be determined. In this study, a population (CT) suspected to be resistant to sulfometuron and hexazinone was collected from a Christmas tree plantation.<br><br>RESULTS: The CT population is resistant to at least six herbicides with four different mechanisms of action: atrazine (>16-fold), diuron (2.4-fold), glyphosate (7.4-fold), hexazinone (3.1-fold), imazapyr (1.8-fold) and sulfometuron (>16-fold). Two mutations, Trp-591-Leu and Ser-264-Gly, were identified in the acetolactate synthase (ALS) and psbA gene respectively. No previously reported mutation in the 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene was found. Less shikimic acid accumulated in the CT plants than in the susceptible plants after treatment with glyphosate at 0.6 kg AE ha(-1) .<br><br>CONCLUSION: This study suggests that the multiple resistance patterns of Lolium perenne spp. multiflorum populations can be complex, but that chemical control options to manage these populations exist. These remaining chemical options should be integrated with non-chemical management strategies to slow the spread of multiple-resistant biotypes in agroecosystems.}, }
@article {pmid24303739, year = {2013}, author = {Yavnai, N and Aizenbud, D}, title = {[Orthodontic silicone positioner for the treatment of oral symptoms in Amyotrophic Lateral Sclerosis (ALS) patients].}, journal = {Refu'at ha-peh veha-shinayim (1993)}, volume = {30}, number = {3}, pages = {22-9, 61}, pmid = {24303739}, issn = {0792-9935}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Deglutition Disorders/etiology/therapy ; Humans ; Orthodontic Appliance Design ; *Orthodontic Appliances, Removable ; Quality of Life ; Sialorrhea/etiology/prevention &amp; control ; Silicones/*chemistry ; }, abstract = {ALS is considered a neurodegenerative disorder caused by progressive death of specific neuronal populations within the gray matter of the central nervous system. The cause of cell death is unknown and patients with ALS will live 3 to 5 years from disease onset. A common cause of death is neuromuscular respiratory failure or cardiac arrhythmias due to insufficient oxygen. The patients develop multiple symptoms and the focus of management is to maintain their quality of life. Orofacial manifestations in ALS are secondary to motor deficits, resulting in dysphagia, muscle spasticity, rigidity and tremor of the orofacial musculature, which can induce soft tissue trauma and sialorrhea. In this report the management of ALS oral symptoms, by means of an elastic silicone full coverage occlusal splint, often used as an orthodontic positioner, is discussed, as well as its advantages and alternatives. The positioner was easily tolerated by the patients who reported improvement in soft tissue trauma lesions due to accidental self biting, and improved control of the drooling due to excessive saliva and difficulty in swallowing.}, }
@article {pmid24303073, year = {2013}, author = {Kim, SM and Kim, H and Lee, JS and Park, KS and Jeon, GS and Shon, J and Ahn, SW and Kim, SH and Lee, KM and Sung, JJ and Lee, KW}, title = {Intermittent hypoxia can aggravate motor neuronal loss and cognitive dysfunction in ALS mice.}, journal = {PloS one}, volume = {8}, number = {11}, pages = {e81808}, pmid = {24303073}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology/physiopathology ; Animals ; Disease Models, Animal ; Female ; Hypoxia/*metabolism ; Inflammation/metabolism/pathology ; Male ; Mice ; Motor Neurons/*metabolism/*pathology ; Muscle Strength ; Oxidative Stress ; Psychomotor Performance ; Rotarod Performance Test ; Signal Transduction ; }, abstract = {BACKGROUND: Patients with ALS may be exposed to variable degrees of chronic intermittent hypoxia. However, all previous experimental studies on the effects of hypoxia in ALS have only used a sustained hypoxia model and it is possible that chronic intermittent hypoxia exerts effects via a different molecular mechanism from that of sustained hypoxia. No study has yet shown that hypoxia (either chronic intermittent or sustained) can affect the loss of motor neurons or cognitive function in an in vivo model of ALS.<br><br>OBJECTIVE: To evaluate the effects of chronic intermittent hypoxia on motor and cognitive function in ALS mice.<br><br>METHODS: Sixteen ALS mice and 16 wild-type mice were divided into 2 groups and subjected to either chronic intermittent hypoxia or normoxia for 2 weeks. The effects of chronic intermittent hypoxia on ALS mice were evaluated using the rotarod, Y-maze, and wire-hanging tests. In addition, numbers of motor neurons in the ventral horn of the spinal cord were counted and western blot analyses were performed for markers of oxidative stress and inflammatory pathway activation.<br><br>RESULTS: Compared to ALS mice kept in normoxic conditions, ALS mice that experienced chronic intermittent hypoxia had poorer motor learning on the rotarod test, poorer spatial memory on the Y-maze test, shorter wire hanging time, and fewer motor neurons in the ventral spinal cord. Compared to ALS-normoxic and wild-type mice, ALS mice that experienced chronic intermittent hypoxia had higher levels of oxidative stress and inflammation.<br><br>CONCLUSIONS: Chronic intermittent hypoxia can aggravate motor neuronal death, neuromuscular weakness, and probably cognitive dysfunction in ALS mice. The generation of oxidative stress with activation of inflammatory pathways may be associated with this mechanism. Our study will provide insight into the association of hypoxia with disease progression, and in turn, the rationale for an early non-invasive ventilation treatment in patients with ALS.}, }
@article {pmid24301650, year = {2013}, author = {Bharadwaj, PR and Bates, KA and Porter, T and Teimouri, E and Perry, G and Steele, JW and Gandy, S and Groth, D and Martins, RN and Verdile, G}, title = {Latrepirdine: molecular mechanisms underlying potential therapeutic roles in Alzheimer's and other neurodegenerative diseases.}, journal = {Translational psychiatry}, volume = {3}, number = {12}, pages = {e332}, pmid = {24301650}, issn = {2158-3188}, support = {G12 MD007591/MD/NIMHD NIH HHS/United States ; }, mesh = {Alzheimer Disease/*drug therapy ; Animals ; Cognition/drug effects ; Humans ; Huntington Disease/*drug therapy ; Indoles/pharmacology/*therapeutic use ; Neurodegenerative Diseases/drug therapy ; Neuroprotective Agents/pharmacology/*therapeutic use ; Nootropic Agents/pharmacology/*therapeutic use ; }, abstract = {Latrepirdine (Dimebon(TM)) was originally marketed as a non-selective antihistamine in Russia. It was repurposed as an effective treatment for patients suffering from Alzheimer's disease (AD) and Huntington's disease (HD) following preliminary reports showing its neuroprotective functions and ability to enhance cognition in AD and HD models. However, latrepirdine failed to show efficacy in phase III trials in AD and HD patients following encouraging phase II trials. The failure of latrepirdine in the clinical trials has highlighted the importance of understanding the precise mechanism underlying its cognitive benefits in neurodegenerative diseases before clinical evaluation. Latrepirdine has shown to affect a number of cellular functions including multireceptor activity, mitochondrial function, calcium influx and intracellular catabolic pathways; however, it is unclear how these properties contribute to its clinical benefits. Here, we review the studies investigating latrepirdine in cellular and animal models to provide a complete evaluation of its mechanisms of action in the central nervous system. In addition, we review recent studies that demonstrate neuroprotective functions for latrepirdine-related class of molecules including the β-carbolines and aminopropyl carbazoles in AD, Parkinson's disease and amyotrophic lateral sclerosis models. Assessment of their neuroprotective effects and underlying biological functions presents obvious value for developing structural analogues of latrepirdine for dementia treatment.}, }
@article {pmid24296360, year = {2014}, author = {Diard-Detoeuf, C and Dangoumau, A and Limousin, N and Biberon, J and Vourc'h, P and Andres, CR and de Toffol, B and Praline, J}, title = {Association of a paraneoplastic motor neuron disease with anti-Ri antibodies and a novel SOD1 I18del mutation.}, journal = {Journal of the neurological sciences}, volume = {337}, number = {1-2}, pages = {212-214}, doi = {10.1016/j.jns.2013.11.025}, pmid = {24296360}, issn = {1878-5883}, mesh = {Aged, 80 and over ; Animals ; Antibodies/blood ; Antigens, Neoplasm/*immunology ; Female ; Humans ; Models, Molecular ; Motor Neuron Disease/complications/*genetics ; Nerve Tissue Proteins/*immunology ; Neuro-Oncological Ventral Antigen ; Paraneoplastic Syndromes/complications/*genetics ; RNA-Binding Proteins/*immunology ; Sequence Deletion/*genetics ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {INTRODUCTION: Whether motor neuron diseases (MNDs) can be considered in some cases of paraneoplastic syndromes is controversial. We report a case of rapidly progressive motor neuronopathy following a diagnosis of breast carcinoma, with a presence of anti-Ri antibodies, and a novel SOD1 gene mutation.<br><br>OBSERVATION: An 80-year-old woman with mucinous adenocarcinoma of the left breast for 4 years developed sub-acute quadriparesis. Myography revealed chronic denervation signs. The patient had serum anti-Ri onconeural antibodies. The diagnosis of paraneoplastic MND was established. Because of a familial history of ALS, a genetic analysis for familial ALS was performed. We identified a novel heterozygous mutation in SOD1 gene, SOD I18del. This mutation may reflect a genetic predisposition to develop a MND, inducing fragility of motor neurons. Neurological improvement was observed after three months of both intravenous gamma globulin and corticosteroids.<br><br>CONCLUSION: The present observation supports the idea that MND can be considered as a paraneoplastic syndrome. A combination of anti-Ri onconeural antibodies and a particular SOD1 gene mutation, consisting in risk factor, might be in cause in the process of motor neuron death. When in doubt, paraneoplastic cause should be suspected in the differential diagnosis of MND. Immunotherapy treatment may lead to a favorable outcome.}, }
@article {pmid24292800, year = {2014}, author = {Nuzzo, D and Picone, P and Caruana, L and Vasto, S and Barera, A and Caruso, C and Di Carlo, M}, title = {Inflammatory mediators as biomarkers in brain disorders.}, journal = {Inflammation}, volume = {37}, number = {3}, pages = {639-648}, pmid = {24292800}, issn = {1573-2576}, mesh = {Biomarkers ; Humans ; Inflammation/immunology/pathology ; Inflammation Mediators/*metabolism ; Neurodegenerative Diseases/*diagnosis ; }, abstract = {Neurodegenerative diseases such as Alzheimer, Parkinson, amyotrophic lateral sclerosis, and Huntington are incurable and debilitating conditions that result in progressive death of the neurons. The definite diagnosis of a neurodegenerative disorder is disadvantaged by the difficulty in obtaining biopsies and thereby to validate the clinical diagnosis with pathological results. Biomarkers are valuable indicators for detecting different phases of a disease such as prevention, early onset, treatment, progression, and monitoring the effect of pharmacological responses to a therapeutic intervention. Inflammation occurs in neurodegenerative diseases, and identification and validation of molecules involved in this process could be a strategy for finding new biomarkers. The ideal inflammatory biomarker needs to be easily measurable, must be reproducible, not subject to wide variation in the population, and unaffected by external factors. Our review summarizes the most important inflammation biomarkers currently available, whose specificity could be utilized for identifying and monitoring distinctive phases of different neurodegenerative diseases.}, }
@article {pmid24291920, year = {2013}, author = {Ishiai, S}, title = {[Rehabilitation for patients with cerebral infarction after transplantation of autologous human mesenchymal stem cells].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {53}, number = {11}, pages = {1177-1179}, doi = {10.5692/clinicalneurol.53.1177}, pmid = {24291920}, issn = {1882-0654}, mesh = {Adult ; Aged ; Autografts ; Cerebral Infarction/diagnosis/physiopathology/*rehabilitation/*therapy ; Feasibility Studies ; Female ; Humans ; Male ; *Mesenchymal Stem Cell Transplantation ; Middle Aged ; Motor Activity ; Regenerative Medicine/methods ; Safety ; Treatment Outcome ; }, abstract = {We participated as physiatrists in Honmou et al's study that designed to assess feasibility and safety of transplantation of autologous human mesenchymal stem cells in patients with cerebral infarction, and tried to detect improvements that were distinguishable from usual course of rehabilitation. Improvements of motor function were found in rather small functional units, such as movements in one of the fingers, toes, and a single joint of an extremity. In the methods of evaluation, Brunnstrom stage may detect gross changes, while the more detailed scales were necessary for assessment of recovery after transplantation of stem cells. In the investigator-initiated clinical trial of stem cell therapy for stroke, we are going to include fine-grained evaluation methods and investigate the most suitable technique of rehabilitation for patients after treatment.}, }
@article {pmid24291866, year = {2013}, author = {Egawa, N and Inoue, H}, title = {[ALS disease modeling and drug screening using patient-specific iPS cells].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {53}, number = {11}, pages = {1020-1022}, doi = {10.5692/clinicalneurol.53.1020}, pmid = {24291866}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics/*pathology ; Anacardic Acids/pharmacology/therapeutic use ; Animals ; Cell Differentiation ; DNA-Binding Proteins/genetics ; Disease Models, Animal ; Drug Discovery ; *Drug Evaluation, Preclinical ; Humans ; Induced Pluripotent Stem Cells/*cytology ; Molecular Targeted Therapy ; *Motor Neurons/cytology/metabolism/pathology ; Mutation ; Neurites/pathology ; Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder in which motor neuron (MN) loss in the spinal cord leads to progressive paralysis and death. Cytosolic aggregations in ALS MNs are composed of Tar DNA-binding protein-43 (TDP-43). Genetic analysis has identified more than twenty mutations of TDP-43 in ALS cases. Although accumulating evidence provides several hypotheses of disease mechanism, it is still needed to discover effective cure for ALS. We aimed to reveal cellular phenotypes in ALS MNs for identifying a drug-screening target for ALS using patient-specific induced pluripotent stem cells (iPSCs). To generate patient-specific iPSCs, dermal fibroblasts were obtained by biopsy from ALS patients carrying mutant TDP-43. The fibroblasts were reprogrammed by retrovirus or episomal vectors. Disease-specific iPSCs were differentiated into MNs expressing HB9 and SMI-32. Despite short culture period, ALS MNs recapitulated several disease phenotypes including detergent-insoluble TDP-43, shortened neurites and cellular vulnerability that observed in patient and animal models. Anacardic acid treatment reverted those phenotypes. Disease-specific iPSCs might provide a first step for drug-screening platform for ALS using patient-specific iPSCs.}, }
@article {pmid24291785, year = {2014}, author = {Tognolini, M and Hassan-Mohamed, I and Giorgio, C and Zanotti, I and Lodola, A}, title = {Therapeutic perspectives of Eph-ephrin system modulation.}, journal = {Drug discovery today}, volume = {19}, number = {5}, pages = {661-669}, doi = {10.1016/j.drudis.2013.11.017}, pmid = {24291785}, issn = {1878-5832}, mesh = {Animals ; Arteriosclerosis/drug therapy/metabolism ; Arthritis/drug therapy/metabolism ; Ephrins/*antagonists &amp; inhibitors/*physiology ; Humans ; Protein Binding/physiology ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; Receptors, Eph Family/*antagonists &amp; inhibitors/*physiology ; }, abstract = {Eph receptors are the largest class of kinase receptors and, together with their ligands ephrins, they have a primary role in embryogenesis. Their expression has been found deregulated in several cancer tissues and, in many cases, abnormal levels of these proteins have been correlated to a poor prognosis. Recently, the Eph-ephrin system was found to be deregulated in other pathological processes, involving the nervous and cardiovascular systems. The increasing body of evidence supports the Eph-ephrin system as a target not only for the treatment of solid tumors, but also to face other critical diseases such as amyotrophic lateral sclerosis and diabetes driving current efforts toward the development of pharmacological tools potentially able to treat these pathologies.}, }
@article {pmid24291725, year = {2014}, author = {Yue, X and Hariri, DJ and Caballero, B and Zhang, S and Bartlett, MJ and Kaut, O and Mount, DW and Wüllner, U and Sherman, SJ and Falk, T}, title = {Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson's disease.}, journal = {Neuroscience}, volume = {258}, number = {}, pages = {385-400}, pmid = {24291725}, issn = {1873-7544}, support = {P30 CA023074/CA/NCI NIH HHS/United States ; R25 HL108837/HL/NHLBI NIH HHS/United States ; T35 HL007479/HL/NHLBI NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Animals ; Cell Line, Tumor ; Corpus Striatum/drug effects/physiopathology ; Disease Models, Animal ; Glial Cell Line-Derived Neurotrophic Factor/*pharmacology ; Humans ; Male ; Motor Activity/drug effects ; Neurons/drug effects/physiology ; Nootropic Agents/*pharmacology ; Oxidopamine ; Parkinson Disease/*drug therapy/physiopathology ; Rats ; Rats, Sprague-Dawley ; Substantia Nigra/drug effects/physiopathology ; Vascular Endothelial Growth Factor B/*pharmacology ; }, abstract = {Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson's disease (PD) by testing an expanded dose range of VEGF-B (1 and 10 μg) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 μg), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 μg VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p=1.9e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p=0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy controls and PD patients, in neuronal cells that show co-expression with neuromelanin. These results have demonstrated that VEGF-B has potential as a neuroprotective agent for PD therapy and should be further investigated.}, }
@article {pmid24291399, year = {2014}, author = {Dal Vechio, FH and Cerqueira, F and Augusto, O and Lopes, R and Demasi, M}, title = {Peptides that activate the 20S proteasome by gate opening increased oxidized protein removal and reduced protein aggregation.}, journal = {Free radical biology &amp; medicine}, volume = {67}, number = {}, pages = {304-313}, doi = {10.1016/j.freeradbiomed.2013.11.017}, pmid = {24291399}, issn = {1873-4596}, mesh = {Amino Acid Sequence ; Animals ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Enzyme Activators/chemical synthesis/*pharmacology ; Humans ; Molecular Sequence Data ; Neurons/chemistry/*drug effects/enzymology ; Oxidation-Reduction ; Oxidative Stress ; Pancreatitis-Associated Proteins ; Peptides/chemical synthesis/*pharmacology ; Proteasome Endopeptidase Complex/chemistry/*metabolism ; Protein Aggregates ; Protein Aggregation, Pathological/*prevention &amp; control ; Proteolysis ; Rabbits ; Saccharomyces cerevisiae/chemistry/*drug effects/enzymology ; Saccharomyces cerevisiae Proteins/chemistry/metabolism ; }, abstract = {The proteasome is a multicatalytic protease that is responsible for the degradation of the majority of intracellular proteins. Its role is correlated with several major regulatory pathways that are involved in cell cycle control, signaling, and antigen presentation, as well as in the removal of oxidatively damaged proteins. Although several proteasomal catalytic inhibitors have been described, very few activators have been reported to date. Some reports in the literature highlight the cellular protective effects of proteasome activation against oxidative stress and its effect on increased life span. In this work, we describe a peptide named proteasome-activating peptide 1 (PAP1), which increases the chymotrypsin-like proteasomal catalytic activity and, consequently, proteolytic rates both in vitro and in culture. PAP1 proteasomal activation is mediated by the opening of the proteasomal catalytic chamber. We also demonstrate that the observed proteasomal activation protected cells from oxidative stress; further, PAP1 prevented protein aggregation in a cellular model of amyotrophic lateral sclerosis. The role of 20SPT gate opening underlying protection against oxidative stress was also explored in yeast cells. The present data indicate the importance of proteasomal activators as potential drugs for the treatment of pathologies associated with the impaired removal of damaged proteins, which is observed in many neurodegenerative diseases.}, }
@article {pmid24285970, year = {2013}, author = {Kim, JS and Son, TO and Youn, J and Ki, CS and Cho, JW}, title = {Non-Ataxic Phenotypes of SCA8 Mimicking Amyotrophic Lateral Sclerosis and Parkinson Disease.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {9}, number = {4}, pages = {274-279}, pmid = {24285970}, issn = {1738-6586}, abstract = {BACKGROUND: Spinocerebellar ataxia (SCA) type 8 (SCA8) is an inherited neurodegenerative disorder caused by the expansion of untranslated CTA/CTG triplet repeats on 13q21. The phenomenology of SCA8 is relatively varied when compared to the other types of SCAs and its spectrum is not well established.<br><br>CASE REPORT: Two newly detected cases of SCA8 with the nonataxic phenotype and unusual clinical manifestations such as dopaminergic-treatment-responsive parkinsonism and amyotrophic lateral sclerosis (ALS) are described herein. Family A expressed good dopaminergic treatment-responsive parkinsonism as an initial manifestation and developed mild cerebellar ataxia with additional movements, including dystonic gait and unusual oscillatory movement of the trunk, during the disease course. The proband of family B presented as probable ALS with cerebellar atrophy on brain MRI, with a positive family history (a brother with typical cerebellar ataxia) and genetic confirmation for SCA8.<br><br>CONCLUSIONS: Our findings support that the non-ataxic phenotypes could be caused by a mutation of the SCA8 locus which might affect neurons other than the cerebellum.}, }
@article {pmid24278423, year = {2013}, author = {Miyagawa, Y and Ogawa, J and Iwata, Y and Koizumi, N and Mishiba, K}, title = {An attempt to detect siRNA-mediated genomic DNA modification by artificially induced mismatch siRNA in Arabidopsis.}, journal = {PloS one}, volume = {8}, number = {11}, pages = {e81326}, pmid = {24278423}, issn = {1932-6203}, mesh = {Acetolactate Synthase/genetics ; Arabidopsis/*genetics ; Arabidopsis Proteins/*genetics ; Gene Expression ; *Gene Expression Regulation, Plant ; Gene Order ; Gene Silencing ; Gene Targeting ; Plants, Genetically Modified ; *RNA Interference ; RNA, Messenger/genetics ; RNA, Small Interfering/*genetics ; }, abstract = {Although tremendous progress has been made in recent years in identifying molecular mechanisms of small interfering RNA (siRNA) functions in higher plants, the possibility of direct interaction between genomic DNA and siRNA remains an enigma. Such an interaction was proposed in the 'RNA cache' hypothesis, in which a mutant allele is restored based on template-directed gene conversion. To test this hypothesis, we generated transgenic Arabidopsis thaliana plants conditionally expressing a hairpin dsRNA construct of a mutated acetolactate synthase (mALS) gene coding sequence, which confers chlorsulfuron resistance, in the presence of dexamethasone (DEX). In the transgenic plants, suppression of the endogenous ALS mRNA expression as well as 21-nt mALS siRNA expression was detected after DEX treatment. After screening >100,000 progeny of the mALS siRNA-induced plants, no chlorsulfuron-resistant progeny were obtained. Further experiments using transgenic calli also showed that DEX-induced expression of mALS siRNA did not affect the number of chlorsulfuron-resistant calli. No trace of cytosine methylation of the genomic ALS region corresponding to the dsRNA region was observed in the DEX-treated calli. These results do not necessarily disprove the 'RNA cache' hypothesis, but indicate that an RNAi machinery for ALS mRNA suppression does not alter the ALS locus, either genetically or epigenetically.}, }
@article {pmid24238996, year = {2014}, author = {Makioka, K and Yamazaki, T and Takatama, M and Ikeda, M and Okamoto, K}, title = {Immunolocalization of Smurf1 in Hirano bodies.}, journal = {Journal of the neurological sciences}, volume = {336}, number = {1-2}, pages = {24-28}, doi = {10.1016/j.jns.2013.09.028}, pmid = {24238996}, issn = {1878-5883}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*pathology ; Female ; HeLa Cells ; Hippocampus/*chemistry/pathology ; Humans ; Inclusion Bodies/*chemistry/pathology ; Male ; Middle Aged ; Ubiquitin-Protein Ligases/*analysis/physiology ; }, abstract = {The Smad ubiquitination regulatory factor 1 (Smurf1) is one of the E3 ubiquitin ligases and is related to multiple biological processes. Despite the various roles played by this protein, there is no report on the function of Smurf1 in neurodegeneration. Hirano bodies (HBs) are intracellular structures within neuronal processes and were first described in the hippocampus of individuals with amyotrophic lateral sclerosis and the parkinsonism-dementia complex of Guam. In addition, the number of HBs increases in the brains of patients with Alzheimer's disease (AD) compared with age-matched non-demented control individuals. In this study, we immunohistochemically demonstrated that Smurf1 localized in HBs in the brains of patients with AD by using plural anti-Smurf1 antibodies, and Smurf1 co-localized with HBs marker proteins by using confocal microscopy. Moreover, we demonstrated that Smurf1 localized in HB-like F-actin aggregates in a cell culture system via treatment with the actin-stabilizing toxin jasplakinolide (jpk). Smurf1 represents a novel protein component of HBs, to be included in an expanding list of HB-associated proteins.}, }
@article {pmid24237597, year = {2014}, author = {Adini, B and Cohen, R and Glassberg, E and Azaria, B and Simon, D and Stein, M and Klein, Y and Peleg, K}, title = {Reconsidering policy of casualty evacuation in a remote mass-casualty incident.}, journal = {Prehospital and disaster medicine}, volume = {29}, number = {1}, pages = {91-95}, doi = {10.1017/S1049023X13008935}, pmid = {24237597}, issn = {1049-023X}, mesh = {Ambulances ; *Disaster Planning ; Emergency Medical Services/*organization &amp; administration ; Emergency Service, Hospital/*organization &amp; administration ; Humans ; Injury Severity Score ; *Mass Casualty Incidents ; Motor Vehicles ; Patient Transfer/*organization &amp; administration ; Triage ; Wounds and Injuries/*diagnosis/*therapy ; }, abstract = {OBJECTIVES: Inappropriate distribution of casualties in mass-casualty incidents (MCIs) may overwhelm hospitals. This study aimed to review the consequences of evacuating casualties from a bus accident to a single peripheral hospital and lessons learned regarding policy of casualty evacuation.<br><br>METHODS: Medical records of all casualties relating to evacuation times, injury severity, diagnoses, treatments, resources utilized and outcomes were independently reviewed by two senior trauma surgeons. In addition, four senior trauma surgeons reviewed impact of treatment provided on patient outcomes. They reviewed the times for the primary and secondary evacuation, injury severity, diagnoses, surgical treatments, resources utilized, and the final outcomes of the patients at the point of discharge from the tertiary care hospital.<br><br>RESULTS: Thirty-one survivors were transferred to the closest local hospital; four died en route to hospital or within 30 minutes of arrival. Twenty-seven casualties were evacuated by air from the local hospital within 2.5 to 6.15 hours to Level I and II hospitals. Undertriage of 15% and overtriage of seven percent were noted. Four casualties did not receive treatment that might have improved their condition at the local hospital.<br><br>CONCLUSIONS: In MCIs occurring in remote areas, policy makers should consider revising the current evacuation plan so that only immediate unstable casualties should be transferred to the closest primary hospital. On site Advanced Life Support (ALS) should be administered to non-severe casualties until they can be evacuated directly to tertiary care hospitals. First responders must be trained to provide ALS to non-severe casualties until evacuation resources are available.}, }
@article {pmid24217191, year = {2013}, author = {Zarowitz, BJ and O'Shea, T}, title = {Clinical, behavioral, and treatment differences in nursing facility residents with dementia, with and without pseudobulbar affect symptomatology.}, journal = {The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists}, volume = {28}, number = {11}, pages = {713-722}, doi = {10.4140/TCP.n.2013.713}, pmid = {24217191}, issn = {2331-0936}, mesh = {Affective Symptoms/diagnosis/*epidemiology/etiology ; Aged ; Aged, 80 and over ; Alzheimer Disease/*complications ; Antidepressive Agents/administration &amp; dosage/therapeutic use ; Antipsychotic Agents/administration &amp; dosage/therapeutic use ; Crying ; Databases, Factual ; Dementia/*complications ; Depression/*diagnosis ; Female ; Humans ; Male ; Middle Aged ; Nursing Homes ; Prevalence ; Retrospective Studies ; }, abstract = {OBJECTIVES: Characterize the prevalence and impact of crying and tearfulness as symptoms that may be suggestive of pseudobulbar affect (PBA) in residents of nursing facilities, including those with Alzheimer's disease (AD) and non-AD [non-AD-associated] associated dementia.<br><br>DESIGN: Data were extracted retrospectively from a large repository of de-identified and linked Minimum Data Set 2.0 (MDS) and prescription claims records for the period between October 1, 2009, and September 30, 2010. A score of 1 or 2 on MDS item E1m ("crying, tearfulness") was used to identify potential PBA.<br><br>SETTING: 19,000 nursing facilities in 48 states.<br><br>PATIENTS/PARTICIPANTS: Prescription and MDS records of nursing facility residents.<br><br>MAIN OUTCOME MEASURES: Comparison of concomitant diagnoses, MDS mood, and behavioral indicators, and psychopharmacologic medication use, in residents with crying/tearfulness to a control group matched for age, gender, diagnosis of AD or non-AD dementia, and diagnosis of depression.<br><br>RESULTS: A total of 137,829 residents underwent at least one MDS assessment during the study period. Of these, 12,595 (9.1%) had item E1m ("crying, tearfulness") scored as a 1 or 2 on their MDS assessments. Ten thousand residents were then randomly selected from this group and matched to 10,000 controls without "crying, tearfulness" (MDS E1m = 0) for analysis. A total of 4,786 (47.9%) unique residents with "crying, tearfulness" had a diagnosis of AD (8.8%), non-AD dementia (31.5%), or both (7.6%). All of the MDS mood indicators were at least twice as prevalent in this group compared with those without "crying, tearfulness" Additionally, mood symptoms such as anger, worried/pained facial expressions, and repetitive verbalizations; and behavioral symptoms such as verbal/physical abuse and socially inappropriate/disruptive behavior, were more than twice as frequent in the "crying, tearfulness" group. Antipsychotic medications were also used more often in this group (50% vs. 36.1%), as were antidepressants (59.1% vs. 49.8%).<br><br>CONCLUSIONS: In the absence of an International Classification of Diseases 9th edition, Clinical Modification code, the presence of "crying, tearfulness" on MDS 2.0 item E1m was used as a proxy to identify potential PBA. Nursing facility residents with "crying, tearfulness" had a higher prevalence of all mood and behavior indicators as well as psychopharmacological medication use, compared with matched controls without "crying, tearfulness." Similar results were seen in the subgroup of residents with an underlying diagnosis of AD and/or non-AD dementia. Further research should validate the actual prevalence of PBA in this population, and the corresponding impact on resident outcomes.}, }
@article {pmid24215292, year = {2013}, author = {Kimura, Y and Fukushi, J and Hori, S and Matsuda, N and Okatsu, K and Kakiyama, Y and Kawawaki, J and Kakizuka, A and Tanaka, K}, title = {Different dynamic movements of wild-type and pathogenic VCPs and their cofactors to damaged mitochondria in a Parkin-mediated mitochondrial quality control system.}, journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms}, volume = {18}, number = {12}, pages = {1131-1143}, doi = {10.1111/gtc.12103}, pmid = {24215292}, issn = {1365-2443}, mesh = {Adaptor Proteins, Signal Transducing/*metabolism ; Adaptor Proteins, Vesicular Transport ; Adenosine Triphosphatases/genetics/*metabolism ; Amyotrophic Lateral Sclerosis/genetics ; Animals ; Animals, Genetically Modified ; Cell Cycle Proteins/genetics/*metabolism ; Drosophila ; Frontotemporal Dementia/genetics ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins ; Mitochondria/*metabolism/pathology ; Muscular Dystrophies, Limb-Girdle/genetics ; Mutation, Missense ; Myositis, Inclusion Body/genetics ; Nuclear Proteins/*metabolism ; Osteitis Deformans/genetics ; Proteins/*metabolism ; Ubiquitin-Protein Ligases/*metabolism ; Valosin Containing Protein ; }, abstract = {VCP/p97 is a hexameric ring-shaped AAA(+) ATPase that participates in various ubiquitin-associated cellular functions. Mis-sense mutations in VCP gene are associated with the pathogenesis of two inherited diseases: inclusion body myopathy associated with Paget's disease of the bone and front-temporal dementia (IBMPFD) and familial amyotrophic lateral sclerosis (ALS). These pathogenic VCPs have higher affinities for several cofactors, including Npl4, Ufd1 and p47. In Parkin-dependent mitochondrial quality control systems, VCP migrates to damaged mitochondria (e.g., those treated with uncouplers) to aid in the degradation of mitochondrial outer membrane proteins and to eliminate mitochondria. We showed that endogenous Npl4 and p47 also migrate to mitochondria after uncoupler treatment, and Npl4, Ufd1 or p47 silencing causes defective mitochondria clearance after uncoupler treatment. Moreover, pathogenic VCPs show impaired migration to mitochondria, and the exogenous pathogenic VCP expression partially inhibits Npl4 and p47 localization to mitochondria. These results suggest that the increased affinities of pathogenic VCPs for these cofactors cause the impaired movement of pathogenic VCPs. In adult flies, exogenous expression of wild-type VCP, but not pathogenic VCPs, reduces the number of abnormal mitochondria in muscles. Failure of pathogenic VCPs to function on damaged mitochondria may be related to the pathogenesis of IBMPFD and ALS.}, }
@article {pmid24194474, year = {2014}, author = {Wicks, P and Sulham, KA and Gnanasakthy, A}, title = {Quality of life in organ transplant recipients participating in an online transplant community.}, journal = {The patient}, volume = {7}, number = {1}, pages = {73-84}, pmid = {24194474}, issn = {1178-1653}, mesh = {Adolescent ; Adult ; Aged ; Female ; Humans ; *Internet ; Male ; Middle Aged ; *Quality of Life ; *Self-Help Groups ; Socioeconomic Factors ; *Transplants ; }, abstract = {BACKGROUND: The PatientsLikeMe Organ Transplants online community allows patients to share detailed health information for research.<br><br>OBJECTIVES: The objectives of our study were to describe and contrast data collected through an online community with the broader organ transplant population.<br><br>METHODS: Quantitative data were examined with respect to basic demographic characteristics and quantitative data including treatment, symptoms, side effects, and the PatientsLikeMe Quality of Life (PLMQOL) scale. Qualitative data including forum discussion posts and treatment evaluations were examined to support future development of standardized questions that could be added to the platform. Online data were compared with US national registry data from the United Network for Organ Sharing (UNOS).<br><br>RESULTS: Within 30 days of account creation, 1,924 single-organ transplant patients provided spontaneous, patient-reported data in the form of 915 reported symptoms, 938 treatment episodes, and 1,215 PLMQOL assessments. Relative to patients in the UNOS registry, online participants were more likely to be female, younger, and white. Lung transplant patients had worse quality-of-life scores than other organs. Average organ transplant quality-of-life scores were most similar to those of HIV patients, faring better than patients with epilepsy, fibromyalgia, mood disorders, Parkinson's disease, multiple sclerosis, or ALS. Site users generated 2,169 posts to 346 unique topic threads in the transplants forum.<br><br>CONCLUSIONS: Organ transplant patients are willing to report detailed health data through online communities across key domains-symptoms, treatment effects, and generic quality of life-that constitute the essential core of patient-reported outcomes. Patient-reported outcomes captured online have the potential to accelerate learning about patient experiences but suffer methodological challenges that must be overcome to maximize their utility.}, }
@article {pmid24189048, year = {2014}, author = {Yilmaz, S and Unal, F and Yilmaz, E and Yüzbaşioğlu, D and Erkal İlhan, S}, title = {Evaluation of the genotoxicity of clomiphene citrate.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {759}, number = {}, pages = {21-27}, doi = {10.1016/j.mrgentox.2013.07.014}, pmid = {24189048}, issn = {1383-5718}, mesh = {Adult ; *Chromosome Aberrations ; Clomiphene/*toxicity ; DNA Damage ; Female ; Humans ; Lymphocytes/drug effects/ultrastructure ; Micronuclei, Chromosome-Defective ; Mutagenicity Tests ; Selective Estrogen Receptor Modulators/*toxicity ; }, abstract = {Clomiphene citrate (CC) is a selective estrogen-receptor modulator that is primarily used to enhance follicular development in women receiving in vitro fertilization (IVF) treatment. Although some studies suggested large increases in ovarian cancer risk related to fertility medications, this association has not been confirmed in other studies. Whether there could be a residual, small risk is still an open question. It is known that genomic instability and multiple genetic changes may be required in carcinogenesis. Genomic instability such as single-base changes, chromosomal rearrangements or aneuploidy may accelerate this process. Genomic instability is not only central to carcinogenesis, but it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy. For these reasons, this study was planned to examine genotoxic effects of CC in human lymphocytes by use of the chromosome aberration (CA) assay, the micronucleus (MN) test, the comet assay, and the test for bacterial mutagenicity in Salmonella typhimurium strains TA98 and TA100 (Ames test). Concentrations of 0.40, 0.80, 1.60, and 3.20μg/ml of CC significantly increased the frequency of chromosomal aberrations (p<0.01 and p<0.001) and micronuclei (p<0.05, p<0.01 and p<0.001) in cultured human lymphocytes, and of DNA damage (tail length, p<0.05, except 0.80μg/ml) in isolated lymphocytes compared with their respective controls. The highest CC concentration at 24h and highest two concentrations after the 48-h treatment significantly decreased the mitotic index. The Ames test showed that the concentrations of CC used in this study induced neither base-pair substitutions nor frame-shift mutations in S. typhimurium strains TA98 and TA100.}, }
@article {pmid24182372, year = {2013}, author = {Lorenzl, S and Nübling, G and Perrar, KM and Voltz, R}, title = {Palliative treatment of chronic neurologic disorders.}, journal = {Handbook of clinical neurology}, volume = {118}, number = {}, pages = {133-139}, doi = {10.1016/B978-0-444-53501-6.00010-X}, pmid = {24182372}, issn = {0072-9752}, mesh = {Chronic Disease ; Humans ; Nervous System Diseases/*therapy ; Palliative Care/*methods ; }, abstract = {Patients with chronic neurologic disorders suffer from the burden of disease progression without the hope for a cure. Therefore, symptom management and palliative care approaches should be included from the beginning of the illness. Palliative care aims at improving a patient's quality of life by alleviating suffering due to physical, psychosocial, and spiritual factors. Since no curative and only limited life-prolonging treatment options are available for most chronic neurologic disorders, a palliative care approach can help to create a treatment plan that considers all aspects of the disease. We have provided palliative care approaches for the most common neurodegenerative disorders like dementia, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. A palliative approach to neurologic disorders does not simply mean limiting treatment and focusing on pain. Instead, the whole unit of care, consisting of the patient, relatives, and caregivers, should be perceived with all their needs.}, }
@article {pmid24177067, year = {2014}, author = {Keifer, OP and O'Connor, DM and Boulis, NM}, title = {Gene and protein therapies utilizing VEGF for ALS.}, journal = {Pharmacology &amp; therapeutics}, volume = {141}, number = {3}, pages = {261-271}, pmid = {24177067}, issn = {1879-016X}, support = {T32 GM008169/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/physiopathology/*therapy ; Animals ; Clinical Trials as Topic ; Disease Models, Animal ; Drug Design ; Gene Expression Regulation ; Genetic Therapy/*methods ; Humans ; Mice ; Proteins/pharmacology/therapeutic use ; Receptors, Vascular Endothelial Growth Factor/metabolism ; Vascular Endothelial Growth Factor A/*genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is usually fatal within 2-5years. Unfortunately, the only treatment currently available is riluzole, which has a limited efficacy. As a redress, there is an expanding literature focusing on other potential treatments. One such potential treatment option utilizes the vascular endothelial growth factor (VEGF) family, which includes factors that are primarily associated with angiogenesis but are now increasingly recognized to have neurotrophic effects. Reduced expression of a member of this family, VEGF-A, in mice results in neurodegeneration similar to that of ALS, while treatment of animal models of ALS with either VEGF-A gene therapy or VEGF-A protein has yielded positive therapeutic outcomes. These basic research findings raise the potential for a VEGF therapy to be translated to the clinic for the treatment of ALS. This review covers the VEGF family, its receptors and neurotrophic effects as well as VEGF therapy in animal models of ALS and advances towards clinical trials.}, }
@article {pmid24173773, year = {2013}, author = {Guha, N and Erotokritou-Mulligan, I and Nevitt, SP and Francis, M and Bartlett, C and Cowan, DA and Bassett, EE and Sönksen, PH and Holt, RI}, title = {Biochemical markers of recombinant human insulin-like growth factor-I (rhIGF-I)/rhIGF binding protein-3 (rhIGFBP-3) misuse in athletes.}, journal = {Drug testing and analysis}, volume = {5}, number = {11-12}, pages = {843-849}, doi = {10.1002/dta.1562}, pmid = {24173773}, issn = {1942-7611}, mesh = {Adolescent ; Adult ; Athletes ; Biomarkers/blood ; Bone and Bones/chemistry ; Collagen/analysis ; Female ; Humans ; Insulin-Like Growth Factor Binding Protein 3/administration &amp; dosage/*analysis ; Insulin-Like Growth Factor I/administration &amp; dosage/*analysis ; Male ; Recombinant Proteins/administration &amp; dosage/analysis ; Substance Abuse Detection/methods ; Young Adult ; }, abstract = {Insulin-like growth factor-I (IGF-I) is reportedly misused by elite athletes, either alone or with growth hormone (GH). The GH-2000 and GH-2004 research groups previously developed a method for detecting GH misuse based on the GH-sensitive markers IGF-I and procollagen type III amino-terminal propeptide (P-III-NP). Both markers increase in response to rhIGF-I/rhIGF binding protein-3 (rhIGFBP-3) administration in recreational athletes. The aim of this pilot study was to assess the effect of rhIGF-I/rhIGFBP-3 administration on other serum markers of the GH-IGF axis and on other bone and collagen markers. Twenty-six female and 30 male recreational athletes were randomized to 28 days' treatment with placebo or rhIGF-I/rhIGFBP-3 complex, followed by 56 days' washout. GH-IGF axis markers (IGFBP-2, IGFBP-3, acid-labile subunit (ALS) and IGF-II) and bone and collagen markers (procollagen type I carboxy-terminal propeptide (PICP), type I collagen cross-linked carboxy-terminal telopeptide (ICTP) and osteocalcin) were measured using commercial immunoassays. In women in the high dose treatment group, mean IGF-II decreased by 53% (P=0.0028) on Day 21. Mean IGFBP-2 increased by 119% (P=0.0039) and mean ALS decreased by 40% (P=0.0022) on Day 21. There were no significant changes in IGFBP-3, osteocalcin, ICTP or PICP. In men in the high dose group, mean IGF-II decreased by 51% on Day 21 (P<0.0001). Mean IGFBP-2 increased by 125% on Day 21 (P=0.0003). There were no significant changes in IGFBP-3, ALS, osteocalcin, ICTP or PICP. Serum IGFBP-2 and IGF-II may be useful markers of rhIGF-I/rhIGFBP-3 administration in both women and men while ALS may also be a useful marker in women; these markers are now undergoing further evaluation.}, }
@article {pmid24171950, year = {2014}, author = {Genç, B and Özdinler, PH}, title = {Moving forward in clinical trials for ALS: motor neurons lead the way please.}, journal = {Drug discovery today}, volume = {19}, number = {4}, pages = {441-449}, pmid = {24171950}, issn = {1878-5832}, support = {R01 AG017139/AG/NIA NIH HHS/United States ; T32 AG020506/AG/NIA NIH HHS/United States ; 5T32AG020506-09/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*physiopathology ; Animals ; Clinical Trials as Topic ; Glutamic Acid/metabolism ; Humans ; Mitochondria/physiology ; Motor Neurons/*physiology ; Nerve Growth Factors/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most complex motor neuron diseases. Even though scientific discoveries are accelerating with an unprecedented pace, to date more than 30 clinical trials have ended with failure and staggering frustration. There are too many compounds that increase life span in mice, but too little evidence that they will improve human condition. Increasing the chances of success for future clinical trials requires advancement of preclinical tests. Recent developments, which enable the visualization of diseased motor neurons, have the potential to bring novel insight. As we change our focus from mice to motor neurons, it is possible to foster a new vision that translates into effective and long-term treatment strategies in ALS and related motor neuron disorders (MND).}, }
@article {pmid24168240, year = {2013}, author = {Cai, M and Choi, SM and Song, BK and Son, I and Kim, S and Yang, EJ}, title = {Scolopendra subspinipes mutilans attenuates neuroinflammation in symptomatic hSOD1(G93A) mice.}, journal = {Journal of neuroinflammation}, volume = {10}, number = {}, pages = {131}, pmid = {24168240}, issn = {1742-2094}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/pathology ; Animals ; Blotting, Western ; Brain Stem/*drug effects/immunology/pathology ; Disease Models, Animal ; Diterpene Alkaloids ; Drugs, Chinese Herbal/*pharmacology ; Fluorescent Antibody Technique ; Humans ; Immunohistochemistry ; Inflammation/immunology/pathology ; Mice ; Mice, Transgenic ; Oxidative Stress/*drug effects ; Spinal Cord/*drug effects/immunology/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disorder characterized by selective motor neuron death in the spinal cord, brainstem, and motor cortex. Neuroinflammation is one of several pathological causes of degenerating motor neurons and is induced by activated microglial cells and astrocytes in ALS.Scolopendra subspinipes mutilans (SSM) is utilized in traditional Chinese and Korean medicine for the treatment of a variety of diseases, such as cancer, apoplexy, and epilepsy. However, the mechanisms underlying the effects of SSM are currently unclear, even though SSM increases immune and antibiotic activity.<br><br>METHODS: To determine the effects of SSM on symptomatic hSOD1G93A transgenic mice, SSM (2.5 &#x3bc;&#x2113;/g) was injected bilaterally at the Zusanli (ST36) acupoint three times per week for two&#xa0;weeks. The effects of SSM treatment on anti-neuroinflammation in the brainstem and spinal cord of hSOD1G93A mice were assessed via Nissl and Fluoro-Jade B (FJB) staining, and immunohistochemistry using Iba-1, CD14, HO1, and NQO1 proteins was evaluated by Western blotting.<br><br>RESULTS: In this study, we investigated whether SSM affects neuroinflammation in the spinal cord of symptomatic hSOD1G93A transgenic mice. We found that SSM treatment attenuated the loss of motor neurons and reduced the activation of microglial cells and astrocytes. Furthermore, we demonstrated that SSM administration in this animal model of ALS suppressed oxidative stress in the brainstem and spinal cord by 1.6- and 1.8-fold, respectively.<br><br>CONCLUSIONS: Our findings suggest that SSM, which has previously been used in complementary and alternative medicine (CAM), might also be considered as an anti-neuroinflammatory therapy for neurodegenerative diseases.}, }
@article {pmid24158151, year = {2013}, author = {Holbrook, DS and Jackson, MC}, title = {Use of an alternative light source to assess strangulation victims.}, journal = {Journal of forensic nursing}, volume = {9}, number = {3}, pages = {140-145}, doi = {10.1097/JFN.0b013e31829beb1e}, pmid = {24158151}, issn = {1939-3938}, mesh = {Adult ; Asphyxia/*diagnosis/nursing ; *Crime Victims ; Female ; *Fluorescence ; Forensic Pathology/*instrumentation ; Humans ; *Light ; Male ; Middle Aged ; Neck Injuries/*diagnosis/nursing ; Wounds, Nonpenetrating/diagnosis ; Young Adult ; }, abstract = {Alternative light sources (ALSs) are commonly used at crime scenes and in forensic laboratories to collect evidence such as latent fingerprints, body fluids, hair, and fibers. This article describes the use of this technology to reveal soft tissue injuries that are not visible to the naked or unaided eye in patients who report strangulation. The value of this information to the medical, nursing, and judicial systems is discussed. The records of the 172 strangulation patients seen in our forensic nurse examiner program between 2009 and 2010 were reviewed. The SPEX Crimescope (SPEX Forensics, Edison, New Jersey) was used during the assessment of all of them. Ninety-three percent of the patients had no visible evidence of external injuries on physical examination. The ALS revealed positive findings of intradermal injuries in 98% of that group. Information obtained with ALS devices helps medical and nursing practitioners understand the gravity of patients' injuries, influences medical treatment decisions and follow-up care, and supports the prosecution of the perpetrators of crimes of violence. Educational programs about the application of ALS and the interpretation of its findings are valuable for medical, nursing, and other forensic disciplines.}, }
@article {pmid24157492, year = {2014}, author = {Ramírez-Jarquín, UN and Lazo-Gómez, R and Tovar-Y-Romo, LB and Tapia, R}, title = {Spinal inhibitory circuits and their role in motor neuron degeneration.}, journal = {Neuropharmacology}, volume = {82}, number = {}, pages = {101-107}, doi = {10.1016/j.neuropharm.2013.10.003}, pmid = {24157492}, issn = {1873-7064}, mesh = {Animals ; Anterior Horn Cells/physiology ; Humans ; Motor Neuron Disease/*physiopathology ; Motor Neurons/*physiology ; Nerve Degeneration/*physiopathology ; Neural Inhibition/*physiology ; Renshaw Cells/physiology ; Spinal Cord/*physiopathology ; }, abstract = {In the spinal cord neuronal activity is controlled by the balance between excitatory and inhibitory neurotransmission, mediated mainly by the neurotransmitters glutamate and GABA/glycine, respectively. Alterations of this equilibrium have been associated with spinal motor neuron hyperexcitability and degeneration, which can be induced by excitotoxicity or by decreasing inhibitory neurotransmission. Here we review the ventral horn neuronal network and the possible involvement of inhibitory circuits in the mechanisms of degeneration of motor neurons characteristic of amyotrophic lateral sclerosis (ALS). Whereas glutamate mediated excitotoxicity seems to be an important factor, recent experimental and histopathological evidence argue in favor of a decreased activity of the inhibitory circuits controlling motor neuron excitability, mainly the recurrent inhibition exerted by Renshaw cells. A decreased Renshaw cell activity may be caused by cell loss or by a reduction of its inhibitory action secondary to a decreased excitation from cholinergic interneurons. Ultimately, inhibitory failure by either mechanism might lead to motor neuron degeneration, and this suggests inhibitory circuits and Renshaw cells as pharmacologic targets for ALS treatment.}, }
@article {pmid24155688, year = {2013}, author = {Lladó, J and Tolosa, L and Olmos, G}, title = {Cellular and molecular mechanisms involved in the neuroprotective effects of VEGF on motoneurons.}, journal = {Frontiers in cellular neuroscience}, volume = {7}, number = {}, pages = {181}, pmid = {24155688}, issn = {1662-5102}, abstract = {Vascular endothelial growth factor (VEGF), originally described as a factor with a regulatory role in vascular growth and development, it is also known for its direct effects on neuronal cells. The discovery in the past decade that transgenic mice expressing reduced levels of VEGF developed late-onset motoneuron pathology, reminiscent of amyotrophic lateral sclerosis (ALS), opened a new field of research on this disease. VEGF has been shown to protect motoneurons from excitotoxic death, which is a relevant mechanism involved in motoneuron degeneration in ALS. Thus, VEGF delays motoneuron degeneration and increases survival in animal models of ALS. VEGF exerts its anti-excitotoxic effects on motoneurons through molecular mechanisms involving the VEGF receptor-2 resulting in the activation of the PI3-K/Akt signaling pathway, upregulation of GluR2 subunit of AMPA receptors, inhibition of p38MAPK, and induction of the anti-apoptotic molecule Bcl-2. In addition, VEGF acts on astrocytes to reduce astroglial activation and to induce the release of growth factors. The potential use of VEGF as a therapeutic tool in ALS is counteracted by its vascular effects and by its short effective time frame. More studies are needed to assess the optimal isoform, route of administration, and time frame for using VEGF in the treatment of ALS.}, }
@article {pmid24154801, year = {2013}, author = {Finsterer, J and Stöllberger, C}, title = {Unclassified cardiomyopathies in neuromuscular disorders.}, journal = {Wiener medizinische Wochenschrift (1946)}, volume = {163}, number = {21-22}, pages = {505-513}, pmid = {24154801}, issn = {1563-258X}, mesh = {Cardiomyopathies/*classification/*diagnosis/therapy ; Heart Ventricles/pathology ; Humans ; Isolated Noncompaction of the Ventricular Myocardium ; Myocardium/pathology ; Neuromuscular Diseases/*classification/*diagnosis/therapy ; Takotsubo Cardiomyopathy/classification/diagnosis/therapy ; Ventricular Dysfunction, Left/classification/diagnosis/therapy ; }, abstract = {OBJECTIVES: Unclassified cardiomyopathies (CMPs) include left ventricular hypertrabeculation or noncompaction (LVHT) and Takotsubo syndrome (TTS). Unclassified CMPs are frequently associated with noncardiac disease, including neuromuscular disorders (NMDs). This review aims at summarizing and discussing recent findings concerning the association of NMDs with unclassified CMPs.<br><br>METHODS: Literature search using the database PubMed from 1966 to June 2013 was performed.<br><br>RESULTS: LVHT has been described in association with dystrophinopathies, myotonic dystrophies, zaspopathies, laminopathies, dystrobrevinopathies, oculopharyngeal muscular dystrophy, tropomyosin-1 mutations, multiminicore disease, Danon disease, mitochondrial disorders, myoadenylate deaminase deficiency, Pompe's disease, glycogen storage disease-IV, fatty acid oxidation disorder, Barth syndrome, ryanodine receptor mutation, inclusion body myopathy, dystrophic epidermolysis bullosa, Charcot-Marie-Tooth neuropathy, hereditary cobolamine deficiency, beta-thalassemia, poliomyelitis, and Friedreich ataxia. Takotsubo syndrome has been described in association with myasthenia gravis, amyotrophic lateral sclerosis, Guillain-Barre syndrome, rhabdomyolysis, mitochondrial disorder, hypokalemia-related myopathy, syndrome malin, hereditary sensorimotor neuropathy, Beals syndrome, polymyalgia rheumatica, and unclassified myopathy. It is important for treating physicians to know about these associations because treatment and outcome of LVHT, including artificial ventilation, are determined by the presence or absence of an NMD. There are also indications that LVHT in NMDs favors the development of TTS.<br><br>CONCLUSIONS: LVHT and TTS may be associated with NMDs. The pathogenetic link between unclassified CMPs and NMDs remains elusive. Outcome of LVHT and treatment of TTS are additionally determined by the presence or absence of an NMD.}, }
@article {pmid24148693, year = {2013}, author = {Meamar, R and Nasr-Esfahani, MH and Mousavi, SA and Basiri, K}, title = {Stem cell therapy in amyotrophic lateral sclerosis.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {20}, number = {12}, pages = {1659-1663}, doi = {10.1016/j.jocn.2013.04.024}, pmid = {24148693}, issn = {1532-2653}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Animals ; Disease Models, Animal ; Humans ; Motor Neurons/*pathology ; Stem Cell Transplantation/*methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of upper and lower motor neurons, characterized by progressive muscular atrophy and weakness which culminates in death within 2-5 years. Despite various hypotheses about the responsible mechanisms, the etiology of ALS remains incompletely understood. However, it has been recently postulated that stem cell therapy could potentially target several mechanisms responsible for the etiology of ALS and other nervous system disorders, and could be regarded as one of the most promising therapeutic strategies for ALS treatment. We present a brief review of different methods of stem cell therapy in ALS patients and discuss the results with different cell types and routes of administration.}, }
@article {pmid24141020, year = {2014}, author = {Peviani, M and Salvaneschi, E and Bontempi, L and Petese, A and Manzo, A and Rossi, D and Salmona, M and Collina, S and Bigini, P and Curti, D}, title = {Neuroprotective effects of the Sigma-1 receptor (S1R) agonist PRE-084, in a mouse model of motor neuron disease not linked to SOD1 mutation.}, journal = {Neurobiology of disease}, volume = {62}, number = {}, pages = {218-232}, doi = {10.1016/j.nbd.2013.10.010}, pmid = {24141020}, issn = {1095-953X}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Brain-Derived Neurotrophic Factor/metabolism ; Disease Models, Animal ; Female ; Locomotion/drug effects ; Male ; Mice ; Mice, Transgenic ; Morpholines/*therapeutic use ; Motor Neuron Disease/*drug therapy/genetics ; Motor Neurons/metabolism/pathology ; Mutation ; Neuroglia/metabolism ; Neuroprotective Agents/*therapeutic use ; Receptors, sigma/*agonists/*metabolism ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Sigma-1 Receptor ; }, abstract = {The identification of novel molecular targets crucially involved in motor neuron degeneration/survival is a necessary step for the development of hopefully more effective therapeutic strategies for amyotrophic lateral sclerosis (ALS) patients. In this view, S1R, an endoplasmic reticulum (ER)-resident receptor with chaperone-like activity, has recently attracted great interest. S1R is involved in several processes leading to acute and chronic neurodegeneration, including ALS pathology. Treatment with the S1R agonist PRE-084 improves locomotor function and motor neuron survival in presymptomatic and early symptomatic mutant SOD1-G93A ALS mice. Here, we tested the efficacy of PRE-084 in a model of spontaneous motor neuron degeneration, the wobbler mouse (wr) as a proof of concept that S1R may be regarded as a key therapeutic target also for ALS cases not linked to SOD1 mutation. Increased staining for S1R was detectable in morphologically spared cervical spinal cord motor neurons of wr mice both at early (6th week) and late (12th week) phases of clinical progression. S1R signal was also detectable in hypertrophic astrocytes and reactive microglia of wr mice. Chronic treatment with PRE-084 (three times a week, for 8weeks), starting at symptom onset, significantly increased the levels of BDNF in the gray matter, improved motor neuron survival and ameliorated paw abnormality and grip strength performance. In addition, the treatment significantly reduced the number of reactive astrocytes whereas, that of CD11b+ microglial cells was increased. A deeper evaluation of microglial markers revealed significant increased number of cells positive for the pan-macrophage marker CD68 and of CD206+ cells, involved in tissue restoration, in the white matter of PRE-084-treated mice. The mRNA levels of TNF-α and IL-1β were not affected by PRE-084 treatment. Thus, our results support pharmacological manipulation of S1R as a promising strategy to cure ALS and point to increased availability of growth factors and modulation of astrocytosis and of macrophage/microglia as part of the mechanisms involved in S1R-mediated neuroprotection.}, }
@article {pmid24140266, year = {2014}, author = {van den Heuvel, DM and Harschnitz, O and van den Berg, LH and Pasterkamp, RJ}, title = {Taking a risk: a therapeutic focus on ataxin-2 in amyotrophic lateral sclerosis?.}, journal = {Trends in molecular medicine}, volume = {20}, number = {1}, pages = {25-35}, doi = {10.1016/j.molmed.2013.09.001}, pmid = {24140266}, issn = {1471-499X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism/therapy ; Animals ; Ataxins ; DNA-Binding Proteins/genetics/metabolism/toxicity ; Humans ; Motor Neurons/metabolism ; Nerve Tissue Proteins/*genetics/*metabolism ; Peptides ; Protein Binding ; RNA/genetics/metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; Risk Factors ; Trinucleotide Repeat Expansion ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the loss of lower and upper motor neurons leading to progressive muscle weakness and respiratory insufficiency. No treatment is currently available to cure ALS. Recent progress has led to the identification of several novel genetic determinants of this disease, including repeat expansions in the ataxin-2 (ATXN2) gene. Ataxin-2 is mislocalized in ALS patients and represents a relatively common susceptibility gene in ALS, making it a promising therapeutic target. In this review, we summarize genetic and pathological data implicating ataxin-2 in ALS, discuss potential disease mechanisms linked to altered ataxin-2 localization or function, and propose potential strategies for therapeutic intervention in ALS based on ataxin-2.}, }
@article {pmid24139699, year = {2014}, author = {Vishnu, VY and Modi, M and Prabhakar, S and Bhansali, A and Goyal, MK}, title = {"A" motor neuron disease.}, journal = {Journal of the neurological sciences}, volume = {336}, number = {1-2}, pages = {251-253}, doi = {10.1016/j.jns.2013.10.003}, pmid = {24139699}, issn = {1878-5883}, mesh = {Adrenal Insufficiency/complications/*diagnosis/*physiopathology ; Adult ; Electromyography/methods ; Esophageal Achalasia/complications/*diagnosis/*physiopathology ; Humans ; Male ; Motor Neuron Disease/complications/*diagnosis/*physiopathology ; }, abstract = {IMPORTANCE: Allgrove syndrome is a rare autosomal recessive disorder characterised by achalasia, alacrima, adrenal insufficiency, autonomic dysfunction and amyotrophy. The syndrome has been described in childhood and adult presentation, as in our case, is very rare. There is a considerable delay in diagnosis due to lack of awareness about the syndrome.<br><br>OBSERVATIONS: We report a single case of a 36 year old man who was initially diagnosed and treated for achalasia cardia in our institute 14 years before. After 8 years he presented again with weakness and wasting predominantly distally. He had tongue fasciculations, brisk reflexes and extensor plantar. After supportive electrophysiological studies he was diagnosed as Amyotrophic lateral sclerosis. After 5 years he presented with generalised fatigue without any significant worsening of his neurological status. On reevaluation he had alacrimia, autonomic dysfunction and mild ACTH resistance.<br><br>CONCLUSIONS AND RELEVANCE: Allgrove syndrome may be an underdiagnosed cause of multisystem neurological disease due to the heterogeneous clinical presentation as well as for ignorance of clinician about the syndrome. Based on our case, we also believe that there does exist a subgroup of patients who follow a less severe and chronic course. Recognition of syndrome allows for treatment of autonomic dysfunction, adrenal insufficiency and dysphagia.}, }
@article {pmid24136581, year = {2014}, author = {Jeitner, TM and Cooper, AJ}, title = {Inhibition of human glutamine synthetase by L-methionine-S,R-sulfoximine-relevance to the treatment of neurological diseases.}, journal = {Metabolic brain disease}, volume = {29}, number = {4}, pages = {983-989}, pmid = {24136581}, issn = {1573-7365}, support = {R01 ES008421/ES/NIEHS NIH HHS/United States ; R03 NS074286/NS/NINDS NIH HHS/United States ; R01 DK016739-22/DK/NIDDK NIH HHS/United States ; R01 ES 008421/ES/NIEHS NIH HHS/United States ; R03-NS074286/NS/NINDS NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Bacterial Proteins/antagonists &amp; inhibitors ; Convulsants/*pharmacology ; Dogs/metabolism ; Enzyme Inhibitors/*pharmacology ; Glutamate-Ammonia Ligase/*antagonists &amp; inhibitors ; Humans ; Kinetics ; Methionine Sulfoximine/*pharmacology ; Nerve Tissue Proteins/*antagonists &amp; inhibitors ; Nervous System Diseases/*drug therapy/enzymology ; Plant Proteins/antagonists &amp; inhibitors ; Protein Binding ; Recombinant Fusion Proteins/drug effects ; Saccharomyces cerevisiae Proteins/antagonists &amp; inhibitors ; Sheep/metabolism ; Species Specificity ; }, abstract = {At high concentrations, the glutamine synthetase inhibitor L-methionine-S,R-sulfoximine (MSO) is a convulsant, especially in dogs. Nevertheless, sub-convulsive doses of MSO are neuroprotective in rodent models of hyperammonemia, acute liver disease, and amyotrophic lateral sclerosis and suggest MSO may be clinically useful. Previous work has also shown that much lower doses of MSO are required to produce convulsions in dogs than in primates. Evidence from the mid-20th century suggests that humans are also less sensitive. In the present work, the inhibition of recombinant human glutamine synthetase by MSO is shown to be biphasic-an initial reversible competitive inhibition (K i 1.19 mM) is followed by rapid irreversible inactivation. This K i value for the human enzyme accounts, in part, for relative insensitivity of primates to MSO and suggests that this inhibitor could be used to safely inhibit glutamine synthetase activity in humans.}, }
@article {pmid24134124, year = {2013}, author = {Christou, YA and Ohyama, K and Placzek, M and Monk, PN and Shaw, PJ}, title = {Wild-type but not mutant SOD1 transgenic astrocytes promote the efficient generation of motor neuron progenitors from mouse embryonic stem cells.}, journal = {BMC neuroscience}, volume = {14}, number = {}, pages = {126}, pmid = {24134124}, issn = {1471-2202}, mesh = {Animals ; Astrocytes/*metabolism ; Cell Differentiation/drug effects/*genetics ; Cells, Cultured ; Culture Media, Conditioned/pharmacology ; Embryonic Stem Cells/cytology ; Humans ; Immunohistochemistry ; Mice ; Mice, Transgenic ; Motor Neurons/*cytology ; Neural Stem Cells/*cytology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {BACKGROUND: The efficient derivation of mature (Hb9+) motor neurons from embryonic stem cells is a sought-after goal in the understanding, and potential treatment, of motor neuron diseases. Conditions that promote the robust generation of motor neuron progenitors from embryonic stem cells and that promote the survival of differentiated motor neurons ex vivo are likely, therefore, to be critical in future biological/therapeutic/screening approaches. Previous studies have shown that astrocytes have a protective effect on differentiated motor neurons (in vivo and ex vivo), but it remains unclear whether astrocytes also play a beneficial role in the support of motor neuron progenitors. Here we explore the effect of murine astrocyte-conditioned medium on monolayer cultures of mouse embryonic stem cell-derived motor neuron progenitors.<br><br>RESULTS: Our data show that wild-type astrocyte-conditioned medium significantly increases the number of Olig2+/Hb9- progenitors, which subsequently differentiate into Hb9+/Islet1+ post-mitotic motor neurons. Intriguingly, while astrocyte-conditioned medium derived from mice transgenic for wild-type human SOD1 mimics the effect of wild-type astrocytes, conditioned medium derived from astrocytes carrying an amyotrophic lateral sclerosis-related SOD1-G93A mutation shows no such beneficial effect. The effect of astrocyte-conditioned medium, moreover, is specific to motor neurons: we find that interneurons generated from mouse embryonic stem cells are unaffected by conditioned media from any type of astrocyte.<br><br>CONCLUSIONS: Our study indicates that conditioned medium derived from wild type astrocytes enhances the efficient generation of motor neurons from mouse embryonic stem cells by enhancing motor neuron progenitors. In contrast, conditioned medium from SOD1-G93A astrocytes does not show a similar enhancing effect.}, }
@article {pmid24129262, year = {2014}, author = {Bame, M and Grier, RE and Needleman, R and Brusilow, WS}, title = {Amino acids as biomarkers in the SOD1(G93A) mouse model of ALS.}, journal = {Biochimica et biophysica acta}, volume = {1842}, number = {1}, pages = {79-87}, doi = {10.1016/j.bbadis.2013.10.004}, pmid = {24129262}, issn = {0006-3002}, mesh = {Age Factors ; Amino Acids/*blood ; Amyotrophic Lateral Sclerosis/*blood/drug therapy/genetics/pathology ; Animals ; Biomarkers/blood ; Disease Models, Animal ; Female ; Glutamate-Ammonia Ligase/antagonists &amp; inhibitors/blood ; Humans ; Longevity/drug effects ; Male ; Metabolome/drug effects ; Methionine Sulfoximine/pharmacology ; Methylation ; Mice ; Mice, Transgenic ; *Mutation ; Sex Factors ; Superoxide Dismutase/*blood/genetics ; Superoxide Dismutase-1 ; }, abstract = {The development of therapies for Amyotrophic Lateral Sclerosis (ALS) has been hindered by the lack of biomarkers for both identifying early disease and for monitoring the effectiveness of drugs. The identification of ALS biomarkers in presymptomatic individuals might also provide clues to the earliest biochemical correlates of the disease. Previous attempts to use plasma metabolites as biomarkers have led to contradictory results, presumably because of heterogeneity in both the underlying genetics and the disease stage in the clinical population. To eliminate these two sources of heterogeneity we have characterized plasma amino acids and other metabolites in the SOD1(G93A) transgenic mouse model for ALS. Presymptomatic SOD1(G93A) mice have significant differences in concentrations of several plasma metabolites compared to wild type animals, most notably in the concentrations of aspartate, cystine/cysteine, and phosphoethanolamine, and in changes indicative of methylation defects. There are significant changes in amino acid compositions between 50 and 70days of age in both the SOD1(G93A) and wild type mice, and several of the age-related and disease-related differences in metabolite concentration were also gender-specific. Many of the SOD1(G93A)-related differences could be altered by treatment of mice with methionine sulfoximine, which extends the lifespan of this mouse, inhibits glutamine synthetase, and modifies brain methylation reactions. These studies show that assaying plasma metabolites can effectively distinguish transgenic mice from wild type, suggesting that one or more plasma metabolites might be useful biomarkers for the disease in humans, especially if genetic and longitudinal analysis is used to reduce population heterogeneity.}, }
@article {pmid24126226, year = {2013}, author = {Gerardo-Nava, J and Mayorenko, II and Grehl, T and Steinbusch, HW and Weis, J and Brook, GA}, title = {Differential pattern of neuroprotection in lumbar, cervical and thoracic spinal cord segments in an organotypic rat model of glutamate-induced excitotoxicity.}, journal = {Journal of chemical neuroanatomy}, volume = {53}, number = {}, pages = {11-17}, doi = {10.1016/j.jchemneu.2013.09.007}, pmid = {24126226}, issn = {1873-6300}, mesh = {Animals ; Cell Survival/drug effects ; Cervical Vertebrae ; Excitatory Amino Acid Antagonists/*pharmacology ; Glutamic Acid/*toxicity ; Immunohistochemistry ; Lumbosacral Region ; Motor Neurons/*drug effects/*metabolism ; Neuroprotective Agents/*pharmacology ; Organ Culture Techniques ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/drug effects/metabolism ; Thoracic Vertebrae ; }, abstract = {Glutamate-induced excitotoxicity is a major contributor to motor neuron (MN) degeneration in disorders such as amyotrophic lateral sclerosis (ALS), stroke and spinal cord injury. Numerous in vitro and in vivo models have been developed to evaluate the efficacy and mode of action of neuroprotective agents. However, the dominance of glutamate receptor-subtype in the different regions of the spinal cord in these models has generally been overlooked. This study first compared the neuroprotective effect of administering glutamate receptor antagonists, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), into a serum-free excitotoxic organotypic in vitro system, on the survival of MNs located in the lumbar area of spinal cord. The poor neuroprotection provided by MK-801 (NMDA (N-methyl-D-aspartate) antagonist) in comparison to CNQX (AMPA/KA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate) antagonist), raised the hypothesis that the extent of engagement by glutamate receptor sub-types in the mechanism of excitotoxicity may differ within different populations of MNs. The consequent examination of MN susceptibility to glutamate-induced excitotoxicity in relation to the rostro-caudal level from which MN originated revealed a differential glutamate receptor sub-type dominance at different spinal cord regions (i.e. cervical, thoracic and lumbar). In the cervical and lumbar regions, the AMPA receptor was the main contributor to MN excitotoxicity, whereas in thoracic regions, the NMDA receptor was the main contributor. This study provides a new way of looking at mechanisms leading to glutamate-induced excitotoxicity in MN and may therefore be important for the development of treatment strategies in protection of spinal MNs in neurodegenerative disease and traumatic injury.}, }
@article {pmid24124634, year = {2013}, author = {Gordon, PH}, title = {Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials.}, journal = {Aging and disease}, volume = {4}, number = {5}, pages = {295-310}, pmid = {24124634}, issn = {2152-5250}, abstract = {Amyotrophic lateral sclerosis (ALS), first described by Jean-Martin Charcot in the 1870s, is an age-related disorder that leads to degeneration of motor neurons. The disease begins focally in the central nervous system and then spreads relentlessly. The clinical diagnosis, defined by progressive signs and symptoms of upper and lower motor neuron dysfunction, is confirmed by electromyography. Additional testing excludes other conditions. The disease is heterogeneous, but most patients die of respiratory muscle weakness less than 3 years from symptom-onset. Like other age-related neurodegenerative diseases, ALS has genetic and environmental triggers. Of the five to 10% of cases that are inherited, mutations have been discovered for a high proportion. In addition to genetic factors, age, tobacco use, and athleticism may contribute to sporadic ALS, but important etiologies are unidentified for most patients. Complex pathophysiological processes, including mitochondrial dysfunction, aggregation of misfolded protein, oxidative stress, excitotoxicity, inflammation and apoptosis, involve both motor neurons and surrounding glial cells. There is clinical and pathological overlap with other neurodegenerative diseases, particularly frontotemporal dementia. The mechanisms leading to disease propagation in the brain are a current focus of research. To date, one medication, riluzole, licensed in 1996, has been proved to prolong survival in ALS. Numerous clinical trials have so far been unable to identify another neuroprotective agent. Researchers now aim to slow disease progression by targeting known pathophysiological pathways or genetic defects. Current approaches are directed at muscle proteins such as Nogo, energetic balance, cell replacement, and abnormal gene products resulting from mutations. Until better understanding of the causes and mechanisms underlying progression lead to more robust neuroprotective agents, symptomatic therapies can extend life and improve quality of life. Palliative care programs such as hospice give emotional and physical support to patients and families throughout much of the disease course.}, }
@article {pmid24120466, year = {2013}, author = {Haidet-Phillips, AM and Gross, SK and Williams, T and Tuteja, A and Sherman, A and Ko, M and Jeong, YH and Wong, PC and Maragakis, NJ}, title = {Altered astrocytic expression of TDP-43 does not influence motor neuron survival.}, journal = {Experimental neurology}, volume = {250}, number = {}, pages = {250-259}, doi = {10.1016/j.expneurol.2013.10.004}, pmid = {24120466}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Animals ; Astrocytes/*metabolism ; Cell Survival ; Coculture Techniques ; DNA-Binding Proteins/*genetics/metabolism ; Disease Models, Animal ; Immunoblotting ; Immunohistochemistry ; Mice ; Mice, Transgenic ; Motor Neurons/*pathology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {The role of glia as a contributing factor to motor neuron (MN) death in amyotrophic lateral sclerosis (ALS) is becoming increasingly appreciated. However, most studies implicating astrocytes have focused solely on models of ALS caused by superoxide dismutase 1 (SOD1) mutations. The goal of our study was to determine whether astrocytes contribute to wild-type MN death in the case of ALS caused by mutations in tar-DNA binding protein 43 (TDP-43). Since it is currently unknown how TDP-43 mutations cause disease, we derived astrocytes for study from both gain and loss of function mouse models of TDP-43. Astrocytes overexpressing mutant TDP-43(A315T) as well as astrocytes lacking TDP-43 were morphologically indistinguishable from wild-type astrocytes in vitro. Furthermore, astrocytes with these TDP-43 alterations did not cause the death of wild-type MNs in co-culture. To investigate the in vivo effects of TDP-43 alterations in astrocytes, glial-restricted precursors were transplanted to the wild-type rat spinal cord where they differentiated into astrocytes and interacted with host MNs. Astrocytes with TDP-43 alterations did not cause host wild-type MN damage although they were capable of engrafting and interacting with host MNs with the same efficiency as wild-type astrocytes. These data indicate that astrocytes do not adopt the same toxic phenotype as mutant SOD1 astrocytes when TDP-43 is mutated or expression levels are modified. Our study reinforces the heterogeneity in ALS disease mechanisms and highlights the potential for future screening subsets of ALS patients prior to treatment with cell type-directed therapies.}, }
@article {pmid24116037, year = {2013}, author = {Tuohimaa, P and Wang, JH and Khan, S and Kuuslahti, M and Qian, K and Manninen, T and Auvinen, P and Vihinen, M and Lou, YR}, title = {Gene expression profiles in human and mouse primary cells provide new insights into the differential actions of vitamin D3 metabolites.}, journal = {PloS one}, volume = {8}, number = {10}, pages = {e75338}, pmid = {24116037}, issn = {1932-6203}, mesh = {Animals ; Calcifediol/*pharmacology ; Calcitriol/*pharmacology ; Cell Cycle/drug effects ; Cell Differentiation/drug effects ; Cholecalciferol/*metabolism/pharmacology ; Fibroblasts/*drug effects/metabolism ; Gene Expression/drug effects ; Gene Expression Profiling ; Humans ; Mice ; Mice, Knockout ; Stromal Cells/*drug effects/metabolism ; }, abstract = {1α,25-Dihydroxyvitamin D3 (1α,25(OH)2D3) had earlier been regarded as the only active hormone. The newly identified actions of 25-hydroxyvitamin D3 (25(OH)D3) and 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3) broadened the vitamin D3 endocrine system, however, the current data are fragmented and a systematic understanding is lacking. Here we performed the first systematic study of global gene expression to clarify their similarities and differences. Three metabolites at physiologically comparable levels were utilized to treat human and mouse fibroblasts prior to DNA microarray analyses. Human primary prostate stromal P29SN cells (hP29SN), which convert 25(OH)D3 into 1α,25(OH)2D3 by 1α-hydroxylase (encoded by the gene CYP27B1), displayed regulation of 164, 171, and 175 genes by treatment with 1α,25(OH)2D3, 25(OH)D3, and 24R,25(OH)2D3, respectively. Mouse primary Cyp27b1 knockout fibroblasts (mCyp27b1 (-/-)), which lack 1α-hydroxylation, displayed regulation of 619, 469, and 66 genes using the same respective treatments. The number of shared genes regulated by two metabolites is much lower in hP29SN than in mCyp27b1 (-/-). By using DAVID Functional Annotation Bioinformatics Microarray Analysis tools and Ingenuity Pathways Analysis, we identified the agonistic regulation of calcium homeostasis and bone remodeling between 1α,25(OH)2D3 and 25(OH)D3 and unique non-classical actions of each metabolite in physiological and pathological processes, including cell cycle, keratinocyte differentiation, amyotrophic lateral sclerosis signaling, gene transcription, immunomodulation, epigenetics, cell differentiation, and membrane protein expression. In conclusion, there are three distinct vitamin D3 hormones with clearly different biological activities. This study presents a new conceptual insight into the vitamin D3 endocrine system, which may guide the strategic use of vitamin D3 in disease prevention and treatment.}, }
@article {pmid24113586, year = {2013}, author = {Liu, YC and Chiang, PM and Tsai, KJ}, title = {Disease animal models of TDP-43 proteinopathy and their pre-clinical applications.}, journal = {International journal of molecular sciences}, volume = {14}, number = {10}, pages = {20079-20111}, pmid = {24113586}, issn = {1422-0067}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; DNA-Binding Proteins/*metabolism ; Disease Models, Animal ; Frontotemporal Lobar Degeneration/metabolism/pathology ; Humans ; TDP-43 Proteinopathies/*metabolism/*pathology ; }, abstract = {Frontotemperal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are two common neurodegenerative diseases. TDP-43 is considered to be a major disease protein in FTLD/ALS, but it's exact role in the pathogenesis and the effective treatments remains unknown. To address this question and to determine a potential treatment for FTLD/ALS, the disease animal models of TDP-43 proteinopathy have been established. TDP-43 proteinopathy is the histologic feature of FTLD/ALS and is associated with disease progression. Studies on the disease animal models with TDP-43 proteinopathy and their pre-clinical applications are reviewed and summarized. Through these disease animal models, parts of TDP-43 functions in physiological and pathological conditions will be better understood and possible treatments for FTLD/ALS with TDP-43 proteinopathy may be identified for possible clinical applications in the future.}, }
@article {pmid24113175, year = {2013}, author = {Huang, G and Lee, X and Bian, Y and Shao, Z and Sheng, G and Pepinsky, RB and Mi, S}, title = {Death receptor 6 (DR6) antagonist antibody is neuroprotective in the mouse SOD1G93A model of amyotrophic lateral sclerosis.}, journal = {Cell death &amp; disease}, volume = {4}, number = {10}, pages = {e841}, pmid = {24113175}, issn = {2041-4889}, mesh = {Amino Acid Substitution/genetics ; Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/*pathology/physiopathology ; Animals ; Antibodies, Blocking/*pharmacology/*therapeutic use ; Axons/drug effects/pathology ; Caspase 3/metabolism ; Cell Survival/drug effects ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Motor Activity/drug effects ; Motor Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/pharmacology/*therapeutic use ; Phosphorylation/drug effects ; Postmortem Changes ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Messenger/genetics/metabolism ; Rats ; Receptors, Tumor Necrosis Factor/*antagonists &amp; inhibitors/genetics/metabolism ; Spinal Cord/drug effects/metabolism/pathology ; Superoxide Dismutase/*genetics ; Up-Regulation/drug effects/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of motor neurons, axon degeneration, and denervation of neuromuscular junctions (NMJ). Here we show that death receptor 6 (DR6) levels are elevated in spinal cords from post-mortem samples of human ALS and from SOD1(G93A) transgenic mice, and DR6 promotes motor neuron death through activation of the caspase 3 signaling pathway. Blocking DR6 with antagonist antibody 5D10 promotes motor neuron survival in vitro via activation of Akt phosphorylation and inhibition of the caspase 3 signaling pathway, after growth factor withdrawal, sodium arsenite treatment or co-culture with SOD1(G93A) astrocytes. Treatment of SOD1(G93A) mice at an asymptomatic stage starting on the age of 42 days with 5D10 protects NMJ from denervation, decreases gliosis, increases survival of motor neurons and CC1(+) oligodendrocytes in spinal cord, decreases phosphorylated neurofilament heavy chain (pNfH) levels in serum, and promotes motor functional improvement assessed by increased grip strength. The combined data provide clear evidence for neuroprotective effects of 5D10. Blocking DR6 function represents a new approach for the treatment of neurodegenerative disorders involving motor neuron death and axon degeneration, such as ALS.}, }
@article {pmid24108104, year = {2014}, author = {Wang, H and Yang, B and Qiu, L and Yang, C and Kramer, J and Su, Q and Guo, Y and Brown, RH and Gao, G and Xu, Z}, title = {Widespread spinal cord transduction by intrathecal injection of rAAV delivers efficacious RNAi therapy for amyotrophic lateral sclerosis.}, journal = {Human molecular genetics}, volume = {23}, number = {3}, pages = {668-681}, pmid = {24108104}, issn = {1460-2083}, support = {UL1 TR000161/TR/NCATS NIH HHS/United States ; 5R01-NS050557-05/NS/NINDS NIH HHS/United States ; R01 NS076991/NS/NINDS NIH HHS/United States ; RC2-NS070-342/NS/NINDS NIH HHS/United States ; R01NS059708/NS/NINDS NIH HHS/United States ; UL1RR 031982/RR/NCRR NIH HHS/United States ; 1R01NS076991/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; Callithrix ; Central Nervous System/physiology ; Cerebrospinal Fluid/physiology ; Dependovirus/*genetics ; Female ; Genetic Therapy/methods ; Genetic Vectors/*administration &amp; dosage/pharmacokinetics ; Green Fluorescent Proteins/genetics ; HEK293 Cells ; Humans ; Injections, Spinal ; Mice ; Mice, Transgenic ; RNA Interference ; *Spinal Cord/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Transduction, Genetic/*methods ; Transgenes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) causes motor neuron degeneration and paralysis. No treatment can significantly slow or arrest the disease progression. Mutations in the SOD1 gene cause a subset of familial ALS by a gain of toxicity. In principle, these cases could be treated with RNAi that destroys the mutant mRNA, thereby abolishing the toxic protein. However, no system is available to efficiently deliver the RNAi therapy. Recombinant adenoassociated virus (rAAV) is a promising vehicle due to its long-lasting gene expression and low toxicity. However, ALS afflicts broad areas of the central nervous system (CNS). A lack of practical means to spread rAAV broadly has hindered its application in treatment of ALS. To overcome this barrier, we injected several rAAV serotypes into the cerebrospinal fluid. We found that some rAAV serotypes such as rAAVrh10 and rAAV9 transduced cells throughout the length of the spinal cord following a single intrathecal injection and in the broad forebrain following a single injection into the third ventricle. Furthermore, a single intrathecal injection of rAAVrh10 robustly transduced motor neurons throughout the spinal cord in a non-human primate. These results suggested a therapeutic potential of this vector for ALS. To test this, we injected a rAAVrh10 vector that expressed an artificial miRNA targeting SOD1 into the SOD1G93A mice. This treatment knocked down the mutant SOD1 expression and slowed the disease progression. Our results demonstrate the potential of rAAVs for delivering gene therapy to treat ALS and other diseases that afflict broad areas of the CNS.}, }
@article {pmid24105464, year = {2014}, author = {Choksi, DK and Roy, B and Chatterjee, S and Yusuff, T and Bakhoum, MF and Sengupta, U and Ambegaokar, S and Kayed, R and Jackson, GR}, title = {TDP-43 Phosphorylation by casein kinase Iε promotes oligomerization and enhances toxicity in vivo.}, journal = {Human molecular genetics}, volume = {23}, number = {4}, pages = {1025-1035}, doi = {10.1093/hmg/ddt498}, pmid = {24105464}, issn = {1460-2083}, mesh = {Amyotrophic Lateral Sclerosis/enzymology ; Animals ; Animals, Genetically Modified ; Casein Kinase 1 epsilon/chemistry/genetics/*metabolism ; Cell Line, Tumor ; DNA-Binding Proteins/biosynthesis/*genetics ; Drosophila Proteins/chemistry/genetics/*metabolism ; Drosophila melanogaster ; Humans ; Imaginal Discs/metabolism ; Mutation, Missense ; Phosphorylation ; Protein Multimerization ; *Protein Processing, Post-Translational ; Rats ; }, abstract = {Dominant mutations in transactive response DNA-binding protein-43 (TDP-43) cause amyotrophic lateral sclerosis. TDP-43 inclusions occur in neurons, glia and muscle in this disease and in sporadic and inherited forms of frontotemporal lobar degeneration. Cytoplasmic localization, cleavage, aggregation and phosphorylation of TDP-43 at the Ser409/410 epitope have been associated with disease pathogenesis. TDP-43 aggregation is not a common feature of mouse models of TDP-43 proteinopathy, and TDP-43 is generally not thought to acquire an amyloid conformation or form fibrils. A number of putative TDP-43 kinases have been identified, but whether any of these functions to regulate TDP-43 phosphorylation or toxicity in vivo is not known. Here, we demonstrate that human TDP-43(Q331K) undergoes cytoplasmic localization and aggregates when misexpressed in Drosophila when compared with wild-type and M337V forms. Coexpression of Q331K with doubletime (DBT), the fly homolog of casein kinase Iε (CKIε), enhances toxicity. There is at best modest basal phosphorylation of misexpressed human TDP-43 in Drosophila, but coexpression with DBT increases Ser409/410 phosphorylation of all TDP-43 isoforms tested. Phosphorylation of TDP-43 in the fly is specific for DBT, as it is not observed using the validated tau kinases GSK-3β, PAR-1/MARK2 or CDK5. Coexpression of DBT with TDP-43(Q331K) enhances the formation of high-molecular weight oligomeric species coincident with enhanced toxicity, and treatment of recombinant oligomeric TDP-43 with rat CKI strongly enhances its toxicity in mammalian cell culture. These data identify CKIε as a potent TDP-43 kinase in vivo and implicate oligomeric species as the toxic entities in TDP-43 proteinopathies.}, }
@article {pmid24101939, year = {2013}, author = {Lee, S and Kim, S}, title = {The effects of sa-am acupuncture treatment on respiratory physiology parameters in amyotrophic lateral sclerosis patients: a pilot study.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2013}, number = {}, pages = {506317}, pmid = {24101939}, issn = {1741-427X}, abstract = {Respiratory dysfunction and complications are the most common causes of death in amyotrophic lateral sclerosis. This is a pilot study to observe the changes in respiratory physiology parameters after Sa-am acupuncture treatment. Eighteen ALS patients received Sa-am acupuncture treatment twice a day for 5 days. The EtCO2, SpO2, RR, and pulse rate were measured for 15 min before and during treatment, using capnography and oximetry. Correlation of K-ALSFRS-R scores against measured parameters showed that patients who had high K-ALSFRS-R scores had greater changes in pulse rate after acupuncture stimulation; they also showed a decrease in EtCO2, RR, and pulse rate and an increase in SpO2. A comparison of the mean values of these different parameters before and after Sa-am acupuncture stimulation revealed statistically significant differences (P < 0.05) in SpO2 and pulse rate, but none in EtCO2 and RR. Sa-am acupuncture treatment on ALS patients seems to be more effective in the early stages of the disease. In light of increased SpO2 values, Sa-am acupuncture appears to have a greater effect on inspiration rather than on expiration. As a pilot study of acupuncture on ALS patients, this study could be used as a basis for future research.}, }
@article {pmid24093081, year = {2013}, author = {Ramanan, VK and Saykin, AJ}, title = {Pathways to neurodegeneration: mechanistic insights from GWAS in Alzheimer's disease, Parkinson's disease, and related disorders.}, journal = {American journal of neurodegenerative disease}, volume = {2}, number = {3}, pages = {145-175}, pmid = {24093081}, issn = {2165-591X}, support = {P30 AG010133/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; RC2 AG036535/AG/NIA NIH HHS/United States ; T32 GM077229/GM/NIGMS NIH HHS/United States ; R01 AG019771/AG/NIA NIH HHS/United States ; S10 RR027710/RR/NCRR NIH HHS/United States ; UL1 RR025761/RR/NCRR NIH HHS/United States ; R01 LM011360/LM/NLM NIH HHS/United States ; C06 RR020128/RR/NCRR NIH HHS/United States ; }, abstract = {The discovery of causative genetic mutations in affected family members has historically dominated our understanding of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Nevertheless, most cases of neurodegenerative disease are not explained by Mendelian inheritance of known genetic variants, but instead are thought to have a complex etiology with numerous genetic and environmental factors contributing to susceptibility. Although unbiased genome-wide association studies (GWAS) have identified novel associations to neurodegenerative diseases, most of these hits explain only modest fractions of disease heritability. In addition, despite the substantial overlap of clinical and pathologic features among major neurodegenerative diseases, surprisingly few GWAS-implicated variants appear to exhibit cross-disease association. These realities suggest limitations of the focus on individual genetic variants and create challenges for the development of diagnostic and therapeutic strategies, which traditionally target an isolated molecule or mechanistic step. Recently, GWAS of complex diseases and traits have focused less on individual susceptibility variants and instead have emphasized the biological pathways and networks revealed by genetic associations. This new paradigm draws on the hypothesis that fundamental disease processes may be influenced on a personalized basis by a combination of variants - some common and others rare, some protective and others deleterious - in key genes and pathways. Here, we review and synthesize the major pathways implicated in neurodegeneration, focusing on GWAS from the most prevalent neurodegenerative disorders, AD and PD. Using literature mining, we also discover a novel regulatory network that is enriched with AD- and PD-associated genes and centered on the SP1 and AP-1 (Jun/Fos) transcription factors. Overall, this pathway- and network-driven model highlights several potential shared mechanisms in AD and PD that will inform future studies of these and other neurodegenerative disorders. These insights also suggest that biomarker and treatment strategies may require simultaneous targeting of multiple components, including some specific to disease stage, in order to assess and modulate neurodegeneration. Pathways and networks will provide ideal vehicles for integrating relevant findings from GWAS and other modalities to enhance clinical translation.}, }
@article {pmid24093046, year = {2013}, author = {Pan, W and Su, X and Bao, J and Wang, J and Zhu, J and Cai, D and Yu, L and Zhou, H}, title = {Open Randomized Clinical Trial on JWSJZ Decoction for the Treatment of ALS Patients.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2013}, number = {}, pages = {347525}, pmid = {24093046}, issn = {1741-427X}, abstract = {Objective. To investigate the efficacy and safety of the traditional Chinese medicine Jiawei Sijunzi (JWSJZ) decoction for the treatment of patients with amyotrophic lateral sclerosis (ALS). Methods. Forty-eight patients with ALS were divided into a JWSJZ group (n = 24) and a control group (n = 24) using a randomized number method. Together with the basic treatment for ALS, JWSJZ decoction was added to the treatment regimen of patients in the JWSJZ group or Riluzole was administered to the control group for 6 months. Neurologists evaluated the treated and control patients using the ALS functional rating scale (ALSFRS) before, 3 and 6 months after starting the additional treatments. Results. The ALSFRS scores in both groups were lower 3 and 6 months after treatment than before. There was a significant difference at 6 months after treatment between the subgroups of patients with ALS whose limbs were the initial site of attack. No serious adverse effects were observed in the JWSJZ group. Conclusion. JWSJZ decoction may be a safe treatment for ALS, and may have delayed the development of ALS, especially in the subgroup of patients in whom the limbs were attacked first when compared with Riluzole treatment.}, }
@article {pmid24092395, year = {2014}, author = {Cha, JR and St Louis, KJ and Tradewell, ML and Gentil, BJ and Minotti, S and Jaffer, ZM and Chen, R and Rubenstein, AE and Durham, HD}, title = {A novel small molecule HSP90 inhibitor, NXD30001, differentially induces heat shock proteins in nervous tissue in culture and in vivo.}, journal = {Cell stress &amp; chaperones}, volume = {19}, number = {3}, pages = {421-435}, pmid = {24092395}, issn = {1466-1268}, support = {R21 NS066129/NS/NINDS NIH HHS/United States ; 1R21NS066129-01/NS/NINDS NIH HHS/United States ; MOP-77743/CAPMC/CIHR/Canada ; }, mesh = {Animals ; Calcium/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Ganglia, Spinal/drug effects/metabolism ; Green Fluorescent Proteins/metabolism ; HSP90 Heat-Shock Proteins/*antagonists &amp; inhibitors/metabolism ; Heat-Shock Proteins/*metabolism ; Homeostasis/drug effects ; Inclusion Bodies/metabolism ; Lactones/administration &amp; dosage/pharmacokinetics/*pharmacology ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondrial Dynamics/drug effects ; Motor Neurons/drug effects/metabolism ; Nerve Tissue/drug effects/*metabolism ; Oximes/administration &amp; dosage/pharmacokinetics/*pharmacology ; Phosphorylation/drug effects ; Small Molecule Libraries/administration &amp; dosage/pharmacokinetics/*pharmacology ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; Tissue Culture Techniques ; }, abstract = {Heat shock proteins (HSPs) are attractive therapeutic targets for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), characterized by aberrant formation of protein aggregates. Although motor neurons have a high threshold for activation of HSP genes, HSP90 inhibitors are effective inducers. This study evaluated NXD30001, a novel, small molecule HSP90 inhibitor based on the radicicol backbone, for its ability to induce neuronal HSPs and for efficacy in an experimental model of ALS based on mutations in superoxide-dismutase 1 (SOD1). In motor neurons of dissociated murine spinal cord cultures, NXD30001-induced expression of HSP70/HSPA1 (iHSP70) and its co-chaperone HSP40/DNAJ through activation of HSF1 and exhibited a protective profile against SOD1(G93A) similar to geldanamycin, but with less toxicity. Treatment prevented protein aggregation, mitochondrial fragmentation, and motor neuron death, important features of mutant SOD1 toxicity, but did not effectively prevent aberrant intracellular Ca(2+) accumulation. NXD30001 distributed to brain and spinal cord of wild-type and SOD1(G93A) transgenic mice following intraperitoneal injection; however, unlike in culture, in vivo levels of SOD1 were not reduced. NXD30001-induced expression of iHSP70 in skeletal and cardiac muscle and, to a lesser extent, in kidney, but not in liver, spinal cord, or brain, with either single or repeated administration. NXD30001 is a very useful experimental tool in culture, but these data point to the complex nature of HSP gene regulation in vivo and the necessity for early evaluation of the efficacy of novel HSP inducers in target tissues in vivo.}, }
@article {pmid24085347, year = {2013}, author = {Iguchi, Y and Katsuno, M and Ikenaka, K and Ishigaki, S and Sobue, G}, title = {Amyotrophic lateral sclerosis: an update on recent genetic insights.}, journal = {Journal of neurology}, volume = {260}, number = {11}, pages = {2917-2927}, pmid = {24085347}, issn = {1432-1459}, mesh = {Adaptor Proteins, Signal Transducing ; Adenosine Triphosphatases/genetics ; Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Ataxins ; Autophagy-Related Proteins ; C9orf72 Protein ; Cell Cycle Proteins/genetics ; D-Amino-Acid Oxidase/genetics ; DNA-Binding Proteins/genetics ; Flavoproteins/genetics ; Genetic Predisposition to Disease/*genetics ; Humans ; Membrane Transport Proteins ; Mice ; Mutation/genetics ; Nerve Tissue Proteins/genetics ; Phosphoric Monoester Hydrolases ; Profilins/genetics ; Proteins/genetics ; RNA-Binding Protein FUS/genetics ; Receptors, sigma/genetics ; Transcription Factor TFIIIA/genetics ; Ubiquitins/genetics ; Valosin Containing Protein ; Sigma-1 Receptor ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting both upper and lower motor neurons. The prognosis for ALS is extremely poor, but there is a limited course of treatment with only one approved medication. A most striking recent discovery is that TDP-43 is identified as a key molecule that is associated with both sporadic and familial forms of ALS. TDP-43 is not only a pathological hallmark, but also a genetic cause for ALS. Subsequently, a number of ALS-causative genes have been found. Above all, the RNA-binding protein, such as FUS, TAF15, EWSR1 and hnRNPA1, have structural and functional similarities to TDP-43, and physiological functions of some molecules, including VCP, UBQLN2, OPTN, FIG4 and SQSTM1, are involved in a protein degradation system. These discoveries provide valuable insight into the pathogenesis of ALS, and open doors for developing an effective disease-modifying therapy.}, }
@article {pmid24070404, year = {2014}, author = {Gomeni, R and Fava, M and , }, title = {Amyotrophic lateral sclerosis disease progression model.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {15}, number = {1-2}, pages = {119-129}, doi = {10.3109/21678421.2013.838970}, pmid = {24070404}, issn = {2167-9223}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*epidemiology/*physiopathology ; Databases, Factual/statistics &amp; numerical data ; *Disease Progression ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; *Models, Statistical ; Predictive Value of Tests ; Software ; Young Adult ; }, abstract = {Our objective was to develop: 1) a longitudinal model to describe amyotrophic lateral sclerosis (ALS) disease progression using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R); and 2) a probabilistic model to estimate the presence of clusters of trajectories in ALS progression over 12 months of treatment. Three hundred and thirty-eight patients treated with placebo from the PRO-ACT database were included in the analyses. A non-linear Weibull model best described the ALS disease progression, and a stepwise logistic regression approach was used to select the variables predicting a slow or fast disease progression. Results identified two clusters of trajectories: 1) slow disease progressors (46% of patients with a change from baseline of 13%); 2) fast disease progressors (54% of patients with a change from baseline of 49%). ROC curve analysis estimated the optimal cut-off for classifying patients as slow or fast disease progressors given ALSFRS-R measurements at 2-4 weeks. Results showed that the degree of ALS disease progression quantified by the ALSFRS-R symptomatic change on placebo is highly heterogeneous. In conclusion, this finding indicates the potential interest of disease progression models for implementing a population enrichment strategy to control the level of heterogeneity in the patients included in new trials.}, }
@article {pmid24070095, year = {2013}, author = {Kaushik, DK and Basu, A}, title = {A friend in need may not be a friend indeed: role of microglia in neurodegenerative diseases.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {12}, number = {6}, pages = {726-740}, doi = {10.2174/18715273113126660170}, pmid = {24070095}, issn = {1996-3181}, mesh = {Alzheimer Disease/metabolism/pathology ; Animals ; Brain/metabolism/*pathology ; Humans ; Inflammation Mediators/physiology ; Microglia/metabolism/*pathology/*physiology ; Multiple Sclerosis/metabolism/pathology ; Neurodegenerative Diseases/metabolism/*pathology ; Parkinson Disease/metabolism/pathology ; }, abstract = {Inflammation plays a critical role in the progression of neurodegenerative diseases. Microglia are the resident macrophages of the central nervous system (CNS) which actively take part in the neuronal development of CNS and are involved in clearance of pathogens as well as cellular debris from the system upon insult to this organization. Chronic activation of microglia in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) as well as inflammatory conditions of CNS such as multiple sclerosis (MS) results in overall upregulation of pro-inflammatory cytokines and chemokines in the brain parenchyma. This compromises the neuronal health which further activates microglia by releasing death associated molecules such as neuromelanin, Aβ peptides and cellular debris at the lesion site thereby forming a vicious cycle of disease advancement. Targeting microglial activation has proven to be a viable option in the treatment of inflammation related neurodegenerative diseases. This review will discuss the central position of inflammation and therapeutic strategies aiming to alleviate disease progression in some of the important inflammatory conditions of CNS.}, }
@article {pmid24069165, year = {2013}, author = {Sun, H and Bénardais, K and Stanslowsky, N and Thau-Habermann, N and Hensel, N and Huang, D and Claus, P and Dengler, R and Stangel, M and Petri, S}, title = {Therapeutic potential of mesenchymal stromal cells and MSC conditioned medium in Amyotrophic Lateral Sclerosis (ALS)--in vitro evidence from primary motor neuron cultures, NSC-34 cells, astrocytes and microglia.}, journal = {PloS one}, volume = {8}, number = {9}, pages = {e72926}, pmid = {24069165}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Apoptosis/drug effects ; Astrocytes/drug effects/*metabolism ; Cells, Cultured ; Chemokine CX3CL1/metabolism ; Ciliary Neurotrophic Factor/metabolism ; Culture Media, Conditioned/pharmacology ; Glial Cell Line-Derived Neurotrophic Factors/metabolism ; Humans ; Mesenchymal Stem Cells/drug effects/*metabolism ; Mice ; Microglia/drug effects/*metabolism ; Motor Neurons/drug effects/*metabolism ; Staurosporine/pharmacology ; }, abstract = {Administration of mesenchymal stromal cells (MSC) improves functional outcome in the SOD1G93A mouse model of the degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) as well as in models of other neurological disorders. We have now investigated the effect of the interaction between MSC and motor neurons (derived from both non-transgenic and mutant SOD1G93A transgenic mice), NSC-34 cells and glial cells (astrocytes, microglia) (derived again from both non-transgenic and mutant SOD1G93A ALS transgenic mice) in vitro. In primary motor neurons, NSC-34 cells and astrocytes, MSC conditioned medium (MSC CM) attenuated staurosporine (STS) - induced apoptosis in a concentration-dependent manner. Studying MSC CM-induced expression of neurotrophic factors in astrocytes and NSC-34 cells, we found that glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) gene expression in astrocytes were significantly enhanced by MSC CM, with differential responses of non-transgenic and mutant astrocytes. Expression of Vascular Endothelial Growth Factor (VEGF) in NSC-34 cells was significantly upregulated upon MSC CM-treatment. MSC CM significantly reduced the expression of the cytokines TNFα and IL-6 and iNOS both in transgenic and non-transgenic astrocytes. Gene expression of the neuroprotective chemokine Fractalkine (CX3CL1) was also upregulated in mutant SOD1G93A transgenic astrocytes by MSC CM treatment. Correspondingly, MSC CM increased the respective receptor, CX3CR1, in mutant SOD1G93A transgenic microglia. Our data demonstrate that MSC modulate motor neuronal and glial response to apoptosis and inflammation. MSC therefore represent an interesting candidate for further preclinical and clinical evaluation in ALS.}, }
@article {pmid24067168, year = {2014}, author = {Dreyer, P and Lorenzen, CK and Schou, L and Felding, M}, title = {Survival in ALS with home mechanical ventilation non-invasively and invasively: a 15-year cohort study in west Denmark.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {15}, number = {1-2}, pages = {62-67}, doi = {10.3109/21678421.2013.837929}, pmid = {24067168}, issn = {2167-9223}, mesh = {Adult ; Age Factors ; Aged ; Amyotrophic Lateral Sclerosis/complications/*mortality/*therapy ; Cohort Studies ; Denmark ; Female ; *Home Care Services ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Proportional Hazards Models ; Respiration, Artificial/*methods ; Respiratory Insufficiency/etiology/mortality/*therapy ; }, abstract = {Our objective was to describe patient characteristics, survival and long-term outcome in amyotrophic lateral sclerosis (ALS) patients treated with non-invasive and invasive home mechanical ventilation (HMV). A single-centre cohort study over a 15-years period (1998-2012) was performed. All ALS patients admitted to the centre were enrolled in the study. All patients were offered treatment with non-invasive and/or invasive HMV. The patients were divided into four groups: 1) no treatment; 2) treatment with non-invasive HMV; 3) treatment with non-invasive HMV followed by invasive HMV by tracheostomy; and 4) treatment with invasive HMV by tracheostomy. Patient characteristics and effects on survival were studied. Four hundred and thirty-one patients with ALS were admitted to a referral respiratory care unit (RCU) in the period January 1998 to June 2012. The average treatment time in the groups was: 1) 22.9 months (range 1-164); 2) 25.8 months (range 1-145); 3) 56.8 months (range 14-207); and 4) 33.8 months (range 6-88). Non-invasive HMV followed by invasive HMV is a possible treatment of respiratory symptoms in ALS and has a significant effect on survival.}, }
@article {pmid24066863, year = {2013}, author = {O'Leary, VB and Ovsepian, SV and Bodeker, M and Dolly, JO}, title = {Improved lentiviral transduction of ALS motoneurons in vivo via dual targeting.}, journal = {Molecular pharmaceutics}, volume = {10}, number = {11}, pages = {4195-4206}, doi = {10.1021/mp400247t}, pmid = {24066863}, issn = {1543-8392}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Cells, Cultured ; Central Nervous System/*cytology ; Female ; Glycoproteins/chemistry ; Green Fluorescent Proteins/metabolism ; Lentivirus/*genetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Spinal Cord/cytology ; Streptavidin/*chemistry ; Tetanus Toxin/chemistry/*therapeutic use ; }, abstract = {Treatment of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, is hampered by its complex etiology and lack of efficient means for targeted transfer of therapeutics into motoneurons. The objective of this research was engineering of a versatile motoneuron targeting adapter--a full-length atoxic tetanus toxin fused to core-streptavidin (CS-TeTIM)--for retro-axonal transduction of viral vectors; validation of the targeting efficiency of CS-TeTIM in vivo, by expression of green fluorescence protein (GFP) reporter in motoneurons of presymptomatic and symptomatic ALS-like SOD1(G93A) mice, and comparison with age-matched controls; and appraisal of lentiviral transduction with CS-TeTIM relative to (1) a HC binding fragment of tetanus toxin CS-TeTx(HC), (2) rabies glycoprotein (RG), and (3) a CS-TeTIM-RG dual targeting approach. CS-TeTIM and CS-TeTx(HC) were engineered using recombinant technology and site-directed mutagenesis. Biotinylated vectors, pseudotyped with vesicular stomatitis virus glycoprotein (VSV-G) or RG, were linked to these adaptors and injected intraperitoneally (ip) into presymptomatic (12 weeks old), symptomatic SOD1(G93A) (22 weeks old) or wild type control mice, followed by monitoring of GFP expression in the spinal cord and supraspinal motor structures with quantitative PCR and immuno-histochemistry. Transcripts were detected in the spinal cord and supraspinal motor structures of all mice 2 weeks after receiving a single ip injection, although in symptomatic SOD1(G93A) animals reporter RNA levels were lower compared to presymptomatic and wild-type controls irrespective of the targeting approach. GFP transduction with CS-TeTIM proved more efficient than CS-TeTx(HC) across all groups while CS-TeTIM-RG dual-targeted vectors yielded the highest transcript numbers. Importantly, in both wild-type and presymptomatic SOD1(G93A) mice strong colabeling of choline-acetyltransferase (ChAT) and GFP was visualized in neurons of the brain stem and spinal cord. CS-TeTIM, a versatile adaptor protein for targeted lentiviral transduction of motoneurons, has been engineered and its competence assessed relative to CS-TeTx(HC) and RG. Evidence has been provided that highlights the potential usefulness of this novel recombinant tool for basic research with implications for improved transfer of therapeutic candidates into motoneurons for the amelioration of ALS and related diseases.}, }
@article {pmid24023695, year = {2013}, author = {Novoselov, SS and Mustill, WJ and Gray, AL and Dick, JR and Kanuga, N and Kalmar, B and Greensmith, L and Cheetham, ME}, title = {Molecular chaperone mediated late-stage neuroprotection in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {8}, number = {8}, pages = {e73944}, pmid = {24023695}, issn = {1932-6203}, support = {G0700412/MRC_/Medical Research Council/United Kingdom ; MR/K000608/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology/physiopathology ; Animals ; Body Weight ; Cattle ; Cell Survival ; Disease Models, Animal ; Disease Progression ; Female ; HSP40 Heat-Shock Proteins/*metabolism ; Humans ; Longevity ; Male ; Mice ; Mice, Transgenic ; Models, Biological ; Molecular Chaperones/*metabolism ; Motor Neurons/pathology ; Muscles/physiopathology ; Neuroprotective Agents/*metabolism ; Organ Size ; Protein Structure, Quaternary ; Spinal Cord/metabolism/pathology/physiopathology ; Superoxide Dismutase/chemistry/*genetics/metabolism ; Ubiquitination ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of motor neurons in the spinal cord, brain stem, and motor cortex. Mutations in superoxide dismutase (SOD1) are associated with familial ALS and lead to SOD1 protein misfolding and aggregation. Here we show that the molecular chaperone, HSJ1 (DNAJB2), mutations in which cause distal hereditary motor neuropathy, can reduce mutant SOD1 aggregation and improve motor neuron survival in mutant SOD1 models of ALS. Overexpression of human HSJ1a (hHSJ1a) in vivo in motor neurons of SOD1(G93A) transgenic mice ameliorated disease. In particular, there was a significant improvement in muscle force, increased motor unit number and enhanced motor neuron survival. hHSJ1a was present in a complex with SOD1(G93A) and led to reduced SOD1 aggregation at late stages of disease progression. We also observed altered ubiquitin immunoreactivity in the double transgenic animals, suggesting that ubiquitin modification might be important for the observed improvements. In a cell model of SOD1(G93A) aggregation, HSJ1a preferentially bound to mutant SOD1, enhanced SOD1 ubiquitylation and reduced SOD1 aggregation in a J-domain and ubiquitin interaction motif (UIM) dependent manner. Collectively, the data suggest that HSJ1a acts on mutant SOD1 through a combination of chaperone, co-chaperone and pro-ubiquitylation activity. These results show that targeting SOD1 protein misfolding and aggregation in vivo can be neuroprotective and suggest that manipulation of DnaJ molecular chaperones might be useful in the treatment of ALS.}, }
@article {pmid24018744, year = {2013}, author = {Tanaka, H}, title = {[Old or new medicine? Vitamin B12 and peripheral nerve neuropathy].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {65}, number = {9}, pages = {1077-1082}, pmid = {24018744}, issn = {1881-6096}, mesh = {Humans ; Neural Conduction/drug effects ; Neurons/drug effects ; Peripheral Nervous System Diseases/*drug therapy ; Signal Transduction/drug effects ; Vitamin B 12/analogs &amp; derivatives/*pharmacology/therapeutic use ; }, abstract = {Methylcobalamin is a vitamin B12 analog that is necessary for nervous system maintenance. Although methylcobalamin has some positive effects on peripheral nervous system disorders, the mechanism through which it affects neurons are not entirely known. Recent studies have revealed its intracellular signaling pathway and some of its molecular actions on neurons. In this article, I review interactions between methylcobalamin and neurons that have been revealed through in vitro studies, in vivo studies, and clinical use. Methylcobalamin participates in nervous system maintenance through several mechanisms. Methylcobalamin is an active form of vitamin B12, and a coenzyme of methionine synthase, which is required for DNA and protein methylation. In addition, methylcobalamin facilitates neurite outgrowth and inhibits neural apoptosis through the Erk1/2 and Akt signaling pathways. Treatment with high doses of methylcobalamin ameliorates symptoms and negative electrophysiological findings in animal models of peripheral nerve neuropathy and in patients with carpal tunnel syndrome and amyotrophic lateral sclerosis. Thus, high-dose methylcobalamin has great potential for treating nervous system disorders. Further investigations with methylcobalamin may help elucidate its mechanisms of action, which may further enable us to treat many nervous system disorders.}, }
@article {pmid24018694, year = {2014}, author = {Riley, J and Glass, J and Feldman, EL and Polak, M and Bordeau, J and Federici, T and Johe, K and Boulis, NM}, title = {Intraspinal stem cell transplantation in amyotrophic lateral sclerosis: a phase I trial, cervical microinjection, and final surgical safety outcomes.}, journal = {Neurosurgery}, volume = {74}, number = {1}, pages = {77-87}, doi = {10.1227/NEU.0000000000000156}, pmid = {24018694}, issn = {1524-4040}, support = {R01 NS077982/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*surgery ; Female ; Fetal Stem Cells/*transplantation ; Humans ; Injections, Spinal ; Male ; Microinjections ; Middle Aged ; Neural Stem Cells/*transplantation ; Postoperative Complications/pathology ; Stem Cell Transplantation/adverse effects/*methods ; }, abstract = {BACKGROUND: The first US Food and Drug Administration approved clinical trial for a stem cell-based treatment of amyotrophic lateral sclerosis has now been completed.<br><br>OBJECTIVE: Primary aims assessed the safety of a direct microinjection-based technique and the toxicity of neural stem cell transplantation to the ventral horn of the cervical and thoracolumbar spinal cord. Results from thoracolumbar-only microinjection groups have been previously published. Cervical and cervical plus thoracolumbar microinjection group perioperative morbidity results are presented.<br><br>METHODS: Eighteen microinjection procedures (n = 12 thoracolumbar [T10/11], n = 6 cervical [C3-5]) delivered NSI-566RSC (Neuralstem, Inc), a human neural stem cell, to 15 patients in 5 cohorts. Each injection series comprised 5 injections of 10 &#x3bc;L at 4-mm intervals. The patients in group A (n = 6) were nonambulatory and received unilateral (n = 3) or bilateral (n = 3) thoracolumbar microinjections. The patients in groups B to E were ambulatory and received either unilateral (group B, n = 3) or bilateral (group C, n = 3) thoracolumbar microinjection. Group D and E patients received unilateral cervical (group D, n = 3) or cervical plus bilateral thoracolumbar microinjection (group E, n = 3).<br><br>RESULTS: Unilateral cervical (group D, n = 3) and cervical plus thoracolumbar (group E, n = 3) microinjections to the ventral horn have been completed in ambulatory patients. One patient developed a postoperative kyphotic deformity prompting completion of a laminoplasty in subsequent patients. Another required reoperation for wound dehiscence and infection. The solitary patient with bulbar amyotrophic lateral sclerosis required perioperative reintubation.<br><br>CONCLUSION: Delivery of a cellular payload to the cervical or thoracolumbar spinal cord was well tolerated by the spinal cord in this vulnerable population. This encouraging finding supports consideration of this delivery approach for neurodegenerative, oncologic, and traumatic spinal cord afflictions.}, }
@article {pmid23999914, year = {2014}, author = {Hölscher, C}, title = {Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases.}, journal = {The Journal of endocrinology}, volume = {221}, number = {1}, pages = {T31-41}, doi = {10.1530/JOE-13-0221}, pmid = {23999914}, issn = {1479-6805}, mesh = {Animals ; Glucagon-Like Peptide 1/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/*therapeutic use ; }, abstract = {The incretin hormone glucagon-like peptide 1 (GLP-1) has many effects in the body. It is best known for the 'incretin effect', facilitating insulin release from the pancreas under hyperglycaemic conditions. Building on this, GLP-1 mimetics have been developed as a treatment for type 2 diabetes. In the course of monitoring of patients, it has become apparent that GLP-1 mimetics have a range of other physiological effects in the body. In preclinical trials, a substantial body of evidence has been built that these mimetics have neuroprotective and anti-inflammatory effects. GLP-1 also has very similar growth-factor-like properties to insulin, which is presumably the underlying basis of the neuroprotective effects. In preclinical studies of Alzheimer's disease (AD), Parkinson's disease (PD), stroke and other neurodegenerative disorders, it has been shown that most GLP-1 mimetics cross the blood-brain barrier and show impressive neuroprotective effects in numerous studies. In animal models of AD, GLP-1 mimetics such as exendin-4, liraglutide and lixisenatide have shown protective effects in the CNS by reducing β-amyloid plaques, preventing loss of synapses and memory impairments, and reducing oxidative stress and the chronic inflammatory response in the brain. In animal models of PD, exendin-4 showed protection of dopaminergic neurons in the substantia nigra and prevention of dopamine loss in the basal ganglia while preserving motor control. These encouraging findings have spawned several clinical trials, some of which have shown encouraging initial results. Therefore, GLP-1 mimetics show great promise as a novel treatment for neurodegenerative conditions.}, }
@article {pmid23994186, year = {2013}, author = {Seo, J and Howell, MD and Singh, NN and Singh, RN}, title = {Spinal muscular atrophy: an update on therapeutic progress.}, journal = {Biochimica et biophysica acta}, volume = {1832}, number = {12}, pages = {2180-2190}, pmid = {23994186}, issn = {0006-3002}, support = {R01 NS055925/NS/NINDS NIH HHS/United States ; R21 NS072259/NS/NINDS NIH HHS/United States ; R21 NS080294/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Muscular Atrophy, Spinal/*therapy ; }, abstract = {Humans have two nearly identical copies of survival motor neuron gene: SMN1 and SMN2. Deletion or mutation of SMN1 combined with the inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA affects 1 in ~6000 live births, a frequency much higher than in several genetic diseases. The major known defect of SMN2 is the predominant exon 7 skipping that leads to production of a truncated protein (SMNΔ7), which is unstable. Therefore, SMA has emerged as a model genetic disorder in which almost the entire disease population could be linked to the aberrant splicing of a single exon (i.e. SMN2 exon 7). Diverse treatment strategies aimed at improving the function of SMN2 have been envisioned. These strategies include, but are not limited to, manipulation of transcription, correction of aberrant splicing and stabilization of mRNA, SMN and SMNΔ7. This review summarizes up to date progress and promise of various in vivo studies reported for the treatment of SMA.}, }
@article {pmid23984863, year = {2013}, author = {Stokholm, MG and Bisgård, C and Vilholm, OJ}, title = {Safety and administration of treatment with botulinum neurotoxin for sialorrhoea in ALS patients: review of the literature and a proposal for tailored treatment.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {7-8}, pages = {516-520}, doi = {10.3109/21678421.2013.830312}, pmid = {23984863}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*epidemiology/physiopathology ; Botulinum Toxins/adverse effects/*therapeutic use ; Botulinum Toxins, Type A/adverse effects/*therapeutic use ; Deglutition Disorders/chemically induced ; Humans ; Sialorrhea/*drug therapy/*epidemiology/physiopathology ; Treatment Outcome ; }, abstract = {Botulinum neurotoxin (BoNT) is a second-line treatment of sialorrhoea in ALS (amyotrophic lateral sclerosis) patients. This article is a review of the published literature concerning safety and administration of this treatment to ALS patients. A PubMed search was performed. All original publications on BoNT treatment of sialorrhoea in ALS patients were included in the review. Only a few adverse events were observed concerning treatment with BoNT. The studies performed to date have applied different treatment strategies with different dosages. In conclusion, BoNT treatment for sialorrhoea in ALS patients is safe with few adverse effects. The authors advocate for the implementation of a personalized treatment strategy. Special precautions must be taken when patients do not have the assistance of a ventilator and a feeding tube.}, }
@article {pmid23983902, year = {2013}, author = {Milani, P and Ambrosi, G and Gammoh, O and Blandini, F and Cereda, C}, title = {SOD1 and DJ-1 converge at Nrf2 pathway: a clue for antioxidant therapeutic potential in neurodegeneration.}, journal = {Oxidative medicine and cellular longevity}, volume = {2013}, number = {}, pages = {836760}, pmid = {23983902}, issn = {1942-0994}, mesh = {Animals ; Antioxidants/*therapeutic use ; Humans ; Intracellular Signaling Peptides and Proteins/*metabolism ; NF-E2-Related Factor 2/*metabolism ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Oncogene Proteins/*metabolism ; Oxidative Stress/drug effects ; Protein Deglycase DJ-1 ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Neurodegenerative diseases share diverse pathological features and among these oxidative stress (OS) plays a leading role. Impaired activity and reduced expression of antioxidant proteins have been reported as common events in several aging-associated disorders. In this review paper, we first provide an overview of the involvement of reactive oxygen species- (ROS-) induced oxidative damage in Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Subsequently, we focus on DJ-1 and SOD1 proteins, which are involved in PD and ALS and also exert a prominent role in the interaction between redox homeostasis and neurodegeneration. Interestingly, recent studies demonstrated that DJ-1 and SOD1 are both tightly connected with Nrf2 protein, a transcriptional factor and master regulator of the expression of many antioxidant/detoxification genes. Nrf2 is emerging as a key neuroprotective protein in neurodegenerative diseases, since it helps neuronal cells to cope with toxic insults and OS. We herein summarize the recent literature providing a detailed picture of the promising therapeutic efficacy of Nrf2 natural and synthetic inducers as disease-modifying molecules for the treatment of neurodegenerative diseases.}, }
@article {pmid23983606, year = {2013}, author = {Willard, SS and Koochekpour, S}, title = {Glutamate signaling in benign and malignant disorders: current status, future perspectives, and therapeutic implications.}, journal = {International journal of biological sciences}, volume = {9}, number = {7}, pages = {728-742}, pmid = {23983606}, issn = {1449-2288}, support = {P30 CA016056/CA/NCI NIH HHS/United States ; }, mesh = {Clinical Trials as Topic ; Excitatory Amino Acid Antagonists/therapeutic use ; Female ; Glutamic Acid/*physiology ; Humans ; Male ; Neoplasms/*physiopathology ; Neurodegenerative Diseases/*physiopathology ; Neurotransmitter Agents ; Receptors, Ionotropic Glutamate/*physiology ; Receptors, Metabotropic Glutamate/*physiology ; Signal Transduction/*physiology ; }, abstract = {Glutamate, a nonessential amino acid, is the major excitatory neurotransmitter in the central nervous system. As such, glutamate has been shown to play a role in not only neural processes, such as learning and memory, but also in bioenergetics, biosynthetic and metabolic oncogenic pathways. Glutamate has been the target of intense investigation for its involvement not only in the pathogenesis of benign neurodegenerative diseases (NDDs) such as Parkinson's disease, Alzheimer's disease, schizophrenia, multiple sclerosis, and amyotropic lateral sclerosis (ALS), but also in carcinogenesis and progression of malignant diseases. In addition to its intracellular activities, glutamate in secreted form is a phylogenetically conserved cell signaling molecule. Glutamate binding activates multiple major receptor families including the metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs), both of which have been implicated in various signaling pathways in cancer. Inhibition of extracellular glutamate release or glutamate receptor activation via competitive or non-competitive antagonists decreases growth, migration and invasion and induces apoptosis in breast cancer, melanoma, glioma and prostate cancer cells. In this review, we discuss the current state of glutamate signaling research as it relates to benign and malignant diseases. In addition, we provide a synopsis of clinical trials using glutamate antagonists for the treatment of NDD and malignant diseases. We conclude that in addition to its potential role as a metabolic biomarker, glutamate receptors and glutamate-initiated signaling pathways may provide novel therapeutic opportunities for cancer.}, }
@article {pmid23973733, year = {2013}, author = {Vere Hodge, RA}, title = {Meeting report: 26th International Conference on Antiviral Research.}, journal = {Antiviral research}, volume = {100}, number = {1}, pages = {276-285}, pmid = {23973733}, issn = {1872-9096}, mesh = {Animals ; Antiviral Agents/chemistry/*pharmacology ; Clinical Trials as Topic ; Drug Design ; Humans ; Virus Diseases/diagnosis/*drug therapy/virology ; Virus Physiological Phenomena/drug effects ; Viruses/*drug effects ; }, abstract = {The 26th International Conference on Antiviral Research (ICAR) was held in San Francisco, California from May 11 to 15, 2013. This article summarizes the principal invited lectures at the meeting. The opening symposium on the legacy of the late Antonín Holý included presentations on his pioneering work with nucleotide analogs, which led to the development of several antiviral drugs including tenofovir. This drug has transformed the treatment of HIV infection and has recently become the first-line therapy for chronic hepatitis B. The Gertrude Elion Award lecturer described the anti-HIV activities of the CCR5 inhibitor cenicriviroc and the reverse transcriptase inhibitor festinavir®, and also reviewed the evaluation of biodegradable nanoparticles with adjuvant activity. The William Prusoff Award winner reported on the creation of NAOMI, a computer model with 21 enzymes to predict the activity of nucleoside analogs against hepatitis C virus (HCV). Other invited lecturers discussed the development of countermeasures against severe dengue and the potential of RNA virus capping and repair enzymes as drug targets. Topics in the clinical symposium included the current status of the anti-HCV compounds sovaprevir, ACH-3102, miravirsen and ALS-2200; the evaluation of single-tablet regimens for HIV infection; and the investigation of cytomegalovirus resistance to CMX001. Two chemistry minisymposia examined strategies and tactics in drug design and the use of in drug discovery.}, }
@article {pmid23969235, year = {2013}, author = {Milani, P and Amadio, M and Laforenza, U and Dell'Orco, M and Diamanti, L and Sardone, V and Gagliardi, S and Govoni, S and Ceroni, M and Pascale, A and Cereda, C}, title = {Posttranscriptional regulation of SOD1 gene expression under oxidative stress: Potential role of ELAV proteins in sporadic ALS.}, journal = {Neurobiology of disease}, volume = {60}, number = {}, pages = {51-60}, doi = {10.1016/j.nbd.2013.08.005}, pmid = {23969235}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; ELAV Proteins/*metabolism ; Female ; *Gene Expression Regulation ; Humans ; Male ; Middle Aged ; Oxidative Stress/*genetics ; Superoxide Dismutase/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Increased levels of SOD1 mRNA have been observed in sporadic ALS patients (SALS) compared to controls. Hence, the understanding of the mechanisms by which SOD1 gene expression is modulated may shed new light on SOD1 involvement in ALS. Of interest, some adenine/uracil-rich elements (AREs) in SOD1 3'-untranslated region have been identified. These sequences represent the docking sites for several RNA-binding proteins such as ELAV proteins (ELAVs), positive regulators of gene expression. We first investigated in SH-SY5Y cells whether SOD1 mRNA represents a target of ELAVs. Results from RNA Electrophoretic Mobility Shift and RNA-immunoprecipitation assays showed a molecular interaction between ELAVs and SOD1 mRNA. We also observed that the treatment with H2O2 induced a significant increase of the amount of SOD1 mRNA bound by ELAVs and an up-regulation of SOD1 protein levels. We found a specific increase in ELAV/HuR phosphorylation, suggesting activation of this protein, in peripheral blood mononuclear cells from SALS patients compared to controls. Finally, we found increased levels of ELAV proteins in the motor cortex and spinal cord from SALS patients compared to controls, in parallel with SOD1 up-regulation in the same areas. This study suggests, for the first time, that ELAVs are involved in the regulation of SOD1 gene expression at post-transcriptional level and that these proteins are more activated in ALS pathology. The link between ELAVs and SOD1 may open novel perspectives for ALS research, paving the way for new therapeutic options.}, }
@article {pmid23967343, year = {2013}, author = {Pinkernelle, J and Fansa, H and Ebmeyer, U and Keilhoff, G}, title = {Prolonged minocycline treatment impairs motor neuronal survival and glial function in organotypic rat spinal cord cultures.}, journal = {PloS one}, volume = {8}, number = {8}, pages = {e73422}, pmid = {23967343}, issn = {1932-6203}, mesh = {Animals ; Anti-Bacterial Agents/*pharmacology/toxicity ; Cell Culture Techniques ; Cell Movement/drug effects ; Cell Survival/drug effects ; Coculture Techniques ; Minocycline/*pharmacology/toxicity ; Motor Neurons/*drug effects ; Neuroglia/*drug effects/*metabolism ; Organ Culture Techniques ; Rats ; Spinal Cord/*drug effects ; Time Factors ; }, abstract = {BACKGROUND: Minocycline, a second-generation tetracycline antibiotic, exhibits anti-inflammatory and neuroprotective effects in various experimental models of neurological diseases, such as stroke, Alzheimer's disease, amyotrophic lateral sclerosis and spinal cord injury. However, conflicting results have prompted a debate regarding the beneficial effects of minocycline.<br><br>METHODS: In this study, we analyzed minocycline treatment in organotypic spinal cord cultures of neonatal rats as a model of motor neuron survival and regeneration after injury. Minocycline was administered in 2 different concentrations (10 and 100 &#xb5;M) at various time points in culture and fixed after 1 week.<br><br>RESULTS: Prolonged minocycline administration decreased the survival of motor neurons in the organotypic cultures. This effect was strongly enhanced with higher concentrations of minocycline. High concentrations of minocycline reduced the number of DAPI-positive cell nuclei in organotypic cultures and simultaneously inhibited microglial activation. Astrocytes, which covered the surface of the control organotypic cultures, revealed a peripheral distribution after early minocycline treatment. Thus, we further analyzed the effects of 100 &#xb5;M minocycline on the viability and migration ability of dispersed primary glial cell cultures. We found that minocycline reduced cell viability, delayed wound closure in a scratch migration assay and increased connexin 43 protein levels in these cultures.<br><br>CONCLUSIONS: The administration of high doses of minocycline was deleterious for motor neuron survival. In addition, it inhibited microglial activation and impaired glial viability and migration. These data suggest that especially high doses of minocycline might have undesired affects in treatment of spinal cord injury. Further experiments are required to determine the conditions for the safe clinical administration of minocycline in spinal cord injured patients.}, }
@article {pmid23965408, year = {2013}, author = {Lacomis, D and El-Dokla, A}, title = {What's in the literature?.}, journal = {Journal of clinical neuromuscular disease}, volume = {15}, number = {1}, pages = {34-42}, doi = {10.1097/CND.0b013e3182a3b21c}, pmid = {23965408}, issn = {1537-1611}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Humans ; Muscular Diseases/drug therapy ; Muscular Dystrophy, Duchenne/drug therapy ; Myasthenia Gravis/therapy ; *Neuromuscular Diseases ; }, abstract = {In amyotrophic lateral sclerosis (ALS), a recent double-blind placebo-controlled trial of acetyl-L-carnitine along with riluzole showed probable benefit in 42 patients compared with 40 patients who received placebo. Using an electrophysiologic measure devised to differentiate ALS from other neuromuscular conditions, a "splint-hand index" was devised and is reviewed. Analysis of skin in ALS may also be of interest, and there was a report of accumulation of fused in sarcoma protein in the epidermis of ALS patients. With regard to myasthenia gravis, there is another report that early treatment of ocular symptoms with corticosteroids may prevent the development of generalized symptoms. A new study of thymus histopathology in muscle-specific tyrosine kinase (MuSK) myasthenia gravis is covered and another article on the use of thymectomy. In Duchenne muscular dystrophy, the best method of administrating corticosteroids is still being debated, and a long-term study of daily versus intermittent prednisolone is reviewed. The study showed less sustained benefit from the intermittent prednisolone but with a better side effect profile. According to 2 recent reports, it seems that titin mutations may be an underrecognized cause of myopathy with early respiratory failure in adults. Keeping with the respiratory failure theme, there was also an interesting article on the long-term benefits and side effects of cyclosporine in patients with interstitial lung disease from antisynthetase syndrome. Finally, the spectrum of small fiber neuropathy may be expanding to include a causative role in some patients with fibromyalgia syndrome and in juveniles with diffuse pain and a possible autoimmune predisposition.}, }
@article {pmid23962993, year = {2013}, author = {Fehlings, MG and Wilson, JR and Karadimas, SK and Arnold, PM and Kopjar, B}, title = {Clinical evaluation of a neuroprotective drug in patients with cervical spondylotic myelopathy undergoing surgical treatment: design and rationale for the CSM-Protect trial.}, journal = {Spine}, volume = {38}, number = {22 Suppl 1}, pages = {S68-75}, doi = {10.1097/BRS.0b013e3182a7e9b0}, pmid = {23962993}, issn = {1528-1159}, mesh = {Cervical Vertebrae/*drug effects/pathology/surgery ; Clinical Trials, Phase III as Topic ; Combined Modality Therapy ; Humans ; Neuroprotective Agents/therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole/*therapeutic use ; Spinal Cord Diseases/*drug therapy/surgery ; Spondylosis/*drug therapy/surgery ; Treatment Outcome ; }, abstract = {STUDY DESIGN: Descriptive article and narrative review.<br><br>OBJECTIVE: To explain the rationale and design of the cervical spondylotic myelopathy (CSM)-Protect clinical trial that aims to elucidate the efficacy and safety of riluzole in the context of CSM.<br><br>SUMMARY OF BACKGROUND DATA: CSM is the most common cause of spinal cord-related dysfunction internationally. Although surgery is effective in preventing the progression of impairment, and in some cases improving functional outcomes, many patients continue to exhibit significant disability in the postoperative setting. Evidence from preclinical studies suggests that glutamate-related excitotoxicity may contribute to the pathology of CSM and that administration of the sodium and glutamate-blocking medication riluzole, when combined with spinal cord decompression, may mitigate this effect and improve neurobehavioral outcomes. Although riluzole is FDA approved and has been shown to be safe and effective in the context of amyotrophic lateral sclerosis, its efficacy and safety in the context of CSM remain unknown.<br><br>METHODS: Descriptive article with narrative review of the literature.<br><br>RESULTS: In addition to providing pertinent preclinical background on the topic, this descriptive article and narrative review discusses the design and current status of an ongoing phase III randomized controlled trial evaluating the efficacy and safety of riluzole, combined with surgical decompression, in the treatment of CSM.<br><br>CONCLUSION: On the basis of current projections, we estimate that the interim analysis for this study will take place in the spring of 2014, at which time an adaptive sample size adjustment may take place.}, }
@article {pmid23962609, year = {2013}, author = {Moraes, CT and Anderson, V and Mohan, C and , }, title = {Translational research in primary mitochondrial diseases: challenges and opportunities.}, journal = {Mitochondrion}, volume = {13}, number = {6}, pages = {945-952}, doi = {10.1016/j.mito.2013.08.002}, pmid = {23962609}, issn = {1872-8278}, mesh = {Humans ; Mitochondrial Diseases/*physiopathology ; *Translational Research, Biomedical ; }, abstract = {On March 8–9, 2012, the NIH intramural and extramural research communities as well as representatives from industries and foundations with a common interest in primary mitochondrial diseases met in Bethesda to identify the major barriers to the development of better treatment for mitochondrial diseases. Besides the importance to the patient population, it has become clear in the last decade that advances in understanding and treating primary mitochondrial diseases will impact research into a large number of degenerative conditions known to have a significant mitochondrial dysfunction component in their pathogenic mechanisms (secondary mitochondrial diseases) that affect millions of people, including Alzheimer’s disease, Parkinson’s disease,diabetes, ALS, autism spectrum disorders, and many others. We would like to make this discussion available to the scientific community, as it provides a framework on how patient advocacy groups, individual academic units, pharmaceutical companies, and the NIH can interact to address problems related to mitochondrial diseases.The main goals of this workshop were as follows: (1) to share information related to primary mitochondrial disease among the NIH Intramural and Extramural Research Program Investigators, (2) to develop and/or enhance systems to facilitate future collaboration and sharing of information, (3) to survey obstacles, needs and priorities of primary mitochondrial diseases research, and (4) to develop mechanisms to enhance translation of basic science discoveries to diagnostics and therapeutics.}, }
@article {pmid23952668, year = {2013}, author = {McAllum, EJ and Lim, NK and Hickey, JL and Paterson, BM and Donnelly, PS and Li, QX and Liddell, JR and Barnham, KJ and White, AR and Crouch, PJ}, title = {Therapeutic effects of CuII(atsm) in the SOD1-G37R mouse model of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {7-8}, pages = {586-590}, doi = {10.3109/21678421.2013.824000}, pmid = {23952668}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/*genetics ; Animals ; Coordination Complexes ; Copper/*therapeutic use ; *Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Mice ; Mice, Transgenic ; Organometallic Compounds/*therapeutic use ; Random Allocation ; Superoxide Dismutase/*genetics ; Thiosemicarbazones/*therapeutic use ; Treatment Outcome ; }, abstract = {Our objective was to assess the copper(II) complex of diacetylbis(4-methylthiosemicarbazone) [Cu(II)(atsm)] for its preclinical potential as a novel therapeutic for ALS. Experimental paradigms used were designed to assess Cu(II)(atsm) efficacy relative to treatment with riluzole, as a function of dose administered, and when administered post symptom onset. Mice expressing human Cu/Zn superoxide dismutase harbouring the disease-causing G37R mutation (SOD1-G37R) were used and effects of Cu(II)(atsm) determined by assessing mouse survival and locomotor function (rotarod assay). Cu(II)(atsm) improved SOD1-G37R mouse survival and locomotor function in a dose-dependent manner. The highest dose tested improved survival by 26%. Riluzole had a modest effect on mouse survival (3.3%) but it did not improve locomotor function. Cotreatment with Cu(II)(atsm) did not alter the protective activity of Cu(II)(atsm) administered on its own. Commencing treatment with Cu(II)(atsm) after the onset of symptoms was less effective than treatments that commenced before symptom onset but still significantly improved locomotor function and survival. Improved locomotor function and survival of SOD1-G37R mice supports the potential for Cu(II)(atsm) as a novel treatment option for ALS.}, }
@article {pmid23946489, year = {2013}, author = {Ricard, MJ and Gudas, LJ}, title = {Cytochrome p450 cyp26a1 alters spinal motor neuron subtype identity in differentiating embryonic stem cells.}, journal = {The Journal of biological chemistry}, volume = {288}, number = {40}, pages = {28801-28813}, pmid = {23946489}, issn = {1083-351X}, support = {R01 CA043796/CA/NCI NIH HHS/United States ; T32 CA062948/CA/NCI NIH HHS/United States ; R01CA43796/CA/NCI NIH HHS/United States ; }, mesh = {Aldehyde Dehydrogenase/metabolism ; Aldehyde Dehydrogenase 1 Family ; Animals ; Biomarkers/metabolism ; *Cell Differentiation/drug effects ; Cytochrome P-450 Enzyme System/deficiency/*metabolism ; Embryonic Stem Cells/*cytology/drug effects/*enzymology ; Hedgehog Proteins/pharmacology ; Homeodomain Proteins/genetics/metabolism ; Immunohistochemistry ; Mice ; Motor Neurons/*cytology/drug effects/*enzymology ; Retinal Dehydrogenase ; Retinoic Acid 4-Hydroxylase ; Spinal Cord/*cytology ; Transcription Factors/metabolism ; Tretinoin/pharmacology ; }, abstract = {The ability to differentiate embryonic stem cells (ESCs) into specific cell types is critical for improved regenerative medicine strategies, cancer chemotherapeutic approaches, and regimens to combat chronic diseases associated with aging. Subclasses of motor neurons (MNs) are generated at different positions along the rostrocaudal axis of the spinal cord, and the signals that specify MN subtype fates remain poorly defined. We show here that the cytochrome P450 enzyme Cyp26a1, which metabolizes all-trans-retinoic acid (RA) and thereby reduces RA levels, plays a crucial role in specifying MN columnar subtypes. Lack of Cyp26a1 in ESCs during differentiation to spinal MNs increases Aldh1a2 (RALDH2) and Hoxc6, markers of the Hox-dependent, lateral motor column (LMC) subtype identity. In contrast, Lhx3, a marker for median motor column identity, showed lower expression in Cyp26a1(-/-)-derived MNs compared with WT. Without Cyp26a1, an increase in intracellular RA concentration plus sonic hedgehog agonist treatment confer an LMC fate on differentiating MNs. Our data suggest a strategy for increasing LMC-type MNs from ESCs by blocking Cyp26a1 in cell replacement/ESC differentiation therapy to treat neurodegenerative diseases, such as amyotrophic lateral sclerosis.}, }
@article {pmid23944684, year = {2013}, author = {Dorst, J and Cypionka, J and Ludolph, AC}, title = {High-caloric food supplements in the treatment of amyotrophic lateral sclerosis: a prospective interventional study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {7-8}, pages = {533-536}, doi = {10.3109/21678421.2013.823999}, pmid = {23944684}, issn = {2167-9223}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diet therapy/physiopathology ; Body Weight/*physiology ; Dietary Carbohydrates/*administration &amp; dosage ; Dietary Fats/*administration &amp; dosage ; *Dietary Supplements ; Early Medical Intervention/methods ; Energy Intake/*physiology ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; Treatment Outcome ; }, abstract = {Weight loss is an independent prognostic factor in amyotrophic lateral sclerosis (ALS). We investigated whether the body weight of ALS patients who previously lost weight can be stabilized by a high-caloric diet. For this purpose we compared two different high-caloric food supplements: one with high fat content and one with high carbohydrate content. Twenty-six patients were randomly allocated to one of the therapeutic groups. Body weight, ALS functional rating scale-revised (ALSFRS-R), static vital capacity (SVC), bioelectrical impedance analysis (BIA), metabolic serum parameters, and adverse events were investigated. Results showed that body weight of ALS patients could be stabilized in both therapeutic groups after 12 weeks of therapy (p = 0.008). The effect was greater in the group with high fat supplement though not statistically significant (p = 0.37). In conclusion, high-caloric food supplements with high fat as well as high carbohydrate content are both suitable to stabilize the body weight of ALS patients. The effect of a high fat diet might be more pronounced. Since body weight is an independent prognostic factor in ALS it is possible that a high-caloric food supplement improves survival in ALS. However, this hypothesis can only be tested by conducting a placebo-controlled double-blinded trial of sufficient power.}, }
@article {pmid23936040, year = {2013}, author = {Lucchetti, J and Marino, M and Papa, S and Tortarolo, M and Guiso, G and Pozzi, S and Bonetto, V and Caccia, S and Beghi, E and Bendotti, C and Gobbi, M}, title = {A mouse model of familial ALS has increased CNS levels of endogenous ubiquinol9/10 and does not benefit from exogenous administration of ubiquinol10.}, journal = {PloS one}, volume = {8}, number = {7}, pages = {e69540}, pmid = {23936040}, issn = {1932-6203}, support = {TCR08002/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/blood/*metabolism/pathology ; Animals ; Brain/drug effects/metabolism/pathology ; Central Nervous System/drug effects/*metabolism/pathology ; Disease Models, Animal ; Disease Progression ; Humans ; Mice ; Mice, Transgenic ; Spinal Cord/drug effects/metabolism/pathology ; Superoxide Dismutase/metabolism ; Ubiquinone/administration &amp; dosage/*analogs &amp; derivatives/blood/metabolism/pharmacology ; }, abstract = {Oxidative stress and mitochondrial impairment are the main pathogenic mechanisms of Amyotrophic Lateral Sclerosis (ALS), a severe neurodegenerative disease still lacking of effective therapy. Recently, the coenzyme-Q (CoQ) complex, a key component of mitochondrial function and redox-state modulator, has raised interest for ALS treatment. However, while the oxidized form ubiquinone10 was ineffective in ALS patients and modestly effective in mouse models of ALS, no evidence was reported on the effect of the reduced form ubiquinol10, which has better bioavailability and antioxidant properties. In this study we compared the effects of ubiquinone10 and a new stabilized formulation of ubiquinol10 on the disease course of SOD1(G93A) transgenic mice, an experimental model of fALS. Chronic treatments (800 mg/kg/day orally) started from the onset of disease until death, to mimic the clinical trials that only include patients with definite ALS symptoms. Although the plasma levels of CoQ10 were significantly increased by both treatments (from <0.20 to 3.0-3.4 µg/mL), no effect was found on the disease progression and survival of SOD1(G93A) mice. The levels of CoQ10 in the brain and spinal cord of ubiquinone10- or ubiquinol10-treated mice were only slightly higher (≤10%) than the endogenous levels in vehicle-treated mice, indicating poor CNS availability after oral dosing and possibly explaining the lack of pharmacological effects. To further examine this issue, we measured the oxidized and reduced forms of CoQ9/10 in the plasma, brain and spinal cord of symptomatic SOD1(G93A) mice, in comparison with age-matched SOD1(WT). Levels of ubiquinol9/10, but not ubiquinone9/10, were significantly higher in the CNS, but not in plasma, of SOD1(G93A) mice, suggesting that CoQ redox system might participate in the mechanisms trying to counteract the pathology progression. Therefore, the very low increases of CoQ10 induced by oral treatments in CNS might be not sufficient to provide significant neuroprotection in SOD1(G93A) mice.}, }
@article {pmid23934648, year = {2014}, author = {Liu, Y and Yu, JT and Zong, Y and Zhou, J and Tan, L}, title = {C9ORF72 mutations in neurodegenerative diseases.}, journal = {Molecular neurobiology}, volume = {49}, number = {1}, pages = {386-398}, pmid = {23934648}, issn = {1559-1182}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; C9orf72 Protein ; Frontotemporal Dementia/genetics/pathology ; Humans ; Mutation/*genetics ; Neurodegenerative Diseases/*genetics/pathology ; Proteins/*genetics ; }, abstract = {Recent works have demonstrated an expansion of the GGGGCC hexanucleotide repeat in the first intron of chromosome 9 open reading frame 72 (C9ORF72), encoding an unknown C9ORF72 protein, which was responsible for an unprecedented large proportion of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases of European ancestry. C9ORF72 is expressed in most tissues including the brain. Emerging evidence has demonstrated that C9ORF72 mutations could reduce the level of C9ORF72 variant 1, which may influence protein expression and the formation of nuclear RNA foci. The spectrum of mutations is broad and provides new insight into neurological diseases. Clinical manifestations of diseases related with C9ORF72 mutations can vary from FTD, ALS, primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), Huntington disease-like syndrome (HDL syndrome), to Alzheimer's disease. In this article, we will review the brief characterizations of the C9ORF72 gene, the expansion mutations, the related disorders, and their features, followed by a discussion of the deficiency knowledge of C9ORF72 mutations. Based on the possible pathological mechanisms of C9ORF72 mutations in ALS and FTD, we can find new targets for the treatment of C9ORF72 mutation-related diseases. Future studies into the mechanisms, taking into consideration the discovery of those disorders, will significantly accelerate new discoveries in this field, including targeting identification of new therapy.}, }
@article {pmid23933981, year = {2013}, author = {Bittner, S and Ruck, T and Schuhmann, MK and Herrmann, AM and Moha ou Maati, H and Bobak, N and Göbel, K and Langhauser, F and Stegner, D and Ehling, P and Borsotto, M and Pape, HC and Nieswandt, B and Kleinschnitz, C and Heurteaux, C and Galla, HJ and Budde, T and Wiendl, H and Meuth, SG}, title = {Endothelial TWIK-related potassium channel-1 (TREK1) regulates immune-cell trafficking into the CNS.}, journal = {Nature medicine}, volume = {19}, number = {9}, pages = {1161-1165}, pmid = {23933981}, issn = {1546-170X}, mesh = {Actins/metabolism ; Animals ; Anticonvulsants/pharmacology ; Blood-Brain Barrier/immunology/*metabolism ; Brain/immunology/*metabolism ; Cell Adhesion Molecules/biosynthesis/immunology ; Cell Movement ; Cells, Cultured ; Coculture Techniques ; Dendritic Cells ; Down-Regulation ; Encephalomyelitis, Autoimmune, Experimental/drug therapy/metabolism ; Endothelial Cells/*metabolism ; Female ; HEK293 Cells ; Humans ; Intercellular Adhesion Molecule-1/immunology/metabolism ; Interferon-alpha/pharmacology ; Leukocytes/metabolism ; Linseed Oil/administration &amp; dosage ; MAP Kinase Signaling System ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myelin-Oligodendrocyte Glycoprotein ; Peptide Fragments ; Potassium Channels, Tandem Pore Domain/genetics/*metabolism ; Riluzole/pharmacology ; Transendothelial and Transepithelial Migration ; }, abstract = {The blood-brain barrier (BBB) is an integral part of the neurovascular unit (NVU). The NVU is comprised of endothelial cells that are interconnected by tight junctions resting on a parenchymal basement membrane ensheathed by pericytes, smooth muscle cells and a layer of astrocyte end feet. Circulating blood cells, such as leukocytes, complete the NVU. BBB disruption is common in several neurological diseases, but the molecular mechanisms involved remain largely unknown. We analyzed the role of TWIK-related potassium channel-1 (TREK1, encoded by KCNK2) in human and mouse endothelial cells and the BBB. TREK1 was downregulated in endothelial cells by treatment with interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Blocking TREK1 increased leukocyte transmigration, whereas TREK1 activation had the opposite effect. We identified altered mitogen-activated protein (MAP) kinase signaling, actin remodeling and upregulation of cellular adhesion molecules as potential mechanisms of increased migration in TREK1-deficient (Kcnk2(-/-)) cells. In Kcnk2(-/-) mice, brain endothelial cells showed an upregulation of the cellular adhesion molecules ICAM1, VCAM1 and PECAM1 and facilitated leukocyte trafficking into the CNS. Following the induction of experimental autoimmune encephalomyelitis (EAE) by immunization with a myelin oligodendrocyte protein (MOG)35-55 peptide, Kcnk2(-/-) mice showed higher EAE severity scores that were accompanied by increased cellular infiltrates in the central nervous system (CNS). The severity of EAE was attenuated in mice given the amyotrophic lateral sclerosis drug riluzole or fed a diet enriched with linseed oil (which contains the TREK-1 activating omega-3 fatty acid α-linolenic acid). These beneficial effects were reduced in Kcnk2(-/-) mice, suggesting TREK-1 activating compounds may be used therapeutically to treat diseases related to BBB dysfunction.}, }
@article {pmid23933405, year = {2013}, author = {Funakoshi-Hirose, I and Aki, T and Unuma, K and Funakoshi, T and Noritake, K and Uemura, K}, title = {Distinct effects of methamphetamine on autophagy-lysosome and ubiquitin-proteasome systems in HL-1 cultured mouse atrial cardiomyocytes.}, journal = {Toxicology}, volume = {312}, number = {}, pages = {74-82}, doi = {10.1016/j.tox.2013.07.016}, pmid = {23933405}, issn = {1879-3185}, mesh = {Animals ; Autophagy/*drug effects ; Cells, Cultured ; Central Nervous System Stimulants/*toxicity ; Heme Oxygenase-1/physiology ; Lysosomes/*drug effects ; Methamphetamine/*toxicity ; Mice ; Myocytes, Cardiac/*drug effects/metabolism ; NF-E2-Related Factor 2/physiology ; Proteasome Endopeptidase Complex/*physiology ; Ubiquitin/*metabolism ; }, abstract = {The aim of this study is to investigate the molecular mechanism underling the cardiotoxicity of methamphetamine, a psychostimulant drug that is currently abused in the world. A mouse atrial cardiac cell line, HL-1, which retains phenotypes of cardiac cells and serves as a useful model for examining cardiac pathophysiology, was used for this purpose. During treatment with 1mM methamphetamine (MAP) for 3-48h, massive but transient cytoplasmic vacuolization (3-12h) followed by an intracellular accumulation of granules (24-48h) was observed under light microscopy. The vacuoles were surrounded by the lysosome membrane marker LAMP1, while the granules colocalized with the autophagy markers LC3 and p62 as well as ubiquitinated proteins. Western blot analysis showed that LC3 was activated during MAP administration, although p62 was not degraded but rather accumulated. Concordant with p62 accumulation, the nuclear translocation of an anti-oxidative transcription factor, Nrf2, and the subsequent induction of its target gene, HO-1, was observed, suggesting an impairment of autophagic protein degradation and the subsequent activation of the p62/Nrf2/HO-1 pathway. In addition, proteomic analysis revealed a reduction in myosin heavy chain (MHC) protein levels during MAP administration. The ubiquitination of MHC and the induction of the muscle sarcomere protein-specific E3 ubiquitin ligases MuRF1 and atrogin-1 were proved by immunoprecipitation and quantitative real-time PCR, respectively. Taken together, the vacuolization of lysosomes and the subsequent accumulation of autophagosomes indicate an impairment of autophagic protein degradation during MAP administration; on the other hand, the ubiquitination and subsequent degradation of MHC indicate the proper progression of proteasomal degradation.}, }
@article {pmid23931813, year = {2013}, author = {Pradat, PF and Delanian, S}, title = {Late radiation injury to peripheral nerves.}, journal = {Handbook of clinical neurology}, volume = {115}, number = {}, pages = {743-758}, doi = {10.1016/B978-0-444-52902-2.00043-6}, pmid = {23931813}, issn = {0072-9752}, mesh = {Humans ; Peripheral Nervous System Diseases/diagnosis/*etiology ; Radiation Injuries/*complications ; }, abstract = {Although the peripheral nerve has often been considered as radioresistant, clinical practice demonstrates the occurrence of radiation-induced peripheral neuropathies. Because these complications appear late, usually several years after the course of radiotherapy, their occurrence is explained by improvement in the prognosis of several cancers. Their physiopathology is not fully understood. Compression by radio-induced fibrosis probably plays a central role but direct injury to nerves and blood vessels is probably also involved. The most frequent and best known form of postradiation neuropathy is brachial plexopathy, which may follow irradiation for breast cancer. Recent reports demonstrate that postradiation neuropathies show a great heterogeneity, particularly in the anatomical sites, but also in the clinical, electrophysiological, and neuroimaging features. The link with radiotherapy may be difficult for the clinician to establish. Patients with radiation-induced lumbosacral radiculoplexopathy may be misdiagnosed with amyotrophic lateral sclerosis as they often present with pure lower motor neuron syndrome, or with leptomeningeal metastases since nodular MRI enhancement of the nerve roots of the cauda equina and increased CSF protein content can be observed. From a pathophysiological perspective, radiation-induced neuropathy offers an interesting model for deciphering the mechanisms of peripheral neuropathies due to environmental factors. Recent developments show promising strategies for the prevention and treatment of these complications, which have a considerable impact on a patient's quality of life.}, }
@article {pmid23931799, year = {2013}, author = {Gabbai, AA and Castelo, A and Oliveira, AS}, title = {HIV peripheral neuropathy.}, journal = {Handbook of clinical neurology}, volume = {115}, number = {}, pages = {515-529}, doi = {10.1016/B978-0-444-52902-2.00029-1}, pmid = {23931799}, issn = {0072-9752}, mesh = {HIV Infections/*complications ; Humans ; Peripheral Nervous System Diseases/complications/*etiology/*virology ; }, abstract = {Peripheral neuropathies are the most common neurological manifestations occurring in HIV-infected individuals. Distal symmetrical sensory neuropathy is the most common form encountered today and is one of the few that are specific to HIV infection or its treatment. The wide variety of other neuropathies is akin to the neuropathies seen in the general population and should be managed accordingly. In the pre-ART era, neuropathies were categorized according to the CD4 count and HIV viral load. In the early stages of HIV infection when CD4 count is high, the inflammatory demyelinating neuropathies predominate and in the late stages with the decline of CD4 count opportunistic infection-related neuropathies prevail. That scenario has changed with the present almost universal use of ART (antiretroviral therapy). Hence, HIV-associated peripheral neuropathies are better classified according to their clinical presentations: distal symmetrical polyneuropathy, acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), mononeuropathies, mononeuropathies multiplex and cranial neuropathies, autonomic neuropathy, lumbosacral polyradiculomyelopathy, and amyotrophic lateral sclerosis (ALS)-like motor neuropathy. Treated with ART, HIV-infected individuals are living longer and are at a higher risk of metabolic and age-related complications; moreover they are also prone to the potentially neurotoxic effects of ART. There are no epidemiological data regarding the incidence and prevalence of the peripheral neuropathies. In the pre-ART era, most data were from case reports, series of patients, and pooled autopsy data. At that time the histopathological evidence of neuropathies in autopsy series was almost 100%. In large prospective cohorts presently being evaluated, it has been found that 57% of HIV-infected individuals have distal symmetrical sensory neuropathy and 38% have neuropathic pain. It is now clear that distal symmetrical sensory neuropathy is caused predominantly by the ART's neurotoxic effect but may also be caused by the HIV itself. With a sizeable morbidity, the neuropathic pain caused by distal symmetrical sensory neuropathy is very difficult to manage; it is often necessary to change the ART regimen before deciding upon the putative role of HIV infection itself. If the change does not improve the pain, there are few options available; the most common drugs used for neuropathic pain are usually not effective. One is left with cannabis, which cannot be recommended as routine therapy, recombinant human nerve growth factor, which is unavailable, and topical capsaicin with its side-effects. Much has been done to and learned from HIV infection in humans; HIV-infected individuals, treated with ART, are now dying mostly from cardiovascular disease and non-AIDS-related cancers. It hence behooves us to find new approaches to mitigate the residual neurological morbidity that still impacts the quality of life of that population.}, }
@article {pmid23909852, year = {2013}, author = {Pitkänen, A and Nehlig, A and Brooks-Kayal, AR and Dudek, FE and Friedman, D and Galanopoulou, AS and Jensen, FE and Kaminski, RM and Kapur, J and Klitgaard, H and Löscher, W and Mody, I and Schmidt, D}, title = {Issues related to development of antiepileptogenic therapies.}, journal = {Epilepsia}, volume = {54 Suppl 4}, number = {0 4}, pages = {35-43}, pmid = {23909852}, issn = {1528-1167}, support = {R01 NS038595/NS/NINDS NIH HHS/United States ; R01 NS044370/NS/NINDS NIH HHS/United States ; DP1 OD003347/OD/NIH HHS/United States ; N01NS42359/NS/NINDS NIH HHS/United States ; R01 NS040337/NS/NINDS NIH HHS/United States ; R01 NS020253/NS/NINDS NIH HHS/United States ; R21 NS079135/NS/NINDS NIH HHS/United States ; R01 NS079274/NS/NINDS NIH HHS/United States ; R25 NS070682/NS/NINDS NIH HHS/United States ; R01 NS045144/NS/NINDS NIH HHS/United States ; RC1 NS068938/NS/NINDS NIH HHS/United States ; R21 NS049525/NS/NINDS NIH HHS/United States ; R01 NS075429/NS/NINDS NIH HHS/United States ; R25 NS065733/NS/NINDS NIH HHS/United States ; R44 NS064661/NS/NINDS NIH HHS/United States ; R21 NS072258/NS/NINDS NIH HHS/United States ; R01 NS030549/NS/NINDS NIH HHS/United States ; R01 NS031718/NS/NINDS NIH HHS/United States ; R56 NS020253/NS/NINDS NIH HHS/United States ; R21 NS078333/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Animals ; Anticonvulsants/adverse effects/*therapeutic use ; Child ; Chronic Disease ; Controlled Clinical Trials as Topic ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Approval ; *Drug Discovery ; *Drug Evaluation, Preclinical ; Drug Resistance ; Drugs, Investigational/adverse effects/*therapeutic use ; Evidence-Based Medicine ; Humans ; National Institute of Neurological Disorders and Stroke (U.S.) ; United States ; }, abstract = {Several preclinical proof-of-concept studies have provided evidence for positive treatment effects on epileptogenesis. However, none of these hypothetical treatments has advanced to the clinic. The experience in other fields of neurology such as stroke, Alzheimer's disease, or amyotrophic lateral sclerosis has indicated several problems in the design of preclinical studies, which likely contribute to failures in translating the positive preclinical data to the clinic. The Working Group on "Issues related to development of antiepileptogenic therapies" of the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) has considered the possible problems that arise when moving from proof-of-concept antiepileptogenesis (AEG) studies to preclinical AEG trials, and eventually to clinical AEG trials. This article summarizes the discussions and provides recommendations on how to design a preclinical AEG monotherapy trial in adult animals. We specifically address study design, animal and model selection, number of studies needed, issues related to administration of the treatment, outcome measures, statistics, and reporting. In addition, we give recommendations for future actions to advance the preclinical AEG testing.}, }
@article {pmid23923068, year = {2013}, author = {Mitra, NK and Goh, TE and Bala Krishnan, T and Nadarajah, VD and Vasavaraj, AK and Soga, T}, title = {Effect of intra-cisternal application of kainic acid on the spinal cord and locomotor activity in rats.}, journal = {International journal of clinical and experimental pathology}, volume = {6}, number = {8}, pages = {1505-1515}, pmid = {23923068}, issn = {1936-2625}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Animals ; *Disease Models, Animal ; Excitatory Amino Acid Agonists/*administration &amp; dosage ; Immunohistochemistry ; Kainic Acid/*administration &amp; dosage ; Male ; Motor Activity/*drug effects/physiology ; Neurons/pathology ; Rats ; Rats, Wistar ; Spinal Cord/*drug effects/pathology/physiology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease of idiopathic etiology. Glutamate excitotoxicity is one of the proposed hypotheses causing progressive death of motor neurons. We aimed to develop an experimental animal model of this disease to enhance the knowledge of pathophysiological mechanism of ALS. Male Wistar rats were infused with Kainic acid (KA) intra-cisternally for 5 days at the dosage of 50 fmol/day and 150 fmol/day. Locomotor activity, sensory function and histological changes in cervical and lumbar sections of spinal cord were evaluated. Glial Fibrillary Acidic Protein (GFAP) and Neurofilament Protein (NFP) were used as immunohistochemical marker for reactive astrogliosis and neuronal damage respectively. Specific Superoxide Dismutase (SOD) activity of spinal cord was estimated. The locomotor activity in the parameter of observed mean action time remained reduced on 14(th) day after administration of KA. Spinal motor neurons under Nissl stain showed pyknosis of nucleus and vacuolation of neuropil. GFAP expression increased significantly in the lumbar section of the spinal cord with high dose of KA treatment (p<0.05). NFP was expressed in axonal fibres around the neurons in KA-treated rats. A significant increase in specific SOD activity in both cervical and lumbar sections of the spinal cord was found with low dose of KA treatment (p<0.05). This study concludes that spinal cord damage with some features similar to ALS can be produced by low dose intra-cisternal administration of KA.}, }
@article {pmid23923031, year = {2013}, author = {Tada, S and Yasui, T and Nakatsuji, Y and Okuno, T and Koda, T and Mochizuki, H and Sakoda, S and Kikutani, H}, title = {BAFF controls neural cell survival through BAFF receptor.}, journal = {PloS one}, volume = {8}, number = {7}, pages = {e70924}, pmid = {23923031}, issn = {1932-6203}, mesh = {Animals ; B-Cell Activating Factor/genetics/*metabolism ; B-Cell Activation Factor Receptor/genetics/*metabolism ; B-Lymphocytes/metabolism ; Bone Marrow Cells/metabolism ; Cell Line ; Cell Survival/genetics ; Gene Expression ; Humans ; Mice ; Mice, Knockout ; Neurons/*metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Various neuroprotective factors have been shown to help prevention of neuronal cell death, which is responsible for the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, most of these therapeutic potentials have been tested by administration of recombinant proteins, transgenic expression or virus vector-mediated gene transfer. Therefore, it remains to be clarified whether any endogenous factors has advantage for neuroprotection in a pathological nervous system. Here we show the role of BAFF-R signaling pathway in the control of neural cell survival. Both B cell-activating factor (BAFF) and its receptor (BAFF-R) are expressed in mouse neurons and BAFF-R deficiency reduces the survival of primary cultured neurons. Although many studies have so far addressed the functional role of BAFF-R on the differentiation of B cells, impaired BAFF-R signaling resulted in accelerated disease progression in an animal model of inherited ALS. We further demonstrate that BAFF-R deficient bone marrow cells or genetic depletion of B cells does not affect the disease progression, indicating that BAFF-mediated signals on neurons, not on B cells, support neural cell survival. These findings suggest opportunities to improve therapeutic outcome for patients with neurodegenerative diseases by synthesized BAFF treatment.}, }
@article {pmid23920243, year = {2013}, author = {Skorupa, A and Urbach, S and Vigy, O and King, MA and Chaumont-Dubel, S and Prehn, JH and Marin, P}, title = {Angiogenin induces modifications in the astrocyte secretome: relevance to amyotrophic lateral sclerosis.}, journal = {Journal of proteomics}, volume = {91}, number = {}, pages = {274-285}, doi = {10.1016/j.jprot.2013.07.028}, pmid = {23920243}, issn = {1876-7737}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Animals, Newborn ; Astrocytes/cytology/*metabolism ; Cell Communication ; Cell Survival ; Culture Media, Conditioned/chemistry ; Disease Progression ; Extracellular Matrix/metabolism ; *Gene Expression Regulation ; Mice ; Mice, Inbred C57BL ; Motor Neurons/metabolism ; Mutation ; Neurons/metabolism ; Proteome ; Proteomics ; Ribonuclease, Pancreatic/*metabolism ; }, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting lower and upper motoneurons. Recent studies have shown that both motor neurons and non-neuronal neighbouring cells such as astrocytes and microglia contribute to disease pathology. Loss-of-function mutations in the angiogenin (ANG) gene have been identified in ALS patients. Angiogenin is enriched in motor neurons and exerts neuroprotective effects in vitro and in vivo. We have recently shown that motoneurons secrete angiogenin, and that secreted angiogenin is exclusively taken up by astrocytes, suggesting a paracrine mechanism of neuroprotection. To gain insights into astrocyte effectors of angiogenin-induced neuroprotection, we examined alterations in the astrocyte secretome induced by angiogenin treatment using quantitative proteomics based on Stable Isotope Labelling by Amino Acids in Cell Culture (SILAC). We identified 2128 proteins in conditioned media from primary cultured mouse astrocytes, including 1247 putative secreted proteins. Of these, 60 proteins showed significant regulation of secretion in response to angiogenin stimulation. Regulated proteins include chemokines and cytokines, proteases and protease inhibitors as well as proteins involved in reorganising the extracellular matrix. In conclusion, this proteomic analysis increases our knowledge of the astrocyte secretome and reveals potential molecular substrates underlying the paracrine, neuroprotective effects of angiogenin.<br><br>BIOLOGICAL SIGNIFICANCE: This study provides the most extensive list of astrocyte-secreted proteins available and reveals novel potential molecular substrates of astrocyte-neuron communication. It also identifies a set of astrocyte-derived proteins that might slow down ALS disease progression. It should be relevant to a large readership of neuroscientists and clinicians, in particular those with an interest in the physiological and pathological roles of astrocytes and in the molecular and cellular mechanisms underlying neurodegenerative disorders.}, }
@article {pmid23920043, year = {2013}, author = {Iacobazzi, V and Castegna, A and Infantino, V and Andria, G}, title = {Mitochondrial DNA methylation as a next-generation biomarker and diagnostic tool.}, journal = {Molecular genetics and metabolism}, volume = {110}, number = {1-2}, pages = {25-34}, doi = {10.1016/j.ymgme.2013.07.012}, pmid = {23920043}, issn = {1096-7206}, mesh = {*Biomarkers ; DNA Methylation/*genetics ; DNA, Mitochondrial/*genetics ; *Epigenesis, Genetic ; Humans ; Mitochondria/genetics/metabolism ; S-Adenosylhomocysteine ; }, abstract = {Recent expansion of our knowledge on epigenetic changes strongly suggests that not only nuclear DNA (nDNA), but also mitochondrial DNA (mtDNA) may be subjected to epigenetic modifications related to disease development, environmental exposure, drug treatment and aging. Thus, mtDNA methylation is attracting increasing attention as a potential biomarker for the detection and diagnosis of diseases and the understanding of cellular behavior in particular conditions. In this paper we review the current advances in mtDNA methylation studies with particular attention to the evidences of mtDNA methylation changes in diseases and physiological conditions so far investigated. Technological advances for the analysis of epigenetic variations are promising tools to provide insights into methylation of mtDNA with similar resolution levels as those reached for nDNA. However, many aspects related to mtDNA methylation are still unclear. More studies are needed to understand whether and how changes in mtDNA methylation patterns, global and gene specific, are associated to diseases or risk factors.}, }
@article {pmid23917850, year = {2013}, author = {Foerster, BR and Welsh, RC and Feldman, EL}, title = {25 years of neuroimaging in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {9}, number = {9}, pages = {513-524}, pmid = {23917850}, issn = {1759-4766}, support = {R01 NS052514/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/pathology/physiopathology ; Biomarkers ; History, 20th Century ; History, 21st Century ; Humans ; Magnetic Resonance Imaging/history/*methods/trends ; Neuroimaging/history/*methods/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease for which a precise cause has not yet been identified. Standard CT or MRI evaluation does not demonstrate gross structural nervous system changes in ALS, so conventional neuroimaging techniques have provided little insight into the pathophysiology of this disease. Advanced neuroimaging techniques--such as structural MRI, diffusion tensor imaging and proton magnetic resonance spectroscopy--allow evaluation of alterations of the nervous system in ALS. These alterations include focal loss of grey and white matter and reductions in white matter tract integrity, as well as changes in neural networks and in the chemistry, metabolism and receptor distribution in the brain. Given their potential for investigation of both brain structure and function, advanced neuroimaging methods offer important opportunities to improve diagnosis, guide prognosis, and direct future treatment strategies in ALS. In this article, we review the contributions made by various advanced neuroimaging techniques to our understanding of the impact of ALS on different brain regions, and the potential role of such measures in biomarker development.}, }
@article {pmid23910738, year = {2014}, author = {Murphy, RM and Fallat, LM and Kish, JP}, title = {Axial loading screw fixation for chevron type osteotomies of the distal first metatarsal: a retrospective outcomes analysis.}, journal = {The Journal of foot and ankle surgery : official publication of the American College of Foot and Ankle Surgeons}, volume = {53}, number = {1}, pages = {52-54}, doi = {10.1053/j.jfas.2013.06.013}, pmid = {23910738}, issn = {1542-2224}, mesh = {Adolescent ; Adult ; Aged ; Bone Screws ; Female ; Hallux Valgus/*surgery ; Humans ; Male ; Metatarsal Bones/*surgery ; Middle Aged ; Osteotomy/*instrumentation/methods ; Retrospective Studies ; Treatment Outcome ; Young Adult ; }, abstract = {The distal chevron osteotomy is a widely accepted technique for the treatment of hallux abductovalgus deformity. Although the osteotomy is considered to be stable, displacements of the capital fragment has been described. We propose a new method for fixation of the osteotomy involving the axial loading screw (ALS) used in addition to single screw fixation. We believe this method will provide a more mechanically stable construct. We reviewed the charts of 46 patients in whom 52 feet underwent a distal chevron osteotomy that was fixated with either 1 screw or 2 screws that included the ALS. We hypothesized that the ALS group would have fewer displacements and would heal more quickly than the single screw fixation group. We found that the group with ALS fixation had healed at a mean of 6.5 weeks and that the group with single screw fixation had healed at 9.53 weeks (p = .001). Also, 8 cases occurred of displacement of the capital fragment in the single screw, control group compared with 2 cases of displacement in the ALS group. However, this finding was not statistically significant. The addition of the ALS to single screw fixation allowed the patients to heal approximately 3 weeks earlier than single screw fixation alone. The ALS is a fixation option for the surgeon to consider when osseous correction of hallux abducto valgus is performed.}, }
@article {pmid23909244, year = {2013}, author = {Sattler, R and Tyler, B and Hoover, B and Coddington, LT and Recinos, V and Hwang, L and Brem, H and Rothstein, JD}, title = {Increased expression of glutamate transporter GLT-1 in peritumoral tissue associated with prolonged survival and decreases in tumor growth in a rat model of experimental malignant glioma.}, journal = {Journal of neurosurgery}, volume = {119}, number = {4}, pages = {878-886}, pmid = {23909244}, issn = {1933-0693}, support = {P30 CA006973/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Astrocytes/drug effects/*metabolism/pathology ; Brain/drug effects/*metabolism/pathology ; Brain Neoplasms/drug therapy/*metabolism/pathology ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Disease Models, Animal ; Excitatory Amino Acid Transporter 2/genetics/*metabolism ; Gliosarcoma/drug therapy/*metabolism/pathology ; Neurons/drug effects/metabolism/pathology ; Rats ; Rats, Inbred F344 ; Thiamphenicol/pharmacology/therapeutic use ; }, abstract = {OBJECT: Gliomas are known to release excessive amounts of glutamate, inducing glutamate excitotoxic cell death in the peritumoral region and allowing the tumor to grow and to expand. Glutamate transporter upregulation has been shown to be neuroprotective by removing extracellular glutamate in a number of preclinical animal models of neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson disease as well as psychiatric disorders such as depression. The authors therefore hypothesized that the protective mechanism of glutamate transporter upregulation would be useful for the treatment of gliomas as well.<br><br>METHODS: In this study 9L gliosarcoma cells were treated with a glutamate transporter upregulating agent, thiamphenicol, an antibiotic approved in Europe, which has been shown previously to increase glutamate transporter expression and has recently been validated in a human Phase I biomarker trial for glutamate transporter upregulation. Cells were monitored in vitro for glutamate transporter levels and cell proliferation. In vivo, rats were injected intracranially with 9L cells and were treated with increasing doses of thiamphenicol. Animals were monitored for survival. In addition, postmortem brain tissue was analyzed for tumor size, glutamate transporter levels, and neuron count.<br><br>RESULTS: Thiamphenicol showed little effects on proliferation of 9L gliosarcoma cells in vitro and did not change glutamate transporter levels in these cells. However, when delivered locally in an experimental glioma model in rats, thiamphenicol dose dependently (10-5000 &#x3bc;M) significantly increased survival up to 7 days and concomitantly decreased tumor size from 46.2 mm(2) to 10.2 mm(2) when compared with lesions in nontreated controls. Furthermore, immunohistochemical and biochemical analysis of peritumoral tissue confirmed an 84% increase in levels of glutamate transporter protein and a 72% increase in the number of neuronal cells in the tissue adjacent to the tumor.<br><br>CONCLUSIONS: These results show that increasing glutamate transporter expression in peritumoral tissue is neuroprotective. It suggests that glutamate transporter upregulation for the treatment of gliomas should be further investigated and potentially be part of a combination therapy with standard chemotherapeutic agents.}, }
@article {pmid23899525, year = {2013}, author = {Jeon, GS and Kim, JE and Ahn, SW and Park, KS and Hong, YH and Ye, IH and Park, JS and Kim, SH and Lee, KW and Kim, SM and Sung, JJ}, title = {Effect of JGK-263 as a new glycogen synthase kinase-3β inhibitor on extrinsic apoptosis pathway in motor neuronal cells.}, journal = {Biochemical and biophysical research communications}, volume = {439}, number = {2}, pages = {309-314}, doi = {10.1016/j.bbrc.2013.07.080}, pmid = {23899525}, issn = {1090-2104}, mesh = {Animals ; Apoptosis/*drug effects ; Cell Line ; Cell Survival/drug effects ; Glycogen Synthase Kinase 3/*antagonists &amp; inhibitors/metabolism ; Glycogen Synthase Kinase 3 beta ; Mice ; Motor Neurons/cytology/*drug effects/metabolism ; Protein Kinase Inhibitors/*pharmacology ; Signal Transduction/drug effects ; }, abstract = {Glycogen synthase kinase-3β (GSK-3β) has been identified as one of the important pathogenic mechanisms in motor neuronal death. GSK-3β inhibitor has been investigated as a modulator of apoptosis and has been shown to confer significant protective effects on cell death in neurodegenerative diseases. However, GSK-3β is known to have paradoxical effects on apoptosis subtypes, i.e., pro-apoptotic in mitochondrial-associated intrinsic apoptosis, but anti-apoptotic in death receptor-related extrinsic apoptosis. In this study, we evaluated the effect of a new GSK-3β inhibitor (JGK-263) on motor neuron cell survival and apoptosis, by using low to high doses of JGK-263 after 48 h of serum withdrawal, and monitoring changes in extrinsic apoptosis pathway components, including Fas, FasL, cleaved caspase-8, p38α, and the Fas-Daxx interaction. Cell survival peaked after treatment of serum-deprived cells with 50 μM JGK-263. The present study showed that treatment with JGK-263 reduced serum-deprivation-induced motor neuronal apoptosis by inactivating not only the intrinsic, but also the extrinsic apoptosis pathway. These results suggest that JGK-263 has a neuroprotective effect through effective modulation of the extrinsic apoptosis pathway in motor neuron degeneration.}, }
@article {pmid23892338, year = {2014}, author = {Finsterer, J and Mahjoub, SZ}, title = {Fatigue in healthy and diseased individuals.}, journal = {The American journal of hospice &amp; palliative care}, volume = {31}, number = {5}, pages = {562-575}, doi = {10.1177/1049909113494748}, pmid = {23892338}, issn = {1938-2715}, mesh = {Acute Disease ; Age Factors ; Biomarkers ; Chronic Disease ; Complementary Therapies ; Diagnostic Techniques and Procedures ; Diet ; Exercise ; Fatigue/*classification/diagnosis/*etiology/therapy ; Female ; Health Status ; Humans ; Male ; Mental Health ; Neuromuscular Diseases/*complications ; Prevalence ; Sex Factors ; }, abstract = {OBJECTIVES: Although fatigue is experienced by everyone, its definition and classification remains under debate.<br><br>METHODS: A review of the previously published data on fatigue.<br><br>RESULTS: Fatigue is influenced by age, gender, physical condition, type of food, latency to last meal, mental status, psychological conditions, personality type, life experience, and the health status of an individual. Fatigue may not only be a symptom but also a measurable and quantifiable dimension, also known as fatigability. Additionally, it may be classified as a condition occurring at rest or under exercise or stress, as physiologic reaction or pathologic condition, as spontaneous phenomenon or triggerable state, as resistant or irresistant to preconditioning, training, or attitude, as prominent or collateral experience, and as accessible or inaccessible to any type of treatment or intervention. Fatigue may be the sole symptom of a disease or one among others. It may be also classified as acute or chronic. Quantification of fatigability is achievable by fatigue scores, force measurement, electromyography, or other means. Fatigue and fatigability need to be delineated from conditions such as sleepiness, apathy, exhaustion, exercise intolerance, lack of vigor, weakness, inertia, or tiredness. Among neurological disorders, the prevalence of fatigue is particularly increased in multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease, traumatic brain injury, stroke, and bleeding and also in neuromuscular disorders. Fatigue may be influenced by training, mental preconditioning, or drugs.<br><br>CONCLUSIONS: Fatigue needs to be recognized as an important condition that is not only a symptom but may also be quantified and can be modified by various measures depending on the underlying cause.}, }
@article {pmid23891729, year = {2013}, author = {Kim, J and Kim, TY and Cho, KS and Kim, HN and Koh, JY}, title = {Autophagy activation and neuroprotection by progesterone in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {59}, number = {}, pages = {80-85}, doi = {10.1016/j.nbd.2013.07.011}, pmid = {23891729}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/pathology/physiopathology ; Animals ; Animals, Newborn ; Astrocytes/drug effects ; Autophagy/*drug effects ; Cell Count ; Cells, Cultured ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Humans ; In Vitro Techniques ; Male ; Mice ; Mice, Transgenic ; Motor Activity/drug effects/genetics ; Motor Neurons/drug effects ; Neuroprotective Agents/*therapeutic use ; Progesterone/*therapeutic use ; Spinal Cord/cytology ; Superoxide Dismutase/genetics ; Survival Analysis ; Time Factors ; Transcription Factor TFIIH ; Transcription Factors/metabolism ; }, abstract = {Progesterone (PG) exerts neuroprotective effects under conditions such as brain ischemia, traumatic brain injury, and spinal cord injury. Previously, we reported that PG activates autophagy, a potential neuroprotective mechanism, in cortical astrocytes. In the present study, we explored the possibility that PG, by activating autophagy in spinal cord cells, protects against motoneuron degeneration in transgenic (Tg) mice expressing the human G93A-SOD1 (superoxide dismutase 1) mutant, a model of amyotrophic lateral sclerosis. PG treatment increased autophagic flux in G93A-SOD1 Tg spinal cord astrocyte cultures and mice. In addition, PG treatment reduced mutant SOD1 protein levels and motoneuronal death. Inhibition of autophagy with 3-methyladenine (3MA) reversed these PG effects, indicating that activation of autophagy contributed to the PG neuroprotection. PG effects in vivo were tested by intraperitoneally injecting male G93A-SOD1 Tg mice with different doses of PG (2, 4, or 8mg/kg) or vehicle from 70days of age until death. Measurements of motor functions using rota-rod tests showed that the onset of symptoms was not different among groups, but the progression of motor dysfunction was significantly delayed in the PG-treated group compared with the vehicle control group. The average lifespan was also prolonged in the PG-injected group. Histological examinations revealed that PG treatment substantially reduced the death of spinal motoneurons at 14weeks of age with a concomitant decrease in mutant SOD1 levels. Our results demonstrated that PG delays neurodegenerative progress in G93A-SOD1 transgenic mice, possibly through activation of autophagy in the spinal cord.}, }
@article {pmid23886855, year = {2013}, author = {Engskog, MK and Karlsson, O and Haglöf, J and Elmsjö, A and Brittebo, E and Arvidsson, T and Pettersson, C}, title = {The cyanobacterial amino acid β-N-methylamino-l-alanine perturbs the intermediary metabolism in neonatal rats.}, journal = {Toxicology}, volume = {312}, number = {}, pages = {6-11}, doi = {10.1016/j.tox.2013.07.010}, pmid = {23886855}, issn = {1879-3185}, mesh = {Amino Acids/metabolism ; Amino Acids, Diamino/*toxicity ; Animals ; Animals, Newborn ; Brain/*drug effects/metabolism/pathology ; Cyanobacteria Toxins ; Energy Metabolism/drug effects ; Excitatory Amino Acid Agonists/*toxicity ; Magnetic Resonance Spectroscopy ; Rats ; Rats, Wistar ; }, abstract = {The neurotoxic amino acid β-N-methylamino-l-alanine (BMAA) is produced by most cyanobacteria. BMAA is considered as a potential health threat because of its putative role in neurodegenerative diseases. We have previously observed cognitive disturbances and morphological brain changes in adult rodents exposed to BMAA during the development. The aim of this study was to characterize changes of major intermediary metabolites in serum following neonatal exposure to BMAA using a non-targeted metabolomic approach. NMR spectroscopy was used to obtain serum metabolic profiles from neonatal rats exposed to BMAA (40, 150, 460mg/kg) or vehicle on postnatal days 9-10. Multivariate data analysis of binned NMR data indicated metabolic pattern differences between the different treatment groups. In particular five metabolites, d-glucose, lactate, 3-hydroxybutyrate, creatine and acetate, were changed in serum of BMAA-treated neonatal rats. These metabolites are associated with changes in energy metabolism and amino acid metabolism. Further statistical analysis disclosed that all the identified serum metabolites in the lowest dose group were significantly (p<0.05) decreased. The neonatal rat model used in this study is so far the only animal model that displays significant biochemical and behavioral effects after a low short-term dose of BMAA. The demonstrated perturbation of intermediary metabolism may contribute to BMAA-induced developmental changes that result in long-term effects on adult brain function.}, }
@article {pmid25206509, year = {2013}, author = {Guo, C and Sun, L and Chen, X and Zhang, D}, title = {Oxidative stress, mitochondrial damage and neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {8}, number = {21}, pages = {2003-2014}, pmid = {25206509}, issn = {1673-5374}, abstract = {Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxidative stress is characterized by the overproduction of reactive oxygen species, which can induce mitochondrial DNA mutations, damage the mitochondrial respiratory chain, alter membrane permeability, and influence Ca(2+) homeostasis and mitochondrial defense systems. All these changes are implicated in the development of these neurodegenerative diseases, mediating or amplifying neuronal dysfunction and triggering neurodegeneration. This paper summarizes the contribution of oxidative stress and mitochondrial damage to the onset of neurodegenerative eases and discusses strategies to modify mitochondrial dysfunction that may be attractive therapeutic interventions for the treatment of various neurodegenerative diseases.}, }
@article {pmid23876328, year = {2013}, author = {Dachs, E and Piedrafita, L and Hereu, M and Esquerda, JE and Calderó, J}, title = {Chronic treatment with lithium does not improve neuromuscular phenotype in a mouse model of severe spinal muscular atrophy.}, journal = {Neuroscience}, volume = {250}, number = {}, pages = {417-433}, doi = {10.1016/j.neuroscience.2013.07.026}, pmid = {23876328}, issn = {1873-7544}, mesh = {Animals ; Blotting, Western ; Cell Count ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Image Processing, Computer-Assisted ; Immunohistochemistry ; In Situ Nick-End Labeling ; Lithium Chloride/blood/*therapeutic use ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/physiology ; Muscle, Skeletal/drug effects/metabolism ; Muscular Atrophy, Spinal/*drug therapy/*physiopathology ; Mutation/genetics/physiology ; Oncogene Protein v-akt/biosynthesis/genetics ; Phenotype ; Postural Balance/genetics/physiology ; Psychomotor Performance/drug effects ; Reflex/physiology ; Spinal Cord/drug effects/metabolism/pathology ; Survival of Motor Neuron 1 Protein/genetics/physiology ; }, abstract = {Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by defective levels of the survival motor neuron (SMN) protein. SMA causes spinal motoneuron (MN) loss, and progressive muscle weakness and paralysis. Currently, there is no effective therapy to cure this disease. Although different strategies focused on increasing the expression of functional SMN protein have been assayed, numerous SMN-independent therapeutic approaches have been demonstrated to have potential effectiveness in improving the SMA phenotype in mouse models and clinical trials. Recent works have shown that compounds which inhibit GSK-3β activity are effective in promoting MN survival and ameliorating lifespan in models of MN diseases including SMA. Taking into account the reported neuroprotective actions of lithium (Li) through the inhibition of GSK-3β in different studies, we tested here its potential efficiency as a therapeutic agent in a mouse model of severe SMA (SMNΔ7 mice). We show that the chronic treatment with Li initiated before the appearance of disease symptoms, although inhibited GSK-3β, did not improve the median survival, motor behavior, and spinal MN loss linked to SMA. Li administration did not either ameliorate the microglial and astroglial reaction in the spinal cord or the depletion of glutamatergic synapses on MNs observed in SMNΔ7 animals. Moreover, Li treatment did not mitigate muscle atrophy or calcitonin gene-related peptide (CGRP) downregulation in the neuromuscular junctions linked to the disease. However, a significant reduction in apoptotic cell death found in the skeletal muscle of SMA mice was observed after Li treatment.}, }
@article {pmid23866691, year = {2013}, author = {Kim, SH and Jung, SY and Lee, KW and Lee, SH and Cai, M and Choi, SM and Yang, EJ}, title = {Bee venom effects on ubiquitin proteasome system in hSOD1(G85R)-expressing NSC34 motor neuron cells.}, journal = {BMC complementary and alternative medicine}, volume = {13}, number = {}, pages = {179}, pmid = {23866691}, issn = {1472-6882}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism ; Animals ; Apitherapy ; Autophagy ; Bee Venoms/*pharmacology ; *Bees ; Endoplasmic Reticulum Chaperone BiP ; Humans ; Mice ; Motor Neurons/*drug effects/metabolism ; Mutation ; Proteasome Endopeptidase Complex/*metabolism ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; Transfection ; Ubiquitin/*metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results from a progressive loss of motor neurons. Familial ALS (fALS) is caused by missense mutations in Cu, Zn-superoxide dismutase 1 (SOD1) that frequently result in the accumulation of mutant protein aggregates that are associated with impairments in the ubiquitin-proteasome system (UPS). UPS impairment has been implicated in many neurological disorders. Bee venom (BV) extracted from honey bees has been used as a traditional medicine for treating inflammatory diseases and has been shown to attenuate the neuroinflammatory events that occur in a symptomatic ALS animal model.<br><br>METHODS: NSC34 cells were transiently transfected with a WT or G85R hSOD1-GFP construct for 24 hrs and then stimulated with 2.5 &#x3bc;g/ml BV for 24 hrs. To determine whether a SOD1 mutation affects UPS function in NSC34 cells, we examined proteasome activity and performed western blotting and immunofluorescence using specific antibodies, such as anti-misfolded SOD1, anti-ubiquitin, anti-GRP78, anti-LC3, and anti-ISG15 antibodies.<br><br>RESULTS: We found that GFP-hSOD1G85R overexpression induced SOD1 inclusions and reduced proteasome activity compared with the overexpression of GFP alone in NSC34 motor neuronal cells. In addition, we also observed that BV treatment restored proteasome activity and reduced the accumulation of ubiquitinated and misfolded SOD1 in GFP-hSOD1G85R-overexpressing NSC34 motor neuronal cells. However, BV treatment did not activate the autophagic pathway in these cells.<br><br>CONCLUSION: Our findings suggest that BV may rescue the impairment of the UPS in ALS models.}, }
@article {pmid23864030, year = {2013}, author = {Pandya, RS and Zhu, H and Li, W and Bowser, R and Friedlander, RM and Wang, X}, title = {Therapeutic neuroprotective agents for amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {70}, number = {24}, pages = {4729-4745}, pmid = {23864030}, issn = {1420-9071}, support = {K01 NS055072/NS/NINDS NIH HHS/United States ; R01 NS077284/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology/genetics ; Animals ; Anti-Inflammatory Agents/therapeutic use ; Antioxidants/therapeutic use ; Apoptosis/drug effects ; Disease Models, Animal ; Disease Progression ; Humans ; Mice ; Mitochondria/drug effects ; Motor Neurons/drug effects ; Mutant Proteins/genetics/metabolism ; Neuroprotective Agents/*therapeutic use ; Proteolysis ; Riluzole/therapeutic use ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal chronic neurodegenerative disease whose hallmark is proteinaceous, ubiquitinated, cytoplasmic inclusions in motor neurons and surrounding cells. Multiple mechanisms proposed as responsible for ALS pathogenesis include dysfunction of protein degradation, glutamate excitotoxicity, mitochondrial dysfunction, apoptosis, oxidative stress, and inflammation. It is therefore essential to gain a better understanding of the underlying disease etiology and search for neuroprotective agents that might delay disease onset, slow progression, prolong survival, and ultimately reduce the burden of disease. Because riluzole, the only Food and Drug Administration (FDA)-approved treatment, prolongs the ALS patient's life by only 3 months, new therapeutic agents are urgently needed. In this review, we focus on studies of various small pharmacological compounds targeting the proposed pathogenic mechanisms of ALS and discuss their impact on disease progression.}, }
@article {pmid23856645, year = {2013}, author = {Pasinetti, GM and Bilski, AE and Zhao, W}, title = {Sirtuins as therapeutic targets of ALS.}, journal = {Cell research}, volume = {23}, number = {9}, pages = {1073-1074}, pmid = {23856645}, issn = {1748-7838}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism ; Animals ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; Enzyme Inhibitors/pharmacology ; Humans ; Mice ; Mitochondria/metabolism ; Resveratrol ; Sirtuins/drug effects/*metabolism ; Stilbenes/pharmacology ; }, abstract = {Sirtuins have received a lot of attention in biological functions associated with metabolism, survival development, and most recently, neurodegeneration. The versatile role of sirtuins can be readily redirected for drug discovery studies for novel treatment in amyotrophic lateral sclerosis (ALS), as presented in this highlight, by sirtuin-mediated ketogenic responses influencing mitochondrial function.}, }
@article {pmid23856242, year = {2013}, author = {Bowen, RC and Wang, Y and Balbuena, L and Houmphan, A and Baetz, M}, title = {The relationship between mood instability and depression: implications for studying and treating depression.}, journal = {Medical hypotheses}, volume = {81}, number = {3}, pages = {459-462}, doi = {10.1016/j.mehy.2013.06.010}, pmid = {23856242}, issn = {1532-2777}, mesh = {Depression/complications/*diagnosis/*physiopathology ; Factor Analysis, Statistical ; Humans ; Mood Disorders/complications/*physiopathology ; Surveys and Questionnaires ; United Kingdom ; }, abstract = {BACKGROUND: Most individuals with depressed mood report mood fluctuations (Mood Instability) within hours or days. This is not recognized in diagnostic criteria or standard rating scales for depression.<br><br>HYPOTHESIS: That mood instability is a distinct component of the development of depression that has been omitted from criteria for depression because of reliance on retrospective recall and structured interviews. The inclusion of Mood Instability would enhance research into causes and treatment of depression.<br><br>STUDIES: We examined three datasets that used retrospective and prospective measures of depressed symptom ratings and mood instability to determine the relationship between the two. Study 1 used data from the 1991 UK Health and Lifestyle Surveys (HALS). Studies 2 and 3 used clinical samples. The scales used to assess mood instability were the mood instability factor from the Eysenck Personality Inventory Neuroticism Scale, the Affective Lability Scale (ALS), and the Visual Analogue Depression Scale (VAS). The depression scales (depressive symptoms) were the General Health Questionnaire (GHQ) depression factor, the Beck Depression Inventory IA (BDI) and the mean from the Visual Analogue Depression Scale (VAS). We used partial correlation analysis to assess the association between mood instability and depression and exploratory factor analysis to determine the factor structure of items pooled from the mood instability and depression scales from studies 1 and 2.<br><br>RESULTS: Mood Instability was found to be moderately associated with depressive symptoms. The Pearson's r-values ranged from 0.49 to 0.57. The correlation was lower when recalling mood in the past. The factor analytic solution supported the hypothesis that MI and depressive symptoms are related but distinct constructs.<br><br>CONCLUSIONS: Reliance exclusively on the retrospective assessment of depressive symptoms has occluded the widespread occurrence of mood instability. Including Mood Instability in diagnostic and assessment criteria would enhance causal and treatment research in depression.}, }
@article {pmid23851366, year = {2013}, author = {Castillo, K and Nassif, M and Valenzuela, V and Rojas, F and Matus, S and Mercado, G and Court, FA and van Zundert, B and Hetz, C}, title = {Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons.}, journal = {Autophagy}, volume = {9}, number = {9}, pages = {1308-1320}, doi = {10.4161/auto.25188}, pmid = {23851366}, issn = {1554-8635}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Autophagy/*drug effects/genetics ; Cell Survival/drug effects ; Cytoprotection/drug effects ; *Disease Progression ; Forkhead Box Protein O1 ; Forkhead Transcription Factors/metabolism ; Gene Expression Regulation/drug effects ; Humans ; Longevity/drug effects ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/*drug effects/metabolism/*pathology ; Mutation/genetics ; Neuroglia/drug effects/metabolism/pathology ; Protein Structure, Quaternary ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/pathology ; Superoxide Dismutase/chemistry/genetics ; Transcription, Genetic/drug effects ; Trehalose/administration &amp; dosage/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron disease with no current effective treatment. Accumulation of abnormal protein inclusions containing SOD1, TARDBP, FUS, among other proteins, is a pathological hallmark of ALS. Autophagy is the major degradation pathway involved in the clearance of damaged organelles and protein aggregates. Although autophagy has been shown to efficiently degrade ALS-linked mutant protein in cell culture models, several studies suggest that autophagy impairment may also contribute to disease pathogenesis. In this report, we tested the potential use of trehalose, a disaccharide that induces MTOR-independent autophagy, in the development of experimental ALS. Administration of trehalose to mutant SOD1 transgenic mice significantly prolonged life span and attenuated the progression of disease signs. These effects were associated with decreased accumulation of SOD1 aggregates and enhanced motoneuron survival. The protective effects of trehalose were associated with increased autophagy levels in motoneurons. Cell culture experiments demonstrated that trehalose led to mutant SOD1 degradation by autophagy in NSC34 motoneuron cells and also protected primary motoneurons against the toxicity of conditioned media from mutant SOD1 transgenic astrocytes. At the mechanistic level, trehalose treatment led to a significant upregulation in the expression of key autophagy-related genes at the mRNA level including Lc3, Becn1, Sqstm1 and Atg5. Consistent with these changes, trehalose administration enhanced the nuclear translocation of FOXO1, an important transcription factor involved in the activation of autophagy in neurons. This study suggests a potential use of trehalose and enhancers of MTOR-independent autophagy for the treatment of ALS.}, }
@article {pmid23850769, year = {2013}, author = {Krishnamurthy, K and Mehta, B and Singh, M and Tewari, BP and Joshi, PG and Joshi, NB}, title = {Depalmitoylation preferentially downregulates AMPA induced Ca2+ signaling and neurotoxicity in motor neurons.}, journal = {Brain research}, volume = {1529}, number = {}, pages = {143-153}, doi = {10.1016/j.brainres.2013.06.039}, pmid = {23850769}, issn = {1872-6240}, mesh = {Animals ; Calcium/metabolism ; Calcium Signaling/*drug effects/physiology ; Cell Survival/drug effects ; Cells, Cultured ; Disks Large Homolog 4 Protein ; Embryo, Mammalian ; Hypoglycemic Agents/toxicity ; Intracellular Signaling Peptides and Proteins/metabolism ; Lipoylation/drug effects/*physiology ; Membrane Proteins/metabolism ; Microtubule-Associated Proteins/metabolism ; Motor Neurons/*drug effects/*metabolism ; Palmitates/toxicity ; Rats ; Rats, Sprague-Dawley ; Receptors, AMPA/*metabolism ; Sodium/metabolism ; Spinal Cord/cytology ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/*pharmacology ; }, abstract = {Excessive activation of AMPA receptor has been implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). However, it is not clear why motor neurons are preferentially sensitive to AMPA receptor mediated excessive [Ca(2+)]i rise and excitotoxicity. In the present study we examined whether palmitoylation regulates Ca(2+) permeability of AMPA receptor and excitotoxicity in cultured spinal cord neurons. We adapted chronic 2-bromopalmitate (2-BrP) treatment to achieve depalmitoylation and examined its effect on the cytotoxicity in spinal cord neurons exposed to AMPA. The change in AMPA induced signaling and cytotoxicity in motor neurons and other spinal neurons under identical conditions of exposure to AMPA was studied. 2-BrP treatment inhibited AMPA induced rise in [Ca(2+)]i and cytotoxicity in both types of neurons but the degree of inhibition was significantly higher in motor neurons as compared to other spinal neurons. The AMPA induced [Na(+)]i rise was moderately affected in both type of neurons on depalmitoylation. Depalmitoylation reduced the expression levels of AMPA receptor subunits (GluR1 and GluR2) and also PSD-95 but stargazin levels remained unaffected. Our results demonstrate that 2-BrP attenuates AMPA receptor activated Ca(2+) signaling and cytotoxicity preferentially in motor neurons and suggest that AMPA receptor modulation by depalmitoylation could play a significant role in preventing motor neuron degeneration.}, }
@article {pmid23848967, year = {2013}, author = {Körner, S and Hendricks, M and Kollewe, K and Zapf, A and Dengler, R and Silani, V and Petri, S}, title = {Weight loss, dysphagia and supplement intake in patients with amyotrophic lateral sclerosis (ALS): impact on quality of life and therapeutic options.}, journal = {BMC neurology}, volume = {13}, number = {}, pages = {84}, pmid = {23848967}, issn = {1471-2377}, mesh = {*Amyotrophic Lateral Sclerosis/complications/psychology/therapy ; Cohort Studies ; *Deglutition Disorders/etiology/psychology/therapy ; Endoscopy, Gastrointestinal/methods ; Female ; Health Surveys ; Humans ; Male ; Middle Aged ; Nutrition Therapy/*methods ; Outpatients ; *Quality of Life ; Regression Analysis ; Surveys and Questionnaires ; Weight Loss/*physiology ; }, abstract = {BACKGROUND: Weight loss is a frequent feature in the motor neuron disease Amyotrophic lateral sclerosis (ALS). In this study we investigated possible causes of weight loss in ALS, its impact on mood/quality of life (QOL) and the benefit of high calorie nutritional/other dietary supplements and percutaneous endoscopic gastrostomy (PEG).<br><br>METHODS: 121 ALS patients were interviewed and answered standardized questionnaires (Beck depression inventory - II, SF36 Health Survey questionnaire, revised ALS functional rating scale). Two years after the initial survey we performed a follow-up interview.<br><br>RESULTS: In our ALS-cohort, 56.3% of the patients suffered from weight loss. Weight loss had a negative impact on QOL and was associated with a shorter survival. Patients who took high calorie nutritional supplements respectively had a PEG stated a great benefit regarding weight stabilization and/or QOL.38.2% of our patients had significant weight loss without suffering from dysphagia. To clarify the reasons for weight loss in these patients, we compared them with patients without weight loss. The two groups did not differ regarding severity of disease, depression, frontotemporal dementia or fasciculations, but patients with weight loss declared more often increased respiratory work.<br><br>CONCLUSIONS: Weight loss is a serious issue in ALS and cannot always be attributed to dysphagia. Symptomatic treatment of weight loss (high calorie nutritional supplements and/ or PEG) should be offered more frequently.}, }
@article {pmid23848820, year = {2013}, author = {Yu, F and Wang, Z and Tanaka, M and Chiu, CT and Leeds, P and Zhang, Y and Chuang, DM}, title = {Posttrauma cotreatment with lithium and valproate: reduction of lesion volume, attenuation of blood-brain barrier disruption, and improvement in motor coordination in mice with traumatic brain injury.}, journal = {Journal of neurosurgery}, volume = {119}, number = {3}, pages = {766-773}, pmid = {23848820}, issn = {1933-0693}, support = {Z01 MH002468-21//Intramural NIH HHS/United States ; }, mesh = {Animals ; Antimanic Agents/administration &amp; dosage/*pharmacology ; Blood-Brain Barrier/*drug effects/metabolism ; Brain Injuries/complications/*drug therapy/etiology ; Disease Models, Animal ; Drug Therapy, Combination ; Lithium/administration &amp; dosage/*pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Movement Disorders/*drug therapy/etiology ; Valproic Acid/administration &amp; dosage/*pharmacology ; }, abstract = {OBJECT: Although traumatic brain injury (TBI) is the leading cause of death and morbidity in young adults, no effective pharmaceutical treatment is available. By inhibiting glycogen synthase kinase-3 (GSK-3) and histone deacetylases (HDACs), respectively, lithium and valproate (VPA) have beneficial effects in diverse neurodegenerative diseases. Furthermore, in an excitotoxic neuronal model and in animal models of amyotrophic lateral sclerosis, Huntington disease, and stroke, combined treatment with lithium and VPA produces more robust neuroprotective effects than treatment with either agent alone. Building on previous work that establishes that therapeutic doses of either lithium or VPA have beneficial effects in mouse models of TBI, this study evaluated the effects of combined treatment with subeffective doses of lithium and VPA in a mouse model of TBI.<br><br>METHODS: Male C57BL/6 mice underwent TBI and were subsequently treated with lithium, VPA, or a combination of lithium and VPA 15 minutes post-TBI and once daily thereafter for up to 3 weeks; all doses were subeffective (1 mEq/kg of lithium and 200 mg/kg of VPA). Assessed parameters included lesion volume via H &amp; E staining; blood-brain barrier (BBB) integrity via immunoglobulin G extravasation; neurodegeneration via Fluoro-Jade B staining; motor coordination via a beam-walk test; and protein levels of acetylhistone H3, phospho-GSK-3&#x3b2;, and &#x3b2;-catenin via Western blotting.<br><br>RESULTS: Posttrauma treatment with combined subeffective doses of lithium and VPA significantly reduced lesion volume, attenuated BBB disruption, and mitigated hippocampal neurodegeneration 3 days after TBI. As expected, subeffective doses of lithium or VPA alone did not have these beneficial effects. Combined treatment also improved motor coordination starting from Day 7 and persisting at least 21 days after TBI. Acetylation of histone H3, an index of HDAC inhibition, was robustly increased by the combined treatment 3 days after TBI.<br><br>CONCLUSIONS: Cotreatment with subeffective doses of lithium and VPA significantly attenuated TBI-induced brain lesion, BBB disruption, and neurodegeneration, and robustly improved long-term functional recovery. These findings suggest that potentiating histone acetylation by HDAC inhibition is probably part of the mechanism underlying the beneficial effects associated with this combined treatment for TBI. Because both lithium and VPA have a long history of safe clinical use, the results suggest that using a combination of these 2 agents at subtherapeutic doses to treat patients with TBI may also reduce side effects and enhance tolerability.}, }
@article {pmid23844663, year = {2013}, author = {Gendron, TF and Cosio, DM and Petrucelli, L}, title = {c9RAN translation: a potential therapeutic target for the treatment of amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Expert opinion on therapeutic targets}, volume = {17}, number = {9}, pages = {991-995}, doi = {10.1517/14728222.2013.818659}, pmid = {23844663}, issn = {1744-7631}, support = {R01 AG026251/AG/NIA NIH HHS/United States ; R21 NS074121-01/NS/NINDS NIH HHS/United States ; R21 NS084528-01/NS/NINDS NIH HHS/United States ; R01 NS077402/NS/NINDS NIH HHS/United States ; R01 ES20395/ES/NIEHS NIH HHS/United States ; R21 NS084528/NS/NINDS NIH HHS/United States ; R01 NS063964/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics ; Animals ; C9orf72 Protein ; Chromosomes, Human, Pair 9 ; DNA Repeat Expansion ; Frontotemporal Dementia/drug therapy/*genetics ; Humans ; Protein Biosynthesis ; Proteins/*genetics ; }, abstract = {A hexanucleotide (GGGGCC) repeat expansion within a non-coding region of the C9ORF72 gene is the most common mutation associated with both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Elucidating how these expanded repeats (GGGGCCexp) cause 'c9FTD/ALS' has since become an important goal of the FTD/ALS field. GGGGCCexp transcripts aggregate into discrete nuclear structures, termed RNA foci. This phenomenon, observed in various repeat expansion disorders, is associated with RNA-binding protein sequestration. Of note, recent findings show that GGGGCCexp transcripts also succumb to an alternative fate: repeat-associated non-ATG translation (RAN translation). This unconventional mode of translation, which occurs in the absence of an initiating codon, results in the production of polyGA, polyGP and polyGR peptides. Antibodies generated against these peptides detect high molecular weight, insoluble material in brain homogenates, as well as neuronal inclusions throughout the central nervous system of c9FTD/ALS cases. Given that both foci formation and RAN translation in c9FTD/ALS require the synthesis of GGGGCCexp RNA, therapeutic strategies that target these transcripts and result in their neutralization or degradation could effectively block these two potential pathogenic mechanisms and provide a much needed treatment for c9FTD/ALS.}, }
@article {pmid23835137, year = {2013}, author = {Nishimoto, Y and Nakagawa, S and Hirose, T and Okano, HJ and Takao, M and Shibata, S and Suyama, S and Kuwako, K and Imai, T and Murayama, S and Suzuki, N and Okano, H}, title = {The long non-coding RNA nuclear-enriched abundant transcript 1_2 induces paraspeckle formation in the motor neuron during the early phase of amyotrophic lateral sclerosis.}, journal = {Molecular brain}, volume = {6}, number = {}, pages = {31}, pmid = {23835137}, issn = {1756-6606}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*metabolism/*pathology ; Animals ; Case-Control Studies ; Cell Nucleus Structures/*metabolism/ultrastructure ; Cells, Cultured ; DNA-Binding Proteins/metabolism ; Female ; HeLa Cells ; Humans ; Male ; Mice ; Models, Biological ; Motor Neurons/*metabolism/pathology/ultrastructure ; Protein Binding ; RNA, Long Noncoding/*metabolism ; RNA-Binding Protein FUS/metabolism ; Spinal Cord/metabolism/pathology ; }, abstract = {BACKGROUND: A long non-coding RNA (lncRNA), nuclear-enriched abundant transcript 1_2 (NEAT1_2), constitutes nuclear bodies known as "paraspeckles". Mutations of RNA binding proteins, including TAR DNA-binding protein-43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS), have been described in amyotrophic lateral sclerosis (ALS). ALS is a devastating motor neuron disease, which progresses rapidly to a total loss of upper and lower motor neurons, with consciousness sustained. The aim of this study was to clarify the interaction of paraspeckles with ALS-associated RNA-binding proteins, and to identify increased occurrence of paraspeckles in the nucleus of ALS spinal motor neurons.<br><br>RESULTS: In situ hybridization (ISH) and ultraviolet cross-linking and immunoprecipitation were carried out to investigate interactions of NEAT1_2 lncRNA with ALS-associated RNA-binding proteins, and to test if paraspeckles form in ALS spinal motor neurons. As the results, TDP-43 and FUS/TLS were enriched in paraspeckles and bound to NEAT1_2 lncRNA directly. The paraspeckles were localized apart from the Cajal bodies, which were also known to be related to RNA metabolism. Analyses of 633 human spinal motor neurons in six ALS cases showed NEAT1_2 lncRNA was upregulated during the early stage of ALS pathogenesis. In addition, localization of NEAT1_2 lncRNA was identified in detail by electron microscopic analysis combined with ISH for NEAT1_2 lncRNA. The observation indicating specific assembly of NEAT1_2 lncRNA around the interchromatin granule-associated zone in the nucleus of ALS spinal motor neurons verified characteristic paraspeckle formation.<br><br>CONCLUSIONS: NEAT1_2 lncRNA may act as a scaffold of RNAs and RNA binding proteins in the nuclei of ALS motor neurons, thereby modulating the functions of ALS-associated RNA-binding proteins during the early phase of ALS. These findings provide the first evidence of a direct association between paraspeckle formation and a neurodegenerative disease, and may shed light on the development of novel therapeutic targets for the treatment of ALS.}, }
@article {pmid23831027, year = {2013}, author = {Nonaka, T and Masuda-Suzukake, M and Arai, T and Hasegawa, Y and Akatsu, H and Obi, T and Yoshida, M and Murayama, S and Mann, DM and Akiyama, H and Hasegawa, M}, title = {Prion-like properties of pathological TDP-43 aggregates from diseased brains.}, journal = {Cell reports}, volume = {4}, number = {1}, pages = {124-134}, doi = {10.1016/j.celrep.2013.06.007}, pmid = {23831027}, issn = {2211-1247}, support = {089701/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Apoptosis ; Brain/*metabolism ; Cell Line, Tumor ; Exosomes/metabolism ; Frontotemporal Dementia/*metabolism ; HEK293 Cells ; Humans ; Inclusion Bodies/*metabolism ; Phosphorylation ; *Polymerization ; Proteasome Endopeptidase Complex/*metabolism ; Protein Denaturation ; Proteolysis ; Ubiquitination ; }, abstract = {TDP-43 is the major component protein of ubiquitin-positive inclusions in brains of patients with frontotemporal lobar degeneration (FTLD-TDP) or amyotrophic lateral sclerosis (ALS). Here, we report the characterization of prion-like properties of aggregated TDP-43 prepared from diseased brains. When insoluble TDP-43 from ALS or FTLD-TDP brains was introduced as seeds into SH-SY5Y cells expressing TDP-43, phosphorylated and ubiquitinated TDP-43 was aggregated in a self-templating manner. Immunoblot analyses revealed that the C-terminal fragments of insoluble TDP-43 characteristic of each disease type acted as seeds, inducing seed-dependent aggregation of TDP-43 in these cells. The seeding ability of insoluble TDP-43 was unaffected by proteinase treatment but was abrogated by formic acid. One subtype of TDP-43 aggregate was resistant to boiling treatment. The insoluble fraction from cells harboring TDP-43 aggregates could also trigger intracellular TDP-43 aggregation. These results indicate that insoluble TDP-43 has prion-like properties that may play a role in the progression of TDP-43 proteinopathy.}, }
@article {pmid23829360, year = {2014}, author = {Velayudhan, L and Van Diepen, E and Marudkar, M and Hands, O and Suribhatla, S and Prettyman, R and Murray, J and Baillon, S and Bhattacharyya, S}, title = {Therapeutic potential of cannabinoids in neurodegenerative disorders: a selective review.}, journal = {Current pharmaceutical design}, volume = {20}, number = {13}, pages = {2218-2230}, doi = {10.2174/13816128113199990434}, pmid = {23829360}, issn = {1873-4286}, support = {G0501775/MRC_/Medical Research Council/United Kingdom ; NIHR-CS-011-001/DH_/Department of Health/United Kingdom ; MR/J012149/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Alzheimer Disease/drug therapy/etiology ; Amyotrophic Lateral Sclerosis/drug therapy/etiology ; Animals ; Brain Ischemia/drug therapy/etiology ; Cannabinoids/*therapeutic use ; Endocannabinoids/physiology ; Humans ; Huntington Disease/drug therapy/etiology ; Multiple Sclerosis/drug therapy/etiology ; Neurodegenerative Diseases/*drug therapy ; Parkinson Disease/drug therapy/etiology ; }, abstract = {The endocannabinoid system (ECS) is now recognised as an important modulator of various central nervous system processes. More recently, an increasing body of evidence has accumulated to suggest antioxidant, anti-inflammatory and neuroprotective roles of ECS. In this review we discuss the role and therapeutic potential of ECS in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, Huntington's disease, Tourette's syndrome, brain ischemia and amyotrophic lateral sclerosis (ALS). Elements of the ECS, such as fatty acid amide hydrolase or the cannabinoid receptors are now considered as promising pharmacological targets for some diseases. Although still preliminary, recent reports suggest that modulation of the ECS may constitute a novel approach for the treatment of AD. There are windows of opportunity in conditions caused by acute events such as trauma and ischemia as well in conditions that may involve altered functionality of the target receptors of the ECS, such as in AD. The ECS changes in Parkinson's disease could be compensatory as well as pathogenic of the illness process and needs further understanding and clinical studies are still in the preliminary stage. There is not enough evidence to support use of cannabinoids in treating Huntington's disease, tics and obsessive compulsive behaviour in Tourette's syndrome. Evidence on therapeutic use of cannabinoids in multiple sclerosis and ALS is currently limited. A major challenge for future research is the development of novel compounds with more selectivity for various components of the ECS which could target different neurotoxic pathways and be used in combination therapy.}, }
@article {pmid23824486, year = {2013}, author = {Bruneteau, G and Simonet, T and Bauché, S and Mandjee, N and Malfatti, E and Girard, E and Tanguy, ML and Behin, A and Khiami, F and Sariali, E and Hell-Remy, C and Salachas, F and Pradat, PF and Fournier, E and Lacomblez, L and Koenig, J and Romero, NB and Fontaine, B and Meininger, V and Schaeffer, L and Hantaï, D}, title = {Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression.}, journal = {Brain : a journal of neurology}, volume = {136}, number = {Pt 8}, pages = {2359-2368}, doi = {10.1093/brain/awt164}, pmid = {23824486}, issn = {1460-2156}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Disease Progression ; Female ; Histone Deacetylases/*genetics/metabolism ; Humans ; Male ; MicroRNAs/*genetics/metabolism ; Middle Aged ; Motor Neurons/*metabolism/pathology ; Muscle, Skeletal/*innervation/metabolism/pathology ; Neuromuscular Junction/genetics/metabolism/pathology ; Repressor Proteins/*genetics/metabolism ; Survivors ; Up-Regulation ; }, abstract = {Amyotrophic lateral sclerosis is a typically rapidly progressive neurodegenerative disorder affecting motor neurons leading to progressive muscle paralysis and death, usually from respiratory failure, in 3-5 years. Some patients have slow disease progression and prolonged survival, but the underlying mechanisms remain poorly understood. Riluzole, the only approved treatment, only modestly prolongs survival and has no effect on muscle function. In the early phase of the disease, motor neuron loss is initially compensated for by collateral reinnervation, but over time this compensation fails, leading to progressive muscle wasting. The crucial role of muscle histone deacetylase 4 and its regulator microRNA-206 in compensatory reinnervation and disease progression was recently suggested in a mouse model of amyotrophic lateral sclerosis (transgenic mice carrying human mutations in the superoxide dismutase gene). Here, we sought to investigate whether the microRNA-206-histone deacetylase 4 pathway plays a role in muscle compensatory reinnervation in patients with amyotrophic lateral sclerosis and thus contributes to disease outcome differences. We studied muscle reinnervation using high-resolution confocal imaging of neuromuscular junctions in muscle samples obtained from 11 patients with amyotrophic lateral sclerosis, including five long-term survivors. We showed that the proportion of reinnervated neuromuscular junctions was significantly higher in long-term survivors than in patients with rapidly progressive disease. We analysed the expression of muscle candidate genes involved in the reinnervation process and showed that histone deacetylase 4 upregulation was significantly greater in patients with rapidly progressive disease and was negatively correlated with the extent of muscle reinnervation and functional outcome. Conversely, the proposed regulator of histone deacetylase 4, microRNA-206, was upregulated in both patient groups, but did not correlate with disease progression or reinnervation. We conclude that muscle expression of histone deacetylase 4 may be a key factor for muscle reinnervation and disease progression in patients with amyotrophic lateral sclerosis. Specific histone deacetylase 4 inhibitors may then constitute a therapeutic approach to enhancing motor performance and slowing disease progression in amyotrophic lateral sclerosis.}, }
@article {pmid23819500, year = {2013}, author = {Danielsson, J and Inomata, K and Murayama, S and Tochio, H and Lang, L and Shirakawa, M and Oliveberg, M}, title = {Pruning the ALS-associated protein SOD1 for in-cell NMR.}, journal = {Journal of the American Chemical Society}, volume = {135}, number = {28}, pages = {10266-10269}, doi = {10.1021/ja404425r}, pmid = {23819500}, issn = {1520-5126}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/metabolism ; HeLa Cells ; Humans ; Models, Molecular ; *Nuclear Magnetic Resonance, Biomolecular ; Superoxide Dismutase/*chemistry/metabolism ; }, abstract = {To efficiently deliver isotope-labeled proteins into mammalian cells poses a main challenge for structural and functional analysis by in-cell NMR. In this study we have employed cell-penetrating peptides (CPPs) to deliver the ALS-associated protein superoxide dismutase (SOD1) into HeLa cells. Our results show that, although full-length SOD1 cannot be efficiently internalized, a variant in which the active-site loops IV and VII have been truncated (SOD1(ΔIVΔVII)) yields high cytosolic delivery. The reason for the enhanced delivery of SOD1(ΔIVΔVII) seems to be the elimination of negatively charged side chains, which alters the net charge of the CPP-SOD1 complex from neutral to +4. The internalized SOD1(ΔIVΔVII) protein displays high-resolution in-cell NMR spectra similar to, but not identical to, those of the lysate of the cells. Spectral differences are found mainly in the dynamic β strands 4, 5, and 7, triggered by partial protonation of the His moieties of the Cu-binding site. Accordingly, SOD1(ΔIVΔVII) doubles here as an internal pH probe, revealing cytosolic acidification under the experimental treatment. Taken together, these observations show that CPP delivery, albeit inefficient at first trials, can be tuned by protein engineering to allow atomic-resolution NMR studies of specific protein structures that have evaded other in-cell NMR approaches: in this case, the structurally elusive apoSOD1 barrel implicated as precursor for misfolding in ALS.}, }
@article {pmid23819039, year = {2013}, author = {Lazarev, VF and Sverchinskyi, DV and Ippolitova, MV and Stepanova, AV and Guzhova, IV and Margulis, BA}, title = {Factors Affecting Aggregate Formation in Cell Models of Huntington's Disease and Amyotrophic Lateral Sclerosis.}, journal = {Acta naturae}, volume = {5}, number = {2}, pages = {81-89}, pmid = {23819039}, issn = {2075-8251}, abstract = {Most neurodegenerative pathologies stem from the formation of aggregates of mutant proteins, causing dysfunction and ultimately neuronal death. This study was aimed at elucidating the role of the protein factors that promote aggregate formation or prevent the process, respectively, glyceraldehyde-3-dehydrogenase (GAPDH) and tissue transglutaminase (tTG) and Hsp70 molecular chaperone. The siRNA technology was used to show that the inhibition of GAPDH expression leads to a 45-50% reduction in the aggregation of mutant huntingtin, with a repeat of 103 glutamine residues in a model of Huntington's disease (HD). Similarly, the blockage of GAPDH synthesis was found for the first time to reduce the degree of aggregation of mutant superoxide dismutase 1 (G93A) in a model of amyotrophic lateral sclerosis (ALS). The treatment of cells that imitate HD and ALS with a pharmacological GAPDH inhibitor, hydroxynonenal, was also shown to reduce the amount of the aggregating material in both disease models. Tissue transglutaminase is another factor that promotes the aggregation of mutant proteins; the inhibition of its activity with cystamine was found to prevent aggregate formation of mutant huntingtin and SOD1. In order to explore the protective function of Hsp70 in the control of the aggregation of mutant huntingtin, a cell model with inducible expression of the chaperone was used. The amount and size of polyglutamine aggregates were reduced by increasing the intracellular content of Hsp70. Thus, pharmacological regulation of the function of three proteins, GAPDH, tTG, and Hsp70, can affect the pathogenesis of two significant neurodegenerative diseases.}, }
@article {pmid23813494, year = {2013}, author = {Su, XW and Lee, SY and Mitchell, RM and Stephens, HE and Simmons, Z and Connor, JR}, title = {H63D HFE polymorphisms are associated with increased disease duration and decreased muscle superoxide dismutase-1 expression in amyotrophic lateral sclerosis patients.}, journal = {Muscle &amp; nerve}, volume = {48}, number = {2}, pages = {242-246}, doi = {10.1002/mus.23740}, pmid = {23813494}, issn = {1097-4598}, mesh = {Adult ; Aged ; Aged, 80 and over ; *Amyotrophic Lateral Sclerosis/enzymology/genetics/pathology ; Female ; Gene Expression Regulation/*genetics ; Genetic Association Studies ; Genotype ; Hemochromatosis Protein ; Histidine/genetics ; Histocompatibility Antigens Class I/*genetics ; Humans ; Male ; Membrane Proteins/*genetics ; Middle Aged ; Muscle, Skeletal/*enzymology ; Phenylalanine/genetics ; Polymorphism, Single Nucleotide/*genetics ; Superoxide Dismutase/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {INTRODUCTION: H63D HFE polymorphisms increase the risk of neurodegenerative disorders and, specifically, may increase amyotrophic lateral sclerosis (ALS) risk. Investigating the physiological alterations induced by H63D polymorphisms in ALS patients may elucidate mechanisms by which this genotype alters disease.<br><br>METHODS: Clinical measures and muscle biopsies were available from patients previously diagnosed with ALS who underwent HFE genotyping. Clinical outcomes and SOD1 protein expression were analyzed using standard statistical analyses.<br><br>RESULTS: ALS patients harboring H63D HFE (n = 16) had 28.1 months longer average disease duration and 39.3% lower muscle SOD1 protein than ALS patients with wild-type HFE (n = 22).<br><br>CONCLUSIONS: Combined with previous reports suggesting the H63D polymorphism is associated with ALS, these results support a model wherein the H63D polymorphism is involved in ALS by means of pathways involving SOD1 but may limit cellular damage in individuals who develop disease. The association between HFE genotype and disease duration has important implications for clinical care and treatment trials.}, }
@article {pmid23809589, year = {2013}, author = {Ofran, Y and Yovchev, I and Hiller, N and Cohen, J and Rubin, SA and Schwartz, I and Meiner, Z}, title = {Correlation between time to diagnosis and rehabilitation outcomes in patients with spinal dural arteriovenous fistula.}, journal = {The journal of spinal cord medicine}, volume = {36}, number = {3}, pages = {200-206}, pmid = {23809589}, issn = {1079-0268}, mesh = {Adult ; Aged ; Central Nervous System Vascular Malformations/complications/*diagnosis/*rehabilitation ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Prognosis ; *Recovery of Function ; Spinal Cord Diseases/complications/*diagnosis/*rehabilitation ; Time ; Treatment Outcome ; }, abstract = {BACKGROUND: Spinal dural arteriovenous fistulas (SDAVFs) are the most common spinal vascular malformations and can be a significant cause of myelopathy although they are under diagnosed. Surgical or embolization treatment of SDAVFs improved significantly in the last decade. However, a high percentage of patients are still left with severe disability.<br><br>OBJECTIVE: To describe the correlation between time to diagnosis and the rehabilitation outcomes of eight patients with SDAVFs.<br><br>DESIGN: Retrospective chart study of all SDAVF patients in 20 years.<br><br>SETTING: A tertiary university rehabilitation center.<br><br>MAIN OUTCOME MEASURES: The lower extremities motor score (LEMS), Functional Independence Measure (FIM), Spinal Cord Independence Measure (SCIM) and Walking Scale for Spinal Cord Injury (WISC II). Overall prognosis was evaluated using the Aminoff-Logue scale (ALS).<br><br>RESULTS: There were seven men and one woman with mean age of 61.3 &#xb1; 15 (30-72) and mean time until the diagnosis of SDAVF of 265.5 &#xb1; 245 days (4-730). At the end of rehabilitation period, five of the eight patients remained wheelchair dependent. Strong correlation was found between LEMS, FIM, SCIM, and WISC II scores and the functional level according to the ALS scale. A significant correlation was found between time to diagnosis and the height of the SDAVF, the clinical and rehabilitation outcomes. Patients with high SDAVF which were diagnosed late had the poorest prognosis.<br><br>CONCLUSIONS: The potential for functional ambulation in patients with SDAVF is related to the time of intervention. This finding emphasizes the important of early diagnosis and early intervention in SDAVF.}, }
@article {pmid23808257, year = {2013}, author = {Trifonov, VR and Tikhomirov, AO and Khasanov, AF and Nazmutdinov, RR and Sharafutdinov, RKh}, title = {[Clinical case of amyotrophic lateral sclerosis management and treatment in the non-core clinic].}, journal = {Anesteziologiia i reanimatologiia}, volume = {}, number = {1}, pages = {55-57}, pmid = {23808257}, issn = {0201-7563}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*therapy ; Delivery of Health Care/*organization &amp; administration ; Humans ; Male ; Middle Aged ; Russia ; }, abstract = {The article points out the problems of amyotrophic lateral sclerosis (ALS) diagnostics, management and treatment in the non-core clinic (oncological dispensary intensive care unit). There is no legislative base for medical and social protection of patients with ALS in Russia. Article stresses the need to attract the attention of Ministry of healthcare of Russia to this problem.}, }
@article {pmid23798570, year = {2013}, author = {Dang, TN and Dobson-Stone, C and Glaros, EN and Kim, WS and Hallupp, M and Bartley, L and Piguet, O and Hodges, JR and Halliday, GM and Double, KL and Schofield, PR and Crouch, PJ and Kwok, JB}, title = {Endogenous progesterone levels and frontotemporal dementia: modulation of TDP-43 and Tau levels in vitro and treatment of the A315T TARDBP mouse model.}, journal = {Disease models &amp; mechanisms}, volume = {6}, number = {5}, pages = {1198-1204}, pmid = {23798570}, issn = {1754-8411}, mesh = {Aged ; Amino Acid Substitution/*genetics ; Animals ; Cohort Studies ; DNA-Binding Proteins/genetics/*metabolism ; Demography ; *Disease Models, Animal ; Female ; Frontotemporal Dementia/*metabolism/physiopathology/*therapy ; Humans ; Male ; Mice ; Mice, Neurologic Mutants ; Middle Aged ; Motor Activity ; Progesterone/*metabolism/pharmacology/therapeutic use ; tau Proteins/*metabolism ; }, abstract = {Frontotemporal dementia (FTD) is associated with motor neurone disease (FTD-MND), corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS). Together, this group of disorders constitutes a major cause of young-onset dementia. One of the three clinical variants of FTD is progressive nonfluent aphasia (PNFA), which is focused on in this study. The steroid hormone progesterone (PROG) is known to have an important role as a neurosteroid with potent neuroprotective and promyelination properties. In a case-control study of serum samples (39 FTD, 91 controls), low serum PROG was associated with FTD overall. In subgroup analysis, low PROG levels were significantly associated with FTD-MND and CBS, but not with PSPS or PNFA. PROG levels of >195 pg/ml were significantly correlated with lower disease severity (frontotemporal dementia rating scale) for individuals with CBS. In the human neuroblastoma SK-N-MC cell line, exogenous PROG (9300-93,000 pg/ml) had a significant effect on overall Tau and nuclear TDP-43 levels, reducing total Tau levels by ∼1.5-fold and increasing nuclear TDP-43 by 1.7- to 2.0-fold. Finally, elevation of plasma PROG to a mean concentration of 5870 pg/ml in an Ala315Thr (A315T) TARDBP transgenic mouse model significantly reduced the rate of loss of locomotor control in PROG-treated, compared with placebo, mice. The PROG treatment did not significantly increase survival of the mice, which might be due to the limitation of the transgenic mouse to accurately model TDP-43-mediated neurodegeneration. Together, our clinical, cellular and animal data provide strong evidence that PROG could be a valid therapy for specific related disorders of FTD.}, }
@article {pmid23797033, year = {2013}, author = {D'Amico, E and Factor-Litvak, P and Santella, RM and Mitsumoto, H}, title = {Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis.}, journal = {Free radical biology &amp; medicine}, volume = {65}, number = {}, pages = {509-527}, pmid = {23797033}, issn = {1873-4596}, support = {1R01ES016348/ES/NIEHS NIH HHS/United States ; P42 ES010349/ES/NIEHS NIH HHS/United States ; P30ES009089/ES/NIEHS NIH HHS/United States ; R01 ES016348/ES/NIEHS NIH HHS/United States ; R03 CA159427/CA/NCI NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; R03CA159427/CA/NCI NIH HHS/United States ; R01 ES005116/ES/NIEHS NIH HHS/United States ; R01 ES017024/ES/NIEHS NIH HHS/United States ; 1R01ES017024/ES/NIEHS NIH HHS/United States ; 1R01ES0122315/ES/NIEHS NIH HHS/United States ; R01ES005116/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Humans ; Nerve Degeneration/*physiopathology ; Oxidative Stress/*physiology ; }, abstract = {Sporadic amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological diseases; most patients die within 3 to 4 years after symptom onset. Oxidative stress is a disturbance in the pro-oxidative/antioxidative balance favoring the pro-oxidative state. Autopsy and laboratory studies in ALS indicate that oxidative stress plays a major role in motor neuron degeneration and astrocyte dysfunction. Oxidative stress biomarkers in cerebrospinal fluid, plasma, and urine are elevated, suggesting that abnormal oxidative stress is generated outside of the central nervous system. Our review indicates that agricultural chemicals, heavy metals, military service, professional sports, excessive physical exertion, chronic head trauma, and certain foods might be modestly associated with ALS risk, with a stronger association between risk and smoking. At the cellular level, these factors are all involved in generating oxidative stress. Experimental studies indicate that a combination of insults that induce modest oxidative stress can exert additive deleterious effects on motor neurons, suggesting that multiple exposures in real-world environments are important. As the disease progresses, nutritional deficiency, cachexia, psychological stress, and impending respiratory failure may further increase oxidative stress. Moreover, accumulating evidence suggests that ALS is possibly a systemic disease. Laboratory, pathologic, and epidemiologic evidence clearly supports the hypothesis that oxidative stress is central in the pathogenic process, particularly in genetically susceptive individuals. If we are to improve ALS treatment, well-designed biochemical and genetic epidemiological studies, combined with a multidisciplinary research approach, are needed and will provide knowledge crucial to our understanding of ALS etiology, pathophysiology, and prognosis.}, }
@article {pmid23795307, year = {2013}, author = {Ciesler, J and Sari, Y}, title = {Neurotrophic Peptides: Potential Drugs for Treatment of Amyotrophic Lateral Sclerosis and Alzheimer's disease.}, journal = {Open journal of neuroscience}, volume = {3}, number = {}, pages = {}, pmid = {23795307}, issn = {2075-9088}, support = {R21 AA016115/AA/NIAAA NIH HHS/United States ; R21 AA017735/AA/NIAAA NIH HHS/United States ; }, abstract = {Neurodegenerative diseases are characterized by the progressive loss of neurons and glial cells in the central nervous system correlated to their symptoms. Among these neurodegenerative diseases are Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Neurodegeneration is mostly restricted to specific neuronal populations: cholinergic neurons in AD and motoneurons in ALS. The demonstration that the onset and progression of neurodegenerative diseases in models of transgenic mice, in particular, is delayed or improved by the application of neurotrophic factors and derived peptides from neurotrophic factors has emphasized their importance in neurorestoration. A range of neurotrophic factors and growth peptide factors derived from activity-dependent neurotrophic factor/activity-dependent neuroprotective protein has been suggested to restore neuronal function, improve behavioral deficits and prolong the survival in animal models. In this review article, we focus on the role of trophic peptides in the improvement of AD and ALS. An understanding of the molecular pathways involved with trophic peptides in these neurodegenerative diseases may shed light on potential therapies.}, }
@article {pmid23789484, year = {2013}, author = {Drouet, A}, title = {[Management of muscle cramp: what's to be done?].}, journal = {La Revue du praticien}, volume = {63}, number = {5}, pages = {619-623}, pmid = {23789484}, issn = {0035-2640}, mesh = {Aged ; Aged, 80 and over ; Algorithms ; Diagnosis, Differential ; Electromyography ; Humans ; Muscle Cramp/complications/diagnosis/*therapy ; Pain/diagnosis/etiology ; Severity of Illness Index ; }, abstract = {Muscle cramp is characterized by involuntary, painful, visible contraction of a muscle (or a part of muscle) and is always associated with irregular repetitive firing of motor unit action potentials (200 à 300 Hz) which is caused by hyperexcitability of intramuscular terminal motor axons. It's a common condition in normal people, but most commonly in young people (pregnancy, exercise) and more in the elderly (50% after 65 years-old). A careful history and examination should allow the physician to determine the significance of cramp. ENMG and biological tests are needed in cases of severe symptoms (severity and frequency of cramps) and/or abnormal examination. Idiopathic and secondary (drug or metabolic disorders) cramps are the most common groups, but it's very important to search the motor unit diseases (neuropathy, radiculopathy, plexopathy, neuromyotonia, and a cramp fasciculation syndrome which can preceded ALS). The first goal in management of cramp is to determine if there is an underlying cause and the second to use physical measures (stretching), because, pharmacologic treatments have a moderate interest because of the potential of toxicity (quinine sulfate) or a little effectiveness (vitamin B complex, naftidrofuryl, and calcium channel blockers such as diltiazem, gabapentin). Isolated cramp doesn't need treatment.}, }
@article {pmid23791710, year = {2013}, author = {Sharma, S and Moon, CS and Khogali, A and Haidous, A and Chabenne, A and Ojo, C and Jelebinkov, M and Kurdi, Y and Ebadi, M}, title = {Biomarkers in Parkinson's disease (recent update).}, journal = {Neurochemistry international}, volume = {63}, number = {3}, pages = {201-229}, doi = {10.1016/j.neuint.2013.06.005}, pmid = {23791710}, issn = {1872-9754}, mesh = {Biomarkers/*metabolism ; Humans ; Parkinson Disease/*metabolism ; }, abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disorder mostly affecting the aging population over sixty. Cardinal symptoms including, tremors, muscle rigidity, drooping posture, drooling, walking difficulty, and autonomic symptoms appear when a significant number of nigrostriatal dopaminergic neurons are already destroyed. Hence we need early, sensitive, specific, and economical peripheral and/or central biomarker(s) for the differential diagnosis, prognosis, and treatment of PD. These can be classified as clinical, biochemical, genetic, proteomic, and neuroimaging biomarkers. Novel discoveries of genetic as well as nongenetic biomarkers may be utilized for the personalized treatment of PD during preclinical (premotor) and clinical (motor) stages. Premotor biomarkers including hyper-echogenicity of substantia nigra, olfactory and autonomic dysfunction, depression, hyposmia, deafness, REM sleep disorder, and impulsive behavior may be noticed during preclinical stage. Neuroimaging biomarkers (PET, SPECT, MRI), and neuropsychological deficits can facilitate differential diagnosis. Single-cell profiling of dopaminergic neurons has identified pyridoxal kinase and lysosomal ATPase as biomarker genes for PD prognosis. Promising biomarkers include: fluid biomarkers, neuromelanin antibodies, pathological forms of α-Syn, DJ-1, amyloid β and tau in the CSF, patterns of gene expression, metabolomics, urate, as well as protein profiling in the blood and CSF samples. Reduced brain regional N-acetyl-aspartate is a biomarker for the in vivo assessment of neuronal loss using magnetic resonance spectroscopy and T2 relaxation time with MRI. To confirm PD diagnosis, the PET biomarkers include [(18)F]-DOPA for estimating dopaminergic neurotransmission, [(18)F]dG for mitochondrial bioenergetics, [(18)F]BMS for mitochondrial complex-1, [(11)C](R)-PK11195 for microglial activation, SPECT imaging with (123)Iflupane and βCIT for dopamine transporter, and urinary salsolinol and 8-hydroxy, 2-deoxyguanosine for neuronal loss. This brief review describes the merits and limitations of recently discovered biomarkers and proposes coenzyme Q10, mitochondrial ubiquinone-NADH oxidoreductase, melatonin, α-synculein index, Charnoly body, and metallothioneins as novel biomarkers to confirm PD diagnosis for early and effective treatment of PD.}, }
@article {pmid23791309, year = {2013}, author = {Alavi, A and Nafissi, S and Shamshiri, H and Nejad, MM and Elahi, E}, title = {Identification of mutation in NPC2 by exome sequencing results in diagnosis of Niemann-Pick disease type C.}, journal = {Molecular genetics and metabolism}, volume = {110}, number = {1-2}, pages = {139-144}, doi = {10.1016/j.ymgme.2013.05.019}, pmid = {23791309}, issn = {1096-7206}, mesh = {Adolescent ; Adult ; Carrier Proteins/*genetics ; Child ; Exome/genetics ; Female ; Genetic Testing ; Genotype ; Glycoproteins/*genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Iran ; Male ; *Mutation ; Niemann-Pick Disease, Type C/*diagnosis/*genetics/pathology ; Pedigree ; Phenotype ; Vesicular Transport Proteins ; }, abstract = {We report identification of a homozygous mutation in NPC2 in two Iranian siblings with a neurologic dysfunction whose disease had not been diagnosed prior to our genetic analysis. The mutation was identified by exome sequencing. The finding resulted in diagnosis of Niemann-Pick disease type C (NPC) in the siblings, and initiation of treatment with Miglustat. The clinical features of the patients are presented. It has been suggested that NPC is under diagnosed, particularly when presentations are not very severe, as was the situation in the cases studied here. NPC is a fatal autosomal recessive disorder clinically characterized by hepatosplenomegaly and progressive neurological deterioration. At the cellular level, it causes aberrant cholesterol trafficking and accumulation of unesterified cholesterol in lysosomes. Mutations in NPC1 and NPC2 are cause of disease in respectively, 95% and 5% of NPC patients. The p.Pro120Ser causing mutation in NPC2 observed in the Iranian patients was earlier observed in the only other NPC2 patient reported from the Middle East. The study demonstrates that in addition to greatly facilitating gene discovery, exome sequencing has notable potentials for diagnosis, particularly for diagnosis of atypical cases.}, }
@article {pmid23785039, year = {2013}, author = {Han, H and Yu, Q and Cawthray, GR and Powles, SB}, title = {Enhanced herbicide metabolism induced by 2,4-D in herbicide susceptible Lolium rigidum provides protection against diclofop-methyl.}, journal = {Pest management science}, volume = {69}, number = {9}, pages = {996-1000}, doi = {10.1002/ps.3552}, pmid = {23785039}, issn = {1526-4998}, mesh = {2,4-Dichlorophenoxyacetic Acid/*metabolism/pharmacology ; Halogenated Diphenyl Ethers/*metabolism/pharmacology ; *Herbicide Resistance ; Herbicides/*metabolism/pharmacology ; Lolium/drug effects/*metabolism ; }, abstract = {BACKGROUND: The auxinic herbicide 2,4-D amine is known, in vitro, as a cytochrome P450 inducer. The current study uses 2,4-D pre-treatment, at the whole plant level, to study mechanism(s) of non-target site based herbicide resistance to the ACCase-inhibiting herbicide diclofop-methyl in Lolium rigidum.<br><br>RESULTS: The 2,4-D pre-treatment caused up to 10-fold shift in LD50 and GR50 in dose-response to subsequently applied diclofop-methyl in a herbicide susceptible L. rigidum population. Foliar uptake and translocation of (14) C-diclofop-methyl did not differ in 2,4-D pre-treated versus untreated plants. HPLC analysis revealed that de-esterification of diclofop-methyl to toxic diclofop acid was similar, but further metabolism of diclofop acid to non-toxic metabolites was significantly (1.8-fold) faster in 2,4-D pre-treated than untreated plants. HPLC profile of major polar metabolites was similar when L. rigidum and diclofop-methyl tolerant wheat were compared, but wheat metabolised diclofop acid three-fold faster than L. rigidum. In addition, 2,4-D pre-treatment also induced cross-protection against the ALS-inhibiting herbicide chlorsulfuron, and the known P450 inhibitor malathion can reverse this effect.<br><br>CONCLUSIONS: Protection against diclofop-methyl provided by 2,4-D pre-treatment in susceptible L. rigidum is associated with higher rates of herbicide metabolism, mirroring that identified in field-evolved, non-target site-based diclofop-methyl resistant populations. 2,4-D may induce higher level expression of herbicide-metabolising genes hence providing protection, and therefore, this 2,4-D induction system can be used, in combination with other genomic approaches, to assist isolating cytochrome P450 and other genes that are involved in herbicide metabolism and endow herbicide resistance in L. rigidum.}, }
@article {pmid23777615, year = {2013}, author = {Dall'Igna, OP and Bobermin, LD and Souza, DO and Quincozes-Santos, A}, title = {Riluzole increases glutamate uptake by cultured C6 astroglial cells.}, journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience}, volume = {31}, number = {7}, pages = {482-486}, doi = {10.1016/j.ijdevneu.2013.06.002}, pmid = {23777615}, issn = {1873-474X}, mesh = {Analysis of Variance ; Animals ; Astrocytes/*drug effects/metabolism ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Antagonists/*pharmacology ; Excitatory Amino Acid Transporter 3/metabolism ; Glioma/pathology ; Glutamic Acid/*metabolism ; Glutathione/metabolism ; L-Lactate Dehydrogenase/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Riluzole/*pharmacology ; S100 Calcium Binding Protein beta Subunit/metabolism ; Time Factors ; }, abstract = {Riluzole is a drug approved for the treatment of amyotrophic lateral sclerosis (ALS) and may be effective for the treatment of other neurodegenerative and neuropsychiatric disorders. Riluzole exerts diverse actions on the central nervous system, including altering glutamate release and uptake, and therefore act diminishing glutamate extracellular levels, but the underlying mechanism of these actions is still unknown. Here, we demonstrate that riluzole stimulated glutamate uptake and augmented the expression of the glutamate EAAC1 transporter in C6 astroglial cell cultures. The effect of riluzole on glutamate uptake was reduced to below controls when it was co-administered with inhibitors of protein kinase C (PKC; bisindolylmaleimide II), phosphatidylinositol 3-kinase (PI3K; wortmannin) and fibroblast growth factor receptor 1 (FGFR1; PD173074). Riluzole also decreased reactive oxygen species load with no effect on glutathione levels. This study investigates three independent intracellular pathways and the mechanism of action of riluzole on glutamate metabolism.}, }
@article {pmid23773350, year = {2013}, author = {Ayach, L and Curti, C and Montana, M and Pisano, P and Vanelle, P}, title = {[Amyotrophic lateral sclerosis: update on etiological treatment].}, journal = {Therapie}, volume = {68}, number = {2}, pages = {93-106}, doi = {10.2515/therapie/2013012}, pmid = {23773350}, issn = {0040-5957}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*etiology/*therapy ; Animals ; Disease Models, Animal ; Disease Progression ; Humans ; Longitudinal Studies ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Stem Cell Transplantation ; Survival ; }, abstract = {Amyotrophic lateral sclerosis is a rare neurodegenerative disease. It is characterized by motoneurons progressive degeneration. Associated with a paralysis of the legs, arms and the respiratory muscles, its evolution is lethal. Riluzole is the only drug available with an marketing authorisation (autorisation de mise sur le marché [AMM]) in this indication. In the beginning stages of the disease it demonstrated a modest efficacy by prolonging survival for a few months. Although the physiopathological mechanisms of this disease have not been totally solved, the progression of knowledge in recent years in this area led to the development of a large number of neuroprotective agents which showed effective results in animal models of ALS and which could be good candidates for the treatment of ALS. Several clinical trials have been conducted about antiglutamatergic, antioxidant, antiapoptotic agents and growing cell factors but they failed to demonstrate efficacy on survival or quality of life. Therefore, clinical trials using innovative therapeutics and stem cells are ongoing and offer more distant hope.}, }
@article {pmid23766784, year = {2013}, author = {Limpert, AS and Mattmann, ME and Cosford, ND}, title = {Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS).}, journal = {Beilstein journal of organic chemistry}, volume = {9}, number = {}, pages = {717-732}, pmid = {23766784}, issn = {1860-5397}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with few therapeutic options. While several gene mutations have been implicated in ALS, the exact cause of neuronal dysfunction is unknown and motor neurons of affected individuals display numerous cellular abnormalities. Ongoing efforts to develop novel ALS treatments involve the identification of small molecules targeting specific mechanisms of neuronal pathology, including glutamate excitotoxicity, mutant protein aggregation, endoplasmic reticulum (ER) stress, loss of trophic factors, oxidative stress, or neuroinflammation. Herein, we review recent advances in the discovery and preclinical characterization of lead compounds that may ultimately provide novel drugs to treat patients suffering from ALS.}, }
@article {pmid23764602, year = {2013}, author = {Alvarado, A and Vesvikar, M and Cisneros, JF and Maere, T and Goethals, P and Nopens, I}, title = {CFD study to determine the optimal configuration of aerators in a full-scale waste stabilization pond.}, journal = {Water research}, volume = {47}, number = {13}, pages = {4528-4537}, doi = {10.1016/j.watres.2013.05.016}, pmid = {23764602}, issn = {1879-2448}, mesh = {Aerobiosis ; Computer Simulation ; *Hydrodynamics ; Models, Theoretical ; Oxygen/analysis ; *Ponds ; Thermodynamics ; Time Factors ; *Waste Disposal, Fluid ; }, abstract = {Aerated lagoons (ALs) are important variants of the pond wastewater treatment technology that have not received much attention in the literature. The hydraulic behaviour of ALs and especially the Facultative aerated lagoons (FALs) is very complex since the aeration in these systems is designed for oxygen transfer but not necessarily to create complete mixing. In this work, the energy expenditure of the aerators was studied by means of a scenario analysis. 3D CFD models (one phase and multiphase) of a 3 ha FAL in a waste stabilization pond system in Cuenca (Ecuador) were built for different configurations of aerators. The thrust produced by the aerators was modelled by an external momentum source applied as velocity vectors into the pond fluid. The predictions of a single phase model were in satisfactory agreement with experimental results. Subsequently, a scenario analysis assessing several aeration schemes with different numbers of aerators in operation were tested with respect to velocity profiles and residence time distribution (RTD) curves. This analysis showed that the aeration scheme with all 10 aerators switched on produces a similar hydraulic behaviour compared to using only 6 or 8 aerators. The current operational schemes comprise of switching off some aerators during the peak hours of the day and operating all 10 aerators during night. This current practice could be economically replaced by continuously operating 4 or 6 aerators without significantly affecting the overall mixing. Furthermore, a continuous mixing regime minimises the sediment oxygen demand enhancing the oxygen levels in the pond.}, }
@article {pmid23763343, year = {2013}, author = {Takata, M and Tanaka, H and Kimura, M and Nagahara, Y and Tanaka, K and Kawasaki, K and Seto, M and Tsuruma, K and Shimazawa, M and Hara, H}, title = {Fasudil, a rho kinase inhibitor, limits motor neuron loss in experimental models of amyotrophic lateral sclerosis.}, journal = {British journal of pharmacology}, volume = {170}, number = {2}, pages = {341-351}, pmid = {23763343}, issn = {1476-5381}, mesh = {1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/administration &amp; dosage/*analogs &amp; derivatives/pharmacology ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Disease Models, Animal ; Disease Progression ; Dose-Response Relationship, Drug ; Male ; Mice, Transgenic ; Motor Neurons/*drug effects/pathology ; Neuroprotective Agents/pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/administration &amp; dosage/*pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Survival Rate ; rho-Associated Kinases/antagonists &amp; inhibitors ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with no effective treatment. Fasudil hydrochloride (fasudil), a potent rho kinase (ROCK) inhibitor, is useful for the treatment of ischaemic diseases. In previous reports, fasudil improved pathology in mouse models of Alzheimer's disease and spinal muscular atrophy, but there is no evidence in that it can affect ALS. We therefore investigated its effects on experimental models of ALS.<br><br>EXPERIMENTAL APPROACH: In mice motor neuron (NSC34) cells, the neuroprotective effect of hydroxyfasudil (M3), an active metabolite of fasudil, and its mechanism were evaluated. Moreover, the effects of fasudil, 30 and 100 mg&#xb7;kg(-1), administered via drinking water to mutant superoxide dismutase 1 (SOD1(G93A)) mice were tested by measuring motor performance, survival time and histological changes, and its mechanism investigated.<br><br>KEY RESULTS: M3 prevented motor neuron cell death induced by SOD1(G93A). Furthermore, M3 suppressed both the increase in ROCK activity and phosphorylated phosphatase and tensin homologue deleted on chromosome 10 (PTEN), and the reduction in phosphorylated Akt induced by SOD1(G93A). These effects of M3 were attenuated by treatment with a PI3K inhibitor (LY294002). Moreover, fasudil slowed disease progression, increased survival time and reduced motor neuron loss, in SOD1(G93A) mice. Fasudil also attenuated the increase in ROCK activity and PTEN, and the reduction in Akt in SOD1(G93A) mice.<br><br>CONCLUSIONS AND IMPLICATIONS: These findings indicate that fasudil may be effective at suppressing motor neuron degeneration and symptom progression in ALS. Hence, fasudil may have potential as a therapeutic agent for ALS treatment.}, }
@article {pmid23762114, year = {2013}, author = {Yang, EJ and Choi, SM}, title = {α -Synuclein Modification in an ALS Animal Model.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2013}, number = {}, pages = {259381}, pmid = {23762114}, issn = {1741-427X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressively paralytic neurodegenerative disease that can be caused by mutations in Cu/Zn-superoxide dismutase 1 (SOD1). Transgenic mice that overexpress mutant SOD1 develop paralysis and accumulate aggregates of mutant protein in the brainstem and spinal cord. Bee venom (BV), which is also known as apitoxin, is extracted from honeybees and is commonly used in oriental medicine for the treatment of chronic rheumatoid arthritis and osteoarthritis. The purpose of the present study was to determine whether BV affects misfolded protein aggregates such as alpha-synuclein, which is a known pathological marker in Parkinson disease, and ubiquitin-proteasomal activity in hSOD1(G93A) mutant mice. BV was bilaterally administered into a 98-day-old hSOD1(G93A) animal model. We found that BV-treated hSOD1(G93A) transgenic mice showed reduced detergent-insoluble polymerization and phosphorylation of α -synuclein. Furthermore, phosphorylated or nitrated α -synuclein was significantly reduced in the spinal cords and brainstems of BV-treated hSOD1(G93A) mice and reduced proteasomal activity was revealed in the brainstems of BV-treated symptomatic hSOD1(G93A). From these findings, we suggest that BV treatment attenuates the dysfunction of the ubiquitin-proteasomal system in a symptomatic hSOD1(G93A) ALS model and may help to slow motor neuron loss caused by misfolded protein aggregates in ALS models.}, }
@article {pmid23752092, year = {2013}, author = {Caioli, S and Pieri, M and Antonini, A and Guglielmotti, A and Severini, C and Zona, C}, title = {Monocyte Chemoattractant Protein-1 upregulates GABA-induced current: evidence of modified GABAA subunit composition in cortical neurons from the G93A mouse model of Amyotrophic Lateral Sclerosis.}, journal = {Neuropharmacology}, volume = {73}, number = {}, pages = {247-260}, doi = {10.1016/j.neuropharm.2013.05.045}, pmid = {23752092}, issn = {1873-7064}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Cells, Cultured ; Cerebral Cortex/drug effects/physiology ; Chemokine CCL2/antagonists &amp; inhibitors/*pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Flumazenil/pharmacology ; GABA-A Receptor Antagonists/pharmacology ; Humans ; Male ; Membrane Potentials/drug effects/physiology ; Mice ; Mice, Transgenic ; Neurons/drug effects/physiology ; Protein Subunits/metabolism ; Receptors, GABA-A/*metabolism ; Spinal Cord/drug effects/physiology ; gamma-Aminobutyric Acid/pharmacology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that affects upper and lower motor neurons. Previous evidence has indicated that excitotoxic cell death in ALS may remarkably depend on Cl(-) ion influx through the GABA(A) receptors. In this study we have analysed the effect of Monocyte Chemoattractant Protein-1 (MCP-1), a chemokine expressed to a higher level in ALS patients, on GABAA receptors in cultured cortical neurons from a genetic model of ALS (G93A) and compared with wild type SOD1 (SOD1) and their corresponding non transgenic littermates (Control). By performing electrophysiological experiments we have observed that, in cortical neurons MCP-1 (2-150 ng/ml) induced an enhancement of GABA-evoked currents that was significantly higher in G93A neurons compared to controls. The effect of MCP-1 was not dependent on the activation of its receptor CCR2, while it was blocked by flumazenil, the antagonist of benzodiazepine sites. Analysis of GABAA receptor subunit composition has indicated an altered subunit expression level in G93A cortical neurons compared to controls. Instead, in cultured spinal neurons MCP-1 induced a significant reduction of GABA-evoked currents, also through the benzodiazepine sites, indicating a region-specific mechanism of action. However, no differences were observed in the current reduction between the three neuronal populations. These findings provide the first evidence that MCP-1, acting on benzodiazepine sites, can modulate the GABA-evoked currents, depending on the subunit composition of GABA(A) receptor. In cortical neurons MCP-1 upmodulates the GABA-evoked current and this effect is exacerbated in the mutated neurons. It is reasonable to assume that the higher Cl(-) influx through GABA(A) receptors in the presence of MCP-1 in mutated cortical neurons may induce an excitotoxicity acceleration. Agents able to block the MCP-1 production may then prove useful for ALS treatment.}, }
@article {pmid23746533, year = {2013}, author = {Kang, SC and Hwang, SJ and Wu, PY and Tsai, CP}, title = {The utilization of hospice care among patients with motor neuron diseases: the experience in Taiwan from 2005 to 2010.}, journal = {Journal of the Chinese Medical Association : JCMA}, volume = {76}, number = {7}, pages = {390-394}, doi = {10.1016/j.jcma.2013.03.012}, pmid = {23746533}, issn = {1728-7731}, mesh = {Adult ; Aged, 80 and over ; Female ; Hospice Care/*statistics &amp; numerical data ; Humans ; Intubation, Gastrointestinal ; Male ; Middle Aged ; Motor Neuron Disease/*therapy ; Physicians, Family ; Respiration, Artificial ; Taiwan ; Time Factors ; }, abstract = {BACKGROUND: The nature and extent of how patients with motor neuron diseases (MNDs) utilize hospice care in Taiwan remains unclear. This study aims to investigate the use of hospice care in Taiwan by patients with MND, and those factors that affect the extent, the cost, and the quality of their hospice treatment and care.<br><br>METHODS: We analyzed data from hospice care inpatient claims of MNDs, using the National Health Insurance Research Database of Taiwan during 2005-2010.<br><br>RESULTS: Thirty patients and 58 related discharges were enrolled into our study, which consisted of 13 males and 17 females, with a mean age 58.3 years. Of that total, 27 of them (90%) had amyotrophic lateral sclerosis, and four (13.3%) had comorbid cancers; 17 died during hospice care. Acute low respiratory conditions (31.0%) accounted for the most common acute comorbidity. Noninvasive ventilation care was performed in only 13 (22.4%) of the discharges. In contrast to nasogastric intubation (40 discharges, 69.0%), no gastrostomy/jejunostomy was noted. These procedures bore no relationship to results observed in the discharges. Family physicians provided most inpatient hospice services (74.1%). Respiratory problems were the major causes of death (70.6% of decedents). The mean inpatient costs of hospice care were noticeably reduced from previously established nationwide mean costs.<br><br>CONCLUSION: Hospice care can save costs for patients with terminal MNDs, and family physicians play a valuable role in caring for these patients. However, respiratory and feeding problems are prevalent, yet there are proven benefits when noninvasive ventilation care and gastrostomy/jejunostomy are promoted.}, }
@article {pmid23744169, year = {2013}, author = {Skoczyński, S and Tażbirek, M and Pierzchała, W}, title = {[Non-invasive ventilation in treatment of adults with chronic respiratory failure].}, journal = {Pneumonologia i alergologia polska}, volume = {81}, number = {4}, pages = {380-389}, pmid = {23744169}, issn = {0867-7077}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/epidemiology/therapy ; Causality ; Comorbidity ; Humans ; Noninvasive Ventilation/*methods ; Pulmonary Disease, Chronic Obstructive/epidemiology/therapy ; Respiratory Insufficiency/epidemiology/*therapy ; Sleep Apnea, Central/epidemiology/therapy ; }, abstract = {Non-invasive mechanical ventilation (NIV) is a modern method of chronic respiratory failure (CRF) treatment. With the development of medicine and society known as "western", the number of elderly people, in whom there is overlapping of chronic diseases such as COPD, is growing. In adult population NIV is used in the treatment of neuromuscular diseases such as amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy. The other main indications include restrictive diseases such as kyphoscoliosis, pulmonary diseases with COPD which is the primary indication, and various forms of central apnea syndrome with epidemiologically essential role of obesity hypoventilation syndrome (OHS). In each of those indications, and in different patients, the mode and ventilation intensity may significantly differ. The aim of this review is to disseminate knowledge on the potential role of NIV in adults with CRF. This paper attempts to analyze the available knowledge concerning NIV in adults with CRF. Special attention is paid to the potential pathomechanisms which should become the subject of future research.}, }
@article {pmid23741042, year = {2013}, author = {Bellingham, MC}, title = {Pre- and postsynaptic mechanisms underlying inhibition of hypoglossal motor neuron excitability by riluzole.}, journal = {Journal of neurophysiology}, volume = {110}, number = {5}, pages = {1047-1061}, doi = {10.1152/jn.00587.2012}, pmid = {23741042}, issn = {1522-1598}, mesh = {Animals ; Excitatory Amino Acid Antagonists/*pharmacology ; Excitatory Postsynaptic Potentials/*drug effects ; Female ; Hypoglossal Nerve/cytology ; In Vitro Techniques ; Male ; Medulla Oblongata/*physiology ; Motor Neurons/*physiology ; Rats ; Riluzole/*pharmacology ; Synapses/*physiology ; }, abstract = {Riluzole is the sole treatment for amyotrophic lateral sclerosis (ALS), but its therapeutically relevant actions on motor neurons are not well defined. Whole cell patch-clamp recordings were made from hypoglossal motor neurons (HMs, n = 25) in brain stem slices from 10- to 23-day-old rats anesthetized with pentobarbital sodium to investigate the hypothesis that riluzole inhibits HMs by multiple mechanisms. Riluzole (20 μM) hyperpolarized HMs by decreasing an inward current, inhibited voltage-gated persistent Na(+) and Ca(2+) currents activated by slow voltage ramps, and negatively shifted activation of the hyperpolarization-activated cationic current (IH). Repetitive firing of HMs was strongly inhibited by riluzole, which also increased action potential threshold voltage and rheobase and decreased amplitude and maximum rise slope but did not alter the maximal afterhyperpolarization amplitude or decay time constant. HM rheobase was inversely correlated with persistent Na(+) current density. Glutamatergic synaptic transmission was inhibited by riluzole by both pre- and postsynaptic effects. Riluzole decreased activity-dependent glutamate release, as shown by decreased amplitude of evoked and spontaneous excitatory postsynaptic currents (EPSCs), decreased paired-pulse ratio, and decreased spontaneous, but not miniature, EPSC frequency. However, riluzole also decreased miniature EPSC amplitude and the inward current evoked by local application of glutamate onto HMs, suggesting a reduction of postsynaptic glutamate receptor sensitivity. Riluzole thus has a marked inhibitory effect on HM activity by membrane hyperpolarization, decreasing firing and inhibiting glutamatergic excitation by both pre- and postsynaptic mechanisms. These results broaden the range of mechanisms controlling motor neuron inhibition by riluzole and are relevant to researchers and clinicians interested in understanding ALS pathogenesis and treatment.}, }
@article {pmid23740607, year = {2013}, author = {Brettschneider, J and Kurent, J and Ludolph, A}, title = {Drug therapy for pain in amyotrophic lateral sclerosis or motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {2013}, number = {6}, pages = {CD005226}, pmid = {23740607}, issn = {1469-493X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*complications ; Humans ; Motor Neuron Disease/complications ; Pain/*drug therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is the most common neurodegenerative disorder of the motor system in adults. Pain in ALS is a frequent symptom especially in the later stages of disease and can have a pronounced influence on quality of life and suffering. Treatment of pain therefore should be recognised as an important aspect of palliative care in ALS. This is an update of a review first published in 2008.<br><br>OBJECTIVES: To systematically review the evidence for the efficacy of drug therapy in relieving pain in ALS. We also aimed to evaluate possible adverse effects associated with the different drugs and their influence on survival and quality of life.<br><br>SEARCH METHODS: On 2 July 2012, we searched the following databases: the Cochrane Neuromuscular Disease Group Specialized Register (2 July 2012), CENTRAL (2012, Issue 6 in The Cochrane Library), MEDLINE (January 1966 to June 2012), EMBASE (January 1980 to June 2012), CINAHL (January 1982 to June 2012), AMED (January 1985 to June 2012) and LILACS (January 1982 to June 2012). We checked the bibliographies of trials identified and contacted other disease experts to identify further published and unpublished trials.<br><br>SELECTION CRITERIA: We searched for randomised or quasi-randomised controlled trials on drug therapy for pain in amyotrophic lateral sclerosis.<br><br>DATA COLLECTION AND ANALYSIS: We collected data using a specially designed form and analysed them using the Cochrane Review Manager software.<br><br>MAIN RESULTS: We found no randomised or quasi-randomised controlled trials on drug therapy for pain in ALS or MND.<br><br>AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials about the management of pain in ALS. Further research on this important aspect of palliative care in ALS is needed. Randomised controlled trials should be initiated to determine the effectiveness of different analgesics for treatment of pain in ALS.}, }
@article {pmid23732987, year = {2013}, author = {Nanou, A and Higginbottom, A and Valori, CF and Wyles, M and Ning, K and Shaw, P and Azzouz, M}, title = {Viral delivery of antioxidant genes as a therapeutic strategy in experimental models of amyotrophic lateral sclerosis.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {21}, number = {8}, pages = {1486-1496}, pmid = {23732987}, issn = {1525-0024}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/therapy ; Animals ; Astrocytes/metabolism ; Cell Line ; Dependovirus/genetics ; Disease Models, Animal ; Gene Expression ; Gene Transfer Techniques ; Genetic Therapy ; Genetic Vectors/*genetics ; Humans ; Lentivirus/genetics ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism ; NF-E2-Related Factor 2/genetics ; Oxidative Stress/*genetics ; Peroxiredoxin III/genetics ; Signal Transduction ; Superoxide Dismutase/genetics/metabolism ; Transduction, Genetic ; *Transgenes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with no effective treatment to date. Despite its multi-factorial aetiology, oxidative stress is hypothesized to be one of the key pathogenic mechanisms. It is thus proposed that manipulation of the expression of antioxidant genes that are downregulated in the presence of mutant SOD1 may serve as a therapeutic strategy for motor neuronal protection. Lentiviral vectors expressing either PRDX3 or NRF2 genes were tested in the motor neuronal-like NSC34 cell line, and in the ALS tissue culture model, NSC34 cells expressing the human SOD1(G93A) mutation. The NSC34 SOD1(G93A) cells overexpressing either PRDX3 or NRF2 showed a significant decrease in endogenous oxidation stress levels by 40 and 50% respectively compared with controls, whereas cell survival was increased by 30% in both cases. The neuroprotective potential of those two genes was further investigated in vivo in the SOD1(G93A) ALS mouse model, by administering intramuscular injections of adenoassociated virus serotype 6 (AAV6) expressing either of the target genes at a presymptomatic stage. Despite the absence of a significant effect in survival, disease onset or progression, which can be explained by the inefficient viral delivery, the promising in vitro data suggest that a more widespread CNS delivery is needed.}, }
@article {pmid23728676, year = {2013}, author = {Fang, J and Zhou, M and Yang, M and Zhu, C and He, L}, title = {Repetitive transcranial magnetic stimulation for the treatment of amyotrophic lateral sclerosis or motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {2013}, number = {5}, pages = {CD008554}, pmid = {23728676}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/therapy ; Randomized Controlled Trials as Topic ; Transcranial Magnetic Stimulation/*methods ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurodegenerative disease without effective therapies. Several studies have suggested that repetitive transcranial magnetic stimulation (rTMS) may have positive benefit in ALS. However, the efficacy and safety of this therapy remain uncertain. This is the first update of a review published in 2011.<br><br>OBJECTIVES: To determine the clinical efficacy and safety of rTMS for treating ALS.<br><br>SEARCH METHODS: On 30 July 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (2012, issue 7 in The Cochrane Library), MEDLINE (1966 to July 2012), EMBASE (1980 to July 2012), CINAHL (1937 to July 2012), Science Citation Index Expanded (January 1945 to July 2012), AMED (January 1985 to July 2012). We searched the Chinese Biomedical Database (1979 to August 2012). We also searched for ongoing studies on clinicaltrials.gov (August 2012).<br><br>SELECTION CRITERIA: Randomised and quasi-randomised controlled trials assessing the therapeutic efficacy and safety of rTMS for patients with a clinical diagnosis of ALS.Comparisons eligible for inclusion were:1. rTMS versus no intervention;2. rTMS versus sham rTMS;3. rTMS versus physiotherapy;4. rTMS versus medications;5. rTMS + other therapies or drugs versus sham rTMS + the same therapies or drugs;6. different methods of application of rTMS such as high-frequency (> 1Hz) compared to low-frequency (&#x2264; 1Hz) rTMS.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently selected papers, assessed risk of bias and extracted data. We resolved disagreements through discussion. We contacted study authors for additional information.<br><br>MAIN RESULTS: Three randomised, placebo-controlled trials with a total of 50 participants were included in the review. All three trials compared rTMS with sham TMS. All the trials were of poor methodological quality and were insufficiently homogeneous to allow the pooling of results. Moreover, the high rate of attrition further increased the risk of bias. None of the trials provided detailed data on the ALS Functional Rating Scale-Revised (ALSFRS-R) scores at six months follow-up which was pre-assigned as our primary outcome. One trial contained data in a suitable form for quantitative analysis of our secondary outcomes. No difference was seen between rTMS and sham rTMS using the ALSFRS-R scores and manual muscle testing (MMT) scores at 12 months follow-up in this trial. Additionally, none of the trials reported any adverse events associated with the use of rTMS. However, in view of the small sample size, the methodological limitations and incomplete outcome data, treatment with rTMS cannot be judged as completely safe.<br><br>AUTHORS' CONCLUSIONS: There is currently insufficient evidence to draw conclusions about the efficacy and safety of rTMS in the treatment of ALS. Further studies may be helpful if their potential benefit is weighed against the impact of participation in a randomised controlled trial on people with ALS.}, }
@article {pmid23727509, year = {2013}, author = {Marconi, S and Bonaconsa, M and Scambi, I and Squintani, GM and Rui, W and Turano, E and Ungaro, D and D'Agostino, S and Barbieri, F and Angiari, S and Farinazzo, A and Constantin, G and Del Carro, U and Bonetti, B and Mariotti, R}, title = {Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model.}, journal = {Neuroscience}, volume = {248}, number = {}, pages = {333-343}, doi = {10.1016/j.neuroscience.2013.05.034}, pmid = {23727509}, issn = {1873-7544}, mesh = {Adiposity ; Amyotrophic Lateral Sclerosis/pathology/physiopathology/*therapy ; Animals ; Disease Models, Animal ; Fibroblast Growth Factor 2/metabolism ; Glial Cell Line-Derived Neurotrophic Factor/metabolism ; Male ; Mesenchymal Stem Cell Transplantation/*methods ; Mesenchymal Stem Cells/*cytology/physiology ; Mice ; Mice, Transgenic ; *Motor Activity ; Motor Neurons/*cytology/metabolism/physiology ; *Neuroprotective Agents ; Spinal Cord/cytology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Treatment Outcome ; Up-Regulation ; }, abstract = {Therapeutic strategies for the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) are actually minimally effective on patients' survival and quality of life. Although stem cell therapy has raised great expectations, information on the involved molecular mechanisms is still limited. Here we assessed the efficacy of the systemic administration of adipose-derived mesenchymal stem cells (ASC), a previously untested stem cell population, in superoxide-dismutase 1 (SOD1)-mutant transgenic mice, the animal model of familial ALS. The administration of ASC to SOD1-mutant mice at the clinical onset significantly delayed motor deterioration for 4-6 weeks, as shown by clinical and neurophysiological tests. Neuropathological examination of ASC-treated SOD1-mutant mice at day 100 (i.e. the time of their best motor performance) revealed a higher number of lumbar motorneurons than in phosphate-buffered saline-treated SOD1-mutant mice and a restricted number of undifferentiated green fluorescent protein-labeled ASC in the spinal cord. By examining the spinal cord tissue factors that may prolong neuronal survival, we found a significant up-regulation in levels of glial-derived neurotrophic factor (GDNF) and basic fibroblast growth factor (bFGF) after ASC treatment. Considering that ASC produce bFGF but not GDNF, these findings indicate that ASC may promote neuroprotection either directly and/or by modulating the secretome of local glial cells toward a neuroprotective phenotype. Such neuroprotection resulted in a strong and long-lasting effect on motor performance and encourages the use of ASC in human pathologies, in which current therapies are not able to maintain a satisfying neurological functional status.}, }
@article {pmid23722329, year = {2013}, author = {Inagawa, S and Yamashita, S and Hiramatsu, H and Kamiya, M and Tanaka, T and Sakahara, H and Aoyama, H}, title = {Clinical results after the multidisciplinary treatment of spinal arteriovenous fistulas.}, journal = {Japanese journal of radiology}, volume = {31}, number = {7}, pages = {455-464}, pmid = {23722329}, issn = {1867-108X}, mesh = {Adult ; Aged ; Aged, 80 and over ; Angiography/*methods ; Arteriovenous Fistula/*diagnostic imaging/*therapy ; Central Nervous System Vascular Malformations/*diagnostic imaging/*therapy ; Embolization, Therapeutic ; Female ; Gait Disorders, Neurologic/classification ; Humans ; Infant ; Male ; Middle Aged ; Retrospective Studies ; Treatment Outcome ; }, abstract = {PURPOSE: We retrospectively evaluated the clinical outcome after multidisciplinary treatment of spinal arteriovenous fistulas (AVFs) in terms of the Aminoff-Logue grading scale (ALS) to depict the outcome in a perspective pertinent to the quality of everyday living.<br><br>MATERIALS AND METHODS: Twenty-six spinal AVFs in 25 patients were angiographically diagnosed from April 1998 through April 2012 and treated by endovascular embolization or surgery. When both treatment procedures seemed feasible, embolization was undertaken as the initial treatment. Motor and gait disturbance at follow-up was retrospectively graded according to ALS.<br><br>RESULTS: All lesions were localized at the thoracolumbar or sacral levels and include six epidural AVFs with intradural venous reflux, 14 dural AVFs, and six perimedullary AVFs. Embolization was performed as the initial treatment for 17 lesions, while open surgery was performed for the others as well as for residual or recurrent lesions after embolization. All lesions were completely occluded except three perimedullary AVFs. At clinical follow-up of 1-153&#xa0;months (mean 53.3), amelioration of gait disturbance with reduction of ALS scores was noted for 13 lesions and amelioration of micturition for 13 lesions as well.<br><br>CONCLUSION: Clinical functional status was improved for half of the lesions after the multidisciplinary treatment.}, }
@article {pmid23721573, year = {2013}, author = {Akizuki, M and Yamashita, H and Uemura, K and Maruyama, H and Kawakami, H and Ito, H and Takahashi, R}, title = {Optineurin suppression causes neuronal cell death via NF-κB pathway.}, journal = {Journal of neurochemistry}, volume = {126}, number = {6}, pages = {699-704}, doi = {10.1111/jnc.12326}, pmid = {23721573}, issn = {1471-4159}, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Animals ; Antineoplastic Agents, Phytogenic/pharmacology ; Blotting, Western ; Cell Count ; Cell Cycle Proteins ; Cell Death/*genetics/*physiology ; Cells, Cultured ; Coloring Agents ; Eye Proteins/*genetics ; Genes, Reporter ; Genes, p53/genetics ; Luciferases/genetics ; Membrane Transport Proteins ; Mice ; Mutation/*physiology ; NF-kappa B/antagonists &amp; inhibitors/*genetics/*physiology ; Neurons/*physiology ; Plasmids/genetics ; RNA, Small Interfering/pharmacology ; Real-Time Polymerase Chain Reaction ; Signal Transduction/genetics/physiology ; Transfection ; Trypan Blue ; Tumor Necrosis Factor-alpha/genetics ; Withanolides/pharmacology ; }, abstract = {Mutations in more than 10 genes are reported to cause familial amyotrophic lateral sclerosis (ALS). Among these genes, optineurin (OPTN) is virtually the only gene that is considered to cause classical ALS by a loss-of-function mutation. Wild-type optineurin (OPTN(WT)) suppresses nuclear factor-kappa B (NF-κB) activity, but the ALS-causing mutant OPTN is unable to suppress NF-κB activity. Therefore, we knocked down OPTN in neuronal cells and examined the resulting NF-κB activity and phenotype. First, we confirmed the loss of the endogenous OPTN expression after siRNA treatment and found that NF-κB activity was increased in OPTN-knockdown cells. Next, we found that OPTN knockdown caused neuronal cell death. Then, overexpression of OPTN(WT) or OPTN(E) (50K) with intact NF-κB-suppressive activity, but not overexpression of ALS-related OPTN mutants, suppressed the neuronal death induced by OPTN knockdown. This neuronal cell death was inhibited by withaferin A, which selectively inhibits NF-κB activation. Lastly, involvement of the mitochondrial proapoptotic pathway was suggested for neuronal death induced by OPTN knockdown. Taken together, these results indicate that inappropriate NF-κB activation is the pathogenic mechanism underlying OPTN mutation-related ALS. Among the genes for typical amyotrophic lateral sclerosis (ALS) phenotypes, optineurin (OPTN) is virtually the only gene in which a loss-of-function mutation is considered as the principal disease mechanism. We found that OPTN knockdown induced neuronal cell death via NF-κB activation. Furthermore, proapoptotic molecules such as p53 and Bax representing downstream targets of NF-κB are suggested to be involved in neuronal death.}, }
@article {pmid23708282, year = {2013}, author = {Lozano, VA and Escandar, GM}, title = {Second-order advantage with excitation-emission photoinduced fluorimetry for the determination of the antiepileptic carbamazepine in environmental waters.}, journal = {Analytica chimica acta}, volume = {782}, number = {}, pages = {37-45}, doi = {10.1016/j.aca.2013.04.020}, pmid = {23708282}, issn = {1873-4324}, mesh = {Algorithms ; Anticonvulsants/analysis ; Argentina ; Calibration ; Carbamazepine/*analysis ; Drinking Water/analysis ; Fluorescence ; Fluorometry/instrumentation/*methods ; Least-Squares Analysis ; Photochemistry/instrumentation/methods ; Rivers/chemistry ; Ultraviolet Rays ; Water Pollutants, Chemical/*analysis ; }, abstract = {A photochemically induced fluorescence system combined with second-order chemometric analysis for the determination of the anticonvulsant carbamazepine (CBZ) is presented. CBZ is a widely used drug for the treatment of epilepsy and is included in the group of emerging contaminant present in the aquatic environment. CBZ is not fluorescent in solution but can be converted into a fluorescent compound through a photochemical reaction in a strong acid medium. The determination is carried out by measuring excitation-emission photoinduced fluorescence matrices of the products formed upon ultraviolet light irradiation in a laboratory-constructed reactor constituted by two simple 4 W germicidal tubes. Working conditions related to both the reaction medium and the photoreactor geometry are optimized by an experimental design. The developed approach enabled the determination of CBZ at trace levels without the necessity of applying separation steps, and in the presence of uncalibrated interferences which also display photoinduced fluorescence and may be potentially present in the investigated samples. Different second-order algorithms were tested and successful resolution was achieved using multivariate curve resolution-alternating least-squares (MCR-ALS). The study is employed for the discussion of the scopes and yields of each of the applied second-order chemometric tools. The quality of the proposed method is probed through the determination of the studied emerging pollutant in both environmental and drinking water samples. After a pre-concentration step on a C18 membrane using 50.0 mL of real water samples, a prediction relative error of 2% and limits of detection and quantification of 0.2 and 0.6 ng mL(-1) were respectively obtained.}, }
@article {pmid23706004, year = {2014}, author = {Sheng, H and Chaparro, RE and Sasaki, T and Izutsu, M and Pearlstein, RD and Tovmasyan, A and Warner, DS}, title = {Metalloporphyrins as therapeutic catalytic oxidoreductants in central nervous system disorders.}, journal = {Antioxidants &amp; redox signaling}, volume = {20}, number = {15}, pages = {2437-2464}, doi = {10.1089/ars.2013.5413}, pmid = {23706004}, issn = {1557-7716}, mesh = {Animals ; Antioxidants/chemistry/*pharmacology/*therapeutic use ; Central Nervous System Diseases/diagnosis/*drug therapy/metabolism ; Humans ; Metalloporphyrins/chemistry/*pharmacology/*therapeutic use ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; }, abstract = {SIGNIFICANCE: Metalloporphyrins, characterized by a redox-active transitional metal (Mn or Fe) coordinated to a cyclic porphyrin core ligand, mitigate oxidative/nitrosative stress in biological systems. Side-chain substitutions tune redox properties of metalloporphyrins to act as potent superoxide dismutase mimics, peroxynitrite decomposition catalysts, and redox regulators of transcription factor function. With oxidative/nitrosative stress central to pathogenesis of CNS injury, metalloporphyrins offer unique pharmacologic activity to improve the course of disease.<br><br>RECENT ADVANCES: Metalloporphyrins are efficacious in models of amyotrophic lateral sclerosis, Alzheimer's disease, epilepsy, neuropathic pain, opioid tolerance, Parkinson's disease, spinal cord injury, and stroke and have proved to be useful tools in defining roles of superoxide, nitric oxide, and peroxynitrite in disease progression. The most substantive recent advance has been the synthesis of lipophilic metalloporphyrins offering improved blood-brain barrier penetration to allow intravenous, subcutaneous, or oral treatment.<br><br>CRITICAL ISSUES: Insufficient preclinical data have accumulated to enable clinical development of metalloporphyrins for any single indication. An improved definition of mechanisms of action will facilitate preclinical modeling to define and validate optimal dosing strategies to enable appropriate clinical trial design. Due to previous failures of "antioxidants" in clinical trials, with most having markedly less biologic activity and bioavailability than current-generation metalloporphyrins, a stigma against antioxidants has discouraged the development of metalloporphyrins as CNS therapeutics, despite the consistent definition of efficacy in a wide array of CNS disorders.<br><br>FUTURE DIRECTIONS: Further definition of the metalloporphyrin mechanism of action, side-by-side comparison with "failed" antioxidants, and intense effort to optimize therapeutic dosing strategies are required to inform and encourage clinical trial design.}, }
@article {pmid23705902, year = {2013}, author = {Siirala, W and Aantaa, R and Olkkola, KT and Saaresranta, T and Vuori, A}, title = {Is the effect of non-invasive ventilation on survival in amyotrophic lateral sclerosis age-dependent?.}, journal = {BMC palliative care}, volume = {12}, number = {}, pages = {23}, pmid = {23705902}, issn = {1472-684X}, abstract = {BACKGROUND: Hypoventilation due to respiratory muscle atrophy is the most common cause of death as a result of amyotrophic lateral sclerosis (ALS). Patients aged over 65 years and presenting bulbar symptoms are likely to have a poorer prognosis. The aim of the study was to assess the possible impact of age and treatment with non-invasive ventilation (NIV) on survival in ALS. Based on evidence from earlier studies, it was hypothesized that NIV increases rates of survival regardless of age.<br><br>METHODS: Eighty-four patients diagnosed with ALS were followed up on from January 2001 to June 2012. These patients were retrospectively divided into two groups according to their age at the time of diagnosis: Group 1 comprised patients aged&#x2009;&#x2264;&#x2009;65&#xa0;years while Group 2 comprised those aged&#x2009;>&#x2009;65&#xa0;years. Each group included 42 patients. NIV was tolerated by 23 patients in Group 1 and 18 patients in Group 2. Survival was measured in months from the date of diagnosis.<br><br>RESULTS: The median age in Group 1 was 59&#xa0;years (range 49 - 65) and 76&#xa0;years in Group 2 (range 66 - 85). Among patients in Group 1 there was no difference in probability of survival between the NIV users and non-users (Hazard Ratio&#x2009;=&#x2009;0.88, 95% CI 0.44 - 1.77, p&#x2009;=&#x2009;0.7). NIV users in Group 2 survived longer than those following conventional treatment (Hazard Ratio&#x2009;=&#x2009;0.25, CI 95% 0.11 - 0.55, p <0.001). ALS patients in Group 2 who did not use NIV had a 4-fold higher risk for death compared with NIV users.<br><br>CONCLUSIONS: This retrospective study found that NIV use was associated with improved survival outcomes in ALS patients older than 65&#xa0;years. Further studies in larger patient populations are warranted to determine which factors modify survival outcomes in ALS.}, }
@article {pmid23696687, year = {2013}, author = {Vianello, A and Savoia, F and Pipitone, E and Nordio, B and Gallina, G and Paladini, L and Concas, A and Arcaro, G and Gallan, F and Pegoraro, E}, title = {"Hospital at home" for neuromuscular disease patients with respiratory tract infection: a pilot study.}, journal = {Respiratory care}, volume = {58}, number = {12}, pages = {2061-2068}, doi = {10.4187/respcare.02501}, pmid = {23696687}, issn = {1943-3654}, mesh = {Adult ; Aged ; Costs and Cost Analysis ; Female ; *Home Care Services, Hospital-Based/economics/statistics &amp; numerical data ; *Hospitalization/economics/statistics &amp; numerical data ; Hospitals, University/statistics &amp; numerical data ; Humans ; Italy ; Male ; Middle Aged ; *Neuromuscular Diseases/complications/therapy ; Outcome and Process Assessment, Health Care ; Patient Selection ; Pilot Projects ; *Respiratory Tract Infections/etiology/therapy ; Survival Analysis ; Treatment Failure ; Treatment Outcome ; }, abstract = {BACKGROUND: The "hospital-at-home" model may provide adequate care without an adverse effect on clinical outcome, and is generally well received by users. Our objective was to compare hospital-at-home and in-patient hospital care for neuromuscular disease (NMD) patients with respiratory tract infections.<br><br>METHODS: We conducted a prospective randomized controlled trial in a university teaching hospital offering secondary care service to a population of approximately 500,000. We recruited selected NMD patients with respiratory tract infection for whom hospital admission had been recommended after medical assessment. Hospital-at-home was provided as an alternative to in-patient admission. The main outcome measures were need for hospitalization, treatment failure, time to recovery, death during the first 3 months following exacerbation, and cost of patient care.<br><br>RESULTS: Among 59 consecutive NMD patients eligible for the study, 53 met the criteria for hospital-at-home. Twenty-six subjects were randomized to home care and 27 to hospital care. No significant differences were found in treatment failure (8/26 vs 13/27, P = .19), time to recovery (8.9 &#xb1; 4.6 vs 9 &#xb1; 8.9 d, P = .21), or mortality at 3 months (3/26 vs 4/27 deaths, P = .42) between the groups. Hospital-at-home failure was independently correlated with type of NMD (P = .004) with an odds ratio of failure of 17.3 (95% CI 2.1 to infinity) for subjects with amyotrophic lateral sclerosis. The total and daily direct cost of patient healthcare was significantly lower for the subjects who were successfully treated at home, compared to the hospitalized individuals.<br><br>CONCLUSIONS: Hospital-at-home is an effective alternative to hospital admission for selected NMD patients with respiratory tract infections.}, }
@article {pmid23696493, year = {2013}, author = {Liu, M and Cui, L and Guan, Y and Li, B and Du, H}, title = {Single-fiber electromyography in amyotrophic lateral sclerosis and cervical spondylosis.}, journal = {Muscle &amp; nerve}, volume = {48}, number = {1}, pages = {137-139}, doi = {10.1002/mus.23767}, pmid = {23696493}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Electromyography/*methods ; Female ; Humans ; Male ; Middle Aged ; Muscle Fibers, Skeletal/*physiology ; Spondylosis/*diagnosis/*physiopathology ; }, abstract = {INTRODUCTION: Cervical spondylosis (CS) is a common disease in adults and may coexist with amyotrophic lateral sclerosis (ALS). It is important to detect ALS coexisting with CS (ALS-cs) at an early stage, especially when surgical treatment of CS is planned.<br><br>METHODS: Single-fiber electromyography was performed in 26 patients with ALS, 19 with ALS-cs, and 22 with CS.<br><br>RESULTS: Mean jitter, percentage of jitter >55 &#x3bc;s, and percentage of impulse blocking were not statistically different between ALS and ALS-cs cases, but they were significantly lower in CS. Mean fiber density was not statistically different among the 3 groups. The percentage of pairs with jitter >55 &#x3bc;s exceeding 40% and mean jitter exceeding 55 &#x3bc;s had high sensitivity and specificity in the diagnosis of ALS.<br><br>CONCLUSIONS: Single-fiber electromyography can supply valuable information in helping to differentiate ALS from CS.}, }
@article {pmid23695230, year = {2013}, author = {Kunze, A and Lengacher, S and Dirren, E and Aebischer, P and Magistretti, PJ and Renaud, P}, title = {Astrocyte-neuron co-culture on microchips based on the model of SOD mutation to mimic ALS.}, journal = {Integrative biology : quantitative biosciences from nano to macro}, volume = {5}, number = {7}, pages = {964-975}, doi = {10.1039/c3ib40022k}, pmid = {23695230}, issn = {1757-9708}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics/*pathology ; Animals ; Astrocytes/cytology/*enzymology ; Cell Communication/genetics/physiology ; Coculture Techniques ; Mice ; Microfluidics/methods ; Microscopy, Confocal ; Motor Neurons/cytology/*enzymology ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; Synapsins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. ALS is believed to be a non-cell autonomous condition, as other cell types, including astrocytes, have been implicated in disease pathogenesis. Hence, to facilitate the development of therapeutics against ALS, it is crucial to better understand the interactions between astrocytes and neural cells. Furthermore, cell culture assays are needed that mimic the complexity of cell to cell communication at the same time as they provide control over the different microenvironmental parameters. Here, we aim to validate a previously developed microfluidic system for an astrocyte-neuron cell culture platform, in which astrocytes have been genetically modified to overexpress either a human wild-type (WT) or a mutated form of the super oxide dismutase enzyme 1 (SOD1). Cortical neural cells were co-cultured with infected astrocytes and studied for up to two weeks. Using our microfluidic device that prevents direct cell to cell contact, we could evaluate neural cell response in the vicinity of astrocytes. We showed that neuronal cell density was reduced by about 45% when neurons were co-cultured with SOD-mutant astrocytes. Moreover, we demonstrated that SOD-WT overexpressing astrocytes reduced oxidative stress on cortical neurons that were in close metabolic contact. In contrast, cortical neurons in metabolic contact with SOD-mutant astrocytes lost their synapsin protein expression after severe glutamate treatment, an indication of the toxicity potentiating effect of the SOD-mutant enzyme.}, }
@article {pmid23686823, year = {2013}, author = {DeVos, SL and Miller, TM}, title = {Antisense oligonucleotides: treating neurodegeneration at the level of RNA.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {10}, number = {3}, pages = {486-497}, pmid = {23686823}, issn = {1878-7479}, support = {NIH/NINDS K08NS074194/NS/NINDS NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; R01 NS078398/NS/NINDS NIH HHS/United States ; K08 NS074194/NS/NINDS NIH HHS/United States ; NIH/NINDS R01NS078398/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*metabolism/*therapy ; Neuroprotective Agents/*therapeutic use ; Oligodeoxyribonucleotides, Antisense/*therapeutic use ; RNA/*metabolism ; }, abstract = {Adequate therapies are lacking for Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and other neurodegenerative diseases. The ability to use antisense oligonucleotides (ASOs) to target disease-associated genes by means of RNA may offer a potent approach for the treatment of these, and other, neurodegenerative disorders. In modifying the basic backbone chemistry, chemical groups, and target sequence, ASOs can act through numerous mechanisms to decrease or increase total protein levels, preferentially shift splicing patterns, and inhibit microRNAs, all at the level of the RNA molecule. Here, we discuss many of the more commonly used ASO chemistries, as well as the different mechanisms of action that can result from these specific chemical modifications. When applied to multiple neurodegenerative mouse models, ASOs that specifically target the detrimental transgenes have been shown to rescue disease associated phenotypes in vivo. These supporting mouse model data have moved the ASOs from the bench to the clinic, with two neuro-focused human clinical trials now underway and several more being proposed. Although still early in development, translating ASOs into human patients for neurodegeneration appears promising.}, }
@article {pmid23673277, year = {2013}, author = {Song, L and Gao, Y and Zhang, X and Le, W}, title = {Galactooligosaccharide improves the animal survival and alleviates motor neuron death in SOD1G93A mouse model of amyotrophic lateral sclerosis.}, journal = {Neuroscience}, volume = {246}, number = {}, pages = {281-290}, doi = {10.1016/j.neuroscience.2013.05.002}, pmid = {23673277}, issn = {1873-7544}, mesh = {Amyotrophic Lateral Sclerosis/*diet therapy/metabolism/mortality ; Animals ; Cell Death/physiology ; *Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/metabolism ; Oligosaccharides/*administration &amp; dosage ; *Prebiotics ; *Superoxide Dismutase/biosynthesis/genetics ; Survival Rate/trends ; *Yogurt ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disease caused by selective degeneration and death of motor neurons. So far very limited therapeutic options have emerged to treat this fatal disease. Homocysteine (Hcy) lowering drugs have been suggested to be a palliative therapy of this disease. Folate, Vitamin B12 (VitB12) and Vitamin B6 (VitB6) are important elements involved in the Hcy metabolism and we proposed that medications which could promote the absorption of folate, VitB12 and VitB6 might have benefit for ALS. Galactooligosaccharides (GOS) is a prebiotic which could significantly improve the absorption and syntheses of B Vitamins. To investigate whether GOS could provide neuroprotective effect in ALS, we applied GOS and GOS-rich prebiotic yogurt in SOD1(G93A) mice and assessed their effects on the disease progression of ALS. Our results showed that GOS and prebiotics yogurt administration significantly delayed the disease onset and prolonged the lifespan in SOD1(G93A) mice. Also, these products increased the concentration of folate, VitB12 and reduced the level of Hcy. Moreover, we found that both GOS and prebiotics yogurt attenuated motor neurons loss, improved the atrophy and mitochondrial activity in myocyte. Furthermore, we demonstrated that GOS and GOS-rich prebiotic treatment suppressed the activation of astrocytes and microglia and regulated several inflammatory- and apoptosis-related factors. Our findings suggested that GOS might have therapeutic potential for ALS, and GOS-rich prebiotic yogurt might be considered as a nutritional therapy for this disease.}, }
@article {pmid23669351, year = {2013}, author = {Minegishi, Y and Iejima, D and Kobayashi, H and Chi, ZL and Kawase, K and Yamamoto, T and Seki, T and Yuasa, S and Fukuda, K and Iwata, T}, title = {Enhanced optineurin E50K-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma.}, journal = {Human molecular genetics}, volume = {22}, number = {17}, pages = {3559-3567}, doi = {10.1093/hmg/ddt210}, pmid = {23669351}, issn = {1460-2083}, mesh = {Animals ; Cell Cycle Proteins ; Disease Models, Animal ; Endoplasmic Reticulum/metabolism ; Glaucoma, Open-Angle/*genetics/metabolism ; Gliosis ; HEK293 Cells ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Membrane Transport Proteins ; Mice ; Mice, Transgenic ; Protein Serine-Threonine Kinases/*genetics/*metabolism ; Pyrimidines/adverse effects ; Retina ; Thiophenes/adverse effects ; Transcription Factor TFIIIA/chemistry/*genetics/metabolism ; }, abstract = {Glaucoma is the leading cause for blindness affecting 60 million people worldwide. The optineurin (OPTN) E50K mutation was first identified in familial primary open-angle glaucoma (POAG), the onset of which is not associated with intraocular pressure (IOP) elevation, and is classified as normal-tension glaucoma (NTG). Optineurin (OPTN) is a multifunctional protein and its mutations are associated with neurodegenerative diseases such as POAG and amyotrophic lateral sclerosis (ALS). We have previously described an E50K mutation-carrying transgenic (E50K-tg) mouse that exhibited glaucomatous phenotypes of decreased retinal ganglion cells (RGCs) and surrounding cell death at normal IOP. Further phenotypic analysis of these mice revealed persistent reactive gliosis and E50K mutant protein deposits in the outer plexiform layer (OPL). Over-expression of E50K in HEK293 cells indicated accumulation of insoluble OPTN in the endoplasmic reticulum (ER). This phenomenon was consistent with the results seen in neurons derived from induced pluripotent stem cells (iPSCs) from E50K mutation-carrying NTG patients. The E50K mutant strongly interacted with TANK-binding kinase 1 (TBK1), which prohibited the proper oligomerization and solubility of OPTN, both of which are important for OPTN intracellular transition. Treatment with a TBK1 inhibitor, BX795, abrogated the aberrant insolubility of the E50K mutant. Here, we delineated the intracellular dynamics of the endogenous E50K mutant protein for the first time and demonstrated how this mutation causes OPTN insolubility, in association with TBK1, to evoke POAG.}, }
@article {pmid23658503, year = {2013}, author = {Verkhratsky, A and Rodríguez, JJ and Parpura, V}, title = {Astroglia in neurological diseases.}, journal = {Future neurology}, volume = {8}, number = {2}, pages = {149-158}, pmid = {23658503}, issn = {1479-6708}, support = {R01 MH069791/MH/NIMH NIH HHS/United States ; R21 HD078678/HD/NICHD NIH HHS/United States ; }, abstract = {Astroglia encompass a subset of versatile glial cells that fulfill a major homeostatic role in the mammalian brain. Since any brain disease results from failure in brain homeostasis, astroglial cells are involved in many, if not all, aspects of neurological and/or psychiatric disorders. In this article, the roles of astrocytes as homeostatic cells in healthy and diseased brains are surveyed. These cells can mount the defence response to the insult of the brain, astrogliosis, when and where they display hypertrophy. Interestingly, astrocytes can alternatively display atrophy in some pathological conditions. Various pathologies, including Alexander and Alzheimer's diseases, amyotrophic lateral sclerosis, stroke and epilepsy, to mention a few, are discussed. Astrocytes could represent a novel target for medical intervention in the treatment of brain disorders.}, }
@article {pmid23656470, year = {2013}, author = {Hosny, KM and Ahmed, OA and Al-Abdali, RT}, title = {Enteric-coated alendronate sodium nanoliposomes: a novel formula to overcome barriers for the treatment of osteoporosis.}, journal = {Expert opinion on drug delivery}, volume = {10}, number = {6}, pages = {741-746}, doi = {10.1517/17425247.2013.799136}, pmid = {23656470}, issn = {1744-7593}, mesh = {Alendronate/chemistry/*pharmacokinetics ; Animals ; Biological Availability ; Bone Density Conservation Agents/chemistry/*pharmacokinetics ; Chemistry, Pharmaceutical ; Coated Materials, Biocompatible/*chemistry ; *Drug Delivery Systems ; Hydrogen-Ion Concentration ; Intestinal Absorption ; Intestinal Mucosa/metabolism ; Liposomes ; Male ; Osteoporosis/*drug therapy ; Particle Size ; Polymethacrylic Acids/*chemistry ; Rabbits ; }, abstract = {BACKGROUND AND OBJECTIVES: Alendronate sodium (ALS) is the most common drug used for the treatment of osteoporosis. The challenges facing ALS use include: very poor oral bioavailability (0.6%), esophageal ulcers, and complicated instructions for its use. The objective of this research is to utilize nanotechnology to formulate ALS into enteric-coated nanoliposomes (NLS) to overcome the previously mentioned drawbacks.<br><br>METHODS: NLS were prepared with lipid components of phosphatidylcholine (PC), cholesterol (CH), and lecithin (Lec) in ratios 4:1:1, 4:2:1, 4:3:1, and 4:4:1, respectively. Formulas that showed the highest entrapment efficiency were prepared either alone or mixed with positive and negative charge-inducing agents and coated with Eudragit L100. Eudragit-coated NLS (EuC-NLS) were evaluated for particle size, zeta potential, morphological examination, and drug release in pH 1.2 and pH 7.4 media. The pharmacokinetic study was carried out in rabbits.<br><br>RESULTS: Spherical NLS were successfully developed with a mean size range from 70 to 150 nm. EuC-NLS with PC:CH:Lec:dicetyl phosphate (4:3:1:1) successfully resist the release of ALS in acidic environments and enhanced the bioavailability in rabbits 12-fold compared with the marketed tablets.<br><br>CONCLUSIONS: EuC-NLS is a promising novel formula for ALS with higher bioavailability and a lower dose, avoiding the side effects of esophageal ulceration.}, }
@article {pmid23651424, year = {2014}, author = {Caputo, A}, title = {Exploring quality of life in Italian patients with rare disease: a computer-aided content analysis of illness stories.}, journal = {Psychology, health &amp; medicine}, volume = {19}, number = {2}, pages = {211-221}, doi = {10.1080/13548506.2013.793372}, pmid = {23651424}, issn = {1465-3966}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*psychology ; Anorectal Malformations ; Anus, Imperforate/*psychology ; Cluster Analysis ; Computers/statistics &amp; numerical data ; Familial Primary Pulmonary Hypertension ; Humans ; Hypertension, Pulmonary/*psychology ; Italy ; Narration ; Poland Syndrome/*psychology ; Qualitative Research ; Quality of Life/*psychology ; Rare Diseases/*psychology ; }, abstract = {The present study used a narrative-based approach to identify common themes that characterized the illness experience and quality of life of patients affected by rare disease (RD). Textual data were comprised of illness stories written by 32 adult Italian patients (eight men and 24 women), with the following RD diagnoses: amyotrophic lateral sclerosis (n = 12), anorectal atresia (n = 4), Poland syndrome (n = 4), and idiopathic pulmonary hypertension (n = 12). Computer-aided content analysis was performed to detect the main themes (cluster analysis) and latent factors (correspondence analysis) emerging in patients' narratives, and to test their association with gender and diagnosis. Four thematic domains were detected in the textual corpus, which are respectively referred to as: hopelessness (12.74%), need for autonomy (38.43%), search for normalcy (11.89%), and expectations of recovery (36.94%). Three latent factors explained the overall data variance: the relationship with social and medical healthcare providers (F1), adjustment processes to disease and social limitations (F2), and self-beliefs and coping (F3). Some differences were revealed with respect to patient gender and diagnosis. Illness stories highlight the significant relationship of RD patients with healthcare services and their need for a holistic approach because of the lack of effective treatment. Physical limitation and emotional distress do not necessarily seem to overlap for adjustment and quality of life (QoL). Overall, the perception of illness chronicity is likely to affect patients' self-beliefs and coping with more than their feeling of abnormalcy, that is the less salient theme.}, }
@article {pmid23650430, year = {2013}, author = {Díaz-Lobato, S and Folgado, MA and Chapa, A and Mayoralas Alises, S}, title = {Efficacy of high-flow oxygen by nasal cannula with active humidification in a patient with acute respiratory failure of neuromuscular origin.}, journal = {Respiratory care}, volume = {58}, number = {12}, pages = {e164-7}, doi = {10.4187/respcare.02115}, pmid = {23650430}, issn = {1943-3654}, mesh = {*Acidosis, Respiratory/blood/etiology ; Acute Disease ; Aged ; Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Blood Gas Analysis ; Catheters ; Female ; Humans ; *Hypercapnia/blood/etiology ; Noninvasive Ventilation/adverse effects/methods ; Oxygen/administration &amp; dosage/pharmacokinetics ; *Oxygen Inhalation Therapy/instrumentation/methods ; *Respiratory Insufficiency/diagnosis/etiology/physiopathology/therapy ; Treatment Outcome ; }, abstract = {The treatment of choice for patients with respiratory failure of neuromuscular origin, especially in patients with hypercapnic respiratory acidosis, is noninvasive ventilation (NIV). Endotracheal intubation and invasive ventilation are indicated for patients with severe respiratory compromise or failure of NIV. In recent years, high-flow oxygen therapy and active humidification devices have been introduced, and emerging evidence suggests that high-flow oxygen may be effective in various clinical settings, such as acute respiratory failure, after cardiac surgery, during sedation and analgesia, in acute heart failure, in hypoxemic respiratory distress, in do-not-intubate patients, in patients with chronic cough and copious secretions, pulmonary fibrosis, or cancer, in critical areas and the emergency department. We report on a patient with amyotrophic lateral sclerosis who arrived at the emergency department with acute hypercapnic respiratory failure. She did not tolerate NIV and refused intubation, but was treated successfully with heated, humidified oxygen via high-flow nasal cannula. Arterial blood analysis after an hour on high-flow nasal cannula showed improved pH, P(aCO2), and awareness. The respiratory acidosis was corrected, and she was discharged after 5 days of hospitalization. Her response to high-flow nasal cannula was similar to that expected with NIV. We discuss the mechanisms of action of heated, humidified high-flow oxygen therapy.}, }
@article {pmid23650123, year = {2014}, author = {Iwakami, S and Uchino, A and Kataoka, Y and Shibaike, H and Watanabe, H and Inamura, T}, title = {Cytochrome P450 genes induced by bispyribac-sodium treatment in a multiple-herbicide-resistant biotype of Echinochloa phyllopogon.}, journal = {Pest management science}, volume = {70}, number = {4}, pages = {549-558}, doi = {10.1002/ps.3572}, pmid = {23650123}, issn = {1526-4998}, mesh = {Amino Acid Sequence ; Benzoates/metabolism/*toxicity ; Cytochrome P-450 Enzyme System/*genetics/metabolism ; Echinochloa/*genetics/metabolism ; Gene Expression ; Herbicide Resistance/*genetics ; Polymorphism, Genetic ; Pyrimidines/metabolism/*toxicity ; }, abstract = {BACKGROUND: Incremental herbicide metabolism by cytochrome P450 monooxygenases (P450s) has been proposed as the basis for resistance to bispyribac-sodium (bispyribac) in a multiple-herbicide-resistant biotype of Echinochloa phyllopogon. Upon exposure to bispyribac, strong induction of bispyribac-metabolising P450 activity has been reported in the resistant line, indicating that P450s induced by bispyribac are involved in the bispyribac resistance.<br><br>RESULTS: A polymerase chain reaction (PCR)-based cloning strategy was used to isolate 39 putative P450 genes from the bispyribac-resistant line of E. phyllopogon. Expression analysis by real-time PCR revealed that seven of the isolated genes were upregulated in response to bispyribac treatment of seedlings at the three-leaf stage. The transcript levels and protein sequences of the seven genes were compared between the bispyribac-resistant line and a susceptible line. CYP71AK2 and CYP72A254 were transcribed prominently in the bispyribac-resistant line. Amino acid polymorphisms were found in three genes, including CYP72A254.<br><br>CONCLUSION: Upregulated expression of these genes is consistent with the inducible herbicide-metabolising P450 activity under bispyribac stress that was reported in a previous study. This is the first study to compare P450 genes in arable weed species in order to elucidate the mechanism for P450-mediated herbicide resistance.}, }
@article {pmid23649659, year = {2013}, author = {He, YY and Zhang, XY and Yung, WH and Zhu, JN and Wang, JJ}, title = {Role of BDNF in central motor structures and motor diseases.}, journal = {Molecular neurobiology}, volume = {48}, number = {3}, pages = {783-793}, pmid = {23649659}, issn = {1559-1182}, mesh = {Animals ; Brain-Derived Neurotrophic Factor/*metabolism ; Electrophysiological Phenomena ; Humans ; Motor Neuron Disease/*metabolism/*pathology/physiopathology ; Motor Neurons/*metabolism/*pathology ; Signal Transduction ; }, abstract = {Brain-derived neurotrophic factor (BDNF), belonging to the neurotrophic family of growth factors, has a widespread distribution in the central and peripheral nervous systems. In central motor structures including the motor cortex, cerebellum, basal ganglia, and spinal cord, BDNF exerts both neurotrophic and direct electrophysiological effects via a high-affinity tyrosine receptor kinase B receptor and a common low-affinity p75 neurotrophin receptor. The underlying signaling pathways mainly involve mitogen-activated protein kinase cascades, phosphatidylinositol 3-kinase pathway, and phospholipase C-γ pathway. The loss of BDNF usually leads to neurodegeneration in these motor centers and eventually results in several severe motor diseases, such as amyotrophic lateral sclerosis, spinocerebellar ataxias, Parkinson's disease, Huntington's disease, as well as vestibular syndrome. In this review, we summarize the recent understanding of functions of BDNF in motor structures and suggest that BDNF may be a potent candidate for the treatment of these neurodegenerative motor diseases.}, }
@article {pmid23643615, year = {2013}, author = {Diestre Ortín, G and González Sequero, V and Collell Domènech, N and Pérez López, F and Hernando Robles, P}, title = {[Advance care planning and severe chronic diseases].}, journal = {Revista espanola de geriatria y gerontologia}, volume = {48}, number = {5}, pages = {228-231}, doi = {10.1016/j.regg.2013.01.001}, pmid = {23643615}, issn = {1578-1747}, mesh = {Advance Care Planning/*statistics &amp; numerical data ; Aged ; *Chronic Disease ; Female ; Humans ; Male ; Retrospective Studies ; Severity of Illness Index ; }, abstract = {INTRODUCTION: Advanced care planning (ACP) helps in make decisions on the health problems of people who have lost the capacity for informed consent. It has proven particularly useful in addressing the end of life. The aim of this study was to determine the prevalence of ACP in patients with severe chronic diseases.<br><br>MATERIAL AND METHODS: Review of medical records of patients with dementia, amyotrophic lateral sclerosis, Parkinson's disease, chronic obstructive pulmonary disease or interstitial lung disease, heart failure, chronic kidney disease on dialysis and cancer, all in advanced stages. We collected data on living wills or registered prior decisions by the physician according to clinical planned.<br><br>RESULTS: A total of 135 patients were studied. There was a record of ACP in 22 patients (16.3%). In most of them it was planned not to start any vital treatment in the event of high risk of imminent death and lacking the ability to make decisions. Only two patients were had a legal living will.<br><br>CONCLUSION: The registration of ACP is relatively low, and this can affect decision-making in accordance with the personal values of patients when they do not have the capacity to exercise informed consent.}, }
@article {pmid23640381, year = {2014}, author = {Zhang, L and Zhang, J and Shea, K and Xu, L and Tobin, G and Knapton, A and Sharron, S and Rouse, R}, title = {Autophagy in pancreatic acinar cells in caerulein-treated mice: immunolocalization of related proteins and their potential as markers of pancreatitis.}, journal = {Toxicologic pathology}, volume = {42}, number = {2}, pages = {435-457}, doi = {10.1177/0192623313486967}, pmid = {23640381}, issn = {1533-1601}, mesh = {Acinar Cells/chemistry/cytology/drug effects/metabolism ; Amylases/blood ; Animals ; Autophagy/*drug effects ; Biomarkers/analysis/metabolism ; Ceruletide/*toxicity ; Immunohistochemistry ; Lipase/blood ; Male ; Mice ; Mice, Inbred C57BL ; Necrosis ; Pancreas/cytology/*drug effects/*metabolism ; Pancreatitis/*chemically induced/enzymology/*metabolism/physiopathology ; Proteins/*analysis/metabolism ; }, abstract = {Drug-induced pancreatitis (DIP) is an underdiagnosed condition that lacks sensitive and specific biomarkers. To better understand the mechanisms of DIP and to identify potential tissue biomarkers, we studied experimental pancreatitis induced in male C57BL/6 mice by intraperitoneal injection of caerulein (10 or 50 μg/kg) at 1-hr intervals for a total of 7 injections. Pancreata from caerulein-treated mice exhibited consistent acinar cell autophagy and apoptosis with infrequent necrosis. Kinetic assays for serum amylase and lipase also showed a dose-dependent increase. Terminal deoxynucleotidyl transferase-mediated biotin-dNTP nick labeling (TUNEL) detected dose-dependent acinar cell apoptosis. By light microscopy, autophagy was characterized by the formation of autophagosomes and autolysosomes (ALs) within the cytoplasm of acinar cells. Immunohistochemical studies with specific antibodies for proteins related to autophagy and pancreatic stress were conducted to evaluate these proteins as potential biomarkers of pancreatitis. Western blots were used to confirm immunohistochemical results using pancreatic lysates from control and treated animals. Autophagy was identified as a contributing process in caerulein-induced pancreatitis and proteins previously associated with autophagy were upregulated following caerulein treatment. Autophagosomes and ALs were found to be a common pathway, in which cathepsins, lysosome-associated membrane protein 2, vacuole membrane protein 1, microtubule-associated protein 1 light chain 3 (LC3), autophagy-related protein 9, Beclin1, and pancreatitis-associated proteins were simultaneously involved in response to caerulein stimulus. Regenerating islet-derived 3 gamma (Reg3γ), a pancreatic acute response protein, was dose-dependently induced in caerulein-treated mice and colocalized with the autophagosomal marker, LC3. This finding supports Reg3γ as a candidate biomarker for pancreatic injury.}, }
@article {pmid23638043, year = {2013}, author = {Le Pichon, CE and Dominguez, SL and Solanoy, H and Ngu, H and Lewin-Koh, N and Chen, M and Eastham-Anderson, J and Watts, R and Scearce-Levie, K}, title = {EGFR inhibitor erlotinib delays disease progression but does not extend survival in the SOD1 mouse model of ALS.}, journal = {PloS one}, volume = {8}, number = {4}, pages = {e62342}, pmid = {23638043}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Astrocytes/drug effects/metabolism/pathology ; Biomarkers/metabolism ; Disease Models, Animal ; *Disease Progression ; ErbB Receptors/*antagonists &amp; inhibitors/metabolism ; Erlotinib Hydrochloride ; Humans ; Longevity/drug effects ; Mice ; Mice, Transgenic ; Microglia/drug effects/metabolism/pathology ; Motor Neurons/drug effects/metabolism/pathology ; Neuromuscular Junction/drug effects/metabolism/pathology ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology/*therapeutic use ; Quinazolines/pharmacology/*therapeutic use ; Spinal Cord/drug effects/metabolism/pathology ; Staining and Labeling ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; Survival Analysis ; Synapses/drug effects/metabolism/pathology ; Time Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive paralysis due to motor neuron death. Several lines of published evidence suggested that inhibition of epidermal growth factor receptor (EGFR) signaling might protect neurons from degeneration. To test this hypothesis in vivo, we treated the SOD1 transgenic mouse model of ALS with erlotinib, an EGFR inhibitor clinically approved for oncology indications. Although erlotinib failed to extend ALS mouse survival it did provide a modest but significant delay in the onset of multiple behavioral measures of disease progression. However, given the lack of protection of motor neuron synapses and the lack of survival extension, the small benefits observed after erlotinib treatment appear purely symptomatic, with no modification of disease course.}, }
@article {pmid23631872, year = {2013}, author = {Jouroukhin, Y and Ostritsky, R and Assaf, Y and Pelled, G and Giladi, E and Gozes, I}, title = {NAP (davunetide) modifies disease progression in a mouse model of severe neurodegeneration: protection against impairments in axonal transport.}, journal = {Neurobiology of disease}, volume = {56}, number = {}, pages = {79-94}, doi = {10.1016/j.nbd.2013.04.012}, pmid = {23631872}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/pathology/psychology ; Animals ; Axonal Transport/*drug effects ; Blotting, Western ; Body Weight/drug effects ; Brain/pathology ; Contrast Media ; Disease Progression ; Female ; Magnetic Resonance Imaging ; Male ; Manganese ; Mice ; Mice, Inbred C57BL ; Neurodegenerative Diseases/*drug therapy/pathology/psychology ; Neuroprotective Agents/*pharmacology ; Oligopeptides/*pharmacology ; Phosphorylation ; Psychomotor Performance/drug effects ; Spinal Cord/pathology ; Tubulin/metabolism ; Tyrosine/metabolism ; Ventral Tegmental Area/pathology ; tau Proteins/metabolism ; }, abstract = {NAP (davunetide) is a novel neuroprotective compound with mechanism of action that appears to involve microtubule (MT) stabilization and repair. To evaluate, for the first time, the impact of NAP on axonal transport in vivo and to translate it to neuroprotection in a severe neurodegeneration, the SOD1-G93A mouse model for amyotrophic lateral sclerosis (ALS) was used. Manganese-enhanced magnetic resonance imaging (MRI), estimating axonal transport rates, revealed a significant reduction of the anterograde axonal transport in the ALS mice compared to healthy control mice. Acute NAP treatment normalized axonal transport rates in these ALS mice. Tau hyperphosphorylation, associated with MT dysfunction and defective axonal transport, was discovered in the brains of the ALS mice and was significantly reduced by chronic NAP treatment. Furthermore, in healthy wild type (WT) mice, NAP reversed axonal transport disruption by colchicine, suggesting drug-dependent protection against axonal transport impairment through stabilization of the neuronal MT network. Histochemical analysis showed that chronic NAP treatment significantly protected spinal cord motor neurons against ALS-like pathology. Sequential MRI measurements, correlating brain structure with ALS disease progression, revealed a significant damage to the ventral tegmental area (VTA), indicative of impairments to the dopaminergic pathways relative to healthy controls. Chronic daily NAP treatment of the SOD1-G93A mice, initiated close to disease onset, delayed degeneration of the trigeminal, facial and hypoglossal motor nuclei as was significantly apparent at days 90-100 and further protected the VTA throughout life. Importantly, protection of the VTA was significantly correlated with longevity and overall, NAP treatment significantly prolonged life span in the ALS mice.}, }
@article {pmid23620776, year = {2013}, author = {Yip, PK and Pizzasegola, C and Gladman, S and Biggio, ML and Marino, M and Jayasinghe, M and Ullah, F and Dyall, SC and Malaspina, A and Bendotti, C and Michael-Titus, A}, title = {The omega-3 fatty acid eicosapentaenoic acid accelerates disease progression in a model of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {8}, number = {4}, pages = {e61626}, pmid = {23620776}, issn = {1932-6203}, mesh = {Administration, Oral ; Amyotrophic Lateral Sclerosis/blood/*pathology/physiopathology ; Animals ; Axons/drug effects/metabolism/pathology ; Dietary Supplements ; Disease Models, Animal ; *Disease Progression ; Eicosapentaenoic Acid/administration &amp; dosage/*adverse effects/blood ; Female ; Humans ; Lipid Metabolism/drug effects ; Lipid Peroxidation/drug effects ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Activity/drug effects ; Motor Neurons/drug effects/metabolism/pathology ; Mutant Proteins/metabolism ; Neuroglia/drug effects/metabolism/pathology ; Spinal Cord/drug effects/pathology/physiopathology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Survival Analysis ; Tyrosine/analogs &amp; derivatives/metabolism ; Vacuoles/drug effects/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease characterised by loss of motor neurons that currently has no cure. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), have many health benefits including neuroprotective and myoprotective potential. We tested the hypothesis that a high level of dietary EPA could exert beneficial effects in ALS. The dietary exposure to EPA (300 mg/kg/day) in a well-established mouse model of ALS expressing the G93A superoxide dismutase 1 (SOD1) mutation was initiated at a pre-symptomatic or symptomatic stage, and the disease progression was monitored until the end stage. Daily dietary EPA exposure initiated at the disease onset did not significantly alter disease presentation and progression. In contrast, EPA treatment initiated at the pre-symptomatic stage induced a significantly shorter lifespan. In a separate group of animals sacrificed before the end stage, the tissue analysis showed that the vacuolisation detected in G93A-SOD1 mice was significantly increased by exposure to EPA. Although EPA did not alter motor neurone loss, EPA reversed the significant increase in activated microglia and the astrocytic activation seen in G93A-SOD1 mice. The microglia in the spinal cord of G93A-SOD1 mice treated with EPA showed a significant increase in 4-hydroxy-2-hexenal, a highly toxic aldehydic oxidation product of omega-3 fatty acids. These data show that dietary EPA supplementation in ALS has the potential to worsen the condition and accelerate the disease progression. This suggests that great caution should be exerted when considering dietary omega-3 fatty acid supplements in ALS patients.}, }
@article {pmid23615918, year = {2013}, author = {Simon, A and Graf, N and Furtwängler, R}, title = {Results of a multicentre survey evaluating clinical practice of port and Broviac management in paediatric oncology.}, journal = {Klinische Padiatrie}, volume = {225}, number = {3}, pages = {145-151}, doi = {10.1055/s-0033-1333762}, pmid = {23615918}, issn = {1439-3824}, mesh = {Adolescent ; Antineoplastic Agents/*administration &amp; dosage ; Austria ; Bacteremia/epidemiology/etiology/prevention &amp; control ; Bone Marrow Transplantation ; Cancer Care Facilities ; Catheter-Related Infections/epidemiology/etiology/prevention &amp; control ; Catheterization, Central Venous/*instrumentation/standards/*statistics &amp; numerical data ; Child ; Combined Modality Therapy ; Cross-Sectional Studies ; Disinfection/methods/standards ; Germany ; Health Surveys ; Hematopoietic Stem Cell Transplantation ; Humans ; Induction Chemotherapy ; Inservice Training ; Manikins ; Neoplasm Recurrence, Local/drug therapy ; Neoplasms/*therapy ; Switzerland ; Utilization Review/statistics &amp; numerical data ; }, abstract = {BACKGROUND: More than 80% of all paediatric oncology patients have a long term central -catheter (CVAD; port or Broviac type). Many aspects considering the use of CVADs have not been studied.<br><br>PATIENTS: Children and adolescents treated in Paediatric Oncology centres.<br><br>METHODEN: Internet-based multicentre survey related to the use of CVADs conducted in cooperation with the German Society of Paediatric Oncology and Haematology (GPOH).<br><br>RESULTS: 29 centres participated; 25 German participants represented at about 50% of all paediatric oncology centres in Germany. Which CVAD type is preferred depends on the centre and not on the underlying malignancy. Most centres implant the CVAD at the beginning of induction therapy for paediatric ALL. Port-needles are changed and Broviacs are flushed once a week. The i. v. system is changed every 72 h. 93% of all units use antiseptics at the Broviac entry site and at the CVAD hub. Only a few centres use antimicrobial lock solutions (ALs) for prophylaxis of bloodstream infections (BSI). Most units use ALs or ethanol locks as adjuvant treatment for CVAD-associated BSIs. Only 42% of all centres have performed a prospective surveillance of BSIs in 2011.<br><br>CONCLUSIONS: Beside differences between centres in some issues, many procedures have been implemented consensualy in paediatric oncology units. In terms of common experience, it is -possible to describe a good clinical practice. The proportion of units performing a prospective systematic surveillance of BSIs should be increased.}, }
@article {pmid23613814, year = {2013}, author = {Broering, TJ and Wang, H and Boatright, NK and Wang, Y and Baptista, K and Shayan, G and Garrity, KA and Kayatekin, C and Bosco, DA and Matthews, CR and Ambrosino, DM and Xu, Z and Babcock, GJ}, title = {Identification of human monoclonal antibodies specific for human SOD1 recognizing distinct epitopes and forms of SOD1.}, journal = {PloS one}, volume = {8}, number = {4}, pages = {e61210}, pmid = {23613814}, issn = {1932-6203}, support = {R01 NS067206/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/enzymology ; Animals ; Antibodies, Monoclonal/administration &amp; dosage/biosynthesis/*immunology/therapeutic use ; Antibody Affinity ; Antibody Specificity/*immunology ; Epitopes/chemistry/*immunology ; HEK293 Cells ; Humans ; Hydrophobic and Hydrophilic Interactions ; Immunoprecipitation ; Mice ; Mice, Transgenic ; Mutant Proteins/metabolism ; Protein Binding ; Protein Conformation ; Superoxide Dismutase/chemistry/*immunology ; }, abstract = {Mutations in the gene encoding human SOD1 (hSOD1) can cause amyotrophic lateral sclerosis (ALS) yet the mechanism by which mutant SOD1 can induce ALS is not fully understood. There is currently no cure for ALS or treatment that significantly reduces symptoms or progression. To develop tools to understand the protein conformations present in mutant SOD1-induced ALS and as possible immunotherapy, we isolated and characterized eleven unique human monoclonal antibodies specific for hSOD1. Among these, five recognized distinct linear epitopes on hSOD1 that were not available in the properly-folded protein but were available on forms of protein with some degree of misfolding. The other six antibodies recognized conformation-dependent epitopes that were present in the properly-folded protein with two different recognition profiles: three could bind hSOD1 dimer or monomer and the other three were specific for hSOD1 dimer only. Antibodies with the capacity to bind hSOD1 monomer were able to prevent increased hydrophobicity when mutant hSOD1 was exposed to increased temperature and EDTA, suggesting that the antibodies stabilized the native structure of hSOD1. Two antibodies were tested in a G93A mutant hSOD1 transgenic mouse model of ALS but did not yield a statistically significant increase in overall survival. It may be that the two antibodies selected for testing in the mouse model were not effective for therapy or that the model and/or route of administration were not optimal to produce a therapeutic effect. Therefore, additional testing will be required to determine therapeutic potential for SOD1 mutant ALS and potentially some subset of sporadic ALS.}, }
@article {pmid23613806, year = {2013}, author = {Berry, JD and Shefner, JM and Conwit, R and Schoenfeld, D and Keroack, M and Felsenstein, D and Krivickas, L and David, WS and Vriesendorp, F and Pestronk, A and Caress, JB and Katz, J and Simpson, E and Rosenfeld, J and Pascuzzi, R and Glass, J and Rezania, K and Rothstein, JD and Greenblatt, DJ and Cudkowicz, ME and , }, title = {Design and initial results of a multi-phase randomized trial of ceftriaxone in amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {8}, number = {4}, pages = {e61177}, pmid = {23613806}, issn = {1932-6203}, support = {U01 NS049640/NS/NINDS NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; U01 NS049640-05/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/*drug therapy ; Anti-Bacterial Agents/adverse effects/blood/pharmacokinetics/*therapeutic use ; Ceftriaxone/adverse effects/blood/pharmacokinetics/*therapeutic use ; Demography ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; *Research Design ; }, abstract = {OBJECTIVES: Ceftriaxone increases expression of the astrocytic glutamate transporter, EAAT2, which might protect from glutamate-mediated excitotoxicity. A trial using a novel three stage nonstop design, incorporating Phases I-III, tested ceftriaxone in ALS. Stage 1 determined the cerebrospinal fluid pharmacokinetics of ceftriaxone in subjects with ALS. Stage 2 evaluated safety and tolerability for 20-weeks. Analysis of the pharmacokinetics, tolerability, and safety was used to determine the ceftriaxone dosage for Stage 3 efficacy testing.<br><br>METHODS: In Stage 1, 66 subjects at ten clinical sites were enrolled and randomized equally into three study groups receiving intravenous placebo, ceftriaxone 2 grams daily or ceftriaxone 4 grams daily divided BID. Participants provided serum and cerebrospinal fluid for pharmacokinetic analysis on study day 7. Participants continued their assigned treatment in Stage 2. The Data and Safety Monitoring Board (DSMB) reviewed the data after the last participants completed 20 weeks on study drug.<br><br>RESULTS: Stage 1 analysis revealed linear pharmacokinetics, and CSF trough levels for both dosage levels exceeding the pre-specified target trough level of 1 &#xb5;M (0.55 &#xb5;g/mL). Tolerability (Stages 1 and 2) results showed that ceftriaxone at dosages up to 4 grams/day was well tolerated at 20 weeks. Biliary adverse events were more common with ceftriaxone but not dose-dependent and improved with ursodeoxycholic (ursodiol) therapy.<br><br>CONCLUSIONS: The goals of Stages 1 and 2 of the ceftriaxone trial were successfully achieved. Based on the pre-specified decision rules, the DSMB recommended the use of ceftriaxone 4 g/d (divided BID) for Stage 3, which recently closed.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT00349622.}, }
@article {pmid23598234, year = {2013}, author = {Sosa, V and Serrano, N and Ariño, C and Manuel Díaz-Cruz, J and Esteban, M}, title = {Can bismuth film screen printed carbon electrodes be used to study complexation?.}, journal = {Talanta}, volume = {107}, number = {}, pages = {356-360}, doi = {10.1016/j.talanta.2013.01.033}, pmid = {23598234}, issn = {1873-3573}, mesh = {Bismuth/*chemistry ; Cadmium/*chemistry ; Carbon/*chemistry ; Chelating Agents/chemistry ; Coordination Complexes/*chemistry ; Electrochemical Techniques ; Electrodes ; Glutathione/*chemistry ; Phytochelatins/*chemistry ; }, abstract = {Ex- situ bismuth film on commercial screen-printed carbon electrodes (BiSPCE) has been used for the first time for the analysis of the complexation of Cd(2+) by thiol containing compounds as glutathione (GSH) and phytochelatin (γ-Glu-Cys)2-Gly (PC2). Reproducibility of data is quite satisfactory and allows their treatment by multivariate curve resolution by alternating least squares (MCR-ALS). Unitary voltammograms and concentration profiles provided by MCR-ALS confirm the formation of 1:1 and 1:2 Cd(2+):GSH and 1:2 Cd(2+):PC2 complexes. These results are in agreement with those previously obtained by mercury electrodes, and allow us to propose the use of BiSPCE for further studies on complexation.}, }
@article {pmid23595219, year = {2013}, author = {Zinkie, S and Gentil, BJ and Minotti, S and Durham, HD}, title = {Expression of the protein chaperone, clusterin, in spinal cord cells constitutively and following cellular stress, and upregulation by treatment with Hsp90 inhibitor.}, journal = {Cell stress &amp; chaperones}, volume = {18}, number = {6}, pages = {745-758}, pmid = {23595219}, issn = {1466-1268}, support = {MOP77743//Canadian Institutes of Health Research/Canada ; }, mesh = {Amino Acid Substitution ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Astrocytes/cytology/metabolism ; Benzoquinones/*pharmacology ; Cells, Cultured ; Clusterin/*metabolism ; Disease Models, Animal ; Female ; HSP90 Heat-Shock Proteins/*antagonists &amp; inhibitors/metabolism ; Lactams, Macrocyclic/*pharmacology ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/cytology/metabolism ; Spinal Cord/cytology/*metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Temperature ; Up-Regulation/*drug effects ; }, abstract = {Clusterin, a protein chaperone found at high levels in physiological fluids, is expressed in nervous tissue and upregulated in several neurological diseases. To assess relevance to amyotrophic lateral sclerosis (ALS) and other motor neuron disorders, clusterin expression was evaluated using long-term dissociated cultures of murine spinal cord and SOD1(G93A) transgenic mice, a model of familial ALS. Motor neurons and astrocytes constitutively expressed nuclear and cytoplasmic forms of clusterin, and secreted clusterin accumulated in culture media. Although clusterin can be stress inducible, heat shock failed to increase levels in these neural cell compartments despite robust upregulation of stress-inducible Hsp70 (HspA1) in non-neuronal cells. In common with HSPs, clusterin was upregulated by treatment with the Hsp90 inhibitor, geldanamycin, and thus could contribute to the neuroprotection previously identified for such compounds in disease models. Clusterin expression was not altered in cultured motor neurons expressing SOD1(G93A) by gene transfer or in presymptomatic SOD1(G93A) transgenic mice; however, clusterin immunolabeling was weakly increased in lumbar spinal cord of overtly symptomatic mice. More striking, mutant SOD1 inclusions, a pathological hallmark, were strongly labeled by anti-clusterin. Since secreted, as well as intracellular, mutant SOD1 contributes to toxicity, the extracellular chaperoning property of clusterin could be important for folding and clearance of SOD1 and other misfolded proteins in the extracellular space. Evaluation of chaperone-based therapies should include evaluation of clusterin as well as HSPs, using experimental models that replicate the control mechanisms operant in the cells and tissue of interest.}, }
@article {pmid23593276, year = {2013}, author = {Lewis, CA and Manning, J and Barr, C and Peake, K and Humphries, RK and Rossi, F and Krieger, C}, title = {Myelosuppressive conditioning using busulfan enables bone marrow cell accumulation in the spinal cord of a mouse model of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {8}, number = {4}, pages = {e60661}, pmid = {23593276}, issn = {1932-6203}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*immunology/surgery ; Animals ; Bone Marrow Cells/*cytology/*drug effects/immunology ; *Bone Marrow Transplantation ; Busulfan/*pharmacology ; Cell Count ; Disease Models, Animal ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mutation ; Phenotype ; Spinal Cord/*immunology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Transplantation Conditioning/*methods ; }, abstract = {Myeloablative preconditioning using irradiation is the most commonly used technique to generate rodents having chimeric bone marrow, employed for the study of bone marrow-derived cell accumulation in the healthy and diseased central nervous system. However, irradiation has been shown to alter the blood-brain barrier, potentially creating confounding artefacts. To better study the potential of bone marrow-derived cells to function as treatment vehicles for neurodegenerative diseases alternative preconditioning regimens must be developed. We treated transgenic mice that over-express human mutant superoxide dismutase 1, a model of amyotrophic lateral sclerosis, with busulfan to determine whether this commonly used chemotherapeutic leads to stable chimerism and promotes the entry of bone marrow-derived cells into spinal cord. Intraperitoneal treatment with busulfan at 60 mg/kg or 80 mg/kg followed by intravenous injection of green fluorescent protein-expressing bone marrow resulted in sustained levels of chimerism (~80%). Bone marrow-derived cells accumulated in the lumbar spinal cord of diseased mice at advanced stages of pathology at both doses, with limited numbers of bone marrow derived cells observed in the spinal cords of similarly treated, age-matched controls; the majority of bone marrow-derived cells in spinal cord immunolabelled for macrophage antigens. Comparatively, significantly greater numbers of bone marrow-derived cells were observed in lumbar spinal cord following irradiative myeloablation. These results demonstrate bone marrow-derived cell accumulation in diseased spinal cord is possible without irradiative preconditioning.}, }
@article {pmid23590262, year = {2013}, author = {Benditt, JO and Boitano, LJ}, title = {Pulmonary issues in patients with chronic neuromuscular disease.}, journal = {American journal of respiratory and critical care medicine}, volume = {187}, number = {10}, pages = {1046-1055}, doi = {10.1164/rccm.201210-1804CI}, pmid = {23590262}, issn = {1535-4970}, mesh = {Chronic Disease ; Humans ; Neuromuscular Diseases/*complications ; Respiration Disorders/*complications/therapy ; Respiration, Artificial/methods ; }, abstract = {Patients with chronic neuromuscular diseases such as spinal cord injury, amyotrophic lateral sclerosis, and muscular dystrophies experience respiratory complications that are cared for by the respiratory practitioner. An organized anatomical approach for evaluation and treatment is helpful to provide appropriate clinical care. Effective noninvasive strategies for management of hypoventilation, sleep-disordered breathing, and cough insufficiency are available for these patients.}, }
@article {pmid23590138, year = {2013}, author = {Hozumi, I}, title = {Roles and therapeutic potential of metallothioneins in neurodegenerative diseases.}, journal = {Current pharmaceutical biotechnology}, volume = {14}, number = {4}, pages = {408-413}, doi = {10.2174/1389201011314040004}, pmid = {23590138}, issn = {1873-4316}, mesh = {Animals ; Antioxidants/pharmacology/therapeutic use ; Brain/drug effects/metabolism ; Humans ; Metallothionein/*pharmacology/*therapeutic use ; Neurodegenerative Diseases/*drug therapy/metabolism ; }, abstract = {Metallothionein (MT) is a small molecular and multi-functional protein containing four atoms of copper (Cu) and three atoms of zinc (Zn) per molecule. It was isolated from the horse kidney in 1957 and half a century has passed since then. Although MT was found to work as a modulator of Zn and induce anti-oxidant reaction, the precise functions and its functional mechanisms remain to be elucidated. Over the years, a new isoform of MT, MT-III (also called growth inhibitory factor (GIF)), has been found in the brain, which was markedly diminished in the brain of Alzheimer's disease (AD). Many new findings on MT have been discovered in neurodegenerative diseases other than AD such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), prion disease, brain trauma, brain ischemia, and psychiatric diseases. In ALS in particular, MTs were markedly diminished in the spinal cord of patients with ALS. Initially, MT, which easily binds to cadmium (Cd) and copper (Cu), was considered to be toxic to our bodies. Molecular biological technologies enabled the production of recombinant MT saturated with zinc (Zn). MT has a high potential for the treatment of neurodegenerative diseases such as ALS, AD, and PD owing to its various functions including anti-oxidant properties and modulators not only for Zn but for Cu in the extra- and intracellular spaces. On the other hand, there are still various problems on MT to be elucidated in detail, including their binding proteins and functional mechanisms.}, }
@article {pmid23583883, year = {2013}, author = {Cervetto, C and Frattaroli, D and Maura, G and Marcoli, M}, title = {Motor neuron dysfunction in a mouse model of ALS: gender-dependent effect of P2X7 antagonism.}, journal = {Toxicology}, volume = {311}, number = {1-2}, pages = {69-77}, doi = {10.1016/j.tox.2013.04.004}, pmid = {23583883}, issn = {1879-3185}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/*physiopathology ; Animals ; *Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/*physiology ; Purinergic P2X Receptor Antagonists/pharmacology/*therapeutic use ; Receptors, Purinergic P2X7/*metabolism ; *Sex Characteristics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative progressive currently untreatable disease, characterized by selective motor neuron degeneration; the incidence and prevalence of ALS are greater in men than in women. Although some important mechanisms that might contribute to the death of motor neurons have been identified, the mechanisms underlying disease pathophysiology are still uncertain. In particular, the mechanisms underlying the role of gender in ALS and whether treatments should take into account sexual dimorphism remain only partially understood. Recently, the P2X7 receptor for ATP was reported to display neurotoxic potential in motor neuron disorders, and antagonism of the receptor has been suggested to be helpful in these disorders. Studying transgenic mice with superoxide dismutase 1 gene mutations, widely used as model for ALS, may provide a better understanding of pathogenic mechanisms and of toxicity towards motor neurons, also possibly helping to understand whether treatments for ALS should take into account sexual dimorphism. The aim of the work was (1) investigating on gender-dependence of disease progression in the standard model for ALS - the transgenic mouse bearing superoxide dismutase 1 gene mutations - and (2) assessing if a P2X7 receptor antagonist treatment should take into account sexual dimorphism. We evaluated if gender affect the disease course, the motor performance, the weight loss and the lifespan in mice overexpressing mutant superoxide dismutase 1. We measured motor impairment, motor strength and coordination by rotarod and grip strength testing. Further, we assessed if a treatment with the P2X7 receptor antagonist Brilliant Blue G - a dye that can cross the blood-brain barrier, has low toxicity, and has exhibited therapeutic effects in animal models of neurodegenerative diseases - impact on the disease progression, in male and female ALS mice. We found that (1) the onset and the disease progression, and the survival were dependent on gender: male performed worst than female, lost body weight and died before; (2) treatment with the P2X7 receptor antagonist Brilliant Blue G ameliorated the disease progression. The treatment effect was gender-dependent: amelioration was greater in male than in female. In conclusions, we suggest that not only pathogenetic mechanism of motor neuron toxicity but also the drug treatment effectiveness may depend on gender; sexual dimorphism should be considered when investigating on ALS treatment efficacy in the ALS animal model. Our findings also point on the potential relevance of P2X7 receptor antagonism for ALS treatment, and highlight the importance of adopting a sex-specific approach to searching for treatment of ALS.}, }
@article {pmid23583762, year = {2013}, author = {Verheyen, A and Peeraer, E and Lambrechts, D and Poesen, K and Carmeliet, P and Shibuya, M and Pintelon, I and Timmermans, JP and Nuydens, R and Meert, T}, title = {Therapeutic potential of VEGF and VEGF-derived peptide in peripheral neuropathies.}, journal = {Neuroscience}, volume = {244}, number = {}, pages = {77-89}, doi = {10.1016/j.neuroscience.2013.03.050}, pmid = {23583762}, issn = {1873-7544}, mesh = {Activating Transcription Factor 3/*metabolism ; Animals ; Diabetes Mellitus, Experimental/drug therapy/metabolism ; *Drug Evaluation, Preclinical ; Ganglia, Spinal/*drug effects/metabolism ; Glucose/antagonists &amp; inhibitors/toxicity ; Male ; Mice ; Mice, Transgenic ; Neuroprotective Agents/*pharmacology/therapeutic use ; Paclitaxel/antagonists &amp; inhibitors/toxicity ; Peptide Fragments/*pharmacology/therapeutic use ; Peripheral Nervous System Diseases/*drug therapy ; Rats ; Vascular Endothelial Growth Factor A/*pharmacology/therapeutic use ; Vascular Endothelial Growth Factor Receptor-2/genetics ; }, abstract = {Besides its prominent role in angiogenesis, the vascular endothelial growth factor (VEGF) also exerts important protective effects on neurons. In particular, mice expressing reduced levels of VEGF suffer from late-onset motor neuron degeneration, whereas VEGF delivery significantly delays motor neuron death in ALS mouse models, at least partly through neuroprotective effects. Additionally, VEGF protects dorsal root ganglion (DRG) neurons against paclitaxel-induced neurotoxicity. Here, we demonstrate that VEGF also protects DRG neurons against hyperglycemia-induced neuronal stress as a model of diabetes-induced peripheral neuropathy. Specifically, VEGF decreased expression of the stress-related gene activating transcription factor 3 (ATF3) in DRG neurons isolated from streptozotocin-induced diabetic mice (ex vivo) and in isolated DRG neurons exposed to high glucose concentrations (in vitro). In vivo, local VEGF application also protected against paclitaxel- and diabetes-induced neuropathies without causing side effects. A small synthetic VEGF mimicking pentadecapeptide (QK) exerted similar effects on DRG cultures: the peptide reduced ATF3 expression in vitro and ex vivo in paclitaxel- and hyperglycemia-induced models of neuropathy to a similar extent as the full-length recombinant VEGF protein. By using transgenic mice selectively overexpressing the VEGF receptor 2 in postnatal neurons, these neuroprotective effects were shown to be mediated through VEGF receptor 2. Overall, these results underscore the potential of VEGF and VEGF-derived peptides for the treatment of peripheral neuropathies.}, }
@article {pmid23583391, year = {2013}, author = {Kim, Y and Park, JH and Jang, JY and Rhim, H and Kang, S}, title = {Characterization and Hsp104-induced artificial clearance of familial ALS-related SOD1 aggregates.}, journal = {Biochemical and biophysical research communications}, volume = {434}, number = {3}, pages = {521-526}, doi = {10.1016/j.bbrc.2013.03.107}, pmid = {23583391}, issn = {1090-2104}, mesh = {Adenosine Triphosphate/metabolism ; Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Animals ; Fluorescence Resonance Energy Transfer ; Heat-Shock Proteins/*physiology ; Humans ; Hydrolysis ; Mice ; Mutant Proteins/genetics/metabolism ; Saccharomyces cerevisiae Proteins/*physiology ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Hsp104, a molecular chaperone protein, originates from Saccharomyces cerevisiae and shows potential for development as a therapeutic disaggregase for the treatment of neurodegenerative disorders. This study shows that aggregates of mutant superoxide dismutase 1 (SOD1), which cause amyotrophic lateral sclerosis (ALS), are disaggregated by Hsp104 in an ATP-dependent manner. Mutant SOD1 aggregates were first characterized using fluorescence loss in photobleaching experiments based on the reduced mobility of aggregated proteins. Hsp104 restored the mobility of mutant SOD1 proteins to a level comparable with that of the wild-type. However, ATPase-deficient Hsp104 mutants did not restore mobility, suggesting that, rather than preventing aggregation, Hsp104 disaggregates mutant SOD1 after it has aggregated. Despite the restored mobility, however, mutant SOD1 proteins existed as trimers or other higher-order structures, rather than as naturally occurring dimers. This study sheds further light on the mechanisms underlying the disaggregation of SOD1 mutant aggregates in ALS.}, }
@article {pmid23582371, year = {2016}, author = {Gamez, J and Salvado, M and Martínez de la Ossa, A and Badia, M}, title = {Lithium for treatment of amyotrophic lateral sclerosis: much ado about nothing.}, journal = {Neurologia (Barcelona, Spain)}, volume = {31}, number = {8}, pages = {550-561}, doi = {10.1016/j.nrl.2013.02.001}, pmid = {23582371}, issn = {1578-1968}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Lithium Compounds/*therapeutic use ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Treatment Outcome ; }, abstract = {INTRODUCTION: Lithium was proposed in 2008 as an effective candidate in the treatment of ALS after a report claimed that it was able to delay functional deterioration by 40% and that none of the 16 patients treated with a combination of lithium plus riluzole had died during a 15-month follow-up period. The excellent results of this pilot study engendered considerable optimism among patients, their families, patients' associations, and the scientific community. This report sparked numerous phase ii clinical trials. Many patients who were not included in these studies used all resources at their disposal to access the drug as treatment under a compassionate use programme.<br><br>OBJECTIVES: To evaluate the effectiveness of lithium in ALS using a meta-analysis of the information reported in 12 studies which were examined for methodological quality.<br><br>MATERIAL AND METHODS: . Searches were performed using MEDLINE, EMBASE, the Cochrane Neuromuscular Disease Group Trials Register, ClinicalTrials.gov, and EudraCT (January 1996-August 2012).<br><br>RESULTS: To date, we have information on more 1100 patients treated with lithium. Unfortunately, the results do not confirm the positive effect described in the pilot study, which suggests that this drug is not effective at slowing disease progression. Two trials had to be suspended before the scheduled completion date due to the ineffectiveness of the drug as well as numerous adverse effects. A recently published study also ruled out any possible modest effect.<br><br>CONCLUSIONS: There is evidence to suggest that lithium has no short-term benefits in ALS. A comparison of the group of patients treated with lithium+riluzole and the control group treated with riluzole alone showed no statistically significant differences in rates of functional decline, deterioration of respiratory function, or survival time. Furthermore, there was no evidence that it was more effective than the placebo.}, }
@article {pmid23575853, year = {2013}, author = {Dimitriadi, M and Kye, MJ and Kalloo, G and Yersak, JM and Sahin, M and Hart, AC}, title = {The neuroprotective drug riluzole acts via small conductance Ca2+-activated K+ channels to ameliorate defects in spinal muscular atrophy models.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {33}, number = {15}, pages = {6557-6562}, pmid = {23575853}, issn = {1529-2401}, support = {P01 NS066888/NS/NINDS NIH HHS/United States ; P30 HD018655/HD/NICHD NIH HHS/United States ; NS066888/NS/NINDS NIH HHS/United States ; P30 HD18655/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Axons/drug effects/ultrastructure ; Caenorhabditis elegans ; Cells, Cultured ; Disease Models, Animal ; Gene Knockdown Techniques/methods ; Hippocampus/drug effects/metabolism ; Muscular Atrophy, Spinal/*drug therapy/genetics ; Mutation ; Neurons/cytology ; Neuroprotective Agents/*pharmacology/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Riluzole/*pharmacology/therapeutic use ; Small-Conductance Calcium-Activated Potassium Channels/*agonists ; Survival of Motor Neuron 1 Protein/genetics ; }, abstract = {Spinal muscular atrophy (SMA), a recessive neuromuscular disorder, is caused by diminished function of the Survival Motor Neuron (SMN) protein. To define the cellular processes pertinent to SMA, parallel genetic screens were undertaken in Drosophila and Caenorhabditis elegans SMA models to identify modifiers of the SMN loss of function phenotypes. One class of such genetic modifiers was the small conductance, Ca(2+)-activated K(+) (SK) channels. SK channels allow efflux of potassium ions when intracellular calcium increases and can be activated by the neuroprotective drug riluzole. The latter is the only drug with proven, albeit modest, efficacy in the treatment of amyotrophic lateral sclerosis. It is unclear if riluzole can extend life span or ameliorate symptoms in SMA patients as previous studies were limited and of insufficient power to draw any conclusions. The critical biochemical target of riluzole in motor neuron disease is not known, but the pharmacological targets of riluzole include SK channels. We examine here the impact of riluzole in two different SMA models. In vertebrate neurons, riluzole treatment restored axon outgrowth caused by diminished SMN. Additionally, riluzole ameliorated the neuromuscular defects in a C. elegans SMA model and SK channel function was required for this beneficial effect. We propose that riluzole improves motor neuron function by acting on SK channels and suggest that SK channels may be important therapeutic targets for SMA patients.}, }
@article {pmid23562846, year = {2013}, author = {Maier, O and Böhm, J and Dahm, M and Brück, S and Beyer, C and Johann, S}, title = {Differentiated NSC-34 motoneuron-like cells as experimental model for cholinergic neurodegeneration.}, journal = {Neurochemistry international}, volume = {62}, number = {8}, pages = {1029-1038}, doi = {10.1016/j.neuint.2013.03.008}, pmid = {23562846}, issn = {1872-9754}, mesh = {Animals ; Base Sequence ; *Cell Differentiation/drug effects ; Cell Line, Tumor ; Choline O-Acetyltransferase/metabolism ; DNA Primers ; Glutamic Acid/pharmacology ; Hydrogen Peroxide/pharmacology ; Mice ; *Models, Biological ; Motor Neurons/*cytology/enzymology ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Alpha-motoneurons appear to be exceedingly affected in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Morphological and physiological degeneration of this neuronal phenotype is typically characterized by a marked decrease of neuronal markers and by alterations of cholinergic metabolism such as reduced choline acetyltransferase (ChAT) expression. The motoneuron-like cell line NSC-34 is a hybrid cell line produced by fusion of neuroblastoma with mouse motoneuron-enriched primary spinal cord cells. In order to further establish this cell line as a valid model system to investigate cholinergic neurodegeneration, NSC-34 cells were differentiated by serum deprivation and additional treatment with all-trans retinoic acid (atRA). Cell maturation was characterized by neurite outgrowth and increased expression of neuronal and cholinergic markers, including MAP2, GAP-43 and ChAT. Subsequently, we used differentiated NSC-34 cells to study early degenerative responses following exposure to various neurotoxins (H2O2, TNF-α, and glutamate). Susceptibility to toxin-induced cell death was determined by means of morphological changes, expression of neuronal marker proteins, and the ratio of pro-(Bax) to anti-(Bcl-2) apoptotic proteins. NSC-34 cells respond to low doses of neurotoxins with increased cell death of remaining undifferentiated cells with no obvious adverse effects on differentiated cells. Thus, the different vulnerability of differentiated and undifferentiated NSC-34 cells to neurotoxins is a key characteristic of NSC-34 cells and has to be considered in neurotoxic studies. Nonetheless, application of atRA induced differentiation of NSC-34 cells and provides a suitable model to investigate molecular events linked to neurodegeneration of differentiated neurons.}, }
@article {pmid23560624, year = {2013}, author = {Börjesson, A and Grundmark, B and Olaisson, H and Waldenlind, L}, title = {Is there a link between amyotrophic lateral sclerosis and treatment with TNF-alpha inhibitors?.}, journal = {Upsala journal of medical sciences}, volume = {118}, number = {3}, pages = {199-200}, pmid = {23560624}, issn = {2000-1967}, mesh = {Adalimumab ; Adverse Drug Reaction Reporting Systems ; Amyotrophic Lateral Sclerosis/*etiology ; Antibodies, Monoclonal/adverse effects ; Antibodies, Monoclonal, Humanized/adverse effects ; Antirheumatic Agents/adverse effects ; Arthritis, Rheumatoid/complications/therapy ; Databases, Pharmaceutical ; Etanercept ; Europe ; Humans ; Immunoglobulin G/adverse effects ; Infliximab ; Pharmacovigilance ; Receptors, Tumor Necrosis Factor ; Tumor Necrosis Factor-alpha/*antagonists &amp; inhibitors ; }, }
@article {pmid23553522, year = {2013}, author = {Wang, S and Guan, Y and Chen, Y and Li, X and Zhang, C and Yu, L and Zhou, F and Wang, X}, title = {Role of Wnt1 and Fzd1 in the spinal cord pathogenesis of amyotrophic lateral sclerosis-transgenic mice.}, journal = {Biotechnology letters}, volume = {35}, number = {8}, pages = {1199-1207}, doi = {10.1007/s10529-013-1199-1}, pmid = {23553522}, issn = {1573-6776}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Cells, Cultured ; Disease Models, Animal ; Frizzled Receptors/genetics/*metabolism ; Gene Expression Profiling ; Mice ; Mice, Transgenic ; Spinal Cord/*pathology ; Wnt1 Protein/genetics/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by chronic progressive degeneration of motor neurons resulting in muscular atrophy, paralysis, and ultimately death. We have investigated the expression of Wnt1 and Fzd1 in the spinal cords of SOD1G93A ALS transgenic mice, SOD1G93A-transfected N2a cells, and primary cultured astrocytes from SOD1G93A transgenic mice. In addition, we provided further insight into the role of Wnt1 and Fzd1 in the pathogenesis of ALS transgenic mice and discuss the mechanisms underlying the Wnt signal pathway which may be useful in the treatment of ALS. The results indicate the involvement of Wnt1 and Fzd1 in the pathogenesis and development of ALS.}, }
@article {pmid23544978, year = {2013}, author = {Grumbles, RM and Liu, Y and Thomas, CM and Wood, PM and Thomas, CK}, title = {Acute stimulation of transplanted neurons improves motoneuron survival, axon growth, and muscle reinnervation.}, journal = {Journal of neurotrauma}, volume = {30}, number = {12}, pages = {1062-1069}, pmid = {23544978}, issn = {1557-9042}, support = {NS-39098/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Axons ; Axotomy ; Cell Survival ; Disease Models, Animal ; *Electric Stimulation ; Female ; Motor Neurons/*physiology/*transplantation ; Muscle, Skeletal/*innervation ; Nerve Regeneration/*physiology ; Neurodegenerative Diseases/surgery ; Rats ; Rats, Inbred F344 ; Sciatic Nerve/surgery ; Spinal Cord Injuries/surgery ; }, abstract = {Few options exist for treatment of pervasive motoneuron death after spinal cord injury or in neurodegenerative diseases such as amyotrophic lateral sclerosis. Local transplantation of embryonic motoneurons into an axotomized peripheral nerve is a promising approach to arrest the atrophy of denervated muscles; however, muscle reinnervation is limited by poor motoneuron survival. The aim of the present study was to test whether acute electrical stimulation of transplanted embryonic neurons promotes motoneuron survival, axon growth, and muscle reinnervation. The sciatic nerve of adult Fischer rats was transected to mimic the widespread denervation seen after disease or injury. Acutely dissociated rat embryonic ventral spinal cord cells were transplanted into the distal tibial nerve stump as a neuron source for muscle reinnervation. Immediately post-transplantation, the cells were stimulated at 20 Hz for 1 h. Other groups were used to control for the cell transplantation and stimulation. When neurons were stimulated acutely, there were significantly more neurons, including cholinergic neurons, 10 weeks after transplantation. This led to enhanced numbers of myelinated axons, reinnervation of more muscle fibers, and more medial and lateral gastrocnemius muscles were functionally connected to the transplant. Reinnervation reduced muscle atrophy significantly. These data support the concept that electrical stimulation rescues transplanted motoneurons and facilitates muscle reinnervation.}, }
@article {pmid23541756, year = {2013}, author = {Miller, TM and Pestronk, A and David, W and Rothstein, J and Simpson, E and Appel, SH and Andres, PL and Mahoney, K and Allred, P and Alexander, K and Ostrow, LW and Schoenfeld, D and Macklin, EA and Norris, DA and Manousakis, G and Crisp, M and Smith, R and Bennett, CF and Bishop, KM and Cudkowicz, ME}, title = {An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study.}, journal = {The Lancet. Neurology}, volume = {12}, number = {5}, pages = {435-442}, pmid = {23541756}, issn = {1474-4465}, support = {R01NS078398/NS/NINDS NIH HHS/United States ; K08NS074194/NS/NINDS NIH HHS/United States ; R01 NS078398/NS/NINDS NIH HHS/United States ; UL1TR000448/TR/NCATS NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; K08 NS074194/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Double-Blind Method ; Female ; Humans ; Injections, Spinal ; Male ; Middle Aged ; Oligodeoxyribonucleotides, Antisense/administration &amp; dosage/*therapeutic use ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Treatment Outcome ; }, abstract = {BACKGROUND: Mutations in SOD1 cause 13% of familial amyotrophic lateral sclerosis. In the SOD1 Gly93Ala rat model of amyotrophic lateral sclerosis, the antisense oligonucleotide ISIS 333611 delivered to CSF decreased SOD1 mRNA and protein concentrations in spinal cord tissue and prolonged survival. We aimed to assess the safety, tolerability, and pharmacokinetics of ISIS 333611 after intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis.<br><br>METHODS: In this randomised, placebo-controlled, phase 1 trial, we delivered ISIS 333611 by intrathecal infusion using an external pump over 11&#xb7;5 h at increasing doses (0&#xb7;15 mg, 0&#xb7;50 mg, 1&#xb7;50 mg, 3&#xb7;00 mg) to four cohorts of eight patients with SOD1-positive amyotrophic lateral sclerosis (six patients assigned to ISIS 333611, two to placebo in each cohort). We did the randomisation with a web-based system, assigning patients in blocks of four. Patients and investigators were masked to treatment assignment. Participants were allowed to re-enrol in subsequent cohorts. Our primary objective was to assess the safety and tolerability of ISIS 333611. Assessments were done during infusion and over 28 days after infusion. This study was registered with Clinicaltrials.gov, number NCT01041222.<br><br>FINDINGS: Seven of eight (88%) patients in the placebo group versus 20 of 24 (83%) in the ISIS 333611 group had adverse events. The most common events were post-lumbar puncture syndrome (3/8 [38%] vs 8/24 [33%]), back pain (4/8 [50%] vs 4/24 [17%]), and nausea (0/8 [0%] vs 3/24 [13%]). We recorded no dose-limiting toxic effects or any safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611. Re-enrolment and re-treatment were also well tolerated.<br><br>INTERPRETATION: This trial is the first clinical study of intrathecal delivery of an antisense oligonucleotide. ISIS 333611 was well tolerated when administered as an intrathecal infusion. Antisense oligonucleotides delivered to the CNS might be a feasible treatment for neurological disorders.<br><br>FUNDING: The ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals.}, }
@article {pmid25258700, year = {2013}, author = {Carman, A and Kishinevsky, S and Koren, J and Lou, W and Chiosis, G}, title = {Chaperone-dependent Neurodegeneration: A Molecular Perspective on Therapeutic Intervention.}, journal = {Journal of Alzheimer's disease &amp; Parkinsonism}, volume = {2013}, number = {Suppl 10}, pages = {}, pmid = {25258700}, issn = {2161-0460}, support = {R01 CA172546/CA/NCI NIH HHS/United States ; R21 AG028811/AG/NIA NIH HHS/United States ; U01 AG032969/AG/NIA NIH HHS/United States ; }, abstract = {Maintenance of cellular homeostasis is regulated by the molecular chaperones. Under pathogenic conditions, aberrant proteins are triaged by the chaperone network. These aberrant proteins, known as "clients," have major roles in the pathogenesis of numerous neurological disorders, including tau in Alzheimer's disease, α-synuclein and LRRK2 in Parkinson's disease, SOD-1, TDP-43 and FUS in amyotrophic lateral sclerosis, and polyQ-expanded proteins such as huntingtin in Huntington's disease. Recent work has demonstrated that the use of chemical compounds which inhibit the activity of molecular chaperones subsequently alter the fate of aberrant clients. Inhibition of Hsp90 and Hsc70, two major molecular chaperones, has led to a greater understanding of how chaperone triage decisions are made and how perturbing the chaperone system can promote clearance of these pathogenic clients. Described here are major pathways and components of several prominent neurological disorders. Also discussed is how treatment with chaperone inhibitors, predominately Hsp90 inhibitors which are selective for a diseased state, can relieve the burden of aberrant client signaling in these neurological disorders.}, }
@article {pmid23539154, year = {2013}, author = {Moser, JM and Bigini, P and Schmitt-John, T}, title = {The wobbler mouse, an ALS animal model.}, journal = {Molecular genetics and genomics : MGG}, volume = {288}, number = {5-6}, pages = {207-229}, pmid = {23539154}, issn = {1617-4623}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/drug therapy/*etiology/physiopathology ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Disease Models, Animal ; Humans ; Male ; Mice ; Molecular Sequence Data ; Motor Neuron Disease/*etiology ; Mutation ; Spermatogenesis/genetics ; Vesicular Transport Proteins/*genetics ; }, abstract = {This review article is focused on the research progress made utilizing the wobbler mouse as animal model for human motor neuron diseases, especially the amyotrophic lateral sclerosis (ALS). The wobbler mouse develops progressive degeneration of upper and lower motor neurons and shows striking similarities to ALS. The cellular effects of the wobbler mutation, cellular transport defects, neurofilament aggregation, neuronal hyperexcitability and neuroinflammation closely resemble human ALS. Now, 57 years after the first report on the wobbler mouse we summarize the progress made in understanding the disease mechanism and testing various therapeutic approaches and discuss the relevance of these advances for human ALS. The identification of the causative mutation linking the wobbler mutation to a vesicle transport factor and the research focussed on the cellular basis and the therapeutic treatment of the wobbler motor neuron degeneration has shed new light on the molecular pathology of the disease and might contribute to the understanding the complexity of ALS.}, }
@article {pmid23537713, year = {2013}, author = {Zhang, Y and Cook, A and Kim, J and Baranov, SV and Jiang, J and Smith, K and Cormier, K and Bennett, E and Browser, RP and Day, AL and Carlisle, DL and Ferrante, RJ and Wang, X and Friedlander, RM}, title = {Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {55}, number = {}, pages = {26-35}, pmid = {23537713}, issn = {1095-953X}, support = {K01 NS055072/NS/NINDS NIH HHS/United States ; R01 NS039324/NS/NINDS NIH HHS/United States ; R01 NS051756/NS/NINDS NIH HHS/United States ; KO1 NS055072/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Analysis of Variance ; Animals ; Antioxidants/*therapeutic use ; Caspase 3/metabolism ; Cell Death/*drug effects/*ethics ; Cytochromes c/metabolism ; Disease Models, Animal ; Disease Progression ; Enzyme-Linked Immunosorbent Assay ; Melatonin/*therapeutic use ; Mice ; Mice, Transgenic ; Receptor, Melatonin, MT1/metabolism ; Signal Transduction/*drug effects ; Superoxide Dismutase/genetics ; }, abstract = {Caspase-mediated cell death contributes to the pathogenesis of motor neuron degeneration in the mutant SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS), along with other factors such as inflammation and oxidative damage. By screening a drug library, we found that melatonin, a pineal hormone, inhibited cytochrome c release in purified mitochondria and prevented cell death in cultured neurons. In this study, we evaluated whether melatonin would slow disease progression in SOD1(G93A) mice. We demonstrate that melatonin significantly delayed disease onset, neurological deterioration and mortality in ALS mice. ALS-associated ventral horn atrophy and motor neuron death were also inhibited by melatonin treatment. Melatonin inhibited Rip2/caspase-1 pathway activation, blocked the release of mitochondrial cytochrome c, and reduced the overexpression and activation of caspase-3. Moreover, for the first time, we determined that disease progression was associated with the loss of both melatonin and the melatonin receptor 1A (MT1) in the spinal cord of ALS mice. These results demonstrate that melatonin is neuroprotective in transgenic ALS mice, and this protective effect is mediated through its effects on the caspase-mediated cell death pathway. Furthermore, our data suggest that melatonin and MT1 receptor loss may play a role in the pathological phenotype observed in ALS. The above observations indicate that melatonin and modulation of Rip2/caspase-1/cytochrome c or MT1 pathways may be promising therapeutic approaches for ALS.}, }
@article {pmid23533690, year = {2013}, author = {Parakh, S and Spencer, DM and Halloran, MA and Soo, KY and Atkin, JD}, title = {Redox regulation in amyotrophic lateral sclerosis.}, journal = {Oxidative medicine and cellular longevity}, volume = {2013}, number = {}, pages = {408681}, pmid = {23533690}, issn = {1942-0994}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/physiopathology ; Animals ; Autophagy ; Axonal Transport ; Cholesterol/metabolism ; Endoplasmic Reticulum Stress ; Glutamic Acid/metabolism ; Humans ; Lipid Peroxidation ; Mitochondria/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Protein Disulfide-Isomerases/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results from the death of upper and lower motor neurons. Due to a lack of effective treatment, it is imperative to understand the underlying mechanisms and processes involved in disease progression. Regulations in cellular reduction/oxidation (redox) processes are being increasingly implicated in disease. Here we discuss the possible involvement of redox dysregulation in the pathophysiology of ALS, either as a cause of cellular abnormalities or a consequence. We focus on its possible role in oxidative stress, protein misfolding, glutamate excitotoxicity, lipid peroxidation and cholesterol esterification, mitochondrial dysfunction, impaired axonal transport and neurofilament aggregation, autophagic stress, and endoplasmic reticulum (ER) stress. We also speculate that an ER chaperone protein disulphide isomerase (PDI) could play a key role in this dysregulation. PDI is essential for normal protein folding by oxidation and reduction of disulphide bonds, and hence any disruption to this process may have consequences for motor neurons. Addressing the mechanism underlying redox regulation and dysregulation may therefore help to unravel the molecular mechanism involved in ALS.}, }
@article {pmid23526405, year = {2012}, author = {Xu, Z and Li, H and Jin, P}, title = {Epigenetics-Based Therapeutics for Neurodegenerative Disorders.}, journal = {Current translational geriatrics and experimental gerontology reports}, volume = {1}, number = {4}, pages = {229-236}, pmid = {23526405}, issn = {2162-4941}, support = {R01 NS051630/NS/NINDS NIH HHS/United States ; R01 NS079625/NS/NINDS NIH HHS/United States ; R21 NS067461/NS/NINDS NIH HHS/United States ; }, abstract = {Epigenetic regulation, such as DNA methylation and histone modification, is implicated in the aberrant changes in gene expression that occur during the progression of neurodegeneration. Many epigenetics-based drugs have been developed recently for the treatment of some neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases. Here we review recent studies that highlight the role of epigenetic modifications in neurodegeneration, among them DNA methylation and demethylation and histone acetylation and deacetylation; we also explore the possibility of using epigenetics-based therapeutics to treat neurodegenerative disorders.}, }
@article {pmid23523267, year = {2013}, author = {Valente, T and Straccia, M and Gresa-Arribas, N and Dentesano, G and Tusell, JM and Serratosa, J and Mancera, P and Solà, C and Saura, J}, title = {CCAAT/enhancer binding protein δ regulates glial proinflammatory gene expression.}, journal = {Neurobiology of aging}, volume = {34}, number = {9}, pages = {2110-2124}, doi = {10.1016/j.neurobiolaging.2013.02.007}, pmid = {23523267}, issn = {1558-1497}, mesh = {Amyotrophic Lateral Sclerosis/therapy ; Animals ; Astrocytes/metabolism/*pathology ; CCAAT-Enhancer-Binding Protein-delta/antagonists &amp; inhibitors/metabolism/*physiology/toxicity ; Cells, Cultured ; Cyclooxygenase 2/metabolism ; Gene Expression Regulation/*genetics ; Humans ; Interleukin-6/metabolism ; Mice ; Microglia/metabolism/*pathology ; Molecular Targeted Therapy ; Neurogenic Inflammation/*genetics/pathology ; Nitric Oxide Synthase Type II/metabolism ; Superoxide Dismutase/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {The transcription factor CCAAT/enhancer binding protein δ (C/EBPδ) is expressed in activated astrocytes and microglia and can regulate the expression of potentially detrimental proinflammatory genes. The objective of this study was to determine the role of C/EBPδ in glial activation. To this end, glial activation was analyzed in primary glial cultures and in the central nervous system from wild type and C/EBPδ(-/-) mice. In vitro studies showed that the expression of proinflammatory genes nitric oxide (NO)synthase-2, cyclooxygenase-2, and interleukin (IL)-6 in glial cultures, and the neurotoxicity elicited by microglia in neuron-microglia cocultures, were decreased in the absence of C/EBPδ when cultures were treated with lipopolysaccharide (LPS) and interferon γ, but not with LPS alone. In C/EBPδ(-/-) mice, systemic LPS-induced brain expression of NO synthase-2, tumor necrosis factor-α, IL-1β, and IL-6 was attenuated. Finally, increased C/EBPδ nuclear expression was observed in microglial cells from amyotrophic lateral sclerosis patients and G93A-SOD1 mice spinal cord. These results demonstrate that C/EBPδ plays a key role in the regulation of proinflammatory gene expression in glial activation and suggest that C/EBPδ inhibition has potential for the treatment of neurodegenerative disorders, in particular, amyotrophic lateral sclerosis.}, }
@article {pmid23519768, year = {2014}, author = {Zhang, X and Hong, YL and Xu, DS and Feng, Y and Zhao, LJ and Ruan, KF and Yang, XJ}, title = {A review of experimental research on herbal compounds in amyotrophic lateral sclerosis.}, journal = {Phytotherapy research : PTR}, volume = {28}, number = {1}, pages = {9-21}, doi = {10.1002/ptr.4960}, pmid = {23519768}, issn = {1099-1573}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Calcium/metabolism ; Excitatory Amino Acids/antagonists &amp; inhibitors ; Humans ; Inflammation/drug therapy ; Oxidative Stress/*drug effects ; Plant Extracts/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease worldwide, leading to progressive muscle atrophy and paralysis. The limited success of conventional treatment for ALS has prompted investigations into complementary and alternative therapies. Herbal remedies provide good prospects of ALS prevention and treatment, with advantages such as multiple targets, multiple links, and few side effects. Studies in vitro and in vivo have shown that herbs have a great potential for treatment of ALS, with therapeutic effects against oxidative stress, excitatory amino acid toxicity, neuroinflammation, and calcium cytotoxicity. Active monomers or ingredients extracted from herbs are considered promising candidates for ALS. Therefore, we review recent experimental research on monomers and compounds isolated from herbal remedies for preventing and treating ALS.}, }
@article {pmid23517137, year = {2013}, author = {Wu, Y and Satkunendrarajah, K and Teng, Y and Chow, DS and Buttigieg, J and Fehlings, MG}, title = {Delayed post-injury administration of riluzole is neuroprotective in a preclinical rodent model of cervical spinal cord injury.}, journal = {Journal of neurotrauma}, volume = {30}, number = {6}, pages = {441-452}, pmid = {23517137}, issn = {1557-9042}, mesh = {Animals ; Cervical Vertebrae ; *Disease Models, Animal ; Drug Evaluation, Preclinical/methods ; Evoked Potentials, Somatosensory/drug effects/physiology ; Female ; Motor Activity/drug effects/physiology ; Neuroprotective Agents/*administration &amp; dosage ; Rats ; Rats, Wistar ; Riluzole/*administration &amp; dosage ; Spinal Cord Injuries/pathology/*physiopathology/*prevention &amp; control ; Time Factors ; }, abstract = {Riluzole, a sodium/glutamate antagonist has shown promise as a neuroprotective agent. It is licensed for amyotrophic lateral sclerosis and is in clinical trial development for spinal cord injury (SCI). This study investigated the therapeutic time-window and pharmacokinetics of riluzole in a rodent model of cervical SCI. Rats were treated with riluzole (8 mg/kg) at 1 hour (P1) and 3 hours (P3) after injury or with vehicle. Afterward, P1 and P3 groups received riluzole (6 (mg/kg) every 12 hours for 7 days. Both P1 and P3 animals had significant improvements in locomotor recovery as measured by open field locomotion (BBB score, BBB subscore). Von Frey stimuli did not reveal an increase in at level or below level mechanical allodynia. Sensory-evoked potential recordings and quantification of axonal cytoskeleton demonstrated a riluzole-mediated improvement in axonal integrity and function. Histopathological and retrograde tracing studies demonstrated that delayed administration leads to tissue preservation and reduces apoptosis and inflammation. High performance liquid chromatography (HPLC) was undertaken to examine the pharmacokinetics of riluzole. Riluzole penetrates the spinal cord in 15 min, and SCI slowed elimination of riluzole from the spinal cord, resulting in a longer half-life and higher drug concentration in spinal cord and plasma. Initiation of riluzole treatment 1 and 3 hours post-SCI led to functional, histological, and molecular benefits. While extrapolation of post-injury time windows from rat to man is challenging, evidence from SCI-related biomarker studies would suggest that the post-injury time window is likely to be at least 12 hours in man.}, }
@article {pmid23515294, year = {2013}, author = {Maruyama, H and Morino, H and Izumi, Y and Noda, K and Kawakami, H}, title = {Convenient diagnosis of spinal and bulbar muscular atrophy using a microchip electrophoresis system.}, journal = {American journal of neurodegenerative disease}, volume = {2}, number = {1}, pages = {35-39}, pmid = {23515294}, issn = {2165-591X}, abstract = {Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive motor neuron disease. Lower and primary sensory neuronopathy is one of the major neuropathological changes that occurs in SBMA. However, many sings are common to SBMA and amyotrophic lateral sclerosis (ALS), and SBMA patients are sometimes diagnosed with ALS. Leuprorelin may be used to treat SBMA, but an accurate diagnosis is necessary for treatment and care. Genetic diagnosis can be performed to detect the expansion of a CAG repeat in the androgen receptor gene in SBMA patients. To screen for this expansion, we used a microchip electrophoresis system. The discrepancy between the actual repeat length and that found by the microchip electrophoresis system was roughly dependent on the repeat length. The mean difference was -6.8 base pairs (bp) in SBMA patients, -0.30 bp in controls. The microchip electrophoresis results were approximately 2 CAG repeats shorter than the actual repeat length in SBMA patients. Using this method, we screened our ALS samples (31 were familial, 271 were sporadic): 4 subjects were diagnosed with SBMA; 2 had familial ALS, and 2 had sporadic ALS (0.7%). The microchip electrophoresis system is semi-quantitative, convenient and useful for screening a large number of samples.}, }
@article {pmid23508986, year = {2013}, author = {Mulligan, VK and Chakrabartty, A}, title = {Protein misfolding in the late-onset neurodegenerative diseases: common themes and the unique case of amyotrophic lateral sclerosis.}, journal = {Proteins}, volume = {81}, number = {8}, pages = {1285-1303}, doi = {10.1002/prot.24285}, pmid = {23508986}, issn = {1097-0134}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; Humans ; Models, Molecular ; Mutation ; Neurodegenerative Diseases/genetics/metabolism/*pathology ; *Protein Folding ; Superoxide Dismutase/analysis/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Enormous strides have been made in the last 100 years to extend human life expectancy and to combat the major infectious diseases. Today, the major challenges for medical science are age-related diseases, including cancer, heart disease, lung disease, renal disease, and late-onset neurodegenerative disease. Of these, only the neurodegenerative diseases represent a class of disease so poorly understood that no general strategies for prevention or treatment exist. These diseases, which include Alzheimer's disease, Parkinson's disease, Huntington's disease, the transmissible spongiform encephalopathies, and amyotrophic lateral sclerosis (ALS), are generally fatal and incurable. The first section of this review summarizes the diversity and common features of the late-onset neurodegenerative diseases, with a particular focus on protein misfolding and aggregation-a recurring theme in the molecular pathology. The second section focuses on the particular case of ALS, a late-onset neurodegenerative disease characterized by the death of central nervous system motor neurons, leading to paralysis and patient death. Of the 10% of ALS cases that show familial inheritance (familial ALS), the largest subset is caused by mutations in the SOD1 gene, encoding the Cu, Zn superoxide dismutase (SOD1). The unusual kinetic stability of SOD1 has provided a unique opportunity for detailed structural characterization of conformational states potentially involved in SOD1-associated ALS. This review discusses past studies exploring the stability, folding, and misfolding behavior of SOD1, as well as the therapeutic possibilities of using detailed knowledge of misfolding pathways to target the molecular mechanisms underlying ALS and other neurodegenerative diseases.}, }
@article {pmid23500882, year = {2013}, author = {Lee, KW and Ji, HM and Kim, DW and Choi, SM and Kim, S and Yang, EJ}, title = {Effects of Hominis placenta on LPS-induced cell toxicity in BV2 microglial cells.}, journal = {Journal of ethnopharmacology}, volume = {147}, number = {2}, pages = {286-292}, doi = {10.1016/j.jep.2013.02.033}, pmid = {23500882}, issn = {1872-7573}, mesh = {Animals ; Anti-Inflammatory Agents/*pharmacology ; Cell Death/drug effects ; Cell Line ; Cyclooxygenase 2/metabolism ; Female ; Humans ; Lipopolysaccharides ; Mice ; Microglia/*drug effects/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Nitric Oxide Synthase Type II/antagonists &amp; inhibitors/metabolism ; Placental Extracts/*pharmacology ; Pregnancy ; }, abstract = {Hominis placenta (HP) dried placenta extracted from pregnant women after delivery has been widely used to treat chronic inflammatory diseases. HP has been reported to be effective to alleviate the arthritic symptoms by modulating the expression of inflammatory factors in adjuvant-induced arthritis rats. However, the mechanism of action of HP is unknown. Neuroinflammation has been implicated in the pathogenesis of several neurodegenerative disease, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotropic lateral sclerosis (ALS). Activated microglia produce large amounts of toxic soluble factors, which can be responsible for the neurodegenerative disease. Chronic microglial activation leads to neuroinflammation, which contributes to neuronal dysfunction, injury and loss in these diseases. Lipopolysaccharide (LPS) is widely used for neuroinflammation caused by microglial activation of immune cells in the central nervous system (CNS) and subsequent release of inflammatory or neurotoxic factors. In the present study, we investigated the effects and signaling pathway of HP in the LPS induced BV2 microglial cells.<br><br>MATERIALS AND METHOD: BV2 microglial cells were pretreated with 50 &#x3bc;M HP for 2h prior to 2 &#x3bc;g/ml LPS for 15 min. Cell viability was determined by MTT assay. The level of protein expression was analyzed by western blot. Immunofluorescence was performed with an anti-COX2 antibody in BV2 cells.<br><br>RESULTS: HP decreased LPS-induced microglial cell death by 24% and inhibited LPS-induced activation of c-Jun N-terminal kinase (JNK) by 23% and p42/44MAP kinase (ERK) by 34% treatment of LPS. In addition, HP attenuated LPS-induced pro-inflammatory proteins such as iNOS and COX2 in microglial cells 34% and 28% respectively.<br><br>CONCLUSIONS: Our data shows that HP has a protective role against LPS stimulation through inhibition of MAPK signaling and suppression of inflammation caused by neurotoxin including LPS. These findings suggest that HP could be a potential therapeutic agent of neurodegenerative diseases which accompanied with microglial activation.}, }
@article {pmid23500004, year = {2013}, author = {Tsai, T and Klausmeyer, A and Conrad, R and Gottschling, C and Leo, M and Faissner, A and Wiese, S}, title = {7,8-Dihydroxyflavone leads to survival of cultured embryonic motoneurons by activating intracellular signaling pathways.}, journal = {Molecular and cellular neurosciences}, volume = {56}, number = {}, pages = {18-28}, doi = {10.1016/j.mcn.2013.02.007}, pmid = {23500004}, issn = {1095-9327}, mesh = {Animals ; Cell Growth Processes ; Cell Survival ; Cells, Cultured ; Dose-Response Relationship, Drug ; Flavones/*pharmacology ; Hippocampus/cytology/embryology ; *MAP Kinase Signaling System ; Mice ; Motor Neurons/*drug effects/metabolism/physiology ; Neurites/drug effects/metabolism/physiology ; Neuroprotective Agents/*pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Receptor, trkB/agonists/metabolism ; Spinal Cord/cytology/embryology ; }, abstract = {Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family and a ligand for the tropomyosin-receptor kinase B (TrkB), mediates neuronal survival, differentiation, and synaptic plasticity. However, BDNF is not used to treat neurodegenerative diseases because of its poor pharmacokinetic profile, side effects, and absence of survival properties in clinical trials. Consequently, alternative approaches such as TrkB receptor agonist application are gaining importance. 7,8-Dihydroxyflavone (7,8-DHF), a member of the flavonoid family, has been described as a robust TrkB receptor agonist in hippocampal neurons. Nevertheless, the influence of 7,8-DHF on motoneurons, one of the main targets of BDNF in vivo, is so far unknown. Therefore, we investigated the impact of 7,8-DHF treatment on primary cultured mouse motoneurons. Indeed, we found an activation of the TrkB receptor. Moreover, 7,8-DHF application promotes survival and neurite growth of cultured motoneurons and these effects appear dose-dependent. To investigate the PI3K/AKT and MAPK pathway activation in 7,8-DHF treated motoneurons, we developed a high-density culture system of primary mouse motoneurons. Analysis of both pathways demonstrated a PI3K/AKT but not MAPK pathway activation in cultured motoneurons. This is in contrast to previously published reports about BDNF-mediated activation of TrkB. The lack of MAPK pathway activation is also in contrast to what has been found for hippocampal neurons that indeed show MAPK activation after 7,8-DHF treatment. The ability of 7,8-DHF to imitate BDNF function in motoneurons by using Trk receptor signaling would provide a new approach for the treatment of motoneuron diseases, but needs a more detailed analysis of the activation profile of 7,8-DHF.}, }
@article {pmid23497933, year = {2013}, author = {Martinez, L and Lamaze, R and Clément-Duchêne, C}, title = {[Primary lateral sclerosis and lung adenocarcinoma].}, journal = {Revue des maladies respiratoires}, volume = {30}, number = {3}, pages = {227-230}, doi = {10.1016/j.rmr.2012.12.003}, pmid = {23497933}, issn = {1776-2588}, mesh = {Adenocarcinoma/*complications/diagnostic imaging/drug therapy/secondary ; Adrenal Cortex Hormones/administration &amp; dosage ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carboplatin/administration &amp; dosage ; Causality ; Diagnosis, Differential ; Dysarthria/etiology ; Electromyography ; Fatal Outcome ; Female ; Gefitinib ; Glutamates/administration &amp; dosage ; Guanine/administration &amp; dosage/analogs &amp; derivatives ; Humans ; Lung Neoplasms/*complications/diagnostic imaging/drug therapy ; Lymphatic Metastasis ; Middle Aged ; Motor Neuron Disease/*complications/diagnosis ; Motor Neurons/physiology ; Multimodal Imaging ; Paraneoplastic Syndromes, Nervous System/diagnosis ; Pemetrexed ; Pleural Effusion, Malignant/etiology ; Positron-Emission Tomography ; Quadriplegia/etiology ; Quinazolines/administration &amp; dosage ; Tomography, X-Ray Computed ; }, abstract = {INTRODUCTION: Lung cancer is frequently associated with paraneoplastic syndromes, sometimes uncommon, among which motor neurone disease is sometimes described, including primary lateral sclerosis, a disorder characterized by slowly progressive cortico-spinal dysfunction due to the degeneration of the upper motor neurone.<br><br>CASE REPORT: We report a case of primary lateral sclerosis developing in a young woman 9 months after the diagnosis of metastatic adenocarcinoma of the lung. Our patient showed a spastic quadriparesis, dysarthria and bulbar symptoms without amyotrophy nor fasciculation. The electromyogram showed isolated upper motor neurone involvement. Cerebral and medullary imaging and CSF analysis showed no abnormality and onconeuronal antibodies were negative. The neurological symptoms and the cancer deteriorated simultaneously and our patient died 6 months after the onset of neurological symptoms.<br><br>CONCLUSION: Motor neurone involvement is rare but some case reports describe an association with neoplasia without formal confirmation of a paraneoplastic syndrome. Our case is the first report of primary lateral sclerosis in a young woman diagnosed during the treatment of lung adenocarcinoma.}, }
@article {pmid23486603, year = {2013}, author = {Mukhamedyarov, MA and Rizvanov, AA and Safiullov, ZZ and Izmailov, AA and Sharifullina, GA and Solovieva, VV and Fedotova, VY and Salafutdinov, II and Cherenkova, EE and Bashirov, FV and Kaligin, MS and Abdulkhakov, SR and Shmarov, MM and Logunov, DY and Naroditsky, BS and Kiyasov, AP and Zefirov, AL and Islamov, RR}, title = {Analysis of the efficiency of gene-cell therapy in transgenic mice with amyotrophic lateral sclerosis phenotype.}, journal = {Bulletin of experimental biology and medicine}, volume = {154}, number = {4}, pages = {558-561}, doi = {10.1007/s10517-013-1999-2}, pmid = {23486603}, issn = {1573-8221}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/*therapy ; Animals ; Cell- and Tissue-Based Therapy/methods ; Genetic Therapy/methods ; Humans ; Mice ; Mice, Transgenic ; Superoxide Dismutase/genetics/*metabolism ; Transplantation, Heterologous ; Vascular Endothelial Growth Factor A/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by progressive death of cerebral and spinal motorneurons. Using behavioral tests we studied the efficiency of gene-cell therapy in SOD1 G93A transgenic mice receiving xenotransplantation of human umbilical cord blood mononuclear cells genetically modified with adenoviral vectors encoding vascular endothelial growth factor (VEGF) and reporter green fluorescent protein (EGFP) genes. The cells were transplanted to mice on week 27 of life (preclinical stage of the disease). Behavioral tests (open field, grip strength test) showed that transplantation of umbilical cord blood mononuclear cells expressing VEGF significantly improved the parameters of motor and explorative activity, grip strength, and animal survival. Thus, gene-cell therapy based on genetically modified mononuclear cells expressing VEGF can be efficient for the treatment of amyotrophic lateral sclerosis.}, }
@article {pmid23483597, year = {2013}, author = {Pilon, AC and Carneiro, RL and Carnevale Neto, F and da S Bolzani, V and Castro-Gamboa, I}, title = {Interval multivariate curve resolution in the dereplication of HPLC-DAD data from Jatropha gossypifolia.}, journal = {Phytochemical analysis : PCA}, volume = {24}, number = {4}, pages = {401-406}, doi = {10.1002/pca.2423}, pmid = {23483597}, issn = {1099-1565}, mesh = {Chromatography, High Pressure Liquid/instrumentation/*methods ; Flavonoids/analysis/chemistry ; Glucosides/analysis/chemistry ; Glycosides/analysis/chemistry ; Jatropha/*chemistry ; Least-Squares Analysis ; *Multivariate Analysis ; Plant Extracts/analysis/chemistry ; Plants, Medicinal/chemistry ; Ultraviolet Rays ; }, abstract = {INTRODUCTION: Jatropha gossypifolia has been used quite extensively by traditional medicine for the treatment of several diseases in South America and Africa. This medicinal plant has therapeutic potential as a phytomedicine and therefore the establishment of innovative analytical methods to characterise their active components is crucial to the future development of a quality product.<br><br>OBJECTIVE: To enhance the chromatographic resolution of HPLC-UV-diode-array detector (DAD) experiments applying chemometric tools.<br><br>METHODS: Crude leave extracts from J. gossypifolia were analysed by HPLC-DAD. A chromatographic band deconvolution method was designed and applied using interval multivariate curve resolution by alternating least squares (MCR-ALS).<br><br>RESULTS: The MCR-ALS method allowed the deconvolution from up to 117% more bands, compared with the original HPLC-DAD experiments, even in regions where the UV spectra showed high similarity. The method assisted in the dereplication of three C-glycosylflavones isomers: vitexin/isovitexin, orientin/homorientin and schaftoside/isoschaftoside.<br><br>CONCLUSION: The MCR-ALS method is shown to be a powerful tool to solve problems of chromatographic band overlapping from complex mixtures such as natural crude samples.}, }
@article {pmid23475704, year = {2013}, author = {Bois, M and Singh, S and Samlalsingh, A and Lipke, PN and Garcia, MC}, title = {Does Candida albicans Als5p amyloid play a role in commensalism in Caenorhabditis elegans?.}, journal = {Eukaryotic cell}, volume = {12}, number = {5}, pages = {703-711}, pmid = {23475704}, issn = {1535-9786}, support = {R01 GM098616/GM/NIGMS NIH HHS/United States ; SC1 GM083756/GM/NIGMS NIH HHS/United States ; GM083756/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyloid/*physiology ; Animals ; Caenorhabditis elegans/cytology/*microbiology ; Candida albicans/*physiology ; Cell Adhesion ; Cell Adhesion Molecules/*biosynthesis/genetics ; Fungal Proteins/*biosynthesis/genetics ; Host-Pathogen Interactions ; Intestines/microbiology ; Oocytes/physiology ; Oogenesis ; Recombinant Proteins/biosynthesis/genetics ; Saccharomyces cerevisiae/metabolism/pathogenicity ; }, abstract = {Candida albicans, a dimorphic fungus and an opportunistic pathogen, possesses a myriad of adherence factors, including members of the agglutinin-like sequence (Als) family of mannoproteins. The adhesin Als5p mediates adhesion to many substrates and is upregulated during commensal interactions but is downregulated during active C. albicans infections. An amyloid-forming core sequence at residues 325 to 331 is important for Als5p function, because a single-amino-acid substitution at position 326 (V326N) greatly reduces Als5p-mediated adherence. We evaluated the role of Als5p in host-microbe interactions by using Caenorhabditis elegans nematodes as a host model and feeding them Saccharomyces cerevisiae expressing Als5p on the surface. Als5p-expressing yeast had 8.5- and 3.5-fold-increased intestinal accumulation rates compared to Als5p-nonexpressing S. cerevisiae or yeast expressing amyloid-deficient Als5p(V326N), respectively. Surprisingly, this accumulation delayed S. cerevisiae-induced killing of C. elegans. The median survival time was nearly twice as long as that of nematodes fed nonexpressing or non-amyloid-forming Als5p(V326N)-expressing S. cerevisiae. Treatment with the amyloid-inhibiting dye Congo red or repression of Als5p expression abrogated the protective effect of Als5p. Furthermore, Als5p had no effect on oocyte quantity or quality, since nematodes fed either empty vector (EV)- or Als5p(V326N)-expressing S. cerevisiae had similar egg-laying and egg-hatching rates. This study is the first, to our knowledge, to show that expression of an amyloid-forming protein can attenuate pathogenicity in C. elegans.}, }
@article {pmid23474331, year = {2013}, author = {Duportets, L and Maria, A and Vitecek, S and Gadenne, C and Debernard, S}, title = {Steroid hormone signaling is involved in the age-dependent behavioral response to sex pheromone in the adult male moth Agrotis ipsilon.}, journal = {General and comparative endocrinology}, volume = {186}, number = {}, pages = {58-66}, doi = {10.1016/j.ygcen.2013.02.024}, pmid = {23474331}, issn = {1095-6840}, mesh = {Aging/*physiology ; Animals ; Ecdysterone/antagonists &amp; inhibitors/*pharmacology ; Male ; Moths ; Receptors, Steroid/metabolism ; Reproduction/drug effects/physiology ; Sex Attractants/*pharmacology ; Signal Transduction/drug effects/physiology ; Triterpenes/*pharmacology ; }, abstract = {In most animals, including insects, male reproduction depends on the detection and processing of female-produced sex pheromones. In the male moth, Agrotis ipsilon, both behavioral response and neuronal sensitivity in the primary olfactory center, the antennal lobe (AL), to female sex pheromone are age- and hormone-dependent. In many animal species, steroids are known to act at the brain level to modulate the responsiveness to sexually relevant chemical cues. We aimed to address the hypothesis that the steroidal system and in particular 20-hydroxyecdysone (20E), the main insect steroid hormone, might also be involved in this olfactory plasticity. Therefore, we first cloned the nuclear ecdysteroid receptor EcR (AipsEcR) and its partner Ultraspiracle (AipsUSP) of A. ipsilon, the expression of which increased concomitantly with age in ALs. Injection of 20E into young sexually immature males led to an increase in both responsiveness to sex pheromone and amount of AipsEcR and AipsUSP in their ALs. Conversely, the behavioral response decreased in older, sexually mature males after injection of cucurbitacin B (CurB), an antagonist of the 20E/EcR/USP complex. Also, the amount of AipsEcR and AipsUSP significantly declined after treatment with CurB. These results suggest that 20E is involved in the expression of sexual behavior via the EcR/USP signaling pathway, probably acting on central pheromone processing in A. ipsilon.}, }
@article {pmid23467067, year = {2013}, author = {Hoogwerf, D and van Doorn, J and Maartense, E}, title = {The insulin-like growth factor-system in a patient with diffuse large B-cell non-Hodgkin's lymphoma and lactic acidosis.}, journal = {Annals of clinical biochemistry}, volume = {50}, number = {Pt 2}, pages = {169-172}, doi = {10.1258/acb.2012.012125}, pmid = {23467067}, issn = {1758-1001}, mesh = {Acidosis, Lactic/*complications ; Aged ; Humans ; Lymphoma, Large B-Cell, Diffuse/*blood/*complications/therapy ; Male ; Somatomedins/*metabolism ; }, abstract = {Lactic acidosis is a rare complication of haematological malignancies with a poor prognostic outcome and unclear aetiology. Possible mechanisms include high rate of glycolysis by cancer cells, in part due to over-expression of hexokinase II. The insulin-like growth factor (IGF)-system has an important role in normal as well as tumour cell growth. We present a case of a 79-year-old man with a diffuse large B-cell lymphoma and lactic acidosis. Initially, the patient was successfully treated according to the R-CHOP scheme. After recurrence of disease, the patient was treated according to a protocol of the Dutch-Belgian Haemato-Oncology Group (HOVON-85 study). Eleven months after completion of the last therapy, the patient still appeared to be in complete remission. Serum levels of IGFs, pro-IGF-IIE[68-88], IGF binding proteins (IGFBPs)-1 to -4, acid labile subunit (ALS), as well as ternary IGF-I-IGFBP-3-ALS complex formation, were determined in samples taken before, during and after treatment, respectively. Before treatment patient's serum concentration of the growth hormone-dependent parameters of the IGF-system and IGF-II were clearly reduced when compared with patient's values during remission of disease. On the other hand, during acidosis a relatively higher proportion of IGFs is present in binary complexes, instead of 150 kDa complexes, that may allow an increased access of IGFs to target cells including the malignant ones. Pretreatment serum levels of IGFBP-1 and -2 were elevated, decreased during therapy and normalized at remission. Especially IGFBP-2 seems a suitable marker for disease activity.}, }
@article {pmid23466699, year = {2013}, author = {Ringer, C and Büning, LS and Schäfer, MK and Eiden, LE and Weihe, E and Schütz, B}, title = {PACAP signaling exerts opposing effects on neuroprotection and neuroinflammation during disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {54}, number = {}, pages = {32-42}, pmid = {23466699}, issn = {1095-953X}, support = {ZIA MH002386-26/ImNIH/Intramural NIH HHS/United States ; ZIA MH002386-27/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Disease Models, Animal ; Disease Progression ; Humans ; Immunohistochemistry ; In Situ Hybridization ; Inflammation/metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Nerve Degeneration/*metabolism/pathology ; Pituitary Adenylate Cyclase-Activating Polypeptide/*metabolism ; Signal Transduction/*physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic peptide with autocrine neuroprotective and paracrine anti-inflammatory properties in various models of acute neuronal damage and neurodegenerative diseases. Therefore, we examined a possible beneficial role of endogenous PACAP in the superoxide dismutase 1, SOD1(G93A), mouse model of amyotrophic lateral sclerosis (ALS), a lethal neurodegenerative disease particularly affecting somatomotor neurons. In wild-type mice, somatomotor and visceromotor neurons in brain stem and spinal cord were found to express the PACAP specific receptor PAC1, but only visceromotor neurons expressed PACAP as a potential autocrine source of regulation of these receptors. In SOD1(G93A) mice, only a small subset of the surviving somatomotor neurons showed induction of PACAP mRNA, and somatomotor neuron degeneration was unchanged in PACAP-deficient SOD1(G93A) mice. Pre-ganglionic sympathetic visceromotor neurons were found to be resistant in SOD1(G93A) mice, while pre-ganglionic parasympathetic neurons degenerated during ALS disease progression in this mouse model. PACAP-deficient SOD1(G93A) mice showed even greater pre-ganglionic parasympathetic neuron loss compared to SOD1(G93A) mice, and additional degeneration of pre-ganglionic sympathetic neurons. Thus, constitutive expression of PACAP and PAC1 may confer neuroprotection to central visceromotor neurons in SOD1(G93A) mice via autocrine pathways. Regarding the progression of neuroinflammation, the switch from amoeboid to hypertrophic microglial phenotype observed in SOD1(G93A) mice was absent in PACAP-deficient SOD1(G93A) mice. Thus, endogenous PACAP may promote microglial cytodestructive functions thought to drive ALS disease progression. This hypothesis was consistent with prolongation of life expectancy and preserved tongue motor function in PACAP-deficient SOD1(G93A) mice, compared to SOD1(G93A) mice. Given the protective role of PACAP expression in visceromotor neurons and the opposing effect on microglial function in SOD1(G93A) mice, both PACAP agonism and antagonism may be promising therapeutic tools for ALS treatment, if stage of disease progression and targeting the specific auto- and paracrine signaling pathways are carefully considered.}, }
@article {pmid23466470, year = {2013}, author = {Greenwood, DI}, title = {Nutrition management of amyotrophic lateral sclerosis.}, journal = {Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition}, volume = {28}, number = {3}, pages = {392-399}, doi = {10.1177/0884533613476554}, pmid = {23466470}, issn = {1941-2452}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diet therapy ; Body Mass Index ; Enteral Nutrition/methods ; Gastrostomy/methods ; Humans ; Intubation, Gastrointestinal/methods ; Malnutrition/*diagnosis/diet therapy/etiology ; *Nutritional Requirements ; Nutritional Status ; Parenteral Nutrition/methods ; Quality of Life ; Vital Capacity ; Weight Loss ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease with high risk of malnutrition. Symptoms of dysphagia, depression, cognitive impairment, difficulty with self-feeding and meal preparation, hypermetabolism, anxiety, respiratory insufficiency, and fatigue with meals increase the risk of malnutrition. Malnutrition negatively affects prognosis and quality of life, making early and frequent nutrition assessment and intervention essential. Implementation of an adequate calorie diet, dietary texture modification, use of adaptive eating utensils, and placement of a feeding tube aid in preventing malnutrition. When nutrition status is compromised by dysphagia and weight loss (5%-10% of usual body weight) or body mass index <20 kg/m(2) without weight loss and when forced vital capacity is >50%, a percutaneous endoscopic gastrostomy placement is indicated. When forced vital capacity is <50%, a radiologically inserted gastrostomy is the preferred means of enteral placement due to lessened aspiration and respiratory risk. Parenteral nutrition (PN) is indicated only when enteral nutrition (EN) is contraindicated or impossible. This article reviews the background of ALS, nutrition implications and risk of malnutrition, treatment strategies to prevent malnutrition, the role of EN and PN, and feeding tube placement methods according to disease stage.}, }
@article {pmid23453347, year = {2013}, author = {,  and Morrison, KE and Dhariwal, S and Hornabrook, R and Savage, L and Burn, DJ and Khoo, TK and Kelly, J and Murphy, CL and Al-Chalabi, A and Dougherty, A and Leigh, PN and Wijesekera, L and Thornhill, M and Ellis, CM and O'Hanlon, K and Panicker, J and Pate, L and Ray, P and Wyatt, L and Young, CA and Copeland, L and Ealing, J and Hamdalla, H and Leroi, I and Murphy, C and O'Keeffe, F and Oughton, E and Partington, L and Paterson, P and Rog, D and Sathish, A and Sexton, D and Smith, J and Vanek, H and Dodds, S and Williams, TL and Steen, IN and Clarke, J and Eziefula, C and Howard, R and Orrell, R and Sidle, K and Sylvester, R and Barrett, W and Merritt, C and Talbot, K and Turner, MR and Whatley, C and Williams, C and Williams, J and Cosby, C and Hanemann, CO and Iman, I and Philips, C and Timings, L and Crawford, SE and Hewamadduma, C and Hibberd, R and Hollinger, H and McDermott, C and Mils, G and Rafiq, M and Shaw, PJ and Taylor, A and Waines, E and Walsh, T and Addison-Jones, R and Birt, J and Hare, M and Majid, T}, title = {Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial.}, journal = {The Lancet. Neurology}, volume = {12}, number = {4}, pages = {339-345}, pmid = {23453347}, issn = {1474-4465}, support = {G0701923/MRC_/Medical Research Council/United Kingdom ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; NF-SI-0512-10082/DH_/Department of Health/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/*mortality ; Double-Blind Method ; Female ; Humans ; Lithium Carbonate/therapeutic use ; Male ; Middle Aged ; Neuroprotective Agents/therapeutic use ; Survival Rate/trends ; Treatment Outcome ; }, abstract = {BACKGROUND: Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS.<br><br>METHODS: The lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31.<br><br>FINDINGS: Between May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank &#x3c7;(2) on 1 df=1&#xb7;64; p=0&#xb7;20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0&#xb7;71 (95% CI 0&#xb7;40-1&#xb7;24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event.<br><br>INTERPRETATION: We found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments.<br><br>FUNDING: The Motor Neurone Disease Association of Great Britain and Northern Ireland.}, }
@article {pmid23448465, year = {2013}, author = {Garbes, L and Riessland, M and Wirth, B}, title = {Histone acetylation as a potential therapeutic target in motor neuron degenerative diseases.}, journal = {Current pharmaceutical design}, volume = {19}, number = {28}, pages = {5093-5104}, doi = {10.2174/13816128113199990356}, pmid = {23448465}, issn = {1873-4286}, mesh = {Acetylation/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy/enzymology/metabolism ; Animals ; Bulbo-Spinal Atrophy, X-Linked/drug therapy/enzymology/metabolism ; Disease Models, Animal ; Histone Deacetylase Inhibitors/therapeutic use ; Histones/*metabolism ; Humans ; Mice ; *Molecular Targeted Therapy ; Motor Neuron Disease/*drug therapy/enzymology/metabolism ; Motor Neurons/*drug effects/enzymology/metabolism ; Muscular Atrophy, Spinal/drug therapy/enzymology/metabolism ; Nerve Tissue Proteins/*antagonists &amp; inhibitors/metabolism ; Neuroprotective Agents/*therapeutic use ; Protein Processing, Post-Translational/*drug effects ; }, abstract = {Among hereditary diseases, the group of motor neuron diseases (MNDs) includes some of the most devastating and rapidly progressive lethal conditions. Although degeneration of motor neurons is common to all of them, the phenotypic spectrum of MNDs is relatively broad and ranges from perinatal conditions like spinal muscular atrophy (SMA) to adult-onset diseases such as amyotrophic lateral sclerosis (ALS). While the understanding of the pathology of the diseases is constantly growing, the development of therapeutic approaches lags behind. In fact, there is no approved therapy for MNDs available at the moment. Recent findings demonstrated the existence of some patterns that are shared by several MNDs such as transcriptional dysregulation. In addition, conditions like SMA or certain types of Charcot-Marie-Tooth disease provide some defined targets which may be amenable to therapeutic approaches. Consequently, counteracting this dysregulation may be a valuable therapeutic option and ameliorate disease progression in MND patients. The feasibility of such an approach has been proven during the past years by the epigenetic treatment of various neoplastic entities with histone deacetylase inhibitors (HDACi). On these grounds, also epigenetic therapy of MNDs has become a promising option. So far, several HDACi have been tested in vitro and in animal models and some proceeded further and were evaluated in clinical trials. This review will summarize the advances of HDACi in MNDs and will give a perspective where the road will lead us.}, }
@article {pmid23445362, year = {2013}, author = {Zhang, Y and Benmohamed, R and Huang, H and Chen, T and Voisine, C and Morimoto, RI and Kirsch, DR and Silverman, RB}, title = {Arylazanylpyrazolone derivatives as inhibitors of mutant superoxide dismutase 1 dependent protein aggregation for the treatment of amyotrophic lateral sclerosis.}, journal = {Journal of medicinal chemistry}, volume = {56}, number = {6}, pages = {2665-2675}, pmid = {23445362}, issn = {1520-4804}, support = {R43 NS057849/NS/NINDS NIH HHS/United States ; 1R43NS057849/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Caco-2 Cells ; Humans ; Mice ; *Mutation ; Protein Multimerization/*drug effects ; Protein Structure, Quaternary ; Pyrazolones/*chemistry/pharmacokinetics/*pharmacology/therapeutic use ; Structure-Activity Relationship ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {The arylsulfanylpyrazolone and aryloxanylpyrazolone scaffolds previously were reported to inhibit Cu/Zn superoxide dismutase 1 dependent protein aggregation and to extend survival in the ALS mouse model. However, further evaluation of these compounds indicated weak pharmacokinetic properties and a relatively low maximum tolerated dose. On the basis of an ADME analysis, a new series of compounds, the arylazanylpyrazolones, has been synthesized, and structure-activity relationships were determined. The SAR results showed that the pyrazolone ring is critical to cellular protection. The NMR, IR, and computational analyses suggest that phenol-type tautomers of the pyrazolone ring are the active pharmacophore with the arylazanylpyrazolone analogues. A comparison of experimental and calculated IR spectra is shown to be a valuable method to identify the predominant tautomer.}, }
@article {pmid23441623, year = {2013}, author = {Garrido-Mesa, N and Zarzuelo, A and Gálvez, J}, title = {Minocycline: far beyond an antibiotic.}, journal = {British journal of pharmacology}, volume = {169}, number = {2}, pages = {337-352}, pmid = {23441623}, issn = {1476-5381}, mesh = {Animals ; Anti-Bacterial Agents/*pharmacology/therapeutic use ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; Apoptosis/drug effects ; Disease Models, Animal ; Humans ; Inflammation/drug therapy/pathology ; Minocycline/*pharmacology/therapeutic use ; Neurodegenerative Diseases/drug therapy/physiopathology ; Neuroprotective Agents/*pharmacology/therapeutic use ; }, abstract = {Minocycline is a second-generation, semi-synthetic tetracycline that has been in therapeutic use for over 30 years because of its antibiotic properties against both gram-positive and gram-negative bacteria. It is mainly used in the treatment of acne vulgaris and some sexually transmitted diseases. Recently, it has been reported that tetracyclines can exert a variety of biological actions that are independent of their anti-microbial activity, including anti-inflammatory and anti-apoptotic activities, and inhibition of proteolysis, angiogenesis and tumour metastasis. These findings specifically concern to minocycline as it has recently been found to have multiple non-antibiotic biological effects that are beneficial in experimental models of various diseases with an inflammatory basis, including dermatitis, periodontitis, atherosclerosis and autoimmune disorders such as rheumatoid arthritis and inflammatory bowel disease. Of note, minocycline has also emerged as the most effective tetracycline derivative at providing neuroprotection. This effect has been confirmed in experimental models of ischaemia, traumatic brain injury and neuropathic pain, and of several neurodegenerative conditions including Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, multiple sclerosis and spinal cord injury. Moreover, other pre-clinical studies have shown its ability to inhibit malignant cell growth and activation and replication of human immunodeficiency virus, and to prevent bone resorption. Considering the above-mentioned findings, this review will cover the most important topics in the pharmacology of minocycline to date, supporting its evaluation as a new therapeutic approach for many of the diseases described herein.}, }
@article {pmid23440294, year = {2013}, author = {Gordon, PH and Mehal, JM and Holman, RC and Rowland, LP and Rowland, AS and Cheek, JE}, title = {Incidence of amyotrophic lateral sclerosis among American Indians and Alaska natives.}, journal = {JAMA neurology}, volume = {70}, number = {4}, pages = {476-480}, doi = {10.1001/jamaneurol.2013.929}, pmid = {23440294}, issn = {2168-6157}, mesh = {Age Factors ; Aged ; Amyotrophic Lateral Sclerosis/*epidemiology/*ethnology ; Female ; Humans ; Incidence ; Indians, North American/*ethnology ; Inuit/*ethnology ; Male ; Middle Aged ; Motor Neuron Disease/epidemiology/ethnology ; Prevalence ; Sex Factors ; United States/epidemiology/ethnology ; United States Indian Health Service ; }, abstract = {IMPORTANCE: More thorough evaluation of amyotrophic lateral sclerosis (ALS) and motor neuron disease in unique populations could provide clues to etiologies for these idiopathic conditions, and educational programs for American Indian and Alaska Native (AI/AN) people and health care professionals on reservations could improve awareness, understanding, diagnosis, and treatment. In the ongoing search for susceptibility genes, studying particular racial groups, such as AI/ANs,might facilitate the identification of new mutations.<br><br>OBJECTIVE: To provide better understanding of ALS and secondarily of motor neuron disease among AI/AN people by estimating the incidence and prevalence among AI/ANs served by the Indian Health Service health care system.<br><br>DESIGN AND SETTING: Analysis of electronic records for AI/ANs with ALS and with motor neuron disease separately for the calendar years 2002-2009 using inpatient and outpatient visit data from the Indian Health Service, which provides health care to eligible AI/ANs nationwide.<br><br>PARTICIPANTS: Cases were defined by at least 2 inpatient or outpatient visits with the diagnosis.<br><br>MAIN OUTCOME MEASURES: Crude and age-adjusted incidence and prevalence rates were calculated.<br><br>RESULTS: Seventy-one AI/ANs were diagnosed with ALS, yielding an average annual crude incidence rate of 0.63 cases per 100 000 and an age-adjusted incidence of 0.92. The median age at onset was 56.0 years and was higher among women than men (62.0 vs 55.0 years; P=.06). Age-specific incidence increased to 70 to 74 years. The crude and age-adjusted point prevalence rates were 2.00 and 4.12, respectively. The crude and age-adjusted incidence rates for motor neuron disease were 1.08 and 1.50, respectively. The annual rates were unchanged across the study period.<br><br>CONCLUSIONS AND RELEVANCE: The incidence of ALS among AI/ANs appears to be lower than that reported for white populations, a finding congruent with reports of other minority populations. Community-based studies are important to confirm these findings and to examine reasons for the low rate of ALS among AI/ANs.}, }
@article {pmid23431306, year = {2013}, author = {Vitacca, M and Vianello, A and , }, title = {Respiratory outcomes of patients with amyotrophic lateral sclerosis: an Italian nationwide survey.}, journal = {Respiratory care}, volume = {58}, number = {9}, pages = {1433-1441}, doi = {10.4187/respcare.02236}, pmid = {23431306}, issn = {1943-3654}, mesh = {Advance Directives/statistics &amp; numerical data ; Amyotrophic Lateral Sclerosis/*epidemiology/*therapy ; Continuity of Patient Care/statistics &amp; numerical data ; Cough ; *Health Care Surveys ; Health Education/statistics &amp; numerical data ; *Hospital Units ; Humans ; Italy ; Neuromuscular Diseases/epidemiology/therapy ; Noninvasive Ventilation ; Palliative Care/statistics &amp; numerical data ; Patient Care Team ; Prognosis ; Respiratory Function Tests/statistics &amp; numerical data ; Respiratory Muscles ; Tracheostomy/statistics &amp; numerical data ; }, abstract = {BACKGROUND: Despite recommendations, respiratory therapies remain partially underutilized in patients with amyotrophic lateral sclerosis (ALS), and different practices are described in different countries. We surveyed attitudes and practice in Italy on ALS and other neuromuscular diseases (NMDs).<br><br>METHODS: A questionnaire on ALS/NMD management was mailed to 178 pneumology units, which we classified into high-volume and low-volume centers according to the number of ALS/NMD patients followed in the last 5 years.<br><br>RESULTS: Seventy-six pneumology units (43%) responded, and the responding units had 1,772 ALS patients and 1,490 NMD patients. Difficulty clearing respiratory secretions and disturbed sleep were the main reasons the ALS patients were referred to pneumology units. Vital capacity (measured in the sitting position) and arterial blood gases were measured regularly, while respiratory muscle function and cough ability were routinely assessed in over 85% of the pneumology units (mainly in high-volume centers), and 94% of pneumology units could provide noninvasive ventilation. Treatment of NMDs was similar to that of ALS, except for tracheostomy, which was less frequently performed in patients with NMDs. A multidisciplinary team approach to care was employed in approximately 90% of the responding pneumology units. Approximately a third of the units accessed palliative care services.<br><br>CONCLUSIONS: Combined pulmonary function evaluation, long-term noninvasive ventilation, and assisted cough have become usual practices for ALS patients. Italian practices for ALS did not significantly differ from the approach to other NMDs.}, }
@article {pmid23421098, year = {2012}, author = {Tkaczyk, M and Florek, E and Piekoszewski, W}, title = {[Marihuana and cannobinoids as medicaments].}, journal = {Przeglad lekarski}, volume = {69}, number = {10}, pages = {1095-1097}, pmid = {23421098}, issn = {0033-2240}, mesh = {Arthritis, Rheumatoid/drug therapy ; Cannabidiol ; Cannabinoids/*therapeutic use ; Cannabis ; Contraindications ; Dronabinol/analogs &amp; derivatives/therapeutic use ; Drug Combinations ; Humans ; Inflammatory Bowel Diseases/drug therapy ; Multiple Sclerosis/drug therapy ; Muscle Spasticity/drug therapy ; Nausea/*drug therapy ; Nervous System Diseases/*drug therapy ; Pain/drug therapy ; Plant Extracts/administration &amp; dosage ; Vomiting/drug therapy ; }, abstract = {Biological activity of cannabinoids is caused by binding to two cannabinoid receptors CB1 and CB2. Psychoactive is not only tetrahydrocannabinol (THC) but also: cannabidiol, cannabigerol or cannabichromen. Formerly, the usefulness of hemp was assessed in the relation to temporary appeasement of the symptoms of some ailments as nausea or vomiting. Present discoveries indicates that cannabis-based drugs has shown ability to alleviate of autoimmunological disorders such as: Multiple sclerosis (MS), Rheumatoid arthritis (RA) or inflammatory bowel disease. Another studies indicates that cannabinoids play role in treatment of neurological disorders like Alzheimer disease or Amyotrophic lateral sclerosis (ALS) or even can reduce spreading of tumor cells. Cannabinoids stand out high safety profile considering acute toxicity, it is low possibility of deadly overdosing and side-effects are comprise in range of tolerated side-effects of other medications. In some countries marinol and nabilone are used as anti vomiting and nausea drug. First cannabis-based drug containg naturally occurring cannabinoids is Sativex. Sativex is delivered in an mucosal spray for patients suffering from spasticity in MS, pain relevant with cancer and neuropathic pain of various origin. Despite the relatively low acute toxicity of cannabinoids they should be avoid in patients with psychotic disorders, pregnant or breastfeeding woman. Cannabinoids prolong a time of reaction and decrease power of concentration that's why driving any vehicles is forbidden. Cannabis side-effects varies and depend from several factors like administrated dose, rout of administration and present state of mind. After sudden break from long-lasting use, withdrawal symptoms can appear, although they entirely disappear after a week or two.}, }
@article {pmid23415312, year = {2013}, author = {Ash, PE and Bieniek, KF and Gendron, TF and Caulfield, T and Lin, WL and Dejesus-Hernandez, M and van Blitterswijk, MM and Jansen-West, K and Paul, JW and Rademakers, R and Boylan, KB and Dickson, DW and Petrucelli, L}, title = {Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS.}, journal = {Neuron}, volume = {77}, number = {4}, pages = {639-646}, pmid = {23415312}, issn = {1097-4199}, support = {R21 NS074121-01/NS/NINDS NIH HHS/United States ; P50 NS72187/NS/NINDS NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; R21 NS074121/NS/NINDS NIH HHS/United States ; R01 NS063964/NS/NINDS NIH HHS/United States ; P50 NS072187/NS/NINDS NIH HHS/United States ; R01 ES20395/ES/NIEHS NIH HHS/United States ; R01 ES020395/ES/NIEHS NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; R01 NS080882/NS/NINDS NIH HHS/United States ; R01 AG026251/AG/NIA NIH HHS/United States ; R01 NS077402/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Chromosomes, Human, Pair 9/*metabolism ; DNA Repeat Expansion/*genetics ; Frontotemporal Dementia/*genetics ; Gene Expression/genetics ; Genotype ; Humans ; Peptides/*genetics ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders with clinical, genetic, and neuropathological overlap. Hexanucleotide (GGGGCC) repeat expansions in a noncoding region of C9ORF72 are the major genetic cause of FTD and ALS (c9FTD/ALS). The RNA structure of GGGGCC repeats renders these transcripts susceptible to an unconventional mechanism of translation-repeat-associated non-ATG (RAN) translation. Antibodies generated against putative GGGGCC repeat RAN-translated peptides (anti-C9RANT) detected high molecular weight, insoluble material in brain homogenates, and neuronal inclusions throughout the CNS of c9FTD/ALS cases. C9RANT immunoreactivity was not found in other neurodegenerative diseases, including CAG repeat disorders, or in peripheral tissues of c9FTD/ALS. The specificity of C9RANT for c9FTD/ALS is a potential biomarker for this most common cause of FTD and ALS. These findings have significant implications for treatment strategies directed at RAN-translated peptides and their aggregation and the RNA structures necessary for their production.}, }
@article {pmid23407618, year = {2013}, author = {Finsterer, J and Stöllberger, C}, title = {Apply Awaji-shima Consensus Conference Criteria Before Diagnosing Amyotrophic Lateral Sclerosis.}, journal = {The open neurology journal}, volume = {7}, number = {}, pages = {4-6}, pmid = {23407618}, issn = {1874-205X}, abstract = {OBJECTIVES: ALS may be diagnosed although affection of other organs suggests another pathogenetic back-ground.<br><br>CASE REPORT: In a 72yo non-smoking male progressive gait disturbance with recurrent falls since 2y was initially attributed to axonal polyneuropathy. Additionally, he had arterial hypertension, diabetes, hyperlipidemia, hyperuricemia, hyper-CK-emia, hepatopathy, atrial fibrillation, recurrent heart-failure, pulmonary hypertension, mitral insufficiency, and restrictive cardiomyopathy. Possible causes of polyneuropathy were diabetes, long-standing alcoholism, folate-deficiency, or hereditary disease. Later the patient was re-diagnosed as ALS despite absence of upper motor-neuron or bulbar signs, the presence of multiple risk factors for polyneuropathy, of stocking-type sensory disturbances, and of cardiac abnormalities, which could explain dyspnea. Misdiagnosing polyneuropathy as ALS stigmatized the patient and prevented him from further diagnostic work-up for cardiac disease and adequate treatment for heart-failure. Though the diagnosis of ALS was withdrawn, he was put on comfort care and opiates were given when dyspnea acutely deteriorated to death without further cardiac or pulmonary investigations or specific cardiac treatment.<br><br>CONCLUSIONS: ALS should be diagnosed only if the Awaji-shima criteria are fulfilled and if all differential diagnoses were profoundly excluded. Respiratory insufficiency should not be attributed to bulbar involvement in ALS as long as cardiac, pulmonary, or myopathic causes were excluded.}, }
@article {pmid23401502, year = {2013}, author = {Wu, WF and Tan, XJ and Dai, YB and Krishnan, V and Warner, M and Gustafsson, J&#xc5;}, title = {Targeting estrogen receptor β in microglia and T cells to treat experimental autoimmune encephalomyelitis.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {110}, number = {9}, pages = {3543-3548}, pmid = {23401502}, issn = {1091-6490}, mesh = {Animals ; Benzopyrans/pharmacology/*therapeutic use ; Down-Regulation/drug effects ; Encephalomyelitis, Autoimmune, Experimental/*drug therapy/enzymology/*immunology/pathology ; Estrogen Receptor alpha/metabolism ; Estrogen Receptor beta/*metabolism ; Female ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; Mice ; Microglia/drug effects/*metabolism/pathology ; *Molecular Targeted Therapy ; NF-kappa B/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Spinal Cord/drug effects/enzymology/pathology ; T-Lymphocytes/drug effects/*metabolism/pathology ; }, abstract = {A therapeutic goal in the treatment of certain CNS diseases, including multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson disease, is to down-regulate inflammatory pathways. Inflammatory molecules produced by microglia are responsible for removal of damaged neurons, but can cause collateral damage to normal neurons located close to defective neurons. Although estrogen can inactivate microglia and inhibit the recruitment of T cells and macrophages into the CNS, there is controversy regarding which of the two estrogen receptors (ERs), ERα or ERβ, mediates the beneficial effects in microglia. In this study, we found that ERβ, but not ERα, is expressed in microglia. Using the experimental autoimmune encephalomyelitis (EAE) model in SJL/J mice, we evaluated the benefit of an ERβ agonist as a modulator of neuroinflammation. Treatment of EAE mice with LY3201, a selective ERβ agonist provided by Eli Lilly, resulted in marked reduction of activated microglia in the spinal cord. LY3201 down-regulated the nuclear transcription factor NF-κB, as well as the NF-κB-induced gene inducible nitric oxide synthase in microglia and CD3(+) T cells. In addition, LY3201 inhibited T-cell reactivity through regulation of indoleamine-2,3-dioxygenase. In the EAE model, treatment with LY3201 decreased mortality in the first 2 wk after disease onset, and also reduced the severity of symptoms in mice surviving for 4 wk. Our data show that ERβ-selective agonists, by modulating the immune system in both microglia and T cells, offer promise as a useful class of drugs for treating degenerative diseases of the CNS.}, }
@article {pmid23393972, year = {2012}, author = {Khataee, AR and Naseri, A and Zarei, M and Safarpour, M and Moradkhannejhad, L}, title = {Chemometrics approach for determination and optimization of simultaneous photooxidative decolourization of a mixture of three textile dyes.}, journal = {Environmental technology}, volume = {33}, number = {19-21}, pages = {2305-2317}, doi = {10.1080/09593330.2012.665495}, pmid = {23393972}, issn = {0959-3330}, mesh = {Analysis of Variance ; Coloring Agents/analysis/*chemistry ; *Photochemical Processes ; Spectrophotometry, Ultraviolet ; Textile Industry ; Water Pollutants, Chemical/*analysis ; }, abstract = {In this paper simultaneous photooxidation of three textile dyes (CI Basic Red 46 (BR46), Malachite Green (MG) and CI Basic Blue 3 (BB3)) by UV/H2O2 process is reported. A rapid analytical methodology based on recording UV-Vis spectra during the photooxidative decolourization process and the data treatment using multivariate curve resolution with alternating least squares (MCR-ALS) was developed. The three textile dyes were quantified simultaneously despite the overlap of their spectra. Also, the central composite design was applied for optimization of the photooxidative decolourization of the solution containing three dyes using the UV/H2O2 process. The investigated factors (variables) were the reaction time, initial concentration of the three dyes and initial concentration of H2O2. The optimum initial concentration of the three dyes, H2O2 initial concentration and reaction time were found to be 4 mg/L, 48 mg/L and 30 min, respectively. The photodegradation products of three dyes were identified by the GC-MS technique.}, }
@article {pmid23393146, year = {2013}, author = {Malik, B and Nirmalananthan, N and Gray, AL and La Spada, AR and Hanna, MG and Greensmith, L}, title = {Co-induction of the heat shock response ameliorates disease progression in a mouse model of human spinal and bulbar muscular atrophy: implications for therapy.}, journal = {Brain : a journal of neurology}, volume = {136}, number = {Pt 3}, pages = {926-943}, pmid = {23393146}, issn = {1460-2156}, support = {G0601943/MRC_/Medical Research Council/United Kingdom ; MR/K000608/1/MRC_/Medical Research Council/United Kingdom ; R01 NS041648/NS/NINDS NIH HHS/United States ; R01 NS41648/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Blotting, Western ; Disease Models, Animal ; Disease Progression ; Heat-Shock Proteins/*metabolism ; Heat-Shock Response/*drug effects/physiology ; Hydroxylamines/*pharmacology ; Male ; Mice ; Muscular Disorders, Atrophic/*metabolism ; Neuroprotective Agents/*pharmacology ; Real-Time Polymerase Chain Reaction ; }, abstract = {Spinal and bulbar muscular atrophy, also known as Kennedy's disease, is an adult-onset hereditary neurodegenerative disorder caused by an expansion of the polyglutamine repeat in the first exon in the androgen receptor gene. Pathologically, the disease is defined by selective loss of spinal and bulbar motor neurons causing bulbar, facial and limb weakness. Although the precise disease pathophysiology is largely unknown, it appears to be related to abnormal accumulation of the pathogenic androgen receptor protein within the nucleus, leading to disruption of cellular processes. Using a mouse model of spinal and bulbar muscular atrophy that exhibits many of the characteristic features of the human disease, in vivo physiological assessment of muscle function revealed that mice with the pathogenic expansion of the androgen receptor develop a motor deficit characterized by a reduction in muscle force, abnormal muscle contractile characteristics, loss of functional motor units and motor neuron degeneration. We have previously shown that treatment with arimoclomol, a co-inducer of the heat shock stress response, delays disease progression in the mutant superoxide dismutase 1 mouse model of amyotrophic lateral sclerosis, a fatal motor neuron disease. We therefore evaluated the therapeutic potential of arimoclomol in mice with spinal and bulbar muscular atrophy. Arimoclomol was administered orally, in drinking water, from symptom onset and the effects established at 18 months of age, a late stage of disease. Arimoclomol significantly improved hindlimb muscle force and contractile characteristics, rescued motor units and, importantly, improved motor neuron survival and upregulated the expression of the vascular endothelial growth factor which possess neurotrophic activity. These results provide evidence that upregulation of the heat shock response by treatment with arimoclomol may have therapeutic potential in the treatment of spinal and bulbar muscular atrophy and may also be a possible approach for the treatment of other neurodegenerative diseases.}, }
@article {pmid23384285, year = {2013}, author = {Kim, SU and Lee, HJ and Kim, YB}, title = {Neural stem cell-based treatment for neurodegenerative diseases.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {33}, number = {5}, pages = {491-504}, doi = {10.1111/neup.12020}, pmid = {23384285}, issn = {1440-1789}, mesh = {Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Animals ; Cell- and Tissue-Based Therapy ; Humans ; Huntington Disease/therapy ; Neural Stem Cells/*transplantation ; Neurodegenerative Diseases/*therapy ; Parkinson Disease/therapy ; Stem Cell Transplantation ; }, abstract = {Human neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) are caused by a loss of neurons and glia in the brain or spinal cord. Neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs) and neural stem cells (NSCs), and stem cell-based cell therapies for neurodegenerative diseases have been developed. A recent advance in generation of a new class of pluripotent stem cells, induced pluripotent stem cells (iPSCs), derived from patients' own skin fibroblasts, opens doors for a totally new field of personalized medicine. Transplantation of NSCs, neurons or glia generated from stem cells in animal models of neurodegenerative diseases, including PD, HD, ALS and AD, demonstrates clinical improvement and also life extension of these animals. Additional therapeutic benefits in these animals can be provided by stem cell-mediated gene transfer of therapeutic genes such as neurotrophic factors and enzymes. Although further research is still needed, cell and gene therapy based on stem cells, particularly using neurons and glia derived from iPSCs, ESCs or NSCs, will become a routine treatment for patients suffering from neurodegenerative diseases and also stroke and spinal cord injury.}, }
@article {pmid23383387, year = {2012}, author = {Kolarcik, CL and Bowser, R}, title = {Retinoid signaling alterations in amyotrophic lateral sclerosis.}, journal = {American journal of neurodegenerative disease}, volume = {1}, number = {2}, pages = {130-145}, pmid = {23383387}, issn = {2165-591X}, support = {R01 NS061867/NS/NINDS NIH HHS/United States ; R56 NS061867/NS/NINDS NIH HHS/United States ; T32 EB001026/EB/NIBIB NIH HHS/United States ; TL1 RR024155/RR/NCRR NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease for which effective therapeutic interventions and an understanding of underlying disease mechanism are lacking. A variety of biochemical pathways are believed to contribute to the pathophysiology of ALS that are common to both sporadic and familial forms of the disease. Evidence from both human and animal studies indicates that expression of retinoid signaling genes is altered in ALS and may contribute to motor neuron loss. Our goals were to examine the expression and distribution of proteins of the retinoid signaling pathway in spinal cord samples from patients with sporadic and familial ALS and to evaluate the role of these proteins in motor neuron cell survival. In sporadic ALS, the cytoplasmic binding protein that facilitates nuclear translocation of retinoic acid, cellular retinoic acid binding protein-II (CRABP-II), was localized to the nucleus and retinoic acid receptor β (RARβ) was significantly increased in motor neuron nuclei when compared to either familial ALS patients or non-neurologic disease controls. Motor neurons with increased nuclear RARβ were negative for markers of apoptosis. Pre-treatment of primary motor neuron-enriched cultures with a pan-RAR or RARβ-specific agonist decreased motor neuron cell death associated with oxidative injury/stress while a RARβ-specific antagonist enhanced cell death. Our data suggest retinoid signaling is altered in ALS and increased nuclear RARβ occurs in motor neurons of sporadic ALS patients. Activation of RARβ protects motor neurons from oxidative-induced cell death.}, }
@article {pmid23373475, year = {2013}, author = {Georgoulopoulou, E and Fini, N and Vinceti, M and Monelli, M and Vacondio, P and Bianconi, G and Sola, P and Nichelli, P and Mandrioli, J}, title = {The impact of clinical factors, riluzole and therapeutic interventions on ALS survival: a population based study in Modena, Italy.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {5-6}, pages = {338-345}, doi = {10.3109/21678421.2013.763281}, pmid = {23373475}, issn = {2167-9223}, mesh = {Age Factors ; Aged ; Amyotrophic Lateral Sclerosis/classification/mortality/*therapy ; Cohort Studies ; *Enteral Nutrition ; Excitatory Amino Acid Antagonists/*therapeutic use ; Female ; Humans ; Italy ; Kaplan-Meier Estimate ; Male ; Middle Aged ; *Noninvasive Ventilation ; Prognosis ; Proportional Hazards Models ; Prospective Studies ; Riluzole/*therapeutic use ; Sex Factors ; Tracheostomy ; Treatment Outcome ; }, abstract = {The prognostic role of riluzole, enteral nutrition (EN), non-invasive ventilation (NIV) and interdisciplinary care in ALS is still debated. A population based study has been performed focusing on ALS survival, with particular attention to prognostic factors and therapeutic intervention. All patients diagnosed with ALS between 2000 and 2009 and residing in Modena, Italy, have been registered. A centre for motor neuron disease (MND) has been active in our province since 2000, in addition to a prospective registry collecting all incident cases. One hundred and ninety-three incident cases have been collected during the 10 years of the study. Results demonstrated that median survival was 41 months (the overall three-year and five-year survival rates being 54.36% and 28.81%, respectively). Based on univariate analysis, factors related to survival were: age at diagnosis, gender, site of onset, phenotype, riluzole treatment and tracheostomy. In the Cox multivariable model, the factors independently related to a longer survival were age (p < 0.01), site of onset (p = 0.02) and riluzole treatment (p < 0.01), with a median gain in survival of 29 months (patients aged < 55 years compared with patients ≥ 55 years), 20 months (spinal versus bulbar onset), and 12 months (riluzole, yes vs. no), respectively. In conclusion, the study has confirmed the prognostic role of clinical features, but has surprisingly demonstrated that riluzole prolonged life significantly longer than NIV and EN. This observational study described the effects of ALS management in a setting that may approximate routine clinical practice more closely than randomized controlled trial (RCT); effects of uncontrolled potential confounders, however, cannot be excluded.}, }
@article {pmid23373317, year = {2012}, author = {Aoki, M}, title = {[Restorative therapy in amyotrophic lateral sclerosis].}, journal = {Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology}, volume = {32}, number = {5-6}, pages = {287-292}, pmid = {23373317}, issn = {1340-2544}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Animals ; Disease Models, Animal ; Disease Progression ; Hepatocyte Growth Factor/administration &amp; dosage/therapeutic use ; Humans ; Motor Neurons/cytology/metabolism ; Spinal Cord/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. About 10% of all ALS cases are familial; approximately 20% of familial ALS cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene. We developed rats that express a human SOD1 transgene with ALS-associated mutations, developing striking motor neuron degeneration and paralysis. The larger size of this rat model as compared with the ALS mice, will facilitate studies involving manipulations of spinal fluid and the spinal cord. Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. We administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to the transgenic rats at the onset of paralysis for 4 weeks. Intrathecal administration of hrHGF attenuated motor neuron degeneration and prolonged the duration of the disease by 63%. To translate this strategy to human treatment, we induced a contusive cervical spinal cord injury in the common marmoset, a primate, and then administered hrHGF intrathecally. The intrathecal administration of hrHGF promoted functional recovery. These results prompted further clinical trials in ALS using continuous intrathecal administration of hrHGF.}, }
@article {pmid25568837, year = {2013}, author = {Zhang, M and Hubbard, J and Rudnicki, SA and Johansen, CS and Dalton, K and Heiman-Patterson, T and Forshew, DA and Wills, AM}, title = {Survey of current enteral nutrition practices in treatment of amyotrophic lateral sclerosis.}, journal = {e-SPEN journal}, volume = {8}, number = {1}, pages = {e25-e28}, pmid = {25568837}, issn = {2212-8263}, support = {UL1 RR025758/RR/NCRR NIH HHS/United States ; }, abstract = {BACKGROUND AND AIMS: Enteral nutrition (EN) is commonly prescribed for dysphagia and weight loss in amyotrophic lateral sclerosis (ALS), but there are currently no ALS-specific EN guidelines. We aimed to survey current practices prescribing EN to ALS patients.<br><br>METHODS: An online survey was distributed using list servers administered by the Academy of Nutrition and Dietetics (AND), Muscular Dystrophy Association (MDA), and ALS Association (ALSA).<br><br>RESULTS: A total of 148 dietitians, nurses, and physicians participated in the survey, of whom 50% were dietitians and 68% were associated with an ALS clinic. Only 47% of respondents reported their patients to be fully compliant with EN recommendations. Side effects (fullness, diarrhea, constipation, and bloating) were the most important reason for patient noncompliance, followed by dependence on caregivers. By contrast, only 3% of providers rated depression/hopelessness as the most important reason for noncompliance. Half of those surveyed reported that more than 25% of patients continued to lose weight after starting EN.<br><br>CONCLUSIONS: Our survey results show a high frequency of gastrointestinal side effects and weight loss in ALS patients receiving EN. These findings may be limited by sampling error and non-response bias. Prospective studies are needed to help establish EN guidelines for ALS.}, }
@article {pmid23364049, year = {2013}, author = {Taes, I and Timmers, M and Hersmus, N and Bento-Abreu, A and Van Den Bosch, L and Van Damme, P and Auwerx, J and Robberecht, W}, title = {Hdac6 deletion delays disease progression in the SOD1G93A mouse model of ALS.}, journal = {Human molecular genetics}, volume = {22}, number = {9}, pages = {1783-1790}, doi = {10.1093/hmg/ddt028}, pmid = {23364049}, issn = {1460-2083}, support = {231138/ERC_/European Research Council/International ; }, mesh = {Acetylation ; Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Axonal Transport/genetics ; Axons/pathology ; Disease Models, Animal ; Disease Progression ; Female ; *Gene Deletion ; Histone Deacetylase 6 ; Histone Deacetylases/*genetics/metabolism ; Male ; Mice ; Mice, Transgenic ; Sirtuin 2/*genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Tubulin/metabolism ; }, abstract = {Defects in axonal transport are thought to contribute to the pathogenesis of neurodegenerative disease. Because α-tubulin acetylation facilitates axonal transport, inhibition of the α-tubulin deacetylating enzymes, histone deacetylase 6 (Hdac6) and silent information regulator 2 (Sirt2), is thought to be an interesting therapeutic strategy for these conditions. Amyotrophic lateral sclerosis (ALS) is a one such rapidly progressive and fatal neurodegenerative disorder, in which axonal transport defects have been found in vitro and in vivo. To establish whether the inhibition of Hdac6 or Sirt2 may be of interest for ALS treatment, we investigated whether deleting Hdac6 or Sirt2 from the superoxide dismutase 1, SOD1(G93A) mouse affects the motor neuron degeneration in this ALS model. Deletion of Hdac6 significantly extended the survival of SOD1(G93A) mice without affecting disease onset, and maintained motor axon integrity. This protective effect was associated with increased α-tubulin acetylation. Deletion of Sirt2 failed to affect the disease course, but also did not modify α-tubulin acetylation. These findings show that Hdac6, rather than Sirt2, is a therapeutic target for the treatment of ALS. Moreover, Sirt2 appears not to be a major α-tubulin deacetylase in the nervous system.}, }
@article {pmid23358745, year = {2013}, author = {Cuhls, H and Radbruch, L and Brunsch-Radbruch, A and Schmidt-Wolf, G and Rolke, R}, title = {[Pain management in palliative care. Current aspects of medicinal therapy].}, journal = {Der Internist}, volume = {54}, number = {2}, pages = {254, 256-62}, pmid = {23358745}, issn = {1432-1289}, mesh = {Analgesics, Opioid/*therapeutic use ; Humans ; Pain Management/*methods/*trends ; Pain Measurement/*methods/*trends ; Palliative Care/*methods/*trends ; }, abstract = {Palliative care patients do not only suffer from cancer pain but also from painful muscle spasticity due to multiple sclerosis, amyotrophic lateral sclerosis, after stroke or due to dementia if damage of the pyramidal motor system is present. Centrally active muscle relaxants can be helpful also when used as coanalgesics for cancer pain. In addition to opioids other coanalgesics, such as tricyclic antidepressants or serotonin/noradrenalin reuptake inhibitors as well as anticonvulsants (sodium channel and calcium channel blockers) can be helpful if neuropathic cancer pain is present. Idiopathic Parkinsonism or multiple system atrophy leads more to a painful rigor and pain control should be supported here by optimal adjustment of L-DOPA or DOPA agonist therapy. However, pain treatment should always address the psychological, social and spiritual demands of the patient.}, }
@article {pmid23345638, year = {2013}, author = {Restivo, DA and Casabona, A and Nicotra, A and Zappia, M and Elia, M and Romano, MC and Alfonsi, E and Marchese-Ragona, R}, title = {ALS dysphagia pathophysiology: differential botulinum toxin response.}, journal = {Neurology}, volume = {80}, number = {7}, pages = {616-620}, doi = {10.1212/WNL.0b013e318281cc1b}, pmid = {23345638}, issn = {1526-632X}, mesh = {Age Factors ; Aged ; Amyotrophic Lateral Sclerosis/*complications ; Botulinum Toxins, Type A/*therapeutic use ; Deglutition Disorders/*drug therapy/*etiology ; Electromyography ; Esophageal Sphincter, Upper/drug effects/physiopathology ; Female ; Fluoroscopy ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Neuromuscular Agents/*therapeutic use ; Pharyngeal Muscles/drug effects/physiopathology ; Severity of Illness Index ; Statistics, Nonparametric ; Video Recording ; }, abstract = {OBJECTIVES: This study looked at the effect of botulinum toxin type A (BoTox-A) in patients with amyotrophic lateral sclerosis (ALS) with dysphagia due to isolated upper motor neuron (UMN) involvement or combined UMN/lower motor neuron (LMN) impairment associated with oral phase or oropharyngeal muscles involvement. Establishing whether different pathophysiologic mechanisms underlie different responses to BoTox-A treatment may have important implications for patient management.<br><br>PATIENTS AND METHODS: We screened 35 patients with sporadic ALS with dysphagia and included in the study 20 out of 35 with upper esophageal sphincter (UES) hyperactivity. We divided these 20 patients into 2 groups, based on the presence or absence of LMN impairment. Irrespective of the groups, we treated all 20 patients with BoTox-A injected into the UES. The study outcome was dysphagia severity scored using the Penetration/Aspiration Scale (PAS), measured before and 2, 4, and 20 weeks after injection.<br><br>RESULTS: Significant mean PAS reduction was noted at weeks 2 and 4. The botulinum-dependent PAS reduction was entirely associated with the variability shown by the group of patients with no sign of LMN impairment (group 2) and was not observed in group 1.<br><br>CONCLUSIONS: The significant improvement observed in patients with isolated UES dysfunction suggests that a different pathophysiology of ALS dysphagia predisposes patients to a different response to treatment with BoTox-A. This treatment may represent an alternative treatment to percutaneous endoscopic gastrostomy (PEG) or prolong PEG-free time.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that botulinum is more effective at 2 and 4 weeks in improving dysphagia in patients with ALS with UES hyperactivity without LMN involvement (vs those with LMN involvement).}, }
@article {pmid23345247, year = {2013}, author = {Armstrong, GA and Drapeau, P}, title = {Calcium channel agonists protect against neuromuscular dysfunction in a genetic model of TDP-43 mutation in ALS.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {33}, number = {4}, pages = {1741-1752}, pmid = {23345247}, issn = {1529-2401}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology/*physiopathology ; Animals ; Calcium Channel Agonists/*pharmacology ; DNA-Binding Proteins/genetics ; Disease Models, Animal ; Humans ; Immunohistochemistry ; Motor Activity/physiology ; Mutation ; Neuromuscular Junction/drug effects/*pathology ; Patch-Clamp Techniques ; Zebrafish ; }, abstract = {TAR DNA binding protein (TDP-43, encoded by the TARDBP gene) has recently been shown to be associated with amyotrophic lateral sclerosis (ALS), but the early pathophysiological deficits causing impairment in motor function are unknown. Here we expressed the wild-type human gene (wtTARDBP) or the ALS mutation G348C (mutTARDBP) in zebrafish larvae and characterized their motor (swimming) activity and the structure and function of their neuromuscular junctions (NMJs). Of these groups only mutTARDBP larvae showed impaired swimming and increased motoneuron vulnerability with reduced synaptic fidelity, reduced quantal transmission, and more orphaned presynaptic and postsynaptic structures at the NMJ. Remarkably, all behavioral and cellular features were stabilized by chronic treatment with either of the L-type calcium channel agonists FPL 64176 or Bay K 8644. These results indicate that expression of mutTARDBP results in defective NMJs and that calcium channel agonists could be novel therapeutics for ALS.}, }
@article {pmid23323713, year = {2013}, author = {Berry, JD and Miller, R and Moore, DH and Cudkowicz, ME and van den Berg, LH and Kerr, DA and Dong, Y and Ingersoll, EW and Archibald, D}, title = {The Combined Assessment of Function and Survival (CAFS): a new endpoint for ALS clinical trials.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {3}, pages = {162-168}, doi = {10.3109/21678421.2012.762930}, pmid = {23323713}, issn = {2167-9223}, mesh = {*Activities of Daily Living/psychology ; Amyotrophic Lateral Sclerosis/mortality/psychology/*therapy ; Clinical Trials as Topic/methods/standards ; Clinical Trials, Phase II as Topic/methods/standards ; Clinical Trials, Phase III as Topic/methods/standards ; Endpoint Determination/methods/*standards ; Humans ; Outcome Assessment, Health Care/methods/*standards ; *Recovery of Function/physiology ; Survival Rate/trends ; }, abstract = {Our objective was to describe a new endpoint for amyotrophic lateral sclerosis (ALS), the Combined Assessment of Function and Survival (CAFS). CAFS ranks patients' clinical outcomes based on survival time and change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. Each patient's outcome is compared to every other patient's outcome, assigned a score, and the summed scores are ranked. The mean rank score for each treatment group can then be calculated. A higher mean CAFS score indicates a better group outcome. Historically, ALS clinical trials have assessed survival and function as independent endpoints. Combined endpoints have been used in other diseases to decrease the confounding effect of mortality on analysis of functional outcomes. We explored the application of a similar approach in ALS, the CAFS endpoint, which was used as a pre-specified secondary analysis in a phase II study of dexpramipexole. Those results and some hypothetical examples based on modeling exercises are presented here. CAFS is the primary endpoint of a dexpramipexole phase III study in ALS. In conclusion, the CAFS is a robust statistical tool for ALS clinical trials and appropriately accounts for and weights mortality in the analysis of function.}, }
@article {pmid23323138, year = {2012}, author = {Bae, JS and Hong, YH and Baek, W and Sohn, EH and Cho, JY and Kim, BJ and Kim, SH and , }, title = {Current status of the diagnosis and management of amyotrophic lateral sclerosis in Korea: a multi-center cross-sectional study.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {8}, number = {4}, pages = {293-300}, pmid = {23323138}, issn = {1738-6586}, abstract = {BACKGROUND AND PURPOSE: Recently published, evidence-based guidelines should alter the management of amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). However, the newest recommendations for ALS/MND therapy are not reflected in actual clinical practice. We sought to evaluate the current status of the diagnosis and management of ALS in Korea.<br><br>METHODS: The Korean ALS/MND research group was organized in 2010, involving more than 50 neurologists from neuromuscular centers in Korea. Participating centers collected data from April to September 2010 on the diagnosis and management of patients with ALS. Data forms from the ALS patient care database, which is a component of the ALS clinical assessment, research, and education program (http://www.outcomes-umassmed.org/ALS/), were modified and used for data collection.<br><br>RESULTS: In total, 373 sporadic ALS cases from 35 centers were enrolled. The demographic features and clinical findings were similar to those in previous reports from other countries. The mean age at onset was 50-60 years, and a slight male predominance was observed. The enrolled patients predominantly showed focal onset of cervical or lumbosacral symptoms. Only about one-half of the indicated patients (31.4%) received a physician's recommendation for a parenteral gastrostomy, and 18.1% underwent the procedure. Noninvasive ventilation was recommended in 23% of patients, but applied in only 9.5% of them. Tracheostomy was performed in 12.7% of patients.<br><br>CONCLUSIONS: The demographic and clinical features of the diagnosis and management of ALS in Korea are similar to those reported in other countries; however, supportive management, as recommended in evidence-based guidelines, are not yet widely recommended or performed for patients with ALS in Korea.}, }
@article {pmid23321002, year = {2013}, author = {Tokuda, E and Okawa, E and Watanabe, S and Ono, S and Marklund, SL}, title = {Dysregulation of intracellular copper homeostasis is common to transgenic mice expressing human mutant superoxide dismutase-1s regardless of their copper-binding abilities.}, journal = {Neurobiology of disease}, volume = {54}, number = {}, pages = {308-319}, doi = {10.1016/j.nbd.2013.01.001}, pmid = {23321002}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Chelating Agents/pharmacology ; Copper/*metabolism ; Disease Models, Animal ; Homeostasis ; Humans ; Mice ; Mice, Transgenic ; Molybdenum/pharmacology ; Motor Neurons/drug effects/metabolism/pathology ; Mutation ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Over 170 mutations in superoxide dismutase-1 (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). The properties of SOD1 mutants differ considerably including copper-binding abilities. Nevertheless, they cause the same disease phenotype, suggesting a common neurotoxic pathway. We have previously reported that copper homeostasis is disturbed in spinal cords of SOD1(G93A) mice. However, it is unknown whether copper dyshomeostasis is induced by other SOD1 mutants. Using the additional mouse strains SOD1(G127insTGGG), SOD1(G85R), and SOD1(D90A), which express SOD1 mutants with different copper-binding abilities, we show that copper dyshomeostasis is common to SOD1 mutants. The SOD1 mutants shifted the copper trafficking systems toward copper accumulation in spinal cords of the mice. Copper contents bound to the SOD1 active site varied considerably between SOD1 mutants. Still, copper bound to other ligands in the spinal cord were markedly increased in all. Zinc was also increased, whereas there were no changes in magnesium, calcium, aluminum, manganese and iron. Further support for a role of copper dyshomeostasis in ALS was gained from results of pharmacological intervention. Ammonium tetrathiomolybdate (TTM), a copper chelating agent, prolonged survival and slowed the disease progression of SOD1(G93A) mice, even when the treatment was started after the disease onset. TTM markedly attenuated pathology, including the loss of motor neurons and axons, and atrophy of skeletal muscles. Additionally, TTM decreased amounts of SOD1 aggregates. We propose that pharmacological agents that are capable of modulating copper dyshomeostasis, such as TTM, might be beneficial for the treatment of ALS caused by SOD1 mutations.}, }
@article {pmid23312666, year = {2013}, author = {Simmons, Z}, title = {Rehabilitation of motor neuron disease.}, journal = {Handbook of clinical neurology}, volume = {110}, number = {}, pages = {483-498}, doi = {10.1016/B978-0-444-52901-5.00041-1}, pmid = {23312666}, issn = {0072-9752}, mesh = {Humans ; Mental Health ; Motor Neuron Disease/psychology/*rehabilitation ; *Physical Therapy Modalities ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS), the most common adult motor neuron disease, is an acquired disorder that results in loss of function in multiple domains. Although there is no treatment that can halt or reverse this progressive condition, there are many opportunities for interventions that can lead to improved quality of life for the patient and caregiver. Physical and occupational therapy can assist with mobility and activities of daily living. Interventions by speech pathology can optimize nutrition and communication. Respiratory function can be managed noninvasively or invasively. Depression, hopelessness, anxiety, and other mental health issues can and should be aggressively addressed and treated. Many symptoms such as pseudobulbar affect, sialorrhea, constipation, spasticity, and cramps can be treated effectively with medications. Spirituality and religion are important issues to address, as are end-of-life concerns, including advance directives, hospice, and the dying process. In contrast to the discouraging view that "there is nothing we can do," a broad approach to management, through collaboration with a multidisciplinary team, will permit the ALS physician to make a meaningful difference in the lives of individuals living with ALS.}, }
@article {pmid23306556, year = {2013}, author = {Behan, AT and Breen, B and Hogg, M and Woods, I and Coughlan, K and Mitchem, M and Prehn, JH}, title = {Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration.}, journal = {Cell death and differentiation}, volume = {20}, number = {4}, pages = {589-598}, pmid = {23306556}, issn = {1476-5403}, mesh = {Acid Sensing Ion Channels/chemistry/genetics/*metabolism ; Acids/*toxicity ; Amiloride/analogs &amp; derivatives/pharmacology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Apoptosis/drug effects ; Cells, Cultured ; Disease Models, Animal ; Humans ; Longevity ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Motor Neurons/cytology/drug effects/*metabolism ; Mutation ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition with no cure. Mitochondrial dysfunction, Ca(2+) overloading and local hypoxic/ischemic environments have been implicated in the pathophysiology of ALS and are conditions that may initiate metabolic acidosis in the affected tissue. We tested the hypothesis that acidotoxicity and acid-sensing ion channels (ASICs) are involved in the pathophysiology of ALS. We found that motoneurons were selectively vulnerable to acidotoxicity in vitro, and that acidotoxicity was partially reduced in asic1a-deficient motoneuron cultures. Cross-breeding of SOD1(G93A) ALS mice with asic1a-deficient mice delayed the onset and progression of motor dysfunction in SOD1 mice. Interestingly, we also noted a strong increase in ASIC2 expression in motoneurons of SOD1 mice and sporadic ALS patients during disease progression. Pharmacological pan-inhibition of ASIC channels with the lipophilic amiloride derivative, 5-(N,N-dimethyl)-amiloride hydrochloride, potently protected cultured motoneurons against acidotoxicity, and, given post-symptom onset, significantly improved lifespan, motor performance and motoneuron survival in SOD1 mice. Together, our data provide strong evidence for the involvement of acidotoxicity and ASIC channels in motoneuron degeneration, and highlight the potential of ASIC inhibitors as a new treatment approach for ALS.}, }
@article {pmid23300829, year = {2012}, author = {Corcia, P and Tauber, C and Vercoullie, J and Arlicot, N and Prunier, C and Praline, J and Nicolas, G and Venel, Y and Hommet, C and Baulieu, JL and Cottier, JP and Roussel, C and Kassiou, M and Guilloteau, D and Ribeiro, MJ}, title = {Molecular imaging of microglial activation in amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {7}, number = {12}, pages = {e52941}, pmid = {23300829}, issn = {1932-6203}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diagnostic imaging/metabolism ; Brain/*diagnostic imaging/metabolism ; Female ; Humans ; Inflammation/diagnostic imaging/metabolism ; Male ; Microglia/*diagnostic imaging/metabolism ; Middle Aged ; Molecular Imaging ; Neuroimaging ; Radionuclide Imaging ; Receptors, GABA/*metabolism ; }, abstract = {There is growing evidence of activated microglia and inflammatory processes in the cerebral cortex in amyotrophic lateral sclerosis (ALS). Activated microglia is characterized by increased expression of the 18 kDa translocator protein (TSPO) in the brain and may be a useful biomarker of inflammation. In this study, we evaluated neuroinflammation in ALS patients using a radioligand of TSPO, (18)F-DPA-714. Ten patients with probable or definite ALS (all right-handed, without dementia, and untreated by riluzole or other medication that might bias the binding on the TSPO), were enrolled prospectively and eight healthy controls matched for age underwent a PET study. Comparison of the distribution volume ratios between both groups were performed using a Mann-Whitney's test. Significant increase of distribution of volume ratios values corresponding to microglial activation was found in the ALS sample in primary motor, supplementary motor and temporal cortex (p = 0.009, p = 0.001 and p = 0.004, respectively). These results suggested that the cortical uptake of (18)F-DPA-714 was increased in ALS patients during the "time of diagnosis" phase of the disease. This finding might improve our understanding of the pathophysiology of ALS and might be a surrogate marker of efficacy of treatment on microglial activation.}, }
@article {pmid23295632, year = {2014}, author = {Wilson, JR and Fehlings, MG}, title = {Riluzole for acute traumatic spinal cord injury: a promising neuroprotective treatment strategy.}, journal = {World neurosurgery}, volume = {81}, number = {5-6}, pages = {825-829}, doi = {10.1016/j.wneu.2013.01.001}, pmid = {23295632}, issn = {1878-8769}, mesh = {Animals ; Humans ; Neuroprotective Agents/*therapeutic use ; Neurotoxins/metabolism ; Riluzole/*therapeutic use ; Spinal Cord Injuries/*drug therapy/metabolism ; Voltage-Gated Sodium Channels/metabolism ; }, abstract = {BACKGROUND: Over the years, understanding of the specific secondary injury mechanisms that follow traumatic spinal cord injury (SCI) has improved. These pathologic mechanisms collectively serve to increase the extent of neural tissue injury, reducing prospects for neurologic recovery. An enhanced understanding of the pathobiology of SCI has permitted investigation of therapies targeting specific elements of this pathologic cascade. It is now known that the continuous posttraumatic activation of neuronal voltage-gated sodium ion channels leads to increased rates of cell death through the development of cellular swelling, acidosis, and glutaminergic excitotoxicity. The objective herein is to provide an update regarding the current status of the potential neuroprotective drug riluzole in the treatment of traumatic SCI.<br><br>METHODS: Narrative review and summary paper.<br><br>RESULTS: Riluzole is a sodium channel-blocking benzothiazole anticonvulsant drug that is approved by the U.S. Food and Drug Administration for the treatment of amyotrophic lateral sclerosis and has shown efficacy in preclinical models of SCI in reducing the extent of sodium and glutamate mediated secondary injury. This drug is currently under early stages of clinical investigation in SCI and shows promise as an acute neuroprotective therapy in this context.<br><br>CONCLUSION: This article reviews the biologic rationale, existing preclinical evidence, and emerging clinical data for riluzole in the treatment of traumatic SCI.}, }
@article {pmid23286744, year = {2013}, author = {Knippenberg, S and Skripuletz, T and Rath, KJ and Thau, N and Gudi, V and Pul, R and Körner, S and Dengler, R and Stangel, M and Petri, S}, title = {CDP-choline is not protective in the SOD1-G93A mouse model of ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {4}, pages = {284-290}, doi = {10.3109/21678421.2012.745569}, pmid = {23286744}, issn = {2167-9223}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*pathology/prevention &amp; control ; Animals ; Cytidine Diphosphate Choline/*administration &amp; dosage ; *Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuroprotective Agents/administration &amp; dosage ; Random Allocation ; Superoxide Dismutase/*genetics ; }, abstract = {Important pathogenic factors in ALS include excitotoxicity and oxidative stress. Cytidine 5-diphosphocholine (CDP-choline) has recently been reported to have neuroprotective effects in animal models for neurodegenerative diseases, attributable to its anti-glutamatergic, anti-excitotoxic, anti-apoptotic and membrane-preserving properties. In this study we administered either CDP-choline or vehicle to transgenic SOD1-G93A mice daily via intraperitoneal (i.p.) injection starting before disease onset (day 30). By monitoring of survival, motor function, weight and general condition we examined possible therapeutic effects. Additional animals were used for histological studies to determine the effect of CDP-choline on motor neuron survival, astrocytosis and myelination in the spinal cord. Results showed that CDP-choline treatment modified neither the deterioration of general condition nor the loss of body weight. Survival of CDP-choline treated animals was not prolonged compared to vehicle treated controls. None of the behavioural motor function tests revealed differences between groups and no differences in motor neuron survival, astrocytosis or myelination were detected by histological analyses. In conclusion, our data from the transgenic mouse model do not strongly support further clinical validation of CDP-choline for the treatment of ALS.}, }
@article {pmid23282201, year = {2013}, author = {Pastor, D and Viso-León, MC and Botella-López, A and Jaramillo-Merchan, J and Moraleda, JM and Jones, J and Martínez, S}, title = {Bone marrow transplantation in hindlimb muscles of motoneuron degenerative mice reduces neuronal death and improves motor function.}, journal = {Stem cells and development}, volume = {22}, number = {11}, pages = {1633-1644}, pmid = {23282201}, issn = {1557-8534}, mesh = {Animals ; Bone Marrow Cells/metabolism ; *Bone Marrow Transplantation ; Cell Survival ; Cell- and Tissue-Based Therapy ; Disease Models, Animal ; Glial Cell Line-Derived Neurotrophic Factor/genetics/*metabolism ; Green Fluorescent Proteins/genetics ; Hindlimb/surgery ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Motor Neurons/physiology ; Muscle, Skeletal/*innervation/*metabolism ; Nerve Degeneration/metabolism/therapy ; Neurodegenerative Diseases/*therapy ; Recovery of Function ; Spinal Cord/cytology/*metabolism ; }, abstract = {Bone marrow has proved to be an adequate source of stem cells for the treatment of numerous disorders, including neurodegenerative diseases. Bone marrow can be easily and relatively painlessly extracted from a patient or allogenic donor and then transplanted into the degenerative area. Here, the grafted cells will activate a number of mechanisms in order to protect, repair, and/or regenerate the damaged tissue. These properties make the bone marrow a feasible source for cell therapy. In this work, we transplanted bone marrow cells into a mouse model of motoneuron degeneration, with the particularity of placing the cells in the hindlimb muscles rather than in the spinal cord where neuronal degeneration occurs. To this end, we analyze the possibility for the transplanted cells to increase the survival rate of the spinal cord motoneurons by axonal-guided retrograde neurotrophism. As a result, the mice significantly improved their motor functions. This coincided with an increased number of motoneurons innervating the treated muscle compared with the neurons innervating the non-treated contralateral symmetric muscle. In addition, we detected an increase in glial-derived neurotrophic factor in the spinal cord, a neurotrophic factor known to be involved in the rescue of degenerating motoneurons, exerting a neuroprotective effect. Thus, we have proved that bone marrow injected into the muscles is capable of rescuing these motoneurons from death, which may be a possible therapeutic approach for spinal cord motoneuron degenerative diseases, such as amyotrophic lateral sclerosis.}, }
@article {pmid23281147, year = {2013}, author = {Anagnostou, E and Rentzos, M and Alexakis, T and Zouvelou, V and Zambelis, T and Evdokimidis, I}, title = {Volume matters: the influence of different botulinum toxin-A dilutions for sialorrhea in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {47}, number = {2}, pages = {276-278}, doi = {10.1002/mus.23692}, pmid = {23281147}, issn = {1097-4598}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications ; Botulinum Toxins, Type A/*administration &amp; dosage/therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Neuromuscular Agents/*administration &amp; dosage/therapeutic use ; Sialorrhea/*drug therapy/etiology ; Treatment Outcome ; }, abstract = {INTRODUCTION: We aimed to determine the effect of different botulinum toxin-A (BTX-A) dilutions on the treatment efficacy and side effects for amyotrophic lateral sclerosis (ALS) related sialorrhea.<br><br>METHODS: Ten patients were enrolled in the study. BTX-A dilution for Group A was 100 U in 1 ml of saline, whereas the dilution for Group B was 100 U in 2 ml of saline. Both groups received 20 U of BTX-A in each parotid gland, and assessments were made by means of the Drooling Impact Scale, items 1 and 3 of the ALS functional rating scale, and visual analog scales for drooling and swallowing function.<br><br>RESULTS: Although both groups exhibited a similar improvement in drooling, Group B had a mild but significant deterioration in bulbar function that was not evident in Group A.<br><br>CONCLUSIONS: These results suggest that BTX-A has a safer profile when reconstituted with 1 ml instead of 2 ml of saline.}, }
@article {pmid23280792, year = {2012}, author = {Fujisawa, T and Homma, K and Yamaguchi, N and Kadowaki, H and Tsuburaya, N and Naguro, I and Matsuzawa, A and Takeda, K and Takahashi, Y and Goto, J and Tsuji, S and Nishitoh, H and Ichijo, H}, title = {A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants.}, journal = {Annals of neurology}, volume = {72}, number = {5}, pages = {739-749}, doi = {10.1002/ana.23668}, pmid = {23280792}, issn = {1531-8249}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*immunology ; Animals ; Antibodies, Monoclonal/*metabolism ; Cell Death ; Cells, Cultured ; Culture Media, Serum-Free/pharmacology ; Disease Models, Animal ; Gene Expression Regulation/genetics ; Humans ; Immunoprecipitation ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred ICR ; Mice, Transgenic ; Motor Neurons/pathology/*physiology ; Mutation/genetics ; Protein Binding/genetics ; Protein Conformation ; Spinal Cord/pathology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Transfection ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by the selective loss of upper and lower motoneurons. Although >100 different Cu, Zn superoxide dismutase (SOD1) mutations have been identified in ALS patients, it remains controversial whether all of them are disease-causative mutations. Therefore, it is necessary to develop molecular mechanism-based diagnosis and treatment of ALS caused by SOD1 mutations.<br><br>METHODS: We previously reported that 3 pathogenic mutations of SOD1 cause chronic endoplasmic reticulum (ER) stress by inducing the binding of SOD1 to Derlin-1, a component of the ER homeostatic machinery. Here, we systematically analyzed 132 SOD1 mutants and found that most have a constitutively exposed Derlin-1-binding region (DBR) that is occluded in the wild-type protein. To develop the novel molecular mechanism-based antibody that can specifically recognize the aberrant structure of toxic SOD1 mutants, we generated the monoclonal antibody against the DBR.<br><br>RESULTS: MS785, a monoclonal antibody generated against the DBR, distinguished most ALS-causative SOD1 mutants from both wild-type and nontoxic mutants. Moreover, MS785 recognized endogenous SOD1 in B lymphocytes derived from 14 ALS patients carrying SOD1 mutations but not from 11 healthy controls.<br><br>INTERPRETATION: This is the first study to address the common property of all ALS-causative SOD1 mutants. MS785 is the first molecular mechanism-based antibody that was shown to be able to distinguish ALS-linked toxic SOD1 mutants from both wild-type and nontoxic mutants. MS785 may thus become an innovative tool for the diagnosis of ALS.}, }
@article {pmid23276136, year = {2013}, author = {Leone, S and Noera, G and Bertolini, A}, title = {Melanocortins as innovative drugs for ischemic diseases and neurodegenerative disorders: established data and perspectives.}, journal = {Current medicinal chemistry}, volume = {20}, number = {6}, pages = {735-750}, pmid = {23276136}, issn = {1875-533X}, mesh = {Amino Acid Sequence ; Animals ; Anti-Inflammatory Agents/chemistry/pharmacology/*therapeutic use ; Central Nervous System Agents/chemistry/pharmacology/*therapeutic use ; Humans ; Inflammation/drug therapy/immunology/physiopathology ; Ischemia/*drug therapy/immunology/physiopathology ; Melanocortins/chemistry/pharmacology/*therapeutic use ; Molecular Sequence Data ; Neurodegenerative Diseases/*drug therapy/immunology/physiopathology ; Receptors, Melanocortin/agonists ; }, abstract = {Ischemic insults and neurodegenerative diseases are by far the leading cause of mortality and disability. Whole-body hypoperfusion, as it occurs in polytraumatic and hemorrhagic shock, is alike an increasingly frequent condition, especially due to traffic accidents, wars and acts of terrorism. It is now clearly established that inflammatory processes play a fundamental role in the pathophysiology of both hypoperfusion/ischemia damage (be it generalized to the whole body, as in the case of shock, or limited to individual organs) and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis). On the other hand, concurrent animal and human data show that melanocortin peptides with agonist activity at melanocortin MC3/MC4 receptors are highly effective in different shock conditions as well as in conditions of ischemia/ischemia-reperfusion of individual organs (heart, brain, intestine, kidney, etc.), and accumulating evidence indicates that such effects of melanocortins are mostly due to quite peculiar antiinflammatory mechanisms. Melanocortins have also long been known (i) to exert important neurotrophic effects, not only during fetal development but also in adulthood, in different animal models of brain lesions; (ii) to reduce the morphological correlates of brain aging; (iii) to retard the behavioral deficits that develop during the aging process. Moreover, recent data from different laboratories show that after brain ischemic episodes melanocortins activate the transcription of neurotrophins and their receptors in the cerebral cortex and in the hippocampus, and increase the proliferation of progenitor neuron cells. The above arguments support the view that pharmacokinetically suitable agonists at MC3/MC4 melanocortin receptors may represent a completely innovative class of drugs for an effective treatment of both ischemic and neurodegenerative diseases.}, }
@article {pmid26316993, year = {2013}, author = {Sheikh, S and Safia,  and Haque, E and Mir, SS}, title = {Neurodegenerative Diseases: Multifactorial Conformational Diseases and Their Therapeutic Interventions.}, journal = {Journal of neurodegenerative diseases}, volume = {2013}, number = {}, pages = {563481}, pmid = {26316993}, issn = {2090-858X}, abstract = {Neurodegenerative diseases are multifactorial debilitating disorders of the nervous system that affect approximately 30 millionindividuals worldwide. Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis diseases are the consequence of misfolding and dysfunctional trafficking of proteins. Beside that, mitochondrial dysfunction, oxidative stress, and/or environmental factors strongly associated with age have also been implicated in causing neurodegeneration. After years of intensive research, considerable evidence has accumulated that demonstrates an important role of these factors in the etiology of common neurodegenerative diseases. Despite the extensive efforts that have attempted to define the molecular mechanisms underlying neurodegeneration, many aspects of these pathologies remain elusive. However, in order to explore the therapeutic interventions directed towards treatment of neurodegenerative diseases, neuroscientists are now fully exploiting the data obtained from studies of these basic mechanisms that have gone awry. The novelty of these mechanisms represents a challenge to the identification of viable drug targets and biomarkers for early diagnosis of the diseases. In this paper, we are reviewing various aspects associated with the disease and the recent trends that may have an application for the treatment of the neurodegenerative disorders.}, }
@article {pmid25562650, year = {2013}, author = {Lee, JJ and Yokota, T}, title = {Antisense therapy in neurology.}, journal = {Journal of personalized medicine}, volume = {3}, number = {3}, pages = {144-176}, pmid = {25562650}, issn = {2075-4426}, abstract = {Antisense therapy is an approach to fighting diseases using short DNA-like molecules called antisense oligonucleotides. Recently, antisense therapy has emerged as an exciting and promising strategy for the treatment of various neurodegenerative and neuromuscular disorders. Previous and ongoing pre-clinical and clinical trials have provided encouraging early results. Spinal muscular atrophy (SMA), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), Fukuyama congenital muscular dystrophy (FCMD), dysferlinopathy (including limb-girdle muscular dystrophy 2B; LGMD2B, Miyoshi myopathy; MM, and distal myopathy with anterior tibial onset; DMAT), and myotonic dystrophy (DM) are all reported to be promising targets for antisense therapy. This paper focuses on the current progress of antisense therapies in neurology.}, }
@article {pmid25408873, year = {2013}, author = {Liu, Y and Yang, R and He, Z and Gao, WQ}, title = {Generation of functional organs from stem cells.}, journal = {Cell regeneration (London, England)}, volume = {2}, number = {1}, pages = {1}, pmid = {25408873}, issn = {2045-9769}, abstract = {We are now well entering the exciting era of stem cells. Potential stem cell therapy holds great promise for the treatment of many diseases such as stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral-sclerosis, myocardial infarction, muscular dystrophy, diabetes, and etc. It is generally believed that transplantation of specific stem cells into the injured tissue to replace the lost cells is an effective way to repair the tissue. In fact, organ transplantation has been successfully practiced in clinics for liver or kidney failure. However, the severe shortage of donor organs has been a major obstacle for the expansion of organ transplantation programs. Toward that direction, generation of transplantable organs using stem cells is a desirable approach for organ replacement and would be of great interest for both basic and clinical scientists. Here we review recent progress in the field of organ generation using various methods including single adult tissue stem cells, a blastocyst complementation system, tissue decellularization/recellularization and a combination of stem cells and tissue engineering.}, }
@article {pmid25264500, year = {2013}, author = {Cousins, R and Ando, H and Thornton, E and Chakrabarti, B and Angus, R and Young, C}, title = {Determinants of accepting non-invasive ventilation treatment in motor neurone disease: a quantitative analysis at point of need.}, journal = {Health psychology and behavioral medicine}, volume = {1}, number = {1}, pages = {47-58}, pmid = {25264500}, issn = {2164-2850}, abstract = {Objectives: Motor neurone disease (MND) progressively damages the nervous system causing wasting to muscles, including those used for breathing. There is robust evidence that non-invasive ventilation (NIV) relieves respiratory symptoms and improves quality of life in MND. Nevertheless, about a third of those who would benefit from NIV decline the treatment. The purpose of the study was to understand this phenomenon. Design: A cross-sectional quantitative analysis. Methods: Data including age, sex, MND symptomatology, general physical and mental health and psychological measures were collected from 27 patients and their family caregivers at the point of being offered ventilatory support based on physiological markers. Results: Quantitative analyses indicated no difference in patient characteristics or symptomatology between those who tolerated (n = 17) and those who declined (n = 10) NIV treatment. A comparison of family caregivers found no differences in physical or mental health or in caregiving distress, emphasising that this was high in both groups; however, family caregivers supporting NIV treatment were significantly more resilient, less neurotic and less anxious than family caregivers who did not. Regression analyses, forcing MND symptoms to enter the equation first, found caregiver resilience:commitment the strongest predictor of uptake of NIV treatment adding 22% to the 56% explained variance. Conclusion: Patients who tolerated NIV treatment had family caregivers who cope through finding meaning and purpose in their situation. Psychological support and proactive involvement for family caregivers in the management of the illness situation is indicated if acceptance of NIV treatment is to be maximised in MND.}, }
@article {pmid25063512, year = {2013}, author = {Lin, F and Qin, ZH}, title = {Degradation of misfolded proteins by autophagy: is it a strategy for Huntington's disease treatment?.}, journal = {Journal of Huntington's disease}, volume = {2}, number = {2}, pages = {149-157}, doi = {10.3233/JHD-130052}, pmid = {25063512}, issn = {1879-6397}, mesh = {Autophagy/*physiology ; Carbamazepine/therapeutic use ; Humans ; Huntingtin Protein ; Huntington Disease/drug therapy/genetics/*metabolism ; Lithium/therapeutic use ; Mutant Proteins/*metabolism ; Nerve Tissue Proteins/*metabolism ; Oxazoles/therapeutic use ; Peptides/metabolism ; Rilmenidine ; Sirolimus/analogs &amp; derivatives/therapeutic use ; Trehalose/therapeutic use ; Trinucleotide Repeat Expansion/genetics ; Valproic Acid/therapeutic use ; }, abstract = {Autophagy is a degradation pathway for long-lived cytoplasmic proteins, protein complexes, or damaged organelles. The accumulation and aggregation of misfolded proteins are hallmarks of several neurodegenerative diseases. Many researchers have reported that autophagy degrades disease-causing misfolded and aggregated proteins, including mutant huntingtin (Htt) in Huntington's disease, mutant synuclein in familial Parkingson's disease, mutant Cu, Zn-Superoxide dismutase (SOD1) in familial amyotrophic lateral sclerosis. In this review, we will bring up new evidence to elucidate the involvement of autophagy in degradation of mutant Htt, discuss the mechanisms regulating the degradation of mutant Htt by autophagy and the therapeutic effects of drugs that enhance autophagy to improve clearance of mutant Htt. We propose that enhancement of autophagy by drugs may be a strategy to treat or retard progression of Huntington's disease.}, }
@article {pmid23271639, year = {2013}, author = {Sun, H and Knippenberg, S and Thau, N and Ragancokova, D and Körner, S and Huang, D and Dengler, R and Döhler, K and Petri, S}, title = {Therapeutic potential of N-acetyl-glucagon-like peptide-1 in primary motor neuron cultures derived from non-transgenic and SOD1-G93A ALS mice.}, journal = {Cellular and molecular neurobiology}, volume = {33}, number = {3}, pages = {347-357}, pmid = {23271639}, issn = {1573-6830}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/*pathology ; Animals ; Astrocytes/drug effects/metabolism/pathology ; Calcium/metabolism ; Calcium Signaling/drug effects ; Cells, Cultured ; Coculture Techniques ; Cytosol/drug effects/metabolism ; Female ; Fluorometry ; Glucagon-Like Peptide 1/pharmacology/*therapeutic use ; Glucagon-Like Peptide-1 Receptor ; Humans ; Intracellular Space/metabolism ; Kainic Acid/toxicity ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/metabolism/*pathology ; Neuroprotective Agents/pharmacology/therapeutic use ; Neurotoxins/toxicity ; Receptors, Glucagon/metabolism ; Superoxide Dismutase/*genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons (MN) in the motor cortex, brain stem, and spinal cord. In the present study, we established an ALS in vitro model of purified embryonic MNs, derived from non-transgenic and mutant SOD1-G93A transgenic mice, the most commonly used ALS animal model. MNs were cultured together with either non-transgenic or mutant SOD1-G93A astrocyte feeder layers. Cell viability following exposure to kainate as excitotoxic stimulus was assessed by immunocytochemistry and calcium imaging. We then examined the neuroprotective effects of N-acetyl-GLP-1(7-34) amide (N-ac-GLP-1), a long-acting, N-terminally acetylated, C-terminally truncated analog of glucagon-like peptide-1 (GLP-1). GLP-1 has initially been studied as a treatment for type II diabetes based on its function as insulin secretagogue. We detected neuroprotective effects of N-ac-GLP-1 in our in vitro system, which could be attributed to an attenuation of intracellular calcium transients, not only due to these antiexcitotoxic capacities but also with respect to the increasing knowledge about metabolic deficits in ALS which could be positively influenced by N-ac-GLP-1, this compound represents an interesting novel candidate for further in vivo evaluation in ALS.}, }
@article {pmid23270406, year = {2012}, author = {Siirala, W and Saaresranta, T and Vuori, A and Salanterä, S and Olkkola, KT and Aantaa, R}, title = {Using respiratory rate and thoracic movement to assess respiratory insufficiency in amyotrophic lateral sclerosis: a preliminary study.}, journal = {BMC palliative care}, volume = {11}, number = {}, pages = {26}, pmid = {23270406}, issn = {1472-684X}, abstract = {BACKGROUND: Hypoventilation due to respiratory insufficiency is the most common cause of death in amyotrophic lateral sclerosis (ALS) and non-invasive ventilation (NIV) can be used as a palliative treatment. The current guidelines recommend performing spirometry, and recording nocturnal oxyhemoglobin saturation and arterial blood gas analysis to assess the severity of the hypoventilation. We examined whether the respiratory rate and thoracic movement were reliable preliminary clinical signs in the development of respiratory insufficiency in patients with ALS.<br><br>METHODS: We measured the respiratory rate and thoracic movement, performed respiratory function tests and blood gas analysis, and recorded subjective hypoventilation symptoms in 42 ALS patients over a 7-year period. We recommended NIV if the patient presented with hypoventilation matching the current guidelines. We divided patients retrospectively into two groups: those to whom NIV was recommended within 6 months of the diagnosis (Group 1) and those to whom NIV was recommended 6 months after the diagnosis (Group 2). We used the Mann Whitney U test for comparisons between the two groups.<br><br>RESULTS: The mean partial pressure of arterial carbon dioxide in the morning in Group 1 was 6.3 (95% confidence interval 5.6-6.9) kPa and in Group 2 5.3 (5.0-5.6) kPa (p = 0.007). The mean respiratory rate at the time of diagnosis in Group 1 was 21 (18-24) breaths per minute and 16 (14-18) breaths per minute in Group 2 (p = 0.005). The mean thoracic movement was 2.9 (2.2-3.6) cm in Group 1 and 4.0 (3.4-4.8) cm in Group 2 (p = 0.01). We observed no other differences between the groups.<br><br>CONCLUSIONS: Patients who received NIV within six months of the diagnosis of ALS had higher respiratory rates and smaller thoracic movement compared with patients who received NIV later. Further studies with larger numbers of patients are needed to establish if these measurements can be used as a marker of hypoventilation in ALS.}, }
@article {pmid23265729, year = {2013}, author = {Martí-Aluja, I and Ruisánchez, I and Larrechi, MS}, title = {Quantitative analysis of the effect of zidovudine, efavirenz, and ritonavir on insulin aggregation by multivariate curve resolution alternating least squares of infrared spectra.}, journal = {Analytica chimica acta}, volume = {760}, number = {}, pages = {16-24}, doi = {10.1016/j.aca.2012.10.057}, pmid = {23265729}, issn = {1873-4324}, mesh = {Alkynes ; Anti-HIV Agents/*analysis ; Benzoxazines/*analysis ; Cyclopropanes ; Humans ; Insulin/chemistry/*metabolism ; Kinetics ; Least-Squares Analysis ; Magnetic Resonance Spectroscopy ; Microscopy, Electron, Scanning ; Ritonavir/*analysis ; *Spectrophotometry, Infrared ; Zidovudine/*analysis ; }, abstract = {Quantification of the effect of antiretroviral drugs on the insulin aggregation process is an important area of research due to the serious metabolic diseases observed in AIDS patients after prolonged treatment with these drugs. In this work, multivariate curve resolution alternating least squares (MCR-ALS) was applied to infrared monitoring of the insulin aggregation process in the presence of three antiretroviral drugs to quantify their effect. To evidence concentration dependence in this process, mixtures at two different insulin:drug molar ratios were used. The interaction between insulin and each drug was analysed by (1)H NMR spectroscopy. In all cases, the aggregation process was monitored during 45 min by infrared spectroscopy. The aggregates were further characterised by scanning electron microscopy (SEM). MCR-ALS provided the spectral and concentration profiles of the different insulin-drug conformations that are involved in the process. Their feasible band boundaries were calculated using the MCR-BANDS methodology. The kinetic profiles describe the aggregation pathway and the spectral profiles characterise the conformations involved. The retrieved results show that each of the three drugs modifies insulin conformation in a different way, promoting the formation of aggregates. Ritonavir shows the strongest promotion of aggregation, followed by efavirenz and zidovudine. In the studied concentration range, concentration dependence was only observed for zidovudine, with shorter aggregation time obtained as the amount of zidovudine increased. This factor also affected the aggregation pathway.}, }
@article {pmid23265356, year = {2013}, author = {Hoffmann, M}, title = {Linking respiratory chain uncoupling to amyotrophic lateral sclerosis implies potential treatment with herbal extracts containing genipin.}, journal = {Medical hypotheses}, volume = {80}, number = {3}, pages = {327}, doi = {10.1016/j.mehy.2012.11.045}, pmid = {23265356}, issn = {1532-2777}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; *Electron Transport ; Humans ; Iridoids/*pharmacology ; Mitochondria, Muscle/drug effects/metabolism ; Models, Theoretical ; Plant Extracts/*pharmacology ; }, }
@article {pmid23250913, year = {2013}, author = {Ching, JK and Elizabeth, SV and Ju, JS and Lusk, C and Pittman, SK and Weihl, CC}, title = {mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy.}, journal = {Human molecular genetics}, volume = {22}, number = {6}, pages = {1167-1179}, pmid = {23250913}, issn = {1460-2083}, support = {P30 NS057105/NS/NINDS NIH HHS/United States ; AG042095/AG/NIA NIH HHS/United States ; K02 AG042095/AG/NIA NIH HHS/United States ; NS057105/NS/NINDS NIH HHS/United States ; AG031867/AG/NIA NIH HHS/United States ; P30 AR057235/AR/NIAMS NIH HHS/United States ; R01 AG031867/AG/NIA NIH HHS/United States ; }, mesh = {Adenosine Triphosphatases/genetics/*metabolism ; Animals ; Autophagy ; Cell Cycle Proteins/genetics/*metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myositis, Inclusion Body/genetics/*metabolism/pathology/physiopathology ; Signal Transduction ; TOR Serine-Threonine Kinases/genetics/*metabolism ; Vacuoles/*metabolism/pathology ; Valosin Containing Protein ; }, abstract = {Autophagy is dysfunctional in many degenerative diseases including myopathies. Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM) associated with Paget's disease of the bone, fronto-temporal dementia and amyotrophic lateral sclerosis (IBMPFD/ALS). VCP is necessary for protein degradation via the proteasome and lysosome. IBMPFD/ALS mutations in VCP disrupt autophagosome and endosome maturation resulting in vacuolation, weakness and muscle atrophy. To understand the regulation of autophagy in VCP-IBM muscle, we examined the AKT/FOXO3 and mammalian target of rapamycin (mTOR) pathways. Basal Akt and FOXO3 phosphorylation was normal. In contrast, the phosphorylation of mTOR targets was decreased. Consistent with this, global protein translation was diminished and autophagosome biogenesis was increased in VCP-IBM muscle. Further mTORC1 inhibition with rapamycin hastened weakness, atrophy and vacuolation in VCP-IBM mice. This was accompanied by the accumulation of autophagic substrates such as p62, LC3II and ubiquitinated proteins. The decrease in mTOR signaling was partially rescued by insulin and to a lesser extent by amino acid (AA) stimulation in VCP-IBM muscle. Cells expressing catalytically inactive VCP or treated with a VCP inhibitor also failed to activate mTOR upon nutrient stimulation. Expression of a constitutively active Rheb enhanced mTOR activity and increased the fiber size in VCP-IBM mouse skeletal muscle. These studies suggest that VCP mutations may disrupt mTOR signaling and contribute to IBMPFD/ALS disease pathogenesis. Treatment of some autophagic disorders with mTOR inhibitors such as rapamycin may worsen disease.}, }
@article {pmid23237905, year = {2013}, author = {Roussel, BD and Kruppa, AJ and Miranda, E and Crowther, DC and Lomas, DA and Marciniak, SJ}, title = {Endoplasmic reticulum dysfunction in neurological disease.}, journal = {The Lancet. Neurology}, volume = {12}, number = {1}, pages = {105-118}, doi = {10.1016/S1474-4422(12)70238-7}, pmid = {23237905}, issn = {1474-4465}, support = {G1002610/WT_/Wellcome Trust/United Kingdom ; G1002610/MRC_/Medical Research Council/United Kingdom ; 089703/WT_/Wellcome Trust/United Kingdom ; GGP11057/TI_/Telethon/Italy ; G0901786/MRC_/Medical Research Council/United Kingdom ; 100140/WT_/Wellcome Trust/United Kingdom ; G0700990/MRC_/Medical Research Council/United Kingdom ; G0601840/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyloid beta-Peptides/genetics ; Animals ; Endoplasmic Reticulum/*pathology/physiology ; Humans ; Nervous System Diseases/genetics/*pathology/*physiopathology ; Protein Folding ; Signal Transduction/physiology ; Unfolded Protein Response/genetics ; }, abstract = {Endoplasmic reticulum (ER) dysfunction might have an important part to play in a range of neurological disorders, including cerebral ischaemia, sleep apnoea, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, the prion diseases, and familial encephalopathy with neuroserpin inclusion bodies. Protein misfolding in the ER initiates the well studied unfolded protein response in energy-starved neurons during stroke, which is relevant to the toxic effects of reperfusion. The toxic peptide amyloid β induces ER stress in Alzheimer's disease, which leads to activation of similar pathways, whereas the accumulation of polymeric neuroserpin in the neuronal ER triggers a poorly understood ER-overload response. In other neurological disorders, such as Parkinson's and Huntington's diseases, ER dysfunction is well recognised but the mechanisms by which it contributes to pathogenesis remain unclear. By targeting components of these signalling responses, amelioration of their toxic effects and so the treatment of a range of neurodegenerative disorders might become possible.}, }
@article {pmid23235621, year = {2012}, author = {Pastula, DM and Moore, DH and Bedlack, RS}, title = {Creatine for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {12}, number = {12}, pages = {CD005225}, pmid = {23235621}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Creatine/*administration &amp; dosage/adverse effects ; Disease Progression ; Humans ; Motor Neuron Disease/drug therapy/mortality ; Neuroprotective Agents/*administration &amp; dosage/adverse effects ; Randomized Controlled Trials as Topic ; Vital Capacity/drug effects ; }, abstract = {BACKGROUND: Creatine, a naturally-occurring nitrogenous organic acid involved in adenosine triphosphate (ATP) production, has been shown to increase survival in mouse models of amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND). Results from human trials, however, have been mixed. Given conflicting results regarding the efficacy of creatine, we conducted a systematic review, which was updated in 2012.<br><br>OBJECTIVES: To systematically examine the efficacy of creatine efficacy in prolonging ALS survival and in slowing ALS disease progression.<br><br>SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (16 July 2012), CENTRAL (2012, issue 7 in the Cochrane Library), MEDLINE (January 1966 to July 2012) and EMBASE (January 1980 to July 2012) for any trial involving creatine in the treatment of ALS.&#xa0;We also contacted experts in the field for any additional studies.<br><br>SELECTION CRITERIA: Randomized trials of treatment with creatine or placebo in patients diagnosed with ALS. Our primary outcome was tracheostomy-free survival time; secondary outcomes were ALS progression as measured by changes in ALS functional rating revised scores (ALSFRS-R) and per cent predicted forced vital capacity (FVC) over time.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, assessed risk of bias and extracted data. We obtained and analyzed individual participant data from each study.<br><br>MAIN RESULTS: We included three trials involving 386 participants randomized to either creatine 5 to 10 g per day or placebo.&#xa0;When we updated the searches in 2012 we found no additional trials. Creatine was reportedly well-tolerated in all three included studies, with no evidence of renal failure or serious adverse events specifically attributable to creatine. Using a pooled log-rank statistical test, we found no statistical difference in survival between the placebo and creatine groups across all three studies (Chi(2) = 0.09, P = 0.76).&#xa0;In addition, we found no statistical difference in ALSFRS-R slopes between the two groups across all three studies using a pooled linear mixed-effects model (slope difference of +0.03 ALSFRS-R/month in the creatine group; P = 0.76). Interestingly, there was a trend towards slightly worsened FVC slope in the creatine group (slope difference of -0.63 FVC/month in the creatine group) using a pooled linear mixed-effects model across the two studies which included FVC as an outcome, but this difference was not statistically significant (P = 0.054).<br><br>AUTHORS' CONCLUSIONS: In patients already diagnosed with clinically probable or definite ALS, creatine at doses ranging from 5 to 10 g per day did not have a statistically significant effect on survival, ALSFRS-R progression or percent predicted FVC progression.}, }
@article {pmid23225328, year = {2013}, author = {Collavo, A and Strek, H and Beffa, R and Sattin, M}, title = {Management of an ACCase-inhibitor-resistant Lolium rigidum population based on the use of ALS inhibitors: weed population evolution observed over a 7 year field-scale investigation.}, journal = {Pest management science}, volume = {69}, number = {2}, pages = {200-208}, doi = {10.1002/ps.3449}, pmid = {23225328}, issn = {1526-4998}, mesh = {Acetolactate Synthase/*antagonists &amp; inhibitors/genetics/metabolism ; Acetyl-CoA Carboxylase/*antagonists &amp; inhibitors/genetics/metabolism ; *Biological Evolution ; Enzyme Inhibitors/*pharmacology ; *Herbicide Resistance ; Lolium/*drug effects/enzymology/genetics ; Sulfonylurea Compounds/*pharmacology ; Triticum/growth &amp; development ; Weed Control/*methods ; }, abstract = {BACKGROUND: A 7 year experiment was set up in 2002 to evaluate the long-term effects of weed management strategies based on graminicidal sulfonylureas (SUs) on the evolution of a Lolium rigidum population resistant to ACCase inhibitors in a continuous wheat cropping system. The strategies included the continued use of ALS inhibitors, the continued application of ACCase inhibitors and a simple resistance management strategy based on a biennial rotation of herbicide mode of action (MoA).<br><br>RESULTS: The efficacy of the tested SUs in the field decreased significantly, starting from the fourth treatment in all control strategies. Regardless of control strategy, the few survivors of the ALS treatment in the third season produced a significant number of ACCase- and ALS-resistant (multiple-resistant) progeny. Continuous ALS and biennial rotation of herbicides reduced weed densities, but L. rigidum conserved its ACCase resistance trait. Enhanced metabolism was detected in ALS-resistant plants, whereas target site was primarily involved in the ACCase-resistant individuals.<br><br>CONCLUSION: At the end of the experiment, multiple-resistant individuals were found in all samples coming from the control strategies investigated. The biennial rotation between ALS and other MoA appeared to delay the development of resistance to SUs over continuous treatments, but additional measures will likely need to be taken in order to make this sustainable in the long term, whereas the field efficacy of SUs remained relatively high until the end of the experiment. Integrated weed management with more diversity should be introduced in oversimplified cropping systems in order to sustainably manage resistant L. rigidum populations.}, }
@article {pmid23220913, year = {2013}, author = {Nichols, NL and Gowing, G and Satriotomo, I and Nashold, LJ and Dale, EA and Suzuki, M and Avalos, P and Mulcrone, PL and McHugh, J and Svendsen, CN and Mitchell, GS}, title = {Intermittent hypoxia and stem cell implants preserve breathing capacity in a rodent model of amyotrophic lateral sclerosis.}, journal = {American journal of respiratory and critical care medicine}, volume = {187}, number = {5}, pages = {535-542}, pmid = {23220913}, issn = {1535-4970}, support = {T32 HL007654/HL/NHLBI NIH HHS/United States ; RR023916/RR/NCRR NIH HHS/United States ; T32 OD010423/OD/NIH HHS/United States ; P01 NS057778/NS/NINDS NIH HHS/United States ; HL007654/HL/NHLBI NIH HHS/United States ; T32 RR023916/RR/NCRR NIH HHS/United States ; NS057778/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Brain-Derived Neurotrophic Factor/biosynthesis ; Glial Cell Line-Derived Neurotrophic Factor/metabolism ; Hypoxia ; Inspiratory Capacity ; Male ; Motor Neurons/metabolism ; Phrenic Nerve/metabolism/physiopathology ; Rats ; Rats, Sprague-Dawley ; Rats, Transgenic ; Respiratory Insufficiency/*prevention &amp; control ; Respiratory Therapy/*methods ; *Stem Cell Transplantation ; Superoxide Dismutase ; }, abstract = {RATIONALE: Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease causing paralysis and death from respiratory failure. Strategies to preserve and/or restore respiratory function are critical for successful treatment. Although breathing capacity is maintained until late in disease progression in rodent models of familial ALS (SOD1(G93A) rats and mice), reduced numbers of phrenic motor neurons and decreased phrenic nerve activity are observed. Decreased phrenic motor output suggests imminent respiratory failure.<br><br>OBJECTIVES: To preserve or restore phrenic nerve activity in SOD1(G93A) rats at disease end stage.<br><br>METHODS: SOD1(G93A) rats were injected with human neural progenitor cells (hNPCs) bracketing the phrenic motor nucleus before disease onset, or exposed to acute intermittent hypoxia (AIH) at disease end stage.<br><br>MEASUREMENTS AND MAIN RESULTS: The capacity to generate phrenic motor output in anesthetized rats at disease end stage was: (1) transiently restored by a single presentation of AIH; and (2) preserved ipsilateral to hNPC transplants made before disease onset. hNPC transplants improved ipsilateral phrenic motor neuron survival.<br><br>CONCLUSIONS: AIH-induced respiratory plasticity and stem cell therapy have complementary translational potential to treat breathing deficits in patients with ALS.}, }
@article {pmid23217569, year = {2012}, author = {Bame, M and Pentiak, PA and Needleman, R and Brusilow, WS}, title = {Effect of sex on lifespan, disease progression, and the response to methionine sulfoximine in the SOD1 G93A mouse model for ALS.}, journal = {Gender medicine}, volume = {9}, number = {6}, pages = {524-535}, doi = {10.1016/j.genm.2012.10.014}, pmid = {23217569}, issn = {1878-7398}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*enzymology/physiopathology ; Animals ; Disease Models, Animal ; Disease Progression ; Enzyme Inhibitors/*therapeutic use ; Female ; Glutamate-Ammonia Ligase/antagonists &amp; inhibitors/*metabolism ; Kaplan-Meier Estimate ; Longevity ; Male ; Methionine Sulfoximine/*therapeutic use ; Mice ; Mice, Transgenic ; Muscle, Skeletal/physiopathology ; Orchiectomy ; Ovariectomy ; Sex Factors ; Superoxide Dismutase/genetics ; Time Factors ; }, abstract = {OBJECTIVE: To investigate the role of sex and the role of ammonia and amino acid metabolism, specifically the activity of glutamine synthetase, in survival and disease progression in amyotrophic lateral sclerosis.<br><br>METHODS: We tested treatment with methionine sulfoximine (MSO) on the lifespan and neuromuscular ability of male and female SOD1 mice as measured by their ability to maintain their grip on an inverted wire grid. We also tested the effects of castration and ovariectomization on those measurements.<br><br>RESULTS: MSO treatment improves the survival of both male and female mice, but the effects are significantly greater on female mice. Saline-treated (control) female mice have delayed neuromuscular degeneration compared with saline-treated male mice, and MSO further delays disease progression in females, to a greater extent than in males. Ovariectomization or castration completely eliminates the effect of the drug on either survival or neuromuscular deterioration.<br><br>CONCLUSIONS: Sex is an important factor in disease progression and the response of SOD1 mice to a drug targeting a central enzyme in nitrogen metabolism, with female sex hormones playing a greater role than male sex hormones. Glutamine synthetase, or its reactants and products, therefore plays a role in this disease, and the sex specificity of treatments aimed at this or other metabolic targets may therefore be an important factor in the development of therapies to treat amyotrophic lateral sclerosis.}, }
@article {pmid23196568, year = {2012}, author = {Warita, H and Kato, M and Suzuki, N and Itoyama, Y and Aoki, M}, title = {[Clinical translation of hepatocyte growth factor for amyotrophic lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {52}, number = {11}, pages = {1214-1217}, doi = {10.5692/clinicalneurol.52.1214}, pmid = {23196568}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Clinical Trials, Phase I as Topic ; Hepatocyte Growth Factor/*administration &amp; dosage ; Humans ; Rats ; Rats, Transgenic ; Recombinant Proteins/administration &amp; dosage ; Translational Research, Biomedical ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by selective loss of motor neurons. Approximately 20% of familial ALS cases are linked to mutations in Cu/Zn superoxide dismutase (SOD1) gene. Previously, we developed a transgenic rat model of ALS overexpressing mutant SOD1 protein. The rat model facilitates preclinical ALS research employing various therapeutic approaches such as intrathecal administration, cell transplantation, and viral vector-mediated gene transduction to the affected central nervous system. Hepatocyte growth factor (HGF) is a pleiotropic growth factor and also a potent survival-promoting factor for motor neurons. To examine its therapeutic effect on ALS, we administered human recombinant HGF (hrHGF) to the transgenic ALS rats. In contrast with vehicle-treated rats, continuous intrathecal infusion of hrHGF attenuated spinal motor neuron degeneration and prolonged the duration of the disease, even with administration from the onset of symptoms. To translate the strategy to human treatment, we performed dose-finding and safety studies using non-human primate model of contusive cervical spinal cord injury. Introducing exogenous HGF protein also revealed a distinct therapeutic effect with functional recovery. Given the therapeutic potential of hrHGF on ALS, we started a novel phase I clinical trial for ALS patients in Tohoku University Hospital.}, }
@article {pmid23196476, year = {2012}, author = {Sawamoto, K}, title = {[Regenerating neurons by using endogenous neuronal progenitor cells].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {52}, number = {11}, pages = {939-941}, doi = {10.5692/clinicalneurol.52.939}, pmid = {23196476}, issn = {1882-0654}, mesh = {Animals ; Brain/pathology ; Humans ; Nerve Regeneration/*physiology ; Neurodegenerative Diseases/therapy ; Neurons/*physiology ; Stem Cells/*physiology ; }, abstract = {Currently, there is no effective treatment for the neuronal loss caused by neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) or ischemic stroke. However, recent studies have shown that endogenous neural progenitor cells continuously generate new neurons in the subventricular zone (SVZ) of the adult mammalian brain. Some of these new neurons migrate to the injured site and differentiate into mature neurons. Such new neurons may be able to replace degenerated neurons and improve or repair neurological deficits. To establish a neuroregenerative therapy using this endogenous system, endogenous regulatory mechanisms must be understood. Here, we review current knowledge on the generation of new neurons in the adult brain and discuss their potential for use in replacing neurons lost to neurodegenerative diseases, including ALS, and to ischemic stroke.}, }
@article {pmid23196468, year = {2012}, author = {Matsui, N}, title = {[Multifocal motor neuropathy: current review of epidemiology and treatment].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {52}, number = {11}, pages = {920-922}, doi = {10.5692/clinicalneurol.52.920}, pmid = {23196468}, issn = {1882-0654}, mesh = {Adult ; Female ; Humans ; Male ; Motor Neuron Disease/*epidemiology/therapy ; Polyneuropathies/*epidemiology/therapy ; }, abstract = {The diagnosis of multifocal motor neuropathy (MMN) is often missed because MMN disguises itself as a motor neuron disease and is considered relatively rare. Detailed epidemiological studies of MMN have not been undertaken. We therefore conducted a nationwide survey of MMN in comparison with amyotrophic lateral sclerosis (ALS). This retrospective study examined 47 patients with MMN and 1,051 patients with ALS from major neuromuscular centers in Japan from 2005 to 2009. MMN had a younger age of onset and was more common in males than ALS. The ratio of MMN to ALS patients (0-0.10) varied among the centers, but mostly converged to 0.05. The prevalence was estimated to be 0.3 cases for MMN and 6.63 cases for ALS per 100,000 persons. Twenty-five MMN patients (54.2%) showed conduction block. Thirty-four (75%) of 45 MMN patients received intravenous immunoglobulin exhibited a favorable outcome. It is expected that more sensitive indicators of conduction block or focal demyelinating lesions than currently available MMN diagnostic criteria would further increase the ratio of MMN to ALS patients and the total number of MMN patients who can benefit from treatment. MMN is by no means a rare disorder but should be accurately diagnosed in all neuromuscular centers.}, }
@article {pmid23186535, year = {2012}, author = {Sha, SJ and Boxer, A}, title = {Treatment implications of C9ORF72.}, journal = {Alzheimer's research &amp; therapy}, volume = {4}, number = {6}, pages = {46}, pmid = {23186535}, issn = {1758-9193}, support = {R01 AG031278/AG/NIA NIH HHS/United States ; R01 AG038791/AG/NIA NIH HHS/United States ; }, abstract = {Frontotemporal dementia (FTD) is a common dementia syndrome in patients under the age of 65 years with many features overlapping with amyotrophic lateral sclerosis (ALS). The link between FTD and ALS has been strengthened by the discovery that a hexanucleotide repeat expansion in a non-coding region of the C9ORF72 gene causes both familial and sporadic types of these two diseases. As we begin to understand the pathophysiological mechanisms by which this mutation leads to FTD and ALS (c9FTD/ALS), new targets for disease-modifying therapies will likely be unveiled. Putative C9ORF72 expansion pathogenic mechanisms include loss of C9ORF72 protein function, sequestration of nucleic acid binding proteins due to expanded hexanucleotide repeats, or a combination of the two. New animal models and other research tools informed by work in other repeat expansion neurodegenerative diseases such as the spinocerebellar ataxias will help to elucidate the mechanisms of C9ORF72-mediated disease. Similarly, re-examining previous studies of drugs developed to treat ALS in light of this new mutation may identify novel FTD treatments. Ultimately, research consortiums incorporating animal models and well-characterized clinical populations will be necessary to fully understand the natural history of the c9FTD/ALS clinical phenotypes and identify biomarkers and therapeutic agents that can cure the most common form of genetically determined FTD and ALS.}, }
@article {pmid23178912, year = {2013}, author = {Hadzhieva, M and Kirches, E and Wilisch-Neumann, A and Pachow, D and Wallesch, M and Schoenfeld, P and Paege, I and Vielhaber, S and Petri, S and Keilhoff, G and Mawrin, C}, title = {Dysregulation of iron protein expression in the G93A model of amyotrophic lateral sclerosis.}, journal = {Neuroscience}, volume = {230}, number = {}, pages = {94-101}, doi = {10.1016/j.neuroscience.2012.11.021}, pmid = {23178912}, issn = {1873-7544}, mesh = {Cation Transport Proteins/genetics/*metabolism ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Fluoresceins/metabolism ; Gene Expression Regulation, Neoplastic/drug effects/*physiology ; Humans ; Iron/metabolism ; Iron-Binding Proteins/genetics/*metabolism ; Mitochondria/drug effects/genetics ; Mitochondrial Proteins/genetics/*metabolism ; Neuroblastoma/pathology/ultrastructure ; Oxidative Stress/genetics/physiology ; RNA, Messenger ; Reactive Oxygen Species ; Receptors, Transferrin/genetics/*metabolism ; Superoxide Dismutase/genetics/*metabolism ; Transfection ; Tretinoin/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by selective loss of motor neurons which leads to progressive paralysis and death by respiratory failure. Although the cause of sporadic ALS is still unknown, oxidative stress is suggested to play a major role in the pathogenesis of this disease and of the rare familial form, which often exhibits mutations of the superoxide dismutase 1 (SOD1) gene. Since enhanced iron levels are discussed to participate in oxidative stress and neuronal death, we analyzed the expression levels of Fe-related mRNAs in a cell culture ALS model with the G93A mutation of SOD1. We observed an increased total iron content in G93A-SOD1 SH-SY5Y neuroblastoma cells compared to wild-type (WT)-SOD1 cells. mRNA expression for transferrin receptor 1 (TfR1) and divalent metal transporter 1 was increased in G93A-SOD1 cells, which was in accordance with higher iron uptake. Experiments with the iron chelator deferoxamine revealed a normal reaction of WT and mutant cells to cytoplasmic iron depletion, i.e. TfR1 upregulation, suggesting a basically conserved function of the iron-responsive element/iron regulatory protein (IRE/IRP) pathway, designed to adapt gene expression to iron levels. Expression levels of mitoferrin 1 and 2, frataxin, and iron-sulfur cluster scaffold protein were also significantly increased in G93A-SOD1 cells, suggesting higher mitochondrial iron import and utilization in biosynthetic pathways within the mitochondria. Moreover, expression of these transcripts was further enhanced, if G93A-SOD1 cells were differentiated by retinoic acid (RA). Since RA treatment increased cytoplasmic reactive oxygen species (ROS) levels in these cells, an IRE/IRP independent, ROS-mediated mechanism may account for dysregulation of iron-related genes.}, }
@article {pmid23175187, year = {2013}, author = {Chang, CP and Su, YC and Hu, CW and Lei, HY}, title = {TLR2-dependent selective autophagy regulates NF-κB lysosomal degradation in hepatoma-derived M2 macrophage differentiation.}, journal = {Cell death and differentiation}, volume = {20}, number = {3}, pages = {515-523}, pmid = {23175187}, issn = {1476-5403}, mesh = {Adaptor Proteins, Signal Transducing/antagonists &amp; inhibitors/genetics/metabolism ; Animals ; *Autophagy ; Autophagy-Related Protein 5 ; Bone Marrow Cells/cytology ; Carcinoma, Hepatocellular/metabolism ; Cell Differentiation ; Cell Line, Tumor ; Culture Media, Conditioned/pharmacology ; Cytokines/metabolism ; Female ; Lysosomes/drug effects/*metabolism ; Macrolides/pharmacology ; Macrophages/*cytology/drug effects/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Microtubule-Associated Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Phosphorylation ; RNA Interference ; RNA, Small Interfering/metabolism ; Sequestosome-1 Protein ; Toll-Like Receptor 2/*metabolism ; Transcription Factor RelA/*metabolism ; }, abstract = {Autophagy is a lysosomal pathway for cellular homeostasis control. Both non-selective bulk autophagy and selective autophagy of specific proteins or organelles have been found. Selective autophagy prevents cells from pathogen invasion and stress damage, but its role in regulating transcriptional factors is not clear. Using a macrophage cell differentiation model, the role of autophagy in nuclear factor-κB (NF-κB) regulation is investigated. The bone marrow-derived macrophages (BMDMs) will differentiate into a M2-like phenotype in the presence of hepatoma tumor cell condition medium (CM). The TLR2 signaling drives this M2 polarization and causes NF-κB p65 degradation via lysosome-dependent pathway. The CM-induced ubiquitinated- NF-κB p65 forms aggresome-like structures (ALS) in the cytoplasm of cultured and hepatoma-associated M2 macrophages. This NF-κB p65-contained ALS is recognized by p62/SQSTM1 and degraded by selective autophagy. Treatment with the lysosomal inhibitor bafilomycin A1 or the knockdown of Atg5 can prevent CM-induced NK-κB p65 degradation and induce M2 macrophages to produce a high level of pro-inflammatory cytokines. Furthermore, TLR2 signal induces sustained phosphorylation of extracellular signal-regulated kinase 1/2 to facilitate this autophagy-dependent NF-κB regulation. Our finding provides a novel pathway of NF-κB regulation by p62/SQSTM1-mediated selective autophagy.}, }
@article {pmid23164337, year = {2012}, author = {Zhang, R and Bures, M and Höffler, HK and Zinne, N and Länger, F and Bisdas, T and Haverich, A and Krüger, M}, title = {TissuePatch™ as a novel synthetic sealant for repair of superficial lung defect: in vitro tests results.}, journal = {Annals of surgical innovation and research}, volume = {6}, number = {1}, pages = {12}, pmid = {23164337}, issn = {1750-1164}, abstract = {BACKGROUND: Controversies surrounding the efficacy of surgical sealants against alveolar air leaks (AAL) in lung surgery abound in the literature. We sought to test the sealing efficacy of a novel synthetic sealant, TissuePatch™ in an in vitro lung model.<br><br>METHODS: The lower lobe of freshly excised swine lung (n&#x2009;=&#x2009;10) was intubated and ventilated. A superficial parenchymal defect (40&#x2009;&#xd7;&#x2009;25 mm) was created, followed by AAL assessment. After sealant application, AAL was assessed again until burst failure occurred. The length of defect was recorded to evaluate the elasticity of the sealant.<br><br>RESULTS: Superficial parenchymal defects resulted in AAL increasing disproportionally with ascending maximal inspiratory pressure (Pmax). Multiple linear regression analysis revealed strong correlation between AAL and Pmax, compliance, resistance. After sealant application, AAL was sealed in all ten tests at an inspired tidal volume (TVi) of 400 ml, in nine tests at TVi&#x2009;=&#x2009;500 ml, in seven at TVi&#x2009;=&#x2009;600 ml and in five at TVi&#x2009;=&#x2009;700 ml. The mean burst pressure was 42&#x2009;&#xb1;&#x2009;9 mBar. Adhesive and cohesive sealant failures were found in six and three tests respectively. The length of defect before sealant failure was 8.9&#x2009;&#xb1;&#x2009;4.9% larger than that at TVi&#x2009;=&#x2009;400 ml, demonstrating an adequate elasticity of this sealant film.<br><br>CONCLUSIONS: TissuePatch&#x2122; may be a reliable sealant for alternative or adjunctive treatment for repair of superficial parenchymal defects in lung surgery. The clinical benefits of this sealant should be confirmed by prospective, randomised controlled clinical trials. ABSTRAKT:<br><br>HINTERGRUND: Die Wirksamkeit von chirurgischen Klebstoffen zur Pr&#xe4;vention von alveolo-pleuralem Luftleck (APL) ist trotz zunehmenden klinischen Anwendungen in Lungenchirurgie immer noch kontrovers diskutiert. Wir evaluierten die Abdichtungswirksamkeit von einem neuartigen synthetischen Kleber, TissuePatch&#x2122; mittels eines in vitro Lungenmodels. METHODE: Der Unterlappen von frisch entnommenen Schweinlungen (n&#x2009;=&#x2009;10) wurde intubiert und beatmet. Eine pleurale L&#xe4;sion (40&#x2009;&#xd7;&#x2009;25 mm) wurde erstellt und APL mit steigendem inspiratorischem Tidalvolumen (TVi) untersucht. Nach Applikation von TissuePatch&#x2122; wurde APL auf die gleiche Weise gemessen bis zur Auftritt von Kleberbruch. Zur Untersuchung der Elastizit&#xe4;t des Klebers wurde die L&#xe4;nge der pleuralen L&#xe4;sion gemessen. ERGEBNIS: Pleurale L&#xe4;sion f&#xfc;hrte bei aufsteigendem maximalem inspiratorischem Druck (Pmax) zu &#xfc;berproportionalem Anstieg von APL. Multiple lineare Regressionsanalyse ergab eine starke Korrelation zwischen APL und Pmax, Lungencompliance sowie Widerstand. Nach der Applikation von Klebstoff wurde APL bei TVi&#x2009;=&#x2009;400 ml in allen zehn Testen versiegelt, bei TVi&#x2009;=&#x2009;500 ml in neun Testen, bei TVi&#x2009;=&#x2009;600 ml in sieben und bei TVi&#x2009;=&#x2009;700 ml in f&#xfc;nf Testen. Der mittlere Pmax, der zu Kleberbruch f&#xfc;hrte, betrug 42&#x2009;&#xb1;&#x2009;9 mBar. Bei den Versuchen wurden adh&#xe4;siver und koh&#xe4;siver Kleberbruch in jeweils sechs und drei Testen gefunden. Die L&#xe4;nge der pleuralen L&#xe4;sion vor dem Kleberbruch war 8,9&#x2009;&#xb1;&#x2009;4,9% gr&#xf6;&#xdf;er als die bei TVi&#x2009;=&#x2009;400 ml.<br><br>SCHLUSSFOLGERUNG: Unsere Versuche zeigten eine zuverl&#xe4;ssige Versiegelung von TissuePatch&#x2122; unter mechanischer Ventilation. Die klinische N&#xfc;tzlichkeit vom Kleber als unterst&#xfc;tzende Ma&#xdf;nahme zur Pr&#xe4;vention von alveolo-pleuralem Luftleck in Lungenchirurgie sollte durch prospektive, randomisierte kontrollierte klinische Studien best&#xe4;tigt werden.}, }
@article {pmid23162510, year = {2012}, author = {Palmieri, A and Kleinbub, JR and Calvo, V and Sorarù, G and Grasso, I and Messina, I and Sambin, M}, title = {Efficacy of hypnosis-based treatment in amyotrophic lateral sclerosis: a pilot study.}, journal = {Frontiers in psychology}, volume = {3}, number = {}, pages = {465}, pmid = {23162510}, issn = {1664-1078}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and its devastating neurodegenerative consequences have an inevitably psychological impact on patients and their caregivers: however, although it would be strongly needed, there is a lack of research on the efficacy of psychological intervention. Our aim was to investigate the effect of hypnosis-based intervention on psychological and perceived physical wellbeing in patients and the indirect effect on caregivers.<br><br>METHODS: We recruited eight ALS volunteers patients as a pilot sample for an hypnosis intervention and self-hypnosis training protocol lasting 1&#x2009;month. Anxiety and depression level was measured in patients and caregivers at pre and post treatment phase. Quality of life and perceived physical symptoms changes were also investigated in patients.<br><br>RESULTS: One month pre-post treatment improvement in depression, anxiety, and quality of life was clearly clinically observed and confirmed by psychometric analyses on questionnaire data. Moreover, decreases in physical symptoms such as pain, sleep disorders, emotional lability, and fasciculations were reported by our patients. Improvements in caregiver psychological wellbeing, likely as a consequence of patients psychological and perceived physical symptomatology improvement, were also observed.<br><br>CONCLUSION: To the best of our knowledge, even if at a preliminary level, this is the first report on efficacy psychological intervention protocol on ALS patients. The findings provide initial support for using hypnosis and self-hypnosis training to manage some ALS physical consequences and mainly to cope its dramatic psychological implications for patients and, indirectly, for their caregivers.}, }
@article {pmid23157231, year = {2013}, author = {Meyer, M and Gonzalez Deniselle, MC and Gargiulo-Monachelli, G and Lima, A and Roig, P and Guennoun, R and Schumacher, M and De Nicola, AF}, title = {Progesterone attenuates several hippocampal abnormalities of the Wobbler mouse.}, journal = {Journal of neuroendocrinology}, volume = {25}, number = {3}, pages = {235-243}, doi = {10.1111/jne.12004}, pmid = {23157231}, issn = {1365-2826}, mesh = {Animals ; Brain-Derived Neurotrophic Factor/genetics ; Doublecortin Protein ; Female ; Fluorescent Antibody Technique ; Glial Fibrillary Acidic Protein/metabolism ; Hippocampus/abnormalities/*drug effects/metabolism ; In Situ Hybridization ; Male ; Mice ; Progesterone/*pharmacology ; RNA, Messenger/genetics ; }, abstract = {It is now recognised that progesterone plays a protective role for diseases of the central nervous system. In the Wobbler mouse, a model of motoneurone degeneration, progesterone treatment prevents spinal cord neuropathology and clinical progression of the disease. However, neuropathological and functional abnormalities have also been discovered in the brain of Wobbler mice and patients with amyotrophic lateral sclerosis. The present study examined the hippocampus of control and afflicted Wobbler mice and the changes in response to progesterone treatment. Mice received either a single progesterone implant (20 mg for 18 days). We found that the hippocampal pathology of the untreated Wobblers involved a decreased expression of brain-derived neurotrophic factor (BDNF) mRNA, decreased astrogliosis in the stratum lucidum, stratum radiatum and stratum lacunosum-moleculare, decreased doublecortin (DCX)-positive neuroblasts in the subgranular zone of the dentate gyrus and a decreased density of GABA immunoreactive hippocampal interneurones and granule cells of the dentate gyrus. Although progesterone did not change the normal parameters of control mice, it attenuated several hippocampal abnormalities in Wobblers. Thus, progesterone increased hippocampal BDNF mRNA expression, decreased glial fibrillary acidic protein-positive astrocytes and increased the number of GABAergic interneurones and granule cells. The number of DCX expressing neuroblasts and immature neurones remained impaired in both progesterone-treated and untreated Wobblers. In conclusion, progesterone treatment exerted beneficial effects on some aspects of hippocampal neuropathology, suggesting its neuroprotective role in the brain, in agreement with previous data obtained in the spinal cord of Wobbler mice.}, }
@article {pmid23152212, year = {2012}, author = {Beauverd, M and Mitchell, JD and Wokke, JH and Borasio, GD}, title = {Recombinant human insulin-like growth factor I (rhIGF-I) for the treatment of amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {11}, number = {11}, pages = {CD002064}, pmid = {23152212}, issn = {1469-493X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy ; Disease Progression ; Humans ; Insulin-Like Growth Factor I/*therapeutic use ; Male ; Randomized Controlled Trials as Topic ; Recombinant Proteins/therapeutic use ; Severity of Illness Index ; }, abstract = {BACKGROUND: Recombinant human insulin-like growth factor I (rhIGF-I) is a possible disease modifying therapy for amyotrophic lateral sclerosis (ALS, which is also known as motor neuron disease (MND)).<br><br>OBJECTIVES: To examine the efficacy of rhIGF-I in affecting disease progression, impact on measures of functional health status, prolonging survival and delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival in ALS. Occurrence of adverse events was also reviewed.<br><br>SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (21 November 2011), CENTRAL (2011, Issue 4), MEDLINE (January 1966 to November 2011) and EMBASE (January 1980 to November 2011) and sought information from the authors of randomised clinical trials and manufacturers of rhIGF-I.<br><br>SELECTION CRITERIA: We considered all randomised controlled clinical trials involving rhIGF-I treatment of adults with definite or probable ALS according to the El Escorial Criteria. The primary outcome measure was change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score after nine months of treatment and secondary outcome measures were change in AALSRS at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: Each author independently graded the risk of bias in the included studies. The lead author extracted data and the other authors checked them. We generated some missing data by making ruler measurements of data in published graphs. We collected data about adverse events from the included trials.<br><br>MAIN RESULTS: We identified three randomised controlled trials (RCTs) of rhIGF-I, involving 779 participants, for inclusion in the analysis. In a European trial (183 participants) the mean difference (MD) in change in AALSRS total score after nine months was -3.30 (95% confidence interval (CI) -8.68 to 2.08). In a North American trial (266 participants), the MD after nine months was -6.00 (95% CI -10.99 to -1.01). The combined analysis from both RCTs showed a MD after nine months of -4.75 (95% CI -8.41 to -1.09), a significant difference in favour of the treated group. The secondary outcome measures showed non-significant trends favouring rhIGF-I. There was an increased risk of injection site reactions with rhIGF-I (risk ratio 1.26, 95% CI 1.04 to 1.54). . A second North American trial (330 participants) used a novel primary end point involving manual muscle strength testing. No differences were demonstrated between the treated and placebo groups in this study. All three trials were at high risk of bias.<br><br>AUTHORS' CONCLUSIONS: Meta-analysis revealed a significant difference in favour of rhIGF-I treatment; however, the quality of the evidence from the two included trials was low. A third study showed no difference between treatment and placebo. There is no evidence for increase in survival with IGF1. All three included trials were at high risk of bias.}, }
@article {pmid23145119, year = {2012}, author = {Zhao, W and Varghese, M and Vempati, P and Dzhun, A and Cheng, A and Wang, J and Lange, D and Bilski, A and Faravelli, I and Pasinetti, GM}, title = {Caprylic triglyceride as a novel therapeutic approach to effectively improve the performance and attenuate the symptoms due to the motor neuron loss in ALS disease.}, journal = {PloS one}, volume = {7}, number = {11}, pages = {e49191}, pmid = {23145119}, issn = {1932-6203}, support = {R24 CA095823/CA/NCI NIH HHS/United States ; 1 S10 RR0 9145-01/RR/NCRR NIH HHS/United States ; 5R24 CA095823-04/CA/NCI NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Animals ; Animals, Genetically Modified ; Caprylates/*pharmacology ; Disease Models, Animal ; Energy Metabolism/drug effects ; Humans ; Ketones/blood ; Mice ; Mitochondria/genetics/metabolism ; *Motor Neurons/drug effects/metabolism/pathology ; Oxygen Consumption ; Spinal Cord/drug effects/metabolism/pathology ; Superoxide Dismutase/genetics/metabolism ; Triglycerides/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and finally death. ALS patients suffer from asthenia and their progressive weakness negatively impacts quality of life, limiting their daily activities. They have impaired energy balance linked to lower activity of mitochondrial electron transport chain enzymes in ALS spinal cord, suggesting that improving mitochondrial function may present a therapeutic approach for ALS. When fed a ketogenic diet, the G93A ALS mouse shows a significant increase in serum ketones as well as a significantly slower progression of weakness and lower mortality rate. In this study, we treated SOD1-G93A mice with caprylic triglyceride, a medium chain triglyceride that is metabolized into ketone bodies and can serve as an alternate energy substrate for neuronal metabolism. Treatment with caprylic triglyceride attenuated progression of weakness and protected spinal cord motor neuron loss in SOD1-G93A transgenic animals, significantly improving their performance even though there was no significant benefit regarding the survival of the ALS transgenic animals. We found that caprylic triglyceride significantly promoted the mitochondrial oxygen consumption rate in vivo. Our results demonstrated that caprylic triglyceride alleviates ALS-type motor impairment through restoration of energy metabolism in SOD1-G93A ALS mice, especially during the overt stage of the disease. These data indicate the feasibility of using caprylic acid as an easily administered treatment with a high impact on the quality of life of ALS patients.}, }
@article {pmid23144905, year = {2012}, author = {Li, R and Strykowski, R and Meyer, M and Mulcrone, P and Krakora, D and Suzuki, M}, title = {Male-specific differences in proliferation, neurogenesis, and sensitivity to oxidative stress in neural progenitor cells derived from a rat model of ALS.}, journal = {PloS one}, volume = {7}, number = {11}, pages = {e48581}, pmid = {23144905}, issn = {1932-6203}, support = {R21 NS061049/NS/NINDS NIH HHS/United States ; R21NS06104/NS/NINDS NIH HHS/United States ; 9U54TR000021/TR/NCATS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Cell Cycle Proteins/metabolism ; Cell Differentiation/genetics ; Cell Proliferation ; Disease Models, Animal ; Female ; Male ; Mutant Proteins/metabolism ; Neural Stem Cells/metabolism/*pathology ; *Neurogenesis ; *Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; *Sex Characteristics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Transgenes ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor dysfunction and the loss of large motor neurons in the spinal cord and brain stem. A clear genetic link to point mutations in the superoxide dismutase 1 (SOD1) gene has been shown in a small group of familial ALS patients. The exact etiology of ALS is still uncertain, but males have consistently been shown to be at a higher risk for the disease than females. Here we present male-specific effects of the mutant SOD1 transgene on proliferation, neurogenesis, and sensitivity to oxidative stress in rat neural progenitor cells (rNPCs). E14 pups were bred using SOD1(G93A) transgenic male rats and wild-type female rats. The spinal cord and cortex tissues were collected, genotyped by PCR using primers for the SOD1(G93A) transgene or the male-specific Sry gene, and cultured as neurospheres. The number of dividing cells was higher in male rNPCs compared to female rNPCs. However, SOD1(G93A) over-expression significantly reduced cell proliferation in male cells but not female cells. Similarly, male rNPCs produced more neurons compared to female rNPCs, but SOD1(G93A) over-expression significantly reduced the number of neurons produced in male cells. Finally we asked whether sex and SOD1(G93A) transgenes affected sensitivity to oxidative stress. There was no sex-based difference in cell viability after treatment with hydrogen peroxide or 3-morpholinosydnonimine, a free radical-generating agent. However, increased cytotoxicity by SOD1(G93A) over-expression occurred, especially in male rNPCs. These results provide essential information on how the mutant SOD1 gene and sexual dimorphism are involved in ALS disease progression.}, }
@article {pmid23143660, year = {2013}, author = {Li, S and Sheng, J and Hu, JK and Yu, W and Kishikawa, H and Hu, MG and Shima, K and Wu, D and Xu, Z and Xin, W and Sims, KB and Landers, JE and Brown, RH and Hu, GF}, title = {Ribonuclease 4 protects neuron degeneration by promoting angiogenesis, neurogenesis, and neuronal survival under stress.}, journal = {Angiogenesis}, volume = {16}, number = {2}, pages = {387-404}, pmid = {23143660}, issn = {1573-7209}, support = {R01 CA105241/CA/NCI NIH HHS/United States ; R01 NS065237/NS/NINDS NIH HHS/United States ; R01 NS073873/NS/NINDS NIH HHS/United States ; R01 NS 065237/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Base Sequence ; Cell Line ; DNA Primers ; Humans ; In Situ Hybridization ; Mice ; *Neovascularization, Physiologic ; *Neurogenesis ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Ribonucleases/genetics/*metabolism ; }, abstract = {Altered RNA processing is an underlying mechanism of amyotrophic lateral sclerosis (ALS). Missense mutations in a number of genes involved in RNA function and metabolisms are associated with ALS. Among these genes is angiogenin (ANG), the fifth member of the vertebrate-specific, secreted ribonuclease superfamily. ANG is an angiogenic ribonuclease, and both its angiogenic and ribonucleolytic activities are important for motor neuron health. Ribonuclease 4 (RNASE4), the fourth member of this superfamily, shares the same promoters with ANG and is co-expressed with ANG. However, the biological role of RNASE4 is unknown. To determine whether RNASE4 is involved in ALS pathogenesis, we sequenced the coding region of RNASE4 in ALS and control subjects and characterized the angiogenic, neurogenic, and neuroprotective activities of RNASE4 protein. We identified an allelic association of SNP rs3748338 with ALS and demonstrated that RNASE4 protein is able to induce angiogenesis in in vitro, ex vivo, and in vivo assays. RNASE4 also induces neural differentiation of P19 mouse embryonal carcinoma cells and mouse embryonic stem cells. Moreover, RNASE4 not only stimulates the formation of neurofilaments from mouse embryonic cortical neurons, but also protects hypothermia-induced degeneration. Importantly, systemic treatment with RNASE4 protein slowed weight loss and enhanced neuromuscular function of SOD1 (G93A) mice.}, }
@article {pmid23141749, year = {2013}, author = {Roger, A and Quilez, E and Depreux, N and Farre, M and , }, title = {DIRAE study: seasonal allergic rhinitis distribution in Spain.}, journal = {Allergologia et immunopathologia}, volume = {41}, number = {3}, pages = {151-157}, doi = {10.1016/j.aller.2012.03.005}, pmid = {23141749}, issn = {1578-1267}, mesh = {Adrenal Cortex Hormones/therapeutic use ; Adult ; Allergy and Immunology ; Anti-Allergic Agents/therapeutic use ; Asthma/epidemiology ; Comorbidity ; Complementary Therapies/statistics &amp; numerical data ; Conjunctivitis, Allergic/epidemiology ; Cross-Sectional Studies ; Desensitization, Immunologic/statistics &amp; numerical data ; Female ; Health Surveys ; Histamine Antagonists/therapeutic use ; Humans ; Male ; Middle Aged ; Patient Satisfaction ; Physicians/psychology/statistics &amp; numerical data ; Practice Patterns, Physicians'/statistics &amp; numerical data ; Prevalence ; Primary Health Care ; Rhinitis, Allergic, Seasonal/drug therapy/*epidemiology/therapy ; Sample Size ; Severity of Illness Index ; Spain/epidemiology ; Surveys and Questionnaires ; Treatment Outcome ; Vasoconstrictor Agents/therapeutic use ; }, abstract = {BACKGROUND: National epidemiological study to observe if among patients with pollinic seasonal allergic rhinitis (SAR), there are differences between those visited by primary care physicians (GPs) or allergists (ALs).<br><br>METHODS: 758 and 739 adults were recruited respectively by GPs and ALs. The physicians filled in a questionnaire: ARIA classification, prescribed treatment, and asthma incidence. The patient completed a visual analogical scale (VAS) to evaluate the severity of the rhinitis. Rhinitis control (controlled, partially controlled, and not controlled) was assessed by physician and patient.<br><br>RESULTS: No significant differences were found among patients visited by GPs or ALs concerning the ARIA classification and rhinitis severity. Treatment with oral antihistamines was 92.3% and 89.3% for GPs and ALs, respectively. The use of nasal corticosteroids was 76.7% and 60.4% for GP and AL patients, respectively. 31.9% of the patients visited by the ALs were treated with immunotherapy. The use of alternative medicine was 10.9% and 7.6% in GP and AL patients, respectively. The perception of "controlled" rhinitis was similar among patients (40.0%) and doctors (40.1%), although patients referred differences depending if they were visited by GP (44.8%) or AL (34.9%). Asthma prevalence was higher in those who suffered persistent as compared to intermittent rhinitis (OR=1.81, 95% CI: 1.39-2.36, p<0.001), and moderate/severe vs. mild rhinitis (OR=1.68, 95% CI: 1.05-2.68, p=0.029).<br><br>CONCLUSION: The patients with pollinic SAR visited by GPs or ALs show no differences in severity. Less than half of the patients can be considered as "controlled".}, }
@article {pmid23137745, year = {2012}, author = {Carter, GT and Joyce, NC and Abresch, AL and Smith, AE and VandeKeift, GK}, title = {Using palliative care in progressive neuromuscular disease to maximize quality of life.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {23}, number = {4}, pages = {903-909}, doi = {10.1016/j.pmr.2012.08.002}, pmid = {23137745}, issn = {1558-1381}, mesh = {Chronic Pain/etiology/therapy ; Humans ; Neuromuscular Diseases/complications/*therapy ; *Palliative Care ; *Quality of Life ; }, abstract = {This article discusses the role of palliative care in the treatment pathway of patients with progressive neuromuscular disease (NDM), including amyotrophic lateral sclerosis and Duchenne muscular dystrophy (DMD). People with severe NMDs like DMD are now living much longer, well in to adulthood. This makes them suitable for the medical model of palliative care. Yet palliative medicine is a new area, especially for "adults" with DMD. Strategies for identifying the most effective modalities to alleviate suffering in patients with an NMD receiving palliative services and creating best practice standards in pain and symptom management for this patient population are discussed.}, }
@article {pmid23135021, year = {2012}, author = {Prabhakar, S and Marwaha, N and Lal, V and Sharma, RR and Rajan, R and Khandelwal, N}, title = {Autologous bone marrow-derived stem cells in amyotrophic lateral sclerosis: a pilot study.}, journal = {Neurology India}, volume = {60}, number = {5}, pages = {465-469}, doi = {10.4103/0028-3886.103185}, pmid = {23135021}, issn = {0028-3886}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/mortality/*surgery ; Bone Marrow Cells/physiology ; *Bone Marrow Transplantation ; Disability Evaluation ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Pilot Projects ; Retrospective Studies ; Severity of Illness Index ; Stem Cell Transplantation/*methods ; Survival Analysis ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no effective treatment. Stem cell therapy may be one of the promising treatment options for such patients.<br><br>AIM: To assess the feasibility, efficacy and safety of autologous bone marrow-derived stem cells in patients of ALS.<br><br>SETTINGS AND DESIGN: We conducted an open-label pilot study of autologous bone marrow-derived stem cells in patients with ALS attending the Neurology Clinic of a tertiary care referral centre.<br><br>MATERIALS AND METHODS: Ten patients with ALS with mean revised ALS Functional Rating Scale (ALSFRS-R) score of 30.2 (&#xb1; 10.58) at baseline received intrathecal autologous bone marrow-derived stem cells. Primary end point was improvement in the ALSFRS-R score at 90, 180, 270 and 365 days post therapy. Secondary endpoints included ALSFRS-R subscores, time to 4-point deterioration, median survival and reported adverse events. Paired t-test was used to compare changes in ALSFRS-R from baseline and Kaplan-Meier analysis was used for survival calculations.<br><br>RESULTS: There was no significant deterioration in ALSFRS-R composite score from baseline at one-year follow-up (P=0.090). The median survival post procedure was 18.0 months and median time to 4-point deterioration was 16.7 months. No significant adverse events were reported.<br><br>CONCLUSION: Autologous bone marrow-derived stem cell therapy is safe and feasible in patients of ALS. Short-term follow-up of ALSFRS-R scores suggests a trend towards stabilization of disease. However, the benefit needs to be confirmed in the long-term follow-up period.}, }
@article {pmid23129563, year = {2013}, author = {Krüger, T and Lautenschläger, J and Grosskreutz, J and Rhode, H}, title = {Proteome analysis of body fluids for amyotrophic lateral sclerosis biomarker discovery.}, journal = {Proteomics. Clinical applications}, volume = {7}, number = {1-2}, pages = {123-135}, doi = {10.1002/prca.201200067}, pmid = {23129563}, issn = {1862-8354}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*metabolism/therapy ; Biomarkers/analysis/metabolism ; Body Fluids/*metabolism ; Humans ; Proteome/analysis/*metabolism ; *Proteomics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of motor neurons leading to death of the patients, mostly within 2-5 years after disease onset. The pathomechanism of motor neuron degeneration is only partially understood and therapeutic strategies based on mechanistic insights are largely ineffective. The discovery of reliable biomarkers of disease diagnosis and progression is the sine qua non of both the revelation of insights into the ALS pathomechanism and the assessment of treatment efficacies. Proteomic approaches are an important pillar in ALS biomarker discovery. Cerebrospinal fluid is the most promising body fluid for differential proteome analyses, followed by blood (serum, plasma), and even urine and saliva. The present study provides an overview about reported peptide/protein biomarker candidates that showed significantly altered levels in certain body fluids of ALS patients. These findings have to be discussed according to proposed pathomechanisms to identify modifiers of disease progression and to pave the way for the development of potential therapeutic strategies. Furthermore, limitations and advantages of proteomic approaches for ALS biomarker discovery in different body fluids and reliable validation of biomarker candidates have been addressed.}, }
@article {pmid23123559, year = {2013}, author = {Brugger, H and Durrer, B and Elsensohn, F and Paal, P and Strapazzon, G and Winterberger, E and Zafren, K and Boyd, J and , }, title = {Resuscitation of avalanche victims: Evidence-based guidelines of the international commission for mountain emergency medicine (ICAR MEDCOM): intended for physicians and other advanced life support personnel.}, journal = {Resuscitation}, volume = {84}, number = {5}, pages = {539-546}, doi = {10.1016/j.resuscitation.2012.10.020}, pmid = {23123559}, issn = {1873-1570}, mesh = {*Avalanches ; Disaster Victims ; Evidence-Based Emergency Medicine/*methods ; Heart Arrest/*therapy ; Humans ; Hypothermia/*therapy ; Life Support Care/*methods ; Resuscitation/*methods ; Transportation of Patients ; }, abstract = {BACKGROUND: In North America and Europe ∼150 persons are killed by avalanches every year.<br><br>METHODS: The International Commission for Mountain Emergency Medicine (ICAR MEDCOM) systematically developed evidence-based guidelines and an algorithm for the management of avalanche victims using a worksheet of 27 Population Intervention Comparator Outcome questions. Classification of recommendations and level of evidence are ranked using the American Heart Association system.<br><br>RESULTS AND CONCLUSIONS: If lethal injuries are excluded and the body is not frozen, the rescue strategy is governed by the duration of snow burial and, if not available, by the victim's core-temperature. If burial time &#x2264;35 min (or core-temperature &#x2265;32 &#xb0;C) rapid extrication and standard ALS is important. If burial time >35 min and core-temperature <32 &#xb0;C, treatment of hypothermia including gentle extrication, full body insulation, ECG and core-temperature monitoring is recommended, and advanced airway management if appropriate. Unresponsive patients presenting with vital signs should be transported to a hospital capable of active external and minimally invasive rewarming such as forced air rewarming. Patients with cardiac instability or in cardiac arrest (with a patent airway) should be transported to a hospital for extracorporeal membrane oxygenation or cardiopulmonary bypass rewarming. Patients in cardiac arrest should receive uninterrupted CPR; with asystole, CPR may be terminated (or withheld) if a patient is lethally injured or completely frozen, the airway is blocked and duration of burial >35 min, serum potassium >12 mmol L(-1), risk to the rescuers is unacceptably high or a valid do-not-resuscitate order exists. Management should include spinal precautions and other trauma care as indicated.}, }
@article {pmid23117224, year = {2013}, author = {Lee, CT and Chiu, YW and Wang, KC and Hwang, CS and Lin, KH and Lee, IT and Tsai, CP}, title = {Riluzole and prognostic factors in amyotrophic lateral sclerosis long-term and short-term survival: a population-based study of 1149 cases in Taiwan.}, journal = {Journal of epidemiology}, volume = {23}, number = {1}, pages = {35-40}, pmid = {23117224}, issn = {1349-9092}, mesh = {Adult ; Age Distribution ; Aged ; Amyotrophic Lateral Sclerosis/mortality/*therapy ; Databases, Factual ; Female ; Follow-Up Studies ; *Gastrostomy ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; *Positive-Pressure Respiration ; Prognosis ; Retrospective Studies ; Riluzole/*therapeutic use ; Risk Factors ; Sex Distribution ; Socioeconomic Factors ; Survival Analysis ; Taiwan/epidemiology ; Time Factors ; *Tracheotomy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare disease in Taiwan; thus, estimation of ALS mortality is difficult. We evaluated factors associated with ALS survival in Taiwan.<br><br>METHODS: The study enrolled 1149 Taiwanese with a primary diagnosis of ALS during 1999-2008. Follow-up information was available for all patients; mean (SD) duration of follow-up was 2.91 (2.62) years. Medical interventions, including noninvasive positive pressure ventilation (NIPPV), tracheotomy, gastrostomy, and riluzole, were included in time-dependent survival analysis.<br><br>RESULTS: Of the 1149 ALS patients, 438 (38.12%) died during follow-up. Mortality in the first year was 16%, which was 13 times (95% CI 11.1-15.2) the age- and sex-standardized rate of the general population in Taiwan. The average annual crude mortality rate was 13.1% (person-years). Factors significantly associated with increased mortality were male sex, advanced age, rural residence, lower economic status, no tracheotomy, and no riluzole treatment. Significant predictors of long-term versus average survival were younger age at diagnosis, being a dependent or receiving social welfare, and NIPPV support. Significant predictors of short-term versus average survival were older age, being employed, no tracheotomy, and no riluzole use.<br><br>CONCLUSIONS: The results support the use of riluzole to improve ALS survival. Patients who received riluzole and underwent tracheotomy had the best survival.}, }
@article {pmid23110908, year = {2012}, author = {De Martino, C and Caiazzo, P and Albano, M and Pastore, M and Tramutoli, PR and Rocca, R and Botte, M and Sigillito, A}, title = {Acute afferent loop obstruction treated by endoscopic decompression. Case report and review of literature.}, journal = {Annali italiani di chirurgia}, volume = {83}, number = {6}, pages = {555-558}, pmid = {23110908}, issn = {0003-469X}, mesh = {Acute Disease ; Afferent Loop Syndrome/*surgery ; Decompression, Surgical/*methods ; *Endoscopy, Gastrointestinal ; Humans ; Male ; Middle Aged ; }, abstract = {Afferent loop syndrome (ALS) is a rare complication of Billroth-II gastrojejunostomy. Most cases of ALS are caused by obstruction from adhesions, kinking at the anastomosis, internal hernia, stomal stenosis, malignancy, or inflammation surrounding the anastomosis. A 61-years old man, who had undergone gastric resection 30 years before, was admitted at emergency room with severe abdominal pain in acute onset, nausea and vomiting. Ultrasonography and multi-detector computed tomography suggested acute ALS, due probably to adhesions or internal hernia. The patient was conducted to digestive endoscopy unit and successfully treated with endoscopic decompression of dilated afferent loop. Open surgery is actually considered the gold-standard in treatment of ALS. However, some surgeons report a few cases treated by laparoscopic surgery, interventional radiology techniques, endoscopic decompression. Authors suggest endoscopic decompression of acute ALS due to adhesions or internal hernia as the first treatment, especially in high-surgical-risk patients.}, }
@article {pmid23109883, year = {2012}, author = {Lee, DH and Gold, R and Linker, RA}, title = {Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters.}, journal = {International journal of molecular sciences}, volume = {13}, number = {9}, pages = {11783-11803}, pmid = {23109883}, issn = {1422-0067}, mesh = {Animals ; Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Dimethyl Fumarate ; Fumarates/*therapeutic use ; Humans ; Immunosuppressive Agents/*therapeutic use ; Mice ; Multiple Sclerosis/*drug therapy/metabolism/pathology ; NF-E2-Related Factor 2/metabolism ; Neurodegenerative Diseases/*drug therapy/metabolism/pathology ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress/drug effects ; Transcription, Genetic/drug effects ; }, abstract = {Oxidative stress plays a crucial role in many neurodegenerative conditions such as Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's as well as Huntington's disease. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis (MS). Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic-progressive MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment. Here, fumaric acid esters (FAE) are a new, orally available treatment option which had already been tested in phase II/III MS trials demonstrating beneficial effects on relapse rates and magnetic resonance imaging markers. In vitro, application of dimethylfumarate (DMF) leads to stabilization of Nrf2, activation of Nrf2-dependent transcriptional activity and abundant synthesis of detoxifying proteins. Furthermore, application of FAE involves direct modification of the inhibitor of Nrf2, Kelch-like ECH-associated protein 1. On cellular levels, the application of FAE enhances neuronal survival and protects astrocytes against oxidative stress. Increased levels of Nrf2 are detected in the central nervous system of DMF treated mice suffering from experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In EAE, DMF ameliorates the disease course and improves preservation of myelin, axons and neurons. Finally, Nrf2 is also up-regulated in the spinal cord of autopsy specimens from untreated patients with MS, probably as part of a naturally occurring anti-oxidative response. In summary, oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapies like FAE.}, }
@article {pmid23109841, year = {2012}, author = {Maiese, K and Chong, ZZ and Shang, YC and Wang, S}, title = {Erythropoietin: new directions for the nervous system.}, journal = {International journal of molecular sciences}, volume = {13}, number = {9}, pages = {11102-11129}, pmid = {23109841}, issn = {1422-0067}, mesh = {Apoptosis/physiology ; Disease Progression ; Erythropoietin/*metabolism ; Humans ; Nervous System/metabolism/*pathology ; Neurodegenerative Diseases/*pathology/prevention &amp; control/therapy ; Oxidative Stress/physiology ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Receptors, Erythropoietin/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Wnt1 Protein/metabolism ; }, abstract = {New treatment strategies with erythropoietin (EPO) offer exciting opportunities to prevent the onset and progression of neurodegenerative disorders that currently lack effective therapy and can progress to devastating disability in patients. EPO and its receptor are present in multiple systems of the body and can impact disease progression in the nervous, vascular, and immune systems that ultimately affect disorders such as Alzheimer's disease, Parkinson's disease, retinal injury, stroke, and demyelinating disease. EPO relies upon wingless signaling with Wnt1 and an intimate relationship with the pathways of phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR). Modulation of these pathways by EPO can govern the apoptotic cascade to control β-catenin, glycogen synthase kinase-3β, mitochondrial permeability, cytochrome c release, and caspase activation. Yet, EPO and each of these downstream pathways require precise biological modulation to avert complications associated with the vascular system, tumorigenesis, and progression of nervous system disorders. Further understanding of the intimate and complex relationship of EPO and the signaling pathways of Wnt, PI 3-K, Akt, and mTOR are critical for the effective clinical translation of these cell pathways into robust treatments for neurodegenerative disorders.}, }
@article {pmid23108236, year = {2013}, author = {Wang, IF and Tsai, KJ and Shen, CK}, title = {Autophagy activation ameliorates neuronal pathogenesis of FTLD-U mice: a new light for treatment of TARDBP/TDP-43 proteinopathies.}, journal = {Autophagy}, volume = {9}, number = {2}, pages = {239-240}, doi = {10.4161/auto.22526}, pmid = {23108236}, issn = {1554-8635}, mesh = {Animals ; *Autophagy ; DNA-Binding Proteins/*metabolism ; Frontotemporal Dementia/*etiology/*therapy ; Mice ; Mice, Transgenic ; Models, Biological ; Neurons/*pathology ; Signal Transduction ; }, abstract = {The administration of rapamycin, an MTOR-dependent autophagy activator, for the treatment of neurodegenerative diseases has been tested in several animal models. Thus, whether autophagy activation would lead to the clearance of abnormal accumulation of aggregated proteins in neurodegenerative diseases is worthy of exploration. We have recently shown that rapamycin administration at the early pathological stage of a mouse model with frontotemporal lobar dementia (FTLD-U) characterized with cytoplasmic TARDBP/TDP-43(+)/ubiquitin(+) inclusions (UBIs) in the diseased neurons could rescue the learning/memory deficiency and the abnormal motor function disorder of the mice. This was accompanied by a decreased level of CASP3/caspase-3 and a reduction of the neuronal loss in the mouse forehead. Moreover, autophagy activation at a late pathological stage also could improve motor function, which was accompanied by a reduction of the TARDBP(+) UBIs. This study has set the principal for therapy of neurodegenerative diseases with the TARDBP protein, i.e., amyotrophic lateral sclerosis (ALS)-TDP and FTLD-TDP43, with the use of autophagy activators.}, }
@article {pmid23102375, year = {2012}, author = {Lee, KW and Jung, SY and Choi, SM and Yang, EJ}, title = {Effects of ginsenoside Re on LPS-induced inflammatory mediators in BV2 microglial cells.}, journal = {BMC complementary and alternative medicine}, volume = {12}, number = {}, pages = {196}, pmid = {23102375}, issn = {1472-6882}, mesh = {Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Cell Line ; Ginsenosides/pharmacology/*therapeutic use ; Inflammation/chemically induced/*drug therapy/metabolism ; Inflammation Mediators/*metabolism ; Lipopolysaccharides ; Mice ; Microglia/*drug effects/metabolism ; Neurodegenerative Diseases/drug therapy/metabolism/pathology ; Neuroprotective Agents/pharmacology/therapeutic use ; Panax/*chemistry ; *Phytotherapy ; Plant Extracts/pharmacology/therapeutic use ; Signal Transduction ; }, abstract = {BACKGROUND: Microglial activation plays an important role in neurodegenerative diseases by producing several pro-inflammatory enzymes and pro-inflammatory cytokines. Lipopolysaccharide (LPS)-induced inflammation leads to the activation of microglial cells in the central nervous system (CNS) and is associated with the pathological mechanisms of neurodegenerative diseases, including PD, AD, and ALS. Ginseng is a natural antioxidant used in herbal medicine and contains ginsenosides (Rb1, Rg1, Rg3, Re, and Rd), which have anti-neoplastic and anti-stress properties.This study demonstrates the involvement of the anti-inflammatory signaling pathway, ginsenoside-Re (G-Re), which is one of the ginsenosides mediated by LPS-induced neuroinflammation in BV2 microglial cells.<br><br>METHODS: BV2 microglial cells were pretreated with 2 &#x3bc;g/ml G-Re and stimulated with 1 &#x3bc;g/ml LPS to induce neuroinflammation. To investigate the effect of G-Re on LPS-induced cell signaling, we performed western blotting and immunofluorescence using specific antibodies, such as phospho-p38, COX2, and iNOS.<br><br>RESULTS: Pretreatment with 2 &#x3bc;g/ml G-Re was neuroprotective against 1 &#x3bc;g/ml LPS-treated microglial cells. The neuroprotective events induced by G-Re treatment in neuroinflammation occurred via the phospho-p38, iNOS, and COX2 signaling pathways in BV2 cells.<br><br>CONCLUSION: Taken together, we suggest that G-Re exerts a beneficial effect on neuroinflammatory events in neurodegenerative diseases.}, }
@article {pmid23098801, year = {2013}, author = {Lee, M and McGeer, E and McGeer, PL}, title = {Neurotoxins released from interferon-gamma-stimulated human astrocytes.}, journal = {Neuroscience}, volume = {229}, number = {}, pages = {164-175}, doi = {10.1016/j.neuroscience.2012.10.033}, pmid = {23098801}, issn = {1873-7544}, mesh = {Astrocytes/cytology/drug effects/*metabolism ; Cell Death/*drug effects ; Cell Line, Tumor ; Cells, Cultured ; Culture Media, Conditioned ; Dinoprostone/metabolism ; Humans ; Interferon-gamma/*pharmacology ; Interleukin-6/*metabolism ; NADPH Oxidases/metabolism ; Neurotoxins/*metabolism ; Peptide Hydrolases/metabolism ; }, abstract = {Astrocytes become activated in degenerative neurological diseases. In order to gain a greater understanding of the inflammatory factors released upon activation, we stimulated adult human astrocytes with interferon-gamma and examined the resultant conditioned medium (CM) for toxicity against differentiated human neuroblastoma SH-SY5Y cells. Cell death was measured by lactate dehydrogenase release assay. We then used various treatments of the media to determine the distribution and nature of the toxic components. Removal of interleukin-6 by a specific antibody reduced the toxicity by 22%. Blockade of proteases with an inhibitor cocktail reduced it by a further 22%. When oxygen-free radical production was blocked with NADPH oxidase inhibitors, the toxicity was reduced by 15.4%. When prostaglandin production was blocked by cyclooxygenase inhibitors, the toxicity of the CM was reduced by 14.5%. When glutamate was removed by treatment with glutamate decarboxylase, the toxicity was reduced by 10.3%. When the inhibitors were added together to the astrocyte culture, the total toxicity of the CM was reduced by 91%. This was in reasonable agreement with the 85.37% total obtained by adding the individual components. The data show that activated astrocytes release a specific combination of neurotoxic compounds. They suggest that effective anti-inflammatory treatment of such neurodegenerative diseases as Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis could be improved by using an appropriate combination of anti-inflammatory agents instead of relying on any single agent.}, }
@article {pmid23096027, year = {2012}, author = {Levitskiĭ, GN and Gilod, VM and Levin, OS}, title = {[A specific phobia of amyotrophic lateral sclerosis (ALS phobia)].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {112}, number = {8}, pages = {4-6}, pmid = {23096027}, issn = {1997-7298}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*psychology ; Female ; Humans ; Male ; Middle Aged ; Phobic Disorders/*diagnosis/drug therapy/*etiology ; Severity of Illness Index ; }, abstract = {A specific phobia of amyotrophic lateral sclerosis (ALS phobia) was not previously described in the literature. We examined 21 patients, 11 men and 10 women, aged 28-72 years, with symptoms of this phobia. Only 23% of patients had a history of the psychiatric disorder in the past. The duration of phobia symptoms was significantly higher in patients with moderate and severe phobia than in mild cases (1.5±0.6 and 5.0±1.1 months respectively; р<0.05). The severity of ALS phobia was correlated with its duration (r= -0.5; p=0.004). The primary character of phobia was established in 52.4% of patients basing on the regression of phobia symptoms assessed by the Hamilton anxiety scale after psychotherapy and pharmacotherapy (17±4 and 3±1 scores before and 3 months after treatment, respectively; p<0.05).}, }
@article {pmid23095749, year = {2012}, author = {Tashiro, Y and Urushitani, M and Inoue, H and Koike, M and Uchiyama, Y and Komatsu, M and Tanaka, K and Yamazaki, M and Abe, M and Misawa, H and Sakimura, K and Ito, H and Takahashi, R}, title = {Motor neuron-specific disruption of proteasomes, but not autophagy, replicates amyotrophic lateral sclerosis.}, journal = {The Journal of biological chemistry}, volume = {287}, number = {51}, pages = {42984-42994}, pmid = {23095749}, issn = {1083-351X}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/*pathology ; Animals ; *Autophagy ; Behavior, Animal ; Cell Cycle Proteins ; DNA-Binding Proteins/metabolism ; Eye Proteins/metabolism ; Membrane Transport Proteins ; Mice ; Mice, Knockout ; Motor Neurons/*enzymology/*pathology ; Neuroglia/metabolism/pathology ; Organ Specificity ; Phenotype ; Proteasome Endopeptidase Complex/*metabolism ; Protein Subunits/metabolism ; RNA-Binding Protein FUS/metabolism ; Spinal Cord/pathology ; Time Factors ; Ubiquitin/metabolism ; }, abstract = {Evidence suggests that protein misfolding is crucially involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, controversy still exists regarding the involvement of proteasomes or autophagy in ALS due to previous conflicting results. Here, we show that impairment of the ubiquitin-proteasome system, but not the autophagy-lysosome system in motor neurons replicates ALS in mice. Conditional knock-out mice of the proteasome subunit Rpt3 in a motor neuron-specific manner (Rpt3-CKO) showed locomotor dysfunction accompanied by progressive motor neuron loss and gliosis. Moreover, diverse ALS-linked proteins, including TAR DNA-binding protein 43 kDa (TDP-43), fused in sarcoma (FUS), ubiquilin 2, and optineurin were mislocalized or accumulated in motor neurons, together with other typical ALS hallmarks such as basophilic inclusion bodies. On the other hand, motor neuron-specific knock-out of Atg7, a crucial component for the induction of autophagy (Atg7-CKO), only resulted in cytosolic accumulation of ubiquitin and p62, and no TDP-43 or FUS pathologies or motor dysfunction was observed. These results strongly suggest that proteasomes, but not autophagy, fundamentally govern the development of ALS in which TDP-43 and FUS proteinopathy may play a crucial role. Enhancement of proteasome activity may be a promising strategy for the treatment of ALS.}, }
@article {pmid23047912, year = {2013}, author = {Okle, O and Stemmer, K and Deschl, U and Dietrich, DR}, title = {L-BMAA induced ER stress and enhanced caspase 12 cleavage in human neuroblastoma SH-SY5Y cells at low nonexcitotoxic concentrations.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {131}, number = {1}, pages = {217-224}, doi = {10.1093/toxsci/kfs291}, pmid = {23047912}, issn = {1096-0929}, mesh = {Amino Acids, Diamino/*toxicity ; Amyotrophic Lateral Sclerosis/chemically induced/epidemiology/metabolism ; Caspase 12/*metabolism ; Cell Culture Techniques ; Cell Line, Tumor ; Cell Survival/drug effects ; Cyanobacteria Toxins ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum Stress/*drug effects ; Excitatory Amino Acid Agonists/*toxicity ; Guam/epidemiology ; HEK293 Cells ; Humans ; Parkinson Disease/epidemiology/metabolism ; Protein Binding ; Protein Folding ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Supranuclear Palsy, Progressive/chemically induced/epidemiology/metabolism ; Ubiquitinated Proteins/metabolism ; }, abstract = {The cyanobacterial β-N-methylamino-L-alanine (L-BMAA) is described as a low-potency excitotoxin, possibly a factor in the increased incidence of amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) in Guam. The latter association is intensively disputed, as L-BMAA concentrations required for toxic effects exceed those assumed to occur via food. The question thus was raised whether L-BMAA leads to neurodegeneration at nonexcitotoxic conditions. Using human SH-SY5Y neuroblastoma cells, L-BMAA-transport, incorporation into proteins, and subsequent impairment of cellular protein homeostasis were investigated. Binding of L-BMAA to intracellular proteins, but no clear protein incorporation was detected in response to (14)C-L-BMAA exposures. Nevertheless, low L-BMAA concentrations (≥ 0.1mM, 48 h) increased protein ubiquitination, 20S proteasomal and caspase 12 activity, expression of the endoplasmic reticulum (ER) stress marker CHOP, and enhanced phosphorylation of elf2α in SH-SY5Y cells. In contrast, high L-BMAA concentrations (≥ 1mM, 48 h) increased reactive oxygen species and protein oxidization, which were partially ameliorated by coincubation with vitamin E. L-BMAA-mediated cytotoxicity was observable 48 h following ≥ 2mM L-BMAA treatment. Consequently, the data presented here suggest that low L-BMAA concentrations result in a dysregulation of the cellular protein homeostasis with ensuing ER stress that is independent from high-concentration effects such as excitotoxicity and oxidative stress. Thus, the latter could be a contributing factor in the onset and slow progression of ALS/PDC in Guam.}, }
@article {pmid23029057, year = {2012}, author = {Gerber, YN and Sabourin, JC and Hugnot, JP and Perrin, FE}, title = {Unlike physical exercise, modified environment increases the lifespan of SOD1G93A mice however both conditions induce cellular changes.}, journal = {PloS one}, volume = {7}, number = {9}, pages = {e45503}, pmid = {23029057}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/genetics/mortality ; Animals ; Environment ; *Life Expectancy ; Male ; Mice ; Motor Neurons/metabolism ; Neuroglia/metabolism ; Neuromuscular Junction/metabolism ; *Physical Exertion ; Spinal Cord/cytology/metabolism ; Superoxide Dismutase/*genetics/*metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by a gradual muscular paralysis resulting from progressive motoneurons death. ALS etiology remains unknown although it has been demonstrated to be a multifactorial disease involving several cellular partners. There is currently no effective treatment. Even if the effect of exercise is under investigation for many years, whether physical exercise is beneficial or harmful is still under debate.<br><br>METHODS AND FINDINGS: We investigated the effect of three different intensities of running exercises on the survival of SOD1(G93A) mice. At the early-symptomatic stage (P60), males were isolated and randomly assigned to 5 conditions: 2 sedentary groups ("sedentary" and "sedentary treadmill" placed on the inert treadmill), and 3 different training intensity groups (5 cm/s, 10 cm/s and 21 cm/s; 15 min/day, 5days/week). We first demonstrated that an appropriate "control" of the environment is of the utmost importance since comparison of the two sedentary groups evidenced an 11.6% increase in survival in the "sedentary treadmill" group. Moreover, we showed by immunohistochemistry that this increased lifespan is accompanied with motoneurons survival and increased glial reactivity in the spinal cord. In a second step, we showed that when compared with the proper control, all three running-based training did not modify lifespan of the animals, but result in motoneurons preservation and changes in glial cells activation.<br><br>CONCLUSIONS/SIGNIFICANCE: We demonstrate that increase in survival induced by a slight daily modification of the environment is associated with motoneurons preservation and strong glial modifications in the lumbar spinal cord of SOD1(G93A). Using the appropriate control, we then demonstrate that all running intensities have no effect on the survival of ALS mice but induce cellular modifications. Our results highlight the critical importance of the control of the environment in ALS studies and may explain discrepancy in the literature regarding the effect of exercise in ALS.}, }
@article {pmid23027932, year = {2012}, author = {Tesla, R and Wolf, HP and Xu, P and Drawbridge, J and Estill, SJ and Huntington, P and McDaniel, L and Knobbe, W and Burket, A and Tran, S and Starwalt, R and Morlock, L and Naidoo, J and Williams, NS and Ready, JM and McKnight, SL and Pieper, AA}, title = {Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {109}, number = {42}, pages = {17016-17021}, pmid = {23027932}, issn = {1091-6490}, support = {P01 CA095471/CA/NCI NIH HHS/United States ; R01 MH087986/MH/NIMH NIH HHS/United States ; R01MH087986/MH/NIMH NIH HHS/United States ; P01CA095471/CA/NCI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*prevention &amp; control ; Animals ; Carbazoles/chemical synthesis/chemistry/pharmacokinetics/*pharmacology ; Indoles/pharmacokinetics/pharmacology ; Mice ; Motor Activity/drug effects/physiology ; Motor Neurons/*cytology/drug effects ; Neuroprotective Agents/*pharmacology ; Polymerase Chain Reaction ; Rotarod Performance Test ; Spinal Cord/*cytology/drug effects ; }, abstract = {We previously reported the discovery of P7C3, an aminopropyl carbazole having proneurogenic and neuroprotective properties in newborn neural precursor cells of the hippocampal dentate gyrus. We have further found that chemicals having efficacy in this in vivo screening assay also protect dopaminergic neurons of the substantia nigra following exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a mouse model of Parkinson disease. Here, we provide evidence that an active analog of P7C3, known as P7C3A20, protects ventral horn spinal cord motor neurons from cell death in the G93A-SOD1 mutant mouse model of amyotrophic lateral sclerosis (ALS). P7C3A20 is efficacious in this model when administered at disease onset, and protection from cell death correlates with preservation of motor function in assays of walking gait and in the accelerating rotarod test. The prototypical member of this series, P7C3, delays disease progression in G93A-SOD1 mice when administration is initiated substantially earlier than the expected time of symptom onset. Dimebon, an antihistaminergic drug with significantly weaker proneurogenic and neuroprotective efficacy than P7C3, confers no protection in this ALS model. We propose that the chemical scaffold represented by P7C3 and P7C3A20 may provide a basis for the discovery and optimization of pharmacologic agents for the treatment of ALS.}, }
@article {pmid23019386, year = {2012}, author = {Pratt, AJ and Getzoff, ED and Perry, JJ}, title = {Amyotrophic lateral sclerosis: update and new developments.}, journal = {Degenerative neurological and neuromuscular disease}, volume = {2012}, number = {2}, pages = {1-14}, pmid = {23019386}, issn = {1179-9900}, support = {R01 GM039345/GM/NIGMS NIH HHS/United States ; R03 AR059968/AR/NIAMS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease. It is typically characterized by adult-onset degeneration of the upper and lower motor neurons, and is usually fatal within a few years of onset. A subset of ALS patients has an inherited form of the disease, and a few of the known mutant genes identified in familial cases have also been found in sporadic forms of ALS. Precisely how the diverse ALS-linked gene products dictate the course of the disease, resulting in compromised voluntary muscular ability, is not entirely known. This review addresses the major advances that are being made in our understanding of the molecular mechanisms giving rise to the disease, which may eventually translate into new treatment options.}, }
@article {pmid23000247, year = {2012}, author = {Kanno, T and Tanaka, K and Yanagisawa, Y and Yasutake, K and Hadano, S and Yoshii, F and Hirayama, N and Ikeda, JE}, title = {A novel small molecule, N-(4-(2-pyridyl)(1,3-thiazol-2-yl))-2-(2,4,6-trimethylphenoxy) acetamide, selectively protects against oxidative stress-induced cell death by activating the Nrf2-ARE pathway: therapeutic implications for ALS.}, journal = {Free radical biology &amp; medicine}, volume = {53}, number = {11}, pages = {2028-2042}, doi = {10.1016/j.freeradbiomed.2012.09.010}, pmid = {23000247}, issn = {1873-4596}, mesh = {Acetamides/*pharmacology ; Acetylcysteine/pharmacology ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology/physiopathology ; Animals ; *Antioxidant Response Elements ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/genetics/metabolism ; Cell Survival/drug effects ; Drug Evaluation, Preclinical ; Enzyme Induction/drug effects ; Enzyme Inhibitors/pharmacology ; Female ; Free Radical Scavengers/*pharmacology ; Gene Expression Regulation/drug effects ; Glutamate-Cysteine Ligase/antagonists &amp; inhibitors/metabolism ; HeLa Cells ; Heme Oxygenase-1/antagonists &amp; inhibitors/metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Lipid Peroxidation ; Male ; Metabolic Detoxication, Phase II/genetics ; Mice ; Mice, Transgenic ; NAD(P)H Dehydrogenase (Quinone)/antagonists &amp; inhibitors/metabolism ; NF-E2-Related Factor 2/*metabolism/physiology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Thiazoles/*pharmacology ; }, abstract = {Antioxidant defense is crucial in restoring cellular redox homeostasis. Recent findings have suggested that oxidative stress plays pivotal roles in the pathogenesis of many neurodegenerative diseases. Thus, an anti-oxidative stress remedy might be a promising means for the treatment of such disorders. In this study, we employed a novel ligand-based virtual screening system and identified a novel small molecule, N-(4-(2-pyridyl)(1,3-thiazol-2-yl))-2-(2,4,6-trimethylphenoxy) acetamide (CPN-9), which selectively suppressed oxidative stress-induced cell death in a cell-type-independent manner. CPN-9 upregulates NF-E2-related factor 2 (Nrf2), a key transcriptional regulator of the expression of phase II detoxification enzymes and antioxidant proteins, and Nrf2-regulated factors such as heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutamate-cysteine ligase modifier subunit (GCLM). The CPN-9-mediated upregulation of HO-1, NQO1, and GCLM was abolished by Nrf2 knockdown. Moreover, the antioxidant N-acetylcysteine reduced the protective effect of CPN-9 against oxidative stress-induced cell death with concomitant diminishing of Nrf2 nuclear translocation. These results indicate that CPN-9 exerts its activity via the reactive oxygen species-dependent activation of the Nrf2 signaling pathway in cultured cells. It is noteworthy that the postonset systemic administration of CPN-9 to a transgenic ALS mouse model carrying the H46R mutation in the human Cu/Zn superoxide dismutase (SOD1) gene sustained motor functions and delayed disease progression after onset. Collectively, CPN-9 is a novel Nrf2 activator and a neuroprotective candidate for the treatment of neurodegenerative diseases, including ALS.}, }
@article {pmid22998138, year = {2012}, author = {Clemente, S}, title = {Amyotrophic lateral sclerosis treatment with ultramicronized palmitoylethanolamide: a case report.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {11}, number = {7}, pages = {933-936}, doi = {10.2174/1871527311201070933}, pmid = {22998138}, issn = {1996-3181}, mesh = {Administration, Sublingual ; Amides ; Amyotrophic Lateral Sclerosis/*diet therapy ; Anti-Inflammatory Agents, Non-Steroidal/administration &amp; dosage/chemistry/*therapeutic use ; *Dietary Supplements ; Endocannabinoids/administration &amp; dosage/chemistry/*therapeutic use ; Ethanolamines/administration &amp; dosage/chemistry/*therapeutic use ; Humans ; Male ; Middle Aged ; Palmitic Acids/administration &amp; dosage/chemistry/*therapeutic use ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons which leads to muscular atrophy, paralysis and death in 3-5 years from starting symptoms. This disorder is accompanied by noteworthy spinal inflammation mediated in particular by microglia and mast cells. No effective therapy is available. This report describes the effects of administering the anti-inflammatory agent palmitoylethanolamide in a case of sporadic amyotrophic lateral sclerosis. Palmitoylethanolamide treatment led to an improved clinical picture, as evidenced by electromyographic analysis and pulmonary function. Conceivably, the action of palmitoylethanolamide could result, in part, from its ability to dampen mast cell and microglia activation.}, }
@article {pmid22997668, year = {2012}, author = {Sempsrott, J and Schmidt, A and Hawkins, S and Bledsoe, B}, title = {Silent struggle.}, journal = {JEMS : a journal of emergency medical services}, volume = {37}, number = {7}, pages = {60, 62, 64 passim}, pmid = {22997668}, issn = {0197-2510}, mesh = {*Drowning ; Emergency Medical Services/*organization &amp; administration ; Emergency Treatment/*methods ; Humans ; *Near Drowning ; }, abstract = {The past 40-50 years of research and experience have given us improved knowledge of the pathophysiology and treatment of drowning injuries. Still, an all-too-common event, the morbidity and mortality of drowning can be mitigated by prevention, recognition and target treatment. Old terms, such as "near drowning" and "secondary drowning," are confusing and misleading, and use of these terms should be abandoned. Most importantly, EMS personnel should understand that drowning is a hypoxic event resulting from submersion in a liquid. Most BLS and ALS strategies are designed to treat cardiac causes of respiratory and cardiac arrests (with recent change to a CAB algorithm). Drowning, however, is initially a purely hypoxic event and should be treated as such with ventilation and oxygenation (with an ABC algorithm). EMS and the fire service, because of their presence in the community, are uniquely positioned to play a major role in drowning prevention and treatment.}, }
@article {pmid22995100, year = {2012}, author = {Bentley, B and Aoun, SM and O'Connor, M and Breen, LJ and Chochinov, HM}, title = {Is dignity therapy feasible to enhance the end of life experience for people with motor neurone disease and their family carers?.}, journal = {BMC palliative care}, volume = {11}, number = {}, pages = {18}, pmid = {22995100}, issn = {1472-684X}, abstract = {BACKGROUND: Development of interventions that address psychosocial and existential distress in people with motor neurone disease (MND) or that alleviate caregiver burden in MND family carers have often been suggested in the research literature. Dignity therapy, which was developed to reduce psychosocial and existential distress at the end of life, has been shown to benefit people dying of cancer and their families. These results may not be transferable to people with MND. The objectives of this study are to assess the feasibility, acceptability and potential effectiveness of dignity therapy to enhance the end of life experience for people with motor neurone disease and their family carers.<br><br>METHODS/DESIGN: This is a cross-sectional study utilizing a single treatment group and a pre/post test design. The study population will comprise fifty people diagnosed with MND and their nominated family carers. Primarily quantitative outcomes will be gathered through measures assessed at baseline and at approximately one week after the intervention. Outcomes for participants include hopefulness, spirituality and dignity. Outcomes for family carers include perceived caregiver burden, hopefulness and anxiety/depression. Feedback and satisfaction with the intervention will be gathered through a questionnaire.<br><br>DISCUSSION: This detailed research will explore if dignity therapy has the potential to enhance the end of life experience for people with MND and their family carers, and fill a gap for professionals who are called on to address the spiritual, existential and psychosocial needs of their MND patients and families.<br><br>TRIAL REGISTRATION: ACTRN Trial Number: ACTRN12611000410954.}, }
@article {pmid22989267, year = {2012}, author = {Zaider, T and Manne, S and Nelson, C and Mulhall, J and Kissane, D}, title = {Loss of masculine identity, marital affection, and sexual bother in men with localized prostate cancer.}, journal = {The journal of sexual medicine}, volume = {9}, number = {10}, pages = {2724-2732}, pmid = {22989267}, issn = {1743-6109}, support = {P30 CA006927/CA/NCI NIH HHS/United States ; R01 CA140297/CA/NCI NIH HHS/United States ; }, mesh = {*Adaptation, Psychological ; Cross-Sectional Studies ; Erectile Dysfunction/*psychology ; Female ; Humans ; Male ; *Masculinity ; Middle Aged ; Prostatectomy/*adverse effects ; Prostatic Neoplasms/*psychology/*surgery ; Quality of Life ; Sexual Behavior/*psychology ; Surveys and Questionnaires ; }, abstract = {INTRODUCTION: Erectile dysfunction (ED) is one of the most frequent sources of distress after treatment for prostate cancer (PCa), yet evidence suggests that men do not easily adjust to loss of sexual function over time. A hypothesized determinant of men's adaptation to ED is the degree to which they experience a loss of masculine identity in the aftermath of PCa treatment.<br><br>AIMS: The aims of this study were (i) to describe the prevalence of concerns related to diminished masculinity among men treated for localized PCa; (ii) to determine whether diminished masculinity is associated with sexual bother, after controlling for sexual functioning status; and (iii) to determine whether men's marital quality moderates the association between diminished masculinity and sexual bother.<br><br>METHODS: We analyzed cross-sectional data provided by 75 men with localized PCa who were treated at one of two cancer centers. Data for this study were provided at a baseline assessment as part of their enrollment in a pilot trial of a couple-based intervention.<br><br>MAIN OUTCOME MEASURES: The sexual bother subscale from the Prostate Health-Related Quality-of-Life Questionnaire and the Masculine Self-Esteem and Marital Affection subscales from Clark et&#x2003;al's PCa-related quality-of-life scale.<br><br>RESULTS: Approximately one-third of men felt they had lost a dimension of their masculinity following treatment. Diminished masculinity was the only significant, independent predictor of sexual bother, even after accounting for sexual functioning status. The association between diminished masculinity and sexual bother was strongest for men whose spouses perceived low marital affection.<br><br>CONCLUSIONS: Diminished masculinity is a prominent, yet understudied concern for PCa survivors. Regardless of functional status, men who perceive a loss of masculinity following treatment may be more likely to be distressed by their ED. Furthermore, its impact on adjustment in survivorship may rely on the quality of their intimate relationships.}, }
@article {pmid22987690, year = {2012}, author = {Healy, BC and Schoenfeld, D}, title = {Comparison of analysis approaches for phase III clinical trials in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {46}, number = {4}, pages = {506-511}, doi = {10.1002/mus.23392}, pmid = {22987690}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/*mortality/*therapy ; Clinical Trials, Phase III as Topic/*methods ; Computer Simulation ; Humans ; Longitudinal Studies/methods ; Proportional Hazards Models ; Randomized Controlled Trials as Topic/*methods ; Sample Size ; Survival Analysis ; }, abstract = {INTRODUCTION: In this study we explore several methods for incorporating survival information in the analysis of Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) scores.<br><br>METHODS: ALSFRS scores and patient survival times were simulated based on estimates from a recent clinical trial. Six analysis approaches were applied to the data. Each approach was based on ALSFRS scores, the survival time, or a combination of the 2. The power of each approach to detect potential treatment effects was estimated.<br><br>RESULTS: When the treatment acted solely on the change in ALSFRS, the shared parameter model provided the most power, although all of the models based on random effects were similar. As the effect on survival increased, rank-based analysis showed potential gains in power. Survival analysis was superior under a small effect on ALSFRS and a larger effect on mortality.<br><br>CONCLUSIONS: The shared parameter model and rank-based approach can offer improvements in power over traditional approaches.}, }
@article {pmid22985432, year = {2013}, author = {Rudnicki, SA and Berry, JD and Ingersoll, E and Archibald, D and Cudkowicz, ME and Kerr, DA and Dong, Y}, title = {Dexpramipexole effects on functional decline and survival in subjects with amyotrophic lateral sclerosis in a Phase II study: subgroup analysis of demographic and clinical characteristics.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {1}, pages = {44-51}, doi = {10.3109/17482968.2012.723723}, pmid = {22985432}, issn = {2167-9223}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy/*mortality ; Benzothiazoles/*administration &amp; dosage ; Dopamine Agonists/administration &amp; dosage ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Middle Aged ; Pramipexole ; Prevalence ; Recovery of Function/*drug effects ; Risk Factors ; Survival Analysis ; Survival Rate ; Treatment Outcome ; United States/epidemiology ; Young Adult ; }, abstract = {Our objective was to explore treatment effects in patient subgroups using post hoc analyses of data from part 2 of the dexpramipexole Phase II study. Subjects with amyotrophic lateral sclerosis (ALS) received dexpramipexole 300 mg/day or 50 mg/day for 24 weeks. Treatment effects on the slope of the revised ALS Functional Rating Score (ALSFRS-R) and Combined Assessment of Function and Survival (CAFS) were evaluated in dichotomized subgroups: riluzole use, gender, site of symptom onset. Other subgroups were dichotomized using median baseline values for age, ALSFRS-R, slow vital capacity, symptom duration, diagnostic delay, and progression rate. Results showed that there was a 21% reduction in ALSFRS-R decline favoring the 300-mg vs. 50-mg arm (p = 0.177); mean CAFS ranking was significantly higher in the 300-mg vs. 50-mg arm (52.4 vs. 41.1; p = 0.046). Trends were recapitulated in virtually all subgroups. Generally, ALSFRS-R decline was reduced and CAFS rankings were higher in the 300-mg vs. 50-mg arm across subgroups. CAFS rankings were significantly higher in the 300-mg vs. 50-mg arm among subjects with ALSFRS-R scores ≤35, symptom duration <18.7 months, or progression rate ≥ 0.7 points/month (p < 0.03). In conclusion, the observed benefit of 300- vs. 50-mg dexpramipexole on functional decline and survival was generally consistent among subjects regardless of baseline characteristics.}, }
@article {pmid22985381, year = {2012}, author = {Fehlings, MG and Wilson, JR and Frankowski, RF and Toups, EG and Aarabi, B and Harrop, JS and Shaffrey, CI and Harkema, SJ and Guest, JD and Tator, CH and Burau, KD and Johnson, MW and Grossman, RG}, title = {Riluzole for the treatment of acute traumatic spinal cord injury: rationale for and design of the NACTN Phase I clinical trial.}, journal = {Journal of neurosurgery. Spine}, volume = {17}, number = {1 Suppl}, pages = {151-156}, doi = {10.3171/2012.4.AOSPINE1259}, pmid = {22985381}, issn = {1547-5646}, mesh = {Humans ; Neuroprotective Agents/*therapeutic use ; *Research Design ; Riluzole/*therapeutic use ; Spinal Cord Injuries/*drug therapy ; }, abstract = {In the immediate period after traumatic spinal cord injury (SCI) a variety of secondary injury mechanisms combine to gradually expand the initial lesion size, potentially leading to diminished neurological outcomes at long-term follow-up. Riluzole, a benzothiazole drug, which has neuroprotective properties based on sodium channel blockade and mitigation of glutamatergic toxicity, is currently an approved drug that attenuates the extent of neuronal degeneration in patients with amyotrophic lateral sclerosis. Moreover, several preclinical SCI studies have associated riluzole administration with improved functional outcomes and increased neural tissue preservation. Based on these findings, riluzole has attracted considerable interest as a potential neuroprotective drug for the treatment of SCI. Currently, a Phase I trial evaluating the safety and pharmacokinetic profile of riluzole in human SCI patients is being conducted by the North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury. The current review summarizes the existing preclinical and clinical literature on riluzole, provides a detailed description of the Phase I trial, and suggests potential opportunities for future investigation. Clinical trial registration no.: NCT00876889.}, }
@article {pmid22985379, year = {2012}, author = {Chow, DS and Teng, Y and Toups, EG and Aarabi, B and Harrop, JS and Shaffrey, CI and Johnson, MM and Boakye, M and Frankowski, RF and Fehlings, MG and Grossman, RG}, title = {Pharmacology of riluzole in acute spinal cord injury.}, journal = {Journal of neurosurgery. Spine}, volume = {17}, number = {1 Suppl}, pages = {129-140}, doi = {10.3171/2012.5.AOSPINE12112}, pmid = {22985379}, issn = {1547-5646}, mesh = {Adolescent ; Adult ; Aged ; Biological Availability ; Chromatography, High Pressure Liquid ; Female ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*pharmacokinetics/therapeutic use ; Pilot Projects ; Riluzole/*pharmacokinetics/therapeutic use ; Spinal Cord Injuries/*drug therapy ; }, abstract = {OBJECT: The aim of this paper was to characterize individual and population pharmacokinetics of enterally administered riluzole in a Phase 1 clinical trial of riluzole as a neuroprotective agent in adults 18-70 years old with acute spinal cord injury (SCI).<br><br>METHODS: Thirty-five individuals with acute SCI, American Spinal Injury Association Impairment Scale Grades A-C, neurological levels from C-4 to T-12, who were enrolled in the Phase 1 clinical trial sponsored by the North American Clinical Trials Network for Treatment of Spinal Cord Injury, received 50 mg riluzole twice daily for 28 doses. The first dose was administered at a mean of 8.7 &#xb1; 2.2 hours postinjury. Trough plasma samples were collected within 1 hour predose, and peak plasma samples were collected 2 hours postdose on Days 3 and 14 of treatment. Riluzole concentrations were quantified by high-performance liquid chromatography assay. The data were analyzed for individual and population pharmacokinetics using basic structural and covariate models. The pharmacokinetic measures studied were the peak concentration (C(max)), trough concentration (C(min)), systemic exposure (AUC(0-12)), clearance (CL/F), and volume of distribution (V_F) normalized by the bioavailability (F).<br><br>RESULTS: The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher CL and larger V. The pharmacokinetics of riluzole (C(max), C(min), AUC(0-12), CL, and V) changed during the acute and subacute phases of SCI during the 14 days of therapy. It was consistently observed in patients at all clinical sites that C(max), C(min), and AUC(0-12) (128.9 ng/ml, 45.6 ng/ml, and 982.0 ng &#xd7; hr/ml, respectively) were significantly higher on Day 3 than on Day 14 (76.5 ng/ml, 19.1 ng/ml, and 521.0 ng &#xd7; hr/ml, respectively). These changes resulted from lower CL (49.5 vs 106.2 L/hour) and smaller V (557.1 vs 1297.9/L) on Day 3. No fluid imbalance or cytochrome P 1A2 induction due to concomitant medications was identified during the treatment course to account for such increases in V and CL, respectively. Possible mechanisms underlying these changes are discussed.<br><br>CONCLUSIONS: This is the first report of clinical pharmacokinetics of riluzole in patients with SCI. The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher clearance and larger volume of distribution in SCI patients. The finding in SCI patients of an increase in the clearance and distribution of riluzole between the 3rd and 14th days after SCI, with a lower plasma concentration of riluzole on the 14th day, stresses the importance of monitoring changes in drug metabolism after SCI in interpreting the safety and efficacy of therapeutic drugs that are used in clinical trials in SCI. Clinical trial registration no.: NCT00876889.}, }
@article {pmid22983450, year = {2012}, author = {Benze, G and Geyer, A and Alt-Epping, B and Nauck, F}, title = {[Treatment of nausea and vomiting with 5HT3 receptor antagonists, steroids, antihistamines, anticholinergics, somatostatinantagonists, benzodiazepines and cannabinoids in palliative care patients : a systematic review].}, journal = {Schmerz (Berlin, Germany)}, volume = {26}, number = {5}, pages = {481-499}, pmid = {22983450}, issn = {1432-2129}, mesh = {Adrenal Cortex Hormones/adverse effects/therapeutic use ; Antiemetics/adverse effects/*therapeutic use ; Benzodiazepines/adverse effects/therapeutic use ; Cholinergic Antagonists/adverse effects/therapeutic use ; Drug Therapy, Combination ; Evidence-Based Medicine ; Germany ; Histamine Antagonists/adverse effects/therapeutic use ; Nausea/*drug therapy ; Palliative Care/*methods ; Serotonin 5-HT3 Receptor Antagonists/adverse effects/therapeutic use ; Somatostatin/analogs &amp; derivatives ; Vomiting/*drug therapy ; }, abstract = {BACKGROUND: Various recommendations exist for the treatment of nausea and vomiting in palliative care but only few studies and even less systematic reviews look into antiemetic therapy for patients receiving palliative care.<br><br>OBJECTIVES: This systematic review aims to analyze the current evidence for antiemetic treatment with 5HT3 receptor antagonists, steroids, antihistamines, anticholinergics, somatostatin analogs, benzodiazepines and cannabinoids in palliative care patients with far advanced cancer not receiving chemotherapy or radiotherapy, acquired immune deficiency syndrome (AIDS), chronic obstructive pulmonary disease (COPD), progressive heart failure, amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). Results regarding evidence of treatment with prokinetic and neuroleptic agents will be published separately.<br><br>METHODS: The electronic databases PubMed and EmBase were systematically searched for studies (published 1966-2011) dealing with antiemetic therapy in palliative care and electronic retrieval was completed by manual searching. Studies with patients undergoing chemotherapy or radiotherapy, pediatric studies and studies published in languages other than English or German were excluded. Studies addressing therapy with 5HT3 receptor antagonists, steroids, antihistamines, anticholinergics, somatostatin analogs, benzodiazepines or cannabinoids were identified and selected for this systematic review.<br><br>RESULTS: In the general search 75 relevant studies were found. Of those 36 addressed 5HT3 receptor antagonists, steroids, antihistamines, anticholinergics, somatostatin analogs, benzodiazepines and cannabinoids, 13 considered 5HT3 receptor antagonists, 10 somatostatin antagonists, 9 steroids, 5 cannabinoids, 4 anticholinergics, 1 antihistamines and none benzodiazepines. Furthermore six systematic reviews exist. Evidence for any drug used as an antiemetic is low. Concerning 5HT3 receptor antagonists data are insufficient for recommendations on the treatment of patients with AIDS and MS due to the small size of included patient groups. For patients with cancer contradictory results were published: the larger studies showed a positive effect of 5HT3 receptor antagonists and better efficacy, as compared to metoclopramide, dexamethasone and neuroleptics. Heterogeneous results were found for steroids, with a positive trend for patients with cancer. Data are insufficient for antihistamines. Studies prove effectiveness of butylscopolammonium in the treatment of nausea and vomiting caused by malignant gastrointestinal obstruction, whereas octreotide is superior to butylscopolammonium. Regarding benzodiazepines for symptom control of nausea and vomiting in palliative care patients no studies were detected. Cannabinoids were found to relieve nausea and vomiting in patients with cancer and AIDS but with notable side effects. Furthermore, the studies compared cannabinoids to less recent antiemetic drugs but not, for example to 5HT3 receptor antagonists. Regarding symptom control of nausea and vomiting in patients with COPD, progressive heart failure and ALS no studies were undertaken in patients receiving palliative care.<br><br>CONCLUSIONS: In palliative care patients with nausea and vomiting 5HT3 receptor antagonists can be used if treatment with other antiemetics, such as metoclopramide and neuroleptics is not sufficient. There is a trend that steroids in combination with other antiemetics improve symptom relief. Cannabinoids rather have a status as a second line antiemetic. In cases of nausea and vomiting caused by malignant gastrointestinal obstruction octreotide showed the best and butylscopolammonium bromide the second best results. Concerning antihistamines and benzodiazepines insufficient data was found. Recommendations in the literature are mainly based on studies in patients with cancer. The overall strength of evidence is low. More well designed studies in palliative care patients are needed in order to provide evidence-based therapy. The English full text version of this article will be available in SpringerLink as of November 2012 (under "Supplemental").}, }
@article {pmid22972143, year = {2012}, author = {Garrison, SR and Allan, GM and Sekhon, RK and Musini, VM and Khan, KM}, title = {Magnesium for skeletal muscle cramps.}, journal = {The Cochrane database of systematic reviews}, volume = {2012}, number = {9}, pages = {CD009402}, pmid = {22972143}, issn = {1469-493X}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Age Factors ; Cross-Over Studies ; Female ; Humans ; Magnesium/*therapeutic use ; Male ; Muscle Cramp/*drug therapy/etiology ; *Muscle, Skeletal ; Pregnancy ; Pregnancy Complications/*drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Skeletal muscle cramps are common and often presented to physicians in association with pregnancy, advanced age, exercise or disorders of the motor neuron (such as amyotrophic lateral sclerosis). Magnesium supplements are marketed for the prophylaxis of cramps but the efficacy of magnesium for this indication has never been evaluated by systematic review.<br><br>OBJECTIVES: To assess the effects of magnesium supplementation compared to no treatment, placebo control or other cramp therapies in people with skeletal muscle cramps. &#xa0;<br><br>SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (11 October 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 3), MEDLINE (January 1966 to September 2011), EMBASE (January 1980 to September 2011), LILACS (January 1982 to September 2011), CINAHL Plus (January 1937 to September 2011), AMED (January 1985 to October 2011) and SPORTDiscus (January 1975 to September 2011).<br><br>SELECTION CRITERIA: Randomized controlled trials (RCTs) of magnesium supplementation (in any form) to prevent skeletal muscle cramps in any patient group (i.e. all clinical presentations of cramp). We considered comparisons of magnesium with no treatment, placebo control, or other therapy.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion and extracted data. Two authors assessed risk of bias. We attempted to contact all study authors and obtained patient level data for three of the included trials, one of which was unpublished. All data on adverse effects were collected from the included RCTs.<br><br>MAIN RESULTS: We identified seven trials (five parallel, two cross-over) enrolling a total of 406 individuals amongst whom 118 cross-over participants additionally served as their own controls. Three trials enrolled women with pregnancy-associated leg cramps (N = 202) and four trials enrolled idiopathic cramp sufferers (N = 322 including cross-over controls). Magnesium was compared to placebo in six trials and to no treatment in one trial.For idiopathic cramps (largely older adults presumed to have nocturnal leg cramps), differences in measures of cramp frequency, magnesium versus placebo, were small, not statistically significant, and without heterogeneity (I(2) = 0%). This includes the primary endpoint, percentage change from baseline in the number of cramps per week at four weeks (-3.93%, 95% confidence interval (CI) -21.12% to 13.26%, moderate quality evidence) and the difference in the number of cramps per week at four weeks (0.01 cramps/week, 95% CI -0.52 to 0.55, moderate quality evidence). The percentage of individuals experiencing a 25% or better reduction in cramp rate from baseline was also no different, being 8% lower in the magnesium group (95% CI -28% to 12%, moderate quality evidence). Similarly, no statistically significant difference was found at four weeks in measures of cramp intensity (moderate quality evidence) or cramp duration (low quality evidence).Meta-analysis was not possible for trials of pregnancy-associated leg cramps. The single study comparing magnesium to no treatment failed to find statistically significant benefit on a three-point ordinal scale of overall treatment efficacy. The two trials comparing magnesium to placebo differed in that one trial found no benefit on frequency or intensity measures while the other found benefit for both.Withdrawals due to adverse events were not significantly different than placebo. While we could not determine the number of subjects with minor adverse events, studies of oral magnesium generally described potential side effects as similar in frequency to placebo.<br><br>AUTHORS' CONCLUSIONS: It is unlikely that magnesium supplementation provides clinically meaningful cramp prophylaxis to older adults experiencing skeletal muscle cramps. In contrast, for those experiencing pregnancy-associated rest cramps the literature is conflicting and further research in this patient population is needed. We found no randomized controlled trials evaluating magnesium for exercise-associated muscle cramps or disease state-associated muscle cramps (for example amyotrophic lateral sclerosis/motor neuron disease).}, }
@article {pmid22970725, year = {2013}, author = {Cleary, S and Misiaszek, JE and Kalra, S and Wheeler, S and Johnston, W}, title = {The effects of lung volume recruitment on coughing and pulmonary function in patients with ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {14}, number = {2}, pages = {111-115}, doi = {10.3109/17482968.2012.720262}, pmid = {22970725}, issn = {2167-9223}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*complications/diagnosis/*rehabilitation ; Cough/diagnosis/*etiology/*prevention &amp; control ; Female ; Humans ; Insufflation/*methods ; Male ; Middle Aged ; Respiratory Insufficiency/diagnosis/*etiology/*rehabilitation ; Treatment Outcome ; }, abstract = {Our objective was to study the intensity and duration of the effects of lung volume recruitment, a manual breath stacking technique, on pulmonary function and coughing in individuals with amyotrophic lateral sclerosis (ALS). Twenty-nine individuals with ALS participated in this study. A cross-over research design was used to compare effects of lung volume recruitment to a control condition. Treatment outcome measures included forced vital capacity (FVC), sniff nasal pressure (SnP) and peak cough flow (PCF). Results demonstrated that LVR had a significantly positive effect on FVC for up to 15 min following treatment but did not have a facilitative effect on SnP at any time-point. LVR had a significantly positive effect on PCF during unassisted coughing at both 15 min and 30 min following treatment, and there was no significant decrease in flow rates from baseline to 30 min later. In conclusion, lung volume recruitment may be an effective treatment for improving coughing and pulmonary function in individuals with ALS. Future research should be focused on determining patient characteristics that contribute to response to treatment, as well as randomized controlled trials of the technique.}, }
@article {pmid22968365, year = {2012}, author = {Benze, G and Alt-Epping, B and Geyer, A and Nauck, F}, title = {[Treatment of nausea and vomiting with prokinetics and neuroleptics in palliative care patients : a review].}, journal = {Schmerz (Berlin, Germany)}, volume = {26}, number = {5}, pages = {500-514}, pmid = {22968365}, issn = {1432-2129}, mesh = {Antiemetics/adverse effects/*therapeutic use ; Antipsychotic Agents/adverse effects/*therapeutic use ; Chronic Disease/drug therapy ; Domperidone/adverse effects/therapeutic use ; Dopamine Antagonists/adverse effects/*therapeutic use ; Drug Therapy, Combination ; Evidence-Based Medicine/methods ; Gastrointestinal Motility/drug effects ; Germany ; Humans ; Metoclopramide/adverse effects/*therapeutic use ; Nausea/*drug therapy ; Palliative Care/*methods ; Randomized Controlled Trials as Topic ; Vomiting/*drug therapy ; }, abstract = {BACKGROUND: Many recommendations concerning the treatment of nausea and vomiting in palliative care patients exist but what is the evidence for this? Most studies dealing with this topic have focused on cancer patients under chemotherapy and/or radiation therapy or on patients with postoperative nausea. Cancer patients without chemotherapy or radiation therapy, patients without postoperative nausea, and patients having other diseases with palliative care aspects, such as acquired immunodeficiency syndrome (AIDS), chronic obstructive pulmonary disease (COPD), progressive heart failure, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) have been underrepresented in studies on nausea and vomiting so far.<br><br>OBJECTIVES: The aim of this review was to determine the level of evidence for the treatment of nausea and vomiting with prokinetics and neuroleptics in palliative care patients suffering from far advanced cancer and no longer being treated with chemotherapy or radiation therapy, AIDS, COPD, progressive heart failure, ALS or MS.<br><br>METHODS: Two different electronic databases (PubMed und Embase) were used to identify studies. Furthermore, a hand search for related articles was performed. No restriction was made concerning study types. Studies with patients undergoing chemotherapy radiation therapy or suffering from postoperative nausea, pediatric studies and studies published neither in English nor in German were excluded.<br><br>RESULTS: A total of 30 studies fulfilling the inclusion criteria were found. All studies focused on cancer patients. Despite intensive research studies in patients with AIDS, COPD, heart failure, ALS or MS were not detected. Metoclopramide is seen as an effective drug in many studies whereas the evidence for it is moderate at best. Within the group of neuroleptics, levosupiride and levomepromazine seem to have good antiemetic potential but the evidence level is low.<br><br>CONCLUSION: In patients with advanced cancer not being treated with chemotherapy or radiation therapy, metoclopramide can be used to reduce nausea and vomiting. Neuroleptics, such as levosulpiride or levomepromazine are alternatives but their adverse effects have to be considered carefully. The evidence level for prokinetics and neuroleptics is moderate to low. Concerning palliative care of patients with diseases other than cancer no studies exist. More well designed studies in palliative care patients are needed in order to facilitate evidence based antiemetic therapy. The English full text version of this article will be available in SpringerLink as of November 2012 (under "Supplemental").}, }
@article {pmid22956874, year = {2012}, author = {Corcia, P and Gordon, PH}, title = {Amyotrophic lateral sclerosis and the clinical potential of dexpramipexole.}, journal = {Therapeutics and clinical risk management}, volume = {8}, number = {}, pages = {359-366}, pmid = {22956874}, issn = {1178-203X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that leads to progressive weakness from loss of motor neurons and death on average in less than 3 years after symptom onset. No clear causes have been found and just one medication, riluzole, extends survival. Researchers have identified some of the cellular processes that occur after disease onset, including mitochondrial dysfunction, protein aggregation, oxidative stress, excitotoxicity, inflammation, and apoptosis. Mitochondrial disease may be a primary event in neurodegeneration or occur secondary to other cellular processes, and may itself contribute to oxidative stress, excitotoxicity, and apoptosis. Clinical trials currently aim to slow disease progression by testing drugs that impact one or more of these pathways. While every agent tested in the 18 years after the approval of riluzole has been ineffective, basic and clinical research methods in ALS have become dramatically more sophisticated. Dexpramipexole (RPPX), the R(+) enantiomer of pramiprexole, which is approved for symptomatic treatment of Parkinson disease, carries perhaps the currently largest body of pre-and early clinical data that support testing in ALS. The neuroprotective properties of RPPX in various models of neurodegeneration, including the ALS murine model, may be produced through protective actions on mitochondria. Early phase trials in human ALS suggest that the drug can be taken safely by patients in doses that provide neuroprotection in preclinical models. A Phase III trial to test the efficacy of RPPX in ALS is underway.}, }
@article {pmid22956189, year = {2012}, author = {Jouroukhin, Y and Ostritsky, R and Gozes, I}, title = {D-NAP prophylactic treatment in the SOD mutant mouse model of amyotrophic lateral sclerosis: review of discovery and treatment of tauopathy.}, journal = {Journal of molecular neuroscience : MN}, volume = {48}, number = {3}, pages = {597-602}, pmid = {22956189}, issn = {1559-1166}, mesh = {Amyotrophic Lateral Sclerosis/*prevention &amp; control ; Animals ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuroprotective Agents/pharmacology/therapeutic use ; Oligopeptides/chemistry/pharmacology/*therapeutic use ; Phosphorylation/drug effects ; Point Mutation ; Protein Processing, Post-Translational/drug effects ; Recombinant Fusion Proteins/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Tauopathies/classification/*drug therapy/genetics ; tau Proteins/*metabolism/physiology ; }, abstract = {Davunetide (NAP) is a leading drug candidate being tested against tauopathy. Davunetide is an eight-amino-acid peptide fragment derived by structure-activity studies from activity-dependent neuroprotective protein, activity-dependent neuroprotective protein (ADNP). ADNP is essential for brain formation. ADNP haploinsufficiency in mice results in tauopathy and cognitive deficits ameliorated by davunetide treatment. This article summarizes in brief recent reviews about NAP protection against tauopathy including the all D-amino acid analogue-D-NAP (AL-408). D-NAP was discovered to have similar neuroprotective functions to NAP in vitro. Here, D-NAP was tested as prophylactic as well as therapeutic treatment for amytrophic lateral sclerosis (ALS) in the widely used TgN(SOD1-G93A)1Gur transgenic mouse model. Results showed D-NAP-associated prophylactic protection, thus daily treatment starting from day 2 of age resulted in a prolonged life course in the D-NAP-treated mice, which was coupled to a significant decrease in tau hyperphosphorylation. These studies correlate protection against tau hyperphosphorylation and longevity in a severe model of ALS-like motor impairment and early mortality. NAP is a first-in-class drug candidate/investigation compound providing neuroprotection coupled to inhibition of tau pathology. D-NAP (AL-408) is a pipeline product.}, }
@article {pmid22952827, year = {2012}, author = {Dibaj, P and Zschüntzsch, J and Steffens, H and Scheffel, J and Göricke, B and Weishaupt, JH and Le Meur, K and Kirchhoff, F and Hanisch, UK and Schomburg, ED and Neusch, C}, title = {Influence of methylene blue on microglia-induced inflammation and motor neuron degeneration in the SOD1(G93A) model for ALS.}, journal = {PloS one}, volume = {7}, number = {8}, pages = {e43963}, pmid = {22952827}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology/physiopathology ; Animals ; Animals, Genetically Modified ; Cell Survival/drug effects ; Cytokines/metabolism ; Disease Models, Animal ; Disease Progression ; Female ; Inflammation/metabolism/pathology ; Male ; Methylene Blue/*pharmacology ; Mice ; Microglia/*drug effects/metabolism/*pathology ; Motor Activity/drug effects ; Motor Neurons/*drug effects/*pathology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Time Factors ; }, abstract = {Mutations in SOD1 cause hereditary variants of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS). Pathophysiology of the disease is non-cell-autonomous, with toxicity deriving also from glia. In particular, microglia contribute to disease progression. Methylene blue (MB) inhibits the effect of nitric oxide, which mediates microglial responses to injury. In vivo 2P-LSM imaging was performed in ALS-linked transgenic SOD1(G93A) mice to investigate the effect of MB on microglia-mediated inflammation in the spinal cord. Local superfusion of the lateral spinal cord with MB inhibited the microglial reaction directed at a laser-induced axon transection in control and SOD1(G93A) mice. In vitro, MB at high concentrations inhibited cytokine and chemokine release from microglia of control and advanced clinical SOD1(G93A) mice. Systemic MB-treatment of SOD1(G93A) mice at early preclinical stages significantly delayed disease onset and motor dysfunction. However, an increase of MB dose had no additional effect on disease progression; this was unexpected in view of the local anti-inflammatory effects. Furthermore, in vivo imaging of systemically MB-treated mice also showed no alterations of microglia activity in response to local lesions. Thus although systemic MB treatment had no effect on microgliosis, instead, its use revealed an important influence on motor neuron survival as indicated by an increased number of lumbar anterior horn neurons present at the time of disease onset. Thus, potentially beneficial effects of locally applied MB on inflammatory events contributing to disease progression could not be reproduced in SOD1(G93A) mice via systemic administration, whereas systemic MB application delayed disease onset via neuroprotection.}, }
@article {pmid22951705, year = {2012}, author = {Intiso, D and Basciani, M}, title = {Botulinum toxin use in neuro-rehabilitation to treat obstetrical plexus palsy and sialorrhea following neurological diseases: a review.}, journal = {NeuroRehabilitation}, volume = {31}, number = {2}, pages = {117-129}, doi = {10.3233/NRE-2012-0781}, pmid = {22951705}, issn = {1878-6448}, mesh = {Anti-Dyskinesia Agents/*therapeutic use ; Botulinum Toxins/*therapeutic use ; *Brachial Plexus Neuropathies/drug therapy/etiology/rehabilitation ; *Cerebral Palsy/drug therapy/etiology/rehabilitation ; Humans ; Nervous System Diseases/*complications ; *Sialorrhea/drug therapy/etiology/rehabilitation ; }, abstract = {In neuro-rehabilitation, botulinum toxin (BTX) as adjunct to other interventions can result in a useful therapeutic tool treating disabled people. Other than spasticity, numerous motor and non motor disorders can complicate clinical course and hamper rehabilitative process of neurological impaired patients. A review of BTX use in treating muscular imbalance of children with obstetrical brachial plexus palsy and in reducing sialorrhea following neurological diseases including amyotrophic lateral sclerosis (ASL), Parkinson disease and cerebral palsy (CP) is provided. Clinicians have to face unique and difficult to treat clinical conditions such as ulcers, sores and abnormal posture and movement disorders due to neurological affections. BTX effectiveness in treating some of these conditions is also provided. Since, neurologically disabled subjects can show complex dysfunction, prior to initiating BTX therapy, specific functional limitations, goals and expected outcomes of treatment should be evaluated and discussed with family and caregivers.}, }
@article {pmid22950490, year = {2012}, author = {Seltman, RE and Matthews, BR}, title = {Frontotemporal lobar degeneration: epidemiology, pathology, diagnosis and management.}, journal = {CNS drugs}, volume = {26}, number = {10}, pages = {841-870}, pmid = {22950490}, issn = {1179-1934}, support = {P30 AG010133/AG/NIA NIH HHS/United States ; }, mesh = {Frontotemporal Dementia/diagnosis/epidemiology/pathology/therapy ; Frontotemporal Lobar Degeneration/*diagnosis/epidemiology/pathology/*therapy ; Humans ; Neurodegenerative Diseases/diagnosis/epidemiology/pathology/therapy ; }, abstract = {Frontotemporal lobar degeneration (FTLD) describes a spectrum of clinically, pathologically and genetically heterogeneous neurodegenerative disorders of unknown aetiology. FTLD spectrum disorders collectively represent a leading cause of early-onset dementia, with most cases presenting between 45 and 64 years of age. FTLD is characterized by progressive changes in behaviour, executive dysfunction and/or language impairment and can be differentiated clinically into three frontotemporal dementia (FTD) syndromes as follows: (i) behavioural variant (bvFTD); (ii) semantic dementia (SD); and (iii) progressive nonfluent aphasia (PNFA). Additionally, there is a significant clinical, pathological and genetic overlap between FTD and motor neuron disease/amyotrophic lateral sclerosis (FTD-ALS) and the atypical parkinsonian syndromes, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). bvFTD is characterized by progressive behavioural impairment and a decline in executive function with frontal lobe-predominant atrophy, SD by a loss of object knowledge with prominent anomia and asymmetrical atrophy of the anterior temporal lobes and PNFA by expressive or motor speech deficits with predominantly left peri-sylvian atrophy. Recent advances in molecular biology and immunohistochemical staining techniques have further classified the FTLD spectrum disorders based upon the predominant neuropathological protein into three main categories: (i) microtubule-associated protein tau (FTLD-TAU); (ii) TAR DNA-binding protein-43 (FTLD-TDP); and (iii) fused in sarcoma protein (FTLD-FUS). Up to 40% of FTD patients report a family history of neurodegenerative illness, and one-third to one-half of familial cases of FTD follow an autosomal dominant inheritance pattern. Mutations in MAPT, PGRN, TARDBP, VCP and CHMP2B have been described, along with a recently identified C9ORF72 hexanucleotide repeat expansion. To date, there are no US FDA-approved treatments or disease-modifying therapies for FTD. Pharmacological strategies have focused on neurotransmitter replacement and modulation for the treatment of behavioural, motor and cognitive symptoms of FTD, and include selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics, acetylcholinesterase inhibitors and glutamate NMDA receptor antagonists. At present, adequate management of FTD symptoms involves a combination of pharmacological therapy with behavioural, physical and environmental modification techniques.}, }
@article {pmid22938097, year = {2012}, author = {Hölscher, C}, title = {Potential role of glucagon-like peptide-1 (GLP-1) in neuroprotection.}, journal = {CNS drugs}, volume = {26}, number = {10}, pages = {871-882}, pmid = {22938097}, issn = {1179-1934}, mesh = {Animals ; Clinical Trials, Phase II as Topic ; Glucagon-Like Peptide 1/*metabolism ; Humans ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neuroprotective Agents/*pharmacology/*therapeutic use ; Randomized Controlled Trials as Topic ; Risk Factors ; }, abstract = {The current understanding of neurodegenerative processes in sporadic diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) or multiple sclerosis is very limited. Several risk factors have been identified that may shed light on the underlying mechanisms that initiate the neurodegeneration. Type 2 diabetes mellitus has been identified as a risk factor for AD and PD. In AD patients, desensitization of insulin receptors in the brain has been shown, even in non-diabetic patients. Insulin acts as a growth factor in the brain and supports neuronal repair, dendritic sprouting and synaptogenesis, and protection from oxidative stress. Importantly, several drugs have been developed to treat type 2 diabetes that re-sensitize insulin receptors and may be of use to prevent neurodegenerative processes. Glucagon-like peptide-1 (GLP-1) is a hormone that facilitates insulin release under high blood sugar conditions. Interestingly, GLP-1 also has very similar growth factor-like properties to insulin, and has been shown to reduce a range of degenerative processes. In pre-clinical studies, GLP-1 and longer-lasting protease-resistant analogues cross the blood-brain barrier, protect memory formation (AD) or motor activity (PD), protect synapses and synaptic functions, enhance neurogenesis, reduce apoptosis, protect neurons from oxidative stress, and reduce plaque formation and the chronic inflammation response in the brains of mouse models of AD, PD, amyotrophic lateral sclerosis, stroke and other degenerative diseases. GLP-1 signalling does not affect blood sugar levels in non-diabetic people and therapies that affect GLP-1 signalling have a good safety profile as shown by the chronic application of drugs currently on the market (liraglutide, Victoza(®); NovoNordisk, Copenhagen, Denmark, and exendin-4, Byetta(®); Amylin, San Diego, CA, USA). Based on the extensive evidence, several clinical trials are currently underway, testing liraglutide and exendin-4 in AD and PD patients. Therefore, GLP-1 analogues show great promise as a novel treatment for AD or other neurodegenerative conditions.}, }
@article {pmid22932872, year = {2012}, author = {Wang, IF and Guo, BS and Liu, YC and Wu, CC and Yang, CH and Tsai, KJ and Shen, CK}, title = {Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {109}, number = {37}, pages = {15024-15029}, pmid = {22932872}, issn = {1091-6490}, mesh = {Analysis of Variance ; Animals ; Autophagy/*drug effects ; Blotting, Western ; Carbamazepine/pharmacology ; Caspase 3/metabolism ; Fluorometry ; Frontotemporal Dementia/*complications/*drug therapy/physiopathology ; In Situ Nick-End Labeling ; Maze Learning/drug effects ; Memory Disorders/drug therapy ; Mice ; Psychomotor Performance/drug effects ; Rotarod Performance Test ; Sirolimus/*pharmacology/therapeutic use ; Spermidine/pharmacology ; TDP-43 Proteinopathies/*complications/*drug therapy/physiopathology ; TOR Serine-Threonine Kinases/antagonists &amp; inhibitors ; Tamoxifen/pharmacology ; }, abstract = {TDP-43 is a multifunctional DNA/RNA-binding protein that has been identified as the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral sclerosis (ALS). Unfortunately, effective drugs for these neurodegenerative diseases are yet to be developed. We have tested the therapeutic potential of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three other autophagy activators (spermidine, carbamazepine, and tamoxifen) in a FTLD-U mouse model with TDP-43 proteinopathies. Rapamycin treatment has been reported to be beneficial in some animal models of neurodegenerative diseases but not others. Furthermore, the effects of rapamycin treatment in FTLD-U have not been investigated. We show that rapamycin treatment effectively rescues the learning/memory impairment of these mice at 3 mo of age, and it significantly slows down the age-dependent loss of their motor function. These behavioral improvements upon rapamycin treatment are accompanied by a decreased level of caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice. Furthermore, the number of cells with cytosolic TDP-43 (+) inclusions and the amounts of full-length TDP-43 as well as its cleavage products (35 kDa and 25 kDa) in the urea-soluble fraction of the cellular extract are significantly decreased upon rapamycin treatment. These changes in TDP-43 metabolism are accompanied by rapamycin-induced decreases in mTOR-regulated phospho-p70 S6 kinase (P-p70) and the p62 protein, as well as increases in the autophagic marker LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest that autophagy activation is a potentially useful route for the therapy of neurodegenerative diseases with TDP-43 proteinopathies.}, }
@article {pmid22919531, year = {2012}, author = {Capitano, S and Donatelli, G and Boccoli, G}, title = {Superior Mesenteric Artery Syndrome-Believe in it! Report of a Case.}, journal = {Case reports in surgery}, volume = {2012}, number = {}, pages = {282646}, pmid = {22919531}, issn = {2090-6919}, abstract = {We present a case of a man with amyotrophic lateral sclerosis who developed superior mesenteric artery syndrome (SMAS) following the confection of feeding jejunostomy. He was successfully managed by conservative treatment. Left lateral positioning during enteral feeding allowed quick resolution of the occlusive state. Various surgical interventions have been associated with SMAS, directly or indirectly, by reducing the width of the aortomesenteric angle. The operative stress was probably what triggered symptomatology in our patient thus to conclude that the surgical stress should be considered as a causal factor triggering the SMAS in a context of other predisposing factors.}, }
@article {pmid22919482, year = {2012}, author = {Krakora, D and Macrander, C and Suzuki, M}, title = {Neuromuscular junction protection for the potential treatment of amyotrophic lateral sclerosis.}, journal = {Neurology research international}, volume = {2012}, number = {}, pages = {379657}, pmid = {22919482}, issn = {2090-1860}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by the progressive degeneration of upper and lower motor neurons (MNs), leading to muscular atrophy and eventual respiratory failure. ALS research has primarily focused on mechanisms regarding MN cell death; however, degenerative processes in the skeletal muscle, particularly involving neuromuscular junctions (NMJs), are observed in the early stages of and throughout disease progression. According to the "dying-back" hypothesis, NMJ degeneration may not only precede, but actively cause upper and lower MN loss. The importance of NMJ pathology has relatively received little attention in ALS, possibly because compensatory mechanisms mask NMJ loss for prolonged periods. Many mechanisms explaining NMJ degeneration have been proposed such as the disruption of anterograde/retrograde axonal transport, irregular cellular metabolism, and changes in muscle gene and protein expression. Neurotrophic factors, which are known to have neuroprotective and regenerative properties, have been intensely investigated for their therapeutic potential in both the preclinical and clinical setting. Additional research should focus on the potential of preserving NMJs in order to delay or prevent disease progression.}, }
@article {pmid22918487, year = {2012}, author = {Collins, MP}, title = {The vasculitic neuropathies: an update.}, journal = {Current opinion in neurology}, volume = {25}, number = {5}, pages = {573-585}, doi = {10.1097/WCO.0b013e3283580432}, pmid = {22918487}, issn = {1473-6551}, mesh = {Animals ; Diagnosis, Differential ; Humans ; Infections/complications/diagnosis ; Peripheral Nervous System Diseases/classification/epidemiology/*pathology ; Vasa Nervorum/*pathology ; Vasculitis/classification/epidemiology/*pathology ; }, abstract = {PURPOSE OF REVIEW: Vasculitic neuropathy is a heterogeneous disorder that usually occurs in systemic diseases, but less commonly appears as nonsystemic vasculitic neuropathy (NSVN). This review is intended to highlight recent developments in the field of vasculitic neuropathies.<br><br>RECENT FINDINGS: A Peripheral Nerve Society guideline provides data-driven consensus recommendation on classification of vasculitic neuropathies and diagnosis/treatment of NSVN. NSVN is sometimes accompanied by subclinical inflammation of adjacent skin. Amyotrophic lateral sclerosis with sensory involvement can mimic NSVN. Systemic vasculitides with neuropathy include polyarteritis nodosa, microscopic polyangiitis (MPA), rheumatoid vasculitis, Churg-Strauss syndrome (CSS), and hepatitis C-related mixed cryoglobulinemic vasculitis (MCV). At autopsy, MPA affects limb nerves diffusely, with maximal damage in proximal/middle segments. CSS can be accompanied by antineutrophil cytoplasmic antibodies (ANCAs), but most patients with neuropathy lack ANCAs. Cryoglobulinemic neuropathies are usually caused by vasculitis, irrespective of phenotype. Two randomized trials revealed rituximab to be noninferior to cyclophosphamide for inducing remission in ANCA-associated vasculitis. Many reports also document efficacy of rituximab in MCV.<br><br>SUMMARY: Consensus guidelines on NSVN should be evaluated prospectively. MPA-associated vasculitic neuropathy results from vasculitic lesions distributed diffusely throughout peripheral extremity nerves. Rituximab is effective for ANCA-associated and cryoglobulinemic vasculitis with neuropathy.}, }
@article {pmid22916141, year = {2012}, author = {Hefferan, MP and Galik, J and Kakinohana, O and Sekerkova, G and Santucci, C and Marsala, S and Navarro, R and Hruska-Plochan, M and Johe, K and Feldman, E and Cleveland, DW and Marsala, M}, title = {Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation.}, journal = {PloS one}, volume = {7}, number = {8}, pages = {e42614}, pmid = {22916141}, issn = {1932-6203}, support = {089701/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*surgery ; Animals ; Electric Stimulation ; Evoked Potentials, Motor ; Humans ; Mutation ; Neural Stem Cells/*transplantation ; Rats ; Rats, Transgenic ; Spinal Cord/*surgery ; *Stem Cell Transplantation ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Synapses/physiology ; }, abstract = {BACKGROUND: Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherited form of Amyotrophic Lateral Sclerosis (ALS). Mutant synthesis in motor neurons drives disease onset and early disease progression. Previous experimental studies have shown that spinal grafting of human fetal spinal neural stem cells (hNSCs) into the lumbar spinal cord of SOD1(G93A) rats leads to a moderate therapeutical effect as evidenced by local α-motoneuron sparing and extension of lifespan. The aim of the present study was to analyze the degree of therapeutical effect of hNSCs once grafted into the lumbar spinal ventral horn in presymptomatic immunosuppressed SOD1(G93A) rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1(G93A) animals.<br><br>METHODS/PRINCIPAL FINDINGS: Presymptomatic SOD1(G93A) rats (60-65 days old) received spinal lumbar injections of hNSCs. After cell grafting, disease onset, disease progression and lifespan were analyzed. In separate symptomatic SOD1(G93A) rats, the presence and functional conductivity of descending motor tracts (corticospinal and rubrospinal) was analyzed by spinal surface recording electrodes after electrical stimulation of the motor cortex. Silver impregnation of lumbar spinal cord sections and descending motor axon counting in plastic spinal cord sections were used to validate morphologically the integrity of descending motor tracts. Grafting of hNSCs into the lumbar spinal cord of SOD1(G93A) rats protected &#x3b1;-motoneurons in the vicinity of grafted cells, provided transient functional improvement, but offered no protection to &#x3b1;-motoneuron pools distant from grafted lumbar segments. Analysis of motor-evoked potentials recorded from the thoracic spinal cord of symptomatic SOD1(G93A) rats showed a near complete loss of descending motor tract conduction, corresponding to a significant (50-65%) loss of large caliber descending motor axons.<br><br>CONCLUSIONS/SIGNIFICANCE: These data demonstrate that in order to achieve a more clinically-adequate treatment, cell-replacement/gene therapy strategies will likely require both spinal and supraspinal targets.}, }
@article {pmid22907221, year = {2012}, author = {Gruis, KL and Lechtzin, N}, title = {Respiratory therapies for amyotrophic lateral sclerosis: a primer.}, journal = {Muscle &amp; nerve}, volume = {46}, number = {3}, pages = {313-331}, doi = {10.1002/mus.23282}, pmid = {22907221}, issn = {1097-4598}, mesh = {Amyotrophic Lateral Sclerosis/complications/*therapy ; Evidence-Based Medicine ; Humans ; Respiratory Insufficiency/etiology/*therapy ; Respiratory Therapy/adverse effects/*methods ; }, abstract = {Respiratory complications are a common cause of morbidity and mortality in amyotrophic lateral sclerosis (ALS). Treatment of respiratory insufficiency with noninvasive ventilation (NIV) improves ALS patients' quality of life and survival. Evidence-based practice guidelines for the management of ALS patients recommend treatment of respiratory insufficiency with NIV as well as consideration of insufflation/exsufflation to improve clearance of airway secretions. Despite these recommendations respiratory therapies remain underused. In this review we provide a practical guide for the clinician to prescribe and manage respiratory therapies for the patient with ALS.}, }
@article {pmid22892214, year = {2012}, author = {McDonnell, ME and Vera, MD and Blass, BE and Pelletier, JC and King, RC and Fernandez-Metzler, C and Smith, GR and Wrobel, J and Chen, S and Wall, BA and Reitz, AB}, title = {Riluzole prodrugs for melanoma and ALS: design, synthesis, and in vitro metabolic profiling.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {20}, number = {18}, pages = {5642-5648}, pmid = {22892214}, issn = {1464-3391}, support = {R43 CA156781/CA/NCI NIH HHS/United States ; R44 CA156781/CA/NCI NIH HHS/United States ; R43 CA156781-01/CA/NCI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Cytochrome P-450 CYP1A2/biosynthesis/metabolism ; *Drug Design ; Drug Stability ; Humans ; Melanoma/*drug therapy/metabolism ; Mice ; Microsomes, Liver/metabolism ; Molecular Structure ; Prodrugs/*chemical synthesis/chemistry/metabolism/*pharmacology ; Riluzole/blood/chemical synthesis/*metabolism/*pharmacology ; }, abstract = {Riluzole (1) is an approved therapeutic for the treatment of ALS and has also demonstrated anti-melanoma activity in metabotropic glutamate GRM1 positive cell lines, a mouse xenograft assay and human clinical trials. Highly variable drug exposure following oral administration among patients, likely due to variable first pass effects from heterogeneous CYP1A2 expression, hinders its clinical use. In an effort to mitigate effects of this clearance pathway and uniformly administer riluzole at efficacious exposure levels, several classes of prodrugs of riluzole were designed, synthesized, and evaluated in multiple in vitro stability assays to predict in vivo drug levels. The optimal prodrug would possess the following profile: stability while transiting the digestive system, stability towards first pass metabolism, and metabolic lability in the plasma releasing riluzole. (S)-O-Benzyl serine derivative 9 was identified as the most promising therapeutically acceptable prodrug.}, }
@article {pmid22879928, year = {2012}, author = {Parker, SJ and Meyerowitz, J and James, JL and Liddell, JR and Nonaka, T and Hasegawa, M and Kanninen, KM and Lim, S and Paterson, BM and Donnelly, PS and Crouch, PJ and White, AR}, title = {Inhibition of TDP-43 accumulation by bis(thiosemicarbazonato)-copper complexes.}, journal = {PloS one}, volume = {7}, number = {8}, pages = {e42277}, pmid = {22879928}, issn = {1932-6203}, mesh = {Coordination Complexes/*pharmacology ; Copper/*pharmacology ; Cytoplasmic Granules/drug effects/metabolism ; DNA-Binding Proteins/*metabolism ; ELAV Proteins/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; HeLa Cells ; Humans ; Mitochondria/drug effects/metabolism ; Neuroprotective Agents/pharmacology ; Neurotoxins/toxicity ; Paraquat/toxicity ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology ; Protein Structure, Quaternary ; Protein Transport/drug effects ; Thiosemicarbazones/*pharmacology ; Ubiquitin/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, motor neuron disease with no effective long-term treatment options. Recently, TDP-43 has been identified as a key protein in the pathogenesis of some cases of ALS. Although the role of TDP-43 in motor neuron degeneration is not yet known, TDP-43 has been shown to accumulate in RNA stress granules (SGs) in cell models and in spinal cord tissue from ALS patients. The SG association may be an early pathological change to TDP-43 metabolism and as such a potential target for therapeutic intervention. Accumulation of TDP-43 in SGs induced by inhibition of mitochondrial activity can be inhibited by modulation of cellular kinase activity. We have also found that treatment of cells and animal models of neurodegeneration, including an ALS model, with bioavailable bis(thiosemicarbazonato)copper(II) complexes (Cu(II)(btsc)s) can modulate kinase activity and induce neuroprotective effects. In this study we examined the effect of diacetylbis(-methylthiosemicarbazonato)copper(II) (Cu(II)(atsm)) and glyoxalbis(-methylthiosemicarbazonato)copper(II) (Cu(II)(gtsm)) on TDP-43-positive SGs induced in SH-SY5Y cells in culture. We found that the Cu(II)(btsc)s blocked formation of TDP-43-and human antigen R (HuR)-positive SGs induced by paraquat. The Cu(II)(btsc)s protected neurons from paraquat-mediated cell death. These effects were associated with inhibition of ERK phosphorylation. Co-treatment of cultures with either Cu(II)(atsm) or an ERK inhibitor, PD98059 both prevented ERK activation and blocked formation of TDP-43-and HuR-positive SGs. Cu(II)(atsm) treatment or ERK inhibition also prevented abnormal ubiquitin accumulation in paraquat-treated cells suggesting a link between prolonged ERK activation and abnormal ubiquitin metabolism in paraquat stress and inhibition by Cu. Moreover, Cu(II)(atsm) reduced accumulation of C-terminal (219-414) TDP-43 in transfected SH-SY5Y cells. These results demonstrate that Cu(II)(btsc) complexes could potentially be developed as a neuroprotective agent to modulate neuronal kinase function and inhibit TDP-43 aggregation. Further studies in TDP-43 animal models are warranted.}, }
@article {pmid22873722, year = {2012}, author = {Bhutani, H and Anand, A}, title = {Biomarkers in amyotrophic lateral sclerosis: is there a neurovascular pathway?.}, journal = {Current neurovascular research}, volume = {9}, number = {4}, pages = {302-309}, doi = {10.2174/156720212803530654}, pmid = {22873722}, issn = {1875-5739}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*pathology/physiopathology ; Animals ; Biomarkers/metabolism ; Cell Hypoxia/physiology ; Humans ; Neurons/*pathology ; Oxidative Stress/physiology ; Signal Transduction/*physiology ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {The establishment of a link between VEGF, hypoxia and ALS pathogenesis placed angiogenic factors and oxidative stress at the focal point for further studies. Recreation of a phenotype strikingly similar to that of mutant SOD1 mouse and human ALS, like muscle weakness and atrophy owing to lower motor neuron degeneration was observed following the targeted deletion of the hypoxia response element (HRE) from promoter of mouse vascular endothelial growth factor (VEGF). The crucial link between vasculature, angiogenic molecules and motor neuron degeneration has thus been constantly scrutinized. In this review, we have proposed to correlate human, in vitro and cadaveric studies so as to find out whether molecules like VEGF and various others, at the interface of neurovascular network and oxidative stress, have a prognostic, diagnostic and therapeutic potential for treatment of a fatal neurodegenerative disorder namely ALS.}, }
@article {pmid22871074, year = {2012}, author = {Saenger, S and Holtmann, B and Nilges, MR and Schroeder, S and Hoeflich, A and Kletzl, H and Spooren, W and Ostrowitzki, S and Hanania, T and Sendtner, M and Metzger, F}, title = {Functional improvement in mouse models of familial amyotrophic lateral sclerosis by PEGylated insulin-like growth factor I treatment depends on disease severity.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {5}, pages = {418-429}, doi = {10.3109/17482968.2012.679944}, pmid = {22871074}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Disease Models, Animal ; Disease Progression ; Insulin-Like Growth Factor I/*therapeutic use ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects/metabolism ; Severity of Illness Index ; }, abstract = {Insulin-like growth factor I (IGF-I) has been successfully tested in the SOD1-G93A mouse model of familial amyotrophic lateral sclerosis (ALS) and proposed for clinical treatment. However, beneficial effects required gene therapy or intrathecal application. Circumventing the dosing issues we recently found that polyethylene glycol (PEG) modified IGF-I (PEG-IGF-I) modulated neuromuscular function after systemic application, and protected against disease progression in a motor neuron disease model. Here we investigated its effects in two SOD1-G93A mouse lines, the G1L with a milder and the G1H with a more severe phenotype. Results showed that in G1L mice, PEG-IGF-I treatment significantly improved muscle force, motor coordination and animal survival. In contrast, treatment of G1H mice with PEG-IGF-I or IGF-I even at high doses did not beneficially affect survival or functional outcomes despite increased signalling in brain and spinal cord by both agents. In conclusion, the data point towards further investigation of the therapeutic potential of PEG-IGF-I in ALS patients with less severe clinical phenotypes.}, }
@article {pmid22869031, year = {2013}, author = {Steele, JW and Ju, S and Lachenmayer, ML and Liken, J and Stock, A and Kim, SH and Delgado, LM and Alfaro, IE and Bernales, S and Verdile, G and Bharadwaj, P and Gupta, V and Barr, R and Friss, A and Dolios, G and Wang, R and Ringe, D and Protter, AA and Martins, RN and Ehrlich, ME and Yue, Z and Petsko, GA and Gandy, S}, title = {Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain.}, journal = {Molecular psychiatry}, volume = {18}, number = {8}, pages = {882-888}, pmid = {22869031}, issn = {1476-5578}, support = {U54 RR022220/RR/NCRR NIH HHS/United States ; P01AG10491/AG/NIA NIH HHS/United States ; R01 NS075685/NS/NINDS NIH HHS/United States ; P01 AG010491/AG/NIA NIH HHS/United States ; P50 AG005138/AG/NIA NIH HHS/United States ; U54RR022220/RR/NCRR NIH HHS/United States ; R01 NS060123/NS/NINDS NIH HHS/United States ; P50AG05138/AG/NIA NIH HHS/United States ; P30 NS061777/NS/NINDS NIH HHS/United States ; R01NS060123/NS/NINDS NIH HHS/United States ; T32 GM062754/GM/NIGMS NIH HHS/United States ; T32GM062754/GM/NIGMS NIH HHS/United States ; S10 RR022415/RR/NCRR NIH HHS/United States ; }, mesh = {Amyloid beta-Peptides ; Animals ; Autophagy/*drug effects ; Brain/drug effects/metabolism ; Cell Death/drug effects ; Cells, Cultured ; Humans ; Indoles/*pharmacology ; Male ; Mice ; Neuroprotective Agents/*pharmacology/therapeutic use ; Peptide Fragments ; Saccharomyces cerevisiae ; alpha-Synuclein/*antagonists &amp; inhibitors/metabolism/toxicity ; }, abstract = {Latrepirdine (Dimebon; dimebolin) is a neuroactive compound that was associated with enhanced cognition, neuroprotection and neurogenesis in laboratory animals, and has entered phase II clinical trials for both Alzheimer's disease and Huntington's disease (HD). Based on recent indications that latrepirdine protects cells against cytotoxicity associated with expression of aggregatable neurodegeneration-related proteins, including Aβ42 and γ-synuclein, we sought to determine whether latrepirdine offers protection to Saccharomyces cerevisiae. We utilized separate and parallel expression in yeast of several neurodegeneration-related proteins, including α-synuclein (α-syn), the amyotrophic lateral sclerosis-associated genes TDP43 and FUS, and the HD-associated protein huntingtin with a 103 copy-polyglutamine expansion (HTT gene; htt-103Q). Latrepirdine effects on α-syn clearance and toxicity were also measured following treatment of SH-SY5Y cells or chronic treatment of wild-type mice. Latrepirdine only protected yeast against the cytotoxicity associated with α-syn, and this appeared to occur via induction of autophagy. We further report that latrepirdine stimulated the degradation of α-syn in differentiated SH-SY5Y neurons, and in mouse brain following chronic administration, in parallel with elevation of the levels of markers of autophagic activity. Ongoing experiments will determine the utility of latrepirdine to abrogate α-syn accumulation in transgenic mouse models of α-syn neuropathology. We propose that latrepirdine may represent a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, which might yield clinical benefit for synucleinopathies including Parkinson's disease, Lewy body dementia, rapid eye movement (REM) sleep disorder and/or multiple system atrophy, following optimization of its pro-autophagic and pro-neurogenic activities.}, }
@article {pmid22865541, year = {2013}, author = {Chow, AM and Tang, DW and Hanif, A and Brown, IR}, title = {Induction of heat shock proteins in cerebral cortical cultures by celastrol.}, journal = {Cell stress &amp; chaperones}, volume = {18}, number = {2}, pages = {155-160}, pmid = {22865541}, issn = {1466-1268}, mesh = {Animals ; Blotting, Western ; Cells, Cultured ; Cerebral Cortex/cytology/*drug effects/metabolism ; HSP27 Heat-Shock Proteins/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Heat-Shock Proteins/*metabolism ; Heme Oxygenase-1/metabolism ; Pentacyclic Triterpenes ; Potassium Channel Blockers/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Temperature ; Triterpenes/*pharmacology ; }, abstract = {Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS) are 'protein misfolding disorders' of the mature nervous system that are characterized by the accumulation of protein aggregates and selective cell loss. Different brain regions are impacted, with Alzheimer's affecting cells in the cerebral cortex, Parkinson's targeting dopaminergic cells in the substantia nigra and ALS causing degeneration of cells in the spinal cord. These diseases differ widely in frequency in the human population. Alzheimer's is more frequent than Parkinson's and ALS. Heat shock proteins (Hsps) are 'protein repair agents' that provide a line of defense against misfolded, aggregation-prone proteins. We have suggested that differing levels of constitutively expressed Hsps (Hsc70 and Hsp27) in neural cell populations confer a variable buffering capacity against 'protein misfolding disorders' that correlates with the relative frequencies of these neurodegenerative diseases. The high relative frequency of Alzheimer's may due to low levels of Hsc70 and Hsp27 in affected cell populations that results in a reduced defense capacity against protein misfolding. Here, we demonstrate that celastrol, but not classical heat shock treatment, is effective in inducing a set of neuroprotective Hsps in cultures derived from cerebral cortices, including Hsp70, Hsp27 and Hsp32. This set of Hsps is induced by celastrol at 'days in vitro' (DIV) 13 when cultured cortical cells reached maturity. The inducibility of a set of neuroprotective Hsps in mature cortical cultures at DIV13 suggests that celastrol is a potential agent to counter Alzheimer's disease, a neurodegenerative 'protein misfolding disorder' of the adult brain that targets cells in the cerebral cortex.}, }
@article {pmid22863620, year = {2012}, author = {Butovsky, O and Siddiqui, S and Gabriely, G and Lanser, AJ and Dake, B and Murugaiyan, G and Doykan, CE and Wu, PM and Gali, RR and Iyer, LK and Lawson, R and Berry, J and Krichevsky, AM and Cudkowicz, ME and Weiner, HL}, title = {Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS.}, journal = {The Journal of clinical investigation}, volume = {122}, number = {9}, pages = {3063-3087}, pmid = {22863620}, issn = {1558-8238}, support = {P30 NS047243/NS/NINDS NIH HHS/United States ; R01 AG027437/AG/NIA NIH HHS/United States ; R01 NS088137/NS/NINDS NIH HHS/United States ; AG027437/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/*immunology/pathology ; Animals ; Antibodies, Monoclonal/administration &amp; dosage ; Antigens, CD/genetics/metabolism ; Antigens, Ly/genetics/immunology/metabolism ; Apoptosis ; Apyrase/genetics/metabolism ; Cell Proliferation ; Chemotaxis ; Female ; Gene Regulatory Networks ; Humans ; *Immunomodulation ; Inflammation Mediators/metabolism ; Macrophages, Alveolar/metabolism ; Male ; Metabolic Networks and Pathways ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; MicroRNAs/*genetics/metabolism ; Microglia/immunology/pathology ; Monocytes/*immunology/metabolism/pathology ; Oligonucleotide Array Sequence Analysis ; RNA Interference ; Rats ; Rats, Inbred Lew ; Spinal Cord/*immunology/pathology ; Spleen/immunology/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Transcription Factors/genetics/metabolism ; Transcriptome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with neuronal cell death that is thought to involve aberrant immune responses. Here we investigated the role of innate immunity in a mouse model of ALS. We found that inflammatory monocytes were activated and that their progressive recruitment to the spinal cord, but not brain, correlated with neuronal loss. We also found a decrease in resident microglia in the spinal cord with disease progression. Prior to disease onset, splenic Ly6Chi monocytes expressed a polarized macrophage phenotype (M1 signature), which included increased levels of chemokine receptor CCR2. As disease onset neared, microglia expressed increased CCL2 and other chemotaxis-associated molecules, which led to the recruitment of monocytes to the CNS by spinal cord-derived microglia. Treatment with anti-Ly6C mAb modulated the Ly6Chi monocyte cytokine profile, reduced monocyte recruitment to the spinal cord, diminished neuronal loss, and extended survival. In humans with ALS, the analogous monocytes (CD14+CD16-) exhibited an ALS-specific microRNA inflammatory signature similar to that observed in the ALS mouse model, linking the animal model and the human disease. Thus, the profile of monocytes in ALS patients may serve as a biomarker for disease stage or progression. Our results suggest that recruitment of inflammatory monocytes plays an important role in disease progression and that modulation of these cells is a potential therapeutic approach.}, }
@article {pmid22841860, year = {2012}, author = {Walsh, FS and Rutkowski, JL}, title = {Myostatin as a therapeutic target in Amyotrophic lateral sclerosis.}, journal = {Neurochemistry international}, volume = {61}, number = {6}, pages = {931-935}, doi = {10.1016/j.neuint.2012.07.016}, pmid = {22841860}, issn = {1872-9754}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*therapy ; Antibodies, Monoclonal/*immunology ; Clinical Trials as Topic ; Humans ; Myostatin/*drug effects/immunology ; }, abstract = {Amyotrophic Lateral Sclerosis is a devastating neurological disease that is inevitably fatal after 3-5years duration. Treatment options are minimal and as such new therapeutic modalities are required. In this review, we discuss the role of the myostatin pathway as a modulator of skeletal muscle mass and therapeutic approaches using biological based therapies. Both monoclonal antibodies to myostatin and a soluble receptor decoy to its high affinity receptor have been used in clinical trials of neuromuscular diseases and while there have been efficacy signals with the latter approach there have also been safety issues. Our approach is to target the high affinity receptor-binding site on myostatin and to develop a next generation set of therapeutic reagents built on a novel protein scaffold. This is the natural single domain VNAR found in sharks which is extremely versatile and has the ability to develop products with superior properties compared to existing therapeutics.}, }
@article {pmid22841708, year = {2012}, author = {Goto, JJ and Koenig, JH and Ikeda, K}, title = {The physiological effect of ingested β-N-methylamino-L-alanine on a glutamatergic synapse in an in vivo preparation.}, journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP}, volume = {156}, number = {3-4}, pages = {171-177}, doi = {10.1016/j.cbpc.2012.07.004}, pmid = {22841708}, issn = {1532-0456}, mesh = {6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology ; Amino Acids, Diamino/*pharmacology ; Animals ; Behavior, Animal/drug effects/physiology ; Drosophila melanogaster/*drug effects/physiology ; Excitatory Amino Acid Antagonists/pharmacology ; Female ; Motor Neurons/drug effects/physiology ; Muscle Fibers, Skeletal/physiology ; Receptors, AMPA/antagonists &amp; inhibitors ; Receptors, Glutamate/drug effects/physiology ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors/physiology ; Synapses/drug effects/*physiology ; Synaptic Potentials/*drug effects/physiology ; Wings, Animal/drug effects/physiology ; }, abstract = {The neurotoxin, BMAA (β-N-methylamino-L-alanine), may be a risk factor for amyotrophic lateral sclerosis (ALS), Parkinson's (PD) and Alzheimer's (AD) disease. In vivo experiments have demonstrated that BMAA can cause a number of motor dysfunctions if ingested or injected, and in vitro experiments show that this toxin binds to glutamate receptors with deleterious results. Also, BMAA exists in the human food chain worldwide, and has been detected in the brains of ALS and AD patients. This paper offers the first demonstration by intracellular recording of the effect of ingested BMAA on the postsynaptic response of an identified glutamatergic cell in a living, undissected organism (Drosophila melanogaster), and correlates these observations with the specific motor dysfunctions that result from ingestion. The results suggest that BMAA acts as a glutamate agonist, causing NMDA receptor channels to remain open for prolonged periods of time, thereby damaging the cell by excitotoxicity. The effect on the postsynaptic response became apparent days before the function of the postsynaptic cell (wing beat) became affected. Severely depolarized cells were able to fully recover with the removal of BMAA from the food source, suggesting that blocking BMAA binding in the brain might be a good treatment strategy.}, }
@article {pmid22840647, year = {2012}, author = {Culzoni, MJ and Aucelio, RQ and Escandar, GM}, title = {High-performance liquid chromatography with fast-scanning fluorescence detection and multivariate curve resolution for the efficient determination of galantamine and its main metabolites in serum.}, journal = {Analytica chimica acta}, volume = {740}, number = {}, pages = {27-35}, doi = {10.1016/j.aca.2012.06.034}, pmid = {22840647}, issn = {1873-4324}, mesh = {Algorithms ; Chromatography, High Pressure Liquid ; *Fluorescence ; Galantamine/*blood/chemistry/*metabolism ; Humans ; Multivariate Analysis ; Software ; Spectrometry, Fluorescence ; }, abstract = {Based on green analytical chemistry principles, an efficient approach was applied for the simultaneous determination of galantamine, a widely used cholinesterase inhibitor for the treatment of Alzheimer's disease, and its major metabolites in serum samples. After a simple serum deproteinization step, second-order data were rapidly obtained (less than 6 min) with a chromatographic system operating in the isocratic regime using ammonium acetate/acetonitrile (94:6) as mobile phase. Detection was made with a fast-scanning spectrofluorimeter, which allowed the efficient collection of data to obtain matrices of fluorescence intensity as a function of retention time and emission wavelength. Successful resolution was achieved in the presence of matrix interferences in serum samples using multivariate curve resolution-alternating least-squares (MCR-ALS). The developed approach allows the quantification of the analytes at levels found in treated patients, without the need of applying either preconcentration or extraction steps. Limits of detection in the range between 8 and 11 ng mL(-1), relative prediction errors from 7 to 12% and coefficients of variation from 4 to 7% were achieved.}, }
@article {pmid22837812, year = {2012}, author = {Zhang, Y and Benmohamed, R and Zhang, W and Kim, J and Edgerly, CK and Zhu, Y and Morimoto, RI and Ferrante, RJ and Kirsch, DR and Silverman, RB}, title = {Chiral cyclohexane 1,3-diones as inhibitors of mutant SOD1-dependent protein aggregation for the treatment of ALS.}, journal = {ACS medicinal chemistry letters}, volume = {3}, number = {7}, pages = {584-587}, pmid = {22837812}, issn = {1948-5875}, support = {R43 NS057849/NS/NINDS NIH HHS/United States ; }, abstract = {Cyclohexane 1,3-diones were identified as a class of molecules exhibiting a protective effect against mutant SOD1 induced toxicity in PC-12 cells, but an optimized analogue had little or no effect on life extension in the G93A SOD1 mouse model for amyotrophic lateral sclerosis (ALS). Additional testing showed that these compounds were inactive in neurons and further analogue synthesis was carried out to identify compounds with neuronal activity. Starting from two racemic derivatives that were active in cortical neurons, two potent analogues (1b and 2b) were resolved, which were protective against mutant SOD1 induced toxicity in PC-12 cells. Both compounds were found to be active in cortical neurons and presented good ADME profiles in vitro. On the basis of these results, an ALS mouse trial with 1b was carried out, which showed slightly greater life extension than the FDA-approved ALS drug riluzole, thereby validating cyclohexane 1,3-diones as a novel therapeutic class for the treatment of ALS.}, }
@article {pmid22833725, year = {2012}, author = {Su, K and Bourdette, D and Forte, M}, title = {Genetic inactivation of mitochondria-targeted redox enzyme p66ShcA preserves neuronal viability and mitochondrial integrity in response to oxidative challenges.}, journal = {Frontiers in physiology}, volume = {3}, number = {}, pages = {285}, pmid = {22833725}, issn = {1664-042X}, support = {R01 GM069883/GM/NIGMS NIH HHS/United States ; R01 NS057433/NS/NINDS NIH HHS/United States ; }, abstract = {Mitochondria are essential to neuronal viability and function due to their roles in ATP production, intracellular calcium regulation, and activation of apoptotic pathways. Accordingly, mitochondrial dysfunction has been indicated in a wide variety of neurodegenerative diseases, including Alzheimer's disease (AD), Huntington's disease, amyotrophic lateral sclerosis, stroke, and multiple sclerosis (MS). Recent evidence points to the permeability transition pore (PTP) as a key player in mitochondrial dysfunction in these diseases, in which pathologic opening leads to mitochondrial swelling, rupture, release of cytochrome c, and neuronal death. Reactive oxygen species (ROS), which are inducers of PTP opening, have been prominently implicated in the progression of many of these neurodegenerative diseases. In this context, inactivation of a mitochondria-targeted redox enzyme p66ShcA (p66) has been recently shown to prevent the neuronal cell death leading to axonal severing in the murine model of MS, experimental autoimmune encephalomyelitis (EAE). To further characterize the response of neurons lacking p66, we assessed their reaction to treatment with stressors implicated in neurodegenerative pathways. Specifically, p66-knockout (p66-KO) and wild-type (WT) neurons were treated with hydrogen peroxide (H(2)O(2)) and nitric oxide (NO), and assessed for cell viability and changes in mitochondrial properties, including morphology and ROS production. The results showed that p66-KO neurons had greater survival following treatment with each stressor and generated less ROS when compared to WT neurons. Correspondingly, mitochondria in p66-KO neurons showed diminished morphological changes in response to these challenges. Overall, these findings highlight the importance of developing mitochondria-targeted therapeutics for neurodegenerative disorders, and emphasize p66, mitochondrial ROS, and the PTP as key targets for maintaining mitochondrial and neuronal integrity.}, }
@article {pmid22830016, year = {2012}, author = {Levine, TD and Bowser, R and Hank, NC and Gately, S and Stephan, D and Saperstein, DS and Van Keuren-Jensen, K}, title = {A Pilot Trial of Pioglitazone HCl and Tretinoin in ALS: Cerebrospinal Fluid Biomarkers to Monitor Drug Efficacy and Predict Rate of Disease Progression.}, journal = {Neurology research international}, volume = {2012}, number = {}, pages = {582075}, pmid = {22830016}, issn = {2090-1860}, abstract = {Objectives. To determine if therapy with pioglitazone HCl and tretinoin could slow disease progression in patients with ALS. Levels of tau and pNFH in the cerebrospinal fluid were measured to see if they could serve as prognostic indicators. Methods. 27 subjects on stable doses of riluzole were enrolled. Subjects were randomized to receive pioglitazone 30 mg/d and tretinoin 10 mg/BID for six months or two matching placebos. ALSFRS-R scores were followed monthly. At baseline and at the final visit, lumbar punctures (LPs) were performed to measure cerebrospinal fluid (CSF) biomarker levels. Results. Subjects treated with tretinoin, pioglitazone, and riluzole had an average rate of decline on the ALSFRS-R scale of -1.02 points per month; subjects treated with placebo and riluzole had a rate of decline of -.86 (P = .18). Over six months of therapy, CSF tau levels decreased in subjects randomized to active treatment and increased in subjects on placebo. Further higher levels of pNF-H at baseline correlated with a faster rate of progression. Conclusion. ALS patients who were treated with tretinoin and pioglitazone demonstrated no slowing on their disease progression. Interestingly, the rate of disease progression was strongly correlated with levels of pNFH in the CSF at baseline.}, }
@article {pmid22824638, year = {2012}, author = {Ciccolella, M and Catteruccia, M and Benedetti, S and Moroni, I and Uziel, G and Pantaleoni, C and Chiapparini, L and Bizzi, A and D'Amico, A and Fattori, F and Salsano, ML and Pastore, A and Tozzi, G and Piemonte, F and Bertini, E}, title = {Brown-Vialetto-van Laere and Fazio-Londe overlap syndromes: a clinical, biochemical and genetic study.}, journal = {Neuromuscular disorders : NMD}, volume = {22}, number = {12}, pages = {1075-1082}, doi = {10.1016/j.nmd.2012.05.007}, pmid = {22824638}, issn = {1873-2364}, mesh = {Adolescent ; Bulbar Palsy, Progressive/complications/diagnosis/drug therapy/*genetics ; Child ; Child, Preschool ; Deafness/complications/genetics ; Disease Progression ; Evoked Potentials, Auditory, Brain Stem/drug effects/genetics ; Female ; Genetic Predisposition to Disease/*genetics ; Hearing Loss, Sensorineural/complications/diagnosis/drug therapy/*genetics ; Humans ; Male ; Motor Neurons/drug effects/pathology ; Mutation/genetics ; Riboflavin/blood/therapeutic use ; Treatment Outcome ; }, abstract = {Brown-Vialetto-van Laere (BVVL) and Fazio-Londe (FL) are rare and clinically overlapping motor neurons syndromes. Recently BVVL has been associated with mutations in C20orf54/hRFT2 and defective riboflavin transport. We compared clinical and laboratory features of 6 patients (age range 11-17 years), with features of BVVL and FL overlap syndromes. Patients were assessed as following: blood levels of riboflavin and redox status, electrophysiological, neuroradiological and pulmonary studies, ALS functional rating scale and molecular genetic analysis. Two patients manifested deafness at ages of 3 and 10 years, and developed later subacute progressive ponto-bulbar palsy. A third patient markedly improved after intravenous immunoglobulins (IVIG), but then relapsed remaining unresponsive to treatment; he was not deaf although had abnormal auditory evoked responses (BAERs). The remaining 3 patients had no deafness, although likewise manifested subacute progressive ponto-bulbar palsy. We found hRFT2 mutations in 3/6 patients manifesting deafness or abnormal BAERs. No patient had reduced riboflavin blood levels. However, on riboflavin supplementation (10mg/kg/day) the most severely affected BVVL patient stopped progression of symptoms following 8 months of treatment. BVVL and FL are severe progressive diseases with overlapping symptoms although only hRFT2 mutated patients manifest deafness. Riboflavin supplementation seems to stabilize and improve progression of the disease.}, }
@article {pmid22823500, year = {2013}, author = {Das, A and Wallace, G and Reiter, RJ and Varma, AK and Ray, SK and Banik, NL}, title = {Overexpression of melatonin membrane receptors increases calcium-binding proteins and protects VSC4.1 motoneurons from glutamate toxicity through multiple mechanisms.}, journal = {Journal of pineal research}, volume = {54}, number = {1}, pages = {58-68}, pmid = {22823500}, issn = {1600-079X}, support = {NS-41088/NS/NINDS NIH HHS/United States ; NS-38146/NS/NINDS NIH HHS/United States ; R01 NS031622/NS/NINDS NIH HHS/United States ; R01 NS038146/NS/NINDS NIH HHS/United States ; NS-31622/NS/NINDS NIH HHS/United States ; R01 NS041088/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/drug effects ; Calbindins/biosynthesis ; Cell Line ; Cell Survival/drug effects ; Gene Knockdown Techniques ; Glutamic Acid/*toxicity ; Mice ; Motor Neurons/*drug effects/metabolism ; Nerve Tissue Proteins/drug effects ; Neuroprotective Agents/pharmacology ; Parvalbumins/biosynthesis ; RNA, Small Interfering/pharmacology ; Receptor, Melatonin, MT1/genetics ; Receptor, Melatonin, MT2/genetics ; Receptors, G-Protein-Coupled/drug effects ; Receptors, Melatonin/*biosynthesis ; }, abstract = {Melatonin has shown particular promise as a neuroprotective agent to prevent motoneuron death in animal models of both amyotrophic lateral sclerosis (ALS) and spinal cord injuries (SCI). However, an understanding of the roles of endogenous melatonin receptors including MT1, MT2, and orphan G-protein receptor 50 (GPR50) in neuroprotection is lacking. To address this deficiency, we utilized plasmids for transfection and overexpression of individual melatonin receptors in the ventral spinal cord 4.1 (VSC4.1) motoneuron cell line. Receptor-mediated cytoprotection following exposure to glutamate at a toxic level (25 μm) was determined by assessing cell viability, apoptosis, and intracellular free Ca(2+) levels. Our findings indicate a novel role for MT1 and MT2 for increasing expression of the calcium-binding proteins calbindin D28K and parvalbumin. Increased levels of calbindin D28K and parvalbumin in VSC4.1 cells overexpressing MT1 and MT2 were associated with cytoprotective effects including inhibition of proapoptotic signaling, downregulation of inflammatory factors, and expression of prosurvival markers. Interestingly, the neuroprotective effects conferred by overexpression of MT1 and/or MT2 were also associated with increases in the estrogen receptor β (ERβ): estrogen receptor α (ERα) ratio and upregulation of angiogenic factors. GPR50 did not exhibit cytoprotective effects. To further confirm the involvement of the melatonin receptors, we silenced both MT1 and MT2 in VSC4.1 cells using RNA interference technology. Knockdown of MT1 and MT2 led to an increase in glutamate toxicity, which was only partially reversed by melatonin treatment. Taken together, our findings suggest that the neuroprotection against glutamate toxicity exhibited by melatonin may depend on MT1 and MT2 but not GPR50.}, }
@article {pmid22821110, year = {2012}, author = {Kakuta, T and Hirata, H and Soda, S and Shiobara, T and Watanabe, M and Tatewaki, M and Fukushima, F and Chibana, K and Sugiyama, K and Arima, M and Koichi, H and Fukuda, T and Fukushima, Y}, title = {Riluzole-induced lung injury in two patients with amyotrophic lateral sclerosis.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {51}, number = {14}, pages = {1903-1907}, doi = {10.2169/internalmedicine.51.6522}, pmid = {22821110}, issn = {1349-7235}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy ; Excitatory Amino Acid Antagonists/adverse effects ; Female ; Humans ; Lung Injury/*chemically induced/diagnosis/drug therapy ; Neuroprotective Agents/adverse effects ; Prednisolone/therapeutic use ; Riluzole/*adverse effects ; }, abstract = {Riluzole has recently been proven as the first effective drug for the treatment of amyotrophic lateral sclerosis (ALS). We report two rare cases of lung injury caused by riluzole therapy in patients with ALS. Chest radiographs showed bilateral lower lobe, dorsal-dominant ground glass opacity, and/or consolidation. A drug lymphocyte stimulation test (DLST) of peripheral blood or bronchoalveolar lavage cells was positive for riluzole. Histopathological examination of lung biopsy specimens revealed lung injury without fungoid granuloma, vasculitis, or diffuse alveolar damage. To the best of our knowledge, this is the first report of riluzole-induced lung injury with positive DLST results.}, }
@article {pmid22819354, year = {2012}, author = {Tramonti, F and Bongioanni, P and Fanciullacci, C and Rossi, B}, title = {Balancing between autonomy and support: coping strategies by patients with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {320}, number = {1-2}, pages = {106-109}, doi = {10.1016/j.jns.2012.07.006}, pmid = {22819354}, issn = {1878-5883}, mesh = {*Adaptation, Psychological ; Age Factors ; Amyotrophic Lateral Sclerosis/*psychology ; Disease Progression ; Female ; Gastrostomy/*psychology ; Humans ; Male ; Middle Aged ; *Personal Autonomy ; Respiration, Artificial/psychology ; Sex Characteristics ; *Social Support ; Surveys and Questionnaires ; }, abstract = {Amyotrophic lateral sclerosis (ALS) makes a strong psychological impact, and the study of efforts by patients to cope with the course of the disease could be an important first step in the optimisation of care treatment. With this aim, in our study we assessed the coping strategies by a population of ALS patients, according to some clinical parameters and the worsening of the disease. We have administered the MND coping scale to 62 patients, firstly at the admission to our neurorehabilitation unit and secondly after 1year. Each factor score has been related to age and progression of the disease, and comparisons between males and females have also been made. The increasing relevance of seeking support from families and technological devices is probably the most interesting finding: such a result stimulates remarkable considerations about the proper balance between such support and patients' autonomy. As a whole, data confirm the importance of a proper and well-timed psychological intervention for patients and their families. In detail, improving adaptive coping strategies, together with sustaining those which tend to weaken along the progression of the disease, could be an important goal in psychological counselling for both patients and family members.}, }
@article {pmid22815892, year = {2012}, author = {Lu, CH and Petzold, A and Kalmar, B and Dick, J and Malaspina, A and Greensmith, L}, title = {Plasma neurofilament heavy chain levels correlate to markers of late stage disease progression and treatment response in SOD1(G93A) mice that model ALS.}, journal = {PloS one}, volume = {7}, number = {7}, pages = {e40998}, pmid = {22815892}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Animals ; Biomarkers/metabolism ; Disease Models, Animal ; Disease Progression ; Enzyme-Linked Immunosorbent Assay/methods ; Female ; Hydroxylamines/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Muscles/metabolism ; Neurofilament Proteins/*blood/*chemistry ; Phosphorylation ; Spinal Cord/metabolism ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Treatment Outcome ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder characterised by progressive degeneration of motor neurons leading to death, typically within 3-5 years of symptom onset. The diagnosis of ALS is largely reliant on clinical assessment and electrophysiological findings. Neither specific investigative tools nor reliable biomarkers are currently available to enable an early diagnosis or monitoring of disease progression, hindering the design of treatment trials.<br><br>In this study, using the well-established SOD1(G93A) mouse model of ALS and a new in-house ELISA method, we have validated that plasma neurofilament heavy chain protein (NfH) levels correlate with both functional markers of late stage disease progression and treatment response. We detected a significant increase in plasma levels of phosphorylated NfH during disease progression in SOD1(G93A) mice from 105 days onwards. Moreover, increased plasma NfH levels correlated with the decline in muscle force, motor unit survival and, more significantly, with the loss of spinal motor neurons in SOD1 mice during this critical period of decline. Importantly, mice treated with the disease modifying compound arimoclomol had lower plasma NfH levels, suggesting plasma NfH levels could be validated as an outcome measure for treatment trials.<br><br>CONCLUSIONS/SIGNIFICANCE: These results show that plasma NfH levels closely reflect later stages of disease progression and therapeutic response in the SOD1(G93A) mouse model of ALS and may potentially be a valuable biomarker of later disease progression in ALS.}, }
@article {pmid22810870, year = {2011}, author = {Dombovy, ML}, title = {Neurorehabilitation for other neurologic disorders.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {17}, number = {3 Neurorehabilitation}, pages = {606-616}, doi = {10.1212/01.CON.0000399075.07686.3f}, pmid = {22810870}, issn = {1080-2371}, abstract = {Rehabilitation treatment and the interdisciplinary approach to care may improve the function of those with progressive neurologic disorders such as multiple sclerosis, Parkinson disease, ALS, muscular dystrophy, and neuropathy. Appropriate goals and therapies are specific to the stage of the disease as well as the needs and values of the individual patient. Preliminary evidence exists to support moderate aerobic and strengthening regimens in these patients. Close monitoring and avoidance of fatigue are paramount. Assistive technologies play an ever-increasing role in maintaining independence during all stages of the disease.}, }
@article {pmid22800896, year = {2012}, author = {Feng, XH and Yuan, W and Peng, Y and Liu, MS and Cui, LY}, title = {Therapeutic effects of dl-3-n-butylphthalide in a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Chinese medical journal}, volume = {125}, number = {10}, pages = {1760-1766}, pmid = {22800896}, issn = {2542-5641}, mesh = {Administration, Oral ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Benzofurans/administration &amp; dosage/*therapeutic use ; Disease Models, Animal ; Female ; Immunohistochemistry ; Mice ; Mice, Transgenic ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive death of the upper and lower motor neurons. Transgenic mice over-expressing a mutant form of the human SOD1 gene develop an ALS-like phenotype. Currently, there is no effective treatment or drug for the fatal disease. Previous studies reported potent efficacy of dl-3-n-butylphthalide (DL-NBP) for several neurodegenerative disorders and cerebral ischemia. SOD1-G93A mice are a mouse model of ALS. In this study, we investigated the efficacy of DL-NBP on this ALS mouse model.<br><br>METHODS: Sixty SOD1-G93A female mice were divided into four groups. The vehicle control group received 0 mg&#xd7;kg(-1)&#xd7;d(-1) DL-NBP. The experimental groups received DL-NBP with doses of 30, 60 or 120 mg&#xd7;kg(-1)&#xd7;d(-1), respectively. For measurement of motor activity, the hanging wire test and rotarod test were performed. Survival statistics were analyzed by Kaplan-Meier survival curves. The body weight of each mouse was recorded twice per week. The statistical motor unit number estimation (MUNE) technique was used to estimate the number of functioning motor units in gastrocnemius muscle. Muscle morphology was evaluated by hematoxylin and eosin staining. Motor neuron quantitation was performed by Nissl staining and microglia activation was observed by immunohistochemistry.<br><br>RESULTS: Oral administration of 60 mg&#xd7;kg(-1)&#xd7;d(-1)1 DL-NBP significantly prolonged survival ((164.78 &#xb1; 16.67) days) of SOD1-G93A mice compared with vehicle control ((140.00 &#xb1; 16.89) days). Treating mice with DL-NBP (60 mg&#xd7;kg(-1)&#xd7;d(-1)) significantly decreased the progression rate of motor deficits and suppressed body weight reduction. Furthermore, we found that treating SOD1-G93A mice with DL-NBP (60 mg&#xd7;kg(-1)&#xd7;d(-1)) slowed the rate of MUNE reduction (P < 0.01). Motor neurons were remarkably preserved in the anterior horns in mice treated with DL-NBP (60 mg&#xd7;kg(-1)&#xd7;d(-1)) at the stage of 19 weeks (P < 0.01). Treating mice with DL-NBP (60 mg&#xd7;kg(-1)&#xd7;d(-1)) significantly reduced CD11b immunoreactivity compared with vehicle control mice (P < 0.05). No significant effect was observed in mice treated with DL-NBP of 30 or 120 mg&#xd7;kg(-1)&#xd7;d(-1).<br><br>CONCLUSIONS: The post-disease-onset administration of DL-NBP significantly prolonged survival and improved motor performance in SOD1-G93A mice. DL-NBP may be a potential therapeutic agent for ALS.}, }
@article {pmid22800606, year = {2012}, author = {Cappello, V and Vezzoli, E and Righi, M and Fossati, M and Mariotti, R and Crespi, A and Patruno, M and Bentivoglio, M and Pietrini, G and Francolini, M}, title = {Analysis of neuromuscular junctions and effects of anabolic steroid administration in the SOD1G93A mouse model of ALS.}, journal = {Molecular and cellular neurosciences}, volume = {51}, number = {1-2}, pages = {12-21}, doi = {10.1016/j.mcn.2012.07.003}, pmid = {22800606}, issn = {1095-9327}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Anabolic Agents/*pharmacology ; Animals ; Disease Models, Animal ; Humans ; Male ; Mice ; Mice, Transgenic ; Mitochondria/ultrastructure ; Muscle Fibers, Skeletal/drug effects/pathology/physiology ; Mutation ; Nandrolone/*pharmacology ; Neuromuscular Junction/drug effects/genetics/physiopathology/*ultrastructure ; Presynaptic Terminals/physiology/ultrastructure ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; Synaptic Vesicles/ultrastructure ; }, abstract = {Several lines of evidence indicate that neuromuscular junction (NMJ) destruction and disassembly is an early phenomenon in amyotrophic lateral sclerosis (ALS). Here we analyzed by confocal and electron microscopy the NMJ structure in the diaphragm of SOD1G93A mice at symptom onset. In these mice, which provide a model for familial ALS, diaphragm denervation (~50%) as well as gastrocnemius denervation (~40%) was found. In addition, the size of the synaptic vesicle pool was reduced and alterations of mitochondria were observed in approximately 40% of the remaining presynaptic terminals. Chronic treatment of SOD1G93A mice with the anabolic steroid nandrolone during the presymptomatic stage preserved the diaphragm muscle mass and features indicative of synaptic activity. These features were represented by the number of vesicles docked within 200 nm from the presynaptic membrane and area of acetylcholine receptor clusters. Structural preservation of mitochondria was documented in presynaptic terminals. However, innervation of diaphragm muscle fibers was only slightly increased in nandrolone-treated SOD1-mutant mice. Altogether the results point out and define fine structural alterations of diaphragm NMJs in the murine model of familial ALS at symptom onset, and indicate that nandrolone may prevent or delay structural alterations in NMJ mitochondria and stimulate presynaptic activity but does not prevent muscle denervation during the disease.}, }
@article {pmid22763933, year = {2012}, author = {Jung, HH and Neumann, M and Bloch, KE}, title = {[Amyotrophic lateral sclerosis--diagnosis and treatment].}, journal = {Praxis}, volume = {101}, number = {14}, pages = {907-914}, doi = {10.1024/1661-8157/a000988}, pmid = {22763933}, issn = {1661-8157}, mesh = {Activities of Daily Living/classification ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy/genetics/mortality ; Animals ; Cause of Death ; Cross-Sectional Studies ; DNA Mutational Analysis ; Diagnosis, Differential ; Disease Models, Animal ; Excitatory Amino Acid Antagonists/administration &amp; dosage/adverse effects ; Female ; Genetic Predisposition to Disease/genetics ; Humans ; Male ; Middle Aged ; Motor Neurons/pathology ; Neurologic Examination ; Palliative Care ; Riluzole/administration &amp; dosage/adverse effects ; Spinal Cord/pathology ; Survival Analysis ; TDP-43 Proteinopathies/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) represents the most common motoneuron disorder in adulthood. It is characterized by selective degeneration of the motoneurons. About 10% of patients have a genetically determined ALS. Clinically, ALS is characterized by coexistence of signs of the first motoneuron, such as spasticity and hyperreflexia, as well as the second motoneuron, such as muscular atrophy and fasciculations. If such signs are present in at least three regions and if other possible causes have been excluded, a definite diagnosis of ALS can be made based on the revised El-Escorial criteria. Initial manifestations are often focalized and generalization develops during the course. The glutamate antagonist riluzole is worldwide the only approved ALS treatment. However, symptomatic treatments to ameliorate spasticity, drooling, speech and swallowing problems, and assisted ventilation to treat respiratory failure are essential.}, }
@article {pmid22761934, year = {2012}, author = {Yanpallewar, SU and Barrick, CA and Buckley, H and Becker, J and Tessarollo, L}, title = {Deletion of the BDNF truncated receptor TrkB.T1 delays disease onset in a mouse model of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {7}, number = {6}, pages = {e39946}, pmid = {22761934}, issn = {1932-6203}, support = {//Intramural NIH HHS/United States ; }, mesh = {Adenosine/analogs &amp; derivatives/pharmacology ; Adenosine A2 Receptor Agonists/pharmacology ; Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Brain-Derived Neurotrophic Factor/*metabolism ; Disease Models, Animal ; Disease Progression ; Mice ; Phenethylamines/pharmacology ; Receptor, trkB/genetics/*physiology ; Superoxide Dismutase/genetics ; }, abstract = {Brain Derived Neurotrophic Factor (BDNF) exerts strong pro-survival effects on developing and injured motoneurons. However, in clinical trials, BDNF has failed to benefit patients with amyotrophic lateral sclerosis (ALS). To date, the cause of this failure remains unclear. Motoneurons express the TrkB kinase receptor but also high levels of the truncated TrkB.T1 receptor isoform. Thus, we investigated whether the presence of this receptor may affect the response of diseased motoneurons to endogenous BDNF. We deleted TrkB.T1 in the hSOD1(G93A) ALS mouse model and evaluated the impact of this mutation on motoneuron death, muscle weakness and disease progression. We found that TrkB.T1 deletion significantly slowed the onset of motor neuron degeneration. Moreover, it delayed the development of muscle weakness by 33 days. Although the life span of the animals was not affected we observed an overall improvement in the neurological score at the late stage of the disease. To investigate the effectiveness of strategies aimed at bypassing the TrkB.T1 limit to BDNF signaling we treated SOD1 mutant mice with the adenosine A2A receptor agonist CGS21680, which can activate motoneuron TrkB receptor signaling independent of neurotrophins. We found that CGS21680 treatment slowed the onset of motor neuron degeneration and muscle weakness similarly to TrkB.T1 removal. Together, our data provide evidence that endogenous TrkB.T1 limits motoneuron responsiveness to BDNF in vivo and suggest that new strategies such as Trk receptor transactivation may be used for therapeutic intervention in ALS or other neurodegenerative disorders.}, }
@article {pmid22750289, year = {2012}, author = {Isonaka, R and Katakura, T and Kawakami, T}, title = {Effect of inhibition of superoxide dismutase on motor neurons during growth: comparison of phosphorylated and non-phosphorylated neurofilament-containing spinal neurons by histogram distribution.}, journal = {Brain research}, volume = {1470}, number = {}, pages = {11-16}, doi = {10.1016/j.brainres.2012.06.014}, pmid = {22750289}, issn = {1872-6240}, mesh = {Animals ; Cells, Cultured ; Ditiocarb/pharmacology ; Dose-Response Relationship, Drug ; Embryo, Mammalian ; Enzyme Inhibitors/pharmacology ; Motor Neurons/cytology/drug effects/*metabolism ; Neurites/physiology ; Neurofilament Proteins/*metabolism ; Phosphorylation/drug effects ; Rats ; Rats, Wistar ; Spinal Cord/*cytology ; Superoxide Dismutase/antagonists &amp; inhibitors/*metabolism ; Time Factors ; }, abstract = {We reported recently that non-phosphorylated neurofilaments (NF)-positive neurons were more sensitive to the growth inhibitory effects of Cu/Zn superoxide dismutase (SOD1) than phosphorylated NF-positive neurons. The findings suggested that non-phosphorylated NF-positive neurons, presumed to represent spinal motor neurons, are more vulnerable to oxidative stress than other neurons, and thus explain in part the selective degeneration of motor neurons in amyotrophic lateral sclerosis. The present investigation is an extension to our previous study and examined the neurite growth process in the presence of diethyldithiocarbamate (DDC), an SOD1 inhibitor. Non-phosphorylated NF, representing spinal motor neurons, and phosphorylated NF, representing other spinal neurons, were stained with SMI-32 and SMI-31 antibodies, respectively. The distribution histogram of neurite length after treatment with 0 nM DDC (control) for 72 h appeared flatter compared with that of 24h. Although the addition of DDC (1 nM, 10 nM, 100 nM, or 1000 nM) to the culture medium for 72 h shifted the histogram of neurite length to a shorter range in a concentration-dependent manner, the neurite of SMI-31-immunoreactive neurons grew under DDC. On the other hand, DDC-treatment for 72 h altered the neurite growth of SMI-32-immunoreactive neurons compared with that for 24-h. The results suggest that SOD1 inhibition, representing accumulation of endogenous oxidative stress, suppresses neurite growth of spinal motor neurons, and that the growth of spinal motor neurons is more sensitive to oxidative stress than other types of neurons.}, }
@article {pmid22746022, year = {2012}, author = {Wakimoto, M and Nagata, H and Kumagai, M and Miyata, M and Iwabuchi, Y and Suzuki, K}, title = {[Anesthetic management for a patient with amyotrophic lateral sclerosis; the neuromuscular monitoring was useful to determine appropriate dosages of rocuronium].}, journal = {Masui. The Japanese journal of anesthesiology}, volume = {61}, number = {6}, pages = {599-601}, pmid = {22746022}, issn = {0021-4892}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*surgery ; Androstanols/*administration &amp; dosage ; Anesthesia, General ; Baclofen/administration &amp; dosage ; Humans ; Infusion Pumps, Implantable ; Injections, Spinal ; Male ; Middle Aged ; Monitoring, Physiologic/*methods ; Muscle Relaxants, Central/administration &amp; dosage ; Neuromuscular Nondepolarizing Agents/*administration &amp; dosage ; Rocuronium ; }, abstract = {We experienced an anesthetic management with rocuronium and neurostimulator for a surgical patient with amyotrophic lateral sclerosis. A 61-year-old man was scheduled for intrathecal baclofen pump implantation as treatment for his spasticity under general anesthesia. After oxygenation and totally intravenous induction with propofol and remifentanil, we administered 10 mg of rocuronium repeatedly monitoring with neurostimulator. When dosage of rocuronium reached 20 mg, train-of-four count reached 1 and his trachea was intubated without coughing or moving. Anesthesia was maintained intravenously. Train-of-four ratio recovered to 95%, 22 minutes after the first administration of rocuronium. Operation was accomplished uneventfully with no additional rocuronium. Bispectral index value recovered to 98 and the patient awoke and breathed spontaneously 19 minutes after termination of administration of anesthetic agents. We could confirm his stable and adequate respiration and trachea was extubated without reversal of rocuronium. In the postanesthesia care unit, he showed no discomfort and was returned to the ward. His symptoms did not deteriorate postoperatively and he was discharged on the 36th postoperative day.}, }
@article {pmid22745655, year = {2012}, author = {Knippenberg, S and Thau, N and Dengler, R and Brinker, T and Petri, S}, title = {Intracerebroventricular injection of encapsulated human mesenchymal cells producing glucagon-like peptide 1 prolongs survival in a mouse model of ALS.}, journal = {PloS one}, volume = {7}, number = {6}, pages = {e36857}, pmid = {22745655}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/*therapy ; Animals ; Female ; Glucagon-Like Peptide 1/genetics/*metabolism ; Humans ; Male ; Mesenchymal Stem Cells/*cytology/physiology ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism ; Nitric Oxide Synthase Type I/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {BACKGROUND: As pharmacological therapies have largely failed so far, stem cell therapy has recently come into the focus of ALS research. Neuroprotective potential was shown for several types of stem and progenitor cells, mainly due to release of trophic factors. In the present study, we assessed the effects of intracerebroventricular injection of glucagon-like peptide 1 (GLP-1) releasing mesenchymal stromal cells (MSC) in mutant SOD1 (G93A) transgenic mice.<br><br>To improve the neuroprotective effects of native MSC, they had been transfected with a plasmid vector encoding a GLP-1 fusion gene prior to the injection, as GLP-1 was shown to exhibit neuroprotective properties before. Cells were encapsulated and therefore protected against rejection. After intracerebroventricular injection of these GLP-1 MSC capsules in presymptomatic SOD1 (G93A) mice, we assessed possible protective effects by survival analysis, measurement of body weight, daily monitoring and evaluation of motor performance by rotarod and footprint analyses. Motor neuron numbers in the spinal cord as well as the amount of astrocytosis, microglial activation, heat shock response and neuronal nitric oxide synthase (nNOS) expression were analyzed by immunohistological methods. Treatment with GLP-1 producing MSC capsules significantly prolonged survival by 13 days, delayed symptom onset by 15 days and weight loss by 14 days and led to significant improvements in motor performance tests compared to vehicle treated controls. Histological data are mainly in favour of anti-inflammatory effects of GLP-1 producing MSC capsules with reduced detection of inflammatory markers and a significant heat shock protein increase.<br><br>CONCLUSION/SIGNIFICANCE: Intracerebroventricular injection of GLP-1 MSC capsules shows neuroprotective potential in the SOD1 (G93A) mouse model.}, }
@article {pmid22742419, year = {2012}, author = {Joshi, G and Johnson, JA}, title = {The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases.}, journal = {Recent patents on CNS drug discovery}, volume = {7}, number = {3}, pages = {218-229}, pmid = {22742419}, issn = {2212-3954}, support = {R01 ES008089/ES/NIEHS NIH HHS/United States ; R29 ES008089/ES/NIEHS NIH HHS/United States ; R01 ES010042/ES/NIEHS NIH HHS/United States ; ES08089/ES/NIEHS NIH HHS/United States ; P50 AG033514/AG/NIA NIH HHS/United States ; ES10042/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Antioxidant Response Elements/*drug effects ; Brain/drug effects/metabolism ; Drugs, Investigational/chemistry/pharmacology/*therapeutic use ; Humans ; Intracellular Signaling Peptides and Proteins/agonists/antagonists &amp; inhibitors/metabolism ; Kelch-Like ECH-Associated Protein 1 ; *Molecular Targeted Therapy ; NF-E2-Related Factor 2/agonists/antagonists &amp; inhibitors/*metabolism ; Nerve Tissue Proteins/agonists/antagonists &amp; inhibitors/metabolism ; Neurodegenerative Diseases/*drug therapy/metabolism ; Neurons/drug effects/metabolism ; Neuroprotective Agents/chemistry/pharmacology/*therapeutic use ; Oxidative Stress ; Patents as Topic ; Signal Transduction/*drug effects ; }, abstract = {Modulation of NF-E2 related factor 2 (Nrf2) has been shown in several neurodegenerative disorders. The overexpression of Nrf2 has become a potential therapeutic avenue for various neurodegenerative disorders such as Parkinson, Amyotrophic lateral sclerosis, and Alzheimer's disease. The expression of phase II detoxification enzymes is governed by the cis-acting regulatory element known as antioxidant response element (ARE). The transcription factor Nrf2 binds to ARE thereby transcribing multitude of antioxidant genes. Keap1, a culin 3-based E3 ligase that targets Nrf2 for degradation, sequesters Nrf2 in cytoplasm. Disruption of Keap1-Nrf2 interaction or genetic overexpression of Nrf2 can increase the endogenous antioxidant capacity of the brain thereby rendering protection against oxidative stress in neurodegenerative disorders. This review primarily focuses on recent patents that target Nrf2 overexpression as a promising therapeutic strategy for the treatment of neurodegenerative disorders.}, }
@article {pmid22741814, year = {2012}, author = {Dunkel, P and Chai, CL and Sperlágh, B and Huleatt, PB and Mátyus, P}, title = {Clinical utility of neuroprotective agents in neurodegenerative diseases: current status of drug development for Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis.}, journal = {Expert opinion on investigational drugs}, volume = {21}, number = {9}, pages = {1267-1308}, doi = {10.1517/13543784.2012.703178}, pmid = {22741814}, issn = {1744-7658}, mesh = {Alzheimer Disease/drug therapy/physiopathology ; Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Animals ; *Drug Design ; Humans ; Huntington Disease/drug therapy/physiopathology ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neuroprotective Agents/pharmacology/*therapeutic use ; Parkinson Disease/drug therapy/physiopathology ; }, abstract = {INTRODUCTION: According to the definition of the Committee to Identify Neuroprotective Agents in Parkinson's Disease (CINAPS), "neuroprotection would be any intervention that favourably influences the disease process or underlying pathogenesis to produce enduring benefits for patients" [Meissner W, et al. Trends Pharmacol Sci 2004;25:249-253]. Preferably, neuroprotective agents should be used before or eventually during the prodromal phase of the diseases that could start decades before the appearance of symptoms. Although several symptomatic drugs are available, a disease-modifying agent is still elusive.<br><br>AREAS COVERED: The aim of the present review is to give an overview of neuroprotective agents being currently investigated for the treatment of AD, PD, HD and ALS in clinical phases.<br><br>EXPERT OPINION: Development of effective neuroprotective therapies resulting in clinically meaningful results is hampered by several factors in all research stages, both conceptual and methodological. Novel solutions might be offered by evaluation of new targets throughout clinical studies, therapies emerging from drug repositioning approaches, multi-target approaches and network pharmacology.}, }
@article {pmid22740598, year = {2012}, author = {Johnson, JO and Gibbs, JR and Megarbane, A and Urtizberea, JA and Hernandez, DG and Foley, AR and Arepalli, S and Pandraud, A and Simón-Sánchez, J and Clayton, P and Reilly, MM and Muntoni, F and Abramzon, Y and Houlden, H and Singleton, AB}, title = {Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease.}, journal = {Brain : a journal of neurology}, volume = {135}, number = {Pt 9}, pages = {2875-2882}, pmid = {22740598}, issn = {1460-2156}, support = {/WT_/Wellcome Trust/United Kingdom ; Z01 AG 000958-08/AG/NIA NIH HHS/United States ; G1001253/MRC_/Medical Research Council/United Kingdom ; G0802760/MRC_/Medical Research Council/United Kingdom ; G108/638/MRC_/Medical Research Council/United Kingdom ; /ImNIH/Intramural NIH HHS/United States ; }, mesh = {Alleles ; Bulbar Palsy, Progressive/*genetics ; Child ; Child, Preschool ; *Exome ; Female ; Gene Frequency ; Genotype ; Hearing Loss, Sensorineural/*genetics ; Humans ; Male ; Motor Neuron Disease/*genetics ; *Mutation ; Pedigree ; Polymorphism, Single Nucleotide ; Receptors, G-Protein-Coupled/*genetics ; }, abstract = {Brown-Vialetto-Van Laere syndrome was first described in 1894 as a rare neurodegenerative disorder characterized by progressive sensorineural deafness in combination with childhood amyotrophic lateral sclerosis. Mutations in the gene, SLC52A3 (formerly C20orf54), one of three known riboflavin transporter genes, have recently been shown to underlie a number of severe cases of Brown-Vialetto-Van Laere syndrome; however, cases and families with this disease exist that do not appear to be caused by SLC52A3 mutations. We used a combination of linkage and exome sequencing to identify the disease causing mutation in an extended Lebanese Brown-Vialetto-Van Laere kindred, whose affected members were negative for SLC52A3 mutations. We identified a novel mutation in a second member of the riboflavin transporter gene family (gene symbol: SLC52A2) as the cause of disease in this family. The same mutation was identified in one additional subject, from 44 screened. Within this group of 44 patients, we also identified two additional cases with SLC52A3 mutations, but none with mutations in the remaining member of this gene family, SLC52A1. We believe this strongly supports the notion that defective riboflavin transport plays an important role in Brown-Vialetto-Van Laere syndrome. Initial work has indicated that patients with SLC52A3 defects respond to riboflavin treatment clinically and biochemically. Clearly, this makes an excellent candidate therapy for the SLC52A2 mutation-positive patients identified here. Initial riboflavin treatment of one of these patients shows promising results.}, }
@article {pmid22739839, year = {2013}, author = {Pandi-Perumal, SR and BaHammam, AS and Brown, GM and Spence, DW and Bharti, VK and Kaur, C and Hardeland, R and Cardinali, DP}, title = {Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes.}, journal = {Neurotoxicity research}, volume = {23}, number = {3}, pages = {267-300}, pmid = {22739839}, issn = {1476-3524}, mesh = {Aging/drug effects/metabolism/*physiology ; Animals ; Antioxidants/*therapeutic use ; Apoptosis/drug effects ; Brain Injuries/drug therapy ; Circadian Rhythm/physiology ; Clinical Trials as Topic ; Double-Blind Method ; Drug Evaluation, Preclinical ; Free Radicals/metabolism ; Homeostasis/physiology ; Humans ; Light ; Melatonin/agonists/pharmacology/*physiology/therapeutic use ; Mice ; Mice, Transgenic ; Mitochondria/metabolism ; Multicenter Studies as Topic ; Nerve Tissue Proteins/biosynthesis/physiology ; Neurodegenerative Diseases/metabolism/*prevention &amp; control ; Neurons/metabolism/pathology ; Neuroprotective Agents/pharmacology/*therapeutic use ; Oxidative Stress/drug effects ; Pineal Gland/metabolism/radiation effects ; Sleep Initiation and Maintenance Disorders/drug therapy ; Tryptophan/metabolism ; }, abstract = {The pineal product melatonin has remarkable antioxidant properties. It is secreted during darkness and plays a key role in various physiological responses including regulation of circadian rhythms, sleep homeostasis, retinal neuromodulation, and vasomotor responses. It scavenges hydroxyl, carbonate, and various organic radicals as well as a number of reactive nitrogen species. Melatonin also enhances the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase, and by augmenting glutathione levels. Melatonin preserves mitochondrial homeostasis, reduces free radical generation and protects mitochondrial ATP synthesis by stimulating Complexes I and IV activities. The decline in melatonin production in aged individuals has been suggested as one of the primary contributing factors for the development of age-associated neurodegenerative diseases. The efficacy of melatonin in preventing oxidative damage in either cultured neuronal cells or in the brains of animals treated with various neurotoxic agents, suggests that melatonin has a potential therapeutic value as a neuroprotective drug in treatment of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and brain trauma. Therapeutic trials with melatonin indicate that it has a potential therapeutic value as a neuroprotective drug in treatment of AD, ALS, and HD. In the case of other neurological conditions, like PD, the evidence is less compelling. Melatonin's efficacy in combating free radical damage in the brain suggests that it can be a valuable therapeutic agent in the treatment of cerebral edema following traumatic brain injury or stroke. Clinical trials employing melatonin doses in the range of 50-100 mg/day are warranted before its relative merits as a neuroprotective agent is definitively established.}, }
@article {pmid22728481, year = {2012}, author = {Ikeda, K and Hirayama, T and Takazawa, T and Kawabe, K and Iwasaki, Y}, title = {Relationships between disease progression and serum levels of lipid, urate, creatinine and ferritin in Japanese patients with amyotrophic lateral sclerosis: a cross-sectional study.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {51}, number = {12}, pages = {1501-1508}, doi = {10.2169/internalmedicine.51.7465}, pmid = {22728481}, issn = {1349-7235}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*blood/physiopathology ; Asian People ; Case-Control Studies ; Creatinine/blood ; Cross-Sectional Studies ; Disease Progression ; Female ; Ferritins/blood ; Humans ; Lipids/blood ; Logistic Models ; Male ; Middle Aged ; Uric Acid/blood ; Vital Capacity ; }, abstract = {OBJECTIVE: Previous studies have reported distinct serological profiles of lipid, urate and ferritin in Western patients with amyotrophic lateral sclerosis (ALS). We aimed to examine the levels of these serological factors and their relationship to disease progression in Japanese ALS patients.<br><br>METHODS: Ninety-two patients with definite or probable ALS who fulfilled the revised El Escorial criteria were analyzed for clinical and serological variables. Serological data at the time diagnosed with ALS were compared to those of 92 age/sex/body mass index-matched healthy controls.<br><br>RESULTS: Compared to controls, urate and creatinine (Cr) levels were decreased and ferritin levels were increased significantly in sera of male and female patients with ALS. Significant increases of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels were found in female ALS patients. The annual decline of ALS Functional Rating Scale-Revised (ALS-FRS) and forced vital capacity (FVC) were inversely correlated with serum TC, LDL-C, Cr and urate levels, and were positively correlated with serum ferritin levels. Multivariate analysis showed that the rapid worsening of annual ALS-FRS and FVC was associated with serum levels of TC, LDL-C, Cr, urate and ferritin.<br><br>CONCLUSION: The present study indicated that serum levels of TC, LDL-C, Cr, urate and ferritin were correlated with clinical deterioration in ALS patients. These results are similar to those in Western patients. Metabolic and nutritional conditions of lipid, urate and iron could contribute to disease progression in ALS patients. Further studies investigating high nutrition diets and iron chelation for the treatment of ALS are warranted.}, }
@article {pmid22728077, year = {2012}, author = {Takata, T and Kimura, Y and Ohnuma, Y and Kawawaki, J and Kakiyama, Y and Tanaka, K and Kakizuka, A}, title = {Rescue of growth defects of yeast cdc48 mutants by pathogenic IBMPFD-VCPs.}, journal = {Journal of structural biology}, volume = {179}, number = {2}, pages = {93-103}, doi = {10.1016/j.jsb.2012.06.005}, pmid = {22728077}, issn = {1095-8657}, mesh = {Adenosine Triphosphatases/genetics/*metabolism ; Cell Cycle Proteins/genetics/*metabolism ; Flow Cytometry ; Frontotemporal Dementia/*enzymology ; Genetic Complementation Test ; Humans ; Muscular Dystrophies, Limb-Girdle/*enzymology ; Mutation ; Myositis, Inclusion Body/*enzymology ; Osteitis Deformans/*enzymology ; Valosin Containing Protein ; Yeasts/*enzymology/genetics/*growth &amp; development ; }, abstract = {VCP/p97/Cdc48 is a hexameric ring-shaped AAA ATPase that participates in a wide variety of cellular functions. VCP is a very abundant protein in essentially all types of cells and is highly conserved among eukaryotes. To date, 19 different single amino acid-substitutions in VCP have been reported to cause IBMPFD (inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia), an autosomal dominant inherited human disease. Moreover, several similar single amino acid substitutions have been proposed to associate with a rare subclass of familial ALS. The mechanisms by which these mutations contribute to the pathogenesis are unclear. To elucidate potential functional differences between wild-type and pathogenic VCPs, we expressed both VCPs in yeast cdc48 mutants. We observed that all tested pathogenic VCPs suppressed the temperature-sensitive phenotype of cdc48 mutants more efficiently than wild-type VCP. In addition, pathogenic VCPs, but not wild-type VCP, were able to rescue a lethal cdc48 disruption. In yeast, pathogenic VCPs, but not wild-type VCP, formed apparent cytoplasmic foci, and these foci were transported to budding sites by the Myo2/actin-mediated transport machinery. The foci formation of pathogenic VCPs appeared to be associated with their suppression of the temperature-sensitive phenotype of cdc48 mutants. These results support the idea that the pathogenic VCP mutations create dominant gain-of-functions rather than a simple loss of functional VCP. Their unique properties in yeast could provide a convenient drug-screening system for the treatment of these diseases.}, }
@article {pmid22721865, year = {2012}, author = {Nakamura, C and Bromberg, M and Bhargava, S and Wicks, P and Zeng-Treitler, Q}, title = {Mining online social network data for biomedical research: a comparison of clinicians' and patients' perceptions about amyotrophic lateral sclerosis treatments.}, journal = {Journal of medical Internet research}, volume = {14}, number = {3}, pages = {e90}, pmid = {22721865}, issn = {1438-8871}, support = {R21 NS067463/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*psychology/*therapy ; *Attitude of Health Personnel ; *Biomedical Research ; *Data Mining ; Humans ; *Information Storage and Retrieval ; *Social Networking ; }, abstract = {BACKGROUND: While only one drug is known to slow the progress of amyotrophic lateral sclerosis (ALS), numerous drugs can be used to treat its symptoms. However, very few randomized controlled trials have assessed the efficacy, safety, and side effects of these drugs. Due to this lack of randomized controlled trials, consensus among clinicians on how to treat the wide range of ALS symptoms and the efficacy of these treatments is low. Given the lack of clinical trials data, the wide range of reported symptoms, and the low consensus among clinicians on how to treat those symptoms, data on the prevalence and efficacy of treatments from a patient's perspective could help advance the understanding of the symptomatic treatment of ALS.<br><br>OBJECTIVE: To compare clinicians' and patients' perspectives on the symptomatic treatment of ALS by comparing data from a traditional survey study of clinicians with data from a patient social network.<br><br>METHODS: We used a survey of clinicians' perceptions by Forshew and Bromberg as our primary data source and adjusted the data from PatientsLikeMe to allow for comparisons. We first extracted the 14 symptoms and associated top four treatments listed by Forshew and Bromberg. We then searched the PatientsLikeMe database for the same symptom-treatment pairs. The PatientsLikeMe data are structured and thus no preprocessing of the data was required.<br><br>RESULTS: After we eliminated pairs with a small sample, 15 symptom-treatment pairs remained. All treatments identified as useful were prescription drugs. We found similarities and discrepancies between clinicians' and patients' perceptions of treatment prevalence and efficacy. In 7 of the 15 pairs, the differences between the two groups were above 10%. In 3 pairs the differences were above 20%. Lorazepam to treat anxiety and quinine to treat muscle cramps were among the symptom-treatment pairs with high concordance between clinicians' and patients' perceptions. Conversely, amitriptyline to treat labile emotional effect and oxybutynin to treat urinary urgency displayed low agreement between clinicians and patients.<br><br>CONCLUSIONS: Assessing and comparing the efficacy of the symptomatic treatment of a complex and rare disease such as ALS is not easy and needs to take both clinicians' and patients' perspectives into consideration. Drawing a reliable profile of treatment efficacy requires taking into consideration many interacting aspects (eg, disease stage and severity of symptoms) that were not covered in the present study. Nevertheless, pilot studies such as this one can pave the way for more robust studies by helping researchers anticipate and compensate for limitations in their data sources and study design.}, }
@article {pmid22721255, year = {2012}, author = {Pagnini, F and Banfi, P and Lunetta, C and Rossi, G and Castelnuovo, G and Marconi, A and Fossati, F and Corbo, M and Molinari, E}, title = {Respiratory function of people with amyotrophic lateral sclerosis and caregiver distress level: a correlational study.}, journal = {BioPsychoSocial medicine}, volume = {6}, number = {1}, pages = {14}, pmid = {22721255}, issn = {1751-0759}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rare, fatal neurodegenerative disorder with no curative treatment characterized by degeneration of motor neurons involving a progressive impairment of motor and respiratory functions. Most patients die of ventilator respiratory failure. Caregivers have a great influence on the patient"s quality of life as well as on the quality of care. Home influence of the caregiver on patient care is notable. To date, no study has investigated how psychological issues of caregivers would influence respiratory variables of ALS patients. The study aimed at finding out if there is a relationship between the respiratory function of ALS patients and the level of distress of their caregivers.<br><br>METHODS: A cross-sectional study was conducted to investigate respiratory issues (PCF and FVC) and the perception of social support of ALS patients. Caregivers filled questionnaires about trait anxiety, depression, and burden of care. Forty ALS patients and their caregivers were recruited.<br><br>RESULTS: FVC and PCF were positively related to patient perception of social support and negatively related to caregiver anxiety, depression, and burden.<br><br>DISCUSSION: The distress of ALS caregivers is related to patient respiratory issues. The first and more intuitive explanation emphasizes the impact that the patient's clinical condition has with respect to the caregiver. However, it is possible to hypothesize that if caregivers feel psychologically better, their patient's quality of life improves and that a condition of greater well-being and relaxation could also increase ventilatory capacity. Furthermore, care management could be carried out more easily by caregivers who pay more attention to the patient's respiratory needs.<br><br>CONCLUSION: Patient perception of social support and caregiver distress are related to respiratory issues in ALS.}, }
@article {pmid22715372, year = {2012}, author = {Dupuis, L and Dengler, R and Heneka, MT and Meyer, T and Zierz, S and Kassubek, J and Fischer, W and Steiner, F and Lindauer, E and Otto, M and Dreyhaupt, J and Grehl, T and Hermann, A and Winkler, AS and Bogdahn, U and Benecke, R and Schrank, B and Wessig, C and Grosskreutz, J and Ludolph, AC and , }, title = {A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {7}, number = {6}, pages = {e37885}, pmid = {22715372}, issn = {1932-6203}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Animals ; Anticonvulsants/*administration &amp; dosage ; Disease-Free Survival ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Hypoglycemic Agents/*administration &amp; dosage ; Male ; Mice ; Middle Aged ; Pioglitazone ; Riluzole/*administration &amp; dosage ; Survival Rate ; Thiazolidinediones/*administration &amp; dosage ; }, abstract = {BACKGROUND: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS).<br><br>METHODS/PRINCIPAL FINDINGS: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p&#x200a;=&#x200a;0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated.<br><br>CONCLUSION/SIGNIFICANCE: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole.<br><br>TRIAL REGISTRATION: Clinicaltrials.gov NCT00690118.}, }
@article {pmid22703530, year = {2012}, author = {Murinson, BB and Haughey, NJ and Maragakis, NJ}, title = {Selected statins produce rapid spinal motor neuron loss in vitro.}, journal = {BMC musculoskeletal disorders}, volume = {13}, number = {}, pages = {100}, pmid = {22703530}, issn = {1471-2474}, support = {R01 AG023471/AG/NIA NIH HHS/United States ; R21 MH072534/MH/NIMH NIH HHS/United States ; K08NS048146/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Biomarkers/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Fatty Acids, Monounsaturated/toxicity ; Fluvastatin ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*toxicity ; Immunohistochemistry ; Indoles/toxicity ; Motor Neurons/*drug effects/metabolism/pathology ; Neurites/drug effects/pathology ; Pravastatin/toxicity ; Rats ; Schwann Cells/*drug effects/metabolism/pathology ; Simvastatin/toxicity ; Spinal Nerves/*drug effects/metabolism/pathology ; Time Factors ; Tissue Culture Techniques ; }, abstract = {BACKGROUND: Hmg-CoA reductase inhibitors (statins) are widely used to prevent disease associated with vascular disease and hyperlipidemia. Although side effects are uncommon, clinical observations suggest statin exposure may exacerbate neuromuscular diseases, including peripheral neuropathy and amyotrophic lateral sclerosis. Although some have postulated class-effects, prior studies of hepatocytes and myocytes indicate that the statins may exhibit differential effects. Studies of neuronal cells have been limited.<br><br>METHODS: We examined the effects of statins on cultured neurons and Schwann cells. Cultured spinal motor neurons were grown on transwell inserts and assessed for viability using immunochemical staining for SMI-32. Cultured cortical neurons and Schwann cells were assessed using dynamic viability markers.<br><br>RESULTS: 7 days of exposure to fluvastatin depleted spinal motor neurons in a dose-dependent manner with a KD of&#x2009;<&#x2009;2&#x2009;&#x3bc;M. Profound neurite loss was observed after 4 days exposure in culture. Other statins were found to produce toxic effects at much higher concentrations. In contrast, no such toxicity was observed for cultured Schwann cells or cortical neurons.<br><br>CONCLUSIONS: It is known from pharmacokinetic studies that daily treatment of young adults with fluvastatin can produce serum levels in the single micromolar range. We conclude that specific mechanisms may explain neuromuscular disease worsening with statins and further study is needed.}, }
@article {pmid22698482, year = {2012}, author = {Ahn, SW and Kim, JE and Park, KS and Choi, WJ and Hong, YH and Kim, SM and Kim, SH and Lee, KW and Sung, JJ}, title = {The neuroprotective effect of the GSK-3β inhibitor and influence on the extrinsic apoptosis in the ALS transgenic mice.}, journal = {Journal of the neurological sciences}, volume = {320}, number = {1-2}, pages = {1-5}, doi = {10.1016/j.jns.2012.05.038}, pmid = {22698482}, issn = {1878-5883}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism/*physiopathology ; Animals ; Apoptosis/*drug effects/physiology ; Caspase 8/metabolism ; Cell Count/methods/statistics &amp; numerical data ; Disease Models, Animal ; Fas-Associated Death Domain Protein/metabolism ; Glycogen Synthase Kinase 3/*antagonists &amp; inhibitors ; Glycogen Synthase Kinase 3 beta ; Mice ; Mice, Transgenic ; Motor Neurons/*physiology ; Neuroprotective Agents/metabolism/*pharmacology ; Phosphorylation/drug effects ; Rotarod Performance Test/methods/statistics &amp; numerical data ; Signal Transduction/drug effects/physiology ; Spinal Cord/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Thiazoles/pharmacology/*therapeutic use ; Urea/*analogs &amp; derivatives/pharmacology/therapeutic use ; fas Receptor/metabolism ; }, abstract = {BACKGROUND: Glycogen synthase kinase-3β (GSK-3β) activity plays a central role in motor neuron degeneration. We hypothesized that GSK-3β inhibitor would prolong the survival of motor neuron and suppress the disease progression in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: A total of 40 transgenic mice harboring the human G93A mutated SOD1 gene and 14 wild type mice were used following confirmation of their genotype. The 40 transgenic mice were divided into 2 groups; ALS transgenic mice_control and ALS transgenic mice_GSK-3&#x3b2; inhibitor treatment. The clinical status, rotarod test and survival of the transgenic ALS mice and wild-type mice were evaluated. Additionally, motor neuron counting, GSK-3&#x3b2; activity and extrinsic apoptotic signals in spinal cord were also investigated.<br><br>RESULTS: The treatment with GSK-3&#x3b2; inhibitor showed excellent motor ability and delay of the symptom onset and survival in the ALS transgenic mice. However, after clinical symptoms developed, the neuroprotective effect of GSK-3&#x3b2; inhibitor was not significant. And the biochemical results revealed the weakly increased extrinsic apoptotic signals in the ALS transgenic mice by GSK-3&#x3b2; inhibitor treatment.<br><br>CONCLUSION: The present study suggests that GSK-3&#x3b2; inhibitor would be a novel promising therapeutic strategy in ALS; however neuroprotective effect of GSK-3&#x3b2; inhibitor may be reduced via extrinsic apoptosis or non-neuronal patho-mechanism in late-stage of disease.}, }
@article {pmid22691937, year = {2012}, author = {Komaki, S and Ishikawa, K and Arakawa, Y}, title = {Trk and cAMP-dependent survival activity of adenosine A(2A) agonist CGS21680 on rat motoneurons in culture.}, journal = {Neuroscience letters}, volume = {522}, number = {1}, pages = {21-24}, doi = {10.1016/j.neulet.2012.06.003}, pmid = {22691937}, issn = {1872-7972}, mesh = {Adenosine/*analogs &amp; derivatives/pharmacology ; Adenosine A2 Receptor Agonists/*pharmacology ; Animals ; Brain-Derived Neurotrophic Factor/pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Cyclic AMP/*physiology ; Cyclic AMP-Dependent Protein Kinases/antagonists &amp; inhibitors/physiology ; Humans ; Motor Neurons/cytology/*drug effects/metabolism ; Neuroprotective Agents/pharmacology ; Phenethylamines/*pharmacology ; Rats ; Rats, Wistar ; Receptor, Adenosine A2A/*metabolism ; Receptor, trkA/antagonists &amp; inhibitors/*physiology ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology ; }, abstract = {The survival activity of adenosine A(2A) agonist CGS21680 on motoneurons in culture through the transactivation of neurotrophin receptor TrkB has been reported previously; however, since adenosine A(2A) receptor belongs to a Gs-protein-coupled receptor, we investigated the involvement of the cAMP pathway in the survival activity of CGS21680 using purified motoneurons in culture. CGS21680 alone showed only small survival activity, but the activity was significantly enhanced by the addition of a phosphodiesterase inhibitor, IBMX. This survival activity was partially inhibited by a protein kinase A inhibitor H89 or a neurotrophin receptor tyrosine kinase inhibitor K252a, and was completely inhibited by their combination. These results indicate that the survival activity of CGS21680 on motoneurons is exerted by the mixed effect of the adenylate cyclase-cAMP-PKA pathway and transactivation of Trk neurotrophin receptor. Under conditions in which the maximum survival of motoneurons was supported by sufficient concentrations of brain-derived neurotrophic factor (BDNF), a TrkB ligand, the addition of 100μM AMPA for 3 days led to significant cell death. Treatment with CGS21680 and IBMX protected motoneurons from the toxicity of AMPA, further supporting the presence of a TrkB-independent pathway of CGS21680 activity and suggesting a novel therapeutic approach to motoneuron diseases such as amyotrophic lateral sclerosis.}, }
@article {pmid22680643, year = {2012}, author = {Rao, PS and Sari, Y}, title = {Glutamate transporter 1: target for the treatment of alcohol dependence.}, journal = {Current medicinal chemistry}, volume = {19}, number = {30}, pages = {5148-5156}, pmid = {22680643}, issn = {1875-533X}, support = {R01 AA019458/AA/NIAAA NIH HHS/United States ; R01AA019458/AA/NIAAA NIH HHS/United States ; }, mesh = {Alcohol Drinking ; Alcoholism/drug therapy/*metabolism/physiopathology ; Amino Acid Transport System X-AG/*metabolism ; Animals ; Humans ; Illicit Drugs/pharmacology ; }, abstract = {Emerging evidence indicates that many aspects of alcohol and drug dependence involve changes in glutamate transmission. A number of studies have reported that drugs of abuse, including alcohol and cocaine, alter glutamate transport. Extracellular glutamate is regulated by a number of glutamate transporters in various brain regions. Of these transporters, glutamate transporter (GLT1) is a key player in the removal of most of the extracellular glutamate. Similar to neurodegenerative disease models, in which there is dysfunction of the glutamatergic excitatory system, the role of GLT1 has been tested in drug dependence models that show dysfunction of glutamate transmission. We and others have recently found that ceftriaxone, an FDA-approved drug known to elevate GLT1 expression, attenuates cue-induced cocaine relapse. Moreover, we recently found that alcohol-preferring rats treated with ceftriaxone showed a significant dosedependent reduction in alcohol consumption. We also demonstrated that ceftriaxone-induced upregulation of GLT1 expression was associated with increases in glutamate uptake in Huntington's disease mouse model. Importantly, ceftriaxone is currently in clinical trials for the treatment of amyotrophic lateral sclerosis. This review provides information about the potential therapeutic role of GLT1 for the treatment of alcohol abuse and dependence.}, }
@article {pmid22670883, year = {2012}, author = {Rutkove, SB and Caress, JB and Cartwright, MS and Burns, TM and Warder, J and David, WS and Goyal, N and Maragakis, NJ and Clawson, L and Benatar, M and Usher, S and Sharma, KR and Gautam, S and Narayanaswami, P and Raynor, EM and Watson, ML and Shefner, JM}, title = {Electrical impedance myography as a biomarker to assess ALS progression.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {5}, pages = {439-445}, pmid = {22670883}, issn = {1471-180X}, support = {K24 NS060951/NS/NINDS NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*mortality/*physiopathology ; Clinical Trials as Topic ; Disease Progression ; *Electric Impedance ; Female ; Humans ; Male ; Middle Aged ; Muscle, Skeletal/physiopathology ; Myography/*methods ; Survival Rate ; Time Factors ; Young Adult ; }, abstract = {Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM's potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique's correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials.}, }
@article {pmid22668777, year = {2012}, author = {Wang, L and Pytel, P and Feltri, ML and Wrabetz, L and Roos, RP}, title = {Selective knockdown of mutant SOD1 in Schwann cells ameliorates disease in G85R mutant SOD1 transgenic mice.}, journal = {Neurobiology of disease}, volume = {48}, number = {1}, pages = {52-57}, doi = {10.1016/j.nbd.2012.05.014}, pmid = {22668777}, issn = {1095-953X}, support = {R01 NS055256/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Animals ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Motor Neurons/*metabolism/pathology ; Schwann Cells/*metabolism ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Mutants of superoxide dismutase type 1 (mtSOD1) that have full dismutase activity (e.g., G37R) as well as none (e.g., G85R) cause familial amyotrophic lateral sclerosis (FALS), indicating that mtSOD1-induced FALS results from a toxicity rather than loss in SOD1 enzymatic activity. Still, it has remained unclear whether mtSOD1 dismutase activity can influence disease. A previous study demonstrated that Cre-mediated knockdown of G37R expression in Schwann cells (SCs) of G37R transgenic mice shortened the late phase of disease and survival. These results suggested that the neuroprotective effect of G37R expressed in SCs was greater than its toxicity, presumably because its dismutase activity counteracted reactive oxygen species (ROS). In order to further investigate this, we knocked down G85R in SCs by crossing G85R(flox) mice with myelin-protein-zero (P(0)):Cre mice, which express Cre recombinase in SCs. Knockdown of G85R in SCs of G85R mice delayed disease onset and extended survival indicating that G85R expression in SCs is neurotoxic. These results demonstrate differences in the effect on disease of dismutase active vs. inactive mtSOD1 suggesting that both a loss as well as gain in function of mtSOD1 influence FALS pathogenesis. The results suggest that mtSOD1-induced FALS treatment may have to be adjusted depending on the cell type targeted and particular mtSOD1 involved.}, }
@article {pmid22654722, year = {2011}, author = {Heneka, MT and Reyes-Irisarri, E and Hüll, M and Kummer, MP}, title = {Impact and Therapeutic Potential of PPARs in Alzheimer's Disease.}, journal = {Current neuropharmacology}, volume = {9}, number = {4}, pages = {643-650}, pmid = {22654722}, issn = {1875-6190}, abstract = {Peroxisome proliferator activated receptors (PPARs) are well studied for their role of peripheral metabolism, but they also may be involved in the pathogenesis of various disorders of the central nervous system (CNS) including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's and, Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases, lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the deposition of the β-amyloid peptide in extracellular plaques and ongoing neurodegeneration. Non-steroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARγ. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARγ. Several lines of evidence have supported this hypothesis, using AD related transgenic cellular and animal models. Stimulation of PPARγ by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic and insulin sensitizing effects may account for the observed effects. Several clinical trials already revealed promising results using PPARγ agonists, therefore PPARγ represents an attractive therapeutic target for the treatment of AD.}, }
@article {pmid22645080, year = {2013}, author = {Saifudin, A and Kadota, S and Tezuka, Y}, title = {Protein tyrosine phosphatase 1B inhibitory activity of Indonesian herbal medicines and constituents of Cinnamomum burmannii and Zingiber aromaticum.}, journal = {Journal of natural medicines}, volume = {67}, number = {2}, pages = {264-270}, pmid = {22645080}, issn = {1861-0293}, mesh = {Alstonia/chemistry ; Asteraceae/chemistry ; Cinnamomum/*chemistry ; Curcuma/chemistry ; Cymbopogon/chemistry ; Melaleuca/chemistry ; Molecular Structure ; Plant Extracts/*chemistry/*pharmacology ; Plants, Medicinal/*chemistry ; Protein Tyrosine Phosphatase, Non-Receptor Type 1/*antagonists &amp; inhibitors ; Syzygium/chemistry ; Zingiberaceae/*chemistry ; }, abstract = {We screened water and methanol extracts of 28 Indonesian medicinal plants for their protein tyrosine phosphatase 1B (PTP1B) inhibitory activities. Nine water extracts, i.e., Alstonia scholaris leaf, Blumea balsamifera, Cinnamomum burmannii, Cymbopogon nardus, Melaleuca leucadendra, Phyllanthus niruri, Piper nigrum, Syzygium aromaticum, and Sy. polyanthum, exhibited ≥70 % inhibition at 25 μg/mL, whereas 11 methanol extracts, i.e., Als. scholaris, Andrographis paniculata, B. balsamifera, Ci. burmannii, Curcuma heyneana, Glycyrrhiza glabra, M. leucadendra, Punica granatum, Rheum palmatum, Sy. polyanthum, and Z. aromaticum, exhibited ≥70 % inhibition at 25 μg/mL. Water extracts of B. balsamifera (IC50, 2.26 μg/mL) and M. leucadendra (IC50, 2.05 μg/mL), and methanol extracts of Ci. burmannii (IC50, 2.47 μg/mL), Pu. granatum (IC50, 2.40 μg/mL), and Sy. polyanthum (IC50, 1.03 μg/mL) exhibited strong inhibitory activity, which was comparable with that of the positive control, RK-682 (IC50, 2.05 μg/mL). The PTP1B inhibitory activity of the constituents of Ci. burmannii and Z. aromaticum was then evaluated. 5'-Hydroxy-5-hydroxymethyl-4″,5″-methylenedioxy-1,2,3,4-dibenzo-1,3,5-cycloheptatriene (2; IC50, 29.7 μM) and trans-cinnamaldehyde (5; IC50, 57.6 μM) were the active constituents of Ci. burmannii, while humulatrien-5-ol-8-one (21; IC50, 27.7 μM), kaempferol-3,4'-di-O-methyl ether (32; IC50, 17.5 μM), and (S)-6-gingerol (33; IC50, 28.1 μM) were those of Z. aromaticum. These results suggest that these medicinal plants may contribute to the treatment and/or prevention of type II diabetes and/or obesity through PTP1B inhibition.}, }
@article {pmid22643836, year = {2012}, author = {Sorce, S and Krause, KH and Jaquet, V}, title = {Targeting NOX enzymes in the central nervous system: therapeutic opportunities.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {69}, number = {14}, pages = {2387-2407}, pmid = {22643836}, issn = {1420-9071}, mesh = {Central Nervous System Diseases/enzymology/pathology/*therapy ; Enzyme Inhibitors/therapeutic use ; Humans ; NADPH Oxidases/antagonists &amp; inhibitors/*metabolism ; Protein Isoforms/antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/metabolism ; Small Molecule Libraries/chemical synthesis/chemistry/therapeutic use ; }, abstract = {Among the pathogenic mechanisms underlying central nervous system (CNS) diseases, oxidative stress is almost invariably described. For this reason, numerous attempts have been made to decrease reactive oxygen species (ROS) with the administration of antioxidants as potential therapies for CNS disorders. However, such treatments have always failed in clinical trials. Targeting specific sources of reactive oxygen species in the CNS (e.g. NOX enzymes) represents an alternative promising option. Indeed, NOX enzymes are major generators of ROS, which regulate progression of CNS disorders as diverse as amyotrophic lateral sclerosis, schizophrenia, Alzheimer disease, Parkinson disease, and stroke. On the other hand, in autoimmune demyelinating diseases, ROS generated by NOX enzymes are protective, presumably by dampening the specific immune response. In this review, we discuss the possibility of developing therapeutics targeting NADPH oxidase (NOX) enzymes for the treatment of different CNS pathologies. Specific compounds able to modulate the activation of NOX enzymes, and the consequent production of ROS, could fill the need for disease-modifying drugs for many incurable CNS pathologies.}, }
@article {pmid22627119, year = {2012}, author = {Man, RE and Sasongko, MB and Sanmugasundram, S and Nicolaou, T and Jing, X and Wang, JJ and Wong, TY and Lamoureux, EL}, title = {Longer axial length is protective of diabetic retinopathy and macular edema.}, journal = {Ophthalmology}, volume = {119}, number = {9}, pages = {1754-1759}, doi = {10.1016/j.ophtha.2012.03.021}, pmid = {22627119}, issn = {1549-4713}, mesh = {Aged ; Axial Length, Eye/*pathology ; Biometry ; Blood Glucose/metabolism ; Cross-Sectional Studies ; Diabetes Mellitus, Type 1/complications ; Diabetes Mellitus, Type 2/complications ; Diabetic Retinopathy/diagnosis/epidemiology/*prevention &amp; control ; Female ; Glycated Hemoglobin/metabolism ; Humans ; Lipids/blood ; Macular Edema/diagnosis/epidemiology/*prevention &amp; control ; Male ; Middle Aged ; Odds Ratio ; Refractive Errors/*complications/diagnosis ; Risk Factors ; Tomography, Optical Coherence ; }, abstract = {PURPOSE: To assess the association of ocular biometric parameters and refractive error with diabetic retinopathy (DR) and diabetic macular edema (DME) in persons with diabetes.<br><br>DESIGN: Cross-sectional, clinic-based study.<br><br>PARTICIPANTS: Patients with diabetes aged 18 years or more from the Royal Victorian Eye and Ear Hospital, Victoria, Australia.<br><br>METHODS: Spherical equivalent (SE) refraction was assessed using objective autorefraction. Axial length (AL), corneal curvature (CC), and anterior chamber depth (ACD) were measured using the IOLMaster (Carl Zeiss Meditech AG, Jena, Germany). Diabetic retinopathy was graded from 2-field retinal photographs using the modified Airlie House classification system. Diabetic macular edema was defined as absent or present from fundus photographs and confirmed by optical coherence tomography (Stratus, Carl Zeiss Meditech AG).<br><br>MAIN OUTCOME MEASURES: Severity of DR was grouped as no DR, mild DR (Early Treatment of Diabetic Retinopathy Study [ETDRS] = 20), moderate DR (ETDRS = 31-43), and severe DR (ETDRS >43). Diabetic macular edema severity was classified as mild, moderate, or severe.<br><br>RESULTS: A total of 208 of 630 eyes (33.0%) had DR. In multivariate models, eyes with longer AL were less likely to have mild (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.41-0.83; P = 0.006 per mm increase), moderate (OR, 0.73; 95% CI, 0.60-0.88; P = 0.002), and severe DR (OR, 0.67; 95% CI, 0.53-0.85; P=0.01), and had a lesser risk of mild (OR, 0.70; 95% CI, 0.56-0.86; P < 0.001) and moderate DME (OR, 0.72; 95% CI, 0.56-0.93; P=0.002) but not severe DME. No association was found for SE, ACD, and CC with DR.<br><br>CONCLUSIONS: In persons with diabetes, eyes with longer ALs are less likely to have DR and DME.}, }
@article {pmid22621959, year = {2012}, author = {Steyn, FJ and Ngo, ST and Lee, JD and Leong, JW and Buckley, AJ and Veldhuis, JD and McCombe, PA and Chen, C and Bellingham, MC}, title = {Impairments to the GH-IGF-I axis in hSOD1G93A mice give insight into possible mechanisms of GH dysregulation in patients with amyotrophic lateral sclerosis.}, journal = {Endocrinology}, volume = {153}, number = {8}, pages = {3735-3746}, doi = {10.1210/en.2011-2171}, pmid = {22621959}, issn = {1945-7170}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Blotting, Western ; Fluorescent Antibody Technique ; Growth Hormone/genetics/*metabolism ; Humans ; Insulin-Like Growth Factor I/genetics/*metabolism ; Male ; Mice ; Mice, Transgenic ; Muscle, Skeletal/metabolism ; Real-Time Polymerase Chain Reaction ; Receptor, IGF Type 1/genetics/metabolism ; Receptors, Somatotropin/genetics/metabolism ; Somatomedins/genetics/metabolism ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {GH deficiency has been found in subjects with amyotrophic lateral sclerosis (ALS). Disrupted endocrine function could contribute to the progressive muscle loss and hypermetabolism seen in ALS. It is not possible to study all the elements of the GH-IGF-I axis in ALS patients. Consequently, it remains unclear whether dysfunctional GH secretion contributes to disease pathogenesis and why GH and IGF-I directed treatment strategies are ineffective in human ALS. The hSOD1(G93A) transgenic mouse model is useful for the detailed investigation of the pathogenesis of ALS. We report that symptomatic male hSOD1(G93A) transgenic mice exhibit a deficiency in GH secretion similar to that seen in human ALS. Further characterization of the GH-IGF-I axis in hSOD1(G93A) mice reveals central and peripheral abnormalities that are not found in wild-type age-matched controls. Specifically, we observe aberrant endogenous pulsatile GH secretion, reduced pituitary GH content, and decreased circulating levels of IGF-I, indicating global GH deficiency in hSOD1(G93A) mice. Furthermore, a reduction in the expression of the IGF-I receptor α-subunit in skeletal muscle and lumbar spinal cords of hSOD1(G93A) mice suggests impaired IGF-I signaling within these tissues. This is the first account of disrupted GH secretion in a transgenic mouse model of ALS. These observations are essential for the development of effective GH and IGF-I targeted therapies in ALS.}, }
@article {pmid22606355, year = {2012}, author = {Yoo, YE and Ko, CP}, title = {Dihydrotestosterone ameliorates degeneration in muscle, axons and motoneurons and improves motor function in amyotrophic lateral sclerosis model mice.}, journal = {PloS one}, volume = {7}, number = {5}, pages = {e37258}, pmid = {22606355}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/pathology/physiopathology ; Androgens/metabolism ; Animals ; Axons/drug effects/pathology ; Body Weight/drug effects ; Dihydrotestosterone/*therapeutic use ; Disease Models, Animal ; Gene Expression/drug effects ; Humans ; Insulin-Like Growth Factor I/genetics ; Insulin-Like Growth Factor II/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Motor Neurons/drug effects/pathology/physiology ; Motor Skills/drug effects ; Muscle Proteins/genetics ; Muscle Strength/drug effects ; Muscle, Skeletal/drug effects/innervation/pathology/physiopathology ; Muscular Atrophy/drug therapy/pathology ; Neuromuscular Junction/drug effects/pathology ; Neuroprotective Agents/therapeutic use ; Superoxide Dismutase/genetics ; Tripartite Motif Proteins ; Ubiquitin-Protein Ligases/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by a progressive loss of motoneurons. The clinical symptoms include skeletal muscle weakness and atrophy, which impairs motor performance and eventually leads to respiratory failure. We tested whether dihydrotestosterone (DHT), which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS. A silastic tube containing DHT crystals was implanted subcutaneously in SOD1-G93A mice at early symptomatic age when decreases in body weight and grip-strength were observed as compared to wild-type mice. DHT-treated SOD1-G93A mice demonstrated ameliorated muscle atrophy and increased body weight, which was associated with stronger grip-strength. DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport. DHT treatment attenuated neuromuscular junction denervation, and axonal and motoneuron loss. DHT-treated SOD1-G93A mice demonstrated improvement in motor behavior as assessed by rota-rod and gait analyses, and an increased lifespan. Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients.}, }
@article {pmid22596264, year = {2013}, author = {Cifra, A and Mazzone, GL and Nistri, A}, title = {Riluzole: what it does to spinal and brainstem neurons and how it does it.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {19}, number = {2}, pages = {137-144}, doi = {10.1177/1073858412444932}, pmid = {22596264}, issn = {1089-4098}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Brain Stem/*drug effects/metabolism ; Excitatory Amino Acid Antagonists/*pharmacology/therapeutic use ; Glutamic Acid/metabolism ; Humans ; Motor Neurons/*drug effects/metabolism ; Neuroprotective Agents/*pharmacology/therapeutic use ; Riluzole/*pharmacology/therapeutic use ; Spinal Cord/*drug effects/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (Lou Gehrig's disease) is a devastating neurodegenerative disorder for which the only licensed treatment is riluzole. Although riluzole clinical efficacy is rather limited, its use has important implications for identifying those parameters that might improve its clinical benefits (dose, timing, disease stage) and for its off-label administration in other neurodegenerative diseases, such as spinal cord injury. Studies of riluzole also have an intrinsically heuristic value to unveil mechanisms regulating the excitability of brain and spinal neurons because this drug is a pharmacological tool to probe the function of certain ion channels, or to study neurotransmitter release processes, and intracellular neuroprotective pathways. The present review focuses on how riluzole acts on brain and spinal neurons within motor networks, what mechanisms can be deduced from its effects, and what conditions may favor its use to contrast neurodegeneration or to ameliorate late symptoms like spasticity. Taking as an example the experimental neurodegeneration caused by overactivation of glutamatergic synapses (excitotoxicity), it seems likely that protection of motor networks by riluzole involves selected administration timing and dosing to target processes for releasing glutamate from very active synapses or for dampening repetitive firing by hyperfunctional motor cells.}, }
@article {pmid22593178, year = {2013}, author = {McMahon-Parkes, K}, title = {Rationality, religion and refusal of treatment in an ambulance revisited.}, journal = {Journal of medical ethics}, volume = {39}, number = {9}, pages = {587-590}, doi = {10.1136/medethics-2011-100079}, pmid = {22593178}, issn = {1473-4257}, mesh = {Ambulances ; Decision Making/*ethics ; Ethics, Clinical ; Ethics, Medical ; Humans ; Informed Consent/ethics ; Male ; *Personal Autonomy ; *Religion and Medicine ; Treatment Refusal/*ethics ; }, abstract = {In their recent article, Erbay et al considered whether a seriously injured patient should be able to refuse treatment if the refusal was based on a (mis)interpretation of religious doctrine. They argued that in such a case 'what is important…is whether the teaching or philosophy used as a reference point has been in fact correctly perceived' (p 653). If it has not been, they asserted that this eroded the patient's capacity to make an autonomous decision and that therefore, in such cases, it is the role of the healthcare professional (HCP) to 'assist patients to think more clearly and rationally' (p 653). There are, however, a number of problems with the reasons why Erbay et al suggest we should help patients to rationalise their decisions and how HCPs should go about this. In this article, the author explores some of their main arguments regarding consent and rationality (particularly in relation to religious beliefs), as well as Erbay et al's normative claim that HCPs have an obligation to promote autonomy by helping patients to come to a 'rational' decision. Ultimately, the author agrees that the (temporary) solution to the dilemma presented in this scenario (which was to insert an intravenous cannula into the patient in order to allow an infusion of fluids in the event that he changed his mind) seemed both pragmatic and ethically permissible. However, it is suggested that the arguments which underpin this conclusion in Erbay et al's article are largely unsound.}, }
@article {pmid22591194, year = {2012}, author = {Kalmar, B and Edet-Amana, E and Greensmith, L}, title = {Treatment with a coinducer of the heat shock response delays muscle denervation in the SOD1-G93A mouse model of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {4}, pages = {378-392}, doi = {10.3109/17482968.2012.660953}, pmid = {22591194}, issn = {1471-180X}, support = {//Medical Research Council/United Kingdom ; }, mesh = {Acetylcholinesterase/*drug effects/metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Choline O-Acetyltransferase/*drug effects/metabolism ; Disease Models, Animal ; Disease Progression ; GPI-Linked Proteins/drug effects/metabolism ; HSP70 Heat-Shock Proteins/drug effects/metabolism ; Heat-Shock Response ; Hydroxylamines/*pharmacology ; Longitudinal Studies ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects/metabolism ; Muscle Fibers, Fast-Twitch/drug effects/metabolism ; Muscle Fibers, Slow-Twitch/drug effects/metabolism ; Muscle, Skeletal/drug effects/*innervation/metabolism ; Neuromuscular Junction/*drug effects/metabolism ; Succinate Dehydrogenase/drug effects/metabolism ; Superoxide Dismutase/genetics ; }, abstract = {We undertook a longitudinal study of the histological and biochemical changes at the neuromuscular junction (NMJ) in muscles of SOD1-G93A mice. We also assessed these functions in mice treated with a known heat shock protein inducer, arimoclomol. Tissue samples of treated and untreated mSOD mice were analysed for AChE and ChAT enzyme activities as markers of neuromuscular function. Sections of hindlimb muscles (TA, EDL and soleus) were also stained for succinate dehydrogenase and silver cholinesterase activities as well as for immunohistochemistry. Hsp70 levels were also measured from muscle samples using ELISA. Results showed that denervation and nerve sprouting were present at symptom onset in fast muscles, although slow muscles remained fully innervated. Cholinergic enzyme activities were reduced prior to denervation and declined further with disease progression. Reduction of endplate size, a slow to fast shift in muscle phenotype was also observed. Treatment with arimoclomol delayed the appearance of these changes, increased innervation, cholinergic enzyme activities and endplate size and reversed muscle fibre transformation. These beneficial effects of arimoclomol in muscles were accompanied by an increase in Hsp70 expression. In conclusion, our results indicate that pharmacological targeting of muscles at early stages of disease may be a successful strategy to ameliorate disease progression in ALS.}, }
@article {pmid22565043, year = {2012}, author = {Riley, J and Federici, T and Polak, M and Kelly, C and Glass, J and Raore, B and Taub, J and Kesner, V and Feldman, EL and Boulis, NM}, title = {Intraspinal stem cell transplantation in amyotrophic lateral sclerosis: a phase I safety trial, technical note, and lumbar safety outcomes.}, journal = {Neurosurgery}, volume = {71}, number = {2}, pages = {405-16; discussion 416}, doi = {10.1227/NEU.0b013e31825ca05f}, pmid = {22565043}, issn = {1524-4040}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications/diagnosis/*surgery ; Female ; Humans ; Injections, Spinal/adverse effects ; Lumbar Vertebrae/*surgery ; Male ; Middle Aged ; Nervous System Diseases/*etiology/prevention &amp; control ; Stem Cell Transplantation/*adverse effects/*methods ; Treatment Outcome ; }, abstract = {BACKGROUND: No United States-based clinical trials have attempted delivery of biological therapies directly to the spinal cord for treatment of amyotrophic lateral sclerosis (ALS) because of the lack of a meaningful US Food and Drug Administration-authorized cell candidate and a validated delivery approach.<br><br>OBJECTIVE: To assess safety of delivery of a neural stem cell-based treatment into the upper lumbar segments of the ALS spinal cord in the first US Food and Drug Administration-authorized phase I trial.<br><br>METHODS: Each microinjection series comprised 5 injections (10 &#x3bc;L/injection) separated by 4 mm. Each injection deposited 100,000 neural stem cells derived from a fetal spinal cord. Twelve patients were treated with either unilateral or bilateral injections. Group A, nonambulatory patients, underwent unilateral (n = 3) or bilateral (n = 3) lumbar microinjections. Groups B and C were ambulatory (n = 3 each) and, respectively, received unilateral or bilateral injections. Patients are followed clinically and radiologically to assess potential toxicity of the procedure.<br><br>RESULTS: Twelve patients have received a transplant. There was one instance of transient intraoperative somatosensory-evoked potentials depression. In the immediate postoperative period, there was 1 episode of urinary retention requiring Foley catheter reinsertion. By discharge, none had a documented motor function decrement. Two patients required readmission and reoperation for cerebrospinal fluid leak or suprafascial wound dehiscence (n = 1 each). Two deaths occurred at 8 and 13 months postsurgery; neither was related to the surgical transplant.<br><br>CONCLUSION: Our experience in 12 patients supports the procedural safety of unilateral and bilateral intraspinal lumbar microinjection. Completion of this phase I safety trial is planned by proceeding to cervical and combined cervical + lumbar microinjections in ALS patients.}, }
@article {pmid22558300, year = {2012}, author = {Gerber, YN and Sabourin, JC and Rabano, M and Vivanco, Md and Perrin, FE}, title = {Early functional deficit and microglial disturbances in a mouse model of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {7}, number = {4}, pages = {e36000}, pmid = {22558300}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*physiopathology ; Animals ; Astrocytes/pathology ; Disease Models, Animal ; Flow Cytometry ; Humans ; Mice ; Mice, Transgenic ; Microglia/*pathology ; Motor Activity/physiology ; Mutation/genetics ; Neuromuscular Junction/pathology/physiopathology ; Spinal Cord/pathology/physiopathology ; Superoxide Dismutase/genetics ; Time Factors ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by selective motoneurons degeneration. There is today no clear-cut pathogenesis sequence nor any treatment. However growing evidences are in favor of the involvement, besides neurons, of several partners such as glia and muscles. To better characterize the time course of pathological events in an animal model that recapitulates human ALS symptoms, we investigated functional and cellular characteristics of hSOD1(G93A) mice.<br><br>METHODS AND FINDINGS: We have evaluated locomotor function of hSOD1(G93A) mice through dynamic walking patterns and spontaneous motor activity analysis. We detected early functional deficits that redefine symptoms onset at 60 days of age, i.e. 20 days earlier than previously described. Moreover, sequential combination of these approaches allows monitoring of motor activity up to disease end stage. To tentatively correlate early functional deficit with cellular alterations we have used flow cytometry and immunohistochemistry approaches to characterize neuromuscular junctions, astrocytes and microglia. We show that (1) decrease in neuromuscular junction's number correlates with motor impairment, (2) astrocytes number is not altered at pre- and early-symptomatic ages but intraspinal repartition is modified at symptoms onset, and (3) microglia modifications precede disease onset. At pre-symptomatic age, we show a decrease in microglia number whereas at onset of the disease two distinct microglia sub-populations emerge.<br><br>CONCLUSIONS: In conclusion, precise motor analysis updates the onset of the disease in hSOD1(G93A) mice and allows locomotor monitoring until the end stage of the disease. Early functional deficits coincide with alterations of neuromuscular junctions. Importantly, we identify different sets of changes in microglia before disease onset as well as at early-symptomatic stage. This finding not only brings a new sequence of cellular events in the natural history of the disease, but it may also provide clues in the search for biomarkers of the disease, and potential therapeutic targets.}, }
@article {pmid22555651, year = {2012}, author = {Yunusova, Y and Green, JR and Greenwood, L and Wang, J and Pattee, GL and Zinman, L}, title = {Tongue movements and their acoustic consequences in amyotrophic lateral sclerosis.}, journal = {Folia phoniatrica et logopaedica : official organ of the International Association of Logopedics and Phoniatrics (IALP)}, volume = {64}, number = {2}, pages = {94-102}, pmid = {22555651}, issn = {1421-9972}, support = {R01 DC009890/DC/NIDCD NIH HHS/United States ; R01DC009890/DC/NIDCD NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*physiopathology ; Articulation Disorders/*etiology/physiopathology ; Biomechanical Phenomena ; Female ; Humans ; Male ; Middle Aged ; Movement ; Muscle Weakness/etiology ; Severity of Illness Index ; Speech Acoustics ; Speech Intelligibility ; Tongue/*physiopathology ; }, abstract = {OBJECTIVE: The relations between acoustic measures and their articulatory bases have rarely been tested in dysarthria but are important for diagnostic and treatment purposes. We tested the association between acoustic measures of F2 range and F2 slope with kinematic measures of tongue movement displacement and speed in individuals with amyotrophic lateral sclerosis (ALS) and healthy controls speaking at normal and slow rates. Relations between acoustic and kinematic measures and speech intelligibility were examined.<br><br>RESULTS: As healthy controls reduced their speaking rate, their F2 slopes and movement speeds decreased. In talkers with ALS, acoustic and kinematic variables were associated with changes in speaking rate, characteristic of disease progression. Participants with slow rate had shallower F2 slopes and slower movement speeds than those with normal rate. Relations between F2 range and tongue displacement were weaker. F2 slope, displacement, and duration were correlated with speech intelligibility most consistently.<br><br>CONCLUSION: Findings suggested that F2 slope is a useful marker for tracking disease progression in ALS. F2 slope reflects changes in tongue function with disease progression and is linked to speech intelligibility. Changes in movement speed, however, might be the earliest sign of disease in the tongue.}, }
@article {pmid22542767, year = {2012}, author = {Bahus, MK and Steen, PA and Førde, R}, title = {Law, ethics and clinical judgment in end-of-life decisions--how do Norwegian doctors think?.}, journal = {Resuscitation}, volume = {83}, number = {11}, pages = {1369-1373}, doi = {10.1016/j.resuscitation.2012.04.008}, pmid = {22542767}, issn = {1873-1570}, mesh = {Advance Directives/*ethics/*legislation &amp; jurisprudence ; Amyotrophic Lateral Sclerosis/therapy ; *Attitude of Health Personnel ; Decision Making ; Humans ; Judgment ; Life Support Care/*ethics/*legislation &amp; jurisprudence ; Norway ; *Physicians ; Surveys and Questionnaires ; }, abstract = {AIM: According to Norwegian law, an autonomous patient has the right to refuse life-prolonging treatment. If the patient is not defined as dying, however, health personnel are obliged to instigate life-saving treatment in an emergency situation even against the patient's wishes. The purpose of this study was to investigate how doctors' attitudes and knowledge agree with these legal provisions, and how the statutory provision on emergency situations influences the principle of patient autonomy for severely ill, but not dying, patients.<br><br>METHOD: A strategic sample of 1175 Norwegian doctors who are specialists in internal medicine, paediatrics, surgery, neurology and neurosurgery received a mail questionnaire about decisions on end-of-life care in hypothetical scenarios. The case presented concerns a 45-year-old autonomous patient diagnosed with end-stage ALS who declines ventilatory treatment. Recipients were randomly selected from the membership roster of the Norwegian Medical Association. 640 (54.5%) responded; of these, 406 had experience with end-of-life decisions.<br><br>RESULTS: 56.1% (221/394) stated that ALS patients in such situations can always refuse life-prolonging treatment, and 42.4% (167/394) were of the opinion that the patient can normally refuse life-prolonging treatment. 1.5% (6/394) stated that the patient cannot refuse life-prolonging treatment.<br><br>CONCLUSIONS: The answers indicate that the respondents include patients' refusal in an overall clinical judgement, and interpret patients' right to decline life-saving treatment in different ways. This may reflect the complex legal situation in Norway regarding patient autonomy with respect to the right of severely ill, but not dying, patients' right to decline acute life-saving treatment.}, }
@article {pmid22542526, year = {2012}, author = {Mulligan, VK and Kerman, A and Laister, RC and Sharda, PR and Arslan, PE and Chakrabartty, A}, title = {Early steps in oxidation-induced SOD1 misfolding: implications for non-amyloid protein aggregation in familial ALS.}, journal = {Journal of molecular biology}, volume = {421}, number = {4-5}, pages = {631-652}, doi = {10.1016/j.jmb.2012.04.016}, pmid = {22542526}, issn = {1089-8638}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Hydrogen Peroxide/metabolism ; Models, Chemical ; Models, Molecular ; Oxidation-Reduction ; Protein Denaturation ; *Protein Folding ; Protein Multimerization ; Superoxide Dismutase/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Among the diseases of protein misfolding, amyotrophic lateral sclerosis (ALS) is unusual in that the proteinaceous neuronal inclusions that are the hallmark of the disease have neither the classic fibrillar appearance of amyloid by transmission electron microscopy nor the affinity for the dye Congo red that is a defining feature of amyloid. Mutations in the Cu, Zn superoxide dismutase (SOD1) cause the largest subset of inherited ALS cases. The mechanism by which this highly stable enzyme misfolds to form non-amyloid aggregates is currently poorly understood, as are the stresses that initiate misfolding. The oxidative damage hypothesis proposes that SOD1's normal free radical scavenger role puts it at risk of oxidative damage and that it is this damage that triggers the misfolding primed by mutation. Here, we present evidence that hydrogen peroxide treatment, which generates free radical species at the SOD1 active site, causes oxidative damage to active-site histidine residues, leading to major structural changes and non-amyloid aggregation similar to that seen in ALS. Time-resolved measurements of release of bound metal ligands, exposure of hydrophobic surface area, and alterations in the SOD1 proton NMR spectrum have allowed us to model the early structural changes occurring as SOD1 misfolds, prior to aggregation. ALS-causing SOD1 mutations apparently alter this pathway by increasing exposure of buried epitopes in misfolded species populated at endpoint. We have identified a well-populated early misfolding intermediate that could serve as a target for therapies designed to block downstream misfolding and aggregation events and thereby treat SOD1-associated ALS.}, }
@article {pmid22538313, year = {2012}, author = {Simmons, Z}, title = {What's in the literature?.}, journal = {Journal of clinical neuromuscular disease}, volume = {13}, number = {3}, pages = {162-167}, doi = {10.1097/CND.0b013e31824db0fe}, pmid = {22538313}, issn = {1537-1611}, mesh = {Humans ; *Muscular Diseases ; *Peripheral Nervous System Diseases ; }, abstract = {The neuromuscular literature over the past 3 months has been diverse, including useful information on the epidemiology of several disorders. Our understanding of the genetics of amyotrophic lateral sclerosis continues to grow, and in the process, it makes the distinction between familial and sporadic forms of the disorder increasingly murky. Some interesting articles about peripheral neuropathy provide insight into relationships with diabetes and with Parkinson disease and summarize the state of knowledge of the increasingly complex topic of hereditary neuropathies in children. Epidemiology and electrodiagnosis of lateral femoral cutaneous neuropathy is nicely discussed in 2 articles. Several muscle diseases, including Pompe disease, sporadic inclusion body myositis, and the congenital myopathies, receive attention in articles that provide very useful information for the clinician, and there is a treatment-oriented article on dystrophinopathies, which makes for excellent reading. There are also discussions of several uncommon disorders, including a mitochondrial myopathy, periodic paralysis, and congenital myasthenic syndromes, which are helpful in providing information to clinicians who may see such disorders only infrequently.}, }
@article {pmid22507682, year = {2012}, author = {Chen, L and Chen, D and Xi, H and Wang, Q and Liu, Y and Zhang, F and Wang, H and Ren, Y and Xiao, J and Wang, Y and Huang, H}, title = {Olfactory ensheathing cell neurorestorotherapy for amyotrophic lateral sclerosis patients: benefits from multiple transplantations.}, journal = {Cell transplantation}, volume = {21 Suppl 1}, number = {}, pages = {S65-77}, doi = {10.3727/096368912X633789}, pmid = {22507682}, issn = {1555-3892}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/physiopathology/*surgery ; Cell Transplantation/*methods ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Nerve Regeneration/*physiology ; Olfactory Bulb/*cytology/physiopathology ; Young Adult ; }, abstract = {Our previous series of studies have proven that olfactory ensheathing cell (OEC) transplantation appears to be able to slow the rate of clinical progression after OEC transplantation in the first 4 months and cell intracranial (key points for neural network restoration, KPNNR) and/or intraspinal (impaired segments) implants provide benefit for patients (including both the bulbar onset and limb onset subtypes) with amyotrophic lateral sclerosis (ALS). Here we report the results of cell therapy in patients with ALS on the basis of long-term observation following multiple transplants. From March of 2003 to January of 2010, 507 ALS patients received our cellular treatment. Among them, 42 patients underwent further OEC therapy by the route of KPNNR for two or more times (two times in 35 patients, three times in 5 patients, four times in 1 patient, and five times in 1 patient). The time intervals are 13.1 (6-60) months between the first therapy and the second one, 15.2 (8-24) months between the second therapy and the third one, 16 (6-26) months between the third therapy and the fourth one, and 9 months between the fourth therapy and the fifth time. All of the patients exhibited partial neurological functional recovery after each cell-based administration. Firstly, the scores of the ALS Functional Rating Scale (ALS-FRS) and ALS Norris Scale increased by 2.6 + 2.4 (0-8) and 4.9 + 5.2 (0-20) after the first treatment, 1.1 + 1.3 (0-5) and 2.3 + 2.9 (0-13) after the second treatment, 1.1 + 1.5 (0-4), and 3.4 + 6.9 (0-19) after the third treatment, 0.0 + 0.0 (0-0), and 2.5 + 3.5 (0-5) after the fourth treatment, and 1 point after the fifth cellular therapy, which were evaluated by independent neurologists. Secondly, the majority of patients have achieved improvement in electromyogram (EMG) assessments after the first, second, third, and fourth cell transplantation. After the first treatment, among the 42 patients, 36 (85.7%) patients' EMG test results improved, the remaining 6 (14.3%) patients' EMG results showed no remarkable change. After the second treatment, of the 42 patients, 30 (71.4%) patients' EMG results improved, 11 (26.2%) patients showed no remarkable change, and 1 (2.4%) patient became worse. After the third treatment, out of the 7 patients, 4 (57.1%) patients improved, while the remaining 3 (42.9%) patients showed no change. Thirdly, the patients have partially recovered their breathing ability as demonstrated by pulmonary functional tests. After the first treatment, 20 (47.6%) patients' pulmonary function ameliorated. After the second treatment, 18 (42.9%) patients' pulmonary function improved. After the third treatment, 2 (28.6%) patients recovered some pulmonary function. After the fourth and fifth treatment, patients' pulmonary function did not reveal significant change. The results show that multiple doses of cellular therapy definitely serve as a positive role in the treatment of ALS. This repeated and periodic cell-based therapy is strongly recommended for the patients, for better controlling this progressive deterioration disorder.}, }
@article {pmid22507681, year = {2012}, author = {Moviglia, GA and Moviglia-Brandolino, MT and Varela, GS and Albanese, G and Piccone, S and Echegaray, G and Martinez, G and Blasseti, N and Farias, J and Farina, P and Perusso, A and Gaeta, CA}, title = {Feasibility, safety, and preliminary proof of principles of autologous neural stem cell treatment combined with T-cell vaccination for ALS patients.}, journal = {Cell transplantation}, volume = {21 Suppl 1}, number = {}, pages = {S57-63}, doi = {10.3727/096368912X633770}, pmid = {22507681}, issn = {1555-3892}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/immunology/*surgery/*therapy ; Combined Modality Therapy ; Female ; Humans ; Immunotherapy, Adoptive/*methods ; Male ; Middle Aged ; Neural Stem Cells/*transplantation ; T-Lymphocytes/*immunology ; Transplantation, Autologous ; }, abstract = {Uncontrolled activation of the innate immune system promotes the deterioration of neurons in different neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). T-cell vaccination (TCV) was developed by Irun Cohen and coworkers at the Weizmann Institute of Science (Israel) during the late 1970s and has been demonstrated to be an effective treatment for human autoimmune diseases and a regulator of macrophage activation in animal models. We treated seven ALS patients with this cell therapy and were able to slow or stop disease progression in the affected individuals. The median survival, which is 3.5 years, was extended to 6 years. They were also treated with autologous adult neural stem cells associated with effector T cells. The observed neurologic improvements after treatment lasted for at least 1 year. Clinical recovery in the treated ALS patients was confirmed by an independent, skilled neurologist using the ALS Functional Rating Scale-Revised (ALSFRS-R). TCV in conjunction with an autologous neural stem cell treatment might be a feasible, minimally invasive, safe, and effective approach to obtain enduring therapeutic effects in ALS patients.}, }
@article {pmid22523565, year = {2012}, author = {Audet, JN and Gowing, G and Paradis, R and Soucy, G and Julien, JP}, title = {Ablation of proliferating cells in the CNS exacerbates motor neuron disease caused by mutant superoxide dismutase.}, journal = {PloS one}, volume = {7}, number = {4}, pages = {e34932}, pmid = {22523565}, issn = {1932-6203}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/pathology ; Animals ; Cell Proliferation/drug effects ; Cytarabine/pharmacology ; Disease Models, Animal ; Disease Progression ; Humans ; Insulin-Like Growth Factor I/metabolism ; Interleukin-6/metabolism ; Mice ; Mice, Transgenic ; Microglia/drug effects ; Motor Neuron Disease/*complications ; Superoxide Dismutase/*genetics ; Transforming Growth Factor beta/metabolism ; }, abstract = {Proliferation of glia and immune cells is a common pathological feature of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Here, to investigate the role of proliferating cells in motor neuron disease, SOD1(G93A) transgenic mice were treated intracerebroventicularly (i.c.v.) with the anti-mitotic drug cytosine arabinoside (Ara-C). I.c.v. delivery of Ara-C accelerated disease progression in SOD1(G93A) mouse model of ALS. Ara-C treatment caused substantial decreases in the number of microglia, NG2+ progenitors, Olig2+ cells and CD3+ T cells in the lumbar spinal cord of symptomatic SOD1(G93A) transgenic mice. Exacerbation of disease was also associated with significant alterations in the expression inflammatory molecules IL-1β, IL-6, TGF-β and the growth factor IGF-1.}, }
@article {pmid22513921, year = {2012}, author = {Baldinger, R and Katzberg, HD and Weber, M}, title = {Treatment for cramps in amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD004157}, doi = {10.1002/14651858.CD004157.pub2}, pmid = {22513921}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Muscle Cramp/*drug therapy/etiology ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Cramps are painful, involuntary muscle contractions. They commonly affect people with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) at all stages of the disease. To date, the treatment of muscle cramps in ALS has been largely empirical without any evidence from randomised controlled trials.<br><br>OBJECTIVES: To systematically assess the effect of interventions on muscle cramps as a primary or secondary endpoint or adverse event in people with ALS/MND.<br><br>SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (14 February 2011), the Cochrane Central Register of Controlled Trials (Issue 1, 2011 in The Cochrane Library), MEDLINE (January 1966 to January 2011) and EMBASE (January 1980 to January 2011) and reference lists of articles searched using the terms motor neuron disease, motor neurone disease, motoneuron disease or amyotrophic lateral sclerosis. We contacted authors of trials for further information.<br><br>SELECTION CRITERIA: We included all randomised and quasi-randomised trials of oral medications in people with ALS which assessed cramps as a primary or secondary outcome measure or as an adverse event. We also included trials using subcutaneous or intravenous medications or physical therapy.<br><br>DATA COLLECTION AND ANALYSIS: All authors applied the selection criteria and assessed study quality independently, and all authors performed independent data extraction.<br><br>MAIN RESULTS: Twenty studies including 4789 participants were identified. Only one trial, of tetrahydrocannabinol (THC), assessed cramps as the primary endpoint. Thirteen studies assessed cramps as a secondary endpoint. The medications comprised vitamin E, baclofen, riluzole, L-threonine, xaliproden, indinavir, and memantine. Six studies assessed cramps as an adverse event. The medications comprised creatine, gabapentin, dextromethorphan, quinidine, and lithium. In all 20 studies no favourable effect for the treatment of cramps in ALS/MND could be demonstrated, but many studies were underpowered to draw a definite conclusion. A meta-analysis of two small studies showed a statistically nonsignificant result for the amino acid L-threonine for the treatment of cramps in ALS/MND. No study was identified using physical therapy as a therapeutic intervention for cramps.<br><br>AUTHORS' CONCLUSIONS: There is no evidence to support the use of any intervention for muscle cramps in ALS/MND. More and larger randomised controlled trials evaluating treatments for muscle cramps in ALS/MND are needed.}, }
@article {pmid22493728, year = {2012}, author = {Pokrishevsky, E and Grad, LI and Yousefi, M and Wang, J and Mackenzie, IR and Cashman, NR}, title = {Aberrant localization of FUS and TDP43 is associated with misfolding of SOD1 in amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {7}, number = {4}, pages = {e35050}, pmid = {22493728}, issn = {1932-6203}, support = {74580//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Axons/metabolism/pathology ; Cell Line, Tumor ; Cells, Cultured ; DNA-Binding Proteins/*chemistry/genetics/metabolism ; Female ; Humans ; Immunohistochemistry ; Mice ; Motor Neurons/*metabolism/pathology ; Neuroblastoma ; Protein Conformation ; *Protein Folding ; RNA-Binding Protein FUS/*chemistry/genetics/metabolism ; Spinal Cord/*metabolism/pathology ; Superoxide Dismutase/*chemistry/genetics/metabolism ; Superoxide Dismutase-1 ; Transfection ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is incurable and characterized by progressive paralysis of the muscles of the limbs, speech and swallowing, and respiration due to the progressive degeneration of voluntary motor neurons. Clinically indistinguishable ALS can be caused by genetic mutations of Cu/Zn superoxide dismutase (SOD1), TAR-DNA binding protein 43 (TDP43), or fused in sarcoma/translocated in liposarcoma (FUS/TLS), or can occur in the absence of known mutation as sporadic disease. In this study, we tested the hypothesis that FUS/TLS and TDP43 gain new pathogenic functions upon aberrant accumulation in the cytosol that directly or indirectly include misfolding of SOD1.<br><br>Patient spinal cord necropsy immunohistochemistry with SOD1 misfolding-specific antibodies revealed misfolded SOD1 in perikarya and motor axons of SOD1-familial ALS (SOD1-FALS), and in motor axons of R521C-FUS FALS and sporadic ALS (SALS) with cytoplasmic TDP43 inclusions. SOD1 misfolding and oxidation was also detected using immunocytochemistry and quantitative immunoprecipitation of human neuroblastoma SH-SY5Y cells as well as cultured murine spinal neural cells transgenic for human wtSOD1, which were transiently transfected with human cytosolic mutant FUS or TDP43, or wtTDP43.<br><br>CONCLUSION/SIGNIFICANCE: We conclude that cytosolic mislocalization of FUS or TDP43 in vitro and ALS in vivo may kindle wtSOD1 misfolding in non-SOD1 FALS and SALS. The lack of immunohistochemical compartmental co-localization of misfolded SOD1 with cytosolic TDP43 or FUS suggests an indirect induction of SOD1 misfolding followed by propagation through template directed misfolding beyond its site of inception. The identification of a final common pathway in the molecular pathogenesis of ALS provides a treatment target for this devastating disease.}, }
@article {pmid22484281, year = {2012}, author = {Benga, I and Benga, O}, title = {Implications of water channel proteins in selected neurological disorders: epilepsies, muscular dystrophies, amyotrophic lateral sclerosis, neuromyelitis optica, Parkinson's disease, and spongiform encephalopathies.}, journal = {Molecular aspects of medicine}, volume = {33}, number = {5-6}, pages = {590-604}, doi = {10.1016/j.mam.2012.03.003}, pmid = {22484281}, issn = {1872-9452}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Aquaporins/antagonists &amp; inhibitors/*metabolism ; Autoantibodies/biosynthesis/immunology ; Biomarkers/metabolism ; Cell Membrane/metabolism ; Cell Membrane Permeability ; Epilepsy/*metabolism/pathology ; Humans ; Immunoglobulin G/biosynthesis/immunology ; Muscular Dystrophy, Duchenne/*metabolism/pathology ; Neuromyelitis Optica/*metabolism/pathology ; Parkinson Disease/*metabolism/pathology ; Prion Diseases/*metabolism/pathology ; Water/*metabolism ; Water-Electrolyte Balance/physiology ; }, abstract = {The aim of this article is to describe the roles of water channel proteins (WCPs) in some neurological diseases in which the implications of these proteins became obvious in the decades after the discovery of WCPs of their presence in the CNS. The diseases which were selected for this review include: epilepsies, muscular dystrophies, amyotrophic lateral sclerosis, neuromyelitis optica, Parkinson's disease, and spongiform encephalopathies. The priorities of Benga group from Cluj-Napoca, Romania, are mentioned, such as the idea of a generalized membrane defect affecting water permeability in epilepsy and in Duchenne muscular dystrophy. Some of these neurological disorders discussed in this article appeared to be water channelopathies. A typical example is neuromyelitis optica (NMO), in which the identification of the specific marker autoantibody against aquaporin 4 in the sera of patients was a milestone in the diagnosis. This has aided understanding of the pathogenesis of NMO and led to better control of its treatment. However, further studies are needed to characterize the function and regulation of WCPs in other neurological diseases, in particular to determine if modulation of WCP function may provide a novel approach to therapy in such diseases.}, }
@article {pmid22482614, year = {2012}, author = {Reniers, B and Landry, G and Eichner, R and Hallil, A and Verhaegen, F}, title = {In vivo dosimetry for gynaecological brachytherapy using a novel position sensitive radiation detector: feasibility study.}, journal = {Medical physics}, volume = {39}, number = {4}, pages = {1925-1935}, doi = {10.1118/1.3693049}, pmid = {22482614}, issn = {0094-2405}, mesh = {Brachytherapy/*instrumentation ; Equipment Design ; Equipment Failure Analysis ; Feasibility Studies ; Female ; Genital Neoplasms, Female/*radiotherapy ; Humans ; Radiometry/*instrumentation ; Radiotherapy Dosage ; Reproducibility of Results ; Sensitivity and Specificity ; }, abstract = {PURPOSE: In gynecological radiotherapy with high dose rate (HDR)(192)Ir brachytherapy, the treatment complexity has increased due to improved optimization techniques and dose constraints. As a consequence, it has become more important to verify the dose delivery to the target and also to the organs at risk (e.g., the bladder). In vivo dosimetry, where dosimeters are placed in or on the patient, is one way of verifying the dose but until recently this was hampered by motion of the radiation detectors with respect to the source. The authors present a novel dosimetry method using a position sensitive radiation detector.<br><br>METHODS: The prototype RADPOS system (Best Medical Canada) consists of a metal oxide field effect transistor (MOSFET) dosimeter coupled to a position-sensor, which deduces its 3D position in a magnetic field. To assess the feasibility of in vivo dosimetry based on the RADPOS system, different characteristics of the detector need to be investigated. Using a PMMA phantom, the positioning accuracy of the RADPOS system was quantified by comparing position readouts with the known position of the detector along the x and y-axes. RADPOS dose measurements were performed at various distances from a Nucletron(192)Ir source in a PMMA phantom to evaluate the energy dependence of the MOSFET. A sensitivity analysis was performed by calculating the dose after varying (1) the position of the RADPOS detector to simulate organ motion and (2) the position of the first dwell position to simulate errors in delivery. The authors also performed an uncertainty analysis to determine the action level (AL) that should be used during in vivo dosimetry.<br><br>RESULTS: Positioning accuracy is found to be within 1 mm in the 1-10 cm range from the origin along the x-axis (away from the transmitter), meeting the requirements for in vivo dosimetry. Similar results are obtained for the other axes. The ALs are chosen to take into account the total uncertainty on the measurements. As a consequence for in vivo dosimetry, it is determined that the RADPOS sensor, if placed, for example, in the bladder Foley balloon, would detect a 2 mm motion of the bladder, at a 5% chance of a false positive, with an AL limit of 9% of the dose delivered. The authors found that source position errors, caused by, e.g., a wrong first dwell position, are more difficult to detect; indeed, with our single RADPOS detector, positioned in the bladder, dwell position errors below 5 mm and resulting in a dose error within 10%, could be detected in the tandem but not in the colpostats. A possible solution to improve error detection is to use multiple MOSFETs to obtain multiple dose values.<br><br>CONCLUSIONS: In this study, the authors proposed a dosimetry procedure, based on the novel RADPOS system, to accurately determine the position of the radiation dosimeter with respect to the applicator. The authors found that it is possible to monitor the delivered dose in a point and compare it to the predetermined dose. This allows in principle the detection of problems such as bladder motion/filling or source mispositioning. Further clinical investigation is warranted.}, }
@article {pmid22482522, year = {2012}, author = {Nevens, F and Laleman, W}, title = {Artificial liver support devices as treatment option for liver failure.}, journal = {Best practice &amp; research. Clinical gastroenterology}, volume = {26}, number = {1}, pages = {17-26}, doi = {10.1016/j.bpg.2012.01.002}, pmid = {22482522}, issn = {1532-1916}, mesh = {Equipment Design ; Hepatic Encephalopathy/therapy ; Humans ; Liver Failure/*therapy ; Liver Failure, Acute/therapy ; Liver Transplantation ; *Liver, Artificial ; Sorption Detoxification/instrumentation ; }, abstract = {Non-biological artificial liver support (ALS) devices aim to remove albumin-bound and water-soluble toxins arising as a result of liver failure. They do not directly improve the liver synthetic capacity. The currently most used devices combine haemodialysis with albumin dialysis (MARS) or plasma separation and filtration (Prometheus). These devices have been used as a treatment for different types of liver failure: acute liver failure, acute-on-chronic liver failure and primary non- or poor-function after liver transplantation. Overall these devices are found to be safe. The following beneficial effects have been documented: improvement of jaundice, amelioration of haemodynamic instability, reduction of portal hypertension, lowering of intracranial pressure and improvement of hepatic encephalopathy. However, recently multicentre controlled trials failed to show a beneficial effect on transplant-free survival. Therefore the use of these devices at present seems only justified as a bridge to liver transplantation.}, }
@article {pmid22481270, year = {2012}, author = {Uccelli, A and Milanese, M and Principato, MC and Morando, S and Bonifacino, T and Vergani, L and Giunti, D and Voci, A and Carminati, E and Giribaldi, F and Caponnetto, C and Bonanno, G}, title = {Intravenous mesenchymal stem cells improve survival and motor function in experimental amyotrophic lateral sclerosis.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {18}, number = {1}, pages = {794-804}, pmid = {22481270}, issn = {1528-3658}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/mortality/*therapy ; Animals ; Aspartic Acid/metabolism ; Cell Movement ; Central Nervous System/metabolism/physiopathology ; Disease Progression ; Female ; Humans ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/metabolism ; Mice ; Mice, Transgenic ; *Motor Activity ; Oxidative Stress ; Spinal Cord/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Despite some advances in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis, significant achievements in treating this disease are still lacking. Mesenchymal stromal (stem) cells (MSCs) have been shown to be effective in several models of neurological disease. To determine the effects of the intravenous injection of MSCs in an ALS mouse model during the symptomatic stage of disease, MSCs (1 × 10[6]) were intravenously injected in mice expressing human superoxide dismutase 1 (SOD1) carrying the G93A mutation (SOD1/G93A) presenting with experimental ALS. Survival, motor abilities, histology, oxidative stress markers and [[3]H]D-aspartate release in the spinal cord were investigated. MSC injection in SOD1/G93A mice improved survival and motor functions compared with saline-injected controls. Injected MSCs scantly home to the central nervous system and poorly engraft. We observed a reduced accumulation of ubiquitin agglomerates and of activated astrocytes and microglia in the spinal cord of MSC-treated SOD1/G93A mice, with no changes in the number of choline acetyltransferase- and glutamate transporter type 1-positive cells. MSC administration turned around the upregulation of metallothionein mRNA expression and of the activity of the antioxidant enzyme glutathione S-transferase, both associated with disease progression. Last, we observed that MSCs reverted both spontaneous and stimulus-evoked neuronal release of [[3]H]D-aspartate, a marker of endogenous glutamate, which is upregulated in SOD1/G93A mice. These findings suggest that intravenous administration of MSCs significantly improves the clinical outcome and pathological scores of mutant SOD1/G93A mice, thus providing the rationale for their exploitation for the treatment of ALS.}, }
@article {pmid22480308, year = {2012}, author = {Carbone, M and Duty, S and Rattray, M}, title = {Riluzole neuroprotection in a Parkinson's disease model involves suppression of reactive astrocytosis but not GLT-1 regulation.}, journal = {BMC neuroscience}, volume = {13}, number = {}, pages = {38}, pmid = {22480308}, issn = {1471-2202}, mesh = {Animals ; Astrocytes/drug effects/metabolism/pathology ; Corpus Striatum/drug effects/metabolism/pathology ; Disease Models, Animal ; Dopaminergic Neurons/*drug effects/metabolism/pathology ; Excitatory Amino Acid Transporter 2/*metabolism ; Gliosis/*drug therapy/metabolism/pathology ; Male ; Nerve Degeneration/*drug therapy/metabolism/pathology ; Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/*pharmacology/therapeutic use ; Oxidopamine ; Parkinson Disease, Secondary/chemically induced/*drug therapy/metabolism/pathology ; Rats ; Rats, Sprague-Dawley ; Riluzole/*pharmacology/therapeutic use ; Substantia Nigra/drug effects/metabolism/pathology ; Tyrosine 3-Monooxygenase/metabolism ; }, abstract = {BACKGROUND: Riluzole is a neuroprotective drug used in the treatment of motor neurone disease. Recent evidence suggests that riluzole can up-regulate the expression and activity of the astrocyte glutamate transporter, GLT-1. Given that regulation of glutamate transport is predicted to be neuroprotective in Parkinson's disease, we tested the effect of riluzole in parkinsonian rats which had received a unilateral 6-hydroxydopamine injection into the median forebrain bundle.<br><br>RESULTS: Rats were treated with intraperitoneal riluzole (4 mg/kg or 8 mg/kg), 1 hour before the lesion then once daily for seven days. Riluzole produced a modest but significant attenuation of dopamine neurone degeneration, assessed by suppression of amphetamine-induced rotations, preservation of tyrosine hydroxylase positive neuronal cell bodies in the substantia nigra pars compacta and attenuation of striatal tyrosine hydroxylase protein loss. Seven days after 6-hydroxydopamine lesion, reactive astrocytosis was observed in the striatum, as determined by increases in expression of glial fibrillary acidic protein, however the glutamate transporter, GLT-1, which is also expressed in astrocytes was not regulated by the lesion.<br><br>CONCLUSIONS: The results confirm that riluzole is a neuroprotective agent in a rodent model of parkinson's disease. Riluzole administration did not regulate GLT-1 levels but significantly reduced GFAP levels, in the lesioned striatum. Riluzole suppression of reactive astrocytosis is an intriguing finding which might contribute to the neuroprotective effects of this drug.}, }
@article {pmid22472631, year = {2013}, author = {Chan-Il, C and Young-Don, L and Heejaung, K and Kim, SH and Suh-Kim, H and Kim, SS}, title = {Neural induction with neurogenin 1 enhances the therapeutic potential of mesenchymal stem cells in an amyotrophic lateral sclerosis mouse model.}, journal = {Cell transplantation}, volume = {22}, number = {5}, pages = {855-870}, doi = {10.3727/096368912X637019}, pmid = {22472631}, issn = {1555-3892}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics/*metabolism ; Bone Marrow Cells/cytology ; Chemokine CCL2/genetics/metabolism ; Disease Models, Animal ; Disease Progression ; Humans ; Male ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*cytology/metabolism ; Mice ; Mice, Transgenic ; Motor Neurons/*metabolism ; Nerve Tissue Proteins/genetics/*metabolism ; Receptors, CCR2/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Transplantation, Heterologous ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by progressive dysfunction and degeneration of motor neurons in the central nervous system (CNS). In the absence of effective drug treatments for ALS, stem cell treatment has emerged as a candidate therapy for this disease. To date, however, there is no consensus protocol that stipulates stem cell types, transplantation timing, or frequency. Using an ALS mouse model carrying a high copy number of a mutant human superoxide dismutase-1 (SOD1)(G93A) transgene, we investigated the effect of neural induction on the innate therapeutic potential of mesenchymal stem cells (MSCs) in relation to preclinical transplantation parameters. In our study, the expression of monocyte chemoattractant protein-1 (MCP-1) was elevated in the ALS mouse spinal cord. Neural induction of MSCs with neurogenin 1 (Ngn1) upregulated the expression level of the MCP-1 receptor, CCR2, and enhanced the migration activity toward MCP-1 in vitro. Ngn1-expressing MSCs (MSCs-Ngn1) showed a corresponding increase in tropism to the CNS after systemic transplantation in ALS mice. Notably, MSCs-Ngn1 delayed disease onset if transplanted during preonset ages,whereas unprocessed MSCs failed to do so. If transplanted near the onset ages, a single treatment with MSCs-Ngn1 was sufficient to enhance motor functions during the symptomatic period (15–17 weeks), whereas unprocessed MSCs required repeated transplantation to achieve similar levels of motor function improvement. Our data indicate that systemically transplanted MSCs-Ngn1 can migrate to the CNS and exert beneficial effects on host neural cells for an extended period of time through paracrine functions, suggesting a potential benefit of neural induction of transplanted MSCs in long-term treatment of ALS.}, }
@article {pmid22464590, year = {2012}, author = {Budych, K and Helms, TM and Schultz, C}, title = {How do patients with rare diseases experience the medical encounter? Exploring role behavior and its impact on patient-physician interaction.}, journal = {Health policy (Amsterdam, Netherlands)}, volume = {105}, number = {2-3}, pages = {154-164}, doi = {10.1016/j.healthpol.2012.02.018}, pmid = {22464590}, issn = {1872-6054}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Child, Preschool ; Epidermolysis Bullosa/diagnosis/psychology/therapy ; Female ; Health Policy ; Hepatolenticular Degeneration/diagnosis/psychology/therapy ; Humans ; Infant ; Interviews as Topic ; Iron Metabolism Disorders ; Male ; Middle Aged ; Muscular Dystrophy, Duchenne/diagnosis/psychology/therapy ; Neuroaxonal Dystrophies/diagnosis/psychology/therapy ; Physician's Role/psychology ; *Physician-Patient Relations ; Rare Diseases/diagnosis/*psychology/therapy ; Role ; Young Adult ; }, abstract = {OBJECTIVES: Empirical research shows that patients with severe illnesses prefer the physician to dominate decision processes and provide the information needed. However, in rare diseases, due to the low prevalence and the lack of expertise, the patient is forced to become knowledgeable about his own disease state. Objectives of this study were to describe the experiences of patient-physician interaction in rare diseases, to develop an empirically derived typology of interaction patterns and to explore the antecedents of these interaction patterns, with a special focus on role behavior. Building on these results, implications for health care policy are made.<br><br>METHODS: We designed an exploratory study as a series of semi-standardized interviews with patients suffering from rare diseases. We extracted the following six rare diseases: amyotrophic lateral sclerosis, Duchenne muscular dystrophy, epidermolysis bullosa, Marfan syndrome, neurodegeneration with brain iron accumulation and Wilson's disease. A total of 107 interviews were recorded, transcribed and analyzed thematically in accordance with the grounded theory tradition.<br><br>RESULTS: As suggested, insufficient expertise of the healthcare providers proved to be a major problem in the highly specialized treatment process of rare diseases. Here, the patient often becomes an expert in his disease. Therefore, we identified the patient-directed interaction as a widely experienced communication pattern among patients with rare diseases. Our study also showed that role discrepancies have a major impact on communication processes in this context.<br><br>CONCLUSIONS: People with rare diseases often face challenges, due to the low prevalence and the resulting lack of knowledge of their healthcare providers. Communication processes in this context are mainly affected by the role behavior of both the patient and provider. The present study showed the relevance of the provider's ability to acknowledge the active role of the patient as an informed, involved and interactive partner in the treatment process. However, allowing the patient to control therapy may require a change of mind-set with some long-standing traditional roles in healthcare.}, }
@article {pmid22457769, year = {2012}, author = {Boccitto, M and Lamitina, T and Kalb, RG}, title = {Daf-2 signaling modifies mutant SOD1 toxicity in C. elegans.}, journal = {PloS one}, volume = {7}, number = {3}, pages = {e33494}, pmid = {22457769}, issn = {1932-6203}, support = {R21 NS060754/NS/NINDS NIH HHS/United States ; R01NS052325/NS/NINDS NIH HHS/United States ; R01 NS052325/NS/NINDS NIH HHS/United States ; R21NS060754/NS/NINDS NIH HHS/United States ; R01 AA017580/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Caenorhabditis elegans/enzymology/*metabolism/physiology ; Caenorhabditis elegans Proteins/*metabolism ; Locomotion ; RNA Interference ; Receptor, Insulin/*metabolism ; *Signal Transduction ; Solubility ; Superoxide Dismutase/genetics/*metabolism/toxicity ; Superoxide Dismutase-1 ; }, abstract = {The DAF-2 Insulin/IGF-1 signaling (IIS) pathway is a strong modifier of Caenorhabditis elegans longevity and healthspan. As aging is the greatest risk factor for developing neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS), we were interested in determining if DAF-2 signaling modifies disease pathology in mutant superoxide dismutase 1 (SOD1) expressing C. elegans. Worms with pan-neuronal G85R SOD1 expression demonstrate significantly impaired locomotion as compared to WT SOD1 expressing controls and they develop insoluble SOD1 aggregates. Reductions in DAF-2 signaling, either through a hypomorphic allele or neuronally targeted RNAi, decreases the abundance of aggregated SOD1 and results in improved locomotion in a DAF-16 dependant manner. These results suggest that manipulation of the DAF-2 Insulin/IGF-1 signaling pathway may have therapeutic potential for the treatment of ALS.}, }
@article {pmid22453893, year = {2012}, author = {Günther, R and Suhr, M and Koch, JC and Bähr, M and Lingor, P and Tönges, L}, title = {Clinical testing and spinal cord removal in a mouse model for amyotrophic lateral sclerosis (ALS).}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {61}, pages = {}, pmid = {22453893}, issn = {1940-087X}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology/physiopathology ; Animals ; *Disease Models, Animal ; Mice ; Spinal Cord/metabolism/*pathology/physiopathology/*surgery ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in progressive degeneration of motoneurons. Peak of onset is around 60 years for the sporadic disease and around 50 years for the familial disease. Due to its progressive course, 50% of the patients die within 30 months of symptom onset. In order to evaluate novel treatment options for this disease, genetic mouse models of ALS have been generated based on human familial mutations in the SOD gene, such as the SOD1 (G93A) mutation. Most important aspects that have to be evaluated in the model are overall survival, clinical course and motor function. Here, we demonstrate the clinical evaluation, show the conduction of two behavioural motor tests and provide quantitative scoring systems for all parameters. Because an in depth analysis of the ALS mouse model usually requires an immunohistochemical examination of the spinal cord, we demonstrate its preparation in detail applying the dorsal laminectomy method. Exemplary histological findings are demonstrated. The comprehensive application of the depicted examination methods in studies on the mouse model of ALS will enable the researcher to reliably test future therapeutic options which can provide a basis for later human clinical trials.}, }
@article {pmid22446540, year = {2011}, author = {Kisby, G and Palmer, V and Lasarev, M and Fry, R and Iordanov, M and Magun, E and Samson, L and Spencer, P}, title = {Does the cycad genotoxin MAM implicated in Guam ALS-PDC induce disease-relevant changes in mouse brain that includes olfaction?.}, journal = {Communicative &amp; integrative biology}, volume = {4}, number = {6}, pages = {731-734}, pmid = {22446540}, issn = {1942-0889}, support = {R01 GM089859/GM/NIGMS NIH HHS/United States ; U19 ES011384/ES/NIEHS NIH HHS/United States ; }, abstract = {Western Pacific amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC), a prototypical neurodegenerative disease (tauopathy) affecting distinct genetic groups with common exposure to neurotoxic chemicals in cycad seed, has many features of Parkinson's and Alzheimer's diseases (AD), including early olfactory dysfunction. Guam ALS-PDC incidence correlates with cycad flour content of cycasin and its aglycone methylazoxymethanol (MAM), which produces persistent DNA damage (O(6)-methylguanine) in the brains of mice lacking O(6)-methylguanine methyltransferase (Mgmt(-/-)). We described in Mgmt(-/-)mice up to 7 days post-MAM treatment that brain DNA damage was linked to brain gene expression changes found in human neurological disease, cancer, and skin and hair development. This addendum reports 6 months post-MAM treatment- related brain transcriptional changes as well as elevated mitogen activated protein kinases and increased caspase-3 activity, both of which are involved in tau aggregation and neurofibrillary tangle formation typical of ALS-PDC and AD, plus transcriptional changes in olfactory receptors. Does cycasin act as a "slow (geno)toxin" in ALS-PDC?}, }
@article {pmid22431338, year = {2012}, author = {Deflorio, C and Palma, E and Conti, L and Roseti, C and Manteca, A and Giacomelli, E and Catalano, M and Limatola, C and Inghilleri, M and Grassi, F}, title = {Riluzole blocks human muscle acetylcholine receptors.}, journal = {The Journal of physiology}, volume = {590}, number = {10}, pages = {2519-2528}, pmid = {22431338}, issn = {1469-7793}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Cholinergic Antagonists/*pharmacology ; Female ; HEK293 Cells ; Humans ; Male ; Middle Aged ; Muscle, Skeletal/*drug effects/physiology ; Neuroprotective Agents/*pharmacology ; Oocytes/drug effects/physiology ; Receptors, Cholinergic/*physiology ; Riluzole/*pharmacology ; Satellite Cells, Skeletal Muscle/physiology ; Xenopus laevis ; }, abstract = {Riluzole, the only drug available against amyotrophic lateral sclerosis (ALS), has recently been shown to block muscle ACh receptors (AChRs), raising concerns about possible negative side-effects on neuromuscular transmission in treated patients. In this work we studied riluzole's impact on the function of muscle AChRs in vitro and on neuromuscular transmission in ALS patients, using electrophysiological techniques. Human recombinant AChRs composed of α(1)β(1)δ subunits plus the γ or ε subunit (γ- or ε-AChR) were expressed in HEK cells or Xenopus oocytes. In both preparations, riluzole at 0.5 μm, a clinically relevant concentration, reversibly reduced the amplitude and accelerated the decay of ACh-evoked current if applied before coapplication with ACh. The action on γ-AChRs was more potent and faster than on ε-AChRs. In HEK outside-out patches, riluzole-induced block of macroscopic ACh-evoked current gradually developed during the initial milliseconds of ACh presence. Single channel recordings in HEK cells and in human myotubes from ALS patients showed that riluzole prolongs channel closed time, but has no effect on channel conductance and open duration. Finally, compound muscle action potentials (CMAPs) evoked by nerve stimulation in ALS patients remained unaltered after a 1 week suspension of riluzole treatment. These data indicate that riluzole, while apparently safe with regard to synaptic transmission, may affect the function of AChRs expressed in denervated muscle fibres of ALS patients, with biological consequences that remain to be investigated.}, }
@article {pmid22424481, year = {2012}, author = {Hu, Y and Zhao, Y and Zhao, X and Kumar, JL}, title = {High rate nitrogen removal in an alum sludge-based intermittent aeration constructed wetland.}, journal = {Environmental science &amp; technology}, volume = {46}, number = {8}, pages = {4583-4590}, doi = {10.1021/es204105h}, pmid = {22424481}, issn = {1520-5851}, mesh = {Alum Compounds ; Animal Husbandry ; Denitrification ; Industrial Waste ; Nitrification ; Nitrites ; Nitrogen/*isolation &amp; purification/metabolism ; Poaceae/metabolism ; Waste Disposal, Fluid/instrumentation/*methods ; Water Pollutants, Chemical/*isolation &amp; purification/metabolism ; Water Purification ; Wetlands ; }, abstract = {A new development on treatment wetland technology for the purpose of achieving high rate nitrogen removal from high strength wastewater has been made in this study. The laboratory scale alum sludge-based intermittent aeration constructed wetland (AlS-IACW) was integrated with predenitrification, intermittent aeration, and step-feeding strategies. Results obtained from 280 days of operation have demonstrated extraordinary nitrogen removal performance with mean total nitrogen (TN) removal efficiency of 90% under high N loading rate (NLR) of 46.7 g N m(-2) d(-1). This performance was a substantial improvement compared to the reported TN removal performance in literature. Most significantly, partial nitrification and simultaneous nitrification denitrification (SND) via nitrite was found to be the main nitrogen conversion pathways in the AlS-IACW system under high dissolved oxygen concentrations (3-6 mg L(-1)) without specific control. SND under high dissolved oxygen (DO) brings high nitrogen conversion rates. Partial nitrification and SND via nitrite can significantly reduce the demand for organic carbon compared with full nitrification and denitrification via nitrate (up to 40%). Overall, these mechanisms allow the system to maintaining efficient and high rate TN removal even under carbon limiting conditions.}, }
@article {pmid22424123, year = {2012}, author = {Ignjatović, A and Stević, Z and Lavrnić, D and Nikolić-Kokić, A and Blagojević, D and Spasić, M and Spasojević, I}, title = {Inappropriately chelated iron in the cerebrospinal fluid of amyotrophic lateral sclerosis patients.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {4}, pages = {357-362}, doi = {10.3109/17482968.2012.665929}, pmid = {22424123}, issn = {1471-180X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/*metabolism ; Case-Control Studies ; Cerebrospinal Fluid/metabolism ; Electron Spin Resonance Spectroscopy ; Female ; Humans ; Hydroxyl Radical/cerebrospinal fluid/*metabolism ; Iron/cerebrospinal fluid/*metabolism ; *Ligands ; Male ; Middle Aged ; Oxidation-Reduction ; *Oxidative Stress ; }, abstract = {ALS is characterized by oxidative damage in the brain and cerebrospinal fluid, which is exerted by pro-oxidative activity of iron. Such activity of iron can be drastically increased in the presence of inappropriate iron ligands that catalyze redox cycling of iron, thereby promoting hydroxyl radical generation. The aim of our study was to determine the relative level of inappropriate iron ligands in the cerebrospinal fluid of ALS patients. To determine the levels of inappropriate iron ligands and redox activity of iron in cerebrospinal fluid (10 samples from ALS patients and 10 controls), we applied electron paramagnetic resonance spectroscopy. We have shown that cerebrospinal fluid of ALS patients comprises two-fold increased level of inappropriate iron ligands, proportionally increasing iron redox activity and hydroxyl radical production compared to controls. In conclusion, our results strongly support the pro-oxidative/detrimental role of inappropriately chelated iron in ALS pathophysiology. The identification of biomolecules that form such iron complexes and their therapeutic targeting may represent the future of ALS treatment.}, }
@article {pmid22419278, year = {2012}, author = {Miller, RG and Mitchell, JD and Moore, DH}, title = {Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).}, journal = {The Cochrane database of systematic reviews}, volume = {2012}, number = {3}, pages = {CD001447}, pmid = {22419278}, issn = {1469-493X}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Excitatory Amino Acid Antagonists/adverse effects/*therapeutic use ; Humans ; Life Expectancy ; Neuroprotective Agents/adverse effects/*therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole/adverse effects/*therapeutic use ; Tracheostomy ; }, abstract = {BACKGROUND: Riluzole is approved for the treatment of amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy.<br><br>OBJECTIVES: To examine the efficacy of riluzole in prolonging survival and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival, and to assess the effect of riluzole upon functional health.<br><br>SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (20 April 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2), MEDLINE (1966 to April 2011), EMBASE (1980 to May 2011) and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field.<br><br>SELECTION CRITERIA: Types of studies: randomized controlled trials<br><br>TYPES OF PARTICIPANTS: adults with a diagnosis of amyotrophic lateral sclerosis Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality with riluzole 50 mg, 100 mg and 200 mg; neurologic function, muscle strength and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: One author performed data extraction and two other authors checked them. One author checked the data and entered them into the computer. The other authors verified the data entry. We obtained missing data from the trial authors whenever possible.<br><br>MAIN RESULTS: The four trials examining tracheostomy-free survival included a total of 974 riluzole-treated patients and 503 placebo-treated patients. No new randomized controlled trials were found when we updated the searches for this update in 2011. The methodological quality was acceptable and three trials were easily comparable, although one trial (169 participants) included older patients in more advanced stages of amyotrophic lateral sclerosis and one (195 participants) had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (hazard ratio (HR) 0.80, 95% confidence internal (CI) 0.64 to 0.99, P= 0.042) and there was no evidence of heterogeneity (P = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P < 0.0001) and the overall treatment effect was reduced but still significant (HR 0.84, 95% CI 0.698 to 0.997, P= 0.046). This represented a 9% gain in the probability of surviving one year (49% in the placebo and 58% in the riluzole group), and increased median survival from 11.8 to 14.8 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A three-fold increase in serum alanine transferase was more frequent in riluzole-treated patients than controls (mean difference 2.62, 95% CI 1.59 to 4.31).<br><br>AUTHORS' CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.}, }
@article {pmid22416219, year = {2012}, author = {Lee, S and Kim, Y and Li, E and Park, S}, title = {Ghrelin protects spinal cord motoneurons against chronic glutamate excitotoxicity by inhibiting microglial activation.}, journal = {The Korean journal of physiology &amp; pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology}, volume = {16}, number = {1}, pages = {43-48}, pmid = {22416219}, issn = {2093-3827}, abstract = {Glutamate excitotoxicity is emerging as a contributor to degeneration of spinal cord motoneurons in amyotrophic lateral sclerosis (ALS). Recently, we have reported that ghrelin protects motoneurons against chronic glutamate excitotoxicity through the activation of extracellular signal-regulated kinase 1/2 and phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3β pathways. Previous studies suggest that activated microglia actively participate in the pathogenesis of ALS motoneuron degeneration. However, it is still unknown whether ghrelin exerts its protective effect on motoneurons via inhibition of microglial activation. In this study, we investigate organotypic spinal cord cultures (OSCCs) exposed to threohydroxyaspartate (THA), as a model of excitotoxic motoneuron degeneration, to determine if ghrelin prevents microglial activation. Exposure of OSCCs to THA for 3 weeks produced typical motoneuron death, and treatment of ghrelin significantly attenuated THA-induced motoneuron loss, as previously reported. Ghrelin prevented THA-induced microglial activation in the spinal cord and the expression of pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1β. Our data indicate that ghrelin may act as a survival factor for motoneurons by functioning as a microglia-deactivating factor and suggest that ghrelin may have therapeutic potential for the treatment of ALS and other neurodegenerative disorders where inflammatory responses play a critical role.}, }
@article {pmid22415942, year = {2012}, author = {Glass, JD and Boulis, NM and Johe, K and Rutkove, SB and Federici, T and Polak, M and Kelly, C and Feldman, EL}, title = {Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients.}, journal = {Stem cells (Dayton, Ohio)}, volume = {30}, number = {6}, pages = {1144-1151}, doi = {10.1002/stem.1079}, pmid = {22415942}, issn = {1549-4918}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*surgery ; Disease Progression ; Humans ; Injections, Spinal ; Lumbosacral Region/surgery ; Male ; Middle Aged ; Neural Stem Cells/*transplantation ; Spinal Cord/pathology/surgery ; Stem Cell Transplantation/*methods ; Treatment Outcome ; }, abstract = {Advances in stem cell biology have generated intense interest in the prospect of transplanting stem cells into the nervous system for the treatment of neurodegenerative diseases. Here, we report the results of an ongoing phase I trial of intraspinal injections of fetal-derived neural stems cells in patients with amyotrophic lateral sclerosis (ALS). This is a first-in-human clinical trial with the goal of assessing the safety and tolerability of the surgical procedure, the introduction of stem cells into the spinal cord, and the use of immunosuppressant drugs in this patient population. Twelve patients received either five unilateral or five bilateral (10 total) injections into the lumbar spinal cord at a dose of 100,000 cells per injection. All patients tolerated the treatment without any long-term complications related to either the surgical procedure or the implantation of stem cells. Clinical assessments ranging from 6 to 18 months after transplantation demonstrated no evidence of acceleration of disease progression due to the intervention. One patient has shown improvement in his clinical status, although these data must be interpreted with caution since this trial was neither designed nor powered to measure treatment efficacy. These results allow us to report success in achieving the phase I goal of demonstrating safety of this therapeutic approach. Based on these positive results, we can now advance this trial by testing intraspinal injections into the cervical spinal cord, with the goal of protecting motor neuron pools affecting respiratory function, which may prolong life for patients with ALS.}, }
@article {pmid22413952, year = {2012}, author = {Cozzolino, M and Pesaresi, MG and Gerbino, V and Grosskreutz, J and Carrì, MT}, title = {Amyotrophic lateral sclerosis: new insights into underlying molecular mechanisms and opportunities for therapeutic intervention.}, journal = {Antioxidants &amp; redox signaling}, volume = {17}, number = {9}, pages = {1277-1330}, doi = {10.1089/ars.2011.4328}, pmid = {22413952}, issn = {1557-7716}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics/*metabolism ; Animals ; Humans ; Motor Neurons/metabolism/pathology ; }, abstract = {Recent years have witnessed a renewed interest in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS), a late-onset progressive degeneration of motor neurons. The discovery of new genes associated with the familial form of the disease, along with a deeper insight into pathways already described for this disease, has led scientists to reconsider previous postulates. While protein misfolding, mitochondrial dysfunction, oxidative damage, defective axonal transport, and excitotoxicity have not been dismissed, they need to be re-examined as contributors to the onset or progression of ALS in the light of the current knowledge that the mutations of proteins involved in RNA processing, apparently unrelated to the previous "old partners," are causative of the same phenotype. Thus, newly envisaged models and tools may offer unforeseen clues on the etiology of this disease and hopefully provide the key to treatment.}, }
@article {pmid22409357, year = {2012}, author = {Hayes-Punzo, A and Mulcrone, P and Meyer, M and McHugh, J and Svendsen, CN and Suzuki, M}, title = {Gonadectomy and dehydroepiandrosterone (DHEA) do not modulate disease progression in the G93A mutant SOD1 rat model of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {3}, pages = {311-314}, pmid = {22409357}, issn = {1471-180X}, support = {P51 RR000167/RR/NCRR NIH HHS/United States ; 1 UL1 RR025011/RR/NCRR NIH HHS/United States ; UL1 RR025011/RR/NCRR NIH HHS/United States ; R21 NS061049/NS/NINDS NIH HHS/United States ; P01 NS057778/NS/NINDS NIH HHS/United States ; RR000167/RR/NCRR NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*genetics/*physiopathology ; Animals ; Animals, Genetically Modified ; Dehydroepiandrosterone/*therapeutic use ; Disease Models, Animal ; *Disease Progression ; Female ; Humans ; Male ; Orchiectomy ; Ovariectomy ; Rats ; Sex Factors ; Superoxide Dismutase/*genetics ; Survival Analysis ; }, abstract = {Epidemiological studies have shown a higher incidence of amyotrophic lateral sclerosis (ALS) in men than women. Interestingly, there are clear gender differences in disease onset and progression in rodent models of familial ALS overexpressing mutated human superoxide dismutase-1 (SOD1-G93A). In the present study we sought to determine whether the alterations of serum steroid levels by gonadectomy or chronic treatment of neuroprotective neurosteroids can modulate disease onset and progression in a rat model of ALS (SOD1-G93A transgenic rats). Presymptomatic SOD1-G93A rats were gonadectomized or treated with a neurosteroid dehydroepiandrosterone (DHEA) using silastic tubing implants. Disease onset and progression of the animals were determined by the routine analyses of locomotor testing using the Basso-Beattie-Bresnahan (BBB) score. Although sexual dimorphism was observed in intact and gonadectomized SOD1-G93A rats, there was no significant effect of gonadectomy on disease onset and progression. DHEA treatment did not alter disease progression or survival in SOD1-G93A rats. Our results indicate that gonadal steroids or neurosteroids are not one of the possible modulators for the occurrence or disease progression in a rat model of ALS. Further analysis will be necessary to understand how sexual dimorphism is involved in ALS disease progression.}, }
@article {pmid22402718, year = {2012}, author = {Aoki, M}, title = {[Hepatocyte growth factor therapy for amyotrophic lateral sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {64}, number = {3}, pages = {245-254}, pmid = {22402718}, issn = {1881-6096}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Callithrix ; Disease Models, Animal ; Hepatocyte Growth Factor/*therapeutic use ; Humans ; Mice ; Rats ; Recombinant Proteins ; Superoxide Dismutase/genetics ; Translational Research, Biomedical ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. Approximately 20% of familial ALS cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene. We generated rats that express a human SOD1 transgene with two different ALS-associated mutations and found that these rats develop remarkable motor neuron degeneration and paralysis. This rat model, because of the larger size of the animals as compared to ALS-affected mice, will facilitate studies involving manipulation of the cerebrospinal fluid (CSF) (e.g., implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) or spinal cord (e.g., direct administration of viral- and cell-mediated therapies). The hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. To examine its protective effect on motor neurons and its therapeutic potential, we administered human recombinant HGF (hrHGF) to the transgenic rats, by continuous intrathecal delivery, for 4 weeks from the onset of paralysis. Intrathecal administration of hrHGF attenuated motor neuron degeneration and prolonged the duration of the disease 62.7% compared with the contrast group. Our results indicated the therapeutic efficacy of continuous intrathecal administration of hrHGF in ALS rats. To explore the potential use of this treatment strategy in humans, we induced a contusive cervical spinal cord injury in the common marmoset, a primate, and then administered hrHGF intrathecally. The intrathecal administration of hrHGF promoted functional recovery. These projects have been supported by the "Super Special Consortium for Supporting the Development of Cutting-edge Medical Care" (tokku), a special program organized by the Cabinet Office of the Japanese government (research representative: Hideyuki Okano, M.D., Ph.D., Professor at Keio University).}, }
@article {pmid22402592, year = {2012}, author = {Amin, RM and Hauser, C and Kinzler, I and Rueck, A and Scalfi-Happ, C}, title = {Evaluation of photodynamic treatment using aluminum phthalocyanine tetrasulfonate chloride as a photosensitizer: new approach.}, journal = {Photochemical &amp; photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology}, volume = {11}, number = {7}, pages = {1156-1163}, doi = {10.1039/c2pp05411f}, pmid = {22402592}, issn = {1474-9092}, mesh = {Apoptosis/*drug effects/radiation effects ; Cell Line, Tumor ; Cytochromes c/chemistry/metabolism ; Humans ; Indoles/chemistry/*toxicity ; Light ; Microscopy, Confocal ; Organometallic Compounds/chemistry/*toxicity ; Photochemotherapy ; Photosensitizing Agents/chemistry/*toxicity ; Spectrum Analysis, Raman ; }, abstract = {Photodynamic therapy (PDT) has been the subject of several clinical studies. Evidence to date suggests that direct cell death may involve apoptosis. T(24) cells (bladder cancer cells, ATCC-Nr. HTB-4) were subjected to PDT with aluminum phthalocyanine tetrasulfonate chloride (AlS(4)Pc-Cl) and red laser light at 670 nm. Morphological changes after PDT were visualized under confocal microscopy. Raman microspectroscopy is considered as one of the newly established methods used for the detection of cytochrome c as an apoptotic marker. Results showed that PDT treated T(24) cells seem to undergo apoptosis after irradiation with 3 J cm(-2). Cytochrome c could not be detected from cells incubated with AlS(4)Pc-Cl using Raman spectroscopy whereas AlS(4)Pc-Cl seems to interfere with the Raman spectrum of cytochrome c.}, }
@article {pmid22397256, year = {2011}, author = {Lusić, I and Dzamonja, G and Titlić, M and Bilić, I and Sodić, L and Lusić, L and Filipović-Grcić, P}, title = {Psychometric validation of the Croatian version of the Quality of Life in Epilepsy Inventory (QOLIE-31).}, journal = {Collegium antropologicum}, volume = {35}, number = {4}, pages = {1177-1184}, pmid = {22397256}, issn = {0350-6134}, mesh = {Adolescent ; Adult ; Aged ; Croatia ; Epilepsy/*psychology ; Female ; Humans ; Male ; Middle Aged ; *Psychometrics ; *Quality of Life ; Reproducibility of Results ; Surveys and Questionnaires ; }, abstract = {The primary goals of this study were to adapt the Quality of Life in Epilepsy Inventory-31 items (QOLIE-31) questionnaire to the Croatian language and to assess the translated questionnaire's psychometric properties. Translation/retranslation of the English version of the QOLIE-31 was done, and all steps for cross-cultural adaptation process were performed properly by an expert committee. Later, QOLIE-31 questionnaires and previously validated Short Form-36 (SF-36) outcome instruments were given to 200 patients with epilepsy. 172 patients (86%) responded to the first set of questionnaires, and 114 of the first time respondents (66%) returned their second survey. The two measures of reliability as internal consistency and reproducibility were determined by Cronbach alpha statistics and intraclass correlation coefficient, respectively. Concurrent validity was measured by comparing with a SF-36 questionnaire, and measurement was made using the Pearson correlation coefficient (r). The study demonstrated satisfactory internal consistency with high Cronbach a values for all of the corresponding domains (seizure worry 0.84, medication effects 0.80, emotional well-being 0.73, energy/fatigue 0.76, cognitive functioning 0.71, social functioning 0.77, overall quality of life 0.65). The intraclass correlation coefficient for six domains of QOLIE-31 questionnaire demonstrated excellent test/retest reproducibility (ICC > or = 0.75), and good test/retest reproducibility (ICC 0.71) in one domain (cognitive functioning). Considering concurrent validity, three domains had excellent correlation (r = 0.75-1), while 11 had good correlation (r = 0.50 to 0.75), and 3 had moderate correlation (r = 0.25-0.50). This study demonstrated that, if measures are to be used across cultures, the items must not only be translated well linguistically but also must be culturally adapted to maintain the content validity of the instrument at a conceptual level across different cultures. Croatian version of QOLIE-31 will be a valuable contribution to outcome measurement in epilepsy patients, particularly in the context of treatment trials, but als in a wider research context.}, }
@article {pmid22391662, year = {2012}, author = {Torres, AL}, title = {The management of respiratory insufficiency in patients with ALS at or near the end of life.}, journal = {Home healthcare nurse}, volume = {30}, number = {3}, pages = {186-94; quiz 194-6}, doi = {10.1097/NHH.0b013e318246d45a}, pmid = {22391662}, issn = {1539-0713}, mesh = {Amyotrophic Lateral Sclerosis/complications/*nursing ; *Clinical Competence ; Education, Nursing, Continuing ; Female ; Humans ; Male ; Nurse's Role ; Respiratory Insufficiency/etiology/*nursing ; Terminal Care/*standards ; United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease causing progressive paralysis and eventual death, usually from respiratory failure. Treatment for ALS is focused primarily on optimal symptom management because there is no known cure. Respiratory symptoms that occur are related to the disease process and can be very distressing for patients and their loved ones. Recommendations on the management of respiratory insufficiency are provided to help guide clinicians caring for patients with ALS.}, }
@article {pmid22390177, year = {2012}, author = {Prell, T and Lautenschläger, J and Witte, OW and Carri, MT and Grosskreutz, J}, title = {The unfolded protein response in models of human mutant G93A amyotrophic lateral sclerosis.}, journal = {The European journal of neuroscience}, volume = {35}, number = {5}, pages = {652-660}, doi = {10.1111/j.1460-9568.2012.08008.x}, pmid = {22390177}, issn = {1460-9568}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/*genetics/pathology ; Animals ; Cell Line, Tumor ; *Disease Models, Animal ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation/*physiology ; Organ Culture Techniques ; Superoxide Dismutase/*biosynthesis/*genetics/physiology ; Unfolded Protein Response/*physiology ; }, abstract = {Recent studies indicate that endoplasmic reticulum (ER) stress is involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS). ER stress occurs when the ER-mitochondria calcium cycle (ERMCC) is disturbed and misfolded proteins accumulate in the ER. To cope with ER stress, the cell engages the unfolded protein response (UPR). While activation of the UPR has been shown in some ALS models and tissues, ER stress elements have not been studied directly in motor neurons. Here we investigated the expression of XBP1 and ATF6α and phosphorylation of eIF2α, and their modulation, in mutated SOD1(G93A) NSC34 and animal model of ALS. Expression of XBP1 and ATF6α mRNA and protein was enhanced in SOD1(G93A) NSC34 cells. Activation of ATF6α and XBP1 and phosphorylation of eIF2α were detectable in mutated SOD1(G93A) motor but not in wild-type motor neurons. Treatment with the ER stressor thapsigargin enhanced phosphorylation of eIF2α and activated proteolysis of ATF6α and splicing of XBP1 in NSC34 and motor neurons in a time-dependent manner. The present study thus provides direct evidence of activated UPR in motor neurons which overexpress human pathogenic mutant SOD1(G93A) , providing evidence that ER stress plays a major role in ALS.}, }
@article {pmid22384217, year = {2012}, author = {Bigini, P and Diana, V and Barbera, S and Fumagalli, E and Micotti, E and Sitia, L and Paladini, A and Bisighini, C and De Grada, L and Coloca, L and Colombo, L and Manca, P and Bossolasco, P and Malvestiti, F and Fiordaliso, F and Forloni, G and Morbidelli, M and Salmona, M and Giardino, D and Mennini, T and Moscatelli, D and Silani, V and Cova, L}, title = {Longitudinal tracking of human fetal cells labeled with super paramagnetic iron oxide nanoparticles in the brain of mice with motor neuron disease.}, journal = {PloS one}, volume = {7}, number = {2}, pages = {e32326}, pmid = {22384217}, issn = {1932-6203}, mesh = {Amniotic Fluid/*cytology ; Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Bisbenzimidazole/pharmacology ; Brain/*metabolism ; Cell Nucleus/metabolism ; Cell Proliferation ; Cell Separation ; Cell Survival ; Disease Models, Animal ; Ferric Compounds/*pharmacology ; Fetal Stem Cells/*cytology ; Flow Cytometry ; Heterozygote ; Humans ; Light ; Magnetic Resonance Imaging/methods ; Magnetics ; Magnetite Nanoparticles/*chemistry ; Mice ; Microscopy, Electron, Transmission/methods ; Phenotype ; Scattering, Radiation ; Time Factors ; }, abstract = {Stem Cell (SC) therapy is one of the most promising approaches for the treatment of Amyotrophic Lateral Sclerosis (ALS). Here we employed Super Paramagnetic Iron Oxide nanoparticles (SPIOn) and Hoechst 33258 to track human Amniotic Fluid Cells (hAFCs) after transplantation in the lateral ventricles of wobbler (a murine model of ALS) and healthy mice. By in vitro, in vivo and ex vivo approaches we found that: 1) the main physical parameters of SPIOn were maintained over time; 2) hAFCs efficiently internalized SPIOn into the cytoplasm while Hoechst 33258 labeled nuclei; 3) SPIOn internalization did not alter survival, cell cycle, proliferation, metabolism and phenotype of hAFCs; 4) after transplantation hAFCs rapidly spread to the whole ventricular system, but did not migrate into the brain parenchyma; 5) hAFCs survived for a long time in the ventricles of both wobbler and healthy mice; 6) the transplantation of double-labeled hAFCs did not influence mice survival.}, }
@article {pmid22384126, year = {2012}, author = {Li, Y and Chigurupati, S and Holloway, HW and Mughal, M and Tweedie, D and Bruestle, DA and Mattson, MP and Wang, Y and Harvey, BK and Ray, B and Lahiri, DK and Greig, NH}, title = {Exendin-4 ameliorates motor neuron degeneration in cellular and animal models of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {7}, number = {2}, pages = {e32008}, pmid = {22384126}, issn = {1932-6203}, support = {AG18379/AG/NIA NIH HHS/United States ; R01 AG018884/AG/NIA NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; AG18884/AG/NIA NIH HHS/United States ; R01 AG018379/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Apoptosis ; Cell Line ; Choline O-Acetyltransferase/metabolism ; Disease Models, Animal ; Exenatide ; Glucagon-Like Peptide 1/antagonists &amp; inhibitors/metabolism ; Glucose Tolerance Test/methods ; Hydrogen Peroxide/pharmacology ; Hypoglycemic Agents/pharmacology ; Insulin/metabolism ; Male ; Mice ; Motor Neurons/*metabolism ; Oxidative Stress ; Peptides/*pharmacology ; Spinal Cord/metabolism ; Staurosporine/pharmacology ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; Venoms/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by a progressive loss of lower motor neurons in the spinal cord. The incretin hormone, glucagon-like peptide-1 (GLP-1), facilitates insulin signaling, and the long acting GLP-1 receptor agonist exendin-4 (Ex-4) is currently used as an anti-diabetic drug. GLP-1 receptors are widely expressed in the brain and spinal cord, and our prior studies have shown that Ex-4 is neuroprotective in several neurodegenerative disease rodent models, including stroke, Parkinson's disease and Alzheimer's disease. Here we hypothesized that Ex-4 may provide neuroprotective activity in ALS, and hence characterized Ex-4 actions in both cell culture (NSC-19 neuroblastoma cells) and in vivo (SOD1 G93A mutant mice) models of ALS. Ex-4 proved to be neurotrophic in NSC-19 cells, elevating choline acetyltransferase (ChAT) activity, as well as neuroprotective, protecting cells from hydrogen peroxide-induced oxidative stress and staurosporine-induced apoptosis. Additionally, in both wild-type SOD1 and mutant SOD1 (G37R) stably transfected NSC-19 cell lines, Ex-4 protected against trophic factor withdrawal-induced toxicity. To assess in vivo translation, SOD1 mutant mice were administered vehicle or Ex-4 at 6-weeks of age onwards to end-stage disease via subcutaneous osmotic pump to provide steady-state infusion. ALS mice treated with Ex-4 showed improved glucose tolerance and normalization of behavior, as assessed by running wheel, compared to control ALS mice. Furthermore, Ex-4 treatment attenuated neuronal cell death in the lumbar spinal cord; immunohistochemical analysis demonstrated the rescue of neuronal markers, such as ChAT, associated with motor neurons. Together, our results suggest that GLP-1 receptor agonists warrant further evaluation to assess whether their neuroprotective potential is of therapeutic relevance in ALS.}, }
@article {pmid22381097, year = {2012}, author = {Klein, M}, title = {Postoperative non-steroidal anti-inflammatory drugs and colorectal anastomotic leakage. NSAIDs and anastomotic leakage.}, journal = {Danish medical journal}, volume = {59}, number = {3}, pages = {B4420}, pmid = {22381097}, issn = {2245-1919}, mesh = {*Anastomosis, Surgical ; Anastomotic Leak/*chemically induced ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*adverse effects/therapeutic use ; Collagen/drug effects/metabolism ; Colorectal Surgery ; Confidence Intervals ; Cyclooxygenase 2 Inhibitors/adverse effects/therapeutic use ; Diclofenac/adverse effects/therapeutic use ; Female ; Humans ; Logistic Models ; Male ; Odds Ratio ; Pain, Postoperative/prevention &amp; control ; Postoperative Complications/*chemically induced/etiology/prevention &amp; control ; Rats ; Rats, Wistar ; Risk Factors ; Statistics as Topic ; }, abstract = {Anastomotic leakage (AL) is the most important and one of the most serious complications after colorectal resections with primary anastomosis. Any factors that contribute to increase the risk of AL should be identified and--if possible--eliminated. Non-steroidal anti-inflammatory drugs (NSAIDs) are often used for treating pain after surgical procedures, among these also colorectal resections. The objective of this Ph.d. thesis was to investigate whether the use of NSAIDs in the postoperative period increases the risk of AL, and investigate the effect on pathophysiological mechanisms. In order to achieve this, the following studies were performed. Study I was a retrospective, case-control study in 75 patients undergoing laparoscopic colorectal resection for colorectal cancer. 33 of these patients received the NSAID diclofenac in the postoperative period; the remaining 42 did not receive any NSAID. There were significantly more ALs among the patients receiving diclofenac (7/33 vs. 1/42, p=0.018). In uni- and multivariate logistic regression analyses, diclofenac was the only factor associated with increased AL rate. This study functioned as a hypothesis generating study and laid the ground for the subsequent studies. Study II was an experimental, randomized, case-control study in 32 Wistar rats. The rats had a colonic anastomosis performed and were randomized to diclofenac or placebo treatment. After three days, the rats were sacrificed and the anastomoses were harvested. First, the anastomotic strengths were tested by longitudinal; subsequently, the levels of the enzyme cyclooxygenase-2 (COX-2) in the anastomotic tissues were measured. There was no difference among the groups with regard to anastomotic strength, but the animals treated with diclofenac had significantly lower COX-2 levels (median (range) 1.30 (0.42-3.31) ng/mg vs. 2.44 (0.88 - 18.94) ng/mg, p<0.001). This study showed that the used dose of diclofenac was sufficient and relevant, but did not show a direct damaging effect on the anastomoses due to NSAID treatment. Study III was also an experimental, randomized, case-control study. This time round, 60 Wistar rats were included. Again, colonic anastomoses were performed and the rats were randomized to diclofenac or placebo. Also, expanded polytetrafluoruethylene (ePTFE) tubes were placed under the skin of the rats. In this material, substituents of connective tissue accumulate and the amount of accumulation can be measured. After 7 days, the rats were sacrificed and, again, anastomotic strengths were measured along with collagen content in the ePTFE tubes. Anastomotic strength was similar in the two groups while collagen accumulation was significantly decreased among the rats treated with diclofenac (median (i.q.r.) 0.29 (0.13-0.47) vs. 0.47 (0.28-0.62) mcg/mg, p = 0.03). This study for the first time showed that NSAID inhibit subcutaneous collagen formation and that this formation is reversely correlated to anastomotic strength. This information can be used in further studies in this subject. Study IV was the final experimental case-control study in 40 Wistar rats. This time, in order to more easily extrapolate experimental results to daily clinical life, the colonic anastomoses were sutured with the same type of suture material as used in the clinical setting. Thus, half the anastomoses was performed with resorbable suture; the other half with non-resorbable suture. None of the rats received NSAID. The breaking strength was compared and found similar in the two groups. This study showed that experimental studies can be optimized in order to make comparisons and extrapolations to the clinical setting easier. Study V was a database study based on data from the Danish Colorectal Cancer Group's (DCCG) prospective database and electronically registered medical records. From the database information on demographic, surgical and postoperative variables (including AL) were provided. Information on NSAID consumption was retrieved by individual searches in the patients' medical records. Based on these data, uni- and multivariate logistic regression analyses were performed. These analyses identified NSAID treatment in the postoperative period as an individual risk factor for AL. Other risk factors identified were consistent with the available literature. The detrimental effect of the NSAIDs are possibly due to an effect on collagen metabolism leading to weakened tissue around the anastomosis and/or on the risk of thrombosis formation leading to more thromboses in the vessels supplying the anastomosis, thereby limiting anastomotic blood flow. In conclusion, the studies included in this thesis have elucidated some of the physiological and pathophysiological mechanisms involved in anastomotic healing and leakage, and furthermore have shown that the use of NSAIDs in the postoperative period increase the risk of AL in patients undergoing colorectal surgery with primary anastomosis. Based on the findings in these studies, and based on existing knowledge, it is recommended that NSAIDs be abandoned after colorectal resection with primary anastomosis. It should be investigated whether the NSAIDs are also harmful to other types of anastomoses and after other surgical procedures where early tissue healing is crucial.}, }
@article {pmid22378918, year = {2012}, author = {Verstraete, E and Veldink, JH and Huisman, MH and Draak, T and Uijtendaal, EV and van der Kooi, AJ and Schelhaas, HJ and de Visser, M and van der Tweel, I and van den Berg, LH}, title = {Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {83}, number = {5}, pages = {557-564}, doi = {10.1136/jnnp-2011-302021}, pmid = {22378918}, issn = {1468-330X}, mesh = {Activities of Daily Living ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/blood/*drug therapy/*mortality ; Double-Blind Method ; Drug Therapy, Combination/adverse effects ; Female ; Humans ; Lithium Carbonate/adverse effects/blood/*therapeutic use ; Male ; Middle Aged ; Pulmonary Ventilation/drug effects ; Riluzole/therapeutic use ; Survival Rate ; Vital Capacity/drug effects ; }, abstract = {OBJECTIVES: To determine the safety and efficacy of lithium for the treatment of amyotrophic lateral sclerosis (ALS) in a randomised, placebo controlled, double blind, sequential trial.<br><br>METHODS: Between November 2008 and June 2011, 133 patients were randomised to receive lithium carbonate (target blood level 0.4-0.8 mEq/l) or placebo as add-on treatment with riluzole. The primary endpoint was survival, defined as death, tracheostomal ventilation or non-invasive ventilation for more than 16 h/day. Secondary outcome measures consisted of the revised ALS Functional Rating Scale and forced vital capacity. Analysis was by intention to treat and according to a sequential trial design.<br><br>RESULTS: 61 patients reached a primary endpoint, 33 of 66 in the lithium group and 28 of 67 patients in the placebo group. Lithium did not significantly affect survival (cumulative survival probability of 0.73 in the lithium group (95% CI 0.63 to 0.86) vs 0.75 in the placebo group (95% CI 0.65 to 0.87) at 12 months and 0.62 in the lithium group (95% CI 0.50 to 0.76) vs 0.67 in the placebo group (95% CI 0.56 to 0.81) at 16 months). Secondary outcome measures did not differ between treatment groups. No major safety concerns were encountered.<br><br>CONCLUSIONS: This trial, designed to detect a modest effect of lithium, did not demonstrate any beneficial effect on either survival or functional decline in patients with ALS.<br><br>TRIAL REGISTRATION NUMBER: NTR1448. Name of trial registry: Lithium trial in ALS.}, }
@article {pmid24932066, year = {2012}, author = {Weismer, G and Yunusova, Y and Bunton, K}, title = {Measures to Evaluate the Effects of DBS on Speech Production.}, journal = {Journal of neurolinguistics}, volume = {25}, number = {4}, pages = {74-94}, pmid = {24932066}, issn = {0911-6044}, support = {R01 DC003723/DC/NIDCD NIH HHS/United States ; R01 DC003723-01A1/DC/NIDCD NIH HHS/United States ; }, abstract = {The purpose of this paper is to review and evaluate measures of speech production that could be used to document effects of Deep Brain Stimulation (DBS) on speech performance, especially in persons with Parkinson disease (PD). A small set of evaluative criteria for these measures is presented first, followed by consideration of several speech physiology and speech acoustic measures that have been studied frequently and reported on in the literature on normal speech production, and speech production affected by neuromotor disorders (dysarthria). Each measure is reviewed and evaluated against the evaluative criteria. Embedded within this review and evaluation is a presentation of new data relating speech motions to speech intelligibility measures in speakers with PD, amyotrophic lateral sclerosis (ALS), and control speakers (CS). These data are used to support the conclusion that at the present time the slope of second formant transitions (F2 slope), an acoustic measure, is well suited to make inferences to speech motion and to predict speech intelligibility. The use of other measures should not be ruled out, however, and we encourage further development of evaluative criteria for speech measures designed to probe the effects of DBS or any treatment with potential effects on speech production and communication skills.}, }
@article {pmid22371074, year = {2012}, author = {Pacher, P and Mackie, K}, title = {Interplay of cannabinoid 2 (CB2) receptors with nitric oxide synthases, oxidative and nitrative stress, and cell death during remote neurodegeneration.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {90}, number = {4}, pages = {347-351}, pmid = {22371074}, issn = {1432-1440}, support = {Z99 AA999999//Intramural NIH HHS/United States ; Z01 AA000375-02//Intramural NIH HHS/United States ; ZIA AA000375-05//Intramural NIH HHS/United States ; ZIA AA000375-04//Intramural NIH HHS/United States ; Z01 AA000375-03//Intramural NIH HHS/United States ; ZIA AA000375-06//Intramural NIH HHS/United States ; }, mesh = {Animals ; Brain Injuries/*metabolism ; Male ; Neurons/*pathology ; Neuroprotective Agents/*metabolism ; Nitric Oxide Synthase Type I/*genetics ; Nitric Oxide Synthase Type II/*genetics ; Receptor, Cannabinoid, CB2/*metabolism ; }, abstract = {Remote neuronal degeneration and death/injury, which often occur in regions remote but functionally connected to the primary lesion site, may play a pivotal role in extending neuronal damage/dysfunction following traumatic brain injury, stroke, or peripheral nerve injury, as well as in chronic neurodegenerative diseases such as multiple sclerosis and amyotrophic lateral sclerosis. Even though the precise mechanisms of remote neuronal injury are poorly understood and no efficacious treatment options are available, it involves glial activation, inflammation, oxidative/nitrative stress, and apoptotic cell death. The newly discovered endocannabinoid signaling system consisting of endocannabinoids (endogenous bioactive lipid mediators), their synthetic and metabolizing enzymes, and their primary G protein-coupled cannabinoid 1 and 2 (CB(1) and CB(2)) receptors has been implicated in the regulation of numerous physiological and pathological processes/functions, including those associated with neurodegeneration. Using a well-characterized rodent model of remote neuronal degeneration, Oddi et al. (J Mol Med 2012, in press, DOI 10.1007/s00109-012-0884-1) have demonstrated that targeting CB(2) cannabinoid receptors may represent a promising novel approach to attenuate this pathological process. This editorial discusses the clinical significance of these interesting observations and the mechanisms of the possible interplay of CB(2) receptors with nitric oxide synthases, oxidative and nitrative stress, and cell death during remote neurodegeneration.}, }
@article {pmid22369784, year = {2012}, author = {Sunyach, C and Michaud, M and Arnoux, T and Bernard-Marissal, N and Aebischer, J and Latyszenok, V and Gouarné, C and Raoul, C and Pruss, RM and Bordet, T and Pettmann, B}, title = {Olesoxime delays muscle denervation, astrogliosis, microglial activation and motoneuron death in an ALS mouse model.}, journal = {Neuropharmacology}, volume = {62}, number = {7}, pages = {2346-2352}, doi = {10.1016/j.neuropharm.2012.02.013}, pmid = {22369784}, issn = {1873-7064}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Cell Death/drug effects/physiology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Cholestenones/pharmacology/*therapeutic use ; *Disease Models, Animal ; Gliosis/*drug therapy/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/*drug effects/metabolism ; Motor Neurons/*drug effects/pathology ; *Muscle Denervation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. The pathology is mimicked to a striking degree in transgenic mice carrying familial ALS-linked SOD1 gene mutations. Olesoxime (TRO19622), a novel neuroprotective and reparative compound identified in a high-throughput screen based on motoneuron (MN) survival, delays disease onset and improves survival in mutant SOD1(G93A) mice, a model for ALS. The present study further analyses the cellular basis for the protection provided by olesoxime at the neuromuscular junctions (NMJ) and the spinal cord. Studies were carried out at two disease stages, 60 days, presymptomatic and 104 days, symptomatic. Cohorts of wild type and SOD1(G93A) mice were randomized to receive olesoxime-charged food pellets or normal diet from day 21 onward. Analysis showed that olesoxime initially reduced denervation from 60 to 30% compared to SOD1(G93A) mice fed with control food pellets while at the symptomatic stage only a few NMJs were still preserved. Immunostaining of cryostat sections of the lumbar spinal cord with VAChT to visualize MNs, GFAP for astrocytes and Iba1 for microglial cells showed that olesoxime strongly reduced astrogliosis and microglial activation and prevented MN loss. These studies suggest that olesoxime exerts its protective effect on multiple cell types implicated in the disease process in SOD1(G93A) mice, slowing down muscle denervation, astrogliosis, microglial activation and MN death. A Phase 3 clinical study in ALS patients will determine whether olesoxime could be beneficial for the treatment of ALS.}, }
@article {pmid22364637, year = {2012}, author = {Alavian, KN and Dworetzky, SI and Bonanni, L and Zhang, P and Sacchetti, S and Mariggio, MA and Onofrj, M and Thomas, A and Li, H and Mangold, JE and Signore, AP and Demarco, U and Demady, DR and Nabili, P and Lazrove, E and Smith, PJ and Gribkoff, VK and Jonas, EA}, title = {Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetic efficiency.}, journal = {Brain research}, volume = {1446}, number = {}, pages = {1-11}, pmid = {22364637}, issn = {1872-6240}, support = {NS064967/NS/NINDS NIH HHS/United States ; R01 NS045876/NS/NINDS NIH HHS/United States ; R56 NS064967/NS/NINDS NIH HHS/United States ; R37 NS045876/NS/NINDS NIH HHS/United States ; R01 NS064967/NS/NINDS NIH HHS/United States ; NS045876/NS/NINDS NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/metabolism ; Adrenergic beta-Antagonists/*pharmacology ; Analysis of Variance ; Animals ; Biophysical Phenomena/drug effects ; Brain/cytology ; Cell Survival/drug effects ; Cells, Cultured ; Cyclosporine/pharmacology ; Dose-Response Relationship, Drug ; Energy Metabolism/*drug effects ; Enzyme Inhibitors/pharmacology ; Humans ; Male ; Membrane Potential, Mitochondrial/*drug effects ; Mice ; Mitochondria/*drug effects ; Mitochondrial Membranes/drug effects ; Neuroblastoma/pathology/ultrastructure ; Neurons/*ultrastructure ; Oligopeptides/pharmacology ; Oxygen Consumption/drug effects ; Patch-Clamp Techniques ; Propranolol/*pharmacology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Cellular stress or injury can result in mitochondrial dysfunction, which has been linked to many chronic neurological disorders including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Stressed and dysfunctional mitochondria exhibit an increase in large conductance mitochondrial membrane currents and a decrease in bioenergetic efficiency. Inefficient energy production puts cells, and particularly neurons, at risk of death when energy demands exceed cellular energy production. Here we show that the candidate ALS drug dexpramipexole (DEX; KNS-760704; ((6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) and cyclosporine A (CSA) inhibited increases in ion conductance in whole rat brain-derived mitochondria induced by calcium or treatment with a proteasome inhibitor, although only CSA inhibited calcium-induced permeability transition in liver-derived mitochondria. In several cell lines, including cortical neurons in culture, DEX significantly decreased oxygen consumption while maintaining or increasing production of adenosine triphosphate (ATP). DEX also normalized the metabolic profile of injured cells and was protective against the cytotoxic effects of proteasome inhibition. These data indicate that DEX increases the efficiency of oxidative phosphorylation, possibly by inhibition of a CSA-sensitive mitochondrial conductance.}, }
@article {pmid22361843, year = {2012}, author = {Khansari, PS and Sperlagh, B}, title = {Inflammation in neurological and psychiatric diseases.}, journal = {Inflammopharmacology}, volume = {20}, number = {3}, pages = {103-107}, pmid = {22361843}, issn = {1568-5608}, mesh = {Animals ; Humans ; Immunotherapy/adverse effects/methods/trends ; Inflammation/pathology/psychology/therapy ; Mental Disorders/*pathology/*psychology/therapy ; Nervous System Diseases/*pathology/*psychology/therapy ; }, abstract = {In recent years, compelling evidence suggests that inflammation plays a critical role in the pathology of a vast number of neurological diseases such as stroke, Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis as well as neuropsychiatric diseases such as major depression and schizophrenia. Despite emerging evidence in human and animal models alike, modulating inflammatory responses have yet to be proven as an effective treatment to prevent or delay the progression of these diseases. The primary focus of this special edition is to highlight some of our current findings on the complexities of targeting neuroinflammation as a novel therapy, and its role in neurological and psychiatric disorders.}, }
@article {pmid22359076, year = {2012}, author = {Larijani, B and Esfahani, EN and Amini, P and Nikbin, B and Alimoghaddam, K and Amiri, S and Malekzadeh, R and Yazdi, NM and Ghodsi, M and Dowlati, Y and Sahraian, MA and Ghavamzadeh, A}, title = {Stem cell therapy in treatment of different diseases.}, journal = {Acta medica Iranica}, volume = {50}, number = {2}, pages = {79-96}, pmid = {22359076}, issn = {1735-9694}, mesh = {Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Animals ; Humans ; Inflammatory Bowel Diseases/therapy ; Multiple Sclerosis/therapy ; Muscular Dystrophy, Duchenne/therapy ; Parkinson Disease/therapy ; Spinal Cord Injuries/therapy ; *Stem Cell Transplantation ; }, abstract = {Stem cells are undifferentiated cells with the ability of proliferation, regeneration, conversion to differentiated cells and producing various tissues. Stem cells are divided into two categories of embryonic and adult. In another categorization stem cells are divided to Totipotent, Multipotent and Unipotent cells.So far usage of stem cells in treatment of various blood diseases has been studied (such as lymphoblastic leukemia, myeloid leukemia, thalassemia, multiple myeloma and cycle cell anemia). In this paper the goal is evaluation of cell therapy in treatment of Parkinson's disease, Amyotrophic lateral sclerosis, Alzheimer, Stroke, Spinal Cord Injury, Multiple Sclerosis, Radiation Induced Intestinal Injury, Inflammatory Bowel Disease, Liver Disease, Duchenne Muscular Dystrophy, Diabetes, Heart Disease, Bone Disease, Renal Disease, Chronic Wounds, Graft-Versus-Host Disease, Sepsis and Respiratory diseases. It should be mentioned that some disease that are the target of cell therapy are discussed in this article.}, }
@article {pmid22357218, year = {2012}, author = {Jung, YW and Hysolli, E and Kim, KY and Tanaka, Y and Park, IH}, title = {Human induced pluripotent stem cells and neurodegenerative disease: prospects for novel therapies.}, journal = {Current opinion in neurology}, volume = {25}, number = {2}, pages = {125-130}, pmid = {22357218}, issn = {1473-6551}, support = {P01 GM099130/GM/NIGMS NIH HHS/United States ; GM099130-01/GM/NIGMS NIH HHS/United States ; }, mesh = {Cell Differentiation ; Cell Proliferation ; Humans ; Kruppel-Like Factor 4 ; Neurodegenerative Diseases/*surgery ; Pluripotent Stem Cells/*physiology ; Stem Cell Transplantation/*methods ; }, abstract = {PURPOSE OF REVIEW: The lack of effective treatments for various neurodegenerative disorders has placed huge burdens on society. We review the current status in applying induced pluripotent stem cell (iPSC) technology for the cellular therapy, drug screening, and in-vitro modeling of neurodegenerative diseases.<br><br>RECENT FINDINGS: iPSCs are generated from somatic cells by overexpressing four reprogramming factors (Oct4, Sox2, Klf4, and Myc). Like human embryonic stem cells, iPSCs have features of self-renewal and pluripotency, and allow in-vitro disease modeling, drug screening, and cell replacement therapy. Disease-specific iPSCs were derived from patients of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. Neurons differentiated from these iPSCs recapitulated the in-vivo phenotypes, providing platforms for drug screening. In the case of Parkinson's disease, iPSC-derived dopaminergic neurons gave positive therapeutic effect on a rodent Parkinson's disease model as a proof of principle in using iPSCs as sources of cell replacement therapy. Beyond iPSC technology, much effort is being made to generate neurons directly from dermal fibroblasts with neuron-specific transcription factors, which does not require making iPSCs as an intermediate cell type.<br><br>SUMMARY: We summarize recent progress in using iPSCs for modeling the progress and treatment of neurodegenerative diseases and provide evidence for future perspectives in this field.}, }
@article {pmid22351797, year = {2012}, author = {Seeber, AA and Hijdra, A and Vermeulen, M and Willems, DL}, title = {Discussions about treatment restrictions in chronic neurologic diseases: a structured review.}, journal = {Neurology}, volume = {78}, number = {8}, pages = {590-597}, doi = {10.1212/WNL.0b013e318247cc56}, pmid = {22351797}, issn = {1526-632X}, mesh = {Chronic Disease ; *Decision Making ; Humans ; Nervous System Diseases/*therapy ; Professional-Family Relations ; *Terminal Care ; }, abstract = {OBJECTIVE: Many incurable neurologic diseases have predictable complications during their course or at their end stage. Timely discussions of potential treatment restrictions may improve the quality of treatment decisions toward the end of life. What is known about the actual practice of these discussions?<br><br>METHODS: We performed a literature search in MEDLINE, EMBASE, and CINAHL for empirical studies about discussions and decisions to restrict treatment in the course of 6 conditions: motor neuron disease (amyotrophic lateral sclerosis [ALS]), primary malignant brain tumors, multiple sclerosis, stroke, Parkinson disease, and dementia (Alzheimer disease).<br><br>RESULTS: In 10 of 43 studies, the actual practice of decision-making was studied; in the remaining 33, caregivers were interviewed about this practice. Three scenarios were described: 1) acute devastating disease (severe stroke); 2) stable severe neurologic deficit with complications (poststroke brain damage); and 3) chronic progressive disease with complications (dementia and ALS). We found no studies concerning the other conditions. In all 3 scenarios, discussions and decisions seemed to be mostly triggered by the occurrence of life-threatening situations, either caused by the disease itself (1), or complications (2 and 3, including many patients with ALS). Some ALS studies showed that timely discussion of treatment options improved end-of-life decision-making.<br><br>CONCLUSIONS: The actual practice of discussions about treatment restrictions in chronic neurologic disease has hardly been studied. The currently available empirical data suggest that discussions are mainly triggered by life-threatening situations, whereas anticipation of such situations may be beneficial for patients and their families.}, }
@article {pmid22351600, year = {2012}, author = {Eitan, E and Tichon, A and Gazit, A and Gitler, D and Slavin, S and Priel, E}, title = {Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis.}, journal = {EMBO molecular medicine}, volume = {4}, number = {4}, pages = {313-329}, pmid = {22351600}, issn = {1757-4684}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics/*prevention &amp; control ; Animals ; Brain/drug effects/*enzymology/metabolism ; Cell Survival/drug effects ; Male ; Mice ; Neuroprotective Agents/pharmacology/*therapeutic use ; Oxidative Stress/drug effects ; Phenols/pharmacology/*therapeutic use ; Spinal Cord/drug effects/*enzymology/metabolism ; Telomerase/genetics/*metabolism ; Triphenylmethyl Compounds/pharmacology/*therapeutic use ; Up-Regulation/drug effects ; }, abstract = {Telomerase is expressed in the neonatal brain, in distinct regions of adult brain, and was shown to protect developing neurons from apoptosis. Telomerase reactivation by gene manipulation reverses neurodegeneration in aged telomerase-deficient mice. Hence, we and others hypothesized that increasing telomerase expression by pharmaceutical compounds may protect brain cells from death caused by damaging agents. In this study, we demonstrate for the first time that the novel compound AGS-499 increases telomerase activity and expression in the mouse brain and spinal cord (SC). It exerts neuroprotective effects in NMDA-injected CD-1 mice, delays the onset and progression of the amyotrophic lateral sclerosis (ALS) disease in SOD1 transgenic mice, and, after the onset of ALS, it increases the survival of motor neurons in the SC by 60%. The survival of telomerase-expressing cells (i.e. motor neurons), but not telomerase-deficient cells, exposed to oxidative stress was increased by AGS-499 treatment, suggesting that the AGS-499 effects are telomerase-mediated. Therefore, a controlled and transient increase in telomerase expression and activity in the brain by AGS-499 may exert neuroprotective effects.}, }
@article {pmid22336799, year = {2012}, author = {Ashworth, NL and Satkunam, LE and Deforge, D}, title = {Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {2}, pages = {CD004156}, doi = {10.1002/14651858.CD004156.pub4}, pmid = {22336799}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Exercise Therapy/*methods ; Humans ; Muscle Spasticity/etiology/*therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Spasticity commonly affects patients with motor neuron disease. It is likely to contribute to worsening muscle dysfunction, increased difficulty with activities of daily living and deteriorating quality of life. This is an update of a review first published in 2003 and previously updated in 2005 and 2008.<br><br>OBJECTIVES: The objective of this review is to systematically review treatments for spasticity in amyotrophic lateral sclerosis, also known as motor neuron disease.<br><br>SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (4 July 2011), CENTRAL (2011, Issue 2), MEDLINE (January 1966 to July 2011), EMBASE (January 1980 to July 2011), CINAHL Plus (January 1937 to July 2011), AMED (January 1985 to July 2011) and LILACS (January 1982 to July 2011). We reviewed the bibliographies of the randomized controlled trials identified, and contacted authors and experts in the field.<br><br>SELECTION CRITERIA: We included quasi-randomized or randomized controlled trials of participants with probable or definite amyotrophic lateral sclerosis according to the El Escorial diagnostic criteria (or a revised version) or the Airlie House revision. We would have included trials of physical therapy, modalities, prescription medications, non-prescription medications, chemical neurolysis, surgical interventions, and alternative therapies. Our primary outcome measure was reduction in spasticity at three months or greater as measured by the Ashworth (or modified Ashworth) spasticity scale. Our secondary outcome measures were: validated measures based on history, physical examination, physiological measures, measures of function, measures of quality of life, all adverse events, and measures of cost.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently screened the abstracts of potential trials retrieved from the searches. Two authors extracted the data. We also contacted the author of the paper and obtained information not available in the published article. All three authors assessed the methodological quality of all included trials independently.<br><br>MAIN RESULTS: We identified only one randomized controlled trial that met our inclusion criteria and no further trials were identified in subsequent updates. The included study was a trial of moderate intensity, endurance type exercise versus 'usual activities' in 25 patients with amyotrophic lateral sclerosis. The risk of bias was high and no adverse events were reported. At three months patients performing the 15 minute twice daily exercises had significantly less spasticity overall (mean reduction of -0.43, 95% confidence interval (CI) -1.03 to +0.17 in the treatment group versus an increase of +0.25, 95% CI -0.46 to +0.96 in control) but the mean change between groups was not significant (-0.68, 95% CI -1.62 to +0.26), as measured by the Ashworth scale (possible scores 0 to 5, where higher is worse).<br><br>AUTHORS' CONCLUSIONS: The single trial performed was too small to determine whether individualized moderate intensity endurance type exercises for the trunk and limbs are beneficial or harmful. No other medical, surgical or alternative treatment and therapy has been evaluated in a randomized fashion in this patient population. More research is needed.}, }
@article {pmid22334165, year = {2012}, author = {Blackhall, LJ}, title = {Amyotrophic lateral sclerosis and palliative care: where we are, and the road ahead.}, journal = {Muscle &amp; nerve}, volume = {45}, number = {3}, pages = {311-318}, doi = {10.1002/mus.22305}, pmid = {22334165}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/complications/psychology/therapy ; Decision Making ; Dyspnea/etiology/therapy ; Humans ; Mood Disorders/etiology/therapy ; *Pain Management ; *Palliative Care/methods/trends ; Respiratory Insufficiency/etiology/therapy ; Sialorrhea/etiology/therapy ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) have high symptom burdens, including pain, fatigue, dyspnea, and sialorrhea, and they must make difficult decisions about the use of life-prolonging therapies, such as long-term mechanical ventilation. The impact of ALS is also felt by family caregivers who often struggle to meet the heavy physical, financial, and emotional demands associated with the illness. Expert multidisciplinary care may improve both quality and length of life of patients with ALS. However, although advances have been made in the treatment of some symptoms, others, including pain management, remain poorly studied. Involvement of palliative care specialists as part of the ALS multidisciplinary team is recommended, as we continue to work toward improving the quality of life for patients and their families.}, }
@article {pmid22323869, year = {2012}, author = {Min, JH and Hong, YH and Sung, JJ and Kim, SM and Lee, JB and Lee, KW}, title = {Oral solubilized ursodeoxycholic acid therapy in amyotrophic lateral sclerosis: a randomized cross-over trial.}, journal = {Journal of Korean medical science}, volume = {27}, number = {2}, pages = {200-206}, pmid = {22323869}, issn = {1598-6357}, mesh = {Administration, Oral ; Amyotrophic Lateral Sclerosis/*drug therapy ; Cholagogues and Choleretics/pharmacology/therapeutic use ; Cross-Over Studies ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Placebo Effect ; Severity of Illness Index ; Ursodeoxycholic Acid/pharmacology/*therapeutic use ; Vital Capacity/drug effects ; }, abstract = {To evaluate the efficacy and safety of ursodeoxycholic acid (UDCA) with oral solubilized formula in amyotrophic lateral sclerosis (ALS) patients, patients with probable or definite ALS were randomized to receive oral solubilized UDCA (3.5 g/140 mL/day) or placebo for 3 months after a run-in period of 1 month and switched to receive the other treatment for 3 months after a wash-out period of 1 month. The primary outcome was the rate of progression, assessed by the Appel ALS rating scale (AALSRS), and the secondary outcomes were the revised ALS functional rating scale (ALSFRS-R) and forced vital capacity (FVC). Fifty-three patients completed either the first or second period of study with only 16 of 63 enrolled patients given both treatments sequentially. The slope of AALSRS was 1.17 points/month lower while the patients were treated with UDCA than with placebo (95% CI for difference 0.08-2.26, P = 0.037), whereas the slopes of ALSFRS-R and FVC did not show significant differences between treatments. Gastrointestinal adverse events were more common with UDCA (P < 0.05). Oral solubilized UDCA seems to be tolerable in ALS patients, but we could not make firm conclusion regarding its efficacy, particularly due to the high attrition rate in this cross-over trial.}, }
@article {pmid22319507, year = {2012}, author = {Clos, AL and Kayed, R and Lasagna-Reeves, CA}, title = {Association of skin with the pathogenesis and treatment of neurodegenerative amyloidosis.}, journal = {Frontiers in neurology}, volume = {3}, number = {}, pages = {5}, pmid = {22319507}, issn = {1664-2295}, abstract = {Amyloidosis are a large group of conformational diseases characterized by abnormal protein folding and assembly which results in the accumulation of insoluble protein aggregates that may accumulate systemically or locally in certain organs or tissue. In local amyloidosis, amyloid deposits are restricted to a particular organ or tissue. Alzheimer's, Parkinson's disease, and amyotrophic lateral sclerosis are some examples of neurodegenerative amyloidosis. Local manifestation of protein aggregation in the skin has also been reported. Brain and skin are highly connected at a physiological and pathological level. Recently several studies demonstrated a strong connection between brain and skin in different amyloid diseases. In the present review, we discuss the relevance of the "brain-skin connection" in different neurodegenerative amyloidosis, not only at the pathological level, but also as a strategy for the treatment of these diseases.}, }
@article {pmid22306345, year = {2012}, author = {Caraci, F and Battaglia, G and Sortino, MA and Spampinato, S and Molinaro, G and Copani, A and Nicoletti, F and Bruno, V}, title = {Metabotropic glutamate receptors in neurodegeneration/neuroprotection: still a hot topic?.}, journal = {Neurochemistry international}, volume = {61}, number = {4}, pages = {559-565}, doi = {10.1016/j.neuint.2012.01.017}, pmid = {22306345}, issn = {1872-9754}, mesh = {Allosteric Regulation ; Animals ; Haplorhini ; Mice ; Neuroprotective Agents/pharmacology ; Receptors, Metabotropic Glutamate/*metabolism ; }, abstract = {Moving from early studies, we here review the most recent evidence linking metabotropic glutamate (mGlu) receptors to processes of neurodegeneration/neuroprotection. The use of knockout mice and subtype-selective drugs has increased our knowledge of the precise role played by individual mGlu receptor subtypes in these processes. Activation of mGlu1 and mGlu5 receptors may either amplify or reduce neuronal damage depending on the context and the nature of the toxic insults. In contrast, mGlu1 and mGlu5 receptors antagonists are consistently protective in in vitro and in vivo models of neuronal death. A series of studies suggest that mGlu1 receptor antagonists or negative allosteric modulators (NAMs) are promising candidates for the treatment of ischemic brain damage, whereas mGlu5 receptor NAMs, which have been clinically developed for the treatment of Parkinson's disease (PD) and l-DOPA-induced dyskinesias, protect nigro-striatal dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice and monkeys. Activation of glial mGlu3 receptors promotes the formation of various neurotrophic factors, such as transforming growth factor-β (TGF-β), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF). Hence, selective mGlu3 receptor agonists or positive allosteric modulators (PAMs) (not yet available) are potentially helpful in the treatment of chronic neurodegenerative disorders such as PD, Alzheimer's disease (AD), and amyotrophic lateral sclerosis. Selective mGlu2 receptor PAMs should be used with caution in AD patients because these drugs are shown to amplify β-amyloid neurotoxicity. Finally, mGlu4 receptor agonists/PAMs share with mGlu5 receptor NAMs the ability to improve motor symptoms associated with PD and attenuate nigro-striatal degeneration at the same time. No data are yet available on the role of mGlu7 and mGlu8 receptors in neurodegeneration/neuroprotection.}, }
@article {pmid22300014, year = {2012}, author = {Arenas, A and Giurfa, M and Sandoz, JC and Hourcade, B and Devaud, JM and Farina, WM}, title = {Early olfactory experience induces structural changes in the primary olfactory center of an insect brain.}, journal = {The European journal of neuroscience}, volume = {35}, number = {5}, pages = {682-690}, doi = {10.1111/j.1460-9568.2012.07999.x}, pmid = {22300014}, issn = {1460-9568}, mesh = {Animals ; Animals, Newborn ; Arthropod Antennae/growth &amp; development ; Bees/*growth &amp; development ; Brain/growth &amp; development ; Insecta ; Learning/*physiology ; *Odorants ; Olfactory Pathways/*growth &amp; development ; Olfactory Perception/*physiology ; }, abstract = {The antennal lobe (AL) is the first olfactory center of the insect brain and is constituted of different functional units, the glomeruli. In the AL, odors are coded as spatiotemporal patterns of glomerular activity. In honeybees, olfactory learning during early adulthood modifies neural activity in the AL on a long-term scale and also enhances later memory retention. By means of behavioral experiments, we first verified that olfactory learning between the fifth and eighth day of adulthood induces better retention performances at a late adult stage than the same experience acquired before or after this period. We checked that the specificity of memory for the odorants used was improved. We then studied whether such early olfactory learning also induces long-term structural changes in the AL consistent with the formation of long-term olfactory memories. We also measured the volume of 15 identified glomeruli in the ALs of 17-day-old honeybees that either experienced an odor associated with sucrose solution between the fifth and eighth day of adulthood or were left untreated. We found that early olfactory experience induces glomerulus-selective increases in volume that were specific to the learned odor. By comparing our volumetric measures with calcium-imaging recordings from a previous study, performed in 17-day-old bees subjected to the same treatment and experimental conditions, we found that glomeruli that showed structural changes after early learning were those that exhibited a significant increase in neural activity. Our results make evident a correlation between structural and functional changes in the AL following early olfactory learning.}, }
@article {pmid22299822, year = {2012}, author = {Shi, Q and Lees, JR and Scott, DW and Farber, DL and Bartlett, ST}, title = {Endogenous expansion of regulatory T cells leads to long-term islet graft survival in diabetic NOD mice.}, journal = {American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons}, volume = {12}, number = {5}, pages = {1124-1132}, doi = {10.1111/j.1600-6143.2011.03943.x}, pmid = {22299822}, issn = {1600-6143}, mesh = {Animals ; Antilymphocyte Serum/*administration &amp; dosage ; Autoimmunity ; Diabetes Mellitus, Type 1/immunology/*therapy ; Female ; Fluorescent Antibody Technique ; Forkhead Transcription Factors/metabolism ; Graft Survival/*immunology ; Immunoenzyme Techniques ; Islets of Langerhans/*immunology ; Islets of Langerhans Transplantation/*immunology ; Lymph Nodes/*immunology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; T-Lymphocytes, Regulatory/*immunology ; Transplantation Tolerance/immunology ; }, abstract = {Donor pancreatic lymph node cells (PLNC) protect islet transplants in Non-obese diabetic (NOD) mice. We hypothesized that induced FoxP3(+) regulatory T cells (Tregs) were required for long-term islet engraftment. NOD or NOD.NON mice were treated with ALS (antilymphocyte serum) and transplanted with NOR islets +/-PLNC (5 × 10(7)). In vivo proliferation and expansion of FoxP3(+) Tregs was monitored in spleen and PLN from ALS- and ALS/PLNC-treated recipient mice. Anti-CD25 depletion was used to determine the necessity of Tregs for tolerance. FoxP3(+) numbers significantly increased in ALS/PLNC-treated recipients compared to ALS-treated mice. In ALS/PLNC-treated mice, recipient-derived Tregs localized to the transplanted islets, and this was associated with intact, insulin-producing β cells. Proliferation and expansion of FoxP3(+) Tregs was markedly increased in PLNC-treated mice with accepted islet grafts, but not in diabetic mice not receiving PLNC. Deletion of Tregs with anti-CD25 antibodies prevented islet graft tolerance and resulted in rejection. Adoptive transfer of Tregs to secondary NOD.scid recipients inhibited autoimmunity by cotransferred NOD effector T cells. Treg expansion induced by ALS/PLNC-treatment promoted long term islet graft survival. Strategies leading to Treg proliferation and localization to the transplant site represent a therapeutic approach to controlling recurrent autoimmunity.}, }
@article {pmid22298416, year = {2012}, author = {Rathore, KI and Redensek, A and David, S}, title = {Iron homeostasis in astrocytes and microglia is differentially regulated by TNF-α and TGF-β1.}, journal = {Glia}, volume = {60}, number = {5}, pages = {738-750}, doi = {10.1002/glia.22303}, pmid = {22298416}, issn = {1098-1136}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Animals, Newborn ; Astrocytes/metabolism/*physiology ; Cation Transport Proteins/antagonists &amp; inhibitors/biosynthesis/genetics/physiology ; Cells, Cultured ; Homeostasis/*physiology ; Iron/metabolism/*physiology ; Mice ; Mice, Inbred C57BL ; Microglia/metabolism/*physiology ; Transforming Growth Factor beta1/*physiology ; Tumor Necrosis Factor-alpha/*physiology ; Ferroportin ; }, abstract = {Abnormal iron homeostasis is increasingly thought to contribute to the pathogenesis of several neurodegenerative disorders. We have previously reported impaired iron homeostasis in a mouse model of spinal cord injury and in a mouse model of amyotrophic lateral sclerosis. Both these disorders are associated with CNS inflammation. However, what effect inflammation, and in particular, inflammatory cytokines have on iron homeostasis in CNS glia remains largely unknown. Here we report that the proinflammatory cytokine TNF-α, and the anti-inflammatory cytokine TGF-β1 affect iron homeostasis in astrocytes and microglia in distinct ways. Treatment of astrocytes in vitro with TNF-α induced the expression of the iron importer "divalent iron transporter 1" (DMT1) and suppressed the expression of the iron exporter ferroportin (FPN). However, TGF-β1 had no effect on DMT1 expression but increased the expression of FPN in astrocytes. In microglia, on the other hand, both cytokines caused induction of DMT1 and suppression of FPN expression. Iron influx and efflux assays in vitro confirmed that iron homeostasis in astrocytes and microglia is differentially regulated by these cytokines. In particular, TNF-α caused an increase in iron uptake and retention by both astrocytes and microglia, while TGF-β1 promoted iron efflux from astrocytes but caused iron retention in microglia. These data suggest that these two cytokines, which are expressed in CNS inflammation in injury and disease, can have profound and divergent effects on iron homeostasis in astrocytes and microglia.}, }
@article {pmid22292845, year = {2012}, author = {Rubin, AD and Griffin, GR and Hogikyan, ND and Feldman, EL}, title = {A new member of the multidisciplinary ALS team: the otolaryngologist.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {2}, pages = {229-232}, doi = {10.3109/17482968.2011.643898}, pmid = {22292845}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/*therapy ; Disease Management ; Female ; Humans ; *Interdisciplinary Communication ; Middle Aged ; *Otolaryngology ; *Patient Care Team ; }, abstract = {The multidisciplinary approach to treatment of amyotrophic lateral sclerosis (ALS) has improved the overall care of patients suffering from this disease (1 , 2). This approach typically has included neurologists, physiatrists, occupational therapists, respiratory therapists and speech therapists. Dysphonia, dysarthria, and dysphagia are three of the most common bulbar manifestations of ALS, and are often the presenting symptoms in bulbar-onset patients. Despite this, otolaryngologists are often not included in ALS management until a tracheostomy is considered. The otolaryngologist can play an important role in early diagnosis and subsequent management of bulbar manifestations of ALS, and would be a valuable member of the multidisciplinary team.}, }
@article {pmid22292840, year = {2012}, author = {Lautenschlaeger, J and Prell, T and Grosskreutz, J}, title = {Endoplasmic reticulum stress and the ER mitochondrial calcium cycle in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {13}, number = {2}, pages = {166-177}, doi = {10.3109/17482968.2011.641569}, pmid = {22292840}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Calcium/*metabolism ; DNA-Binding Proteins/metabolism ; Endoplasmic Reticulum/*physiology/ultrastructure ; Endoplasmic Reticulum Stress/*physiology ; Golgi Apparatus/physiology/ultrastructure ; Humans ; Mitochondria/*metabolism ; Unfolded Protein Response/*physiology ; }, abstract = {The endoplasmic reticulum (ER) is a multifunctional organelle involved in protein synthesis, processing and folding, in intracellular transport and calcium signalling. ER stress can be triggered by depletion of ER calcium content and the accumulation of un- and mis-folded proteins, and relays stress signals to the ER mitochondria calcium cycle (ERMCC) and to the nucleus and protein translation machinery. The ensuing unfolded protein response (UPR) helps to cope with ER stress. Total protein synthesis is inhibited to keep protein load low, while the synthesis of ER chaperones, which assist protein folding, is induced. If cell integrity cannot be restored, signal cascades mediating cell death are activated. This review focuses on the role of ER stress and the UPR in the pathology of amyotrophic lateral sclerosis (ALS). The triggers for ER stress are as yet unclear, but induction of UPR sensor proteins, up-regulation of chaperones and induction of cell death proteins have been described in human post mortem ALS tissue and in mutant superoxide dismutase-1 (SOD1) expressing models of ALS. TDP-43 and VAPB seem to be involved in UPR signalling as well. Recent reports raise hope that UPR sensor proteins become effective therapeutic targets in the treatment of ALS.}, }
@article {pmid22285784, year = {2012}, author = {Mitchell, CS and Lee, RH}, title = {Cargo distributions differentiate pathological axonal transport impairments.}, journal = {Journal of theoretical biology}, volume = {300}, number = {}, pages = {277-291}, pmid = {22285784}, issn = {1095-8541}, support = {NS069616/NS/NINDS NIH HHS/United States ; R01 NS062200/NS/NINDS NIH HHS/United States ; NS062200/NS/NINDS NIH HHS/United States ; R01 NS062200-03/NS/NINDS NIH HHS/United States ; K01 NS069616/NS/NINDS NIH HHS/United States ; K01 NS069616-01A1/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/physiopathology ; Animals ; Axonal Transport/*physiology ; Disease Models, Animal ; Humans ; Mice ; *Models, Neurological ; Molecular Motor Proteins/physiology ; Neurodegenerative Diseases/*physiopathology ; Neurofilament Proteins/physiology ; Protein Folding ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Axonal transport is an essential process in neurons, analogous to shipping goods, by which energetic and cellular building supplies are carried downstream (anterogradely) and wastes are carried upstream (retrogradely) by molecular motors, which act as cargo porters. Impairments in axonal transport have been linked to devastating and often lethal neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis, Huntington's, and Alzheimer's. Axonal transport impairment types include a decrease in available motors for cargo transport (motor depletion), the presence of defective or non-functional motors (motor dilution), and the presence of increased or larger cargos (protein aggregation). An impediment to potential treatment identification has been the inability to determine what type(s) of axonal transport impairment candidates that could be present in a given disease. In this study, we utilize a computational model and common axonal transport experimental metrics to reveal the axonal transport impairment general characteristics or "signatures" that result from three general defect types of motor depletion, motor dilution, and protein aggregation. Our results not only provide a means to discern these general impairments types, they also reveal key dynamic and emergent features of axonal transport, which potentially underlie multiple impairment types. The identified characteristics, as well as the analytical method, can be used to help elucidate the axonal transport impairments observed in experimental and clinical data. For example, using the model-predicted defect signatures, we identify the defect candidates, which are most likely to be responsible for the axonal transport impairments in the G93A SOD1 mouse model of ALS.}, }
@article {pmid22283698, year = {2012}, author = {Pandya, RS and Mao, LL and Zhou, EW and Bowser, R and Zhu, Z and Zhu, Y and Wang, X}, title = {Neuroprotection for amyotrophic lateral sclerosis: role of stem cells, growth factors, and gene therapy.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {12}, number = {1}, pages = {15-27}, pmid = {22283698}, issn = {1875-6166}, support = {K01 NS055072/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*therapy ; Animals ; Genetic Therapy/*methods/trends ; Humans ; Intercellular Signaling Peptides and Proteins/*physiology ; Neuroprotective Agents/*administration &amp; dosage/chemistry ; Stem Cell Transplantation/*methods/trends ; Stem Cells/*physiology ; }, abstract = {Various molecular mechanisms including apoptosis, inflammation, oxidative stress, mitochondrial dysfunction and excitotoxicity have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), though the exact mechanisms have yet to be specified. Furthermore, the underlying restorative molecular mechanisms resulting in neuronal and/or non-neuronal regeneration have to be yet elucidated. Therapeutic agents targeting one or more of these mechanisms to combat either initiation or progression of the disease are under research. Novel treatments including stem cell therapy, growth factors, and gene therapy might prolong survival and delay progression of symptoms. Harnessing the regenerative potential of the central nervous system would be a novel approach for the treatment of motor neuron death resulting from ALS. Endogenous neural replacement, if augmented with administration of exogenous growth factors or with pharmaceuticals that increase the rate of neural progenitor formation, neural migration, and neural maturation could slow the rate of cell loss enough to result in clinical improvement. In this review, we discuss the impact of therapeutic treatment involving stem cell therapy, growth factors, gene therapy, and combination therapy on disease onset and progression of ALS. In addition, we summarize human clinical trials of stem cell therapy, growth factor therapy, and gene therapy in individuals with ALS.}, }
@article {pmid22283411, year = {2012}, author = {Dreyer, PS and Felding, M and Klitnæs, CS and Lorenzen, CK}, title = {Withdrawal of invasive home mechanical ventilation in patients with advanced amyotrophic lateral sclerosis: ten years of Danish experience.}, journal = {Journal of palliative medicine}, volume = {15}, number = {2}, pages = {205-209}, doi = {10.1089/jpm.2011.0133}, pmid = {22283411}, issn = {1557-7740}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*therapy ; *Decision Making/ethics ; Deep Sedation ; Denmark ; Female ; *Home Care Services/ethics ; Humans ; Life Support Care/ethics ; Male ; Middle Aged ; Quadriplegia/*therapy ; *Respiration, Artificial/ethics ; Retrospective Studies ; *Withholding Treatment/ethics ; }, abstract = {BACKGROUND: Due to the growing use of home mechanical ventilation in amyotrophic lateral sclerosis (ALS), physicians are increasingly confronted with patients seeking discontinuation of therapy. Yet there are few systematic investigations of the withdrawal of invasive home mechanical ventilation (IHMV). This article aims to describe the medical and patient-related aspects of terminating IHMV in patients with advanced stage ALS.<br><br>METHODS: A retrospective, descriptive study was made of all ALS patients cared for at our center from 2002 to 2009 who decided to withdraw their consent for IHMV.<br><br>RESULTS: All 12 ALS patients (4 females) received continuous IHMV. They had a median age of 61 years (range, 39-69 years). In all cases advance directives for end of life care, particularly concerning withdrawal of treatment, were discussed before the initiation of IHMV. The median time from initiation of IHMV to the decision to terminate treatment was 22 months (range, 1-35 months). The reasons for requests were for all patients a general loss of "meaning in life." Deep sedation was achieved with high dose morphine and diazepam before disconnecting the ventilator.<br><br>CONCLUSION: Patients' requests for the withdrawal of IHMV in advanced stage ALS was related to a perceived "loss of meaning in life." Termination of treatment was performed under deep sedation as a medically, legally, and ethically justified procedure.}, }
@article {pmid22277481, year = {2011}, author = {Yamamoto, T}, title = {[Evaluation and treatment of dysphagia in amyotrophic lateral sclerosis and Parkinson's disease].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {51}, number = {11}, pages = {1072-1074}, doi = {10.5692/clinicalneurol.51.1072}, pmid = {22277481}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Deglutition Disorders/*etiology/*physiopathology/therapy ; Humans ; Parkinson Disease/*complications ; }, abstract = {As both amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) exhibit a variety of patterns of dysphagia, appropriate symptomatic treatment is provided after evaluation of swallowing function through videofluoroscopic examination of swallowing. In ALS, disease progression is rapid, therefore, respiratory function, swallowing function and nutritional status should be evaluated regularly. When the oral or pharyngeal stage of swallowing are affected early in dysphagia, adjusting swallowing volume and varying consistency can be beneficial in ALS. When all stages of swallowing are impaired in ALS, such complications as pneumonia, dehydration and malnutrition, are observed. In such patients, it is necessary to consider an alternative to oral dietary intake. In PD, dysphagia is not necessarily associated with severity of parkinsonism and can appear at any time during the course of the disease. Dysphagia in PD can occur at any stage of swallowing and frequently accompanies multiple abnormalities. In particular, aspiration is an important risk factor for pneumonia in PD. The effect of L-dopa treatment for dysphagia is often insufficient; however, this treatment remains the first choice because dysphagia is exacerbated during off state. Rehabilitation for dysphagia in PD has also some effect.}, }
@article {pmid22277466, year = {2011}, author = {Komori, T}, title = {[Several approaches for quality of life in intractable disease].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {51}, number = {11}, pages = {1024-1026}, doi = {10.5692/clinicalneurol.51.1024}, pmid = {22277466}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; *Nervous System Diseases/physiopathology ; *Quality of Life ; }, abstract = {Life quality is various among patients. In this article, it is shown that several progresses of both physical and psychological care for those patients during resent 15 years which we have had Japanese National Project for the quality of life in intractable diseases. Of course total cure of the disease is the best for the patients, but the second best is continuous better patient care. Total respiratory care of amyotrophic lateral sclerosis including non-invasive positive pressure ventilation and systematic approach of respiratory rehabilitation are good examples of better physical care. The approach with SEIQoL-DW is another good trial to evaluate and maintain their psychological condition. These should be also useful to another intractable diseases such as multi-system atrophy, spino-cerebellar atrophy or Parkinson disease. Long term contribution of multi-disciplinary care team of individual patient has to be needed to make the better effort for the patient support now. We should have more options of treatment, rehabilitation or social life support those with which the patients could decide to have their favorable life with intractable disease.}, }
@article {pmid22276904, year = {2012}, author = {Gnanapavan, S and Grant, D and Pryce, G and Jackson, S and Baker, D and Giovannoni, G}, title = {Neurofilament a biomarker of neurodegeneration in autoimmune encephalomyelitis.}, journal = {Autoimmunity}, volume = {45}, number = {4}, pages = {298-303}, doi = {10.3109/08916934.2012.654865}, pmid = {22276904}, issn = {1607-842X}, mesh = {Amyotrophic Lateral Sclerosis/pathology ; Animals ; Autoantibodies/blood ; Biomarkers/blood ; Disease Models, Animal ; Disease Progression ; Encephalomyelitis, Autoimmune, Experimental/blood/*immunology/*pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Multiple Sclerosis/pathology ; Neurodegenerative Diseases/blood/*immunology/*pathology ; Neurofilament Proteins/*blood/immunology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Monitoring neuroaxonal loss in multiple sclerosis is an important objective to study the pathogenesis and response to treatment of the disease. The release of neurofilaments is a potential surrogate biomarker of neurodegeneration. One route to explore this aspect further is through the use of animal models that have well-defined, and predictable, disease courses. The release of neurofilaments into plasma across the course of relapsing-remitting and secondary progressive experimental autoimmune encephalomyelitis in Biozzi ABH was assessed, as well as measuring anti-neurofilament antibodies using ELISA. It was found that there was an immediate release in neurofilaments into the blood following the initial paralytic attack. Neurofilament release was continuous in relapse and remission but returned towards baseline in chronic disease, as animals entered the post-relapsing progressive phase of the disease. This was mirrored by a loss of neurofilament-specific antibodies. In contrast neurofilament levels increased dramatically as neurodegeneration and clinical disease occurred in the G93A SOD1 transgenic C57BL/6 x SJL mice, model of amyotrophic lateral sclerosis. These data further support neurofilament levels as a good surrogate measure of neurodegeneration and their potential use as a surrogate endpoint in neuroprotective studies.}, }
@article {pmid22271664, year = {2012}, author = {Roche, JC and Rojas-Garcia, R and Scott, KM and Scotton, W and Ellis, CE and Burman, R and Wijesekera, L and Turner, MR and Leigh, PN and Shaw, CE and Al-Chalabi, A}, title = {A proposed staging system for amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {135}, number = {Pt 3}, pages = {847-852}, pmid = {22271664}, issn = {1460-2156}, support = {089701//Wellcome Trust/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; G0701923/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Age of Onset ; Aged ; Amyotrophic Lateral Sclerosis/classification/diagnosis/*pathology ; Cohort Studies ; Disease Progression ; Female ; Follow-Up Studies ; Gastrostomy ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Models, Statistical ; Patient Selection ; Prognosis ; Reproducibility of Results ; Respiration, Artificial ; Sex Factors ; Survival Analysis ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons, with a median survival of 2-3 years. Although various phenotypic and research diagnostic classification systems exist and several prognostic models have been generated, there is no staging system. Staging criteria for amyotrophic lateral sclerosis would help to provide a universal and objective measure of disease progression with benefits for patient care, resource allocation, research classifications and clinical trial design. We therefore sought to define easily identified clinical milestones that could be shown to occur at specific points in the disease course, reflect disease progression and impact prognosis and treatment. A tertiary referral centre clinical database was analysed, consisting of 1471 patients with amyotrophic lateral sclerosis seen between 1993 and 2007. Milestones were defined as symptom onset (functional involvement by weakness, wasting, spasticity, dysarthria or dysphagia of one central nervous system region defined as bulbar, upper limb, lower limb or diaphragmatic), diagnosis, functional involvement of a second region, functional involvement of a third region, needing gastrostomy and non-invasive ventilation. Milestone timings were standardized as proportions of time elapsed through the disease course using information from patients who had died by dividing time to a milestone by disease duration. Milestones occurred at predictable proportions of the disease course. Diagnosis occurred at 35% through the disease course, involvement of a second region at 38%, a third region at 61%, need for gastrostomy at 77% and need for non-invasive ventilation at 80%. We therefore propose a simple staging system for amyotrophic lateral sclerosis. Stage 1: symptom onset (involvement of first region); Stage 2A: diagnosis; Stage 2B: involvement of second region; Stage 3: involvement of third region; Stage 4A: need for gastrostomy; and Stage 4B: need for non-invasive ventilation. Validation of this staging system will require further studies in other populations, in population registers and in other clinic databases. The standardized times to milestones may well vary between different studies and populations, although the stages themselves and their meanings are likely to remain unchanged.}, }
@article {pmid22262194, year = {2012}, author = {Romi, F and Helgeland, G and Gilhus, NE}, title = {Serum levels of matrix metalloproteinases: implications in clinical neurology.}, journal = {European neurology}, volume = {67}, number = {2}, pages = {121-128}, doi = {10.1159/000334862}, pmid = {22262194}, issn = {1421-9913}, mesh = {Humans ; Matrix Metalloproteinases/*blood ; Nervous System Diseases/*blood/*enzymology ; }, abstract = {Matrix metalloproteinases (MMPs) are zinc-dependent enzymes involved in remodeling extracellular matrix and cell-matrix interactions. A pathogenic role of MMPs in neurological disorders is likely. This paper focuses on serological clinical aspects only. In multiple sclerosis, higher serum MMP-3 is seen during relapses. Lower serum MMP-8 and -9 levels correlate with fewer contrast-enhanced T(2)-weighted MRI lesions, and serum MMP-9 can be used in monitoring treatment. In myasthenia gravis, serum MMP-2, -3, and -9 levels are elevated in both generalized and ocular diseases. A proportion of the patients have markedly increased serum MMP-3. In acute stroke, higher serum MMP-9 correlates with larger infarct volume, stroke severity, and worse functional outcome, and serum MMP-3 is significantly lower than in several other neurological disorders and healthy controls. In amyotrophic lateral sclerosis, serum MMP-2 correlates with disease progression, and both serum MMP-1 and -2 are elevated. In Alzheimer's disease, serum MMP-3, -9, and -10 are elevated. In migraine, serum MMP-2 is elevated, and also MMP-9 in those patients with migraine without aura. MMP-9 is implicated in the pathogenesis of experimental epilepsy. A pathogenic role of MMPs in these conditions could be related to their ability to degrade extracellular matrix. MMPs may also facilitate autoimmunity.}, }
@article {pmid22252449, year = {2012}, author = {Mueller, C and Tang, Q and Gruntman, A and Blomenkamp, K and Teckman, J and Song, L and Zamore, PD and Flotte, TR}, title = {Sustained miRNA-mediated knockdown of mutant AAT with simultaneous augmentation of wild-type AAT has minimal effect on global liver miRNA profiles.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {20}, number = {3}, pages = {590-600}, pmid = {22252449}, issn = {1525-0024}, support = {HL69877/HL/NHLBI NIH HHS/United States ; P30 DK032520/DK/NIDDK NIH HHS/United States ; P30 DK32520/DK/NIDDK NIH HHS/United States ; R37 GM062862/GM/NIGMS NIH HHS/United States ; R01 HL069877/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Base Sequence ; Dependovirus/genetics ; *Gene Expression Profiling ; Gene Expression Regulation ; Gene Knockdown Techniques ; Gene Order ; *Gene Silencing ; Gene Transfer Techniques ; Genetic Vectors/genetics ; Humans ; Liver/*metabolism ; Mice ; Mice, Transgenic ; MicroRNAs/chemistry/*genetics/*metabolism ; Mutation ; alpha 1-Antitrypsin/*genetics ; }, abstract = {α-1 antitrypsin (AAT) deficiency can exhibit two pathologic states: a lung disease that is primarily due to the loss of AAT's antiprotease function, and a liver disease resulting from a toxic gain-of-function of the PiZ-AAT (Z-AAT) mutant protein. We have developed several recombinant adeno-associated virus (rAAV) vectors that incorporate microRNA (miRNA) sequences targeting the AAT gene while also driving the expression of miRNA-resistant wild-type AAT-PiM (M-AAT) gene, thus achieving concomitant Z-AAT knockdown in the liver and increased expression of M-AAT. Transgenic mice expressing the human PiZ allele treated with dual-function rAAV9 vectors showed that serum PiZ was stably and persistently reduced by an average of 80%. Treated animals showed knockdown of Z-AAT in liver and serum with concomitant increased serum M-AAT as determined by allele-specific enzyme-linked immunosorbent assays (ELISAs). In addition, decreased globular accumulation of misfolded Z-AAT in hepatocytes and a reduction in inflammatory infiltrates in the liver was observed. Results from microarray studies demonstrate that endogenous miRNAs were minimally affected by this treatment. These data suggests that miRNA mediated knockdown does not saturate the miRNA pathway as has been seen with viral vector expression of short hairpin RNAs (shRNAs). This safe dual-therapy approach can be applied to other disorders such as amyotrophic lateral sclerosis, Huntington disease, cerebral ataxia, and optic atrophies.}, }
@article {pmid22245498, year = {2012}, author = {Berger, JV and Dumont, AO and Focant, MC and Vergouts, M and Sternotte, A and Calas, AG and Goursaud, S and Hermans, E}, title = {Opposite regulation of metabotropic glutamate receptor 3 and metabotropic glutamate receptor 5 by inflammatory stimuli in cultured microglia and astrocytes.}, journal = {Neuroscience}, volume = {205}, number = {}, pages = {29-38}, doi = {10.1016/j.neuroscience.2011.12.044}, pmid = {22245498}, issn = {1873-7544}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Animals ; Animals, Newborn ; Astrocytes/metabolism/*physiology ; Gene Expression Regulation/physiology ; Humans ; Inflammation Mediators/*physiology ; Microglia/metabolism/*physiology ; Primary Cell Culture ; Rats ; Rats, Sprague-Dawley ; Rats, Transgenic ; Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate/genetics/*metabolism ; }, abstract = {Metabotropic glutamate receptors (mGluRs) were previously shown to modulate several essential functions in glial cells, including cell proliferation, glutamate uptake, neurotrophic support, and inflammatory responses. As these receptors are regularly proposed as promising targets for the treatment of a wide range of neurological disorders, we herein examined the reciprocal modulation of glial mGluRs by inflammation. Such regulation of mGluRs was also studied in cultures from an experimental model of amyotrophic lateral sclerosis (ALS). Indeed, ALS is characterized by increased neuroinflammation, and glial cell cultures derived from the animal model (rat expressing hSOD1(G93A)) show enhanced glial reactivity. Within 72 h, the pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) induced an increase in mGluR3 and a decrease in mGluR5 gene expression. A similar regulation of these receptors was observed in microglia 48 h after an initial 4-h exposure to lipopolysaccharide. In hSOD1(G93A)-derived glial cultures, the gene up-regulation of mGluR3 (but not the gene down-regulation of mGluR5) was found to be enhanced in both astrocytes and microglia. Together, these results indicate that an inflammatory environment triggers an opposite regulation in the gene expression of the two predominant mGluR subtypes found in glial cells, and that these regulations were particularly robust in hSOD1(G93A) glial cultures. As neuroinflammation commonly occurs in several nervous diseases, its influence on mGluR expression should be taken into account when considering these receptors as future drug targets.}, }
@article {pmid22230045, year = {2012}, author = {Audet, JN and Soucy, G and Julien, JP}, title = {Methylene blue administration fails to confer neuroprotection in two amyotrophic lateral sclerosis mouse models.}, journal = {Neuroscience}, volume = {209}, number = {}, pages = {136-143}, doi = {10.1016/j.neuroscience.2011.12.047}, pmid = {22230045}, issn = {1873-7544}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Antioxidants/*pharmacology ; Blotting, Western ; DNA-Binding Proteins/metabolism ; Disease Models, Animal ; Drug Therapy, Combination ; Enzyme Inhibitors/pharmacology ; Immunohistochemistry ; Lithium/administration &amp; dosage ; Methylene Blue/*pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Spinal Cord/pathology ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Approximately 20% cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Recent studies have shown that methylene blue (MB) was efficient in conferring protection in several neurological disorders. MB was found to improve mitochondrial function, to reduce reactive oxygen species, to clear aggregates of toxic proteins, and to act as a nitric oxide synthase inhibitor. These pleiotropic effects of relevance to ALS pathogenesis led us to test MB in two models of ALS, SOD1(G93A) mice and TDP-43(G348C) transgenic mice. Intraperitoneal administration of MB at two different doses was initiated at the beginning of disease onset, at 90 days of age in SOD1(G93A) and at 6 months of age in TDP-43(G348C) mice. Despite its established neuroprotective properties, MB failed to confer protection in both mouse models of ALS. The lifespan of SOD1(G93A) mice was not affected by MB treatment. The declines in motor function, reflex score, and body weight of SOD1(G93A) mice remained unchanged. MB treatment had no effect on motor neuron loss and aggregation or misfolding of SOD1. A combination of MB with lithium also failed to provide benefits in SOD1(G93A) mice. In TDP-43(G348C) mice, MB failed to improve motor function. Cytosolic translocation of TDP-43, ubiquitination and inflammation remained also unchanged after MB treatment of TDP-43(G348C) mice.}, }
@article {pmid22214450, year = {2012}, author = {Bařinka, C and Rojas, C and Slusher, B and Pomper, M}, title = {Glutamate carboxypeptidase II in diagnosis and treatment of neurologic disorders and prostate cancer.}, journal = {Current medicinal chemistry}, volume = {19}, number = {6}, pages = {856-870}, pmid = {22214450}, issn = {1875-533X}, support = {R01 CA134675/CA/NCI NIH HHS/United States ; CA 134675/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Glutamate Carboxypeptidase II/antagonists &amp; inhibitors/*metabolism ; Humans ; Male ; Nervous System Diseases/diagnosis/drug therapy/*metabolism ; Prostatic Neoplasms/diagnosis/drug therapy/*metabolism ; }, abstract = {Glutamate carboxypeptidase II (GCPII) is a membrane-bound binuclear zinc metallopeptidase with the highest expression levels found in the nervous and prostatic tissue. Throughout the nervous system, glia-bound GCPII is intimately involved in the neuron-neuron and neuron-glia signaling via the hydrolysis of N-acetylaspartylglutamate (NAAG), the most abundant mammalian peptidic neurotransmitter. The inhibition of the GCPII-controlled NAAG catabolism has been shown to attenuate neurotoxicity associated with enhanced glutamate transmission and GCPII-specific inhibitors demonstrate efficacy in multiple preclinical models including traumatic brain injury, stroke, neuropathic and inflammatory pain, amyotrophic lateral sclerosis, and schizophrenia. The second major area of pharmacological interventions targeting GCPII focuses on prostate carcinoma; GCPII expression levels are highly increased in androgen-independent and metastatic disease. Consequently, the enzyme serves as a potential target for imaging and therapy. This review offers a summary of GCPII structure, physiological functions in healthy tissues, and its association with various pathologies. The review also outlines the development of GCPII-specific small-molecule compounds and their use in preclinical and clinical settings.}, }
@article {pmid22212489, year = {2012}, author = {Kassa, R and Monterroso, V and Wentzell, J and Ramos, AL and Couchi, E and Lecomte, MC and Iordanov, M and Kretzschmar, D and Nicolas, G and Tshala-Katumbay, D}, title = {Proximal giant neurofilamentous axonopathy in mice genetically engineered to resist calpain and caspase cleavage of α-II spectrin.}, journal = {Journal of molecular neuroscience : MN}, volume = {47}, number = {3}, pages = {631-638}, pmid = {22212489}, issn = {1559-1166}, support = {K01 NS052183/NS/NINDS NIH HHS/United States ; K01 NS052183-04/NS/NINDS NIH HHS/United States ; R01 GM089859/GM/NIGMS NIH HHS/United States ; NS052183/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/chemically induced/enzymology/genetics ; Animals ; Calpain/*genetics/metabolism ; Carrier Proteins/genetics/*metabolism ; Caspases/*genetics/metabolism ; Disease Models, Animal ; Genetic Engineering/*methods ; Giant Axonal Neuropathy/chemically induced/enzymology/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Microfilament Proteins/genetics/*metabolism ; Spectrin/genetics/*metabolism ; }, abstract = {We use 1,2-diacetylbenzene (1,2-DAB) to probe molecular mechanisms of proximal giant neurofilamentous axonopathy (PGNA), a pathological hallmark of amyotrophic lateral sclerosis. The spinal cord proteome of rodents displaying 1,2-DAB PGNA suggests a reduction in the abundance of α-II spectrin (Spna2), a key protein in the maintenance of axonal integrity. Protein immunoblotting indicates that this reduction is due to Spna2 degradation. We investigated the importance of such degradation in 1,2-DAB PGNA. Spna2 mutant mice lacking a calpain- and/or caspase-sensitive domain (CSD), thus hypothetically resistant to 1,2-DAB, and wild-type littermates, were treated with 1,2-DAB, 35 mg/kg/day, or saline control, for 3 weeks. 1,2-DAB induced motor weakness and PGNA, irrespective of the genotype. Spna2-calpain breakdown products were not detected in mutant mice, which displayed a normal structure of the nervous system under saline treatment. Intriguingly, treatment with 1,2-DAB reduced the abundance of the caspase-specific 120-kDa Spna2 breakdown products. Our findings indicate that degradation of Spna2 by calpain- and/or caspase is not central to the pathogenesis of 1,2-DAB axonopathy. In addition, the Spna2-CSD seems to be not required for the maintenance of the cytoskeleton integrity. Our conceptual framework offers opportunities to study the role of calpain-caspase cross talk, including that of the protease degradomics, in models of axonal degeneration.}, }
@article {pmid22210713, year = {2012}, author = {Willenbrock, S and Knippenberg, S and Meier, M and Hass, R and Wefstaedt, P and Nolte, I and Murua Escobar, H and Petri, S}, title = {In vivo MRI of intraspinally injected SPIO-labelled human CD34+ cells in a transgenic mouse model of ALS.}, journal = {In vivo (Athens, Greece)}, volume = {26}, number = {1}, pages = {31-38}, pmid = {22210713}, issn = {1791-7549}, mesh = {Amyotrophic Lateral Sclerosis/*diagnostic imaging/genetics/*surgery ; Animals ; Antigens, CD34/metabolism ; Cell Count ; Cell Line ; Cell Movement ; Contrast Media ; Cord Blood Stem Cell Transplantation/*methods ; Disease Models, Animal ; Ferric Compounds ; Fetal Blood/cytology/metabolism ; Humans ; Magnetic Resonance Imaging/instrumentation/*methods ; Magnetite Nanoparticles ; Mice ; Mice, Transgenic ; Mutation ; Phantoms, Imaging ; Radiography ; Superoxide Dismutase/genetics ; Time Factors ; }, abstract = {BACKGROUND/AIM: Administration of stem cells is a promising novel approach for treatment of neurodegenerative diseases. For in vivo monitoring of transplanted cells, non-invasive imaging modalities are needed. In this study we determined the tracking efficiency of a superparamagnetic iron oxide (SPIO)-labelled canine cell line (MTH53A) in vitro as well as the human CD34(+) umbilical cord blood stem cells (hUCBCs) in vitro and in vivo efficiency by magnetic resonance imaging (MRI).<br><br>MATERIALS AND METHODS: SPIO-labelled MTH53A cells and hUCBCs were scanned in agar gel phantoms at 1.0 T or 7.0 T. For in vivo detection, 100,000 labelled hUCBCs were injected into the spinal cord of a transgenic amyotrophic lateral sclerosis (ALS) mouse and scanned at 7.0 T.<br><br>RESULTS: In vitro, 100,000 MTH53A cells and 250,000 hUCBCs were visible at 1.0 T. Scanning with 7.0 T revealed 25,000 detectable MTH53A cells. In vivo, 7.0 T MRI showed clear signals of 100,000 implanted cells.<br><br>CONCLUSION: MRI combined with SPIO nanoparticles provides valuable potential for non-invasive, non-toxic in vivo tracking of cells implanted into the spinal cord.}, }
@article {pmid22206942, year = {2012}, author = {Fontanilla, CV and Wei, X and Zhao, L and Johnstone, B and Pascuzzi, RM and Farlow, MR and Du, Y}, title = {Caffeic acid phenethyl ester extends survival of a mouse model of amyotrophic lateral sclerosis.}, journal = {Neuroscience}, volume = {205}, number = {}, pages = {185-193}, doi = {10.1016/j.neuroscience.2011.12.025}, pmid = {22206942}, issn = {1873-7544}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/*physiopathology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use ; Caffeic Acids/*pharmacology/therapeutic use ; Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Mice, Transgenic ; Neuroprotective Agents/pharmacology/therapeutic use ; Phenylethyl Alcohol/*analogs &amp; derivatives/pharmacology/therapeutic use ; Survival Rate ; Treatment Outcome ; }, abstract = {There is currently very limited effective pharmacological treatment for amyotrophic lateral sclerosis. Recent evidence suggests that caffeic acid phenethyl ester has strong anti-inflammatory, anti-oxidative, and anti-neuronal death properties; thus, the present study tested the effects of caffeic acid phenethyl ester in mice expressing a mutant superoxide dismutase (SOD1(G93A)) linked to human amyotrophic lateral sclerosis. Administration of caffeic acid phenethyl ester after symptom onset significantly increased the post-onset survival and lifespan of SOD1(G93A) mice. Moreover, immunohistochemical analysis detected less activation of microglia and astrocytes and higher motor neuron counts at an early symptomatic stage (7 days following onset) in the spinal cords of SOD1(G93A) mice given caffeic acid phenethyl ester treatment. Additionally, lower levels of phosphorylated p38, a mitogen-activated protein kinase that is involved in both inflammation and neuronal death, were observed in the spinal cords of SOD1(G93A) mice treated with caffeic acid phenethyl ester for 7 days. These results indicate that caffeic acid phenethyl ester may represent a novel and effective therapeutic for the treatment of amyotrophic lateral sclerosis, and these significant neuroprotective effects observed in a commonly used amyotrophic lateral sclerosis mouse model validate the therapeutic potential of caffeic acid phenethyl ester for slowing disease progression by attenuating the neuroinflammation and motor neuron cell death associated with clinical amyotrophic lateral sclerosis pathology.}, }
@article {pmid22196509, year = {2011}, author = {Liang, S and Christner, D and Du Laux, S and Laurent, D}, title = {Significant neurological improvement in two patients with amyotrophic lateral sclerosis after 4 weeks of treatment with acupuncture injection point therapy using enercel.}, journal = {Journal of acupuncture and meridian studies}, volume = {4}, number = {4}, pages = {257-261}, doi = {10.1016/j.jams.2011.09.017}, pmid = {22196509}, issn = {2093-8152}, mesh = {*Acupuncture Points ; Amyotrophic Lateral Sclerosis/*drug therapy ; Female ; Humans ; Injections ; Male ; Middle Aged ; Plant Extracts/*administration &amp; dosage ; Plants, Medicinal/*chemistry ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, uniformly fatal, degenerative disorder of the upper motor neurons that does not currently have an effective treatment regimen. Here, we report two patients with ALS who were treated with 4 weeks of acupuncture injection point therapy using Enercel. These patients were administered 0.25-0.5 cc Enercel Plus IM to specific acupuncture points for 5 days per week for 4 weeks. Patient #1 presented with flaccid paralysis of all four extremities and impaired speech and swallowing. By Week 4, she demonstrated significant improvement in her motor strength in all four extremities (R>L) and improved speech and swallowing. However, she did not continue to receive the Enercel acupoint injections, and she subsequently demonstrated a slow, progressive loss of neurological function during the ensuing 3 months, as shown on follow-up examinations. Patient #2 had significantly impaired speech and mild motor loss in the upper extremities and the left leg. After 4 weeks of treatment, his voice had significantly improved to the point where his speech was understandable and his motor functions had returned to normal. He continued receiving Enercel acupoint injections during the 3-month follow-up period and his clinical improvements were maintained. Thus, these two patients with ALS showed clinical improvements after 4 weeks of Enercel acupoint injection therapy. Follow-up data suggests that ongoing therapy may be necessary in order to maintain these positive effects. This preliminary study merits further study and confirmation.}, }
@article {pmid22191331, year = {2012}, author = {Chen, T and Benmohamed, R and Kim, J and Smith, K and Amante, D and Morimoto, RI and Kirsch, DR and Ferrante, RJ and Silverman, RB}, title = {ADME-guided design and synthesis of aryloxanyl pyrazolone derivatives to block mutant superoxide dismutase 1 (SOD1) cytotoxicity and protein aggregation: potential application for the treatment of amyotrophic lateral sclerosis.}, journal = {Journal of medicinal chemistry}, volume = {55}, number = {1}, pages = {515-527}, pmid = {22191331}, issn = {1520-4804}, support = {R43 NS057849/NS/NINDS NIH HHS/United States ; 1R43NS057849/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Blood-Brain Barrier/metabolism ; Caco-2 Cells ; Cell Membrane Permeability ; Cytochrome P-450 Enzyme Inhibitors ; Drug Design ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels/antagonists &amp; inhibitors ; Ethers/chemical synthesis/pharmacokinetics/pharmacology ; HEK293 Cells ; Humans ; In Vitro Techniques ; Mice ; Microsomes, Liver/metabolism ; Mutation ; Neurons/cytology/drug effects ; Pyrazoles/*chemical synthesis/pharmacokinetics/pharmacology ; Pyrazolones/*chemical synthesis/pharmacokinetics/pharmacology ; Rats ; Rats, Sprague-Dawley ; Solubility ; Structure-Activity Relationship ; Sulfones/chemical synthesis/pharmacokinetics/pharmacology ; Superoxide Dismutase/*antagonists &amp; inhibitors/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure. The arylsulfanyl pyrazolone (ASP) scaffold was one of the active scaffolds identified in a cell-based high throughput screening assay targeting mutant Cu/Zn superoxide dismutase 1 (SOD1) induced toxicity and aggregation as a marker for ALS. The initial ASP hit compounds were potent and had favorable ADME properties but had poor microsomal and plasma stability. Here, we identify the microsomal metabolite and describe synthesized analogues of these ASP compounds to address the rapid metabolism. Both in vitro potency and pharmacological properties of the ASP scaffold have been dramatically improved via chemical modification to the corresponding sulfone and ether derivatives. One of the ether analogues (13), with superior potency and in vitro pharmacokinetic properties, was tested in vivo for its pharmacokinetic profile, brain penetration, and efficacy in an ALS mouse model. The analogue showed sustained blood and brain levels in vivo and significant activity in the mouse model of ALS, thus validating the new aryloxanyl pyrazolone scaffold as an important novel therapeutic lead for the treatment of this neurodegenerative disorder.}, }
@article {pmid22189273, year = {2012}, author = {Zhang, W and Benmohamed, R and Arvanites, AC and Morimoto, RI and Ferrante, RJ and Kirsch, DR and Silverman, RB}, title = {Cyclohexane 1,3-diones and their inhibition of mutant SOD1-dependent protein aggregation and toxicity in PC12 cells.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {20}, number = {2}, pages = {1029-1045}, pmid = {22189273}, issn = {1464-3391}, support = {R43 NS057849/NS/NINDS NIH HHS/United States ; R43 NS057849-01A1/NS/NINDS NIH HHS/United States ; 1R43NS057849/NS/NINDS NIH HHS/United States ; AL093052//PHS HHS/United States ; }, mesh = {Amino Acid Substitution ; Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Blood-Brain Barrier/metabolism ; Cyclohexanones/*chemistry/*pharmacology/therapeutic use/toxicity ; Cyclopropanes/*chemistry/therapeutic use/toxicity ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Mutation ; Neurons/drug effects ; PC12 Cells ; Phenyl Ethers/*chemistry/therapeutic use/toxicity ; Rats ; Superoxide Dismutase/*antagonists &amp; inhibitors/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Currently, there is only one FDA-approved treatment for ALS (riluzole), and that drug only extends life, on average, by 2-3 months. Mutations in Cu/Zn superoxide dismutase (SOD1) are found in familial forms of the disease and have played an important role in the study of ALS pathophysiology. On the basis of their activity in a PC12-G93A-YFP high-throughput screening assay, several bioactive compounds have been identified and classified as cyclohexane-1,3-dione (CHD) derivatives. A concise and efficient synthetic route has been developed to provide diverse CHD analogs. The structural modification of the CHD scaffold led to the discovery of a more potent analog (26) with an EC(50) of 700 nM having good pharmacokinetic properties, such as high solubility, low human and mouse metabolic potential, and relatively good plasma stability. It was also found to efficiently penetrate the blood-brain barrier. However, compound 26 did not exhibit any significant life span extension in the ALS mouse model. It was found that, although 26 was active in PC12 cells, it had poor activity in other cell types, including primary cortical neurons, indicating that it can penetrate into the brain, but is not active in neuronal cells, potentially due to poor selective cell penetration. Further structural modification of the CHD scaffold was aimed at improving global cell activity as well as maintaining potency. Two new analogs (71 and 73) were synthesized, which had significantly enhanced cortical neuronal cell permeability, as well as similar potency to that of 26 in the PC12-G93A assay. These CHD analogs are being investigated further as novel therapeutic candidates for ALS.}, }
@article {pmid22166418, year = {2012}, author = {Youdim, MB}, title = {M30, a brain permeable multitarget neurorestorative drug in post nigrostriatal dopamine neuron lesion of parkinsonism animal models.}, journal = {Parkinsonism &amp; related disorders}, volume = {18 Suppl 1}, number = {}, pages = {S151-4}, doi = {10.1016/S1353-8020(11)70047-5}, pmid = {22166418}, issn = {1873-5126}, mesh = {Animals ; Corpus Striatum/drug effects/*metabolism ; *Disease Models, Animal ; Dopaminergic Neurons/*drug effects/*metabolism/pathology ; Drug Delivery Systems/methods ; Humans ; Hydroxyquinolines/administration &amp; dosage/*metabolism ; Mice ; Parkinsonian Disorders/*drug therapy/*metabolism/pathology ; Permeability/drug effects ; Substantia Nigra/drug effects/*metabolism/pathology ; }, abstract = {The anti-Parkinson iron chelator brain selective monoamine oxidase (MAO) AB inhibitor M30 [5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline] was shown to possess neuroprotective activities in vitro and in vivo, against several insults applicable to several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease (PD) and ALS. We examined the effect of M30 on a pre-existing lesion induced by the parkinsonism-inducing toxin, MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In this neurorescue/neurorestorative paradigm, M30 was orally administered to mice for 14 days (2.5-5 mg/kg/day) following post MPTP or lactacystin lesion and was shown to significantly elevate striatal dopamine, serotonin and noradrenaline levels, reduce their metabolism, and elevate tyrosine-hydroxylase protein levels. Importantly, M30 elevated MPTP-reduced dopaminergic and transferrin receptor cell count in the substantia nigra pars compacta (SNpc). Finally, M30 was shown to decrease mitosis and elevate HIF (hypoxia induced factor) which regulates the neurotrophins BDNF, GDNF, VEGF and erythropoietin by elevating their brain levels, thus providing additional protection. These findings indicates that brain-permeable M30 has neurorestorative activity, which may clearly be of clinical importance for the treatment of PD.}, }
@article {pmid22183268, year = {2012}, author = {Pagnini, F and Lunetta, C and Banfi, P and Rossi, G and Fossati, F and Marconi, A and Castelnuovo, G and Corbo, M and Molinari, E}, title = {Pain in Amyotrophic Lateral Sclerosis: a psychological perspective.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {33}, number = {5}, pages = {1193-1196}, pmid = {22183268}, issn = {1590-3478}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*psychology ; Humans ; Pain/*etiology/*psychology ; Quality of Life ; Surveys and Questionnaires ; }, abstract = {Pain in Amyotrophic Lateral Sclerosis is often underestimated and untreated by clinicians and few studies have investigated its specific features and impact. Pain experience was investigated with the Italian Questionnaire of Pain, together with the McGill Quality of Life Questionnaire for quality of life (QoL), at a baseline and at a 4-month follow-up. About half of ALS patients reported pain, described as nagging, sore, annoying, boring and exhausting, with periodic but enduring episodes. Pain was related with QoL and its intensity was able to predict QoL worsening. Obtained results indicate the importance of clinical investigation of pain in ALS patients and of the intervention with anti-pain treatment whenever necessary.}, }
@article {pmid22180738, year = {2011}, author = {Naumenko, N and Pollari, E and Kurronen, A and Giniatullina, R and Shakirzyanova, A and Magga, J and Koistinaho, J and Giniatullin, R}, title = {Gender-Specific Mechanism of Synaptic Impairment and Its Prevention by GCSF in a Mouse Model of ALS.}, journal = {Frontiers in cellular neuroscience}, volume = {5}, number = {}, pages = {26}, pmid = {22180738}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motoneurons which progresses differentially in males and females for unknown reason. Here we measured gender differences in pre- and post-synaptic parameters of the neuromuscular transmission in a mutant G93A-SOD1 mouse model of ALS. Using intracellular microelectrode technique we recorded miniature and evoked end-plate potentials (MEPPs and EPPs) in the diaphragm muscle of G93A-SOD1 mice at early symptomatic stage. While no evident alterations in the amplitude of MEPPs was observed in male or female G93A-SOD1 mice, G93A-SOD1 mice displayed dramatically reduced probability of spontaneous acetylcholine release. In contrast, the EPPs evoked by single nerve stimulation had unchanged amplitude and quantal content. In males, but not females, this was accompanied by reduced readily releasable transmitter pool. Transmitter release in both sexes was sensitive to the inhibitory action of reactive oxygen species (ROS), but the production of ROS was increased in the spinal cords of male but not female G93A-SOD1 mice. Treatment with granulocyte colony stimulating factor (GCSF), which we previously found to be beneficial in males, attenuated the increased ROS production indicating involvement of the antioxidant mechanisms and improved ALS-induced synaptic dysfunctions only in males being ineffective in females. Consistent with our findings at synaptic level, GCSF did not change the survival rate or motor performance of female ALS mice. In summary, neuromuscular transmission in ALS mice is impaired at early symptomatic stage when a dramatic presynaptic decline of spontaneous release occurs. Beneficial effects of GCSF treatment on survival in males may be explained by GCSF-improved presynaptic functions in male G93A-SOD1 mice. Development of efficient treatment strategies for ALS may need to be directed in a gender-specific manner.}, }
@article {pmid22179976, year = {2012}, author = {Bachurin, SO and Shelkovnikova, TA and Ustyugov, AA and Peters, O and Khritankova, I and Afanasieva, MA and Tarasova, TV and Alentov, II and Buchman, VL and Ninkina, NN}, title = {Dimebon slows progression of proteinopathy in γ-synuclein transgenic mice.}, journal = {Neurotoxicity research}, volume = {22}, number = {1}, pages = {33-42}, pmid = {22179976}, issn = {1476-3524}, support = {//Wellcome Trust/United Kingdom ; 075615//Wellcome Trust/United Kingdom ; 116/ALZS_/Alzheimer's Society/United Kingdom ; 075615/Z/04/z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Disease Models, Animal ; Disease Progression ; Indoles/*therapeutic use ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects ; Neuroprotective Agents/*therapeutic use ; Rotarod Performance Test ; Spinal Cord/*drug effects ; gamma-Synuclein/genetics/metabolism ; }, abstract = {Intermediates and final products of protein aggregation play crucial role in the development of degenerative changes in a number of neurological diseases. Pathological protein aggregation is currently regarded as one of the most promising therapeutic targets for treatment of these diseases. Transgenic mouse models of proteinopathies are an effective tool for screening and validation of compounds, which can selectively affect metabolism of aggregate-prone proteins. In this study, we assessed effects of dimebon, a compound with known neuroprotective properties, on a recently established transgenic mouse model recapitulating key pathological features of amyotrophic lateral sclerosis (ALS) as the consequence of neuron-specific overexpression of γ-synuclein. Cohorts of experimental transgenic mice received dimebon in drinking water with this chronic treatment starting either before or after the onset of clinical signs of pathology. We detected statistically significant improvement of motor performance in a rotarod test in both dimebon-treated animal groups, with more pronounced effect in a group that received dimebon from an earlier age. We also revealed substantially reduced number of amyloid inclusions, decreased amount of insoluble γ-synuclein species and a notable amelioration of astrogliosis in the spinal cord of dimebon-treated compared with control transgenic animals. However, dimebon did not prevent the loss of spinal motor neurons in this model. Our results demonstrated that chronic dimebon administration is able to slow down but not halt progression of γ-synucleinopathy and resulting signs of pathology in transgenic animals, suggesting potential therapeutic use of this drug for treatment of this currently incurable disease.}, }
@article {pmid22163168, year = {2011}, author = {Rasekh, HR and Imani, A and Karimi, M and Golestani, M}, title = {Cost-utility analysis of immune tolerance induction therapy versus on-demand treatment with recombinant factor VII for hemophilia A with high titer inhibitors in Iran.}, journal = {ClinicoEconomics and outcomes research : CEOR}, volume = {3}, number = {}, pages = {207-212}, pmid = {22163168}, issn = {1178-6981}, abstract = {BACKGROUND: In developing countries, the treatment of hemophilia patients with inhibitors is presently the most challenging and serious issue in hemophilia management, direct costs of clotting factor concentrates accounting for >98% of the highest economic burden absorbed for the health care of patients in this setting. In the setting of chronic diseases, cost-utility analysis, which takes into account the beneficial effects of a given treatment/health care intervention in terms of health-related quality of life, is likely to be the most appropriate approach.<br><br>OBJECTIVE: The aim of this study was to assess the incremental cost-effectiveness ratios of immune tolerance induction (ITI) therapy with plasma-derived factor VIII concentrates versus on-demand treatment with recombinant-activated FVIIa (rFVIIa) in hemophilia A with high titer inhibitors from an Iranian Ministry of Health perspective.<br><br>METHODS: This study was based on the study of Knight et al, which evaluated the cost- effectiveness ratios of different treatments for hemophilia A with high-responding inhibitors. To adapt Knight et al's results to the Iranian context, a few clinical parameters were varied, and cost data were replaced with the corresponding Iranian estimates of resource use. The time horizon of the analysis was 10 years. One-way sensitivity analyses were performed, varying the cost of the clotting factor, the drug dose, and the administration frequency, to test the robustness of the analysis.<br><br>RESULTS: Comparison of the incremental cost-effectiveness ratios between the three ITI protocols and the on-demand regimen with rFVIIa shows that all three ITI protocols dominate the on-demand regimen with rFVIIa. Between the ITI protocols the low-dose ITI protocol dominates both the Bonn ITI protocol and the Malm&#xf6; ITI protocol and would be the preferred ITI protocol. All of the three ITI protocols dominate the on-demand strategy, as they have both a lower average lifetime cost and higher quality-adjusted life-years (QALYs) gained. The cost per QALY gained for the Bonn ITI protocol compared with the Malm&#xf6; ITI protocol was $249,391.84. The cost per QALY gained for the Bonn ITI protocol compared with the low-dose ITI protocol was $842,307.69.<br><br>CONCLUSION: The results of data derived from our study suggest that the low-dose ITI protocol may be a less expensive and/or more cost-effective option compared with on-demand first-line treatment with rFVIIa.}, }
@article {pmid22161544, year = {2012}, author = {Olson, SD and Pollock, K and Kambal, A and Cary, W and Mitchell, GM and Tempkin, J and Stewart, H and McGee, J and Bauer, G and Kim, HS and Tempkin, T and Wheelock, V and Annett, G and Dunbar, G and Nolta, JA}, title = {Genetically engineered mesenchymal stem cells as a proposed therapeutic for Huntington's disease.}, journal = {Molecular neurobiology}, volume = {45}, number = {1}, pages = {87-98}, pmid = {22161544}, issn = {1559-1182}, support = {1R01GM099688/GM/NIGMS NIH HHS/United States ; 2P51RR000169-49/RR/NCRR NIH HHS/United States ; R01 GM099688/GM/NIGMS NIH HHS/United States ; 1R01 HL073256-01/HL/NHLBI NIH HHS/United States ; 5P30AG010129-19/AG/NIA NIH HHS/United States ; P51 RR000169/RR/NCRR NIH HHS/United States ; R01 HL073256/HL/NHLBI NIH HHS/United States ; P30 AG010129/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Disease Models, Animal ; Genetic Engineering/*methods/trends ; Humans ; Huntington Disease/pathology/physiopathology/*therapy ; Mesenchymal Stem Cell Transplantation/*methods/trends ; Mesenchymal Stem Cells/*metabolism ; Nerve Growth Factors/biosynthesis/genetics/*metabolism ; }, abstract = {There is much interest in the use of mesenchymal stem cells/marrow stromal cells (MSC) to treat neurodegenerative disorders, in particular those that are fatal and difficult to treat, such as Huntington's disease. MSC present a promising tool for cell therapy and are currently being tested in FDA-approved phase I-III clinical trials for many disorders. In preclinical studies of neurodegenerative disorders, MSC have demonstrated efficacy, when used as delivery vehicles for neural growth factors. A number of investigators have examined the potential benefits of innate MSC-secreted trophic support and augmented growth factors to support injured neurons. These include overexpression of brain-derived neurotrophic factor and glial-derived neurotrophic factor, using genetically engineered MSC as a vehicle to deliver the cytokines directly into the microenvironment. Proposed regenerative approaches to neurological diseases using MSC include cell therapies in which cells are delivered via intracerebral or intrathecal injection. Upon transplantation, MSC in the brain promote endogenous neuronal growth, encourage synaptic connection from damaged neurons, decrease apoptosis, reduce levels of free radicals, and regulate inflammation. These abilities are primarily modulated through paracrine actions. Clinical trials for MSC injection into the central nervous system to treat amyotrophic lateral sclerosis, traumatic brain injury, and stroke are currently ongoing. The current data in support of applying MSC-based cellular therapies to the treatment of Huntington's disease is discussed.}, }
@article {pmid22138725, year = {2012}, author = {Etkind, SN}, title = {Terminal sedation: an emotional decision in end-of-life care.}, journal = {Journal of medical ethics}, volume = {38}, number = {8}, pages = {508-509}, doi = {10.1136/medethics-2011-100213}, pmid = {22138725}, issn = {1473-4257}, mesh = {*Deep Sedation ; Disease Progression ; Fatal Outcome ; Hospice Care/ethics ; Humans ; Hypnotics and Sedatives/*therapeutic use ; Male ; Motor Neuron Disease/*psychology ; Patient Rights/ethics ; Physician-Patient Relations/*ethics ; Stress, Psychological/*etiology/therapy ; Terminal Care/*ethics ; }, abstract = {A patient with end-stage motor neurone disease was admitted for hospice care with worsening bulbar symptoms. Although he initially walked onto the ward he became very distressed and asked for sedation. After much discussion, this man was deeply sedated, and after some harrowing days, died. Was it right to provide terminal sedation? What should the threshold be for such treatment? How should our personal reservations affect how we approach the distressed patient in an end-of-life situation?}, }
@article {pmid22133678, year = {2012}, author = {Tsuji, H and Nonaka, T and Yamashita, M and Masuda-Suzukake, M and Kametani, F and Akiyama, H and Mann, DM and Tamaoka, A and Hasegawa, M}, title = {Epitope mapping of antibodies against TDP-43 and detection of protease-resistant fragments of pathological TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, journal = {Biochemical and biophysical research communications}, volume = {417}, number = {1}, pages = {116-121}, doi = {10.1016/j.bbrc.2011.11.066}, pmid = {22133678}, issn = {1090-2104}, support = {089701//Wellcome Trust/United Kingdom ; }, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Antibodies/chemistry/*immunology ; Antibodies, Monoclonal/chemistry/immunology ; Brain/immunology/metabolism ; Brain Chemistry ; DNA-Binding Proteins/chemistry/*immunology/metabolism ; *Epitope Mapping ; Frontotemporal Lobar Degeneration/*metabolism ; Humans ; Mice ; Molecular Sequence Data ; Peptide Hydrolases/chemistry ; }, abstract = {TAR DNA-binding protein of 43 kDa (TDP-43) is the major component of the intracellular inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we show that both monoclonal (60019-2-Ig) and polyclonal (10782-2-AP) anti-TDP-43 antibodies recognize amino acids 203-209 of human TDP-43. The monoclonal antibody labeled human TDP-43 by recognizing Glu204, Asp205 and Arg208, but failed to react with mouse TDP-43. The antibodies stained the abnormally phosphorylated C-terminal fragments of 24-26 kDa in addition to normal TDP-43 in ALS and FTLD brains. Immunoblot analysis after protease treatment demonstrated that the epitope of the antibodies (residues 203-209) constitutes part of the protease-resistant domain of TDP-43 aggregates which determine a common characteristic of the pathological TDP-43 in both ALS and FTLD-TDP. The antibodies and methods used in this study will be useful for the characterization of abnormal TDP-43 in human materials, as well as in vitro and animal models for TDP-43 proteinopathies.}, }
@article {pmid22124037, year = {2012}, author = {Moreno-Igoa, M and Calvo, AC and Ciriza, J and Muñoz, MJ and Zaragoza, P and Osta, R}, title = {Non-viral gene delivery of the GDNF, either alone or fused to the C-fragment of tetanus toxin protein, prolongs survival in a mouse ALS model.}, journal = {Restorative neurology and neuroscience}, volume = {30}, number = {1}, pages = {69-80}, doi = {10.3233/RNN-2011-0621}, pmid = {22124037}, issn = {1878-3627}, mesh = {Age Factors ; Age of Onset ; Amyotrophic Lateral Sclerosis/*genetics/*therapy ; Analysis of Variance ; Animals ; Apoptosis/drug effects/physiology ; Caspase 3/metabolism ; Disease Models, Animal ; Gene Expression Regulation/drug effects/physiology ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Nerve Growth Factors/biosynthesis/*therapeutic use ; Peptide Fragments/genetics/metabolism/*therapeutic use ; Proto-Oncogene Proteins c-akt/metabolism ; Superoxide Dismutase/genetics ; Tetanus Toxin/genetics/metabolism/*therapeutic use ; }, abstract = {PURPOSE AND BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease with no effective therapy. Glial-cell line derived neurotrophic factor (GDNF) has been translated to clinical trials for treatment of ALS and its selective delivery to the motoneurons could improve its therapeutic abilities.<br><br>METHODS: To test this idea, we genetically fused GDNF to the C-fragment of tetanus toxin (TTC), a peptide able to specifically deliver molecules to motoneurons.<br><br>RESULTS: Single intramuscular administration of naked-DNA encoding GDNF or GDNF-TTC significantly delayed the onset of symptoms and functional deficits into the SODG93A mouse model of ALS, prolonging their lifespan.<br><br>CONCLUSIONS: We have demonstrated a neuroprotective effect of GDNF-TTC as shown by the activation of survival pathways and inhibition of apoptotic proteins, such as Akt phosphorylation, or reduced caspase-3 activation respectively. However, the GDNF fusion with TTC did not improve the therapeutic effects when compared to GDNF alone.}, }
@article {pmid22122965, year = {2012}, author = {Knippenberg, S and Thau, N and Schwabe, K and Dengler, R and Schambach, A and Hass, R and Petri, S}, title = {Intraspinal injection of human umbilical cord blood-derived cells is neuroprotective in a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Neuro-degenerative diseases}, volume = {9}, number = {3}, pages = {107-120}, doi = {10.1159/000331327}, pmid = {22122965}, issn = {1660-2862}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/*therapy ; Animals ; Cell Survival ; Disease Models, Animal ; Disease Progression ; Female ; Fetal Blood/*cytology ; Gliosis/pathology/prevention &amp; control ; Humans ; Injections, Spinal ; Male ; Mice ; Mice, Transgenic ; Motor Activity ; Motor Neurons/*pathology ; Spinal Cord/*pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Treatment Outcome ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons in the spinal cord, brain stem and motor cortex and has only marginal therapeutic options. Adult stem cells have recently come into the focus of neurological research. While replacement of motor neurons by stem cells currently appears not feasible, there is evidence that non-neuronal cells can be neuroprotective.<br><br>OBJECTIVE: Therefore, we evaluated the effects of direct intraspinal administration of human umbilical cord blood cells in a G93A transgenic mouse model of ALS before (day 40) and after symptom onset (day 90).<br><br>METHODS: Treatment effects were assessed by survival analysis, behavioral tests, histological and biochemical analyses.<br><br>RESULTS: Treatment at early stages increased survival, led to significant improvements in motor performance and significantly reduced motor neuron loss and astrogliosis in the spinal cord. Interestingly females tended to respond better to treatment than males.<br><br>CONCLUSION: This study confirms the neuroprotective potential of human umbilical cord blood cells and encourages further investigations.}, }
@article {pmid22117694, year = {2012}, author = {Thompson, M and Marecki, JC and Marinesco, S and Labrie, V and Roder, JC and Barger, SW and Crow, JP}, title = {Paradoxical roles of serine racemase and D-serine in the G93A mSOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {120}, number = {4}, pages = {598-610}, pmid = {22117694}, issn = {1471-4159}, support = {5R01NS040819-08/NS/NINDS NIH HHS/United States ; R01 NS040819/NS/NINDS NIH HHS/United States ; P01 AG012411/AG/NIA NIH HHS/United States ; P01AG012411/AG/NIA NIH HHS/United States ; R01 NS040819-09/NS/NINDS NIH HHS/United States ; R21 AG033215/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*metabolism/pathology ; Animals ; *Disease Models, Animal ; Disease Progression ; Female ; Humans ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; Microglia/enzymology/metabolism/pathology ; *Mutation ; Racemases and Epimerases/chemistry/deficiency/*physiology ; Serine/antagonists &amp; inhibitors/biosynthesis/*physiology ; Superoxide Dismutase/chemistry/genetics/*physiology ; Superoxide Dismutase-1 ; Up-Regulation/genetics ; }, abstract = {D-serine is an endogenous neurotransmitter that binds to the NMDA receptor, thereby increasing the affinity for glutamate, and the potential for excitotoxicity. The primary source of D-serine in vivo is enzymatic racemization by serine racemase (SR). Regulation of D-serine in vivo is poorly understood, but is thought to involve a combination of controlled production, synaptic reuptake by transporters, and intracellular degradation by D-amino acid oxidase (DAO). However, SR itself possesses a well-characterized eliminase activity, which effectively degrades D-serine as well. D-serine is increased two-fold in spinal cords of G93A Cu,Zn-superoxide dismutase (SOD1) mice--the standard model of amyotrophic lateral sclerosis (ALS). ALS mice with SR disruption show earlier symptom onset, but survive longer (progression phase is slowed), in an SR-dependent manner. Paradoxically, administration of D-serine to ALS mice dramatically lowers cord levels of D-serine, leading to changes in the onset and survival very similar to SR deletion. D-serine treatment also increases cord levels of the alanine-serine-cysteine transporter 1 (Asc-1). Although the mechanism by which SOD1 mutations increases D-serine is not known, these results strongly suggest that SR and D-serine are fundamentally involved in both the pre-symptomatic and progression phases of disease, and offer a direct link between mutant SOD1 and a glial-derived toxic mediator.}, }
@article {pmid22108590, year = {2012}, author = {Hemendinger, RA and Armstrong, EJ and Radio, N and Brooks, BR}, title = {Neurotoxic injury pathways in differentiated mouse motor neuron-neuroblastoma hybrid (NSC-34D) cells in vitro--limited effect of riluzole on thapsigargin, but not staurosporine, hydrogen peroxide and homocysteine neurotoxicity.}, journal = {Toxicology and applied pharmacology}, volume = {258}, number = {2}, pages = {208-215}, doi = {10.1016/j.taap.2011.10.022}, pmid = {22108590}, issn = {1096-0333}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Apoptosis/*drug effects ; Calcium/metabolism ; Caspase 3/metabolism ; Caspase 7/metabolism ; Cell Line ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum/metabolism ; Homocysteine/administration &amp; dosage/toxicity ; Hybrid Cells ; Hydrogen Peroxide/administration &amp; dosage/toxicity ; Mice ; Motor Neurons/drug effects/metabolism ; Neuroblastoma/metabolism ; Neuroprotective Agents/*pharmacology ; Neurotoxins/administration &amp; dosage/*toxicity ; Riluzole/*pharmacology ; Staurosporine/administration &amp; dosage/toxicity ; Thapsigargin/administration &amp; dosage/toxicity ; }, abstract = {The neuroblastoma-spinal motor neuron fusion cell line, NSC-34, in its differentiated form, NSC-34D, permits examining the effects of riluzole, a proven treatment for amyotrophic lateral sclerosis (ALS) on cell death induction by staurosporine (STS), thapsigargin (Thaps), hydrogen peroxide (H(2)O(2)) and homocysteine (HCy). These neurotoxins, applied exogenously, have mechanisms of action related to the various proposed molecular pathogenetic pathways in ALS and are differentiated from endogenous cell death that is associated with cytoplasmic aggregate formation in motor neurons. Nuclear morphology, caspase-3/7 activation and high content imaging were used to assess toxicity of these neurotoxins with and without co-treatment with riluzole, a benzothiazole compound with multiple pharmacological actions. STS was the most potent neurotoxin at killing NSC-34D cells with a toxic concentration at which 50% of maximal cell death is achieved (TC(50)=0.01μM), followed by Thaps (TC(50)=0.9μM) and H(2)O(2) (TC(50)=15μM) with HCy requiring higher concentrations to kill at the same level (TC(50)=2200μM). Riluzole provided neurorescue with a 20% absolute reduction (47.6% relative reduction) in apoptotic cell death against Thaps-induced NSC-34D cell (p≤0.05), but had no effect on STS-, H(2)O(2)- and HCy-induced NSC-34D cell death. This effect of riluzole on Thaps induction of cell death was independent of caspase-3/7 activation. Riluzole mitigated a toxin that can cause intracellular calcium dysregulation associated with endoplasmic reticulum (ER) stress but not toxins associated with other cell death mechanisms.}, }
@article {pmid22105211, year = {2011}, author = {Vlam, L and van der Pol, WL and Cats, EA and Straver, DC and Piepers, S and Franssen, H and van den Berg, LH}, title = {Multifocal motor neuropathy: diagnosis, pathogenesis and treatment strategies.}, journal = {Nature reviews. Neurology}, volume = {8}, number = {1}, pages = {48-58}, pmid = {22105211}, issn = {1759-4766}, mesh = {Humans ; Motor Neuron Disease/*diagnosis/*physiopathology/therapy ; Polyneuropathies/*diagnosis/*physiopathology/therapy ; }, abstract = {Multifocal motor neuropathy (MMN) is a rare inflammatory neuropathy characterized by slowly progressive, asymmetric distal limb weakness without sensory loss. The clinical presentation of MMN may mimic amyotrophic lateral sclerosis, other variants of motor neuron disease, or chronic inflammatory demyelinating polyneuropathy with asymmetric onset. Differentiation is important, as these diseases differ in prognosis and treatment. The electrophysiological finding of conduction block in the absence of abnormalities in sensory nerves is the hallmark of MMN, but can be difficult to detect. Intravenous immunoglobulin is efficacious in most patients, but long-term maintenance therapy does not prevent slowly progressive axonal degeneration. Moreover, cyclophosphamide, although effective, has substantial adverse effects, and the efficacy of other immunosuppressive drugs, including rituximab, is not established. The underlying pathological mechanisms of MMN are unclear, but IgM autoantibodies against the ganglioside GM1 may cause changes in nodal and perinodal structures that compromise nerve conduction. Further elucidation of the disease mechanisms may ultimately lead to improved treatment strategies. In this Review, we discuss the diagnostic criteria for MMN, and provide an update on the current understanding of MMN pathogenesis. We also describe available treatments and promising new therapeutic strategies.}, }
@article {pmid22102982, year = {2011}, author = {Grabrucker, AM and Rowan, M and Garner, CC}, title = {Brain-Delivery of Zinc-Ions as Potential Treatment for Neurological Diseases: Mini Review.}, journal = {Drug delivery letters}, volume = {1}, number = {1}, pages = {13-23}, pmid = {22102982}, issn = {2210-3031}, support = {F31 NS066786-03/NS/NINDS NIH HHS/United States ; P01 NS053862/NS/NINDS NIH HHS/United States ; R21 MH091471/MH/NIMH NIH HHS/United States ; R21 MH091471-02/MH/NIMH NIH HHS/United States ; }, abstract = {Homeostasis of metal ions such as Zn(2+) is essential for proper brain function. Moreover, the list of psychiatric and neurodegenerative disorders involving a dysregulation of brain Zn(2+)-levels is long and steadily growing, including Parkinson's and Alzheimer's disease as well as schizophrenia, attention deficit and hyperactivity disorder, depression, amyotrophic lateral sclerosis, Down's syndrome, multiple sclerosis, Wilson's disease and Pick's disease. Furthermore, alterations in Zn(2+)-levels are seen in transient forebrain ischemia, seizures, traumatic brain injury and alcoholism. Thus, the possibility of altering Zn(2+)-levels within the brain is emerging as a new target for the prevention and treatment of psychiatric and neurological diseases. Although the role of Zn(2+) in the brain has been extensively studied over the past decades, methods for controlled regulation and manipulation of Zn(2+) concentrations within the brain are still in their infancy. Since the use of dietary Zn(2+) supplementation and restriction has major limitations, new methods and alternative approaches are currently under investigation, such as the use of intracranial infusion of Zn(2+) chelators or nanoparticle technologies to elevate or decrease intracellular Zn(2+) levels. Therefore, this review briefly summarizes the role of Zn(2+) in psychiatric and neurodegenerative diseases and highlights key findings and impediments of brain Zn(2+)-level manipulation. Furthermore, some methods and compounds, such as metal ion chelation, redistribution and supplementation that are used to control brain Zn(2+)-levels in order to treat brain disorders are evaluated.}, }
@article {pmid22101998, year = {2011}, author = {Jóźwiak, S and Kossoff, EH and Kotulska-Jóźwiak, K}, title = {Dietary treatment of epilepsy: rebirth of an ancient treatment.}, journal = {Neurologia i neurochirurgia polska}, volume = {45}, number = {4}, pages = {370-378}, doi = {10.1016/s0028-3843(14)60108-0}, pmid = {22101998}, issn = {0028-3843}, mesh = {Child ; Child Welfare ; Diet, Carbohydrate-Restricted/*methods ; Diet, Ketogenic/*methods ; Dietary Fats/*administration &amp; dosage ; Epilepsy/*diet therapy/metabolism ; Humans ; Ketones/metabolism ; }, abstract = {Since its introduction in 1921, the ketogenic diet has been in continuous use for children with difficult-to-control epilepsy. After decades of relative disuse, it is now both extremely popular and well studied, with approximately two-thirds of children demonstrating significant seizure reduction after 6 months. It is being used for less intractable seizures in children as well as recently adults. Modifications that help improve tolerability include the medium chain triglyceride diet, modified Atkins diet, and low glycemic index treatment. Major side effects include acidosis, increased cholesterol, kidney stones, gastroesophageal reflux, and growth disturbance. However, these side effects are usually treatable and nowadays often even preventable. Future non-epilepsy indications such as Alzheimer disease, amyotrophic lateral sclerosis, autism, and brain tumors are under active investigation. This dietary treatment for epilepsy has undergone a rebirth. Its widespread use in Poland and Europe is a welcome additional treatment for those with drug-resistant epilepsy.}, }
@article {pmid22101764, year = {2011}, author = {Cudkowicz, M and Bozik, ME and Ingersoll, EW and Miller, R and Mitsumoto, H and Shefner, J and Moore, DH and Schoenfeld, D and Mather, JL and Archibald, D and Sullivan, M and Amburgey, C and Moritz, J and Gribkoff, VK}, title = {The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis.}, journal = {Nature medicine}, volume = {17}, number = {12}, pages = {1652-1656}, pmid = {22101764}, issn = {1546-170X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Benzothiazoles/adverse effects/*therapeutic use ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Mitochondria/drug effects ; Muscle Strength/drug effects ; Muscles/*physiopathology ; Pramipexole ; Riluzole/therapeutic use ; Single-Blind Method ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron dysfunction and loss, rapidly progressive muscle weakness, wasting and death. Many factors, including mitochondrial dysfunction, may contribute to ALS pathogenesis. Riluzole, which has shown only modest benefits in a measure of survival time without demonstrated effects on muscle strength or function, is the only approved treatment for ALS. We tested the putative mitochondrial modulator dexpramipexole (KNS-760704; (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) in subjects with ALS in a two-part, double-blind safety and tolerability study, with a preliminary assessment of its effects on functional decline and mortality. In part 1, the effects of dexpramipexole (50, 150 or 300 mg d(-1)) versus placebo were assessed over 12 weeks. In part 2, after a 4-week, single-blind placebo washout, continuing subjects were re-randomized to dexpramipexole at 50 mg d(-1) or 300 mg d(-1) as double-blind active treatment for 24 weeks. Dexpramipexole was safe and well tolerated. Trends showing a dose-dependent attenuation of the slope of decline of the ALS Functional Rating Scale-Revised (ALSFRS-R) in part 1 and a statistically significant (P = 0.046) difference between groups in a joint rank test of change from baseline in ALSFRS-R and mortality in part 2 strongly support further testing of dexpramipexole in ALS.}, }
@article {pmid22094924, year = {2012}, author = {Nizzardo, M and Simone, C and Falcone, M and Riboldi, G and Rizzo, F and Magri, F and Bresolin, N and Comi, GP and Corti, S}, title = {Research advances in gene therapy approaches for the treatment of amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {69}, number = {10}, pages = {1641-1650}, pmid = {22094924}, issn = {1420-9071}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; Dependovirus ; Disease Models, Animal ; Genetic Therapy/*trends ; Genetic Vectors/therapeutic use ; Mice ; Neuroprotective Agents/therapeutic use ; RNA Interference ; Rats ; Superoxide Dismutase/antagonists &amp; inhibitors/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease of motor neurons that causes progressive muscle weakness, paralysis, and premature death. No effective therapy is available. Research in the motor neuron field continues to grow, and recent breakthroughs have demonstrated the possibility of completely achieving rescue in animal models of spinal muscular atrophy, a genetic motor neuron disease. With adeno-associated virus (AAV) vectors, gene transfer can be achieved with systemic non-invasive injection and minimal toxicity. In the context of this success, we review gene therapy approaches for ALS, considering what has been done and the possible future directions for effective application of the latest generation of vectors for clinical translation. We focus on recent developments in the areas of RNA/antisense-mediated silencing of specific ALS causative genes like superoxide dismutase-1 and other molecular pathogenetic targets, as well as the administration of neuroprotective factors with viral vectors. We argue that gene therapy offers new opportunities to open the path for clinical progress in treating ALS.}, }
@article {pmid22696959, year = {2011}, author = {De Cauwer, B and Rombaut, R and Bulcke, R and Reheul, D}, title = {Sensitivity of Echinochloa muricata and Echinochloa crus-galli to HPPD- and ALS-inhibiting herbicides in corn.}, journal = {Communications in agricultural and applied biological sciences}, volume = {76}, number = {3}, pages = {513-520}, pmid = {22696959}, issn = {1379-1176}, mesh = {4-Hydroxyphenylpyruvate Dioxygenase/*antagonists &amp; inhibitors/genetics/metabolism ; Acetolactate Synthase/*antagonists &amp; inhibitors/genetics/metabolism ; Echinochloa/*drug effects/enzymology/genetics ; Enzyme Inhibitors/*pharmacology ; Herbicides/*pharmacology ; Plant Proteins/*antagonists &amp; inhibitors/genetics/metabolism ; Weed Control ; Zea mays/*growth &amp; development ; }, abstract = {Until recently Echinochloa muricata var. microstachya Wiegand (rough barnyardgrass), an alien species native to North America, was completely overlooked in Belgium due to its close morphological resemblance to Echinochloa crus-galli (L.) P. Beauv. (barnyardgrass). E. muricata var. microstachya has gradually spread and is now locally naturalized and abundant in and along maize fields. One of the possible reasons for its expansion in maize fields, besides e.g. the lack of crop rotation, might be a lower sensitivity to postemergence herbicides acting against panicoid grasses, in particular 4-hydroxyphenyl pyruvate dioxygenase (HPPD)-inhibiting herbicides and acetolactate synthase (ALS) inhibiting herbicides. Dose-response pot experiments were conducted in the greenhouse to evaluate the effectiveness of four HPPD-inhibitor herbicides [topramezone (ARIETTA), mesotrione (CALLISTO), tembotrione (LAUDIS), sulcotrione (MIKADO) and the ALS-inhibitor herbicide nicosulfuron (KELVIN) for controlling local populations of E. crus-galli and E. muricata. Pots were planted with 25 seeds, thinned afterwards to 5 plants (one week after sowing) and irrigated by overhead sprinklers. Herbicides were applied at the 3-4 leaf stage (BBCH stage 13-14). Fresh biomass was harvested 28 d after treatment. In another dose-response pot experiment, the influence of leaf stage at time of herbicide application on efficacy of topramezone for (rough) barnyardgrass control was evaluated. Sensitivity to HPPD-inhibitor herbicides topramezone and sulcotrione was significantly lower for E. muricata populations than for E. crus-galli populations. However, nicosulfuron sensitivity of both species was similar. Compared to E. crus-galli, sensitivity of E. muricata to topramezone was more dependent on leaf stage. Due to the intragenus variability in sensitivity to HPPD-inhibitor herbicides, higher awareness is required for presence of E. muricata plants in maize fields in order to avoid insufficient "barnyardgrass" control.}, }
@article {pmid23199069, year = {2010}, author = {Benkler, C and Offen, D and Melamed, E and Kupershmidt, L and Amit, T and Mandel, S and Youdim, MB and Weinreb, O}, title = {Recent advances in amyotrophic lateral sclerosis research: perspectives for personalized clinical application.}, journal = {The EPMA journal}, volume = {1}, number = {2}, pages = {343-361}, pmid = {23199069}, issn = {1878-5077}, abstract = {Treatment of amyotrophic lateral sclerosis (ALS) has been fueled, in part, by frustration over the shortcomings of the symptomatic drugs available, since these do not impede the progression of this disease. Currently, over 150 different potential therapeutic agents or strategies have been tested in preclinical models of ALS. Unfortunately, therapeutic modifiers of murine ALS have failed to be successfully translated into strategies for patients, probably because of differences in pharmacokinetics of the therapeutic agents, route of delivery, inefficiency of the agents to affect the distinct pathologies of the disease or inherent limitations of the available animal models. Given the multiplicity of the pathological mechanisms implicated in ALS, new therapies should consider the simultaneous manipulation of multiple targets. Additionally, a better management of ALS therapy should include understanding the interactions between potential risk factors, biomarkers and heterogeneous clinical features of the patients, aiming to manage their adverse events or personalize the safety profile of these agents. This review will discuss novel pharmacological approaches concerning adjusted therapy for ALS patients: iron-binding brain permeable multimodal compounds, genetic manipulation and cell-based treatment.}, }
@article {pmid23199068, year = {2010}, author = {Nefussy, B and Drory, VE}, title = {Moving toward a predictive and personalized clinical approach in amyotrophic lateral sclerosis: novel developments and future directions in diagnosis, genetics, pathogenesis and therapies.}, journal = {The EPMA journal}, volume = {1}, number = {2}, pages = {329-341}, pmid = {23199068}, issn = {1878-5077}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that affects upper and lower motor neurons in the brain and spinal cord, with progressive weakness and atrophy of most muscles in the body and is almost always fatal within 3-5 years. A small proportion of cases are familial, and remarkable achievements have been made during the last years in understanding the genetics of the disease. In spite of this, the basic pathogenic mechanisms underlying the sporadic disease are still poorly understood. There is urgent need for better understanding of the pathogenic processes in order to be able to develop effective treatments. The present review will focus on recent knowledge gained in diagnosis, genetics, pathogenesis and therapies in ALS. Future development of diagnostic technologies integrating genetic, environmental and individual information will enable us to predict a population at risk for ALS. New treatments actually in development will help improve the medical management of ALS patients, taking into consideration individual traits, as genetic background, and pave a way for a more effective personalized diagnostic and treatment approach.}, }
@article {pmid24198520, year = {2010}, author = {Cova, L and Silani, V}, title = {Amyotrophic lateral sclerosis: applications of stem cells - an update.}, journal = {Stem cells and cloning : advances and applications}, volume = {3}, number = {}, pages = {145-156}, pmid = {24198520}, issn = {1178-6957}, abstract = {Neurodegenerative diseases are a growing public health challenge, and amyotrophic lateral sclerosis (ALS) remains a fatal incurable disease. The advent of stem cell therapy has opened new horizons for both researchers and ALS patients, desperately looking for a treatment. ALS must be considered a systemic disease affecting many cell phenotypes besides motor neurons, even outside the central nervous system. Cell replacement therapy needs to address the specific neurobiological issues of ALS to safely and efficiently reach clinical settings. Moreover, the enormous potential of induced pluripotent cells directly derived from patients for modeling and understanding the pathological mechanisms, in correlation with the discoveries of new genes and animal models, provides new opportunities that need to be integrated with previously described transplantation strategies. Finally, a careful evaluation of preclinical data in conjunction with wary patient choice in clinical trials needs to be established in order to generate meaningful results.}, }
@article {pmid22239691, year = {2000}, author = {Bein, E and Anderson, T and Strupp, H and Henry, W and Schacht, T and Binder, J and Butler, S}, title = {The effects of training in time-limited dynamic psychotherapy: changes in therapeutic outcome.}, journal = {Psychotherapy research : journal of the Society for Psychotherapy Research}, volume = {10}, number = {2}, pages = {119-132}, doi = {10.1080/713663669}, pmid = {22239691}, issn = {1050-3307}, abstract = {The present study explored the effects on therapeutic outcomes of training therapists in brief manualized therapy. As part of the Vanderbilt II project, each of 16 therapists (8 psychiatrists and 8 clinical psychologists) treated 2 moderately disturbed adult patients using his or her customary short-term treatment methods; they then received a year of training in a manualized form of brief dynamic therapy, Time-Limited Dynamic Psychotherapy (TLDP); finally, they administered TLDP to 2 additional patients. It was hypothesized that training would result in improved outcomes generally and that differentially greater improvement would be seen in patients commonly considered less suitable for brief dynamic therapy. Outcome data obtained at termination failed to support either hypothesis. Measurements of interpersonal dependency obtained at a one-year follow-up were consistent with the first hypothesis, but the follow-up data were inconsistent with the second. A systematic review of the 32 posttraining cases suggested that the majority of the therapists had not achieved basic competence at TLDP. Die hier beschriebene Studie untersucht die Wirkungen eines Trainings in manualisierter Kurzzeitherapie auf das Therapierergebnis. Als Teil des Vanderbilt II Projektes behandelten jeweils 16 Therapeuten (8 Psychiater und 8 klinische Psychologen) zwei mittelgradig beeinrächtigte erwachsene Patienten mit den ihnen vertrauten Kurzzeitbehandlungsmethoden. Danach wurden sie über ein Jahr in einer manualisierten Form psychodynamischer Kurzzeittherapie ausgebildet und wandten diese Therapie auf zwei weitere Patienten an. Es wurde angenommen, dass die Ausbildung in besseren Ergebnisdaten, die bei Ende der Therapie erhoben wurden, konnten diese Hypothese nicht bestätigen. Maße für die interpersonale Abhängigkeit zu einem Einjahreskatamnesezeitpunkt waren mit der ersten Hypothese konform, aber inkonsistent mit der zweiten. Eine systematische Untersuchung der 32 nach der Ausbildung behandelten Fälle legt nahe, dass die Mehrzahl der Therapeuten keine grundlegende Kompetenz in zeitlich limitierter dynamischer Psychotherapie erworben hatte. Cette éude explore les effets sur les résultats thérapeutiques de la formation des thérapeutes dans une thérapie brève, manualissée. Dans le cadre du projet Vanderbilt II, chacun des 16 thérapeutes (8 psychiatrs et 8 psychologues cliniciens) a traité deux patients adultes modérément perturbés, chacun par sa méthode habituelle de thérapie brève; ensuite ils ont reçu une formation d'une année dans une méthode manualisée de thérapie brève, la Psychothérapie Dynamique Limitée dans le Temps (TLDP); pour finir, ils ont appliqué la TLDP à de meilleurs résultats en général, et qu'une amélioration comparativement plus importante sera observée chez des patients habituellement considérés comme moins adaptés à une thérapie dynamique brè. Les résultats obtenus à la terminaison n'ont pu confirmer aucune de ces hypothèses. Des mesures de la dépendance interpersonnelle une année après étaient consistantes avec la première hypothèse, mais les données catamnestiques étaient inconsistantes avec la deuxième. Une revue systématique des 32 cas après formation a suggéré que la majorité des thérapeutes n'avait pas acquis une compétence de base en TLDP. Este estudio exploró la efectividad del entrenamiento de terapeutas en una terapia breve manualizada. Como parte del proyecto Vanderbilt II, dieciséis terapeutas (ocho psiquiatras y ocho psicólogos clínicos) trataron dos pacientes adultos mooderadamente perturbados con sus métodos habituales de tratamiento a corto plazo. Estos terapeutas recibieron luego un año de entrenamiento en terapia dinámica breve manualizada que se Ilamó Psicoterapia Dinámica de Tiempo limitado (TLDP). Finalmente, administraron esta TLDP a dos pacientes más. La hipótesis fue que el entrenamiento ilevaría, en general, a resultados mejores y que habría mayor mejoramiento en pacientes menos aptos para una terapia dinámica breve. Los resultados a la terminación no apoyaron ninguna de las dos hipótesis. Las mediciones de dependencia interpersonal al año de seguimiento resultaron consistentes con la primera hipótesis, mientras que los resultados de seguimiento fueron inconsistentes con la segunda. Una revisión sistemática de los treinta y dos casos luego del entrenamiento sugiere que la mayoría de los terapeutas no había l.}, }
@article {pmid22151116, year = {1999}, author = {Krames, E and Buchser, E and Hassenbusch, SJ and Levy, R}, title = {Future trends in the development of local drug delivery systems: intraspinal, intracerebral, and intraparenchymal therapies.}, journal = {Neuromodulation : journal of the International Neuromodulation Society}, volume = {2}, number = {2}, pages = {133-148}, doi = {10.1046/j.1525-1403.1999.00133.x}, pmid = {22151116}, issn = {1094-7159}, abstract = {Due to successful use of intrathecal drug delivery in the management of refractory pain and spasticity, new agents and indications are now being investigated. Preclinical studies of neurotrophic factors, molecules necessary for neuroneal survival and development, suggest that these agents may be beneficial for patients with neurologic disorders. Because neurotrophic factors do not cross the blood-brain barrier following systemic administration, local delivery routes, including intrathecal, intracerebroventrical, and intraparenchymal routes, are being studied; research is being conducted on intrathecal delivery for amyotrophic lateral sclerosis (ALS), intracerebroventricular delivery for Parkinson's disease and Alzheimer's disease, and intrahippocampal delivery for seizure disorders. Treatment of other neurologic disorders, such as brain tumors and HIV-related viral infections, also may be optimized by methods of local drug delivery, including intratumoral and intraparenchymal administration of potentially effective agents. Intraspinal, intratumoral, and intraparenchymal routes of administration are speculated to become critical components of treatment for a variety of neurological indications.}, }
@article {pmid24522853, year = {1968}, author = {Elstner, E and Pistorius, E and Böger, P and Trebst, A}, title = {[The role of plastocyanin and cytochrome f in photosynthetic electron transport].}, journal = {Planta}, volume = {79}, number = {2}, pages = {146-161}, pmid = {24522853}, issn = {0032-0935}, abstract = {The dependence of photosynthetic NADP reduction on plastocyanin in three different fragmented systems from spinach chloroplasts was investigated. 1. In sonicated chloroplasts oxygen evolution and NADP reduction is restored by the addition of 3 mμmoles of plastocyanin obtained from spinach. Thirty mμmoles of cytochrome552 from Euglena replaces plastocyanin at pH 7.4 to about 75% and at pH 8.0 to only about 30%. NADP reduction at the expense of an artificial donor system by the same sonicated chloroplast preparation is, however, restored by plastocyanin and cytochrome552 equally well. 2. It is already well documented that in digitonin fragmented chloroplasts NADP reduction at the expense of an artificial donor system is stimulated by the addition of plastocyanin. Cytochrome552 from Euglena is as effective as plastocyanin in this system. 3. Heptane treatment of chloroplasts followed by water extraction also leads to the liberation of plastocyanin. NADP reduction in heptane treated chloroplasts at the expense of an artificial donor system is stimulated either by the addition of plastocyanin or of cytochrome552. These results show that in three different types of particles from spinach chloroplasts both plastocyanin (spinach) and cytochrome552 (Euglena) are equally effective als electron donors for pigment system I of photosynthesis, coupled to NADP reduction. This conclusion follows from the fact that both are equally effective in stimulating NADP reduction at the expense of an artificial electron donor system. In sonicated chloroplasts plastocyanin seems to be the better electron acceptor for electrons coming from the photooxidation of water by light reaction II, since addition of plastocyanin to a system depending on oxygen evolution yields better rates than addition of cytochrome552.In order to explain the result that there are two possible electron donors for pigment system I it is suggested that there are two-perhaps spatially separated-pigment systems I in photosynthesis which are participating in a non-cyclic or a cyclic electron transport system and which are either coupled to plastocyanin or to cytochrome f. The difference in rates mentioned above may indicate that plastocyanin is a component of non-cyclic and cytochrome f of cyclic electron flow. The cyclic system can be converted into a non-cyclic system by the addition of an artificial electron donor and NADP.}, }
@article {pmid22091594, year = {2011}, author = {de Carvalho, M and Pinto, S}, title = {Lithium treatment in amyotrophic lateral sclerosis: do we have enough trials?.}, journal = {Expert review of neurotherapeutics}, volume = {11}, number = {12}, pages = {1693-1698}, doi = {10.1586/ern.11.164}, pmid = {22091594}, issn = {1744-8360}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder; riluzole is marginally effective, and as a consequence a large number of trials are regularly reported. Lithium raised marked enthusiasm based on the report of a pilot study that suggested very positive results. Two previous trials were negative, applying a different methodology. The reviewed article reports the results of a third trial using a historical control group. In this trial, lithium was detrimental to ALS progression. Two more trials testing lithium in ALS are in progress. This study is discussed in the context of the great competitive effort that was derived from the unsupported hope created by a false-positive preliminary study.}, }
@article {pmid22090490, year = {2011}, author = {Chestnut, BA and Chang, Q and Price, A and Lesuisse, C and Wong, M and Martin, LJ}, title = {Epigenetic regulation of motor neuron cell death through DNA methylation.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {31}, number = {46}, pages = {16619-16636}, pmid = {22090490}, issn = {1529-2401}, support = {R01 NS065895-01/NS/NINDS NIH HHS/United States ; NS034100/NS/NINDS NIH HHS/United States ; R01 NS052098/NS/NINDS NIH HHS/United States ; NS052098/NS/NINDS NIH HHS/United States ; R01 AG016282-01A1/AG/NIA NIH HHS/United States ; R01 NS034100/NS/NINDS NIH HHS/United States ; R01 NS079348/NS/NINDS NIH HHS/United States ; R01 NS052098-02/NS/NINDS NIH HHS/United States ; AG016282/AG/NIA NIH HHS/United States ; R01 AG016282/AG/NIA NIH HHS/United States ; NS065895/NS/NINDS NIH HHS/United States ; R01 NS065895/NS/NINDS NIH HHS/United States ; R01 NS034100-04/NS/NINDS NIH HHS/United States ; }, mesh = {5-Methylcytosine/analogs &amp; derivatives ; Age Factors ; Amyloid Precursor Protein Secretases/genetics/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Animals ; Apoptosis/drug effects/*genetics ; Aspartic Acid Endopeptidases/genetics/metabolism ; Camptothecin/pharmacology ; Caspase 3/metabolism ; Cell Line, Transformed ; Central Nervous System/growth &amp; development/metabolism ; Cytosine/analogs &amp; derivatives/metabolism ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA Methylation/*genetics ; DNA Methyltransferase 3A ; Disease Models, Animal ; Enzyme Inhibitors/pharmacology ; Epigenomics/*methods ; Gene Expression Regulation, Developmental/drug effects/genetics ; Green Fluorescent Proteins/genetics ; Humans ; Indoles/pharmacology ; Mice ; Mice, Transgenic ; Motor Neurons/*physiology ; Mutation/genetics ; Phthalimides ; Propionates/pharmacology ; RNA, Small Interfering/genetics/metabolism ; Sciatic Neuropathy/metabolism/pathology ; Superoxide Dismutase/metabolism ; Transfection ; Tryptophan/analogs &amp; derivatives ; Up-Regulation/drug effects/*genetics ; }, abstract = {DNA methylation is an epigenetic mechanism for gene silencing engaged by DNA methyltransferase (Dnmt)-catalyzed methyl group transfer to cytosine residues in gene-regulatory regions. It is unknown whether aberrant DNA methylation can cause neurodegeneration. We tested the hypothesis that Dnmts can mediate neuronal cell death. Enforced expression of Dnmt3a induced degeneration of cultured NSC34 cells. During apoptosis of NSC34 cells induced by camptothecin, levels of Dnmt1 and Dnmt3a increased fivefold and twofold, respectively, and 5-methylcytosine accumulated in nuclei. Truncation mutation of the Dnmt3a catalytic domain and Dnmt3a RNAi blocked apoptosis of cultured neurons. Inhibition of Dnmt catalytic activity with RG108 and procainamide protected cultured neurons from excessive DNA methylation and apoptosis. In vivo, Dnmt1 and Dnmt3a are expressed differentially during mouse brain and spinal cord maturation and in adulthood when Dnmt3a is abundant in synapses and mitochondria. Dnmt1 and Dnmt3a are expressed in motor neurons of adult mouse spinal cord, and, during their apoptosis induced by sciatic nerve avulsion, nuclear and cytoplasmic 5-methylcytosine immunoreactivity, Dnmt3a protein levels and Dnmt enzyme activity increased preapoptotically. Inhibition of Dnmts with RG108 blocked completely the increase in 5-methycytosine and the apoptosis of motor neurons in mice. In human amyotrophic lateral sclerosis (ALS), motor neurons showed changes in Dnmt1, Dnmt3a, and 5-methylcytosine similar to experimental models. Thus, motor neurons can engage epigenetic mechanisms to drive apoptosis, involving Dnmt upregulation and increased DNA methylation. These cellular mechanisms could be relevant to human ALS pathobiology and disease treatment.}, }
@article {pmid22084410, year = {2011}, author = {Swarup, V and Phaneuf, D and Dupré, N and Petri, S and Strong, M and Kriz, J and Julien, JP}, title = {Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB-mediated pathogenic pathways.}, journal = {The Journal of experimental medicine}, volume = {208}, number = {12}, pages = {2429-2447}, pmid = {22084410}, issn = {1540-9538}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Analysis of Variance ; Animals ; Blotting, Western ; DNA Primers/genetics ; DNA-Binding Proteins/genetics/*metabolism ; Electrophoretic Mobility Shift Assay ; Enzyme-Linked Immunosorbent Assay ; Humans ; Immunoprecipitation ; Mass Spectrometry ; Mice ; Mice, Transgenic ; Microscopy, Fluorescence ; Neuroglia/metabolism ; Neuromuscular Junction/drug effects/*metabolism ; Neurons/metabolism ; RNA Interference ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/*physiology ; Spinal Cord/cytology/pathology ; Transcription Factor RelA/antagonists &amp; inhibitors/*metabolism ; Transgenes/genetics ; Withanolides/pharmacology ; }, abstract = {TDP-43 (TAR DNA-binding protein 43) inclusions are a hallmark of amyotrophic lateral sclerosis (ALS). In this study, we report that TDP-43 and nuclear factor κB (NF-κB) p65 messenger RNA and protein expression is higher in spinal cords in ALS patients than healthy individuals. TDP-43 interacts with and colocalizes with p65 in glial and neuronal cells from ALS patients and mice expressing wild-type and mutant TDP-43 transgenes but not in cells from healthy individuals or nontransgenic mice. TDP-43 acted as a co-activator of p65, and glial cells expressing higher amounts of TDP-43 produced more proinflammatory cytokines and neurotoxic mediators after stimulation with lipopolysaccharide or reactive oxygen species. TDP-43 overexpression in neurons also increased their vulnerability to toxic mediators. Treatment of TDP-43 mice with Withaferin A, an inhibitor of NF-κB activity, reduced denervation in the neuromuscular junction and ALS disease symptoms. We propose that TDP-43 deregulation contributes to ALS pathogenesis in part by enhancing NF-κB activation and that NF-κB may constitute a therapeutic target for the disease.}, }
@article {pmid22081209, year = {2011}, author = {Carrì, MT and Cozzolino, M}, title = {SOD1 and mitochondria in ALS: a dangerous liaison.}, journal = {Journal of bioenergetics and biomembranes}, volume = {43}, number = {6}, pages = {593-599}, pmid = {22081209}, issn = {1573-6881}, support = {GGP07018/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Animals ; Calcium/metabolism ; Energy Metabolism/genetics ; Humans ; Mitochondria/*enzymology/genetics ; *Protein Folding ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Mutant Cu,Zn superoxide dismutase (mutSOD1) is found in a subset of patients with familial amyotrophic lateral sclerosis (ALS), a fatal progressive paralysis due to loss of motor neurons. In the present article, we review existing evidence linking the expression of mutSOD1 to the many facets of mitochondrial dysfunction in ALS, with a focus on recent studies suggesting that the association and misfolding of the mutant protein (and possibly of the wild type protein as well) within these organelles is causally linked to their functional and structural alterations. Energy deficit, calcium mishandling and oxidative stress are paralleled by alteration in mitochondrial motility, dynamics and turnover and most probably lead to mitochondria-dependent cell death. Thus, the development of new, selective mitochondria-targeted therapies may constitute a promising approach in the treatment of SOD1-linked ALS.}, }
@article {pmid22072391, year = {2012}, author = {Martorana, F and Brambilla, L and Valori, CF and Bergamaschi, C and Roncoroni, C and Aronica, E and Volterra, A and Bezzi, P and Rossi, D}, title = {The BH4 domain of Bcl-X(L) rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals.}, journal = {Human molecular genetics}, volume = {21}, number = {4}, pages = {826-840}, doi = {10.1093/hmg/ddr513}, pmid = {22072391}, issn = {1460-2083}, support = {GGP05244/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Animals ; Astrocytes/cytology/drug effects/*metabolism/*pathology ; *Calcium Signaling/drug effects ; Cell Death/drug effects ; Female ; Gene Expression Regulation ; Humans ; Male ; Mice ; Mice, Transgenic ; Peptides/chemistry/metabolism/pharmacology ; Protein Structure, Tertiary ; Psychomotor Performance/drug effects ; Receptors, Kainic Acid/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Survival Analysis ; bcl-X Protein/*chemistry/*metabolism/pharmacology ; }, abstract = {Collective evidence indicates that motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is non-cell-autonomous and requires the interaction with the neighboring astrocytes. Recently, we reported that a subpopulation of spinal cord astrocytes degenerates in the microenvironment of motor neurons in the hSOD1(G93A) mouse model of ALS. Mechanistic studies in vitro identified a role for the excitatory amino acid glutamate in the gliodegenerative process via the activation of its inositol 1,4,5-triphosphate (IP(3))-generating metabotropic receptor 5 (mGluR5). Since non-physiological formation of IP(3) can prompt IP(3) receptor (IP(3)R)-mediated Ca(2+) release from the intracellular stores and trigger various forms of cell death, here we investigated the intracellular Ca(2+) signaling that occurs downstream of mGluR5 in hSOD1(G93A)-expressing astrocytes. Contrary to wild-type cells, stimulation of mGluR5 causes aberrant and persistent elevations of intracellular Ca(2+) concentrations ([Ca(2+)](i)) in the absence of spontaneous oscillations. The interaction of IP(3)Rs with the anti-apoptotic protein Bcl-X(L) was previously described to prevent cell death by modulating intracellular Ca(2+) signals. In mutant SOD1-expressing astrocytes, we found that the sole BH4 domain of Bcl-X(L), fused to the protein transduction domain of the HIV-1 TAT protein (TAT-BH4), is sufficient to restore sustained Ca(2+) oscillations and cell death resistance. Furthermore, chronic treatment of hSOD1(G93A) mice with the TAT-BH4 peptide reduces focal degeneration of astrocytes, slightly delays the onset of the disease and improves both motor performance and animal lifespan. Our results point at TAT-BH4 as a novel glioprotective agent with a therapeutic potential for ALS.}, }
@article {pmid22070610, year = {2012}, author = {Feng, Z and Gao, F}, title = {Stem cell challenges in the treatment of neurodegenerative disease.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {18}, number = {2}, pages = {142-148}, pmid = {22070610}, issn = {1755-5949}, mesh = {Alzheimer Disease/pathology/surgery ; Amyotrophic Lateral Sclerosis/pathology/surgery ; Animals ; Clinical Trials as Topic ; Humans ; Neurodegenerative Diseases/pathology/*surgery ; Parkinson Disease/pathology/surgery ; Stem Cell Transplantation/*methods/*trends ; Stem Cells/physiology ; Treatment Outcome ; }, abstract = {Neurodegenerative diseases result from the gradual and progressive loss of neural cells and lead to nervous system dysfunction. The rapidly advancing stem cell field is providing attractive alternative options for fighting these diseases. Results have provided proof of principle that cell replacement can work in humans with Parkinson's disease (PD). However, three clinical studies of cell transplantation were published that found no net benefit, while patients in two of the studies developed dyskinesias that persisted despite reductions in treatment. Induced pluripotent stem cells (iPSC) have major potential advantages because patient-specific neuroblasts are suitable for transplantation, avoid immune reactions, and can be produced without the use of human ES cells (hESC). Although iPSCs have not been successfully used in clinical trials for PD, patients with amyotrophic lateral sclerosis (ALS) were treated with autologous stem cells and, though they had some degree of decline one year after treatment, they were still improved compared with the preoperative period or without any drug therapy. In addition, neural stem cells (NSCs), via brain-derived neurotrophic factor (BDNF), have been shown to ameliorate complex behavioral deficits associated with widespread Alzheimer's disease (AD) pathology in a transgenic mouse model of AD. So far, the FDA lists 18 clinical trials treating multiple sclerosis (MS), but most are in preliminary stages. This article serves as an overview of recent studies in stem cell and regenerative approaches to the above chronic neurodegenerative disorders. There are still many obstacles to the use of stem cells as a cure for neurodegenerative disease, especially because we still don't fully understand the true mechanisms of these diseases. However, there is hope in the potential of stem cells to help us learn and understand a great deal more about the mechanisms underlying these devastating neurodegenerative diseases.}, }
@article {pmid22069580, year = {2010}, author = {Drachman, DB and Adams, RN and Balasubramanian, U and Lu, Y}, title = {Strategy for treating motor neuron diseases using a fusion protein of botulinum toxin binding domain and streptavidin for viral vector access: work in progress.}, journal = {Toxins}, volume = {2}, number = {12}, pages = {2872-2889}, pmid = {22069580}, issn = {2072-6651}, mesh = {Animals ; Botulinum Toxins, Type A/chemistry/*genetics ; Cell Line, Tumor ; Chick Embryo ; Dependovirus/genetics ; Genetic Therapy ; Genetic Vectors ; Mice ; Motor Neuron Disease/*therapy ; Protein Structure, Tertiary ; Rats ; Recombinant Fusion Proteins/*therapeutic use ; Streptavidin/*genetics ; }, abstract = {Although advances in understanding of the pathogenesis of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) have suggested attractive treatment strategies, delivery of agents to motor neurons embedded within the spinal cord is problematic. We have designed a strategy based on the specificity of botulinum toxin, to direct entry of viral vectors carrying candidate therapeutic genes into motor neurons. We have engineered and expressed fusion proteins consisting of the binding domain of botulinum toxin type A fused to streptavidin (SAv). This fusion protein will direct biotinylated viral vectors carrying therapeutic genes into motor nerve terminals where they can enter the acidified endosomal compartments, be released and undergo retrograde transport, to deliver the genes to motor neurons. Both ends of the fusion proteins are shown to be functionally intact. The binding domain end binds to mammalian nerve terminals at neuromuscular junctions, ganglioside GT1b (a target of botulinum toxin), and a variety of neuronal cells including primary chick embryo motor neurons, N2A neuroblastoma cells, NG108-15 cells, but not to NG CR72 cells, which lack complex gangliosides. The streptavidin end binds to biotin, and to a biotinylated Alexa 488 fluorescent tag. Further studies are in progress to evaluate the delivery of genes to motor neurons in vivo, by the use of biotinylated viral vectors.}, }
@article {pmid22035690, year = {2011}, author = {Stern, RA and Riley, DO and Daneshvar, DH and Nowinski, CJ and Cantu, RC and McKee, AC}, title = {Long-term consequences of repetitive brain trauma: chronic traumatic encephalopathy.}, journal = {PM &amp; R : the journal of injury, function, and rehabilitation}, volume = {3}, number = {10 Suppl 2}, pages = {S460-7}, doi = {10.1016/j.pmrj.2011.08.008}, pmid = {22035690}, issn = {1934-1563}, mesh = {Age Factors ; Athletic Injuries/complications ; Brain/*pathology ; Brain Concussion/*complications ; Brain Injury, Chronic/diagnosis/*etiology ; Humans ; Microscopy ; Risk Factors ; Sex Factors ; }, abstract = {Chronic traumatic encephalopathy (CTE) has been linked to participation in contact sports such as boxing and American football. CTE results in a progressive decline of memory and cognition, as well as depression, suicidal behavior, poor impulse control, aggressiveness, parkinsonism, and, eventually, dementia. In some individuals, it is associated with motor neuron disease, referred to as chronic traumatic encephalomyelopathy, which appears clinically similar to amyotrophic lateral sclerosis. Results of neuropathologic research has shown that CTE may be more common in former contact sports athletes than previously believed. It is believed that repetitive brain trauma, with or possibly without symptomatic concussion, is responsible for neurodegenerative changes highlighted by accumulations of hyperphosphorylated tau and TDP-43 proteins. Given the millions of youth, high school, collegiate, and professional athletes participating in contact sports that involve repetitive brain trauma, as well as military personnel exposed to repeated brain trauma from blast and other injuries in the military, CTE represents an important public health issue. Focused and intensive study of the risk factors and in vivo diagnosis of CTE will potentially allow for methods to prevent and treat these diseases. Research also will provide policy makers with the scientific knowledge to make appropriate guidelines regarding the prevention and treatment of brain trauma in all levels of athletic involvement as well as the military theater.}, }
@article {pmid22056419, year = {2012}, author = {Feng, X and Peng, Y and Liu, M and Cui, L}, title = {DL-3-n-butylphthalide extends survival by attenuating glial activation in a mouse model of amyotrophic lateral sclerosis.}, journal = {Neuropharmacology}, volume = {62}, number = {2}, pages = {1004-1010}, doi = {10.1016/j.neuropharm.2011.10.009}, pmid = {22056419}, issn = {1873-7064}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism ; Animals ; Benzofurans/pharmacology/*therapeutic use ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects/metabolism ; Neuroglia/*drug effects/metabolism ; Neuroprotective Agents/pharmacology/*therapeutic use ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease characterized by progressive muscular atrophy, paralysis and bulbar symptoms. Transgenic mice over-expressing human mutant Cu/Zn superoxide dismutase-1 (SOD1) mimicked the pathological phenotype of ALS. dl-3-n-butylphthalide (dl-NBP) has been demonstrated to play a neuroprotective role in cerebral ischemia, vascular dementia, and Alzheimer's disease. In the current study, we examined the effect of dl-NBP in Tg (SOD1-G93A) transgenic mice, a well-studied model of ALS. Following the symptomatic onset of disease, oral administration of dl-NBP significantly improved motor performance, extended the survival interval, attenuated motor neuron loss, and delayed motor unit reduction compared to vehicle controls. These observations were further corroborated by the significant reduction in immunoreactivity of CD11b and glial fibrillary acidic protein (GFAP), markers for microglia and astrocytes, respectively. Additionally, downregulation of nuclear factor κB (NF-κB) p65 and tumor necrosis factor-α (TNF-α) protein levels and a slight upregulation of NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were found in the spinal cord of Tg (SOD1-G93A) mice treated by dl-NBP. These results suggest that dl-NBP might be a promising compound in the treatment of ALS. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.}, }
@article {pmid22052286, year = {2012}, author = {Fuentealba, RA and Marasa, J and Diamond, MI and Piwnica-Worms, D and Weihl, CC}, title = {An aggregation sensing reporter identifies leflunomide and teriflunomide as polyglutamine aggregate inhibitors.}, journal = {Human molecular genetics}, volume = {21}, number = {3}, pages = {664-680}, pmid = {22052286}, issn = {1460-2083}, support = {R01 AG031867/AG/NIA NIH HHS/United States ; P50 CA94056/CA/NCI NIH HHS/United States ; AG031867/AG/NIA NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Cell Line ; Crotonates/*pharmacology ; Drug Evaluation, Preclinical/methods ; HEK293 Cells ; Humans ; Hydroxybutyrates ; Isoxazoles/*pharmacology ; Leflunomide ; Luciferases, Firefly/analysis/genetics ; Molecular Sequence Data ; Nerve Tissue Proteins/chemistry/genetics ; Nitriles ; Peptides/*chemistry ; Pyrimidines/biosynthesis ; Recombinant Fusion Proteins/analysis/chemistry ; Toluidines/*pharmacology ; }, abstract = {Intracellular protein aggregation is a common pathologic feature in neurodegenerative diseases such as Huntington' disease, amyotrophic lateral sclerosis and Parkinson' disease. Although progress towards understanding protein aggregation in vitro has been made, little of this knowledge has translated to patient therapy. Moreover, mechanisms controlling aggregate formation and catabolism in cellulo remain poorly understood. One limitation is the lack of tools to quantitatively monitor protein aggregation and disaggregation. Here, we developed a protein-aggregation reporter that uses huntingtin exon 1 containing 72 glutamines fused to the N-terminal end of firefly luciferase (httQ72-Luc). httQ72-Luc fails to aggregate unless seeded by a non-luciferase-containing polyglutamine (polyQ) protein such as Q80-cfp. Upon co-aggregation, httQ72-luc becomes insoluble and loses its enzymatic activity. Using httQ72-Luc with Q80(CFP/YFP) as seeds, we screened the Johns Hopkins Clinical Compound Library and identified leflunomide, a dihydroorotate dehydrogenase inhibitor with immunosuppressive and anti-psoriatic activities, as a novel drug that prevents polyQ aggregation. Leflunomide and its active metabolite teriflunomide inhibited protein aggregation independently of their known role in pyrimidine biosynthesis, since neither uridine treatment nor other pyrimidine biosynthesis inhibitors affected polyQ aggregation. Inducible cell line and cycloheximide-chase experiments indicate that these drugs prevent incorporation of expanded polyQ into an aggregate. This study demonstrates the usefulness of luciferase-based protein aggregate reporters for high-throughput screening applications. As current trials are under-way for teriflunomide in the treatment of multiple sclerosis, we propose that this drug be considered a possible therapeutic agent for polyQ diseases.}, }
@article {pmid22047468, year = {2011}, author = {Venizelos, A and Park, Y and Fisher, MA}, title = {A patient with amyotrophic lateral sclerosis and atypical clinical and electrodiagnostic features: a case report.}, journal = {Journal of medical case reports}, volume = {5}, number = {}, pages = {538}, pmid = {22047468}, issn = {1752-1947}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis is a rapidly progressive, fatal neurodegenerative disorder for which there is no effective treatment. The diagnosis is dependent on the clinical presentation and consistent electrodiagnostic studies. Typically, there is a combination of upper and lower motor neuron signs as well as electrodiagnostic studies indicative of diffuse motor axonal injury. The presentation of amyotrophic lateral sclerosis, however, may be variable. At the same time, the diagnosis is essential for patient prognosis and management. It is therefore important to appreciate the range of possible presentations of amyotrophic lateral sclerosis.<br><br>CASE PRESENTATION: We present the case of a 57-year-old Caucasian man with pathological findings on postmortem examination consistent with amyotrophic lateral sclerosis but atypical clinical and electrodiagnostic features. He died after a rapid course of progressive weakness. The patient did not respond to immunosuppressive therapy.<br><br>CONCLUSION: Amyotrophic lateral sclerosis should be considered in patients with a rapidly progressive, unexplained neuropathic process. This should be true even if there are atypical clinical and electrodiagnostic findings. Absence of response to therapy and the development of upper motor neuron signs should reinforce the possibility that amyotrophic lateral sclerosis may be present. Since amyotrophic lateral sclerosis is a fatal illness, however, the possibility of this disease in patients with atypical clinical features should not diminish the need for a thorough diagnostic evaluation and treatment trials.}, }
@article {pmid22045940, year = {2011}, author = {Nutt, D}, title = {Low serotonergic tone and elevated risk for substance misuse.}, journal = {The British journal of psychiatry : the journal of mental science}, volume = {199}, number = {5}, pages = {353-354}, doi = {10.1192/bjp.bp.110.090589}, pmid = {22045940}, issn = {1472-1465}, support = {G1002226/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Cocaine/*pharmacology ; Cocaine-Related Disorders/*metabolism ; Corpus Striatum/*metabolism ; Dopamine/*metabolism ; Dopamine Uptake Inhibitors/*pharmacology ; Female ; Humans ; Male ; Serotonin/*metabolism ; }, abstract = {Cox et al's paper addresses an issue that has long been assumed to be a central aspect of brain function - the interplay of different neurotransmitters - but for which we have very little evidence so far. It is currently unclear whether these findings will have implications for the treatment of those with cocaine or other substance dependence.}, }
@article {pmid22041967, year = {2012}, author = {Raghavan, A and Shah, ZA}, title = {Sirtuins in neurodegenerative diseases: a biological-chemical perspective.}, journal = {Neuro-degenerative diseases}, volume = {9}, number = {1}, pages = {1-10}, pmid = {22041967}, issn = {1660-2862}, support = {R00 AT004197/AT/NCCIH NIH HHS/United States ; R00AT004197/AT/NCCIH NIH HHS/United States ; }, mesh = {Aging ; Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Brain Ischemia/drug therapy ; Group III Histone Deacetylases/chemistry/metabolism/therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy ; Parkinson Disease/drug therapy ; Protein Structure, Tertiary ; *Sirtuins/chemistry/metabolism/therapeutic use ; Substrate Specificity ; }, abstract = {Sirtuins, commonly known as NAD(+)-dependent class III histone deacetylase enzymes, have been extensively studied to evaluate their potential role in different disease states. Based on the published literature, sirtuins have been implicated in providing a myriad of intrinsic and extrinsic biological effects, which in turn may play an important role in the treatment of various disorders such as type II diabetes, obesity, cancer, aging and different neurodegenerative diseases. In particular, a number of studies have unequivocally supported the idea of sirtuins having therapeutic potential in neurodegenerative diseases such as stroke, ischemic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. To exploit the therapeutic potential of sirtuins, their manipulation in terms of development of small-molecule modulators, inhibitors and analogs has increased dramatically since their inception, in both scientific and industrial worlds. Studies on the structure and catalytic core of sirtuins along with chemical mechanisms and substrate specificity have provided important input into the design and synthesis of sirtuin modulators. To study the role of sirtuins in the biological system, it has become extremely important to understand the molecular and chemical structure of sirtuins. In this review, we have discussed the biological role of sirtuins in various neurodegenerative diseases, and also provided an insight into their chemical structure.}, }
@article {pmid22040776, year = {2012}, author = {McLennan, S}, title = {CPR policies and the patient's best interests.}, journal = {Resuscitation}, volume = {83}, number = {2}, pages = {168-170}, doi = {10.1016/j.resuscitation.2011.10.007}, pmid = {22040776}, issn = {1873-1570}, mesh = {Cardiopulmonary Resuscitation/*standards ; Humans ; *Policy ; *Quality Improvement ; }, abstract = {Standard hospital CPR policies in many countries require CPR to be attempted on all patients having a cardiac arrest unless a Not-for-CPR order is in place. It has recently been shown that this approach is legally inappropriate in New Zealand. It appears that this argument may also potentially apply in other common law countries given the role that 'best interests' has in these jurisdictions in providing treatment to patients lacking decision-making capacity. Not-for-CPR orders provide an important and transparent mechanism for making advanced decisions regarding resuscitation. However, advanced planning is not always possible and it is legally inappropriate to require CPR to be performed when it is not in the patient's best interests. Notwithstanding the difficult practical balance that exists at the time of arrest between initiating CPR without delay or interruption for it to be effective for those whom CPR is in their best interests, and recognising as quickly as possible those patients for who CPR is not appropriate, it is argued that policies should be modified to allow clinicians to consider whether CPR is appropriate at time of arrest. Such a change may require ALS training to include a stronger emphasis on early recognition of patients for whom CPR is not in their best interests.}, }
@article {pmid22038570, year = {2011}, author = {Wąsowicz, W and Cieślak, M and Palus, J and Stańczyk, M and Dziubałtowska, E and Stępnik, M and Düchler, M}, title = {Evaluation of biological effects of nanomaterials. Part I. Cyto- and genotoxicity of nanosilver composites applied in textile technologies.}, journal = {International journal of occupational medicine and environmental health}, volume = {24}, number = {4}, pages = {348-358}, doi = {10.2478/s13382-011-0041-z}, pmid = {22038570}, issn = {1896-494X}, mesh = {Biological Assay/methods ; Cytotoxins/*analysis/genetics/*poisoning ; DNA Damage/drug effects ; Humans ; Mutagens/*analysis/*poisoning ; Nanostructures/*poisoning ; Occupational Exposure/adverse effects/analysis ; Poland ; Reactive Oxygen Species/analysis ; Silver/*adverse effects/*metabolism ; *Textile Industry ; }, abstract = {OBJECTIVES: The aim of this study was to investigate the cyto- and genotoxicity of nanocomposites (NCs) and generation of reactive oxygen species (ROS) as a result of particle-cell interactions.<br><br>MATERIALS AND METHODS: Titanium dioxide (TiO(2)-Ag) and ion-exchange resin (Res-Ag), both coated with silver (Ag), were examined. The murine macrophage J774A.1 cells were incubated in vitro with NC at different concentrations for 24 h. Cytotoxicity was analyzed by the methylthiazolyldiphenyl-tetrazolium bromide reduction test (MTT reduction test). ROS generation was assessed by incubation of cells with dichlorodihydrofluorescein diacetate (DCF) and flow cytometry. DNA damage was detected by comet assay and included single-strand breaks (SSB), alkali-labile sites (ALS) and oxidative DNA damage after formamidopyrimidine glycosylase (FPG) treatment. The tail moment was used as an indicator of DNA damage.<br><br>RESULTS: TiO(2)-Ag was not cytotoxic up to 200 &#x3bc;g/ml, whereas IC(50) for Res-Ag was found to be 23 &#x3bc;g/ml. Intracellular ROS levels were elevated after 4 h of exposure to Res-Ag at the concentration of 50 &#x3bc;g/ml. Both types of NC induced fragmentation of DNA strands, but only one of the composites caused damage to purine bases. TiO(2)-Ag induced SSB of DNA at concentrations of 10 and 5 &#x3bc;g/ml. For Res-Ag, a concentration-dependent increase in tail moments was observed.<br><br>CONCLUSIONS: Silver-coated nanocomposites (both TiO(2)-Ag and Res-Ag) may cause genotoxic effects in murine macrophages J774A.1. Res-Ag increased generation of ROS which suggested that toxicity of Res-Ag in murine macrophages is likely to be mediated through oxidative stress. This paper will support industry and regulators alike in the assessment of hazards and risks and methods for their mitigation at the earliest possible stage in material and product development.}, }
@article {pmid22033929, year = {2011}, author = {Soon, CPW and Donnelly, PS and Turner, BJ and Hung, LW and Crouch, PJ and Sherratt, NA and Tan, JL and Lim, NK and Lam, L and Bica, L and Lim, S and Hickey, JL and Morizzi, J and Powell, A and Finkelstein, DI and Culvenor, JG and Masters, CL and Duce, J and White, AR and Barnham, KJ and Li, QX}, title = {Diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)) protects against peroxynitrite-induced nitrosative damage and prolongs survival in amyotrophic lateral sclerosis mouse model.}, journal = {The Journal of biological chemistry}, volume = {286}, number = {51}, pages = {44035-44044}, pmid = {22033929}, issn = {1083-351X}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Antioxidants/chemistry ; Astrocytes/cytology ; Coordination Complexes ; Copper/chemistry ; DNA-Binding Proteins/pharmacology ; Disease Models, Animal ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/cytology ; Neurodegenerative Diseases/embryology ; Neurons/metabolism ; Organometallic Compounds/*chemistry ; Oxidative Stress ; Oxygen/chemistry ; Peroxynitrous Acid/*metabolism ; Spinal Cord/pathology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Thiosemicarbazones/*chemistry ; Transgenes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive paralyzing disease characterized by tissue oxidative damage and motor neuron degeneration. This study investigated the in vivo effect of diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)), which is an orally bioavailable, blood-brain barrier-permeable complex. In vitro the compound inhibits the action of peroxynitrite on Cu,Zn-superoxide dismutase (SOD1) and subsequent nitration of cellular proteins. Oral treatment of transgenic SOD1G93A mice with CuII(atsm) at presymptomatic and symptomatic ages was performed. The mice were examined for improvement in lifespan and motor function, as well as histological and biochemical changes to key disease markers. Systemic treatment of SOD1G93A mice significantly delayed onset of paralysis and prolonged lifespan, even when administered to symptomatic animals. Consistent with the properties of this compound, treated mice had reduced protein nitration and carbonylation, as well as increased antioxidant activity in spinal cord. Treatment also significantly preserved motor neurons and attenuated astrocyte and microglial activation in mice. Furthermore, CuII(atsm) prevented the accumulation of abnormally phosphorylated and fragmented TAR DNA-binding protein-43 (TDP-43) in spinal cord, a protein pivotal to the development of ALS. CuII(atsm) therefore represents a potential new class of neuroprotective agents targeting multiple major disease pathways of motor neurons with therapeutic potential for ALS.}, }
@article {pmid22033150, year = {2012}, author = {Bendotti, C and Marino, M and Cheroni, C and Fontana, E and Crippa, V and Poletti, A and De Biasi, S}, title = {Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: implication for protein aggregation and immune response.}, journal = {Progress in neurobiology}, volume = {97}, number = {2}, pages = {101-126}, doi = {10.1016/j.pneurobio.2011.10.001}, pmid = {22033150}, issn = {1873-5118}, support = {GGP06063/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*immunology/*metabolism ; Animals ; Humans ; Immunity/*physiology ; Inflammation ; Mice ; Proteasome Endopeptidase Complex/genetics/*metabolism ; Protein Folding ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Ubiquitin/genetics/*metabolism ; }, abstract = {The ubiquitin-proteasome system (UPS) is the major intracellular proteolytic mechanism controlling the degradation of misfolded/abnormal proteins. A common hallmark in amyotrophic lateral sclerosis (ALS) and in other neurodegenerative disorders is the accumulation of misfolded/abnormal proteins into the damaged neurons, leading to the formation of cellular inclusions that are mostly ubiquitin-positive. Although proteolysis is a complex mechanism requiring the participation of different pathways, the abundant accumulation of ubiquitinated proteins strongly suggests an important contribution of UPS to these neuropathological features. The use of cellular and animal models of ALS, particularly those expressing mutant SOD1, the gene mutation most represented in familiar ALS, has provided significant evidence for a role of UPS in protein inclusions formation and motor neuron death. This review will specifically discuss this piece of evidence and provide suggestions of potential strategies for therapeutic intervention. We will also discuss the finding that, unlike the constitutive proteasome subunits, the inducible subunits are overexpressed early during disease progression in SOD1 mice models of ALS. These subunits form the immunoproteasome and generate peptides for the major histocompatibility complex class I molecules, suggesting a role of this system in the immune responses associated with the pathological features of ALS. Since recent discoveries indicate that innate and adaptive immunity may influence the disease process, in this review we will also provide evidence of a possible connection between immune-inflammatory reactions and UPS function, in the attempt to better understand the etiopathology of ALS and to identify appropriate targets for novel treatment strategies of this devastating disease.}, }
@article {pmid22032111, year = {2011}, author = {Orrell, RW}, title = {GPs have key role in managing motor neurone disease.}, journal = {The Practitioner}, volume = {255}, number = {1743}, pages = {19-22, 2}, pmid = {22032111}, issn = {0032-6518}, mesh = {Diagnosis, Differential ; *General Practice ; Humans ; Motor Neuron Disease/*diagnosis/physiopathology/*therapy ; Physical Examination ; }, abstract = {Motor neurone disease (MND) is a rapidly progressive neurodegenerative condition. It affects people of all ages, but is more common with increasing age (especially over 50 years) and men are affected twice as often as women. The causes remain unknown, although around 5% of cases have a genetic basis. Survival is usually only three to five years from diagnosis. MND affects both upper and lower motor neurones, with variable contributions. The nerve involvement in MND usually has a focal onset, is asymmetrical, but tends to spread to adjacent regions of the body. If the affected region is in the legs, a common presenting feature is tripping, falls or foot drop. If it is in the arms there may be difficulty with fine tasks such as fastening buttons, or raising an arm, and if the cranial nerves are affected there may be slurring of speech, or difficulty swallowing. Key to the diagnosis is evidence of progression, and this may lead to some delay in considering and also confirming the diagnosis. When examining the patient, evidence of more widespread neuromuscular involvement should be looked for. In a patient with foot drop, and fasciculation of the tongue, MND would be a likely diagnosis. Upper motor neurone involvement may be readily determined by examining the reflexes. Brisk reflexes, in the arms, legs or jaw, in the context of features of lower motor neurone denervation are highly suggestive of MND. Suspicion of MND should lead to referral for a neurology opinion. The most useful investigation is likely to be EMG with nerve conduction studies, and probably MRI scan of relevant areas. Blood tests are arranged to screen for any other causative condition. Riluzole is a disease modifying drug licensed to extend the life of patients with MND. There is no treatment that will reverse, or halt, progression of the disease.}, }
@article {pmid22019434, year = {2011}, author = {Ruiz-Juretschke, F and Perez-Calvo, JM and Castro, E and García-Leal, R and Mateo-Sierra, O and Fortea, F and Iza, B and Garbizu, JM and Villoria, F}, title = {A single-center, long-term study of spinal dural arteriovenous fistulas with multidisciplinary treatment.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {18}, number = {12}, pages = {1662-1666}, doi = {10.1016/j.jocn.2011.03.008}, pmid = {22019434}, issn = {1532-2653}, mesh = {Adult ; Aged ; Central Nervous System Vascular Malformations/*therapy ; Disability Evaluation ; *Embolization, Therapeutic ; Female ; Follow-Up Studies ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Retrospective Studies ; Spinal Cord/*abnormalities/blood supply ; Spinal Cord Diseases/*therapy ; Treatment Outcome ; }, abstract = {Spinal dural arteriovenous fistulas (SDAVF) are the most frequently occurring vascular malformations of the spinal cord but their optimal treatment remains contentious. We retrospectively analyzed 19 consecutive patients treated between 1996 and 2007. Endovascular embolization was considered the first treatment option for nine patients. Ten patients did not fulfill the endovascular indications and underwent surgery. Four patients required a second treatment with surgery: three following failed embolization and one following surgery. Clinical outcomes were assessed using the Aminoff-Logue disability scale (ALS). The mean follow-up time was 36 months (range=4-103 months). At follow-up, 79% of patients showed stabilization or improvement on the ALS. The overall efficacy of embolization was 55.6%, compared to 100% with surgery (p=0.03). Multidisciplinary treatment with embolization or surgery offers good long-term results. Whenever embolization does not ensure a complete closure of the venous side of the fistula, surgery should be considered as the first treatment because of its lower late recurrence rate.}, }
@article {pmid22017410, year = {2011}, author = {Khomane, KS and Meena, CL and Jain, R and Bansal, AK}, title = {Novel thyrotropin-releasing hormone analogs: a patent review.}, journal = {Expert opinion on therapeutic patents}, volume = {21}, number = {11}, pages = {1673-1691}, doi = {10.1517/13543776.2011.623127}, pmid = {22017410}, issn = {1744-7674}, mesh = {Animals ; Central Nervous System Diseases/*drug therapy/physiopathology ; *Drug Design ; Half-Life ; Humans ; Patents as Topic ; Receptors, Thyrotropin-Releasing Hormone/drug effects/metabolism ; Thyrotropin-Releasing Hormone/analogs &amp; derivatives/pharmacokinetics/*pharmacology ; Tissue Distribution ; }, abstract = {INTRODUCTION: The potential therapeutic applications of thyrotropin-releasing hormone (TRH) have attracted attention, based on its broad-spectrum neuropharmacological action rather than its endocrine properties. These central nervous system (CNS)-mediated effects provide the rationale for use of TRH and its analogs in the treatment of brain and spinal injury, and CNS disorders like schizophrenia, Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis, Parkinson's disease, depression, shock and ischemia.<br><br>AREAS COVERED: This review summarizes the patent literature and advances in the discovery and development of novel TRH analogs over the past 20 years. It provides a comprehensive overview of the development of new TRH analogs, giving emphasis to their pharmaceutical profile.<br><br>EXPERT OPINION: The use of TRH in the treatment of various CNS disorders has been proven clinically. However, TRH itself is a poor drug candidate due to its short plasma half-life (5 min), poor biopharmaceutical properties (low intestinal and CNS permeability) and endocrine side effect. Nevertheless, researchers have come up with metabolically stable, more potent and selective TRH analogs and prodrugs. Taltirelin, one of the TRH analogs, has been approved under the trade name of Ceredist(&#xae;) in Japan for the treatment of spinocerebellar degeneration. Several other TRH analogs are in various stages of preclinical or clinical development.}, }
@article {pmid22013242, year = {2012}, author = {Chiò, A and Calvo, A and Moglia, C and Gamna, F and Mattei, A and Mazzini, L and Mora, G and , }, title = {Non-invasive ventilation in amyotrophic lateral sclerosis: a 10 year population based study.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {83}, number = {4}, pages = {377-381}, doi = {10.1136/jnnp-2011-300472}, pmid = {22013242}, issn = {1468-330X}, mesh = {Adult ; Age of Onset ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/mortality/*therapy ; Comorbidity ; Disease-Free Survival ; Female ; Humans ; Italy ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Neurology/*statistics &amp; numerical data ; Population Surveillance ; Practice Patterns, Physicians'/*statistics &amp; numerical data ; Respiration, Artificial/*statistics &amp; numerical data ; Respiratory Insufficiency/mortality/prevention &amp; control ; Sex Distribution ; Sex Factors ; Socioeconomic Factors ; Surveys and Questionnaires ; Survival Rate ; Tertiary Prevention ; }, abstract = {OBJECTIVE: To evaluate the clinical characteristics and outcome of non-invasive ventilation (NIV) in an epidemiological based series of amyotrophic lateral sclerosis (ALS) patients.<br><br>METHODS: The study was performed using data from the Piemonte and Valle d'Aosta Register for ALS, a prospective epidemiological register enrolling all ALS incident cases in two Italian regions.<br><br>RESULTS: Among the 1260 patients incident in the period 1995-2004, 259 (20.6%) underwent NIV. Young male patients and subjects attending the tertiary ALS centres were more likely to undergo NIV. There was a progressive significant increase in the use of NIV during the study but was limited to patients attending the ALS tertiary centres. Median survival after NIV was 289 days (95% CI 255 to 333).<br><br>CONCLUSIONS: In an epidemiological setting, NIV represents an increasingly utilised option for the treatment of respiratory disturbances in ALS and has favourable effects on survival, in particular among patients followed by tertiary ALS centres. Sociocultural factors, such as age, gender and marital status, strongly influence the probability of undergoing NIV. Efforts should be made to remove these obstacles in order to spread the use of NIV in all ALS patients with respiratory failure.}, }
@article {pmid22013234, year = {2012}, author = {Schuster, JE and Fu, R and Siddique, T and Heckman, CJ}, title = {Effect of prolonged riluzole exposure on cultured motoneurons in a mouse model of ALS.}, journal = {Journal of neurophysiology}, volume = {107}, number = {1}, pages = {484-492}, pmid = {22013234}, issn = {1522-1598}, support = {F31 NS-060532/NS/NINDS NIH HHS/United States ; NS-050162/NS/NINDS NIH HHS/United States ; R01 NS077863/NS/NINDS NIH HHS/United States ; NS-03482/NS/NINDS NIH HHS/United States ; R01 NS034382/NS/NINDS NIH HHS/United States ; }, mesh = {Action Potentials/*drug effects ; Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Animals ; Cells, Cultured ; *Disease Models, Animal ; Female ; Male ; Mice ; Motor Neurons/*drug effects ; Neuronal Plasticity/*drug effects ; Neuroprotective Agents/administration &amp; dosage ; Riluzole/*administration &amp; dosage ; }, abstract = {Riluzole is the only FDA-approved drug to treat amyotrophic lateral sclerosis, but its long-term effects on motoneurons are unknown. Therefore, we treated primary mouse spinal cord cultures with 2 μM riluzole for 4-9 days and then used whole cell patch clamp to record the passive and active properties of both wild-type and SOD1(G93A) motoneurons. At this concentration, riluzole blocks >50% of the sodium component of a persistent inward current that plays a major role in determining motoneuron excitability. Prolonged riluzole treatment significantly decreased the amplitude of the persistent inward current. This effect was specific for SOD1(G93A) motoneurons, where the amplitude decreased by 55.4%. In addition, prolonged treatment hyperpolarized the resting membrane potential as well as the voltage onset and voltage maximum of the persistent inward current (∼2-3 mV in each case). These effects appeared to offset one another and resulted in no change in the firing properties. In a subset of cells, acute reapplication of 2 μM riluzole during the recording decreased repetitive firing and the persistent inward current, which is consistent with the normal effects of riluzole. The downregulation of the persistent inward current in response to prolonged riluzole administration is in contrast to the strong upregulation of this same current after descending neuromodulatory drive to the cord is lost following spinal injury. This dichotomy suggests that decreased activation of G protein-coupled pathways can induce upregulation in the persistent inward current but that direct channel block is ineffective.}, }
@article {pmid21998752, year = {2011}, author = {Moumen, A and Virard, I and Raoul, C}, title = {Accumulation of wildtype and ALS-linked mutated VAPB impairs activity of the proteasome.}, journal = {PloS one}, volume = {6}, number = {10}, pages = {e26066}, pmid = {21998752}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; COS Cells ; Chlorocebus aethiops ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum Stress/genetics ; Gene Expression Regulation/genetics ; Humans ; Mutant Proteins/chemistry/*genetics/*metabolism ; *Mutation ; Proteasome Endopeptidase Complex/*metabolism ; Protein Stability ; Protein Transport/genetics ; Proteolysis ; Ubiquitin/metabolism ; Ubiquitination/genetics ; Vesicular Transport Proteins/chemistry/*genetics/*metabolism ; }, abstract = {Cellular homeostasis relies on a tight control of protein synthesis, folding and degradation, in which the endoplasmic reticulum (ER) quality control and the ubiquitin proteasome system (UPS) have an instrumental function. ER stress and aberrant accumulation of misfolded proteins represent a pathological signature of amyotrophic lateral sclerosis (ALS), a fatal paralytic disorder caused by the selective degeneration of motoneurons in the brain and spinal cord. Mutations in the ER-resident protein VAPB have been associated with familial forms of the disease. ALS-linked mutations cause VAPB to form cytoplasmic aggregates. We previously demonstrated that viral-mediated expression of both wildtype and mutant human VAPB (hVAPB) leads to an ER stress response that contributes to the selective death of motoneurons. However, the mechanisms behind ER stress, defective UPS and hVAPB-associated motoneuron degeneration remain elusive. Here, we show that the overexpression of wildtype and mutated hVAPB, which is found to be less stable than the wildtype protein, leads to the abnormal accumulation of ubiquitin and ubiquitin-like protein conjugates in non-human primate cells. We observed that overexpression of both forms of hVAPB elicited an ER stress response. Treatment of wildtype and mutated hVAPB expressing cells with the ER stress inhibitor salubrinal diminished the burden of ubiquitinated proteins, suggesting that ER stress contributes to the impairment of proteasome function. We also found that both wildtype and mutated hVAPB can associate with the 20S proteasome, which was found to accumulate at the ER with wildtype hVAPB or in mutant hVAPB aggregates. Our results suggest that ER stress and corruption of the proteasome function might contribute to the aberrant protein homeostasis associated with hVAPB.}, }
@article {pmid21998625, year = {2011}, author = {Lougheed, R and Turnbull, J}, title = {Lack of effect of methylene blue in the SOD1 G93A mouse model of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {6}, number = {10}, pages = {e23141}, pmid = {21998625}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/pathology/physiopathology ; Animals ; Disease Models, Animal ; Disease Progression ; Female ; Male ; Methylene Blue/*pharmacology/therapeutic use ; Mice ; Mice, Congenic ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Survival Analysis ; Treatment Outcome ; }, abstract = {BACKGROUND: Methylene blue (MB) is a drug with a long history and good safety profile, and with recently-described features desirable in a treatment for ALS.<br><br>We tested oral MB in inbred high-copy number SOD1 G93A mice, at 25 mg/kg/day beginning at 45 days of age. We measured disease onset, progression, and survival. There was no difference in disease onset between MB-treated mice and controls, although subgroup analysis showed a modest but statistically significant delay in disease onset in MB-treated female mice only (control 122 &#xb1; 10.2 versus MB 129 &#xb1; 10.0 days). MB-treated mice of both sexes spent more time in less severe stages of disease, and less time in later, more severe stages of disease. There was a non-significant trend to longer survival in MB-treated animals (control males reached endpoint at 161 &#xb1; 14.1 days, versus 166 &#xb1; 10.0 days for MB-treated animals, and control females reached endpoint at 171 &#xb1; 6.2 days versus 173 &#xb1; 13.4 days for MB-treated animals).<br><br>CONCLUSIONS/SIGNIFICANCE: In spite of a strong theoretical rationale, MB had no significant effects on onset or survival in the inbred SOD1 G93A mouse model of ALS.}, }
@article {pmid21996525, year = {2012}, author = {Messina, P and Beghi, E}, title = {Modeling drop-outs in amyotrophic lateral sclerosis.}, journal = {Contemporary clinical trials}, volume = {33}, number = {1}, pages = {218-222}, doi = {10.1016/j.cct.2011.09.013}, pmid = {21996525}, issn = {1559-2030}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*therapy ; Antidepressive Agents/therapeutic use ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Lithium Compounds/*therapeutic use ; Male ; Middle Aged ; *Models, Statistical ; Patient Dropouts/*statistics &amp; numerical data ; Time Factors ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) clinical trials suffer a large proportion of drop-outs. Ignoring missing data can lead not only to underpowered tests, but also to selection bias. Current strategies for handling not at random missing data have several limitations. To determine the most effective approach, we compared the standard procedures with the pattern mixture model, using the data from a randomized dose-finding trial on lithium for the treatment of ALS, which reported a high rate of drop-outs (68.4%). We evaluated the ALS Functional Rating Scale-Revised (ALSFRS-R) profile using mixed effect models on different reference populations (1. Intention-to-treat, 2. "Completers", 3. Last observation carried forward, 4. "0-imputation"). All four strategies have limitations on account of: 1. Violation of the "missing completely at random" assumption of the mixed model; 2. Underpowered results on selected patients; 3. Underestimation of the time effect on ALSFRS-R decline and misuse of the assumption that those who discontinued could not get worse; 4. Overestimation of the time effect on ALSFRS-R decline and misuse of the assumption that those who discontinued could not have scores different from zero. The pattern mixture models fitted better than models that did not consider the missing data pattern effect (p=0.006 and p=0.0002). Pattern mixture model thus seem superior and we recommend its use to obtain more accurate estimates even when the information is missing.}, }
@article {pmid21989247, year = {2011}, author = {Hardiman, O and van den Berg, LH and Kiernan, MC}, title = {Clinical diagnosis and management of amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {7}, number = {11}, pages = {639-649}, pmid = {21989247}, issn = {1759-4766}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Humans ; Neuroprotective Agents/therapeutic use ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in progressive loss of bulbar and limb function. Patients typically die from respiratory failure within 3 years of symptom onset. The incidence of ALS in Europe is 2-3 cases per 100,000 individuals in the general population, and the overall lifetime risk of developing the disease is 1:400. ALS is familial in 5% of cases, and shows a Mendelian pattern of inheritance. ALS is recognized to overlap with frontotemporal dementia. Diagnosis is made on clinical grounds, using internationally recognized consensus criteria, after exclusion of conditions that can mimic ALS. The Revised ALS Functional Rating Scale is currently the most widely used assessment tool; scores are used to predict survival, and have been employed extensively in clinical trials. Riluzole remains the only effective drug, and extends the average survival of patients by 3-6 months. Optimal treatment is based on symptom management and preservation of quality of life, provided in a multidisciplinary setting. The discovery of further effective disease-modifying therapies remains a critical need for patients with this devastating condition.}, }
@article {pmid21987545, year = {2011}, author = {Simone, IL and Ruggieri, M and Tortelli, R and Ceci, E and D'Errico, E and Leo, A and Zoccolella, S and Mastrapasqua, M and Capozzo, R and Livrea, P and Logroscino, G}, title = {Serum N-acetylaspartate level in amyotrophic lateral sclerosis.}, journal = {Archives of neurology}, volume = {68}, number = {10}, pages = {1308-1312}, doi = {10.1001/archneurol.2011.217}, pmid = {21987545}, issn = {1538-3687}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*blood/pathology ; Aspartic Acid/*analogs &amp; derivatives/blood ; Case-Control Studies ; Chromatography, Liquid/methods ; Female ; Humans ; Italy ; Logistic Models ; Magnetic Resonance Spectroscopy/methods ; Male ; Mass Spectrometry/methods ; Middle Aged ; Protons ; }, abstract = {BACKGROUND: N -acetylaspartate (NAA) level is a biomarker of functional integrity and vitality in neurons. In vivo multisection proton ((1)H)-magnetic resonance spectroscopy studies indicate that NAA level decreases in specific cortical brain areas of patients with amyotrophic lateral sclerosis (ALS).<br><br>OBJECTIVE: To study NAA level in serum samples as a possible biomarker of ALS.<br><br>DESIGN: Serum NAA assay by liquid chromatography-mass spectrometry in a case-control series.<br><br>SETTING: Department of Neurological and Psychiatric Sciences, Policlinico, University of Bari, Bari, Italy.<br><br>PATIENTS: One hundred twelve consecutive patients with ALS and 51 age- and sex-matched healthy control subjects.<br><br>MAIN OUTCOME MEASURES: General estimating equations tested associations between serum NAA level and clinical variables in patients with ALS.<br><br>RESULTS: Serum NAA level was significantly higher in ALS cases than in controls. Multivariate logistic regression analysis showed a direct association between serum NAA level and the presence of ALS. After stratifying serum NAA level based on the median value (0.171 mmol/L), the age- and sex-adjusted odds ratio for ALS was 19.97 (95% confidence interval, 7.18-55.55) (P < .001). N -acetylaspartate level did not differ across ALS clinical phenotypes. Riluzole treatment did not affect NAA level. A significant correlation was found between serum NAA level and ALS progression rate.<br><br>CONCLUSIONS: High serum NAA level was found in patients with ALS, which may relate to greater excretion of NAA into the blood circulation following increased release of this metabolite from damaged neurons. The correlation between serum NAA level and disease progression rate suggests that it may be a useful biomarker of ALS.}, }
@article {pmid21979788, year = {2012}, author = {Peterson, R and Turnbull, J}, title = {Sonic hedgehog is cytoprotective against oxidative challenge in a cellular model of amyotrophic lateral sclerosis.}, journal = {Journal of molecular neuroscience : MN}, volume = {47}, number = {1}, pages = {31-41}, pmid = {21979788}, issn = {1559-1166}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Cell Line ; Hedgehog Proteins/genetics/*physiology ; Humans ; Hydrogen Peroxide/*toxicity ; Mice ; Neurons/cytology/drug effects/*metabolism ; Oxidants/toxicity ; Oxidative Stress/drug effects/*physiology ; }, abstract = {We have previously demonstrated that primary cilia on spinal motor neurons are reduced in G93A SOD1 (mSOD) mice, a mouse model of amyotrophic lateral sclerosis (ALS). Sonic hedgehog (Shh) signaling involves the primary cilium and Shh has been shown to be cytoprotective in models of other neurodegenerative diseases. Thus, the Shh signaling pathway may bear further study in ALS. Accordingly, we established that interference with the Shh pathway (with the Shh antagonist cyclopamine or with miRNA 3245p) sensitized HT22 cells, while augmentation of the Shh pathway (with Shh or the Shh agonist purmorphamine) protected cells against hydrogen peroxide (H2O2) challenge. We ectopically expressed mSOD, human wild-type SOD1 (wtSOD), or an empty vector in HT22 cells. Compared to empty vector, wtSOD decreased cell death and mSOD increased cell death in response to H2O2 challenge. Treatment with cyclopamine or miRNA 3245p sensitized all three transfections to H2O2 challenge. Treatment with recombinant human Shh or purmorphamine decreased cell death after H2O2 challenge, an effect more pronounced in mSOD cells. Compared with empty vector, overexpression of wtSOD increased Shh and Gli transcript levels and increased activity in a Gli-responsive reporter assay. Overexpression of mSOD did not change Shh transcript levels, but decreased Gli transcript levels, especially Gli3, and reduced activity in a Gli reporter assay. These results suggest that overexpression of mSOD but not wtSOD reduces signaling in the Shh pathway and renders mSOD cells more susceptible to H2O2 challenge, and that treatment with Shh or Shh agonists is cytoprotective to mSOD cells. Shh or Shh agonists merit further consideration as potential therapy in ALS.}, }
@article {pmid21972798, year = {2012}, author = {Chiò, A and Canosa, A and Gallo, S and Moglia, C and Ilardi, A and Cammarosano, S and Papurello, D and Calvo, A}, title = {Pain in amyotrophic lateral sclerosis: a population-based controlled study.}, journal = {European journal of neurology}, volume = {19}, number = {4}, pages = {551-555}, doi = {10.1111/j.1468-1331.2011.03540.x}, pmid = {21972798}, issn = {1468-1331}, mesh = {Activities of Daily Living ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*epidemiology ; Community Health Planning ; Female ; Humans ; Italy ; Male ; Middle Aged ; Pain/drug therapy/*epidemiology/psychology ; Pain Management ; Pain Measurement ; Prevalence ; }, abstract = {BACKGROUND AND PURPOSE: To assess the prevalence and characteristics of pain in an epidemiological series of patients with amyotrophic lateral sclerosis (ALS) compared to population-based controls.<br><br>METHODS: Of the 183 patients with ALS resident in the province of Torino, Italy, 160 accepted to be interviewed. Controls were randomly selected from the lists of general practitioners. Pain was assessed using the Brief Pain Inventory.<br><br>RESULTS: Patients with ALS reported pain more frequently than controls [91 (56.9%) vs. 53 (33.1%); P = 0.001]. Pain frequency and intensity were correlated with a worse functional score and a longer disease duration. In patients with ALS, pain was more frequently located at the extremities (P = 0.006). Pain interfered with all areas of daily function, but patients reported a greater interference than controls in the domains of enjoyment of life and relation with other people. Sixty-four patients (70.3% of those with pain) and 24 controls (45.3% of those with pain) (P = 0.003) were treated for pain, most frequently with non-steroidal anti-inflammatory drugs. ALS cases were also more frequently prescribed non-opioid analgesics and opioids than controls.<br><br>CONCLUSIONS: Our study indicates that pain is frequent in all stages of ALS, but that it often goes underrecognized and undertreated. It is significantly more frequent in patients with ALS than in population-based controls. Future studies need to clarify the mechanisms of pain in ALS and determine the most effective treatment strategy.}, }
@article {pmid21970974, year = {2011}, author = {Yamada, J and Jinno, S}, title = {Alterations in neuronal survival and glial reactions after axotomy by ceftriaxone and minocycline in the mouse hypoglossal nucleus.}, journal = {Neuroscience letters}, volume = {504}, number = {3}, pages = {295-300}, doi = {10.1016/j.neulet.2011.09.051}, pmid = {21970974}, issn = {1872-7972}, mesh = {Animals ; Astrocytes/*drug effects ; Axotomy/*adverse effects ; Ceftriaxone/pharmacology/*therapeutic use ; Cell Survival ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Drug Interactions ; Glial Fibrillary Acidic Protein ; Hypoglossal Nerve Injuries/*drug therapy/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Microglia/*drug effects ; Minocycline/pharmacology/*therapeutic use ; Motor Neuron Disease ; Nerve Tissue Proteins/biosynthesis/genetics ; Neurons/*drug effects ; Neuroprotective Agents/pharmacology/*therapeutic use ; }, abstract = {Some antibiotics are suggested to exert neuroprotective effects via regulation of glial responses. Attenuation of microglial activation by minocycline prevents neuronal death in a variety of experimental models for neurological diseases, such as cerebral ischemia, Parkinson's and Huntington's disease. Ceftriaxone delays loss of neurons in genetic animal models of amyotrophic lateral sclerosis through upregulation of astrocytic glutamate transporter expression (GLT-1). However, it remains largely unknown whether these antibiotics are able to protect neurons in axotomy models for progressive motor neuron diseases. Recent studies have shown that the axotomized motoneurons of the adult rat can survive, whereas those of the adult mouse undergo neuronal degeneration. We thus examined the possible effects of ceftriaxone and minocycline on neuronal loss and glial reactions in the mouse hypoglossal nucleus after axotomy. The survival rate of lesioned motoneurons at 28 days after axotomy (D28) was significantly improved by ceftriaxone and minocycline treatment. There were no significant differences in the cellular densities of astrocytes between ceftriaxone-treated and saline-treated animals. Ceftriaxone administration increased the expression of GLT-1 in the hypoglossal nucleus, while it suppressed the reactive increase of glial fibrillary acidic protein (GFAP) expression to control level. The cellular densities of microglia at D28 were significantly lower in minocycline-treated mice than in saline-treated mice. The time course analysis showed that immediate increase in microglia at D3 and D7 was not suppressed by minocycline. The present observations show that minocycline and ceftriaxone promote survival of lesioned motoneurons in the mouse hypoglossal nucleus, and also suggest that alterations in glial responses might be involved in neuroprotective actions of antibiotics.}, }
@article {pmid21964848, year = {2011}, author = {Halperin, JJ}, title = {Nervous system lyme disease: is there a controversy?.}, journal = {Seminars in neurology}, volume = {31}, number = {3}, pages = {317-324}, doi = {10.1055/s-0031-1287652}, pmid = {21964848}, issn = {1098-9021}, mesh = {Animals ; Borrelia/*pathogenicity ; Humans ; Lyme Neuroborreliosis/complications/*diagnosis/*therapy ; Nervous System Diseases/etiology/*microbiology ; }, abstract = {Infection with the tick-borne spirochete, BORRELIA BURGDORFERI, affects the nervous system in well-defined ways. Accurate diagnostic tools and effective therapeutic regimens are now well established. Persistent misconceptions about (1) the role and interpretation of laboratory tests, (2) what is and is not evidence of nervous system infection, and (3) what constitutes an expected response to treatment have fostered widespread perceptions that this disease is highly controversial. Infection causes the classically described triad of meningitis, radiculoneuritis, and cranial neuritis; however, virtually every known neurologic disorder has been blamed on this infection. For most (multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease), evidence is scant, nonexistent, or coincidental. For some (cerebral vasculitis with stroke, optic neuritis) a few case reports suggest a rare possible causal link.}, }
@article {pmid21964637, year = {2011}, author = {Sipp, D}, title = {The unregulated commercialization of stem cell treatments: a global perspective.}, journal = {Frontiers of medicine}, volume = {5}, number = {4}, pages = {348-355}, pmid = {21964637}, issn = {2095-0225}, mesh = {Amyotrophic Lateral Sclerosis/*economics/therapy ; Complementary Therapies/economics/ethics/legislation &amp; jurisprudence ; Evidence-Based Medicine/economics/legislation &amp; jurisprudence/standards ; Fraud/economics/prevention &amp; control ; Global Health ; Government Regulation ; Health Policy ; Humans ; Internationality ; Marketing of Health Services/*economics/ethics/legislation &amp; jurisprudence ; Stem Cell Transplantation/*economics/ethics/legislation &amp; jurisprudence ; Stem Cells/*cytology ; }, abstract = {Research into the biological properties and clinical potential of stem cells has spurred strong public investment, industry development, media coverage, and patient interest in recent years. To date, however, few clinical applications of demonstrated safety and efficacy have been developed with the exception of uses of hematopoietic stem cells in the treatment of diseases of the blood and immune systems. This lack of an evidence basis notwithstanding, hundreds of companies and private clinics around the world now sell putative stem cell treatments for an enormously broad range of medical and quality-of-life conditions. This represents a major challenge for legitimate scientists working in the field, for authorities seeking to protect their constituencies, and for patients and consumers targeted by such companies' marketing strategies. In this review, I provide an overview of the global industry in pseudomedical stem cell treatments, with an investigation of claims in a single disease area (amyotrophic lateral sclerosis), and make recommendations for the introduction and enforcement of appropriate regulatory responses to this problem.}, }
@article {pmid21963648, year = {2011}, author = {Jablonka, S and Holtmann, B and Sendtner, M and Metzger, F}, title = {Therapeutic effects of PEGylated insulin-like growth factor I in the pmn mouse model of motoneuron disease.}, journal = {Experimental neurology}, volume = {232}, number = {2}, pages = {261-269}, doi = {10.1016/j.expneurol.2011.09.015}, pmid = {21963648}, issn = {1090-2430}, mesh = {Animals ; Cell Survival/drug effects ; Cells, Cultured ; Disease Models, Animal ; *Drug Design ; Female ; Fetus/cytology ; In Vitro Techniques ; Insulin-Like Growth Factor I/*analogs &amp; derivatives/*pharmacokinetics ; Mice ; Mice, Inbred Strains ; Mice, Mutant Strains ; Motor Neuron Disease/*drug therapy ; Motor Neurons/cytology/*drug effects ; Nerve Fibers, Myelinated/drug effects ; Phrenic Nerve/cytology ; Polyethylene Glycols/*pharmacokinetics ; Pregnancy ; Recombinant Proteins/pharmacology ; Spinal Cord/cytology ; }, abstract = {Based on its potent neurotrophic and myotrophic activities, insulin-like growth factor I (IGF-I) has been proposed for treatment of neuromuscular disorders such as muscular dystrophies and amyotrophic lateral sclerosis (ALS). However, the short half life in the circulation limits its use in vivo. At least in mouse models, beneficial effects are generally only observed by dosing regimens such as minipumps or gene therapy that are difficult to translate to patients. We have developed a polyethylene glycol coupled IGF-I (PEG-IGF-I) that could circumvent these problems by longer half-life, showing all features of a therapeutic agent supporting muscular and neuronal function. Here we investigated its effects in the pmn mutant mouse, a model with typical dying-back motoneuron degeneration. In vitro, PEG-IGF-I and rhIGF-I profoundly promoted survival axonal growth of wild-type as well as pmn mutant embryonic motoneurons, suggesting that PEG-IGF-I had a fully conserved neurotrophic activity via its receptor. In vivo, treatment of pmn mutant mice with PEG-IGF-I prolonged survival, protected against late stage weight loss and significantly maintained muscle force and motor coordination. Consistently, PEG-IGF-I treatment rescued facial and lumbar motoneurons from cell death and partially preserved phrenic nerve myelinated axons. The data support that PEG-IGF-I could be used for treatment of neuromuscular diseases in a clinically feasible manner.}, }
@article {pmid21954839, year = {2012}, author = {Mazzini, L and Mareschi, K and Ferrero, I and Miglioretti, M and Stecco, A and Servo, S and Carriero, A and Monaco, F and Fagioli, F}, title = {Mesenchymal stromal cell transplantation in amyotrophic lateral sclerosis: a long-term safety study.}, journal = {Cytotherapy}, volume = {14}, number = {1}, pages = {56-60}, doi = {10.3109/14653249.2011.613929}, pmid = {21954839}, issn = {1477-2566}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/pathology/psychology/*surgery ; Bone Marrow/pathology ; Brain/diagnostic imaging/*pathology ; Female ; Follow-Up Studies ; Humans ; Italy ; Magnetic Resonance Imaging ; Male ; *Mesenchymal Stem Cell Transplantation ; Middle Aged ; Radiography ; Spinal Cord/diagnostic imaging/pathology/*surgery ; Transplantation, Autologous ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND AIMS: Mesenchymal stem cells/marrow stromal cells (MSC) represent a promising tool for stem cell-based clinical trials in amyotrophic lateral sclerosis (ALS). We present the results of long-term monitoring of 19 ALS patients enrolled in two phase I clinical trials of autologous MSC transplantation.<br><br>METHODS: Nineteen patients (11 male and eightfemale) with ALS were enrolled in two consecutive phase I clinical trials. The patients were followed-up for 6-9 months and then treated with autologous MSC isolated from bone marrow and implanted into the dorsal spinal cord with a surgical procedure. The patients were monitored regularly before and after transplantation with clinical, psychological and neuroradiologic assessments every 3 months, at the tertiary referral ALS center in Novara (Italy), until death.<br><br>RESULTS: Follow-up brain magnetic resonance imaging (MRI) revealed no structural changes (including tumor formation) relative to the baseline throughout the follow-up. There was no deterioration in the psychosocial status and all patients coped well. No clear clinical benefits were detected in these patients but the recruitment and selection of appropriate patients into larger trials will be needed to test the efficacy of the treatment.<br><br>CONCLUSIONS: This study is the first to show the safety of MSC transplantation in the central nervous system during a follow-up of nearly 9 years, and is in support of applying MSC-based cellular clinical trials to neurodegenerative disorders.}, }
@article {pmid21948012, year = {2011}, author = {Arias, M}, title = {[Neurology of laughter and humour: pathological laughing and crying].}, journal = {Revista de neurologia}, volume = {53}, number = {7}, pages = {415-421}, pmid = {21948012}, issn = {1576-6578}, mesh = {*Brain/anatomy &amp; histology/physiology/physiopathology ; Crying/*physiology ; Humans ; Laughter/*physiology ; Magnetic Resonance Imaging ; Syndrome ; }, abstract = {INTRODUCTION: Laughter, which is usually a healthy biological phenomenon, may be also a symptom of several severe brain pathologies.<br><br>AIM: To review the neurobiological bases of laughter and humour, as well as those of pathological laughing and crying syndrome.<br><br>DEVELOPMENT: At the mesencephalic-pontine junction there is a central coordinator of the nuclei that innervate the muscles involved in laughter (facial expression, respiratory and phonatory). This centre receives connections from three systems: inhibitory (pre-motor and motor cortex), excitatory (temporal cortex, amygdala, hypothalamus) and modulator (cerebellum). Humour is a complex phenomenon with a range of components: the perception of the unexpected incongruence (occipitotemporal area, prefrontal cortex), emotional (reward circuit) and volitional (temporal and frontal cortex). Functional magnetic resonance imaging studies do not reveal a markedly prominent role of the right frontal lobe in processing humour, as had been suggested in the classical studies. The causes of pathological laughing and crying syndrome can be classified in two groups: altered behaviour with unmotivated happiness (Angelman syndrome, schizophrenia, manias, dementia) and interference with the inhibitory/excitatory mechanisms (gelastic epilepsy, fou rire prodromique in strokes, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and Parkinson-plus, traumatic injuries, tumours). Serotonin and noradrenalin reuptake inhibitors, levodopa, lamotrigine and the association of dextromethorphan/quinidine can be effective in certain cases of pathological laughing and crying.<br><br>CONCLUSIONS: As human neurobiological phenomena, laughter and humour also belong to the field of clinical neurology; their processing is affected in a number of different diseases and, in certain cases, effective treatment can be established.}, }
@article {pmid21947135, year = {2011}, author = {Gordon, PH and Meininger, V}, title = {How can we improve clinical trials in amyotrophic lateral sclerosis?.}, journal = {Nature reviews. Neurology}, volume = {7}, number = {11}, pages = {650-654}, pmid = {21947135}, issn = {1759-4766}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; *Clinical Trials as Topic ; Disease Models, Animal ; Humans ; Neuroprotective Agents/*therapeutic use ; Translational Research, Biomedical/methods ; }, abstract = {Since the approval of riluzole for the treatment of amyotrophic lateral sclerosis (ALS) 17 years ago, more than 30 large clinical trials have been conducted, but none has proved successful. The failure to translate positive preclinical results into the clinical setting raises questions about the validity of the rodent model that is used to study ALS, and about the quality of both preclinical and clinical studies. However, the greatest challenge is the disease itself as, with rare exceptions, the causes are unknown. In this Perspectives article, we highlight key issues related to the pathophysiology, preclinical studies and clinical trials that should be addressed in the future. These areas include the relationships between different disease mechanisms, the challenges presented by the heterogeneity of the disease, and the need for early intervention, optimal dose selection and effective biomarkers.}, }
@article {pmid21946609, year = {2011}, author = {Lepore, AC}, title = {Intraspinal cell transplantation for targeting cervical ventral horn in amyotrophic lateral sclerosis and traumatic spinal cord injury.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {55}, pages = {}, pmid = {21946609}, issn = {1940-087X}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*surgery ; Animals ; Anterior Horn Cells/pathology ; Humans ; Mice ; Neural Stem Cells/*transplantation ; Rats ; Spinal Cord Injuries/pathology/*surgery ; }, abstract = {Respiratory compromise due to phrenic motor neuron loss is a debilitating consequence of a large proportion of human traumatic spinal cord injury (SCI) cases (1) and is the ultimate cause of death in patients with the motor neuron disorder, amyotrophic laterals sclerosis (ALS) (2). ALS is a devastating neurological disorder that is characterized by relatively rapid degeneration of upper and lower motor neurons. Patients ultimately succumb to the disease on average 2-5 years following diagnosis because of respiratory paralysis due to loss of phrenic motor neuron innnervation of the diaphragm (3). The vast majority of cases are sporadic, while 10% are of the familial form. Approximately twenty percent of familial cases are linked to various point mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene on chromosome 21 (4). Transgenic mice (4,5) and rats (6) carrying mutant human SOD1 genes ((G93A, G37R, G86R, G85R)) have been generated, and, despite the existence of other animal models of motor neuron loss, are currently the most highly used models of the disease. Spinal cord injury (SCI) is a heterogeneous set of conditions resulting from physical trauma to the spinal cord, with functional outcome varying according to the type, location and severity of the injury (7). Nevertheless, approximately half of human SCI cases affect cervical regions, resulting in debilitating respiratory dysfunction due to phrenic motor neuron loss and injury to descending bulbospinal respiratory axons (1). A number of animal models of SCI have been developed, with the most commonly used and clinically-relevant being the contusion (8). Transplantation of various classes of neural precursor cells (NPCs) is a promising therapeutic strategy for treatment of traumatic CNS injuries and neurodegeneration, including ALS and SCI, because of the ability to replace lost or dysfunctional CNS cell types, provide neuroprotection, and deliver gene factors of interest (9). Animal models of both ALS and SCI can model many clinically-relevant aspects of these diseases, including phrenic motor neuron loss and consequent respiratory compromise (10,11). In order to evaluate the efficacy of NPC-based strategies on respiratory function in these animal models of ALS and SCI, cellular interventions must be specifically directed to regions containing therapeutically relevant targets such as phrenic motor neurons. We provide a detailed protocol for multi-segmental, intraspinal transplantation of NPCs into the cervical spinal cord ventral gray matter of neurodegenerative models such as SOD1(G93A) mice and rats, as well as spinal cord injured rats and mice (11).}, }
@article {pmid21944626, year = {2011}, author = {Luján, JJ and Németh, ZH and Barratt-Stopper, PA and Bustami, R and Koshenkov, VP and Rolandelli, RH}, title = {Factors influencing the outcome of intestinal anastomosis.}, journal = {The American surgeon}, volume = {77}, number = {9}, pages = {1169-1175}, pmid = {21944626}, issn = {1555-9823}, mesh = {Anastomosis, Surgical/methods ; Anastomotic Leak/epidemiology/*prevention &amp; control ; Digestive System Surgical Procedures/*methods ; Female ; Follow-Up Studies ; Gastrointestinal Diseases/*surgery ; Humans ; Incidence ; Intestines/*surgery ; Male ; Middle Aged ; New Jersey/epidemiology ; Prospective Studies ; Risk Assessment ; Risk Factors ; Survival Rate ; Treatment Outcome ; }, abstract = {Anastomotic leak (AL) is one of the most serious complications after gastrointestinal surgery. All patients aged 16 years or older who underwent a surgery with single intestinal anastomosis at Morristown Medical Center from January 2006 to June 2008 were entered into a prospective database. To compare the rate of AL, patients were divided into the following surgery-related groups: 1) stapled versus hand-sewn, 2) small bowel versus large bowel, 3) right versus left colon, 4) emergent versus elective, 5) laparoscopic versus converted (laparoscopic to open) versus open, 6) inflammatory bowel disease versus non inflammatory bowel disease, and 7) diverticulitis versus nondiverticulitis. We also looked for surgical site infection, estimated intraoperative blood loss, blood transfusion, comorbidities, preoperative chemotherapy, radiation, and anticoagulation treatment. The overall rate of AL was 3.8 per cent. Mortality rate was higher among patients with ALs (13.3%) versus patients with no AL (1.7%). Open surgery had greater risk of AL than laparoscopic operations. Surgical site infection and intraoperative blood transfusions were also associated with significantly higher rates of AL. Operations involving the left colon had greater risk of AL when compared with those of the right colon, sigmoid, and rectum. Prior chemotherapy, anticoagulation, and intraoperative blood loss all increased the AL rates. In conclusion, we identified several significant risk factors for ALs. This knowledge should help us better understand and prevent this serious complication, which has significant morbidity and mortality rates.}, }
@article {pmid21941544, year = {2012}, author = {Intiso, D}, title = {Therapeutic use of botulinum toxin in neurorehabilitation.}, journal = {Journal of toxicology}, volume = {2012}, number = {}, pages = {802893}, pmid = {21941544}, issn = {1687-8205}, abstract = {The botulinum toxins (BTX), type A and type B by blocking vesicle acetylcholine release at neuro-muscular and neuro-secretory junctions can result efficacious therapeutic agents for the treatment of numerous disorders in patients requiring neuro-rehabilitative intervention. Its use for the reduction of focal spasticity following stroke, brain injury, and cerebral palsy is provided. Although the reduction of spasticity is widely demonstrated with BTX type A injection, its impact on the improvement of dexterity and functional outcome remains controversial. The use of BTX for the rehabilitation of children with obstetrical brachial plexus palsy and in treating sialorrhea which can complicate the course of some severe neurological diseases such as amyotrophic lateral sclerosis and Parkinson's disease is also addressed. Adverse events and neutralizing antibodies formation after repeated BTX injections can occur. Since impaired neurological persons can have complex disabling feature, BTX treatment should be viewed as adjunct measure to other rehabilitative strategies that are based on the individual's residual ability and competence and targeted to achieve the best functional recovery. BTX therapy has high cost and transient effect, but its benefits outweigh these disadvantages. Future studies must clarify if this agent alone or adjunctive to other rehabilitative procedures works best on functional outcome.}, }
@article {pmid21936930, year = {2011}, author = {Al-Chalabi, A and Shaw, PJ and Young, CA and Morrison, KE and Murphy, C and Thornhill, M and Kelly, J and Steen, IN and Leigh, PN and , }, title = {Protocol for a double-blind randomised placebo-controlled trial of lithium carbonate in patients with amyotrophic lateral sclerosis (LiCALS) [Eudract number: 2008-006891-31].}, journal = {BMC neurology}, volume = {11}, number = {}, pages = {111}, pmid = {21936930}, issn = {1471-2377}, support = {G0701923/MRC_/Medical Research Council/United Kingdom ; LEIGH/RF/JUL08/6345/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Clinical Protocols ; Double-Blind Method ; Drug Therapy, Combination/statistics &amp; numerical data ; Female ; Humans ; Lithium Carbonate/adverse effects/*therapeutic use ; Male ; Neuroprotective Agents/adverse effects/*therapeutic use ; Placebos/therapeutic use ; Psychiatric Status Rating Scales ; Riluzole/therapeutic use ; Severity of Illness Index ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disorder characterised by loss of motor neurons leading to severe weakness and death from respiratory failure within 3-5 years. Riluzole prolongs survival in ALS. A published report has suggested a dramatic effect of lithium carbonate on survival. 44 patients were studied, with 16 randomly selected to take LiCO3 and riluzole and 28 allocated to take riluzole alone. In the group treated with lithium, no patients had died (i.e., 100% survival) at the end of the study (15 months from entry), compared to 71% surviving in the riluzole-only group. Although the trial can be criticised on several grounds, there is a substantial rationale from other laboratory studies that lithium is worth investigating therapeutically in amyotrophic lateral sclerosis.<br><br>METHODS/DESIGN: LiCALS is a multi-centre double-blind randomised parallel group controlled trial of the efficacy, safety, and tolerability of lithium carbonate (LiCO3) at doses to achieve stable 'therapeutic' plasma levels (0.4-0.8 mmol/L), plus standard treatment, versus matched placebo plus standard treatment, in patients with amyotrophic lateral sclerosis. The study will be based in the UK, in partnership with the MND Association and DeNDRoN (the Dementias and Neurodegnerative Diseases Clinical Research Network). 220 patients will be recruited. All patients will be on the standard treatment for ALS of riluzole 100 mg daily. The primary outcome measure will be death from any cause at 18 months defined from the date of randomisation. Secondary outcome measures will be changes in three functional rating scales, the ALS Functional Rating Scale-Revised, The EuroQOL (EQ-5D), and the Hospital Anxiety and Depression Scale.Eligible patients will have El Escorial Possible, Laboratory-supported Probable, Probable or Definite amyotrophic lateral sclerosis with disease duration between 6 months and 36 months (inclusive), vital capacity &#x2265; 60% of predicted within 1 month prior to randomisation and age at least18 years.<br><br>DISCUSSION: Patient recruitment began in June 2009 and the last patient is expected to complete the trial protocol in November 2011.<br><br>TRIAL REGISTRATION: Current controlled trials ISRCTN83178718.}, }
@article {pmid21935731, year = {2012}, author = {Zhao, ST and Huang, XT and Zhang, C and Ke, Y}, title = {Humanin protects cortical neurons from ischemia and reperfusion injury by the increased activity of superoxide dismutase.}, journal = {Neurochemical research}, volume = {37}, number = {1}, pages = {153-160}, pmid = {21935731}, issn = {1573-6903}, mesh = {Cerebral Cortex/*cytology/enzymology/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/*physiology ; L-Lactate Dehydrogenase/metabolism ; Malondialdehyde/metabolism ; Neurons/*cytology/enzymology/metabolism ; Reperfusion Injury/*pathology ; Superoxide Dismutase/*metabolism ; }, abstract = {The neuroprotective effects of superoxide dismutase (SOD) against hypoxia/reperfusion (I/R) injury and of humanin (HN) against toxicity by familial amyotrophic lateral sclerosis (ALS)-related mutant SOD led us to hypothesize that HN might have a role to increase the activity of SOD, which might be involved in the protective effects of HN on neuron against Alzheimer's disease-unrelated neurotoxicities. In the present study, we found that 4 h ischemia and 24 h reperfusion induced a significant increase in lactate dehydrogenase (LDH) release, malondialdehyde (MDA) formation and the number of karyopyknotic nuclei (4',6-diamidino-2-phenylindole dihydrochloride nuclear dyeing) and a decrease in the number of Calcein-AM-positive living cells and cell viability. Pretreatment of the cells with HN led to a significant decrease in LDH release, MDA formation and the number of karyopyknotic nuclei, and an increase in the number of Calcein-AM-positive living cells and cell viability in neurons treated with I/R. We also found a significant decrease in SOD activity in neurons treated with I/R only, while pre-treatment with HN before I/R induced a significant increase in the activity of SOD as compared with the I/R group. Our findings implied that HN protects cortical neurons from I/R injury by the increased SOD activity and that the protective effect of HN on neurons against I/R is concentration-dependent.}, }
@article {pmid21921534, year = {2010}, author = {Kawahara, Y}, title = {[Implications of microRNA dysfunction in the pathogenesis of ALS].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {50}, number = {11}, pages = {979-981}, doi = {10.5692/clinicalneurol.50.979}, pmid = {21921534}, issn = {1882-0654}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/therapy ; DNA-Binding Proteins/*physiology ; Humans ; MicroRNAs/*metabolism ; Molecular Targeted Therapy ; Motor Neurons/pathology ; }, abstract = {Recent studies have identified mutations in the genes encoding TDP-43 and FUS/TLS in patients with amyotrophic lateral sclerosis (ALS). Both TDP-43 and FUS/TLS display all the characteristics of a heterogeneous nuclear ribonucleoprotein, which regulates various aspects of RNA processing. In addition, TDP-43 is partly cleared from the nuclei of neurons containing cytoplasmic aggregates, suggesting loss of normal TDP-43 function in the nucleus, leading to defects or alterations in RNA metabolism, plays, at least in part, a causative role in the pathogenesis of ALS. TDP-43 has been reported to be involved in the Drosha complex required for the biogenesis of microRNAs. The high expression level of microRNAs and the exclusive expression of certain microRNAs in the central nervous system highlights their biological importance at all stages of neural development as well as in differentiated neurons. In addition, the altered expression of certain microRNAs has been implicated in the pathogenesis of neurodegenerative diseases. Therefore, elucidation of the role of TDP-43 in microRNA biogenesis as a component of the Drosha complex is indispensable to understanding pathophysiology of ALS. In addition, the identification of TDP-43-regulated microRNAs associated with motor neuron death is expected to further contribute to the development of novel therapeutic strategies for ALS treatment.}, }
@article {pmid21913120, year = {2011}, author = {Lepore, AC and Maragakis, NJ}, title = {Stem cell transplantation for spinal cord neurodegeneration.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {793}, number = {}, pages = {479-493}, pmid = {21913120}, issn = {1940-6029}, support = {F32 NS059155/NS/NINDS NIH HHS/United States ; R01 NS041680/NS/NINDS NIH HHS/United States ; R01-NS41680/NS/NINDS NIH HHS/United States ; F32-NS059155/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*surgery ; Animals ; Female ; Male ; Mice ; Neural Stem Cells/transplantation ; Rats ; Stem Cell Transplantation/*methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a disorder that affects 30,000 individuals in the USA alone, is characterized by relatively rapid degeneration of upper and lower motor neurons, with death normally occurring 2-5 years following diagnosis due to respiratory paralysis. Transplantation of various classes of neural precursor cells (NPCs) is a promising therapeutic strategy for the treatment of traumatic CNS injury and neurodegeneration, including ALS, because of the ability to replace lost or dysfunctional CNS cell types, provide neuroprotection, and deliver gene factors of interest. In order to target cellular therapy to diaphragmatic dysfunction in models of ALS, NPCs can be transplanted specifically into the cervical spinal cord ventral gray matter of both SOD1G93A rats and mice. The SOD1G93A rats and mice are currently the most well-studied animal model of the disease.}, }
@article {pmid21909419, year = {2011}, author = {Kaneb, HM and Sharp, PS and Rahmani-Kondori, N and Wells, DJ}, title = {Metformin treatment has no beneficial effect in a dose-response survival study in the SOD1(G93A) mouse model of ALS and is harmful in female mice.}, journal = {PloS one}, volume = {6}, number = {9}, pages = {e24189}, pmid = {21909419}, issn = {1932-6203}, support = {//Medical Research Council/United Kingdom ; }, mesh = {Aging/drug effects/pathology ; Amino Acid Substitution/*genetics ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Body Weight/drug effects ; Cell Count ; Disease Models, Animal ; Disease Progression ; Dose-Response Relationship, Drug ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Metformin/*adverse effects/pharmacology/*therapeutic use ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/pathology ; Superoxide Dismutase/*genetics ; Treatment Outcome ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a devastating neurological disorder characterized by selective degeneration of upper and lower motor neurons. The primary triggers for motor neuron degeneration are unknown but inflammation, oxidative stress and mitochondrial defects have been identified as potential contributing factors. Metformin is an anti-type II diabetes drug that has anti-inflammatory and anti-oxidant properties, can bring about mitochondrial biogenesis and has been shown to attenuate pathology in mouse models of Huntington's disease and multiple sclerosis. We therefore hypothesized that it might increase survival in the SOD1(G93A) murine model of ALS.<br><br>Treatment of male and female SOD1(G93A) mice (n&#x200a;=&#x200a;&#x2265;6 per sex) with 2 mg/ml metformin in the drinking water from 35 days, resulted in a significant increase in motor unit survival, as measured by in vivo electrophysiology at 100 days, in male EDL muscles (24+/-2 vs. 14+/-2 motor units, p<0.005) and female TA muscles (21+/-1 vs. 15+/-2 motor units, P&#x200a;=&#x200a;0.0134). We therefore continued to test the effect of 0.5, 2 and 5 mg/ml metformin in the drinking water from 35 days on disease onset and progression (identified by twice weekly determination of weight and neurological score) as well as survival in male and female SOD1(G93A) mice (n&#x200a;=&#x200a;&#x2265;14 per sex). Results for all groups were compared using Kaplan-Meier time to event analyses. In this survival study, metformin was unable to reduce pathology at any dose and had an unexpected dose-dependent negative effect on the onset of neurological symptoms (P&#x200a;=&#x200a;0.0236) and on disease progression (P&#x200a;=&#x200a;0.0362) in female mice.<br><br>CONCLUSIONS/SIGNIFICANCE: This study suggests that metformin is a poor candidate for clinical trial in ALS patients and that the possibility of harmful effects of metformin in female ALS patients with type II diabetes should be investigated.}, }
@article {pmid21904789, year = {2011}, author = {Gowing, G and Svendsen, CN}, title = {Stem cell transplantation for motor neuron disease: current approaches and future perspectives.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {8}, number = {4}, pages = {591-606}, pmid = {21904789}, issn = {1878-7479}, mesh = {Animals ; Humans ; Mice ; Motor Neuron Disease/*surgery ; Neurons/*physiology ; Stem Cell Transplantation/*methods/trends ; }, abstract = {Motor neuron degeneration leading to muscle atrophy and death is a pathological hallmark of disorders, such as amyotrophic lateral sclerosis or spinal muscular atrophy. No effective treatment is available for these devastating diseases. At present, cell-based therapies targeting motor neuron replacement, support, or as a vehicle for the delivery of neuroprotective molecules are being investigated. Although many challenges and questions remain, the beneficial effects observed following transplantation therapy in animal models of motor neuron disease has sparked hope and a number of clinical trials. Here, we provide a comprehensive review of cell-based therapeutics for motor neuron disorders, with a particular emphasis on amyotrophic lateral sclerosis.}, }
@article {pmid21904562, year = {2012}, author = {Lee, SM and Yang, EJ and Choi, SM and Kim, SH and Baek, MG and Jiang, JH}, title = {Effects of bee venom on glutamate-induced toxicity in neuronal and glial cells.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2012}, number = {}, pages = {368196}, pmid = {21904562}, issn = {1741-4288}, abstract = {Bee venom (BV), which is extracted from honeybees, is used in traditional Korean medical therapy. Several groups have demonstrated the anti-inflammatory effects of BV in osteoarthritis both in vivo and in vitro. Glutamate is the predominant excitatory neurotransmitter in the central nervous system (CNS). Changes in glutamate release and uptake due to alterations in the activity of glutamate transporters have been reported in many neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. To assess if BV can prevent glutamate-mediated neurotoxicity, we examined cell viability and signal transduction in glutamate-treated neuronal and microglial cells in the presence and absence of BV. We induced glutamatergic toxicity in neuronal cells and microglial cells and found that BV protected against cell death. Furthermore, BV significantly inhibited the cellular toxicity of glutamate, and pretreatment with BV altered MAP kinase activation (e.g., JNK, ERK, and p38) following exposure to glutamate. These findings suggest that treatment with BV may be helpful in reducing glutamatergic cell toxicity in neurodegenerative diseases.}, }
@article {pmid21903615, year = {2012}, author = {Carder, PC}, title = {"Learning about your residents": how assisted living residence medication aides decide to administer pro re nata medications to persons with dementia.}, journal = {The Gerontologist}, volume = {52}, number = {1}, pages = {46-55}, doi = {10.1093/geront/gnr099}, pmid = {21903615}, issn = {1758-5341}, mesh = {Adult ; Allied Health Personnel/education/*psychology ; Assisted Living Facilities ; Caregivers ; *Decision Making ; Dementia/*drug therapy ; Female ; Humans ; Interviews as Topic ; Knowledge ; Male ; Middle Aged ; Nonprescription Drugs/*therapeutic use ; Oregon ; Organizational Policy ; Prescription Drugs/*therapeutic use ; Young Adult ; }, abstract = {PURPOSE: This study identified how unlicensed staff members decide to administer medications prescribed pro re nata (PRN) to residents of assisted living (AL) settings designated for persons with dementia. Theories of knowledge, including explicit and implicit knowledge, discretion, and judgment, guided the analysis.<br><br>DESIGN AND METHODS: Data were collected and analyzed using qualitative methods. The staff members responsible for medication administration were shadowed for 6 consecutive days in three Oregon ALs. In-person interviews were conducted with 16 staff members, and residents' medication records were reviewed.<br><br>RESULTS: Medication aides' decisions to administer PRN medications were informed by resident request, interpretation of resident-specific actions, training and experience, and setting-specific practices. The theme, learning about your residents, was consistent across settings.<br><br>IMPLICATIONS: By administering PRN medications, medication aides play an important role in the daily care and comfort of AL residents with dementia. Policy makers need information about whether to permit unlicensed staff to administer medications and the level of training to require. This research suggests that training should recognize the tacit knowledge of practicing medication aides. Despite the role that PRN medications can play in the daily comfort and well-being of AL residents, little is known about as-needed medications prescribed versus those actually used across settings; also needed is an understanding of how other health professionals are involved in treatment plans that include medications.}, }
@article {pmid21901724, year = {2011}, author = {Guo, J and Zhou, M and Yang, M and Zhu, C and He, L}, title = {Repetitive transcranial magnetic stimulation for the treatment of amyotrophic lateral sclerosis or motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {9}, pages = {CD008554}, doi = {10.1002/14651858.CD008554.pub2}, pmid = {21901724}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Motor Neuron Disease/therapy ; Randomized Controlled Trials as Topic ; Transcranial Magnetic Stimulation/*methods ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurodegenerative disease without effective therapies. Several studies have suggested that repetitive transcranial magnetic stimulation (rTMS) may have positive benefit in ALS. However, the efficacy and safety of this therapy remain uncertain.<br><br>OBJECTIVES: We aimed to determine the clinical efficacy and safety of rTMS for treating ALS.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (July 2010), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2010), MEDLINE (1966 to July 2010), EMBASE (1980 to July 2010), CINAHL (1937 to July 2010), Science Citation Index Expanded (January 1945 to June 2010), AMED (January 1985 to July 2010) and the Chinese Biomedical Database (1979 to September 2010). We also searched for ongoing studies on clinicaltrials.gov (September 2010).<br><br>SELECTION CRITERIA: Randomised and quasi-randomised controlled trials assessing the therapeutic efficacy and safety of rTMS for patients with a clinical diagnosis of ALS.Comparisons eligible for inclusion were:1. rTMS versus no intervention;2. rTMS versus sham rTMS;3. rTMS versus physiotherapy;4. rTMS versus medications;5. rTMS + other therapies or drugs versus sham rTMS + the same therapies or drugs;6. different methods of application of rTMS such as high-frequency (> 1Hz) compared to low-frequency (&#x2264; 1Hz) rTMS.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently selected papers, assessed risk of bias and extracted data. We resolved disagreements through discussion. We contacted study authors for additional information.<br><br>MAIN RESULTS: Three randomised, placebo-controlled trials with a total of 50 participants were included in the review. All the trials were of poor methodological quality and were insufficiently homogeneous to allow the pooling of results. Moreover, the high rate of attrition further increased the risk of bias. None of the trials provided detailed data on the ALS Functional Rating Scale-Revised (ALSFRS-R) scores at six months follow-up which was pre-assigned as our primary outcome. One trial contained data in a suitable form for quantitative analysis of our secondary outcomes. No difference was seen between rTMS and sham rTMS using the ALSFRS-R scores and manual muscle testing (MMT) scores at 12 months follow-up in this trial. Additionally, none of the trials reported any adverse events associated with the use of rTMS. However, in view of the small sample size, the methodological limitations and incomplete outcome data, treatment with rTMS cannot be judged as completely safe.<br><br>AUTHORS' CONCLUSIONS: There is currently insufficient evidence to draw conclusions about the efficacy and safety of rTMS in the treatment of ALS. Further studies may be helpful if their potential benefit is weighed against the impact of participation in a randomised controlled trial on people with ALS.}, }
@article {pmid21901585, year = {2011}, author = {Chiu, AY and Rao, MS}, title = {Cell-based therapy for neural disorders--anticipating challenges.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {8}, number = {4}, pages = {744-752}, pmid = {21901585}, issn = {1878-7479}, mesh = {Animals ; Cell Differentiation ; Cell- and Tissue-Based Therapy/*methods ; Humans ; Nervous System Diseases/*surgery ; Stem Cells/*physiology ; }, abstract = {Neurological syndromes, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis, and lysosomal storage disorders, such as Battens disease, are devastating because they result in increasing loss of cognitive and physical function. Sadly, no drugs are currently available to halt their progression. The relative paucity of curative approaches for these and other conditions of the nervous system have led to a widespread evaluation of alternative treatment modalities including cell-based interventions. Several cell types have been tested successfully in animal models where safety and efficacy have been demonstrated. Early clinical trials have also been initiated in humans, and some have shown a degree of success albeit on a more limited scale than in animal experiments. Recent demonstrations that pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, can differentiate into a variety of specific neural phenotypes has stimulated worldwide enthusiasm for developing cell-based intervention of neurological disease. Indeed, several groups are preparing investigational new drug applications to treat disorders as diverse as macular degeneration, lysosomal storage diseases, and Parkinson's disease. It is noteworthy that cell replacement therapies for neurological conditions face key challenges, some of which are unique, because of the development and organization of the nervous system, its metabolism, and connectivity. Choice of the cell (or cells), the process of manufacturing them, defining the delivery pathway, developing and testing in an appropriate preclinical model, selecting a patient population, and visualizing and following or monitoring patients all pose specific issues as related to the central and peripheral nervous systems. In this review, we address a myriad of challenges that are solvable, but require careful planning and attention to the special demands of the human nervous system.}, }
@article {pmid21896316, year = {2011}, author = {Wang, J and Zhang, Y and Tang, L and Zhang, N and Fan, D}, title = {Protective effects of resveratrol through the up-regulation of SIRT1 expression in the mutant hSOD1-G93A-bearing motor neuron-like cell culture model of amyotrophic lateral sclerosis.}, journal = {Neuroscience letters}, volume = {503}, number = {3}, pages = {250-255}, doi = {10.1016/j.neulet.2011.08.047}, pmid = {21896316}, issn = {1872-7972}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Annexin A5 ; Blotting, Western ; Cell Death/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Flow Cytometry ; Fluorescent Antibody Technique ; Humans ; Mitochondria/drug effects/metabolism ; Motor Neurons/*drug effects ; Mutation/physiology ; *Neuroprotective Agents ; Niacinamide/pharmacology ; Propidium ; Real-Time Polymerase Chain Reaction ; Resveratrol ; Sirtuin 1/*biosynthesis/genetics ; Stilbenes/*pharmacology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Tetrazolium Salts ; Thiazoles ; Up-Regulation/drug effects ; }, abstract = {Resveratrol has recently been widely reported to be an age-delaying and neuroprotective compound, and it appears to produce these benefits by activating silent mating type information regulation 2 homolog 1 (SIRT1). However, the role that SIRT1 activation plays in the pathogenesis of amyotrophic lateral sclerosis (ALS) remains unclear. In the present study, SIRT1 expression was found to be much lower in the mutant hSOD1G93A-bearing VSC4.1 cells compared to hSOD1wt cells when both were cultured in low-serum medium, indicating the involvement of SIRT1 activation defects in the pathogenesis of ALS under energetic stress. Further investigation revealed that a 24-h treatment with 0.5-20μM resveratrol had a dose-dependent protective effect on this ALS cell model, and the effects of resveratrol on increasing cell viability, preventing cell apoptosis and elevating cellular ATP levels through promoting mitochondria biogenesis were blocked by SIRT1 inhibition. This further demonstrated a role for SIRT1 activation in the protection of neuronal cells from degeneration. These findings suggest that resveratrol can protect the ALS cell model from mutant SOD1-mediated toxicity through up-regulating the expression of SIRT1, which represents a potential therapeutic target for preventing the motor neuron degeneration in ALS patients.}, }
@article {pmid21893073, year = {2011}, author = {Wen, Y and Zhang, PP and An, J and Yu, YX and Wu, MH and Sheng, GY and Fu, JM and Zhang, XY}, title = {Diepoxybutane induces the formation of DNA-DNA rather than DNA-protein cross-links, and single-strand breaks and alkali-labile sites in human hepatocyte L02 cells.}, journal = {Mutation research}, volume = {716}, number = {1-2}, pages = {84-91}, doi = {10.1016/j.mrfmmm.2011.08.007}, pmid = {21893073}, issn = {0027-5107}, mesh = {Air Pollutants/*toxicity ; Carcinogens/*toxicity ; Cell Death/drug effects ; Cell Line ; Comet Assay ; DNA/chemistry/*drug effects ; DNA Breaks, Single-Stranded/*drug effects ; Epoxy Compounds/*toxicity ; Hepatocytes/drug effects ; Humans ; }, abstract = {1,3-Butadiene (BD) is an air pollutant and a known carcinogen. 1,2,3,4-Diepoxybutane (DEB), one of the major in vivo metabolites of BD, is considered the ultimate culprit of BD mutagenicity/carcinogenicity. DEB is a bifunctional alkylating agent, being capable of inducing the formation of monoalkylated DNA adducts and DNA cross-links, including DNA-DNA and DNA-protein cross-links (DPC). In the present study, we investigated DEB-caused DNA cross-links and breaks in human hepatocyte L02 cells using comet assay. With alkaline comet assay, it was observed that DNA migration increased with the increase of DEB concentration at lower concentrations (10-200μM); however, at higher concentrations (200-1000μM), DNA migration decreased with the increase of DEB concentration. This result indicated the presence of cross-links at >200μM, which was confirmed by the co-treatment experiments using the second genotoxic agents, tert-butyl hydroperoxide and methyl methanesulfonate. At 200μM, which appeared as a threshold, the DNA migration-retarding effect of cross-links was just observable by the co-treatment experiments. At <200μM, the effect of cross-links was too weak to be detected. The DEB-induced cross-links were determined to be DNA-DNA ones rather than DPC through incubating the liberated DNA with proteinase K prior to unwinding and electrophoresis. However, at the highest DEB concentration tested (1000μM), a small proportion of DPC could be formed. In addition, the experiments using neutral and weakly alkaline comet assays showed that DEB did not cause double-strand breaks, but did induce single-strand breaks (SSB) and alkali-labile sites (ALS). Since SSB and ALS are repaired more rapidly than cross-links, the results suggested that DNA-DNA cross-links, rather than DPC, were probably responsible for mutagenicity/carcinogenicity of DEB.}, }
@article {pmid21892569, year = {2011}, author = {López Gómez, JJ and Ballesteros Pomar, MD and Vázquez Sánchez, F and Vidal Casariego, A and Calleja Fernández, A and Cano Rodríguez, I}, title = {[Effect of nutritional support on survival in patients with amyotrophic lateral sclerosis].}, journal = {Nutricion hospitalaria}, volume = {26}, number = {3}, pages = {515-521}, doi = {10.1590/S0212-16112011000300013}, pmid = {21892569}, issn = {1699-5198}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*therapy ; Cohort Studies ; Disease Progression ; Female ; Humans ; Male ; Malnutrition/etiology ; Middle Aged ; *Nutritional Support ; Retrospective Studies ; Survival ; }, abstract = {INTRODUCTION: Malnutrition affects morbidity and mortality of patients with ALS. The nutrition unit should evaluate these patients early and regularly providing the necessary steps in the evolution of the disease.<br><br>METHODS: A retrospective cohort study in which we analyzed 46 patients diagnosed with ALS, 21 of them received nutritional therapy. We studied age, mode of onset, date of entry into a nutritional protocol, placement of PEG and survival. We performed a test of Breslow comparing patients who were at nutritional protocol with those not receiving nutritional support, and those who received early nutritional therapy with those with delayed nutrition.<br><br>RESULTS: There was an increase in median survival for patients in nutritional therapy in bulbar ALS (452 vs 55 days) and in spinal ALS (1,798 vs 357 days) (p = 0.002). The median delay in the initiation of nutritional therapy in spinal ALS was 557 days while in bulbar ALS was 230 days. The survival in the spinal ALS of those who entered into nutritional protocol before the median survival was 325 days to 181 days (p = 0.09) while in bulbar ALS those who entered before had a median survival of 435 days to 177 days (p = 0.38).<br><br>CONCLUSIONS: The entry of patients with ALS in a nutritional protocol increases survival. There is an advantage in the evolution of patients with early nutritional treatment.}, }
@article {pmid21888026, year = {2011}, author = {Von Lueder, TG and Melsom, MN and Atar, D and Agewall, S}, title = {Amyotrophic lateral sclerosis (ALS), a novel rare cause of elevated plasma troponin T levels.}, journal = {Clinical laboratory}, volume = {57}, number = {7-8}, pages = {615-618}, pmid = {21888026}, issn = {1433-6510}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*blood/complications/*diagnosis ; Biomarkers ; Cell Hypoxia ; Coronary Disease/diagnosis ; *Diagnostic Errors ; Disease Progression ; Dyspnea/etiology ; Fatal Outcome ; Follow-Up Studies ; Humans ; Hypoxia/etiology/pathology ; Male ; Myocardial Infarction/diagnosis ; Myocardium/immunology/metabolism/pathology ; Pulmonary Disease, Chronic Obstructive/diagnosis ; Respiratory Insufficiency/etiology ; Troponin T/*blood ; }, abstract = {In this article, we report on a patient with chronic and modestly elevated plasma troponin T (TnT) levels and frequent hospitalizations following the first admission until his death one year later. The patient was initially admitted for dyspnea and discharged from hospital with a diagnosis of non-ST elevation acute myocardial infarction (AMI). Coronary angiography and echocardiography were normal, but the patient received the (false) diagnosis of AMI at two further admissions, based purely on elevated TnT. Shortly thereafter, severe respiratory failure with restrictive-type spirometry pattern became the predominant clinical symptom, with constantly elevated TnT levels at frequent re-admissions. Due to inconsistent follow-up by primarily junior and non-specialist staff at a number of different wards, pulmonary function tests and previous smoking history were mis-interpreted as typical of chronic obstructive pulmonary disease (COPD). The patient received standard COPD treatment without any improvement. After a year of gradually worsening respiratory failure and repeated hospitalizations, thorough assessment by a pulmonologist and neurologist established the final diagnosis of amyotrophic lateral sclerosis (ALS). The patient died shortly thereafter. While progressive respiratory failure is well-known to determine morbidity and mortality in patients with ALS, chronically elevated TnT levels in the absence of coronary artery disease have, to our best knowledge, not been described so far. We suggest that chronic myocardial hypoxia due to ALS-related hypoxic respiratory failure was the most likely underlying etiology for the elevated TnT levels seen here but other mechanism such as immune-mediated myocardial injury cannot be excluded.}, }
@article {pmid21886282, year = {2011}, author = {Sigurdson, LA}, title = {Amyotrophic lateral sclerosis presenting as upper limb weakness in a 35 year old female: a case report.}, journal = {The Journal of the Canadian Chiropractic Association}, volume = {55}, number = {3}, pages = {204-210}, pmid = {21886282}, issn = {1715-6181}, abstract = {Chiropractors regularly assess and provide treatment for a variety of neuromuscular complaints. Many of these respond well to conservative care however some represent conditions that must be referred for further evaluation. This article chronicles the management of a patient who presented with upper limb weakness and was subsequently diagnosed with amyotrophic lateral sclerosis (ALS). Chiropractors should be informed of the nature and presentation of this disease to facilitate early diagnosis and treatment.}, }
@article {pmid21880878, year = {2011}, author = {Rodriguez-Murphy, E and Marti-Bonmati, E and Camps-Seguí, E and Bagán, JV}, title = {Manually guided botulinum toxin type A submandibular injections for the treatment of sialorrhea in tube-fed patients with advanced amyotrophic lateral sclerosis.}, journal = {American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists}, volume = {68}, number = {18}, pages = {1680-1681}, doi = {10.2146/ajhp100343}, pmid = {21880878}, issn = {1535-2900}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*physiopathology ; Botulinum Toxins, Type A/*administration &amp; dosage ; Enteral Nutrition ; Female ; Humans ; Injections ; Male ; Middle Aged ; Neurotoxins/*administration &amp; dosage ; Sialorrhea/*drug therapy/etiology ; Submandibular Gland ; Treatment Outcome ; }, }
@article {pmid21876068, year = {2011}, author = {Fidler, JA and Treleaven, CM and Frakes, A and Tamsett, TJ and McCrate, M and Cheng, SH and Shihabuddin, LS and Kaspar, BK and Dodge, JC}, title = {Disease progression in a mouse model of amyotrophic lateral sclerosis: the influence of chronic stress and corticosterone.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {25}, number = {12}, pages = {4369-4377}, pmid = {21876068}, issn = {1530-6860}, support = {R01NS064492/NS/NINDS NIH HHS/United States ; R01 NS064492-03/NS/NINDS NIH HHS/United States ; R01 NS064492-01A1/NS/NINDS NIH HHS/United States ; R01 NS064492-02/NS/NINDS NIH HHS/United States ; RC2NS069476-01/NS/NINDS NIH HHS/United States ; RC2 NS069476/NS/NINDS NIH HHS/United States ; R01 NS064492/NS/NINDS NIH HHS/United States ; T32 NS077984/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics/metabolism ; Animals ; Corticosterone/blood/*metabolism/pharmacology ; Disease Models, Animal ; Disease Progression ; Female ; Humans ; Male ; Mice ; Mice, Mutant Strains ; Mice, Transgenic ; Models, Biological ; Mutant Proteins/genetics/metabolism ; Restraint, Physical/adverse effects ; Stress, Physiological ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron cell loss, muscular atrophy, and a shortened life span. Survival is highly variable, as some patients die within months, while others live for many years. Exposure to stress or the development of a nonoptimal stress response to disease might account for some of this variability. We show in the SOD1(G93A) mouse model of ALS that recurrent exposure to restraint stress led to an earlier onset of astrogliosis and microglial activation within the spinal cord, accelerated muscular weakness, and a significant decrease in median survival (105 vs. 122 d) when compared to nonstressed animals. Moreover, during normal disease course, ALS mice display a cacostatic stress response by developing an aberrant serum corticosterone circadian rhythm. Interestingly, we also found that higher corticosterone levels were significantly correlated with both an earlier onset of paralysis (males: r(2)=0.746; females: r(2)=0.707) and shorter survival times (males: r(2)=0.680; females: r(2)=0.552) in ALS mice. These results suggest that stress is capable of accelerating disease progression and that strategies that modulate glucocorticoid metabolism might be a viable treatment approach for ALS.}, }
@article {pmid21872441, year = {2012}, author = {Hartman, AL}, title = {Neuroprotection in metabolism-based therapy.}, journal = {Epilepsy research}, volume = {100}, number = {3}, pages = {286-294}, pmid = {21872441}, issn = {1872-6844}, support = {K12 NS001696/NS/NINDS NIH HHS/United States ; K12 NS001696-05/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/*diet therapy ; Animals ; *Caloric Restriction ; *Diet, Ketogenic ; Humans ; Neurodegenerative Diseases/*diet therapy ; Neuroprotective Agents/therapeutic use ; Parkinson Disease/*diet therapy ; }, abstract = {Metabolism-based therapy has been used successfully in the treatment of seizures but study of its use in other neurodegenerative disorders is growing. Data demonstrating the use of different forms of metabolism-based therapy in human trials of Alzheimer disease and Parkinson disease are discussed. Animal and in vitro studies have shed light on metabolism-based therapy's mechanisms in these diseases, as well as ALS, aging, ischemia, trauma and mitochondrial cytopathies. Additional insights may be obtained by considering the role of metabolism-based therapy in cell disability and death (specifically apoptosis, excitotoxicity, and autophagy).}, }
@article {pmid21870889, year = {2011}, author = {Bar-Or, A and Rieckmann, P and Traboulsee, A and Yong, VW}, title = {Targeting progressive neuroaxonal injury: lessons from multiple sclerosis.}, journal = {CNS drugs}, volume = {25}, number = {9}, pages = {783-799}, pmid = {21870889}, issn = {1179-1934}, mesh = {Animals ; Clinical Trials, Phase II as Topic ; Disease Progression ; Humans ; Multiple Sclerosis/diagnosis/*pathology/*therapy ; Neurodegenerative Diseases/*diagnosis/pathology/*therapy ; Randomized Controlled Trials as Topic ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuroaxonal injury, suggesting a common pathophysiological pathway. Identification and development of neuroprotective therapies for such diseases has proven a major challenge, particularly because of an already substantial neuroaxonal compromise at the time of initial onset of clinical symptoms. Methods for early identification of neurodegeneration are therefore vital to ensure that neuroprotective therapies are applied as early as possible. Recent investigations have enhanced our understanding of the role of neuroaxonal injury in multiple sclerosis (MS). As MS generally manifests earlier in life and can be diagnosed much earlier in the course of the disease than the above-mentioned 'classic' neurodegenerative diseases, it is possible that MS could be used as a model disease to study degeneration and regeneration of the CNS. The mechanism of neuroaxonal injury in MS is believed to be inflammation-led neurodegeneration; however, the reverse may also be true (i.e. neuroaxonal degeneration may precede inflammation). Animal models of PD, AD and ALS have shown that it is likely that most cases of disease are due to initial inflammation, followed by a degenerative process, providing a parallel between MS and the classic neurodegenerative diseases. Other common factors between MS and the neurodegenerative diseases include iron and mitochondrial dysregulation, abnormalities in α-synuclein and tau protein, and a number of immune mediators. Conventional MRI techniques, using markers such as T2-weighted lesions, gadolinium-enhancing lesions and T1-weighted hypointensities, are readily available and routinely used in clinical practice; however, the utility of these MRI measures to predict disease progression in MS is limited. More recently, MRI techniques that provide more pathology-specific data have been applied in MS studies, including magnetic resonance spectroscopy, magnetization transfer ratio and myelin water imaging. Optical coherence tomography (OCT) is a non-MRI technique that quantifies optic nerve integrity and retinal ganglion cell loss as markers of neuroaxonal injury; more research is needed to evaluate whether information obtained from OCT is a reliable marker of axonal injury and long-term disability in MS. Using these advanced techniques, it may become possible to follow degeneration and regeneration longitudinally in patients with MS and to better differentiate the effects of drugs under investigation. Currently available immune-directed therapies that are approved by the US FDA for the first-line treatment of MS (interferon-β and glatiramer acetate) have been shown to decelerate the inflammatory process in MS; however, such therapy is less effective in preventing the progression of the disease and neuroaxonal injury. The use of MS as a clinical model to study modulation of neuroaxonal injury in the brain could have direct implications for the development of treatment strategies in neurodegenerative diseases such as AD, PD and ALS.}, }
@article {pmid21867702, year = {2011}, author = {Tanaka, K and Kanno, T and Yanagisawa, Y and Yasutake, K and Hadano, S and Yoshii, F and Ikeda, JE}, title = {Bromocriptine methylate suppresses glial inflammation and moderates disease progression in a mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {232}, number = {1}, pages = {41-52}, doi = {10.1016/j.expneurol.2011.08.001}, pmid = {21867702}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/immunology/physiopathology ; Animals ; Anterior Horn Cells/*drug effects/pathology ; Bromocriptine/*pharmacology ; Disease Models, Animal ; Disease Progression ; Dopamine Agonists/*pharmacology ; Inflammation/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Neuroglia/*drug effects/*immunology ; Neuronal Apoptosis-Inhibitory Protein/metabolism ; Receptors, Dopamine D2/agonists ; Spinal Cord/drug effects/immunology/physiopathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Treatment Outcome ; Up-Regulation/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by a selective loss of upper and lower motor neurons. Since oxidative stress plays a crucial role in the progression of motor neuron loss observed in ALS, anti-oxidative agents could be an important therapeutic means for the ALS treatment. We have previously developed a drug screening system allowing the identification of small chemical compounds that upregulate endogenous neuronal apoptosis inhibitory protein (NAIP), an oxidative stress-induced cell death suppressor. Using this system, we identified the dopamine D2 receptor agonist bromocriptine (BRC) as one of NAIP-upregulating compounds. In this study, to prove the efficacy of BRC in ALS, we conducted a set of preclinical studies using a transgenic ALS mouse model carrying the H46R mutation in the human Cu/Zn superoxide dismutase (SOD1) gene ALS(SOD1(H46R)) by the post-onset administration of BRC. ALS(SOD1(H46R)) mice receiving BRC showed sustained motor functions and modest prolonged survival after onset. Further, BRC treatment delayed anterior horn cell loss, and reduced the number of reactive astrocytes and the level of inflammatory factors such as inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)-α in the spinal cord of late symptomatic mice. In vitro study showed the reduced level of extracellular TNF-α after lipopolysaccharide (LPS) exposure in BRC-treated mouse astrocytes. BRC-treated ALS(SOD1(H46R)) mice also showed a reduced level of oxidative damage in the spinal cord. Notably, BRC treatment resulted in an upregulation of anti-oxidative stress genes, activating transcription factor 3 (ATF3) and heme oxygenase-1 (HO-1), and the generation of a glutathione (GSH) in SH-SY5Y cultured neuronal cells in a dopamine receptor-independent manner. These results imply that BRC protects motor neurons from the oxidative injury via suppression of astrogliosis in the spinal cord of ALS(SOD1(H46R)) mice. Thus, BRC might be a promising therapeutic agent for the treatment of ALS.}, }
@article {pmid21866427, year = {2011}, author = {Niazi, AU and Mocon, A and Varadi, RG and Chan, VW and Okrainec, A}, title = {Ondine's curse: anesthesia for laparoscopic implantation of a diaphragm pacing stimulation system.}, journal = {Canadian journal of anaesthesia = Journal canadien d'anesthesie}, volume = {58}, number = {11}, pages = {1034-1038}, doi = {10.1007/s12630-011-9580-9}, pmid = {21866427}, issn = {1496-8975}, mesh = {Anesthesia/*methods ; Diaphragm/*physiology ; *Electric Stimulation Therapy ; Female ; Humans ; *Laparoscopy ; Middle Aged ; Monitoring, Physiologic ; Sleep Disorders, Intrinsic/*therapy ; }, abstract = {PURPOSE: Central alveolar hypoventilation syndrome (CAHS) is a rare disease characterized by the loss of autonomic control of breathing. This condition causes hypoventilation and obstruction during sleep. Throughout their lives, these patients require ventilatory assistance by means of positive pressure ventilation to their lungs via mask, tracheotomy, or other means, such as phrenic nerve pacers. The diaphragm pacing stimulation system (DPSS) is a new treatment where electrodes are implanted into the diaphragm and cause contraction on stimulation. The DPSS has been used successfully in tetraplegic patients and patients suffering from amyotrophic lateral sclerosis (ALS). It has been shown to improve quality of life and to extend survival in patients with advanced respiratory muscle weakness. In our case, we describe the perioperative management of an adult patient with acquired CAHS who presented for laparoscopic DPSS insertion.<br><br>CLINICAL FEATURES: Our patient was a 50-yr-old female who developed CAHS at age thirteen after contracting encephalitis. Since the onset of her disease, she had been managed with positive pressure ventilation to her lungs via mask. Due to her longstanding disease, she presented with pulmonary hypertension and cor pulmonale and was scheduled for laparoscopic DPSS implantation. Our anesthetic technique included a total intravenous technique with remifentanil and propofol, and her trachea was intubated without the use of muscle relaxants. The pacemakers were switched on when the patient emerged from anesthesia, which provided her with ventilatory support and allowed us to extubate her trachea.<br><br>CONCLUSION: We present the successful anesthetic management of an adult patient with CAHS undergoing laparoscopic DPSS insertion.}, }
@article {pmid21864284, year = {2011}, author = {Sanmartin, C and Plano, D and Font, M and Palop, JA}, title = {Selenium and clinical trials: new therapeutic evidence for multiple diseases.}, journal = {Current medicinal chemistry}, volume = {18}, number = {30}, pages = {4635-4650}, doi = {10.2174/092986711797379249}, pmid = {21864284}, issn = {1875-533X}, mesh = {Animals ; Antioxidants/therapeutic use ; Arthritis, Rheumatoid/drug therapy/physiopathology ; Cardiovascular Diseases/drug therapy ; Clinical Trials as Topic ; Depression/drug therapy ; Diabetes Mellitus/drug therapy ; HIV Infections/prevention &amp; control ; HIV-1/drug effects ; Humans ; Leishmaniasis/drug therapy ; Micronutrients/physiology ; Neoplasms/drug therapy/prevention &amp; control ; Neurodegenerative Diseases/drug therapy ; Pancreatitis/physiopathology ; Selenium/adverse effects/metabolism/physiology/*therapeutic use ; Selenoproteins/physiology ; Thyroid Diseases/drug therapy/physiopathology ; }, abstract = {The understanding of the essential role of selenium (Se) in human health has increased substantially in recent decades. Micronutrient deficiencies are very common in the general population and may be even more common in patients with different pathologies due to genetic or environmental causes and prescription drug use. Selenium is used by people in the prevention and/or treatment of different disorders including cardiovascular disease, osteoarthritis, rheumatoid arthritis, hypothyroidism, stroke, atherosclerosis, cancer susceptibility and treatment, HIV, AIDS, neuronal diseases such as Alzheimer or amyotrophic lateral sclerosis, pancreatitis, depression, and diabetes amongst others. Several mechanisms have been suggested to mediate the biological effects of Se and these include antioxidant defence systems, synthesis and stability of metabolites that act as intermediates implicated in diverse selenoproteins expression pathways oxidative metabolism, immune system modulation, DNA intercalators, kinase regulation, enzymatic cofactor, and gene expression. A number of clinical trials in recent years have provided convincing evidence of the central role of this element, either alone or in combination with other micronutrients or antioxidants, in the prevention and treatment of multiple diseases. Based on these studies this review focuses on the advances made so far in the study of mechanisms and applications of selenium compounds that could be suitable for chronic diseases.}, }
@article {pmid21849797, year = {2011}, author = {Jiang, JH and Yang, EJ and Baek, MG and Kim, SH and Lee, SM and Choi, SM}, title = {Anti-inflammatory effects of electroacupuncture in the respiratory system of a symptomatic amyotrophic lateral sclerosis animal model.}, journal = {Neuro-degenerative diseases}, volume = {8}, number = {6}, pages = {504-514}, doi = {10.1159/000327911}, pmid = {21849797}, issn = {1660-2862}, mesh = {Adaptor Proteins, Signal Transducing/biosynthesis ; Amyotrophic Lateral Sclerosis/*complications/pathology ; Animals ; Blotting, Western ; Cell Count ; Cell Survival/physiology ; Cytoskeletal Proteins/biosynthesis ; *Electroacupuncture ; Extracellular Signal-Regulated MAP Kinases/biosynthesis ; Female ; Immunohistochemistry ; Inflammation/*therapy ; Interleukin-6/biosynthesis ; Lung/metabolism ; Male ; Mice ; Mice, Transgenic ; NF-kappa B/biosynthesis ; Nuclear Proteins/biosynthesis ; Oncogene Protein v-akt/biosynthesis ; Respiratory Tract Diseases/*etiology/pathology/*therapy ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Tumor Necrosis Factor-alpha/biosynthesis ; rac GTP-Binding Proteins/biosynthesis ; }, abstract = {BACKGROUND: Because amyotrophic lateral sclerosis (ALS) is a progressive inflammatory disease, treatment of the pulmonary system plays a key role in ALS patients' care. Previous studies have mainly examined the pathological mechanism of ALS in the central nervous system; however, there has been relatively little research regarding the pulmonary system in ALS animal models. In inflammatory diseases, including asthma and arthritis, electroacupuncture (EA) is commonly used for its anti-inflammatory effects. The goal of this study was to determine whether EA treatment affects inflammation in the pulmonary system in an ALS animal model.<br><br>METHODS: EA treatment at ST36 (Zusanli) acupoint was performed with 14-week-old hSOD1(G93A) transgenic mice. Immunohistochemical analysis was performed using anti-ionized calcium binding adaptor molecule 1 (Iba-1) and anti-tumor necrosis factor alpha (TNF-&#x3b1;) antibodies. To investigate the expression level of inflammatory proteins, Western blot analyses were performed using anti-Iba-1, anti-TNF-&#x3b1;, anti-nuclear factor kappa B (NF-&#x3ba;B), and anti-interleukin 6 (IL-6) antibodies. The activation of Ser435-phospho-specific RAC-alpha serine/threonine-protein kinase 1 (pAKT) and the increase of phosphorylated extracellular-signal-regulated kinases (pERK) protein in lung tissues of EA-treated and untreated hSOD1(G93A) mice were also evaluated by Western blot.<br><br>RESULTS: EA treatment decreased the expression of the proinflammatory proteins such as TNF-&#x3b1; and IL-6, pNF-&#x3ba;B, and Iba-1 and increased the level of activated pAKT and pERK compared to control hSOD1(G93A) mice.<br><br>CONCLUSIONS: Our findings suggest that EA could be an effective anti-inflammatory treatment for the respiratory impairment that occurs in ALS animal models.}, }
@article {pmid21849339, year = {2012}, author = {O'Neill, CL and Williams, TL and Peel, ET and McDermott, CJ and Shaw, PJ and Gibson, GJ and Bourke, SC}, title = {Non-invasive ventilation in motor neuron disease: an update of current UK practice.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {83}, number = {4}, pages = {371-376}, doi = {10.1136/jnnp-2011-300480}, pmid = {21849339}, issn = {1468-330X}, mesh = {Humans ; Motor Neuron Disease/complications/*therapy ; Neurology/*statistics &amp; numerical data ; Palliative Care/statistics &amp; numerical data ; Population Surveillance ; Practice Patterns, Physicians'/*statistics &amp; numerical data ; Referral and Consultation/statistics &amp; numerical data ; Respiration, Artificial/*statistics &amp; numerical data ; Respiratory Function Tests/statistics &amp; numerical data ; Respiratory Insufficiency/diagnosis/etiology/*prevention &amp; control ; Surveys and Questionnaires ; United Kingdom ; }, abstract = {BACKGROUND: In motor neurone disease (MND), respiratory muscle weakness causes substantial morbidity, and death is usually due to respiratory failure. Non-invasive ventilation (NIV) improves symptoms, quality of life and survival, but previous surveys showed that few patients with MND received NIV.<br><br>METHODS: A postal survey was conducted of the clinical application of NIV in MND among consultant neurologists in the UK. The results were compared with those of a similar survey done in 2000.<br><br>FINDINGS: Over 12 months, 612 patients were referred for NIV of whom 444 were successfully established on treatment (72.5% success rate). 38% of responding neurologists assessed respiratory function at presentation and 20% routinely monitored respiratory function; 32% relied on symptoms as the only criterion for NIV referral and 43% used a combination of symptoms and physiological impairment. 75% of responding neurologists accessed specialist palliative care services for their patients towards the end of life and 69% at an earlier stage.<br><br>INTERPRETATION: Compared with 2000, there has been a marked increase in the number of patients referred for, and currently using, NIV (2.6 and 3.4-fold, respectively). The proportion successfully established on NIV has also increased, suggesting more appropriate selection and/or improvement in the methods of using NIV in this challenging group of patients. However, monitoring of respiratory function is suboptimal and uncontrolled oxygen is sometimes used inappropriately before the terminal phase.}, }
@article {pmid21844342, year = {2011}, author = {Li, C and Xiao, P and Gray, SJ and Weinberg, MS and Samulski, RJ}, title = {Combination therapy utilizing shRNA knockdown and an optimized resistant transgene for rescue of diseases caused by misfolded proteins.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {108}, number = {34}, pages = {14258-14263}, pmid = {21844342}, issn = {1091-6490}, support = {R01 DK084033/DK/NIDDK NIH HHS/United States ; R01 AI072176/AI/NIAID NIH HHS/United States ; U54 AR056953/AR/NIAMS NIH HHS/United States ; 1R01AI080726/AI/NIAID NIH HHS/United States ; 5U54AR056953/AR/NIAMS NIH HHS/United States ; R01 AI080726/AI/NIAID NIH HHS/United States ; 5R01AI072176/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Combined Modality Therapy ; Dependovirus/genetics ; *Gene Knockdown Techniques ; Gene Silencing ; Genetic Vectors/genetics ; Injections, Intramuscular ; Liver/metabolism ; Mice ; Mice, Mutant Strains ; Proteostasis Deficiencies/blood/*therapy ; RNA, Messenger/genetics/metabolism ; RNA, Small Interfering/administration &amp; dosage/*metabolism ; Serotyping ; Transduction, Genetic ; Transgenes/*genetics ; alpha 1-Antitrypsin/blood/genetics ; }, abstract = {Molecular knockdown of disease proteins and restoration of wild-type activity represent a promising but challenging strategy for the treatment of diseases that result from the accumulation of misfolded proteins (i.e., Huntington disease, amyotrophic lateral sclerosis, and α-1 antitrypsin deficiency). In this study we used alpha-1 antitrypsin (AAT) deficiency with the piZZ mutant phenotype as a model system to evaluate the efficiency of gene-delivery approaches that both silence the piZZ transcript (e.g., shRNA) and restore circulating wild-type AAT expression from resistant codon-optimized AAT (AAT-opt) transgene cassette using adeno-associated virus (AAV) vector delivery. After systemic injection of a self-complimentary AAV serotype 8 (scAAV8) vector encoding shRNA in piZZ transgenic mice, both mutant AAT mRNA in the liver and defected serum protein level were inhibited by 95%, whereas liver pathology, as monitored by dPAS and fibrosis staining, reversed. To restore blood AAT levels in AAV8/shRNA-treated mice, several strategies to restore functional AAT levels were tested, including using AAV AAT-opt transgene cassettes targeted to muscle and liver, or combination vectors carrying piZZ shRNA and AAT-opt transgenes separately, or a single bicistronic AAV vector. With these molecular approaches, we observed over 90% knockdown of mutant AAT with a 13- to 30-fold increase of circulating wild-type AAT protein from the shRNA-resistant AAT-opt cassette. The molecular approaches applied in this study can simultaneously prevent liver pathology and restore blood AAT concentration in AAT deficiencies. Based on these observations, similar gene-therapy strategies could be considered for any diseases caused by accumulation of misfolded proteins.}, }
@article {pmid21830350, year = {2011}, author = {Omura, Y and O'Young, B and Jones, M and Pallos, A and Duvvi, H and Shimotsuura, Y}, title = {Caprylic acid in the effective treatment of intractable medical problems of frequent urination, incontinence, chronic upper respiratory infection, root canalled tooth infection, ALS, etc., caused by asbestos &amp; mixed infections of Candida albicans, Helicobacter pylori &amp; cytomegalovirus with or without other microorganisms &amp; mercury.}, journal = {Acupuncture &amp; electro-therapeutics research}, volume = {36}, number = {1-2}, pages = {19-64}, doi = {10.3727/036012911803860886}, pmid = {21830350}, issn = {0360-1293}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Asbestos/*adverse effects ; Candidiasis/*complications ; Caprylates/*therapeutic use ; Chronic Disease ; Cytomegalovirus Infections/*complications ; Helicobacter Infections/*complications ; *Helicobacter pylori ; Humans ; Respiratory Tract Infections/*drug therapy ; Root Canal Therapy/adverse effects ; Urinary Incontinence/*drug therapy ; Urination Disorders/*drug therapy ; }, abstract = {There are many causes of frequent urination. Whenever water or fluids are consumed, the patient has to urinate within 10 or 20 min. Often urinary bladder examinations &amp; blood tests show no significant abnormalities, &amp; treatment by anti-bacterial or anti-viral agents does not improve the symptoms significantly. In intractable frequent urination with difficulty holding urine, as well as other intractable medical problems such as frequent coughing, white pus in gingiva, infection of the apex of a root canalled tooth, slow-healing wounds, &amp; ALS, the authors often found coexisting mixed infections of Candida albicans (C.A.), Helicobacter pylori (H.P.), &amp; Cytomegalovirus (CMV) with or without additional bacterial (Chlamydia trachomatis, etc.) or viral infections &amp; increased Asbestos, with or without Hg deposits. We often found various degrees of mixed infections with C.A., H.P., &amp; CMV in the external sphincters of the urethra &amp; in the Trigone of the urinary bladder which consists of (1) a horizontal, band-like area between the 2 ureter openings &amp; (2) the funnel shaped part of the Trigone at the lower half of the urinary bladder. In the coexistence of significant amounts of C.A., H.P. &amp; CMV, the infection cannot be reduced by otherwise effective medicines for H.P. &amp; CMV. However, one optimal dose of Diflucan, or Caprylic acid taken orally or externally applied, rapidly reduced the symptoms significantly. We found the best treatment is to give a combination of an optimal dose of Caprylic acid orally in the form of "CaprilyCare" or "Caprylic Acid," with a capsule of Omega-3 Fish Oil as an anti-viral agent, Amoxicillin, Substance Z &amp; a Cilantro tablet. We found that an optimal dose of Caprylic acid increases normal cell telomere (NCT) to a desirable 750 ng BDORT units while Diflucan increases NCT by only 25 ng BDORT units, &amp; with Omega-3 fish oil, leads to a mutual cancellation of both drugs. Thus, Caprylic acid is superior to &amp; less expensive than Diflucan, &amp; has potential application for anti-cancer, anti-aging, anti-Alzheimer's disease, anti-Autism, anti-infection, &amp; general circulatory improvement.}, }
@article {pmid21826267, year = {2011}, author = {Pagani, MR and Gonzalez, LE and Uchitel, OD}, title = {Autoimmunity in amyotrophic lateral sclerosis: past and present.}, journal = {Neurology research international}, volume = {2011}, number = {}, pages = {497080}, pmid = {21826267}, issn = {2090-1860}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting particularly motor neurons for which no cure or effective treatment is available. Although the cause of ALS remains unknown, accumulative evidence suggests an autoimmune mechanism of pathogenesis. In this paper, we will summarize the current research related to autoimmunity in the sporadic form of ALS and discuss the potential underlying pathogenic mechanisms and perspectives. Presented data supports the view that humoral immune responses against motor nerve terminals can initiate a series of physiological changes leading to alteration of calcium homeostasis. In turn, loss of calcium homeostasis may induce neuronal death through apoptotic signaling pathways. Additional approaches identifying specific molecular features of this hypothesis are required, which will hopefully allow us to develop techniques of early diagnosis and effective therapies.}, }
@article {pmid21825986, year = {2011}, author = {Finsterer, J and Papić, L and Auer-Grumbach, M}, title = {Motor neuron, nerve, and neuromuscular junction disease.}, journal = {Current opinion in neurology}, volume = {24}, number = {5}, pages = {469-474}, doi = {10.1097/WCO.0b013e32834a9448}, pmid = {21825986}, issn = {1473-6551}, mesh = {Animals ; Disease Models, Animal ; Humans ; *Motor Neuron Disease/classification/genetics/pathology/therapy ; *Neuromuscular Junction Diseases/classification/genetics/pathology/therapy ; *Peripheral Nervous System Diseases/classification/genetics/pathology/therapy ; }, abstract = {PURPOSE OF REVIEW: The aim is to review the most relevant findings published during the last year concerning clinical, genetic, pathogenic, and therapeutic advances in motor neuron disease, neuropathies, and neuromuscular junction disorders.<br><br>RECENT FINDINGS: Studies on animal and cell models have improved the understanding of how mutated survival motor neuron protein in spinal muscular atrophy governs the pathogenetic processes. New phenotypes of SOD1 mutations have been described. Moreover, animal models enhanced the insight into the pathogenetic background of sporadic and familial amyotrophic lateral sclerosis. Novel treatment options for motor neuron disease have been described in humans and animal models. Considerable progress has been achieved also in elucidating the genetic background of many forms of inherited neuropathies and high clinical and genetic heterogeneity has been demonstrated. Mutations in MuSK and GFTP1 have been shown to cause new types of congenital myasthenic syndromes. A third type of autoantibodies (Lrp4) has been detected to cause myasthenia gravis.<br><br>SUMMARY: Advances in the clinical and genetic characterization of motor neuron diseases, neuropathies, and neuromuscular transmission defects have important implications on the fundamental understanding, diagnosis, and management of these disorders. Identification of crucial steps of the pathogenetic process may provide the basis for the development of novel therapeutic strategies.}, }
@article {pmid21824113, year = {2012}, author = {Nomura, M and Oketa, Y and Yasui, K and Ishikawa, H and Ono, S}, title = {Expression of hepatocyte growth factor in the skin of amyotrophic lateral sclerosis.}, journal = {Acta neurologica Scandinavica}, volume = {125}, number = {6}, pages = {389-397}, doi = {10.1111/j.1600-0404.2011.01579.x}, pmid = {21824113}, issn = {1600-0404}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Disease Progression ; Epidermal Cells ; Epidermis/metabolism ; Female ; Hepatocyte Growth Factor/*metabolism ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Skin/*metabolism/*pathology ; }, abstract = {OBJECTIVES: Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. Overexpression of neuronal HGF has been shown to result in the attenuation of neuronal cell death and progression of disease in a familial amyotrophic lateral sclerosis (ALS) transgenic mouse model. HGF might be beneficial for motor neuron survival and is a good candidate agent for the treatment of ALS. So far, studies of the skin of ALS have shown unique pathological and biochemical abnormalities. However, there has been no study of HGF in ALS skin.<br><br>MATERIALS AND METHODS: We made a quantitative immunohistochemical study of the expression of HGF in the skin from 19 patients with sporadic ALS and 16 controls.<br><br>RESULTS: Hepatocyte growth factor immunoreactivity was positive in the epidermis, some dermal blood vessels, and glands in patients with ALS. These findings became more conspicuous as ALS progressed. The optical density for HGF immunoreactivity of the nucleus and the cytoplasm in the epidermis in ALS was significantly higher (P < 0.001 and P < 0.001) than in controls. There was a significant positive relation (r = 0.53, P < 0.02 and r = 0.73, P < 0.001) between HGF immunoreactivity and duration of illness in the nucleus and the cytoplasm in the epidermis in patients with ALS.<br><br>CONCLUSIONS: These findings suggest that changes in HGF in ALS skin are related to the disease process and that metabolic alterations of HGF may take place in the skin of patients with ALS.}, }
@article {pmid21824087, year = {2011}, author = {Orsucci, D and Mancuso, M and Ienco, EC and LoGerfo, A and Siciliano, G}, title = {Targeting mitochondrial dysfunction and neurodegeneration by means of coenzyme Q10 and its analogues.}, journal = {Current medicinal chemistry}, volume = {18}, number = {26}, pages = {4053-4064}, doi = {10.2174/092986711796957257}, pmid = {21824087}, issn = {1875-533X}, support = {GUP09004/TI_/Telethon/Italy ; }, mesh = {Animals ; Humans ; Micronutrients/metabolism/pharmacology/*therapeutic use ; Mitochondria/*metabolism ; Mitochondrial Diseases/*drug therapy/metabolism/physiopathology ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/metabolism/physiopathology ; Ubiquinone/*analogs &amp; derivatives/metabolism/pharmacology/physiology/*therapeutic use ; }, abstract = {Coenzyme Q10 is a small electron carrier of the respiratory chain with antioxidant properties, widely used for the treatment of mitochondrial disorders. Mitochondrial diseases are neuromuscular disorders caused by impairment of the respiratory chain and increased generation of reactive oxygen species. Coenzyme Q10 supplementation is fundamental in patients with primary coenzyme Q10 deficiency. Furthermore, coenzyme Q10 and its analogues, idebenone and mitoquinone (or MitoQ), have been also used in the treatment of other neurogenetic/neurodegenerative disorders. In Friedreich ataxia idebenone may reduce cardiac hypertrophy and, at higher doses, also improve neurological function. These compounds may also play a potential role in other conditions which have been linked to mitochondrial dysfunction, such as Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and Alzheimer disease. This review introduces mitochondrial disorders and Friedreich ataxia as two paradigms of the tight links existing between oxidative stress, respiratory chain dysfunction and neurodegeneration, and focuses on current and emerging therapeutic uses of coenzyme Q10 and idebenone in neurology.}, }
@article {pmid21819217, year = {2011}, author = {Ayloo, SM and Masrur, MA and Bianco, FM and Giulianotti, PC}, title = {Robotic Roux-en-Y duodenojejunostomy for superior mesenteric artery syndrome: operative technique.}, journal = {Journal of laparoendoscopic &amp; advanced surgical techniques. Part A}, volume = {21}, number = {9}, pages = {841-844}, doi = {10.1089/lap.2011.0070}, pmid = {21819217}, issn = {1557-9034}, mesh = {Adult ; Anastomosis, Roux-en-Y/*methods ; Blood Loss, Surgical ; Duodenostomy/*methods ; Duodenum/diagnostic imaging/*surgery ; Humans ; Jejunostomy/*methods ; Male ; Robotics/*methods ; Superior Mesenteric Artery Syndrome/*surgery ; Tomography, X-Ray Computed ; }, abstract = {BACKGROUND: Superior mesenteric artery (SMA) syndrome, also known as Wilkie's syndrome, is a rare condition characterized by vascular compression of the duodenum that leads to intestinal obstruction. While there have been a few recent case reports of laparoscopic duodenojejunostomy performed as an option for surgical treatment, the role of the da Vinci(®) robot in superior mesenteric syndrome has been underestimated. The authors report a robotic Roux-en-Y duodenojejunostomy for the treatment of SMA syndrome.<br><br>MATERIALS AND METHODS: A 39-year-old man with a history of Amyotrophic lateral sclerosis presented with an upper gastrointestinal obstruction with distended abdomen. A computed tomography scan showed a transition in the third portion of the duodenum where the SMA vessels crossed over, with a decompressed jejunum. He was identified as a candidate for a duodenojejunostomy. The da Vinci Surgical System was used to mobilize the colon and duodenum, and a Roux-en-Y duodenojejunostomy was performed with hand-sewn anastomosis.<br><br>RESULTS: There were no intraoperative complications. The blood loss was minimal and operative time was 120 minutes. The postoperative course was uneventful with resolution of intestinal obstruction.<br><br>CONCLUSION: Robotic Roux-en-Y duodenojejunostomy as a surgical option for treatment of SMA syndrome is safe, feasible, and a valid alternative to open surgery with the added benefits of a minimally invasive approach.}, }
@article {pmid21813139, year = {2011}, author = {Boumédiène, F and Druet-Cabanac, M and Marin, B and Preux, PM and Allée, P and Couratier, P}, title = {Contribution of geolocalisation to neuroepidemiological studies: incidence of ALS and environmental factors in Limousin, France.}, journal = {Journal of the neurological sciences}, volume = {309}, number = {1-2}, pages = {115-122}, doi = {10.1016/j.jns.2011.07.002}, pmid = {21813139}, issn = {1878-5883}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*epidemiology/*etiology ; Cluster Analysis ; Environmental Exposure/*adverse effects ; France/epidemiology ; Humans ; Incidence ; Industry/trends ; Risk Factors ; }, abstract = {This article aimed to detect clusters of amyotrophic lateral sclerosis (ALS) and their relationships with exposure of the population to various environmental factors in the Limousin region of France. Methods used were extensively described. We adopted a geographical approach that revealed variations in the incidence of ALS and permitted us to identify three regional clusters and their spatial spread. We considered environmental factors and the potent locations or source of substances or activities hypothesized to be associated with ALS. Notably, we determined which industrial activities seem to affect the incidence of ALS in Limousin. The results were interpreted at a regional level. Among the 50 factors this article considered, paper paste and water treatment plants were particularly geostatistically significant and deserve special attention in the ongoing investigations into high resolution spatial clusters (geographical and epidemiological studies).}, }
@article {pmid21812628, year = {2011}, author = {Cordes, AL and Jahn, K and Hass, R and Schwabe, K and Weissinger, EM and Ganser, A and Götz, F and Dengler, R and Krauss, JK and Petri, S}, title = {Intramedullary spinal cord implantation of human CD34+ umbilical cord-derived cells in ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {12}, number = {5}, pages = {325-330}, doi = {10.3109/17482968.2011.580850}, pmid = {21812628}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*surgery ; Antigens, CD34/*administration &amp; dosage ; Cord Blood Stem Cell Transplantation/ethics/*methods ; Follow-Up Studies ; Histocompatibility Testing/ethics/methods ; Humans ; Male ; Middle Aged ; Spinal Cord/pathology/*surgery ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with marginal therapeutic options. Degeneration of motor neurons in the primary motor cortex, brainstem and spinal cord lead to rapidly progressive paralysis and finally to death due to respiratory failure. As pharmacological therapies have failed to provide sufficient neuroprotective effects in ALS, transplantation of stem or progenitor cells is considered a promising treatment strategy. Cell transplantation approaches in ALS mainly aim to generate a neuroprotective environment for degenerating motor neurons by transplantation of non-neuronal cells, rather than to replace lost motor neurons. We present a 63-year-old male patient suffering from ALS who underwent intramedullary thoracic spinal cord implantation of human CD34(+) umbilical cord-derived haematopoietic progenitor cells with a three-year follow up after transplantation.}, }
@article {pmid21808983, year = {2012}, author = {Lulé, D and Pauli, S and Altintas, E and Singer, U and Merk, T and Uttner, I and Birbaumer, N and Ludolph, AC}, title = {Emotional adjustment in amyotrophic lateral sclerosis (ALS).}, journal = {Journal of neurology}, volume = {259}, number = {2}, pages = {334-341}, pmid = {21808983}, issn = {1432-1459}, mesh = {*Adaptation, Psychological ; Amyotrophic Lateral Sclerosis/*psychology ; Female ; Humans ; Male ; Middle Aged ; *Quality of Life ; *Social Adjustment ; }, abstract = {Despite the devastating motor impairment, a significant number of patients with amyotrophic lateral sclerosis (ALS) maintain a good psychosocial adjustment. Here we investigated whether this is specific for ALS or a more general characteristic of terminal disease. Psychosocial adjustment was investigated in 30 ALS patients, 29 cancer patients in palliative treatment and 29 age-, gender- and level of education-matched healthy controls. Subjective quality of life (sQoL), degree of depressive symptoms and coping were evaluated as measures of psychosocial adjustment. Personality factors were described. ALS and cancer patients showed a good psychosocial adjustment. Subjective QoL and depression did not differ significantly. Both patient groups presented a good sQoL. The level of mild depressive symptoms in both patient groups was similar and none showed clinically relevant depression. ALS patients expressed fewer active coping strategies than cancer patients which were explained by gender differences. Both patient groups showed comparable psychosocial adjustment to their disease. Overall, in terminally ill patients the psychological response to the prognosis is not associated with neurobiological changes (e.g., associated with subclinical deficits in ALS) or with physical decline.}, }
@article {pmid21806316, year = {2011}, author = {Habib, AA and Mitsumoto, H}, title = {Emerging drugs for amyotrophic lateral sclerosis.}, journal = {Expert opinion on emerging drugs}, volume = {16}, number = {3}, pages = {537-558}, doi = {10.1517/14728214.2011.604312}, pmid = {21806316}, issn = {1744-7623}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Clinical Trials as Topic ; Drug Evaluation, Preclinical/methods ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease that results in increasing disability and that is uniformly fatal. Since its approval in the 1990s, riluzole remains the sole treatment for ALS offering modest survival benefit. While significant advances have been made in the symptomatic management of the disease, more effective drug therapy targeting disease progression is sorely needed.<br><br>AREAS COVERED: Advances in the understanding of pathogenic mechanisms involved in disease development and progression have provided multiple avenues for developing effective treatment strategies. This review highlights recent discoveries relating to these diverse mechanisms and their implications for the development of drug therapy. Previous human clinical trials that have targeted these pathways are mentioned and ongoing drug trials are discussed.<br><br>EXPERT OPINION: The search for effective drug therapy faces important challenges in the areas of basic science and animal research, translation of these results into human clinical trials, inherent bias in human studies and issues related to delays in clinical diagnosis. How these issues may be addressed and why ALS research constitutes fertile grounds for drug development not only for this devastating disease, but also for other more prevalent neurodegenerative diseases, is discussed in this review.}, }
@article {pmid21796424, year = {2012}, author = {Lee, M and Kwon, BM and Suk, K and McGeer, E and McGeer, PL}, title = {Effects of obovatol on GSH depleted glia-mediated neurotoxicity and oxidative damage.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {7}, number = {1}, pages = {173-186}, pmid = {21796424}, issn = {1557-1904}, mesh = {Anti-Inflammatory Agents/*pharmacology ; Antioxidants/pharmacology ; Biphenyl Compounds/*pharmacology ; Cell Line ; Glutathione/metabolism ; Humans ; Inflammation/*prevention &amp; control ; Neuroglia/*drug effects ; Neuroprotective Agents/pharmacology ; Oxidative Stress/*drug effects ; Phenyl Ethers/*pharmacology ; }, abstract = {Earlier studies indicate that obovatol (OBO), isolated from a medicinal herb Magnolia obovata, has anti-inflammatory and anti-oxidative properties. Depletion of glutathione (GSH) in glial cells with the γ-glutamylcysteine synthase inhibitor D,L-buthionine-S,R-sulfoximine (BSO) is known to produce oxidative stress which, in turn, induces these cells to secrete inflammatory cytokines and other neurotoxic substances. In the present study, we investigated the ability of OBO to protect SH-SY5Y neuroblastoma cells from this effect. Human microglia, astrocytes and their surrogate THP-1 and U373 cell lines were activated by treatment with BSO. Such treatment depleted their intracellular GSH and increased levels of damage to DNA, lipids and proteins (8-OHdG, lipid peroxide, protein carbonyls and 3-nitrotyrosine), and activated the inflammatory pathways P38 MAP kinase and NFκB. These are accompanied by release of proinflammatory factors such as TNFα, IL-6 and nitric oxide. Their conditioned media were toxic to SH-SY5Y cells. All these effects were attenuated by pre-treatment with OBO. Prior treatment of SH-SY5Y cells with OBO also attenuated THP-1 or U373 conditioned media neurotoxicity and also reduced oxidative damage produced by treatment with hydrogen peroxide or BSO. Prior treatment with OBO potentiated survival of SH-SY5Y cells exposed to conditioned medium from BSO-treated THP-1, U373 cells, microglia and astrocytes. The data indicate that OBO could be anti-inflammatory, anti-oxidative and neuroprotective, and be an effective agent for inhibiting pathogenesis in neurological diseases such as Alzheimer disease, Parkinson disease and amyotrophic lateral sclerosis in which glial-mediated neuroinflammation and oxidative stress are thought to contribute to disease progression.}, }
@article {pmid21796043, year = {2011}, author = {Clarke, K and Levine, T}, title = {Clinical recognition and management of amyotrophic lateral sclerosis: the nurse's role.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {43}, number = {4}, pages = {205-214}, doi = {10.1097/JNN.0b013e3182212a6c}, pmid = {21796043}, issn = {1945-2810}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*nursing/therapy ; Combined Modality Therapy ; Delayed Diagnosis ; Diagnosis, Differential ; Disease Progression ; Humans ; *Nurse's Role ; Nursing Assessment ; *Nursing Diagnosis ; Palliative Care/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, causes a progressive wasting and loss of the upper and lower motor neurons that facilitate the movement of body parts. At onset, ALS patients may show symptoms such as muscle weakness, atrophy, hyperreflexia, or bulbar symptoms such as dysphagia or dysarthria. Deterioration progresses rapidly, and the later stages of ALS are characterized by severely limited mobility and respiratory failure, which is the primary cause of death. There is no specific diagnostic test for ALS, and there are a number of other conditions that may resemble ALS, making a diagnosis difficult. The variability of the initial presentation combined with the broad differential diagnosis may result in significant delays in diagnosis or, in some cases, misdiagnosis, which in turn have a negative impact on patient outcomes. There is no cure for ALS; however, many of the symptoms are treatable, and the physical and psychological symptoms are best managed through the efforts of a coordinated, multidisciplinary team. Nurses play a critical role in the clinical management of ALS and may be involved in coordinating the activities of the team, facilitating treatment, and helping patients and caregivers in making informed treatment and end-of-life decisions. Drug therapy for ALS is currently limited to riluzole; however, patients may be treated with a number of nonpharmacologic methods on the basis of their symptoms. A number of other treatment modalities, such as stem-cell-based therapy or gene therapy, and an array of neuroprotective clinical trials are currently under development for the treatment of ALS. Nurses may also have a key role in these various ALS studies.}, }
@article {pmid21792905, year = {2011}, author = {Kim, K and Lee, SG and Kegelman, TP and Su, ZZ and Das, SK and Dash, R and Dasgupta, S and Barral, PM and Hedvat, M and Diaz, P and Reed, JC and Stebbins, JL and Pellecchia, M and Sarkar, D and Fisher, PB}, title = {Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics.}, journal = {Journal of cellular physiology}, volume = {226}, number = {10}, pages = {2484-2493}, pmid = {21792905}, issn = {1097-4652}, support = {R01 CA134721-02/CA/NCI NIH HHS/United States ; P01 NS031492/NS/NINDS NIH HHS/United States ; P01 NS31492/NS/NINDS NIH HHS/United States ; R01 CA134721/CA/NCI NIH HHS/United States ; R03 MH093195/MH/NIMH NIH HHS/United States ; P01 NS031492-15/NS/NINDS NIH HHS/United States ; R01 CA134721-01A1/CA/NCI NIH HHS/United States ; R03 MH093195-01/MH/NIMH NIH HHS/United States ; }, mesh = {Animals ; Excitatory Amino Acid Transporter 2/genetics/metabolism/*physiology ; Glutamic Acid/metabolism/*physiology ; Humans ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neuroprotective Agents/*pharmacology/*therapeutic use ; }, abstract = {Glutamate is an essential excitatory neurotransmitter regulating brain functions. Excitatory amino acid transporter (EAAT)-2 is one of the major glutamate transporters expressed predominantly in astroglial cells and is responsible for 90% of total glutamate uptake. Glutamate transporters tightly regulate glutamate concentration in the synaptic cleft. Dysfunction of EAAT2 and accumulation of excessive extracellular glutamate has been implicated in the development of several neurodegenerative diseases including Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Analysis of the 2.5 kb human EAAT2 promoter showed that NF-κB is an important regulator of EAAT2 expression in astrocytes. Screening of approximately 1,040 FDA-approved compounds and nutritionals led to the discovery that many β-lactam antibiotics are transcriptional activators of EAAT2 resulting in increased EAAT2 protein levels. Treatment of animals with ceftriaxone (CEF), a β-lactam antibiotic, led to an increase of EAAT2 expression and glutamate transport activity in the brain. CEF has neuroprotective effects in both in vitro and in vivo models based on its ability to inhibit neuronal cell death by preventing glutamate excitotoxicity. CEF increases EAAT2 transcription in primary human fetal astrocytes through the NF-κB signaling pathway. The NF-κB binding site at -272 position was critical in CEF-mediated EAAT2 protein induction. These studies emphasize the importance of transcriptional regulation in controlling glutamate levels in the brain. They also emphasize the potential utility of the EAAT2 promoter for developing both low and high throughput screening assays to identify novel small molecule regulators of glutamate transport with potential to ameliorate pathological changes occurring during and causing neurodegeneration.}, }
@article {pmid21790808, year = {2011}, author = {Johann, S and Dahm, M and Kipp, M and Zahn, U and Beyer, C}, title = {Regulation of choline acetyltransferase expression by 17 β-oestradiol in NSC-34 cells and in the spinal cord.}, journal = {Journal of neuroendocrinology}, volume = {23}, number = {9}, pages = {839-848}, doi = {10.1111/j.1365-2826.2011.02192.x}, pmid = {21790808}, issn = {1365-2826}, mesh = {Animals ; Cell Differentiation ; Cell Line ; Choline O-Acetyltransferase/genetics/*metabolism ; Estradiol/*pharmacology/physiology ; Estrogen Receptor alpha/genetics/metabolism ; Female ; Gene Expression Regulation, Enzymologic ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Motor Neurons/*drug effects/*enzymology/physiology ; Nuclear Receptor Coactivators/genetics/metabolism ; Signal Transduction ; Spinal Cord/cytology/*drug effects/*enzymology ; }, abstract = {Motoneurones located in the ventral horn of the spinal cord conciliate cholinergic innervation of skeletal muscles. These neurones appear to be exceedingly affected in neurodegenerative diseases such as amyotrophic lateral sclerosis. The dysfunction of motoneurones is typically accompanied by alterations of cholinergic metabolism and signalling, as demonstrated by a decrease in choline acetyltransferase (ChAT) expression. 17 β-Oestradiol (E(2)) is generally accepted as neuroprotective factor in the brain under acute toxic and neurodegenerative conditions and also appears to exert a protective role for motoneurones. In the present study, we attempted to analyse the role of E(2) signalling on ChAT expression in the motoneurone-like cell line NSC-34 and in vivo. In a first step, we demonstrated the presence of oestrogen receptor α and β in NSC-34 cells, as well as in the cervical and lumbar parts, of the male mouse spinal cord. Subsequently, we investigated the effect of E(2) treatment on ChAT expression. The application of E(2) significantly increased the transcription of ChAT in NSC-34 cells and in the cervical but not lumbar part of the spinal cord. Our results indicate that E(2) can influence the cholinergic system by increasing ChAT expression in the mouse spinal cord. This mechanism might support motoneurones, in addition to survival-promoting mechanisms, in the temporal balance toxic or neurodegenerative challenges.}, }
@article {pmid21778357, year = {2011}, author = {Ersson, C and Möller, L}, title = {The effects on DNA migration of altering parameters in the comet assay protocol such as agarose density, electrophoresis conditions and durations of the enzyme or the alkaline treatments.}, journal = {Mutagenesis}, volume = {26}, number = {6}, pages = {689-695}, doi = {10.1093/mutage/ger034}, pmid = {21778357}, issn = {1464-3804}, mesh = {Alkalies/*pharmacology ; Cell Line ; Comet Assay/*methods ; DNA/*metabolism ; DNA Damage ; DNA-Formamidopyrimidine Glycosylase/*metabolism ; Dose-Response Relationship, Radiation ; Electricity ; *Electrophoresis, Agar Gel ; Gamma Rays ; Humans ; Hydrogen Peroxide/pharmacology ; Sepharose/*chemistry ; Time Factors ; }, abstract = {The single cell gel electrophoresis (comet assay) is a popular method for measuring DNA migration as an estimate of DNA damage. No standardised comet assay protocol exists, which make comparisons between studies complicated. In a previous inter-laboratory validation study of the comet assay, we identified important parameters in the protocol that might affect DNA migration. The aim of this study was to assess how different comet assay protocols affect DNA migration. The results in this study suggest that (i) there is a significant linear dose-response relationship between the agarose gel's density and DNA migration and that damaged cells are more sensitive to the agarose gel's density; (ii) incubation with formamidopyrimidine DNA glycosylase for 10 min is inadequate, whereas 30 min is sufficient; (iii) the typically used 20 min of alkaline treatment might be to short when analysing samples that contain particular alkali-labile sites (ALS) and (iv) the duration of electrophoresis as well as the strength of the electric field applied affects the DNA migration. By using protocol-specific calibration curves, it is possible to reduce the variation in DNA migration caused by differences in comet assay protocols. This does, however, not completely remove the impact of the durations of alkaline treatment and electrophoresis when analysing cells containing ALS that are relatively resistant to high alkaline treatment.}, }
@article {pmid21766021, year = {2011}, author = {Handy, CR and Krudy, C and Boulis, N and Federici, T}, title = {Pain in amyotrophic lateral sclerosis: a neglected aspect of disease.}, journal = {Neurology research international}, volume = {2011}, number = {}, pages = {403808}, pmid = {21766021}, issn = {2090-1860}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive loss of motor neurons, muscle wasting, and respiratory dysfunction. With disease progression, secondary symptoms arise creating new problematic conditions for ALS patients. Amongst these is pain. Although not a primary consequence of disease, pain occurs in a substantial number of individuals. Yet, studies investigating its pathomechanistic properties in the ALS patient are lacking. Therefore, more exploratory efforts into its scope, severity, impact, and treatment should be initiated. Several studies investigating the use of Clostridial neurotoxins for the reduction of pain in ALS patients suggest the potential for a neural specific approach involving focal drug delivery. Gene therapy represents a way to accomplish this. Therefore, the use of viral vectors to express transgenes that modulate the nociceptive cascade could prove to be an effective way to achieve meaningful benefit in conditions of pain in ALS.}, }
@article {pmid21761185, year = {2011}, author = {Zipp, F and Gold, R}, title = {[Neuroprotection in the treatment of multiple sclerosis].}, journal = {Der Nervenarzt}, volume = {82}, number = {8}, pages = {973-977}, pmid = {21761185}, issn = {1433-0407}, mesh = {Alemtuzumab ; Anti-Inflammatory Agents/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antibodies, Neoplasm/therapeutic use ; Axons/drug effects/immunology/pathology ; Brain/drug effects/immunology/pathology ; Cell Death/drug effects/physiology ; Disease Progression ; Humans ; Immunologic Factors/therapeutic use ; Multiple Sclerosis/*drug therapy/immunology/pathology ; Nerve Regeneration/drug effects ; Neurodegenerative Diseases/*drug therapy/immunology/pathology ; Neurons/drug effects/immunology/pathology ; Neuroprotective Agents/*therapeutic use ; Prognosis ; Retrograde Degeneration/drug therapy/immunology/pathology ; Spinal Cord/drug effects/immunology/pathology ; }, abstract = {Atrophy, the wasting or shrinkage of tissue, of the nervous system is the main feature of neurodegeneration, i.e. the umbrella term for the progressive loss of structure or function of neurons. Loss of neurons due to cell death and axonal degeneration characterize neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis. In these illnesses, it still has to be elucidated to which extent inflammation is part of the pathology. Conversely, in chronic inflammation of the central nervous system (CNS), atrophy has previously also been described and neurodegeneration is discussed as a pathologic feature. The most frequent chronic inflammatory disease of the CNS is multiple sclerosis (MS), which leads to devastating relapsing-remitting symptoms and disability during the relapses, increasingly during the course of disease in patients. Meanwhile it became clear that axons already reveal pathology early in the disease and neurons are affected in the cortex and the spinal cord, albeit to a different extent. The broadening of understanding neurodegenerative aspects of MS pathology demands and creates new therapeutic strategies. Current medication used in MS treatment as well as medications about to be approved are primarily anti-inflammatory therapies. By modulating the immune system and thereby blocking key steps of the pathology, the immunomodulation therapies in MS have a slight impact on disability progression. There is, however, clinical and experimental data concerning the potential neuroprotective properties of novel therapies. Combining anti-inflammatory and direct neuroprotective or even neuroregenerative therapy strategies would be a step forward in the treatment of multiple sclerosis.}, }
@article {pmid21745124, year = {2011}, author = {Zhang, Y and Schuff, N and Woolley, SC and Chiang, GC and Boreta, L and Laxamana, J and Katz, JS and Weiner, MW}, title = {Progression of white matter degeneration in amyotrophic lateral sclerosis: A diffusion tensor imaging study.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {12}, number = {6}, pages = {421-429}, pmid = {21745124}, issn = {1471-180X}, support = {P41 RR023953/RR/NCRR NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*pathology/*physiopathology ; Cross-Sectional Studies ; Diffusion Tensor Imaging/*methods ; Disease Progression ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Nerve Degeneration/*pathology/physiopathology ; Nerve Fibers, Myelinated/*pathology ; Pyramidal Tracts/pathology ; }, abstract = {Whether longitudinal diffusion tensor MRI imaging (DTI) can capture disease progression in patients with amyotrophic lateral sclerosis (ALS) is unclear. The primary goal of this study was to determine if DTI detects progression of the corticospinal tracts (CST) degeneration in ALS. Seventeen ALS patients and 19 age- and gender-matched healthy controls were scanned with DTI at baseline for cross-sectional analyses. For longitudinal analyses, the ALS patients had repeat DTI scans after eight months. Tractography of the CST was used to guide regions-of-interest (ROI) analysis and complemented by a voxelwise analysis. Cross-sectional study found that baseline FA of the right superior CST was markedly reduced in ALS patients compared to controls. The FA reductions in this region correlated with the disease severity in ALS patients. Longitudinal study found that FA change rate of the right superior CST significantly declined over time. In conclusion, longitudinal DTI study captures progression of upper motor fiber degeneration in ALS. DTI can be useful for monitoring ALS progression and efficacy of treatment interventions.}, }
@article {pmid21743136, year = {2011}, author = {Chiu, CT and Chuang, DM}, title = {Neuroprotective action of lithium in disorders of the central nervous system.}, journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences}, volume = {36}, number = {6}, pages = {461-476}, pmid = {21743136}, issn = {1672-7347}, support = {ZIA MH002468-23//Intramural NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System Diseases/*drug therapy ; Humans ; Lithium/*pharmacology/*therapeutic use ; Neurodegenerative Diseases/*drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use ; Nootropic Agents/pharmacology/therapeutic use ; }, abstract = {Substantial in vitro and in vivo evidence of neurotrophic and neuroprotective effects of lithium suggests that it may also have considerable potential for the treatment of neurodegenerative conditions. Lithium's main mechanisms of action appear to stem from its ability to inhibit glycogen synthase kinase-3 activity and also to induce signaling mediated by brain-derived neurotrophic factor. This in turn alters a wide variety of downstream effectors, with the ultimate effect of enhancing pathways to cell survival. In addition, lithium contributes to calcium homeostasis. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, for instance, it suppresses the calcium-dependent activation of pro-apoptotic signaling pathways. By inhibiting the activity of phosphoinositol phosphatases, it decreases levels of inositol 1,4,5-trisphosphate, a process recently identified as a novel mechanism for inducing autophagy. These mechanisms allow therapeutic doses of lithium to protect neuronal cells from diverse insults that would otherwise lead to massive cell death. Lithium, moreover, has been shown to improve behavioral and cognitive deficits in animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, and Huntington's, Alzheimer's, and Parkinson's diseases. Since lithium is already FDA-approved for the treatment of bipolar disorder, our conclusions support the notion that its clinical relevance can be expanded to include the treatment of several neurological and neurodegenerative-related diseases.}, }
@article {pmid21740381, year = {2011}, author = {Rizvanov, AA and Gulluoglu, S and Yalvaç, ME and Palotás, A and Islamov, RR}, title = {RNA interference and amyotrophic lateral sclerosis.}, journal = {Current drug metabolism}, volume = {12}, number = {7}, pages = {679-683}, doi = {10.2174/138920011796504464}, pmid = {21740381}, issn = {1875-5453}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics/*therapy ; Animals ; Cell Death/physiology ; Genetic Therapy/*trends ; Humans ; Mutation/genetics ; RNA Interference/*physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neuro-degenerative disorder characterized by progressive loss of motor neurons. The etiology and molecular pathogenesis of cell death in most sub-types of the disease are largely unknown. The best documented cause of moto-neuron degeneration is the mutation in the superoxide dismutase-1 (SOD1) gene, which occurs in 10% of the familial forms of ALS. Discovery of RNA interference (RNAi), which plays an important role in the regulation of gene expression, has proven to be a powerful tool to study the pathogenesis and to develop innovative treatment options for hereditary diseases, including familial variants of ALS. This review summarizes current research advances in RNAi in relation to ALS.}, }
@article {pmid21733494, year = {2011}, author = {Mancuso, R and Oliván, S and Osta, R and Navarro, X}, title = {Evolution of gait abnormalities in SOD1(G93A) transgenic mice.}, journal = {Brain research}, volume = {1406}, number = {}, pages = {65-73}, doi = {10.1016/j.brainres.2011.06.033}, pmid = {21733494}, issn = {1872-6240}, mesh = {Analysis of Variance ; Animals ; Disease Progression ; Electromyography ; Extremities/physiopathology ; Gait Disorders, Neurologic/*genetics/pathology/*physiopathology ; Humans ; Locomotion/genetics ; Mice ; Mice, Transgenic ; Motor Activity/genetics ; Neural Conduction/genetics ; Psychomotor Performance/physiology ; Rotarod Performance Test ; Sciatic Nerve/physiopathology ; Superoxide Dismutase/*genetics ; Time Factors ; Video Recording ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of upper and lower motoneurons. Clinically, it is manifested by weakness, muscle atrophy and progressive paralysis and ends up with patients' death 2-5 years after diagnosis. Although these symptoms lead in many cases to gait deficits in patients, an exhaustive locomotor profile of animal models mimicking the disease has not been assessed yet. In this work we evaluated the locomotor performance of the SOD1(G93A) mouse model of ALS using computerized treadmill gait analysis. SOD1(G93A) mice presented early (8 weeks of age) gait abnormalities, evidenced by an increase in the time of the propulsion phase of hindlimb stance. The alterations progressed during the disease until a complete disturbance of normal gait. This finding is meaningful to the field because the identification of a significant difference in a functional endpoint as early as 8 weeks might be a step forward resolving the debate about treatment of mice prior to the symptomatic phase in efficacy studies. These results also point out that digitizing analysis of treadmill locomotion may be useful to evaluate whether new therapeutic approaches are improving functional outcome of the animals.}, }
@article {pmid21726879, year = {2011}, author = {Kasarskis, EJ and Hodskins, J and St Clair, WH}, title = {Unilateral parotid electron beam radiotherapy as palliative treatment for sialorrhea in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {308}, number = {1-2}, pages = {155-157}, doi = {10.1016/j.jns.2011.06.016}, pmid = {21726879}, issn = {1878-5883}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/complications/diagnostic imaging/*radiotherapy ; Female ; Humans ; Male ; Middle Aged ; Palliative Care/*methods ; Parotid Gland/diagnostic imaging/*radiation effects ; *Particle Accelerators/instrumentation ; Radiography ; Sialorrhea/diagnostic imaging/etiology/*radiotherapy ; }, abstract = {When ALS patients experience oropharyngeal weakness, sialorrhea can become a considerable challenge. Drooling has a profound negative impact in patient's quality of life causing embarrassing social situations. Several therapeutic modalities, including anticholinergic drugs, botulinum toxin injection, and radiotherapy have emerged as treatments for drooling in ALS. This retrospective case series study examined the effect of palliative radiotherapy in controlling problematic oral secretions in 10 ALS patients refractory to medical management. External electron beam radiation was targeted to a single parotid gland unilaterally with a total dose of 1500 cGy in 3 fractions at a depth determined by CT scanning. One patient received additional radiotherapy to the contralateral parotid due to persistent secretions. All patients reported improvement with a reduction in the intensity and amount of drooling. In 5 of 10 patients, anticholinergics were discontinued and were reduced in another two. There were no major side effects of treatment. We conclude that unilateral parotid electron radiotherapy provides satisfactory relief from sialorrhea in ALS patients and should be considered as a therapeutic option for patients who are refractory to medical management.}, }
@article {pmid21726643, year = {2011}, author = {Caioli, S and Curcio, L and Pieri, M and Antonini, A and Marolda, R and Severini, C and Zona, C}, title = {Substance P receptor activation induces downregulation of the AMPA receptor functionality in cortical neurons from a genetic model of Amyotrophic Lateral Sclerosis.}, journal = {Neurobiology of disease}, volume = {44}, number = {1}, pages = {92-101}, doi = {10.1016/j.nbd.2011.06.008}, pmid = {21726643}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Animals ; Blotting, Western ; Cell Survival/genetics ; Cells, Cultured ; Cerebral Cortex/drug effects/*physiology ; Down-Regulation/drug effects ; Electrophysiological Phenomena ; Excitatory Amino Acid Agonists/pharmacology ; Excitatory Postsynaptic Potentials/drug effects ; Glutamic Acid/physiology ; Humans ; Immunohistochemistry ; Kainic Acid/pharmacology ; Mice ; Mice, Transgenic ; Neurokinin-1 Receptor Antagonists ; Neurons/drug effects/*metabolism ; Patch-Clamp Techniques ; Receptors, AMPA/biosynthesis/*drug effects ; Receptors, Neurokinin-1/biosynthesis/*drug effects ; Synaptic Transmission/genetics/physiology ; }, abstract = {Substance P (SP), a neuropeptide member of the tachykinin (TK) family, has a functional role both in physiological and pathological conditions, including Amyotrophic Lateral Sclerosis disease. One hypothesis of the selective motor neuron death in ALS involves the excitatory neurotransmitter glutamate, because these neurons are extremely susceptible to excessive stimulation of AMPA receptors. It has been reported that SP exerts its action against a variety of insults including excitotoxicity, and that altered levels of SP have been observed in the cerebrospinal fluid (CSF) of patients with ALS. Here we have analyzed the interaction between SP and AMPA receptor functionality, both in Control cortical neurons in culture and in those obtained from a genetic mouse model of ALS (G93A). Our studies demonstrate that SP reduces the kainate-activated currents in Control and G93A neurons and that this reduction is significantly higher in the mutated neurons. SP effect is mediated by its receptor NK1 because GR 82334 (5 μM), a NK1 competitive antagonist, is able to suppress the current reduction. Analysis of miniature excitatory postsynaptic currents (mEPSCs) in Control and G93A neurons indicates that SP (200 nM) is able to significantly decrease the mEPSC amplitudes in G93A neurons, whereas it is ineffective on Control mEPSCs. Western blotting experiments in cultures and cortical tissues show a higher NK1 expression level in G93A mice compared to that of Control. This is also confirmed by immunocytochemistry experiments in cultured neurons. In addition, the amount of GluR1 subunit AMPA receptors is not modified following SP exposure, indicating a non internalization of the AMPA receptors. Finally, toxicity experiments have revealed that SP is able to rescue G93A cortical cells whereas it is ineffective on those of Control. These findings provide the first evidence of SP having a physiological and protective role in the G93A mouse model of ALS, and may suggest the possible use of SP as a clinical therapeutic treatment.}, }
@article {pmid21725240, year = {2011}, author = {de Carvalho, M and Swash, M}, title = {Amyotrophic lateral sclerosis: an update.}, journal = {Current opinion in neurology}, volume = {24}, number = {5}, pages = {497-503}, doi = {10.1097/WCO.0b013e32834916a9}, pmid = {21725240}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Biomarkers/analysis ; Early Diagnosis ; Electrodiagnosis ; Frontotemporal Lobar Degeneration/diagnosis/*genetics/pathology/therapy ; Humans ; }, abstract = {PURPOSE OF REVIEW: The aim is to review recent publications on amyotrophic lateral sclerosis (ALS).<br><br>RECENT FINDINGS: The Awaji recommendations for electrophysiological diagnosis will permit earlier clinical trials entry. The use of ultrasound to visualize fasciculations, even in deep muscles, will contribute to earlier diagnosis, as well. Unfortunately, recent clinical trials in ALS have been disappointing, as illustrated by the negative lithium trials. New, less expensive, trial designs and the inclusion of patients early in the course of ALS are positive approaches for future trials. The search for ALS biomarkers continues and a number of encouraging reports have been published, but no features unique to ALS have yet transformed this field. The most exciting advances in ALS arise from protein studies and genetics. Recognition that the ubiquitinated cytosolic inclusions in sporadic ALS, as well as in some patients with frontotemporal dementia (FTD), contain TDP-43, and that some familial cases (and a few sporadic cases) have mutations of the TDP-43 gene has transformed previous concepts on ALS pathogenesis. Other newly recognized mutations linked to ALS, such as fused-in-sarcoma (FUS) and valosin-containing protein (VCP), have not only widened the spectrum of genes involved in ALS but also consolidated the close relation between ALS and FTD.<br><br>SUMMARY: ALS research is entering a new phase that should generate new proposals regarding putative therapies, or strategies for disease treatment. A continuing difficulty, however, is early clinical diagnosis and, especially, the need for identification of a unique biomarker, sensitive to clinical change in the course of the disease.}, }
@article {pmid21723884, year = {2011}, author = {Schäfer, S and Hermans, E}, title = {Reassessment of motor-behavioural test analyses enables the detection of early disease-onset in a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Behavioural brain research}, volume = {225}, number = {1}, pages = {7-14}, doi = {10.1016/j.bbr.2011.06.019}, pmid = {21723884}, issn = {1872-7549}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/genetics/*physiopathology ; Analysis of Variance ; Animals ; Body Weight/genetics ; Disease Models, Animal ; Exploratory Behavior/*physiology ; Female ; Hand Strength/*physiology ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Activity/genetics/*physiology ; Sex Factors ; Superoxide Dismutase/genetics ; }, abstract = {As a model for amyotrophic lateral sclerosis (ALS), transgenic hSOD1(G93A) mice constitute the standard tool for evaluating future therapeutic strategies. Due to axonal retraction from neuromuscular junctions, the animals suffer from muscle wasting leading to weakness and paralysis of the extremities, which in early stages can be detected by measuring weight loss. Suspecting that underlying mechanisms might yield subtle neuromuscular abnormalities ahead of weight loss onset, we wanted to determine a behavioural test to detect disease onset time earlier. We compared the monitoring of weight with the "forced" examination of grip strength and the investigation of freely behaving animals within an open field. Additionally, we compared two different data analysis methods: (1) two-way ANOVA with Bonferroni correction (2) break point analysis calculating symptom onset time points for each animal. Break point analysis revealed onset times that significantly preceded those obtained by standard two-way ANOVA. Open field analysis of freely moving animals could not give an advantage over weight loss measurements. Grip strength assessment of hindlimbs detected disease onset 36 days before the first evidence of weight loss, providing a maximal treatment window of 84 days on average before the death of male animals. We conclude that grip strength analysis of hindlimbs is a very sensitive and reproducible motor behavioural test, which can even be applied to small cohorts of animals. Combined with break point analysis, it represents the method of choice to detect early disease onset in hSOD1(G93A) mice.}, }
@article {pmid21719875, year = {2011}, author = {Pitman, A and Osborn, DP}, title = {Cross-cultural attitudes to help-seeking among individuals who are suicidal: new perspective for policy-makers.}, journal = {The British journal of psychiatry : the journal of mental science}, volume = {199}, number = {1}, pages = {8-10}, doi = {10.1192/bjp.bp.110.087817}, pmid = {21719875}, issn = {1472-1465}, support = {G0802441/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Cross-Cultural Comparison ; *Health Services Needs and Demand ; Humans ; Mental Health Services ; Patient Acceptance of Health Care/*psychology ; *Suicide Prevention ; }, abstract = {World Mental Health Survey data demonstrate that a high proportion of people who are suicidal receive no treatment and that, contrary to previous assumptions, attitudes to treatment constitute greater barriers to help-seeking than do stigma or structural/financial constraints. We explore how suicide-prevention policy-makers might respond to Bruffaerts et al's findings.}, }
@article {pmid21716648, year = {2011}, author = {Wyatt, TJ and Rossi, SL and Siegenthaler, MM and Frame, J and Robles, R and Nistor, G and Keirstead, HS}, title = {Human motor neuron progenitor transplantation leads to endogenous neuronal sparing in 3 models of motor neuron loss.}, journal = {Stem cells international}, volume = {2011}, number = {}, pages = {207230}, pmid = {21716648}, issn = {1687-9678}, abstract = {Motor neuron loss is characteristic of many neurodegenerative disorders and results in rapid loss of muscle control, paralysis, and eventual death in severe cases. In order to investigate the neurotrophic effects of a motor neuron lineage graft, we transplanted human embryonic stem cell-derived motor neuron progenitors (hMNPs) and examined their histopathological effect in three animal models of motor neuron loss. Specifically, we transplanted hMNPs into rodent models of SMA (Δ7SMN), ALS (SOD1 G93A), and spinal cord injury (SCI). The transplanted cells survived and differentiated in all models. In addition, we have also found that hMNPs secrete physiologically active growth factors in vivo, including NGF and NT-3, which significantly enhanced the number of spared endogenous neurons in all three animal models. The ability to maintain dying motor neurons by delivering motor neuron-specific neurotrophic support represents a powerful treatment strategy for diseases characterized by motor neuron loss.}, }
@article {pmid21715542, year = {2011}, author = {Grussendorf, M and Reiners, C and Paschke, R and Wegscheider, K and , }, title = {Reduction of thyroid nodule volume by levothyroxine and iodine alone and in combination: a randomized, placebo-controlled trial.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {96}, number = {9}, pages = {2786-2795}, pmid = {21715542}, issn = {1945-7197}, mesh = {Adolescent ; Adult ; Aged ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Germany ; Humans ; Iodine/*therapeutic use ; Male ; Middle Aged ; Prospective Studies ; Thyroid Nodule/*diagnostic imaging/*drug therapy ; Thyroxine/*therapeutic use ; Treatment Outcome ; Ultrasonography ; }, abstract = {CONTEXT: Nodular goiter is common worldwide, but there is still debate over the medical treatment.<br><br>OBJECTIVE: The objective of the study was the measurement of the effect of a treatment with (nonsuppressive) T(4), iodine, or a combination of both compared with placebo on volume of thyroid nodules and thyroid.<br><br>DESIGN: This was a multicenter, randomized, double-blind trial in patients with nodular goiter in Germany [LISA (Levothyroxin und Iodid in der Strumatherapie Als Mono-oder Kombinationstherapie) trial].<br><br>SETTING: The study was conducted in outpatient clinics in university hospitals and regional hospitals and private practices.<br><br>PARTICIPANTS: One thousand twenty-four consecutively screened and centrally randomized euthyroid patients aged 18-65 yr with one or more thyroid nodules (minimal diameter 10 mm) participated in the study.<br><br>INTERVENTION: Intervention included placebo, iodine (I), T(4), or T(4)+I for 1 yr. T(4) doses were adapted for a TSH target range of 0.2-0.8 mU/liter.<br><br>OUTCOME MEASURES: The primary end point was percent volume reduction of all nodules measured by ultrasound, and the main secondary end point was a change in goiter volume.<br><br>RESULTS: Nodule volume reductions were -17.3% [95% confidence interval (CI) -24.8/-9.0%, P < 0.001] in the T(4)+I group, -7.3% (95% CI -15.0/+1.2%, P = 0.201) in the T(4) group, and -4.0% (95% CI -11.4/+4.2%, P = 0.328) in the I group as compared with placebo. In direct comparison, the T(4)+I therapy was significantly superior to T(4) (P = 0.018) or I (P = 0.003). Thyroid volume reductions were -7.9% (95% CI -11.8/-3.9%, P < 0.001), -5.2% (95% CI -8.7/-1.6%, P = 0.024) and -2.5% (95% CI -6.2/+1.4%, P = 0.207), respectively. The T(4)+I therapy was significantly superior to I (P = 0.034) but not to T(4) (P = 0.190).<br><br>CONCLUSION: In a region with a sufficient iodine supply, a 1-yr therapy with a combination of I and T(4) with incomplete suppression of thyrotropin reduced thyroid nodule volume further than either component alone or placebo.}, }
@article {pmid21712989, year = {2011}, author = {Takeuchi, H and Mizoguchi, H and Doi, Y and Jin, S and Noda, M and Liang, J and Li, H and Zhou, Y and Mori, R and Yasuoka, S and Li, E and Parajuli, B and Kawanokuchi, J and Sonobe, Y and Sato, J and Yamanaka, K and Sobue, G and Mizuno, T and Suzumura, A}, title = {Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer's disease.}, journal = {PloS one}, volume = {6}, number = {6}, pages = {e21108}, pmid = {21712989}, issn = {1932-6203}, mesh = {Alzheimer Disease/*physiopathology ; Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Anti-Inflammatory Agents/chemistry/metabolism/therapeutic use ; Behavior, Animal/physiology ; Carbenoxolone/chemistry/metabolism/therapeutic use ; *Disease Progression ; Female ; Gap Junctions/*metabolism ; Glycyrrhetinic Acid/analogs &amp; derivatives/metabolism/therapeutic use ; Humans ; Ion Channels/*metabolism ; Male ; Memory Disorders/drug therapy ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/cytology/metabolism ; Spinal Cord/pathology ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {BACKGROUND: Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases.<br><br>METHODS AND FINDINGS: In this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid &#x3b2; deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model.<br><br>CONCLUSIONS: Our results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal death in various neurodegenerative diseases.}, }
@article {pmid21712032, year = {2011}, author = {Yoo, YE and Ko, CP}, title = {Treatment with trichostatin A initiated after disease onset delays disease progression and increases survival in a mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {231}, number = {1}, pages = {147-159}, doi = {10.1016/j.expneurol.2011.06.003}, pmid = {21712032}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Animals ; Disease Models, Animal ; Disease Progression ; Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Hydroxamic Acids/*pharmacology/therapeutic use ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects/pathology ; Neuromuscular Junction/*drug effects/pathology ; Spinal Cord/*drug effects/metabolism ; Survival Rate ; }, abstract = {Recent studies suggest that progressive motoneuron death in amyotrophic lateral sclerosis (ALS) is non-cell autonomous and may involve the participation of non-neuronal cells such as glial cells and skeletal muscle. Therefore, a drug that targets motoneurons as well as neighboring non-neuronal cells might be a potential therapeutic strategy to delay disease progression in ALS. Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, has shown protective effects in multiple cell types implicated in ALS by resetting gene transcription profiles through increased histone acetylation. To test whether TSA could serve as a potential therapeutic agent, we intraperitoneally injected TSA from postnatal day 90 (P90), after disease symptoms appear, until P120 or the end-stage in SOD1-G93A mice. We found that TSA ameliorated motoneuron death and axonal degeneration in SOD1-G93A mice. Reduced gliosis and upregulation of the glutamate transporter (GLT-1) were also observed in the spinal cord of TSA-treated SOD1-G93A mice. In addition, TSA ameliorated muscle atrophy and neuromuscular junction (NMJ) denervation, which are the pathological characteristics of ALS found in skeletal muscle. Improved morphology in TSA-treated SOD1-G93A mice was accompanied by enhanced motor functions as assessed by rota-rod and grip strength analyses. Furthermore, TSA treatment significantly increased the mean survival duration after the treatment by 18% and prolonged lifespan by 7%. Our findings suggest that TSA may provide a potential therapy to slow disease progression as well as to enhance motor performance to improve the quality of life for ALS patients.}, }
@article {pmid21711557, year = {2011}, author = {Pollari, E and Savchenko, E and Jaronen, M and Kanninen, K and Malm, T and Wojciechowski, S and Ahtoniemi, T and Goldsteins, G and Giniatullina, R and Giniatullin, R and Koistinaho, J and Magga, J}, title = {Granulocyte colony stimulating factor attenuates inflammation in a mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {8}, number = {}, pages = {74}, pmid = {21711557}, issn = {1742-2094}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology/physiopathology ; Animals ; Cells, Cultured ; Disease Models, Animal ; Disease Progression ; Filgrastim ; Granulocyte Colony-Stimulating Factor/pharmacology/*therapeutic use ; Humans ; Inflammation/*drug therapy/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/cytology/drug effects/physiology ; Muscle, Skeletal/cytology/drug effects/pathology ; Neurons/cytology/drug effects/physiology ; Neuroprotective Agents/pharmacology/therapeutic use ; Polyethylene Glycols ; Recombinant Proteins/pharmacology/therapeutic use ; Spinal Cord/cytology ; Spleen/cytology/drug effects ; Superoxide Dismutase/immunology ; Survival Rate ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {BACKGROUND: Granulocyte colony stimulating factor (GCSF) is protective in animal models of various neurodegenerative diseases. We investigated whether pegfilgrastim, GCSF with sustained action, is protective in a mouse model of amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease with manifestations of upper and lower motoneuron death and muscle atrophy accompanied by inflammation in the CNS and periphery.<br><br>METHODS: Human mutant G93A superoxide dismutase (SOD1) ALS mice were treated with pegfilgrastim starting at the presymptomatic stage and continued until the end stage. After long-term pegfilgrastim treatment, the inflammation status was defined in the spinal cord and peripheral tissues including hematopoietic organs and muscle. The effect of GCSF on spinal cord neuron survival and microglia, bone marrow and spleen monocyte activation was assessed in vitro.<br><br>RESULTS: Long-term pegfilgrastim treatment prolonged mutant SOD1 mice survival and attenuated both astro- and microgliosis in the spinal cord. Pegfilgrastim in SOD1 mice modulated the inflammatory cell populations in the bone marrow and spleen and reduced the production of pro-inflammatory cytokine in monocytes and microglia. The mobilization of hematopoietic stem cells into the circulation was restored back to basal level after long-term pegfilgrastim treatment in SOD1 mice while the storage of Ly6C expressing monocytes in the bone marrow and spleen remained elevated. After pegfilgrastim treatment, an increased proportion of these cells in the degenerative muscle was detected at the end stage of ALS.<br><br>CONCLUSIONS: GCSF attenuated inflammation in the CNS and the periphery in a mouse model of ALS and thereby delayed the progression of the disease. This mechanism of action targeting inflammation provides a new perspective of the usage of GCSF in the treatment of ALS.}, }
@article {pmid21706151, year = {2012}, author = {Saccà, F and Quarantelli, M and Rinaldi, C and Tucci, T and Piro, R and Perrotta, G and Carotenuto, B and Marsili, A and Palma, V and De Michele, G and Brunetti, A and Brescia Morra, V and Filla, A and Salvatore, M}, title = {A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results.}, journal = {Journal of neurology}, volume = {259}, number = {1}, pages = {132-138}, pmid = {21706151}, issn = {1432-1459}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Arginine ; Choline/blood ; Creatine/blood ; Double-Blind Method ; Endpoint Determination ; Female ; Hormones/*blood ; Human Growth Hormone/blood/*therapeutic use ; Humans ; Image Processing, Computer-Assisted ; Insulin Resistance ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/analysis ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Motor Cortex/pathology ; Neuroimaging ; Neuroprotective Agents/therapeutic use ; Recombinant Proteins/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease with motor neuron degeneration. Riluzole is the only available treatment. Two-thirds of ALS patients present with growth hormone (GH) deficiency. The aim of this study is to determine if add-on of GH to riluzole, with an individually regulated dose based on Insulin-like growth factor 1 (IGF-I) production, was able to reduce neuronal loss in the motor cortex, reduce mortality, and improve motor function of ALS patients. Patients with definite/probable ALS, in treatment with riluzole, aged 40-85 years, and with disease duration ≤3 years were enrolled. The study was randomized, placebo controlled, and double blind. Before treatment, patients were tested with a GH releasing hormone (GHRH) + arginine test. The initial dose of GH was 2 IU s.c. every other day, and was progressively increased to a maximum of 8 IU. Primary endpoint was N-acetylaspartate/(creatine + choline) (NAA/Cre + Cho) ratio in motor cortex assessed by magnetic resonance spectroscopy performed at months 0, 6, and 12. Secondary endpoints were mortality and ALS functional rating scale revised (ALSFRS-R). The NAA/(Cre + Cho) ratio decreased in all patients who completed the trial. No significant difference was noted between treated and placebo group. At baseline, although IGF-I levels were within the normal range, 73% of patients had GH deficiency, being severe in half of them. Compared with bulbar onset, spinal-onset patients showed more depressed GH response to the GHRH + arginine stimulation test (10.4 ± 7.0 versus 15.5 ± 8.1 ng/mL; p < 0.05). Insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] increased from 2.1 ± 1.0 at baseline to 4.6 ± 1.9 at 12 months (p < 0.001). Insulin-like growth factor (IGF) binding protein 3 (IGFBP-3) decreased from 8,435 ± 4,477 ng/mL at baseline to 3,250 ± 1,780 ng/mL at 12 months (p < 0.001). The results show that GH exerted no effect on cerebral NAA or clinical progression assessed by ALSFRS-R. Two-thirds of ALS patients had GH deficit, with higher levels in the bulbar-onset group. During follow-up, patients showed progressive increase in HOMA-IR and decrease in IGFBP-3 levels.}, }
@article {pmid21704075, year = {2011}, author = {Volonté, C and Apolloni, S and Carrì, MT and D'Ambrosi, N}, title = {ALS: focus on purinergic signalling.}, journal = {Pharmacology &amp; therapeutics}, volume = {132}, number = {1}, pages = {111-122}, doi = {10.1016/j.pharmthera.2011.06.002}, pmid = {21704075}, issn = {1879-016X}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/epidemiology/*metabolism ; Humans ; Molecular Targeted Therapy ; Receptors, Purinergic/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most common neuromuscular diseases. It is devastating and fatal, causing progressive paralysis of all voluntary muscles and eventually death, while sparing cognitive functions. A pathological hallmark of ALS is neuroinflammation mediated by non-neuronal cells in the nervous system, such as microglia and astrocytes that accelerate the disease progression. Scientists have neither found a unique key mechanism, nor an effective treatment against ALS, supposedly because it is a multi-factorial and multi-systemic disease. Extracellular purines and pyrimidines are widespread and powerful physiopathological molecules, signalling to most cell types and directing cell-to-cell communication networks. They are instrumental for instance for neurotransmission, muscle contraction and immune surveillance. Recent work has reported the crucial involvement of purinergic pathways in many neurodegenerative and neuroinflammatory diseases, comprising ALS. Especially P2 receptors for ATP, P1 receptors for adenosine, and nucleotide transporters were found to be modulated in ALS cells and tissues, playing a potential role in the disease. Given the composite cellular cross-talk occurring during ALS and the established action of extracellular purines/pyrimidines as neuron-to-glia alarm signal in the nervous system, a mutual query in these two fields should now be whether, how and when purinergic would meet ALS. In this review, we will highlight the early cellular and molecular purinergic cross-talk that participates to ALS etiopathology, with the conviction that better understanding of purinergic dynamics might provide original research perspectives, stimulate alternative disease modelling, and the design and testing of more powerful targeted therapeutics against this relentlessly progressive disorder.}, }
@article {pmid21699269, year = {2011}, author = {Xu, X and Warrington, AE and Bieber, AJ and Rodriguez, M}, title = {Enhancing CNS repair in neurological disease: challenges arising from neurodegeneration and rewiring of the network.}, journal = {CNS drugs}, volume = {25}, number = {7}, pages = {555-573}, pmid = {21699269}, issn = {1179-1934}, support = {R01NS032129/NS/NINDS NIH HHS/United States ; R01 NS032129/NS/NINDS NIH HHS/United States ; R01 NS032129-14/NS/NINDS NIH HHS/United States ; R01 CA096859-02/CA/NCI NIH HHS/United States ; R01 CA104996/CA/NCI NIH HHS/United States ; R01 NS048357/NS/NINDS NIH HHS/United States ; R01 CA104996-07/CA/NCI NIH HHS/United States ; R01 NS024180/NS/NINDS NIH HHS/United States ; R01 NS024180-21/NS/NINDS NIH HHS/United States ; R01 CA096859/CA/NCI NIH HHS/United States ; R21 NS073684/NS/NINDS NIH HHS/United States ; R01 GM092993/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Blood-Brain Barrier/metabolism ; Central Nervous System Diseases/physiopathology/*therapy ; Humans ; Nerve Net/metabolism ; *Nerve Regeneration ; Neurodegenerative Diseases/physiopathology/*therapy ; Stem Cell Transplantation/methods ; }, abstract = {Repair of the central nervous system (CNS) constitutes an integral part of treating neurological disease and plays a crucial role in restoring CNS architecture and function. Distinct strategies have been developed to reconstruct the damaged neural tissue, with many tested preclinically in animal models. We review cell replacement-based repair strategies. By taking spinal cord injury, cerebral ischaemia and degenerative CNS disorders as examples for CNS repair, we discuss progress and potential problems in utilizing embryonic stem cells and adult neural/non-neural stem cells to repair cell loss in the CNS. Nevertheless, CNS repair is not simply a matter of cell transplantation. The major challenge is to induce regenerating neural cells to integrate into the neural network and compensate for damaged neural function. The neural cells confront an environment very different from that of the developmental stage in which these cells differentiate to form interwoven networks. During the repair process, one of the challenges is neurodegeneration, which can develop from interrupted innervations to/from the targets, chronic inflammation, ischaemia, aging or idiopathic neural toxicity. Neurodegeneration, which occurs on the basis of a characteristic vascular and neural web, usually presents as a chronically progressive process with unknown aetiology. Currently, there is no effective treatment to stop or slow down neurodegeneration. Pathological changes from patients with Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis indicate a broken homeostasis in the CNS. We discuss how the blood-brain barrier and neural networks are formed to maintain CNS homeostasis and their contribution to neurodegeneration in diseased conditions. Another challenge is that some inhibitors produced by CNS injury do not facilitate the regenerating neural cells to incorporate into a pre-existing network. We review glial responses to CNS injury. Of note, the reactive astrocytes not only encompass the lesions/pathogens but may also form glial scars to impede regenerating axons from traversing the lesions. In addition, myelin debris can prevent axon growth. Myelination enables saltatory transduction of electrical impulses along axonal calibers and actually provides trophic support to stabilize the axons. Therefore, repair strategies should be designed to promote axonal growth, myelination and modulate astrocytic responses. Finally, we discuss recent progress in developing human monoclonal IgMs that regulate CNS homeostasis and promote neural regeneration.}, }
@article {pmid21684323, year = {2011}, author = {Wang, P and Li, B and Zhou, L and Fei, E and Wang, G}, title = {The KDEL receptor induces autophagy to promote the clearance of neurodegenerative disease-related proteins.}, journal = {Neuroscience}, volume = {190}, number = {}, pages = {43-55}, doi = {10.1016/j.neuroscience.2011.06.008}, pmid = {21684323}, issn = {1873-7544}, mesh = {Autophagy/*physiology ; Cells ; Cells, Cultured ; Endoplasmic Reticulum/*metabolism ; Enzyme Inhibitors/pharmacology ; Humans ; Mitogen-Activated Protein Kinases/metabolism ; Neurodegenerative Diseases/*metabolism ; RNA, Small Interfering ; Receptors, Peptide/*metabolism ; Signal Transduction/drug effects/physiology ; Thapsigargin/pharmacology ; Up-Regulation/drug effects ; }, abstract = {Endoplasmic reticulum (ER) stress is involved in neurodegenerative diseases, and the KDEL (Lys-Asp-Glu-Leu motif) receptor (KDELR) plays a key role in ER quality control and in the ER stress response. The subcellular distribution of KDELR is dynamic and related to its ligand binding status and its expression level. Here, we show that KDELR mRNA is upregulated upon thapsigargin treatment, which induces ER stress. Moreover, overexpressed KDELR partially redistributes to the lysosome and activates autophagy. The R169N mutant, a ligand binding-defective form of KDELR, and D193N, a transport-defective form of KDELR, both fail to trigger autophagy. Overexpression of KDELR activates extracellular signal-regulated kinases (ERKs). Both the activation of ERKs and autophagy induced by KDELR could be blocked by PD98059, an inhibitor of mitogen extracellular kinase 1 (MEK1). The overexpression of some neurodegenerative disease-related proteins, such as amyotrophic lateral sclerosis (ALS)-linked G93A superoxide dismutase 1 (SOD1), Parkinson's disease-associated A53T alpha-synuclein and Huntington's disease-related expanded huntingtin, increase the mRNA levels of KDELR. Moreover, the overexpressed KDELR promotes the clearance of these disease proteins through autophagy. Taken together, our data provide evidence that KDELR, as a novel inducer of autophagy, participates in the degradation of misfolded neurodegenerative disease-related proteins.}, }
@article {pmid21682930, year = {2011}, author = {Yang, EJ and Kim, SH and Yang, SC and Lee, SM and Choi, SM}, title = {Melittin restores proteasome function in an animal model of ALS.}, journal = {Journal of neuroinflammation}, volume = {8}, number = {}, pages = {69}, pmid = {21682930}, issn = {1742-2094}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*enzymology/genetics/pathology ; Animals ; Behavior, Animal/drug effects ; Brain Stem/cytology/drug effects/enzymology/pathology ; Cell Death/drug effects ; Disease Models, Animal ; Humans ; Male ; Melitten/*pharmacology/*therapeutic use ; Mice ; Mice, Transgenic ; Motor Activity/drug effects ; Nerve Degeneration/pathology/physiopathology ; Proteasome Endopeptidase Complex/*drug effects/*metabolism ; Protein Folding/drug effects ; Rotarod Performance Test ; Spinal Cord/cytology/drug effects/enzymology/pathology ; Superoxide Dismutase/genetics/metabolism ; Survival Rate ; alpha-Synuclein/chemistry/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a paralyzing disorder characterized by the progressive degeneration and death of motor neurons and occurs both as a sporadic and familial disease. Mutant SOD1 (mtSOD1) in motor neurons induces vulnerability to the disease through protein misfolding, mitochondrial dysfunction, oxidative damage, cytoskeletal abnormalities, defective axonal transport- and growth factor signaling, excitotoxicity, and neuro-inflammation.Melittin is a 26 amino acid protein and is one of the components of bee venom which is used in traditional Chinese medicine to inhibit of cancer cell proliferation and is known to have anti-inflammatory and anti-arthritic effects.The purpose of the present study was to determine if melittin could suppress motor neuron loss and protein misfolding in the hSOD1G93A mouse, which is commonly used as a model for inherited ALS. Meltittin was injected at the 'ZuSanLi' (ST36) acupuncture point in the hSOD1G93A animal model. Melittin-treated animals showed a decrease in the number of microglia and in the expression level of phospho-p38 in the spinal cord and brainstem. Interestingly, melittin treatment in symptomatic ALS animals improved motor function and reduced the level of neuron death in the spinal cord when compared to the control group. Furthermore, we found increased of α-synuclein modifications, such as phosphorylation or nitration, in both the brainstem and spinal cord in hSOD1G93A mice. However, melittin treatment reduced α-synuclein misfolding and restored the proteasomal activity in the brainstem and spinal cord of symptomatic hSOD1G93A transgenic mice.Our research suggests a potential functional link between melittin and the inhibition of neuroinflammation in an ALS animal model.}, }
@article {pmid21681448, year = {2012}, author = {Speyer, CL and Smith, JS and Banda, M and DeVries, JA and Mekani, T and Gorski, DH}, title = {Metabotropic glutamate receptor-1: a potential therapeutic target for the treatment of breast cancer.}, journal = {Breast cancer research and treatment}, volume = {132}, number = {2}, pages = {565-573}, pmid = {21681448}, issn = {1573-7217}, support = {P30 CA022453/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/administration &amp; dosage/*pharmacology ; Apoptosis/drug effects ; Breast Neoplasms/*drug therapy/genetics/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Agonists/pharmacology ; Excitatory Amino Acid Antagonists/administration &amp; dosage/*pharmacology ; Female ; Humans ; Injections, Intraperitoneal ; Mice ; Mice, Nude ; Naphthalenes/administration &amp; dosage/*pharmacology ; Phenotype ; Quisqualic Acid/pharmacology ; RNA Interference ; Receptors, Metabotropic Glutamate/*drug effects/genetics/metabolism ; Riluzole/administration &amp; dosage/*pharmacology ; Signal Transduction/drug effects ; Time Factors ; Transfection ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {Metabotropic glutamate receptors are G-protein-coupled receptors normally expressed in the central nervous system where they mediate neuronal excitability, synaptic plasticity, and feedback inhibition of neurotransmitter release. However, recent data suggest that these receptors are also expressed and functional in some cancers, most notably melanoma. We detected the expression of metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in triple negative breast cancer cells and evaluated its role in regulating the pro-proliferative phenotype of these cells. mGluR1 inhibitors (Riluzole or BAY36-7620) inhibited the proliferation of triple negative breast cancer cells in a time- and dose-dependent manner and this inhibition correlated with increased apoptosis as demonstrated by increase in PARP cleavage products and Annexin V staining. mGluR1 knockdown using Lentiviral constructs expressing shRNA targeting GRM1 also inhibited proliferation compared to non-silencing controls. In addition, treatment of mice bearing MDA-MB-231 xenografts with Riluzole or BAY36-7620, by intraperitoneal injection, resulted in a significant reduction in tumor volume of up to 80%. Moreover, Riluzole was effective against triple negative breast cancer xenografts in mice at doses equivalent to those currently being used in humans for the treatment of amyotrophic lateral sclerosis. Our observations implicate mGluR1 and glutamate signaling as a promising new molecular target for the treatment of breast cancer. Even more promising, Riluzole, because it is an oral drug that can be administered with low toxicity, represents a promising approach in the treatment of triple negative breast cancer.}, }
@article {pmid21678037, year = {2012}, author = {Souayah, N and Coakley, KM and Chen, R and Ende, N and McArdle, JJ}, title = {Defective neuromuscular transmission in the SOD1 G93A transgenic mouse improves after administration of human umbilical cord blood cells.}, journal = {Stem cell reviews and reports}, volume = {8}, number = {1}, pages = {224-228}, pmid = {21678037}, issn = {2629-3277}, support = {NS 045979/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*therapy ; Animals ; *Cord Blood Stem Cell Transplantation ; Disease Models, Animal ; Electric Stimulation ; Female ; Humans ; Mice ; Mice, Transgenic ; Muscle, Skeletal/innervation/pathology/physiopathology ; Mutation, Missense ; Neuromuscular Junction/enzymology/*physiopathology ; Superoxide Dismutase/genetics/*metabolism ; *Synaptic Transmission ; }, abstract = {To assess the effect of human umbilical cord blood (hUCB) transplantation on neuromuscular transmission in SOD1(G93A) transgenic mice, we studied the probability of neuromuscular transmission (PNMT), a relevant physiological indicator of motor nerve function, in 3 SOD1(G93A) mice transplanted with hUCB and compared to PNMT in 4 SOD1(G93A) mice without cell transplantation and 3 non-mutant SOD1 transgenic mice. For preparations isolated from non-mutant SOD1 transgenic mice, PNMT was 0.93 and 0.84 during the first 5 s of 70 and 90 Hz trains, respectively. PNMT gradually declined to 0.77 and 0.42 at the end of the trains. In striking contrast, PNMT for preparations from non-treated mutant SOD1(G93A) mice was 0.52 and 0.36 in the first 5 s of 70 and 90 Hz trains, respectively (p<0.05). Treatment with hUCB significantly (p<0.05) improved PNMT in SOD1(G93A) preparations. That is, the initial 5 s PNMT was 0.88 and 0.68 for the 70 and 90 Hz stimuli, respectively. We concluded that hUCB transplantation significantly improved PNMT for muscles removed from SOD1(G93A) mice. Testing PNMT in the SOD1(G93A) mouse model could be used as a simple in vitro protocol to detect a positive cellular response to therapeutic interventions in ALS.}, }
@article {pmid21678031, year = {2011}, author = {Hasegawa, M and Nonaka, T and Tsuji, H and Tamaoka, A and Yamashita, M and Kametani, F and Yoshida, M and Arai, T and Akiyama, H}, title = {Molecular dissection of TDP-43 proteinopathies.}, journal = {Journal of molecular neuroscience : MN}, volume = {45}, number = {3}, pages = {480-485}, pmid = {21678031}, issn = {1559-1166}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Antibodies/metabolism ; Brain/metabolism/pathology ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; Humans ; Immunoblotting ; Intranuclear Inclusion Bodies/metabolism/pathology ; Peptide Fragments/genetics/metabolism ; Phosphorylation ; Protein Conformation ; TDP-43 Proteinopathies/genetics/*metabolism/*pathology ; }, abstract = {TDP-43 has been identified as a major component of ubiquitin-positive tau-negative cytoplasmic inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and in amyotrophic lateral sclerosis (ALS). We raised antibodies to phosphopeptides representing 36 out of 64 candidate phosphorylation sites of human TDP-43 and showed that the antibodies to pS379, pS403/404, pS409, pS410 and pS409/410 labeled the inclusions, but not the nuclei. Immunoblot analyses demonstrated that the antibodies recognized TDP-43 at ~45 kDa, smearing substances and 18-26 kDa C-terminal fragments. Furthermore, the band patterns of the C-terminal fragments differed between neuropathological subtypes, but were indistinguishable between brain regions and spinal cord in each individual patient. Protease treatment of Sarkosyl-insoluble TDP-43 suggests that the different band patterns of the C-terminal fragments reflect different conformations of abnormal TDP-43 molecules between the diseases. These results suggest that molecular species of abnormal TDP-43 are different between the diseases and that they propagate from affected cells to other cells during disease progression and determine the clinicopathological phenotypes of the diseases.}, }
@article {pmid21672211, year = {2011}, author = {van Groenestijn, AC and van de Port, IG and Schröder, CD and Post, MW and Grupstra, HF and Kruitwagen, ET and van der Linde, H and van Vliet, RO and van de Weerd, MG and van den Berg, LH and Lindeman, E}, title = {Effects of aerobic exercise therapy and cognitive behavioural therapy on functioning and quality of life in amyotrophic lateral sclerosis: protocol of the FACTS-2-ALS trial.}, journal = {BMC neurology}, volume = {11}, number = {}, pages = {70}, pmid = {21672211}, issn = {1471-2377}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*psychology/*rehabilitation ; Cognitive Behavioral Therapy/*methods ; Exercise/*physiology ; Exercise Therapy/*methods ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Patient Compliance ; Single-Blind Method ; Time Factors ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder affecting motor neurons in the spinal cord, brainstem and motor cortex, leading to muscle weakness. Muscle weakness may result in the avoidance of physical activity, which exacerbates disuse weakness and cardiovascular deconditioning. The impact of the grave prognosis may result in depressive symptoms and hopelessness. Since there is no cure for ALS, optimal treatment is based on symptom management and preservation of quality of life (QoL), provided in a multidisciplinary setting. Two distinctly different therapeutic interventions may be effective to improve or preserve daily functioning and QoL at the highest achievable level: aerobic exercise therapy (AET) to maintain or enhance functional capacity and cognitive behavioural therapy (CBT) to improve coping style and cognitions in patients with ALS. However, evidence to support either approach is still insufficient, and the underlying mechanisms of the approaches remain poorly understood. The primary aim of the FACTS-2-ALS trial is to study the effects of AET and CBT, in addition to usual care, compared to usual care alone, on functioning and QoL in patients with ALS.<br><br>METHODS/DESIGN: A multicentre, single-blinded, randomized controlled trial with a postponed information model will be conducted. A sample of 120 patients with ALS (1 month post diagnosis) will be recruited from 3 university hospitals and 1 rehabilitation centre. Patients will be randomized to one of three groups i.e. (1) AET + usual care, (2) CBT + usual care, (3) Usual care. AET consists of a 16-week aerobic exercise programme, on 3 days a week. CBT consists of individual psychological support of patients in 5 to 10 sessions over a 16-week period. QoL, functioning and secondary outcome measures will be assessed at baseline, immediately post intervention and at 3- and 6-months follow-up.<br><br>DISCUSSION: The FACTS-2-ALS study is the first theory-based randomized controlled trial to evaluate the effects, and the maintenance of effects, of AET and CBT on functioning and QoL in patients with ALS. The results of this study are expected to generate new evidence for the effect of multidisciplinary care of persons with ALS.<br><br>TRIAL REGISTRATION: Dutch Trial Register NTR1616.}, }
@article {pmid21669495, year = {2011}, author = {Kallick, CA}, title = {Ehrlichia and bone marrow cells: could Ehrlichial infection explain the unsuspected etiology of some diseases of the immune system?.}, journal = {Medical hypotheses}, volume = {77}, number = {3}, pages = {374-379}, doi = {10.1016/j.mehy.2011.05.019}, pmid = {21669495}, issn = {1532-2777}, mesh = {Adolescent ; Bone Marrow Cells/*microbiology ; *Ehrlichia ; Ehrlichiosis/*complications ; Female ; Humans ; Immune System Diseases/*etiology/*microbiology ; Male ; Middle Aged ; T-Lymphocytes/immunology ; Transcription, Genetic/physiology ; }, abstract = {A large group of diseases of unknown etiology, including leukemia, systemic lupus erythematosus, myelodysplastic disease, multiple sclerosis, amyotrophic lateral sclerosis, and rheumatoid arthritis, all present with some elements of immune system disturbance. The Ehrlichia/anaplasma (EA) are an obscure group of obligate parasitic intracellular pathogens that excrete intracellularly a substance called host transcriptional protein, which can alter transcription in cell division. Infection with EA may lead to changes in transcription in proliferating cells, such as those in the marrow, and alter the biology of the products such as T and B cells. Normally 60% of B cells produced in the marrow may be self reactive, but are eliminated before release from the marrow. Changes in transcription could allow self reactive cells to escape into the peripheral circulation and injure normal tissue, creating the dysfunctions which characterize the different immune system diseases and give them their separate identities. A number of studies previously published, and new information presented here, suggest that EA infections may be an underlying, undiagnosed cause for these and other immune system diseases. This hypothesis, long overlooked, has never been subjected to adequate, rigorous study sufficient to prove or disprove its truth. If so, patients may be treated with antibiotics, and marrow transplant manipulations already used in treatment of diseases such as lupus and leukemia may become more effective.}, }
@article {pmid21651477, year = {2011}, author = {Palomo, V and Perez, DI and Gil, C and Martinez, A}, title = {The potential role of glycogen synthase kinase 3 inhibitors as amyotrophic lateral sclerosis pharmacological therapy.}, journal = {Current medicinal chemistry}, volume = {18}, number = {20}, pages = {3028-3034}, doi = {10.2174/092986711796391697}, pmid = {21651477}, issn = {1875-533X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Clinical Trials as Topic ; Glycogen Synthase Kinase 3/*antagonists &amp; inhibitors/metabolism ; Humans ; Protein Kinase Inhibitors/*chemistry/pharmacology/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Lately, this disease has often been related to the protein kinase called glycogen synthase kinase 3 (GSK-3), through the experimental evidence of alterations of this enzyme on ALS patients. Therefore, there have been several experimental studies using GSK-3 inhibitors, in cellular and animal models and also in clinical studies that showed the potential of the therapeutic role of these molecules. GSK-3 inhibitors might play a pivotal role in the pharmacology of ALS disease with no curative treatment nowadays. In this review we give an overview of the current research in the area, showing all the evidences of the implication of dysfunctional GSK-3 in this disease on one hand, and on the other presenting the potential role of the GSK-3 inhibitors as a future pharmacological ALS therapy.}, }
@article {pmid21647936, year = {2011}, author = {Boutahar, N and Wierinckx, A and Camdessanche, JP and Antoine, JC and Reynaud, E and Lassabliere, F and Lachuer, J and Borg, J}, title = {Differential effect of oxidative or excitotoxic stress on the transcriptional profile of amyotrophic lateral sclerosis-linked mutant SOD1 cultured neurons.}, journal = {Journal of neuroscience research}, volume = {89}, number = {9}, pages = {1439-1450}, doi = {10.1002/jnr.22672}, pmid = {21647936}, issn = {1097-4547}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Analysis of Variance ; Animals ; Cell Survival ; Cells, Cultured ; Cerebral Cortex/cytology/metabolism ; Gene Expression Profiling ; Gene Expression Regulation/*drug effects ; Humans ; Hydrogen Peroxide/pharmacology ; Mice ; Mice, Neurologic Mutants ; Mice, Transgenic ; N-Methylaspartate/pharmacology ; Neurons/*metabolism ; Neurotoxins/pharmacology ; Oligonucleotide Array Sequence Analysis ; Oxidants/pharmacology ; Oxidative Stress ; Statistics, Nonparametric ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of motor neurons. The causes of most cases of ALS are as yet undefined. In a previous study, it was shown that N-methyl-D-aspartate (NMDA) and H(2)O(2) stimuli reduce neuronal survival in cortical neurons in culture (Boutahar et al., 2008). To identify variations in gene expression in response to these neurotoxins in transgenic vs. control cortical neurons cultures, both microarray and RT-PCR analysis were performed. High-density oligonucleotide microarrays showed changes in the expression of about 600 genes involved in protein degradation, neurotrophic factors pathway, cell cycle, inflammation, cytoskeleton, cell adhesion, transcription, or signalling. The most up-regulated genes following H(2)O(2) treatment were involved in cytoskeletal organization and axonal transport, such as ARAP2, KIF17, and DKK2, or in trophic factors pathways, such as insulin-like growth factor-binding protein 4 (IGFBP4), FGF17, and serpin2. The most down-regulated genes were involved in ion transport, such as TRPV1. After NMDA treatment, the most up-regulated genes were involved in protein degradation, such as ubiquitin-conjugating enzyme E2I and cathepsin H, and the most down-regulated genes were involved in ion transport, such as SCN7A. We conclude that these neurotoxins act through different transcriptional inductions, and these changes may reflect an adaptative cellular response to the cellular stress induced by the neurotoxins involved in ALS in the presence of mutant human SOD1.}, }
@article {pmid21645698, year = {2011}, author = {Siano, GG and Pérez, IS and García, MD and Galera, MM and Goicoechea, HC}, title = {Multivariate curve resolution modeling of liquid chromatography-mass spectrometry data in a comparative study of the different endogenous metabolites behavior in two tomato cultivars treated with carbofuran pesticide.}, journal = {Talanta}, volume = {85}, number = {1}, pages = {264-275}, doi = {10.1016/j.talanta.2011.03.064}, pmid = {21645698}, issn = {1873-3573}, mesh = {Carbofuran/*metabolism/pharmacology ; Chromatography, Liquid ; Kinetics ; Solanum lycopersicum/drug effects/*metabolism ; Mass Spectrometry/*methods ; Metabolomics/*methods ; Multivariate Analysis ; Pesticides/metabolism/pharmacology ; Stress, Physiological ; }, abstract = {A metabonomic study based on the application of multivariate curve resolution and alternating least squares (MCR-ALS) to three-way data sets obtained by liquid chromatography coupled to mass spectrometry detection (LC-MS) was carried out for Rambo and Raf tomato cultivars treated with carbofuran pesticide. Samples were picked up during a 21 days period after treatment and analyzed by LC-MS in scan mode, along with the corresponding blank samples. Then, MCR-ALS was applied to the three-way data sets using column wise augmented matrices, and the evolutionary profiles as a function of the time after treatment were estimated for the metabolites present in both cultivars, as well as their corresponding pure spectra estimations. A comparative study using those estimations showed that some of these metabolites followed different behavior for the different cultivars after treatment. Since all treated and untreated Rambo and Raf samples were picked up according to the same sampling protocol and in a similar state of maturation, any difference in the behavior between profiles can be interpreted as an effect due to the presence of pesticide and to the kind of cultivar. Based on this hypothesis, several PLS-DA approaches were tested to check if it would be possible to classify samples by using the metabolites MCR estimations. Results showed that PLS-DA models for classification of treated or non-treated (blank) samples were the best ones obtained (98.44% of correct classifications for the validation set), which supports the stress effects related to carbofuran treatment. In addition, excellent discrimination among the four groups could be attained (89.06% of correct classifications for the validation set).}, }
@article {pmid21638124, year = {2011}, author = {Shindo, G and Endo, T and Onda, M and Miyamoto, Y and Kaneko, T and Goto, S}, title = {Immuno-cell therapy with antecedent surgery has superior actuarial survival to immuno-cell therapy without antecedent surgery for advanced cancers.}, journal = {Cancer immunology, immunotherapy : CII}, volume = {60}, number = {10}, pages = {1397-1403}, pmid = {21638124}, issn = {1432-0851}, mesh = {Adult ; Aged ; Aged, 80 and over ; Cancer Vaccines/*immunology ; Combined Modality Therapy ; Dendritic Cells/immunology/*transplantation ; Female ; Humans ; Immunotherapy/*methods ; Kaplan-Meier Estimate ; Lymphocyte Transfusion ; Lymphocytes/*immunology ; Male ; Middle Aged ; Neoplasms/*mortality/*therapy ; }, abstract = {BACKGROUND: Immuno-cell therapy using activated lymphocytes (ALs) and/or dendritic cells (DCs) is considered one of the less toxic supportive therapies compared with conventional chemotherapy and radiotherapy, especially for the treatment for advanced cancers. To improve the efficacy of immuno-cell therapy for such cancer, clinical data were analyzed in this preliminary study.<br><br>PATIENTS AND METHODS: The clinical data of 38 consecutive patients with advanced cancer who underwent at least one course of treatment with ALs and/or matured DCs, with or without antecedent surgery or additional conventional chemotherapy and/or radiotherapy, were evaluated.<br><br>RESULTS: Of the 23 patients who received surgery before immuno-cell therapy, 2 (8.7%) showed a complete response (CR) and 15 (65%) showed a partial response (PR) or prolonged stable disease (SD). Of the 15 remaining patients who did not undergo antecedent surgery, there was no CR but 7 (46%) showed PR or prolonged SD. Actuarial survival is one of the important indices for the evaluation of anticancer therapies that present longer durable efficacy of immunotherapy compared with conventional anticancer chemotherapy and radiotherapy, and actuarial survival analysis revealed that immuno-cell therapy with antecedent surgery afforded significantly longer survival than immuno-cell therapy without antecedent surgery (P&#xa0;<&#xa0;0.001).<br><br>CONCLUSION: Antecedent surgical resection of tumors is advisable for obtaining better efficacy of immuno-cell therapy, even in advanced cancer patients.}, }
@article {pmid21637388, year = {2011}, author = {Shin, E and Shin, S and Kong, H and Lee, S and Do, SG and Jo, TH and Park, YI and Lee, CK and Hwang, IK and Kim, K}, title = {Dietary Aloe Reduces Adipogenesis via the Activation of AMPK and Suppresses Obesity-related Inflammation in Obese Mice.}, journal = {Immune network}, volume = {11}, number = {2}, pages = {107-113}, pmid = {21637388}, issn = {2092-6685}, abstract = {BACKGROUND: Metabolic disorders, including type II diabetes and obesity, present major health risks in industrialized countries. AMP-activated protein kinase (AMPK) has become the focus of a great deal of attention as a novel therapeutic target for the treatment of metabolic syndromes. In this study, we evaluated whether dietary aloe could reduce obesity-induced inflammation and adipogenesis.<br><br>METHODS: Male C57BL/6 obese mice fed a high-fat diet for 54 days received a supplement of aloe formula (PAG, ALS, Aloe QDM, and Aloe QDM complex) or pioglitazone (PGZ) and were compared with unsupplemented controls (high-fat diet; HFD) or mice fed a regular diet (RD). RT-PCR and western blot analysis were used to quantify the expression of obesity-induced inflammation.<br><br>RESULTS: Aloe QDM complex down-regulated fat size through suppressed expression of scavenger receptors on adipose tissue macrophages (ATMs) compared with HFD. Both white adipose tissue (WATs) and muscle exhibited increased AMPK activation through aloe supplementation, and in particular, the Aloe QDM complex. Obesity-induced inflammatory cytokines (IL-1&#x3b2; and -6) and HIF1&#x3b1; mRNA and protein were decreased markedly, as was macrophage infiltration by the Aloe QDM complex. Further, the Aloe QDM complex decreased the translocation of NF-&#x3ba;B p65 from the cytosol in the WAT.<br><br>CONCLUSION: Dietary aloe formula reduced obesity-induced inflammatory responses by activation of AMPK in muscle and suppression of proinflammatory cytokines in the WAT. Additionally, the expression of scavenger receptors in the ATM and activation of AMPK in WAT led to reduction in the percent of body fat. Thus, we suggest that the effect of the Aloe QDM complex in the WAT and muscle are related to activation of AMPK and its use as a nutritional intervention against T2D and obesity-related inflammation.}, }
@article {pmid21626035, year = {2011}, author = {Devigili, G and Uçeyler, N and Beck, M and Reiners, K and Stoll, G and Toyka, KV and Sommer, C}, title = {Vasculitis-like neuropathy in amyotrophic lateral sclerosis unresponsive to treatment.}, journal = {Acta neuropathologica}, volume = {122}, number = {3}, pages = {343-352}, doi = {10.1007/s00401-011-0837-8}, pmid = {21626035}, issn = {1432-0533}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*pathology/therapy ; Antigens, CD/metabolism ; Biopsy ; Complement Membrane Attack Complex/metabolism ; Cytokines/metabolism ; Electrophysiology ; Female ; Humans ; Immunotherapy/adverse effects ; Leukemic Infiltration/pathology/physiopathology ; Male ; Middle Aged ; Neural Conduction/physiology ; Reaction Time/physiology ; Retrospective Studies ; Statistics, Nonparametric ; Sural Nerve/*pathology/physiopathology ; T-Lymphocytes/pathology ; Vascular Endothelial Growth Factor A/metabolism ; Vasculitis/*pathology/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with variable involvement of other systems. A pathogenetic role of immune-mediated mechanisms has been suggested. We retrospectively analyzed sural nerve pathology and the clinical course in 18 patients with ALS. These patients had undergone sural nerve biopsy because of clinical or neurophysiological signs indicating sensory involvement (ALS+). Eleven of the 18 ALS+ patients had inflammatory cell infiltrates (ALS(vasc)) resembling infiltrates seen in patients with vasculitic neuropathy. Data were compared with the 7 patients without vasculitic infiltrates (ALS(nonvasc)) and with those of 16 patients with isolated peripheral nerve vasculitis (NP(vasc)). Biopsy specimens were processed with standard histological stains and with immunohistochemistry for a panel of inflammatory markers, with the hypothesis that the composition of infiltrates should differ between ALS(vasc) and NP(vasc). Immunoreactive cells were quantified in a blinded manner. Unlike patients with NP(vasc), those with ALS(vasc) had only minor neurophysiological abnormalities in the sural nerve and, except for the infiltrates, almost normal nerve morphology on semithin sections. The difference in epineurial T cell count was significant between ALS(vasc) and ALS(nonvasc) (p = 0.031). Surprisingly, the cellular composition of epineurial infiltrates in sural nerve biopsies was indistinguishable between ALS(vasc) and NP(vasc) despite a significant difference in fiber pathology (p < 0.0001). Standard immunosuppressive treatment did not prevent clinical progression of the motor neuron disease in any of the patients with ALS(vasc). ALS(vasc) appears as a neuropathological subtype in ALS+ suggesting immune-mediated disease components but without response to standard immunosuppressive treatment.}, }
@article {pmid21626001, year = {2011}, author = {Petri, S and Meyer, T}, title = {[Motor neuron diseases].}, journal = {Der Nervenarzt}, volume = {82}, number = {6}, pages = {697-706}, pmid = {21626001}, issn = {1433-0407}, mesh = {Humans ; Models, Biological ; Motor Neuron Disease/diagnosis/*physiopathology/*therapy ; Spinal Cord/*physiopathology ; }, abstract = {Motor neuron diseases (MND) are a group of neurodegenerative disorders which are present in clinical, prognostic and genetic diversity. The most common MND are amyotrophic lateral sclerosis (ALS), proximal spinal muscular atrophy (SMA) and various forms of hereditary and sporadic lower motor neuron syndromes including hereditary motor neuropathies (HMN). Familial and "sporadic" forms of ALS and lower motor neuron syndromes are known. The essential pathogenic findings in MND have emerged from molecular biological examinations of the hereditary forms of MND. In ALS, one consistent neuropathological feature is intraneuronal protein inclusions which arise from TDP-43, FUS, SOD1 or ataxin-2 aggregations. TDP-43, FUS, SOD1 and ataxin-2 are multifunctional DNA/RNA-binding proteins which are involved in transcription regulation. SMA and HMN are associated with different genes whose gene products may also be involved in RNA processing. A disturbance in the regulation of RNA possibly represents an overlapping pathophysiological characteristic in MND. The elucidation of common pathways in the cascade of motor neuron degeneration is an essential point of departure for molecular genetically defined treatment strategies both in ALS and in hereditary and sporadic lower motor neuron syndromes.}, }
@article {pmid21623665, year = {2011}, author = {Paizs, M and Tortarolo, M and Bendotti, C and Engelhardt, JI and Siklós, L}, title = {Talampanel reduces the level of motoneuronal calcium in transgenic mutant SOD1 mice only if applied presymptomatically.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {12}, number = {5}, pages = {340-344}, pmid = {21623665}, issn = {1471-180X}, mesh = {Animals ; Benzodiazepines/*administration &amp; dosage ; Calcium/*metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Mice, Transgenic ; Motor Neurons/*drug effects/*metabolism ; Superoxide Dismutase/biosynthesis/*genetics ; Superoxide Dismutase-1 ; }, abstract = {We tested the efficacy of treatment with talampanel in a mutant SOD1 mouse model of ALS by measuring intracellular calcium levels and loss of spinal motor neurons. We intended to mimic the clinical study; hence, treatment was started when the clinical symptoms were already present. The data were compared with the results of similar treatment started at a presymptomatic stage. Transgenic and wild-type mice were treated either with talampanel or with vehicle, starting in presymptomatic or symptomatic stages. The density of motor neurons was determined by the physical disector, and their intracellular calcium level was assayed electron microscopically. Results showed that motor neurons in the SOD1 mice exhibited an elevated calcium level, which could be reduced, but not restored, with talampanel only when the treatment was started presymptomatically. Treatment in either presymptomatic or symptomatic stages failed to rescue the motor neurons. We conclude that talampanel reduces motoneuronal calcium in a mouse model of ALS, but its efficacy declines as the disease progresses, suggesting that medication initiation in the earlier stages of the disease might be more effective.}, }
@article {pmid21623598, year = {2011}, author = {Juan, YH and Yu, CY and Hsu, HH and Huang, GS and Chan, DC and Liu, CH and Tung, HJ and Chang, WC}, title = {Using multidetector-row CT for the diagnosis of afferent loop syndrome following gastroenterostomy reconstruction.}, journal = {Yonsei medical journal}, volume = {52}, number = {4}, pages = {574-580}, pmid = {21623598}, issn = {1976-2437}, mesh = {Adult ; Afferent Loop Syndrome/*diagnostic imaging ; Aged ; Aged, 80 and over ; Female ; Gastroenterostomy/*adverse effects ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Tomography, X-Ray Computed/*methods ; }, abstract = {PURPOSE: To assess the clinical manifestations and multidetector-row computed tomography (MDCT) findings of afferent loop syndrome (ALS) and to determine the role of MDCT on treatment decisions.<br><br>MATERIALS AND METHODS: From January 2004 to December 2008, 1,100 patients had undergone gastroenterostomy reconstruction in our institution. Of these, 22 (2%) patients were diagnosed as ALS after surgery that included Roux-en-Y gastroenterotomy (n=9), Billroth-II gastrojejunostomy (n=7), and Whipple's operation (n=6). Clinical manifestations and MDCT features of these patients were recorded and statistically analyzed. The presumed etiologies of obstruction shown on the MDCT were correlated with clinical information and confirmed by surgery or endoscopic biopsy.<br><br>RESULTS: The most common clinical symptom was acute abdominal pain, presenting in 18 patients (82%). We found that a fluid-filled C-shaped afferent loop in combination with valvulae conniventes projecting into the lumen was the most common MDCT features of ALS. Malignant causes of ALS, such as local recurrence and carcinomatosis, are the most common etiologies of obstruction. These etiologies and associated complications can be predicted 100% by MDCT.<br><br>CONCLUSION: Our results suggest that MDCT is a reliable modality for assessing the etiologies of ALS and guiding treatment decisions.}, }
@article {pmid21591411, year = {2011}, author = {Hori, S}, title = {[New evidences in the 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care with Treatment Recommendations].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {69}, number = {4}, pages = {605-611}, pmid = {21591411}, issn = {0047-1852}, mesh = {Cardiopulmonary Resuscitation/*standards ; Humans ; Life Support Care/*standards ; Practice Guidelines as Topic/*standards ; }, abstract = {Key changes in Guideline 2010 by Japanese Resuscitation Council were described and the reasons of the change were explained based on 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care with Treatment Recommendations. In BLS, the value of chest compression was further emphasized and it became an initial skill of CPR In ALS, post resuscitation care was systemized by incorporating hypothermia, PCI, and other diagnostic and therapeutic modalities. Indication of hypothermia was further expanded to non-VF categories. Use of AED was expanded to infant. Education, Implementation and Teams were newly included as a chapter to promote the knowledge and skill of resuscitation science into the society.}, }
@article {pmid21586603, year = {2011}, author = {Johnson, FO and Yuan, Y and Hajela, RK and Chitrakar, A and Parsell, DM and Atchison, WD}, title = {Exposure to an environmental neurotoxicant hastens the onset of amyotrophic lateral sclerosis-like phenotype in human Cu2+/Zn2+ superoxide dismutase 1 G93A mice: glutamate-mediated excitotoxicity.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {338}, number = {2}, pages = {518-527}, pmid = {21586603}, issn = {1521-0103}, support = {T32 ES007255/ES/NIEHS NIH HHS/United States ; R01-ES03299/ES/NIEHS NIH HHS/United States ; R21-ES014357/ES/NIEHS NIH HHS/United States ; 5T32-ES007255/ES/NIEHS NIH HHS/United States ; R21 ES014357/ES/NIEHS NIH HHS/United States ; R01 ES003299/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/chemically induced/*enzymology/*genetics ; Animals ; Excitatory Amino Acid Agonists/toxicity ; Genetic Predisposition to Disease ; Glutamic Acid/*toxicity ; Humans ; Male ; Methylmercury Compounds/*toxicity ; Mice ; Mice, Transgenic ; *Phenotype ; Superoxide Dismutase/biosynthesis/*genetics ; }, abstract = {Mice expressing the human Cu(2+)/Zn(2+) superoxide dismutase 1 (hSOD1) gene mutation (hSOD1(G93A); G93A) were exposed to methylmercury (MeHg) at concentrations that did not cause overt motor dysfunction. We hypothesized that low concentrations of MeHg could hasten development of the amyotrophic lateral sclerosis (ALS)-like phenotype in G93A mice. MeHg (1 or 3 ppm/day in drinking water) concentration-dependently accelerated the onset of rotarod failure in G93A, but not wild-type, mice. At the time of rotarod failure, MeHg increased Fluo-4 fluorescence (free intracellular calcium concentration [Ca(2+)](i)) in soma of brainstem-hypoglossal nucleus. These motor neurons control intrinsic and some extrinsic tongue function and exhibit vulnerability in bulbar-onset ALS. The α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione reduced [Ca(2+)](i) in all G93A mice, irrespective of MeHg treatment. N-acetyl spermine, which antagonizes Ca(2+)-permeable AMPA receptors, further reduced [Ca(2+)](i) more effectively in MeHg-treated than untreated G93A mice, suggesting that MeHg-treated mice have a greater Ca(2+)-permeable AMPA receptor contribution. The non-Ca(2+) divalent cation chelator N,N,N',N'-tetrakis(pyridylmethyl)ethylenediamine reduced Fluo-4 fluorescence in all G93A mice; FluoZin-(Zn(2+) indicator) fluorescence was increased in all MeHg-treated mice. Thus in G93A mice Zn(2+) apparently contributed measurably to the MeHg-induced effect. This is the initial demonstration of accelerated onset of ALS-like phenotype in a genetically susceptible organism by exposure to low concentrations of an environmental neurotoxicant. Increased [Ca(2+)](i) induced by the G93A-MeHg interaction apparently was associated with Ca(2+)-permeable AMPA receptors and may contribute to the hastened development of ALS-like phenotypes by subjecting motor neurons to excessive elevation of [Ca(2+)](i), leading to excitotoxic cell death.}, }
@article {pmid21570450, year = {2011}, author = {Kupershmidt, L and Weinreb, O and Amit, T and Mandel, S and Bar-Am, O and Youdim, MB}, title = {Novel molecular targets of the neuroprotective/neurorescue multimodal iron chelating drug M30 in the mouse brain.}, journal = {Neuroscience}, volume = {189}, number = {}, pages = {345-358}, doi = {10.1016/j.neuroscience.2011.03.040}, pmid = {21570450}, issn = {1873-7544}, mesh = {Animals ; Antioxidants/metabolism ; Brain/*drug effects/metabolism ; Gene Expression Profiling ; Hydroxyquinolines/*pharmacology ; Hypoxia-Inducible Factor 1, alpha Subunit/physiology ; Iron Chelating Agents/*pharmacology ; Liver/metabolism ; Mice ; Myocardium/metabolism ; Nerve Growth Factors/metabolism ; Neuroprotective Agents/*pharmacology ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Spinal Cord/metabolism ; }, abstract = {The novel multifunctional brain permeable iron, chelator M30 [5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline] was shown to possess neuroprotective activities in vitro and in vivo, against several insults applicable to various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In the present study, we demonstrate that systemic chronic administration of M30 resulted in up-regulation of hypoxia-inducible factor (HIF)-1α protein levels in various brain regions (e.g. cortex, striatum, and hippocampus) and spinal cord of adult mice. Real-time RT-PCR revealed that M30 differentially induced HIF-1α-dependent target genes, including vascular endothelial growth factor (VEGF), erythropoietin (EPO), enolase-1, transferrin receptor (TfR), heme oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS), and glucose transporter (GLUT)-1. In addition, mRNA expression levels of the growth factors, brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) and three antioxidant enzymes (catalase, superoxide dismutase (SOD)-1, and glutathione peroxidase (GPx)) were up-regulated by M30 treatment in a brain-region-dependent manner. Signal transduction immunoblotting studies revealed that M30 induced a differential enhanced phosphorylation of protein kinase C (PKC), mitogen-activated protein kinase (MAPK)/ERK kinase (MEK), protein kinase B (PKB/Akt), and glycogen synthase kinase-3β (GSK-3β). Together, these results suggest that the multifunctional iron chelator M30 can up-regulate a number of neuroprotective-adaptive mechanisms and pro-survival signaling pathways in the brain that might function as important therapeutic targets for the drug in the context of neurodegenerative disease therapy.}, }
@article {pmid21563158, year = {2011}, author = {Young, CA and Ellis, C and Johnson, J and Sathasivam, S and Pih, N}, title = {Treatment for sialorrhea (excessive saliva) in people with motor neuron disease/amyotrophic lateral sclerosis.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {5}, pages = {CD006981}, doi = {10.1002/14651858.CD006981.pub2}, pmid = {21563158}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Botulinum Toxins/*administration &amp; dosage ; Botulinum Toxins, Type A ; Humans ; Motor Neuron Disease/complications ; Neuromuscular Agents/*administration &amp; dosage ; Parotid Gland ; Randomized Controlled Trials as Topic ; Salivation/drug effects ; Sialorrhea/*drug therapy/etiology ; Submandibular Gland ; }, abstract = {BACKGROUND: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis, is a progressive, neurodegenerative condition which may cause dysphagia, as well as limb weakness, dysarthria, emotional lability and respiratory failure. Since normal salivary production is 0.5 to 1.5 litres daily, loss of salivary clearance due to dysphagia leads to salivary pooling and sialorrhea, often resulting in distress and inconvenience to patients.<br><br>OBJECTIVES: To systematically review evidence on treatment of sialorrhea in MND, including medications, radiotherapy and surgery.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (1 October 2010), the Cochrane Central Register of Controlled Trials)(CENTRAL) (The Cochrane Library issue 3, 2010), MEDLINE (January 1966 to September 2010), EMBASE (January 1980 to September 2010), AMED (1985 to September 2010) and CINAHL Plus (January 1937 September 2010). All bibliographies of the identified randomized trials were reviewed and authors contacted as needed. Known experts in the field were contacted to identify further published and unpublished papers.<br><br>SELECTION CRITERIA: We included randomized and quasi-randomised controlled studies on any intervention for sialorrhea and related symptoms, in people with MND.<br><br>DATA COLLECTION AND ANALYSIS: Review authors summarised data independently in a customised data collection form and confirmed data presented in Cochrane Review Manager software.<br><br>MAIN RESULTS: Only one randomized controlled trial was identified. This was a well designed study of botulinum toxin B injected into parotid and submandibular glands of 20 patients, which showed positive results for four weeks (Jackson 2009). There was low risk of bias in the study and no significant adverse events reported.<br><br>AUTHORS' CONCLUSIONS: There is some evidence for use of botulinum toxin injections to salivary glands for the treatment of sialorrhea in MND. Further research is required on this important symptom. Data are needed on the problem of sialorrhea in MND and its measurement, both by patient self report measures and objective tests. These will allow the development of better randomized controlled trials.}, }
@article {pmid21555177, year = {2011}, author = {Bakalos, G and Mamali, M and Komninos, C and Koukou, E and Tsantilas, A and Tzima, S and Rosenberg, T}, title = {Advanced life support versus basic life support in the pre-hospital setting: a meta-analysis.}, journal = {Resuscitation}, volume = {82}, number = {9}, pages = {1130-1137}, doi = {10.1016/j.resuscitation.2011.04.006}, pmid = {21555177}, issn = {1873-1570}, mesh = {*Advanced Cardiac Life Support ; Cardiopulmonary Resuscitation/methods ; Emergency Medical Services/*methods ; Female ; Greece ; Heart Arrest/*mortality/*therapy ; Humans ; Male ; Risk Assessment ; Survival Analysis ; }, abstract = {BACKGROUND: The scientific evidence of a beneficial effect of ALS in pre-hospital treatment in trauma patients or patients with any acute illness is scarce. The objective of this systematic review of controlled studies was to examine whether ALS, as opposed to BLS, increases patient survival in pre-hospital treatment and if so, to identify the patient groups that gain benefit.<br><br>METHODS: A systematic review of studies published in the databases Medline (PubMed), EMBASE, Cochrane Library and Scopus up to July 31st, 2010. Controlled studies comparing survival after the pre-hospital ALS treatment versus BLS treatment in trauma patients or patients with cardiac arrest were included.<br><br>RESULTS: We identified 1081 studies of which 18 met our inclusion criteria. In nine of 18 studies including 16,857 trauma patients in the intervention group, ALS care did not increase survival compared to BLS treatment (pooled OR 0.892, 95% CI, 0.775-1.026). In nine of 18 studies including 7659 patients with cardiac arrest in the intervention group, ALS care increased survival compared to BLS treatment (OR 1.468, 95% CI, 1.257-1.715). Most subgroup analyses revealed no significant interactions, but data from six trials, where ALS was provided by physicians, increases the probability of survival at hospital discharge even more (OR 2.047, 95% CI 1.593-2.631).<br><br>CONCLUSION: Implementation of ALS care to non-traumatic cardiac arrest patients can increase survival and further research is unlikely to change our confidence in the estimate of the effect. On the contrary, in trauma patients our meta-analysis revealed that ALS care is not associated with increased survival. However, only few controlled studies of sufficient quality and strength examining survival with pre-hospital ALS treatment exist.}, }
@article {pmid21554032, year = {2011}, author = {Cooper-Knock, J and Ahmedzai, SH and Shaw, P}, title = {The use of subcutaneous glycopyrrolate in the management of sialorrhoea and facilitating the use of non-invasive ventilation in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {12}, number = {6}, pages = {464-465}, doi = {10.3109/17482968.2011.584195}, pmid = {21554032}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Female ; Glycopyrrolate/administration &amp; dosage/*therapeutic use ; Humans ; Injections, Subcutaneous ; Middle Aged ; Sialorrhea/*drug therapy/*etiology ; Treatment Outcome ; Ventilation/*methods ; }, abstract = {Sialorrhoea is a recognized complication of bulbar amyotrophic lateral sclerosis (ALS) that leads to an increased risk of potentially harmful aspiration and often prevents patients from tolerating non-invasive ventilation (NIV). A case of treatment-resistant sialorrhoea in bulbar ALS is described where subcutaneous glycopyrrolate was effective without significant side-effects. The patient went on to markedly increase the length of time she could tolerate NIV each night.}, }
@article {pmid21554030, year = {2011}, author = {Atassi, N and Cudkowicz, ME and Schoenfeld, DA}, title = {Advanced statistical methods to study the effects of gastric tube and non-invasive ventilation on functional decline and survival in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {12}, number = {4}, pages = {272-277}, pmid = {21554030}, issn = {1471-180X}, support = {T32 NS048005/NS/NINDS NIH HHS/United States ; T32 NS048005-06/NS/NINDS NIH HHS/United States ; T32NS048005/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/*therapy ; Clinical Trials as Topic ; *Data Interpretation, Statistical ; Databases, Factual ; *Disease Progression ; *Enteral Nutrition ; Humans ; *Positive-Pressure Respiration ; Retrospective Studies ; *Survival Analysis ; }, abstract = {A few studies suggest that non-invasive ventilation (1) and gastric tube (G-tube) may have a positive impact on survival but the effect on functional decline is unclear. Confounding by indication may have produced biased estimates of the benefit seen in some of these retrospective studies. The objective of this study was to evaluate the effects of G-tube and NIV on survival and functional decline using advanced statistical models that adjust for confounding by indications. A database of 331 subjects enrolled in previous clinical trials in ALS was available for analysis. Marginal structural models (MSM) were used to compare the mortality hazards and ALSFRS-R slopes between treatment and non-treatment groups, after adjusting for confounding by indication. Results showed that the placement of a G-tube was associated with an additional 1.42 units/month decline in the ALSFRS-R slope (p < 0.0001) and increased mortality hazard of 0.28 (p = 0.02). The use of NIV had no significant effect on ALSFRS-R decline or mortality. In conclusion, marginal structural models can be used to adjust for confounding by indication in retrospective ALS studies. G-tube placement could be followed by a faster rate of functional decline and increased mortality. Our results may suffer from some of the limitations of retrospective analyses.}, }
@article {pmid21538464, year = {2011}, author = {Piscopo, P and Crestini, A and Adduci, A and Ferrante, A and Massari, M and Popoli, P and Vanacore, N and Confaloni, A}, title = {Altered oxidative stress profile in the cortex of mice fed an enriched branched-chain amino acids diet: possible link with amyotrophic lateral sclerosis?.}, journal = {Journal of neuroscience research}, volume = {89}, number = {8}, pages = {1276-1283}, doi = {10.1002/jnr.22655}, pmid = {21538464}, issn = {1097-4547}, mesh = {Amino Acids, Branched-Chain/*administration &amp; dosage ; Amyotrophic Lateral Sclerosis/etiology ; Animals ; Apolipoproteins E/genetics/metabolism ; Brain/*drug effects/metabolism ; *Diet ; Down-Regulation/drug effects/genetics ; Globins/genetics/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/*drug effects/genetics ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Up-Regulation/genetics ; }, abstract = {Branched-chain amino acids (BCAAs), valine, isoleucine, and leucine, are widely used among athletes as dietary integrators. Although the occurrence of untoward effects of BCCA supplementation, with particular regard to neurological disturbances, cannot be excluded, no specific studies have been performed so far. The aim of this work was to evaluate the effects of a diet enriched in BCAAs on the expression of oxidative stress pathway genes in the brain of C57Bl/6J mice. Animals were fed a standard or a BCAA diet for 95 days starting from postnatal day 21 until sacrifice. BCAA treatment, at doses comparable to human usage, significantly down-regulated the expression of some antioxidant genes, while up-regulating the expression of some oxygen transporters. In conclusion, it appears that BCAAs administered by diet could alter some specific oxidative stress pathways in the brain. Caution should thus be exercised in the widespread use of BCAAs as dietary integrators in sports practice.}, }
@article {pmid21537948, year = {2011}, author = {Seyhan, AA}, title = {RNAi: a potential new class of therapeutic for human genetic disease.}, journal = {Human genetics}, volume = {130}, number = {5}, pages = {583-605}, pmid = {21537948}, issn = {1432-1203}, mesh = {Alzheimer Disease/drug therapy/genetics/therapy ; Amyotrophic Lateral Sclerosis/drug therapy/genetics/therapy ; Anemia, Sickle Cell/drug therapy/genetics/therapy ; Animals ; Clinical Trials as Topic ; Genes, Dominant ; Genetic Diseases, Inborn/drug therapy/*therapy ; Genetic Therapy/*methods ; Humans ; Huntington Disease/drug therapy/genetics/therapy ; Mice ; *Molecular Targeted Therapy ; Muscular Dystrophies/drug therapy/genetics/therapy ; Neoplasms/drug therapy/genetics/therapy ; Parkinson Disease/drug therapy/genetics/therapy ; Point Mutation ; *RNA Interference ; Rats ; Spinocerebellar Ataxias/drug therapy/genetics/therapy ; }, abstract = {Dominant negative genetic disorders, in which a mutant allele of a gene causes disease in the presence of a second, normal copy, have been challenging since there is no cure and treatments are only to alleviate the symptoms. Current therapies involving pharmacological and biological drugs are not suitable to target mutant genes selectively due to structural indifference of the normal variant of their targets from the disease-causing mutant ones. In instances when the target contains single nucleotide polymorphism (SNP), whether it is an enzyme or structural or receptor protein are not ideal for treatment using conventional drugs due to their lack of selectivity. Therefore, there is a need to develop new approaches to accelerate targeting these previously inaccessible targets by classical therapeutics. Although there is a cooling trend by the pharmaceutical industry for the potential of RNA interference (RNAi), RNAi and other RNA targeting drugs (antisense, ribozyme, etc.) still hold their promise as the only drugs that provide an opportunity to target genes with SNP mutations found in dominant negative disorders, genes specific to pathogenic tumor cells, and genes that are critical for mediating the pathology of various other diseases. Because of its exquisite specificity and potency, RNAi has attracted a considerable interest as a new class of therapeutic for genetic diseases including amyotrophic lateral sclerosis, Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), spinocerebellar ataxia, dominant muscular dystrophies, and cancer. In this review, progress and challenges in developing RNAi therapeutics for genetic diseases will be discussed.}, }
@article {pmid21530509, year = {2011}, author = {Lim, E and Lee, S and Li, E and Kim, Y and Park, S}, title = {Ghrelin protects spinal cord motoneurons against chronic glutamate-induced excitotoxicity via ERK1/2 and phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3β pathways.}, journal = {Experimental neurology}, volume = {230}, number = {1}, pages = {114-122}, doi = {10.1016/j.expneurol.2011.04.003}, pmid = {21530509}, issn = {1090-2430}, mesh = {Animals ; Animals, Newborn ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation, Enzymologic/drug effects ; Ghrelin/*pharmacology ; Glutamic Acid/toxicity ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Mitogen-Activated Protein Kinase 3/metabolism ; Motor Neurons/*drug effects/enzymology ; Nerve Tissue Proteins/metabolism ; Neuroprotective Agents/*pharmacology ; Organ Culture Techniques ; Phosphatidylinositol 3-Kinase/*metabolism ; Protein Serine-Threonine Kinases/*metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Ghrelin/metabolism ; Spinal Cord/*cytology ; }, abstract = {Excitotoxic degeneration of spinal cord motoneurons has been proposed as a pathogenic mechanism in amyotrophic lateral sclerosis (ALS). Recently, we have reported that ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R) 1a, functions as a neuroprotective factor in various animal models of neurodegenerative diseases. In this study, the potential neuroprotective effects of ghrelin against chronic glutamate-induced cell death were studied by exposing organotypic spinal cord cultures (OSCC) to threohydroxyaspartate (THA), as a model of excitotoxic motoneuron degeneration. Ghrelin receptor was expressed on spinal cord motoneurons. Exposure of OSCC to THA for 3 weeks resulted in a significant loss of motoneurons. However, THA-induced loss of motoneurons was significantly reduced by treatment of ghrelin. Exposure of OSCC to the receptor-specific antagonist D-Lys-3-GHRP-6 abolished the protective effect of ghrelin against THA. Treatment of spinal cord cultures with ghrelin caused rapid phosphorylation of extracellular signal-regulated kinase 1/2, Akt, and glycogen synthase kinase-3β (GSK-3β). The effect of ghrelin on motoneuron survival was blocked by the MEK inhibitor PD98059 and the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002. Taken together, these findings indicate that ghrelin has neuroprotective effects against chronic glutamate toxicity by activating the MAPK and PI3K/Akt signaling pathways and suggest that administration of ghrelin may have the potential therapeutic value for the prevention of motoneuron degeneration in human ALS. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3β in motoneurons contributes to the protective effect of ghrelin.}, }
@article {pmid21524271, year = {2011}, author = {Kertesz, A}, title = {The overlapping syndromes of the pick complex.}, journal = {Current Alzheimer research}, volume = {8}, number = {3}, pages = {224-228}, doi = {10.2174/156720511795563791}, pmid = {21524271}, issn = {1875-5828}, mesh = {DNA-Binding Proteins/metabolism ; Frontotemporal Dementia/metabolism/*pathology/*psychology ; Humans ; Neuropsychological Tests ; Pick Disease of the Brain/metabolism/pathology/psychology ; Syndrome ; }, abstract = {A significant expansion of knowledge in the last few years, especially in the molecular biology of frontotemporal dementia (FTD) is summarized. This condition, formerly known as Pick's disease and considered rare, is estimated to be 12-15% of all dementias and 30-50% early onset ones. The clinical picture is protean, mainly a behavioural and language impairment, but the extrapyramidal syndromes of CBD and PSP are often seen and conversely FTD and progressive aphasia often has motor symptoms, including ALS. These seemingly different presentations converge, as one or other areas in the brain are affected. Our experience with FTD in a clinical cohort, with high rate of autopsy confirmation is presented. Less than half of the cases are tauopathies, the majority has been discovered to have a TDP-43 and most recently a FUS proteinopathy, shared with ALS, opening potential opportunities for pharmacological approaches to treatment. Tau and progranulin mutations on Ch-17 and some others, point to molecular mechanisms. A glossary is provided to navigate the complex terminology.}, }
@article {pmid21519169, year = {2011}, author = {Park, JW and Lee, JH and Kim, SJ and Park, HW and Kim, HS and Shin, WG and Kim, KH and Kim, HY}, title = {[A case of acute pancreatitis due to afferent loop syndrome with internal hernia].}, journal = {The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi}, volume = {57}, number = {3}, pages = {194-197}, doi = {10.4166/2011.57.3.194}, pmid = {21519169}, issn = {2233-6869}, mesh = {Acute Disease ; Afferent Loop Syndrome/complications/*diagnosis/surgery ; Endoscopy, Gastrointestinal ; Gallstones ; Hernia, Abdominal/*complications ; Humans ; Male ; Middle Aged ; Pancreatitis/*diagnosis/etiology ; Radiography, Abdominal ; Tomography, X-Ray Computed ; }, abstract = {Acute pancreatitis and afferent loop syndrome (ALS) have similar symptoms and physical findings. Accurate early diagnosis is essential, as the management of acute pancreatitis is predominantly conservative whereas ALS usually requires surgery. We experienced one case of pancreatitis due to ALS with internal hernia. Laboratory findings of patient showed elevated serum amylase, lipase and WBC count. One day after admission, diagnosis was modified as acute pancreatitis caused by ALS on computed tomography. Patient was managed with surgical treatment and operation finding revealed ALS due to internal hernia. He was recovered well after surgical treatment and discharged without significant sequelae.}, }
@article {pmid21516084, year = {2011}, author = {Wicks, P and Vaughan, TE and Massagli, MP and Heywood, J}, title = {Accelerated clinical discovery using self-reported patient data collected online and a patient-matching algorithm.}, journal = {Nature biotechnology}, volume = {29}, number = {5}, pages = {411-414}, pmid = {21516084}, issn = {1546-1696}, mesh = {*Algorithms ; Amyotrophic Lateral Sclerosis/*drug therapy ; Case-Control Studies ; Female ; Humans ; *Internet ; Lithium Carbonate/blood/*therapeutic use ; Male ; Middle Aged ; Riluzole/administration &amp; dosage ; Risk Factors ; *Self Report ; Sex Distribution ; Treatment Outcome ; }, abstract = {Patients with serious diseases may experiment with drugs that have not received regulatory approval. Online patient communities structured around quantitative outcome data have the potential to provide an observational environment to monitor such drug usage and its consequences. Here we describe an analysis of data reported on the website PatientsLikeMe by patients with amyotrophic lateral sclerosis (ALS) who experimented with lithium carbonate treatment. To reduce potential bias owing to lack of randomization, we developed an algorithm to match 149 treated patients to multiple controls (447 total) based on the progression of their disease course. At 12 months after treatment, we found no effect of lithium on disease progression. Although observational studies using unblinded data are not a substitute for double-blind randomized control trials, this study reached the same conclusion as subsequent randomized trials, suggesting that data reported by patients over the internet may be useful for accelerating clinical discovery and evaluating the effectiveness of drugs already in use.}, }
@article {pmid21506897, year = {2011}, author = {Yang, R and Huang, R and Chen, D and Song, W and Zeng, Y and Zhao, B and Zhou, D and Shang, HF}, title = {Causes and places of death of patients with amyotrophic lateral sclerosis in south-west China.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {12}, number = {3}, pages = {206-209}, doi = {10.3109/17482968.2011.572979}, pmid = {21506897}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/complications/*mortality ; *Cause of Death ; China ; Female ; Hospitals ; Humans ; Kaplan-Meier Estimate ; Male ; Respiratory Insufficiency/etiology ; Surveys and Questionnaires ; }, abstract = {Understanding the causes and places of death of amyotrophic lateral sclerosis (ALS) patients leads to the development of better treatment modalities. The present study aimed to identify the causes and places of death of ALS patients in south-west China. A total of 139 ALS patients (89 males and 50 females) were regularly followed up in the Department of Neurology, West China Hospital of Sichuan University from 2004 to 2010 until their deaths. Information on the causes and places of death was provided by family members, caregivers, or family physicians. Overall, 91 patients (65.5%) died of respiratory failure, 36 patients (25.9%) died of nutritional causes due to dysphagia, five patients (3.6%) met sudden deaths, three patients (2.2%) died of heart related causes, and four patients (2.9%) died of unknown reasons. Of the 139 patients, 114 (82%) died at home. Consistent with reports in the literature, respiratory failure is the leading cause of death in ALS patients. However, unlike in other studies, the second leading cause is nutrition related. Most patients die at home. The inconsistencies of these results with foreign studies may be attributable to economic and cultural differences. The findings have significant implications on the treatment modalities and palliative care for ALS patients in China.}, }
@article {pmid21499822, year = {2011}, author = {Sharma, RK and Hughes, MT and Nolan, MT and Tudor, C and Kub, J and Terry, PB and Sulmasy, DP}, title = {Family understanding of seriously-ill patient preferences for family involvement in healthcare decision making.}, journal = {Journal of general internal medicine}, volume = {26}, number = {8}, pages = {881-886}, pmid = {21499822}, issn = {1525-1497}, support = {R01 NR010733/NR/NINR NIH HHS/United States ; K12 HS019464/HS/AHRQ HHS/United States ; 1R03DA029448-01/DA/NIDA NIH HHS/United States ; }, mesh = {Adult ; Aged ; *Comprehension ; Critical Illness/*psychology/therapy ; Cross-Sectional Studies ; *Decision Making ; Delivery of Health Care/*methods ; Family/*psychology ; Female ; Humans ; Male ; Middle Aged ; Patient Preference/*psychology ; Pilot Projects ; Terminal Care/methods/psychology ; }, abstract = {BACKGROUND: Surrogate accuracy in predicting patient treatment preferences (i.e., what patients want) has been studied extensively, but it is not known whether surrogates can predict how patients want loved ones to make end-of-life decisions on their behalf.<br><br>OBJECTIVE: To evaluate the ability of family members to correctly identify the preferences of seriously-ill patients regarding family involvement in decision making.<br><br>DESIGN: Cross-sectional survey.<br><br>PARTICIPANTS: Twenty-five pancreatic cancer and 27 amyotrophic lateral sclerosis (ALS) patients and their family members (52 dyads total).<br><br>MAIN MEASURES: Patients and family members completed the Decision Control Preferences (DCP) scale regarding patient preferences for family involvement in health care decisions using conscious and unconscious scenarios.<br><br>KEY RESULTS: Patient and family member agreement was 56% (29/52 dyads) for the conscious scenario (kappa 0.29) and 46% (24/52 dyads) for the unconscious scenario (kappa 0.15). Twenty-four family members identified the patient's preference as independent in the unconscious scenario, but six of these patients actually preferred shared decision making and six preferred reliant decision making. In the conscious scenario, preference for independent decision making was associated with higher odds of patient-family agreement (AOR 5.28, 1.07-26.06). In the unconscious scenario, cancer patients had a higher odds of agreement than ALS patients (AOR 3.86; 95% CI 1.02-14.54).<br><br>CONCLUSION: Family members were often unable to correctly identify patient preferences for family involvement in end-of-life decision making, especially when patients desired that decisions be made using the best-interest standard. Clinicians and family members should consider explicitly eliciting patient preferences for family involvement in decision making. Additional research is still needed to identify interventions to improve family member understanding of patient preferences regarding the decision-making process itself.}, }
@article {pmid21498943, year = {2011}, author = {Yamashita, S and Ueda, A and Hirahara, T and Kimura, E and Hirano, T and Uchino, M}, title = {Fulminant myelopathy following neurogenic proximal weakness associated with human T-cell lymphotropic virus type I infection.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {50}, number = {8}, pages = {919-924}, doi = {10.2169/internalmedicine.50.4647}, pmid = {21498943}, issn = {1349-7235}, mesh = {Aged ; Glucocorticoids/administration &amp; dosage ; Humans ; Magnetic Resonance Imaging ; Male ; Muscle Weakness/pathology/physiopathology ; Muscular Atrophy/pathology/physiopathology ; Paraparesis, Tropical Spastic/*diagnosis/drug therapy/pathology/physiopathology ; Prednisolone/administration &amp; dosage ; Time Factors ; }, abstract = {We report a patient with human T-cell lymphotropic virus type I (HTLV-I) infection, who presented with proximal extremity neurogenic muscular weakness followed by fulminant myelopathy, but with no upper motor symptoms. The symptoms were inconsistent with the World Health Organization or El Escorial criteria for HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) or amyotrophic lateral sclerosis (ALS). This case indicates that fulminant myelopathy without upper motor neuronal symptoms may occur long after the onset of HTLV-I-associated neurogenic proximal muscular weakness. Additionally, we report that treatment with high-dose steroid pulse therapy partially improves symptoms of lightning pain and sensory disturbance.}, }
@article {pmid21491358, year = {2011}, author = {Barkmeier-Kraemer, J and Lato, A and Wiley, K}, title = {Development of a speech treatment program for a client with essential vocal tremor.}, journal = {Seminars in speech and language}, volume = {32}, number = {1}, pages = {43-57}, doi = {10.1055/s-0031-1271974}, pmid = {21491358}, issn = {1098-9056}, mesh = {Articulation Disorders/diagnosis/etiology/physiopathology ; Essential Tremor/complications/diagnosis/physiopathology/*therapy ; Female ; Humans ; Middle Aged ; Phonation ; Speech ; Speech Acoustics ; Speech Articulation Tests ; Speech Perception ; *Speech Therapy ; Stroboscopy ; Videotape Recording ; Voice ; Voice Disorders/complications/diagnosis/physiopathology/*therapy ; }, abstract = {Vocal tremor is characterized by involuntary rhythmic modulations of pitch and loudness and is best perceived during sustained phonation of vowels. It is most often present in individuals affected by neurogenic disorders such as Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular dystrophy, spasmodic dysphonia, and essential tremor. Vocal tremor does not appear to be responsive to systemic pharmaceutical management but may benefit from injection of botulinum toxin (i.e., Botox) into affected musculature. However, many individuals do not tolerate the potential side effects of severe breathiness and difficulty swallowing associated with Botox injections. In this article, we summarize the speech evaluation and treatment methods successfully used with an individual with essential vocal tremor. Methods used for characterizing the individual's vocal tremor patterns and the ensuing rationale for behavioral intervention is provided. The outcomes of this case example motivated consideration of speech treatment as a beneficial strategy for some individuals with vocal tremor.}, }
@article {pmid21488479, year = {2011}, author = {Galante, E and Gazzi, L and Caffarra, S}, title = {Psychological activities in neurorehabilitation: from research to clinical practice.}, journal = {Giornale italiano di medicina del lavoro ed ergonomia}, volume = {33}, number = {1 Suppl A}, pages = {A19-28}, pmid = {21488479}, issn = {1592-7830}, mesh = {Biomedical Research ; Humans ; Nervous System Diseases/*psychology/*rehabilitation ; *Psychotherapy ; }, abstract = {The goal of the present review was to present a critical description of psychological research and practice in neurorehabilitation with regard to the efficacy of treatments proposed in the clinical and neuropsychological field. PubMed, Web of Science and Cochrane databases were searched by using the keywords "psychological intervention" and one of the following neurological diseases: "stroke", "TBI", "Parkinson", "ALS", "multiple sclerosis", "dementia". Randomized and pseudo-randomized trials, reviews and single case studies were included. We identified 134 papers: 54 concerning dementia, 24 stroke, 20 multiple sclerosis, 16 Parkinson, 13 TBI and 7 ALS. Most of these papers concern the evaluation of the effectiveness of psychological treatments in chronic or progressive neurological diseases. However, they are often characterized by methodological limitations, such as a small sample size, absence of a follow-up study or a control group. Further, high quality studies could help better understand treatment effects. There was some evidence for effectiveness of cognitive-behavioural and cognitive therapies, often applied both in clinical and neuropsychological interventions. Evidence coming from individualized treatment and single case studies are also described. In line with the data collected, we summarize some evidence available for psychological testing and treatment and argue that a multidisciplinary approach and a multidimensional evaluation should be adopted. According to this position, both randomized trials and single-case studies could be taken into account. Finally, it is proposed that in order to establish the efficacy of a given treatment, both standardized and individualized measures are to be used.}, }
@article {pmid21479202, year = {2011}, author = {Kim, SM and Park, KS and Nam, H and Ahn, SW and Kim, S and Sung, JJ and Lee, KW}, title = {Capnography for assessing nocturnal hypoventilation and predicting compliance with subsequent noninvasive ventilation in patients with ALS.}, journal = {PloS one}, volume = {6}, number = {3}, pages = {e17893}, pmid = {21479202}, issn = {1932-6203}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*complications/*physiopathology ; Capnography/*methods ; Carbon Dioxide/analysis ; *Darkness ; Demography ; Female ; Humans ; Hypoventilation/complications/*diagnosis/physiopathology/therapy ; Male ; Middle Aged ; Oximetry ; *Patient Compliance ; ROC Curve ; Reproducibility of Results ; Respiration ; *Respiration, Artificial ; Supine Position/physiology ; Wakefulness/physiology ; }, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) suffer from hypoventilation, which can easily worsen during sleep. This study evaluated the efficacy of capnography monitoring in patients with ALS for assessing nocturnal hypoventilation and predicting good compliance with subsequent noninvasive ventilation (NIV) treatment.<br><br>METHODS: Nocturnal monitoring and brief wake screening by capnography/pulse oximetry, functional scores, and other respiratory signs were assessed in 26 patients with ALS. Twenty-one of these patients were treated with NIV and had their treatment compliance evaluated.<br><br>RESULTS: Nocturnal capnography values were reliable and strongly correlated with the patients' respiratory symptoms (R(2)&#x200a;= 0.211-0.305, p = 0.004-0.021). The duration of nocturnal hypercapnea obtained by capnography exhibited a significant predictive power for good compliance with subsequent NIV treatment, with an area-under-the-curve value of 0.846 (p = 0.018). In contrast, no significant predictive values for nocturnal pulse oximetry or functional scores for nocturnal hypoventilation were found. Brief waking supine capnography was also useful as a screening tool before routine nocturnal capnography monitoring.<br><br>CONCLUSION: Capnography is an efficient tool for assessing nocturnal hypoventilation and predicting good compliance with subsequent NIV treatment of ALS patients, and may prove useful as an adjunctive tool for assessing the need for NIV treatment in these patients.}, }
@article {pmid21476614, year = {2011}, author = {Garnock-Jones, KP}, title = {Dextromethorphan/quinidine: in pseudobulbar affect.}, journal = {CNS drugs}, volume = {25}, number = {5}, pages = {435-445}, pmid = {21476614}, issn = {1179-1934}, mesh = {Amyotrophic Lateral Sclerosis/*complications/psychology ; Crying ; Dextromethorphan/adverse effects/pharmacokinetics/*therapeutic use ; Drug Combinations ; Emotions ; Female ; Humans ; Laughter ; Male ; Mood Disorders/*complications/*drug therapy ; Multiple Sclerosis/*complications/psychology ; Quinidine/adverse effects/pharmacokinetics/*therapeutic use ; }, abstract = {Pseudobulbar affect is characterized by uncontrollable, inappropriate laughing and/or crying that is either unrelated or out of proportion to the emotions felt by the patient and occurs in patients with neurological disorders, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis or traumatic brain injury. Dextromethorphan/quinidine is indicated in the US for the treatment of pseudobulbar affect. Dextromethorphan, when its metabolism is inhibited by the coadministration of quinidine, has been shown to have a positive effect on the symptoms of pseudobulbar affect. Dextromethorphan/quinidine 20 mg/10 mg twice daily was associated with a significantly greater decrease in the rate of pseudobulbar affect episodes per day (primary endpoint) than placebo in the 12-week, randomized, double-blind, placebo-controlled, multicentre STAR trial (Safety, Tolerability, And efficacy Results trial of AVP-923 in PBA [pseudobulbar affect]) involving patients with pseudobulbar affect and ALS or multiple sclerosis. Moreover, the mean change from baseline in Center for Neurologic Study-Lability Scale score at 12 weeks was significantly greater among recipients of dextromethorphan/quinidine 20 mg/10 mg twice daily than those receiving placebo. Dextromethorphan/quinidine 20 mg/10 mg twice daily was generally well tolerated. The drug has been shown to cause dosage-dependent corrected QT interval (QTc) prolongation; however, in the STAR trial, dextromethorphan/quinidine 20 mg/10 mg twice daily appeared to be well tolerated with regard to QTc prolongation.}, }
@article {pmid21473943, year = {2011}, author = {Krishnamurthy, PK and Sigurdsson, EM}, title = {Therapeutic applications of antibodies in non-infectious neurodegenerative diseases.}, journal = {New biotechnology}, volume = {28}, number = {5}, pages = {511-517}, pmid = {21473943}, issn = {1876-4347}, support = {R01 AG032611/AG/NIA NIH HHS/United States ; R01 AG020197/AG/NIA NIH HHS/United States ; R01 NS077239/NS/NINDS NIH HHS/United States ; R01 AG020197-06A2/AG/NIA NIH HHS/United States ; AG032611/AG/NIA NIH HHS/United States ; R01 AG020197-01/AG/NIA NIH HHS/United States ; R01 AG032611-01/AG/NIA NIH HHS/United States ; AG020197/AG/NIA NIH HHS/United States ; DK075494/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antibodies/immunology/*therapeutic use ; Disease Progression ; Humans ; Immunologic Techniques ; Immunotherapy ; Neurodegenerative Diseases/*drug therapy/immunology/pathology ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, Huntington's disease (HD) or amyotrophic lateral sclerosis (ALS) are all characterised histologically by the presence of deposits of misfolded proteins, tau and amyloid-β, α-synuclein, huntingtin or superoxide dismutase, respectively. Currently, these illnesses do not have any disease modifying treatment options. A novel therapeutic strategy that is being pursued is immunomodulation, which is using the body's immune system to target the self-proteins that are deposited. Most of these promising approaches are still in preclinical development while some have progressed to Phase III clinical trials. As new insights are gained, it is hoped that these immunotherapies will be effective tools at slowing the progression of these debilitating diseases.}, }
@article {pmid21467921, year = {2011}, author = {Flaherty-Craig, CV and Brothers, A and Yang, C and Svoboda, R and Simmons, Z}, title = {Declines in problem solving and anosognosia in amyotrophic lateral sclerosis: application of Guilford's structure of intellect theory.}, journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology}, volume = {24}, number = {1}, pages = {26-34}, doi = {10.1097/WNN.0b013e3182138454}, pmid = {21467921}, issn = {1543-3641}, support = {C06RR016499/RR/NCRR NIH HHS/United States ; M01RR10732/RR/NCRR NIH HHS/United States ; }, mesh = {Aged ; Agnosia/complications/diagnosis/psychology ; Amyotrophic Lateral Sclerosis/complications/pathology/*psychology ; *Awareness ; Case-Control Studies ; Cognition Disorders/*diagnosis/etiology/psychology ; Diagnostic Self Evaluation ; Female ; Frontal Lobe/pathology ; Frontotemporal Lobar Degeneration/complications/*diagnosis/psychology ; Humans ; Male ; Middle Aged ; Neuropsychological Tests ; Problem Solving ; Reference Values ; *Self Concept ; Temporal Lobe/pathology ; Time Factors ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multisystem disorder in which frontotemporal dysfunction without overt dementia is relatively common. Accordingly, there is need for a valid, brief, motor-free cognitive examination conducive to the ALS Clinic.<br><br>OBJECTIVE: To validate a brief examination against a comprehensive neuropsychological battery to determine its sensitivity in identifying deficits in judgment and problem solving. We enrolled 13 individuals with intact brief examinations, 25 individuals with 1 or more impaired brief examination measures, and 18 healthy volunteers. Cognitive brief examination measures were classified into factors based on Guilford's Structure of Intellect theory. Cognitive anosognosia ratios were calculated to examine the degree of "unawareness of cognitive deficit."<br><br>RESULTS: Statistically significant correlations were evidenced for each brief examination and comprehensive examination measure categorized by the same Guilford factor. In comparison to healthy controls, insight to level of cognitive abilities was significantly compromised for cognitively impaired ALS patients, with respect to their ratings of their responses to comprehension tasks assessing convergent and divergent production.<br><br>CONCLUSIONS: Brief examination measures of verbal fluency and problem solving may serve as sensitive indicators of emerging difficulties in ALS patients with frontotemporal dysfunction. The prevalence of cognitive anosognosia warrants further attention because of its impact on treatment compliance, safety and quality of life for ALS patients with frontotemporal dysfunction.}, }
@article {pmid21465752, year = {2010}, author = {Feigenberg, Z}, title = {[The pre-hospital medical treatment of the victims of multi-casualty incidents caused by explosions of suicide bombers during the Al-Aksa Intifada--April 2001 to December 2004: the activity and experience gained by the teams of Magen David Adom in Israel].}, journal = {Harefuah}, volume = {149}, number = {7}, pages = {413-7, 483, 482}, pmid = {21465752}, issn = {0017-7768}, mesh = {Bombs ; Decision Making ; Emergency Medical Services/*organization &amp; administration ; Humans ; Israel ; *Mass Casualty Incidents ; Suicide ; *Terrorism ; Time Factors ; Triage/organization &amp; administration ; }, abstract = {UNLABELLED: This article deals with the pre-hospital medical treatment provided by Magen David Adom (MDA) teams to the victims of 36 multi-casualty incidents caused by suicide bombers during the Al-Aksa Intifada. A total of 2048 people were injured in those 36 incidents--an average of 57 injured per incident. The data collection and analysis is based on operational and medical debriefing performed after each incident, with the participation of all MDA teams that treated and evacuated injured that were defined as urgent. The medical debriefing focused on: triage--the definition of the injured situation: urgent or not urgent, priority for treatment and priority for evacuation; the Level of treatment--advanced life support (ALS) (paramedics and physicians) in comparison with basic life support (BLS) [medics]; life saving procedures performed on the scene; and the way in which the teams on the scene decided on the hospital in the region to evacuate the injured.<br><br>DATA COLLECTED: MDA forces amassed [average per incident)--42 ambulances and 116 health providers. The timetable from the time of the explosion (average per incident] included: arrival of first ambulance--3.9 minutes and the evacuation of the first urgently injured from scene--10.7 minutes. The evacuation of the last urgently injured from the scene was 25.2 minutes.<br><br>DATA ANALYZED: Triage data showed that: 70% of the injured defined on the scene as urgent had a moderate--ISS > 9, or severe ISS> 16 injury. Life-saving procedures were performed on the scene on 99 victims [24% of all injured defined as urgent by MDA teams). Findings on decision-making regarding which hospital to evacuate the urgently injured revealed: 9 incidents took place in regions where Level 1 trauma centers were not available--all urgently injured were evacuated to regional hospitals, 63% of these patients were secondarily transferred to a Level 1 trauma center. In 27 incidents--one or more Level 1 trauma centers were available in the region and 71% of the urgently injured were transported directly from the scene to Level 1 trauma centers. Only 12% of those transported to regional hospitals were secondarily transported to Level 1 trauma centers. Even in multi-casualty incidents caused by explosions of suicide bombers, incidents that are characterized by stress, confusion and chaos--MDA teams succeeded in organizing the medical activity on the scene, acted professionally and provided medical treatment to those who were severely injured. This pre-hospital performance of MDA teams had a significant contribution to the successful treatment of the victims of those events by the entire trauma system in Israel.}, }
@article {pmid21457778, year = {2011}, author = {Neymotin, A and Calingasan, NY and Wille, E and Naseri, N and Petri, S and Damiano, M and Liby, KT and Risingsong, R and Sporn, M and Beal, MF and Kiaei, M}, title = {Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis.}, journal = {Free radical biology &amp; medicine}, volume = {51}, number = {1}, pages = {88-96}, pmid = {21457778}, issn = {1873-4596}, support = {R21 NS062302/NS/NINDS NIH HHS/United States ; R21 NS062302-01A2/NS/NINDS NIH HHS/United States ; NS062302/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism ; Animals ; Cell Line ; Cell Nucleus/enzymology ; Disease Models, Animal ; Inflammation/metabolism ; Major Histocompatibility Complex/genetics ; Mice ; Mice, Transgenic ; Mitochondria/metabolism ; NF-E2-Related Factor 2/biosynthesis/genetics/*metabolism ; Neurodegenerative Diseases/genetics ; Oleanolic Acid/*analogs &amp; derivatives/metabolism/pharmacology/therapeutic use ; Oxidative Stress ; Proteins/genetics/*metabolism ; RNA, Messenger/biosynthesis ; Signal Transduction ; Superoxide Dismutase/biosynthesis/genetics ; Vesicular Transport Proteins ; }, abstract = {Oxidative damage, neuroinflammation, and mitochondrial dysfunction contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), and these pathologic processes are tightly regulated by the Nrf2/ARE (NF-E2-related factor 2/antioxidant response element) signaling program. Therefore, modulation of the Nrf2/ARE pathway is an attractive therapeutic target for neurodegenerative diseases such as ALS. We examined two triterpenoids, CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) ethylamide and CDDO trifluoroethylamide (CDDO-TFEA), that potently activate Nrf2/ARE in a cell culture model of ALS and in the G93A SOD1 mouse model of ALS. Treatment of NSC-34 cells stably expressing mutant G93A SOD1 with CDDO-TFEA upregulated Nrf2 expression and resulted in translocation of Nrf2 into the nucleus. Western blot analysis showed an increase in the expression of Nrf2/ARE-regulated proteins. When treatment started at a "presymptomatic age" of 30days, both of these compounds significantly attenuated weight loss, enhanced motor performance, and extended the survival of G93A SOD1 mice. Treatment started at a "symptomatic age," as assessed by impaired motor performance, was neuroprotective and slowed disease progression. These findings provide further evidence that compounds that activate the Nrf2/ARE signaling pathway may be useful in the treatment of ALS.}, }
@article {pmid21456887, year = {2011}, author = {Iwamoto, J and Takeda, T and Matsumoto, H}, title = {Efficacy of oral bisphosphonates for preventing hip fracture in disabled patients with neurological diseases: a meta-analysis of randomized controlled trials among the Japanese population.}, journal = {Current medical research and opinion}, volume = {27}, number = {6}, pages = {1141-1148}, doi = {10.1185/03007995.2011.570747}, pmid = {21456887}, issn = {1473-4877}, mesh = {Administration, Oral ; Aged ; Bone Density Conservation Agents/administration &amp; dosage/adverse effects/*therapeutic use ; Diphosphonates/administration &amp; dosage/adverse effects/*therapeutic use ; *Persons with Disabilities ; Female ; Hip Fractures/complications/*prevention &amp; control ; Humans ; Japan ; Male ; Nervous System Diseases/*complications ; *Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVE: Neurological diseases such as amyotrophic lateral sclerosis (ALS), stroke, and Parkinson's disease cause disability and immobilization that increases the risk of hip fracture. The purpose of the present study was to clarify the efficacy of oral bisphosphonates for preventing hip fracture in disabled patients with such neurological diseases.<br><br>METHODS: A literature search (PubMed) was done from 1995 to the present for randomized controlled trials (RCTs), and a meta-analysis was conducted.<br><br>RESULTS: Seven RCTs met the criteria, including two of etidronate (ALS and stroke), two of alendronate (stroke and Parkinson's disease), and three of risedronate (stroke and Parkinson's disease). All of the RCTs were performed on Japanese patients. According to the results of pooled data analysis, the relative risk (95% confidence interval) of hip fracture in patients receiving etidronate, alendronate, and risedronate treatment compared with placebo or active control treatment was 0.16 (0.03-0.87), 0.29 (0.10-0.80), and 0.24 (0.10-0.58), respectively, suggesting a reduction of risk by more than 70% with oral bisphosphonates. There was no statistical evidence of heterogeneity among RCTs, and publication bias was not identified by the funnel plot and Begg's rank correlation test. No severe adverse events due to oral bisphosphonate treatment were reported.<br><br>LIMITATION: It remains uncertain whether the findings are relevant for Western patients with an increased risk of hip fracture due to neurological diseases.<br><br>CONCLUSION: A meta-analysis of RCTs suggested that oral bisphosphonate treatment prevents hip fracture in disabled Japanese patients with neurological diseases, including ALS, stroke, and Parkinson's disease. Oral bisphosphonate treatment was well tolerated by such patients.}, }
@article {pmid21455838, year = {2011}, author = {Naganska, E and Matyja, E}, title = {Amyotrophic lateral sclerosis - looking for pathogenesis and effective therapy.}, journal = {Folia neuropathologica}, volume = {49}, number = {1}, pages = {1-13}, pmid = {21455838}, issn = {1509-572X}, mesh = {*Amyotrophic Lateral Sclerosis/etiology/pathology/therapy ; Humans ; Neuroprotective Agents/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons in the spinal cord, brain stem and motor cortex which dramatically reduces life expectancy. ALS occurs either in familial or, more frequently, in sporadic forms. It finally results in death due to respiratory failure that occurs typically 2-5 years after the disease onset. Although the aetiology of ALS remains largely unclear, its heterogeneity suggests that a combination of various factors, including endogenous and/or environmental ones, may be implicated in progressive motor neuron stress that results in the activation of different cell death pathways. Interactions between genetic, environmental, and age-dependent risk factors have been hypothesized to trigger disease onset. Despite extensive neurobiological, molecular and genetic research, at the beginning of the 21st century ALS still remains one of the most devastating neurodegenerative diseases because of the lack of effective therapeutic strategies. It is a challenge for the clinical and scientific community. Better understanding of the aetiology of amyotrophic lateral sclerosis is necessary to develop effective treatment of this progressive neurodegenerative disease. This review presents the current state of knowledge in ALS research.}, }
@article {pmid21448659, year = {2011}, author = {Beal, MF}, title = {Neuroprotective effects of creatine.}, journal = {Amino acids}, volume = {40}, number = {5}, pages = {1305-1313}, doi = {10.1007/s00726-011-0851-0}, pmid = {21448659}, issn = {1438-2199}, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/antagonists &amp; inhibitors ; Animals ; Creatine/administration &amp; dosage/*pharmacology ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism ; Neuroprotective Agents/administration &amp; dosage/*pharmacology ; Nitro Compounds/antagonists &amp; inhibitors ; Propionates/antagonists &amp; inhibitors ; }, abstract = {There is a substantial body of literature, which has demonstrated that creatine has neuroprotective effects both in vitro and in vivo. Creatine can protect against excitotoxicity as well as against β-amyloid toxicity in vitro. We carried out studies examining the efficacy of creatine as a neuroprotective agent in vivo. We demonstrated that creatine can protect against excitotoxic lesions produced by N-methyl-D: -aspartate. We also showed that creatine is neuroprotective against lesions produced by the toxins malonate and 3-nitropropionic acid (3-NP) which are reversible and irreversible inhibitors of succinate dehydrogenase, respectively. Creatine produced dose-dependent neuroprotective effects against MPTP toxicity reducing the loss of dopamine within the striatum and the loss of dopaminergic neurons in the substantia nigra. We carried out a number of studies of the neuroprotective effects of creatine in transgenic mouse models of neurodegenerative diseases. We demonstrated that creatine produced an extension of survival, improved motor performance, and a reduction in loss of motor neurons in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). Creatine produced an extension of survival, as well as improved motor function, and a reduction in striatal atrophy in the R6/2 and the N-171-82Q transgenic mouse models of Huntington's disease (HD), even when its administration was delayed until the onset of disease symptoms. We recently examined the neuroprotective effects of a combination of coenzyme Q10 (CoQ10) with creatine against both MPTP and 3-NP toxicity. We found that the combination of CoQ and creatine together produced additive neuroprotective effects in a chronic MPTP model, and it blocked the development of alpha-synuclein aggregates. In the 3-NP model of HD, CoQ and creatine produced additive neuroprotective effects against the size of the striatal lesions. In the R6/2 transgenic mouse model of HD, the combination of CoQ and creatine produced additive effects on improving survival. Creatine may stabilize mitochondrial creatine kinase, and prevent activation of the mitochondrial permeability transition. Creatine, however, was still neuroprotective in mice, which were deficient in mitochondrial creatine kinase. Administration of creatine increases the brain levels of creatine and phosphocreatine. Due to its neuroprotective effects, creatine is now in clinical trials for the treatment of Parkinson's disease (PD) and HD. A phase 2 futility trial in PD showed approximately a 50% improvement in Unified Parkinson's Disease Rating Scale at one year, and the compound was judged to be non futile. Creatine is now in a phase III clinical trial being carried out by the NET PD consortium. Creatine reduced plasma levels of 8-hydroxy-2-deoxyguanosine in HD patients phase II trial and was well-tolerated. Creatine is now being studied in a phase III clinical trial in HD, the CREST trial. Creatine, therefore, shows great promise in the treatment of a variety of neurodegenerative diseases.}, }
@article {pmid21446901, year = {2011}, author = {Starakis, I and Panos, G and Koutras, A and Mazokopakis, EE}, title = {Pathogens and chronic or long-term neurologic disorders.}, journal = {Cardiovascular &amp; hematological disorders drug targets}, volume = {11}, number = {1}, pages = {40-52}, doi = {10.2174/187152911795945123}, pmid = {21446901}, issn = {2212-4063}, mesh = {Chronic Disease ; Humans ; Infections/*complications ; Mental Disorders/*microbiology ; Neurodegenerative Diseases/*microbiology ; }, abstract = {Infections of the central nervous system may provoke glial and autoimmune responses but a definitive linkage between these infections and the pathogenesis of chronic neurologic disorders is still elusive. There are controversial reports implicating infectious agents in the pathogenetic mechanisms of chronic or long-term neurologic disorders, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease and autistic spectrum disorders, but the specific role of bacterial or viral infections in the pathogenesis of these medical entities has not been fully elucidated. Up till now, the evidence is distant from definite, but certain cases may be attributed to infections in the millieu of multiple toxic events such as trauma, nutritional deficits, immune dysregulation and excitotoxicity in genetically vulnerable indiniduals. There is an ongoing debate concering the direct involvement of various infectious agents in the neurodegenerative and neurobehavioral diseases pathogenesis and/or their contribution to the deterioration of the disease or co-morbidity in these patients. These patients are exceptionally difficult to be treated by using single therapeutic modalities, because their disese is multifocal and treatment is aimed to control signs and symptoms rather than the true causes of the disease and its progressive course. Furthermore, even if these causative links were indetifiable, our therapeutic interventions would come too late due to the irreversible damages at the time of the initiation of treatment. Our aim is to comprehensively review all available data suggesting that infections could be common antecedent events of progressive neurologic degenerative or behavioural diseases.}, }
@article {pmid21443969, year = {2011}, author = {Cifra, A and Nani, F and Nistri, A}, title = {Respiratory motoneurons and pathological conditions: lessons from hypoglossal motoneurons challenged by excitotoxic or oxidative stress.}, journal = {Respiratory physiology &amp; neurobiology}, volume = {179}, number = {1}, pages = {89-96}, doi = {10.1016/j.resp.2011.03.017}, pmid = {21443969}, issn = {1878-1519}, mesh = {Animals ; Excitatory Amino Acid Agents/*toxicity ; Humans ; Hypoglossal Nerve/drug effects/*pathology/physiology ; Motor Neurons/drug effects/*pathology/physiology ; Neurodegenerative Diseases/chemically induced/*pathology/physiopathology ; Oxidative Stress/drug effects/*physiology ; Respiratory Mechanics/drug effects/*physiology ; }, abstract = {Hypoglossal motoneurons (HMs) are respiration-related brainstem neurons that command rhythmic contraction of the tongue muscles in concert with the respiratory drive. In experimental conditions, HMs can exhibit a range of rhythmic patterns that may subserve different motor outputs and functions. Neurodegenerative diseases like amyotrophic lateral sclerosis (ALS; Lou-Gehrig disease) often damage HMs with distressing symptoms like dysarthria, dysphagia and breathing difficulty related to degeneration of respiratory motoneurons. While the cause of ALS remains unclear, early diagnosis remains an important goal for potential treatment because fully blown clinical symptoms appear with degeneration of about 30% motoneurons. Using a simple in vitro model of the rat brainstem to study the consequences of excitotoxicity or oxidative stress (believed to occur during the onset of ALS) on HMs, it is possible to observe distinct electrophysiological effects associated with HM experimental pathology. In fact, excitotoxicity caused by glutamate uptake block triggers sustained bursting and enhanced synaptic transmission, whereas oxidative stress generates slow depolarization, augmented repeated firing, and decreased synaptic transmission. In either case, only a subpopulation of HMs shows abnormal functional changes. Although these two insults induce separate functional signatures, the consequences on HMs after a few hours are similar and are preceded by activation of the stress transcription factor ATF-3. The deleterious action of excitotoxicity is inhibited by early administration of riluzole, a drug currently employed for the symptomatic treatment of ALS, demonstrating that this in vitro model can be useful for testing potential neuroprotective agents.}, }
@article {pmid21441972, year = {2011}, author = {Chen, C and Xiao, SF}, title = {Induced pluripotent stem cells and neurodegenerative diseases.}, journal = {Neuroscience bulletin}, volume = {27}, number = {2}, pages = {107-114}, pmid = {21441972}, issn = {1995-8218}, mesh = {Animals ; Disease Models, Animal ; Humans ; Induced Pluripotent Stem Cells/*physiology/*transplantation ; Neurodegenerative Diseases/*surgery ; }, abstract = {Neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Amyotrophic Lateral Sclerosis, are characterized by idiopathic neuron loss in different regions of the central nervous system, which contributes to the relevant dysfunctions in the patients. The application of cell replacement therapy using human embryonic stem (hES) cells, though having attracted much attention, has been hampered by the intrinsic ethical problems. It has been demonstrated that adult somatic cells can be reprogrammed into the embryonic state, called induced pluripotent stem (iPS) cells. It is soon realized that iPS cells may be an alternative source for cell replacement therapy, because it raises no ethical problems and using patient-specific iPS cells for autologous transplantation will not lead to immunological rejection. What's more, certain types of neurons derived from patient-specific iPS cells may display disease-relevant phenotypes. Thus, patient-specific iPS cells can provide a unique opportunity to directly investigate the pathological properties of relevant neural cells in individual patient, and to study the vulnerability of neural cells to pathogenic factors in vitro, which may help reveal the pathogenesis of many neurodegenerative diseases. In this review, the recent development in cellular treatment of neurodegenerative diseases using iPS cells was summarized, and the potential value of iPS cells in the modeling of neurodegenerative disease was discussed.}, }
@article {pmid21425112, year = {2011}, author = {Soler, B and Fadic, R and von Bernhardi, R}, title = {[Stem cells therapy in amyotrophic lateral sclerosis treatment. A critical view].}, journal = {Revista de neurologia}, volume = {52}, number = {7}, pages = {426-434}, pmid = {21425112}, issn = {1576-6578}, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology/*surgery ; Animals ; Cell- and Tissue-Based Therapy/*methods ; Clinical Trials as Topic ; Disease Progression ; Humans ; Mesenchymal Stem Cells/cytology/*physiology ; *Stem Cell Transplantation ; Treatment Outcome ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. At present, there are not curative therapies for ALS. Pathogenic and progression mechanisms suggest the existence of oxidative stress, abnormal intracellular protein aggregation, mitochondrial dysfunction, axonal transport impairment, impairment of trophic support, altered glial cell function, and glutamate excitoxicity.<br><br>AIM: To evaluate therapeutic results with adult stem cell for ALS treatment.<br><br>DEVELOPMENT: Stem cells represent a potential therapeutic strategy, because their biological mechanisms could act on several of the pathogenic mechanisms proposed for ALS. Bone marrow mesenchymal stem cells are especially interesting among adult stem cells. Mesenchymal stem cells can differentiate in all central nervous system cells and potentially replace them. Furthermore, they have immunomodulatory effects, secreting, especially in neuroinflammatory environments, neurotrophic and antiinflammatory factors. Studies in murine models of ALS show decrease of inflammation and disease progression, and increase on animal highly heterogeneous, suggest that mesenchymal stem cells transplant in ALS appears to be safe. However, they fail showing clinical improvement of patients.<br><br>CONCLUSION: Additional preclinical studies are necessary to refine this therapeutic approach, to assess long term survival and differentiation of mesenchymal stem cells, dosing, biological activity and safety should be conducted before any planning further human testing occurs.}, }
@article {pmid21423758, year = {2011}, author = {Duning, T and Schiffbauer, H and Warnecke, T and Mohammadi, S and Floel, A and Kolpatzik, K and Kugel, H and Schneider, A and Knecht, S and Deppe, M and Schäbitz, WR}, title = {G-CSF prevents the progression of structural disintegration of white matter tracts in amyotrophic lateral sclerosis: a pilot trial.}, journal = {PloS one}, volume = {6}, number = {3}, pages = {e17770}, pmid = {21423758}, issn = {1932-6203}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/blood/*drug therapy/*pathology ; Demography ; Diffusion Tensor Imaging ; *Disease Progression ; Endpoint Determination ; Female ; Granulocyte Colony-Stimulating Factor/adverse effects/*therapeutic use ; Humans ; Male ; Middle Aged ; Neuropsychological Tests ; Pilot Projects ; Recombinant Proteins ; }, abstract = {BACKGROUND: The hematopoietic protein Granulocyte-colony stimulating factor (G-CSF) has neuroprotective and -regenerative properties. The G-CSF receptor is expressed by motoneurons, and G-CSF protects cultured motoneuronal cells from apoptosis. It therefore appears as an attractive and feasible drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). The current pilot study was performed to determine whether treatment with G-CSF in ALS patients is feasible.<br><br>METHODS: Ten patients with definite ALS were entered into a double-blind, placebo-controlled, randomized trial. Patients received either 10 &#xb5;g/kg BW G-CSF or placebo subcutaneously for the first 10 days and from day 20 to 25 of the study. Clinical outcome was assessed by changes in the ALS functional rating scale (ALSFRS), a comprehensive neuropsychological test battery, and by examining hand activities of daily living over the course of the study (100 days). The total number of adverse events (AE) and treatment-related AEs, discontinuation due to treatment-related AEs, laboratory parameters including leukocyte, erythrocyte, and platelet count, as well as vital signs were examined as safety endpoints. Furthermore, we explored potential effects of G-CSF on structural cerebral abnormalities on the basis of voxel-wise statistics of Diffusion Tensor Imaging (DTI), brain volumetry, and voxel-based morphometry.<br><br>RESULTS: Treatment was well-tolerated. No significant differences were found between groups in clinical tests and brain volumetry from baseline to day 100. However, DTI analysis revealed significant reductions of fractional anisotropy (FA) encompassing diffuse areas of the brain when patients were compared to controls. On longitudinal analysis, the placebo group showed significant greater and more widespread decline in FA than the ALS patients treated with G-CSF.<br><br>CONCLUSIONS: Subcutaneous G-CSF treatment in ALS patients appears as feasible approach. Although exploratory analysis of clinical data showed no significant effect, DTI measurements suggest that the widespread and progressive microstructural neural damage in ALS can be modulated by G-CSF treatment. These findings may carry significant implications for further clinical trials on ALS using growth factors.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT00298597.}, }
@article {pmid21419529, year = {2011}, author = {Rodríguez de Rivera, FJ and Oreja Guevara, C and Sanz Gallego, I and San José Valiente, B and Santiago Recuerda, A and Gómez Mendieta, MA and Arpa, J and Díez Tejedor, E}, title = {Outcome of patients with amyotrophic lateral sclerosis attending in a multidisciplinary care unit.}, journal = {Neurologia (Barcelona, Spain)}, volume = {26}, number = {8}, pages = {455-460}, doi = {10.1016/j.nrl.2011.01.021}, pmid = {21419529}, issn = {1578-1968}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/*therapy ; Disease Progression ; Female ; *Hospital Units ; Humans ; *Interprofessional Relations ; Male ; Middle Aged ; Prospective Studies ; Spain ; *Treatment Outcome ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a disease with very poor prognosis, and a mortality of 50% at 18 months after diagnosis. Multidisciplinary units attempt to improve the quality of life and survival of patients with ALS. The aim of this study is to evaluate every 3 months, over a 24-month period, the outcome of patients treated at the ALS unit since the time of diagnosis.<br><br>MATERIAL AND METHODS: We performed a prospective observational study of patients treated in the ALS unit following a clinical pathway since the time of diagnosis with quarterly reviews from 2006 to 2010. The age of onset, functional impairment (ALSFRS-r), impairment of respiratory function, dysphagia and signs of depression and/or cognitive impairment were evaluated in relation to the initial location symptoms (bulbar [B], upper limbs [UL], lower limbs [LL]).<br><br>RESULTS: A total of 42 patients (30 males and 12 females) were evaluated (mean age at onset of 57.97 years old, SD 14.56). There was an even distribution by location of onset of symptoms (B 14 patients, UL 14, LL 14.) Functional impairment (B -26,89 points, UL -22,48 points, LL -22,66 points), the need for use of BIPAP (B 64.28%; UL 35.71%; LL 50%), the presence of dysphagia (B 85.71; UL 42.85; LL 71.42%), signs of depression (B 78.57%; UL 35.71%; LL 64.28%) and cognitive impairment (B 42.85%; UL 21.42; LL 35.71%) was higher at 24 months of progression in patients with bulbar onset. There was no difference in mortality data (23.80% overall).<br><br>CONCLUSIONS: The treatment in multidisciplinary units does not change the neurological progression of the disease, but increases the survival of ALS patients regardless of their initial onset, emphasising the use of multidisciplinary care.}, }
@article {pmid21418619, year = {2011}, author = {Calvo, AC and Moreno-Igoa, M and Mancuso, R and Manzano, R and Oliván, S and Muñoz, MJ and Penas, C and Zaragoza, P and Navarro, X and Osta, R}, title = {Lack of a synergistic effect of a non-viral ALS gene therapy based on BDNF and a TTC fusion molecule.}, journal = {Orphanet journal of rare diseases}, volume = {6}, number = {}, pages = {10}, pmid = {21418619}, issn = {1750-1172}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/*therapy ; Animals ; Behavior, Animal/physiology ; Brain-Derived Neurotrophic Factor/*pharmacology ; Female ; Gene Expression Profiling ; Genetic Therapy/*methods ; Histocytochemistry ; Kaplan-Meier Estimate ; Male ; Mice ; Mice, Transgenic ; Motor Activity/physiology ; Neural Conduction/physiology ; Plasmids/genetics ; Random Allocation ; Recombinant Fusion Proteins/*pharmacology ; Spinal Cord/pathology ; Tetanus Toxin/*pharmacology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is one of the most devastating neurodegenerative diseases. Neurotrophic factors have been widely tested to counteract neurodegenerative conditions, despite their unspecific neuronal access. The non-toxic C-terminal fragment of the tetanus toxin (TTC) heavy chain has been studied not only as a carrier molecule to the CNS but also as a neuroprotective agent. Because the neurotrophic effects of BDNF have been demonstrated in vitro and in vivo, the question addressed in this work is whether a fusion molecule of BDNF-TTC may have a synergistic effect and enhance the neuroprotective properties of TTC alone in a mouse model of ALS.<br><br>METHODS: Recombinant plasmid constructs (pCMV-TTC and pCMV-BDNF-TTC) were injected into the quadriceps femoris and triceps brachialis muscles of SOD1(G93A) transgenic mice at 8 weeks of age. The hanging wire and rotarod tests were performed to assess motor coordination, strength and balance. Electrophysiological tests, morphological assays of spinal cord sections of L2 and L4 segments, and gene and protein expression analyses were performed. The Kaplan-Meier survival analysis test was used for comparisons of survival. Multiple comparisons of data were analyzed using a one-way analysis of variance (ANOVA).<br><br>RESULTS: Treatment with the fusion-molecule BDNF-TTC and with TTC alone significantly delayed the onset of symptoms and functional deficits of SOD1(G93A) mice. Muscle innervation was partially preserved with these treatments, and the number of surviving motoneurons in L2 spinal cord segment was increased particularly by the fusion protein induction. Inhibition of pro-apoptotic protein targets (caspase-3 and Bax) and significant phosphorylation of Akt and ERK were also found in the spinal cord of treated mice.<br><br>CONCLUSIONS: Significant improvements in behavioral and electrophysiological results, motoneuron survival and anti-apoptotic/survival-activated pathways were observed with BDNF-TTC treatment. However, no synergistic effect was found for this fusion molecule. Although BDNF in the fusion molecule is capable of activating autocrine and neuroprotective pathways, TTC treatment alone yielded similar neuroprotection. Therefore, an accurate study of the neuroprotective effects of TTC fusion molecules should be performed to obtain a better understanding of its effects.}, }
@article {pmid21413884, year = {2011}, author = {Guy, N and Bourry, N and Dallel, R and Dualé, C and Verrelle, P and Lapeyre, M and Clavelou, P}, title = {Comparison of radiotherapy types in the treatment of sialorrhea in amyotrophic lateral sclerosis.}, journal = {Journal of palliative medicine}, volume = {14}, number = {4}, pages = {391-395}, doi = {10.1089/jpm.2010.0308}, pmid = {21413884}, issn = {1557-7740}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*physiopathology ; Dose-Response Relationship, Radiation ; Female ; France ; Humans ; Male ; Middle Aged ; Outcome Assessment, Health Care ; Radiotherapy/*methods ; Salivary Glands/radiation effects ; Sialorrhea/*radiotherapy ; }, abstract = {OBJECTIVES: Many patients with amyotrophic lateral sclerosis (ALS) develop progressive difficulty swallowing secretions, leading to drooling. Although external beam radiation is considered to be an effective and well-tolerated treatment, the optimum schedule in terms of dose, target, radiation type, and number of fractions is unknown. The aim of this observational study was to define the most effective schedule for salivary gland irradiation and to compare electron and photon radiotherapy.<br><br>METHODS: Sixteen patients with ALS (12 females and 4 males) with drooling, enrolled for external radiation of salivary glands between 2002 and 2007, were included. Patients received different treatment protocols according to the decision of their radiotherapist. Efficacy and safety were assessed at 1 and 6 months after treatment by a neurologist and a radiotherapist using a 4-point Likert patient improvement scale, as follows: 0 (no change), 1 (slight improvement), 2 (good improvement), and 3 (very good improvement).<br><br>RESULTS: Radiotherapy for drooling was shown to be safe and effective in ALS patients with duration of effect expected up to 6 months. Eighty percent of patients felt improved at 1 month and 43% at 6 months after external radiation. Patients with sustained improvement at 6 months were treated with electron therapy (>8 MeV; p&#x2009;=&#x2009;0.02).<br><br>CONCLUSIONS: Electron-based radiotherapy, delivered as five 4Gy fractions to a total dose of 20 Gy, encompassing the whole of the submandibular gland and sparing the upper part of the parotid gland, can be proposed as a safe and effective schedule for the treatment of sialorrhea in patients with ALS.}, }
@article {pmid21413090, year = {2011}, author = {Ginsburg, I and Rozenstein-Tsalkovich, L and Koren, E and Rosenmann, H}, title = {The herbal preparation Padma® 28 protects against neurotoxicity in PC12 cells.}, journal = {Phytotherapy research : PTR}, volume = {25}, number = {5}, pages = {740-743}, doi = {10.1002/ptr.3459}, pmid = {21413090}, issn = {1099-1573}, mesh = {Alzheimer Disease/chemically induced/prevention &amp; control ; Amyloid beta-Peptides/adverse effects ; Animals ; Antioxidants/pharmacology ; Cell Survival/drug effects ; Europe ; Glutamates/toxicity ; Humans ; MPTP Poisoning/chemically induced/prevention &amp; control ; Medicine, East Asian Traditional ; Neurotoxicity Syndromes/*prevention &amp; control ; Neurotoxins/*toxicity ; Oxidative Stress/*drug effects ; PC12 Cells/drug effects ; Plant Extracts/*pharmacology/therapeutic use ; Plant Preparations/*pharmacology/therapeutic use ; Polyphenols/pharmacology ; Rats ; Tibet ; United States ; }, abstract = {Padma® 28 is a multicompound herbal preparation based on the camphor formulas from traditional Tibetan medicine (TTM). It contains a variety of different secondary plant substances, which include terpenes and polyphenols such as flavonoids and tannins. As a rich source of antioxidant polyphenols, this herbal Padma 28 preparation seems to be a promising candidate for the treatment of degenerative diseases such as Alzheimer's disease (AD), a condition involving oxidative stress. Moreover, polyphenols have also been shown to mitigate AD neuropathology. The study investigated the protective effect of Padma 28 and of certain polyphenols on the neurotoxicity of PC12 cells induced by the neurotoxins: amyloid-beta (Aβ), glutamate, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3-nitropropionate (3-NP), known to be involved in AD, Parkinson's disease (PD), amyotrophic-lateral-sclerosis (ALS) and Huntington's disease (HD), respectively. The decrease in cell viability induced by each of the toxins was significantly attenuated by Padma 28 treatment. Also, a decrease in the oxidative capacity of PC12 cells treated with Padma 28 was noted, indicating that the decrease in cell viability induced by the toxins might have been the result of an oxidative stress which could be attenuated by Padma 28 acting as a potent antioxidant. Padma 28, which is available in Europe and USA, seems to be a promising candidate for the treatment of CNS diseases.}, }
@article {pmid21403864, year = {2011}, author = {Turturici, G and Sconzo, G and Geraci, F}, title = {Hsp70 and its molecular role in nervous system diseases.}, journal = {Biochemistry research international}, volume = {2011}, number = {}, pages = {618127}, pmid = {21403864}, issn = {2090-2255}, abstract = {Heat shock proteins (HSPs) are induced in response to many injuries including stroke, neurodegenerative disease, epilepsy, and trauma. The overexpression of one HSP in particular, Hsp70, serves a protective role in several different models of nervous system injury, but has also been linked to a deleterious role in some diseases. Hsp70 functions as a chaperone and protects neurons from protein aggregation and toxicity (Parkinson disease, Alzheimer disease, polyglutamine diseases, and amyotrophic lateral sclerosis), protects cells from apoptosis (Parkinson disease), is a stress marker (temporal lobe epilepsy), protects cells from inflammation (cerebral ischemic injury), has an adjuvant role in antigen presentation and is involved in the immune response in autoimmune disease (multiple sclerosis). The worldwide incidence of neurodegenerative diseases is high. As neurodegenerative diseases disproportionately affect older individuals, disease-related morbidity has increased along with the general increase in longevity. An understanding of the underlying mechanisms that lead to neurodegeneration is key to identifying methods of prevention and treatment. Investigators have observed protective effects of HSPs induced by preconditioning, overexpression, or drugs in a variety of models of brain disease. Experimental data suggest that manipulation of the cellular stress response may offer strategies to protect the brain during progression of neurodegenerative disease.}, }
@article {pmid21402972, year = {2011}, author = {Yarn, JC}, title = {Disappointments in medicine: lack of effective treatment for neurological disorders like ALS.}, journal = {Canadian family physician Medecin de famille canadien}, volume = {57}, number = {3}, pages = {333}, pmid = {21402972}, issn = {1715-5258}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Treatment Outcome ; }, }
@article {pmid21397513, year = {2011}, author = {Liakopoulos, OJ and Hristov, N and Buckberg, GD and Triana, J and Trummer, G and Allen, BS}, title = {Resuscitation after prolonged cardiac arrest: effects of cardiopulmonary bypass and sodium-hydrogen exchange inhibition on myocardial and neurological recovery.}, journal = {European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery}, volume = {40}, number = {4}, pages = {978-984}, pmid = {21397513}, issn = {1873-734X}, support = {R01-HL-71729-04/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Cardiopulmonary Bypass/*methods ; Cardiopulmonary Resuscitation/*methods ; Combined Modality Therapy ; Disease Models, Animal ; Guanidines/pharmacology/therapeutic use ; Heart Arrest/complications/physiopathology/*therapy ; Hemodynamics/drug effects/physiology ; Myocardial Reperfusion Injury/prevention &amp; control ; Nervous System Diseases/etiology/*prevention &amp; control ; Seizures/etiology/therapy ; Sodium-Hydrogen Exchangers/*antagonists &amp; inhibitors ; Sulfones/pharmacology/therapeutic use ; Sus scrofa ; Treatment Outcome ; }, abstract = {OBJECTIVE: To determine if cardiopulmonary bypass (CPB), together with inhibition of the sodium-hydrogen exchanger (NHE), limits myocardial and neurological injury and improves recovery after prolonged (unwitnessed) cardiac arrest (CA), as NHE inhibition improved recovery after deep hypothermic circulatory arrest.<br><br>METHODS: Twenty-seven pigs (31-39 kg) underwent 15 min of prolonged (no-flow) CA followed by 10 min of cardiopulmonary resuscitation-advanced life support (CPR-ALS). Subjects with restoration of spontaneous circulation (ROSC) during CPR-ALS received either no drug (n=6) or an inhibitor of the NHE (HOE-642; n=5). In the 16 unsuccessfully resuscitated animals, peripheral normothermic CPB was instituted, and either no drug (n=9) or similar HOE-642 (n=7) therapy started. Hemodynamic data, a species-specific neurological deficit score (0=normal to 500=brain death), and mortality were recorded at 24h, and biochemical variables of organ injury measured.<br><br>RESULTS: CPR-ALS restored ROSC in 41% (11/27) of animals, but was unsuccessful in 59% (16/27) that required CPB. Without CPB, HOE-642 increased cardiac index and decreased vascular resistance; with CPB, HOE-642 caused higher pump flows (3.4&#xb1;0.6 l min(-1)m(-2) vs 2.5&#xb1;0.7 l min(-1)m(-2); p<0.001) and higher post-arrest cardiac index; but animals required more vasopressors (p=0.019) from drug-induced vasodilation. No differences between biochemical markers of oxidative and organ injury and overall 24-h mortality (20%) were found between groups. Neurological score was improved at 24h compared with 4h only after HOE-642 treatment with (150&#xb1;34 vs 220&#xb1;43; p=0.003) or without CPB (162&#xb1;39 vs 238&#xb1;48; p&#x2264;0.001), but failed to reach statistical difference with respect to the untreated group.<br><br>CONCLUSIONS: CPB is an effective resuscitative tool to treat prolonged CA but there is limited improvement of neurological function. NHE inhibition augments cardiac and neurological function, but its effect was less pronounced than in other studies.}, }
@article {pmid21391854, year = {2011}, author = {Lunn, JS and Sakowski, SA and Federici, T and Glass, JD and Boulis, NM and Feldman, EL}, title = {Stem cell technology for the study and treatment of motor neuron diseases.}, journal = {Regenerative medicine}, volume = {6}, number = {2}, pages = {201-213}, pmid = {21391854}, issn = {1746-076X}, support = {T32 NS007222/NS/NINDS NIH HHS/United States ; T32 NS007222-28/NS/NINDS NIH HHS/United States ; T32 NS007222&#x2011;28/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Animals ; Biomedical Research/*methods ; Clinical Trials, Phase I as Topic ; Humans ; Models, Biological ; Motor Neuron Disease/*etiology/*therapy ; Stem Cell Transplantation/*methods ; Stem Cells/*physiology ; Translational Research, Biomedical/methods ; }, abstract = {Amyotrophic lateral sclerosis and spinal muscular atrophy are devastating neurodegenerative diseases that lead to the specific loss of motor neurons. Recently, stem cell technologies have been developed for the investigation and treatment of both diseases. Here we discuss the different stem cells currently being studied for mechanistic discovery and therapeutic development, including embryonic, adult and induced pluripotent stem cells. We also present supporting evidence for the utilization of stem cell technology in the treatment of amyotrophic lateral sclerosis and spinal muscular atrophy, and describe key issues that must be considered for the transition of stem cell therapies for motor neuron diseases from bench to bedside. Finally, we discuss the first-in-human Phase I trial currently underway examining the safety and feasibility of intraspinal stem cell injections in amyotrophic lateral sclerosis patients as a foundation for translating stem cell therapies for various neurological diseases.}, }
@article {pmid21382304, year = {2011}, author = {Woolley, JD and Khan, BK and Murthy, NK and Miller, BL and Rankin, KP}, title = {The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease.}, journal = {The Journal of clinical psychiatry}, volume = {72}, number = {2}, pages = {126-133}, pmid = {21382304}, issn = {1555-2101}, support = {P50 AG023501/AG/NIA NIH HHS/United States ; P01 AG019724-01A1/AG/NIA NIH HHS/United States ; P01 AG017586/AG/NIA NIH HHS/United States ; R01 CA094143/CA/NCI NIH HHS/United States ; 5-P01 AG19724/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; P50 AG023501-01/AG/NIA NIH HHS/United States ; R25 MH060482/MH/NIMH NIH HHS/United States ; }, mesh = {Adjustment Disorders/diagnosis/epidemiology/genetics/psychology ; Age of Onset ; Aged ; Anxiety Disorders/diagnosis/epidemiology/genetics/psychology ; Bipolar Disorder/diagnosis/epidemiology/genetics/psychology ; Comorbidity ; Cross-Sectional Studies ; Depressive Disorder, Major/diagnosis/psychology ; Female ; Genetic Predisposition to Disease/genetics ; Humans ; Male ; Mental Disorders/*diagnosis/epidemiology/genetics/*psychology ; Middle Aged ; Neurocognitive Disorders/*diagnosis/epidemiology/genetics/*psychology ; Neurodegenerative Diseases/*diagnosis/epidemiology/genetics/*psychology ; Retrospective Studies ; Risk Factors ; Schizophrenia/diagnosis/epidemiology/genetics ; Schizophrenic Psychology ; }, abstract = {OBJECTIVE: To identify rates of and risk factors for psychiatric diagnosis preceding the diagnosis of neurodegenerative disease.<br><br>METHOD: Systematic, retrospective, blinded chart review was performed of 252 patients with a neurodegenerative disease diagnosis seen in our specialty clinic between 1999 and 2008. Neurodegenerative disease diagnoses included behavioral-variant frontotemporal dementia (n = 69), semantic dementia (n = 41), and progressive nonfluent aphasia (n = 17) (all meeting Neary research criteria); Alzheimer's disease (n = 65) (National Institute of Neurologic and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association research criteria); corticobasal degeneration (n = 25) (Boxer research criteria); progressive supranuclear palsy (n = 15) (Litvan research criteria); and amyotrophic lateral sclerosis (n = 20) (El Escorial research criteria). Reviewers remained blinded to each patient's final neurodegenerative disease diagnosis while reviewing charts. Extensive caregiver interviews were conducted to ensure accurate and reliable diagnostic histories. For each patient, we recorded history of psychiatric diagnosis, family psychiatric and neurologic history, age at symptom onset, and demographic information.<br><br>RESULTS: A total of 28.2% of patients with a neurodegenerative disease received a prior psychiatric diagnosis. Depression was the most common psychiatric diagnosis in all groups. Behavioral-variant frontotemporal dementia patients received a prior psychiatric diagnosis significantly more often (50.7%; P < .001) than patients with Alzheimer's disease (23.1%), semantic dementia (24.4%), or progressive nonfluent aphasia (11.8%) and were more likely to receive diagnoses of bipolar disorder or schizophrenia than were patients with other neurodegenerative diseases (P < .001). Younger age (P < .001), higher education (P < .05), and a family history of psychiatric illness (P < .05) increased the rate of prior psychiatric diagnosis in patients with behavioral-variant frontotemporal dementia. Cognitive, behavioral, and emotional characteristics did not distinguish patients who did or did not receive a prior psychiatric diagnosis.<br><br>CONCLUSIONS: Neurodegenerative disease is often misclassified as psychiatric disease, with behavioral-variant frontotemporal dementia patients at highest risk. While this study cannot rule out the possibility that psychiatric disease is an independent risk factor for neurodegenerative disease, when patients with neurodegenerative disease are initially classified with psychiatric disease, the patient may receive delayed, inappropriate treatment and be subject to increased distress. Physicians should consider referring mid- to late-life patients with new-onset neuropsychiatric symptoms for neurodegenerative disease evaluation.}, }
@article {pmid21381286, year = {2010}, author = {Blanquer, M and Pérez Espejo, MA and Iniesta, F and Gómez Espuch, J and Meca, J and Villaverde, R and Izura, V and de Mingo, P and Martínez-Lage, J and Martínez, S and Moraleda, JM}, title = {[Bone marrow stem cell transplantation in amyotrophic lateral sclerosis: technical aspects and preliminary results from a clinical trial].}, journal = {Methods and findings in experimental and clinical pharmacology}, volume = {32 Suppl A}, number = {}, pages = {31-37}, pmid = {21381286}, issn = {0379-0355}, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology/*surgery ; Animals ; *Bone Marrow Transplantation/adverse effects/methods ; Centrifugation, Density Gradient ; Disease Progression ; Humans ; Injections, Spinal ; Mice ; Motor Neurons/*pathology ; *Nerve Degeneration ; *Nerve Regeneration ; Time Factors ; Transplantation, Autologous ; Treatment Outcome ; Vital Capacity ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) experience progressive and irreversible paralysis as a result of the continued loss of motor neurons, which leads to death in less than five years. To date, there is no treatment that can change the progression of this disease. Bone marrow stem cells have shown neural regenerative and neural repairing properties. Specifically, our group showed in a murine model of the disease that these cells, when injected in the spinal cord, can rescue motor neurons through the secretion of GDNF. Based on these results, we designed a phase I/II clinical trial for the purpose of demonstrating the viability of the intraspinal injection of autologous bone marrow mononuclear cells in patients with bulbar onset ALS, with an evolution between 6 and 36 months, with a forced vital capacity (FVC) 50% and T90 29%. This article describes the technique for extracting 60 mL of bone marrow used for the intervention, processing it by density gradient, and the neurosurgical technique used for implanting it. After 6 months of follow-up, the few adverse events reported in the first seven patients included seem to show that the procedure is safe and viable. Most of these patients, including two with a rapid deterioration, have stabilized the progression of their FVC and the neurologic scales measured. The data obtained so for seem to justify the design of new trials more oriented toward the efficacy of the procedure.}, }
@article {pmid21375347, year = {2011}, author = {Xia, G and Benmohamed, R and Kim, J and Arvanites, AC and Morimoto, RI and Ferrante, RJ and Kirsch, DR and Silverman, RB}, title = {Pyrimidine-2,4,6-trione derivatives and their inhibition of mutant SOD1-dependent protein aggregation. Toward a treatment for amyotrophic lateral sclerosis.}, journal = {Journal of medicinal chemistry}, volume = {54}, number = {7}, pages = {2409-2421}, pmid = {21375347}, issn = {1520-4804}, support = {R43 NS057849/NS/NINDS NIH HHS/United States ; R43 NS057849-01A1/NS/NINDS NIH HHS/United States ; 1R43NS057849/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Humans ; Models, Molecular ; Mutant Proteins/*chemistry/genetics ; *Mutation ; PC12 Cells ; Protein Multimerization/*drug effects ; Protein Structure, Quaternary ; Pyrimidines/chemical synthesis/*chemistry/*pharmacology/therapeutic use ; Rats ; Superoxide Dismutase/*chemistry/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness, paralysis, and death, most often from respiratory failure. The only FDA-approved drug for the treatment of ALS, riluzole, only extends the median survival in patients by 2-3 months. There is an urgent need for novel therapeutic strategies for this devastating disease. Using a high-throughput screening assay targeting an ALS cultured cell model (PC12-G93A-YFP cell line), we previously identified three chemotypes that were neuroprotective. We present a further detailed analysis of one promising scaffold from that group, pyrimidine-2,4,6-triones (PYTs), characterizing a number of PYT analogues using SAR and ADME. The PYT compounds show good potency, superior ADME data, low toxicity, brain penetration, and excellent oral bioavailability. Compounds from this series show 100% efficacy in the protection assay with a good correlation in activity between the protection and protein aggregation assays. The modifications of the PYT scaffold presented here suggest that this chemical structure may be a novel drug candidate scaffold for use in clinical trials in ALS.}, }
@article {pmid21372794, year = {2011}, author = {Yunusova, Y and Green, JR and Wang, J and Pattee, G and Zinman, L}, title = {A protocol for comprehensive assessment of bulbar dysfunction in amyotrophic lateral sclerosis (ALS).}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {48}, pages = {}, pmid = {21372794}, issn = {1940-087X}, support = {R01DCO09890-02//PHS HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*physiopathology ; Bulbar Palsy, Progressive/diagnosis/*physiopathology ; Diaphragm/physiopathology ; Humans ; Speech/physiology ; }, abstract = {Improved methods for assessing bulbar impairment are necessary for expediting diagnosis of bulbar dysfunction in ALS, for predicting disease progression across speech subsystems, and for addressing the critical need for sensitive outcome measures for ongoing experimental treatment trials. To address this need, we are obtaining longitudinal profiles of bulbar impairment in 100 individuals based on a comprehensive instrumentation-based assessment that yield objective measures. Using instrumental approaches to quantify speech-related behaviors is very important in a field that has primarily relied on subjective, auditory-perceptual forms of speech assessment(1). Our assessment protocol measures performance across all of the speech subsystems, which include respiratory, phonatory (laryngeal), resonatory (velopharyngeal), and articulatory. The articulatory subsystem is divided into the facial components (jaw and lip), and the tongue. Prior research has suggested that each speech subsystem responds differently to neurological diseases such as ALS. The current protocol is designed to test the performance of each speech subsystem as independently from other subsystems as possible. The speech subsystems are evaluated in the context of more global changes to speech performance. These speech system level variables include speaking rate and intelligibility of speech. The protocol requires specialized instrumentation, and commercial and custom software. The respiratory, phonatory, and resonatory subsystems are evaluated using pressure-flow (aerodynamic) and acoustic methods. The articulatory subsystem is assessed using 3D motion tracking techniques. The objective measures that are used to quantify bulbar impairment have been well established in the speech literature and show sensitivity to changes in bulbar function with disease progression. The result of the assessment is a comprehensive, across-subsystem performance profile for each participant. The profile, when compared to the same measures obtained from healthy controls, is used for diagnostic purposes. Currently, we are testing the sensitivity and specificity of these measures for diagnosis of ALS and for predicting the rate of disease progression. In the long term, the more refined endophenotype of bulbar ALS derived from this work is expected to strengthen future efforts to identify the genetic loci of ALS and improve diagnostic and treatment specificity of the disease as a whole. The objective assessment that is demonstrated in this video may be used to assess a broad range of speech motor impairments, including those related to stroke, traumatic brain injury, multiple sclerosis, and Parkinson disease.}, }
@article {pmid21365842, year = {2010}, author = {Li, LG and Zuo, YP and Yuan, DH}, title = {[Hard and soft tissue changes following the treatment of Class II division 1 malocclusion using twin-block appliance].}, journal = {Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology}, volume = {28}, number = {6}, pages = {637-640}, pmid = {21365842}, issn = {1000-1182}, mesh = {*Cephalometry ; Face ; Humans ; Malocclusion ; *Mandible ; }, abstract = {OBJECTIVE: To investigate the hard and soft tissue changes following the treatment of Class II division 1 malocclusion using Twin-block appliance.<br><br>METHODS: 50 Class II division 1 malocclusion subjects whose handwrist radiographs were in FG-G stage were selected. One group (27 patients) was treated with Twin-block appliance, the other group (23 patients) was observed without treatment The acquired data of cephalometric of two groups were analyzed statistically with SPSS 11.0.<br><br>RESULTS: Soft tissue changes, Ls-E, Li-E, U1-Stms, Stms-Stmi, NsLs-FH, LsNsLi, LsNsPg', the angle of H decreased. Sn-Stms, Stmi-Me', Ns-Me', Sn-Me', NsLi-FH, NsPg'-FH, A'Ls-FH, B'Li-FH, LiB' Pg', CmSnLs, GSnPg', the angle of Z increased, there was statistically significant difference (P < 0.05). Hard tissue changes, SNB, L1-NB, IMPA increased, ANB, U1-SN, U1-NA, FMIA decreased, there was statistically significant difference (P < 0.05).<br><br>CONCLUSION: Sagittal relationship between upper- and lower-jaws is effectively improved after orthopedics with Twin-block appliance. Lower face height increases. Soft tissue profile tends to be straight-styled.}, }
@article {pmid21361856, year = {2011}, author = {Rybakowski, JK}, title = {Lithium in neuropsychiatry: a 2010 update.}, journal = {The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry}, volume = {12}, number = {5}, pages = {340-348}, doi = {10.3109/15622975.2011.559274}, pmid = {21361856}, issn = {1814-1412}, mesh = {Antidepressive Agents/*therapeutic use ; Antimanic Agents/*therapeutic use ; Brain/drug effects ; Dementia/drug therapy ; Humans ; Lithium Compounds/*therapeutic use ; Mood Disorders/*drug therapy ; Neuroimaging ; }, abstract = {OBJECTIVES. More than 60 years have passed since the introduction of lithium into modern psychiatry and special issues of Bipolar Disorders in 2009 and Neuropsychobiology in 2010 were devoted to this anniversary. Notwithstanding such a long tradition, a number of key articles on the neuropsychiatric aspects of lithium have appeared in recent years. METHODS. This update was based on the most important original papers and reviews on lithium published in recent years. The main topics were the efficacy of lithium in mood disorders, with a special focus on cognitive functions, the neuroprotective effects of this ion and the potential of using lithium in neurology. RESULTS. Clinical studies and reviews point to lithium being still a cornerstone for the prophylaxis of mood disorders, especially bipolar. The pro-cognitive and antisuicidal properties of lithium have been confirmed as an augmentation of antidepressants in treatment-resistant depression. The neuroprotective effects of lithium have been evidenced in both experimental research and in clinical studies using brain imaging. The possible use of lithium in the prophylaxis of dementia and in neurodegenerative disorders, such as Huntington's disease and amyotrophic lateral sclerosis is discussed. CONCLUSIONS. Although not promoted by pharmaceutical companies, lithium remains a highly important drug in neuropsychiatry.}, }
@article {pmid21349470, year = {2012}, author = {Núñez-Batalla, F and Díaz-Molina, JP and Costales-Marcos, M and Moreno Galindo, C and Suárez-Nieto, C}, title = {[Neurolaryngology].}, journal = {Acta otorrinolaringologica espanola}, volume = {63}, number = {2}, pages = {132-140}, doi = {10.1016/j.otorri.2010.12.003}, pmid = {21349470}, issn = {1988-3013}, mesh = {Algorithms ; Botulinum Toxins, Type A/therapeutic use ; Diagnostic Techniques, Neurological ; Electric Stimulation Therapy ; Electromyography ; Genetic Therapy ; Humans ; Laryngeal Diseases/diagnosis/*etiology/therapy ; Laryngeal Muscles/innervation/physiopathology ; Laryngeal Nerves/physiopathology ; Laryngoscopy ; Motor Neurons/physiology ; Nerve Net/physiology ; Nerve Transfer ; Nervous System Diseases/*complications/diagnosis/physiopathology/therapy ; Neurologic Examination ; Neurophysiology ; Physical Examination ; Sound Spectrography ; Voice Disorders/diagnosis/etiology/therapy ; }, abstract = {The neuroanatomy of voice and speech is complex. An intricate neural network is responsible for ensuring the main functions of the larynx: airway protection, cough and Valsalva production, and providing voice. Coordination of these roles is very susceptible to disruption by neurological disorders. Neurological disorders that affect laryngeal function include Parkinson's disease, stroke, amyotrophic lateral sclerosis, multiple sclerosis, dystonia and essential tremor. A thorough neurological evaluation should be routine for any patient presenting with voice complaints suggestive of neurogenic cause. Endoscopic visualisation of the larynx using a dynamic voice assessment with a flexible laryngoscope is a crucial part of the evaluation and ancillary tests are sometimes performed. Otolaryngologic evaluation is important in the diagnosis and treatment of neurological disorders that affect laryngeal function.}, }
@article {pmid21346313, year = {2011}, author = {Wang, Q and Zhang, X and Chen, S and Zhang, X and Zhang, S and Youdium, M and Le, W}, title = {Prevention of motor neuron degeneration by novel iron chelators in SOD1(G93A) transgenic mice of amyotrophic lateral sclerosis.}, journal = {Neuro-degenerative diseases}, volume = {8}, number = {5}, pages = {310-321}, doi = {10.1159/000323469}, pmid = {21346313}, issn = {1660-2862}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics/prevention &amp; control ; Animals ; Iron Chelating Agents/metabolism/pharmacology/*therapeutic use ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/*enzymology/pathology ; Nerve Degeneration/enzymology/*genetics/*prevention &amp; control ; Oxidative Stress/genetics ; Random Allocation ; Superoxide Dismutase/*genetics/metabolism ; }, abstract = {BACKGROUND: The causes of amyotrophic lateral sclerosis (ALS) are largely unknown. Oxidative stress is considered to play a major role in motor neuron degeneration associated with iron homeostasis disturbance.<br><br>OBJECTIVE: Iron chelation treatment might be a potential therapeutic approach on the basis of its ability to reduce the oxygen free radical generation caused by iron accumulation.<br><br>METHODS AND RESULTS: In the present study, we applied the brain-permeable iron chelators VK-28 and M30 in a G93A mutant superoxide dismutase 1 transgenic (SOD1(G93A)) mouse model of ALS and found that VK-28 and M30 significantly delayed disease onset, extended the life span and reduced spinal cord motor neuron loss. Furthermore, we documented that both iron chelators significantly attenuated the elevated iron level and transferrin receptor expression, decreased oxygen free radicals and suppressed microglial and astrocytic activation in the spinal cords of the SOD1(G93A) mice. Moreover, we demonstrated that both iron chelators were able to decrease TDP-43 protein aggregation and the proapoptotic molecule Bax, and to enhance antiapoptotic protein Bcl-2 expression, in the ALS mice.<br><br>CONCLUSIONS: These results provide evidence that iron is involved in the pathogenesis of ALS and iron chelation therapy may have the potential for the prevention and treatment of ALS.}, }
@article {pmid21333475, year = {2011}, author = {Kogashiwa, Y and Oishi, N and Yamauchi, K and Kohno, N}, title = {Advanced hypopharyngeal cancer with amyotrophic lateral sclerosis.}, journal = {Auris, nasus, larynx}, volume = {38}, number = {6}, pages = {750-752}, doi = {10.1016/j.anl.2011.01.005}, pmid = {21333475}, issn = {1879-1476}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Carcinoma, Squamous Cell/complications/*therapy ; Chemoradiotherapy ; Humans ; Hypopharyngeal Neoplasms/complications/*therapy ; Lymphatic Metastasis ; Male ; Middle Aged ; }, abstract = {We present a case of advanced hypopharyngeal cancer occurring in a patient with amyotrophic lateral sclerosis (ALS). A 58-year-old man diagnosed with ALS 2 years previously noticed a mass in his neck and dysphagia. We diagnosed him as having hypopharyngeal squamous cell carcinoma with the left cervical lymph node metastases (T3N2bM0) and treated with concurrent chemoradiotherapy. During and after the treatment, his neurological symptoms showed no worse signs. The patient has been cancer-free for 13 months after concurrent chemoradiotherapy. The influence of ALS on the patients' quality of life (QOL) and/or prognosis had to be taken into consideration when determining an appropriate treatment for the hypopharyngeal cancer. To the best of our knowledge, this may be the first case with ALS who was treated for hypopharyngeal cancer.}, }
@article {pmid21325259, year = {2011}, author = {Cho, SY and Kim, SY and Jeon, YL and Oh, SH and Cho, EH and Lee, WI and Cho, KS and Park, TS}, title = {A novel three-way Ph variant t(8;9;22) in adult acute lymphoblastic leukemia.}, journal = {Annals of clinical and laboratory science}, volume = {41}, number = {1}, pages = {71-78}, pmid = {21325259}, issn = {1550-8080}, mesh = {Adult ; Base Sequence ; Bone Marrow/pathology ; Chromosomes, Human, Pair 22/*genetics ; Chromosomes, Human, Pair 8/*genetics ; Chromosomes, Human, Pair 9/*genetics ; Fusion Proteins, bcr-abl/metabolism ; Gene Rearrangement ; Humans ; Male ; Middle Aged ; Molecular Sequence Data ; *Philadelphia Chromosome ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics/pathology ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Analysis, DNA ; *Translocation, Genetic ; }, abstract = {Although three-way Philadelphia (Ph) variant translocation has been uncommonly (3~8%) reported in chronic myeloid leukemia (CML), it has been even more rarely described in acute leukemias (ALs). When we reviewed the Mitelman database and the literature, we found about 595 three-way Ph variant cases; among these, only 39 three-way Ph variant translocations in AL were documented. Here, we report a novel three-way Ph variant case of t(8;9;22) in adult acute lymphoblastic leukemia (ALL). Based on bone marrow morphology, chromosome fluorescent in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), and flow cytometrry, this patient was diagnosed with B lymphoblastic leukemia/lymphoma associated with both t(8;9;22) (q21;q34;q11.2) and BCR/ABL1 rearrangement (e1a2 type). Because of the rarity of reported AL patients with three-way Ph variant, further studies on their prognosis and treatment response to imatinib mesylate are necessary.}, }
@article {pmid21324003, year = {2011}, author = {Cifra, A and Nani, F and Nistri, A}, title = {Riluzole is a potent drug to protect neonatal rat hypoglossal motoneurons in vitro from excitotoxicity due to glutamate uptake block.}, journal = {The European journal of neuroscience}, volume = {33}, number = {5}, pages = {899-913}, doi = {10.1111/j.1460-9568.2010.07579.x}, pmid = {21324003}, issn = {1460-9568}, mesh = {Action Potentials/drug effects/physiology ; Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Aspartic Acid/pharmacology ; Astrocytes/cytology/drug effects/metabolism ; Bicuculline/pharmacology ; Biomarkers/metabolism ; Convulsants/pharmacology ; Excitatory Amino Acid Antagonists/pharmacology/therapeutic use ; GABA-A Receptor Antagonists/pharmacology ; Glutamic Acid/*metabolism ; Hypoglossal Nerve/*cytology ; Motor Neurons/cytology/*drug effects/*metabolism ; Neuroprotective Agents/*pharmacology/therapeutic use ; Patch-Clamp Techniques ; Rats ; Riluzole/*pharmacology/therapeutic use ; Strychnine/pharmacology ; }, abstract = {Excitotoxic damage to motoneurons is thought to be an important contribution to the pathogenesis of amyotrophic lateral sclerosis (ALS), a slowly developing degeneration of motoneurons that, in most cases of sporadic occurrence, is associated with impaired glial glutamate uptake. Riluzole is the only drug licensed for symptomatic ALS treatment and is proposed to delay disease progression. As riluzole is administered only after full ALS manifestation, it is unclear if its early use might actually prevent motoneuron damage. We explored this issue by using, as a simple in vitro model, hypoglossal motoneurons (a primary target of ALS) of the neonatal rat brainstem slice preparation exposed to excitotoxic stress due to glutamate uptake block by DL-threo-β-benzyloxyaspartate (TBOA). TBOA evoked sustained network bursting, early (1 h) enhancement of the S100B immunostaining of gray matter astrocytes, and activated the motoneuronal stress ATF-3 transcription factor; 4 h later, loss (30%) of motoneuron staining ensued and pyknosis appeared. Riluzole (5 μM; applied 15 min after TBOA) inhibited bursting, decreased the frequency of spontaneous glutamatergic events, reversed changes in S100B immunostaining and prevented late loss of motoneuron staining. These results show that excitotoxicity induced by glutamate uptake block developed slowly, and was sensed by glia and motoneurons with delayed cell death. Our data provide novel evidence for the neuroprotective action of riluzole on motoneurons and glia when applied early after an excitotoxic stimulus.}, }
@article {pmid21323493, year = {2011}, author = {, }, title = {ALSUntangled No. 9: Blue-green algae (Spirulina) as a treatment for ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {12}, number = {2}, pages = {153-155}, doi = {10.3109/17482968.2011.553796}, pmid = {21323493}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; *Cyanobacteria ; Disease Models, Animal ; Disease Progression ; Humans ; Mice ; *Spirulina ; Treatment Outcome ; }, }
@article {pmid21321491, year = {2011}, author = {Bertorini, TE and Rashed, H and Zeno, M and Tolley, EA and Igarashi, M and Li, YD}, title = {Effects of 3-4 diaminopyridine (DAP) in motor neuron diseases.}, journal = {Journal of clinical neuromuscular disease}, volume = {12}, number = {3}, pages = {129-137}, doi = {10.1097/CND.0b013e3182095b2b}, pmid = {21321491}, issn = {1537-1611}, mesh = {4-Aminopyridine/*analogs &amp; derivatives/therapeutic use ; Adult ; Aged ; Aged, 80 and over ; Amifampridine ; Cross-Over Studies ; Double-Blind Method ; Electrophysiology ; Fatigue/drug therapy/etiology ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/complications/*drug therapy ; Muscle Weakness/drug therapy/etiology ; Potassium Channel Blockers/*therapeutic use ; }, abstract = {OBJECTIVE: To study the safety of 3-4 diaminopyridine (DAP) in patients with motor neuron diseases and to examine its efficacy in reducing muscle fatigue and weakness and in improving objective parameters of muscle function.<br><br>DESIGN: Assessments of safety included a questionnaire of symptoms, clinical examination, blood testing, and electrocardiography at each visit; efficacy was assessed by subjective scores of fatigue and weakness; an Amyotrophic Lateral Sclerosis Functional Rating Scale and functional ability scores, including timed verbal scores; manual muscle testing; grip dynamometry; pulmonary function tests; timed functional tests; and electrophysiological studies.<br><br>PARTICIPANTS: Thirteen subjects with amyotrophic lateral sclerosis and seven subjects with only a lower motor neuron syndrome.<br><br>MAIN OUTCOMES: Assess tolerability of DAP and determine if there was symptomatic improvement of muscle fatigue. SECONDARY OUTCOME: To determine the effects of DAP on objective parameters of muscle function.<br><br>RESULTS: The drug was well tolerated with only four subjects reporting tingling of lips and fingers during the active drug period. The subjective scores for fatigue and weakness showed a mild improvement after 4 weeks on DAP compared with placebo. A significant benefit of DAP was also demonstrated in the timed verbal scores.<br><br>CONCLUSION: 3-4 DAP appeared to be safe and produced subjective benefit in motor neuron diseases. The drug could be added for symptomatic treatment in these diseases. Larger studies are necessary to demonstrate efficacy.}, }
@article {pmid21310542, year = {2011}, author = {Karam, C and Scelsa, SN}, title = {Can vitamin D delay the progression of ALS?.}, journal = {Medical hypotheses}, volume = {76}, number = {5}, pages = {643-645}, doi = {10.1016/j.mehy.2011.01.021}, pmid = {21310542}, issn = {1532-2777}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology/*therapy ; Axons/metabolism ; Calcium/metabolism ; Disease Progression ; Gliosis/metabolism ; Humans ; Inflammation ; Models, Biological ; Models, Theoretical ; Motor Neurons/metabolism ; Nerve Regeneration ; Vascular Endothelial Growth Factor A/metabolism ; Vitamin D/*metabolism/therapeutic use ; }, abstract = {The pathogenesis of amyotrophic lateral sclerosis (ALS) is multifactorial and a treatment targeting only one aspect of the disease is unlikely to be beneficial. Vitamin D is safe and may delay progression of ALS by acting on several aspects of the disease. In this article we explore how vitamin D may promote VGEF, IGF-1 and axonal regeneration delaying ALS progression. In addition, we discuss how vitamin D may increase calcium binding protein in motor neuron cells conferring a greater resistance to the underlying disease process, as seen in the oculomotor nerve and Onuf's nucleus. Finally, we discuss vitamin D immunomodulator role, decreasing the reactive gliosis in ALS.}, }
@article {pmid21305570, year = {2011}, author = {Lange, DJ and Nijjar, R and Voustianiouk, A and Seidel, G and Panchal, J and Wang, AK}, title = {Do A-waves help predict intravenous immunoglobulin response in multifocal motor neuropathy without block?.}, journal = {Muscle &amp; nerve}, volume = {43}, number = {4}, pages = {537-542}, doi = {10.1002/mus.21914}, pmid = {21305570}, issn = {1097-4598}, mesh = {Adult ; Female ; Humans ; Immunoglobulins, Intravenous/*administration &amp; dosage ; Male ; Middle Aged ; Muscle Strength/*drug effects/physiology ; Neural Conduction/*drug effects/physiology ; Pilot Projects ; Polyneuropathies/*drug therapy/*physiopathology ; Predictive Value of Tests ; Treatment Outcome ; }, abstract = {INTRODUCTION: Are there electrophysiological findings that predict response to intravenous immunoglobulin (IVIg) in patients with lower motor neuron (LMN) syndromes without multifocal conduction block (MCB)?<br><br>METHODS: We enrolled 9 patients with LMN syndromes without MCB to receive 18 weeks of IVIg therapy. Response was measured at weeks 2 and 18 using the Appel Amyotrophic Lateral Sclerosis (AALS) score (includes grip and pincer strength measures), ALS Functional Rating Scale (ALSFRS), and electrophysiological measures, including motor unit estimates (MUNEs).<br><br>RESULTS: No change occurred in AALS or ALSFRS scores posttreatment. Grip/pincer strength increased in 7 patients (P = 0.028) after initial treatment (responders); 2 showed no improvement (non-responders). No electrophysiological measure changed after treatment in either group but MUNEs trended higher (P = 0.055). "Abnormal A-waves" (complex, repetitive biphasic, or present in multiple nerves) occurred in pretreatment studies more often in responders (P = 0.028).<br><br>DISCUSSION: "Abnormal A-waves" may signal IVIg-responsive LMN syndromes even if conduction block is absent.}, }
@article {pmid21296666, year = {2011}, author = {Tradewell, ML and Cooper, LA and Minotti, S and Durham, HD}, title = {Calcium dysregulation, mitochondrial pathology and protein aggregation in a culture model of amyotrophic lateral sclerosis: mechanistic relationship and differential sensitivity to intervention.}, journal = {Neurobiology of disease}, volume = {42}, number = {3}, pages = {265-275}, doi = {10.1016/j.nbd.2011.01.016}, pmid = {21296666}, issn = {1095-953X}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Calcium/*metabolism ; Cells, Cultured ; Disease Models, Animal ; Membrane Potential, Mitochondrial/physiology ; Mice ; Microscopy, Confocal ; Mitochondria/*metabolism/pathology ; Motor Neurons/*metabolism/pathology ; Proteasome Endopeptidase Complex/metabolism ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; }, abstract = {The combination of Ca(2+) influx during neurotransmission and low cytosolic Ca(2+) buffering contributes to the preferential vulnerability of motor neurons in amyotrophic lateral sclerosis (ALS). This study investigated the relationship among Ca(2+) accumulation in intracellular compartments, mitochondrial abnormalities, and protein aggregation in a model of familial ALS (fALS1). Human SOD1, wild type (SOD1(WT)) or with the ALS-causing mutation G93A (SOD1(G93A)), was expressed in motor neurons of dissociated murine spinal cord-dorsal root ganglia (DRG) cultures. Elevation of mitochondrial Ca(2+) ([Ca(2+)](m)), decreased mitochondrial membrane potential (Δψ) and rounding of mitochondria occurred early, followed by increased endoplasmic reticular Ca(2+) ([Ca(2+)](ER)), elevated cytosolic Ca(2+) ([Ca(2+)](c)), and subsequent appearance of SOD1(G93A) inclusions (a consequence of protein aggregation). [Ca(2+)](c) was elevated to a greater extent in neurons with inclusions than in those with diffusely distributed SOD1(G93A) and promoted aggregation of mutant protein, not vice versa: both [Ca(2+)](c) and the percentage of neurons with SOD1(G93A) inclusions were reduced by co-expressing the cytosolic Ca(2+)-buffering protein, calbindin D-28K; treatment with the heat shock protein inducer, geldanamycin, prevented inclusions but not the increase in [Ca(2+)](c), [Ca(2+)](m) or loss of Δψ, and inhibiting proteasome activity with epoxomicin, known to promote aggregation of disease-causing mutant proteins including SOD1(G93A), had no effect on Ca(2+) levels. Both expression of SOD1(G93A) and epoxomicin-induced inhibition of proteasome activity caused mitochondrial rounding, independent of Ca(2+) dysregulation and reduced Δψ. That geldanamycin prevented inclusions and mitochondrial rounding, but not Ca(2+) dysregulation or loss of Δψ indicates that chaperone-based therapies to prevent protein aggregation may require co-therapy to address these other underlying mechanisms of toxicity.}, }
@article {pmid21295555, year = {2011}, author = {Tsuchioka, M and Hisaoka, K and Yano, R and Shibasaki, C and Kajiatani, N and Takebayashi, M}, title = {Riluzole-induced glial cell line-derived neurotrophic factor production is regulated through fibroblast growth factor receptor signaling in rat C6 glioma cells.}, journal = {Brain research}, volume = {1384}, number = {}, pages = {1-8}, doi = {10.1016/j.brainres.2011.01.100}, pmid = {21295555}, issn = {1872-6240}, mesh = {Animals ; CREB-Binding Protein/genetics/metabolism ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Drug Interactions ; Enzyme Inhibitors/pharmacology ; Excitatory Amino Acid Antagonists/*pharmacology ; Gene Expression Regulation, Neoplastic/*drug effects ; Glial Cell Line-Derived Neurotrophic Factor/genetics/*metabolism ; Glioma/pathology ; Glutamic Acid/pharmacology ; RNA, Messenger/metabolism ; Rats ; Receptors, Fibroblast Growth Factor/*metabolism ; Riluzole/*pharmacology ; Signal Transduction/*drug effects ; }, abstract = {Riluzole is approved for the treatment of amyotrophic lateral sclerosis (ALS); however, recent accumulating evidence suggests that riluzole is also effective for the treatment of psychiatric disorders, such as mood disorders. Plastic change in the brain induced by neurotrophic factors/growth factors is thought to be involved in the mechanism of antidepressants. This study investigated the mechanism of riluzole-induced glial cell line-derived neurotrophic factor (GDNF) production in rat C6 glioma cells (C6 cells), a model of astrocytes. The study investigated the phosphorylation of cAMP response element binding protein (CREB), an important transcriptional factor of the gdnf gene, and found that riluzole increased CREB phosphorylation in a time-dependent manner, peaking at 40min after treatment. The riluzole-induced CREB phosphorylation was completely blocked by a mitogen-activated protein kinase kinase (MEK) inhibitor (U0126). Riluzole increased extracellular signal-regulated kinase (ERK) activation prior to CREB phosphorylation. These results suggest that riluzole rapidly activates the MEK/ERK/CREB pathway. Furthermore, two types of fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors (SU5402 and PD173074) completely blocked riluzole-induced CREB phosphorylation. In addition, riluzole rapidly phosphorylated FGFR substrate 2α (FRS2α), a major adaptor protein of FGFR. These findings suggest that riluzole induces CREB phosphorylation through FGFR. In addition, PD173074 inhibited riluzole-induced GDNF production. In contrast, l-glutamate and a glutamate transporter inhibitor (t-PDC) did not yield any effects in either CREB phosphorylation or GDNF production. These findings suggest that riluzole rapidly activates a MEK/ERK/CREB pathway through FGFR in a glutamate transporter-independent manner, followed by GDNF expression in C6 cells.}, }
@article {pmid21292280, year = {2011}, author = {Hozumi, I and Hasegawa, T and Honda, A and Ozawa, K and Hayashi, Y and Hashimoto, K and Yamada, M and Koumura, A and Sakurai, T and Kimura, A and Tanaka, Y and Satoh, M and Inuzuka, T}, title = {Patterns of levels of biological metals in CSF differ among neurodegenerative diseases.}, journal = {Journal of the neurological sciences}, volume = {303}, number = {1-2}, pages = {95-99}, doi = {10.1016/j.jns.2011.01.003}, pmid = {21292280}, issn = {1878-5883}, mesh = {Aged ; Alzheimer Disease/cerebrospinal fluid/pathology ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/pathology ; Female ; Humans ; Image Processing, Computer-Assisted ; Male ; Mass Spectrometry ; Metals/*cerebrospinal fluid ; Metals, Heavy/cerebrospinal fluid ; Middle Aged ; Neurodegenerative Diseases/*cerebrospinal fluid/pathology ; Parkinson Disease/cerebrospinal fluid/pathology ; }, abstract = {We measured the levels of some biological metals: copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), and zinc (Zn) in the cerebrospinal fluid (CSF) in patients with neurodegenerative diseases (52 patients with amyotrophic lateral sclerosis (ALS)), 21 patients with Alzheimer's disease (AD), and 20 patients with Parkinson's disease (PD) by inductively coupled plasma mass spectrometry (ICP-MS). The diagnoses were additionally supported by neuroimaging techniques for AD and PD. In ALS, the levels of Mg (p<0.01 significant difference), Fe, Cu (p<0.05), and Zn (p<0.10) in CSF were higher than those in controls. Some patients showed very high levels of Cu and Zn before the critical deterioration of the disease. In AD, the levels of Cu and Zn in CSF were significantly higher in patients with late-onset AD (p<0.01). In PD, we found significantly increased levels of especially Cu and Zn in particular (p<0.01) and Mn (p<0.05) in CSF. A multiple comparison test suggested that the increased level of Mg in ALS and that of Mn in PD were the pathognomonic features. These findings suggest that Cu and Zn in particular play important roles in the onset and/or progression of ALS, AD, and PD. Therefore, Cu-chelating agents and modulators of Cu and Zn such as metallothionein (MT) can be new candidates for the treatment of ALS, AD, and PD.}, }
@article {pmid21170888, year = {2010}, author = {Trepiccione, F and Christensen, BM}, title = {Lithium-induced nephrogenic diabetes insipidus: new clinical and experimental findings.}, journal = {Journal of nephrology}, volume = {23 Suppl 16}, number = {}, pages = {S43-8}, pmid = {21170888}, issn = {1121-8428}, mesh = {Animals ; Diabetes Insipidus, Nephrogenic/*chemically induced ; Glycogen Synthase Kinase 3/physiology ; Glycogen Synthase Kinase 3 beta ; Humans ; Kidney/metabolism ; Kidney Tubules, Collecting/metabolism ; Lithium/metabolism/*toxicity ; }, abstract = {Lithium (Li+) salts are widely used to treat bipolar mood disorders. Recent trials suggest a potential efficacy also in the treatment of amyotrophic lateral sclerosis and Alzheimer's disease. Li+ is freely filtered by the glomerulus and mainly reabsorbed in the proximal convoluted tubule. Reabsorption in the distal nephron becomes significant under sodium-restricted conditions. Nevertheless, the distal nephron is greatly affected by Li+ even under normal sodium intake. Polyuria, renal tubular acidosis and finally chronic renal failure are the most frequent adverse effects. The occurrence of an overt nephrogenic diabetes insipidus (NDI) limits Li+ usage and imposes suspension. The molecular mechanisms of Li+-related urinary concentration defect involve a dysregulation of the aquaporin system in principal cells of the collecting duct. ENaC is crucial as the entry route for intracellular Li+ accumulation. The basolateral exit route is not clearly identified, but some evidence suggests Na+/H+ exchanger 1 (NHE1) as a potential candidate. Li+ promotes polyuria mainly counteracting the intracellular vasopressin signaling. An additional role of the inner medullary interstitial cells and PGE-2 pathway has to be considered. The GSK3ß cascade is also regulated by Li+. GSK3ß inhibition could lead not only to the polyuria, but also to the Li+-dependent proliferative effect on principal cells. Cellular reorganization of the collecting duct and microcysts are the main pathological findings during Li+ treatment. Their relationship with the urinary concentration defect and an eventual Li+-induced ciliopathy has to been investigated. Li+-induced NDI has been a matter of investigation since the early 1970s. This manuscript reports the latest clinical and experimental findings in combination with the older fundamental results.}, }
@article {pmid21280084, year = {2011}, author = {Douville, R and Liu, J and Rothstein, J and Nath, A}, title = {Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis.}, journal = {Annals of neurology}, volume = {69}, number = {1}, pages = {141-151}, pmid = {21280084}, issn = {1531-8249}, support = {R01 NS039253-11/NS/NINDS NIH HHS/United States ; R01 NS039253/NS/NINDS NIH HHS/United States ; R01NS0333958/NS/NINDS NIH HHS/United States ; R01 NS056884/NS/NINDS NIH HHS/United States ; R01 NS056884-05/NS/NINDS NIH HHS/United States ; R01NS039253/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*genetics/physiopathology/*virology ; Brain/*physiopathology/*virology ; Cerebral Cortex/physiopathology/virology ; Cytogenetics ; Endogenous Retroviruses/genetics/*isolation &amp; purification ; Female ; Gene Expression ; Gene Frequency/genetics ; Humans ; Male ; Middle Aged ; Motor Neurons/*virology ; RNA, Messenger/genetics ; Reverse Transcriptase Polymerase Chain Reaction/statistics &amp; numerical data ; Transcriptional Activation/physiology ; Viral Proteins/genetics ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons, of unknown etiology. Previous studies showed reverse transcriptase in serum of ALS patients at levels comparable to human immunodeficiency virus-infected patients; however, the source and significance of the retroviral elements is uncertain.<br><br>METHODS: Expression of a human endogenous retrovirus (HERV-K) was determined in autopsy brain tissue of patients with ALS and compared to control populations by real-time polymerase chain reaction followed by sequencing of the amplified genes and confirmed by immunostaining.<br><br>RESULTS: HERV-K pol transcripts were increased in patients with ALS compared to those with chronic systemic illness, but could not be detected in Parkinson disease or in the accidental death controls. Sequencing revealed several actively transcribed loci in the HML-2 and 3 subfamilies of HERV-K, with a specific pattern of expression including intact open reading frames and the transcription of a unique locus in ALS. The frequency of intact pol transcripts was highest in the motor cortex, and the reverse transcriptase protein was localized to cortical neurons of ALS patients. HERV-K expression strongly correlated with TDP-43, a multifunctional protein known to be dysregulated in ALS.<br><br>INTERPRETATION: We have identified a specific pattern of HERV-K expression in ALS, which may potentially define the pathophysiology of ALS. Targeting of activated genome-encoded retroviral elements may open new prospects for the treatment of ALS.}, }
@article {pmid21276928, year = {2011}, author = {Mather, RC and Orlando, LA and Henderson, RA and Lawrence, JT and Taylor, DC}, title = {A predictive model of shoulder instability after a first-time anterior shoulder dislocation.}, journal = {Journal of shoulder and elbow surgery}, volume = {20}, number = {2}, pages = {259-266}, doi = {10.1016/j.jse.2010.10.037}, pmid = {21276928}, issn = {1532-6500}, mesh = {Adolescent ; Adult ; Female ; Humans ; Joint Instability/*etiology ; Male ; Markov Chains ; Models, Statistical ; Monte Carlo Method ; Outcome Assessment, Health Care ; Shoulder Dislocation/*complications ; *Shoulder Joint ; Young Adult ; }, abstract = {INTRODUCTION: Management of a first-time anterior shoulder dislocation (FTASD) involves important clinical and policy decisions. Predictive disease modeling can improve the quality of information disseminated in treatment discussions. In this paper, we describe a general-purpose, publicly available model and illustrate its potential as a tool for management of a FTASD.<br><br>METHODS: A Markov decision model of the natural history of a FTASD was constructed. Outcome probabilities and effectiveness were derived from the literature or estimated by expert opinion where necessary. Outcomes were the Western Ontario Shoulder Instability index (WOSI) and the probability of a patient experiencing recurrent instability, undergoing surgical stabilization, and having a stable shoulder at 10&#xa0;years. The model was both internally and externally validated. Outcomes were examined for specific cases.<br><br>RESULTS: The model was effectively externally validated against two studies, a Swedish prospective cohort of Hovelius et al and Botonni et al's military cohort. It can produce detailed outcome predictions for individuals; eg, an 18-year-old man has a 77% risk of dislocation in year 1 and a 32% chance of having a stable shoulder in 10 years.<br><br>CONCLUSION: Detailed and specific information about prognosis is critical in the management of a FTASD. Disease modeling lends itself well to these needs and allows improved shared decision-making. Our model was externally validated and can predict specific outcomes. As a publically available resource, it will allow physicians to accurately predict the expected outcome of treatment based on covariates, patient demographics, and their own surgical success rates.}, }
@article {pmid21274688, year = {2011}, author = {Tartaglia, MC and Rosen, HJ and Miller, BL}, title = {Neuroimaging in dementia.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {8}, number = {1}, pages = {82-92}, pmid = {21274688}, issn = {1878-7479}, support = {P01 AG019724/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/complications/diagnosis ; Dementia/*diagnosis/etiology ; Frontotemporal Dementia/complications/diagnosis ; Humans ; *Magnetic Resonance Imaging/methods ; *Positron-Emission Tomography/methods ; }, abstract = {Dementia is a common illness with an incidence that is rising as the aged population increases. There are a number of neurodegenerative diseases that cause dementia, including Alzheimer's disease, dementia with Lewy bodies, and frontotemporal dementia, which is subdivided into the behavioral variant, the semantic variant, and nonfluent variant. Numerous other neurodegenerative illnesses have an associated dementia, including corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington's disease, progressive supranuclear palsy, multiple system atrophy, Parkinson's disease dementia, and amyotrophic lateral sclerosis. Vascular dementia and AIDS dementia are secondary dementias. Diagnostic criteria have relied on a constellation of symptoms, but the definite diagnosis remains a pathologic one. As treatments become available and target specific molecular abnormalities, differentiating amongst the various primary dementias early on becomes essential. The role of imaging in dementia has traditionally been directed at ruling out treatable and reversible etiologies and not to use imaging to better understand the pathophysiology of the different dementias. Different brain imaging techniques allow the examination of the structure, biochemistry, metabolic state, and functional capacity of the brain. All of the major neurodegenerative disorders have relatively specific imaging findings that can be identified. New imaging techniques carry the hope of revolutionizing the diagnosis of neurodegenerative disease so as to obtain a complete molecular, structural, and metabolic characterization, which could be used to improve diagnosis and to stage each patient and follow disease progression and response to treatment. Structural and functional imaging modalities contribute to the diagnosis and understanding of the different dementias.}, }
@article {pmid21259343, year = {2011}, author = {Guidubaldi, A and Fasano, A and Ialongo, T and Piano, C and Pompili, M and Mascianà, R and Siciliani, L and Sabatelli, M and Bentivoglio, AR}, title = {Botulinum toxin A versus B in sialorrhea: a prospective, randomized, double-blind, crossover pilot study in patients with amyotrophic lateral sclerosis or Parkinson's disease.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {26}, number = {2}, pages = {313-319}, doi = {10.1002/mds.23473}, pmid = {21259343}, issn = {1531-8257}, support = {GGP10121/TI_/Telethon/Italy ; }, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*complications ; Botulinum Toxins/*therapeutic use ; Botulinum Toxins, Type A/*therapeutic use ; Cross-Over Studies ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Parkinson Disease/*complications ; Pilot Projects ; Prospective Studies ; Sialorrhea/complications/*therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: Either botulinum toxins (BoNTs) A and B have been used for improving drooling in different neurological conditions.<br><br>METHODS: Consecutive patients affected by Amyotrophic Lateral Sclerosis (ALS) or Parkinson's Disease (PD) accompanied by severe drooling were randomized to receive botulinum neurotoxin type A (BoNT-A) or B (BoNT-B) injections into the salivary glands. Following the first treatment, when sialorrhea returned to baseline (at least three months after the first injection), subjects were re-treated with the other serotype. Ultrasound-guided injections into parotid and submandibular glands were bilaterally performed: total doses were 250 U BoNT-A (Dysport) and 2500 U BoNT-B (Neurobloc). Objective (cotton roll weight) and subjective (ad hoc clinical scales) evaluations were performed at baseline, after 1 and 4 weeks, and every 4 weeks until drooling returned to baseline.<br><br>RESULTS: Twenty-seven patients (15 ALS and 12 PD) were enrolled, fourteen completed the study. BoNT-A and BoNT-B treatments gave both subjective and objective improvements in all patients. The latency was significantly shorter after BoNT-B treatments (3.2 &#xb1; 3.7 days) compared to BoNT-A (6.6 &#xb1; 4.1 days; P = 0.002). The mean benefit duration was similar at 75 and 90 days for BoNT-A and BoNT-B, respectively (P = NS). The only toxin-related side effect was a change to saliva thickness.<br><br>CONCLUSIONS: Either 250 U Dysport or 2500 U Neurobloc have similar effectiveness and safety in controlling sialorrhea. BoNT-B has a shorter latency and comparable duration. Cost analysis, considering the doses used in this study protocol favored BoNT-B treatment.}, }
@article {pmid21258799, year = {2011}, author = {Padovan, M and Caniatti, LM and Trotta, F and Govoni, M}, title = {Concomitant rheumatoid arthritis and amyotrophic lateral sclerosis: report of two new cases and review of literature.}, journal = {Rheumatology international}, volume = {31}, number = {6}, pages = {715-719}, pmid = {21258799}, issn = {1437-160X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*pathology ; Antibodies, Monoclonal/therapeutic use ; Antirheumatic Agents/therapeutic use ; Arthritis, Rheumatoid/complications/drug therapy/*pathology ; Bulbar Palsy, Progressive/etiology/pathology ; Female ; Humans ; Infliximab ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors ; }, abstract = {To describe a rare association between rheumatoid arthritis (RA) and amyotrophic lateral sclerosis (ALS). Two new cases of patients with RA who developed amyotrophic lateral sclerosis (ALS), one receiving anti-TNFα agents, were reported. Only other five cases of this rare association have been previously described in literature. The simultaneous presence of the two diseases represents a difficult diagnostic challenge because RA may mimic some musculoskeletal symptoms of ALS. There is no evidence in favor of a common pathophysiologic mechanism, and thus the possibility of a fortuitous association must be raised. A neurotoxic side effect of various drugs for RA treatment could be considered. Casual or causal association remains a difficult choice. The possibility of a coincidental association must be raised but neurologic side effects of TNFα blockers lead to discussion.}, }
@article {pmid21254083, year = {2011}, author = {Chiò, A and Mora, G and La Bella, V and Caponnetto, C and Mancardi, G and Sabatelli, M and Siciliano, G and Silani, V and Corbo, M and Moglia, C and Calvo, A and Mutani, R and Rutella, S and Gualandi, F and Melazzini, M and Scimè, R and Petrini, M and Bondesan, P and Garbelli, S and Mantovani, S and Bendotti, C and Tarella, C and , }, title = {Repeated courses of granulocyte colony-stimulating factor in amyotrophic lateral sclerosis: clinical and biological results from a prospective multicenter study.}, journal = {Muscle &amp; nerve}, volume = {43}, number = {2}, pages = {189-195}, doi = {10.1002/mus.21851}, pmid = {21254083}, issn = {1097-4598}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/*drug therapy ; Cytokines/blood/cerebrospinal fluid ; Disability Evaluation ; Female ; Follow-Up Studies ; Granulocyte Colony-Stimulating Factor/blood/cerebrospinal fluid/*therapeutic use ; Humans ; Male ; Middle Aged ; Pilot Projects ; Prospective Studies ; Surveys and Questionnaires ; Treatment Outcome ; }, abstract = {Granulocyte colony-stimulating factor (G-CSF) induces a transient mobilization of hematopoietic progenitor cells from bone marrow to peripheral blood. Our aim was to evaluate safety of repeated courses of G-CSF in patients with amyotrophic lateral sclerosis (ALS), assessing disease progression and changes in chemokine and cytokine levels in serum and cerebrospinal fluid (CSF). Twenty-four ALS patients entered an open-label, multicenter trial in which four courses of G-CSF and mannitol were administered at 3-month intervals. Levels of G-CSF were increased after treatment in the serum and CSF. Few and transitory adverse events were observed. No significant reduction of the mean monthly decrease in ALSFRS-R score and forced vital capacity was observed. A significant reduction in CSF levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-17 (IL-17) was observed. G-CSF treatment was safe and feasible in a multicenter series of ALS patients. A decrease in the CSF levels of proinflammatory cytokines MCP-1 and IL-17 was found, indicating a G-CSF-induced central anti-inflammatory response.}, }
@article {pmid21252621, year = {2011}, author = {Nassif, M and Hetz, C}, title = {Targeting autophagy in ALS: a complex mission.}, journal = {Autophagy}, volume = {7}, number = {4}, pages = {450-453}, doi = {10.4161/auto.7.4.14700}, pmid = {21252621}, issn = {1554-8635}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Autophagy/*physiology ; Disease Models, Animal ; Lysosomes/metabolism ; Mice ; Mice, Knockout ; Models, Biological ; Mutation ; Neurodegenerative Diseases/metabolism ; Neurons/pathology ; Protein Denaturation ; Protein Folding ; }, abstract = {Several neurodegenerative diseases share a common neuropathology, primarily featuring the presence of abnormal protein inclusions in the brain containing specific misfolded proteins. Strategies to decrease the load of protein aggregates and oligomers are considered relevant targets for therapeutic intervention. Many studies indicate that macroautophagy is a selective and efficient mechanism for the degradation of misfolded mutant proteins related to neurodegeneration, without affecting the levels of the corresponding wild-type form. In fact, activation of autophagy by rapamycin treatment decreases the accumulation of protein aggregates and alleviates disease features in animal models of Huntington disease and other disorders affecting the nervous system. Recent evidence, however, indicates that the expression of several disease-related genes may actually impair autophagy activity at different levels, including omegasome formation, substrate recognition, lysosomal acidity and autophagosome membrane nucleation. A recent report from Zhang and co-workers indicates that treatment of an amyotrophic lateral sclerosis (ALS) mouse model with rapamycin actually exacerbates neuronal loss and disease progression, associated with enhanced apoptosis. This study reflects the need for a better understanding of the contribution of autophagy to ALS and other neurodegenerative diseases since this pathway may not only operate as a cleaning-up mechanism. Then, autophagy impairment may be part of the pathological mechanisms underlying the disease, whereas augmenting autophagy levels above a certain threshold could lead to detrimental effects in neuronal function and survival. Combinatorial strategies to repair the autophagy deficit and also enhance the activation of the pathway may result in a beneficial impact to decrease the content of protein aggregates and damaged organelles, improving neuronal function and survival.}, }
@article {pmid21252034, year = {2011}, author = {Frost, J and Okun, S and Vaughan, T and Heywood, J and Wicks, P}, title = {Patient-reported outcomes as a source of evidence in off-label prescribing: analysis of data from PatientsLikeMe.}, journal = {Journal of medical Internet research}, volume = {13}, number = {1}, pages = {e6}, pmid = {21252034}, issn = {1438-8871}, mesh = {Amitriptyline/adverse effects/therapeutic use ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Benzhydryl Compounds/therapeutic use ; Cognition Disorders/drug therapy ; Community Networks/statistics &amp; numerical data ; Decision Making, Organizational ; Fatigue/drug therapy ; Humans ; Internet ; Modafinil ; *Off-Label Use ; Patient-Centered Care/organization &amp; administration ; *Patients ; Saliva/drug effects/metabolism ; *Self Report ; Sleep Stages/drug effects ; Treatment Outcome ; }, abstract = {BACKGROUND: Evaluating a new use for an existing drug can be expensive and time consuming. Providers and patients must all too often rely upon their own individual-level experience to inform clinical practice, which generates only anecdotal and unstructured data. While academic-led clinical trials are occasionally conducted to test off-label uses of drugs with expired patents, this is relatively rare. In this work, we explored how a patient-centered online research platform could supplement traditional trials to create a richer understanding of medical products postmarket by efficiently aggregating structured patient-reported data. PatientsLikeMe is a tool for patients, researchers, and caregivers (currently 82,000 members across 11 condition-based communities) that helps users make treatment decisions, manage symptoms, and improve outcomes. Members enter demographic information, longitudinal treatment, symptoms, outcome data, and treatment evaluations. These are reflected back as longitudinal health profiles and aggregated reports. Over the last 3 years, patients have entered treatment histories and evaluations on thousands of medical products. These data may aid in evaluating the effectiveness and safety of some treatments more efficiently and over a longer period of time course than is feasible through traditional trials.<br><br>OBJECTIVE: The objective of our study was to examine the illustrative cases of amitriptyline and modafinil - drugs commonly used off-label.<br><br>METHODS: We analyzed patient-reported treatment histories and drug evaluations for each drug, examining prevalence, treatment purpose, and evaluations of effectiveness, side effects, and burden.<br><br>RESULTS: There were 1948 treatment histories for modafinil and 1394 treatment reports for amitriptyline reported across five PatientsLikeMe communities (multiple sclerosis, Parkinson's disease, mood conditions, fibromyalgia/chronic fatigue syndrome, and amyotrophic lateral sclerosis). In these reports, the majority of members reported taking the drug for off-label uses. Only 34 of the 1755 (1%) reporting purpose used modafinil for an approved purpose (narcolepsy or sleep apnea). Only 104 out of 1197 members (9%) reported taking amitriptyline for its approved indication, depression. Members taking amitriptyline for off-label purposes rated the drug as more effective than those who were taking it for its approved indication. While dry mouth is a commonly reported side effect of amitriptyline for most patients, 88 of 220 (40%) of people with amyotrophic lateral sclerosis on the drug reported taking advantage of this side effect to treat their symptom of excess saliva.<br><br>CONCLUSIONS: Patient-reported outcomes, like those entered within PatientsLikeMe, offer a unique real-time approach to understand utilization and performance of treatments across many conditions. These patient-reported data can provide a new source of evidence about secondary uses and potentially identify targets for treatments to be studied systematically in traditional efficacy trials.}, }
@article {pmid21249229, year = {2011}, author = {Baratchi, S and Kanwar, RK and Kanwar, JR}, title = {Survivin mutant protects differentiated dopaminergic SK-N-SH cells against oxidative stress.}, journal = {PloS one}, volume = {6}, number = {1}, pages = {e15865}, pmid = {21249229}, issn = {1932-6203}, mesh = {Antioxidants ; Cell Death/drug effects/genetics ; Cell Line, Tumor ; Dopamine/metabolism ; Humans ; Hydrogen Peroxide ; Inhibitor of Apoptosis Proteins/*pharmacokinetics ; Mutant Proteins/*pharmacology ; *Neurons ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/*drug effects/genetics ; Survivin ; }, abstract = {Oxidative stress is due to an imbalance of antioxidant/pro-oxidant homeostasis and is associated with the progression of several neurological diseases, including Parkinson's and Alzheimer's disease and amyotrophic lateral sclerosis. Furthermore, oxidative stress is responsible for the neuronal loss and dysfunction associated with disease pathogenesis. Survivin is a member of the inhibitors of the apoptosis (IAP) family of proteins, but its neuroprotective effects have not been studied. Here, we demonstrate that SurR9-C84A, a survivin mutant, has neuroprotective effects against H2O2-induced neurotoxicity. Our results show that H2O2 toxicity is associated with an increase in cell death, mitochondrial membrane depolarisation, and the expression of cyclin D1 and caspases 9 and 3. In addition, pre-treatment with SurR9-C84A reduces cell death by decreasing both the level of mitochondrial depolarisation and the expression of cyclin D1 and caspases 9 and 3. We further show that SurR9-C84A increases the antioxidant activity of GSH-peroxidase and catalase, and effectively counteracts oxidant activity following exposure to H2O2. These results suggest for the first time that SurR9-C84A is a promising treatment to protect neuronal cells against H2O2-induced neurotoxicity.}, }
@article {pmid21243238, year = {2010}, author = {Chieia, MA and Oliveira, AS and Silva, HC and Gabbai, AA}, title = {Amyotrophic lateral sclerosis: considerations on diagnostic criteria.}, journal = {Arquivos de neuro-psiquiatria}, volume = {68}, number = {6}, pages = {837-842}, doi = {10.1590/s0004-282x2010000600002}, pmid = {21243238}, issn = {1678-4227}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis ; Electromyography ; False Negative Reactions ; Female ; Humans ; Male ; Middle Aged ; Neurologic Examination ; Young Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, compromising the motor neuron, characterized by progressive muscle weakness, with reserved prognosis. The diagnosis is based on inclusion and exclusion clinical criteria, since there is no specific confirmation test. The objective of this research is to critically examine the main diagnosis instrument - El Escorial revisited, from the World Federation of Neurology (1998). Of the 540 patients with initial ALS diagnosis, either probable or definite, seen at UNIFESP-EPM, 190 underwent thorough investigation, following regular clinical and therapeutic treatment for over two years. Thirty patients (15.78%) had their diagnosis completely changed. The false-positive diagnoses were related to: early age, clinical presentation of symmetry, weakness greater than atrophy, symptomatic exacerbation. In addition, three patients with myasthenia gravis developed framework for ALS, suggesting the post-synaptic disability as a sign of early disease.}, }
@article {pmid21237187, year = {2011}, author = {Hemendinger, RA and Armstrong, EJ and Brooks, BR}, title = {Methyl Vitamin B12 but not methylfolate rescues a motor neuron-like cell line from homocysteine-mediated cell death.}, journal = {Toxicology and applied pharmacology}, volume = {251}, number = {3}, pages = {217-225}, doi = {10.1016/j.taap.2011.01.003}, pmid = {21237187}, issn = {1096-0333}, mesh = {Animals ; Apoptosis/drug effects ; Caspase 3/drug effects/metabolism ; Caspase 7/drug effects/metabolism ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Homocysteine/administration &amp; dosage/*toxicity ; Inhibitory Concentration 50 ; Mice ; Motor Neurons/*drug effects/metabolism ; Neuroblastoma/metabolism ; Neuroprotective Agents/administration &amp; dosage/pharmacology ; Reactive Oxygen Species/metabolism ; Tetrahydrofolates/administration &amp; dosage/*pharmacology ; Time Factors ; Vitamin B 12/administration &amp; dosage/*analogs &amp; derivatives/pharmacology ; Vitamin B Complex/administration &amp; dosage/*pharmacology ; }, abstract = {Homocysteine is an excitatory amino acid implicated in multiple diseases including amyotrophic lateral sclerosis (ALS). Information on the toxicity of homocysteine in motor neurons is limited and few studies have examined how this toxicity can be modulated. In NSC-34D cells (a hybrid cell line derived from motor neuron-neuroblastoma), homocysteine induces apoptotic cell death in the millimolar range with a TC50 (toxic concentration at which 50% of maximal cell death is achieved) of 2.2 mM, confirmed by activation of caspase 3/7. Induction of apoptosis was independent of short-term reactive oxygen species (ROS) generation. Methyl Vitamin B12 (MeCbl) and methyl tetrahydrofolate (MTHF), used clinically to treat elevated homocysteine levels, were tested for their ability to reverse homocysteine-mediated motor neuron cell death. MeCbl in the micromolar range was able to provide neuroprotection (2 h pretreatment prior to homocysteine) and neurorescue (simultaneous exposure with homocysteine) against millimolar homocysteine with an IC50 (concentration at which 50% of maximal cell death is inhibited) of 0.6 μM and 0.4 μM, respectively. In contrast, MTHF (up to 10 μM) had no effect on homocysteine-mediated cell death. MeCbl inhibited caspase 3/7 activation by homocysteine in a time- and dose-dependent manner, whereas MTHF had no effect. We conclude that MeCbl is effective against homocysteine-induced cell death in motor neurons in a ROS-independent manner, via a reduction in caspase activation and apoptosis. MeCbl decreases Hcy induced motor neuron death in vitro in a hybrid cell line derived from motor neuron-neuroblastoma and may play a role in the treatment of late stage ALS where HCy levels are increased in animal models of ALS.}, }
@article {pmid21232601, year = {2011}, author = {D'Antoni, S and Berretta, A and Seminara, G and Longone, P and Giuffrida-Stella, AM and Battaglia, G and Sortino, MA and Nicoletti, F and Catania, MV}, title = {A prolonged pharmacological blockade of type-5 metabotropic glutamate receptors protects cultured spinal cord motor neurons against excitotoxic death.}, journal = {Neurobiology of disease}, volume = {42}, number = {3}, pages = {252-264}, doi = {10.1016/j.nbd.2011.01.013}, pmid = {21232601}, issn = {1095-953X}, mesh = {Analysis of Variance ; Animals ; Astrocytes/cytology/drug effects/metabolism ; Blotting, Western ; Brain-Derived Neurotrophic Factor/metabolism ; Cell Death/*drug effects ; Cells, Cultured ; Chromones/pharmacology ; Enzyme-Linked Immunosorbent Assay ; Excitatory Amino Acid Agonists/pharmacology ; Excitatory Amino Acid Antagonists/pharmacology ; Immunohistochemistry ; Motor Neurons/cytology/*drug effects/metabolism ; Neuroprotective Agents/pharmacology ; Pyridines/pharmacology ; Rats ; Rats, Wistar ; Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate/antagonists &amp; inhibitors/*metabolism ; Spinal Cord/cytology/*drug effects/metabolism ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology ; }, abstract = {The causes of amyotrophic lateral sclerosis (ALS) are mostly undefined; however, excitotoxic injury and astrogliosis may contribute to motor neuron (MN) degeneration. Group I metabotropic glutamate (mGlu) receptors are over-expressed in reactive astrocytes in ALS, but the functional significance of this over-expression is presently unknown. We examined the role of group I mGlu receptors on excitotoxic death of spinal cord MNs grown in cultures enriched of astrocytes bearing a reactive phenotype. A prolonged exposure to the selective non-competitive mGlu5 receptor antagonist MPEP reduced AMPA-mediated toxicity and cobalt uptake in MNs. Expression levels of the GluR1 (but not GluR2) AMPA receptor subunit and levels of brain-derived neurotrophic factor (BDNF) were reduced in mixed spinal cord cultures pretreated with MPEP. In addition, neuroprotection by MPEP was less than additive with that produced by a neutralizing anti-BDNF antibody and a treatment with exogenous BDNF masked the protective effect of MPEP, suggesting that mGlu5 receptors and BDNF converge in facilitating excitotoxic MN death. The protective effect of MPEP was absent in cultures with a reduced number of astrocytes. We suggest that blocking astrocytic mGlu5 receptors is a potential therapeutic strategy in ALS.}, }
@article {pmid21228095, year = {2011}, author = {LeBon, B and Fisher, S}, title = {Case report: Maintaining and withdrawing long-term invasive ventilation in a patient with MND/ALS in a home setting.}, journal = {Palliative medicine}, volume = {25}, number = {3}, pages = {262-265}, doi = {10.1177/0269216310389224}, pmid = {21228095}, issn = {1477-030X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*complications ; Caregivers/education ; Dyspnea/therapy ; *Home Care Services ; Humans ; Hypnotics and Sedatives/administration &amp; dosage ; Male ; Quality of Life ; Respiration, Artificial/*methods ; Respiratory Insufficiency/etiology/*therapy ; Terminal Care/*methods ; *Withholding Treatment/standards ; }, abstract = {Long-term home-based invasive ventilation in patients with motor neurone disease/amyotrophic lateral sclerosis (MND/ALS) remains rare in the UK. We describe a case of an MND/ALS patient who was treated with long-term invasive ventilation at home but subsequently requested its withdrawal despite a seemingly stable period of his illness. We also discuss the impact of the delivery of this treatment and its withdrawal on his carers, primary healthcare team, community trust managers and specialist palliative care team.}, }
@article {pmid21225518, year = {2010}, author = {Gołąb-Janowska, M and Honczarenko, K and Stankiewicz, J}, title = {Usefulness of the ALSAQ-5 scale in evaluation of quality of life in amyotrophic lateral sclerosis.}, journal = {Neurologia i neurochirurgia polska}, volume = {44}, number = {6}, pages = {560-566}, doi = {10.1016/s0028-3843(14)60153-5}, pmid = {21225518}, issn = {0028-3843}, mesh = {*Activities of Daily Living ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*psychology ; Disability Evaluation ; Female ; *Health Status ; Humans ; Male ; Middle Aged ; *Quality of Life ; Surveys and Questionnaires/*standards ; }, abstract = {BACKGROUND AND PURPOSE: The evaluation of quality of life (QoL) is one of the most important factors in complex care of patients. The aim of the study was to estimate the usefulness of the shortened QoL-evaluating scale ALSAQ-5 in patients with amyotrophic lateral sclerosis and to establish the relationship between QoL and age, sex, duration of the disease, education and treatment.<br><br>MATERIAL AND METHODS: Forty-four patients (24 males and 20 females) aged between 34 and 81 years (mean 58.9) were studied. The QoL was evaluated with the ALSAQ-40 and ALSAQ-5 scales. Patients could score between 0 and 100 pts in both scales (higher score denotes worse QoL). Mann-Whitney U-test, Wilcoxon test, Kolmogorov-Smirnov test and Spearman rank correlation coefficient were used for statistical analysis.<br><br>RESULTS: The QoL was worsened by limited physical mobi-lity (ALSAQ-40: 22.5-100 pts, mean 80.8; ALSAQ-5: 25-100 pts, mean 88.6), reduced daily living/independence (ALSAQ-40: 7.5-100 pts, mean 76.0; ALSAQ-5: 0-100 pts, mean 75), communication disturbances (ALSAQ-40: 17.9-100 pts, mean 75.2; ALSAQ-5: 0-100, mean 73.9), and emotional functioning (ALSAQ-40: 5-100 pts, mean 64.9; ALSAQ-5: 0-100, mean 73.9). Eating and drinking dysfunctions (ALSAQ-40: 0-100 pts, mean 66.3; ALSAQ-5: 0-100, mean 67) had a smaller influence on QoL.<br><br>CONCLUSIONS: Initial analysis shows that ALSAQ-5 is a sensitive and reliable instrument for the estimation of QoL of patients with amyotrophic lateral sclerosis. As there are no statistical differences in QoL estimation using ALSAQ-40 and ALSAQ-5, ALSAQ-5 seems to be more useful in clinical practice.}, }
@article {pmid21222602, year = {2011}, author = {Budini, M and Baralle, FE and Buratti, E}, title = {Regulation of gene expression by TDP-43 and FUS/TLS in frontotemporal lobar degeneration.}, journal = {Current Alzheimer research}, volume = {8}, number = {3}, pages = {237-245}, doi = {10.2174/156720511795563719}, pmid = {21222602}, issn = {1875-5828}, support = {GGP06147/TI_/Telethon/Italy ; }, mesh = {Animals ; DNA-Binding Proteins/*genetics/metabolism ; Frontotemporal Lobar Degeneration/*genetics/metabolism ; Gene Expression Regulation/*genetics ; Humans ; RNA-Binding Protein FUS/*genetics/*physiology ; }, abstract = {Two proteins have recently received considerable attention in the neurodegenerative research field: TDP-43 and FUS/TLS. The reason is that both proteins have been found to represent major protein components of the intracellular inclusions occurring in the neuronal tissues of patients affected by Fronto Temporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. One of the most interesting features of this discovery is that both proteins have in common several structural properties. In particular, they are multifunctional RNA-binding proteins (RBPs) already known to play a role in several cellular processes such as transcription, pre-mRNA splicing, and mRNA stability. The potential consequences of changes in their intracellular localization and protein modification status (phosphorylation, ubiquitination, and cleavage) on neuronal metabolism represent one of the major research challenges faced today by researchers. There is hope that a detailed knowledge of the gain- or loss-of-function mechanisms mediated by alterations in these proteins in the neuronal environment may provide novel therapeutic strategies for the treatment of these diseases. Here, we aim to provide an updated review of ways by which TDP-43 and FUS/TLS influence gene expression. In particular, we will focus on the characterized properties of both proteins that involve gene transcription and also RNA splicing, transport and stability processes.}, }
@article {pmid21222600, year = {2011}, author = {Ferrari, R and Kapogiannis, D and Huey, ED and Momeni, P}, title = {FTD and ALS: a tale of two diseases.}, journal = {Current Alzheimer research}, volume = {8}, number = {3}, pages = {273-294}, pmid = {21222600}, issn = {1875-5828}, support = {R99 AG999999/AG/NIA NIH HHS/United States ; Z99 AG999999/ImNIH/Intramural NIH HHS/United States ; ZIA AG000975/ImNIH/Intramural NIH HHS/United States ; ZIA AG000975-02/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/epidemiology/*genetics/*pathology ; Comorbidity ; Frontotemporal Dementia/epidemiology/*genetics/*pathology ; Humans ; }, abstract = {The first reports of disorders that in terms of cognitive and behavioral symptoms resemble frontotemporal dementia (FTD) and in terms of motor symptoms resemble amyotrophic lateral sclerosis (ALS) bring us back to the second half of the 1800s. Over the last 150 years, and especially in the last two decades, there has been growing evidence that FTD signs can be seen in patients primarily diagnosed with ALS, implying clinical overlap among these two disorders. In the last decade pathological investigations and genetic screening have contributed tremendously in elucidating the pathology and genetic variability associated with FTD and ALS. To the most important recentdiscoveries belong TAR DNA binding protein [TARDBP or TDP-43] and the fused in sarcoma gene [FUS] and their implication in these disorders.FTD and ALS are the focus of this review which aims to 1. summarize clinical features by describing the diagnostic criteria and specific symptomatology, 2. describe the morphological aspects and related pathology, 3. describe the genetic factors associated with the diseases and 4. summarize the current status of clinical trials and treatment options. A better understanding of the clinical, pathological and genetic features characterizing FTD and ALS will shed light into overlaps among these two disorders and the underpinning mechanisms that contribute to the onset and development. Nevertheless, advancements in the knowledge of the biology of these two disorders will help developing novel and, hopefully, more effective diagnostic and treatment options.}, }
@article {pmid21218003, year = {2010}, author = {Kumar, SP and Jim, A}, title = {Physical therapy in palliative care: from symptom control to quality of life: a critical review.}, journal = {Indian journal of palliative care}, volume = {16}, number = {3}, pages = {138-146}, pmid = {21218003}, issn = {1998-3735}, abstract = {Physiotherapy is concerned with identifying and maximizing movement potential, within the spheres of promotion, prevention, treatment and rehabilitation. Physical therapists practice in a broad range of inpatient, outpatient, and community-based settings such as hospice and palliative care centers where as part of a multidisciplinary team of care, they address the physical and functional dimensions of the patients' suffering. Physiotherapy treatment methods like therapeutic exercise, electrical modalities, thermal modalities, actinotherapy, mechanical modalities, manual physical therapy and assistive devices are useful for a range of life-threatening and life-limiting conditions like cancer and cancer-associated conditions; HIV; neurodegenerative disorders like amyotrophic lateral sclerosis, multiple sclerosis; respiratory disorders like idiopathic pulmonary fibrosis; and altered mental states. The professional armamentarium is still expanding with inclusion of other miscellaneous techniques which were also proven to be effective in improving quality of life in these patients. Considering the scope of physiotherapy in India, and in palliative care, professionals in a multidisciplinary palliative care team need to understand and mutually involve toward policy changes to successfully implement physical therapeutic palliative care delivery.}, }
@article {pmid21215776, year = {2011}, author = {Maraldi, T and Riccio, M and Zambonin, L and Vinceti, M and De Pol, A and Hakim, G}, title = {Low levels of selenium compounds are selectively toxic for a human neuron cell line through ROS/RNS increase and apoptotic process activation.}, journal = {Neurotoxicology}, volume = {32}, number = {2}, pages = {180-187}, doi = {10.1016/j.neuro.2010.10.008}, pmid = {21215776}, issn = {1872-9711}, mesh = {Apoptosis/drug effects/*physiology ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; Dose-Response Relationship, Drug ; Humans ; Nerve Degeneration/chemically induced/metabolism ; Neurons/drug effects/*metabolism ; Reactive Oxygen Species/*metabolism ; Selenium Compounds/*administration &amp; dosage/*toxicity ; }, abstract = {Organic and inorganic selenium compounds were used to examine whether low selenium concentration is able to trigger apoptotic degeneration in a human neuron cell line in vitro and to explore changes in reactive oxygen and nitrogen species and antioxidant protein content during the apoptotic processes. The results indicated that: (1) SKNBE neuroblastoma cells treated with sodium selenite, sodium selenate and seleno-methionine (0.1, 0.5 and 0.5 μM, respectively) for 24h exhibited a viability decrease, unlike kidney or prostatic cells; (2) the PARP (poly-ADP-ribose-polymerase) degradation and caspase activation detected by Western blot and flow cytometry fluorimetric examination showed induction of apoptosis; (3) during selenium treatment, a ROS/RNS increase occurred despite the GSH increment, as revealed by fluorimetric analysis; (4) the RNS production could be blocked by a peroxynitrite scavenger; (5) after exposure to selenium compounds, the concentration of nitric oxide synthase, manganese superoxide dismutase (SOD2), P-NF-kB (phospho nuclear factor kB), glutathione reductase and glutathione peroxidase increased, whereas that of P-ERK (phospho extracellular signal-regulated kinase) decreased; (6) selenium presence induced copper/zinc superoxide dismutase (SOD1) translocation into mitochondria, in a way similar to what is observed in amyotrophic lateral sclerosis (ALS). This study supports epidemiologic studies showing the possibility that excess environmental exposure to Se represents a risk factor for a devastating human neurodegenerative disease.}, }
@article {pmid21207577, year = {2011}, author = {Nakashima, S and Ando, H and Imamura, A and Yuki, N and Ishida, H and Kiso, M}, title = {A first total synthesis of a hybrid-type ganglioside associated with amyotrophic lateral sclerosis-like disorder.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {17}, number = {2}, pages = {588-597}, doi = {10.1002/chem.201002184}, pmid = {21207577}, issn = {1521-3765}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Brain/metabolism ; Cattle ; Ceramides/metabolism ; *Gangliosides/blood/chemical synthesis/chemistry/immunology ; Humans ; Naphthols ; Nuclear Magnetic Resonance, Biomolecular ; Trisaccharides/blood/chemistry ; }, abstract = {The hybrid ganglioside X1, which was identified in the bovine brain, was synthesized for the first time. Ganglioside X1 is believed to be involved in the development of amyotrophic lateral sclerosis-like disorders in patients with neurological disorders after treatment with bovine brain gangliosides. A convergent approach using two branched glycan units, the GM2-core trisaccharide and the lacto-ganglio tetrasaccharide, efficiently provided the highly branched heptasaccharide part of ganglioside X1, which was conjugated with the ceramide part to produce the protected ganglioside X1. Global deprotection delivered homogenous ganglioside X1, with which serum from the patient was reacted.}, }
@article {pmid21198339, year = {2011}, author = {Møller, E and Karlsborg, M and Bardow, A and Lykkeaa, J and Nissen, FH and Bakke, M}, title = {Treatment of severe drooling with botulinum toxin in amyotrophic lateral sclerosis and Parkinson's disease: efficacy and possible mechanisms.}, journal = {Acta odontologica Scandinavica}, volume = {69}, number = {3}, pages = {151-157}, doi = {10.3109/00016357.2010.545035}, pmid = {21198339}, issn = {1502-3850}, mesh = {Acetylcholine/metabolism ; Aged ; Algorithms ; Amyotrophic Lateral Sclerosis/*complications ; Botulinum Toxins, Type A/administration &amp; dosage/pharmacology/*therapeutic use ; Female ; Humans ; Injections ; Male ; Neuromuscular Agents/administration &amp; dosage/pharmacology/*therapeutic use ; Parkinson Disease/*complications ; Parotid Gland/drug effects ; Prospective Studies ; Saliva/chemistry/metabolism ; Salivation/drug effects ; Secretory Rate/drug effects ; Sialorrhea/*drug therapy/etiology ; Submandibular Gland/drug effects ; Ultrasonography, Interventional ; }, abstract = {OBJECTIVE: Drooling in neurodegenerative diseases is associated with social impediment. Previous treatments of drooling have little effect or are effective but with severe side effects. Therefore, there is a need to test new methods such as the use of botulinum toxin type A (BTX-A).<br><br>MATERIAL AND METHODS: This open, prospective study deals with treatment of drooling in 12 patients with amyotrophic lateral sclerosis and three with Parkinson's disease. Injections of BTX-A (Botox) were given into the parotid (25-40 units) and submandibular (15-30 units) glands with ultrasonographic guidance. After BTX-A treatment, the patients were followed for 2 months with evaluations every second week by means of self-assessed rating scales for drooling intensity, discomfort and treatment effect, and determination of unstimulated whole saliva (UWS) flow rate, and inorganic and organic UWS composition. The treatment was repeated up to four times, but seven patients dropped out shortly after the first treatment due to marked worsening of their disease-related condition.<br><br>RESULTS: Drooling and flow were reduced (P < 0.05) 2 weeks after treatment, without side-effects. The maximal reductions during the observation period were 40% for drooling and 30% for flow. There was a systematic variation in flow during the observation period, with an initial decrease and then an increase followed by a second decrease. Amylase activity and total protein concentration generally increased with decreasing flow (P &#x2264; 0.03).<br><br>CONCLUSION: Inhibition of acetylcholine release from postganglionic parasympathetic nerve endings by injection of BTX-A into salivary glands seemed useful for secondary sialorrhoea, although cyclic variations in flow may occur, possibly due to transitory sprouting and regeneration.}, }
@article {pmid21193837, year = {2011}, author = {Zhang, X and Li, L and Chen, S and Yang, D and Wang, Y and Zhang, X and Wang, Z and Le, W}, title = {Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model of amyotrophic lateral sclerosis.}, journal = {Autophagy}, volume = {7}, number = {4}, pages = {412-425}, doi = {10.4161/auto.7.4.14541}, pmid = {21193837}, issn = {1554-8635}, mesh = {Adaptor Proteins, Signal Transducing/metabolism ; Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Animals ; Autophagy ; Caspase 3/metabolism ; Disease Models, Animal ; Heat-Shock Proteins/metabolism ; Immunosuppressive Agents/pharmacology ; Mice ; Mitochondria/metabolism ; Motor Neurons/*pathology ; Neurodegenerative Diseases/*pathology ; Poly(ADP-ribose) Polymerases/metabolism ; Sequestosome-1 Protein ; Sirolimus/*pharmacology ; Spinal Cord/metabolism ; Superoxide Dismutase/*physiology ; Superoxide Dismutase-1 ; TOR Serine-Threonine Kinases/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Aberrant protein misfolding may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS) but the detailed mechanisms are largely unknown. Our previous study has shown that autophagy is altered in the mouse model of ALS. In the present study, we systematically investigated the correlation of the autophagic alteration with the motor neurons (MNs) degeneration in the ALS mice. We have demonstrated that the autophagic protein marker LC3-II is markedly and specifically increased in the spinal cord MNs of the ALS mice. Electron microscopy and immunochemistry studies have shown that autophagic vacuoles are significantly accumulated in the dystrophic axons of spinal cord MNs of the ALS mice. All these changes in the ALS mice appear at the age of 90 d when the ALS mice display modest clinical symptoms; and they become prominent at the age of 120 d. The clinical symptoms are correlated with the progression of MNs degeneration. Moreover, we have found that p62/SQSTM1 is accumulated progressively in the spinal cord, indicating that the possibility of impaired autophagic flux in the SOD1(G93A) mice. Furthermore, to our surprise, we have found that treatment with autophagy enhancer rapamycin accelerates the MNs degeneration, shortens the life span of the ALS mice, and has no obvious effects on the accumulation of SOD1 aggregates. In addition, we have demonstrated that rapamycin treatment in the ALS mice causes more severe mitochondrial impairment, higher Bax levels and greater caspase-3 activation. These findings suggest that selective degeneration of MNs is associated with the impairment of the autophagy pathway and that rapamycin treatment may exacerbate the pathological processing through apoptosis and other mechanisms in the ALS mice.}, }
@article {pmid21185943, year = {2011}, author = {Underwood, CK and Kurniawan, ND and Butler, TJ and Cowin, GJ and Wallace, RH}, title = {Non-invasive diffusion tensor imaging detects white matter degeneration in the spinal cord of a mouse model of amyotrophic lateral sclerosis.}, journal = {NeuroImage}, volume = {55}, number = {2}, pages = {455-461}, doi = {10.1016/j.neuroimage.2010.12.044}, pmid = {21185943}, issn = {1095-9572}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Anisotropy ; *Diffusion Tensor Imaging ; Disease Models, Animal ; Disease Progression ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microscopy, Electron, Transmission ; Motor Neurons/pathology ; Nerve Degeneration/*pathology ; Spinal Cord/*pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by selective degeneration of motor neurons. Here we examine the ability of magnetic resonance imaging (MRI) to measure axonal degeneration in the lumbar spinal cord of the SOD1 mouse model of ALS. Diffusion tensor imaging (DTI) was successful in detecting axonal spinal cord damage in vivo. Fractional anisotropy (FA) values were reduced exclusively in the ventral white matter tracts of the lumbar spinal cord of ALS-affected SOD1 mice compared to wild-type littermates, with this effect becoming more pronounced with disease progression. The reduced FA values were therefore limited to white matter tracts arising from the motor neurons, whereas sensory white matter fibers were preserved. Significant decreases in water diffusion parallel to the white matter fibers or axial diffusivity were observed in the SOD1 mice, which can be attributed to the axonal degeneration observed by electron microscopy. At the same time, radial diffusivity perpendicular to the spinal column increased in the SOD1 mice, reflecting reduced myelination. These results demonstrate the usefulness of MRI in tracking disease progression in live animals and will aid in the assessment of treatment efficacy. This method could also potentially be adapted to aid the diagnosis and assessment of ALS progression in humans.}, }
@article {pmid21185345, year = {2011}, author = {Mori, A and Yamashita, S and Uchino, K and Suga, T and Ikeda, T and Takamatsu, K and Ishizaki, M and Koide, T and Kimura, E and Mita, S and Maeda, Y and Hirano, T and Uchino, M}, title = {Derlin-1 overexpression ameliorates mutant SOD1-induced endoplasmic reticulum stress by reducing mutant SOD1 accumulation.}, journal = {Neurochemistry international}, volume = {58}, number = {3}, pages = {344-353}, doi = {10.1016/j.neuint.2010.12.010}, pmid = {21185345}, issn = {1872-9754}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics/*metabolism ; Animals ; Autophagy/genetics ; Cell Line, Tumor ; Down-Regulation/genetics ; Endoplasmic Reticulum/enzymology/*metabolism ; Humans ; Membrane Proteins/*biosynthesis/genetics ; Mice ; Mutation/physiology ; Neurons/enzymology/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; RNA, Messenger/biosynthesis ; Stress, Physiological/*genetics ; Superoxide Dismutase/antagonists &amp; inhibitors/*genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Unfolded protein responses, including induction of stress sensor kinases, chaperones, and apoptotic mediators, are involved in the familial amyotrophic lateral sclerosis (ALS) model related to mutant Cu/Zn superoxide dismutase (SOD1) and sporadic ALS. We hypothesized that the endoplasmic reticulum-resident factor Derlin-1 plays a pivotal role in the regulation of misfolded proteins evoked by mutant SOD1. We show that Derlin-1 overexpression reduced mutant SOD1-induced cell toxicity and increased cell viability by suppressing the activation of the ER stress pathway factors: immunoglobulin-binding protein, activating transcription factor 6 p50, and C/EBP homologous protein. Interestingly, exogenous Derlin-1 resulted in a decrease in the amount of mutant SOD1, and a lesser decrease in that of wild-type SOD1, in transfected cells. Reduced SOD1 protein expression was observed in the microsomal fraction of wild-type and mutant SOD1 cells. Our results indicate that Derlin-1 regulates the turn over of SOD1 by promoting the proteasomal and autophagosomal degradation of SOD1 protein, but not by decreasing mutant SOD1 mRNA levels. Insights into the effects of Derlin-1 on mutant SOD1 may facilitate advancements in the treatment of motor neuron degeneration associated with ALS.}, }
@article {pmid21182524, year = {2011}, author = {Chen, Y and Brew, BJ and Guillemin, GJ}, title = {Characterization of the kynurenine pathway in NSC-34 cell line: implications for amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {118}, number = {5}, pages = {816-825}, doi = {10.1111/j.1471-4159.2010.07159.x}, pmid = {21182524}, issn = {1471-4159}, mesh = {Animals ; Cell Line, Transformed ; Dose-Response Relationship, Drug ; Drug Interactions ; Hydrolases/metabolism ; Interferon-gamma/pharmacology ; Iron Chelating Agents/pharmacology ; Kynurenine/*metabolism ; L-Lactate Dehydrogenase/metabolism ; Mice ; Microglia/drug effects/metabolism ; Motor Neurons/drug effects/*metabolism ; Picolinic Acids/pharmacology ; Signal Transduction/drug effects/*physiology ; Time Factors ; Tryptophan/analogs &amp; derivatives/pharmacology ; Tryptophan Oxygenase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron degenerative disease for which the aetiology is still unknown. The kynurenine pathway (KP) is a major degradative pathway of tryptophan ultimately leading to the production of NAD(+) and is also one of the major regulatory mechanisms of the immune response. The KP is known to be involved in several neuroinflammatory disorders. Among the KP intermediates, quinolinic acid (QUIN) is a potent excitotoxin, while kynurenic acid and picolinic acid are both neuroprotectant. This study aimed to (i) characterize the components of the KP in NSC-34 cells (a rodent motor neuron cell line) and (ii) assess the effects of QUIN on the same cells. RT-PCR and immunocytochemistry were used to characterize the KP enzymes, and lactate dehydrogenase (LDH) test was used to assess the effect of QUIN in the absence and presence of NMDA receptor antagonists, kynurenines and 1-methyl tryptophan. Our data demonstrate that a functional KP is present in NSC-34 cells. LDH tests showed that (i) QUIN toxicity on NSC-34 cells increases with time and concentration; (ii) NMDA antagonists, 2-amino-5-phosphonopentanoic acid, MK-801 and memantine, can partially decrease QUIN toxicity; (iii) kynurenic acid can decrease LDH release in a linear manner, whereas picolinic acid does the same but non-linearly; and (iv) 1-methyl tryptophan is effective in decreasing QUIN release by the rodent microglial cell line BV-2 and thus protects NSC-34 from cell death. There is currently a lack of effective treatment for ALS and our in vitro results provide a novel therapeutic strategy for ALS patients.}, }
@article {pmid21181695, year = {2010}, author = {Ran, Y and Hadad, E and Daher, S and Ganor, O and Kohn, J and Yegorov, Y and Bartal, C and Ash, N and Hirschhorn, G}, title = {QuikClot Combat Gauze use for hemorrhage control in military trauma: January 2009 Israel Defense Force experience in the Gaza Strip--a preliminary report of 14 cases.}, journal = {Prehospital and disaster medicine}, volume = {25}, number = {6}, pages = {584-588}, doi = {10.1017/s1049023x00008797}, pmid = {21181695}, issn = {1049-023X}, mesh = {*Bandages ; Hemorrhage/*therapy ; Hemostatics/*administration &amp; dosage ; Humans ; Israel ; Kaolin/administration &amp; dosage ; *Military Personnel ; *Warfare ; Wounds and Injuries/*therapy ; }, abstract = {BACKGROUND: Standard gauze field dressings and direct pressure occasionally are inadequate for the control of hemorrhage. QuikClot® Combat Gauze™ (QCG) combines surgical gauze with an inorganic material and is approved by the Food and Drug Administration and by the Israeli Standards Institute for external hemorrhage control. The purpose of this article is to report clinical use of this dressing during Operation Cast Lead in the Gaza strip during January 2009.<br><br>METHODS: QuikClot Combat Gauze and the QCG guidelines were issued to advanced life support (ALS) providers during the preparations for the Operation. All cases of injuries involving hemorrhage were reviewed, as well as interviews with the ALS providers (physicians and paramedics) and injured soldiers.<br><br>RESULTS: Fourteen uses of QCG were reported and reviewed (out of a total of 56 hemostatic interventions in 35 cases). Dressings were applied to injuries to the head, neck, axilla, buttocks, abdomen, back, and pelvis in 10 cases, and to extremities in four cases. In 13 cases (93%), injuries were caused by blast or gunshot mechanisms. The success rate was reported as 79% (11/14). Failure to control hemorrhage was reported in three cases in three different locations: neck, buttock, and thigh. All failures were attributed to severe soft tissue and vascular injuries. No complications or adverse events were reported.<br><br>CONCLUSIONS: This report on the clinical field use of the QCG dressing by ALS providers suggests that it is an effective and safe product, and applicable for prehospital treatment of combat casualties. This report further suggests that QCG should be issued to medics as well as ALS providers. Larger clinical investigations are needed to confirm these findings.}, }
@article {pmid21175864, year = {2011}, author = {Mori, F and Tanji, K and Kakita, A and Takahashi, H and Wakabayashi, K}, title = {Enhancement of native and phosphorylated TDP-43 immunoreactivity by proteinase K treatment following autoclave heating.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {31}, number = {4}, pages = {401-404}, doi = {10.1111/j.1440-1789.2010.01184.x}, pmid = {21175864}, issn = {1440-1789}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/metabolism ; Brain/metabolism/pathology ; DNA-Binding Proteins/*metabolism ; *Endopeptidase K ; Frontotemporal Lobar Degeneration/*diagnosis/metabolism ; Humans ; Immunohistochemistry/*methods ; Inclusion Bodies/metabolism ; Middle Aged ; Neuropil Threads/metabolism ; Phosphorylation ; Spinal Cord/metabolism/pathology ; }, abstract = {TDP-43 is a major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 (FTLD-TDP). To evaluate the effectiveness of proteinase K (PK) treatment in antigen retrieval for native and phosphorylated TDP-43 protein, we examined the temporal cortex and spinal cord from patients with sporadic ALS and FTLD-TDP and control subjects. PK treatment following heat retrieval enhanced the immunoreactivity for native TDP-43 in controls as well as for native and phosphorylated TDP-43 in ALS and FTLD-TDP. A significant number of TDP-43-positive neuropil threads were demonstrated in lesions, in which routine immunohistochemistry revealed that the predominant inclusions are cytoplasmic. This retrieval method is the best of immunohistochemical techniques for demonstrating TDP-43 pathology, especially in the neuropil.}, }
@article {pmid21174364, year = {2010}, author = {}, title = {Neuroprotection in amyotrophic lateral sclerosis: from pathology to treatment. Proceedings of a meeting. September 2009. Pisa, Italy.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {3}, pages = {258-382}, pmid = {21174364}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*therapy ; Animals ; Humans ; Neuroprotective Agents/therapeutic use ; }, }
@article {pmid21168638, year = {2010}, author = {Inoue, K and Watanabe, T and Maruoka, N and Kuroki, Y and Takahashi, H and Yoshiba, M}, title = {Japanese-style intensive medical care improves prognosis for acute liver failure and the perioperative management of liver transplantation.}, journal = {Transplantation proceedings}, volume = {42}, number = {10}, pages = {4109-4112}, doi = {10.1016/j.transproceed.2010.09.073}, pmid = {21168638}, issn = {1873-2623}, mesh = {Humans ; Japan ; Liver Failure, Acute/*therapy ; *Liver Transplantation ; *Liver, Artificial ; Perioperative Care ; Prognosis ; Survival Rate ; }, abstract = {The Japanese style of intensive medical care for acute liver failure has yielded high survival rates. The care system comprises artificial liver support (ALS) together with treatment for the underlying disease. Plasma exchange in combination with high-volume hemodiafiltration using an high performance membrane has become the standard ALS system. It is safe, efficiently removing more low and middle molecular weight toxic substances than other methods because of the large volumes of buffer (more than 200 L per session), resulting in recovery from coma in patients with severe fulminant hepatitis, a status comparable with the ahepatic state. This ALS is therefore an effective tool to sustain patients with fulminant hepatitis in a favorable condition until liver function recovers or liver transplantation becomes available. The accompanying treatment for underlying disease serves to limit the liver destruction that hampers regeneration. The treatment has remarkably improved the prognosis for patients with subacute types of fulminant hepatitis, which generally carry a less favorable prognosis than the acute type. This treatment system thus provides more time for physicians to assess the indications for liver transplantation as well as giving the patient a greater chance of undergoing transplantation.}, }
@article {pmid21168408, year = {2011}, author = {Keller, AF and Gravel, M and Kriz, J}, title = {Treatment with minocycline after disease onset alters astrocyte reactivity and increases microgliosis in SOD1 mutant mice.}, journal = {Experimental neurology}, volume = {228}, number = {1}, pages = {69-79}, doi = {10.1016/j.expneurol.2010.12.010}, pmid = {21168408}, issn = {1090-2430}, support = {142739//Canadian Institutes of Health Research/Canada ; 171955//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/*genetics ; Animals ; Astrocytes/drug effects/*metabolism ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Neurologic Mutants ; Mice, Transgenic ; Microglia/drug effects/*metabolism ; Minocycline/pharmacology/*therapeutic use ; Random Allocation ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Treatment Outcome ; }, abstract = {Several reports have demonstrated that attenuation of microglial activation by minocycline, an antimicrobial drug with anti-inflammatory properties, delays disease progression in a mouse model of ALS. However, the negative results obtained in recent clinical trials raised some questions regarding the role of inflammatory response and glial cells as a therapeutic target in ALS. To investigate this controversy we took advantage of a mouse model for live imaging of neuroinflammatory responses in ALS (GFAP-luc/ SOD1(G93A) reporter mouse) and analyzed in real time the effects of minocycline treatment initiated at different stages of the disease. To our surprise, unlike neuroprotection that is conferred when minocycline is administered pre-symptomatically, treatment with minocycline initiated after the disease onset significantly altered glial responses and exaggerated neuroinflammation. Further analysis revealed that the late minocycline treatment was associated with significant induction of the end-stage GFAP-biophotonic signals, expression levels of connexin 43, a major protein of astrocytic gap junction and markers of microglial activation, such as Iba1 and CD68. The results of our study suggest that when administered at later stages of disease, once microglial cells are chronically reactive, minocycline may not have anti-inflammatory properties, and contrary to expectations, may alter astrocyte reactivity and increase microgliosis. Finally, our results further suggest the existence of close interactions/communication between activated microglia and astrocytes in late stage ALS.}, }
@article {pmid21163822, year = {2011}, author = {Rizvanov, AA and Guseva, DS and Salafutdinov, II and Kudryashova, NV and Bashirov, FV and Kiyasov, AP and Yalvaç, ME and Gazizov, IM and Kaligin, MS and Sahin, F and Mukhamedyarov, MA and Palotás, A and Islamov, RR}, title = {Genetically modified human umbilical cord blood cells expressing vascular endothelial growth factor and fibroblast growth factor 2 differentiate into glial cells after transplantation into amyotrophic lateral sclerosis transgenic mice.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {236}, number = {1}, pages = {91-98}, doi = {10.1258/ebm.2010.010172}, pmid = {21163822}, issn = {1535-3699}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/physiopathology/*therapy ; Animals ; *Cord Blood Stem Cell Transplantation/methods ; Electroporation ; Fetal Blood/metabolism/physiology/*transplantation ; Fibroblast Growth Factor 2/biosynthesis/*physiology ; Fluorescent Antibody Technique ; Hematopoietic Stem Cells ; Humans ; Mice ; Mice, Transgenic ; Neuroglia/metabolism/*physiology ; Reverse Transcriptase Polymerase Chain Reaction ; Vascular Endothelial Growth Factor A/biosynthesis/*physiology ; }, abstract = {Current therapy of a number of neuropsychiatric maladies has only symptomatic modality. Effective treatment of these neuro-degenerative diseases, including amyotrophic lateral sclerosis (ALS), may benefit from combined gene/stem-cell approaches. In this report, mononuclear fraction of human umbilical cord blood cells (hUCBCs) were transfected by electroporation with dual plasmid constructs, simultaneously expressing vascular endothelial growth factor 165 (VEGF(165)) and human fibroblast growth factor 2 (FGF(2)) (pBud-VEGF-FGF(2)). These genetically modified hUCBCs were injected retro-orbitally into presymptomatic ALS transgenic animal models ((G)93(A) mice). Lumbar spinal cords of rodents were processed for immunofluoresent staining with antibodies against human nuclear antigen (HNA), oligodendrocyte-specific protein, S100, iba1, neuronal β(3)-tubulin and CD34. Co-localization of HNA and S100 was found in the spinal cord of mice after transplantation of genetically modified hUCBCs over-expressing VEGF-FGF(2). Double staining in control animals treated with unmodified hUCBCs, however, revealed HNA+ cells expressing iba1 and CD34. Neuron-specific β(3)-tubulin or oligodendrocyte-specific protein were not expressed in hUCBCs in either control or experimental mice. These results demonstrate that genetically naïve hUCBCs may differentiate into endothelial (CD34+) and microglial (iba1+) cells; however when over-expressing VEGF-FGF(2), hUCBCs transform into astrocytes (S100+). Autocrine regulation of VEGF and FGF(2) on hUCBCs, signal molecules from dying motor neurons in spinal cord, as well as self-differentiating potential may provide a unique microenvironment for the transformation of hUCBCs into astrocytes that eventually serve as a source of growth factors to enhance the survive potential of surrounding cells in the diseased regions.}, }
@article {pmid21154151, year = {2010}, author = {Cheah, BC and Kiernan, MC}, title = {Dexpramipexole, the R(+) enantiomer of pramipexole, for the potential treatment of amyotrophic lateral sclerosis.}, journal = {IDrugs : the investigational drugs journal}, volume = {13}, number = {12}, pages = {911-920}, pmid = {21154151}, issn = {2040-3410}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Benzothiazoles/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use ; Dopamine Agonists/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use ; Drugs, Investigational/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use ; Humans ; Isomerism ; Pramipexole ; }, abstract = {Dexpramipexole (KNS-760704), the R(+) enantiomer of pramipexole, is under development by Knopp Neurosciences and Biogen Idec as a potential neuroprotective therapy for amyotrophic lateral sclerosis (ALS), a universally fatal neurodegenerative disease. Pramipexole, exclusively the S(-) enantiomer, is a non-ergot dopaminergic autoreceptor agonist that is currently marketed for use in the treatment of Parkinson's disease and restless legs syndrome. Pramipexole has been proposed to exert a broad spectrum of neuroprotective properties, primarily through antioxidant effects, inhibiting apoptotic enzymes and preserving mitochondrial structure and activity. More recent work has suggested that pramipexole possesses anti-excitotoxic properties, raising the possibility of beneficial effects in patients with ALS. However, pramipexole has high intrinsic dopaminergic receptor activity and, consequently, dose-limiting side effects, including orthostatic hypotension and hallucination, are frequent. Dexpramipexole exhibits significantly lower affinity for dopaminergic receptors, thereby making it unlikely to be associated with dopaminergic side effects. In clinical trials to date, dexpramipexole has been safe and well tolerated at doses up to 67-fold higher than the maximum recommended daily dose of pramipexole in patients with Parkinson's disease, and has demonstrated signs of neuroprotective benefit. This report summarizes the chemical and pharmacological properties of dexpramipexole and describes the potential utility of the drug in the pharmaceutical development pipeline.}, }
@article {pmid21151573, year = {2010}, author = {Shimazawa, M and Tanaka, H and Ito, Y and Morimoto, N and Tsuruma, K and Kadokura, M and Tamura, S and Inoue, T and Yamada, M and Takahashi, H and Warita, H and Aoki, M and Hara, H}, title = {An inducer of VGF protects cells against ER stress-induced cell death and prolongs survival in the mutant SOD1 animal models of familial ALS.}, journal = {PloS one}, volume = {5}, number = {12}, pages = {e15307}, pmid = {21151573}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Aniline Compounds/pharmacology ; Animals ; Cell Death ; Cell Survival ; Disease Models, Animal ; Disease Progression ; Endoplasmic Reticulum/*metabolism ; Humans ; Mice ; Mice, Transgenic ; *Mutation ; Oligonucleotide Array Sequence Analysis ; Piperazines/pharmacology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease, and recent evidence has suggested that endoplasmic reticulum (ER) stress signaling is involved in the pathogenesis of ALS. Here we identified a small molecule, SUN N8075, which has a marked protective effect on ER stress-induced cell death, in an in vitro cell-based screening, and its protective mechanism was mediated by an induction of VGF nerve growth factor inducible (VGF): VGF knockdown with siRNA completely abolished the protective effect of SUN N8075 against ER-induced cell death, and overexpression of VGF inhibited ER-stress-induced cell death. VGF level was lower in the spinal cords of sporadic ALS patients than in the control patients. Furthermore, SUN N8075 slowed disease progression and prolonged survival in mutant SOD1 transgenic mouse and rat models of ALS, preventing the decrease of VGF expression in the spinal cords of ALS mice. These data suggest that VGF plays a critical role in motor neuron survival and may be a potential new therapeutic target for ALS, and SUN N8075 may become a potential therapeutic candidate for treatment of ALS.}, }
@article {pmid21147075, year = {2011}, author = {Guo, Y and Zhang, K and Wang, Q and Li, Z and Yin, Y and Xu, Q and Duan, W and Li, C}, title = {Neuroprotective effects of diallyl trisulfide in SOD1-G93A transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Brain research}, volume = {1374}, number = {}, pages = {110-115}, doi = {10.1016/j.brainres.2010.12.014}, pmid = {21147075}, issn = {1872-6240}, mesh = {Allyl Compounds/*therapeutic use ; Amyotrophic Lateral Sclerosis/*enzymology/genetics/*prevention &amp; control ; Animals ; *Disease Models, Animal ; Female ; Garlic ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuroprotective Agents/*therapeutic use ; Oils ; Random Allocation ; Sulfides/*therapeutic use ; Superoxide Dismutase/*biosynthesis/genetics ; }, abstract = {Diallyl trisulfide (DATS) is one of the major constituents in garlic oil and has been documented to transcriptionally activate phase II enzymes. The purpose of this study is to evaluate the effects of DATS in prolonging disease duration and survival in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). SOD1-G93A transgenic mice were randomly divided into DATS-treated group (80mg/kg/d, p.o.) and vehicle-treated group at disease onset stage. Oral administration of DATS beginning at clinical onset stage significantly prolonged disease duration and extended life span for about one week. DATS treatment induced HO-1 and reduced GFAP expression in the lumbar spinal cord of SOD1-G93A transgenic mice. This study indicates that DATS has multifunctional neuroprotective effects in SOD1-G93A transgenic mice.}, }
@article {pmid21144012, year = {2010}, author = {Dantuma, E and Merchant, S and Sugaya, K}, title = {Stem cells for the treatment of neurodegenerative diseases.}, journal = {Stem cell research &amp; therapy}, volume = {1}, number = {5}, pages = {37}, pmid = {21144012}, issn = {1757-6512}, mesh = {Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Cell- and Tissue-Based Therapy/*methods ; Humans ; Multiple Sclerosis/therapy ; Neurodegenerative Diseases/*therapy ; Parkinson Disease/therapy ; *Stem Cell Transplantation ; Stem Cells/metabolism ; }, abstract = {Stem cells offer an enormous pool of resources for the understanding of the human body. One proposed use of stem cells has been as an autologous therapy. The use of stem cells for neurodegenerative diseases has become of interest. Clinical applications of stem cells for Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis will increase in the coming years, and although great care will need to be taken when moving forward with prospective treatments, the application of stem cells is highly promising.}, }
@article {pmid21140194, year = {2011}, author = {Arciello, M and Capo, CR and D'Annibale, S and Cozzolino, M and Ferri, A and Carrì, MT and Rossi, L}, title = {Copper depletion increases the mitochondrial-associated SOD1 in neuronal cells.}, journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine}, volume = {24}, number = {2}, pages = {269-278}, doi = {10.1007/s10534-010-9392-3}, pmid = {21140194}, issn = {1572-8773}, mesh = {Animals ; Blotting, Western ; Cell Line ; Cell Line, Tumor ; Copper/*deficiency ; Humans ; Immunohistochemistry ; Mice ; Mitochondria/drug effects/*metabolism ; Neurons/drug effects/*metabolism ; Superoxide Dismutase/*metabolism ; Superoxide Dismutase-1 ; Trientine/pharmacology ; }, abstract = {The role of copper in the toxicity of mutant copper-dependent enzyme superoxide dismutase (SOD1) found in patients affected with the familial form of amyotrophic lateral sclerosis (fALS) is widely debated. Here we report that treatment of human neuroblastoma cells SH-SY5Y with a specific copper chelator, triethylene tetramine (Trien) induces the decrease of intracellular copper level, paralleled by decreased activity of SOD1. A comparable effect is observed in mouse NSC-34-derived cells, a motoneuronal model, transfected for the inducible expression of either wild-type or G93A mutant human SOD1, one of the mutations associated with fALS. In both cell types, the drop of SOD1 activity is not paralleled by the same extent of decrease in SOD1 protein content. This discrepancy can be explained by the occurrence of a fraction of copper-free SOD1 upon copper depletion, which is demonstrated by the partial recovery of the enzyme activity after the addition of copper sulphate to homogenates of SH-SY5Y cells. Furthermore, copper depletion produces the enrichment of the physiological mitochondrial fraction of SOD1 protein, in both cells models. However, increasing the fraction of mitochondrial, possibly copper-free, mutant human SOD1 does not further alter mitochondrial morphology in NSC-34-derived cells. Thus, copper deficiency is not a factor which may worsen mitochondrial damage, which is one of the earliest events in fALS associated with mutant SOD1.}, }
@article {pmid21139572, year = {2011}, author = {Henriques, A and Pitzer, C and Dittgen, T and Klugmann, M and Dupuis, L and Schneider, A}, title = {CNS-targeted viral delivery of G-CSF in an animal model for ALS: improved efficacy and preservation of the neuromuscular unit.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {19}, number = {2}, pages = {284-292}, pmid = {21139572}, issn = {1525-0024}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; Dependovirus/genetics ; Disease Models, Animal ; Female ; Genetic Therapy/*methods ; Genetic Vectors/genetics ; Granulocyte Colony-Stimulating Factor/genetics/*physiology ; Immunohistochemistry ; Injections, Intramuscular ; Injections, Spinal ; Mice ; Mice, Inbred C57BL ; Motor Neurons/metabolism ; Sciatic Nerve/injuries ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motoneurons. We have recently uncovered a new neurotrophic growth factor, granulocyte-colony stimulating factor (G-CSF), which protects α-motoneurons, improves functional outcome, and increases life expectancy of SOD-1 (G93A) mice when delivered subcutaneously. However, chronic systemic delivery of G-CSF is complicated by elevation of neutrophilic granulocytes. Here, we used adeno-associated virus (AAV) to directly target and confine G-CSF expression to the spinal cord. Whereas intramuscular injection of AAV failed to transduce motoneurons retrogradely, and caused a high systemic load of G-CSF, intraspinal delivery led to a highly specific enrichment of G-CSF in the spinal cord with moderate peripheral effects. Intraspinal delivery improved motor functions, delayed disease progression, and increased survival by 10%, longer than after systemic delivery. Mechanistically, we could show that G-CSF in addition to rescuing motoneurons improved neuromuscular junction (NMJ) integrity and enhanced motor axon regeneration after nerve crush injury. Collectively, our results show that intraspinal delivery improves efficacy of G-CSF treatment in an ALS mouse model while minimizing the systemic load of G-CSF, suggesting a new therapeutic option for ALS treatment.}, }
@article {pmid21133819, year = {2011}, author = {Kuzma-Kozakiewicz, M and Kwiecinski, H}, title = {New therapeutic targets for amyotrophic lateral sclerosis.}, journal = {Expert opinion on therapeutic targets}, volume = {15}, number = {2}, pages = {127-143}, doi = {10.1517/14728222.2011.542152}, pmid = {21133819}, issn = {1744-7631}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/physiopathology/*therapy ; Animals ; Clinical Trials as Topic ; Disease Models, Animal ; Humans ; *Molecular Targeted Therapy ; Motor Neurons/pathology ; Nerve Degeneration/genetics/pathology ; Oligonucleotides, Antisense/genetics/*pharmacology ; *RNA Interference ; RNA, Small Interfering/genetics/metabolism ; Signal Transduction ; *Stem Cell Transplantation ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological disorders, affecting approximately half a million people worldwide. Currently there is no cure or prevention for ALS. Although ALS is a rare condition, it places a tremendous socioeconomic burden on patients, family members, caregivers and health systems.<br><br>AREAS COVERED: The review examines the mechanisms that may contribute to motor neuron degeneration in ALS, among which oxidative damage, glutatamate excitoxicity, mitochondrial dysfunction, impaired axonal transport, apoptotic cell death, growth factor deficiency, glial cell pathology and abnormal RNA metabolism are potential targets for ALS treatment. The article provides an overview of clinical trials performed to date in attempts to treat ALS with regard to molecular mechanisms and pathways they act on. It also discusses new trials based on recently developed molecular biology techniques.<br><br>EXPERT OPINION: Despite significant effectiveness of several potential therapeutics observed in preclinical trials, the results were not translatable to patients with ALS. The development of effective treatments of ALS strictly depends on understanding the primary cause of the disease. This goal will only be achieved when we identify the trigger point for motor neuron death in ALS.}, }
@article {pmid21129596, year = {2010}, author = {Muñoz Blanco, JL}, title = {[Catastrophic neuromuscular diseases].}, journal = {Neurologia (Barcelona, Spain)}, volume = {25 Suppl 1}, number = {}, pages = {37-45}, doi = {10.1016/S0213-4853(10)70049-9}, pmid = {21129596}, issn = {1578-1968}, mesh = {*Acute Disease ; Guillain-Barre Syndrome/complications/diagnosis/physiopathology/therapy ; Humans ; Muscular Diseases/complications/diagnosis/physiopathology/therapy ; Myasthenia Gravis/complications/diagnosis/physiopathology/therapy ; Neuromuscular Diseases/*complications/diagnosis/*physiopathology/therapy ; Polyneuropathies/complications/diagnosis/physiopathology/therapy ; Prognosis ; Respiratory Insufficiency/*etiology/physiopathology/therapy ; Spirometry/instrumentation/methods ; }, abstract = {Neurologists should anticipate and recognize the onset of respiratory failure in patients with neuromuscular diseases. Symptoms vary according to the speed of onset of respiratory muscle weakness. Catastrophic situations usually occur in three clinical scenarios: 1) incorrect management of acute respiratory failure of neuromuscular origin, autonomic dysfunction or during general anaesthesia of patients with neuromuscular diseases ; 2) incorrect prognosis and treatment due to the lack of a correct diagnosis. This situation is more common in ventilated patients with associated muscular weakness, acute neuropathies or motor neuron disease, and 3) inappropriate medical intervention in patients with neuromuscular disease with a definitive diagnosis but longstanding disease (amyotrophic lateral sclerosis, spinal muscular atrophy, myotonic dystrophy and other muscular dystrophies).}, }
@article {pmid21126160, year = {2011}, author = {Shimizu, T and Honda, M and Ohashi, T and Tsujino, M and Nagaoka, U and Kawata, A and Watabe, K and Matsubara, S and Hayashi, H}, title = {Hyperosmolar hyperglycemic state in advanced amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {12}, number = {5}, pages = {379-381}, doi = {10.3109/17482968.2010.539234}, pmid = {21126160}, issn = {1471-180X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*blood/complications/pathology/*physiopathology ; Blood Glucose/metabolism ; Female ; Glucose Tolerance Test ; Humans ; Hyperglycemia/etiology/*physiopathology ; Insulin/metabolism ; Insulin Resistance ; Insulin Secretion ; Male ; Middle Aged ; Muscle, Skeletal/metabolism ; Osmolar Concentration ; }, abstract = {Our objective was to describe cases of hyperosmolar hyperglycemic state (HHS) in advanced amyotrophic lateral sclerosis (ALS) patients and discuss its pathophysiology. Five ventilator-dependent patients with ALS, with no previous history of diabetes, showed development of marked hyperglycemia (plasma glucose levels of 755-1544 mg/dl) after preceding infectious episodes. All patients had severe generalized muscle wasting and tetraplegia. The initial manifestations of HHS were fever, drowsiness, or polyuria. Hydration and intravenous insulin therapy were markedly effective, resulting in favorable recovery without the necessity of chronic medication for hyperglycemia in all cases. Seventy-five grams oral glucose tolerance tests performed via feeding tubes in two patients after the successful treatment of HHS revealed increased insulin resistance and diminished early-phase insulin secretion with preserved total insulin secretion. In conclusion, a marked loss of skeletal muscle, the largest glucose consumer of the human body, with background abnormality of early-phase insulin secretion, might be a causative factor of HHS in advanced ALS.}, }
@article {pmid21123936, year = {2010}, author = {Ishizaki, F and Koyama, T and Sunayashiki, T and Murata, Y and Iida, T and Harada, T}, title = {[Control of bone remodeling by nervous system. Bone metabolic changes in neurological diseases].}, journal = {Clinical calcium}, volume = {20}, number = {12}, pages = {1841-1849}, pmid = {21123936}, issn = {0917-5857}, mesh = {Bone Diseases, Metabolic/*etiology/*metabolism ; *Bone Remodeling ; Bone Resorption/etiology/metabolism ; Bone and Bones/*metabolism ; Cardiovascular Diseases/complications/metabolism ; Fractures, Spontaneous/etiology/prevention &amp; control ; Humans ; Neurodegenerative Diseases/*complications/*metabolism ; }, abstract = {We introduced the relationship between bone change and neurological disturbance in the patients with cerebrovascular disease (CVD) , Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) . High incidence of osteoporosis and right/left difference in osteopenia are found in the diseases. CVD and PD patients with asymmetrical osteopenia show an association between clinical symptoms, peripheral circulatory symptoms, and predominant osteopenia. Although the muscle strength of PD patients was normal, the more severely affected side for PD symptoms and autonomic symptoms coincided with predominant osteopenia in the body. Increased bone resorption was detected in ALS patients. We speculated that neurological disturbances affect the remodeling of local sites of the bone. We have to start treatment from an early stage of the neurological disease to prevent a fracture.}, }
@article {pmid21122476, year = {2010}, author = {Geffard, M and de Bisschop, L and Duleu, S and Hassaine, N and Mangas, A and Coveñas, R}, title = {Endotherapia: a new frontier in the treatment of multiple sclerosis and other chronic diseases.}, journal = {Discovery medicine}, volume = {10}, number = {54}, pages = {443-451}, pmid = {21122476}, issn = {1944-7930}, mesh = {Antibodies/blood ; Bacteria/pathogenicity ; Chronic Disease ; Clinical Trials as Topic ; Female ; Humans ; Immunotherapy/*methods ; Male ; Multiple Sclerosis/*therapy ; }, abstract = {Currently, several drugs are accessible for the treatment of many chronic diseases (multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, etc.), but most of them have a large list of side effects. Here, we propose a new therapeutic approach called Endotherapia for the treatment of chronic diseases. This approach combines a biomedical evaluation of circulating immunoglobulins directed against specific self-antigens and self-antigens modified by free radicals. The therapy proposed here is a "tailor-made" combination of small molecules (e.g., fatty acids and vitamins) linked to a non-immunogenic chain of poly-L.Lysine (PLL). Each individual linkage or PLL derivative offers great advantages, such as an increase in the half-life of the active small molecules. Endotherapia also involves clinical aspects, allowing an exact diagnosis of the disease and the identification of specific circulating antibodies in the serum of patients in several clinical trials (e.g., multiple sclerosis). Endotherapia has been shown to be very safe. In summary, Endotherapia is the result of an immunopathological strategy addressing chronic incurable diseases with a multifactorial etiology. In light of the results obtained, it seems that Endotherapia is a promising therapy for chronic diseases, with no side effects, which is evidently mandatory in the management of long-term pathologies.}, }
@article {pmid21112435, year = {2010}, author = {Sanjak, M and Bravver, E and Bockenek, WL and Norton, HJ and Brooks, BR}, title = {Supported treadmill ambulation for amyotrophic lateral sclerosis: a pilot study.}, journal = {Archives of physical medicine and rehabilitation}, volume = {91}, number = {12}, pages = {1920-1929}, doi = {10.1016/j.apmr.2010.08.009}, pmid = {21112435}, issn = {1532-821X}, mesh = {Activities of Daily Living ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/physiopathology/*rehabilitation ; Analysis of Variance ; Exercise Therapy/*methods ; Female ; Humans ; Male ; Middle Aged ; Pilot Projects ; Psychomotor Performance ; Treatment Outcome ; Walking ; }, abstract = {OBJECTIVES: To determine the feasibility, tolerability, safety, and exercise treatment-effect size of repetitive rhythmic exercise mediated by supported treadmill ambulation training (STAT) for patients with amyotrophic lateral sclerosis (ALS).<br><br>DESIGN: Interventional with repeated-measures design.<br><br>SETTING: Multidisciplinary ALS clinic at academic medical center.<br><br>PARTICIPANTS: Convenience sample of patients with ALS (N=9) who were ambulatory with assistive devices (Sinaki-Mulder stages II-III).<br><br>INTERVENTIONS: Repetitive rhythmic exercise-STAT (30min total; 5min of exercise intercalated with 5min of rest) performed 3 times a week for 8 weeks.<br><br>MAIN OUTCOME MEASURE: ALS Functional Rating Scale-Revised (ALSFRS-R), percentage of predicted vital capacity (VC), total lower-extremities manual muscle test (MMT), rate of perceived exertion (RPE), Fatigue Severity Scale (FSS), and maximum voluntary isometric contraction (MVIC) in 10 lower and 10 upper extremities. Gait performance, which included walking distance, speed, steps, and stride length, was evaluated during treadmill and ground 6-minute walk tests (6MWTs) and 25-foot walk test (25FWT).<br><br>RESULTS: Feasibility issues decreased screened participants by 4 patients (31%). Nine patients were enrolled, but 6 patients (67%) completed the study and 3 (23% of original cohort; 33% of enrolled cohort) could not complete the exercise intervention because of non-ALS-related medical problems. Tolerability of the intervention measures during the treadmill 6MWT showed improvement in RPE (P&#x2264;.05) and FSS score (P&#x2265;.05). Safety measures (ALSFRS-R, VC, MMT) showed no decrease and showed statistical improvement in ALSFRS-R score (P&#x2264;.05) during the study interval. Exercise treatment-effect size showed variable improvements. Gait speed, distance, and stride length during the treadmill 6MWT improved significantly (P&#x2264;.05) after 4 weeks and improvements were maintained after 8 weeks compared with baseline. Walking distance during the ground 6MWT increased significantly after 4 weeks and was maintained after 8 weeks compared with baseline (P&#x2264;.05). Walking speed during the 25FWT and lower-extremity MVIC improved, but were not statistically significant.<br><br>CONCLUSIONS: Repetitive rhythmic exercise-STAT is feasible, tolerated, and safe for patients with ALS. Repetitive rhythmic exercise-STAT treatment-effect size across a number of ALS-related measures was consistent with improved work capacity and gait function in patients with ALS who are dependent on assistive devices for ambulation. Repetitive rhythmic exercise-STAT should be evaluated further in larger studies to determine the stability of this improved function in relation to the rate of progression of the underlying ALS.}, }
@article {pmid21107897, year = {2010}, author = {Baber, Z and Haghighat, N}, title = {Glutamine synthetase gene expression and glutamate transporters in C6-glioma cells.}, journal = {Metabolic brain disease}, volume = {25}, number = {4}, pages = {413-418}, pmid = {21107897}, issn = {1573-7365}, mesh = {Amino Acid Transport System X-AG/biosynthesis/*genetics ; Animals ; Brain Neoplasms/metabolism ; Cell Line, Tumor ; DNA Primers ; Estradiol/pharmacology ; Excitatory Amino Acid Transporter 1/biosynthesis/genetics ; Excitatory Amino Acid Transporter 2/biosynthesis/genetics ; Gene Expression Regulation, Enzymologic/*drug effects/*genetics ; Glioma/metabolism ; Glutamate-Ammonia Ligase/*genetics ; Immunohistochemistry ; RNA/biosynthesis/genetics ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Glutamine synthetase (GS) is the major glutamate-forming enzyme of vertebrae and is accepted to be a marker of astroglial cells. Maturation of astroglial cells is characterized by an increase in GS activity, and the regulation of this enzyme is the topic of many publications. The amino acid glutamate is the major excitatory neurotransmitter in the brain and mediates normal excitatory synaptic transmission by interaction with postsynaptic receptors. Glutamate also acts as a potent neurotoxin when present at high concentration. Glutamate neurotoxicity plays an important role in the pathophysiology of many neurological disorders, such as Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis. In the normal condition, L-glutamate is predominantly taken up, metabolized and recycled by astrocytes through the glutamate transporters (GLAST/GLT1) and glutamine synthetase (GS) catalytic activity. Because of the fundamental role of these glutamate transporters and the glutamine synthetase enzyme in controlling cerebral glutamate level, regulation of GS and studying of the glutamate transporters in glial cells is important. Astrocytes are supportive cells and act as the site of detoxification of glutamate in the brain. However, their isolation from the brain is a tedious, costly and time consuming procedure. On the other hand, the C6-glioma cells are readily available on the market. They are well characterized and have been a useful model for CNS glia in many laboratories. For this study, we used the C6-glioma cell line as a model system. We examined the presence or absence of glial specific glutamate transporters (GLTI and GLAST) in C6-glioma cells, which was done by immunocytochemistry. We also examined glutamine synthetase gene expression in these cells by treatment of the C6-glioma cells with estrogen (17ß estradiol). The findings from this study provide useful information about C6-glioma cells which makes the study of the CNS tremendously inexpensive.}, }
@article {pmid21099736, year = {2011}, author = {Raore, B and Federici, T and Taub, J and Wu, MC and Riley, J and Franz, CK and Kliem, MA and Snyder, B and Feldman, EL and Johe, K and Boulis, NM}, title = {Cervical multilevel intraspinal stem cell therapy: assessment of surgical risks in Gottingen minipigs.}, journal = {Spine}, volume = {36}, number = {3}, pages = {E164-71}, doi = {10.1097/BRS.0b013e3181d77a47}, pmid = {21099736}, issn = {1528-1159}, support = {K02 NS059416/NS/NINDS NIH HHS/United States ; 5K02NS059416./NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Cell Line ; Cell Survival/physiology ; Cervical Vertebrae/pathology/*surgery ; Female ; Graft Survival/physiology ; Humans ; Injections, Spinal ; Laminectomy/methods ; Microinjections ; *Postoperative Complications/prevention &amp; control ; Recovery of Function/physiology ; Risk Factors ; Spinal Cord/pathology/*surgery ; Stem Cell Transplantation/adverse effects/instrumentation/*methods ; Swine ; Swine, Miniature ; }, abstract = {STUDY DESIGN: Assessment of long-term surgical risks from multiple intraspinal cell injections.<br><br>OBJECTIVE: To prove that multilevel-targeted cell injection to the spinal cord can be a feasible and safe procedure.<br><br>SUMMARY OF BACKGROUND DATA: Neural cell transplantation has been proposed as a treatment for a variety of neurologic disorders, including degenerative, ischemic, autoimmune, and traumatic etiologies. Among these diseases, the lack of effective treatment for amyotrophic lateral sclerosis has prompted the search for cell-based neuroprotection or motor neuron-replacement therapies.<br><br>METHODS: Fifteen female minipigs, divided into 3 experimental groups, underwent either 5 or 10 unilateral injections of neural stem cells or 10 vehicle injections into the C3-C5 segments of the spinal cord, using a device and technique developed for safe and accurate injection into the human spinal cord. All animals received intravenous Tacrolimus (0.025 mg/kg) BID during the course of the study. Sensory and motor functions as well as general morbidity were assessed for 28 days. Full necropsy was performed and spinal cords were analyzed for graft survival. This study was performed under Good Laboratory Practice conditions.<br><br>RESULTS: Neither mortality nor permanent surgical complications were observed within the 28-day study period. All animals returned to preoperative baseline showing full motor function recovery. Graft survival was demonstrated by immunohistochemistry.<br><br>CONCLUSION: Clinically acceptable neural progenitor survival, distribution, and density were achieved using the number of injections and surgical techniques specifically developed for this purpose.}, }
@article {pmid21098299, year = {2010}, author = {Auclair, JR and Boggio, KJ and Petsko, GA and Ringe, D and Agar, JN}, title = {Strategies for stabilizing superoxide dismutase (SOD1), the protein destabilized in the most common form of familial amyotrophic lateral sclerosis.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {107}, number = {50}, pages = {21394-21399}, pmid = {21098299}, issn = {1091-6490}, support = {R21 NS071256/NS/NINDS NIH HHS/United States ; 1R21NS071256/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Animals ; Cross-Linking Reagents/chemistry ; Disulfides/chemistry ; *Enzyme Stability ; Humans ; Maleimides/chemistry ; Mice ; Molecular Structure ; Mutation ; Protein Multimerization ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Sulfhydryl Compounds/chemistry ; Superoxide Dismutase/chemistry/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disorder characterized by the death of both upper and lower motor neurons and by 3- to 5-yr median survival postdiagnosis. The only US Food and Drug Administration-approved drug for the treatment of ALS, Riluzole, has at best, moderate effect on patient survival and quality of life; therefore innovative approaches are needed to combat neurodegenerative disease. Some familial forms of ALS (fALS) have been linked to mutations in the Cu/Zn superoxide dismutase (SOD1). The dominant inheritance of mutant SOD1 and lack of symptoms in knockout mice suggest a "gain of toxic function" as opposed to a loss of function. A prevailing hypothesis for the mechanism of the toxicity of fALS-SOD1 variants, or the gain of toxic function, involves dimer destabilization and dissociation as an early step in SOD1 aggregation. Therefore, stabilizing the SOD1 dimer, thus preventing aggregation, is a potential therapeutic strategy. Here, we report a strategy in which we chemically cross-link the SOD1 dimer using two adjacent cysteine residues on each respective monomer (Cys111). Stabilization, measured as an increase in melting temperature, of ∼20 °C and ∼45 °C was observed for two mutants, G93A and G85R, respectively. This stabilization is the largest for SOD1, and to the best of our knowledge, for any disease-related protein. In addition, chemical cross-linking conferred activity upon G85R, an otherwise inactive mutant. These results demonstrate that targeting these cysteine residues is an important new strategy for development of ALS therapies.}, }
@article {pmid21095130, year = {2011}, author = {Chen, T and Benmohamed, R and Arvanites, AC and Ralay Ranaivo, H and Morimoto, RI and Ferrante, RJ and Watterson, DM and Kirsch, DR and Silverman, RB}, title = {Arylsulfanyl pyrazolones block mutant SOD1-G93A aggregation. Potential application for the treatment of amyotrophic lateral sclerosis.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {19}, number = {1}, pages = {613-622}, pmid = {21095130}, issn = {1464-3391}, support = {R01 AG031311/AG/NIA NIH HHS/United States ; R43 NS057849/NS/NINDS NIH HHS/United States ; R43 NS057849-01A1/NS/NINDS NIH HHS/United States ; 1R43NS057849/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Enzyme Inhibitors/*pharmacology ; Humans ; Magnetic Resonance Spectroscopy ; Mice ; Pyrazolones/*pharmacology ; Spectrometry, Mass, Electrospray Ionization ; Superoxide Dismutase/*antagonists &amp; inhibitors/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure. Mutations in copper/zinc superoxide dismutase 1 (SOD1) have been implicated in the pathophysiology of this disease. Using a high-throughput screening assay expressing mutant G93A SOD1, two bioactive chemical hit compounds (1 and 2), identified as arylsulfanyl pyrazolones, were identified. The structural optimization of this scaffold led to the generation of a more potent analogue (19) with an EC(50) of 170nM. To determine the suitability of this class of compounds for further optimization, 1 was subjected to a battery of pharmacokinetic assays; most of the properties of 1 were good for a screening hit, except it had a relatively rapid clearance and short microsomal half-life stability. Compound 2 was found to be blood-brain barrier penetrating with a brain/plasma ratio=0.19. The optimization of this class of compounds could produce novel therapeutic candidates for ALS patients.}, }
@article {pmid21092256, year = {2010}, author = {Ryynänen, OP and Iirola, T and Reitala, J and Pälve, H and Malmivaara, A}, title = {Is advanced life support better than basic life support in prehospital care? A systematic review.}, journal = {Scandinavian journal of trauma, resuscitation and emergency medicine}, volume = {18}, number = {}, pages = {62}, pmid = {21092256}, issn = {1757-7241}, mesh = {*Advanced Cardiac Life Support ; Emergency Medical Services/*methods/standards ; Humans ; *Life Support Care ; Outcome Assessment, Health Care ; Quality-Adjusted Life Years ; Survival Analysis ; }, abstract = {BACKGROUND: Prehospital care is classified into ALS- (advanced life support) and BLS- (basic life support) levels according to the methods used. ALS-level prehospital care uses invasive methods, such as intravenous fluids, medications and intubation. However, the effectiveness of ALS care compared to BLS has been questionable.<br><br>AIM: The aim of this systematic review is to compare the effectiveness of ALS- and BLS-level prehospital care.<br><br>MATERIAL AND METHODS: In a systematic review, articles where ALS-level prehospital care was compared to BLS-level or any other treatment were included. The outcome variables were mortality or patient's health-related quality of life or patient's capacity to perform daily activities.<br><br>RESULTS: We identified 46 articles, mostly retrospective observational studies. The results on the effectiveness of ALS in unselected patient cohorts are contradictory. In cardiac arrest, early cardiopulmonary resuscitation and defibrillation are essential for survival, but prehospital ALS interventions have not improved survival. Prehospital thrombolytic treatment reduces mortality in patients having a myocardial infarction. The majority of research into trauma favours BLS in the case of penetrating trauma and also in cases of short distance to a hospital. In patients with severe head injuries, ALS provided by paramedics and intubation without anaesthesia can even be harmful. If the prehospital care is provided by an experienced physician and by a HEMS organisation (Helicopter Emergency Medical Service), ALS interventions may be beneficial for patients with multiple injuries and severe brain injuries. However, the results are contradictory.<br><br>CONCLUSIONS: ALS seems to improve survival in patients with myocardial infarction and BLS seems to be the proper level of care for patients with penetrating injuries. Some studies indicate a beneficial effect of ALS among patients with blunt head injuries or multiple injuries. There is also some evidence in favour of ALS among patients with epileptic seizures as well as those with a respiratory distress.}, }
@article {pmid21086185, year = {2011}, author = {Grehl, T and Rupp, M and Budde, P and Tegenthoff, M and Fangerau, H}, title = {Depression and QOL in patients with ALS: how do self-ratings and ratings by relatives differ?.}, journal = {Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation}, volume = {20}, number = {4}, pages = {569-574}, pmid = {21086185}, issn = {1573-2649}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/physiopathology/*psychology ; *Depression ; *Family ; Female ; Humans ; Male ; Middle Aged ; *Quality of Life ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease affecting the motor nervous system and currently lacking effective means of treatment. The focus of ALS treatment therefore lies in palliative treatment from a multidisciplinary team. Published findings regarding affective components and patients' perceived quality-of-life (QoL) as well as comparative reports of family members/caregivers remain equivocal.<br><br>METHODS: In this study, 41 ALS patients and their relatives were enrolled in a study employing the 12-item ALS-Depression-Inventory (ADI-12) and the Munich quality-of-life dimensions list (MLDL). The ALS-functional rating scale (ALSFRS-R) was used to evaluate physical disabilities.<br><br>RESULTS: The ADI-12 depression scale data identified nine patients with depressive disorders; the patients had satisfactory QoL outcomes on the MLDL. The results did not differ significantly between ALS patients and their relatives.<br><br>CONCLUSIONS: Thus, in agreement with other studies, QoL and emerging depression do not automatically coincide with patients' physical impairments of the patients. This "well-being paradox" is currently not well understood, and further studies are needed to optimize the treatment of patients through the course of disease progression.}, }
@article {pmid21082892, year = {2010}, author = {Joyce, N and Annett, G and Wirthlin, L and Olson, S and Bauer, G and Nolta, JA}, title = {Mesenchymal stem cells for the treatment of neurodegenerative disease.}, journal = {Regenerative medicine}, volume = {5}, number = {6}, pages = {933-946}, pmid = {21082892}, issn = {1746-076X}, support = {R01 DK061848/DK/NIDDK NIH HHS/United States ; R01 GM099688/GM/NIGMS NIH HHS/United States ; 1R01 HL073256-01/HL/NHLBI NIH HHS/United States ; S10 RR026825/RR/NCRR NIH HHS/United States ; R01 HL073256-06/HL/NHLBI NIH HHS/United States ; 5P30AG010129-19/AG/NIA NIH HHS/United States ; S10 RR026825-01/RR/NCRR NIH HHS/United States ; R01 HL073256/HL/NHLBI NIH HHS/United States ; P30 AG010129/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Clinical Trials as Topic ; Humans ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*cytology ; Neurodegenerative Diseases/pathology/*therapy ; Neurotransmitter Agents/metabolism ; Wound Healing ; }, abstract = {Mesenchymal stem cells/marrow stromal cells (MSCs) present a promising tool for cell therapy, and are currently being tested in US FDA-approved clinical trials for myocardial infarction, stroke, meniscus injury, limb ischemia, graft-versus-host disease and autoimmune disorders. They have been extensively tested and proven effective in preclinical studies for these and many other disorders. There is currently a great deal of interest in the use of MSCs to treat neurodegenerative diseases, in particular for those that are fatal and difficult to treat, such as Huntington's disease and amyotrophic lateral sclerosis. Proposed regenerative approaches to neurological diseases using MSCs include cell therapies in which cells are delivered via intracerebral or intrathecal injection. Upon transplantation into the brain, MSCs promote endogenous neuronal growth, decrease apoptosis, reduce levels of free radicals, encourage synaptic connection from damaged neurons and regulate inflammation, primarily through paracrine actions. MSCs transplanted into the brain have been demonstrated to promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons. Therapies will capitalize on the innate trophic support from MSCs or on augmented growth factor support, such as delivering brain-derived neurotrophic factor or glial-derived neurotrophic factor into the brain to support injured neurons, using genetically engineered MSCs as the delivery vehicles. Clinical trials for MSC injection into the CNS to treat traumatic brain injury and stroke are currently ongoing. The current data in support of applying MSC-based cellular therapies to the treatment of neurodegenerative disorders are discussed.}, }
@article {pmid21077031, year = {2010}, author = {Nasiłowski, J and Szkulmowski, Z and Migdał, M and Andrzejewski, W and Drozd, W and Czajkowska-Malinowska, M and Opuchlik, A and Chazan, R}, title = {[Prevalence of home mechanical ventilation in Poland].}, journal = {Pneumonologia i alergologia polska}, volume = {78}, number = {6}, pages = {392-398}, pmid = {21077031}, issn = {0867-7077}, mesh = {Adult ; Age Distribution ; Aged ; Amyotrophic Lateral Sclerosis/epidemiology/*therapy ; Child ; Female ; Home Care Services/*statistics &amp; numerical data ; Humans ; Lung Diseases/epidemiology/*therapy ; Male ; Middle Aged ; Muscular Dystrophies/therapy ; Neuromuscular Diseases/epidemiology/*therapy ; Poland/epidemiology ; Prevalence ; Quality of Life ; Respiration, Artificial/*statistics &amp; numerical data ; Respiratory Function Tests ; Surveys and Questionnaires ; Thoracic Diseases/*therapy ; Ventilators, Mechanical/*statistics &amp; numerical data ; }, abstract = {INTRODUCTION: Home mechanical ventilation (HMV) is increasingly used in the treatment of chronic respiratory failure thanks to rapid technological development, increasing number of elderly people and extension of indications. The aim of the study was to assess: prevalence of HMV in Poland, the proportions of lung disease and neuromuscular patients using HMV and the type of interface (invasive v. non-invasive).<br><br>MATERIAL AND METHODS: The questionnaire was send to all institutions providing HMV in Poland and to regional departments of National Health System (NHS).<br><br>RESULTS: All NHS departments responded. They reported 846 HMV users, 31% of children. The prevalence of HMV in Poland was assessed as 2,2 patient per 100.000 population without striking differences between provinces. Among 39 HMV centers in Poland 12 (31%) answered. They reported 206 patients (24% of all HMV users). Proportion of ventilation mode consisted of 59% (122 pts) treated via a tracheostomy and 41% (84 pts) with non invasive ventilation (NIV). 168 patients (82%) had neuromuscular diseases (ND), majority of them muscular dystrophy - 57 patients (34% of ND) and amyotrophic lateral sclerosis - 39 patients (23% of ND). There were only 38 patients (18%) with lung and thoracic cage diseases: 17 with COPD and 10 with kyphoscoliosis.<br><br>CONCLUSIONS: The prevalence of HMV treatment in Poland has developed dramatically in the last decade, but is still very low comparing to other European countries, especially due to very low number of patients with lung and chest wall diseases. The prevalence of invasive mode of ventilation is extremely high. The most important factors which inhibit development of HMV in Poland are: omission of respiratory physicians in the process of qualification, lack of national guidelines, sophisticated demands for HMV providers. The awareness of the need of HMV especially in patients with respiratory failure due to obesity hypoventilation syndrome and restrictive lung diseases should be increased among chest physicians.}, }
@article {pmid21073276, year = {2011}, author = {Benmohamed, R and Arvanites, AC and Kim, J and Ferrante, RJ and Silverman, RB and Morimoto, RI and Kirsch, DR}, title = {Identification of compounds protective against G93A-SOD1 toxicity for the treatment of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {12}, number = {2}, pages = {87-96}, pmid = {21073276}, issn = {1471-180X}, support = {R43 NS057849/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/pathology/physiopathology ; Animals ; Benzoquinones/pharmacology ; Cell Death/drug effects ; Cytoprotection ; *Drug Design ; Drug Evaluation, Preclinical ; High-Throughput Screening Assays ; Humans ; Lactams, Macrocyclic/pharmacology ; Leupeptins/pharmacology ; Macrolides/pharmacology ; Mutant Proteins/metabolism ; PC12 Cells ; Rats ; Recombinant Fusion Proteins/genetics/metabolism ; Small Molecule Libraries ; Superoxide Dismutase/genetics/*metabolism ; }, abstract = {The underlying cause of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder, remains unknown. However, there is strong evidence that one pathophysiological mechanism, toxic protein misfolding and/or aggregation, may trigger motor neuron dysfunction and loss. Since the clinical and pathological features of sporadic and familial ALS are indistinguishable, all forms of the disease may be better understood and ultimately treated by studying pathogenesis and therapy in models expressing mutant forms of SOD1. We developed a cellular model in which cell death depended on the expression of G93A-SOD1, a mutant form of superoxide dismutase found in familial ALS patients that produces toxic protein aggregates. This cellular model was optimized for high throughput screening to identify protective compounds from a >50,000 member chemical library. Three novel chemical scaffolds were selected for further study following screen implementation, counter-screening and secondary testing, including studies with purchased analogs. All three scaffolds blocked SOD1 aggregation in high content screening assays and data on the optimization and further characterization of these compounds will be reported separately. These data suggest that optimization of these chemicals scaffolds may produce therapeutic candidates for ALS patients.}, }
@article {pmid21071151, year = {2011}, author = {Krause, M and Rodrigues-Krause, Jda C}, title = {Extracellular heat shock proteins (eHSP70) in exercise: Possible targets outside the immune system and their role for neurodegenerative disorders treatment.}, journal = {Medical hypotheses}, volume = {76}, number = {2}, pages = {286-290}, doi = {10.1016/j.mehy.2010.10.025}, pmid = {21071151}, issn = {1532-2777}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Anti-Inflammatory Agents/pharmacology ; Axons/pathology ; *Exercise ; Exocytosis ; Glucose/metabolism ; HSP70 Heat-Shock Proteins/*metabolism ; HSP72 Heat-Shock Proteins/metabolism ; Humans ; Immune System ; Models, Biological ; Motor Neurons/metabolism/pathology ; Neurodegenerative Diseases/*metabolism/*therapy ; Oxidation-Reduction ; }, abstract = {The intracellular heat shock protein 70kDa (iHSP70) is a universal marker of stress protein whose expression is induced by different cell stressors, such as heat, metabolite deprivation, redox imbalances and also during physical exercise. The activation of the iHSP70 is sine qua non for the promotion of tissue repair, since the expression of this chaperone confers cytoprotection and also exerts anti-inflammatory effects. On the other hand, exercise also induces the appearance of HSP70 in the extracellular medium (eHSP70) but, so far, the eHSP70 function has been mainly attributed to the activation of the immune system, seeming to perform an opposite function from the iHSP70. Since a moderate intensity exercise bout induces a general anti-inflammatory response even in the presence of an elevated eHSP70, this protein could carry out other functions rather than immune activation. Because exercise generates heat and metabolic challenges (especially on glucose metabolism) we suggests that the motoneurons, a very active (possibly one of the most stressed cells during exercise) and also very sensitive cells to heat and glucose metabolism imbalances, could be the major sites for the eHSP70 function. Due to the importance of the iHSP70 for repair and stress adaptation, this protein must be present in abundance on the site of stress and, because of its intrinsic inability response to stress [low heat shock factor 1 (HSF-1) activation] and the structure of the motoneurons (very long cells), the iHSP70, produced on the very far nucleus, is not appropriately transported through the axon to the axon terminal, were it is required. Then, during the exercise, the released eHSP70 can be internalized by the motoneurons and act as intracellular chaperons, protecting this cell against oxidative damage, protein denaturation and many others. Since a decreased iHSP70 expression capacity is associated with neurodegeneration diseases (such as Parkinson, polyglutamine, Amyotrophic lateral sclerosis, Alzheimer's, Huntington's and many others), the understanding of the physiological function of the extracellular HSP70 could be helpful on the treatment of neurodegenerative and other neuronal diseases. Besides that, it could explain some of the beneficial effects of the pharmacological HSP70 activators and also the beneficial effects of the exercise among neuronal cells during neurodegenerative-inducing diseases.}, }
@article {pmid21068071, year = {2011}, author = {Das, A and Smith, JA and Gibson, C and Varma, AK and Ray, SK and Banik, NL}, title = {Estrogen receptor agonists and estrogen attenuate TNF-α-induced apoptosis in VSC4.1 motoneurons.}, journal = {The Journal of endocrinology}, volume = {208}, number = {2}, pages = {171-182}, pmid = {21068071}, issn = {1479-6805}, support = {NS-41088/NS/NINDS NIH HHS/United States ; R01 NS031622/NS/NINDS NIH HHS/United States ; R01 NS045967/NS/NINDS NIH HHS/United States ; NS-45967/NS/NINDS NIH HHS/United States ; C06 RR015455/RR/NCRR NIH HHS/United States ; C06 RRO15455//PHS HHS/United States ; NS-31622/NS/NINDS NIH HHS/United States ; R01 NS041088/NS/NINDS NIH HHS/United States ; R01 NS057811/NS/NINDS NIH HHS/United States ; NS-57811/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*drug effects ; Biomarkers/metabolism ; Calcium Channels, L-Type/metabolism ; Cell Death/drug effects ; Cell Fusion ; Cell Line ; Cell Line, Tumor ; Embryo, Mammalian/cytology ; Estrogens/*pharmacology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Hybrid Cells/metabolism ; Motor Neurons/*drug effects ; Neuroblastoma/pathology ; Neuroprotective Agents/pharmacology ; Nitriles/pharmacology ; Phenols/pharmacology ; Phosphorylation/drug effects ; Pyrazoles/pharmacology ; Rats ; Receptors, Estrogen/*agonists ; Signal Transduction/drug effects ; Spinal Cord/embryology ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {Tumor necrosis factor-alpha (TNF-α) may cause apoptosis and inflammation in amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI). Recent studies suggest that estrogen (EST) provides neuroprotection against SCI. We tested whether 1,3,5-tris (4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) (EST receptor alpha (ERα) agonist), 2,3-bis (4-hydroxyphenyl) propionitrile (DPN) (EST receptor beta (ERβ) agonist), or EST itself would prevent apoptosis in VSC4.1 motoneurons following exposure to TNF-α. Cells were exposed to TNF-α and 15 min later treated with PPT, DPN, or EST. Posttreatment with 50 nM PPT, 50 nM DPN, or 150 nM EST prevented cell death in VSC4.1 motoneurons. Treatment of VSC4.1 motoneurons with PPT, DPN, or EST induced overexpression of ERα, ERβ, or both, which contributed to neuroprotection by upregulating expression of anti-apoptotic proteins (p-AKT, p-CREB, Bcl-2, and p-Src). Our analyses also revealed that EST agonists and EST increased phosphorylation of extracellular signal-regulated kinase (ERK). The L-type Ca(2+) channel inhibitor, nifedipine (10 μM), partially inhibited EST agonist and EST-induced increase in phosphorylated ERK expression. The mitogen-activated protein kinase inhibitor, PD98059 (5 μM), partially prevented ER agonists and EST from providing neuroprotection to TNF-α toxicity. Presence of the nuclear ER antagonist, ICI 182 780 (10 μM), blocked the neuroprotection provided by all three ER agonists tested. Taken together, our data indicate that both ERα and ERβ contribute to PPT, DPN, or EST-mediated neuroprotection with similar signaling profiles. Our data strongly imply that PPT, DPN, or EST can be used as effective neuroprotective agents to attenuate motoneuron death in ALS and SCI.}, }
@article {pmid21059646, year = {2011}, author = {Shen, X and Ying, H and Qiu, Y and Park, JS and Shyam, R and Chi, ZL and Iwata, T and Yue, BY}, title = {Processing of optineurin in neuronal cells.}, journal = {The Journal of biological chemistry}, volume = {286}, number = {5}, pages = {3618-3629}, pmid = {21059646}, issn = {1083-351X}, support = {EY01792/EY/NEI NIH HHS/United States ; P30 EY001792/EY/NEI NIH HHS/United States ; R01 EY005628/EY/NEI NIH HHS/United States ; R01 EY018828/EY/NEI NIH HHS/United States ; EY005628/EY/NEI NIH HHS/United States ; EY003890/EY/NEI NIH HHS/United States ; R01 EY003890/EY/NEI NIH HHS/United States ; EY018828/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Apoptosis ; *Autophagy ; Cell Cycle Proteins ; Cell Line ; Eye Proteins ; Humans ; Membrane Transport Proteins ; Mice ; Mice, Transgenic ; Neurons/cytology/*metabolism ; PC12 Cells ; Proteasome Endopeptidase Complex/*metabolism ; Rats ; Retina ; Transcription Factor TFIIIA/*metabolism ; *Ubiquitination ; }, abstract = {Optineurin is a gene linked to amyotrophic lateral sclerosis, Paget disease of bone, and glaucoma, a major blinding disease. Mutations such as E50K were identified in glaucoma patients. We investigated herein the involvement of ubiquitin-proteasome pathway (UPP) and autophagy, two major routes for protein clearance, in processing of optineurin in a retinal ganglion cell model line RGC5 and neuronal PC12 cells. It was found that the endogenous optineurin level in neuronal cells was increased by treatment of proteasomal inhibitor but not by autophagic and lysosomal inhibitors. Multiple bands immunoreactive to anti-ubiquitin were seen in the optineurin pulldown, indicating that optineurin was ubiquitinated. In cells overexpressing wild type and E50K optineurin, the level of the proteasome regulatory β5 subunit (PSMB5, indicative of proteasome activity) was reduced, whereas that for autophagy marker microtubule-associated protein 1 light chain 3 was enhanced compared with controls. Autophagosome formation was detected by electron microscopy. The foci formed after optineurin transfection were increased upon treatment of an autophagic inhibitor but were decreased by treatment of an inducer, rapamycin. Moreover, the level of optineurin-triggered apoptosis was reduced by rapamycin. This study thus provides compelling evidence that in a normal homeostatic situation, the turnover of endogenous optineurin involves mainly UPP. When optineurin is up-regulated or mutated, the UPP function is compromised, and autophagy comes into play. A decreased PSMB5 level and an induced autophagy were also demonstrated in vivo in retinal ganglion cells of E50K transgenic mice, validating and making relevant the in vitro findings.}, }
@article {pmid21056813, year = {2010}, author = {Schmiesing, CA and Lee, J and Morton, JM and Brock-Utne, JG}, title = {Laparoscopic diaphragmatic pacer placement--a potential new treatment for ALS patients: a brief description of the device and anesthetic issues.}, journal = {Journal of clinical anesthesia}, volume = {22}, number = {7}, pages = {549-552}, doi = {10.1016/j.jclinane.2009.09.010}, pmid = {21056813}, issn = {1873-4529}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Anesthesia, General/methods ; Diaphragm/physiopathology ; Electric Stimulation Therapy/*methods ; Equipment Design ; Female ; Humans ; Laparoscopy/methods ; Male ; Middle Aged ; Respiratory Paralysis/etiology/*therapy ; }, abstract = {The Diaphragm Pacing Stimulator (DPS) has been used to treat ventilatory insufficiency in quadriplegic patients. The FDA approved a trial using the DPS in patients with amyotrophic lateral sclerosis (ALS). Three patients with advanced ALS, who underwent laparoscopic diaphragmatic pacer placement, and their general anesthetic management, are presented.}, }
@article {pmid21056589, year = {2011}, author = {Nutini, M and Frazzini, V and Marini, C and Spalloni, A and Sensi, SL and Longone, P}, title = {Zinc pre-treatment enhances NMDAR-mediated excitotoxicity in cultured cortical neurons from SOD1(G93A) mouse, a model of amyotrophic lateral sclerosis.}, journal = {Neuropharmacology}, volume = {60}, number = {7-8}, pages = {1200-1208}, doi = {10.1016/j.neuropharm.2010.11.001}, pmid = {21056589}, issn = {1873-7064}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Cell Culture Techniques ; Cell Death/drug effects ; Cerebral Cortex/drug effects/metabolism ; Disease Models, Animal ; Excitatory Amino Acid Agonists/metabolism ; Female ; Humans ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/metabolism/pathology ; N-Methylaspartate/metabolism ; Neurons/*drug effects/metabolism/pathology ; Neurotoxins/*toxicity ; Neurotransmitter Agents/toxicity ; Reactive Oxygen Species/metabolism ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Superoxide Dismutase/genetics/*metabolism ; Zinc/*toxicity ; }, abstract = {Zn[2]+ is co-released at glutamatergic synapses throughout the central nervous system and acts as a neuromodulator for glutamatergic neurotransmission, as a key modulator of NMDA receptor functioning. Zn[2]+ is also implicated in the neurotoxicity associated with several models of acute brain injury and neurodegeneration. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons in the spinal cord and cortex. In this study, we have investigated the modulatory role exerted by Zn[2]+ in NMDA-mediated neurotoxicity in either near-pure or mixed cortical cultured neurons obtained from either mice over-expressing the G93A mutant form of Cu/Zn superoxide dismutase (SOD1) human gene, a gene linked to familial ALS, or wild type (WT) mice. To that aim, SOD1(G93A) or WT cultures were exposed to either NMDA by itself or to Zn[2]+ prior to a toxic challenge with NMDA, and neuronal loss evaluated 24 h later. While we failed to observe any significant difference between NMDA and Zn[2]+/NMDA-mediated toxicity in mixed SOD1(G93A) or WT cortical cultures, different vulnerability to these toxic paradigms was found in near-pure neuronal cultures. In the WT near-pure neuronal cultures, a brief exposure to sublethal concentrations of Zn[2]+-enhanced NMDA receptor-mediated cell death, an effect that was far more pronounced in the SOD1(G93A) cultures. This increased excitotoxicity in SOD1(G93A) near-pure neuronal cultures appears to be mediated by a significant increase in NMDA-dependent rises of intraneuronal Ca[2]+ levels as well as enhanced production of cytosolic reactive oxygen species, while the injurious process seems to be unrelated to activation of nNOS or ERK1/2 pathways. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.}, }
@article {pmid21044297, year = {2010}, author = {Moreno-Igoa, M and Manzano, R and Oliván, S and Calvo, AC and Toivonen, JM and Osta, R}, title = {Effects of gene therapy on muscle 18S rRNA expression in mouse model of ALS.}, journal = {BMC research notes}, volume = {3}, number = {}, pages = {275}, pmid = {21044297}, issn = {1756-0500}, abstract = {BACKGROUND: The efficiency of gene therapy experiments is frequently evaluated by measuring the impact of the treatment on the expression of genes of interest by quantitative real time PCR (qRT-PCR) and by normalizing these values to those of housekeeping (HK) genes constitutively expressed throughout the experiment. The objective of this work was to study the effects of muscle gene therapy on the expression of 18 S ribosomal RNA (Rn18S), a commonly used HK gene.<br><br>FINDINGS: Mouse model of motor neuron disease (SOD1-G93A) was injected intramuscularly with Brain-derived neurotrophic factor (BDNF-TTC) encoding or control naked DNA plasmids. qRT-PCR expression analysis was performed for BDNF and HK genes Rn18 S, glyceraldehyde-3-phosphate dehydrogenase (Gapdh) and &#x3b2;-actin (Actb). We report that elevated BDNF expression in the injected muscle was accompanied with increased Rn18 S expression, whereas Gapdh and Actb were not affected. Increased "ribosomal output" upon BDNF stimulation was supported by increased steady-state levels of ribosomal protein mRNAs.<br><br>CONCLUSIONS: Ribosomal RNA transcription may be directly stimulated by administration of trophic factors. Caution should be taken in using Rn18 S as a HK gene in experiments where muscle metabolism is likely to be altered by therapeutic intervention.}, }
@article {pmid21037550, year = {2010}, author = {Inoue, K and Watanabe, T and Hirasawa, H and Yoshiba, M}, title = {Liver support systems as perioperative care in liver transplantation-historical perspective and recent progress in Japan.}, journal = {Minerva gastroenterologica e dietologica}, volume = {56}, number = {3}, pages = {345-353}, pmid = {21037550}, issn = {1121-421X}, mesh = {History, 20th Century ; Humans ; Japan ; *Liver Transplantation/history ; *Liver, Artificial/history ; Perioperative Care/*methods ; }, abstract = {A meta-analysis of the efficacy of artificial liver support (ALS) systems for fulminant hepatic failure (FHF) by the Cochrane Hepato-Biliary Group suggested that all ALS systems previously developed are ineffective for FHF. This supports the view that the only treatment of choice for FHF is immediate liver transplantation. Plasma exchange, in combination with high-volume hemodiafiltration or high-flow continuous hemodiafiltration using large pore membranes, which was excluded from the Cochrane meta-analysis because of the lack of randomized control trials, has become a standard ALS system in Japan. This system is safe, and it efficiently removes more low and middle molecular weight toxic substances than other methods by using a large volume of buffers (more than 200 L per session), resulting in recovery from coma in patients with severe FHF comparable to an ahepatic state. These artificial liver support systems are effective tools for sustaining patients with FHF in a favorable condition until liver function recovers or liver transplantation becomes available.}, }
@article {pmid21030340, year = {2010}, author = {Cozzani, E and Christana, K and Rongioletti, F and Rebora, A and Parodi, A}, title = {Lupus erythematosus tumidus: clinical, histopathological and serological aspects and therapy response of 21 patients.}, journal = {European journal of dermatology : EJD}, volume = {20}, number = {6}, pages = {797-801}, doi = {10.1684/ejd.2010.1098}, pmid = {21030340}, issn = {1167-1122}, mesh = {Adult ; Aged ; Female ; Fluorescent Antibody Technique, Direct ; Humans ; Immunoelectrophoresis ; Lupus Erythematosus, Cutaneous/blood/immunology/*pathology/*therapy ; Male ; Middle Aged ; Sunlight/adverse effects ; }, abstract = {Twenty-one Caucasian patients (12 women and 9 men) were diagnosed as having lupus erythematosus tumidus by clinical and histopathological criteria. They were analysed by blood tests, histopathology and immunological studies and their response to treatment was recorded. While blood tests yielded non contributory results, histopathology showed in all cases a superficial and deep lymphocytic infiltrate with a perivascular and periadnexal involvement and an interstitial dermal deposition of mucin. Minimal epidermal changes were observed in 13 cases. In particular, epidermal atrophy was found in 8 specimens, hyperkeratosis in 8, parakeratosis in 2, acanthosis in 3 and spongiosis in 1. Four patients showed a slight vacuolar degeneration and periodic acid-Schiff staining showed a thickened basal membrane zone in two. Direct immunofluorescence was positive in 16 of the 19 patients tested. Antinuclear antibodies were negative in all 21 patients in indirect immunofluorescence. Antimalarials cleared the lesions within 12 weeks in 16 patients. Fourteen of them relapsed about 3 weeks after the first sun exposure, but were successfully controlled with the same treatment within a maximum of 12 weeks. Spontaneous resolution of the skin lesions was never observed. Altogether, some evidence of heterogeneity is suggested, some cases strictly satisfying Kuhn et al's criteria, others resembling discoid lupus more closely.}, }
@article {pmid20971133, year = {2011}, author = {Gould, TW and Oppenheim, RW}, title = {Motor neuron trophic factors: therapeutic use in ALS?.}, journal = {Brain research reviews}, volume = {67}, number = {1-2}, pages = {1-39}, pmid = {20971133}, issn = {1872-6321}, support = {R01 NS048982/NS/NINDS NIH HHS/United States ; R01 NS048982-04/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/*pathology ; Animals ; Disease Models, Animal ; Humans ; Mice ; Motor Neurons/*drug effects/metabolism/pathology ; Nerve Degeneration/*drug therapy/metabolism/*pathology ; Nerve Growth Factors/*pharmacology/physiology/therapeutic use ; }, abstract = {The modest effects of neurotrophic factor (NTF) treatment on lifespan in both animal models and clinical studies of Amyotropic Lateral Sclerosis (ALS) may result from any one or combination of the four following explanations: 1.) NTFs block cell death in some physiological contexts but not in ALS; 2.) NTFs do not rescue motoneurons (MNs) from death in any physiological context; 3.) NTFs block cell death in ALS but to no avail; and 4.) NTFs are physiologically effective but limited by pharmacokinetic constraints. The object of this review is to critically evaluate the role of both NTFs and the intracellular cell death pathway itself in regulating the survival of spinal and cranial (lower) MNs during development, after injury and in response to disease. Because the role of molecules mediating MN survival has been most clearly resolved by the in vivo analysis of genetically engineered mice, this review will focus on studies of such mice expressing reporter, null or other mutant alleles of NTFs, NTF receptors, cell death or ALS-associated genes.}, }
@article {pmid20971081, year = {2011}, author = {Seo, JS and Baek, IS and Leem, YH and Kim, TK and Cho, Y and Lee, SM and Park, YH and Han, PL}, title = {SK-PC-B70M alleviates neurologic symptoms in G93A-SOD1 amyotrophic lateral sclerosis mice.}, journal = {Brain research}, volume = {1368}, number = {}, pages = {299-307}, doi = {10.1016/j.brainres.2010.10.048}, pmid = {20971081}, issn = {1872-6240}, mesh = {Aldehydes/metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Anterior Horn Cells/drug effects/*pathology ; Cell Survival/drug effects ; Choline O-Acetyltransferase/metabolism ; Disease Models, Animal ; Lipid Peroxidation/drug effects ; Malondialdehyde/metabolism ; Mice ; Mice, Transgenic ; Motor Activity/*drug effects ; Saponins/*pharmacology ; Spinal Cord/drug effects/pathology/*physiopathology ; Superoxide Dismutase/*genetics ; }, abstract = {SK-PC-B70M, an oleanolic-glycoside saponins fraction extracted from the root of Pulsatilla koreana, carries active ingredient(s) that protects the cytotoxicity induced by Aβ(1-42) in SK-N-SH cells. It was recently demonstrated that SK-PC-B70M improved scopolamine-induced deficits of memory consolidation and spatial working memory in rats, and reduced Aβ levels and plaque deposition in the brains of the Tg2576 mouse model of Alzheimer disease. In the present study, we investigated whether SK-PC-B70M produces helpful effects on the pathology of the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis (ALS). Administration of SK-PC-B70M (100 or 400 mg/kg/day) from 8 weeks to 16 weeks of age attenuated neurological deficits of G93A-SOD1 mice in several motor-function-related behavioral tests. SK-PC-B70M treatment significantly suppressed the accumulation of the by-products of lipid peroxidation, malonedialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE), in the spinal cord of G93A-SOD1 mice. Moreover, histologic analysis stained with cresyl violet or anti-choline acetyltransferase (ChAT) revealed that SK-PC-B70M suppressed neuronal loss in the ventral horn of the spinal cords of G93A-SOD1 mice. These results suggest that SK-PC-B70M affords a beneficial effect on neurologic deficits of G93A-SOD1 ALS mice.}, }
@article {pmid20964996, year = {2010}, author = {Galán, L and Guerrero-Sola, A and Gómez-Pinedo, U and Matias-Guiu, J}, title = {[Cell therapy in amyotrophic lateral sclerosis: science and controversy].}, journal = {Neurologia (Barcelona, Spain)}, volume = {25}, number = {8}, pages = {467-469}, pmid = {20964996}, issn = {0213-4853}, mesh = {Amyotrophic Lateral Sclerosis/*surgery ; *Cell- and Tissue-Based Therapy ; Clinical Trials as Topic/ethics/standards ; Humans ; Neurodegenerative Diseases/surgery ; *Stem Cell Transplantation/ethics/standards ; }, abstract = {Stem cell therapy is seen as a possible alternative for the treatment of different degenerative diseases, among which includes amyotrophic lateral sclerosis (ALS). Despite there being basic research works with this therapy in ALS, the mechanism of action of the implanted cells are still unclear. It is also unclear which type of cells to use (bone marrow, fat, dental pulp, etc.), or the most ideal administration route. Furthermore, clinical trials with mesenchymal stem cells are not very conclusive, therefore it has not been convincingly established as an alternative therapy in ALS or any other neurodegenerative disease. Despite the scientific evidence, several clinical trials have been conducted in the last few years that offer stem cell treatments for neurodegenerative diseases, giving rise to what is known as "cellular tourism". This phenomenon has set off alarms and reactions in the scientific community. The application of these therapies must be performed following the good clinical practice guidelines in research, evidence based methodology and international ethical and scientific recommendations.}, }
@article {pmid20962539, year = {2010}, author = {Baade, PD and Herrero Hernández, E and Freedman, DM and Smithers, BM and Fritschi, L}, title = {No role for melanoma treatment in the association between melanoma and amyotrophic lateral sclerosis or Parkinson's disease.}, journal = {Neuroepidemiology}, volume = {35}, number = {4}, pages = {303-304}, pmid = {20962539}, issn = {1423-0208}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Melanoma/*complications/*therapy ; Parkinson Disease/*complications ; }, }
@article {pmid20960930, year = {2010}, author = {Yajima, R and Kasuga, K and Sato, T and Ikeuchi, T and Nishizawa, M}, title = {[A case of amyotrophic lateral sclerosis/frontotemporal lobar degeneration with apraxia of eyelid opening].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {50}, number = {9}, pages = {645-650}, doi = {10.5692/clinicalneurol.50.645}, pmid = {20960930}, issn = {0009-918X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*physiopathology ; Apraxias/*complications ; Eyelids/*physiopathology ; Frontotemporal Lobar Degeneration/complications/*physiopathology ; Humans ; Male ; }, abstract = {We report the case of a 76-year-old man with apraxia of eyelid opening (AEO) and amyotrophic lateral sclerosis with dementia (ALS-D)/frontotemporal lobar degeneration with motor neuron disease (FTLD-MND). The initial symptom was AEO. Neurological examination revealed mainly bulbar symptoms with a neurogenic pattern on needle electromyograms of the tongue muscles and the biceps muscles. Furthermore, he developed severe dementia with frontal lobe dysfunction and progressive non-fluent aphasia. Brain magnetic resonance imaging revealed severe cerebral atrophy and leukoaraiosis in the bilateral frontal lobes and the anterior part of the bilateral temporal lobes; brain 99mTc ethyl cysteinate dimer single photon emission computed tomography (ECD SPECT) showed hypoperfusion in the same areas. The patient showed improvement in stereotyped behavior and AEO after treatment with 50 mg/day of fluvoxamine maleate (the initial dose was 25 mg/day). Because serotonin receptors are markedly reduced in the frontal and temporal cortexes of patients with FTLD, we considered that dysfunction of the serotonergic system in the frontotemporal lobe caused AEO. Considering the findings of this case along with those of previous reports, we propose that there is a relatively homogeneous development of ALS-D/FTLD-MND with AEO.}, }
@article {pmid20959524, year = {2011}, author = {Bozik, ME and Mather, JL and Kramer, WG and Gribkoff, VK and Ingersoll, EW}, title = {Safety, tolerability, and pharmacokinetics of KNS-760704 (dexpramipexole) in healthy adult subjects.}, journal = {Journal of clinical pharmacology}, volume = {51}, number = {8}, pages = {1177-1185}, doi = {10.1177/0091270010379412}, pmid = {20959524}, issn = {1552-4604}, mesh = {Adult ; Benzothiazoles/administration &amp; dosage/*adverse effects/analysis/*pharmacokinetics ; Dopamine Agonists/administration &amp; dosage/*adverse effects/analysis/*pharmacokinetics ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drugs, Investigational/administration &amp; dosage/*adverse effects/analysis/*pharmacokinetics ; Female ; Food-Drug Interactions ; Half-Life ; Humans ; Intestinal Absorption ; Male ; Metabolic Clearance Rate ; Middle Aged ; Plasma/chemistry ; Pramipexole ; Urine/chemistry ; }, abstract = {Dexpramipexole (KNS-760704; [6R]-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) is a novel synthetic amino-benzothiazole in development for the treatment of amyotrophic lateral sclerosis (ALS). Preclinical studies have shown that dexpramipexole is neuroprotective in vitro and in vivo, is highly orally bioavailable and water soluble, and rapidly achieves and maintains high central nervous system concentrations relative to plasma. Two phase 1 clinical studies were conducted to assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of dexpramipexole in 54 healthy male and female adults. The effect of food on the single-dose PK of dexpramipexole was also evaluated. Single doses (50 mg, 150 mg, or 300 mg) and multiple doses (50 mg twice daily, 100 mg twice daily, or 150 mg twice daily) of dexpramipexole over 4.5 days were safe and well tolerated. Dexpramipexole was rapidly absorbed, with time to maximum plasma concentration ranging from 1.8 to 2.6 hours and half-life ranging from 6.4 to 8.1 hours under fasted conditions, and was mostly eliminated in urine as unchanged parent drug (84%-90% of dose). Food had no effect on the single-dose PK of dexpramipexole. These findings support the ongoing development of dexpramipexole for the treatment of ALS and further evaluation of the compound's therapeutic potential in other neurodegenerative diseases.}, }
@article {pmid20954888, year = {2011}, author = {Hama, A and Sagen, J}, title = {Antinociceptive effect of riluzole in rats with neuropathic spinal cord injury pain.}, journal = {Journal of neurotrauma}, volume = {28}, number = {1}, pages = {127-134}, doi = {10.1089/neu.2010.1539}, pmid = {20954888}, issn = {1557-9042}, mesh = {Animals ; Hyperalgesia/drug therapy/etiology ; Injections, Intraperitoneal ; Injections, Intraventricular ; Injections, Spinal ; Male ; Motor Activity/drug effects ; Neuralgia/*drug therapy/etiology ; Neuroprotective Agents/*administration &amp; dosage ; Rats ; Rats, Sprague-Dawley ; Riluzole/*administration &amp; dosage ; Spinal Cord Injuries/complications/*drug therapy ; }, abstract = {Symptoms of neuropathic spinal cord injury (SCI) pain include cutaneous hypersensitivity and spontaneous pain below the level of the injury. Riluzole, an FDA-approved drug for the treatment of amyotrophic lateral sclerosis, has been demonstrated to attenuate neural excitotoxicity by blocking the effects of the excitatory amino acid glutamate on glutamate receptors and by inhibiting voltage-gated Na(+) and Ca(2+) channels. Neuropathic pain in rat models of SCI is thought to be mediated by dysfunctional ion channels and glutamate receptors expressed on CNS neurons. Thus riluzole's mechanism of action could be relevant in treating neuropathic SCI pain. The current study evaluated the antinociceptive potential of riluzole in rats following a SCI. Four weeks after a brief compressive injury to the mid-thoracic spinal cord, rats displayed significantly decreased hind paw withdrawal thresholds, suggestive of below-level cutaneous hypersensitivity. A single systemic dose of riluzole (8 mg/kg) injected intraperitoneally (i.p.) reversed cutaneous hypersensitivity in SCI rats. To identify riluzole's CNS site of action, riluzole was injected intrathecally (i.t.) and intracerebroventricularly (i.c.v.) in SCI rats. Significant antinociceptive effects were obtained following i.c.v., but not i.t., injection. Systemic riluzole was also antinociceptive in uninjured rats, increasing the latency to respond to an acute noxious thermal stimulus in the tail flick test. Unlike in SCI rats, however, riluzole was not effective when administered directly into the CNS, indicating a peripherally mediated antinociceptive mechanism. Although riluzole appears to have a general antinociceptive effect, the site of action may be model dependent. In total, these data indicate that riluzole may be an effective clinical analgesic for the treatment of below-level neuropathic SCI pain. Although the exact mechanism of action is not clear, there is a predominant supraspinal component of riluzole-induced antinociception in SCI rats.}, }
@article {pmid20950451, year = {2010}, author = {Yang, EJ and Jiang, JH and Lee, SM and Yang, SC and Hwang, HS and Lee, MS and Choi, SM}, title = {Bee venom attenuates neuroinflammatory events and extends survival in amyotrophic lateral sclerosis models.}, journal = {Journal of neuroinflammation}, volume = {7}, number = {}, pages = {69}, pmid = {20950451}, issn = {1742-2094}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*therapy ; Analysis of Variance ; Animals ; Bee Venoms/*therapeutic use ; Blotting, Western ; Brain Stem/*metabolism ; Disease Models, Animal ; Immunohistochemistry ; Kaplan-Meier Estimate ; Longevity/*physiology ; Male ; Mice ; Mice, Transgenic ; Neurons/*metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rotarod Performance Test ; Signal Transduction/physiology ; Spinal Cord/*metabolism ; Statistics, Nonparametric ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease affecting the central nervous system that is either sporadic or familial origin and causing the death of motor neurons. One of the genetic factors contributing to the etiology of ALS is mutant SOD1 (mtSOD1), which induces vulnerability of motor neurons through protein misfolding, mitochondrial dysfunction, oxidative damage, cytoskeletal abnormalities, defective axonal transport, glutamate excitotoxicity, inadequate growth factor signaling, and neuroinflammation. Bee venom has been used in the practice of Oriental medicine and evidence from the literature indicates that BV plays an anti-inflammatory or anti-nociceptive role against inflammatory reactions associated with arthritis and other inflammatory diseases. The purpose of the present study was to determine whether bee venom suppresses motor neuron loss and microglial cell activation in hSOD1G93A mutant mice.<br><br>METHODS: Bee venom (BV) was bilaterally injected (subcutaneously) into a 14-week-old (98 day old) male hSOD1G93A animal model at the Zusanli (ST36) acupoint, which is known to mediate an anti-inflammatory effect. For measurement of motor activity, rotarod test was performed and survival statistics were analyzed by Kaplan-Meier survival curves. The effects of BV treatment on anti-neuroinflammation of hSOD1G93A mice were assessed via immunoreactions using Iba 1 as a microglia marker and TNF-&#x3b1; antibody. Activation of ERK, Akt, p38 MAP Kinase (MAPK), and caspase 3 proteins was evaluated by western blotting.<br><br>RESULTS: BV-treated mutant hSOD1 transgenic mice showed a decrease in the expression levels of microglia marker and phospho-p38 MAPK in the spinal cord and brainstem. Interestingly, treatment of BV in symptomatic ALS animals improved motor activity and the median survival of the BV-treated group (139 &#xb1; 3.5 days) was 18% greater than control group (117 &#xb1; 3.1 days). Furthermore, we found that BV suppressed caspase-3 activity and blocked the defects of mitochondrial structure and cristae morphology in the lumbar spinal cord of hSOD1G93A mice at the symptomatic stage.<br><br>CONCLUSION: From these findings, our research suggests BV could be a potential therapeutic agent for anti-neuroinflammatory effects in an animal model of ALS.}, }
@article {pmid20948999, year = {2010}, author = {Liu-Yesucevitz, L and Bilgutay, A and Zhang, YJ and Vanderweyde, T and Citro, A and Mehta, T and Zaarur, N and McKee, A and Bowser, R and Sherman, M and Petrucelli, L and Wolozin, B}, title = {Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue.}, journal = {PloS one}, volume = {5}, number = {10}, pages = {e13250}, pmid = {20948999}, issn = {1932-6203}, support = {ES15567/ES/NIEHS NIH HHS/United States ; R21 NS066108/NS/NINDS NIH HHS/United States ; R01 NS041786/NS/NINDS NIH HHS/United States ; R01 ES015567/ES/NIEHS NIH HHS/United States ; NS41786/NS/NINDS NIH HHS/United States ; NS66108/NS/NINDS NIH HHS/United States ; R21 NS073679/NS/NINDS NIH HHS/United States ; R01 ES020395/ES/NIEHS NIH HHS/United States ; T32 GM008541/GM/NIGMS NIH HHS/United States ; }, mesh = {Blotting, Western ; Brain/cytology/*metabolism/pathology ; Cells, Cultured ; Cytoplasm/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Frontotemporal Lobar Degeneration/*metabolism/pathology ; Gene Knockdown Techniques ; Humans ; Mutation ; }, abstract = {Tar DNA Binding Protein-43 (TDP-43) is a principle component of inclusions in many cases of frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). TDP-43 resides predominantly in the nucleus, but in affected areas of ALS and FTLD-U central nervous system, TDP-43 is aberrantly processed and forms cytoplasmic inclusions. The mechanisms governing TDP-43 inclusion formation are poorly understood. Increasing evidence indicates that TDP-43 regulates mRNA metabolism by interacting with mRNA binding proteins that are known to associate with RNA granules. Here we show that TDP-43 can be induced to form inclusions in cell culture and that most TDP-43 inclusions co-localize with SGs. SGs are cytoplasmic RNA granules that consist of mixed protein-RNA complexes. Under stressful conditions SGs are generated by the reversible aggregation of prion-like proteins, such as TIA-1, to regulate mRNA metabolism and protein translation. We also show that disease-linked mutations in TDP-43 increased TDP-43 inclusion formation in response to stressful stimuli. Biochemical studies demonstrated that the increased TDP-43 inclusion formation is associated with accumulation of TDP-43 detergent insoluble complexes. TDP-43 associates with SG by interacting with SG proteins, such as TIA-1, via direct protein-protein interactions, as well as RNA-dependent interactions. The signaling pathway that regulates SGs formation also modulates TDP-43 inclusion formation. We observed that inclusion formation mediated by WT or mutant TDP-43 can be suppressed by treatment with translational inhibitors that suppress or reverse SG formation. Finally, using Sudan black to quench endogenous autofluorescence, we also demonstrate that TDP-43 positive-inclusions in pathological CNS tissue co-localize with multiple protein markers of stress granules, including TIA-1 and eIF3. These data provide support for accumulating evidence that TDP-43 participates in the SG pathway.}, }
@article {pmid20920073, year = {2010}, author = {Green, AJ and De-Vries, K}, title = {Cannabis use in palliative care - an examination of the evidence and the implications for nurses.}, journal = {Journal of clinical nursing}, volume = {19}, number = {17-18}, pages = {2454-2462}, doi = {10.1111/j.1365-2702.2010.03274.x}, pmid = {20920073}, issn = {1365-2702}, mesh = {Amyotrophic Lateral Sclerosis ; *Evidence-Based Medicine ; Humans ; *Marijuana Smoking ; Multiple Sclerosis ; *Nursing Care ; Palliative Care/*methods ; Quality of Life ; United Kingdom ; }, abstract = {AIM AND OBJECTIVE: Examine the pharmaceutical qualities of cannabis including a historical overview of cannabis use. Discuss the use of cannabis as a clinical intervention for people experiencing palliative care, including those with life-threatening chronic illness such as multiple sclerosis and motor neurone disease [amyotrophic lateral sclerosis] in the UK.<br><br>BACKGROUND: The non-medicinal use of cannabis has been well documented in the media. There is a growing scientific literature on the benefits of cannabis in symptom management in cancer care. Service users, nurses and carers need to be aware of the implications for care and treatment if cannabis is being used medicinally.<br><br>DESIGN: A comprehensive literature review.<br><br>METHOD: Literature searches were made of databases from 1996 using the term cannabis and the combination terms of cannabis and palliative care; symptom management; cancer; oncology; chronic illness; motor neurone disease/amyotrophic lateral sclerosis; and multiple sclerosis. Internet material provided for service users searching for information about the medicinal use of cannabis was also examined.<br><br>RESULTS: The literature on the use of cannabis in health care repeatedly refers to changes for users that may be equated with improvement in quality of life as an outcome of its use. This has led to increased use of cannabis by these service users. However, the cannabis used is usually obtained illegally and can have consequences for those who choose to use it for its therapeutic value and for nurses who are providing care.<br><br>Questions and dilemmas are raised concerning the role of the nurse when caring and supporting a person making therapeutic use of cannabis.}, }
@article {pmid20887684, year = {2011}, author = {Sanberg, PR and Eve, DJ and Willing, AE and Garbuzova-Davis, S and Tan, J and Sanberg, CD and Allickson, JG and Cruz, LE and Borlongan, CV}, title = {The treatment of neurodegenerative disorders using umbilical cord blood and menstrual blood-derived stem cells.}, journal = {Cell transplantation}, volume = {20}, number = {1}, pages = {85-94}, doi = {10.3727/096368910X532855}, pmid = {20887684}, issn = {1555-3892}, mesh = {Adult Stem Cells/*cytology/transplantation ; Blood Cells/*cytology ; Fetal Blood/*cytology ; Humans ; Neurodegenerative Diseases/*therapy ; *Stem Cell Transplantation ; }, abstract = {Stem cell transplantation is a potentially important means of treatment for a number of disorders. Two different stem cell populations of interest are mononuclear umbilical cord blood cells and menstrual blood-derived stem cells. These cells are relatively easy to obtain, appear to be pluripotent, and are immunologically immature. These cells, particularly umbilical cord blood cells, have been studied as either single or multiple injections in a number of animal models of neurodegenerative disorders with some degree of success, including stroke, Alzheimer's disease, amyotrophic lateral sclerosis, and Sanfilippo syndrome type B. Evidence of anti-inflammatory effects and secretion of specific cytokines and growth factors that promote cell survival, rather than cell replacement, have been detected in both transplanted cells.}, }
@article {pmid20874702, year = {2011}, author = {Campos, HC and da Rocha, MD and Viegas, FP and Nicastro, PC and Fossaluzza, PC and Fraga, CA and Barreiro, EJ and Viegas, C}, title = {The role of natural products in the discovery of new drug candidates for the treatment of neurodegenerative disorders I: Parkinson's disease.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {10}, number = {2}, pages = {239-250}, doi = {10.2174/187152711794480483}, pmid = {20874702}, issn = {1996-3181}, mesh = {Biological Products/chemistry/metabolism/*therapeutic use ; Central Nervous System/physiopathology ; *Drug Discovery ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/*drug therapy/pathology/physiopathology ; Neuroprotective Agents/*therapeutic use ; Parkinson Disease/*drug therapy/metabolism/physiopathology ; }, abstract = {Neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS) are currently incurable pathologies with huge social and economic impacts closely related to the increasing of life expectancy in modern times. Although the clinical and neuropathological aspects of these debilitating disorders are distinct, they share a pattern of neurodegeneration in anatomically or functionally related regions. For each disease, presently available treatments only address symptoms and do not alter the course or progression of the underlying diseases. In this context, the search for new effective chemical entities, capable of acting on diverse biochemical targets, with new mechanisms of action and low toxicity are genuine challenges to research groups and the pharmaceutical industry. This medical need has led to the reemerging of modern natural products chemistry that has yielded sophisticated and complex new lead molecules for drug discovery and development. In this review we discuss some of the main contributions of the natural products chemistry that covers multiple and varied plant species. Advances in the discovery of active constituents of plants, herbs, and extracts prescribed by traditional medicine practices for the treatment of senile neurodegenerative disorders, especially for PD, in the period after the 2000s is reviewed. The most important contributions from the 1990s are also discussed. The review also focuses on the pharmacological mechanisms of action that might underlie the purported beneficial improvements in memory and cognition, neurovascular function, and in neuroprotection. It is concluded that natural product chemistry brings tremendous diversity and historical precedent to a huge area of unmet medical need.}, }
@article {pmid20859261, year = {2010}, author = {Dodge, JC and Treleaven, CM and Fidler, JA and Hester, M and Haidet, A and Handy, C and Rao, M and Eagle, A and Matthews, JC and Taksir, TV and Cheng, SH and Shihabuddin, LS and Kaspar, BK}, title = {AAV4-mediated expression of IGF-1 and VEGF within cellular components of the ventricular system improves survival outcome in familial ALS mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {18}, number = {12}, pages = {2075-2084}, pmid = {20859261}, issn = {1525-0024}, support = {R01NS064492/NS/NINDS NIH HHS/United States ; RC2 NS069476-02/NS/NINDS NIH HHS/United States ; RC2 NS069476-01/NS/NINDS NIH HHS/United States ; RC2 NS069476/NS/NINDS NIH HHS/United States ; R01 NS064492/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*therapy ; Animals ; Central Nervous System/metabolism ; Dependovirus/genetics ; Disease Models, Animal ; Disease-Free Survival ; Embryonic Stem Cells ; Female ; *Genetic Therapy ; Immunohistochemistry ; Insulin-Like Growth Factor I/genetics/*metabolism ; Male ; Mice ; Mice, Transgenic ; Reverse Transcriptase Polymerase Chain Reaction ; Vascular Endothelial Growth Factor A/genetics/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron cell death in the cortex, brainstem, and spinal cord. Extensive efforts have been made to develop trophic factor-based therapies to enhance motor neuron survival; however, achievement of adequate therapeutic delivery to all regions of the corticospinal tract has remained a significant challenge. Here, we show that adeno-associated virus serotype 4 (AAV4)-mediated expression of insulin-like growth factor-1 (IGF-1) or vascular endothelial growth factor (VEGF)-165 in the cellular components of the ventricular system including the ependymal cell layer, choroid plexus [the primary cerebrospinal fluid (CSF)-producing cells of the central nervous system (CNS)] and spinal cord central canal leads to trophic factor delivery throughout the CNS, delayed motor decline and a significant extension of survival in SOD1(G93A) transgenic mice. Interestingly, when IGF-1- and VEGF-165-expressing AAV4 vectors were given in combination, no additional benefit in efficacy was observed suggesting that these trophic factors are acting on similar signaling pathways to modestly slow disease progression. Consistent with these findings, experiments conducted in a recently described in vitro cell culture model of ALS led to a similar result, with both IGF-1 and VEGF-165 providing significant motor neuron protection but in a nonadditive fashion. These findings support the continued investigation of trophic factor-based therapies that target the CNS as a potential treatment of ALS.}, }
@article {pmid20857664, year = {2010}, author = {Kimura, M and Saito, S}, title = {[Anesthesia for patients with neurological diseases].}, journal = {Masui. The Japanese journal of anesthesiology}, volume = {59}, number = {9}, pages = {1100-1104}, pmid = {20857664}, issn = {0021-4892}, mesh = {Anesthesia/*methods ; Demyelinating Diseases/*complications ; Humans ; Neurodegenerative Diseases/*complications ; Perioperative Care/methods ; Spinal Cord Injuries/complications ; }, abstract = {Several surgical treatments can be employed for the patients with neurological disorders, such as multiple sclerosis, Guillain-Barré syndrome, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer disease and spinal cord injury. It is possible that anesthesia related complications are induced in these neurologically complicated patients in the perioperative period. Respiratory dysfunction and autonomic nervous system dysfunction are most common in this population. Respiratory muscle weakness and bulbar palsy may cause aspiration pneumonia. Sometimes, postoperative ventilatory support is mandatory in these patients. Autonomic nervous system dysfunction may cause hypotension secondary to postural changes, blood loss, or positive airway pressure. Some therapeutic agents prescribed for neurological symptoms have drug interaction with anesthetic agents. Patients with motor neuron disease should be considered to be vulnerable to hyperkalemia in response to a depolarizing muscle relaxant. Although perioperative treatment guideline for most neurologic disorders has not been reported to lessen perioperative morbidity, knowledge of the clinical features and the interaction of common anesthetics with the drug therapy is important in planning intraoperative and postoperative management.}, }
@article {pmid20849322, year = {2010}, author = {Chen, Z and Turner, MR}, title = {The internet for self-diagnosis and prognostication in ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {6}, pages = {565-567}, pmid = {20849322}, issn = {1471-180X}, support = {G0701923/MRC_/Medical Research Council/United Kingdom ; TURNER/NOV07/6501/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Humans ; *Internet ; Patient Education as Topic ; Prognosis ; }, abstract = {Persons with ALS, and those close to them, may use the internet to explore symptoms prior to formal diagnosis, and as a source of information about prognosis and treatment thereafter. We used an internet search engine to rank the sensitivity of a variety of symptom search terms a patient might use for the diagnosis of ALS/MND. We also studied search engine responses to questions about life expectancy and possible 'cure'. An internet search engine in relation to ALS currently lacks sensitivity, and results varied greatly with only minor differences in the search terms used. The prognostic information did not reflect the inherent heterogeneity. Results in relation to 'cure' were misleading and may promulgate false hopes. There is a need to guide those with ALS (and particularly their children) to sources of reliable web-based information in addition to open discussion.}, }
@article {pmid20845315, year = {2010}, author = {Sporer, KA and Craig, AM and Johnson, NJ and Yeh, CC}, title = {Does emergency medical dispatch priority predict delphi process-derived levels of prehospital intervention?.}, journal = {Prehospital and disaster medicine}, volume = {25}, number = {4}, pages = {309-317}, doi = {10.1017/s1049023x00008244}, pmid = {20845315}, issn = {1049-023X}, mesh = {*Advanced Cardiac Life Support ; California ; Delphi Technique ; Emergency Service, Hospital/*organization &amp; administration ; Humans ; Retrospective Studies ; Sensitivity and Specificity ; Triage/*methods ; }, abstract = {OBJECTIVE: The Medical Priority Dispatch System (MPDS) is an emergency medical dispatch system widely used to prioritize 9-1-1 calls and optimize resource allocation. This study evaluates whether the assigned priority predicts a Delphi process-derived level of prehospital intervention in each emergency medical dispatch category.<br><br>METHODS: All patients given a MPDS priority in a suburban California county from 2004-2006 were included. A Delphi process of emergency medical services (EMS) professionals in another system developed the following categories of prehospital treatment representing increasing acuity, which were adapted for this study: advanced life support (ALS) intervention, ALS-Stat, and ALS-Critical. The sensitivities and specificities of MPDS priority for level of prehospital intervention were determined for each MPDS category. Likelihood ratios of low and high priority dispatch codes for the level of prehospital intervention also were calculated for each MPDS category.<br><br>RESULTS: A total of 65,268 patients met inclusion criteria, representing 61% of EMS calls during the study period. The overall sensitivities of high-priority dispatch codes for ALS, ALS-Stat, and ALS-Critical interventions were 83% (95% confidence interval 83-84%), 83% (82-84%), and 94% (92-96%). Overall specificities were: ALS, 32% (31-32%); ALS-Stat, 31% (30-31%); and ALS-Critical 28% (28-29%). Compared to calls assigned to a low priority, calls with high-priority dispatch codes were more likely to receive ALS interventions by 22%, ALS-Stat by 20%, and ALS-Critical by 32%. A low priority dispatch code decreased the likelihood of ALS interventions by 48%, ALS-Stat by 45%, and ALS-Critical by 80%. Among high-priority dispatch codes, the rates of interventions were: ALS 26%, ALS-Stat 22%, and ALS-Critical 1.5%, all of which were significantly greater than low-priority calls (p<0.05) [ALS 13%, ALS-Stat 11%, and ALS-Critical 0.2%]. Major MPDS were categories with high sensitivities (>95%) for ALS interventions included breathing problems, cardiac or respiratory arrest/death, chest pain, stroke, and unconscious/fainting; these categories had an average specificity of 3%. Medical Priority Dispatch System categories such as back pain, unknown problem, and traumatic injury had sensitivities for ALS interventions<15%.<br><br>CONCLUSIONS: The MPDS is moderately sensitive for the Delphi process derived ALS, ALS-Stat, and ALS-Critical intervention levels, but nonspecific. A low MPDS priority is predictive of no prehospital intervention. A high priority, however, is of little predictive value for ALS, ALS-Stat, or ALS-Critical interventions.}, }
@article {pmid20839238, year = {2010}, author = {Pioro, EP and Brooks, BR and Cummings, J and Schiffer, R and Thisted, RA and Wynn, D and Hepner, A and Kaye, R and , }, title = {Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect.}, journal = {Annals of neurology}, volume = {68}, number = {5}, pages = {693-702}, doi = {10.1002/ana.22093}, pmid = {20839238}, issn = {1531-8249}, mesh = {Adolescent ; Adult ; Affective Symptoms/*drug therapy ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/complications ; Dextromethorphan/*administration &amp; dosage/adverse effects ; Dose-Response Relationship, Drug ; Drug Combinations ; Electrocardiography/drug effects ; Female ; Humans ; Male ; Middle Aged ; Multiple Sclerosis/complications ; Oxygen/blood ; Quinidine/*administration &amp; dosage/adverse effects ; }, abstract = {OBJECTIVE: To evaluate dextromethorphan combined with ultra low-dose quinidine (DMq) for treating pseudobulbar affect (PBA) in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS).<br><br>METHODS: In a 12-week randomized, double-blind trial, ALS and MS patients with clinically significant PBA (a baseline score &#x2265;13 on the Center for Neurologic Studies-Lability Scale [CNS-LS]) were maintained, twice daily, on placebo, DMq at 30/10mg (DMq-30), or DMq at 20/10mg (DMq-20).<br><br>RESULTS: In 326 randomized patients (of whom 283, or 86.8%, completed the study), the PBA-episode daily rate was 46.9% (p < 0.0001) lower for DMq-30 than for placebo and 49.0% (p < 0.0001) lower for DMq-20 than for placebo by longitudinal negative binomial regression, the prespecified primary analysis. Mean CNS-LS scores decreased by 8.2 points for DMq-30 and 8.2 for DMq-20, vs 5.7 for placebo (p= 0.0002 and p= 0.0113, respectively). Other endpoints showing statistically significant DMq benefit included, for both dosage levels, the likelihood of PBA remission during the final 14 days and, for the higher dosage, improvement on measures of social functioning and mental health. Both dosages were safe and well tolerated.<br><br>INTERPRETATION: DMq markedly reduced PBA frequency and severity, decreasing the condition's detrimental impact on a patient's life, with satisfactory safety and high tolerability. The findings expand the clinical evidence that DMq may be an important treatment for patients suffering from the socially debilitating symptoms of PBA.}, }
@article {pmid20832409, year = {2010}, author = {Carunchio, I and Curcio, L and Pieri, M and Pica, F and Caioli, S and Viscomi, MT and Molinari, M and Canu, N and Bernardi, G and Zona, C}, title = {Increased levels of p70S6 phosphorylation in the G93A mouse model of Amyotrophic Lateral Sclerosis and in valine-exposed cortical neurons in culture.}, journal = {Experimental neurology}, volume = {226}, number = {1}, pages = {218-230}, doi = {10.1016/j.expneurol.2010.08.033}, pmid = {20832409}, issn = {1090-2430}, mesh = {Action Potentials/drug effects ; Amino Acids, Branched-Chain/metabolism ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Animals ; Blotting, Western ; Cell Survival/drug effects ; Cells, Cultured ; Cerebral Cortex/cytology/drug effects/*metabolism ; Dose-Response Relationship, Drug ; Electrophysiology ; Humans ; Immunosuppressive Agents/pharmacology ; Intracellular Signaling Peptides and Proteins/metabolism ; Mice ; Mice, Transgenic ; Neurons/drug effects/*metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases/metabolism ; Sirolimus/pharmacology ; Sodium Channels/drug effects ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; TOR Serine-Threonine Kinases ; Valine/*pharmacology ; }, abstract = {The higher risk factor for Amyotrophic Lateral Sclerosis (ALS) among Italian soccer players is a question that is still debated. One of the hypotheses that have been formulated to explain a possible link between ALS and soccer players is related to the abuse of dietary supplements and drugs for enhancing sporting performance. In particular, it has been reported that branched-chain amino acids (BCAAs) are widely used among athletes as nutritional supplements. To observe the possible effect of BCAAs on neuronal electrical properties, we performed electrophysiological experiments on Control cultured cortical neurons and on neurons after BCAA treatment. BCAA-treated neurons showed hyperexcitability and rapamycin was able to suppress it and significantly reduce the level of mTOR, Akt and p70S6 phosphorylation. Interestingly, the hyperexcitability previously reported in cortical neurons from a genetic mouse model of ALS (G93A) was also reversed by rapamycin treatment. Moreover, both G93A and valine-treated neurons presented significantly higher levels of Pp70S6 when compared to control neurons, strongly indicating the involvement of this substrate in ALS pathology. Finally, we performed electrophysiological experiments on motor cortex slices from Control and G93A mice and those fed with a BCAA-enriched diet. We observed that neuron excitability was comparable between G93A and BCAA-enriched diet mice, but was significantly higher than in Control mice. These findings, besides strongly indicating that BCAAs specifically induce hyperexcitability, seem to suggest the involvement of p70S6 substrate in ALS pathology.}, }
@article {pmid20832222, year = {2010}, author = {Khiat, A and D'Amour, M and Souchon, F and Boulanger, Y}, title = {MRS study of the effects of minocycline on markers of neuronal and microglial integrity in ALS.}, journal = {Magnetic resonance imaging}, volume = {28}, number = {10}, pages = {1456-1460}, doi = {10.1016/j.mri.2010.06.032}, pmid = {20832222}, issn = {1873-5894}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/*metabolism ; Anti-Bacterial Agents/therapeutic use ; Biomarkers/analysis ; Brain/drug effects/*metabolism ; Female ; Humans ; Magnetic Resonance Imaging/*methods ; Male ; Microglia/drug effects/*metabolism ; Middle Aged ; Minocycline/*administration &amp; dosage ; Neurons/drug effects/*metabolism ; Tissue Distribution ; }, abstract = {OBJECTIVE: Magnetic resonance spectroscopy (MRS) allows to monitor brain metabolites noninvasively in amyotrophic lateral sclerosis (ALS). The objective of this study was to use MRS to monitor the effect of minocycline treatment (200 mg/day) over a short period (6 weeks) on the brain metabolites in the precentral gyrus and brainstem in newly diagnosed ALS patients.<br><br>METHODS: Ten ALS patients (not on riluzole treatment) were recruited and submitted to single-voxel proton MRS longitudinal examinations (1) before minocycline treatment, (2) 3 weeks and (3) 6 weeks after initiation of treatment.<br><br>RESULTS: Results did not show the expected decrease of N-acetylaspartate/creatine (NAA/Cr) in the precentral gyrus, and an increased NAA/Cr ratio in the brainstem suggested neuronal recovery. The myo-inositol (mI)/Cr ratio was unchanged in the precentral gyrus, but increased in the brainstem, indicating a glial reaction.<br><br>CONCLUSIONS: MRS results suggest that minocycline treatment could be beneficial in the early stages of ALS.}, }
@article {pmid20827423, year = {2010}, author = {Li, S and Hu, GF}, title = {Angiogenin-mediated rRNA transcription in cancer and neurodegeneration.}, journal = {International journal of biochemistry and molecular biology}, volume = {1}, number = {1}, pages = {26-35}, pmid = {20827423}, issn = {2152-4114}, support = {R01 CA105241/CA/NCI NIH HHS/United States ; R01 CA105241-05/CA/NCI NIH HHS/United States ; R01 NS065237/NS/NINDS NIH HHS/United States ; R01 NS065237-01A1/NS/NINDS NIH HHS/United States ; }, abstract = {Angiogenin (ANG) is a 14 kDa angiogenic ribonuclease that is upregulated in a variety of human cancers. Accumulating evidence indicates that the angiogenic activity of ANG is related to its ability in regulating ribosomal RNA (rRNA) transcription. ANG is translocated to the nucleus of growth-stimulated endothelial cells where it accumulates in the nucleolus, binds to the promoter region of ribosomal DNA (rDNA), and stimulates rRNA transcription. This normally well-controlled process of nuclear translocation of ANG is hijacked by cancer cells that constitutively uptake ANG and translocate it into the nucleus so that rRNA is constantly transcribed to meet a higher metabolic requirement of this cells. Nuclear translocation of ANG therefore controls the rate of rRNA transcription and has been shown to be a molecular target for cancer drug development. Recently, ANG has also been shown to play a role in motor neuron physiology. Loss-of-function mutations in the coding region of ANG gene have been found in patients with amyotrophic lateral sclerosis (ALS). A deficiency in ANG function may result in insufficient rRNA transcription in motor neurons that require robust ribosome biogenesis due to the demand of long axonal transport. Haploinsufficiency of ANG has thus been implicated in ALS pathogenesis, and ANG has been shown to promote motor neuron survival both in vitro and in vivo. Promotion of ANG expression or activity has been recognized as a therapeutic opportunity for ALS treatment.}, }
@article {pmid20827122, year = {2010}, author = {Mondok, A and Aranyi, Z and Kovacs, GG and Czirjak, S and Pusztai, P and Varga, I and Racz, K}, title = {Rapid progression of amyotrophic lateral sclerosis in an acromegalic patient after surgical resection of a growth hormone-producing pituitary adenoma.}, journal = {The neurologist}, volume = {16}, number = {5}, pages = {315-318}, doi = {10.1097/NRL.0b013e3181b46fef}, pmid = {20827122}, issn = {2331-2637}, mesh = {*Acromegaly/drug therapy/physiopathology/surgery ; Aged ; *Amyotrophic Lateral Sclerosis/etiology/physiopathology ; Antineoplastic Agents, Hormonal/therapeutic use ; *Disease Progression ; Fatal Outcome ; Female ; *Growth Hormone-Secreting Pituitary Adenoma/complications/drug therapy/surgery ; Human Growth Hormone/deficiency/therapeutic use ; Humans ; Insulin-Like Growth Factor I/metabolism ; Octreotide/therapeutic use ; *Pituitary Neoplasms/complications/drug therapy/surgery ; }, abstract = {INTRODUCTION: Insulin-like growth factor-1 (IGF-1) promotes the survival of neurons, mediates neuritic growth, and in 1 clinical trial human recombinant IGF-1 delayed the progression of functional impairment and decline of health-related quality of life in patients with amyotrophic lateral sclerosis (ALS).<br><br>CASE REPORT: We describe a case of a 65-year-old woman with a 2-year history of symptoms and signs of acromegaly because of a pituitary microadenoma. The patient posed a challenging diagnostic dilemma because of the presence of dysarthria, which was initially considered as the consequence of acromegaly. After octreotide long-acting release (LAR) treatment, the patient underwent uneventful pituitary surgery. Although postoperative evaluation indicated a cure of acromegaly, progressive bulbar symptoms developed, which were followed by upper limb weakness and muscle atrophy. Neurologic investigations confirmed the diagnosis of ALS and riluzole therapy was given. One year after surgery growth-hormone deficiency was diagnosed, but a trial with human recombinant growth hormone failed to produce any significant improvement. Two years after surgery the patient died of a sudden respiratory arrest. Histopathologic examination of the brain and spinal cord confirmed the diagnosis of ALS.<br><br>CONCLUSIONS: This is the first report showing a rapid progression of ALS after a surgical cure of coexisting acromegaly presumably because of cessation of high endogenous IGF-I levels.}, }
@article {pmid20825775, year = {2011}, author = {Alter, SM and Merlin, MA}, title = {Nosocomial and community-acquired infection rates of patients treated by prehospital advanced life support compared with other admitted patients.}, journal = {The American journal of emergency medicine}, volume = {29}, number = {1}, pages = {57-64}, doi = {10.1016/j.ajem.2009.07.020}, pmid = {20825775}, issn = {1532-8171}, mesh = {Advanced Cardiac Life Support/adverse effects/*statistics &amp; numerical data ; Aged ; Community-Acquired Infections/*epidemiology ; Confidence Intervals ; Cross Infection/*epidemiology ; Emergency Medical Services/*statistics &amp; numerical data ; Female ; Hospitalization/*statistics &amp; numerical data ; Humans ; Male ; Middle Aged ; New Jersey/epidemiology ; Odds Ratio ; Retrospective Studies ; }, abstract = {OBJECTIVES: Nosocomial infections are a large burden to both patients and health care organizations, causing hospitals to take measures in an attempt to reduce microorganism transmission. Patients treated by emergency medical services are one population that has not been studied regarding infection rates. This study examines admitted patients treated by advanced life support (ALS) and their likelihood of having community-acquired and nosocomial infections.<br><br>METHODS: A retrospective cohort study was conducted of 154&#x2005;318 admitted patients between 2003 and 2007. Subjects identified as having either community-acquired or nosocomial infections were grouped based on infection type and ALS treatment. The proportion of infected patients among total hospital admissions in each of these groups was calculated and compared using odds ratios (ORs).<br><br>RESULTS: A total of 5418 patients had at least 1 infection while admitted (3653 nosocomial, 1765 community). The probability of an ALS patient getting a nosocomial infection was 3.20% versus 2.28% for non-ALS patients (OR, 1.42; 95% confidence interval [CI], 1.28-1.57). There was no significant difference in community-acquired infections between ALS and non-ALS-treated groups (1.22% vs 1.14%; OR, 1.08; 95% CI, 0.92-1.26).<br><br>CONCLUSIONS: Despite having similar rates of community-acquired infections, patients admitted after ALS treatment had significantly greater risk for nosocomial infections. Because causality is not established, it remains unknown whether paramedic interventions contributed to the increased rate. Quite possibly, these patients are more susceptible to virulent organisms; however, prospective research is needed to identify causal relationships. Thus, treatment by ALS can be used as an identifier of patients at an increased risk of acquiring nosocomial infections.}, }
@article {pmid20813874, year = {2010}, author = {Antonietti, L and Sheth, SA and Halbach, VV and Higashida, RT and Dowd, CF and Lawton, MT and English, JD and Hetts, SW}, title = {Long-term outcome in the repair of spinal cord perimedullary arteriovenous fistulas.}, journal = {AJNR. American journal of neuroradiology}, volume = {31}, number = {10}, pages = {1824-1830}, pmid = {20813874}, issn = {1936-959X}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Angiography ; Arteriovenous Fistula/diagnostic imaging/*surgery/*therapy ; Child ; Child, Preschool ; *Embolization, Therapeutic ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Postoperative Complications ; Retrospective Studies ; Spinal Cord/blood supply ; Treatment Outcome ; *Vascular Surgical Procedures ; Young Adult ; }, abstract = {BACKGROUND AND PURPOSE: The natural history of PMAVFs, also known as type IV spinal cord AVFs, is incompletely understood. Both open surgical and endovascular approaches have been described as treatment modalities for this disease. The goal of this study was to evaluate the long-term outcome of patients with PMAVFs treated at a single tertiary care institution.<br><br>MATERIALS AND METHODS: We conducted a retrospective study of 32 patients with PMAVFs, evaluated between 1983 and 2009. Data were gathered by reviewing outpatient clinic notes, operative and radiologic reports, and spinal angiograms. The PMAVFs were categorized into 1 of 3 types based on the angiographic imaging criteria. Pretreatment and posttreatment ambulation and micturition symptoms were quantified by using the ALS.<br><br>RESULTS: Thirty patients underwent corrective procedures, 4 by embolization alone, 11 by surgery alone, and 15 with a combination of the 2. Twenty-eight patients underwent follow-up spinal angiography, with residual shunt noted in 6 patients. The mean follow-up period was 54 months (range, 1-228 months). Analysis of the ALS scores revealed that treatment of PMAVFs, independent of technique, resulted in significant improvement in ambulation but inconsistent changes in micturition. In addition, residual fistula at the time of the follow-up angiogram was associated with worsened neurologic status or lack of improvement. Outcome analysis based on fistula type showed dramatic improvement in ALS ambulation scores (62%) for type 3 fistulas, compared with types 1 and 2 (26% and 27%, respectively).<br><br>CONCLUSIONS: Significant improvement in ambulation but in not micturition was observed following treatment. Residual fistula on follow-up angiography was associated with progressive worsening or lack of improvement in neurologic function. Patients with type 3 fistulas were shown to benefit most from treatment, with marked improvement in posttreatment ambulation scores. As endovascular and surgical techniques continue to evolve, further studies are warranted.}, }
@article {pmid20732599, year = {2010}, author = {Coates, JR and Wininger, FA}, title = {Canine degenerative myelopathy.}, journal = {The Veterinary clinics of North America. Small animal practice}, volume = {40}, number = {5}, pages = {929-950}, doi = {10.1016/j.cvsm.2010.05.001}, pmid = {20732599}, issn = {1878-1306}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy/*veterinary ; Animals ; Dog Diseases/diagnosis/*genetics/therapy ; Dogs ; Female ; Genetic Predisposition to Disease ; Male ; Muscular Diseases/diagnosis/genetics/therapy/*veterinary ; Mutation, Missense ; Species Specificity ; Superoxide Dismutase/*genetics ; }, abstract = {Canine degenerative myelopathy (DM) is an adult-onset fatal neurodegenerative disease that occurs in many breeds. The initial upper motor neuron spastic paraparesis and general proprioceptive ataxia in the pelvic limbs progress to a flaccid lower motor neuron tetraparesis. Recently, a missense mutation in the superoxide dismutase 1 (SOD1) gene was found to be a risk factor for DM, suggesting that DM is similar to some forms of human amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). This article reviews the current knowledge of canine DM with regard to its signalment, clinical spectrum, diagnostic approach, and treatment. The implications of the SOD1 mutation on both diseases are discussed, comparing pathogenic mechanisms while conveying perspectives to translational medicine.}, }
@article {pmid20726497, year = {2010}, author = {Veldink, JH and Weikamp, J and Schelhaas, HJ and van den Berg, LH}, title = {[Amyotrophic lateral sclerosis].}, journal = {Nederlands tijdschrift voor tandheelkunde}, volume = {117}, number = {7-8}, pages = {380-382}, doi = {10.5177/ntvt.2010.08.10122}, pmid = {20726497}, issn = {0028-2200}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/mortality/*therapy ; Humans ; Muscles/*physiopathology ; Neuroprotective Agents/*therapeutic use ; Quality of Life ; Riluzole/*therapeutic use ; Survival Analysis ; Time Factors ; }, abstract = {Amyotrophic lateral sclerosis is one of the most severe and disabling diseases of the nervous system. Amyotrophic lateral sclerosis leads to the progressive weakening of the muscles in the arms, legs, face, mouth and trunk. The onset of the disease is insidious, starting with weakness in the hands or feet or with slurred speech. The weakness worsens and patients pass away as a result of weakness of the respiratory muscles on average within 3 years of the onset of the disease. In the Netherlands, approximately 400 patients are diagnosed with amyotrophic lateral sclerosis every year. There is no diagnostic test for this neuro-muscular disease; the diagnosis is established by excluding other disorders that resemble amyotrophic lateral sclerosis. Only one drug is able to inhibit the progression of the disease to any extent: riluzole. Treatment, therefore, is mainly focused on supportive measures and those which enhance the quality of life optimally.}, }
@article {pmid20721828, year = {2010}, author = {Martin, LJ}, title = {Olesoxime, a cholesterol-like neuroprotectant for the potential treatment of amyotrophic lateral sclerosis.}, journal = {IDrugs : the investigational drugs journal}, volume = {13}, number = {8}, pages = {568-580}, pmid = {20721828}, issn = {2040-3410}, support = {R01 NS065895-01/NS/NINDS NIH HHS/United States ; R01 NS052098/NS/NINDS NIH HHS/United States ; NS052098/NS/NINDS NIH HHS/United States ; R01 AG016282-01A1/AG/NIA NIH HHS/United States ; R01 NS052098-02/NS/NINDS NIH HHS/United States ; AG016282/AG/NIA NIH HHS/United States ; R01 NS065895/NS/NINDS NIH HHS/United States ; R01 AG016282/AG/NIA NIH HHS/United States ; NS065895/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Cholestenones/adverse effects/pharmacology/*therapeutic use ; Humans ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Permeability Transition Pore ; Neuroprotective Agents/adverse effects/pharmacology/*therapeutic use ; }, abstract = {Effective therapies are needed for amyotrophic lateral sclerosis (ALS), a debilitating and fatal motor neuron disease. Cell and animal models of ALS are beginning to reveal possible principles governing the biology of motor neuron-selective vulnerability that implicate mitochondria and the mitochondrial permeability pore (mPTP). Proteins associated with the mPTP are known to be enriched in motor neurons and the genetic deletion of a major regulator of the mPTP has robust effects in ALS transgenic mice, delaying disease onset and extending survival. Thus, the mPTP is a rational, mechanism-based target for the development of drugs designed to treat ALS. Trophos SA has discovered olesoxime (TRO-19622), a small-molecule with a cholesterol-like structure, which has remarkable neuroprotective properties for motor neurons in cell culture and in rodents. Olesoxime appears to act on mitochondria, possibly at the mPTP. Phase I clinical trials of olesoxime have been completed successfully. Olesoxime is well tolerated and achieves levels predicted to be clinically effective when administered orally. It has been granted orphan drug status for the treatment of ALS in the US and for the treatment of spinal muscular atrophy in the EU. Phase II/III clinical trials are in progress in Europe.}, }
@article {pmid20717630, year = {2010}, author = {Chen, J and Wang, ZF}, title = {[Roles of cyclin-dependent kinase 5 in central nervous system development and neurodegenerative diseases].}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {62}, number = {4}, pages = {295-308}, pmid = {20717630}, issn = {0371-0874}, mesh = {Alzheimer Disease/physiopathology ; Animals ; Central Nervous System/*growth &amp; development ; Cyclin-Dependent Kinase 5/*physiology ; Humans ; Huntington Disease/physiopathology ; Neurodegenerative Diseases/enzymology/*physiopathology ; Neuronal Plasticity/*physiology ; Neurons/cytology ; Parkinson Disease/physiopathology ; Synaptic Transmission/physiology ; }, abstract = {Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase, and plays multiple roles in neuron development and synaptic plasticity. The active form of Cdk5 is found primarily in the central nervous system (CNS) due to its activator proteins p35 or p39 ubiquitously expressed in neuronal cells. Normally, the transcription and activity of Cdk5 are strictly regulated by several ways. In the physiological condition, Cdk5 plays a key role in the CNS development by phosphorylating the specific serine or threonine site of numerous substrate proteins that are closely associated with the neuronal migration, synaptogenesis, synaptic transmission as well as synaptic plasticity. Under pathological conditions, p35 can be truncated into p25, which can strongly and consistently activate Cdk5, change the cellular localization of Cdk5 and lead to neuronal death ultimately. The increasing evidence has showed that Cdk5 is involved in the pathogenesis of many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis etc., indicating that Cdk5 may be a potential target in the treatment of the neurodegenerative diseases. In this article, we reviewed the recent progress regarding the roles of Cdk5 in CNS development and neurodegenerative diseases.}, }
@article {pmid20713046, year = {2010}, author = {McDowell, KA and Hadjimarkou, MM and Viechweg, S and Rose, AE and Clark, SM and Yarowsky, PJ and Mong, JA}, title = {Sleep alterations in an environmental neurotoxin-induced model of parkinsonism.}, journal = {Experimental neurology}, volume = {226}, number = {1}, pages = {84-89}, pmid = {20713046}, issn = {1090-2430}, support = {R01 HL085037/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Arousal/drug effects ; Cycas/chemistry/toxicity ; Data Interpretation, Statistical ; Electroencephalography/drug effects ; Electromyography ; Environmental Exposure ; Hypothalamic Hormones/biosynthesis ; Immunohistochemistry ; Intracellular Signaling Peptides and Proteins/physiology ; Male ; Melanins/biosynthesis ; Nerve Degeneration/pathology ; Neuropeptides/biosynthesis/physiology ; Neurotoxins/*toxicity ; Orexins ; Parkinson Disease, Secondary/*chemically induced/*physiopathology/psychology ; Pituitary Hormones/biosynthesis ; Proto-Oncogene Proteins c-fos/biosynthesis ; Rats ; Rats, Sprague-Dawley ; Seeds/chemistry ; Sleep/*physiology ; Sleep, REM ; Synaptic Transmission/drug effects/physiology ; }, abstract = {Parkinson's disease (PD) is classically defined as a motor disorder resulting from decreased dopamine production in the basal ganglia circuit. In an attempt to better diagnose and treat PD before the onset of severe motor dysfunction, recent attention has focused on the early, non-motor symptoms, which include but are not limited to sleep disorders such as excessive daytime sleepiness (EDS) and REM behavioral disorder (RBD). However, few animal models have been able to replicate both the motor and non-motor symptoms of PD. Here, we present a progressive rat model of parkinsonism that displays disturbances in sleep/wake patterns. Epidemiological studies elucidated a link between the Guamanian variant of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) and the consumption of flour made from the washed seeds of the plant Cycas micronesica (cycad). Our study examined the effects of prolonged cycad consumption on sleep/wake activity in male, Sprague-Dawley rats. Cycad-fed rats exhibited an increase in length and/or number of bouts of rapid eye movement (REM) sleep and Non-REM (NREM) sleep at the expense of wakefulness during the active period when compared to control rats. This hypersomnolent behavior suggests an inability to maintain arousal. In addition, cycad-fed rats had significantly fewer orexin cells in the hypothalamus. Our results reveal a novel rodent model of parkinsonism that includes an EDS-like syndrome that may be associated with a dysregulation of orexin neurons. Further characterization of this early, non-motor symptom, may provide potential therapeutic interventions in the treatment of PD.}, }
@article {pmid20705090, year = {2010}, author = {Chiu, CT and Chuang, DM}, title = {Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders.}, journal = {Pharmacology &amp; therapeutics}, volume = {128}, number = {2}, pages = {281-304}, pmid = {20705090}, issn = {1879-016X}, support = {//Intramural NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/drug effects/physiology ; Bipolar Disorder/diagnosis/*drug therapy/metabolism ; Central Nervous System Diseases/diagnosis/*drug therapy/metabolism ; Clinical Trials as Topic/methods ; Drug Evaluation, Preclinical/methods ; Humans ; Lithium/*pharmacology/*therapeutic use ; Neurodegenerative Diseases/diagnosis/*drug therapy/metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {Lithium has been used clinically to treat bipolar disorder for over half a century, and remains a fundamental pharmacological therapy for patients with this illness. Although lithium's therapeutic mechanisms are not fully understood, substantial in vitro and in vivo evidence suggests that it has neuroprotective/neurotrophic properties against various insults, and considerable clinical potential for the treatment of several neurodegenerative conditions. Evidence from pharmacological and gene manipulation studies support the notion that glycogen synthase kinase-3 inhibition and induction of brain-derived neurotrophic factor-mediated signaling are lithium's main mechanisms of action, leading to enhanced cell survival pathways and alteration of a wide variety of downstream effectors. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, lithium also contributes to calcium homeostasis and suppresses calcium-dependent activation of pro-apoptotic signaling pathways. In addition, lithium decreases inositol 1,4,5-trisphosphate by inhibiting phosphoinositol phosphatases, a process recently identified as a novel mechanism for inducing autophagy. Through these mechanisms, therapeutic doses of lithium have been demonstrated to defend neuronal cells against diverse forms of death insults and to improve behavioral as well as cognitive deficits in various animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, as well as Huntington's, Alzheimer's, and Parkinson's diseases, among others. Several clinical trials are also underway to assess the therapeutic effects of lithium for treating these disorders. This article reviews the most recent findings regarding the potential targets involved in lithium's neuroprotective effects, and the implication of these findings for the treatment of a variety of diseases.}, }
@article {pmid20698807, year = {2011}, author = {Beghi, E and Chiò, A and Couratier, P and Esteban, J and Hardiman, O and Logroscino, G and Millul, A and Mitchell, D and Preux, PM and Pupillo, E and Stevic, Z and Swingler, R and Traynor, BJ and Van den Berg, LH and Veldink, JH and Zoccolella, S and , }, title = {The epidemiology and treatment of ALS: focus on the heterogeneity of the disease and critical appraisal of therapeutic trials.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {12}, number = {1}, pages = {1-10}, pmid = {20698807}, issn = {1471-180X}, support = {ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; ZIA AG000933-05/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/drug therapy/*epidemiology/metabolism/*therapy ; Antioxidants/therapeutic use ; Clinical Trials as Topic ; Enteral Nutrition ; Europe/epidemiology ; Glutamic Acid/metabolism ; Humans ; Incidence ; Intercellular Signaling Peptides and Proteins/therapeutic use ; Middle Aged ; Prognosis ; Randomized Controlled Trials as Topic ; Registries ; Research Design ; Respiration, Artificial ; Riluzole/therapeutic use ; Treatment Outcome ; United States/epidemiology ; White People/statistics &amp; numerical data ; }, abstract = {Abstract Effective treatments for amyotrophic lateral sclerosis (ALS) have remained elusive. Only riluzole, a drug thought to affect glutamate metabolism, improves survival albeit to modest extent. Explanations for the negative results of therapeutic trials include a likely heterogeneity, both in disease susceptibility and pathogenic mechanisms, and faulty methodology of clinical trials. Further understanding of these factors will lead to improvements in patient stratification, and in the design of future clinical trials.}, }
@article {pmid20679994, year = {2010}, author = {Domené, HM and Scaglia, PA and Jasper, HG}, title = {Deficiency of the insulin-like growth factor-binding protein acid-labile subunit (ALS) of the circulating ternary complex in children with short stature.}, journal = {Pediatric endocrinology reviews : PER}, volume = {7}, number = {4}, pages = {339-346}, pmid = {20679994}, issn = {1565-4753}, mesh = {Animals ; Body Height ; Body Weight ; Bone and Bones/metabolism ; Carrier Proteins/genetics/metabolism ; Child ; Glycoproteins/*deficiency/genetics/metabolism ; Growth Disorders/genetics/*metabolism ; Humans ; Insulin Resistance ; Insulin-Like Growth Factor Binding Protein 3/*deficiency/genetics/metabolism ; Insulin-Like Growth Factor I/*deficiency/genetics/metabolism ; Male ; Mice ; }, abstract = {The acid-labile subunit (ALS) protein is a key component of the circulating 150-kDa IGF ternary complex. The main role of ALS is the extension of IGF-I half life by protecting it from degradation and preventing the passage of IGF-I to the extravascular compartment. In humans, complete ALS deficiency is characterized by severe reduction of IGF-I and IGFBP-3 that remain low after GH treatment, associated with mild growth retardation, much less pronounced than the IGF-I deficit. Pubertal delay in boys and insulin insensitivity are common findings. At least 21 patients with ALS deficiency have been described presenting 16 different homozygous or compound heterozygous inactivating mutations of the IGFALS gene. Although the effect of ALS deficiency on prenatal growth is still uncertain, postnatal growth is clearly affected, with the majority of the patients presenting a height between -2 to -3 SDS before and during puberty. In the assessment of a child with short stature ALS deficiency should be considered in those patients presenting: 1) a normal response to GH stimulation test, 2) low IGF-I levels associated with more profoundly reduced IGFBP-3 levels, 3) a mild growth retardation, apparently out of proportion to the degree of IGF-I and IGFBP-3 deficits, 4) lack of response to an IGF generation test and 5) insulin insensitivity. The relatively mild growth retardation in relation to the severe IGF-I deficit might be related to the preserved autocrine/paracrine action of locally produced IGF-I. The observation that in families of ALS deficient patients, heterozygous carriers for IGFALS gene mutations are shorter than their wild type relatives and the relatively high frequency of heterozygosity for this gene in children with idiopathic short stature suggests a requirement of normal levels of ALS for the attainment of maximal growth potential.}, }
@article {pmid20679254, year = {2010}, author = {Fonagy, P}, title = {Psychotherapy research: do we know what works for whom?.}, journal = {The British journal of psychiatry : the journal of mental science}, volume = {197}, number = {2}, pages = {83-85}, doi = {10.1192/bjp.bp.110.079657}, pmid = {20679254}, issn = {1472-1465}, mesh = {Humans ; *Patient Selection ; *Psychotherapy ; Randomized Controlled Trials as Topic ; Research ; Treatment Outcome ; }, abstract = {Clinical decision-making about suitability for psychological therapies is hampered by limitations of psychotherapy research and our lack of understanding of therapeutic mechanisms. Watzke et al's important randomised controlled study offers apparent validation for clinical judgement in relation to suitability for psychodynamic psychotherapy but also highlights the negative effects of unselected assignment to this type of treatment. Here, I consider why systematic selection for this form of treatment may be important and suggest how the limited effectiveness of psychodynamic therapy for an unselected group of patients may be addressed by more systematic treatment delivery and the ongoing monitoring of intermediate treatment outcomes.}, }
@article {pmid20661453, year = {2010}, author = {Luo, J}, title = {Lithium-mediated protection against ethanol neurotoxicity.}, journal = {Frontiers in neuroscience}, volume = {4}, number = {}, pages = {41}, pmid = {20661453}, issn = {1662-453X}, support = {R01 AA015407/AA/NIAAA NIH HHS/United States ; R01 AA017226/AA/NIAAA NIH HHS/United States ; R21 AA019693/AA/NIAAA NIH HHS/United States ; }, abstract = {Lithium has long been used as a mood stabilizer in the treatment of manic-depressive (bipolar) disorder. Recent studies suggest that lithium has neuroprotective properties and may be useful in the treatment of acute brain injuries such as ischemia and chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. One of the most important neuroprotective properties of lithium is its anti-apoptotic action. Ethanol is a neuroteratogen and fetal alcohol spectrum disorders (FASD) are caused by maternal ethanol exposure during pregnancy. FASD is the leading cause of mental retardation. Ethanol exposure causes neuroapoptosis in the developing brain. Ethanol-induced loss of neurons in the central nervous system underlies many of the behavioral deficits observed in FASD. Excessive alcohol consumption is also associated with Wernicke-Korsakoff syndrome and neurodegeneration in the adult brain. Recent in vivo and in vitro studies indicate that lithium is able to ameliorate ethanol-induced neuroapoptosis. Lithium is an inhibitor of glycogen synthase kinase 3 (GSK3) which has recently been identified as a mediator of ethanol neurotoxicity. Lithium's neuroprotection may be mediated by its inhibition of GSK3. In addition, lithium also affects many other signaling proteins and pathways that regulate neuronal survival and differentiation. This review discusses the recent evidence of lithium-mediated protection against ethanol neurotoxicity and potential underlying mechanisms.}, }
@article {pmid20659772, year = {2010}, author = {Yamasaki, R and Tanaka, M and Fukunaga, M and Tateishi, T and Kikuchi, H and Motomura, K and Matsushita, T and Ohyagi, Y and Kira, J}, title = {Restoration of microglial function by granulocyte-colony stimulating factor in ALS model mice.}, journal = {Journal of neuroimmunology}, volume = {229}, number = {1-2}, pages = {51-62}, doi = {10.1016/j.jneuroim.2010.07.002}, pmid = {20659772}, issn = {1872-8421}, mesh = {Adenosine Triphosphate/pharmacology ; Amyotrophic Lateral Sclerosis/drug therapy/genetics/*pathology ; Animals ; Axotomy/methods ; Brain-Derived Neurotrophic Factor/genetics/metabolism ; Cell Count/methods ; Cell Movement/drug effects ; Cells, Cultured ; Disease Models, Animal ; Disease Progression ; Gene Expression Regulation/drug effects ; Glial Cell Line-Derived Neurotrophic Factor/genetics/metabolism ; Granulocyte Colony-Stimulating Factor/*pharmacology ; Humans ; Hypoglossal Nerve/cytology/drug effects/pathology ; Hypoglossal Nerve Injuries ; Macrophages/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/*drug effects/physiology ; Motor Neurons/drug effects/metabolism ; NF-kappa B/metabolism ; Nerve Degeneration/*drug therapy/etiology ; Recovery of Function/*drug effects ; STAT3 Transcription Factor/genetics/metabolism ; Signal Transduction/drug effects ; Spinal Cord/pathology ; Superoxide Dismutase/genetics ; }, abstract = {We studied the effects of G-CSF on microglial reactions in mutant SOD1 (mSOD1)-Tg (G93A) ALS model mice. Following hypoglossal axotomy, the numbers of neurons and microglia expressing GDNF were significantly lower in mSOD1-Tg mice than in non-transgenic (NTG) littermates. This decrease in the number of neurons after axotomy and a decrease in the number of large myelinated axons in mSOD1-Tg mice over the disease course were improved by G-CSF, which also increased microglial recruitment. Impaired migration of cultured mSOD1-Tg microglia to MCP-1 was recovered following G-CSF treatment. Restoration of microglial responses by G-CSF may contribute to its neuroprotective effects.}, }
@article {pmid20655970, year = {2011}, author = {Liscic, RM and Breljak, D}, title = {Molecular basis of amyotrophic lateral sclerosis.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {35}, number = {2}, pages = {370-372}, doi = {10.1016/j.pnpbp.2010.07.017}, pmid = {20655970}, issn = {1878-4216}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism/pathology ; Cognition Disorders/genetics/*metabolism/pathology ; DNA-Binding Proteins/genetics/metabolism ; Frontotemporal Lobar Degeneration/*genetics/*metabolism ; Humans ; Neurodegenerative Diseases/*genetics/*metabolism/pathology ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disorder of motor neuron degeneration with unclear etiology and no effective treatment to date. ALS is, however, increasingly recognized as a multisystem disorder associated with impaired cognition. The overlap between ALS and dementia at clinical, genetic and neuropathologic levels indicates a spectrum of clinical phenotypes that may include features of frontotemporal lobar degeneration (FTLD). Most cases of ALS are sporadic (SALS), but approximately 10% of all ALS cases are familial ALS (FALS). Mutations in the Cu/Zn superoxide dismutase-1 gene (SOD-1) occur in about 20% of FALS cases. Mutations in the TAR DNA-binding protein 43 gene (TARDBP or TDP-43) may occur in 3-4% of FALS cases, and less frequently, in FTLD. Recently, mutations in the fused in sarcoma/translation in liposarcoma gene (FUS/TLS) were identified as causing about 4-5% of FALS, SALS, and FTLD cases, but not SOD-1 ALS cases, indicating a pathogenic role of FUS, together with TDP-43, in possibly all types of ALS, except for SOD-1 linked ALS. TDP-43 and FUS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis. Thus, TARDBP and FUS/TLS mutations define a novel class of neurodegenerative diseases called TDP-43- and FUS-proteinopathies, in which both misfolded proteins are novel targets for the development of therapeutics in this spectrum of diseases. However, SOD-1 linked ALS may have a pathogenic pathway distinct from other types of ALS.}, }
@article {pmid20653686, year = {2011}, author = {Sunico, CR and Domínguez, G and García-Verdugo, JM and Osta, R and Montero, F and Moreno-López, B}, title = {Reduction in the motoneuron inhibitory/excitatory synaptic ratio in an early-symptomatic mouse model of amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {21}, number = {1}, pages = {1-15}, pmid = {20653686}, issn = {1750-3639}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*pathology ; Analysis of Variance ; Animals ; Blotting, Western ; Disease Models, Animal ; Immunohistochemistry ; Mice ; Mice, Transgenic ; Microscopy, Confocal ; Microscopy, Electron ; Motor Neurons/metabolism/*pathology ; Nerve Degeneration/genetics/metabolism/*pathology ; Nitric Oxide/metabolism ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Synapses/genetics/metabolism/*pathology ; Vesicular Glutamate Transport Protein 2/metabolism ; Vesicular Inhibitory Amino Acid Transport Proteins/metabolism ; }, abstract = {Excitotoxicity is a widely studied mechanism underlying motoneuron degeneration in amyotrophic lateral sclerosis (ALS). Synaptic alterations that produce an imbalance in the ratio of inhibitory/excitatory synapses are expected to promote or protect against motoneuron excitotoxicity. In ALS patients, motoneurons suffer a reduction in their synaptic coverage, as in the transition from the presymptomatic (2-month-old) to early-symptomatic (3-month-old) stage of the hSOD1(G93A) mouse model of familial ALS. Net synapse loss resulted from inhibitory bouton loss and excitatory synapse gain. Furthermore, in 3-month-old transgenic mice, remaining inhibitory but not excitatory boutons attached to motoneurons showed reduction in the active zone length and in the spatial density of synaptic vesicles in the releasable pool near the active zone. Bouton degeneration/loss seems to be mediated by bouton vacuolization and by mechanical displacement due to swelling vacuolated dendrites. In addition, chronic treatment with a nitric oxide (NO) synthase inhibitor avoided inhibitory loss but not excitatory gain. These results indicate that NO mediates inhibitory loss occurring from the pre- to early-symptomatic stage of hSOD1(G93A) mice. This work contributes new insights on ALS pathogenesis, recognizing synaptic re-arrangement onto motoneurons as a mechanism favoring disease progression rather than as a protective homeostatic response against excitotoxic events.}, }
@article {pmid20633427, year = {2010}, author = {Di Lazzaro, V and Dileone, M and Pilato, F and Profice, P and Cioni, B and Meglio, M and Papacci, F and Sabatelli, M and Musumeci, G and Ranieri, F and Tonali, PA}, title = {Long-term motor cortex stimulation for amyotrophic lateral sclerosis.}, journal = {Brain stimulation}, volume = {3}, number = {1}, pages = {22-27}, doi = {10.1016/j.brs.2009.04.004}, pmid = {20633427}, issn = {1876-4754}, mesh = {Aged ; *Amyotrophic Lateral Sclerosis/physiopathology/therapy ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Motor Cortex/*physiology/physiopathology ; Transcranial Magnetic Stimulation/*methods ; Treatment Outcome ; }, abstract = {BACKGROUND: Motor cortex stimulation has been proposed for treatment of amyotrophic lateral sclerosis (ALS) and preliminary studies have reported a slight reduction of disease progression using both invasive and noninvasive repetitive stimulation of the motor cortex.<br><br>OBJECTIVE: The aim of this proof of principle study was to investigate the effects of motor cortex stimulation performed for a prolonged period (about 2 years) on ALS progression.<br><br>METHODS: Two patients were included in the study; the first patient was treated with monthly cycles of repetitive transcranial magnetic stimulation (rTMS) and the second one was treated with chronic epidural motor cortex stimulation. The rate of progression of the disease before and during treatment was compared.<br><br>RESULTS: The treatments were well tolerated by the patients. Both patients deteriorated during treatment; however, the patient treated with rTMS showed a slight reduction in deterioration rate.<br><br>CONCLUSIONS: Although we cannot be sure whether the effects observed in the patient treated with rTMS can be attributed to this form of stimulation, our study set the groundwork for possible future studies investigating the effects of rTMS, for a prolonged period, on a larger group of ALS patients.}, }
@article {pmid20626250, year = {2010}, author = {Markert, CD and Kim, E and Gifondorwa, DJ and Childers, MK and Milligan, CE}, title = {A single-dose resveratrol treatment in a mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of medicinal food}, volume = {13}, number = {5}, pages = {1081-1085}, doi = {10.1089/jmf.2009.0243}, pmid = {20626250}, issn = {1557-7600}, mesh = {Acetylation/drug effects ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Body Weight/drug effects ; Diet ; Disease Models, Animal ; Longevity/drug effects ; Mice ; Mice, Mutant Strains ; Mutation ; Psychomotor Performance/drug effects ; Resveratrol ; Sirtuin 1/metabolism ; Stilbenes/*administration &amp; dosage ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {The underlying causes of denervation of the neuromuscular junction and eventual motor neuron death in amyotrophic lateral sclerosis (ALS) have not been resolved. The superoxide dismutase 1 (SOD1)(G93A) mutant mouse is a frequently used animal model of ALS. We hypothesized that resveratrol (RSV), a polyphenolic molecule that enhances mammalian NAD(+)-dependent SIRT1 deacetylases and may increase life span, would improve motor function and survival in the SOD1 mouse model via modulation of p53 acetylation. Data were collected for mean survival times, neuromuscular performance on the ROTOR-ROD™ (San Diego Instruments, San Diego, CA, USA), body weight, and p53 acetylation. Mean survival times were not statistically different (P=.23) between control and experimental (RSV-fed) groups (mean +/- SD, control [n=11] 138 +/- 6 days vs. experimental [n=10] 135 +/- 8 days). Performance was not significantly different between groups at time points corresponding to 50%, 80%, and 90% mean life span (P=.46), nor did RSV treatment attenuate body weight loss. Thus although manipulation of SIRT1 deacetylase activity has effects at the protein level in healthy aging organisms, we conclude that RSV treatment does not lead to functional improvement or increased longevity in a mouse model of ALS. We speculate that RSV-mediated modulation of p53 acetylation is either incapable of increasing or insufficient to increase motor performance and longevity in this model of ALS.}, }
@article {pmid20623531, year = {2010}, author = {Pyo, JS and Ko, YS and Kim, WH and Kim, M and Lee, KW and Nam, SY and Chung, HY and Cho, SJ and Baik, TK and Lee, BL}, title = {Impairment of nuclear factor-kappaB activation increased glutamate excitotoxicity in a motoneuron-neuroblastoma hybrid cell line expressing mutant (G93A) Cu/Zn-superoxide dismutase.}, journal = {Journal of neuroscience research}, volume = {88}, number = {11}, pages = {2494-2503}, doi = {10.1002/jnr.22397}, pmid = {20623531}, issn = {1097-4547}, mesh = {Animals ; Biotransformation/physiology ; Caspase 3/metabolism ; Cell Death ; Cell Line ; Cell Nucleus/enzymology/metabolism ; Cell Survival/drug effects ; Cytoplasm/enzymology/metabolism ; Fluorescent Dyes ; Genetic Vectors ; Glutamic Acid/*toxicity ; Humans ; Hybrid Cells ; Immunohistochemistry ; Indoles ; Luciferases/metabolism ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/*metabolism ; Mutation/genetics/physiology ; NF-kappa B/*metabolism ; Neuroblastoma/metabolism ; Receptors, Glutamate/metabolism ; Retroviridae/genetics ; Superoxide Dismutase/*genetics/*metabolism ; }, abstract = {Mutations in the superoxide dismutase 1 (SOD1) gene are linked to glutamate excitotoxicity in familial amyotrophic lateral sclerosis (fALS), but the underlying mechanism remains unclear. We investigated whether nuclear factor-kappaB (NF-kappaB) activation is involved in glutamate excitotoxicity by using motor neuron-neuroblastoma hybrid cells that expressed a mutant (G93A) SOD1 (mtSOD1) or wild-type SOD1 (wtSOD1). MtSOD1 cells were more vulnerable to glutamate excitotoxicity than wtSOD1 cells and showed higher NF-kappaB activity, higher nuclear cRel expression, and lower nuclear RelA expression under basal conditions. Glutamate treatment increased NF-kappaB activation along with nuclear expressions of RelA and cRel in wtSOD1 cells but induced only weak nuclear RelA expression in mtSOD1 cells. Suppression of NF-kappaB activation using transfection of the superrepressive mutant form of IkappaBalpha (mIkappaBalpha) inhibited nuclear RelA expression in both types of SOD1 cells, which increased glutamate excitotoxicity in wtSOD1 cells but not in mtSOD1 cells. Furthermore, immunohistochemistry confirmed stronger RelA immunoreactivity in the nuclei of motor neurons of spinal cord in wild-type SOD1 transgenic mice than in those in SOD1 G93A transgenic mice. In addition, we found that glutamate treatment decreased XIAP expression and increased caspase-3 activity in mtSOD1 cells and mIkappaBalpha-overexpressing wtSOD1 cells. Our results suggest that glutamate excitotoxicity in motor neurons of SOD1-linked fALS is attributable, at least in part, to the impairment of IkappaBalpha-dependent RelA activation and subsequent apoptosis mediated by XIAP inhibition and caspase-3 activation.}, }
@article {pmid20623527, year = {2010}, author = {Zhang, Y and Zheng, Y and Zhang, YP and Shields, LB and Hu, X and Yu, P and Burke, DA and Wang, H and Jun, C and Byers, J and Whittemore, SR and Shields, CB}, title = {Enhanced adenoviral gene delivery to motor and dorsal root ganglion neurons following injection into demyelinated peripheral nerves.}, journal = {Journal of neuroscience research}, volume = {88}, number = {11}, pages = {2374-2384}, doi = {10.1002/jnr.22394}, pmid = {20623527}, issn = {1097-4547}, support = {RR015576/RR/NCRR NIH HHS/United States ; }, mesh = {Adenoviridae/*genetics ; Animals ; Blotting, Western ; Demyelinating Diseases/chemically induced/*pathology ; Enterovirus ; Female ; Ganglia, Spinal/*physiology ; Gene Transfer Techniques ; Green Fluorescent Proteins/genetics ; Immunohistochemistry ; Locomotion/physiology ; Lysophosphatidylcholines ; Mice ; Mice, Inbred C57BL ; Motor Neurons/*physiology ; Neuritis/chemically induced/pathology ; Neurons/*physiology ; Peripheral Nerves/*physiology ; Receptors, Virus/genetics ; Sciatic Nerve/metabolism/pathology ; Sensation/physiology ; }, abstract = {Injection of viral vectors into peripheral nerves may transfer specific genes into their dorsal root ganglion (DRG) neurons and motoneurons. However, myelin sheaths of peripheral axons block the entry of viral particles into nerves. We studied whether mild, transient peripheral nerve demyelination prior to intraneural viral vector injection would enhance gene transfer to target DRG neurons and motoneurons. The right sciatic nerve of C57BL/6 mice was focally demyelinated with 1% lysolecithin, and the left sciatic nerve was similarly injected with saline (control). Five days after demyelination, 0.5 microl of Ad5-GFP was injected into both sciatic nerves at the site of previous injection. The effectiveness of gene transfer was evaluated by counting GFP(+) neurons in the DRGs and ventral horns. After peripheral nerve demyelination, there was a fivefold increase in the number of infected DRG neurons and almost a 15-fold increase in the number of infected motoneurons compared with the control, nondemyelinated side. Focal demyelination reduced the myelin sheath barrier, allowing greater virus-axon contact. Increased CXADR expression on the demyelinated axons facilitated axoplasmic viral entry. No animals sustained any prolonged neurological deficits. Increased gene delivery into DRG neurons and motoneurons may provide effective treatment for amyotrophic lateral sclerosis, pain, and spinal cord injury.}, }
@article {pmid20620171, year = {2011}, author = {Takahashi, K and Murasawa, H and Yamaguchi, K and Yamada, M and Nakatani, A and Yoshida, M and Iwai, T and Inagaki, M and Yamada, M and Saitoh, A}, title = {Riluzole rapidly attenuates hyperemotional responses in olfactory bulbectomized rats, an animal model of depression.}, journal = {Behavioural brain research}, volume = {216}, number = {1}, pages = {46-52}, doi = {10.1016/j.bbr.2010.07.002}, pmid = {20620171}, issn = {1872-7549}, mesh = {Analysis of Variance ; Animals ; Behavior, Animal/drug effects ; Chromatography, High Pressure Liquid ; Depressive Disorder/*drug therapy ; Disease Models, Animal ; Emotions/*drug effects ; Glutamic Acid/metabolism ; Male ; Microdialysis ; Olfactory Bulb/*surgery ; Prefrontal Cortex/drug effects/metabolism ; Rats ; Rats, Wistar ; Riluzole/*pharmacology/therapeutic use ; Statistics, Nonparametric ; }, abstract = {Growing evidence indicates that the glutamatergic neurotransmitter system is central to the neurobiology and treatment of depression. Riluzole, a drug currently used to slow the progression of amyotrophic lateral sclerosis (ALS), directly affects the glutamatergic system. In this study, we investigated the effects of riluzole in olfactory bulbectomy (OBX) rats, an animal model of depression. The olfactory bulbs in rats were removed by suction. The emotionality of rats was measured by scoring their responses to given stimuli, i.e., attack, startle, struggle, and fight responses. The OBX rats chronically treated with vehicle for 7 days at 14 days following surgery showed significant increases in emotionality responses. Single (1st day administration) and subchronic (7th day administration) riluzole treatment (1-10 mg/kg, po) significantly and dose-dependently reduced hyperemotional responses in OBX rats. Both single and subchronic riluzole treatment (10 mg/kg, po) had no significant effects on the emotional responses in sham operated rats. In addition, we demonstrated that single riluzole treatment (10 mg/kg, po) significantly decreased extracellular glutamate levels in medial prefrontal cortex of OBX rats by in vivo microdialysis. We provide the first experimental evidence that riluzole rapidly attenuated hyperemotional responses in OBX rats, an animal model of depression.}, }
@article {pmid20616033, year = {2010}, author = {Meissner, F and Molawi, K and Zychlinsky, A}, title = {Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {107}, number = {29}, pages = {13046-13050}, pmid = {20616033}, issn = {1091-6490}, mesh = {Amino Acid Substitution/genetics ; Amyloid/chemistry ; Amyotrophic Lateral Sclerosis/drug therapy/*enzymology/*etiology ; Animals ; Autophagy ; Caspase 1/metabolism ; Cytoplasm/enzymology ; Disease Progression ; Enzyme Activation ; Humans ; Interleukin 1 Receptor Antagonist Protein/therapeutic use ; Interleukin-1beta/*metabolism ; Mice ; Microglia/enzymology ; Mutant Proteins/chemistry/*metabolism ; Protein Conformation ; Protein Folding ; Superoxide Dismutase/chemistry/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {ALS is a fatal motor neuron disease of adult onset. Neuroinflammation contributes to ALS disease progression; however, the inflammatory trigger remains unclear. We report that ALS-linked mutant superoxide dismutase 1 (SOD1) activates caspase-1 and IL-1beta in microglia. Cytoplasmic accumulation of mutant SOD1 was sensed by an ASC containing inflammasome and antagonized by autophagy, limiting caspase-1-mediated inflammation. Notably, mutant SOD1 induced IL-1beta correlated with amyloid-like misfolding and was independent of dismutase activity. Deficiency in caspase-1 or IL-1beta or treatment with recombinant IL-1 receptor antagonist (IL-1RA) extended the lifespan of G93A-SOD1 transgenic mice and attenuated inflammatory pathology. These findings identify microglial IL-1beta as a causative event of neuroinflammation and suggest IL-1 as a potential therapeutic target in ALS.}, }
@article {pmid20613515, year = {2010}, author = {Bedlack, RS}, title = {Amyotrophic lateral sclerosis: current practice and future treatments.}, journal = {Current opinion in neurology}, volume = {23}, number = {5}, pages = {524-529}, doi = {10.1097/WCO.0b013e32833c7ac2}, pmid = {20613515}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Biomarkers ; Cognition Disorders/diagnosis ; Evidence-Based Medicine ; Forecasting ; Humans ; Neuroprotective Agents/therapeutic use ; Palliative Care ; Riluzole/therapeutic use ; Survival Rate ; }, abstract = {PURPOSE OF REVIEW: Knowledge of amyotrophic lateral sclerosis, and in particular the care of patients with it, is evolving exponentially. More than 1700 articles with the phrase 'amyotrophic lateral sclerosis' have been published in the past 2 years; these form the basis for this timely review.<br><br>RECENT FINDINGS: In part 1, I give an update on the care of patients with amyotrophic lateral sclerosis, including ways to speed diagnosis, optimal use of riluzole, multidisciplinary teams, mechanical ventilation, gastrostomy tubes, lipid-lowering agents and symptom management. Although care has become more evidence-based, there remain a number of quandaries; for these, I will provide suggestions based upon my own experience. In part 2, I identify some exciting new treatment options that are under study. These include agents designed for novel targets within motor neurons and nonneuronal cells, agents designed for specific amyotrophic lateral sclerosis subtypes and interesting new technologies. Finally, in part 3, I define current barriers to developing even better therapeutics and offer ways around them.<br><br>SUMMARY: The care of patients with amyotrophic lateral sclerosis has evolved and is now more evidence-based than ever before. Exciting new therapies are currently being tested, which may revolutionize care even further. Barriers exist, but they are surmountable.}, }
@article {pmid20602248, year = {2010}, author = {Galat, A and Bua, J}, title = {Molecular aspects of cyclophilins mediating therapeutic actions of their ligands.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {67}, number = {20}, pages = {3467-3488}, pmid = {20602248}, issn = {1420-9071}, support = {D43 TW007888/TW/FIC NIH HHS/United States ; D43TW007888/TW/FIC NIH HHS/United States ; }, mesh = {Animals ; Conserved Sequence/genetics ; Cyclophilins/chemistry/*metabolism ; Cyclosporine/chemistry/*metabolism/*therapeutic use ; Disease ; Humans ; Ligands ; }, abstract = {Cyclosporine A (CsA) is an immunosuppressive cyclic peptide that binds with a high affinity to 18 kDa human cyclophilin-A (hCyPA). CsA and its several natural derivatives have some pharmacological potential in treatment of diverse immune disorders. More than 20 paralogues of CyPA are expressed in the human body while expression levels and functions of numerous ORFs encoding cyclophilin-like sequences remain unknown. Certain derivatives of CsA devoid of immunosuppressive activity may have some potential in treatments of Alzheimer diseases, Hepatitis C and HIV infections, amyotrophic lateral sclerosis, congenital muscular dystrophy, asthma and various parasitic infections. Here, we discuss structural and functional aspects of the human cyclophilins and their interaction with various intra-cellular targets that can be under the control of CsA or its complexes with diverse cyclophilins that are selectively expressed in different cellular compartments. Some molecular aspects of the cyclophilins expressed in parasites invading humans and causing diseases were also analyzed.}, }
@article {pmid20600637, year = {2010}, author = {Bartolomucci, A and Pasinetti, GM and Salton, SR}, title = {Granins as disease-biomarkers: translational potential for psychiatric and neurological disorders.}, journal = {Neuroscience}, volume = {170}, number = {1}, pages = {289-297}, doi = {10.1016/j.neuroscience.2010.06.057}, pmid = {20600637}, issn = {1873-7544}, mesh = {Amino Acid Sequence ; Animals ; Biomarkers/metabolism ; Chromogranins/cerebrospinal fluid/*genetics/metabolism ; Genetic Markers/genetics ; Humans ; Mental Disorders/diagnosis/*genetics ; Molecular Sequence Data ; Nervous System Diseases/diagnosis/*genetics ; Protein Biosynthesis/*genetics ; }, abstract = {The identification of biomarkers represents a fundamental medical advance that can lead to an improved understanding of disease pathogenesis, and holds the potential to define surrogate diagnostic and prognostic endpoints. Because of the inherent difficulties in assessing brain function in patients and objectively identifying neurological and cognitive/emotional symptoms, future application of biomarkers to neurological and psychiatric disorders is extremely desirable. This article discusses the biomarker potential of the granin family, a group of acidic proteins present in the secretory granules of a wide variety of endocrine, neuronal and neuroendocrine cells: chromogranin A (CgA), CgB, Secretogranin II (SgII), SgIII, HISL-19 antigen, 7B2, NESP55, VGF and ProSAAS. Their relative abundance, functional significance, and secretion into the cerebrospinal fluid (CSF), saliva, and the general circulation have made granins tractable targets as biomarkers for many diseases of neuronal and endocrine origin, recently impacting diagnosis of a number of neurological and psychiatric disorders including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, and schizophrenia. Although research has not yet validated the clinical utility of granins as surrogate endpoints for the progression or treatment of neurological or psychiatric disease, a growing body of experimental evidence indicates that the use of granins as biomarkers might be of great potential clinical interest. Advances that further elucidate the mechanism(s) of action of granins, coupled with improvements in biomarker technology and direct clinical application, should increase the translational effectiveness of this family of proteins in disease diagnosis and drug discovery.}, }
@article {pmid20600320, year = {2010}, author = {Blanquer, M and Pérez-Espejo, MA and Martínez-Lage, JF and Iniesta, F and Martinez, S and Moraleda, JM}, title = {A surgical technique of spinal cord cell transplantation in amyotrophic lateral sclerosis.}, journal = {Journal of neuroscience methods}, volume = {191}, number = {2}, pages = {255-257}, doi = {10.1016/j.jneumeth.2010.06.014}, pmid = {20600320}, issn = {1872-678X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/pathology/physiopathology/*surgery ; Bone Marrow Transplantation/*methods/pathology ; Cell- and Tissue-Based Therapy/*methods ; Female ; Humans ; Male ; Middle Aged ; Nerve Regeneration/physiology ; Neurosurgical Procedures/methods ; Postoperative Complications/pathology/physiopathology/prevention &amp; control ; Recovery of Function/physiology ; Spinal Cord/pathology/physiopathology/*surgery ; Stem Cell Transplantation/*methods ; Stereotaxic Techniques/instrumentation ; Treatment Outcome ; }, abstract = {We report an original method for implanting bone marrow stem cells within the spinal cord parenchyma. This method was used for the experimental treatment of patients diagnosed with amyotrophic lateral sclerosis. The methodology is reproducible and devoid of major complications even in patients showing significant spinal atrophy. Therefore, this report describes a surgical procedure that could be used in other experimental treatments involving the intraspinal delivery of stem cells.}, }
@article {pmid20599974, year = {2010}, author = {Lee, JH and Tigchelaar, S and Liu, J and Stammers, AM and Streijger, F and Tetzlaff, W and Kwon, BK}, title = {Lack of neuroprotective effects of simvastatin and minocycline in a model of cervical spinal cord injury.}, journal = {Experimental neurology}, volume = {225}, number = {1}, pages = {219-230}, doi = {10.1016/j.expneurol.2010.06.018}, pmid = {20599974}, issn = {1090-2430}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Cervical Vertebrae ; Disease Models, Animal ; Drug Therapy, Combination/methods ; Minocycline/*administration &amp; dosage/therapeutic use ; Myelitis/*drug therapy ; Nerve Regeneration/drug effects/physiology ; Neuroprotective Agents/*administration &amp; dosage/therapeutic use ; Oxidative Stress/drug effects/physiology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Recovery of Function/drug effects/physiology ; Simvastatin/*administration &amp; dosage/therapeutic use ; Spinal Cord Injuries/*drug therapy ; Treatment Failure ; }, abstract = {Minocycline, a commonly prescribed tetracycline antibiotic, has shown promise as a potential therapeutic agent in animal models of numerous neurologic disorders such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Huntington's disease, stroke, and spinal cord injury (SCI). Simvastatin is one of many hydroxymethylglutaryl-coenzyme-A reductase inhibitors prescribed to lower cholesterol. These drugs are also known to reduce inflammation and oxidative stress, improve endothelial function, and modulate the immune system in stroke, traumatic brain injury, and SCI. As both drugs have translational potential, we evaluated their neuroprotective properties here in a clinically relevant model of contusive cervical spinal cord injury. Sprague-Dawley rats underwent a unilateral cervical contusion SCI at C5 and were randomized to receive: 1. Minocycline 90 mg/kg x 3 days, 2. Simvastatin 20 mg/kg x 7 days, 3. Simvastatin 20 mg/kg x 7 days then 5mg/kg x 35 days, or 4. Saline (Control). Behavioral recovery was assessed over 6 weeks using the horizontal ladder test, cylinder rearing test, modified Montoya staircase test and grooming test. Forepaw sensitivity was also assessed using the electronic von Frey Aesthesiometer. The corticospinal and rubrospinal tracts were traced and the spinal cords were harvested 7 weeks after injury. The extent of gray matter and white matter sparing and corticospinal and rubrospinal tract sprouting were evaluated in cross sections of the spinal cord. In the end, neither minocycline nor simvastatin treatment was associated with improved performance on the behavioral tests, as compared to saline controls. Performance on the horizontal ladder test, cylinder rearing test, and von Frey sensory test were similar among all groups. Animals treated for 42 days with simvastatin scored significantly higher in the grooming score compared to other groups, but retrieved significantly fewer pellets on the modified Montoya staircase test than control and minocycline treated animals. Histologically, there were no significant differences in white and gray matter sparing and in the extent of corticospinal and rubrospinal sprouting between the four groups. In conclusion, both minocycline and simvastatin failed to improve functional and histological recovery in our model of contusive cervical spinal cord injury.}, }
@article {pmid20592948, year = {2010}, author = {Henriques, A and Pitzer, C and Schneider, A}, title = {Neurotrophic growth factors for the treatment of amyotrophic lateral sclerosis: where do we stand?.}, journal = {Frontiers in neuroscience}, volume = {4}, number = {}, pages = {32}, pmid = {20592948}, issn = {1662-453X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive loss of motoneurons, motor weakness and death within 3-5 years after disease onset. Therapeutic options remain limited despite substantial number of approaches that have been tested clinically. Many neurotrophic growth factors are known to promote the survival of neurons and foster regeneration in the central nervous system. Various neurotrophic factors have been investigated pre-clinically and clinically for the treatment of ALS. Although pre-clinical data appeared promising, no neurotrophic factors succeeded yet in a clinical phase III trial. In this review we discuss the rationale behind those factors, possible reasons for clinical failures, and argue for a renewal of hope in this powerful class of drugs for the treatment of ALS.}, }
@article {pmid20587497, year = {2010}, author = {Matuz, T and Birbaumer, N and Hautzinger, M and Kübler, A}, title = {Coping with amyotrophic lateral sclerosis: an integrative view.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {81}, number = {8}, pages = {893-898}, doi = {10.1136/jnnp.2009.201285}, pmid = {20587497}, issn = {1468-330X}, mesh = {*Adaptation, Psychological ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*psychology ; Cognition/physiology ; Depression/etiology/psychology ; Disability Evaluation ; Female ; Humans ; Male ; Middle Aged ; Neuropsychological Tests ; Paralysis/etiology/psychology ; Parenteral Nutrition ; Predictive Value of Tests ; Quality of Life ; Regression Analysis ; Respiration, Artificial ; Social Support ; Treatment Outcome ; }, abstract = {OBJECTIVES: To identify predictors of psychosocial adjustment to motor neurone disease.<br><br>METHODS: A total of 27 individuals with a confirmed diagnosis of amyotrophic lateral sclerosis (ALS) participated in the study. The ALS functional rating scale mean score indicated a high physical impairment of the sample. Months since diagnosis varied between 4 and 129 (median 36). Adjustment outcomes were severity of depressive symptoms and individual quality of life (QoL). Predictors included social support, cognitive appraisal, coping strategies and illness parameters.<br><br>RESULTS: Multiple regression analysis revealed that approximately 60% of the variance of depression and QoL were accounted for by social support, coping strategies and cognitive appraisal. The degree of physical impairment did not explain any variance of the adjustment outcomes. The best predictors for the severity of depressive symptoms were perceived social support and appraisal of coping potential (internal locus of control) and for individual QoL perceived social support.<br><br>CONCLUSIONS: The focus on medical issues in treatment of ALS is not sufficient. A palliative approach to ALS must equally imply advice with regards to adequate coping strategies, provide the adequate amount of disease- and support-related information at any one time, and encourage patients to seek social support. Sufficient medication and psychotherapy has to be provided for those patients who show depressive symptoms or disorder.}, }
@article {pmid20586670, year = {2010}, author = {Gamez, J and Carmona, F and Raguer, N and Ferrer-Sancho, J and Martín-Henao, GA and Martí-Beltrán, S and Badia, M and Gratacós, M and Rodriguez-Gónzalez, E and Seoane, JL and Pallero-Castillo, M and Burgos, R and Puiggros, C and Pasarin, A and Bori-Fortuny, I}, title = {Cellular transplants in amyotrophic lateral sclerosis patients: an observational study.}, journal = {Cytotherapy}, volume = {12}, number = {5}, pages = {669-677}, doi = {10.3109/14653241003774037}, pmid = {20586670}, issn = {1477-2566}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/pathology/physiopathology/*therapy ; Antigens, CD34/biosynthesis ; Bone Marrow/pathology ; Cells, Cultured ; Clinical Trials as Topic ; Disease Progression ; Female ; Fetal Research ; Follow-Up Studies ; Humans ; Male ; Medical Tourism ; *Mesenchymal Stem Cell Transplantation/adverse effects/ethics ; Mesenchymal Stem Cells/*metabolism/pathology ; Middle Aged ; Neuroglia/pathology/transplantation ; Olfactory Bulb/pathology ; Spain ; Stromal Cells/pathology/transplantation ; }, abstract = {BACKGROUND AIMS: Cytotherapy is a promising option for neurodegenerative disease treatment. Because of the fatal prognosis and imperative need for effective treatment, amyotrophic lateral sclerosis (ALS) patients request this therapy before its effectiveness has been verified. The increase in clinics offering cytotherapies but providing little scientific information has prompted considerable medical tourism. We present an observational study of Spanish ALS patients receiving cytotherapy, analyzing the experiences arising from the treatment (TX) and considering two progression markers, FVC and ALSFRS-R.<br><br>METHODS: Twelve ALS patients with a mean age of 48.6 years (SD 12.8) received cytotherapy 26.9 months (SD 15.8) after clinical onset. ALSFRS-R and FVC at TX were 32.3 (SD 6.8) and 63.4% (SD 15.3), respectively. TX involved transplants of olfactory ensheathing cells in three patients, and autologous mesenchymal stromal cells in the remainder.<br><br>RESULTS: One patient died 33 months post-TX after surviving for 49 months. Five required mechanical non-invasive home ventilation 7.4 months post-TX. Two required invasive ventilation 13 months post-TX. Five patients needed gastrostomy feeding 23.3 months post-TX. Survival between clinical onset and the study end date was 50 months (SD 17.2). No significant adverse events or changes in the decline of FVC and ALSFRS-R compared with the disease's natural history were observed.<br><br>CONCLUSIONS: Our observations suggest that these therapies do not halt the course of the disease. Cytotherapy cannot yet be considered a curative treatment for ALS.}, }
@article {pmid20582873, year = {2010}, author = {Phukan, J}, title = {Arimoclomol, a coinducer of heat shock proteins for the potential treatment of amyotrophic lateral sclerosis.}, journal = {IDrugs : the investigational drugs journal}, volume = {13}, number = {7}, pages = {482-496}, pmid = {20582873}, issn = {2040-3410}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Chaperonins/agonists ; Drugs, Investigational/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use ; Heat-Shock Proteins/*metabolism ; Heat-Shock Response/drug effects ; Humans ; Hydroxylamines/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use ; Nerve Degeneration/drug therapy/prevention &amp; control ; Neurons/drug effects ; Neuroprotective Agents/adverse effects/pharmacokinetics/pharmacology/therapeutic use ; Stress, Physiological ; Up-Regulation/*drug effects ; }, abstract = {Recent years have seen an explosion of research into increasingly prevalent neurodegenerative diseases. Arimoclomol (BRX-220), being developed by CytRx Corp, is an oral therapeutic candidate for the treatment of amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease. ALS is a fatal, incurable disorder, which can present as sporadic (90 to 95% of cases) or familial (5 to 10% of cases) forms. The etiology of sporadic ALS remains unknown and much of the understanding of ALS pathogenesis has been derived through study of its familial forms; in particular, through study of autosomal dominant mutations in the SOD1 (copper/zinc superoxide dismutase) gene, which cause approximately 20% of familial ALS cases. Under conditions of excessive stress, arimoclomol induces amplification of the cytoprotective heat shock response in order to protect motor neurons from death. Comprehensive in vivo and in vitro studies demonstrated its effect in the prevention of neuronal loss and promotion of motor neuron survival, even after symptom onset. Clinical trials have reported good tolerability and safety. This paper discusses the rationale for arimoclomol use in ALS, the preclinical and clinical evidence collected to date, the likelihood of its promising preclinical results translating to humans, and the relevance of this research for neurodegeneration as a whole.}, }
@article {pmid20577972, year = {2011}, author = {Perez, DI and Gil, C and Martinez, A}, title = {Protein kinases CK1 and CK2 as new targets for neurodegenerative diseases.}, journal = {Medicinal research reviews}, volume = {31}, number = {6}, pages = {924-954}, doi = {10.1002/med.20207}, pmid = {20577972}, issn = {1098-1128}, mesh = {Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Binding, Competitive ; Casein Kinase I/*metabolism ; Casein Kinase II/*metabolism ; Drug Design ; Enzyme Inhibitors/pharmacology ; Humans ; Inhibitory Concentration 50 ; Mice ; Neurodegenerative Diseases/*drug therapy/enzymology ; Parkinson Disease/drug therapy ; Phosphorylation ; Rats ; }, abstract = {Following the discovery of the human kinome, protein kinases have become the second most important group of drug targets as they can be modulated by small ligand molecules. Moreover, orally active protein kinase inhibitors have recently reached the market and there are many more in clinical trials. The lack of treatments for neurodegenerative diseases has increased human and financial efforts in the search for new therapeutic targets that could provide new effective drug candidates. The importance of kinases in the molecular pathway of neuronal survival is under study, but different key pathways have been described. New roles for the old casein kinases 1 and 2, currently known as protein kinases CK1 and CK2, have recently been discovered in the molecular pathology of different neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. The search for specific inhibitors of these enzymes has become an important challenge for the treatment of these devastating diseases. The role of these two kinases in the molecular pathology of different neurodegenerative diseases together with different chemical families that are able to more or less specifically inhibit CK1 and CK2 are discussed in this review.}, }
@article {pmid20577219, year = {2011}, author = {Sakai, R and Kanamori, H and Nakaseko, C and Yoshiba, F and Fujimaki, K and Sakura, T and Fujisawa, S and Kawai, N and Onoda, M and Matsushima, T and Maruta, A and Sakamaki, H and Okamoto, S}, title = {Air-leak syndrome following allo-SCT in adult patients: report from the Kanto Study Group for Cell Therapy in Japan.}, journal = {Bone marrow transplantation}, volume = {46}, number = {3}, pages = {379-384}, doi = {10.1038/bmt.2010.129}, pmid = {20577219}, issn = {1476-5365}, mesh = {Adolescent ; Adult ; Female ; Hematopoietic Stem Cell Transplantation/*adverse effects/methods ; Humans ; Japan ; Male ; Mediastinal Emphysema/*etiology ; Middle Aged ; Pneumothorax/*etiology ; Retrospective Studies ; Risk Factors ; Transplantation Conditioning/adverse effects/methods ; Young Adult ; }, abstract = {We retrospectively investigated air-leak syndrome (ALS), including pneumothorax and mediastinal/s.c. emphysema, following allogeneic hematopoietic SCT. Eighteen patients (1.2%) developed ALS among 1515 undergoing SCT between 1994 and 2005 at the nine hospitals participating in the Kanto Study Group on Cell Therapy. The median onset of ALS was at 575 days (range: 105-1766) after SCT and 14 patients (77.8%) had experienced late onset noninfectious pulmonary complications (LONIPC) before ALS. Chronic GVHD (cGVHD) was the strongest risk factor for ALS (odds ratio 13.5, P=0.013 by multivariate analysis). Repeat SCT, male sex and age <38 years at the time of transplantation were also significant risk factors for ALS. Patients with ALS had a significantly worse survival rate than those without ALS (61.5 vs 14.9% at 3 years; P=0.000). The main cause of death was respiratory complications in 8 of the 18 patients. In conclusion, ALS is a rare complication of SCT that is more likely to occur in relatively young male patients with cGVHD and/or LONIPC. It is possible that better understanding and treatment of LONIPC may lead to prevention of ALS.}, }
@article {pmid20565334, year = {2010}, author = {Amante, DJ and Kim, J and Carreiro, ST and Cooper, AC and Jones, SW and Li, T and Moody, JP and Edgerly, CK and Bordiuk, OL and Cormier, K and Smith, K and Ferrante, RJ and Rusche, J}, title = {Uridine ameliorates the pathological phenotype in transgenic G93A-ALS mice.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {6}, pages = {520-530}, doi = {10.3109/17482968.2010.491867}, pmid = {20565334}, issn = {1471-180X}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*pathology/*physiopathology ; Animals ; Anterior Horn Cells/drug effects/metabolism/pathology ; Behavior, Animal/drug effects/physiology ; Body Weight/drug effects ; Deoxyguanosine/analogs &amp; derivatives/urine ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Energy Metabolism/physiology ; Humans ; Kaplan-Meier Estimate ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuroprotective Agents/pharmacology/*therapeutic use ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/cytology/drug effects/pathology ; Superoxide Dismutase/genetics/*metabolism ; Survival Rate ; Uridine/pharmacology/*therapeutic use ; }, abstract = {There is strong evidence from studies in humans and animal models to suggest the involvement of energy metabolism defects in neurodegenerative diseases. Uridine, a pyrimidine nucleoside, has been suggested to be neuroprotective in neurological disorders by improving bioenergetic effects, increasing ATP levels and enhancing glycolytic energy production. We assessed whether uridine treatment extended survival and improved the behavioral and neuropathological phenotype observed in G93A-ALS mice. In vitro and in vivo pharmacokinetic analyses in mutant SOD models provided optimal dose and assurance that uridine entered the brain. A dose-ranging efficacy trial in G93A mice was performed using survival, body weight, open-field analysis, and neuropathology as outcome measures. Urinary levels of 8-hydroxy-2'-deoxyguanosine, identifying DNA oxidative damage, were measured and used as a pharmacodynamic biomarker. Uridine administration significantly extended survival in a dose-dependent manner in G93A mice, while improving the behavioral and neuropathological phenotype. Uridine increased survival by 17.4%, ameliorated body weight loss, enhanced motor performance, reduced gross lumbar and ventral horn atrophy, attenuated lumbar ventral horn neuronal cell death, and decreased reactive astrogliosis. Consistent with a therapeutic effect, uridine significantly reduced urinary 8-hydroxy-2'-deoxyguanosine in G93A mice. These data suggest that uridine may be a therapeutic candidate in ALS patients.}, }
@article {pmid20564566, year = {2010}, author = {Sasabe, J and Aiso, S}, title = {Aberrant control of motoneuronal excitability in amyotrophic lateral sclerosis: excitatory glutamate/D-serine vs. inhibitory glycine/gamma-aminobutanoic acid (GABA).}, journal = {Chemistry &amp; biodiversity}, volume = {7}, number = {6}, pages = {1479-1490}, doi = {10.1002/cbdv.200900306}, pmid = {20564566}, issn = {1612-1880}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/therapy ; Excitatory Amino Acids/metabolism ; Glutamic Acid/*metabolism ; Glycine/*metabolism ; Motor Neurons/metabolism ; Neurotransmitter Agents/metabolism ; Receptors, Glutamate/metabolism ; Serine/*metabolism ; gamma-Aminobutyric Acid/*metabolism ; }, abstract = {The mechanism underlying selective motoneuronal loss in amyotrophic lateral sclerosis (ALS) remains uncertain. The pathogenesis appears to be a complex and multifactorial process. Glutamate excitotoxicity to motoneuron is one of the most intensely investigated targets for the treatment of ALS, and excessive motoneuronal excitation by glutamate through ionotropic glutamate receptors has been mainly demonstrated. However, development of clinically effective drug targeting glutamate is sometimes difficult, because some aspects of glutamergic signals also could be beneficial, as the injured neurons attempt to recruit endogenous recovery. This review is focused on identifying other mechanisms of imbalanced excitation in ALS motoneurons including excitation-modulating D-serine and inhibitory glycine/GABA. Further, validation of these mechanisms might ultimately lead us to new therapeutic targets for ALS.}, }
@article {pmid20558463, year = {2010}, author = {Clemens, KE and Jaspers, B and Klaschik, E and Nieland, P}, title = {Evaluation of the clinical effectiveness of physiotherapeutic management of lymphoedema in palliative care patients.}, journal = {Japanese journal of clinical oncology}, volume = {40}, number = {11}, pages = {1068-1072}, doi = {10.1093/jjco/hyq093}, pmid = {20558463}, issn = {1465-3621}, mesh = {Aged ; Drainage ; Female ; Humans ; Lymphedema/*etiology/*therapy ; Male ; Neoplasms/complications/pathology/therapy ; *Palliative Care ; *Physical Therapy Modalities ; Retrospective Studies ; Survival Rate ; Treatment Outcome ; }, abstract = {OBJECTIVE: Lymphoedema is a common sequela of cancer or its treatment that affects lymph node drainage. The physiotherapist, as member of the multiprofessional team in palliative care, is one of the keys to successful rehabilitation and management of patients with cancer and non-malignant motoneuron disease such as amyotrophic lateral sclerosis and palliative care needs. The aim of the study was to evaluate the frequency and effect of manual lymphatic drainage in palliative care patients with lymphoedema in a far advanced stage of their disease.<br><br>METHODS: Retrospective study (reflexive control design) of data of the 208 patients admitted to our palliative care unit from January 2007 to December 2007. Demographic and disease-related data (diagnosis, symptoms, Karnofsky performance status and effect of manual lymphatic drainage interventions) were documented and compared.<br><br>STATISTICS: mean &#xb1; SD, median; Wilcoxon's test.<br><br>RESULTS: Of the 208 patients, 90 who reported symptom load due to lymphoedema were included; 67 (74.4%) had pain, 23 (25.6%) dyspnoea due to progredient trunk oedema. Mean age 65.5 &#xb1; 13.0 years; 33 (36.7%) male; Karnofsky index 50% (30-80%), mean length of stay 15.6 &#xb1; 8.0 days. The mean number of physiotherapeutic treatment interventions was 7.0 &#xb1; 5.8. Manual lymphatic drainage was well tolerated in 83 (92.2%) patients; 63 of 67 (94.0%) patients showed a clinically relevant improvement in pain, and 17 of 23 (73.9%) in dyspnoea.<br><br>CONCLUSIONS: The majority of the patients showed a clinical improvement in the intensity of symptoms after manual lymphatic drainage.}, }
@article {pmid20557668, year = {2010}, author = {Lemoignan, J and Ells, C}, title = {Amyotrophic lateral sclerosis and assisted ventilation: how patients decide.}, journal = {Palliative &amp; supportive care}, volume = {8}, number = {2}, pages = {207-213}, doi = {10.1017/S1478951510000027}, pmid = {20557668}, issn = {1478-9523}, mesh = {Activities of Daily Living ; Adaptation, Psychological ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*psychology ; Communication ; *Decision Making ; Family/psychology ; Fear ; Female ; Humans ; Male ; Middle Aged ; Patient Acceptance of Health Care/*psychology ; Patient Education as Topic ; Personal Autonomy ; Qualitative Research ; Quality of Life/psychology ; Quebec ; Respiration, Artificial/methods/*psychology ; Respiratory Insufficiency/etiology/*therapy ; Social Support ; Surveys and Questionnaires ; Terminal Care ; }, abstract = {BACKGROUND: Throughout the course of their illness, people with amyotrophic lateral sclerosis (ALS) must make many treatment decisions; however, none has such a significant impact on quality of life and survival as decisions about assisted ventilation.<br><br>OBJECTIVE: The purpose of this study was to better understand the experience of decision-making about assisted ventilation for ALS patients.<br><br>METHODS: Using qualitative phenomenology methodology, 10 semi-structured interviews were conducted with persons with ALS and their caregivers to elicit factors that are pertinent to their decision-making process about assisted ventilation.<br><br>RESULTS: Six main themes emerged from the interviews. (1) the meaning of the intervention - participants made a sharp distinction between non-invasive ventilation, which they viewed as a means to relieve symptoms of respiratory failure, and invasive ventilation, which they viewed as taking over their breathing and thereby saving their life when they otherwise would die, (2) the importance of context - including functional status, available supports, and financial implications, (3) the importance of values - with respect to communication, relationships, autonomy, life, and quality of life, (4) the effect of fears - particularly respiratory distress, chocking, running out of air, and the process of death itself, (5) the need for information - how use of assisted ventilation would impact daily life, how death from respiratory failure would occur, how caregivers and persons with ALS differ in their information needs and common misconceptions, and (6) adaptation to or acceptance of the intervention - a lengthy process that involved gradual familiarization with the equipment and its benefits.<br><br>SIGNIFICANCE OF THE RESEARCH: People with ALS and caregivers value autonomy in decision-making about assisted ventilation. Their decision-making process is neither wholly rational nor self-interested, and includes factors that health professionals should anticipate and address. Discussions about assisted ventilation and timing should be tailored to each individual and undertaken periodically.}, }
@article {pmid20556799, year = {2010}, author = {Yoshida, M and Takahashi, Y and Koike, A and Fukuda, Y and Goto, J and Tsuji, S}, title = {A mutation database for amyotrophic lateral sclerosis.}, journal = {Human mutation}, volume = {31}, number = {9}, pages = {1003-1010}, doi = {10.1002/humu.21306}, pmid = {20556799}, issn = {1098-1004}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Base Sequence ; *Databases, Genetic ; Humans ; Mutation/*genetics ; }, abstract = {An amyotrophic lateral sclerosis (ALS) mutation database has been constructed as a publicly accessible online resource for recording the nucleotide and amino acid variants identified in genes associated with ALS, along with corresponding clinical conditions. The database currently consists of more than 600 entries, including about 180 unique variants found in 25 disease-causative or disease-related genes. In addition to published data collected from literature, novel variants identified by microarray resequencing in our laboratory are incorporated into the database. Every reported gene has a respective page that provides information on its variation positions with various statistics, clinical characteristics, and primary references, as well as gene-sequence and protein-structure information that will assist in assessing variation significance. Users can access a homology search function to find variations in arbitrary sequences of interest and to check if they have already been described in the database. This database is expected to fulfill an essential need in terms of integrating comprehensive information on genetic and clinical data related to ALS, which will subsequently deepen our understanding of the possible mechanisms of the disease, as well as help with the clinical practice and treatment of ALS. The database is accessible at: https://reseq.lifesciencedb.jp/resequence/SearchDisease.do?targetId=1. Data submission is open to all researchers and is highly encouraged.}, }
@article {pmid20556761, year = {2010}, author = {Pastula, DM and Moore, DH and Bedlack, RS}, title = {Creatine for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {6}, pages = {CD005225}, doi = {10.1002/14651858.CD005225.pub2}, pmid = {20556761}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Creatine/*administration &amp; dosage/adverse effects ; Disease Progression ; Humans ; Motor Neuron Disease/drug therapy/mortality ; Neuroprotective Agents/*administration &amp; dosage/adverse effects ; Randomized Controlled Trials as Topic ; Vital Capacity/drug effects ; }, abstract = {BACKGROUND: Creatine, a naturally-occurring nitrogenous organic acid involved in adenosine triphosphate (ATP) production, has been shown to increase survival in mouse models of amyotrophic lateral sclerosis (ALS). Results from human trials, however, have been mixed. Given conflicting results regarding creatine's efficacy, we conducted a systematic review.<br><br>OBJECTIVES: To systematically examine creatine's efficacy in prolonging ALS survival and in slowing ALS disease progression.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library issue 4, 2009), MEDLINE and EMBASE in October 2009 for any trial involving creatine in the treatment of ALS. We also contacted experts in the field for any additional studies.<br><br>SELECTION CRITERIA: Randomized trials of treatment with creatine or placebo in patients diagnosed with ALS. Our primary outcome was tracheostomy-free survival time; secondary outcomes were ALS progression as measured by changes in ALS functional rating revised scores (ALSFRS-R) and percent predicted forced vital capacity (FVC) over time.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, assessed risk of bias and extracted data. We obtained and analyzed individual participant data from each study.<br><br>MAIN RESULTS: We included three trials involving 386 participants randomized to either creatine 5 to 10 g per day or placebo. Creatine was reportedly well-tolerated in all three included studies, with no evidence of renal failure or serious adverse events specifically attributable to creatine. Using a pooled log-rank statistical test, we found no statistical difference in survival between the placebo and creatine groups across all three studies (Chi(2) = 0.09, P = 0.76). In addition, we found no statistical difference in ALSFRS-R slopes between the two groups across all three studies using a pooled linear mixed-effects model (slope difference of +0.03 ALSFRS-R/month in the creatine group; P = 0.76). Interestingly, there was a trend towards slightly worsened FVC slope in the creatine group (slope difference of -0.63 FVC/month in the creatine group) using a pooled linear mixed-effects model across the two studies which included FVC as an outcome, but this difference was not statistically significant (P = 0.054).<br><br>AUTHORS' CONCLUSIONS: In patients already diagnosed with clinically probable or definite amyotrophic lateral sclerosis (ALS), creatine at doses ranging from 5 to 10 g per day did not have a statistically significant effect on survival, ALS functional rating revised scores (ALSFRS-R) progression or percent predicted forced vital capacity (FVC) progression.}, }
@article {pmid20554882, year = {2010}, author = {Davis-López de Carrizosa, MA and Morado-Díaz, CJ and Morcuende, S and de la Cruz, RR and Pastor, AM}, title = {Nerve growth factor regulates the firing patterns and synaptic composition of motoneurons.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {30}, number = {24}, pages = {8308-8319}, pmid = {20554882}, issn = {1529-2401}, mesh = {Abducens Nerve/physiology ; Action Potentials/*drug effects/physiology ; Analysis of Variance ; Animals ; Axotomy/methods ; Brain Stem/cytology ; Carbazoles/pharmacology ; Cats ; Choline O-Acetyltransferase/metabolism ; Drug Interactions ; Enzyme Inhibitors/pharmacology ; Eye Movements/physiology ; Female ; Functional Laterality ; Gene Expression Regulation/drug effects ; Gene Products, rex/pharmacology ; Glial Fibrillary Acidic Protein/metabolism ; Indole Alkaloids/pharmacology ; Motor Neurons/*drug effects/metabolism ; Nerve Growth Factor/*pharmacology ; Receptor, Nerve Growth Factor/metabolism ; Receptor, trkA/metabolism ; Recruitment, Neurophysiological/drug effects/physiology ; Synapses/drug effects/*physiology ; Synaptophysin/metabolism ; Vesicular Inhibitory Amino Acid Transport Proteins/metabolism ; }, abstract = {Target-derived neurotrophins exert powerful synaptotrophic actions in the adult brain and are involved in the regulation of different forms of synaptic plasticity. Target disconnection produces a profound synaptic stripping due to the lack of trophic support. Consequently, target reinnervation leads to synaptic remodeling and restoration of cellular functions. Extraocular motoneurons are unique in that they normally express the TrkA neurotrophin receptor in the adult, a feature not seen in other cranial or spinal motoneurons, except after lesions such as axotomy or in neurodegenerative diseases like amyotrophic lateral sclerosis. We investigated the effects of nerve growth factor (NGF) by retrogradely delivering this neurotrophin to abducens motoneurons of adult cats. Axotomy reduced the density of somatic boutons and the overall tonic and phasic firing modulation. Treatment with NGF restored synaptic inputs and firing modulation in axotomized motoneurons. When K252a, a selective inhibitor of tyrosine kinase activity, was applied to specifically test TrkA effects, the NGF-mediated restoration of synapses and firing-related parameters was abolished. Discharge variability and recruitment threshold were, however, increased by NGF compared with control or axotomized motoneurons. Interestingly, these parameters returned to normal following application of REX, an antibody raised against neurotrophin receptor p75 (p75(NTR)). In conclusion, NGF, acting retrogradely through TrkA receptors, supports afferent boutons and regulates the burst and tonic signals correlated with eye movements. On the other hand, p75(NTR) activation regulates recruitment threshold, which impacts on firing regularity. To our knowledge, this is the first report showing powerful synaptotrophic effects of NGF on motoneurons in vivo.}, }
@article {pmid20542858, year = {2010}, author = {Wicks, P and Massagli, M and Frost, J and Brownstein, C and Okun, S and Vaughan, T and Bradley, R and Heywood, J}, title = {Sharing health data for better outcomes on PatientsLikeMe.}, journal = {Journal of medical Internet research}, volume = {12}, number = {2}, pages = {e19}, pmid = {20542858}, issn = {1438-8871}, mesh = {Adult ; *Community Participation ; Cross-Sectional Studies ; Data Display ; *Decision Support Techniques ; *Disease Management ; Female ; Health Records, Personal ; Humans ; Information Dissemination/*methods ; *Internet ; Male ; Middle Aged ; *Online Systems ; Physician-Patient Relations ; Population Surveillance ; Rare Diseases/diagnosis/therapy ; Self Care/*methods ; Self-Help Groups ; Social Support ; }, abstract = {BACKGROUND: PatientsLikeMe is an online quantitative personal research platform for patients with life-changing illnesses to share their experience using patient-reported outcomes, find other patients like them matched on demographic and clinical characteristics, and learn from the aggregated data reports of others to improve their outcomes. The goal of the website is to help patients answer the question: "Given my status, what is the best outcome I can hope to achieve, and how do I get there?"<br><br>OBJECTIVE: Using a cross-sectional online survey, we sought to describe the potential benefits of PatientsLikeMe in terms of treatment decisions, symptom management, clinical management, and outcomes.<br><br>METHODS: Almost 7,000 members from six PatientsLikeMe communities (amyotrophic lateral sclerosis [ALS], Multiple Sclerosis [MS], Parkinson's Disease, human immunodeficiency virus [HIV], fibromyalgia, and mood disorders) were sent a survey invitation using an internal survey tool (PatientsLikeMe Lens).<br><br>RESULTS: Complete responses were received from 1323 participants (19% of invited members). Between-group demographics varied according to disease community. Users perceived the greatest benefit in learning about a symptom they had experienced; 72% (952 of 1323) rated the site "moderately" or "very helpful." Patients also found the site helpful for understanding the side effects of their treatments (n = 757, 57%). Nearly half of patients (n = 559, 42%) agreed that the site had helped them find another patient who had helped them understand what it was like to take a specific treatment for their condition. More patients found the site helpful with decisions to start a medication (n = 496, 37%) than to change a medication (n = 359, 27%), change a dosage (n = 336, 25%), or stop a medication (n = 290, 22%). Almost all participants (n = 1,249, 94%) were diagnosed when they joined the site. Most (n = 824, 62%) experienced no change in their confidence in that diagnosis or had an increased level of confidence (n = 456, 34%). Use of the site was associated with increasing levels of comfort in sharing personal health information among those who had initially been uncomfortable. Overall, 12% of patients (n = 151 of 1320) changed their physician as a result of using the site; this figure was doubled in patients with fibromyalgia (21%, n = 33 of 150). Patients reported community-specific benefits: 41% of HIV patients (n = 72 of 177) agreed they had reduced risky behaviors and 22% of mood disorders patients (n = 31 of 141) agreed they needed less inpatient care as a result of using the site. Analysis of the Web access logs showed that participants who used more features of the site (eg, posted in the online forum) perceived greater benefit.<br><br>CONCLUSIONS: We have established that members of the community reported a range of benefits, and that these may be related to the extent of site use. Third party validation and longitudinal evaluation is an important next step in continuing to evaluate the potential of online data-sharing platforms.}, }
@article {pmid20531383, year = {2010}, author = {Schwartz, M and Shechter, R}, title = {Systemic inflammatory cells fight off neurodegenerative disease.}, journal = {Nature reviews. Neurology}, volume = {6}, number = {7}, pages = {405-410}, pmid = {20531383}, issn = {1759-4766}, mesh = {Adaptive Immunity/physiology ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Humans ; Immune System Diseases/pathology ; Inflammation/immunology/*pathology ; Leukocytes/*physiology ; Macrophages/physiology ; Microglia/physiology ; Neurodegenerative Diseases/drug therapy/immunology/*pathology ; }, abstract = {Treatment of Alzheimer disease or amyotrophic lateral sclerosis with anti-inflammatory drugs (to prevent disease or slow its progression) has yielded mixed results, despite evidence indicating that local cytotoxic inflammation occurs in these conditions. Here, through consideration of the importance of immune cell origin (resident versus blood-derived immune cells) and activity (pro-inflammatory versus anti-inflammatory activity) under neurodegenerative conditions, we propose a model that reconciles these seemingly inconsistent data. We suggest that systemic immune cells (CD4(+) T cells and peripheral blood-derived monocytes) must be recruited to the CNS to modify potentially destructive local inflammation, and that the failure of systemic anti-inflammatory drug therapies to arrest neurodegenerative disease progression might result from drug-induced suppression of such recruitment. Thus, we propose that an appreciation of the distinctive temporal and spatial contributions of resident and systemic leukocytes to disease progression is essential for the development of effective therapeutic regimens.}, }
@article {pmid20521074, year = {2010}, author = {Palmieri, A and Sorarù, G and Albertini, E and Semenza, C and Vottero-Ris, F and D'Ascenzo, C and Querin, G and Zennaro, A and Pegoraro, E and Angelini, C}, title = {Psychopathological features and suicidal ideation in amyotrophic lateral sclerosis patients.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {31}, number = {6}, pages = {735-740}, pmid = {20521074}, issn = {1590-3478}, support = {GUP03556/TI_/Telethon/Italy ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/diagnosis/*pathology/*psychology ; Disease Progression ; Early Diagnosis ; Female ; Humans ; Male ; Mental Disorders/diagnosis/pathology/psychology ; Middle Aged ; Predictive Value of Tests ; Risk Factors ; Rorschach Test/standards ; *Suicidal Ideation ; }, abstract = {Psychopathological diagnosis has become increasingly important in amyotrophic lateral sclerosis (ALS), since the recent emphasis on the comprehensive management and end-of-life decisions. Rorschach test is the third most commonly used psychological instrument worldwide and can offer a different approach from self-reporting questionnaires, mainly providing information on issues of which individuals may be unaware or unwilling to admit to. Forty-two ALS patients underwent a psychopathological assessment with the Rorschach test. Psychopathological data were also correlated with skeletal muscle strength as measured by MRC scale and functional evaluation as ALSFRSr and FVC values. Psychopathological features, including suicidial ideation, were more frequent in the recently diagnosed ALS patients. These features were observed to be different according to the kind of functional impairment. Rorschach test may be an useful tool to assess psychopathological features in ALS. Results of our study highlight the need of an early psychopathological diagnosis and specific psychotherapeutic treatment in patients with ALS.}, }
@article {pmid20520853, year = {2010}, author = {Kaundal, RK and Sharma, SS}, title = {Peroxisome proliferator-activated receptor gamma agonists as neuroprotective agents.}, journal = {Drug news &amp; perspectives}, volume = {23}, number = {4}, pages = {241-256}, doi = {10.1358/dnp.2010.23.4.1437710}, pmid = {20520853}, issn = {0214-0934}, mesh = {Alzheimer Disease/drug therapy ; Amyloid Precursor Protein Secretases/genetics ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Aspartic Acid Endopeptidases/genetics ; Brain Ischemia/drug therapy ; Humans ; Matrix Metalloproteinase Inhibitors ; Multiple Sclerosis/drug therapy ; Neuroprotective Agents/*pharmacology/therapeutic use ; PPAR gamma/*agonists/physiology ; Parkinson Disease/drug therapy ; }, abstract = {Peroxisome proliferator-activated receptor gamma (PPARgamma) has already been considered as an attractive therapeutic target for the treatment of metabolic disorders. Recently, PPARgamma agonists were shown to effectively attenuate oxidative stress, inflammation and apoptosis in the central nervous system. There are several preclinical and clinical studies indicating neuroprotective potential of PPARgamma agonists in the treatment of cerebral ischemia, Parkinson's disease, Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis. In these disorders, apart from inhibiting oxidative stress, inflammation and apoptosis, PPARgamma agonists have the potential to modulate various signaling molecules/pathways, including matrix metalloproteinase-9, mitogen-activated protein kinases, signal transducer and activator of transcription, mitochondrial uncoupling protein 2, mitoNEET expression, amyloid precursor protein degradation, beta-site amyloid precursor protein cleaving enzyme 1 and Wnt signaling. This article discusses evidence and mechanisms supporting the neuroprotective effects of PPARgamma agonists in central nervous system disorders.}, }
@article {pmid20498181, year = {2010}, author = {Weber, M and Goldman, B and Truniger, S}, title = {Tetrahydrocannabinol (THC) for cramps in amyotrophic lateral sclerosis: a randomised, double-blind crossover trial.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {81}, number = {10}, pages = {1135-1140}, doi = {10.1136/jnnp.2009.200642}, pmid = {20498181}, issn = {1468-330X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*drug therapy ; Appetite/drug effects ; Cross-Over Studies ; Depression/drug therapy ; Double-Blind Method ; Dronabinol/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Muscle Cramp/complications/*drug therapy ; Quality of Life ; Severity of Illness Index ; Sleep Wake Disorders/complications/drug therapy ; }, abstract = {BACKGROUND: Many patients with amyotrophic lateral sclerosis (ALS) experience cramps during the course of the disease but so far, none of the medications used has been of proven benefit. The objective was to determine the effect of orally administered tetrahydrocannabinol (THC) on cramps in ALS patients.<br><br>METHODS: The authors conducted a randomised, double-blind, placebo-controlled crossover trial in 27 ALS patients suffering from moderate to severe (visual analogue scale (VAS); VAS&#x2265;4) daily cramps. There were 7 women and 20 men with a mean age of 57 years and a mean functional ALS score (ALSFRS-R) of 38.4. Patients were randomly assigned to receive 5 mg THC twice daily followed by placebo or vice versa. Each treatment period lasted for 2 weeks and was preceded by a 2-week drug-free observation period (run-in, wash-out period respectively). The primary outcome measure was change in cramp intensity as assessed by a VAS. Secondary outcome measures included the number of cramps per day, number of cramps during daytime and bedtime, intensity of fasciculations (VAS) as well as validated measures of quality of life (ALSAQ-40), quality of sleep (SDQ), appetite (FAACT) and depression (HADS).<br><br>RESULTS: Complete data were available from 22 patients. THC was well tolerated. There was no evidence for a treatment effect on cramp intensity, number of cramps, fasciculation intensity or any of the other secondary outcome measures.<br><br>CONCLUSIONS: This interventional study with orally administered THC 5 mg twice daily did not demonstrate subjective improvement of cramp intensity in ALS patients.}, }
@article {pmid20496041, year = {2010}, author = {de Vries, MK and van Drumpt, AS and van Royen, BJ and van Denderen, JC and Manoliu, RA and van der Horst-Bruinsma, IE}, title = {Discovertebral (Andersson) lesions in severe ankylosing spondylitis: a study using MRI and conventional radiography.}, journal = {Clinical rheumatology}, volume = {29}, number = {12}, pages = {1433-1438}, pmid = {20496041}, issn = {1434-9949}, mesh = {Adult ; Aged ; Antibodies, Monoclonal/pharmacology/therapeutic use ; Female ; Humans ; Infliximab ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Radiography ; Spine/*diagnostic imaging ; Spondylitis, Ankylosing/*diagnostic imaging/drug therapy ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors ; Young Adult ; }, abstract = {The objective of this study is to investigate the prevalence of Andersson lesions (AL) in ankylosing spondylitis (AS) patients who will start anti-tumor necrosis factor (TNF) treatment. Radiographs and magnetic resonance imaging (MRI) of the spine were performed before therapy with anti-TNF. ALs were defined as discovertebral endplate destructions on MRI, associated with bone marrow edema and fat replacement or sclerosis, a decreased signal on T1, enhancement after contrast administration (gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA)), and increased signal on T2 and short tau inversion recovery (STIR). Additionally, conventional radiography showed a fracture line, irregular endplates, and increased sclerosis of adjacent vertebral bodies. Fifty-six AS patients were included, 68% males, mean age of 43 years, and mean disease duration of 11 years. The mean bath ankylosing spondylitis disease activity index was 6.4, and 24% of all patients had ankylosis. Only one patient showed a discovertebral abnormality with bone marrow edema of more than 50% of the vertebral bodies adjacent to the intervertebral disk of T7/T8 and T9/T10, a hypodense signal area on T1, and a high signal on STIR. Irregular endplates were depicted, and T1 after Gd-DTPA demonstrated high signal intensity around the disk margins. However, no fracture line was visible on conventional radiology, and therefore, this case was not considered to be an AL. No AL was detected in our AS patients, who were candidates for anti-TNF treatment. One patient showed a discovertebral abnormality on MRI, without a fracture line on conventional radiology. The relative small proportion of patients with a long-established disease might explain this finding for, particularly, an ankylosed spine is prone to develop an AL.}, }
@article {pmid20486802, year = {2010}, author = {Coutts, M and Kong, LX and Keirstead, HS}, title = {A model of motor neuron loss: selective deficits after ricin injection.}, journal = {Journal of neurotrauma}, volume = {27}, number = {7}, pages = {1333-1342}, doi = {10.1089/neu.2010.1285}, pmid = {20486802}, issn = {1557-9042}, mesh = {Animals ; *Disease Models, Animal ; Female ; Motor Neuron Disease/chemically induced/*pathology/physiopathology ; Motor Neurons/*drug effects/*pathology ; Neurotoxins/*toxicity ; Rats ; Rats, Sprague-Dawley ; Ricin/*toxicity ; Sciatic Neuropathy/chemically induced/*pathology/physiopathology ; }, abstract = {This study characterizes a model of motor neuron (MN) loss on the molecular, cellular, and behavioral levels. Injection of the toxic lectin Ricinus communis agglutinin I (RCA I or ricin) caused cellular deficit and loss of function by damaging the sciatic nerve. Since the sciatic nerve supplies movement to most of the lower limb, damaging this motor system models lower limb paralysis and the deficits that occur in diseases like amyotrophic lateral sclerosis (ALS) and infantile progressive spinal muscular atrophy (SMA). We used motor-, sensorimotor-, locomotor-, and reflex-based tests to demonstrate loss of function after ricin injection. Loss of function was also demonstrated by decreased retrograde transport, and supported by measurements of muscle wasting. Histochemical and molecular methods were used to characterize sciatic nerve damage in axons and cell bodies, including apoptotic cell death in MNs. This battery of tests documents the extent of the ricin-induced damage and provides a baseline that can be used to judge the efficacy of MN treatment strategies in preclinical studies.}, }
@article {pmid20485543, year = {2010}, author = {Garbuzova-Davis, S and Woods, RL and Louis, MK and Zesiewicz, TA and Kuzmin-Nichols, N and Sullivan, KL and Miller, AM and Hernandez-Ontiveros, DG and Sanberg, PR}, title = {Reduction of circulating endothelial cells in peripheral blood of ALS patients.}, journal = {PloS one}, volume = {5}, number = {5}, pages = {e10614}, pmid = {20485543}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*blood/*pathology ; CD146 Antigen/metabolism ; Case-Control Studies ; *Cell Movement ; Demography ; Endothelial Cells/metabolism/*pathology ; Female ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) treatment is complicated by the various mechanisms underlying motor neuron degeneration. Recent studies showed that the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) are compromised in an animal model of ALS due to endothelial cell degeneration. A later study demonstrated a loss of endothelium integrity in the spinal cords of ALS patients. Since circulating endothelial cells (CECs) in the peripheral blood are associated with endothelium damage, being detached dysfunctional endothelial cells, we hypothesized that CEC levels may reflect endothelium condition in ALS patients.<br><br>CEC levels were estimated in whole blood smears from ALS patients with moderate stage ((M)ALS), severe stage ((S)ALS), and healthy controls by CD146 expression using immunocytochemistry. A significant reduction of CECs was detected in (M)ALS and (S)ALS patients.<br><br>CONCLUSIONS/SIGNIFICANCE: CECs did not predict endothelium state in ALS patients; however, endothelial damage and/or impaired endothelium repair may occur in ALS leading to BBB/BSCB dysfunction. Reduced CECs in peripheral blood of ALS patients may indicate different mechanisms of endothelial damage and repair, rather than only detachment of dysfunctional endothelial cells. Although a potential mechanism of CEC reduction is discussed, establishing a reliable indicator of endothelial dysfunction/damage is important for evaluation of BBB/BSCB status in ALS patients during disease progression.}, }
@article {pmid20478608, year = {2010}, author = {Yekhlef, F and Decup, D and Niclot, P and Servan, J and Descombes, S and Richecoeur, J and Ollivier, A}, title = {[Medico-economic assessment of the Pontoise Hospital stroke unit].}, journal = {Revue neurologique}, volume = {166}, number = {11}, pages = {901-908}, doi = {10.1016/j.neurol.2010.03.009}, pmid = {20478608}, issn = {0035-3787}, mesh = {Adult ; Aged ; Aged, 80 and over ; Cerebral Hemorrhage/economics/therapy ; Cerebral Infarction/economics/therapy ; Costs and Cost Analysis ; Diagnosis-Related Groups ; Female ; France ; Hospital Costs ; Hospital Units/*economics/*organization &amp; administration ; Hospitalization/economics ; Humans ; Ischemic Attack, Transient/economics/therapy ; Length of Stay ; Male ; Middle Aged ; Stroke/*economics/mortality/*therapy ; Young Adult ; }, abstract = {INTRODUCTION: Annually, approximately 120,000 people in France have a stroke. Various controlled studies have pointed out the benefits of treatment in a stroke unit (SU). The objective of this study was to evaluate, from a medical point of view, the economic impact of the Pontoise Hospital SU.<br><br>PATIENTS AND METHODS: Based on the national cost study (NCS [&#xe9;tude nationale des co&#xfb;ts: ENC]) we analyzed data of five diagnosis related groups (DRG) which have a principle diagnosis in relation with stroke. This work was limited to strokes and transient ischemic events in adults and excluded sub-arachnoid hemorrhage. Medical and economic parameters were collected over the period from January to October 2006 and compared with those of the same period in 2005, that is to say before the opening of the SU.<br><br>RESULTS: Three hundred and twenty-three hospital stays occurred between January 1st and October 31st, 2006 and 216 during the same time period before the opening of the SU, an increase of approximately 50% of all stroke-related admissions in our hospital. The number of stays carried out in the neurology unit increased by 29%. There was no significant difference between the two periods regarding age (median 69 versus 70 years) and sex- ratio. Average length of stay (ALS) was the same (9 days). There were no significant differences concerning the death rate (5.6% versus 6.2%) and that of discharge to home (44.6% versus 44.4%). The cost by stay in 2006 was 3534 euros [median; min 664-max 57,542] versus 3541 euros in 2005 [681-35,149] (p=0.57). Analysis by DRG highlighted an increase in the cost for serious strokes, cerebral infarctions and hemorrhages. For transitory ischemic events, the cost and the ALS decreased.<br><br>CONCLUSION: After the opening of the SU, there was an increase in the activity without an increase in the total cost. This could be related in part to the limited means allocated to the stroke unit at its opening (in particular medical staff). The NCS can be used to evaluate the activity of a stroke unit. This work could be completed on a larger number of units or in several units of different size.}, }
@article {pmid20467996, year = {2010}, author = {Myers, LA and Russi, CS and Schultz, JL}, title = {Paramedic intercepts with basic life support ambulance services in rural Minnesota.}, journal = {Prehospital and disaster medicine}, volume = {25}, number = {2}, pages = {159-163}, doi = {10.1017/s1049023x00007901}, pmid = {20467996}, issn = {1049-023X}, mesh = {Adolescent ; Adult ; Advanced Cardiac Life Support/statistics &amp; numerical data ; Ambulances/*organization &amp; administration ; Cardiopulmonary Resuscitation/*statistics &amp; numerical data ; Child ; Emergency Medical Technicians/*organization &amp; administration ; Female ; Humans ; Male ; Middle Aged ; Minnesota ; Multi-Institutional Systems ; *Needs Assessment ; Retrospective Studies ; Rural Health Services/organization &amp; administration ; Wisconsin ; }, abstract = {INTRODUCTION: In rural Minnesota, it is common for paramedics providing advanced life support (ALS) to rendezvous with ambulances providing only basic life support (BLS). These "intercepts" presumably allow for a higher level of care when patients have certain problems or need ALS interventions. The aim of this study was to review and understand the frequency of paramedic intercepts with regard to the actual care rendered and transport urgency (lights and sirens vs. none).<br><br>METHODS: All paramedic intercepts occurring between January 2003 and December 2007 for one multi-site emergency medical services (EMS) provider were reviewed for ALS interventions and treatments provided. In addition, the urgency of responses to the dispatch call or "intercept" and transport to a receiving facility were analyzed.<br><br>RESULTS: During the study period, 1,675 paramedic intercepts occurred and were reviewed. The ALS ambulances responded to the dispatch emergently (lights and sirens) in 97.5% of intercepts (1,633), but emergently transported only 24.2% of the patients (405). Paramedics performed no interventions above BLS levels in 11.6% (194) of the cases. Of the remaining 1,481 patients who received ALS interventions, 955 (64.4%) received no treatment or diagnostic testing other than electrocardiographic monitoring, intravenous access, or both.<br><br>CONCLUSIONS: A significant discrepancy between emergent responses and actual ALS care rendered during intercept calls was demonstrated. Given the significant rate of EMS worker fatalities and transferable patient care costs, further study is needed to determine whether costs and safety are potentially improved by decreasing emergent responses. Future directions include developing or emulating Medical Priority Dispatch System triage protocols for advanced services providing intercepts. In addition, further study of patient outcomes between intercept and non-intercept cases is necessary.}, }
@article {pmid20467334, year = {2010}, author = {Janssen, C and Schmalbach, S and Boeselt, S and Sarlette, A and Dengler, R and Petri, S}, title = {Differential histone deacetylase mRNA expression patterns in amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {69}, number = {6}, pages = {573-581}, doi = {10.1097/NEN.0b013e3181ddd404}, pmid = {20467334}, issn = {1554-6578}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Brain/*metabolism ; Case-Control Studies ; Female ; Gene Expression/genetics ; Histone Deacetylases/*genetics/metabolism ; Humans ; Immunohistochemistry ; In Situ Hybridization ; Male ; Middle Aged ; Neurons/metabolism ; RNA, Messenger/genetics/metabolism ; Spinal Cord/*metabolism ; }, abstract = {Histone deacetylases (HDACs) are important regulators of gene expression and cell differentiation. The HDAC inhibitors have recently been considered as potential novel neuroprotective drugs for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). A major limitation, however, lies in the broad spectrum of action of currently available HDAC inhibitors that may cause a variety of toxic side effects. The mRNA expression levels of the HDAC isoforms HDACs 1 to 11 have previously been characterized in rat brain but have not been studied in human tissue. Using in situ hybridization histochemistry and immunohistochemistry we assessed the distribution and expression levels of HDACs 1to 11 in postmortem ALS and control brain and spinal cord specimens (n = 6 cases each) to determine alterations in the mRNA expression pattern that could provide a basis for disease-specific therapies. We found a reduction of HDAC 11 mRNA and increased HDAC 2 levels in ALS brain and spinal cord compared with controls. A more precise knowledge of the disease-related expression pattern could lead to the development of more specific pharmacotherapeutic approaches.}, }
@article {pmid20464297, year = {2010}, author = {Silva, LB and Mourão, LF and Silva, AA and Lima, NM and Almeida, SR and Franca, MC and Nucci, A and Amaya-Farfán, J}, title = {Effect of nutritional supplementation with milk whey proteins in amyotrophic lateral sclerosis patients.}, journal = {Arquivos de neuro-psiquiatria}, volume = {68}, number = {2}, pages = {263-268}, doi = {10.1590/s0004-282x2010000200021}, pmid = {20464297}, issn = {1678-4227}, mesh = {Adult ; Alanine Transaminase/blood ; Amyotrophic Lateral Sclerosis/*diet therapy/enzymology ; Aspartate Aminotransferases/blood ; Creatine Kinase/blood ; *Dietary Supplements ; Double-Blind Method ; Female ; Humans ; Lymphocyte Count ; Male ; Middle Aged ; Milk Proteins/*administration &amp; dosage ; Prospective Studies ; Starch/*administration &amp; dosage ; Weight Gain ; Whey Proteins ; }, abstract = {OBJECTIVE: We evaluated the efficacy of oral supplementation with milk whey proteins and modified starch (70%WPI:30%MS), on nutritional and functional parameters of patients with ALS.<br><br>METHOD: A prospective randomized double-blind study was performed with 16 ALS patients, divided in two groups, the treatment group received (70%WPI:30%MS) and the control group received (maltodextrin). They underwent prospective nutritional and functional assessment for 4 months.<br><br>RESULTS: Patients in the treatment group presented weight gain, increased body mass index (BMI), increased arm muscle area and circumference, higher albumin, white blood cell and total lymphocyte counts, and reduced creatine-kinase, aspartate aminotransferase and alanine aminotransferase. In the control group, biochemical parameters did not change, but weight and BMI declined.<br><br>CONCLUSION: Our results indicate that the agglomerate 70%WPI:30%MS may be useful in the nutritional therapy of patients with ALS.}, }
@article {pmid20463464, year = {2010}, author = {Price, S and Uddin, S and Quinn, T}, title = {Echocardiography in cardiac arrest.}, journal = {Current opinion in critical care}, volume = {16}, number = {3}, pages = {211-215}, doi = {10.1097/MCC.0b013e3283399d4c}, pmid = {20463464}, issn = {1531-7072}, mesh = {Algorithms ; Cardiopulmonary Resuscitation/*methods ; *Critical Illness ; Echocardiography ; Embolism/diagnosis/diagnostic imaging ; Emergency Service, Hospital/organization &amp; administration ; Heart Arrest/*diagnostic imaging/prevention &amp; control/therapy ; Heart Diseases/diagnosis/diagnostic imaging ; Hemodynamics ; Humans ; Intensive Care Units/*organization &amp; administration ; Thrombosis/diagnosis/diagnostic imaging ; }, abstract = {PURPOSE OF REVIEW: Successful resuscitation requires potentially reversible causes to be diagnosed and reversed, and many of these can readily be diagnosed using echocardiography. Although members of the resuscitation team routinely use adjuncts to their clinical examination in order to differentiate these causes, the use of echocardiography is not yet considered standard. The purpose of this review is to discuss the potential for echocardiography to aid diagnosis and treatment during resuscitation, together with some of the perceived challenges that currently limit its widespread use.<br><br>RECENT FINDINGS: Many studies have demonstrated the value of echocardiography in the assessment of critically ill patients in the intensive care unit and emergency room settings, including more recently the use of focused echocardiography. This can be performed within the time frame allowed during the pulse check of the advanced life support (ALS) algorithm. ALS-compliant focused echocardiography can be taught to nonexpert practitioners such that high-quality cardiopulmonary resuscitation is not compromised while diagnosing/excluding some of the potential causes of cardiac arrest.<br><br>SUMMARY: Persistent and worsening haemodynamic instability are regarded as clear indications for echocardiography. The focused application of this well established technique within the ALS algorithm provides the resuscitation team with a potentially powerful diagnostic tool that can be used to diagnose/exclude some of the potentially treatable causes of cardiac arrest as well as to guide therapeutic interventions. The impact of routine periresuscitation echocardiography on patient outcomes both for in-hospital and prehospital care remains an exciting avenue for future research.}, }
@article {pmid20463400, year = {2010}, author = {Shi, P and Wei, Y and Zhang, J and Gal, J and Zhu, H}, title = {Mitochondrial dysfunction is a converging point of multiple pathological pathways in amyotrophic lateral sclerosis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {20 Suppl 2}, number = {}, pages = {S311-24}, doi = {10.3233/JAD-2010-100366}, pmid = {20463400}, issn = {1875-8908}, support = {P20RR020171/RR/NCRR NIH HHS/United States ; R01NS049126/NS/NINDS NIH HHS/United States ; R11AG032567/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics/*pathology ; Animals ; Axonal Transport/physiology ; Homeostasis/physiology ; Humans ; Mitochondrial Diseases/*complications/genetics/*pathology ; Models, Biological ; Mutation/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {A better understanding of the etiology of amyotrophic lateral sclerosis (ALS) is needed to develop effective therapies for the treatment of this fatal neurodegenerative disease. Extensive studies have produced a general agreement that ALS is likely to be a multifactorial and multisystem disease. Many mechanisms have been postulated to be involved in the pathology of ALS, such as oxidative stress, glutamate excitotoxicity, mitochondrial damage, defective axonal transport, glia cell pathology, and aberrant RNA metabolism. Mitochondria have shown to be an early target in ALS pathogenesis and contribute to the disease progression. Morphological and functional defects in mitochondria were found in both human patients and ALS mice overexpressing mutant SOD1. Mutant SOD1 was found to be preferentially associated with mitochondria and subsequently impair mitochondrial function. Recent studies suggest that axonal transport of mitochondria along microtubules is disrupted in ALS. Furthermore, new evidence suggests that mitochondrial fission and fusion as well as mitophagy clearance may also be affected by mutant SOD1. These results also illustrate the critical importance of maintaining proper mitochondrial function in axons and neuromuscular junctions, supporting the emerging "dying-back" axonopathy model of ALS. In this review, we will discuss findings supporting that mitochondrial dysfunction is likely to be a converging point of multiple pathways underlying the ALS pathogenesis and progression.}, }
@article {pmid20460191, year = {2010}, author = {Yang, EJ and Jiang, JH and Lee, SM and Hwang, HS and Lee, MS and Choi, SM}, title = {Electroacupuncture reduces neuroinflammatory responses in symptomatic amyotrophic lateral sclerosis model.}, journal = {Journal of neuroimmunology}, volume = {223}, number = {1-2}, pages = {84-91}, doi = {10.1016/j.jneuroim.2010.04.005}, pmid = {20460191}, issn = {1872-8421}, mesh = {Amyotrophic Lateral Sclerosis/*immunology/pathology/*therapy ; Animals ; *Disease Models, Animal ; *Electroacupuncture/methods ; Humans ; Inflammation/immunology/pathology/therapy ; Male ; Mice ; Mice, Transgenic ; Motor Skills Disorders/immunology/pathology/therapy ; Neurons/*immunology/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a paralyzing disorder that is characterized by the progressive degeneration and death of motor neurons. Acupuncture or electroacupuncture (EA) has been used for the treatment of various conditions including osteoarthritis, asthma, and other types of chronic pain conditions. It has been hypothesized that acupuncture exerts anti-inflammatory and anti-nociceptive effects on inflammatory reactions processes. The purpose of this study was to determine whether acupuncture at a specific acupoint could produce anti-inflammatory responses and suppress motor neuron loss in the hG93ASOD1 mouse, commonly used as a model for inherited ALS. We delivered EA at the Zusanli (ST36) acupuncture point in the symptomatic hSOD1G93A animal model. The EA-treated mutant hSOD1 transgenic mice showed decreases in microglial cell activity and TNF-alpha expression in the spinal cord and brain stem. Furthermore, EA significantly improved motor activity compared to the control group and reduced neuronal cell loss in hSOD1G93A mice. Our research suggests a potential functional link between EA therapy and anti-neuroinflammatory response in an ALS animal model.}, }
@article {pmid20450936, year = {2010}, author = {Knippenberg, S and Thau, N and Dengler, R and Petri, S}, title = {Significance of behavioural tests in a transgenic mouse model of amyotrophic lateral sclerosis (ALS).}, journal = {Behavioural brain research}, volume = {213}, number = {1}, pages = {82-87}, doi = {10.1016/j.bbr.2010.04.042}, pmid = {20450936}, issn = {1872-7549}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/psychology ; Animals ; Behavior, Animal ; Body Weight ; Disability Evaluation ; Disease Models, Animal ; Disease Progression ; Female ; Gait ; Humans ; Male ; Mice ; Mice, Transgenic ; Mutation, Missense ; *Neuropsychological Tests ; Sex Factors ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Time Factors ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating adult-onset motor neuron disorder with marginal therapeutic options. The disease is characterized by progressive degeneration of motor neurons in spinal cord and motor cortex. Transgenic mice carrying the G93A mutation of the superoxide dismutase 1 (SOD1) gene develop a neurodegenerative disease closely mimicking human ALS. Several methods are currently used to record disease onset and progression of the animals in preclinical studies. For the interpretation of these preclinical trials, it is important to assess neurological function as sensitively as possible. In the present study, five different parameters (rotarod performance, weight, footprint analysis for both step length and runtime and the general condition of the mice scored from 1 to 5) were compared with respect to their significance to detect symptom onset and to monitor disease progression in transgenic G93A ALS mice. The rotarod and footprint analyses were performed weekly while the weight was recorded up to three times a week at later time points. General condition was assessed daily. First deficits were detected by rotarod testing and step length analyses. General condition score and weight showed first changes two weeks later. For preclinical testing of novel drug treatments rotarod and footprint analysis for step length therefore seem to be the most effective methods to detect symptom onset and potential treatment induced improvements.}, }
@article {pmid20439484, year = {2010}, author = {Carter, GT and Abood, ME and Aggarwal, SK and Weiss, MD}, title = {Cannabis and amyotrophic lateral sclerosis: hypothetical and practical applications, and a call for clinical trials.}, journal = {The American journal of hospice &amp; palliative care}, volume = {27}, number = {5}, pages = {347-356}, doi = {10.1177/1049909110369531}, pmid = {20439484}, issn = {1938-2715}, support = {R21 NS041639/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antineoplastic Agents/pharmacology ; Antioxidants/pharmacology ; Cannabinoids/administration &amp; dosage/*pharmacology ; *Cannabis ; Clinical Trials as Topic ; *Disease Models, Animal ; Drug Therapy, Combination ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects ; Nerve Degeneration/drug therapy ; Phytotherapy/*methods ; }, abstract = {Significant advances have increased our understanding of the molecular mechanisms of amyotrophic lateral sclerosis (ALS), yet this has not translated into any greatly effective therapies. It appears that a number of abnormal physiological processes occur simultaneously in this devastating disease. Ideally, a multidrug regimen, including glutamate antagonists, antioxidants, a centrally acting anti-inflammatory agent, microglial cell modulators (including tumor necrosis factor alpha [TNF-alpha] inhibitors), an antiapoptotic agent, 1 or more neurotrophic growth factors, and a mitochondrial function-enhancing agent would be required to comprehensively address the known pathophysiology of ALS. Remarkably, cannabis appears to have activity in all of those areas. Preclinical data indicate that cannabis has powerful antioxidative, anti-inflammatory, and neuroprotective effects. In the G93A-SOD1 ALS mouse, this has translated to prolonged neuronal cell survival, delayed onset, and slower progression of the disease. Cannabis also has properties applicable to symptom management of ALS, including analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. With respect to the treatment of ALS, from both a disease modifying and symptom management viewpoint, clinical trials with cannabis are the next logical step. Based on the currently available scientific data, it is reasonable to think that cannabis might significantly slow the progression of ALS, potentially extending life expectancy and substantially reducing the overall burden of the disease.}, }
@article {pmid20435394, year = {2010}, author = {Zimmer, M and Wassmer, R and Latasch, L and Oberndörfer, D and Wilken, V and Ackermann, H and Breitkreutz, R}, title = {Initiation of risk management: incidence of failures in simulated Emergency Medical Service scenarios.}, journal = {Resuscitation}, volume = {81}, number = {7}, pages = {882-886}, doi = {10.1016/j.resuscitation.2010.03.009}, pmid = {20435394}, issn = {1873-1570}, mesh = {Allied Health Personnel/*organization &amp; administration ; Asthma/therapy ; Cardiopulmonary Resuscitation/*methods ; Clinical Competence ; Communication ; Confidence Intervals ; Emergencies ; Emergency Medical Services/*organization &amp; administration ; Female ; Germany ; Humans ; Incidence ; Interprofessional Relations ; Male ; Multiple Trauma/therapy ; Needs Assessment ; Patient Simulation ; Pulmonary Embolism/therapy ; Risk Management/*organization &amp; administration ; Treatment Failure ; Video Recording ; }, abstract = {AIM: This study is a description of the rate of unsafe acts and communication events in simulations of Emergency Medical Service (EMS) mission-based scenarios as first response for risk management and patient safety.<br><br>SUBJECTS AND METHODS: The study involved video-based observation of German paramedic teams (n=40) during simulated EMS missions. Teams were randomised to four types of scenarios: advanced life support (ALS), bronchial asthma (BA), pulmonary embolism (PE) and multiple trauma (MT). All predefined events were analysed.<br><br>RESULTS: In a total of 40 scenarios, paramedics committed more than seven unsafe acts per scenario (7.4+/-3.8, mean+/-standard deviation, 95% confidence interval (CI): 6.6-8.3). In detail, there were unsafe acts for ALS (6.8+/-3.9, 95% CI: 5.2-8.5), in BA (8.1+/-3.9, 95% CI: 6.4-9.8), in PE (4.0+/-1.6, 95% CI: 3.0-5.0) and in MT (9.3+/-3.2, 95% CI: 7.8-10.7). Strategies of diagnosis and treatment were heterogeneous chronologically and methodically. Bad communication events were noted with a mean of 3.9+/-1.6 (95% CI: 3.1-4.6) within the scenarios. All the handovers (100%) between paramedics and emergency physician were incomplete, and 53.7+/-11.0% (95% CI: 48.5-58.8%) of information of realised actions and status of patient were missed in handover.<br><br>CONCLUSION: A subset of German paramedics caused many unsafe acts and dangerous communication in simulations that may affect real-life work. We suggest paramedics should take part in a need-based education programme and communication training.}, }
@article {pmid20433414, year = {2010}, author = {Piepers, S and van den Berg, LH}, title = {No benefits from experimental treatment with olfactory ensheathing cells in patients with ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {3}, pages = {328-330}, doi = {10.3109/17482961003663555}, pmid = {20433414}, issn = {1471-180X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*complications/*therapy ; Cell Transplantation/*methods ; Female ; *Fetal Tissue Transplantation ; Fetus ; Humans ; Male ; Middle Aged ; Muscle Strength/physiology ; Olfaction Disorders/*etiology/*surgery ; Olfactory Bulb/cytology/*transplantation ; Prospective Studies ; Treatment Outcome ; }, abstract = {Cell based therapies may be promising options for treating ALS. These therapies aim at neuronal replacement or they may prevent dysfunctional motor neurons from dying. Conflicting results on transplantation of olfactory ensheathing cells (OECs) in ALS mouse models indicate that this technique is not yet ready to progress to clinical trials. A Chinese group has nevertheless treated ALS patients with OECs. We carried out a prospective study of seven patients who underwent OEC treatment in China, following them from four months before departure until one year after treatment. Muscle strength, level of daily functioning and respiratory capacity were measured at regular intervals. Three patients reported subjective positive effects directly after treatment. No individual objective improvement was measured, and outcome measures gradually declined in all patients. Two patients had severe side-effects. Based on our findings in these ALS patients who underwent experimental OEC treatment, we conclude that there are no indications that this treatment is beneficial.}, }
@article {pmid20422280, year = {2010}, author = {Ragancokova, D and Song, Y and Nau, H and Dengler, R and Krampfl, K and Petri, S}, title = {Modulation of synaptic transmission and analysis of neuroprotective effects of valproic Acid and derivates in rat embryonic motoneurons.}, journal = {Cellular and molecular neurobiology}, volume = {30}, number = {6}, pages = {891-900}, pmid = {20422280}, issn = {1573-6830}, mesh = {Animals ; Cells, Cultured ; Embryo, Mammalian/*cytology ; Motor Neurons/cytology/*drug effects/*physiology ; Neuroprotective Agents/chemistry/*pharmacology ; Patch-Clamp Techniques ; Rats ; Rats, Sprague-Dawley ; Synaptic Transmission/*drug effects ; Valproic Acid/*analogs &amp; derivatives/chemistry/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis is a devastating motoneuron disorder for which no effective treatment exists. There is some evidence for neuroprotective effects of valproic acid (VPA). The beneficial effects, however, are limited due to the adverse effects of VPA. To overcome this problem, a number of VPA derivates with fewer side effects have been synthesized. In the present study, we investigated the viability of highly purified embryonic motoneurons cultured on glial feeder layers, composed of either astrocytes or Schwann cells, or in monoculture, in presence of VPA and its three derivates 3-propyl-heptanoic acid (3-PHA), PE-4-yn enantiomers (R- and S-PE-4-yn). An excitotoxic stimulus, kainate (KA), was added at day in vitro 9 (DIV9) and the neuroprotective effect of either simultaneous incubation (DIV9) or pre-incubation (DIV1) of VPA and its derivates was tested. The survival of motoneurons under simultaneous application of KA and VPA derivates was not remarkably increased. Pre-incubation with VPA and even more with the derivates before the addition of KA, however, significantly reduced their vulnerability against the KA-induced neurotoxic effect. Our data suggest that the neuroprotective capacities of VPA and its three derivates tested here drastically increase when they are added several days before KA. Most prominent neuroprotective effects were seen for the PE-4-yn enantiomers. Patch-clamp experiments revealed an antiexcitotoxic effect of the S-PE-4-yn enantiomer that reduces the frequency of postsynaptic currents and enhances the inhibitory postsynaptic transmission dependent on the co-culture condition.}, }
@article {pmid20420119, year = {2010}, author = {Kertesz, A}, title = {Frontotemporal dementia, Pick's disease.}, journal = {Ideggyogyaszati szemle}, volume = {63}, number = {1-2}, pages = {4-12}, pmid = {20420119}, issn = {0019-1442}, mesh = {Aphasia/etiology ; *Frontotemporal Dementia/complications/diagnosis/epidemiology/genetics/therapy ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Motor Neuron Disease/complications ; Mutation ; *Pick Disease of the Brain/complications/diagnosis/epidemiology/genetics/therapy ; Prognosis ; Progranulins ; Semantics ; tau Proteins/genetics ; }, abstract = {A significant expansion of knowledge in the last few years, especially in the molecular biology of frontotemporal dementia (FTD) is summarized. This condition, formerly known as Pick's disease and considered rare, is estimated to be 12-15% of all dementias and 30-50% early onset ones. The clinical picture is protean, mainly a behavioural and language impairment, but the extrapyramidal syndromes of CBD and PSP also belong. These seemingly different presentations converge, as one or other areas in the brain are affected. Less than half of the cases are tauopathies, the majority has been discovered to have a TDP-43 and most recently a FUS proteinopathy, shared with ALS, opening potential opportunities for pharmacological approaches to treatment. Tau and progranulin mutations on Ch-17 and some others, point to molecular mechanisms. A glossary is provided to navigate the complex terminology.}, }
@article {pmid20414791, year = {2010}, author = {Payer, M and Sottas, C and Bonvin, C}, title = {Superficial siderosis of the central nervous system: secondary progression despite successful surgical treatment, mimicking amyotrophic lateral sclerosis. Case report and review.}, journal = {Acta neurochirurgica}, volume = {152}, number = {8}, pages = {1411-1416}, doi = {10.1007/s00701-010-0653-2}, pmid = {20414791}, issn = {0942-0940}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*etiology/pathology ; Diagnosis, Differential ; Disease Progression ; Fatal Outcome ; Female ; Hematoma, Subdural, Spinal/*complications/pathology/surgery ; Hemosiderosis/*diagnosis/*etiology/pathology ; Humans ; Middle Aged ; }, abstract = {Superficial siderosis of the central nervous system is a rare disorder with hemosiderin deposition in the spinal and cranial leptomeninges and subpial layer, mostly from repetitive subarachnoid hemorrhage. Progressive sensorineural deafness, cerebellar ataxia, and pyramidal signs comprise the typical clinical presentation. We describe a 47-year-old patient, who showed initial 2-year improvement after successful occlusion of an intradural bleeding source at T4. Secondary progression of symptoms without further bleedings was noted thereafter, with a clinical picture of amyotrophic lateral sclerosis. This case illustrates that the disease may progress secondarily even without re-bleedings, and that secondary progression might be due to a similar pathomechanism as in amyotrophic lateral sclerosis.}, }
@article {pmid20413882, year = {2010}, author = {Burrell, JR and Hodges, JR}, title = {From FUS to Fibs: what's new in frontotemporal dementia?.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {21}, number = {2}, pages = {349-360}, doi = {10.3233/JAD-2010-091513}, pmid = {20413882}, issn = {1875-8908}, mesh = {*Frontotemporal Dementia/genetics/pathology/physiopathology ; Humans ; *Primary Progressive Nonfluent Aphasia/genetics/pathology/physiopathology ; *TDP-43 Proteinopathies/genetics/pathology/physiopathology ; }, abstract = {Frontotemporal dementia (FTD) is an important cause of non-Alzheimer's dementia and is the second most common cause of young onset dementia. FTD presents with progressive changes in behavior and personality (behavioral variant FTD) or language deficits (also known as primary progressive aphasia), although both commonly coexist. Patients with progressive aphasia are subclassified according to the pattern of language deficits into those with progressive non-fluent aphasia (PNFA) and semantic dementia (SD). FTD is pathologically heterogeneous, both macroscopically and on a molecular level, with tau positive, TDP-43 positive, and FUS positive intraneuronal inclusions recognized on immunohistochemical analysis. TDP-43 positive inclusions are also a feature of amyotrophic lateral sclerosis pathology, corroborating the observation of overlapping clinical features between the two conditions and reaffirming the FTD-ALS disease spectrum. Most FTD cases are sporadic, but an important minority is inherited in an autosomal dominant fashion, most commonly due to MAPT or progranulin gene mutations. Familial clusters of FTD and amyotrophic lateral sclerosis are also recognized but poorly understood. This paper reviews the clinical phenotypes, assessment and treatment of FTD in light of recent pathological and genetic discoveries.}, }
@article {pmid20406186, year = {2010}, author = {Murri, L}, title = {Neuroprotection in amyotrophic lateral sclerosis: from pathology to treatment.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {3}, pages = {258}, doi = {10.2174/187152710791292675}, pmid = {20406186}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/*pathology ; Animals ; Disease Models, Animal ; Drug Delivery Systems ; Humans ; Motor Neurons/drug effects/metabolism/*pathology ; Nerve Degeneration/*drug therapy/etiology/*pathology ; }, }
@article {pmid20406183, year = {2010}, author = {Schmalbach, S and Petri, S}, title = {Histone deacetylation and motor neuron degeneration.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {3}, pages = {279-284}, doi = {10.2174/187152710791292684}, pmid = {20406183}, issn = {1996-3181}, mesh = {Acetylation/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy/enzymology/genetics/*pathology ; Animals ; Histone Deacetylases/*metabolism ; Humans ; Motor Neurons/drug effects/*enzymology/*pathology ; Nerve Degeneration/drug therapy/*enzymology/genetics/*pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with progressive muscular wasting and paralysis due to loss of motor neurons in the primary motor cortex, brainstem and spinal cord. Alterations of transcriptional activity due to an unbalance of the activity of histone acetyl transferases (HAT) and histone deacetylases (HDACs) have been described in a variety of neurodegenerative conditions in vitro and in vivo. HDACs can be grouped into four different classes with distinct cellular localization and functions. HDAC inhibitors have recently been discovered as potential neuroprotective drugs for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). A major limitation, however, lies in the broad spectrum of action of currently available HDAC inhibitors causing a variety of toxic side effects.}, }
@article {pmid20406180, year = {2010}, author = {Siciliano, G and Carlesi, C and Pasquali, L and Piazza, S and Pietracupa, S and Fornai, F and Ruggieri, S and Murri, L}, title = {Clinical trials for neuroprotection in ALS.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {3}, pages = {305-313}, doi = {10.2174/187152710791292648}, pmid = {20406180}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism/*pathology ; Animals ; Clinical Trials as Topic/*trends ; Humans ; Neuropharmacology/methods/*trends ; Neuroprotective Agents/*pharmacology/therapeutic use ; Neurotoxins/antagonists &amp; inhibitors ; }, abstract = {Owing to uncertainty on the pathogenic mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) riluzole remains the only available therapy, with only marginal effects on disease survival. Here we review some of the recent advances in the search for disease-modifying drugs for ALS based on their putative neuroprotective effetcs. A number of more or less established agents have recently been investigated also in ALS for their potential role in neuroprotection and relying on antiglutamatergic, antioxidant or antiapoptotic strategies. Among them Talampanel, beta-lactam antibiotics, Coenzyme Q10, and minocycline have been investigated. Progress has also been made in exploiting growth factors for the treatment of ALS, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, such as heat-shock protein co-inducers, which upregulate cell stress responses, and agents promoting autophagy and mitochondriogenesis, such as lithium and rapamycin. More recently, alterations of mRNA processing were described as a pathogenic mechanism in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations. This knowledge is expected to improve our understanding of the pathogenetic mechanism in ALS and developing more effective therapies.}, }
@article {pmid20406179, year = {2010}, author = {Silani, V and Calzarossa, C and Cova, L and Ticozzi, N}, title = {Stem cells in amyotrophic lateral sclerosis: motor neuron protection or replacement?.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {9}, number = {3}, pages = {314-324}, doi = {10.2174/187152710791292666}, pmid = {20406179}, issn = {1996-3181}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*therapy ; Animals ; Disease Models, Animal ; Humans ; Motor Neurons/*pathology/physiology ; Nerve Degeneration/etiology/pathology/therapy ; Stem Cell Transplantation/*methods/*trends ; Stem Cells/*pathology/physiology ; }, abstract = {Given the lack of effective drug treatments for amyotrophic lateral sclerosis (ALS), compelling preclinical data on stem cell research has targeted this disease as a candidate for stem cell treatment. Stem cell transplantation has been effective in several animal models, but the underlying biological pathways of restorative processes are still unresolved. Several mechanisms such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation may explain positive therapeutic results in preclinical animal models, in addition to replacement of lost motor neurons. The clinical target in ALS has shifted from being neuroncentered to focus on the interaction between motor neurons and non-neuronal cells (mainly astroglial or microglial). In fact, one of the fundamental unanswered questions in ALS is whether and how much motor neuron death depends on neighboring cells, and how wildtype non-neuronal cells may protect motor neurons expressing an ALS-causing mutation. Lately, motor neuron replacement has been successfully achieved in animal models with reinnervation of the muscle target. Even if many biological issues need to be solved in preclinical models, preliminary stem cell transplantation trials have been performed in ALS patients with conflicting results. The review discusses relevant topics regarding the application of stem cell research to ALS focusing on their therapeutic relevance and mechanisms of action.}, }
@article {pmid20401600, year = {2010}, author = {Kraft, P and Beck, M and Grimm, A and Wessig, C and Reiners, K and Toyka, KV}, title = {[Amyotrophic lateral sclerosis: management of bulbar symptoms].}, journal = {Der Nervenarzt}, volume = {81}, number = {10}, pages = {1218-1225}, pmid = {20401600}, issn = {1433-0407}, mesh = {Affective Symptoms/diagnosis/physiopathology/therapy ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/psychology/*therapy ; Antidepressive Agents/therapeutic use ; Combined Modality Therapy ; Communication Devices for People with Disabilities ; Deglutition Disorders/diagnosis/physiopathology/*therapy ; Dysarthria/diagnosis/physiopathology/*therapy ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Palliative Care/*methods ; *Patient Care Team ; Pseudobulbar Palsy/diagnosis/physiopathology/*therapy ; Quality of Life/psychology ; Randomized Controlled Trials as Topic ; Riluzole/therapeutic use ; Sialorrhea/diagnosis/physiopathology/*therapy ; }, abstract = {Symptomatic treatment of amyotrophic lateral sclerosis (ALS) is relevant in preventing complications and improving quality of life as long as curative therapies are still out of sight. About one third of ALS patients show disabling problems associated with dysarthria, dysphagia, sialorrhea, and a pseudobulbar affective disorder already in the early stages of ALS. A multidisciplinary approach is the cornerstone of symptomatic treatment of bulbar and pseudobulbar ALS features. Except for riluzole randomized controlled trials are lacking. Here, we review the current views with regard to epidemiology, pathophysiology, diagnosis, and practical aspects of treating bulbar and pseudobulbar symptoms.}, }
@article {pmid20399067, year = {2010}, author = {Castigliego, L and Armani, A and Grifoni, G and Rosati, R and Mazzi, M and Gianfaldoni, D and Guidi, A}, title = {Effects of growth hormone treatment on the expression of somatotropic axis genes in the skeletal muscle of lactating Holstein cows.}, journal = {Domestic animal endocrinology}, volume = {39}, number = {1}, pages = {40-53}, doi = {10.1016/j.domaniend.2010.02.001}, pmid = {20399067}, issn = {1879-0054}, mesh = {5' Untranslated Regions/genetics ; Animals ; Cattle/*metabolism ; Female ; Gene Expression/*drug effects ; Genetic Variation/genetics ; Growth Hormone/*administration &amp; dosage/blood ; Insulin-Like Growth Factor Binding Proteins/genetics ; Insulin-Like Growth Factor I/analysis/genetics ; Insulin-Like Growth Factor II/genetics ; Lactation/*physiology ; Muscle, Skeletal/chemistry/*metabolism ; Polymerase Chain Reaction ; RNA, Messenger/analysis ; Receptor, IGF Type 1/genetics ; Receptors, Somatotropin/*genetics ; Recombinant Proteins/administration &amp; dosage ; Somatomedins/*genetics ; }, abstract = {This study focused on the expression of somatotropic axis genes in the skeletal muscle of dairy cattle. A slow-release recombinant bovine growth hormone (GH) (rbGH) formulation was administered to 5 cows, and saline solution (control) was administered to another 5 cows every 2 wk for a total of 10 wk, starting from the peak of lactation. Tissue and blood samples were collected on days 2 and 14 after each rbGH injection. As target genes insulin-like growth factor (IGF)-1, IGF-2, IGFBPs (1, 2, 3, 4, 5, 6), acute labile subunit (ALS), IGF-1 receptor (IGF-1R), GH receptor (GHR), and the known GHR 5'-UTR variants were selected as target genes, and their relative expression was measured using real-time polymerase chain reaction. In GH-treated cows, an increase in expression was observed for GHR 5'-UTR variant 1I on day 14 (P < 0.05), whereas a significant down-regulation of GHR (P < 0.05) was found after comparing values of treated cows between day 2 and day 14. However, only IGF binding proteins (BP)-5 was found to be appreciably up-regulated in GH-treated cows (P < 0.001), which may indicate the importance of this gene in the overall molecular response to GH administration. Our study indicated that GH treatment did not affect the expression of most somatotropic axis genes, despite the marked increase in GH and IGF-1 in blood (P < 0.001). Nor did it have a large impact on the proportion of GHR 5'-UTR variants in the skeletal muscle of lactating cows. Finally, although we observed a significant variation in the expression of some genes, it would appear that the differences between GH-treated cows and controls were not great enough to be considered as reliable indirect indicators of GH treatment in dairy cattle.}, }
@article {pmid20394738, year = {2010}, author = {Arun, P and Moffett, JR and Namboodiri, AM}, title = {Riluzole decreases synthesis of N-acetylaspartate and N-acetylaspartylglutamate in SH-SY5Y human neuroblastoma cells.}, journal = {Brain research}, volume = {1334}, number = {}, pages = {25-30}, doi = {10.1016/j.brainres.2010.04.001}, pmid = {20394738}, issn = {1872-6240}, mesh = {Aspartic Acid/*analogs &amp; derivatives/metabolism ; Cell Line, Tumor ; Chromatography, High Pressure Liquid/methods ; Dipeptides/*metabolism ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Antagonists/*pharmacology ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; Neuroblastoma ; Riluzole/*pharmacology ; Time Factors ; }, abstract = {N-acetylaspartate (NAA) is present at very high concentrations in the brain and is used as a non-invasive marker of neuronal viability in magnetic resonance spectroscopy. N-acetylaspartylglutamate (NAAG) is an acetylated dipeptide formed from NAA, and may be an agonist of the mGluR3 receptor. Both NAA and NAAG are synthesized primarily in neurons. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder resulting in motor neuron death, and progressive paralysis. Levels of both NAA and NAAG are reported to be decreased in ALS. Riluzole is a glutamatergic modulating agent used to treat ALS, but there are conflicting results in the literature concerning the recovery of NAA after riluzole treatment. We studied the effects of riluzole on the biosynthesis of both NAA and NAAG in SH-SY5Y human neuroblastoma cells. We used two methodologies to examine the effect; one involving radiolabel incorporation from corresponding substrates into NAA and NAAG, and the other involving the measurement of endogenous NAA and NAAG levels using HPLC. We show that riluzole treatment, which decreases glutamatergic neuronal excitation, decreases the synthesis and levels of both NAA and NAAG in SH-SY5Y cells in a dose and time dependant manner. These results suggest that the synthesis of NAA and NAAG may be coupled to glutamatergic neurotransmission, and further investigations along these lines are warranted.}, }
@article {pmid20388032, year = {2010}, author = {Bigham, BL and Koprowicz, K and Aufderheide, TP and Davis, DP and Donn, S and Powell, J and Suffoletto, B and Nafziger, S and Stouffer, J and Idris, A and Morrison, LJ and , }, title = {Delayed prehospital implementation of the 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiac care.}, journal = {Prehospital emergency care}, volume = {14}, number = {3}, pages = {355-360}, pmid = {20388032}, issn = {1545-0066}, support = {U01 HL077866/HL/NHLBI NIH HHS/United States ; U01 HL077871/HL/NHLBI NIH HHS/United States ; HL077867/HL/NHLBI NIH HHS/United States ; U01 HL077881/HL/NHLBI NIH HHS/United States ; HL077873/HL/NHLBI NIH HHS/United States ; HL077871/HL/NHLBI NIH HHS/United States ; HL077881/HL/NHLBI NIH HHS/United States ; HL077908/HL/NHLBI NIH HHS/United States ; U01 HL077887/HL/NHLBI NIH HHS/United States ; U01 HL077885/HL/NHLBI NIH HHS/United States ; /CAPMC/CIHR/Canada ; U01 HL077865/HL/NHLBI NIH HHS/United States ; U01 HL077863/HL/NHLBI NIH HHS/United States ; U01 HL077908/HL/NHLBI NIH HHS/United States ; HL077866/HL/NHLBI NIH HHS/United States ; U01 HL077873/HL/NHLBI NIH HHS/United States ; HL077872/HL/NHLBI NIH HHS/United States ; HL077863/HL/NHLBI NIH HHS/United States ; HL077887/HL/NHLBI NIH HHS/United States ; 5U01//PHS HHS/United States ; U01 HL077867/HL/NHLBI NIH HHS/United States ; HL077885/HL/NHLBI NIH HHS/United States ; HL077865/HL/NHLBI NIH HHS/United States ; U01 HL077872/HL/NHLBI NIH HHS/United States ; }, mesh = {*American Heart Association ; Canada ; Cardiopulmonary Resuscitation/*methods ; *Emergency Medical Services ; *Guideline Adherence ; *Guidelines as Topic ; Health Care Surveys ; Heart Arrest/therapy ; Humans ; United States ; }, abstract = {INTRODUCTION: In 2005, the American Heart Association (AHA) released guidelines to improve survival rates from out-of-hospital cardiac arrest (OHCA).<br><br>OBJECTIVE: To determine if, and when, emergency medical services (EMS) agencies participating in the Resuscitation Outcomes Consortium (ROC) implemented these guidelines.<br><br>METHODS: We contacted 178 EMS agencies and completed structured telephone interviews with 176 agencies. The survey collected data on specific treatment protocols before and after implementation of the 2005 guidelines as well as the date of implementation crossover (the "crossover date"). The crossover date was then linked to a database describing the size, type, and structure of each agency. Descriptive statistics and regression were used to examine patterns in time to crossover.<br><br>RESULTS: The 2005 guidelines were implemented by 174 agencies (99%). The number of days from guideline release to implementation was as follows: mean 416 (standard deviation 172), median 415 (range 49-750). There was no difference in time to implementation in fire-based agencies (mean 432), nonfire municipal agencies (mean 365), and private agencies (mean 389, p = 0.31). Agencies not providing transport took longer to implement than agencies that transported patients (463 vs. 384 days, p = 0.004). Agencies providing only basic life support (BLS) care took longer to implement than agencies who provided advanced life support (ALS) care (mean 462 vs. 397 days, p = 0.03). Larger agencies (>10 vehicles) were able to implement the guidelines more quickly than smaller agencies (mean 386 vs. 442 days, p = 0.03). On average, it took 8.9 fewer days to implement the guidelines for every 50% increase in EMS-treated runs/year to which an agency responded.<br><br>CONCLUSION: ROC EMS agencies required an average of 416 days to implement the 2005 AHA guidelines for OHCA. Small EMS agencies, BLS-only agencies, and nontransport agencies took longer than large agencies, agencies providing ALS care, and transport agencies, respectively, to implement the guidelines. Causes of delays to guideline implementation and effective methods for rapid EMS knowledge translation deserve investigation.}, }
@article {pmid20383521, year = {2010}, author = {Winter, Y and Schepelmann, K and Spottke, AE and Claus, D and Grothe, C and Schröder, R and Heuss, D and Vielhaber, S and Tackenberg, B and Mylius, V and Reese, JP and Kiefer, R and Schrank, B and Oertel, WH and Dodel, R}, title = {Health-related quality of life in ALS, myasthenia gravis and facioscapulohumeral muscular dystrophy.}, journal = {Journal of neurology}, volume = {257}, number = {9}, pages = {1473-1481}, pmid = {20383521}, issn = {1432-1459}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/epidemiology/psychology ; Comorbidity ; Cross-Sectional Studies ; Female ; Germany/epidemiology ; *Health Status ; Humans ; Male ; Middle Aged ; Muscular Dystrophy, Facioscapulohumeral/*diagnosis/epidemiology/psychology ; Myasthenia Gravis/*diagnosis/epidemiology/psychology ; Predictive Value of Tests ; *Quality of Life/psychology ; }, abstract = {Neuromuscular disorders are rare diseases with a chronic and debilitating course. Unfortunately, data on the health-related quality of life (HRQoL) in neuromuscular diseases are limited. The objective of this multicentre cross-sectional study was to compare the HRQoL in patients with amyotrophic lateral sclerosis (ALS), facioscapulohumeral muscular dystrophy (FSHD) and myasthenia gravis (MG) and to identify the determinants of the HRQoL in these diseases. We recruited 91 consecutive outpatients with ALS (n = 37), FSHD (n = 17) or MG (n = 37) in seven specialized German health centres. The HRQoL was determined using the 36-Item Short Form Health Survey (SF-36) and the EuroQol (EQ-5D). Independent predictors of the HRQoL were identified using multiple regression analysis. The HRQoL in all domains of the SF-36, except for bodily pain, was significantly reduced. The domains related to physical health (physical functioning, physical role) were most affected. The EQ-5D-index score was most reduced in ALS (0.54) and least reduced in MG (0.89). Independent predictors of a reduced HRQoL were disease severity and depression in ALS, and disease severity, depression, older age and increased body-mass index in MG. The patterns of HRQoL-impairment in neuromuscular disorders share some common features, such as a more pronounced reduction in the HRQoL related to physical health, but there are a number of disease-specific features that should be considered in outcomes of clinical trials and treatment guidelines. In addition to the treatment of motor symptoms, greater attention should be paid to the treatment of depression, which was found to be among the independent predictors of the HRQoL in ALS and MG.}, }
@article {pmid20377511, year = {2010}, author = {Cheah, BC and Vucic, S and Krishnan, AV and Kiernan, MC}, title = {Riluzole, neuroprotection and amyotrophic lateral sclerosis.}, journal = {Current medicinal chemistry}, volume = {17}, number = {18}, pages = {1942-1199}, doi = {10.2174/092986710791163939}, pmid = {20377511}, issn = {1875-533X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Clinical Trials as Topic ; Humans ; Neuroprotective Agents/chemistry/pharmacokinetics/pharmacology/*therapeutic use ; Riluzole/chemistry/pharmacokinetics/pharmacology/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease of the human motor system. Aetiological mechanisms implicated in the development of ALS have been linked to the glutamatergic neurotransmitter system, with destruction of motor neurons triggered through excessive activation of glutamate receptors at the synaptic cleft. This 'excitotoxicity' theory of ALS gave rise to the development of therapeutic approaches and ultimately clinical trials involving riluzole, initially thought to act solely as an inhibitor of glutamate release. Subsequent effects of riluzole have been postulated to include indirect antagonism of glutamate receptors, in addition to inactivation of neuronal voltage-gated Na+ channels. Riluzole remains the only disease-modifying therapy available to patients with ALS. Despite having been clinically available since the mid-1990 s, the in vivo pharmacological targets of riluzole have been poorly defined. An improved understanding concerning the potential neuroprotective mechanisms of riluzole may unearth pathophysiological processes that mediate neurodegeneration in ALS. The present review summarises the known chemical and pharmacological properties of riluzole. The failure of other putative neuroprotective therapies to demonstrate positive treatment outcomes in this intractable disease will be reviewed. Finally, the hypothesis that Na+ conductances may be involved in the processes of neuronal and axonal degeneration in ALS will be explored.}, }
@article {pmid20377403, year = {2010}, author = {Youngquist, ST and McIntosh, SE and Swanson, ER and Barton, ED}, title = {Air ambulance transport times and advanced cardiac life support interventions during the interfacility transfer of patients with acute ST-segment elevation myocardial infarction.}, journal = {Prehospital emergency care}, volume = {14}, number = {3}, pages = {292-299}, doi = {10.3109/10903121003760192}, pmid = {20377403}, issn = {1545-0066}, mesh = {Adolescent ; Adult ; Advanced Cardiac Life Support/*methods ; Aged ; Aged, 80 and over ; *Air Ambulances ; *Electrocardiography ; Female ; Humans ; Male ; Medical Records Systems, Computerized ; Middle Aged ; Myocardial Infarction/*diagnosis/*physiopathology/therapy ; *Patient Transfer ; Retrospective Studies ; Time Factors ; United States ; Young Adult ; }, abstract = {OBJECTIVES: To characterize transport times for the interfacility air ambulance transport of patients with acute ST-segment elevation myocardial infarction (STEMI), to estimate the proportion of patients at risk of in-transport clinical decompensation, and to explore associated risk factors for such.<br><br>METHODS: The electronic medical records of 35 air ambulance programs in the United States from December 2003 through December 2008 were reviewed. We defined clinical decompensation during transport as the combined outcome of either cardiopulmonary arrest or the receipt of any of a prespecified set of advanced life support (ALS) interventions. Multiple logistic regression employing generalized estimating equations to model autocorrelation of measures within air ambulance programs was used to explore the relationship between time from dispatch to transport and the outcome of interest.<br><br>RESULTS: Three thousand seven hundred sixty-seven transports of STEMI patients were identified during the period of interest. Eighty-five percent of rotor wing transports (median 80 minutes, interquartile range [IQR] 66-104) and 7% of fixed-wing transports (median 162 minutes, IQR 142-210) attained a total transfer time of < or = 2 hours. Clinical decompensation in transport occurred in 182 of 3,767 (4.8%, 95% confidence interval [CI] 4.2-5.6%) transports. The most frequent critical ALS interventions were the administration of antiarrhythmics and the initiation of vasopressors. The odds ratios (ORs) for clinical decompensation comparing higher pretransport time quartiles with the lowest quartile (i.e., Q1: 6-50 minutes) were as follows: Q4: 82-1,500 minutes, OR 2.5 (95% CI 1.3-4.8, p = 0.007); Q3: 64-81 minutes, OR 1.9 (95% CI 1.0-3.6, p = 0.0499); and Q2: 51-63 minutes, OR 1.45 (95% CI 0.7-3.1, p = 0.34). Cardiac arrest or need for an ALS intervention prior to transport and a history of diabetes were also predictive of the outcome of interest.<br><br>CONCLUSIONS: The majority of interfacility rotor-wing air ambulance transfers of patients with STEMI achieved a total transfer time of < or = 2 hours. Clinical decompensation requiring ALS treatment occurred in a small percentage of patients. Diabetes, prior arrest or decompensation, and delays to transport were associated with clinical decompensation in the air. Efforts to reduce delays to transport may reduce this risk in transported patients.}, }
@article {pmid20373255, year = {2010}, author = {Olney, N and Rosen, H}, title = {AVP-923, a combination of dextromethorphan hydrobromide and quinidine sulfate for the treatment of pseudobulbar affect and neuropathic pain.}, journal = {IDrugs : the investigational drugs journal}, volume = {13}, number = {4}, pages = {254-265}, pmid = {20373255}, issn = {2040-3410}, support = {T32 AG023481/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Clinical Trials as Topic ; Dextromethorphan/adverse effects/chemistry/pharmacokinetics/*therapeutic use ; Diabetic Neuropathies/*drug therapy ; Drug Combinations ; Humans ; Mood Disorders/*drug therapy ; Quinidine/adverse effects/chemistry/pharmacokinetics/*therapeutic use ; }, abstract = {AVANIR Pharmaceuticals Inc, under license from Irisys Research &amp; Development, is developing AVP-923 (Zenvia, Neurodex) for the treatment of pseudobulbar affect (PBA; in collaboration with Medison Pharma Ltd) and neuropathic pain associated with diabetic peripheral neuropathy. PBA, the main indication of AVP-923, is a neurological disorder characterized by uncontrollable and unpredictable episodes of laughing and/or crying. AVP-923 consists of a combination of the NMDA antagonist/sigma1 receptor agonist dextromethorphan hydrobromide (DM) and the cytochrome P450 2D6 (CYP2D6) enzyme inhibitor quinidine sulfate (Q). DM has been under investigation for several years as a neuroprotective agent in stroke, neurosurgery and amyotrophic lateral sclerosis (ALS); however, it is rapidly metabolized by CYP2D6, reducing the drug's bioavailability at neuronal targets. The inclusion of Q inhibits the rapid first-pass metabolism of DM to increase systemic concentrations of the drug in the plasma and, in theory, increase the potential efficacy. The initial clinical data for AVP-923 in the treatment of PBA demonstrated the combination was effective, but exhibited significant side effects. Of particular concern to the FDA were increased QTc intervals reported in patients dosed with a 30-/30-mg dose of DM/Q. A subsequent phase III clinical trial assessing a lower dose of AVP-923 (20 or 30 mg DM/10 mg Q) for the treatment of PBA in patients with ALS or multiple sclerosis was implemented by AVANIR and demonstrated a favorable safety profile of AVP-923 while maintaining efficacy. Pending approval of the data from the FDA, AVP-923 would be the first FDA-approved treatment for PBA.}, }
@article {pmid20370778, year = {2010}, author = {Haukoos, JS and Witt, G and Gravitz, C and Dean, J and Jackson, DM and Candlin, T and Vellman, P and Riccio, J and Heard, K and Kazutomi, T and Luyten, D and Pineda, G and Gunter, J and Biltoft, J and Colwell, C and ,  and , }, title = {Out-of-hospital cardiac arrest in denver, colorado: epidemiology and outcomes.}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {17}, number = {4}, pages = {391-398}, pmid = {20370778}, issn = {1553-2712}, support = {K02 HS017526/HS/AHRQ HHS/United States ; K08 DA020573/DA/NIDA NIH HHS/United States ; K08 DA020573-02/DA/NIDA NIH HHS/United States ; K08 DA020573-03/DA/NIDA NIH HHS/United States ; }, mesh = {Age Distribution ; Aged ; Cardiopulmonary Resuscitation/methods ; *Cause of Death ; Cohort Studies ; Colorado/epidemiology ; Confidence Intervals ; Emergency Medical Services/methods/*standards ; Female ; Follow-Up Studies ; Heart Arrest/diagnosis/*mortality/*therapy ; Humans ; Incidence ; Male ; Middle Aged ; Neurologic Examination ; Odds Ratio ; Patient Discharge/statistics &amp; numerical data ; Probability ; Registries ; Retrospective Studies ; Risk Assessment ; Sex Distribution ; Survival Analysis ; Urban Population ; }, abstract = {OBJECTIVES: The annual incidence of out-of-hospital cardiac arrest (OOHCA) in the United States is approximately 6 per 10,000 population and survival remains low. Relatively little is known about the performance characteristics of a two-tiered emergency medical services (EMS) system split between fire-based basic life support (BLS) dispersed from fixed locations and hospital-based advanced life support (ALS) dispersed from nonfixed locations. The objectives of this study were to describe the incidence of OOHCA in Denver, Colorado, and to define the prevalence of survival with good neurologic function in the context of this particular EMS system.<br><br>METHODS: This was a retrospective cohort study using standardized abstraction methodology. A two-tiered hospital-based EMS system for the County of Denver and 10 receiving hospitals were studied. Consecutive adult patients who experienced nontraumatic OOHCA from January 1, 2003, through December 31, 2004, were enrolled. Demographic, prehospital arrest characteristics, treatment data, and survival data using the Utstein template were collected. Good neurologic survival was defined by a Cerebral Performance Categories (CPC) score of 1 or 2.<br><br>RESULTS: During the study period, 1,985 arrests occurred. Of these, 715 (36%) had attempted resuscitation by paramedics and constitute our study sample. The median age was 65 years (interquartile range = 52-78 years), 69% were male, 41% had witnessed arrest, 25% had bystander cardiopulmonary resuscitation (CPR) performed, and 30% had ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) as their initial rhythm. Of the 715 patients, 545 (76%) were transported to a hospital, 223 (31%) had return of spontaneous circulation (ROSC), 175 (25%) survived to hospital admission, 58 (8%) survived to hospital discharge, and 42 (6%, 95% confidence interval [CI] = 4% to 8%) had a good neurologic outcome.<br><br>CONCLUSIONS: Out-of-hospital cardiac arrest survival in Denver, Colorado, is similar to that of other United States communities. This finding provides the basis for future epidemiologic and health services research in the out-of-hospital and ED settings in our community.}, }
@article {pmid20370663, year = {2010}, author = {Pawlyk, AC and Cassel, JA and Reitz, AB}, title = {Current nervous system related drug targets for the treatment of amyotrophic lateral sclerosis.}, journal = {Current pharmaceutical design}, volume = {16}, number = {18}, pages = {2053-2073}, doi = {10.2174/138161210791293024}, pmid = {20370663}, issn = {1873-4286}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/physiopathology ; Animals ; DNA-Binding Proteins/metabolism ; *Drug Delivery Systems ; *Drug Discovery ; Humans ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and ultimately fatal indication that is the most prevalent adult-onset motoneuron disorder. ALS imparts tremendous suffering upon patients and caregivers alike. Exciting new insight has been obtained as to the etiology and initiation of the disease during the past decade, particularly affecting the larger, sporadic patient population. An important new discovery is the involvement of the TAR DNA binding protein (TDP-43) based upon genetic evidence and the presence of the cytosolic ubiquitylated TDP-43 aggregates found during post-mortem analysis of damaged motoneurons in the spinal cord of ALS patients. Superoxide dismutase SOD1 continues to be of interest for the approximately 20% of the familial ALS patients who have the inherited form of the disease (approximately 15% of the total), but SOD1 does not appear to be as relevant as was once imagined for the sporadic patent population. We can now target specific biochemical pathways and deficits via traditional drug discovery efforts and may thus be able to achieve more effective therapeutic relief for patients who suffer from this disease. In this review we present a comprehensive discussion of current molecular targets and pathways that are of interest to small molecule drug discovery efforts for the treatment of ALS.}, }
@article {pmid20363190, year = {2010}, author = {Aggarwal, SP and Zinman, L and Simpson, E and McKinley, J and Jackson, KE and Pinto, H and Kaufman, P and Conwit, RA and Schoenfeld, D and Shefner, J and Cudkowicz, M and , }, title = {Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.}, journal = {The Lancet. Neurology}, volume = {9}, number = {5}, pages = {481-488}, pmid = {20363190}, issn = {1474-4465}, support = {U01 NS049640/NS/NINDS NIH HHS/United States ; U01 NS049640-03S1/NS/NINDS NIH HHS/United States ; U01 NS049640-04S1/NS/NINDS NIH HHS/United States ; UL1 TR000454/TR/NCATS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Disease Progression ; Double-Blind Method ; Drug Therapy, Combination ; Drug-Related Side Effects and Adverse Reactions ; Humans ; Intention to Treat Analysis ; Lithium/administration &amp; dosage/*adverse effects ; Male ; *Medical Futility ; Middle Aged ; Patient Selection ; Prognosis ; Riluzole/administration &amp; dosage/*adverse effects ; Treatment Outcome ; }, abstract = {BACKGROUND: In a pilot study, lithium treatment slowed progression of amyotrophic lateral sclerosis (ALS). We aimed to confirm or disprove these findings by assessing the safety and efficacy of lithium in combination with riluzole in patients with ALS.<br><br>METHODS: We did a double-blind, placebo-controlled trial with a time-to-event design. Between January and June, 2009, patients with ALS who were taking a stable dose of riluzole for at least 30 days were randomly assigned (1:1) by a centralised computer to receive either lithium or placebo. Patients, caregivers, investigators, and all site study staff with the exception of site pharmacists were masked to treatment assignment. The primary endpoint was the time to an event, defined as a decrease of at least six points on the revised ALS functional rating scale score or death. Interim analyses were planned for when 84 patients had been allocated treatment, 6 months later or after 55 events, and after 100 events. Analysis was by intention to treat. The stopping boundary for futility at the first interim analysis was a p value of at least 0.68. We used a log-rank test to compare the distributions of the time to an event between the lithium and placebo groups. This trial is registered with ClinicalTrials.gov, NCT00818389.<br><br>FINDINGS: At the first interim analysis, 22 of 40 patients in the lithium group had an event compared with 20 of 44 patients in the placebo group (log rank p=0.51). The hazard ratio of reaching the primary endpoint was 1.13 (95% CI 0.61-2.07). The study was stopped at the first interim analysis because criterion for futility was met (p=0.78). The difference in mean decline in the ALS functional rating scale score between the lithium group and the placebo group was 0.15 (95% CI -0.43 to 0.73, p=0.61). There were no major safety concerns. Falls (p=0.04) and back pain (p=0.05) were more common in the lithium group than in the placebo group.<br><br>INTERPRETATION: We found no evidence that lithium in combination with riluzole slows progression of ALS more than riluzole alone. The time-to-event endpoint and use of prespecified interim analyses enabled a clear result to be obtained rapidly. This design should be considered for future trials testing the therapeutic efficacy of drugs that are easily accessible to people with ALS.<br><br>FUNDING: National Institute of Neurological Disorders and Stroke, ALS Association, and ALS Society of Canada.}, }
@article {pmid20353779, year = {2010}, author = {Bari, M and Rapino, C and Mozetic, P and Maccarrone, M}, title = {The endocannabinoid system in gp120-mediated insults and HIV-associated dementia.}, journal = {Experimental neurology}, volume = {224}, number = {1}, pages = {74-84}, doi = {10.1016/j.expneurol.2010.03.025}, pmid = {20353779}, issn = {1090-2430}, mesh = {AIDS Dementia Complex/*metabolism ; Animals ; Brain/*metabolism ; Cannabinoid Receptor Modulators/*metabolism ; Cytoprotection/physiology ; *Endocannabinoids ; HIV Envelope Protein gp120/*metabolism ; Humans ; Neurodegenerative Diseases/metabolism ; Neurons/metabolism ; Receptors, Cannabinoid/metabolism ; Signal Transduction/physiology ; }, abstract = {Endocannabinoids (eCBs) include a group of lipid mediators that act as endogenous agonists at cannabinoid (CB(1), CB(2)) and vanilloid (TRPV1) receptors. In the last two decades a number of eCBs-metabolizing enzymes have been discovered that, together with eCBs and congeners, target receptors and proteins responsible for their transport and intracellular trafficking form the so-called "endocannabinoid system" (ECS). Within the central nervous system ECS elements participate in neuroprotection against neuroinflammatory/neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. More recently, a role for eCBs has been documented also in human immunodeficiency virus-1 (HIV-1) envelope glycoprotein gp120-mediated insults, and in HIV-associated dementia (HAD). The modulation of ECS in the latter disease conditions is the subject of this review, that will also address the molecular mechanisms underlying the neuroprotective effects of eCBs. In particular, the interactions between neurons and glia during neuroinflammation, and the alterations of ECS in these cells upon gp120 insults and HAD will be discussed, along with the potential therapeutic exploitation of ECS-oriented drugs for the treatment of HAD and related disorders.}, }
@article {pmid20353778, year = {2010}, author = {Rossi, S and Bernardi, G and Centonze, D}, title = {The endocannabinoid system in the inflammatory and neurodegenerative processes of multiple sclerosis and of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {224}, number = {1}, pages = {92-102}, doi = {10.1016/j.expneurol.2010.03.030}, pmid = {20353778}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Cannabinoid Receptor Modulators/*metabolism ; *Endocannabinoids ; Humans ; Inflammation/metabolism/pathology ; Multiple Sclerosis/*metabolism/pathology ; Nerve Degeneration/*metabolism/pathology ; Neurons/metabolism/pathology ; }, abstract = {Multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) are chronic diseases of the central nervous system (CNS), featured by a complex interplay between inflammation and neurodegeneration. Increasing evidence supports the involvement of the endocannabinoid system (ECS) in both inflammatory and neurodegenerative processes typical of these pathological conditions. Exogenous or endogenous cannabinoids regulate the function of immune system by limiting immune response. On the other hand, by preventing excitotoxic damage, cannabinoids protect neuronal integrity and function. Of note, the ECS not only plays a role as modulator of disease processes, but it can also be disrupted by the same diseases. Agents modulating cannabinoid receptors or endocannabinoid tone provide promising therapeutic opportunities in the treatment of inflammatory neurodegenerative disorders of the CNS.}, }
@article {pmid20350352, year = {2010}, author = {Mitrecić, D and Nicaise, C and Gajović, S and Pochet, R}, title = {Distribution, differentiation, and survival of intravenously administered neural stem cells in a rat model of amyotrophic lateral sclerosis.}, journal = {Cell transplantation}, volume = {19}, number = {5}, pages = {537-548}, doi = {10.3727/096368910X498269}, pmid = {20350352}, issn = {1555-3892}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/pathology/*therapy ; Animals ; Apoptosis/physiology ; Cell Differentiation/physiology ; Disease Models, Animal ; Humans ; Injections, Intravenous ; Intermediate Filament Proteins/biosynthesis ; Nerve Tissue Proteins/biosynthesis ; Nestin ; Neural Stem Cells/*cytology/metabolism/pathology/*transplantation ; Rats ; Rats, Sprague-Dawley ; Stem Cell Transplantation/methods ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {The transplantation of neural stem cells (NSCs) is a challenging therapeutic strategy for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). To provide insight into the potential of the intravenous delivery of NSCs, we evaluated the delivery of NSCs marked with green fluorescent protein to the central nervous system (CNS) via intravenous tail vein injections in an ALS model. The injected cell fates were followed 1, 3, and 7 days after transplantation. The highest efficiency of cell delivery to the CNS was found in symptomatic ALS (up to 13%), moderate in presymptomatic ALS (up to 6%), and the lowest in wild-type animals (up to 0.3%). NSCs injected into ALS animals preferentially colonized the motor cortex, hippocampus, and spinal cord, and their differentiation was characterized by a decrease of nestin expression and the appearance of MAP2-, GFAP-, O4-, and CD68-positive cells. Tumor necrosis factor (TNF) administration increased the CNS delivery of transplanted cells in wild-type and presymptomatic, but not ALS symptomatic animals. Moreover, a TNF-related increase in NSC differentiation and survival was detected. Apoptosis was detected as the main cause of the loss of transplanted cells and it was influenced by TNF. Although 3 days after TNF treatment cell death was accelerated, TNF slowed down apoptosis after 7 days. This study provides elementary facts about the process occurring after NSCs leave the blood stream and enter the nervous tissue affected by inflammation/degeneration, which should help facilitate the planning of future bench-to-bedside translational projects.}, }
@article {pmid20348957, year = {2010}, author = {Lincecum, JM and Vieira, FG and Wang, MZ and Thompson, K and De Zutter, GS and Kidd, J and Moreno, A and Sanchez, R and Carrion, IJ and Levine, BA and Al-Nakhala, BM and Sullivan, SM and Gill, A and Perrin, S}, title = {From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis.}, journal = {Nature genetics}, volume = {42}, number = {5}, pages = {392-399}, pmid = {20348957}, issn = {1546-1718}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Animals ; CD40 Ligand/*antagonists &amp; inhibitors/immunology ; Disease Models, Animal ; Female ; Gene Expression Profiling ; Humans ; Immune System ; Inflammation ; Macrophages/metabolism ; Male ; Mice ; Mice, Transgenic ; Signal Transduction ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Using unbiased transcript profiling in an ALS mouse model, we identified a role for the co-stimulatory pathway, a key regulator of immune responses. Furthermore, we observed that this pathway is upregulated in the blood of 56% of human patients with ALS. A therapy using a monoclonal antibody to CD40L was developed that slows weight loss, delays paralysis and extends survival in an ALS mouse model. This work demonstrates that unbiased transcript profiling can identify cellular pathways responsive to therapeutic intervention in a preclinical model of human disease.}, }
@article {pmid20345765, year = {2010}, author = {Gros-Louis, F and Soucy, G and Larivière, R and Julien, JP}, title = {Intracerebroventricular infusion of monoclonal antibody or its derived Fab fragment against misfolded forms of SOD1 mutant delays mortality in a mouse model of ALS.}, journal = {Journal of neurochemistry}, volume = {113}, number = {5}, pages = {1188-1199}, doi = {10.1111/j.1471-4159.2010.06683.x}, pmid = {20345765}, issn = {1471-4159}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/immunology/*therapy ; Animals ; Antibodies, Monoclonal/administration &amp; dosage/*therapeutic use ; Blotting, Western ; Disease Progression ; Epitopes/genetics ; Fluorescent Antibody Technique ; Immunization, Passive ; Immunoglobulin Fab Fragments/*pharmacology ; Immunoglobulins/pharmacology ; Immunohistochemistry ; Immunoprecipitation ; Immunotherapy ; Injections, Intraventricular ; Metals/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; *Protein Folding ; Superoxide Dismutase/*antagonists &amp; inhibitors/*genetics ; Superoxide Dismutase-1 ; }, abstract = {The finding of a secretion pathway and toxicity for mutant superoxide dismutase 1 (SOD1) raised up the possibility of using immunization approaches to reduce or neutralize the burden of toxic SOD1 species in the nervous system. Here we tested a passive immunization approach based on intracerebroventricular infusion in G93A-SOD1 mice of monoclonal antibodies specific to misfolded forms of SOD1 (mSOD1). We tested two monoclonal antibodies that bind distinct epitopes in mSOD1 and that do not bind to intact wild-type (WT) SOD1. One antibody succeeded in reducing the level of mSOD1 by 23% in the spinal cord and in prolonging the lifespan of G93A-SOD1 mice in proportion to the duration of treatment. However, another monoclonal antibody binding to a different SOD1 epitope failed to confer protection indicating that not all anti-SOD1 antibodies might be suitable for immunotherapy. Interestingly, the variable Fab fragment of an anti-SOD1 antibody was sufficient to confer some protection in G93A-SOD1 mice. The partial dispensability of Fc region should offer some advantages for development of immunotherapy with antibodies of smaller molecular size and low immunogenicity. From these results, we propose that passive immunization strategies should be considered as potential avenues for treatment of familial amyotrophic lateral sclerosis caused by SOD1 mutations.}, }
@article {pmid20345752, year = {2010}, author = {Johnstone, D and Milward, EA}, title = {Molecular genetic approaches to understanding the roles and regulation of iron in brain health and disease.}, journal = {Journal of neurochemistry}, volume = {113}, number = {6}, pages = {1387-1402}, doi = {10.1111/j.1471-4159.2010.06697.x}, pmid = {20345752}, issn = {1471-4159}, mesh = {Animals ; Brain/*metabolism ; *Brain Diseases/genetics/metabolism/pathology ; Gene Expression Regulation/*genetics ; Genetic Predisposition to Disease/genetics ; Hemochromatosis Protein ; Histocompatibility Antigens Class I/genetics ; Humans ; Iron/*metabolism/toxicity ; Membrane Proteins/genetics ; Molecular Biology ; Polymorphism, Genetic/genetics ; }, abstract = {Iron is essential in the brain, yet too much iron can be toxic. Tight regulation of iron in the brain may involve intrinsic mechanisms that control internal homeostasis independent of systemic iron status. Iron abnormalities occur in various neurological disorders, usually with symptoms or neuropathology associated with movement impairment or behavioral disturbances rather than cognitive impairment or dementia. Consistent with this, polymorphisms in the HFE gene, associated with the iron overload disorder hemochromatosis, show stronger associations with the movement disorder amyotrophic lateral sclerosis (motor neuron disease) than with cognitive impairment. Such associations may arise because certain brain regions involved in movement or executive control are particularly iron-rich, notably the basal ganglia, and may be highly reliant on iron. Various mechanisms, including iron redistribution causing functional iron deficiency, lysosomal and mitochondrial abnormalities or oxidative damage, could underlie iron-related neuropathogenesis. Clarifying how iron contributes causatively to neurodegeneration may improve treatment options in a range of neurodegenerative disorders. This review considers how modern molecular genetic approaches can be applied to resolve the complex molecular systems and pathways by which brain iron homeostasis is regulated and the molecular changes that occur with iron dyshomeostasis and neuropathogenesis.}, }
@article {pmid20236142, year = {2011}, author = {Bellingham, MC}, title = {A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade?.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {17}, number = {1}, pages = {4-31}, pmid = {20236142}, issn = {1755-5949}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Brain/*drug effects/physiopathology ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Antagonists/pharmacology/*therapeutic use ; Humans ; Middle Aged ; Motor Neurons/*drug effects ; Neuroprotective Agents/pharmacology/*therapeutic use ; Riluzole/pharmacology/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease of adults which preferentially attacks the neuromotor system. Riluzole has been used as the only approved treatment for amyotrophic lateral sclerosis since 1995, but its mechanism(s) of action in slowing the progression of this disease remain obscure. Searching PubMed for "riluzole" found 705 articles published between January 1996 and June 2009. A systematic review of this literature found that riluzole had a wide range of effects on factors influencing neural activity in general, and the neuromotor system in particular. These effects occurred over a large dose range (<1 μM to >1 mM). Reported neural effects of riluzole included (in approximate ascending order of dose range): inhibition of persistent Na(+) current = inhibition of repetitive firing < potentiation of calcium-dependent K(+) current < inhibition of neurotransmitter release < inhibition of fast Na(+) current < inhibition of voltage-gated Ca(2+) current = promotion of neuronal survival or growth factors < inhibition of voltage-gated K(+) current = modulation of two-pore K(+) current = modulation of ligand-gated neurotransmitter receptors = potentiation of glutamate transporters. Only the first four of these effects commonly occurred at clinically relevant concentrations of riluzole (plasma levels of 1-2 μM with three- to four-fold higher concentrations in brain tissue). Treatment of human ALS patients or transgenic rodent models of ALS with riluzole most commonly produced a modest but significant extension of lifespan. Riluzole treatment was well tolerated in humans and animals. In animals, despite in vitro evidence that riluzole may inhibit rhythmic motor behaviors, in vivo administration of riluzole produced relatively minor effects on normal respiration parameters, but inhibited hypoxia-induced gasping. This effect may have implications for the management of hypoventilation and sleep-disordered breathing during end-stage ALS in humans.}, }
@article {pmid20235756, year = {2010}, author = {Felgoise, SH and Chakraborty, BH and Bond, E and Rodriguez, J and Bremer, BA and Walsh, SM and Lai, EC and McCluskey, L and Simmons, Z}, title = {Psychological morbidity in ALS: the importance of psychological assessment beyond depression alone.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {4}, pages = {351-358}, doi = {10.3109/17482961003667630}, pmid = {20235756}, issn = {1471-180X}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*epidemiology/physiopathology/*psychology ; Behavioral Symptoms/diagnosis/*epidemiology ; Female ; Humans ; Male ; Mental Disorders/diagnosis/*epidemiology ; Middle Aged ; Morbidity ; Muscle Strength/physiology ; Quality of Life ; Severity of Illness Index ; }, abstract = {The assessment of psychological morbidity in patients with ALS has centered around depression, hopelessness, and anxiety. The Brief Symptom Inventory (BSI) offers an opportunity to explore psychological morbidity more broadly. We administered this instrument to 111 patients with ALS as part of a larger study of quality of life. Scores of ALS patients on the Global Severity Index and Positive Symptom Distress Index were comparable to the majority of distressed psychiatric outpatients and significantly higher than those of non-patient adults. Among BSI subscales, scores on the Anxiety, Depression, Phobic Anxiety, and Somatization subscales also were not significantly different from distressed adult psychiatric outpatients, and were greater than normal mean scores for a non-patient population sample. Based on these data, ALS patients appear to be significantly more distressed than non-patients in the identified areas, and as distressed as approximately 68% of a distressed psychiatric outpatient sample. In conclusion, a substantial number of individuals with ALS experience psychological distress of various types. Because psychological health impacts lifespan and quality of life in these individuals, broadly-based mental health assessment and treatment should remain an important part of care for patients with ALS. The effects of physical symptoms on responses to questions used to assess psychological distress must be considered.}, }
@article {pmid20223753, year = {2010}, author = {Wong, M and Martin, LJ}, title = {Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice.}, journal = {Human molecular genetics}, volume = {19}, number = {11}, pages = {2284-2302}, pmid = {20223753}, issn = {1460-2083}, support = {AG016282/AG/NIA NIH HHS/United States ; NS034100/NS/NINDS NIH HHS/United States ; NS052098/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/complications/*metabolism/pathology ; Animals ; Blotting, Southern ; Blotting, Western ; DNA Primers/genetics ; Immunohistochemistry ; Mice ; Mice, Transgenic ; Motor Neurons/*pathology ; Muscle, Skeletal/*metabolism/pathology ; Nerve Degeneration/etiology/*metabolism ; Neuromuscular Junction/*pathology ; Polymerase Chain Reaction ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons (MNs) that causes skeletal muscle paralysis. Familial forms of ALS are linked to mutations in the superoxide dismutase-1 (SOD1) gene. The mechanisms of human SOD1 (hSOD1) toxicity to MNs are unknown. We hypothesized that skeletal muscle is a primary site of pathogenesis in ALS that triggers MN degeneration. We created transgenic (tg) mice expressing wild-type-, G37R- and G93A-hSOD1 gene variants only in skeletal muscle. These tg mice developed age-related neurologic and pathologic phenotypes consistent with ALS. Affected mice showed limb weakness and paresis with motor deficits. Skeletal muscles developed severe pathology involving oxidative damage, protein nitration, myofiber cell death and marked neuromuscular junction (NMJ) abnormalities. Spinal MNs developed distal axonopathy and formed ubiquitinated inclusions and degenerated through an apoptotic-like pathway involving capsase-3. Mice expressing wild-type and mutant forms of hSOD1 developed MN pathology. These results demonstrate that human SOD1 in skeletal muscle has a causal role in ALS and identify a new non-autonomous mechanism for MN degeneration explaining their selective vulnerability. The discovery of instigating molecular toxicities or disease progression determinants within skeletal muscle could be very valuable for the development of new effective therapies for the treatment and cure of ALS.}, }
@article {pmid20202083, year = {2010}, author = {Yamashita, S and Mori, A and Kimura, E and Mita, S and Maeda, Y and Hirano, T and Uchino, M}, title = {DJ-1 forms complexes with mutant SOD1 and ameliorates its toxicity.}, journal = {Journal of neurochemistry}, volume = {113}, number = {4}, pages = {860-870}, doi = {10.1111/j.1471-4159.2010.06658.x}, pmid = {20202083}, issn = {1471-4159}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/physiopathology ; Animals ; Apoptosis/physiology ; Cell Survival/physiology ; Cells, Cultured ; Female ; Humans ; Macromolecular Substances/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Middle Aged ; Motor Neurons/metabolism ; Nerve Degeneration/genetics/metabolism/physiopathology ; Oncogene Proteins/cerebrospinal fluid/genetics/*metabolism ; Oxidative Stress/physiology ; Peroxiredoxins ; Protein Binding/physiology ; Protein Deglycase DJ-1 ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; Up-Regulation/physiology ; }, abstract = {Mutations in Cu/Zn superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS), which could be attributed to the toxic properties of the misfolded protein, oxidative stress, and mitochondrial dysfunction. DJ-1 - a causative agent of familial Parkinson's disease PARK7 - is responsible for inducing antioxidative reaction. In this study, we showed the up-regulation of DJ-1 protein levels in mutant SOD1 transgenic mice through the lifespan were observed in the motor neurons. We demonstrated biochemically DJ-1 formed complexes with mutant SOD1 in the cell lysates. Furthermore, DJ-1 over-expression resulted in increased cell viability and reduced cell toxicity in mutant SOD1-transfected neuronal cells, because of improvement in apoptotic pathway and reduction in oxidative stress levels. We also evaluated DJ-1 levels in CSF collected from sporadic ALS patients and controls subjects. The CSF DJ-1 levels were significantly higher in patients with sporadic ALS than in control subjects. These results show that DJ-1 may be associated with sporadic and familial ALS pathogenesis. Therefore, insight into the effects of DJ-1 on mutant SOD1-mediated toxicity may provide a therapeutic advance for the treatment of motor neuron degeneration in ALS.}, }
@article {pmid20199228, year = {2010}, author = {Seymour, CW and Cooke, CR and Mikkelsen, ME and Hylton, J and Rea, TD and Goss, CH and Gaieski, DF and Band, RA}, title = {Out-of-hospital fluid in severe sepsis: effect on early resuscitation in the emergency department.}, journal = {Prehospital emergency care}, volume = {14}, number = {2}, pages = {145-152}, pmid = {20199228}, issn = {1545-0066}, support = {F32 HL103098/HL/NHLBI NIH HHS/United States ; KL2 RR025015/RR/NCRR NIH HHS/United States ; T32 HL007287/HL/NHLBI NIH HHS/United States ; T32 HL07287/HL/NHLBI NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Cohort Studies ; *Early Diagnosis ; Emergency Medical Services ; *Emergency Service, Hospital ; Female ; Humans ; *Infusions, Intravenous ; Male ; Middle Aged ; Outcome Assessment, Health Care ; Retrospective Studies ; Sepsis/diagnosis/*therapy ; *Severity of Illness Index ; }, abstract = {BACKGROUND: Early identification and treatment of patients with severe sepsis improves outcome, yet the role of out-of-hospital intravenous (IV) fluid is unknown.<br><br>OBJECTIVE: To determine if the delivery of out-of-hospital fluid in patients with severe sepsis is associated with reduced time to achievement of goal-oriented resuscitation in the emergency department (ED).<br><br>METHODS: We performed a secondary data analysis of a retrospective cohort study in a metropolitan, tertiary care, university-based medical center supported by a two-tiered system of out-of-hospital emergency medical services (EMS) providers. We studied the association between delivery of out-of-hospital fluid by advanced life support (ALS) providers and the achievement of resuscitation endpoints (central venous pressure [CVP] > or =8 mmHg, mean arterial pressure [MAP] > or =65 mmHg, and central venous oxygen saturation [ScvO(2)] > or =70%) within six hours after triage during early goal-directed therapy (EGDT) in the ED.<br><br>RESULTS: Twenty five (48%) of 52 patients transported by ALS with severe sepsis received out-of-hospital fluid. Data for age, gender, source of sepsis, and presence of comorbidities were similar between patients who did and did not receive out-of-hospital fluid. Patients receiving out-of-hospital fluid had lower out-of-hospital mean (+/- standard deviation) systolic blood pressure (95 +/- 40 mmHg vs. 117 +/- 29 mmHg; p = 0.03) and higher median (interquartile range) Sequential Organ Failure Assessment (SOFA) scores in the ED (7 [5-8] vs. 4 [4-6]; p = 0.01) than patients not receiving out-of-hospital fluid. Despite greater severity of illness, patients receiving out-of-hospital fluid approached but did not attain a statistically significant increase in the likelihood of achieving MAP > or =65 mmHg within six hours after ED triage (70% vs. 44%, p = 0.09). On average, patients receiving out-of-hospital fluid received twice the fluid volume within one hour after ED triage (1.1 L [1.0-2.0 L] vs. 0.6 L [0.3-1.0 L]; p = 0.01). No difference in achievement of goal CVP (72% vs. 60%; p = 0.6) or goal ScvO(2) (54% vs. 36%; p = 0.25) was observed between groups.<br><br>CONCLUSIONS: Less than half of patients with severe sepsis transported by ALS received out-of-hospital fluid. Patients receiving out-of-hospital IV access and fluids approached but did not attain a statistically significant increase in the likelihood of achieving goal MAP during EGDT. These preliminary findings require additional investigation to evaluate the optimal role of out-of-hospital resuscitation in treating patients with severe sepsis.}, }
@article {pmid20169434, year = {2011}, author = {Del Barco, DG and Pérez-Saad, H and Rodríguez, V and Marín, J and Falcón, V and Martín, J and Cibrian, D and Berlanga, J}, title = {Therapeutic effect of the combined use of growth hormone releasing peptide-6 and epidermal growth factor in an axonopathy model.}, journal = {Neurotoxicity research}, volume = {19}, number = {1}, pages = {195-209}, pmid = {20169434}, issn = {1476-3524}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Axons/drug effects/*pathology ; Cell Survival/physiology ; *Disease Models, Animal ; Drug Therapy, Combination ; Epidermal Growth Factor/*administration &amp; dosage ; Female ; Growth Hormone-Releasing Hormone/*administration &amp; dosage ; Mice ; Mice, Inbred C57BL ; Neuroprotective Agents/administration &amp; dosage ; Oligopeptides/*administration &amp; dosage ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease of the central nervous system characterized by loss of spinal motor neurons, for which no effective treatment exists. Epidermal growth factor (EGF) and growth hormone releasing peptide-6 (GHRP-6) have been considered as good candidates for the treatment of this disease, due to their well documented effects in eliciting pleiotrophic and cell survival mechanisms. The aim of the present work was to evaluate the separate and combined effects of both peptides in an experimental animal model of ALS, the proximal axonopathy induced by 1,2 diacetylbenzene (1,2 DAB) in mice. The evaluations were conducted by means of behavioral tests (trapeze, tail suspension, gait pattern, and open field) and by recording the complex muscle action potential (CMAP) in three different hind limb segments: proximal S1, medial S2, and distal S3. Intraperitoneal daily administration of 1,2 DAB produced significant reduction in body weight, muscle strength, extensor reflex, spontaneous activity, and changes in gait pattern parameters. In parallel 1,2 DAB produced significant prolongation of onset latency and decrease in amplitude of CMAP and in the integrated complex action potential index. Daily administration of the separate compounds did not accelerate the recovery of the affected parameters, except for the gait pattern. The combined treatment produced significant improvement in behavioral parameters, as well as in electrophysiological recovery, particularly in the proximal segment of CMAP. The latter results confirm the proximal character of 1,2 DAB neuropathy, and suggest that combined therapy with EGF and GHRP-6 might be a good therapeutic strategy for the treatment of ALS.}, }
@article {pmid20152809, year = {2010}, author = {Wu, X and Kihara, T and Akaike, A and Niidome, T and Sugimoto, H}, title = {PI3K/Akt/mTOR signaling regulates glutamate transporter 1 in astrocytes.}, journal = {Biochemical and biophysical research communications}, volume = {393}, number = {3}, pages = {514-518}, doi = {10.1016/j.bbrc.2010.02.038}, pmid = {20152809}, issn = {1090-2104}, mesh = {Animals ; Astrocytes/*metabolism ; Cells, Cultured ; Excitatory Amino Acid Transporter 2/*metabolism ; Intracellular Signaling Peptides and Proteins/antagonists &amp; inhibitors/*metabolism ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Phosphorylation ; Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/*metabolism ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/*metabolism ; Rats ; Rats, Wistar ; TOR Serine-Threonine Kinases ; }, abstract = {Reduction in or dysfunction of glutamate transporter 1 (GLT1) is linked to several neuronal disorders such as stroke, Alzheimer's disease, and amyotrophic lateral sclerosis. However, the detailed mechanism underlying GLT1 regulation has not been fully elucidated. In the present study, we first demonstrated the effects of mammalian target of rapamycin (mTOR) signaling on GLT1 regulation. We prepared astrocytes cultured in astrocyte-defined medium (ADM), which contains several growth factors including epidermal growth factor (EGF) and insulin. The levels of phosphorylated Akt (Ser473) and mTOR (Ser2448) increased, and GLT1 levels were increased in ADM-cultured astrocytes. Treatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor or an Akt inhibitor suppressed the phosphorylation of Akt (Ser473) and mTOR (Ser2448) as well as decreased ADM-induced GLT1 upregulation. Treatment with the mTOR inhibitor rapamycin decreased GLT1 protein and mRNA levels. In contrast, rapamycin did not affect Akt (Ser473) phosphorylation. Our results suggest that mTOR is a downstream target of the PI3K/Akt pathway regulating GLT1 expression.}, }
@article {pmid20152807, year = {2010}, author = {Gu, R and Hou, X and Pang, R and Li, L and Chen, F and Geng, J and Xu, Y and Zhang, C}, title = {Human adipose-derived stem cells enhance the glutamate uptake function of GLT1 in SOD1(G93A)-bearing astrocytes.}, journal = {Biochemical and biophysical research communications}, volume = {393}, number = {3}, pages = {481-486}, doi = {10.1016/j.bbrc.2010.02.029}, pmid = {20152807}, issn = {1090-2104}, mesh = {Adipose Tissue/*cytology ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/therapy ; Animals ; Astrocytes/*metabolism ; Caspase Inhibitors ; Cells, Cultured ; Coculture Techniques ; Excitatory Amino Acid Transporter 2/*biosynthesis ; Glutamic Acid/*metabolism ; Hepatocyte Growth Factor/biosynthesis ; Humans ; Insulin-Like Growth Factor I/biosynthesis ; Mice ; Mice, Transgenic ; Stem Cells/*metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Up-Regulation ; Vascular Endothelial Growth Factor A/biosynthesis ; }, abstract = {Impaired glutamate uptake function of astrocytes associated with accumulation of extracellular glutamate is a well-documented feature of amyotrophic lateral sclerosis (ALS). Enhancing the uptake function of astrocytic glutamate transport 1 (GLT1) may be a potential treatment for this disease. Human adipose-derived stem cells (hADSCs) are capable of secreting a large number of cytokines which exhibit diverse pharmacological effects. Therefore, we investigate the influence of the soluble factors released by hADSCs on the GLT1 in primary astrocytes cultured from SOD1(G93A) mice, a widely studied mutant human SOD1 transgenic model of ALS. Our data indicate that soluble factors from hADSCs significantly upregulate the expression of GLT1 in SOD1(G93A)-bearing astrocytes, which result in enhanced glutamate uptake function. The upregulation of GLT1 is accompanied by the inhibition of caspase-3 activation in mutant astrocytes. In addition, we find that hADSCs cocultured with SOD1(G93A)-bearing astrocytes produce more VEGF, HGF and IGF-1, which are reported to have neuroprotective effects. Our results suggest that hADSCs may be a potential candidate in cellular therapy for ALS.}, }
@article {pmid20147656, year = {2010}, author = {Rule, RR and Schuff, N and Miller, RG and Weiner, MW}, title = {Gray matter perfusion correlates with disease severity in ALS.}, journal = {Neurology}, volume = {74}, number = {10}, pages = {821-827}, pmid = {20147656}, issn = {1526-632X}, support = {P50 AG023501/AG/NIA NIH HHS/United States ; P41 RR 023953/RR/NCRR NIH HHS/United States ; R01 AG10897/AG/NIA NIH HHS/United States ; R01 NS 44887/NS/NINDS NIH HHS/United States ; P01AG012435/AG/NIA NIH HHS/United States ; P50AG23501/AG/NIA NIH HHS/United States ; P01AG19724/AG/NIA NIH HHS/United States ; R01AG032306/AG/NIA NIH HHS/United States ; K01 HL73152/HL/NHLBI NIH HHS/United States ; U01AG024904/AG/NIA NIH HHS/United States ; P41 RR023953/RR/NCRR NIH HHS/United States ; R24 RR021992/RR/NCRR NIH HHS/United States ; R01NS031966/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*pathology/physiopathology ; Brain/*pathology ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Regression Analysis ; Severity of Illness Index ; }, abstract = {OBJECTIVE: The goal of this study is to determine if regional brain perfusion, as measured by arterial spin labeling (ASL) MRI, is correlated with clinical measures of amyotrophic lateral sclerosis (ALS) disease severity. The presence of such a relationship would indicate a possible role for ASL perfusion as a marker of disease severity and upper motor neuron involvement in ALS.<br><br>METHODS: Disease severity was assessed in 16 subjects with ALS (age 54 +/- 11) using the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) and the pulmonary function measure, forced vital capacity (FVC). Upper motor neuron involvement was assessed by testing rapid tapping of the fingers and feet. Magnetic resonance perfusion images were coregistered with structural T1-weighted MRI, corrected for partial volume effects using the structural images and normalized to a study-specific atlas. Correlations between perfusion and ALS disease severity were analyzed, using statistical parametric mapping, and including age as a factor. Analyses were adjusted for multiple clusters.<br><br>RESULT: ALS severity, as measured by the ALSFRS and FVC, was correlated with gray matter perfusion. This correlation was predominantly observed in the hemisphere contralateral to the more affected limbs. ALSFRS scores correlated with perfusion in the contralateral frontal and parietal lobe (p < 0.001) and ipsilateral frontal lobe (p < 0.02). FVC scores correlated with gray matter perfusion in contralateral frontal lobe (p < 0.001). Upper motor neuron involvement, as measured by rapid finger tapping, correlated bilaterally with perfusion in the middle cingulate gyrus (p < 0.001).<br><br>CONCLUSION: Amyotrophic lateral sclerosis (ALS) severity is correlated with brain perfusion as measured by arterial spin labeling (ASL) perfusion. This correlation appears to be independent of brain atrophy. ASL perfusion may be a useful tool for monitoring disease progression and assessing treatment effects in ALS.}, }
@article {pmid20142861, year = {2009}, author = {Nalini, A and Desai, A and Mahato, SK}, title = {Flail arm-like syndrome associated with HIV-1 infection.}, journal = {Annals of Indian Academy of Neurology}, volume = {12}, number = {2}, pages = {127-130}, pmid = {20142861}, issn = {1998-3549}, abstract = {During the last 20 years at least 23 cases of motor neuron disease have been reported in HIV-1 seropositive patients. In this report we describe the clinical picture of a young man with HIV-1 clade C infection and flail arm-like syndrome, who we were able to follow-up for a long period. We investigated and prospectively monitored a 34-year-old man with features of flail arm syndrome, who developed the weakness and wasting 1 year after being diagnosed with HIV-1 infection after a routine blood test. He presented in 2003 with progressive, symmetrical wasting and weakness of the proximal muscles of the upper limb of 2 years' duration. He had severe wasting and weakness of the shoulder and arm muscles. There were no pyramidal signs. He has been on HAART for the last 4 years and the weakness or wasting has not worsened. At the last follow-up in July 2007, the patient had the same neurological deficit and no other symptoms or signs of HIV-1 infection. MRI of the spinal cord in 2007 showed characteristic T2 hyperintense signals in the central part of the spinal cord, corresponding to the central gray matter. Thus, our patient had HIV-1 clade C infection associated with a 'flail arm-like syndrome.' The causal relationship between HIV-1 infection and amyotrophic lateral sclerosis (ALS)-like syndrome is still uncertain. The syndrome usually manifests as a lower motor neuron syndrome, as was seen in our young patient. It is known that treatment with antiretroviral therapy (ART) stabilizes/improves the condition. In our patient the weakness and atrophy remained stable over a period of 3.5 years after commencing HAART regimen.}, }
@article {pmid20138212, year = {2010}, author = {Caragounis, A and Price, KA and Soon, CP and Filiz, G and Masters, CL and Li, QX and Crouch, PJ and White, AR}, title = {Zinc induces depletion and aggregation of endogenous TDP-43.}, journal = {Free radical biology &amp; medicine}, volume = {48}, number = {9}, pages = {1152-1161}, doi = {10.1016/j.freeradbiomed.2010.01.035}, pmid = {20138212}, issn = {1873-4596}, mesh = {Animals ; Blotting, Western ; Cell Line ; Cell Survival/drug effects ; Chlorides/*toxicity ; DNA-Binding Proteins/*drug effects/*metabolism ; Fluorescent Antibody Technique ; Humans ; Inclusion Bodies/*drug effects/metabolism/pathology ; Neurodegenerative Diseases/metabolism/pathology/physiopathology ; Neurons/*drug effects/metabolism/pathology ; Oxidative Stress/drug effects/physiology ; Rats ; Zinc Compounds/*toxicity ; }, abstract = {Ubiquitinated neuronal aggregates containing TDP-43 are pathological hallmarks in the spectrum of frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS). In affected neurons, TDP-43 undergoes C-terminal fragmentation, phosphorylation, and ubiquitination and forms aggregates in the cytoplasm or nucleus. Although in vitro studies have been able to recapitulate these features using transfected cell culture models, little is known about the biochemical mechanisms that underlie pathological changes to endogenous TDP-43. As altered metal ion homeostasis and increased oxidative stress are central features of neurodegeneration, including FTLD and ALS, we sought to determine the affects of these factors on endogenous TDP-43 metabolism in mammalian cells. Treatment of SY5Y neuronal-like cells expressing endogenous TDP-43 with zinc (Zn) induced depletion of TDP-43 expression and formation of inclusions that were TDP-43 positive. TDP-43 was also detected in the cytosol of Zn-affected cells but this was not aggregated. No evidence of C-terminal fragmentation, phosphorylation, or ubiquitination was observed. The depletion and aggregation of TDP-43 were associated with the specific action of Zn but were not seen with copper, iron, or H(2)O(2). These studies describe for the first time specific induction of endogenous TDP-43 aggregation in neuronal-like cells and suggest that specific Zn-associated processes could affect TDP-43 metabolism in neurodegenerative diseases.}, }
@article {pmid20138122, year = {2010}, author = {Milane, A and Fernandez, C and Dupuis, L and Buyse, M and Loeffler, JP and Farinotti, R and Meininger, V and Bensimon, G}, title = {P-glycoprotein expression and function are increased in an animal model of amyotrophic lateral sclerosis.}, journal = {Neuroscience letters}, volume = {472}, number = {3}, pages = {166-170}, doi = {10.1016/j.neulet.2010.01.078}, pmid = {20138122}, issn = {1872-7972}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/*biosynthesis ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters/biosynthesis ; Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Biological Transport ; Blood-Brain Barrier/metabolism ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Mutation ; Neuroprotective Agents/metabolism ; Riluzole/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {The efflux pumps located at the blood-brain barrier (BBB) prevent drugs entering the brain. As such, efflux pumps are a major obstacle to drug brain distribution. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with little therapeutics available: riluzole is the only drug approved in its treatment. The lack of response to treatment in ALS may be, at least in part, due to increased activities of efflux pumps in relation to disease, leading to subtherapeutic brain concentrations of drugs. In the present study, we used a transgenic mouse model of ALS (G86R mSOD1 mice) to test this hypothesis. Expression and functionality of P-glycoprotein (ABCB1, P-gp) and Breast Cancer Resistance Protein (ABCG2, BCRP), two major efflux pumps, were studied. We observed an increased P-gp expression (1.5-fold) in presymptomatic mSOD1 mice compared to wild-type controls. Consistent with this, P-gp function was also increased by 1.5-fold and riluzole brain disposition was decreased by 1.7-fold in mSOD1 mice. Contrasting with this, BCRP expression and function were unaltered by the pathology. These results demonstrate that BBB transport proteins are modified in G86R mSOD1 mice ALS model. Such findings underline potential problems in extrapolating the results of animal studies to humans and developing clinical trials, especially for drugs transported by P-gp.}, }
@article {pmid20132084, year = {2010}, author = {Karam, C and Scelsa, SN and Macgowan, DJ}, title = {The clinical course of progressive bulbar palsy.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {4}, pages = {364-368}, doi = {10.3109/17482960903513159}, pmid = {20132084}, issn = {1471-180X}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/diagnosis ; Bulbar Palsy, Progressive/classification/*diagnosis/*mortality ; *Disease Progression ; Electromyography/methods ; Female ; Humans ; Kaplan-Meier Estimate ; Magnetic Resonance Imaging/methods ; Male ; Middle Aged ; Retrospective Studies ; }, abstract = {Our objective was to study the clinical course of patients diagnosed with progressive bulbar palsy (PBP). We reviewed all 392 medical records of ALS patients seen between 1 January 2000 and 31 July 2007. Patients with isolated PBP at presentation were selected and classified into those with normal EMG of the limbs (PBP-N) and those with active denervation on EMG (PBP-A). We studied the time to progression of these patients to ALS. We compared patients with PBP-N to patients with PBP-A. Fifteen patients were diagnosed with PBP-N. The remaining 17 had PBP-A. Thirteen of the 15 patients with PBP-N (87%) progressed to definite ALS. The two patients who did not progress to ALS died at 22 and 60 months, respectively. The median survival time was 35 months for the PBP-N group and 40 months for the PBP-A group (p = 0.92). Except for the rate of depression, patients with PBP-N did not differ from patients with PBP-A in the basic demographics, time of presentation, clinical course, survival and treatment received. All patients with FTD died within 40 months of onset of symptoms. In conclusion, almost all PBP patients progress to ALS regardless of the presence of upper motor signs or generalized denervation on EMG of the limbs.}, }
@article {pmid20127552, year = {2010}, author = {Kirk, R}, title = {Clinical trials in CNS--SMi's eighth annual conference.}, journal = {IDrugs : the investigational drugs journal}, volume = {13}, number = {2}, pages = {66-69}, pmid = {20127552}, issn = {2040-3410}, mesh = {Animals ; Central Nervous System Agents/*pharmacology ; Central Nervous System Diseases/*drug therapy/physiopathology ; Clinical Trials as Topic ; Drug Delivery Systems ; Drug Design ; Drugs, Investigational/*pharmacology ; Humans ; }, abstract = {The SMi's Eighth Annual Conference on Clinical Trials in CNS, held in London, included topics covering new therapeutic developments in the field of CNS disorders. This conference report highlights selected presentations on emerging clinical targets for the treatment of Alzheimer's disease, achievements of the Alzheimer's Disease Neuroimaging Initiative, computational assessment methods applicable to Alzheimer's disease and to the monitoring of suicidality, the accelerated antidepressive effect of PNB-01 (PharmaNeuroBoost NV; comprising a combination of pipamperone and citalopram), and clinical trials in amyotrophic lateral sclerosis and spinal muscular atrophy. Investigational drugs discussed also include begacestat (Pfizer Inc) and olesoxime (Trophos SA).}, }
@article {pmid20116097, year = {2010}, author = {Grosskreutz, J and Van Den Bosch, L and Keller, BU}, title = {Calcium dysregulation in amyotrophic lateral sclerosis.}, journal = {Cell calcium}, volume = {47}, number = {2}, pages = {165-174}, doi = {10.1016/j.ceca.2009.12.002}, pmid = {20116097}, issn = {1532-1991}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism/pathology/physiopathology ; Animals ; Brain Stem/pathology ; Calcium/*metabolism ; *Calcium Signaling ; Cell Death ; Humans ; Motor Neurons/*metabolism/pathology ; Neuroprotective Agents/therapeutic use ; Receptors, AMPA/metabolism ; Riluzole/therapeutic use ; Spinal Cord/pathology ; }, abstract = {In the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS), motor neurons degenerate with signs of organelle fragmentation, free radical damage, mitochondrial Ca2+ overload, impaired axonal transport and accumulation of proteins in intracellular inclusion bodies. Subgroups of motor neurons of the brainstem and the spinal cord expressing low amounts of Ca2+ buffering proteins are particularly vulnerable. In ALS, chronic excitotoxicity mediated by Ca2+-permeable AMPA type glutamate receptors seems to initiate a self-perpetuating process of intracellular Ca2+ dysregulation with consecutive endoplasmic reticulum Ca2+ depletion and mitochondrial Ca2+ overload. The only known effective treatment, riluzole, seems to reduce glutamatergic input. This review introduces the hypothesis of a "toxic shift of Ca2+" within the endoplasmic reticulum-mitochondria Ca2+ cycle (ERMCC) as a key mechanism in motor neuron degeneration, and discusses molecular targets which may be of interest for future ERMCC modulating neuroprotective therapies.}, }
@article {pmid20091630, year = {2010}, author = {Simon, ST and Higginson, IJ and Booth, S and Harding, R and Bausewein, C}, title = {Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {1}, pages = {CD007354}, doi = {10.1002/14651858.CD007354.pub2}, pmid = {20091630}, issn = {1469-493X}, support = {PB-PG-0808-17311/DH_/Department of Health/United Kingdom ; }, mesh = {Adult ; Benzodiazepines/*therapeutic use ; Dyspnea/*drug therapy/etiology ; Humans ; Lung Neoplasms/*complications ; Pulmonary Disease, Chronic Obstructive/*complications ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Breathlessness is one of the most common symptoms experienced in the advanced stages of malignant and non-malignant disease. Benzodiazepines are widely used for the relief of breathlessness in advanced diseases and are regularly recommended in the literature. However, the evidence for their use for this symptom is unclear.<br><br>OBJECTIVES: To determine the efficacy of benzodiazepines for the relief of breathlessness in patients with advanced disease.<br><br>SEARCH STRATEGY: We searched 14 electronic databases up to September 2009. We checked the reference lists of all relevant studies, key textbooks, reviews, and websites. We contacted investigators and specialists in palliative care for unpublished data.<br><br>SELECTION CRITERIA: We included randomised controlled trials (RCTs) and controlled clinical trials (CCTs) assessing the effect of benzodiazepines in relieving breathlessness in patients with advanced stages of cancer, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), motor neurone disease (MND), and idiopathic pulmonary fibrosis (IPF).<br><br>DATA COLLECTION AND ANALYSIS: Two review authors independently assessed identified titles and abstracts. Three independent review authors performed assessment of all potentially relevant studies (full text), data extraction, and assessment of methodological quality. We carried out meta-analysis where appropriate.<br><br>MAIN RESULTS: Seven studies were identified, including 200 analysed participants with advanced cancer and COPD. Analysis of all seven studies (including a meta-analysis of six out of seven studies) did not show a beneficial effect of benzodiazepines for the relief of breathlessness in patients with advanced cancer and COPD. Furthermore, no significant effect could be observed in the prevention of breakthrough dyspnoea in cancer patients. Sensitivity analysis demonstrated no significant differences regarding type of benzodiazepine, dose, route and frequency of delivery, duration of treatment, or type of control.<br><br>AUTHORS' CONCLUSIONS: There is no evidence for a beneficial effect of benzodiazepines for the relief of breathlessness in patients with advanced cancer and COPD. There is a slight but non-significant trend towards a beneficial effect but the overall effect size is small. Benzodiazepines caused more drowsiness as an adverse effect compared to placebo, but less compared to morphine. These results justify considering benzodiazepines as a second or third-line treatment within an individual therapeutic trial, when opioids and non-pharmacological measures have failed to control breathlessness. Although a few good quality studies were included in this review, there is still a further need for well-conducted and adequately powered studies.}, }
@article {pmid20089625, year = {2010}, author = {Hirano, Y and Yamazaki, Y}, title = {Ethical issues in invasive mechanical ventilation for amyotrophic lateral sclerosis.}, journal = {Nursing ethics}, volume = {17}, number = {1}, pages = {51-63}, doi = {10.1177/0969733009350945}, pmid = {20089625}, issn = {1477-0989}, mesh = {*Adaptation, Psychological ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/ethnology/*nursing/psychology/therapy ; Conflict, Psychological ; Decision Making/*ethics ; Family Relations ; Female ; Humans ; Japan ; Life Support Care/*ethics/psychology ; Male ; Middle Aged ; Personal Autonomy ; Respiration, Artificial/*ethics/nursing/psychology ; }, abstract = {Currently in Japan, discontinuing an invasive mechanical ventilator (IMV) is illegal; therefore IMV-related decision making is a crucial issue. This study examined IMV decision-making factors and psychological conflict in 50 patients with amyotrophic lateral sclerosis. The Herth Hope Index was used for the assessment of pre- and post-IMV conflict. Interviews identified some decision-making factors: patient's decision, patient's and family's mutual decision, family's decision, and emergency-induced without patient's or family's consent. Participants who experienced no IMV-related regret received sufficient prior IMV education from physicians and nurses, and time for reflection and family consultation. Their hope was similar to their pre-onset levels. Patients who received no prior IMV education accepted treatment as a natural progression. Their hope levels were lower than pre-onset. Those who received only a brief prior IMV explanation rejected the ventilator, experiencing regret if they were given an emergency IMV. Their hope levels were among the lowest. However, some of these patients managed to overcome their regret through being helped by nurses. Sufficient physician explanation and nursing advocacy for autonomous patient decision making are critical for improving hope in this patient group.}, }
@article {pmid20088765, year = {2010}, author = {Orlacchio, A and Bernardi, G and Orlacchio, A and Martino, S}, title = {Stem cells: an overview of the current status of therapies for central and peripheral nervous system diseases.}, journal = {Current medicinal chemistry}, volume = {17}, number = {7}, pages = {595-608}, doi = {10.2174/092986710790416272}, pmid = {20088765}, issn = {1875-533X}, support = {GGP06209/TI_/Telethon/Italy ; }, mesh = {Adult Stem Cells/cytology/metabolism ; Embryonic Stem Cells/cytology/metabolism ; Humans ; Induced Pluripotent Stem Cells/cytology/metabolism ; Neurodegenerative Diseases/*therapy ; Peripheral Nervous System Diseases/*therapy ; *Stem Cell Transplantation ; Stem Cells/*cytology/metabolism ; }, abstract = {In regenerative medicine, stem cells are currently considered ideal candidates for the treatment of diseases and injuries of the nervous system, for which, at present, there are no effective treatments. Promising results have been shown by clinical trials for neurodegenerative diseases such as Parkinson's diseases, but also for demyelinising disorders and traumatic lesions of the brain and spinal cord. The proof-of-principle is that the replacement of damaged cells and the restoration of function can be accomplished by the transplantation of embryonic or adult stem cells. Advancements in stem cell biology were recently propelled by the ability to generate induced pluripotent stem (iPS) cells from fibroblasts of several neurodegenerative diseases (e.g. Parkinson's and Huntington's diseases, Amyotrophic Lateral Sclerosis and Spinal Muscular Atrophy). In this review, we discuss the molecular basis of stem cell therapy and the advancement of research on regenerative medicine for diseases and injuries of the nervous system.}, }
@article {pmid20084835, year = {2009}, author = {Van Damme, P}, title = {The role of AMPA receptors and VEGF in ALS.}, journal = {Verhandelingen - Koninklijke Academie voor Geneeskunde van Belgie}, volume = {71}, number = {4}, pages = {241-250}, pmid = {20084835}, issn = {0302-6469}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*metabolism ; Animals ; Calcium/metabolism ; Humans ; Motor Neurons/*metabolism ; Neurotoxins/*adverse effects ; Receptors, AMPA/antagonists &amp; inhibitors/*physiology ; Receptors, Glutamate/metabolism ; Vascular Endothelial Growth Factor A/*physiology ; }, abstract = {The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is a complex and multifactorial process. Both excitotoxicity (excessive stimulation of glutamate receptors) and a shortage of the vascular endothelial growth factor (VEGF) have been implicated in the disease pathogenesis. In this study, both disease mechanisms were further characterized and their therapeutic potential was evaluated. Motor neurons were found to be particularly vulnerable to AMPA receptor stimulation (one subtype of glutamate receptors) and the toxicity was initiated by the influx of calcium ions through the AMPA receptors. Only AMPA receptors that lack a certain subunit (GluR2) are permeable to calcium ions, and compared to other neurons motor neurons had low GluR2 levels. Reducing GluR2 levels aggravated motor neuron death in culture and accelerated the process of motor neuron degeneration in vivo. The regulation of GluR2 expression was investigated further. Astrocytes were found to influence neuronal GluR2 expression and thus their vulnerability to excitotoxicity. In addition, the growth factor VEGF, which could slow down motor neuron degeneration in rats, stimulated GluR2 expression in motor neurons and protected against excessive AMPA receptor stimulation, providing a link between two important disease mechanisms in ALS. Clinical trials with AMPA receptor antagonists and VEGF will hopefully lead to a better treatment of patients with ALS.}, }
@article {pmid20071543, year = {2010}, author = {Duplan, L and Bernard, N and Casseron, W and Dudley, K and Thouvenot, E and Honnorat, J and Rogemond, V and De Bovis, B and Aebischer, P and Marin, P and Raoul, C and Henderson, CE and Pettmann, B}, title = {Collapsin response mediator protein 4a (CRMP4a) is upregulated in motoneurons of mutant SOD1 mice and can trigger motoneuron axonal degeneration and cell death.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {30}, number = {2}, pages = {785-796}, pmid = {20071543}, issn = {1529-2401}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; Animals ; Axons/physiology ; Cell Death/genetics ; Cells, Cultured ; Disease Models, Animal ; Electroporation/methods ; Embryo, Mammalian ; Green Fluorescent Proteins/genetics ; Humans ; Mice ; Mice, Mutant Strains ; Motor Neurons/*metabolism/pathology ; Nerve Degeneration/etiology/*genetics ; Nerve Tissue Proteins/genetics/*metabolism ; Nitric Oxide/pharmacology ; Proteomics/methods ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods ; Spinal Cord/cytology ; Superoxide Dismutase/*genetics ; Up-Regulation/drug effects/*genetics ; Vesicular Acetylcholine Transport Proteins/metabolism ; }, abstract = {Embryonic motoneurons from mutant SOD1 (mSOD1) mouse models of amyotrophic lateral sclerosis (ALS), but not wild-type motoneurons, can be triggered to die by exposure to nitric oxide (NO), leading to activation of a motoneuron-specific signaling pathway downstream of the death receptor Fas/CD95. To identify effectors of mSOD1-dependent cell death, we performed a proteomic analysis. Treatment of cultured mSOD1 motoneurons with NO led to a 2.5-fold increase in levels of collapsin response mediator protein 4a (CRMP4a). In vivo, the percentage of mSOD1 lumbar motoneurons expressing CRMP4 in mSOD1 mice increased progressively from presymptomatic to early-onset stages, reaching a maximum of 25%. Forced adeno-associated virus (AAV)-mediated expression of CRMP4a in wild-type motoneurons in vitro triggered a process of axonal degeneration and cell death affecting 60% of motoneurons, whereas silencing of CRMP4a in mSOD1 motoneurons protected them from NO-induced death. In vivo, AAV-mediated overexpression of CRMP4a but not CRMP2 led to the death of 30% of the lumbar motoneurons and an 18% increase in denervation of neuromuscular junctions in the gastrocnemius muscle. Our data identify CRMP4a as a potential early effector in the neurodegenerative process in ALS.}, }
@article {pmid20060132, year = {2010}, author = {Ghoddoussi, F and Galloway, MP and Jambekar, A and Bame, M and Needleman, R and Brusilow, WS}, title = {Methionine sulfoximine, an inhibitor of glutamine synthetase, lowers brain glutamine and glutamate in a mouse model of ALS.}, journal = {Journal of the neurological sciences}, volume = {290}, number = {1-2}, pages = {41-47}, doi = {10.1016/j.jns.2009.11.013}, pmid = {20060132}, issn = {1878-5883}, support = {R01 DA016736/DA/NIDA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism/physiopathology ; Animals ; Biomarkers/analysis/blood ; Corpus Striatum/drug effects/metabolism ; Disease Models, Animal ; Down-Regulation/drug effects/physiology ; Excitatory Amino Acid Antagonists/*pharmacology/therapeutic use ; Glutamate-Ammonia Ligase/antagonists &amp; inhibitors/metabolism ; Glutamic Acid/metabolism ; Glutamine/antagonists &amp; inhibitors/metabolism ; Glutathione/metabolism ; Humans ; Kaplan-Meier Estimate ; Magnetic Resonance Spectroscopy ; Methionine Sulfoximine/*pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; Motor Cortex/drug effects/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Neurotoxins/antagonists &amp; inhibitors/metabolism ; Oxidative Stress/drug effects/physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Treatment Outcome ; gamma-Aminobutyric Acid/metabolism ; }, abstract = {In an effort to alter the levels of neurochemicals involved in excitotoxicity, we treated mice with methionine sulfoximine (MSO), an inhibitor of glutamine synthetase. Since glutamate toxicity has been proposed as a mechanism for the degeneration of motor neurons in a variety of neurodegenerative diseases, we tested the effects of MSO on the transgenic mouse that overexpresses the mutant human SOD1(G93A) gene, an animal model for the primary inherited form of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS). This treatment in vivo reduced glutamine synthetase activity measured in vitro by 85%. Proton magnetic resonance spectroscopy, with magic angle spinning of intact samples of brain tissue, showed that MSO treatment reduced brain levels of glutamine by 60% and of glutamate by 30% in both the motor cortex and the anterior striatum, while also affecting levels of GABA and glutathione. Kaplan-Meyer survival analysis revealed that MSO treatment significantly extended the lifespan of these mice by 8% (p<0.01). These results show that in the SOD1(G93A) model of neurodegenerative diseases, the concentration of brain glutamate (determined with (1)H-MRS) can be lowered by inhibiting in vivo the synthesis of glutamine with non-toxic doses of MSO.}, }
@article {pmid20052865, year = {2009}, author = {Adler, D and Contal, O and Janssens, JP}, title = {[A lung specialist in ALS care: towards less pessimism].}, journal = {Revue medicale suisse}, volume = {5}, number = {226}, pages = {2329-32, 2334-5}, pmid = {20052865}, issn = {1660-9379}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis/*therapy ; Blood Gas Analysis ; Congresses as Topic ; Cough/etiology ; Evidence-Based Medicine ; Humans ; Oximetry ; Positive-Pressure Respiration/instrumentation/*methods ; Prognosis ; Pulmonary Ventilation ; Respiratory Insufficiency/diagnosis/therapy ; Respiratory Therapy/methods ; Respiratory Tract Diseases/*diagnosis/etiology/*therapy ; Spirometry ; Treatment Outcome ; Weight Loss ; }, abstract = {Specialized and multidisciplinary care is needed for patients with amyotrophic lateral sclerosis (ALS). Respiratory failure secondary to respiratory muscle dysfunction, ineffective cough, weight loss and progressive loss of autonomy should always be sought and explored. Very few tests are needed to assess a patient with ALS: spirometry, blood gases, nocturnal oximetry, cough peak-flow, and follow-up of body weight. Patients should be informed clearly as to the nature and evolution of ALS, and as to the potential benefits and disadvantages associated with each treatment modality in order to be involved in therapeutic decisions. This evidence-based review focuses on respiratory care of patients with ALS.}, }
@article {pmid21395520, year = {2010}, author = {Mankikar, SD}, title = {Stem cells: a new paradigm in medical therapeutics.}, journal = {Journal of long-term effects of medical implants}, volume = {20}, number = {3}, pages = {219-250}, doi = {10.1615/jlongtermeffmedimplants.v20.i3.50}, pmid = {21395520}, issn = {1050-6934}, mesh = {Bioreactors ; Cell Culture Techniques ; Humans ; *Stem Cell Transplantation/trends ; *Stem Cells ; *Tissue Engineering ; }, abstract = {Even though the stem cells have been studied for decades, only during the past few years has there been an overwhelming proliferation of publications covering isolation, cultivation and utilization of the body's master cells. This paper attempts to summarize the recent studies in the field of stem cells. A number of studies have reported the existence of multipotent stem cells in the cord, cord blood, placenta, bone marrow, brain, heart, teeth, skin, liver, hair follicles and many other tissues and organs, giving rise to cell types other than their tissue of origin. Increased therapeutic use of stem cells has resulted in scientific methods of collection, testing, processing and storage of these cells, with minimal cell damage and differentiation. Cell expansion, bioreactors and tissue engineering are employed extensively to improve the cell dose and outcome. Stem cell infusion, transplantation and implantation are accepted curative therapies for many malignant and non-malignant conditions. Stem cell therapies also provide alternative solutions for the repair and regeneration of various tissues and organs. There has been a dramatic improvement in the understanding of immunosuppressive properties of stem cells on various immune cell types. Stem cells are found to secrete angiogenic cytokines that increase neovascularization. They bring the promise of curing a disease state as these cells normally regenerate tissues in a healthy organism. Stem cell transplantation, in isolation or in combination with other procedures, has been found to be effective. Stem cell therapy is also seen as a possible alternative for the treatment of different diseases such as juvenile diabetes, amyotrophic lateral sclerosis, cerebral palsy, stroke, spinal cord injury and Parkinson's disease. Regenerative medicine using human stem cells is one of the new and promising fields for treating various intractable diseases and damaged organs.}, }
@article {pmid21387816, year = {2010}, author = {Banach, M and Rakowicz, M}, title = {[Electrophysiological diagnosis of arnyotrophic lateral sclerosis].}, journal = {Przeglad lekarski}, volume = {67}, number = {9}, pages = {736-740}, pmid = {21387816}, issn = {0033-2240}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Electromyography ; Humans ; Transcranial Magnetic Stimulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of unclear etiology. Diagnostic challenges often appear already at the early stage of the disease. Detecting developed neuropathies on time, including multifocal motor neuropathy with a conduction block, allows administering a treatment, which can prove to be successful quickly. Electrophysiological studies assess the lesion of the peripheral and central motor neuron and serve as markers supporting the diagnosis of ALS. Electromyographic and neurographic studies make it possible to take an objective look at the involvement of the peripheral nervous system and constitute, apart form the clinical assessment, an important element of the ALS diagnosis. Transcranial magnetic stimulation, augmented with a new method of triple stimulation technique (TST) helps in the diagnosis of lesions in the cortico-bulbar and cortico-spinal tract in patients with no clinical symptoms of the upper motor neuron involvement. Additionally, this technique allows making the diagnosis of the conduction block localized in the proximal nerve segments, especially when the results of neurographic studies are not unequivocal. In experimental studies assessing responses to treatment attempts and monitoring the development of the disease there has been used the MUNE method (motor unit number estimation), which informs of the number of active motor neurons. In this review there have been described the up-to-date electrophysiological methods, facilitating the diagnosis and monitoring of the progressive lesion of the lower and upper motor neuron in patients with amyotrophic lateral sclerosis. Besides, there have been presented other clinical syndromes, which must be distinguished from amyotrophic lateral sclerosis.}, }
@article {pmid20043239, year = {2010}, author = {Shiina, Y and Arima, K and Tabunoki, H and Satoh, J}, title = {TDP-43 dimerizes in human cells in culture.}, journal = {Cellular and molecular neurobiology}, volume = {30}, number = {4}, pages = {641-652}, pmid = {20043239}, issn = {1573-6830}, mesh = {Adult ; Aged ; Animals ; Brain/cytology/metabolism ; Cell Line ; DNA-Binding Proteins/*chemistry/genetics/*metabolism ; Female ; Humans ; Male ; Middle Aged ; *Protein Multimerization ; *Protein Structure, Quaternary ; Protein Structure, Tertiary ; }, abstract = {TAR DNA-binding protein-43 (TDP-43) is a 43-kDa nuclear protein involved in regulation of gene expression. Abnormally, phosphorylated, ubiquitinated, and aggregated TDP-43 constitute a principal component of neuronal and glial cytoplasmic and nuclear inclusions in the brains of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS), although the molecular mechanism that triggers aggregate formation remains unknown. By Western blot analysis using anti-TDP-43 antibodies, we identified a band with an apparent molecular mass of 86-kDa in HEK293, HeLa, and SK-N-SH cells in culture. It was labeled with both N-terminal-specific and C-terminal-specific TDP-43 antibodies, enriched in the cytosolic fraction, and the expression levels were reduced by TDP-43 siRNA but unaltered by treatment with MG-132 or by expression of ubiqulin-1 or casein kinase-1. By immunoprecipitation analysis, we found the interaction between the endogenous full-length TDP-43 and the exogenous Flag-tagged TDP-43, and identified the N-terminal half of TDP-43 spanning amino acid residues 3-183 as an intermolecular interaction domain. When the tagged 86-kDa tandemly connected dimer of TDP-43 was overexpressed in HEK293, it was sequestered in the cytoplasm and promoted an accumulation of high-molecular-mass TDP-43-immunoreactive proteins. Furthermore, the 86-kDa band was identified in the immunoblot of human brain tissues, including those of ALS. These results suggest that the 86-kDa band represents dimerized TDP-43 expressed constitutively in normal cells under physiological conditions.}, }
@article {pmid20030263, year = {2009}, author = {Kuzuhara, S}, title = {[History of neurology and education on neurology in Japan].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {49}, number = {11}, pages = {968-971}, doi = {10.5692/clinicalneurol.49.968}, pmid = {20030263}, issn = {0009-918X}, mesh = {Certification ; Congresses as Topic/history ; Curriculum ; Education, Medical/*history ; History, 20th Century ; History, 21st Century ; Humans ; Japan/epidemiology ; Nervous System Diseases/history/therapy ; Neurology/education/*history ; Societies, Medical/history/organization &amp; administration ; Specialty Boards/history ; }, abstract = {The first medical society of Japanese neurologists and psychiatrists was founded in 1902, but psychiatrists gradually dominated in number. New "Japanese Society of Neurology" (JSN) was founded in 1960. The number of members was only 643 in 1960, while it rose up to 8,555 in 2009, including regular, junior, senior and associate members. JSN contributed much to solve the causes and treatment of the medicosocial and iatrogenic diseases such as Minamata disease and SMON (subacute myelopticoneuropathy) at its early period. In undergraduate education at medical school neurology is one of the core subjects in the curriculum, and almost all the 80 medical schools have at least one faculty neurologist. The Board of neurology of JSN was started in 1975, as the third earliest of the Japanese Medical Associations. It takes at least 6 years' clinical training after graduating from the medical school to take the neurology Board examinations. By 2009, 4,000 members passed the Board examinations. In 2002 JSN published evidence-based "Treatment Guidelines 2002" of 6 diseases: Parkinson's disease, stroke, chronic headache, dementia and ALS. As to the international issues, JSN hosted the 12th World Congress of Neurology in 1981, and international activities markedly increased after that. The first informal meeting with JSN and Korean Neurological Association (KNA) was held at the 48th JSN Annual Meeting in Nagoya in May 2007. In May 2008 the KNA-JSN 1st Joint symposium was held at the 49th Annual Meeting of JSN in Yokohama on "International comparison of neurological disorders: focusing on spinocerebellar atrophies (SCA) and epilepsies". In May 2009, KNA-JNS 2 nd Joint Symposium was held at the 50th JSN Annual Meeting in Sendai, inviting a speaker from Taiwan Neurological Society, on the subject "History and Education of Neurology in Japan, Korea and Taiwan". In this symposium, a strategy to make up the Northeast Asian Neurological Association was discussed.}, }
@article {pmid20030209, year = {2009}, author = {Hasegawa, M and Nonaka, T and Yamashita, M and Kametani, F and Arai, T and Yoshida, M and Hashizume, Y and Tsuchiya, K and Akiyama, H}, title = {[TDP-43 proteinopathies, toward understanding of the molecular pathogenesis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {49}, number = {11}, pages = {783-785}, doi = {10.5692/clinicalneurol.49.783}, pmid = {20030209}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/etiology/genetics ; Brain/*metabolism ; Clinical Trials, Phase II as Topic ; DNA-Binding Proteins/genetics/*metabolism ; Drug Design ; Humans ; Mutation ; Nuclear Localization Signals ; Phosphorylation ; TDP-43 Proteinopathies/drug therapy/*etiology/genetics ; Ubiquitin ; }, abstract = {The TDP-43 proteinopathies: Toward understanding of the molecular pathogenesis. TAR DNA binding protein of 43 kDa (TDP-43), a heterogeneous nuclear ribonucleoprotein was identified as a major component of ubiquitin-positive inclusions in FTLD and ALS, and the concept of TDP-43 proteinopathies was proposed. Immunoblot and immunohistochemical analyses using multiple anti-phosphorylated TDP-43 antibodies revealed that hyperphosphorylated 18-26 kDa C-terminal fragments in addition to the full-length TDP-43 are major constituents of inclusions in FTLD-U and ALS. Recent discovery of mutations in the TDP-43 gene in familial and sporadic ALS, indicating that abnormality of TDP-43 protein cause neurodegeneration. It also strongly suggests that aggregation of TDP-43 or the process is responsible for neurodegeneration in FTLD-U and ALS. To investigate the molecular mechanisms of aggregation of TDP-43, we have established two cellular models for intracellular aggregates of TDP-43 similar to those in brains of TDP-43 proteinopathies patients. The first consists of SH-SY5Y cells expressing mutant TDP-43 that lacks both the nuclear localization signal (NLS) and residues 187-192 (deltaNLS &amp; 187-192). The second model consists of SH-SY5Y cells expressing an aggregation-prone TDP-43 C-terminal fragment as a green fluorescent protein (GFP)-fusion. In these cells, round structures positive for both anti-pS409/410 and anti-Ub are observed. These results suggest that intracellular localization of TDP-43, truncation of TDP-43 and proteasomal dysfunction of cells may be involved in the pathological process of TDP-43 proteinopathies. We also found that two small compounds that have been reported to be beneficial in phase II clinical trials of Alzheimer's disease, inhibited the formation of TDP-43 aggregates in these two cellular models, suggesting that these compounds may be effective for the treatment of ALS and FTLD-U.}, }
@article {pmid20026137, year = {2010}, author = {Van Kampen, JM and Eckman, CB}, title = {Agonist-induced restoration of hippocampal neurogenesis and cognitive improvement in a model of cholinergic denervation.}, journal = {Neuropharmacology}, volume = {58}, number = {6}, pages = {921-929}, pmid = {20026137}, issn = {1873-7064}, support = {R01 AG032297-04/AG/NIA NIH HHS/United States ; R01 AG032297/AG/NIA NIH HHS/United States ; R01 AG032297-02/AG/NIA NIH HHS/United States ; R01 AG032297-01A1/AG/NIA NIH HHS/United States ; R01 AG032297-03/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcholine/metabolism ; Animals ; Brain Diseases/*drug therapy/physiopathology ; CA1 Region, Hippocampal/drug effects/physiopathology ; Cell Proliferation/drug effects ; Choline O-Acetyltransferase/metabolism ; Cholinergic Agents/*pharmacology ; Cognition/*drug effects ; Disease Models, Animal ; Female ; Hippocampus/*drug effects/physiopathology ; Maze Learning/drug effects ; Memory/drug effects ; Muscarinic Agonists/*pharmacology ; Muscarinic Antagonists/pharmacology ; Neurogenesis/*drug effects ; Rats ; Rats, Sprague-Dawley ; Receptor, Muscarinic M1/agonists/antagonists &amp; inhibitors/metabolism ; Receptors, Muscarinic/metabolism ; Space Perception/drug effects ; }, abstract = {Loss of basal forebrain cholinergic innervation of the hippocampus and severe neuronal loss within the hippocampal CA1 region are early hallmarks of Alzheimer's disease, and are strongly correlated with cognitive status. Various therapeutic approaches involve attempts to enhance neurotransmission or to provide some level of neuroprotection for remaining cells. An alternative approach may involve the generation of new cells to replace those lost in AD. Indeed, a simple shift in the balance between cell generation and cell loss may slow disease progression and possibly even reverse existing cognitive deficits. One potential neurogenic regulator might be acetylcholine, itself, which has been shown to play a critical role in hippocampal development. Here, we report the effects of various cholinergic compounds on indices of hippocampal neurogenesis, demonstrating a significant induction following pharmacological activation of muscarinic M1 receptors, located on hippocampal progenitors in the adult brain. This is the first report that a small-molecule agonist may induce neurogenesis in the hippocampal CA1 region. Furthermore, such treatment reversed deficits in markers of neurogenesis and spatial working memory triggered by cholinergic denervation in a rodent model. This study suggests the use of small molecule, receptor agonists may represent a novel means to trigger the restoration of specific neuronal populations lost to a variety of neurodegenerative disorders, such as Parkinson's, Alzheimer's, Huntington's and Amyotrophic Lateral Sclerosis.}, }
@article {pmid20021336, year = {2009}, author = {Chen, Y and Meininger, V and Guillemin, GJ}, title = {Recent advances in the treatment of amyotrophic lateral sclerosis. Emphasis on kynurenine pathway inhibitors.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {9}, number = {1}, pages = {32-39}, doi = {10.2174/187152409787601941}, pmid = {20021336}, issn = {1875-6166}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/drug therapy/*metabolism ; Animals ; Brain/drug effects/*pathology ; D-Aspartic Acid/metabolism ; Functional Laterality/*physiology ; Humans ; Japan ; Kynurenic Acid/*antagonists &amp; inhibitors/metabolism ; Kynurenine/*antagonists &amp; inhibitors/metabolism ; Motor Neurons/*drug effects/physiology ; N-Methylaspartate/metabolism ; Quinolinic Acid/*metabolism ; Riluzole/*therapeutic use ; Signal Transduction/drug effects ; Tryptophan/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult onset, progressive and fatal motor neuron degenerative disease [1]. The aetiology of ALS is currently unknown, though strongly suggested to be multifactorial. Recently, the kynurenine pathway (KP) has emerged as a potential contributing factor [2]. The KP is a major route for the metabolism of tryptophan, generating neuroactive intermediates in the process. These catabolites include the excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist, quinolinic acid (QUIN) [3] and the neuroprotective NMDA receptor antagonist, kynurenic acid (KYNA) [4,5]. These catabolites appear to play a key role in the communication between the nervous and immune systems, and also in modulating cell proliferation and tissue function [6]. As the cause of ALS is still unknown, there is presently no efficient treatment for it. Currently, Riluzole is the drug of choice but its effect is relatively modest [7]. Targeting the KP, hence, could offer a new therapeutic option to improve ALS treatment [8]. Several drugs that block the KP are already under investigation by our laboratory and others, some of which are in or about to enter clinical trials for other diseases. For example, the KP inhibitors, Teriflunomide (Sanofi-Aventis) and Laquinimod (Teva Neuroscience). Recently, a KP inhibitor has also reached the Japan market as an immunomodulative drug [9]: Tranilast/Rizaben (Angiogen Ltd.) is an anthranilic acid derivative [8]. Finally, the 8-hydroxyquinolinine metal attenuating compounds, Clioquinol and PBT2, interestingly have close structural similarity with KYNA and QUIN. Such drugs would open a new and important therapeutic door for ALS.}, }
@article {pmid20017723, year = {2010}, author = {Mancuso, M and Orsucci, D and Volpi, L and Calsolaro, V and Siciliano, G}, title = {Coenzyme Q10 in neuromuscular and neurodegenerative disorders.}, journal = {Current drug targets}, volume = {11}, number = {1}, pages = {111-121}, doi = {10.2174/138945010790031018}, pmid = {20017723}, issn = {1873-5592}, mesh = {Animals ; Humans ; Mitochondrial Diseases/drug therapy/metabolism ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neuromuscular Diseases/*drug therapy/*metabolism ; Ubiquinone/*analogs &amp; derivatives/deficiency/physiology/therapeutic use ; }, abstract = {Coenzyme Q10 (CoQ10, or ubiquinone) is an electron carrier of the mitochondrial respiratory chain (electron transport chain) with antioxidant properties. In view of the involvement of CoQ10 in oxidative phosphorylation and cellular antioxidant protection a deficiency in this quinone would be expected to contribute to disease pathophysiology by causing a failure in energy metabolism and antioxidant status. Indeed, a deficit in CoQ10 status has been determined in a number of neuromuscular and neurodegenerative disorders. Primary disorders of CoQ10 biosynthesis are potentially treatable conditions and therefore a high degree of clinical awareness about this condition is essential. A secondary loss of CoQ10 status following HMG-Coa reductase inhibitor (statins) treatment has be implicated in the pathophysiology of the myotoxicity associated with this pharmacotherapy. CoQ10 and its analogue, idebenone, have been widely used in the treatment of neurodegenerative and neuromuscular disorders. These compounds could potentially play a role in the treatment of mitochondrial disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological and muscular diseases, from primary CoQ10 deficiency to neurodegenerative disorders. We also briefly report a case of the myopathic form of CoQ10 deficiency.}, }
@article {pmid20015852, year = {2010}, author = {Orrell, RW}, title = {Motor neuron disease: systematic reviews of treatment for ALS and SMA.}, journal = {British medical bulletin}, volume = {93}, number = {}, pages = {145-159}, doi = {10.1093/bmb/ldp049}, pmid = {20015852}, issn = {1471-8391}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Databases as Topic ; Humans ; Motor Neuron Disease/therapy ; Muscular Atrophy, Spinal/*therapy ; Neuroprotective Agents/*therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole/*therapeutic use ; }, abstract = {INTRODUCTION: There is no curative treatment for the common motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy. Nevertheless, there is an increasing volume of published studies. This review assesses the current evidence for treatment of these conditions.<br><br>SOURCES OF DATA: Primarily, the systematic reviews of the Cochrane Collaboration, with additional reference to other systematic reviews and online sites.<br><br>AREAS OF AGREEMENT: Riluzole remains the only medication with demonstrated efficacy and regulatory approval for the treatment of ALS. AREAS OF CONTROVERSY, GROWING POINTS, AND AREAS TIMELY FOR DEVELOPING RESEARCH: The design of clinical trials and the publication of unsatisfactory studies, in both human and animal models, continue to cause confusion in advising on patient management. Improvements in trial design, critical assessment of studies for publication and avoidance of bias towards publication of positive results are needed. A better understanding of pathogenesis should lead to more potent interventions.}, }
@article {pmid20007187, year = {2010}, author = {Pellis, T and Kohl, P}, title = {Extracorporeal cardiac mechanical stimulation: precordial thump and precordial percussion.}, journal = {British medical bulletin}, volume = {93}, number = {}, pages = {161-177}, doi = {10.1093/bmb/ldp045}, pmid = {20007187}, issn = {1471-8391}, support = {G0400145/MRC_/Medical Research Council/United Kingdom ; /BHF_/British Heart Foundation/United Kingdom ; }, mesh = {Cardiopulmonary Resuscitation/*methods/standards ; Electrophysiologic Techniques, Cardiac ; Heart Arrest/*therapy ; Heart Massage/*methods/standards ; Humans ; Physical Stimulation/methods ; }, abstract = {INTRODUCTION: External cardiac mechanical stimulation is one of the fastest resuscitative manoeuvres possible in the emergency setting. Precordial thump (PT), initially reported for treatment of atrio-ventricular block, has been subsequently described to cardiovert also ventricular tachycardia (VT) and fibrillation (VF). PT efficacy, mechanics and mechanisms remain poorly characterized.<br><br>SOURCES OF DATA: Appropriate MESH and free terms were searched on PubMed, Embase and the Cochrane Library. Cross-referencing from articles and reviews, and forward search using SCOPUS and Google scholar have also been performed. Pre-set inclusion and exclusion criteria were applied to retrieved references on PT, which were then reviewed, summarized and interpreted.<br><br>AREAS OF AGREEMENT: PT is not effective in treating VF, and of limited use for VT, although it has a very good safety profile (97% no changed/improved rhythm). If delivered, PT should be applied as early as possible after cardiac arrest, and cardio-pulmonary resuscitation (CPR) should begin with no delay if not effective.<br><br>AREAS OF CONTROVERSY: A relatively large fraction of reported positive outcomes (both for PT and the less forceful but serially applied precordial percussion) in witnessed asystole should be considered when critically reviewing present CPR recommendations. In addition, mechanisms, energy requirements and timing are analysed and discussed.<br><br>The 2005 ALS guidelines recommend PT delivery only by healthcare professionals trained in the technique. The use of training aids should therefore be explored, regardless of whether they are based on stand-alone devices or integrated within resuscitation mannequins.}, }
@article {pmid19929743, year = {2009}, author = {Bradley, WG}, title = {Possible therapy for ALS based on the cyanobacteria/BMAA hypothesis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10 Suppl 2}, number = {}, pages = {118-123}, doi = {10.3109/17482960903285951}, pmid = {19929743}, issn = {1471-180X}, mesh = {Amino Acids/therapeutic use ; Amino Acids, Diamino/analysis/metabolism/*toxicity ; Amino Acids, Dicarboxylic/analysis/metabolism/*toxicity ; Amino Acyl-tRNA Synthetases/antagonists &amp; inhibitors/drug effects ; Amyotrophic Lateral Sclerosis/*chemically induced/diagnosis/*therapy ; Cyanobacteria/chemistry/*physiology ; Enzyme Inhibitors/therapeutic use ; Hair/chemistry ; Humans ; Neurotoxins/analysis/metabolism/*toxicity ; Protein Transport/drug effects ; }, abstract = {Although the cyanobacteria/BMAA hypothesis of the cause of ALS and other age-related neurodegenerative diseases remains to be proven, it is not too early to ask whether treatment would be possible if the hypothesis were correct. This paper reviews the possible ways that chronic BMAA neurotoxicity could be prevented or treated.}, }
@article {pmid19966907, year = {2009}, author = {Spindler, M and Beal, MF and Henchcliffe, C}, title = {Coenzyme Q10 effects in neurodegenerative disease.}, journal = {Neuropsychiatric disease and treatment}, volume = {5}, number = {}, pages = {597-610}, pmid = {19966907}, issn = {1176-6328}, abstract = {Coenzyme Q10 (CoQ10) is an essential cofactor in the mitochondrial respiratory chain, and as a dietary supplement it has recently gained attention for its potential role in the treatment of neurodegenerative disease. Evidence for mitochondrial dysfunction in neurodegenerative disorders derives from animal models, studies of mitochondria from patients, identification of genetic defects in patients with neurodegenerative disease, and measurements of markers of oxidative stress. Studies of in vitro models of neuronal toxicity and animal models of neurodegenerative disorders have demonstrated potential neuroprotective effects of CoQ10. With this data in mind, several clinical trials of CoQ10 have been performed in Parkinson's disease and atypical Parkinson's syndromes, Huntington's disease, Alzheimer disease, Friedreich's ataxia, and amyotrophic lateral sclerosis, with equivocal findings. CoQ10 is widely available in multiple formulations and is very well tolerated with minimal adverse effects, making it an attractive potential therapy. Phase III trials of high-dose CoQ10 in large sample sizes are needed to further ascertain the effects of CoQ10 in neurodegenerative diseases.}, }
@article {pmid19966906, year = {2009}, author = {Zoccolella, S and Santamato, A and Lamberti, P}, title = {Current and emerging treatments for amyotrophic lateral sclerosis.}, journal = {Neuropsychiatric disease and treatment}, volume = {5}, number = {}, pages = {577-595}, pmid = {19966906}, issn = {1176-6328}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a relatively rare neurodegenerative disorder of both upper and lower motoneurons. Currently, the management of ALS is essentially symptoms-based, and riluzole, an antiglutamatergic agent, is the only drug for the treatment of ALS approved by the food and drug administration.<br><br>OBJECTIVE: We reviewed current literature concerning emerging treatments for amyotrophic lateral sclerosis.<br><br>METHODS: A Medline literature search was performed to identify all studies on ALS treatment published from January 1st, 1986 through August 31st, 2009. We selected papers concerning only disease-modifying therapy.<br><br>RESULTS: Forty-eight compounds were identified and reviewed in this study.<br><br>CONCLUSIONS: Riluzole is the only compound that demonstrated a beneficial effect on ALS patients, but with only modest increase in survival. Although several drugs showed effective results in the animal models for ALS, none of them significantly prolonged survival or improved quality of life of ALS patients. Several factors have been implicated in explaining the predominantly negative results of numerous randomized clinical trials in ALS, including methodological problems in the use of animal-drug screening, the lack of assessment of pharmacokinetic profile of the drugs, and methodological pitfalls of clinical trials in ALS patients.}, }
@article {pmid19961264, year = {2010}, author = {Pascuzzi, RM and Shefner, J and Chappell, AS and Bjerke, JS and Tamura, R and Chaudhry, V and Clawson, L and Haas, L and Rothstein, JD}, title = {A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {3}, pages = {266-271}, doi = {10.3109/17482960903307805}, pmid = {19961264}, issn = {1471-180X}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/blood/*drug therapy/pathology ; Benzodiazepines/blood/*therapeutic use ; Disability Evaluation ; Double-Blind Method ; Electrocardiography/methods ; Excitatory Amino Acid Antagonists/blood/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Muscle Strength/drug effects ; Muscle, Skeletal/drug effects/physiopathology ; Neurologic Examination ; Time Factors ; Treatment Outcome ; Young Adult ; }, abstract = {Our objective was to determine if chronic treatment with the non-competitive AMPA antagonist talampanel is efficacious and safe in subjects with ALS. A double-blind, placebo-controlled, multicenter, randomized clinical trial of nine months treatment duration was conducted in 59 subjects with ALS, with 40 subjects receiving talampanel 50 mg p.o. t.i.d, and 19 subjects receiving placebo. Primary outcome measure was rate of decline in isometric arm strength (as measured by change in arm strength megaslope of the Tufts Quantitative Neuromuscular Exam (TQNE)). Other efficacy endpoints included rate of decline in respiratory function, isometric leg strength, bulbar function, fine motor function, the ALS Functional Rating Scale (ALSFRS), and survival. Secondary safety outcome measures were frequency of adverse events, neurological status, plasma concentration of talampanel, vital signs, routine laboratory tests, and electrocardiograms. Decline in muscle strength was 15% less in talampanel treated subjects, and decline in ALSFRS was 30% slower in talampanel treated subjects. Talampanel was safe in subjects with ALS. Mortality rates (8% talampanel, 5% placebo) and drug discontinuation rates (25% talampanel, 16% placebo) were similar in active treatment and placebo groups. Dizziness and somnolence occurred significantly more often in talampanel treated subjects. Although no efficacy measure reached statistical significance, there was a repeated trend toward slower decline in ALSFRS and isometric muscle strength in talampanel treated subjects. Talampanel was well tolerated in subjects with ALS. Although certain adverse events occurred more frequently in the active treatment group, the rate of subject drop-out after nine months did not exceed that seen in other trials. These findings provide strong support for a phase III trial to determine the efficacy of talampanel in subjects with ALS.}, }
@article {pmid19961263, year = {2010}, author = {Cudkowicz, ME and Katz, J and Moore, DH and O'Neill, G and Glass, JD and Mitsumoto, H and Appel, S and Ravina, B and Kieburtz, K and Shoulson, I and Kaufmann, P and Khan, J and Simpson, E and Shefner, J and Levin, B and Cwik, V and Schoenfeld, D and Aggarwal, S and McDermott, MP and Miller, RG}, title = {Toward more efficient clinical trials for amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {3}, pages = {259-265}, doi = {10.3109/17482960903358865}, pmid = {19961263}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Biomarkers ; Clinical Trials, Phase II as Topic/*methods ; Humans ; Neuroprotective Agents/pharmacology/*therapeutic use ; Research Design ; Riluzole/pharmacology/*therapeutic use ; Treatment Outcome ; }, abstract = {More than 30 phase II or III clinical trials have been carried out in amyotrophic lateral sclerosis (ALS). Only riluzole, however, has been shown to extend survival and/or time to tracheostomy. Many early ALS trials lacked solid pharmacodynamic and pharmacokinetic data for the treatment being tested, challenging the interpretation of the efficacy and pathway relevance. Understanding of the genetics and pathophysiology of ALS has improved considerably in the past decade, but biomarkers of disease activity remain lacking. A more efficient approach to early phase clinical trials is needed to accelerate the identification of useful agents for ALS. Here we summarize our current thinking about phase II design options and the potential benefits of a clinical trial network for phase II trials in ALS.}, }
@article {pmid19952312, year = {2009}, author = {Mitka, M}, title = {New guidelines suggest ways to optimize treatment, care of patients with ALS.}, journal = {JAMA}, volume = {302}, number = {21}, pages = {2303-2304}, doi = {10.1001/jama.2009.1710}, pmid = {19952312}, issn = {1538-3598}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; *Practice Guidelines as Topic ; }, }
@article {pmid19951254, year = {2010}, author = {Taha, MF}, title = {Cell based-gene delivery approaches for the treatment of spinal cord injury and neurodegenerative disorders.}, journal = {Current stem cell research &amp; therapy}, volume = {5}, number = {1}, pages = {23-36}, doi = {10.2174/157488810790442778}, pmid = {19951254}, issn = {2212-3946}, mesh = {Animals ; *Cell Transplantation ; Cytoprotection ; Disease Models, Animal ; *Genetic Therapy ; Genetic Vectors/genetics ; Humans ; Nerve Growth Factors/genetics/metabolism ; Neurodegenerative Diseases/pathology/physiopathology/*therapy ; Neurons/pathology ; Recovery of Function ; Retroviridae/genetics ; Spinal Cord Injuries/pathology/physiopathology/*therapy ; Stem Cells/*metabolism/pathology ; Transgenes/genetics ; }, abstract = {Cell based-gene delivery has provided an important therapeutic strategy for different disorders in the recent years. This strategy is based on the transplantation of genetically modified cells to express specific genes and to target the delivery of therapeutic factors, especially for the treatment of cancers and neurological, immunological, cardiovascular and heamatopoietic disorders. Although, preliminary reports are encouraging, and experimental studies indicate functionally and structurally improvements in the animal models of different disorders, universal application of this strategy for human diseases requires more evidence. There are a number of parameters that need to be evaluated, including the optimal cell source, the most effective gene/genes to be delivered, the optimal vector and method of gene delivery into the cells and the most efficient route for the delivery of genetically modified cells into the patient. Also, some obstacles have to be overcome, including the safety and usefulness of the approaches and the stability of the improvements. Here, recent studies concerning with the cell-based gene delivery for spinal cord injury and some neurodegenerative disorders such as amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease are briefly reviewed, and their exciting consequences are discussed.}, }
@article {pmid19943351, year = {2009}, author = {Mitrecić, D and Gajović, S and Pochet, R}, title = {Toward the treatments with neural stem cells: experiences from amyotrophic lateral sclerosis.}, journal = {Anatomical record (Hoboken, N.J. : 2007)}, volume = {292}, number = {12}, pages = {1962-1967}, doi = {10.1002/ar.20971}, pmid = {19943351}, issn = {1932-8494}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Cell Culture Techniques ; Cell Differentiation/physiology ; Cell Separation/methods ; Graft Survival/immunology ; Humans ; Mesoderm/cytology/physiology/transplantation ; Neurogenesis/physiology ; Rats ; Stem Cell Transplantation/*methods/trends ; Stem Cells/cytology/*physiology ; Transplantation, Autologous/methods ; }, abstract = {Common pathological features of neurodegenerative diseases are progressive dysfunction and neuronal death. In amyotrophic lateral sclerosis (ALS), motor neurons are selectively affected, leading to death because of paralysis. The main therapeutic goal in neurodegenerative diseases is to diminish neural dysfunction and to replace non-functional cells with the new ones. "Cell-oriented" treatment strategies include isolation of neural stem cells (NSC), their controlled differentiation, and cellular injections targeting the affected region. Beneficial effects of injected cells result from the combination of cell replacement and secretion of the growth factors. Here, we summarize the current state of isolation and differentiation of NSC, and emphasize the embryo tail bud as a particular region where neuroepithelium differentiates from undifferentiated mesenchymal cells over the course of normal development. The possibility to obtain cells from autologous mesenchyme capable of integrating into affected regions represents a major challenge whose achievement should circumvent the pitfall of the immune reaction against transplanted cells. We also present our own results: when intravenously injected in symptomatic ALS rats, NSC migrated to the motor cortex and continued to differentiate. Thus, we illustrate that the use of NSC in rodent models of ALS may represent a paradigm for other neurodegenerative diseases.}, }
@article {pmid19940183, year = {2009}, author = {Rudrabhatla, P and Albers, W and Pant, HC}, title = {Peptidyl-prolyl isomerase 1 regulates protein phosphatase 2A-mediated topographic phosphorylation of neurofilament proteins.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {29}, number = {47}, pages = {14869-14880}, pmid = {19940183}, issn = {1529-2401}, support = {//Intramural NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/enzymology/genetics/physiopathology ; Animals ; Axonal Transport/drug effects/physiology ; Cells, Cultured ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation, Enzymologic/*physiology ; Green Fluorescent Proteins/metabolism ; Humans ; MAP Kinase Signaling System/drug effects/physiology ; Middle Aged ; NIMA-Interacting Peptidylprolyl Isomerase ; Neurodegenerative Diseases/*enzymology/genetics/physiopathology ; Neurofilament Proteins/*metabolism ; Neurons/*enzymology/pathology ; Peptidylprolyl Isomerase/antagonists &amp; inhibitors/genetics/*metabolism ; Phosphorylation/drug effects ; Protein Phosphatase 2/antagonists &amp; inhibitors/*metabolism ; Protein Structure, Tertiary/physiology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {In normal neurons, neurofilament (NF) proteins are phosphorylated in the axonal compartment. However, in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), NF proteins are aberrantly hyperphosphorylated within the cell bodies. The aberrant hyperphosphorylation of NF accumulations found in neurodegeneration could be attributable to either deregulation of proline-directed Ser/Thr kinase(s) activity or downregulation of protein phosphatase(s) activity. In this study, we found that protein phosphatase 2A (PP2A) expression is high in neuronal cell bodies and that inhibition of PP2A activity by okadaic acid (OA), microcystin LR (mLR), or fostriecin (Fos) leads to perikaryal hyperphosphorylation of NF. Peptidyl-prolyl isomerase Pin1 inhibits the dephosphorylation of NF by PP2A in vitro. In cortical neurons, Pin1 modulates the topographic phosphorylation of the proline-directed Ser/Thr residues within the tail domain of NF proteins by inhibiting the dephosphorylation by PP2A. Inhibition of Pin1 inhibits OA-induced aberrant perikaryal phosphorylation of NF. Treatment of cortical neurons with OA or Fos prevents the general anterograde transport of transfected green fluorescent protein-high-molecular-mass (NF-H) into axons caused by hyperphosphorylation of NF-H, and inhibition of Pin1 rescues this effect. Furthermore, inhibition of Pin1 inhibits the OA- or Fos-induced neuronal apoptosis. We show that OA-induced hyperphosphorylation of NF is a consequence of dephosphorylation of NF and is independent of c-Jun N-terminal protein kinase, extracellular signal-regulated kinase, and cyclin-dependent kinase-5 pathways. This study highlights a novel signaling role of PP2A by Pin1 and implicates Pin1 as a therapeutic target to reduce aberrant phosphorylation of NF proteins in neurodegenerative disorders such as AD, PD, and ALS.}, }
@article {pmid19938902, year = {2009}, author = {Lanka, V and Wieland, S and Barber, J and Cudkowicz, M}, title = {Arimoclomol: a potential therapy under development for ALS.}, journal = {Expert opinion on investigational drugs}, volume = {18}, number = {12}, pages = {1907-1918}, doi = {10.1517/13543780903357486}, pmid = {19938902}, issn = {1744-7658}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Clinical Trials as Topic ; Cytoprotection/drug effects ; Drug Approval ; Drug Evaluation, Preclinical ; Heat-Shock Proteins/biosynthesis/drug effects ; Humans ; Hydroxylamines/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use ; }, abstract = {Arimoclomol, an amplifier of heat shock protein expression involved in cellular stress response, has emerged as a potential therapeutic candidate in amyotrophic lateral sclerosis (ALS) in recent years. Treatment with arimoclomol was reported to improve survival and muscle function in a mouse model of motor neuron disease. Several single- and multiple-dose safety studies have been completed in healthy control subjects. A 3-month Phase IIa study in people with ALS demonstrated safety at dosages up to 300 mg/day and another study is currently recruiting participants with familial ALS caused by mutations in the superoxide dismutase gene. We review the rationale for testing arimoclomol in sporadic and familial ALS in the context of available safety and pharmacokinetic data. Published and unpublished literature relative to the drug in the past two decades is discussed. The current review attempts to bring together our existing understanding of the actions of arimoclomol with the disease profile of ALS. The pharmacological profile of arimoclomol and the available preclinical data make it a promising therapeutic possibility in ALS.}, }
@article {pmid19935406, year = {2010}, author = {Parry, GJ and Rodrigues, CM and Aranha, MM and Hilbert, SJ and Davey, C and Kelkar, P and Low, WC and Steer, CJ}, title = {Safety, tolerability, and cerebrospinal fluid penetration of ursodeoxycholic Acid in patients with amyotrophic lateral sclerosis.}, journal = {Clinical neuropharmacology}, volume = {33}, number = {1}, pages = {17-21}, doi = {10.1097/WNF.0b013e3181c47569}, pmid = {19935406}, issn = {1537-162X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/blood/*cerebrospinal fluid/*drug therapy ; Analysis of Variance ; Bile Acids and Salts/blood/cerebrospinal fluid ; Blood-Brain Barrier/drug effects ; Cholagogues and Choleretics/adverse effects/blood/*cerebrospinal fluid/pharmacology/*therapeutic use ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Tolerance ; Female ; Humans ; Male ; Middle Aged ; Time Factors ; Treatment Outcome ; Ursodeoxycholic Acid/adverse effects/blood/*cerebrospinal fluid/pharmacology/*therapeutic use ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis is a progressive degenerative disease, which typically leads to death in 3 to 5 years. Neuronal cell death offers a potential target for therapeutic intervention. Ursodeoxycholic acid is a cytoprotective, endogenous bile acid that has been shown to be neuroprotective in experimental Huntington and Alzheimer diseases, retinal degeneration, and ischemic and hemorrhagic stroke. The objective of this research was to study the safety and the tolerability of ursodeoxycholic acid in amyotrophic lateral sclerosis and document effective and dose-dependent cerebrospinal fluid penetration.<br><br>METHODS: Eighteen patients were randomly assigned to receive ursodeoxycholic acid at doses of 15, 30, and 50 mg/kg of body weight per day. Serum and cerebrospinal fluid were obtained for analysis after 4 weeks of treatment. Treatment-emergent clinical and laboratory events were monitored weekly.<br><br>RESULTS: Our data indicated that ursodeoxycholic acid is well tolerated by all subjects at all doses. We also showed that ursodeoxycholic acid is well absorbed after oral administration and crosses the blood-brain barrier in a dose-dependent manner.<br><br>CONCLUSIONS: These results show excellent safety and tolerability of ursodeoxycholic acid. The drug penetrates the cerebrospinal fluid in a dose-dependent manner. A large, placebo-controlled clinical trial is needed to assess the efficacy of ursodeoxycholic acid in treating amyotrophic lateral sclerosis.}, }
@article {pmid19932742, year = {2010}, author = {Calderó, J and Brunet, N and Tarabal, O and Piedrafita, L and Hereu, M and Ayala, V and Esquerda, JE}, title = {Lithium prevents excitotoxic cell death of motoneurons in organotypic slice cultures of spinal cord.}, journal = {Neuroscience}, volume = {165}, number = {4}, pages = {1353-1369}, doi = {10.1016/j.neuroscience.2009.11.034}, pmid = {19932742}, issn = {1873-7544}, mesh = {Animals ; Apoptosis/drug effects ; Autophagy/drug effects ; Calcium/metabolism ; Cell Death/drug effects ; Chick Embryo ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Excitatory Amino Acid Agonists/toxicity ; Glycogen Synthase Kinase 3/antagonists &amp; inhibitors/metabolism ; Glycogen Synthase Kinase 3 beta ; In Vitro Techniques ; Kainic Acid/toxicity ; Lithium/administration &amp; dosage/*pharmacology ; Motor Neurons/*drug effects/physiology/ultrastructure ; Neuroprotective Agents/administration &amp; dosage/*pharmacology ; Riluzole/administration &amp; dosage/pharmacology ; Signal Transduction/drug effects ; Spinal Cord/*drug effects/physiology/ultrastructure ; }, abstract = {Several studies have reported the neuroprotective effects of lithium (Li) suggesting its potential in the treatment of neurological disorders, among of them amyotrophic lateral sclerosis (ALS). Although the cause of motoneuron (MN) death in ALS remains unknown, there is evidence that glutamate-mediated excitotoxicity plays an important role. In the present study we used an organotypic culture system of chick embryo spinal cord to explore the presumptive neuroprotective effects of Li against kainate-induced excitotoxic MN death. We found that chronic treatment with Li prevented excitotoxic MN loss in a dose dependent manner and that this effect was mediated by the inhibition of glycogen synthase kinase-3beta (GSK-3beta) signaling pathway. This neuroprotective effect of Li was potentiated by a combined treatment with riluzole. Nevertheless, MNs rescued by Li displayed structural changes including accumulation of neurofilaments, disruption of the rough endoplasmic reticulum and free ribosome loss, and accumulation of large dense core vesicles and autophagic vacuoles. Accompanying these changes there was an increase in immunostaining for (a) phosphorylated neurofilaments, (b) calcitonin gene-related peptide (CGRP) and (c) the autophagic marker LC3. Chronic Li treatment also resulted in a reduction in the excitotoxin-induced rise in intracellular Ca(2+) in MNs. In contrast to the neuroprotection against excitotoxicity, Li was not able to prevent normal programmed (apoptotic) MN death in the chick embryo when chronically administered in ovo. In conclusion, these results show that although Li is able to prevent excitotoxic MN death by targeting GSK-3beta, this neuroprotective effect is associated with conspicuous cytopathological changes.}, }
@article {pmid19929745, year = {2010}, author = {Gilio, F and Iacovelli, E and Frasca, V and Gabriele, M and Giacomelli, E and Picchiori, F and Soldo, P and Cipriani, AM and Ruoppolo, G and Inghilleri, M}, title = {Botulinum toxin type A for the treatment of sialorrhoea in amyotrophic lateral sclerosis: a clinical and neurophysiological study.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {4}, pages = {359-363}, doi = {10.3109/17482960903264998}, pmid = {19929745}, issn = {1471-180X}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/complications/drug therapy ; Botulinum Toxins, Type A/pharmacology/*therapeutic use ; Case-Control Studies ; Dose-Response Relationship, Drug ; Electric Stimulation/methods ; Electromyography/methods ; Evoked Potentials, Motor/*drug effects ; Female ; Humans ; Male ; Middle Aged ; Muscle, Skeletal/*physiopathology ; Neuromuscular Agents/pharmacology/*therapeutic use ; Pain Measurement ; Parotid Gland/drug effects/physiology ; Prospective Studies ; Sialorrhea/*drug therapy/etiology ; }, abstract = {Botulinum toxin type A (BoNT/A) has been proposed as an alternative treatment for sialorrhoea in patients with amyotrophic lateral sclerosis (ALS). In an open-label prospective study, BoNT/A was injected into the parotid glands bilaterally using anatomic landmarks in 26 ALS patients with bulbar symptoms. Two weeks after injection the severity of sialorrhoea and the related disability were evaluated subjectively and objectively. A group of healthy subjects acted as controls for saliva production. Patients also underwent electrophysiological tests to evaluate possible toxin effects in the nearby non-injected muscles by comparing the amplitude of compound motor action potentials (cMAPs) elicited by electrical stimulation and recorded from the orbicularis oculi and masseter muscles. After BoNT/A injections, of the 26 patients treated, 23 reported that the severity of sialorrhoea improved and the disabling symptoms diminished. Cotton roll weight also decreased after BoNT/A injection, suggesting a reduction in saliva production. Two patients complained of dry mouth. BoNT/A injection left the cMAP amplitude unchanged, suggesting that botulinum toxin does not significantly affect the non-injected facial and masticatory muscles. In conclusion, intraparotid anatomically-guided BoNT/A injection is an effective, easy, and safe treatment for sialorrhoea in patients with bulbar symptoms related to ALS.}, }
@article {pmid19926674, year = {2010}, author = {de Paiva, E and Giannoni, RA and Velasco, AF and Brito, RR and Dovales, AC and de Sá, LV and da Rosa, LA}, title = {Radiometric survey of teletherapy treatment rooms in Brazil.}, journal = {Radiation protection dosimetry}, volume = {138}, number = {4}, pages = {402-406}, doi = {10.1093/rpd/ncp264}, pmid = {19926674}, issn = {1742-3406}, mesh = {Algorithms ; Brazil ; Cesium Radioisotopes ; Health Surveys ; Humans ; Neutrons ; Occupational Exposure ; *Particle Accelerators ; Radiation Dosage ; Radiation Injuries/*prevention &amp; control ; *Radiation Monitoring ; *Radiation Protection ; Radiology Department, Hospital/*standards ; *Radiotherapy, High-Energy ; }, abstract = {The Brazilian national regulatory authority, National Commission of Nuclear Energy, requires that dose rates in the vicinity of teletherapy treatment rooms do not exceed the permissible limits for workers as well as members of the public, depending on the place considered. At the end of 2005, the Brazilian national regulatory authority reduced the permissible dose limit for controlled areas from 1000 to 400 microSv week(-1). Therefore, the aim of this work is to verify the adequacy of structural shielding to this new limit for telecobalt units that had their sources changed and clinic linear accelerators (ALs) installed before the end of 2005. Considering the ALs, measurements of dose rates in controlled areas did not exceed the new permissible limit, excepting for a single case. In the case of (60)Co units, a similar situation is observed for controlled areas, although several non-conformities to the limit of uncontrolled area could be observed.}, }
@article {pmid19922142, year = {2009}, author = {Garvey, CM and Boylan, KB and Salassa, JR and Kennelly, KD}, title = {Total laryngectomy in patients with advanced bulbar symptoms of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {5-6}, pages = {470-475}, doi = {10.3109/17482960802578373}, pmid = {19922142}, issn = {1471-180X}, mesh = {Adult ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/surgery ; Female ; Humans ; *Laryngectomy ; Male ; Middle Aged ; Retrospective Studies ; Treatment Outcome ; Young Adult ; }, abstract = {Our objectives were to 1) increase awareness of total laryngectomy (TL) as a treatment for complications of bulbar weakness in patients with amyotrophic lateral sclerosis (ALS) and outline specific surgical indications; 2) educate physicians about the surgical procedure, peri-operative course and benefits from having a TL; and 3) retrospectively review the clinical course of Mayo Clinic-Florida patients with ALS who had a TL. The method used was a retrospective review of patients recommended to undergo TL for advanced bulbar symptoms related to ALS at the Mayo Clinic in Jacksonville, Florida. Between January 1999 and September 2008, 15 patients with severe bulbar symptoms associated with ALS were recommended to undergo TL. Only five patients opted for the surgery. All patients were aphonic at time of surgery with a multitude of bulbar symptoms. Average surgical time was 114 min (range 87-162 min). No intraoperative complications were reported. All patients and caregivers were pleased with the results of the TL. In conclusion, TL is a relatively safe, quick and uncomplicated surgical procedure that should be considered earlier and more frequently in the treatment plan of patients with advanced bulbar symptoms due to ALS. We recommend considering TL in patients with aspiration problems who are unable to phonate intelligibly.}, }
@article {pmid19922137, year = {2009}, author = {Corcia, P and Camu, W and Praline, J and Gordon, PH and Vourch, P and Andres, C}, title = {The importance of the SMN genes in the genetics of sporadic ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {5-6}, pages = {436-440}, doi = {10.3109/17482960902759162}, pmid = {19922137}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/physiopathology/therapy ; Gene Dosage ; Genetic Therapy ; Humans ; MEDLINE ; Muscular Atrophy, Spinal/genetics ; Review Literature as Topic ; Survival of Motor Neuron 1 Protein/*genetics/metabolism ; Survival of Motor Neuron 2 Protein/*genetics/metabolism ; }, abstract = {The human genome contains two SMN (survival motor neuron) genes: SMN1, the telomeric gene whose homozygous deletion causes spinal muscular atrophy (SMA), and SMN2, the centromeric version whose copy number modulates the phenotype of SMA. We performed a Medline search and reviewed all of the publications that focus on SMN1 and SMN2 in amyotrophic lateral sclerosis (ALS) to analyse whether these genes also act as risk factors or phenotypic modulators in ALS. While homozygous deletion of SMN1 was not associated in ALS, abnormal SMN1 copy numbers significantly increased the risk of ALS. The role of the SMN2 gene in ALS needs further clarification. The existence of abnormal SMN1 copy numbers in ALS provides additional evidence that gene copy number variants may contribute to neurodegeneration and might open new approaches to treatment.}, }
@article {pmid19922135, year = {2009}, author = {Zhang, Y and Wang, L and Fu, Y and Song, H and Zhao, H and Deng, M and Zhang, J and Fan, D}, title = {Preliminary investigation of effect of granulocyte colony stimulating factor on amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {5-6}, pages = {430-431}, doi = {10.3109/17482960802588059}, pmid = {19922135}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Granulocyte Colony-Stimulating Factor/*therapeutic use ; Humans ; Muscle, Skeletal/physiopathology ; Treatment Outcome ; }, abstract = {We investigated the safety and efficacy of the granulocyte colony stimulating factor (G-CSF) in 13 patients with amyotrophic lateral sclerosis (ALS). Five-day administration of 2 microg/kg once a day was followed by a six-month observation period. The primary and secondary endpoints were the changes of ALS functional rating scale (ALSFRS) and the compound muscle action potential (CMAP) amplitude, respectively. We found that the declines of ALSFRS and CMAP amplitude after G-CSF administration were significantly less than those measured prior to the treatment. The results suggest G-CSF is safe in ALS patients, and may affect the rate of motor decline.}, }
@article {pmid19922132, year = {2009}, author = {Lauria, G and Campanella, A and Filippini, G and Martini, A and Penza, P and Maggi, L and Antozzi, C and Ciano, C and Beretta, P and Caldiroli, D and Ghelma, F and Ferrara, G and Ghezzi, P and Mantegazza, R}, title = {Erythropoietin in amyotrophic lateral sclerosis: a pilot, randomized, double-blind, placebo-controlled study of safety and tolerability.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {5-6}, pages = {410-415}, doi = {10.3109/17482960902995246}, pmid = {19922132}, issn = {1471-180X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Double-Blind Method ; Erythropoietin/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Patient Selection ; Placebos/*therapeutic use ; Recombinant Proteins ; Survival Rate ; Treatment Outcome ; }, abstract = {Preclinical studies demonstrated that erythropoietin is neuroprotective in different models of peripheral and central nervous system diseases. We investigated safety and tolerability of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS). We performed a phase II double-blind, randomized, placebo-controlled study. After screening, 23 patients were randomly assigned to rhEPO or placebo arm. Patients were examined during a six-month lead-in period, and then they received fortnightly either 40,000 units of rhEPO or placebo for 24 months. Primary outcomes were adverse events, safety, and death or tracheotomy. Treatment was safe and well tolerated. One patient in the rhEPO arm dropped out for a superficial phlebitis. Median values of haematocrit, haemoglobin, red cells, and reticulocytes were non-significantly higher in rhEPO than placebo arm. Haemoglobin did not increase >1 g/dl between subsequent doses. Anti-rhEPO antibodies were not detected. Survival and slope of ALSFRS-R curves did not significantly differ between treatment groups. RhEPO treatment was safe and well tolerated in ALS patients. Our results suggest that larger studies are warranted to confirm safety of treatment and to investigate different dose schedule and efficacy.}, }
@article {pmid19922130, year = {2009}, author = {Stommel, EW and Cohen, JA and Fadul, CE and Cogbill, CH and Graber, DJ and Kingman, L and Mackenzie, T and Channon Smith, JY and Harris, BT}, title = {Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: a phase II open label clinical trial.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {5-6}, pages = {393-404}, pmid = {19922130}, issn = {1471-180X}, support = {P30 CA023108/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/blood/*drug therapy/immunology/pathology ; Animals ; Cytokines/blood ; Disease Models, Animal ; Disease Progression ; Dose-Response Relationship, Drug ; Female ; Humans ; Immunosuppressive Agents/*therapeutic use ; Male ; Mice ; Mice, Transgenic ; Middle Aged ; Quality of Life ; Surveys and Questionnaires ; Thalidomide/*therapeutic use ; Treatment Outcome ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/immunology ; }, abstract = {Neuroinflammation through the cytokine, tumor necrosis factor-alpha (TNF-alpha) is thought to play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We conducted a preliminary phase II trial of thalidomide, which reduces levels of TNF-alpha pre-transcriptionally and post-transcriptionally in vivo and has been shown to prolong disease duration and extend the lifespan of transgenic animal models of ALS. Patients who met diagnostic criteria for ALS received thalidomide at escalating doses to a target dose of 400 mg/day. The primary endpoints in the trial were the ALS Functional Rating Scale (ALSFRS) and pulmonary function testing (PFT) curves after nine months of thalidomide treatment that were compared to historical controls. Secondary endpoints were: survival stratified for newly diagnosed and progressive disease, toxicity, quality of life, and serum cytokine measurements. Twenty-three patients were enrolled, but only 18 were evaluable for the primary outcome. There was no improvement in the ALSFRS or PFT compared to historical controls. Thalidomide had several side-effects in our ALS patients. There was no significant shift in cytokine profile after treatment compared to baseline. In conclusion, treatment of ALS with the TNF-alpha inhibitor, thalidomide, does not appear to effectively modulate disease progression and can cause adverse effects.}, }
@article {pmid19922129, year = {2009}, author = {Cheah, BC and Boland, RA and Brodaty, NE and Zoing, MC and Jeffery, SE and McKenzie, DK and Kiernan, MC}, title = {INSPIRATIonAL--INSPIRAtory muscle training in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {5-6}, pages = {384-392}, doi = {10.3109/17482960903082218}, pmid = {19922129}, issn = {1471-180X}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Female ; Forced Expiratory Volume ; Humans ; Male ; Middle Aged ; Muscle Strength/*physiology ; *Respiration ; Respiratory Paralysis/physiopathology ; Respiratory Therapy/instrumentation/*methods ; Treatment Outcome ; Vital Capacity/physiology ; Young Adult ; }, abstract = {Respiratory impairment, due to respiratory muscle weakness, is a major cause of morbidity and mortality in patients with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). Threshold loading may strengthen the inspiratory muscles and thereby improve patient prognosis. A phase II, double-blind, randomized-controlled trial was undertaken to determine whether a 12-week inspiratory muscle training programme attenuated the decline in respiratory function and inspiratory muscle strength in patients with ALS/MND. Nine patients were randomized to inspiratory muscle training and 10 to sham training. Primary endpoints were respiratory function (forced vital capacity, vital capacity), lung volumes and inspiratory muscle strength. Patients were assessed before, during and immediately after a 12-week training period, and at eight weeks follow-up. While improvements in inspiratory muscle strength were observed in both treatment arms, there was a non-significant increase in maximum inspiratory pressure of 6.1% in the experimental group compared to controls (standard error of mean, 6.93%; 95% confidence interval -8.58 -20.79; p=0.39). The gains in inspiratory muscle strength were partially reversed during a period of training cessation. In conclusion, inspiratory muscle training may potentially strengthen the inspiratory muscles and slow the decline in respiratory function in patients with ALS/MND.}, }
@article {pmid19922128, year = {2009}, author = {Meininger, V and Drory, VE and Leigh, PN and Ludolph, A and Robberecht, W and Silani, V}, title = {Glatiramer acetate has no impact on disease progression in ALS at 40 mg/day: a double- blind, randomized, multicentre, placebo-controlled trial.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {5-6}, pages = {378-383}, doi = {10.3109/17482960902803432}, pmid = {19922128}, issn = {1471-180X}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology/*physiopathology ; Animals ; *Disease Progression ; Double-Blind Method ; Female ; Glatiramer Acetate ; Humans ; Immunosuppressive Agents/*therapeutic use ; Male ; Middle Aged ; Outcome Assessment, Health Care ; Peptides/*therapeutic use ; Placebos/*therapeutic use ; Treatment Outcome ; Young Adult ; }, abstract = {Our objective was to assess the efficacy and safety of 40 mg/day glatiramer acetate (GA) in patients with ALS. We conducted a double-blind, randomized, placebo-controlled, multicentre trial. Three hundred and sixty-six patients with definite, probable or probable laboratory supported ALS and a slow vital capacity > or = 70% were randomly assigned to treatment with placebo or 40 mg GA daily. The primary intention-to-treat analysis was the comparison between the two treated groups of the rates of deterioration on the ALSFRSR scale. The secondary outcome measure was time to death, tracheostomy or permanent assisted ventilation. Safety and tolerability of GA were evaluated. After 52 weeks of follow-up, the slope of the ALSFRSR score was comparable in the both groups (placebo, -1.00+/-0.06/month; GA, -1.05+/-0.06/month; p=0.48). The secondary endpoint was non-significant with 159 patients (87.4%) alive in the placebo group and 162 patients (88.1%) in the GA group (log rank, p=0.75). The most common events were the injection site reactions (76.1% in the GA group, 14.8% in the placebo group), comparable to the known profile of 20 mg GA. In conclusion, GA at a dose of 40 mg/day did not show any beneficial effect in ALS patients, and safety and tolerability of GA were good in this population.}, }
@article {pmid19922118, year = {2009}, author = {Chiò, A and Logroscino, G and Hardiman, O and Swingler, R and Mitchell, D and Beghi, E and Traynor, BG and , }, title = {Prognostic factors in ALS: A critical review.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {5-6}, pages = {310-323}, pmid = {19922118}, issn = {1471-180X}, support = {ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; ZIA AG000933-05/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*diagnosis/pathology/physiopathology/psychology ; Biomarkers/metabolism ; *Clinical Trials as Topic/classification ; Disease Progression ; Humans ; Nutritional Status ; Prognosis ; Prospective Studies ; Respiration ; Retrospective Studies ; Severity of Illness Index ; Survival Rate ; }, abstract = {We have performed a systematic review to summarize current knowledge concerning factors related to survival in ALS and to evaluate the implications of these data for clinical trials design. The median survival time from onset to death ranges from 20 to 48 months, but 10-20% of ALS patients have a survival longer than 10 years. Older age and bulbar onset are consistently reported to have a worse outcome. There are conflicting data on gender, diagnostic delay and El Escorial criteria. The rate of symptom progression was revealed to be an independent prognostic factor. Psychosocial factors, FTD, nutritional status, and respiratory function are also related to ALS outcome. The effect of enteral nutrition on survival is still unclear, while NIPPV has been found to improve survival. There are no well established biological markers of progression, although some are likely to emerge in the near future. These findings have relevant implications for the design of future trials. Randomization, besides the type of onset, should take into account age, respiratory status at entry, and a measure of disease progression pre-entry. Alternative trial designs can include the use of natural history controls, the so-called minimization method for treatment allocation, and the futility approach.}, }
@article {pmid19921501, year = {2010}, author = {Moreno-Igoa, M and Calvo, AC and Penas, C and Manzano, R and Oliván, S and Muñoz, MJ and Mancuso, R and Zaragoza, P and Aguilera, J and Navarro, X and Osta Pinzolas, R}, title = {Fragment C of tetanus toxin, more than a carrier. Novel perspectives in non-viral ALS gene therapy.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {88}, number = {3}, pages = {297-308}, pmid = {19921501}, issn = {1432-1440}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; Apoptosis ; Disease Models, Animal ; Genetic Therapy/*methods ; Humans ; Mice ; Mice, Transgenic ; Peptide Fragments/*genetics ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Tetanus Toxin/*genetics ; }, abstract = {The non-toxic carboxy-terminal fragment of tetanus toxin heavy chain (TTC) has been implicated in the activation of cascades responsible for trophic actions and neuroprotection by inhibition of apoptosis. Previous in vitro studies have described signalling pathways that underlie the administration of TTC to neurons. We investigated whether these properties were maintained in a mouse model of neurodegenerative disease. Naked DNA encoding for TTC was injected intramuscularly and neuromuscular function and clinical behaviour were monitored until endstage in the transgenic SOD1G93A mouse model that expresses a mutant variant of human superoxide dismutase 1 (SOD1). Our results indicate that TTC treatment ameliorated the decline of hindlimb muscle innervation, significantly delayed the onset of symptoms and functional deficits, improved spinal motor neuron survival, and prolonged lifespan. Furthermore, we found that caspase-1 and caspase-3 proapoptotic genes were down-regulated in the spinal cord of treated mice. Western blot analysis showed that the active form of caspase-3 was also down-regulated after TTC treatment and survival signals, such as the significant phosphorylation of serine/threonine protein kinase Akt, were also detected. These results suggest that fragment C of tetanus toxin, TTC, provides a potential therapy for neurodegenerative diseases.}, }
@article {pmid19919605, year = {2010}, author = {Giordana, MT and Grifoni, S and Votta, B and Magistrello, M and Vercellino, M and Pellerino, A and Navone, R and Valentini, C and Calvo, A and Chiò, A}, title = {Neuropathology of olfactory ensheathing cell transplantation into the brain of two amyotrophic lateral sclerosis (ALS) patients.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {20}, number = {4}, pages = {730-737}, pmid = {19919605}, issn = {1750-3639}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/*surgery ; Brain/*pathology ; Cell Transplantation/methods/*pathology ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Neuroglia/pathology/*transplantation ; Olfactory Bulb/*cytology/transplantation ; Treatment Outcome ; }, abstract = {Although a large number of amyotrophic lateral sclerosis (ALS) patients have undergone transplantation procedures with olfactory ensheathing cells (OECs) in the Bejing Hospital, to our knowledge, no post-mortem neuropathologic analyses have been performed. We examined the post-mortem brain of two Italian patients affected by ALS who underwent cellular transplantation in Beijing with their consent. Our aim was to assess the events following the graft procedure to possibly support the rationale of the treatment strategy. The neuropathologic findings were analyzed on the basis of the limited awareness of the experimental conditions and discussed in relation to the safety, efficacy and long-term outcome of the transplanted cells. Islands of quiescent, undifferentiated cells within the delivery track persisting for up to 12 months-24 months were found. Prominent glial and inflammatory reaction around the delivery track strongly supports the encasement of the graft. Evidence of axonal regeneration, neuronal differentiation and myelination was not seen. The surgical procedure of implantation was not compatible with a neurotrophic effect. The OEC transplantation did not modify the neuropathology of ALS in the two patients. In conclusion, the present neuropathologic analysis does not support a beneficial effect of fetal OEC implantation into the frontal lobes of ALS patients.}, }
@article {pmid19913979, year = {2010}, author = {Saybolt, MD and Alter, SM and Dos Santos, F and Calello, DP and Rynn, KO and Nelson, DA and Merlin, MA}, title = {Naloxone in cardiac arrest with suspected opioid overdoses.}, journal = {Resuscitation}, volume = {81}, number = {1}, pages = {42-46}, doi = {10.1016/j.resuscitation.2009.09.016}, pmid = {19913979}, issn = {1873-1570}, mesh = {Adult ; Aged ; Confidence Intervals ; Drug Overdose ; Electrocardiography ; Emergency Medical Services/organization &amp; administration ; Female ; Heart Arrest/*chemically induced/*drug therapy ; Humans ; Male ; Middle Aged ; Naloxone/*therapeutic use ; Narcotic Antagonists/*therapeutic use ; Narcotics/*poisoning ; Retrospective Studies ; Treatment Outcome ; }, abstract = {INTRODUCTION: Naloxone's use in cardiac arrest has been of recent interest, stimulated by conflicting results in both human case reports and animal studies demonstrating antiarrhythmic and positive ionotropic effects. We hypothesized that naloxone administration during cardiac arrest, in suspected opioid overdosed patients, is associated with a change in cardiac rhythm.<br><br>METHODS: From a database of 32,544 advanced life support (ALS) emergency medical dispatches between January 2003 and December 2007, a retrospective chart review was completed of patients receiving naloxone in cardiac arrest. Forty-two patients in non-traumatic cardiac arrest were identified. Each patient received naloxone because of suspicion by a paramedic of acute opioid use.<br><br>RESULTS: Fifteen of the 36 (42%) (95% confidence interval [CI]: 26-58) patients in cardiac arrest who received naloxone in the pre-hospital setting had an improvement in electrocardiogram (EKG) rhythm. Of the participants who responded to naloxone, 47% (95% CI: 21-72) (19% [95% CI: 7-32] of all study subjects) demonstrated EKG rhythm changes immediately following the administration of naloxone.<br><br>DISCUSSION: Although we cannot support the routine use of naloxone during cardiac arrest, we recommend its administration with any suspicion of opioid use. Due to low rates of return of spontaneous circulation and survival during cardiac arrest, any potential intervention leading to rhythm improvement is a reasonable treatment modality.}, }
@article {pmid19901163, year = {2009}, author = {van der Graaff, MM and Grolman, W and Westermann, EJ and Boogaardt, HC and Koelman, H and van der Kooi, AJ and Tijssen, MA and de Visser, M}, title = {Vocal cord dysfunction in amyotrophic lateral sclerosis: four cases and a review of the literature.}, journal = {Archives of neurology}, volume = {66}, number = {11}, pages = {1329-1333}, doi = {10.1001/archneurol.2009.250}, pmid = {19901163}, issn = {1538-3687}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/*pathology/physiopathology ; Dyspnea/etiology ; Electromyography ; Female ; Humans ; Male ; Middle Aged ; Vocal Cords/*pathology ; }, abstract = {We describe 4 patients with amyotrophic lateral sclerosis (ALS) and glottic narrowing due to vocal cord dysfunction, and review the literature found using the following search terms: amyotrophic lateral sclerosis, motor neuron disease, stridor, laryngospasm, vocal cord abductor paresis, and hoarseness. Neurological literature rarely reports vocal cord dysfunction in ALS, in contrast to otolaryngology literature (4%-30% of patients with ALS). Both infranuclear and supranuclear mechanisms may play a role. Vocal cord dysfunction can occur at any stage of disease and may account for sudden death in ALS. Treatment of severe cases includes acute airway management and tracheotomy.}, }
@article {pmid19874893, year = {2010}, author = {Ferrucci, M and Spalloni, A and Bartalucci, A and Cantafora, E and Fulceri, F and Nutini, M and Longone, P and Paparelli, A and Fornai, F}, title = {A systematic study of brainstem motor nuclei in a mouse model of ALS, the effects of lithium.}, journal = {Neurobiology of disease}, volume = {37}, number = {2}, pages = {370-383}, doi = {10.1016/j.nbd.2009.10.017}, pmid = {19874893}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology/physiopathology ; Animals ; Axons/drug effects/pathology ; Biomarkers/analysis/metabolism ; Brain Mapping/methods ; Brain Stem/*drug effects/pathology/physiopathology ; Choline O-Acetyltransferase/analysis/metabolism ; Cranial Nerves/*drug effects/pathology/physiopathology ; Cytoprotection/drug effects/physiology ; Disease Models, Animal ; Drug Administration Schedule ; Facial Nerve/drug effects/pathology/physiopathology ; Humans ; Hypoglossal Nerve/drug effects/pathology/physiopathology ; Lithium/*pharmacology/therapeutic use ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/*metabolism/pathology ; Nerve Degeneration/drug therapy/physiopathology/prevention &amp; control ; Neuroprotective Agents/*pharmacology/therapeutic use ; Treatment Outcome ; Trigeminal Nerve/drug effects/pathology/physiopathology ; Vagus Nerve/drug effects/pathology/physiopathology ; }, abstract = {Transgenic mice expressing the human superoxide dismutase 1 (SOD-1) mutant at position 93 (G93A) develop a phenotype resembling amyotrophic lateral sclerosis (ALS). In fact, G93A mice develop progressive motor deficits which finally lead to motor palsy and death. This is due to the progressive degeneration of motor neurons in the ventral horn of the spinal cord. Although a similar loss is reported for specific cranial motor nuclei, only a few studies so far investigated degeneration in a few brainstem nuclei. We recently reported that chronic lithium administration delays onset and duration of the disease, while reducing degeneration of spinal motor neuron. In the present study, we extended this investigation to all somatic motor nuclei of the brain stem in the G93A mice and we evaluated whether analogous protective effects induced by lithium in the spinal cord were present at the brain stem level. We found that all motor but the oculomotor nuclei were markedly degenerated in G93A mice, and chronic treatment with lithium significantly attenuated neurodegeneration in the trigeminal, facial, ambiguus, and hypoglossal nuclei. Moreover, in the hypoglossal nucleus, we found that recurrent collaterals were markedly lost in G93A mice while they were rescued by chronic lithium administration.}, }
@article {pmid19874396, year = {2010}, author = {Witgert, M and Salamone, AR and Strutt, AM and Jawaid, A and Massman, PJ and Bradshaw, M and Mosnik, D and Appel, SH and Schulz, PE}, title = {Frontal-lobe mediated behavioral dysfunction in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {17}, number = {1}, pages = {103-110}, doi = {10.1111/j.1468-1331.2009.02801.x}, pmid = {19874396}, issn = {1468-1331}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*epidemiology/*psychology ; Cognition Disorders/*diagnosis/*epidemiology ; Comorbidity ; Decision Making/physiology ; Disability Evaluation ; Female ; Frontal Lobe/*physiopathology ; Humans ; Male ; Mental Disorders/diagnosis/epidemiology ; Middle Aged ; Neuropsychological Tests ; Predictive Value of Tests ; Prevalence ; Severity of Illness Index ; }, abstract = {BACKGROUND: Cognitive impairment secondary to frontal lobe atrophy exists in 40-60% of Amyotrophic Lateral Sclerosis (ALS) cases. We aimed to determine the prevalence of frontal-lobe mediated behavioral impairment in (ALS) and to ascertain its relationship to cognitive impairment.<br><br>METHODS: Two-hundred and twenty five patients diagnosed with sporadic ALS were evaluated for behavioral dysfunction using the Frontal Systems Behavior Scale (FrSBe), a validated measure used to examine frontal-lobe mediated behaviors, specifically apathy, executive dysfunction and disinhibition; a total behavior score is also provided. Additionally, a subset of patients also underwent a comprehensive neuropsychological evaluation.<br><br>RESULTS: Changes in the total FrSBe scores were observed in 24.4% of the patients and 39.6% of the patients had impairment in at least one behavioral domain with symptoms of Apathy being the most common (31.1%). Cognitively impaired ALS patients had worse total (P = 0.05) and apathy scores (P < 0.01); however, behavioral dysfunction was also present in 16% of the cognitively intact patients. Half of the behaviorally intact patients exhibited cognitive impairment. Significant correlations were observed for performance on certain neuropsychological tests (Animal fluency, Block Design, Logical Memory I and Verbal Series Attention Test) and severity of behavioral dysfunction on certain FrSBe sub scores.<br><br>CONCLUSIONS: Frontal-lobe mediated behavioral dysfunction appears to be common in ALS. Cognitively impaired ALS patients had greater behavioral dysfunction. Recognition of behavioral and cognitive dysfunction may assist health-care providers and care-givers recognize changes in decision-making capacity and treatment compliance of patients with ALS.}, }
@article {pmid19864454, year = {2009}, author = {Ester, WA and van Duyvenvoorde, HA and de Wit, CC and Broekman, AJ and Ruivenkamp, CA and Govaerts, LC and Wit, JM and Hokken-Koelega, AC and Losekoot, M}, title = {Two short children born small for gestational age with insulin-like growth factor 1 receptor haploinsufficiency illustrate the heterogeneity of its phenotype.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {94}, number = {12}, pages = {4717-4727}, doi = {10.1210/jc.2008-1502}, pmid = {19864454}, issn = {1945-7197}, mesh = {Adult ; Body Height/*genetics ; Child, Preschool ; Chromosome Deletion ; Chromosomes, Human, Pair 15 ; Cohort Studies ; DNA/genetics ; Female ; Fibroblasts/metabolism ; *Genetic Heterogeneity ; Growth/genetics ; Haplotypes ; Humans ; Infant ; Infant, Newborn ; Infant, Small for Gestational Age/*growth &amp; development ; Male ; Phenotype ; Polymorphism, Single Nucleotide ; Pregnancy ; Receptor, IGF Type 1/*deficiency/*genetics ; Signal Transduction/physiology ; Skin/cytology ; }, abstract = {CONTEXT: Small for gestational age (SGA)-born children comprise a heterogeneous group in which only few genetic causes have been identified.<br><br>OBJECTIVE: To determine copy number variations in 18 growth-related genes in 100 SGA children with persistent short stature.<br><br>METHODS: Copy number variations in 18 growth-related genes (SHOX, GH1, GHR, IGF1, IGF1R, IGF2, IGFBP1-6, NSD1, GRB10, STAT5B, ALS, SOCS2, and SOCS3) were determined by an "in house" multiplex ligation-dependent probe amplification kit. The deletions were further characterized by single-nucleotide polymorphism array analysis.<br><br>RESULTS: Two heterozygous de novo insulin-like growth factor 1 receptor (IGF1R) deletions were found: a deletion of the complete IGF1R gene (15q26.3, exons 1-21), including distally flanking sequences, and a deletion comprising exons 3-21, extending further into the telomeric region. In one case, serum IGF-I was low (-2.78 sd score), probably because of a coexisting growth hormone (GH) deficiency. Both children increased their height during GH treatment (1 mg/m(2) per day). Functional studies in skin fibroblast cultures demonstrated similar levels of IGF1R autophosphorylation and a reduced activation of protein kinase B/Akt upon a challenge with IGF-I in comparison with controls.<br><br>CONCLUSIONS: IGF1R haploinsufficiency was present in 2 of 100 short SGA children. GH therapy resulted in moderate catch-up growth in our patients. A review of the literature shows that small birth size, short stature, small head size, relatively high IGF-I levels, developmental delay, and micrognathia are the main predictors for an IGF1R deletion.}, }
@article {pmid19860657, year = {2009}, author = {Hester, ME and Foust, KD and Kaspar, RW and Kaspar, BK}, title = {AAV as a gene transfer vector for the treatment of neurological disorders: novel treatment thoughts for ALS.}, journal = {Current gene therapy}, volume = {9}, number = {5}, pages = {428-433}, doi = {10.2174/156652309789753383}, pmid = {19860657}, issn = {1875-5631}, support = {P20 RR015576/RR/NCRR NIH HHS/United States ; R01 NS064492/NS/NINDS NIH HHS/United States ; UL1 RR025755/RR/NCRR NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Blood-Brain Barrier ; Dependovirus/*genetics ; Gene Transfer Techniques ; *Genetic Therapy ; *Genetic Vectors ; Humans ; }, abstract = {Therapeutic delivery to the central nervous system has challenged scientists and clinicians due to the difficulty in delivering molecules and genes in an efficient manner across the blood brain barrier (BBB). This has particularly hampered efforts to deliver therapeutics to widely dispersed neurons that perish in diseases such as Amyotrophic Lateral Sclerosis (ALS), a disease affecting motor neurons throughout the brainstem and the entire spinal cord. Gene therapy has offered several potential routes to overcome the difficulties in delivering therapeutics to the brain and spinal cord. Adeno-associated viral vectors (AAV) have taken center stage for gene delivery to the central nervous system, given their ability to express genes in post mitotic cells for long periods with minimal to no toxicity. This review will focus on recent approaches to treat motor neuron disease, in particular ALS using AAV vectors.}, }
@article {pmid19860122, year = {2009}, author = {Margetić, P and Elabjer, E and Milosević, M and Skoro, I and Milanov, B and Stancić, M}, title = {Anterior neurodecompression of kyphotic spondylogenic myelopathy Ranawat grade III and posterior decompression of lordotic spine improve walking ability.}, journal = {Collegium antropologicum}, volume = {33}, number = {3}, pages = {899-905}, pmid = {19860122}, issn = {0350-6134}, mesh = {Aged ; Decompression, Surgical/*methods ; Female ; Humans ; Kyphosis/diagnostic imaging/physiopathology/*surgery ; Lordosis/diagnostic imaging/physiopathology/*surgery ; Male ; Middle Aged ; Radiography ; Spondylosis/diagnostic imaging/physiopathology/*surgery ; *Walking ; }, abstract = {Cervical spondylosis is common condition rarely associated with radiculomyelopathy which surgical treatment, according to meta-analysis, is not better than nonsurgical. Our hypothesis was that neurodecompression which type is chosen according to spinal alignment should result in better functional improvement comparing with nonsurgical treatment. Between January 1, 1998 and December 31, 2007 a total of 77 patients with spondylogenic myelopathy were selected for the study. The inclusion criteria were symptoms and signs of myelopathy Ranawat grade III. Exclusion criteria were amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). The curvature of the cervical spine was determined by Ishihara index. Anterior corpectomies and fusion was performed in the kyphotic spines, laminectomy with fusion in patients with neutral position, and open door laminoplasty in lordotic spines. Clinical improvement was assessed as differences between preoperative and 1-year follow up Nurick, modified Japanese Orthopedic Association (mJOA) myelopathy scales and walking test. Preoperative and postoperative transverse cord area and subarachnoid space were measured. Forty-four male and 31 female patients were surgically treated. Two patients with electrophysiological signs of ALS were excluded. Preoperative and postoperative mean +/- SD mJOA index was 9.15 +/- 1 and 13.01 +/- 1.4 (p < 0.001), Nurick grading scale 3.05 +/- 0.7 and 1.8 +/- 0.6 (p < 0.001), walking time (sec) 64.4 +/- 3.2 and 46.2 +/- 3.3 (p < 0.001), and number of steps 69.7 +/- 4.4 and 57.6 +/- 2.8 (p < 0.001) respectively. Preoperative and postoperative transverse cord area (mean +/- SD, mm2) was 46.7 +/- 5.4 and 60.2 +/- 2.6 (p < 0.001), and subarachnoid space 48.0 +/- 4.9 and 68.8 +/- 8.5 (p < 0.001) respectively. Our results showed that surgical treatment is beneficial for patients with spondylogenic myelopathy.}, }
@article {pmid19858352, year = {2009}, author = {Frost, J and Massagli, M}, title = {PatientsLikeMe the case for a data-centered patient community and how ALS patients use the community to inform treatment decisions and manage pulmonary health.}, journal = {Chronic respiratory disease}, volume = {6}, number = {4}, pages = {225-229}, doi = {10.1177/1479972309348655}, pmid = {19858352}, issn = {1479-9731}, mesh = {*Activities of Daily Living ; Amyotrophic Lateral Sclerosis/complications/*therapy ; Community Networks/*statistics &amp; numerical data ; *Decision Making, Organizational ; Humans ; Lung Diseases/etiology/*prevention &amp; control ; Outcome Assessment, Health Care/*methods ; Patient-Centered Care/*organization &amp; administration ; Quality of Life ; }, abstract = {What happens when patients go online to not only discuss health and daily living but to share detailed health data? PatientsLikeMe is an online platform where patients with life-altering conditions share structured information about symptoms, treatments, and outcomes, view individual and aggregated reports of these data, and discuss health and garner support on forums and through private messages. In this case study, we describe the components of this platform and how people with Amyotrophic lateral sclerosis have used the site to manage and improve pulmonary health. A qualitative analysis of forum content containing preset terms reveals patterns in use. As in other online communities, members of PatientsLikeMe offer one another support based on their own personal experience and advise each other on both medical issues and how to improve day-to-day life. Unique to this patient platform, members tailor questions and consults by referencing concrete data displayed for each patient member. PatientsLikeMe adds data into patient investigations on how to improve daily life and long term health outcomes.}, }
@article {pmid19852992, year = {2010}, author = {Cleren, C and Calingasan, NY and Starkov, A and Jacquard, C and Chen, J and Brouillet, E and Beal, MF}, title = {Promethazine protects against 3-nitropropionic acid-induced neurotoxicity.}, journal = {Neurochemistry international}, volume = {56}, number = {2}, pages = {208-212}, pmid = {19852992}, issn = {1872-9754}, support = {P01 AG014930/AG/NIA NIH HHS/United States ; R01 NS039258/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/chemically induced/*prevention &amp; control ; Animals ; Brain Ischemia/chemically induced/*prevention &amp; control ; Disease Models, Animal ; Huntington Disease/chemically induced/*prevention &amp; control ; Male ; Mice ; Neuroprotective Agents/*pharmacology ; Nitro Compounds/*toxicity ; Promethazine/*pharmacology ; Propionates/*toxicity ; Rats ; Rats, Inbred Lew ; Succinate Dehydrogenase/metabolism ; }, abstract = {Promethazine (PMZ), an FDA-approved antihistaminergic drug, was identified as a potentially neuroprotective compound in a NINDS screening program. It was shown to protect against ischemia in mice, to delay disease onset in a mouse model of amyotrophic lateral sclerosis and to inhibit Ca(2+)-induced mitochondrial permeability transition in rat liver mitochondria. We investigated whether PMZ could protect against the neurotoxic effects induced by 3-nitropropionic acid (3-NP), an inhibitor of the succinate dehydrogenase, used to model Huntington's disease (HD) in rats. Lewis rats receiving chronic subcutaneous infusion of 3-NP were treated with PMZ. The findings indicate that chronic PMZ treatment significantly reduced 3-NP-induced striatal lesion volume, loss of GABAergic neurons and number of apoptotic cells in the striatum. PMZ showed a strong neuroprotective effect against 3-NP toxicity in vivo.}, }
@article {pmid19845829, year = {2010}, author = {Arciello, M and Capo, CR and Cozzolino, M and Ferri, A and Nencini, M and Carrì, MT and Rossi, L}, title = {Inactivation of cytochrome c oxidase by mutant SOD1s in mouse motoneuronal NSC-34 cells is independent from copper availability but is because of nitric oxide.}, journal = {Journal of neurochemistry}, volume = {112}, number = {1}, pages = {183-192}, doi = {10.1111/j.1471-4159.2009.06441.x}, pmid = {19845829}, issn = {1471-4159}, mesh = {Animals ; Cell Line, Tumor ; Cell Survival/genetics ; Copper/deficiency/*physiology ; Electron Transport Complex IV/antagonists &amp; inhibitors/genetics/*metabolism ; Enzyme Activation/genetics ; Humans ; Mice ; Motor Neurons/*enzymology/metabolism ; *Mutation ; Nitric Oxide/*physiology ; Superoxide Dismutase/*genetics/toxicity ; Superoxide Dismutase-1 ; }, abstract = {The copper-enzyme cytochrome c oxidase (Cytox) has been indicated as a primary molecular target of mutant copper, zinc superoxide dismutase (SOD1) in familial amyotrophic lateral sclerosis (fALS); however, the mechanism underlying its inactivation is still unclear. As the toxicity of mutant SOD1s could arise from their selective recruitment to mitochondria, it is conceivable that they might compete with Cytox for the mitochondrial copper pool causing Cytox inactivation. To investigate this issue, we used mouse motoneuronal neuroblastoma x spinal cord cell line-34, stably transfected for the inducible expression of low amounts of wild-type or mutant (G93A, H46R, and H80R) human SOD1s and compared the effects observed on Cytox with those obtained by copper depletion. We demonstrated that all mutants analyzed induced cell death and decreased the Cytox activity, but not the protein content of the Cytox subunit II, at difference with copper depletion that also affected subunit II protein. Copper supplementation did not counteract mutant hSOD1s toxicity. Otherwise, the treatment of neuroblastoma x spinal cord cell line-34 expressing G93A, H46R, or H80R hSOD1 mutants, and showing constitutive expression of iNOS and nNOS, with either a NO scavenger, or NOS inhibitors prevented the inhibition of Cytox activity and rescued cell viability. These results support the involvement of NO in mutant SOD1s-induced Cytox damage, and mitochondrial toxicity.}, }
@article {pmid19841487, year = {2009}, author = {Bodar, EJ and Simon, A and de Visser, M and van der Meer, JW}, title = {Complete remission of severe idiopathic cold urticaria on interleukin-1 receptor antagonist (anakinra).}, journal = {The Netherlands journal of medicine}, volume = {67}, number = {9}, pages = {302-305}, pmid = {19841487}, issn = {1872-9061}, mesh = {Amyotrophic Lateral Sclerosis/complications ; Antirheumatic Agents/*therapeutic use ; Cold Temperature/*adverse effects ; Fatal Outcome ; Female ; Humans ; Interleukin 1 Receptor Antagonist Protein/*therapeutic use ; Middle Aged ; Receptors, Interleukin-1/*antagonists &amp; inhibitors ; Remission Induction ; Urticaria/complications/*drug therapy/etiology ; }, abstract = {UNLABELLED: A 62-year-old patient had suffered from severe cold intolerance with an urticarial rash and oropharyngeal angio-oedema upon cold exposure since early childhood. This could be provoked by the ice cube test and by exposure in a cold room. Her family history was negative, and she did not carry any mutations in the NRLP3 gene. Treatment with IL-1 receptor antagonist anakinra resulted in complete resolution of these symptoms, with a radical beneficial change in her quality of life. In recent years this patient had developed progressive neurological symptoms leading to a diagnosis of amyotrophic lateral sclerosis (ALS), which seems unrelated to the idiopathic cold urticaria. The neurological symptoms did not respond to anakinra treatment and were eventually fatal.<br><br>CONCLUSION: We describe the first case of IL-1RA treatment in idiopathic cold urticaria with good response. Anakinra had no effect on the progression of her symptoms of ALS.}, }
@article {pmid19839933, year = {2009}, author = {Romero, J and Orgado, JM}, title = {Cannabinoids and neurodegenerative diseases.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {8}, number = {6}, pages = {440-450}, doi = {10.2174/187152709789824589}, pmid = {19839933}, issn = {1996-3181}, mesh = {Animals ; Cannabinoids/metabolism/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neuroprotective Agents/metabolism/*therapeutic use ; }, abstract = {Although significant advances have taken place in recent years on our understanding of the molecular mechanisms of different neurodegenerative diseases, its translation into effective therapeutic treatments has not been as successful as could be expected. There is still a dramatic lack of curative treatments for the most frequent disorders and only symptomatic relief for many others. Under this perspective, the search for novel therapeutic approaches is demanding and significant attention and efforts have been directed to studying additional neurotransmission systems including the endocannabinoid system (ECS). The neuroprotective properties of exogenous as well as endogenous cannabinoids have been known for years and the underlying molecular mechanisms have been recently unveiled. As discussed later, antioxidative, antiglutamatergic and antiinflammatory effects are now recognized as derived from cannabinoid action and are known to be of common interest for many neurodegenerative processes. Thus, these characteristics make cannabinoids attractive candidates for the development of novel therapeutic strategies [1]. The present review will focus on the existing data regarding the possible usefulness of cannabinoid agents for the treatment of relevant neurological pathologies for our society such as Alzheimer's disease, multiple sclerosis, Huntington's disease and amyotrophic lateral sclerosis.}, }
@article {pmid19833436, year = {2009}, author = {Xiao, WH and Zheng, FY and Bennett, GJ and Bordet, T and Pruss, RM}, title = {Olesoxime (cholest-4-en-3-one, oxime): analgesic and neuroprotective effects in a rat model of painful peripheral neuropathy produced by the chemotherapeutic agent, paclitaxel.}, journal = {Pain}, volume = {147}, number = {1-3}, pages = {202-209}, pmid = {19833436}, issn = {1872-6623}, support = {R01 NS052255/NS/NINDS NIH HHS/United States ; R01 NS052255-04/NS/NINDS NIH HHS/United States ; }, mesh = {Analysis of Variance ; Animals ; Area Under Curve ; Cholestenones/*administration &amp; dosage/blood ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Administration Routes ; Drug Administration Schedule ; Drug Interactions ; Evoked Potentials/drug effects ; Hyperalgesia/chemically induced/drug therapy ; Male ; Nerve Fibers/metabolism/pathology/physiology ; Neuralgia/*chemically induced/pathology/*prevention &amp; control ; Neuroprotective Agents/*administration &amp; dosage/blood ; Paclitaxel/adverse effects/*analogs &amp; derivatives ; Pain Measurement/methods ; Pain Threshold/drug effects ; Rats ; Rats, Sprague-Dawley ; Ubiquitin Thiolesterase/metabolism ; }, abstract = {Olesoxime is a small cholesterol-like molecule that was discovered in a screening program aimed at finding treatment for amyotrophic lateral sclerosis and other diseases where motor neurons degenerate. In addition to its neuroprotective and pro-regenerative effects on motor neurons in vitro and in vivo, it has been shown to have analgesic effects in rat models of painful peripheral neuropathy due to vincristine and diabetes. We used a rat model of painful peripheral neuropathy produced by the chemotherapeutic agent, paclitaxel, to determine whether olesoxime could reverse established neuropathic pain. In addition, we determined whether giving olesoxime during the exposure to paclitaxel could prevent the development of the neuropathic pain syndrome and the accompanying degeneration of the terminal arbors of sensory fibers in the epidermis. Olesoxime significantly reduced established mechano-allodynia and mechano-hyperalgesia. There was no indication of tolerance to the effect during five days of dosing and the analgesia persisted for 5-10 days after the last injection. Giving olesoxime during the exposure to paclitaxel significantly and permanently reduced the severity of mechano-allodynia and mechano-hyperalgesia and significantly reduced the amount of sensory terminal arbor degeneration. Olesoxime targets mitochondrial proteins and its effects are consistent with the mitotoxicity hypothesis for paclitaxel-evoked painful peripheral neuropathy. We conclude that olesoxime may be useful clinically for both the prevention and treatment of paclitaxel-evoked painful peripheral neuropathy.}, }
@article {pmid19833209, year = {2010}, author = {Papadimitriou, D and Le Verche, V and Jacquier, A and Ikiz, B and Przedborski, S and Re, DB}, title = {Inflammation in ALS and SMA: sorting out the good from the evil.}, journal = {Neurobiology of disease}, volume = {37}, number = {3}, pages = {493-502}, pmid = {19833209}, issn = {1095-953X}, support = {NS11766/NS/NINDS NIH HHS/United States ; P50 NS038370/NS/NINDS NIH HHS/United States ; R21 NS062180-01/NS/NINDS NIH HHS/United States ; NS042269/NS/NINDS NIH HHS/United States ; R01 AG021617-05/AG/NIA NIH HHS/United States ; R01 NS051419/NS/NINDS NIH HHS/United States ; R21 NS064191/NS/NINDS NIH HHS/United States ; P01 NS011766/NS/NINDS NIH HHS/United States ; NS062180/NS/NINDS NIH HHS/United States ; R01 NS062055/NS/NINDS NIH HHS/United States ; R21 NS062180-02/NS/NINDS NIH HHS/United States ; NS062055/NS/NINDS NIH HHS/United States ; R01 AG021617/AG/NIA NIH HHS/United States ; P01 NS011766-310040/NS/NINDS NIH HHS/United States ; NS38370/NS/NINDS NIH HHS/United States ; P50 NS038370-115286/NS/NINDS NIH HHS/United States ; R01 NS042269-04/NS/NINDS NIH HHS/United States ; R21 NS064191-01A1/NS/NINDS NIH HHS/United States ; R21 NS062180/NS/NINDS NIH HHS/United States ; AG 21617/AG/NIA NIH HHS/United States ; R01 NS042269-05A2/NS/NINDS NIH HHS/United States ; R21 NS072182/NS/NINDS NIH HHS/United States ; NS064191/NS/NINDS NIH HHS/United States ; R01 NS062055-01A1/NS/NINDS NIH HHS/United States ; R01 NS042269/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*immunology/physiopathology ; Astrocytes/immunology ; Cytoprotection/physiology ; Gliosis/genetics/*immunology/physiopathology ; Humans ; Microglia/immunology ; Muscular Atrophy, Spinal/genetics/*immunology/physiopathology ; Myelitis/genetics/*immunology/physiopathology ; Nerve Degeneration/immunology/physiopathology ; Neuroglia/*immunology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Indices of neuroinflammation are found in a variety of diseases of the CNS including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Over the years, neuroinflammation, in degenerative disorders of the CNS, has evolved from being regarded as an innocent bystander accomplishing its housekeeping function secondary to neurodegeneration to being considered as a bona fide contributor to the disease process and, in some situations, as a putative initiator of the disease. Herein, we will review neuroinflammation in both ALS and SMA not only from the angle of neuropathology but also from the angle of its potential role in the pathogenesis and treatment of these two dreadful paralytic disorders.}, }
@article {pmid19825405, year = {2010}, author = {Ansorena, E and Garbayo, E and Lanciego, JL and Aymerich, MS and Blanco-Prieto, MJ}, title = {Production of highly pure human glycosylated GDNF in a mammalian cell line.}, journal = {International journal of pharmaceutics}, volume = {385}, number = {1-2}, pages = {6-11}, doi = {10.1016/j.ijpharm.2009.10.015}, pmid = {19825405}, issn = {1873-3476}, mesh = {Animals ; Biological Assay ; Biotechnology/*methods ; Cation Exchange Resins ; Cell Differentiation/drug effects ; Chromatography, Gel ; Chromatography, Ion Exchange ; Fibroblasts/*metabolism ; Glial Cell Line-Derived Neurotrophic Factor/*biosynthesis/genetics/isolation &amp; purification/pharmacology ; Glycosylation ; Humans ; Neurons/drug effects/pathology ; PC12 Cells ; Phenotype ; *Protein Processing, Post-Translational ; Rats ; Recombinant Proteins/biosynthesis ; Spectrometry, Mass, Electrospray Ionization ; Tandem Mass Spectrometry ; Transduction, Genetic ; }, abstract = {The administration of glial cell line-derived neurotrophic factor (GDNF) has emerged as a promising strategy for the treatment of several diseases of the nervous system as Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury and nerve regeneration as well as ocular diseases and drug addictions. A procedure for the purification of human recombinant glycosylated GDNF using a mammalian expression system as the source of the protein is discussed in the present paper. The neurotrophic factor was purified using cation exchange chromatography and gel filtration. A human cell line was chosen as the source of therapeutic protein, since a recombinant protein with a structure and glycosylation pattern equivalent to the native form is desirable for its prospective therapeutic utilization. The activity of the highly pure protein obtained was confirmed with a cell-based bioassay. The purified protein is suitable for its in vivo evaluation in animals and for possible subsequent clinical application.}, }
@article {pmid19822873, year = {2009}, author = {Miller, RG and Jackson, CE and Kasarskis, EJ and England, JD and Forshew, D and Johnston, W and Kalra, S and Katz, JS and Mitsumoto, H and Rosenfeld, J and Shoesmith, C and Strong, MJ and Woolley, SC and , }, title = {Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.}, journal = {Neurology}, volume = {73}, number = {15}, pages = {1227-1233}, pmid = {19822873}, issn = {1526-632X}, support = {R01NS045087-01A2/NS/NINDS NIH HHS/United States ; R01 NS 44887/NS/NINDS NIH HHS/United States ; N01-AR-2250/AR/NIAMS NIH HHS/United States ; R01-NS045087/NS/NINDS NIH HHS/United States ; 1U01 NS049640/NS/NINDS NIH HHS/United States ; U01NS042685-0/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*therapy ; Cognition Disorders/*diagnosis ; Dementia/diagnosis ; Evidence-Based Medicine ; Fatigue/drug therapy ; Humans ; Muscle Cramp/drug therapy ; Palliative Care/methods ; *Patient Care Team ; Pseudobulbar Palsy/drug therapy ; Sialorrhea/drug therapy/radiotherapy ; Terminal Care/methods ; Truth Disclosure ; }, abstract = {OBJECTIVE: To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include breaking the news, multidisciplinary clinics, symptom management, cognitive and behavioral impairment, communication, and palliative care for patients with ALS.<br><br>RESULTS: The authors identified 2 Class I studies, 8 Class II studies, and 30 Class III studies in ALS, but many important areas have been little studied. More high-quality, controlled studies of symptomatic therapies and palliative care are needed to guide management and assess outcomes in patients with ALS.<br><br>RECOMMENDATIONS: Multidisciplinary clinic referral should be considered for managing patients with ALS to optimize health care delivery and prolong survival (Level B) and may be considered to enhance quality of life (Level C). For the treatment of refractory sialorrhea, botulinum toxin B should be considered (Level B) and low-dose radiation therapy to the salivary glands may be considered (Level C). For treatment of pseudobulbar affect, dextromethorphan and quinidine should be considered if approved by the US Food and Drug Administration (Level B). For patients who develop fatigue while taking riluzole, withholding the drug may be considered (Level C). Because many patients with ALS demonstrate cognitive impairment, which in some cases meets criteria for dementia, screening for cognitive and behavioral impairment should be considered in patients with ALS (Level B). Other management strategies all lack strong evidence.}, }
@article {pmid19818912, year = {2009}, author = {Lulé, D and Zickler, C and Häcker, S and Bruno, MA and Demertzi, A and Pellas, F and Laureys, S and Kübler, A}, title = {Life can be worth living in locked-in syndrome.}, journal = {Progress in brain research}, volume = {177}, number = {}, pages = {339-351}, doi = {10.1016/S0079-6123(09)17723-3}, pmid = {19818912}, issn = {1875-7855}, mesh = {Adaptation, Psychological/*physiology ; Consciousness Disorders/complications/*psychology ; Depression/etiology/psychology ; Persons with Disabilities/psychology ; Humans ; Quadriplegia/complications/*psychology ; *Quality of Life ; Surveys and Questionnaires ; }, abstract = {The locked-in syndrome (LIS) describes patients who are awake and conscious but severely deefferented leaving the patient in a state of almost complete immobility and loss of verbal communication. The etiology ranges from acute (e.g., brainstem stroke, which is the most frequent cause of LIS) to chronic causes (e.g., amyotrophic lateral sclerosis; ALS). In this article we review and present new data on the psychosocial adjustment to LIS. We refer to quality of life (QoL) and the degree of depressive symptoms as a measure of psychosocial adjustment. Various studies suggest that despite their extreme motor impairment, a significant number of LIS patients maintain a good QoL that seems unrelated to their state of physical functioning. Likewise, depression is not predicted by the physical state of the patients. A successful psychological adjustment to the disease was shown to be related to problem-oriented coping strategies, like seeking for information, and emotional coping strategies like denial--the latter may, nevertheless, vary with disease stage. Perceived social support seems to be the strongest predictor of psychosocial adjustment. QoL in LIS patients is often in the same range as in age-matched healthy individuals. Interestingly, there is evidence that significant others, like primary caregivers or spouses, rate LIS patients' QoL significantly lower than the patients themselves. With regard to depressed mood, ALS patients without symptoms focus significantly more often on internal factors that can be retained in the course of the disease contrary to patients with depressive symptoms who preferably name external factors as very important, such as health, which will degrade in the course of the disease. Typically, ALS patients with a higher degree of depressive symptoms experience significantly less "very pleasant" situations. The herein presented data strongly question the assumption among doctors, health-care workers, lay persons, and politicians that severe motor disability necessarily is intolerable and leads to end-of-life decisions or euthanasia. Existing evidence supports that biased clinicians provide less-aggressive medical treatment in LIS patients. Thus, psychological treatment for depression, effective strategies for coping with the disease, and support concerning the maintenance of the social network are needed to cope with the disease. Novel communication devices and assistive technology now offers an increasing number of LIS patients to resume a meaningful life and an active role in society.}, }
@article {pmid19814656, year = {2009}, author = {Porzner, M and Müller, T and Seufferlein, T}, title = {SR 57746A/xaliproden, a non-peptide neurotrophic compound: prospects and constraints for the treatment of nervous system diseases.}, journal = {Expert opinion on investigational drugs}, volume = {18}, number = {11}, pages = {1765-1772}, doi = {10.1517/13543780903329089}, pmid = {19814656}, issn = {1744-7658}, mesh = {Animals ; Clinical Trials as Topic ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Humans ; Naphthalenes/adverse effects/pharmacology/*therapeutic use ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neuroprotective Agents/adverse effects/pharmacology/*therapeutic use ; Pyridines/adverse effects/pharmacology/*therapeutic use ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease or amyotrophic lateral sclerosis as well as peripheral neuropathies are difficult to treat due to a limited range of effective drugs. Neurotrophic growth factors promote neuronal survival and differentiation and could hence be interesting tools to treat these diseases. Their therapeutic use is limited due their short half-life, their inability to cross the BBB and potential side effects including tumor promotion. SR 57746A is a non-peptide, orally active compound that exhibits neuroprotective effects in various model systems in vitro and in vivo. SR 57746A shows--amongst other activities--agonistic activity on 5-HT(1A) receptors. Several clinical trials examined SR 57746A in patients with Alzheimer's disease, amyotrophic lateral sclerosis or chemotherapy-induced peripheral sensory neuropathy. This article reviews the preclinical and clinical data on SR 57746A and points out potential future applications of this compound. However, due to disapointing results in phase III trials, Sanofi-Aventis recently decided to discontinue the development of this drug.}, }
@article {pmid19805745, year = {2009}, author = {MacFarlane, PM and Mitchell, GS}, title = {Episodic spinal serotonin receptor activation elicits long-lasting phrenic motor facilitation by an NADPH oxidase-dependent mechanism.}, journal = {The Journal of physiology}, volume = {587}, number = {Pt 22}, pages = {5469-5481}, pmid = {19805745}, issn = {1469-7793}, support = {R01 HL080209/HL/NHLBI NIH HHS/United States ; R01 HL-080209/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetophenones/administration &amp; dosage ; Animals ; Enzyme Inhibitors/administration &amp; dosage ; Injections, Spinal ; Long-Term Potentiation/drug effects/*physiology ; Male ; Motor Neurons/drug effects/*physiology ; NADPH Oxidases/antagonists &amp; inhibitors/*physiology ; Phrenic Nerve/drug effects/*physiology ; Rats ; Rats, Sprague-Dawley ; Receptors, Serotonin/metabolism/*physiology ; Serotonin/administration &amp; dosage ; Spinal Cord/drug effects/enzymology/*physiology ; }, abstract = {Phrenic long-term facilitation (pLTF) is a serotonin (5-HT)-dependent augmentation of phrenic motor output induced by acute intermittent hypoxia (AIH). AIH-induced pLTF requires spinal NADPH oxidase activity and reactive oxygen species (ROS) formation. Since 5-HT receptor activation stimulates NADPH oxidase activity in some cell types, we tested the hypothesis that episodic spinal 5-HT receptor activation (without AIH) is sufficient to elicit an NADPH oxidase-dependent facilitation of phrenic motor output (pMF). In anaesthetised, artificially ventilated adult male rats, episodic intrathecal 5-HT injections (3 x 6 microl injections at 5 min intervals) into the cerebrospinal fluid (CSF) near cervical spinal segments containing the phrenic motor nucleus elicited a progressive increase in integrated phrenic nerve burst amplitude (i.e. pMF) lasting at least 60 min post-5-HT administration. Hypoglossal (XII) nerve activity was unaffected, suggesting that effective doses of 5-HT did not reach the brainstem. A single 5-HT injection was without effect. 5-HT-induced pMF was dose dependent, but exhibited a bell-shaped dose-response curve. Activation of different 5-HT receptor subtypes, specifically 5-HT(2) versus 5-HT(7) receptors, may underlie the bell-shaped dose-response curve via a mechanism of 'cross-talk' inhibition. Pre-treatment with NADPH oxidase inhibitors, apocynin or diphenylenodium (DPI), blocked 5-HT induced pMF. Thus, episodic spinal 5-HT receptor activation is sufficient to elicit pMF by an NADPH oxidase-dependent mechanism, suggesting common mechanisms of ROS formation with AIH-induced pLTF. An understanding of the mechanisms giving rise to AIH-induced pLTF and 5-HT induced pMF may inspire novel therapeutic strategies for respiratory insufficiency in diverse conditions, such as sleep apnoea, cervical spinal injury or amyotrophic lateral sclerosis.}, }
@article {pmid19805546, year = {2009}, author = {Lu, L and Wang, S and Zheng, L and Li, X and Suswam, EA and Zhang, X and Wheeler, CG and Nabors, LB and Filippova, N and King, PH}, title = {Amyotrophic lateral sclerosis-linked mutant SOD1 sequesters Hu antigen R (HuR) and TIA-1-related protein (TIAR): implications for impaired post-transcriptional regulation of vascular endothelial growth factor.}, journal = {The Journal of biological chemistry}, volume = {284}, number = {49}, pages = {33989-33998}, pmid = {19805546}, issn = {1083-351X}, support = {R01 CA112397/CA/NCI NIH HHS/United States ; R01 NS064133/NS/NINDS NIH HHS/United States ; K08 NS057664-01A2/NS/NINDS NIH HHS/United States ; K08 NS057664-02/NS/NINDS NIH HHS/United States ; K08 NS057664/NS/NINDS NIH HHS/United States ; I01 BX003035/BX/BLRD VA/United States ; NS057664/NS/NINDS NIH HHS/United States ; T32 NS048039/NS/NINDS NIH HHS/United States ; NS064133/NS/NINDS NIH HHS/United States ; NS058538/NS/NINDS NIH HHS/United States ; R21 NS058538/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Antigens, Surface/metabolism ; Cytoplasm/metabolism ; ELAV Proteins ; ELAV-Like Protein 1 ; Mice ; Models, Biological ; *Mutation ; Neurons/metabolism ; Polyribosomes/metabolism ; RNA, Messenger/metabolism ; RNA-Binding Proteins/*metabolism ; Ribonucleases/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase/*genetics/*metabolism ; Superoxide Dismutase-1 ; Vascular Endothelial Growth Factor A/*metabolism ; }, abstract = {Down-regulation of vascular endothelial growth factor (VEGF) in the mouse leads to progressive and selective degeneration of motor neurons similar to amyotrophic lateral sclerosis (ALS). In mice expressing ALS-associated mutant superoxide dismutase 1 (SOD1), VEGF mRNA expression in the spinal cord declines significantly prior to the onset of clinical manifestations. In vitro models suggest that dysregulation of VEGF mRNA stability contributes to that decline. Here, we show that the major RNA stabilizer, Hu Antigen R (HuR), and TIA-1-related protein (TIAR) colocalize with mutant SOD1 in mouse spinal cord extracts and cultured glioma cells. The colocalization was markedly reduced or abolished by RNase treatment. Immunoanalysis of transfected cells indicated that colocalization occurred in insoluble aggregates and inclusions. RNA immunoprecipitation showed a significant loss of VEGF mRNA binding to HuR and TIAR in mutant SOD1 cells, and there was marked depletion of HuR from polysomes. Ectopic expression of HuR in mutant SOD1 cells more than doubled the mRNA half-life of VEGF and significantly increased expression to that of wild-type SOD1 control. Cellular effects produced by mutant SOD1, including impaired mitochondrial function and oxidative stress-induced apoptosis, were reversed by HuR in a gene dose-dependent pattern. In summary, our findings indicate that mutant SOD1 impairs post-transcriptional regulation by sequestering key regulatory RNA-binding proteins. The rescue effect of HuR suggests that this impairment, whether related to VEGF or other potential mRNA targets, contributes to cytotoxicity in ALS.}, }
@article {pmid19796283, year = {2010}, author = {Niebroj-Dobosz, I and Janik, P and Sokołowska, B and Kwiecinski, H}, title = {Matrix metalloproteinases and their tissue inhibitors in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {17}, number = {2}, pages = {226-231}, doi = {10.1111/j.1468-1331.2009.02775.x}, pmid = {19796283}, issn = {1468-1331}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*blood/*cerebrospinal fluid ; Case-Control Studies ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Male ; Matrix Metalloproteinase 1/blood/cerebrospinal fluid ; Matrix Metalloproteinase 2/blood/cerebrospinal fluid ; Matrix Metalloproteinase 9/blood/cerebrospinal fluid ; Matrix Metalloproteinases/*blood/*cerebrospinal fluid ; Middle Aged ; Severity of Illness Index ; Tissue Inhibitor of Metalloproteinase-1/blood/cerebrospinal fluid ; Tissue Inhibitor of Metalloproteinase-2/blood/cerebrospinal fluid ; Tissue Inhibitor of Metalloproteinases/*blood/*cerebrospinal fluid ; }, abstract = {BACKGROUND AND PURPOSE: Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). We investigated the expression of MMPs and tissue inhibitors of matrix metalloproteinases (TIMPs) in serum and cerebrospinal fluid (CSF) correlating the results with age, disease duration and the clinical course.<br><br>METHODS: The material consisted of 30 ALS patients and 15 age-matched healthy controls. ELISA method to determine the expression of MT-MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 in serum and CSF was used. MMP-2 and MMP-9 by zymography was also tested.<br><br>RESULTS: In serum MT-MMP-1, MMP-2, MMP-9 and TIMP-1 expression was increased, especially in mild ALS cases. TIMP-2 values were normal. In CSF MT-MMP-1, MMP-2 and TIMP-1 level was either increased or normal, that of MMP-9 was decreased. TIMP-2 did not change. No correlation of MMPs and TIMP-1 expression in serum and CSF and the age of the patients was found. A correlation was observed between MMPs and TIMPs and disease duration.<br><br>CONCLUSIONS: Increased level of MMPs and TIMP-1 of ALS patients may reflect the degeneration process of motor neurons and skeletal muscles and/or is associated with tissues remodeling. The low level of MMP-9 in CSF may result from impaired balance between MMP-9 and TIMP-1 and/or its increased intrathecal degradation and physical clearance. Although the role of changed MMPs/TIMPs level in the pathogenesis of ALS is not clear their analysis in serum may be used as prognostic factor and a potential marker for monitoring treatment effects.}, }
@article {pmid19794369, year = {2009}, author = {Mimica, N and Drmić, S and Presecki, P}, title = {Involuntary emotional expression disorder in Alzheimer's disease - psychopharmacotherapy aspects.}, journal = {Psychiatria Danubina}, volume = {21}, number = {3}, pages = {425-428}, pmid = {19794369}, issn = {0353-5053}, mesh = {Affective Symptoms/*drug therapy/psychology ; Alzheimer Disease/*drug therapy/psychology ; Clinical Trials as Topic ; Combined Modality Therapy ; Croatia ; *Crying ; Dextromethorphan/therapeutic use ; Drug Approval ; Drug Combinations ; Expressed Emotion/*drug effects ; Humans ; *Laughter ; Psychotropic Drugs/*therapeutic use ; Quinidine/therapeutic use ; United States ; }, abstract = {Involuntary emotional expression disorder (IEED) is syndrome characterized with relatively stereotypical episodes of uncontrollable crying and/or laughing. Additionally, this syndrome can include irritability, anger and frustration. This syndrome is common among a number of neurologic diseases like patients with a stroke or traumatic brain injury (TBI), patients with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), as well as dementias such as Alzheimer's disease (AD), and motor disorders such as Parkinson's disease (PD). IEED is very common but misdiagnosed and consequently undertreated. Prevalence of IEED in AD is between 15-39%. Recent controlled clinical studies suggest that dextromethorphan (DM) and quinidine (Q) is an effective treatment for IEED. United States Food and Drug Administration (FDA) has accepted for filing and review its New Drug Application (NDA) for Zenvia (dextromethorphan hydrobromide and quinidine sulfate capsules) for the treatment of IEED. In Republic of Croatia current treatment involves antidepressants (tricyclic and selective serotonin reuptake inhibitors), antipsychotic agents, anxiolytics, antidementives and mood stabilizers. New promising treatment can reduce the frequency of episodes and improve the quality of life of patients and their families and caregivers.}, }
@article {pmid19782443, year = {2009}, author = {Patel, BP and Hamadeh, MJ}, title = {Nutritional and exercise-based interventions in the treatment of amyotrophic lateral sclerosis.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {28}, number = {6}, pages = {604-617}, doi = {10.1016/j.clnu.2009.06.002}, pmid = {19782443}, issn = {1532-1983}, mesh = {Amyotrophic Lateral Sclerosis/*diet therapy/*therapy ; Animals ; Clinical Trials as Topic ; *Exercise ; Humans ; *Nutritional Status ; Treatment Outcome ; }, abstract = {BACKGROUND &amp; AIMS: Disease pathogenesis in amyotrophic lateral sclerosis (ALS) involves a number of interconnected mechanisms all resulting in the rapid deterioration of motor neurons. The main mechanisms include enhanced free radical production, protein misfolding, aberrant protein aggregation, excitotoxicity, mitochondrial dysfunction, neuroinflammation and apoptosis. The aim of this review is to assess the efficacy of using nutrition- and exercise-related interventions to improve disease outcomes in ALS.<br><br>METHODS: Studies involving nutrition or exercise in human and animal models of ALS were reviewed.<br><br>RESULTS: Treatments conducted in animal models of ALS have not consistently translated into beneficial results in clinical trials due to poor design, lack of power and short study duration, as well as differences in the genetic backgrounds, treatment dosages and disease pathology between animals and humans. However, vitamin E, folic acid, alpha lipoic acid, lyophilized red wine, coenzyme Q10, epigallocatechin gallate, Ginkgo biloba, melatonin, Cu chelators, and regular low and moderate intensity exercise, as well as treatments with catalase and l-carnitine, hold promise to mitigating the effects of ALS, whereas caloric restriction, malnutrition and high-intensity exercise are contraindicated in this disease model.<br><br>CONCLUSIONS: Improved nutritional status is of utmost importance in mitigating the detrimental effects of ALS.}, }
@article {pmid19775313, year = {2009}, author = {Sener, A and Tang, AL and Farber, DL}, title = {Memory T-cell predominance following T-cell depletional therapy derives from homeostatic expansion of naive T cells.}, journal = {American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons}, volume = {9}, number = {11}, pages = {2615-2623}, doi = {10.1111/j.1600-6143.2009.02820.x}, pmid = {19775313}, issn = {1600-6143}, mesh = {Animals ; Antibodies, Monoclonal/immunology/pharmacology ; Antilymphocyte Serum ; CD4 Lymphocyte Count ; CD4-Positive T-Lymphocytes/*cytology/*immunology ; Cell Division/immunology ; Homeostasis/immunology ; Immunologic Memory/*immunology ; Immunophenotyping ; Isoantigens/immunology ; *Leukocyte Reduction Procedures ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; *Transplantation Immunology ; }, abstract = {T-cell depletion reportedly leads to alterations in the T-cell compartment with predominant survival of memory phenotype CD4 T cells. Here, we asked whether the prevalence of memory T cells postdepletion results from their inherent resistance to depletion and/or to the homeostatic expansion of naive T cells and their phenotypic conversion to memory, which is known to occur in lymphopenic conditions. Using a 'mosaic memory' mouse model with trackable populations of alloreactive memory T cells, we found that treatment with murine antithymocyte globulin (mATG) or antilymphocyte serum (ALS) effectively depleted alloreactive memory CD4 T cells, followed by rapid homeostatic proliferation of endogenous CD4 T cells peaking at 4 days postdepletion, with no homeostatic advantage to the antigen-specific memory population. Interestingly, naive (CD44lo) CD4 T cells exhibited the greatest increase in homeostatic proliferation following mATG treatment, divided more extensively compared to memory (CD44hi) CD4 T cells and converted to a memory phenotype. Our results provide novel evidence that memory CD4 T cells are susceptible to lymphodepletion and that the postdepletional T-cell compartment is repopulated to a significant extent by homeostatically expanded naive T cells in a mouse model, with important important implications for immune alterations triggered by induction therapy.}, }
@article {pmid19774819, year = {2009}, author = {El-Adl, G and Mostafa, MF and Khalil, MA and Enan, A}, title = {Titanium elastic nail fixation for paediatric femoral and tibial fractures.}, journal = {Acta orthopaedica Belgica}, volume = {75}, number = {4}, pages = {512-520}, pmid = {19774819}, issn = {0001-6462}, mesh = {Adolescent ; *Bone Nails ; Child ; Elasticity ; Female ; Femoral Fractures/diagnostic imaging/*surgery ; Fracture Fixation, Intramedullary/instrumentation/*methods ; Humans ; Length of Stay ; Male ; Prospective Studies ; Radiography ; Tibial Fractures/diagnostic imaging/*surgery ; Titanium ; }, abstract = {The aim of this prospective study was to evaluate the results of treatment of paediatric femoral and/or tibial diaphyseal fractures with titanium elastic nails (TENs). Sixty six patients with 48 femoral and 25 tibial fractures were followed-up for 15 to 24 months. The outcome rating system proposed by Flynn et al was used to evaluate the final results. Most patients (56.1%) were operated between 2 to 4 days after injury; a traction table was used in 54.8% of cases. The average operative time was 28 minutes, and the average hospital stay was 5.7 days. Postoperative immobilisation was used in 30% of cases, mostly with femoral fractures. The fractures united in an average time period of 85 days; 89% had united within 3 months. The nails were removed in 87.8% of cases after an average of 5.9 months. The following complications were noted: soft tissue and skin problem (9.1%) in relation to nail ends at the entry points, limb-length discrepancy (9.1%), malunion (4.5%). Based on Flynn et al's outcome rating system, 75.8% of the results were excellent, 24.2% were satisfactory and there were no poor results. With good knowledge of the technique of TEN fixation for paediatric femoral and tibial fractures, excellent and satisfactory results were achieved in all cases, with few minor complications. TENs can give stable fixation allowing early mobilisation and shorter hospitalisation with less disruption of patient and family life.}, }
@article {pmid19769515, year = {2009}, author = {Uchida, K and Nakajima, H and Yayama, T and Sato, R and Kobayashi, S and Kokubo, Y and Mwaka, ES and Baba, H}, title = {Anterior and posterior decompressive surgery for progressive amyotrophy associated with cervical spondylosis: a retrospective study of 51 patients.}, journal = {Journal of neurosurgery. Spine}, volume = {11}, number = {3}, pages = {330-337}, doi = {10.3171/2009.3.SPINE08635}, pmid = {19769515}, issn = {1547-5654}, mesh = {Adult ; Aged ; *Cervical Vertebrae ; Cohort Studies ; Decompression, Surgical/*methods ; Female ; Humans ; Male ; Middle Aged ; Muscle Weakness/etiology/pathology/therapy ; Muscular Atrophy/etiology/pathology/*therapy ; Retrospective Studies ; Spinal Cord Compression/complications/pathology/*surgery ; Spondylosis/complications/*pathology/*surgery ; Treatment Outcome ; }, abstract = {OBJECT: The aims of this study were to review the clinicoradiological findings in patients who underwent decompressive surgery for proximal and distal types of muscle atrophy caused by cervical spondylosis and to discuss the outcome and techniques of surgical intervention.<br><br>METHODS: Fifty-one patients (43 men and 8 women) with proximal (37, with arm drop) and distal muscle atrophy (14, with wrist drop) underwent cervical decompression (39 anterior decompressions and 12 open-door C3-7 laminoplasties with microsurgical foraminotomy) for muscle weakness in the upper extremities. The clinical course, type of spinal cord compression, abnormal signal intensity on high-resolution MR imaging, and postdecompression improvement in muscle power were reviewed at a mean follow-up of 2.6 years (range 0.8-9.4 years).<br><br>RESULTS: The most commonly affected vertebrae were C4-5 and C5-6, and C5-6 and C6-7 in patients with proximal or distal muscle atrophy, respectively; the respective numbers of affected vertebrae were 1.5 and 2.2. Transaxial MR imaging showed medial compression of the spinal cord in 20 patients (in 12 with proximal and 8 with distal muscle atrophy), paramedial compression in 22 (17 and 5 patients, respectively), and foraminal compression in 9 (8 and 1 patient, respectively). Increased signal intensity on MR imaging was observed in 85.0, 22.7, and 11.1% of cases of medial, paramedial, and foraminal compression, respectively. Increased signal intensity at the affected muscle segment level was observed in 52.9, 40.0, and 0% of cases, respectively. Sixty-two percent of patients with proximal muscle atrophy gained 1 or more grades of muscle power on manual muscle testing (MMT), whereas 64.3% with distal muscle atrophy failed to gain even 1 grade of improvement. The recovery of muscle power correlated with disease duration and the percent voltage of Erb point or wrist-stimulated muscle evoked potentials but not with preoperative MMT, longitudinal range of spinal cord compression, signal change on T2-weighted MR imaging, or surgical procedure.<br><br>CONCLUSIONS: Surgical outcome in patients with distal muscle atrophy was inferior to that in patients with proximal atrophy. The distal type was characterized by a long preoperative period, a greater number of cervical spine misalignments, a narrow spinal canal, and increased signal intensity on T2-weighted MR imaging. It is essential to perform a careful neurological evaluation, including sensory examination of the lower limbs, as well as neuroradiological and neurophysiological assessments to avoid confusion with motor neuron disease and to detect the coexistence of amyotrophic lateral sclerosis, especially when surgical treatment of cervical spondylosis is planned. The results of careful physical examination, MR imaging studies, and electromyography studies should be comprehensively evaluated to ascertain the pathophysiology of the muscle atrophy. It is very important to distinguish the pathophysiology caused by nerve root impingements from anterior horn dysfunction when making decisions about treatment strategy. Surgical treatment--with or without foraminotomy--for amyotrophy in cervical spondylosis requires urgent action with regard to human neuroanatomy and neural innervation of the paralyzed muscles.}, }
@article {pmid19767153, year = {2009}, author = {Shen, YX and Fan, ZH and Zhao, JG and Zhang, P}, title = {The application of platelet-rich plasma may be a novel treatment for central nervous system diseases.}, journal = {Medical hypotheses}, volume = {73}, number = {6}, pages = {1038-1040}, doi = {10.1016/j.mehy.2009.05.021}, pmid = {19767153}, issn = {1532-2777}, mesh = {Central Nervous System Diseases/*therapy ; Humans ; *Platelet-Rich Plasma ; }, abstract = {As a potential biological product, platelet-rich plasma (PRP) has been widely utilized in the areas of oral and maxillofacial reconstruction, bone and soft tissue restoration and wound healing. A recent study reported that the application of PRP on interrupted sciatic nerve could promote remyelinization of peripheral nerve. This renovated a notion that the application of PRP might extend to the nervous system. Most central nervous system (CNS) diseases have a series of common pathological changes in the later period of diseases which induce neurons and glia apoptosis and aggravate neurological dysfunction. It has been demonstrated that the potent restorative function of PRP is mainly based on neurotrophic capacity of preparation rich in growth factors (PRGFs) and scaffolding effect of platelet-rich gel (PRG), all of which could be certified to ameliorate the pathological process of CNS diseases. In view of this, we propose a hypothesis that the application of PRP and its derivatives might provide a novel therapeutic approach for CNS diseases, especially for traumatic brain or spinal cord injury, autoimmune diseases and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.}, }
@article {pmid19764743, year = {2009}, author = {Sánchez Pérez, I and Culzoni, MJ and Siano, GG and Gil García, MD and Goicoechea, HC and Martínez Galera, M}, title = {Detection of unintended stress effects based on a metabonomic study in tomato fruits after treatment with carbofuran pesticide. Capabilities of MCR-ALS applied to LC-MS three-way data arrays.}, journal = {Analytical chemistry}, volume = {81}, number = {20}, pages = {8335-8346}, doi = {10.1021/ac901119h}, pmid = {19764743}, issn = {1520-6882}, mesh = {Carbofuran/*pharmacology ; Fruit/*drug effects/*metabolism/physiology ; Least-Squares Analysis ; Solanum lycopersicum/*drug effects/metabolism/physiology ; Metabolomics/*methods ; Multivariate Analysis ; Pesticides/*pharmacology ; Stress, Physiological/*drug effects ; }, abstract = {A chemometric strategy based on multivariate curve resolution and alternating least-squares (MCR-ALS) applied to LC-MS three-way data arrays has been developed to perform a metabonomic study in tomato (Lycopersicon esculentum) fruits (cultivar Rambo) following treatment with carbofuran. This methodology has proved to be adequate for the detection of unintended stress effects due to the previous treatment with this pesticide. MCR-ALS was performed on augmented matrices built with the LC-MS three-way data obtained from treated and nontreated samples through the sampling time. The strategy allowed us to obtain the concentration and spectra profiles of the main components (previously estimated with the SVD algorithm) from samples treated with pesticide as well as from blank samples, showing how they vary with time after plants treatment with the pesticide. In addition, a simple resolved mass spectrum was obtained corresponding to the peaks of a particular component in all matrices, thus avoiding ambiguity in the compound identity assignment. Different time profiles were found for some metabolites in treated and nontreated samples, which demonstrate that the presence of pesticide causes changes thorough time in the behavior of certain endogenous tomato metabolites as a result of physiological stress.}, }
@article {pmid19762902, year = {2009}, author = {McElhiney, MC and Rabkin, JG and Gordon, PH and Goetz, R and Mitsumoto, H}, title = {Prevalence of fatigue and depression in ALS patients and change over time.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {80}, number = {10}, pages = {1146-1149}, doi = {10.1136/jnnp.2008.163246}, pmid = {19762902}, issn = {1468-330X}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/complications/physiopathology/*psychology ; Depressive Disorder/*epidemiology ; Fatigue/*epidemiology ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Prevalence ; Risk Factors ; Severity of Illness Index ; Vital Capacity ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) patients report both fatigue and depression. It is not clear how frequently each occurs, to what extent they occur together, how each relates to ALS disease status, or their stability over time.<br><br>OBJECTIVE: To assess frequency and persistence of fatigue and depression, and relationship to ALS disease status, for patients attending an ALS interdisciplinary centre for routine 3-month visits.<br><br>METHOD: Measures included the Fatigue Severity Scale, Patient Health Questionnaire-9. ALS Functional Rating Scale -- Revised and forced vital capacity, rate of disease progression, and bulbar/nonbulbar disease onset.<br><br>RESULTS: 223 patients completed the ratings once; of these, 113 completed them twice, and 65 on three visits. At baseline, 44% (99/223) had clinically significant fatigue, including 34 patients who also had a depressive disorder; 7% (16/223) had major or minor depression only, and 48% (108/223) had neither condition. Fatigue was associated with greater ALS severity, but depression was not. Among the 113 patients seen 3 months later, 75% (33/44) who were fatigued at Time 1 remained fatigued, while 48% (10/21) remained depressed. New-onset fatigue was reported by 22% (25/113), and new-onset depression by 6% (7/113). For the 65 patients seen a third time, rates remained nearly the same.<br><br>CONCLUSION: Fatigue was more prevalent and persistent than depression, although 15% (34/223) of patients had both conditions. Fatigue but not depression was associated with ALS severity. The two conditions appear to be independent, although sometimes co-occurring, and both warrant consideration in evaluating patient functioning and treatment.}, }
@article {pmid19761955, year = {2009}, author = {Blatzheim, K}, title = {Interdisciplinary palliative care, including massage, in treatment of amyotrophic lateral sclerosis.}, journal = {Journal of bodywork and movement therapies}, volume = {13}, number = {4}, pages = {328-335}, doi = {10.1016/j.jbmt.2008.04.040}, pmid = {19761955}, issn = {1532-9283}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; *Massage ; *Palliative Care ; *Patient Care Team ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurological disease that affects approximately 20,000 Americans. Symptoms include muscle weakness, fatigue, twitching, atrophy, spasticity, pain, oropharyngeal dysfunction, pseudobulbar affect, weight loss, and respiratory impairment. Death occurs within 3-5 yr after onset of symptoms, with diagnosis taking from 11 to 17.5 months. The only FDA-approved drug for ALS is Riluzole, which only increases the life expectancy by a few months. All other treatments for ALS provide symptom management to improve the patient's quality of life. An interdisciplinary palliative care team for the ALS patient helps to reduce the stress that the illness places on families. Massage can be a useful adjunctive treatment for spasticity and pain when medication side effects are unwanted. A holistic interdisciplinary palliative care team supports both the patient and the family improving their quality of life.}, }
@article {pmid19751204, year = {2009}, author = {Cuny, GD}, title = {Kinase inhibitors as potential therapeutics for acute and chronic neurodegenerative conditions.}, journal = {Current pharmaceutical design}, volume = {15}, number = {34}, pages = {3919-3939}, doi = {10.2174/138161209789649330}, pmid = {19751204}, issn = {1873-4286}, mesh = {Humans ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/chemistry/*therapeutic use ; Phosphotransferases/*antagonists &amp; inhibitors ; }, abstract = {Kinases, which number > 500 in humans, are a class of enzymes that participate in an array of important functions within normal cellular physiology and during various pathological conditions. Due to the key role of kinases in the regulation of all aspects of cellular signaling and the well established contribution of kinase dysregulation to the etiology of many human pathologies, the development of kinase inhibitors has emerged as a therapeutic strategy for the treatment of human disease, including most notably oncology. Difficulties generating selective inhibitors have hampered their use in other therapeutic areas with less tolerance for off-target effects. However, with an increasing understanding of kinase structures and with the advent of newer inhibitor design strategies more highly selective inhibitors are beginning to emerge. This has prompted interest in utilizing kinase inhibitors in therapeutic areas beyond oncology, including acute and chronic neurodegenerative conditions for which disease modify therapies are lacking. This review provides a background in acute (i.e. brain ischemia and traumatic brain injury) and chronic (i.e. Alzheimer's, Parkinson's, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis) neurodegenerative conditions. Then, the role of several kinase (i.e. JNK3, p38 MAPK, ERK, PKC, ROCKII, GSK3, Cdk5, MLK, EphB3 kinase, RIP1 kinase, LRRK2, TTBK1, ASK1, CK, DAPK, and PKN1) that could serve as potential therapeutic targets for these maladies are reviewed.}, }
@article {pmid19739346, year = {2009}, author = {Apóstol-González, S and Herrera, J}, title = {[Subtrochanteric fractures treated with interlocking endomedullary nailing].}, journal = {Acta ortopedica mexicana}, volume = {23}, number = {3}, pages = {130-136}, pmid = {19739346}, issn = {2306-4102}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Bone Nails ; Female ; *Fracture Fixation, Intramedullary ; Hip Fractures/*surgery ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Young Adult ; }, abstract = {OBJECTIVE: Determine the efficacy of the treatment of subtrochanteric femur fractures with interlocking endomedullary nailing.<br><br>MATERIAL AND METHODS: This is a retrospective observational descriptive study. The clinical series reported analyzes the results of nineteen patients with a diagnosis of subtrochanteric fracture who were treated at various hospitals during the period 2000-2004. The fracture was classified according to the AO criteria and the Russell-Taylor classification. The final assessment is described using Sanders et al's Traumatic Hip Assessment Scale.<br><br>RESULTS: The series includes thirteen male and six female patients. Mean age was 36 years. The mechanism of injury was motor vehicle accidents and gunshot wound. Mean follow-up was 18 months. Fracture healing time was 3 months. In two patients healing occurred in varus (< 50) and they have shortening < 2 cm. According to the score in the Sanders et al scale, 10 results were excellent, 8 good and one fair.<br><br>CONCLUSIONS: We recommend the use of a monoblock-type of interlocking endomedullary nail to treat subtrochanteric fractures. This method is an alternative to closed interlocking endomedullary nailing.}, }
@article {pmid19733563, year = {2009}, author = {Neymotin, A and Petri, S and Calingasan, NY and Wille, E and Schafer, P and Stewart, C and Hensley, K and Beal, MF and Kiaei, M}, title = {Lenalidomide (Revlimid) administration at symptom onset is neuroprotective in a mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {220}, number = {1}, pages = {191-197}, pmid = {19733563}, issn = {1090-2430}, support = {R01 NS044154/NS/NINDS NIH HHS/United States ; NS044154/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*immunology/metabolism ; Animals ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; Antineoplastic Agents/pharmacology/therapeutic use ; Body Weight/drug effects/immunology ; Cell Survival/drug effects/immunology ; Cytokines/drug effects/metabolism ; Disease Models, Animal ; Humans ; Immunologic Factors/pharmacology/therapeutic use ; Lameness, Animal/drug therapy/physiopathology/prevention &amp; control ; Lenalidomide ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/immunology/pathology ; Nerve Degeneration/drug therapy/immunology/prevention &amp; control ; Spinal Cord/*drug effects/*immunology/physiopathology ; Survival Rate ; Thalidomide/*analogs &amp; derivatives/pharmacology/therapeutic use ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which is currently untreatable. Inflammation plays a major role in the pathogenesis of motor neuron death in ALS. Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and Fas ligand (FasL) are amongst the most important mediators of neuro-inflammation. We have previously demonstrated that elevation of these pro-inflammatory cytokines occurs in both ALS transgenic mice and in human ALS postmortem spinal cord tissues. Lenalidomide is a potent immunomodulatory agent, with the ability to down-regulate pro-inflammatory cytokines and up-regulate anti-inflammatory cytokines. We previously reported the neuroprotective effects of lenalidomide, when treatment was started 2 months prior to onset of disease in the G93A SOD1 transgenic mouse model of ALS. Since in ALS patients, treatment can only begin after the appearance of symptoms, we sought to determine the efficacy of lenalidomide administration starting at symptom onset in the G93A SOD1 mice. We found that lenalidomide treatment extended the survival interval from the age of onset by 18.3 days (approximately 45%). Additionally, lenalidomide treatment improved rotarod performance, reduced weight loss, and attenuated neuronal cell death in the lumbar spinal cord. Qualitative histological analysis showed that lenalidomide treatment modestly reduced the expression of the proinflammatory cytokines Fas Ligand, IL-1beta, TNF-alpha and CD40 ligand. RNA protection Assay (RPA) on a pre-selected panel of cytokines showed that proinflammatory cytokines were reduced and anti-inflammatory cytokines were up-regulated. These data encourage further clinical evaluation of lenalidomide as therapeutic strategy to block or slow disease progression in human ALS patients.}, }
@article {pmid19732936, year = {2009}, author = {Han, A and Yue, L and Li, Z and Wang, H and Wang, Y and Ye, Q and Lu, L and Gan, J}, title = {Plant availability and phytotoxicity of soil bound residues of herbicide ZJ0273, a novel acetolactate synthase potential inhibitor.}, journal = {Chemosphere}, volume = {77}, number = {7}, pages = {955-961}, doi = {10.1016/j.chemosphere.2009.08.008}, pmid = {19732936}, issn = {1879-1298}, mesh = {Acetolactate Synthase/*antagonists &amp; inhibitors/metabolism ; Agriculture ; Benzoates/metabolism/*toxicity ; Enzyme Inhibitors/metabolism/*toxicity ; Herbicides/metabolism/*toxicity ; Oryza/drug effects ; Pesticide Residues/metabolism/*toxicity ; Seedlings/drug effects ; *Soil ; Soil Pollutants/metabolism/*toxicity ; Zea mays ; }, abstract = {The plant availability and phytotoxicity of soil bound residues (BR) of herbicide ZJ0273, a novel acetolactate synthase (ALS) potential inhibitor, to rice (Oryza sativa L.) and corn (Zea mays L.) was investigated in three different soils including a Fluvio-marine yellow loamy soil (S(1)), a Red clayey soil (S(2)), and a Coastal saline soil (S(3)), using (14)C-labeling tracer and bioassay techniques. When soils were amended with BR at 0.6, 1.2 and 1.8 nmol g(-1), dose-dependent and significant inhibition was observed for rice seedlings within 14d after treatment, but no significant inhibition occurred to corn seedlings in the same treatment. Radioactive analysis of soil extracts following sequential extractions showed that the (14)C labeled residues of ZJ0273 were released from the amended soil BR upon planting. For example, when amended with 1.8 nmol g(-1), about 68.3%, 57.0%, and 61.1%, respectively, of the added BR were released in S(1), S(2), and S(3) planted with rice seedlings, whereas 38.9%, 32.7% and 32.6% became available for uptake in the corresponding soils planted with corn seedlings. The released compounds were identified as ZJ0273 and its degradation products M1 and M2, with M2 as the primary component. Bioassay on rice showed that concentration for 50% inhibition (IC(50)) of ZJ0273, M1, and M2 were 33.16, 1.93 and 0.49 microM, respectively. Therefore, BR formed after application of ZJ0273 may become available for plant uptake during rice cultivation and lead to phytotoxic effects, and the phytotoxicity is mainly caused by the release of the biologically active metabolite M2. This knowledge is valuable for designing crop rotation practices so that crop injury and yield losses due to carry-over herbicide phytotoxicity may be avoided.}, }
@article {pmid19722069, year = {2009}, author = {Oliveira, AS and Pereira, RD}, title = {Amyotrophic lateral sclerosis (ALS): three letters that change the people's life. For ever.}, journal = {Arquivos de neuro-psiquiatria}, volume = {67}, number = {3A}, pages = {750-782}, doi = {10.1590/s0004-282x2009000400040}, pmid = {19722069}, issn = {1678-4227}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/etiology/psychology/therapy ; Animals ; Clinical Trials as Topic ; Humans ; *Life Change Events ; Prognosis ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor nervous system. It causes progressive and cumulative physical disabilities in patients, and leads to eventual death due to respiratory muscle failure. The disease is diverse in its presentation, course, and progression. We do not yet fully understand the cause or causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. Currently, we rely on a multidisciplinary approach to symptomatically manage and care for patients who have ALS. Although amyotrophic lateral sclerosis and its variants are readily recognized by neurologists, about 10% of patients are misdiagnosed, and delays in diagnosis are common. Prompt diagnosis, sensitive communication of the diagnosis, the involvement of the patient and their family, and a positive care plan are prerequisites for good clinical management. A multidisciplinary, palliative approach can prolong survival and maintain quality of life. Treatment with Riluzole improves survival but has a marginal effect on the rate of functional deterioration, whereas non-invasive ventilation prolongs survival and improves or maintains quality of life. In this review, we discuss the diagnosis, management, and how to cope with impaired function and end of life on the basis of our experience, the opinions of experts, existing guidelines, and clinical trials. Multiple problems require a multidisciplinary approach including aggressive symptomatic management, rehabilitation to maintain motor function, nutritional support (enteric feeding, gastrostomy), respiratory support (non invasive home ventilation, invasive ventilation, tracheotomy), augmentative communication devices, palliative care, psychological support for both patients and families (because family members so often play a central role in management and care), communication between the care team, the patient and his or her family, and recognition of the clinical and social effects of cognitive impairment. Social, bioethical, and financial issues as well as advance directives should be addressed. A plethora of evidence-based guidelines should be compiled into an internationally agreed guideline of best practice. The multidisciplinary team has changed the history of disease, with still no curative therapy available.}, }
@article {pmid19719072, year = {2009}, author = {Brophy, JR}, title = {Skills review: the CHF patient. A review of BLS ssessment and care of the congestive heart failure patient.}, journal = {EMS magazine}, volume = {38}, number = {8}, pages = {60-61}, pmid = {19719072}, issn = {1946-4967}, mesh = {Clinical Competence ; Dyspnea/etiology/therapy ; Emergency Medical Services ; Heart Failure/diagnosis/*therapy ; Humans ; }, abstract = {As an EMT-B, there will be times when your assessment and treatment skills will be put to the test as you find yourself on scene with a critical patient and no ALS backup. Your ability to recognize patients with critical symptoms and do the most good for them within the EMT-B scope of practice could have a tremendous impact on patient survival. The importance of rapid but accurate assessment of both the clinical presentation and the patient's history cannot be overemphasized. This article will review BLS assessment and care of the congestive heart failure (CHF) patient.}, }
@article {pmid21180622, year = {2009}, author = {Ludolph, AC and Jesse, S}, title = {Evidence-based drug treatment in amyotrophic lateral sclerosis and upcoming clinical trials.}, journal = {Therapeutic advances in neurological disorders}, volume = {2}, number = {5}, pages = {319-326}, pmid = {21180622}, issn = {1756-2864}, abstract = {Amyotrophic Lateral sclerosis/motor neuron disease is a severe neurodegenerative disease characterized by upper and Lower motor neuron degeneration for which there is no truly effective treatment. Several therapies have shown promise in preclinical models of motor neuron disease; however, most of them failed in human studies, so that the noticeable progress in understanding the cellular mechanisms of motor neuron degeneration has not been matched with the development of therapeutic strategies to prevent disease progression or to extend survival longer than achieved by riluzole. We review treatment development in motor neuron disease and discuss the strengths and limitations of past as well as upcoming clinical trials.}, }
@article {pmid19716395, year = {2009}, author = {Lee, J and Boo, JH and Ryu, H}, title = {The failure of mitochondria leads to neurodegeneration: Do mitochondria need a jump start?.}, journal = {Advanced drug delivery reviews}, volume = {61}, number = {14}, pages = {1316-1323}, pmid = {19716395}, issn = {1872-8294}, support = {P30 AG013846/AG/NIA NIH HHS/United States ; NS52724/NS/NINDS NIH HHS/United States ; R01 NS052724/NS/NINDS NIH HHS/United States ; R01 NS052724-05/NS/NINDS NIH HHS/United States ; P30 AG13846/AG/NIA NIH HHS/United States ; }, mesh = {Drug Delivery Systems/*methods ; Humans ; Mitochondria/drug effects/*metabolism ; Mitochondrial Diseases/*metabolism ; Neurodegenerative Diseases/etiology/*metabolism ; }, abstract = {Mitochondria are the power engine generating biochemical energy in the cell. Mitochondrial dysfunction and bioenergy deficiency is closely linked to the pathogenesis of neurodegenerative disorders. Mitochondria play a variety of roles by integrating extracellular signals and executing important intracellular events in neuronal survival and death. In this context, the regulation of mitochondrial function via therapeutic approaches may exert some salutary and neuroprotective mechanisms. Understanding the relationship of mitochondria-dependent pathogenesis may provide important pharmacological utility in the treatment of neurodegenerative conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Parkinson's disease. Indeed, the modulation of mitochondrial pathways is rapidly emerging as a novel therapeutic target. This review focuses on how mitochondria are involved in neurodegeneration and what therapeutics are available to target mitochondrial pathways.}, }
@article {pmid19697878, year = {2009}, author = {Banno, H and Katsuno, M and Suzuki, K and Iguchi, Y and Adachi, H and Tanaka, F and Sobue, G}, title = {[Molecular-targeted therapy for motor neuron disease].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {61}, number = {8}, pages = {891-900}, pmid = {19697878}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*therapy ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Butyrates/administration &amp; dosage ; DNA-Binding Proteins/genetics ; Dyslipidemias ; Free Radical Scavengers/therapeutic use ; Heat-Shock Proteins/antagonists &amp; inhibitors ; Histone Deacetylase Inhibitors ; Humans ; Leuprolide/therapeutic use ; Male ; Mice ; Muscular Disorders, Atrophic/*genetics/*therapy ; Mutation ; Nerve Growth Factors/therapeutic use ; Receptors, Androgen/physiology ; Superoxide Dismutase/genetics/physiology ; Superoxide Dismutase-1 ; }, abstract = {The mechanisms underlying selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remain unknown. There have been several important clinical trials on the treatment of ALS and treatment efficacy studies using mouse (SOD1) models of ALS. The latter revealed that diminished mutant SOD1 expression in the astrocytes delayed microglial activation and slowed disease progression. Dyslipidemia has been reported to have a protective effect in ALS patients. Current evidence has implicated a 43-kDa TAR DNA-binding protein (TDP-43) in the pathologenesis of ALS. Several mutations in TDP-43 were discovered in families with inherited motor neuron disease. Although phase III trials revealed that creatine monohydrate and IGF-1 was not beneficial for patients with ALS, favorable outcomes in SOD1 mice were reported with lithium, NADPH oxidase inhibitor, free-radical scavenger, and ammonium tetrathiomolybdate. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease affecting only males. Animal studies have revealed that the pathogenesis of SBMA depends on the serum testosterone level and that androgen deprivation mitigates neurodegeneration through inhibition of nuclear accumulation of the pathogenic androgen receptor (AR). Our studies have also identified several candidates for the treatment of SBMA. Selective inhibition of heat shock protein (HSP) facilitates the proteasomal degradation of pathogenic AR, leading to improvements in the signs and symptoms of SBMA mice. Oral administration of sodium butyrate--a histone deacetylase inhibitor--resulted in the improvement of neurological dysfunction in the SBMA mouse model, although its therapeutic dose range is narrow.}, }
@article {pmid19686775, year = {2010}, author = {Chapter, MC and White, CM and DeRidder, A and Chadwick, W and Martin, B and Maudsley, S}, title = {Chemical modification of class II G protein-coupled receptor ligands: frontiers in the development of peptide analogs as neuroendocrine pharmacological therapies.}, journal = {Pharmacology &amp; therapeutics}, volume = {125}, number = {1}, pages = {39-54}, pmid = {19686775}, issn = {1879-016X}, support = {Z01 AG000318-01/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Animals ; *Drug Design ; Humans ; Ligands ; Molecular Sequence Data ; Molecular Structure ; Neurosecretory Systems/*drug effects/metabolism ; Neurotransmitter Agents/chemistry/pharmacokinetics/*pharmacology/therapeutic use ; Peptide Hormones/chemistry/pharmacokinetics/*pharmacology/therapeutic use ; Receptors, G-Protein-Coupled/*drug effects/metabolism ; Receptors, Gastrointestinal Hormone/drug effects/metabolism ; Structure-Activity Relationship ; }, abstract = {Recent research and clinical data have begun to demonstrate the huge potential therapeutic importance of ligands that modulate the activity of the secretin-like, Class II, G protein-coupled receptors (GPCRs). Ligands that can modulate the activity of these Class II GPCRs may have important clinical roles in the treatment of a wide variety of conditions such as osteoporosis, diabetes, amyotrophic lateral sclerosis and autism spectrum disorders. While these receptors present important new therapeutic targets, the large glycoprotein nature of their cognate ligands poses many problems with respect to therapeutic peptidergic drug design. These native peptides often exhibit poor bioavailability, metabolic instability, poor receptor selectivity and resultant low potencies in vivo. Recently, increased attention has been paid to the structural modification of these peptides to enhance their therapeutic efficacy. Successful modification strategies have included d-amino acid substitutions, selective truncation, and fatty acid acylation of the peptide. Through these and other processes, these novel peptide ligand analogs can demonstrate enhanced receptor subtype selectivity, directed signal transduction pathway activation, resistance to proteolytic degradation, and improved systemic bioavailability. In the future, it is likely, through additional modification strategies such as addition of circulation-stabilizing transferrin moieties, that the therapeutic pharmacopeia of drugs targeted towards Class II secretin-like receptors may rival that of the Class I rhodopsin-like receptors that currently provide the majority of clinically used GPCR-based therapeutics. Currently, Class II-based drugs include synthesized analogs of vasoactive intestinal peptide for type 2 diabetes or parathyroid hormone for osteoporosis.}, }
@article {pmid19682544, year = {2009}, author = {Di Lazzaro, V and Pilato, F and Profice, P and Ranieri, F and Musumeci, G and Florio, L and Beghi, E and Frisullo, G and Capone, F and Sabatelli, M and Tonali, PA and Dileone, M}, title = {Motor cortex stimulation for ALS: a double blind placebo-controlled study.}, journal = {Neuroscience letters}, volume = {464}, number = {1}, pages = {18-21}, doi = {10.1016/j.neulet.2009.08.020}, pmid = {19682544}, issn = {1872-7972}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/*therapy ; Brain-Derived Neurotrophic Factor/biosynthesis/blood ; Double-Blind Method ; Female ; Humans ; Leukocytes, Mononuclear/metabolism ; Male ; Middle Aged ; Motor Cortex/*physiopathology ; Pilot Projects ; Transcranial Magnetic Stimulation ; }, abstract = {Preliminary data suggest that repetitive transcranial magnetic stimulation (rTMS) of the brain may produce a modest slowing of disease progression in amyotrophic lateral sclerosis (ALS). The present study was designed to test the hypothesis that rTMS given as continuous theta burst stimulation (cTBS), repeated monthly for one year, would affect ALS progression. We performed a double blind, placebo-controlled trial. Twenty patients with ALS were randomly allocated to blinded real or placebo stimulation. cTBS of the motor cortex was performed for five consecutive days every month for one year. Primary outcome was the rate of decline as evaluated with the revised ALS functional rating scale (ALSFRS-R). Treatment was well tolerated. There was no significant difference in the ALSFRS-R score deterioration between patients treated with real or placebo stimulation. ALSFRS-R mean scores declined from 32.0 (SD 7.1) at study entry to 23.1 (SD 6.3) at 12 months in patients receiving real cTBS and from 31.3 (SD 6.9) to 21.2 (SD 6.0) in those receiving placebo stimulation. Although cTBS proved a safe procedure, on the basis of the present findings a larger randomized confirmatory trial seems unjustified in ALS patients, at least in advanced stage of the disease.}, }
@article {pmid19672955, year = {2009}, author = {Lunn, JS and Sakowski, SA and Kim, B and Rosenberg, AA and Feldman, EL}, title = {Vascular endothelial growth factor prevents G93A-SOD1-induced motor neuron degeneration.}, journal = {Developmental neurobiology}, volume = {69}, number = {13}, pages = {871-884}, pmid = {19672955}, issn = {1932-846X}, support = {T32 NS007222/NS/NINDS NIH HHS/United States ; T32 NS007222-26/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/pathology ; Analysis of Variance ; Animals ; Blotting, Western ; Cell Death/genetics ; Cytoprotection ; Disease Models, Animal ; Immunohistochemistry ; In Situ Nick-End Labeling ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects/metabolism/pathology ; Nerve Degeneration/genetics/metabolism/pathology ; Receptors, Vascular Endothelial Growth Factor/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Spinal Cord/cytology/drug effects/*metabolism ; Superoxide Dismutase/*genetics ; Vascular Endothelial Growth Factors/metabolism/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by selective loss of motor neurons (MNs). Twenty percent of familial ALS cases are associated with mutations in Cu(2+)/Zn(2+) superoxide dismutase (SOD1). To specifically understand the cellular mechanisms underlying mutant SOD1 toxicity, we have established an in vitro model of ALS using rat primary MN cultures transfected with an adenoviral vector encoding a mutant SOD1, G93A-SOD1. Transfected cells undergo axonal degeneration and alterations in biochemical responses characteristic of cell death such as activation of caspase-3. Vascular endothelial growth factor (VEGF) is an angiogenic and neuroprotective growth factor that can increase axonal outgrowth, block neuronal apoptosis, and promote neurogenesis. Decreased VEGF gene expression in mice results in a phenotype similar to that seen in patients with ALS, thus linking loss of VEGF to the pathogenesis of MN degeneration. Decreased neurotrophic signals prior to and during disease progression may increase MN susceptibility to mutant SOD1-induced toxicity. In this study, we demonstrate a decrease in VEGF and VEGFR2 levels in the spinal cord of G93A-SOD1 ALS mice. Furthermore, in isolated MN cultures, VEGF alleviates the effects of G93A-SOD1 toxicity and neuroprotection involves phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling. Overall, these studies validate the usefulness of VEGF as a potential therapeutic factor for the treatment of ALS and give valuable insight into the responsible signaling pathways and mechanisms involved.}, }
@article {pmid19672653, year = {2009}, author = {Cenedese, A and Monneuse, O and Gruner, L and Tissot, E and Mennesson, N and Barth, X}, title = {Initial management of extensive mesenteric venous thrombosis: retrospective study of nine cases.}, journal = {World journal of surgery}, volume = {33}, number = {10}, pages = {2203-2208}, pmid = {19672653}, issn = {1432-2323}, mesh = {Adult ; Aged ; Aged, 80 and over ; Algorithms ; Anticoagulants ; Female ; Humans ; Intestines/*blood supply ; Ischemia/diagnostic imaging/etiology/*therapy ; Male ; Mesenteric Vascular Occlusion/complications/diagnostic imaging/*therapy ; Middle Aged ; Retrospective Studies ; Short Bowel Syndrome/prevention &amp; control ; Tomography, X-Ray Computed ; Treatment Outcome ; Venous Thrombosis/complications/diagnostic imaging/*therapy ; }, abstract = {BACKGROUND: The development of mesenteric venous thrombosis (MVT) does not necessarily require surgical intervention. The aim of this study was to assess the efficacy of avoiding early operative intervention, which can lead to significant sacrifice of the small bowel.<br><br>METHODS: Patients with MVT were identified using the inpatient registry for the years between 2003 and 2007. Each patient's past medical history, history of prior deep venous thrombosis or hypercoagulable state, clinical and biologic presentation, and computed tomography (CT) results were analyzed. The proportion of ischemic bowel observed on the CT scans was compared with the length of the bowel resected.<br><br>RESULTS: Nine patients were admitted for extensive MVT during the time period evaluated (six men, three women). All CT scans demonstrated signs of severe bowel ischemia, with a mean ischemic bowel proportion of 21% (range 5-45%). Four patients received medical management alone. Five patients underwent surgery. The mean admission time for these patients prior to the operation was 14.8 days (6-36 days). Surgery was required only in cases of intestinal perforation. The mean length of the bowel resections was 33 cm (20-45 cm). At 6 months after admission, none of the patients required parenteral nutrition. The mean follow-up evaluation period was 27 months (15-38 months). One patient died secondary to amyotrophic lateral sclerosis during the follow-up.<br><br>CONCLUSIONS: Initial nonsurgical management comprised of inpatient observation on a surgical ward along with systemic anticoagulation must be considered an alternative treatment strategy for MVT. This strategy delays surgery and therefore avoids short bowel syndrome.}, }
@article {pmid19670321, year = {2009}, author = {Bowser, R and Lacomis, D}, title = {Applying proteomics to the diagnosis and treatment of ALS and related diseases.}, journal = {Muscle &amp; nerve}, volume = {40}, number = {5}, pages = {753-762}, pmid = {19670321}, issn = {1097-4598}, support = {R01 NS042724/NS/NINDS NIH HHS/United States ; R21 ES013469/ES/NIEHS NIH HHS/United States ; R01 NS042724-04/NS/NINDS NIH HHS/United States ; R21 ES013469-02/ES/NIEHS NIH HHS/United States ; NS042724/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/metabolism/*therapy ; Animals ; Biomarkers/metabolism ; Humans ; Nervous System Diseases/diagnosis/metabolism/therapy ; Proteomics/*methods/trends ; }, abstract = {Protein-based biomarkers for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases (MNDs) have many potential clinical utilities, including diagnostic, prognostic, and drug development indications. During the past decade a number of potential protein biomarkers have been proposed for MNDs. Further verification studies, followed by large validation and qualification studies, are required to advance these initial discoveries toward clinical use. Study of additional patient populations, including disease mimics, is required during the validation phase of biomarker development. Important regulatory issues are discussed that will affect the timing and strategy for biomarker assay development in ALS and other MNDs. The continued development of protein biomarkers for MNDs requires extensive collaboration between academic clinicians and scientists in conjunction with the biotechnology and pharmaceutical industries.}, }
@article {pmid19657198, year = {2009}, author = {Linde, K}, title = {St. John's wort - an overview.}, journal = {Forschende Komplementarmedizin (2006)}, volume = {16}, number = {3}, pages = {146-155}, doi = {10.1159/000209290}, pmid = {19657198}, issn = {1661-4127}, mesh = {Antidepressive Agents/adverse effects/*therapeutic use ; Depressive Disorder/*drug therapy ; Depressive Disorder, Major/*drug therapy ; Herb-Drug Interactions ; Humans ; *Hypericum ; *Phytotherapy ; Plant Extracts/adverse effects/*therapeutic use ; Randomized Controlled Trials as Topic ; Risk Factors ; Somatoform Disorders/drug therapy ; }, abstract = {This article aims to summarize the current state of knowledge on St. John's wort (Hypericum perforatum L.) which is one of the oldest and best investigated medicinal herbs. Dried alcoholic extracts are the most important preparations on the market although a variety of other preparations are available. Depressive disorders according to modern diagnostic standards are the best known and most widely investigated indication although the more traditional, broader indication of 'psycho-vegetative disorders, depressive disorders, anxiety and/or nervous agitation', including diagnoses such as somatoform disorders, might more adequately describe what Hypericum extracts are actually used for by many practitioners. The exact mechanisms of action are still unclear, but the available research clearly shows that various bioactive constituents contribute to the clinical effects reported, often in a synergistic manner. Hypericum extracts have consistently shown activity in pharmacological models related to antidepressant effects. Randomized clinical trials show that Hypericum extracts are more effective than placebo and similarly effective as standard antidepressants while having better tolerability in the acute treatment of major depressive episodes. The most important risk associated with Hypericum extracts are interactions with other drugs. Therefore, physicians need to be informed whether their patients take St. John's wort products. If the risk of interactions is adequately taken into account, high quality Hypericum extracts are an effective and safe tool in the hand of qualified health profession-als in primary care.}, }
@article {pmid19651651, year = {2009}, author = {Cifra, A and Nani, F and Sharifullina, E and Nistri, A}, title = {A repertoire of rhythmic bursting produced by hypoglossal motoneurons in physiological and pathological conditions.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {364}, number = {1529}, pages = {2493-2500}, pmid = {19651651}, issn = {1471-2970}, mesh = {Action Potentials/drug effects/physiology ; Animals ; Brain Stem/*physiology ; Glutamic Acid/metabolism ; Humans ; Hydrogen Peroxide/toxicity ; Hypoglossal Nerve/*physiology ; Mice ; *Models, Biological ; Motor Neurons/drug effects/*physiology ; Neurodegenerative Diseases/etiology/*physiopathology ; Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects/physiology ; *Periodicity ; Riluzole/pharmacology ; Synaptic Transmission/drug effects/*physiology ; Tongue/innervation/*physiology ; }, abstract = {The brainstem nucleus hypoglossus contains motoneurons that provide the exclusive motor nerve supply to the tongue. In addition to voluntary tongue movements, tongue muscles rhythmically contract during a wide range of physiological activities, such as respiration, swallowing, chewing and sucking. Hypoglossal motoneurons are destroyed early in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease often associated with a deficit in the transport system of the neurotransmitter glutamate. The present study shows how periodic electrical discharges of motoneurons are mainly produced by a neuronal network that drives them into bursting mode via glutamatergic excitatory synapses. Burst activity is, however, modulated by the intrinsic properties of motoneurons that collectively synchronize their discharges via gap junctions to create 'group bursters'. When glial uptake of glutamate is blocked, a distinct form of pathological bursting spontaneously emerges and leads to motoneuron death. Conversely, H(2)O(2)-induced oxidative stress strongly increases motoneuron excitability without eliciting bursting. Riluzole (the only drug currently licensed for the treatment of ALS) suppresses bursting of hypoglossal motoneurons caused by blockage of glutamate uptake and limits motoneuron death. These findings highlight how different patterns of electrical oscillations of brainstem motoneurons underpin not only certain physiological activities, but also motoneuron death induced by glutamate transporter impairment.}, }
@article {pmid19651206, year = {2010}, author = {Martin, LJ}, title = {The mitochondrial permeability transition pore: a molecular target for amyotrophic lateral sclerosis therapy.}, journal = {Biochimica et biophysica acta}, volume = {1802}, number = {1}, pages = {186-197}, pmid = {19651206}, issn = {0006-3002}, support = {R01 NS052098/NS/NINDS NIH HHS/United States ; NS052098/NS/NINDS NIH HHS/United States ; R01 AG016282-09/AG/NIA NIH HHS/United States ; AG016282/AG/NIA NIH HHS/United States ; R01 NS065895/NS/NINDS NIH HHS/United States ; R01 AG016282/AG/NIA NIH HHS/United States ; NS065895/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*metabolism ; Animals ; Cell Death ; Humans ; Mice ; Mitochondria/metabolism ; Mitochondrial Membrane Transport Proteins/*metabolism ; Mitochondrial Permeability Transition Pore ; Models, Biological ; }, abstract = {Effective therapies are needed for the treatment of amyotrophic lateral sclerosis (ALS), a fatal type of motor neuron disease. Morphological, biochemical, molecular genetic, and cell/animal model studies suggest that mitochondria have potentially diverse roles in neurodegenerative disease mechanisms and neuronal cell death. In human ALS, abnormalities have been found in mitochondrial structure, mitochondrial respiratory chain enzymes, and mitochondrial cell death proteins indicative of some non-classical form of programmed cell death. Mouse models of ALS are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria. This minireview summarizes work on the how malfunctioning mitochondria might contribute to neuronal death in ALS through the biophysical entity called the mitochondrial permeability pore (mPTP). The major protein components of the mPTP are enriched in mouse motor neurons. Early in the course of disease in ALS mice expressing human mutant superoxide dismutase-1, mitochondria in motor neurons undergo trafficking abnormalities and dramatic remodeling resulting in the formation of mega-mitochondria and coinciding with increased protein carbonyl formation and nitration of mPTP components. The genetic deletion of a major mPTP component, cyclophilin D, has robust effects in ALS mice by delaying disease onset and extending survival. Thus, attention should be directed to the mPTP as a rational target for the development of drugs designed to treat ALS.}, }
@article {pmid19649300, year = {2009}, author = {Gill, A and Kidd, J and Vieira, F and Thompson, K and Perrin, S}, title = {No benefit from chronic lithium dosing in a sibling-matched, gender balanced, investigator-blinded trial using a standard mouse model of familial ALS.}, journal = {PloS one}, volume = {4}, number = {8}, pages = {e6489}, pmid = {19649300}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Body Weight ; *Disease Models, Animal ; Female ; Humans ; Lithium Carbonate/administration &amp; dosage/*therapeutic use ; Male ; Mice ; Proportional Hazards Models ; Severity of Illness Index ; Survival Analysis ; }, abstract = {BACKGROUND: In any animal model of human disease a positive control therapy that demonstrates efficacy in both the animal model and the human disease can validate the application of that animal model to the discovery of new therapeutics. Such a therapy has recently been reported by Fornai et al. using chronic lithium carbonate treatment and showing therapeutic efficacy in both the high-copy SOD1G93A mouse model of familial amyotrophic lateral sclerosis (ALS), and in human ALS patients.<br><br>Seeking to verify this positive control therapy, we tested chronic lithium dosing in a sibling-matched, gender balanced, investigator-blinded trial using the high-copy (average 23 copies) SOD1G93A mouse (n = 27-28/group). Lithium-treated mice received single daily 36.9 mg/kg i.p. injections from 50 days of age through death. This dose delivered 1 mEq/kg (6.94 mg/kg/day lithium ions). Neurological disease severity score and body weight were determined daily during the dosing period. Age at onset of definitive disease and survival duration were recorded. Summary measures from individual body weight changes and neurological score progression, age at disease onset, and age at death were compared using Kaplan-Meier and Cox proportional hazards analysis. Our study did not show lithium efficacy by any measure.<br><br>CONCLUSIONS/SIGNIFICANCE: Rigorous survival study design that includes sibling matching, gender balancing, investigator blinding, and transgene copy number verification for each experimental subject minimized the likelihood of attaining a false positive therapeutic effect in this standard animal model of familial ALS. Results from this study do not support taking lithium carbonate into human clinical trials for ALS.}, }
@article {pmid19638399, year = {2009}, author = {Kupershmidt, L and Weinreb, O and Amit, T and Mandel, S and Carri, MT and Youdim, MB}, title = {Neuroprotective and neuritogenic activities of novel multimodal iron-chelating drugs in motor-neuron-like NSC-34 cells and transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {23}, number = {11}, pages = {3766-3779}, doi = {10.1096/fj.09-130047}, pmid = {19638399}, issn = {1530-6860}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Apoptosis/drug effects ; Brain-Derived Neurotrophic Factor/biosynthesis ; Cell Differentiation/drug effects ; Cell Line ; Disease Models, Animal ; Extracellular Signal-Regulated MAP Kinases/metabolism ; GAP-43 Protein/biosynthesis ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Hydrogen Peroxide/toxicity ; Hydroxyquinolines/therapeutic use ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Iron Chelating Agents/*therapeutic use ; Mice ; Mice, Transgenic ; Molsidomine/analogs &amp; derivatives/toxicity ; Motor Neurons/*drug effects/metabolism ; Neurites/drug effects/physiology ; Neuroprotective Agents/*therapeutic use ; Phosphopyruvate Hydratase/biosynthesis ; Piperazines/therapeutic use ; Proto-Oncogene Proteins c-akt/metabolism ; Receptors, Transferrin/biosynthesis ; Signal Transduction/drug effects ; Superoxide Dismutase/toxicity ; Superoxide Dismutase-1 ; Vascular Endothelial Growth Factor A/biosynthesis ; }, abstract = {Novel therapeutic approaches for the treatment of neurodegenerative disorders comprise drug candidates designed specifically to act on multiple central nervous system targets. We have recently synthesized multifunctional, nontoxic, brain-permeable iron-chelating drugs, M30 and HLA20, possessing the N-propargylamine neuroprotective moiety of rasagiline (Azilect) and the iron-chelating moiety of VK28. The present study demonstrates that M30 and HLA20 possess a wide range of pharmacological activities in mouse NSC-34 motor neuron cells, including neuroprotective effects against hydrogen peroxide- and 3-morpholinosydnonimine-induced neurotoxicity, induction of differentiation, and up-regulation of hypoxia-inducible factor (HIF)-1alpha and HIF-target genes (enolase1 and vascular endothelial growth factor). Both compounds induced NSC-34 neuritogenesis, accompanied by a marked increase in the expression of brain-derived neurotrophic factor and growth-associated protein-43, which was inhibited by PD98059 and GF109203X, indicating the involvement of mitogen-activated protein kinase and protein kinase C pathways. A major finding was the ability of M30 to significantly extend the survival of G93A-SOD1 amyotrophic lateral sclerosis mice and delay the onset of the disease. These properties of the novel multimodal iron-chelating drugs possessing neuroprotective/neuritogenic activities may offer future therapeutic possibilities for motor neurodegenerative diseases.}, }
@article {pmid19635362, year = {2009}, author = {Fernández, C and Larrechi, MS and Callao, MP}, title = {Study of the influential factors in the simultaneous photocatalytic degradation process of three textile dyes.}, journal = {Talanta}, volume = {79}, number = {5}, pages = {1292-1297}, doi = {10.1016/j.talanta.2009.05.045}, pmid = {19635362}, issn = {1873-3573}, mesh = {Coloring Agents/chemistry/*radiation effects ; Hydrogen-Ion Concentration ; Kinetics ; *Photolysis ; Rhodamines ; *Textiles ; Titanium ; }, abstract = {The influence of several factors in the simultaneous photocatalytic degradation of three textile dyes - Acid Red 97, Acid Orange 61 and Acid Brown 425 - has been studied using a fractional factorial design 2(5-1). The considered factors were: the initial concentration of each dye, the catalyst concentration (TiO(2)) and pH. First, we developed a rapid analytical methodology based on recording UV-visible spectra during the degradation process and a data treatment using multivariate curve resolution with alternating least squares (MCR-ALS), which enabled the three dyes to be quantified simultaneously despite the overlap of their spectra. The kinetic constant of degradation for each dye in all the experiments was evaluated. In all cases the degradation followed a first order kinetics. For a significance level of 5%, the most important factor in the photodegradation of each dye is the concentration of Acid Red 97, the degradation is more effective at higher pHs and, in the studied range, the concentration of the catalyst is not important.}, }
@article {pmid19634179, year = {2009}, author = {Brunet, N and Tarabal, O and Esquerda, JE and Calderó, J}, title = {Excitotoxic motoneuron degeneration induced by glutamate receptor agonists and mitochondrial toxins in organotypic cultures of chick embryo spinal cord.}, journal = {The Journal of comparative neurology}, volume = {516}, number = {4}, pages = {277-290}, doi = {10.1002/cne.22118}, pmid = {19634179}, issn = {1096-9861}, mesh = {Animals ; Calcium Signaling/drug effects ; Chick Embryo ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Agonists/*toxicity ; Glutamic Acid/toxicity ; Kainic Acid/toxicity ; Malonates/toxicity ; Mitochondria/drug effects ; Motor Neuron Disease/*pathology ; Motor Neurons/drug effects/*pathology ; N-Methylaspartate/toxicity ; Nerve Degeneration/*chemically induced/pathology ; Neuroprotective Agents/pharmacology ; Neurotoxins/toxicity ; Nitro Compounds/toxicity ; Organ Culture Techniques ; Propionates/toxicity ; Riluzole/pharmacology ; Spinal Cord/drug effects/*pathology ; }, abstract = {Glutamate receptor-mediated excitotoxicity and mitochondrial dysfunction appear to play an important role in motoneuron (MN) degeneration in amyotrophic lateral sclerosis (ALS). In the present study we used an organotypic slice culture of chick embryo spinal cord to explore the responsiveness of mature MNs to different excitotoxic stimuli and mitrochondrial inhibition. We found that, in this system, MNs are highly vulnerable to excitotoxins such as glutamate, N-methyl-D-aspartate (NMDA), and kainate (KA), and that the neuroprotective drug riluzole rescues MNs from KA-mediated excitotoxic death. MNs are also sensitive to chronic mitochondrial inhibition induced by malonate and 3-nitropropionic acid (3-NP) in a dose-dependent manner. MN degeneration induced by treatment with mitochondrial toxins displays structural changes similar to those seen following excitotoxicity and can be prevented by applying either the antiexcitotoxic drug 6-cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX) or riluzole. Excitotoxicity results in an increased frequency of normal spontaneous Ca2+ oscillations in MNs, which is followed by a sustained deregulation of intracellular Ca2+. Tolerance to excitotoxic MN death resulting from chronic exposure to excitotoxins correlates with a reduced excitotoxin-induced increase in intracellular Ca2+ and increased thapsigargin-sensitive Ca2+ stores.}, }
@article {pmid19634028, year = {2010}, author = {Pereira, EA and Turner, MR and Wass, JA and Talbot, K}, title = {Reduction of elevated IGF-1 levels in coincident amyotrophic lateral sclerosis and acromegaly.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {1-2}, pages = {255-257}, pmid = {19634028}, issn = {1471-180X}, support = {G0701923/MRC_/Medical Research Council/United Kingdom ; TURNER/NOV07/6501/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Acromegaly/blood/complications/drug therapy ; Amyotrophic Lateral Sclerosis/*blood/*complications ; Antineoplastic Agents/therapeutic use ; Fatal Outcome ; Humans ; Insulin-Like Growth Factor I/*metabolism ; Male ; Middle Aged ; Peptides, Cyclic/*therapeutic use ; Somatostatin/*analogs &amp; derivatives/therapeutic use ; }, abstract = {We report a patient presenting with ALS in whom acromegaly was later confirmed. Insulin-like growth factor-1 (IGF-1) has been tried in the treatment of ALS and despite equivocal results from clinical trials, efforts have continued to try to harness the significant positive effects on motor neuron growth observed in vitro and in survival of mouse models of the disease. One subsequent study has reported an association between higher circulating serum IGF-1 levels and longer disease duration in ALS patients. Concern therefore arose in our case that treatment of the acromegaly with a somatostatin analogue might adversely affect the natural course of his ALS through lowering of potentially beneficial IGF-1 levels. Through clinical observation and prognostic modelling we suggest that this concern was unfounded. The potential interaction of these two rarely coincident disorders in our patient is discussed.}, }
@article {pmid19629566, year = {2010}, author = {Schepelmann, K and Winter, Y and Spottke, AE and Claus, D and Grothe, C and Schröder, R and Heuss, D and Vielhaber, S and Mylius, V and Kiefer, R and Schrank, B and Oertel, WH and Dodel, R}, title = {Socioeconomic burden of amyotrophic lateral sclerosis, myasthenia gravis and facioscapulohumeral muscular dystrophy.}, journal = {Journal of neurology}, volume = {257}, number = {1}, pages = {15-23}, pmid = {19629566}, issn = {1432-1459}, mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/drug therapy/*economics/therapy ; Cross-Sectional Studies ; Dementia/economics ; Female ; Germany ; Health Care Costs ; Health Expenditures ; Humans ; Insurance, Health ; Male ; Middle Aged ; Muscular Dystrophy, Facioscapulohumeral/drug therapy/*economics/therapy ; Myasthenia Gravis/drug therapy/*economics/therapy ; Socioeconomic Factors ; Young Adult ; }, abstract = {Neuromuscular disorders (NMD) are chronic devastating diseases. The aim of this multicenter cross-sectional study was to evaluate the socioeconomic impact of three NMDs in Germany. Patients (n = 107) with amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG) or facioscapulohumeral muscular dystrophy (FSHD) were recruited consecutively in seven centers in Germany. The health-economic data were collected using a "bottom-up" approach consisting of comprehensive questionnaires and patient diaries. Costs were evaluated from the societal perspective in 2009 Euros (EUR). Total annual costs from the societal perspective were EUR 36,380 (95% CI 27,090-47,970) per patient in ALS, EUR 26,240 (95% CI 17,770-37,940) in FSHD and EUR 14,950 (95% CI 10,470-21,730) in MG. The main components of costs were the expenditures of health insurance and the loss of productivity of patients and their caregivers. The following independent cost-driving factors were identified: disease severity, assistance in activities of daily living (ADL), dementia and younger age in ALS, disease severity in FSHD and assistance in ADL, disease severity and assistance in ADL in MG. The socioeconomic burden of NMDs in Germany is considerable. Further studies evaluating both the health-economic and clinical effects of NMD treatment as well as disease management programs and benchmarking activities are necessary.}, }
@article {pmid19626161, year = {2008}, author = {Lulé, D and Häcker, S and Ludolph, A and Birbaumer, N and Kübler, A}, title = {Depression and quality of life in patients with amyotrophic lateral sclerosis.}, journal = {Deutsches Arzteblatt international}, volume = {105}, number = {23}, pages = {397-403}, pmid = {19626161}, issn = {1866-0452}, abstract = {INTRODUCTION: There is increasing debate on the issue of whether to facilitate the end-of-life decisions of severely disabled patients with diseases such as amyotrophic lateral sclerosis (ALS). Our two studies were intended to explore the emotional state and quality of life of patients with ALS.<br><br>METHODS: Two studies were performed to investigate depression and the quality of life in ALS patients: one was a longitudinal study, the other a comparison of ALS patients to normal control subjects.<br><br>RESULTS: These studies found no correlation between physical disability in ALS and either depression or the quality of life. The severity of depression was found to be inversely related to educational status. In ALS patients the quality of life was comparable with healthy controls.<br><br>DISCUSSION: The rationale for not providing life-sustaining treatment to severely disabled patients is that a poor quality of life is expected after such treatment. Our studies have shown, however, that ALS patients can experience a satisfactory quality of life without depressive manifestations even if they are severely physically impaired, including in the terminal phase.}, }
@article {pmid19626053, year = {2009}, author = {Hwang, DH and Lee, HJ and Park, IH and Seok, JI and Kim, BG and Joo, IS and Kim, SU}, title = {Intrathecal transplantation of human neural stem cells overexpressing VEGF provide behavioral improvement, disease onset delay and survival extension in transgenic ALS mice.}, journal = {Gene therapy}, volume = {16}, number = {10}, pages = {1234-1244}, doi = {10.1038/gt.2009.80}, pmid = {19626053}, issn = {1476-5462}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Animals ; Disease Models, Animal ; Graft Survival ; Humans ; Injections, Spinal ; Mice ; Mice, Transgenic ; Microscopy, Fluorescence ; Motor Activity/physiology ; Motor Neurons/metabolism ; Neurons/metabolism/*transplantation ; Spinal Cord/metabolism ; Stem Cell Transplantation/*methods ; Stem Cells/metabolism ; Survival Analysis ; Vascular Endothelial Growth Factor A/*biosynthesis/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult onset motoneuron disease. The etiology and precise pathogenic mechanisms of the disease remain unknown, and there is no effective treatment. Vascular endothelial growth factor (VEGF) has recently been shown to exert direct neurotrophic and neuroprotective effects in animal models of ALS. Here we show that intrathecal transplantation of immortalized human neural stem cells (NSCs) overexpressing human VEGF gene (HB1.F3.VEGF) significantly delayed disease onset and prolonged the survival of the SOD1G93A mouse model of ALS. At 4 weeks, post-transplantation grafted cells were found within the gray matter of the spinal cord. Furthermore, transplanted F3.VEGF cells that express neuronal phenotype (MAP2+) were found in the anterior horn of the spinal cord gray matter indicating that the transplanted human NSCs migrated into the gray matter, took the correct structural position, integrated into the spinal cord anterior horn and differentiated into motoneurons. Intrathecal transplantation of F3.VEGF cells provides a neuroprotective effect in the diseased spinal cord by concomitant downregulation of proapoptotic proteins and upregulation of antiapoptotic proteins. Our results suggest that this treatment modality of intrathecal transplantation of human NSCs genetically modified to overexpress neurotrophic factor(s) might be of value in the treatment of ALS patients without significant adverse effects.}, }
@article {pmid19621534, year = {2009}, author = {Ferullo, CM and Mascolo, M and Ferrandes, G and Caponnetto, C}, title = {[Amyotrophic lateral sclerosis: an assessment of the needs of patients and caregivers in the Liguria region of Italy].}, journal = {Giornale italiano di medicina del lavoro ed ergonomia}, volume = {31}, number = {1 Suppl A}, pages = {A16-23}, pmid = {19621534}, issn = {1592-7830}, mesh = {Adaptation, Psychological ; Adult ; Amyotrophic Lateral Sclerosis/diagnosis/*psychology ; Caregivers/*psychology/statistics &amp; numerical data ; Counseling/methods ; Decision Making ; Female ; Health Surveys ; Humans ; Italy ; Male ; Middle Aged ; *Needs Assessment ; *Palliative Care ; Patients/*psychology/statistics &amp; numerical data ; Professional-Family Relations ; Self-Help Groups ; Social Isolation/psychology ; Social Support ; Stress, Psychological ; Surveys and Questionnaires ; }, abstract = {UNLABELLED: Two surveys were carried out to assess ALS patients and caregivers' care and treatment needs in Liguria Region mainly during the first stage of the disease. One inquiry concerned patients during their first year of illness--the other concerned caregivers during different stages of the disease, excepting the terminal one.<br><br>METHODS: A semistructured interview was given to 18 patients during first year from diagnosis. The Caregivers Needs Assessment questionnaire was administered to 27 caregivers during different phases of their parents' illness.<br><br>RESULTS: The clinical interview emphasized that the patients need to be prepared for the future. In spite of strong (75%), or uncontrolled (50%) emotional aspects, in our group an active and fighting attitude (45%) prevailed. Caregivers' needs appeared to be generally high for the whole group, they mainly requested to be enabled to meet the appropriate assistance, to be informed on the cure and to cooperate and be involved in decision taking. Needs for spiritual, psychological or self-help and support group were apparently little required but during the first year emotional and social support are more desired.<br><br>CONCLUSION: This survey shows that the psychological support for such patients must be planned for each of them and trimmed upon their single peculiarities after a careful evaluation and enhancement of their capability in facing difficulties. Caregivers barely asked for personal help or support--rather they asked to be enabled to tackle the practical aspects of the disease and for an improved cooperation share with doctors.}, }
@article {pmid19618103, year = {2009}, author = {Prieto, R and Pascual, JM and Gutiérrez, R and Santos, E}, title = {Recovery from paraplegia after the treatment of spinal dural arteriovenous fistula: case report and review of the literature.}, journal = {Acta neurochirurgica}, volume = {151}, number = {11}, pages = {1385-1397}, doi = {10.1007/s00701-009-0439-6}, pmid = {19618103}, issn = {0942-0940}, mesh = {Aged ; Central Nervous System Vascular Malformations/pathology/*physiopathology/surgery ; Disease Progression ; Female ; Gait Disorders, Neurologic/etiology/*physiopathology/surgery ; Humans ; Male ; Middle Aged ; Paraplegia/etiology/*physiopathology/surgery ; Prognosis ; Recovery of Function/physiology ; Spinal Cord/pathology/*physiopathology ; Spinal Cord Diseases/pathology/*physiopathology/surgery ; Treatment Outcome ; }, abstract = {BACKGROUND: Spinal dural arteriovenous fistula (SDAVF) is a rare and enigmatic disease. Functional outcome is particularly uncertain for the small group of patients that are unable to stand at the time of diagnosis (grade 5 gait disturbance on the Aminoff-Logue scale, ALS). The objective of this study is to examine the final functional outcome of patients with SDAVF in grade 5 gait ALS before treatment.<br><br>METHODS: We conducted a PubMed search using the keyword "spinal dural arteriovenous fistula." A review of the clinical series and single well-detailed case reports of SDAVF gathered 106 patients with grade 5 gait ALS on the initial examination. Additionally, we report the case of a 56-year-old man presenting acute paraplegia and urinary retention on admission who had complained of sporadic motor and sphincter disturbances for 1 year. Spine T2-weighted MR imaging showed a central hyperintensity within the spinal cord, and the angiography demonstrated a T-11 SDAVF. Interruption of the fistula was performed through an urgent one-level laminectomy.<br><br>RESULTS: Grade 5 gait ALS was present in 25% of the patients with SDAVF included in the clinical series. Latest follow-up showed that gait disturbance improved in 73% of patients after treatment, although less than 6% became grade 1 gait ALS. Micturition disturbances improved in 39%. Exploration of our patient showed improvement to grade 1 gait ALS 1 year after the surgical treatment.<br><br>CONCLUSION: Interruption of SDAVF in paraplegic patients may improve the final functional gait outcome in some cases. No complete recovery (grade 0 gait ALS) was achieved after treatment. Micturition disturbances had a worse prognosis than motor deficits.}, }
@article {pmid19609632, year = {2010}, author = {Gal, S and Zheng, H and Fridkin, M and Youdim, MB}, title = {Restoration of nigrostriatal dopamine neurons in post-MPTP treatment by the novel multifunctional brain-permeable iron chelator-monoamine oxidase inhibitor drug, M30.}, journal = {Neurotoxicity research}, volume = {17}, number = {1}, pages = {15-27}, pmid = {19609632}, issn = {1476-3524}, mesh = {3,4-Dihydroxyphenylacetic Acid/metabolism ; Analysis of Variance ; Animals ; Brain Chemistry/drug effects ; Cell Division/drug effects ; Chromatography, High Pressure Liquid/methods ; Corpus Striatum/*pathology ; Disease Models, Animal ; Dopamine/*metabolism ; Dose-Response Relationship, Drug ; Drug Interactions ; Electrochemistry/methods ; Homovanillic Acid/metabolism ; Hydroxyquinolines/*therapeutic use ; MPTP Poisoning/*drug therapy/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Neurons/*drug effects ; Receptors, Transferrin/metabolism ; Serotonin/metabolism ; Substantia Nigra/*pathology ; Time Factors ; Tyrosine 3-Monooxygenase/metabolism ; }, abstract = {The anti-Parkinson iron chelator-monoamine oxidase inhibitor M30 [5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline] was shown to possess neuroprotective activities in vitro and in vivo, against several insults applicable to several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and ALS. In the present study we sought to examine the effect of M30 on a pre-existing lesion induced by the parkinsonism-inducing toxin, MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In this neurorescue paradigm, M30 orally administered to mice for 14 days (2.5 mg/kg/day) following MPTP was shown to significantly elevate striatal dopamine levels, reduce its metabolism, and elevate tyrosine-hydroxylase protein levels (from 25.86 +/- 5.10 to 68.35 +/- 10.67% of control) and activity (from 7.52 +/- 0.98 to 16.33 +/- 2.92 pmol/mg protein/min). Importantly, M30 elevated MPTP-reduced dopaminergic (from 62.8 +/- 4.1 to 84.2 +/- 5.9% of control) and transferrin receptor (from 31.3 +/- 2.6 to 80.4 +/- 7.6% of control) cell count in the SNpc. Finally, M30 was shown to decrease mitosis, thus providing additional protection. These findings suggest that brain-permeable M30 may clearly be of clinical importance for the treatment of PD.}, }
@article {pmid19607994, year = {2009}, author = {Birbaumer, N and Ramos Murguialday, A and Weber, C and Montoya, P}, title = {Neurofeedback and brain-computer interface clinical applications.}, journal = {International review of neurobiology}, volume = {86}, number = {}, pages = {107-117}, doi = {10.1016/S0074-7742(09)86008-X}, pmid = {19607994}, issn = {0074-7742}, mesh = {*Biofeedback, Psychology ; Brain/blood supply/*physiology ; *Communication Devices for People with Disabilities ; Humans ; Image Processing, Computer-Assisted ; Magnetic Resonance Imaging ; *Man-Machine Systems ; Oxygen/blood ; *User-Computer Interface ; }, abstract = {Most of the research devoted to BMI development consists of methodological studies comparing different online mathematical algorithms, ranging from simple linear discriminant analysis (LDA) (Dornhege et al., 2007) to nonlinear artificial neural networks (ANNs) or support vector machine (SVM) classification. Single cell spiking for the reconstruction of hand movements requires different statistical solutions than electroencephalography (EEG)-rhythm classification for communication. In general, the algorithm for BMI applications is computationally simple and differences in classification accuracy between algorithms used for a particular purpose are small. Only a very limited number of clinical studies with neurological patients are available, most of them single case studies. The clinical target populations for BMI-treatment consist primarily of patients with amyotrophic lateral sclerosis (ALS) and severe CNS damage including spinal cord injuries and stroke resulting in substantial deficits in communication and motor function. However, an extensive body of literature started in the 1970s using neurofeedback training. Such training implemented to control various EEG-measures provided solid evidence of positive effects in patients with otherwise pharmacologically intractable epilepsy, attention deficit disorder, and hyperactivity ADHD. More recently, the successful introduction and testing of real-time fMRI and a NIRS-BMI opened an exciting field of interest in patients with psychopathological conditions.}, }
@article {pmid19593125, year = {2009}, author = {Van Damme, P and Robberecht, W}, title = {Recent advances in motor neuron disease.}, journal = {Current opinion in neurology}, volume = {22}, number = {5}, pages = {486-492}, doi = {10.1097/WCO.0b013e32832ffbe3}, pmid = {19593125}, issn = {1473-6551}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*therapy ; DNA-Binding Proteins/genetics ; Genetic Predisposition to Disease ; Genotype ; Humans ; Mutation ; Patient Care Team ; Positive-Pressure Respiration ; Riluzole/therapeutic use ; Treatment Outcome ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is the most common and most aggressive form of adult onset motor neuron degeneration. Despite intensive research, riluzole remains the only drug with proven efficacy. The cause and pathogenesis of the motor neuron degeneration in ALS appears to be a complex and multifactorial process. In this study, we review recent advances in our understanding of the molecular basis of sporadic and familial forms of ALS and improvements in the treatment of ALS patients.<br><br>RECENT FINDINGS: The discovery of mutations in the DNA/RNA-binding proteins transactive response DNA-binding protein 43 (TDP-43) and fused in sarcoma in familial ALS and the cytosolic sequestration of TDP-43 occurring in sporadic ALS opens new avenues in ALS research and suggests that altered RNA processing may be involved in the disease pathogenesis. The survival of ALS patients continues to increase most likely due to noninvasive respiratory ventilation, early percutaneous endoscopic gastrostomy and multidisciplinary care in ALS clinics.<br><br>SUMMARY: Recent insights in the pathology and genetics of ALS have improved our understanding of motor neuron degeneration and will hopefully lead to novel treatment strategies in ALS. Awaiting these, the beneficial effect of multidisciplinary care of ALS patients on survival and quality of life has become clear.}, }
@article {pmid19582217, year = {2009}, author = {Choonara, YE and Pillay, V and Du Toit, LC and Modi, G and Naidoo, D and Ndesendo, VMK and Sibambo, SR}, title = {Trends in the molecular pathogenesis and clinical therapeutics of common neurodegenerative disorders.}, journal = {International journal of molecular sciences}, volume = {10}, number = {6}, pages = {2510-2557}, pmid = {19582217}, issn = {1422-0067}, mesh = {Alzheimer Disease/drug therapy/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Anticonvulsants/therapeutic use ; Antipsychotic Agents/therapeutic use ; Cholinergic Antagonists/therapeutic use ; Dopamine Agents/therapeutic use ; Humans ; Huntingtin Protein ; Huntington Disease/drug therapy/metabolism/pathology ; Nerve Tissue Proteins/metabolism ; Neurodegenerative Diseases/drug therapy/metabolism/*pathology ; Neurons/metabolism ; Parkinson Disease/drug therapy/metabolism/pathology ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; }, abstract = {The term neurodegenerative disorders, encompasses a variety of underlying conditions, sporadic and/or familial and are characterized by the persistent loss of neuronal subtypes. These disorders can disrupt molecular pathways, synapses, neuronal subpopulations and local circuits in specific brain regions, as well as higher-order neural networks. Abnormal network activities may result in a vicious cycle, further impairing the integrity and functions of neurons and synapses, for example, through aberrant excitation or inhibition. The most common neurodegenerative disorders are Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis and Huntington's disease. The molecular features of these disorders have been extensively researched and various unique neurotherapeutic interventions have been developed. However, there is an enormous coercion to integrate the existing knowledge in order to intensify the reliability with which neurodegenerative disorders can be diagnosed and treated. The objective of this review article is therefore to assimilate these disorders' in terms of their neuropathology, neurogenetics, etiology, trends in pharmacological treatment, clinical management, and the use of innovative neurotherapeutic interventions.}, }
@article {pmid19567181, year = {2009}, author = {Xiang, PC and Yang, H and Guo, WA and Zhang, S and Song, LP and Ju, LX and Zhang, X and Zhang, EM and Yang, JN and Sun, J}, title = {[The clinical application of bi-level positive airway pressure noninvasive ventilator for home mechanical ventilation via tracheostomy in patients with amyotrophic lateral sclerosis].}, journal = {Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases}, volume = {32}, number = {2}, pages = {107-110}, pmid = {19567181}, issn = {1001-0939}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*therapy ; Blood Gas Analysis ; Feasibility Studies ; Female ; Humans ; Male ; Middle Aged ; Positive-Pressure Respiration ; *Respiration, Artificial ; *Tracheotomy ; Treatment Outcome ; }, abstract = {OBJECTIVE: To study the feasibility of the bi-level positive airway pressure (BiPAP) non-invasive ventilator used in home mechanical ventilation for long-term tracheostomy-mechanical ventilation (TMV) in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Sixteen patients (12 men and 4 women, mean age 59 years) with ALS were selected for this study at Respiratory Department of the Shougang Hospital, Peking University from January 2002 to March 2008. After the disease had been controlled by anti-infective therapy and comprehensive treatment, the patients received TMV, through the improved ("Xiang's" connection) non-invasive BiPAP ventilator connected with tracheotomy tube, and on-going home mechanical ventilation (HMV). The blood gas was evaluated during invasive ventilation and non-invasive ventilation before discharge. Family members of the patients were trained for the use of non-invasive ventilators. The use of ventilators and the patients' condition were regularly followed and the survival rate calculated. Statistical analysis was carried out by using one-way ANOVA.<br><br>RESULTS: There was no statistical difference in the blood gas before the use of non-invasive ventilator, 2 h and 1 d after the use of non-invasive ventilator, and before discharge, PaCO2 [(36+/-10), (42+/-11), (41+/-10), (42+/-11) mm Hg (1 mm Hg=0.133 kPa)], PaO2 [(84+/-11), (81+/-12), (87+/-14), (86+/-12) mm Hg], SaO2 [(96.7+/-1.3)%, (96.5+/-0.8)%, (96.8+/-1.2)%, (96.5+/-1.0)%] respectively, (F=1.21, 0.59, 0.97, 0.41, respectively, all P>0.05). All patients had no complaint of uncomfortable use, no intolerance to ventilators, and no ventilator breakdown. Fifteen patients were alive at the end of the follow-up (July 31, 2008). The mean time of using non-invasive ventilator was 39 months (range 4 to 66 months).<br><br>CONCLUSION: For ALS patients who need long-term ventilation support, the use of BiPAP non-invasive ventilators is a safe and effective alternative for invasive ventilators.}, }
@article {pmid21475541, year = {2009}, author = {Ul Hassan, A and Hassan, G and Rasool, Z}, title = {Role of stem cells in treatment of neurological disorder.}, journal = {International journal of health sciences}, volume = {3}, number = {2}, pages = {227-233}, pmid = {21475541}, issn = {1658-7774}, abstract = {Stem cells or mother or queen of all cells are pleuropotent and have the remarkable potential to develop into many different cell types in the body. Serving as a sort of repair system for the body, they can theoretically divide without limit to replenish other cells as long as the person or animal is alive. When a stem cell divides, each new cell has the potential to either remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell. Stem cells differ from other kinds of cells in the body. All stem cells regardless of their source have three general properties:They are unspecialized; one of the fundamental properties of a stem cell is that it does not have any tissue-specific structures that allow it to perform specialized functions.They can give rise to specialized cell types. These unspecialized stem cells can give rise to specialized cells, including heart muscle cells, blood cells, or nerve cells.They are capable of dividing and renewing themselves for long periods. Unlike muscle cells, blood cells, or nerve cells -- which do not normally replicate themselves - stem cells may replicate many times. A starting population of stem cells that proliferates for many months in the laboratory can yield millions of cells. Today, donated organs and tissues are often used to replace those that are diseased or destroyed. Unfortunately, the number of people needing a transplant far exceeds the number of organs available for transplantation. Pleuropotent stem cells offer the possibility of a renewable source of replacement cells and tissues to treat a myriad of diseases, conditions, and disabilities including Parkinson's and Alzheimer's diseases, spinal cord injury, stroke, Cerebral palsy, Battens disease, Amyotrophic lateral sclerosis, restoration of vision and other neuro degenerative diseases as well.}, }
@article {pmid19565489, year = {2009}, author = {Baragi, VM and Becher, G and Bendele, AM and Biesinger, R and Bluhm, H and Boer, J and Deng, H and Dodd, R and Essers, M and Feuerstein, T and Gallagher, BM and Gege, C and Hochgürtel, M and Hofmann, M and Jaworski, A and Jin, L and Kiely, A and Korniski, B and Kroth, H and Nix, D and Nolte, B and Piecha, D and Powers, TS and Richter, F and Schneider, M and Steeneck, C and Sucholeiki, I and Taveras, A and Timmermann, A and Van Veldhuizen, J and Weik, J and Wu, X and Xia, B}, title = {A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models.}, journal = {Arthritis and rheumatism}, volume = {60}, number = {7}, pages = {2008-2018}, doi = {10.1002/art.24629}, pmid = {19565489}, issn = {0004-3591}, mesh = {Animals ; Cartilage, Articular/drug effects/pathology/surgery ; Cattle ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology/*therapeutic use ; Humans ; Interleukin-1alpha/pharmacology ; Iodoacetates/pharmacology/therapeutic use ; Iodoacetic Acid/adverse effects ; Male ; *Matrix Metalloproteinase Inhibitors ; Musculoskeletal System/drug effects/*pathology ; Oncostatin M/pharmacology ; Osteoarthritis/chemically induced/*drug therapy/pathology ; Rats ; Rats, Sprague-Dawley ; Treatment Outcome ; }, abstract = {OBJECTIVE: Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity.<br><br>METHODS: Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)-induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors.<br><br>RESULTS: A number of non-hydroxamic acid-containing compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompetitive inhibition, and Dixon plot analysis from competition studies with a zinc chelator (acetoxyhydroxamic acid) and ALS 1-0635 demonstrated nonexclusive binding. ALS 1-0635 inhibited bovine articular cartilage degradation in a dose-dependent manner (48.7% and 87.1% at 500 nM and 5,000 nM, respectively) and was effective in inhibiting interleukin-1alpha- and oncostatin M-induced C1,C2 release in human OA cartilage cultures. ALS 1-0635 modulated cartilage damage in the rat MIA model (mean +/- SEM damage score 1.3 +/- 0.3, versus 2.2 +/- 0.4 in vehicle-treated animals). Most significantly, when treated twice daily with oral ALS 1-0635, rats with surgically induced medial meniscus tear exhibited histologic evidence of chondroprotection and reduced cartilage degeneration, without observable musculoskeletal toxicity.<br><br>CONCLUSION: The compounds investigated in this study represent a novel class of MMP-13 inhibitors. They are mechanistically distinct from previously reported broad-spectrum MMP inhibitors and do not exhibit the problems previously associated with these inhibitors, including selectivity, poor pharmacokinetics, and MSS liability. MMP-13 inhibitors exert chondroprotective effects and can potentially modulate joint pain, and are, therefore, uniquely suited as potential disease-modifying osteoarthritis drugs.}, }
@article {pmid19565379, year = {2009}, author = {Tanaka, K and Saura, R and Houraiya, K and Tanimura, H}, title = {A simple and useful hand orthosis for patients with amyotrophic lateral sclerosis: a simple web spacer for thumb opposition weakness.}, journal = {Disability and rehabilitation. Assistive technology}, volume = {4}, number = {5}, pages = {364-366}, doi = {10.1080/17483100902988946}, pmid = {19565379}, issn = {1748-3115}, mesh = {Activities of Daily Living ; Aged ; Amyotrophic Lateral Sclerosis/physiopathology/psychology/*rehabilitation ; *Braces ; Female ; *Hand ; Hand Strength ; Humans ; Thumb ; }, abstract = {PURPOSE: To evaluate the clinical efficacy of simple web spacer for thumb opposition weakness in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHOD: Observational survey. Setting. Hospital in Japan.<br><br>RESULTS: The average grip strength with and without the web spacer was 8.25 +/- 1.74 kg and 8.13 +/- 1.91 kg, respectively. The lateral pinch strength was 0.83 +/- 0.45 kg and 0.93 +/- 0.47 kg. The palp pinch strength was 0.37 +/- 0.24 kg and 0.22 +/- 0.16 kg. In observation of activities of daily living (ADL) the movements of fingers required for palp pinching such as grasping buttons, flipping the pages of a book, and picking up small things were more easily carried out when wearing.<br><br>CONCLUSIONS: The simple web spacer, which improves precision hand motion and facilitates grasping, should be considered in the treatment of patients with ALS.}, }
@article {pmid19562978, year = {2009}, author = {Krittayaphong, R and Saengsung, P and Chawaruechai, T and Udompunturak, S and Sahasakul, Y}, title = {Early defibrillation: a key for successful outcome of in-hospital cardiac arrest.}, journal = {Journal of the Medical Association of Thailand = Chotmaihet thangphaet}, volume = {92 Suppl 2}, number = {}, pages = {S1-5}, pmid = {19562978}, issn = {0125-2208}, mesh = {Adult ; Aged ; Cohort Studies ; *Electric Countershock ; Female ; Heart Arrest/mortality/*therapy ; Hospital Mortality ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Thailand ; Time Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: The objectives of this study were to determine 1) the rate of delayed defibrillation and 2) the importance of early defibrillation in patients with cardiac arrest who need defibrillation in a large tertiary care hospital.<br><br>MATERIAL AND METHOD: We analyzed data from Siriraj cardiopulmonary resuscitation (CPR) registry from January 2005 to December 2007. The registry recorded setting and cause of cardiac arrest, timing of cardiac arrest and time initiation of each step of treatment such as basic life support (BLS), advanced life support (ALS), defibrillation, medication, time of defibrillation. Outcome was recorded as return of spontaneous circulation (ROSC) which lasted at least 20 minutes and discharge from hospital.<br><br>RESULTS: A total of 2160 in-hospital cardiac arrest records were sent to CPR center and were evaluated. 612 patients (28.3%) needed defibrillation. Average age was 57.1 +/- 21.2 years. Among patients who needed defibrillation, 250 patients (40.8) had early defibrillation. Median time to defibrillation after the detection of cardiac arrest was 8 (3, 15) minutes. Factors associated with delayed defibrillation were the patients being in non-intensive care unit (non-ICU) wards, being in wards without standby defibrillator, and female gender. 283 patients (46.2%) had ROSC after CPR and 50 patients (8.2%) survived to discharge from hospital. Time to defibrillation was the most important predictor for ROSC and survival to discharge.<br><br>CONCLUSION: Among in-hospital patients with cardiac arrest and who needed defibrillation, early defibrillation is the major key to a successful outcome.}, }
@article {pmid19560462, year = {2009}, author = {Yamashita, M and Nonaka, T and Arai, T and Kametani, F and Buchman, VL and Ninkina, N and Bachurin, SO and Akiyama, H and Goedert, M and Hasegawa, M}, title = {Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models.}, journal = {FEBS letters}, volume = {583}, number = {14}, pages = {2419-2424}, doi = {10.1016/j.febslet.2009.06.042}, pmid = {19560462}, issn = {1873-3468}, support = {MC_U105184291/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Cell Line/*drug effects/metabolism ; DNA-Binding Proteins/*metabolism ; Dementia/metabolism/pathology ; Enzyme Inhibitors/*pharmacology ; Humans ; Inclusion Bodies/drug effects/metabolism/pathology ; Indoles/*pharmacology ; Methylene Blue/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) are major neurodegenerative diseases with TDP-43 pathology. Here we investigated the effects of methylene blue (MB) and dimebon, two compounds that have been reported to be beneficial in phase II clinical trials of Alzheimer's disease (AD), on the formation of TDP-43 aggregates in SH-SY5Y cells. Following treatment with 0.05 microM MB or 5 microM dimebon, the number of TDP-43 aggregates was reduced by 50% and 45%, respectively. The combined use of MB and dimebon resulted in a 80% reduction in the number. These findings were confirmed by immunoblot analysis. The results indicate that MB and dimebon may be useful for the treatment of ALS, FTLD-U and other TDP-43 proteinopathies.}, }
@article {pmid19557103, year = {2009}, author = {Staines, DR and Brenu, EW and Marshall-Gradisnik, S}, title = {Postulated vasoactive neuropeptide immunopathology affecting the blood-brain/blood-spinal barrier in certain neuropsychiatric fatigue-related conditions: A role for phosphodiesterase inhibitors in treatment?.}, journal = {Neuropsychiatric disease and treatment}, volume = {5}, number = {}, pages = {81-89}, pmid = {19557103}, issn = {1176-6328}, abstract = {Neuropsychiatric symptoms occur in a number of neurological fatigue-related conditions including multiple sclerosis (MS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and chronic fatigue syndrome (CFS). These conditions have been attributed variably to neuroinflammatory and neurodegenerative processes. While autoimmune pathology, at least in part, has long been suspected in these conditions proof has been elusive. Autoimmune pathomechanisms affecting the blood-brain barrier (BBB) or blood-spinal barrier (BSB) may predispose the BBB/BSB to 'leakiness' and be a precursor to additional autoimmune events resulting in neuroinflammatory or neurodegenerative processes. The aim of the paper is to postulate immunopathology of the cerebrospinal perivascular compartment involving certain vasoactive neuropeptides, specifically pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP), in the etiology of certain neuropsychiatric fatigue-related conditions such as MS, ALS, PD, and CFS. Vasoactive neuropeptides (VNs) such as PACAP and VIP have critical roles as neurotransmitters, vasodilators including perfusion and hypoxia regulators, and immune and nociception modulators. PACAP and VIP are widely distributed in the central nervous system (CNS) and have key roles in CNS blood vessels including maintaining functional integrity of the BBB and BSB. Autoimmunity affecting these VNs would likely have a detrimental effect on BBB and BSB functioning arguably predisposing to further pathological processes. Virchow-Robin spaces (VRS) are perivascular compartments surrounding small vessels within the CNS which contribute to the BBB and BSB integrity and contain PACAP and VIP receptors. Autoimmunity of these receptors would likely affect BBB and VRS function and therefore may contribute to the etiology of these conditions by affecting CNS and immunological homeostasis, including promoting neuropsychological symptomatology. PACAP and VIP, as potent activators of adenylate cyclase (AC), have a key role in cyclic adenosine monophosphate (cAMP) production affecting regulatory T cell (Treg) and other immune functions. Phosphodiesterase enzymes (PDEs) catalyze cAMP and PDE inhibitors (PDEIs) maintain cAMP levels and have proven and well known therapeutic benefit in animal models such as experimental allergic encephalomyelitis (EAE). Therefore PDEIs may have a role in therapy for certain neuropsychiatric fatigue-related conditions.}, }
@article {pmid19556916, year = {2009}, author = {Lui, AJ and Byl, NN}, title = {A systematic review of the effect of moderate intensity exercise on function and disease progression in amyotrophic lateral sclerosis.}, journal = {Journal of neurologic physical therapy : JNPT}, volume = {33}, number = {2}, pages = {68-87}, doi = {10.1097/NPT.0b013e31819912d0}, pmid = {19556916}, issn = {1557-0576}, mesh = {Amyotrophic Lateral Sclerosis/*rehabilitation ; Animals ; Disease Progression ; Exercise Therapy/*methods ; Humans ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is an idiopathic disease of adults affecting upper and lower motor neurons. In one to four years, progressive weakness, spasticity, and respiratory insufficiency compromise independence and survival. Current medical treatment is limited to medication and supportive care. The benefit and harm of moderate physical exercise are controversial. This review examined current research related to moderate exercise for maintaining independence without accelerating disease progression in persons with ALS.<br><br>METHODS: An evidence-based search was conducted using keywords alone and in combination (ALS, exercise, Lou Gehrig's disease, physical therapy) to search PubMed, PEDro, Hooked on Evidence, Ovid, and Cochrane databases. Human and animal models were included and graded on level of evidence and strength of recommendations for developing guidelines to practice. A secondary reviewer evaluated all selected studies, and statistics were calculated.<br><br>RESULTS: The search yielded the following nine studies: four small clinical studies, one clinical systematic review, and four randomized, controlled trials based on animal models. In human studies, there were small to moderate effect sizes supporting the benefit of moderate exercise in persons with early-stage ALS, with no adverse affects on disease progression or survival time. In transgenic mice with superoxide dismutase-1 ALS, moderate exercise most often had a moderate effect size for increasing life span.<br><br>DISCUSSION AND CONCLUSION: Large randomized clinical trials are needed to develop specific exercise guidelines. However, evidence suggests that moderate exercise is not associated with adverse outcomes in persons with early-stage ALS. Moderate exercise programs can be safely adapted to abilities, interests, specific response to exercise, accessibility, and family support.}, }
@article {pmid19551535, year = {2010}, author = {Zoccolella, S and Bendotti, C and Beghi, E and Logroscino, G}, title = {Homocysteine levels and amyotrophic lateral sclerosis: A possible link.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {1-2}, pages = {140-147}, doi = {10.3109/17482960902919360}, pmid = {19551535}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*blood/*epidemiology ; Animals ; Homocysteine/*blood ; Humans ; Hyperhomocysteinemia/*blood/*epidemiology ; Oxidative Stress ; Risk Factors ; }, abstract = {Homocysteine (Hcy) exerts multiple neurotoxic mechanisms that have also been shown to be relevant in the pathogenesis of amyotrophic lateral sclerosis (ALS). We reviewed the published evidence to assess possible correlations between Hcy and ALS. A Medline literature search was performed to identify all studies on Hcy and ALS or motor neurons published from 1 January 1966 through 28 February 2009. Twelve studies (one in vitro, eight in vivo, and three studies on human subjects) were reviewed. The in vitro and in vivo animal studies showed that Hcy can damage motor neurons by inducing oxidative stress and stimulating excitotoxic receptors. In preliminary studies on human subjects, ALS subjects had higher median Hcy levels compared to age- and sex-matched controls. Higher Hcy levels were also correlated with a possible marker of disease progression. Finally, a short-term treatment with a high dose of methylcobalamin, which reduces Hcy levels, was effective in improving compound motor action potentials in patients with ALS. In conclusion, several types of evidence show that accumulation of Hcy may increase the risk and progression of motoneuronal degeneration. If this is confirmed, early interventions to decrease Hcy levels may be useful to modify ALS progression and possibly onset.}, }
@article {pmid19548774, year = {2009}, author = {Harel, NY and Cudkowicz, ME and Brown, RH and Strittmatter, SM}, title = {Serum Nogo-A levels are not elevated in amyotrophic lateral sclerosis patients.}, journal = {Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals}, volume = {14}, number = {6}, pages = {414-417}, pmid = {19548774}, issn = {1366-5804}, support = {K08 NS056212-03/NS/NINDS NIH HHS/United States ; R37 NS033020/NS/NINDS NIH HHS/United States ; R01 NS056485/NS/NINDS NIH HHS/United States ; R01 NS039962-10/NS/NINDS NIH HHS/United States ; K08 NS056212/NS/NINDS NIH HHS/United States ; R01 NS039962/NS/NINDS NIH HHS/United States ; R01 NS042304-08/NS/NINDS NIH HHS/United States ; R01 NS042304/NS/NINDS NIH HHS/United States ; R37 NS033020-17/NS/NINDS NIH HHS/United States ; R01 NS056485-04/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Biomarkers/analysis/*blood ; Case-Control Studies ; Humans ; Immunoassay/methods ; Lanthanoid Series Elements ; Muscle, Skeletal/chemistry ; }, abstract = {Improved biomarkers would facilitate the diagnosis and treatment of amyotrophic lateral sclerosis (ALS). Muscle content of the neuritic outgrowth inhibitor Nogo-A is increased in patients with ALS and other denervating conditions. Seeking a less invasive diagnostic method, we sought to determine whether or not Nogo increases in the serum of ALS patients. We developed a dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA) protocol to screen serum samples from 172 ALS patients and 172 healthy controls for Nogo-A immunoreactivity. Unexpectedly, there was a trend toward decreased levels of serum Nogo-A in ALS. Mean serum Nogo-A level in ALS patients was 0.71 nM (95% confidence interval (CI) 0.42-1.00), as opposed to 1.15 nM (95% CI 0.72-1.59) in healthy controls. A significantly larger percentage of healthy control sera (11.0% vs 4.7%) displayed markedly elevated levels of Nogo-A. Additional study is required to determine the factors that lead to elevated Nogo-A levels in a subset of both ALS patients and healthy controls.}, }
@article {pmid19542735, year = {2009}, author = {Lombardi, G and Minuto, F and Tamburrano, G and Ambrosio, MR and Arnaldi, G and Arosio, M and Chiarini, V and Cozzi, R and Grottoli, S and Mantero, F and Bogazzi, F and Terzolo, M and Tita, P and Boscani, PF and Colao, A}, title = {Efficacy of the new long-acting formulation of lanreotide (lanreotide Autogel) in somatostatin analogue-naive patients with acromegaly.}, journal = {Journal of endocrinological investigation}, volume = {32}, number = {3}, pages = {202-209}, pmid = {19542735}, issn = {1720-8386}, mesh = {Acromegaly/*drug therapy/etiology ; Adenoma/drug therapy ; Adult ; Aged ; Algorithms ; Antineoplastic Agents/administration &amp; dosage/adverse effects ; Delayed-Action Preparations/administration &amp; dosage/adverse effects ; Female ; Gels/administration &amp; dosage/adverse effects ; Growth Hormone-Secreting Pituitary Adenoma/drug therapy ; Humans ; Male ; Middle Aged ; Peptides, Cyclic/*administration &amp; dosage/adverse effects ; Somatostatin/administration &amp; dosage/adverse effects/*analogs &amp; derivatives ; Treatment Outcome ; Young Adult ; }, abstract = {OBJECTIVE: To evaluate efficacy and safety of lanreotide autogel (ATG) 120 mg injections every 4-8 weeks in somatostatin analogue-naïve patients with acromegaly.<br><br>DESIGN: Open, non-comparative, phase III, multicenter clinical study.<br><br>METHODS: Fifty-one patients (28 women, aged 19-78 yr): 39 newly diagnosed (de novo) and 12 who had previously undergone unsuccessful surgery (post-op, 11 macro and 1 micro) were studied. ATG 120 mg was initially given every 8 weeks for 24 weeks and subsequently changed according to GH levels: if <or=2.5 microg/l every 8 weeks (group A, 17 patients); if 2.5-5 microg/l every 6 weeks (group B, 15 patients); and if >5 microg/l every 4 weeks (group C, 19 patients). Treatment duration was 48-52 weeks. The primary objective was to control GH and IGF-I levels (GH<or=2.5 microg/l and IGF-I normalized for age/gender). Secondary objectives were to assess GH, IGF-I, and acid-labile subunit (ALS) decrease, improvement of clinical symptoms and quality of life (QoL).<br><br>RESULTS: GH levels normalized in 32 patients (63%), similarly in de novo and post-op patients (72% vs 50%, p=0.48); in 100% of group A, in 73% of group B and in 21% of group C (p<0.0001). IGF-I levels normalized in 19 patients (37%), similarly in the de novo and post-op patients (33% vs 50%, p=0.48): in 65% of group A, 33% of group B, and in 16% of group C. Circulating GH levels decreased by 80+/-17%, IGF-I levels by 44+/-27%, and ALS by 30+/-17%. Symptoms (hyperhidrosis (68.6%), swelling (68.6%), asthenia (58.8%), spine arthralgia (54.9%), and paresthesias (52.9%) and QoL (from 9.1+/-7.9 to 6.1+/-6.6) significantly improved (p<0.001). No patient withdrew from the study because of adverse events (AE). The most frequent AE was diarrhea (76.2% of patients): at study end 16 mild and 1 moderate diarrhea were recorded. Gallstones developed in 12% of patients.<br><br>CONCLUSION: ATG 120 mg in somatostatin-na&#xef;ve patients with acromegaly controls GH secretion in 63% and IGF-I secretion in 37% during a 48-52 week period without any difference between de novo and post-op patients. The treatment was associated with improvement in clinical symptoms and QoL and with a good, safe profile.}, }
@article {pmid19501384, year = {2009}, author = {Qian, H and Hu, H and Mao, Y and Ma, J and Zhang, A and Liu, W and Fu, Z}, title = {Enantioselective phytotoxicity of the herbicide imazethapyr in rice.}, journal = {Chemosphere}, volume = {76}, number = {7}, pages = {885-892}, doi = {10.1016/j.chemosphere.2009.05.009}, pmid = {19501384}, issn = {1879-1298}, mesh = {Acetolactate Synthase/genetics/metabolism ; Catalase/metabolism ; Herbicides/chemistry/*toxicity ; Malondialdehyde/metabolism ; Nicotinic Acids/chemistry/*toxicity ; Oryza/*drug effects/growth &amp; development ; Peroxidase/metabolism ; Plant Roots/growth &amp; development/metabolism ; Plant Shoots/growth &amp; development/metabolism ; Seedlings/drug effects/metabolism ; Stereoisomerism ; Superoxide Dismutase/metabolism ; }, abstract = {Research increasingly suggests that enantiomer selectivity may be a part of the toxicological effects of chiral contaminants. In this study, we selected Japonica rice variety Xiushui 63 seedlings to evaluate the enantioselectivity of imazethapyr (IM). Significant differences in rice seedling morphology, antioxidant enzyme, oxidant marker and gene transcription were observed between the two IM enantiomers. In the seedling morphological assay, IM enantiomers inhibited elongation of primary roots and shoots, and reduced the number of adventitious roots and the density of root hairs. The inhibitory effects were enhanced with increasing concentrations of IM. The maximal root relative inhibition rate reached 80.4%, 67.0%, and 73.5% for R-(-)-IM, S-(+)-IM and racemate at the concentration of 0.5 mg L(-1), respectively, and the maximal shoot relative inhibition rate reached 77.7%, 26.9%, and 61.7%, respectively. The activities of SOD, POD and CAT and the content of MDA increased at 0.5 mg L(-1) of R-(-)-IM treatment, and were 1.8, 3.3, 1.4, and 2.2 times, respectively, over the activities S-(+)-IM. Real-time PCR showed that R-(-)-IM minimized the transcript abundance of ALS in shoot tissue to 12.2% of the S-(+)-IM, and minimized the transcript abundance of PC in seed to 9.2% of the S-(+)-IM. R-(-)-IM maximized the transcript abundance of beta-amylase in shoots to 8.6-time of the S-(+)-IM. Results from this study imply that R-(-)-IM has stronger toxicity on the growth of rice than S-(+)-IM.}, }
@article {pmid19494733, year = {2009}, author = {Simmons, Z}, title = {What's in the Literature?.}, journal = {Journal of clinical neuromuscular disease}, volume = {10}, number = {4}, pages = {202-207}, doi = {10.1097/CND.0b013e3181a7b35f}, pmid = {19494733}, issn = {1537-1611}, mesh = {DNA-Binding Proteins/metabolism ; Humans ; Neuromuscular Diseases/*complications/epidemiology/etiology/therapy ; Peripheral Nervous System Diseases/*complications/epidemiology/etiology/therapy ; }, abstract = {Peripheral neuropathies are among the most common disorders seen by neuromuscular specialists. Several of the articles in this issue's review focus on diagnosis, treatment, and prognosis of disorders of peripheral nerve, including some which address important issues relating to chronic inflammatory demyelinating polyneuropathy. Motor neuron diseases continue to be somewhat disproportionately represented, likely due to the devastating nature of amyotrophic lateral sclerosis. The TAR DNA-binding protein-43 (TDP-43) story as outlined in 2 of the articles is fascinating, particularly with regard to etiopathogenesis, whereas other articles focus on epidemiology, diagnosis, treatment, and symptom management, including some insights into Kennedy disease. Myotonic dystrophy and other muscle diseases are presented with some welcome news on treatment and management.}, }
@article {pmid19488532, year = {2009}, author = {Hobaika, AB and Neves, BS}, title = {Combined spinal-epidural block in a patient with amyotrophic lateral sclerosis: case report.}, journal = {Revista brasileira de anestesiologia}, volume = {59}, number = {2}, pages = {206-209}, doi = {10.1590/s0034-70942009000200008}, pmid = {19488532}, issn = {1806-907X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; *Anesthesia, Epidural ; *Anesthesia, Spinal ; Female ; Hip Fractures/*complications/*surgery ; Humans ; Middle Aged ; Risk Factors ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis starts between the fifth and sixth decades of life, causing degeneration and death of upper and lower motor neurons. When the muscles responsible for ventilation are affected, the patient dies of respiratory failure within a few years.<br><br>CASE REPORT: This is a 63 years old female with amyotrophic lateral sclerosis who underwent surgical treatment of a transtrochanteric fracture of the femur. The patient presented weakness of upper and lower limbs and dysarthria, and she was awake and oriented. Respiratory function: ineffective cough, decreased strength of the intercostal muscles and diaphragm, and reduction of the breath sounds in both lung bases. Initially, the L3/L4 epidural space was punctured and a silicon catheter was introduced to 5 cm. This was followed by a spinal puncture in the L4/L5 space and the administration of 7.5 mg of hyperbaric bupivacaine. This was followed by the administration of 37 mg of 0.37% ropivacaine through the epidural catheter for a sensitive blockade up to T10. The procedure evolved without complications and the patient was discharged from the hospital after three days.<br><br>CONCLUSIONS: The evidence has demonstrated that neuroaxis blocks can be safely performed in patients with amyotrophic lateral sclerosis since it avoids manipulation of the airways and respiratory complications.}, }
@article {pmid19480880, year = {2009}, author = {Park, JH and Kang, SW}, title = {Percutaneous radiologic gastrostomy in patients with amyotrophic lateral sclerosis on noninvasive ventilation.}, journal = {Archives of physical medicine and rehabilitation}, volume = {90}, number = {6}, pages = {1026-1029}, doi = {10.1016/j.apmr.2008.12.006}, pmid = {19480880}, issn = {1532-821X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/mortality/*rehabilitation/surgery ; Cohort Studies ; Enteral Nutrition/*methods ; Feasibility Studies ; Female ; *Gastrostomy ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Rehabilitation Centers ; Respiration, Artificial ; Survival Analysis ; Vital Capacity ; }, abstract = {OBJECTIVE: To determine the safety and feasibility of percutaneous radiologic gastrostomy (PRG) tube placement in patients with amyotrophic lateral sclerosis (ALS) with too low a vital capacity to be weaned off noninvasive positive pressure ventilation (NPPV).<br><br>DESIGN: Five-year follow-up cohort study.<br><br>SETTING: Inpatient pulmonary rehabilitation hospital.<br><br>PARTICIPANTS: Patients with ALS (N=25) with dysphagia on NPPV.<br><br>INTERVENTIONS: PRG tube placement was performed. During the procedure, all subjects used NPPV via nasal masks. No sedatives or narcotics were administered for premedication.<br><br>MAIN OUTCOME MEASURES: Success and complication rates after PRG tube placement, and mean survival after the procedure.<br><br>RESULTS: For the 25 patients enrolled, mean percent forced vital capacity (FVC) was 33.3+/-17.8% seated (n=19) and 25.3+/-12.0% supine (n=18). FVCs could not be measured in patients who could not tolerate being off NPPV. PRG placement was 100% successful technically. Mean survival for the 25 patients was 32.1 months.<br><br>CONCLUSIONS: The application of NPPV during PRG was found to be a successful, safe means of providing nutritional care for patients with ALS with too low an FVC to be off NPPV. We advocate that PRG be considered the treatment of choice for nutritional care in patients with ALS on NPPV.}, }
@article {pmid19477958, year = {2009}, author = {Sumner, CJ and Wee, CD and Warsing, LC and Choe, DW and Ng, AS and Lutz, C and Wagner, KR}, title = {Inhibition of myostatin does not ameliorate disease features of severe spinal muscular atrophy mice.}, journal = {Human molecular genetics}, volume = {18}, number = {17}, pages = {3145-3152}, pmid = {19477958}, issn = {1460-2083}, support = {R01 NS062869/NS/NINDS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; K22-NS0048199-01/NS/NINDS NIH HHS/United States ; }, mesh = {Activin Receptors, Type II/administration &amp; dosage ; Animals ; Disease Models, Animal ; Down-Regulation ; Female ; Follistatin/genetics/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Activity/drug effects ; Muscle, Skeletal/drug effects/metabolism ; Muscular Atrophy, Spinal/drug therapy/genetics/*metabolism/physiopathology ; Myostatin/genetics/*metabolism ; Signal Transduction ; }, abstract = {There is currently no treatment for the inherited motor neuron disease, spinal muscular atrophy (SMA). Severe SMA causes lower motor neuron loss, impaired myofiber development, profound muscle weakness and early mortality. Myostatin is a transforming growth factor-beta family member that inhibits muscle growth. Loss or blockade of myostatin signaling increases muscle mass and improves muscle strength in mouse models of primary muscle disease and in the motor neuron disease, amyotrophic lateral sclerosis. In this study, we evaluated the effects of blocking myostatin signaling in severe SMA mice (hSMN2/delta7SMN/mSmn(-/-)) by two independent strategies: (i) transgenic overexpression of the myostatin inhibitor follistatin and (ii) post-natal administration of a soluble activin receptor IIB (ActRIIB-Fc). SMA mice overexpressing follistatin showed little increase in muscle mass and no improvement in motor function or survival. SMA mice treated with ActRIIB-Fc showed minimal improvement in motor function, and no extension of survival compared with vehicle-treated mice. Together these results suggest that inhibition of myostatin may not be a promising therapeutic strategy in severe forms of SMA.}, }
@article {pmid19459941, year = {2009}, author = {Tartari, S and D'Alessandro, G and Babetto, E and Rizzardini, M and Conforti, L and Cantoni, L}, title = {Adaptation to G93Asuperoxide dismutase 1 in a motor neuron cell line model of amyotrophic lateral sclerosis: the role of glutathione.}, journal = {The FEBS journal}, volume = {276}, number = {10}, pages = {2861-2874}, doi = {10.1111/j.1742-4658.2009.07010.x}, pmid = {19459941}, issn = {1742-4658}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/pathology ; Cell Line ; Glutamate-Cysteine Ligase/metabolism ; Glutathione/metabolism ; Humans ; *Models, Biological ; Motor Neurons/*enzymology ; Superoxide Dismutase/chemistry/*metabolism ; }, abstract = {Motor neuron degeneration in amyotrophic lateral sclerosis involves oxidative damage. Glutathione (GSH) is critical as an antioxidant and a redox modulator. We used a motor neuronal cell line (NSC-34) to investigate whether wild-type and familial amyotrophic lateral sclerosis-linked G93A mutant Cu,Zn superoxide dismutase (wt/G93ASOD1) modified the GSH pool and glutamate cysteine ligase (GCL), the rate-limiting enzyme for GSH synthesis. We studied the effect of various G93ASOD1 levels and exposure times. Mutant Cu,Zn superoxide dismutase induced an adaptive process involving the upregulation of GSH synthesis, even at very low expression levels. However, cells with a high level of G93ASOD1 cultured for 10 weeks showed GSH depletion and a decrease in expression of the modulatory subunit of GCL. These cells also had lower levels of GSH and GCL activity was not induced after treatment with the pro-oxidant tert-butylhydroquinone. Cells with a low level of G93ASOD1 maintained higher GSH levels and GCL activity, showing that the exposure time and the level of the mutant protein modulate GSH synthesis. We conclude that failure of the regulation of the GSH pathway caused by G93ASOD1 may contribute to motor neuron vulnerability and we identify this pathway as a target for therapeutic intervention.}, }
@article {pmid19455452, year = {2009}, author = {Bedlack, R and Hardiman, O}, title = {ALSUntangled (ALSU): a scientific approach to off-label treatment options for people with ALS using tweets and twitters.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {3}, pages = {129-130}, doi = {10.1080/17482960903015986}, pmid = {19455452}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Decision Making ; Drug Labeling ; Humans ; *Internet ; Prescription Drugs/*therapeutic use ; }, }
@article {pmid19449238, year = {2010}, author = {Nefussy, B and Artamonov, I and Deutsch, V and Naparstek, E and Nagler, A and Drory, VE}, title = {Recombinant human granulocyte-colony stimulating factor administration for treating amyotrophic lateral sclerosis: A pilot study.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {11}, number = {1-2}, pages = {187-193}, doi = {10.3109/17482960902933809}, pmid = {19449238}, issn = {1471-180X}, mesh = {Action Potentials/drug effects ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Disease Progression ; Female ; Follow-Up Studies ; Granulocyte Colony-Stimulating Factor/*administration &amp; dosage/adverse effects ; Hematopoietic Stem Cell Mobilization/*methods ; Humans ; Male ; Middle Aged ; Muscle Strength/drug effects ; Patient Dropouts ; Pilot Projects ; Placebos ; Recombinant Proteins ; Treatment Failure ; Vital Capacity/drug effects ; }, abstract = {Granulocyte-colony stimulating factor (G-CSF) is used to mobilize CD34+ haematopoietic stem cells from the bone marrow to the peripheral blood. We proposed to use cell subsets induced by G-CSF to slow down disease progression in patients with amyotrophic lateral sclerosis (ALS). Patients with definite or probable ALS were assigned in a double-blind manner to receive G-CSF or placebo every three months for a year. The primary outcome measure was the functional decline, measured by the revised ALS Functional Rating Scale, Revised (ALSFRS-R) score. Secondary outcome measures included vital capacity, manual muscle strength, compound muscle action potential amplitudes, neurophysiological index, and McGill single item quality of life score (QoL). Thirty-nine patients were enrolled. Seventeen patients who received G-CSF and 18 who received placebo were evaluated. G-CSF was effective in mobilizing CD34+ to blood. The outcome measures used showed no statistically significant benefit, although there was a trend of slowing disease progression following two G-CSF treatments, as shown by lower slopes of ALSFRS-R and QoL in the first six treatment months. The treatment had no major side-effects. G-CSF administration in ALS patients caused successful mobilization of autologous bone marrow cells, but was not effective in slowing down disease deterioration.}, }
@article {pmid19447293, year = {2009}, author = {Sawada, J and Yamashita, T and Aizawa, H and Aburakawa, Y and Hasebe, N and Kwak, S}, title = {Effects of antidepressants on GluR2 Q/R site-RNA editing in modified HeLa cell line.}, journal = {Neuroscience research}, volume = {64}, number = {3}, pages = {251-258}, doi = {10.1016/j.neures.2009.03.009}, pmid = {19447293}, issn = {1872-8111}, mesh = {Adenosine Deaminase/biosynthesis/genetics ; Amitriptyline/administration &amp; dosage ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Antidepressive Agents/*administration &amp; dosage ; Arginine/metabolism ; Cyclopropanes/administration &amp; dosage ; Desipramine/administration &amp; dosage ; Fluoxetine/administration &amp; dosage ; Fluvoxamine/administration &amp; dosage ; Glutamine/metabolism ; HeLa Cells ; Humans ; Imipramine/administration &amp; dosage ; Milnacipran ; Morpholines/administration &amp; dosage ; Paroxetine/administration &amp; dosage ; RNA Editing/*drug effects ; RNA, Messenger/genetics/metabolism ; RNA-Binding Proteins ; Reboxetine ; Receptors, AMPA/genetics/*metabolism ; }, abstract = {Marked reduction of RNA editing at the glutamine (Q)/arginine (R) site of the glutamate receptor subunit type 2 (GluR2) in motor neurons may be a contributory cause of neuronal death specifically in sporadic ALS. It has been shown that deregulation of RNA editing of several mRNAs plays a causative role in diseases of the central nervous system such as depression. We analyzed the effects of eight antidepressants on GluR2 Q/R site-RNA editing in a modified HeLa cell line that stably expresses half-edited GluR2 pre-mRNA. We also measured changes in RNA expression levels of adenosine deaminase acting on RNA type 2 (ADAR2), the specific RNA editing enzyme of the GluR2 Q/R site, and GluR2, in order to assess the molecular mechanism causing alteration of this site-editing. The editing efficiency at the GluR2 Q/R site was significantly increased after treatment with seven out of eight antidepressants at a concentration of no more than 10 microM for 24h. The relative abundance of ADAR2 mRNA to GluR2 pre-mRNA or to beta-actin mRNA was increased after treatment with six of the effective antidepressants, whereas it was unchanged after treatment with milnacipran. Our results suggest that antidepressants have the potency to enhance GluR2 Q/R site-editing by either upregulating the ADAR2 mRNA expression level or other unidentified mechanisms. It may be worth investigating the in vivo efficacy of antidepressants with a specific therapeutic strategy for sporadic ALS in view.}, }
@article {pmid19441922, year = {2009}, author = {Taupin, P}, title = {Brevetoxin derivative compounds for stimulating neuronal growth: University of North Carolina at Wilmington: WO2008131411 .}, journal = {Expert opinion on therapeutic patents}, volume = {19}, number = {2}, pages = {269-274}, doi = {10.1517/13543770802665725}, pmid = {19441922}, issn = {1744-7674}, mesh = {Animals ; Humans ; Marine Toxins/*pharmacology ; Nervous System Diseases/drug therapy/physiopathology ; Neurites/drug effects/metabolism ; Neurodegenerative Diseases/drug therapy/physiopathology ; Neurons/*drug effects/metabolism ; Oxocins/*pharmacology ; Patents as Topic ; Receptors, N-Methyl-D-Aspartate/drug effects/metabolism ; Signal Transduction ; }, abstract = {The application is in the field of neuronal growth and the activity of brevetoxins and their derivatives. It aims to characterize the activity of four generic formulae of brevetoxin derivatives--formulae I, II, III, and IV--and their compounds on the growth of neurites. The activity of the brevetoxin derivative compounds was tested on primary cultures of neocortical neurons. It was assayed in the presence and absence of antagonists of receptors and second-messenger signaling pathways, particulary NMDA receptors and the calmodulin-dependent protein-kinase kinase pathway. Brevetoxin derivatives stimulate neurite growth, particularly the growth of minor processes from which the axons form, on neurons in primary cultures. The activity is mediated by voltage-gated sodium channels and the N-methyl-d-aspartate-mediated intracellular Ca(2+) pathway. The application claims the use of the four generic formulae of brevetoxin derivatives (I, II, III, and IV) and their compounds for enhancing neuronal growth and for the treatment of neurodegenerative diseases and neurological disorders and injuries, such as Alzheimer's disease, amyotrophic lateral sclerosis, cerebral strokes, traumatic brain, and spinal cord injuries.}, }
@article {pmid19429076, year = {2009}, author = {Stevenson, A and Yates, DM and Manser, C and De Vos, KJ and Vagnoni, A and Leigh, PN and McLoughlin, DM and Miller, CC}, title = {Riluzole protects against glutamate-induced slowing of neurofilament axonal transport.}, journal = {Neuroscience letters}, volume = {454}, number = {2}, pages = {161-164}, doi = {10.1016/j.neulet.2009.02.061}, pmid = {19429076}, issn = {0304-3940}, support = {G0000749/MRC_/Medical Research Council/United Kingdom ; G0501573/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Analysis of Variance ; Animals ; Axonal Transport/*drug effects ; Axons/*drug effects/physiology ; Brain/drug effects/physiology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Antagonists/*pharmacology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Glutamic Acid/*toxicity ; Immunohistochemistry ; Neurofilament Proteins/*metabolism ; Neurons/drug effects/physiology ; Neuroprotective Agents/*pharmacology ; Phosphorylation/drug effects ; Rats ; Riluzole/*pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Riluzole is the only drug approved for the treatment of amyotrophic lateral sclerosis (ALS) but its precise mode of action is not properly understood. Damage to axonal transport of neurofilaments is believed to be part of the pathogenic mechanism in ALS and this has been linked to defective glutamate handling and increased phosphorylation of neurofilament side-arm domains. Here, we show that riluzole protects against glutamate-induced slowing of neurofilament transport. Protection is associated with decreased neurofilament side-arm phosphorylation and inhibition of the activities of two neurofilament kinases, ERK and p38 that are activated in ALS. Thus, the anti-glutamatergic properties of riluzole include protection against glutamate-induced changes to neurofilament phosphorylation and transport.}, }
@article {pmid19427829, year = {2009}, author = {Lee, J and Ryu, H and Kowall, NW}, title = {Motor neuronal protection by L-arginine prolongs survival of mutant SOD1 (G93A) ALS mice.}, journal = {Biochemical and biophysical research communications}, volume = {384}, number = {4}, pages = {524-529}, pmid = {19427829}, issn = {1090-2104}, support = {P30 AG013846/AG/NIA NIH HHS/United States ; NS52724/NS/NINDS NIH HHS/United States ; R01 NS052724/NS/NINDS NIH HHS/United States ; R01 NS052724-03/NS/NINDS NIH HHS/United States ; P30 AG013846-09/AG/NIA NIH HHS/United States ; P30 AG13846/AG/NIA NIH HHS/United States ; }, mesh = {Amino Acid Substitution ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Arginase/metabolism ; Arginine/*therapeutic use ; *Cytoprotection ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects/immunology/metabolism ; Mutation ; Neuroprotective Agents/*therapeutic use ; Spermidine/immunology/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive paralysis due to motor neuron degeneration. Despite the fact that many different therapeutic strategies have been applied to prevent disease progression, no cure or effective therapy is currently available for ALS. We found that L-arginine protects cultured motor neurons from excitotoxic injury. We also found that L-arginine supplementation both prior to and after the onset of motor neuron degeneration in mtSOD1 (G93A) transgenic ALS mice significantly slowed the progression of neuropathology in lumbar spinal cord, delayed onset of motor dysfunction, and prolonged life span. Moreover, L-arginine treatment was associated with preservation of arginase I activity and neuroprotective polyamines in spinal cord motor neurons. Our findings show that L-arginine has potent in vitro and in vivo neuroprotective properties and may be a candidate for therapeutic trials in ALS.}, }
@article {pmid19427472, year = {2009}, author = {Le Dréau, Y and Dupuy, N and Gaydou, V and Joachim, J and Kister, J}, title = {Study of jojoba oil aging by FTIR.}, journal = {Analytica chimica acta}, volume = {642}, number = {1-2}, pages = {163-170}, doi = {10.1016/j.aca.2008.12.001}, pmid = {19427472}, issn = {1873-4324}, mesh = {Hot Temperature ; Least-Squares Analysis ; Multivariate Analysis ; Oxidation-Reduction ; Principal Component Analysis ; Software ; Spectroscopy, Fourier Transform Infrared/*methods ; Time Factors ; Waxes/*chemistry ; }, abstract = {As the jojoba oil was used in cosmetic, pharmaceutical, dietetic food, animal feeding, lubrication, polishing and bio-diesel fields, it was important to study its aging at high temperature by oxidative process. In this work a FT-MIR methodology was developed for monitoring accelerate oxidative degradation of jojoba oils. Principal component analysis (PCA) was used to differentiate various samples according to their origin and obtaining process, and to differentiate oxidative conditions applied on oils. Two spectroscopic indices were calculated to report simply the oxidation phenomenon. Results were confirmed and deepened by multivariate curve resolution-alternative least square method (MCR-ALS). It allowed identifying chemical species produced or degraded during the thermal treatment according to a SIMPLISMA pretreatment.}, }
@article {pmid19426166, year = {2009}, author = {Besheer, J and Lepoutre, V and Hodge, CW}, title = {Preclinical evaluation of riluzole: assessments of ethanol self-administration and ethanol withdrawal symptoms.}, journal = {Alcoholism, clinical and experimental research}, volume = {33}, number = {8}, pages = {1460-1468}, pmid = {19426166}, issn = {1530-0277}, support = {R01 AA016629/AA/NIAAA NIH HHS/United States ; R01 AA016629-03/AA/NIAAA NIH HHS/United States ; P60 AA011605/AA/NIAAA NIH HHS/United States ; R01 AA014983-05/AA/NIAAA NIH HHS/United States ; AA014983/AA/NIAAA NIH HHS/United States ; P60 AA011605-090008/AA/NIAAA NIH HHS/United States ; AA011605/AA/NIAAA NIH HHS/United States ; P60 AA011605-100008/AA/NIAAA NIH HHS/United States ; R01 AA014983/AA/NIAAA NIH HHS/United States ; R37 AA014983/AA/NIAAA NIH HHS/United States ; P60 AA011605-080008/AA/NIAAA NIH HHS/United States ; R01 AA014983-04/AA/NIAAA NIH HHS/United States ; P50 AA011605/AA/NIAAA NIH HHS/United States ; }, mesh = {Alcohol Drinking/physiopathology/*prevention &amp; control ; Alcohol Withdrawal Seizures/physiopathology/*prevention &amp; control ; Animals ; Anticonvulsants/therapeutic use ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical/methods ; Ethanol/*administration &amp; dosage ; Male ; Mice ; Mice, Inbred C57BL ; Reinforcement Schedule ; Riluzole/*therapeutic use ; Self Administration ; }, abstract = {BACKGROUND: Many of the neurobehavioral effects of ethanol are mediated by inhibition of excitatory N-methyl-D-aspartate (NMDA) and enhancement of inhibitory gamma-amino-butyric-acid (GABA) receptor systems. There is growing interest in drugs that alter these systems as potential medications for problems associated with alcoholism. The drug riluzole, approved for treatment of amyotrophic lateral sclerosis (ALS), inhibits NMDA and enhances GABA(A) receptor system activity. This study was designed to determine the preclinical efficacy of riluzole to modulate ethanol self-administration and withdrawal.<br><br>METHODS: Male C57BL/6J mice were trained to lever press on a concurrent fixed-ratio 1 schedule of ethanol (10% v/v) versus water reinforcement during daily 16-hour sessions. Riluzole (1 to 40 mg/kg, IP) was evaluated on ethanol self-administration after acute and chronic (2 week) treatment. To determine if riluzole influences ethanol withdrawal-associated seizures, mice were fed an ethanol-containing or control liquid diet for 18 days. The effects of a single injection of riluzole (30 mg/kg) were examined on handling-induced convulsions after ethanol withdrawal.<br><br>RESULTS: Acute riluzole (30 and 40 mg/kg) reduced ethanol self-administration during the first 4 hours of the session, which corresponds to the known pharmacokinetics of this drug. Ethanol self-administration was also reduced by riluzole after chronic treatment. Riluzole (30 mg/kg) significantly decreased the severity of ethanol-induced convulsions 2 hours after ethanol withdrawal.<br><br>CONCLUSIONS: These results demonstrate that riluzole decreases ethanol self-administration and may reduce ethanol withdrawal severity in mice. Thus, riluzole may have utility in the treatment of problems associated with alcoholism.}, }
@article {pmid19418288, year = {2009}, author = {Pérez-Martínez, DA}, title = {[The role of lithium in neurodegenerative diseases: new registries for old actors].}, journal = {Neurologia (Barcelona, Spain)}, volume = {24}, number = {3}, pages = {143-146}, pmid = {19418288}, issn = {0213-4853}, mesh = {Animals ; Glycogen Synthase Kinase 3/antagonists &amp; inhibitors ; Humans ; Lithium Compounds/*therapeutic use ; Neurodegenerative Diseases/*drug therapy/metabolism ; Phosphorylation ; tau Proteins/metabolism ; }, abstract = {INTRODUCTION: Lithium has been used for more than one century in medicine. Currently, it is used effectively in acute phase treatment and in the prevention of manic-depressive symptoms of patients with bipolar disorder. Lithium acts by inhibiting a protein- kinase called glycogen synthase kinase 3 (GSK3) that has important actions on the intracellular signal transmission by protein phosphorylation.<br><br>METHOD: A review has been made of the studies conducted in vivo and in vitro on the utility of lithium in animal models of neurodegenerative disease and its efficacy in studies performed in humans.<br><br>DEVELOPMENT: Research on lithium on GSK-3 inhibition in animal models of disease with aggregates of hyperphosphorylated protein tau and Alzheimer's disease has provided promising results. Inhibition of this enzyme also seems to have a neuroprotector effect in other neurodegenerative disease models such as amyotrophic lateral sclerosis, spinocerebellar ataxia type 1 and Huntington's disease. There is indirect evidence in humans on a possible neuroprotector effect in chronic patients with bipolar disorder and on slow down of the progression of the disease in patients with amyotrophic lateral sclerosis.<br><br>CONCLUSIONS: Lithium, and in a more extensive way, GSK-3 inhibitors, are proposed as a new drug generation with potential action on the progression of different neurodegenerative diseases, especially those related with abnormal aggregation of the protein tau.}, }
@article {pmid19412814, year = {2009}, author = {Wuolikainen, A and Hedenström, M and Moritz, T and Marklund, SL and Antti, H and Andersen, PM}, title = {Optimization of procedures for collecting and storing of CSF for studying the metabolome in ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {4}, pages = {229-236}, doi = {10.1080/17482960902871009}, pmid = {19412814}, issn = {1471-180X}, mesh = {Adult ; Aged ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/metabolism/physiopathology ; Animals ; Biomarkers/*cerebrospinal fluid ; Carbon Dioxide/metabolism ; Cerebrospinal Fluid/chemistry/*metabolism ; Gas Chromatography-Mass Spectrometry/methods ; Humans ; Hydrogen-Ion Concentration ; *Metabolome ; Middle Aged ; Nuclear Magnetic Resonance, Biomolecular ; Reproducibility of Results ; Specimen Handling/*methods ; }, abstract = {There is a need for biomarkers for early diagnosis, development and evaluation of treatment efficacy in amyotrophic lateral sclerosis (ALS). We aimed to investigate if pre-analytical factors induce artefacts in metabolomic data of cerebrospinal fluid (CSF) from patients with ALS. CSF from 16 patients was studied using a statistical experimental design protocol with the following parameters: storage temperature (-80 degrees C/ - 20 degrees C), type of collection tube (polypropylene/polystyrene), and time delay from collecting to freezing (0, 10, 30, 90, 150 min). Gas chromatography-mass spectrometry was used to analyse CSF from 12 of the patients while CSF from one patient was analysed with nuclear magnetic resonance spectroscopy. The extent of CO(2) evaporization from CSF collected in tubes of different sizes at different temperatures and with/without lid were studied in three addtional patients. We found that alterations in storage temperature affect the metabolite composition of CSF more than any other studied pre-analytical parameter. CO(2) evaporization may induce artefacts in the metabolome by increasing the pH. In conclusion, minimization of evaluated artefacts can be obtained by collecting the CSF directly into tubes with tightly sealed lids in N(2)(l) and after freezing transfer of the tubes to -80 degrees C to minimize evaporation of CO(2).}, }
@article {pmid19409391, year = {2009}, author = {Jarriault, D and Barrozo, RB and de Carvalho Pinto, CJ and Greiner, B and Dufour, MC and Masante-Roca, I and Gramsbergen, JB and Anton, S and Gadenne, C}, title = {Age-dependent plasticity of sex pheromone response in the moth, Agrotis ipsilon: combined effects of octopamine and juvenile hormone.}, journal = {Hormones and behavior}, volume = {56}, number = {1}, pages = {185-191}, doi = {10.1016/j.yhbeh.2009.04.005}, pmid = {19409391}, issn = {1095-6867}, mesh = {Action Potentials/drug effects/physiology ; Aging/*physiology ; Animals ; Behavior, Animal/drug effects/physiology ; Chromatography, High Pressure Liquid ; Juvenile Hormones/*metabolism ; Male ; Mianserin/administration &amp; dosage ; Microelectrodes ; Moths/*physiology ; Motor Activity/drug effects/physiology ; Neurons/drug effects/physiology ; Octopamine/*metabolism ; Phenylcarbamates/administration &amp; dosage ; Physical Stimulation ; Receptors, Biogenic Amine/antagonists &amp; inhibitors ; Sensory Thresholds/drug effects/physiology ; Sex Attractants/*metabolism ; }, abstract = {Male moths use sex pheromones to find their mating partners. In the moth, Agrotis ipsilon, the behavioral response and the neuron sensitivity within the primary olfactory centre, the antennal lobe (AL), to sex pheromone increase with age and juvenile hormone (JH) biosynthesis. By manipulating the JH level, we previously showed that JH controls this age-dependent neuronal plasticity, and that its effects are slow (within 2 days). We hypothesized that the hormonal effect might be indirect, and one neuromodulator candidate, which might serve as a mediator, is octopamine (OA). Here, we studied the effects of OA and an OA receptor antagonist, mianserin, on behavioral and AL neuron responses of mature and immature males during stimulation with sex pheromone. Our results indicate that, although OA injections enhanced the behavioral pheromone response in mature males, OA had no significant effect on behavior in immature males. However, mianserin injections decreased the behavioral response in mature males. AL neuron sensitivity increased after OA treatment in immature males, and decreased after mianserin treatment in mature males. Determination of OA levels in ALs of immature and mature males did not reveal any difference. To study the possible interactive effects of JH and OA, the behavioral pheromone response was analyzed in JH-deprived mature males injected with OA, and in immature males injected with fenoxycarb, a JH agonist, and mianserin. Results show that both JH and OA are necessary to elicit a behavioral response of A. ipsilon males to sex pheromone.}, }
@article {pmid19405100, year = {2009}, author = {Asmussen, JW and Von Sperling, ML and Penkowa, M}, title = {Intraneuronal signaling pathways of metallothionein.}, journal = {Journal of neuroscience research}, volume = {87}, number = {13}, pages = {2926-2936}, doi = {10.1002/jnr.22118}, pmid = {19405100}, issn = {1097-4547}, mesh = {Animals ; Apoptosis/drug effects ; Cells, Cultured/drug effects ; Cerebellum/cytology ; Drug Evaluation, Preclinical ; Heterotrimeric GTP-Binding Proteins/physiology ; Metallothionein/administration &amp; dosage/*pharmacology/physiology ; Nerve Tissue Proteins/*physiology ; Neurites/*drug effects ; Neuroprotective Agents/administration &amp; dosage/*pharmacology ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology ; Protein Kinases/physiology ; Protein Processing, Post-Translational/drug effects ; Proto-Oncogene Proteins c-jun/physiology ; Rabbits ; Rats ; Rats, Wistar ; STAT3 Transcription Factor/physiology ; Signal Transduction/*drug effects/physiology ; Type C Phospholipases/antagonists &amp; inhibitors/physiology ; }, abstract = {Metallothionein (MT) belongs to a family of metal-binding cysteine-rich proteins comprising several structurally related proteins implicated in tissue protection and regeneration after injuries and functioning as antiapoptotic antioxidants in neurological disorders. This has been demonstrated in animals receiving MT treatment and in mice with endogenous MT overexpression or null mutation during various experimental models of neuropathology, and also in patients with Alzheimer's disease and amyotrophic lateral sclerosis. Exogenously applied MT increases neurite outgrowth and neuronal survival in rat cerebellar, hippocampal, dopaminergic, and cortical neurons in vitro. In this study, the intraneuronal signaling involved in MT-mediated neuritogenesis was examined. The MT-induced neurite outgrowth in cultures of cerebellar granule neurons was dependent on activation of a heterotrimeric G-protein-coupled pathway but not on protein tyrosine kinases or on receptor tyrosine kinases. Activation of phospholipase C was necessary for MT-induced neurite outgrowth, and furthermore it was shown that inhibition of several intracellular protein kinases, such as protein kinase A, protein kinase C, phosphatidylinositol 3-kinase, Ca(2+)/calmodulin kinase-II, and mitogen-activated protein kinase kinase, abrogated the MT-mediated neuritogenic response. In addition, exogenously applied MT resulted in a decrease in phosphorylation of intraneuronal kinases implicated in proinflammatory reactions and apoptotic cell death, such as glycogen synthase-serine kinase 3alpha, Jun, and signal transducer and activator of transcription 3. This paper elucidates the intraneuronal molecular signaling involved in neuroprotective effects of MT.}, }
@article {pmid19386672, year = {2009}, author = {Selman, L and Higginson, IJ and Agupio, G and Dinat, N and Downing, J and Gwyther, L and Mashao, T and Mmoledi, K and Moll, AP and Sebuyira, LM and Panajatovic, B and Harding, R}, title = {Meeting information needs of patients with incurable progressive disease and their families in South Africa and Uganda: multicentre qualitative study.}, journal = {BMJ (Clinical research ed.)}, volume = {338}, number = {}, pages = {b1326}, pmid = {19386672}, issn = {1756-1833}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Caregivers ; Female ; HIV Infections/complications/*therapy ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*therapy ; Neoplasms/complications/*therapy ; Palliative Care/standards ; Patient Education as Topic/*standards ; Patient Satisfaction ; Personal Satisfaction ; Rural Health ; South Africa ; *Terminally Ill ; Uganda ; Urban Health ; Young Adult ; }, abstract = {OBJECTIVES: To explore the information needs of patients with progressive, life limiting disease and their family caregivers in South Africa and Uganda and to inform clinical practice and policy in this emerging field.<br><br>DESIGN: Semistructured qualitative interview study.<br><br>SETTING: Four palliative care services in South Africa and one in Uganda, covering rural, urban, and peri-urban locations.<br><br>PARTICIPANTS: 90 patients and 38 family caregivers enrolled in palliative care services; 28 patients had cancer, 61 had HIV infection (including 6 dual HIV/cancer diagnoses), and 1 had motor neurone disease.<br><br>RESULTS: Five themes emerged from the data. (1) INFORMATION SOURCES: a lack of information from general healthcare providers meant that patients and caregivers had to draw on alternative sources of information. (2) Information needs: patients and caregivers reported needing more information in the key areas of the causes and progression of the disease, its symptoms and treatment, and financial/social support. (3) Impact of unmet needs: poor provision of information had a detrimental effect on patients' and caregivers' ability to cope. (4) Communication: negative experiences of communication with general healthcare staff were reported (misinformation, secrecy, insensitivity). (5) Barriers to effective provision of information: barriers related to symptoms, culture, time constraints in hospital, and paternalism in general health care.<br><br>CONCLUSIONS: Lack of information was a major theme for both patients and carers, who had important unanswered questions relating to living with a progressive incurable disease. Evidence based recommendations for clinicians are presented, including the proactive provision of information tailored to individual patients and families.}, }
@article {pmid19382170, year = {2009}, author = {Simmons, Z}, title = {Can we eliminate placebo in ALS clinical Trials?.}, journal = {Muscle &amp; nerve}, volume = {39}, number = {6}, pages = {861-865}, doi = {10.1002/mus.21358}, pmid = {19382170}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials, Phase II as Topic/adverse effects/*standards ; Controlled Clinical Trials as Topic/adverse effects/*standards ; Drug-Related Side Effects and Adverse Reactions ; Excitatory Amino Acid Antagonists/administration &amp; dosage/adverse effects ; Humans ; *Placebos ; Research Design/standards ; Riluzole/administration &amp; dosage/adverse effects ; Sample Size ; United States ; United States Food and Drug Administration ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease with limited treatment options. Controlled studies are a necessary part of Phase II and Phase III assessments of proposed therapies. Due to the relatively small number of patients with ALS, several study designs have been proposed to improve the efficiency of Phase II studies. Some of these advocate the use of historical controls in place of placebo controls. However, the characteristics of historical controls may not mirror those of patients in the treatment group. Novel study designs can be used to decrease the number of patients required for Phase II studies. The use of placebo controls rather than historical controls in these novel study designs likely leads to better predictions of treatments that will be successful in Phase III studies. There is general agreement on the necessity of placebo controls in Phase III studies.}, }
@article {pmid19380972, year = {2009}, author = {Pedersen, BS and Jeberg, KA and Koerner, C and Balslev, C and Andersen, PO and Jensen, MK and Lyng, KM}, title = {IT for advanced life support in hospitals.}, journal = {Studies in health technology and informatics}, volume = {143}, number = {}, pages = {429-434}, pmid = {19380972}, issn = {0926-9630}, mesh = {*Advanced Cardiac Life Support ; Decision Support Systems, Clinical ; Denmark ; *Hospital Information Systems ; Humans ; Research Design ; }, abstract = {In this study we analyzed how IT support can be established for the treatment and documentation of advanced life support (ALS) in a hospital. In close collaboration with clinical researchers, a running prototype of an IT solution to support the clinical decisions in ALS was developed and tried out in a full scale simulation environment. We have named this IT solution the CardioData Prototype.}, }
@article {pmid19364361, year = {2009}, author = {Ludolph, AC and Kassubek, J and Landwehrmeyer, BG and Mandelkow, E and Mandelkow, EM and Burn, DJ and Caparros-Lefebvre, D and Frey, KA and de Yebenes, JG and Gasser, T and Heutink, P and Höglinger, G and Jamrozik, Z and Jellinger, KA and Kazantsev, A and Kretzschmar, H and Lang, AE and Litvan, I and Lucas, JJ and McGeer, PL and Melquist, S and Oertel, W and Otto, M and Paviour, D and Reum, T and Saint-Raymond, A and Steele, JC and Tolnay, M and Tumani, H and van Swieten, JC and Vanier, MT and Vonsattel, JP and Wagner, S and Wszolek, ZK and , }, title = {Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.}, journal = {European journal of neurology}, volume = {16}, number = {3}, pages = {297-309}, pmid = {19364361}, issn = {1468-1331}, support = {P50 AG008702/AG/NIA NIH HHS/United States ; P50 AG008702-11A19002/AG/NIA NIH HHS/United States ; P50 NS040256/NS/NINDS NIH HHS/United States ; P50-NS40256/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Biomarkers ; Dementia/complications/genetics/physiopathology ; Drug Design ; Geography ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ; Models, Biological ; Mutation ; Niemann-Pick Disease, Type C/complications/diagnosis/physiopathology ; Parkinson Disease, Postencephalitic/complications/physiopathology ; Parkinsonian Disorders/*complications/pathology/physiopathology/therapy ; Pick Disease of the Brain/complications/pathology ; Protein Serine-Threonine Kinases/genetics ; Supranuclear Palsy, Progressive/complications/diagnosis/physiopathology ; Tauopathies/*complications/pathology/physiopathology/therapy ; tau Proteins/genetics ; }, abstract = {Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.}, }
@article {pmid19337331, year = {2009}, author = {Holmøy, T and Aarrestad, S and Engstrand, P and Ottesen, S and Syse, A and Førde, R}, title = {[Termination of mechanical ventilation in amyotrophic lateral sclerosis].}, journal = {Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke}, volume = {129}, number = {7}, pages = {628-631}, doi = {10.4045/tidsskr.08.0006}, pmid = {19337331}, issn = {0807-7096}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*therapy ; Decision Making/ethics ; Humans ; Male ; Middle Aged ; Palliative Care/ethics/legislation &amp; jurisprudence ; Patient Rights/ethics/legislation &amp; jurisprudence ; *Respiration, Artificial/ethics ; *Resuscitation Orders/ethics/legislation &amp; jurisprudence ; *Withholding Treatment/ethics/legislation &amp; jurisprudence ; }, abstract = {BACKGROUND: Mechanical ventilation may relieve symptoms and prolong life for patients with amyotrophic lateral sclerosis, but may also prolong suffering. More knowledge is needed on ethical, legal and medical aspects upon termination.<br><br>MATERIAL AND METHODS: Two cases are discussed in light of relevant laws and literature, as well as the authors' own research and clinical experience.<br><br>RESULTS: A patient who had first declined life-sustaining treatment eventually chose to undergo tracheostomy. He later approached a locked-in state and wanted to terminate the treatment. Another patient reported poor quality of life and wanted to die, but declined to make a statement on refusal of resuscitation in case of an emergency. He was later resuscitated from CO2 narcosis and received non-invasive ventilation. He repeated that he wanted to die, but did not decide to terminate the ventilator until he was offered palliative treatment. Both patients received morphin and anxiolytics, and died shortly after the ventilator was withdrawn.<br><br>INTERPRETATION: Mechanical ventilation can be terminated in line with good medical and ethical standards, and will then usually be legal. Patients have a legal right to refuse life-sustaining treatment, but not everybody want to make decisions regarding their own death. Fear of conducting euthanasia may prolong the patient's death process and prevent adequate palliative treatment.}, }
@article {pmid19332122, year = {2009}, author = {Turner, BJ and Parkinson, NJ and Davies, KE and Talbot, K}, title = {Survival motor neuron deficiency enhances progression in an amyotrophic lateral sclerosis mouse model.}, journal = {Neurobiology of disease}, volume = {34}, number = {3}, pages = {511-517}, doi = {10.1016/j.nbd.2009.03.005}, pmid = {19332122}, issn = {1095-953X}, support = {MC_U137761449/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism/mortality ; Animals ; Cell Line ; Cell Nucleus/metabolism ; Disease Models, Animal ; Disease Progression ; Female ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; Mutation, Missense ; Neurons/drug effects/metabolism ; Oxidants/pharmacology ; Paraquat/pharmacology ; RNA, Messenger/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; Survival of Motor Neuron 1 Protein/*genetics/metabolism ; }, abstract = {Mutations in the ubiquitously expressed survival motor neuron 1 (SMN1) and superoxide dismutase 1 (SOD1) genes are selectively lethal to motor neurons in spinal muscular atrophy (SMA) and familial amyotrophic lateral sclerosis (ALS), respectively. Genetic association studies provide compelling evidence that SMN1 and SMN2 genotypes encoding lower SMN protein levels are implicated in sporadic ALS, suggesting that SMN expression is a potential determinant of ALS severity. We therefore sought genetic evidence of SMN involvement in ALS by generating transgenic mutant SOD1 mice on an Smn deficient background. Partial genetic disruption of Smn significantly worsened motor performance and survival in transgenic SOD1(G93A) mice. Furthermore, ALS-linked mutant SOD1 expression severely reduced SMN protein levels, but not transcript, in neuronal culture and mouse models from early presymptomatic disease. SMN protein depletion was linked to the nuclear compartment and a physical interaction between SMN and mutant SOD1 was confirmed in mouse spinal cord. Treatment with the environmental toxin paraquat also depleted SMN protein, implicating oxidative stress in the mechanism underlying SMN deficiency in familial ALS and potentially sporadic disease. In contrast, transgenic SOD1(WT) overexpression in SMA type I mice was incapable of modulating SMN protein levels or disease progression. These data establish that SMN deficiency accelerates phenotypic severity in transgenic familial ALS mice, consistent with an enhancing genetic modifier role. We therefore propose that SMN replacement and upregulation strategies considered for SMA therapy may have protective potential for ALS.}, }
@article {pmid19323496, year = {2009}, author = {Yasuor, H and Osuna, MD and Ortiz, A and Saldaín, NE and Eckert, JW and Fischer, AJ}, title = {Mechanism of resistance to penoxsulam in late watergrass [ Echinochloa phyllopogon (Stapf) Koss.].}, journal = {Journal of agricultural and food chemistry}, volume = {57}, number = {9}, pages = {3653-3660}, doi = {10.1021/jf8039999}, pmid = {19323496}, issn = {1520-5118}, mesh = {Acetolactate Synthase/antagonists &amp; inhibitors/metabolism ; Cytochrome P-450 Enzyme System/metabolism ; Drug Synergism ; Echinochloa/*drug effects/enzymology/growth &amp; development ; Enzyme Inhibitors/pharmacology ; Herbicide Resistance ; Herbicides/*pharmacology ; Malathion/pharmacology ; Oryza/growth &amp; development ; Sulfonamides/metabolism/*pharmacology ; Thiocarbamates/pharmacology ; Uridine/*analogs &amp; derivatives/metabolism/pharmacology ; }, abstract = {Late watergrass [ Echinochloa phyllopogon (Stapf.) Koss.] is a major weed of California rice that has evolved P450-mediated metabolic resistance to multiple herbicides. Resistant (R) populations are also poorly controlled by the recently introduced herbicide penoxsulam. Ratios (R/S) of the R to susceptible (S) GR(50) (herbicide rate for 50% growth reduction) ranged from 5 to 9. Although specific acetolactate synthase (ALS) activity was 1.7 higher in R than in S plants, the enzyme in R plants was about 6 times more susceptible to the herbicide. R plants exhibited faster (2.8 times) oxidative [(14)C]-penoxsulam metabolism than S plants 24 h after treatment. Addition of malathion (P450 inhibitor) enhanced herbicide phytotoxicity and reduced penoxsulam metabolism in R plants. Tank mixtures with thiobencarb (can induce P450) antagonized penoxsulam toxicity in R plants, suggesting penoxsulam may be broken down by a thiobencarb-inducible enzyme. These results suggest E. phyllopogon resistance to penoxsulam is mostly due to enhanced herbicide metabolism, possibly via P450 monooxidation.}, }
@article {pmid19322031, year = {2009}, author = {Park, S and Kim, HT and Yun, S and Kim, IS and Lee, J and Lee, IS and Park, KI}, title = {Growth factor-expressing human neural progenitor cell grafts protect motor neurons but do not ameliorate motor performance and survival in ALS mice.}, journal = {Experimental &amp; molecular medicine}, volume = {41}, number = {7}, pages = {487-500}, pmid = {19322031}, issn = {1226-3613}, mesh = {Adenoviridae/genetics ; Amyotrophic Lateral Sclerosis/metabolism/mortality/*therapy ; Animals ; Astrocytes/metabolism ; Brain/*embryology ; Cell Differentiation ; Disease Models, Animal ; Excitatory Amino Acid Transporter 2/metabolism ; Female ; Fetal Stem Cells/*metabolism ; Genetic Vectors ; Humans ; Immunoenzyme Techniques ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/*physiology ; Nerve Growth Factors/*metabolism ; *Stem Cell Transplantation ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Transfection ; Vascular Endothelial Growth Factor A/genetics/metabolism ; }, abstract = {Neural progenitor cells (NPs) have shown several promising benefits for the treatment of neurological disorders. To evaluate the therapeutic potential of human neural progenitor cells (hNPs) in amyotrophic lateral sclerosis (ALS), we transplanted hNPs or growth factor (GF)-expressing hNPs into the central nervous system (CNS) of mutant Cu/Zn superoxide dismutase (SOD1(G93A)) transgenic mice. The hNPs were engineered to express brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), VEGF, neurotrophin-3 (NT-3), or glial cell-derived neurotrophic factor (GDNF), respectively, by adenoviral vector and GDNF by lentiviral vector before transplantation. Donor-derived cells engrafted and migrated into the spinal cord or brain of ALS mice and differentiated into neurons, oligodendrocytes, or glutamate transporter-1 (GLT1)-expressing astrocytes while some cells retained immature markers. Transplantation of GDNF- or IGF-1-expressing hNPs attenuated the loss of motor neurons and induced trophic changes in motor neurons of the spinal cord. However, improvement in motor performance and extension of lifespan were not observed in all hNP transplantation groups compared to vehicle-injected controls. Moreover, the lifespan of GDNF-expressing hNP recipient mice by lentiviral vector was shortened compared to controls, which was largely due to the decreased survival times of female animals. These results imply that although implanted hNPs differentiate into GLT1-expressing astrocytes and secrete GFs, which maintain dying motor neurons, inadequate trophic support could be harmful and there is sexual dimorphism in response to GDNF delivery in ALS mice. Therefore, additional therapeutic approaches may be required for full functional recovery.}, }
@article {pmid19309797, year = {2009}, author = {Maragakis, NJ}, title = {Rethinking a drug treatment failure on a traditional ALS target.}, journal = {Experimental neurology}, volume = {216}, number = {2}, pages = {254-257}, doi = {10.1016/j.expneurol.2008.12.025}, pmid = {19309797}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/cerebrospinal fluid/*drug therapy/metabolism ; Animals ; Disease Models, Animal ; Excitatory Amino Acid Transporter 2/drug effects/metabolism ; Glutamic Acid/cerebrospinal fluid/metabolism ; Humans ; Masoprocol/pharmacology/therapeutic use ; Treatment Failure ; }, abstract = {In a recent issue of Experimental Neurology, Boston-Howes and colleagues used an assay of glutamate transport to screen 1040 FDA approved drugs in an attempt to identify compounds that would increase glutamate transport, a central function of astrocytes, and a potential biological target for neuroprotection for a variety of neurological disorders. They identified the compound nordihydroguaiaretic acid (NDGA) as a particularly good candidate for inducing glutamate transport. Pharmacological increases in glutamate transport could have a number of potential applications to diseases of the nervous system where glutamate excitotoxicity is thought to be a contributing factor to pathogenesis including Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, stroke, and epilepsy among others. They chose to test this compound in a model of Amyotrophic Lateral Sclerosis (ALS)--the SOD1G93A mouse. In both human ALS and rodent models of the disease, glutamate excitotoxicity and abnormalities in glutamate transporter biology more specifically, have been implicated in ALS disease propagation. Interestingly, while the authors nicely demonstrate that NDGA has a biological effect on glutamate transport in normal (wild type) central nervous system tissues both in vitro and in vivo, it was the somewhat unexpected (and often overlooked) findings in the ALS mouse model that makes this manuscript notable and suggests that rethinking translational approaches to drug therapies in ALS may be on the horizon.}, }
@article {pmid19308767, year = {2009}, author = {Pizzasegola, C and Caron, I and Daleno, C and Ronchi, A and Minoia, C and Carrì, MT and Bendotti, C}, title = {Treatment with lithium carbonate does not improve disease progression in two different strains of SOD1 mutant mice.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {4}, pages = {221-228}, doi = {10.1080/17482960902803440}, pmid = {19308767}, issn = {1471-180X}, support = {GGP06063/TI_/Telethon/Italy ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/physiopathology/veterinary ; Animals ; Antimanic Agents/pharmacology/*therapeutic use ; Behavior, Animal/drug effects/physiology ; Biomarkers/metabolism ; Body Weight ; Disease Models, Animal ; Disease Progression ; Female ; Humans ; Lithium Carbonate/pharmacology/*therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Phenotype ; Spinal Cord/metabolism/pathology ; *Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Survival Rate ; }, abstract = {It has been shown that chronic treatment with lithium carbonate (Li(2)CO(3)) in presymptomatic SOD1G93A transgenic male mice, a model of ALS, was able to remarkably increase their lifespan through the activation of autophagy and the promotion of mitochondriogenesis and neurogenesis. This prompted us to test the lithium effect also in female SOD1G93A mice with two phenotypes of different disease severity. Female SOD1G93A mice of C57BL/6J or 129S2/Sv genetic background were treated daily with Li(2)CO(3) 37 mg/kg (1 mEq/kg) i.p. starting from age 75 days until death. Grip strength, latency to fall on rotarod and body weight were monitored twice weekly. At the time of death the spinal cord was removed to assess the number of motor neurons and to measure the expression of a marker of autophagy (LCII) and the activity of mitochondrial complex IV. We observed a significant anticipation of the onset and reduced survival in 129Sv/G93A and no effect in C57/G93A mice treated with lithium compared to vehicle treated mice. Moreover, lithium neither exerted neuroprotective effects nor increased the expression of LCII and the activity of mitochondrial complex IV in the spinal cord. The present study does not identify any therapeutic or neuroprotective effect of lithium in SOD1G93A female mice.}, }
@article {pmid19303440, year = {2009}, author = {Quinones, MP and Kaddurah-Daouk, R}, title = {Metabolomics tools for identifying biomarkers for neuropsychiatric diseases.}, journal = {Neurobiology of disease}, volume = {35}, number = {2}, pages = {165-176}, doi = {10.1016/j.nbd.2009.02.019}, pmid = {19303440}, issn = {1095-953X}, support = {R01 NS054008/NS/NINDS NIH HHS/United States ; R24 GM078233/GM/NIGMS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Animals ; Biomarkers/*metabolism ; Bipolar Disorder/genetics/metabolism/therapy ; Depressive Disorder/genetics/metabolism/therapy ; Depressive Disorder, Major/genetics/metabolism/therapy ; Environment ; Humans ; Huntington Disease/genetics/metabolism/therapy ; Mental Disorders/genetics/*metabolism/therapy ; Metabolomics/*methods ; Motor Neuron Disease/genetics/metabolism/therapy ; Parkinson Disease/genetics/metabolism/therapy ; Schizophrenia/genetics/metabolism/therapy ; }, abstract = {The repertoire of biochemicals (or small molecules) present in cells, tissue, and body fluids is known as the metabolome. Today, clinicians utilize only a very small part of the information contained in the metabolome, as revealed by the quantification of a limited set of analytes to gain information on human health. Examples include measuring glucose or cholesterol to monitor diabetes and cardiovascular health, respectively. With a focus on comprehensively studying the metabolome, the rapidly growing field of metabolomics captures the metabolic state of organisms at the global or "-omics" level. Given that the overall health status of an individual is captured by his or her metabolic state, which is a reflection of what has been encoded by the genome and modified by environmental factors, metabolomics has the potential to have a great impact upon medical practice by providing a wealth of relevant biochemical data. Metabolomics promises to improve current, single metabolites-based clinical assessments by identifying metabolic signatures (biomarkers) that embody global biochemical changes in disease, predict responses to treatment or medication side effects (pharmachometabolomics). State of the art metabolomic analytical platforms and informatics tools are being used to map potential biomarkers for a multitude of disorders including those of the central nervous system (CNS). Indeed, CNS disorders are linked to disturbances in metabolic pathways related to neurotransmitter systems (dopamine, serotonin, GABA and glutamate); fatty acids such as arachidonic acid-cascade; oxidative stress and mitochondrial function. Metabolomics tools are enabling us to map in greater detail perturbations in many biochemical pathways and links among these pathways this information is key for development of biomarkers that are disease-specific. In this review, we elaborate on some of the concepts and technologies used in metabolomics and its promise for biomarker discovery. We also highlight early findings from metabolomic studies in CNS disorders such as schizophrenia, Major Depressive Disorder (MDD), Bipolar Disorder (BD), Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD).}, }
@article {pmid19299456, year = {2009}, author = {Ueki, I and Giesy, SL and Harvatine, KJ and Kim, JW and Boisclair, YR}, title = {The acid-labile subunit is required for full effects of exogenous growth hormone on growth and carbohydrate metabolism.}, journal = {Endocrinology}, volume = {150}, number = {7}, pages = {3145-3152}, pmid = {19299456}, issn = {1945-7170}, support = {R01 DK051624/DK/NIDDK NIH HHS/United States ; DK-51624/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Blood Glucose/metabolism ; Carbohydrate Metabolism/*drug effects ; Female ; Growth Hormone/*physiology ; Insulin/blood ; Insulin-Like Growth Factor Binding Protein 3/biosynthesis ; Insulin-Like Growth Factor I/biosynthesis ; Male ; Mice ; Muscle, Skeletal/drug effects/metabolism ; Weight Gain/drug effects ; }, abstract = {Normal postnatal growth is dependent in part on overlapping actions of GH and IGF-I. These actions reflect GH stimulation of IGF-I production in liver and extrahepatic tissues, representing respectively the endocrine and autocrine/paracrine arms of the IGF system. Recent experiments in genetically modified mice show that each source of IGF-I can compensate for absence of the other but do not resolve their relative role in postnatal growth. In an effort to address this issue, we studied the GH responsiveness of mice harboring a null mutation of the acid-labile subunit (ALS). Null ALS mice have a substantial reduction in endocrine IGF-I but, unlike other models of plasma IGF-I deficiency, have no obvious additional endocrine defects. Wild type and null ALS mice of both sexes received daily sc injections of saline or recombinant bovine GH between d 35 and 63 of postnatal age. The GH-stimulated body weight gain of null ALS mice was reduced by more than 30% relative to wild type mice, irrespective of sex. Reductions in GH responsiveness were also seen for kidney and linear growth. Absence of ALS eliminated the ability of GH to increase plasma IGF-I despite intact GH-dependent stimulation of IGF-I expression in liver, adipose tissue, and skeletal muscle. GH treatment was also less efficient in antagonizing insulin action in null ALS mice. Overall, these results suggest that the GH effects mediated by endocrine IGF-I depends on ALS, and accordingly null ALS mice are less responsive to exogenous GH therapy.}, }
@article {pmid19296491, year = {2009}, author = {Crochemore, C and Virgili, M and Bonamassa, B and Canistro, D and Pena-Altamira, E and Paolini, M and Contestabile, A}, title = {Long-term dietary administration of valproic acid does not affect, while retinoic acid decreases, the lifespan of G93A mice, a model for amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {39}, number = {4}, pages = {548-552}, doi = {10.1002/mus.21260}, pmid = {19296491}, issn = {0148-639X}, mesh = {Acetylcholinesterase/metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*mortality ; Animal Feed ; Animals ; Antineoplastic Agents/*pharmacology ; Choline O-Acetyltransferase/metabolism ; Disease Models, Animal ; Female ; GABA Agents/*pharmacology ; Gene Dosage ; Humans ; Life Expectancy ; Male ; Mice ; Mice, Transgenic ; Nerve Degeneration/drug therapy/mortality ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Tretinoin/*pharmacology ; Valproic Acid/*pharmacology ; }, abstract = {Mice bearing the mutated gene for Cu/Zn superoxide dismutase (G93A) are a good model for human amyotrophic lateral sclerosis (ALS). They develop progressive limb paralysis paralleled by loss of motor neurons of the cervical and lumbar spinal cord, which starts at 3-3.5 months of age and ends with death at 4-5 months. Several treatments have been attempted to delay clinical symptoms and to extend lifespan, and some have had modest beneficial effects. One such treatment, based on long-term administration of valproic acid (VPA), resulted in controversial results. We report here that, while dietary supplementation with high VPA dosage slows down motor neuron death, as assessed by measurement of a specific marker for cholinergic neurons in the spinal cord, it has no significant effect on lifespan. Recently, the hypothesis has been put forward that a deficiency of retinoic acid (RA) and its signaling may have a role in ALS. We report that long-term dietary supplementation with RA has no effect on the decrease of the cholinergic marker in the spinal cord, but it significantly shortens lifespan of G93A mice.}, }
@article {pmid19294549, year = {2009}, author = {Lunn, JS and Hefferan, MP and Marsala, M and Feldman, EL}, title = {Stem cells: comprehensive treatments for amyotrophic lateral sclerosis in conjunction with growth factor delivery.}, journal = {Growth factors (Chur, Switzerland)}, volume = {27}, number = {3}, pages = {133-140}, doi = {10.1080/08977190902814855}, pmid = {19294549}, issn = {1029-2292}, support = {R01 NS040386/NS/NINDS NIH HHS/United States ; R01 NS051644/NS/NINDS NIH HHS/United States ; NS051644-01A2/NS/NINDS NIH HHS/United States ; NS40386/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/therapy ; Axons/physiology ; Humans ; Intercellular Signaling Peptides and Proteins/pharmacology/*therapeutic use ; Motor Neurons/*cytology/physiology ; Oxidative Stress ; Stem Cell Transplantation ; Stem Cells/*cytology/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by loss of both upper and lower motor neurons. ALS progression is complex and likely due to cellular dysfunction at multiple levels, including mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress, axonal dysfunction, reactive astrocytosis, and mutant superoxide dismutase expression, therefore, treatment must provide neuronal protection from multiple insults. A significant amount of ALS research focuses on growth factor-based therapies. Growth factors including insulin-like growth factor-I, vascular endothelial growth factor, brain-derived neurotrophic factor, and glial-derived neurotrophic factor exhibit robust neuroprotective effects on motor neurons in ALS models. Issues concerning growth factor delivery, stability and unwanted side effects slow the transfer of these treatments to human ALS patients. Stem cells represent a new therapeutic approach offering both cellular replacement and trophic support for the existing population. Combination therapy consisting of stem cells expressing beneficial growth factors may provide a comprehensive treatment for ALS.}, }
@article {pmid19285073, year = {2009}, author = {Morrison, BM and Lachey, JL and Warsing, LC and Ting, BL and Pullen, AE and Underwood, KW and Kumar, R and Sako, D and Grinberg, A and Wong, V and Colantuoni, E and Seehra, JS and Wagner, KR}, title = {A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {217}, number = {2}, pages = {258-268}, doi = {10.1016/j.expneurol.2009.02.017}, pmid = {19285073}, issn = {1090-2430}, mesh = {Activin Receptors, Type II/metabolism/*therapeutic use ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/physiopathology ; Animals ; Body Weight/drug effects/physiology ; CHO Cells ; Cricetinae ; Cricetulus ; Disease Models, Animal ; Female ; Male ; Mice ; Mice, Transgenic ; Muscle Strength/drug effects/physiology ; Muscle Weakness/*drug therapy/etiology/physiopathology ; Muscle, Skeletal/drug effects/metabolism ; Myostatin/*antagonists &amp; inhibitors/metabolism ; Recombinant Fusion Proteins/chemical synthesis/therapeutic use ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurologic disease characterized by progressive weakness that results in death within a few years of onset by respiratory failure. Myostatin is a member of the TGF-beta superfamily that is predominantly expressed in muscle and acts as a negative regulator of muscle growth. Attenuating myostatin has previously been shown to produce increased muscle mass and strength in normal and disease animal models. In this study, a mouse model of ALS (SOD1(G93A) transgenic mice) was treated with a soluble activin receptor, type IIB (ActRIIB.mFc) which is a putative endogenous signaling receptor for myostatin in addition to other ligands of the TGF-beta superfamily. ActRIIB.mFc treatment produces a delay in the onset of weakness, an increase in body weight and grip strength, and an enlargement of muscle size whether initiated pre-symptomatically or after symptom onset. Treatment with ActRIIB.mFc did not increase survival or neuromuscular junction innervation in SOD1(G93A) transgenic mice. Pharmacologic treatment with ActRIIB.mFc was superior in all measurements to genetic deletion of myostatin in SOD1(G93A) transgenic mice. The improved function of SOD1(G93A) transgenic mice following treatment with ActRIIB.mFc is encouraging for the development of TGF-beta pathway inhibitors to increase muscle strength in patients with ALS.}, }
@article {pmid19284546, year = {2009}, author = {Carratù, P and Spicuzza, L and Cassano, A and Maniscalco, M and Gadaleta, F and Lacedonia, D and Scoditti, C and Boniello, E and Di Maria, G and Resta, O}, title = {Early treatment with noninvasive positive pressure ventilation prolongs survival in Amyotrophic Lateral Sclerosis patients with nocturnal respiratory insufficiency.}, journal = {Orphanet journal of rare diseases}, volume = {4}, number = {}, pages = {10}, pmid = {19284546}, issn = {1750-1172}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*complications/*mortality/therapy ; Female ; Humans ; Male ; Middle Aged ; *Positive-Pressure Respiration ; Respiratory Function Tests ; Respiratory Insufficiency/*mortality/physiopathology/*therapy ; Survival ; Survival Analysis ; Treatment Outcome ; Vital Capacity ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which rapidly leads to chronic respiratory failure requiring mechanical ventilation. Currently, forced vital capacity (FVC) < 50% is considered as physiologic marker for admitting patients to Noninvasive Positive Pressure Ventilation (NPPV) intervention, although it has been recently shown the median survival of patients with baseline FVC < 75% much shorter than median survival of patients with baseline FVC > 75%, independently by any treatment.<br><br>AIM: To assess the role of NPPV in improving outcome of ALS, a retrospective analysis was performed to investigate 1 year survival of ALS patients with FVC < 75% and nocturnal respiratory insufficiency, treated with NPPV, compared to a well-matched population of ALS patients, who refused or was intolerant to NPPV.<br><br>METHODS: We investigated seventy-two consecutive ALS patients who underwent pulmonary function test. Forty-four presented a FVC > 75% and served as control group. Twenty-eight patients presented a FVC < 75% and showed, at polysomnography analysis, nocturnal respiratory insufficiency, requiring NPPV; sixteen were treated with NPPV, while twelve refused or were intolerant.<br><br>RESULTS: Increased survival rate at 1 year in patients with FVC < 75% treated with NPPV, as compared to those who refused or could not tolerate NPPV (p = 0.02), was observed. The median rate of decline in FVC% was slower in NPPV patients than in patients who did not use NPPV (95% CI: 0.72 to 1.85; p < 0.0001).<br><br>CONCLUSION: This report demonstrates that early treatment with NPPV prolongs survival and reduces decline of FVC% in ALS.}, }
@article {pmid19270441, year = {2009}, author = {Pinkhardt, EH and Sperfeld, AD and Gdynia, HJ and Ludolph, AC and Kassubek, J}, title = {The combination of dopa-responsive parkinsonian syndrome and motor neuron disease.}, journal = {Neuro-degenerative diseases}, volume = {6}, number = {3}, pages = {95-101}, doi = {10.1159/000207795}, pmid = {19270441}, issn = {1660-2862}, mesh = {Adult ; Aged ; Antiparkinson Agents/therapeutic use ; Dopamine Agents/therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*complications/pathology/*physiopathology ; Parkinsonian Disorders/*complications/pathology/*physiopathology ; Syndrome ; }, abstract = {BACKGROUND: Idiopathic Parkinson's syndrome (IPS) and motor neuron disorders (MND) are generally considered as distinct clinicopathological entities. However, cooccurrence of different neurodegenerative disorders is more frequent than would be expected. Therefore, there is an ongoing discussion whether some entities represent parts of a common spectrum.<br><br>OBJECTIVE AND METHODS: We describe clinical hallmarks and treatment options in a group of 8 patients who had combined features of both a dopa-responsive parkinsonian syndrome and MND.<br><br>RESULTS: All patients exhibited a typical clinical picture of IPS, and all were treated with levodopa or other dopaminergic drugs with good clinical response. The patients also showed clinical and electrophysiological signs of upper and/or lower motor neuron degeneration. Noticeably, in contrast to well-known distinct entities like the amyotrophic lateral sclerosis-parkinsonism/ dementia complex in southwest New Guinea, we did not observe any cognitive decline during the observation period except in 1 patient.<br><br>CONCLUSION: This comorbidity of two neurodegenerative diseases supports the ongoing discussion of a pathophysiological and clinical overlap of disease processes. Due to the potent pharmacological options for the IPS symptoms in these overlap syndromes, these patients should be offered optimal symptomatic dopaminergic therapy.}, }
@article {pmid19259649, year = {2009}, author = {Rizvanov, AA and Mukhamedyarov, MA and Palotás, A and Islamov, RR}, title = {Retrogradely transported siRNA silences human mutant SOD1 in spinal cord motor neurons.}, journal = {Experimental brain research}, volume = {195}, number = {1}, pages = {1-4}, pmid = {19259649}, issn = {1432-1106}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; Disease Models, Animal ; Humans ; Lumbosacral Region ; Mice ; Motor Neurons/drug effects/*metabolism ; RNA, Messenger/metabolism ; RNA, Small Interfering/*metabolism/pharmacology ; Sciatic Nerve/drug effects/physiology ; Spinal Cord/*pathology ; Superoxide Dismutase/*genetics/metabolism ; }, abstract = {The transgenic mouse model of familial amyotrophic lateral sclerosis (ALS) expressing human mutant ((G)93(A)) copper/zinc superoxide dismutase (SOD(1)) is an attractive model for studying the therapeutic effects of RNA interference (RNAi) because of the specific silencing of the mutant gene expression. We studied small interfering RNA (siRNA)-mediated down-regulation of human mutant (G)93(A) SOD(1) gene in lumbar spinal cord of ALS mice. siRNA was applied onto the proximal nerve stump of severed sciatic nerves. One day after surgery the lumbar spinal cords were processed for RT-PCR examination. Treatment with specific siRNA resulted in 48% decrease in human SOD(1) mRNA levels in lumbar spinal cord, but had no effect on the abundance of mouse ChAT and SNAP(25) mRNAs which were used as randomly selected internal controls, the mark of a specific silencing of SOD(1). Our findings demonstrate for the first time that siRNA, targeting mutant human SOD(1) mRNA, is taken up by the sciatic nerve, retrogradely transported to the perikarya of motor neurons, and inhibits mutant SOD(1) mRNA in (G)93(A) transgenic ALS mice.}, }
@article {pmid19252282, year = {2009}, author = {Sekiya, M and Ichiyanagi, T and Ikeshiro, Y and Yokozawa, T}, title = {The Chinese prescription Wen-Pi-Tang extract delays disease onset in amyotrophic lateral sclerosis model mice while attenuating the activation of glial cells in the spinal cord.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {32}, number = {3}, pages = {382-388}, doi = {10.1248/bpb.32.382}, pmid = {19252282}, issn = {0918-6158}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*prevention &amp; control ; Animals ; Drugs, Chinese Herbal/pharmacology/*therapeutic use ; Heme Oxygenase-1/biosynthesis ; Mice ; Mice, Transgenic ; Microglia/drug effects/pathology ; Motor Neurons/drug effects/pathology ; Mutation ; Neuroglia/*drug effects/pathology ; Nitric Oxide Synthase/biosynthesis ; Oxidative Stress ; Spinal Cord/*drug effects/metabolism/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the selective loss of motor neurons. There is no effective treatment or drug against ALS, and the precise mechanisms leading to the selective loss of motor neurons are still unknown. We investigated the effect of a Chinese prescription, Wen-Pi-Tang, on the ALS model mouse SOD1(G93A). Although the oral administration of Wen-Pi-Tang extract to SOD1(G93A) mice had no significant effect on body weight loss and survival time, Wen-Pi-Tang delayed disease onset. Therefore, we evaluated immunohistological changes in the spinal cord of SOD1(G93A) mice during the early disease period, and found that Wen-Pi-Tang extract inhibited neuronal loss in the lumbar segment of the spinal cord of mice. Furthermore, increased astrocytes and microglial cells, which increase prior to neuronal loss, in spinal cords were significantly reduced in the Wen-Pi-Tang treated group. Since oxidative markers, heme oxygenase-1 and inducible nitric oxide synthase, in the spinal cord were also reduced as well as the change in microglia, the administration of Wen-Pi-Tang was thought to delay disease onset by inhibiting glial cell activation.}, }
@article {pmid19241985, year = {2009}, author = {Samphao, S and Eremin, JM and El-Sheemy, M and Eremin, O}, title = {Treatment of established breast cancer in post-menopausal women: role of aromatase inhibitors.}, journal = {The surgeon : journal of the Royal Colleges of Surgeons of Edinburgh and Ireland}, volume = {7}, number = {1}, pages = {42-55}, doi = {10.1016/s1479-666x(09)80066-8}, pmid = {19241985}, issn = {1479-666X}, mesh = {Aged ; Aromatase Inhibitors/*therapeutic use ; Breast Neoplasms/*drug therapy/pathology ; Female ; Humans ; Middle Aged ; *Postmenopause ; }, abstract = {Endocrine therapy plays a crucial and historically important role in the treatment ofwomen with hormone-responsive breast cancer. Tamoxifen has been the standard endocrine treatment for advanced and early-stage breast cancer for almost three decades. However, patients receiving tamoxifen may either fail to respond or develop disease recurrence following completion of therapy. The aromatase inhibitors (Als) have become the new and alternative modalities of endocrine treatment for post-menopausal women with oestrogen receptor-positive breast cancer, as a result of promising data from randomised trials in metastatic and locally advanced breast cancers. Recently, the results from several large, randomised, controlled adjuvant trials have provided further evidence that the use of Als, either as initial treatment or sequentially after tamoxifen, improves disease-free survival and, in certain patients, overall survival. With relatively short-term follow-up, the use of Als has been shown to be safe and welltolerated. Nevertheless, some detrimental adverse effects, particularly skeletal-related events or cardiovascular disease, remain important issues of concern and warrant continued monitoring and follow-up. The optimal use of Als, the appropriate timing of treatment, and the superiority of individual agents are under investigation. Use of Als in women with chemotherapy-induced amenorrhoea should be cautious due to the possibility of return of ovarian function. Cost-effectiveness and quality of life remain issues of interest since the high and ever increasing incidence of breast cancer has contributed to significant healthcare costs and patients with breast cancer following appropriate treatment are living longer but not necessarily being cured of their diseases.}, }
@article {pmid19235108, year = {2008}, author = {Saadatnia, M and Fatehi, F and Basiri, K and Sariaslani, P}, title = {ALS-LAUS syndrome in a patient with high level of antiphospholipid antibodies: a case report.}, journal = {Neurologia i neurochirurgia polska}, volume = {42}, number = {6}, pages = {546-549}, pmid = {19235108}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/*blood/*diagnosis/therapy ; Antibodies, Antiphospholipid/*blood ; Diagnosis, Differential ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/diagnosis ; Plasma Exchange/methods ; Prednisolone/administration &amp; dosage ; Syndrome ; Treatment Outcome ; }, abstract = {When evaluating a patient with amyotrophic lateral sclerosis (ALS), a number of other motor neuron disorders and related motor syndromes should be considered. Herein, we describe a 55-year-old Persian man with typical presentation of ALS in whom based on further finding of elevated level of antiphospholipid antibodies, final diagnosis of ALS with laboratory abnormalities of uncertain significance (ALS-LAUS) was made. With respect to persistent increased titre of antiphospholipid antibodies, he was treated with plasma exchange and prednisolone. After 3 months of treatment, the symptoms improved and antiphospholipid antibody titres decreased. To the best of our knowledge, this is the first case of ALS-LAUS accompanied by high titre of antiphospholipid antibodies with response to plasma exchange and corticosteroids.}, }
@article {pmid19231200, year = {2009}, author = {Eisen, A}, title = {Amyotrophic lateral sclerosis: A 40-year personal perspective.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {16}, number = {4}, pages = {505-512}, doi = {10.1016/j.jocn.2008.07.072}, pmid = {19231200}, issn = {0967-5868}, mesh = {Amyotrophic Lateral Sclerosis/complications/genetics/pathology/*therapy ; Animals ; Enteral Nutrition/methods ; Gastrostomy/methods ; Genetic Therapy/methods ; Humans ; Palliative Care ; }, abstract = {Amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND) shares with other neurodegenetrative disorders of the aging nervous system a polygenic, multifactorial aetiology. Less than 10% are familial and these too probably are associated with several interactive genes. The onset of ALS predates development of clinical symptoms by an unknown interval which may extend several years. The cause of neurodegeneration remains unknown but a common end-point is protein misfolding which in turn causes cell function failure. The complex nature of ALS has hindered therapeutic advances. In recent years longer survival is attributable largely to institution of non-invasive ventilation with BiPAP and timely implementation of percutaneous endoscopic gastrostomy (PEG) feeding. Symptomatic treatment has advanced improving quality of life. Several encouraging avenues of therapy for ALS are beginning to be emerge raising hope for real benefit. They include protective autoimmunity, vaccines against misfolded protein epitopes and other deleterious species, new drug delivery systems employing nanotechnology and the potential of stem cell therapy.}, }
@article {pmid19230774, year = {2009}, author = {Bezprozvanny, I}, title = {Calcium signaling and neurodegenerative diseases.}, journal = {Trends in molecular medicine}, volume = {15}, number = {3}, pages = {89-100}, pmid = {19230774}, issn = {1471-4914}, support = {R01 NS056224/NS/NINDS NIH HHS/United States ; R01 NS056224-03/NS/NINDS NIH HHS/United States ; }, mesh = {Aging ; Animals ; Calcium/*antagonists &amp; inhibitors/metabolism ; *Calcium Signaling/drug effects ; Humans ; Neurodegenerative Diseases/drug therapy/*physiopathology ; Neurons/pathology/physiology ; }, abstract = {Neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and spinocerebellar ataxias (SCAs), present an enormous medical, social, financial and scientific problem. Recent evidence indicates that neuronal calcium (Ca2+) signaling is abnormal in many of these disorders. Similar, but less severe, changes in neuronal Ca2+ signaling occur as a result of the normal aging process. The role of aberrant neuronal Ca2+ signaling in the pathogenesis of neurodegenerative disorders is discussed here. The potential utility of Ca2+ blockers for treatment of these disorders is also highlighted. It is reasoned that Ca2+ blockers will be most beneficial clinically when used in combination with other disease-specific therapeutic approaches.}, }
@article {pmid19225228, year = {2009}, author = {Enaka, M and Hagihara, M and Sakai, R and Oshima, R and Ito, S and Motohashi, K and Maruta, A and Ishigatsubo, Y and Kanamori, H}, title = {[Air-leak syndrome in patients with non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation].}, journal = {[Rinsho ketsueki] The Japanese journal of clinical hematology}, volume = {50}, number = {1}, pages = {39-43}, pmid = {19225228}, issn = {0485-1439}, mesh = {Adolescent ; Fatal Outcome ; Female ; Graft vs Host Disease/etiology/therapy ; Hematologic Neoplasms/complications/*therapy ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Humans ; Lung Diseases/*etiology/therapy ; Male ; Mediastinal Emphysema/*etiology/therapy ; Middle Aged ; Pneumothorax/*etiology/therapy ; Subcutaneous Emphysema/*etiology/therapy ; Syndrome ; Transplantation, Homologous ; Treatment Outcome ; Young Adult ; }, abstract = {We reported 5 patients who developed air-leak syndrome (ALS) including pneumothorax, pneumomediastinum and subcutaneous emphysema after allogeneic stem cell transplantation (SCT). The underlying diseases were AML (n=2), ALL (n=1), MDS (n=1), and CML (n=1). All patients received allogeneic SCT from related donors including 2 donors with HLA mismatch. Total body irradiation was performed as a conditioning regimen in all patients. Late-onset noninfectious pulmonary complications (LONIPC) were detected in all patients before the development of ALS. The interval from diagnosis of LONIPC to onset of ALS was 10-360 days (median, 20 days). Four of 5 patients were treated with corticosteroid for chronic graft-versus-host disease and/or LONIPC. To date, three patients have died of respiratory failure. The others are currently alive and one of these surviving patients is receiving home oxygen treatment. Physicians should be aware of this rare complication following LONIPC, because treatment of ALS is difficult in some patients.}, }
@article {pmid19224316, year = {2009}, author = {Phukan, J and Hardiman, O}, title = {The management of amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {256}, number = {2}, pages = {176-186}, pmid = {19224316}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/complications/psychology/*therapy ; Caregivers/ethics/psychology/statistics &amp; numerical data ; Cognition Disorders/etiology/psychology/*therapy ; Genetic Predisposition to Disease/genetics ; Long-Term Care/ethics/methods/psychology ; Palliative Care/methods/standards ; Physician-Patient Relations/ethics ; Respiration, Artificial/standards ; Respiratory Insufficiency/etiology/physiopathology/therapy ; Withholding Treatment/ethics/standards ; }, abstract = {The terms amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND) refer to a condition characterized by motor system degeneration with relative preservation of other pathways. Although there have been advances in symptomatic treatment, ALS remains an incurable condition. Advances in ALS management prolong survival but simultaneously raise challenging ethical dilemmas for physicians, patients and their families. Here, we review current practice in the management of ALS including pharmacological treatment, nutritional management, respiratory care, and evolving strategies in the management of cognitive impairment.}, }
@article {pmid19217130, year = {2009}, author = {Meininger, V and Antoine, JC and Arne-Bes, MC and Broussolle, E and Bruneteau, G and Camdessanche, JP and Camu, W and Carluer, L and Cintas, P and Clavelou, P and Corcia, P and Couratier, P and Danel-Brunaud, V and Desnuelle, C and Destée, A and Dib, M and Fleury, MC and Furby, A and Giroud, M and Gonzales, J and Guy, N and Kolev, I and Lacomblez, L and Lardillier-Noel, D and Le Forestier, N and Maugin, D and Nicolas, G and Pittion, S and Pouget, J and Pradat, PF and Rousso, E and Salachas, F and Soriani, MH and Tranchant, C and Vandenberghe, N and Verschueren, A and Viader, F and Vial, C}, title = {[Internet and amyotrophic lateral sclerosis treatment: what is wrong?].}, journal = {Revue neurologique}, volume = {165}, number = {3}, pages = {207-210}, doi = {10.1016/j.neurol.2009.01.003}, pmid = {19217130}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Drug Approval ; Drug Evaluation, Preclinical ; France ; Humans ; Insulin-Like Growth Factor I/*therapeutic use ; Intercellular Signaling Peptides and Proteins/*therapeutic use ; *Internet ; Lithium Compounds/*therapeutic use ; United States ; United States Food and Drug Administration ; }, }
@article {pmid19216324, year = {2009}, author = {Morier, J and Du Pasquier, R and Kuntzer, T and Michel, P and Nater, B and Niederhauser, J and Rossetti, AO and Schluep, M and Vingerhoets, F}, title = {[Therapeutic advances in neurology].}, journal = {Revue medicale suisse}, volume = {5}, number = {185}, pages = {39-44, 46-8}, pmid = {19216324}, issn = {1660-9379}, mesh = {Humans ; Nervous System Diseases/*therapy ; Neurology/*trends ; }, abstract = {The neurology field has been greatly improved in 2008. The therapeutic window of intravenous thrombolysis for acute ischemic stoke is extended to 4 h 30. New studies show that the clinical progression of Parkinson's disease might be slowed by some medication. Deep brain stimulation may be beneficial early in the course of the disease. Tysabri and Fingolimod in multiple sclerosis are discussed. The pharmacopoeia for epilepsy is in constant development with new products recently released in Switzerland. CGRP receptor antagonists are about to be launched as a promising acute migraine treatment. The pharmacological approach in amyotrophic lateral sclerosis patients might be improved according to research results.}, }
@article {pmid19208404, year = {2009}, author = {Rabkin, JG and Gordon, PH and McElhiney, M and Rabkin, R and Chew, S and Mitsumoto, H}, title = {Modafinil treatment of fatigue in patients with ALS: a placebo-controlled study.}, journal = {Muscle &amp; nerve}, volume = {39}, number = {3}, pages = {297-303}, doi = {10.1002/mus.21245}, pmid = {19208404}, issn = {0148-639X}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*complications ; Benzhydryl Compounds/*therapeutic use ; Central Nervous System Stimulants/*therapeutic use ; Double-Blind Method ; Fatigue/*drug therapy/*etiology ; Female ; Humans ; Male ; Middle Aged ; Modafinil ; Psychiatric Status Rating Scales ; Severity of Illness Index ; Surveys and Questionnaires ; Treatment Outcome ; }, abstract = {Our objective was to determine whether modafinil alleviates fatigue in patients with amyotrophic lateral sclerosis (ALS). A placebo controlled trial with a 3:1 modafinil:placebo randomization in doses up to 300 mg/day for 4 weeks was followed by 8 weeks of open maintenance treatment. The primary endpoint was the Clinical Global Impressions-Improvement Scale. Secondary endpoints were the Fatigue Severity Scale, Epworth Sleepiness Scale, Beck Depression Inventory, Role Function Scale, and visual analog scales. Analysis of covariance was used to assess change at Week 4. Thirty-two patients were randomized; 29 completed the 4-week trial. In intention to treat (ITT) analysis, the response was 76% for modafinil versus 14% for placebo. In a completer analysis, the modafinil response rate was 86%, and the placebo response rate remained 14%. The number needed to treat was 1.6 (ITT). No medically serious adverse events were reported. Modafinil may be a promising intervention for fatigue in ALS patients. Replication in a larger study is needed.}, }
@article {pmid19200033, year = {2009}, author = {Kastenholz, B and Garfin, DE}, title = {Medicinal plants: a natural chaperones source for treating neurological disorders.}, journal = {Protein and peptide letters}, volume = {16}, number = {2}, pages = {116-120}, doi = {10.2174/092986609787316234}, pmid = {19200033}, issn = {0929-8665}, mesh = {Alzheimer Disease/drug therapy ; Copper/metabolism ; Drug Discovery ; Ginkgo biloba/chemistry ; Humans ; Metalloproteins/chemistry/pharmacology ; Molecular Chaperones/*chemistry/pharmacology ; Nervous System Diseases/*drug therapy ; Nuclear Magnetic Resonance, Biomolecular ; Phytotherapy ; Plant Extracts/*chemistry/pharmacology ; Plant Proteins/*chemistry/pharmacology ; Plants, Medicinal/*chemistry ; Protein Folding/drug effects ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Currently, no pharmaceuticals for the etiological treatment of neurodegenerative protein-misfolding diseases (e.g., ALS, Alzheimer's or prion diseases) are available. In this brief communication the development of chaperone-based medications from medicinal plants (e.g., Ginkgo biloba) are reviewed as referred to specific protein-protein interactions of plant metallochaperones and human enzymes. It is indicated that bioactive copper chaperones for superoxide dismutase isolated from medicinal plants may be lead molecules for drug development in several diseases concerning metal ion metabolisms of man and animals.}, }
@article {pmid19198769, year = {2009}, author = {Rosenbloom, AL}, title = {Mecasermin (recombinant human insulin-like growth factor I).}, journal = {Advances in therapy}, volume = {26}, number = {1}, pages = {40-54}, doi = {10.1007/s12325-008-0136-5}, pmid = {19198769}, issn = {1865-8652}, mesh = {Cardiovascular Diseases/drug therapy ; Central Nervous System Diseases/drug therapy ; Clinical Trials as Topic ; Diabetes Mellitus, Type 1/drug therapy ; Diabetes Mellitus, Type 2/drug therapy ; Dose-Response Relationship, Drug ; Growth Disorders/*drug therapy/physiopathology ; Growth Hormone/metabolism ; Human Growth Hormone/therapeutic use ; Humans ; Insulin Resistance ; Insulin-Like Growth Factor Binding Protein 3/therapeutic use ; Insulin-Like Growth Factor I/administration &amp; dosage/adverse effects/*therapeutic use ; Janus Kinase 2/metabolism ; Osteoporosis, Postmenopausal/drug therapy ; Receptor, IGF Type 1/metabolism ; Recombinant Proteins/administration &amp; dosage/adverse effects/*therapeutic use ; Time Factors ; }, abstract = {Growth hormone (GH) exercises its growth effects by stimulating insulin-like growth factor I (IGF-I) synthesis in the liver (endocrine IGF-I) and by inducing chondrocyte differentiation/replication and local production of IGF-I (paracrine/autocrine IGF-I). Injectable recombinant human (rh)IGF-I (mecasermin) has been available for nearly 20 years for treatment of the rare instances of GH insensitivity caused by GH receptor defects or GH-inhibiting antibodies. Full restoration of normal growth, as occurs with rhGH replacement of GH deficiency, is not seen, presumably because only the endocrine deficiency is addressed. RhIGF-I has also been effective as an insulin-sensitizing agent in severe insulin-resistant conditions. Although the insulin-sensitizing effect may benefit both type 1 and type 2 diabetes, there are no ongoing clinical trials because of concern about risk of retinopathy and other complications. Promotion of rhIGF-I for treatment of idiopathic short stature has been intensive, with neither data nor rationale suggesting that there might be a better response than has been documented with rhGH. Other applications that have either been considered or are undergoing clinical trial are based on the ubiquitous tissue-building properties of IGF-I and include chronic liver disease, cystic fibrosis, wound healing, AIDS muscle wasting, burns, osteoporosis, Crohn's disease, anorexia nervosa, Werner syndrome, X-linked severe combined immunodeficiency, Alzheimer's disease, muscular dystrophy, amyotrophic lateral sclerosis, hearing loss prevention, spinal cord injury, cardiovascular protection, and prevention of retinopathy of prematurity. The most frequent side effect is hypoglycemia, which is readily controlled by administration with meals. Other common adverse effects involve hyperplasia of lymphoid tissue, which may require tonsillectomy/adenoidectomy, accumulation of body fat, and coarsening of facies. The anti-apoptotic properties of IGF-I are implicated in cancer pathogenesis-a concern for long-term therapy. It is unlikely that mecasermin will be useful beyond the orphan indications of severe insulin resistance and GH insensitivity.}, }
@article {pmid19193833, year = {2009}, author = {Raqib, R and Mondal, D and Karim, MA and Chowdhury, F and Ahmed, S and Luby, S and Cravioto, A and Andersson, J and Sack, D}, title = {Detection of antibodies secreted from circulating Mycobacterium tuberculosis-specific plasma cells in the diagnosis of pediatric tuberculosis.}, journal = {Clinical and vaccine immunology : CVI}, volume = {16}, number = {4}, pages = {521-527}, pmid = {19193833}, issn = {1556-679X}, mesh = {Adolescent ; Antibodies, Bacterial/*analysis ; Cells, Cultured ; Child ; Child, Preschool ; Culture Media/*chemistry ; Enzyme-Linked Immunosorbent Assay/methods ; Female ; Humans ; Immunoglobulin G/analysis ; Infant ; Leukocytes, Mononuclear/immunology ; Male ; Mycobacterium tuberculosis/*immunology ; Plasma Cells/*immunology ; Sensitivity and Specificity ; Tuberculosis/*diagnosis ; }, abstract = {Diagnosis of tuberculosis (TB) in children is difficult because symptoms are often nonspecific or absent in infected children, diagnostic specimens are difficult to obtain from younger children, and >50% have negative TB cultures. Thus, there is an urgent need for improved diagnosis of pediatric TB. This study aimed to evaluate the diagnostic value of a new serological method, the ALS (antibodies in lymphocyte supernatant) assay, for the diagnosis of active TB in children with clinically identified TB. The ALS test is based on the concept that antigen-specific plasma cells are present in the circulation only at times of acute infection and not in latency. A cross-sectional study of pediatric patients (age range, 11 to 167 months) who were clinically identified as TB (n = 58) or non-TB (n = 16) patients was conducted, and they were monitored for 6 months. Healthy children (n = 58) were enrolled as controls. Spontaneous release of TB antigen-specific antibodies by in vitro-cultured, unstimulated peripheral blood mononuclear cells was assessed by an enzyme-linked immunosorbent assay using Mycobacterium bovis bacillus Calmette-Guérin (BCG) as the detecting antigen. Of the patients clinically diagnosed with TB, 15% had culture-confirmed TB, 64% were positive for TB by clinically established scoring charts (K. Edwards, P. N. G. Med. J. 30: 169-178, 1987; G. Stegen, K. Jones, and P. Kaplan, Pediatrics 43: 260-263, 1969; and stop TB Partnership, Childhood TB subgroup, World Health Organization, Int. J. Tuberc. Lung Dis. 10: 1091-1097, 2006), and 91% were TB positive by the ALS method. All TB patients had significantly higher BCG-specific ALS titers at enrollment (optical density [OD], 1.06 +/- 0.32) than healthy-control children (OD, 0.18 +/- 0.06) and non-TB children (OD, 0.21 +/- 0.10) (P = 0.001). The ALS titers declined in children with active disease from enrollment through 6 months following anti-TB therapy (P = 0.001). The ALS assay is a novel diagnostic method with potential applications in the diagnosis of pediatric TB and in subsequent monitoring of treatment effectiveness.}, }
@article {pmid19192871, year = {2009}, author = {Huang, H and Chen, L and Xi, H and Wang, Q and Zhang, J and Liu, Y and Zhang, F}, title = {[Olfactory ensheathing cells transplantation for central nervous system diseases in 1,255 patients].}, journal = {Zhongguo xiu fu chong jian wai ke za zhi = Zhongguo xiufu chongjian waike zazhi = Chinese journal of reparative and reconstructive surgery}, volume = {23}, number = {1}, pages = {14-20}, pmid = {19192871}, issn = {1002-1892}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Cell Culture Techniques ; *Cell Transplantation ; Central Nervous System Diseases/*surgery ; Child ; Child, Preschool ; Female ; Follow-Up Studies ; Humans ; Infant ; Male ; Middle Aged ; Nerve Regeneration ; Olfactory Bulb/*cytology/embryology ; }, abstract = {OBJECTIVE: To analyze the therapeutic effect of olfactory ensheathing cells (OECs) transplantation for central nervous system diseases.<br><br>METHODS: Between November 2001 and January 2008, 1,255 participants with central nervous system diseases were enrolled in this clinical study for fetal OECs transplantation. There were 928 males and 327 females aged 1.2-87 (mean 40) years. The course of disease was (4.52 +/- 4.67) years. Among them, 656 participants suffered from chronic spinal cord injury (SCI), 457 amyotrophic lateral sclerosis (ALS), 68 cerebral palsy (CP), 20 multiple sclerosis (MS), 11 the sequelae of stoke, 10 ataxia, and 33 residual diseases. The participants came from 71 countries or regions. Accidentally abortional fetal olfactory bulbs were donated voluntarily and were cultured for 2 weeks, then were transplanted.<br><br>RESULTS: One thousand one hundred and twenty-eight cases were followed up for 2-8 weeks (mean 4 weeks) to obtain integrated data. Among them, the neurological functional amelioration was noticed in 994 participants with the overall short-term improvement rate of 88.12%. Seventy-six patients experienced the various perioperative complications with the incidence rate of 6.74%. One hundred and twenty patients with SCI received over 1 year follow-up. And according to ASIA assessment, motor scores increased from (39.82 +/- 20.25) to (44.55 +/- 18.99) points, light touch scores from (51.56 +/- 25.89) to (59.81 +/- 27.72) points, pain scores from (50.36 +/- 27.44) to (57.09 +/- 28.51) points for foreign patients (P < 0.05); motor scores increased from (40.52 +/- 20.80) to (46.45 +/- 20.35) points, light touch scores from (55.64 +/- 26.32) to (68.64 +/- 25.89) points, pain scores from (57.05 +/- 26.00) to (66.13 +/- 24.29) points for good rehabilitation Chinese patients (overall P < 0.05); motor scores from (37.03 +/- 18.52) to (38.03 +/- 18.50 points (P < 0.05), light touch scores from (45.88 +/- 22.56) to (46.63 +/- 23.09) points (P > 0.05), pain scores from (45.25 +/- 23.68) to (45.28 +/- 23.63) points (P > 0.05) for poor rehabilitation Chinese patients. Compared foreign patients and good rehabilitation Chinese patients with poor rehabilitation Chinese patients, difference in score change was remarkable (P < 0.05). One hundred and six cases of ALS, 32 CP, 8 MS, 7 ataxia, and 2 stroke sequelae were followed up for 3-48, 3-36, 2-20, 7-17, 6 and 24 months, One hundred and six cases of respectively. Majority of them (113/155, 72.9%) were benefited from OECs transplantation.<br><br>CONCLUSION: OECs transplantation into brain and spinal cord is feasible and safe . The therapeutic strategy is valuable treatment for such central nervous system diseases such as chronic SCI, ALS, CP and stroke sequelae and can improve the patients' neurological functions and/or decrease the progressive deterioration.}, }
@article {pmid19191307, year = {2009}, author = {Miller, RG and Anderson, F and Brooks, BR and Mitsumoto, H and Bradley, WG and Ringel, SP and , }, title = {Outcomes research in amyotrophic lateral sclerosis: lessons learned from the amyotrophic lateral sclerosis clinical assessment, research, and education database.}, journal = {Annals of neurology}, volume = {65 Suppl 1}, number = {}, pages = {S24-8}, doi = {10.1002/ana.21556}, pmid = {19191307}, issn = {1531-8249}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/epidemiology/*therapy ; Databases, Factual ; Female ; Gulf War ; Humans ; Incidence ; Male ; Middle Aged ; Monitoring, Physiologic ; North America/epidemiology ; Outcome Assessment, Health Care ; Practice Guidelines as Topic ; Research/*trends ; }, abstract = {OBJECTIVE: To examine the care of patients with ALS following the publication of the standardized recommendations for the management of patients with amyotrophic lateral sclerosis (ALS) published in 1999 by the American Academy of Neurology.<br><br>METHODS: Specific aspects of ALS patient management have been evaluated serially using a national Amyotrophic Lateral Sclerosis Clinical Assessment, Research, and Education (ALS CARE) database to encourage compliance with these recommendations and to assure continuing quality improvement.<br><br>RESULTS: The most recent analysis of 5,600 patients shows interesting epidemiological observations and treatment trends. Proper management of many ALS symptoms has increased substantially since the first publication of the guidelines, and awareness of pseudobulbar affect has increased. Other recommendations are underutilized: Only 9% undergo percutaneous endoscopic gastrostomy, although this procedure was recommended in 22% of patients; and noninvasive positive pressure ventilation was used by only 21% of patients despite being associated with improved 5-year survival rates.<br><br>INTERPRETATION: This observational database has been a useful tool in monitoring compliance with the standard of care for patients with ALS and may have resulted in greater adherence to guidelines.}, }
@article {pmid19191058, year = {2009}, author = {Martinez, HR and Gonzalez-Garza, MT and Moreno-Cuevas, JE and Caro, E and Gutierrez-Jimenez, E and Segura, JJ}, title = {Stem-cell transplantation into the frontal motor cortex in amyotrophic lateral sclerosis patients.}, journal = {Cytotherapy}, volume = {11}, number = {1}, pages = {26-34}, doi = {10.1080/14653240802644651}, pmid = {19191058}, issn = {1477-2566}, mesh = {AC133 Antigen ; Adult ; Amyotrophic Lateral Sclerosis/mortality/*surgery ; Antigens, CD/metabolism ; Female ; Filgrastim ; Glycoproteins/metabolism ; Granulocyte Colony-Stimulating Factor/administration &amp; dosage ; Hematopoietic Stem Cell Transplantation/*methods ; Hematopoietic Stem Cells/drug effects/physiology ; Humans ; Male ; Middle Aged ; Motor Cortex/*surgery ; Peptides/metabolism ; Recombinant Proteins ; Transplantation, Autologous/methods ; }, abstract = {BACKGROUND AIMS: Amyotrophic lateral sclerosis (ALS) is characterized by the selective death of motor neurons. CD133(+) stem cells are known to have the capacity to differentiate into neural lineages. Stem cells may provide an alternative treatment for ALS and other neurodegenerative diseases.<br><br>METHODS: Five men and five women (aged 38-62 years) with confirmed ALS were included in this study. Our institutional ethics and research committees approved the protocol. After informed consent was obtained, patients underwent Hidrogen-Magnetic Resonance Imaging (H-MRI) spectroscopy and were given scores according to an ALS functional rating scale, Medical Research Council power muscle scale and daily living activities. Bone marrow was stimulated with 300 microg filgrastim subcutaneously daily for 3 days. Peripheral blood mononuclear cells were obtained after admission by leukapheresis. The cell suspension was conjugated with anti-human CD133 superparamagnetic microbeads, and linked cells were isolated in a magnetic field. The isolated cells (2.5-7.5x10(5)) were resuspended in 300 microL of the patient's cerebrospinal fluid, and implanted in motor cortexes using a Hamilton syringe. Ten patients with confirmed ALS without transplantation were used as a control group. Patients were followed up for a period of 1 year.<br><br>RESULTS: The autologous transplantation of CD133(+) stem cells into the frontal motor cortex is a safe and well-tolerated procedure in ALS patients. The survival of treated patients was statistically higher (P=0.01) than untreated control patients.<br><br>CONCLUSIONS: Stem-cell transplantation in the motor cortex delays ALS progression and improves quality of life.}, }
@article {pmid19185395, year = {2010}, author = {Bogaert, E and Van Damme, P and Poesen, K and Dhondt, J and Hersmus, N and Kiraly, D and Scheveneels, W and Robberecht, W and Van Den Bosch, L}, title = {VEGF protects motor neurons against excitotoxicity by upregulation of GluR2.}, journal = {Neurobiology of aging}, volume = {31}, number = {12}, pages = {2185-2191}, doi = {10.1016/j.neurobiolaging.2008.12.007}, pmid = {19185395}, issn = {1558-1497}, mesh = {Animals ; Calcium Signaling/physiology ; Cells, Cultured ; Coculture Techniques ; Injections, Intraventricular/methods ; Motor Neurons/*metabolism/physiology ; Nerve Degeneration/metabolism/physiopathology/*therapy ; Neurotoxins/*antagonists &amp; inhibitors/pharmacology ; Rats ; Rats, Wistar ; Receptors, AMPA/*biosynthesis/genetics/physiology ; Spinal Cord/cytology/metabolism/physiology ; Up-Regulation/*physiology ; Vascular Endothelial Growth Factor A/administration &amp; dosage/*physiology ; }, abstract = {Influx of Ca(2+) ions through the α-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptors is toxic to neurons and contributes to motor neuron degeneration observed in amyotrophic lateral sclerosis (ALS). The Ca(2+) permeability of the AMPA receptor depends on its subunit composition. If the GluR2 subunit is present in the receptor complex, the AMPA receptor is impermeable to Ca(2+). In this study, we identified vascular endothelial growth factor-A (VEGF) as a GluR2 inducing molecule. Cultured motor neurons pretreated with VEGF displayed higher GluR2 levels. This resulted in AMPA receptor currents with a low relative Ca(2+) permeability and in motor neurons that were less vulnerable to AMPA receptor-mediated excitotoxicity. This effect of VEGF was mediated through the VEGFR2 present on the motor neurons and was due to stimulation of GluR2 transcription. Intracerebroventricular treatment with VEGF similarly induced GluR2 expression in the ventral spinal cord of rats and this mechanism contributes to the protective effect of VEGF on motor neurons.}, }
@article {pmid19183864, year = {2009}, author = {Kalmar, B and Greensmith, L}, title = {Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects.}, journal = {Cellular &amp; molecular biology letters}, volume = {14}, number = {2}, pages = {319-335}, pmid = {19183864}, issn = {1689-1392}, support = {G0601943/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Apoptosis ; Cells, Cultured ; HSP70 Heat-Shock Proteins/metabolism ; *Heat-Shock Response/drug effects ; Hydroxylamines/pharmacology ; Mice ; Motor Neurons/cytology/*metabolism ; Neuroprotective Agents/pharmacology ; Oxidative Stress ; Pentacyclic Triterpenes ; Rats ; Staurosporine/pharmacology ; Triterpenes/pharmacology ; }, abstract = {Pharmacological up-regulation of heat shock proteins (hsps) rescues motoneurons from cell death in a mouse model of amyotrophic lateral sclerosis. However, the relationship between increased hsp expression and neuronal survival is not straightforward. Here we examined the effects of two pharmacological agents that induce the heat shock response via activation of HSF-1, on stressed primary motoneurons in culture. Although both arimoclomol and celastrol induced the expression of Hsp70, their effects on primary motoneurons in culture were significantly different. Whereas arimoclomol had survival-promoting effects, rescuing motoneurons from staurosporin and H(2)O(2) induced apoptosis, celastrol not only failed to protect stressed motoneurons from apoptosis under same experimental conditions, but was neurotoxic and induced neuronal death. Immunostaining of celastrol-treated cultures for hsp70 and activated caspase-3 revealed that celastrol treatment activates both the heat shock response and the apoptotic cell death cascade. These results indicate that not all agents that activate the heat shock response will necessarily be neuroprotective.}, }
@article {pmid19160266, year = {2009}, author = {Benatar, M and Kurent, J and Moore, DH}, title = {Treatment for familial amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {2009}, number = {1}, pages = {CD006153}, pmid = {19160266}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Celecoxib ; Creatine/therapeutic use ; Fructose/analogs &amp; derivatives/therapeutic use ; Humans ; Motor Neuron Disease/drug therapy ; Neuroprotective Agents/therapeutic use ; Pyrazoles/therapeutic use ; Randomized Controlled Trials as Topic ; Sulfonamides/therapeutic use ; Topiramate ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a rare neurodegenerative disease. Approximately 5% to 7% of ALS/MND patients report a family history of a similarly affected relative. Superoxide dismutase-1 gene mutations are the cause in about 20% of familial cases. In those with non-familial (sporadic) ALS/MND the cause is unknown. Also unknown is whether patients with familial and sporadic ALS/MND respond differently to treatment.<br><br>OBJECTIVES: To systematically review the literature and to answer the specific question: 'Is there a difference in the response to treatment between patients with sporadic and familial forms of ALS?'<br><br>SEARCH STRATEGY: In May 2006 we searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (January 1966 to May 2006) and EMBASE (January 1980 to May 2006) for randomized controlled trials (RCTs). Two review authors read the titles and abstracts of all articles and reviewed the full text of all possibly relevant articles. We scanned references of all included trials to identify additional relevant articles. For all trials eligible for inclusion we contacted the authors to request the necessary raw data.<br><br>SELECTION CRITERIA: Studies had to meet two criteria: (a) randomized controlled study design, and (b) inclusion of patients with both familial and sporadic ALS/MND.<br><br>DATA COLLECTION AND ANALYSIS: We attempted to contact authors of all trials that met inclusion criteria. We obtained data regarding ALS/MND type (sporadic versus familial), treatment assignment (active versus placebo), survival and ALS Functional Rating Scale scores for four large RCTs that included 822 sporadic and 41 familial ALS patients. We could not obtain data from 25 potentially eligible studies (17 trial authors could not be contacted and eight were unwilling to provide data).<br><br>MAIN RESULTS: There was no statistical evidence for a different response to treatment in patients with familial ALS/MND compared to those with sporadic ALS/MND. The pooled estimate of the hazard ratio for the interaction term (treatment x familial ALS) suggested a more beneficial response with respect to survival among patients with familial ALS/MND, but the result was not statistically significant. Estimates of the rate of decline on the ALS Functional Rating Scale also suggested a slightly better response to treatment among those with familial ALS/MND, but the result was not statistically significant.<br><br>AUTHORS' CONCLUSIONS: Future RCTs should document whether patients with familial ALS/MND are included and the presence or absence of a mutation in the superoxide dismutase-1 gene amongst those with familial ALS/MND.}, }
@article {pmid19159793, year = {2009}, author = {Le Dréau, Y and Dupuy, N and Artaud, J and Ollivier, D and Kister, J}, title = {Infrared study of aging of edible oils by oxidative spectroscopic index and MCR-ALS chemometric method.}, journal = {Talanta}, volume = {77}, number = {5}, pages = {1748-1756}, doi = {10.1016/j.talanta.2008.10.012}, pmid = {19159793}, issn = {1873-3573}, mesh = {*Food Analysis ; Food Preservation ; Oxidants ; Oxidation-Reduction ; Plant Oils/*standards ; Spectroscopy, Fourier Transform Infrared/*methods ; }, abstract = {One of the most suitable analytical techniques used for edible oil quality control is Fourier transform mid infrared spectroscopy (FT-MIR). FT-MIR spectroscopy was used to continuously characterize the aging of various edible oils thanks to a specific aging cell. There were differences in the spectra of fresh and aged oils from different vegetable sources, which provide the basis of a method to classify them according to the oxidative spectroscopic index value. The use of chemometric treatment such as multivariate curve resolution-alternative least square (MCR-ALS) made it possible to extract the spectra of main formed and degraded species. The concentration profiles gave interesting information about the ability of the various oils to support the oxidative treatment and showed that all oils present the same aging process. Both methods led to concordant results in terms of induction times determined by the oxidative spectroscopic index and the appearance of oxidation products revealed by MCR-ALS.}, }
@article {pmid19158288, year = {2009}, author = {Jeong, SY and Rathore, KI and Schulz, K and Ponka, P and Arosio, P and David, S}, title = {Dysregulation of iron homeostasis in the CNS contributes to disease progression in a mouse model of amyotrophic lateral sclerosis.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {29}, number = {3}, pages = {610-619}, pmid = {19158288}, issn = {1529-2401}, mesh = {Age Factors ; Aldehydes/therapeutic use ; Amyotrophic Lateral Sclerosis/*complications/drug therapy/genetics/*pathology ; Animals ; Body Weight/drug effects/genetics ; Cation Transport Proteins/genetics/metabolism ; Central Nervous System/*metabolism ; Cyclooxygenase 1/genetics/metabolism ; Disease Models, Animal ; Disease Progression ; Ferrozine ; Gene Expression Regulation/genetics ; Glial Fibrillary Acidic Protein/metabolism ; Homeostasis ; Hydrazones/therapeutic use ; Indoles ; Iron/*metabolism ; Iron Chelating Agents/therapeutic use ; Membrane Proteins/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondria/metabolism ; Mutation ; Phosphopyruvate Hydratase/metabolism ; Receptors, Transferrin/genetics/metabolism ; Sciatic Neuropathy/metabolism ; Superoxide Dismutase/genetics ; Ferroportin ; }, abstract = {Amyotrophic lateral sclerosis (ALS), characterized by degeneration of spinal motor neurons, consists of sporadic and familial forms. One cause of familial ALS is missense mutations in the superoxide dismutase 1 (SOD1) gene. Iron accumulation occurs in the CNS of both forms of ALS; however, its contribution to the pathogenesis of ALS is not known. We examined the role of iron in a transgenic mouse line overexpressing the human SOD1(G37R) mutant. We show that multiple mechanisms may underlie the iron accumulation in neurons and glia in SOD1(G37R) transgenic mice. These include dysregulation of proteins involved in iron influx and sensing of intracellular iron; iron accumulation in ventral motor neurons secondary to blockage of anterograde axonal transport; and increased mitochondrial iron load in neurons and glia. We also show that treatment of SOD1(G37R) mice with an iron chelator extends life span by 5 weeks, accompanied by increased survival of spinal motor neurons and improved locomotor function. These data suggest that iron chelator therapy might be useful for the treatment of ALS.}, }
@article {pmid19152036, year = {2009}, author = {Segal, E and Sandovsky-Losica, H}, title = {Immunization protocols for use in animal models of candidiasis.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {499}, number = {}, pages = {27-34}, doi = {10.1007/978-1-60327-151-6_4}, pmid = {19152036}, issn = {1064-3745}, mesh = {Animals ; Antigens, Fungal/*administration &amp; dosage/immunology ; Candidiasis/*immunology/microbiology ; Disease Models, Animal ; Female ; Fungal Vaccines/*administration &amp; dosage/immunology ; Humans ; Immunization/*methods ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred ICR ; }, abstract = {Immunoprotection during most forms of candidiasis (oropharyngeal, invasive) is lacking since most candidiasis patients are immunosuppressed either as a result of their allogeneic transplant, cancer chemotherapy, or HIV infection. Consequently, immunization might be considered as an unlikely way to protect patients from such infection. Nonetheless, there are a number of investigations that indicate active immunization or the passive treatment with hyperimmune, specific antibodies can result in protection in models of experimental candidiasis. The former subject, active immunization, is the subject of this chapter. We focus on recent efforts with the Als family of cell wall proteins to serve as a model, and also offer immunization methods in candidiasis models that can be adapted to any antigen of the organism.}, }
@article {pmid19150438, year = {2009}, author = {Pankonin, MS and Sohi, J and Kamholz, J and Loeb, JA}, title = {Differential distribution of neuregulin in human brain and spinal fluid.}, journal = {Brain research}, volume = {1258}, number = {}, pages = {1-11}, doi = {10.1016/j.brainres.2008.12.047}, pmid = {19150438}, issn = {1872-6240}, support = {NS 43943/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/cerebrospinal fluid ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid ; Astrocytes/metabolism ; Autopsy ; Blotting, Western ; Brain/*metabolism ; Extracellular Matrix/metabolism ; Heparin/metabolism ; Humans ; Immunohistochemistry ; Multiple Sclerosis/cerebrospinal fluid ; Nerve Fibers, Myelinated/metabolism ; Neuregulin-1/blood/*cerebrospinal fluid/*metabolism ; Neurons/metabolism ; Parkinson Disease/cerebrospinal fluid ; }, abstract = {The neuregulins are a family of polypeptide factors implicated in a wide range of neurological and psychiatric disorders including multiple sclerosis, schizophrenia, and Alzheimer's disease. Many alternatively-spliced forms of the NRG1 gene are released as soluble factors that can diffuse to near and distant sites within the nervous system where they can accumulate through binding to highly specific heparan-sulfate proteoglycans in the extracellular matrix. Here we have determined the sites of synthesis and accumulation of heparin-binding neuregulin forms in human neocortex, white matter, cerebral spinal fluid, and serum by immunostaining and measurement of neuregulin activity. While neuregulin precursors are expressed predominately within cortical neurons, soluble neuregulin accumulates preferentially on the surface of white matter astrocytes. Consistently, neuregulin activity can be released from the extracellular matrix of human brain by protease treatment. Neuregulin activity is also detectable in human cerebral spinal fluid where its expression appears to be altered in neuronal disorders. While cerebral spinal fluid neuregulin levels were unaltered in patients with multiple sclerosis, they were slightly reduced in amyotrophic lateral sclerosis and Parkinson's disease (p<0.15), but significantly increased in Alzheimer's disease (p<0.01). While not detected in human serum, a novel neuregulin antagonist activity was identified in human serum that could have prevented its detection. These results suggest that human neuregulin is selectively targeted from cortical neurons to white matter extracellular matrix where it exists in steady-state equilibrium with cerebral spinal fluid where it has the potential to serve as a biological marker in human neuronal disorders.}, }
@article {pmid19146924, year = {2009}, author = {Milane, A and Vautier, S and Chacun, H and Meininger, V and Bensimon, G and Farinotti, R and Fernandez, C}, title = {Interactions between riluzole and ABCG2/BCRP transporter.}, journal = {Neuroscience letters}, volume = {452}, number = {1}, pages = {12-16}, doi = {10.1016/j.neulet.2008.12.061}, pmid = {19146924}, issn = {0304-3940}, mesh = {ATP Binding Cassette Transporter, Subfamily B/deficiency ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters/genetics/*metabolism ; Animals ; Biological Transport/drug effects/genetics ; Brain/drug effects/metabolism ; Cell Line, Tumor ; Choriocarcinoma ; Female ; Gene Expression/drug effects ; Humans ; Mice ; Mice, Knockout ; Neoplasm Proteins/genetics/*metabolism ; Neuroprotective Agents/*metabolism/pharmacology ; Prazosin/metabolism ; RNA, Messenger/metabolism ; Riluzole/*metabolism/pharmacology ; Transfection/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative fatal disease. Drugs used in this disease need to cross the blood-brain barrier (BBB). Only riluzole is approved for ALS treatment. We have investigated riluzole as a breast cancer resistance protein (BCRP) substrate by studying its brain transport in CF1 mdr1a (-/-) mice and its intracellular uptake on BeWo cells (human placental choriocarcinoma cell line). We have also investigated the effect of riluzole on BCRP expression level and on its activity using the prazocin as a test probe for brain transport and intracellular uptake. Assays on mdr1a (-/-) mice and BeWo cells showed a higher uptake of riluzole when pretreated with a BCRP inhibitor. After repeated doses of riluzole, BCRP activity was increased in CF1 mdr1a (-/-) mice, riluzole uptake was decrease and both BCRP expression and activity were increased in BeWo cells. In conclusion, we report in this study that riluzole is transported by BCRP at the BBB level and can enhance its function. These results taken with our previous studies on riluzole and P-glycoprotein show that drug-drug interactions between riluzole and efflux transporters substrates may occur at the BBB level and should be taken into account in future clinical trial design in ALS.}, }
@article {pmid19144125, year = {2009}, author = {Federici, T and Kutner, R and Zhang, XY and Kuroda, H and Tordo, N and Boulis, NM and Reiser, J}, title = {Comparative analysis of HIV-1-based lentiviral vectors bearing lyssavirus glycoproteins for neuronal gene transfer.}, journal = {Genetic vaccines and therapy}, volume = {7}, number = {}, pages = {1}, pmid = {19144125}, issn = {1479-0556}, support = {R01 NS044832/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: The delivery of therapeutic genes to the central nervous system (CNS) using viral vectors represents an appealing strategy for the treatment of nerve injury and disorders of the CNS. Important factors determining CNS targeting include tropism of the viral vectors and retrograde transport of the vector particles. Retrograde transport of equine anemia virus (EIAV)-based lentiviral vectors pseudotyped with the glycoprotein derived from the Rabies virus RabERA strain from peripheral muscle to spinal motor neurons (MNs) was previously reported. Despite therapeutic effects achieved in mouse models of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), the efficiency of this approach needs to be improved for clinical translation. To date there has not been a quantitative assessment of pseudotyped HIV-1-based lentiviral vectors to transduce MNs. Here, we describe quantitative tests to analyze the retrograde transport capacity of HIV-1 vectors pseudotyped with the G glycoprotein derived from Rabies and Rabies-related viruses (Lyssaviruses).<br><br>METHODS: With a view toward optimizing the retrograde transport properties of HIV-1-based lentiviral vectors, we compared the glycoproteins from different enveloped viruses belonging to the Rhabdoviridae family, genus Lyssavirus, and evaluated their ability to transduce specific cell populations and promote retrograde axonal transport. We first tested the transduction performance of these pseudotypes in vitro in SH-SY5Y neuroblastoma cells, NSC-34 neuroblastoma-spinal cord hybrid cells, and primary mixed spinal cord and pure astrocyte cultures. We then analyzed the uptake and retrograde transport of these pseudotyped vectors in vitro, using Campenot chambers. Finally, intraneural injections were performed to evaluate the in vivo retrograde axonal transport of these pseudotypes.<br><br>RESULTS: Both the in vitro and in vivo studies demonstrated that lentiviral vectors pseudotyped with the glycoprotein derived from the Rabies virus PV strain possessed the best performance and neuronal tropism among the vectors tested.<br><br>CONCLUSION: Our results indicate that HIV-1-based lentiviral vectors pseudotyped with the Rabies PV glycoprotein might provide important vehicles for CNS targeting by peripheral injection in the treatment of motor neuron diseases (MND), pain, and neuropathy.}, }
@article {pmid19143012, year = {2009}, author = {Moges, H and Vasconcelos, OM and Campbell, WW and Borke, RC and McCoy, JA and Kaczmarczyk, L and Feng, J and Anders, JJ}, title = {Light therapy and supplementary Riboflavin in the SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis (FALS).}, journal = {Lasers in surgery and medicine}, volume = {41}, number = {1}, pages = {52-59}, doi = {10.1002/lsm.20732}, pmid = {19143012}, issn = {1096-9101}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology/*radiotherapy ; Animals ; Combined Modality Therapy ; Disease Models, Animal ; Lasers, Semiconductor/*therapeutic use ; *Low-Level Light Therapy ; Mice ; Mice, Transgenic ; Riboflavin/*therapeutic use ; Superoxide Dismutase ; Superoxide Dismutase-1 ; Vitamin B Complex/*therapeutic use ; }, abstract = {BACKGROUND AND OBJECTIVE: Familial amyotrophic lateral sclerosis (FALS) is a neurodegenerative disease characterized by progressive loss of motor neurons and death. Mitochondrial dysfunction and oxidative stress play an important role in motor neuron loss in ALS. Light therapy (LT) has biomodulatory effects on mitochondria. Riboflavin improves energy efficiency in mitochondria and reduces oxidative injury. The purpose of this study was to examine the synergistic effect of LT and riboflavin on the survival of motor neurons in a mouse model of FALS.<br><br>G93A SOD1 transgenic mice were divided into four groups: Control, Riboflavin, Light, and Riboflavin+Light (combination). Mice were treated from 51 days of age until death. A single set of LT parameters was used: 810 nm diode laser, 140-mW output power, 1.4 cm(2) spot area, 120 seconds treatment duration, and 12 J/cm(2) energy density. Behavioral tests and weight monitoring were done weekly. At end stage of the disease, mice were euthanized, survival data was collected and immunohistochemistry and motor neuron counts were performed.<br><br>RESULTS: There was no difference in survival between groups. Motor function was not significantly improved with the exception of the rotarod test which showed significant improvement in the Light group in the early stage of the disease. Immunohistochemical expression of the astrocyte marker, glial fibrilary acidic protein, was significantly reduced in the cervical and lumbar enlargements of the spinal cord as a result of LT. There was no difference in the number of motor neurons in the anterior horn of the lumbar enlargement between groups.<br><br>CONCLUSIONS: The lack of significant improvement in survival and motor performance indicates study interventions were ineffective in altering disease progression in the G93A SOD1 mice. Our findings have potential implications for the conceptual use of light to treat other neurodegenerative diseases that have been linked to mitochondrial dysfunction.}, }
@article {pmid19137121, year = {2008}, author = {Rosen, H}, title = {Dextromethorphan/quinidine sulfate for pseudobulbar affect.}, journal = {Drugs of today (Barcelona, Spain : 1998)}, volume = {44}, number = {9}, pages = {661-668}, pmid = {19137121}, issn = {1699-3993}, support = {P50 AG023501/AG/NIA NIH HHS/United States ; P01 AG019724-080005/AG/NIA NIH HHS/United States ; 1 P50 AG-03-006-01/AG/NIA NIH HHS/United States ; P50 AG023501-066166/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; 2 P01 AG019724-06/AG/NIA NIH HHS/United States ; }, mesh = {Antidepressive Agents, Tricyclic/therapeutic use ; Clinical Trials as Topic ; Dextromethorphan/adverse effects/pharmacology/*therapeutic use ; Drug Combinations ; Humans ; Pseudobulbar Palsy/diagnosis/*drug therapy/physiopathology ; Quinidine/adverse effects/pharmacology/*therapeutic use ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; }, abstract = {A new agent containing a combination of dextromethorphan (DM) and quinidine (Q) is currently under development for the treatment of pseudobulbar affect (PBA). PBA is a disorder of emotional regulation, characterized by uncontrollable outbursts of laughing and/or crying that are disproportionate to the emotions being experienced. The pathophysiology of PBA is currently unknown, although the disorder is thought to occur exclusively in the setting of neurological disease. The most influential theory on PBA posits that emotional outbursts are being generated autonomously in the brain stem due to loss of regulatory control by the frontal lobe. Although rarely life-threatening, PBA can have significant impact on patient quality of life, and thus merits treatment. There are currently no approved treatments for PBA. Several agents have been found to be effective in small placebo-controlled trials and case series, with the most commonly used agents being tricyclic antidepressants and selective serotonin reuptake inhibitors. Both these treatments are inexpensive and relatively low-risk, although the quality and quantity of data available on their efficacy are not optimal. DM has several pharmacological mechanisms of action relevant to the brain. It is an N-methyl-D-aspartate (NMDA) receptor antagonist, which prompted investigators to study its potential for slowing progression in amyotrophic lateral sclerosis (ALS), where glutamate toxicity is thought to be a factor. The combination agent DM/Q was developed to slow the metabolism of DM by P450 2D6 enzymes in the liver. DM/Q was not effective in slowing ALS progression, but patients noted that it helped to control their emotional outbursts, suggesting it might be useful as a treatment for PBA. DM is also a sigma-1 receptor agonist. These receptors are widely distributed in the brain, but probably most heavily in the limbic system, suggesting that DM may exert its emotion-controlling effects via these receptors. The endogenous ligands for sigma-1 receptors are not altogether known, although they appear to include gonadal steroids. DM/Q was recently shown to be effective in reducing the severity of PBA in two large studies of ALS and multiple sclerosis, which are probably the most common neurological settings. These are the largest treatment studies of PBA ever done. The agent was safe and relatively well tolerated. Further studies are being conducted to see if efficacy can be maintained with lower doses of quinidine. If DM/Q is approved by the U.S. Food and Drug Administration for treatment of PBA, it would be the first agent approved for this purpose. Currently, the antidepressants are probably the most attractive pharmacologic options for treatment of PBA. The choice of whether to use DM/Q in this setting will likely depend on individual patient factors as well as cost.}, }
@article {pmid19134494, year = {2009}, author = {Cohen, SM and Elackattu, A and Noordzij, JP and Walsh, MJ and Langmore, SE}, title = {Palliative treatment of dysphonia and dysarthria.}, journal = {Otolaryngologic clinics of North America}, volume = {42}, number = {1}, pages = {107-21, x}, doi = {10.1016/j.otc.2008.09.010}, pmid = {19134494}, issn = {0030-6665}, mesh = {Amyotrophic Lateral Sclerosis/complications ; Communication Devices for People with Disabilities ; Disease Progression ; Dysarthria/etiology/*therapy ; Dysphonia/etiology/*therapy ; Humans ; Laryngectomy ; Multiple Sclerosis/complications ; *Palliative Care ; Parkinson Disease/therapy ; Prognosis ; Quality of Life ; Stroke/complications/therapy ; Vocal Cord Paralysis/therapy ; }, abstract = {The focus of this article is the palliative treatment of a variety of dysphonic conditions. Symptomatic relief of hoarseness can be achieved by voice therapy, augmentative alternative communication modalities, and surgery. The causes of dysphonia addressed herein include amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, stroke, head and neck cancers requiring glossectomy or laryngectomy, unilateral vocal fold paralysis, and presbyphonia. Palliative treatment of dysphonia and voice disorders provides symptomatic relief but not a cure of the underlying disease state. For these patients there are a number of palliative interventions that can greatly improve their quality of life.}, }
@article {pmid19130895, year = {2009}, author = {Liu, R and Ström, AL and Zhai, J and Gal, J and Bao, S and Gong, W and Zhu, H}, title = {Enzymatically inactive adenylate kinase 4 interacts with mitochondrial ADP/ATP translocase.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {41}, number = {6}, pages = {1371-1380}, pmid = {19130895}, issn = {1878-5875}, support = {P20RR020171/RR/NCRR NIH HHS/United States ; P20 RR020171/RR/NCRR NIH HHS/United States ; R01 NS049126/NS/NINDS NIH HHS/United States ; R01 NS049126-03/NS/NINDS NIH HHS/United States ; P42 ES007380/ES/NIEHS NIH HHS/United States ; P42 ES007380-119005/ES/NIEHS NIH HHS/United States ; R01 DA027569/DA/NIDA NIH HHS/United States ; P42 ES007380-109005/ES/NIEHS NIH HHS/United States ; S10 RR023684/RR/NCRR NIH HHS/United States ; R01NS049126/NS/NINDS NIH HHS/United States ; P42ES 07380/ES/NIEHS NIH HHS/United States ; R01 MH098891/MH/NIMH NIH HHS/United States ; S10 RR023684-01/RR/NCRR NIH HHS/United States ; R01 NS049126-04/NS/NINDS NIH HHS/United States ; P20 RR020171-057026/RR/NCRR NIH HHS/United States ; }, mesh = {Adenylate Kinase/chemistry/genetics/*metabolism ; Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/enzymology ; Animals ; Blotting, Western ; Cell Hypoxia/physiology ; Cell Line ; Cytochromes c/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Mice ; Mice, Transgenic ; Mitochondria/*enzymology ; Mitochondrial ADP, ATP Translocases/chemistry/*metabolism ; Molecular Sequence Data ; Oxidative Stress ; RNA, Small Interfering/*chemistry ; }, abstract = {Adenylate kinase 4 (AK4) is a unique member with no enzymatic activity in vitro in the adenylate kinase (AK) family although it shares high sequence homology with other AKs. It remains unclear what physiological function AK4 might play or why it is enzymatically inactive. In this study, we showed increased AK4 protein levels in cultured cells exposed to hypoxia and in an animal model of the neurodegenerative disease amyotrophic lateral sclerosis. We also showed that short hairpin RNA (shRNA)-mediated knockdown of AK4 in HEK293 cells with high levels of endogenous AK4 resulted in reduced cell proliferation and increased cell death. Furthermore, we found that AK4 over-expression in the neuronal cell line SH-SY5Y with low endogenous levels of AK4 protected cells from H(2)O(2) induced cell death. Proteomic studies revealed that the mitochondrial ADP/ATP translocases (ANTs) interacted with AK4 and higher amount of ANT was co-precipitated with AK4 when cells were exposed to H(2)O(2) treatment. In addition, structural analysis revealed that, while AK4 retains the capability of binding nucleotides, AK4 has a glutamine residue instead of a key arginine residue in the active site well conserved in other AKs. Mutation of the glutamine residue to arginine (Q159R) restored the adenylate kinase activity with GTP as substrate. Collectively, these results indicate that the enzymatically inactive AK4 is a stress responsive protein critical to cell survival and proliferation. It is likely that the interaction with the mitochondrial inner membrane protein ANT is important for AK4 to exert the protective benefits to cells under stress.}, }
@article {pmid19128208, year = {2008}, author = {Chen, LW and Yung, KK and Chan, YS and Shum, DK and Bolam, JP}, title = {The proNGF-p75NTR-sortilin signalling complex as new target for the therapeutic treatment of Parkinson's disease.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {7}, number = {6}, pages = {512-523}, doi = {10.2174/187152708787122923}, pmid = {19128208}, issn = {1996-3181}, mesh = {Adaptor Proteins, Vesicular Transport/*metabolism/physiology ; Animals ; Antiparkinson Agents/metabolism/pharmacology/*therapeutic use ; Drug Delivery Systems/*methods/trends ; Humans ; Nerve Growth Factor/*metabolism ; Parkinson Disease/drug therapy/*metabolism ; Protein Precursors/*metabolism ; Receptor, Nerve Growth Factor/*metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {Growing evidence has shown that the p75 neurotrophin receptor (p75NTR) may play important roles in controlling neuronal survival or cell apoptosis within the central nervous system in development, and in pathological or neural injury. Recent studies have further revealed that p75NTR acts as a "molecular signal switch" that determines cell death or survival by three processes. First, pro-nerve growth factor (proNGF) triggers cell apoptosis by its high affinity binding to p75NTR, while NGF induces neuronal survival with low-affinity binding. Second, p75NTR mediates cell death by combining with co-receptor sortilin, whereas it promotes neuronal survival through combination with proNGF. Third, release of the intracellular domain chopper or cleavaged "short p75NTR" can independently initiate neuronal apoptosis. We have identified the cell self-destructive proNGF-p75NTR-sortilin signalling apparatus assembled in ventral tier dopamine neurons of the substantia nigra pars compacta, suggesting that p75NTR signalling might be involved in selective cell death mechanisms of substantia nigra neurons or disease progression of Parkinson's disease (PD). In addition, experimental manipulation of p75NTR benefited cell survival of cholinergic or motor neurons and improved disease progression of the neurodegenerative diseases Alzheimer's disease and Amyotrophic lateral sclerosis. The proNGF-p75NTR-sortilin signalling complex may thus provide new target for neuroprotection of substantia nigra neurons and the therapeutic treatment of PD.}, }
@article {pmid19125952, year = {2008}, author = {Inoue, K and Kourin, A and Watanabe, T and Yamada, M and Yasuda, H and Yoshiba, M}, title = {Plasma exchange in combination with online-hemodiafiltration as a promising method for purifying the blood of fulminant hepatitis patients.}, journal = {Hepatology research : the official journal of the Japan Society of Hepatology}, volume = {38 Suppl 1}, number = {}, pages = {S46-51}, doi = {10.1111/j.1872-034X.2008.00426.x}, pmid = {19125952}, issn = {1386-6346}, abstract = {BACKGROUND: Fulminant hepatitis is an intractable disease caused by various etiological agents. Artificial liver support (ALS) is a symptomatic treatment used to control serious symptoms, such as bleeding tendency, hepatic coma, and brain edema.<br><br>METHODS: The present study involved four patients with fulminant hepatitis who were admitted to Showa University Fujigaoka Hospital between January 2007 and June 2007. All four patients were subacute type disease of indeterminate etiology. The four patients were placed on an ALS system that comprised plasma exchange and online hemodiafiltration. The effect of the ALS on various symptoms of fulminant hepatitis was evaluated, and the levels of glutamine in the patients' plasma samples and the discarded buffer were assayed using automatic analyser.<br><br>RESULTS: Three of the four patients regained full consciousness and survived. The remaining patient died despite recovering from hepatic coma with ALS. The plasma glutamine levels were significantly reduced by artificial liver support. The estimated distribution volume of removed Gln ranged from 30 L to 60 L.<br><br>CONCLUSIONS: Plasma exchange in combination with online hemodiafiltration is a promising and effective method for purifying the blood of patients with fulminant hepatitis.}, }
@article {pmid19117803, year = {2009}, author = {Yokoi, T and Oda, S and Shiga, H and Matsuda, K and Sadahiro, T and Nakamura, M and Hirasawa, H}, title = {Efficacy of high-flow dialysate continuous hemodiafiltration in the treatment of fulminant hepatic failure.}, journal = {Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis}, volume = {40}, number = {1}, pages = {61-70}, doi = {10.1016/j.transci.2008.11.006}, pmid = {19117803}, issn = {1473-0502}, mesh = {Adult ; Coma/mortality/therapy ; Disease-Free Survival ; Female ; Hemodiafiltration/*methods ; Humans ; Liver Failure, Acute/mortality/*therapy ; Male ; Middle Aged ; Retrospective Studies ; Survival Rate ; }, abstract = {We compared the clinical efficacy of high-flow dialysate continuous hemodiafiltration (HFCHDF) performed as artificial liver support (ALS) in fulminant hepatic failure (FHF) with those of conventional ALS techniques. Ninety patients were divided into non-HFCHDF and HFCHDF groups. Rate of recovery from coma was significantly higher in the HFCHDF group (70.2%) than in the non-HFCHDF group (44.2%) (p<0.01). The excellent recovery rate from coma achieved in patients with FHF by HFCHDF may be due to its enhanced capacity for liver support enabling efficient removal of substances causing hepatic coma from blood. HFCHDF should thus be useful for ALS.}, }
@article {pmid20222611, year = {2009}, author = {Marechal, PY and Henriet, F and Bodson, B}, title = {Treatment influence on herbicide resistance level of Belgian Alopecurus myosuroides populations (black-grass).}, journal = {Communications in agricultural and applied biological sciences}, volume = {74}, number = {2}, pages = {505-514}, pmid = {20222611}, issn = {1379-1176}, mesh = {Belgium ; Brassica rapa/*drug effects/growth &amp; development ; Herbicide Resistance ; Herbicides/*toxicity ; Oxazoles/toxicity ; Poaceae/*drug effects/*growth &amp; development ; Propionates/toxicity ; Quinolines ; Sulfonamides/toxicity ; Sulfonylurea Compounds/toxicity ; }, abstract = {Black-grass is a common grass weed, widely spread in Northern Europe and also in Belgium. For ages, it has been an increasing problem in industrial crops, especially winter cereals. Therefore, farmers started to spray herbicide intensively and soon cases of failure occurred for different molecules and different modes of action. Black-grass populations have been tested in greenhouses to assess the influence of an herbicide treatment as to the resistance level regarding three different herbicides: chlortoluron, fenoxaprop-P and mesosulfuron+iodosulfuron. Black-grass seeds were collected in field trials in six locations in Belgium, on individuals which have survived the herbicide treatment. Each population comes from trial plots, measuring 2 meters wide by 5 meters long and characterized by a single or a combination of products. Herbicides sprayed were isoproturon, flufenacet+diflufenican, ACCase inhibitors and ALS inhibitors. Seeds were also collected in the untreated plots. The population present in these last ones corresponds to the former population, before the herbicide selection pressure was applied. In the glasshouse assay, this population was used as the standard population to compare with other populations issued from the same field. The 'R' rating system was set up with this population to assess the evolution of resistance level, year in, year out. Rothamsted and Peldon populations were also included as cross-reference. Each field population presented different behaviours towards herbicide applied in greenhouses and some cases of resistance can be highlighted. Generally, a reduction of treatment efficiency between field and greenhouse results was clearly visible for the whole of studied active ingredients. Indeed, a distribution shift of the populations towards higher resistance classes could be observed. This is particularly remarkable for active ingredients sharing the same mode of action. For example, it has been found that populations already sprayed with fenoxaprop-P on the field showed a higher resistance level to fenoxaprop-P than to mesosulfuron in the greenhouse test.}, }
@article {pmid20222608, year = {2009}, author = {Moss, SR and Hull, R and Marshall, R}, title = {Control of Alopecurus myosuroides (black-grass) resistant to mesosulfuron+iodosulfuron.}, journal = {Communications in agricultural and applied biological sciences}, volume = {74}, number = {2}, pages = {479-488}, pmid = {20222608}, issn = {1379-1176}, support = {//Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Drug Combinations ; Herbicide Resistance ; Phenylurea Compounds/toxicity ; Poaceae/*drug effects/genetics/*growth &amp; development ; Seeds/drug effects/genetics/physiology ; Sulfonamides/*toxicity ; Sulfonylurea Compounds/*toxicity ; Triticum/drug effects/growth &amp; development ; }, abstract = {Resistance to the ALS inhibitor mesosulfuron+iodosulfuron ('Atlantis') had been identified in 293 populations of A. myosuroides in the UK by 2008. Two field trials were conducted in winter wheat crops where ALS target site resistance (Pro197Thr) occurred. Mesosulfuron+iodosulfuron (12+2.4 g a.i. ha(-1)) gave 73% - 79% reductions in head numbers in Town Mead field, but only -7% - 5% reductions in Long Covert. Mixtures and sequences improved overall control. Pre-emergence flufenacet+pendimethalin (240+1200 g a.i. ha(-1)) followed by mesosulfuron+ iodosulfuron plus pendimethalin (1320 g a.i. ha(-1)) or clodinafop+trifluralin (30+960 g a.i. ha(-1)) gave 93 - 98% reductions in Town Mead but only 60 - 73% reductions in Long Covert. A non-ALS treatment of pre-emergence flufenacet+pendimethalin followed by isoproturon+pendimethalin (1500+1320 g a.i. ha(-1)) in late October and clodinafop+trifluralin in November or February achieved 97% and 93% reductions in the two trials. Seed samples collected from surviving plants were evaluated in glasshouse assays to quantify any changes in the incidence of resistance. There was an increase in the proportion of plants resistant to mesosulfuron+iodosulfuron regardless of whether it was used alone, in mixture or sequence. No such changes occured with non-ALS treatments. The trials highlight the difficulty of achieving adequate control with alternative herbicides, especially as isoproturon and trifluralin will not be available for use in the UK after 2009.}, }
@article {pmid20124773, year = {2009}, author = {Engert, RB and Weiner, R and Weiner, S and Matkowitz, R and Göttig, S and Daskalakis, M and Merkle, R}, title = {[The gastric balloon--a retrospective cohort analysis of 634 patients].}, journal = {Obesity facts}, volume = {2 Suppl 1}, number = {Suppl 1}, pages = {24-26}, pmid = {20124773}, issn = {1662-4025}, mesh = {Adult ; Body Mass Index ; Catheterization/adverse effects/*instrumentation ; Cohort Studies ; Female ; *Gastric Balloon ; Humans ; Male ; Obesity/*therapy ; Retrospective Studies ; Risk Assessment ; Severity of Illness Index ; Time Factors ; Treatment Outcome ; Weight Loss ; }, abstract = {HINTERGRUND: Der temporÄre Einsatz eines Magenballons zur Behandlung der Adipositas Grad1 und 2 nimmt weltweit zu; bei der Adipositas Grad 3 wird der Magenballon als adjuvantes Hilfsmittel zur prÄoperativen Gewichtsreduktion implantiert. Ziel dieser retrospektiven Kohorten analyse ist, die Wirksamkeit des Magenballons auf Gewichtsreduzierung und das Risikoprofil der Methode zu evaluieren.<br><br>METHODEN: Retrospektive Kohortenanalysen aus 4 Adipositas-Zentren, in denen der Magenballon seit 2001 regelm&#xc4;&#xdf;ig implantiert wurde.<br><br>ERGEBNISSE: Von Februar2001 bis April 2008 wurde bei 634 Patienten ein Magenballon implantiert (BIBTM Intragastric Balloon System; Allergan Medical, Irvine, CA, USA). Die Geschlechterverteilung war 31,5% M&#xc4;nnerzu 68,5% Frauen; das Durchschnittsalter betrug 41,5 Jahre. Das durchschnittliche Ausgangsgewicht lag bei 126 kg. Der initiale BMI bei Implantation des Magenballons war 42,5 kg/m[2]. Die Implantation der Prothese war in allen F&#xc4;llen unkompliziert. Der durchschnittliche Gewichtsverlust lag bei 20,75 kg bzw. 7,05 BMI-Punkten.<br><br>SUMMARY: The Gastric Balloon &#x2014; a Retrospective Cohort Analysis with 634 Patients<br><br>BACKGROUND: The temporary use of a gastric balloon for the treatment of obesity grade 1 and 2 is increasing worldwide, whereas in grade 3 obesity, it is implanted as a tool for preoperative adjuvant weight loss. The aim of this retrospective cohort analysis is to evaluate the effectiveness of weight reduction and to describe the risk profile of the method.<br><br>METHODS: Retrospective cohort analysis of 4 obesity centers where gastric balloons had been regularly implanted since 2001.<br><br>RESULTS: Between February 2001 and April 2008, the gastric balloon (BIBTM Intragastric Balloon System; Allergan Medical, Irvine, CA, USA) was implanted in 634 patients. The gender ratio was 31.5% males to 68.5% females; the average age was 41.5 years. The average initial weight was 126 kg. The initial BMI at implantation of the gastric balloon was 42.5 kg/m2. The implantation of the prosthesis was uncomplicated in all cases. Average weight loss was 20.75 kg or 7.05 BMI points, respectively.}, }
@article {pmid19112545, year = {2008}, author = {Esparza, J and Hinojosa, J and García-Recuero, I and Romance, A and Pascual, B and Martínez de Aragón, A}, title = {Surgical treatment of isolated and syndromic craniosynostosis. Results and complications in 283 consecutive cases.}, journal = {Neurocirugia (Asturias, Spain)}, volume = {19}, number = {6}, pages = {509-529}, doi = {10.1016/s1130-1473(08)70201-x}, pmid = {19112545}, issn = {1130-1473}, mesh = {Child ; Child, Preschool ; Craniosynostoses/*surgery ; Humans ; Infant ; Male ; Neurosurgical Procedures/adverse effects/*methods ; Plastic Surgery Procedures/adverse effects/*methods ; Syndrome ; }, abstract = {OBJECTIVE: To review the results and complications of the surgical treatment of craniosynostosis in 283 consecutive patients treated between 1999 and 2007.<br><br>PATIENTS AND METHODS: Our series consisted of 330 procedures performed in 283 patients diagnosed with scaphocephaly (n=155), trigonocephaly (n=50), anterior plagiocephaly (n=28), occipital plagiocephaly (n=1), non-syndromic multi-suture synostosis (n=20), and with diverse craniofacial syndromes (n=32; 11 Crouzon, 11 Apert, 7 Pfeiffer, 2 Saethre-Chotzen, and 2 clover-leaf skull). We used the classification of Whitaker et al. to evaluate the surgical results. Complications of each technique and time of patients' hospitalization were also recorded. The surgeries were classified in 12 different types according to the techniques used. Type I comprised endoscopic assisted osteotomies for sagittal synostosis (42 cases). Type II included sagittal suturectomy and expanding osteotomies (46 cases). Type III encompassed procedures similar to type II but that included frontal dismantling or frontal osteotomies in scaphocephaly (59 cases). Type IV referred to complete cranial vault remodelling (holocranial dismantling) in scaphocephaly (13 cases). Type V belonged to fronto-orbital remodelling without fronto-orbital bandeau in trigonocephaly (50 cases). Type VI included fronto-orbital remodelling without fronto-orbital bandeau in plagiocephaly (14 cases). In Type VII cases of plagiocephaly with frontoorbital remodelling and fronto-orbital bandeau were comprised (14 cases). Type VIII consisted of occipital advancement in posterior plagiocephaly (1 case). Type IX included standard bilateral fronto-orbital advancement with expanding osteotomies (30 cases). Type X was used in multi-suture craniosynostosis (15 cases) and consisted of holocranial dismantling (complete cranial vault remodelling). Type XI included occipital and suboccipital craniectomies in multiple suture craniosynostosis (10 cases) and Type XII instances of fronto-orbital distraction (26 cases).<br><br>RESULTS: The mortality rate of the series was 2 out of 283 cases (0.7%). These 2 patients died one year after surgery. All complications were resolved without permanent deficit. Mean age at surgery was 6.75 months. According to Whitaker et al's classification, 191 patients were classified into Category I (67.49%), 51 into Category II (18.02%), 30 into Category III (10.6%) and 14 into Category IV (4.90%). Regarding to craniofacial conformation, 85.5 % of patients were considered as a good result and 15.5% of patients as a poor result. Of the patients with poor results, 6.36% were craniofacial syndromes, 2.12% had anterior plagiocephaly and 1.76% belonged to non-syndromic craniosynostosis. The most frequent complication was postoperative hyperthermia of undetermined origin (13.43% of the cases), followed by infection (7.5%), subcutaneous haematoma (5.3%), dural tears (5%), and CSF leakage (2.5%). The number of complications was higher in the group of re-operated patients (12.8% of all). In this subset of reoperations, infection accounted for 62.5%, dural tears for 93% and CSF leaks for 75% of the total. In regard to the surgical procedures, endoscopic assisted osteotomies presented the lowest rate of complications, followed by standard fronto-orbital advancement in multiple synostosis, trigonocephaly and plagiocephaly. The highest number of complications occurred in complete cranial vault remodelling (holocranial dismantling) in scaphocephaly and multiple synostoses and after the use of internal osteogenic distractors. Of note, are two cases of iatrogenic basal encephalocele that occurred after combined fronto-facial distraction.<br><br>CONCLUSIONS: The best results were obtained in patients with isolated craniosynostosis and the worst in cases with syndromic and multi-suture craniosynostosis. The rate and severity of complications were related to the type of surgical procedure and was higher among patients undergoing re-operations. The mean time of hospitalization was also modified by these factors. Finally, we report our considerations for the management of craniosynostosis taking into account each specific technique and the age at surgery, complication rates and the results of the whole series.}, }
@article {pmid19112544, year = {2008}, author = {Martínez-Lage, JF}, title = {Comments to Esparza et al's article "Surgical treatment of isolated and syndromic craniosynostosis. Results and complications in 283 consecutive cases".}, journal = {Neurocirugia (Asturias, Spain)}, volume = {19}, number = {6}, pages = {507-508}, doi = {10.1016/s1130-1473(08)70200-8}, pmid = {19112544}, issn = {1130-1473}, mesh = {Craniosynostoses/pathology/*surgery ; Humans ; Infant ; Neurosurgical Procedures/adverse effects/*methods ; Plastic Surgery Procedures/adverse effects/*methods ; Syndrome ; }, }
@article {pmid19110600, year = {2008}, author = {Zavalishin, IA and Bochkov, NP and Suslina, ZA and Zakharova, MN and Tarantul, VZ and Naroditskiy, BS and Suponeva, NA and Illarioshkin, SN and Shmarov, MM and Logunov, DY and Tutyhina, IL and Verkhovskaya, LV and Sedova, ES and Vasiliev, AV and Brylev, LV and Ginzburg, AL}, title = {Gene therapy of amyotrophic lateral sclerosis.}, journal = {Bulletin of experimental biology and medicine}, volume = {145}, number = {4}, pages = {483-486}, doi = {10.1007/s10517-008-0124-4}, pmid = {19110600}, issn = {0007-4888}, mesh = {Adenoviridae/genetics ; Adult ; Amyotrophic Lateral Sclerosis/genetics/mortality/*therapy ; Angiotensinogen/*administration &amp; dosage/adverse effects/genetics ; Cells, Cultured ; Female ; Genetic Therapy/adverse effects/*methods ; Genetic Vectors/administration &amp; dosage/adverse effects ; Humans ; Injections, Intramuscular ; Male ; Middle Aged ; Placebos ; Transgenes/genetics ; Treatment Outcome ; Vascular Endothelial Growth Factor A/*administration &amp; dosage/adverse effects/genetics ; }, abstract = {Two-year experiments were performed to evaluate the neurotrophic effect of hypoxia-inducible factors (vascular endothelial growth factor and angiogenin) expressed in recombinant human adenoviruses in amyotrophic lateral sclerosis. Randomized placebo-controlled trial demonstrated safety and good tolerability of the recombinant antiviral drugs. The life span of patients under conditions of hypoxia increased after treatment with the test drug, which was probably related to improved resistance of motoneurons. The presence of virus-neutralizing antibodies decreases the effectiveness of adenoviral vectors, which necessitates differential approach to the selection of patients and continuous monitoring of gene therapy.}, }
@article {pmid19096133, year = {2008}, author = {Ciriza, J and Moreno-Igoa, M and Calvo, AC and Yague, G and Palacio, J and Miana-Mena, FJ and Muñoz, MJ and Zaragoza, P and Brûlet, P and Osta, R}, title = {A genetic fusion GDNF-C fragment of tetanus toxin prolongs survival in a symptomatic mouse ALS model.}, journal = {Restorative neurology and neuroscience}, volume = {26}, number = {6}, pages = {459-465}, pmid = {19096133}, issn = {0922-6028}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*microbiology ; Analysis of Variance ; Animals ; Apoptosis/drug effects ; Caspase 3/metabolism ; Cells, Cultured ; Cerebral Cortex/cytology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Gene Transfer Techniques ; Glial Cell Line-Derived Neurotrophic Factor/*therapeutic use ; Humans ; Mice ; Mice, Transgenic ; Neuroblastoma ; Neurons/drug effects/metabolism ; Oncogene Protein v-akt/metabolism ; Peptide Fragments/*therapeutic use ; Recombinant Fusion Proteins/*therapeutic use ; Superoxide Dismutase/genetics ; Survival Analysis ; Tetanus Toxin/*therapeutic use ; Transfection ; }, abstract = {PURPOSE: Amyotrophic Lateral Sclerosis (ALS) is a paralyzing disorder that kills individuals within three to five years of onset without any possibility for effective treatment. One proposed therapy has been the use of neurotrophic factors to inhibit the apoptosis of motorneurones. At the present, one way to deliver neurotrophic factors after intramuscular injection to the motor neurones is through the use of adenoviral vectors. An alternative strategy is the use of the atoxic C fragment of tetanus toxin (TTC) as a neurotrophic factor carrier for motorneurones.<br><br>METHODS: We have produced the recombinant protein fusion Glial Derived Neurotrophic Factor and C fragment of tetanus toxin (GDNF-TTC) and we have tested its antiapoptotic activity in degeneration culture cells and in the symptomatic SOD;{G93A} transgenic animal model for ALS.<br><br>RESULTS: We demonstrated that GDNF-TTC induces the neuronal survival Akt kinase pathway in mouse cortical culture neurons and~maintains its antiapoptotic neuronal activity in Neuro2A cells. Moreover, we have found that genetic fusion is able to increase survival by 9 days and improves life quality in symptomatic ALS animal models.<br><br>CONCLUSION: These results suggest that recombinant GDNF-TTC fusion protein intramuscular injections provide a potential therapy for ALS treatment.}, }
@article {pmid19089442, year = {2009}, author = {Ricci, F and Missiroli, F and Regine, F and Grossi, M and Dorin, G}, title = {Indocyanine green enhanced subthreshold diode-laser micropulse photocoagulation treatment of chronic central serous chorioretinopathy.}, journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie}, volume = {247}, number = {5}, pages = {597-607}, pmid = {19089442}, issn = {1435-702X}, mesh = {Adult ; Chronic Disease ; *Coloring Agents ; Fluorescein Angiography ; Follow-Up Studies ; Humans ; *Indocyanine Green ; *Laser Coagulation ; Lasers, Semiconductor/*therapeutic use ; Male ; Middle Aged ; Prospective Studies ; Retinal Detachment/etiology/physiopathology/surgery ; Retinal Diseases/etiology/physiopathology/*surgery ; Retinal Pigment Epithelium/pathology ; Serum ; Tomography, Optical Coherence ; Treatment Outcome ; Visual Acuity/physiology ; }, abstract = {PURPOSE: To assess the efficacy and safety of indocyanine green (ICG) dye-enhanced subthreshold diode-laser micropulse (SDM) photocoagulation in patients with chronic central serous chorioretinopathy (CCSC) with no spontaneous resolution 6 months after the onset of the disease.<br><br>STUDY DESIGN: Interventional prospective non-comparative case series of seven patients presenting with CCSC with well-defined active leaking sites (ALS) suitable for laser treatment and with serous neuroepithelial detachment persisting for 6 or more months.<br><br>METHODS: SDM treatment was performed 15 minutes after the injection of 25 mg of ICG in 2 cc of 5% glucose solution. ALS were treated with a series of 50 500-ms exposures separated by 500-ms pauses. Each 500-ms exposure delivered a train of 250 micropulses at 10% duty cycle and 500 mW power. ICG angiographic images were taken after the treatment without new ICG injection, to check for the presence of laser-induced spots of background hypofluorescence at the treated leakage sites.<br><br>RESULTS: Within 7-14 days after treatment, all the patients showed improved visual acuity and reduction of serous neuroepithelial detachment on OCT. No signs of laser lesions were visible at fundus examination and on fluorescein angiography. In a period ranging from 4 to 8 weeks, the neuroepithelial detachment was completely resolved in five patients and reduced in two patients. At the 12-month follow-up visits, no recurrence had occurred in the patients, with resolution of the serous neuro-epithelial detachment, and no worsening of the serous detachment or of VA was noted in the patients with incomplete recovery.<br><br>CONCLUSIONS: These preliminary results suggest that ICG dye-enhanced SMD photocoagulation appears to be an effective treatment, and can represent a viable approach for the management of CSCC with persistent serous neuroepithelial detachment. Post-treatment ICG angiography, without new ICG dye injection, can be used to verify the placement of the SDM laser applications.}, }
@article {pmid19084147, year = {2008}, author = {Johannes, RS}, title = {Epidemiology of early-onset bloodstream infection and implications for treatment.}, journal = {American journal of infection control}, volume = {36}, number = {10}, pages = {S171.e13-7}, doi = {10.1016/j.ajic.2008.10.003}, pmid = {19084147}, issn = {1527-3296}, mesh = {Age Factors ; Anti-Bacterial Agents/therapeutic use ; Bacteremia/classification/*epidemiology/microbiology/therapy ; Community-Acquired Infections/classification/*epidemiology/microbiology/therapy ; Cross Infection/*epidemiology/microbiology/therapy ; Fungemia/classification/epidemiology/microbiology/therapy ; Hospital Mortality ; Humans ; Infectious Disease Transmission, Professional-to-Patient/*statistics &amp; numerical data ; Intensive Care Units ; Length of Stay ; Logistic Models ; Methicillin-Resistant Staphylococcus aureus/isolation &amp; purification ; Multivariate Analysis ; Odds Ratio ; Risk Factors ; Staphylococcal Infections/etiology/mortality ; Time Factors ; }, abstract = {UNLABELLED: HEALTH CARE-ASSOCIATED INFECTIONS: For over 35 years, infections have been divided into hospital acquired or community acquired. In 2002, in a study of bloodstream infections (BSIs), Friedman et al first suggested creating a new classification: health care-associated BSIs. Kollef et al furthered the concept of health care-associated infection in a 2005 population-based study of culture-positive pneumonia cases. Although the site of infection differed, Kollef et al's results supported Friedman et al's original concept. Then in 2006, Kollef et al reported a population-based study focused specifically on BSIs. Of 6697 reported cases, 468 (7%) had hospital-acquired BSIs; 3705 (55.3%) health care-associated BSIs; and 2524 (37.7%) community-acquired BSIs. The clinical features of those with health care-associated BSIs differed from those with community-acquired BSIs. For several organisms, including Staphylococcus aureus, Streptococcus pneumoniae, and gram-negative organisms, the frequencies for health care-associated and hospital-acquired BSIs were similar to each other but significantly different from community-acquired BSIs. After controlling for several clinical features, methicillin-resistant Staphylococcus aureus had the largest odds ratio for predicting in-hospital mortality. Both hospital-acquired and health care-acquired cases were independent risk factors for in-hospital mortality.<br><br>IMPLICATIONS FOR TREATMENT: Is more aggressive, empiric, gram-positive therapy warranted for this potentially sicker patient group? Wunderink pointed out the potential unintended consequences of such an approach and the paucity of good tools for early recognition of sickest patients. A study by Shorr et al of systemic inflammatory response syndrome, organ dysfunction, and mortality suggested that there may be approaches that could be used to stratify cases into high-risk groups who may benefit from more aggressive therapy. Most recently, Micek et al found that in health care-associated pneumonia cases, inappropriate initial empiric antibiotic treatment is an independent predictor of mortality. Treatment recommendations are evolving.<br><br>SUMMARY: For pneumonia and BSIs, health care-associated infections appear to be distinct entities. However, operational definitions still vary. Compared with hospital-acquired cases, health care-associated cases have different clinical characteristics. The outcomes of health care-associated infections tend to be intermediate of the community-acquired and hospital-acquired groups. Further research is urgently needed on the implications of health care-associated infection for early therapy.}, }
@article {pmid19081372, year = {2008}, author = {Mattson, MP and Gleichmann, M and Cheng, A}, title = {Mitochondria in neuroplasticity and neurological disorders.}, journal = {Neuron}, volume = {60}, number = {5}, pages = {748-766}, pmid = {19081372}, issn = {1097-4199}, support = {Z01 AG000317-07/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Electron Transport Complex I/metabolism ; Humans ; Mitochondria/*physiology ; Mitochondrial Proteins/metabolism ; Models, Biological ; Nervous System Diseases/*pathology/*physiopathology ; Neuronal Plasticity/*physiology ; }, abstract = {Mitochondrial electron transport generates the ATP that is essential for the excitability and survival of neurons, and the protein phosphorylation reactions that mediate synaptic signaling and related long-term changes in neuronal structure and function. Mitochondria are highly dynamic organelles that divide, fuse, and move purposefully within axons and dendrites. Major functions of mitochondria in neurons include the regulation of Ca(2+) and redox signaling, developmental and synaptic plasticity, and the arbitration of cell survival and death. The importance of mitochondria in neurons is evident in the neurological phenotypes in rare diseases caused by mutations in mitochondrial genes. Mitochondria-mediated oxidative stress, perturbed Ca(2+) homeostasis, and apoptosis may also contribute to the pathogenesis of prominent neurological diseases including Alzheimer's, Parkinson's, and Huntington's diseases; stroke; amyotrophic lateral sclerosis; and psychiatric disorders. Advances in understanding the molecular and cell biology of mitochondria are leading to novel approaches for the prevention and treatment of neurological disorders.}, }
@article {pmid19075629, year = {2008}, author = {Lundberg, C and Björklund, T and Carlsson, T and Jakobsson, J and Hantraye, P and Déglon, N and Kirik, D}, title = {Applications of lentiviral vectors for biology and gene therapy of neurological disorders.}, journal = {Current gene therapy}, volume = {8}, number = {6}, pages = {461-473}, doi = {10.2174/156652308786847996}, pmid = {19075629}, issn = {1566-5232}, mesh = {Animals ; Ciliary Neurotrophic Factor/metabolism ; Clinical Trials as Topic ; Gene Expression Regulation ; Genetic Engineering/methods ; Genetic Therapy/*methods ; Genetic Vectors ; Glial Cell Line-Derived Neurotrophic Factor/metabolism ; Humans ; Huntington Disease/genetics/therapy ; Lentivirus/*genetics ; Nerve Growth Factors/metabolism ; Nervous System Diseases/*genetics/*therapy ; Parkinson Disease/genetics/therapy ; RNA Interference ; }, abstract = {Recombinant lentiviral vectors (rLV) are powerful tools for gene transfer to the central nervous system (CNS) and hold great potential as a therapeutic gene therapy strategy for neurological disorders. Recent data indicate that rLVs are suitable for functional studies in the CNS by over expression or knock down of specific proteins. Based on a variety of lentiviruses species, different vector systems have been developed. However, the most commonly used rLV vector is based on the human immunodeficiency virus 1 (HIV-1). Here we describe the use of such vectors to achieve cell-specific transgene expression in the brain. In this setting, rLVs are versatile tools both due to their relatively large cloning capacity and their ability to transduce non-dividing cells. Furthermore, we discuss the preclinical development of gene therapy based on enzyme replacement and/or delivery of neurotrophic factors for neurodegenerative diseases and CNS manifestations of lysosomal storage diseases. Neuroprotective strategies that aim to deliver glial cell line-derived neurotrophic factor and ciliary neurotrophic factor for Parkinson's and Huntington's diseases in particular have been documented with success in appropriate animal models. More recently, rLVs were shown to be suitable to express small interfering RNA for treatment in models of Alzheimer's disease and amyotrophic lateral sclerosis. Finally, we present a review of the use of rLVs to model neurodegenerative diseases. rLVs have proven to be a very versatile tool to create genetic models of both Parkinson's and Huntington's diseases and thus provide possibilities to study complex genetic interactions in otherwise wild-type animals evading the necessity to create transgenic mice. Moreover, the potential of these vectors in the development of gene therapy to treat neurological disorders is considerable, which is supported by the fact that clinical trials using rLVs are underway.}, }
@article {pmid19050293, year = {2008}, author = {Woodruff, TM and Costantini, KJ and Crane, JW and Atkin, JD and Monk, PN and Taylor, SM and Noakes, PG}, title = {The complement factor C5a contributes to pathology in a rat model of amyotrophic lateral sclerosis.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {181}, number = {12}, pages = {8727-8734}, doi = {10.4049/jimmunol.181.12.8727}, pmid = {19050293}, issn = {1550-6606}, support = {072231//Wellcome Trust/United Kingdom ; }, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/drug therapy/*immunology/*pathology ; Animals ; Complement C3/antagonists &amp; inhibitors/biosynthesis ; Complement C3b/biosynthesis ; Complement C5a/*physiology ; Disease Models, Animal ; Female ; Humans ; Male ; Molecular Sequence Data ; Peptides, Cyclic/therapeutic use ; Rats ; Rats, Transgenic ; Receptor, Anaphylatoxin C5a/antagonists &amp; inhibitors/biosynthesis ; Spinal Cord/immunology/metabolism/pathology ; Superoxide Dismutase/genetics ; Up-Regulation/genetics/immunology ; }, abstract = {Complement activation products are elevated in the cerebrospinal fluid and spinal cord of patients with amyotrophic lateral sclerosis (ALS). In this study, we demonstrate complement system involvement in a rodent model of ALS (human SOD1(G93A) transgenic rats). With end-stage disease, SOD1(G93A) rats displayed marked deposition of C3/C3b, and a significant up-regulation of the C5aR in the lumbar spinal cord. This was associated with increased numbers of C5aR-positive astrocytes. However, expression of C5L2, the alternative receptor for C5a, was highest on motor neurons early in the disease process. To determine the contribution of C5a to the pathology displayed by this model of ALS, rats were administered an orally active, selective C5aR antagonist (PMX205; 1 mg/kg/day, oral). Animals treated with PMX205 displayed a significant extension of survival time and a reduction in end-stage motor scores, as compared with vehicle-treated rats. PMX205-treated animals also displayed reduced levels of astroglial proliferation in the lumbar spinal cord. This study provides the first demonstration of an involvement of C5a in an ALS model and suggests that inhibitors of complement activation could be beneficial in the treatment of this neurodegenerative disease.}, }
@article {pmid19038252, year = {2009}, author = {Riddoch-Contreras, J and Yang, SY and Dick, JR and Goldspink, G and Orrell, RW and Greensmith, L}, title = {Mechano-growth factor, an IGF-I splice variant, rescues motoneurons and improves muscle function in SOD1(G93A) mice.}, journal = {Experimental neurology}, volume = {215}, number = {2}, pages = {281-289}, doi = {10.1016/j.expneurol.2008.10.014}, pmid = {19038252}, issn = {1090-2430}, support = {G0601943/MRC_/Medical Research Council/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/*physiopathology/*therapy ; Animals ; Cell Count ; Disease Models, Animal ; Humans ; Insulin-Like Growth Factor I/biosynthesis/genetics/*therapeutic use ; Isotonic Contraction/drug effects/physiology ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects/physiology ; Muscle Fatigue/drug effects/physiology ; Muscle Strength/drug effects/physiology ; Muscle, Skeletal/metabolism/pathology/*physiopathology ; Organ Size/drug effects/physiology ; Succinate Dehydrogenase/metabolism ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motoneuron degeneration. Although viral delivery of IGF-I has shown therapeutic efficacy in the SOD1(G93A) mouse model of ALS, clinical trials of IGF-I in ALS patients have led to conflicting results. Here we examine the effects of an IGF-I splice variant, mechano-growth factor (MGF) which has previously been shown to have greater neuroprotective effects than IGF-I in a number of models of neurodegeneration. A mammalian expression plasmid containing either MGF or, for comparison, the IGF-I cDNA sequence was delivered to the hindlimb muscles of SOD1(G93A) mice at 70 days of age, at symptom onset. Treatment with either IGF-I or MGF resulted in a significant improvement in hindlimb muscle strength, and an increase in motor unit and motoneuron survival. Significantly more motoneurons survived in MGF treated mice.}, }
@article {pmid19029516, year = {2008}, author = {Sorenson, EJ and Windbank, AJ and Mandrekar, JN and Bamlet, WR and Appel, SH and Armon, C and Barkhaus, PE and Bosch, P and Boylan, K and David, WS and Feldman, E and Glass, J and Gutmann, L and Katz, J and King, W and Luciano, CA and McCluskey, LF and Nash, S and Newman, DS and Pascuzzi, RM and Pioro, E and Sams, LJ and Scelsa, S and Simpson, EP and Subramony, SH and Tiryaki, E and Thornton, CA}, title = {Subcutaneous IGF-1 is not beneficial in 2-year ALS trial.}, journal = {Neurology}, volume = {71}, number = {22}, pages = {1770-1775}, pmid = {19029516}, issn = {1526-632X}, support = {R01 NS042759-05/NS/NINDS NIH HHS/United States ; R01 NS 42759/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Central Nervous System Agents/*administration &amp; dosage/adverse effects ; Deglutition ; Double-Blind Method ; Female ; Hand Strength ; Humans ; Injections, Subcutaneous ; Insulin-Like Growth Factor I/*administration &amp; dosage/adverse effects ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Research Design ; Thromboembolism/chemically induced ; Time Factors ; Tracheostomy ; Treatment Failure ; }, abstract = {BACKGROUND: Previous human clinical trials of insulin-like growth factor type I (IGF-1) in amyotrophic lateral sclerosis (ALS) have been inconsistent. This phase III, randomized, double-blind, placebo-controlled study was undertaken to address whether IGF-1 benefited patients with ALS.<br><br>METHODS: A total of 330 patients from 20 medical centers were randomized to receive 0.05 mg/kg body weight of human recombinant IGF-1 given subcutaneously twice daily or placebo for 2 years. The primary outcome measure was change in their manual muscle testing score. Secondary outcome measures included tracheostomy-free survival and rate of change in the revised ALS functional rating scale. Intention to treat analysis was used.<br><br>RESULTS: There was no difference between treatment groups in the primary or secondary outcome measures after the 2-year treatment period.<br><br>CONCLUSIONS: Insulin-like growth factor type I does not provide benefit for patients with amyotrophic lateral sclerosis.}, }
@article {pmid19021894, year = {2008}, author = {Kowalik, MM and Smiatacz, T and Pajuro, R and Skowroński, R and Trocha, H and Nyka, W and Raczyńska, K and Wujtewicz, M}, title = {Anaesthesia for ophthalmologic surgical procedures in a patient with advanced amyotrophic lateral sclerosis: a case report.}, journal = {Cases journal}, volume = {1}, number = {1}, pages = {338}, pmid = {19021894}, issn = {1757-1626}, abstract = {INTRODUCTION: Anaesthesia procedures for surgical interventions in patients with amyotrophic lateral sclerosis (ALS) are not commonly found in clinical practice, and often have special considerations that must be taken into account in treatment planning. As a result, these procedures are rarely subject to publication, rendering it difficult for the anaesthesiologists to find useful and reliable information on this topic. ALS also presents a contraindication to the use of nondepolarising neuromuscular blocking drugs during general anaesthesia.<br><br>CASE PRESENTATION: In the case presented here, a 52-year old, White man, the progression of the disease to tetraparesis and respiratory failure, in addition to having the patient on chronic mechanical ventilation support, provided additional challenges to the handling team. The maturation of cataracts severely impaired communication with the patient, and surgical treatment of the cataract presented the only means to save communication. Such interventions are generally performed under local anaesthesia with the advice of the attending anaesthesiologist. However, in this case the patients' announcements during the operation would be unreadable to the advising anaesthesiologist. Here, the authors share experiences from a successfully applied combination of topical and general anaesthesia for two cataract operations and a vitrectomy. This was tolerated well by the patient, and without any side-effects.<br><br>CONCLUSION: The applied treatment resulted in a substantial improvement of the vision and allowed communication to be maintained with the patient.}, }
@article {pmid19019302, year = {2008}, author = {Aggarwal, S and Cudkowicz, M}, title = {ALS drug development: reflections from the past and a way forward.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {5}, number = {4}, pages = {516-527}, pmid = {19019302}, issn = {1933-7213}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/pathology/*therapy ; Animals ; Clinical Trials as Topic ; Humans ; Neuroprotective Agents/therapeutic use ; Research Design ; Riluzole/therapeutic use ; Treatment Outcome ; }, abstract = {Tremendous advances in our understanding of pathogenesis of amyotrophic lateral sclerosis (ALS) have provided a rich pipeline of drugs for clinical trialists. At least 32 unique compounds have been tested. Nevertheless, riluzole is currently the only treatment that prolongs survival. We present a critical overview of past clinical trials, how therapies are selected for testing in people, challenges with ALS clinical trial design and conduct, and ways to best move forward.}, }
@article {pmid19015387, year = {2008}, author = {Beaulieu, JM and Caron, MG}, title = {Looking at lithium: molecular moods and complex behaviour.}, journal = {Molecular interventions}, volume = {8}, number = {5}, pages = {230-241}, doi = {10.1124/mi.8.5.8}, pmid = {19015387}, issn = {1534-0384}, support = {DA-13511/DA/NIDA NIH HHS/United States ; MH-40159/MH/NIMH NIH HHS/United States ; MH-73853/MH/NIMH NIH HHS/United States ; NS-19576/NS/NINDS NIH HHS/United States ; }, mesh = {Affect/*drug effects ; Animals ; Antipsychotic Agents/*pharmacology/therapeutic use ; Arrestins/metabolism ; Behavior/*drug effects ; Glycogen Synthase Kinase 3/antagonists &amp; inhibitors/metabolism ; Humans ; Inositol/metabolism ; Lithium Compounds/*pharmacology/therapeutic use ; Protein Phosphatase 2/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Receptors, G-Protein-Coupled/metabolism ; Second Messenger Systems/physiology ; beta-Arrestin 2 ; beta-Arrestins ; }, abstract = {Lithium and other mood-stabilizing drugs are used for the management of bipolar mood disorders and, to a lesser extent, for augmentation of other psychoactive drugs. Lithium also has neuroprotective properties that may be useful for treatment of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. Over the years, lithium has been shown to inhibit inositol monophosphatases and glycogen synthase kinase 3, but the relevance of such enzyme inhibition to the therapeutic effects of lithium has remained difficult to assess. Here, we provide an overview of recent advances in the identification of molecular mechanisms involved in the regulation of behavior by lithium. We also highlight recent findings suggesting that lithium could exert some of its behavioral effects by acting on a dopamine receptor regulated signaling complex composed of Akt, protein phosphatase 2A, and the multifunctional protein scaffold beta-arrestin 2.}, }
@article {pmid19012065, year = {2009}, author = {Deda, H and Inci, MC and Kürekçi, AE and Sav, A and Kayihan, K and Ozgün, E and Ustünsoy, GE and Kocabay, S}, title = {Treatment of amyotrophic lateral sclerosis patients by autologous bone marrow-derived hematopoietic stem cell transplantation: a 1-year follow-up.}, journal = {Cytotherapy}, volume = {11}, number = {1}, pages = {18-25}, doi = {10.1080/14653240802549470}, pmid = {19012065}, issn = {1477-2566}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*surgery ; Female ; Follow-Up Studies ; *Hematopoietic Stem Cell Transplantation ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Transplantation, Autologous ; Treatment Outcome ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of spinal cord and cortical motoneurons. Despite improved understanding of the mechanisms underlying ALS, in clinical practice the management of ALS remains essentially supportive and focused on symptom relief. However, over the past few years stem cell research has expanded greatly as a tool for developing potential new therapies for treating incurable neurodegenerative diseases.<br><br>METHODS: Thirteen patients with sporadic amyotrophic lateral sclerosis (SALS) were included in this study, and bone marrow (BM)-derived hematopoietic progenitor stem cells were used. We selected patients with bulbar involvement and severe loss of movement. Our aim was to put the stem cells into the end of the brain stem and at the beginning of the spinal cord because the blood-brain barrier is intact in ALS and this region was the most affected part in our patients. Under general anesthesia, a total laminectomy was performed at the C1-C2 level. Stem cells were injected to the anterior part of the spinal cord.<br><br>RESULTS: During the follow-up of 1 year after stem cell implantation, nine patients became much better compared with their pre-operative status, confirmed by electro neuro myography (ENMG). One patient was stable without any decline or improvement in his status. Three patients died 1.5, 2 and 9 months, respectively, after stem cell therapy as a result of lung infection and myocardial infarction (MI).<br><br>DISCUSSION: These results show that stem cell therapy is a safe, effective and promising treatment for ALS patients.}, }
@article {pmid19008722, year = {2008}, author = {Thöne-Reineke, C and Neumann, C and Namsolleck, P and Schmerbach, K and Krikov, M and Schefe, JH and Lucht, K and Hörtnagl, H and Godes, M and Müller, S and Rumschüssel, K and Funke-Kaiser, H and Villringer, A and Steckelings, UM and Unger, T}, title = {The beta-lactam antibiotic, ceftriaxone, dramatically improves survival, increases glutamate uptake and induces neurotrophins in stroke.}, journal = {Journal of hypertension}, volume = {26}, number = {12}, pages = {2426-2435}, doi = {10.1097/HJH.0b013e328313e403}, pmid = {19008722}, issn = {0263-6352}, mesh = {Animals ; Anti-Bacterial Agents/*pharmacology ; Body Temperature/physiology ; Brain/blood supply ; Brain Infarction/pathology ; Ceftriaxone/*pharmacology ; Cerebrovascular Disorders/complications ; Disease Models, Animal ; Excitatory Amino Acid Transporter 2/metabolism ; Glutamic Acid/*metabolism ; Interleukin-6/metabolism ; Male ; Nerve Growth Factors/*metabolism ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Regional Blood Flow/drug effects/physiology ; Stroke/etiology/*metabolism/*mortality ; Survival Rate ; }, abstract = {OBJECTIVE: Ceftriaxone has been reported to reduce neuronal damage in amyotrophic lateral sclerosis and in an in-vitro model of neuronal ischaemia through increased expression and activity of the glutamate transporter, GLT1. We tested the effects of ceftriaxone on mortality, neurological outcome, and infarct size in experimental stroke in rats and looked for underlying mechanisms.<br><br>METHODS: Male normotensive Wistar rats received ceftriaxone (200 mg/kg intraperitoneal) as a single injection 90 min after middle cerebral artery occlusion (90 min with reperfusion). Forty-eight hours after middle cerebral artery occlusion, infarct size (MRI) and neurological deficits were estimated. GLT1 expression was determined by real time RT-PCR, immunoblotting and promoter reporter assay, astrocyte GLT1 activity by measuring glutamate uptake. Bacterial load in various organs was measured by real time RT-PCR, neurotrophins and IL-6 by immunoblotting.<br><br>RESULTS: Ceftriaxone dramatically reduced early (24-h) mortality from 34.5% (vehicle treatment, n = 29) to 0% (P < 0.01, n = 19). In a subgroup, followed up for 4 weeks, mortality persisted at 0%. Ceftriaxone strongly tended to reduce infarct size, it significantly improved neuronal survival within the penumbra, reduced neurological deficits (P < 0.001) and led to an upregulation of neurotrophins (P < 0.01) in the peri-infarct zone. Ceftriaxone did not increase GLT1 expression, but increased GLT1 activity (P < 0.05).<br><br>CONCLUSION: Ceftriaxone causes a significant reduction in acute stroke mortality in a poststroke treatment regimen in animal studies. Improved neurological performance and survival may be due to neuroprotection by activation of GLT1 and a stimulation of neurotrophins resulting in an increased number of surviving neurons in the penumbra.}, }
@article {pmid19005780, year = {2008}, author = {Adhihetty, PJ and Beal, MF}, title = {Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases.}, journal = {Neuromolecular medicine}, volume = {10}, number = {4}, pages = {275-290}, pmid = {19005780}, issn = {1559-1174}, support = {P01 AG014930/AG/NIA NIH HHS/United States ; P01 AG014930-09/AG/NIA NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Creatine/metabolism/*pharmacology/therapeutic use ; Dietary Supplements ; Energy Metabolism/*drug effects/physiology ; Humans ; Mitochondria/*drug effects/metabolism ; Mitochondrial Diseases/*drug therapy/*metabolism/physiopathology ; Neurodegenerative Diseases/*drug therapy/*metabolism/physiopathology ; Phosphocreatine/metabolism ; }, abstract = {Substantial evidence indicates bioenergetic dysfunction and mitochondrial impairment contribute either directly and/or indirectly to the pathogenesis of numerous neurodegenerative disorders. Treatment paradigms aimed at ameliorating this cellular energy deficit and/or improving mitochondrial function in these neurodegenerative disorders may prove to be useful as a therapeutic intervention. Creatine is a molecule that is produced both endogenously, and acquired exogenously through diet, and is an extremely important molecule that participates in buffering intracellular energy stores. Once creatine is transported into cells, creatine kinase catalyzes the reversible transphosphorylation of creatine via ATP to enhance the phosphocreatine energy pool. Creatine kinase enzymes are located at strategic intracellular sites to couple areas of high energy expenditure to the efficient regeneration of ATP. Thus, the creatine kinase/phosphocreatine system plays an integral role in energy buffering and overall cellular bioenergetics. Originally, exogenous creatine supplementation was widely used only as an ergogenic aid to increase the phosphocreatine pool within muscle to bolster athletic performance. However, the potential therapeutic value of creatine supplementation has recently been investigated with respect to various neurodegenerative disorders that have been associated with bioenergetic deficits as playing a role in disease etiology and/or progression which include; Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease. This review discusses the contribution of mitochondria and bioenergetics to the progression of these neurodegenerative diseases and investigates the potential neuroprotective value of creatine supplementation in each of these neurological diseases. In summary, current literature suggests that exogenous creatine supplementation is most efficacious as a treatment paradigm in Huntington's and Parkinson's disease but appears to be less effective for ALS and Alzheimer's disease.}, }
@article {pmid18999176, year = {2008}, author = {Frost, JH and Massagli, MP and Wicks, P and Heywood, J}, title = {How the Social Web Supports patient experimentation with a new therapy: The demand for patient-controlled and patient-centered informatics.}, journal = {AMIA ... Annual Symposium proceedings. AMIA Symposium}, volume = {2008}, number = {}, pages = {217-221}, pmid = {18999176}, issn = {1942-597X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Blogging/*organization &amp; administration ; Consumer Health Information/*methods ; Humans ; Lithium Compounds/*therapeutic use ; Massachusetts ; Patient Participation/*methods ; Patient-Centered Care/*methods ; }, abstract = {The Internet is not simply being used to search for information about disease and treatment. It is also being used by online disease-focused communities to organize their own experience base and to harness their own talent and insight in service to the cause of achieving better health outcomes. We describe how news of a possible effect of lithium on the course of Amyotrophic Lateral Sclerosis (ALS) was acquired by and diffused through an on-line community and led to participation in a patient-driven observational study of lithium and ALS. Our discussion suggests how the social web drives demand for patient-centered health informatics.}, }
@article {pmid18998692, year = {2008}, author = {Lin, CC and Teng, TM and Tsai, CC and Liao, HY and Liu, RS}, title = {Gold-catalyzed deoxygenative nazarov cyclization of 2,4-dien-1-als for stereoselective synthesis of highly substituted cyclopentenes.}, journal = {Journal of the American Chemical Society}, volume = {130}, number = {48}, pages = {16417-16423}, doi = {10.1021/ja806415t}, pmid = {18998692}, issn = {1520-5126}, abstract = {Treatment of 2,4-dien-1-als with allylsilanes and PPh(3)AuSbF(6) (3 mol %) led to formation of 1,4-bis(allyl)cyclopentenyl products; this gold catalyst is superior to commonly used Lewis acids according to catalyst screening. Such gold-catalyzed deoxygenative cyclizations are compatible with various oxygen-, amine-, sulfur-, hydrogen-, and carbon-based nucleophiles. The value of this new catalysis is demonstrated by the diverse annulations of 2,4-dien-1-als with electron-rich alkenes and arenes, providing an easy access to complicated cyclopentenyl frameworks. Structural analysis of annulation products reveals evidence for the participation of Nazarov cyclization. This deoxygenative cyclization is extensible to a tandem intramolecular cyclization/nucleophilic addition cascade, giving polycyclic carbo- or oxacyclic compounds with controlled stereochemistry. This new gold catalysis is applied to a short synthesis of natural compounds of the brazilane family, including brazilane, O-trimethyl-, and O-tetramethyl brazilane.}, }
@article {pmid18991666, year = {2008}, author = {Miyaoka, T}, title = {Clinical potential of minocycline for schizophrenia.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {7}, number = {4}, pages = {376-381}, doi = {10.2174/187152708786441858}, pmid = {18991666}, issn = {1996-3181}, mesh = {Animals ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; Antipsychotic Agents/pharmacology/*therapeutic use ; Apoptosis/drug effects/physiology ; Humans ; Microglia/drug effects ; Minocycline/pharmacology/*therapeutic use ; Nerve Degeneration/drug therapy/physiopathology/prevention &amp; control ; Neuroprotective Agents/pharmacology/therapeutic use ; Schizophrenia/*drug therapy ; Treatment Outcome ; }, abstract = {Minocycline, an antibiotic of the tetracycline family, has been shown to display neurorestorative or neuroprotective properties in various models of neurodegenerative diseases. In particular, it has been shown to delay motor alterations, inflammation and apoptosis in models of Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease. Despite controversies about its efficacy, the relative safety and tolerability of minocycline have led to various clinical trials. Recently, we reported the antipsychotic effects of minocycline in patients with schizophrenia. In a pilot investigation, we administered minocycline as an open-label adjunct to antipsychotic medication to patients with schizophrenia. The results of this trial suggested that minocycline might be a safe and effective adjunct to antipsychotic medications, and that augmentation with minocycline may prove to be a viable strategy for "boosting" antipsychotic efficacy and for treating schizophrenia. The present review summarizes the available data supporting the clinical testing of minocycline for patients with schizophrenia. In addition, we extend our discussion to the potential applications of minocycline for combining this treatment with cellular and molecular therapy.}, }
@article {pmid18990309, year = {2008}, author = {Barañano, KW and Hartman, AL}, title = {The ketogenic diet: uses in epilepsy and other neurologic illnesses.}, journal = {Current treatment options in neurology}, volume = {10}, number = {6}, pages = {410-419}, pmid = {18990309}, issn = {1092-8480}, support = {K12 NS001696/NS/NINDS NIH HHS/United States ; K12 NS001696-05/NS/NINDS NIH HHS/United States ; }, abstract = {The ketogenic diet is well established as therapy for intractable epilepsy. It should be considered first-line therapy in glucose transporter type 1 and pyruvate dehydrogenase deficiency. It should be considered early in the treatment of Dravet syndrome and myoclonic-astatic epilepsy (Doose syndrome). Initial studies indicate that the ketogenic diet appears effective in other metabolic conditions, including phosphofructokinase deficiency and glycogenosis type V (McArdle disease). It appears to function in these disorders by providing an alternative fuel source. A growing body of literature suggests the ketogenic diet may be beneficial in certain neurodegenerative diseases, including Alzheimer disease, Parkinson's disease, and amyotrophic lateral sclerosis. In these disorders, the ketogenic diet appears to be neuroprotective, promoting enhanced mitochondrial function and rescuing adenosine triphosphate production. Dietary therapy is a promising intervention for cancer, given that it may target the relative inefficiency of tumors in using ketone bodies as an alternative fuel source. The ketogenic diet also may have a role in improving outcomes in trauma and hypoxic injuries.}, }
@article {pmid18977395, year = {2009}, author = {Kim, HS and Suh, YH}, title = {Minocycline and neurodegenerative diseases.}, journal = {Behavioural brain research}, volume = {196}, number = {2}, pages = {168-179}, doi = {10.1016/j.bbr.2008.09.040}, pmid = {18977395}, issn = {1872-7549}, mesh = {Animals ; Anti-Bacterial Agents/*pharmacology/therapeutic use ; *Anti-Inflammatory Agents, Non-Steroidal ; Apoptosis/drug effects ; Humans ; Minocycline/*pharmacology/therapeutic use ; Neurodegenerative Diseases/*drug therapy/pathology ; *Neuroprotective Agents ; Signal Transduction/drug effects ; }, abstract = {Minocycline is a semi-synthetic, second-generation tetracycline analog which is effectively crossing the blood-brain barrier, effective against gram-positive and -negative infections. In addition to its own antimicrobacterial properties, minocycline has been reported to exert neuroprotective effects over various experimental models such as cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, Parkinson's disease, kainic acid treatment, Huntington' disease and multiple sclerosis. Minocycline has been focused as a neuroprotective agent over neurodegenerative disease since it has been first reported that minocycline has neuroprotective effects in animal models of ischemic injury [Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koisinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 1998;95:15769-74; Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 1999;96:13496-500]. Recently, the effect of minocycline on Alzheimer's disease has been also reported. Although its precise primary target is not clear, the action mechanisms of minocycline for neuroprotection reported so far are; via; the inhibition of mitochondrial permeability-transition mediated cytochrome c release from mitochondria, the inhibition of caspase-1 and -3 expressions, and the suppression of microglial activation, involvement in some signaling pathways, metalloprotease activity inhibition. Because of the high tolerance and the excellent penetration into the brain, minocycline has been clinically tried for some neurodegenerative diseases such as stroke, multiple sclerosis, spinal cord injury, amyotropic lateral sclerosis, Hungtington's disease and Parkinson's disease. This review will briefly summarize the effects and action mechanisms of minocycline on neurodegenerative diseases.}, }
@article {pmid18970506, year = {2006}, author = {Pasamontes, A and Callao, MA}, title = {Optimization by means of responses surface of an analytical sequence using a sequential injection system.}, journal = {Talanta}, volume = {68}, number = {5}, pages = {1617-1622}, doi = {10.1016/j.talanta.2005.08.033}, pmid = {18970506}, issn = {1873-3573}, abstract = {An experimental design method was applied to determine the optimum working conditions for sequential injection analysis (SIA) to obtain second-order data that will be treated using multivariate curve resolution with alternating least squares (MCR-ALS). The critical step is to design an analytical sequence that provides relevant information. This sequence depends on parameters related to the system, the chemical reaction, and the chemometric treatment of the data. Also, from the multiple responses that quantify the quality of this analytical sequence, a single response is determined from the desirability function. This method involves a factor-screening step, in which both the global desirability function and the individual responses are considered and a response surface-modelling step, in which the most relevant factors are considered.}, }
@article {pmid18955116, year = {2008}, author = {Rohde, G and Kermer, P and Reed, JC and Bähr, M and Weishaupt, JH}, title = {Neuron-specific overexpression of the co-chaperone Bcl-2-associated athanogene-1 in superoxide dismutase 1(G93A)-transgenic mice.}, journal = {Neuroscience}, volume = {157}, number = {4}, pages = {844-849}, doi = {10.1016/j.neuroscience.2008.09.055}, pmid = {18955116}, issn = {0306-4522}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/genetics/metabolism/mortality/pathology ; Animals ; DNA-Binding Proteins/genetics/*metabolism ; Disease Models, Animal ; Gene Expression Regulation/*drug effects ; Humans ; Mice ; Mice, Transgenic ; Motor Activity/genetics ; Motor Neurons/*metabolism ; Phosphopyruvate Hydratase/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Spinal Cord/pathology ; Superoxide Dismutase/*genetics ; Survival Analysis ; Transcription Factors/genetics/*metabolism ; }, abstract = {Bcl-2-associated athanogene-1 (BAG1) binds heat-shock protein 70 (Hsp70)/Hsc70, increases intracellular chaperone activity in neurons and proved to be protective in several models for neurodegeneration. Mutations in the superoxide dismutase 1 (SOD1) gene account for approximately 20% of familial amyotrophic lateral sclerosis (ALS) cases. A common property shared by all mutant SOD1 (mtSOD1) species is abnormal protein folding and the propensity to form aggregates. Toxicity and aggregate formation of mutant SOD1 can be overcome by enhanced chaperone function in vitro. Moreover, expression of mtSOD1 decreases BAG1 levels in a motoneuronal cell line. Thus, several lines of evidence suggested a protective role of BAG1 in mtSOD1-mediated motoneuron degeneration. To explore the therapeutic potential of BAG1 in a model for ALS, we generated SOD1G93A/BAG1 double transgenic mice expressing BAG1 in a neuron-specific pattern. Surprisingly, substantially increased BAG1 protein levels in spinal cord neurons did not significantly alter the phenotype of SOD1G93A-transgenic mice. Hence, expression of BAG1 is not sufficient to protect against mtSOD1-induced motor dysfunction in vivo. Our work shows that, in contrast to the in vitro situation, modulation of multiple cellular functions in addition to enhanced expression of a single chaperone is required to protect against SOD1 toxicity, highlighting the necessity of combined treatment strategies for ALS.}, }
@article {pmid18949074, year = {2008}, author = {Bernd, K}, title = {Phytochemical approach and bioanalytical strategy to develop chaperone-based medications.}, journal = {The open biochemistry journal}, volume = {2}, number = {}, pages = {44-48}, pmid = {18949074}, issn = {1874-091X}, abstract = {Currently, no pharmaceuticals for the etiological treatment of degenerative protein-misfolding diseases (e.g., ALS, Alzheimer's or prion diseases) are commercially available. In this technical note theoretical considerations and practical approaches concerning the development of chaperone-based medications from medicinal plants (e.g., Ginkgo biloba) are reviewed and discussed in detail. Phytochaperones and other agents isolated from medicinal plants are proposed to serve as the general basis of drug development in protein-misfolding diseases.}, }
@article {pmid18944021, year = {2002}, author = {Kim, YH and Kim, KH}, title = {Abscission Layer Formation as a Resistance Response of Peruvian Apple Cactus Against Glomerella cingulata.}, journal = {Phytopathology}, volume = {92}, number = {9}, pages = {964-969}, doi = {10.1094/PHYTO.2002.92.9.964}, pmid = {18944021}, issn = {0031-949X}, abstract = {Stem disks from 2-year-old cacti Cereus tetragonus (susceptible) and C. peruvianus (resistant) were inoculated in the center (pith) with Glomerella cingulata isolated from Colletotrichum stem rot in three-angled cacti. The susceptible cactus became extensively colonized, whereas colonization was limited to a small area in the resistant cactus. The resistant cactus formed prominent abscission layers (ALs) in parenchyma internal to the inoculation site. Ethanol extracts of the fungal culture also stimulated AL formation in the resistant cactus. Initial cell division followed at 2 to 4 days after treatment, and layering of multiple cells at 7 days after treatment. After 10 days, the outer layers were sometimes sloughed from the inner layers. No AL formation was induced in susceptible C. tetragonus treated with ethanol extract or in untreated control cacti. Light and electron microscopy revealed that initial cell division occurred by cell wall formation, and that an additional cell wall was layered in pre-existing parenchyma cells without ordinary cell division. Later, separation layers formed in ALs where inner cell walls appeared to be thickened secondarily, and the cell walls and middle lamella within the layer dissolved. These results suggest that AL formation in the resistant cactus is induced by fungal metabolites, and that it serves as a histological barrier against anthracnose pathogens.}, }
@article {pmid18937955, year = {2009}, author = {Danel-Brunaud, V and Laurier, L and Parent, K and Moreau, C and Defebvre, L and Jacquemin, D and Destée, A}, title = {[Issues of France's "Leonetti Act": Involvement of amyotrophic lateral sclerosis patients in prior discussions concerning respiratory support and end-of-life care].}, journal = {Revue neurologique}, volume = {165}, number = {2}, pages = {170-177}, doi = {10.1016/j.neurol.2008.08.008}, pmid = {18937955}, issn = {0035-3787}, mesh = {Death, Sudden, Cardiac ; Female ; France ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*therapy ; *Personal Autonomy ; Suicide ; Terminal Care/*legislation &amp; jurisprudence ; Tracheotomy ; Ventilators, Mechanical ; }, abstract = {In accordance with the principle of personal autonomy, expert consensus statements on amyotrophic lateral sclerosis (ALS) recommend early engagement with terminal-phase patients on the type of symptomatic treatment to be administered in the event of respiratory failure, since decompensation progresses too rapidly to allow time for a discussion. The French Parliamentary Act on Patients' Rights and End-of-Life Care (dated 22 April 2005) grants individuals the right to refuse unreasonable treatment and obliges physicians to take account of any prior instructions given by a person before he/she became incapable of communicating. The provision of prior instructions is a very reassuring situation for the physician: the autonomous patient indicates his or her choice of end-of-life care. However, there are two pitfalls which must be avoided: (i) holding a discussion for the sole purpose of obtaining prior instructions and (ii) not acknowledging the patient's vulnerability. The present study dealt with 35 ALS patients for whom the question of either intensive care or palliative end-of-life care remained open. Even though the great majority of these individuals were keen to know their exact state of health, 48% refused to consider this circumstance and only 20% expressed prior instructions. These results prompted us to question the ethical dimension of the concept of autonomy beyond its founding formulation: can one envisage an incapacity to confront oneself with the existential question of possible death? In 80% of cases, the physician will have to take a care decision in the absence of any prior instructions from the patient. This amounts to more than respecting a person's autonomy and involves exercising medical responsibility.}, }
@article {pmid18929119, year = {2008}, author = {Whitcup, SM}, title = {Clinical trials in neuroprotection.}, journal = {Progress in brain research}, volume = {173}, number = {}, pages = {323-335}, doi = {10.1016/S0079-6123(08)01123-0}, pmid = {18929119}, issn = {1875-7855}, mesh = {Disease Progression ; Endpoint Determination ; Glaucoma/pathology/therapy ; Humans ; Kaplan-Meier Estimate ; Neurodegenerative Diseases/pathology/*therapy ; Neuroprotective Agents/*therapeutic use ; Optic Nerve Diseases/pathology/therapy ; Randomized Controlled Trials as Topic/*methods ; Visual Fields/physiology ; }, abstract = {Neuroprotection is a therapeutic approach that aims to prevent neuronal degeneration and loss of function. Research has focused on developing neuroprotective agents for the therapy of various degenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and glaucoma. Clinical trials for the evaluation of neuroprotective agents pose unique challenges in terms of experimental design and data interpretation. In order to generate meaningful results, clinical trials on neuroprotective agents should ideally be designed to minimize the potential for bias and optimize the ability to detect the neuroprotective effect of a therapeutic intervention in as short a time as possible. Key issues for the design of clinical trials of neuroprotective therapies include identifying appropriate endpoints and determining the ideal timing of the intervention. Neuroprotection trials in glaucoma must be designed to distinguish between the neuroprotective effects of the therapy and the protective effect of intraocular pressure lowering. The choice of suitable functional endpoints in glaucoma trials is also a critical consideration. For example, visual field loss can be used as a functional endpoint; however, it occurs slowly and may require many years before meaningful changes occur. New methods for assessing visual function may be useful for assessing neuroprotective effects of therapeutic interventions. Although there have been a plethora of medications studied for neuroprotective effects in clinical trials, few have been approved by regulatory agencies for use in patients. Despite these challenges, properly designed clinical trials with validated endpoints will yield the most useful information on the neuroprotective effects of therapy, and may provide new treatment options to prevent the loss of neurologic function, including vision.}, }
@article {pmid18855638, year = {2008}, author = {Conti, E and Musumeci, MB and Assenza, GE and Quarta, G and Autore, C and Volpe, M}, title = {Recombinant human insulin-like growth factor-1: a new cardiovascular disease treatment option?.}, journal = {Cardiovascular &amp; hematological agents in medicinal chemistry}, volume = {6}, number = {4}, pages = {258-271}, doi = {10.2174/187152508785909456}, pmid = {18855638}, issn = {1871-5257}, mesh = {Animals ; Cardiovascular Diseases/*drug therapy/etiology ; Endocrine System Diseases/drug therapy ; Heart Failure/drug therapy ; Humans ; Insulin-Like Growth Factor I/physiology/*therapeutic use ; Myocardial Ischemia/drug therapy ; Recombinant Proteins/therapeutic use ; }, abstract = {The Insulin-like growth factor-1 (IGF-1) system is dynamic and complex, involving many binding proteins, binding-protein-related proteases, and receptors. It has emerged in time as a powerful defence to life processes of many cytotypes, tissues and systems. Mainly in body metabolism, diabetes and cardiovascular system, but also in brain and kidney, IGF-1 plays a key role in maintaining homeostasis, increasing progenitor cell potential, and improving physiologic performance both in rest and stress conditions. Its vasculoprotective and insulin sensitizing ability exerts a protective role on flow-metabolism coupling and organs function. Therapeutical human use of recombinant human IGF-1 (rhIGF-1) has been widely applied only in Laron syndrome, while being verified in many randomized controlled trials to improve glycemic control in type 1 and type 2 diabetes, and proposed in neurological disease such as amyotrophic lateral sclerosis, multiple sclerosis and Alzheimer disease. Sparse evidence exists moreover about rhIGF-1 use in insulin resistance, burns, catabolic and post-surgery states, acute and chronic renal failure, amyotrophic lateral and multiple sclerosis, brain injury, and immunoincompetence. Along with these data, results are available on cardiovascular benefit of administration of other growth factors, such as erythropoietin and vascular endothelial growth factor, or on cardiovascular side effects of growth factor antagonists such as trastuzumab in cancer therapy. We intended therefore to summarize in this review available human and animals evidence about rhIGF-1 effects on different systems with insights on rhIGF-1 cardiovascular effects. In view of its ability to improve flow-metabolism coupling, IGF-1 could indeed represent a new cardiovascular disease treatment option for many cardiac disorders such as ischemic heart disease and heart failure.}, }
@article {pmid18840345, year = {2008}, author = {García, V and Marquina, I and Olabarri, A and Miranda, G and Rubiera, G and Baena, MI}, title = {[Negative results associated with medication in the emergency department of a hospital].}, journal = {Farmacia hospitalaria : organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria}, volume = {32}, number = {3}, pages = {157-162}, pmid = {18840345}, issn = {1130-6343}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Child, Preschool ; Cross-Sectional Studies ; *Drug-Related Side Effects and Adverse Reactions/*epidemiology ; *Emergency Service, Hospital ; Female ; Humans ; Infant ; Male ; Middle Aged ; Prevalence ; Severity of Illness Index ; Young Adult ; }, abstract = {OBJECTIVE: To find out the prevalence of negative results associated with medication (herein referred to as NRM) in patients attending the emergency department. To classify the results by severity, avoidability and cost, as well as to establish the factors associated with their appearance.<br><br>METHOD: Observational, descriptive and cross-sectional study carried out in the emergency department of a tertiary hospital. Patient surveys and emergency department records were used as sources of information. The Dader Method and guidelines from the Third Consensus of Granada were used. Pearson's chi2 test was used to find the association between age, gender and number of drugs and showing signs of NRM. Avoidability was measured using Baena et al's criteria and severity was assessed according to whether or not the patient had been admitted into an observation stall or on to a hospital ward.<br><br>RESULTS: 24.4% of patients visited the emergency department because of NRM. 16.1% needed to be hospitalised to solve their health issue. 83.9% of all patients with NRM and 77.3% of those hospitalised due to NRM could have been avoided. Statistically, there was a higher prevalence of NRM in patients taking 5 or more different drugs. An estimated euro 14,666,178 was spent on treating avoidable NRM cases in 2003.<br><br>CONCLUSIONS: The prevalence of NRM in those who attended the emergency department, the high percentage of avoidability and the cost imposed on the Health Service seem to sufficiently argue a case for the consideration that NRM as a problem which requires the implementation of prevention programmes based on drug-treatment monitoring.}, }
@article {pmid18835867, year = {2008}, author = {Pitzer, C and Krüger, C and Plaas, C and Kirsch, F and Dittgen, T and Müller, R and Laage, R and Kastner, S and Suess, S and Spoelgen, R and Henriques, A and Ehrenreich, H and Schäbitz, WR and Bach, A and Schneider, A}, title = {Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {131}, number = {Pt 12}, pages = {3335-3347}, pmid = {18835867}, issn = {1460-2156}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Apoptosis/drug effects ; Cells, Cultured ; Disease Models, Animal ; Disease Progression ; Drug Evaluation, Preclinical/methods ; Female ; Filgrastim ; Granulocyte Colony-Stimulating Factor/administration &amp; dosage/pharmacology/*therapeutic use ; Humans ; Infusions, Subcutaneous ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/drug effects/metabolism ; Mutation ; Receptors, Granulocyte Colony-Stimulating Factor/metabolism ; Recombinant Proteins ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Spinal Cord/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive loss of motoneurons, motor weakness and death within 1-5 years after disease onset. Therapeutic options remain limited despite a substantial number of approaches that have been tested clinically. In particular, various neurotrophic factors have been investigated. Failure in these trials has been largely ascribed to problems of insufficient dosing or inability to cross the blood-brain barrier (BBB). We have recently uncovered the neurotrophic properties of the haematopoietic protein granulocyte-colony stimulating factor (G-CSF). The protein is clinically well tolerated and crosses the intact BBB. This study examined the potential role of G-CSF in motoneuron diseases. We investigated the expression of the G-CSF receptor in motoneurons and studied effects of G-CSF in a motoneuron cell line and in the SOD1(G93A) transgenic mouse model. The neurotrophic growth factor was applied both by continuous subcutaneous delivery and CNS-targeted transgenic overexpression. This study shows that given at the stage of the disease where muscle denervation is already evident, G-CSF leads to significant improvement in motor performance, delays the onset of severe motor impairment and prolongs overall survival of SOD1(G93A)tg mice. The G-CSF receptor is expressed by motoneurons and G-CSF protects cultured motoneuronal cells from apoptosis. In ALS mice, G-CSF increased survival of motoneurons and decreased muscular denervation atrophy. We conclude that G-CSF is a novel neurotrophic factor for motoneurons that is an attractive and feasible drug candidate for the treatment of ALS.}, }
@article {pmid18819027, year = {2008}, author = {Badayan, I and Cudkowicz, ME}, title = {Is it too soon for mesenchymal stem cell trials in people with ALS?.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {9}, number = {6}, pages = {321-322}, doi = {10.1080/17482960802425559}, pmid = {18819027}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*surgery ; Animals ; Clinical Trials as Topic/*trends ; Humans ; Mesenchymal Stem Cell Transplantation/*methods/trends ; Pilot Projects ; Time Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting primarily the motor neurons. Stem cell therapy is under development as a possible treatment approach. A pilot study of intraspinal injections of mesenchymal stem cells (MSC) was conducted in 9 participants. We review this paper, the rationale, preclinical data and study design.}, }
@article {pmid18802797, year = {2008}, author = {Gámez, J}, title = {[Minocycline for the treatment of amyotrophic lateral sclerosis: neuroprotector or neurotoxin? Reflections on another failure of translational medicine].}, journal = {Neurologia (Barcelona, Spain)}, volume = {23}, number = {8}, pages = {484-493}, pmid = {18802797}, issn = {0213-4853}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Anti-Bacterial Agents/therapeutic use ; Clinical Trials as Topic ; *Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Minocycline/*therapeutic use ; Neuroprotective Agents/therapeutic use ; Neurotoxins/therapeutic use ; Treatment Outcome ; }, abstract = {A recent publication of the results of a clinical trial of minocycline in 412 ALS patient has aroused considerable controversy in the ALS scientific community. As on previous occasions, the results obtained in the laboratory are not reproduced in clinical practice. The reasons for this new disappointment in translational medicine are analysed by applying the successes obtained in the experimental animal model for ALS to humans. The most frequently suggested causes for explaining these continuous failures are unawareness of the correct dosage to be used, the ideal duration of the clinical trial in phase III, sample size, the search for a primary outcome for measurement other than survival, the need for biomarkers giving information on the progression of the disease and whether this is modified by the introduction of the drug for study. Debate focuses on whether the transgenic mouse model of ALS which expresses SOD1 mutations which we have been using for more than a decade is an exact reflection of the clinical profile and the physiopathogenic mechanisms present in patients with spo- radic ALS. There is the possibility that depending on the dose administered, minocycline can be a neuroprotector or a neurotoxin. In other words, at a dose of 200 mg/day, this drug behaves like <<Dr. Jekyll>> and like <<Mr. Hyde>> at doses of 400 mg. For the authors of the trial, this possibility does not seem to be the cause of the disappointing results obtained. However, they acknowledge that one of the limitations of their study was that it was impossible to compare the effects of minocycline in the patient after receiving 200 or 400 mg. For many other researchers running ongoing clinical trials in both ALS and other neurological diseases, the dose of 200 mg/day is chosen as ideal for testing the effectiveness of minocycline in patients. The strategy of administering the maximum dose of a drug to be tested may give rise to misleading results. We agree with the opinion of other authors, who say that minocycline should be given a second chance.}, }
@article {pmid18801114, year = {2008}, author = {Gribkoff, VK and Bozik, ME}, title = {KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2, 6-benzothiazole-diamine dihydrochloride monohydrate] for the treatment of amyotrophic lateral sclerosis.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {14}, number = {3}, pages = {215-226}, pmid = {18801114}, issn = {1755-5930}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Benzothiazoles/chemistry/*pharmacology/therapeutic use ; Dopamine Agonists/chemistry/*therapeutic use ; Humans ; Mitochondria/drug effects/metabolism ; Neuroprotective Agents/chemistry/*therapeutic use ; Pramipexole ; Stereoisomerism ; }, abstract = {Developing effective treatments for chronic neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) has proven extremely difficult. ALS is universally fatal, characterized by progressive weakness due to the degeneration of upper and lower motor neurons, and leads eventually to respiratory failure which is the usual cause of death. Only a single treatment has been approved, the modestly effective nonspecific neuroprotectant Rilutek (riluzole; 2-amino-6-(trifluoromethoxy)benzothiazole). KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride, RPPX], a synthetic amino-benzothiazole with demonstrated activity in maintaining mitochondrial function, is being developed as a treatment for ALS. It has proven to be effective in multiple in vitro and in vivo assays of neuroprotection, including the G93A-SOD1 mutant mouse model; however, its specific mechanism of action remains unknown. The potential of KNS-760604 as a treatment for ALS was first suggested by studies showing that its optical enantiomer, Mirapex[(6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine; pramipexole dihydrochloride; PPX], a high-affinity agonist at dopamine D2, D3, and D4 receptors, exhibits important neuroprotective properties independent of its dopamine receptor agonism. In cell-based assays, both RPPX and PPX reduce the production of reactive oxygen species (ROS), attenuate the activation of apoptotic pathways, and increase cell survival in response to a variety of neurotoxins. However, PPX has limited utility as a clinical neuroprotective agent because the drug concentrations required for neuroprotection would likely produce unacceptable dopaminergic side effects. RPPX, on the other hand, while possessing the same neuroprotective potential as PPX, is a much lower-affinity dopamine receptor agonist and may therefore be more useful in the treatment of ALS. This review will examine the data supporting the hypothesis that the RPPX may have therapeutic potential for the treatment of neurodegenerative disorders including ALS. In addition, we will briefly review recent preclinical data in support of RPPX, and discuss the current status of its clinical development.}, }
@article {pmid18800007, year = {2008}, author = {Venneti, S and Wang, G and Nguyen, J and Wiley, CA}, title = {The positron emission tomography ligand DAA1106 binds with high affinity to activated microglia in human neurological disorders.}, journal = {Journal of neuropathology and experimental neurology}, volume = {67}, number = {10}, pages = {1001-1010}, pmid = {18800007}, issn = {0022-3069}, support = {K24 MH001717/MH/NIMH NIH HHS/United States ; R01 MH071151/MH/NIMH NIH HHS/United States ; K24 MH01717/MH/NIMH NIH HHS/United States ; R01 MH064921/MH/NIMH NIH HHS/United States ; K24 MH001717-09/MH/NIMH NIH HHS/United States ; R01 MH071151-04S1/MH/NIMH NIH HHS/United States ; R01 MH64921/MH/NIMH NIH HHS/United States ; R01 MH 71151/MH/NIMH NIH HHS/United States ; R01 MH071151-05/MH/NIMH NIH HHS/United States ; R21 AG025829/AG/NIA NIH HHS/United States ; K24 MH001717-10/MH/NIMH NIH HHS/United States ; R21 AG025829-02/AG/NIA NIH HHS/United States ; R01 MH071151-04/MH/NIMH NIH HHS/United States ; }, mesh = {Acetamides/*pharmacokinetics ; Aged ; Aged, 80 and over ; Autoradiography ; Brain/pathology ; Female ; Humans ; Inflammation/diagnostic imaging/pathology ; Isoquinolines/pharmacokinetics ; Male ; Microglia/*diagnostic imaging/*metabolism ; Middle Aged ; Nervous System Diseases/*diagnostic imaging/*metabolism ; Phenyl Ethers/*pharmacokinetics ; Positron-Emission Tomography ; Radiopharmaceuticals/*pharmacokinetics ; }, abstract = {Chronic microglial activation is an important component of many neurological disorders, and imaging activated microglia in vivo will enable the detection and improved treatment of neuroinflammation. 1-(2-chlorphenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carbox-amide (PK11195), a peripheral benzodiazepine receptor ligand, has been used to image neuroinflammation, but the extent to which PK11195 binding distinguishes activated microglia and reactive astrocytes is unclear. Moreover, PK11195 may lack sufficient sensitivity for detecting mild neuroinflammation. We hypothesized that N-(2,5-dimethoxybenzyl)-N-(4-fluoro-2-phenoxyphenyl) acetamide (DAA1106), a new ligand that binds specifically to peripheral benzodiazepine receptor, binds to activated microglia in human neurological diseases with higher affinity than does PK11195. We therefore compared the pharmacological binding properties of [3H](R)-PK11195 and [3H]DAA1106 in postmortem tissues from patients with cerebral infarcts, amyotrophic lateral sclerosis, Alzheimer disease, frontotemporal dementia, and multiple sclerosis (n=10 each). In all diseases, [3H]DAA1106 showed a higher binding affinity as reflected by lower dissociation constant (KD) values than that of [3H](R)-PK11195. Moreover, specific binding of both ligands correlated with the presence of activated microglia identified by immunohistochemistry in situ. We conclude that 1) ligands that bind peripheral benzodiazepine receptor mainly label activated microglia in human neurological disorders and that 2) DAA1106 may possess binding characteristics superior to those of PK11195, which may be beneficial for in vivo positron emission tomography imaging.}, }
@article {pmid18793759, year = {2008}, author = {Cooke, MS and Duarte, TL and Cooper, D and Chen, J and Nandagopal, S and Evans, MD}, title = {Combination of azathioprine and UVA irradiation is a major source of cellular 8-oxo-7,8-dihydro-2'-deoxyguanosine.}, journal = {DNA repair}, volume = {7}, number = {12}, pages = {1982-1989}, doi = {10.1016/j.dnarep.2008.08.007}, pmid = {18793759}, issn = {1568-7864}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Antimetabolites, Antineoplastic/*pharmacology ; Azathioprine/*pharmacology ; Cell Survival/drug effects/radiation effects ; Cells, Cultured ; Comet Assay ; DNA/drug effects/radiation effects ; DNA Damage/drug effects/radiation effects ; DNA Glycosylases/metabolism ; Deoxyguanosine/*analogs &amp; derivatives/metabolism ; Dose-Response Relationship, Radiation ; Fibroblasts/drug effects/metabolism/radiation effects ; Humans ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Thioguanine/pharmacology ; *Ultraviolet Rays ; }, abstract = {Thiopurine antimetabolites, such as azathioprine (Aza) and 6-thioguanine (6-TG), are widely used in the treatment of cancer, inflammatory conditions and organ transplantation patients. Recent work has shown that cells treated with 6-TG and UVA generate ROS, with implied oxidatively generated modification of DNA. In a study of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in renal transplant patients, we provided the first in vivo evidence linking Aza and oxidatively damaged DNA. Using the hOGG1 comet assay, we herein demonstrate high levels of 8-oxodG and alkali-labile sites (ALS) in cells treated with biologically relevant doses of 6-TG, or Aza, plus UVA. This damage was induced dose-dependently. Surprisingly, given the involvement of 6-TG incorporation into DNA in its therapeutic effect, significant amounts of 8-oxodG and ALS were induced in quiescent cells, although less than in proliferating cells. We speculate that some activity of hOGG1 towards unirradiated, 6-TG treated cells, implies possible recognition of 6-TG or derivatives thereof. This is the first report to conclusively demonstrate oxidatively damaged DNA in cells treated with thiopurines and UVA. These data indicate that Aza-derived oxidative stress will occur in the skin of patients on Aza, following even low level UVA exposure. This is a probable contributor to the increased risk of non-melanoma skin cancer in these patients. However, as oxidative stress is unlikely to be involved in the therapeutic effects of Aza, intercepting ROS production in the skin could be a viable route by which this side effect may be minimised.}, }
@article {pmid18792849, year = {2009}, author = {Flaherty-Craig, C and Brothers, A and Dearman, B and Eslinger, P and Simmons, Z}, title = {Penn State screen exam for the detection of frontal and temporal dysfunction syndromes: application to ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {2}, pages = {107-112}, doi = {10.1080/17482960802378980}, pmid = {18792849}, issn = {1471-180X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications ; Cognition Disorders/*diagnosis/*etiology/physiopathology ; Early Diagnosis ; Frontal Lobe/*physiopathology ; Humans ; Mass Screening/methods ; Middle Aged ; Neurologic Examination/*methods ; Temporal Lobe/*physiopathology ; }, abstract = {We improved standard treatment approaches by systematically addressing cognitive and behavioral change in association with frontal and temporal dysfunction in ALS. We evaluated the profile of inchange 198 ALS patients with a 20-minute screen exam. Significant deficiencies in letter fluency and reading comprehension (N=59) were found in 22.7% and 12.8% of limb onset and 36.4% and 20% of bulbar-onset patients. Deficiencies in abstract reasoning and judgment were found in 17%, and 29.5% of limb onset and 19.2%, and 46.7% of bulbar-onset patients. Significant behavioral change (N=89) was also reported in 2.4% of limb onset and 4.3% of bulbar-onset patients. Accommodations were provided from the time of initial detection of acquired deficiencies, with the goal of optimizing the patient's role in decision making throughout the process of treatment planning and implementation. This screen is of practical clinical value for assessment and intervention of deficiencies that affect treatment and quality of life.}, }
@article {pmid18790056, year = {2008}, author = {Ferri, A and Nencini, M and Cozzolino, M and Carrara, P and Moreno, S and Carrì, MT}, title = {Inflammatory cytokines increase mitochondrial damage in motoneuronal cells expressing mutant SOD1.}, journal = {Neurobiology of disease}, volume = {32}, number = {3}, pages = {454-460}, doi = {10.1016/j.nbd.2008.08.004}, pmid = {18790056}, issn = {1095-953X}, mesh = {Animals ; Blotting, Western ; Cell Death ; Cell Line ; Gene Expression ; Glutathione/metabolism ; Interferon-gamma/*metabolism ; Mice ; Microscopy, Electron ; Microscopy, Fluorescence ; Mitochondria/chemistry/*physiology/ultrastructure ; Motor Neurons/*physiology/ultrastructure ; Mutant Proteins/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {Recent studies indicate that molecular signals from microglia determine disease progression in transgenic mice overexpressing mutant superoxide dismutase (mutSOD1) typical of amyotrophic lateral sclerosis patients and that toxicity of mutSOD1 in motor neurons descends from its tendency to associate with mitochondria. To assess whether the neurotoxicity of mutSOD1 is influenced by signals from glia, we challenged motoneuronal cells overexpressing either wild-type or mutant SOD1 with inflammatory cytokines. We have obtained evidence that combined treatment with tumor necrosis factor alpha and interferon gamma increases the fraction of both wtSOD1 and mutSOD1 associated with mitochondria, but these inflammatory cytokines dramatically alter morphological features and functionality of mitochondria only in cells expressing mutSOD1. As an effect downstream the increase in mitochondria-associated mutSOD1, the ratio between reduced and oxidized glutathione further shifts toward the oxidized form in this compartment and a clear death phenotype is evoked upon treatment with inflammatory cytokines. These results suggest that signals coming from non-neuronal cells contribute to death of motor neurons induced by mutSOD1 through reinforcement of mitochondrial damage.}, }
@article {pmid18784263, year = {2008}, author = {Mizuguchi, Y and Chen, J and Seshan, SV and Poppas, DP and Szeto, HH and Felsen, D}, title = {A novel cell-permeable antioxidant peptide decreases renal tubular apoptosis and damage in unilateral ureteral obstruction.}, journal = {American journal of physiology. Renal physiology}, volume = {295}, number = {5}, pages = {F1545-53}, pmid = {18784263}, issn = {1931-857X}, support = {P01-DA-08924/DA/NIDA NIH HHS/United States ; R-01-DK-58355/DK/NIDDK NIH HHS/United States ; R01-DA-073595/DA/NIDA NIH HHS/United States ; }, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Animals ; Antioxidants/pharmacology/therapeutic use ; Apoptosis/*drug effects ; Cell Proliferation/drug effects ; Cytokines/genetics/metabolism ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Fibroblasts/drug effects/metabolism/pathology ; Gene Expression/drug effects ; Heme Oxygenase-1/metabolism ; Intermediate Filament Proteins/metabolism ; Kidney/*drug effects/metabolism/pathology ; Macrophages/drug effects/metabolism/pathology ; Oligopeptides/pharmacology/*therapeutic use ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, CCR1/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factor RelA/genetics/metabolism ; Transforming Growth Factor beta/genetics/metabolism ; Ureteral Obstruction/*drug therapy/metabolism/pathology ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; }, abstract = {Unilateral ureteral obstruction (UUO) is characterized by decreases in renal function, increased interstitial fibrosis, tubular apoptosis, and cellular infiltration. It has been suggested that inhibition of tubular apoptosis may protect against renal damage in obstruction. We have recently developed a series of peptides which are concentrated in the inner mitochondrial membrane and prevent cell death. These peptides are also active in vivo, in myocardial infraction, ischemic brain injury, and amyotrophic lateral sclerosis models. We therefore used SS-31, a prototype of these peptides, and assessed its effects on renal damage and oxidative stress in a 14-day obstruction model. SS-31 (1 or 3 mg/kg) or saline was given 1 day before and throughout the 14 days of obstruction. Kidneys were harvested and assessed for apoptosis (terminal transferase-dUTP-nick-end labeling, caspase 3 expression), fibrosis (trichrome staining), macrophage infiltration, fibroblast expression (immunoperoxidase), and oxidative damage (8-OH deoxyguanosine and heme oxygenase-1 expression), cytokines, and signaling pathways (transforming growth factor-beta, CCR-1, p38-MAPK, NF-kappaB). SS-31 significantly attenuated the effects of obstruction on all aspects of renal damage which were examined, with both the 1 and 3 mg/kg doses showing efficacy. We noted increased oxidative stress in obstruction, which was also attenuated by SS-31 treatment. Signaling via NF-kappaB and p38 MAPK pathways were both affected by SS-31 treatment. This study provides a proof of concept that peptides which protect mitochondria in vitro can provide protection from renal damage in a UUO model. The mechanism by which protection is afforded requires further studies both in vitro and in vivo.}, }
@article {pmid18782012, year = {2008}, author = {Cabral, GA and Griffin-Thomas, L}, title = {Cannabinoids as therapeutic agents for ablating neuroinflammatory disease.}, journal = {Endocrine, metabolic &amp; immune disorders drug targets}, volume = {8}, number = {3}, pages = {159-172}, pmid = {18782012}, issn = {1871-5303}, support = {R01 DA005832/DA/NIDA NIH HHS/United States ; R01 DA005832-14/DA/NIDA NIH HHS/United States ; R01 DA029532/DA/NIDA NIH HHS/United States ; R01 DA05832/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Cannabinoid Receptor Modulators/metabolism/physiology ; Cannabinoids/metabolism/*therapeutic use ; Humans ; Immunity/drug effects ; Inflammation/*drug therapy ; Nervous System Diseases/*drug therapy ; Receptors, Cannabinoid/drug effects ; Signal Transduction/drug effects ; }, abstract = {Cannabinoids have been reported to alter the activities of immune cells in vitro and in vivo. These compounds may serve as ideal agents for adjunct treatment of pathological processes that have a neuroinflammatory component. As highly lipophilic molecules, they readily access the brain. Furthermore, they have relatively low toxicity and can be engineered to selectively target cannabinoid receptors. To date, two cannabinoid receptors have been identified, characterized and designated CB(1) and CB(2). CB(1) appears to be constitutively expressed within the CNS while CB(2) apparently is induced during inflammation. The inducible nature of expression of CB(2) extends to microglia, the resident macrophages of the brain that play a critical role during early stages of inflammation in that compartment. Thus, the cannabinoid-cannabinoid receptor system may prove therapeutically manageable in ablating neuropathogenic disorders such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, HIV encephalitis, closed head injury, and granulomatous amebic encephalitis.}, }
@article {pmid18781981, year = {2008}, author = {Bilsland, LG and Greensmith, L}, title = {The endocannabinoid system in amyotrophic lateral sclerosis.}, journal = {Current pharmaceutical design}, volume = {14}, number = {23}, pages = {2306-2316}, doi = {10.2174/138161208785740081}, pmid = {18781981}, issn = {1873-4286}, support = {G0601943/MRC_/Medical Research Council/United Kingdom ; /CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*physiopathology ; Animals ; Cannabinoid Receptor Modulators/*metabolism ; Cannabinoids/*pharmacology ; Drug Delivery Systems ; *Endocannabinoids ; Humans ; Motor Neurons/pathology ; Neuroprotective Agents/pharmacology ; Receptor, Cannabinoid, CB1/drug effects/metabolism ; Receptor, Cannabinoid, CB2/drug effects/metabolism ; Riluzole/pharmacology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative condition characterised by the selective loss of motor neurons from the spinal cord, brainstem and motor cortex. Although the pathogenic mechanisms that underlie ALS are not yet fully understood, there is significant evidence that several neurotoxic mechanisms including excitotoxicity, inflammation and oxidative stress, all contribute to disease pathogenesis. Furthermore, recent results have established that although primarily a motor neuron specific disorder, ALS is not cell-autonomous and non-neuronal cells including astroglia and microglia play a critical role in mechanism of disease. Currently the only licensed therapy available for the treatment of ALS is the anti-glutamatergic agent Riluzole, which has limited therapeutic effects. However, there is increasing evidence that cannabinoids and manipulation of the endocannabinoid system may have therapeutic value in ALS, in addition to other neurodegenerative conditions. Cannabinoids exert anti-glutamatergic and anti-inflammatory actions through activation of the CB(1) and CB(2) receptors, respectively. Activation of CB(1) receptors may therefore inhibit glutamate release from presynaptic nerve terminals and reduce the postsynaptic calcium influx in response to glutamate receptor stimulation. Meanwhile, CB(2) receptors may influence inflammation, whereby receptor activation reduces microglial activation, resulting in a decrease in microglial secretion of neurotoxic mediators. Finally, cannabinoid agents may also exert anti-oxidant actions by a receptor-independent mechanism. Therefore the ability of cannabinoids to target multiple neurotoxic pathways in different cell populations may increase their therapeutic potential in the treatment of ALS. Recent studies investigating this potential in models of ALS, in particular those that focus on strategies that activate CB(2) receptors, are discussed in this review.}, }
@article {pmid18778111, year = {2008}, author = {Schwartz, M and Bukshpan, S and Kunis, G}, title = {Application of glatiramer acetate to neurodegenerative diseases beyond multiple sclerosis: the need for disease-specific approaches.}, journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy}, volume = {22}, number = {5}, pages = {293-299}, doi = {10.2165/00063030-200822050-00002}, pmid = {18778111}, issn = {1173-8804}, mesh = {Animals ; Autoimmunity ; Brain/immunology ; Glatiramer Acetate ; Humans ; Multiple Sclerosis/*therapy ; Neurodegenerative Diseases/*therapy ; Peptides/adverse effects/*immunology ; T-Lymphocytes/immunology ; *Vaccination ; }, abstract = {Adaptive and innate immunity, if well controlled, contribute to the maintenance of the CNS, as well as to downregulation of adverse acute and chronic neurological conditions. T cells that recognize CNS antigens are needed to activate resident immune cells and to recruit blood-borne monocytes, which act to restore homeostasis and facilitate repair. However, boosting such a T-cell response in a risk-free way requires a careful choice of the antigen, carrier, and regimen. A single vaccination with CNS-derived peptides or their weak agonists reduces neuronal loss in animal models of acute neurodegeneration. Repeated injections are needed to maintain a long-lasting effect in chronic neurodegenerative conditions, yet the frequency of the injections seems to have a critical effect on the outcome. An example is glatiramer acetate, a compound that is administered in a daily regimen to patients with multiple sclerosis. A single injection of glatiramer acetate, with or without an adjuvant, is neuroprotective in some animal models of acute CNS injuries. However, in an animal model of amyotrophic lateral sclerosis, a single injection of adjuvant-free glatiramer acetate is insufficient, while daily injections are not only ineffective but can carry an increased risk of mortality in female mice.Thus, considering immune-based therapies as a single therapy, rather than as a family of therapies that are regimen dependent, may be misleading. Moreover, the vaccination regimen and administration of a compound, even one shown to be safe in humans for the treatment of a particular neurodegenerative disease, must be studied in preclinical experiments before it is tested in a clinical trial for a novel indication; otherwise, an effective drug in a certain regimen for one disease may be ineffective or even carry risks when used for another disorder.}, }
@article {pmid18757636, year = {2008}, author = {Astrow, AB and Sood, JR and Nolan, MT and Terry, PB and Clawson, L and Kub, J and Hughes, M and Sulmasy, DP}, title = {Decision-making in patients with advanced cancer compared with amyotrophic lateral sclerosis.}, journal = {Journal of medical ethics}, volume = {34}, number = {9}, pages = {664-668}, pmid = {18757636}, issn = {1473-4257}, support = {1 R01 NR005224-01A1/NR/NINR NIH HHS/United States ; R01 NR005224-01A1/NR/NINR NIH HHS/United States ; R01 NR005224/NR/NINR NIH HHS/United States ; R01 NR005224-02/NR/NINR NIH HHS/United States ; R01 NR005224-03/NR/NINR NIH HHS/United States ; }, mesh = {Adult ; *Advance Care Planning ; Aged ; Amyotrophic Lateral Sclerosis/psychology/*therapy ; *Decision Making ; Epidemiologic Methods ; Female ; Humans ; Male ; Maryland ; Middle Aged ; Neoplasms/psychology/*therapy ; Terminal Care/*psychology ; Terminally Ill/*psychology ; }, abstract = {AIM: Patients with advanced cancer need information about end-of-life treatment options in order to make informed decisions. Clinicians vary in the frequency with which they initiate these discussions.<br><br>PATIENTS AND METHODS: As part of a long-term longitudinal study, patients with an expected 2-year survival of less than 50% who had advanced gastrointestinal or lung cancer or amyotrophic lateral sclerosis (ALS) were interviewed. Each patient's medical record was reviewed at enrollment and at 3 months for evidence of the discussion of patient wishes concerning ventilator support, artificial nutrition and hydration (ANH), resuscitation (DNR) and hospice care. A Kaplan-Meier analysis was also performed and 2-year survival calculated.<br><br>RESULTS: 60 cancer and 32 ALS patients were enrolled. ALS patients were more likely than cancer patients to have evidence of discussion about their wishes for ventilator support (31% vs 0%, p<0.001), ANH (38% vs 0%, p<0.001), DNR (25% vs 0%, p<0.001) and hospice care (22% vs 5%, p = 0.03). At 6 months, 91% of ALS patients were alive compared with 62% of cancer patients; at 2 years, 63% of ALS patients were alive compared with 23% of cancer patients (p<0.001).<br><br>CONCLUSIONS: Cancer patients were less likely than ALS patients to have had documented advanced care planning discussions despite worse survival. This may reflect perceptions that ALS has a more predictable course, that advanced cancer has a greater number of treatment options, or differing views about hope. Nevertheless, cancer patients may be less adequately prepared for end-of-life decision-making.}, }
@article {pmid18751914, year = {2008}, author = {Adibhatla, RM and Hatcher, JF}, title = {Altered lipid metabolism in brain injury and disorders.}, journal = {Sub-cellular biochemistry}, volume = {49}, number = {}, pages = {241-268}, pmid = {18751914}, issn = {0306-0225}, support = {NS42008/NS/NINDS NIH HHS/United States ; R01 NS042008-04/NS/NINDS NIH HHS/United States ; R01 NS042008-03/NS/NINDS NIH HHS/United States ; R01 NS042008-01A2/NS/NINDS NIH HHS/United States ; R01 NS042008/NS/NINDS NIH HHS/United States ; R01 NS042008-02/NS/NINDS NIH HHS/United States ; }, mesh = {1-Alkyl-2-acetylglycerophosphocholine Esterase/metabolism ; Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Apolipoproteins E/metabolism ; Atherosclerosis/complications/metabolism ; Bipolar Disorder/metabolism ; Brain Diseases/*metabolism ; Brain Injuries/*metabolism ; Central Nervous System Diseases/*metabolism ; Cholesterol/metabolism ; Cytokines/metabolism ; Group II Phospholipases A2/metabolism ; Humans ; Inflammation/physiopathology ; *Lipid Metabolism ; Lipid Peroxidation ; Membrane Lipids/metabolism ; Niemann-Pick Diseases/metabolism ; Oxidative Stress ; Parkinson Disease/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; Risk Factors ; Schizophrenia/metabolism ; Sphingomyelin Phosphodiesterase/metabolism ; Spinal Cord Injuries/metabolism ; Stroke/etiology/metabolism ; }, abstract = {Deregulated lipid metabolism may be of particular importance for CNS injuries and disorders, as this organ has the highest lipid concentration next to adipose tissue. Atherosclerosis (a risk factor for ischemic stroke) results from accumulation of LDL-derived lipids in the arterial wall. Pro-inflammatory cytokines (TNF-alpha and IL-1), secretory phospholipase A2 IIA and lipoprotein-PLA2 are implicated in vascular inflammation. These inflammatory responses promote atherosclerotic plaques, formation and release of the blood clot that can induce ischemic stroke. TNF-alpha and IL-1 alter lipid metabolism and stimulate production of eicosanoids, ceramide, and reactive oxygen species that potentiate CNS injuries and certain neurological disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Low levels of neurosteroids were related to poor outcome in many brain pathologies. Apolipoprotein E is the principal cholesterol carrier protein in the brain, and the gene encoding the variant Apolipoprotein E4 is a significant risk factor for Alzheimer's disease. Parkinson's disease is to some degree caused by lipid peroxidation due to phospholipases activation. Niemann-Pick diseases A and B are due to acidic sphingomyelinase deficiency, resulting in sphingomyelin accumulation, while Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes, resulting in defective cholesterol transport and cholesterol accumulation. Multiple sclerosis is an autoimmune inflammatory demyelinating condition of the CNS. Inhibiting phospholipase A2 attenuated the onset and progression of experimental autoimmune encephalomyelitis. The endocannabinoid system is hypoactive in Huntington's disease. Ethyl-eicosapetaenoate showed promise in clinical trials. Amyotrophic lateral sclerosis causes loss of motorneurons. Cyclooxygenase-2 inhibition reduced spinal neurodegeneration in amyotrophic lateral sclerosis transgenic mice. Eicosapentaenoic acid supplementation provided improvement in schizophrenia patients, while the combination of (eicosapentaenoic acid + docosahexaenoic acid) provided benefit in bipolar disorders. The ketogenic diet where >90% of calories are derived from fat is an effective treatment for epilepsy. Understanding cytokine-induced changes in lipid metabolism will promote novel concepts and steer towards bench-to-bedside transition for therapies.}, }
@article {pmid18721116, year = {2008}, author = {Zarate, CA and Manji, HK}, title = {Riluzole in psychiatry: a systematic review of the literature.}, journal = {Expert opinion on drug metabolism &amp; toxicology}, volume = {4}, number = {9}, pages = {1223-1234}, pmid = {18721116}, issn = {1742-5255}, support = {Z01 MH002828-05/ImNIH/Intramural NIH HHS/United States ; Z01 MH002857-03/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Clinical Trials as Topic ; Dose-Response Relationship, Drug ; Drug Interactions ; Female ; Humans ; Male ; Mental Disorders/*drug therapy ; Neuroprotective Agents/*administration &amp; dosage/adverse effects/pharmacokinetics ; Riluzole/*administration &amp; dosage/adverse effects/pharmacokinetics ; }, abstract = {BACKGROUND: The glutamate system seems to be an important contributor to the pathophysiology of mood and anxiety disorders. Thus, glutamatergic modulators are reasonable candidate drugs to test in patients with mood and anxiety disorders. Riluzole, a neuroprotective agent with anticonvulsant properties approved for the treatment of amyotrophic lateral sclerosis (ALS) is one such agent.<br><br>OBJECTIVE: To assess the potential risks and benefits of riluzole treatment in psychiatric patients.<br><br>METHODS: A PubMed search was performed using the keywords 'riluzole', 'inhibitor of glutamate release' and 'glutamatergic modulator' to identify all clinical studies and case reports involving riluzole in psychiatric patients.<br><br>RESULTS/CONCLUSION: Riluzole's side effect profile is favorable and preliminary results regarding riluzole for the treatment of severe mood, anxiety and impulsive disorders are encouraging.}, }
@article {pmid18719018, year = {2008}, author = {Sullivan, KA and Kim, B and Feldman, EL}, title = {Insulin-like growth factors in the peripheral nervous system.}, journal = {Endocrinology}, volume = {149}, number = {12}, pages = {5963-5971}, pmid = {18719018}, issn = {0013-7227}, support = {U01 DK076160/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Gene Expression ; Humans ; Insulin-Like Growth Factor Binding Proteins/genetics/metabolism/physiology ; Models, Biological ; Peripheral Nervous System/*metabolism/physiology ; Receptors, Somatomedin/genetics/metabolism/physiology ; Signal Transduction/genetics/physiology ; Somatomedins/genetics/*metabolism/physiology ; }, abstract = {IGF-I and -II are potent neuronal mitogens and survival factors. The actions of IGF-I and -II are mediated via the type I IGF receptor (IGF-IR) and IGF binding proteins regulate the bioavailability of the IGFs. Cell viability correlates with IGF-IR expression and intact IGF-I/IGF-IR signaling pathways, including activation of MAPK/phosphatidylinositol-3 kinase. The expression of IGF-I and -II, IGF-IR, and IGF binding proteins are developmentally regulated in the central and peripheral nervous system. IGF-I therapy demonstrates mixed therapeutic results in the treatment of peripheral nerve injury, neuropathy, and motor neuron diseases such as amyotrophic lateral sclerosis. In this review we discuss the role of IGFs during peripheral nervous system development and the IGF signaling system as the potential therapeutic target for the treatment of nerve injury and motor neuron diseases.}, }
@article {pmid18718468, year = {2008}, author = {Ito, H and Wate, R and Zhang, J and Ohnishi, S and Kaneko, S and Ito, H and Nakano, S and Kusaka, H}, title = {Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice.}, journal = {Experimental neurology}, volume = {213}, number = {2}, pages = {448-455}, doi = {10.1016/j.expneurol.2008.07.017}, pmid = {18718468}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*enzymology ; Animals ; Antipyrine/administration &amp; dosage/*analogs &amp; derivatives ; Edaravone ; Female ; Humans ; Male ; Mice ; Mice, Transgenic ; Motor Skills/*drug effects/*physiology ; Motor Skills Disorders/drug therapy/enzymology ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; Time Factors ; }, abstract = {Edaravone is a free-radical scavenger, an agent being widely used for cerebral ischemia in Japan. To evaluate its efficacy for possible treatment of amyotrophic lateral sclerosis (ALS), we performed a randomized blind trial in ALS model mice. After identification of the clinical onset in each female G93A mutant SOD1 transgenic mouse, we intraperitoneally administered multiple doses of edaravone to the mice and observed their motor symptoms. We also counted the number of lumbar motoneurons, determined the 3-nitrotyrosine/tyrosine ratio, and evaluated the abnormal SOD1 aggregation in the spinal cord at the 10th day after the edaravone injection. Edaravone significantly slowed the motor decline of the transgenic mice. The remaining motoneurons were significantly preserved in the higher-dose edaravone-administered group, and the 3-nitrotyrosine/tyrosine ratios were reduced dose-dependently. Intriguingly, the area of abnormal SOD1 deposition in the spinal cord was significantly decreased in the higher-dose edaravone-administered group. Our results indicate that edaravone was effective to slow symptom progression and motor neuron degeneration in the ALS model mice. These favorable actions might be attributable to the yet unidentified mechanism responsible for reducing the deposition of mutant SOD1.}, }
@article {pmid18717831, year = {2008}, author = {Panah, FG and Rezai, SM and Ahmadian, L}, title = {The influence of ceramic surface treatments on the micro-shear bond strength of composite resin to IPS Empress 2.}, journal = {Journal of prosthodontics : official journal of the American College of Prosthodontists}, volume = {17}, number = {5}, pages = {409-414}, doi = {10.1111/j.1532-849X.2007.00296.x}, pmid = {18717831}, issn = {1532-849X}, mesh = {Air Abrasion, Dental ; Analysis of Variance ; *Composite Resins ; *Dental Bonding ; Dental Etching/methods ; *Dental Porcelain ; Dental Stress Analysis ; Equipment Failure Analysis ; Lithium Compounds ; Microscopy, Electron, Scanning ; Resin Cements ; Shear Strength ; Silanes ; Surface Properties ; }, abstract = {PURPOSE: An increasing demand for esthetic restorations has resulted in the development of new ceramic systems, but fracture of veneering ceramics still remains the primary cause of failure. Porcelain repair frequently involves replacement with composite resin, but the bond strength between composite resin and all-ceramic coping materials has not been studied extensively. The purpose of this study was to evaluate the influence of different ceramic surface treatments on the micro-shear bond strength of composite resin to IPS Empress 2 coping material.<br><br>MATERIALS AND METHODS: Sixteen 7 x 7 x 1 mm(3) lithia disilicate-based core ceramic plates were fabricated using the lost wax technique. The plates were divided into eight groups, and eight different surface treatments were performed: (1) no treatment (NT); (2) airborne-particle abrasion with 50-mum alumina particles (Al); (3) acid etching with 9.6% hydrofluoric acid for 1 min (HF); (4) silane coating (S); (5) AlHF; (6) AlS; (7) HFS; and (8) AlHFS. Then, ten composite resin cylinders (0.8-mm diameter x 0.5-mm height) were light-polymerized onto the ceramic plates in each group. Each specimen was subjected to a shear load at a crosshead speed of 0.5 mm/min until fracture occurred. The fracture sites were examined with scanning electron microscopy (SEM) to determine the location of failure during debonding and to examine the surface treatment effects. One-way analysis of variance (ANOVA) and multiple comparison (Dunnet T3) tests were used for statistical analysis of data.<br><br>RESULTS: The mean micro-shear bond strength values (SD) in MPa were--NT: 4.10 (3.06), Al: 7.56 (4.11), HF: 14.04 (2.60), S: 14.58 (2.14), AlHF: 15.56 (3.36), AlS: 23.02 (4.17), HFS: 24.7 (4.43), AlHFS: 26.0 (3.71). ANOVA indicated the influence of surface treatment was significant (p < 0.0001). SEM analysis did not reveal entirely cohesive failure in any composite or ceramic.<br><br>CONCLUSION: The micro-shear bond strength of a composite resin to IPS Empress 2 was significantly different depending on the surface treatment method. Among the investigated methods, silane coating after airborne-particle abrasion and etching was the most effective surface treatment in terms of bond strength increase.}, }
@article {pmid18704227, year = {2008}, author = {Sarkar, S and Rubinsztein, DC}, title = {Small molecule enhancers of autophagy for neurodegenerative diseases.}, journal = {Molecular bioSystems}, volume = {4}, number = {9}, pages = {895-901}, doi = {10.1039/b804606a}, pmid = {18704227}, issn = {1742-2051}, support = {064354/WT_/Wellcome Trust/United Kingdom ; G0600194/MRC_/Medical Research Council/United Kingdom ; G0600194(77639)/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Autophagy/*physiology ; Inositol/metabolism ; Models, Biological ; Neurodegenerative Diseases/*metabolism/therapy ; Protein Folding ; Protein Kinases/metabolism ; Proteins/chemistry/metabolism ; Signal Transduction ; Sirolimus/metabolism ; TOR Serine-Threonine Kinases ; Trehalose/metabolism ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, prion diseases and polyglutamine disorders, including Huntington's disease and various spinocerebellar ataxias, are associated with the formation of protein aggregates. These aggregates and/or their precursors are thought to be toxic disease-causing species. Autophagy is a major degradation pathway for intracytosolic aggregate-prone proteins, including those associated with neurodegeneration. It is a constitutive self-degradative process involved both in the basal turnover of cellular components and in response to nutrient starvation in eukaryotes. Enhancing autophagy may be a possible therapeutic strategy for neurodegenerative disorders where the mutant proteins are autophagy substrates. In cell and animal models, chemical induction of autophagy protects against the toxic insults of these mutant aggregate-prone proteins by enhancing their clearance. We will discuss various autophagy-inducing small molecules that have emerged in the past few years that may be leads towards the treatment of such devastating diseases.}, }
@article {pmid18700928, year = {2008}, author = {Schober, MS and Chidlow, G and Wood, JP and Casson, RJ}, title = {Bioenergetic-based neuroprotection and glaucoma.}, journal = {Clinical &amp; experimental ophthalmology}, volume = {36}, number = {4}, pages = {377-385}, doi = {10.1111/j.1442-9071.2008.01740.x}, pmid = {18700928}, issn = {1442-9071}, mesh = {Animals ; Calcium/metabolism ; Cell Death ; Energy Metabolism/*drug effects ; Free Radical Scavengers/therapeutic use ; Glaucoma/*etiology/physiopathology/*prevention &amp; control ; Glucose/metabolism ; Humans ; Lactic Acid/metabolism ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Permeability Transition Pore ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress ; Retina/*metabolism ; Retinal Ganglion Cells ; }, abstract = {Primary open-angle glaucoma (POAG) is a pressure-sensitive optic neuropathy which results in the death of retinal ganglion cells and causes associated loss of vision. Presently, the only accepted treatment strategy is to lower the intraocular pressure; however, for some patients this is insufficient to prevent progressive disease. Although the pathogenesis of POAG remains unclear, there is considerable evidence that energy failure at the optic nerve head may be involved. Neuroprotection, a strategy which directly enhances the survival of neurons, is desirable, but remains clinically elusive. One particular form of neuroprotection involves the notion of enhancing the energy supply of neurons. These 'bioenergetic' methods of neuroprotection have proven successful in animal models of other neurodegenerative diseases and conditions, including Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and traumatic brain injury, but have been relatively unexplored in glaucoma models. This review focuses on some of the potential approaches for bioenergetic neuroprotection in the retina, including increasing the energy buffering capacity of damaged cells, decreasing the permeability of the mitochondrial membrane pore and free radical scavenging.}, }
@article {pmid18698875, year = {2008}, author = {Pittenger, C and Coric, V and Banasr, M and Bloch, M and Krystal, JH and Sanacora, G}, title = {Riluzole in the treatment of mood and anxiety disorders.}, journal = {CNS drugs}, volume = {22}, number = {9}, pages = {761-786}, pmid = {18698875}, issn = {1172-7047}, support = {T32 MH019961/MH/NIMH NIH HHS/United States ; T32-MH19961/MH/NIMH NIH HHS/United States ; }, mesh = {Animals ; Anxiety Disorders/*drug therapy ; Excitatory Amino Acid Antagonists/pharmacology/*therapeutic use ; Humans ; Models, Biological ; Mood Disorders/*drug therapy ; Nervous System Diseases/drug therapy ; Receptors, Glutamate/physiology ; Riluzole/pharmacology/*therapeutic use ; }, abstract = {Recent advances implicate amino acid neurotransmission in the pathophysiology and treatment of mood and anxiety disorders. Riluzole, which is approved and marketed for the treatment of amyotrophic lateral sclerosis, is thought to be neuroprotective through its modulation of glutamatergic neurotransmission. Riluzole has multiple molecular actions in vitro; the two that have been documented to occur at physiologically realistic drug concentrations and are therefore most likely to be clinically relevant are inhibition of certain voltage-gated sodium channels, which can lead to reduced neurotransmitter release, and enhanced astrocytic uptake of extracellular glutamate.Although double-blind, placebo-controlled trials are lacking, several open-label trials have suggested that riluzole, either as monotherapy or as augmentation of standard therapy, reduces symptoms of obsessive-compulsive disorder, unipolar and bipolar depression, and generalized anxiety disorder. In studies of psychiatrically ill patients conducted to date, the drug has been quite well tolerated; common adverse effects include nausea and sedation. Elevation of liver function tests is common and necessitates periodic monitoring, but has been without clinical consequence in studies conducted to date in psychiatric populations. Case reports suggest utility in other conditions, including trichotillomania and self-injurious behaviour associated with borderline personality disorder. Riluzole may hold promise for the treatment of several psychiatric conditions, possibly through its ability to modulate pathologically dysregulated glutamate levels, and merits further investigation.}, }
@article {pmid18697338, year = {2008}, author = {Camu, W}, title = {[Epidemiology and treatment of amyotrophic lateral sclerosis].}, journal = {Soins; la revue de reference infirmiere}, volume = {}, number = {726}, pages = {40-43}, pmid = {18697338}, issn = {0038-0814}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*epidemiology/etiology/*therapy ; Causality ; Diagnosis, Differential ; Excitatory Amino Acid Antagonists/therapeutic use ; France/epidemiology ; Humans ; Incidence ; Palliative Care/organization &amp; administration ; Patient Care Team/organization &amp; administration ; Prevalence ; Prognosis ; Riluzole/therapeutic use ; }, }
@article {pmid18691571, year = {2008}, author = {Morita, E and Watanabe, Y and Ishimoto, M and Nakano, T and Kitayama, M and Yasui, K and Fukada, Y and Doi, K and Karunaratne, A and Murrell, WG and Sutharsan, R and Mackay-Sim, A and Hata, Y and Nakashima, K}, title = {A novel cell transplantation protocol and its application to an ALS mouse model.}, journal = {Experimental neurology}, volume = {213}, number = {2}, pages = {431-438}, doi = {10.1016/j.expneurol.2008.07.011}, pmid = {18691571}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*surgery ; Animals ; Cell Transplantation/methods/trends ; Cells, Cultured ; *Disease Models, Animal ; Female ; Male ; Mesenchymal Stem Cell Transplantation/*methods/trends ; Mesenchymal Stem Cells/cytology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Olfactory Mucosa/cytology/transplantation ; Rats ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease, which selectively affects motor neurons throughout the central nervous system. The extensive distribution of motor neurons is an obstacle to applying cell transplantation therapy for the treatment of ALS. To overcome this problem, we developed a cell transplantation method via the fourth cerebral ventricle in mice. We used mouse olfactory ensheathing cells (OECs) and rat mesenchymal stem cells (MSCs) as donor cells. OECs are reported to promote regeneration and remyelination in the spinal cord, while MSCs have a capability to differentiate into several types of specific cells including neural cells. Furthermore both types of cells can be relatively easily obtained by biopsy in human. Initially, we confirmed the safety of the operative procedure and broad distribution of grafted cells in the spinal cord using wild-type mice. After transplantation, OECs distributed widely and survived as long as 100 days after transplantation, with a time-dependent depletion of cell number. In ALS model mice, OEC transplantation revealed no adverse effects but no significant differences in clinical evaluation were found between OEC-treated and non-transplanted animals. After MSC transplantation into the ALS model mice, females, but not males, showed a statistically longer disease duration than the non-transplanted controls. We conclude that intrathecal transplantation could be a promising way to deliver donor cells to the central nervous system. Further experiments to elucidate relevant conditions for optimal outcomes are required.}, }
@article {pmid18688762, year = {2009}, author = {Cudkowicz, ME and Andres, PL and Macdonald, SA and Bedlack, RS and Choudry, R and Brown, RH and Zhang, H and Schoenfeld, DA and Shefner, J and Matson, S and Matson, WR and Ferrante, RJ and , }, title = {Phase 2 study of sodium phenylbutyrate in ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {2}, pages = {99-106}, doi = {10.1080/17482960802320487}, pmid = {18688762}, issn = {1471-180X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Anticonvulsants/administration &amp; dosage/blood ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Enzyme Inhibitors/*administration &amp; dosage/adverse effects/*pharmacokinetics ; Female ; *Histone Deacetylase Inhibitors ; Histone Deacetylases/metabolism ; Humans ; Male ; Middle Aged ; Motor Neurons/drug effects/enzymology ; Phenylacetates/administration &amp; dosage/blood ; Phenylbutyrates/*administration &amp; dosage/adverse effects/*pharmacokinetics ; }, abstract = {The objective of the study was to establish the safety and pharmacodynamics of escalating dosages of sodium phenylbutyrate (NaPB) in participants with ALS. Transcription dysregulation may play a role in the pathogenesis of ALS. Sodium phenylbutyrate, a histone deacetylase inhibitor, improves transcription and post-transcriptional pathways, promoting cell survival in a mouse model of motor neuron disease. Forty research participants at eight sites enrolled in an open-label study. Study medication was increased from 9 to 21 g/day. The primary outcome measure was tolerability. Secondary outcome measures included adverse events, blood histone acetylation levels, and NaPB blood levels at each dosage. Twenty-six participants completed the 20-week treatment phase. NaPB was safe and tolerable. No study deaths or clinically relevant laboratory changes occurred with NaPB treatment. Histone acetylation was decreased by approximately 50% in blood buffy-coat specimens at screening and was significantly increased after NaPB administration. Blood levels of NaPB and the primary metabolite, phenylacetate, increased with dosage. While the majority of subjects tolerated higher dosages of NaPB, the lowest dose (9 g/day), was therapeutically efficient in improving histone acetylation levels.}, }
@article {pmid18685417, year = {2008}, author = {Tripodoro, VA and De Vito, EL}, title = {Management of dyspnea in advanced motor neuron diseases.}, journal = {Current opinion in supportive and palliative care}, volume = {2}, number = {3}, pages = {173-179}, doi = {10.1097/SPC.0b013e32830c9049}, pmid = {18685417}, issn = {1751-4266}, mesh = {Advance Directives ; Dyspnea/etiology/*therapy ; Humans ; Motor Neuron Disease/*complications ; Positive-Pressure Respiration/*methods ; Terminal Care/organization &amp; administration ; }, abstract = {PURPOSE OF REVIEW: Patients with amyotrophic lateral sclerosis or motor neuron disease (ALS/MND) invariably develop respiratory muscle weakness and most die from pulmonary complications. Little evidence is available that identifies optimal management approaches for caring for the dying patient. This review discusses the state of the art on dyspnea in advanced ALS/MND and its treatment.<br><br>RECENT FINDINGS: Multiple observational studies have demonstrated that noninvasive positive pressure ventilation is beneficial in ALS/MND. It is a relatively safe intervention in the late stages of disease with additional survival benefits when it is started relatively early and it can improve survival. Despite guidelines related to pulmonary function testing about the use of noninvasive positive pressure ventilation, the factors, which are most closely associated with noninvasive positive pressure ventilation utilization, are dyspnea and orthopnea.<br><br>SUMMARY: In ALS/MND, loss of function relentlessly progresses, and subsequent death occurs mostly in a predictable manner. Therefore, the end of life care is heavily influenced by the type and quality of care provided from the earliest stages. Most patients with ALS/MND develop dyspnea, agitation, anxiety and air hunger in the final phase. Noninvasive positive pressure ventilation has become the standard of care for patients with ALS/MND and advanced respiratory insufficiency. A multidisciplinary approach is strongly recommended.}, }
@article {pmid18684235, year = {2008}, author = {Rocha-González, HI and Ambriz-Tututi, M and Granados-Soto, V}, title = {Resveratrol: a natural compound with pharmacological potential in neurodegenerative diseases.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {14}, number = {3}, pages = {234-247}, pmid = {18684235}, issn = {1755-5930}, mesh = {Animals ; Humans ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/chemistry/pharmacokinetics/*pharmacology ; Pain/drug therapy ; Resveratrol ; Sesquiterpenes ; Stilbenes/chemistry/pharmacokinetics/*pharmacology ; Terpenes/*pharmacology ; Phytoalexins ; }, abstract = {Resveratrol is a phytoalexin structurally related to stilbenes, which is synthesized in considerable amounts in the skin of grapes, raspberries, mulberries, pistachios and peanuts, and by at least 72 medicinal and edible plant species in response to stress conditions. It was isolated in 1940 and did not maintain much interest for around five decades until its role in treatment of cardiovascular diseases was suggested. To date, resveratrol has been identified as an agent that may be useful to treat cancer, pain, inflammation, tissue injury, and other diseases. However, currently the attention is being focused in analyzing its properties against neurodegenerative diseases and as antiaging compound. It has been reported that resveratrol shows effects in in vitro models of epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and nerve injury. However, evidences in vivo as well as in human beings are still lacking. Thus, further investigations on the pharmacological effects of resveratrol in vivo are necessary before any conclusions on its effects on neurodegenerative diseases can be obtained.}, }
@article {pmid18682744, year = {2008}, author = {Yang, J and Bridges, K and Chen, KY and Liu, AY}, title = {Riluzole increases the amount of latent HSF1 for an amplified heat shock response and cytoprotection.}, journal = {PloS one}, volume = {3}, number = {8}, pages = {e2864}, pmid = {18682744}, issn = {1932-6203}, mesh = {Cell Survival/drug effects ; DNA-Binding Proteins/biosynthesis/*genetics ; Excitatory Amino Acid Agonists/pharmacology ; Genes, Reporter ; HeLa Cells ; Heat Shock Transcription Factors ; Hot Temperature ; Humans ; Luciferases/genetics ; Neurodegenerative Diseases/drug therapy/physiopathology ; Neurons/drug effects/physiology ; Riluzole/*pharmacology ; Spinal Cord/embryology/physiology ; Transcription Factors/biosynthesis/*genetics ; }, abstract = {BACKGROUND: Induction of the heat shock response (HSR) and increased expression of the heat shock proteins (HSPs) provide mechanisms to ensure proper protein folding, trafficking, and disposition. The importance of HSPs is underscored by the understanding that protein mis-folding and aggregation contribute centrally to the pathogenesis of neurodegenerative diseases.<br><br>We used a cell-based hsp70-luciferease reporter gene assay system to identify agents that modulate the HSR and show here that clinically relevant concentrations of the FDA-approved ALS drug riluzole significantly increased the heat shock induction of hsp70-luciferse reporter gene. Immuno-Western and -cytochemical analysis of HSF1 show that riluzole increased the amount of cytosolic HSF1 to afford a greater activation of HSF1 upon heat shock. The increased HSF1 contributed centrally to the cytoprotective activity of riluzole as hsf1 gene knockout negated the synergistic activity of riluzole and conditioning heat shock to confer cell survival under oxidative stress. Evidence of a post-transcriptional mechanism for the increase in HSF1 include: quantitation of mRNA(hsf1) by RT-PCR showed no effect of either heat shock or riluzole treatment; riluzole also increased the expression of HSF1 from a CMV-promoter; analysis of the turnover of HSF1 by pulse chase and immunoprecipitation show that riluzole slowed the decay of [(35)S]labeled-HSF1. The effect of riluzole on HSF1 was qualitatively different from that of MG132 and chloroquine, inhibitors of the proteasome and lysosome, respectively, and appeared to involve the chaperone-mediated autophagy pathway as RNAi-mediated knockdown of CMA negated its effect.<br><br>CONCLUSION/SIGNIFICANCE: We show that riluzole increased the amount of HSF1 to amplify the HSR for cytoprotection. Our study provides novel insight into the mechanism that regulates HSF1 turnover, and identifies the degradation of HSF1 as a target for therapeutics intervention.}, }
@article {pmid18678378, year = {2008}, author = {Drory, VE and Bronipolsky, T and Artamonov, I and Nefussy, B}, title = {Influence of statins treatment on survival in patients with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {273}, number = {1-2}, pages = {81-83}, doi = {10.1016/j.jns.2008.06.022}, pmid = {18678378}, issn = {0022-510X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/*mortality ; Female ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*adverse effects ; Longitudinal Studies ; Male ; Middle Aged ; Proportional Hazards Models ; Retrospective Studies ; Survival Analysis ; }, abstract = {BACKGROUND: Statins are increasingly recognized as causing muscle damage and, more rarely, peripheral neuropathy. A preliminary report that there are more cases of amyotrophic lateral sclerosis (ALS) among people treated with statins caused considerable concern. We considered the possibility that statins could affect survival in patients already diagnosed as having amyotropic lateral sclerosis who were taking statins for dyslipidemia.<br><br>METHODS: We reviewed the clinical charts of 459 patients with ALS followed-up in our clinic between 1997 and 2007. Retrieved data included age, all administered medications, form of ALS at onset and survival. We compared the survival rates of patients taking any statins with that of patients not taking statins, while adjusting for other factors which influence disease progression, such as age, gender and ALS form at onset.<br><br>RESULTS: 72 patients were on statins for dyslipidemia at disease onset. The doses ranged from 10-60 mg daily and varied throughout the disease course. As expected, the patients on statins were older than the non-treated ones (65.7+/-9 versus 57.5+/-13 years, respectively). After correcting for age, gender and disease form, there was no significant difference in survival between the groups.<br><br>CONCLUSION: Our findings indicate that statins treatment for dyslipidemia in patients with ALS does not carry any survival risks.}, }
@article {pmid18673445, year = {2008}, author = {Kalmar, B and Novoselov, S and Gray, A and Cheetham, ME and Margulis, B and Greensmith, L}, title = {Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1 mouse model of ALS.}, journal = {Journal of neurochemistry}, volume = {107}, number = {2}, pages = {339-350}, doi = {10.1111/j.1471-4159.2008.05595.x}, pmid = {18673445}, issn = {1471-4159}, support = {G0401350/MRC_/Medical Research Council/United Kingdom ; G0601943/MRC_/Medical Research Council/United Kingdom ; G0700412/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*metabolism/pathology ; Animals ; Disease Models, Animal ; Disease Progression ; Female ; HSP70 Heat-Shock Proteins/*metabolism ; Humans ; Hydroxylamines/*therapeutic use ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/physiology ; Muscle, Skeletal/drug effects/pathology/physiopathology ; Spinal Cord/pathology ; Statistics, Nonparametric ; Superoxide Dismutase/genetics ; Survival Analysis ; Ubiquitin/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motoneuron degeneration, resulting in muscle paralysis and death, typically within 1-5 years of diagnosis. Although the pathogenesis of ALS remains unclear, there is evidence for the involvement of proteasome dysfunction and heat shock proteins in the disease. We have previously shown that treatment with a co-inducer of the heat shock response called arimoclomol is effective in the SOD(G93A) mouse model of ALS, delaying disease progression and extending the lifespan of SOD(G93A) mice (Kieran et al. 2004). However, this previous study only examined the effects arimoclomol when treatment was initiated in pre- or early symptomatic stages of the disease. Clearly, to be of benefit to the majority of ALS patients, any therapy must be effective after symptom onset. In order to establish whether post-symptomatic treatment with arimoclomol is effective, in this study we carried out a systematic assessment of different treatment regimes in SOD(G93A) mice. Treatment with arimoclomol from early (75 days) or late (90 days) symptomatic stages significantly improved muscle function. Treatment from 75 days also significantly increased the lifespan of SOD(G93A) mice, although treatment from 90 days has no significant effect on lifespan. The mechanism of action of arimoclomol involves potentiation of the heat shock response, and treatment with arimoclomol increased Hsp70 expression. Interestingly, this up-regulation in Hsp70 was accompanied by a decrease in the number of ubiquitin-positive aggregates in the spinal cord of treated SOD(G93A) mice, suggesting that arimoclomol directly effects protein aggregation and degradation.}, }
@article {pmid18673377, year = {2008}, author = {Huang, H and Chen, L and Xi, H and Wang, H and Zhang, J and Zhang, F and Liu, Y}, title = {Fetal olfactory ensheathing cells transplantation in amyotrophic lateral sclerosis patients: a controlled pilot study.}, journal = {Clinical transplantation}, volume = {22}, number = {6}, pages = {710-718}, doi = {10.1111/j.1399-0012.2008.00865.x}, pmid = {18673377}, issn = {1399-0012}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*therapy ; *Cell Transplantation ; Cells, Cultured ; Female ; *Fetal Tissue Transplantation ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Olfactory Bulb/cytology/metabolism/*transplantation ; Pilot Projects ; Receptor, Nerve Growth Factor/metabolism ; Young Adult ; }, abstract = {This study was designed to clarify whether transplantation of fetal olfactory ensheathing cells (OECs) would affect the clinical course of patients with amyotrophic lateral sclerosis (ALS). Thirty-five patients with probable or definite ALS were enrolled from December 2004 to September 2006; 15 patients received OECs transplantation and 20 patients did not receive OECs transplantation. OECs were cultured and injected into the bilateral corona radiata involving the pyramidal tracts of the frontal lobes. The primary end point used to indicate effectiveness was the rate of change according to the ALS Functional Rating Scale (ALS-FRS) total score. All patients were tested five times at baseline and monthly intervals during a four-month follow-up period using assessment of ALS-FRS. Thirty-one patients (14 in the OECs treated group and 17 in the controls) completed the four-month study; the remaining four patients were lost to follow-up. Patients' data were analyzed four months after OECs transplantation and at the end of the controlled period. There was no significant difference in the rate of progression as measured by the ALS-FRS total score during the first two months (p > 0.05). The functional deterioration, however, was significantly slower in the treated group than in the control group during the last two months (p < 0.05). The mean (+/-SD) change for the ALS-FRS total score was 0.07 +/- 4.18 for the treated group and 6.12 +/- 5.49 for the control group (p = 0.002) during the four months. Of the 14 patients in the treatment group, seven experienced neurological functional improvements, two were stable compared with their clinical status at entry, and the ALS-FRS scores in the other five decreased by a mean of 4.4. Of the 17 patients in the control group, only one patient's condition remained stable while the ALS-FRS scores in the other 16 decreased by a mean of 6.5. The result indicates OECs transplantation appears to be able to slow the rate of clinical progression of ALS in the first four months posttransplantation.}, }
@article {pmid18646122, year = {2008}, author = {Brettschneider, J and Kurent, J and Ludolph, A and Mitchell, JD}, title = {Drug therapy for pain in amyotrophic lateral sclerosis or motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {3}, pages = {CD005226}, doi = {10.1002/14651858.CD005226.pub2}, pmid = {18646122}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Motor Neuron Disease/complications ; Pain/*drug therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is the most common neurodegenerative disorder of the motor system in adults. Pain in ALS is a frequent symptom especially in the later stages of disease and can have a pronounced influence on quality of life and suffering. Treatment of pain therefore should be recognised as an important aspect of palliative care in ALS.<br><br>OBJECTIVES: To systematically review the evidence for the efficacy of drug therapy in relieving pain in ALS. We also aimed to evaluate possible adverse effects associated with the different drugs and their influence on survival and quality of life.<br><br>SEARCH STRATEGY: The authors searched the following databases: the Cochrane Neuromuscular Disease Group Trials Register (October 2007), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 1), MEDLINE (January 1966 to October 2007), EMBASE (January 1980 to October 2007), CINAHL (January 1982 to October 2007), AMED (January 1985 to October 2007) and LILACS (January 1982 to October 2007). We checked the bibliographies of trials identified and contacted other disease experts to identify further published and unpublished trials.<br><br>SELECTION CRITERIA: We searched for randomised or quasi-randomised controlled trials on drug therapy for pain in amyotrophic lateral sclerosis.<br><br>DATA COLLECTION AND ANALYSIS: Data were collected using a specially designed form and analysed using the Cochrane Review Manager software.<br><br>MAIN RESULTS: No randomised or quasi-randomised controlled trials on drug therapy for pain in ALS or MND were found.<br><br>AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials about the management of pain in ALS. Further research on this important aspect of palliative care in ALS is needed. Randomised controlled trials should be initiated to determine the effectiveness of different analgesics for treatment of pain in ALS.}, }
@article {pmid18645613, year = {2008}, author = {Kummer, MP and Heneka, MT}, title = {PPARs in Alzheimer's Disease.}, journal = {PPAR research}, volume = {2008}, number = {}, pages = {403896}, pmid = {18645613}, issn = {1687-4757}, abstract = {Peroxisome proliferator-activated receptors (PPARs) are well studied for their peripheral physiological and pathological impact, but they also play an important role for the pathogenesis of various disorders of the central nervous system (CNS) like multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the neurodegeneration and the deposition of the beta-amyloid peptide in extracellular plaques. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARgamma. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARgamma. Several lines of evidence have supported this hypothesis, using AD-related transgenic cellular and animal models. Stimulation of PPARgamma receptors by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic, and insulin sensitising effects may account for the observed effects. Several clinical trials already revealed promising results using PPAR agonists, therefore PPARs represent an attractive therapeutic target for the treatment of AD.}, }
@article {pmid18640245, year = {2008}, author = {Feng, HL and Leng, Y and Ma, CH and Zhang, J and Ren, M and Chuang, DM}, title = {Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model.}, journal = {Neuroscience}, volume = {155}, number = {3}, pages = {567-572}, pmid = {18640245}, issn = {0306-4522}, support = {Z01 MH002468-20/ImNIH/Intramural NIH HHS/United States ; Z99 MH999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Adjuvants, Immunologic/*therapeutic use ; Age Factors ; Amyotrophic Lateral Sclerosis/complications/*drug therapy/genetics/mortality ; Animals ; Anticonvulsants/*therapeutic use ; Behavior, Animal/drug effects ; Disease Models, Animal ; Drug Therapy, Combination ; Glycogen Synthase Kinase 3/metabolism ; Hindlimb Suspension/methods ; Humans ; Lithium Chloride/*therapeutic use ; Mice ; Mice, Transgenic ; Motor Activity/drug effects ; Muscle Strength/drug effects ; Mutation ; Nervous System Diseases/*drug therapy/etiology ; Psychomotor Performance/drug effects ; Reflex/drug effects ; Rotarod Performance Test/methods ; Superoxide Dismutase/genetics ; Survival Analysis ; Valproic Acid/*therapeutic use ; }, abstract = {Lithium and valproic acid (VPA) are two primary drugs used to treat bipolar disorder, and have been shown to have neuroprotective properties in vivo and in vitro. A recent study demonstrated that combined treatment with lithium and VPA elicits synergistic neuroprotective effects against glutamate excitotoxicity in cultured brain neurons, and the synergy involves potentiated inhibition of glycogen synthase kinase-3 (GSK-3) activity through enhanced GSK-3 serine phosphorylation [Leng Y, Liang MH, Ren M, Marinova Z, Leeds P, Chuang DM (2008) Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition. J Neurosci 28:2576-2588]. We therefore investigated the effects of lithium and VPA cotreatment on the disease symptom onset, survival time and neurological deficits in cooper zinc superoxide dismutase (SOD1) G93A mutant mice, a commonly used mouse model of amyotrophic lateral sclerosis (ALS). The G93A ALS mice received twice daily i.p. injections with LiCl (60 mg/kg), VPA (300 mg/kg) or lithium plus VPA, starting from the 30(th) day after birth and continuing until death. We found that combined treatment with lithium and VPA produced a greater and more consistent effect in delaying the onset of disease symptoms, prolonging the lifespan and decreasing the neurological deficit scores, compared with the results of monotreatment with lithium or VPA. Moreover, lithium in conjunction with VPA was more effective than lithium or VPA alone in enhancing the immunostaining of phospho-GSK-3beta(Ser9) in brain and lumbar spinal cord sections. To our knowledge, this is the first demonstration of enhanced neuroprotection by a combinatorial approach using mood stabilizers in a mouse ALS model. Our results suggest that clinical trials using lithium and VPA in combination for ALS patients are a rational strategy.}, }
@article {pmid18637059, year = {2008}, author = {Hiramatsu, A and Takahashi, S and Aikata, H and Azakami, T and Katamura, Y and Kawaoka, T and Uka, K and Yamashina, K and Takaki, S and Kodama, H and Jeong, SC and Imamura, M and Kawakami, Y and Chayama, K}, title = {Etiology and outcome of acute liver failure: retrospective analysis of 50 patients treated at a single center.}, journal = {Journal of gastroenterology and hepatology}, volume = {23}, number = {8 Pt 1}, pages = {1216-1222}, doi = {10.1111/j.1440-1746.2008.05402.x}, pmid = {18637059}, issn = {1440-1746}, mesh = {Adult ; Female ; Humans ; Liver Failure, Acute/*etiology/*therapy ; *Liver Transplantation ; *Liver, Artificial ; Male ; Middle Aged ; Retrospective Studies ; Treatment Outcome ; }, abstract = {BACKGROUND AND AIM: Acute liver failure (ALF) remains a devastating disease carrying considerable mortality. Since deceased donor liver transplantation is rarely performed in Japan, the artificial liver support system (ALS) and living donor liver transplantation (LDLT) are the main modalities used for treatment of ALF. The aim of this study was to analyze the outcome of ALF patients and to evaluate therapies for ALF according to etiology.<br><br>METHODS: Fifty consecutive patients with ALF were treated between January 1990 and December 2006. Prior to 1997, patients received ALS only. After 1997, ALS and/or LDLT were applied. LDLT was performed in 10 patients.<br><br>RESULTS: Four of 15 (27%) pre-1997 ALF patients survived, and 16 of 35 (46%) post-1997 ALF patients survived, including eight who underwent LDLT. The causes of ALF were acute hepatitis B virus (HBV) infection in 18%, severe acute exacerbation (SAE) of chronic HBV infection in 18%, autoimmune hepatitis (AIH) in 8%, and cryptogenic hepatitis in 44%. In total, 67% of the patients with ALF caused by acute HBV infection and AIH were cured without LDLT; only 11% of patients with ALF caused by SAE of HBV and 24% of cryptogenic hepatitis were successfully treated without LDLT. Notably, 80% of patients with cryptogenic hepatitis who underwent LDLT survived.<br><br>CONCLUSION: Since 1997, the survival rate of ALF patients has increased, mainly due to the introduction of LDLT. Liver transplantation should be performed especially in patients with ALF caused by SAE of HBV and cryptogenic hepatitis.}, }
@article {pmid18634762, year = {2008}, author = {Rohn, TT}, title = {Caspase-cleaved TAR DNA-binding protein-43 is a major pathological finding in Alzheimer's disease.}, journal = {Brain research}, volume = {1228}, number = {}, pages = {189-198}, pmid = {18634762}, issn = {0006-8993}, support = {P20 RR016454/RR/NCRR NIH HHS/United States ; P20 RR016454-066710/RR/NCRR NIH HHS/United States ; P20 RR016454-076944/RR/NCRR NIH HHS/United States ; P20RR016454/RR/NCRR NIH HHS/United States ; }, mesh = {Alzheimer Disease/*metabolism/pathology ; Animals ; Autopsy ; Blotting, Western ; Brain/*metabolism/pathology ; Caspases/*metabolism ; Cell Line, Tumor ; DNA-Binding Proteins/genetics/*metabolism ; HeLa Cells ; Hippocampus/metabolism/pathology ; Humans ; Immunoglobulin Fragments/genetics/metabolism ; Inclusion Bodies/metabolism/pathology ; Mice ; Neurofibrillary Tangles/metabolism/pathology ; Neurons/metabolism/pathology ; Plaque, Amyloid/metabolism/pathology ; Recombinant Proteins/metabolism ; Ubiquitin/metabolism ; }, abstract = {The TAR DNA-binding protein-43 (TDP-43) has been identified as a major constituent of inclusions found in frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). To determine a possible role for TDP-43 in Alzheimer's disease (AD), a site-directed caspase-cleavage antibody to TDP-43 based upon a known caspase-3 cleavage consensus site within TDP- 43 at position D219 was designed. In vitro, this antibody labeled the predicted 25 kDa caspase-cleavage fragment of TDP-43 without labeling full-length TDP-43 following digestion of recombinant TDP-43 with caspase-3 or treatment of HeLa cells with staurosporine. Application of this antibody in postmortem brain sections indicated the presence of caspase-cleaved TDP-43 in Hirano bodies, tangles, reactive astrocytes and neuritic plaques of the AD brain. Caspase-cleaved TDP-43 also co-localized with ubiquitin labeled neurons as well as dystrophic neurites within plaque regions. These results suggest that caspase-cleaved TDP-43 is a major pathological finding in AD and may contribute to the neurodegeneration associated with this disease.}, }
@article {pmid18634615, year = {2007}, author = {Miller, KR and Streit, WJ}, title = {The effects of aging, injury and disease on microglial function: a case for cellular senescence.}, journal = {Neuron glia biology}, volume = {3}, number = {3}, pages = {245-253}, doi = {10.1017/S1740925X08000136}, pmid = {18634615}, issn = {1741-0533}, abstract = {Neuroinflammation resulting from chronic reactive microgliosis is thought to contribute to age-related neurodegeneration, as well as age-related neurodegenerative diseases, specifically Alzheimer's disease (AD). Support of this theory comes from studies reporting a progressive, age-associated increase in microglia with an activated phenotype. Although the underlying cause(s) of this microglial reactivity is idiopathic, an accepted therapeutic strategy for the treatment of AD is inhibition of microglial activation using anti-inflammatory agents. Although the effectiveness of anti-inflammatory treatment for AD remains equivocal, microglial inhibition is being tested as a potential treatment for additional neurodegenerative disorders including amyotrophic lateral sclerosis and Parkinson's disease. Given the important and necessary functions of microglia in normal brain, careful evaluation of microglial function in the aged brain is a necessary first step in targeting more precise treatment strategies for aging-related neurodegenerative diseases. Studies from our laboratory have shown multiple age-related changes in microglial morphology and function that are suggestive of cellular senescence. In this manuscript, we review current knowledge of microglia in the aging brain and present new, unpublished work that further supports the theory that microglia experience an age-related decline in proliferative function as a result of cellular senescence.}, }
@article {pmid18625421, year = {2008}, author = {Distad, BJ and Meekins, GD and Liou, LL and Weiss, MD and Carter, GT and Miller, RG}, title = {Drug therapy in amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {633-51, xi-xii}, doi = {10.1016/j.pmr.2008.04.005}, pmid = {18625421}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; Humans ; Immunologic Factors/*therapeutic use ; Neuroprotective Agents/*therapeutic use ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating condition characterized by progressive muscle wasting, inanition, respiratory failure, and death within approximately 2 to 5 years of onset. ALS is among the most common neuromuscular conditions, with an overall prevalence in the world of approximately 5 to 7 cases/100,000 population. Epidemiologic studies have identified some potential risk factors for developing ALS, including a high-fat, low-fiber diet; cigarette smoking; slimness and athleticism; and living in urban areas. Between 5% and 10% of ALS is genetic, with up to 11 genetic loci identified. Although understanding of the pathophysiology of this disease has advanced over the past 60 years, scant progress has been made regarding effective treatment. The authors review the current understanding of the pathogenic mechanisms of ALS and approaches to treating the disease.}, }
@article {pmid18625419, year = {2008}, author = {Woolley, SC and Jonathan S Katz, }, title = {Cognitive and behavioral impairment in amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {607-17, xi}, doi = {10.1016/j.pmr.2008.04.002}, pmid = {18625419}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/*complications/psychology ; Cognition/physiology ; Cognition Disorders/*etiology ; Humans ; Mental Disorders/*etiology ; }, abstract = {Cognitive impairment in amyotrophic lateral sclerosis (ALS) is correlated with pathologic and radiographic changes in cerebral cortex beyond the motor regions. Clinically, evidence of impairment can be detected in up to 50 percent of patients through direct neuropsychological testing, although frank frontotemporal dementia (FTD) occurs in a limited percentage. Behavioral changes are also common and can be characterized primarily by the presence of increased apathy. Determining the underlying causes of cognitive or behavioral change may be confounded by several disease-related factors, including fatigue, respiratory compromise, depression, and treatment with medications such as riluzole. Studies assessing the evolution and relative risk for cognitive and behavioral impairment in ALS suggest at least two types of patients: those who have clear FTD in whom cognitive decline develops gradually and those who have mild cognitive or behavioral impairments in whom progression either does not occur or is difficult to detect. Limited data suggest that cognition and behavior influence compliance, management, and survival, although this requires further assessment.}, }
@article {pmid18625417, year = {2008}, author = {Rosenfeld, J and Ellis, A}, title = {Nutrition and dietary supplements in motor neuron disease.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {573-89, x}, pmid = {18625417}, issn = {1047-9651}, support = {R01 AT000967-03/AT/NCCIH NIH HHS/United States ; }, mesh = {*Dietary Supplements ; Humans ; Motor Neuron Disease/*diet therapy ; Nutrition Therapy/*methods ; Nutritional Support/*methods ; }, abstract = {Compromised nutrition leading to weight loss is a common and significant problem in the amyotrophic lateral sclerosis (ALS) patient population. The benefit of aggressive and early nutritional therapy can profoundly influence the disease course, quality of life, and survival. This article reviews the role of nutrition, both as sustenance and treatment for patients who have ALS. Self-medication with dietary supplements has become increasingly popular within this patient population. Despite their popularity, the efficacy of these compounds has been largely unsupported by formal clinical trials. Available data will be highlighted to provide a basis upon which to advise patients requesting guidance.}, }
@article {pmid18625416, year = {2008}, author = {Benditt, JO and Boitano, L}, title = {Respiratory treatment of amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {559-72, x}, doi = {10.1016/j.pmr.2008.02.007}, pmid = {18625416}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/*rehabilitation ; Humans ; Respiratory Therapy/*methods ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease with no known cure. The major cause of mortality and major morbidities is related to the effects of the disease on the muscles of the respiratory system (ie, the inspiratory, expiratory, and upper airway muscles). Dyspnea, swallowing difficulties, sialorrhea, and impaired cough are all symptoms that can be palliated through pharmacologic and nonpharmacologic means. Noninvasive positive pressure ventilation, in particular, is a technique that not only relieves dyspnea but may also extend the lives of patients who have this disease. It should be offered to all patients who have amyotrophic lateral sclerosis with a forced vital capacity of less than 50 percent.}, }
@article {pmid18625414, year = {2008}, author = {Lou, JS}, title = {Fatigue in amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {19}, number = {3}, pages = {533-43, ix}, doi = {10.1016/j.pmr.2008.02.001}, pmid = {18625414}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Disease Progression ; Humans ; Muscle Fatigue/*physiology ; Prognosis ; Quality of Life ; Severity of Illness Index ; }, abstract = {Fatigue is a common and potentially debilitating symptom of amyotrophic lateral sclerosis (ALS). Questionnaire studies show that ALS subjects have increased subjective fatigue. Physiologic studies demonstrate that ALS subjects have increased physical fatigue, both central and peripheral in origin. No treatment has been proved effective through evidence-based medicine; however, modafinil (Provigil) may be a helpful pharmacologic treatment. Palliative care measures, such as noninvasive ventilation and high-frequency chest wall oscillation, may also reduce fatigue.}, }
@article {pmid18625223, year = {2008}, author = {Boston-Howes, W and Williams, EO and Bogush, A and Scolere, M and Pasinelli, P and Trotti, D}, title = {Nordihydroguaiaretic acid increases glutamate uptake in vitro and in vivo: therapeutic implications for amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {213}, number = {1}, pages = {229-237}, pmid = {18625223}, issn = {1090-2430}, support = {R01 NS044292/NS/NINDS NIH HHS/United States ; R01 NS044292-06/NS/NINDS NIH HHS/United States ; R21 NS046631-02/NS/NINDS NIH HHS/United States ; R01-NS44292/NS/NINDS NIH HHS/United States ; R21 NS046631/NS/NINDS NIH HHS/United States ; R21-NS058475/NS/NINDS NIH HHS/United States ; }, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/*metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/physiopathology ; Animals ; Cell Line ; Central Nervous System/*drug effects/metabolism/physiopathology ; Cyclooxygenase Inhibitors/pharmacology ; Drug Resistance ; Glutamic Acid/*metabolism ; Humans ; Masoprocol/*pharmacology ; Mice ; Mice, Transgenic ; Neurotoxins/antagonists &amp; inhibitors/metabolism ; Presynaptic Terminals/drug effects/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Synaptic Transmission/drug effects ; Treatment Failure ; Up-Regulation/drug effects ; }, abstract = {Synaptic accumulation of glutamate causes neuronal death in many neurodegenerative pathologies including amyotrophic lateral sclerosis. Drugs capable of increasing glutamate uptake could therefore be therapeutically effective. We screened in a cell-based assay a library of 1040 FDA-approved drugs and nutrients for compounds that could enhance glutamate uptake. Nordihydroguaiaretic acid (NDGA), an anti-inflammatory drug that inhibits lipoxygensases, potently enhanced glutamate uptake in MN-1 cells. Given subcutaneously at 1 mg/day for 30 days in mice, NDGA increased glutamate uptake in spinal cord synaptosomes persistently throughout the treatment. However, when administered following the same regimen to the SOD1-G93A transgenic mouse model of ALS at disease onset, NDGA did not extend survival of these mice. We found that NDGA failed to sustain increased glutamate uptake in the SOD1-G93A mice despite an initial upregulation measured during the first 10 days of treatment. SOD1-G93A mice displayed a progressive increase in spinal cord expression levels of the efflux transporter P-glycoprotein beginning at disease onset. This increase was not mediated by the NDGA treatment because it was measured in untreated SOD1-G93A mice. Since P-glycoproteins control the extrusion of a broad range of toxins and xenobiotics and are responsible for drug resistance in many diseases including cancer and brain diseases such as epilepsy, we propose that the failure of NDGA in maintaining glutamate uptake upregulated in SOD1-G93A mice and its therapeutic inefficacy are due to acquired pharmacoresistance mediated by the increased expression of P-glycoprotein.}, }
@article {pmid18618304, year = {2009}, author = {Del Signore, SJ and Amante, DJ and Kim, J and Stack, EC and Goodrich, S and Cormier, K and Smith, K and Cudkowicz, ME and Ferrante, RJ}, title = {Combined riluzole and sodium phenylbutyrate therapy in transgenic amyotrophic lateral sclerosis mice.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {2}, pages = {85-94}, doi = {10.1080/17482960802226148}, pmid = {18618304}, issn = {1471-180X}, mesh = {Acetylation/drug effects ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/mortality ; Animals ; Anterior Horn Cells/drug effects ; Body Weight/drug effects ; Drug Synergism ; Drug Therapy, Combination ; Female ; Histones/metabolism ; Humans ; Male ; Mice ; Mice, Transgenic ; Muscle Strength/drug effects ; NF-kappa B p50 Subunit/metabolism ; Neuroprotective Agents/*pharmacology ; Phenotype ; Phenylbutyrates/*pharmacology ; Riluzole/*pharmacology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Recent evidence suggests that transcriptional dysregulation may play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS). The histone deacetylase inhibitor, sodium phenylbutyrate (NaPB), is neuroprotective and corrects aberrant gene transcription in ALS mice and has recently been shown to be safe and tolerable in ALS patients while improving hypoacetylation. Since many patients are already on riluzole, it is important to ensure that any proposed therapy does not result in negative synergy with riluzole. The combined treatment of riluzole and NaPB significantly extended survival and improved both the clinical and neuropathological phenotypes in G93A transgenic ALS mice beyond either agent alone. Combination therapy increased survival by 21.5%, compared to the separate administration of riluzole (7.5%) and NaPB (12.8%), while improving both body weight loss and grip strength. The data show that the combined treatment was synergistic. In addition, riluzole/NaPB treatment ameliorated gross lumbar and ventral horn atrophy, attenuated lumbar ventral horn neuronal cell death, and decreased reactive astrogliosis. Riluzole/NaPB administration increased acetylation at H4 and increased NF-kappaB p50 translocation to the nucleus in G93A mice, consistent with a therapeutic effect. These data suggest that NaPB may not interfere with the pharmacologic action of riluzole in ALS patients.}, }
@article {pmid18617166, year = {2008}, author = {Tokuda, E and Ono, S and Ishige, K and Watanabe, S and Okawa, E and Ito, Y and Suzuki, T}, title = {Ammonium tetrathiomolybdate delays onset, prolongs survival, and slows progression of disease in a mouse model for amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {213}, number = {1}, pages = {122-128}, doi = {10.1016/j.expneurol.2008.05.011}, pmid = {18617166}, issn = {1090-2430}, mesh = {Amino Acid Sequence/drug effects ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/physiopathology ; Animals ; Chelating Agents/pharmacology/therapeutic use ; Copper/*metabolism ; Cysteine/metabolism ; Disease Models, Animal ; Disease Progression ; Enzyme Inhibitors/pharmacology/therapeutic use ; Female ; Humans ; Lipid Peroxidation/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Molybdenum/*pharmacology/therapeutic use ; Spinal Cord/*drug effects/metabolism/physiopathology ; Superoxide Dismutase/*antagonists &amp; inhibitors/chemistry/metabolism ; Survival Rate ; Treatment Outcome ; }, abstract = {Mutations in copper/zinc superoxide dismutase (SOD1) cause a form of familial amyotrophic lateral sclerosis (ALS). The pathogenesis of familial ALS may be associated with aberrant copper chemistry through a cysteine residue in mutant SOD1. Ammonium tetrathiomolybdate (TTM) is a copper-chelating drug that is capable of removing a copper ion from copper-thiolate clusters, such as SOD1. We found that TTM exerted therapeutic benefits in a mouse model of familial ALS (SOD1(G93A)). TTM treatment significantly delayed disease onset, slowed disease progression and prolonged survival by approximately 20%, 42% and 25%, respectively. TTM also effectively depressed the spinal copper ion level and inhibited lipid peroxidation, with a significant suppression of SOD1 enzymatic activity in SOD1(G93A). These results support the hypothesis that aberrant copper chemistry through a cysteine residue plays a critical role in mutant SOD1 toxicity and that TTM may be a promising therapy for familial ALS with SOD1 mutants.}, }
@article {pmid18608103, year = {2008}, author = {Rosenfeld, J and King, RM and Jackson, CE and Bedlack, RS and Barohn, RJ and Dick, A and Phillips, LH and Chapin, J and Gelinas, DF and Lou, JS}, title = {Creatine monohydrate in ALS: effects on strength, fatigue, respiratory status and ALSFRS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {9}, number = {5}, pages = {266-272}, pmid = {18608103}, issn = {1471-180X}, support = {R01 AT000967-01A1/AT/NCCIH NIH HHS/United States ; R01-AT00967-01/AT/NCCIH NIH HHS/United States ; }, mesh = {Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Biomarkers/metabolism ; Creatine/*pharmacology/*therapeutic use/urine ; Disease Progression ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Muscle Fatigue/*drug effects ; Muscle Strength/*drug effects ; Placebos ; Quality of Life ; Survival Rate ; Treatment Outcome ; Vital Capacity/*drug effects ; }, abstract = {Our objective was to determine the effect of creatine monohydrate on disease progression in patients with amyotrophic lateral sclerosis (ALS). One hundred and seven patients with the diagnosis of probable or definite ALS, of less than five years duration from symptom onset, were randomized to either treatment with daily creatine monohydrate (5 g/d) or placebo. In this multicenter, double-blinded study we followed changes in disease progression: using quantitative measures of strength via maximal isometric voluntary contraction, forced vital capacity, ALSFRS, quality of life, fatigue and survival. Patients were followed for nine months. The results showed that creatine monohydrate did not significantly improve motor, respiratory or functional capacity in this patient population. The drug was well tolerated and the study groups well balanced, especially considering the absence of forced vital capacity criteria for entrance into the study. There was a trend toward improved survival in patients taking daily creatine monohydrate and this was identical to the trend seen in another recently published report of creatine in ALS patients 1. In conclusion, creatine monohydrate (5 g/d) did not have an obvious benefit on the multiple markers of disease progression measured over nine months. We measured fatigue during isometric contraction and found no significant improvement despite anecdotal patient reports prior to and during the study. The trend toward improved survival was also found in another recently completed blinded trial using creatine monohydrate. Further investigation on the possible survival benefit of creatine in this patient population is ongoing.}, }
@article {pmid18608100, year = {2009}, author = {Sakowski, SA and Schuyler, AD and Feldman, EL}, title = {Insulin-like growth factor-I for the treatment of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {2}, pages = {63-73}, pmid = {18608100}, issn = {1471-180X}, support = {T32 NS007222/NS/NINDS NIH HHS/United States ; T32 NS007222-26/NS/NINDS NIH HHS/United States ; T32 NS 007222-26/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Animals ; Clinical Trials as Topic ; Disease Models, Animal ; Humans ; Insulin-Like Growth Factor I/*therapeutic use ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects both upper and lower motorneurons (MN) resulting in weakness, paralysis and subsequent death. Insulin-like growth factor-I (IGF-I) is a potent neurotrophic factor that has neuroprotective properties in the central and peripheral nervous systems. Due to the efficacy of IGF-I in the treatment of other diseases and its ability to promote neuronal survival, IGF-I is being extensively studied in ALS therapeutic trials. This review covers in vitro and in vivo studies examining the efficacy of IGF-I in ALS model systems and also addresses the mechanisms by which IGF-I asserts its effects in these models, the status of the IGF-I system in ALS patients, results of clinical trials, and the need for the development of better delivery mechanisms to maximize IGF-I efficacy. The knowledge obtained from these studies suggests that IGF-I has the potential to be a safe and efficacious therapy for ALS.}, }
@article {pmid18608093, year = {2008}, author = {Gordon, PH and Cheung, YK and Levin, B and Andrews, H and Doorish, C and Macarthur, RB and Montes, J and Bednarz, K and Florence, J and Rowin, J and Boylan, K and Mozaffar, T and Tandan, R and Mitsumoto, H and Kelvin, EA and Chapin, J and Bedlack, R and Rivner, M and McCluskey, LF and Pestronk, A and Graves, M and Sorenson, EJ and Barohn, RJ and Belsh, JM and Lou, JS and Levine, T and Saperstein, D and Miller, RG and Scelsa, SN and , }, title = {A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {9}, number = {4}, pages = {212-222}, pmid = {18608093}, issn = {1471-180X}, support = {RR-00109/RR/NCRR NIH HHS/United States ; MO1 RR023940/RR/NCRR NIH HHS/United States ; 5M01RR 00827-29/RR/NCRR NIH HHS/United States ; UL1RR024992/RR/NCRR NIH HHS/United States ; UL1 RR024992/RR/NCRR NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy ; Celecoxib ; Creatine/administration &amp; dosage/*therapeutic use ; Double-Blind Method ; Drug Eruptions ; Drug Therapy, Combination ; Female ; Humans ; Male ; Middle Aged ; Minocycline/administration &amp; dosage/adverse effects/*therapeutic use ; Neuroprotective Agents/administration &amp; dosage/*therapeutic use ; Patient Selection ; Pyrazoles/administration &amp; dosage/*therapeutic use ; Sulfonamides/administration &amp; dosage/*therapeutic use ; Treatment Outcome ; }, abstract = {Combining agents with different mechanisms of action may be necessary for meaningful results in treating ALS. The combinations of minocycline-creatine and celecoxib-creatine have additive effects in the murine model. New trial designs are needed to efficiently screen the growing number of potential neuroprotective agents. Our objective was to assess two drug combinations in ALS using a novel phase II trial design. We conducted a randomized, double-blind selection trial in sequential pools of 60 patients. Participants received minocycline (100 mg)-creatine (10 g) twice daily or celecoxib (400 mg)-creatine (10 g) twice daily for six months. The primary objective was treatment selection based on which combination best slowed deterioration in the ALS Functional Rating Scale-Revised (ALSFRS-R); the trial could be stopped after one pool if the difference between the two arms was adequately large. At trial conclusion, each arm was compared to a historical control group in a futility analysis. Safety measures were also examined. After the first patient pool, the mean six-month decline in ALSFRS-R was 5.27 (SD=5.54) in the celecoxib-creatine group and 6.47 (SD=9.14) in the minocycline-creatine group. The corresponding decline was 5.82 (SD=6.77) in the historical controls. The difference between the two sample means exceeded the stopping criterion. The null hypothesis of superiority was not rejected in the futility analysis. Skin rash occurred more frequently in the celecoxib-creatine group. In conclusion, the celecoxib-creatine combination was selected as preferable to the minocycline-creatine combination for further evaluation. This phase II design was efficient, leading to treatment selection after just 60 patients, and can be used in other phase II trials to assess different agents.}, }
@article {pmid18608090, year = {2008}, author = {Orrell, RW and Lane, RJ and Ross, M}, title = {A systematic review of antioxidant treatment for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {9}, number = {4}, pages = {195-211}, doi = {10.1080/17482960801900032}, pmid = {18608090}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Antioxidants/*therapeutic use ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {Free radical accumulation and oxidative stress have been proposed as contributing to the progression of amyotrophic lateral sclerosis (motor neuron disease). A range of antioxidant medications is available, and has been studied. We aimed to examine the effects of antioxidant medication in the treatment of people with amyotrophic lateral sclerosis, and searched the Cochrane Neuromuscular Disease Group Trials register (August 2005), MEDLINE (January 1966 to August 2005), EMBASE (January 1980 to August 2005) and other sources. Selection criteria were all randomized or quasi-randomized controlled trials of antioxidant treatment for amyotrophic lateral sclerosis. The authors independently applied the selection criteria, assessed study quality and two authors performed independent data extraction. The search identified 23 studies for consideration but only nine studies met the inclusion criteria. Only two studies used our predetermined primary outcome measure as the primary outcome measure (survival at 12 months treatment). However, sufficient data were available from four studies to allow analysis of this outcome measure, and a meta-analysis was performed. In the individual studies no significant effect was observed for vitamin E 500 mg twice daily; vitamin E 1 g five times daily; acetylcysteine 50 mg/kg daily subcutaneous infusion; or a combination of L-methionine 2 g, vitamin E 400 International Units, and selenium 0.03 mg three times daily (Alsemet). No significant effect on the primary outcome measure was observed in a meta analysis of all antioxidants combined. No significant differences were demonstrated in any of the secondary outcome measures. In the opinion of the reviewers, there is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect, but this was not supported by the analysis we used. Generally, the studies were poorly designed, and underpowered, with low numbers of participants and of short duration. Further well-designed trials of medications such as vitamin C and E are unlikely to be performed. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trial. The high tolerance and safety, and relatively low cost of vitamins C and E, and other considerations related to the lack of other effective treatments for amyotrophic lateral sclerosis, explain the continuing use of these vitamins by physicians and people with amyotrophic lateral sclerosis. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.}, }
@article {pmid18608089, year = {2008}, author = {Caraganis, A and Benn, S and Cudkowicz, M and Brown, RH}, title = {Thrombopoietin is ineffective in a mouse model of motor neuron disease.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {9}, number = {6}, pages = {354-358}, doi = {10.1080/17482960802103040}, pmid = {18608089}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Animals ; *Disease Models, Animal ; Female ; Male ; Mice ; Mice, Transgenic ; Motor Neuron Disease/*drug therapy/genetics/pathology ; Thrombopoietin/*therapeutic use ; }, abstract = {This study assessed the therapeutic efficacy of thrombopoietin (TPO) in the mouse model of ALS using two treatment paradigms. TPO was administered either daily or in 13-day treatment cycles to SOD1-G93A mice. Quantitative analysis of platelet levels, VEGF and TGF-beta1 trophic factors were assessed. The effect of TPO on disease progression was analyzed by behavioral analysis and clinical examination. TPO treatment increased levels of platelets and TGF-beta1 but not VEGF. This treatment did not affect onset or survival in these mice. Although biologically active, demonstrated by increased platelet and TGF-beta1 levels, rmTPO did not attenuate disease progression in ALS mice.}, }
@article {pmid18608087, year = {2009}, author = {van der Steen, I and van den Berg, JP and Buskens, E and Lindeman, E and van den Berg, LH}, title = {The costs of amyotrophic lateral sclerosis, according to type of care.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {10}, number = {1}, pages = {27-34}, doi = {10.1080/17482960802103131}, pmid = {18608087}, issn = {1471-180X}, mesh = {*Amyotrophic Lateral Sclerosis/economics/therapy ; Caregivers ; *Cost of Illness ; Cross-Sectional Studies ; *Health Care Costs ; Humans ; Netherlands ; Patient Care Team ; Quality of Health Care ; Quality of Life ; Surveys and Questionnaires ; }, abstract = {Our objective was to estimate the economic burden of patients with amyotrophic lateral sclerosis (ALS) and to examine the effect of treatment in a multidisciplinary ALS treatment centre versus general care on costs and to describe differences in costs according to clinical characteristics. In a cross-sectional study 208 patients with ALS and their caregivers were interviewed and were asked to fill in a cost diary for six months. Patients were divided in groups according to type of treatment they received and according to clinical characteristics (site of onset, severity). The direct healthcare and non-healthcare costs were calculated according to Dutch guidelines for cost analysis in healthcare research, standardized for the year 2003. Ninety-eight patients were included when they had filled in the cost diary for at least three months and were affected for three years or less. Mean monthly costs were 1336 euros for the group receiving multidisciplinary care and 1271 euros for those receiving general care. This study shows that the costs of multidisciplinary ALS care were practically identical to the costs of general care. Earlier study showed that patients receiving multidisciplinary care had a better quality of life; therefore, the present study encourages the formation of multidisciplinary teams of professionals specialized in ALS care to further improve standards of care and QoL of patients suffering from ALS.}, }
@article {pmid18598229, year = {2008}, author = {Tumani, H and Teunissen, C and Süssmuth, S and Otto, M and Ludolph, AC and Brettschneider, J}, title = {Cerebrospinal fluid biomarkers of neurodegeneration in chronic neurological diseases.}, journal = {Expert review of molecular diagnostics}, volume = {8}, number = {4}, pages = {479-494}, doi = {10.1586/14737159.8.4.479}, pmid = {18598229}, issn = {1744-8352}, mesh = {*Apoptosis ; Axons/*metabolism/pathology ; Biomarkers/*cerebrospinal fluid ; Gliosis/*cerebrospinal fluid/diagnosis/pathology ; Humans ; Neurodegenerative Diseases/*cerebrospinal fluid/diagnosis/pathology ; }, abstract = {Chronic neurological diseases (CND) like amyotrophic lateral sclerosis (ALS), dementia or multiple sclerosis (MS) share a chronic progressive course of disease that frequently leads to the common pathological pathway of neurodegeneration, including neuroaxonal damage, apoptosis and gliosis. There is an ongoing search for biomarkers that could support early diagnosis of CND and help to identify responders to interventions in therapeutic treatment trials. Cerebrospinal fluid (CSF) is a promising source of biomarkers in CND, since the CSF compartment is in close anatomical contact with the brain interstitial fluid, where biochemical changes related to CND are reflected. We review recent advances in CSF biomarkers research in CND and thereby focus on markers associated with neurodegeneration.}, }
@article {pmid18592728, year = {2008}, author = {Grujic, J and Coutaz, M and Morisod, J}, title = {[Amyotrophic lateral sclerosis also threatens the octogenarian].}, journal = {Revue medicale suisse}, volume = {4}, number = {159}, pages = {1353-1357}, pmid = {18592728}, issn = {1660-9379}, mesh = {Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Diagnosis, Differential ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, incurable, mostly declared near the age of sixty-seventy, but more rarely for the older individuals. Because presenting symptoms are non specific (muscle weakness, functional decline, loss of ambulation, dyspnea, dysphagia), diagnosis in early stages may be difficult and delayed, particularly on polymorbid older patients. Symptomatic management is the mainstay of treatment for ALS; care in multidisciplinary team, with maximal psychologic support, is associated with enhanced quality of life. In this article we remind markings aspects of ALS of the older subject, in the light of the follow-up of five patients in our geriatric service.}, }
@article {pmid19750024, year = {2008}, author = {Maiese, K and Chong, ZZ and Shang, YC and Hou, J}, title = {Therapeutic promise and principles: metabotropic glutamate receptors.}, journal = {Oxidative medicine and cellular longevity}, volume = {1}, number = {1}, pages = {1-14}, pmid = {19750024}, issn = {1942-0994}, support = {P30 ES06639/ES/NIEHS NIH HHS/United States ; R01 NS053946-01A2/NS/NINDS NIH HHS/United States ; R01 NS053946-03/NS/NINDS NIH HHS/United States ; P30 ES006639/ES/NIEHS NIH HHS/United States ; R01 NS053946-02/NS/NINDS NIH HHS/United States ; R01 NS053946/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Glutamic Acid/metabolism ; Humans ; Molecular Targeted Therapy/*methods ; Oxidative Stress/physiology ; Receptors, Metabotropic Glutamate/*metabolism ; Signal Transduction ; }, abstract = {For a number of disease entities, oxidative stress becomes a significant factor in the etiology and progression of cell dysfunction and injury. Therapeutic strategies that can identify novel signal transduction pathways to ameliorate the toxic effects of oxidative stress may lead to new avenues of treatment for a spectrum of disorders that include diabetes, Alzheimer's disease, Parkinson's disease and immune system dysfunction. In this respect, metabotropic glutamate receptors (mGluRs) may offer exciting prospects for several disorders since these receptors can limit or prevent apoptotic cell injury as well as impact upon cellular development and function. Yet the role of mGluRs is complex in nature and may require specific mGluR modulation for a particular disease entity to maximize clinical efficacy and limit potential disability. Here we discuss the potential clinical translation of mGluRs and highlight the role of novel signal transduction pathways in the metabotropic glutamate system that may be vital for the clinical utility of mGluRs.}, }
@article {pmid18587708, year = {2008}, author = {Matyja, E and Taraszewska, A and Nagańska, E and Grieb, P and Rafałowska, J}, title = {CDP-choline protects motor neurons against apoptotic changes in a model of chronic glutamate excitotoxicity in vitro.}, journal = {Folia neuropathologica}, volume = {46}, number = {2}, pages = {139-148}, pmid = {18587708}, issn = {1641-4640}, mesh = {Animals ; Animals, Newborn ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/*metabolism ; Cytidine Diphosphate Choline/administration &amp; dosage/*pharmacology ; Glutamic Acid/*metabolism ; In Vitro Techniques ; Motor Neuron Disease/*drug therapy/*pathology ; Nerve Degeneration/*drug therapy/*pathology ; Neuroglia/drug effects/ultrastructure ; Neurotoxins/*metabolism ; Rats ; Spinal Cord/*drug effects/*pathology ; }, abstract = {Cytidine-5-diphosphocholine (CDP-choline, citicoline) is an endogenous nucleoside involved in generation of phospholipids, membrane formation and its repair. It demonstrates beneficial effects in certain central nervous system injury models, including cerebral ischaemia, neurodegenerative disorders and spinal cord injury. Defective neuronal and/or glial glutamate transport is claimed to contribute to progressive loss of motor neurons (MNs) in amyotrophic lateral sclerosis (ALS). Our previous ultrastructural studies, performed on an organotypic tissue culture model of chronic glutamate excitotoxicity, documented a subset of various modes of MN death including necrotic, apoptotic and autophagocytic cell injury. The aim of this ultrastructural study was to determine the potential neuroprotective effect of CDP-choline on neuronal changes in a glutamate excitotoxic ALS model in vitro. Organotypic cultures of the rat lumbar spinal cord subjected to 100 microM DL-threo-beta-hydroxyaspartate (THA) were pretreated with 100 microM of CDP-choline. The exposure of spinal cord cultures to CDP-choline and THA distinctly reduced the development of typical apoptotic changes, whereas both necrotic and autophagocytic THA-induced MN injury occurred. These results indicate that CDP-choline treatment might exert a neuroprotective effect against neuronal apoptotic changes in a model of chronic excitotoxicity in vitro.}, }
@article {pmid18587568, year = {2008}, author = {Andres, RH and Barth, A and Guzman, R and Remonda, L and El-Koussy, M and Seiler, RW and Widmer, HR and Schroth, G}, title = {Endovascular and surgical treatment of spinal dural arteriovenous fistulas.}, journal = {Neuroradiology}, volume = {50}, number = {10}, pages = {869-876}, pmid = {18587568}, issn = {0028-3940}, mesh = {Adult ; Aged ; Central Nervous System Vascular Malformations/surgery/*therapy ; Embolization, Therapeutic/methods ; Female ; Humans ; Male ; Middle Aged ; Neurosurgical Procedures ; Retrospective Studies ; Spinal Cord/*blood supply ; Treatment Outcome ; }, abstract = {INTRODUCTION: The aim of this retrospective study was to evaluate the clinical outcome of patients with spinal dural arteriovenous fistulas (SDAVFs) that were treated with surgery, catheter embolization, or surgery after incomplete embolization.<br><br>METHODS: The study included 21 consecutive patients with SDAVFs of the thoracic, lumbar, or sacral spine who were treated in our institution from 1994 to 2007. Thirteen patients were treated with catheter embolization alone. Four patients underwent hemilaminectomy and intradural interruption of the fistula. Four patients were treated by endovascular techniques followed by surgery. The clinical outcome was assessed using the modified Aminoff-Logue scale (ALS) for myelopathy and the modified Rankin scale (MRS) for general quality of life. Patient age ranged from 44 to 77 years (mean 64.7 years).<br><br>RESULTS: Surgical as well as endovascular treatment resulted in a significant improvement in ALS (-62.5% and -31.4%, respectively, p < 0.05) and a tendency toward improved MRS (-50% and -32%, respectively) scores. Patients that underwent surgery after endovascular treatment due to incomplete occlusion of the fistula showed only a tendency for improvement in the ALS score (-16.7%), whereas the MRS score was not affected.<br><br>CONCLUSION: We conclude that both endovascular and surgical treatment of SDAVFs resulted in a good and lasting clinical outcome in the majority of cases. In specific situations, when a secondary neurosurgical approach was required after endovascular treatment to achieve complete occlusion of the SDAVF, the clinical outcome was rather poor. The best first line treatment modality for each individual patient should be determined by an interdisciplinary team.}, }
@article {pmid18582410, year = {2008}, author = {Balakrishnan, P and Rosen, H}, title = {The causes and treatment of pseudobulbar affect in ischemic stroke.}, journal = {Current treatment options in cardiovascular medicine}, volume = {10}, number = {3}, pages = {216-222}, pmid = {18582410}, issn = {1092-8464}, abstract = {Pseudobulbar affect (PBA) is a disorder of emotional regulation characterized by uncontrollable outbursts of laughing and/or crying that are disproportionate to the emotions being experienced. The pathophysiology of PBA is currently unknown, although the disorder is thought to occur exclusively in the setting of neurologic disease, including stroke. The most influential theory on PBA posits that emotional outbursts are being generated in the brainstem autonomously due to loss of regulatory control by the frontal lobes. Although rarely life threatening, PBA can have significant impact on patients' quality of life and thus merits treatment. Although currently there are no treatments approved by the Food and Drug Administration (FDA) for PBA, tricyclic antidepressants and selective serotonin reuptake inhibitors are commonly used. Both these treatments are inexpensive and relatively low risk, although the quality of the available data on their efficacy is not optimal. Recently, a new agent containing dextromethorphan and quinidine (DM/Q) demonstrated efficacy in treating PBA in two large clinical trials--one in patients with multiple sclerosis and the other in patients with amyotrophic lateral sclerosis. Further studies are being conducted. If DM/Q is approved for PBA treatment, it will be the first agent approved by the FDA for this purpose. The choice of whether to use DM/Q in this setting will likely depend on individual patient factors. Currently, the antidepressants are probably the most attractive pharmacologic options for treating PBA. Although nonpharmacologic therapies have not been studied systematically, they should be explored in cognitively intact patients.}, }
@article {pmid18575617, year = {2008}, author = {Garbuzova-Davis, S and Sanberg, CD and Kuzmin-Nichols, N and Willing, AE and Gemma, C and Bickford, PC and Miller, C and Rossi, R and Sanberg, PR}, title = {Human umbilical cord blood treatment in a mouse model of ALS: optimization of cell dose.}, journal = {PloS one}, volume = {3}, number = {6}, pages = {e2494}, pmid = {18575617}, issn = {1932-6203}, support = {R41 NS046870/NS/NINDS NIH HHS/United States ; IR41NS46870-01A1/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/metabolism/pathology/*therapy ; Animals ; Cytokines/metabolism ; *Disease Models, Animal ; Disease Progression ; *Fetal Blood ; Humans ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a multicausal disease characterized by motor neuron degeneration in the spinal cord and brain. Cell therapy may be a promising new treatment for this devastating disorder. We recently showed that a single low dose (10(6) cells) of mononuclear human umbilical cord blood (MNC hUCB) cells administered intravenously to G93A mice delayed symptom progression and modestly prolonged lifespan. The aim of this pre-clinical translation study is to optimize the dose of MNC hUCB cells to retard disease progression in G93A mice. Three different doses of MNC hUCB cells, 10x10(6), 25x10(6) and 50x10(6), were administered intravenously into pre-symptomatic G93A mice. Motor function tests and various assays to determine cell effects were performed on these mice.<br><br>Our results showed that a cell dose of 25x10(6) cells significantly increased lifespan of mice by 20-25% and delayed disease progression by 15%. The most beneficial effect on decreasing pro-inflammatory cytokines in the brain and spinal cord was found in this group of mice. Human Th2 cytokines were found in plasma of mice receiving 25x10(6) cells, although prevalent human Th1 cytokines were indicated in mice with 50x10(6) cells. High response of splenic cells to mitogen (PHA) was indicated in mice receiving 25x10(6) (mainly) and 10x10(6) cells. Significantly increased lymphocytes and decreased neutrophils in the peripheral blood were found only in animals receiving 25x10(6) cells. Stable reduction in microglia density in both cervical and lumbar spinal cords was also noted in mice administered with 25x10(6) cells.<br><br>CONCLUSIONS/SIGNIFICANCE: These results demonstrate that treatment for ALS with an appropriate dose of MNC hUCB cells may provide a neuroprotective effect for motor neurons through active involvement of these cells in modulating the host immune inflammatory system response.}, }
@article {pmid18574938, year = {2008}, author = {Li, B and Liu, XY and Li, Z and Bu, H and Sun, MM and Guo, YS and Li, CY}, title = {Effect of ALS IgG on motor neurons in organotypic spinal cord cultures.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {35}, number = {2}, pages = {220-225}, doi = {10.1017/s0317167100008672}, pmid = {18574938}, issn = {0317-1671}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*immunology ; Analysis of Variance ; Animals ; Animals, Newborn ; Female ; Humans ; Immunoglobulin G/*pharmacology ; L-Lactate Dehydrogenase/metabolism ; Male ; Middle Aged ; Motor Neurons/*drug effects ; Neurofilament Proteins/metabolism ; Organ Culture Techniques ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/*cytology ; }, abstract = {OBJECTIVE: Reports about the role of autoimmunity in amyotrophic lateral sclerosis (ALS) are inconsistent. The aim of this work was to investigate the effect of IgG from patients with ALS on motor neurons in a physiological-like surrounding.<br><br>METHODS: Using affinity chromatography, IgG from six ALS patients, four disease controls and five healthy subjects was purified. Organotypic spinal cord cultures, which conserve the structure of the spinal cord in a horizontal plane and are suitable for studies with long-term treatment, were used and IgG with different concentrations ranging from 0.05 mg/mL to 0.5 mg/mL was added to the culture medium. Ventral motor neuron survival was evaluated by morphology and SMI-32 immunohistochemistry staining. Lactate dehydrogenase (LDH) level in the culture medium was measured by colorimetry.<br><br>RESULTS: After cultures were treated with ALS IgG for three weeks, the number and morphology of motor neurons showed little change. In addition, there was no significant difference in lactate dehydrogenase release between cultures treated with medium alone, normal control IgG, disease control IgG or ALS IgG.<br><br>CONCLUSIONS: The results indicate that IgG from these ALS patients was insufficient per se to induce motor neuron death in organotypic slice cultures. However, this does not preclude the possibility that other changes may have occurred in the motor neurons. This work offered a new model to evaluate the role of IgG in the pathogenesis of ALS. Organotypic cultures contribute to study of the impact of IgG on motor neurons by mimicking physiological conditions.}, }
@article {pmid18574927, year = {2008}, author = {Rashidipour, O and Chan, KM}, title = {Motor unit number estimation in neuromuscular disease.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {35}, number = {2}, pages = {153-159}, doi = {10.1017/s0317167100008568}, pmid = {18574927}, issn = {0317-1671}, mesh = {Electric Stimulation/methods ; Electromyography/methods ; Evoked Potentials, Motor/physiology ; Humans ; Motor Neurons/*pathology ; Muscle, Skeletal/physiopathology ; Neuromuscular Diseases/*pathology ; }, abstract = {Motor unit number estimation (MUNE) is an electrophysiological method designed to quantify motor unit loss in target muscles of interest. Most of the techniques are noninvasive and are therefore well suited for longitudinal monitoring. In this brief review, we describe the more commonly used techniques and their applications in amyotrophic lateral sclerosis, poliomyelitis, spinal muscular atrophy and hereditary sensorimotor neuropathies. Findings in some of these studies offer important pathophysiological insights. Since conventional electrophysiologic methods are not sensible measures of motor neuronal loss, MUNE could play a potentially important role in the diagnosis, monitoring of disease progression and response to treatment in neuromuscular diseases in which motor unit loss is a major feature.}, }
@article {pmid18574756, year = {2008}, author = {Lanka, V and Cudkowicz, M}, title = {Therapy development for ALS: lessons learned and path forward.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {9}, number = {3}, pages = {131-140}, doi = {10.1080/17482960802112819}, pmid = {18574756}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/physiopathology ; Animals ; Biomarkers/metabolism ; Disease Models, Animal ; Humans ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Several therapies have shown promise in preclinical models of motor neuron disease. Several of these treatment approaches, however, failed in human studies. In moving forward with new promising therapies, it is important to first identify whether the past trials were unsuccessful due to wrong therapy and biological target or because of flaws in trial design and conduct. We review treatment development in ALS and discuss the strengths and limitations of past clinical trials. Better biomarkers of disease and markers of biological activity of the therapies under development are urgently needed. Obtaining information regarding dosage, pharmacokinetics, short-term safety and biological activity in well designed phase I and II studies is critical to the design of phase III trials that will yield meaningful results.}, }
@article {pmid18567360, year = {2008}, author = {Urushitani, M}, title = {[Implications of successful immunotherapy in ALS model mice].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {60}, number = {6}, pages = {643-651}, pmid = {18567360}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/*therapy ; Animals ; Antibodies/administration &amp; dosage ; Chromogranins ; *Disease Models, Animal ; Forecasting ; Humans ; *Immunotherapy/trends ; Immunotherapy, Active ; Mice ; Mice, Transgenic ; Motor Neurons/pathology ; Mutation ; Protein Folding ; Superoxide Dismutase/*genetics/*immunology/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Recent progress in clinical genetics has explored various mutations or associated genes in both familial and sporadic amyotrophic lateral sclerosis (ALS). Mutations in superoxide dismutase 1 (SOD1) account for 20% of familial ALS, and mutant SOD1 transgenic mice are still regarded as the best ALS model animals for the first step of therapeutic estimation. Emerging evidence indicates that SOD1 is secreted in spite of lacking translocation signal. We previously found chromogranins interact with ALS-linked SOD1 mutants, but not with wild-type, and promote the secretion SOD1 mutants. Moreover, extracellular SOD1 mutant activates microglia and kills motor neuron. This scenario may well explain non-cell-autonomous fashion of mutant SOD1-induced pathology in ALS. Accordingly, vaccination targeting extracellular SOD1 mutants significantly delays disease onset and prolongs lifespan of mutant SOD1 transgenic mice. Moreover, intraventricular application of ant-mutant SOD1 antibody also showed beneficial effect. In this review, the rationale between protein misfolding of mutant SOD1 and effect of immunization is delineated and further perspective of this non-invasive treatment not only for mutant SOD1 but also for sporadic ALS is discussed.}, }
@article {pmid18564527, year = {2008}, author = {Woodson, G}, title = {Management of neurologic disorders of the larynx.}, journal = {The Annals of otology, rhinology, and laryngology}, volume = {117}, number = {5}, pages = {317-326}, doi = {10.1177/000348940811700501}, pmid = {18564527}, issn = {0003-4894}, mesh = {Electromyography/methods ; Humans ; *Laryngeal Diseases/diagnosis/etiology/therapy ; Laryngoscopy/methods ; Larynx/*physiopathology ; *Nervous System Diseases/complications/diagnosis/therapy ; Otolaryngology/methods ; Physical Examination/methods ; }, abstract = {OBJECTIVES: I review the literature on management of neurologic disorders of the larynx.<br><br>METHODS: I reviewed the literature on laryngeal physiology, clinical evaluation of laryngeal function, and the clinical presentation and treatment of neurologic disorders that frequently affect the larynx.<br><br>RESULTS: Laryngeal function is complex, as this organ is important in breathing, speech, and swallowing. Coordination of these roles is very susceptible to disruption by neurologic disorders. Diagnosis of neurologic disease is primarily based on history and physical examination; however, the diagnosis of laryngeal dysfunction is frequently overlooked, because the larynx is not easily accessible to examination by non-otolaryngologists. Evaluation of laryngeal function includes listening to the voice, systematic observation of the larynx during speech and nonspeech tasks, and, sometimes, ancillary tests. Neurologic disorders that affect laryngeal function include Parkinson's disease, essential tremor, stroke, amyotrophic lateral sclerosis, multiple sclerosis, and dystonia. The otolaryngologist can sometimes provide treatment to specifically improve symptoms of laryngeal involvement.<br><br>CONCLUSIONS: Otolaryngology consultation is important in the diagnosis and treatment of neurologic disorders that affect laryngeal function. The otolaryngologist should be able to perform a systematic evaluation of laryngeal and pharyngeal function, and should be aware of the clinical presentation of neurologic disorders that affect the larynx.}, }
@article {pmid18560390, year = {2008}, author = {Kühnlein, P and Gdynia, HJ and Sperfeld, AD and Lindner-Pfleghar, B and Ludolph, AC and Prosiegel, M and Riecker, A}, title = {Diagnosis and treatment of bulbar symptoms in amyotrophic lateral sclerosis.}, journal = {Nature clinical practice. Neurology}, volume = {4}, number = {7}, pages = {366-374}, doi = {10.1038/ncpneuro0853}, pmid = {18560390}, issn = {1745-8358}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis/*therapy ; Bulbar Palsy, Progressive/complications/diagnosis/therapy ; Deglutition Disorders/complications/diagnosis/therapy ; Dysarthria/complications/diagnosis/therapy ; Humans ; Speech Disorders/complications/diagnosis/therapy ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor system. Bulbar symptoms such as dysphagia and dysarthria are frequent features of ALS and can result in reductions in life expectancy and quality of life. These dysfunctions are assessed by clinical examination and by use of instrumented methods such as fiberendoscopic evaluation of swallowing and videofluoroscopy. Laryngospasm, another well-known complication of ALS, commonly comes to light during intubation and extubation procedures in patients undergoing surgery. Laryngeal and pharyngeal complications are treated by use of an array of measures, including body positioning, compensatory techniques, voice and breathing exercises, communication devices, dietary modifications, various safety strategies, and neuropsychological assistance. Meticulous monitoring of clinical symptoms and close cooperation within a multidisciplinary team (physicians, speech and language therapists, occupational therapists, dietitians, caregivers, the patients and their relatives) are vital.}, }
@article {pmid18439227, year = {2008}, author = {Tysnes, OB}, title = {Treatment of sialorrhea in amyotrophic lateral sclerosis.}, journal = {Acta neurologica Scandinavica. Supplementum}, volume = {188}, number = {}, pages = {77-81}, doi = {10.1111/j.1600-0404.2008.01037.x}, pmid = {18439227}, issn = {0065-1427}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Sialorrhea/*etiology/*therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating progressive disease of all voluntary muscles. Bulbar symptoms with reduced ability to swallow occur frequently and may also be an early symptom. For some patients drooling may represent a severe social problem.<br><br>AIM: To review the literature on treatment of sialorrhea in ALS and describe possible treatments.<br><br>METHOD: PubMed was searched combining the words amyotrophic or ALS with sialorrhea or drooling. Publications more recent than 2000 were selected.<br><br>RESULTS: A total of 31 publications were found. Of these, 22 are from 2000 or later. Thirteen of the 22 most recent publications are original papers whereas 9 are review articles. Of the original articles, four describe treatment of sialorrhea with radiotherapy, five describe effects of botolinum toxin injections into the salivary grands and two describe serious side-effects of botolinum toxin injections for sialorrhea in ALS. The remaining original articles are case descriptions or practice surveys.<br><br>DISCUSSION: The treatment of sialorrhea in ALS is discussed in the view of current knowledge.}, }
@article {pmid18555873, year = {2008}, author = {Serratrice, G}, title = {[Primary muscle cramps].}, journal = {Revue neurologique}, volume = {164}, number = {5}, pages = {416-425}, doi = {10.1016/j.neurol.2008.02.042}, pmid = {18555873}, issn = {0035-3787}, mesh = {Animals ; Diagnosis, Differential ; Humans ; Muscle Cramp/classification/drug therapy/*physiopathology/*therapy ; Muscle Relaxants, Central/therapeutic use ; Quinine/therapeutic use ; }, abstract = {Primary muscle cramps, without known cause, are very frequent especially in the elderly and during the night. They are different from secondary cramps. Likewise they are to be separated from several syndromes erroneously quoted as cramps. The pathophysiological mechanism seems due to result from an initial dysfunction in the distal part of the motoneuron. When the cramps are severe, differential diagnosis with amyotrophic lateral sclerosis may be difficult. Quinine is the best empiric treatment largely used in spite of moderate side effects.}, }
@article {pmid18551622, year = {2008}, author = {Cudkowicz, ME and Shefner, JM and Simpson, E and Grasso, D and Yu, H and Zhang, H and Shui, A and Schoenfeld, D and Brown, RH and Wieland, S and Barber, JR and , }, title = {Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {38}, number = {1}, pages = {837-844}, doi = {10.1002/mus.21059}, pmid = {18551622}, issn = {0148-639X}, support = {5M01 RR 0082729/RR/NCRR NIH HHS/United States ; M01 RR 01066/RR/NCRR NIH HHS/United States ; M01 RR 01346/RR/NCRR NIH HHS/United States ; M01 RR 023940/RR/NCRR NIH HHS/United States ; M01 RR 10732/RR/NCRR NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Blood-Brain Barrier ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Humans ; Hydroxylamines/*administration &amp; dosage/*adverse effects/pharmacokinetics ; Male ; Middle Aged ; }, abstract = {Arimoclomol is an investigational drug for amyotrophic lateral sclerosis (ALS) that amplifies heat shock protein gene expression during cell stress. The objectives of the present study were to assess the safety, tolerability, and pharmacokinetics of arimoclomol in ALS. Eighty-four participants with ALS received arimoclomol at one of three oral doses (25, 50, or 100 mg three times daily) or placebo. The primary outcome measure was safety and tolerability. A subset of 44 participants provided serum and cerebrospinal fluid (CSF) samples for pharmacokinetic analysis. Participants who completed 12 weeks of treatment could enroll in a 6-month open-label study. Arimoclomol at doses up to 300 mg/day was well tolerated and safe. Arimoclomol resulted in dose-linear pharmacologic exposures and the half-life did not change with continued treatment. Arimoclomol CSF levels increased with dose. Arimoclomol was shown to be safe, and it crosses the blood-brain barrier. Serum pharmacokinetic profiles support dosing of three times per day. An efficacy study in ALS is planned.}, }
@article {pmid18543336, year = {2008}, author = {Ohta, Y and Kamiya, T and Nagai, M and Nagata, T and Morimoto, N and Miyazaki, K and Murakami, T and Kurata, T and Takehisa, Y and Ikeda, Y and Asoh, S and Ohta, S and Abe, K}, title = {Therapeutic benefits of intrathecal protein therapy in a mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of neuroscience research}, volume = {86}, number = {13}, pages = {3028-3037}, doi = {10.1002/jnr.21747}, pmid = {18543336}, issn = {1097-4547}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*pathology ; Animals ; Apoptosis/physiology ; Disease Models, Animal ; Gene Products, tat ; Humans ; In Situ Nick-End Labeling ; Injections, Spinal ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/metabolism/*pathology ; Spinal Cord/drug effects/pathology ; bcl-X Protein/*administration &amp; dosage ; }, abstract = {When fused with the protein transduction domain (PTD) derived from the human immunodeficiency virus TAT protein, proteins can cross the blood-brain barrier and cell membrane and transfer into several tissues, including the brain, making protein therapy feasible for various neurological disorders. We have constructed a powerful antiapoptotic modified Bcl-X(L) protein (originally constructed from Bcl-X(L)) fused with PTD derived from TAT (TAT-modified Bcl-X(L)), and, to examine its clinical effectiveness in a mouse model of familial amyotrophic lateral sclerosis (ALS), transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) bearing a G93A mutation were treated by intrathecal infusion of TAT-modified Bcl-X(L). We demonstrate that intrathecally infused TAT-fused protein was effectively transferred into spinal cord neurons, including motor neurons, and that intrathecal infusion of TAT-modified Bcl-X(L) delayed disease onset, prolonged survival, and improved motor performance. Histological studies show an attenuation of motor neuron loss and a decrease in the number of cleaved caspase 9-, cleaved caspase 3-, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells in the lumbar cords of TAT-modified Bcl-X(L)-treated G93A mice. Our results indicate that intrathecal protein therapy using a TAT-fused protein is an effective clinical tool for the treatment of ALS.}, }
@article {pmid18541989, year = {2008}, author = {Nieuwenhuis-Mark, RE and van Hoek, A and Vingerhoets, A}, title = {Understanding excessive crying in neurologic disorders: nature, pathophysiology, assessment, consequences, and treatment.}, journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology}, volume = {21}, number = {2}, pages = {111-123}, doi = {10.1097/WNN.0b013e31816be8f8}, pmid = {18541989}, issn = {1543-3641}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Antidepressive Agents/therapeutic use ; Brain/drug effects/physiopathology ; Central Nervous System Diseases/diagnosis/*physiopathology ; Crying/*physiology ; Emotions/physiology ; Humans ; Multiple Sclerosis/diagnosis/physiopathology ; Stroke/diagnosis/physiopathology ; }, abstract = {OBJECTIVE: The goal of this review is to provide an overview of the literature on excessive crying (EC) in neurologic disorders.<br><br>BACKGROUND: EC implies that a person has difficulty keeping his emotional behavior under control and it occurs in a number of neurologic disorders.<br><br>METHOD: Intensive literature searches were carried out to address the following 4 questions: (1) What is EC and what effects does it have? (2) In which disorders is EC common? (3) How can EC be diagnosed? and finally, (4) Can EC be treated?<br><br>RESULTS: EC is common in a variety of neurologic disorders including amyotrophic lateral sclerosis, stroke, and multiple sclerosis whereas brain regions implicated may be both focal and/or diffuse. Both in a qualitative and quantitative way, EC does not clearly differ from crying in normal adults. There is a remarkable similarity between the precipitating factors in normal crying and EC. Three questionnaires for the diagnosis of EC have been developed. Treatment with low doses of antidepressants yields promising results.<br><br>CONCLUSIONS: We recommend choosing one term for the phenomenon of EC that does justice to the fact that the threshold for such crying is exceptionally low. This may reduce confusion in the literature and among health professionals. The neurologic origin of EC has yet to be fully mapped out. Antidepressants are the treatment of choice for EC whereas early treatment should be the goal for both patients and their carers.}, }
@article {pmid18539273, year = {2008}, author = {Boucherie, C and Caumont, AS and Maloteaux, JM and Hermans, E}, title = {In vitro evidence for impaired neuroprotective capacities of adult mesenchymal stem cells derived from a rat model of familial amyotrophic lateral sclerosis (hSOD1(G93A)).}, journal = {Experimental neurology}, volume = {212}, number = {2}, pages = {557-561}, doi = {10.1016/j.expneurol.2008.04.030}, pmid = {18539273}, issn = {1090-2430}, mesh = {Amino Acid Transport System X-AG/metabolism ; Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Animals, Genetically Modified ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Gene Expression Regulation/drug effects ; Glial Cell Line-Derived Neurotrophic Factor/metabolism ; Humans ; Mesenchymal Stem Cells/*physiology ; Neuroprotective Agents/pharmacology ; Rats ; Rats, Sprague-Dawley ; Riluzole/pharmacology ; Superoxide Dismutase/*genetics ; }, abstract = {Protection of neurons by stem cells is an attractive challenge in the development of efficient therapies of neurodegenerative diseases. When giving preference to autologous grafts, the bone marrow constitutes a valuable source of adult stem cells. Therefore, we herein studied the acquisition of neuroprotective functions by cultured mesenchymal stem cells (MSCs) exposed to growth factors known to promote the differentiation of neural stem cells into astrocytes. In these conditions, MSCs showed increased transcription and expression of the high-affinity glutamate transporter GLT-1 and functional studies revealed increased aspartate uptake activity. In addition, differentiation was shown to endow the cells with the capacity to respond to riluzole which triggers a robust up-regulation of the GDNF production. In parallel, MSCs derived from the bone marrow of a transgenic rat model of familial ALS (hSOD1(G93A)) were also characterised. Unexpectedly, cells from this rat strain submitted to the differentiation protocol showed modest capacity to take up aspartate and did not respond to the riluzole treatments. These data highlight the neuroprotective potential attributable to MSCs, supporting their use as valuable tools for the treatment of neurodegenerative disorders. However, the cells from the transgenic animal model of ALS appeared deficient in their capacity to gain the neuroprotective properties, raising questions regarding the suitability of autologous stem cell grafts in future therapies against familial forms of this disease.}, }
@article {pmid18537618, year = {2008}, author = {Maurer, MH and Schäbitz, WR and Schneider, A}, title = {Old friends in new constellations--the hematopoetic growth factors G-CSF, GM-CSF, and EPO for the treatment of neurological diseases.}, journal = {Current medicinal chemistry}, volume = {15}, number = {14}, pages = {1407-1411}, doi = {10.2174/092986708784567671}, pmid = {18537618}, issn = {0929-8673}, mesh = {Animals ; Erythropoietin/chemistry/metabolism/*therapeutic use ; Granulocyte Colony-Stimulating Factor/chemistry/metabolism/*therapeutic use ; Granulocyte-Macrophage Colony-Stimulating Factor/chemistry/metabolism/*therapeutic use ; Humans ; Nervous System Diseases/*drug therapy ; }, abstract = {Currently, growth factors which have been identified in hematopoiesis and angiogenesis are re-considered as therapeutical agents in a number of neurological diseases, mainly neurodegenerative disorders like Parkinson's Disease, amyotrophic lateral sclerosis (ALS), or cerebrovascular events such as stroke. Among these growth factors, erythropoietin (EPO) and granulocyte colony-stimulating growth factor (G-CSF) are the most prominent. With regard to neurological disease, EPO has been tested in clinical trials for potential use in stroke, schizophrenia, and addiction, G-CSF is currently under clinical investigation for stroke treatment. The major advantage of these growth factors is their well-described pharmacological behavior and their clinical use over several years. A number of mechanisms of action in the CNS have been identified that are probably important for the beneficial action of these factors in animal models of disease, the most relevant relating to neuroprotection, neuroplasticity and stem cell growth and differentiation. In this review, we will discuss the current efforts and prerequisites of novel growth factor therapies for neurodegenerative diseases with regard to their possible mechanism of action on the molecular level and their effects on brain-derived stem cell populations. Additionally, we will describe the necessities for future research before such therapies can be envisioned.}, }
@article {pmid18515324, year = {2008}, author = {Kelaher, M and Cawson, J and Miller, J and Kavanagh, A and Dunt, D and Studdert, DM}, title = {Use of breast cancer screening and treatment services by Australian women aged 25-44 years following Kylie Minogue's breast cancer diagnosis.}, journal = {International journal of epidemiology}, volume = {37}, number = {6}, pages = {1326-1332}, doi = {10.1093/ije/dyn090}, pmid = {18515324}, issn = {1464-3685}, mesh = {Adult ; Australia ; Biopsy ; Breast Neoplasms/*diagnosis ; *Famous Persons ; Female ; Humans ; Logistic Models ; Mammography ; Mass Media ; *Patient Acceptance of Health Care ; Women/*psychology ; }, abstract = {OBJECTIVE: To examine the effects of the publicity surrounding Kylie Minogue's diagnosis with breast cancer on doctor-referred breast imaging, image-guided biopsy, and cancer excisions among a low-risk population of women in Australia. Method We examine changes in unilateral and bilateral breast imaging, image-guided breast biopsies, and surgical excisions of breast cancer before and after the announcement of Kylie Minogue's diagnosis with breast cancer in May 2005. The study included procedures provided through the Australian public health system to women aged 25-44 years from October 2004 and June 2006.<br><br>RESULTS: The odds of women aged 25-44 years undergoing imaging procedures increased by 20% in the first and second quarters after the Minogue publicity, compared to the preceding two quarters. The volume of biopsies als increased but the biopsy rate, measured as a proportion of imaging procedures, did not change among women aged 25-34 years and decreased among women aged 35-44 years. The volume of operations to excise breast cancers did not change for either age group. Compared to the 6 month period before the publicity, there was a large and significant decrease in the odds that an excision would follow biopsy (25-34 years: OR 95% CI=0.69, 0.48-0.98; 35-44 years: OR 95% CI=0.83, 0.72-0.95).<br><br>CONCLUSIONS: High-publicised illnesses may affect both consumer and provider behaviour. Although they present opportunities to improve public health, they also have the potential to adversely impact the appropriateness and cost-effectiveness of service delivery.}, }
@article {pmid18508343, year = {2008}, author = {Rajabally, YA and Jacob, S}, title = {Chronic inflammatory demyelinating polyneuropathy-like disorder associated with amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {38}, number = {1}, pages = {855-860}, doi = {10.1002/mus.21010}, pmid = {18508343}, issn = {0148-639X}, mesh = {Action Potentials/physiology ; Aged ; Amyotrophic Lateral Sclerosis/*complications/pathology ; Disease Progression ; Electrodiagnosis ; Female ; Humans ; Immunologic Factors/therapeutic use ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Muscle Weakness/etiology/pathology ; Neural Conduction/physiology ; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/*complications/pathology ; }, abstract = {The association between demyelinating neuropathy and amyotrophic lateral sclerosis (ALS) has been reported rarely. We report four patients who presented with clinical features and investigations suggestive of a neuropathy but who later progressed and received a final diagnosis of ALS according to the original El Escorial criteria. Three patients met the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) 2006 definition for "definite" chronic inflammatory demyelinating polyneuropathy (CIDP), as well as the American Academy of Neurology (AAN) 1991 and Nicolas et al. [2002] electrodiagnostic criteria for CIDP. Two of them showed segmental demyelination on teased-fiber preparations and one had a raised cerebrospinal fluid protein level. Another patient met the Nicolas et al. CIDP criteria and presented with brachial plexus hyperintensity on T2-weighted magnetic resonance imaging, indicative of an inflammatory process. No significant objective response to immunomodulatory treatment was observed in any of these patients who all subsequently progressed unfavorably.}, }
@article {pmid18506038, year = {2008}, author = {Yunusova, Y and Weismer, G and Westbury, JR and Lindstrom, MJ}, title = {Articulatory movements during vowels in speakers with dysarthria and healthy controls.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {51}, number = {3}, pages = {596-611}, doi = {10.1044/1092-4388(2008/043)}, pmid = {18506038}, issn = {1092-4388}, support = {R01 DC003723/DC/NIDCD NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications ; Biomechanical Phenomena ; Dysarthria/diagnosis/etiology/*physiopathology ; Female ; Humans ; Male ; Middle Aged ; Parkinson Disease/complications ; *Phonetics ; Severity of Illness Index ; Speech Acoustics ; Speech Perception ; *Speech Production Measurement ; }, abstract = {PURPOSE: This study compared movement characteristics of markers attached to the jaw, lower lip, tongue blade, and dorsum during production of selected English vowels by normal speakers and speakers with dysarthria due to amyotrophic lateral sclerosis (ALS) or Parkinson disease (PD). The study asked the following questions: (a) Are movement measures different for healthy controls and speakers with ALS or PD, and (b) Are articulatory profiles comparable for speakers with ALS and speakers with PD?<br><br>METHOD: Nineteen healthy controls and 15 speakers with dysarthria participated in this study. The severity of dysarthria varied across individuals and between the 2 disorder groups. The stimuli were 10 words (i.e., seed, feed, big, dish, too, shoo, bad, cat, box, and dog) embedded into sentences read at a comfortable reading rate. Movement data were collected using the X-ray microbeam. Movement measures included distances, durations, and average speeds of vowel-related movement strokes.<br><br>RESULTS: Differences were found (a) between speakers with ALS and healthy controls and (b) between speakers with ALS and PD, particularly in movement speed. Tongue movements in PD and ALS were more consistently different from healthy controls than jaw and lower lip movements. This study showed that the effects of neurologic disease on vowel production are often articulator-, vowel-, and context-specific.<br><br>CONCLUSIONS: Differences in severity between the speakers with PD and ALS may have accounted for some of the differences in movement characteristics between the groups. These factors need to be carefully considered when describing the nature of speech disorder and developing empirically based evaluation and treatment strategies for dysarthria.}, }
@article {pmid18504244, year = {2008}, author = {Frost, JH and Massagli, MP}, title = {Social uses of personal health information within PatientsLikeMe, an online patient community: what can happen when patients have access to one another's data.}, journal = {Journal of medical Internet research}, volume = {10}, number = {3}, pages = {e15}, pmid = {18504244}, issn = {1438-8871}, mesh = {Female ; *Health Knowledge, Attitudes, Practice ; Humans ; Internet/*statistics &amp; numerical data ; *Interpersonal Relations ; Male ; Medical Record Linkage/methods ; Motor Neuron Disease/psychology/*therapy ; Patient Acceptance of Health Care/*psychology ; Patient Compliance ; Patient Education as Topic ; Patient Satisfaction ; Patients/*psychology ; Self Care/methods ; United States ; }, abstract = {BACKGROUND: This project investigates the ways in which patients respond to the shared use of what is often considered private information: personal health data. There is a growing demand for patient access to personal health records. The predominant model for this record is a repository of all clinically relevant health information kept securely and viewed privately by patients and their health care providers. While this type of record does seem to have beneficial effects for the patient-physician relationship, the complexity and novelty of these data coupled with the lack of research in this area means the utility of personal health information for the primary stakeholders-the patients-is not well documented or understood.<br><br>OBJECTIVE: PatientsLikeMe is an online community built to support information exchange between patients. The site provides customized disease-specific outcome and visualization tools to help patients understand and share information about their condition. We begin this paper by describing the components and design of the online community. We then identify and analyze how users of this platform reference personal health information within patient-to-patient dialogues.<br><br>METHODS: Patients diagnosed with amyotrophic lateral sclerosis (ALS) post data on their current treatments, symptoms, and outcomes. These data are displayed graphically within personal health profiles and are reflected in composite community-level symptom and treatment reports. Users review and discuss these data within the Forum, private messaging, and comments posted on each other's profiles. We analyzed member communications that referenced individual-level personal health data to determine how patient peers use personal health information within patient-to-patient exchanges.<br><br>RESULTS: Qualitative analysis of a sample of 123 comments (about 2% of the total) posted within the community revealed a variety of commenting and questioning behaviors by patient members. Members referenced data to locate others with particular experiences to answer specific health-related questions, to proffer personally acquired disease-management knowledge to those most likely to benefit from it, and to foster and solidify relationships based on shared concerns.<br><br>CONCLUSIONS: Few studies examine the use of personal health information by patients themselves. This project suggests how patients who choose to explicitly share health data within a community may benefit from the process, helping them engage in dialogues that may inform disease self-management. We recommend that future designs make each patient's health information as clear as possible, automate matching of people with similar conditions and using similar treatments, and integrate data into online platforms for health conversations.}, }
@article {pmid18498055, year = {2010}, author = {Roemmler, J and Bidlingmaier, M and Schopohl, J}, title = {Endogenous estradiol may influence IGF-I levels in acromegalic women treated with pegvisomant.}, journal = {Pituitary}, volume = {13}, number = {1}, pages = {89-93}, pmid = {18498055}, issn = {1573-7403}, mesh = {Acromegaly/blood/*drug therapy ; Estradiol/*blood ; Female ; Human Growth Hormone/*analogs &amp; derivatives/pharmacology/therapeutic use ; Humans ; Insulin-Like Growth Factor I/*analysis ; Middle Aged ; Receptors, Somatotropin/antagonists &amp; inhibitors ; }, abstract = {We present the case of a 46-year-old woman with acromegaly currently being treated with the growth hormone (GH) receptor antagonist pegvisomant showing strongly fluctuating IGF-I levels. We prospectively measured estradiol, IGF-I, IGF-I binding protein, acid labile subunit, basal endogenous GH, binding protein and pegvisomant levels for 6 months every week. Estradiol levels showed a strongly negative correlation with IGF-I (r = -0.733, P < 0.001), and less so with ALS (r = -0.433, P < 0.05) and IGFBP3 (r = -0.590, P < 0.01). Estradiol was not significantly correlated with endogenous GH or pegvisomant levels. Likewise, IGF-I did not correlate with endogenous GH or pegvisomant levels. In our patient, endogenous estradiol levels have a significant influence on IGF-I levels. When female acromegalic patients on permanent pegvisomant treatment show fluctuating IGF-I levels, estradiol levels should be taken into consideration.}, }
@article {pmid18484797, year = {2008}, author = {Corcia, P and Meininger, V}, title = {Management of amyotrophic lateral sclerosis.}, journal = {Drugs}, volume = {68}, number = {8}, pages = {1037-1048}, pmid = {18484797}, issn = {0012-6667}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/genetics/*therapy ; Genetic Counseling ; Humans ; Mutation ; Nutritional Support ; Physical Therapy Modalities ; Speech Therapy ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor neurons, in both the spinal cord and medulla (lower motor neurons) and cerebral cortex (upper motor neurons). Even though ALS remains fatal, several advances have been made during the last decade in improving the consequences of motor dysfunction, quality of life and survival time of patients. Treatment of ALS cannot be restricted to riluzole, the only molecule that has been proved to modify the evolution of the disease. Symptomatic treatments have an important role in controlling the major consequences of the disease, such as pain, sleep disorders, spasticity, hypersialhorroea, emotional lability, depression and digestive disorders (constipation and reflux). All these symptoms need to be recognized and their possible causes identified in order to provide the most appropriate management of patients with ALS. However, an advance in the daily care of patients is the identification of two important phenomena that occur during the evolution of the disease: swallowing difficulties and the occurrence of diaphragmatic dysfunction. For both, specific medical interventions have been developed to allow correction of the consequences (i.e. weight loss and respiratory insufficiency). Although no controlled trials have been performed, observational studies suggest that gastrostomy and non-invasive ventilation may improve at least quality of life and survival. All of these various approaches, pharmaceutical and non-pharmaceutical therapies, are prescribed according to individual symptoms and require the involvement of a large range of health professionals. This multidisciplinary approach in ALS clinics is considered to be one of the more important factors impacting on survival rate and appears to be the gold standard of medical care of ALS patients. Important findings have been made in understanding the nature of the degenerative process that affects the motor neurons. All these data have allowed new therapeutic molecules to be tested alone or in combination with riluzole. Despite the negative results obtained until now, we hope to demonstrate very soon a greater improvement in therapy.}, }
@article {pmid18478527, year = {2008}, author = {Wojda, U and Salinska, E and Kuznicki, J}, title = {Calcium ions in neuronal degeneration.}, journal = {IUBMB life}, volume = {60}, number = {9}, pages = {575-590}, doi = {10.1002/iub.91}, pmid = {18478527}, issn = {1521-6551}, mesh = {Aging/physiology ; Animals ; Calcium/*metabolism ; Calcium Channels/metabolism ; Calcium Signaling/*physiology ; *Homeostasis ; Humans ; Nerve Degeneration/metabolism ; Neurodegenerative Diseases/pathology/physiopathology ; *Neurons/metabolism/pathology ; Receptors, Glutamate/metabolism ; }, abstract = {Neuronal Ca(2+) homeostasis and Ca(2+) signaling regulate multiple neuronal functions, including synaptic transmission, plasticity, and cell survival. Therefore disturbances in Ca(2+) homeostasis can affect the well-being of the neuron in different ways and to various degrees. Ca(2+) homeostasis undergoes subtle dysregulation in the physiological ageing. Products of energy metabolism accumulating with age together with oxidative stress gradually impair Ca(2+) homeostasis, making neurons more vulnerable to additional stress which, in turn, can lead to neuronal degeneration. Neurodegenerative diseases related to aging, such as Alzheimer's disease, Parkinson's disease, or Huntington's disease, develop slowly and are characterized by the positive feedback between Ca(2+) dyshomeostasis and the aggregation of disease-related proteins such as amyloid beta, alfa-synuclein, or huntingtin. Ca(2+) dyshomeostasis escalates with time eventually leading to neuronal loss. Ca(2+) dyshomeostasis in these chronic pathologies comprises mitochondrial and endoplasmic reticulum dysfunction, Ca(2+) buffering impairment, glutamate excitotoxicity and alterations in Ca(2+) entry routes into neurons. Similar changes have been described in a group of multifactorial diseases not related to ageing, such as epilepsy, schizophrenia, amyotrophic lateral sclerosis, or glaucoma. Dysregulation of Ca(2+) homeostasis caused by HIV infection or by sudden accidents, such as brain stroke or traumatic brain injury, leads to rapid neuronal death. The differences between the distinct types of Ca(2+) dyshomeostasis underlying neuronal degeneration in various types of pathologies are not clear. Questions that should be addressed concern the sequence of pathogenic events in an affected neuron and the pattern of progressive degeneration in the brain itself. Moreover, elucidation of the selective vulnerability of various types of neurons affected in the diseases described here will require identification of differences in the types of Ca(2+) homeostasis and signaling among these neurons. This information will be required for improved targeting of Ca(2+) homeostasis and signaling components in future therapeutic strategies, since no effective treatment is currently available to prevent neuronal degeneration in any of the pathologies described here.}, }
@article {pmid18475179, year = {2008}, author = {Chen, X and Zhang, X and Larson, C and Xia, G and Kaufman, DB}, title = {Prolonging islet allograft survival using in vivo bioluminescence imaging to guide timing of antilymphocyte serum treatment of rejection.}, journal = {Transplantation}, volume = {85}, number = {9}, pages = {1246-1252}, pmid = {18475179}, issn = {0041-1337}, support = {R01 DK063565/DK/NIDDK NIH HHS/United States ; R01 DK063565-04/DK/NIDDK NIH HHS/United States ; DK063565/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/administration &amp; dosage/*therapeutic use ; Diabetes Mellitus, Experimental/surgery ; Drug Administration Schedule ; Fireflies ; Genes, Reporter ; Graft Rejection ; Graft Survival/*physiology ; Islets of Langerhans Transplantation/immunology/*methods/physiology ; Luciferases/genetics ; Luminescent Measurements ; Mice ; Mice, Inbred Strains ; Mice, Transgenic ; Models, Animal ; Transplantation, Homologous/physiology ; }, abstract = {BACKGROUND: Bioluminescence imaging (BLI) is a sensitive and noninvasive method for tracking the fate of transplanted islets. The aim of this study was to investigate whether early detection of rejection by BLI can aid in the timing of antilymphocyte serum (ALS) treatment for prolonging islet graft survival.<br><br>METHODS: Transgenic islets (200 per recipient) expressing the firefly luciferase from FVB/NJ strain (H-2q) mice were transplanted under the kidney capsule of streptozotocin-induced diabetic allogeneic Balb/c strain (H-2q) mice. BLI signals and serum glucose levels were measured daily after transplant. Four groups of mice were transplanted: group 1 recipients were untreated controls (n=12), group 2 (n=8) received ALS before transplant, group 3 (n=10) received ALS at a time after transplant when normoglycemic but prompted by a reduction (approximately 30%) in BLI signal intensity for 2 consecutive days, and group 4 (n=5) received ALS after transplant when prompted by blood glucose levels increasing approximately 20% from the normoglycemic baseline (BLI reduction approximately 70%).<br><br>RESULTS: The incidence of graft loss from rejection in groups 1, 2, 3, and 4 was 92.3%, 88%, 40%, and 100%, respectively. The mean (+/-SE) time to graft loss in groups 1, 2, 3 and 4 was 22.5+/-4.8, 29.2+/-9.9, 53.5+/-17.9, and 22.1+/-2.4 days, respectively.<br><br>CONCLUSIONS: Noninvasive imaging modalities of functional islet mass, such as BLI (but not blood glucose levels), can prompt the appropriate timing of ALS treatment of islet allograft rejection and significantly prolong graft survival or protect the grafts from permanent loss.}, }
@article {pmid18475124, year = {2008}, author = {Zanini, R and Aroldi, M and Bonatti, S and Buffoli, F and Izzo, A and Lettieri, C and Romano, M and Tomasi, L and Ferrari, MR}, title = {Impact of prehospital diagnosis in the management of ST elevation myocardial infarction in the era of primary percutaneous coronary intervention: reduction of treatment delay and mortality.}, journal = {Journal of cardiovascular medicine (Hagerstown, Md.)}, volume = {9}, number = {6}, pages = {570-575}, doi = {10.2459/JCM.0b013e3282f2c9bd}, pmid = {18475124}, issn = {1558-2027}, mesh = {Angioplasty, Balloon, Coronary/*mortality ; Cardiac Catheterization ; *Electrocardiography ; *Emergency Medical Services ; Female ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Myocardial Infarction/*diagnosis/mortality/*physiopathology ; Time Factors ; }, abstract = {OBJECTIVES: The aim of the study is to assess, as primary endpoints, in-hospital mortality and percutaneous coronary intervention (PCI) mortality and to compare the outcome in ST elevation myocardial infarction (STEMI) patients with different pathways to a catheterization laboratory in the context of an area with 24 h availability of catheter facilities.<br><br>METHODS: Three hundred and ninety-nine STEMI patients, referred to an interventional centre for primary PCI, were divided into two groups according to the different pathways to the catheterization laboratory. Group A had 263 patients diagnosed following admission to First Aid. Group B had 136 patients diagnosed in a prehospital setting with telemedicine equipment and transferred directly to the interventional centre by advanced life support (ALS) ambulance.<br><br>RESULTS: Significantly shorter treatment delay was observed in group B patients than in group A (262 +/- 112 vs. 148 +/- 81 min in group A vs. B, P < 0.001). A significant reduction in total mortality was observed in group B compared with group A (8.7 vs. 3% in group A vs. B, P < 0.05). After multivariate analysis, predictors of in-hospital mortality are age and Killip class (P < 0.01), different pathways to catheterization laboratory, pre-PCI TIMI flow and onset-to-balloon time (P < 0.05).<br><br>CONCLUSION: The present study shows a reduction in treatment delay and in-hospital mortality by prehospital ECG and direct referral to catheterization laboratory.}, }
@article {pmid18466055, year = {2008}, author = {Ryberg, H and Bowser, R}, title = {Protein biomarkers for amyotrophic lateral sclerosis.}, journal = {Expert review of proteomics}, volume = {5}, number = {2}, pages = {249-262}, doi = {10.1586/14789450.5.2.249}, pmid = {18466055}, issn = {1744-8387}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Biomarkers ; Humans ; Proteins/*analysis ; Proteomics/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with largely unknown pathogenesis that typically results in death within a few years from diagnosis. There are currently no effective therapies for ALS. Clinical diagnosis usually takes several months to complete and the long delay between symptom onset and diagnosis limits the possibilities for effective intervention and clinical trials. The establishment of protein biomarkers for ALS may aid an earlier diagnosis, facilitating the search for effective therapeutic interventions and monitoring drug efficacy during clinical trials. Biomarkers could also be used to discriminate between subtypes of ALS, to measure disease progression and to detect susceptibility for developing ALS or monitor adverse effects of drug treatment. The present review will discuss the opportunities and proteomic platforms used for biomarker discovery efforts in ALS, summarizing putative ALS protein biomarkers identified in different biofluids.}, }
@article {pmid18465624, year = {1998}, author = {Geerts, H}, title = {AIT-082 NeoTherapeutics Inc.}, journal = {IDrugs : the investigational drugs journal}, volume = {1}, number = {6}, pages = {694-699}, pmid = {18465624}, issn = {1369-7056}, abstract = {AIT-082 (an analog of hypoxanthine) is an orally-active nerve growth factor (NGF) agonist under development by NeoTherapeutics as a potential treatment for Alzheimer's disease (AD), stroke and motor neuron disease. A phase II safety and efficacy trial in AD, originally scheduled to begin in the summer of 1997 [283677], began in May 1998 [286975,285562]. The study will enroll more than 60 AD patients [286975]. In February 1998, NeoTherapeutics began a phase I multiple-dose pharmacokinetic study of AIT-082 in 24 healthy elderly volunteers. Subjects of the phase I study will be administered AIT-082 once a day for 7 consecutive days at doses of 100 to 2000 mg per dose [279422]. A limited double-blind, placebo-controlled phase I/II trial in 10 AD patients commenced in Canada in the first quarter of 1997. Treatment with 4000 mg improved memory in 60% of the patients within 3 h, as determined by the word recall test. A decrease in memory was observed in 80% of placebo-treated patients [257132]. A phase I US trial, conducted by the Alzheimer's Disease Cooperative Study, with funding from the National Institute of Aging, began in July 1997. AIT-082 was administered to eight healthy, elderly volunteers as part of an escalating single-dose study. Oral administration of AIT-082 was well-tolerated at high doses [284325] AIT-082 also enhanced memory function in both young adult and aged mice within 2 h of oral administration. Prophylactic treatment prevented or delayed the onset of age-induced memory deficits in mice when administered in drinking water. When memory impairment was produced by brain lesions, the drug restored memory performance and increased the genetic expression of neurotrophin-3 (NT-3), a natural protein growth factor associated with nerve cell function [284325]. AIT-082 appears to have at least three effects on the growth of PC-12 cells in culture. Firstly, it stimulates outgrowth of neurites, secondly it potentiates the growth effects of neurotrophin, and thirdly, it stimulates the synthesis of certain neurotrophins (nerve growth factor, neurotrophin-3 and fibroblast growth factor) and pleiotrophins by astrocytes. These progrowth mechanisms are thought to form the basis of the ability of AIT-082 to restore and prevent age-related working memory deficits in mice [195438]. In October 1997, further preclinical results were presented, demonstrating that treatment with AIT-082 produced an increase in neurotrophic factors following spinal cord injury in rats. This study was conducted at NeoTherapeutics and McMaster University, and was partially funded by the Amyotrophic Lateral Sclerosis Society of Canada. After 7 days of treatment, rats with spinal cord injuries showed an increase in the levels of CNTF and BDNF, naturally occurring growth factors in the spinal cord [267514].}, }
@article {pmid18464925, year = {2008}, author = {Bernardo, A and Minghetti, L}, title = {Regulation of Glial Cell Functions by PPAR-gamma Natural and Synthetic Agonists.}, journal = {PPAR research}, volume = {2008}, number = {}, pages = {864140}, pmid = {18464925}, issn = {1687-4757}, abstract = {In the recent years, the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a well known target for type II diabetes treatment, has received an increasing attention for its therapeutic potential in inflammatory and degenerative brain disorders. PPAR-gamma agonists, which include naturally occurring compounds (such as long chain fatty acids and the cyclopentenone prostaglandin 15-deoxy Delta(12,14) prostaglandin J(2)), and synthetic agonists (among which the thiazolidinediones and few nonsteroidal anti-inflammatory drugs) have shown anti-inflammatory and protective effects in several experimental models of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis and stroke, as well as in few clinical studies. The pleiotropic effects of PPAR-gamma agonists are likely to be mediated by several mechanisms involving anti-inflammatory activities on peripheral immune cells (macrophages and lymphocytes), as well as direct effects on neural cells including cerebral vascular endothelial cells, neurons, and glia. In the present article, we will review the recent findings supporting a major role for PPAR-gamma agonists in controlling neuroinflammation and neurodegeneration through their activities on glial cells, with a particular emphasis on microglial cells as major macrophage population of the brain parenchyma and main actors in brain inflammation.}, }
@article {pmid18464922, year = {2008}, author = {Kiaei, M}, title = {Peroxisome Proliferator-Activated Receptor-gamma in Amyotrophic Lateral Sclerosis and Huntington's Disease.}, journal = {PPAR research}, volume = {2008}, number = {}, pages = {418765}, pmid = {18464922}, issn = {1687-4757}, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and one of the most common adult-onset neurodegenerative diseases with the prevalence of about 5 per 100 000 individuals. It results in the progressive loss of upper and lower motor neurons and leads to gradual muscle weakening ultimately causing paralysis and death. ALS has an obscure cause and currently no effective treatment exists. In this review, a potentially important pathway is described that can be activated by peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists and has the ability to block the neuropathological damage caused by inflammation in ALS and possibly in other neudegenerative diseases like Huntington's disease (HD). Neuroinflammation is a common pathological feature in neurodegenerative diseases. Therefore, PPAR-gamma agonists are thought to be neuroprotective in ALS and HD. We and others have tested the neuroprotective effect of pioglitazone (Actos), a PPAR-gamma agonist, in G93A SOD1 transgenic mouse model of ALS and found significant increase in survival of G93A SOD1 mice. These findings suggest that PPAR-gamma may be an important regulator of neuroinflammation and possibly a new target for the development of therapeutic strategies for ALS. The involvement of PPAR-gamma in HD is currently under investigation, one study finds that the treatment with rosiglitazone had no protection in R6/2 transgenic mouse model of HD. PPAR-gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator that works together with combination of other transcription factors like PPAR-gamma in the regulation of mitochondrial biogenesis. Therefore, PPAR-gamma is a possible target for ALS and HD as it functions as transcription factor that interacts with PGC-1alpha. In this review, the role of PPAR-gamma in ALS and HD is discussed based on the current literature and hypotheses.}, }
@article {pmid18460823, year = {2008}, author = {Kim, KJ and Cho, HS and Choi, SJ and Jeun, SH and Kim, SY and Sung, KW}, title = {Direct effects of riluzole on 5-hydroxytryptamine (5-HT)3 receptor-activated ion currents in NCB-20 neuroblastoma cells.}, journal = {Journal of pharmacological sciences}, volume = {107}, number = {1}, pages = {57-65}, doi = {10.1254/jphs.fp0072095}, pmid = {18460823}, issn = {1347-8613}, mesh = {Animals ; Cell Line, Tumor ; Dopamine/metabolism ; Dose-Response Relationship, Drug ; Humans ; Membrane Potentials ; Neuroblastoma/*metabolism ; Neuroprotective Agents/*pharmacology ; Patch-Clamp Techniques ; Receptors, Serotonin, 5-HT3/metabolism ; Riluzole/*pharmacology ; Serotonin/*metabolism ; *Serotonin 5-HT3 Receptor Antagonists ; Serotonin Antagonists/*pharmacology ; Time Factors ; }, abstract = {The pharmacological action of riluzole, a drug that has been approved as a neuroprotective agent for the treatment of amyotrophic lateral sclerosis, has not yet been established. We examined the effects of riluzole on 5-hydroxytryptamine (5-HT)3) receptors in NCB-20 neuroblastoma cells using the whole-cell voltage clamp technique combined with a fast drug application method. Co-application of riluzole (1 - 300 microM, 5 s) produced a dose-dependent reduction in peak amplitudes and in the rise slope of the currents induced by 2 microM 5-HT. In addition, 5-HT3-mediated currents evoked by dopamine, a partial 5-HT3-receptor agonist, were inhibited by riluzole co-application. These inhibitory effects were clearly shown at low concentrations of 5-HT. The decay time constants of the receptor desensitization and deactivation were also significantly attenuated by riluzole. G-protein inhibitors (pertussis toxin and guanosine 5'-[beta-thio] diphosphate) did not completely block these inhibitory actions of riluzole. These results indicate that riluzole inhibits 5-HT3-induced ion currents directly by slowing channel activation in NCB-20 neuroblastoma cells.}, }
@article {pmid18454605, year = {2008}, author = {Goy, ER and Carter, J and Ganzini, L}, title = {Neurologic disease at the end of life: caregiver descriptions of Parkinson disease and amyotrophic lateral sclerosis.}, journal = {Journal of palliative medicine}, volume = {11}, number = {4}, pages = {548-554}, doi = {10.1089/jpm.2007.0258}, pmid = {18454605}, issn = {1096-6218}, mesh = {Adaptation, Psychological ; Aged ; *Amyotrophic Lateral Sclerosis/mortality/psychology ; Caregivers/*psychology ; Female ; Humans ; Male ; Middle Aged ; Oregon ; Pain Measurement ; Palliative Care/*psychology ; *Parkinson Disease/mortality/psychology ; Psychometrics ; Surveys and Questionnaires ; Washington ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is well recognized as a terminal illness with an established need for palliative care. Parkinson's disease is a substantially more common cause of death, yet little has been written about the palliative needs of these patients at the end of life. To highlight the palliative care needs and experiences of patients with Parkinson's disease and related disorders (PDRD), we compared them to patients with ALS.<br><br>METHODS: Family caregivers of decedent PDRD and ALS patients in Oregon and Washington were surveyed about their loved one's symptoms, treatment preferences, health care usage, and psychosocial experiences during the last month of life.<br><br>RESULTS: Fifty-two PDRD and 50 ALS caregivers completed the survey. Overall suffering (1 = none to 6 = severe) was rated a median of 4 for both groups. Pain was moderately severe or worse in 42% of PDRD patients and 52% of ALS patients; of these, 27% of PDRD and 19% of ALS patients received no pain medication in the last month. PDRD featured more severe effects of confusion than ALS, although less dyspnea and difficulty eating. PDRD patients had significantly shorter hospice enrollments than ALS patients (p < 0.01).<br><br>CONCLUSIONS: In the views of caregivers, suffering associated with ALS is no more severe than suffering associated with PDRD, and both groups appear to have unmet palliative care needs in the last months of life. Studies to define hospice readiness and special needs in hospice might improve end-of-life care for PDRD patients.}, }
@article {pmid18453156, year = {2008}, author = {Matsuyama, Y and Sasagasako, N and Koike, A and Matsuura, M and Koga, T and Kawajiri, M and Ohyagi, Y and Iwaki, T and Kira, J}, title = {[An autopsy case of amyotrophic lateral sclerosis with ampulla cardiomyopathy].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {48}, number = {4}, pages = {249-254}, doi = {10.5692/clinicalneurol.48.249}, pmid = {18453156}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*complications/pathology ; Autopsy ; Humans ; Male ; Middle Aged ; Takotsubo Cardiomyopathy/*complications/pathology ; }, abstract = {We herein report an autopsy case of a 63-year-old man with amyotrophic lateral sclerosis (ALS) who developed "ampulla cardiomyopathy." At the age of 56, he noticed a progressive weakness in his right upper extremity. One year later, a progressive weakness of the left upper extremity began. Dropped head and progressive weakness of the lower extremities emerged at the ages of 61 and 62, respectively. Intravenous immunoglobulin and plasma-exchange therapies did not improve his weakness. At the age of 63, one month before his death, he was hospitalized due to aspiration pneumonia. A tracheostomy was performed to secure his airway. Four days after the operation, an ST elevation of his electrocardiogram was incidentally found on the ECG monitor. An echocardiogram revealed diffuse hypokinesia of the wall of the left ventricle except in the basal portion, which is the typical finding of "ampulla cardiomyopathy." Wall motion of the left ventricle improved and his circulatory condition was stabilized after treatment, but his condition thereafter worsened again and he died 3 weeks later. An autopsy examination revealed diffuse fibrosis and degeneration of the cardiomyofibers. Neuropathological examination revealed neuronal cell loss, Bunina bodies and skein-like inclusions in the hippoglossal nuclei. In the thoracic spinal cord, degenarated anterior horn cells were seen and macrophage permeation in the corticospinal tract were shown by CD68 immunostaining. Therefore, the final neuropathological diagnosis was ALS. This report is the first autopsy case of ALS complicated with "ampulla cardiomyopathy."}, }
@article {pmid19578526, year = {2008}, author = {Jain, MR and Ge, WW and Elkabes, S and Li, H}, title = {Amyotrophic lateral sclerosis: Protein chaperone dysfunction revealed by proteomic studies of animal models.}, journal = {Proteomics. Clinical applications}, volume = {2}, number = {5}, pages = {670-684}, pmid = {19578526}, issn = {1862-8354}, support = {P30 NS046593/NS/NINDS NIH HHS/United States ; P30 NS046593-04/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons and causes progressive muscle weakness and atrophy. The etiology and pathogenesis of ALS are largely unknown and no effective treatment is presently available. About 10% of patients have the familial or inherited form of the disease (fALS), among which 20% is linked to mutations with Cu(2+)/Zn(2+) superoxide dismutase (mSOD1). Transgenic animals expressing human mSOD1 are excellent models for understanding not only fALS but sporadic ALS as well. Pathological features in both ALS patients and mSOD1 transgenic animals' spinal cords share commonalties including the accumulation of misfolded protein inclusions. Recent proteomic investigations on ALS animal models have discovered alterations in protein expression, protein-protein interactions and post-translational modifications. These efforts have revealed aspects of potential pathogenic mechanisms and identified probable therapeutic targets. The present review summarizes the major findings of proteomics studies performed on the mSOD1 mice with particular emphasis on the spinal cord proteome. These results are compared with those reported using cell cultures or specimens obtained from ALS patients. The convergence of pathogenic processes on protein chaperone function, and its relationship to protein degradation, metabolic dysfunction and oxidative signaling events is discussed.}, }
@article {pmid18436268, year = {2008}, author = {Zhang, X and Chen, S and Li, L and Wang, Q and Le, W}, title = {Folic acid protects motor neurons against the increased homocysteine, inflammation and apoptosis in SOD1 G93A transgenic mice.}, journal = {Neuropharmacology}, volume = {54}, number = {7}, pages = {1112-1119}, doi = {10.1016/j.neuropharm.2008.02.020}, pmid = {18436268}, issn = {0028-3908}, mesh = {*Amyotrophic Lateral Sclerosis/blood/drug therapy/pathology ; Animals ; Apoptosis/*drug effects ; Cytokines/metabolism ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay/methods ; Folic Acid/*therapeutic use ; Gas Chromatography-Mass Spectrometry/methods ; Homocysteine/*blood ; Inflammation/*drug therapy/etiology ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects ; Nitric Oxide Synthase Type II/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Random Allocation ; Rotarod Performance Test/methods ; Spinal Cord/pathology ; Superoxide Dismutase/genetics ; Vitamin B 12/therapeutic use ; Vitamin B Complex/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by selective degeneration of motor neurons. Mutations in copper/zinc superoxide dismutase (SOD1) account for 20% cases of familial ALS (fALS), but the underlying pathogenetic mechanisms are largely unknown. Using SOD1(G93A) mice model of ALS, we demonstrated that mutation in SOD1 caused a significant increase in the level of plasma homocysteine (Hcy). To investigate whether Hcy-lowering therapy is beneficial to this disease, we applied folic acid (FA) and vitamin B12 which are important factors involved in the Hcy metabolism to assess the neuroprotective effect of FA and B12 in the SOD1(G93A) mice. Our results showed FA or FA+B12 treatment significantly delayed the disease onset and prolonged the lifespan, accompanied by the significant reduction of motor neuron loss. Furthermore, we found that FA or FA+B12 treatment significantly attenuated the plasma Hcy level, suppressed the activation of microglia and astrocytes, and inhibited the expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in spinal cord. Moreover, FA or FA+B12 treatment decreased the levels of cleaved caspase-3 and poly(ADP-ribose)polymerase (PARP) but up-regulated the level of anti-apoptotic protein Bcl-2. However, B12 treatment alone did not show any significant benefit to this disease. These results provide evidence to demonstrate that elevated Hcy is involved in the pathogenesis of fALS and FA therapy may have therapeutic potential for the treatment of the disease.}, }
@article {pmid18428001, year = {2008}, author = {Kühnlein, P and Kübler, A and Raubold, S and Worrell, M and Kurt, A and Gdynia, HJ and Sperfeld, AD and Ludolph, AC}, title = {Palliative care and circumstances of dying in German ALS patients using non-invasive ventilation.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {9}, number = {2}, pages = {91-98}, doi = {10.1080/17482960701830495}, pmid = {18428001}, issn = {1471-180X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*nursing/*psychology ; *Attitude to Death ; Caregivers/*psychology ; Euthanasia/*psychology ; Female ; Germany ; Humans ; Male ; Middle Aged ; Palliative Care/*psychology ; Positive-Pressure Respiration/*psychology ; Suicide, Assisted/*psychology ; }, abstract = {Non-invasive ventilation (NIV) is known to improve quality of life and to prolong survival in amyotrophic lateral sclerosis (ALS) patients. However, little is known about the circumstances of dying in ventilated ALS patients. In the light of the debate on legalizing euthanasia it is important to provide empirical data about the process of dying in these patients. In a structured interview, 29 family caregivers of deceased ALS patients were asked about their own and the patient's attitude toward physician-assisted suicide (PAS) and euthanasia, circumstances of dying, and the use of palliative medication. Quantitative and qualitative content analysis was performed on the data. Non-recurring suicidal thoughts were reported by five patients. Three patients and seven relatives had thought about PAS. Seventeen caregivers described the patients' death as "peaceful", while choking was reported in six bulbar patients. In final stages of dying, the general practitioner (GP) was involved in the treatment of 10 patients, with palliative medication including sedatives and opiates being administered in eight cases. In conclusion, in contrast to the Netherlands, where 20% of terminal ALS patients die from PAS or euthanasia, only a small minority of our patients seems to have thought about PAS. The legal situation in Germany (where euthanasia is illegal), a bias due to the selection of NIV patients as well as a high percentage of religious patients and those with good levels of social support from family and friends, might account for this. Most of our patients died peacefully at home from carbon dioxide narcosis, but choking was described in some bulbar patients. Thus, palliative care, especially the use of opiates, anxiolytics and sedatives should be optimized, and the involvement of GP should be strongly encouraged, especially in bulbar patients.}, }
@article {pmid18428000, year = {2008}, author = {Nicaise, C and Coupier, J and Dabadie, MP and De Decker, R and Mangas, A and Bodet, D and Poncelet, L and Geffard, M and Pochet, R}, title = {Gemals, a new drug candidate, extends lifespan and improves electromyographic parameters in a rat model of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {9}, number = {2}, pages = {85-90}, doi = {10.1080/17482960701788180}, pmid = {18428000}, issn = {1471-180X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Animals ; Animals, Genetically Modified ; *Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Combinations ; Electromyography/*drug effects ; Longevity/*drug effects ; Muscle Contraction/*drug effects ; Polylysine/administration &amp; dosage/*analogs &amp; derivatives ; Rats/genetics ; Rats, Sprague-Dawley ; Treatment Outcome ; Weight Loss/*drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease involving selective and progressive degeneration and death of motor neurons. ALS is a multifactorial disease in which oxidative stress, glutamate excitotoxicity, intracellular aggregates, neurofilamentous disorganization, zinc excitotoxicity, mitochondrial damage, neuroinflammation, abnormalities in growth factors and apoptosis play a role. Any therapeutic approach to delay or stop the evolution of ALS should therefore ideally target these multiple pathways leading to motor neuron death. We have developed a combination therapy (Gemals) composed of functional polypeptides (fatty acids, free radical scavengers and amino acids linked to poly-L-lysine), chosen according to their known potentiality for regeneration or protection of neuronal components such as myelin, axon transport and mitochondria. We found that Gemals significantly extended lifespan and improved electromyographic parameters in a SOD1(G93A) rat model. The use of two drug concentrations indicated a possible dose dependence. These initial findings open the way to further investigation necessary to validate this new drug as a candidate for ALS treatment.}, }
@article {pmid18425887, year = {2008}, author = {Parton, M and Mitsumoto, H and Leigh, PN}, title = {WITHDRAWN: Amino acids for amyotrophic lateral sclerosis / motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {2}, pages = {CD003457}, doi = {10.1002/14651858.CD003457.pub2}, pmid = {18425887}, issn = {1469-493X}, mesh = {Amino Acids, Branched-Chain/*therapeutic use ; Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Motor Neuron Disease/drug therapy ; Randomized Controlled Trials as Topic ; Threonine/*therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis, also known as motor neuron disease, is a progressive neuromuscular disease that causes disability and eventual death. Various amino acid preparations, the three branched-chain amino acids (L-leucine, L-valine and L-isoleucine) or, alternatively, L-threonine have been used as experimental therapy.<br><br>OBJECTIVES: To examine the efficacy of amino acid therapies in prolonging survival and/or slowing the progression of amyotrophic lateral sclerosis/motor neuron disease.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (searched February 2003), MEDLINE (from January 1966 to December 2002) and EMBASE (from January 1980 to December 2002) databases and reports of specialist conferences. Authors of known studies were contacted.<br><br>SELECTION CRITERIA: We included randomised or quasi-randomised trials of participants with a clinical diagnosis of amyotrophic lateral sclerosis/motor neuron disease treated with all combinations of amino acids. Our primary outcome measure was survival determined by a pooled hazard ratio of all studies. Our secondary outcome measures were (in order of priority): survival at six and 12 months, muscle strength, any validated rating scale of physical function, quality of life, proportion of patients completing therapy and proportion of patients reporting adverse events attributable to treatment.<br><br>DATA COLLECTION AND ANALYSIS: We identified six eligible trials and rejected a further seven because of incomplete data or inadequate duration. Eligible studies were rated for methodological quality and missing data sought from the authors. After this examination two studies were excluded from analysis. Our pooled survival analysis was performed by the Parmar method, other statistical calculations were done using the Review Manager 4.2 software package.<br><br>MAIN RESULTS: No benefit could be demonstrated for either branched-chain amino acids or L-threonine in improving survival in amyotrophic lateral sclerosis/motor neuron disease. Neither could we find evidence of an effect of either treatment on muscle strength or disability as measured by functional rating scales. No study assessed quality of life. Both branched-chain amino acids and L-threonine appeared well tolerated and caused a degree of adverse events comparable to that of the control medication.<br><br>AUTHORS' CONCLUSIONS: There is no evidence to support a beneficial effect of either branched-chain amino acids or L-threonine in amyotrophic lateral sclerosis/motor neuron disease.}, }
@article {pmid18425621, year = {2008}, author = {Meyer, T and Maier, A and Borisow, N and Dullinger, JS and Splettstösser, G and Ohlraun, S and Münch, C and Linke, P}, title = {Thalidomide causes sinus bradycardia in ALS.}, journal = {Journal of neurology}, volume = {255}, number = {4}, pages = {587-591}, pmid = {18425621}, issn = {0340-5354}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*drug therapy/immunology ; Anti-Inflammatory Agents/administration &amp; dosage/adverse effects ; Arrhythmia, Sinus/*chemically induced/physiopathology ; Bradycardia/*chemically induced/physiopathology ; Death, Sudden/etiology ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Therapy, Combination ; Electrocardiography ; Excitatory Amino Acid Antagonists/administration &amp; dosage ; Humans ; Immunosuppressive Agents/administration &amp; dosage/adverse effects ; Inflammation/*drug therapy/immunology ; Middle Aged ; Parasystole/*chemically induced/physiopathology ; Pilot Projects ; Riluzole/administration &amp; dosage ; Thalidomide/administration &amp; dosage/*adverse effects ; Treatment Outcome ; }, abstract = {OBJECTIVE: Neuroinflammation contributes to motor neuron degeneration in ALS. Thalidomide (THL) shows potent anti-inflammatory properties and increased the lifespan in ALS transgenic mice. Thalidomide was therefore suggested as atherapeutic intervention for the treatment of ALS.We conducted a pilot, randomized clinical trial of THL in patients with ALS to assess safety, feasibility, and preliminary estimates of treatment efficacy.<br><br>METHODS: Patients were randomized to THL in combination with riluzole (n = 18) or riluzole alone (n = 19). THL was initiated at 100 mg per day for 6 weeks. Thereafter, the dose was increased every week by 50 mg until reaching the dose of 400 mg per day and planned to continue for another 12 weeks.<br><br>RESULTS: Within 12 weeks of THL treatment, nine THL patients (50%) developed bradycardia defined as a heart rate below 60 beats per minute (bpm) and ranged from 46 to 59 bpm. Mean heart rate dropped by 17 bpm with THL treatment. Severe symptomatic bradycardia of 30 bpm occurred in one patient. A further patient died from sudden unexpected death. The study was terminated prematurely for safety concerns. The secondary outcome variables showed similar results for both groups.<br><br>CONCLUSION: Bradycardia was the most common adverse event of THL treatment in ALS. THL-related bradycardia does not appear to be ALS-specific. It is conceivable, however, that the unexpected frequency and severity of THL-induced bradycardia may be related to subclinical involvement of the autonomic nervous system in ALS. The cardiac toxicity discourages further clinical trials and compassionate use of THL in ALS. ClinicalTrials.gov Identifier: NCT00231140.}, }
@article {pmid18423451, year = {2008}, author = {Tanaka, K and Okada, Y and Kanno, T and Otomo, A and Yanagisawa, Y and Shouguchi-Miyata, J and Suga, E and Kohiki, E and Onoe, K and Osuga, H and Aoki, M and Hadano, S and Itoyama, Y and Ikeda, JE}, title = {A dopamine receptor antagonist L-745,870 suppresses microglia activation in spinal cord and mitigates the progression in ALS model mice.}, journal = {Experimental neurology}, volume = {211}, number = {2}, pages = {378-386}, doi = {10.1016/j.expneurol.2008.02.004}, pmid = {18423451}, issn = {1090-2430}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Cell Movement/*drug effects/physiology ; Disease Models, Animal ; Disease Progression ; Dopamine Antagonists/pharmacology/*therapeutic use ; Female ; Humans ; Male ; Mice ; Mice, Congenic ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/cytology/*drug effects ; Pyridines/pharmacology/*therapeutic use ; Pyrroles/pharmacology/*therapeutic use ; Spinal Cord/*cytology/drug effects/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurons in the motor cortex, brainstem, and spinal cord. It has been shown that oxidative stress plays a pivotal role in the progression of this motor neuron loss. We have previously reported that L-745,870, a dopamine D4 receptor antagonist, selectively inhibits oxidative stress-induced cell death in vitro and exerts a potent neuroprotective effect against ischemia-induced neural cell damage in gerbil. To investigate the efficacy of L-745,870 in the treatment of ALS, we here conducted a chronic administration of L-745,870 to transgenic mice expressing a mutated form of human superoxide dismutase gene (SOD1(H46R)); a mouse model of familial ALS, and assessed whether the mice benefit from this treatment. The pre-onset administration of L-745,870 significantly delayed the onset of motor deficits, slowed the disease progression, and extended a life span in transgenic mice. These animals showed a delayed loss of anterior horn cells in the spinal cord concomitant with a reduced level of microglial activation at a late symptomatic stage. Further, the post-onset administration of L-745,870 to the SOD1(H46R) transgenic mice remarkably slowed the disease progression and extended their life spans. Taken together, our findings in a rodent model of ALS may have implication that L-745,870 is a possible novel therapeutic means to the treatment of ALS.}, }
@article {pmid18417691, year = {2008}, author = {Cassina, P and Cassina, A and Pehar, M and Castellanos, R and Gandelman, M and de León, A and Robinson, KM and Mason, RP and Beckman, JS and Barbeito, L and Radi, R}, title = {Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: prevention by mitochondrial-targeted antioxidants.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {28}, number = {16}, pages = {4115-4122}, pmid = {18417691}, issn = {1529-2401}, support = {ES00240/ES/NIEHS NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; }, mesh = {Amino Acid Substitution/genetics ; Amyotrophic Lateral Sclerosis/metabolism/pathology/prevention &amp; control ; Animals ; Animals, Genetically Modified ; Antioxidants/*administration &amp; dosage ; Astrocytes/drug effects/*enzymology/pathology ; Cells, Cultured ; Drug Delivery Systems/methods ; Mitochondria/drug effects/*enzymology/metabolism ; Motor Neurons/drug effects/*enzymology/pathology ; Nerve Degeneration/*enzymology/genetics/prevention &amp; control ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/*genetics/physiology ; }, abstract = {Mitochondrial dysfunction and oxidative stress contribute to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Recent reports indicate that astrocytes expressing the mutations of superoxide dismutase-1 (SOD1) may contribute to motor neuron injury in ALS. Here, we provide evidence that mitochondrial dysfunction in SOD1(G93A) rat astrocytes causes astrocytes to induce apoptosis of motor neurons. Mitochondria from SOD1(G93A) rat astrocytes displayed a defective respiratory function, including decreased oxygen consumption, lack of ADP-dependent respiratory control, and decreased membrane potential. Protein 3-nitrotyrosine was detected immunochemically in mitochondrial proteins from SOD1(G93A) astrocytes, suggesting that mitochondrial defects were associated with nitroxidative damage. Furthermore, superoxide radical formation in mitochondria was increased in SOD1(G93A) astrocytes. Similar defects were found in mitochondria isolated from the spinal cord of SOD1(G93A) rats, and pretreatment of animals with the spin trap 5,5-dimethyl-1-pyrroline N-oxide restored mitochondrial function, forming adducts with mitochondrial proteins in vivo. As shown previously, SOD1(G93A) astrocytes induced death of motor neurons in cocultures, compared with nontransgenic ones. This behavior was recapitulated when nontransgenic astrocytes were treated with mitochondrial inhibitors. Remarkably, motor neuron loss was prevented by preincubation of SOD1(G93A) astrocytes with antioxidants and nitric oxide synthase inhibitors. In particular, low concentrations (approximately 10 nm) of two mitochondrial-targeted antioxidants, ubiquinone and carboxy-proxyl nitroxide, each covalently coupled to a triphenylphosphonium cation (Mito-Q and Mito-CP, respectively), prevented mitochondrial dysfunction, reduced superoxide production in SOD1(G93A) astrocytes, and restored motor neuron survival. Together, our results indicate that mitochondrial dysfunction in astrocytes critically influences motor neuron survival and support the potential pharmacological utility of mitochondrial-targeted antioxidants in ALS treatment.}, }
@article {pmid18416855, year = {2008}, author = {Sathasivam, S}, title = {Brown-Vialetto-Van Laere syndrome.}, journal = {Orphanet journal of rare diseases}, volume = {3}, number = {}, pages = {9}, pmid = {18416855}, issn = {1750-1172}, mesh = {Adolescent ; Adult ; *Bulbar Palsy, Progressive/diagnosis/epidemiology/physiopathology/therapy ; Child ; Child, Preschool ; Diagnosis, Differential ; Female ; *Hearing Loss, Sensorineural/diagnosis/epidemiology/physiopathology/therapy ; Humans ; Infant ; Infant, Newborn ; Male ; Syndrome ; }, abstract = {The Brown-Vialetto-Van Laere syndrome (BVVL) is a rare neurological disorder characterized by progressive pontobulbar palsy associated with sensorineural deafness. Fifty-eight cases have been reported in just over 100 years. The female to male ratio is approximately 3:1. The age of onset of the initial symptom varies from infancy to the third decade. The syndrome most frequently presents with sensorineural deafness, which is usually progressive and severe. Lower cranial nerve involvement and lower and upper motor neuron limb signs are common neurological features. Other features include respiratory compromise (the most frequent non-neurological finding), limb weakness, slurring of speech, facial weakness, and neck and shoulder weakness. Optic atrophy, retinitis pigmentosa, macular hyperpigmentation, autonomic dysfunction, epilepsy may occur. The etiopathogenesis of the condition remains elusive. Approximately 50% of cases are familial, of which autosomal recessive is suggested. The remaining cases are sporadic. The diagnosis is usually based on the clinical presentation. Investigations (neurophysiological studies, magnetic resonance imaging of the brain, muscle biopsy, cerebrospinal fluid examination) are done to exclude other causes or to confirm the clinical findings. The differential diagnoses include the Fazio-Londe syndrome, amyotrophic lateral sclerosis, Nathalie syndrome, Boltshauser syndrome and Madras motor neuron disease. Treatment with steroids or intravenous immunoglobulin may result in temporary stabilization of the syndrome. However, the mainstays of management are supportive and symptomatic treatment, in particular assisted ventilation and maintenance of nutrition via gastrostomy. The clinical course of BVVL is variable and includes gradual deterioration (almost half of cases), gradual deterioration with stable periods in between (a third of cases) and deterioration with abrupt periods of worsening (just under a fifth of cases). After the initial presentation, one third of patients survive for ten years or longer.}, }
@article {pmid18416436, year = {2008}, author = {Ekegren, T and Hanrieder, J and Bergquist, J}, title = {Clinical perspectives of high-resolution mass spectrometry-based proteomics in neuroscience: exemplified in amyotrophic lateral sclerosis biomarker discovery research.}, journal = {Journal of mass spectrometry : JMS}, volume = {43}, number = {5}, pages = {559-571}, doi = {10.1002/jms.1409}, pmid = {18416436}, issn = {1076-5174}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*metabolism ; Biomarkers/*analysis ; Brain/*metabolism ; Humans ; Mass Spectrometry/*trends ; Nerve Tissue Proteins/*analysis ; Neurosciences/trends ; Proteome/*analysis ; Proteomics/*trends ; }, abstract = {Biomarker discovery is a central application in today's proteomic research. There is an urgent need for valid biomarkers to improve diagnostic tools and treatment in many disorders, such as the rapidly progressing neurodegenerative disorder amyotrophic lateral sclerosis (ALS) that has a fatal outcome in about 3 years and yet no curative treatment. Screening for clinically relevant biomarkers puts high demands on high-throughput, rapid and precise proteomic techniques. There is a large variety in the methods of choice involving mainly gel-based approaches as well as chromatographic techniques for multi-dimensional protein and peptide separations followed by mass spectrometry (MS) analysis. This special feature article will discuss some important aspects of MS-based clinical proteomics and biomarker discovery in the field of neurodegenerative diseases and ALS research respectively, with the aim to provide a prospective view on current and future research aspects in the field. Furthermore, examples for application of high-resolution MS-based proteomic strategies for ALS biomarker discovery will be demonstrated with two studies previously reported by our group. These studies include among others, utilization of capillary liquid chromatography-Fourier transform ion cyclotron resonance mass spectrometry (LC-FTICR-MS) for advanced protein pattern classification in cerebrospinal fluid (CSF) samples of ALS patients as well as highly sensitive protein identification in minimal amounts of postmortem spinal cord tissue and laser micro-dissected motor neurons using FT-ICR-MS in conjunction with nanoflow LC coupled to matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (LC-MALDI-TOF-TOF-MS).}, }
@article {pmid18367867, year = {2008}, author = {Fornai, F and Longone, P and Ferrucci, M and Lenzi, P and Isidoro, C and Ruggieri, S and Paparelli, A}, title = {Autophagy and amyotrophic lateral sclerosis: The multiple roles of lithium.}, journal = {Autophagy}, volume = {4}, number = {4}, pages = {527-530}, doi = {10.4161/auto.5923}, pmid = {18367867}, issn = {1554-8635}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Antipsychotic Agents/pharmacology/therapeutic use ; Astrocytes/cytology/drug effects ; Autophagy/drug effects/*physiology ; Clinical Trials as Topic ; Humans ; Lithium Compounds/pharmacology/*therapeutic use ; Mitochondria/drug effects/ultrastructure ; Neurons/cytology/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/physiology ; Spinal Cord/cytology ; Stem Cells/cytology/drug effects ; }, abstract = {In a pilot clinical study that we recently published we found that lithium administration slows the progression of Amyotrophic Lateral Sclerosis (ALS) in human patients. This clinical study was published in addition with basic (in vitro) and pre-clinical (in vivo) data demonstrating a defect of autophagy as a final common pathway in the genesis of ALS. In fact, lithium was used as an autophagy inducer. In detailing the protective effects of lithium we found for the first time that this drug stimulates the biogenesis of mitochondria in the central nervous system and, uniquely in the spinal cord, it induces neuronogenesis and neuronal differentiation. In particular, the effects induced by lithium can be summarized as follows: (i) the removal of altered mitochondria and protein aggregates; (ii) the biogenesis of well-structured mitochondria; (iii) the suppression of glial proliferation; (iv) the differentiation of newly formed neurons in the spinal cord towards a specific phenotype. In this addendum we focus on defective autophagy as a "leit motif" in ALS and the old and novel features of lithium which bridge autophagy activation to concomitant effects that may be useful for the treatment of a variety of neurodegenerative disorders. In particular, the biogenesis of mitochondria and the increase of calbindin D 28K-positive neurons, which are likely to support powerful neuroprotection towards autophagy failure, mitochondriopathy and neuronal loss in the spinal cord.}, }
@article {pmid18367449, year = {2008}, author = {Wang, H and Ghosh, A and Baigude, H and Yang, CS and Qiu, L and Xia, X and Zhou, H and Rana, TM and Xu, Z}, title = {Therapeutic gene silencing delivered by a chemically modified small interfering RNA against mutant SOD1 slows amyotrophic lateral sclerosis progression.}, journal = {The Journal of biological chemistry}, volume = {283}, number = {23}, pages = {15845-15852}, pmid = {18367449}, issn = {0021-9258}, support = {R01NS048145/NS/NINDS NIH HHS/United States ; R21NS053770/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/enzymology/genetics/therapy ; Amyotrophic Lateral Sclerosis/enzymology/genetics/*therapy ; Animals ; Cell Line ; Chronic Disease ; Disease Models, Animal ; *Gene Silencing ; *Genetic Therapy ; Humans ; Mice ; *Mutation ; Parkinson Disease/enzymology/genetics/therapy ; RNA Stability/drug effects/genetics ; RNA, Small Interfering/genetics/*pharmacology ; Superoxide Dismutase/*antagonists &amp; inhibitors/genetics ; Superoxide Dismutase-1 ; }, abstract = {Inherited neurodegenerative diseases, such as Huntington disease and subset of Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis, are caused by the mutant genes that have gained undefined properties that harm cells in the nervous system, causing neurodegeneration and clinical phenotypes. Lowering the mutant gene expression is predicted to slow the disease progression and produce clinical benefit. Administration of small interfering RNA (siRNA) can silence specific genes. However, long term delivery of siRNA to silence the mutant genes, a requirement for treatment of these chronic central nervous system (CNS) diseases, remains a critical unsolved issue. Here we designed and tested a chemically stabilized siRNA against human Cu,Zn-superoxide dismutase (SOD1) in a mouse model for amyotrophic lateral sclerosis. We show that the modified siRNA has enhanced stability and retains siRNA activity. Administration of this siRNA at the disease onset by long term infusion into the CNS resulted in widespread distribution of this siRNA, knocked down the mutant SOD1 expression, slowed the disease progression, and extended the survival. These results bring RNA interference therapy one step closer to its clinical application for treatment of chronic, devastating, and fatal CNS disorders.}, }
@article {pmid18367440, year = {2008}, author = {Hemendinger, RA and Armstrong, EJ and Persinski, R and Todd, J and Mougeot, JL and Volvovitz, F and Rosenfeld, J}, title = {Huperzine A provides neuroprotection against several cell death inducers using in vitro model systems of motor neuron cell death.}, journal = {Neurotoxicity research}, volume = {13}, number = {1}, pages = {49-61}, pmid = {18367440}, issn = {1029-8428}, mesh = {Alkaloids ; Animals ; Apoptosis/*drug effects ; Aspartic Acid/analogs &amp; derivatives/toxicity ; Carbonyl Cyanide m-Chlorophenyl Hydrazone/toxicity ; Cell Line ; Drug Interactions ; Enzyme Inhibitors/toxicity ; Hydrogen Peroxide/toxicity ; Ionophores/toxicity ; Motor Neurons/cytology/*drug effects ; Neuroprotective Agents/*pharmacology ; Organ Culture Techniques ; Oxidants/toxicity ; Rats ; Rats, Sprague-Dawley ; Sesquiterpenes/*pharmacology ; Spinal Cord/*drug effects/pathology ; Staurosporine/toxicity ; Thapsigargin/toxicity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting from the progressive loss of motor neurons in the spinal cord and brain. To date, clinically effective neuroprotective agents have not been available. The current study demonstrates for the first time that huperzine A, a potential neuroprotective agent, has the ability to protect a motor neuron-like cell line and motor neurons in spinal cord organotypic cultures from toxin-induced cell death. The neuroblastoma-spinal motor neuron fusion cell line, NSC34 and rat spinal cord organotypic cultures (OTC) were exposed to cell death inducers for 24 h or 14 d, respectively, with and without pre-treatment with huperzine A. The inducers used here include: staurosporine, thapsigargin, hydrogen peroxide (H2O2), carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and L-(-)-threo-3-hydroxyaspartic acid (THA). These agents were selected as they induce apoptosis/necrosis via mechanisms implicated in patients with generalized motor neuron disease. Cell death was determined in NSC34 cells by metabolic activity, caspase activity/expression and by nuclear morphology and in the OTCs, using immunohistochemistry and Western blot analysis. Nuclear staining of NSC34 cells revealed cell death induced by staurosporine, thapsigargin, H2O2 and CCCP. This induction was significantly reduced with 2 h pre-treatment with 10 microM huperzine A (maximum, 35% rescue; p 0.05) following exposure to staurosporine, thapsigargin and H2O2 but not with CCCP. These data were supported by the metabolic assays and caspase activity. In addition, pre-treatment with huperzine A dramatically improved motor neuron survival, based on choline acetyltransferase (ChAT) expression analysis in OTCs following exposure to THA, and compared to THA-treated control cultures. These studies are currently being extended to include other inducers and with additional compounds as potential drug therapies that could be used in combination for the treatment of patients with ALS.}, }
@article {pmid18365116, year = {2008}, author = {Alberich, A and Díaz-Cruz, JM and Ariño, C and Esteban, M}, title = {Combined use of the potential shift correction and the simultaneous treatment of spectroscopic and electrochemical data by multivariate curve resolution: analysis of a Pb(II)-phytochelatin system.}, journal = {The Analyst}, volume = {133}, number = {4}, pages = {470-477}, doi = {10.1039/b718285f}, pmid = {18365116}, issn = {1364-5528}, mesh = {Animals ; Circular Dichroism ; Lead/*chemistry ; Least-Squares Analysis ; Models, Chemical ; Phytochelatins/*chemistry ; Polarography ; }, abstract = {The combined use of differential pulse polarography (DPP), circular dichroism (CD) and multivariate curve resolution by alternating least squares (MCR-ALS), with potential shift correction for data analysis, provides valuable information on the complexation of Pb(ii) by the phytochelatin (gamma-Glu-Cys)(3)-Gly (PC(3)). All data confirm the formation of the predominant 1 : 1 Pb-PC(3) complex. However, in the presence of an excess of Pb(ii), the same complex seems to be present but with some modification in its structure. This is suggested by the shift towards more negative potentials of the DPP signal, and by a dramatic change in CD spectra. This evolution seems to be more related to a conformational change of the complex than with a modification of the electrochemical process kinetics.}, }
@article {pmid18351522, year = {2008}, author = {Lomen-Hoerth, C}, title = {Amyotrophic lateral sclerosis from bench to bedside.}, journal = {Seminars in neurology}, volume = {28}, number = {2}, pages = {205-211}, doi = {10.1055/s-2008-1062265}, pmid = {18351522}, issn = {0271-8235}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*etiology/therapy ; Animals ; Biomarkers/analysis/metabolism ; Central Nervous System/*metabolism/pathology/*physiopathology ; Diagnosis, Differential ; Disease Models, Animal ; Disease Progression ; Humans ; Long-Term Care/methods/standards ; Motor Neurons/*metabolism/pathology ; Nerve Degeneration/metabolism/pathology/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease for which there are currently no significant treatments to alter the fatal outcome. The cause of the disease is still elusive, except in familial cases where significant advances have been made in identifying new genetic causes. ALS is a relatively rare disease affecting approximately 1 in 100,000 people equally across geographic and ethnic distributions. It is a difficult disease to diagnose, and there are many mimics of ALS. Overlap with dementia may provide new clues to the etiology and treatment. There have been many advances in symptomatic treatments and improvements in the quality of life for ALS patients due to technological advancements.}, }
@article {pmid18346633, year = {2008}, author = {Lam, VW and Taylor, CF and Laurence, JM and Wang, C and Sharland, AF and McCaughan, GW and Hodgkinson, S and Allen, RD and Hall, BM and Bishop, GA}, title = {Heart allograft acceptance induced by anti-CD3 antibody in high-responder rats: effect on foxp3 and cytokine expression and graft infiltration.}, journal = {Transplant immunology}, volume = {19}, number = {1}, pages = {20-24}, doi = {10.1016/j.trim.2008.01.002}, pmid = {18346633}, issn = {0966-3274}, mesh = {Animals ; Antibodies/*immunology/metabolism ; CD3 Complex/*immunology ; Cytokines/immunology/*metabolism ; Forkhead Transcription Factors/immunology/*metabolism ; *Graft Survival ; Heart Transplantation/*immunology ; Rats ; T-Lymphocytes/immunology/metabolism ; Transplantation, Homologous ; }, abstract = {The ability of anti-T cell monoclonal antibody G4.18 and polyclonal anti-lymphocyte serum (ALS) to induce long-term graft survival was examined in a high-responder rat heart transplant model. Heterotopic heart allografts were performed from PVG rat strain donors to high-responder Lewis recipients. Immunosuppressive properties of G4.18 and ALS were investigated by immunohistochemistry and PCR analysis. Untreated graft rejection was 8.5 days while treatment with 1 ml ALS prolonged survival to 11.5 days (p=0.01). Treatment with 7 mg/kg G4.18 on days 1 and 3 prolonged survival to >100 days (p=0.002 vs. control and p=0.002 vs. ALS) but did not induce tolerance. Acceptance was associated with marked inhibition of cellular infiltration and inflammatory cytokine expression and only a brief, slight increase in Foxp3:T cell ratio in the graft and no increase in the spleen. In conclusion, G4.18 treatment led to long-term heart transplant survival associated with marked inhibition of early inflammation. Failure to develop tolerance was associated with a lack of early accumulation of Foxp3 cells in the graft or spleen.}, }
@article {pmid18334130, year = {2008}, author = {Thibodeaux, LS and Gutierrez, A}, title = {Management of symptoms in amyotrophic lateral sclerosis.}, journal = {Current treatment options in neurology}, volume = {10}, number = {2}, pages = {77-85}, pmid = {18334130}, issn = {1092-8480}, abstract = {The mainstay of treatment of amyotrophic lateral sclerosis (ALS) is management of symptoms. Health care providers involved in the care of ALS patients should be armed with the most current knowledge about symptomatic management of these patients so that an aggressive approach to controlling symptoms can be undertaken at the most appropriate time. Among the important modalities is noninvasive positive pressure ventilation, which has been shown to improve not only quality of life but also survival. Similarly, clinicians should consider earlier intervention with enteral feeding. Palliative care should begin soon after ALS is diagnosed.}, }
@article {pmid18319614, year = {2008}, author = {An, JJ and Lee, YP and Kim, SY and Lee, SH and Kim, DW and Lee, MJ and Jeong, MS and Jang, SH and Kang, JH and Kwon, HY and Kang, TC and Won, MH and Cho, SW and Kwon, OS and Lee, KS and Park, J and Eum, WS and Choi, SY}, title = {Transduction of familial amyotrophic lateral sclerosis-related mutant PEP-1-SOD proteins into neuronal cells.}, journal = {Molecules and cells}, volume = {25}, number = {1}, pages = {55-63}, pmid = {18319614}, issn = {1016-8478}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Astrocytes/cytology/*physiology ; Cell Survival ; Cells, Cultured ; Cysteamine/*analogs &amp; derivatives/metabolism ; Heat-Shock Proteins/genetics/metabolism ; Humans ; Oxidative Stress ; Peptides/genetics/*metabolism ; Rats ; Rats, Wistar ; Recombinant Fusion Proteins/genetics/*metabolism ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; *Transduction, Genetic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the selective death of motor neurons. Mutations in the SOD1 gene are responsible for a familial form of ALS (FALS). Although many studies suggest that mutant SOD1 proteins are cytotoxic, the mechanism is not fully understood. To investigate the role of mutant SOD1 in FALS, human SOD1 genes were fused with a PEP-1 peptide in a bacterial expression vector to produce in-frame PEP-1-SOD fusion proteins (wild type and mutants). The expressed and purified PEP-1-SOD fusion proteins were efficiently transduced into neuronal cells. Neurones harboring the A4V, G93A, G85R, and D90A mutants of PEP-1-SOD were more vulnerable to oxidative stress induced by paraquat than those harboring wild-type proteins. Moreover, neurones harboring the mutant SOD proteins had lower heat shock protein (Hsp) expression levels than those harboring wild-type SOD. The effects of the transduced SOD1 fusion proteins may provide an explanation for the association of SOD1 with FALS, and Hsps could be candidate agents for the treatment of ALS.}, }
@article {pmid18317986, year = {2008}, author = {Kalbitz, F}, title = {[NIV--modes and prognosis].}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {62 Suppl 1}, number = {}, pages = {S7-S10}, doi = {10.1055/s-2007-1016428}, pmid = {18317986}, issn = {1438-8790}, mesh = {Cough/etiology/*prevention &amp; control/*rehabilitation ; Germany ; Humans ; Neuromuscular Diseases/complications/*rehabilitation ; Prognosis ; Respiration, Artificial/instrumentation/*methods/*trends ; }, abstract = {Non-invasive (NIV) as well as invasive mechanical ventilation are established for the treatment of ventilatory failure in neuromuscular diseases. The EUROVENT study provides data about mechanical ventilation at home. In this survey there is a trend towards pressure-derived ventilation in these patient groups. Volume-cycled ventilators had been used in 41% patients with neuromuscular diseases. During the past decade a remarkable change towards pressure-cycled ventilation has occurred. Two recently published, randomised cross-over studies demonstrated equal efficacy of volume-cycled ventilation compared to pressure-cycled ventilation in terms of gas exchange and sleep efficacy in chronic ventilatory failure. In both groups the median survival times were equal. In respiratory muscle failure, assisted ventilation, assist/controlled ventilation as well as controlled ventilation are applied. Between 1977 and 2001, long-term survival improved in patients with Duchenne muscular dystrophy (DMD) in Denmark based on a strict organisation of care, home ventilation as standard treatment and the establishment of centres for home ventilation. The proportion of ventilated patients rose from 0.9% to 43.4% of all DMD patients. The median survival of an untreated DMD patient is 9.7 months. Simonds demonstrated a 5-year survival rate of 73% in these groups of patients under home mechanical ventilation. In patients with the more rapidly deteriorating amyotrophic lateral sclerosis, the efficacy of home ventilation is less impressive and bulbar involvement serves as an independent negative predictor.}, }
@article {pmid18312546, year = {2008}, author = {Shibata, N and Kawaguchi-Niida, M and Yamamoto, T and Toi, S and Hirano, A and Kobayashi, M}, title = {Effects of the PPARgamma activator pioglitazone on p38 MAP kinase and IkappaBalpha in the spinal cord of a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {28}, number = {4}, pages = {387-398}, doi = {10.1111/j.1440-1789.2008.00890.x}, pmid = {18312546}, issn = {0919-6544}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Blotting, Western ; Calcium-Binding Proteins/biosynthesis ; DNA-Binding Proteins ; Disease Models, Animal ; Female ; Glial Fibrillary Acidic Protein/biosynthesis ; Humans ; I-kappa B Proteins/*drug effects ; Image Processing, Computer-Assisted ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microfilament Proteins ; Microglia/drug effects/metabolism ; Mutation ; NF-KappaB Inhibitor alpha ; Nerve Tissue Proteins/biosynthesis ; Neurons/drug effects/metabolism ; Nuclear Proteins/biosynthesis ; PPAR gamma/drug effects/metabolism ; Pioglitazone ; Spinal Cord/*drug effects/enzymology/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Thiazolidinediones/*pharmacology ; p38 Mitogen-Activated Protein Kinases/*drug effects ; }, abstract = {Emerging evidence suggests the involvement of programmed cell death and inflammation in amyotrophic lateral sclerosis (ALS). To assess molecular pathological effects of the anti-inflammatory peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist pioglitazone in ALS, we verified changes in the population of neurons, astrocytes, and microglia in the ventral horns of spinal cord lumbar segments from the pioglitazone-treated and non-treated groups of mice carrying a transgene for G93A mutant human superoxide dismutase-1 (SOD1) (ALS mice) and non-transgenic littermates (control mice), performed immunohistochemical and immunoblot analyses of PPARgamma, active form of phosphorylated p38 mitogen-activated protein kinase (p-p38) and inhibitor of nuclear factor-kappaB (NF-kappaB)-alpha (IkappaBalpha) in the spinal cords, and compared the results between the different groups. Image analysis revealed that optical density of NeuN-immunoreactive neurons was significantly lower in the non-treated groups of presymptomatic and advanced ALS mice than in the non-treated groups of age-matched control mice and was recovered with pioglitazone treatment, and that optical densities of GFAP-immunoreactive astrocytes and Iba1-immunoreactive microglia were significantly higher in the non-treated group of advanced ALS mice than in the non-treated group of control mice and were recovered with pioglitazone treatment. Immunohistochemical analysis demonstrated that immunoreactivities for PPARgamma and p-p38 were mainly localized in neurons, and that IkappaBalpha immunoreactivity was mainly localized in astrocytes and microglia. Immunoblot analysis showed that pioglitazone treatment resulted in no significant change in nuclear PPARgamma-immunoreactive density, a significant decrease in cytosolic p-p38-immunoreactive density, and a significant increase in cytosolic IkappaBalpha-immunoreactive density. Our results suggest that pioglitazone protects motor neurons against p38-mediated neuronal death and NF-kappaB-mediated glial inflammation via a PPARgamma-independent mechanism.}, }
@article {pmid18304580, year = {2008}, author = {Zanette, G and Forgione, A and Manganotti, P and Fiaschi, A and Tamburin, S}, title = {The effect of repetitive transcranial magnetic stimulation on motor performance, fatigue and quality of life in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {270}, number = {1-2}, pages = {18-22}, doi = {10.1016/j.jns.2008.01.011}, pmid = {18304580}, issn = {0022-510X}, mesh = {Aged ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology/therapy ; Analysis of Variance ; Fatigue/etiology/*therapy ; Female ; Humans ; Isotonic Contraction/physiology/*radiation effects ; Male ; Middle Aged ; Motor Activity/physiology/*radiation effects ; *Quality of Life ; Time Factors ; Transcranial Magnetic Stimulation/*methods ; Treatment Outcome ; }, abstract = {BACKGROUND: The treatment of amyotrophic lateral sclerosis (ALS) is still disappointing. Repetitive transcranial magnetic stimulation (rTMS) has been suggested to modify the rate of disease progression in ALS.<br><br>OBJECTIVE: In a pilot controlled study, we tested the effect of 5-Hz rTMS on motor performance, fatigue and quality of life (QoL) in ALS.<br><br>METHODS: Ten ALS patients underwent a two-week period of daily active or sham 5-Hz rTMS. Outcome measures were assessed with functional, fatigue and QoL scales. Muscle strength was evaluated with the MRC scale and measured with isometric and isokinetic dynamometer.<br><br>RESULTS: Significant difference at the end of rTMS treatment was found for QoL, maximum voluntary isometric contraction and isokinetic average power when comparing active vs sham treatment. These changes were transitory and outcome measures were not significant two weeks after discontinuation of rTMS.<br><br>CONCLUSIONS: Though preliminary, our results suggest that 5-Hz rTMS may improve motor function and QoL in ALS. The present data indicate the need of a double-blind therapeutic trial of rTMS in ALS.}, }
@article {pmid18303472, year = {2008}, author = {Meijer, JW and van Kuijk, AA and Geurts, AC and Schelhaas, HJ and Zwarts, MJ}, title = {Acute deterioration of bulbar function after botulinum toxin treatment for sialorrhoea in amyotrophic lateral sclerosis.}, journal = {American journal of physical medicine &amp; rehabilitation}, volume = {87}, number = {4}, pages = {321-324}, doi = {10.1097/PHM.0b013e318164a931}, pmid = {18303472}, issn = {0894-9115}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Apnea/*chemically induced ; Botulinum Toxins, Type A/administration &amp; dosage/*adverse effects ; Deglutition Disorders/chemically induced/drug therapy ; Fatal Outcome ; Female ; Humans ; Injections ; Middle Aged ; Neuromuscular Agents/administration &amp; dosage/*adverse effects ; Parotid Gland/drug effects ; Sialorrhea/*drug therapy/etiology ; Submandibular Gland/drug effects ; }, abstract = {Transcutaneous botulinum toxin injection in the salivary glands was introduced in 2000 as a new treatment for sialorrhoea in amyotrophic lateral sclerosis (ALS). We describe an ALS patient who developed serious complications of botulinum toxin treatment for sialorrhoea, and we review the relevant literature. A 64-yr-old woman with bulbar ALS for 6 mos was treated for disabling sialorrhoea. She had moderate dysphagia, but she was able to swallow. The submandibular and parotid glands were injected transcutaneously, under ultrasound guidance, with botulinum toxin (Dysport), 80 U on each side. Four days later, her bulbar function rapidly deteriorated, resulting in complete aphagia and anarthria on the fifth day. A PEG catheter was placed. Although according to the literature this treatment can be made safer by cautiously increasing the dosage and injecting the parotid glands first, BTX should not be the first-line treatment of sialorrhoea in ALS; comparative studies of BTX, amitryptiline, scopolamine, and radiation should be performed first.}, }
@article {pmid18291574, year = {2008}, author = {Fernández-Ruiz, J and Pazos, MR and García-Arencibia, M and Sagredo, O and Ramos, JA}, title = {Role of CB2 receptors in neuroprotective effects of cannabinoids.}, journal = {Molecular and cellular endocrinology}, volume = {286}, number = {1-2 Suppl 1}, pages = {S91-6}, doi = {10.1016/j.mce.2008.01.001}, pmid = {18291574}, issn = {0303-7207}, mesh = {Animals ; Cannabinoids/*pharmacology ; Humans ; Neuroprotective Agents/*pharmacology ; Receptor, Cannabinoid, CB2/*metabolism ; Signal Transduction/drug effects ; }, abstract = {CB2 receptors, the so-called peripheral cannabinoid receptor type, were first described in the immune system, but they have been recently identified in the brain in healthy conditions and, in particular, after several types of cytotoxic stimuli. Specifically, CB2 receptors were identified in microglial cells, astrocytes and, to a lesser extent, in certain subpopulations of neurons. Given the lack of psychoactivity demonstrated by selective CB2 receptor agonists, this receptor becomes an interesting target for the treatment of neurological diseases, in particular, the case of certain neurodegenerative disorders in which induction/up-regulation of CB2 receptors has been already demonstrated. These disorders include Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and others. Interestingly, in experimental models of these disorders, the activation of CB2 receptors has been related to a delayed progression of neurodegenerative events, in particular, those related to the toxic influence of microglial cells on neuronal homeostasis. The present article will review the evidence supporting that CB2 receptors might represent a key element in the endogenous response against different types of cytotoxic events, and that this receptor type may be a clinically promising target for the control of brain damage in neurodegenerative disorders.}, }
@article {pmid18283399, year = {2008}, author = {Costa, J and Rocha, ML and Ferreira, J and Evangelista, T and Coelho, M and de Carvalho, M}, title = {Botulinum toxin type-B improves sialorrhea and quality of life in bulbaronset amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {255}, number = {4}, pages = {545-550}, pmid = {18283399}, issn = {0340-5354}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/*drug therapy/physiopathology ; Botulinum Toxins/*administration &amp; dosage/adverse effects ; Botulinum Toxins, Type A ; Humans ; Infant ; Male ; Mastication/drug effects/physiology ; Middle Aged ; Neuromuscular Agents/administration &amp; dosage/adverse effects ; Pain/chemically induced/physiopathology ; Parasympathetic Nervous System/drug effects/immunology/physiopathology ; Parasympatholytics/administration &amp; dosage/adverse effects ; Patient Satisfaction ; Pilot Projects ; Prospective Studies ; *Quality of Life ; Salivary Glands/drug effects/innervation/physiopathology ; Sialorrhea/*drug therapy/*etiology/physiopathology ; Treatment Outcome ; }, abstract = {BACKGROUND: Sialorrhea is a disabling problem in bulbaronset amyotrophic lateral sclerosis (ALS). Botulinum toxin (BTX) type A and B have been proposed as alternatives to traditional treatments.<br><br>OBJECTIVES: To evaluate the efficacy and safety of BTX type B in the treatment of sialorrhea in patients with bulbar-onset ALS.<br><br>METHODS: Open-label prospective study of BTX type B injections in parotids (1000 U) and submandibular (250 U) glands using anatomic landmarks. Primary outcome was rate of responders (improvement > 50% on visual analogue scales (VAS) of severity and disability of sialorrhea) 1 month post-treatment. Other outcomes included subjective (drooling and quality of daily living questionnaires) and objective (cotton roll weights and number of paper handkerchiefs used) evaluations. Safety evaluations included questionnaires regarding brain stem symptoms.<br><br>RESULTS: Sixteen ALS patients were included. At 1 month the rate of responders was 75% with a mean reduction of 70% in severity and disabling VASs. Fifteen patients (94 %) reported some benefit with drooling reduction. In objective measurements there was a reduction over 60 % in saliva production and in the number of handkerchiefs used. Onset of effect occurred within 3 days. Most patients reported better quality of living. The most frequent side-effects were viscous saliva, local pain, chewing weakness and respiratory infection. There were no changes in blood pressure or cardiac rate. At 3 months, there was still a positive effect in all outcomes. All patients except one manifested their willingness to repeat treatment.<br><br>CONCLUSIONS: Anatomic guided BTX type B injections seem effective and safe to treat sialorrhea in bulbar-onset ALS.}, }
@article {pmid18282652, year = {2008}, author = {Turner, BJ and Talbot, K}, title = {Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS.}, journal = {Progress in neurobiology}, volume = {85}, number = {1}, pages = {94-134}, doi = {10.1016/j.pneurobio.2008.01.001}, pmid = {18282652}, issn = {0301-0082}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics/therapy ; Animals ; Humans ; Mice ; Mice, Knockout ; Mice, Transgenic ; Models, Biological ; Motor Neurons/enzymology/metabolism/pathology ; *Mutation ; Superoxide Dismutase/*genetics/metabolism ; }, abstract = {Gain-of-function mutations in the Cu,Zn-superoxide dismutase (SOD1) gene are implicated in progressive motor neuron death and paralysis in one form of inherited amyotrophic lateral sclerosis (ALS). At present, transgenic expression of 12 human SOD1 mutations driven by the endogenous promoter is disease-causative and uniformly lethal in mice and rats, despite tremendous biochemical and biophysical variation between the mutants tested. This contrasts with the subclinical motor neuron disease phenotypes of wild-type SOD1 transgenic and knockout mice. Molecular mechanisms such as glutamate-induced excitotoxicity, axonal transport blockade, mitochondrial dysfunction, neuroinflammation and apoptosis triggered by mutant SOD1 catalysed oxidative reactions and/or protein misfolding are proposed to drive ALS pathogenesis. Around 100 genetic cross-breeding experiments with transgenic mutant SOD1 mice have been performed to verify these mechanisms in vivo. Furthermore, mounting evidence from mice with cell restrictive, repressible or chimeric expression of mutant SOD1 transgenes and bone marrow transplants supports non-neuronal origins of neuroprotection in ALS. Transgenic mutant SOD1 rodents have also provided the benchmark preclinical tool for evaluation of over 150 potential therapeutic anti-oxidant, anti-aggregation, anti-glutamatergic, anti-inflammatory, anti-apoptotic and neurotrophic pharmacological agents. Recent promising findings from gene and antisense therapies, cell replacement and combinatorial drug approaches in transgenic mutant SOD1 rodents are also emerging, but await successful translation in patients. This review summarises the wealth of known genetic and therapeutic modifiers in rodent models with SOD1 mutations and discusses these in the wider context of ALS pathoetiology and treatment.}, }
@article {pmid18279484, year = {2008}, author = {Zetterberg, H and Rüetschi, U and Portelius, E and Brinkmalm, G and Andreasson, U and Blennow, K and Brinkmalm, A}, title = {Clinical proteomics in neurodegenerative disorders.}, journal = {Acta neurologica Scandinavica}, volume = {118}, number = {1}, pages = {1-11}, doi = {10.1111/j.1600-0404.2007.00985.x}, pmid = {18279484}, issn = {1600-0404}, mesh = {Biomarkers/metabolism ; Humans ; Mass Spectrometry ; Neurodegenerative Diseases/diagnosis/genetics/*metabolism ; *Proteomics ; }, abstract = {Neurodegenerative disorders are characterized by neuronal impairment that eventually leads to neuronal death. In spite of the brain's known capacity for regeneration, lost neurons are difficult to replace. Therefore, drugs aimed at inhibiting neurodegenerative processes are likely to be most effective if the treatment is initiated as early as possible. However, clinical manifestations in early disease stages are often numerous, subtle and difficult to diagnose. This is where biomarkers that specifically reflect onset of pathology, directly or indirectly, may have a profound impact on diagnosis making in the future. A triplet of biomarkers for Alzheimer's disease (AD), total and hyperphosphorylated tau and the 42 amino acid isoform of beta-amyloid, has already been established for early detection of AD before the onset of dementia. However, more biomarkers are needed both for AD and for other neurodegenerative disorders, such as Parkinson's disease, frontotemporal dementia and amyotrophic lateral sclerosis. This review provides an update on recent advances in clinical neuroproteomics, a biomarker discovery field that has expanded immensely during the last decade, and gives an overview of the most commonly used techniques and the major clinically relevant findings these techniques have lead to.}, }
@article {pmid18270879, year = {2008}, author = {Wang, H and Larriviere, KS and Keller, KE and Ware, KA and Burns, TM and Conaway, MA and Lacomis, D and Pattee, GL and Phillips, LH and Solenski, NJ and Zivkovic, SA and Bennett, JP}, title = {R+ pramipexole as a mitochondrially focused neuroprotectant: initial early phase studies in ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {9}, number = {1}, pages = {50-58}, doi = {10.1080/17482960701791234}, pmid = {18270879}, issn = {1471-180X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Benzothiazoles/*metabolism/pharmacology/*therapeutic use ; Dose-Response Relationship, Drug ; Female ; Free Radical Scavengers/metabolism/pharmacology ; Humans ; Male ; Middle Aged ; Mitochondria/*drug effects/metabolism/pathology ; Neuroprotective Agents/*metabolism/pharmacology/*therapeutic use ; Pramipexole ; Time Factors ; }, abstract = {R+ pramipexole (PPX) is a lipophilic cation that concentrates into brain and mitochondria and efficiently scavenges reactive oxygen and nitrogen species (RONS). Under the auspices of a Physician-Sponsor IND, R+PPX was dosed to small numbers of ALS patients for tolerability and safety while efficacy measures were also collected. The purpose of this paper is to describe the outcomes of these initial clinical studies. In a futility design study, 30 patients with early SALS were evaluated monthly for ALSFRS-R scores and FVC measurements for three months during lead-in, followed by open-label dosing at 30 mg/day of R+PPX for the next six months. In the dose escalation study, 10 subjects with early ALS received daily doses of R+PPX from 10 mg t.i.d. to 100 mg t.i.d. over seven weeks. In the open-label extension analysis, subjects from the initial studies were treated with 30 mg/day for at least six months, then switched to 60 mg/day. R+PPX was tolerated well in all studies. In the futility study, slopes of decline in ALSFRS-R scores and neurophysiological index (NI) values yielded non-significant reductions during treatment. In the dose-escalation study, all subjects increased daily R+PPX intake safely to 100 mg t.i.d. Markers of ALS did not change (ALSFRS-R) or improved (FVC). Trough and peak plasma (PPX) increased linearly with dosing, and several subjects achieved plasma (PPX) >1 microM. In the open-label extension protocol, changing from 30 to 60 mg/day caused a non-significant 17% reduction in slope of decline of ALSFRS-R. It was concluded that R+PPX was tolerated well in long-term dosing at 30 and 60 mg/day. Encouraging but non-significant effects of R+PPX on ALS decline were observed. High doses of R+PPX were tolerated well and yielded neuroprotective plasma levels. These findings support longer-term testing of higher R+PPX doses as a potential disease-altering therapy for SALS.}, }
@article {pmid18250315, year = {2008}, author = {Fornai, F and Longone, P and Cafaro, L and Kastsiuchenka, O and Ferrucci, M and Manca, ML and Lazzeri, G and Spalloni, A and Bellio, N and Lenzi, P and Modugno, N and Siciliano, G and Isidoro, C and Murri, L and Ruggieri, S and Paparelli, A}, title = {Lithium delays progression of amyotrophic lateral sclerosis.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {105}, number = {6}, pages = {2052-2057}, pmid = {18250315}, issn = {1091-6490}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Disease Models, Animal ; Disease Progression ; Humans ; Lithium Compounds/pharmacology/*therapeutic use ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects ; Spinal Cord/drug effects ; }, abstract = {ALS is a devastating neurodegenerative disorder with no effective treatment. In the present study, we found that daily doses of lithium, leading to plasma levels ranging from 0.4 to 0.8 mEq/liter, delay disease progression in human patients affected by ALS. None of the patients treated with lithium died during the 15 months of the follow-up, and disease progression was markedly attenuated when compared with age-, disease duration-, and sex-matched control patients treated with riluzole for the same amount of time. In a parallel study on a genetic ALS animal model, the G93A mouse, we found a marked neuroprotection by lithium, which delayed disease onset and duration and augmented the life span. These effects were concomitant with activation of autophagy and an increase in the number of the mitochondria in motor neurons and suppressed reactive astrogliosis. Again, lithium reduced the slow necrosis characterized by mitochondrial vacuolization and increased the number of neurons counted in lamina VII that were severely affected in saline-treated G93A mice. After lithium administration in G93A mice, the number of these neurons was higher even when compared with saline-treated WT. All these mechanisms may contribute to the effects of lithium, and these results offer a promising perspective for the treatment of human patients affected by ALS.}, }
@article {pmid18238900, year = {2008}, author = {Kim, HJ and Fan, X and Gabbi, C and Yakimchuk, K and Parini, P and Warner, M and Gustafsson, JA}, title = {Liver X receptor beta (LXRbeta): a link between beta-sitosterol and amyotrophic lateral sclerosis-Parkinson's dementia.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {105}, number = {6}, pages = {2094-2099}, pmid = {18238900}, issn = {1091-6490}, mesh = {ATP-Binding Cassette Transporters/metabolism ; Amyotrophic Lateral Sclerosis/*chemically induced ; Animals ; Cholesterol/blood ; DNA-Binding Proteins/genetics/*physiology ; Dopamine/metabolism ; Immunohistochemistry ; Intestinal Mucosa/metabolism ; Liver X Receptors ; Male ; Mice ; Mice, Knockout ; Motor Neurons/drug effects/enzymology ; Orphan Nuclear Receptors ; Parkinsonian Disorders/*etiology ; Receptors, Cytoplasmic and Nuclear/genetics/*physiology ; Sitosterols/blood/*toxicity ; Spinal Cord/drug effects/pathology ; Substantia Nigra/drug effects/pathology ; Tyrosine 3-Monooxygenase/metabolism ; }, abstract = {Administration of beta-sitosterol (42 mg/kg per day) for 3 weeks to 8-month-old male LXRbeta-/- mice resulted in the death of motor neurons in the lumbar region of the spinal cord and loss of tyrosine hydroxylase-positive dopaminergic neurons in the substantia nigra. In mice at 5 months of age, beta-sitosterol had no observed toxicity but at 16 months of age, it caused severe paralysis and symptoms typical of dopaminergic dysfunction in LXRbeta-/- mice. WT mice were not affected by these doses of beta-sitosterol. In 5-month-old mice, levels of the intestinal transporters, ABCG5/8 and Niemann-Pick C1 Like 1, were not affected by loss of liver X receptor (LXR) beta and/or treatment with beta-sitosterol nor were there changes in plasma levels of cholesterol or beta-sitosterol. In 8-month-old LXRbeta-/- mice there was activation of microglia in the substantia nigra pars reticulata and aggregates of ubiquitin and TDP-43 in the cytoplasm of large motor neurons in the lumbar spinal cord. Brain cholesterol concentrations were higher in LXRbeta-/- than in their WT counterparts, and treatment with beta-sitosterol reduced brain cholesterol in both WT and LXRbeta-/- mice. In LXRbeta-/- mice but not in WT mice levels of 24-hydrocholesterol were increased upon beta-sitosterol treatment. These data indicate that multiple mechanisms are involved in the sensitivity of LXRbeta-/- mice to beta-sitosterol. These include activation of microglia, accumulation of protein aggregates in the cytoplasm of large motor neurons, and depletion of brain cholesterol.}, }
@article {pmid18230874, year = {2008}, author = {Peysson, S and Vandenberghe, N and Philit, F and Vial, C and Petitjean, T and Bouhour, F and Bayle, JY and Broussolle, E}, title = {Factors predicting survival following noninvasive ventilation in amyotrophic lateral sclerosis.}, journal = {European neurology}, volume = {59}, number = {3-4}, pages = {164-171}, doi = {10.1159/000114037}, pmid = {18230874}, issn = {1421-9913}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/diagnosis/*mortality/*therapy ; Confidence Intervals ; *Continuous Positive Airway Pressure ; Female ; Humans ; Male ; Middle Aged ; Odds Ratio ; Predictive Value of Tests ; Prognosis ; Respiration, Artificial/*methods ; Retrospective Studies ; Survival Analysis ; Time Factors ; }, abstract = {BACKGROUND/AIMS: The involvement of respiratory muscles is a major predicting factor for survival in amyotrophic lateral sclerosis (ALS). Recent studies show that noninvasive ventilation (NIV) can relieve symptoms of alveolar hypoventilation. However, factors predicting survival in ALS patients when treated with NIV need to be clarified.<br><br>METHODS: We conducted a retrospective study of 33 consecutive ALS patients receiving NIV. Ten patients had bulbar onset. We determined the median survivals from onset, diagnosis and initiation of NIV and factors predicting survival. Statistical analysis was performed using the Kaplan-Meier test and Cox proportional hazard models.<br><br>RESULTS: The median initial and maximal total uses of NIV were 10 and 14 h/24h. The overall median survival from ALS onset was 34.2 months and worsened with increasing age and bulbar onset of the disease. The median survival from initiation of NIV was 8.4 months and was significantly poorer in patients with advanced age or with airway mucus accumulation. Survival from initiation of NIV was not influenced by respiratory parameters or bulbar symptoms.<br><br>CONCLUSION: Advanced age at diagnosis and airway mucus accumulation represent poorer prognostic factors of ALS patients treated with NIV. NIV is a helpful treatment of sleep-disordered breathing, including patients with bulbar involvement.}, }
@article {pmid18221222, year = {2007}, author = {Lecanu, L and Papadopoulos, V}, title = {Cutting-edge patents in Alzheimer's disease drug discovery: anticipation of potential future treatments.}, journal = {Recent patents on CNS drug discovery}, volume = {2}, number = {2}, pages = {113-123}, doi = {10.2174/157488907780832715}, pmid = {18221222}, issn = {1574-8898}, mesh = {Alzheimer Disease/*drug therapy ; Amyloid Precursor Protein Secretases/antagonists &amp; inhibitors ; Amyloid beta-Peptides/immunology ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Calmodulin-Binding Proteins/antagonists &amp; inhibitors ; Chelating Agents/therapeutic use ; Cholinesterase Inhibitors/therapeutic use ; *Drug Design ; Glycogen Synthase Kinase 3/antagonists &amp; inhibitors ; Humans ; Immunization ; Patents as Topic ; }, abstract = {Neurodegenerative disease broadly includes many different diseases, such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's, dementias with Lewy bodies, post-traumatic brain injury, and stroke. Although few common physiopathological changes have been discovered among these conditions, the semiology (if known), the triggered molecular pathways that lead to the observed pathologies, and the symptomatology are essentially different. These differences entail that the treatments, both current and future, have disease-specific indications. This idea led us to believe than it would be quite impossible to comprehensively review the progress made in drug discovery for all the neurodegenerative diseases and, therefore, we focused our attention in this review on the cutting-edge patents that pertain to the treatment of Alzheimer's disease (AD). Basic science discoveries have identified new targets/leads that have led the scientific community to develop new research initiatives in order to develop novel therapeutics entities and approaches. The purpose of this review is to discuss, through cutting-edge patents, the emergence of potential future treatments of AD. We hope to provide the reader with a broader and better understanding of what could be new therapies for AD during the next decade.}, }
@article {pmid18220753, year = {2007}, author = {Beghi, E and Mennini, T and Bendotti, C and Bigini, P and Logroscino, G and Chiò, A and Hardiman, O and Mitchell, D and Swingler, R and Traynor, BJ and Al-Chalabi, A}, title = {The heterogeneity of amyotrophic lateral sclerosis: a possible explanation of treatment failure.}, journal = {Current medicinal chemistry}, volume = {14}, number = {30}, pages = {3185-3200}, doi = {10.2174/092986707782793862}, pmid = {18220753}, issn = {0929-8673}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/epidemiology ; Animals ; Biomarkers ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe clinical condition characterized by upper and lower motor neuron degeneration for which there is no truly effective treatment. The absence of an effective treatment can be explained in part by the complex and heterogeneous genetic, biochemical, and clinical features of ALS. While ALS accounts for the majority of the motor neuron diseases, the recognition of disease variants and mimic syndromes may lead to further insights into possible causes for the generality of ALS. From a biochemical perspective, the process of motor neuron degeneration is complex and the multifactorial influences and potential biomarkers of ALS have never been assessed in the light of the clinical heterogeneity of ALS. Several genes and environmental influences have been suggested as possible risk factors of ALS. A better understanding of interactions between these risk factors, potential biomarkers and heterogeneous clinical features may lead to more clearly defined pathological profiles among individuals or groups of ALS patients and in turn lead to more focused therapeutic trials.}, }
@article {pmid18219391, year = {2008}, author = {Harraz, MM and Marden, JJ and Zhou, W and Zhang, Y and Williams, A and Sharov, VS and Nelson, K and Luo, M and Paulson, H and Schöneich, C and Engelhardt, JF}, title = {SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model.}, journal = {The Journal of clinical investigation}, volume = {118}, number = {2}, pages = {659-670}, pmid = {18219391}, issn = {0021-9738}, support = {P30 DK054759/DK/NIDDK NIH HHS/United States ; R01 DK067928/DK/NIDDK NIH HHS/United States ; DK067928/DK/NIDDK NIH HHS/United States ; P30 DK54759/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetophenones/pharmacology ; Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Animals ; Disease Models, Animal ; Enzyme Inhibitors/pharmacology ; Hydrogen Peroxide/toxicity ; Longevity/drug effects ; Membrane Glycoproteins/metabolism ; Mice ; Mice, Transgenic ; Mutation ; NADPH Oxidase 2 ; NADPH Oxidases/*metabolism ; Neuropeptides/*metabolism ; Oxidation-Reduction ; Superoxide Dismutase/genetics/*physiology ; Superoxide Dismutase-1 ; rac GTP-Binding Proteins/*metabolism ; rac1 GTP-Binding Protein ; }, abstract = {Neurodegeneration in familial amyotrophic lateral sclerosis (ALS) is associated with enhanced redox stress caused by dominant mutations in superoxide dismutase-1 (SOD1). SOD1 is a cytosolic enzyme that facilitates the conversion of superoxide (O(2)(*-)) to H(2)O(2). Here we demonstrate that SOD1 is not just a catabolic enzyme, but can also directly regulate NADPH oxidase-dependent (Nox-dependent) O(2)(*-) production by binding Rac1 and inhibiting its GTPase activity. Oxidation of Rac1 by H(2)O(2) uncoupled SOD1 binding in a reversible fashion, producing a self-regulating redox sensor for Nox-derived O(2)(*-) production. This process of redox-sensitive uncoupling of SOD1 from Rac1 was defective in SOD1 ALS mutants, leading to enhanced Rac1/Nox activation in transgenic mouse tissues and cell lines expressing ALS SOD1 mutants. Glial cell toxicity associated with expression of SOD1 mutants in culture was significantly attenuated by treatment with the Nox inhibitor apocynin. Treatment of ALS mice with apocynin also significantly increased their average life span. This redox sensor mechanism may explain the gain-of-function seen with certain SOD1 mutations associated with ALS and defines new therapeutic targets.}, }
@article {pmid18219386, year = {2008}, author = {Boillée, S and Cleveland, DW}, title = {Revisiting oxidative damage in ALS: microglia, Nox, and mutant SOD1.}, journal = {The Journal of clinical investigation}, volume = {118}, number = {2}, pages = {474-478}, pmid = {18219386}, issn = {0021-9738}, support = {R37 NS027036/NS/NINDS NIH HHS/United States ; }, mesh = {Acetophenones/pharmacology ; Amyotrophic Lateral Sclerosis/*enzymology ; Animals ; Enzyme Inhibitors/pharmacology ; Humans ; Mice ; Microglia/*enzymology/pathology ; Motor Neurons/enzymology ; NADPH Oxidases/antagonists &amp; inhibitors/*metabolism ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; Superoxides/metabolism ; rac1 GTP-Binding Protein/metabolism ; }, abstract = {Mutation in superoxide dismutase-1 (SOD1) causes the inherited degenerative neurological disease familial amyotrophic lateral sclerosis (ALS), a non-cell-autonomous disease: mutant SOD1 synthesis in motor neurons and microglia drives disease onset and progression, respectively. In this issue of the JCI, Harraz and colleagues demonstrate that SOD1 mutants expressed in human cell lines directly stimulate NADPH oxidase (Nox) by binding to Rac1, resulting in overproduction of damaging ROS (see the related article beginning on page 659). Diminishing ROS by treatment with the microglial Nox inhibitor apocynin or by elimination of Nox extends survival in ALS mice, reviving the proposal that ROS mediate ALS pathogenesis, but with a new twist: it's ROS produced by microglia.}, }
@article {pmid18215350, year = {2008}, author = {Geng, CM and Ding, HL}, title = {Double-mismatched siRNAs enhance selective gene silencing of a mutant ALS-causing allele.}, journal = {Acta pharmacologica Sinica}, volume = {29}, number = {2}, pages = {211-216}, doi = {10.1111/j.1745-7254.2008.00740.x}, pmid = {18215350}, issn = {1671-4083}, support = {R01NS048145/NS/NINDS NIH HHS/United States ; }, mesh = {Alleles ; Amyotrophic Lateral Sclerosis/*genetics ; Base Pair Mismatch/drug effects/*genetics ; Cell Line ; Gene Silencing/*drug effects ; Humans ; Mutation/physiology ; Oligonucleotides, Antisense/pharmacology ; RNA, Small Interfering/*pharmacology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {AIM: Our previous study demonstrated an siRNA-mediated, allele-specific silencing of mutant genes that cause amyotrophic lateral sclerosis. To improve siRNA design for better therapeutic use of RNA interference, we systematically tested the base-pairing mismatch strategy in the design of asymmetric siRNA.<br><br>METHODS: A naturally symmetric siRNA that targets the human Cu Zn superoxide dismutase G85R mutant allele was modified by placing either 1 or 2 mismatches at the end of the siRNA from position 1 to 4 at each time. The target preference and silencing efficacy of modified siRNA were measured using a modified dual luciferase system.<br><br>RESULTS: The modification of single base-pairing mismatch successfully achieved the conversion of the siRNA that was originally favored to the antisense of the mutant allele to the one that was favored to the sense strand of the gene. Compared to the single-mismatched siRNA, those with double-mismatch at one end demonstrated an increased asymmetry, and thus, an enhanced specificity and efficacy of gene silencing. In addition, the siRNA with double-mismatch at both ends remained in symmetry.<br><br>CONCLUSION: Our results suggest the effectiveness of converting a symmetric siRNA to an asymmetric one by introducing mismatches into its structure, and the superiority of double-mismatched siRNA to single-mismatched siRNA in producing selective gene silencing resulting from the disruption of siRNA symmetry. The double-mismatch strategy is an improvement of the single-mismatch method and could be useful in the design of effective siRNAs for the treatment of diseases caused by dominant, gain-of-function gene mutations, such as ALS.}, }
@article {pmid18210783, year = {2007}, author = {Asao, H}, title = {[Lessons from Guam ALS/PDC study].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {47}, number = {11}, pages = {717-721}, pmid = {18210783}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*complications/epidemiology ; Dementia/*complications/epidemiology ; Guam/epidemiology ; Humans ; Parkinsonian Disorders/*complications/epidemiology ; Research ; }, abstract = {An extraordinarily high incidence of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) affecting the native population was discovered on the island of Guam a half century ago. Guam ALS is identical to classic ALS clinically and pathologically while PDC is marked by progressive parkinsonism and dementia. The unusual histological finding in these fetal neurodegenerative diseases is the presence of numerous neurofibrillary tangles in a selective topographic distribution unassociated with senile plaques. There have been remarkable advances in field of age-associated neurodegenerative disease after our initial study of Guam cases. Four noteworthy topics are presented in this communication. 1) Clinically, the coexistence of parkinsonism and dementia was frequently recognized in Parkinson disease and Alzheimer disease. Some other new disease entities characterized by coexistence of parkinsonism and dementia have been reported. These include progressive supranuclear palsy, frontotemporal dementia and parkinsonism linked to chromosome 17. 2) Neuropathologically, abundant neurofibrillary tangles unassociated with senile plaques were demonstrated in many diseases such as aftermath of boxing and tangle-only dementia. Furthermore, tau-positive structures were recognized not only in neurons but in glial cells in certain diseases. Tauopathy is one of the current hot research subjects. 3) Familial aggregation of Guam ALS patients provoked investigation of familial ALS elsewhere. Familial motor neuron disease with SOD1 mutation is the target of worldwide intense investigation at the present time. SOD1 gene mutation is, however, not found in Guam ALS. 4) The most striking findings of the Guam study is the gradual decline in the incidence of ALS on Guam during a quarter century and virtual disappearance of new patients. This may be linked to a remarkable change in environment and life style of the Chamorro population. The etiology of ALS is still unknown and no new treatment is available. Guam ALS/PDC is certainly one of the most mysterious riddles among age-associated neurodegenerative diseases during the last half a century.}, }
@article {pmid18210200, year = {2008}, author = {Gilmore, JL and Yi, X and Quan, L and Kabanov, AV}, title = {Novel nanomaterials for clinical neuroscience.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {3}, number = {2}, pages = {83-94}, pmid = {18210200}, issn = {1557-1904}, support = {R01 NS051334-01A1/NS/NINDS NIH HHS/United States ; R01 CA89225/CA/NCI NIH HHS/United States ; R01 NS051334-03/NS/NINDS NIH HHS/United States ; R01 CA089225-06/CA/NCI NIH HHS/United States ; R01 CA116591/CA/NCI NIH HHS/United States ; R01 CA116591-02/CA/NCI NIH HHS/United States ; R01 NS051334-02/NS/NINDS NIH HHS/United States ; R01 NS036229-09/NS/NINDS NIH HHS/United States ; R01 CA089225-05/CA/NCI NIH HHS/United States ; R01 CA116591-01A1/CA/NCI NIH HHS/United States ; R01 CA089225/CA/NCI NIH HHS/United States ; R01 NS051334/NS/NINDS NIH HHS/United States ; R01 NS051335/NS/NINDS NIH HHS/United States ; R01 NS036229/NS/NINDS NIH HHS/United States ; R01 CA116591-03/CA/NCI NIH HHS/United States ; R01 NS36229/NS/NINDS NIH HHS/United States ; R01 NS036229-08/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Biopolymers/chemistry ; Blood-Brain Barrier ; Central Nervous System Diseases/diagnosis/drug therapy ; Coated Materials, Biocompatible ; Drug Delivery Systems ; Drug Evaluation, Preclinical ; Fullerenes/chemistry/therapeutic use/toxicity ; Humans ; Hydrophobic and Hydrophilic Interactions ; Materials Testing ; Nanogels ; *Nanostructures/administration &amp; dosage/chemistry/therapeutic use ; Nanotubes, Carbon/chemistry/toxicity ; Nerve Regeneration/drug effects ; Neurodegenerative Diseases/diagnosis/drug therapy ; Neuroprotective Agents/chemistry/therapeutic use ; Oxidative Stress ; Pharmaceutical Vehicles ; Polyethylene Glycols/administration &amp; dosage ; Polyethyleneimine/administration &amp; dosage ; Tissue Scaffolds ; }, abstract = {Neurodegenerative disorders including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and stroke are rapidly increasing as population ages. The field of nanomedicine is rapidly expanding and promises revolutionary advances to the diagnosis and treatment of devastating human diseases. This paper provides an overview of novel nanomaterials that have potential to improve diagnosis and therapy of neurodegenerative disorders. Examples include liposomes, nanoparticles, polymeric micelles, block ionomer complexes, nanogels, and dendrimers that have been tested clinically or in experimental models for delivery of drugs, genes, and imaging agents. More recently discovered nanotubes and nanofibers are evaluated as promising scaffolds for neuroregeneration. Novel experimental neuroprotective strategies also include nanomaterials, such as fullerenes, which have antioxidant properties to eliminate reactive oxygen species in the brain to mitigate oxidative stress. Novel technologies to enable these materials to cross the blood brain barrier will allow efficient systemic delivery of therapeutic and diagnostic agents to the brain. Furthermore, by combining such nanomaterials with cell-based delivery strategies, the outcomes of neurodegenerative disorders can be greatly improved.}, }
@article {pmid18210046, year = {2008}, author = {Kollewe, K and Dengler, R and Petri, S}, title = {[Amyotrophic lateral sclerosis. Current clinical trials and underlying pathomechanisms].}, journal = {Der Nervenarzt}, volume = {79}, number = {6}, pages = {653-661}, pmid = {18210046}, issn = {0028-2804}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Animals ; Clinical Trials as Topic/*trends ; *Disease Models, Animal ; Drug Evaluation, Preclinical/*trends ; Humans ; Neuroprotective Agents/*therapeutic use ; Riluzole/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to death after 3 to 5 years. The glutamate antagonist Riluzole currently is the only drug with marginal therapeutic benefit, but its effect on survival is modest, with an average increase of only 3-4 months. Therefore symptomatic treatment still is the most important. Further neuroprotective agents are currently under investigation, both in transgenic animal models of ALS and clinical trials in ALS patients. This review summarizes the current state of clinical studies in ALS patients in the context of underlying therapeutic mechanisms.}, }
@article {pmid18208860, year = {2008}, author = {Zéphir, H and Stojkovic, T and Latour, P and Lacour, A and de Seze, J and Outteryck, O and Maurage, CA and Monpeurt, C and Chatelet, P and Ovelacq, E and Vermersch, P}, title = {Relapsing demyelinating disease affecting both the central and peripheral nervous systems.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {79}, number = {9}, pages = {1032-1039}, doi = {10.1136/jnnp.2006.108290}, pmid = {18208860}, issn = {1468-330X}, mesh = {Adult ; Aged ; Biopsy ; Brain/pathology ; Demyelinating Diseases/complications/pathology ; Electromyography/instrumentation ; Evoked Potentials, Visual/*physiology ; Extremities/innervation ; Female ; Hemianopsia/epidemiology ; Humans ; Magnetic Resonance Imaging ; Male ; Multiple Sclerosis, Relapsing-Remitting/*complications/pathology ; Neural Conduction/physiology ; Peripheral Nerves/pathology ; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/*complications/pathology ; Reflex, Abnormal/physiology ; Reflex, Stretch/physiology ; Spinal Cord/*pathology ; }, abstract = {BACKGROUND: Clinical and electromyographic findings of chronic inflammatory demyelinating polyradiculopathy (CIDP) are occasionally observed in patients with multiple sclerosis (MS).<br><br>OBJECTIVE: To define a new inflammatory demyelinating disease unlike MS or CIDP.<br><br>RESULTS: This study reports on five patients with a demyelinating disease affecting the central nervous system (CNS) and peripheral nervous system (PNS). Each case presented a relapsing-remitting course in which CNS involvement preceded PNS involvement. All patients fulfilled Barkhof's criteria on MRI and the McDonald criteria for MS. Two patients had grey matter lesions with typical white matter changes. No systemic inflammatory disease and no metabolic or inflammatory factor for peripheral neuropathy were found. In all cases electromyography showed a demyelinating peripheral neuropathy without conduction block. Four patients fulfilled the European Federation of Neurological Societies/PNS guideline for CIDP and Nicolas et al's criteria for CIDP, one of whom also fulfilled the Ad Hoc Subcommittee criteria for CIDP. Nerve biopsy, performed in two patients, showed histological evidence of CIDP. An improvement in clinical status and neurophysiological parameters was observed in three patients after treatment with either intravenous immunoglobulin (n = 1) or cyclophosphamide (n = 2).<br><br>CONCLUSION: The CNS and PNS demyelination, the absence of oligoclonal bands and the peripheral demyelination without conduction block indicate pathogenic mechanisms different from MS and CIDP. The chronology of events suggests an entity unlike that involved in acute demyelinating encephalomyelitis. Immunological reactivity against antigens common to peripheral and central myelin may explain why the demyelinating disease affected both the CNS and PNS.}, }
@article {pmid18201889, year = {2008}, author = {Bigini, P and Repici, M and Cantarella, G and Fumagalli, E and Barbera, S and Cagnotto, A and De Luigi, A and Tonelli, R and Bernardini, R and Borsello, T and Mennini, T}, title = {Recombinant human TNF-binding protein-1 (rhTBP-1) treatment delays both symptoms progression and motor neuron loss in the wobbler mouse.}, journal = {Neurobiology of disease}, volume = {29}, number = {3}, pages = {465-476}, doi = {10.1016/j.nbd.2007.11.005}, pmid = {18201889}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology/*prevention &amp; control ; Animals ; Cell Count/methods ; Disease Progression ; Female ; Humans ; Male ; Mice ; Mice, Neurologic Mutants ; Motor Neurons/drug effects/*pathology/physiology ; Receptors, Tumor Necrosis Factor, Type I/administration &amp; dosage/*therapeutic use ; Recombinant Proteins/administration &amp; dosage/*therapeutic use ; Tumor Necrosis Factor Decoy Receptors/administration &amp; dosage/*therapeutic use ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/*metabolism ; }, abstract = {TNF-alpha overexpression may contribute to motor neuron death in amyotrophic lateral sclerosis (ALS). We investigated the intracellular pathway associated with TNF-alpha in the wobbler mouse, a murine model of ALS, at the onset of symptoms. TNF-alpha and TNFR1 overexpression and JNK/p38MAPK phosphorylation occurred in neurons and microglia in early symptomatic mice, suggesting that this activation may contribute to motor neuron damage. The involvement of TNF-alpha was further confirmed by the protective effect of treatment with rhTNF-alpha binding protein (rhTBP-1) from 4 to 9 weeks of age. rhTBP-1 reduced the progression of symptoms, motor neuron loss, gliosis and JNK/p38MAPK phosphorylation in wobbler mice, but did not reduce TNF-alpha and TNFR1 levels. rhTBP-1 might possibly bind TNF-alpha and reduce the downstream phosphorylation of two main effectors of the neuroinflammatory response, p38MAPK and JNK.}, }
@article {pmid18198431, year = {2007}, author = {Lewis, M and Rushanan, S}, title = {The role of physical therapy and occupational therapy in the treatment of amyotrophic lateral sclerosis.}, journal = {NeuroRehabilitation}, volume = {22}, number = {6}, pages = {451-461}, pmid = {18198431}, issn = {1053-8135}, mesh = {Amyotrophic Lateral Sclerosis/complications/psychology/*rehabilitation ; Humans ; *Occupational Therapy ; Patient Education as Topic ; *Physical Therapy Modalities ; Range of Motion, Articular ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disease for which there is no cure. There is a general misunderstanding among healthcare professionals of the proper use and potential benefits of physical and occupational therapy to treat the symptoms and resulting loss of independence. These services can help maximize mobility and comfort through equipment prescription, activity adaptation, patient and family education, and the use of appropriate exercise and range of motion techniques. The literature is controversial on the prescription of exercise in this population. Individual muscle strength, fatigue and spasticity must all be taken into account when discussing exercise with persons with ALS. It can be concluded that physical and occupational therapy intervention is beneficial to persons with ALS. However, more research is needed to decisively determine the effects of exercise on the person with ALS.}, }
@article {pmid18198426, year = {2007}, author = {Palovcak, M and Mancinelli, JM and Elman, LB and McCluskey, L}, title = {Diagnostic and therapeutic methods in the management of dysphagia in the ALS population: issues in efficacy for the out-patient setting.}, journal = {NeuroRehabilitation}, volume = {22}, number = {6}, pages = {417-423}, pmid = {18198426}, issn = {1053-8135}, mesh = {*Ambulatory Care ; Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Deglutition Disorders/*diagnosis/etiology/*therapy ; Humans ; Treatment Outcome ; }, abstract = {ALS is a neurodegenerative disease that affects nerve cells in the brain and spinal cord that control voluntary skeletal muscle. The muscle weakness that results from ALS is relentlessly progressive and rehabilitative attempts to strengthen affected muscles usually fail. When managing swallowing and communication disorders in individuals with ALS, the goals are to maximize function and safety through the use of compensatory strategies, energy conservation, and patient and caregiver education and counseling. This paper will review the current methods of assessment and treatment used with this population in the outpatient setting.}, }
@article {pmid18198425, year = {2007}, author = {Ferguson, TA and Elman, LB}, title = {Clinical presentation and diagnosis of amyotrophic lateral sclerosis.}, journal = {NeuroRehabilitation}, volume = {22}, number = {6}, pages = {409-416}, pmid = {18198425}, issn = {1053-8135}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/etiology/physiopathology ; Diagnosis, Differential ; Humans ; Neural Conduction/physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Progressive loss of motor neurons causes Amyotrophic Lateral Sclerosis. Patients complain, most often, of progressive weakness in the distal limbs. However, weakness may manifest in any body segment (bulbar, cervical, thoracic, or lumbosacral). The diagnosis of ALS is suggested by clinical examination that reveals both upper and lower motor neuron failure. Formal diagnostic criteria have been developed and validated. Nerve conduction and electromyography studies improve diagnostic sensitivity and exclude some alternate, treatable diagnoses. Likewise, conventional imaging studies and laboratory evaluation refute other diseases that may masquerade as ALS. Experimental imaging and laboratory evaluations may improve ALS diagnosis in the future. The cause of motor neuron death is not known but inherited forms of motor neuron disease may suggest mechanisms. The goal of ALS treatment is control of the symptoms of progressive weakness, especially respiratory insufficiency and dysphagia and is best managed in an integrated clinic.}, }
@article {pmid18198391, year = {2008}, author = {Riemer, C and Burwinkel, M and Schwarz, A and Gültner, S and Mok, SWF and Heise, I and Holtkamp, N and Baier, M}, title = {Evaluation of drugs for treatment of prion infections of the central nervous system.}, journal = {The Journal of general virology}, volume = {89}, number = {Pt 2}, pages = {594-597}, doi = {10.1099/vir.0.83281-0}, pmid = {18198391}, issn = {0022-1317}, mesh = {Animals ; Central Nervous System Diseases/*drug therapy/mortality ; Curcumin/pharmacology/therapeutic use ; Evaluation Studies as Topic ; Ibuprofen/*adverse effects/pharmacology/therapeutic use ; Memantine/pharmacology/therapeutic use ; Mice ; Minocycline/pharmacology/therapeutic use ; Prion Diseases/*drug therapy/mortality ; }, abstract = {Prion diseases are fatal and at present there are neither cures nor therapies available to delay disease onset or progression in humans. Inspired in part by therapeutic approaches in the fields of Alzheimer's disease and amyotrophic lateral sclerosis, we tested five different drugs, which are known to efficiently pass through the blood-brain barrier, in a murine prion model. Groups of intracerebrally prion-challenged mice were treated with the drugs curcumin, dapsone, ibuprofen, memantine and minocycline. Treatment with antibiotics dapsone and minocycline had no therapeutic benefit. Ibuprofen-treated mice showed severe adverse effects, which prevented assessment of therapeutic efficacy. Mice treated with low- but not high-dose curcumin and mice treated with memantine survived infections significantly longer than untreated controls (P<0.01). These results encourage further research efforts to improve the therapeutic effect of these drugs.}, }
@article {pmid18182045, year = {2008}, author = {Tolosa, L and Mir, M and Asensio, VJ and Olmos, G and Lladó, J}, title = {Vascular endothelial growth factor protects spinal cord motoneurons against glutamate-induced excitotoxicity via phosphatidylinositol 3-kinase.}, journal = {Journal of neurochemistry}, volume = {105}, number = {4}, pages = {1080-1090}, doi = {10.1111/j.1471-4159.2007.05206.x}, pmid = {18182045}, issn = {1471-4159}, mesh = {Animals ; Cell Death/drug effects/physiology ; Cell Survival/drug effects/physiology ; Enzyme Inhibitors/pharmacology ; Excitatory Amino Acid Agents/pharmacology ; Glutamic Acid/*toxicity ; Humans ; Motor Neurons/*drug effects/*enzymology/pathology ; Organ Culture Techniques ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/drug effects/enzymology/pathology ; Vascular Endothelial Growth Factor A/*pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motoneurons. Recently, vascular endothelial growth factor (VEGF) has been identified as a neurotrophic factor and has been implicated in the mechanisms of pathogenesis of ALS and other neurological diseases. The potential neuroprotective effects of VEGF in a rat spinal cord organotypic culture were studied in a model of chronic glutamate excitotoxicity in which glutamate transporters are inhibited by threohydroxyaspartate (THA). Particularly, we focused on the effects of VEGF in the survival and vulnerability to excitotoxicity of spinal cord motoneurons. VEGF receptor-2 was present on spinal cord neurons, including motoneurons. Chronic (3 weeks) treatment with THA induced a significant loss of motoneurons that was inhibited by co-exposure to VEGF (50 ng/mL). VEGF activated the phosphatidylinositol 3-kinase/Akt (PI3-K/Akt) signal transduction pathway in the spinal cord cultures, and the effect on motoneuron survival was fully reversed by the specific PI3-K inhibitor, LY294002. VEGF also prevented the down-regulation of Bcl-2 and survivin, two proteins implicated in anti-apoptotic and/or anti-excitotoxic effects, after THA exposure. Together, these findings indicate that VEGF has neuroprotective effects in rat spinal cord against chronic glutamate excitotoxicity by activating the PI3-K/Akt signal transduction pathway and also reinforce the hypothesis of the potential therapeutic effects of VEGF in the prevention of motoneuron degeneration in human ALS.}, }
@article {pmid18176634, year = {2007}, author = {Adibhatla, RM and Hatcher, JF}, title = {Role of Lipids in Brain Injury and Diseases.}, journal = {Future lipidology}, volume = {2}, number = {4}, pages = {403-422}, pmid = {18176634}, issn = {1746-0875}, support = {R01 NS042008-04/NS/NINDS NIH HHS/United States ; R01 NS042008-03/NS/NINDS NIH HHS/United States ; R01 NS042008-01A2/NS/NINDS NIH HHS/United States ; R01 NS042008/NS/NINDS NIH HHS/United States ; R01 NS042008-02/NS/NINDS NIH HHS/United States ; }, abstract = {Lipid metabolism is of particular interest due to its high concentration in CNS. The importance of lipids in cell signaling and tissue physiology is demonstrated by many CNS disorders and injuries that involve deregulated metabolism. The long suffering lipid field is gaining reputation and respect as evidenced through the Center of Biomedical Research Excellence in Lipidomics and Pathobiology (COBRE), Lipid MAPS (Metabolites And Pathways Strategy) Consortium sponsored by NIH, European initiatives for decoding the lipids through genomic approaches, and Genomics of Lipid-associated Disorder (GOLD) project initiated by Austrian government. This review attempts to provide an overview of the lipid imbalances associated with neurological disorders (Alzheimer's, Parkinson's; Niemann-Pick; Multiple sclerosis, Huntington, amyotrophic lateral sclerosis, schizophrenia, bipolar disorders and epilepsy) and CNS injury (Stroke, traumatic brain injury; and spinal cord injury) and a few provocative thoughts. Lipidomic analyses along with RNA silencing will provide new insights into the role of lipid intermediates in cell signaling and hopefully open new avenues for prevention or treatment options.}, }
@article {pmid20936097, year = {2008}, author = {Ly, PT and Pelech, S and Shaw, CA}, title = {Cholesteryl Glucoside Stimulates Activation of Protein Kinase B/Akt in the Motor Neuron-Derived NSC34 Cell Line.}, journal = {Neurobiology of lipids}, volume = {7}, number = {4}, pages = {620081}, pmid = {20936097}, issn = {1683-5506}, support = {R01 NS051723/NS/NINDS NIH HHS/United States ; R01 NS051723-03/NS/NINDS NIH HHS/United States ; }, abstract = {Steryl glycosides and related compounds are commonly found in the environment and have been associated with neurodegenerative changes in vulnerable individuals. However, their mechanisms of action in mammalian cells have not been well investigated. In the present study the effects of cholesterol glucoside (CG), a variant form of steryl glycoside, was investigated in the motor neuron-derived NSC34 cell line. Prolonged treatment with CG was found to induce cell death in a dose- and time-dependent manner. However, transient exposure of CG preconditioned NSC34 cells for stress from serum deprivation. To study the signaling pathways activated by CG, we employed the Kinetworks™ KPSS 1.3 Phospho-site Screen to track the phosphorylation level of at least 35 diverse signaling proteins. The survival protein kinase B (PKB/Akt) displayed a 2-fold increase in phosphorylation at its Ser-473 activation site following CG stimulation. Akt signaling was important for conferring cytoprotection against serum deprivation-induced stress. Inhibition of phosphatidylinositol 3-kinase (PI3K), which indirectly triggers Akt stimulation, completely abolished CG preconditioning against serum deprivation. Our findings revealed that there may be a PI3K-independent pathway which also mediated Akt Ser-473 phosphorylation. Improved understanding of the mechanisms of action of CG should provide insights to the how other members of the steryl glycoside family induce toxicity in the mouse model of ALS-PDC, and how cells respond to these toxins.}, }
@article {pmid20824024, year = {2008}, author = {Singer, CF}, title = {Neoadjuvant Endocrine Therapy in Breast Cancer.}, journal = {Breast care (Basel, Switzerland)}, volume = {3}, number = {5}, pages = {303-308}, pmid = {20824024}, issn = {1661-3791}, abstract = {Women who suffer from large or locally advanced malignant breast tumors are now commonly treated with preoperative ('neoadjuvant') systemic therapy to improve surgical outcomes and to raise the chances for breast-conserving therapy (BCT). Until recently, chemotherapy was the treatment of choice, and primary systemic endocrine treatment was restricted to medically frail or older women with receptor-positive breast cancer. The development of modern aromatase inhibitors (Als) and their subsequent clinical evaluation in neoadjuvant trials now provides us with an alternative to chemotherapy that is thought to be equally effective, yet considerably better tolerated. Several large prospective trials have compared tamoxifen with the non-steroidal AIs letrozole and anastrozole and the steroidal Al exemestane, with improved outcomes for all AIs in terms of tumor remission and rate of BCT. A number of predictive biomarkers now also allow us to identify those tumors that most likely respond to a certain endocrine regimen.}, }
@article {pmid20021425, year = {2008}, author = {Tauber, SC and Nau, R}, title = {Immunomodulatory properties of antibiotics.}, journal = {Current molecular pharmacology}, volume = {1}, number = {1}, pages = {68-79}, pmid = {20021425}, issn = {1874-4702}, mesh = {Anti-Bacterial Agents/*pharmacology ; Fluoroquinolones/pharmacology ; Humans ; Immunologic Factors/*pharmacology ; Lung Diseases/drug therapy/immunology ; Macrolides/pharmacology ; Neurodegenerative Diseases/drug therapy/immunology ; Protein Synthesis Inhibitors/pharmacology ; Rifampin/pharmacology ; Tetracyclines/pharmacology ; }, abstract = {There is growing evidence that certain antibiotics exert their beneficial effects not only by killing or inhibiting the growth of bacterial pathogens but also indirectly by immunomodulation. This review aims at giving an overview of the immunomodulatory properties of antibiotics in different diseases: The antiinflammatory properties of macrolides in chronic inflammatory pulmonary disorders were recognized more than 15 years ago and have been well documented in the last decade. Recent data suggest that several antibiotics such as tetracyclines and cephalosporins may have a beneficial immunomodulatory or neuroprotective effect on neuroimmunological and neurodegenerative diseases including multiple sclerosis and amyotrophic lateral sclerosis. Moreover, the non-bacteriolytic but bactericidal antibiotics rifampicin, clindamycin and aminoglycosides kill bacteria without releasing high quantities of proinflammtory cell wall components. The use of bactericidal, non-bacteriolytic protein synthesis inhibitors reduces mortality and long-term sequelae in experimental bacterial sepsis, plague and meningitis. Clinically, macrolides have been well established as an adjunctive treatment to beta-lactam antibiotics in pulmonary diseases. For other indications, appropriate clinical trials are necessary before using the immunomodulatory properties of antibiotics in clinical practice.}, }
@article {pmid18158219, year = {2008}, author = {Lule, D and Ludolph, AC and Ludolph, AG}, title = {Neurodevelopmental and neurodegenerative diseases - is there a pathophysiological link? Attention-deficit/hyperactivity disorder and amyotrophic lateral sclerosis as examples.}, journal = {Medical hypotheses}, volume = {70}, number = {6}, pages = {1133-1138}, doi = {10.1016/j.mehy.2007.11.002}, pmid = {18158219}, issn = {0306-9877}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Attention Deficit Disorder with Hyperactivity/*physiopathology ; Humans ; *Models, Neurological ; *Neurobiology ; Neurodegenerative Diseases/*physiopathology ; Risk Factors ; }, abstract = {Attention-deficit/hyperactivity disorder (ADHD), the most common neurobehavioural disorder and amyotrophic lateral sclerosis (ALS), the most common adult motoneuron disease, may be two distinct entities on first sight. This paper aims to highlight parallels concerning clinical features and neurobiology. The presence of increased physical and psychological activity and largely non-progressive frontal dysfunction associated with impaired executive control and decreased attention are characteristic clinical features of both, ADHD and ALS. At the neurobiological level, there is evidence for hyperactivity in the glutamatergic system and a - potentially related - dopaminergic hypoactivity in ADHD and ALS. The clinical features of ALS resembling ADHD are particularly characteristic for the premorbid stage of the patient. Therefore, we hypothesize that clinical features of ADHD may be a risk factor for the development of ALS. This hypothesis is currently of unknown pathogenetic, but of potential future therapeutic relevance. Our hypothesis of a link between ADHD and ALS could also be considered as an example how research on neurodevelopmental diseases might influence the understanding and possibly the prevention and treatment of neurodegenerative diseases.}, }
@article {pmid18154926, year = {2008}, author = {Boutahar, N and Reynaud, E and Lassabliere, F and Borg, J}, title = {Timing differences of signaling response in neuron cultures activated by glutamate analogue or free radicals.}, journal = {Brain research}, volume = {1191}, number = {}, pages = {20-29}, doi = {10.1016/j.brainres.2007.11.016}, pmid = {18154926}, issn = {0006-8993}, mesh = {Animals ; Cell Death/drug effects/physiology ; Cells, Cultured ; Cerebral Cortex/cytology/metabolism ; Excitatory Amino Acid Agonists/metabolism/pharmacology ; Extracellular Signal-Regulated MAP Kinases/drug effects/*metabolism ; Free Radicals/metabolism ; Gene Expression Profiling ; Gene Expression Regulation/drug effects/physiology ; Hydrogen Peroxide/pharmacology ; Mice ; N-Methylaspartate/metabolism ; Neurons/cytology/*metabolism ; Neurotoxins/pharmacology ; Oxidants/pharmacology ; Oxidative Stress/drug effects/*physiology ; Proto-Oncogene Proteins c-jun/drug effects/metabolism ; Signal Transduction/drug effects/physiology ; Time Factors ; Tumor Suppressor Protein p53/drug effects/*metabolism ; p21-Activated Kinases/*metabolism ; }, abstract = {Oxidative stress and excitotoxicity are both involved in the pathogenesis of neuronal degenerative diseases like ALS. In order to compare their action, some key proteins involved in their respective signaling pathways, particularly ERK and p53, were analyzed in primary cultures of cortical neurons subjected to NMDA or H(2)O(2) treatment. Early ERK activation was detected after NMDA treatment and was maintained during 24 h, but not after H(2)O(2) treatment. Early p53 expression was also found after NMDA treatment but diminished later. On the other hand, it progressively increased from 6 h to 24 h after H(2)O(2) treatment. Blocking ERK1/2 activation with the upstream inhibitor U0126 inhibited NMDA-mediated p53 expression, suggesting that ERK1/2 signals drive the cells to apoptosis under these conditions. In order to identify the initial membrane target of these neurotoxins, PAK1 was analyzed. Early increase of PAK1 expression was measured after NMDA treatment and was still present after 24 h. Conversely increased PAK1 expression was only detected 24 h after H(2)O(2) treatment. In order to define the components through which NMDA or H(2)O(2) induce the final elements of these pathways, p21 and c-jun, we have performed a detailed functional analysis of c-jun and p21 promoters following plasmid transfection. Both p21 and c-jun were activated after NMDA treatment, but this activation was abolished after H(2)O(2) treatment. We conclude that NMDA induces an early effect that involves activation of p53, ERK, PAK1, p21 and c-jun. On the other hand, H(2)O(2) induces long-term p53 expression, late expression of PAK1 without activation of p21 promoter. The timing differences of the action of these neurotoxins may explain why the presence of both compounds is needed to induce neuronal death.}, }
@article {pmid18098330, year = {2008}, author = {van Kan, HJ and van den Berg, LH and Groeneveld, GJ and van der Straaten, RJ and van Vught, PW and Lie-A-Huen, L and Guchelaar, HJ}, title = {Pharmacokinetics of riluzole: evidence for glucuronidation as a major metabolic pathway not associated with UGT1A1 genotype.}, journal = {Biopharmaceutics &amp; drug disposition}, volume = {29}, number = {3}, pages = {139-144}, doi = {10.1002/bdd.594}, pmid = {18098330}, issn = {0142-2782}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Female ; Genotype ; Glucuronides ; Glucuronosyltransferase/*genetics/metabolism ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*pharmacokinetics ; Riluzole/*pharmacokinetics ; }, abstract = {Pharmacokinetic studies of riluzole show a large inter-individual variability of the drug's clearance and serum concentrations. Optimizing the individual dosage of riluzole may have the potential to improve the effect of riluzole treatment on survival of patients with amyotrophic lateral sclerosis (ALS). Limited data are available on the in vivo metabolic elimination of riluzole. From in vitro experiments, CYP1A2 seems to be mainly involved in riluzole clearance. However, in vitro studies suggest that formation of riluzole-glucuronide plays a role and may determine the drug's pharmacokinetic variability in patients to some extent. In the current study the formation of riluzole-glucuronide was examined in amyotrophic lateral sclerosis (ALS) patients. It also aimed at relating glucuronidation of riluzole to differential UGT1A1*28 genotypes. The formation of riluzole-glucuronide was confirmed in serum from a group of 14 ALS patients taking riluzole. Riluzole-glucuronide concentrations were positively associated with those of riluzole. In a separate group of 131 ALS patients taking riluzole, the UGT1A1*28 genotype was not associated with trough or peak serum concentrations of riluzole. This study provides evidence that the in vivo metabolic elimination of riluzole in ALS patients involves glucuronidation. The results do not indicate that glucuronidation of riluzole highly contributes to the drug's inter-individual pharmacokinetic variability.}, }
@article {pmid18093603, year = {2008}, author = {De Zan, MM and Gil García, MD and Culzoni, MJ and Siano, RG and Goicoechea, HC and Martínez Galera, M}, title = {Solving matrix-effects exploiting the second order advantage in the resolution and determination of eight tetracycline antibiotics in effluent wastewater by modelling liquid chromatography data with multivariate curve resolution-alternating least squares and unfolded-partial least squares followed by residual bilinearization algorithms I. Effect of signal pre-treatment.}, journal = {Journal of chromatography. A}, volume = {1179}, number = {2}, pages = {106-114}, doi = {10.1016/j.chroma.2007.11.091}, pmid = {18093603}, issn = {0021-9673}, mesh = {Algorithms ; Chromatography, High Pressure Liquid/*methods ; Models, Theoretical ; Tetracyclines/*analysis/isolation &amp; purification ; Waste Disposal, Fluid ; Water Pollutants, Chemical/*analysis ; }, abstract = {The effect of piecewise direct standardization (PDS) and baseline correction approaches was evaluated in the performance of multivariate curve resolution (MCR-ALS) algorithm for the resolution of three-way data sets from liquid chromatography with diode-array detection (LC-DAD). First, eight tetracyclines (tetracycline, oxytetracycline, chlorotetracycline, demeclocycline, methacycline, doxycycline, meclocycline and minocycline) were isolated from 250 mL effluent wastewater samples by solid-phase extraction (SPE) with Oasis MAX 500 mg/6 mL cartridges and then separated on an Aquasil C18 150 mm x 4.6mm (5 microm particle size) column by LC and detected by DAD. Previous experiments, carried out with Milli-Q water samples, showed a considerable loss of the most polar analytes (minocycline, oxitetracycline and tetracycline) due to breakthrough. PDS was applied to overcome this important drawback. Conversion of chromatograms obtained from standards prepared in solvent was performed obtaining a high correlation with those corresponding to the real situation (r2 = 0.98). Although the enrichment and clean-up steps were carefully optimized, the sample matrix caused a large baseline drift, and also additive interferences were present at the retention times of the analytes. These problems were solved with the baseline correction method proposed by Eilers. MCR-ALS was applied to the corrected and uncorrected three-way data sets to obtain spectral and chromatographic profiles of each tetracycline, as well as those corresponding to the co-eluting interferences. The complexity of the calibration model built from uncorrected data sets was higher, as expected, and the quality of the spectral and chromatographic profiles was worse.}, }
@article {pmid18074701, year = {2007}, author = {Gilad, I and Byran, E}, title = {Ergonomic evaluation of the ambulance interior to reduce paramedic discomfort and posture stress.}, journal = {Human factors}, volume = {49}, number = {6}, pages = {1019-1032}, doi = {10.1518/001872007X249884}, pmid = {18074701}, issn = {0018-7208}, mesh = {Adult ; *Ambulances ; *Ergonomics ; Female ; Humans ; *Interior Design and Furnishings ; Interviews as Topic ; Israel ; Male ; Observation ; Pain/*prevention &amp; control ; Posture/*physiology ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: This study aims to evaluate safety and accessibility of an advanced life support (ALS) ambulance interior.<br><br>BACKGROUND: The standard ambulance's interior design is unsatisfactory based on perceived discomfort and postures that constrain paramedics and medical staff, resulting in unsafe treatment of patients, mainly when being transported.<br><br>METHODS: Two procedures were used to evaluate performance during a wide range of rescue tasks: a survey, based on questionnaires, interviews, and observation of paramedics performing routine tasks; and upper body and back posture analysis, based on postural considerations.<br><br>RESULTS: Findings revealed that 74% of the paramedics stated that the location of the paramedic's seat is inefficient while they perform clinical procedures; 94% found the bench uncomfortable; 77% felt that the vertical distance between the bench and the stretcher is too far; and 86% needed to steady themselves when the vehicle was moving. Posture analysis showed that paramedics undergo several nonneutral back postures, including twisted back (>20 degrees) and sitting with back flexion between 20 degrees and 45 degrees.<br><br>CONCLUSION: Because the interior of the ALS ambulance was found to be unsatisfactory both to paramedics and patients, alternative design issues are proposed.<br><br>APPLICATION: The suggested practical layout contains four main modifications: (a) replacing the bench with two adjustable paramedic seats, (b) redesigning the medical cabinet for easy access, (c) adding an adjustable folding seat opposite the two new seats, and (d) adding a swiveling base and lifting apparatus that will accommodate the stretcher and enable better accessibility to patients by the paramedic personnel.}, }
@article {pmid18067904, year = {2008}, author = {García, MD and Culzoni, MJ and De Zan, MM and Valverde, RS and Galera, MM and Goicoechea, HC}, title = {Solving matrix effects exploiting the second-order advantage in the resolution and determination of eight tetracycline antibiotics in effluent wastewater by modelling liquid chromatography data with multivariate curve resolution-alternating least squares and unfolded-partial least squares followed by residual bilinearization algorithms II. Prediction and figures of merit.}, journal = {Journal of chromatography. A}, volume = {1179}, number = {2}, pages = {115-124}, doi = {10.1016/j.chroma.2007.11.049}, pmid = {18067904}, issn = {0021-9673}, mesh = {Algorithms ; Chromatography, High Pressure Liquid/*methods ; Multivariate Analysis ; Tetracyclines/*analysis ; Waste Disposal, Fluid ; Water Pollutants, Chemical/*analysis ; }, abstract = {A new powerful algorithm (unfolded-partial least squares followed by residual bilinearization (U-PLS/RBL)) was applied for first time on second-order liquid chromatography with diode array detection (LC-DAD) data and compared with a well-known established method (multivariate curve resolution-alternating least squares (MCR-ALS)) for the simultaneous determination of eight tetracyclines (tetracycline, oxytetracycline, meclocycline, minocycline, metacycline, chlortetracycline, demeclocycline and doxycycline) in wastewaters. Tetracyclines were pre-concentrated using Oasis Max C18 cartridges and then separated on a Thermo Aquasil C18 (150 mm x 4.6mm, 5 microm) column. The whole method was validated using Milli-Q water samples and both univariate and multivariate analytical figures of merit were obtained. Additionally, two data pre-treatment were applied (baseline correction and piecewise direct standardization), which allowed to correct the effect of breakthrough and to reduce the total interferences retained after pre-concentration of wastewaters. The results showed that the eight tetracycline antibiotics can be successfully determined in wastewaters, the drawbacks due to matrix interferences being adequately handled and overcome by using U-PSL/RBL.}, }
@article {pmid18063409, year = {2008}, author = {Chen, R and Cros, D and Curra, A and Di Lazzaro, V and Lefaucheur, JP and Magistris, MR and Mills, K and Rösler, KM and Triggs, WJ and Ugawa, Y and Ziemann, U}, title = {The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {119}, number = {3}, pages = {504-532}, doi = {10.1016/j.clinph.2007.10.014}, pmid = {18063409}, issn = {1388-2457}, mesh = {Electric Stimulation/*methods ; Electromyography/methods/statistics &amp; numerical data ; Evoked Potentials, Motor/physiology ; Humans ; Nervous System Diseases/*diagnosis/physiopathology ; Neural Conduction/physiology ; Transcranial Magnetic Stimulation/*methods/*statistics &amp; numerical data ; }, abstract = {The review focuses on the clinical diagnostic utility of transcranial magnetic stimulation (TMS). The central motor conduction time (CMCT) is a sensitive method to detect myelopathy and abnormalities may be detected in the absence of radiological changes. CMCT may also detect upper motor neuron involvement in amyotrophic lateral sclerosis. The diagnostic sensitivity may be increased by using the triple stimulation technique (TST), by combining several parameters such as CMCT, motor threshold and silent period, or by studying multiple muscles. In peripheral facial nerve palsies, TMS may be used to localize the site of nerve dysfunction and clarify the etiology. TMS measures also have high sensitivity in detecting lesions in multiple sclerosis and abnormalities in CMCT or TST may correlate with motor impairment and disability. Cerebellar stimulation may detect lesions in the cerebellum or the cerebellar output pathway. TMS may detect upper motor neuron involvement in patients with atypical parkinsonism and equivocal signs. The ipsilateral silent period that measures transcallosal inhibition is a potential method to distinguish between different parkinsonian syndromes. Short latency afferent inhibition (SAI), which is related to central cholinergic transmission, is reduced in Alzheimer's disease. Changes in SAI following administration of cholinesterase inhibitor may be related to the long-term efficacy of this treatment. The results of MEP measurement in the first week after stroke correlate with functional outcome. We conclude that TMS measures have demonstrated diagnostic utility in myelopathy, amyotrophic lateral sclerosis and multiple sclerosis. TMS measures have potential clinical utility in cerebellar disease, dementia, facial nerve disorders, movement disorders, stroke, epilepsy, migraine and chronic pain.}, }
@article {pmid18060051, year = {2007}, author = {Gwinn, K and Corriveau, RA and Mitsumoto, H and Bednarz, K and Brown, RH and Cudkowicz, M and Gordon, PH and Hardy, J and Kasarskis, EJ and Kaufmann, P and Miller, R and Sorenson, E and Tandan, R and Traynor, BJ and Nash, J and Sherman, A and Mailman, MD and Ostell, J and Bruijn, L and Cwik, V and Rich, SS and Singleton, A and Refolo, L and Andrews, J and Zhang, R and Conwit, R and Keller, MA and , }, title = {Amyotrophic lateral sclerosis: an emerging era of collaborative gene discovery.}, journal = {PloS one}, volume = {2}, number = {12}, pages = {e1254}, pmid = {18060051}, issn = {1932-6203}, support = {N01-NS-2-2349/NS/NINDS NIH HHS/United States ; G0701075/MRC_/Medical Research Council/United Kingdom ; M01 RR000109/RR/NCRR NIH HHS/United States ; R01 NS045294/NS/NINDS NIH HHS/United States ; R01 NS045294-01/NS/NINDS NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; R01 NS048125-01/NS/NINDS NIH HHS/United States ; R01 NS045087-01/NS/NINDS NIH HHS/United States ; R01 NS045087/NS/NINDS NIH HHS/United States ; RR-00109/RR/NCRR NIH HHS/United States ; R01 NS049640-01/NS/NINDS NIH HHS/United States ; R01 NS044887-01/NS/NINDS NIH HHS/United States ; R01 NS044887/NS/NINDS NIH HHS/United States ; R01 NS042759-01/NS/NINDS NIH HHS/United States ; R01 NS049640/NS/NINDS NIH HHS/United States ; R01 NS042759/NS/NINDS NIH HHS/United States ; R01 NS048125/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Case-Control Studies ; Cell Line, Transformed ; Chromosome Mapping ; Databases, Genetic ; Genetic Predisposition to Disease ; Genome, Human ; Genotype ; Humans ; Motor Neuron Disease/*genetics ; Phenotype ; Polymorphism, Single Nucleotide ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered. However, most forms of the disease are not obviously familial. Recent advances in human genetics have enabled genome-wide analyses of single nucleotide polymorphisms (SNPs) that make it possible to study complex genetic contributions to human disease. Genome-wide SNP analyses require a large sample size and thus depend upon collaborative efforts to collect and manage the biological samples and corresponding data. Public availability of biological samples (such as DNA), phenotypic and genotypic data further enhances research endeavors. Here we discuss a large collaboration among academic investigators, government, and non-government organizations which has created a public repository of human DNA, immortalized cell lines, and clinical data to further gene discovery in ALS. This resource currently maintains samples and associated phenotypic data from 2332 MND subjects and 4692 controls. This resource should facilitate genetic discoveries which we anticipate will ultimately provide a better understanding of the biological mechanisms of neurodegeneration in ALS.}, }
@article {pmid18057767, year = {2007}, author = {Hattori, H and Nagata, E and Ishihara, T and Jinnouchi, K and Ogawa, Y and Nagai, T and Suzuki, S and Shimizu, T and Hamada, J and Suzuki, N}, title = {Inflammatory myopathy with anti-Golgi antibody and anti-SS-A/Ro antibody.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {46}, number = {23}, pages = {1927-1930}, doi = {10.2169/internalmedicine.46.0362}, pmid = {18057767}, issn = {1349-7235}, mesh = {Aged ; Antibodies, Antinuclear/*analysis/immunology ; Autoantigens/*immunology ; Female ; Golgi Apparatus/immunology ; Humans ; Microscopy, Confocal ; Myositis/*immunology ; }, abstract = {We report a 74-year-old woman with anit-Golgi antibody and anti-SS-A/Ro antibody who contracted inflammatory myopahy presenting 'ALS-like' symptoms. We identified anti-Golgi antibody directly using confocal microscopy and successfully treated her with steroid. This report suggests that there is a new categorized subgroup of inflammatory myopathy with these specific antibodies and the pattern of autoantibody in these patients indicates the specific clinical course and treatment strategy.}, }
@article {pmid18055818, year = {2007}, author = {Yoo, MH and Yoon, YH and Chung, H and Cho, KS and Koh, JY}, title = {Insulin increases retinal hemorrhage in mild oxygen-induced retinopathy in the rat: inhibition by riluzole.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {48}, number = {12}, pages = {5671-5676}, doi = {10.1167/iovs.07-0395}, pmid = {18055818}, issn = {0146-0404}, mesh = {Animals ; Animals, Newborn ; Blotting, Western ; Dextrans ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Excitatory Amino Acid Antagonists/*therapeutic use ; Fluorescein Angiography ; Fluoresceins ; Humans ; Hypoglycemic Agents/*adverse effects ; Infant, Newborn ; Injections, Intraperitoneal ; Insulin/*adverse effects ; Matrix Metalloproteinases/metabolism ; Oxygen/toxicity ; Rats ; Rats, Sprague-Dawley ; Retinal Hemorrhage/chemically induced/*prevention &amp; control ; Retinal Vessels/drug effects ; Retinopathy of Prematurity/chemically induced/*prevention &amp; control ; Riluzole/*therapeutic use ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {PURPOSE: Although hyperglycemia is likely the main stimulus for VEGF induction in diabetic retinopathy (DR), a switch from oral hypoglycemic therapy to parenteral insulin injection, despite producing better glucose control, sometimes paradoxically aggravates DR. The induction of VEGF by insulin, as observed in certain conditions, may be a plausible mechanism for this phenomenon. In the present study, to determine the role of insulin in proliferative diabetic retinopathy, the authors examined whether insulin treatment affected the outcome of oxygen-induced retinopathy (OIR) in rats and whether the anti-amyotrophic lateral sclerosis (ALS) drug riluzole with protein kinase C-inhibiting activity can attenuate the effects of insulin.<br><br>METHODS: To examine in vivo the effects of insulin, mild OIR was produced in 7-day-old rat pups by raising them with a nursing mother in a 55% oxygen environment for 5 days. After that, rat pups were injected daily with subcutaneous saline or insulin (4 U/d) with or without additional riluzole injection (10 mg/kg/d, intraperitoneally) for 5 days in room air.<br><br>RESULTS: Insulin treatment substantially increased VEGF levels, extraretinal vessel formation, matrix metalloproteinase activity, and the extent of retinal hemorrhage in rat pups with mild OIR compared with saline controls. Riluzole substantially reduced all these changes induced by insulin.<br><br>CONCLUSIONS: In the present study, OIR was used as a surrogate model for DR because the core pathology and the VEGF-mediated mechanism are shared by both conditions. As in human DR, in rat pups with mild OIR, insulin treatment aggravated retinal hemorrhage, which was blocked by riluzole. Riluzole is a Food and Drug Administration-approved anti-ALS drug with a favorable adverse effect profile. It may be useful as an anti-VEGF treatment in DR, especially in reducing the retinal hemorrhage that often occurs shortly after the switch from oral hypoglycemics to parenteral insulin.}, }
@article {pmid18055102, year = {2008}, author = {Andreadou, E and Kapaki, E and Kokotis, P and Paraskevas, GP and Katsaros, N and Libitaki, G and Zis, V and Sfagos, C and Vassilopoulos, D}, title = {Plasma glutamate and glycine levels in patients with amyotrophic lateral sclerosis: the effect of riluzole treatment.}, journal = {Clinical neurology and neurosurgery}, volume = {110}, number = {3}, pages = {222-226}, doi = {10.1016/j.clineuro.2007.10.018}, pmid = {18055102}, issn = {0303-8467}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*blood/*drug therapy ; Chromatography, High Pressure Liquid ; Disease Progression ; Female ; Glutamic Acid/*blood ; Glycine/*blood ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Riluzole/*therapeutic use ; Sex Characteristics ; }, abstract = {OBJECTIVES: Defective glutamate (glu) metabolism and excitotoxicity have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Moreover, glycine (gly) has been shown to potentiate excitatory transmission. The "antiglutamatergic" agent riluzole has been shown to prolong survival in ALS. The aim of the study was to investigate a possible effect of riluzole on plasma glu and gly levels, correlating with clinical response to treatment.<br><br>PATIENTS AND METHODS: Plasma concentrations of glu and gly were measured in 20 healthy volunteers and 22 ALS patients before treatment and after 6 months on riluzole.<br><br>RESULTS: At baseline, increased plasma glu correlated with spinal onset and male gender whereas gly levels did not differ between patients and controls. No significant change was observed for both amino acids post-treatment, despite a lower rate of disease progression.<br><br>CONCLUSION: These results suggest that riluzole may affect disease progression without a significant impact on plasma glu and gly levels, possibly indicating different mechanisms of drug action.}, }
@article {pmid18054961, year = {2008}, author = {Choi, CI and Lee, YD and Gwag, BJ and Cho, SI and Kim, SS and Suh-Kim, H}, title = {Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice.}, journal = {Journal of the neurological sciences}, volume = {268}, number = {1-2}, pages = {40-47}, doi = {10.1016/j.jns.2007.10.024}, pmid = {18054961}, issn = {0022-510X}, mesh = {Age of Onset ; *Amyotrophic Lateral Sclerosis/drug therapy/mortality/physiopathology ; Analysis of Variance ; Animals ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay/methods ; Estradiol/*therapeutic use ; Estrogens/*therapeutic use ; Female ; Humans ; Male ; Mice ; Mice, Transgenic ; Motor Activity/*drug effects ; Organ Size/drug effects ; Ovariectomy/methods ; Probability ; Psychomotor Performance/*drug effects ; Reaction Time/drug effects ; Sex Factors ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease which is caused by degeneration of motor neurons in the central nervous system. The incidence of ALS is higher in men than women, but the female advantage disappears with increased age. Here, we report evidence that the female advantage is due to the protective role of estrogen. In an ALS mouse model carrying the human Cu/Zn superoxide dismutase (hSOD1) G93A transgene, ovariectomy did not alter the onset age of the disease while reducing the female lifespan by 7 days and making it comparable to that of the male transgenic mice. Treatment of ovariectomized females with 17beta-estradiol (E2) did not delay the onset of disease, but prevented progression of ALS motor dysfunctions as shown by extension reflex test for a limited time window. Importantly, E2 treatment rescued the lifespans in overiectomized females. These findings will provide important new insights to interpretation of disease progression in post-menopausal female ALS patients.}, }
@article {pmid19513129, year = {2007}, author = {Joo, IS and Hwang, DH and Seok, JI and Shin, SK and Kim, SU}, title = {Oral administration of memantine prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {3}, number = {4}, pages = {181-186}, pmid = {19513129}, issn = {1738-6586}, abstract = {BACKGROUND AND PURPOSE: N-methyl-D-aspartate (NMDA)-mediated neurotoxicity and oxidative stress have been implicated in the etiology of amyotrophic lateral sclerosis (ALS). Memantine is a low-affinity, noncompetitive NMDA receptor antagonist that may protect against motor neuron degeneration.<br><br>METHODS: Thirty transgenic mice expressing the G93A SOD1 mutation were randomly divided into control, low-dose memantine (30 mg/kg/day), and high-dose memantine (90 mg/kg/day) groups, with memantine supplied daily with drinking water beginning at 75 days of age. Body weight, survival, and behavioral performances including a rotarod test, paw grip endurance, and hindlimb extension reflex were assessed in the control and memantine-diet groups.<br><br>RESULTS: Clinical symptoms were evident in the G93A transgenic mice by 11 weeks of age. Memantine was tolerated well. Compared to control, mice treated with memantine performed better in the rotarod test and hindlimb extension reflex. Moreover, low-dose memantine treatment significantly prolonged the survival of the transgenic mice relative to control mice (141 vs 134 days, p<0.05).<br><br>CONCLUSIONS: These findings suggest that memantine, even when administered at the time of symptom onset, has beneficial effects on patients with ALS.}, }
@article {pmid18048013, year = {2008}, author = {Burdo, J and Schubert, D and Maher, P}, title = {Glutathione production is regulated via distinct pathways in stressed and non-stressed cortical neurons.}, journal = {Brain research}, volume = {1189}, number = {}, pages = {12-22}, pmid = {18048013}, issn = {0006-8993}, support = {R01 AG025337/AG/NIA NIH HHS/United States ; R01 AG025337-03/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Cerebral Cortex/drug effects/*metabolism/physiopathology ; Dose-Response Relationship, Drug ; Extracellular Signal-Regulated MAP Kinases/drug effects/metabolism ; Flavonoids/pharmacology ; Flavonols ; Glutathione/antagonists &amp; inhibitors/*metabolism ; MAP Kinase Signaling System/drug effects/physiology ; Molsidomine/analogs &amp; derivatives/toxicity ; NF-E2-Related Factor 2/drug effects/metabolism ; Neurons/drug effects/*metabolism ; Neuroprotective Agents/pharmacology ; Nitric Oxide Donors/toxicity ; Nitro Compounds/metabolism ; Oxidative Stress/drug effects/*physiology ; Peroxynitrous Acid/*metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-myc/drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects/*physiology ; }, abstract = {Peroxynitrite-mediated damage has been linked to numerous neurological and neurodegenerative diseases, including stroke, Alzheimer's and Parkinson's Diseases, amyotrophic lateral sclerosis and multiple sclerosis. Studies on the toxic effects of peroxynitrite in neurons have focused primarily on adverse effects resulting from the nitration of cellular proteins as the principal mode of toxicity while the consequences of the modulation of kinase pathways by peroxynitrite have received relatively less attention. Our results show that treatment of primary rat neurons with the peroxynitrite donor, SIN-1, leads to decreases in glutathione (GSH) levels and cell viability via a novel extracellular-signal-related kinase (ERK)/c-Myc phosphorylation pathway and a reduction in the nuclear expression of NF-E2-related factor-2 (Nrf2) that down-regulate the expression of glutamate cysteine ligase, the rate limiting enzyme for GSH synthesis. The flavonoid fisetin protects against the SIN-1-mediated alterations in ERK/c-Myc phosphorylation, nuclear Nrf2 levels, glutamate cysteine ligase levels, GSH concentration and cell viability. We also show that inhibition of mitogen-activated protein kinase kinase or Raf kinase can increase GSH levels in unstressed primary rat neurons through the same ERK/c-Myc phosphorylation pathway. Together, these results demonstrate that distinct signaling pathways modulate GSH metabolism in unstressed and stressed cortical neurons.}, }
@article {pmid18045911, year = {2007}, author = {Gifondorwa, DJ and Robinson, MB and Hayes, CD and Taylor, AR and Prevette, DM and Oppenheim, RW and Caress, J and Milligan, CE}, title = {Exogenous delivery of heat shock protein 70 increases lifespan in a mouse model of amyotrophic lateral sclerosis.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {27}, number = {48}, pages = {13173-13180}, pmid = {18045911}, issn = {1529-2401}, support = {NS36081/NS/NINDS NIH HHS/United States ; NS46615/NS/NINDS NIH HHS/United States ; R01 NS036081/NS/NINDS NIH HHS/United States ; R29 NS036081/NS/NINDS NIH HHS/United States ; R01 NS046615/NS/NINDS NIH HHS/United States ; }, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*drug therapy/*mortality/pathology/physiopathology ; Analysis of Variance ; Animals ; Behavior, Animal ; *Disease Models, Animal ; HSP70 Heat-Shock Proteins/*administration &amp; dosage/metabolism ; Hindlimb/pathology ; Mice ; Mice, Transgenic ; Motor Activity/drug effects ; Motor Neurons/drug effects ; Neuromuscular Junction ; Neuroprotective Agents/*therapeutic use ; Riluzole/therapeutic use ; Spinal Cord/drug effects/pathology ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder that results in the progressive loss of motoneurons (MNs) in the CNS. Several survival and death mechanisms of MNs have been characterized and it has been determined that MNs do not appear to mount a complete stress response, as determined by the lack of heat shock protein 70 (Hsp70) upregulation after several stress paradigms. Hsp70 has been shown to confer neuroprotection and the insufficient availability of Hsp70 may contribute to MNs' susceptibility to death in ALS mice. In this study, recombinant human Hsp70 (rhHsp70) was intraperitoneally injected three times weekly, beginning at postnatal day 50 until endstage, to G93A mutant SOD1 (G93A SOD1) mice. The administration of rhHsp70 was effective at increasing lifespan, delaying symptom onset, preserving motor function and prolonging MN survival. Interestingly, injected rhHsp70 localized to skeletal muscle and was not readily detected in the CNS. Treatment with rhHsp70 also resulted in an increased number of innervated neuromuscular junctions compared with control tissue. Together these results suggest rhHsp70 may delay disease progression in the G93A SOD1 mouse via a yet to be identified peripheral mechanism.}, }
@article {pmid18045546, year = {2008}, author = {Du, T and Ciccotosto, GD and Cranston, GA and Kocak, G and Masters, CL and Crouch, PJ and Cappai, R and White, AR}, title = {Neurotoxicity from glutathione depletion is mediated by Cu-dependent p53 activation.}, journal = {Free radical biology &amp; medicine}, volume = {44}, number = {1}, pages = {44-55}, doi = {10.1016/j.freeradbiomed.2007.09.001}, pmid = {18045546}, issn = {0891-5849}, mesh = {3T3 Cells ; Animals ; Buthionine Sulfoximine/pharmacology ; Cell Death/physiology ; Cerebral Cortex/cytology ; Copper/*metabolism ; DNA Damage ; Enzyme Inhibitors/pharmacology ; Free Radicals/metabolism ; Gene Expression Regulation ; *Glutathione/deficiency ; Glutathione Synthase/antagonists &amp; inhibitors ; Mice ; Neurodegenerative Diseases/etiology/metabolism ; Neurons/cytology/metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; }, abstract = {Loss of intracellular neuronal glutathione (GSH) is an important feature of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The consequences of GSH depletion include increased oxidative damage to proteins, lipids, and DNA and subsequent cytotoxic effects. GSH is also an important modulator of cellular copper (Cu) homeostasis and altered Cu metabolism is central to the pathology of several neurodegenerative diseases. The cytotoxic effects of Cu in cells depleted of GSH are not well understood. We have previously reported that depletion of neuronal GSH levels results in cell death from trace levels of extracellular Cu due to elevated Cu(I)-mediated free radical production. In this study we further examined the molecular pathway of trace Cu toxicity in neurons and fibroblasts depleted of GSH. Treatment of primary cortical neurons or 3T3 fibroblasts with the glutathione synthetase inhibitor buthionine sulfoximine resulted in substantial loss of intracellular GSH and increased cytotoxicity. We found that both neurons and fibroblasts revealed increased expression and activation of p53 after depletion of GSH. The increased p53 activity was induced by extracellular trace Cu. Furthermore, we showed that in GSH-depleted cells, Cu induced an increase in oxidative stress resulting in DNA damage and activation of p53-dependent cell death. These findings may have important implications for neurodegenerative disorders that involve GSH depletion and aberrant Cu metabolism.}, }
@article {pmid18033645, year = {2007}, author = {Tomik, B}, title = {[Diagnosis and treatment of amyotrophic lateral sclerosis according to EFNS recommendations (2005)].}, journal = {Neurologia i neurochirurgia polska}, volume = {41}, number = {5}, pages = {445-456}, pmid = {18033645}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Humans ; *Palliative Care ; *Patient Care Team ; *Quality of Life ; }, abstract = {The article is focused on recent EFNS recommendations for the diagnosis and management of amyotrophic lateral sclerosis (ALS). In the commentary, the need for use of EFNS recommendations for ALS in clinical practice in Poland is emphasized. The importance of 1) complex respiratory and nutritional care, 2) symptomatic treatment, 3) multidisciplinary teamwork and palliative care, as well as 4) an individual rehabilitation programme and 5) communication status improvement, is stressed as a necessary step for improving the quality of life of Polish ALS patients.}, }
@article {pmid18032672, year = {2007}, author = {Steckley, D and Karajgikar, M and Dale, LB and Fuerth, B and Swan, P and Drummond-Main, C and Poulter, MO and Ferguson, SS and Strasser, A and Cregan, SP}, title = {Puma is a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {27}, number = {47}, pages = {12989-12999}, pmid = {18032672}, issn = {1529-2401}, mesh = {Animals ; Apoptosis/genetics/*physiology ; Apoptosis Regulatory Proteins ; Cells, Cultured ; Cerebral Cortex/chemistry/cytology/metabolism ; Gene Expression Regulation/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neurons/chemistry/*metabolism/pathology ; Oxidative Stress/genetics/*physiology ; Tumor Suppressor Proteins/deficiency/genetics/*physiology ; bcl-2-Associated X Protein/genetics/*metabolism/physiology ; }, abstract = {Oxidative stress has been implicated as a key trigger of neuronal apoptosis in stroke and neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The Bcl-2 homology 3 (BH3)-only subfamily of Bcl-2 genes consists of multiple members that can be activated in a cell-type- and stimulus-specific manner to promote cell death. In the present study, we demonstrate that, in cortical neurons, oxidative stress induces the expression of the BH3-only members Bim, Noxa, and Puma. Importantly, we have determined that Puma-/- neurons, but not Bim-/- or Noxa-/- neurons, are remarkably resistant to the induction of apoptosis by multiple oxidative stressors. Furthermore, we have determined that Bcl-2-associated X protein (Bax) is also required for oxidative stress induced cell death and that Puma plays a dominant role in regulating Bax activation. Specifically, we have established that the induction of Puma, but not Bim or Noxa, is necessary and sufficient to induce a conformational change in Bax to its active state, its translocation to the mitochondria and mitochondrial membrane permeabilization. Finally, we demonstrate that whereas both Puma and Bim(EL) can bind to the antiapoptotic family member Bcl-X(L), only Puma was found to associate with Bax. This suggests that in addition to neutralizing antiapoptotic members, Puma may play a dominant role by complexing with Bax and directly promoting its activation. Overall, we have identified Puma as a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis, and suggest that Puma may be an effective therapeutic target for the treatment of a number of neurodegenerative conditions.}, }
@article {pmid17997855, year = {2007}, author = {Goos, M and Zech, WD and Jaiswal, MK and Balakrishnan, S and Ebert, S and Mitchell, T and Carrì, MT and Keller, BU and Nau, R}, title = {Expression of a Cu,Zn superoxide dismutase typical for familial amyotrophic lateral sclerosis increases the vulnerability of neuroblastoma cells to infectious injury.}, journal = {BMC infectious diseases}, volume = {7}, number = {}, pages = {131}, pmid = {17997855}, issn = {1471-2334}, mesh = {Acetylcysteine/pharmacology ; Amyotrophic Lateral Sclerosis/enzymology/genetics/pathology ; Antigens, CD/metabolism ; Antigens, Differentiation, Myelomonocytic/metabolism ; Antioxidants/pharmacology ; Apoptosis/*drug effects/genetics ; Bacterial Proteins/pharmacology ; Calcium/metabolism ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects/genetics ; Cells, Cultured ; Coculture Techniques ; Humans ; Immunohistochemistry ; Lipopeptides ; Macrophages/cytology/drug effects/metabolism ; Monocytes/cytology/drug effects/metabolism ; Mutation ; Neuroblastoma/enzymology/genetics/pathology ; Peptides/pharmacology ; Streptolysins/*pharmacology ; Superoxide Dismutase/genetics/*metabolism ; Toll-Like Receptor 2/antagonists &amp; inhibitors ; Transfection ; }, abstract = {BACKGROUND: Infections can aggravate the course of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Mutations in the anti-oxidant enzyme Cu,Zn superoxide dismutase (EC 1.15.1.1, SOD1) are associated with familial ALS. Streptococcus pneumoniae, the most frequent respiratory pathogen, causes damage by the action of the cholesterol-binding virulence factor pneumolysin and by stimulation of the innate immune system, particularly via Toll-like-receptor 2.<br><br>METHODS: SH-SY5Y neuroblastoma cells transfected with the G93A mutant of SOD1 typical for familial ALS (G93A-SOD1) and SH-SY5Y neuroblastoma cells transfected with wildtype SOD1 were both exposed to pneumolysin and in co-cultures with cultured human macrophages treated with the Toll like receptor 2 agonist N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-[R]-cysteinyl-[S]-seryl-[S]-lysyl-[S]-lysyl-[S]-lysyl-[S]-lysyl-[S]-lysine x 3 HCl (Pam3CSK4). Cell viability and apoptotic cell death were compared morphologically and by in-situ tailing. With the help of the WST-1 test, cell viability was quantified, and by measurement of neuron-specific enolase in the culture supernatant neuronal damage in co-cultures was investigated. Intracellular calcium levels were measured by fluorescence analysis using fura-2 AM.<br><br>RESULTS: SH-SY5Y neuroblastoma cells transfected with the G93A mutant of SOD1 typical for familial ALS (G93A-SOD1) were more vulnerable to the neurotoxic action of pneumolysin and to the attack of monocytes stimulated by Pam3CSK4 than SH-SY5Y cells transfected with wild-type human SOD1. The enhanced pneumolysin toxicity in G93A-SOD1 neuronal cells depended on the inability of these cells to cope with an increased calcium influx caused by pores formed by pneumolysin. This inability was caused by an impaired capacity of the mitochondria to remove cytoplasmic calcium. Treatment of G93A-SOD1 SH-SY5Y neuroblastoma cells with the antioxidant N-acetylcysteine reduced the toxicity of pneumolysin.<br><br>CONCLUSION: The particular vulnerability of G93A-SOD1 neuronal cells to hemolysins and inflammation may be partly responsible for the clinical deterioration of ALS patients during infections. These findings link infection and motor neuron disease and suggest early treatment of respiratory infections in ALS patients.}, }
@article {pmid17996007, year = {2008}, author = {Väyrynen, T and Kuisma, M and Määttä, T and Boyd, J}, title = {Medical futility in asystolic out-of-hospital cardiac arrest.}, journal = {Acta anaesthesiologica Scandinavica}, volume = {52}, number = {1}, pages = {81-87}, doi = {10.1111/j.1399-6576.2007.01461.x}, pmid = {17996007}, issn = {1399-6576}, mesh = {Adolescent ; Adult ; Advanced Cardiac Life Support/mortality/*statistics &amp; numerical data ; Aged ; Aged, 80 and over ; Brain Damage, Chronic/epidemiology/etiology ; Cardiopulmonary Resuscitation/mortality/*statistics &amp; numerical data ; Female ; Finland/epidemiology ; Follow-Up Studies ; Guideline Adherence/statistics &amp; numerical data ; Heart Arrest/etiology/*mortality/therapy ; Hospital Mortality ; Humans ; Hypothermia/complications ; Male ; *Medical Futility ; Middle Aged ; Near Drowning/complications ; Practice Guidelines as Topic ; Prognosis ; *Resuscitation Orders ; Survival Analysis ; Time Factors ; Treatment Outcome ; }, abstract = {OBJECTIVES: To study the factors associated with short- and long-term survival after asystolic out-of-hospital cardiac arrest, with a reference to medical futility.<br><br>METHODS: This is a retrospective observational study conducted in Helsinki, Finland during 1 January 1997 to 31 December 2005. All out-of-hospital cardiac arrests were prospectively registered in the cardiac arrest database. Of 3291 arrests, 1455 had asystole as the first registered rhythm. These patients represent the study population.<br><br>RESULTS: A short time interval to the initiation of advanced life support (ALS) was associated with a long-term benefit, but a short first responding unit (FRU) response time had only a short-term benefit. Conversion of asystole into a shockable rhythm provided only a short-term benefit. The prognosis was poor if the FRU response time was over 10 min or the ALS response time was over 11 min in bystander-witnessed arrests, and if the duration of resuscitation was over 8 min in emergency medical services (EMS)-witnessed arrests. Bystander-CPR was associated with increased 30-day mortality. The 30-day survival rate after an unwitnessed arrest (n=548) was 0.5%. All survivors in this group were either hypothermic or were victims of near-drowning.<br><br>CONCLUSIONS: Resuscitation should be withheld in cases of unwitnessed asystole, excluding cases of hypothermia and near-drowning. The prognosis is poor if the FRU response time is over 10 min or the ALS response time is over 10-15 min in bystander-witnessed arrests. The decision of whether or not to attempt resuscitation should not be influenced by the presence of bystander-CPR. Early initiation of ALS should be prioritised in the treatment of out-of-hospital asystole.}, }
@article {pmid17994638, year = {2008}, author = {Arakawa, T and Niikura, T and Arisaka, F and Kita, Y}, title = {Activity-dependent neurotrophic factor, ADNF, determines the structure characteristics of Colivelin, a fusion protein of ADNF9 and Humanin analog.}, journal = {Journal of peptide science : an official publication of the European Peptide Society}, volume = {14}, number = {5}, pages = {631-636}, doi = {10.1002/psc.959}, pmid = {17994638}, issn = {1075-2617}, mesh = {Amino Acid Sequence ; Circular Dichroism ; Drug Stability ; Humans ; Intracellular Signaling Peptides and Proteins/*chemistry/genetics ; Molecular Sequence Data ; Molecular Structure ; Multiprotein Complexes/chemistry ; Nerve Tissue Proteins/*chemistry/genetics ; Oligopeptides/*chemistry/genetics ; Protein Structure, Secondary ; Solutions ; Ultracentrifugation ; }, abstract = {A 24-amino acid long peptide, Humanin, protects neurons from Alzheimer's disease (AD)-related cell toxicities at sub-nM-uM concentrations. Activity-dependent neurotrophic factor (ADNF) is a glia-derived neurotrophic peptide, which protects neurons from tetrodoxin treatment and AD-related and amyotrophic lateral sclerosis-related insults at fM concentrations. An attempt was made to further improve the activity of Humanin by fusing this peptide to ADNF9, a 9-amino acid long core peptide of the ADNF. This fusion resulted in a novel molecule, termed Colivelin, with the neuroprotective activity at fM range, which is approximately 10(3)-10(7) fold higher than the activity of Humanin and Humanin analogs and follows the activity profile of fM-active ADNF9. We have characterized the structural properties of Colivelin and compared with those of ADNF9 and Humanin in water and phosphate-buffered saline (PBS). The secondary structure of Colivelin was similar to that of ADNF9, but not that of Humanin, and hence was not the average of the contributions of the two peptides fused. Colivelin was stable and monomeric in PBS, consistent with the monomeric property of ADNF9, while Humanin showed strong tendency to self-associate. Thus, it is evident that the structural properties of Colivelin resemble those of ADNF9, rather than those of Humanin.}, }
@article {pmid17993769, year = {2007}, author = {Morselli, LL and Bongioanni, P and Genovesi, M and Licitra, R and Rossi, B and Murri, L and Bogazzi, F and Cecconi, E and Martino, E and Gasperi, M}, title = {Impairment of GH secretion in amyotrophic lateral sclerosis is not affected by riluzole treatment.}, journal = {Journal of endocrinological investigation}, volume = {30}, number = {9}, pages = {767-770}, pmid = {17993769}, issn = {1720-8386}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*blood/*drug therapy ; Body Mass Index ; Excitatory Amino Acid Antagonists/*therapeutic use ; Female ; Growth Hormone/blood/drug effects/*metabolism ; Humans ; Male ; Middle Aged ; Riluzole/*therapeutic use ; Severity of Illness Index ; Time Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS), the most common motor neurone disorder in human adults, is characterized by selective and progressive degeneration of upper and lower motor neurones in the central nervous system. The main currently available drug for ALS treatment is riluzole, a compound that acts through inhibition of glutamate release, postsynaptic receptor activation, and voltage-sensitive channel inhibition. GH secretion, evaluated by GHRH+arginine (ARG) test, has recently been reported to be impaired in most untreated ALS patients. The aim of the present study was to evaluate whether riluzole administration could interfere with GH secretion and therefore with the diagnosis of adult GH deficiency. Ten patients (6 males, 4 females, mean age 59+/-11 yr) were studied performing GHRH+ARG test before and 3 months after starting riluzole treatment (100 mg/day). Blood samples for GH were collected at baseline, at 30 and 60 min. Both before and during riluzole treatment, 5 patients showed GH deficiency and 5 patients had a normal GH response according to body mass index (BMI). Mean peak GH levels were similar before and during riluzole treatment (13.4+/-10 vs 14.2+/-10.1 microg/l, p=ns). No significant correlation was observed between GH concentrations and age, BMI, disease duration, severity or clinical (bulbar/spinal) form. In conclusion, the present data confirm that GH secretion is impaired in a new series of ALS patients and indicate that riluzole treatment does not interfere with GH secretion. Thus, evaluation of GH secretion in ALS patients can also be performed without withdrawing riluzole treatment.}, }
@article {pmid17984685, year = {2007}, author = {Ishigaki, A and Aoki, M and Nagai, M and Warita, H and Kato, S and Kato, M and Nakamura, T and Funakoshi, H and Itoyama, Y}, title = {Intrathecal delivery of hepatocyte growth factor from amyotrophic lateral sclerosis onset suppresses disease progression in rat amyotrophic lateral sclerosis model.}, journal = {Journal of neuropathology and experimental neurology}, volume = {66}, number = {11}, pages = {1037-1044}, doi = {10.1097/nen.0b013e318159886b}, pmid = {17984685}, issn = {0022-3069}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Animals, Genetically Modified ; Blotting, Western ; Caspases/drug effects/metabolism ; Disease Models, Animal ; Disease Progression ; Enzyme-Linked Immunosorbent Assay ; Excitatory Amino Acid Transporter 2/drug effects/metabolism ; Hepatocyte Growth Factor/*administration &amp; dosage ; Humans ; Immunohistochemistry ; Infusion Pumps, Implantable ; Injections, Spinal ; Motor Neurons/*drug effects ; Nerve Degeneration/*drug therapy ; Proto-Oncogene Proteins c-met/metabolism ; RNA, Messenger/analysis ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; Spinal Cord/*drug effects/metabolism/pathology ; X-Linked Inhibitor of Apoptosis Protein/drug effects/metabolism ; }, abstract = {Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. We showed that introduction of the HGF gene into neurons of G93A transgenic mice attenuates motor neuron degeneration and increases the lifespan of these mice. Currently, treatment regimens using recombinant protein are closer to clinical application than gene therapy. To examine its protective effect on motor neurons and therapeutic potential we administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to G93A transgenic rats at doses of 40 or 200 microg and 200 microg at 100 days of age (the age at which pathologic changes of the spinal cord appear, but animals show no clinical weakness) and at 115 days (onset of paralysis), respectively, for 4 weeks each. Intrathecal administration of hrHGF attenuates motor neuron degeneration and prolonged the duration of the disease by 63%, even with administration from the onset of paralysis. Our results indicated the therapeutic efficacy of continuous intrathecal administration of hrHGF in transgenic rats and should lead to the consideration for further clinical trials in amyotrophic lateral sclerosis using continuous intrathecal administration of hrHGF.}, }
@article {pmid17980667, year = {2007}, author = {Gordon, PH and Moore, DH and Miller, RG and Florence, JM and Verheijde, JL and Doorish, C and Hilton, JF and Spitalny, GM and MacArthur, RB and Mitsumoto, H and Neville, HE and Boylan, K and Mozaffar, T and Belsh, JM and Ravits, J and Bedlack, RS and Graves, MC and McCluskey, LF and Barohn, RJ and Tandan, R and , }, title = {Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial.}, journal = {The Lancet. Neurology}, volume = {6}, number = {12}, pages = {1045-1053}, doi = {10.1016/S1474-4422(07)70270-3}, pmid = {17980667}, issn = {1474-4422}, support = {R01 NS45294/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Anti-Bacterial Agents/*therapeutic use ; Confidence Intervals ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Minocycline/*therapeutic use ; Muscle, Skeletal/drug effects ; Outcome Assessment, Health Care/methods ; Psychomotor Performance/drug effects ; Quality of Life ; Survival Analysis ; Vital Capacity/drug effects ; }, abstract = {BACKGROUND: Minocycline has anti-apoptotic and anti-inflammatory effects in vitro, and extends survival in mouse models of some neurological conditions. Several trials are planned or are in progress to assess whether minocycline slows human neurodegeneration. We aimed to test the efficacy of minocycline as a treatment for amyotrophic lateral sclerosis (ALS).<br><br>METHODS: We did a multicentre, randomised placebo-controlled phase III trial. After a 4-month lead-in phase, 412 patients were randomly assigned to receive placebo or minocycline in escalating doses of up to 400 mg/day for 9 months. The primary outcome measure was the difference in rate of change in the revised ALS functional rating scale (ALSFRS-R). Secondary outcome measures were forced vital capacity (FVC), manual muscle testing (MMT), quality of life, survival, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00047723.<br><br>FINDINGS: ALSFRS-R score deterioration was faster in the minocycline group than in the placebo group (-1.30 vs -1.04 units/month, 95% CI for difference -0.44 to -0.08; p=0.005). Patients on minocycline also had non-significant tendencies towards faster decline in FVC (-3.48 vs -3.01, -1.03 to 0.11; p=0.11) and MMT score (-0.30 vs -0.26, -0.08 to 0.01; p=0.11), and greater mortality during the 9-month treatment phase (hazard ratio=1.32, 95% CI 0.83 to 2.10; p=0.23) than did patients on placebo. Quality-of-life scores did not differ between the treatment groups. Non-serious gastrointestinal and neurological adverse events were more common in the minocycline group than in the placebo group, but these events were not significantly related to the decline in ALSFRS-R score.<br><br>INTERPRETATION: Our finding that minocycline has a harmful effect on patients with ALS has implications for trials of minocycline in patients with other neurological disorders, and for how potential neuroprotective agents are screened for use in patients with ALS.}, }
@article {pmid17978775, year = {2007}, author = {Fuster Torres, MA and Berini Aytés, L and Gay Escoda, C}, title = {Salivary gland application of botulinum toxin for the treatment of sialorrhea.}, journal = {Medicina oral, patologia oral y cirugia bucal}, volume = {12}, number = {7}, pages = {E511-7}, pmid = {17978775}, issn = {1698-6946}, mesh = {Botulinum Toxins, Type A/*administration &amp; dosage ; Humans ; Injections, Intralesional ; Neurotoxins/*administration &amp; dosage ; Salivary Glands ; Sialorrhea/*drug therapy/etiology ; }, abstract = {Sialorrhea or excessive salivation, and drooling, are common and disabling manifestations in different neurological disorders. A review is made of the literature, based on a PubMed search, selecting those articles describing clinical trials involving the injection of botulinum toxin A in the salivary glands of patients with different diseases characterized by sialorrhea. The most frequently treated diseases were infant cerebral palsy (30%), Parkinson's disease (20%) and amyotrophic lateral sclerosis (15%). Over half of the authors injected the product into the parotid glands, 9.5% into the submaxillary glands, and 38% into both. The total doses of toxin injected varied from 10-100 units of Botox or 30-450 units of Dysport according to the different authors. A reduction was observed in the production of saliva following these injections, and the duration of the therapeutic effect was 1.5-6 months. Six articles (30%) described the presence of adverse effects such as dysphagia, xerostomia and chewing difficulties. Most of the clinical studies involved small patient samples, with no blinding or randomization, and no control group. Moreover, no data are available on the efficacy and adverse effects of treatment in the context of long-term prospective studies. The effective therapeutic dose and ideal form of application remain to be established, and require the conduction of further controlled clinical trials involving large sample sizes.}, }
@article {pmid17969557, year = {2007}, author = {Federici, T and Boulis, N}, title = {Gene therapy for peripheral nervous system diseases.}, journal = {Current gene therapy}, volume = {7}, number = {4}, pages = {239-248}, doi = {10.2174/156652307781369083}, pmid = {17969557}, issn = {1566-5232}, support = {K08 NS43305/NS/NINDS NIH HHS/United States ; }, mesh = {Charcot-Marie-Tooth Disease/therapy ; Diabetic Neuropathies/therapy ; Genetic Therapy/*methods ; Genetic Vectors ; Humans ; Models, Neurological ; Motor Neuron Disease/therapy ; Nerve Degeneration/therapy ; Nerve Regeneration ; Pain Management ; Peripheral Nerve Injuries ; Peripheral Nervous System Diseases/*therapy ; Viruses/genetics ; }, abstract = {Peripheral nerve diseases, also known as peripheral neuropathies, affect 15-20 million of Americans and diabetic neuropathy is the most common condition. Currently, the treatment of peripheral neuropathies is more focused on managing pain rather than providing permissive conditions for regeneration. Despite advances in microsurgical techniques, including nerve grafting and reanastomosis, axonal regeneration after peripheral nerve injury remains suboptimal. Also, no satisfactory treatments are available at this time for peripheral neurodegeneration occurring in motor neuron diseases (MND), including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Peripheral nerves have the inherent capacity of regeneration. Gene therapy strategies focused on neuroprotection may help optimizing axonal regrowth. A better understanding of the cellular and molecular events involved in axonal degeneration and regeneration have helped researchers to identify targets for intervention. This review summarizes the current state on the clinical experience as well as gene therapy strategies for peripheral neuropathies, including MND, peripheral nerve injury, neuropathic pain, and diabetic neuropathy.}, }
@article {pmid17969361, year = {2007}, author = {Funakoshi, H and Ohya, W and Kadoyama, K and Nakamura, T}, title = {[ALS and neurotrophic factors--HGF as a novel neurotrophic and neuroregenerative factor].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1195-1202}, pmid = {17969361}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*etiology ; Animals ; Clinical Trials as Topic ; Disease Models, Animal ; Glial Cell Line-Derived Neurotrophic Factor/physiology/therapeutic use ; Hepatocyte Growth Factor/genetics/*physiology/therapeutic use ; Humans ; Mice ; Nerve Growth Factors/physiology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motoneurons and their axons. Although a variety of responsive mutations in superoxide dismutase-1 (SOD1) have been identified in familial cases, more than 90% of ALS cases are sporadic. Therefore, the most beneficial approach to treatment would be to find the common pathological pathway that functions in both familial and sporadic cases during disease onset and progression. Neurotrophic factors may function to prevent the neuronal death and axonal degeneration in ALS that is thought to be the result of aberrant apoptotic cell death. Here we summarize the potential role of classical neurotrophic factors in ALS. We also describe the potential role of hepatocyte growth factor (HGF), a novel neurotrophic factor, in retarding the progression of the disease in a transgenic mouse model expressing SOD1G93A (G93A). In addition to direct neurotrophic activities, HGF functions on the astrocytes of G93A mice to maintain levels of EAAT2, a glial-specific glutamate transporter that might be responsible for the reduction of glutamatergic neurotoxicity of motoneurons. Furthermore, HGF is capable of reducing astrocytosis and microglial accumulation, and thus supports the attention of a glial-dependent mechanism of ALS progression. Although it is a challenging issue, recent advancements in the elucidation of the role of neurotrophic factors in ALS raise the possibility of their use in the treatment of ALS and related disorders.}, }
@article {pmid17969358, year = {2007}, author = {Hasegawa, M and Arai, T}, title = {[Component of ubiquitin-positive inclusions in ALS].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1171-1177}, pmid = {17969358}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/metabolism/pathology/therapy ; Animals ; DNA-Binding Proteins/*metabolism ; Frontal Lobe/cytology/pathology ; Humans ; Inclusion Bodies/*metabolism ; Motor Neurons/cytology/pathology ; Nerve Degeneration ; Phosphorylation ; Temporal Lobe/cytology/pathology ; Ubiquitin/*metabolism ; }, abstract = {TAR DNA-binding protein of 43 kDa (TDP-43), a heterogeneous nuclear ribonucleoprotein that functions in regulating transcription and alternative splicing, was identified as a component of ubiquitin-positive tau-negative cytoplasimic inclusions in frontotemporal lobar degeneration (FTLD-U), and subsequently of ubiquitin-positive skein-like inclusions in amyotrophic lateral sclerosis (ALS). Dephosphorylation treatment of sarkosyl-insoluble fractions have suggested that abnormal phosphorylation takes place in the deposited TDP-43. The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of TDP-43. This article reviews the ubiquitin-positive inclusions in ALS and the recent discovery of TDP-43 in tau-negative inclusions in FTLD-U and ALS. We also discuss the biological implications of these findings for the pathogenesis of ALS.}, }
@article {pmid17969354, year = {2007}, author = {Izumi, Y and Kaji, R}, title = {[Clinical trials of ultra-high-dose methylcobalamin in ALS].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {10}, pages = {1141-1147}, pmid = {17969354}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology/physiopathology ; Animals ; Disease Progression ; Double-Blind Method ; Glutamic Acid/toxicity ; Humans ; Pulse Therapy, Drug ; Randomized Controlled Trials as Topic ; Rats ; Time Factors ; Vitamin B 12/administration &amp; dosage/*analogs &amp; derivatives ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting both upper and lower motor neurons. Weakness may begin in the legs, hands, proximal arms, or pharynx. The course is relentless and progressive without remissions, relapses, or even stable plateaus. There is no effective drug therapy for ALS, although riluzole has been shown to prolong life in sufferers, without tracheostomy. A vitamin B12 analog, methylcobalamin, has a protective effect on cultured cortical neurons against glutamate-induced cytotoxicity. We have shown the ultra-high-dose methylcobalamin (25 mg/day i.m.) slows down the progressive reduction of the CMAP (compound muscle action potential) amplitudes in ALS in the short term (4 weeks). The latencies of SSR (sympathetic skin response) were shorter after treatment (50 mg/day i.v., 2 weeks). In the long-term effect of methylcobalamin (50 mg/day i.m., twice a week), the survival time (or the period to become respirator-bound) was significantly longer in the treated group than in the untreated. Larger-scale randomized double blind trial was started in Japan in order to evaluate the long-term efficacy and the safety of ultra-high-dose methylcobalamin for sporadic or familial cases of ALS.}, }
@article {pmid17963733, year = {2007}, author = {Lepore, AC and Haenggeli, C and Gasmi, M and Bishop, KM and Bartus, RT and Maragakis, NJ and Rothstein, JD}, title = {Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS.}, journal = {Brain research}, volume = {1185}, number = {}, pages = {256-265}, pmid = {17963733}, issn = {0006-8993}, support = {NS33958/NS/NINDS NIH HHS/United States ; R01 NS041680/NS/NINDS NIH HHS/United States ; R01 NS033958/NS/NINDS NIH HHS/United States ; R01 NS041680-05/NS/NINDS NIH HHS/United States ; R01 NS033958-11/NS/NINDS NIH HHS/United States ; NS41680/NS/NINDS NIH HHS/United States ; }, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*genetics/pathology/physiopathology/*prevention &amp; control ; Animals ; Dependovirus/physiology ; Disease Models, Animal ; Female ; Green Fluorescent Proteins/metabolism ; Injections, Spinal/methods ; Insulin-Like Growth Factor I/*administration &amp; dosage/metabolism ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/pathology ; Neuroprotective Agents/*administration &amp; dosage/metabolism ; Psychomotor Performance/physiology ; Sex Factors ; Spinal Cord/*physiology ; Superoxide Dismutase/genetics ; Time Factors ; Transduction, Genetic ; }, abstract = {The potent neuroprotective activities of neurotrophic factors, including insulin-like growth factor 1 (IGF-1), make them promising candidates for treatment of amyotrophic lateral sclerosis (ALS). In an effort to maximize rate of motor neuron transduction, achieve high levels of spinal IGF-1 and thus enhance therapeutic benefit, we injected an adeno-associated virus 2 (AAV2)-based vector encoding human IGF-1 (CERE-130) into lumbar spinal cord parenchyma of SOD1(G93A) mice. We observed robust and long-term intraspinal IGF-1 expression and partial rescue of lumbar spinal cord motor neurons, as well as sex-specific delayed disease onset, weight loss, decline in hindlimb grip strength and increased animal survival.}, }
@article {pmid17956549, year = {2007}, author = {Jokic, N and Ling, YY and Ward, RE and Michael-Titus, AT and Priestley, JV and Malaspina, A}, title = {Retinoid receptors in chronic degeneration of the spinal cord: observations in a rat model of amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {103}, number = {5}, pages = {1821-1833}, doi = {10.1111/j.1471-4159.2007.04893.x}, pmid = {17956549}, issn = {1471-4159}, mesh = {Amyotrophic Lateral Sclerosis/*complications/genetics/metabolism ; Animals ; Animals, Genetically Modified ; Behavior, Animal ; Body Weight/genetics ; Cell Count/methods ; Disease Models, Animal ; Female ; Gene Expression Profiling/methods ; Glial Fibrillary Acidic Protein/metabolism ; Male ; Motor Activity/genetics ; Motor Neurons/*metabolism ; Mutation/genetics ; Rats ; Rats, Sprague-Dawley ; Retinoid X Receptors/*metabolism ; Spinal Cord/*pathology ; Superoxide Dismutase/genetics ; }, abstract = {Changes in distribution and expression of retinoid receptors may be part of a spinal cord protective response to acute injury and to chronic degeneration. In this study, we have combined RNA and protein expression analysis to characterize the expression profile of retinoid receptors in the lumbar spinal cord of the superoxide dismutase 1 G93A mutant rat model of amyotrophic lateral sclerosis, a fatal neurodegenerative disorder causing extensive motor neuron loss. We also report a nonsignificant change in RNA expression of binding proteins and metabolizing enzymes for retinol and retinoic acid in the mutant rat spinal cord at end-stage disease. Only retinoid X receptor beta (RXRbeta), and to a lesser extent retinoic acid receptor beta and alpha (RARbeta/alpha) were reliably detected in lumbar spinal cord at an early pre-symptomatic phase and throughout the disease progression. The expression of RXRbeta in lamina II neurons in the dorsal horn of transgenic and wild type (WT) animals was associated with extensive astrocyte staining in end-stage lumbar spinal cord from transgenic rats. RARbeta and RARalpha diffuse staining of large motor neurons in the pre-symptomatic transgenic and in the WT lumbar cord appear to decline in end-stage disease, when a selective and strong gamma motor neuron RARalpha staining becomes evident. As gliosis and motor neuron loss are key pathogenic features in amyotrophic lateral sclerosis, the selective expression of retinoid receptors in astrocytes and motor neurons may provide further clues to the role of retinoid signalling in neurodegeneration and suggest new treatment strategies based on retinoid-modulating agents.}, }
@article {pmid17956327, year = {2007}, author = {Wilkerson, JE and Macfarlane, PM and Hoffman, MS and Mitchell, GS}, title = {Respiratory plasticity following intermittent hypoxia: roles of protein phosphatases and reactive oxygen species.}, journal = {Biochemical Society transactions}, volume = {35}, number = {Pt 5}, pages = {1269-1272}, doi = {10.1042/BST0351269}, pmid = {17956327}, issn = {0300-5127}, support = {HL 80209/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Hypoxia/*physiopathology ; *Neuronal Plasticity ; Phosphoprotein Phosphatases/*metabolism ; Reactive Oxygen Species/*metabolism ; *Respiration ; }, abstract = {Plasticity is an important property of the respiratory control system. One of the best-studied models of respiratory plasticity is pLTF (phrenic long-term facilitation). pLTF is a progressive increase in phrenic motor output lasting several hours following acute exposure to intermittent hypoxia. Similar to many other forms of neuroplasticity, pLTF is pattern-sensitive; it is induced by intermittent, but not sustained hypoxia of similar cumulative duration. Our understanding of the cellular/synaptic mechanisms underlying pLTF has increased considerably in recent years. Here, we review accumulating evidence suggesting that the pattern-sensitivity of pLTF arises substantially from differential reactive oxygen species formation and subsequent protein phosphatase inhibition during intermittent compared with sustained hypoxia in or near phrenic motor neurons. A detailed understanding of the cellular/synaptic mechanisms of pLTF may provide the rationale for new pharmacological approaches in the treatment of severe ventilatory control disorders, such as obstructive sleep apnoea and respiratory insufficiency either following spinal cord injury or during neurodegenerative diseases such as amyotrophic lateral sclerosis.}, }
@article {pmid17952635, year = {2007}, author = {Arakawa, T and Niikura, T and Tajima, H and Arisaka, F and Kita, Y}, title = {Structure analysis of activity-dependent neurotrophic factor 9 by circular dichroism and sedimentation equilibrium.}, journal = {Journal of molecular neuroscience : MN}, volume = {33}, number = {3}, pages = {262-267}, pmid = {17952635}, issn = {0895-8696}, mesh = {Animals ; Cells, Cultured ; Circular Dichroism ; Mice ; Neurons/cytology/metabolism ; Neuroprotective Agents/*chemistry/metabolism ; Oligopeptides/*chemistry/metabolism ; *Protein Structure, Secondary ; Ultracentrifugation ; }, abstract = {Activity-dependent neurotrophic factor (ADNF) is a glia-derived neurotrophic peptide, which protects neurons from tetrodoxin treatment and Alzheimer's disease-related and amyotrophic-lateral-sclerosis-related insults at femto-molar concentrations. However, the mechanism of the femto-molar neuroprotection by the peptide has not been elucidated. The characterization of the peptide structure in solution at molecular level should shed light in the mechanism of such extremely high biological activity. From that point of view, the secondary and quaternary structure analysis of ADNF9, an active core fragment peptide of ADNF, was performed by circular dichroism (CD) and sedimentation equilibrium. ADNF9 has also been shown to exhibit a neurotrophic activity in femto-molar concentrations; in this study it showed sub-pM neuroprotective activity against V642I-APP-induced cytotoxity in the mouse primary cortical neuron. CD analysis showed that the secondary structure of ADNF9 is identical in water and phosphate-buffered saline (PBS) and is independent of the peptide concentration. The CD spectra appear to be characterized most likely as disordered. The sedimentation equilibrium experiments demonstrated monomeric structure of the protein over the wide range of peptide concentration. There is a slight enhancement of CD intensity at 37 degrees C relative to 20 degrees C, suggesting a possible hydrophobic association of the peptide. There is no change in the secondary structure in PBS upon freeze-thaw treatment, which has previously been suggested to cause activity loss.}, }
@article {pmid17943766, year = {2007}, author = {Mitchell, JD and Wokke, JH and Borasio, GD}, title = {Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD002064}, doi = {10.1002/14651858.CD002064.pub2}, pmid = {17943766}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Insulin-Like Growth Factor I/*therapeutic use ; Male ; Randomized Controlled Trials as Topic ; Recombinant Proteins/therapeutic use ; }, abstract = {BACKGROUND: Trophic factors, including recombinant human insulin-like growth factor I (rhIGF-I) are possible disease modifying therapies for amyotrophic lateral sclerosis.<br><br>OBJECTIVES: To examine the efficacy of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (March 2006), MEDLINE (January 1966 to March 2006) and EMBASE (January 1980 to March 2006) and asked the authors of randomised clinical trials and manufacturers of recombinant human insulin-like growth factor I.<br><br>SELECTION CRITERIA: We considered all randomised controlled clinical trials involving rhIGF-I treatment of amyotrophic lateral sclerosis in adults with a clinical diagnosis of definite or probable amyotrophic lateral sclerosis according to the El Escorial Criteria. The primary outcome measure was change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score after nine months treatment and secondary outcome measures were change in AALSRS at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: We identified three randomised clinical trials. Only two were included in the analysis. Each author graded the studies for methodological quality. Data were extracted and entered by the lead author and checked by the other two. Some missing data had to be regenerated by calculations based on ruler measurements of data presented in published graphs.<br><br>MAIN RESULTS: In a European trial with 59 participants on placebo and 124 on rhIGF-I, 0.1 mg/kg/day the mean difference (MD) in change in AALSRS total score after nine months was -3.30 (95% confidence interval (CI) -8.68 to 2.08), non-significantly less in the treated than the placebo group. In a North American trial, in which 90 participants on placebo were compared with 89 on recombinant human insulin-like growth factor I 0.05 mg/kg/day, and 87 participants on 0.1 mg/kg/day, the MD after nine months was -6.00 (95%CI -10.99 to -1.01), significantly less on treatment. The combined analysis from both randomised clinical trials showed a weighted mean difference after nine months of -4.75 (95% CI -8.41 to -1.09), a significant difference in favour of the treated group. The secondary outcome measures showed non-significant trends favouring rhIGF-I. Similarly the data with the 0.05 mg/kg/day dose showed trends favouring rhIGF-I at all time points but did not reach significance at the five per cent level at any point. There was an increased risk of injection site reactions with rhIGF-I (relative risk 2.53, 95% CI 1.40 to 4.59).<br><br>AUTHORS' CONCLUSIONS: The available randomised placebo controlled trials do not permit a definitive assessment of the clinical efficacy of rhIGF-I on ALS. More research is needed and one trial is in progress. Future trials should include survival as an outcome measure.}, }
@article {pmid17941851, year = {2007}, author = {Neppelberg, E and Haugen, DF and Thorsen, L and Tysnes, OB}, title = {Radiotherapy reduces sialorrhea in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {14}, number = {12}, pages = {1373-1377}, doi = {10.1111/j.1468-1331.2007.01983.x}, pmid = {17941851}, issn = {1468-1331}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*complications/*physiopathology ; Botulinum Toxins, Type A/administration &amp; dosage ; Female ; Humans ; Male ; Middle Aged ; Parotid Gland/physiopathology/radiation effects ; Preoperative Care ; Prospective Studies ; Radiation Dosage ; Radiotherapy/*methods ; Salivary Glands/physiopathology/*radiation effects ; Sialography ; Sialorrhea/*etiology/physiopathology/*radiotherapy ; Tomography, X-Ray Computed ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. Sialorrhea is a frequent problem in ALS patients with bulbar symptoms, because of progressive weakness of oral, lingual and pharyngeal muscles. This prospective study aimed to investigate the putative effect of palliative single-dose radiotherapy on problematic sialorrhea in patients with ALS. Twenty patients with ALS and problematic drooling were included; 14 were given radiotherapy with a single fraction of 7.5 Grey (Gy). Five patients were treated with botulinum toxin A (BTX-A) injections (20 U) into the parotid glands; two of these were later given radiotherapy. Symptom assessment, clinical examination and measurements of salivary flow (ml/min) were performed before and after treatment (1-2 weeks, 3 months). Salivary secretion was significantly reduced after radiation treatment, with a mean reduction of 60% (1 week) and 51% (2 weeks). Three months post-treatment, 21% reduction of the salivary secretion was observed compared with salivation before treatment. Mean salivary flow was not reduced after BTX-A treatment in five patients. No serious side-effects were observed with either of the two treatment modalities. Single-dose radiotherapy (7.5 Gy) significantly reduces sialorrhea and is an effective and safe palliative treatment in patients with ALS.}, }
@article {pmid17936052, year = {2008}, author = {Weiss, S and Henle, P and Bidlingmaier, M and Moghaddam, A and Kasten, P and Zimmermann, G}, title = {Systemic response of the GH/IGF-I axis in timely versus delayed fracture healing.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {18}, number = {3}, pages = {205-212}, doi = {10.1016/j.ghir.2007.09.002}, pmid = {17936052}, issn = {1096-6374}, mesh = {Adult ; Female ; Fracture Healing/*physiology ; Human Growth Hormone/blood/*metabolism ; Humans ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/analysis/*metabolism ; Male ; Middle Aged ; Time Factors ; }, abstract = {The GH-IGF axis has profound effects on the local and systemic regulation of bone metabolism and may be important for quality of fracture healing. To test the hypothesis that deficiency of the GH/IGF axis may play a role in the pathogenesis of fracture non-union we investigated whether alterations of serum concentrations of the GH-IGF axis could be related to failed fracture healing compared to timely fracture healing in trauma patients. Serum probes were prospectively collected from 186 patients with surgical treatment of long bone fractures up to 6 months after surgery. Samples from 14 patients with atrophic type of non-union have been compared to 14 matched patients with normal bone healing. Postoperative time courses of serum concentrations have been analyzed using commercially available chemiluminescence sandwich assays (GH), fully automated assay systems (IGF-I, IGFBP-3) or sandwich immunometric assays (ALS). Comparison between both collectives revealed significantly lower serum concentrations of GH dependent ALS during early (1st week after surgery) and of both IGFBP-3 and ALS during late stages of fracture healing (6 and 8 weeks after surgery) in non-union patients, coinciding clinically with failed fracture healing. Tendentially lower serum levels of IGF-I in the non-union group over the entire investigation period were statistically not significant. We have been able to show time courses of serum concentrations of the GH/IGF-I axis during normal and failed fracture healing in humans. An impairment of the GH/IGF-I axis might be involved in the biochemical mechanisms determining delayed or failed fracture healing.}, }
@article {pmid17935811, year = {2007}, author = {Kadoyama, K and Funakoshi, H and Ohya, W and Nakamura, T}, title = {Hepatocyte growth factor (HGF) attenuates gliosis and motoneuronal degeneration in the brainstem motor nuclei of a transgenic mouse model of ALS.}, journal = {Neuroscience research}, volume = {59}, number = {4}, pages = {446-456}, doi = {10.1016/j.neures.2007.08.017}, pmid = {17935811}, issn = {0168-0102}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/physiopathology ; Animals ; Apoptosis Regulatory Proteins/drug effects/metabolism ; Astrocytes/drug effects/metabolism/pathology ; Brain Stem/*drug effects/metabolism/physiopathology ; Chemokine CCL2/drug effects/metabolism ; Cranial Nerves/drug effects/metabolism/pathology ; Disease Models, Animal ; Female ; Gliosis/*drug therapy/physiopathology/prevention &amp; control ; Hepatocyte Growth Factor/*pharmacology/therapeutic use ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/drug effects/metabolism/pathology ; Motor Neurons/*drug effects/metabolism/pathology ; Nerve Degeneration/drug therapy/physiopathology/prevention &amp; control ; Neuroprotective Agents/*pharmacology/therapeutic use ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of brainstem and spinal motoneurons. Although prevention of motoneuronal degeneration has been postulated as the primary target for a cure, accumulating evidence suggests that microglial accumulation contributes to disease progression. This study was designed to assess the ability of HGF to modulate microglial accumulation and motoneuronal degeneration in brainstem motor nuclei, using double transgenic mice overexpressing mutated SOD1(G93A) and HGF (G93A/HGF). Histological and immunohistochemical analyses of the tissues of G93A/HGF mice revealed a marked decrease in the number of microglia and reactive astrocytes and an attenuation of the loss of motoneurons in facial and hypoglossal nuclei compared with G93A mice. HGF overexpression attenuated monocyte chemoattractant protein-1 (MCP-1) induction, predominantly in astrocytes; suppressed activation of caspase-1, -3 and -9; and, increased X chromosome-linked inhibition of apoptosis protein (XIAP) in the motoneurons of G93A mice. The implication is that HGF reduces microglial accumulation by suppressing MCP-1 induction and prevents motoneuronal death through inhibition of pro-apoptotic protein activation. These findings suggest that, in addition to direct neurotrophic activity on motoneurons, HGF-suppression of gliosis may retard disease progression, making HGF a potential therapeutic agent for the treatment of ALS patients.}, }
@article {pmid17933231, year = {2007}, author = {Chen, L and Huang, H and Zhang, J and Zhang, F and Liu, Y and Xi, H and Wang, H and Gu, Z and Song, Y and Li, Y and Tan, K}, title = {Short-term outcome of olfactory ensheathing cells transplantation for treatment of amyotrophic lateral sclerosis.}, journal = {Zhongguo xiu fu chong jian wai ke za zhi = Zhongguo xiufu chongjian waike zazhi = Chinese journal of reparative and reconstructive surgery}, volume = {21}, number = {9}, pages = {961-966}, pmid = {17933231}, issn = {1002-1892}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/pathology/*surgery ; *Cell Transplantation/methods ; Cells, Cultured ; Female ; Humans ; Male ; Middle Aged ; Olfactory Bulb/*cytology/embryology/transplantation ; Postoperative Complications ; Recovery of Function ; Retrospective Studies ; Severity of Illness Index ; Treatment Outcome ; Young Adult ; }, abstract = {OBJECTIVE: To determine whether transplanting olfactory ensheathing cells (OECs) is effective in controlling or reversing the deterioration caused by amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Between February 2003 and April 2006, 327 patients (241 males and 86 females) with probable or definite ALS (diagnosed according to the El Escorial criteria) received the OECs transplantation. Their ages ranged from 20 to 84 years (51.6 +/- 11.1 years). The duration of symptoms before surgical treatment was 4.8 months to 13 years (2.9 +/- 2.0 years). OECs were cultured and injected into pathological regions of the spinal cord and/or bilateral corona radiata of the brain; the patients were divided into three groups, group A (cord only, n = 29), group B (cord and brain, n = 6), and group C (brain only, n = 292) based on the transplant sites.<br><br>RESULTS: The patient's neurological function was assessed both before and at 4 weeks after transplantation by using the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) of the ALS CNTF Treatment Study (ACLS). The scores were increased from 17.2 +/- 8.6 pre-operation to 20.1 +/- 9.7 post-operation in group A (P < 0.05), from 24.2 +/- 6.8 to 25.7 +/- 6.6 (P > 0.05) in group B, and from 20.3 +/- 8.6 to 22.0 +/- 9.4 (P < 0.001) in group C. There were no significant difference in increased ALSFRS scores among the three groups (P > 0.05). The total improvement rate of neurological function was 77.1% (252/327). The result of electromyographic examination showed that spontaneous potential diminished and/or disappeared, the amplitude of the motor unit action potential decreased remarkably and the numbers of motor unit action potential greatly increased in 261 cases (79.8%). Sixteen patients (4.9%) experienced the various complications including headache, short-term fever, seizure attack, central nerve system infection, pneumonia, respiratory failure, urinary tract infection, heart failure, and possible pulmonary embolism; of them, there were 4 deaths (1.2%).<br><br>CONCLUSION: These preliminary results suggest that the OECs transplantation is effective in controlling or reversing the physiological deterioration caused by ALS.}, }
@article {pmid17929944, year = {2007}, author = {Huang, Z and Pei, W and Jayaseelan, S and Shi, H and Niu, L}, title = {RNA aptamers selected against the GluR2 glutamate receptor channel.}, journal = {Biochemistry}, volume = {46}, number = {44}, pages = {12648-12655}, doi = {10.1021/bi701036p}, pmid = {17929944}, issn = {0006-2960}, mesh = {Animals ; Animals, Newborn ; Aptamers, Nucleotide/*chemical synthesis/*isolation &amp; purification/pharmacology ; Base Sequence ; Cells, Cultured ; Humans ; Molecular Sequence Data ; Nucleic Acid Conformation ; RNA ; Rats ; Rats, Sprague-Dawley ; Receptors, AMPA/*antagonists &amp; inhibitors/genetics ; Recombinant Proteins/antagonists &amp; inhibitors/genetics ; SELEX Aptamer Technique ; Substrate Specificity ; Transfection ; }, abstract = {The excessive activation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, a subtype of glutamate ion channels, has been implicated in various neurological diseases such as cerebral ischemeia and amyotrophic lateral sclerosis. Inhibitors of AMPA receptors are drug candidates for potential treatment of these diseases. Using the systematic evolution of ligands by exponential enrichment (SELEX), we have selected a group of RNA aptamers against the recombinant GluR2Qflip AMPA receptor transiently expressed in HEK-293 (human embryonic kidney) cells. One of the aptamers, AN58, is shown to competitively inhibit the receptor. The nanomolar affinity of AN58 rivals that of NBQX (6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione), one of the best competitive inhibitors. Like NBQX, AN58 has the highest affinity for GluR2, the selection target, among all AMPA receptor subunits. However, AN58 has a higher selectivity for the GluR4 AMPA receptor subunit and remains potent even at pH = 6.8 (i.e., a clinically relevant acidic pH), as compared with NBQX. Furthermore, this RNA molecule possesses stable physical properties. Therefore, AN58 serves as a unique lead compound for developing water-soluble inhibitors with a nanomolar affinity for GluR2 AMPA receptors.}, }
@article {pmid17785693, year = {2007}, author = {Rosenfeld, RG}, title = {Pharmacogenomics and pharmacoproteomics in the evaluation and management of short stature.}, journal = {European journal of endocrinology}, volume = {157 Suppl 1}, number = {}, pages = {S27-31}, doi = {10.1530/EJE-07-0186}, pmid = {17785693}, issn = {0804-4643}, mesh = {*Body Height ; *Genomics ; Growth Disorders/*diagnosis/*drug therapy ; Humans ; *Pharmacogenetics ; *Proteomics ; }, abstract = {It has long been recognized that growth failure encompasses a diverse spectrum of underlying pathophysiological processes, a characteristic that has significantly impacted both the diagnosis and management of growth disorders. This problem is exacerbated by inherent difficulty in distinguishing the borders between the 'normal range' for stature and defined abnormal growth. Evaluation of GH secretion has proven problematic, both diagnostically and prognostically, except in cases of unequivocal GH deficiency. Measurement of serum concentrations of IGF-I, IGFBP-3, and ALS have proven useful in the assessment of GH responsiveness and have contributed to the concept of primary and secondary 'IGF deficiency'. Nevertheless, there is great need for biochemical and/or molecular biomarkers that could: i) predict short- and long-term responsiveness to various therapeutic modalities, such as GH and IGF-I, and ii) predict potential risk for adverse effects of therapy. Candidate proteins and genes identified to date, and worthy of further evaluation, include IGF-I, IGF-I receptor, GH receptor and its variants (such as exon 3-deleted GHR), STAT5b and short stature homeobox. Proteomic analysis of serum samples pre- and post-treatment and correlation with clinical responsiveness should provide additional candidate biomarkers. Molecular studies to consider include: i) sequencing and mutation analysis of known genetic components of the GH-IGF axis; ii) evaluation of single nucleotide polymorphisms of candidate genes; and iii) identification of new candidate genes. It is proposed that the major target population to study is that of children currently labeled as idiopathic short stature (ISS). These children can be divided into those with: i) primary IGFD, where the focus should be on genes related to GHR, GHR signaling, and IGF-I gene expression, or ii) no IGFD (i.e. 'true ISS'), where the focus should be on genes related to IGFR, IGF signaling and epiphyseal growth.}, }
@article {pmid17924237, year = {2008}, author = {Ramirez, C and Piemonte, ME and Callegaro, D and Da Silva, HC}, title = {Fatigue in amyotrophic lateral sclerosis: frequency and associated factors.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {9}, number = {2}, pages = {75-80}, doi = {10.1080/17482960701642502}, pmid = {17924237}, issn = {1471-180X}, mesh = {Adult ; Age Distribution ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*epidemiology ; Brazil/epidemiology ; Comorbidity ; Educational Status ; Fatigue/*diagnosis/*epidemiology ; Female ; Humans ; Incidence ; Male ; Middle Aged ; Risk Assessment/*methods ; Risk Factors ; Sex Distribution ; Surveys and Questionnaires ; }, abstract = {We aimed to quantify fatigue frequency and evolution in amyotrophic lateral sclerosis (ALS), and to correlate fatigue with factors such as age, sex, educational level, disease duration, functionality, quality of life, dyspnoea, depression and sleepiness. Sixty ALS patients (test group: TG) selected by El Escorial criteria and 60 normal individuals (control group: CG) matched according to sex and age, were followed every three months, during 9 months, by means of self-report scales: Fatigue Assessment Instrument (Fatigue Severity Scale plus three qualitative subscales); ALS Functional Rating Scale; McGill Quality of Life Questionnaire; dyspnoea analogical scale; Beck Depression Inventory and Epworth Sleepiness Scale. Fatigue was reported by 83% of TG (median: 3.6, interquartile range 1.5-5.4), compared with 20% of CG (median: 1, 1-1), and was significantly greater in the TG (p<0.001, Mann-Whitney test). Fatigue severity increased by the ninth month of the study (p=0.0008, Friedman, Müller-Dunn post test). There was no correlation between fatigue and other parameters, except for an inverse correlation with age at disease onset (p=0.0395, Spearman rank correlation). In conclusion, fatigue was frequent in ALS, greater in the youngest patients and worsened during follow-up. Possibly, ALS related fatigue is an independent factor, which deserves individualized approach and treatment.}, }
@article {pmid17917585, year = {2007}, author = {Tovar-Y-Romo, LB and Zepeda, A and Tapia, R}, title = {Vascular endothelial growth factor prevents paralysis and motoneuron death in a rat model of excitotoxic spinal cord neurodegeneration.}, journal = {Journal of neuropathology and experimental neurology}, volume = {66}, number = {10}, pages = {913-922}, doi = {10.1097/nen.0b013e3181567c16}, pmid = {17917585}, issn = {0022-3069}, mesh = {Animals ; Cell Death/drug effects ; Choline O-Acetyltransferase/metabolism ; Hindlimb/physiology ; Immunohistochemistry ; Male ; Motor Neurons/*drug effects ; Nerve Degeneration/chemically induced/*pathology ; Paralysis/*prevention &amp; control ; Psychomotor Performance/drug effects/physiology ; Rats ; Rats, Wistar ; Receptors, AMPA/drug effects ; Spinal Cord Diseases/chemically induced/*pathology ; Vascular Endothelial Growth Factor A/*therapeutic use ; }, abstract = {Vascular endothelial growth factor (VEGF) delays disease onset and progression in transgenic rodent models of familial amyotrophic lateral sclerosis (ALS). Because most cases of ALS are sporadic, it is important to determine whether VEGF can protect motoneurons in a nontransgenic ALS paradigm. We tested this possibility in a new model of chronic excitotoxic spinal neurodegeneration in the rat. Using osmotic minipumps, we continuously infused the glutamate receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) directly in the lumbar spinal cord. The effect of this treatment on motor behavior was assessed with 3 motor performance tests, and neurodegeneration was evaluated by histologic and immunohistochemical analyses. AMPA infusion produced dose-dependent progressive hindlimb motor deficits, reaching complete bilateral paralysis in approximately 10 days, which was correlated with the loss of spinal motoneurons. VEGF administered together with AMPA completely prevented the motor deficits, and the motoneuron death was reduced by more than 75%. Thus, we have developed an in vivo model of progressive spinal motoneuron death due to overactivation of AMPA receptors. The finding that VEGF protected motoneurons from this AMPA receptor-mediated excitotoxic death suggests that it may be a therapeutic agent in sporadic ALS.}, }
@article {pmid17917110, year = {2007}, author = {Charbonnier, F}, title = {Exercise-induced neuroprotection in SMA model mice: a means for determining new therapeutic strategies.}, journal = {Molecular neurobiology}, volume = {35}, number = {3}, pages = {217-223}, pmid = {17917110}, issn = {0893-7648}, mesh = {Animals ; *Exercise ; Humans ; Mice ; Mice, Inbred Strains ; Motor Neurons/physiology ; Neurodegenerative Diseases/*drug therapy/physiopathology ; Neuromuscular Diseases/*drug therapy/physiopathology ; Neuroprotective Agents/*therapeutic use ; Signal Transduction/physiology ; }, abstract = {Due to the prevalence of neuromuscular disorders such as amyotrophic lateral sclerosis and spinal muscular atrophy in modern societies, defining new and efficient strategies for the treatment of these two neurodegenerative diseases has become a vital and still unfulfilled urge. Several lines of experimental evidence have emphasized the benefits of regular exercise training in mouse models for these affections in terms of life span increase and improvement of both motor capacities and motoneuron survival. Identifying molecules that could mimic the neuroprotective effects of exercise represents a promising way to find novel therapies. Some of the effects of exercise are caused by the overproduction of circulating neurotrophic factors, such as IGF-I, whereas others may be due to modifications of the intrinsic properties of the motoneurons within the spinal cord. The causal relationship that links these potential effects of exercise training and the improvement of motor capacity and life span expectancy is consequently discussed.}, }
@article {pmid17916366, year = {2008}, author = {Abe, Y and Miyashita, M and Ito, N and Shirai, Y and Momose, Y and Ichikawa, Y and Tsuji, S and Kazuma, K}, title = {Attitude of outpatients with neuromuscular diseases in Japan to pain and use of analgesics.}, journal = {Journal of the neurological sciences}, volume = {267}, number = {1-2}, pages = {22-27}, doi = {10.1016/j.jns.2007.09.027}, pmid = {17916366}, issn = {0022-510X}, mesh = {Activities of Daily Living/psychology ; Adaptation, Psychological ; Adult ; Analgesics/adverse effects/*therapeutic use ; Anxiety/epidemiology ; *Attitude to Health ; Comorbidity ; Female ; Humans ; Japan/epidemiology ; Male ; Massage/statistics &amp; numerical data ; Neurodegenerative Diseases/*epidemiology ; Neuromuscular Diseases/*epidemiology ; Outpatients/psychology/statistics &amp; numerical data ; Pain/drug therapy/*epidemiology/*psychology ; Pain Measurement/methods ; Patient Acceptance of Health Care ; Patient Education as Topic/statistics &amp; numerical data ; Physician-Patient Relations ; Posture/physiology ; Prevalence ; Surveys and Questionnaires ; }, abstract = {The prevalence of pain and its impact on outpatients with neuromuscular disease, and their attitude towards the use of analgesics were studied. Seventy-eight outpatients at the university hospital, Tokyo, diagnosed with Parkinson's disease, spinocerebellar degeneration, amyotrophic lateral sclerosis, or multiple sclerosis were asked whether they had experienced pain in the preceding week. The Brief Pain Inventory, Japanese version was used to interview participants reporting pain, about its intensity and interference with activities, the way they dealt with it, attitudes to pain and use of analgesics, and desire for treatment. Forty-six participants experienced pain in the preceding week (59%). The mean pain intensity was 4.1 out of 10, and 20% of participants reported that the degree of interference with mobility was at least 6 out of 10. Most participants dealt with their pain without medication, by changing posture frequently or massage. Approximately 80% of participants regarded pain as something they should endure. Half of the participants wanted more information on methods for pain relief. Approximately 80% of participants were anxious about adverse reactions of analgesics. These findings suggest that medical staffs should provide appropriate information and educate their patients.}, }
@article {pmid17914317, year = {2007}, author = {Presecki, P and Mimica, N}, title = {Involuntary emotional expression disorder - new/old disease in psychiatry and neurology.}, journal = {Psychiatria Danubina}, volume = {19}, number = {3}, pages = {184-188}, pmid = {17914317}, issn = {0353-5053}, mesh = {Affective Symptoms/*diagnosis/physiopathology/psychology ; Brain/physiopathology ; Brain Diseases/*diagnosis/physiopathology/psychology ; Crying/*physiology ; Diagnosis, Differential ; Glutamic Acid/physiology ; Humans ; Laughter/*physiology ; Risk Factors ; Stereotyped Behavior/*physiology ; Syndrome ; }, abstract = {Involuntary emotional expression disorder (IEED) is underrecognized by clinicians, misdiagnosed as depression or bipolar disorder and undertreated, because clinicians are unfamiliar with the disorder. An important clinical consideration for IEED is that of distinguishing mood from affect. IEED describes a syndrome of relatively stereotypical episodes of uncontrollable crying and/or laughing, resulting from lesions of multiple types, in multiple brain regions, without an apparent stimulus to trigger such responses. This syndrome is common among a number of neurological diseases like patients with a stroke or traumatic brain injury (TBI), patients with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), as well as dementias such as Alzheimer;s disease (AD), and motor disorders such as Parkinson;s disease (PD). The neuropathological cause and neurochemistry of the disorder remains unclear. There is general agreement that IEED is the result of an injury to the neurological pathways that control the expression of emotions. Adequate treatment can reduce the frequency and improve the quality of life of patients and caregivers.}, }
@article {pmid17911646, year = {2007}, author = {Kroemer, A and Xiao, X and Vu, MD and Gao, W and Minamimura, K and Chen, M and Maki, T and Li, XC}, title = {OX40 controls functionally different T cell subsets and their resistance to depletion therapy.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {179}, number = {8}, pages = {5584-5591}, doi = {10.4049/jimmunol.179.8.5584}, pmid = {17911646}, issn = {0022-1767}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; CD4-Positive T-Lymphocytes/immunology/metabolism ; Cell Survival/genetics/immunology ; Forkhead Transcription Factors/biosynthesis/genetics ; Genes, Reporter ; Graft Rejection/immunology/pathology ; *Immunity, Innate/genetics ; Immunophenotyping ; *Lymphocyte Depletion ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Mice, Knockout ; Mice, Transgenic ; Receptors, OX40/biosynthesis/deficiency/genetics/*physiology ; Skin Transplantation/immunology ; T-Lymphocyte Subsets/cytology/*immunology/*metabolism ; T-Lymphocytes, Regulatory/cytology/immunology/metabolism ; }, abstract = {T cell depletion is a widely used approach in clinical transplantation. However, not all T cells are equally sensitive to depletion therapies and a significant fraction of T cells persists even after aggressive treatment. The functional attributes of such T cells and the mechanisms responsible for their resistance to depletion are poorly studied. In the present study, we showed that CD4(+) T cells that are resistant to polyclonal anti-lymphocyte serum (ALS) mediated depletion exhibit phenotypic features of memory cells and uniformly express OX40 on the cell surface. Studies using the foxp3gfp knockin mice revealed that the remaining CD4(+)OX40(+) cells consist of Foxp3(+) Tregs and Foxp3(-) T effector/memory cells. The ALS-resistant CD4(+)OX40(+) cells failed to mediate skin allograft rejection upon adoptive transferring into congenic Rag(-/-) mice, but removal of Foxp3(+) Tregs from the OX40(+) cells resulted in prompt skin allograft rejection. Importantly, OX40 is critical to survival of both Foxp3(+) Tregs and T effector/memory cells. However, OX40 exhibits opposing effects on the functional status of Foxp3(+) Tregs and T effector/memory cells, as stimulation of OX40 on T effector cells induced amplified cell proliferation but stimulation of OX40 on the Foxp3(+) Tregs impaired their suppressor functions. Our study demonstrates that OX40 is a critical molecule in regulating survival and functions of depletion-resistant T cells; and these findings may have important clinical implications.}, }
@article {pmid17908043, year = {2007}, author = {Avramovich-Tirosh, Y and Reznichenko, L and Mit, T and Zheng, H and Fridkin, M and Weinreb, O and Mandel, S and Youdim, MB}, title = {Neurorescue activity, APP regulation and amyloid-beta peptide reduction by novel multi-functional brain permeable iron- chelating- antioxidants, M-30 and green tea polyphenol, EGCG.}, journal = {Current Alzheimer research}, volume = {4}, number = {4}, pages = {403-411}, doi = {10.2174/156720507781788927}, pmid = {17908043}, issn = {1567-2050}, mesh = {Amyloid beta-Peptides/*metabolism ; Amyloid beta-Protein Precursor/*metabolism ; Animals ; Antioxidants/chemistry/*pharmacology ; Apoptosis/*drug effects ; Catechin/*analogs &amp; derivatives/chemistry/pharmacology ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Hydroxyquinolines/chemistry/*pharmacology ; Mice ; Mice, Inbred C57BL ; Models, Biological ; Neuroblastoma ; }, abstract = {Accumulation of iron at sites where neurons degenerate in Parkinson's disease (PD) and Alzheimer's disease (AD) is thought to have a major role in oxidative stress induced process of neurodegeneration. The novel non-toxic lipophilic brain- permeable iron chelators, VK-28 (5- [4- (2- hydroxyethyl) piperazine-1-ylmethyl]- quinoline- 8- ol) and its multi-functional derivative, M-30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline), as well as the main polyphenol constituent of green tea (-)-epigallocatechin-3-gallate (EGCG), which possesses iron metal chelating, radical scavenging and neuroprotective properties, offer potential therapeutic benefits for these diseases. M-30 and EGCG decreased apoptosis of human SH-SY5Y neuroblastoma cells in a neurorescue, serum deprivation model, via multiple protection mechanisms including: reduction of the pro-apoptotic proteins, Bad and Bax, reduction of apoptosis-associated Ser139 phosphorylated H2A.X and inhibition of the cleavage and activation of caspase-3. M-30 and EGCG also promoted morphological changes, resulting in axonal growth-associated protein-43 (GAP-43) implicating neuronal differentiation. Both compounds significantly reduced the levels of cellular holo-amyloid precursor protein (APP) in SH-SY5Y cells. The ability of theses novel iron chelators and EGCG to regulate APP are in line with the presence of an iron-responsive element (IRE) in the 5'-untranslated region (5'UTR) of APP. Also, EGCG reduced the levels of toxic amyloid-beta peptides in CHO cells over-expressing the APP "Swedish" mutation. The diverse molecular mechanisms and cell signaling pathways participating in the neuroprotective/neurorescue and APP regulation/processing actions of M-30 and EGCG, make these multifunctional compounds potential neuroprotective drugs for the treatment of neurodegenerative diseases, such as PD, AD, Huntington's disease and amyotrophic lateral sclerosis.}, }
@article {pmid17908040, year = {2007}, author = {Tweedie, D and Sambamurti, K and Greig, NH}, title = {TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: new drug candidates and targets.}, journal = {Current Alzheimer research}, volume = {4}, number = {4}, pages = {378-385}, doi = {10.2174/156720507781788873}, pmid = {17908040}, issn = {1567-2050}, support = {R01 AG023055-04/AG/NIA NIH HHS/United States ; R01 AG023055/AG/NIA NIH HHS/United States ; R01 AG023055-05/AG/NIA NIH HHS/United States ; R01 AG023055-03/AG/NIA NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; R01 AG023055-01A1/AG/NIA NIH HHS/United States ; R01 AG023055-02/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Enzyme Inhibitors/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy ; Tumor Necrosis Factor-alpha/physiology/*therapeutic use ; }, abstract = {As the average ages of North Americans and Europeans continue to rise; similarly the incidence of "old age" associated illnesses likewise increases. Most notably among these ailments are conditions linked to dementia-related neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and stroke. While in the early stages, these conditions are associated with cellular dysfunction in distinctly different brain regions, thus affecting different neuronal cell types; it is most likely that the final stages share similar cellular and molecular processes leading to neuronal death and ultimately overt clinical symptoms. In this regard, different environmental and genetic triggers ranging from head trauma to protein mutations and toxicological exposure may instigate a cascade of intracellular events that ultimately lead to neuronal death. One strong candidate trigger protein, and thus a potential target for therapeutic manipulation is the potent pro-inflammatory / pro-apoptotic cytokine, tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is secreted by the brain resident marcophage (the microglial cell) in response to various stimuli. It has been demonstrated to play a major role in central nervous system (CNS) neuroinflammation-mediated cell death in AD, PD and amyotrophic lateral sclerosis (ALS) as well as several other CNS complications. Recently, agents that modulate the levels of circulating peripheral TNF-alpha protein have been shown to be worthwhile therapeutic agents with the use of Enbrel (Etanercept) and Remicade (Infliximab), both of which display beneficial properties against rheumatoid arthritis and other peripheral inflammatory diseases. Unfortunately, these agents are largely unable to penetrate the blood-brain barrier, which severely limits their use in the setting of neuroinflammation in the CNS. However, thalidomide, a small molecule drug, can inhibit TNF-alpha protein synthesis and, unlike larger molecules, is readily capable of crossing the blood-brain barrier. Thus thalidomide and its analogs are excellent candidate agents for use in determining the potential value of anti-TNF-alpha therapies in a variety of diseases underpinned by inflammation within the nervous system. Consequently, we have chosen to discuss the relevance of unregulated TNF-alpha expression in illnesses of the CNS and, to an extent, the peripheral nervous system. Additionally, we consider the utilization of thalidomide-derived agents as anti-TNF-alpha therapeutics in the setting of neuroinflammation.}, }
@article {pmid17898224, year = {2007}, author = {Zhang, YJ and Xu, YF and Dickey, CA and Buratti, E and Baralle, F and Bailey, R and Pickering-Brown, S and Dickson, D and Petrucelli, L}, title = {Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {27}, number = {39}, pages = {10530-10534}, pmid = {17898224}, issn = {1529-2401}, support = {G0400356/MRC_/Medical Research Council/United Kingdom ; R01-AG-026251-01/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/metabolism/physiopathology ; Brain/metabolism/pathology ; Caspase 3/metabolism ; Caspase 7/metabolism ; Cell Line ; DNA-Binding Proteins/*metabolism ; Dementia/*metabolism/physiopathology ; Humans ; Hydrolysis ; Inclusion Bodies/pathology ; Intercellular Signaling Peptides and Proteins/*metabolism ; Progranulins ; Ubiquitin/metabolism ; }, abstract = {TAR DNA binding protein-43 (TDP-43) is the pathologic substrate of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U) and in amyotrophic lateral sclerosis (ALS). Mutations in the progranulin gene (PGRN) have been shown to cause familial FTLD-U. The relationship between progranulin and TDP-43 and their respective roles in neurodegeneration is unknown. We report that progranulin mediates proteolytic cleavage of TDP-43 to generate approximately 35 and approximately 25 kDa species. Suppression of PGRN expression with small interfering RNA leads to caspase-dependent accumulation of TDP-43 fragments that can be inhibited with caspase inhibitor treatment. Cells treated with staurosporine also induced caspase-dependent cleavage and redistribution of TDP-43 from its nuclear localization to cytoplasm. Altered cleavage and redistribution of TDP-43 in cell culture models are similar to findings in FTLD-U and ALS. The results suggest that abnormal metabolism of TDP-43 mediated by progranulin may play a pivotal role in neurodegeneration.}, }
@article {pmid17897874, year = {2007}, author = {Rutkove, SB and Zhang, H and Schoenfeld, DA and Raynor, EM and Shefner, JM and Cudkowicz, ME and Chin, AB and Aaron, R and Shiffman, CA}, title = {Electrical impedance myography to assess outcome in amyotrophic lateral sclerosis clinical trials.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {118}, number = {11}, pages = {2413-2418}, pmid = {17897874}, issn = {1388-2457}, support = {R01 NS042037/NS/NINDS NIH HHS/United States ; RR01032/RR/NCRR NIH HHS/United States ; R01 NS042037-03/NS/NINDS NIH HHS/United States ; M01 RR001032/RR/NCRR NIH HHS/United States ; R01 NS042037-04/NS/NINDS NIH HHS/United States ; R01-NS42037-01A2/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/pathology/*physiopathology ; *Clinical Trials as Topic ; Disease Progression ; *Electric Impedance ; Electric Stimulation ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Muscle Contraction/physiology/radiation effects ; Muscle, Skeletal/*physiopathology ; Myography/*methods ; *Outcome Assessment, Health Care ; Psychomotor Performance/physiology ; Reproducibility of Results ; Time Factors ; }, abstract = {OBJECTIVE: Standard outcome measures used for amyotrophic lateral sclerosis (ALS) clinical trials, including the ALS functional rating scale-revised (ALSFRS-R), maximal voluntary isometric contraction testing (MVICT), and manual muscle testing (MMT), are limited in their ability to detect subtle disease progression. Electrical impedance myography (EIM) is a new non-invasive technique that provides quantitative data on muscle health by measuring localized tissue impedance. This study investigates whether EIM could provide a new outcome measure for use in ALS clinical trials work.<br><br>METHODS: Fifteen ALS patients underwent repeated EIM measurements of one or more muscles over a period of up to 18 months and the primary outcome variable, theta(z-max), measured. The theta(z-max) megascore was then calculated using the same approach as has been applied in the past for MVICT. This and the MMT data were then used to assess each measure's statistical power to detect a given effect on disease progression in a hypothetical planned clinical therapeutic trial.<br><br>RESULTS: theta(z-max) showed a mean decline of about 21% for the test period, averaged across all patients and all tested muscles. The theta(z-max) megascore had a power of 73% to detect a 10% treatment effect in our planned hypothetical trial, as compared to a 28% power for MMT. These results also compared favorably to historical data for ALSFRS-R and MVICT arm megascore from the trial of celecoxib in ALS, where both measures had only a 23% power to detect the same 10% treatment effect.<br><br>CONCLUSIONS: The theta(z-max) megascore may provide a powerful new outcome measure for ALS clinical trials.<br><br>SIGNIFICANCE: The application of EIM to future ALS trials may allow for smaller, faster studies with an improved ability to detect subtle progression of the disease and treatment effects.}, }
@article {pmid17894358, year = {2008}, author = {McClelland, S and Bethoux, FA and Boulis, NM and Sutliff, MH and Stough, DK and Schwetz, KM and Gogol, DM and Harrison, M and Pioro, EP}, title = {Intrathecal baclofen for spasticity-related pain in amyotrophic lateral sclerosis: efficacy and factors associated with pain relief.}, journal = {Muscle &amp; nerve}, volume = {37}, number = {3}, pages = {396-398}, doi = {10.1002/mus.20900}, pmid = {17894358}, issn = {0148-639X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*complications/drug therapy ; Baclofen/*administration &amp; dosage ; Cohort Studies ; Female ; Humans ; Infusion Pumps, Implantable ; Injections, Spinal/methods ; Male ; Middle Aged ; Muscle Relaxants, Central/*administration &amp; dosage ; Muscle Spasticity/*complications/*etiology ; Pain/*drug therapy/etiology ; Pain Measurement ; Retrospective Studies ; }, abstract = {Clinical signs and symptoms of spasticity include hypertonia, involuntary movements (spasms, clonus), decreased range of motion, contractures, and often spasm-related pain. When spasticity is refractory to medical management, patients may be referred for intrathecal baclofen (ITB) pump placement. We reviewed a cohort of amyotrophic lateral sclerosis (ALS) patients with intractable spasticity requiring ITB to further define the impact of ITB on pain relief in this patient population. From 2003 to 2005, eight patients (mean age 43.8 years; 5 men, 3 women) with ALS received ITB for pain associated with intractable spasticity at our institution. Mean disease duration preoperatively was 47.4 months, mean follow-up was 9.8 months, and pain was evaluated using a 0-10 scoring system. All patients experienced spasticity relief in response to a preoperative bolus test injection of ITB (25-50 microg) via lumbar puncture. Following ITB pump placement, the average reduction of pain was 54% (P = 0.0082). Six patients (75%) experienced pain score reduction, three of whom had complete pain relief. Postoperative pain reduction was predicted by the degree of pain reduction following preoperative ITB test injection. These results support ITB as a treatment modality for pain associated with spasticity in ALS.}, }
@article {pmid17892036, year = {2007}, author = {Woldańska-Okońska, M and Czernicki, J}, title = {[Effect of low frequency magnetic fields used in magnetotherapy and magnetostimulation on the rehabilitation results of patients after ischemic stroke].}, journal = {Przeglad lekarski}, volume = {64}, number = {2}, pages = {74-77}, pmid = {17892036}, issn = {0033-2240}, mesh = {Aged ; Brain Ischemia/*rehabilitation ; *Electromagnetic Fields ; Female ; Follow-Up Studies ; Humans ; Magnetics/*therapeutic use ; Male ; Middle Aged ; *Physical Therapy Modalities ; *Stroke Rehabilitation ; Treatment Outcome ; }, abstract = {New methods of rehabilitation should be introduced in order to reduce disability resulting from stroke. During the twelve months of follow-up, effect of low frequency magnetic field (If mf) on the course of patient rehabilitation following ischemic stroke was evaluated on in-patient (acute and subacute period of the stroke) and outpatient (chronic period) basis with the use of Mathew et al's and Barthel's scales. Lf mf (20 procedures of 20-min. duration) of magnetotherapy (I group--placebo, II--group 5.6 mT induction, 10 Hz frequency and sinusoidal shape, III group--2.8 mT induction, 10 Hz frequency and sinusoidal shape) and magnetostimulation (IV group--M1P1 program of Viofor JPS system, 16 min a day) was applied as early as in the subacute period of the stroke (1-8 weeks). The data obtained were presented in the form of percentage changes in the pain levels as well as in the form of the arithmetical mean and standard deviation (X +/- SD). The ANOVA test was used for a statistical evaluation of the data obtained in the tests. The results obtained indicate beneficial effects of If mf in the III and IV group of patients in the Barthel's scale and Mathew scale, which were observed during the examination 12 months after the stroke. The recommended doses of If mf seem to be adequate to obtain therapeutic effects and may be used in the early period of rehabilitation. The neurological and functional improvement persisted for a long-period of the out-patient treatment, which was confirmed during the control examination 12 months after the ischemic stroke. As no adverse effects (which could be attributed to If mf), were observed, this method of physical therapy can be recognized as a safe one and worth making popular in clinical practice.}, }
@article {pmid17891927, year = {2007}, author = {Sívori, M and Rodríguez, GE and Pascansky, D and Sáenz, C and Sica, RE}, title = {Outcome of sporadic amyotrophic lateral sclerosis treated with non-invasive ventilation and riluzole.}, journal = {Medicina}, volume = {67}, number = {4}, pages = {326-330}, pmid = {17891927}, issn = {0025-7680}, mesh = {Adult ; Age Distribution ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/mortality/*therapy ; Argentina/epidemiology ; Combined Modality Therapy/methods ; Female ; Follow-Up Studies ; Humans ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; *Positive-Pressure Respiration ; Riluzole/*therapeutic use ; Survival Analysis ; Treatment Outcome ; }, abstract = {Sporadic amyotrophic lateral sclerosis (sALS) is a progressive degenerative motor neuron disorder lacking specific treatment. Riluzole is the only drug able to modestly slow down the course of the disease. Respiratory insufficiency is the main cause of death; non invasive ventilation (NIV) has shown to improve survival. Our aim was to evaluate the effect of NIV and riluzole on survival. Ninety seven patients with a diagnosis of sALS were assessed and followed up for 60 months. Twenty nine patients received NIV and 68 did not (nNIV). Overall median survival In the NIV group was 15.41 +/- 7.78 months vs. 10.88 +/- 7.78 months in the nNIV group (p= 0.028). Median survival time was not different in patients receiving riluzole (n=44), as compared with those who did not (n=53), although at month 4th and 5th riluzole treated patients showed a modest benefit. In those who only received NIV (n=11) or only riluzole (n=26), survival time was 13.45 +/- 13.44 months and 11.19 +/- 7.79 months, respectively. Patients who received both NIV and riluzole (n=18) had a median survival time of 16.61 +/- 10.97 months vs. 10.69 +/- 7.86 months for those who received only supportive treatment (n=42) (p= 0.021). NIV improved survival in our series of patients. Riluzole did not show any significant impact on survival when employed as the only therapy. Patients receiving both treatments simultaneously had a significant longer survival.}, }
@article {pmid17884681, year = {2007}, author = {Radunović, A and Mitsumoto, H and Leigh, PN}, title = {Clinical care of patients with amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {6}, number = {10}, pages = {913-925}, doi = {10.1016/S1474-4422(07)70244-2}, pmid = {17884681}, issn = {1474-4422}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis/physiopathology/*therapy ; Deglutition Disorders/etiology/therapy ; Disease Progression ; Humans ; Neuroprotective Agents/therapeutic use ; Palliative Care ; Patient Care Team ; Respiration Disorders/etiology/therapy ; Riluzole/therapeutic use ; }, abstract = {Although amyotrophic lateral sclerosis and its variants are readily recognised by neurologists, about 10% of patients are misdiagnosed, and delays in diagnosis are common. Prompt diagnosis, sensitive communication of the diagnosis, the involvement of the patient and their family, and a positive care plan are prerequisites for good clinical management. A multidisciplinary, palliative approach can prolong survival and maintain quality of life. Treatment with riluzole improves survival but has a marginal effect on the rate of functional deterioration, whereas non-invasive ventilation prolongs survival and improves or maintains quality of life. In this Review, we discuss the diagnosis, management, and how to cope with impaired function and end of life on the basis of our experience, the opinions of experts, existing guidelines, and clinical trials. We highlight the need for research on the effectiveness of gastrostomy, access to non-invasive ventilation and palliative care, communication between the care team, the patient and his or her family, and recognition of the clinical and social effects of cognitive impairment. We recommend that the plethora of evidence-based guidelines should be compiled into an internationally agreed guideline of best practice.}, }
@article {pmid17875066, year = {2007}, author = {Dreher, M and Rauter, I and Storre, JH and Geiseler, J and Windisch, W}, title = {When should home mechanical ventilation be started in patients with different neuromuscular disorders?.}, journal = {Respirology (Carlton, Vic.)}, volume = {12}, number = {5}, pages = {749-753}, doi = {10.1111/j.1440-1843.2007.01116.x}, pmid = {17875066}, issn = {1323-7799}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*therapy ; Disease Progression ; Female ; Forced Expiratory Volume ; *Home Care Services, Hospital-Based ; Humans ; Male ; Middle Aged ; Muscular Dystrophy, Duchenne/*therapy ; Neuromuscular Diseases/*therapy ; *Positive-Pressure Respiration ; Prognosis ; *Respiration, Artificial ; Retrospective Studies ; Vital Capacity ; }, abstract = {BACKGROUND AND OBJECTIVES: Current international consensus guidelines identify a number of indicators for the establishment of home mechanical ventilation (HMV) for patients with neuromuscular diseases but do not address the possible clinical differences between each of the underlying disorders. This study assessed the differences in the physiological parameters of patients with neuromuscular disease commenced on HMV for the treatment of symptomatic chronic hypercapnic respiratory failure.<br><br>METHODS: Patients commenced on HMV for the treatment of symptomatic chronic hypercapnic respiratory failure over a 9-year period were studied. Physiological parameters at the time of referral for HMV, impact of HMV and survival were analysed.<br><br>RESULTS: The study recruited 66 patients with neuromuscular disease. Thirty-one patients had rapidly progressive disease: amyotrophic lateral sclerosis (ALS, n = 19), Duchenne muscular dystrophy (DMD, n = 12) and 35 patients had slowly progressive disease. Mean FVC at HMV onset was 40.3 +/- 17.5% predicted in all patients, but was >50% predicted in eight patients (12%). ALS patients were more hypercapnic (P = 0.03) and more hypoxaemic (P < 0.001), but had better FEV(1) at HMV onset, compared with DMD patients (P = 0.005). Maximal inspiratory mouth occlusion pressure (PImax) was 3.0 +/- 1.6 kPa in all patients, but values were lower compared with international consensus guidelines (5.88 kPa). Median survival in DMD, slowly progressive diseases and ALS was 132, 82 and 16 months, respectively (P < 0.001).<br><br>CONCLUSIONS: Blood gases and lung function parameters vary substantially between patients with differing underlying neuromuscular disorders when commenced on HMV for the treatment of symptomatic chronic hypercapnic respiratory failure. In contrast, PImax is equally reduced in all patients and more severely reduced compared with consensus guidelines. The specific underlying neuromuscular disease has a major impact on outcome. Specific selection criteria are needed for the use of HMV in the different diseases that comprise neuromuscular disorders.}, }
@article {pmid17869376, year = {2007}, author = {Rockenstein, E and Crews, L and Masliah, E}, title = {Transgenic animal models of neurodegenerative diseases and their application to treatment development.}, journal = {Advanced drug delivery reviews}, volume = {59}, number = {11}, pages = {1093-1102}, doi = {10.1016/j.addr.2007.08.013}, pmid = {17869376}, issn = {0169-409X}, support = {AG10435/AG/NIA NIH HHS/United States ; AG11385/AG/NIA NIH HHS/United States ; AG18440/AG/NIA NIH HHS/United States ; AG5131/AG/NIA NIH HHS/United States ; NS44233/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/drug therapy/etiology ; Amyloid beta-Protein Precursor/genetics ; Animals ; *Animals, Genetically Modified ; *Disease Models, Animal ; Humans ; Lewy Body Disease/drug therapy/etiology ; Multiple System Atrophy/drug therapy/etiology ; Neurodegenerative Diseases/*drug therapy/etiology ; Parkinson Disease/drug therapy/etiology ; alpha-Synuclein/genetics ; tau Proteins/analysis ; }, abstract = {Neurodegenerative disorders of the aging population affect over 5 million people in the US and Europe alone. The common feature is the progressive accumulation of misfolded proteins with the formation of toxic oligomers. Previous studies show that while in Alzheimer's disease (AD) misfolded amyloid-beta protein accumulates both in the intracellular and extracellular space, in Lewy body disease (LBD), Parkinson's disease (PD), Multiple System Atrophy (MSA), Fronto-Temporal dementia (FTD), prion diseases, amyotrophic lateral sclerosis (ALS) and trinucleotide repeat disorders (TNRD), the aggregated proteins accumulate in the plasma membrane and intracellularly. Protein misfolding and accumulation is the result of an altered balance between protein synthesis, aggregation rate and clearance. Based on these studies, considerable advances have been made in the past years in developing novel experimental models of neurodegenerative disorders. This has been in part driven by the identification of genetic mutations associated with familial forms of these conditions and gene polymorphisms associated with the more common sporadic variants of these diseases. Transgenic and knock out rodents and Drosophila as well as viral vector driven models of Alzheimer's disease (AD), PD, Huntington's disease (HD) and others have been developed, however the focus for this review will be on rodent models of AD, FTD, PD/LBD, and MSA. Promising therapeutic results have been obtained utilizing amyloid precursor protein (APP) transgenic (tg) models of AD to develop therapies including use of inhibitors of the APP-processing enzymes beta- and gamma-secretase as well as vaccine therapies.}, }
@article {pmid17854437, year = {2007}, author = {Dewil, M and Lambrechts, D and Sciot, R and Shaw, PJ and Ince, PG and Robberecht, W and Van den Bosch, L}, title = {Vascular endothelial growth factor counteracts the loss of phospho-Akt preceding motor neurone degeneration in amyotrophic lateral sclerosis.}, journal = {Neuropathology and applied neurobiology}, volume = {33}, number = {5}, pages = {499-509}, doi = {10.1111/j.1365-2990.2007.00850.x}, pmid = {17854437}, issn = {0305-1846}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Blotting, Western ; Female ; Humans ; Immunohistochemistry ; Male ; Mice ; Mice, Transgenic ; Middle Aged ; Motor Neurons/*metabolism/pathology ; Nerve Degeneration/drug therapy ; Neuroprotective Agents/*administration &amp; dosage ; Phosphorylation ; Proto-Oncogene Proteins c-akt/*drug effects/metabolism ; Rats ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Transfection ; Vascular Endothelial Growth Factor A/*administration &amp; dosage ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that results in the selective loss of motor neurones. In the present study, the involvement of the antiapoptotic protein, Akt (protein kinase B), was studied. We found that motor neurones of both sporadic and familial ALS patients lack phospho-Akt, and that motor neurones of mutant SOD1 mice lose activated Akt early in the disease, before the onset of clinical symptoms. In vitro, overexpression of constitutively active Akt protects against mutant SOD1-dependent cell death. In vivo, levels of phospho-Akt in the spinal cord increase after intracerebroventricular administration of vascular endothelial growth factor to mutant SOD1 rats, a treatment we previously described to significantly protect motor neurones. From these results, we conclude that the loss of phospho-Akt could be involved in motor neurone death in ALS, and that therapies upregulating phospho-Akt thus might be of clinical relevance.}, }
@article {pmid17854436, year = {2007}, author = {Christou, YA and Moore, HD and Shaw, PJ and Monk, PN}, title = {Embryonic stem cells and prospects for their use in regenerative medicine approaches to motor neurone disease.}, journal = {Neuropathology and applied neurobiology}, volume = {33}, number = {5}, pages = {485-498}, doi = {10.1111/j.1365-2990.2007.00883.x}, pmid = {17854436}, issn = {0305-1846}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Cell Differentiation ; Embryonic Stem Cells/*physiology ; Humans ; Motor Neuron Disease/*therapy ; Motor Neurons/*cytology ; Nerve Regeneration ; Regenerative Medicine/*methods/trends ; *Stem Cell Transplantation ; }, abstract = {Human embryonic stem cells are pluripotent cells with the potential to differentiate into any cell type in the presence of appropriate stimulatory factors and environmental cues. Their broad developmental potential has led to valuable insights into the principles of developmental and cell biology and to the proposed use of human embryonic stem cells or their differentiated progeny in regenerative medicine. This review focuses on the prospects for the use of embryonic stem cells in cell-based therapy for motor neurone disease or amyotrophic lateral sclerosis, a progressive neurodegenerative disease that specifically affects upper and lower motor neurones and leads ultimately to death from respiratory failure. Stem cell-derived motor neurones could conceivably be used to replace the degenerated cells, to provide authentic substrates for drug development and screening and for furthering our understanding of disease mechanisms. However, to reliably and accurately culture motor neurones, the complex pathways by which differentiation occurs in vivo must be understood and reiterated in vitro by embryonic stem cells. Here we discuss the need for new therapeutic strategies in the treatment of motor neurone disease, the developmental processes that result in motor neurone formation in vivo, a number of experimental approaches to motor neurone production in vitro and recent progress in the application of stem cells to the treatment and understanding of motor neurone disease.}, }
@article {pmid17853944, year = {2007}, author = {Marden, JJ and Harraz, MM and Williams, AJ and Nelson, K and Luo, M and Paulson, H and Engelhardt, JF}, title = {Redox modifier genes in amyotrophic lateral sclerosis in mice.}, journal = {The Journal of clinical investigation}, volume = {117}, number = {10}, pages = {2913-2919}, pmid = {17853944}, issn = {0021-9738}, support = {DK54759/DK/NIDDK NIH HHS/United States ; DK067928/DK/NIDDK NIH HHS/United States ; T32 GM007337/GM/NIGMS NIH HHS/United States ; P30 DK054759/DK/NIDDK NIH HHS/United States ; R01 DK067928/DK/NIDDK NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Animals ; Disease Progression ; Female ; Gene Deletion ; Humans ; Male ; Membrane Glycoproteins/analysis/*antagonists &amp; inhibitors/genetics ; Mice ; Mice, Knockout ; NADH, NADPH Oxidoreductases/analysis/*antagonists &amp; inhibitors/genetics ; NADPH Oxidase 1 ; NADPH Oxidase 2 ; NADPH Oxidases/analysis/*antagonists &amp; inhibitors/genetics ; Oxidation-Reduction ; Oxidative Stress/genetics ; Spinal Cord/enzymology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS), one of the most common adult-onset neurodegenerative diseases, has no known cure. Enhanced redox stress and inflammation have been associated with the pathoprogression of ALS through a poorly defined mechanism. Here we determined that dysregulated redox stress in ALS mice caused by NADPH oxidases Nox1 and Nox2 significantly influenced the progression of motor neuron disease caused by mutant SOD1(G93A) expression. Deletion of either Nox gene significantly slowed disease progression and improved survival. However, 50% survival rates were enhanced significantly more by Nox2 deletion than by Nox1 deletion. Interestingly, female ALS mice containing only 1 active X-linked Nox1 or Nox2 gene also had significantly delayed disease onset, but showed normal disease progression rates. Nox activity in spinal cords from Nox2 heterozygous female ALS mice was approximately 50% that of WT female ALS mice, suggesting that random X-inactivation was not influenced by Nox2 gene deletion. Hence, chimerism with respect to Nox-expressing cells in the spinal cord significantly delayed onset of motor neuron disease in ALS. These studies define what we believe to be new modifier gene targets for treatment of ALS.}, }
@article {pmid17852022, year = {2007}, author = {Ajroud-Driss, S and Saeed, M and Khan, H and Siddique, N and Hung, WY and Sufit, R and Heller, S and Armstrong, J and Casey, P and Siddique, T and Lukas, TJ}, title = {Riluzole metabolism and CYP1A1/2 polymorphisms in patients with ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {8}, number = {5}, pages = {305-309}, doi = {10.1080/17482960701500650}, pmid = {17852022}, issn = {1748-2968}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*blood/drug therapy/*genetics ; Analysis of Variance ; Chromatography, High Pressure Liquid ; Chromosomes, Human, Pair 5 ; Cytochrome P-450 CYP1A1/*genetics ; Cytochrome P-450 CYP1A2/*genetics ; Female ; Genotype ; Humans ; Male ; Mass Spectrometry ; Middle Aged ; Neuroprotective Agents/*blood/therapeutic use ; Pharmacogenetics ; *Polymorphism, Single Nucleotide ; Riluzole/*blood/therapeutic use ; }, abstract = {Riluzole is the only FDA approved drug for the treatment of amyotrophic lateral sclerosis. Riluzole is assumed to be mainly metabolized by the liver cytochrome CYP1A2 and by the extra-hepatic cytochrome CYP1A1. CYP1A2 and CYP1A1 genetic polymorphisms are known, but their relationship to riluzole metabolism in ALS patients has not been investigated. The aim of this study was to determine whether the polymorphisms of the CYP1A2 and the CYP1A1 genes in ALS patients are associated with riluzole metabolic profiles. Thirty-two patients with a diagnosis of probable or definite ALS and who were on riluzole, participated in the study. Trough and peak plasma riluzole levels were measured using analytical chromatography-mass spectrometry methods. Association of the genotypes of the SNPs spanning the CYP1A1 and CYP1A2 genes (including one SNP in the intergenic region) with mean riluzole peak and trough levels was studied using ANOVA and Tukey's HSD. The mean peak riluzole level was 202+/-111 ng/ml and mean trough level 54.3+/-37.5 ng/ml. Our data do not support any association of the four CYP1A1 and CYP1A2 polymorphisms with the riluzole metabolic profile. In conclusion, genetic variations in CYP1A1 and CYP1A2 genes do not seem to influence riluzole levels. Further work is needed to better understand the genetic regulation of CYP1A enzymes and their role in riluzole metabolism.}, }
@article {pmid17852017, year = {2007}, author = {Gordon, PH and Cheng, B and Montes, J and Doorish, C and Albert, SM and Mitsumoto, H}, title = {Outcome measures for early phase clinical trials.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {8}, number = {5}, pages = {270-273}, doi = {10.1080/17482960701547958}, pmid = {17852017}, issn = {1748-2968}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Clinical Trials as Topic/*methods ; Double-Blind Method ; Glatiramer Acetate ; Humans ; Immunosuppressive Agents/*therapeutic use ; *Outcome Assessment, Health Care ; Pain Measurement ; Peptides/*therapeutic use ; Proportional Hazards Models ; Prospective Studies ; Reproducibility of Results ; Research Design ; Severity of Illness Index ; }, abstract = {As the number of potential neuroprotective agents for ALS increases, the need for early phase trials that screen drugs before proceeding to efficacy trials also grows. However, it is not known which outcome measures perform best and also provide the most meaningful information in brief small trials. We assessed the performance of different outcome measures for use in early phase clinical trials in ALS, and determined what degree of change in the ALSFRS-R that patients could perceive. Thirty patients underwent six monthly ALS Functional Rating Scale (ALSFRS-R), forced vital capacity, manual muscle testing (MMT) and quality of life assessments. Patients rated their perceived level of change with algorithm scales. Linear mixed effects models assessed the associations among variables and Cox proportional-hazards models examined the ability to predict survival. The quantity of missing data was assessed using descriptive statistics. Correlations were found between all variables. The ALSFRS-R provided the most complete data (99.5%), showed a large within-subject correlation (0.91), and best predicted survival (p = 0.002). One-unit change in patient-perceived clinical function paralleled a 9-point decrease in the ALSFRS-R (p = 0.025; 95% CI 8, 10). This trial assessed just 30 patients over six months, but the standard outcome measures each performed dependably; all could be used in short-duration, early phase trials. The ALSFRS-R most strongly predicted survival and provided the most complete data, but large changes may be necessary before patients perceive treatment effects.}, }
@article {pmid17852016, year = {2007}, author = {Groeneveld, GJ and Graf, M and van der Tweel, I and van den Berg, LH and Ludolph, AC}, title = {Alternative trial design in amyotrophic lateral sclerosis saves time and patients.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {8}, number = {5}, pages = {266-269}, doi = {10.1080/17482960701419497}, pmid = {17852016}, issn = {1748-2968}, mesh = {Amyotrophic Lateral Sclerosis/*economics/*therapy ; Clinical Trials as Topic/*economics/methods ; Confidence Intervals ; Double-Blind Method ; Humans ; Odds Ratio ; *Research Design ; Retrospective Studies ; Sample Size ; Survival Analysis ; Time Factors ; Vitamin E/*therapeutic use ; }, abstract = {A sequential trial design is an alternative for the classical trial design with a fixed sample size, that permits stopping a trial as soon as enough evidence for a treatment effect, or a lack thereof, is obtained. This study aimed to determine the difference in efficiency of time and patient number between a classical trial design and a sequential trial design. In this study we re-analysed a previously published classically designed clinical trial according to a sequential trial design. We subsequently determined the difference in total running time and patient number. We found that the sequential analysis offered a gain in time of 38%. We conclude that the sequential trial design may in certain situations be superior to the classical design.}, }
@article {pmid17848867, year = {2007}, author = {Werling, LL and Lauterbach, EC and Calef, U}, title = {Dextromethorphan as a potential neuroprotective agent with unique mechanisms of action.}, journal = {The neurologist}, volume = {13}, number = {5}, pages = {272-293}, doi = {10.1097/NRL.0b013e3180f60bd8}, pmid = {17848867}, issn = {1074-7931}, mesh = {Animals ; Clinical Trials as Topic ; Dextromethorphan/pharmacokinetics/*pharmacology/therapeutic use ; Humans ; Nervous System Diseases/drug therapy ; *Neuroprotective Agents ; Receptors, N-Methyl-D-Aspartate/drug effects ; Trauma, Nervous System/drug therapy ; }, abstract = {BACKGROUND: Dextromethorphan (DM) is a widely-used antitussive. DM's complex central nervous system (CNS) pharmacology became of interest when it was discovered to be neuroprotective due to its low-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonism.<br><br>REVIEW SUMMARY: Mounting preclinical evidence has proven that DM has important neuroprotective properties in various CNS injury models, including focal and global ischemia, seizure, and traumatic brain injury paradigms. Many of these protective actions seem functionally related to its inhibitory effects on glutamate-induced neurotoxicity via NMDA receptor antagonist, sigma-1 receptor agonist, and voltage-gated calcium channel antagonist actions. DM's protection of dopamine neurons in parkinsonian models may be due to inhibition of neurodegenerative inflammatory responses. Clinical findings are limited, with preliminary evidence indicating that DM protects against neuronal damage. Negative findings seem to relate to attainment of inadequate DM brain concentrations. Small studies have shown some promise for treatment of perioperative brain injury, amyotrophic lateral sclerosis, and symptoms of methotrexate neurotoxicity. DM safety/tolerability trials in stroke, neurosurgery, and amyotrophic lateral sclerosis patients demonstrated a favorable safety profile. DM's limited clinical benefit is proposed to be associated with its rapid metabolism to dextrorphan, which restricts its central bioavailability and therapeutic utility. Systemic concentrations of DM can be increased via coadministration of low-dose quinidine (Q), which reversibly inhibits its first-pass elimination. Potential drug interactions with DM/Q are discussed.<br><br>CONCLUSIONS: Given the compelling preclinical evidence for neuroprotective properties of DM, initial clinical neuroprotective findings, and clinical demonstrations that the DM/Q combination is well tolerated, this strategy may hold promise for the treatment of various acute and degenerative neurologic disorders.}, }
@article {pmid17847666, year = {2007}, author = {Robinson-Smith, G and Grill, JD}, title = {Recognizing involuntary emotional expression disorder.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {39}, number = {4}, pages = {202-207}, doi = {10.1097/01376517-200708000-00003}, pmid = {17847666}, issn = {0888-0395}, mesh = {*Affect ; Amyotrophic Lateral Sclerosis/epidemiology/psychology ; Brain Injuries/epidemiology/psychology ; Crying ; Diagnosis, Differential ; Drug Therapy ; *Expressed Emotion ; Humans ; Laughter ; Mood Disorders/*diagnosis/epidemiology/psychology ; Multiple Sclerosis/epidemiology/psychology ; Patient Education as Topic ; *Recognition, Psychology ; Self Care ; Teaching/methods ; *Volition ; }, abstract = {Involuntary crying or laughing are symptoms of a condition known as involuntary emotional expression disorder (IEED). This disorder is common among patients with stroke and other neurological disorders, such as multiple sclerosis, amyotrophic lateral sclerosis, and traumatic brain injury. Despite its prevalence, this condition is underrecognized and consequently undertreated in neurological settings. IEED can become disabling for patients who are not accurately diagnosed and treated. Differential diagnosis depends on recognition of the condition as an affective disorder and on its delineation from unipolar depression and other major psychiatric disorders. Clinical evaluation is essential for effective nursing care of this disorder. When the condition is found to be present, effective management must include education, pharmacological treatment, and teaching of self-care strategies. As patient advocates, neuroscience nurses are in a unique position to identify and assess such patients and to effectively guide patients and families in the management of this condition.}, }
@article {pmid17805244, year = {2007}, author = {Heneka, MT and Landreth, GE and Hüll, M}, title = {Drug insight: effects mediated by peroxisome proliferator-activated receptor-gamma in CNS disorders.}, journal = {Nature clinical practice. Neurology}, volume = {3}, number = {9}, pages = {496-504}, doi = {10.1038/ncpneuro0586}, pmid = {17805244}, issn = {1745-8358}, support = {AG16740/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Central Nervous System Diseases/*drug therapy/*metabolism ; Humans ; PPAR gamma/agonists/*physiology ; Pharmaceutical Preparations/*administration &amp; dosage/metabolism ; }, abstract = {The finding that activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) suppresses inflammation in peripheral macrophages and in models of human autoimmune disease instigated the evaluation of this salutary action for the treatment of CNS disorders with an inflammatory component. The fact that NSAIDs delay the onset of and reduce the risk of developing Alzheimer's disease (AD), while also binding to and activating PPARgamma, led to the hypothesis that one dimension of NSAID protection in AD is mediated by PPARgamma. Several lines of evidence from experiments using AD-related transgenic cellular and animal models have supported this hypothesis. The capacity of PPARgamma agonists to elicit anti-inflammatory, anti-amyloidogenic and insulin-sensitizing effects might account for their observed protective effects. Several clinical trials employing PPARgamma agonists have yielded promising results, and further trials are in preparation. Positive outcomes following PPARgamma administration have been obtained in animal models of other neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, both of which are associated with a considerable degree of neuroinflammation. Finally, activation of PPARgamma has been found to be protective in several models of multiple sclerosis. The verification of these findings in human cells prompted the initiation of clinical studies evaluating PPARgamma activation in patients with multiple sclerosis.}, }
@article {pmid17786603, year = {2007}, author = {Zhao, CP and Zhang, C and Zhou, SN and Xie, YM and Wang, YH and Huang, H and Shang, YC and Li, WY and Zhou, C and Yu, MJ and Feng, SW}, title = {Human mesenchymal stromal cells ameliorate the phenotype of SOD1-G93A ALS mice.}, journal = {Cytotherapy}, volume = {9}, number = {5}, pages = {414-426}, doi = {10.1080/14653240701376413}, pmid = {17786603}, issn = {1465-3249}, mesh = {Amyotrophic Lateral Sclerosis/genetics/physiopathology/*therapy ; Animals ; Brain/cytology/physiopathology ; Cell Differentiation/physiology ; Cell Survival/physiology ; Cells, Cultured ; Disease Models, Animal ; Graft Survival/physiology ; Humans ; Injections, Intravenous ; Male ; Mesenchymal Stem Cell Transplantation/*methods ; Mice ; Mice, Transgenic ; Motor Neurons/cytology/enzymology ; Neuroglia/cytology/physiology ; Recovery of Function/physiology ; Risk Assessment ; Spinal Cord/cytology/physiopathology ; Stromal Cells/*physiology/*transplantation ; Superoxide Dismutase/*genetics ; Transplantation, Heterologous ; Treatment Outcome ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, neurodegenerative disease, currently without any effective therapy. Multiple advantages make mesenchymal stromal cells (MSC) a good candidate for cellular therapy in many intractable diseases such as stroke and brain injury. Until now, no irrefutable evidence exists regarding the outcome of MSC transplantation in the mouse model of ALS. The present study was designed to investigate the therapeutic potential of human MSC (hMSC) in the mouse model of ALS (SOD1-G93A mice).<br><br>METHODS: hMSC were isolated from iliac crest aspirates from healthy donors and kept in cell cultures. hMSC of the fifth passage were delivered intravenously into irradiated pre-symptomatic SOD1-G93A mice. Therapeutic effects were analyzed by survival analysis, rotarod test, motor neuron count in spinal cord and electrophysiology. The engraftment and in vivo differentiation of hMSC were examined in the brain and spinal cord of hMSC-transplanted mice.<br><br>RESULTS: After intravenous injection into irradiated pre-symptomatic SOD1-G93A mice, hMSC survived more than 20 weeks in recipient mice, migrated into the parenchyma of brain and spinal cord and showed neuroglia differentiation. Moreover, hMSC-transplanted mice showed significantly delayed disease onset (14 days), increased lifespan (18 days) and delayed disease progression compared with untreated mice.<br><br>DISCUSSION: Our data document the positive effects of hMSC transplantation in the mouse model of ALS. It may signify the potential use of hMSC in treatment of ALS.}, }
@article {pmid17726072, year = {2007}, author = {Domené, HM and Scaglia, PA and Lteif, A and Mahmud, FH and Kirmani, S and Frystyk, J and Bedecarrás, P and Gutiérrez, M and Jasper, HG}, title = {Phenotypic effects of null and haploinsufficiency of acid-labile subunit in a family with two novel IGFALS gene mutations.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {92}, number = {11}, pages = {4444-4450}, doi = {10.1210/jc.2007-1152}, pmid = {17726072}, issn = {0021-972X}, mesh = {Adolescent ; Blotting, Western ; Body Weight/physiology ; Carbohydrate Metabolism/genetics ; Carrier Proteins/*genetics ; Chromatography, Gel ; DNA Mutational Analysis ; Female ; Glycoproteins/deficiency/*genetics ; Gonadal Steroid Hormones/blood ; Growth/genetics/physiology ; Growth Disorders/*genetics ; Humans ; Insulin/blood ; Insulin-Like Growth Factor Binding Protein 3/metabolism ; Insulin-Like Growth Factor I/metabolism ; Lipids/blood ; Male ; Mutation/*genetics ; Phenotype ; Puberty/genetics/physiology ; }, abstract = {CONTEXT: IGF-I deficiency may result from impairment of GH secretion or action, or from defects in IGF-I synthesis, transport, or action. Complete deficiency of the acid-labile subunit (ALS), previously described in two male patients, the only known inherited alteration in IGF-I transport, is characterized by severe circulating IGF-I and IGF binding protein (IGFBP)-3 deficiency with only mild growth retardation.<br><br>OBJECTIVE: Our objective was to study the characterization, at biochemical and molecular levels, of the cause for severe circulating IGF-I and IGFBP-3 deficiency in a male patient with mild growth retardation.<br><br>PATIENTS: We report an adolescent male with delayed growth and pubertal development (Tanner stage I, -2.00 sd score for height at the age of 15.3 yr), profound circulating IGF-I and IGFBP-3 deficiency, and poor response to GH treatment.<br><br>RESULTS: The index case, as well as one of his brothers, and his sister were found to be compound heterozygotes for two novel IGFALS gene mutations: C540R, a missense point mutation; and S195_197Rdup, a 9-bp duplication. The parents and youngest brother were found to be carriers for one of these two mutations. The three affected siblings had marked reduction of IGF-I and IGFBP-3 levels, undetectable serum levels of ALS, inability to form ternary complexes, and moderate insulin resistance. All of them attained a normal near-adult height (between -1.0 and -0.5 sd score), which was nonetheless lower than that of their heterozygous brother. The IGF system was only modestly affected in the heterozygous carriers.<br><br>CONCLUSIONS: This study confirms the critical role of ALS in forming ternary complexes and the maintenance of normal levels of IGF-I and IGFBP-3. Insulin resistance, pubertal delay in male patients, and poor GH responsiveness seem to be frequent findings in ALS deficiency. However, haploinsufficiency of the IGFALS gene has no discernible clinical effects with only modest impact on the IGF system.}, }
@article {pmid17724975, year = {2007}, author = {Bufler, J}, title = {[Diagnosis and treatment of amyotrophic lateral sclerosis].}, journal = {MMW Fortschritte der Medizin}, volume = {149 Suppl 2}, number = {}, pages = {84-87}, pmid = {17724975}, issn = {1438-3276}, mesh = {Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/mortality/physiopathology/therapy ; Diagnosis, Differential ; Disease Progression ; Electromyography ; Humans ; Incidence ; Middle Aged ; Neurologic Examination ; Prevalence ; Time Factors ; }, abstract = {Like Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which a very defined population of neurons selectively degenerates. Muscular atrophy and central paresis develop in ALS patients relatively quickly--usually within months to a few years. Bulbar symptoms such as swallowing disorders and dysarthria are frequently observed in the beginning. The disease progresses steadily and without remission. The average length of survival after diagnosis is two to three years. The diagnosis is made on the basis of a characteristic group of symptoms and confirmed or substantiated through additional clinical neurological tests. Currently, the cause of the disease cannot be treated. Treatment concentrates primarily on symptomatic measures and providing supportive devices.}, }
@article {pmid17719172, year = {2007}, author = {Praline, J and Guennoc, AM and Limousin, N and Hallak, H and de Toffol, B and Corcia, P}, title = {ALS and mercury intoxication: a relationship?.}, journal = {Clinical neurology and neurosurgery}, volume = {109}, number = {10}, pages = {880-883}, doi = {10.1016/j.clineuro.2007.07.008}, pmid = {17719172}, issn = {0303-8467}, mesh = {Activities of Daily Living/classification ; Aged, 80 and over ; Chelating Agents/therapeutic use ; Chronic Disease ; Disease Progression ; Fatal Outcome ; Female ; Humans ; Mercury/urine ; Mercury Poisoning/*complications/diagnosis/drug therapy/pathology ; Motor Neuron Disease/*chemically induced/diagnosis/drug therapy/pathology ; Motor Neurons/drug effects/pathology ; Neurologic Examination ; Succimer/therapeutic use ; }, abstract = {We report the case of an 81-year-old woman in whom clinical signs and features of electromyographic activity patterns were consistent with amyotrophic lateral sclerosis (ALS). Increased blood level and massive urinary excretion of mercury proved mercury intoxication. Despite a chelation treatment with Meso 2-3 dimercaptosuccininc acid (DMSA), she died after 17 months. The pathophysiology of sporadic ALS remains unclear. However, the role of environmental factors has been suggested. Among some environmental factors, exposure to heavy metals has been considered and ALS cases consecutive to occupational intoxication and accidental injection of mercury have been reported. Although no autopsy was performed, we discuss the role of mercury intoxication in the occurrence of ALS in our case, considering the results of experimental studies on the toxicity of mercury for motor neuron.}, }
@article {pmid17716658, year = {2007}, author = {Glas, M and Popp, B and Angele, B and Koedel, U and Chahli, C and Schmalix, WA and Anneser, JM and Pfister, HW and Lorenzl, S}, title = {A role for the urokinase-type plasminogen activator system in amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {207}, number = {2}, pages = {350-356}, doi = {10.1016/j.expneurol.2007.07.007}, pmid = {17716658}, issn = {0014-4886}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/mortality/*pathology/physiopathology ; Analysis of Variance ; Animals ; Caseins/metabolism ; Disease Models, Animal ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation/drug effects/*genetics ; Mice ; Mice, Transgenic ; Motor Activity/drug effects/physiology ; Peptides, Cyclic/pharmacology ; Receptors, Cell Surface/*metabolism ; Receptors, Urokinase Plasminogen Activator ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Spinal Cord/metabolism ; Superoxide Dismutase/genetics ; Survival ; Urokinase-Type Plasminogen Activator/antagonists &amp; inhibitors/*metabolism ; }, abstract = {There is substantial evidence, implicating extracellular matrix (ECM) regulating enzymes in the pathogenesis of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The most important ECM-degrading proteases are serine proteases (plasminogen activators, PA) and matrix metalloproteinases (MMPs). Since the role of MMPs in ALS has been addressed recently, we investigated the expression of the serine protease urokinase-type plasminogen activator (uPA) and its receptor in ALS. Employing rtPCR, zymography and immunohistochemistry we analyzed the expression of uPA and its receptor uPAR in spinal cord tissue of ALS cases and in the G93A SOD1 transgenic mouse. In the ventral horn of the spinal cord of ALS cases we found increased uPAR staining of motor neurons. In G93A mice, the expression profile of uPA and uPAR mRNA was significantly increased starting at the age of 90 days as compared to non-transgenic littermates. The uPA-dependent plasminogen activation in G93A mice at endstage increased markedly compared with controls and immunostaining of the spinal cord from G93A mice revealed increased uPAR immunostaining in neurons. To determine the functional role of uPA, we investigated the effect of intraperitoneal (i.p.) administration of the uPA inhibitor WX-340 (10 mg/kg), starting at the age of 30 days (n=18). Treatment with WX-340 prolonged (p<0.05) survival of the animals (135+/-2 vs. 126+/-3) as well as improving rotarod performance. Our experiments demonstrate that uPA and its receptor are expressed in ALS patients and in an animal model of ALS. Early inhibition with a synthetic uPA inhibitor prolonged the life of the transgenic animals. These findings indicate that the urokinase-type plasminogen activator system may play a role in the complex pathogenesis of ALS.}, }
@article {pmid17714844, year = {2008}, author = {Sofuoglu, M and Waters, AJ and Mooney, M and Kosten, T}, title = {Riluzole and D-amphetamine interactions in humans.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {32}, number = {1}, pages = {16-22}, pmid = {17714844}, issn = {0278-5846}, support = {P50-DA 12762/DA/NIDA NIH HHS/United States ; K01-DA 19466/DA/NIDA NIH HHS/United States ; P50 DA012762/DA/NIDA NIH HHS/United States ; R01 DA014537/DA/NIDA NIH HHS/United States ; R01-DA 14537/DA/NIDA NIH HHS/United States ; P50 DA018197-010003/DA/NIDA NIH HHS/United States ; K01 DA019446/DA/NIDA NIH HHS/United States ; K05 DA000454/DA/NIDA NIH HHS/United States ; K12 00167//PHS HHS/United States ; P50 DA018197/DA/NIDA NIH HHS/United States ; K05-DA0454/DA/NIDA NIH HHS/United States ; }, mesh = {Adult ; Area Under Curve ; Blood Pressure/drug effects ; Central Nervous System Stimulants/*pharmacology ; Cognition/drug effects ; Cross-Over Studies ; Dextroamphetamine/*pharmacology ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Interactions/*physiology ; Female ; Heart Rate/drug effects ; Humans ; Hydrocortisone/blood ; Male ; Neuropsychological Tests ; Outcome Assessment, Health Care/methods ; Reaction Time/drug effects ; Riluzole/*pharmacology ; Time Factors ; }, abstract = {In preclinical studies, medications which decrease glutamate release have been shown to block some of the effects of psychostimulants. One such medication is riluzole, marketed for the treatment of Amyotrophic Lateral Sclerosis (ALS). The goal of this study was to determine riluzole's effects on acute physiological and subjective responses to d-amphetamine in healthy volunteers. Seven male and 5 female subjects participated in an outpatient double-blind, placebo-controlled, crossover study. Across 4 sessions, subjects were randomly assigned to a sequence of 4 oral treatments: placebo, 20 mg D-amphetamine alone, 100 mg riluzole alone, or d-amphetamine plus riluzole. Outcome measures included heart rate, blood pressure, plasma cortisol, performance on the Sustained Attention to Response Test (SART), and subjective measures. d-amphetamine increased heart rate, blood pressure and plasma cortisol levels while inducing psychostimulant-type subjective effects. On the SART, d-amphetamine enhanced the speed of correct responses but also significantly increased the number of errors of commission. Riluzole at 100 mg did not block, the typical subjective and physiological responses to 20 mg D-amphetamine. Riluzole alone induced amphetamine-like subjective responses. On the SART test, riluzole increased the number errors of commission, but unlike d-amphetamine, did not speed reaction time. The mechanism accounting for these findings is unclear, but may involve processes other than decreased glutamate release by riluzole. The effects of glutamate medications on psychostimulant responses need to be further examined.}, }
@article {pmid17712161, year = {2007}, author = {Irwin, D and Lippa, CF and Swearer, JM}, title = {Cognition and amyotrophic lateral sclerosis (ALS).}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {22}, number = {4}, pages = {300-312}, pmid = {17712161}, issn = {1533-3175}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/pathology/therapy ; Cognition Disorders/diagnosis/*epidemiology/therapy ; Cognitive Behavioral Therapy ; Combined Modality Therapy ; Frontal Lobe/pathology ; Humans ; Neuropsychological Tests ; Severity of Illness Index ; Temporal Lobe/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is classically described as a pure motor disease; however, there is growing evidence of a range of cognitive impairment. Cognitive abnormalities include deficiencies in frontal executive skills, varying from mild deficits to meeting criteria for diagnosis of frontotemporal dementia (FTD). Cognitive impairment occurs in sporadic and familial forms of ALS. Patients may present with cognitive deficits before, after, or at the onset of motor neuron disease. Structural and functional imaging studies have shown extramotor cortical degeneration corresponding to levels of frontal executive impairment on neuropsychologic testing. In addition, ALS and a subset of FTD patients display common pathological findings on immunohistochemistry staining. It is believed that these disorders represent a continuum between motor and nonmotor cortical degeneration. The purpose of this article is to review the literature on cognitive deficits in ALS. Identifying changes in cognition is critical for physicians and caregivers of ALS patients, as cognitive decline may interfere with patient compliance. Diagnosis and treatment of cognitive symptoms in ALS patients may improve quality of life.}, }
@article {pmid17709710, year = {2007}, author = {Miller, R and Bradley, W and Cudkowicz, M and Hubble, J and Meininger, V and Mitsumoto, H and Moore, D and Pohlmann, H and Sauer, D and Silani, V and Strong, M and Swash, M and Vernotica, E and , }, title = {Phase II/III randomized trial of TCH346 in patients with ALS.}, journal = {Neurology}, volume = {69}, number = {8}, pages = {776-784}, doi = {10.1212/01.wnl.0000269676.07319.09}, pmid = {17709710}, issn = {1526-632X}, mesh = {Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy ; Apoptosis/*drug effects/physiology ; Central Nervous System/drug effects/enzymology/physiopathology ; Dose-Response Relationship, Drug ; Double-Blind Method ; Enzyme Inhibitors/administration &amp; dosage/adverse effects ; Female ; Glyceraldehyde-3-Phosphate Dehydrogenases/antagonists &amp; inhibitors/metabolism ; Humans ; Male ; Middle Aged ; Nerve Degeneration/*drug therapy/enzymology/prevention &amp; control ; Neuroprotective Agents/administration &amp; dosage/adverse effects ; Oxepins/*administration &amp; dosage/adverse effects ; Placebo Effect ; Treatment Failure ; }, abstract = {BACKGROUND: TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS.<br><br>METHODS: Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patient's rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT).<br><br>RESULTS: Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT).<br><br>CONCLUSION: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.}, }
@article {pmid17704740, year = {2007}, author = {Potebnya, GP and Kudryavets, YY and Lisovenko, GS and Cheremshenko, NL and Voeykova, IM and Trokhimenko, NV and Symchich, TV and Evstrateyva, LM}, title = {Experimental study of the efficacy of combined use of cancer vaccine and interferon.}, journal = {Experimental oncology}, volume = {29}, number = {2}, pages = {102-105}, pmid = {17704740}, issn = {1812-9269}, mesh = {Animals ; Cancer Vaccines/administration &amp; dosage/*therapeutic use ; Carcinoma, Lewis Lung/immunology/*therapy ; Cytotoxicity Tests, Immunologic ; Drug Synergism ; Drug Therapy, Combination ; Interferon-alpha/administration &amp; dosage/*therapeutic use ; Interleukin-1/blood ; Interleukin-2/blood ; Killer Cells, Natural/drug effects ; Lung Neoplasms/immunology/*therapy ; Lymphocyte Activation/drug effects/immunology ; Macrophage Activation/drug effects/immunology ; Macrophages, Peritoneal/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Neoplasm Transplantation ; Survival Rate ; T-Lymphocytes, Cytotoxic/drug effects ; Time Factors ; Transplantation, Homologous ; Tumor Burden/drug effects ; Tumor Necrosis Factor-alpha/biosynthesis ; }, abstract = {AIM: To study in in vivo model the efficacy of combined scheme of administration of cancer vaccine (CV) and interferon (IFN).<br><br>MATERIALS AND METHODS: Lewis lung carcinoma (LLC) was transplanted to male C57Bl mice. For treatment, CV prepared from LLC cells with the use of cytotoxic lectins of B. subtilis B-7025, and preparation of murine IFN-alpha were used. Therapeutic effect was evaluated by measurement of tumor volume and analysis of average life span (ALS) of treated animals. Immunologic study included determination of antitumor cytotoxicity of T-lymphocytes (CTL) and natural killer (NK) cells by radiometric method, functional activity of peritoneal macrophages (MP) - by colorimetric test with nitroazole blue, and evaluation of titers of tumor necrosis factor (TNF) and interleukins-1 and -2 (IL-1, 2).<br><br>RESULTS: It has been shown that the use of IFN preparation significantly elevated efficacy of vaccine therapy of solid form of LLC: duration of latent period of tumor growth elevated by 25%, ALS - by 28%, index of tumor growth inhibition - by 35-40%. Upon combined use of CV and IFN, significant activation of the cells - effectors of nonspecific immune defense (MP), and specific one (CTL) was observed.<br><br>CONCLUSION: The obtained results evidence on perspectiveness of the development of combined schemes of administration of CV and IFN for elevation of the efficacy of vaccine therapy.}, }
@article {pmid17697791, year = {2007}, author = {Hosback, S and Hardiman, O and Nolan, CM and Doyle, MA and Gorman, G and Lynch, C and O'Toole, O and Jakeman, P}, title = {Circulating insulin-like growth factors and related binding proteins are selectively altered in amyotrophic lateral sclerosis and multiple sclerosis.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {17}, number = {6}, pages = {472-479}, doi = {10.1016/j.ghir.2007.06.002}, pmid = {17697791}, issn = {1096-6374}, support = {MC_G0802536/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/blood/*metabolism ; Body Mass Index ; Female ; Humans ; Insulin-Like Growth Factor Binding Proteins/*blood ; Insulin-Like Growth Factor I/*metabolism ; Insulin-Like Growth Factor II/*metabolism ; Male ; Middle Aged ; Multiple Sclerosis/blood/*metabolism ; Reference Values ; Somatomedins/*metabolism ; }, abstract = {OBJECTIVE: To provide a detailed profile of the peripheral IGF system in the neurological conditions; amyotrophic lateral sclerosis (ALS), post polio syndrome (PPS) and multiple sclerosis (MS). To determine whether subsets of patients within the disease groups could be identified in whom one or more components of the IGF regulatory system are altered compared to healthy control subjects matched for age, sex and BMI.<br><br>DESIGN: Three cohorts of patients were recruited, 28 with ALS, 18 with PPS and 23 with MS. Patients were individually matched to a healthy control based on sex, age (+/-3 yr), and BMI (+/-2.5 kg m(-2)). The concentration (ng/ml) of serum IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and acid-labile subunit (microg/ml) was determined by IRMA.<br><br>RESULTS: In ALS patients, there was an increase of 11% in [IGF(TOTAL)] (p=0.042) ([IGF(TOTAL)]=[IGF-I]+[IGF-II]) and [IGFBP-1] was decreased by 34% (p=0.050) compared to matched controls. In "surviving" ALS patients, defined as those ALS patients with long disease duration (+2 SD from the mean survival time for Irish patients post diagnosis), there was an increase in [IGF-I] 36% (p=0.032) and a large decrease in [IGFBP-1] -58% (p=0.020) compared to controls. These differences were not evident in pre-agonal ALS patients. The concentration of serum IGF-I was 38% (p=0.018), acid-labile subunit 17% (p=0.044) and IGFBP-2 43% (p=0.035) higher in MS patients compared to controls. When stratified for interferon-beta (IFN-beta) use, we observed an increase in serum [IGF-I] 52% (p=0.013) and [IGF(TOTAL)] 19% (p=0.043) in MS patients undergoing IFN-beta treatment, but MS patients not undergoing IFN-beta treatment had similar IGF and IGFBP concentration to controls. Serum [IGFBP-3] 18% (p=0.033), [IGFBP-2] 86% (p=0.015) and (acid-labile subunit) 33% (p=0.012) was also higher in IFN-beta patients compared to controls. Stratified by stage of disease the most significant increase in components of the peripheral IGF system was attributed to relapsing-remitting MS patients treated with IFN-beta. All components of the peripheral IGF system in PPS patients were similar to controls.<br><br>CONCLUSIONS: The increase in circulating IGF-I and a reduction in regulatory binding protein IGFBP-1 in ALS patients with a "stable" disease profile suggest a potential change in peripheral IGF bioavailability in these subjects. In MS, we report a change in a number of components of the peripheral IGF system, the observed increase in IGF-I in patients treated with IFN-beta being of most significance as a potential therapeutic biomarker.}, }
@article {pmid17691370, year = {2007}, author = {Panourias, IG and Themistocleous, M and Sakas, DE}, title = {Intrathecal baclofen in current neuromodulatory practice: established indications and emerging applications.}, journal = {Acta neurochirurgica. Supplement}, volume = {97}, number = {Pt 1}, pages = {145-154}, doi = {10.1007/978-3-211-33079-1_20}, pmid = {17691370}, issn = {0065-1419}, mesh = {Baclofen/*therapeutic use ; Electric Stimulation Therapy ; Electrodes, Implanted ; Humans ; Muscle Relaxants, Central/*therapeutic use ; Muscle Spasticity/*drug therapy/etiology/surgery ; Nervous System Diseases/complications ; Spinal Cord/drug effects/*physiology/radiation effects ; }, abstract = {Intrathecal baclofen (ITB) has evolved into a standard treatment for severe spasticity of both spinal and cerebral origin. The accumulated promising data from reported series of patients receiving ITB therapy together with the fact that spastic hypertonia commonly coexists with other neurological disorders have constituted a solid basis for offering this kind of treatment to patients suffering from other movement disorders. These include motor disorders such as dystonia, amyotrophic lateral sclerosis, status dystonicus, Hallervorden-Spatz disease, Freidreich's ataxia, "stiff-man" syndrome, but also vegetative states after revere brain trauma, anoxic encephalopathy or other pathology and more recently, various chronic pain syndromes. In this article, on the basis of the established applications of ITB therapy, we review the important emerging indications of this rewarding neuromodulation method and attempt to identify its future potential beneficial role in other chronic and otherwise refractory neurological disorders.}, }
@article {pmid17688194, year = {2007}, author = {Taylor, DM and Tradewell, ML and Minotti, S and Durham, HD}, title = {Characterizing the role of Hsp90 in production of heat shock proteins in motor neurons reveals a suppressive effect of wild-type Hsf1.}, journal = {Cell stress &amp; chaperones}, volume = {12}, number = {2}, pages = {151-162}, pmid = {17688194}, issn = {1355-8145}, mesh = {Animals ; Carrier Proteins/metabolism ; Co-Repressor Proteins ; DNA-Binding Proteins/*metabolism ; HSP40 Heat-Shock Proteins/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; HSP90 Heat-Shock Proteins/antagonists &amp; inhibitors/*metabolism ; Heat Shock Transcription Factors ; Humans ; Hyperthermia, Induced ; Intracellular Signaling Peptides and Proteins/metabolism ; Mice ; Molecular Chaperones ; Motor Neurons/cytology/*metabolism ; Nuclear Proteins/metabolism ; Promoter Regions, Genetic/genetics ; Transcription Factors/*metabolism ; Up-Regulation/genetics ; }, abstract = {Induction of heat shock proteins (Hsps) is under investigation as treatment for neurodegenerative disorders, yet many types of neurons, including motor neurons that degenerate in amyotrophic lateral sclerosis (ALS), have a high threshold for activation of the major transcription factor mediating stress-induced Hsp upregulation, heat shock transcription factor 1 (Hsf1). Hsf1 is tightly regulated by a series of inhibitory checkpoints that include sequestration in multichaperone complexes governed by Hsp90. This study examined the role of multichaperone complexes in governing the heat shock response in motor neurons. Hsp90 inhibitors induced expression of Hsp70 and Hsp40 and transactivation of a human inducible hsp70 promoter-green fluorescent protein (GFP) reporter construct in motor neurons of dissociated spinal cord-dorsal root ganglion (DRG) cultures. On the other hand, overexpression of activator of Hsp90 adenosine triphosphatase ([ATPase 1], Aha1), which should mobilize Hsf1 by accelerating turnover of mature, adenosine triphosphate-(ATP) bound Hsp90 complexes, and death domain-associated protein (Daxx), which in cell lines has been shown to promote transcription of heat shock genes by relieving inhibition exerted by interactions between nuclear Hsp90/multichaperone complexes and trimeric Hsf1, failed to induce Hsps in the absence or presence of heat shock. These results indicate that disruption of multichaperone complexes alone is not sufficient to activate the neuronal heat shock response. Furthermore, in motor neurons, induction of Hsp70 by Hsp90-inhibiting drugs was prevented by overexpression of wild-type Hsfl, contrary to what would be expected for a classical Hsf1-mediated pathway. These results point to additional differences in regulation of hsp genes in neuronal and nonneuronal cells.}, }
@article {pmid17686041, year = {2007}, author = {Wang, H and Guan, Y and Wang, X and Smith, K and Cormier, K and Zhu, S and Stavrovskaya, IG and Huo, C and Ferrante, RJ and Kristal, BS and Friedlander, RM}, title = {Nortriptyline delays disease onset in models of chronic neurodegeneration.}, journal = {The European journal of neuroscience}, volume = {26}, number = {3}, pages = {633-641}, doi = {10.1111/j.1460-9568.2007.05663.x}, pmid = {17686041}, issn = {0953-816X}, support = {NS039324/NS/NINDS NIH HHS/United States ; NS041635/NS/NINDS NIH HHS/United States ; NS045242/NS/NINDS NIH HHS/United States ; NS045806/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology ; Animals ; Antidepressive Agents, Tricyclic/pharmacology ; Apoptosis/drug effects/physiology ; Brain/*drug effects/metabolism/physiopathology ; Chronic Disease ; Disease Models, Animal ; Disease Progression ; Humans ; Huntington Disease/drug therapy/metabolism/physiopathology ; Male ; Membrane Potential, Mitochondrial/drug effects/physiology ; Mice ; Mice, Transgenic ; Mitochondria/*drug effects/metabolism ; Neurodegenerative Diseases/*drug therapy/metabolism/physiopathology ; Neurons/*drug effects/metabolism ; Neuroprotective Agents/*pharmacology ; Nortriptyline/*pharmacology ; Time Factors ; Treatment Outcome ; }, abstract = {This study was to characterize the neuroprotective effects of nortriptyline, a tricyclic antidepressant, in mouse models of chronic neurodegeneration [amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD)]. Nortriptyline was originally selected from a library screening of 1040 FDA-approved drugs by using isolated mitochondria. It emerged as a strong inhibitor of mitochondrial permeability transition (mPT). Our results showed that nortriptyline significantly delayed disease onset and extended the lifespan of ALS mice although its effect on mortality was less than that on onset. We also tested promethazine, another compound which emerged from the same screening, in ALS mice. Promethazine-treated ALS mice exhibited a significant delay in disease onset but not in mortality. Histochemistry analysis found that nortriptyline treatment indeed protected motor neurons from death and reduced ventral horn atrophy in ALS mice. Furthermore, release of cytochrome c and activation of caspase 3, two molecular phenomena associated with mitochondrial-pathway-mediated cell death, were inhibited by nortriptyline. We also demonstrated similar beneficial effects of nortriptyline in HD mice: it extended the presymptomatic portion of the disease but had no effect on mortality. In an established cellular model of HD, nortriptyline inhibited cell death and decreased loss of mitochondrial membrane potential. In summary, this study indicated the potential therapeutic usefulness of nortriptyline in ALS and HD. In addition, our data suggested a role for mPT in chronic neurodegeneration, particularly at the early rather than the advanced disease stages.}, }
@article {pmid17685869, year = {2007}, author = {Bhatt, JM and Gordon, PH}, title = {Current clinical trials in amyotrophic lateral sclerosis.}, journal = {Expert opinion on investigational drugs}, volume = {16}, number = {8}, pages = {1197-1207}, doi = {10.1517/13543784.16.8.1197}, pmid = {17685869}, issn = {1744-7658}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/epidemiology ; Animals ; Humans ; Randomized Controlled Trials as Topic/*methods/trends ; }, abstract = {Amyotrophic lateral sclerosis is caused by selective degeneration of motor neurons in the brain and spinal cord. There are still no other effective therapies 10 years after the approval of riluzole for the treatment of amyotrophic lateral sclerosis, but advances in drug development and screening are substantially increasing the number of potential therapeutic agents. This review provides an overview of clinical trial methodology in amyotrophic lateral sclerosis followed by a systematic evaluation of drugs that are presently in Phase I, II and III clinical trials. There is an emphasis on the scientific evidence supporting the selection of each drug being tested, as well as on trial design.}, }
@article {pmid17676652, year = {2008}, author = {Rosenblatt, A and Samus, QM and Onyike, CU and Baker, AS and McNabney, M and Mayer, LS and Brandt, J and Lyketsos, CG}, title = {Acetylcholinesterase inhibitors in assisted living: patterns of use and association with retention.}, journal = {International journal of geriatric psychiatry}, volume = {23}, number = {2}, pages = {178-184}, doi = {10.1002/gps.1859}, pmid = {17676652}, issn = {0885-6230}, support = {R01 MH 60626/MH/NIMH NIH HHS/United States ; }, mesh = {Activities of Daily Living ; Aged, 80 and over ; Alzheimer Disease/*drug therapy/psychology ; *Assisted Living Facilities ; Cholinesterase Inhibitors/*therapeutic use ; Dementia/drug therapy/psychology ; Donepezil ; Drug Administration Schedule ; Female ; Galantamine/therapeutic use ; Health Surveys ; Homes for the Aged ; Humans ; Indans/therapeutic use ; Male ; Mental Status Schedule ; Neuropsychological Tests ; Phenylcarbamates/therapeutic use ; Piperidines/therapeutic use ; Retention, Psychology ; Rivastigmine ; Survival Analysis ; Treatment Outcome ; }, abstract = {OBJECTIVES: To describe patterns of Acetylcholinesterase inhibitor (ACI) use in an Assisted Living (AL) population, and the association of ACIs with retention in AL.<br><br>METHODS: As part of the Maryland Assisted Living Study (MD-AL), 198 residents of 22 ALs were evaluated. Dementia was diagnosed in 134, and specifically Alzheimer's disease (AD) in 79, by an expert consensus panel. Data was collected on ACI agent and dose. Vital status and location were recorded every 6 months. Other data included age, duration of residence, general medical health rating (GHMR), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), Cornell Scale for Depression in Dementia (CSDD) and number of non-psychiatric medications.<br><br>RESULTS: The overall ACI treatment rate was 31%. 34.5% of participants with mild to moderate AD were taking ACIs. Only two in seven participants taking rivastigmine were taking an adequate dose. Participants with AD on ACI's did not differ significantly from those not on ACI's in any of the secondary measures except age and duration of residence, those on the agents being somewhat younger and more recently admitted. For participants with AD, only ACI use was significantly associated with retention in AL at 6 months, with a relative risk of death or discharge to higher level care of 0.217. Baseline MMSE was associated with retention for those with non-AD dementia. In a survival analysis ACI use was associated with 228.75 days longer retention in participants with AD.<br><br>CONCLUSION: ACIs have low rates of use in AL and are associated with better retention for residents with AD.}, }
@article {pmid17674406, year = {2008}, author = {Blanco, M and Bautista, M and Alcalá, M}, title = {Preparing calibration sets for use in pharmaceutical analysis by NIR spectroscopy.}, journal = {Journal of pharmaceutical sciences}, volume = {97}, number = {3}, pages = {1236-1245}, doi = {10.1002/jps.21105}, pmid = {17674406}, issn = {0022-3549}, mesh = {Calibration ; Pharmaceutical Preparations/*chemistry ; Spectroscopy, Near-Infrared/*methods ; }, abstract = {A new methodology for constructing calibration sets based on the use of laboratory samples encompassing the same variability sources as production samples was developed. The proposed methodology requires the use of no reference method in order to obtain reference values for the analyte; also, it provides more simple and robust calibration models than does the conventional methodology while retaining its predictive capacity. The procedure involves subjecting a set of laboratory samples spanning the desired API concentration range to a granulation treatment similar to that of the industrial process in order to obtain samples with the same physical variability as the production samples. The laboratory samples thus obtained are used to develop partial least squares (PLS1) calibration models in order to quantify the API in a pharmaceutical granulate. Based on the results obtained in this work, NIR spectroscopy is an effective alternative to the reference methods currently used for calibration. The proposed methodology requires no reference values to construct models; therefore, it can be regarded as an absolute analytical method. Also, it confirms the advantages of NIR spectroscopy as part of the process analytical technology (PAT) used by the pharmaceutical industry. A second aim has been the use of the multiplicative curve resolution-alternating least squares (MCR-ALS) algorithm to examine potential polymorphic transformations of the API during granulation.}, }
@article {pmid17672180, year = {2007}, author = {Buysschaert, I and Carmeliet, P and Dewerchin, M}, title = {Clinical and fundamental aspects of angiogenesis and anti-angiogenesis.}, journal = {Acta clinica Belgica}, volume = {62}, number = {3}, pages = {162-169}, doi = {10.1179/acb.2007.027}, pmid = {17672180}, issn = {1784-3286}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; Angiogenesis Inducing Agents/therapeutic use ; Angiogenesis Inhibitors/therapeutic use ; Angiopoietins/physiology ; Animals ; Cardiovascular Diseases/physiopathology ; Fibroblast Growth Factors/physiology ; Humans ; Myocardial Ischemia/drug therapy ; *Neovascularization, Pathologic/physiopathology ; *Neovascularization, Physiologic/physiology ; Peripheral Vascular Diseases/physiopathology ; Vascular Endothelial Growth Factor A/physiology ; }, abstract = {Insight into the fundamental physiological mechanisms of blood vessel development and neoformation has led to the discovery of multiple angiogenic growth factors and inhibitors. To date, at least 5 angiogenesis inhibitors are readily available for clinical use, mainly in the treatment of cancers and age-related macular degeneration. More inhibitors are yet to come and the indications for their clinical use are expected to broaden. Conversely, the use of angiogenic stimulators, although initially promising in animal models and in small uncontrolled pilot studies in patients with ischaemic heart disease or peripheral arterial occlusive disease, could thus far not show any convincing therapeutic improvement. Challenges still remain as to which angiogenic factor or combination of factors should be administered and in which form (protein versus gene), and what route and duration of administration should be used. Further clinical perspective might come from the recent identification of vascular endothelial growth factor (VEGF) as a modifier of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), and as a promising therapy in the treatment of ALS in preclinical animal models. This review discusses the different clinical trials of angiogenic inhibitors and stimulators, preceded by some fundamental aspects of angiogenesis, giving the clinician a brief overview of the most relevant angiogenic topics.}, }
@article {pmid17668067, year = {2007}, author = {Suzuki, M and McHugh, J and Tork, C and Shelley, B and Klein, SM and Aebischer, P and Svendsen, CN}, title = {GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS.}, journal = {PloS one}, volume = {2}, number = {8}, pages = {e689}, pmid = {17668067}, issn = {1932-6203}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/physiopathology ; Animals ; Astrocytes/cytology/metabolism ; Behavior, Animal/physiology ; Biomarkers/metabolism ; Cell Movement ; Cell Survival/physiology ; Cells, Cultured ; Female ; Fetus/cytology ; Genetic Vectors/genetics/metabolism ; Glial Cell Line-Derived Neurotrophic Factor/genetics/*metabolism ; Humans ; Lentivirus/genetics/metabolism ; Motor Activity/physiology ; Motor Neurons/cytology/*metabolism/pathology ; Muscles/*innervation ; Neuromuscular Junction/ultrastructure ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/cytology/pathology ; Stem Cell Transplantation ; Stem Cells/cytology/*physiology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by rapid loss of muscle control and eventual paralysis due to the death of large motor neurons in the brain and spinal cord. Growth factors such as glial cell line derived neurotrophic factor (GDNF) are known to protect motor neurons from damage in a range of models. However, penetrance through the blood brain barrier and delivery to the spinal cord remains a serious challenge. Although there may be a primary dysfunction in the motor neuron itself, there is also increasing evidence that excitotoxicity due to glial dysfunction plays a crucial role in disease progression. Clearly it would be of great interest if wild type glial cells could ameliorate motor neuron loss in these models, perhaps in combination with the release of growth factors such as GDNF.<br><br>Human neural progenitor cells can be expanded in culture for long periods and survive transplantation into the adult rodent central nervous system, in some cases making large numbers of GFAP positive astrocytes. They can also be genetically modified to release GDNF (hNPC(GDNF)) and thus act as long-term 'mini pumps' in specific regions of the rodent and primate brain. In the current study we genetically modified human neural stem cells to release GDNF and transplanted them into the spinal cord of rats over-expressing mutant SOD1 (SOD1(G93A)). Following unilateral transplantation into the spinal cord of SOD1(G93A) rats there was robust cellular migration into degenerating areas, efficient delivery of GDNF and remarkable preservation of motor neurons at early and end stages of the disease within chimeric regions. The progenitors retained immature markers, and those not secreting GDNF had no effect on motor neuron survival. Interestingly, this robust motor neuron survival was not accompanied by continued innervation of muscle end plates and thus resulted in no improvement in ipsilateral limb use.<br><br>CONCLUSIONS/SIGNIFICANCE: The potential to maintain dying motor neurons by delivering GDNF using neural progenitor cells represents a novel and powerful treatment strategy for ALS. While this approach represents a unique way to prevent motor neuron loss, our data also suggest that additional strategies may also be required for maintenance of neuromuscular connections and full functional recovery. However, simply maintaining motor neurons in patients would be the first step of a therapeutic advance for this devastating and incurable disease, while future strategies focus on the maintenance of the neuromuscular junction.}, }
@article {pmid17653923, year = {2007}, author = {Averill, AJ and Kasarskis, EJ and Segerstrom, SC}, title = {Psychological health in patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {8}, number = {4}, pages = {243-254}, doi = {10.1080/17482960701374643}, pmid = {17653923}, issn = {1748-2968}, mesh = {Amyotrophic Lateral Sclerosis/complications/epidemiology/*psychology ; Depression/epidemiology/etiology/*psychology ; Humans ; Mental Health/*statistics &amp; numerical data ; Prevalence ; Review Literature as Topic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with no known effective treatment or cure. Clinicians often expect that ALS patients will experience depression following the diagnosis because ALS is a terminal disease. The objective of the current study was to examine the evidence from the literature on psychological health in ALS patients in order to determine the prevalence and severity of depression in this population. Twenty-eight studies of ALS patients, conducted over the past 20 years, were reviewed and evaluated. The cumulative evidence suggests that clinically significant depression is neither as prevalent nor as severe as might be expected. Methodological limitations that are inherent to the measurement of depression in ALS, including the lack of appropriate instruments, small sample sizes, and reliance on cross-sectional data, have contributed to the wide range of reported results. We conclude that ALS patients are more likely to present with hopelessness and end-of-life concerns than clinically significant depression. It is important to assess a broad range of potential psychological distress early in the course of ALS, rather than focus specifically on depression, because the manner in which patients cope with their disease can affect their longevity.}, }
@article {pmid17653922, year = {2007}, author = {Mosley, RL and Gordon, PH and Hasiak, CM and Van Wetering, FJ and Mitsumoto, H and Gendelman, HE}, title = {Glatiramer acetate immunization induces specific antibody and cytokine responses in ALS patients.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {8}, number = {4}, pages = {235-242}, doi = {10.1080/17482960701374601}, pmid = {17653922}, issn = {1748-2968}, support = {2R37 NS36126/NS/NINDS NIH HHS/United States ; R21 NS049264/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/blood/drug therapy/*immunology ; Analysis of Variance ; Antibodies/*blood/classification ; Cytokines/*blood ; Enzyme-Linked Immunosorbent Assay/methods ; Flow Cytometry/methods ; Glatiramer Acetate ; Humans ; Immunosuppressive Agents/*immunology/therapeutic use ; Peptides/*immunology/therapeutic use ; Time Factors ; }, abstract = {We assessed humoral and cytokine responses in monthly plasma samples from ALS patients who received glatiramer acetate (GA) immunization every day or every other week, or remained untreated (control) from a six-month phase II trial. Samples were evaluated by GA-specific ELISA assays for detection of combined immunoglobulin (Ig) classes (IgM,A,G), IgG alone, and IgG subclasses (IgG1, IgG2, IgG3, and IgG4). T-helper (Th) type 1 and 2 (Th1 and Th2) cytokine levels were determined by flow cytometric cytokine bead arrays. Fourteen of 21 GA-immunized patients produced anti-GA Ig responses. Those treated every day produced anti-GA responses within one month, while those treated every other week exhibited responses by month two. All anti-GA IgG subclass concentrations were increased in excess of 4.2-fold in plasma from treated patients, and anti-GA IgG1 comprised the majority of the humoral response. Mean plasma cytokine levels were statistically indistinguishable between treatment regimens; however, stratification by patient and time on study showed more prevalent trends in changes of Th1 or Th2 cytokine levels following GA treatment every other week or every day, respectively. These data show significant humoral responses and cytokine trends following GA immunization in ALS patients.}, }
@article {pmid17650766, year = {2006}, author = {Kikutani, T and Tamura, F and Nishiwaki, K}, title = {Case presentation: dental treatment with PAP for ALS patient.}, journal = {The International journal of orofacial myology : official publication of the International Association of Orofacial Myology}, volume = {32}, number = {}, pages = {32-35}, pmid = {17650766}, issn = {0735-0120}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Deglutition Disorders/*etiology/therapy ; Female ; Humans ; Middle Aged ; *Palatal Obturators ; Tongue/physiopathology ; }, abstract = {The aim of this study was to evaluate the effect of Palatal Augmentation Prosthesis (PAP) for an Amyotrophic Lateral Sclerosis (ALS) patient. The patient's palatogram was taken during swallowing to assess her lingual function. A PAP was provided to assist her with feeding and swallowing functions. The patient's lingual pressure strength showed increases, and she was able to feed well using PAP. This devise was useful for assisting lingual dysfunctions due to various diseases.}, }
@article {pmid17645246, year = {2007}, author = {Shintaku, M and Oyanagi, K and Kaneda, D}, title = {Amyotrophic lateral sclerosis with dementia showing clinical parkinsonism and severe degeneration of the substantia nigra: report of an autopsy case.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {27}, number = {3}, pages = {295-299}, doi = {10.1111/j.1440-1789.2007.00763.x}, pmid = {17645246}, issn = {0919-6544}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/drug therapy/*pathology/*physiopathology ; Autopsy ; Dementia/etiology/*pathology ; Diagnosis, Differential ; Dopamine Agents/therapeutic use ; Fatal Outcome ; Humans ; Levodopa/therapeutic use ; Magnetic Resonance Imaging ; Male ; Parkinson Disease/pathology ; Parkinsonian Disorders/*etiology ; Substantia Nigra/*pathology ; }, abstract = {An autopsy case of amyotrophic lateral sclerosis with dementia (ALS-D) showing clinically overt parkinsonism and severe degeneration of the substantia nigra is reported. The patient was a 78-year-old man who died after a 2-year clinical course characterized by parkinsonism that was responsive to Levodopa (L-DOPA) treatment. Motor neuron symptoms and dementia were not apparent ante-mortem. The autopsy demonstrated the severe degeneration of the substantia nigra without alpha-synucleinopathy-related changes. Finely granular mineralization of necrotic neurons was a unique finding in the substantia nigra. The mild loss of spinal anterior horn cells, the appearance of several Bunina bodies and the degeneration of the hippocampal subiculum and temporal cortex were also noted. A small number of ubiquitinated intra-cytoplasmic inclusions were found in neurons of the dentate fascia of the hippocampus and the temporal and frontal cortices. Although the degeneration of the substantia nigra is a common finding in ALS-D, patients seldom develop clinically overt parkinsonism. This case indicates that patients with ALS-D rarely present with predominantly parkinsonian clinical features and these symptoms and signs can be improved by L-DOPA treatment.}, }
@article {pmid17636250, year = {2007}, author = {Lemmens, R and Van Hoecke, A and Hersmus, N and Geelen, V and D'Hollander, I and Thijs, V and Van Den Bosch, L and Carmeliet, P and Robberecht, W}, title = {Overexpression of mutant superoxide dismutase 1 causes a motor axonopathy in the zebrafish.}, journal = {Human molecular genetics}, volume = {16}, number = {19}, pages = {2359-2365}, doi = {10.1093/hmg/ddm193}, pmid = {17636250}, issn = {0964-6906}, mesh = {Animals ; Blotting, Western ; Humans ; Immunohistochemistry ; Motor Neuron Disease/enzymology/*genetics/pathology ; *Mutation ; RNA, Messenger/genetics/metabolism ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; Vascular Endothelial Growth Factor A/genetics/metabolism ; Zebrafish ; }, abstract = {The development of small animal models is of major interest to unravel the pathogenesis and treatment of neurodegenerative diseases, especially because of their potential in large-scale chemical and genetic screening. We have investigated the zebrafish as a model to study amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by the selective loss of motor neurons, caused by mutations in superoxide dismutase 1 (SOD1) in a subset of patients. Overexpression of mutant human SOD1 in zebrafish embryos induced a motor axonopathy that was specific, dose-dependent and found for all mutations studied. Moreover, using this newly established animal model for ALS, we investigated the role of a known modifier in the disease: vascular endothelial growth factor (VEGF). Lowering VEGF induced a more severe phenotype, whereas upregulating VEGF rescued the mutant SOD1 axonopathy. This novel zebrafish model underscores the potential of VEGF for the treatment of ALS and furthermore will permit large-scale genetic and chemical screening to facilitate the identification of new therapeutic targets in motor neuron disease.}, }
@article {pmid17630988, year = {2007}, author = {Petri, S and Calingasan, NY and Alsaied, OA and Wille, E and Kiaei, M and Friedman, JE and Baranova, O and Chavez, JC and Beal, MF}, title = {The lipophilic metal chelators DP-109 and DP-460 are neuroprotective in a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {102}, number = {3}, pages = {991-1000}, doi = {10.1111/j.1471-4159.2007.04604.x}, pmid = {17630988}, issn = {0022-3042}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/physiopathology ; Animals ; Biomarkers/metabolism ; Cell Survival/drug effects/physiology ; Central Nervous System/*drug effects/metabolism/physiopathology ; Chelating Agents/*pharmacology/therapeutic use ; Disease Models, Animal ; Egtazic Acid/*analogs &amp; derivatives/pharmacology/therapeutic use ; Female ; Hypoxia-Inducible Factor 1, alpha Subunit/drug effects/metabolism ; Male ; Membrane Lipids/metabolism ; Metals/*antagonists &amp; inhibitors/metabolism ; Mice ; Mice, Transgenic ; Nerve Degeneration/drug therapy/physiopathology/prevention &amp; control ; Neuroprotective Agents/*pharmacology/therapeutic use ; Oxidative Stress/*drug effects/physiology ; RNA, Messenger/drug effects/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Treatment Outcome ; Vascular Endothelial Growth Factor A/genetics ; }, abstract = {One of the hypotheses for the development of familial amyotrophic lateral sclerosis (ALS) is that mutations in the superoxide dismutase 1 enzyme lead to aberrant properties of the copper within the active site of the enzyme which then causes increased oxidative damage. The lipophilic metal chelators DP-109 and DP-460 which chelate calcium, copper, and zinc were tested in the G93A-transgenic ALS mouse model. Both compounds significantly extended survival, DP-109 (5 mg/kg/day) by 10%, DP-460 (10 mg/kg/day) by 9%. While the effect on survival was relatively small, chelator treatment also improved motor performance, dramatically reduced cell loss in the lumbar spinal cord and decreased reactive astrocytosis and microgliosis. Markers of oxidative damage, tumor necrosis factor (TNF)-alpha and alpha-synuclein were reduced in the lumbar spinal cord of G93A mice treated with DP-109 or DP-460 as compared with vehicle-treated animals. Furthermore, the treatment induced protein expression of the transcription factor hypoxia inducible factor-1alpha and mRNA levels of vascular endothelial growth factor as a corresponding target gene. In line with previous studies using metal chelators in the G93A animal model, our results suggest that these compounds have neuroprotective capacities in ALS.}, }
@article {pmid17622602, year = {2007}, author = {Mitsumoto, H and Rabkin, JG}, title = {Palliative care for patients with amyotrophic lateral sclerosis: "prepare for the worst and hope for the best".}, journal = {JAMA}, volume = {298}, number = {2}, pages = {207-216}, doi = {10.1001/jama.298.2.207}, pmid = {17622602}, issn = {1538-3598}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/economics/etiology/psychology/*therapy ; Caregivers ; Humans ; Male ; Middle Aged ; *Palliative Care ; Patient Care Team ; Physician-Patient Relations ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating terminal neurodegenerative disease with a highly predictable clinical course such that palliative care should begin at or soon after diagnosis. The outcome is certain in most cases. The only medication approved for treatment in the United States, riluzole, extends life by about 2 months. Virtually all skeletal muscles eventually are affected. Multiple problems require a multidisciplinary approach including aggressive symptomatic management, rehabilitation to maintain motor function, nutritional and respiratory support, augmentative communication devices, and psychological support for both patients and families because family members so often play a central role in management and care. Social, bioethical, and financial issues as well as advance directives should be addressed long before enteral feeding or assistive ventilatory support might be considered. Goals of care should be assessed on an ongoing basis. Presenting the unusual case of a patient with ALS who is also a prominent neurologist specializing in ALS, we enumerate issues in management and palliative care applicable to ALS but also to other fatal, progressive neurologic diseases such as Huntington's chorea and late-stage Parkinson disease.}, }
@article {pmid17620231, year = {2007}, author = {Schucher, B and Magnussen, H}, title = {[Mechanical ventilation in chronic ventilatory insufficiency].}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {61}, number = {10}, pages = {644-652}, doi = {10.1055/s-2007-980063}, pmid = {17620231}, issn = {1438-8790}, mesh = {Germany ; Humans ; Lung Diseases/*rehabilitation ; Practice Patterns, Physicians'/trends ; Respiration, Artificial/*methods/*trends ; Respiratory Insufficiency/*nursing/prevention &amp; control/*rehabilitation ; Self Care/*methods/*trends ; }, abstract = {Mechanical ventilation has become an important treatment option in chronic ventilatory failure. There are different diseases which lead to ventilatory failure and to home mechanical ventilation (HMV). A primary loss of in- and expiratory muscle strength is the reason for respiratory deterioration in neuromuscular disease. In most of these diseases ventilatory failure develops because of the progressive character of muscular damage. Initially, ventilatory failure can be found during night-time. In the case of hypercapnia at daytime, life expectancy is strongly reduced, especially in amyotrophic lateral sclerosis and Duchenne muscular dystrophy. HMV leads to a prolongation of life and to an increase in quality of life, if bulbar involvement is not severe. Impressive clinical improvements under HMV have been found in restrictive disorders of the rib cage like kyphoscoliosis or posttuberculosis sequelae, with an increase of quality of life, walking distance and a decrease in pulmonary hypertension. Only few data are published about long-term results of HMV in Obesity Hypoventilation. In terms of retrospective analyses of clinical data HMV seems to improve survival in this population. Some patients only need CPAP treatment, but most patients have to be treated with ventilatory support. The application of HMV in patients with chronic ventilatory failure due to chronic obstructive pulmonary disease (COPD) is growing, but there are controversial results in randomised clinical trials. Analysis of these data suggest better results of HMV in patients with severe hypercapnia, with the application of higher effective ventilatory pressure and a ventilator mode with a significant reduction in the work of breathing. Under such conditions HMV leads to a reduction of hypercapnia, an improvement in sleep quality, walking distance and quality of life, but until now there is no evidence in reduction of mortality in COPD.}, }
@article {pmid17610166, year = {2007}, author = {Galán, L and Vela, A and Guerrero, A and Barcia, JA and García-Verdugo, JM and Matias-Guiu, J}, title = {[Experimental models of amyotrophic lateral sclerosis].}, journal = {Neurologia (Barcelona, Spain)}, volume = {22}, number = {6}, pages = {381-388}, pmid = {17610166}, issn = {0213-4853}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Animals ; *Disease Models, Animal ; Mice ; Rats ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a serious neurodegenerative disease that affects almost selectively motor neurons. Its ethiopathogeny is not fully understood, although there are several mechanisms that could play a role. It has no curative treatment and just a drug (riluzole) and mechanical ventilation has demonstrated to improve survival of these patients. In the last decades experimental models have been developed which have led us to better understand this disease and to design possible therapeutic strategies.<br><br>METHOD: We reviewed published articles concerning experimental models for ALS and neurodegeneratives diseases using the PubMed database.<br><br>RESULTS: Several experimental models for ALS have been described, from animal models (mainly transgenic animals for human mutations in superoxidedismutase [SOD1]) to cellular models, each of them with advantages and objections.<br><br>CONCLUSIONS: ALS experimental models have implied a great advance in the knowledge of this disease and the design of new therapeutic strategies.}, }
@article {pmid17610163, year = {2007}, author = {Rodríguez de Rivera, FJ and Grande, M and García-Caballero, J and Muñoz-Blanco, J and Mora, J and Esteban, J and Guerrero, A and Matias-Guiu, J and de Andrés-Colsa, R and Buey, C and Díez-Tejedor, E}, title = {[Development of a clinical pathway for the attention of patients with amyotrophic lateral sclerosis in a regional network. ALS Assistance Network-Comunidad de Madrid].}, journal = {Neurologia (Barcelona, Spain)}, volume = {22}, number = {6}, pages = {354-361}, pmid = {17610163}, issn = {0213-4853}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; *Community Networks ; *Critical Pathways ; Humans ; Spain ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) requires complex multidisciplinary attention. Clinical pathways are assistance plans for certain diseases with a predictable course. These plans are established in isolated centers, not in multicenter regions. The aim is to develop a clinical pathway capable of organizing and homogenizing assistance given in ALS Assistance Network-Comunidad de Madrid which is made up of five hospitals, from the beginning until the end of the disease.<br><br>METHODS: In successive meetings, neurologists of these hospitals and members of the Madrid Health Service evaluated published therapeutic guidelines and other documents used in ALS assistance. A clinical pathway was developed adapting this information to social-health care conditions in the Comunidad de Madrid following the FOCUS-PDCA model.<br><br>RESULTS: A clinical pathway was created consisting of a scientist-technical framework which arranges the attention in relationship to the diagnosis and treatment, according to the degree of disease progression and a chronogram. This is accompanied by several patient information documents on the disease and the tests that are required, and a patient assistance evaluation form. The standards are established to reach and to promote 354 constant improvement in patient care.<br><br>CONCLUSIONS: Clinical pathway for the ALS assistance in a regional network organizes the attention and cares that the patients must receive from the beginning to the end of the disease. This arrangement and homogenization of the attention improves the quality of patient care, diminishes variability and rationalizes the use of the health care resources.}, }
@article {pmid17604499, year = {2007}, author = {Bedlack, RS and Traynor, BJ and Cudkowicz, ME}, title = {Emerging disease-modifying therapies for the treatment of motor neuron disease/amyotropic lateral sclerosis.}, journal = {Expert opinion on emerging drugs}, volume = {12}, number = {2}, pages = {229-252}, doi = {10.1517/14728214.12.2.229}, pmid = {17604499}, issn = {1744-7623}, support = {//Intramural NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*pathology ; Animals ; Humans ; Motor Neuron Disease/*drug therapy/genetics/*pathology ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects/physiology ; }, abstract = {It has been > 130 years since the first description of the upper and lower motor neuron disease called amyotropic lateral sclerosis (ALS). Sadly, there has been little change in the long interval over which this disease is diagnosed, or in its poor prognosis. Significant gains have been made, however, in understanding its pathophysiology and in symptomatic care. Disease-causing mutations have been identified and used to create animal models. Other identified mutations may increase susceptibility and cause disease only in a particular environment and at a particular age. A number of 'downstream' molecular pathways have been implicated, including transcriptional disturbances, protein aggregation, excitotoxicity, mitochondrial dysfunction, oxidative stress, neuroinflammation, cytoskeletal and axonal transport derangements, growth factor dysregulation and apoptosis. This knowledge has led to an impressive pipeline of candidate therapies that offer hope for finally being able to alter ALS disease progression. These are described and prioritized herein, and suggestions are offered for efficiently sifting through them.}, }
@article {pmid17598979, year = {2007}, author = {Walton-Betancourth, S and Martinelli, CE and Thalange, NK and Dyke, MP and Acerini, CL and White, S and Camacho-Hübner, C and Savage, MO}, title = {Excellent growth response to growth hormone therapy in a child with PTPN11-negative Noonan syndrome and features of growth hormone resistance.}, journal = {Journal of endocrinological investigation}, volume = {30}, number = {5}, pages = {439-441}, pmid = {17598979}, issn = {1720-8386}, mesh = {Child, Preschool ; Female ; Genotype ; Growth Disorders/*drug therapy/*genetics ; Human Growth Hormone/*administration &amp; dosage ; Humans ; Intracellular Signaling Peptides and Proteins/*genetics ; Noonan Syndrome/*drug therapy/*genetics ; Phenotype ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 ; Protein Tyrosine Phosphatases/*genetics ; }, abstract = {We report a child with Noonan syndrome, referred with severe short stature (height--5.4 SD) and biochemical features of GH resistance. The Noonan syndrome phenotype was confirmed by a clinical geneticist, however analysis of the protein tyrosine phosphatase nonreceptor type 11 (PTPN11) gene showed no mutation. Baseline serum IGF-I, IGFbinding protein 3 (IGFBP-3) and acid-labile subunit (ALS) were low, and in an IGF-I generation test, IGF-I did not increase into the normal range and IGFBP-3 and ALS did not change. These results are consistent with GH resistance. Treatment with human GH (hGH) was given in a dose of 0.05 mg/kg/day and height velocity increased from 5.6 to 10.7 cm/yr during the first year, and 8.9 cm/yr during the second year of therapy. Height standard deviation score has increased by 1.85 after 2 and a half yr of therapy. Serum IGF-I, IGFBP-3 and ALS values increased well into the normal range. This case shows that the potential value of GH therapy must be evaluated in each patient individually and that an excellent response may occur in a child with a PTPN11-negative genotype.}, }
@article {pmid17597554, year = {2007}, author = {Rochet, JC}, title = {Novel therapeutic strategies for the treatment of protein-misfolding diseases.}, journal = {Expert reviews in molecular medicine}, volume = {9}, number = {17}, pages = {1-34}, doi = {10.1017/S1462399407000385}, pmid = {17597554}, issn = {1462-3994}, mesh = {Amyloid/adverse effects ; Dimerization ; Drug Design ; Humans ; Neurodegenerative Diseases/*drug therapy/*etiology ; *Protein Denaturation ; Protein Folding ; }, abstract = {Most proteins in the cell adopt a compact, globular fold that determines their stability and function. Partial protein unfolding under conditions of cellular stress results in the exposure of hydrophobic regions normally buried in the interior of the native structure. Interactions involving the exposed hydrophobic surfaces of misfolded protein conformers lead to the formation of toxic aggregates, including oligomers, protofibrils and amyloid fibrils. A significant number of human disorders (e.g. Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and type II diabetes) are characterised by protein misfolding and aggregation. Over the past five years, outstanding progress has been made in the development of therapeutic strategies targeting these diseases. Three promising approaches include: (1) inhibiting protein aggregation with peptides or small molecules identified via structure-based drug design or high-throughput screening; (2) interfering with post-translational modifications that stimulate protein misfolding and aggregation; and (3) upregulating molecular chaperones or aggregate-clearance mechanisms. Ultimately, drug combinations that capitalise on more than one therapeutic strategy will constitute the most effective treatment for patients with these devastating illnesses.}, }
@article {pmid17582695, year = {2008}, author = {Staines, DR}, title = {Are multiple sclerosis and amyotrophic lateral sclerosis autoimmune disorders of endogenous vasoactive neuropeptides?.}, journal = {Medical hypotheses}, volume = {70}, number = {2}, pages = {413-418}, doi = {10.1016/j.mehy.2007.04.038}, pmid = {17582695}, issn = {0306-9877}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/immunology/therapy ; Humans ; Models, Immunological ; Multiple Sclerosis/*etiology/immunology/therapy ; Neuropeptides/*immunology ; Pituitary Adenylate Cyclase-Activating Polypeptide/immunology ; Receptors, G-Protein-Coupled/immunology ; Vasoactive Intestinal Peptide/immunology ; }, abstract = {Autoimmune dysfunction of endogenous vasoactive neuropeptides (VNs) such as vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) has been postulated as a cause for some fatigue-related conditions. VN receptors are class II G protein-coupled receptors (GPCRs) which couple primarily to the adenylate cyclase (AC)-cyclic AMP (cAMP) pathway and cAMP has a central role in neurological metabolism including influencing blood-brain barrier (BBB) and blood-spinal barrier (BSB) permeability, coordinating neuroregulatory pathways, and protecting against neuronal apoptosis. Complex clinical signs occur in multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While traditionally viewed as diseases of the motor system, the clinical picture of these conditions is considerably more complex. Disturbances of cognition and memory, as well as emotional lability occur along with fatigue and motor dysfunction. This paper explores the hypothesis that autoimmune dysfunction of VNs may contribute to MS and ALS. While MS and ALS differ in important respects, they have common pathogenic features including inflammation, oxidative stress and mitochondrial dysfunction. Apoptotic mechanisms are associated with activation of caspase pathways and functional interplay between proinflammatory cytokines, interferon gamma and nitric oxide is suggested associated with oxidative stress and glial activation. Diseases such as MS and ALS may represent related conditions resulting from variation in expression of different receptor subtypes of the VN family. Anatomical differences of these receptors, perhaps in areas overly dependent on a specific VN receptor sub-type, may predispose to autoimmune susceptibility to these conditions, either in impaired expression of receptors or antibody and cellular immune targeting of them. Further studies are required to determine if such VN receptor sub-types of significant specificity exist and if they are susceptible to compromise. This hypothesis, if proven, may have implications for the development of treatment and preventive strategies.}, }
@article {pmid17582439, year = {2008}, author = {Mazzini, L and Mareschi, K and Ferrero, I and Vassallo, E and Oliveri, G and Nasuelli, N and Oggioni, GD and Testa, L and Fagioli, F}, title = {Stem cell treatment in Amyotrophic Lateral Sclerosis.}, journal = {Journal of the neurological sciences}, volume = {265}, number = {1-2}, pages = {78-83}, doi = {10.1016/j.jns.2007.05.016}, pmid = {17582439}, issn = {0022-510X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*surgery ; Bone Marrow Cells/physiology ; Cell Differentiation/physiology ; Cell Proliferation ; Female ; Follow-Up Studies ; Humans ; Male ; Mesenchymal Stem Cell Transplantation/*methods ; Mesenchymal Stem Cells/*physiology ; Middle Aged ; Motor Neurons ; Neurons/*physiology ; Time Factors ; Transplantation, Autologous/methods ; }, abstract = {Amyotrophic Lateral Sclerosis is a progressive fatal neurodegenerative disease that targets motor neurons. Its origin is unknown but a main role of reactive astrogliosis and microglia activation in the pathogenesis has been recently demonstrated. Surrounding neurons with healthy adjoining cells completely stops motor neuron death in some cases. Hence stem cell transplantation might represent a promising therapeutic strategy. In this study MSCs were isolated from bone marrow of 9 patients with definite ALS. Growth kinetics, immunophenotype, telomere length and karyotype were evaluated during in vitro expansion. No significant differences between donors or patients were observed. The patients received intraspinal injections of autologous MSCs at the thoracic level and monitored for 4 years. No significant acute or late side effects were evidenced. No modification of the spinal cord volume or other signs of abnormal cell proliferation were observed. Four patients show a significant slowing down of the linear decline of the forced vital capacity and of the ALS-FRS score. Our results seem to demonstrate that MSCs represent a good chance for stem cell cell-based therapy in ALS and that intraspinal injection of MSCs is safe also in the long term. A new phase 1 study is carried out to verify these data in a larger number of patients.}, }
@article {pmid17571960, year = {2007}, author = {Okouchi, M and Ekshyyan, O and Maracine, M and Aw, TY}, title = {Neuronal apoptosis in neurodegeneration.}, journal = {Antioxidants &amp; redox signaling}, volume = {9}, number = {8}, pages = {1059-1096}, doi = {10.1089/ars.2007.1511}, pmid = {17571960}, issn = {1523-0864}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; R01 DK044510-12S1/DK/NIDDK NIH HHS/United States ; DK43785/DK/NIDDK NIH HHS/United States ; DK44510/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; *Apoptosis ; DNA Damage ; Disease Progression ; Humans ; Models, Biological ; Mutation ; Neurodegenerative Diseases/metabolism/*pathology ; Neurons/*metabolism/*pathology ; Oxidation-Reduction ; Reactive Oxygen Species ; Signal Transduction ; }, abstract = {Apoptosis mediates the precise and programmed natural death of neurons and is a physiologically important process in neurogenesis during maturation of the central nervous system. However, premature apoptosis and/or an aberration in apoptosis regulation is implicated in the pathogenesis of neurodegeneration, a multifaceted process that leads to various chronic disease states, such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) diseases, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and diabetic encephalopathy. The current review focuses on two major areas (a) the fundamentals of apoptosis, which includes elements of the apoptotic machinery, apoptosis inducers, and emerging concepts in apoptosis research, and (b) apoptotic involvement in neurodegenerative disorders, neuroprotective treatment strategies/modalities, and the mechanisms of, and signaling in, neuronal apoptosis. Current and new experimental models for apoptosis research in neurodegenerative diseases are also discussed.}, }
@article {pmid17569571, year = {2008}, author = {Liao, F and Wang, J and He, P}, title = {Multi-resolution entropy analysis of gait symmetry in neurological degenerative diseases and amyotrophic lateral sclerosis.}, journal = {Medical engineering &amp; physics}, volume = {30}, number = {3}, pages = {299-310}, doi = {10.1016/j.medengphy.2007.04.014}, pmid = {17569571}, issn = {1350-4533}, mesh = {Acceleration ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*physiopathology ; Entropy ; *Fractals ; *Gait ; Humans ; Huntington Disease/*physiopathology ; Middle Aged ; Neurologic Examination/methods ; Parkinson Disease/*physiopathology ; Postural Balance ; Posture ; Reference Standards ; Reference Values ; Walking ; }, abstract = {Gait rhythm of patients with Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS) has been studied focusing on the fractal and correlation properties of stride time fluctuations. In this study, we investigated gait asymmetry in these diseases using the multi-resolution entropy analysis of stance time fluctuations. Since stance time is likely to exhibit fluctuations across multiple spatial and temporal scales, the data series were decomposed into appropriate levels by applying stationary wavelet transform. The similarity between two corresponding wavelet coefficient series in terms of their regularities at each level was quantified based on a modified sample entropy method and a weighted sum was then used as gait symmetry index. We found that gait symmetry in subjects with PD and HD, especially with ALS is significantly disturbed. This method may be useful in characterizing certain pathologies of motor control and, possibly, in monitoring disease progression and evaluating the effect of an individual treatment.}, }
@article {pmid17568873, year = {2007}, author = {Paschoal, IA and Villalba, Wde O and Pereira, MC}, title = {Chronic respiratory failure in patients with neuromuscular diseases: diagnosis and treatment.}, journal = {Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia}, volume = {33}, number = {1}, pages = {81-92}, doi = {10.1590/s1806-37132007000100016}, pmid = {17568873}, issn = {1806-3756}, mesh = {Algorithms ; Chronic Disease ; Humans ; Hypoventilation/diagnosis/therapy ; Neuromuscular Diseases/*complications ; Respiration, Artificial ; Respiratory Insufficiency/diagnosis/*etiology/therapy ; Respiratory Muscles/physiopathology ; Respiratory System/physiopathology ; }, abstract = {Neuromuscular diseases affect alveolar air exchange and therefore cause chronic respiratory failure. The onset of respiratory failure can be acute, as in traumas, or progressive (slow or rapid), as in amyotrophic lateral sclerosis, muscular dystrophies, diseases of the myoneural junction, etc. Respiratory muscle impairment also affects cough efficiency and, according to the current knowledge regarding the type of treatment available in Brazil to these patients, it can be said that the high rates of morbidity and mortality in these individuals are more often related to the fact that they cough inefficiently rather than to the fact that they ventilate poorly. In this review, with the objective of presenting the options of devices available to support and substitute for natural ventilation in patients with neuromuscular diseases, we have compiled a brief history of the evolution of orthopedic braces and prostheses used to aid respiration since the end of the 19th century. In addition, we highlight the elements that are fundamental to the diagnosis of alveolar hypoventilation and of failure of the protective cough mechanism: taking of a clinical history; determination of peak cough flow; measurement of maximal inspiratory and expiratory pressures; spirometry in two positions (sitting and supine); pulse oximetry; capnography; and polysomnography. Furthermore, the threshold values available in the literature for the use of nocturnal ventilatory support and for the extension of this support through the daytime period are presented. Moreover, the maneuvers used to increase cough efficiency, as well as the proper timing of their introduction, are discussed.}, }
@article {pmid17565223, year = {2007}, author = {Misra, UK and Kalita, J and Yadav, RK}, title = {A comparison of clinically atypical with typical chronic inflammatory demyelinating polyradiculoneuropathy.}, journal = {European neurology}, volume = {58}, number = {2}, pages = {100-105}, doi = {10.1159/000103645}, pmid = {17565223}, issn = {1421-9913}, mesh = {Action Potentials/physiology/radiation effects ; Adolescent ; Adult ; Aged ; Electric Stimulation/methods ; Electrodiagnosis/*methods ; Female ; Humans ; Male ; Middle Aged ; Neural Conduction/physiology ; Peripheral Nerves/pathology/physiopathology ; *Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/classification/diagnosis/physiopathology ; Prospective Studies ; Reaction Time/physiology/radiation effects ; Retrospective Studies ; Severity of Illness Index ; }, abstract = {BACKGROUND: There is a paucity of prospective studies evaluating the atypical features of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).<br><br>AIMS: To compare clinical and electrodiagnostic features of clinically typical and atypical CIDP patients.<br><br>METHODS: The patients with typical and atypical CIDP diagnosed according to the European Federation of Neurological Societies/Peripheral Nerve Society were included. The disability was graded on a 0-10 scale. Neurophysiological study included motor and sensory nerve conduction and F wave studies of both upper and lower limbs. The patients were treated with prednisolone with or without azathioprine. The outcome was evaluated at 6 months and improvement was defined as at least 2 grades improvement.<br><br>RESULTS: Eight out of 37 CIDP patients had atypical features, which included asymmetry in 2, dysautonomia in 3 and pure motor weakness, amyotrophic-lateral-sclerosis-like syndrome and distal weakness in 1 patient each. Tendon reflexes were retained in 3 patients. The mean duration of symptoms was 43 weeks in the typical and 30 weeks in the atypical group. The age, sex, disability, therapeutic response and neurophysiological features were similar in the 2 groups.<br><br>CONCLUSION: About one fifth of CIDP patients may have atypical clinical features; however, their electrodiagnostic features and response to treatment are no different from typical CIDP.}, }
@article {pmid17564284, year = {2007}, author = {Chetta, A and Aiello, M and Tzani, P and Olivieri, D}, title = {Assessment and monitoring of ventilatory function and cough efficacy in patients with amyotrophic lateral sclerosis.}, journal = {Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace}, volume = {67}, number = {1}, pages = {43-52}, doi = {10.4081/monaldi.2007.509}, pmid = {17564284}, issn = {1122-0643}, mesh = {Amyotrophic Lateral Sclerosis/complications/*physiopathology/therapy ; Cough/*physiopathology ; Drainage, Postural ; Humans ; *Muscle Strength ; Respiration ; Respiration, Artificial ; Respiratory Function Tests/methods ; Respiratory Insufficiency/etiology/physiopathology/therapy ; Respiratory Muscles/*physiopathology ; }, abstract = {Assessing and monitoring respiratory muscle function is crucial in patients with Amyotrophic Lateral Sclerosis, since impaired function can lead to either ventilatory failure or respiratory tract infection. Spirometry, diffusing capacity of the lung, breathing pattern, sleep study, blood gas analysis and respiratory muscle strength tests, as well as cough peak flow and cough expiratory volume measurements can provide relevant information on ventilatory function and cough efficacy. With regard to respiratory muscle strength testing, the rational approach consists in starting with volitional and non-invasive tests and later using invasive and non-volitional tests. This review focuses on both ventilatory and respiratory muscle strength testing, in order to undertake a timely treatment of respiratory failure and/or impaired cough efficacy. So far, the current literature has not highlighted any gold standard which stipulates when to commence ventilation and cough support in patients with Amyotrophic Lateral Sclerosis. A composite set of clinical and functional parameters is required for treatment scheduling to monitor lung involvement and follow-up in these patients.}, }
@article {pmid17556854, year = {2007}, author = {Yorkston, KM}, title = {The degenerative dysarthrias: a window into critical clinical and research issues.}, journal = {Folia phoniatrica et logopaedica : official organ of the International Association of Logopedics and Phoniatrics (IALP)}, volume = {59}, number = {3}, pages = {107-117}, doi = {10.1159/000101769}, pmid = {17556854}, issn = {1421-9972}, mesh = {Dysarthria/*physiopathology ; Humans ; Neurodegenerative Diseases/*physiopathology ; Research/trends ; }, abstract = {Although diversity of symptoms and urgency of needs pose many challenges, management of the degenerative dysarthrias is a crucial aspect of clinical practice. The purpose of this article is to review current research literature on selected degenerative dysarthrias including those associated with Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. These dysarthrias are prevalent yet represent distinct patterns of underlying neuropathology, symptoms, age of onset, and rate of progression. Literature searches including the period 1997-2006 yielded 148 different studies reporting data on communication issues related to dysarthria. By far the largest category of studies was that which provided a basic description of speech production including the neurophysiologic, acoustic, or perceptual properties of dysarthria. Other categories included management (assessment and treatment) and the psychosocial consequences of dysarthria. While the topic of management of degenerative dysarthria is a focused one, it provides a window into many issues critical to the field of communication disorders including fundamental properties of speech production, development of evidence-based treatment techniques, the staging of these techniques into an effective management sequence, and the psychosocial consequences of communication disorders along with techniques to maintain communicative participation in the face of degenerative conditions.}, }
@article {pmid17554784, year = {2007}, author = {Wiksten, M and Väänänen, A and Liesi, P}, title = {Selective overexpression of gamma1 laminin in astrocytes in amyotrophic lateral sclerosis indicates an involvement in ALS pathology.}, journal = {Journal of neuroscience research}, volume = {85}, number = {9}, pages = {2045-2058}, doi = {10.1002/jnr.21314}, pmid = {17554784}, issn = {0360-4012}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Astrocytes/*metabolism ; Blotting, Western ; Cell Survival ; Electrophoresis, Polyacrylamide Gel ; Humans ; Immunohistochemistry ; Laminin/*biosynthesis/physiology ; Motor Neurons/metabolism ; Spinal Cord/metabolism ; }, abstract = {Our earlier studies indicate that the KDI tripeptide of gamma1 laminin reverts paralysis and protects adult rat CNS from excitotoxicity of glutamate and from oxidative stress. Here we show that gamma1 laminin is selectively overexpressed in reactive astrocytes of the amyotrophic lateral sclerosis (ALS) spinal cord, with both gray and white matter astrocytes overexpressing gamma1 laminin. Intensely gamma1 laminin-positive, aggressive-looking reactive astrocytes of the lateral columns of both cervical and thoracic spinal cord surround the lateral ventral horns and roots and extend into the area of the lateral corticospinal tract. In the cervical ALS spinal cord, large numbers of strongly gamma1 laminin-immunoreactive astrocytes are also present in the dorsal columns of the ascending sensory pathways. No other laminin or any other ALS-associated protein localizes in this manner. This unique distribution of gamma1 laminin-immunoreactive astrocytes in the ALS white matter together with our recent results on the efficacy of the KDI domain as a neuronal protector strongly suggest that gamma1 laminin may be expressed by astrocytes of the ALS spinal cord as a protective measure intended to aid neuronal survival. Further comparative studies on ALS spinal cord tissues and those of the animal models of ALS are needed to clarify the specific role of gamma1 laminin and its KDI domain in ALS and its putative interactions with the additional ALS-associated factors, such as excitotoxicity, oxidative stress, and neurofilament accumulation. Most importantly, further studies are urgently needed to test the potential of the KDI tripeptide as a therapeutic treatment for ALS.}, }
@article {pmid17549013, year = {2007}, author = {Irani, DN and Prow, NA}, title = {Neuroprotective interventions targeting detrimental host immune responses protect mice from fatal alphavirus encephalitis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {66}, number = {6}, pages = {533-544}, pmid = {17549013}, issn = {0022-3069}, support = {R01 AI057505/AI/NIAID NIH HHS/United States ; R01 AI057505-03/AI/NIAID NIH HHS/United States ; AI057505/AI/NIAID NIH HHS/United States ; }, mesh = {Administration, Intranasal ; *Alphavirus Infections ; Animals ; Brain/drug effects/pathology ; Central Nervous System/virology ; Disease Susceptibility ; Encephalitis/mortality/*prevention &amp; control/*virology ; Interleukin 1 Receptor Antagonist Protein/administration &amp; dosage/pharmacology ; Interleukin-1/metabolism ; Interleukin-1beta/administration &amp; dosage/pharmacology ; Mice ; Mice, Inbred C57BL ; Microglia/drug effects ; Minocycline/antagonists &amp; inhibitors/*pharmacology ; Neurons/drug effects/pathology ; Neuroprotective Agents/antagonists &amp; inhibitors/*pharmacology ; Oligonucleotide Array Sequence Analysis ; Paralysis/prevention &amp; control ; *Sindbis Virus/physiology ; Spinal Cord/drug effects/pathology ; Viral Load ; Virus Replication/drug effects ; }, abstract = {Systemic treatment with the tetracycline derivative, minocycline, attenuates neurologic deficits in animal models of amyotrophic lateral sclerosis, hypoxic-ischemic brain injury, and multiple sclerosis. Inhibition of microglial activation within the CNS is 1 mechanism proposed to underlie the beneficial effects of the drug in these systems. Given the widening scope of acute viral encephalitis caused by mosquito-borne pathogens, we investigated the therapeutic effects of minocycline in a murine model of fatal alphavirus encephalomyelitis in which widespread microglial activation is known to occur. We found that minocycline conferred significant protection against both paralysis and death, even when started after viral challenge and despite having no effect on CNS virus replication or spread. Further studies demonstrated that minocycline inhibited early virus-induced microglial activation and that diminished CNS production of the inflammatory mediator, interleukin (IL)-1beta, contributed to its protective effect. Therapeutic blockade of IL-1 receptors also conferred significant protection in our model, validating the importance of the IL-1 pathway in disease pathogenesis. We propose that interventions targeting detrimental host immune responses arising from activated microglia may be of benefit in humans with acute viral encephalitis caused by related mosquito-borne pathogens. Such treatments could conceivably act through neuroprotective rather than antiviral mechanisms to generate these clinical effects.}, }
@article {pmid17540579, year = {2007}, author = {Mitne-Neto, M and Ramos, CR and Pimenta, DC and Luz, JS and Nishimura, AL and Gonzales, FA and Oliveira, CC and Zatz, M}, title = {A mutation in human VAP-B--MSP domain, present in ALS patients, affects the interaction with other cellular proteins.}, journal = {Protein expression and purification}, volume = {55}, number = {1}, pages = {139-146}, doi = {10.1016/j.pep.2007.04.007}, pmid = {17540579}, issn = {1046-5928}, mesh = {Amino Acid Substitution ; Amyotrophic Lateral Sclerosis/*genetics/*metabolism ; Cloning, Molecular ; Escherichia coli/genetics ; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/chemistry/*metabolism ; Humans ; Mutation ; Proline/chemistry/genetics ; Protein Interaction Mapping ; Protein Structure, Tertiary/genetics ; Recombinant Proteins/biosynthesis/chemistry/genetics ; Sequence Deletion ; Serine/chemistry/genetics ; Tubulin/chemistry/*metabolism ; Vesicular Transport Proteins/chemistry/*genetics/*metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset Motor Neuron Disease (MND), characterized by motor neurons death in the cortex, brainstem and spinal cord. Ten loci linked to Familial ALS have been mapped. ALS8 is caused by a substitution of a proline by a serine in the Vesicle-Associated Membrane Protein-Associated protein-B/C (VAP-B/C). VAP-B belongs to a highly conserved family of proteins implicated in Endoplasmic Reticulum-Golgi and intra-Golgi transport and microtubules stabilization. Previous studies demonstrated that the P56S mutation disrupts the subcellular localization of VAP-B and that this position would be essential for Unfolded Protein Response (UPR) induced by VAP-B. In the present work we expressed and purified recombinant wild-type and P56S mutant VAP-B-MSP domain for the analysis of its interactions with other cellular proteins. Our findings suggest that the P56S mutation may lead to a less stable interaction of this endoplasmic reticulum protein with at least two other proteins: tubulin and GAPDH. These two proteins have been previously related to other forms of neurodegenerative diseases and are potential key points to understand ALS8 pathogenesis and other forms of MND. Understanding the role of these protein interactions may help the treatment of this devastating disease in the future.}, }
@article {pmid17538783, year = {2007}, author = {Anneser, JM and Jox, RJ and Borasio, GD}, title = {Inappropriate sexual behaviour in a case of ALS and FTD: successful treatment with sertraline.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {8}, number = {3}, pages = {189-190}, doi = {10.1080/17482960601073543}, pmid = {17538783}, issn = {1748-2968}, mesh = {Adult ; Aggression ; Amyotrophic Lateral Sclerosis/*complications/psychology ; Dementia/*complications/psychology ; Fatal Outcome ; Humans ; Male ; Mental Disorders/*drug therapy/*etiology/psychology ; Selective Serotonin Reuptake Inhibitors/*therapeutic use ; Sertraline/*therapeutic use ; *Sexual Behavior ; }, abstract = {In a subset of patients, ALS is associated with frontotemporal dysfunction (ALS-FTD). Clinically, ALS-FTD may present with a variable spectrum of cognitive and behavioural deficits. We report a 53-year-old ALS-FTD patient developing inappropriate sexual behaviour (ISB) manifesting as a vigorous sexual drive with exhausting demands for sexual intercourse and physical aggressions against his wife. This distressing symptom could be alleviated with the selective serotonin reuptake inhibitor sertraline. ISB is an embarrassing symptom for most patients and their caregivers and may therefore be under-reported. Since effective treatment is available, we suggest an open and proactive discussion of sexual issues in this patient group.}, }
@article {pmid17538776, year = {2007}, author = {Kihira, T and Kanno, S and Miwa, H and Okamoto, K and Kondo, T}, title = {The role of exogenous risk factors in amyotrophic lateral sclerosis in Wakayama, Japan.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {8}, number = {3}, pages = {150-156}, doi = {10.1080/17482960601179407}, pmid = {17538776}, issn = {1748-2968}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*epidemiology/pathology/surgery ; Female ; Fractures, Bone/epidemiology ; Humans ; Japan/epidemiology ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Occupations ; Risk Factors ; Spinal Cord Diseases/epidemiology/pathology/surgery ; Spinal Osteophytosis/epidemiology/pathology/surgery ; }, abstract = {The incidence of ALS in Wakayama Prefecture has been markedly higher than that elsewhere in the world. Recently, however, the incidence has gradually decreased, especially in men, and the age at onset has shifted to the elderly, indicating the possible role of exogenous factors in the development of ALS. To evaluate factors related to the disease, we conducted a retrospective study. This study examined 108 patients with definite ALS diagnosed according to El Escorial criteria and 302 neurological controls (older than 40 years old) consecutively admitted to Wakayama Medical Hospital between 1999 and 2004. Having past history of cervical spondylosis or spinal spondylotic myelopathy (CS/SSM) with/without surgical treatment, cervical MRI findings, history of bone fracture, and occupation at onset were compared between the ALS patients and the neurological controls. Among 108 ALS patients, 45.4% had past history of CS/SSM compared to 19.4% of the neurological controls (p<0.0001, OR: 3.725, 95% CI 2.173-6.387). Among the ALS patients, 13% had had surgical treatment for CS/SSM, which was significantly higher than the 4.3% of the neurological controls (p<0.003, OR: 4.333, 95% CI 1.647-11.401). Cervical MRI findings were classified into four grades according to the severity of canal narrowing and compression of the spinal cord. Regarding cervical MRI findings, the percentage of ALS patients who showed canal narrowing and compression of the spinal cord was significantly higher than that of the controls (ALS: 72.0%, the controls: 29.5%, OR: 4.799, 95% CI 2.65-8.70). Comparison of the occupation at disease onset revealed that primary and secondary industrial occupations significantly increased the risk of ALS (2.69, 95% CI 1.40-5.16, 2.81, 95% CI 1.45-5.46, respectively). Conversely, tertiary industrial occupations significantly decreased the risk of ALS (age- and sex-adjusted OR: 0.54, 95% CI 0.30-0.98). In conclusion, CS/SSM, surgical treatment for CS/SSM and occupation at onset are suspected to be risk factors for developing/triggering or worsening ALS.}, }
@article {pmid17537473, year = {2007}, author = {Gonçalves, LR and Sousa-e-Silva, MC and Tomy, SC and Sano-Martins, IS}, title = {Efficacy of serum therapy on the treatment of rats experimentally envenomed by bristle extract of the caterpillar Lonomia obliqua: comparison with epsilon-aminocaproic acid therapy.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {50}, number = {3}, pages = {349-356}, doi = {10.1016/j.toxicon.2007.04.004}, pmid = {17537473}, issn = {0041-0101}, mesh = {Aminocaproic Acid/*therapeutic use ; Animals ; Arthropod Venoms/*toxicity ; *Immunotherapy ; Larva ; Male ; Moths/*metabolism ; Rats ; Rats, Wistar ; Time Factors ; }, abstract = {Large number of accidents caused by contact with Lonomia obliqua caterpillars, with hemorrhagic complications, have occurred in southern Brazil. Based on Venezuelan expertise to treat Lonomia achelous envenomation, the use of the antifibrinolytic drug epsilon-aminocaproic acid (EACA) has been indicated to treat L. obliqua envenomation, although no evidence has been presented to justify its use. Specific antivenom (antilonomic serum (ALS)) that neutralizes toxins that cause envenomation was developed. To compare the effectiveness of such treatments, rats were injected i.d. with the bristle extract of L. obliqua caterpillars and treated 15 min, 1 and 6 h after with saline, ALS, EACA, or with both ALS and EACA. ALS elicited fibrinogen recovery and normalization of thrombin time (TT), prothrombin time (PT) and activated partial thromboplastin time (APTT), independent of when it was administered; however, hematocrit was decreased in the group treated later. Saline or EACA-treated groups presented neither fibrinogen recovery nor normalization of hemostatic parameters. A high death rate was observed in the group treated with EACA 15 min after the envenomation. Prolongation of TT and APTT observed in the group treated with EACA and ALS indicated that this association gave no benefit in relation to the group treated solely with ALS. The results presented herein suggest that ALS is the only effective treatment for envenomation caused by contact with Lonomia obliqua caterpillars and indicate that EACA should not be administered in the initial phase of envenomation.}, }
@article {pmid17531826, year = {2007}, author = {Baumstark-Khan, C and Horneck, G}, title = {Results from the "Technical workshop on genotoxicity biosensing" on the micro-scale fluorometric assay of deoxyribonucleic acid unwinding.}, journal = {Analytica chimica acta}, volume = {593}, number = {1}, pages = {75-81}, doi = {10.1016/j.aca.2007.04.035}, pmid = {17531826}, issn = {1873-4324}, mesh = {Animals ; Biosensing Techniques/methods ; DNA/*chemistry ; *DNA Damage ; Fluorescence ; Fluorometry/*methods ; Mammals ; *Nucleic Acid Denaturation ; }, abstract = {The fluorometric analysis of DNA unwinding (FADU assay) was originally designed for rapid detection of X-ray-induced DNA damage in mammalian cells. This cellular bioassay is based on time-dependent alkaline denaturation of DNA under moderate denaturing conditions (pH 12.2-12.4) starting from ends as well as from all DNA break points (single-strand breaks, SSB; double-strand breaks, DSB; alkali-labile sites, ALS). DNA which remained double-stranded after 30 min of alkaline treatment was detected after neutralisation and immediate fragmentation followed by binding to the Hoechst 33258 dye (bisbenzimide) and fluorescence measures. In the current paper, a modified method was used which allows cell cultivation and chemical treatment in the same microplate (micro-FADU) followed by analysis of 96 samples in a microplate fluorescence reader. Exposure of mammalian cells to chemicals was performed for 60 min on ice thus allowing identification of direct acting substances capable of inducing DNA-strand breaks. As an inter-assay standard the action of hydrogen peroxide was tested in every test plate. The results demonstrate that the micro-FADU assay is suitable to detect the presence of chemically induced strand breaks within 3 h.}, }
@article {pmid17526058, year = {2007}, author = {Kesavapany, S and Zheng, YL and Amin, N and Pant, HC}, title = {Peptides derived from Cdk5 activator p35, specifically inhibit deregulated activity of Cdk5.}, journal = {Biotechnology journal}, volume = {2}, number = {8}, pages = {978-987}, doi = {10.1002/biot.200700057}, pmid = {17526058}, issn = {1860-7314}, mesh = {Animals ; Brain/*enzymology ; Cyclin-Dependent Kinase 5/*metabolism ; Enzyme Activation ; Humans ; Nerve Tissue Proteins/*metabolism ; Neurodegenerative Diseases/*enzymology ; Peptides/*metabolism ; }, abstract = {Normal Cdk5 activity, conferred mainly by association with its primary activator p35, is critical for normal function of the cell and must be tightly regulated. During neurotoxicity, p35 is cleaved to form p25, which becomes a potent and mislocalized hyperactivator of Cdk5, resulting in a deregulation of Cdk5 activity. p25 levels have been found to be elevated in Alzheimer's disease (AD) brain and overexpression of p25 in a transgenic mouse results in the formation of phosphorylated tau, neurofibrillary tangles and cognitive deficits that are pathological hallmarks of AD. p25/Cdk5 also hyperphosphorylates neurofilament proteins that constitute pathological hallmarks found in Parkinson's disease and amyotrophic lateral sclerosis. The selective targeting of p25/Cdk5 activity without affecting p35/Cdk5 activity has been unsuccessful. In this review we detail our recent studies of selective p25/Cdk5 inhibition without affecting p35/Cdk5 or mitotic Cdk activities. We found that a further truncation of p25 to yield a Cdk5 inhibitory peptide (CIP) can specifically inhibit p25/Cdk5 activity in transfected HEK cells and primary cortical neurons. CIP was able to reduce tau hyperphosphorylation and neuronal death induced caused by p25/Cdk5 and further studies with CIP may develop a specific Cdk5 inhibition strategy in the treatment of neurodegeneration.}, }
@article {pmid17526013, year = {2007}, author = {Ducray, AD and Schläppi, JA and Qualls, R and Andres, RH and Seiler, RW and Schlattner, U and Wallimann, T and Widmer, HR}, title = {Creatine treatment promotes differentiation of GABA-ergic neuronal precursors in cultured fetal rat spinal cord.}, journal = {Journal of neuroscience research}, volume = {85}, number = {9}, pages = {1863-1875}, doi = {10.1002/jnr.21337}, pmid = {17526013}, issn = {0360-4012}, mesh = {Animals ; Blotting, Western ; Cell Differentiation/*drug effects ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Choline O-Acetyltransferase/metabolism ; Creatine/*pharmacology ; Creatine Kinase/metabolism ; Energy Metabolism/drug effects ; Female ; Immunohistochemistry ; Mitogen-Activated Protein Kinase 1/genetics ; Neurons/*physiology ; Nitro Compounds/pharmacology ; Pregnancy ; Propionates/pharmacology ; Rats ; Spinal Cord/*cytology ; Stem Cells/*physiology ; Tetrazolium Salts ; Thiazoles ; Tubulin/genetics ; gamma-Aminobutyric Acid/*physiology ; }, abstract = {Creatine is a substrate of cytosolic and mitochondrial creatine kinases. Its supplementation augments cellular levels of creatine and phosphocreatine, the rate of ATP resynthesis, and improves the function of the creatine kinase energy shuttle. High cytoplasmatic total creatine levels have been reported to be neuroprotective by inhibiting apoptosis. In addition, creatine has direct antioxidant effects, which may be of importance in amyotrophic lateral sclerosis. In the present study, we investigated the effects of creatine [5 mM] on survival and differentiation of cultured GABA-immunoreactive (-ir) and choline acetyltransferase (ChAT)-ir rat spinal cord neurons. Furthermore, we addressed the neuroprotective potential of creatine supplementation against 3-nitropropionic acid (3-NP) induced toxicity. General cell survival and total neuronal cell density were not altered by chronic creatine treatment. We found, however, after chronic creatine and short-term creatine exposure a significantly higher density of GABA-ir neurons hinting to a differentiation-inducing mechanism of creatine. This notion is further supported by a significant higher content of GAD after creatine exposure. Creatine supplementation also exerted a partial, but significant neuroprotection for GABA-ir neurons against 3-NP induced toxicity. Interestingly, chronic creatine treatment did not alter cell density of ChAT-ir neurons but promoted their morphologic differentiation. Cell soma size and number of primary neurites per neuron were increased significantly after creatine supplementation. Taken together, creatine supplementation promoted the differentiation or the survival of GABAergic neurons and resulted in partial neuroprotection against 3-NP induced toxicity. The data suggest that creatine may play a critical role during development of spinal cord neurons.}, }
@article {pmid17522299, year = {2007}, author = {Rouaux, C and Panteleeva, I and René, F and Gonzalez de Aguilar, JL and Echaniz-Laguna, A and Dupuis, L and Menger, Y and Boutillier, AL and Loeffler, JP}, title = {Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {27}, number = {21}, pages = {5535-5545}, pmid = {17522299}, issn = {1529-2401}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/mortality/*prevention &amp; control ; Animals ; CREB-Binding Protein/*physiology ; Cell Line, Tumor ; *Disease Models, Animal ; Male ; Mice ; Mice, Transgenic ; Neuroprotective Agents/pharmacology/*therapeutic use ; Oxidative Stress/drug effects/physiology ; Survival Rate ; Valproic Acid/pharmacology/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by motoneuron (MN) degeneration, generalized weakness, and muscle atrophy. The premature death of MNs is thought to be a determinant in the onset of this disease. In a transgenic mouse model of ALS expressing the G86R mutant superoxide dismutase 1 (mSOD1), we demonstrated previously that CREB (cAMP response element-binding protein)-binding protein (CBP) and histone acetylation levels were specifically decreased in nuclei of degenerating MNs. We show here that oxidative stress and mSOD1 overexpression can both impinge on CBP levels by transcriptional repression, in an MN-derived cell line. Histone deacetylase inhibitor (HDACi) treatment was able to reset proper acetylation levels and displayed an efficient neuroprotective capacity against oxidative stress in vitro. Interestingly, HDACi also upregulated CBP transcriptional expression in MNs. Moreover, when injected to G86R mice in vivo, the HDACi sodium valproate (VPA) maintained normal acetylation levels in the spinal cord, efficiently restored CBP levels in MNs, and significantly prevented MN death in these animals. However, despite neuroprotection, mean survival of treated animals was not significantly improved (<5%), and they died presenting the classical ALS symptoms. VPA was not able to prevent disruption of neuromuscular junctions, although it slightly delayed the onset of motor decline and retarded muscular atrophy to some extent. Together, these data show that neuroprotection can improve disease onset, but clearly provide evidence that one can uncouple MN survival from whole-animal survival and point to the neuromuscular junction perturbation as a primary event of ALS onset.}, }
@article {pmid17516042, year = {2007}, author = {Meyer, T and Münch, C and van Landeghem, FK and Borisow, N and Dullinger, J and Linke, P}, title = {[Progressive muscle atrophy. A rarely diagnosed variant of amyotrophic lateral sclerosis].}, journal = {Der Nervenarzt}, volume = {78}, number = {12}, pages = {1383-1388}, pmid = {17516042}, issn = {0028-2804}, mesh = {Amyotrophic Lateral Sclerosis/classification/*diagnosis/*therapy ; Diagnosis, Differential ; Diagnostic Errors/*prevention &amp; control ; Humans ; Muscular Atrophy, Spinal/classification/*diagnosis/*therapy ; Practice Patterns, Physicians'/trends ; }, abstract = {Progressive muscle atrophy (PMA) is a degenerative disease of the lower motor neuron. The course of the illness and the fatal prognosis correspond to those of amyotrophic lateral sclerosis (ALS). Neuropathologic and genetic findings support categorizing PMA within the spectrum of ALS, even though no clinical sign of a disorder of the upper motor neuron is demonstrable. The diagnosis of PMA is based on advanced extremity pareses and atrophies with a high progression rate. Respiratory insufficiency is determinative of the prognosis. Absent or late affection of bulbar functions is characteristic of the disease. Intraneuronal bunina bodies and ubiquitine-positive inclusions, which are established morphologic characteristics of ALS, are found post mortem. The treatment options of riluzol medication, respiratory therapy, and nutrition are analogous to those for typical ALS.}, }
@article {pmid17510731, year = {2007}, author = {Habisch, HJ and Janowski, M and Binder, D and Kuzma-Kozakiewicz, M and Widmann, A and Habich, A and Schwalenstöcker, B and Hermann, A and Brenner, R and Lukomska, B and Domanska-Janik, K and Ludolph, AC and Storch, A}, title = {Intrathecal application of neuroectodermally converted stem cells into a mouse model of ALS: limited intraparenchymal migration and survival narrows therapeutic effects.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {114}, number = {11}, pages = {1395-1406}, pmid = {17510731}, issn = {0300-9564}, mesh = {Aging/physiology ; Amyotrophic Lateral Sclerosis/genetics/physiopathology/*therapy ; Animals ; Cell Count ; Cell Movement/*physiology ; Cell Survival ; Cisterna Magna/physiology ; Disease Progression ; Humans ; Mice ; Mice, Transgenic ; Psychomotor Performance/physiology ; Sample Size ; Spine/*physiology ; *Stem Cell Transplantation ; Subarachnoid Space/physiology ; Superoxide Dismutase/genetics ; }, abstract = {Stem and progenitor cells provide a promising therapeutic strategy for amyotrophic lateral sclerosis (ALS). To comparatively evaluate the therapeutic potentials of human bone marrow-derived mesodermal stromal cells (hMSCs) and umbilical cord blood cells (hUBCs) in ALS, we transplanted hMSCs and hUBCs and their neuroectodermal derivatives (hMSC-NSCs and hUBC-NSCs) into the ALS mouse model over-expressing the G93A mutant of the human SOD1 gene. We used a standardized protocol similar to clinical studies by performing a power calculation to estimate sample size prior to transplantation, matching the treatment groups for gender and hSOD-G93A gene content, and applying a novel method for directly injecting 100,000 cells into the CSF (the cisterna magna). Ten days after transplantation we found many cells within the subarachnoidal space ranging from frontal basal cisterns back to the cisterna magna, but only a few cells around the spinal cord. hMSCs and hMSC-NSCs were also located within the Purkinje cell layer. Intrathecal cell application did not affect survival times of mice compared to controls. Consistently, time of disease onset and first pareses, death weight, and motor neuron count in lumbar spinal cord did not vary between treatment groups. Interestingly, transplantation of hMSCs led to an increase of pre-symptomatic motor performance compared to controls in female animals. The negative outcome of the present study is most likely due to insufficient cell numbers within the affected brain regions (mainly the spinal cord). Further experiments defining the optimal cell dose, time point and route of application and particularly strategies to improve the homing of transplanted cells towards the CNS region of interest are warranted to define the therapeutic potential of mesodermal stem cells for the treatment of ALS.}, }
@article {pmid17507170, year = {2007}, author = {Kim, JE and Kim, DS and Kwak, SE and Choi, HC and Song, HK and Choi, SY and Kwon, OS and Kim, YI and Kang, TC}, title = {Anti-glutamatergic effect of riluzole: comparison with valproic acid.}, journal = {Neuroscience}, volume = {147}, number = {1}, pages = {136-145}, doi = {10.1016/j.neuroscience.2007.04.018}, pmid = {17507170}, issn = {0306-4522}, mesh = {Animals ; Anticonvulsants/*pharmacology ; Dentate Gyrus/drug effects/metabolism ; Disease Models, Animal ; Epilepsy, Absence/chemically induced/drug therapy/metabolism ; Excitatory Postsynaptic Potentials/drug effects ; Limbic System/drug effects/metabolism/physiopathology ; Male ; Pilocarpine ; Rats ; Rats, Sprague-Dawley ; Riluzole/*pharmacology ; Seizures/chemically induced/*drug therapy/metabolism ; Sodium Oxybate ; Status Epilepticus/chemically induced/*drug therapy/metabolism ; Valproic Acid/*pharmacology ; Vesicular Glutamate Transport Protein 1/drug effects/*metabolism ; }, abstract = {Riluzole, an anti-amyotrophic lateral sclerosis drug, known to decrease presynaptic glutamate release, is viewed as a candidate supplementary medication for epilepsy. In the present study, we compared the effects of riluzole and valproate (VPA) in the pilocarpine-induced limbic seizure model and in the gamma-hydroxybutyrate lactone (GBL)-induced absence seizure model. We applied immunohistochemical study for vesicular transporter 1 (VGLUT1) and extracellular recording in the rat dentate gyrus of both pilocarpine- and GBL-induced seizure models to measure effects of riluzole and VPA. Both VPA and riluzole treatments reduced VGLUT1 immunoreactivity. Riluzole treatment completely inhibited pre-ictal spikes and spike-wave discharges in the pilocarpine- and GBL-induced epilepsy models, whereas VPA partially inhibited these phenomena. In both seizure models, the anti-epileptic effects of VPA and riluzole are basically related to anti-glutamatergic (reducing field excitatory postsynaptic potential slope and excitability ratio), not GABAergic (paired-pulse inhibition) effect. Riluzole was more effective at reducing seizure activity in both epilepsy models than VPA. These results suggest that riluzole is a potential antiepileptic drug with activity against limbic seizure and absence seizure.}, }
@article {pmid17496168, year = {2007}, author = {Bordet, T and Buisson, B and Michaud, M and Drouot, C and Galéa, P and Delaage, P and Akentieva, NP and Evers, AS and Covey, DF and Ostuni, MA and Lacapère, JJ and Massaad, C and Schumacher, M and Steidl, EM and Maux, D and Delaage, M and Henderson, CE and Pruss, RM}, title = {Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {322}, number = {2}, pages = {709-720}, doi = {10.1124/jpet.107.123000}, pmid = {17496168}, issn = {0022-3565}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Animals, Newborn ; Binding, Competitive ; Cell Enlargement/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Cholestenones/chemistry/metabolism/*therapeutic use ; Cytochromes c/metabolism ; Female ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondria/drug effects/metabolism ; Motor Neurons/cytology/*drug effects/metabolism ; Nerve Growth Factors/metabolism ; Nerve Regeneration/drug effects ; Neuroprotective Agents/chemistry/metabolism/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA/metabolism ; Sciatic Nerve/drug effects/physiopathology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Survival Analysis ; Voltage-Dependent Anion Channels/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive death of cortical and spinal motor neurons, for which there is no effective treatment. Using a cell-based assay for compounds capable of preventing motor neuron cell death in vitro, a collection of approximately 40,000 low-molecular-weight compounds was screened to identify potential small-molecule therapeutics. We report the identification of cholest-4-en-3-one, oxime (TRO19622) as a potential drug candidate for the treatment of ALS. In vitro, TRO19622 promoted motor neuron survival in the absence of trophic support in a dose-dependent manner. In vivo, TRO19622 rescued motor neurons from axotomy-induced cell death in neonatal rats and promoted nerve regeneration following sciatic nerve crush in mice. In SOD1(G93A) transgenic mice, a model of familial ALS, TRO19622 treatment improved motor performance, delayed the onset of the clinical disease, and extended survival. TRO19622 bound directly to two components of the mitochondrial permeability transition pore: the voltage-dependent anion channel and the translocator protein 18 kDa (or peripheral benzodiazepine receptor), suggesting a potential mechanism for its neuroprotective activity. TRO19622 may have therapeutic potential for ALS and other motor neuron and neurodegenerative diseases.}, }
@article {pmid17488226, year = {2007}, author = {Yun, AJ and Lee, PY and Doux, JD}, title = {Negative pressure ventilation via diaphragmatic pacing: a potential gateway for treating systemic dysfunctions.}, journal = {Expert review of medical devices}, volume = {4}, number = {3}, pages = {315-319}, doi = {10.1586/17434440.4.3.315}, pmid = {17488226}, issn = {1743-4440}, mesh = {Diaphragm/*physiology ; Humans ; Hypoventilation/*therapy ; Respiration, Artificial/*instrumentation ; Sleep Apnea, Central/*therapy ; *Ventilators, Negative-Pressure ; }, abstract = {Programmed diaphragmatic pacing using implanted neuromodulators represents an emerging method for providing pulmonary support using negative pressure ventilation. The implantable, rechargeable, programmable and miniaturized nature of diaphragmatic pacers may obviate many of the management issues associated with noninvasive positive pressure ventilation devices. Closed loop systems may facilitate the implementation of diaphragmatic pacing for the treatment of many indications. They may allow for wider adoption of ventilatory support in central sleep apnea and improve quality of life in diseases of chronic hypoventilation, such as amyotrophic lateral sclerosis. In addition, it might alleviate subclinical hypoventilation--a condition that may affect a significant proportion of the aging population. Diaphragmatic pacing could also reduce sympathetic bias, which may contribute to a wide range of diseases associated with autonomic dysfunction.}, }
@article {pmid17487869, year = {2007}, author = {Henderson, RD and Ridall, PG and Hutchinson, NM and Pettitt, AN and McCombe, PA}, title = {Bayesian statistical MUNE method.}, journal = {Muscle &amp; nerve}, volume = {36}, number = {2}, pages = {206-213}, doi = {10.1002/mus.20805}, pmid = {17487869}, issn = {0148-639X}, mesh = {Action Potentials/*physiology ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*pathology/physiopathology ; *Bayes Theorem ; Dose-Response Relationship, Radiation ; Electric Stimulation ; Female ; Humans ; Male ; Middle Aged ; Motor Neurons/*physiology ; Muscle, Skeletal/*pathology ; Reproducibility of Results ; }, abstract = {We have developed a new method of motor unit number estimation (MUNE) for assessing diseases such as amyotrophic lateral sclerosis (ALS). We used data from the whole stimulus-response curve and then performed a Bayesian statistical analysis. The Bayesian method uses mathematical equations that express the basic elements of motor unit activation after electrical stimulation and allows for the sources of variability and uncertainty in this formulation. The Bayesian MUNE method was used to determine the most probable number of motor units in 8 normal subjects, 49 ALS subjects, and 3 subjects with progressive lower motor neuron (LMN) weakness. In normals the number of motor units was calculated to be 75-85 in hand and 40-58 in foot muscles. In ALS subjects the number of motor units per muscle was less than in normal subjects. In 17 ALS subjects and 3 subjects with LMN weakness the median, ulnar, or peroneal nerve was studied on repeated occasions over an average of 189 days (range 63-1,071) and the number of motor units progressively declined, with a half-life ranging from 62-834 days. The results of our MUNE technique were reproducible on replicate studies. A Bayesian statistical MUNE method is a new approach that can be used to study ALS patients serially for assessment and treatment trials.}, }
@article {pmid17485247, year = {2007}, author = {Galpern, WR and Cudkowicz, ME}, title = {Coenzyme Q treatment of neurodegenerative diseases of aging.}, journal = {Mitochondrion}, volume = {7 Suppl}, number = {}, pages = {S146-53}, doi = {10.1016/j.mito.2007.01.004}, pmid = {17485247}, issn = {1567-7249}, mesh = {*Aging ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Clinical Trials as Topic ; Humans ; Huntington Disease/drug therapy ; Models, Biological ; Mutation ; Neurodegenerative Diseases/*drug therapy/*pathology ; Parkinson Disease/drug therapy/metabolism ; Time Factors ; Treatment Outcome ; Ubiquinone/*therapeutic use ; }, abstract = {The etiology of several neurodegenerative disorders is thought to involve impaired mitochondrial function and oxidative stress. Coenzyme Q-10 (CoQ10) acts both as an antioxidant and as an electron acceptor at the level of the mitochondria. In several animal models of neurodegenerative diseases including amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease, CoQ10 has shown beneficial effects. Based on its biochemical properties and the effects in animal models, several clinical trials evaluating CoQ10 have been undertaken in many neurodegenerative diseases. CoQ10 appears to be safe and well tolerated, and several efficacy trials are planned.}, }
@article {pmid17478583, year = {2007}, author = {Lee, H and Shamy, GA and Elkabetz, Y and Schofield, CM and Harrsion, NL and Panagiotakos, G and Socci, ND and Tabar, V and Studer, L}, title = {Directed differentiation and transplantation of human embryonic stem cell-derived motoneurons.}, journal = {Stem cells (Dayton, Ohio)}, volume = {25}, number = {8}, pages = {1931-1939}, doi = {10.1634/stemcells.2007-0097}, pmid = {17478583}, issn = {1066-5099}, mesh = {Animals ; *Cell Differentiation ; Cells, Cultured ; Chick Embryo ; Coculture Techniques ; Embryonic Stem Cells/*cytology/metabolism ; Gene Expression Profiling ; Humans ; Macaca fascicularis ; Motor Neurons/*cytology/metabolism ; Oligonucleotide Array Sequence Analysis ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/embryology/pathology ; Stem Cell Transplantation/*methods ; Transplantation, Heterologous/pathology ; }, abstract = {Motoneurons represent a specialized class of neurons essential for the control of body movement. Motoneuron loss is the cause of a wide range of neurological disorders including amyotrophic lateral sclerosis and spinal muscular atrophy. Embryonic stem cells are a promising cell source for the study and potential treatment of motoneuron diseases. Here, we present a novel in vitro protocol of the directed differentiation of human embryonic stem cells (hESCs) into engraftable motoneurons. Neural induction of hESCs was induced on MS5 stromal feeders, resulting in the formation of neural rosettes. In response to sonic hedgehog and retinoic acid, neural rosettes were efficiently directed into spinal motoneurons with appropriate in vitro morphological, physiological, and biochemical properties. Global gene expression analysis was used as an unbiased measure to confirm motoneuron identity and type. Transplantation of motoneuron progeny into the developing chick embryo resulted in robust engraftment, maintenance of motoneuron phenotype, and long-distance axonal projections into peripheral host tissues. Transplantation into the adult rat spinal cord yielded neural grafts comprising a large number of human motoneurons with outgrowth of choline acetyltransferase positive fibers. These data provide evidence for in vivo survival of hESC-derived motoneurons, a key requirement in the development of hESC-based cell therapy in motoneuron disease. Disclosure of potential conflicts of interest is found at the end of this article.}, }
@article {pmid17472707, year = {2007}, author = {Guan, YJ and Wang, X and Wang, HY and Kawagishi, K and Ryu, H and Huo, CF and Shimony, EM and Kristal, BS and Kuhn, HG and Friedlander, RM}, title = {Increased stem cell proliferation in the spinal cord of adult amyotrophic lateral sclerosis transgenic mice.}, journal = {Journal of neurochemistry}, volume = {102}, number = {4}, pages = {1125-1138}, doi = {10.1111/j.1471-4159.2007.04610.x}, pmid = {17472707}, issn = {0022-3042}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Bromodeoxyuridine/metabolism ; Cell Count/methods ; *Cell Proliferation ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Microscopy, Confocal/methods ; Nerve Tissue Proteins/metabolism ; Oligodendrocyte Transcription Factor 2 ; Spinal Cord/*pathology ; Statistics, Nonparametric ; Stem Cells/*physiology ; Superoxide Dismutase/genetics ; }, abstract = {Harnessing the regenerative potential of the central nervous system to repopulate depleted cellular populations from endogenous stem cells would be a novel approach for the treatment of neurological diseases resulting from cell death. Consequently, understanding if and how the central nervous system is capable of such regeneration would determine if such an approach is feasible. In this report, we provide evidence of widespread regenerative response in the spinal cord of amyotrophic lateral sclerosis transgenic mice. However, this regenerative response appears to be largely unproductive. We demonstrate that there is significantly increased gliogenesis, but an absence of convincing neurogenesis. The fact that the neurodegenerative process stimulates a regenerative response suggests that the adult spinal cord has at least limited ability for regeneration. Further studies will determine if this endogenous regenerative process can be enhanced and directed so as to slow or even reverse the natural progression of this devastating disease.}, }
@article {pmid17469801, year = {2007}, author = {Jiang, W and Han, Y and Zhou, R and Zhang, L and Liu, C}, title = {DNA is a template for accelerating the aggregation of copper, zinc superoxide dismutase.}, journal = {Biochemistry}, volume = {46}, number = {20}, pages = {5911-5923}, doi = {10.1021/bi062234m}, pmid = {17469801}, issn = {0006-2960}, mesh = {Animals ; Cattle ; Copper/chemistry ; DNA/*chemistry/*metabolism ; DNA-Binding Proteins/biosynthesis/chemistry/*metabolism/ultrastructure ; Humans ; Hydrophobic and Hydrophilic Interactions ; Microscopy, Atomic Force ; Microscopy, Fluorescence ; Spectrometry, Fluorescence ; Static Electricity ; Superoxide Dismutase/biosynthesis/*chemistry/*metabolism/ultrastructure ; Templates, Genetic ; Zinc/chemistry ; }, abstract = {The proteinaceous aggregates rich in copper, zinc superoxide dismutase (SOD1) have been shown to be involved in pathogenesis of amyotrophic lateral sclerosis (ALS). Since negatively charged species such as nucleic acids have frequently been found associated with the proteinaceous deposits in the tissues of patients with amyloid diseases, we examined here the aggregation behavior of SOD1 in the presence of DNA under acidic conditions that facilitate protein aggregation. Several forms of double-stranded DNA were tested to trigger SOD1 aggregation by light scattering, single- and double-fluorescence imaging with dyes, atomic force microscopy, and direct observations under visible light. The results reveal that DNA acts as a template for accelerating the formation of SOD1 aggregates and is incorporated into SOD1 aggregates. The spherical and ellipsoidal SOD1 aggregates were characterized in both hydrated and dried states and have morphology similar to those identified in the diseased neurons. Light scattering experiments indicate that the aggregation first undergoes a rapid phase where the aggregates with average diameters of 40-80 nm rapidly form in <2 min, and then passes through a slow phase where the average diameters of aggregates were increased to at least 200-260 nm in 2 h. All forms of DNAs tested can lead to the aggregation of SOD1 at nanomolar levels. The association of SOD1 with DNA, driven by electrostatic interactions between both, can restrict the orientation of SOD1 molecules and increase a SOD1 population along DNA strands. This facilitates the hydrophobic interactions between SOD1 molecules, as indicated by hydrophobic probe binding and chemical denaturant treatment experiments. Demonstration of the DNA-accelerated aggregation of SOD1 might establish a possible role of DNA in the pathogenesis of some diseases because of the ubiquitous expression of SOD1 and the coexistence of SOD1 and DNA in the crowded molecular environment of a cell.}, }
@article {pmid17469352, year = {2006}, author = {Ito, H and Izumi, Y}, title = {[Development of a community care system for patients with amyotrophic lateral sclerosis in the Hiroshima Bihoku region].}, journal = {Gan to kagaku ryoho. Cancer &amp; chemotherapy}, volume = {33 Suppl 2}, number = {}, pages = {254-256}, pmid = {17469352}, issn = {0385-0684}, mesh = {Aged ; Aged, 80 and over ; *Amyotrophic Lateral Sclerosis/nursing/rehabilitation ; Caregivers ; *Community Health Services ; *Computer Communication Networks ; Female ; Humans ; Long-Term Care ; Male ; Middle Aged ; }, abstract = {To understand the various problems of medical treatment and home care of ALS patients, we analyzed 23 ALS patients who live in the Bihoku region of Hiroshima prefecture. The ages of patients ranged from 50 to 88 years old. One patient was controlled with mechanical ventilation. The patients and their families utilized available home health care services well. A care manager managed to find appropriate resources for the patients as the disease progressed. Although limited in resources, patients' friends and neighbors offered an informal community support. An early approval of support enabled the patient to initiate home care. The incidence of hospitalization due to social reasons was higher in patients without communication to a care manager or without well cooperative support. Assessments of patient and family needs are important for a development of a community care system. It is also essential for all of the patients to have a good cooperative relationship.}, }
@article {pmid17469347, year = {2006}, author = {Namba, R}, title = {[Palliative care at the end of life for intractable neurological diseases].}, journal = {Gan to kagaku ryoho. Cancer &amp; chemotherapy}, volume = {33 Suppl 2}, number = {}, pages = {239-242}, pmid = {17469347}, issn = {0385-0684}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/nursing/*therapy ; Female ; *Home Care Services ; Hospitalization ; Humans ; Male ; Middle Aged ; Pain, Intractable/*therapy ; *Palliative Care ; Positive-Pressure Respiration ; Treatment Refusal ; }, abstract = {Palliative care at the end of life for intractable neurological diseases has come into discussion recently. According to the care guidelines for amyotrophic lateral sclerosis (ALS), suggested by the Japan Neurology Societies, neurological doctors should primarily aim at reducing patients' pain, share decisions with patients, and care for breathing difficulties, pain, and anxieties positively with the use of narcotics, like the care for cancer patients. Between June 2003 and June 2006, 58 of 79 patients (73%) refused a treatment to prolong their life, such as tracheal positive pressure ventilation (TPPV), and 19 of 24 (79%) patients desired to remain at home; these patients represented the majority. I will introduce the examples of ALS patients who refused TPPV, those who had intubation and ventilator attachment unwillingly at the time of emergency medical admission, and those who refused tube feedings. I will also report the practice on a patient with multi-system atrophy who was not self-decisive, the procedure of easing pain and its efficacy on the 9 ALS examples of home death, and the problems seen from 10 examples of death at a hospital. Hereafter, it is necessary to discuss intensely the problems of end-of-life palliative care especially for intractable neurological diseases in order to establish a methodology and to popularize it.}, }
@article {pmid17469116, year = {2007}, author = {Mackenzie, IR and Bigio, EH and Ince, PG and Geser, F and Neumann, M and Cairns, NJ and Kwong, LK and Forman, MS and Ravits, J and Stewart, H and Eisen, A and McClusky, L and Kretzschmar, HA and Monoranu, CM and Highley, JR and Kirby, J and Siddique, T and Shaw, PJ and Lee, VM and Trojanowski, JQ}, title = {Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations.}, journal = {Annals of neurology}, volume = {61}, number = {5}, pages = {427-434}, doi = {10.1002/ana.21147}, pmid = {17469116}, issn = {0364-5134}, support = {AG-13854/AG/NIA NIH HHS/United States ; U01 AG016976/AG/NIA NIH HHS/United States ; U01 AG-16976/AG/NIA NIH HHS/United States ; P01 AG-17586/AG/NIA NIH HHS/United States ; P50-AG05681/AG/NIA NIH HHS/United States ; //Wellcome Trust/United Kingdom ; P30 AG-10124/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*pathology ; DNA-Binding Proteins/*genetics ; Humans ; Immunohistochemistry ; Medulla Oblongata/pathology ; Motor Cortex/pathology ; Mutation/genetics ; Spinal Cord/pathology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Ubiquitin/genetics ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a common, fatal motor neuron disorder with no effective treatment. Approximately 10% of cases are familial ALS (FALS), and the most common genetic abnormality is superoxide dismutase-1 (SOD1) mutations. Most ALS research in the past decade has focused on the neurotoxicity of mutant SOD1, and this knowledge has directed therapeutic strategies. We recently identified TDP-43 as the major pathological protein in sporadic ALS. In this study, we investigated TDP-43 in a larger series of ALS cases (n = 111), including familial cases with and without SOD1 mutations.<br><br>METHODS: Ubiquitin and TDP-43 immunohistochemistry was performed on postmortem tissue from sporadic ALS (n = 59), ALS with SOD1 mutations (n = 15), SOD-1-negative FALS (n = 11), and ALS with dementia (n = 26). Biochemical analysis was performed on representative cases from each group.<br><br>RESULTS: All cases of sporadic ALS, ALS with dementia, and SOD1-negative FALS had neuronal and glial inclusions that were immunoreactive for both ubiquitin and TDP-43. Cases with SOD1 mutations had ubiquitin-positive neuronal inclusions; however, no cases were immunoreactive for TDP-43. Biochemical analysis of postmortem tissue from sporadic ALS and SOD1-negative FALS demonstrated pathological forms of TDP-43 that were absent in cases with SOD1 mutations.<br><br>INTERPRETATION: These findings implicate pathological TDP-43 in the pathogenesis of sporadic ALS. In contrast, the absence of pathological TDP-43 in cases with SOD1 mutations implies that motor neuron degeneration in these cases may result from a different mechanism, and that cases with SOD1 mutations may not be the familial counterpart of sporadic ALS.}, }
@article {pmid17455292, year = {2007}, author = {Pradat, PF and Bruneteau, G and Gonzalez de Aguilar, JL and Dupuis, L and Jokic, N and Salachas, F and Le Forestier, N and Echaniz-Laguna, A and Dubourg, O and Hauw, JJ and Tranchant, C and Loeffler, JP and Meininger, V}, title = {Muscle Nogo-A expression is a prognostic marker in lower motor neuron syndromes.}, journal = {Annals of neurology}, volume = {62}, number = {1}, pages = {15-20}, doi = {10.1002/ana.21122}, pmid = {17455292}, issn = {0364-5134}, mesh = {Adult ; Aged ; Biopsy/methods ; Disease Progression ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*metabolism/*pathology ; Muscle, Skeletal/*metabolism ; Myelin Proteins/*metabolism ; Nogo Proteins ; Prognosis ; Retrospective Studies ; }, abstract = {OBJECTIVE: A proportion of patients with pure lower motor neuron syndrome (LMNS) progress to amyotrophic lateral sclerosis (ALS). Early detection of this progression is impossible, which delays the patient's access to treatment. Muscle expression of Nogo-A is a new candidate marker of ALS. We tested whether detection of Nogo-A in a muscle biopsy from patients with LMNS predicts progression to ALS.<br><br>METHODS: Thirty-three patients who had undergone a muscle biopsy during the diagnostic workup of spinal LMNS were observed for 12 months. Nogo-A expression was measured by Western blot in muscle biopsy samples and compared with the final diagnosis.<br><br>RESULTS: Nogo-A expression was detected in 17 patients and was absent in 16 patients. The detection of Nogo-A in muscle biopsy samples from LMNS patients correctly identified patients who further progressed to ALS with 91% accuracy, 94% sensitivity, and 88% specificity. In patients who later developed typical ALS, Nogo-A may be detected as early as 3 months after the onset of symptoms.<br><br>INTERPRETATION: Nogo-A test is able to identify ALS early in the course of the disease when diagnosis is difficult, requiring further progression. Use of the test in clinical practice may shorten the delay before introduction of neuroprotective drugs or inclusion in clinical trials.}, }
@article {pmid17453639, year = {2007}, author = {Mendoza, M and Gelinas, DF and Moore, DH and Miller, RG}, title = {A comparison of maximal inspiratory pressure and forced vital capacity as potential criteria for initiating non-invasive ventilation in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {8}, number = {2}, pages = {106-111}, doi = {10.1080/17482960601030188}, pmid = {17453639}, issn = {1748-2968}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Female ; Humans ; *Inspiratory Capacity ; Male ; Maximal Voluntary Ventilation ; Middle Aged ; *Patient Selection ; Prognosis ; Reproducibility of Results ; Respiration, Artificial/*methods ; Retrospective Studies ; Sensitivity and Specificity ; *Vital Capacity ; }, abstract = {Using a retrospective analysis of 161 patients with amyotrophic lateral sclerosis (ALS) from the Western ALS study group (WALS) database, the sensitivity of maximal inspiratory pressure (MIP)< -60 cm H(2)O and forced vital capacity (FVC)< 50% as US Medicare thresholds for initiating non-invasive ventilation (NIV) were compared. Sixty-five per cent of patients at enrollment met the MIP criterion, compared with only 8% of patients who met the FVC criterion. There were no cases in which FVC< 50% antedated MIP< -60 cm H(2)O. The longitudinal data showed that patients reached the MIP criterion 4 to 6.5 months earlier than the FVC criterion. For patients with clinical signs and symptoms needing treatment with NIV, a MIP< -60 cm H(2)O allows US clinicians to obtain non-invasive ventilatory support for patients earlier than if using the FVC criterion alone.}, }
@article {pmid17453636, year = {2007}, author = {Jenkinson, C and Harris, R and Fitzpatrick, R}, title = {The Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40): evidence for a method of imputing missing data.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {8}, number = {2}, pages = {90-95}, doi = {10.1080/17482960600989343}, pmid = {17453636}, issn = {1748-2968}, mesh = {Activities of Daily Living ; *Algorithms ; Amyotrophic Lateral Sclerosis/*diagnosis/*epidemiology ; *Data Interpretation, Statistical ; Evidence-Based Medicine/methods ; *Health Status Indicators ; Humans ; Likelihood Functions ; *Quality of Life ; Reproducibility of Results ; Sample Size ; Sensitivity and Specificity ; *Surveys and Questionnaires ; United Kingdom/epidemiology ; }, abstract = {The Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) is the most widely validated measure of health status for use with patients diagnosed with motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). The questionnaire was designed to be used in studies evaluating treatment regimes where missing data may cause problems with data analyses. The purpose of this paper is to evaluate an algorithm for the imputation of missing dimension scores on the ALSAQ-40. We used a postal survey of patients diagnosed with MND/ALS. One thousand, nine hundred and seventy-nine patients were surveyed and 1093 (55.2%) questionnaires returned. Of these, complete ALSAQ-40 data was available in 854 (85.8%) cases. Data were deleted from this complete dataset, and in a randomly selected subset of 100 cases, and then imputed using the Expectation Maximization (EM) algorithm: results were then compared to the dataset prior to data deletion. Descriptive statistics, mean scores and spread of scores were almost identical between original and imputed datasets. Furthermore, the two datasets were highly correlated (intra-class correlation coefficient = 0.95 or greater), and mean differences were small (+/-1.00). We concluded that EM imputation for the ALSAQ-40 provides data that closely mirrors the original when this has been deliberately removed. Consequently, EM is likely to be appropriate for studies using the ALSAQ-40 that contain missing data points.}, }
@article {pmid17453634, year = {2007}, author = {Oates, N and Pamphlett, R}, title = {An epigenetic analysis of SOD1 and VEGF in ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {8}, number = {2}, pages = {83-86}, doi = {10.1080/17482960601149160}, pmid = {17453634}, issn = {1748-2968}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/*metabolism ; Base Sequence ; Epigenesis, Genetic/*genetics ; Female ; Genetic Predisposition to Disease/genetics ; Humans ; Male ; Middle Aged ; Molecular Sequence Data ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Vascular Endothelial Growth Factor A/*genetics ; }, abstract = {Epigenetic silencing of a gene vital for motor neuron function could underlie sporadic ALS. We therefore examined the methylation status of two genes, SOD1 and VEGF, which are implicated in ALS. Methylation in the promoters of these genes was determined in white cell DNA (10 ALS patients) and brain DNA (six ALS patients). The promoter regions were largely unmethylated in all patients. Transcriptional silencing of these genes is therefore unlikely to be a common mechanism in ALS. However, in view of the potential for treatment of epigenetic disorders, promoter methylation in other genes required for motor neuron survival needs to be studied.}, }
@article {pmid17447525, year = {2007}, author = {Mitsumoto, H}, title = {[A strategy to develop effective ALS therapy].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {59}, number = {4}, pages = {383-391}, pmid = {17447525}, issn = {1881-6096}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Humans ; Mice ; Practice Guidelines as Topic ; Randomized Controlled Trials as Topic ; }, abstract = {In the early 1990s, a number of major events took place in the history of the treatment and science of ALS. A cause of familial ALS, the mutation of superoxide dismutase 1, was discovered and very shortly after, an animal model expressing the human SOD1 mutation for familial ALS was generated. Around the same time, the first medication for the treatment of ALS, riluzole, was approved. Clinical neurologists started to focus more attention on quality of life and standardizing care for patients with ALS, including devising approaches for presenting and discussing the diagnosis, using aggressive symptomatic treatments, and developing a multidisciplinary care system. Since then, nutritional and respiratory care has markedly improved. Respiratory care for those with terminal ALS in Japan has been distinct and perhaps more effective compared to the rest of the world, and this unique experience must be broadly published and shared with others. In 1999, the ALS Treatment Guidelines were published by the American Academy of Neurology and are now under revision. A monitoring system to determine the impact the Guidelines had on actual patient care has taught us that caregivers have only slowly accepted the recommendation to improve quality of care. The team approach, using a multidisciplinary care system from diagnosis to the end of life, is essential to improve care for both the patient and family. Coinciding with the progress in ALS treatment, basic science and translational research also produced dramatic progress in ALS drug discovery. Over the past 15 years, more than 25 potential drugs have been tested in randomized controlled trials. Despite this progress, we have no medications other than riluzole. Although it may be true that ALS research is in its early stages compared to research in other diseases with no cure--it is probably behind cancer research by at least 20 or 30 years--we need to drastically change our approach to drug development. At a national level, we need to create a strong, cohesive team with support from a number of funding agencies, oversight from a regulatory agency, and investigators who all think "outside the box." In addition, we should obtain ideas and suggestions from accomplished experts outside of the field of ALS and put competition aside as we work together to develop strategic plans for the ALS drug development that is essential to beat this devastating disease.}, }
@article {pmid17445834, year = {2007}, author = {McLeod, JE and Clarke, DM}, title = {A review of psychosocial aspects of motor neurone disease.}, journal = {Journal of the neurological sciences}, volume = {258}, number = {1-2}, pages = {4-10}, doi = {10.1016/j.jns.2007.03.001}, pmid = {17445834}, issn = {0022-510X}, mesh = {Activities of Daily Living ; Databases, Factual/statistics &amp; numerical data ; Humans ; Interpersonal Relations ; Motor Neuron Disease/*psychology ; Personal Satisfaction ; Quality of Life ; Retrospective Studies ; *Social Support ; Spirituality ; Surveys and Questionnaires ; }, abstract = {Motor neurone disease (MND) is an illness involving the progressive degeneration of upper and lower motor neurones. There is no known cause or cure. The physical aspects of MND frequently receive the majority of attention, with psychosocial aspects accorded secondary importance. We undertook a comprehensive search of the available literature published between 1966 and 2006 on the psychosocial aspects of MND, including quality of life (QoL), depression, social support, life sustaining treatment (LST), coping, spirituality and current practice. The literature identified that QoL correlated more strongly with measures of suffering, social support and hopelessness than with the physical state of the patient. Depression is relatively common (prevalence rates up to 50%), as are other forms of psychological distress in the MND population, and is not associated with illness severity and functional status. Depression strongly correlates with QoL. Social support is often limited for MND patients and this also influences QoL. Hope and hopelessness are important issues for MND patients with hopelessness contributing significantly to suffering and, for some, a desire for hastened death. Choices and decisions about life sustaining treatments pose a burden for patients and carers. Despite the physical and emotional suffering associated with MND, a significant number cope well and find positive meaning in life. Many patients opting for life sustaining treatment report a satisfactory QoL. In conclusion, psychosocial aspects of life are important for patients with MND. Depression and other expressions of distress require recognition and treatment. Issues of hope, spirituality and life and death also require attention in clinical practice. Although guidelines exist to direct physicians to attend to the physical care, there is a distinct lack of guidance to attend to the psychological state of the MND patient.}, }
@article {pmid17439986, year = {2007}, author = {Corti, S and Locatelli, F and Papadimitriou, D and Del Bo, R and Nizzardo, M and Nardini, M and Donadoni, C and Salani, S and Fortunato, F and Strazzer, S and Bresolin, N and Comi, GP}, title = {Neural stem cells LewisX+ CXCR4+ modify disease progression in an amyotrophic lateral sclerosis model.}, journal = {Brain : a journal of neurology}, volume = {130}, number = {Pt 5}, pages = {1289-1305}, doi = {10.1093/brain/awm043}, pmid = {17439986}, issn = {1460-2156}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*surgery ; Animals ; Axons/pathology ; Biomarkers/analysis ; Cell Count ; Cell Differentiation ; Clone Cells ; Disease Models, Animal ; Disease Progression ; Enzyme-Linked Immunosorbent Assay ; Glial Fibrillary Acidic Protein/analysis ; Immunohistochemistry ; Insulin-Like Growth Factor I/analysis ; Lewis X Antigen/analysis/genetics/*metabolism ; Mice ; Mice, Transgenic ; Microscopy, Confocal ; Motor Neurons/pathology ; Multipotent Stem Cells/metabolism/*transplantation ; Nerve Regeneration ; Receptors, CXCR4/analysis/genetics/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Spinal Cord/pathology ; Superoxide Dismutase/genetics ; Vascular Endothelial Growth Factor A/analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by the degeneration of the motor neurons. We tested whether treatment of superoxide dismutase (SOD1)-G93A transgenic mouse, a model of ALS, with a neural stem cell subpopulation double positive for Lewis X and the chemokine receptor CXCR4 (LeX+CXCR4+) can modify the disease's progression. In vitro, after exposure to morphogenetic stimuli, LeX+CXCR4+ cells generate cholinergic motor neuron-like cells upon differentiation. LeX+CXCR4+ cells deriving from mice expressing Green Fluorescent Protein in all tissues or only in motor neurons, after a period of priming in vitro, were grafted into spinal cord of SOD1-G93A mice. Transplanted transgenic mice exhibited a delayed disease onset and progression, and survived significantly longer than non-treated animals by 23 days. Examination of the spinal cord revealed integration of donor-derived cells that differentiated mostly in neurons and in a lower proportion in motor neuron-like cells. Quantification of motor neurons of the spinal cord suggests a significant neuroprotection by LeX+CXCR4+ cells. Both VEGF- and IGF1-dependent pathways were significantly modulated in transplanted animals compared to controls, suggesting a role of these neurotrophins in MN protection. Our results support the therapeutic potential of neural stem cell fractions through both neurogenesis and growth factors release in motor neuron disorders.}, }
@article {pmid17439481, year = {2007}, author = {Koh, SH and Kim, Y and Kim, HY and Cho, GW and Kim, KS and Kim, SH}, title = {Recombinant human erythropoietin suppresses symptom onset and progression of G93A-SOD1 mouse model of ALS by preventing motor neuron death and inflammation.}, journal = {The European journal of neuroscience}, volume = {25}, number = {7}, pages = {1923-1930}, doi = {10.1111/j.1460-9568.2007.05471.x}, pmid = {17439481}, issn = {0953-816X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/pathology/physiopathology ; Animals ; Dinoprostone/metabolism ; Disease Models, Animal ; Disease Progression ; Erythropoietin/pharmacology/*therapeutic use ; Humans ; Inflammation/*drug therapy ; Mice ; Mice, Transgenic ; Motor Neurons/cytology/*drug effects/*physiology ; Recombinant Proteins ; Rotarod Performance Test ; Spinal Cord/metabolism ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; Survival Rate ; }, abstract = {Multifactorial pathogenic mechanisms, including inflammation, attenuated survival signals and enhanced death signals, are involved in amyotrophic lateral sclerosis (ALS). Erythropoietin (EPO) has recently been highlighted as a cytokine with various potent neuroprotective effects, including reduction of inflammation, enhancement of survival signals and prevention of neuronal cell death. This study was undertaken to evaluate the effect of recombinant human EPO (rhEPO) on ALS model mice. We treated 96 ALS model mice with vehicle only, or 1, 2.5 or 5 imu of rhEPO/g of mouse once every other week after they were 60 days old. The treatment significantly prolonged symptom onset and life span, preserved more motor neurons, enhanced survival signals, and attenuated inflammatory signals in a dose-dependent manner. These data suggest that treatment with rhEPO represents a potential therapeutic strategy for ALS.}, }
@article {pmid17434459, year = {2007}, author = {Eve, DJ and Dennis, JS and Citron, BA}, title = {Transcription factor p53 in degenerating spinal cords.}, journal = {Brain research}, volume = {1150}, number = {}, pages = {174-181}, doi = {10.1016/j.brainres.2007.02.088}, pmid = {17434459}, issn = {0006-8993}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/pathology ; Animals ; Behavior, Animal ; Benzothiazoles/pharmacology ; Case-Control Studies ; Caspase 3/metabolism ; Cell Survival/drug effects ; Disease Models, Animal ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation/physiology ; Humans ; Mice ; Mice, Mutant Strains ; Microarray Analysis/methods ; Motor Neurons/drug effects/metabolism ; Nerve Degeneration/*metabolism ; Organ Culture Techniques ; RNA, Messenger/biosynthesis ; Spinal Cord/*pathology ; Toluene/analogs &amp; derivatives/pharmacology ; Tumor Suppressor Protein p53/genetics/*metabolism ; }, abstract = {The causes of spinal cord cell loss in motor neuron disorders such as amyotrophic lateral sclerosis (ALS) are currently unknown. A role can be postulated for the transcription factor p53, which can induce apoptosis via upregulation of proapoptotic genes (e.g., Bax) and inhibition of antiapoptotic genes (e.g., Bcl-2). A model of motor neuron loss is the wobbler mouse that exhibits rapid motor neuron cell death as well as motor deficit from 21 days after birth. Affymetrix microarray data from wobbler mice demonstrate a 2.2-fold increase in p53 signal compared with their normal littermates, whereas qRT-PCR of RNA from laser capture microdissected ventral horns of normal and wobbler mice reveals a larger 6.6-fold increase in gene expression and this was supported by western blotting. Human ventral horns obtained from ALS and age-matched normal spinal cords also demonstrated an increase (2.7-fold) in p53 expression as determined by qRT-PCR. Evidence of a causative role for p53 in spinal cord cell death was provided by use of a p53 inhibitor, pifithrin-alpha, in organotypic slice cultures of mouse spinal cord. A 24-h pretreatment with pifithrin-alpha (and continuing in the presence of insult), significantly reduced the toxicity of a 48-h treatment with FeSO(4), tested with the MTT viability assay. These results indicate that p53 plays a functional role in oxidative stress-induced cell death and supports the possibility that elevated p53 could be involved in motor neuron death in ALS and the wobbler mouse.}, }
@article {pmid17433820, year = {2007}, author = {Miller, A and Panitch, H}, title = {Therapeutic use of dextromethorphan: key learnings from treatment of pseudobulbar affect.}, journal = {Journal of the neurological sciences}, volume = {259}, number = {1-2}, pages = {67-73}, doi = {10.1016/j.jns.2006.06.030}, pmid = {17433820}, issn = {0022-510X}, mesh = {Animals ; Brain/drug effects ; Dextromethorphan/*therapeutic use ; Enzyme Inhibitors/therapeutic use ; Excitatory Amino Acid Antagonists/*therapeutic use ; Humans ; Multiple Sclerosis/drug therapy ; Pseudobulbar Palsy/*drug therapy/etiology/pathology ; Quinidine/therapeutic use ; }, abstract = {A variety of neurological conditions and disease states are accompanied by pseudobulbar affect (PBA), an emotional disorder characterized by uncontrollable outbursts of laughing and crying. The causes of PBA are unclear but may involve lesions in neural circuits regulating the motor output of emotional expression. Several agents used in treating other psychiatric disorders have been applied in the treatment of PBA with some success but data are limited and these agents are associated with unpleasant side effects due to nonspecific activity in diffuse neural networks. Dextromethorphan (DM), a widely used cough suppressant, acts at receptors in the brainstem and cerebellum, brain regions implicated in the regulation of emotional output. The combination of DM and quinidine (Q), an enzyme inhibitor that blocks DM metabolism, has recently been tested in phase III clinical trials in patients with multiple sclerosis and amyotrophic lateral sclerosis and was both safe and effective in palliating PBA symptoms. In addition, clinical studies pertaining to the safety and efficacy of DM/Q in a variety of neurological disease states are ongoing.}, }
@article {pmid17433298, year = {2007}, author = {Koh, SH and Kim, Y and Kim, HY and Hwang, S and Lee, CH and Kim, SH}, title = {Inhibition of glycogen synthase kinase-3 suppresses the onset of symptoms and disease progression of G93A-SOD1 mouse model of ALS.}, journal = {Experimental neurology}, volume = {205}, number = {2}, pages = {336-346}, doi = {10.1016/j.expneurol.2007.03.004}, pmid = {17433298}, issn = {0014-4886}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/pathology ; Animals ; Blotting, Western ; Caspase 3/metabolism ; Cell Death/drug effects ; Cyclooxygenase 2/metabolism ; Cytochromes c/metabolism ; Cytosol/enzymology ; Disease Progression ; Enzyme Inhibitors/*therapeutic use ; Glycogen Synthase Kinase 3/*antagonists &amp; inhibitors/*genetics ; Humans ; In Situ Nick-End Labeling ; Intercellular Adhesion Molecule-1/metabolism ; Mice ; Mice, Transgenic ; Motor Neurons/pathology ; Poly(ADP-ribose) Polymerases/metabolism ; Postural Balance/drug effects ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Thiazoles/therapeutic use ; Urea/analogs &amp; derivatives/therapeutic use ; }, abstract = {Glycogen synthase kinase (GSK)-3 has recently been implicated in the pathogenesis of neurodegenerative diseases. Although the neuroprotective effects of GSK-3 inhibitors in Alzheimer's disease have been established, their effects on amyotrophic lateral sclerosis (ALS) have not been well defined. This study was undertaken to evaluate the effects of GSK-3 inhibition in the G93A-SOD1 mouse model of ALS. Groups of G93A-SOD1 mice were treated with varying concentrations of GSK-3 inhibitor VIII, a specific GSK-3 inhibitor that crosses the BBB, intraperitoneally 5 days a week after 60 days of age. The GSK-3 inhibitor VIII treatment significantly delayed the onset of symptoms and prolonged the life span of the animals, and inhibited the activity of GSK-3 in a concentration-dependent manner. Furthermore, this treatment preserved survival signals and attenuated death and inflammatory signals. These data suggest that GSK-3 plays an important role in the pathogenic mechanisms of ALS and that inhibition of GSK-3 could be a potential therapeutic candidate for ALS.}, }
@article {pmid17432958, year = {2007}, author = {Niessen, HG and Debska-Vielhaber, G and Sander, K and Angenstein, F and Ludolph, AC and Hilfert, L and Willker, W and Leibfritz, D and Heinze, HJ and Kunz, WS and Vielhaber, S}, title = {Metabolic progression markers of neurodegeneration in the transgenic G93A-SOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {The European journal of neuroscience}, volume = {25}, number = {6}, pages = {1669-1677}, doi = {10.1111/j.1460-9568.2007.05415.x}, pmid = {17432958}, issn = {0953-816X}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*complications/diagnosis/metabolism ; Analysis of Variance ; Animals ; Aspartic Acid/analogs &amp; derivatives/metabolism ; Disease Models, Animal ; Disease Progression ; Glutamine/metabolism ; Humans ; Magnetic Resonance Spectroscopy/methods ; Mice ; Mice, Transgenic ; Mutation ; Nerve Degeneration/*diagnosis/*etiology ; Superoxide Dismutase/*genetics ; Time Factors ; gamma-Aminobutyric Acid/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. Visualizing corresponding metabolic changes in the brain of patients with ALS with proton magnetic resonance spectroscopy ((1)H-MRS) may provide surrogate markers for an early disease detection, for monitoring the progression and for evaluating a treatment response. The primary objective of our study was to evaluate whether modifications in MR metabolite levels occur before clinical disease onset, and whether these changes are directly linked to a distinct spatial progression pattern in the CNS. Therefore, age-dependent alterations in the cerebral and spinal metabolic profile in the mouse model of ALS overexpressing the mutated human G93A-superoxide dismutase 1 (G93A-SOD1) were determined by high-resolution MRS of tissue extracts at 14.1 Tesla. Both non-transgenic mice (control mice) and transgenic mice overexpressing the non-mutated human SOD1 (tg-SOD1) served as controls. In the spinal cord of G93A-SOD1 mice significantly decreased levels of N-acetyl aspartate were already detected 34 days postpartum, i.e. about 60 days before the average disease onset caused by motor neuron decline. In addition, glutamine and gamma-aminobutyric acid concentrations were significantly diminished at Day 75, which is still in the presymptomatic phase of the disease. These metabolic changes were further progressive in the course of the disease and started to involve the brainstem at Day 75. Overall, high-resolution (1)H-MRS allows a sensitive spatial and temporal metabolite profiling in the presymptomatic phase of ALS even before significant neuronal cell loss occurs.}, }
@article {pmid17426672, year = {2007}, author = {Brooks, BR}, title = {Involuntary emotional expression disorder: treating the untreated.}, journal = {CNS spectrums}, volume = {12}, number = {4 Suppl 5}, pages = {23-27}, doi = {10.1017/s1092852900025980}, pmid = {17426672}, issn = {1092-8529}, mesh = {Affective Symptoms/diagnosis/*drug therapy/psychology ; Antidepressive Agents/adverse effects/therapeutic use ; Clinical Trials as Topic ; Dextromethorphan/adverse effects/therapeutic use ; Dopamine Agents/therapeutic use ; Drug Therapy, Combination ; Humans ; Psychotropic Drugs/adverse effects/*therapeutic use ; Quinidine/adverse effects/therapeutic use ; Treatment Outcome ; }, abstract = {Patients with involuntary emotional expression disorder (IEED) have impaired social and occupational functioning and there is currently no Food an Drug Administration-approved treatment. Treatment options include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), dopaminergic agents, and a combination of dextromethorphan and quinidine. Studies of monaminergic agents have typically been small and executed in single-center settings. Assessment measures generally show significant symptomatic improvements, including a reduction in the number of laughing or crying episodes and improvements in patients' clinical condition. The tolerability profiles of these agents are well defined, and include dizziness, tachycardia and QTc prolongation (TCAs), and sleep and sexual disturbances (SSRIs). The combination of dextromethorphan and quinidine has also been assessed in two large multicenter studies in patients with amyotrophic lateral sclerosis and multiple sclerosis. Compared with placebo and either agent alone, there were significant improvements in symptoms, quality of life, and relationships. The most common side effects were dizziness and nausea, and potential drug interactions with quinidine should also be considered. Choice of treatment should be evidence-based, taking into account both efficacy and tolerability.}, }
@article {pmid17418957, year = {2007}, author = {Stommel, EW and van Hoff, RM and Graber, DJ and Bercury, KK and Langford, GM and Harris, BT}, title = {Tumor necrosis factor-alpha induces changes in mitochondrial cellular distribution in motor neurons.}, journal = {Neuroscience}, volume = {146}, number = {3}, pages = {1013-1019}, doi = {10.1016/j.neuroscience.2007.02.036}, pmid = {17418957}, issn = {0306-4522}, mesh = {Animals ; Apoptosis/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; In Vitro Techniques ; Microscopy, Video ; Mitochondria/*drug effects/ultrastructure ; Motor Neurons/*drug effects/ultrastructure ; Necrosis ; Rats ; Rats, Sprague-Dawley ; Tissue Fixation ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {Motor neuron (MN) mitochondrial abnormalities and elevation in spinal fluid levels of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). The mechanism of neuron death in ALS remains unclear, along with the contributions of mitochondrial dysfunction and inflammation in the process. Cell cultures enriched for MN derived from embryonic rat spinal cords were established and directly exposed in vitro to recombinant TNF-alpha for varying lengths of time. Although cytokine exposure for up to 4 days failed to induce MN death, mitochondrial changes were observed shortly after initiating treatment. Our results demonstrate that TNF-alpha induced mitochondrial redistribution toward the soma in MN. We postulate that inflammation may precede, and in fact cause, the mitochondrial changes observed in ALS tissue.}, }
@article {pmid17418947, year = {2007}, author = {Huang, QY and Yu, L and Ferrante, RJ and Chen, JF}, title = {Mutant SOD1G93A in bone marrow-derived cells exacerbates 3-nitropropionic acid induced striatal damage in mice.}, journal = {Neuroscience letters}, volume = {418}, number = {2}, pages = {175-180}, doi = {10.1016/j.neulet.2007.03.038}, pmid = {17418947}, issn = {0304-3940}, support = {R01 NS041083/NS/NINDS NIH HHS/United States ; NS37403/NS/NINDS NIH HHS/United States ; NS41083/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology ; Animals ; Bone Marrow Cells/enzymology ; Bone Marrow Transplantation ; Corpus Striatum/*drug effects/*metabolism/physiopathology ; Genetic Predisposition to Disease/genetics ; Humans ; Huntington Disease/chemically induced/enzymology/genetics ; Injections, Intraperitoneal/adverse effects ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation/genetics ; Nerve Degeneration/*chemically induced/*genetics/physiopathology ; Neurotoxins ; Nitro Compounds/*toxicity ; Oxidative Stress/genetics ; Propionates/*toxicity ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Transplantation Chimera ; }, abstract = {3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, produces selective lesions in striatal neurons that resemble those observed in Huntington's disease neuropathology. In this study, we evaluated the role of peripheral bone marrow-derived cells (BMDCs) in the 3-NP-induced striatal damage by transplanting bone marrow cells with human SOD1 G93A mutation (mSOD1(G93A)) which induces amyotrophic lateral sclerosis through an unknown gain of toxicity and mitochondrial dysfunction. We assessed striatal damage after 3-NP treatment in the recipient C57BL/6 wild-type (WT) mice that received bone marrow cells from WT or mSOD1(G93A) transgenic donor mice (WT-->WT or mSOD(G93A)-->WT). After intraperitoneal injection of 3-NP, six of the eight mSOD1(G93A)-->WT mice had bilateral striatal lesions while only one out of eight WT-->WT mice had a striatal lesion. The lesion volume was significantly higher in the mSOD1(G93A)-->WT mice than in the WT-->WT mice. However, following an intrastriatal injection of 3-NP, there was no significant difference in the lesion volumes between the WT-->WT mice and mSOD1(G93A)-->WT mice. Thus, the exacerbation of 3-NP-induced striatal damage in mSOD(G93A)-->WT mice was only seen after systemic administration of 3-NP, but not after intrastriatal injection. These results demonstrate that altered SOD1 activity (mSOD(G93A)) in BMDCs affects striatal damage probably through a mechanism involving a systemic factor.}, }
@article {pmid17416829, year = {2007}, author = {Schimrigk, SK and Bellenberg, B and Schlüter, M and Stieltjes, B and Drescher, R and Rexilius, J and Lukas, C and Hahn, HK and Przuntek, H and Köster, O}, title = {Diffusion tensor imaging-based fractional anisotropy quantification in the corticospinal tract of patients with amyotrophic lateral sclerosis using a probabilistic mixture model.}, journal = {AJNR. American journal of neuroradiology}, volume = {28}, number = {4}, pages = {724-730}, pmid = {17416829}, issn = {0195-6108}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*pathology ; Anisotropy ; Diffusion Magnetic Resonance Imaging/*methods ; Echo-Planar Imaging/methods ; Female ; Humans ; Image Processing, Computer-Assisted ; Male ; Middle Aged ; Models, Statistical ; Observer Variation ; Pyramidal Tracts/*pathology ; Reproducibility of Results ; }, abstract = {BACKGROUND AND PURPOSE: In amyotrophic lateral sclerosis (ALS), fiber degeneration within the corticospinal tract (CST) can be quantified by diffusion tensor imaging (DTI) as an indirect marker of upper motor neuron involvement. A new method of measuring quantitative DTI parameters using a probabilistic mixture model for fiber tissue and background in the corticospinal tract of patients with ALS is evaluated.<br><br>MATERIALS AND METHODS: Axial echo-planar imaging (EPI) DTI datasets (6 gradient directions, 10 repetitions) were acquired for 10 patients and 20 healthy control subjects. The diffusion tensor was visualized in a multiplanar viewer using a unique color coding method. Pure fiber tissue inside a region is separated from background and mixture voxels using a probabilistic mixture model. This allows for a reduction of errors as a result of partial volume effects and measurement variability.<br><br>RESULTS: Fractional anisotropy (FA) was measured within the CST at levels ranging from internal capsule to pons. Mean coefficients of variation of intrarater, scan-rescan, and inter-rater reproducibility were 2.4%, 3.0%, and 5.7%, respectively. Optimal measurement positions along the CST with respect to minimum variability and maximum difference between patients and healthy subjects were identified in the caudal half of the internal capsule. Moreover, a negative correlation between the age-corrected FA and the disease duration but not the ALS Severity scale score was found.<br><br>CONCLUSION: The new software for fiber integrity quantification is suited to assess FA in the corticospinal tract with high reproducibility. Thus, this tool can be useful in future studies for monitoring disease status and potential treatment efficiency.}, }
@article {pmid17406652, year = {2007}, author = {Choi, Y and Kim, HS and Shin, KY and Kim, EM and Kim, M and Kim, HS and Park, CH and Jeong, YH and Yoo, J and Lee, JP and Chang, KA and Kim, S and Suh, YH}, title = {Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {32}, number = {11}, pages = {2393-2404}, doi = {10.1038/sj.npp.1301377}, pmid = {17406652}, issn = {0893-133X}, mesh = {Alzheimer Disease/chemically induced/*complications/genetics ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor/genetics ; Analysis of Variance ; Animals ; Avoidance Learning/drug effects ; Brain/pathology ; Case-Control Studies ; Cell Death/drug effects ; *Cognition Disorders/drug therapy/etiology/pathology ; Disease Models, Animal ; Humans ; Male ; Maze Learning/drug effects ; Mice ; Mice, Transgenic ; Minocycline/pharmacology/*therapeutic use ; Nerve Growth Factor/pharmacology ; Neurons/*pathology ; Neuroprotective Agents/pharmacology/*therapeutic use ; PC12 Cells/drug effects ; Peptide Fragments ; Rats ; Rats, Wistar ; Transfection ; }, abstract = {Minocycline is a semi-synthetic tetracycline antibiotic that effectively crosses the blood-brain barrier. Minocycline has been reported to have significant neuroprotective effects in models of cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, and Huntington's and Parkinson's diseases. In this study, we demonstrate that minocycline has neuroprotective effects in in vitro and in vivo Alzheimer's disease models. Minocycline was found to attenuate the increases in the phosphorylation of double-stranded RNA-dependent serine/threonine protein kinase, eukaryotic translation initiation factor-2 alpha and caspase 12 activation induced by amyloid beta peptide1-42 treatment in NGF-differentiated PC 12 cells. In addition, increases in the phosphorylation of eukaryotic translation initiation factor-2 alpha were attenuated by administration of minocycline in Tg2576 mice, which harbor mutated human APP695 gene including the Swedish double mutation and amyloid beta peptide(1-42)-infused rats. We found that minocycline administration attenuated deficits in learning and memory in amyloid beta peptide(1-42)-infused rats. Increased phosphorylated state of eukaryotic translation initiation factor-2 alpha is observed in Alzheimer's disease patients' brains and may result in impairment of cognitive functions in Alzheimer's disease patients by decreasing the efficacy of de novo protein synthesis required for synaptic plasticity. On the basis of these results, minocycline may prove to be a good candidate as an effective therapeutic agent for Alzheimer's disease.}, }
@article {pmid19300558, year = {2007}, author = {Tselis, A and Khan, O and Lisak, RP}, title = {Glatiramer acetate in the treatment of multiple sclerosis.}, journal = {Neuropsychiatric disease and treatment}, volume = {3}, number = {2}, pages = {259-267}, pmid = {19300558}, issn = {1176-6328}, abstract = {Glatiramer acetate is an immunomodulating drug used in the treatment of multiple sclerosis. It consists of a copolymer of amino acid residues in the same stoichiometric proportions as in myelin basic protein. Its mechanism of action is not entirely known and is probably multifaceted, with deletion of some immune cell populations and stimulation of others in these patients. Some mechanisms involve neuroprotectant effects. There is ample evidence of its efficacy in relapsing-remitting disease, using both clinical and imaging measures of disease activity, and in this paper we review the clinical and basic studies of this drug. Finally we discuss how some of its neuroprotectant effects may be useful in neurodegeneration such as is seen in more advanced cases of multiple sclerosis and other diseases such as amyotrophic lateral sclerosis and Parkinson's disease.}, }
@article {pmid17394546, year = {2007}, author = {Ezzi, SA and Urushitani, M and Julien, JP}, title = {Wild-type superoxide dismutase acquires binding and toxic properties of ALS-linked mutant forms through oxidation.}, journal = {Journal of neurochemistry}, volume = {102}, number = {1}, pages = {170-178}, doi = {10.1111/j.1471-4159.2007.04531.x}, pmid = {17394546}, issn = {0022-3042}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Cell Death/genetics/physiology ; Cells, Cultured ; Chromogranin B/metabolism ; Enzyme-Linked Immunosorbent Assay ; Immunoblotting ; Immunoprecipitation ; Mice ; Motor Neurons/physiology ; Mutation/physiology ; Oxidation-Reduction ; Plasmids/genetics ; Protein Binding/genetics ; Protein Folding ; Recombinant Proteins/biosynthesis/genetics/isolation &amp; purification ; Reverse Transcriptase Polymerase Chain Reaction ; Spinal Cord/cytology ; Subcellular Fractions/metabolism ; Superoxide Dismutase/*genetics/metabolism/*toxicity ; Superoxide Dismutase-1 ; Transfection ; Ubiquinone/metabolism ; }, abstract = {Recent studies suggest that superoxide dismutase (SOD1) may represent a major target of oxidative damage in neurodegenerative diseases. To test the possibility that oxidized species of wild-type (WT) SOD1 might be involved in pathogenic processes, we analyzed the properties of the WT human SOD1 protein after its oxidation in vivo or in vitro by hydrogen peroxide (H2O2) treatment. Using transfected Neuro2a cells expressing WT or amyotrophic lateral sclerosis-linked SOD1 species, we show that exposure to H2O2 modifies the properties of WT SOD1. Western blot analysis of immunoprecipitates from cell lysates revealed that, like mutant SOD1, oxidized WT SOD1 can be conjugated with poly-ubiquitin and can interact with Hsp70. Chromogranin B, a neurosecretory protein that interacts with mutant SOD1 but not with WT SOD1, was co-immunoprecipitated with oxidized WT SOD1 from lysates of Neuro2a cells treated with H2O2. Treatment of microglial cells (line BV2) with either oxidized WT SOD1 or mutant SOD1 recombinant proteins induced tumor necrosis factor-alpha and inducible nitric oxide synthase. Furthermore, exposure of cultured motor neurons to oxidized WT SOD1 caused dose-dependent cell death like mutant SOD1 proteins. These results suggest that WT SOD1 may acquire binding and toxic properties of mutant forms of SOD1 through oxidative damage.}, }
@article {pmid17381183, year = {2007}, author = {Kurt, A and Nijboer, F and Matuz, T and Kübler, A}, title = {Depression and anxiety in individuals with amyotrophic lateral sclerosis: epidemiology and management.}, journal = {CNS drugs}, volume = {21}, number = {4}, pages = {279-291}, pmid = {17381183}, issn = {1172-7047}, mesh = {Amyotrophic Lateral Sclerosis/complications ; Anxiety/*epidemiology/etiology/*therapy ; Depression/*epidemiology/etiology/*therapy ; Humans ; Male ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no curative treatment. Considering the devastating nature of the disease, a high prevalence of depression and anxiety in affected patients would be expected. A review of the literature shows prevalence rates for depression in ALS patients ranging from 0% to 44%, but studies using the structured interview according to DSM-IV criteria find highly consistent rates of 9-11%. Prevalence rates for anxiety in ALS range from 0% to 30%. Depression and anxiety appear to be not always properly addressed aspects of ALS, as there are only a few references in the literature about psychological and pharmacological interventions. Additionally, pharmacological antidepressant therapy is often not continuously monitored and its effectiveness remains unevaluated. A review of the literature and our own experiences show that there is a lack of psychological care and, to our knowledge, there is no specific psychological intervention method for ALS patients. Concerning pharmacological treatment of depression in patients with ALS, there is broad consensus among clinical experts that SSRIs and TCAs are helpful, but there have been no controlled clinical studies of these medications in ALS patients. TCAs can be prescribed if anticholinergic effects are desired simultaneously for treating pseudohypersalivation or insomnia. Anxiety is usually treated with anxiolytics, but again there have been no systematic studies of these drugs in patients with ALS. For psychological intervention we suggest a cognitive behavioural approach, which has to be integrated into an intervention programme that includes teaching of appropriate coping strategies and reappraisal skills and encourages engagement in activities that are still practicable and pleasant. We propose that the treatment of depression and anxiety should involve both cognitive behavioural therapy and pharmacological intervention. Pharmacological treatment should be strictly monitored for effectiveness. To date, no clinical trials are available that would allow us to recommend pharmacotherapy over psychotherapy or vice versa; however, evidence from other patient groups, such as elderly patients diagnosed with major depressive disorder, suggests that a combination of both therapies has the potential to also improve depression and anxiety in patients with ALS.}, }
@article {pmid17378888, year = {2007}, author = {Kahl, M and Haase, E and Kocher, T and Rühling, A}, title = {Clinical effects after subgingival polishing with a non-aggressive ultrasonic device in initial therapy.}, journal = {Journal of clinical periodontology}, volume = {34}, number = {4}, pages = {318-324}, doi = {10.1111/j.1600-051X.2007.01056.x}, pmid = {17378888}, issn = {0303-6979}, mesh = {Adult ; Aged ; Analysis of Variance ; Female ; Humans ; Male ; Middle Aged ; Periodontal Attachment Loss/*therapy ; Periodontal Pocket/*therapy ; Prospective Studies ; Root Planing/*instrumentation ; Statistics, Nonparametric ; Ultrasonic Therapy ; }, abstract = {OBJECTIVES: The Vector ultrasonic system provides root debridement supported by different abrasive irrigation fluids. The aim of this study was to investigate the clinical outcome of initial therapy with subgingival low-abrasive debridement.<br><br>MATERIAL AND METHODS: Twenty patients, who had at least two teeth with pocket depths >5 mm in each quadrant, took part in this prospective randomized clinical study. Patients were treated in a split-mouth design as one test quadrant (1) subgingivally with Vector fluid polish (VU-H) and as three control quadrants, (2) with only supragingival polishing (PO-H), (3) with hand instruments (HI-H) performed by a hygienist and (4) with hand instruments (HI-D) performed by a dentist. At baseline, 3 and 6 months after treatment, pocket depths and attachment levels (ALs) were measured and bleeding on probing (BOP) was recorded.<br><br>RESULTS: At 6-month evaluation, all groups showed an improvement in clinical parameters. No statistically significant differences in any of the investigated parameters could be observed between the Vector group and the hand scaling groups, or when comparing the results of the two different operators.<br><br>CONCLUSION: This study demonstrates that Vector treatment with polishing fluid was able to reduce pocket depths and the prevalence of BOP and improve clinical AL in a similar way as scaling with curettes.}, }
@article {pmid17368956, year = {2007}, author = {Kast, RE and Altschuler, EL}, title = {Consideration of acamprosate for treatment of amyotrophic lateral sclerosis.}, journal = {Medical hypotheses}, volume = {69}, number = {4}, pages = {836-837}, doi = {10.1016/j.mehy.2007.01.072}, pmid = {17368956}, issn = {0306-9877}, mesh = {Acamprosate ; Animals ; Calcium/*physiology ; Disease Models, Animal ; Humans ; Mice ; Motor Neuron Disease/*drug therapy/physiopathology ; Motor Neurons/drug effects/physiology ; Taurine/*analogs &amp; derivatives/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease of degeneration of motor neurons. There is no known cure or life extending treatment. Much recent work has suggested that a possible cause of ALS is constitutive opening of the calcium pore in glutamate sensitive AMPA channels secondary to a failure of RNA editing that would change a crucial glutamate in the channel to arginine. Here, we point out that the small molecule pharmaceutical acamprosate, usually used as a drug to maintain alcohol abstinence, may block this calcium pore--as do the related molecules endogenous polyamines such as putrescine, cadaverine, spermidine and spermine--and thus might have use in ALS.}, }
@article {pmid17365122, year = {2007}, author = {Kim, DW and Hong, GH and Lee, HH and Choi, SH and Chun, BG and Won, CK and Hwang, IK and Won, MH}, title = {Effect of colloidal silver against the cytotoxicity of hydrogen peroxide and naphthazarin on primary cultured cortical astrocytes.}, journal = {The International journal of neuroscience}, volume = {117}, number = {3}, pages = {387-400}, doi = {10.1080/00207450600592016}, pmid = {17365122}, issn = {0020-7454}, mesh = {Animals ; Animals, Newborn ; Astrocytes/*drug effects/metabolism ; Cells, Cultured ; Cerebral Cortex/*cytology ; Dose-Response Relationship, Drug ; Drug Interactions ; Hydrogen Peroxide/*toxicity ; L-Lactate Dehydrogenase/metabolism ; Naphthoquinones/*toxicity ; Oxidants/*toxicity ; Rats ; Rats, Sprague-Dawley ; Reactive Nitrogen Species/metabolism ; Silver Compounds/*pharmacology ; Tetrazolium Salts ; Thiazoles ; }, abstract = {One major pathogenesis in degenerative disorders of the central nervous system (CNS), including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and ischemia, is the oxidative stress induced by reactive oxygen species (ROS). The present study investigated the protective effect of colloidal silver, which is widely marketed as a dietary supplement for diseases like diabetes, AIDS, cancer, and various infections, upon the oxidative brain damage induced by H(2)O(2) or naphthazarin treatment. LDH release from primary cultured astrocytes was enhanced by naphthazarin treatment, and this elevation of the LDH concentration in medium was blocked by colloidal silver treatment. However, hydrogen peroxide was little affected by the colloidal silver. Fluorescence of DCF (peroxides) increased in astrocytes incubated with hydrogen peroxide or naphthazarin compared to the control. When exposed to naphthazarin-induced cells, ROS formation appeared to be reduced by colloidal silver. However, intracellular ROS formation in hydrogen peroxide-treated cells slightly reduced by colloidal silver. These results suggest that colloidal silver has a protective activity against the oxidative stress induced by naphthazarin, but not by hydrogen peroxide.}, }
@article {pmid17355545, year = {2007}, author = {Zoccolella, S and Beghi, E and Palagano, G and Fraddosio, A and Guerra, V and Samarelli, V and Lepore, V and Simone, IL and Lamberti, P and Serlenga, L and Logroscino, G and , }, title = {Riluzole and amyotrophic lateral sclerosis survival: a population-based study in southern Italy.}, journal = {European journal of neurology}, volume = {14}, number = {3}, pages = {262-268}, doi = {10.1111/j.1468-1331.2006.01575.x}, pmid = {17355545}, issn = {1468-1331}, mesh = {Adult ; Age Distribution ; Age Factors ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy/*mortality ; Bulbar Palsy, Progressive/drug therapy/mortality ; Central Nervous System/drug effects/metabolism/physiopathology ; Cohort Studies ; Disease Progression ; Early Diagnosis ; Female ; Humans ; Italy/epidemiology ; Longitudinal Studies ; Male ; Middle Aged ; Motor Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/*therapeutic use ; Prospective Studies ; Riluzole/*therapeutic use ; Survival Rate/trends ; Treatment Outcome ; }, abstract = {Riluzole is to date the only treatment that prolongs amyotrophic lateral sclerosis (ALS) survival. However, results on the efficacy of riluzole in observational population-based studies with a longer follow-up are conflicting and it is still unclear if the effect of the drug is limited to an early stage of the disease and to some specific subgroups of patients. The objective is: (i) to evaluate the effect of riluzole on ALS survival in a cohort of incident cases; (ii) to examine whether bulbar-ALS benefits from the medication to a greater extent and (iii) to assess the efficacy of the drug in elderly patients. Source of the study was a prospective population-based registry of ALS established in Puglia, Southern Italy. We examined survival of 126/130 incident ALS cases diagnosed during the period 1998-1999. Seventy-three patients were prescribed riluzole and the remaining 53 were not. Riluzole therapy increased survival rates at 12 months by approximately 10% and prolonged survival by 6 months (18.2 months vs. 12.4; peto-test: 2.78; P = 0.09). This beneficial effect was present amongst bulbar-onset ALS (peto-test: 4.11; P = 0.042), but not in subjects with limb-onset (peto-test: 0.48; P = 0.4). In patients aged >70 years riluzole treatment was associated with an 8 months longer median survival time [15.4 months vs. 7.1] and a reduction in mortality rate at 12 months by 27%, regardless of site of symptoms onset. In multivariate analysis, riluzole use was an independent predictor of survival at 12 months from the diagnosis with borderline significance (P = 0.06). Riluzole was effective amongst cases with bulbar-onset ALS (P = 0.04), whereas in subjects with limb-onset there was no effect on survival at 12 months (P = 0.5). In each model riluzole did not influence survival at 24 months. Conversely, riluzole use was associated with an improvement in survival amongst elderly patients both at 12 (P = 0.07), at 24 months (P = 0.03) and in the entire follow-up period (P < 0.04). In this population-based series, we found that riluzole therapy improves ALS survival. The efficacy of the drug was present amongst bulbar-onset ALS and older patients, but not in subjects with limb-onset. The favourable effect of the drug was transient, as it was lost in prolonged follow-up. Our observations support the use of riluzole at an early stage of ALS in bulbar and elderly patients. However, the appropriate duration of riluzole treatment remains to be established.}, }
@article {pmid17350694, year = {2007}, author = {Centonze, D and Finazzi-Agrò, A and Bernardi, G and Maccarrone, M}, title = {The endocannabinoid system in targeting inflammatory neurodegenerative diseases.}, journal = {Trends in pharmacological sciences}, volume = {28}, number = {4}, pages = {180-187}, doi = {10.1016/j.tips.2007.02.004}, pmid = {17350694}, issn = {0165-6147}, mesh = {Animals ; Cannabinoid Receptor Modulators/antagonists &amp; inhibitors/*metabolism ; Central Nervous System Diseases/drug therapy/*metabolism/pathology ; *Endocannabinoids ; Humans ; Inflammation/metabolism ; Nerve Degeneration ; Receptors, Cannabinoid/metabolism ; }, abstract = {The classical divide between degenerative and inflammatory disorders of the CNS is vanishing as accumulating evidence shows that inflammatory processes are important in the pathophysiology of primarily degenerative disorders, and neurodegeneration complicates primarily inflammatory diseases of the brain and spinal cord. Here, we review the contribution of degenerative and inflammatory processes to CNS disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis and HIV-associated dementia. An early combination of neuroprotective and anti-inflammatory approaches to these disorders seems particularly desirable because isolated treatment of one pathological process might worsen another. We also discuss the apparently unique opportunity to modify neurodegeneration and neuroinflammation simultaneously by pharmacological manipulation of the endocannabinoid system in the CNS and in peripheral immune cells. Current knowledge of this system and its involvement in the above CNS disorders are also reviewed.}, }
@article {pmid17345579, year = {2007}, author = {Lederer, CW and Santama, N}, title = {Amyotrophic lateral sclerosis--the tools of the trait.}, journal = {Biotechnology journal}, volume = {2}, number = {5}, pages = {608-621}, doi = {10.1002/biot.200600247}, pmid = {17345579}, issn = {1860-7314}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*metabolism/*therapy ; Animals ; Biomarkers/*metabolism ; Biotechnology/*methods ; Drug Delivery Systems/*methods ; Humans ; Nerve Tissue Proteins/*metabolism ; }, abstract = {The aim of this review is to analyze how our knowledge on the etiology, pathology, and treatment of amyotrophic lateral sclerosis (ALS) has profited from the application of biotechnology tools for the identification of disease markers, the development of animal disease models, and the design of innovative therapeutics. In humans, ALS-specific clinical, genetic or protein biomarkers, or panels of biomarkers stemming from genomics and proteomics analyses can be critical for early diagnosis, monitoring of disease progression, drug validation in clinical trials, and identification of therapeutic targets for subsequent drug development. At the same time, animal models representing a number of human superoxide dismutase 1 mutations, intermediate-filament disorganization or axonal-transport defects have been invaluable in unraveling aspects of the pathophysiology of the disease; in each case, these only represent a small proportion of all ALS patients. Preclinical and clinical trials, although at present heavily concentrating on pharmacological approaches, are embracing the emerging alternative strategies of stem-cell and gene therapy. In combination with a further subcategorization of patients and the development of corresponding model systems for functional analyses, they will significantly influence the already changing face of ALS therapy.}, }
@article {pmid17338130, year = {2006}, author = {Kumor, K and Pierzchała, K}, title = {[The problem of fatigue in neurological disorders].}, journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)}, volume = {59}, number = {9-10}, pages = {685-691}, pmid = {17338130}, issn = {0043-5147}, mesh = {Chronic Disease ; Depression/etiology/physiopathology ; Disability Evaluation ; Fatigue/diagnosis/*etiology/therapy ; Humans ; Mental Fatigue/etiology/physiopathology ; Multiple Sclerosis/complications/physiopathology ; Nervous System Diseases/*complications/diagnosis ; Parkinson Disease/complications/physiopathology ; Postpoliomyelitis Syndrome/complications/physiopathology ; Severity of Illness Index ; Stroke/complications/physiopathology ; }, abstract = {Fatigue or piercing feeling of weakness, lack of strength and energy or total exhaustion is a common complaint of patients with neurological disorders. From 40 to over 90 per cent of individuals with multiple sclerosis, Parkinson disease, amyotrophic lateral sclerosis, neuroboreliosis, post polio syndrome or stroke confirm its experience. It is not infrequently numbered among most disabling complaints. A separate entity, with fatigue as a cardinal sign, is a chronic fatigue syndrome, a disorder, though controversial, more and more frequently diagnosed. Fatigue ought to be discriminated from fatigability, paresis, somnolence and, first of all depression which commonly coexists in chronic disorders. The assessment is almost entirely based on self-estimate scales filled in by a patient. Attainable results of neuroimaging, electrophysiological, polisomnographic, vegetative, psychological and biochemical surveys have not allowed yet to define the pathogenesis of fatigue. The treatment basis consists of behavioral therapy, psychotherapy and a proper treatment of the basic disease.}, }
@article {pmid19071463, year = {2007}, author = {Gómez, V and Font, J and Callao, MP}, title = {Sequential injection analysis with second-order treatment for the determination of dyes in the exhaustion process of tanning effluents.}, journal = {Talanta}, volume = {71}, number = {3}, pages = {1393-1398}, doi = {10.1016/j.talanta.2006.07.019}, pmid = {19071463}, issn = {1873-3573}, abstract = {A sequential injection (SI)-DAD spectrophotometric method to control the exhaustion of dyes in a mixture of three dyes from a tanning industry process has been developed. It is based on an interdiffusion process of the sample and reagents which leads to a gradual fall in pH through the channel to the detector recording a data matrix. The aim of this paper is to develop a second-order calibration model that is unaffected by interferents by applying multivariate curve resolution with alternating least squares (MCR-ALS). We obtained a linear calibration in the 5-30mgl(-1) range with a correlation coefficient of 0.999 for each dye with detection limits of 2.6, 3.9 and 2.1mgl(-1) for Acid Red, Acid Brown and Acid Orange, respectively. The simultaneous determination of the three dyes from tanning samples showed a satisfactory precision for the three analytes. The method has been validated comparing the concentration of some spiked samples with the expected concentration using a t-paired test. When we used this method to study the exhaustion of dyes, we found that there were several stages in this process. These data may be the key to optimising the exhaustion process.}, }
@article {pmid17322959, year = {2006}, author = {Pozza, AM and Delamura, MK and Ramirez, C and Valério, NI and Marino, LH and Lamari, NM}, title = {Physiotherapeutic conduct in amyotrophic lateral sclerosis.}, journal = {Sao Paulo medical journal = Revista paulista de medicina}, volume = {124}, number = {6}, pages = {350-354}, pmid = {17322959}, issn = {1516-3180}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Breathing Exercises ; Fatigue/therapy ; Humans ; *Physical Therapy Modalities ; Quality of Life ; Respiratory Insufficiency/therapy ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal progressive neurodegenerative disease with multifactorial etiology for which, so far, there is no effective medicinal treatment. However, by means of kinesiotherapy intervention and patient guidance and care, physiotherapy can delay physical functional losses, muscle fatigue and immobility of the joint-muscle system, thereby improving the quality of life. This survey had the aim of reviewing the physiotherapeutic conduct currently used in ALS cases. Monthly monitoring is recommended, with changes in goals and conduct at each stage of the disease, activities to be pursued around the home, and emphasis on stretching, muscle strengthening, posture adequacy and respiratory kinesiotherapy.}, }
@article {pmid17322493, year = {2007}, author = {Morrison, KM and Bidlingmaier, M and Stadler, S and Wu, Z and Skriver, L and Strasburger, CJ}, title = {Sample pre-treatment determines the clinical usefulness of acid-labile subunit immunoassays in the diagnosis of growth hormone deficiency and acromegaly.}, journal = {European journal of endocrinology}, volume = {156}, number = {3}, pages = {331-339}, doi = {10.1530/EJE-06-0592}, pmid = {17322493}, issn = {0804-4643}, mesh = {Acromegaly/blood/*diagnosis ; Adult ; Carrier Proteins/*blood/chemistry ; Chromatography, Gel ; Enzyme-Linked Immunosorbent Assay/methods ; Freezing ; Glycoproteins/*blood/chemistry ; Human Growth Hormone/blood/*deficiency ; Humans ; Immunoassay/methods ; Insulin-Like Growth Factor Binding Protein 3/blood/chemistry ; Male ; Middle Aged ; Reference Values ; Reproducibility of Results ; Sensitivity and Specificity ; }, abstract = {OBJECTIVE: The usefulness of measuring the GH-dependent acid-labile subunit (ALS) in the management of GH deficiency (GHD) and acromegaly remains in question and is investigated in this study, comparing several different immunoassays for ALS.<br><br>METHOD: We compared the diagnostic accuracy of a commercially available polyclonal Ab-based ELISA with SDS pre-treatment (SDS-ELISA) with a monoclonal Ab-based immunofluorometric assay, using two unfolding methods (urea (UREA) and Glycine-HCl (Gly)). The corresponding molecular weight (MW) of ALS and IGFBP-3 immunoreactivity was determined. The clinical usefulness of each assay was examined in adult GH disorders.<br><br>RESULTS: ALS was lower in GHD and higher in acromegaly using all assays. In GHD, UREA had higher sensitivity and specificity than SDS-ELISA (59 and 69% versus 41 and 51% respectively). In acromegaly, sensitivity and specificity was 94 and 87% for UREA, 81 and 36% for Gly, and 44 and 44% for SDS-ELISA. After UREA, immunoreactivity for ALS and IGFBP-3 eluted at their predicted free MW using size-exclusion chromatography, whereas ALS immunoreactivity in SDS (300-600 kDa) and Gly (250-500 kDa) was at a high apparent MW consistent with aggregation.<br><br>CONCLUSION: The diagnostic accuracy of ALS varies with assay choice and pre-treatment modality. UREA, which results in migration of ALS at the expected MW on a sizing column, has the highest specificity and sensitivity. Thus, if measured in an assay in which ALS is unfolded without aggregation, ALS is a clinically highly useful parameter for the assessment of GH.}, }
@article {pmid17320308, year = {2007}, author = {Gracia, MC}, title = {A possible cause and corresponding treatment for inflammatory, auto-immune or auto-aggressive diseases.}, journal = {Medical hypotheses}, volume = {69}, number = {2}, pages = {395-402}, doi = {10.1016/j.mehy.2006.12.030}, pmid = {17320308}, issn = {0306-9877}, mesh = {Autoimmune Diseases/*etiology/prevention &amp; control/psychology/*therapy ; Conditioning, Operant/physiology ; Humans ; Inflammation/*etiology/prevention &amp; control/psychology/*therapy ; }, abstract = {This article develops the idea that many inflammatory, auto-immune or auto-aggressive diseases might result from conditioned responses acquired when occasional, possibly minor pathological conditions, normal organ fatigue, or similar sensations, are reinforced by an intense neural reward coinciding, often by pure bad luck, with these minor troubles. After such conditioning, and especially in times of frustration or distress, the brain will repeatedly try to obtain the reward again by recreating, with an intensity in proportion to the degree of frustration, the sensorial pattern of the initial minor trouble, producing auto-aggressive effects. This leads naturally to the idea of trying to extinguish diseases implying self-aggression by applying negative reinforcement. This behavioural strategy has been tested for some minor or medium-severity inflammatory/auto-immune troubles and, essentially, it works, although it implies practical difficulties that are reviewed in the text. Furthermore, the experience was very limited because of the difficulty of convincing people to try for good a scarcely tested technique requiring intense mental effort and completely different from the medical treatments people are used to. The article describes the physiological-behavioural model underlying our proposal, evaluates different possibilities of treatment, and provides useful practical advice. In particular, it appears that our proposal seems best suited for diseases in which the mental abilities of the person are intact and the inflammatory aggression is clearly identifiable by its symptoms, for example pain, itching, fatigue or paralysis. Possible candidate diseases could be, for example, superficial allergies or irritations, digestive inflammatory problems, rheumatoid or circulatory troubles, or motor neurological diseases like multiple sclerosis, Guillain-Barré syndrome and possibly ALS or Parkinson. The article is completed by some guidelines on the prevention of diseases implying auto-aggression, based on self-control, diet, exercise, mutual help, and avoidance of psychoactive or aggressive agents.}, }
@article {pmid17319446, year = {2006}, author = {Prommer, E}, title = {Modafinil: is it ready for prime time?.}, journal = {Journal of opioid management}, volume = {2}, number = {3}, pages = {130-136}, doi = {10.5055/jom.2006.0022}, pmid = {17319446}, issn = {1551-7489}, mesh = {Attention Deficit Disorder with Hyperactivity/drug therapy ; Benzhydryl Compounds/chemistry/pharmacokinetics/*therapeutic use ; Central Nervous System Stimulants/chemistry/pharmacokinetics/*therapeutic use ; Depression/*drug therapy/etiology ; Fatigue/*drug therapy/etiology ; Humans ; Modafinil ; *Neoplasms/complications ; Pain/*drug therapy/etiology ; Randomized Controlled Trials as Topic ; }, abstract = {Psychostimulants have been used to treat many symptoms associated with advanced cancer. The primary role of psychostimulants in such cases is the treatment of symptoms such as cancer-related fatigue, opioid-induced sedation, depression, and cognitive dysfunction associated with malignancies. These uses for psychostimulants came after approval for treatment of disorders such as attention deficit disorder. Modafinil, a new psychostimulant, is following a similar path after its approval for use in attention deficit disorder in 1998. Modafinil has been used to treat fatigue associated with neurodegenerative disorders such as multiple sclerosis and amyotrophic lateral sclerosis. It is now being increasingly used for cancer-related symptoms targeted by psychostimulants. Preliminary evidence from literature review suggests that modafinil is efficacious in improving opioid-induced sedation, cancer-related fatigue, and depression. There is no evidence to support its use in the treatment of cognitive dysfunction related to cancer or to support its having analgesic properties. Well-designed, randomized, controlled clinical trials are still needed to further elucidate the precise role of this drug in the care of patients with cancer. Specifically, large placebo-controlled trials with modafinil must be conducted in patients with cancer, with specific attention paid to pain control, depression, cognitive function, and adverse effects.}, }
@article {pmid17317654, year = {2006}, author = {Al-Omar, MA}, title = {The X-linked adrenoleukodystrophy (X-ALD) and oxidative stress.}, journal = {Journal of herbal pharmacotherapy}, volume = {6}, number = {3-4}, pages = {125-134}, doi = {10.1080/j157v06n03_07}, pmid = {17317654}, issn = {1522-8940}, mesh = {Adrenoleukodystrophy/metabolism/*therapy ; Amyotrophic Lateral Sclerosis/therapy ; Animals ; Antioxidants/*therapeutic use ; Drug Combinations ; Erucic Acids/*therapeutic use ; Free Radical Scavengers/therapeutic use ; Humans ; *Oxidative Stress ; *Reactive Oxygen Species ; Triolein/*therapeutic use ; }, abstract = {Most of the studies indicate that there is as yet no complete cure for X-ALD. However, methods of the treatment seem to slow rather than treat the disease. One method is the use of Lorenzo's oil in conjunction with a low fat diet, which may help in cerebral X-ALD. X-ALD is in very close resemblance to another neurodegenerative disease, amyotrophic lateral sclerosis (ALS). One of the believed pathomechanisms of ALS is oxidative stress; therefore, this article's emphasis on the role of reactive oxygen species in X-ALD. The aim of the present study was to review the literature concerning the advances in the treatment of X-adrenoleukodystrophy (X-ALD, OMIM # 300100) in the last two decades and to shed more light on the link between oxidative stress and X-ALD. This review article may point to a deficit in reactive oxygen species (ROS) scavenging and/or ROS overproduction being involved in the aetiopathology of these neurodegenerative diseases. Consequently, one of the useful neuronal rescue strategies could be the treatment with antioxidant agents.}, }
@article {pmid17316166, year = {2007}, author = {Harguindey, S and Reshkin, SJ and Orive, G and Arranz, JL and Anitua, E}, title = {Growth and trophic factors, pH and the Na+/H+ exchanger in Alzheimer's disease, other neurodegenerative diseases and cancer: new therapeutic possibilities and potential dangers.}, journal = {Current Alzheimer research}, volume = {4}, number = {1}, pages = {53-65}, doi = {10.2174/156720507779939841}, pmid = {17316166}, issn = {1567-2050}, mesh = {Animals ; Apoptosis/drug effects ; Humans ; *Hydrogen-Ion Concentration ; Intercellular Signaling Peptides and Proteins/*metabolism/therapeutic use ; Models, Biological ; Neoplasms/*metabolism/physiopathology ; Neurodegenerative Diseases/drug therapy/*metabolism/physiopathology ; Sodium-Hydrogen Exchangers/*metabolism ; }, abstract = {Abnormalities in the intricate intracellular signalling pathways play a key role in the deregulation of either spontaneous (normal or pathological) or induced (therapeutic) cell death mechanisms. Some of these pathways are increasingly becoming molecular therapeutic targets in different processes, ranging from neurodegenerative diseases to cancer. Recent discoveries in research and treatment have shown that failure to induce selective cell apoptosis in hyperproliferative processes, like neoplastic diseases, and the failure to prevent spontaneous cell death in neurodegenerative diseases (HNDDs) such as Alzheimer's disease (AD), multiple sclerosis (MS), amyothrophic lateral sclerosis (ALS), Huntington's disease (HD), and retinitis pigmentosa (RP), can be interpreted as problems stemming from the same basic mechanisms but moving in diametrically opposed directions. The integrated approach advanced here represents an interdisciplinary attempt to stimulate an integrated vision of two otherwise widely separated areas of research, experimental neurology and oncology. This kind of approach to the prevention of apoptosis (therapeutic antiapoptosis) and/or other forms of cell death in HNNDs, as well as to resistance to therapeutic apoptosis in cancer (pathological antiapoptosis), has the scope to improve the understanding of the dualistic nature of the basic abnormalities underlying the pathological deregulation of cell death. In this context, an intracellular pH (pH(i))-related approach to these opposed situations is advanced to provide a unified theory of the apoptosis-antiapoptosis machinery. Some potential therapeutic possibilities opened by these lines of research, regarding the utilization of human growth factors and/or cellular anti-acidification measures directed to sustain cellular acid-base homeostasis in different HNNDs are considered because of their potential therapeutic benefit. Finally, we advance some possible dangers and side-effects raised by these very same treatment efforts.}, }
@article {pmid17305588, year = {2007}, author = {Ryu, H and Ferrante, RJ}, title = {Translational therapeutic strategies in amyotrophic lateral sclerosis.}, journal = {Mini reviews in medicinal chemistry}, volume = {7}, number = {2}, pages = {141-150}, doi = {10.2174/138955707779802570}, pmid = {17305588}, issn = {1389-5575}, support = {NS 045242/NS/NINDS NIH HHS/United States ; NS 045806/NS/NINDS NIH HHS/United States ; NS 52724-01/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism/pathology ; Animals ; Disease Models, Animal ; Humans ; Mitochondrial Diseases/drug therapy/metabolism ; Oxidative Stress ; Signal Transduction ; Transcription, Genetic/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a clinically severe and fatal neurodegenerative disease characterized by a loss of both upper and lower motor neurons, resulting in progressive muscle loss and paralysis. While the exact cause of neuronal death in ALS remains unknown, it is proposed that multiple molecular defects trigger motor neuron cell death. These pathophysiological mechanisms include oxidative stress, mitochondrial impairment, protein aggregation, glutamate cytotoxicity, transcription dysfunction, inflammation, and apoptotic cell death. An understanding of how these potential therapeutic targets interrelate will provide direction both in the development of a pharmacotherapy and in the design of clinical trials in ALS. Important issues related to therapeutic development are the principals that should be followed in designing and conducting experiments using genetic animal models and what body of evidence is desirable to fully inform clinical decision making. In the context of ALS, we review some of the salient issues related to the use of genetic models in providing a guide to assessing studies in translating therapeutic strategies to patients with ALS and discuss therapeutic targets and pharmacological approaches to slowing disease progression. As in other neurodegenerative diseases, the most effective neuroprotection may result from combined treatment strategies.}, }
@article {pmid17303360, year = {2007}, author = {Kim, SU}, title = {Genetically engineered human neural stem cells for brain repair in neurological diseases.}, journal = {Brain &amp; development}, volume = {29}, number = {4}, pages = {193-201}, doi = {10.1016/j.braindev.2006.07.012}, pmid = {17303360}, issn = {0387-7604}, mesh = {Animals ; Brain Injuries/etiology/*therapy ; Genetic Engineering/*methods ; Humans ; Nervous System Diseases/complications/therapy ; Neurons/*physiology ; Stem Cell Transplantation/methods ; Stem Cells/*physiology ; }, abstract = {Neural stem cells (NSCs)of the central nervous system (CNS) have recently received a great deal of attention and interest for their therapeutic potential for neurological disorders. NSCs are defined as CNS progenitor cells that have the capacity for self-renewal and multipotent potential to become neurons or glial cells. Recent studies have shown that NSCs isolated from mammalian CNS including human can be propagated in vitro and then implanted into the brain of animal models of human neurological disorders. Recently, we have generated clonally derived immortalized human NSC cell lines via a retroviral vector encoded with v-myc oncogene. One of the human NSC lines, HB1.F3, was utilized in stem-cell based therapy in animal models of human neurological disorders. When F3 human NSCs were implanted into the brain of murine models of lysosomal storage diseases, stroke, Parkinson disease, Huntington disease or stroke, implanted F3 NSCs were found to migrate to the lesion sites, differentiate into neurons and glial cells, and restore functional deficits found in these neurological disorders. In animal models of brain tumors, F3 NSCs could deliver a bioactive therapeutically relevant molecules to effect a significant anti-tumor response intracranial tumor mass. Since these genetically engineered human NSCs are immortalized and continuously multiplying, there would be limitless supply of human neurons for treatment for patients suffering from neurological disorders including stroke, Parkinson disease, Huntington disease, ALS, multiple sclerosis and spinal cord injury. The promising field of stem cell research as it applies to regenerative medicine is still in infancy, but its potential appears limitless, and we are blessed to be involved in this exciting realm of research.}, }
@article {pmid17300945, year = {2007}, author = {Benatar, M}, title = {Lost in translation: treatment trials in the SOD1 mouse and in human ALS.}, journal = {Neurobiology of disease}, volume = {26}, number = {1}, pages = {1-13}, doi = {10.1016/j.nbd.2006.12.015}, pmid = {17300945}, issn = {0969-9961}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics ; Animals ; Disease Models, Animal ; Humans ; Mice ; Publication Bias ; Research Design ; Sex Characteristics ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Survival Analysis ; }, abstract = {Therapeutic success in the superoxide dismutase (SOD1) mouse model of amyotrophic lateral sclerosis (ALS) has not translated into effective therapy for human ALS, calling into question the utility of such preclinical data for identifying therapeutic agents that are worthy of further study in humans. This random effects meta-analysis of treatment trials in the superoxide dismutase (SOD1) mouse was undertaken in order to explore possible reasons for this failure of translational research and to identify potential pharmacological interventions that might be used in either a preventative or therapeutic trial in familial ALS. Among studies in which treatment was initiated presymptomatically, the weighted mean differences (WMDs) comparing the active treatment to control treated animals were 12 days (onset), 13 days (survival) and 5 days (survival interval). Among studies in which treatment was initiated at the time of symptom onset, the WMDs were 15 days (survival) and 8 days (survival interval). Subgroup analysis suggests that drugs such as minocycline and Cox-2 inhibitors with an anti-inflammatory mechanism of action, and anti-oxidative agents such as creatine or the manganese porphyrin AEOL-10150, appear to be the most promising for preventative and therapeutic trials respectively in patients with familial ALS. These conclusions should be tempered by the methodological limitations of the relevant literature.}, }
@article {pmid17279237, year = {2006}, author = {Shoesmith, CL and Strong, MJ}, title = {Amyotrophic lateral sclerosis: update for family physicians.}, journal = {Canadian family physician Medecin de famille canadien}, volume = {52}, number = {12}, pages = {1563-1569}, pmid = {17279237}, issn = {1715-5258}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Contraindications ; Diagnosis, Differential ; Disease Progression ; Enteral Nutrition ; Family Practice ; Humans ; Nutrition Assessment ; Prognosis ; }, abstract = {OBJECTIVE: To discuss the epidemiology, pathogenesis, diagnosis, expected course, prognosis, and treatment of amyotrophic lateral sclerosis (ALS), a degenerative disorder of the nervous system associated with progressive weakness.<br><br>QUALITY OF EVIDENCE: PubMed and the Cochrane Database of Systematic Reviews were searched using the MeSH headings "amyotrophic lateral sclerosis," "therapy," "epidemiology," and "etiology." Articles containing the best available evidence were reviewed. Most provided level II and III evidence. There were some level I drug trials.<br><br>MAIN MESSAGE: Amyotrophic lateral sclerosis is associated with progressive dysarthria, dysphagia, and weakness in the extremities. Diagnosis is based on physical examination, electrophysiology, and excluding other confounding conditions. There is no cure for this devastating disorder. Certain treatments, however, can improve survival and quality of life.<br><br>CONCLUSION: Because ALS is a complex disease, care of ALS patients is best provided at multidisciplinary clinics that specialize in managing patients with this disorder.}, }
@article {pmid17277077, year = {2007}, author = {Urushitani, M and Ezzi, SA and Julien, JP}, title = {Therapeutic effects of immunization with mutant superoxide dismutase in mice models of amyotrophic lateral sclerosis.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {104}, number = {7}, pages = {2495-2500}, pmid = {17277077}, issn = {0027-8424}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Antibodies/administration &amp; dosage/therapeutic use ; Disease Models, Animal ; Humans ; Immunization/*methods ; Mice ; *Mutation, Missense ; Recombinant Proteins ; Superoxide Dismutase/genetics/immunology/*therapeutic use ; Survival Rate ; Treatment Outcome ; }, abstract = {There is emerging evidence for the existence of secretory pathways for superoxide dismutase (SOD1) mutants linked to amyotrophic lateral sclerosis (ALS) and for neurotoxicity of extracellular mutant SOD1. This evidence led us to test immunization protocols aiming to reduce the burden of extracellular SOD1 mutants in nervous tissue of mice models of ALS, by using bacterially purified recombinant SOD1 mutant protein as an immunogen. First, a vaccination was tested on a G37R SOD1 mouse strain with late-onset disease exhibiting levels of mutant SOD1 protein at 4-fold higher than normal SOD1 levels. Repeated injections of adjuvant/SOD1 mutant with a final booster injection before symptoms at 6 months of age were effective in delaying disease onset and extending the life span of G37R SOD1 mice by >4 weeks. Western blot analysis with a monoclonal antibody specific to mutant SOD1 forms provided evidence of clearance of SOD1 species in the spinal cord of vaccinated G37R SOD1 mice. In contrast, this vaccination approach failed to confer significant protection in G93A SOD1 mice with extreme overexpression of mutant SOD1. Nonetheless, a passive immunization through intraventricular infusion of purified anti-human SOD1 antibody with osmotic minipump succeeded in alleviating disease symptoms and prolonging the life span of G93A SOD1 mice. From these results, we propose that immunization strategies should be considered as potential avenues for treatment of familial ALS caused by SOD1 mutations.}, }
@article {pmid17276077, year = {2007}, author = {Haenggeli, C and Julien, JP and Mosley, RL and Perez, N and Dhar, A and Gendelman, HE and Rothstein, JD}, title = {Therapeutic immunization with a glatiramer acetate derivative does not alter survival in G93A and G37R SOD1 mouse models of familial ALS.}, journal = {Neurobiology of disease}, volume = {26}, number = {1}, pages = {146-152}, doi = {10.1016/j.nbd.2006.12.013}, pmid = {17276077}, issn = {0969-9961}, support = {NS33958/NS/NINDS NIH HHS/United States ; }, mesh = {Aging/physiology ; Amyotrophic Lateral Sclerosis/*genetics/*prevention &amp; control ; Animals ; Body Weight/physiology ; Disease Progression ; Dose-Response Relationship, Drug ; Glatiramer Acetate ; *Immunization ; Mice ; Mice, Transgenic ; Neuroprotective Agents/*therapeutic use ; Peptides/*therapeutic use ; Postural Balance/physiology ; Psychomotor Performance/physiology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Survival Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. The cause of motor neuron degeneration remains largely unknown, and there is no potent treatment. Overexpression of various human mutant superoxide dismutase-1 (SOD1) genes in mice and rats recapitulates some of the clinical and pathological characteristics of sporadic and familial ALS. Glatiramer acetate (GA) is an approved drug for the treatment of multiple sclerosis and neuroprotective properties in some neurodegenerative conditions. A recent report suggested that GA immunization could delay disease progression in some, but not all, G93A SOD1 transgenic mouse models of amyotrophic lateral sclerosis (ALS). Moreover, it has been theorized that derivatives of GA could enhance immunogenicity and positively affect disease outcomes. The purpose of our study was to assess the neuroprotective efficacy of TV-5010, a high molecular weight GA, in three different SOD1 mutant mouse models. We used large numbers of two SOD1 transgenic mouse strains overexpressing the G93A mutation, B6SJL-TgN[SOD1-G93A]1Gur and B6.Cg-Tg(SOD1-G93A)1Gur/J, and the SOD1 mutant mouse overexpressing G37R (line 29). Regardless of the frequency of injections and the dose, treatment with TV-5010 was ineffective at altering either disease onset or survival in both SOD1 G93A mutants used and in the SOD1 G37R transgenic mice; in multiple studies, disease was accelerated. These studies suggest that, at a range of dosing regimens and carrier used, TV-5010 immunization was ineffective in delaying disease in multiple preclinical therapeutic models for ALS. The biological response in animals, and ultimate clinical translation, will ultimately be dependent on careful and appropriate dose, route and carrier paradigms.}, }
@article {pmid17259011, year = {2007}, author = {Malaspina, A and Turkheimer, F}, title = {A review of the functional role and of the expression profile of retinoid signaling and of nuclear receptors in human spinal cord.}, journal = {Brain research bulletin}, volume = {71}, number = {5}, pages = {437-446}, doi = {10.1016/j.brainresbull.2006.10.032}, pmid = {17259011}, issn = {0361-9230}, support = {MC_U120085814/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology/therapy ; Animals ; Gene Expression/*physiology ; Humans ; Receptors, Cytoplasmic and Nuclear/*metabolism ; Retinoids/*physiology ; Signal Transduction/*physiology ; *Spinal Cord/embryology/growth &amp; development/metabolism ; }, abstract = {Spinal cord degenerative pathologies in humans cause extensive disability and require a broad range of specialist and palliative medical interventions. In amyotrophic lateral sclerosis (ALS), motor cell loss leads to extensive paralysis and to death from respiratory failure in 3-5 years form disease onset. A wide range of molecular changes forms the basis of spinal cord involvement in ALS, including the reactivation of molecular pathways with potentially neurorestorative properties. Central to this tissue repair mechanism is the differential regulation of components of the retinoid signaling (ReS), a molecular pathway encompassing a variety of proteins functioning as transporters, signaling factors and metabolizing enzymes for retinoic acid. In this paper, we review the strong body of experimental evidence supporting retinoid signaling's primary role in spinal cord embryonic differentiation and its likely survival-promoting function in ALS. We discuss the potential involvement in ALS pathogenesis of a subgroup of nuclear receptors (NRs) that act as functional partners of retinoid receptors in human spinal cord. We also provide a review of the expression profile of 25 ReS and NRs genes in human adult spinal cord and in motor neurons of healthy and ALS individuals, using data retrieved from independent datasets obtained through serial analysis of gene expression and array investigations. Based on published expression data, we outline a tentative expression profile of ReS and functionally synergic NR genes in human spinal cord that could guide further experiments to clarify the role of these molecules in mature nervous tissue and suggest potential treatment strategies that could have therapeutic potentials in ALS.}, }
@article {pmid17257729, year = {2007}, author = {Iga, J and Ueno, S and Yamauchi, K and Numata, S and Tayoshi-Shibuya, S and Kinouchi, S and Nakataki, M and Song, H and Hokoishi, K and Tanabe, H and Sano, A and Ohmori, T}, title = {Gene expression and association analysis of vascular endothelial growth factor in major depressive disorder.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {31}, number = {3}, pages = {658-663}, doi = {10.1016/j.pnpbp.2006.12.011}, pmid = {17257729}, issn = {0278-5846}, mesh = {Adult ; Antidepressive Agents, Second-Generation/therapeutic use ; Case-Control Studies ; Depressive Disorder, Major/drug therapy/*metabolism/pathology/physiopathology ; Female ; Gene Expression Regulation/drug effects/*physiology ; *Genetic Predisposition to Disease ; Humans ; Leukocytes/metabolism ; Male ; Middle Aged ; Paroxetine/therapeutic use ; RNA, Messenger/metabolism ; Vascular Endothelial Growth Factor A/genetics/*metabolism ; }, abstract = {Vascular endothelial growth factor (VEGF) has been implicated in neuronal survival, neuroprotection, regeneration, growth, differentiation, and axonal outgrowth, which are known to be involved in the pathophysiology of major depressive disorder (MDD). Recently, the VEGF mRNA expression in the peripheral leukocytes from Alzheimer's disease or cardiovascular disease was reported to be changed. We hypothesized that the expression of the VEGF mRNA in the peripheral leukocytes may be a good candidate for the biological marker for MDD. Thirty two patients with MDD and age- and sex-matched control subjects were included in this expression study. The VEGF mRNA levels in the peripheral leukocytes from drug-naive MDD patients were significantly higher than those from the control subjects and the magnitude of the decrease of VEGF mRNA after 8-week treatment significantly correlated with clinical improvement. Then, we genotyped two single nucleotide polymorphic markers of VEGF gene, which were reported to be associated with amyotrophic lateral sclerosis and Alzheimer's disease, in patients with MDD and control subjects (n=154, each). We did not find any significant association between these markers and MDD or its clinical subtypes. Our investigation indicates that the higher expression levels of VEGF mRNA in the peripheral leukocytes are associated with the depressive state and their recovery after treatment may be associated with the clinical improvement.}, }
@article {pmid17253482, year = {2007}, author = {Orrell, RW and Lane, RJ and Ross, M}, title = {Antioxidant treatment for amyotrophic lateral sclerosis / motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {2007}, number = {1}, pages = {CD002829}, pmid = {17253482}, issn = {1469-493X}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Antioxidants/*therapeutic use ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Free radical accumulation and oxidative stress have been proposed as contributing to the progression of amyotrophic lateral sclerosis (or motor neuron disease). A range of antioxidant medications are available, and have been studied.<br><br>OBJECTIVES: To examine the effects of antioxidant medication in the treatment of people with amyotrophic lateral sclerosis.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials register (August 2005), MEDLINE (from January 1966 to August 2005), EMBASE (from January 1980 to August 2005) and other sources.<br><br>SELECTION CRITERIA: All randomized or quasi-randomized controlled trials of antioxidant treatment for amyotrophic lateral sclerosis.<br><br>DATA COLLECTION AND ANALYSIS: The authors independently applied the selection criteria, assessed study quality and two authors performed independent data extraction.<br><br>MAIN RESULTS: The search identified 23 studies for consideration but only nine studies met the inclusion criteria. Only two studies used our predetermined primary outcome measure as the primary outcome measure, (survival at 12 months treatment). However, sufficient data were available from four studies to allow analysis of this outcome measure, and a meta-analysis was performed. In the individual studies no significant effect was observed for vitamin E 500 mg twice daily; vitamin E 1 g five times daily; acetylcysteine 50 mg/kg daily subcutaneous infusion; or a combination of L-methionine 2 g, vitamin E 400 International Units, and selenium 3 x 10-5g three times daily (Alsemet). No significant effect on the primary outcome measure was observed in a meta-analysis of all antioxidants combined. No significant differences were demonstrated in any of the secondary outcome measures.<br><br>AUTHORS' CONCLUSIONS: There is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect, but this was not supported by the analysis we used. Generally the studies were poorly designed, and underpowered, with low numbers of participants and of short duration. Further well-designed trials of medications such as vitamin C and E are unlikely to be performed. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trial. The high tolerance and safety, and relatively low cost of vitamins C and E, and other considerations related to the lack of other effective treatments for amyotrophic lateral sclerosis, explain the continuing use of these vitamins by physicians and people with amyotrophic lateral sclerosis. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.}, }
@article {pmid17253460, year = {2007}, author = {Miller, RG and Mitchell, JD and Lyon, M and Moore, DH}, title = {Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {1}, pages = {CD001447}, doi = {10.1002/14651858.CD001447.pub2}, pmid = {17253460}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Excitatory Amino Acid Antagonists/adverse effects/*therapeutic use ; Humans ; Life Expectancy ; Neuroprotective Agents/adverse effects/*therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole/adverse effects/*therapeutic use ; }, abstract = {BACKGROUND: Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy.<br><br>OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Register for randomized trials in December 2004 and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. We searched MEDLINE (January 1966 to August 25 2006) and EMBASE (January 1980 to September 30th 2006).<br><br>SELECTION CRITERIA: Types of studies: randomized trials.<br><br>TYPES OF PARTICIPANTS: adults with a diagnosis of amyotrophic lateral sclerosis. Types of interventions: treatment with riluzole or placebo. Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality with riluzole 50, 100 and 200 mg; neurologic function, muscle strength and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: We identified four eligible randomized trials.<br><br>MAIN RESULTS: The four trials examining tracheostomy-free survival included a total of 974 riluzole treated patients and 503 placebo treated patients. The methodological quality was acceptable and three trials were easily comparable, although one trial included older patients in more advanced stages of amyotrophic lateral sclerosis and one had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (P value = 0.042, hazard ratio 0.80, 95% confidence interval 0.64 to 0.99) and there was no evidence of heterogeneity (P value = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P value < 0.0001) and the random effects model, which takes this into account, resulted in the overall treatment effect estimate falling just short of significance (P value = 0.056, hazard ratio 0.84, 95% confidence interval 0.70 to 1.01). This represented a 9% gain in the probability of surviving one year (57% in the placebo and 66% in the riluzole group). There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (weighted mean difference 2.62, 95% confidence interval 1.59 to 4.31).<br><br>AUTHORS' CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.}, }
@article {pmid17243177, year = {2007}, author = {Calderó, J and Tarabal, O and Casanovas, A and Ciutat, D and Casas, C and Lladó, J and Esquerda, JE}, title = {Excitotoxic motoneuron disease in chick embryo evolves with autophagic neurodegeneration and deregulation of neuromuscular innervation.}, journal = {Journal of neuroscience research}, volume = {85}, number = {12}, pages = {2726-2740}, doi = {10.1002/jnr.21174}, pmid = {17243177}, issn = {0360-4012}, mesh = {Age Factors ; Animals ; Autophagy/drug effects/*physiology ; Calcitonin Gene-Related Peptide/metabolism ; Calcium/metabolism ; Chick Embryo/drug effects ; Curare/pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Interactions ; Excitatory Amino Acid Agonists/pharmacology ; Gene Expression Regulation, Developmental/drug effects ; Microscopy, Electron, Transmission/methods ; Motor Neuron Disease/chemically induced/*pathology ; Motor Neurons/*drug effects/ultrastructure ; N-Methylaspartate/pharmacology ; Nerve Degeneration/*physiopathology ; Neuromuscular Junction/drug effects/*pathology ; Neuromuscular Nondepolarizing Agents/pharmacology ; Receptors, Nicotinic/metabolism ; Spinal Cord/pathology ; Tubulin/metabolism ; }, abstract = {In the chick embryo, in ovo application of NMDA from embryonic day (E) 5 to E9 results in selective damage to spinal cord motoneurons (MNs) that undergo a long-lasting degenerative process without immediate cell death. This contrasts with a single application of NMDA on E8, or later, which induces massive necrosis of the whole spinal cord. Chronic MN degeneration after NMDA implies transient incompetence to develop programmed cell death, altered protein processing within secretory pathways, and late activation of autophagy. Chronic NMDA treatment also results in an enlargement of thapsigargin-sensitive Ca(2+) stores. In particular MN pools, such as sartorius-innervating MNs, the neuropeptide CGRP is accumulated in somas, peripheral axons and neuromuscular junctions after chronic NMDA treatment, but not in embryos paralyzed by chronic administration of curare. Intramuscular axonal branching is also altered severely after NMDA: it usually increases, but in some cases a marked reduction can also be observed. Moreover, innervated muscle postsynaptic sites increase by NMDA, but to a lesser extent than by curare. Because some of these results show interesting homologies with MN pathology in human sporadic ALS, the model presented here provides a valuable tool for advancing in the understanding of some cellular and molecular processes particularly involved in this disease.}, }
@article {pmid17241187, year = {2007}, author = {Rio, A and Cawadias, E}, title = {Nutritional advice and treatment by dietitians to patients with amyotrophic lateral sclerosis/motor neurone disease: a survey of current practice in England, Wales, Northern Ireland and Canada.}, journal = {Journal of human nutrition and dietetics : the official journal of the British Dietetic Association}, volume = {20}, number = {1}, pages = {3-13}, doi = {10.1111/j.1365-277X.2007.00745.x}, pmid = {17241187}, issn = {0952-3871}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Canada ; Dietetics/*standards ; England ; Evidence-Based Medicine ; *Health Knowledge, Attitudes, Practice ; Humans ; Interdisciplinary Communication ; Ireland ; Nutrition Assessment ; Nutritional Requirements ; *Nutritional Support/standards ; Patient Care Team ; Surveys and Questionnaires ; Wales ; }, abstract = {BACKGROUND: The management of amyotrophic lateral sclerosis/motor neurone disease (ALS/MND) has shifted from an attitude of nihilism to treatments that prolong survival and offer hope. Nutrition is an integral component of ALS/MND care requiring coordination among acute and community multi-disciplinary teams (MDT). Evidence-based nutrition guidelines exist for this patient group but their use among dietitians is unknown. The aim of this study was to survey the knowledge, practice and guideline use of dietitians working in ALS/MND centres/clinics across England, Wales, Northern Ireland (EWNI) and Canada.<br><br>METHOD: Dietetic contact details were obtained from the Motor Neurone Disease Association (MNDA) and the ALS Society of Canada (ALSSC) websites. Telephone interviews were conducted with 23 dietitians using a standardized questionnaire.<br><br>RESULTS: Multi-disciplinary team membership was high (78%). Only 22% dietitians had >4-years experience in ALS/MND care. Dietitians reported using body weight, percentage weight loss (PWL) and body mass index (BMI) to assess nutritional status. Equations used to estimate energy and protein requirements differed. Most frequent dietary advice was high calorie, texture modification and prescription nutritional supplements. Artificial nutrition and hydration (ANH) was discussed when patients developed dysphagia, energy intake was inadequate, weight loss of 10% or forced vital capacity (FVC) was reduced. A percutaneous endoscopic gastrostomy (PEG) service was available at all clinics/centres.<br><br>CONCLUSION: Nutritional assessment techniques and dietary advice should be standardized. Dietetic collaboration at national and international level is recommended to reduce professional isolation. Training and support in ALS/MND nutrition should be made available as part of post-dietetic registration. Further dietetic research is required to stimulate nutritional care.}, }
@article {pmid17241118, year = {2007}, author = {Shoemaker, JL and Seely, KA and Reed, RL and Crow, JP and Prather, PL}, title = {The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset.}, journal = {Journal of neurochemistry}, volume = {101}, number = {1}, pages = {87-98}, pmid = {17241118}, issn = {0022-3042}, support = {R01-NS040819/NS/NINDS NIH HHS/United States ; R01 DA013660/DA/NIDA NIH HHS/United States ; R01-DA13660/DA/NIDA NIH HHS/United States ; R01 NS040819/NS/NINDS NIH HHS/United States ; R01 NS040819-05A2/NS/NINDS NIH HHS/United States ; P30 NS047546-03/NS/NINDS NIH HHS/United States ; P30 NS047546/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism ; Animals ; Binding, Competitive/physiology ; Cannabinoid Receptor Modulators/agonists/metabolism ; Cannabinoids/pharmacology/*therapeutic use ; Central Nervous System/*drug effects/metabolism/physiopathology ; Disease Models, Animal ; Disease Progression ; Humans ; Inflammation/drug therapy/metabolism/physiopathology ; Male ; Mice ; Mice, Transgenic ; Neuroprotective Agents/pharmacology/*therapeutic use ; RNA, Messenger/drug effects/metabolism ; Receptor, Cannabinoid, CB2/*agonists/genetics/metabolism ; Spinal Cord/drug effects/metabolism/physiopathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Survival Rate ; Treatment Outcome ; Up-Regulation/drug effects/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, paralysis and death within 2-5 years of diagnosis. Currently, no effective pharmacological agents exist for the treatment of this devastating disease. Neuroinflammation may accelerate the progression of ALS. Cannabinoids produce anti-inflammatory actions via cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), and delay the progression of neuroinflammatory diseases. Additionally, CB2 receptors, which normally exist primarily in the periphery, are dramatically up-regulated in inflamed neural tissues associated with CNS disorders. In G93A-SOD1 mutant mice, the most well-characterized animal model of ALS, endogenous cannabinoids are elevated in spinal cords of symptomatic mice. Furthermore, treatment with non-selective cannabinoid partial agonists prior to, or upon, symptom appearance minimally delays disease onset and prolongs survival through undefined mechanisms. We demonstrate that mRNA, receptor binding and function of CB2, but not CB1, receptors are dramatically and selectively up-regulated in spinal cords of G93A-SOD1 mice in a temporal pattern paralleling disease progression. More importantly, daily injections of the selective CB2 agonist AM-1241, initiated at symptom onset, increase the survival interval after disease onset by 56%. Therefore, CB2 agonists may slow motor neuron degeneration and preserve motor function, and represent a novel therapeutic modality for treatment of ALS.}, }
@article {pmid17226788, year = {2007}, author = {Giordano, A and Galderisi, U and Marino, IR}, title = {From the laboratory bench to the patient's bedside: an update on clinical trials with mesenchymal stem cells.}, journal = {Journal of cellular physiology}, volume = {211}, number = {1}, pages = {27-35}, doi = {10.1002/jcp.20959}, pmid = {17226788}, issn = {0021-9541}, mesh = {Bone Marrow Cells/cytology ; *Cell- and Tissue-Based Therapy/trends ; *Clinical Trials as Topic ; Humans ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*cytology ; }, abstract = {Mesenchymal Stem Cells (MSCs) are non-hematopoietic multi-potent stem-like cells that are capable of differentiating into both mesenchymal and non-mesenchymal lineages. In fact, in addition to bone, cartilage, fat, and myoblasts, it has been demonstrated that MSCs are capable of differentiating into neurons and astrocytes in vitro and in vivo. MSCs are of interest because they are isolated from a small aspirate of bone marrow and can be easily expanded in vitro. As such, these cells are currently being tested for their potential use in cell and gene therapy for a number of human diseases. Nevertheless, there are still some open questions about origin, multipotentiality, and anatomical localization of MSCs. In this review, we discuss clinical trials based on the use of MSCs in cardiovascular diseases, such as treatment of acute myocardial infarction, endstage ischemic heart disease, or prevention of vascular restenosis through stem cell-mediated injury repair. We analyze data from clinical trials for treatment of osteogenesis imperfecta (OI), which is a genetic disease characterized by production of defective type I collagen. We describe progress for neurological disease treatment with MSC transplants. We discuss data on amyotrophic lateral sclerosis (ALS) and on lysosomal storage diseases (Hurler syndrome and metachromatic leukodystrophy). A section of review is dedicated to ongoing clinical trials, involving MSCs in treatment of steroid refractory Graft Versus Host Disease (GVHD); periodontitis, which is a chronic disease affecting periodontium and causing destruction of attachment apparatus, heart failure, and bone fractures. Finally, we will provide information about biotech companies developing MSC therapy.}, }
@article {pmid17225733, year = {2006}, author = {Mummery, CL and van Laake, LW}, title = {[Progress and clashes in stem cell therapy research].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {150}, number = {17}, pages = {943-947}, pmid = {17225733}, issn = {0028-2162}, mesh = {Clinical Trials as Topic ; Evidence-Based Medicine ; Humans ; *Research ; *Stem Cell Transplantation ; Treatment Outcome ; }, abstract = {The concept of stem cell therapy, the repair of damaged or diseased tissue by transplantation of healthy cells, is deceptively simple. This simplicity has led to the hype among desperate patients, their doctors and the media: it would seem that every ailment can be treated with stem cells. At this time, however, the scientific truth is mostly disappointing. The recent claim from Korea of a major breakthrough - the ability to grow stem cells from cloned embryos - turned out to be fraudulent. With the exception ofapplications in haematologic diseases, skin wounds, and bone and cartilage diseases, most of the putative therapeutic applications of stem cell therapy are still under preclinical investigation. These include the treatment of Parkinson's and Alzheimer's disease, paraplegia, cerebral infarction, amyotrophic lateral sclerosis, multiple sclerosis and muscular dystrophy. The treatment of cardiac infarction is currently being investigated in clinical trials.}, }
@article {pmid17218019, year = {2007}, author = {Bespalov, MM and Saarma, M}, title = {GDNF family receptor complexes are emerging drug targets.}, journal = {Trends in pharmacological sciences}, volume = {28}, number = {2}, pages = {68-74}, doi = {10.1016/j.tips.2006.12.005}, pmid = {17218019}, issn = {0165-6147}, mesh = {Animals ; Chronic Disease ; Glial Cell Line-Derived Neurotrophic Factor/*physiology ; Glial Cell Line-Derived Neurotrophic Factor Receptors/*drug effects/*physiology ; Humans ; Molecular Mimicry ; Nerve Growth Factors/pharmacology ; Nervous System Diseases/*drug therapy/*physiopathology ; }, abstract = {Glial-cell-line-derived neurotrophic factor (GDNF) family ligands (GFLs), which consist of GDNF, neurturin, artemin and persephin, regulate the development and maintenance of the nervous system. GDNF protects and repairs dopamine-containing neurons, which degenerate in Parkinson's disease, and motoneurons, which die in amyotrophic lateral sclerosis. GDNF and neurturin have shown promise in clinical trials of Parkinson's disease, and artemin is currently undergoing clinical trials for chronic pain treatment. However, the delivery of GFLs into the brain through invasive approaches such as neurosurgery, viral vectors or by the use of encapsulated cells is associated with multiple obstacles. The development of small molecules that specifically activate GFL receptors and that can be applied systemically would overcome most of these problems. The unique nature of the GFL receptors, recent progress in elucidation of the 3D structures of GFLs and GFL-receptor complexes and the use of high-throughput screening have resulted in the development of the first small molecules that mimic the effects of the different GFLs.}, }
@article {pmid17213728, year = {2007}, author = {Domené, HM and Martínez, AS and Frystyk, J and Bengolea, SV and Ropelato, MG and Scaglia, PA and Chen, JW and Heuck, C and Wolthers, OD and Heinrich, JJ and Jasper, HG}, title = {Normal growth spurt and final height despite low levels of all forms of circulating insulin-like growth factor-I in a patient with acid-labile subunit deficiency.}, journal = {Hormone research}, volume = {67}, number = {5}, pages = {243-249}, doi = {10.1159/000098479}, pmid = {17213728}, issn = {0301-0163}, mesh = {Adult ; Aging/blood/physiology ; *Body Height ; Carrier Proteins ; Follow-Up Studies ; Glycoproteins/*deficiency ; Growth/*physiology ; Growth Disorders/blood/*physiopathology ; Humans ; Insulin-Like Growth Factor I/*analysis ; Male ; }, abstract = {BACKGROUND: In a recently described patient with acid-labile subunit (ALS) deficiency, the inability to form ternary complexes resulted in a marked reduction in circulating total insulin-like growth factor (IGF)-I, whereas skeletal growth was only marginally affected. To further study the role of circulating versus locally produced IGF-I in skeletal growth in this patient, we now describe in detail growth changes and their relationship with several components of the circulating IGF system.<br><br>DESIGN AND METHODS: We followed growth and development up to the final height in a patient with complete ALS deficiency and determined both spontaneous and growth hormone (GH)-stimulated changes in the IGF system, including measurements of total, free and bioactive IGF-I, total IGF-II and insulin-like growth factor binding protein (IGFBP)-1, IGFBP-2 and IGFBP-3.<br><br>RESULTS: The patient had a delayed growth and pubertal onset. Six months of GH treatment had no effect on growth. At the age of 19.3 years, he spontaneously completed puberty and had a normal growth spurt for a late adolescent (peak height velocity of 8.4 cm/year). A normal final height was attained at 21.3 years (167.5 cm; -0.78 SDS). During as well as after puberty, basal levels of total, free and bioactive IGF-I were low, as were total IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3. GH treatment for 6 months normalized free IGF-I and increased bioactive IGF-I, but had no effect on growth velocity.<br><br>CONCLUSIONS: This case story shows that in the presence of complete ALS deficiency, a height within normal limits can be obtained despite low levels of all forms of circulating IGF-I. Furthermore, the patient presented a delayed but normal growth spurt without any marked increment of circulating IGF-I.}, }
@article {pmid17212618, year = {2007}, author = {Harvey, WT and Martz, D}, title = {Motor neuron disease recovery associated with IV ceftriaxone and anti-Babesia therapy.}, journal = {Acta neurologica Scandinavica}, volume = {115}, number = {2}, pages = {129-131}, doi = {10.1111/j.1600-0404.2006.00727.x}, pmid = {17212618}, issn = {0001-6314}, mesh = {Anti-Bacterial Agents/*administration &amp; dosage ; Atovaquone/*administration &amp; dosage ; Ceftriaxone/*administration &amp; dosage ; Drug Administration Schedule ; Drug Therapy, Combination ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Motor Neuron Disease/*drug therapy ; Recovery of Function ; }, abstract = {This report summarizes what we believe to be the first verifiable case of a significant and progressive motor neuron disease (MND) consistent with amyotrophic lateral sclerosis that resolved during treatment with i.v. ceftriaxone plus oral atovaquone and mefloquine. The rationale for use of these antibiotics was (i) positive testing for Borrelia burgdorferi and (ii) red blood cell ring forms consistent with Babesia species infection. The patient has continued to be free of MND signs and symptoms for 15 months, although some symptoms consistent with disseminated Borreliosis remain.}, }
@article {pmid17208444, year = {2007}, author = {Shaw, BF and Valentine, JS}, title = {How do ALS-associated mutations in superoxide dismutase 1 promote aggregation of the protein?.}, journal = {Trends in biochemical sciences}, volume = {32}, number = {2}, pages = {78-85}, doi = {10.1016/j.tibs.2006.12.005}, pmid = {17208444}, issn = {0968-0004}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Enzyme Stability ; Humans ; *Mutation ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {More than 100 different mutations in the gene encoding copper-zinc superoxide dismutase (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS)--a fatal neurodegenerative disease in which aggregation of the SOD1 protein is considered to be the primary mode of pathogenesis. Recent results show that these mutations have remarkably diverse and unexpected effects on the structure, activity and native state stability of SOD1. Intriguingly, many mutations seem to have no measurable effect on the biophysical and biochemical properties of SOD1, except for decreasing the net charge of the protein. Thus, it seems likely that different ALS-associated mutations promote SOD1 aggregation by fundamentally distinct mechanisms. Understanding this complexity has implications for drug development and treatment of the disease.}, }
@article {pmid17196550, year = {2007}, author = {Massignan, T and Casoni, F and Basso, M and Stefanazzi, P and Biasini, E and Tortarolo, M and Salmona, M and Gianazza, E and Bendotti, C and Bonetto, V}, title = {Proteomic analysis of spinal cord of presymptomatic amyotrophic lateral sclerosis G93A SOD1 mouse.}, journal = {Biochemical and biophysical research communications}, volume = {353}, number = {3}, pages = {719-725}, doi = {10.1016/j.bbrc.2006.12.075}, pmid = {17196550}, issn = {0006-291X}, support = {TCP01010/TI_/Telethon/Italy ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Cyclophilin A/genetics ; Disease Models, Animal ; Electrophoresis, Gel, Two-Dimensional ; Female ; Mice ; Mice, Transgenic ; Nerve Tissue Proteins/metabolism ; Phosphorylation ; Protein Isoforms/genetics ; *Proteomics ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Spinal Cord/metabolism ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease, whose primary mechanisms or causes are still not defined and for which no effective treatment is available. We have recently reported that before disease onset the level of tyrosine nitrated proteins is increased in the G93A SOD1 transgenic mouse model of ALS. In the present investigation, we carried out a proteomic analysis of spinal cord extracts from G93A SOD1 mice at the presymptomatic stage of the disease to further unravel primary events in the pathogenesis and tentatively screen for potential pharmacological targets. Using a robust two-dimensional gel electrophoresis-based proteomic approach, we detected a number of proteins differentially represented in presymptomatic mice in comparison with controls. Alterations of these proteins correlate with mitochondrial dysfunction, aggregation, and stress response. Moreover, we found a variation in the isoform pattern of cyclophilin A, a molecular chaperone that protects cells from the oxidative stress.}, }
@article {pmid19771234, year = {2007}, author = {Ding, H and Liao, G and Wang, H and Zhou, Y}, title = {Asymmetrically designed siRNAs and shRNAs enhance the strand specificity and efficacy in RNAi.}, journal = {Journal of RNAi and gene silencing : an international journal of RNA and gene targeting research}, volume = {4}, number = {1}, pages = {269-280}, pmid = {19771234}, issn = {1747-0854}, support = {R01 NS048145/NS/NINDS NIH HHS/United States ; }, abstract = {RNAi can mediate allele-specific silencing, and offers an attractive approach for treatment of human diseases caused by dominant, gain-of-function gene mutations. However, allele-specific silencing requires that the RNAi target the mutated region of the mRNA, limiting the choices of the target sequences. This often results in the use of a suboptimal siRNAs or shRNAs. Unfavorable strand asymmetry, which leads to the sense strand rather than the antisense strand to be incorporated into RNA-induced silencing complex (RISC), can cause poor RNAi efficacy. We systematically tested an approach that places mismatches at or near the 5' of the antisense strand to create favorable strand asymmetry. Here we show that this approach can enhance the RNAi efficacy of not only siRNAs but also shRNAs synthesized from genes, which can be placed in various viral vectors. Thus, this design of asymmetric shRNAs could be potentially used in silencing dominant, gain-of-function gene mutations for gene therapy.}, }
@article {pmid17192933, year = {2006}, author = {Kim, YS and Martinez, T and Deshpande, DM and Drummond, J and Provost-Javier, K and Williams, A and McGurk, J and Maragakis, N and Song, H and Ming, GL and Kerr, DA}, title = {Correction of humoral derangements from mutant superoxide dismutase 1 spinal cord.}, journal = {Annals of neurology}, volume = {60}, number = {6}, pages = {716-728}, doi = {10.1002/ana.21034}, pmid = {17192933}, issn = {0364-5134}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Animals ; Antibodies/*pharmacology/therapeutic use ; Cell Line, Transformed ; Cell Survival/drug effects/physiology ; Coculture Techniques ; Culture Media, Conditioned/chemistry/toxicity ; Disease Models, Animal ; Female ; Free Radical Scavengers/*pharmacology/therapeutic use ; Humans ; Interleukins/*antagonists &amp; inhibitors/metabolism/toxicity ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects/immunology/metabolism ; Nerve Regeneration/drug effects/physiology ; Nitric Oxide/*antagonists &amp; inhibitors/metabolism/toxicity ; Organ Culture Techniques ; Spinal Cord/drug effects/enzymology/physiopathology ; Superoxide Dismutase/genetics/metabolism ; Treatment Outcome ; Vascular Endothelial Growth Factor A/pharmacology/*therapeutic use ; }, abstract = {OBJECTIVE: We sought to define molecular and cellular participants that mediate motor neuron injury in amyotrophic lateral sclerosis using a coculture system.<br><br>METHODS: We cocultured embryonic stem cell-derived motor neurons with organotypic slice cultures from wild-type or SOD1G93A (MT) mice. We examined axon lengths and cell survival of embryonic stem cell-derived motor neurons. We defined and quantified the humoral factors that differed between wild-type and MT organotypic cultures, and then corrected these differences in cell culture.<br><br>RESULTS: MT spinal cord organotypic slices were selectively toxic to motor neurons as defined by axonal lengths and cell survival. MT spinal cord organotypic slices secreted higher levels of nitric oxide, interleukin (IL)-1beta, IL-6, and IL-12p70 and lower levels of vascular endothelial growth factor. The toxicity of MT spinal cord organotypic cultures was reduced and axonal lengths were restored to near normal by coculturing in the presence of reactive oxygen species scavenger, vascular endothelial growth factor, and neutralizing antibodies to IL-1beta, IL-6, and IL-12.<br><br>INTERPRETATION: MT spinal cord organotypic cultures overexpress certain factors and underexpress others, creating a nonpermissive environment for cocultured motor neurons. Correction of these abnormalities as a group, but not individually, restores axonal length to near normal. Such a "cocktail" approach to the treatment of amyotrophic lateral sclerosis should be investigated further.}, }
@article {pmid17187916, year = {2007}, author = {Alfonzo, AV and Simpson, K and Deighan, C and Campbell, S and Fox, J}, title = {Modifications to advanced life support in renal failure.}, journal = {Resuscitation}, volume = {73}, number = {1}, pages = {12-28}, doi = {10.1016/j.resuscitation.2006.07.019}, pmid = {17187916}, issn = {0300-9572}, mesh = {Advance Directives ; Arrhythmias, Cardiac/complications/therapy ; Attitude to Health ; *Cardiopulmonary Resuscitation ; Electric Countershock ; Heart Arrest/*complications/therapy ; Humans ; Renal Dialysis ; Renal Insufficiency/*complications/therapy ; Resuscitation Orders ; Risk Factors ; }, abstract = {The outcome of cardiopulmonary resuscitation (CPR) has been reported to be worse in patients with renal failure compared with those with normal renal function. It is likely that this increased mortality may be at least partly attributable to sub-optimal and highly variable treatment strategies used in cardiac arrest in patients with renal failure, but this issue has not previously been explored. Such patients undoubtedly pose a challenge to advanced life support (ALS) providers, and renal unit staff are not trained to provide specialist advice after a patient has sustained a cardiac arrest. There are few studies investigating the epidemiology, safety or outcome of cardiac arrest in patients with renal failure and there are no generally accepted resuscitation guidelines for this special circumstance. In this article we discuss the unique problems of resuscitating patients with renal failure and propose a suitable management strategy.}, }
@article {pmid17174029, year = {2007}, author = {Park, JH and Hong, YH and Kim, HJ and Kim, SM and Kim, MJ and Park, KS and Sung, JJ and Lee, KW}, title = {Pyruvate slows disease progression in a G93A SOD1 mutant transgenic mouse model.}, journal = {Neuroscience letters}, volume = {413}, number = {3}, pages = {265-269}, doi = {10.1016/j.neulet.2006.11.058}, pmid = {17174029}, issn = {0304-3940}, mesh = {Amyotrophic Lateral Sclerosis/complications/*drug therapy/mortality/pathology ; Analysis of Variance ; Animals ; Disease Models, Animal ; Disease Progression ; Gliosis/drug therapy/etiology ; Mice ; Mice, Transgenic ; Psychomotor Performance/drug effects ; Pyruvic Acid/*therapeutic use ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase/*genetics ; Survival Analysis ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by selective motor neuron death, and currently no effective treatment is available for ALS. In this study, we investigated the neuroprotective effects of pyruvate, which acts as an anti-oxidant and as an energy source. We treated G93A SOD1 transgenic mice with pyruvate (from 70 days of age, i.p., at 1000 mg/kg/week), and found that it prolonged average lifespan by 12.3 days (10.5%), slowed disease progression, and improved motor performance, but did not delay disease onset. Pyruvate treatment was also associated with reduced nitrotyrosine immunoreactivity, gliosis, and increased Bcl-2 expression in the spinal cords of G93A SOD1 transgenic mice. These results suggest that pyruvate treatment may be a potential therapeutic strategy in ALS.}, }
@article {pmid17165671, year = {2006}, author = {Kim, SM and McCulloch, TM and Bae, H and Kim, SJ}, title = {Biomechanical model for muscular dysfunction of the human pharynx using finite element analysis.}, journal = {The Annals of otology, rhinology, and laryngology}, volume = {115}, number = {11}, pages = {864-870}, doi = {10.1177/000348940611501112}, pmid = {17165671}, issn = {0003-4894}, mesh = {Biomechanical Phenomena ; Finite Element Analysis ; Humans ; *Models, Biological ; Muscle Contraction/physiology ; Muscular Diseases/*physiopathology ; Pharyngeal Diseases/*physiopathology ; Pharyngeal Muscles/*physiopathology ; Severity of Illness Index ; }, abstract = {OBJECTIVES: The oropharynx functions to transport food from the oral cavity to the esophagus, as well as to maintain an air passage from the nose to the lungs. By combining data from prior material property experimentation, a 3-dimensional finite element method reconstruction of the pharynx, and the utilization of a optimization process based on an inverse dynamic approach, we can estimate the pressures and associated consecutive pressure gradients created internally when the pharynx functions during swallowing.<br><br>METHODS: In this study, pharyngeal muscular dysfunction was modeled under 3 scenarios of increasing tissue stiffness. This was done by modifications in the stress-strain relationship material property within the finite element method nodes. This mechanical property was used as a surrogate for clinical changes in muscle function complicating neuromuscular disorders, such as stroke and amyotrophic lateral sclerosis. The pharyngeal tissue and deformation of the cross-sectional area of the pharynx were analyzed while increasing the mechanical stiffness by 25%, 50%, and 75%.<br><br>RESULTS: Increases in stiffness resulted in modified pressure-area curves predicting diminished movement, primarily in stiffened regions.<br><br>CONCLUSIONS: These simulation results may act as a clinical index illustrating the association between tissue dysfunction and pharyngeal pressure and movement dysfunction. This type of modeling has the potential to act as an investigational tool, as well as a predictive tool, regarding disease progression, cancer treatment, and perhaps even the effects of aging on swallowing function.}, }
@article {pmid17161642, year = {2007}, author = {Rosengren, L and Parrow, V and Chmielewska, J and Mode, A and Fhölenhag, K}, title = {In vivo evaluation of a novel, orally bioavailable, small molecule growth hormone receptor antagonist.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {17}, number = {1}, pages = {47-53}, doi = {10.1016/j.ghir.2006.10.006}, pmid = {17161642}, issn = {1096-6374}, mesh = {Acromegaly/*drug therapy/pathology ; Administration, Oral ; Animals ; Body Weight/drug effects ; Drug Evaluation, Preclinical ; Human Growth Hormone/administration &amp; dosage ; Hypophysectomy ; Insulin-Like Growth Factor Binding Protein 3/analysis ; Insulin-Like Growth Factor I/analysis ; Liver/chemistry ; Male ; Molecular Weight ; Rats ; Rats, Sprague-Dawley ; Receptor, IGF Type 1/analysis ; Receptors, Somatotropin/analysis/*antagonists &amp; inhibitors ; Sulfonamides/*administration &amp; dosage ; }, abstract = {IGF-I is regarded as the most sensitive marker of growth hormone (GH) secretion in both GH deficient individuals and in individuals with excessive GH production. Studies on the effect of inhibitors of GH action in normal experimental animals are difficult to evaluate due to the complex relationship and feed back mechanisms of the GH/IGF-I system and the hypothalamo-pituitary axis. To circumvent the GH/IGF-I feedback mechanisms, we have used hypophysectomized (HX) rats treated with GH to assess the potential of a new low molecular weight compound, BVT-A ((N-[5-(aminosulfonyl)-2-methylphenyl]-5-bromo-2-furamide), to act as a GH receptor antagonist in vivo. GH treatment of HX rats induced serum IGF-I, body weight and hepatic mRNA levels of IGF-I, IGFBP-3, ALS and the IGF-I and GH receptors. Co-treatment with BVT-A suppressed all the GH-induced effects. We conclude that the GH substituted HX rat is a useful model for studies on GH receptor antagonists, and for the first time, a small molecule GH receptor antagonist with in vivo activity has been revealed. This opens up for development of new drugs for diseases in which lowering of GH receptor activity would be beneficial.}, }
@article {pmid17159125, year = {2006}, author = {Flaherty-Craig, C and Eslinger, P and Stephens, B and Simmons, Z}, title = {A rapid screening battery to identify frontal dysfunction in patients with ALS.}, journal = {Neurology}, volume = {67}, number = {11}, pages = {2070-2072}, doi = {10.1212/01.wnl.0000247667.89251.43}, pmid = {17159125}, issn = {1526-632X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/physiopathology/*psychology ; Cognition Disorders/*diagnosis/physiopathology/*psychology ; Frontal Lobe/physiopathology ; Humans ; Mass Screening/*methods ; Middle Aged ; Neuropsychological Tests ; }, abstract = {We studied the relationship between verbal associative fluency, verbal abstract reasoning, and judgment in ALS using a 20-minute screening evaluation. Deficiencies in these measures were found in 20.0%, 18.6%, and 35.7% of patients with limb-onset ALS and in 37.5%, 25.0%, and 60.0% of patients with bulbar-onset ALS. This simple screen identifies deficits that affect discussions of treatment interventions and end-of-life issues.}, }
@article {pmid17156299, year = {2006}, author = {Ridall, PG and Pettitt, AN and Henderson, RD and McCombe, PA}, title = {Motor unit number estimation--a Bayesian approach.}, journal = {Biometrics}, volume = {62}, number = {4}, pages = {1235-1250}, doi = {10.1111/j.1541-0420.2006.00577.x}, pmid = {17156299}, issn = {0006-341X}, mesh = {Action Potentials ; Amyotrophic Lateral Sclerosis/pathology/physiopathology ; *Bayes Theorem ; Biometry/methods ; Cell Count/statistics &amp; numerical data ; Electric Stimulation ; Humans ; *Models, Neurological ; *Models, Statistical ; Motor Neurons/*cytology/physiology ; Poisson Distribution ; Stochastic Processes ; }, abstract = {All muscle contractions are dependent on the functioning of motor units. In diseases such as amyotrophic lateral sclerosis (ALS), progressive loss of motor units leads to gradual paralysis. A major difficulty in the search for a treatment for these diseases has been the lack of a reliable measure of disease progression. One possible measure would be an estimate of the number of surviving motor units. Despite over 30 years of motor unit number estimation (MUNE), all proposed methods have been met with practical and theoretical objections. Our aim is to develop a method of MUNE that overcomes these objections. We record the compound muscle action potential (CMAP) from a selected muscle in response to a graded electrical stimulation applied to the nerve. As the stimulus increases, the threshold of each motor unit is exceeded, and the size of the CMAP increases until a maximum response is obtained. However, the threshold potential required to excite an axon is not a precise value but fluctuates over a small range leading to probabilistic activation of motor units in response to a given stimulus. When the threshold ranges of motor units overlap, there may be alternation where the number of motor units that fire in response to the stimulus is variable. This means that increments in the value of the CMAP correspond to the firing of different combinations of motor units. At a fixed stimulus, variability in the CMAP, measured as variance, can be used to conduct MUNE using the "statistical" or the "Poisson" method. However, this method relies on the assumptions that the numbers of motor units that are firing probabilistically have the Poisson distribution and that all single motor unit action potentials (MUAP) have a fixed and identical size. These assumptions are not necessarily correct. We propose to develop a Bayesian statistical methodology to analyze electrophysiological data to provide an estimate of motor unit numbers. Our method of MUNE incorporates the variability of the threshold, the variability between and within single MUAPs, and baseline variability. Our model not only gives the most probable number of motor units but also provides information about both the population of units and individual units. We use Markov chain Monte Carlo to obtain information about the characteristics of individual motor units and about the population of motor units and the Bayesian information criterion for MUNE. We test our method of MUNE on three subjects. Our method provides a reproducible estimate for a patient with stable but severe ALS. In a serial study, we demonstrate a decline in the number of motor unit numbers with a patient with rapidly advancing disease. Finally, with our last patient, we show that our method has the capacity to estimate a larger number of motor units.}, }
@article {pmid17153762, year = {2006}, author = {Castellanos Ortega, A and Rey Galán, C and Alvarez Carrillo, A and López-Herce Cid, J and Delgado Domínguez, MA}, title = {[Pediatric advanced life support].}, journal = {Anales de pediatria (Barcelona, Spain : 2003)}, volume = {65}, number = {4}, pages = {342-363}, doi = {10.1016/s1695-4033(06)70207-7}, pmid = {17153762}, issn = {1695-4033}, mesh = {Advanced Cardiac Life Support/methods/*standards ; Child ; Child, Preschool ; Critical Pathways ; Heart Arrest/*therapy ; Humans ; Infant ; Infant, Newborn ; Intubation, Intratracheal/methods/standards ; Pediatrics ; }, abstract = {Advanced life support (ALS) includes all the procedures and maneuvers used to restore spontaneous circulation and breathing, thus minimizing brain injury. The fundamental steps of ALS are airway control with adjuncts, ventilation with 100% oxygen, vascular access and fluid and drug administration, and monitoring to diagnose and treat arrhythmias. Airway control can be achieved by means of oropharyngeal airway, endotracheal intubation, and alternative methods (laryngeal mask and cricothyroidotomy). Vascular access can be achieved by the peripheral venous, intraosseous, central venous, and tracheal routes. The most frequent rhythms found in children with cardiorespiratory arrest are nonshockable (asystole, severe bradycardia, pulseless electrical activity, and complete atrioventricular block). In these cases, adrenaline continues to be the essential drug. Currently, low adrenaline doses (0.01 mg/kg IV and 0.1 mg/kg intratracheal administration) are recommended throughout the resuscitation period. Amiodarone (5 mg/kg) is the drug of choice in cases of ventricular fibrillation refractory to electric shock. The treatment sequence for shockable rhythms (ventricular fibrillation and pulseless ventricular tachycardia) is one 4 J/kg electric shock, followed by cardiopulmonary resuscitation (chest compressions and ventilation) for 2 minutes with subsequent reassessment of the electrocardiographic rhythm. Adrenaline must be administered immediately before the third electric shock and subsequently every 3-5 minutes. Amiodarone must be administered immediately before the fourth shock.}, }
@article {pmid17152798, year = {2006}, author = {Olszewski, J}, title = {[Causes, diagnosis and treatment of neurogenic dysphagia as an interdisciplinary clinical problem].}, journal = {Otolaryngologia polska = The Polish otolaryngology}, volume = {60}, number = {4}, pages = {491-500}, pmid = {17152798}, issn = {0030-6657}, mesh = {Brain Injuries/complications ; Central Nervous System Diseases/*complications ; Deglutition/physiology ; Deglutition Disorders/diagnosis/*etiology/*therapy ; Esophageal Motility Disorders/etiology ; Esophagus/*physiopathology ; Humans ; Neuromuscular Diseases/*complications/physiopathology ; Parkinson Disease/complications ; Pneumonia, Aspiration/etiology ; }, abstract = {The intricate mechanism of swallowing can be divided into three phases: oral, pharyngeal, and esophageal. Dysphagia is a disruption in the swallowing process, which include difficulty in transporting (or a lack of transporting) a food or liquid bolus from the mouth through the pharynx and esophagus into the stomach. Causes of disruptions in the swallowing process can be divided into superior (oropharyngeal) and inferior (esophageal) according to Paradowski et al. Neurlologic dysphagia may be caused by a disruption in different parts of the central nervous system (supranuclear level, level of motor and sensory nuclei taking part in swallowing process, peripherial nerves level and a pathology of muscle cells and spindles) or neuromuscular and muscular disorders. Neuromuscular disorders causes according to Waśko-Czopnik et al. are: stroke, brain tumors, brain injury, bulbar and pseudobulbar paralysis, neurodegenerative diseases (amyotrophic lateral sclerosis, multiple sclerosis), tabes dorsalis, multisystem degenerations, Parkinson's disease, delayed dyskineses, Huntington's disease, myasthenia and myasthenic syndromes, myopathies and peripherial neuropathies. The correct diagnosis evaluation include history taking, physical examination with palpation and consultations (laryngological, gastrological and neurological). According to Halama radiological esophagogram, videofluoroscopy, flexible endoscopic examination, ultrasound examination, manometry, electromyography, scintigraphy and 24 hour pH monitoring are main diagnostic procedures of dysphagia. Some of the reasons for the neurologic dysphagia may be treated by surgical and pharmacological methods. Neurologic dysphagia rehabilitation is difficult, long-lasting and often falling far short of expected results. Primary it should include neurologic cause treatment if it is possible. According to WHO International Classification of Functioning and Health in 2001 non-invasive methods of dysphagia treatment may be divided into reconstitution, compensatory and adaptive techniques. The most popular reconstitution methods are thermal stimulation (Lazzar's) or tactilethermal application (Rosenbeck's) techniques which may be applied for abnormal duration of stage transition (DST). Abnormal duration of stage transition considerably increase probability of aspiration. Dysphagia treatment by compensatory methods consist in various techniques of swallowing and posture changes application. Adaptive techniques include dietary changes--avoiding of sustenances strengthening dysphagia and adequate dietary intake. The basic principle of dysphagia rehabilitation is that the most effective way to regain efficiency is the regeneration on remains of lost function. Carrying out imperfect swallowing acts is probably the best way of increasing effectiveness and efficiency of swallowing. On the other hand imperfect swallowing acts may be hazardous because of the danger of aspiration and inhalation pneumonia.}, }
@article {pmid17131697, year = {2006}, author = {Braat, DD and Mummery, CL and Schattenberg, AV and Borst-Eilers, E}, title = {[Freezing umbilical-cord blood and bone marrow for one's own use: present-day quackery?].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {150}, number = {44}, pages = {2410-2414}, pmid = {17131697}, issn = {0028-2162}, mesh = {Blood Banks ; *Bone Marrow Cells ; *Cord Blood Stem Cell Transplantation ; Female ; *Fetal Blood ; *Health Knowledge, Attitudes, Practice ; Hematologic Neoplasms/therapy ; Histocompatibility ; Humans ; Netherlands ; Pregnancy ; Pregnant People/*psychology ; Tissue and Organ Harvesting ; Transplantation, Autologous ; }, abstract = {In the Netherlands, the practice of private freezing and banking of umbilical-cord blood is increasing. In a questionnaire, Dutch midwives and gynaecologists were asked about their attitude towards cord-blood collection if asked to perform this after delivery. The response rate was 35% (125/356) and 71% (71/100), respectively. Two-thirds of those asked responded that they would comply. The most common application of cord blood is in the treatment of (malignant) blood disorders. The use of autologous cord blood is, however, often not the best choice for treating leukaemia in young children and the number of stem cells is often too low in a single-cord blood sample to treat older children and adults. Although frequently suggested in the lay press, there is no proven effect in other indications, such as amyotrophic lateral sclerosis, multiple sclerosis and myocardial infarction. Information on therapeutic applications of cord blood from companies with commercial interests is leading to the exploitation ofpregnantwomen. The government should consider limiting this practice and prohibiting the activities of these companies in the Netherlands pending scientific evidence for their claims.}, }
@article {pmid17131418, year = {2007}, author = {Tashiro, J and Kikuchi, S and Shinpo, K and Kishimoto, R and Tsuji, S and Sasaki, H}, title = {Role of p53 in neurotoxicity induced by the endoplasmic reticulum stress agent tunicamycin in organotypic slice cultures of rat spinal cord.}, journal = {Journal of neuroscience research}, volume = {85}, number = {2}, pages = {395-401}, doi = {10.1002/jnr.21120}, pmid = {17131418}, issn = {0360-4012}, mesh = {Animals ; Blotting, Western ; Brefeldin A/pharmacology ; Cell Death/drug effects ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum/*drug effects/metabolism/pathology ; Fluorescent Antibody Technique ; Heat-Shock Proteins/drug effects/metabolism ; Molecular Chaperones/drug effects/metabolism ; Neurons/*drug effects/metabolism/pathology ; Neurotoxins/*toxicity ; Organ Culture Techniques ; Protein Synthesis Inhibitors/pharmacology ; Rats ; Spinal Cord/*drug effects/metabolism/pathology ; Tumor Suppressor Protein p53/drug effects/*metabolism ; Tunicamycin/*toxicity ; }, abstract = {The endoplasmic reticulum (ER) is important for maintaining the quality of cellular proteins. Various stimuli can disrupt ER homeostasis and cause the accumulation of unfolded or misfolded proteins, i.e., a state of ER stress. Recently, ER stress has been reported to play an important role in the pathogenesis of neurological disorders such as cerebral ischemia and neurodegenerative diseases, but its involvement in the spinal cord diseases has not been fully discussed. We conducted this study using tunicamycin (Tm) as an ER stress inducer for rat spinal cord in organotypic slice culture, a system that we have recently established. Tm was shown to induce ER stress by increased expression of GRP78. The viability rate of spinal cord neurons decreased in a dose-dependent manner with Tm treatment, and dorsal horn interneurons were more vulnerable to Tm-induced neurotoxicity. A p53 inhibitor significantly increased the viability of dorsal horn interneurons, and immunofluorescence studies showed nuclear accumulation of p53 in the dorsal horns of Tm-treated spinal cord slices. These findings suggest that p53 plays an important role in the killing of dorsal horn interneurons by Tm. In contrast, motor neurons were not protected by the p53 inhibitor, suggesting that the role of p53 may vary between different cell types. This difference might be a clue to the mechanism of the stress-response pathway and might also contribute to the potential application of p53 inhibitors for the treatment of spinal cord diseases, including amyotrophic lateral sclerosis.}, }
@article {pmid17131224, year = {2006}, author = {Fujimoto, K}, title = {Dropped head in Parkinson's disease.}, journal = {Journal of neurology}, volume = {253 Suppl 7}, number = {}, pages = {VII21-26}, pmid = {17131224}, issn = {0340-5354}, mesh = {Female ; Head Movements/*physiology ; History, 19th Century ; History, 20th Century ; Humans ; Male ; Movement Disorders/*etiology/history/pathology ; Neck Muscles/physiopathology ; Parkinson Disease/*complications ; }, abstract = {"A propensity to bend the trunk forward" and "the chin is now almost immovably bent down upon the sternum" were described by James Parkinson in patients with Parkinson's disease (PD). The term "dropped head" was first reported in "Gerlier disease" in Switzerland and 'kubisagari' in Japan and since then also reported in myositis, myopathy, myasthenia gravis, amyotrophic lateral sclerosis, neuropathy, and hypothyroidism. Disproportionate antecollis occurs in about half cases of multiple system atrophy (MSA) and is considered dystonic in nature. Dropped head is considered rare in PD, both in advanced and early stages of PD. However, it is known to progress subacutely over a period of several days. In my experience, dropped head is relatively common in PD. The mechanism of dropped head in PD is either dystonia of flexor neck muscles or weakness of extensor neck muscles. The response of dropped head to various anti-parkinsonian medications is rather inconsistent. Levodopa is reported to induce amelioration in some patients while dopamine agonists can cause deterioration. Muscle afferent block with lidocaine and ethanol is reported to be effective, while the effect of botulinum toxin injection into the affected muscles is limited. The effect of stereotaxic neurosurgery on dropped head is controversial. Early diagnosis and prompt treatment is necessary to prevent muscle damage associated with longterm overstretch of extensor neck muscles.}, }
@article {pmid17128129, year = {2006}, author = {Roy-Bellina, S and Camu, W}, title = {[Psychological treatment for the patient and caregivers during the course of amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S295-4S300}, pmid = {17128129}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; *Caregivers ; Family Health ; Humans ; *Psychotherapy ; }, abstract = {Amyotrophic lateral sclerosis is a devastating disorder for which the psychological consequences of both the diagnosis announcement and the evolution of paralysis not only concern the patient but also his family. The role of the psychologist is to develop an individualized follow up considering the patient in his globality. The first consultation is, ideally, initiated after a medical consultation explaining the importance of the psychological area in ALS patient care. The psychological follow up will consist in an empathic listening of history and problems. Information will also be given to the patient by the psychologist who's role should not be only passive. When talking about "globality" of the psychological intervention for a given patient, his family takes a determinant place. The psychologist should be able to establish a contact with the family members concerned by the daily support to the patient. The psychological processes through which a patient will evolve should be explained to the family. Depression frequently affects family members, and a specific follow up in those cases has to be undertaken as soon as possible. Such a depressive reaction may also take place after death and a psychological follow up do not end after the death of a patient. The role of a psychologist in ALS care ideally takes places in the context of a multidisciplinary team such as a motoneuron clinic now largely available in our country. The burden of care is frequently heavy both for the family and the team of professional carers into and outside the hospital. The psychologist has a role of mediation between those persons, facilitating verbal exchanges, paying attention to specific difficulties and maintaining a fruitful exchange between the carers, the patient and his family. More prospectively, the psychologist also has a pedagogic role for the carers explaining psychological processes and giving clues for a constructive relationship between the patient and his family and also between this patient and his carers.}, }
@article {pmid17128127, year = {2006}, author = {Bardet, L}, title = {[Role of health volunteers for patients with amyotrophic lateral sclerosis and their family].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S284-4S290}, pmid = {17128127}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Follow-Up Studies ; *Hospital Volunteers ; Humans ; }, abstract = {In ALS Centers, the patient receives coordinated care from Health Volunteers and the medical team including specialized physicians, therapists and social workers. There are two types of volunteers: those who assist the patient in hospital, the Medical Volunteers (MV), and those who make home visits, the Home Volunteers (HV). Both are recruited and trained by the ARS and have a single motivation: help the patient's; they are emotionally and morally fully qualified to accomplish their task in accordance with the rules that have been set by the Association. The ALS patient is seen for the first time by the Medical Volunteer at the ALS Center, immediately after his or her disease has been diagnosed by the clinic's director. The MV takes the initiative for the dialogue, which he/she leads gently and tactfully. The discussion is aimed at gathering useful information to be put in the document: "Connaissance du malade" (knowledge of the patient), working out the patient's primary concerns and assessing the carer's commitment, in a friendly atmosphere. Finally the volunteer gives the guidebook, "Livret d'accueil" to the patient. After the conversation, the MV decides which confidential pieces of information are to be passed on to the medical staff with a view to sorting out problems; information is then set the HV who will provide follow up care for this patient. Long-term care management of ALS patients is achieved through three regular monthly appointments at the ALS Center. With the help of the document "Connaissance du malade" the MV keeps better in touch with the patient using the feedback from the HV about what has been going on in the interval between the two visits to the ALS Center. This collaboration enables appropriate follow up care for the patients with clearly-defined objectives: dealing with the patient's anxiety, understanding his/her position at the present time, his/her daily routine and needs, comforting, checking compliance with treatment, counselling and supporting the family, answering delicate questions. Thus, the Health Volunteer's mission contributes meaningfully to medical treatment. This approach likely helps the person affected by ALS to regain the initially deteriorated sense of belonging to the social body.}, }
@article {pmid17128119, year = {2006}, author = {Sancho, PO and Boisson, D}, title = {[Physical therapy in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S253-4S255}, pmid = {17128119}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*rehabilitation ; Humans ; *Physical Therapy Modalities ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease, without any curative treatment. Clinical expression is variable and related to loss of motor neurons in the cortex, brain stem and spinal cord. There is little scientific evidence demonstrating the usefulness of physical therapy in this disease. Only stretching exercises, proprioceptive neuromuscular facilitation techniques and functional mobility training seem to have a real benefit in terms of spasticity, quality-of-life and pain. The main objective of physical therapy appears to be the preservation of optimal quality-of-life throughout the course of this incurable degenerative disease.}, }
@article {pmid17128117, year = {2006}, author = {Cintas, P}, title = {[Drug therapy for symptomatic relief in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S235-4S243}, pmid = {17128117}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*drug therapy ; Humans ; Muscle Spasticity/drug therapy/etiology ; Pain/drug therapy/etiology ; Sialorrhea/drug therapy/etiology ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease that has no curative treatment. However, some symptoms of the disease can respond to specific treatments. The aim of these treatments is to enhance the patient's quality of life and in some instances survival. Besides physical therapy, and nutritional and respiratory supportive systems, several specific medications can be useful. However, despite the frequency of these symptoms, few studies have evaluated the benefit of these medications in ALS. Their use is most often based on clinical experience or on studies conducted in other neurological diseases. So, for most of these medications, available evidence does not permit a precise evaluation if their impact on quality of life and survival.}, }
@article {pmid17128116, year = {2006}, author = {Clavelou, P and Guy, N}, title = {[Symptomatic treatments in amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S228-4S234}, pmid = {17128116}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*therapy ; Humans ; Muscle Spasticity/drug therapy/etiology ; Sialorrhea/etiology/therapy ; }, abstract = {ALS is a progressive, fatal, degenerative motor neuron disease of unknown cause. Although advances in understanding pathophysiology of ALS have stimulated the development of new therapies, most of them remain few efficient or ineffective and the main management of ALS patient, to improve quality of life by alleviating symptoms, is symptomatic treatment. This article discusses the approaches now in use to manage some of the most common symptoms of ALS including the following: spasticity, cramps, pain, laryngospasm, pseudobulbar syndrome, salivation and drooling, sleep disorders and fatigue, constipation and trophic troubles.}, }
@article {pmid17128114, year = {2006}, author = {Dib, M}, title = {[What are the etiological medical therapies in amyotrophic lateral sclerosis?].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S215-4S219}, pmid = {17128114}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology ; Clinical Trials as Topic ; Humans ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {The increasing knowledge about Amyotrophic Lateral sclerosis (ALS) led to the development of the first and only available treatment: riluzole. The efficacy of this drug has been demonstrated in two controlled clinical trials. The data showed that riluzole increases the rates of survival in patients suffering from ALS. This increase was about 25 percent over a period of 12 months of treatment. Since its marketing, the clinical efficacy of riluzole was confirmed in several epidemiological studies. Tested initially because of its anti-glutamates qualities, the exact mechanisms of action responsible for the efficacy of Riluzole in ALS remains unknown. Furthermore, despite a strong rational based on important literature, several other anti-glutamates drugs failed to demonstrate efficacy in ALS, nor did numerous anti-oxydant, neurotrophics, immunomodulators, and favoring mitochondrial metabolism drugs. Despite the low rate of patients showing an increase of liver enzymes, a strict control of liver functions is necessary with a treatment by riluzole. its dose should be increased gradually in case of important fatigue, a change of the general state, or respiratory incapacity. Because of the neuroprotectrives qualities of riluzole, early neuronal death in ALS, the difficulty to confirm early the diagnosis, and the evident interest to treat in the first stage, the treatment of the suspected forms of the disease becomes justifiable. The perspectives of treatment of ALS will depend on our capacity to understand better the physiopathology, the reasons of failures in the past, and to develop new biomarkers. They will depend also on our capacity to include in clinical trials and to follow up over a long time, an important number of patients. Different new methods, as the cellular therapy are in development, and represent a real hope for the future.}, }
@article {pmid17128092, year = {2006}, author = {Magistris, MR}, title = {[Amyotrophic lateral sclerosis: differential diagnosis and frontier forms].}, journal = {Revue neurologique}, volume = {162 Spec No 2}, number = {}, pages = {4S67-4S80}, pmid = {17128092}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Diagnosis, Differential ; Humans ; Motor Neuron Disease/diagnosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) may be mimicked by disorders affecting the different levels of the motor system from cortex to muscle. Clinical heterogeneity is a feature of both ALS and related syndromes allowing for a large differential diagnosis. During the initial stage of a motor disorder false positive and false negative diagnoses of ALS are possible. Examples of disorders that should not be misdiagnosed as ALS, because their prognosis and treatment differ, are multifocal motor neuropathy, Kennedy's bulbospinal atrophy, cervical myelopathy, hyperthyroidism and hyperparathyroidism. Syndromes remote from polio and radiation treatments should be recognised. Eventually, frontier forms of ALS with signs restricted to either the upper or lower motor neurons deserve particular attention. Electrodiagnosis is pivotal to disclose signs and extension of the peripheral motor neuron, to detect and quantify cortico-spinal involvement, to search for specific signs of conditions that mimic ALS. Until specific markers become available, clinical evaluation supported by electrodiagnosis and other ancillary tests are crucial to provide with the correct diagnosis, prognosis and treatment.}, }
@article {pmid17127563, year = {2006}, author = {Yoshino, H and Kimura, A}, title = {Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study).}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {7}, number = {4}, pages = {241-245}, doi = {10.1080/17482960600881870}, pmid = {17127563}, issn = {1748-2968}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Antipyrine/administration &amp; dosage/adverse effects/*analogs &amp; derivatives ; Dose-Response Relationship, Drug ; Edaravone ; Female ; Free Radical Scavengers/administration &amp; dosage/adverse effects ; Humans ; Male ; Middle Aged ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare disease involving selective and progressive degeneration and disappearance of motor neurons. Oxidative stress is believed to contribute to its pathogenesis. We have investigated the efficacy and safety of edaravone, a free radical scavenger previously approved for treatment of acute cerebral infarction, in ALS patients. Within an open trial design, 20 subjects with ALS received either 30 mg (5 subjects) or 60 mg (15 subjects) of edaravone via intravenous drip once per day. Two weeks of administration was followed by a two-week observation period. This four-week cycle was repeated six times. The primary endpoint was the change in the revised ALS functional rating scale (ALSFRS-R) score, while the secondary endpoint was 3-nitrotyrosine (3NT) level in cerebrospinal fluid (CSF). Efficacy was evaluated in the 60 mg group. During the six-month treatment period, the decline in the ALSFRS-R score (2.3+/-3.6 points) was significantly less than that in the six months prior to edaravone administration (4.7+/-2.1 points); the difference between the two was 2.4+/-3.5 points (Wilcoxon signed rank test, p = 0.039). In almost all patients, CSF 3NT, a marker for oxidative stress, was markedly reduced to almost undetectable levels at the end of the six-month treatment period. Data from the present study suggest that edaravone is safe and may delay the progression of functional motor disturbances by reducing oxidative stress in ALS patients.}, }
@article {pmid17127560, year = {2006}, author = {Garbuzova-Davis, S and Willing, AE and Saporta, S and Justen, EB and Misiuta, IE and Dellis, J and Sanberg, PR}, title = {Multiple transplants of hNT cells into the spinal cord of SOD1 mouse model of familial amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {7}, number = {4}, pages = {221-226}, doi = {10.1080/17482960600864470}, pmid = {17127560}, issn = {1748-2968}, mesh = {Amyotrophic Lateral Sclerosis/congenital/*pathology/*surgery ; Animals ; *Disease Models, Animal ; Mice ; Mice, Transgenic ; *Nerve Regeneration ; Neurons/pathology/*transplantation ; Reoperation ; Spinal Cord/*pathology/*surgery ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Survival Rate ; Treatment Outcome ; }, abstract = {hNT cells, derived from a human teratocarcinoma cell line, are versatile neuron-like cells that have been studied as possible treatment vehicles for neurodegenerative diseases. Previously, we showed the postponement of motor deficit symptoms in a G93A mouse model of amyotrophic lateral sclerosis (ALS) by transplanting hNT cells into the lumbar spinal cord. In this study, we examined the engraftment of hNT cells at multiple sites within the lumbar spinal cord by morphological analysis of neuritic process development. Results demonstrated that cells implanted at multiple sites established neuritic processes of different lengths independent of the number of cell implants. The hNT fiber outgrowth was a maximum of 0.15-0.3 mm from the transplants and mostly spread within the gray matter; interconnections between implants were not found. Therefore, we suggest that the observed postponement of motor deficit symptoms in G93A mice was not a result of neuritic outgrowth from the implanted hNT cells.}, }
@article {pmid17127557, year = {2006}, author = {Piepers, S and van den Berg, JP and Kalmijn, S and van der Pol, WL and Wokke, JH and Lindeman, E and van den Berg, LH}, title = {Effect of non-invasive ventilation on survival, quality of life, respiratory function and cognition: a review of the literature.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {7}, number = {4}, pages = {195-200}, doi = {10.1080/14660820500514974}, pmid = {17127557}, issn = {1748-2968}, mesh = {Amyotrophic Lateral Sclerosis/*mortality/*rehabilitation ; Clinical Trials as Topic/statistics &amp; numerical data ; Cognition Disorders/*mortality/prevention &amp; control ; Comorbidity ; Humans ; Hypoventilation/*mortality/*rehabilitation ; Incidence ; Outcome Assessment, Health Care ; Prognosis ; *Quality of Life ; Respiration, Artificial/*statistics &amp; numerical data ; Respiratory Function Tests/statistics &amp; numerical data ; Survival Analysis ; Survival Rate ; Treatment Outcome ; }, abstract = {Symptoms of nocturnal hypoventilation may negatively influence the quality of life (QoL) of ALS patients long before respiratory failure ensues. Non-invasive mechanical ventilation (NIV) is considered a treatment option for nocturnal hypoventilation. The primary objective of NIV is improving quality of life (QoL). It may also prolong life by several months. A systematic review of the literature was performed to analyse what is known of the effect of NIV on survival, QoL and other outcome measures. A computerized literature search was performed to identify controlled clinical trials and observational studies of treatment of ALS-associated nocturnal hypoventilation from 1985 until May 2005. Twelve studies fulfilled the inclusion criteria. Four studies were retrospective, seven prospective and in one study randomization was used. All studies reported beneficial effects of NIV on all outcome measures. In seven studies NIV was associated with prolonged survival in patients tolerant for NIV, and five studies reported an improved QoL. In conclusion, studies on the use of NIV in ALS differ in study design and endpoint definitions. All studies suggest a beneficial effect on QoL and other outcome measures (Evidence level Class II-III). Well-designed randomized controlled trials comparing the effect on QoL and survival have not been performed.}, }
@article {pmid17126543, year = {2007}, author = {Farrero, E and Prats, E and Manresa, F and Escarrabill, J}, title = {Outcome of non-invasive domiciliary ventilation in elderly patients.}, journal = {Respiratory medicine}, volume = {101}, number = {6}, pages = {1068-1073}, doi = {10.1016/j.rmed.2006.10.005}, pmid = {17126543}, issn = {0954-6111}, mesh = {Aged ; Carbon Dioxide/blood ; Female ; Follow-Up Studies ; *Home Care Services, Hospital-Based ; Humans ; Hypercapnia/blood/therapy ; Male ; Oxygen/blood ; Partial Pressure ; Patient Compliance ; Patient Selection ; Respiration, Artificial/adverse effects/*methods ; Respiratory Insufficiency/blood/*therapy ; Spain ; Survival Analysis ; Treatment Outcome ; }, abstract = {STUDY OBJECTIVES: To analyze the short- and long-term effects of domiciliary non-invasive ventilation (NIV) in the elderly.<br><br>METHODS: From 1990 to 2005 all patients who initiated NIV at age 75 or older were included in the study. The mean follow-up period was 36 (24) months. Data were obtained from a database record.<br><br>RESULTS: Forty-three patients, mean age 77 (1.9) years and hypercapnic respiratory failure secondary to restrictive, neuromuscular or hypoventilatory disease were included. The short-term effects included a significant improvement in arterial blood gases and nocturnal desaturations during NIV compared to baseline: PaO(2) increased a mean of 19 mmHg (P<0.0001), PaCO(2) decreased a mean of 16 mmHg (P<0.0001) and nocturnal time with SaO(2)<90% decreased a mean of 72% (P<0.0001). Arterial blood gases while breathing room air also improved significantly at 6 months after NIV initiation. Five patients (11%) discontinued treatment; this group did not differ from patients who continued NIV. Mean compliance was 8.3 (3.1)h/day. In the long-term effects, we observed that the initial improvement of arterial blood gases breathing room air was maintained throughout the followup period. The number of hospital admissions and days of hospital stay decreased significantly (P<0.0001 and 0.001, respectively) after NIV initiation. The poorest survival was observed in ALS patients (median 10.9 (2.3) months) significantly lower than the survival for the other diagnostic groups (median 58.5 (4.8) months), P=0.0013.<br><br>CONCLUSIONS: NIV is an effective treatment in the elderly. It improves arterial blood gases and nocturnal desaturations, decreases hospital admissions and is associated with long survival. So advanced age should not be considered as an exclusion criteria to prescribe NIV.}, }
@article {pmid17122939, year = {2006}, author = {Cereda, C and Cova, E and Di Poto, C and Galli, A and Mazzini, G and Corato, M and Ceroni, M}, title = {Effect of nitric oxide on lymphocytes from sporadic amyotrophic lateral sclerosis patients: toxic or protective role?.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {27}, number = {5}, pages = {312-316}, doi = {10.1007/s10072-006-0702-z}, pmid = {17122939}, issn = {1590-1874}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Analysis of Variance ; Blotting, Western/methods ; Case-Control Studies ; Humans ; Hydrazines/*metabolism/pharmacology ; Lymphocytes/*drug effects/metabolism ; Nitric Oxide/*pharmacology ; Nitric Oxide Donors/pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; Time Factors ; }, abstract = {Markers of oxidative and nitrosative stress have been found in spinal cord, cortex, cerebrospinal fluid and plasma of patients affected by amyotrophic lateral sclerosis (ALS), a fatal disorder characterised by progressive motor neuron degeneration. In this study, we investigated the effect of the NO-releasing agent, diethylamine NONOate (NONO), on lymphocytes from patients affected by the sporadic form of ALS (SALS) and controls by flow cytometry. In the same experimental conditions we investigated the expression of the antioxidant proteins, Bcl-2 and SOD1. Incubation with NONO induced cell damage in control lymphocytes but did not further damage the already affected untreated SALS lymphocytes. The incubation with NONO induced a time-dependent decrease of Bcl-2 and SOD1 in control lymphocytes. Surprisingly, in SALS lymphocytes the NONO treatment increased the expression of these proteins, which in basal conditions was depressed compared to control lymphocytes.}, }
@article {pmid17119468, year = {2006}, author = {Favier, A}, title = {[Oxidative stress in human diseases].}, journal = {Annales pharmaceutiques francaises}, volume = {64}, number = {6}, pages = {390-396}, doi = {10.1016/s0003-4509(06)75334-2}, pmid = {17119468}, issn = {0003-4509}, mesh = {*Disease ; Humans ; Oxidants/metabolism ; Oxidative Stress/*physiology ; }, abstract = {Oxidative stress is an abnormal phenomenon occurring inside our cells or tissues when production of oxygen radicals exceeds their antioxidant capacity. Excess of free radicals damage essential macromolecules of the cell, leading to abnormal gene expression, disturbance in receptor activity, proliferation or cell dye, immunity perturbation, mutagenesis, protein or lipofushin deposition. Numerous human diseases involve during the pathological process such a stress, localized or general (in the same way as inflammation). In many serious diseases such as cancer, ocular degeneration (age related macular degeneration or cataract), neurodegenerative diseases (ataxia, amyotrophic lateral sclerosis, Alzheimer's disease) stress is the factor original. In familial amyotrophic lateral sclerosis the genetic abnormality occurred an abnormal coding for an antioxidant enzyme, copper-zinc super oxide dismutase. In various other diseases oxidative stress occur secondary to the initial disease but plays an important in role immune or vascular complications. This is the case in infectious disease such as AIDS or septic shock, Parkinson's disease or renal failure. So antioxidant treatment seems logical to be tested in these pathologies. But they have to be applied early in the process, before irreversible mechanisms. They need also to be prescribed at low doses as baseline free radical production have to be preserved to maintain useful activity that cannot be suppressed.}, }
@article {pmid17118638, year = {2007}, author = {Laub, M and Midgren, B}, title = {Survival of patients on home mechanical ventilation: a nationwide prospective study.}, journal = {Respiratory medicine}, volume = {101}, number = {6}, pages = {1074-1078}, doi = {10.1016/j.rmed.2006.10.007}, pmid = {17118638}, issn = {0954-6111}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/mortality ; Carbon Dioxide/blood ; Denmark ; Female ; *Home Care Services ; Humans ; Male ; Middle Aged ; Oxygen/blood ; Partial Pressure ; Prognosis ; Prospective Studies ; *Respiration, Artificial ; Respiratory Insufficiency/mortality/*therapy ; Survival Analysis ; }, abstract = {Home mechanical ventilation (HMV) is increasingly used as a therapeutic option to patients with symptomatic chronic hypoventilation. There is, however, a paucity of solid data on factors that could affect prognosis in patients on home ventilation. In the present study, our aim was to study several factors in these patients with potential influence on survival. We examined 1526 adult patients from a nationwide HMV register to which data had been reported prospectively for 10 years. The patients constituted a broad diagnostic spectrum and the primary outcome in this study was death. We found by far the poorest survival rate in the ALS patients with only 5% alive after 5 years. Among the other patient groups the survival pattern was more uniform and the scoliosis, polio and Pickwick patients presented the best survival rate, after 5 years being around 75%. No factors were associated with a greater hazard for death in the ALS patients; in the non-ALS patients, however, negative predictors for survival were age, concomitant use of oxygen therapy, tracheostomy ventilation and start of ventilatory support in an acute clinical setting. Center size or county specific home ventilation treatment prevalence did not affect survival. In conclusion, in a large material of patients on HMV we found by far the poorest survival in the ALS patients. In the non-ALS patients a number of patient-related factors affected survival, while the size of the treating center or the regional treatment prevalence did not.}, }
@article {pmid17117171, year = {2006}, author = {Maragakis, NJ and Rothstein, JD}, title = {Mechanisms of Disease: astrocytes in neurodegenerative disease.}, journal = {Nature clinical practice. Neurology}, volume = {2}, number = {12}, pages = {679-689}, doi = {10.1038/ncpneuro0355}, pmid = {17117171}, issn = {1745-834X}, mesh = {Animals ; Astrocytes/*pathology/*physiology ; Disease Models, Animal ; Humans ; Neurodegenerative Diseases/classification/genetics/*pathology ; }, abstract = {The term neurodegenerative disease refers to the principal pathology associated with disorders such as amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease and Parkinson's disease, and it is presumed that neurodegeneration results in the clinical findings seen in patients with these diseases. Decades of pathological and physiological studies have focused on neuronal abnormalities in these disorders, but it is becoming increasingly evident that astrocytes are also important players in these and other neurological disorders. Our understanding of the normative biology of astrocytes has been aided by the development of animal models in which astrocyte-specific proteins and pathways have been manipulated, and mouse models of neurodegenerative diseases have also revealed astrocyte-specific pathologies that contribute to neurodegeneration. These models have led to the development of targeted therapies for pathways in which astrocytes participate, and this research should ultimately influence the clinical treatment of neurodegenerative disorders.}, }
@article {pmid17114826, year = {2007}, author = {Petrik, MS and Wong, MC and Tabata, RC and Garry, RF and Shaw, CA}, title = {Aluminum adjuvant linked to Gulf War illness induces motor neuron death in mice.}, journal = {Neuromolecular medicine}, volume = {9}, number = {1}, pages = {83-100}, pmid = {17114826}, issn = {1559-1174}, mesh = {Adjuvants, Pharmaceutic/*adverse effects ; Aluminum Hydroxide/*adverse effects ; Animals ; Anthrax Vaccines ; Behavior, Animal/drug effects ; Caspase 3/metabolism ; Male ; Maze Learning/drug effects ; Mice ; Motor Activity/drug effects ; Motor Cortex/drug effects/enzymology/pathology ; Persian Gulf Syndrome/chemically induced/*pathology/psychology ; Spinal Cord/drug effects/enzymology/pathology ; Squalene/*adverse effects ; }, abstract = {Gulf War illness (GWI) affects a significant percentage of veterans of the 1991 conflict, but its origin remains unknown. Associated with some cases of GWI are increased incidences of amyotrophic lateral sclerosis and other neurological disorders. Whereas many environmental factors have been linked to GWI, the role of the anthrax vaccine has come under increasing scrutiny. Among the vaccine's potentially toxic components are the adjuvants aluminum hydroxide and squalene. To examine whether these compounds might contribute to neuronal deficits associated with GWI, an animal model for examining the potential neurological impact of aluminum hydroxide, squalene, or aluminum hydroxide combined with squalene was developed. Young, male colony CD-1 mice were injected with the adjuvants at doses equivalent to those given to US military service personnel. All mice were subjected to a battery of motor and cognitive-behavioral tests over a 6-mo period postinjections. Following sacrifice, central nervous system tissues were examined using immunohistochemistry for evidence of inflammation and cell death. Behavioral testing showed motor deficits in the aluminum treatment group that expressed as a progressive decrease in strength measured by the wire-mesh hang test (final deficit at 24 wk; about 50%). Significant cognitive deficits in water-maze learning were observed in the combined aluminum and squalene group (4.3 errors per trial) compared with the controls (0.2 errors per trial) after 20 wk. Apoptotic neurons were identified in aluminum-injected animals that showed significantly increased activated caspase-3 labeling in lumbar spinal cord (255%) and primary motor cortex (192%) compared with the controls. Aluminum-treated groups also showed significant motor neuron loss (35%) and increased numbers of astrocytes (350%) in the lumbar spinal cord. The findings suggest a possible role for the aluminum adjuvant in some neurological features associated with GWI and possibly an additional role for the combination of adjuvants.}, }
@article {pmid17088947, year = {2006}, author = {Mennini, T and De Paola, M and Bigini, P and Mastrotto, C and Fumagalli, E and Barbera, S and Mengozzi, M and Viviani, B and Corsini, E and Marinovich, M and Torup, L and Van Beek, J and Leist, M and Brines, M and Cerami, A and Ghezzi, P}, title = {Nonhematopoietic erythropoietin derivatives prevent motoneuron degeneration in vitro and in vivo.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {12}, number = {7-8}, pages = {153-160}, pmid = {17088947}, issn = {1076-1551}, mesh = {Animals ; Asialoglycoproteins/*pharmacology ; Behavior, Animal ; Cell Survival/drug effects ; Cells, Cultured ; Cytokine Receptor Common beta Subunit/metabolism ; Erythropoietin/*analogs &amp; derivatives/pharmacology ; Hematopoiesis ; Humans ; Kainic Acid/toxicity ; Mice ; Mice, Neurologic Mutants ; Motor Neurons/cytology/*drug effects/*pathology ; Nerve Degeneration/*prevention &amp; control ; Nerve Growth Factors/pharmacology ; Neuroprotective Agents/pharmacology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/cytology/pathology ; }, abstract = {Chronic treatment with asialo erythropoietin (ASIALO-EPO) or carbamylated erythropoietin (CEPO) improved motor behavior and reduced motoneuron loss and astrocyte and microglia activation in the cervical spinal cord of wobbler mice, an animal model of amyotrophic lateral sclerosis, but had no effect on hematocrit values. ASIALO-EPO and CEPO, like the parent compound EPO, protected primary motoneuron cultures from kainate-induced death in vitro. Both EPO receptor and the common CD131 beta chain were expressed in cultured motoneurons and in the anterior horn of wobbler mice spinal cord. Our results strongly support a role for the common beta chain CD131 in the protective effect of EPO derivatives on motoneuron degeneration. Thus CEPO, which does not bind to the classical homodimeric EPO receptor and is devoid of hematopoietic activity, could be effective in chronic treatment aimed at reducing motoneuron degeneration.}, }
@article {pmid17084815, year = {2006}, author = {Arai, T and Hasegawa, M and Akiyama, H and Ikeda, K and Nonaka, T and Mori, H and Mann, D and Tsuchiya, K and Yoshida, M and Hashizume, Y and Oda, T}, title = {TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.}, journal = {Biochemical and biophysical research communications}, volume = {351}, number = {3}, pages = {602-611}, doi = {10.1016/j.bbrc.2006.10.093}, pmid = {17084815}, issn = {0006-291X}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*metabolism ; Brain/*metabolism ; DNA-Binding Proteins/*metabolism ; Dementia/*metabolism ; Female ; Humans ; Inclusion Bodies/*metabolism ; Male ; Middle Aged ; Tissue Distribution ; Ubiquitin/*metabolism ; tau Proteins/chemistry/*metabolism ; }, abstract = {Ubiquitin-positive tau-negative neuronal cytoplasmic inclusions and dystrophic neurites are common pathological features in frontotemporal lobar degeneration (FTLD) with or without symptoms of motor neuron disease and in amyotrophic lateral sclerosis (ALS). Using biochemical and immunohistochemical analyses, we have identified a TAR DNA-binding protein of 43 kDa (TDP-43), a nuclear factor that functions in regulating transcription and alternative splicing, as a component of these structures in FTLD. Furthermore, skein-like inclusions, neuronal intranuclear inclusions, and glial inclusions in the spinal cord of ALS patients are also positive for TDP-43. Dephosphorylation treatment of the sarkosyl insoluble fraction has shown that abnormal phosphorylation takes place in accumulated TDP-43. The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of TDP-43.}, }
@article {pmid17082170, year = {2006}, author = {Robinson, EM and Phipps, M and Purtilo, RB and Tsoumas, A and Hamel-Nardozzi, M}, title = {Complexities in decision making for persons with disabilities nearing end of life.}, journal = {Topics in stroke rehabilitation}, volume = {13}, number = {4}, pages = {54-67}, doi = {10.1310/tsr1304-54}, pmid = {17082170}, issn = {1074-9357}, mesh = {Aged ; *Decision Making ; Persons with Disabilities/*psychology ; Female ; Humans ; Male ; Middle Aged ; Personal Autonomy ; Personality ; Terminal Care/*ethics ; }, abstract = {Good end-of-life care requires that clinicians, families, and ethicists be aware of biases that influence patient cases, particularly in the acute care setting where the aim is primarily cure and return to optimal functional level. Persons with disabilities may pose unique challenges; their potential for quality of life is viewed through the lens of highly functional clinicians who might have a biased view of the disabled person's quality of life. The authors aim to present three categories of disability that do not claim to be absolute but rather offer clinicians and ethicists a lens through which to reflect on bias that unconsciously may influence their approach to the patient who is seriously ill and may be nearing the end of life. The categories include (a) a person who has lived with a disability from birth or early life, due to trauma or disease, and is now faced with a serious illness that requires that life-sustaining treatment; (b) the otherwise healthy person who acquires a disability through an acute event of disease or trauma and whose condition requires that life-sustaining treatment decisions be made; and (c) the person who has lived with a progressive chronic illness, such as lung or heart disease or amyotrophic lateral sclerosis, and may have gradually adjusted to disabilities imposed by the condition and now is faced with life-sustaining treatment decisions. The concept of inherent dignity (Pellegrino 2005) is suggested as a filtering lens in case consideration.}, }
@article {pmid17072811, year = {2006}, author = {Orient-López, F and Terré-Boliart, R and Guevara-Espinosa, D and Bernabeu-Guitart, M}, title = {[Neurorehabilitation treatment of amyotrophic lateral sclerosis].}, journal = {Revista de neurologia}, volume = {43}, number = {9}, pages = {549-555}, pmid = {17072811}, issn = {0210-0010}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*rehabilitation/therapy ; Humans ; }, abstract = {AIM: To carry out a review of the literature with the aim of defining, evaluating, establishing and making more widely known the value of neurorehabilitation therapy in the different phases of the course of amyotrophic lateral sclerosis (ALS). Special emphasis will be given to the role this type of treatment plays in improving both survival rates and these patients' functional independence and quality of life.<br><br>DEVELOPMENT: Although ALS is a disease that follows an unrelenting course, patients' quality of life, and even their survival time, can be changed dramatically with suitable medical management. Neurorehabilitation therapy consists of an integral process carried out by an interdisciplinary team that includes the basic pharmacological treatment, symptomatic treatment of the associated problems and rehabilitation therapy, the aim being to prolong the functional capacity of these patients and to promote their independence. Its ultimate goal is to ensure the highest possible quality of life throughout the whole health care process.<br><br>CONCLUSIONS: Until a cure is found for ALS, neurorehabilitation therapy is clearly today's most promising therapeutic option as far as improving these patients' quality of life, health and survival rates is concerned. This treatment should not only involve the medical care of the patient, but also provide the appropriate technical aids and home help, together with training and preparation of both the main caregiver and the patient's family. This instruction should cover the whole period from the moment the disease is diagnosed to its terminal phase.}, }
@article {pmid17067837, year = {2006}, author = {Gravholt, CH and Chen, JW and Oxvig, C and Overgaard, MT and Christiansen, JS and Frystyk, J and Flyvbjerg, A}, title = {The GH-IGF-IGFBP axis is changed in Turner syndrome: partial normalization by HRT.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {16}, number = {5-6}, pages = {332-339}, doi = {10.1016/j.ghir.2006.09.001}, pmid = {17067837}, issn = {1096-6374}, mesh = {Adult ; Aprotinin/pharmacology ; Carrier Proteins/blood ; Case-Control Studies ; *Estrogen Replacement Therapy ; Female ; Glycoproteins/blood ; Human Growth Hormone/*blood ; Humans ; In Vitro Techniques ; Insulin-Like Growth Factor Binding Protein 1/blood ; Insulin-Like Growth Factor Binding Protein 2/blood ; Insulin-Like Growth Factor Binding Protein 3 ; Insulin-Like Growth Factor Binding Protein 4/blood ; Insulin-Like Growth Factor Binding Proteins/antagonists &amp; inhibitors/*blood ; Insulin-Like Growth Factor I/*metabolism ; Turner Syndrome/*blood/*drug therapy/genetics ; }, abstract = {BACKGROUND: We recently described increased insulin-like growth factor binding protein 3 (IGFBP-3) proteolysis in the circulation in adult Turner syndrome (TS), with normalization during sex hormone replacement therapy (HRT), suggesting the presence of a sex hormone regulated IGFBP-3 proteolytic activity.<br><br>OBJECTIVE: To study the GH-IGF-IGFBP axis in TS without and during HRT, and to further characterize the nature of the IGFBP-3 proteolytic activity.<br><br>MATERIAL: 23 women with TS before and during HRT, and 24 healthy age-matched women.<br><br>METHODS: The study included measurements of the acid-labile subunit (ALS), IGFBP-1, -2 and -3 (immunoreactive and Western ligand blot (WLB)), IGFBP-4 (WLB) and IGF-I bioactivity. To determine the molecular distribution of IGFBP-3, serum from patient and controls was subjected to neutral size-exclusion chromatography followed by determination of the IGFBP profile by WLB and immunoassay. Finally, the inhibitor characteristic of in vitro IGFBP-3 proteolytic activity in serum was determined.<br><br>RESULTS: Immunoreactive IGF-I was normal, while IGF-I bioactivity was decreased in TS. Immunoreactive IGFBP-1, -2 and -3 were normal, while WLB-IGFBPs were all reduced, but increased in response to HRT. The IGFBP-3 ternary complex was significantly reduced in TS, and increased in response to HRT, while the non-ternary complexed IGFBP-3 remained unaffected by treatment. In vitro IGFBP-3 proteolytic activity in serum was abolished by aprotinin, while EDTA and zinc chloride had no inhibitory effects, suggesting the presence of a serine protease. 17beta-estradiol had no direct inhibitory effect on the IGFBP-3 proteolytic activity in vitro. Size-exclusion chromatography showed that the protease had a molecular mass of more than 500 kDa.<br><br>CONCLUSION: The GH-IGF-IGFBP axis is profoundly disturbed in TS, with a partly normalizing effect of HRT. A sex hormone-dependent IGFBP-3 proteolytic activity (serine protease) leads to destabilization of the 150 kDa IGFBP-3 ternary complex in TS. During HRT both IGFBP-3 proteolytic activity and ternary complex formation is normalized.}, }
@article {pmid17065522, year = {2006}, author = {Chang, B and Dacey, MS and Hawes, NL and Hitchcock, PF and Milam, AH and Atmaca-Sonmez, P and Nusinowitz, S and Heckenlively, JR}, title = {Cone photoreceptor function loss-3, a novel mouse model of achromatopsia due to a mutation in Gnat2.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {47}, number = {11}, pages = {5017-5021}, doi = {10.1167/iovs.05-1468}, pmid = {17065522}, issn = {0146-0404}, support = {CA 34196/CA/NCI NIH HHS/United States ; EY 07003/EY/NEI NIH HHS/United States ; EY 07758/EY/NEI NIH HHS/United States ; EY 11996/EY/NEI NIH HHS/United States ; R01 EY 07060/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Chromosome Mapping ; Color Vision Defects/*genetics/physiopathology ; *Disease Models, Animal ; Electroretinography ; Genetic Linkage ; Genotype ; Heterotrimeric GTP-Binding Proteins/*genetics ; Mice ; Mice, Mutant Strains ; *Mutation, Missense ; Photography ; Polymerase Chain Reaction ; Retinal Cone Photoreceptor Cells/*physiopathology ; Retinal Degeneration/*genetics/physiopathology ; Sequence Analysis, DNA ; }, abstract = {PURPOSE: To report a novel mouse model of achromatopsia with a cpfl3 mutation found in the ALS/LtJ strain.<br><br>METHODS: The effects of a cpfl3 mutation were documented using fundus photography, electroretinography (ERG), and histopathology. Genetic analysis was performed using linkage studies and PCR gene identification.<br><br>RESULTS: Homozygous cpfl3 mice had poor cone-mediated responses on ERG at 3 weeks that became undetectable by 9 months. Rod-mediated waveforms were initially normal, but declined with age. Microscopy of the retinas revealed progressive vacuolization of the photoreceptor outer segments. Immunocytochemistry with cone-specific markers showed progressive loss of labeling for alpha-transducin, but the cone outer segments in the oldest mice examined remained intact and positive with peanut agglutinin (PNA). The cpfl3 mapped to mouse chromosome 3 at the same location as human GNAT2, known to cause achromatopsia. Sequence analysis revealed a missense mutation due to a single base pair substitution in exon 6 in cpfl3.<br><br>CONCLUSIONS: The Gnat2(cpfl3) mutation leads to cone dysfunction and the progressive loss of cone alpha-transducin immunolabeling. Despite a poor cone ERG signal and loss of cone alpha-transducin label, the cones survive at 14 weeks as demonstrated by PNA staining. This mouse model of achromatopsia will be useful in the study of the development, pathophysiology, and treatment of achromatopsia and other cone degenerations. The gene symbol for the cpfl3 mutation has been changed to Gnat2(cpfl3).}, }
@article {pmid17060310, year = {2006}, author = {Carter, GT and Han, JJ and Mayadev, A and Weiss, MD}, title = {Modafinil reduces fatigue in Charcot-Marie-Tooth disease type 1A: a case series.}, journal = {The American journal of hospice &amp; palliative care}, volume = {23}, number = {5}, pages = {412-416}, doi = {10.1177/1049909106292169}, pmid = {17060310}, issn = {1049-9091}, mesh = {Adult ; Aged ; Anxiety/chemically induced ; Benzhydryl Compounds/adverse effects/*therapeutic use ; Central Nervous System Stimulants/adverse effects/*therapeutic use ; Charcot-Marie-Tooth Disease/*complications/diagnosis/genetics ; Diarrhea/chemically induced ; Fatigue/*drug therapy/etiology ; Female ; Headache/chemically induced ; Humans ; Male ; Middle Aged ; Modafinil ; Research Design ; Sleep Initiation and Maintenance Disorders/chemically induced ; Treatment Outcome ; }, abstract = {Charcot-Marie-Tooth disease, the most common hereditary motor and sensory neuropathy, is a slowly progressive disorder characterized by diffuse muscle weakness and prominent distal atrophy that predominantly involves the intrinsic muscles of the feet and the peroneal muscles. It results in marked reduction in functional aerobic capacity during exercise and fatigue is commonly reported. To date, no pharmacologic treatment has been shown to be effective for treating fatigue in Charcot-Marie-Tooth. Modafinil is used to treat the symptoms of fatigue and excessive daytime sleepiness in narcolepsy. However, fatigue and subsequent excessive daytime sleepiness secondary to fatigue are common symptoms in many neurologic disorders. Prior reports on patients with myotonic muscular dystrophy, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis, have shown beneficial effects of modafinil in treating fatigue. We report 4 patients with genetically confirmed Charcot-Marie-Tooth disease who had significant fatigue that was almost completely relieved by modafinil.}, }
@article {pmid17055612, year = {2007}, author = {Lepore, AC and Maragakis, NJ}, title = {Targeted stem cell transplantation strategies in ALS.}, journal = {Neurochemistry international}, volume = {50}, number = {7-8}, pages = {966-975}, doi = {10.1016/j.neuint.2006.09.005}, pmid = {17055612}, issn = {0197-0186}, mesh = {Cell Division ; Hematopoietic Stem Cell Mobilization ; Humans ; Motor Neuron Disease/*therapy ; Neuroglia/transplantation ; Neurons/cytology/transplantation ; Spinal Cord/cytology/pathology ; *Stem Cell Transplantation/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that results in paralysis and ultimately death due to respiratory failure. Transplantation of neural precursor cells (NPCs) derived from the central nervous system is a promising therapeutic strategy for treatment of brain and spinal cord disorders such as ALS. ALS is a particularly challenging disease for designing relevant therapies, and presently no effective treatment exists. Despite such daunting challenges, a number of the potential benefits of NPC transplantation coincide with the neuropathological obstacles associated with ALS, including neuronal and glial replacement and non-replacement functions such as delivery of trophic support. Knowledge of the underlying disease-specific pathways involved in neurodegeneration and the contributions of different cellular subtypes to the disease go hand-in-hand with advances in NPC transplantation biology, and will aid in targeting cell-specific therapies to neurodegenerative disorders such as ALS. It is with these multiple cell targets that NPC transplantation may lend itself well to understanding and possibly slowing disease processes. A number of studies have already demonstrated the potential benefits of cell transplantation in ALS models. Lastly, practical issues such as timing and method of cell delivery, immune suppression, and the need for combinatorial approaches with non-cell based strategies must all be considered for eventual translation to the clinic.}, }
@article {pmid17054441, year = {2006}, author = {Van der Schyf, CJ and Geldenhuys, WJ and Youdim, MB}, title = {Multifunctional drugs with different CNS targets for neuropsychiatric disorders.}, journal = {Journal of neurochemistry}, volume = {99}, number = {4}, pages = {1033-1048}, doi = {10.1111/j.1471-4159.2006.04141.x}, pmid = {17054441}, issn = {0022-3042}, mesh = {Animals ; Brain/drug effects/metabolism/physiopathology ; Brain Chemistry/*drug effects/genetics ; Brain Diseases/*drug therapy/*genetics/physiopathology ; Drug Design ; Humans ; Molecular Structure ; Neurocognitive Disorders/*drug therapy/*genetics/physiopathology ; Neurotransmitter Agents/agonists/biosynthesis/genetics ; Nootropic Agents/chemistry/isolation &amp; purification/pharmacology ; Psychotropic Drugs/chemistry/isolation &amp; purification/*pharmacology ; }, abstract = {The multiple disease etiologies that lead to neuropsychiatric disorders, such as Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis, Huntington disease, schizophrenia, depressive illness and stroke, offer significant challenges to drug discovery efforts aimed at preventing or even reversing the progression of these disorders. Transcriptomic tools and proteomic profiling have clearly indicated that such diseases are multifactorial in origin. Further, they are thought to be initiated by a cascade of molecular events that involve several neurotransmitter systems. In response to this complexity, a new paradigm has recently emerged that challenges the widely held assumption that 'silver bullet' agents are superior to 'dirty drugs' in therapeutic approaches aimed at the prevention or treatment of neuropsychiatric diseases. A similar pattern of drug development has occurred in strategies for the treatment of cancer, AIDS and cardiovascular diseases. In this review, we offer an overview of therapeutic strategies and novel investigative drugs discovered or developed in our own and other laboratories, that address multiple CNS etiological targets associated with an array of neuropsychiatric disorders.}, }
@article {pmid17049562, year = {2006}, author = {Petri, S and Kiaei, M and Wille, E and Calingasan, NY and Flint Beal, M}, title = {Loss of Fas ligand-function improves survival in G93A-transgenic ALS mice.}, journal = {Journal of the neurological sciences}, volume = {251}, number = {1-2}, pages = {44-49}, doi = {10.1016/j.jns.2006.08.013}, pmid = {17049562}, issn = {0022-510X}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*genetics/mortality/*physiopathology ; Animals ; Behavior, Animal ; Cell Count/methods ; Disease Models, Animal ; Fas Ligand Protein/*metabolism/physiology ; Immunohistochemistry/methods ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Activity/physiology ; Motor Neurons/metabolism ; Nitric Oxide Synthase Type I/metabolism ; Probability ; Spinal Cord/pathology ; Superoxide Dismutase/*genetics/metabolism ; Survival Analysis ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {ALS is a devastating neurodegenerative disorder for which no effective treatment exists. The precise molecular mechanisms underlying the selective degeneration of motor neurons are still unknown. A motor neuron specific apoptotic pathway involving Fas and NO has been discovered. Motor neurons from ALS-mice have an increased sensitivity to Fas-induced cell death via this pathway. In this study we therefore crossed G93A-SOD1 overexpressing ALS mice with Fas ligand (FasL) mutant (gld) mice to investigate whether the reduced Fas signaling could have beneficial effects on motor neuron death. G93A-SOD1 mutant mice with a homozygous FasL mutant showed a modest but statistically significant extension of survival, and reduced loss of motor neurons. These results indicate that motor neuron apoptosis triggered by Fas is relevant in ALS pathogenesis.}, }
@article {pmid17037196, year = {2006}, author = {Shan, XY and Li, B and Zhang, JR}, title = {[Produce of marker-free transgenic tobacco plants by FLP/frt recombination system].}, journal = {Sheng wu gong cheng xue bao = Chinese journal of biotechnology}, volume = {22}, number = {5}, pages = {744-750}, doi = {10.1016/s1872-2075(06)60054-x}, pmid = {17037196}, issn = {1000-3061}, mesh = {Base Sequence ; DNA Nucleotidyltransferases/*metabolism ; Molecular Sequence Data ; Plants, Genetically Modified/*genetics ; Polymerase Chain Reaction ; Promoter Regions, Genetic ; *Recombination, Genetic ; Nicotiana/*genetics ; }, abstract = {Selectable marker genes that usually encode antibiotic or herbicide resistances are widely used for the selection of the transgenic plants, but they become unnecessary and undesirable after transformation selection. An important strategy to improve the transgenic plants' biosafety is to eliminate the marker genes after successful selection. In the FLP/frt site-specific system of the 2 microm plasmid of Saccharomyces cerevisiae, the FLP enzyme efficiently catalyzes recombination between two directly repeated FLP recombination target (frt) sites, eliminating the sequence between them. By controlled expression of the FLP recombinase and specific allocation of the frt sites within transgenic constructs, the system can be applied to eliminate the marker genes after selection. Through a series of procedures, the plant FLP/frt site-specific recombination system was constructed, which included the frt containing vector pCAMBIA1300-betA-frt-als-frt and the FLP expression vector pCAMBIA1300-hsp-FLP-hpt. The FLP recombinase gene was introduced into transgenic (betA-frt-als-frt) tobacco plants by re-transformation. In re-transgenic plants, after heat shock treatment, the marker gene als flanked by two identical orientation frt sites could be excised by the inducible expression of FLP recombinase under the control of hsp promoter. Excision of the als gene was found in 41% re-transgenic tobacco plants, which indicated that this systerm could make a great contribution to obtain the marker free transgenic plants.}, }
@article {pmid17034790, year = {2007}, author = {Li, W and Brakefield, D and Pan, Y and Hunter, D and Myckatyn, TM and Parsadanian, A}, title = {Muscle-derived but not centrally derived transgene GDNF is neuroprotective in G93A-SOD1 mouse model of ALS.}, journal = {Experimental neurology}, volume = {203}, number = {2}, pages = {457-471}, doi = {10.1016/j.expneurol.2006.08.028}, pmid = {17034790}, issn = {0014-4886}, support = {NS042794/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/*prevention &amp; control ; Animals ; Astrocytes/metabolism ; Axons/pathology ; Cell Count ; Cell Survival/drug effects ; Central Nervous System/*metabolism ; Denervation ; Female ; Glial Cell Line-Derived Neurotrophic Factor/*biosynthesis/*pharmacology ; Immunohistochemistry ; Longevity/drug effects ; Mice ; Mice, Transgenic ; Microglia/pathology ; Motor Activity/drug effects ; Motor Neurons/drug effects ; Muscle, Skeletal/*metabolism ; Neuromuscular Junction/pathology ; *Neuroprotective Agents ; Postural Balance/drug effects/physiology ; Psychomotor Performance/drug effects ; Spinal Cord/pathology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for motoneurons (MNs), and is considered a potential agent for the treatment of amyotrophic lateral sclerosis (ALS) and other MN diseases. The effectiveness of GDNF may depend significantly upon its route of delivery to MNs. In this study we tested the neuroprotective effects of target-derived and centrally derived GDNF in the G93A-SOD1 mouse model of ALS using a transgenic approach. We found that overexpression of GDNF in the skeletal muscle (Myo-GDNF mice) significantly delayed the onset of disease and increased the life span of G93A-SOD1 mice by 17 days. The duration of disease also increased by 8.5 days, indicating that GDNF slowed down the progression of disease. Locomotor performance in Myo-GDNF/G93A-SOD1 mice was also significantly improved. The behavioral improvement correlated well with anatomical and histological data. We demonstrated that muscle-derived GDNF resulted in increased survival of spinal MNs, and twice as many MNs survived in end-stage double transgenic mice compared to end-stage G93A-SOD1 mice. Muscle-derived GDNF also had profound effects on muscle innervation and axonal degeneration. Significantly higher numbers of completely or partially innervated NMJs and large caliber myelinated axons were found in double transgenic mice. In contrast, we demonstrated that overexpression of GDNF in astrocytes in the CNS (GFAP-GDNF mice) failed to demonstrate any neuroprotective effects in G93A-SOD1 mice both on behavioral and histological levels. These data indicate that retrograde transport and signaling of GDNF is more physiological and effective for ALS treatment than anterogradely transported GDNF.}, }
@article {pmid17028633, year = {2006}, author = {Holmøy, T and Worren, T}, title = {[Communication aids in amyotrophic lateral sclerosis].}, journal = {Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke}, volume = {126}, number = {19}, pages = {2523-2525}, pmid = {17028633}, issn = {0807-7096}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*psychology/therapy ; Cell Phone ; *Communication Devices for People with Disabilities ; Electronic Mail ; Female ; Humans ; Internet ; Male ; Middle Aged ; Nonverbal Communication ; Telecommunications ; }, abstract = {BACKGROUND: Many patients with amyotrophic lateral sclerosis lose the ability to speak, and in late-stage disease also the ability to communicate through gestures. Social isolation is one of the greatest burdens of this disease. Implementation of alternative and augmentative communication can increase the quality of life even in advanced disease.<br><br>MATERIALS AND METHODS: We have systematically recorded alternative and augmentative communication aids given to patients treated by the amyotrophic lateral sclerosis team at Ullev&#xe5;l University Hospital from 1998 to 2005, and evaluated the results in the light of current literature.<br><br>RESULTS: 62 out of 92 patients received alternative and augmentative communication aids. Alternative and augmentative communication was more often used by female than male patients (p = 0.01). Except for two who developed dementia, all patients were able to express basic needs until the terminal stage of the disease.<br><br>INTERPRETATION: Most patients retain enough mobility of head and eyes to use communication aids until the terminal stage. Physicians must know the possibilities and limitations of assisted and augmentative communication in order to give appropriate treatment and information, also concerning life-sustaining treatment.}, }
@article {pmid17028632, year = {2006}, author = {Leirvik, A and Liverød, M and Holmøy, T}, title = {[Quality of life of patients with amyotrophic lateral sclerosis].}, journal = {Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke}, volume = {126}, number = {19}, pages = {2520-2522}, pmid = {17028632}, issn = {0807-7096}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*psychology/therapy ; Persons with Disabilities/psychology ; Humans ; Mental Health ; Patient Care Team ; Patient Education as Topic ; Patient Satisfaction ; *Quality of Life ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) leads to loss of important body functions, a huge need for assistance and is associated with a low quality of life (QoL). We have investigated QoL in ALS patients treated by a multidisciplinary ALS team, and to which degree this team met the patients' needs.<br><br>MATERIAL AND METHODS: The patients' health-related QoL was measured by use of SF-36, and content with the treatment offered by the team was evaluated through a structured interview of 14 ALS patients at the Neurological Department at Ullev&#xe5;l University Hospital, Oslo, Norway.<br><br>RESULTS: The patients reported low scores for physical QoL, but mental QoL was close to that of the general population. The patients were generally content with the treatment given by the ALS team. They were most content with the practical help given to organize their homes and the accessibility of different members of the team. They were least content with the psychological help and the information given to their relatives. Content with treatment was not correlated with self-perceived QoL or with physical disability.<br><br>INTERPRETATION: Our findings suggest that the patients are content with the ALS team, but that their psychological reactions and information to relatives are not handled well enough. Most ALS patients treated by the ALS team experience their life as meaningful, regardless of their degree of neurological dysfunction.}, }
@article {pmid17026833, year = {2006}, author = {Jiang, F and Li, WP and Kwiecien, J and Turnbull, J}, title = {A study of the purine derivative AIT-082 in G93A SOD1 transgenic mice.}, journal = {International journal of immunopathology and pharmacology}, volume = {19}, number = {3}, pages = {489-498}, doi = {10.1177/039463200601900304}, pmid = {17026833}, issn = {0394-6320}, mesh = {Aminobenzoates/*therapeutic use ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Hypoxanthines/*therapeutic use ; Mice ; Mice, Transgenic ; Neuroprotective Agents/*therapeutic use ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {AIT-082 is a purine derivative with neuroprotective and neurotrophic activity that is desirable in a candidate therapy for Amyotrophic Lateral Sclerosis. Consequently, we investigated the effect of AIT-082 in a transgenic mouse model of ALS. AIT-082 (0, 1, 3, 10, 30, 60, 100 mg/kg) was given to TgN(SOD1-G93A)1Gur transgenic mice from age 30 days until death. The age at onset of clinical signs of disease and the age at death were recorded for each animal. Disease progression was measured by the weekly average distance run in a running wheel. Analysis was made by the Kaplan Meier method with log rank statistics, log rank for trend and Cox regression. Neuropathological study of the brain, spinal cord, muscles and other organs was undertaken at death. In a second experiment we studied the effect of AIT-082 (30 mg/kg) at the onset of disease and during survival of transgenic G93A SOD1 mice, beginning dosing at different ages (20, 30, 40, 60, 80 days). Disease onset was mildly earlier (i.e. worse) at 1 and 10 mg/kg AIT-082 and mildly delayed at 30 mg/kg. This improvement did not reach the usual statistical significance. There was no difference in the age at death for any treatment dose. There was no difference in the neuropathology of treated and untreated G93A mice. However, there was an early improvement in the running wheel function at all tested doses. Using Cox regression, after adjustment for sex, the mice in the running wheels had slightly delayed onset of disease without change in survival and, after adjustment for exercise, the female mice had slightly improved survival. Consequently, AIT-082 would not be an attractive candidate for ALS clinical trials as monotherapy and justification for its use in combination therapy would require additional laboratory support. There was dissociation between the endpoints of disease progression (as judged by running wheel performance) and disease onset and survival. AIT-082 improved early running wheel performance yet led to accelerated late decline and had no impact on survival. It is possible that the drug facilitates early sprouting that leads to accelerated late decline.}, }
@article {pmid17022691, year = {2006}, author = {Kolarcik, C and Bowser, R}, title = {Plasma and cerebrospinal fluid-based protein biomarkers for motor neuron disease.}, journal = {Molecular diagnosis &amp; therapy}, volume = {10}, number = {5}, pages = {281-292}, pmid = {17022691}, issn = {1177-1062}, support = {ES013469/ES/NIEHS NIH HHS/United States ; T32 EB001026/EB/NIBIB NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Biomarkers/blood/cerebrospinal fluid ; Blood Proteins/*analysis ; Cerebrospinal Fluid Proteins/*analysis ; Humans ; Molecular Diagnostic Techniques ; Motor Neuron Disease/*diagnosis/metabolism ; Proteomics ; }, abstract = {Motor neuron diseases (MNDs) and, in particular, amyotrophic lateral sclerosis (ALS), are a heterogeneous group of neurologic disorders characterized by the progressive loss of motor function. In ALS, a selective and relentless degeneration of both upper and lower motor neurons occurs, culminating in mortality typically within 5 years of symptom onset. However, survival rates vary among individual patients and can be from a few months to >10 years from diagnosis. Inadequacies in disease detection and treatment, along with a lack of diagnostic and prognostic tools, have prompted many to turn to proteomics-based biomarker discovery efforts. Proteomics refers to the study of the proteins expressed by a genome at a particular time, and the proteome can respond to and reflect the status of an organism, including health and disease states. Although an emerging field, proteomic applications promise to uncover biomarkers critical for differentiating patients with ALS and other MNDs from healthy individuals and from patients affected by other diseases. Ideally, these studies will also provide mechanistic information to facilitate identification of new drug targets for subsequent therapeutic development. In addition to proper experimental design, standard operating procedures for sample acquisition, preprocessing, and storage must be developed. Biological samples typically analyzed in proteomic studies of neurologic diseases include both plasma and cerebrospinal fluid (CSF). Recent studies have identified individual proteins and/or protein panels from blood plasma and CSF that represent putative biomarkers for ALS, although many of these proteins are not unique to this disease. Continued investigations are required to validate these initial findings and to further pursue the role of these proteins as diagnostic biomarkers or surrogate markers of disease progression. Protein biomarkers specific to ALS will additionally function to evaluate drug efficacy in clinical trials and to identify novel targets for drug design. It is hoped that proteomic technologies will soon integrate the basic biology of ALS with mechanistic disease information to achieve success in the clinical setting.}, }
@article {pmid17020749, year = {2006}, author = {Larsen, KE and Benn, SC and Ay, I and Chian, RJ and Celia, SA and Remington, MP and Bejarano, M and Liu, M and Ross, J and Carmillo, P and Sah, D and Phillips, KA and Sulzer, D and Pepinsky, RB and Fishman, PS and Brown, RH and Francis, JW}, title = {A glial cell line-derived neurotrophic factor (GDNF):tetanus toxin fragment C protein conjugate improves delivery of GDNF to spinal cord motor neurons in mice.}, journal = {Brain research}, volume = {1120}, number = {1}, pages = {1-12}, doi = {10.1016/j.brainres.2006.08.079}, pmid = {17020749}, issn = {0006-8993}, support = {R01 NS038679/NS/NINDS NIH HHS/United States ; }, mesh = {Analysis of Variance ; Animals ; Animals, Newborn ; Axotomy/methods ; Cell Survival/drug effects ; Cells, Cultured ; Dopamine/metabolism ; Dose-Response Relationship, Drug ; Glial Cell Line-Derived Neurotrophic Factor/chemistry/*pharmacology ; Humans ; Immunohistochemistry/methods ; Male ; Mesencephalon/cytology ; Mice ; Mice, Inbred C57BL ; Motor Neurons/*drug effects ; Neuroblastoma ; Neuroprotective Agents/*pharmacology ; Peptide Fragments/chemistry/*pharmacology ; Protein Transport/drug effects ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins/pharmacology ; Spinal Cord/*cytology ; Tetanus Toxin/chemistry/*pharmacology ; Tyrosine 3-Monooxygenase/metabolism ; }, abstract = {Glial cell line-derived neurotrophic factor (GDNF) has shown robust neuroprotective and neuroreparative activities in various animal models of Parkinson's Disease or amyotrophic lateral sclerosis (ALS). The successful use of GDNF as a therapeutic in humans, however, appears to have been hindered by its poor bioavailability to target neurons in the central nervous system (CNS). To improve delivery of exogenous GDNF protein to CNS motor neurons, we employed chemical conjugation techniques to link recombinant human GDNF to the neuronal binding fragment of tetanus toxin (tetanus toxin fragment C, or TTC). The predominant species present in the purified conjugate sample, GDNF:TTC, had a molecular weight of approximately 80 kDa as determined by non-reducing SDS-PAGE. Like GDNF, addition of GDNF:TTC to culture media of neuroblastoma cells expressing GFRalpha-1/c-RET produced a dose-dependent increase in cellular phospho-c-RET levels. Treatment of cultured midbrain dopaminergic neurons with either GDNF or the conjugate similarly promoted both DA neuron survival and neurite outgrowth. However, in contrast to mice treated with GDNF by intramuscular injection, mice receiving GDNF:TTC revealed intense GDNF immunostaining associated with spinal cord motor neurons in fixed tissue sections. That GDNF:TTC provided neuroprotection of axotomized motor neurons in neonatal rats further revealed that the conjugate retained its GDNF activity in vivo. These results indicate that TTC can serve as a non-viral vehicle to substantially improve the delivery of functionally active growth factors to motor neurons in the mammalian CNS.}, }
@article {pmid17017544, year = {2006}, author = {Németh, H and Toldi, J and Vécsei, L}, title = {Kynurenines, Parkinson's disease and other neurodegenerative disorders: preclinical and clinical studies.}, journal = {Journal of neural transmission. Supplementum}, volume = {}, number = {70}, pages = {285-304}, doi = {10.1007/978-3-211-45295-0_45}, pmid = {17017544}, issn = {0303-6995}, mesh = {Animals ; Humans ; Kynurenine/*physiology ; Neurodegenerative Diseases/*genetics/metabolism ; Parkinson Disease/*genetics/metabolism ; Quinolinic Acid/metabolism ; Receptors, N-Methyl-D-Aspartate/physiology ; Signal Transduction/physiology ; }, abstract = {The kynurenine pathway is the main pathway of tryptophan metabolism. L-kynurenine is a central compound of this pathway since it can change to the neuroprotective agent kynurenic acid or to the neurotoxic agent quinolinic acid. The break-up of these endogenous compounds' balance can be observable in many disorders. It can be occur in neurodegenerative disorders, such as Parkinson's disease, Huntington's and Alzheimer's disease, in stroke, in epilepsy, in multiple sclerosis, in amyotrophic lateral sclerosis, and in mental failures, such as schizophrenia and depression. The increase of QUIN concentration or decrease of KYNA concentration could enhance the symptoms of several diseases. According to numerous studies, lowered KYNA level was found in patients with Parkinson's disease. It can be also noticeable that KYNA-treatment prevents against the QUIN-induced lesion of rat striatum in animal experiments. Administrating of KYNA can be appear a promising therapeutic approach, but its use is limited because of its poorly transport across the blood-brain barrier. The solution may be the development of KYNA analogues (e.g. glucoseamine-kynurenic acid) which can pass across this barrier and disengaging in the brain, then KYNA can exert its neuroprotective effects binding at the excitatory glutamate receptors, in particular the NMDA receptors. Furthermore, it seems hopeful to use kynurenine derivatives (e.g. 4-chloro-kynurenine) or enzyme inhibitors (e.g. Ro-61-8048) to ensure an increased kynurenic acid concentration in the central nervous system.}, }
@article {pmid17014688, year = {2006}, author = {Weishaupt, JH and Bartels, C and Pölking, E and Dietrich, J and Rohde, G and Poeggeler, B and Mertens, N and Sperling, S and Bohn, M and Hüther, G and Schneider, A and Bach, A and Sirén, AL and Hardeland, R and Bähr, M and Nave, KA and Ehrenreich, H}, title = {Reduced oxidative damage in ALS by high-dose enteral melatonin treatment.}, journal = {Journal of pineal research}, volume = {41}, number = {4}, pages = {313-323}, doi = {10.1111/j.1600-079X.2006.00377.x}, pmid = {17014688}, issn = {0742-3098}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism/pathology ; Animals ; Biomarkers ; Cell Line ; Cytoprotection ; Dose-Response Relationship, Drug ; Female ; Follow-Up Studies ; Glutamic Acid/toxicity ; Humans ; Male ; Melatonin/*therapeutic use ; Mice ; Mice, Transgenic ; Middle Aged ; Neurons/drug effects ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Survival Rate ; Vitamin E/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the collective term for a fatal motoneuron disease of different etiologies, with oxidative stress as a common molecular denominator of disease progression. Melatonin is an amphiphilic molecule with a unique spectrum of antioxidative effects not conveyed by classical antioxidants. In preparation of a possible future clinical trial, we explored the potential of melatonin as neuroprotective compound and antioxidant in: (1) cultured motoneuronal cells (NSC-34), (2) a genetic mouse model of ALS (SOD1(G93A)-transgenic mice), and (3) a group of 31 patients with sporadic ALS. We found that melatonin attenuates glutamate-induced cell death of cultured motoneurons. In SOD1(G93A)-transgenic mice, high-dose oral melatonin delayed disease progression and extended survival. In a clinical safety study, chronic high-dose (300 mg/day) rectal melatonin was well tolerated during an observation period of up to 2 yr. Importantly, circulating serum protein carbonyls, which provide a surrogate marker for oxidative stress, were elevated in ALS patients, but were normalized to control values by melatonin treatment. This combination of preclinical effectiveness and proven safety in humans suggests that high-dose melatonin is suitable for clinical trials aimed at neuroprotection through antioxidation in ALS.}, }
@article {pmid17008387, year = {2007}, author = {Ahtoniemi, T and Goldsteins, G and Keksa-Goldsteine, V and Malm, T and Kanninen, K and Salminen, A and Koistinaho, J}, title = {Pyrrolidine dithiocarbamate inhibits induction of immunoproteasome and decreases survival in a rat model of amyotrophic lateral sclerosis.}, journal = {Molecular pharmacology}, volume = {71}, number = {1}, pages = {30-37}, doi = {10.1124/mol.106.028415}, pmid = {17008387}, issn = {0026-895X}, mesh = {Animals ; Animals, Genetically Modified ; Antioxidants/*pharmacology ; Death ; Disease Models, Animal ; Electrophoretic Mobility Shift Assay ; Humans ; Motor Neuron Disease/*physiopathology ; Neuroglia/enzymology ; Pyrrolidines/*pharmacology ; Rats ; Superoxide Dismutase/genetics ; Survival Rate ; Thiocarbamates/*pharmacology ; }, abstract = {Pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear transcription factor kappa-B (NF-kappaB) and an antioxidant, has beneficial effects in animal models of various diseases, including arthritis, brain ischemia, spinal cord injury, Alzheimer's disease, and Duchenne muscular dystrophy. Because inflammation and oxidative damage are also hallmarks of amyotrophic lateral sclerosis (ALS), we studied the effect of oral PDTC treatment on G93A-superoxide dismutase 1 (SOD1) transgenic (TG) rat model of human ALS and observed that PDTC treatment significantly decreases the survival. PDTC treatment evoked the end stage of the disease at 121 +/- 21 days, whereas untreated TG animals reached the end stage at 141 +/- 13 days (p < 0.01). The DNA binding activity of NF-kappaB was not altered in G93A-SOD1 TG rats by PDTC treatment. The copper concentration in the spinal cord was increased after PDTC treatment both in G93A-SOD1 TG and wild-type rats, suggesting that increased copper may enhance the neurotoxicity of mutant SOD1. The amount of ubiquitinated proteins were significantly higher and proteasomal activity was decreased in the spinal cords of PDTC-treated TG rats compared with other groups, suggesting that PDTC treatment decreases proteasome function. Immunoblotting and immunocytochemistry showed that the level of immunoproteasome but not constitutive proteasome was increased in glia of G93A-SOD1 TG rats along with disease development. PDTC treatment completely blocked the induction of immunoproteasome expression without affecting constitutive proteasome. These results suggest that PDTC acts as an immunoproteasome inhibitor in mutant SOD1 rats and that immunoproteasome may help the nervous system to cope with deleterious effects of SOD1-G93A mutation.}, }
@article {pmid16996272, year = {2006}, author = {Mackenzie, R and Kiernan, M and McKenzie, D and Youl, BD}, title = {Hyperimmune goat serum for amyotrophic lateral sclerosis.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {13}, number = {10}, pages = {1033-1036}, doi = {10.1016/j.jocn.2006.03.009}, pmid = {16996272}, issn = {0967-5868}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*immunology/physiopathology ; Animals ; Anti-Inflammatory Agents/immunology/pharmacology/therapeutic use ; Antibodies/immunology/pharmacology/*therapeutic use ; Disease Progression ; Goats/immunology ; Humans ; Immunotherapy/*methods/trends ; Male ; Motor Neurons/drug effects/immunology/pathology ; Neuroprotective Agents/therapeutic use ; Respiratory Insufficiency/drug therapy/immunology/physiopathology ; Respiratory Muscles/innervation/physiopathology ; Respiratory Paralysis/drug therapy/immunology/physiopathology ; Riluzole/therapeutic use ; Serum/*immunology ; Sodium Channel Blockers/immunology/pharmacology/therapeutic use ; Treatment Outcome ; }, abstract = {The authors report a patient with amyotrophic lateral sclerosis (ALS) who showed a lessening of deterioration in respiratory muscle strength during treatment with hyperimmune goat serum (HGS) (Aimspro). Respiratory function tests (RFTs) were measured by established protocols, and all measurements were expressed as a percentage of normal predicted values. The rate of decline was calculated by linear regression analysis. Respiratory muscle strength decline was less during 13 months of treatment with HGS (mean 1.3% per month, range 0.8-1.7%) compared to the preceding 13 months (mean 2.3% per month, range 1.2-3.1%), while a greater decline would be expected with disease progression. Comparison with similarly affected patients in the literature suggest that a decline of 4-5% per month of predicted values may be expected during the treatment phase.}, }
@article {pmid16986115, year = {2006}, author = {Mueller, SG and Schuff, N and Weiner, MW}, title = {Evaluation of treatment effects in Alzheimer's and other neurodegenerative diseases by MRI and MRS.}, journal = {NMR in biomedicine}, volume = {19}, number = {6}, pages = {655-668}, pmid = {16986115}, issn = {0952-3480}, support = {P01 AA11493/AA/NIAAA NIH HHS/United States ; R01 AG010897/AG/NIA NIH HHS/United States ; P01 AA011493/AA/NIAAA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; P01 AG19724/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/diagnosis/*drug therapy ; Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Clinical Trials as Topic ; Dementia, Vascular/diagnosis/drug therapy ; Humans ; Magnetic Resonance Imaging/*methods ; Magnetic Resonance Spectroscopy/*methods ; Neurodegenerative Diseases/diagnosis/*drug therapy ; Neuroprotective Agents/therapeutic use ; Parkinson Disease/diagnosis/drug therapy ; Positron-Emission Tomography/methods ; Tomography, Emission-Computed, Single-Photon/methods ; Treatment Outcome ; }, abstract = {Neurodegeneration refers to a large clinically and pathologically heterogeneous disease entity associated with slowly progressive neuronal loss in different anatomical and functional systems of the brain. Neurodegenerative diseases often affect cognition, e.g. Alzheimer's disease (AD), dementia with Lewy bodies and vascular dementia, or different aspects of the motor system, e.g., amyotrophic lateral sclerosis, Parkinson's disease and ataxic disorders. Owing to increasing knowledge about the mechanisms leading to neurodegeneration, the development of treatments able to modify the neurodegenerative process becomes possible for the first time. Currently, clinical outcome measures are used to assess the efficacy of such treatments. However, most clinical outcome measures have a low test-retest reliability and thus considerable measurement variance. Therefore, large patient populations and long observation times are needed to detect treatment effects. Furthermore, clinical outcome measures cannot distinguish between symptomatic and disease-modifying treatment effects. Therefore, alternative biomarkers including neuroimaging may take on a more important role in this process. Because MR scanners are widely available and allow for non-invasive detection and quantification of changes in brain structure and metabolism, there is increasing interest in the use of MRI/MRS to monitor objectively treatment effects in clinical trials of neurodegenerative diseases. Particularly volumetric MRI has been used to measure atrophy rates in treatment trials of AD because the relationship between atrophic changes and neuron loss is well established and correlates well with clinical measures. More research is needed to determine the value of other MR modalities, i.e. diffusion, perfusion and functional MRI and MR spectroscopy, for clinical trials with neuroprotective drugs.}, }
@article {pmid16979292, year = {2006}, author = {Di Lazzaro, V and Dileone, M and Pilato, F and Profice, P and Ranieri, F and Musumeci, G and Angelucci, F and Sabatelli, M and Tonali, PA}, title = {Repetitive transcranial magnetic stimulation for ALS. A preliminary controlled study.}, journal = {Neuroscience letters}, volume = {408}, number = {2}, pages = {135-140}, doi = {10.1016/j.neulet.2006.08.069}, pmid = {16979292}, issn = {0304-3940}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*therapy ; Disease Progression ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Placebos ; *Transcranial Magnetic Stimulation ; Treatment Outcome ; }, abstract = {Repetitive transcranial magnetic stimulation (rTMS) of brain can modulate cortical neurotransmission, a novel paradigm of repetitive stimulation termed continuous theta-burst stimulation (cTBS) produces a pronounced and prolonged suppression of motor cortex excitability. The aim of this preliminary study was to investigate whether cTBS of motor cortex could have any beneficial effect in patients with amyotrophic lateral sclerosis (ALS). We performed a double-blind, placebo-controlled trial. Twenty patients with definite ALS were randomly allocated to blinded active or placebo stimulation. Repetitive stimulation of the motor cortex was performed for five consecutive days every month for six consecutive months. The primary outcome was the rate of decline as evaluated with the ALS functional rating scale. The treatment was well tolerated by the patients. Fifteen patients (seven active and eight sham) completed the study and were included in the 6-months analysis. Both active and sham patients deteriorated during treatment, however, active patients showed a modest but significant slowing of the deterioration rate. Though we cannot be sure whether the effects observed can be attributed to cTBS, because of the restricted number of patients studied, further investigation on a larger group of ALS patients is warranted. The results of the pilot study might open up a new therapeutic perspective in ALS based on neuromodulation.}, }
@article {pmid16966530, year = {2006}, author = {Heiman-Patterson, TD and Miller, RG}, title = {NIPPV: a treatment for ALS whose time has come.}, journal = {Neurology}, volume = {67}, number = {5}, pages = {736-737}, doi = {10.1212/01.wnl.0000238978.69141.57}, pmid = {16966530}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Intermittent Positive-Pressure Ventilation/*methods/*trends ; *Ventilators, Mechanical ; }, }
@article {pmid16963406, year = {2006}, author = {De Groot, IJ and Post, MW and Van Heuveln, T and Van Den Berg, LH and Lindeman, E}, title = {Measurement of decline of functioning in persons with amyotrophic lateral sclerosis: responsiveness and possible applications of the Functional Independence Measure, Barthel Index, Rehabilitation Activities Profile and Frenchay Activities Index.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {7}, number = {3}, pages = {167-172}, doi = {10.1080/14660820600640620}, pmid = {16963406}, issn = {1748-2968}, mesh = {*Activities of Daily Living ; Aged ; Amyotrophic Lateral Sclerosis/*physiopathology/psychology/*rehabilitation ; Cohort Studies ; *Disability Evaluation ; Female ; Humans ; Male ; Middle Aged ; *Physical Therapy Modalities ; *Sickness Impact Profile ; }, abstract = {It is important not only to monitor the functional change during the course of ALS, but also to determine whether or not the available help is sufficient. This study was performed to determine which generic assessment instrument is most appropriate. A multicentre cohort of patients with ALS was followed for one year. At baseline, six months, and 1 year four instruments were used: Functional Independence Measure (FIM), Rehabilitation Activities Profile (RAP), Barthel Index (BI), and Frenchay Activities Index (FAI). The responsiveness of the measures was examined using effect sizes and standardized response mean statistics. Seventy-three patients at baseline, 63 after six months and 43 after one year were assessed. If calculated on the group that completed all three assessments, the FIM, BI, and RAP showed moderate effect sizes and standardized response means over a period of six months and large effect sizes over 12 months. Based on their responsiveness FIM, BI, and RAP can be used to evaluate limitations in activities and care needs of persons with ALS and to evaluate treatment results in trials. The FIM was the most responsive instrument, although the BI might be easier to use in clinical practice.}, }
@article {pmid16957081, year = {2006}, author = {Mojsilovic-Petrovic, J and Jeong, GB and Crocker, A and Arneja, A and David, S and Russell, DS and Kalb, RG}, title = {Protecting motor neurons from toxic insult by antagonism of adenosine A2a and Trk receptors.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {26}, number = {36}, pages = {9250-9263}, pmid = {16957081}, issn = {1529-2401}, support = {K08 DA000302-05/DA/NIDA NIH HHS/United States ; R01 NS052325/NS/NINDS NIH HHS/United States ; NS 52325/NS/NINDS NIH HHS/United States ; R01 NS029837/NS/NINDS NIH HHS/United States ; NS 29837/NS/NINDS NIH HHS/United States ; }, mesh = {*Adenosine A2 Receptor Antagonists ; Amyotrophic Lateral Sclerosis/chemically induced/*metabolism/pathology/prevention &amp; control ; Animals ; Brain-Derived Neurotrophic Factor/*metabolism ; Cells, Cultured ; Kainic Acid ; Motor Neurons/drug effects/*metabolism/*pathology ; Neuroprotective Agents/administration &amp; dosage ; Rats ; Rats, Sprague-Dawley ; Receptor Protein-Tyrosine Kinases/*antagonists &amp; inhibitors/metabolism ; Receptor, Adenosine A2A/metabolism ; }, abstract = {The death of motor neurons in amyotrophic lateral sclerosis (ALS) is thought to result from the interaction of a variety of factors including excitotoxicity, accumulation of toxic proteins, and abnormal axonal transport. Previously, we found that the susceptibility of motor neurons to excitotoxic insults can be limited by inhibiting signals evoked by brain-derived neurotrophic factor (BDNF) activation of the receptor tyrosine kinase B (TrkB). Here we show that this can be achieved by direct kinase inhibition or by blockade of a transactivation pathway that uses adenosine A2a receptors and src-family kinases (SFKs). Downstream signaling cascades (such as mitogen-activated protein kinase and phosphatidylinositol-3 kinase) are inhibited by these blockers. In addition to protecting motor neurons from excitotoxic insult, these agents also prevent toxicity that follows from the expression of mutant proteins (G85R superoxide dismutase 1; G59S p150(glued)) that cause familial motor neuron disease. TrkB, adenosine A2a receptors, and SFKs associate into complexes in lipid raft and nonlipid raft membranes and the signaling from lipids rafts may be particularly important because their disruption by cholesterol depletion blocks the ability of BDNF to render motor neurons vulnerable to insult. The neuroprotective versatility of Trk antagonism suggests that it may have broad utility in the treatment of ALS patients.}, }
@article {pmid16945472, year = {2006}, author = {Axelsson, C and Nestin, J and Svensson, L and Axelsson, AB and Herlitz, J}, title = {Clinical consequences of the introduction of mechanical chest compression in the EMS system for treatment of out-of-hospital cardiac arrest-a pilot study.}, journal = {Resuscitation}, volume = {71}, number = {1}, pages = {47-55}, doi = {10.1016/j.resuscitation.2006.02.011}, pmid = {16945472}, issn = {0300-9572}, mesh = {Aged ; Cardiopulmonary Resuscitation/*methods ; Emergency Medical Services/*methods ; Female ; Heart Arrest/mortality/*therapy ; Humans ; Male ; Pilot Projects ; }, abstract = {AIM: To evaluate the outcome among patients suffering from out-of-hospital cardiac arrest (OHCA) after the introduction of mechanical chest compression (MCC) compared with standard cardiopulmonary resuscitation (SCPR) in two emergency medical service (EMS) systems.<br><br>METHODS: The inclusion criterion was witnessed OHCA. The exclusion criteria were age < 18 years, the following judged etiologies behind OHCA: trauma, pregnancy, hypothermia, intoxication, hanging and drowning or return of spontaneous circulation (ROSC) prior to the arrival of the advanced life support (ALS) unit. Two MCC devices were allocated during six-month periods between four ALS units for a period of two years (cluster randomisation).<br><br>RESULTS: In all, 328 patients fulfilled the criteria for participation and 159 were allocated to the MCC tier (the device was used in 66% of cases) and 169 to the SCPR tier. In the MCC tier, 51% had ROSC (primary end-point) versus 51% in the SCPR tier. The corresponding values for hospital admission alive (secondary end-point) were 38% and 37% (NS). In the subset of patients in whom the device was used, the percentage who had ROSC was 49% versus 50% in a control group matched for age, initial rhythm, aetiology, bystander-/crew-witnessed status and delay to CPR. The percentage of patients discharged alive from hospital after OHCA was 8% versus 10% (NS) for all patients and 2% versus 4%, respectively (NS) for the patients in the subset (where the device was used and the matched control population).<br><br>CONCLUSION: In this pilot study, the results did not support the hypothesis that the introduction of mechanical chest compression in OHCA improves outcome. However, there is room for further improvement in the use of the device. The hypothesis that this will improve outcome needs to be tested in further prospective trials.}, }
@article {pmid21049355, year = {2006}, author = {Brunsdon, R and Coltheart, M and Nickels, L and Joy, P}, title = {Developmental prosopagnosia: A case analysis and treatment study.}, journal = {Cognitive neuropsychology}, volume = {23}, number = {6}, pages = {822-840}, doi = {10.1080/02643290500441841}, pmid = {21049355}, issn = {0264-3294}, abstract = {This paper reports a treatment case study focused on face perception impairments designed for AL, an 8-year-old child with prosopagnosia. AL's prosopagnosia was characterized by deficits at the level of structural encoding-that is, he was unable to achieve normal basic perception of faces. This impairment then impacted on all subsequent aspects of familiar- and unfamiliar-face processing. Detailed assessment of feature processing revealed impairments in perception of facial features with a dissociation between relatively good perception of the mouth feature and poor perception of eye and nose features. Interestingly, results also suggested at least partial internal representation of facial features despite long-standing deficits in perception of these features. A treatment programme focused on training in perception, and analysis of facial features and familiar-face naming was conducted. Treatment resulted in excellent face naming for familiar faces, a decreased reliance on nonfacial cues and a reduction in AL's tendency to misidentify unfamiliar faces as family members.}, }
@article {pmid16937918, year = {2006}, author = {Chen, WC and Cheng, HH and Huang, CJ and Chou, CT and Liu, SI and Chen, IS and Hsu, SS and Chang, HT and Huang, JK and Jan, CR}, title = {Effect of riluzole on Ca2+ movement and cytotoxicity in Madin-Darby canine kidney cells.}, journal = {Human &amp; experimental toxicology}, volume = {25}, number = {8}, pages = {461-469}, doi = {10.1191/0960327106het641oa}, pmid = {16937918}, issn = {0960-3271}, mesh = {Animals ; Calcium Signaling/*drug effects ; Cell Line ; Cell Survival/drug effects ; Central Nervous System Agents/*pharmacology ; Dogs ; Kidney/cytology ; Riluzole/*pharmacology ; }, abstract = {Riluzole is a drug used in the treatment of amyotrophic lateral sclerosis; however, its in vitro action is unclear. In this study, the effect of riluzole on intracellular Ca2+ concentration ([Ca2+]i) in Madin-Darby canine kidney (MDCK) cells was investigated using the Ca2+ -sensitive fluorescent dye, fura-2. Riluzole (100-500 microM) caused a rapid and sustained increase of [Ca2+]i in a concentration-dependent manner (EC50 = 150 microM). Some 40 and 50% of this [Ca2+]i increase was prevented by the removal of extracellular Ca2+ and the addition of La3+, respectively, but was unchanged by dihydropyridines, verapamil and diltiazem. In Ca2+ -free medium, thapsigargin - an inhibitor of the endoplasmic reticulum (ER) Caz+ -ATPase--caused a monophasic [Ca2+]i increase, after which the increasing effect of riluzole on [Ca2+]i was attenuated by 70%; in addition, pre-treatment with riluzole abolished thapsigargin-induced [Ca2+]i increases. U73122, an inhibitor of phospholipase C (PLC), abolished ATP (but not riluzole)-induced [Ca2+]i increases. At concentrations of 250 and 500 microM, riluzole killed 40 and 95% cells, respectively. The cytotoxic effect of riluzole (250 microM) was unaltered by pre-chelating cytosolic Ca2+ with BAPTA. Collectively, in MDCK cells, riluzole rapidly increased [Ca2+]i by stimulating extracellular Ca2+ influx via an La3+ -sensitive pathway and intracellular Ca2+ release from the ER via, as yet, unidentified mechanisms. Furthermore, riluzole caused Ca2+ -unrelated cytotoxicity in a concentration-dependent manner.}, }
@article {pmid16934166, year = {2006}, author = {Dhand, UK}, title = {Clinical approach to the weak patient in the intensive care unit.}, journal = {Respiratory care}, volume = {51}, number = {9}, pages = {1024-40; discussion 1040-1}, pmid = {16934166}, issn = {0020-1324}, mesh = {Biopsy ; Clinical Chemistry Tests ; Critical Care/*methods ; Electrophysiology/methods ; Humans ; Muscle Weakness/diagnosis/*etiology/pathology ; Muscles/pathology ; Nerve Tissue/pathology ; Neurologic Examination ; Neuromuscular Diseases/*diagnosis/pathology ; }, abstract = {Motor weakness in a patient in the intensive care unit (ICU) may be related to (1) pre-existing neuromuscular disorder that leads to ICU admission, (2) new-onset or previously undiagnosed neurological disorder, or (3) complications of non-neuromuscular critical illness. Neuromuscular syndromes related to ICU treatment consist of critical illness polyneuropathy, critical illness myopathy, and prolonged neuromuscular blockade, and are now recognized as a frequent cause of newly acquired weakness in ICU patients. Clinical features include quadriparesis, muscle wasting, and difficulty weaning from the ventilator. Evaluation of these patients is based on knowledge of clinical setting and predisposing factors, focused neurological examination, detailed electrophysiological investigation, serum creatine kinase level, other laboratory studies as needed, and histological examination of muscle biopsy. If a central nervous system (brain or spinal cord) lesion is suspected, neuroimaging studies are required. In addition to conventional nerve conduction and needle electromyography, phrenic nerve conduction, diaphragm electromyography, blink reflex, and (recently) the technique of direct muscle stimulation have been employed. Critical illness polyneuropathy is an axonal motor and sensory neuropathy that often follows sepsis and multiorgan failure. Risk factors for critical illness myopathy are corticosteroids and neuromuscular blocking drugs, acute respiratory illness, and organ transplant. Three subtypes (acute necrotizing myopathy, thick myosin filament loss myopathy, and type II fiber atrophy) are recognized. Major differential diagnoses of critical illness related paralysis are incidental Guillain-Barré syndrome and unmasked myasthenia gravis. Rarely, atypical presentation of amyotrophic lateral sclerosis, polymyositis or other myopathies, and precipitation of porphyria or rhabdomyolysis due to drugs used in the ICU have been described. Recently a poliomyelitis-like flaccid paralysis due to West Nile virus infection was reported. A subgroup of patients with myasthenia gravis with muscle-specific tyrosine kinase antibody is noted to present as respiratory crisis. Muscle biopsy in ICU paralysis syndromes may be helpful in arriving at a specific diagnosis or to classify the type of critical illness myopathy. Nerve biopsy is only rarely indicated.}, }
@article {pmid16928982, year = {2006}, author = {Broom, WJ and Auwarter, KE and Ni, J and Russel, DE and Yeh, LA and Maxwell, MM and Glicksman, M and Kazantsev, AG and Brown, RH}, title = {Two approaches to drug discovery in SOD1-mediated ALS.}, journal = {Journal of biomolecular screening}, volume = {11}, number = {7}, pages = {729-735}, doi = {10.1177/1087057106290937}, pmid = {16928982}, issn = {1087-0571}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*enzymology ; Animals ; Cell Line ; Drug Evaluation, Preclinical/*methods ; Enzyme Inhibitors/analysis/chemistry/*pharmacology ; Green Fluorescent Proteins/metabolism ; Humans ; Mice ; Mutant Proteins/metabolism ; PC12 Cells ; Promoter Regions, Genetic/genetics ; Rats ; Recombinant Fusion Proteins/metabolism ; Superoxide Dismutase/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS cases; approximately 25% of these cases are due to mutations in the Cu/Zn superoxide dismutase gene (SOD1). To date, 105 different mutations spanning all 5 exons have been identified in the SOD1 gene. Mutant SOD1-associated ALS is caused by a toxic gain of function of the mutated protein. Therefore, regardless of the specific mechanism whereby mutant SOD1 initiates motor neuron death, the authors hypothesize that measures that decrease levels of mutant SOD1 protein should ameliorate the phenotype in transgenic mice and potentially in patients with SOD1-mediated disease. They have designed 2 cell-based screening assays to identify small, brain-permeant molecules that inactivate expression of the SOD1 gene or increase the degradation of the SOD1 protein. Here they describe the development and optimization of these assays and the results of high-throughput screening using a variety of compound libraries, including a total of more than 116,000 compounds. The majority of the hit compounds identified that down-regulated SOD1 were shown to be toxic in a cell-based viability assay or were nonselective transcription inhibitors, but work is continuing on a number of nonspecific inhibitors of SOD1 expression. Ultimately, the authors believe that these 2 cell-based assays will provide powerful strategies to identify novel therapies for the treatment of inherited SOD1-associated forms of ALS.}, }
@article {pmid16910281, year = {2006}, author = {Bodson, L and Grenade, J and Micheels, J and D'Orio, V}, title = {[The value of mobile intensive care unit (MICU): does it remain to be proven?].}, journal = {Revue medicale de Liege}, volume = {61}, number = {5-6}, pages = {494-499}, pmid = {16910281}, issn = {0370-629X}, mesh = {Belgium ; *Intensive Care Units/standards ; *Mobile Health Units/standards ; Practice Guidelines as Topic ; }, abstract = {Recent international guidelines about emergency situations (ILCOR / ERC) pointed to the need of the whole "chain of survival". ALS, Advanced Life Support (the last and "medical" part of the chain) is important and influences survival rate. If no doubt exists about "what" and "when" to do in such situations, there is no consensus in industrialized countries about "who" should be in charge of such out-of-hospital acute diagnosis and treatment: emergency physicians, emergency nurses, emergency medical technicians (EMT), other "new" professionals ? ... A description of the MICU system in Belgium is given.}, }
@article {pmid16909027, year = {2005}, author = {Meininger, V}, title = {Clinical trials in ALS: what did we learn from recent trials in humans?.}, journal = {Neuro-degenerative diseases}, volume = {2}, number = {3-4}, pages = {208-214}, doi = {10.1159/000089627}, pmid = {16909027}, issn = {1660-2854}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Animals ; Clinical Trials as Topic ; Excitatory Amino Acid Antagonists/therapeutic use ; Female ; Humans ; Male ; Mice ; Middle Aged ; Prognosis ; Riluzole/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. No treatment is currently able to stop the disease process. In the absence of new active compounds there is an urgent need to develop new strategies based on the neuroprotective activity of available drugs. ALS is a heterogeneous disease. To build up these therapeutic trials, we need to have a better understanding of the prognostic factors in this disease. During the Phase IV Rilutek Trial in France, we developed in a large population of patients a prognostic score based on clinical parameters available at the bedside. The most significant variables are vital capacity, spasticity, fasciculations, swallowing, cough and creatininemia. This score proved to be very useful in daily use in the clinic and for planning disease management in ALS as in the design of therapeutic trials. In ALS clinical trials, efficacy can be evaluated using survival or functional parameters. In phase II trials, function remains the most commonly used. In phase III trials, the gold standard endpoint remains the survival rate at month 18. We analyzed the most recent ALS trials published in the literature. This review suggests that in these trials there is a discrepancy between drug effects on survival versus function. These results suggest that a reappraisal of strategies to identify therapeutic targets for ALS is required.}, }
@article {pmid16909021, year = {2005}, author = {Mojsilovic-Petrovic, J and Arneja, A and Kalb, RG}, title = {Enprofylline protects motor neurons from in vitro excitotoxic challenge.}, journal = {Neuro-degenerative diseases}, volume = {2}, number = {3-4}, pages = {160-165}, doi = {10.1159/000089621}, pmid = {16909021}, issn = {1660-2854}, mesh = {Animals ; Animals, Newborn ; Blotting, Western ; Cells, Cultured ; Excitatory Amino Acid Agonists/toxicity ; Excitatory Amino Acid Antagonists/pharmacology ; Kainic Acid/toxicity ; Motor Neurons/*drug effects ; Neuroprotective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptor, trkB/metabolism ; Receptors, Adenosine A2/drug effects/metabolism ; Xanthines/*pharmacology ; }, abstract = {BACKGROUND: The death of motor neurons in amyotrophic lateral sclerosis (ALS) is believed to result, in part, from unrestrained activation of glutamate receptors (excitotoxicity). In some in vitro models, excitotoxic death only occurs if motor neurons develop in the presence of the growth factor, brain-derived neurotrophic factor (BDNF).<br><br>OBJECTIVE: Since the increased vulnerability of motor neurons evoked by BDNF is mediated by activation of TrkB, we sought to identify pharmacological agents that can block this pathway. Adenosine receptors are known to transactivate Trk receptors, leading us to examine the effects of manipulating of adenosine receptor signaling on Trk signaling and excitotoxic sensitivity.<br><br>METHODS: Spinal cord cultures were treated with adenosine receptor agonists and antagonists. The biochemical effects on Trk signaling and excitotoxic motor neuron death were examined.<br><br>RESULTS: We show here that adenosine A(2a) antagonists can reduce activation of Trk receptors and are neuroprotective. Conversely, activating adenosine A(2a) receptors in the absence of BDNF signaling makes motor neurons vulnerable to excitotoxic challenge.<br><br>CONCLUSION: Selective, high-affinity adenosine A(2a) antagonists merit consideration as therapeutic agents for the treatment of ALS.}, }
@article {pmid16909005, year = {2005}, author = {Kiaei, M and Kipiani, K and Petri, S and Chen, J and Calingasan, NY and Beal, MF}, title = {Celastrol blocks neuronal cell death and extends life in transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Neuro-degenerative diseases}, volume = {2}, number = {5}, pages = {246-254}, doi = {10.1159/000090364}, pmid = {16909005}, issn = {1660-2854}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/genetics/*pathology ; Animals ; Astrocytes/drug effects/metabolism ; CD40 Antigens/metabolism ; Cell Count ; Cell Death/drug effects ; Female ; Fluorescent Antibody Technique, Indirect ; Glial Fibrillary Acidic Protein/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Longevity ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/metabolism ; Neuroglia/drug effects ; Neurons/*drug effects/metabolism ; Neuroprotective Agents/*pharmacology/therapeutic use ; Pentacyclic Triterpenes ; Postural Balance/drug effects ; Psychomotor Performance ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Survival Analysis ; Triterpenes/*pharmacology/therapeutic use ; Tumor Necrosis Factor-alpha/metabolism ; Up-Regulation ; }, abstract = {There is substantial evidence that both inflammation and oxidative damage contribute to the pathogenesis of motor neuron degeneration in the G93A SOD1 transgenic mouse model of amyotrophic lateral sclerosis (ALS). Celastrol is a natural product from Southern China, which exerts potent anti-inflammatory and antioxidative effects. It also acts potently to increase expression of heat shock proteins including HSP70. We administered it in the diet to G93A SOD1 mice starting at 30 days of age. Celastrol treatment significantly improved weight loss, motor performance and delayed the onset of ALS. Survival of celastrol-treated G93A mice increased by 9.4% and 13% for 2 mg/kg/day and 8 mg/kg/day doses, respectively. Cell counts of lumbar spinal cord neurons confirmed a protective effect, i.e. 30% increase in neuronal number in the lumbar spinal cords of celastrol-treated animals. Celastrol treatment reduced TNF-alpha, iNOS, CD40, and GFAP immunoreactivity in the lumbar spinal cord sections of celastrol-treated G93A mice compared to untreated G93A mice. TNF-alpha immunoreactivity co-localized with SMI-32 (neuronal marker) and GFAP (astrocyte marker). HSP70 immunoreactivity was increased in lumbar spinal cord neurons of celastrol-treated G93A mice. Celastrol has been widely used in treating inflammatory diseases in man, and is well tolerated; therefore, it may be a promising therapeutic candidate for the treatment of human ALS.}, }
@article {pmid16908980, year = {2004}, author = {Ekestern, E}, title = {Neurotrophic factors and amyotrophic lateral sclerosis.}, journal = {Neuro-degenerative diseases}, volume = {1}, number = {2-3}, pages = {88-100}, doi = {10.1159/000080049}, pmid = {16908980}, issn = {1660-2854}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*physiopathology ; Animals ; Disease Models, Animal ; Humans ; Motor Neurons/pathology ; Nerve Growth Factors/biosynthesis/metabolism/*physiology ; Receptors, Nerve Growth Factor/metabolism ; }, abstract = {The cause of motor neuron death in amyotrophic lateral sclerosis (ALS) remains a mystery. Initial implications of neurotrophic factor impairment involved in disease progression causing selective motor neuron death were brought forward in the late 1980s. These implications were based on several in vitro studies of motor neuron cultures in which a near to complete rescue of axotomized neonatal motor neurons in the presence of supplementary neurotrophic factors were revealed. These findings pawed the way for extensive investigations in experimental animal models of ALS. Neurotrophic factor administration in rodent ALS models demonstrated a remarkable effect on survival of degenerating motor neurons and rescue of axotomized motor neurons, both in vivo and in vitro. In the absence of efficient therapy for ALS, some of these promising neurotrophic factors have been administered to groups of ALS patients, as they appeared available for clinical trials. Up to date, none of tested factors has lived up to expectations, altering the outcome of the disease. This review summarizes current findings on neurotrophic factor expression in ALS tissue and these factors' potential/debatable clinical relevance to ALS and the treatment of ALS. It also discusses possible interventions improving clinical trial design to obtain efficacy of neurotrophic factor treatment in patients suffering from ALS.}, }
@article {pmid16908741, year = {2006}, author = {Czaplinski, A and Yen, AA and Simpson, EP and Appel, SH}, title = {Slower disease progression and prolonged survival in contemporary patients with amyotrophic lateral sclerosis: is the natural history of amyotrophic lateral sclerosis changing?.}, journal = {Archives of neurology}, volume = {63}, number = {8}, pages = {1139-1143}, doi = {10.1001/archneur.63.8.1139}, pmid = {16908741}, issn = {0003-9942}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/*epidemiology/*pathology ; Biomarkers ; Dipeptides/metabolism ; Disease Progression ; Female ; Humans ; Inositol/metabolism ; Magnetic Resonance Spectroscopy ; Male ; Middle Aged ; Survival Analysis ; Time Factors ; }, abstract = {BACKGROUND: In recent years, considerable effort has been made to improve the treatment of patients with amyotrophic lateral sclerosis (ALS). However, despite the increased use of supportive measures, controversy still exists about overall trends in disease progression and survival.<br><br>OBJECTIVE: To analyze whether survival and disease progression in patients with ALS have changed during the past 20 years.<br><br>DESIGN: By using the Kaplan-Meier life-table method, we compared disease progression (measured as time to a 20-point increase in the Appel ALS score) and survival in 1041 patients diagnosed as having ALS between January 1, 1984, and January 1, 1999 (historical group, n = 647), and between January 2, 1999, and November 1, 2004 (contemporary group, n = 394). The Cox proportional hazards model was used for univariate and multivariate analyses.<br><br>RESULTS: The median survival from symptom onset was 4.32 years (95% confidence interval [CI], 3.81-4.84 years) in the contemporary group compared with 3.22 years (95% CI, 3.04-3.41 years) in the historical group (P<.001). The contemporary patients progressed more slowly (10 months to a 20-point increase; 95% CI, 9-13 months) compared with patients in the historical group (9 months to a 20-point increase; 95% CI, 8-9 months) (P<.001). In the multivariate Cox proportional hazards model, the observed outcome improvement over time was independent of confounding factors, such as age, sex, diagnostic delay, site of symptom onset, baseline forced vital capacity, and baseline Appel ALS score, and independent of the use of potentially outcome-modifying therapies (riluzole, noninvasive ventilation, and percutaneous gastrostomy).<br><br>CONCLUSIONS: Contemporary patients had significantly prolonged survival and slower disease progression compared with patients from the historical group. The improved outcome seemed independent of specific ALS outcome-modifying therapies, but we cannot rule out an effect of comorbid conditions, which could have influenced medical treatment and survival. Nevertheless, our observations suggest the possibility that disease course has changed and that ALS is becoming less aggressive over time. Further studies are needed to determine whether there has been a fundamental change in the natural history of the disease or whether our results are because of other unmeasured aspects of improved multidisciplinary care.}, }
@article {pmid16904981, year = {2006}, author = {Shi, Q and Wang, D and Hadley, GA and Farber, DL and Bartlett, ST}, title = {Abrogation of recurrent autoimmunity in the NOD mouse: A critical role for host interleukin 4.}, journal = {Surgery}, volume = {140}, number = {2}, pages = {281-288}, doi = {10.1016/j.surg.2006.05.007}, pmid = {16904981}, issn = {0039-6060}, support = {AI036532/AI/NIAID NIH HHS/United States ; AI065950/AI/NIAID NIH HHS/United States ; AI42092/AI/NIAID NIH HHS/United States ; AI50632/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/therapeutic use ; Autoimmunity/*physiology ; Blood Glucose/metabolism ; Diabetes Mellitus, Type 1/*immunology/metabolism/surgery ; Female ; Graft Survival/*immunology ; Immunosuppressive Agents/therapeutic use ; Interleukin-10/physiology ; Interleukin-4/*physiology ; Islets of Langerhans Transplantation/*immunology ; Lymphocytes/physiology ; Male ; Mice ; Mice, Inbred NOD ; }, abstract = {BACKGROUND: We previously established a clinically relevant strategy to abrogate recurrent autoimmunity and enable long-term islet graft survival, involving antilymphocyte serum (ALS)-depletion of recipient T cells and intraportal administration of donor pancreatic lymph node cells (PLNCs) along with islet grafts. In this study, we investigated whether Th2 cytokines were required for the tolerizing ability of ALS/PLNC treatment in islet transplantation.<br><br>METHODS: ALS-treated diabetic NOD recipient mice, and NOD recipient mice deficient in interleukin 4 (IL-4-/-) or 10 (IL-4/10-/-) were transplanted with NOR or NOD.scid islets intraportally along with donor PLNC. Blood glucose levels were monitored to access graft function, sections of graft-bearing livers were histologically examined, and ELISPOT assays were used to assess cytokine profile and frequency of islet-reactive CD4 T cells.<br><br>RESULTS: We found that ALS/PLNC was not effective in prolonging islet graft survival in diabetic NOD hosts deficient in either IL-4 (NOD.IL-4-/-) or in IL-4 and IL-10 (NOD.IL4-/-/10-/-) (mean survival time, 36 days), contrasting the long-term survival of islet grafts in wild-type NOD mice (mean survival time, > 80 days). In contrast, PLNC deficient in IL-4 promoted long-term graft survival in wild-type NOD hosts similar to that in wild-type PLNC. In wild-type NOD recipients of either wild-type PLNC or IL-4-/- PLNC, the host autoantigen-specific CD4 T cells produced predominately IL-4 coincident with long-term graft survival, whereas, in NOD.IL-4-/- recipients with rejected grafts, the autoreactive T cells produced interferon gamma and low amounts of IL-4.<br><br>CONCLUSIONS: These data demonstrate that abrogation of recurrent autoimmunity requires host IL-4 and that manipulation of the autoreactive cytokine profile in long-term diabetes may be an effective strategy for islet transplant therapies.}, }
@article {pmid16903584, year = {2006}, author = {Ganzini, L}, title = {Artificial nutrition and hydration at the end of life: ethics and evidence.}, journal = {Palliative &amp; supportive care}, volume = {4}, number = {2}, pages = {135-143}, doi = {10.1017/s1478951506060196}, pmid = {16903584}, issn = {1478-9515}, mesh = {Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Gastrostomy/*ethics ; Humans ; Neoplasms/therapy ; Nutritional Support/*ethics ; Palliative Care/*ethics ; Withholding Treatment/*ethics ; }, abstract = {The case of Terri Schiavo resulted in substantial media attention about the use of artificial nutrition and hydration (ANH) especially by percutaneous endoscopic gastrostomy (PEG). In this article, I review ethical and legal principles governing decisions to choose or forgo ANH at the end of life, including issues of autonomy and decision-making capacity, similarities and differences between ANH and other medical treatments, the role of proxies when patients lack decision-making capacity, and the equivalence of withholding and withdrawing treatment. Evidence for palliative or life-sustaining benefits for ANH are reviewed in three disease processes: amyotrophic lateral sclerosis (ALS), cancer, and dementias, including Alzheimer's disease. Although more recent studies suggest a possible palliative role for ANH in ALS and terminal cancer, feeding tubes do not appear to prolong survival or increase comfort in advanced dementia of the Alzheimer's type.}, }
@article {pmid16902995, year = {2006}, author = {Ohta, Y and Nagai, M and Nagata, T and Murakami, T and Nagano, I and Narai, H and Kurata, T and Shiote, M and Shoji, M and Abe, K}, title = {Intrathecal injection of epidermal growth factor and fibroblast growth factor 2 promotes proliferation of neural precursor cells in the spinal cords of mice with mutant human SOD1 gene.}, journal = {Journal of neuroscience research}, volume = {84}, number = {5}, pages = {980-992}, doi = {10.1002/jnr.21017}, pmid = {16902995}, issn = {0360-4012}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; Animals ; Bromodeoxyuridine/metabolism ; Cell Count/methods ; Cell Proliferation/*drug effects ; Disease Models, Animal ; Epidermal Growth Factor/*pharmacology ; Fibroblast Growth Factor 2/*pharmacology ; Fluorescent Antibody Technique/methods ; Gene Expression Regulation/drug effects/physiology ; Humans ; Injections, Spinal/methods ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects ; Nerve Tissue Proteins/metabolism ; Rotarod Performance Test/methods ; Spinal Cord/*pathology ; Statistics, Nonparametric ; Stem Cells/*drug effects ; Superoxide Dismutase/genetics ; }, abstract = {We investigated three steps of neural precursor cell activation--proliferation, migration, and differentiation--in amyotrophic lateral sclerosis spinal cord treated with intrathecal infusion of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2) into the lumbar spinal cord region of normal and symptomatic transgenic (Tg) mice with a mutant human Cu/Zn superoxide dismutase (SOD1) gene. We observed that 5-bromodeoxyuridine (BrdU) + nestin double-labeled neural precursor cells increased in the spinal cords of Tg mice compared with non-Tg mice, with a much greater increase produced by EGF and FGF2 treatment. The number of BrdU + nestin double-labeled cells was larger than that of BrdU + ionized calcium-binding adapter molecule-1 (Iba1), BrdU + glial fibrillary acidic protein (GFAP), or BrdU + highly polysialylated neural cell adhesion molecule (PSA-NCAM) double-labeled cells, but none expressed neuronal nuclear antigen (NeuN). On further analysis of the gray matter of Tg mice, the number of BrdU + nestin and BrdU + PSA-NCAM double-labeled cells increased more in the ventral horns than the dorsal horns, which was again greatly enhanced by EGF and FGF2 treatment. Because neural precursor cells reside close to the ependyma of central canal, the present study suggests that proliferation and migration of neural precursor cells to the ventral horns is greatly activated in symptomatic Tg mice and is further enhanced by EGF and FGF2 treatment and, furthermore, that the neural precursor cells preferentially differentiate into neuronal precursor cells instead of astrocytes in Tg mice with EGF and FGF2 treatment.}, }
@article {pmid16899545, year = {2006}, author = {Lo Coco, D and Marchese, S and Pesco, MC and La Bella, V and Piccoli, F and Lo Coco, A}, title = {Noninvasive positive-pressure ventilation in ALS: predictors of tolerance and survival.}, journal = {Neurology}, volume = {67}, number = {5}, pages = {761-765}, doi = {10.1212/01.wnl.0000227785.73714.64}, pmid = {16899545}, issn = {1526-632X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Demography ; Female ; Follow-Up Studies ; Humans ; Lung/physiopathology ; Male ; Middle Aged ; Multivariate Analysis ; Positive-Pressure Respiration/*methods/*mortality ; Predictive Value of Tests ; Respiratory Function Tests/methods ; Retrospective Studies ; Sickness Impact Profile ; Survival Rate ; Time Factors ; *Ventilators, Mechanical ; }, abstract = {OBJECTIVE: To identify factors associated with tolerance and survival after noninvasive positive-pressure ventilation (NIPPV) and to investigate the influence of NIPPV on lung function in patients with ALS.<br><br>METHODS: NIPPV was offered to 71 patients with ALS in accordance with currently published guidelines. Effects of NIPPV on lung function and factors influencing tolerance and survival after NIPPV were studied.<br><br>RESULTS: Forty-four patients (61.9%; 95% CI: 50.6 to 73.2) tolerated NIPPV (NIPPV use >or=4 h/day) and 27 (38.1%; 95% CI: 26.8 to 49.4) were intolerant (NIPPV use <4 h/day). Patients with mild or moderate bulbar symptoms were more likely to tolerate NIPPV than those with severe impairment (odds ratio = 6.09, 95% CI: 1.18 to 31.52, p = 0.031). After NIPPV introduction, a slower decline in forced vital capacity (FVC) was observed in tolerant vs intolerant patients (p = 0.002). The slope of FVC decline after NIPPV initiation (risk ratio [RR]: 0.78, 95% CI: 0.65 to 0.94, p = 0.01) together with NIPPV tolerance (RR: 0.32, 95% CI: 0.13 to 0.78, p = 0.013) were the only independent predictors of survival in the overall group of patients. In multivariate analysis, body mass index was the most powerful predictor of longer survival after NIPPV in tolerant patients (RR: 0.77, 95% CI: 0.61 to 0.96, p = 0.022).<br><br>CONCLUSION: Survival after noninvasive ventilation was independently related to ventilatory use (>or=4 h/day) and to the modifications of forced vital capacity decline after treatment initiation. The severity of bulbar impairment and the nutritional status of the ALS patients at the introduction of ventilation may predict tolerance and survival.}, }
@article {pmid16898257, year = {2006}, author = {Franssen, H and van den Bergh, PY}, title = {Nerve conduction studies in polyneuropathy: practical physiology and patterns of abnormality.}, journal = {Acta neurologica Belgica}, volume = {106}, number = {2}, pages = {73-81}, pmid = {16898257}, issn = {0300-9009}, mesh = {Adult ; Animals ; Demyelinating Diseases/diagnosis/physiopathology ; Electrodiagnosis/*methods ; Female ; Humans ; Neural Conduction/*physiology ; Polyneuropathies/*diagnosis/*physiopathology ; }, abstract = {Nerve conduction studies are an essential part of the work-up of peripheral neuropathies. Many neuropathic syndromes can be suspected on clinical grounds, but optimal use of nerve conduction study techniques (in combination with needle electromyography) allows diagnostic classification and is therefore crucial to understanding and separation of neuropathies. Multifocal motor neuropathy, for example, may clinically present as ALS. Detection of evidence of demyelination (conduction blocks) leads to the correct diagnosis and to proper treatment. Nerve conduction studies provide essential information on (1) the spatial pattern of neuropathy, (2) the pattern of abnormalities distinguishing between primarily axonal and demyelinating pathology, and (3) the severity of neuropathic damage. This information is very comprehensive since many nerves and long segments of individual nerves can be sampled. Moreover the information is extremely detailed to the extent that the cellular pathology of a patient's neuropathy is usually defined best by physiological testing rather than by biopsy. Neuropathies can be generalized, focal, or multifocal; they can be symmetric or asymmetric; they can be distally predominant or proximal and distal. Primarily axonal neuropathies mainly affect sensory nerve and compound muscle action potential amplitudes, whereas demyelinating neuropathies lead to slowing of nerve conductions, and to increased temporal dispersion or conduction block. Usually, the pattern of demyelination allows to distinguish hereditary (uniform demyelination) from acquired (segmental demyelination) neuropathies. Electrodiagnostic criteria for primary demyelination are helpful to identify acquired demyelinating neuropathies.}, }
@article {pmid16897634, year = {2006}, author = {Galbussera, A and Tremolizzo, L and Brighina, L and Testa, D and Lovati, R and Ferrarese, C and Cavaletti, G and Filippini, G}, title = {Vitamin E intake and quality of life in amyotrophic lateral sclerosis patients: a follow-up case series study.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {27}, number = {3}, pages = {190-193}, doi = {10.1007/s10072-006-0668-x}, pmid = {16897634}, issn = {1590-1874}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy ; Dietary Supplements ; Female ; Follow-Up Studies ; Health Surveys ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/therapeutic use ; *Quality of Life ; Riluzole/therapeutic use ; Vitamin E/*therapeutic use ; Vitamins/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving both upper and lower motor neurons, leading inexorably to death within a few years. Although our understanding of the pathogenesis of this disease has grown at a very fast rate in recent years, we do not yet have effective treatment options that can positively impact the quality of life (QoL) of these patients. Interestingly, increasing experimental evidence suggests that oxidative stress is involved in the pathogenesis of ALS and that vitamin E could reduce neuronal damage. Hence, in this observational study we determined the QoL in 33 ALS patients taking or not taking vitamin E supplementation (600 mg/day), using the Italian version of the Short-Form 36-Item Health Survey (SF-36). No differences were seen between the two groups of patients, therefore we do not recommend routine use of vitamin E in ALS patients, at least in the absence of randomised clinical trials specifically designed for addressing this issue.}, }
@article {pmid16895581, year = {2006}, author = {Petri, S and Kiaei, M and Damiano, M and Hiller, A and Wille, E and Manfredi, G and Calingasan, NY and Szeto, HH and Beal, MF}, title = {Cell-permeable peptide antioxidants as a novel therapeutic approach in a mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {98}, number = {4}, pages = {1141-1148}, doi = {10.1111/j.1471-4159.2006.04018.x}, pmid = {16895581}, issn = {0022-3042}, support = {NIDA08924//PHS HHS/United States ; NINDS 48295//PHS HHS/United States ; }, mesh = {Aging/physiology ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Antioxidants/metabolism/*therapeutic use ; Body Weight/physiology ; Cell Count ; Cell Membrane Permeability ; Cells, Cultured ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Peptides/metabolism/*therapeutic use ; Psychomotor Performance/physiology ; Reactive Oxygen Species/metabolism ; Spinal Cord/pathology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Reactive oxygen species (ROS) play a major role in the pathogenesis of neurodegenerative diseases. They are important contributors to necrotic and apoptotic cell death. A major proportion of cellular ROS is generated at the inner mitochondrial membrane by the respiratory chain. In the present study, we investigated a novel peptide antioxidant (SS-31) targeted to the inner mitochondrial membrane for its therapeutic effects both in vitro and in vivo in the G93A mouse model of amyotrophic lateral sclerosis (ALS). SS-31 protected against cell death induced by hydrogen peroxide in vitro in neuronal cells stably transfected with either wild-type or mutant Cu/Zn superoxide dismutase (SOD1). Daily intraperitoneal injections of SS-31 (5 mg/kg), starting at 30 days of age, led to a significant improvement in survival and motor performance. In comparison with vehicle-treated G93A mice, SS-31-treated mice showed a decreased cell loss and a decrease in immunostaining for markers of oxidative stress in the lumbar spinal cord. This further enhances the concept that pharmacological modification of oxidative stress is a therapeutic option for the treatment of ALS.}, }
@article {pmid16892429, year = {2006}, author = {Shefner, JM and Cudkowicz, M and Brown, RH}, title = {Motor unit number estimation predicts disease onset and survival in a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {34}, number = {5}, pages = {603-607}, doi = {10.1002/mus.20628}, pmid = {16892429}, issn = {0148-639X}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*diagnosis/genetics/*physiopathology ; Animals ; Cell Count/methods ; Disease Models, Animal ; Disease Progression ; Early Diagnosis ; Electric Stimulation/methods ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/pathology/*physiology ; Muscle Fibers, Skeletal/pathology/*physiology ; Muscle, Skeletal/innervation/pathology/*physiopathology ; Neuromuscular Junction/*physiopathology ; Predictive Value of Tests ; Prognosis ; Superoxide Dismutase/genetics ; Survival Rate/trends ; }, abstract = {Motor unit number estimation (MUNE) has proved useful in predicting rate of progression and survival in patients with amyotrophic lateral sclerosis (ALS). In animal models, it has demonstrated physiological effects of experimental medications that were not evident behaviorally. We sought to determine more specifically what aspects of function and survival that MUNE could predict in the G93A transgenic mouse model of ALS. Transgenic mice were examined in two distinct treatment studies, neither of which showed an effect of drug on survival, behavioral measures, or MUNE. MUNE was performed using a modification of the incremental stimulation method by stimulating the sciatic nerve at the sciatic notch, and recording with a circumferential surface electrode around the ipsilateral distal hindlimb. Both limbs were studied and the results averaged. MUNE was performed longitudinally on all animals from near onset to premorbid state. Each study was evaluated separately. For both studies, MUNE at initial study correlated significantly with behavioral determination of disease onset, and MUNE slope from initial to final study correlated significantly with disease duration, as measured from onset to time of death. However, the final MUNE value did not correlate with survival. Thus, in two studies involving animals with quite different disease courses, initial MUNE effectively predicted symptom onset and MUNE slope predicted survival. This suggests that MUNE has potential efficacy as a useful functional outcome measure in both animal and human studies of ALS.}, }
@article {pmid16884573, year = {2006}, author = {Nijeweme-d'Hollosy, WO and Janssen, EP and Huis in 't Veld, RM and Spoelstra, J and Vollenbroek-Hutten, MM and Hermens, HJ}, title = {Tele-treatment of patients with amyotrophic lateral sclerosis (ALS).}, journal = {Journal of telemedicine and telecare}, volume = {12 Suppl 1}, number = {}, pages = {31-34}, doi = {10.1258/135763306777978434}, pmid = {16884573}, issn = {1357-633X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*therapy ; Delivery of Health Care/organization &amp; administration ; Female ; Humans ; Male ; Middle Aged ; Patient Satisfaction ; Physician-Patient Relations ; Quality of Life ; *Remote Consultation ; Social Support ; Videoconferencing ; }, abstract = {Management of patients with amyotrophic lateral sclerosis (ALS) mainly consists of (psycho) social support and advice on activities of daily living. We evaluated the effects of tele-treatment in addition to the conventional method of care in four patients with ALS. A Web application was built with information about ALS and a link to the tele-treatment environment. The latter contained a chat room and a link to start personal computer (PC)-based videoconferencing with a rehabilitation physician. The effect on quality of care was evaluated by questionnaires and interviews. The interviews showed that patients were satisfied with tele-treatment and experienced a pleasant contact during teleconsultations. The rehabilitation physician experienced acceptance of tele-treatment by the patients and a decrease in the time needed for travelling. Tele-treatment was especially suitable for discussing the practical issues about ALS. On the other hand, psychosocial and emotional issues still needed to be discussed during traditional face-to-face contact. Therefore tele-treatment should only be given in addition to face-to-face contact, rather than as a replacement for it.}, }
@article {pmid16878173, year = {2006}, author = {Smith, RA and Miller, TM and Yamanaka, K and Monia, BP and Condon, TP and Hung, G and Lobsiger, CS and Ward, CM and McAlonis-Downes, M and Wei, H and Wancewicz, EV and Bennett, CF and Cleveland, DW}, title = {Antisense oligonucleotide therapy for neurodegenerative disease.}, journal = {The Journal of clinical investigation}, volume = {116}, number = {8}, pages = {2290-2296}, pmid = {16878173}, issn = {0021-9738}, support = {R01 NS027036/NS/NINDS NIH HHS/United States ; R37 NS027036/NS/NINDS NIH HHS/United States ; NS27036/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Base Sequence ; Fibroblasts/drug effects/enzymology ; Macaca mulatta ; Motor Neuron Disease/enzymology ; Neurodegenerative Diseases/*drug therapy ; Oligonucleotides, Antisense/metabolism/pharmacology/*therapeutic use ; Protein Folding ; RNA, Messenger/genetics ; Rats ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Ventricular Function ; }, abstract = {Neurotoxicity from accumulation of misfolded/mutant proteins is thought to drive pathogenesis in neurodegenerative diseases. Since decreasing levels of proteins responsible for such accumulations is likely to ameliorate disease, a therapeutic strategy has been developed to downregulate almost any gene in the CNS. Modified antisense oligonucleotides, continuously infused intraventricularly, have been demonstrated to distribute widely throughout the CNS of rodents and primates, including the regions affected in the major neurodegenerative diseases. Using this route of administration, we found that antisense oligonucleotides to superoxide dismutase 1 (SOD1), one of the most abundant brain proteins, reduced both SOD1 protein and mRNA levels throughout the brain and spinal cord. Treatment initiated near onset significantly slowed disease progression in a model of amyotrophic lateral sclerosis (ALS) caused by a mutation in SOD1. This suggests that direct delivery of antisense oligonucleotides could be an effective, dosage-regulatable means of treating neurodegenerative diseases, including ALS, where appropriate target proteins are known.}, }
@article {pmid16867198, year = {2006}, author = {Lechtzin, N}, title = {Respiratory effects of amyotrophic lateral sclerosis: problems and solutions.}, journal = {Respiratory care}, volume = {51}, number = {8}, pages = {871-81; discussion 881-4}, pmid = {16867198}, issn = {0020-1324}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Female ; Hospice Care ; Humans ; Male ; Positive-Pressure Respiration/*methods/mortality ; *Quality of Life/psychology ; Respiratory Function Tests ; Respiratory Insufficiency/etiology/*therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Most patients die from respiratory complications. Fortunately, there are a growing number of treatment options that can improve both survival and quality of life for patients with ALS. This review discusses the respiratory evaluation and treatment of patients with ALS, about which a great deal is known. It also includes material on related problems, such as speech and swallowing difficulties and end-of-life care.}, }
@article {pmid16862465, year = {2006}, author = {Wiesli, P and Zwimpfer, C and Zapf, J and Schmid, C}, title = {Pregnancy-induced changes in insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), and acid-labile subunit (ALS) in patients with growth hormone (GH) deficiency and excess.}, journal = {Acta obstetricia et gynecologica Scandinavica}, volume = {85}, number = {8}, pages = {900-905}, doi = {10.1080/00016340600676532}, pmid = {16862465}, issn = {0001-6349}, mesh = {Acromegaly/*blood ; Adult ; Carrier Proteins/*blood ; Female ; Glycoproteins/*blood ; Human Growth Hormone/blood ; Humans ; Hypopituitarism/*blood ; Insulin-Like Growth Factor Binding Protein 3/*blood ; Insulin-Like Growth Factor I/*metabolism ; Pregnancy ; Pregnancy Complications/*blood ; }, abstract = {BACKGROUND: Under most circumstances with altered growth hormone (GH) secretion, the changes of insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), and acid-labile subunit (ALS) are in parallel. The aim of the present study was to compare the effects of pregnancy in a hypopituitary patient with those of pregnancy in an acromegalic patient on IGF-I, IGFBP-3, and ALS.<br><br>METHODS AND RESULTS: IGF-I and ALS were low before pregnancy in the hypopituitary patient under glucocorticoid and thyroxine treatment. Gonadotropin treatment allowed her to become pregnant; IGF-I and ALS levels rose in the second half of pregnancy and fell again after delivery. IGF-I concentrations were elevated in the patient with persistent acromegaly before and dropped into the normal range during the first half of pregnancy. In the second half of pregnancy and following delivery, IGF-I levels increased again. IGFBP-3 levels (as assessed by immunoblot analysis as well as by 125I-IGF II ligand blotting) decreased markedly during pregnancy in both patients, suggesting that the placenta rather than pituitary GH regulates IGFBP-3 proteolysis in human pregnancy. The increase of IGF-I (and ALS) during the second half of pregnancy in the individual with pituitary GH deficiency may be attributed to placental GH. The fall of IGF-I (and ALS) into the normal range in the acromegalic patient during the first trimester of pregnancy may be related to decreased production or decreased half-life of these proteins.<br><br>CONCLUSION: Our data suggest that measures to continuously replace GH or to suppress GH secretion during pregnancy in patients with GH deficiency or excess, respectively, may not be warranted.}, }
@article {pmid16861147, year = {2006}, author = {Sandyk, R}, title = {Serotonergic mechanisms in amyotrophic lateral sclerosis.}, journal = {The International journal of neuroscience}, volume = {116}, number = {7}, pages = {775-826}, doi = {10.1080/00207450600754087}, pmid = {16861147}, issn = {0020-7454}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism/pathology ; Animals ; Glutamic Acid/metabolism ; Humans ; Motor Activity/drug effects/physiology ; Neurons/metabolism ; Serotonin/*metabolism/*therapeutic use ; Sleep, REM/drug effects/physiology ; }, abstract = {Serotonin (5-HT) has been intimately linked with global regulation of motor behavior, local control of motoneuron excitability, functional recovery of spinal motoneurons as well as neuronal maturation and aging. Selective degeneration of motoneurons is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Motoneurons that are preferentially affected in ALS are also densely innervated by 5-HT neurons (e.g., trigeminal, facial, ambiguus, and hypoglossal brainstem nuclei as well as ventral horn and motor cortex). Conversely, motoneuron groups that appear more resistant to the process of neurodegeneration in ALS (e.g., oculomotor, trochlear, and abducens nuclei) as well as the cerebellum receive only sparse 5-HT input. The glutamate excitotoxicity theory maintains that in ALS degeneration of motoneurons is caused by excessive glutamate neurotransmission, which is neurotoxic. Because of its facilitatory effects on glutaminergic motoneuron excitation, 5-HT may be pivotal to the pathogenesis and therapy of ALS. 5-HT levels as well as the concentrations 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of 5-HT, are reduced in postmortem spinal cord tissue of ALS patients indicating decreased 5-HT release. Furthermore, cerebrospinal fluid levels of tryptophan, a precursor of 5-HT, are decreased in patients with ALS and plasma concentrations of tryptophan are also decreased with the lowest levels found in the most severely affected patients. In ALS progressive degeneration of 5-HT neurons would result in a compensatory increase in glutamate excitation of motoneurons. Additionally, because 5-HT, acting through presynaptic 5-HT1B receptors, inhibits glutamatergic synaptic transmission, lowered 5-HT activity would lead to increased synaptic glutamate release. Furthermore, 5-HT is a precursor of melatonin, which inhibits glutamate release and glutamate-induced neurotoxicity. Thus, progressive degeneration of 5-HT neurons affecting motoneuron activity constitutes the prime mover of the disease and its progression and treatment of ALS needs to be focused primarily on boosting 5-HT functions (e.g., pharmacologically via its precursors, reuptake inhibitors, selective 5-HT1A receptor agonists/5-HT2 receptor antagonists, and electrically through transcranial administration of AC pulsed picotesla electromagnetic fields) to prevent excessive glutamate activity in the motoneurons. In fact, 5HT1A and 5HT2 receptor agonists have been shown to prevent glutamate-induced neurotoxicity in primary cortical cell cultures and the 5-HT precursor 5-hydroxytryptophan (5-HTP) improved locomotor function and survival of transgenic SOD1 G93A mice, an animal model of ALS.}, }
@article {pmid16858091, year = {2006}, author = {Citerio, G and Galli, D and Pesenti, A}, title = {Early stroke care in Italy--a steep way ahead: an observational study.}, journal = {Emergency medicine journal : EMJ}, volume = {23}, number = {8}, pages = {608-611}, pmid = {16858091}, issn = {1472-0213}, mesh = {Aged ; Aged, 80 and over ; Emergency Medical Services/*standards/statistics &amp; numerical data ; Female ; Humans ; Italy ; Male ; Middle Aged ; Practice Guidelines as Topic ; Prospective Studies ; Stroke/*therapy ; Time Factors ; }, abstract = {OBJECTIVES: To measure the performance of selected Italian emergency medical system (EMS) dispatch centres managing calls for patients suffering from stroke. Data on outcome and on early treatment in the ED were collected.<br><br>METHODS: Prospective data collection for a trimester from interventions for a suspected stroke in 13 EMS dispatch centres over five Italian regions.<br><br>RESULTS: Altogether, 1041 calls for a suspected stroke were analysed. Mean intervals of the sequential phases were 2.3+/-2 minutes between call and ambulance dispatch, 8.4+/-5.5 minutes to reach the patient, 14.5+/-8.5 minutes on the scene, and 40.2+/-16.2 minutes between call and arrival at the ED. Interventions were performed in 56% of cases by a basic life support (BLS) crew, advanced life support (ALS) crews intervened in 28% of cases, and a combination of ALS and BLS in the remaining 16%. Mean diagnostic interval was 99+/-85 minutes between emergency system call and the first CT scan. This was performed 71+/-27 minutes after ED admission. Only 1.6% were admitted to a stroke unit. One month outcome according to GCS was good recovery in 32%, moderate disability in 28%, severe disability in 14%, and death in 25% of the patients.<br><br>CONCLUSIONS: Mean times show a rapid response of the selected EMS dispatch centres to calls for a suspected stroke. Nevertheless, mean times of the ED phase are still unacceptable according to international guidelines such as Brain Attack Coalition and American Stroke Association guidelines. Efforts should be spent to reduce the time between the arrival and the CT scan and more patients should be admitted to a stroke unit.}, }
@article {pmid16857362, year = {2006}, author = {Xia, X and Zhou, H and Huang, Y and Xu, Z}, title = {Allele-specific RNAi selectively silences mutant SOD1 and achieves significant therapeutic benefit in vivo.}, journal = {Neurobiology of disease}, volume = {23}, number = {3}, pages = {578-586}, doi = {10.1016/j.nbd.2006.04.019}, pmid = {16857362}, issn = {0969-9961}, support = {R01NS048145/NS/NINDS NIH HHS/United States ; R21AG023808/AG/NIA NIH HHS/United States ; }, mesh = {Alleles ; Amyotrophic Lateral Sclerosis/genetics/metabolism/*therapy ; Animals ; Central Nervous System/enzymology/pathology/physiopathology ; Disease Models, Animal ; Down-Regulation/genetics ; Gene Silencing/*physiology ; Genetic Therapy/methods/trends ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/enzymology/pathology ; Mutation/*genetics ; RNA Interference/*physiology ; RNA, Small Interfering/genetics/*therapeutic use ; Superoxide Dismutase/*genetics/toxicity ; Superoxide Dismutase-1 ; Survival Rate ; Treatment Outcome ; }, abstract = {RNA interference (RNAi) has the potential to treat diseases caused by dominant, gain-of-function type of gene mutations. In these diseases, one allele is mutated and produces a toxic protein, whereas the other allele is normal and performs vital functions. One challenge in the treatment is to specifically inhibit the mutant allele toxicity while maintaining the normal allele function. To test allele-specific silencing in vivo, we made transgenic mice that express an shRNA against mutant Cu, Zn superoxide dismutase gene (SOD1(G93A)), which causes amyotrophic lateral sclerosis (ALS) by a gain of an unknown toxic property. By crossing this transgenic line with mice that express SOD1(G93A) and mice that express wild-type human SOD1, we found that this shRNA specifically silences the mutant, but not the wild-type SOD1. The silencing of the mutant significantly delayed ALS onset and extended survival. Thus, RNAi can achieve allele-specific silencing and therapeutic benefit in vivo.}, }
@article {pmid16856151, year = {2006}, author = {Bogaert, E and Van Damme, P and Van Den Bosch, L and Robberecht, W}, title = {Vascular endothelial growth factor in amyotrophic lateral sclerosis and other neurodegenerative diseases.}, journal = {Muscle &amp; nerve}, volume = {34}, number = {4}, pages = {391-405}, doi = {10.1002/mus.20609}, pmid = {16856151}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*physiopathology ; Animals ; Central Nervous System Diseases/etiology/physiopathology ; Gene Expression Regulation ; Humans ; Motor Neurons/metabolism/pathology ; Neurodegenerative Diseases/etiology/*physiopathology ; Peripheral Nervous System Diseases/etiology/physiopathology ; Receptors, Vascular Endothelial Growth Factor/genetics/physiology ; Vascular Endothelial Growth Factor A/genetics/*physiology/therapeutic use ; }, abstract = {The angiogenic activity of vascular endothelial growth factor (VEGF) is well known. Recently, it has become evident that VEGF is involved in central nervous system physiology and may play a role in the pathogenesis of neurological diseases. In particular, it may be involved in the mechanism of motor neuron degeneration in amyotrophic lateral sclerosis (ALS), and has been hypothesized to be implicated in the pathogenesis of peripheral neuropathies such as occur in the so-called POEMS syndrome and diabetes. VEGF is also being studied as a possible treatment option in some of these disorders. In this review we critically analyze the data supporting the notion that VEGF is a factor involved in motor neuron degeneration and review the studies linking VEGF to other diseases of the peripheral and central nervous systems.}, }
@article {pmid16837207, year = {2006}, author = {Holzbaur, EL and Howland, DS and Weber, N and Wallace, K and She, Y and Kwak, S and Tchistiakova, LA and Murphy, E and Hinson, J and Karim, R and Tan, XY and Kelley, P and McGill, KC and Williams, G and Hobbs, C and Doherty, P and Zaleska, MM and Pangalos, MN and Walsh, FS}, title = {Myostatin inhibition slows muscle atrophy in rodent models of amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {23}, number = {3}, pages = {697-707}, doi = {10.1016/j.nbd.2006.05.009}, pmid = {16837207}, issn = {0969-9961}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/immunology/physiopathology/*therapy ; Animals ; Animals, Genetically Modified ; Antibodies/immunology/*pharmacology/therapeutic use ; Cell Death/drug effects/physiology ; Diaphragm/immunology/innervation/physiopathology ; Disease Models, Animal ; Female ; Growth Inhibitors/*antagonists &amp; inhibitors/immunology/metabolism ; Humans ; Male ; Mice ; Mice, Knockout ; Motor Neurons/immunology/pathology ; Muscle Weakness/immunology/physiopathology/therapy ; Muscle, Skeletal/immunology/innervation/*physiopathology ; Muscular Atrophy/immunology/physiopathology/*therapy ; Myostatin ; Organ Size/drug effects/immunology ; Rats ; Recovery of Function/drug effects/immunology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Survival Rate ; Transforming Growth Factor beta/*antagonists &amp; inhibitors/immunology/metabolism ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease leading to motor neuron cell death, but recent studies suggest that non-neuronal cells may contribute to the pathological mechanisms involved. Myostatin is a negative regulator of muscle growth whose function can be inhibited using neutralizing antibodies. In this study, we used transgenic mouse and rat models of ALS to test whether treatment with anti-myostatin antibody slows muscle atrophy, motor neuron loss, or disease onset and progression. Significant increases in muscle mass and strength were observed in myostatin-antibody-treated SOD1(G93A) mice and rats prior to disease onset and during early-stage disease. By late stage disease, only diaphragm muscle remained significantly different in treated animals in comparison to untreated controls. Myostatin inhibition did not delay disease onset nor extend survival in either the SOD1(G93A) mouse or rat. Together, these results indicate that inhibition of myostatin does not protect against the onset and progression of motor neuron degenerative disease. However, the preservation of skeletal muscle during early-stage disease and improved diaphragm morphology and function maintained through late stage disease suggest that anti-myostatin therapy may promote some improved muscle function in ALS.}, }
@article {pmid16832072, year = {2006}, author = {Traynor, BJ and Bruijn, L and Conwit, R and Beal, F and O'Neill, G and Fagan, SC and Cudkowicz, ME}, title = {Neuroprotective agents for clinical trials in ALS: a systematic assessment.}, journal = {Neurology}, volume = {67}, number = {1}, pages = {20-27}, doi = {10.1212/01.wnl.0000223353.34006.54}, pmid = {16832072}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials as Topic/*methods ; Evaluation Studies as Topic ; Humans ; Neuroprotective Agents/*therapeutic use ; *Outcome Assessment, Health Care ; }, abstract = {BACKGROUND: Riluzole is currently the only Food and Drug Administration-approved treatment for ALS, but its effect on survival is modest.<br><br>OBJECTIVE: To identify potential neuroprotective agents for testing in phase III clinical trials and to outline which data need to be collected for each drug.<br><br>METHODS: The authors identified 113 compounds by inviting input from academic clinicians and researchers and via literature review to identify agents that have been tested in ALS animal models and in patients with ALS. The list was initially narrowed to 24 agents based on an evaluation of scientific rationale, toxicity, and efficacy in previous animal and human studies. These 24 drugs underwent more detailed pharmacologic evaluation.<br><br>RESULTS: Twenty drugs were selected as suitable for further development as treatments for patients with ALS. Talampanel and tamoxifen have completed early phase II trials and have demonstrated preliminary efficacy. Other agents (ceftriaxone, minocycline, ONO-2506, and IGF-1 polypeptide) are already in phase III trials involving large numbers of patients with ALS. Remaining agents (AEOL 10150, arimoclomol, celastrol, coenzyme Q10, copaxone, IGF-1-viral delivery, memantine, NAALADase inhibitors, nimesulide, scriptaid, sodium phenylbutyrate, thalidomide, trehalose) require additional preclinical animal data, human toxicity and pharmacokinetic data including CNS penetration prior to proceeding to large scale phase III human testing. Further development of riluzole analogues should be considered.<br><br>CONCLUSIONS: Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in ALS.}, }
@article {pmid16830250, year = {2006}, author = {Praxmarer, V and Lahrmann, H}, title = {[Amyotrophic lateral sclerosis--when planning is almost too late].}, journal = {Wiener medizinische Wochenschrift (1946)}, volume = {156}, number = {9-10}, pages = {297-301}, pmid = {16830250}, issn = {0043-5341}, mesh = {Adult ; *Advance Directives/psychology ; Combined Modality Therapy ; Disease Progression ; Dyspnea/psychology/therapy ; Humans ; Male ; Morphine/administration &amp; dosage ; Motor Neuron Disease/psychology/*therapy ; Oxygen Inhalation Therapy ; Palliative Care/*methods/psychology ; *Patient Care Planning ; Patient Care Team ; Patient Participation/psychology ; Terminal Care/*methods/psychology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease with progressive muscle weakness, also affecting respiratory muscles. In the terminal phase most patients experience a progression. Nutrition, speech and breathing capacity decrease. It is important to inform the patient and relatives in time and to give them a chance to decide. "Care Planning" and "Advance Directives" especially concerning ventilation reduces fear and helps the doctors and carers to decide, following the will of the patient. Nobody knows the speed of the progression. The patient in this case had few subjective symptoms at the time of the family conference. Progression till death lasted one month only. Treatment of his dyspnoe was not optimised, but during care all decisions were based on the actual will of the patient. Generally nocturnal hypoventilation, for instance non-invasive ventilation by BiPAP-mode, can relieve symptoms of dyspnoe in ALS patients. Low-dose morphine and/or benzodiazepine relieve respiratory discomfort and remove the negative spiral of dysnoe-fear-dyspnoe. Oxygen therapy is usually not needed (only in the very last stages of the disease) and is not recommended especially during the night. Hypercapnia can occur because of hypoventilation. This can cause growing unconsciousness and maybe death during sleep. Prolonging life is only possible by invasive long-term ventilation with all the problems of intensive care measures. The patient could have been given low dose morphine from the time of the family conference. Ventilation by CPAP-mode was insufficient for him.}, }
@article {pmid16816786, year = {2006}, author = {Cummings, JL and Arciniegas, DB and Brooks, BR and Herndon, RM and Lauterbach, EC and Pioro, EP and Robinson, RG and Scharre, DW and Schiffer, RB and Weintraub, D}, title = {Defining and diagnosing involuntary emotional expression disorder.}, journal = {CNS spectrums}, volume = {11}, number = {S6}, pages = {1-7}, doi = {10.1017/s1092852900026614}, pmid = {16816786}, issn = {1092-8529}, mesh = {Crying ; Depression/*diagnosis/*psychology ; Diagnosis, Differential ; *Expressed Emotion ; Humans ; Stereotyping ; *Volition ; }, abstract = {Uncontrollable episodes of emotional expression occur in a variety of neurological conditions. This emotional disinhibition syndrome is characterized by episodes of crying or laughing that are unrelated to or out of proportion to the eliciting stimulus. This syndrome is common among patients with amyotrophic lateral sclerosis, multiple sclerosis, stroke, and traumatic brain injury and a variety of terms and definitions have been used to describe it. The confusing nomenclature has been a barrier to understanding, diagnosis, and treatment of this disorder. The authors propose a unifying term, involuntary emotional expression disorder (IEED), and provide diagnostic criteria for this disorder.}, }
@article {pmid16806843, year = {2006}, author = {Azzouz, M}, title = {Gene Therapy for ALS: progress and prospects.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {1122-1127}, doi = {10.1016/j.bbadis.2006.05.003}, pmid = {16806843}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; Disease Models, Animal ; Gene Transfer Techniques ; *Genetic Therapy ; *Genetic Vectors ; Humans ; Lentivirus/*genetics ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects ; RNA Interference ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating disease for which there are no effective drug treatments to date. Recent advances in Gene Therapy open up the possibility of developing an effective treatment aiming at halting or delaying the degeneration of motor neurons. Viral vectors such as lentiviral vectors and adeno-associated virus can transfer genes into many different types of primary neurons from a broad range of species including man and the resulting gene expression is long-term. Numerous animal studies have now been undertaken with these vectors and correction of disease models has been obtained. These vectors have been refined to a very high level and can be produced safely for the clinic. However, we believe that there are some major issues that need to be addressed in order to see a Gene Therapy approach with viral vectors proceed to the clinic for ALS patients. This review will describe the general features of lentiviral vectors. It will then describe some key examples of gene transfer and genetic correction in animal models of motor neuron disease. The prospects for the clinical evaluation of lentiviral vectors for the treatment of human motor neuron disease will be outlined.}, }
@article {pmid16806187, year = {2006}, author = {Krishnan, J and Lemmens, R and Robberecht, W and Van Den Bosch, L}, title = {Role of heat shock response and Hsp27 in mutant SOD1-dependent cell death.}, journal = {Experimental neurology}, volume = {200}, number = {2}, pages = {301-310}, doi = {10.1016/j.expneurol.2006.02.135}, pmid = {16806187}, issn = {0014-4886}, mesh = {Animals ; Antirheumatic Agents/pharmacology ; Blotting, Western/methods ; Cell Death/drug effects/genetics ; Cell Line, Tumor ; Cyclosporine/pharmacology ; HSP27 Heat-Shock Proteins ; Heat-Shock Proteins/*physiology ; Heat-Shock Response/drug effects/*physiology ; Humans ; Immunohistochemistry/methods ; Mice ; Mutagenesis/physiology ; Mutant Proteins/*genetics ; Neuroblastoma ; RNA, Messenger/metabolism ; RNA, Small Interfering/pharmacology ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Time Factors ; Transfection/methods ; }, abstract = {The fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS) is characterized by selective loss of motor neurons and mutations in the copper-zinc superoxide dismutase (SOD1) enzyme underlie one form of familial ALS. The pathogenic mechanism of these mutations is elusive but is thought to involve oxidative stress and protein aggregation. These two phenomena are known to induce heat shock proteins (Hsps) which protect stressed cells through their chaperoning and anti-apoptotic activity. In order to investigate the role of Hsp27 in mutant SOD1-dependent cell death, we used mutant and wild type SOD1 overexpressing N2a mouse neuroblastoma cells. Mutant SOD1-dependent cell death could be induced by heat shock, and by treating the cells with cyclosporine A or lactacystin. Transfection with an Hsp27 expression construct did not protect the N2a cells against mutant SOD1-dependent cell death. However, pre-conditioning N2a cells with a mild heat shock was accompanied by a significant upregulation of Hsp27 in the mutant SOD1 cells, and protected these cells against subsequent cell death induced by a more severe heat shock. Selective inhibition of the Hsp27 upregulation, through the use of Hsp27 siRNA, did not attenuate the protective effect of this treatment. These results show that activation of the heat shock response protects cells against mutant SOD1-dependent cell death, but that Hsp27 is not an essential component of the stress response leading to protection.}, }
@article {pmid16805430, year = {2006}, author = {Jeanneteau, F and Chao, MV}, title = {Promoting neurotrophic effects by GPCR ligands.}, journal = {Novartis Foundation symposium}, volume = {276}, number = {}, pages = {181-9; discussion 189-92, 233-7, 275-81}, pmid = {16805430}, issn = {1528-2511}, mesh = {Adenosine/metabolism ; Enzyme Activation ; ErbB Receptors/metabolism ; Humans ; *Ligands ; Nerve Growth Factors/*metabolism/therapeutic use ; Neurons/metabolism ; Receptor, trkA/*metabolism ; Receptors, G-Protein-Coupled/*metabolism ; Signal Transduction/physiology ; Transcriptional Activation ; }, abstract = {The neurotrophins-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3 and NT-4-represent a family of proteins essential for neuronal survival and plasticity. Each neurotrophin can signal through two different transmembrane receptors, Trk receptor tyrosine kinases and the p75 neurotrophin receptor, the first member of the TNF receptor superfamily. Neurotrophic factors play an important role in neurodegenerative diseases, as well as neuropsychiatric disorders such as depression, bipolar disease and eating disorders. Indeed, a number of approaches have been taken to use neurotrophins to treat Alzheimer's dementia, amyotrophic lateral sclerosis and peripheral sensory neuropathy. However, many of these clinical trails have failed, due to problems in delivery and unforeseen side effects of neurotrophic factors. An alternative approach is to use ligands in the G protein-coupled receptor (GPCR) family to transactivate trophic activities. We have discovered that treatment with adenosine, a neuromodulator that acts through G protein-coupled receptors, is capable of activating Trk tyrosine kinase receptors. Transactivation of neurotrophic receptors by GPCR ligands raise the possibility that small molecules may be used to elicit neurotrophic effects for the treatment of neurodegenerative diseases. This approach would allow for selective targeting of neurons that express specific G protein-coupled receptors and trophic factor receptors. GPCRs transduce information provided by extracellular signals to modulate synaptic activity and neurotransmission. In addition to the classical G protein signalling, GPCR ligands also activate receptor tyrosine kinases (RTK), including neurotrophin receptors. Activation of Trk neurotrophin receptors can occur by GPCR ligands in the absence of neurotrophins. Adenosine and PACAP (pituitary adenylate cyclase activating polypeptide) induce Trk activation specifically through their respective GPCRs to promote cell survival. Transactivation of Trks by GPCRs has emerged as a new theme in the biology of neurotrophin function. Although the precise role of transactivation is unknown, one possibility is that it adds a safety factor that might protect neurons from death in the absence of neurotrophins. Abnormal activity of the neurotrophin system has been implicated in several psychiatric and neurobiological illnesses. However, the lack of knowledge about the precise site of neurotrophin dysfunction has compromised the ability to improve the efficacy and the safety of drugs used in treatment modalities. If small-molecule GPCR ligands can ameliorate neuronal cell loss through Trk, transactivation may offer a new strategy for promoting trophic effects during neurodegeneration.}, }
@article {pmid16802291, year = {2006}, author = {Cudkowicz, ME and Shefner, JM and Schoenfeld, DA and Zhang, H and Andreasson, KI and Rothstein, JD and Drachman, DB}, title = {Trial of celecoxib in amyotrophic lateral sclerosis.}, journal = {Annals of neurology}, volume = {60}, number = {1}, pages = {22-31}, doi = {10.1002/ana.20903}, pmid = {16802291}, issn = {0364-5134}, support = {M01 RR01032/RR/NCRR NIH HHS/United States ; M01 RR01346/RR/NCRR NIH HHS/United States ; M01-RR-01066/RR/NCRR NIH HHS/United States ; M01-RR02602/RR/NCRR NIH HHS/United States ; M01-RR07122/RR/NCRR NIH HHS/United States ; M01RR00036/RR/NCRR NIH HHS/United States ; M01RR00109/RR/NCRR NIH HHS/United States ; M01RR06192/RR/NCRR NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Anti-Inflammatory Agents, Non-Steroidal/*administration &amp; dosage/adverse effects ; Celecoxib ; Dinoprostone/blood ; Female ; Humans ; Male ; Middle Aged ; Patient Selection ; Placebos ; Pyrazoles/*administration &amp; dosage/adverse effects ; Sulfonamides/*administration &amp; dosage/adverse effects ; Treatment Outcome ; }, abstract = {OBJECTIVE: To determine whether chronic treatment with celecoxib, a cyclooxygenase-2 inhibitor that has been shown to be beneficial in preclinical testing, is safe and effective in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: A double-blind, placebo-controlled, clinical trial was conducted. Three hundred research subjects with ALS were randomized (2:1) to receive celecoxib (800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function measured by the maximum voluntary isometric contraction strength. Secondary end points included safety, survival, change in cerebrospinal fluid prostaglandin E(2) levels, and changes in the rate of decline of leg and grip strength, vital capacity, ALS Functional Rating Scale-Revised, and motor unit number estimates.<br><br>RESULTS: Celecoxib did not slow the decline in muscle strength, vital capacity, motor unit number estimates, ALS Functional Rating Scale-Revised, or affect survival. Celecoxib was well tolerated and was not associated with an increased frequency of adverse events. Prostaglandin E(2) levels in cerebrospinal fluid were not elevated at baseline and did not decline with treatment.<br><br>INTERPRETATION: At the dosage studied, celecoxib did not have a beneficial effect on research subjects with ALS, and it was safe. A biological effect of celecoxib was not demonstrated in the cerebrospinal fluid. Further studies of celecoxib at a dosage of 800 mg/day in ALS are not warranted.}, }
@article {pmid16793728, year = {2006}, author = {Moviglia, GA and Varela, G and Gaeta, CA and Brizuela, JA and Bastos, F and Saslavsky, J}, title = {Autoreactive T cells induce in vitro BM mesenchymal stem cell transdifferentiation to neural stem cells.}, journal = {Cytotherapy}, volume = {8}, number = {3}, pages = {196-201}, doi = {10.1080/14653240600735958}, pmid = {16793728}, issn = {1465-3249}, mesh = {Amyotrophic Lateral Sclerosis/immunology ; Antigens, CD/analysis ; Autoimmunity/*immunology ; Bone Marrow Cells/cytology ; CD3 Complex/analysis ; Cell Differentiation/*physiology ; Cell Separation/methods ; Cell Shape/physiology ; Coculture Techniques/methods ; Glial Fibrillary Acidic Protein/analysis ; Humans ; Intermediate Filament Proteins/analysis ; Lymphocyte Activation/immunology ; Mesenchymal Stem Cells/chemistry/*cytology ; Nerve Tissue Proteins/analysis/chemistry/immunology ; Nestin ; Neurons/chemistry/*cytology ; Protein Hydrolysates/immunology ; Receptors, Interleukin-2/analysis ; Spinal Cord Injuries/immunology ; Stem Cells/chemistry/*cytology ; T-Lymphocytes/chemistry/cytology/*physiology ; Tubulin/analysis ; }, abstract = {BACKGROUND: The degree of post-injury inflammation of the damaged area of a spinal cord is the main difference between the natural successful repair in inferior vertebrates and failure in superior vertebrates. The treatment of rats with anti-myelin lymphocytes after experimental spinal cord injury induces their functional recovery. On the other hand, mesenchymal stem cells (MSC) from adult BM implanted in injured areas recover the morphology and function of spinal cord in mammals. The purpose of this study was to determine whether there is a direct relationship between anti-nervous tissue T cells and MSC reparatory properties.<br><br>METHODS: Circulating autoreactive lymphocytes of patients with spinal cord injuries and amyotrophic lateral sclerosis were isolated and activated in vitro. These cells were cocultured with autologous MSC for 2-15 days. Cocultures of non-selected lymphocytes were used as controls.<br><br>RESULTS: After 48 h of coculture, MSC adopted a spindle shape with polarization of the cytoplasm that resembled bipolar neurons. Their nuclei diminished the nucleolus number and the chromatin lost its granular appearance. After 15 days of culture the cells developed the typical structure of a neural network. No morphologic changes were observed in control cultures. The differentiated cells reacted positively to tubuline III, GFAP and nestin. No differences were observed between the different patient cell sources.<br><br>DISCUSSION: We observed that autoreactive cells may induce the transdifferentiation of MSC to neural stem cells. This T-cell-MSC interaction may be a common phenomenon during physiologic nerve tissue repair.}, }
@article {pmid16787836, year = {2000}, author = {Garcia de Yebenes, J and Yebenes, J and Mena, MA}, title = {Neurotrophic factors in neurodegenerative disorders: model of Parkinson's disease.}, journal = {Neurotoxicity research}, volume = {2}, number = {2-3}, pages = {115-137}, pmid = {16787836}, issn = {1029-8428}, abstract = {Neurotrophic factors are compounds that enhance neuronal survival and differentiation. Most of these compounds exert their pharmacological actions on selective types of neurons, and therefore, are considered promising new therapeutic agents for the treatment of different neurodegenerative disorders characterized by selective degeneration of certain neuronal groups. Those compounds have been used in humans for several neurological disorders including amyotrophic lateral sclerosis--ciliary derived neurotrophic factor (CNTF) and brain derived neurotrophic factor (BDNF), Alzheimer's disease and peripheral neuropathy--nerve growth factor (NGF) and Parkinson's disease (PD)--glial derived neurotrophic factor (GDNF). In spite of well founded clinical experiments by previous experimental work in animal models some of these trials have been negative. For instance, animal models of PD have shown that several neurotrophic factors, including GDNF and other compounds, reduce apoptosis and increase resistance of dopamine neurons to neurotoxins in vitro. These compounds prevent or recover the damage to dopamine neurons of rodents and primates produced by chemical or mechanical acute lesions including 6-OH-DA, MPTP, methamphetamine and axotomy. The differences between the promising results obtained in experimental models and the lack of clinical results or excessive toxicity found in humans could be attributed to the following reasons: (a) Lack of relevance between the pathogenesis of the experimental lesion and the corresponding neurodegenerative disorder. (b) Poor correlation between results obtained in acute, self-limited, selective deficit produced to experimental animals and those available in more complex, chronic and progressive disorders involving patients. (c) Inadequate delivery of the active product to the target area in the human brain. (d) Poor information from acute experiments in animals which does not predict long-term effects of chronic infusion in humans. Further experimental work, therefore, is needed to transfer these neurotrophic factors to the clinic.}, }
@article {pmid16781706, year = {2006}, author = {Kim, K and Moore, DH and Makriyannis, A and Abood, ME}, title = {AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis.}, journal = {European journal of pharmacology}, volume = {542}, number = {1-3}, pages = {100-105}, doi = {10.1016/j.ejphar.2006.05.025}, pmid = {16781706}, issn = {0014-2999}, support = {DA09158/DA/NIDA NIH HHS/United States ; NS041639/NS/NINDS NIH HHS/United States ; }, mesh = {Amino Acid Substitution/genetics ; Amyotrophic Lateral Sclerosis/genetics/physiopathology/*prevention &amp; control ; Animals ; Cannabinoids/chemistry/pharmacology ; Disease Models, Animal ; Disease Progression ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Mice ; Mice, Transgenic ; Models, Molecular ; Motor Activity/drug effects ; Mutation/genetics ; Receptor, Cannabinoid, CB2/*agonists ; Sex Factors ; Superoxide Dismutase/genetics ; }, abstract = {Effective treatment for amyotrophic lateral sclerosis (ALS) remains elusive. Motor neuron degeneration is the primary pathology in ALS; however non-neuronal cells contribute to the disease process. In particular, inflammatory processes have been shown to play an important role. AM1241 is a cannabinoid CB2 receptor selective agonist that has been shown to be effective in models of inflammation and hyperalgesia. Here we report that treatment with AM1241 was effective at slowing signs of disease progression when administered after onset of signs in an ALS mouse model (hSOD1(G93A) transgenic mice). Administration at the onset of tremors delayed motor impairment in treated mice when compared to vehicle controls. Three conditions of ALS, the loss of motor function, paralysis scoring and weight loss, were analyzed using a mathematical model. Loss of motor function (as assessed by performance on a rotarod) was delayed by 12.5 days in male mice by AM1241. In female mice, AM1241 extended rotarod performance by 3 days, although this was not statistically significant. In male mice, AM1241 also extended by 5 days the time to reach the 50% point on a visually-assessed performance scale. AM1241 did not affect weight loss or survival (129.8+/-1.7 days, vehicle; 129.1+/-7.0 days, AM1241, n=16). As AM1241 was well tolerated by the animals, cannabinoid CB2 receptor-selective compounds may be the basis for developing new drugs for the treatment of ALS and other chronic neurodegenerative diseases.}, }
@article {pmid16768102, year = {2006}, author = {Sugie, M and Ando, N and Ueno, S}, title = {[Usefulness of polysomnography at an early stage of amyotrophic lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {46}, number = {4}, pages = {297-300}, pmid = {16768102}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*complications/diagnosis ; Early Diagnosis ; Humans ; Male ; Middle Aged ; *Polysomnography ; Positive-Pressure Respiration/methods ; Sleep Apnea Syndromes/*diagnosis/*etiology/therapy ; }, abstract = {A 47-year-old man who presented moderate muscle weakness in the neck and all the extremities was diagnosed as having early stage of amyotrophic lateral sclerosis (ALS). He did not have bulbar dysfunction and respiratory distress. His pulmonary function tests and arterial blood gas analysis showed no abnormalities, but polysomnography (PSG) revealed sleep-disordered breathing requiring mechanical support ventilation. Bi-level positive airway pressure treatment was started only at night, which improved both sleep-disordered breathing and daytime activity. PSG should be considered in ALS patients at an early clinical stage in order to predict mild respiratory dysfunction.}, }
@article {pmid16753975, year = {2006}, author = {Chaisson, KM and Walsh, S and Simmons, Z and Vender, RL}, title = {A clinical pilot study: high frequency chest wall oscillation airway clearance in patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {7}, number = {2}, pages = {107-111}, doi = {10.1080/14660820600640570}, pmid = {16753975}, issn = {1748-2968}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications/*therapy ; *Chest Wall Oscillation ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Oxyhemoglobins/metabolism ; Pilot Projects ; Respiratory Tract Diseases/etiology/prevention &amp; control ; Survival Analysis ; Treatment Outcome ; Vital Capacity ; }, abstract = {Respiratory complications are common in patients with amyotrophic lateral sclerosis (ALS) with respiratory failure representing the most common cause of death. Ineffective airway clearance resultant from deficient cough frequently contributes to these abnormalities. We sought to evaluate the effectiveness of high frequency chest wall oscillation (HFCWO) administered through the Vest Airway Clearance System when added to standard care in preventing pulmonary complications and prolonging the time to death in patients with ALS. This is a single center study performed at the Penn State Milton S. Hershey Medical Center (HMC). Nine patients with a diagnosis of ALS and concurrently receiving non-invasive ventilatory support with bi-level positive airway pressure (BiPAP) were recruited from the outpatient clinic at HMC. Four patients were randomized to receive standard care and five patients to receive standard care plus the addition of HFCWO administered twice-daily for 15 min duration. Longitudinal assessments of oxyhemoglobin saturation, forced vital capacity (FVC), and adverse events were obtained until time of death. Pulmonary complications of atelectasis, pneumonia, hospitalization for a respiratory-related abnormality, and tracheostomy with mechanical ventilation were monitored throughout the study duration. No differences were observed between treatment groups in relation to the rate of decline in FVC. The addition of HFCWO airway clearance failed to improve time to death compared to standard treatment alone (340 days +/- 247 vs. 470 days +/- 241; p = 0.26). The random allocation of HFCWO airway clearance to patients with ALS concomitantly receiving BiPAP failed to attain any significant clinical benefits in relation to either loss of lung function or mortality. This study does not exclude the potential benefit of HFCWO in select patients with ALS who have coexistent pulmonary diseases, pre-existent mucus-related pulmonary complications, or less severe levels of respiratory muscle weakness.}, }
@article {pmid16753973, year = {2006}, author = {Gruis, KL and Brown, DL and Weatherwax, KJ and Feldman, EL and Chervin, RD}, title = {Evaluation of sham non-invasive ventilation for randomized, controlled trials in ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {7}, number = {2}, pages = {96-99}, doi = {10.1080/14660820600640604}, pmid = {16753973}, issn = {1748-2968}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Continuous Positive Airway Pressure ; Female ; Humans ; Male ; Middle Aged ; Placebos ; Pulmonary Gas Exchange ; Research Design ; *Respiration, Artificial ; Vital Capacity ; }, abstract = {Non-invasive positive pressure ventilation (NIV) treatment of advanced respiratory insufficiency prolongs survival in ALS. To investigate the critical question of whether earlier initiation of NIV might provide additional benefit, a randomized trial with an appropriate placebo is needed. This study evaluated sub-therapeutic (sham) continuous positive airway pressure as a potential placebo. In a single-blind design, 40 ALS patients with forced vital capacity>50% were randomized to receive 30 seconds (s) of either active NIV, with 8 cm H2O inspiratory and 4 cm H2O expiratory pressure, or sham NIV with<1 cm of H2O continuous positive airway pressure at the mask. A questionnaire was then used to assess whether subjects thought that they had received a "real" or "pretend" treatment trial. The subjects' median age was 60.5 years, and 38% were female. Twelve of 20 subjects (60%) who received active NIV and 7 (35%) of the 20 subjects who received sham thought that they had tried the active treatment (p = 0.11). Only 8 (20%) of all subjects were confident about their determination that they had received "real" or "pretend" NIV. Thus, sub-therapeutic (sham) continuous positive airway pressure is a promising placebo control for NIV trials in ALS.}, }
@article {pmid16753971, year = {2006}, author = {Jackson, CE and Lovitt, S and Gowda, N and Anderson, F and Miller, RG}, title = {Factors correlated with NPPV use in ALS.}, journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases}, volume = {7}, number = {2}, pages = {80-85}, doi = {10.1080/14660820500504587}, pmid = {16753971}, issn = {1748-2968}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications/*therapy ; Databases, Factual ; Dyspnea/etiology/therapy ; Female ; Humans ; Income ; Male ; Middle Aged ; Motor Neurons/physiology ; Positive-Pressure Respiration/*statistics &amp; numerical data ; Sex Factors ; Socioeconomic Factors ; Vital Capacity ; }, abstract = {In spite of emerging evidence of therapeutic benefit from non-invasive positive pressure ventilation (NPPV), only a minority of ALS patients use this therapy. We examined factors which correlate with use of NPPV in ALS patients. Data were analyzed from the ALS CARE Database on the use of NPPV in patients with FVC less than 50% of predicted and probable or definite ALS based on modified El Escorial criteria. Of the 403 eligible patients, 146 (36%) used NPPV. NPPV compliance was strongly correlated with symptoms of dyspnea and orthopnea as well as with the use of other therapies including PEG tubes, augmentative speech devices, and riluzole. Male gender and household income >$80,000 were also associated with higher NPPV use. There was no correlation between age, race, type of insurance, forced vital capacity, duration of symptoms, ALSFRS-R, caregiver burden or quality of life with the use of NPPV. These data suggest that the factors which are most closely associated with NPPV utilization are symptomatic orthopnea and dyspnea. The findings may be useful in designing prospective studies to examine the factors which might explain the underutilization of NPPV and the optimal use of this treatment.}, }
@article {pmid16753239, year = {2006}, author = {Drew, PD and Xu, J and Storer, PD and Chavis, JA and Racke, MK}, title = {Peroxisome proliferator-activated receptor agonist regulation of glial activation: relevance to CNS inflammatory disorders.}, journal = {Neurochemistry international}, volume = {49}, number = {2}, pages = {183-189}, doi = {10.1016/j.neuint.2006.04.003}, pmid = {16753239}, issn = {0197-0186}, support = {NS047546/NS/NINDS NIH HHS/United States ; NS042860/NS/NINDS NIH HHS/United States ; R01 NS042860/NS/NINDS NIH HHS/United States ; P30 NS047546/NS/NINDS NIH HHS/United States ; R01 NS042860-04/NS/NINDS NIH HHS/United States ; P30 NS047546-02/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Anti-Inflammatory Agents/pharmacology ; Central Nervous System/drug effects/*metabolism/physiopathology ; Encephalitis/drug therapy/*metabolism/physiopathology ; Gliosis/drug therapy/*metabolism/physiopathology ; Humans ; Inflammation Mediators/antagonists &amp; inhibitors/metabolism ; Neuroglia/drug effects/*metabolism ; Peroxisome Proliferator-Activated Receptors/agonists/*metabolism ; }, abstract = {Peroxisome proliferator-activated receptors (PPARs) play key roles in lipid metabolism and inflammation. Recent studies indicated that PPARs are also capable of modulating immune responses. Microglia and astrocytes are cells resident to the central nervous system (CNS) that function to protect against environmental insults including pathogens. However, following CNS inflammation, reactive gliosis occurs which is characterized by astrocyte hypertrophy and increased glial proliferation. Under such conditions, glia can become chronically activated and may contribute to the neuropathology associated with a variety of neuroinflammatory disorders including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and stroke. A review of the role of PPAR agonists in modulating glial cell activation is presented. Included is a discussion of the molecular mechanisms of action of these PPAR agonists and the potential utility of these agents for the treatment of neuroinflammatory disorders.}, }
@article {pmid16738060, year = {2006}, author = {Gillingwater, TH and Ingham, CA and Parry, KE and Wright, AK and Haley, JE and Wishart, TM and Arbuthnott, GW and Ribchester, RR}, title = {Delayed synaptic degeneration in the CNS of Wlds mice after cortical lesion.}, journal = {Brain : a journal of neurology}, volume = {129}, number = {Pt 6}, pages = {1546-1556}, doi = {10.1093/brain/awl101}, pmid = {16738060}, issn = {1460-2156}, support = {BB/D001722/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; GR066272/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Corpus Striatum/ultrastructure ; Disease Models, Animal ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Microscopy, Electron ; Neurodegenerative Diseases/*pathology/physiopathology ; Neuronal Plasticity ; Presynaptic Terminals/*ultrastructure ; Synapses/ultrastructure ; Time Factors ; Wallerian Degeneration/*pathology/physiopathology/prevention &amp; control ; }, abstract = {Therapies that might delay degeneration of synapses offer an appealing strategy for treatment of neurodegenerative diseases, including Alzheimer's disease and related dementias, prion diseases, schizophrenia and amyotrophic lateral sclerosis. Analysis of mouse mutants provides one possible avenue towards identifying relevant mechanisms. Here, we used quantitative and serial section electron microscopy to find out whether the onset and time course of pre-synaptic nerve terminal degeneration is delayed in the striatum of Wallerian degeneration slow (Wld(s)) mutant mice. Synaptic degeneration was observed within 48 h of cortical ablation in wild-type mice but was delayed by approximately 1 week in Wld(s) mice. However, the morphological characteristics of degenerating nerve terminals in wild-type and Wld(s) mice were indistinguishable, in contrast to the differences reported previously in studies of the PNS. Surprisingly, the delayed onset of synaptic degeneration was accompanied by an increased incidence of complex synaptic morphologies on post-synaptic spines in the denervated Wld(S) striatum indicating an enhanced plastic response at both injured and uninjured synapses. The data suggest that targeting Wallerian-like mechanisms of synaptic degeneration could lead to the development of new therapies for the treatment of CNS disorders where synapse loss is a primary feature.}, }
@article {pmid19078809, year = {2006}, author = {Cheema, Z and Saperstein, D and Jackson, C and Newman, D}, title = {Neuromuscular Highlights-AAN 2005.}, journal = {Journal of clinical neuromuscular disease}, volume = {7}, number = {4}, pages = {206-209}, doi = {10.1097/01.cnd.0000211404.09693.7d}, pmid = {19078809}, issn = {1537-1611}, abstract = {Summary of Neuromuscular Presentations at the 57 Annual AAN 2005 meeting in Miami Florida on topics of Facioscapulohumeral muscular dystrophy (FSHD), Duchenne muscular dystrophy (DMD), Diabetic Neuropathy, Charco Marie Tooth disease (CMT), Comparison of injected steroids versus Surgery for carpal tunnel syndrome, Rituximab in Anti-MAG associated polyneuropathy, Cannabis based medicine (CBM) in the treatment of neuropathic pain, utility of skin biopsy with intraepidermal nerve fiber density (IENFD) in sensory complaints, comparing sympathetic skin responses (SSRs) and skin biopsy in diagnosing small fiber sensory neuropathy, Chronic inflammatory demyelinating polyneuropathy (CIDP) clinical and electrophysiologic predictors, affect of limb warming in mild ulnar nerve conduction study (NCS) abnormalities, Tamoxifen affect in ALS, open label study of 3,4 DAP, Pyridostigmine and Ephedrine in fast channel syndrome, Mexilitine as an antimyotonia treatment in myotonic dystrophy (DM1), frontal lobe impairment evaluation in DM1 and DM2 patients and phenotype-genotype correlation in patients with dysferlinopathy.}, }
@article {pmid16736475, year = {2006}, author = {Liu, Z and Martin, LJ}, title = {The adult neural stem and progenitor cell niche is altered in amyotrophic lateral sclerosis mouse brain.}, journal = {The Journal of comparative neurology}, volume = {497}, number = {3}, pages = {468-488}, doi = {10.1002/cne.21012}, pmid = {16736475}, issn = {0021-9967}, support = {AG16282/AG/NIA NIH HHS/United States ; NS34100/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics/*pathology ; Animals ; Brain/cytology/metabolism ; Cell Proliferation ; Cells, Cultured ; Cerebral Ventricles/cytology ; Disease Models, Animal ; Humans ; Immunohistochemistry ; Intermediate Filament Proteins/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Neurologic Mutants ; Mice, Transgenic ; Motor Neurons/*cytology/metabolism/pathology ; *Nerve Degeneration ; Nerve Tissue Proteins/metabolism ; Nestin ; Prosencephalon/*cytology/metabolism/pathology ; Stem Cells/*cytology ; Superoxide Dismutase/*deficiency/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal adult human disease caused by motor neuron degeneration. Stem cell therapy might be a treatment for ALS. The adult mammalian forebrain has neural stem cells (NSCs) and neural progenitor cells (NPCs) in the anterior subventricular zone (SVZa), rostral migratory stream (RMS), olfactory bulb (OB) core, and dentate gyrus (DG). These cells could be used to rescue or replace degenerating upper and lower motor neurons through endogenous recruitment or autologous/allogenic transplantation. We evaluated the competency of forebrain NSCs and NPCs in transgenic (tg) mice harboring human mutant superoxide dismutase-1 (mSOD1), a model of ALS. Tg human wild-type SOD1 (wtSOD1) mice and non-tg mice were controls. Bromodeoxyuridine (BrdU) labeling of cells, a marker for cell proliferation and other events, was reduced in a niche-specific pattern in presymptomatic and symptomatic mice, with the SVZa having greater reductions than the RMS, OB, and DG. Different NSC and NPC complements were evaluated by localizing nestin, neural cell adhesion molecule, distalless-2 transcription factor, vimentin, and glial fibrillary acidic protein. In symptomatic mice, NSC markers were reduced, whereas NPC markers were unchanged or elevated. Neurogenesis was preserved in symptomatic mSOD1 mice. NSC/NPC competence assessment in vitro revealed that mSOD1 SVZa cells had the ability to proliferate and form neurospheres but had an impaired response to mitogen stimulation. We conclude that adult mSOD1 ALS mice have abnormalities in forebrain NSCs, but the essential features of NSC/NPCs remained in presymptomatic and symptomatic mice.}, }
@article {pmid16734913, year = {2006}, author = {Magnabosco, JL}, title = {Innovations in mental health services implementation: a report on state-level data from the U.S. Evidence-Based Practices Project.}, journal = {Implementation science : IS}, volume = {1}, number = {}, pages = {13}, pmid = {16734913}, issn = {1748-5908}, abstract = {BACKGROUND: The Evidence-Based Practice (EBP) Project has been investigating the implementation of evidence-based mental health practices (Assertive Community Treatment, Family Psychoeducation, Integrated Dual Diagnosis Treatment, Illness Management and Recovery, and Supported Employment) in state public mental health systems in the United States since 2001. To date, Project findings have yielded valuable insights into implementation strategy characteristics and effectiveness. This paper reports results of an effort to identify and classify state-level implementation activities and strategies employed across the eight states participating in the Project.<br><br>METHODS: Content analysis and Greenhalgh et al's (2004) definition of innovation were used to identify and classify state-level activities employed during three phases of EBP implementation: Pre-Implementation, Initial Implementation and Sustainability Planning. Activities were coded from site visit reports created from documents and notes from key informant interviews conducted during two periods, Fall 2002-Spring 2003, and Spring 2004. Frequency counts and rank-order analyses were used to examine patterns of implementation activities and strategies employed across the three phases of implementation.<br><br>RESULTS: One hundred and six discreet implementation activities and strategies were identified as innovative and were classified into five categories: 1) state infrastructure building and commitment, 2) stakeholder relationship building and communications, 3) financing, 4) continuous quality management, and 5) service delivery practices and training. Implementation activities from different categories were employed at different phases of implementation.<br><br>CONCLUSION: Insights into effective strategies for implementing EBPs in mental health and other health sectors require qualitative and quantitative research that seeks to: a) empirically test the effects of tools and methods used to implement EBPs, and b) establish a stronger evidence-base from which to plan, implement and sustain such efforts. This paper offers a classification scheme and list of innovative implementation activities and strategies. The classification scheme offers potential value for future studies that seek to assess the effects of various implementation processes, and helps establish widely accepted standards and criteria that can be used to assess the value of innovative activities and strategies.}, }
@article {pmid16723044, year = {2006}, author = {Goodall, EF and Morrison, KE}, title = {Amyotrophic lateral sclerosis (motor neuron disease): proposed mechanisms and pathways to treatment.}, journal = {Expert reviews in molecular medicine}, volume = {8}, number = {11}, pages = {1-22}, doi = {10.1017/S1462399406010854}, pmid = {16723044}, issn = {1462-3994}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/genetics/pathology/*therapy ; Animals ; Antioxidants/metabolism/pharmacology ; Apoptosis ; Clinical Trials as Topic ; Cytoskeleton/metabolism ; Genetic Predisposition to Disease ; Humans ; Mice ; Models, Biological ; Motor Neurons/*pathology ; Oxidative Stress ; Protein Binding ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by loss of motor neurons. The cause of disease is unknown other than in the rare cases of familial disease arising from mutations in the superoxide dismutase 1 gene. Many theories for pathogenesis have been proposed - including oxidative stress, excitotoxicity, mitochondrial dysfunction and abnormal protein aggregation - based on studies of human post mortem tissue, research on animal models, and in vitro work. Here we review the evidence for the main pathogenic mechanisms and outline how they might interact to cause motor neuron death. Clinical trials have as yet failed to identify any truly effective therapies in ALS, with only riluzole providing a modest improvement in survival. Ongoing trials are exploring the value of antiglutamatergic agents, including the cephalosporin antibiotic ceftriaxone, as well as antioxidants, mitochondrial enhancers and anti-apoptotic drugs. It is likely that effective therapy will involve combinations of agents acting on different mechanisms. Gene therapy with neurotrophic factors will soon be in clinical trials, while work on stem cell therapy remains preclinical. In addition to finding effective therapies, research also needs to identify early disease markers because therapy is likely to be of most benefit when given early in the course of disease.}, }
@article {pmid16718634, year = {2006}, author = {Ferrante, E and Giavoli, C and Porretti, S and Vassallo, E and Ronchi, CL and Lania, AG and Beck-Peccoz, P and Spada, A}, title = {Evaluation of the components of the insulin-like growth factors system in GH-deficient adults: effects of twelve-month rhGH treatment.}, journal = {Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme}, volume = {38}, number = {5}, pages = {352-355}, doi = {10.1055/s-2006-925402}, pmid = {16718634}, issn = {0018-5043}, mesh = {Adult ; Anthropometry ; Body Mass Index ; Carrier Proteins/blood ; Female ; Glycoproteins/blood ; Human Growth Hormone/*deficiency/*therapeutic use ; Humans ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/analysis ; Insulin-Like Growth Factor II/analysis ; Male ; Middle Aged ; Recombinant Proteins/therapeutic use ; Somatomedins/*analysis ; }, abstract = {The impact of GH deficiency and rhGH replacement therapy on IGF-I, IGFBP-3 and ALS levels has been widely studied. There is less information available on IGF-II levels, the component of the ternary complex poorly dependent on GH. We investigate the components of IGFs system in 36 GHD adults (28M, 8F, age 45 +/- 14 yrs) before and after 12 months of rhGH therapy (mean dose 0.3 +/- 0.1 mg/day). One-hundred healthy sex- and age-matched subjects were studied for comparison. At baseline, GHD patients showed IGF-I and IGF-II levels and IGFs to IGFBP-3 molar ratios that were lower than controls. During therapy, IGF-I levels increased (p < 0.01) to normal range. IGF-II levels, though higher than at baseline (p < 0.01), remained lower than in controls (p < 0.01). ALS and IGFBP-3 significantly increased (p < 0.001). These modifications resulted in normalization in IGF-I to IGFBP-3 ratio, while no change in IGF-II to IGFBP-3 ratio was observed. In conclusion, the increase of serum IGF-II levels during rhGH treatment in GHD patients probably reflects the increase in the other components of ternary complex (ALS and IGFBP-3). However, serum IGF-II levels as well as IGF-II to IGFBP-3 ratio, although increased, were definitely lower than in controls. This last result, given the increasing evidences of a direct implication of IGF-II in cancer, may further confirm the safety of rhGH replacement in adults with severe GHD as diagnosed by appropriate stimulation tests.}, }
@article {pmid16713196, year = {2006}, author = {DiBernardo, AB and Cudkowicz, ME}, title = {Translating preclinical insights into effective human trials in ALS.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {11-12}, pages = {1139-1149}, doi = {10.1016/j.bbadis.2006.03.007}, pmid = {16713196}, issn = {0006-3002}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Clinical Trials as Topic/*methods/standards ; *Disease Models, Animal ; Drug Design ; Humans ; Mice ; Rats ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, adult-onset neurodegenerative disease characterized by selective dysfunction and death of motor neurons in the brain and spinal cord. The disease is typically fatal within 3-5 years of symptom onset. There is no known cure and only riluzole, which was approved by the FDA in 1996 for treatment of ALS, has shown some efficacy in humans. Preclinical insights from model systems continue to furnish ample therapeutic targets, however, translation into effective therapies for humans remains challenging. We present an overview of clinical trial methodology for ALS, including a summary rationale for target selection and challenges to ALS clinical research.}, }
@article {pmid16713179, year = {2006}, author = {Ogawa, N and Minamimura, K and Kodaka, T and Maki, T}, title = {Short administration of polyclonal anti-T cell antibody (ALS) in NOD mice with extensive insulitis prevents subsequent development of autoimmune diabetes.}, journal = {Journal of autoimmunity}, volume = {26}, number = {4}, pages = {225-231}, doi = {10.1016/j.jaut.2006.03.001}, pmid = {16713179}, issn = {0896-8411}, support = {DK60721/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/immunology/*pharmacology ; Diabetes Mellitus, Type 1/immunology/metabolism/*prevention &amp; control ; Female ; Glucose Tolerance Test ; Islets of Langerhans/immunology/*pathology ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Mice, Inbred NOD ; Mice, SCID ; Rabbits ; T-Lymphocytes/immunology ; }, abstract = {Treatment of overtly diabetic NOD mice with antilymphocyte serum (ALS), a polyclonal anti-T cell antibody, leads to cure of diabetes. Here, we investigated whether ALS-treatment of NOD mice after development of extensive insulitis prevents onset of diabetes. Female NOD mice were treated with two doses of ALS at 14, 19 or 23 weeks of age. No further treatment was given. In untreated female NOD mice, diabetes developed starting at 13 weeks and reached 68% by 37 weeks. ALS-treatment at 14, 19 or 23 weeks when histology showed progressive insulitis completely prevented onset of overt diabetes in 9/12, 11/12 or 12/12 mice, respectively. Intraperitoneal glucose tolerance tests in 43 week-old ALS-treated, diabetes-free mice showed a normal pattern. Co-adoptive transfer of lymphoid cells prepared from ALS-treated diabetes-free mice together with splenocytes from overtly diabetic NOD mice resulted in marked delay in diabetes onset in NOD.SCID mice, suggesting the presence of autoimmune regulatory cells in ALS-treated mice. Autoimmune regulatory cells were CD4(+)CD25(+), but not CD4(+)CD25(-), T cells. Thus, treatment of euglycemic individuals who already show signs of autoimmune diabetes with a short course of polyclonal anti-T cell antibody may effectively prevent onset of type 1 diabetes mellitus.}, }
@article {pmid19078785, year = {2005}, author = {Scott, KR and Kothari, MJ and Venkatesh, YS and Murphy, T and Simmons, Z}, title = {Parotid gland injections of botulinum toxin a are effective in treating sialorrhea in amyotrophic lateral sclerosis.}, journal = {Journal of clinical neuromuscular disease}, volume = {7}, number = {2}, pages = {62-65}, doi = {10.1097/01.cnd.0000188865.88167.62}, pmid = {19078785}, issn = {1537-1611}, abstract = {OBJECTIVE: : The objective of this study was to determine the safety and efficacy of botulinum toxin A in ameliorating refractory sialorrhea and improving quality of life in patients with amyotrophic lateral sclerosis.<br><br>MATERIALS AND METHODS: : Six patients with bulbar ALS received bilateral parotid gland injections of botulinum toxin A.<br><br>RESULTS: : No adverse effects occurred. Tissue use decreased in 5 of 7 patients at a dose of 10 units and in 3 of 4 patients at a dose of 20 units. Self-reported quality of life did not change in most.<br><br>CONCLUSIONS: : Parotid gland injections of botulinum toxin appear safe and may be helpful in some patients with ALS for the treatment of sialorrhea.}, }
@article {pmid19078738, year = {2004}, author = {Alexianu, ME and Gooch, CL}, title = {Advances in neuromuscular disease 2003: the year in review.}, journal = {Journal of clinical neuromuscular disease}, volume = {5}, number = {4}, pages = {169-175}, doi = {10.1097/01.cnd.0000127138.99732.28}, pmid = {19078738}, issn = {1537-1611}, abstract = {During 2003, numerous research advances in both clinical neuromuscular disease and in the basic pathophysiology of these disorders were published and/or presented. In this review, we present a few categorical highlights of the year, discussing a new potential treatment of McArdle's disease, proposed new diagnostic criteria for the inflammatory myopathies and their clinical implications, the emerging anti-MuSK antibody syndrome in patients with myasthenia gravis, potential new therapies for the most common hereditary neuropathy (Charcot-Marie-Tooth type 1A), the successful pharmacologic manipulation and its therapeutic implications of the genetic mechanisms underlying spinal muscular atrophy, and several emerging therapeutic strategies in amyotrophic lateral sclerosis. As these reports indicate, clinical and basic research in neuromuscular disease continues to yield important and clinically relevant insights, which are now being rapidly translated into new clinical trials showing therapeutic promise for diseases previously thought untreatable.}, }
@article {pmid19714404, year = {2000}, author = {Meininger, V and Lacomblez, L and Salachas, F}, title = {What has changed with riluzole?.}, journal = {Journal of neurology}, volume = {247 Suppl 6}, number = {}, pages = {VI/19-22}, doi = {10.1007/PL00007784}, pmid = {19714404}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Glutamic Acid/physiology ; Humans ; Neuroprotective Agents/*therapeutic use ; Research/trends ; Riluzole/*therapeutic use ; Treatment Outcome ; }, abstract = {Riluzole, after two significant trials, was introduced as the first standard treatment of amyotrophic lateral sclerosis (ALS) in the early 95'. After 5 years what has changed in the field of ALS? In the field of basic science, riluzole as an active drug has largely contributed to stimulate the research of the possible role of glutamate in the genesis of ALS. However, the apparent simplicity of the relation between the drug and its mechanisms has to modulated in the light of the negativity of other trials (gabapentin) and the display of other mechanisms of the disease and of the compound. Possible relation with other putative mechanisms of ALS, as oxydative stress or growth factors, could be (and probably are) also involved. In the field of its activity, riluzole has an impact on the survival rate which has been largely debated. Comparison with historical databases are supporting the results of the two initial trials. Other information have been published supporting the probable activity of the drug on the muscle strength decline, a controversial matter. They strengthen the initial data and give additional reasons to use riluzole as a standard treatment of patients. In the field of the daily care, riluzole provided a real and unique hope for ALS sufferers. Even if its activity is not as complete as patients would have expected, it provides a hope for slowing down the rate of evolution and abolishes the myth of "no hope, no cure" which was the leitmotiv of patients care until recently. We have to better define the mode of administration with regard to the clinical status of the patients (respiratory disorders, fatigue, stiffness). In the field of care givers, riluzole was one major factor which provided the basis for national and international collaborations either for therapeutic trials or for standard of care. It made possible large collaborative programs in and among many countries. We do hope that this impulse will continue and be stimulated by additional results both in the field of basic science and clinical research.}, }
@article {pmid19714403, year = {2000}, author = {Ludolph, AC}, title = {Treatment of amyotrophic lateral sclerosis - what is the next step?.}, journal = {Journal of neurology}, volume = {247 Suppl 6}, number = {}, pages = {VI/13-8}, doi = {10.1007/PL00007783}, pmid = {19714403}, issn = {1432-1459}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/epidemiology/genetics/prevention &amp; control ; Animals ; Biomarkers ; Disease Models, Animal ; Humans ; Indonesia/epidemiology ; Mice ; Micronesia/epidemiology ; Neuroprotective Agents/therapeutic use ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which was thought to be untreatable. However, recent evidence in both experimental animals and men indicates that antiglutamatergic strategies are the first to have an influence on its pathogenesis and slow down the disease process. Since the effect of drugs is still small, this process cannot only be seen as a success of the present but must also be acknowledged as a basis for future developments. How will future studies be designed? They will have to take into account that the disease presumably has a long preclinical period and they will use a number of novel compounds and treatment strategies which have been shown to be effective in transgenic animal models. This also implies that we are likely to use a combination of therapies and we will try to treat patients early. The latter will be associated with the demand for a novel clinical attitude toward the diagnosis of the disease and the development of novel markers for both the preclinical period and the longitudinal course of the disease.}, }
@article {pmid19078608, year = {2000}, author = {Burns, MT and Juel, VC and Hess, CE and Phillips, LH}, title = {Motor neuron disease and serum monoclonal proteins: poor response to treatment of the paraproteinemia.}, journal = {Journal of clinical neuromuscular disease}, volume = {2}, number = {2}, pages = {70-72}, doi = {10.1097/00131402-200012000-00003}, pmid = {19078608}, issn = {1537-1611}, abstract = {An association between motor neuron disease (MND) and paraproteinemia has been previously reported. In a retrospective study, we found that 13 of 117 (11%) patients with MND who had serum protein electrophoresis studies were found to have a serum M-protem. Eleven of 13 patients had probable or definite amyotrophic lateral sclerosis (ALS), Of the 11 patients with ALS, six were treated with immunotherapy or chemotherapy. Subjective or objective neurologic improvement was not identified in any. Our data support an association between MND and paraproteinemia, but response to treatment of the paraproteinemia was disappointing. Searching for an M-protein in probable or definite ALS may not be therapeutically relevant.}, }
@article {pmid21395835, year = {1997}, author = {Reinsch, N and Dempfle, L}, title = {Investigations on functional traits in Simmental: 1. Treatment costs for ten different diseases.}, journal = {Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie}, volume = {114}, number = {1-6}, pages = {407-417}, doi = {10.1111/j.1439-0388.1997.tb00527.x}, pmid = {21395835}, issn = {0931-2668}, abstract = {All health-related events and treatment costs (by veterinarian and non-veterinarian) were recorded through fortnightly interviews with the herdsmen of 104 Simmental dairy farms in Upper Bavaria from autumn 1987 to spring 1990. The data include 8381 calvings and the subsequent time period. For ten different disease-classes the sum of all treatment costs from calving up to either the subsequent calving or up to culling were computed. A multiplicative model with three covariates was fitted to these observations. The covariates are farm, parity and type of end of lactation (culling or subsequent calving). Farm effects are significant for almost all diseases. The average sum of treatment costs per calving with an associated disease was estimated as the average expected value for this sum, where averaging is over the farms. These costs range from 29 DM (claw disorders) up to 137 DM (dystocia). The average costs per calving (with or without disease) range from 1.59 DM (injuries of the udder) to 10.90 DM (fertility problems). Corresponding costs per cow and year are 1.74 DM and 12.24 DM. ZUSAMMENFASSUNG: Auf 104 Fleckviehbetrieben wurden insgesamt 8381 Kalbungen, alle auf diese Kalbungen folgenden Erkrankungen und die zugehörigen Behandlungskosten erhoben. Für zehn verschiedene Erkrankungsarten wurden jeweils alle Behandlungskosten innerhalb einer Zwischenkalbezit aufsummiert. An diese Beobachtungswerte wurde jeweils ein multiplikatives Modell mit den Einflußfaktoren Betrieb, Laktationsnumner und Art der Zwischenkalbezeit (beendet durch Kalbung bzw. durch Abgang) angepßt. Im Gegensatz zu den beiden anderen Faktoren erweist sich der Betrieb bei fast allen Erkrankungsarten als signifikant. Die durchschnittlichen Kosten innerhalb einer betroffenen Zwischenkalbezeit wurden als durchschnittlicher Erwartungswert über alle Betriebe berechnet. Diese Kosten liegen je nach Erkrankungsart in einem Bereich, der von ca. 29 DM (Klauenerkrankungen) bis zu ca. 137 DM (Schwergeburt) reicht. Umgerechnet auf eine beliebige Kalbung (mit oder ohne folgende Erkrankung) entstehen Kosten zwischen 1,59 DM (Euterverletzungen) und 10,90 DM (Fruchtbarkeitsprobleme). Je Kuh und Jahr betragen die entsprechenden Werte 1,74 DM und 12,24 DM.}, }
@article {pmid21395813, year = {1997}, author = {Oikawa, T and Sato, K}, title = {Treating small herds as fixed or random in an animal model.}, journal = {Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie}, volume = {114}, number = {1-6}, pages = {177-183}, doi = {10.1111/j.1439-0388.1997.tb00503.x}, pmid = {21395813}, issn = {0931-2668}, abstract = {The simulated population was characterized by its small herd size and the occurrence of preferential treatment for animals, which was modelled as a non-random association between sires and herds or as an extra effect due to the sire's genetic advantage. Robustness for prediction was compared between animal models with fixed herd effect and random herd effect. No difference in empirical accuracy was observed between the prediction models if data included only large herds, whereas for data with small herds, the random herd model had a higher accuracy and smaller empirical MSE than the fixed herd model in general. This superiority of the random herd model did not change under selection. The empirical MSE particularly increased when the extra effect, due to the sire's merit, was very large, where the MSE of the random herd model was significantly larger than the fixed herd model. This result suggested a larger bias in the random herd model. On the contrary, the random herd model had a higher accuracy and a lower MSE than the fixed herd model, when the extra effect was small. As the large magnitude of this extra effect is unrealistic, the random herd model is concluded to be superior to the fixed herd model in general. ZUSAMMENFASSUNG: Behandlung kleiner Herden als fixeoder zufällige Größle in einem Tiermodell Die simulierte Population ist charakterisiert durch kleine Herdengrößen und Vorzugsbehandlung von Tieren, was im Modell einmal als nicht-zufällige Assoziation von Stieren und Herden, oder als Extra Einfluß wegen des Zuchtwertes eines Stieres eingebaut wurde. Die Robustheit der Voraussage wurde durch Vergleich von Tiermodellen mit fixen und mit zufaälligem Herdeneffekt geprüft. Bei großen Herden zeigte sich kein Unterschied zwischen den Voraussagemodellen, aber bei kleinen Herden zeigte das Modell mit zufälligen Herdeneinflüssen höhere Genauigkeit und geringeren empirischen MSE, was bei Vorhandensein von Selektion sich nicht änderte. Der empirische MSE nahm zu, wenn die Sonderwirkung des väterlichen Zuchtwertes groß war, wo dann der MSE des zufälligen Herdenmodells größer als beim fixen war, was eine größere Verzerrung in ersterem vermuten läßt. Bei kleinen Extrawirkungen verhielt es sich umgekehrt. Nachdem große Extrawirkungen unrealistisch sein dürgten, sollte im allgemeinen das Modell mit zufälligen Herdenwirkungen überlegen sein.}, }
@article {pmid21319118, year = {1994}, author = {Madrazo, I and Castrejón, H and Franco-Bourland, RE}, title = {Human brain drafting: an approach to the treatment of neurodegenerative diseases.}, journal = {Surgical technology international}, volume = {3}, number = {}, pages = {493-499}, pmid = {21319118}, issn = {1090-3941}, abstract = {The aim of human brain grafting is to deliver adequate amounts of endocrine or neural tissue to neurodegenerated areas of the diseased or lesioned brain for functional recovery. The many options available make brain grafting and other neural grafting procedures potentially applicable for the treatment of varied alterations of the central nervous system, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis, spinal cord lesions, assorted traumatic lesions to the central nervous system, stroke, etc.}, }
@article {pmid21395732, year = {1993}, author = {Longeri, M and Polli, M and Ponti, W and Zanotti, M}, title = {BoLA class I polymorphism and in vitro immune response to M. bovis antigens.}, journal = {Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie}, volume = {110}, number = {1-6}, pages = {335-345}, doi = {10.1111/j.1439-0388.1993.tb00746.x}, pmid = {21395732}, issn = {0931-2668}, abstract = {From a sample of 119 Friesian calves, serologically typed for BoLA class I, 47 subjects were chosen expressing 9 different MHC types (A6, A6.9, A10, A11, A14, A15, A30, W16, M103) with the same age and reared in the same farm conditions. The animals were s.c. injected with a water in oil suspension of killed M. bovis and the treatment was repeated two days later. Before the treatment and 21 days later, calves were bled and on PBM (peripheral blood mononuclear leucocytes) were performed the following tests: 1. Lymphocyte Stimulation with bovine and avian PPDs (Purified protein derivative of Mycobacterium bovis and Mycobacterium avium, respectively). 2. Phagocytic activity towards M. bovis. 3. Class II molecules expression on cell surface. 4. Percentage of leucocyte populations and subpopulations. In the in vitro Lymphocyte Stimulation test, all the animals and classes were responders. Animals bearing A10 BoLA class I presented c.p.m. (counts per minute) and index values higher than the other cattle; these values were significantly positively related both to bovine and avian PPDs (P < .01). By variance analysis A14 BoLA type showed a slight positive significant correlation with more efficient phagocytic activity. BoLA class I type did not seem to significantly affect percentage of class II positive cells and leucocyte percentages on PBM. ZUSAMMENFASSUNG: Der BoLA Klasse I Polymorphismus und in vitro immunologische Antwort gegen die Antigene von M. bovis Aus einer Stichprobe von 119 für BoLA Klasse I serologisch typisierten Friesian Kälber, wurden 47 Subjekte ausgewählt, die 9 verschiedene MHC Typen ausdrückten (A6, A6.9, A10, A11, A14, A15, A30, W16, M103). Alle waren gleich alt und in gleichen Haltungsbedingungen. Die Tiere wurden mit einer Wasser-in-Ol Suspension abgetöteter M. bovis subkutan injiziert und die Behandlung nach zwei Tagen wiederholt. Vor und 21 Tage nach Behandlung wurden die folgenden Tests ausgeführt: 1. Lymphozyten-Stimulationstest mit bovinen und Geflügel PPDs. 2. Phagozyten Aktivität gegen M. bovis. 3. Zeil-Oberflächen, Expression der Klasse II Moleküle. 4. Anteile der Lymphozyten Populationen und Subpopulationen. Im in vitro Lymphozyten-Stimulationstest waren alle Tiere und Klassen responder. Tiere mit A10 BoLA I zeigten höhere c.p.m. und Indexwerte als die anderen; diese Werte waren in signifikant positiver Beziehung mit der PPD von M. bovis und auch mit M. avium (P < .01). BoLA Typ A14 zeigte leicht signifikant positive Korrelation mit wirksamerer Phagozyten Aktivität. BoLA Klasse I Typ scheint nicht den Prozentsatz der positiven Zellen der Klasse II und der Leukozyten der PBM signifikant zu beeinflussen. RESUMEN: Polimorfismo de BoLA clase I y immunidad a los antigenos del M. bovis Se escojeron 47 novillos dentro de un grupo de 119 animales que segun analisis previamente hecha tenian BoLA de clase I. Estos 47 novillos fueron escojidos de manera que tuvieran 9 distintos tipos de MHC (A6, A6.9, A10, A11, A14, A15, A30, W16, M103), la misma edad, las mismas condiciones de cria. Estos animales fueron inoculados subcutaneo con M. bovis matados en una suspension oleosa y la misma inoculacion fue repetida una secunda vez despues de dos dias. Por cada animal se tomaron muestras de sangre antes y 21 dias despues de la inoculacion de arriba. Las muestras de sangre fueron pruebaoas con: 1. Stimulacion Lymhocitaria con PPD bovina y avicola. 2. Actividad phagocitaria a M. bovis. 3. Expresion sobre la superficie celular de moleculas de clase II. 4. Porcentaje de poblaciones y de subpob-laciones de leucocitos. Todos los animales y todos los tipos de MHC dieron respuestas positivas en las pruebas de Stimulacion Lymphocitaria. Los animales que tenian la BoLA A10 presentaron valores de c.p.m. y indices mas altos de los demas animales. Estos valores se encontraron significativamente y positivamente relacionados sea a la PPD bovina que a la PPD avicola. Por medio de la analisis de varianzas se encontro que el tipo BoLA A14 muestraba una correlacion significativa y algo positiva con una mejor actividad fagocitaria. Los tipos de clase BoLA I no parecieron que influenzaran de manera appreciable el porcentaje de positividad por la clase II y el porcentaje de leucocitos en la sangre PBM.}, }
@article {pmid16726846, year = {1990}, author = {Schallenberger, E and Wagner, HG and Papa, R and Hartl, P and Tenhumberg, H}, title = {Endocrinological evaluation of the induction of superovulation with PMSG in water buffalo (Bubalus bubalis).}, journal = {Theriogenology}, volume = {34}, number = {2}, pages = {379-392}, doi = {10.1016/0093-691x(90)90530-7}, pmid = {16726846}, issn = {0093-691X}, abstract = {Ten nonlactating buffalo were superovulated with 3000 IU PMSG. Luteolysis was induced with 500 microg Cloprostenol (PG) 60 and 72 h after PMSG. Five buffalo were alloted for natural mating and five were bred by artificial insemination 60 and 84 h after the first PG treatment. Since four buffalo developed pyometra, only 6 of 10 underwent embryo collection successfully 180 to 190 h after PG. Three buffalo yielded only one morula each, while the remaining three yielded a total of two, three and four morulae and/or blastocysts as well als zero, one and three unfertilized ova, respectively. Six of the ten buffalo were assigned to an intensive blood collection regimen. Mean concentrations of progesterone (ng/ml) increased from 1.9 at PMSG stimulation to 4.8 at induction of luteolysis and decreased to a nadir of 0.2 about 72 h after PG treatment. The preovulatory surge of LH occurred 36 +/- 9 h after PG and was low in magnitude (7.3 +/- 1.3 ng/ml). Stimulation of 3 to 12 follicles resulted in concentrations of estradiol-17beta exceeding 5 pg/ml within 48 h after PMSG treatment and reaching a maximum of 32 +/- 11 pg/ml about the time of the preovulatory surge. Only in two individuals did concentrations decrease below 5 pg/ml within the following 12 h. In the other four buffalo 3 to 10 unovulated structures remained palpable, secreting estradiol-17beta far exceeding the preovulatory concentrations. The fast appearing, low magnitude LH surges were key problems resulting from PMSG treatment. They caused unovulated endocrinologically active follicles. High estrogen levels during the early luteal period may activate subclinical uterine infections, which in turn may negatively affect embryonic development.}, }
@article {pmid18770324, year = {1977}, author = {Vlaovic, MS and Jovanovic, MI and Buening, GM and Loan, RW}, title = {Role of cell-mediated immunity (CMI) in chickens inoculated with avian leukosis/sarcoma virus.}, journal = {Avian pathology : journal of the W.V.P.A}, volume = {6}, number = {2}, pages = {171-179}, doi = {10.1080/03079457708418224}, pmid = {18770324}, issn = {0307-9457}, abstract = {Immunosuppression of chickens infected in ovo with avian leukosis virus (RAV-1) by the injection of antilymphocyte serum (ALS) did not significantly (P > 0.05) alter the incidence or distribution of lesions in chickens between 3 and 6 months of age as compared to control groups. Antilymphocyte serum treatment of Rous sarcoma virus [RSV (RAV-2)]-infected chickens significantly (P < 0.05) inhibited tumour regression and enhanced tumour metastasis. It was concluded that cell-mediated immunity was not a significant factor in effecting the survival of viraemic chickens Viraemic leukosis virus infected-chickens responded as well as normal chickens to sensitization to Mycobacterium tuberculosis H37Ra. The results were based on in vivo wattle tests and in vitro cell-mediated cytotoxicity assays. It was concluded that subclinical avian leukosis virus infection had no effect on the thymus-dependent lymphocyte (T-cell) population associated with cutaneous delayed hypersensitivity and cell-mediated cytotoxicity.}, }
@article {pmid18134149, year = {1949}, author = {LOWE, L}, title = {[About a case of successful treatment of amyotrophic lateral sclerosis].}, journal = {Wiener klinische Wochenschrift}, volume = {61}, number = {23}, pages = {365}, pmid = {18134149}, issn = {0043-5325}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; *Sclerosis ; }, }
@article {pmid20296863, year = {1947}, author = {STINER, O}, title = {[Treatment of amyotrophic lateral sclerosis].}, journal = {Schweizerische medizinische Wochenschrift}, volume = {77}, number = {13}, pages = {381}, pmid = {20296863}, issn = {0036-7672}, mesh = {*Amyotrophic Lateral Sclerosis ; *Baths ; Humans ; *Sclerosis ; }, }
@article {pmid16691366, year = {2006}, author = {Riethmuller-Haage, I and Bastiaans, L and Harbinson, J and Kempenaar, C and Kropff, MJ}, title = {Influence of the acetolactate synthase inhibitor metsulfuron-methyl on the operation, regulation and organisation of photosynthesis in Solanum nigrum.}, journal = {Photosynthesis research}, volume = {88}, number = {3}, pages = {331-341}, pmid = {16691366}, issn = {0166-8595}, mesh = {Acetolactate Synthase/*antagonists &amp; inhibitors ; Arylsulfonates/*pharmacology ; Chlorophyll/metabolism ; Electron Transport ; Herbicides/pharmacology ; Photosynthesis/*drug effects ; Photosystem I Protein Complex ; Photosystem II Protein Complex ; Plant Leaves/drug effects/metabolism ; Solanum nigrum/*drug effects/*metabolism ; }, abstract = {The influence of the acetolactate synthase inhibitor metsulfuron-methyl on the operation of the photosynthetic apparatus was examined on 4-weeks-old climate chamber-grown Solanum nigrum plant. To have an indication on the relative performance of the photosynthetic apparatus of ALS-treated plants, the level of carbon dioxide (CO(2)) fixation, the relative quantum efficiency of photosystem I (Phi(PSI)) or photosystem II (Phi(PSII)) electron transport and leaf chlorophyll content were assessed for both control and treated plants at 2, 4 and 7 days after application of the herbicide. Results indicated a progressive inhibition of the level of CO(2) fixation, the relative quantum efficiency of photosystem I (Phi(PSI)) and II (Phi(PSII)) electron transport and the leaf chlorophyll content already 2 days after application of the herbicide. The linear relationship between the photosystem I and II was unaltered by herbicidal treatment and was sustained under conditions where large changes in pigment composition of the leaves occurred. It appears that the stress-induced loss of leaf chlorophyll is not a catastrophic process but rather is the consequence of a well-organised breakdown of components. Under photorespiratory and non-photorespiratory conditions, the relationship between the index of electron transport flow through photosystem I and II and the rate of CO(2) fixation is altered so that electron transport becomes less efficient at driving CO(2) fixation.}, }
@article {pmid16636239, year = {2006}, author = {Mustfa, N and Walsh, E and Bryant, V and Lyall, RA and Addington-Hall, J and Goldstein, LH and Donaldson, N and Polkey, MI and Moxham, J and Leigh, PN}, title = {The effect of noninvasive ventilation on ALS patients and their caregivers.}, journal = {Neurology}, volume = {66}, number = {8}, pages = {1211-1217}, doi = {10.1212/01.wnl.0000208957.88534.11}, pmid = {16636239}, issn = {1526-632X}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/physiopathology/*psychology/*therapy ; Caregivers/*psychology ; Female ; Humans ; Male ; Middle Aged ; Positive-Pressure Respiration/methods ; Quality of Life ; Respiratory Insufficiency/physiopathology/psychology/therapy ; Severity of Illness Index ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Noninvasive ventilation (NIV) reduces mortality and improves some aspects of quality of life (QoL) in ALS. However, concerns remain that progressive disability may negate these benefits and unnecessarily burden caregivers.<br><br>METHODS: Thirty-nine patients requiring NIV were offered treatment. Twenty-six were established on NIV, but 13 declined or could not tolerate NIV. Fifteen patients without respiratory muscle weakness (RMW) but with similar ALS severity and age were studied in parallel. Caregivers of 21 NIV, 7 untreated, and 10 patients without RMW participated. Patients and caregivers had detailed QoL measurements for 12 months. NIV patients underwent cognitive testing before and after treatment.<br><br>RESULTS: RMW correlated with lower QoL. The median survival of untreated patients (18 days; 95% CI 11 to 25 days) was shorter than for NIV patients (298 days; 95% CI 192 to 404 days) and non-RMW patients (370 days; 95% CI 278 to 462 days; log rank test [2 df] = 81, p = 0.00001). A wide range of QoL measures improved within 1 month of starting NIV, and improvements were maintained for 12 months. QoL of non-RMW patients declined as RMW progressed. Caregivers of NIV and non-RMW patients showed similar increases in burden, but NIV patient caregivers developed a deterioration in the Short Form-36 Vitality score. No improvements were found on measures of learning and recall in the NIV patients.<br><br>CONCLUSIONS: Respiratory muscle weakness has a greater impact on quality of life (QoL) than overall ALS severity. Noninvasive ventilation (NIV) improves QoL despite ALS progression. NIV has no impact on most aspects of caregiver QoL and does not significantly increase caregiver burden or stress.}, }
@article {pmid16634036, year = {2006}, author = {Panitch, HS and Thisted, RA and Smith, RA and Wynn, DR and Wymer, JP and Achiron, A and Vollmer, TL and Mandler, RN and Dietrich, DW and Fletcher, M and Pope, LE and Berg, JE and Miller, A and , }, title = {Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis.}, journal = {Annals of neurology}, volume = {59}, number = {5}, pages = {780-787}, doi = {10.1002/ana.20828}, pmid = {16634036}, issn = {0364-5134}, mesh = {Affect/*drug effects ; Aged ; Crying ; Dextromethorphan/adverse effects/pharmacokinetics/*therapeutic use ; Double-Blind Method ; Drug Combinations ; Excitatory Amino Acid Antagonists/adverse effects/pharmacokinetics/*therapeutic use ; Female ; Humans ; Laughter ; Male ; Middle Aged ; Multiple Sclerosis/*drug therapy/*psychology ; Pain Measurement/drug effects ; Quality of Life ; Quinidine/adverse effects/pharmacokinetics/*therapeutic use ; }, abstract = {OBJECTIVE: To evaluate the efficacy and safety of DM/Q (capsules containing dextromethorphan [DM] and quinidine [Q]) compared with placebo, taken twice daily, for the treatment of pseudobulbar affect over a 12-week period in multiple sclerosis patients.<br><br>METHODS: A total of 150 patients were randomized in a double-blind, placebo-controlled study to assess pseudobulbar affect with the validated Center for Neurologic Study-Lability Scale. Each patient also recorded the number of episodes experienced between visits, estimated quality of life and quality of relationships on visual analog scales, and completed a pain rating scale.<br><br>RESULTS: Patients receiving DM/Q had greater reductions in Center for Neurologic Study-Lability Scale scores than those receiving placebo (p < 0.0001) at all clinic visits (days 15, 29, 57, and 85). All secondary end points also favored DM/Q, including the number of crying or laughing episodes (p <or= 0.0077), quality of life (p < 0.0001), quality of relationships (p = 0.0001), and pain intensity score (p = 0.0271). DM/Q was well tolerated; only dizziness occurred with greater frequency than with placebo.<br><br>INTERPRETATION: Results in multiple sclerosis patients were similar to those of a previous study in amyotrophic lateral sclerosis, demonstrating that DM/Q may be beneficial in treating potentially disabling pseudobulbar affect in a variety of neurological disorders.}, }
@article {pmid16631799, year = {2006}, author = {Gruis, KL and Brown, DL and Lisabeth, LD and Zebarah, VA and Chervin, RD and Feldman, EL}, title = {Longitudinal assessment of noninvasive positive pressure ventilation adjustments in ALS patients.}, journal = {Journal of the neurological sciences}, volume = {247}, number = {1}, pages = {59-63}, doi = {10.1016/j.jns.2006.03.007}, pmid = {16631799}, issn = {0022-510X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/mortality/physiopathology/*therapy ; Female ; Humans ; Male ; Middle Aged ; *Positive-Pressure Respiration ; Retrospective Studies ; Survival Rate ; }, abstract = {The absence of data guiding optimal titration of noninvasive positive pressure ventilation (NIPPV) over time in ALS patients may contribute to the under-prescribing of NIPPV. We conducted a retrospective, single-center, chart review assessment of NIPPV pressure settings used for symptomatic treatment of ALS patients to determine NIPPV adjustments, and to compare survival between those who were tolerant and intolerant to NIPPV. All subjects were started on nocturnal NIPPV at 8 and 3 cm H2O inspiratory and expiratory pressure, respectively. Of the 18 tolerant subjects identified, 4 (22%) had no NIPPV pressure changes before death; 8 (44%), 1 change; 4 (22%), 2 changes; 1 (6%), 3 changes; and 1 (6%), 5 changes. Most pressure changes occurred during the first year of NIPPV initiation. The maximum pressure needed for comfort by any patient in this study was 19/5 cm H2O, while 4 (22%) found the original 8/3 cm H2O settings to be sufficient until death. Subjects in the tolerant group had better survival, when adjusting for age and site of symptom onset (bulbar versus limb), with a hazard ratio of 0.23 [95% confidence interval: 0.10, 0.54]. The current data suggest that ALS patients who are tolerant to NIPPV typically need at least one upward change in pressure settings. Tolerance to relatively low NIPPV inspiratory pressures is associated with improved survival.}, }
@article {pmid16613824, year = {2005}, author = {Tzanela, M and Christoforaki, M and Papastathopoulou, L and Vassiliadi, D and Botoula, E and Trivizas, P and Thalassinos, NC}, title = {Growth hormone binding protein and acid labile subunit levels in the assessment of acromegaly treatment.}, journal = {Hormones (Athens, Greece)}, volume = {4}, number = {3}, pages = {148-154}, doi = {10.14310/horm.2002.11152}, pmid = {16613824}, issn = {1109-3099}, mesh = {Acromegaly/*diagnosis/*drug therapy ; Biomarkers/analysis ; Carrier Proteins/analysis/*metabolism ; Craniotomy/methods ; Cross-Sectional Studies ; Female ; Glucose Tolerance Test ; Growth Hormone/*metabolism ; Humans ; Male ; Middle Aged ; Prognosis ; Retrospective Studies ; Sensitivity and Specificity ; Somatostatin/*analogs &amp; derivatives ; Treatment Outcome ; }, abstract = {OBJECTIVE: Post-treatment monitoring of acromegalic patients is a matter of controversy, as discrepancies between GH and IGF-I levels have been reported. The aim of our study was to evaluate the role of acid-labile subunit (ALS), a component of the 150 kD IGF-I/IGFBP-3/ALS complex, and the growth hormone binding protein (GHBP) in the follow-up of patients with acromegaly after therapeutic intervention.<br><br>DESIGN: Forty-one patients with acromegaly, 10 at the time of diagnosis and 31 post therapeutic intervention, were studied. Patients were evaluated by the determination of baseline (fasting) IGF-I, ALS and GHBP and of glucose and GH during OGTT.<br><br>RESULTS: Significantly lower ALS and higher GHBP levels were detected in successfully treated acromegalics compared to patients before treatment (34.1+/-1.6 vs. 52.8+/-2 mg/L and 0.9+/-0.08 vs 0.4+/-0.1 &#xec;g/L, respectively P<0.05). Furthermore, no difference was noted in ALS and GHBP values between patients successfully treated with either somatostatin analogues or another type of treatment.<br><br>CONCLUSIONS: a) Successfully treated acromegalic patients demonstrate lower ALS and higher GHBP levels than patients before treatment, and b) somatostatin analogue treatment does not have a direct effect on GHBP and ALS concentration in acromegaly. Studies in larger groups of patients are needed to disclose whether these alterations will be useful in the post-treatment assessment of acromegalic patients.}, }
@article {pmid16612515, year = {2005}, author = {Manrique, D}, title = {Application of botulinum toxin to reduce the saliva in patients with amyotrophic lateral sclerosis.}, journal = {Brazilian journal of otorhinolaryngology}, volume = {71}, number = {5}, pages = {566-569}, pmid = {16612515}, issn = {1808-8694}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Botulinum Toxins, Type A/*administration &amp; dosage/adverse effects ; Cholinergic Antagonists/adverse effects ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Neuromuscular Agents/*administration &amp; dosage/adverse effects ; Prospective Studies ; Saliva/*drug effects ; Sialorrhea/*drug therapy/etiology ; }, abstract = {AIM: To demonstrate the effect of local application of Botox(R) in patients with amyotrophic lateral sclerosis (ALS), following our 2002 institutional protocol of sialorrhea treatment.<br><br>STUDY DESIGN: Clinical prospective.<br><br>MATERIAL AND METHOD: Five patients with ALS assisted at Clinic of Otolaryngology of AACD (Associa&#xe7;&#xe3;o de Assist&#xea;ncia &#xe0; Crian&#xe7;a Deficiente). They were all submitted to local application of Botox in salivary glands and followed up for a year. The protocol consisted of clinical questionnaire about the inability of swallowing saliva and its repercussions in quality of life. Patients were submitted to previous odontological treatment, had intolerance to the adverse effects of anti-cholinergic agents and had not used Botox for at least six months. The application was guided by ultrasound and the doses were 30U in one point for submandibular gland, and 20U in two points for each parotid gland, after topic anesthetic with prilocaine.<br><br>RESULTS: Five patients with ALS with sialorrhea, aged 45 to 59 years, were submitted to Botox salivary glands application. We observed that the symptoms of sialorrhea changed dramatically in four patients. Three patients stayed almost four months without complaints with repercussion in quality of life. No patient presented local or systemic effects with local injection of Botox.}, }
@article {pmid16609809, year = {2006}, author = {Kalra, S and Tai, P and Genge, A and Arnold, DL}, title = {Rapid improvement in cortical neuronal integrity in amyotrophic lateral sclerosis detected by proton magnetic resonance spectroscopic imaging.}, journal = {Journal of neurology}, volume = {253}, number = {8}, pages = {1060-1063}, pmid = {16609809}, issn = {0340-5354}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/*physiopathology ; Case-Control Studies ; Cerebral Cortex/*drug effects/metabolism/physiopathology ; Female ; Humans ; *Magnetic Resonance Spectroscopy/methods ; Male ; Middle Aged ; Nerve Regeneration/*drug effects ; Neuroprotective Agents/*therapeutic use ; Protons ; Riluzole/*therapeutic use ; Treatment Outcome ; }, abstract = {Riluzole prolongs survival in amyotrophic lateral sclerosis. The temporal and spatial profile of its effect on the brain is unknown. We used proton magnetic resonance spectroscopic imaging to evaluate the neuronal response to 1 day of riluzole treatment in motor and non-motor regions of the brain. In 10 patients the N-acetylaspartate/total creatine (NAA/Cr) ratio increased in the precentral gyrus and supplementary motor area, but not in the post-central gyrus or parietal lobe. Improvement in cortical neuronal metabolic function in the motor cortex occurs early with riluzole treatment.}, }
@article {pmid16606769, year = {2006}, author = {de Carvalho, M and Swash, M}, title = {Can selection of rapidly progressing patients shorten clinical trials in amyotrophic lateral sclerosis?.}, journal = {Archives of neurology}, volume = {63}, number = {4}, pages = {557-560}, doi = {10.1001/archneur.63.4.557}, pmid = {16606769}, issn = {0003-9942}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy/physiopathology ; Clinical Trials as Topic/*methods/standards ; Disability Evaluation ; Disease Progression ; Electrodiagnosis ; Female ; Humans ; Male ; Middle Aged ; Neural Conduction/physiology ; *Patient Selection ; Peripheral Nerves/physiopathology ; Predictive Value of Tests ; Prospective Studies ; Time Factors ; }, abstract = {BACKGROUND: The marked variability in progression of amyotrophic lateral sclerosis (ALS) requires large numbers of patients to detect a significant effect in current clinical trial designs.<br><br>OBJECTIVE: To test the utility of a lead-in period to assess rate of progression so that patients with rapidly progressive ALS can be selected for subsequent clinical trials.<br><br>DESIGN: Prospective study.<br><br>SETTING: The ALS Center, University of Lisbon, Lisbon, Portugal.<br><br>PATIENTS: Fifty-seven consecutively recruited patients assessed at diagnosis and 3 months later (end of lead-in period).<br><br>INTERVENTIONS: Change in ALS Functional Rating Scale (ALS-FRS) score was analyzed to establish a statistically significant cutoff point to define patients with rapid (group 1) or slow (group 2) progression. Patients from both groups were reexamined 1 and 3 months after the lead-in period.<br><br>MAIN OUTCOME MEASURES: Changes in ALS-FRS score, motor unit number estimation, and neurophysiologic index, and resultant grouping of patients according to rate of progression at 1 and 3 months.<br><br>RESULTS: Both the 80th percentile and 2 SDs above the mean of the change in ALS-FRS score identified the same patients. Twelve patients showed rapid progression (group 1) and 45 showed slow progression (group 2). One month after the lead-in period there was a significant reduction in ALS-FRS score, motor unit number estimation, and neurophysiologic index in group 1, and after 3 months all these measurements changed significantly in both groups.<br><br>CONCLUSIONS: This strategy of selecting patients with rapidly progressing ALS for inclusion in exploratory, short phase II clinical trials offers substantial savings in costs and time, and could accelerate the process of testing potentially useful drugs for the treatment of ALS.}, }
@article {pmid16600496, year = {2006}, author = {Stankovic, RK and Li, Z}, title = {Decreased neurofilament density in large myelinated axons of metallothionein-I, II knockout mice.}, journal = {Neuroscience letters}, volume = {402}, number = {1-2}, pages = {1-6}, doi = {10.1016/j.neulet.2006.03.038}, pmid = {16600496}, issn = {0304-3940}, mesh = {Analysis of Variance ; Animals ; Axons/*metabolism ; Female ; Male ; Metallothionein/*deficiency/metabolism ; Mice ; Mice, Knockout ; Nerve Fibers, Myelinated/*metabolism ; Neurofilament Proteins/*metabolism ; Phrenic Nerve/cytology/metabolism ; Silver Staining/methods ; }, abstract = {Metallothioneins (MTs) are small proteins, two isoforms (I, II) of which bind metals. Their physiological role has been difficult to establish, but recent reports suggested that they serve an important function in nerve repair and in the protection against oxidative stress in the peripheral nervous system. We previously reported a decreased axon calibre in the large myelinated fibres of the phrenic nerve in the MT-I, II double knock out (MT-I, II KO) mouse model. We propose that this could be due to the effects of oxidative stress on neurofilaments (NFs). In this study, we examined the same subset of large myelinated axons using transmission electron microscopy (TEM). There was a decreased NF density in the axons of MT-I, II KO phrenic nerve (P<0.005). This observation may have novel therapeutic implications in the treatment of amyotrophic lateral sclerosis (ALS), particularly as the terminal phases of the disease involve respiratory insufficiency.}, }
@article {pmid16599013, year = {2006}, author = {Yuan, CC}, title = {Laparoscopic uterosacral nerve ablation and chronic pelvic pain.}, journal = {Journal of the Chinese Medical Association : JCMA}, volume = {69}, number = {3}, pages = {101-103}, doi = {10.1016/S1726-4901(09)70185-6}, pmid = {16599013}, issn = {1726-4901}, mesh = {Catheter Ablation/*methods ; Chronic Disease ; Female ; Humans ; Laparoscopy/*methods ; Pelvic Pain/*surgery ; Sacrum/*innervation ; Uterus/*innervation ; }, abstract = {Chronic pelvic pain is a complicated syndrome comprised of different types of pain, including dysmenorrhea, deep dyspareunia, and intermenstrual pain, which can make interpretation difficult. Therefore, investigation of this complex syndrome requires very careful consideration. Accumulating data from several randomized studies, we have now come to realize that LUNA can be an option in a few circumstances, especially for control of menstrual pain without endometriosis; however, its effectiveness may not extend to other indications, such as alleviating secondary dysmenorrhea associated with endometriosis (although it could, however, be reached by presacral neurectomy). Juang et al's article reports a very preliminary experience in the treatment of primary deep dyspareunia, presenting a promising perspective yet without sufficient evidence on the management of deep dyspareunia. A randomized controlled study with an adequate number of patients is warranted.}, }
@article {pmid16585905, year = {2006}, author = {Robert, D and Bianco-Blache, A and Spezza, C and Verschueren, A and Pouget, J and Giovanni, A}, title = {[Assessment of dysarthria and dysphagia in ALS patients].}, journal = {Revue neurologique}, volume = {162}, number = {4}, pages = {445-453}, doi = {10.1016/s0035-3787(06)75035-4}, pmid = {16585905}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Deglutition Disorders/diagnosis/*etiology/physiopathology ; *Diagnostic Techniques, Neurological ; Dysarthria/diagnosis/*etiology/physiopathology ; Electromyography ; Humans ; Manometry ; Physical Examination ; Severity of Illness Index ; Speech Acoustics ; Speech Articulation Tests ; }, abstract = {Swallowing and speech disorders are the dramatic consequences of bulbar and pseudo-bulbar syndrome in ALS. Evaluation is necessary to guide speech therapy and to measure the effects of treatment. This article revues the different examinations used to assess bulbar and pseudobulbar involvement in an ALS patient: oromotor assessment, evaluation of the functions with self assessment, perceptive and objective evaluation of speech disorders, fiberoptic endoscopic evaluation of dysphagia (FEES) and videofluoroscopy.}, }
@article {pmid16571781, year = {2006}, author = {Bilsland, LG and Dick, JR and Pryce, G and Petrosino, S and Di Marzo, V and Baker, D and Greensmith, L}, title = {Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {20}, number = {7}, pages = {1003-1005}, doi = {10.1096/fj.05-4743fje}, pmid = {16571781}, issn = {1530-6860}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Amidohydrolases/genetics ; Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/metabolism ; Animals ; Benzoxazines ; Cannabinoids/*metabolism ; Cell Adhesion Molecules, Neuronal/genetics ; Disease Progression ; Female ; Humans ; Longevity/drug effects ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; Morpholines/*pharmacology/*therapeutic use ; Motor Neurons/metabolism ; Muscle Fatigue/drug effects/genetics ; Muscle, Skeletal/cytology/drug effects ; Naphthalenes/*pharmacology/*therapeutic use ; Neuropeptides/genetics ; Protocadherins ; Receptors, Cell Surface/genetics ; Superoxide Dismutase/*genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of motoneurons in the spinal cord, brain stem, and motor cortex. However, despite intensive research, an effective treatment for this disease remains elusive. In this study we show that treatment of postsymptomatic, 90-day-old SOD1G93A mice with a synthetic cannabinoid, WIN55,212-2, significantly delays disease progression. Furthermore, genetic ablation of the Faah enzyme, which results in raised levels of the endocannabinoid anandamide, prevented the appearance of disease signs in 90-day-old SOD1G93A mice. Surprisingly, elevation of cannabinoid levels with either WIN55,212-2 or Faah ablation had no effect on life span. Ablation of the CB1 receptor, in contrast, had no effect on disease onset in SOD1(G93A) mice but significantly extended life span. Together these results show that cannabinoids have significant neuroprotective effects in this model of ALS and suggest that these beneficial effects may be mediated by non-CB1 receptor mechanisms.}, }
@article {pmid16564029, year = {2006}, author = {Chiba, T and Yamada, M and Sasabe, J and Terashita, K and Aiso, S and Matsuoka, M and Nishimoto, I}, title = {Colivelin prolongs survival of an ALS model mouse.}, journal = {Biochemical and biophysical research communications}, volume = {343}, number = {3}, pages = {793-798}, doi = {10.1016/j.bbrc.2006.02.184}, pmid = {16564029}, issn = {0006-291X}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/pathology ; Animals ; Cell Survival/drug effects ; Disease Models, Animal ; Intracellular Signaling Peptides and Proteins/*therapeutic use ; Mice ; Mice, Transgenic ; Motor Activity/drug effects ; Motor Neurons/drug effects/pathology ; Neuroprotective Agents/*therapeutic use ; Spinal Cord/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Survival Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease for which there is no sufficiently effective therapy. We have reported in our earlier study that intracerebroventricular (i.c.v.) injection of activity-dependent neurotrophic factor (ADNF) improves motor performance of G93A-SOD1 transgenic mice without significant prolongation in survival. Here, we found that i.c.v. injection of a synthetic hybrid peptide named Colivelin composed of ADNF and AGA-(C8R)HNG17, a potent derivative of Humanin that is a bioactive peptide with anti-Alzheimer's disease activity, dose-dependently improved motor performance and prolonged survival of ALS mice. Histological analysis, performed at the age of 120 days, demonstrated increased motoneuronal survival in spinal cords of Colivelin-treated mice as compared with saline- or ADNF-treated mice, indicating that Colivelin is a promising neurotrophic peptide for treatment of ALS.}, }
@article {pmid16563356, year = {2006}, author = {Koyama, S and Arawaka, S and Chang-Hong, R and Wada, M and Kawanami, T and Kurita, K and Kato, M and Nagai, M and Aoki, M and Itoyama, Y and Sobue, G and Chan, PH and Kato, T}, title = {Alteration of familial ALS-linked mutant SOD1 solubility with disease progression: its modulation by the proteasome and Hsp70.}, journal = {Biochemical and biophysical research communications}, volume = {343}, number = {3}, pages = {719-730}, doi = {10.1016/j.bbrc.2006.02.170}, pmid = {16563356}, issn = {0006-291X}, mesh = {Age Factors ; Aging ; Amyotrophic Lateral Sclerosis/diagnosis/*genetics/metabolism ; Animals ; COS Cells ; Chlorocebus aethiops ; Disease Progression ; HSP40 Heat-Shock Proteins/metabolism ; HSP70 Heat-Shock Proteins/*metabolism ; Humans ; Mice ; Mice, Transgenic ; Mutation ; Proteasome Endopeptidase Complex/*metabolism ; Proteasome Inhibitors ; Protein Folding ; Sodium Dodecyl Sulfate/chemistry ; Solubility ; Superoxide Dismutase/*chemistry/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Accumulation of misfolded Cu/Zn superoxide dismutase (SOD1) occurs in patients with a subgroup of familial amyotrophic lateral sclerosis (fALS). To identify the conversion of SOD1 from a normally soluble form to insoluble aggregates, we investigated the change of SOD1 solubility with aging in fALS-linked H46R SOD1 transgenic mice. Mutant SOD1 specifically altered to insoluble forms, which were sequentially separated into Triton X-100-insoluble/sodium dodecyl sulfate (SDS)-soluble and SDS-insoluble/formic acid-soluble species. In spinal cords, the levels of SDS-dissociable soluble SOD1 monomers and SDS-stable soluble dimers were significantly elevated before motor dysfunction onset. In COS-7 cells expressing H46R SOD1, treatment with proteasome inhibitors recapitulated the alteration of SOD1 solubility in transgenic mice. In contrast, overexpression of Hsp70 reduced accumulation of mutant-specific insoluble SOD1. SDS-soluble low molecular weight species of H46R SOD1 may appear as early misfolded intermediates when their concentration exceeds the capacity of the proteasome and molecular chaperones.}, }
@article {pmid16548670, year = {2005}, author = {Zanni, GR and Wick, JY}, title = {The steady, inevitable decline of amyotrophic lateral sclerosis patients.}, journal = {The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists}, volume = {20}, number = {10}, pages = {803-4, 806-8, 810-2}, doi = {10.4140/tcp.n.2005.803}, pmid = {16548670}, issn = {0888-5109}, abstract = {Progressive muscle weakness and fasciculations can indicate developing amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease. Its treatment and prognosis have been unchanged for almost 100 years, although our understanding on a cellular level is better. All ALS patients can be expected to progress to a state that requires complete supportive care.}, }
@article {pmid16547248, year = {2006}, author = {Minamimura, K and Gao, W and Maki, T}, title = {CD4+ regulatory T cells are spared from deletion by antilymphocyte serum, a polyclonal anti-T cell antibody.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {176}, number = {7}, pages = {4125-4132}, doi = {10.4049/jimmunol.176.7.4125}, pmid = {16547248}, issn = {0022-1767}, support = {AII4551//PHS HHS/United States ; DK60721/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antibodies/*immunology ; Antilymphocyte Serum/*immunology ; Biomarkers ; CD4-Positive T-Lymphocytes/*cytology/*immunology/metabolism ; Forkhead Transcription Factors/metabolism ; Gene Expression Regulation/immunology ; Immunity, Innate ; Mice ; Mice, Inbred C57BL ; Phenotype ; Receptors, Interleukin-2/metabolism ; bcl-X Protein/metabolism ; }, abstract = {Broad T cell depletion has been used as an integral part of treatment in transplantation and autoimmune diseases. Following depletion, residual T cells undergo homeostatic proliferation and convert to memory-like T cells. In this study, we investigated the effect of T cell depletion by antilymphocyte serum (ALS), a polyclonal anti-T cell Ab, on CD4(+) regulatory T cells. After ALS treatment, CD4(+)CD25(+) T cells underwent proliferation and expressed a memory T cell marker, CD44. One week after ALS treatment, both CD25(+) and CD25(-) T cells exhibited increased suppression of alloresponses in vitro, which waned thereafter to the levels mediated by naive CD25(+) and CD25(-) T cells. By real-time PCR analyses, ALS treatment of CD4-deficient mice adoptively transferred with Thy1.2(+)CD4(+)CD25(+)Foxp3(+) and Thy1.1(+)CD4(+)CD25(-)Foxp3(-) T cells resulted in the appearance of Thy1.2(+)CD4(+)CD25(-)Foxp3(+) and Thy1.1(+)CD4(+)CD25(+)Foxp3(+) T cells, suggesting the conversion between CD25(+) and CD25(-) T cells. Naive CD25(+) T cells expressed a higher level of intracellular Bcl-x(L) than CD25(-) T cells. Up-regulation of the Bcl-x(L) molecule during ALS-induced homeostatic expansion further promoted survival of CD25(+) and, to a lessor degree, CD25(-) cells. These results indicate that CD25(+) T cells are spared from ALS-mediated deletion, with some CD25(+) T cells converting to CD25(-) T cells, and continue to exhibit regulatory activity. The concomitant presence of T cell deletion and continuous regulatory T cell activity may underlie the therapeutic effect of ALS, particularly in treatment of autoimmune diseases.}, }
@article {pmid16524372, year = {2006}, author = {Vargas, MR and Pehar, M and Cassina, P and Beckman, JS and Barbeito, L}, title = {Increased glutathione biosynthesis by Nrf2 activation in astrocytes prevents p75NTR-dependent motor neuron apoptosis.}, journal = {Journal of neurochemistry}, volume = {97}, number = {3}, pages = {687-696}, doi = {10.1111/j.1471-4159.2006.03742.x}, pmid = {16524372}, issn = {0022-3042}, support = {ES00210/ES/NIEHS NIH HHS/United States ; R03TW006482/TW/FIC NIH HHS/United States ; }, mesh = {Animals ; Animals, Genetically Modified ; Animals, Newborn ; Antioxidants/pharmacology ; Astrocytes/drug effects/*metabolism ; Blotting, Western/methods ; Cell Count/methods ; Cell Survival/drug effects ; Cells, Cultured ; Coculture Techniques/methods ; Drug Interactions ; Embryo, Mammalian ; Enzyme Activation/drug effects ; Fibroblast Growth Factor 1/pharmacology ; Glial Fibrillary Acidic Protein/metabolism ; Glutathione/*biosynthesis/metabolism ; Hydroquinones/pharmacology ; Methionine/analogs &amp; derivatives/pharmacology ; Motor Neurons/*physiology ; NF-E2-Related Factor 2/*metabolism ; Nerve Growth Factor/pharmacology ; Nitrates/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Nitrites/metabolism ; Propionates/pharmacology ; Pyrimidines/pharmacology ; Quinolines/pharmacology ; RNA, Messenger/biosynthesis ; Rats ; Rats, Sprague-Dawley ; Receptor, Nerve Growth Factor/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Spinal Cord/cytology ; Superoxide Dismutase ; Transfection/methods ; Urea/analogs &amp; derivatives/pharmacology ; }, abstract = {Astrocytes may modulate the survival of motor neurons in amyotrophic lateral sclerosis (ALS). We have previously shown that fibroblast growth factor-1 (FGF-1) activates astrocytes to increase secretion of nerve growth factor (NGF). NGF in turn induces apoptosis in co-cultured motor neurons expressing the p75 neurotrophin receptor (p75NTR) by a mechanism involving nitric oxide (NO) and peroxynitrite formation. We show here that FGF-1 increased the expression of inducible nitric oxide synthase and NO production in astrocytes, making adjacent motor neurons vulnerable to NGF-induced apoptosis. Spinal cord astrocytes isolated from transgenic SOD1G93A rats displayed increased NO production and spontaneously induced apoptosis of co-cultured motor neurons. FGF-1 also activates the redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in astrocytes. Because Nrf2 increases glutathione (GSH) biosynthesis, we investigated the role of GSH production by astrocytes on p75NTR-dependent motor neuron apoptosis. The combined treatment of astrocytes with FGF-1 and t-butylhydroquinone (tBHQ) increased GSH production and secretion, preventing motor neuron apoptosis. Moreover, Nrf2 activation in SOD1G93A astrocytes abolished their apoptotic activity. The protection exerted by increased Nrf2 activity was overcome by adding the NO donor DETA-NONOate to the co-cultures or by inhibiting GSH synthesis and release from astrocytes. These results suggest that activation of Nrf2 in astrocytes can reduce NO-dependent toxicity to motor neurons by increasing GSH biosynthesis.}, }
@article {pmid16523990, year = {2006}, author = {Czaplinski, A and Schweikert, K and Strobel, W and Steck, AJ and Weber, M}, title = {[Symptomatic management in amyotrophic lateral sclerosis (ALS)].}, journal = {Praxis}, volume = {95}, number = {8}, pages = {263-8, 269-71}, doi = {10.1024/0369-8394.95.8.263}, pmid = {16523990}, issn = {1661-8157}, mesh = {Disease Progression ; Humans ; Motor Neuron Disease/diagnosis/psychology/*therapy ; *Palliative Care/psychology ; Patient Care Team ; Quality of Life/psychology ; Terminal Care/psychology ; }, abstract = {Although disease-specific treatment of amyotrophic lateral sclerosis is still unsatisfactory, a number of advances have been made in the symptomatic therapy of ALS patients within the last decade. Current data suggest that active and aggressive multidisciplinary management of ALS patients improve their quality of life and prolong their survival. Patient and caregiver communications and decisions are increasingly recognized to be a relevant part of this management. A wide range of supportive and palliative measures, in particular the widely use of symptomatic drugs for pseudobulbar affect, sialorrhea, and sleep disorders is available to relieve patients symptomatology. In addition, patients quality of life has been profoundly improved by the introduction of enteral nutrition and non-invasive ventilation.}, }
@article {pmid16516196, year = {2006}, author = {Lorenzl, S and Narr, S and Angele, B and Krell, HW and Gregorio, J and Kiaei, M and Pfister, HW and Beal, MF}, title = {The matrix metalloproteinases inhibitor Ro 28-2653 [correction of Ro 26-2853] extends survival in transgenic ALS mice.}, journal = {Experimental neurology}, volume = {200}, number = {1}, pages = {166-171}, doi = {10.1016/j.expneurol.2006.01.026}, pmid = {16516196}, issn = {0014-4886}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*enzymology/genetics/mortality ; Animals ; Female ; Male ; Matrix Metalloproteinase 9/metabolism ; *Matrix Metalloproteinase Inhibitors ; Matrix Metalloproteinases/metabolism ; Mice ; Mice, Transgenic ; Piperazines/*therapeutic use ; Protease Inhibitors/pharmacology/*therapeutic use ; Pyrimidines/*therapeutic use ; Survival Rate ; Time Factors ; }, abstract = {In amyotrophic lateral sclerosis (ALS), there is increased expression of matrix metalloproteinases (MMPs) and degradation of the extracellular matrix in postmortem spinal cord tissue. We used zymography and in situ zymography to analyze the expression of MMP-2 and MMP-9 in spinal cord tissue from the G93A transgenic mouse model of ALS. Expression of MMP-9 was increased in the spinal cord of G93A mice. For functional analysis of the role of MMPs, we investigated the effects of oral administration of the MMP inhibitor Ro 28-2653 (100 mg/kg), starting at the age of 30 days (n = 19) and on disease onset (starting at the age of 90 days (n = 10)). Treatment with the MMP inhibitor Ro 28-2653 starting at 30 days of age improved motor performance and significantly (P < 0.05) prolonged the survival time of the animals (136 +/- 12 versus 123 +/- 12 days, mean +/- SD), however, administration at disease onset did not significantly improve survival time. Our experiments show that MMPs are expressed in an animal model of ALS and may play a role in the complex pathophysiologic changes. Early pharmacologic inhibition with a synthetic MMP inhibitor extends survival of the animals which suggest a role of MMPs in the early phase of the disease.}, }
@article {pmid16510725, year = {2006}, author = {Kiaei, M and Petri, S and Kipiani, K and Gardian, G and Choi, DK and Chen, J and Calingasan, NY and Schafer, P and Muller, GW and Stewart, C and Hensley, K and Beal, MF}, title = {Thalidomide and lenalidomide extend survival in a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {26}, number = {9}, pages = {2467-2473}, pmid = {16510725}, issn = {1529-2401}, support = {NS044154/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/mortality ; Analysis of Variance ; Animals ; Cell Count ; Cytokines/metabolism ; *Disease Models, Animal ; Dose-Response Relationship, Drug ; Fas Ligand Protein ; Female ; Fluorescent Antibody Technique/methods ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Immunosuppressive Agents/*therapeutic use ; Lenalidomide ; Male ; Membrane Glycoproteins/metabolism ; Mice ; Mice, Transgenic ; Middle Aged ; Motor Activity/drug effects/physiology ; Neurons/pathology ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Rotarod Performance Test/methods ; Superoxide Dismutase/genetics ; *Survival ; Thalidomide/*analogs &amp; derivatives/*therapeutic use ; Time Factors ; Tumor Necrosis Factor-alpha/metabolism ; Tumor Necrosis Factors/metabolism ; }, abstract = {Accumulating evidence suggests that inflammation plays a major role in the pathogenesis of motor neuron death in amyotrophic lateral sclerosis (ALS). Important mediators of inflammation such as the cytokine tumor necrosis factor-alpha (TNF-alpha) and its superfamily member fibroblast-associated cell-surface ligand (FasL) have been implicated in apoptosis. We found increased TNF-alpha and FasL immunoreactivity in lumbar spinal cord sections of ALS patients and G93A transgenic mice. Both increased TNF-alpha and FasL immunostaining in the lumbar spinal cord of the G93A SOD1 transgenic mice occurred at 40-60 d, well before the onset of symptoms and loss of motor neurons. We tested the neuroprotective effect of thalidomide and its analog lenalidomide, pharmacological agents that inhibit the expression of TNF-alpha and other cytokines by destabilizing their mRNA. Treatment with either thalidomide or lenalidomide attenuated weight loss, enhanced motor performance, decreased motor neuron cell death, and significantly increased the life span in G93A transgenic mice. Treated G93A mice showed a reduction in TNF-alpha and FasL immunoreactivity as well as their mRNA in the lumbar spinal cord. Both compounds also reduced interleukin (IL)-12p40, IL-1alpha, and IL-1beta and increased IL-RA and TGF-beta1 mRNA. Therefore, both thalidomide and lenalidomide bear promise as therapeutic interventions for the treatment of ALS.}, }
@article {pmid16501438, year = {2000}, author = {Caglià, P and Luca, S and Gandolfo, L and Amodeo, C}, title = {Enteral nutrition in patients with chronic neurological diseases.}, journal = {Minerva gastroenterologica e dietologica}, volume = {46}, number = {4}, pages = {199-206}, pmid = {16501438}, issn = {1121-421X}, abstract = {BACKGROUND: Malnutrition is commonly considered an important risk factor that can produce a negative influence on the prognosis of patients with chronic neurological diseases. The reduced caloric or proteic intake due to the motor or cognitive dysfunction, the hypercatabolic state due to infections, the abnormal gastrointestinal motility are the main mechanisms responsible for a state of malnutrition.<br><br>METHODS: Between January and December 1999 fourteen patients with chronic neurological diseases were treated. Ten of them had had a stroke, four due to Amyotrophic Lateral Sclerosis (ALS). After the evaluation of nutritional status the patients received enteral nutrition (EN) by placement of a nasointestinal feeding tube or a Bengmark tube. Glycaemia, blood urea nitrogen, serum creatinine, electrolytes, glycosuria, glutamic-oxalacetic and glutamic pyruvic transaminase were monitored in all patients. Polymeric enteral feeding was administered by an infusion pump. Standard nourished patients (7/14) received a 30 Kcal/kg/day support, the undernourished ones (6 low, 1 moderate malnutrition) received a 35-40 Kcal/kg/day support.<br><br>RESULTS: The complete caloric supply was reached in three-four days. Both of the groups received continuous feeding infusion during hospitalization. For the patients who continued the nutritional support at home (3/14) refeeding was performed only during night-time. In the patients with stroke the optimal/standard weight was reached within one month. In these patients oral nutrition was started within 45 days of treatment taking into account the restored swallowing function. In the patients with ALS the improvement of nutritional standards was reached within the first month and complete restoration within the second/third month.<br><br>CONCLUSIONS: On the basis of our experience enteral nutrition represents an effective refeeding procedure in patients with chronic neurological diseases.}, }
@article {pmid16495003, year = {2006}, author = {Cova, E and Cereda, C and Galli, A and Curti, D and Finotti, C and Di Poto, C and Corato, M and Mazzini, G and Ceroni, M}, title = {Modified expression of Bcl-2 and SOD1 proteins in lymphocytes from sporadic ALS patients.}, journal = {Neuroscience letters}, volume = {399}, number = {3}, pages = {186-190}, doi = {10.1016/j.neulet.2006.01.057}, pmid = {16495003}, issn = {0304-3940}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*pathology ; Blotting, Western/methods ; Case-Control Studies ; Gene Expression Regulation/drug effects/*physiology ; Humans ; Hydrogen Peroxide/pharmacology ; Lymphocytes/drug effects/*metabolism ; Proto-Oncogene Proteins c-bcl-2/*metabolism ; Superoxide Dismutase/*metabolism ; Superoxide Dismutase-1 ; Time Factors ; }, abstract = {Markers of oxidative stress have been found in spinal cord, cortex, cerebrospinal fluid, and plasma of SALS patients. Mitochondrial and calcium metabolism dysfunction were also found in peripheral lymphocytes from SALS patients. In this study, we demonstrate that lymphocytes from SALS patients are more prone to undergo alteration of cell membrane integrity both in basal conditions and following oxidative stress induced by H2O2 treatment. The expression of the antioxidant proteins, Bcl-2, SOD1 and catalase in basal conditions, was significantly lower in lymphocytes from SALS patients than in lymphocytes from age and sex matched controls. Exposure to H2O2 induced a time-dependent decrease of Bcl-2 and SOD1 in control lymphocytes. Conversely, the levels of these proteins remained unchanged in SALS lymphocytes even after 18 h stress. Catalase expression was not significantly modified by oxidative stress. Our results demonstrate that two factors involved in the genesis and/or progression of the familial form of the disease with SOD1 mutation are altered also in the sporadic form of ALS and suggest that the oxidative stress protection pathway is deregulated in lymphocytes from ALS patients.}, }
@article {pmid16491745, year = {2005}, author = {Marzegalli, M and Oltrona, L and Corrada, E and Fontana, G and Klugmann, S}, title = {[The network for the management of acute coronary syndromes in Milan: results of a four-year experience and perspectives of the prehospital and interhospital cardiological network].}, journal = {Italian heart journal : official journal of the Italian Federation of Cardiology}, volume = {6 Suppl 6}, number = {}, pages = {49S-56S}, pmid = {16491745}, issn = {1129-471X}, mesh = {*Advanced Cardiac Life Support ; Ambulances ; Angioplasty, Balloon, Coronary ; *Coronary Care Units ; Electric Countershock ; Electrocardiography ; *Emergency Medical Services ; Humans ; Italy ; Myocardial Infarction/diagnosis/*therapy ; Patient Transfer ; *Telemedicine ; Telephone ; Time Factors ; Ventricular Fibrillation/therapy ; }, abstract = {In patients with acute ST-elevation myocardial infarction (STEMI), in order to shorten the time to definitive treatment, it is essential to coordinate the intervention between the local healthcare system and the hospitals. In 1999, a Working Group for Prehospital Emergency in Cardiology was established in Milan, and a network for 12-lead ECG transmission between advances life support (ALS) ambulances, the headquarter of 118 Rescue Service and the Coronary Care Units (CCU) or Divisions of Cardiology was developed: between February 1, 2001 and May 1, 2005, 6821 patients with suspected heart attack were rescued and their ECG recorded and transmitted (177 patients/month, 20% of them with an ST-segment shift, 11% ST-segment elevation, 9% non-ST-segment elevation, 24% with normal ECG). The rate of false positive automatic diagnosis of acute myocardial infarction was 0.3%, the rate of false negative was 0.8%. Forty-six patients with ventricular fibrillation underwent DC-shock. After May 1, 2004, clinical data of patients with STEMI transferred to the hospitals by ALS ambulances were reported in a database: 82% of the 89 patients were treated with primary angioplasty. The time (median, interquartile ranges) between ECG arrival to the CCU and the ECG report was 2 min (1-5), between ECG arrival to the CCU and patient arrival to the hospital was 34 min (24-42), between ECG arrival to the CCU and primary angioplasty was 69 min (50-93); the door-to-balloon time was 33 min (22-60). The telephone ECG transmission has been demonstrated to be a useful and rapid tool, easy to use; the automatic ECG diagnosis was accurate. In patients with STEMI the telephone ECG transmission shortened the time of delivery of therapy, helped to recover arrhythmic complications, allowed both the coordination between the 118 System and the Divisions of Cardiology and the implementation of the triage for primary angioplasty. Increasing the technological level of the service will be the next step of the program: the protocol will be upgraded in order to increase the number of patients rescued, to shorten the time of operation and to administer prehospital fibrinolytic therapy in selected patients.}, }
@article {pmid16490414, year = {2006}, author = {Pittenger, C and Krystal, JH and Coric, V}, title = {Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder.}, journal = {NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {3}, number = {1}, pages = {69-81}, pmid = {16490414}, issn = {1545-5343}, support = {K05 AA 14906-01/AA/NIAAA NIH HHS/United States ; }, mesh = {Antidepressive Agents, Tricyclic/therapeutic use ; Brain/anatomy &amp; histology/pathology ; Excitatory Amino Acid Antagonists/*therapeutic use ; Glutamic Acid/cerebrospinal fluid/*physiology ; Humans ; Magnetic Resonance Imaging ; Obsessive-Compulsive Disorder/classification/*drug therapy/*physiopathology ; }, abstract = {Obsessive-compulsive disorder (OCD) is a common psychiatric disorder that produces significant morbidity. The introduction of serotonin reuptake inhibitors in the 1980s represented an important advance in the treatment of OCD. However, few patients show complete remission of their symptoms, and some patients show minimal improvement with existing treatments. We review current treatment strategies and initial data supporting the efficacy of glutamate modulating agents as a novel class of pharmaceuticals for the treatment of OCD. Functional neuroimaging studies repeatedly reported metabolic hyperactivity in the cortico-striato-thalamo-cortical circuitry in patients with OCD. Recent magnetic resonance spectroscopy studies provide evidence of elevated glutamate levels in several brain regions in patients suffering from OCD. These findings raised the possibility that agents that reduce glutamate hyperactivity or its consequences in the CNS might be efficacious as novel therapeutic interventions. Indeed, initial evidence from our group suggests that the antiglutamatergic agent riluzole (Rilutek), which was developed for the treatment of amyotrophic lateral sclerosis, is effective in treatment-resistant OCD. Case reports suggest that other agents that modulate glutamatergic activity may likewise be effective. This new application of glutamate modulating agents holds promise for the treatment of this disabling and often inadequately treated disease.}, }
@article {pmid16467855, year = {2006}, author = {Mesters, JR and Barinka, C and Li, W and Tsukamoto, T and Majer, P and Slusher, BS and Konvalinka, J and Hilgenfeld, R}, title = {Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and prostate cancer.}, journal = {The EMBO journal}, volume = {25}, number = {6}, pages = {1375-1384}, pmid = {16467855}, issn = {0261-4189}, mesh = {Amino Acid Sequence ; Binding Sites ; Crystallography, X-Ray ; Enzyme Inhibitors/chemistry/metabolism ; Glutamate Carboxypeptidase II/antagonists &amp; inhibitors/*chemistry/metabolism ; Glutamic Acid/chemistry/metabolism ; Glycosylation ; Humans ; Hydrolysis ; Male ; Models, Molecular ; Molecular Sequence Data ; *Neurons/enzymology/pathology ; Prostatic Neoplasms/*enzymology/pathology ; Protein Conformation ; Protein Folding ; Recombinant Proteins/chemistry/isolation &amp; purification/metabolism ; }, abstract = {Membrane-bound glutamate carboxypeptidase II (GCPII) is a zinc metalloenzyme that catalyzes the hydrolysis of the neurotransmitter N-acetyl-L-aspartyl-L-glutamate (NAAG) to N-acetyl-L-aspartate and L-glutamate (which is itself a neurotransmitter). Potent and selective GCPII inhibitors have been shown to decrease brain glutamate and provide neuroprotection in preclinical models of stroke, amyotrophic lateral sclerosis, and neuropathic pain. Here, we report crystal structures of the extracellular part of GCPII in complex with both potent and weak inhibitors and with glutamate, the product of the enzyme's hydrolysis reaction, at 2.0, 2.4, and 2.2 A resolution, respectively. GCPII folds into three domains: protease-like, apical, and C-terminal. All three participate in substrate binding, with two of them directly involved in C-terminal glutamate recognition. One of the carbohydrate moieties of the enzyme is essential for homodimer formation of GCPII. The three-dimensional structures presented here reveal an induced-fit substrate-binding mode of this key enzyme and provide essential information for the design of GCPII inhibitors useful in the treatment of neuronal diseases and prostate cancer.}, }
@article {pmid16457195, year = {2005}, author = {Shibazaki, S and Nagai, M and Fuchigami, H and Nishina, M and Ohta, A and Kawamura, T and Ohno, Y}, title = {[Chronological analysis of individually linked data for patients with intractable disease receiving public financial aid for treatment].}, journal = {[Nihon koshu eisei zasshi] Japanese journal of public health}, volume = {52}, number = {12}, pages = {1009-1020}, pmid = {16457195}, issn = {0546-1766}, mesh = {Catastrophic Illness/*economics ; Chronology as Topic ; Data Collection ; Female ; Financial Support ; Health Care Costs/statistics &amp; numerical data ; Humans ; Japan ; Male ; Medical Assistance/*economics ; National Health Programs/*statistics &amp; numerical data ; Public Assistance/statistics &amp; numerical data ; }, abstract = {PURPOSE: Nationwide surveys of intractable disease patients receiving public financial aid for treatment were performed by Research Committee for Epidemiology of Intractable Disease (Ministry of Health and Welfare, Japan) 4 times in the past, in 1984, 1988, 1992 and 1997. The purpose of the present study was to clarify the features of continuance with intractable disease patients receiving public financial aid for treatment.<br><br>METHODS: Individual information collected by each nationwide survey was linked using the disease, the residence, the sex, and the birth date. The proportion of intractable disease patients according to receipt duration, kind of medical insurance, sex and age was calculated with reference to the disease and an estimation of the receipt persistence rate was calculated for every year. Moreover, in consideration of variation in the data, average receipt persistence rates over years were also calculated.<br><br>RESULTS: According to observation on individual patient's follow up, the proportion for which financial aid was discontinued within four years was 25%, while 70% continued receiving aid for at least four years and some 55% for eight or nine years. The proportion of those who continue receiving support long-term is high about the so-called autoimmune diseases, such as systemic lupus erythematosus, Beh&#xe7;et's disease, and the aortic syndrome. In contrast, with diseases having a poor prognosis, such as fulminant hepatitis, amyloidosis, and amyotrophic lateral sclerosis, periods of continuance are short. The proportion needing long-term continuation is higher in women than in men, especially with diseases which have long been eligible for support. However, with diseases for which receipt was started recently, there is a tendency for persistence to be higher in men than in women.<br><br>CONCLUSION: With reform of insurance systems, including the medical system for intractable diseases, it is predicted that receipt continuation will change with alteration of social factors, and it is necessary to monitor receipt continuation carefully from now on.}, }
@article {pmid16450149, year = {2006}, author = {Müller, W and Fiebich, BL and Stratz, T}, title = {[5-HT3 receptor antagonist als analgetics in rheumatic diseases].}, journal = {Zeitschrift fur Rheumatologie}, volume = {65}, number = {6}, pages = {546, 548-52}, pmid = {16450149}, issn = {0340-1855}, mesh = {Analgesics/*therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; Dose-Response Relationship, Drug ; Humans ; Indoles/*therapeutic use ; Pain Measurement ; Pain Threshold/drug effects ; Rheumatic Diseases/*drug therapy ; *Serotonin 5-HT3 Receptor Antagonists ; Serotonin Antagonists/*therapeutic use ; Tropisetron ; }, abstract = {Various rheumatic diseases like fibromyalgia, systemic inflammatory rheumatic disorders and localized diseases, such as arthritides and activated arthroses, tendinopathies and periarthropathies, as well as trigger points can be improved considerably by treatment with the 5-HT3 receptor antagonist tropisetron. Particularly in the latter group of diseases, local injections have done surprisingly rapid analgesic action. This effect matches that of local anesthetics, but lasts considerably longer and is comparable to local injections of local anesthetics combined with corticosteroids. The action of the 5-HT3 receptor antagonists can be attributed to an antinociceptive effect that occurs at the same time as an antiphlogistic and probably also an immunosuppressive effect. Whereas an inhibited release of substance P from the nociceptors, and possibly some other neurokins as well, seems to be the most likely explanation for the antinociceptive action, the antiphlogistic effect is primarily due to an inhibited formation of various different phlogistic substances; in some conditions, like systemic inflammatory rheumatic diseases, for example, the 5-HT3 receptor antagonists may exert an immunosuppressive effect in addition to this.}, }
@article {pmid16445350, year = {2006}, author = {Sheta, EA and Appel, SH and Goldknopf, IL}, title = {2D gel blood serum biomarkers reveal differential clinical proteomics of the neurodegenerative diseases.}, journal = {Expert review of proteomics}, volume = {3}, number = {1}, pages = {45-62}, doi = {10.1586/14789450.3.1.45}, pmid = {16445350}, issn = {1744-8387}, mesh = {Biomarkers/blood/chemistry ; Biometry ; Electrophoresis, Gel, Two-Dimensional ; Humans ; Neurodegenerative Diseases/*blood/immunology/*metabolism ; *Proteomics ; }, abstract = {This review addresses the challenges of neuroproteomics and recent progress in biomarkers and tests for neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The review will discuss how the application of quantitative 2D gel electrophoresis, combined with appropriate single-variable and multivariate biostatistics, allows for selection of disease-specific serum biomarkers. It will also address how the use of large cohorts of specifically targeted patient blood serum samples and complimentary age-matched controls, in parallel with the use of selected panels of these biomarkers, are being applied to the development of blood tests to specifically address unmet pressing needs in the differential diagnosis of these diseases, and to provide potential avenues for mechanism-based drug targeting and treatment monitoring. While exploring recent findings in this area, the review discusses differences in critical pathways of immune/inflammation and amyloid formation between Parkinson's disease and amyotrophic lateral sclerosis, as well as discernable synergistic relationships between these pathways that are revealed by this approach. The potential for pathway measurement in blood tests for differential diagnosis, disease burden and therapeutic monitoring is also outlined.}, }
@article {pmid16437474, year = {2006}, author = {Ashworth, NL and Satkunam, LE and Deforge, D}, title = {Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {1}, pages = {CD004156}, doi = {10.1002/14651858.CD004156.pub3}, pmid = {16437474}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; *Exercise Therapy ; Humans ; Muscle Spasticity/etiology/*therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Spasticity commonly affects patients with motor neuron disease. It is likely to contribute to worsening muscle dysfunction, increased difficulty with activities of daily living and deteriorating quality of life.<br><br>OBJECTIVES: The objective of this review is to systematically review treatments for spasticity in amyotrophic lateral sclerosis, also known as motor neuron disease.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (January 2003 and January 2005), MEDLINE (January 1966 to February 2005), EMBASE (January 1980 to February 2005), CINAHL (January 1982 to February 2005), AMED (January 1985 to February 2005) and LILACS (January 1982 to January 2003). We reviewed the bibliographies of the randomized controlled trials identified, and contacted authors and experts in the field.<br><br>SELECTION CRITERIA: We included quasi-randomized or randomized controlled trials of participants with probable or definite amyotrophic lateral sclerosis according to the El Escorial diagnostic criteria (or a revised version) or the Airlie House revision. We would have included trials of physical therapy, modalities, prescription medications, non-prescription medications, chemical neurolysis, surgical interventions, and alternative therapies. Our primary outcome measure was reduction in spasticity at three months or greater as measured by the Ashworth (or modified Ashworth) spasticity scale. Our secondary outcome measures were: validated measures based on history, physical examination, physiological measures, measures of function, measures of quality of life, serious adverse events, and measures of cost.<br><br>DATA COLLECTION AND ANALYSIS: We identified only one randomized controlled trial that met our inclusion criteria. Two authors extracted the data. We also contacted the author of the paper and obtained information not available in the published article.<br><br>MAIN RESULTS: The included study was a trial of moderate intensity, endurance type exercise versus 'usual activities' in 25 patients with amyotrophic lateral sclerosis. At three months patients performing the 15 minute twice daily exercises had significantly less spasticity overall (mean reduction of -0.43, 95% CI -1.03 to +0.17 in the treatment group versus an increase of +0.25, 95% CI -0.46 to +0.96 in control) but the mean change between groups was not significant (-0.68, 95% CI -1.62 to +0.26), as measured by the Ashworth scale.<br><br>AUTHORS' CONCLUSIONS: The single trial performed was too small to determine whether individualised moderate intensity endurance type exercises for the trunk and limbs are beneficial or harmful. No other medical, surgical or alternative treatment and therapy has been evaluated in a randomized fashion in this patient population. More research is needed.}, }
@article {pmid16426523, year = {2006}, author = {Borderías-Clau, L and Garrapiz-López, J and Val-Adán, P and Tordesillas-Lía, C and Alcacera-López, A and Bru-Martín, JL}, title = {[Strong suspicion of lung toxicity due to riluzole].}, journal = {Archivos de bronconeumologia}, volume = {42}, number = {1}, pages = {42-44}, doi = {10.1016/s1579-2129(06)60113-4}, pmid = {16426523}, issn = {0300-2896}, mesh = {Aged ; Excitatory Amino Acid Antagonists/*adverse effects ; Humans ; Lung Diseases/*chemically induced ; Male ; Riluzole/*adverse effects ; }, abstract = {Riluzole is a drug used in the treatment of amyotrophic lateral sclerosis. To date, reports of lung toxicity have been exceptional. We present the case of a 74-year-old man diagnosed with amyotrophic lateral sclerosis. Following 3, 5 months of treatment with riluzole (Rilutek), the patient began to present a clinical picture consisting of nonproductive cough, progressive dyspnea (even with slight exertion), weakness, and radiologic progression with the appearance of predominantly peripheral bilateral pulmonary infiltrates that did not respond to treatment with amoxicillin-clavulanic acid. Bacterial tests did not reveal the presence of germs, nor did other examinations suggest an alternative diagnosis. The patient did not resume treatment with the drug or undergo complementary procedures aimed at obtaining histologic samples. Nevertheless, the coincidence in time, lack of response to antibiotic treatment, remission of symptoms following withdrawal of the drug without initiating any other treatment except 40 mg/d of methylprednisolone for 6 days, absence of alternative diagnoses, and suggestive clinical and radiologic findings all together point to toxicity due to riluzole.}, }
@article {pmid16425674, year = {2006}, author = {Orrell, RW}, title = {AEOL-10150 (Aeolus).}, journal = {Current opinion in investigational drugs (London, England : 2000)}, volume = {7}, number = {1}, pages = {70-80}, pmid = {16425674}, issn = {1472-4472}, mesh = {Animals ; Antioxidants/adverse effects/chemistry/pharmacokinetics/*therapeutic use ; Clinical Trials as Topic ; Humans ; Lung Diseases/drug therapy ; Metalloporphyrins/adverse effects/chemistry/pharmacology/*therapeutic use ; Molecular Structure ; Neoplasms/drug therapy ; Nervous System Diseases/drug therapy ; Neuroprotective Agents/adverse effects/chemistry/pharmacology/*therapeutic use ; Structure-Activity Relationship ; Treatment Outcome ; }, abstract = {AEOL-10150, a small-molecule antioxidant analogous to the catalytic site of superoxide dismutase, is under development by Aeolus (formerly Incara) as a potential subcutaneous treatment for amyotrophic lateral sclerosis (ALS), stroke, spinal cord injury, lung inflammation and mucositis. The compound is currently undergoing a phase I clinical trial for ALS. In October 2005, the company had applied for Fast Track status, and planned to submit a special protocol assessment for a pivotal phase II/III trial.}, }
@article {pmid16425672, year = {2006}, author = {Iłzecka, J}, title = {Does VEGF represent a potential treatment for amyotrophic lateral sclerosis?.}, journal = {Current opinion in investigational drugs (London, England : 2000)}, volume = {7}, number = {1}, pages = {54-59}, pmid = {16425672}, issn = {1472-4472}, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*therapy ; Animals ; *Genetic Therapy ; Humans ; Motor Neurons/metabolism ; *Stem Cell Transplantation ; *Vascular Endothelial Growth Factor A/biosynthesis/genetics/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. The pathogenesis of ALS is unclear and there is no effective treatment. Vascular endothelial growth factor (VEGF) is a cytokine that has a protective function via angiogenic, neurotrophic, gliotrophic and anti-apoptotic activity. Data indicate that VEGF can inhibit neurodegeneration in ALS and may have therapeutic potential in this disease. The use of gene therapy to deliver VEGF into the central nervous system is being evaluated.}, }
@article {pmid16401852, year = {2006}, author = {Meininger, V and Asselain, B and Guillet, P and Leigh, PN and Ludolph, A and Lacomblez, L and Robberecht, W and , }, title = {Pentoxifylline in ALS: a double-blind, randomized, multicenter, placebo-controlled trial.}, journal = {Neurology}, volume = {66}, number = {1}, pages = {88-92}, doi = {10.1212/01.wnl.0000191326.40772.62}, pmid = {16401852}, issn = {1526-632X}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy ; Double-Blind Method ; Drug Interactions/physiology ; Drug Therapy, Combination ; Female ; Humans ; Male ; Middle Aged ; Muscle Weakness/drug therapy/etiology ; Neuroprotective Agents/administration &amp; dosage/adverse effects ; Pentoxifylline/*administration &amp; dosage/adverse effects ; Phosphodiesterase Inhibitors/administration &amp; dosage/adverse effects ; Placebos ; Riluzole/*administration &amp; dosage/adverse effects ; Treatment Failure ; }, abstract = {OBJECTIVE: To assess the efficacy and safety of pentoxifylline, a US Food and Drug Administration-approved drug, in patients with ALS treated with riluzole.<br><br>METHODS: The authors conducted a double-blind, randomized, placebo-controlled, multicenter trial. Four hundred patients with probable or definite ALS and vital capacity less than 100% were randomly assigned to treatment with placebo or 1.2 g pentoxifylline daily. The primary outcome was death. Secondary outcomes were rates of deterioration of ALS Functional Rating Scale-Respiratory and muscle strength. The primary intention-to-treat analysis was the survival comparison of drug vs placebo, assessed before (log-rank test) and after adjustment (Cox model) for predefined prognostic factors.<br><br>RESULTS: At the end of the study, after 547 days of follow-up, 103 patients (51.7%) in the pentoxifylline group and 120 (59.7%) in the placebo group were alive (unadjusted risk 1.28, p = 0.107; adjusted risk 1.43, p = 0.02). In contrast, analysis of secondary outcome functional variables did not show the same negative effect of the drug. The most common adverse reactions were nausea, dysphagia, and flushing, all reversible after stopping the drug.<br><br>CONCLUSIONS: Pentoxifylline is not beneficial in ALS and should be avoided in patients treated with riluzole. The discrepancy between survival and measures of functional changes urges caution in equating these end points in phase III trials, and suggests that both survival and function should be used in phase III trials.}, }
@article {pmid16383239, year = {2005}, author = {He, J and Chen, ZX and Xue, YQ and Pan, JL and He, HL and Li, JQ and Wu, YF and Huang, YP and Zhu, LL}, title = {[Study on clinical and biological characteristics of childhood acute leukemia with MLL gene rearrangements].}, journal = {Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi}, volume = {26}, number = {8}, pages = {477-480}, pmid = {16383239}, issn = {0253-2727}, mesh = {Adolescent ; Child ; Child, Preschool ; Female ; *Gene Rearrangement ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Leukemia/*genetics ; Male ; Myeloid-Lymphoid Leukemia Protein/*genetics ; }, abstract = {OBJECTIVE: To study the clinical and laboratory features of childhood acute leukemia (AL) with MLL gene rearrangements.<br><br>METHODS: Sixteen of 298 cases of childhood AL with MLL rearrangements were studied by using MLL dual-color FISH, multiplex RT-PCR with 13 pairs of primers in combination with R banding karyotype analysis and cell immunophenotyping by flow cytometry.<br><br>RESULTS: Sixteen cases of childhood AL with MLL rearrangements accounted for 5.4% of 298 AL patients, and 56.3% of infant ALs. Among 106 cases analyzed by multiplex RT-PCR, MLL gene rearrangements were found in 11 cases, including MLL/AF4 fusion gene in 2, MLL/AF6 fusion gene in 1, MLL/AF6 and MLL/ELL combined with MLL/ AFX or HOX11 in one case each, MLL/AF9 in 2, MLL/AF10 in 1, MLL/ELL in 2. MLL partial tandem duplication in 1 and activated HOX11 in 1. In 27 cases assayed by FISH, 9 cases (36.0%) were demonstrated MLL gene rearrangements. In 16 patients with MLL gene rearrangements, 14 (87.5%) exhibited clonal chromosome abnormalities involved chromosome 11 in 11 cases: being t(4;11) in 2, t(6;11), t(8;11), t(7;8;11), t(9;11) in each trisomy 11 in 2 and 11q--in 3 cases. Among these 16 patients, 11 were B-ALL, and 5 AML-M5, 3 of the latter were CD7+ and CD2+. Of these 16 patients, 8 received chemotherapy and 7 of them achieved complete remission, while the other 8 patients gave up treatment.<br><br>CONCLUSION: Multiplex RT-PCR combined with FISH provided a more accurate and sensitive method for detection of MLL gene rearrangements. Finding out MLL gene rearrangement is of most importance in guiding therapy and predicting prognosis in childhood AL.}, }
@article {pmid16382340, year = {2005}, author = {Kitzberger, R and Madl, C and Ferenci, P}, title = {Wilson disease.}, journal = {Metabolic brain disease}, volume = {20}, number = {4}, pages = {295-302}, pmid = {16382340}, issn = {0885-7490}, mesh = {Animals ; Brain/pathology ; Copper/metabolism ; Hepatolenticular Degeneration/diagnosis/*metabolism/pathology/psychology ; Humans ; Liver/metabolism ; }, abstract = {Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism, resulting in pathological accumulation of copper in many organs and tissues. The hallmarks of the disease are the presence of liver disease, neurologic symptoms, and Kayser-Fleischer corneal rings. The leading neurologic symptoms in WD are dysathria, dyspraxia, ataxia, and Parkinsonian-like extrapyramidal signs. Changes in the basal ganglia in brain magnetic resonance imaging (MRI) are characteristic features of the disease. In presence of liver cirrhosis, some features may resemble hepatic encephalopathy. Symptoms and MRI abnormalities may be fully reversible on treatment with zinc or copper chelators. Improvement can be monitored by serial recording of brain-stem-evoked responses. The basic defect is an impaired trafficking of copper in hepatocytes. ATP7B is the gene product of the WD gene located on chromosome 13 and resides in hepatocytes in the trans-Golgi network, transporting copper into the secretory pathway for incorporation into apoceruloplasmin and excretion into the bile. While about 40% of patients preset with neurologic symptoms, little is known about the role of copper and ATP7B in the central nervous system. In some brain areas, like in the pineal gland, ATP7B is expressed and functionally active. Increasing evidence supports an important role for metals in neurobiology. Two proteins related to neurodegeneration are copper-binding proteins (1) the amyloid precursor protein (APP), a protein related to Alzheimer's disease, and (2) the Prion protein, related to Creutzfeldt-Jakob disease. A major source of free-radical production in the brain derives from copper. To prevent metal-mediated oxidative stress, cells have evolved complex metal transport systems. APP is a major regulator of neuronal copper homeostasis and has a copper-binding domain (CuBD). The surface location of this site, structural homology of CuBD to copper chaperones, and the role of APP in neuronal copper homeostasis are consistent with the CuBD acting as a neuronal metallotransporter. There are several copper-containing enzymes in the brain, like dopamine beta hydroxylase or Cu/Zn superoxide dismutase (SOD1). Their function may be altered because of copper overload. WD appears to be associated with a dopaminergic deficit. Mutations in the SOD1gene cause familial amyotrophic lateral sclerosis. Survival of transgenic mice with a mutant SOD1 which fails to incorporate Cu((2+)) in its active site was improved by copper depletion. Wilson disease (WD) is an autosomal recessive inherited disorder in which copper pathologically accumulates primarily within the liver and subsequently in the neurologic system and many other organs and tissues. Presence of liver disease, neurologic symptoms, and Kayser-Fleischer corneal rings are the hallmarks of the disease.}, }
@article {pmid16362828, year = {2005}, author = {Rocha, JA and Reis, C and Simões, F and Fonseca, J and Mendes Ribeiro, J}, title = {Diagnostic investigation and multidisciplinary management in motor neuron disease.}, journal = {Journal of neurology}, volume = {252}, number = {12}, pages = {1435-1447}, pmid = {16362828}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/genetics/physiopathology/therapy ; Bulbar Palsy, Progressive ; Diagnosis, Differential ; Diagnostic Imaging/methods ; Electrophysiology/methods ; Humans ; Motor Neuron Disease/classification/*diagnosis/*therapy ; Muscle Weakness/etiology ; Neurologic Examination ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Spinocerebellar Degenerations ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. ALS is a progressive neurodegenerative disorder, involving motor neurons in the cerebral cortex, brainstem and spinal cord, presenting with a combination of upper and lower motor neuron signs. Etiology remains undetermined, although a multifactorial origin is widely accepted including genetic factors, auto-immunity, oxidative stress, glutamate excitotoxicity and abnormal neurofilament aggregation. The absence of specific diagnostic testing, and variable clinical presentations make the diagnosis of ALS challenging, relying upon correlation of clinical, electrophysiological and neuroimaging data. The disease is relentlessly progressive, with dysarthria, dysphagia, tetraparesis, and respiratory insufficiency due to ongoing respiratory muscle paresis. There is no specific treatment for ALS. Riluzole, a glutamate antagonist, is the only FDA approved drug for ALS, but has only a modest effect on survival. The multiplicity and progressiveness of the disabilities in ALS, highlights the need for a coordinated multidisciplinary rehabilitation program managing symptoms, respiratory care, dysphagia and nutrition, dysarthria and communication, physical and occupational therapy. The main goals are to prolong independence, prevent complications and improve quality of life.}, }
@article {pmid16361608, year = {2006}, author = {Waragai, M and Chiba, A and Uchibori, A and Fukushima, T and Anno, M and Tanaka, K}, title = {Anti-Ma2 associated paraneoplastic neurological syndrome presenting as encephalitis and progressive muscular atrophy.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {77}, number = {1}, pages = {111-113}, pmid = {16361608}, issn = {0022-3050}, mesh = {Adult ; Anti-Inflammatory Agents/therapeutic use ; Antibodies, Neoplasm/*immunology ; Antigens, Neoplasm/*immunology ; Brain/*pathology ; Diagnosis, Differential ; Drug Therapy, Combination ; Encephalitis/*diagnosis ; Humans ; Immunoglobulins, Intravenous/therapeutic use ; Magnetic Resonance Imaging ; Male ; Methylprednisolone/therapeutic use ; Muscular Atrophy, Spinal/*diagnosis ; Nerve Tissue Proteins/*immunology ; Paraneoplastic Syndromes, Nervous System/*diagnosis/drug therapy/*immunology ; }, abstract = {A 36 year old man with a history of testicular germ cell tumour presented six months after bilateral orchidectomy with progressive amnesia, irritability, vertical gaze palsy, and generalised seizures. Eight months after initial onset of symptoms, he demonstrated a head drop with muscular atrophy of the upper limbs, shoulder girdle, and posterior neck. He reported no sensory disturbances and his sensory examination was normal. The overall clinical presentation was consistent with motor neurone disease. Cerebrospinal fluid analysis revealed mild pleocytosis and increased protein concentration. Serum and cerebrospinal fluid were positive for the anti-Ma2 antibody by western blot analysis and immunostaining. Abnormal high signal in the grey matter was noted in the cervical spinal cord and brain by T2 weighted magnetic resonance imaging (MRI). The patient was treated with corticosteroids, intravenous immunoglobulin, and antiepileptic medication. The patient improved clinically and symptom progression ceased after initiation of treatment. There was complete resolution of the abnormal brain MRI lesions; however, the cervical spinal cord MRI lesion and muscular atrophy remained unchanged. It is suggested that the anti-Ma2 antibody is involved not only in encephalitis, but may also play a role in the cervical spinal cord lesions resulting in a motor neurone disease-like presentation.}, }
@article {pmid16358333, year = {2006}, author = {Banno, H and Adachi, H and Katsuno, M and Suzuki, K and Atsuta, N and Watanabe, H and Tanaka, F and Doyu, M and Sobue, G}, title = {Mutant androgen receptor accumulation in spinal and bulbar muscular atrophy scrotal skin: a pathogenic marker.}, journal = {Annals of neurology}, volume = {59}, number = {3}, pages = {520-526}, doi = {10.1002/ana.20735}, pmid = {16358333}, issn = {0364-5134}, mesh = {Adult ; Aged ; Antineoplastic Agents, Hormonal/administration &amp; dosage ; Cell Count/methods ; Creatine Kinase/metabolism ; Humans ; Immunohistochemistry/methods ; Leuprolide/administration &amp; dosage ; Male ; Middle Aged ; Muscular Atrophy, Spinal/*genetics/*pathology ; *Mutation ; Peptides/metabolism ; Receptors, Androgen/*genetics/metabolism ; Scrotum/*pathology ; Skin/drug effects/*metabolism/pathology ; Spinal Cord/metabolism/pathology ; Statistics as Topic ; Time Factors ; }, abstract = {OBJECTIVE: Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The nuclear accumulation of mutant AR is central to the pathogenesis of SBMA. Androgen deprivation with leuprorelin inhibits mutant AR accumulation, resulting in rescue of neuronal dysfunction in a mouse model of SBMA. This study aimed to investigate whether mutant AR accumulation in the scrotal skin is an appropriate biomarker of SBMA.<br><br>METHODS: Immunohistochemistry of both scrotal skin and the spinal cord was performed on five autopsied SBMA cases. Neurological severity and scrotal skin findings were studied in another 13 patients. Five other patients received subcutaneous injections of leuprorelin and underwent scrotal skin biopsy.<br><br>RESULTS: The degree of mutant AR accumulation in scrotal skin epithelial cells tended to be correlated with that in the spinal motor neurons in autopsy specimens, and it was well correlated with CAG repeat length and inversely correlated with the amyotrophic lateral sclerosis functional scale. Leuprorelin treatment inhibited mutant AR protein accumulation in the scrotal skin of SBMA patients.<br><br>INTERPRETATION: These observations suggest that scrotal skin biopsy findings are a potent pathogenic marker of SBMA and can be a surrogate end point in therapeutic trials.}, }
@article {pmid16356650, year = {2006}, author = {Koh, SH and Lee, SM and Kim, HY and Lee, KY and Lee, YJ and Kim, HT and Kim, J and Kim, MH and Hwang, MS and Song, C and Yang, KW and Lee, KW and Kim, SH and Kim, OH}, title = {The effect of epigallocatechin gallate on suppressing disease progression of ALS model mice.}, journal = {Neuroscience letters}, volume = {395}, number = {2}, pages = {103-107}, doi = {10.1016/j.neulet.2005.10.056}, pmid = {16356650}, issn = {0304-3940}, mesh = {Amyotrophic Lateral Sclerosis/*prevention &amp; control ; Animals ; Blotting, Western ; Caspase 3 ; Caspases/drug effects/metabolism ; Catechin/*analogs &amp; derivatives/therapeutic use ; Disease Models, Animal ; Disease Progression ; Glycogen Synthase Kinase 3/drug effects/metabolism ; Glycogen Synthase Kinase 3 beta ; Humans ; Mice ; Mice, Transgenic ; Motor Activity/*drug effects ; Mutation ; Neuroprotective Agents/*therapeutic use ; Phosphatidylinositol 3-Kinases/drug effects/metabolism ; Spinal Cord/drug effects ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Epigallocatechin gallate (EGCG) is a constituent of green tea, and increasing evidence suggests that EGCG has neuroprotective effects on oxidative stress-injured neuronal cells, especially motoneurons. Although the neuroprotective effects of EGCG have been demonstrated in Parkinson's and Alzheimer's diseases and ischemic stroke models, there has been no report on the effect of EGCG on an in vivo model of amyotrophic lateral sclerosis (ALS). This study was undertaken to evaluate the effect of EGCG on ALS model mice with the human G93A mutated Cu/Zn-superoxide dismutase (SOD1) gene. We treated each group of 11 ALS model mice with EGCG (1.5, 2.9, and 5.8 microg/g body weight), dissolved in 0.5 ml of 0.9% sterile NaCl, and one group of 11 with 0.5 ml of 0.9% sterile NaCl (control group) intraorally every day after 60 days of age (presymptomatic treatment). The treatment of more than 2.9 microg EGCG/g body weight significantly prolonged the symptom onset and life span, preserved more survival signals, and attenuated death signals. These data suggest that EGCG could be a potential therapeutic candidate for ALS as a disease-modifying agent.}, }
@article {pmid16341066, year = {2005}, author = {Zhou, J and Neale, JH and Pomper, MG and Kozikowski, AP}, title = {NAAG peptidase inhibitors and their potential for diagnosis and therapy.}, journal = {Nature reviews. Drug discovery}, volume = {4}, number = {12}, pages = {1015-1026}, doi = {10.1038/nrd1903}, pmid = {16341066}, issn = {1474-1776}, mesh = {Animals ; Glutamate Carboxypeptidase II/*antagonists &amp; inhibitors ; Humans ; Male ; Nervous System Diseases/diagnosis/drug therapy ; Prostatic Neoplasms/diagnosis/drug therapy ; Protease Inhibitors/chemistry/*therapeutic use ; }, abstract = {Modulation of N-acetyl-L-aspartyl-L-glutamate peptidase activity with small-molecule inhibitors holds promise for a wide variety of diseases that involve glutamatergic transmission, and has implications for the diagnosis and therapy of cancer. This new class of compounds, of which at least one has entered clinical trials and proven to be well tolerated, has demonstrated efficacy in experimental models of pain, schizophrenia, amyotrophic lateral sclerosis, traumatic brain injury and, when appropriately functionalized, can image prostate cancer. Further investigation of these promising drug candidates will be needed to bring them to the marketplace. The recent publication of the X-ray crystal structure for the enzymatic target of these compounds should facilitate the development of other new agents with enhanced activity that could improve both the diagnosis and treatment of neurological disorders.}, }
@article {pmid16326257, year = {2006}, author = {Vesely, MR and Kelemen, MD}, title = {Cardiac risk assessment: matching intensity of therapy to risk.}, journal = {Cardiology clinics}, volume = {24}, number = {1}, pages = {67-78}, doi = {10.1016/j.ccl.2005.09.010}, pmid = {16326257}, issn = {0733-8651}, mesh = {Age Distribution ; Aged ; Aged, 80 and over ; Critical Care/organization &amp; administration/standards ; *Electrocardiography ; Emergency Service, Hospital/*organization &amp; administration ; Female ; Guidelines as Topic/standards ; Humans ; Incidence ; Male ; Middle Aged ; Myocardial Infarction/diagnosis/epidemiology/*therapy ; Prognosis ; Risk Assessment/*methods ; Sensitivity and Specificity ; Severity of Illness Index ; Sex Distribution ; Survival Rate ; Thrombolytic Therapy/methods ; }, abstract = {Simple RSS allow for rapid decision making in the emergency department. The data presented in this article suggest that for patients at the highest risk and the lowest risk for complications of NSTEACS, the scoring systems work well and allow effective triage and treatment. For patients at intermediate risk (30%-40% of all patients who have ACS), however, it is not clear whether early aggressive treatment with cardiac catheterization or routine conservative management should be the standard of care. The consensus guidelines are vague, and the scoring systems discriminate less well for these patients. The authors think that patients at intermediate risk are best served by initial screening with an RSS like the TRS (with risk scores of 3-4), followed by a multimarker strategy to define risk better. They also think that the next step is to design clinical trials to test strategies of care defined prospectively by risk. This step would, in the authors' opinion, begin the next round of the cycle of clinical therapeutics [31]. The treatment of patients who have NSTE ACS has been characterized in the past 2 decades by care based on evidence from many excellent clinical tri-als. The consensus panels have convened and guide patient management. Quality-improvement initiatives such as CRUSADE and GRACE give feedback to improve compliance with guidelines. The understanding of risk is developing with the help of these scoring systems. Discovery is ongoing. The next decade of acute cardiac care will focus on early identification of patients at high risk and on matching the most intensive treatments to the patients most in need. Excessive testing and care promotes cost inefficiency and, perhaps, increased hazard for some patients. New trials are needed to move these new hypotheses back into practice.}, }
@article {pmid16325011, year = {2005}, author = {Pekarik, V}, title = {Design of shRNAs for RNAi-A lesson from pre-miRNA processing: possible clinical applications.}, journal = {Brain research bulletin}, volume = {68}, number = {1-2}, pages = {115-120}, doi = {10.1016/j.brainresbull.2005.08.007}, pmid = {16325011}, issn = {0361-9230}, mesh = {Animals ; Humans ; Huntington Disease/*genetics ; MicroRNAs/*genetics ; *RNA Interference ; RNA Processing, Post-Transcriptional ; Spinocerebellar Ataxias/*genetics ; }, abstract = {RNA interference has become the tool of choice to analyse the loss-of-function of individual genes and has been exploited to identify complex regulatory pathways following genomic screening. RNAi has both admirers and detractors, but is undeniably a technique with great potential, which has come a long way in the short time since its discovery. RNAi utilises cellular machinery associated with the processing of naturally occurring micro RNA (miRNAs). Effective use of RNAi requires detailed knowledge of the individual steps and the proteins involved, as well as the similarities and distinctions between miRNA and siRNA pathways. RNAi was originally induced by the introduction of long double stranded RNAs (dsRNAs) into cells in which the RNA was cleaved into short RNAs which effectively interfered with a transcription of cognate mRNA. More recently an introduction of short approximately 22 nucleotide RNA duplexes has become the standard in short-term experiments, but is insufficient for long-term knock-down assays. Long-term expression of siRNAs has been achieved by in vivo transcription from plasmids coding for short hairpin RNAs (shRNAs). The cellular processing of shRNAs shares common features with the biogenesis of naturally occurring miRNA such as cleavage by nuclear RNase Drosha, export from the nucleus, processing by a cytoplasmic RNase Dicer, and incorporation into the RNA-induced silencing complex (RISC). Each step has a crucial influence on the efficiency of RNAi and their consideration should be a part of a standard experimental design. RNAi has moved from a purely experimental technique to the stage of potential clinical applications. The possible use of RNAi in the treatment of spinocerebellar ataxia or amyotrophic lateral sclerosis, with its advantages and pitfalls and possible extensions to other diseases are discussed.}, }
@article {pmid16324529, year = {2005}, author = {Valdés Chavarri, M and Pascual Figal, D and Prósper Cardoso, F and Moreno Montañés, J and García Olmos, D and Barcia Albacar, JA}, title = {[Regenerative medicine with adult stem cells].}, journal = {Revista clinica espanola}, volume = {205}, number = {11}, pages = {556-564}, doi = {10.1016/s0014-2565(05)72638-2}, pmid = {16324529}, issn = {0014-2565}, mesh = {Brain Diseases/surgery ; Heart Diseases/surgery ; Humans ; Nerve Regeneration ; Regenerative Medicine/methods ; *Stem Cell Transplantation ; }, abstract = {The present state of clinical regenerative medicine with adult stem cells in the cardiology, digestive, corneal and neurological fields are reviewed. From the cardiology point of view, there is clinical experience with bone marrow stem cells and peripheral blood cells and with skeletal myoblasts. At present, the adult stem cells (bone marrow hematopoietic or mesenchymal) constitute the best option for the regeneration of heart tissue, the clinical studies showing favorable results without ethical or safety problems. Most of the studies with skeletal myoblasts have also been demonstrated to significantly contribute to improve heart function, above all, the systolic one. However they have the disadvantage that has not been totally clarified that they induce malignant ventricular arrhythmias. In either case, the clinical studies are in the initial phase and new studies, above all randomized, are necessary. In the digestive field, there is the pioneer experience of the Hospital La Paz on the use of stem cells from abdominal fat in the treatment of fistulous condition of patients with Crohn's disease. In ophthalmology, the limbal corneal transplant is a recognized practice, using cells from the contralateral eye when the damage is in a single eye and cells from a donor when the damage is bilateral. Finally, in the neurological field, different zones of the adult mammal brain where there are stem cells have been identified: the hippocampus, subventricular zone, olfactory bulb and periependymal zone of the spinal cord. On the other hand, neurons may be obtained from adult stem cells from other tissues, such as the bone marrow or adipose tissue, which means a practically unendable source of neural precursors, either by direct implant after their selection or after their in vitro culture. However, most of the experimentation is animal up to now, clinical trails on safety in amyotrophic lateral sclerosis are now being initiated.}, }
@article {pmid16323214, year = {2006}, author = {Tortarolo, M and Grignaschi, G and Calvaresi, N and Zennaro, E and Spaltro, G and Colovic, M and Fracasso, C and Guiso, G and Elger, B and Schneider, H and Seilheimer, B and Caccia, S and Bendotti, C}, title = {Glutamate AMPA receptors change in motor neurons of SOD1G93A transgenic mice and their inhibition by a noncompetitive antagonist ameliorates the progression of amytrophic lateral sclerosis-like disease.}, journal = {Journal of neuroscience research}, volume = {83}, number = {1}, pages = {134-146}, doi = {10.1002/jnr.20715}, pmid = {16323214}, issn = {0360-4012}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality/pathology ; Animals ; Behavior, Animal/drug effects ; Benzodiazepines/pharmacokinetics/*therapeutic use ; Blotting, Western ; Choline O-Acetyltransferase/genetics/metabolism ; Dioxoles/pharmacokinetics/*therapeutic use ; Excitatory Amino Acid Antagonists/pharmacokinetics/*therapeutic use ; Humans ; Immunohistochemistry ; In Situ Hybridization ; Locomotion/drug effects/genetics/physiology ; Mice ; Mice, Transgenic ; Motor Neurons/*physiology ; Postural Balance/drug effects/physiology ; RNA, Messenger/biosynthesis/genetics ; Receptors, AMPA/*antagonists &amp; inhibitors/biosynthesis/genetics ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Survival ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder involving the selective degeneration of motor neurons. In a small proportion of patients, ALS is caused by mutations in copper/zinc superoxide dismutase (SOD1), and mice overexpressing SOD1(G93A) mutant develop a syndrome that closely resembles the human disease. Excitotoxicity mediated by glutamate AMPA receptors has been suggested to be implicated in the selective susceptibility of motor neurons occurring in ALS. In SOD1(G93A) mice, we found that levels of GluR2 AMPA subunit, which plays a pivotal role in the maintenance of calcium impermeability of AMPA receptors, are decreased in spinal motor neurons before symptom onset in concomitance with a modest increase of GluR3 expression, a calcium-permeable AMPA subunit. This effect can result in a higher number of calcium-permeable AMPA receptors on motor neurons of SOD1(G93A) mice, predisposing these cells to be injured by AMPA-mediated glutamate firing. In support of this, we showed that treatment with a new noncompetitive AMPA antagonist, ZK 187638, partially protected motor neurons, improved motor function, and prolonged the survival of SOD1(G93A) mice.}, }
@article {pmid16320313, year = {2006}, author = {Echaniz-Laguna, A and Degos, B and Mohr, M and Kessler, R and Urban-Kraemer, E and Tranchant, C}, title = {A study of three patients with amyotrophic lateral sclerosis and a polyneuropathy resembling CIDP.}, journal = {Muscle &amp; nerve}, volume = {33}, number = {3}, pages = {356-362}, doi = {10.1002/mus.20475}, pmid = {16320313}, issn = {0148-639X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications/genetics/*physiopathology ; Biomarkers ; Electromyography ; Electrophysiology ; Humans ; Male ; Middle Aged ; Motor Neurons/pathology ; Neural Conduction/physiology ; Neurologic Examination ; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/complications/genetics/*physiopathology ; Sciatic Nerve/pathology/physiopathology ; Spinal Cord/pathology ; }, abstract = {We report three patients with a syndrome that fulfilled clinical and laboratory criteria for definite chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who failed immunosuppressive treatment and eventually developed progressive amyotrophic lateral sclerosis (ALS). Mean disease duration was 23 months (13-38) before death. Two patients had a family history of ALS without mutations of the SOD1 gene. Postmortem examination in one patient showed an endoneurial infiltration of mononuclear cells in lumbar roots and distal and proximal peripheral nerves, mainly around myelinated fibers, with demyelination and axonal loss, consistent with CIDP. The spinal cord revealed severe neuronal loss in the anterior horn, axonal loss in the corticospinal tract, and large numbers of phagocytes in the anterior and lateral tracts, indicative of ALS. Whether demyelinating polyneuropathy was coincident with ALS or was a cause or consequence of motor neuron degeneration in these patients remains to be elucidated. This unusual combination may provide an important clue in elucidating the pathogenesis of ALS in some patients.}, }
@article {pmid16319023, year = {2005}, author = {de Carvalho, M and Costa, J and Swash, M}, title = {Clinical trials in ALS: a review of the role of clinical and neurophysiological measurements.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {6}, number = {4}, pages = {202-212}, doi = {10.1080/14660820510011997}, pmid = {16319023}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; *Clinical Trials as Topic ; Data Interpretation, Statistical ; Disease Progression ; Humans ; Neurophysiology ; Quality Control ; *Randomized Controlled Trials as Topic ; Reproducibility of Results ; Survival Rate ; Treatment Outcome ; }, abstract = {We have reviewed all the published clinical trials of ALS and, from those considered sufficiently large, and containing a control group, we have evaluated their methodology with regard to statistical power. This implies a critical analysis of the endpoint measurements. We have concluded that clinical endpoints used in clinical trials of ALS have frequently been insufficiently sensitive, non-linear, or even not intuitively highly relevant to the disease. We suggest that the ALS-FRS, perhaps also MUNE and the Neurophysiological Index, may be the best measures currently available. These techniques have complementary characteristics that allow them to be used to address different aspects of the disease and its treatment in various trials designs. In the past some trials may have failed to demonstrate a treatment effect because the chosen endpoint measures and the trial design were inappropriate.}, }
@article {pmid16314222, year = {2005}, author = {Ritch, R}, title = {Complementary therapy for the treatment of glaucoma: a perspective.}, journal = {Ophthalmology clinics of North America}, volume = {18}, number = {4}, pages = {597-609}, doi = {10.1016/j.ohc.2005.07.004}, pmid = {16314222}, issn = {0896-1549}, mesh = {Complementary Therapies/*methods ; Glaucoma/*drug therapy ; Humans ; *Phytotherapy ; Plant Preparations/*therapeutic use ; Treatment Outcome ; }, abstract = {Although neuroprotective strategies and pharmaceutical agents have been initiated in the treatment of numerous disorders of the central and peripheral nervous systems, including trauma, epilepsy, stroke, Huntington disease, amyotrophic lateral sclerosis,and AIDS dementia, none have yet been applied to the treatment of glaucoma. A prospective, placebo-controlled, multi-institutional trial of memantine is underway. One would not expect the treatment modalities that form the bases of nonpharmaceutical, traditional medical systems to be used to lower IOP. Glaucoma was unknown when these medicinal treatments were developed over the centuries. Their primary use is in improving the cardiovascular and immune systems and in what is now called neuro-protection. Rather than single compounds that target a specific receptor and have demarcated side effects in other systems, plant products are a blend of many compounds and, according to those most versed in them, they achieve a balanced therapy, helping in specific symptomatic complexes while reducing side effects through ameliorating effects in other areas. It is not insignificant that, now that the rain forests are rapidly dwindling, together with their inhabitants and the knowledge of medicinal plants (especially in South America), the pharmaceutical companies are spending large amounts of money in a sudden, almost frantic attempt to gather the knowledge about rainforest plants before all has been completely lost. Proof of effects clinically in a chronic disease such as glaucoma remains largely lacking, and controlled trials are unlikely to be initiated, except perhaps through the National Institutes of Health, because these compounds have been in the public domain for many years. Perhaps those as yet unknown or un-recorded are patentable and perhaps these include drugs known only to small surviving communities of hunter-gatherers, which explains the pharmaceutical interest in these areas. When more accurate and rapid means of assessment of progression of glaucomatous damage than perimetry and optic nerve head photography are eventually developed and trials can be reduced in time, number of subjects, or even the use of nonhuman subjects for the bulk of studies, studies could be done for verification of effect of various compounds and also comparative studies. At the present time, GBE is the best documented of all the complementary medicinal agents and seems to have the greatest potential value. Ginkgo biloba extract has numerous properties that theoretically should be beneficial in treating non-IOP-dependent mechanisms in glaucoma. Its multi-ple beneficial actions, including increased ocular blood flow, antioxidant activity, platelet activating factor inhibitory activity, nitric oxide inhibition, and neuroprotective activity, combine to suggest that GBE could prove to be of major therapeutic value in the treatment of glaucoma.}, }
@article {pmid16302734, year = {2005}, author = {Goto, S and Kaneko, T and Miyamoto, Y and Eriguchi, M and Kato, A and Akeyama, T and Fujimoto, K and Tomonaga, M and Egawa, K}, title = {Combined immunocell therapy using activated lymphocytes and monocyte-derived dendritic cells for malignant melanoma.}, journal = {Anticancer research}, volume = {25}, number = {6A}, pages = {3741-3746}, pmid = {16302734}, issn = {0250-7005}, mesh = {Adult ; Aged ; Antigens, Neoplasm/immunology ; Dendritic Cells/cytology/*immunology ; Epitopes/immunology ; Female ; HLA-A Antigens/immunology ; Humans ; Immunotherapy, Adoptive/*methods ; Lymphocyte Activation ; Male ; Melanoma/*immunology/*therapy ; Middle Aged ; Monocytes/cytology/immunology ; Retrospective Studies ; T-Lymphocytes, Cytotoxic/*immunology ; }, abstract = {BACKGROUND: The beneficial effects of immunocell therapy, using either activated lymphocytes (ALs) or dendritic cells (DCs), in the treatment of melanoma has been demonstrated. DCs are professional antigen-presenting cells that induce cytotoxic T lymphocytes against tumor cells. DC therapy may be promising when combined with ALs.<br><br>PATIENTS AND METHODS: Patients with advanced melanoma, who underwent immunocell therapy with both ALs and DCs, were reviewed. DCs were pulsed with tumor lysates, peptides or both.<br><br>RESULTS: Side-effects were occasional slight fever and skin erythema. Among 8 of the 14 patients treated with immunocell therapy alone, 1 showed a mixed response (MR) and 1 prolonged stable disease (SD). In the remaining 6 patients treated with immunocell therapy and other conventional therapies, 1 CR, 1 MR and 1 prolonged SD for 24 months were observed.<br><br>CONCLUSION: Combined immunocell therapy was well tolerated and showed a relatively high tumor response. This treatment may have therapeutic potential for some refractory malignancies.}, }
@article {pmid16296872, year = {2005}, author = {Dib, M}, title = {Issues for clinical drug development in neurodegenerative diseases.}, journal = {Drugs}, volume = {65}, number = {17}, pages = {2463-2479}, pmid = {16296872}, issn = {0012-6667}, mesh = {Animals ; Biomarkers ; Clinical Trials as Topic ; Genetic Predisposition to Disease ; Humans ; Neurodegenerative Diseases/*drug therapy/genetics/physiopathology ; Neuroprotective Agents ; Survival Analysis ; Treatment Outcome ; }, abstract = {Neurodegenerative diseases pose specific challenges for drug development. These diseases typically have a slow and variable clinical course, an insidious onset, and symptom expression is only observed when a significant proportion of neurons are already lost. It is important to identify vulnerability factors and other determinants of clinical course in order to be able in the future to select patient populations for clinical trials with a predictable prognosis. The neurodegenerative process itself is not amenable to direct observation and, thus, cannot be monitored in clinical trials. For this reason, surrogate biomarkers are required for use as outcome parameters. In this respect, magnetic resonance imaging has proved valuable for assessing disease activity and progression in multiple sclerosis. Rating scales are of use as outcome measures but, as these generally measure symptom severity, they are most appropriate for use in assessing symptomatic treatments. Survival has been used with success as an outcome measure in trials in amyotrophic lateral sclerosis, where disease progression is rapid. The optimal outcome measure, the sample size required and the treatment duration need to be chosen in relation to the phase of the disease. Potential new treatments can be chosen based upon new knowledge of the genetics and physiopathology of neurodegenerative diseases and, in some cases, screened in transgenic mouse models, although it should be recognised that the validity of these models in terms of treatment response has yet to be established empirically.}, }
@article {pmid16289867, year = {2006}, author = {Petri, S and Kiaei, M and Kipiani, K and Chen, J and Calingasan, NY and Crow, JP and Beal, MF}, title = {Additive neuroprotective effects of a histone deacetylase inhibitor and a catalytic antioxidant in a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {22}, number = {1}, pages = {40-49}, doi = {10.1016/j.nbd.2005.09.013}, pmid = {16289867}, issn = {0969-9961}, support = {P30 NS047546/NS/NINDS NIH HHS/United States ; P30 NS047546-02/NS/NINDS NIH HHS/United States ; R01 NS040819/NS/NINDS NIH HHS/United States ; R01 NS040819-05A2/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylation/drug effects ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/physiopathology ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Apoptosis/drug effects/physiology ; Cytoprotection/*drug effects/physiology ; Disease Models, Animal ; Drug Synergism ; Drug Therapy, Combination ; Enzyme Inhibitors/*pharmacology/therapeutic use ; Female ; *Histone Deacetylase Inhibitors ; Histone Deacetylases/metabolism ; Humans ; Male ; Metalloporphyrins/pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; Nerve Degeneration/*drug therapy/physiopathology/prevention &amp; control ; Neuroprotective Agents/*pharmacology/therapeutic use ; Oxidative Stress/drug effects/physiology ; Phenylbutyrates/pharmacology/therapeutic use ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Treatment Outcome ; Up-Regulation/drug effects/physiology ; }, abstract = {ALS is a devastating neurodegenerative disorder for which no effective treatment exists. Multiple molecular mechanisms are involved in the pathogenesis. We tested the catalytic antioxidant AEOL 10150, the histone deacetylase inhibitor phenylbutyrate (PBA), and the combination of PBA and AEOL 10150 in the G93A transgenic mouse model, administered from disease onset. AEOL 10150 alone improved motor function and extended survival by 11%, PBA alone significantly improved motor function and extended survival by 13%. PBA and AEOL 10150 together increased survival by 19%. Increased histone acetylation was confirmed by Western blot. Quantitative real-time RT-PCR analysis revealed upregulation of compounds capable of protecting cells against oxidative stress and apoptosis. Markers of oxidative damage were reduced in the lumbar spinal cord as compared to vehicle administration. These results suggest that agents inhibiting apoptosis and blocking oxidative stress show efficacy in treating mutant-SOD1-associated ALS and that a combination of agents targeting different disease mechanisms may exert additive therapeutic effects.}, }
@article {pmid16288180, year = {2005}, author = {Lefaucheur, JP}, title = {[Transcranial magnetic stimulation: applications in neurology].}, journal = {Revue neurologique}, volume = {161}, number = {11}, pages = {1121-1130}, doi = {10.1016/s0035-3787(05)85182-3}, pmid = {16288180}, issn = {0035-3787}, mesh = {Brain Diseases/*diagnosis ; Brain Mapping ; Evoked Potentials, Motor/physiology ; Humans ; Neural Conduction/physiology ; Neurology/*methods ; Neuronal Plasticity/physiology ; Transcranial Magnetic Stimulation/*instrumentation/methods ; }, abstract = {INTRODUCTION: Transcranial magnetic stimulation (TMS) was first applied to assess conduction time along the corticospinal tract, namely by recording motor evoked potentials.<br><br>STATE OF ART: At present, TMS techniques include cortical excitability and mapping studies using single or paired-pulse paradigms on the one hand, and repetitive TMS to induce cortical plasticity and to modify brain function on the other hand. TMS is a valuable, non-invasive tool in the diagnosis and the pathophysiological assessment of cortical dysfunction involved in various neurological diseases (multiple sclerosis, myelopathy, amyotrophic lateral sclerosis, movement disorders, epilepsy, stroke).<br><br>PERSPECTIVES AND CONCLUSION: In the near future, repetitive TMS could have therapeutic applications in neurology (epilepsy, stroke rehabilitation program) as is already the case in some psychiatric diseases. However, most of the new indications for treatment with cortical stimulation will be based on surgically-implanted neuromodulation procedures.}, }
@article {pmid16282199, year = {2006}, author = {Perk, CG and Mercer, AR}, title = {Dopamine modulation of honey bee (Apis mellifera) antennal-lobe neurons.}, journal = {Journal of neurophysiology}, volume = {95}, number = {2}, pages = {1147-1157}, doi = {10.1152/jn.01220.2004}, pmid = {16282199}, issn = {0022-3077}, mesh = {Animals ; Animals, Newborn ; Bees/*physiology ; Calcium/*metabolism ; Dopamine/*pharmacology ; Membrane Potentials/drug effects/*physiology ; Neurons, Afferent/drug effects/*physiology ; Olfactory Bulb/drug effects/*physiology ; Potassium/*metabolism ; Smell/drug effects/*physiology ; }, abstract = {Primary olfactory centers [antennal lobes (ALs)] of the honey bee brain are invaded by dopamine (DA)-immunoreactive neurons early in development (pupal stage 3), immediately before a period of rapid growth and compartmentalization of the AL neuropil. Here we examine the modulatory actions of DA on honey bee AL neurons during this period. Voltage-clamp recordings in whole cell configuration were used to determine the effects of DA on ionic currents in AL neurons in vitro from pupal bees at stages 4-6 of the nine stages of metamorphic adult development. In approximately 45% of the neurons tested, DA (5-50 x 10(-5) M) reduced the amplitude of outward currents in the cells. In addition to a slowly activating, sustained outward current, DA reduced the amplitude of a rapidly activating, transient outward conductance in some cells. Both of the currents modulated by DA could be abolished by the removal of Ca2+ from the external medium or by treatment of cells with charybdotoxin (2 x 10(-8) M), a blocker of Ca2+-dependent K+ currents in the cells. Ca2+ currents were not affected by DA, nor were A-type K+ currents (I(A)). Results suggest that the delayed rectifier-like current (I(KV)) also remains intact in the presence of DA. Taken together, our data indicate that Ca2+-dependent K+ currents are targets of DA modulation in honey bee AL neurons. This study lends support to the hypothesis that DA plays a role in the developing brain of the bee.}, }
@article {pmid16280684, year = {2005}, author = {Nirmalananthan, N and Greensmith, L}, title = {Amyotrophic lateral sclerosis: recent advances and future therapies.}, journal = {Current opinion in neurology}, volume = {18}, number = {6}, pages = {712-719}, doi = {10.1097/01.wco.0000187248.21103.c5}, pmid = {16280684}, issn = {1350-7540}, support = {G84/6699/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/metabolism/*therapy ; Animals ; Biomedical Research ; Docosahexaenoic Acids/classification/*therapeutic use ; Drug Evaluation, Preclinical ; Forecasting ; Humans ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis is a rare but fatal motoneuron disorder. Despite intensive research riluzole remains the only available therapy, with only marginal effects on survival. Here we review some of the recent advances in the search for a disease-modifying therapy for amyotrophic lateral sclerosis.<br><br>RECENT FINDINGS: A number of established agents have recently been re-investigated for their potential as neuroprotective agents, including beta-lactam antibiotics and minocycline. Progress has also been made in exploiting growth factors for the treatment of amyotrophic lateral sclerosis, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, heat-shock protein co-inducers, which upregulate cell stress responses thereby mediating neuroprotection. Non-drug-based therapies are also under development, with progress in gene-silencing and stem cell therapies.<br><br>SUMMARY: In the past few years, significant advances have been made in both our understanding of amyotrophic lateral sclerosis pathogenesis and the development of new therapeutic approaches. However, caution must be exercised in view of the long-standing failure to successfully transfer therapeutic compounds to the clinic. A deeper awareness in the research community of the need for clinically relevant preclinical studies, coupled with a better understanding of the issues surrounding clinical trial design for amyotrophic lateral sclerosis, offers hope that the growing list of validated preclinical therapeutics can finally yield an effective disease-modifying treatment.}, }
@article {pmid16274998, year = {2006}, author = {Ganel, R and Ho, T and Maragakis, NJ and Jackson, M and Steiner, JP and Rothstein, JD}, title = {Selective up-regulation of the glial Na+-dependent glutamate transporter GLT1 by a neuroimmunophilin ligand results in neuroprotection.}, journal = {Neurobiology of disease}, volume = {21}, number = {3}, pages = {556-567}, doi = {10.1016/j.nbd.2005.08.014}, pmid = {16274998}, issn = {0969-9961}, support = {NS 40151/NS/NINDS NIH HHS/United States ; NS3395/NS/NINDS NIH HHS/United States ; NS36465/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Brain/drug effects/metabolism ; Disease Models, Animal ; Excitatory Amino Acid Transporter 2/*drug effects/metabolism ; Female ; Immunoblotting ; Ligands ; Male ; Mice ; Mice, Transgenic ; Neuroglia/drug effects/*metabolism ; Neuroprotective Agents/*pharmacology ; Organ Culture Techniques ; Pyrrolidines/*pharmacology ; Rats ; Spinal Cord/drug effects/metabolism ; Tacrolimus Binding Proteins/metabolism ; Up-Regulation ; }, abstract = {Excessive accumulation of extracellular glutamate results in neuronal death. Termination of synaptic glutamate transmission and the prevention of excitotoxicity depend on rapid removal of glutamate by high affinity Na+-dependent transporters. The astroglial transporter GLT1 is the predominant subtype, responsible for the bulk of extracellular clearance and for limiting excitotoxicity. This protein is crucial in the prevention of chronic glutamate neurotoxicity, and is markedly decreased in amyotrophic lateral sclerosis (ALS). Recent studies have shown that GLT1 expression can be induced in vitro and in vivo by various factors, but little is known about the signaling pathways mediating its regulation. The FK506-binding protein (FKBP) immunophilins are ubiquitous cytosolic proteins, concentrated in neural tissue (neuroimmunophilins). GPI-1046 is a synthetic, nonimmunosuppressive derivative of FK506 shown to exert neuroprotective and neuroregenerative actions in several systems. In the present study, we demonstrated that GPI-1046 induces selective expression of GLT1 in vitro and in vivo, associated with a marked increase in DHK-sensitive Na+-dependent glutamate transport. Furthermore, treatment with GPI-1046 was shown to protect motor neurons in an in vitro model of chronic excitotoxicity, and to prolong the survival of transgenic ALS mice. These studies suggest that neuroimmunophilins can regulate GLT1 and that their ligands could serve as therapies for neurodegenerative disorders.}, }
@article {pmid16262676, year = {2005}, author = {Wang, R and Zhang, D}, title = {Memantine prolongs survival in an amyotrophic lateral sclerosis mouse model.}, journal = {The European journal of neuroscience}, volume = {22}, number = {9}, pages = {2376-2380}, doi = {10.1111/j.1460-9568.2005.04431.x}, pmid = {16262676}, issn = {0953-816X}, support = {DE015129/DE/NIDCR NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Animals ; Disease Models, Animal ; Excitatory Amino Acid Antagonists/*therapeutic use ; Gene Expression Regulation/drug effects ; Humans ; Immunohistochemistry/methods ; Memantine/*therapeutic use ; Mice ; Mice, Transgenic ; Receptors, N-Methyl-D-Aspartate/metabolism ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase/genetics ; Survival Analysis ; Time Factors ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which results from selective loss of upper and lower motor neurons. Mouse models of ALS, such as one carrying the G93A mutant of the human Cu-Zn superoxide dismutase gene[SOD1(G93A)], develop motor neuron pathology and clinical symptoms similar to those observed in ALS patients. There is compelling evidence that both direct and indirect glutamate toxicity contribute to the pathogenesis of motor neuron degeneration. However, the therapeutic effect of various glutamate receptor antagonists has not been clearly demonstrated. Memantine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. It has been shown to protect neurons against NMDA- or glutamate-induced toxicity in vitro and in animal models of neurodegenerative diseases. In the current study, we have examined the therapeutic efficacy of memantine in an ALS mouse model carrying a high copy number of SOD1(G93A). Memantine treatment significantly delayed the disease progression and increased the life span of SOD1(G93A) mice, from 121.4 +/- 5.5 to 129.7 +/- 4.5 days (P = 0.032). Furthermore, NMDA receptor subunits were reliably detected in the spinal cord of SOD1(G93A) mice and their expression levels were similar to those in the wild-type littermate control. Therefore, the neuroprotective effect of memantine in SOD1(G93A) mice is most probably due to the inhibition of spinal cord NMDA receptors. In view of the long-term usage of memantine for dementia patients, with excellent tolerance and safety, these data suggest that memantine may be used in ALS patients alone or in combination with other therapies to prolong survival.}, }
@article {pmid16248371, year = {2005}, author = {Fukae, J and Motoi, Y and Komatsuzaki, Y and Takanashi, M and Mochizuki, H and Mizuno, Y}, title = {[A 59-year-old woman with personality change and abnormal behavior followed by amyotrophy and dementia].}, journal = {No to shinkei = Brain and nerve}, volume = {57}, number = {9}, pages = {810-820}, pmid = {16248371}, issn = {0006-8969}, mesh = {Amyotrophic Lateral Sclerosis/complications/pathology/*psychology ; *Behavior ; Brain/*pathology ; Dementia/complications/pathology/*psychology ; Diagnosis, Differential ; Female ; Humans ; Middle Aged ; *Personality ; }, abstract = {We report a 59-year-old woman with generalized amyotrophy and dementia. She showed personality change at 53 years of age. When she was 56 years old, she began to show abnormal and violent behaviors. At age 58, she developed dysphagia and amyotrophy of upper limbs. She was admitted to a hospital for the treatment of aspiration pneumonia. She was severely demented and showed pseudobulbar palsy, amyotrophy of tongues, weakness of upper limbs, and pyramidal signs. She was still able to walk by herself. Dementia, pseudobulbar palsy, and amyotrophy progressed rapidly. At age 59, she became bed ridden and required tube feeding. She died by aspiration pneumonia at age 59. The patient was discussed at a neurological CPC and the chief discussant arrived at the conclusion that the patient had ALS dementia. Other possibility discussed was Pick's disease with amyotrophy. Post-mortem examination revealed severe lower motor neuron degeneration. The upper motor neurons were unaffected. Neuronal loss was not observed in the cerebral cortex, but moderate gliosis was seen in the cerebral white matter. In addition, the substantia nigra was moderately degenerated. There were ubiquitin positive neuronal inclusions in the granular cells of the dentate gyrus. Also, Bunina bodies were seen in the neurons of spinal anterior horns. These findings were characteristic pathology for ALS with dementia.}, }
@article {pmid16242643, year = {2005}, author = {Fernandez-Gomez, FJ and Gomez-Lazaro, M and Pastor, D and Calvo, S and Aguirre, N and Galindo, MF and Jordán, J}, title = {Minocycline fails to protect cerebellar granular cell cultures against malonate-induced cell death.}, journal = {Neurobiology of disease}, volume = {20}, number = {2}, pages = {384-391}, doi = {10.1016/j.nbd.2005.03.019}, pmid = {16242643}, issn = {0969-9961}, mesh = {Animals ; Animals, Newborn ; Apoptosis/*drug effects/physiology ; Cardiolipins/drug effects/metabolism ; Caspases/drug effects/metabolism ; Cells, Cultured ; Cerebellar Cortex/drug effects/metabolism/pathology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/toxicity ; Glutathione/metabolism ; Malonates/*antagonists &amp; inhibitors/toxicity ; Minocycline/*pharmacology ; Nerve Degeneration/chemically induced/*drug therapy/prevention &amp; control ; Neurons/*drug effects/metabolism/pathology ; Neuroprotective Agents/*pharmacology ; Neurotoxins/antagonists &amp; inhibitors/toxicity ; Oxidative Stress/drug effects/physiology ; Proto-Oncogene Proteins c-bcl-2/drug effects/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Succinate Dehydrogenase/antagonists &amp; inhibitors/metabolism ; }, abstract = {Experimental and clinical studies support the view that the semisynthetic tetracycline minocycline exhibits neuroprotective roles in several models of neurodegenerative diseases, including ischemia, Huntington, Parkinson diseases, and amyotrophic lateral sclerosis. However, recent evidence indicates that minocycline does not always present beneficial actions. For instance, in an in vivo model of Huntington's disease, it fails to afford protection after malonate intrastriatal injection. Moreover, it reverses the neuroprotective effect of creatine in nigrostriatal dopaminergic neurons. This apparent contradiction prompted us to analyze the effect of this antibiotic on malonate-induced cell death. We show that, in rat cerebellar granular cells, the succinate dehydrogenase inhibitor malonate induces cell death in a concentration-dependent manner. By using DFCA, monochlorobimane and 10-N-nonyl-Acridin Orange to measure, respectively, H2O2-derived oxidant species and reduced forms of GSH and cardiolipin, we observed that malonate induced reactive oxygen species (ROS) production to an extent that surpasses the antioxidant defense capacity of the cells, resulting in GSH depletion and cardiolipin oxidation. The pre-treatment for 4 h with minocycline (10-100 microM) did not present cytoprotective actions. Moreover, minocycline failed to block ROS production and to abrogate malonate-induced oxidation of GSH and cardiolipin. Additional experiments revealed that minocycline was also unsuccessful to prevent the mitochondrial swelling induced by malonate. Furthermore, malonate did not induce the expression of the iNOS, caspase-3, -8, and -9 genes which have been shown to be up-regulated in several models where minocycline resulted cytoprotective. In addition, malonate-induced down-regulation of the antiapoptotic gene Bcl-2 was not prevented by minocycline, controversially the mechanism previously proposed to explain minocycline protective action. These results suggest that the minocycline protection observed in several neurodegenerative disease models is selective, since it is absent from cultured cerebellar granular cells challenged with malonate.}, }
@article {pmid16242126, year = {2005}, author = {Hemendinger, R and Wang, J and Malik, S and Persinski, R and Copeland, J and Emerich, D and Gores, P and Halberstadt, C and Rosenfeld, J}, title = {Sertoli cells improve survival of motor neurons in SOD1 transgenic mice, a model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {196}, number = {2}, pages = {235-243}, doi = {10.1016/j.expneurol.2005.07.025}, pmid = {16242126}, issn = {0014-4886}, mesh = {Amyotrophic Lateral Sclerosis/*surgery ; Animals ; Blotting, Western/methods ; Cell Count ; Cell Survival/physiology ; Cells, Cultured ; Choline O-Acetyltransferase/metabolism ; DNA/analysis ; *Disease Models, Animal ; Female ; Functional Laterality ; GATA4 Transcription Factor/metabolism ; Gene Expression Regulation/physiology ; Humans ; Immunohistochemistry/methods ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/*physiology/transplantation ; Nerve Growth Factors/metabolism ; Sertoli Cells/*physiology/*transplantation ; Spinal Cord/cytology/surgery ; Superoxide Dismutase/genetics ; }, abstract = {Cell replacement therapy has been widely suggested as a treatment for multiple diseases including motor neuron disease. A variety of donor cells have been tested for treatment including isolated preparations from bone marrow and embryonic spinal cord. Another cell source, Sertoli cells, have been successfully used in models of diabetes, Parkinson's disease and Huntington's disease. The ability of these cells to secrete cytoprotective proteins and their role as 'nurse cells' supporting the function of other cell types in the testes suggest their potential use as neuroprotective cells. The current study examines the ability of Sertoli cells injected into the parenchyma of the spinal cord to protect motor neurons in a mouse model for amyotrophic lateral sclerosis. Seventy transgenic mice expressing the mutant (G93A) human Cu-Zn superoxide dismutase (SOD1) received a unilateral spinal injection of Sertoli-enriched testicular cells into the L4-L5 ventral horn (1 x 10(5) cells total) prior to the onset of clinical symptoms. The animals were euthanized at the end stage of the disease. Histological and morphometric analyses of the transplant site were performed. A significant increase in the number of surviving ChAT positive motor neurons was found ipsilateral to the injection compared with contralateral and uninjected spinal cord. The ipsilateral increase in motor neuron density was dependent upon proximity to the injection site. Sections rostral or caudal to the injection site did not display a similar difference in motor neuron density. Implantation of a Sertoli-cell-enriched preparation has a significant neuroprotective benefit to vulnerable motor neurons in the SOD1 transgenic model. The therapeutic benefit may be the result of secreted neurotrophic factors present at a critical stage of motor neuron degeneration in this model.}, }
@article {pmid16240489, year = {2005}, author = {Novakovic, KE and Villemagne, VL and Rowe, CC and Masters, CL}, title = {Rare genetically defined causes of dementia.}, journal = {International psychogeriatrics}, volume = {17 Suppl 1}, number = {}, pages = {S149-94}, doi = {10.1017/s1041610205002012}, pmid = {16240489}, issn = {1041-6102}, mesh = {Amyotrophic Lateral Sclerosis/complications ; Dementia/complications/diagnosis/*genetics ; Diagnosis, Differential ; Energy Metabolism/physiology ; Gerstmann-Straussler-Scheinker Disease/genetics ; Humans ; Huntington Disease/complications ; Insomnia, Fatal Familial/complications/genetics ; Lipoproteins/metabolism ; Nerve Degeneration/complications ; Proteins/metabolism ; Spinocerebellar Ataxias/complications ; Supranuclear Palsy, Progressive/complications ; }, abstract = {Several genetic disorders, though rare, are associated or present with dementia. Developments in the field of genetics are contributing to clarify and expand our knowledge of the complex physiopathological mechanisms leading to neurodegeneration and cognitive decline. Disorders associated with misfolded and aggregated proteins and lipid, metal or energy metabolism are examples of the multifarious disease processes converging in the clinical features of dementia, either as its predominant feature, as in cases of Alzheimer's disease (AD) or frontotemporal dementia (FTD), or as part of a cohort of accompanying or late-developing symptoms, as in Parkinson's disease (PD) or amyotrophic lateral sclerosis with dementia (ALS-D). Awareness of these disorders, allied with recent advances in genetic, biochemical and neuroimaging techniques, may lead to early diagnosis, successful treatment and better prognosis.}, }
@article {pmid16235250, year = {2005}, author = {Narai, H and Nagano, I and Ilieva, H and Shiote, M and Nagata, T and Hayashi, T and Shoji, M and Abe, K}, title = {Prevention of spinal motor neuron death by insulin-like growth factor-1 associating with the signal transduction systems in SODG93A transgenic mice.}, journal = {Journal of neuroscience research}, volume = {82}, number = {4}, pages = {452-457}, doi = {10.1002/jnr.20668}, pmid = {16235250}, issn = {0360-4012}, mesh = {Analysis of Variance ; Animals ; Cell Count/methods ; Cell Death/drug effects ; Dose-Response Relationship, Drug ; Gene Expression Regulation/drug effects ; Humans ; Immunohistochemistry/methods ; Insulin Receptor Substrate Proteins ; Insulin-Like Growth Factor I/*pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/*drug effects ; Phosphoproteins/metabolism ; Receptor, IGF Type 1/metabolism ; Signal Transduction/*drug effects ; Spinal Cord/*cytology ; Superoxide Dismutase/*genetics ; }, abstract = {The role of insulin-like growth factor-1 (IGF-1) in amyotrophic lateral sclerosis (ALS) and its mechanism of action are important from both pathogenic and therapeutic points of view. The present study investigated the changes of IGF-1Rbeta and the key intracellular downstream protein insulin receptor substrate-1 (IRS-1) by using SOD1(G93A) transgenic mice with continuous intrathecal IGF-1 treatment. The number of lumbar spinal motor neurons was preserved with IGF-1 treatment in a dose-dependent manner. The numbers of immunopositive motor neurons for IGF-1Rbeta and IRS-1 were not significantly different between wild-type and Tg mice with vehicle treatment, whereas treatment of Tg mice with IGF-1 decreased the numbers of immunopositive motor neurons in a dose-dependent manner. On the other hand, the ratio of immunopositive motor neurons per total living motor neurons in vehicle-treated mice was greatly increased in Tg mice with vehicle treatment compared with wild-type mice. With IGF-1 treatment, the ratio was dramatically decreased in a dose-dependent manner. These results suggest that IGF-1 treatment prevents motor neuron loss by affecting the signal transduction system through IGF-1R and the main downstream signal, IRS-1.}, }
@article {pmid16235246, year = {2005}, author = {Tsuji, S and Kikuchi, S and Shinpo, K and Tashiro, J and Kishimoto, R and Yabe, I and Yamagishi, S and Takeuchi, M and Sasaki, H}, title = {Proteasome inhibition induces selective motor neuron death in organotypic slice cultures.}, journal = {Journal of neuroscience research}, volume = {82}, number = {4}, pages = {443-451}, doi = {10.1002/jnr.20665}, pmid = {16235246}, issn = {0360-4012}, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Analysis of Variance ; Animals ; Animals, Newborn ; Cell Count/methods ; Cell Death/drug effects ; Cell Survival/drug effects ; Chelating Agents/pharmacology ; Dose-Response Relationship, Drug ; Drug Interactions ; Egtazic Acid/analogs &amp; derivatives/pharmacology ; Gene Expression Regulation/drug effects ; Immunohistochemistry/methods ; Motor Neurons/cytology/*drug effects ; Neurites/drug effects/metabolism ; Neurofilament Proteins/classification/metabolism ; Organ Culture Techniques ; Proteasome Endopeptidase Complex/metabolism ; *Proteasome Inhibitors ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/*cytology ; Time Factors ; }, abstract = {A dysfunctional ubiquitin-proteasome system recently has been proposed to play a role in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We have shown previously that spinal motor neurons are more vulnerable to proteasome inhibition-induced neurotoxicity, using a dissociated culture system. To confirm this toxicity, we used organotypic slice cultures from rat neonatal spinal cords, which conserve the structure of the spinal cord in a horizontal plane, enabling us to identify motor neurons more accurately than in dissociated cultures. Furthermore, such easy identifications make it possible to follow up the course of the degeneration of motor neurons. When a specific proteasome inhibitor, lactacystin (5 microM), was applied to slice cultures, proteasome activity of a whole slice was suppressed below 30% of control. Motor neurons were selectively damaged, especially in neurites, with the increase of phosphorylated neurofilaments. They were eventually lost in a dose-dependent manner (1 microM, P < 0.05; 5 microM, P < 0.01). The low capacity of Ca(2+) buffering is believed to be one of the factors of selectivity for damaged motor neurons in ALS. In our system, negative staining of Ca(2+)-binding proteins supported this notion. An intracellular Ca(2+) chelator, BAPTA-AM (10 microM), exerted a significant protective effect when it was applied with lactacystin simultaneously (P < 0.01). We postulate that proteasome inhibition is an excellent model for studying the mechanisms underlying selective motor neuron death and searching for new therapeutic strategies in the treatment of ALS.}, }
@article {pmid16228969, year = {2006}, author = {Federici, T and Boulis, NM}, title = {Gene-based treatment of motor neuron diseases.}, journal = {Muscle &amp; nerve}, volume = {33}, number = {3}, pages = {302-323}, doi = {10.1002/mus.20439}, pmid = {16228969}, issn = {0148-639X}, support = {K08 NS43305/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/therapy ; Animals ; Apoptosis/physiology ; Gene Silencing ; *Genetic Therapy ; Genetic Vectors ; Humans ; Motor Neuron Disease/*therapy ; Muscular Atrophy, Spinal/therapy ; }, abstract = {Motor neuron diseases (MND), such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are progressive neurodegenerative diseases that share the common characteristic of upper and/or lower motor neuron degeneration. Therapeutic strategies for MND are designed to confer neuroprotection, using trophic factors, anti-apoptotic proteins, as well as antioxidants and anti-excitotoxicity agents. Although a large number of therapeutic clinical trials have been attempted, none has been shown satisfactory for MND at this time. A variety of strategies have emerged for motor neuron gene transfer. Application of these approaches has yielded therapeutic results in cell culture and animal models, including the SOD1 models of ALS. In this study we describe the gene-based treatment of MND in general, examining the potential viral vector candidates, gene delivery strategies, and main therapeutic approaches currently attempted. Finally, we discuss future directions and potential strategies for more effective motor neuron gene delivery and clinical translation.}, }
@article {pmid16220802, year = {2005}, author = {Oczakir, C and Balmer, S and Mericske-Stern, R}, title = {Implant-prosthodontic treatment for special care patients: a case series study.}, journal = {The International journal of prosthodontics}, volume = {18}, number = {5}, pages = {383-389}, pmid = {16220802}, issn = {0893-2174}, mesh = {Adult ; Aged ; Aged, 80 and over ; *Dental Care for Chronically Ill ; Dental Implantation, Endosseous ; *Dental Implants ; Dental Prophylaxis ; *Dental Prosthesis, Implant-Supported ; Female ; Humans ; Life Tables ; Male ; Middle Aged ; Oral Hygiene ; Survival Analysis ; }, abstract = {PURPOSE: The aim of the study was to assess implant survival and complications with implants and prostheses in patients exhibiting a variety of systemic diseases and congenital defects.<br><br>MATERIALS AND METHODS: Patients with specific medical conditions are regularly treated at the Department of Prosthodontics, University of Bern, Switzerland. All those who had received implant-prosthodontic treatment during the past 12 years were reexamined for this study. Among these patients the following diseases were observed: cleft lip/palate (n = 8), Down syndrome (n = 3), Sjogren syndrome and scleroderma (n = 2), ectodermal dysplasia (n = 4), developmental retardation (n = 2), chronic leukemia (n = 2), lichen planus (n = 1), cerebral palsy (n = 1), deaf-muteness (n = 1), amyotrophic lateral sclerosis (n = 1). At the time of the treatment the mean age was 55.6 years. ITI implants had been placed according to a standard protocol with local anesthesia, except for one patient in whom full anesthesia was used. One hundred three implants were loaded and supported a total of 34 fixed or removable prostheses. All patients were appointed to a regular maintenance care program. In the context of the present study, all but 1 patient were reexamined clinically. New radiographs were obtained, and the implants and prostheses assessed. Additional information was obtained from regular records in the patients' charts.<br><br>RESULTS: Three implants were lost in the healing phase, and 1 implant was replaced. Only 1 patient with 4 implants was lost from the study (she had passed away). The survival rate of the loaded implants was 100%. In 1 patient, peri-implant bony defects were detected around all 3 intraforaminal implants. The prosthetic plan was maintained in all patients, and they continued to wear the originally planned type of prosthesis. Complications included insufficient hygiene, soft tissue hyperplasia, extraction of remaining teeth, and minor maintenance or repair of the prostheses.<br><br>CONCLUSIONS: So far, the mostly unknown implications and possible risks for the process of osseointegration and long-term maintenance in patients with such rare diseases and defects has resulted in a rather restricted application of implants. However, from the present results, it appears that implants can successfully be placed and maintained. This is ascribed in part to a strict maintenance care program provided by the caregivers and to a high compliance of the patients who participated in this program to perform good oral hygiene.}, }
@article {pmid16206548, year = {2005}, author = {Houseman, G and Kelley, M}, title = {Early respiratory insufficiency in the ALS patient: a case study.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {37}, number = {4}, pages = {216-218}, doi = {10.1097/01376517-200508000-00009}, pmid = {16206548}, issn = {0888-0395}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Disease Progression ; Humans ; Male ; Middle Aged ; Nurse's Role ; Nursing Assessment ; Oximetry ; Patient Selection ; Polysomnography ; Positive-Pressure Respiration ; Reference Values ; Reproducibility of Results ; Respiratory Function Tests/methods/standards ; Respiratory Insufficiency/*diagnosis/etiology/*therapy ; Sensitivity and Specificity ; Severity of Illness Index ; Supine Position ; Time Factors ; Vital Capacity ; }, abstract = {Respiratory insufficiency is a problem that develops in nearly all people diagnosed with amyotrophic lateral sclerosis (ALS). Noninvasive positive pressure ventilation (NIPPV) is the treatment of choice for ALS patients with respiratory insufficiency. Forced vital capacity (FVC) is the test most commonly used to qualify ALS patients for NIPPV; however, some research suggests FVC may not be the best tool to measure early respiratory insufficiency in all patients with ALS. This case study introduces an ALS patient who had normal FVC results, symptoms of respiratory insufficiency, and abnormal nocturnal oximetry. After NIPPV initiation, the patient reported improved sleep and less daytime fatigue, which he associated with the start of NIPPV treatment.}, }
@article {pmid16201179, year = {2001}, author = {Guo, H and Wu, Q and Xie, S and Zhang, Q and Yang, X and Shao, M}, title = {[Induced tolerance to cardiac allografts with intrathymic injection of donor spleen cells].}, journal = {Zhonghua wai ke za zhi [Chinese journal of surgery]}, volume = {39}, number = {12}, pages = {945-947}, pmid = {16201179}, issn = {0529-5815}, mesh = {Animals ; Antilymphocyte Serum/administration &amp; dosage/*immunology ; Graft Enhancement, Immunologic/*methods ; Heart Transplantation/*immunology ; Immune Tolerance ; Injections, Intraperitoneal ; Isoantigens/administration &amp; dosage/*immunology ; Male ; Rabbits ; Rats ; Rats, Inbred Lew ; Rats, Wistar ; Spleen/cytology ; Transplantation, Heterotopic/immunology ; }, abstract = {OBJECTIVE: To study the methods and mechanisms of immune tolerance in cardiac transplantation.<br><br>METHODS: Male DA rat hearts were transplanted to male Lewis rats using Ono's model and randomly divided into four groups: untreated (group I), intrathymic injection of 2.5 x 10(7) DA splenocytes to Lewis rat (group II), intraperitoneal injection of 1 ml rabbit anti-rat lymphocyte serum (ALS) to Lewis recipient (group III), intrathymic injection of 2.5 x 10(7) DA splenocytes combined with intraperitoneal injection of 1 ml rabbit anti-rat lymphocyte serum (ALS) to Lewis recipient (group IV). 21 days later heart transplantation was performed. Mean survival time (MST), histological changes and mixed lymphocyte reaction (MLR) were measured after operation.<br><br>RESULTS: In the group of intrathymic injection of spleen cells combined with ALS treatment, the survival time of heart allografts [MST: (81.8 +/- 7.6)d] was significantly longer than in the groups I [MST: (7.3 +/- 1.0) d], group II [MST:(7.8+/- 1.0)d], and group III [MST(8.2 +/- 1.2) d, P < 0.01]. Only a few inflammatory cells infiltrated in cardiac allografts in group IV. MLR of group IV were significantly decreased compared with those of the normal control (P < 0.01).<br><br>CONCLUSIONS: The role of thymus as a special site for induction and maintenance of specific immunological unresponsiveness to organ allografts was confirmed. T cell clonal deletion may play an important role in this immune tolerance.}, }
@article {pmid16197815, year = {2005}, author = {Nagano, I and Shiote, M and Murakami, T and Kamada, H and Hamakawa, Y and Matsubara, E and Yokoyama, M and Moritaz, K and Shoji, M and Abe, K}, title = {Beneficial effects of intrathecal IGF-1 administration in patients with amyotrophic lateral sclerosis.}, journal = {Neurological research}, volume = {27}, number = {7}, pages = {768-772}, doi = {10.1179/016164105X39860}, pmid = {16197815}, issn = {0161-6412}, mesh = {Dose-Response Relationship, Drug ; Humans ; *Injections, Spinal ; Insulin-Like Growth Factor I/administration &amp; dosage/*therapeutic use ; Middle Aged ; Motor Neuron Disease/*drug therapy ; Patient Selection ; Treatment Outcome ; }, abstract = {OBJECTIVES: There is currently no effective pharmacological treatment for amyotrophic lateral sclerosis (ALS). In a transgenic mouse model of ALS, intrathecal infusion of insulin-like growth factor (IGF)-1 showed a promising increase in survival. We performed a double-blind clinical trial to assess the effect of intrathecal administration of IGF-1 on disease progression in patients with ALS.<br><br>METHODS: Nine patients with ALS were randomly assigned to receive either a high dose (3 microg/kg of body weight) or low dose (0.5 microg/kg of body weight) of IGF-1 every 2 weeks for 40 weeks. The outcome measurements were the rate of decline of bulbar and limb functions (Norris scales) and forced vital capacity.<br><br>RESULTS: The high-dose treatment slowed a decline of motor functions of the ALS patients in total Norris and limb Norris scales, but not in bulbar Norris or vital capacity. The intrathecal administration of IGF-1 had a modest but significant beneficial effect in ALS patients without any serious adverse effects.<br><br>DISCUSSION: Intrathecal IGF-1 treatment could provide an effective choice for ALS although further studies in more patients are needed to confirm its efficacy and optimize dosages of IGF-1.}, }
@article {pmid16193258, year = {2005}, author = {Pontieri, FE and Ricci, A and Pellicano, C and Benincasa, D and Buttarelli, FR}, title = {Minocycline in amyotrophic lateral sclerosis: a pilot study.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {26}, number = {4}, pages = {285-287}, doi = {10.1007/s10072-005-0474-x}, pmid = {16193258}, issn = {1590-1874}, mesh = {Anticonvulsants/adverse effects/therapeutic use ; Drug Therapy, Combination ; Humans ; Minocycline/adverse effects/*therapeutic use ; Motor Neuron Disease/*drug therapy ; Pilot Projects ; Respiratory Function Tests ; Riluzole/adverse effects/*therapeutic use ; }, abstract = {Recent studies indicate that minocycline exerts neuroprotective effects in vitro and in vivo, and suggest that the drug may represent a novel therapeutic approach to amyotrophic lateral sclerosis (ALS). In this study we investigated the safety of combined treatment with minocycline and riluzole in ALS. Twenty ALS patients were randomised into two groups and administered either riluzole (50 mg b.i.d.) or riluzole and minocycline (100 mg i.d.) for 6 months. Disease progression was measured by means of the ALS-Functional Rating Scale score at monthly intervals. Respiratory function was measured at the beginning of the study and repeated after 3 and 6 months of treatment. Combined treatment with minocycline and riluzole was not followed by significant side effects. This pilot study shows that minocycline and riluzole can be taken safely together. Further trials are needed to assess efficacy of such treatment.}, }
@article {pmid16184763, year = {2005}, author = {Batulan, Z and Nalbantoglu, J and Durham, HD}, title = {Nonsteroidal anti-inflammatory drugs differentially affect the heat shock response in cultured spinal cord cells.}, journal = {Cell stress &amp; chaperones}, volume = {10}, number = {3}, pages = {185-196}, pmid = {16184763}, issn = {1355-8145}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Cell Survival ; Cells, Cultured ; Cyclooxygenase Inhibitors/*pharmacology ; Dose-Response Relationship, Drug ; Glial Fibrillary Acidic Protein/analysis ; HSP70 Heat-Shock Proteins/biosynthesis/metabolism ; Heat-Shock Response/*drug effects ; Mice ; Motor Neurons/drug effects/metabolism ; Mutation ; Neurofilament Proteins/analysis ; Neuroglia/*drug effects/metabolism ; Niflumic Acid/*pharmacology ; Plasmids ; Sodium Salicylate/*pharmacology ; Spinal Cord/*drug effects/embryology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Temperature ; }, abstract = {Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to amplify the heat shock response in cell lines by increasing the binding of heat shock transcription factor-1 to heat shock elements within heat shock gene promoters. Because overexpression of the inducible heat shock protein 70 (Hsp70) was neuroprotective in a culture model of motor neuron disease, this study investigated whether NSAIDs induce Hsp70 and confer cytoprotection in motor neurons of dissociated spinal cord cultures exposed to various stresses. Two NSAIDs, sodium salicylate and niflumic acid, lowered the temperature threshold for induction of Hsp70 in glia but failed to do so in motor neurons. At concentrations that increased Hsp70 in heat shocked glial cells, sodium salicylate failed to delay death of motor neurons exposed to hyperthermia, paraquat-mediated oxidative stress, and glutamate excitotoxicity. Neither sodium salicylate nor the cyclooxygenase-2 inhibitor, niflumic acid, protected motor neurons from the toxicity of mutated Cu/Zn-superoxide dismutase (SOD-1) linked to a familial form of the motor neuron disease, amyotrophic lateral sclerosis. Thus, treatment with 2 types of NSAIDs failed to overcome the high threshold for the activation of heat shock response in motor neurons.}, }
@article {pmid16183560, year = {2005}, author = {Weydt, P and Hong, S and Witting, A and Möller, T and Stella, N and Kliot, M}, title = {Cannabinol delays symptom onset in SOD1 (G93A) transgenic mice without affecting survival.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {6}, number = {3}, pages = {182-184}, doi = {10.1080/14660820510030149}, pmid = {16183560}, issn = {1466-0822}, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/pathology ; Animals ; Disease Models, Animal ; Disease Progression ; Dronabinol/*therapeutic use ; Male ; Mice ; Mice, Transgenic ; Probability ; Psychotropic Drugs/*therapeutic use ; Superoxide Dismutase/*genetics ; Survival ; }, abstract = {Therapeutic options for amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disorder, remain limited. Emerging evidence from clinical studies and transgenic mouse models of ALS suggests that cannabinoids, the bioactive ingredients of marijuana (Cannabis sativa) might have some therapeutic benefit in this disease. However, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the predominant cannabinoid in marijuana, induces mind-altering effects and is partially addictive, compromising its clinical usefulness. We therefore tested whether cannabinol (CBN), a non-psychotropic cannabinoid, influences disease progression and survival in the SOD1 (G93A) mouse model of ALS. CBN was delivered via subcutaneously implanted osmotic mini-pumps (5 mg/kg/day) over a period of up to 12 weeks. We found that this treatment significantly delays disease onset by more than two weeks while survival was not affected. Further research is necessary to determine whether non-psychotropic cannabinoids might be useful in ameliorating symptoms in ALS.}, }
@article {pmid16181084, year = {2004}, author = {Ekshyyan, O and Aw, TY}, title = {Apoptosis: a key in neurodegenerative disorders.}, journal = {Current neurovascular research}, volume = {1}, number = {4}, pages = {355-371}, doi = {10.2174/1567202043362018}, pmid = {16181084}, issn = {1567-2026}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; R01 DK044510-11/DK/NIDDK NIH HHS/United States ; DK 44510/DK/NIDDK NIH HHS/United States ; DK 43785/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; *Apoptosis ; Humans ; Models, Biological ; Neurodegenerative Diseases/classification/*pathology ; }, abstract = {Apoptosis is an important process in the development of the nervous system. Typically, approximately 50% of the neurons apoptose during neurogenesis before the nervous system matures. However, recent paradigms implicate premature apoptosis and/or aberrations in the fine control of neuronal apoptosis in the pathogenesis of a variety of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, stroke, brain trauma, spinal cord injury, and diabetic neuropathy. This review will focus on the current concepts salient to understanding the apoptosis death program, the mediators and control of cellular apoptosis, and the relationship between aberrant apoptosis and genesis of neurodegenerative disorders. The discussion will also highlight current advances in methodology, such as utilization of neuronal cell lines and mutant animal models, in investigations of neuronal apoptotic death. The knowledge of apoptosis mechanisms could underpin the basis for development of novel therapeutic strategies and treatment modalities that are directed at control of the neuronal apoptotic death program.}, }
@article {pmid16181078, year = {2004}, author = {Silani, V and Corbo, M}, title = {Cell-replacement therapy with stem cells in neurodegenerative diseases.}, journal = {Current neurovascular research}, volume = {1}, number = {3}, pages = {283-289}, doi = {10.2174/1567202043362243}, pmid = {16181078}, issn = {1567-2026}, mesh = {Amyotrophic Lateral Sclerosis/surgery ; Humans ; Neurodegenerative Diseases/*surgery ; *Stem Cell Transplantation/adverse effects ; }, abstract = {In the past few years, research on stem cells has expanded greatly as a tool to develop potential therapies to treat incurable neurodegenerative diseases. Stem cell transplantation has been effective in several animal models, but the underlying restorative mechanisms are still unknown. Several mechanisms such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation may explain positive therapeutic results, in addition to replacement of lost cells. The biological issue needs to be clarified in order to maximize the potential for effective therapies. The absence of any effective pharmacological treatment and preliminary data both in experimental and clinical settings has recently identified Amyotrophic Lateral Sclerosis (ALS) as an ideal candidate disease for the development of stem cell therapy in humans. Preliminary stem transplantation trials have already been performed in patients. The review discusses relevant topics regarding the application of stem cell research to ALS but in general to other neurodegenerative diseases debating in particular the issue of transdifferentiation, endogenous neural stem cell, and factors influencing the stem cell fate.}, }
@article {pmid16179515, year = {2005}, author = {Ignacio, S and Moore, DH and Smith, AP and Lee, NM}, title = {Effect of neuroprotective drugs on gene expression in G93A/SOD1 mice.}, journal = {Annals of the New York Academy of Sciences}, volume = {1053}, number = {}, pages = {121-136}, doi = {10.1196/annals.1344.010}, pmid = {16179515}, issn = {0077-8923}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics ; Animals ; Antioxidants/pharmacology ; Apoptosis/genetics ; Carnosine/pharmacology ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Flavanones/pharmacology ; Gene Expression/*drug effects ; Gene Expression Regulation/physiology ; Genetic Markers ; Inflammation/genetics ; Metallothionein/genetics ; Mice ; Mice, Knockout ; Neuroprotective Agents/*pharmacology ; Neurotoxins/metabolism ; Oxidative Stress/drug effects ; RNA/biosynthesis/genetics ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Gene expression analysis is a powerful tool that has been used to define the pathological processes underlying many diseases. Several laboratories, including our own, have used this approach to identify molecular abnormalities in the G93A/SOD1 mouse, an animal model of amyotrophic lateral sclerosis (ALS). Here, we report the results of analysis of an expanded panel of genes throughout the entire lifetime in the spinal cord of these animals. In addition to upregulation of microglia/neuroinflammatory genes identified previously, we observed upregulation of metallothionein-I and -II (MT-I, MT-II). MT-I and MT-II play an important role in disposition of zinc ion, and other studies have also indicated their levels are altered in development of motor neuron disease in these animals. We also analyzed the effect on these expression profiles of several candidate drugs that have been shown to have neuroprotective effects in vivo or in vitro. That is, we asked whether administration to the G93A/SOD1 mice of any of these drugs could reverse the alterations in gene expression patterns that occur as the animals develop. The mice were given daily doses of these drugs when they were 9-11 weeks old, at a stage early in development of motor neuron disease, continuing for 5 weeks, at which time they were sacrificed. Treatment of the mice with l-carnosine, a dipeptide that scavenges free radicals and chelates zinc, did not affect expression of any of the genes altered in these animals. However, it did upregulate 3 genes unaffected by the presence of the G93A/SOD1 mutation: glial fibrillary acidic protein (GFAP), stroma-derived factor-1 (SDF-1), and excitatory amino acid transporter-2 (EAAT2). In contrast, metallothionein-III (MT-III) was downregulated. Treatment of the animals with baicalein, an herbal extract with anti-inflammatory and numerous other effects, downregulated the microglia markers CD68, CD80, and CD86, all of which were upregulated in untreated mutant animals. Baicalein treatment also downregulated tumor necrosis factor receptor (TNFRp55) and upregulated noninducible nitric oxide synthase (nNOS) and glutamine synthase (GS). These 3 genes were unaffected by the presence of the G93A mutation. We discuss the implication of these results for testing the effects of these and other candidate drugs in mutant SOD1 mice.}, }
@article {pmid16169146, year = {2005}, author = {Hoerndli, F and David, DC and Götz, J}, title = {Functional Genomics meets neurodegenerative disorders. Part II: application and data integration.}, journal = {Progress in neurobiology}, volume = {76}, number = {3}, pages = {169-188}, doi = {10.1016/j.pneurobio.2005.07.002}, pmid = {16169146}, issn = {0301-0082}, mesh = {Animals ; Brain/metabolism/pathology/physiopathology ; Brain Chemistry/genetics ; Disease Models, Animal ; Gene Expression Profiling/*methods/trends ; Genomics/*methods/trends ; Humans ; Nerve Tissue Proteins/genetics ; Neurodegenerative Diseases/*genetics/metabolism/physiopathology ; Proteomics/*methods/trends ; }, abstract = {The transcriptomic and proteomic techniques presented in part I (Functional Genomics meets neurodegenerative disorders. Part I: transcriptomic and proteomic technology) of this back-to-back review have been applied to a range of neurodegenerative disorders, including Huntington's disease (HD), Prion diseases (PrD), Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), frontotemporal dementia (FTD) and Parkinson's disease (PD). Samples have been derived either from human brain and cerebrospinal fluid, tissue culture cells or brains and spinal cord of experimental animal models. With the availability of huge data sets it will firstly be a major challenge to extract meaningful information and secondly, not to obtain contradicting results when data are collected in parallel from the same source of biological specimen using different techniques. Reliability of the data highly depends on proper normalization and validation both of which are discussed together with an outlook on developments that can be anticipated in the future and are expected to fuel the field. The new insight undoubtedly will lead to a redefinition and subdivision of disease entities based on biochemical criteria rather than the clinical presentation. This will have important implications for treatment strategies.}, }
@article {pmid16167754, year = {2003}, author = {Solagberu, BA}, title = {A new classification of osteomyelitis for developing countries.}, journal = {East African medical journal}, volume = {80}, number = {7}, pages = {373-378}, doi = {10.4314/eamj.v80i7.8722}, pmid = {16167754}, issn = {0012-835X}, mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; *Developing Countries ; Female ; Humans ; Male ; Middle Aged ; Nigeria ; Osteomyelitis/*classification/diagnostic imaging/pathology ; Prospective Studies ; Radiography ; }, abstract = {BACKGROUND: The term osteomyelitis (OSM) was first coined by Nelaton in 1844. Waldvogel et al, Cierny-Mader, May et al classifications of OSM from developed countries and Meier et al's from Nigeria have been described.<br><br>OBJECTIVE: This new classification was developed to highlight significant pathology seen in developing countries not covered by existing classifications.<br><br>DESIGN: A prospective study.<br><br>SETTING: University of Ilorin Teaching Hospital, Ilorin, Nigeria.<br><br>SUBJECTS: All OSM patients treated from January 1998 to June 2000.<br><br>MAIN OUTCOME MEASURES: Age, sex, clinical features, radiographs and treatment offered were analysed. Five stages were recognised: stage 0 (potential OSM with bone contamination), stage I (early or acute OSM), stage II (intermediate OSM with subperiosteal abscess), stage III (lateorchronic OSM with sequestrum and subdivided into IIIa 'curable', IIIb 'controllable', IIIc 'complicated'). Stage IV (compound OSM) with joint involvement: IVa, if anatomical and IVb if physiological. Patients' haemoglobin (Hb) status is added to the staging, for example stage II (Hb SS).<br><br>RESULTS: All 271 patients comprising 198 males and 73 females (M: F = 2.7: 1) with age range 2-48 years (mean 29.4 +/- 12.2) were studied. Only 93 patients had Hb genotype done; only 42 had Hb S. The stage O had 184 patients (120 open fractures and 64 bone operations). Stage I had nine patients, stage II 19 patients, stage III 51 patients and stage IV eight.<br><br>CONCLUSIONS: This new staging incorporates pre-emptive OSM seen in developing countries where certain practices, if unchecked lead to OSM. The severity of OSM featuring florid disease not common in the developed world, and for which existing classifications did not accommodate, is included.}, }
@article {pmid16155429, year = {2005}, author = {Baltadzhieva, R and Gurevich, T and Korczyn, AD}, title = {Autonomic impairment in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {18}, number = {5}, pages = {487-493}, doi = {10.1097/01.wco.0000183114.76056.0e}, pmid = {16155429}, issn = {1350-7540}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Animals ; Autonomic Nervous System Diseases/*etiology ; Cognition Disorders/etiology ; Digestive System Physiological Phenomena ; Humans ; Pupil/physiology ; Sweat/physiology ; Urination/physiology ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor neurones, but it is increasingly recognized to be a more disseminated disease. The autonomic nervous system may also be involved. Here we review the literature with specific emphasis on autonomic functions in ALS.<br><br>RECENT STUDIES: Ample evidence exists for subclinical dysfunction of cardiovascular, sudomotor, gastrointestinal, salivary and lacrimal regulation, even in early ALS cases. Autonomic disturbances may lead to circulatory collapse or sudden death in respirator dependent patients. Several studies suggest the existence of sympathetic hyperactivity in ALS. We discuss some possible pathophysiological mechanisms of the subtle abnormalities and some clinical and treatment implications.<br><br>SUMMARY: The wide range of autonomic involvement, together with results suggesting cognitive and extrapyramidal dysfunction, supports the view that ALS is a multisystem degenerative disease.}, }
@article {pmid16153434, year = {2005}, author = {Takayashiki, T and Asakura, H and Ku, G and Kataoka, M and Flye, MW}, title = {Infectious tolerance develops after intrathymic alloantigen-induced acceptance of rat heart allografts can be adoptively transferred.}, journal = {Surgery}, volume = {138}, number = {2}, pages = {254-260}, doi = {10.1016/j.surg.2005.06.012}, pmid = {16153434}, issn = {0039-6060}, mesh = {*Adoptive Transfer ; Animals ; Graft Survival/immunology ; Heart Transplantation/*immunology ; Immune Sera ; Immune Tolerance/*immunology ; Immunophenotyping ; Immunosuppression Therapy/methods ; Isoantigens/*immunology ; Male ; Myocardium/immunology/pathology ; Rats ; Rats, Inbred Lew ; Species Specificity ; Spleen/cytology/immunology ; T-Lymphocytes/immunology ; Thymus Gland/*immunology ; }, abstract = {BACKGROUND: We have shown that intrathymic (IT) injection of alloantigen with antirat lymphocyte serum (ALS) treatment can induce donor-specific allograft acceptance. The purpose of this study was to investigate whether T-regulatory (T-reg) cells play a role in the maintenance of donor-specific heart graft tolerance that develops after IT injection of Lewis (LEW, RT1(l)) alloantigen into a Dark Agouti (DA, RT1(a)).<br><br>METHODS: Na&#xef;ve DA rats were injected IT with 2.5 x10(7) LEW donor splenocytes and injected intraperitoneally with 1 mL ALS. Twenty-one days after pretreatment, a LEW or Brown Norway (BN, RT1(n)) heart was transplanted into a treated DA recipient. Splenocytes (1 x 10(8) or 5 x 10(7)) from a LEW heart-tolerant long-term survivor (LTS; >60 days) DA recipient were harvested and adoptively transferred (AT) into an irradiated (450 rad) na&#xef;ve DA rat 24 hours before transplanting a LEW heart.<br><br>RESULTS: All LEW heart allografts were rejected by untreated DA rats in a mean survival time (MST) of 7.4 +/- 1.7 days (n=7). In contrast, 66.7% of LEW heart grafts into IT+ALS-pretreated DA recipients were accepted indefinitely (n=24). When either 1 x 10(8) (n=5) or 5 x 10(7) (n=5) splenocytes from a LEW heart graft-tolerant LTS (>60 days) DA recipient were AT into a new na&#xef;ve DA rat, all new LEW heart grafts were accepted indefinitely.<br><br>CONCLUSIONS: The donor-specific tolerance that develops after IT+ALS-induced LEW heart acceptance by DA recipients can be transferred adoptively to new na&#xef;ve DA recipients, thus indicating that it is infectious tolerance.}, }
@article {pmid16150530, year = {2005}, author = {Thayne, RC and Thomas, DC and Neville, JD and Van Dellen, A}, title = {Use of an impedance threshold device improves short-term outcomes following out-of-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {67}, number = {1}, pages = {103-108}, doi = {10.1016/j.resuscitation.2005.05.009}, pmid = {16150530}, issn = {0300-9572}, mesh = {Adult ; Aged ; Aged, 80 and over ; Cardiopulmonary Resuscitation/*instrumentation/methods ; Case-Control Studies ; *Defibrillators ; Electric Countershock/*instrumentation/methods ; Emergency Medical Services/*methods ; Equipment Design ; Equipment Safety ; Female ; Heart Arrest/*mortality/*therapy ; Humans ; Male ; Middle Aged ; Probability ; Risk Assessment ; Sensitivity and Specificity ; Survival Analysis ; Treatment Outcome ; United Kingdom ; }, abstract = {INTRODUCTION: An impedance threshold device (ITD) has been developed for the treatment of cardiac arrest to augment circulation to the heart and brain during cardiopulmonary resuscitation (CPR). The ITD has ventilation timing lights that flash at 12 min(-1) to discourage excessive ventilation rates.<br><br>HYPOTHESIS: Implementation of the ITD during conventional manual CPR in a large emergency medical services (EMS) system (Staffordshire, UK) is safe, feasible and will improve short-term survival.<br><br>METHODS: ITD use was implemented by the Staffordshire Ambulance Trust, which treats 1600 cardiac arrests per year with 90 advanced life support (ALS) units and an average response time of 6.3 min. During training, rescuers learned to use the ventilation timing lights to discourage hyperventilation. Rescuers applied the device after tracheal intubation. They were trained to allow the chest to recoil fully after each compression. Prospective ITD use in adults receiving conventional manual CPR for non-traumatic cardiac arrest was compared to matched historical controls receiving conventional manual CPR without inspiratory impedance. All received similar ALS care. The primary endpoint was admission to the emergency department (ED) alive following cardiac arrest. Chi-square, Fisher's exact and Kolmogorov-Smirnov tests were used for statistical analyses.<br><br>RESULTS: Survival (alive upon ED admission) in all patients receiving an ITD (61/181 [34%]) improved by 50% compared to historical controls (180/808 [22%]) (P<0.01). Survival in patients presenting in asystole tripled in the group receiving an ITD (26/76 [34%]) compared with historical controls (39/351 [11%]) (P=0.001). There were no significant adverse events.<br><br>CONCLUSIONS: The ITD was used safely and effectively in a large, diverse EMS system and markedly improved short-term survival for adult patients in non-traumatic cardiac arrest.}, }
@article {pmid16131401, year = {2005}, author = {Gruis, KL and Chernew, ME and Brown, DL}, title = {The cost-effectiveness of early noninvasive ventilation for ALS patients.}, journal = {BMC health services research}, volume = {5}, number = {}, pages = {58}, pmid = {16131401}, issn = {1472-6963}, mesh = {Amyotrophic Lateral Sclerosis/complications/economics/*therapy ; *Attitude to Health ; Cost-Benefit Analysis/statistics &amp; numerical data ; Decision Trees ; Fee Schedules ; Health Expenditures ; Humans ; Markov Chains ; Medicare ; Models, Econometric ; Positive-Pressure Respiration/*economics ; Quality of Life ; *Quality-Adjusted Life Years ; Respiratory Insufficiency/etiology/*therapy ; United States ; }, abstract = {BACKGROUND: Optimal timing of noninvasive positive pressure ventilation (NIPPV) initiation in patients with amyotrophic lateral sclerosis (ALS) is unknown, but NIPPV appears to benefit ALS patients who are symptomatic from pulmonary insufficiency. This has prompted research proposals of earlier NIPPV initiation in the ALS disease course in an attempt to further improve ALS patient quality of life and perhaps survival. We therefore used a cost-utility analysis to determine a priori what magnitude of health-related quality of life (HRQL) improvement early NIPPV initiation would need to achieve to be cost-effective in a future clinical trial.<br><br>METHODS: Using a Markov decision analytic model we calculated the benefit in health-state utility that NIPPV initiated at ALS diagnosis must achieve to be cost-effective. The primary outcome was the percent utility gained through NIPPV in relation to two common willingness-to-pay thresholds: 50,000 dollars and 100,000 dollars per quality-adjusted life year (QALY).<br><br>RESULTS: Our results indicate that if NIPPV begun at the time of diagnosis improves ALS patient HRQL as little as 13.5%, it would be a cost-effective treatment. Tolerance of NIPPV (assuming a 20% improvement in HRQL) would only need to exceed 18% in our model for treatment to remain cost-effective using a conservative willingness-to-pay threshold of 50,000 dollars per QALY.<br><br>CONCLUSION: If early use of NIPPV in ALS patients is shown to improve HRQL in future studies, it is likely to be a cost-effective treatment. Clinical trials of NIPPV begun at the time of ALS diagnosis are therefore warranted from a cost-effectiveness standpoint.}, }
@article {pmid16120782, year = {2005}, author = {Schütz, B and Reimann, J and Dumitrescu-Ozimek, L and Kappes-Horn, K and Landreth, GE and Schürmann, B and Zimmer, A and Heneka, MT}, title = {The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {25}, number = {34}, pages = {7805-7812}, pmid = {16120782}, issn = {1529-2401}, support = {R01 DA016768/DA/NIDA NIH HHS/United States ; DA016768/DA/NIDA NIH HHS/United States ; }, mesh = {Administration, Oral ; Amyotrophic Lateral Sclerosis/genetics/pathology/*prevention &amp; control ; Animals ; Humans ; Hypoglycemic Agents/*administration &amp; dosage ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Nerve Degeneration/genetics/pathology/*prevention &amp; control ; Neuroprotective Agents/administration &amp; dosage ; Pioglitazone ; Superoxide Dismutase/biosynthesis/*genetics ; Thiazolidinediones/*administration &amp; dosage ; }, abstract = {Amyotrophic lateral sclerosis (ALS) represents a fatal neurodegenerative disorder characterized by progressive death of the upper and lower motor neurons. Because accompanying inflammation may interact with and promote neurodegeneration, anti-inflammatory treatment strategies are being evaluated. Because peroxisome proliferator-activated receptor gamma (PPARgamma) agonists act as potent anti-inflammatory drugs, we tested whether superoxide dismutase (SOD1)-G93A transgenic mice, a mouse model of ALS, benefit from oral treatment with the PPARgamma agonist pioglitazone (Pio). Pio-treated transgenic mice revealed improved muscle strength and body weight, exhibited a delayed disease onset, and survived significantly longer than nontreated SOD1-G93A mice. Quantification of motor neurons of the spinal cord at day 90 revealed complete neuroprotection by Pio, whereas nontreated SOD1-G93A mice had lost 30% of motor neurons. This was paralleled by preservation of the median fiber diameter of the quadriceps muscle, indicating not only morphological but also functional protection of motor neurons by Pio. Activated microglia were significantly reduced at sites of neurodegeneration in Pio-treated SOD1-G93A mice, as were the protein levels of cyclooxygenase 2 and inducible nitric oxide synthase. Interestingly, mRNA levels of the suppressor of cytokine signaling 1 and 3 genes were increased by Pio, whereas both the mRNA and protein levels of endogenous mouse SOD1 and of transgenic human SOD1 remained unaffected.}, }
@article {pmid16117818, year = {2005}, author = {Nelson, AE and Howe, CJ and Nguyen, TV and Seibel, MJ and Baxter, RC and Handelsman, DJ and Kazlauskas, R and Ho, KK}, title = {Erythropoietin administration does not influence the GH--IGF axis or makers of bone turnover in recreational athletes.}, journal = {Clinical endocrinology}, volume = {63}, number = {3}, pages = {305-309}, doi = {10.1111/j.1365-2265.2005.02342.x}, pmid = {16117818}, issn = {0300-0664}, mesh = {Adult ; Analysis of Variance ; Biomarkers/blood ; Bone Remodeling/*drug effects ; Carrier Proteins/blood ; Collagen/metabolism ; Collagen Type I ; *Doping in Sports ; Erythropoietin/*administration &amp; dosage/analysis ; Glycoproteins/blood ; Humans ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/analysis ; Male ; Peptide Fragments/blood ; Peptides ; Procollagen/blood ; Recombinant Proteins ; Somatomedins/analysis/*metabolism ; *Sports ; }, abstract = {OBJECTIVE: Measurement of biochemical markers of the IGF-system and of collagen turnover is a potential approach to detect GH abuse in sport. These markers are increased in patients on dialysis treated with recombinant human erythropoietin (r-HuEPO), mimicking the effects of GH. The aim was to determine whether r-HuEPO induces similar effects on the IGF-system and collagen turnover in healthy athletes.<br><br>SUBJECTS AND MEASUREMENTS: Young male Caucasian recreational athletes were administered 50 U/kg r-HuEPO (n=14) or placebo (n=16) three times a week for 25 days, followed by a 4-week wash-out period. IGF-I, IGFBP-3, the acid labile subunit (ALS), N-terminal propeptide of type I collagen (PINP), C-terminal telopeptide of type I collagen (ICTP) and N-terminal propeptide of type III collagen (PIIINP) were measured in samples collected at baseline (two samples), after 10, 22 and 24 days of r-HuEPO treatment and at the end of the 4-week wash-out period.<br><br>RESULTS: Treatment with r-HuEPO resulted in approximately threefold elevation of serum EPO and marked elevation of markers of erythropoiesis. There was no significant treatment effect of r-HuEPO compared to baseline on IGF-I, IGFBP-3, ALS, PINP, ICTP or PIIINP.<br><br>CONCLUSIONS: r-HuEPO administration did not change markers of the IGF-system and of collagen turnover in young healthy male athletes. Therefore, use of r-HuEPO in athletes should not affect the validity of a GH doping test using these GH-responsive markers.}, }
@article {pmid16117816, year = {2005}, author = {Resmini, E and Barreca, A and Ferone, D and Giusti, M and Sidoti, M and Minuto, F}, title = {Effect of different therapeutic modalities on spontaneous GH secretion in acromegalic patients.}, journal = {Clinical endocrinology}, volume = {63}, number = {3}, pages = {294-297}, doi = {10.1111/j.1365-2265.2005.02340.x}, pmid = {16117816}, issn = {0300-0664}, mesh = {Acromegaly/*physiopathology/*therapy ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/therapeutic use ; Carrier Proteins/blood ; Female ; Follow-Up Studies ; Glycoproteins/blood ; Growth Hormone/*metabolism ; Humans ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/analysis ; Male ; Middle Aged ; Octreotide/therapeutic use ; Pituitary Irradiation ; Statistics, Nonparametric ; }, abstract = {OBJECTIVES: Three major therapeutic modalities (transsphenoidal surgery, radiotherapy and medical therapy) are currently available for acromegaly. Although surgery is regarded as the primary option, 50--60% of macroadenomas require further treatment in the form of radiotherapy and/or medical therapy. Recent studies have suggested that radiotherapy might damage the normal hypothalamic-pituitary axis and also rarely leads to IGF-I normalization. The aims of this study were: (1) to examine the effect of different therapeutic modalities (transsphenoidal surgery, TSS; radiotherapy, RT; medical treatment with somatostatin analogues, SSA) on the daily spontaneous GH secretory pattern (day curve); and (2) to determine the relationship between the characteristics of the GH secretory pattern and the circulating concentration of IGF-I, acid-labile subunit (ALS) and IGFBP-3.<br><br>DESIGN AND MEASUREMENTS: Spontaneous GH secretion was evaluated at hourly intervals from 0800 to 1800 h. IGF-I, IGFBP-3 and ALS were measured in basal conditions. The mean and the minimum values obtained from the day curve profile and the coefficient of variation (CV) of single values, which are expressions of the magnitude of the spontaneous secretory pulses, were used for statistical analysis.<br><br>PATIENTS: In a group of 45 acromegalic patients (28 women, mean age 51 years, range 26--83 years, and 17 men, mean age 57 years, range 37--78 years) treated with different protocols, including TSS, RT and SSA therapy, we evaluated GH secretion to determine the effect of single treatment options on the spontaneous secretory profile. Subjects were grouped on the basis of different therapeutic modalities: TSS+RT+SSA (group 1), TSS+SSA (group 2), SSA (group 3), TSS (group 4), TSS+RT (group 5). In patients treated with somatostatin analogues (SSA), tests were performed about midway between two injections.<br><br>RESULTS: The number of deficiencies of the other pituitary functions (PD) was significantly higher in the groups that underwent RT (groups 1 and 5) than in the other groups; in both cases, P<0.01. No significant differences were observed with regard to the mean GH, IGF-I, ALS or IGFBP-3 among the different treatment groups. A significant difference in the GH nadir was found between groups 2 and 4 (P=0.042) and between groups 3 and 4 (P=0.015). GH CV showed lower values in subjects who underwent RT (groups 1 and 5) than in the other groups. The difference was statistically significant between group 5 and groups 2, 3 and 4 (P<0.05), between group 1 and groups 3 and 4 (P<0.05), and between groups 2 and 4 (P=0.007).<br><br>CONCLUSIONS: Our data confirm that radiation therapy decreases GH variability, and that this effect is probably due to hypothalamic damage, as already reported by others. In irradiated patients, a single random sample should therefore be sufficient to evaluate spontaneous GH secretion.}, }
@article {pmid16107364, year = {2005}, author = {Ghosh, A and Busby, M and Kennett, R and Mills, K and Donaghy, M}, title = {A practical definition of conduction block in IvIg responsive multifocal motor neuropathy.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {76}, number = {9}, pages = {1264-1268}, pmid = {16107364}, issn = {0022-3050}, mesh = {Action Potentials ; Adult ; Case-Control Studies ; Diagnosis, Differential ; Electrophysiology ; Female ; Humans ; Immunoglobulins, Intravenous/*therapeutic use ; Male ; Middle Aged ; Motor Neuron Disease/*diagnosis/*drug therapy/immunology ; Neural Conduction/*physiology ; }, abstract = {BACKGROUND: Multifocal motor neuropathy with conduction block (MMN) can be mistaken for motor neurone disease or other lower motor neurone syndromes, but is treatable with intravenous immunoglobulin (IvIg). Formal electrophysiological criteria for conduction block (CB) are so stringent that substantial numbers of patients may miss out on appropriate treatment.<br><br>METHODS: Electrophysiological data were collected from 10 healthy volunteers and compared to data from 10 patients who satisfied the clinical criteria for MMN and who responded to IvIg. This produced a definition of CB in MMN patients which was compared with existing definitions to assess "miss rates".<br><br>RESULTS: Mean values for compound muscle action potential area, amplitude, and duration were calculated in normal subjects. Results beyond 3 SD of their respective means were considered abnormal. Using these criteria, CB in the context of MMN was defined as a reduction in negative peak area >23% along a distal nerve segment or >29% across a proximal segment; or a reduction in amplitude >32% across a distal segment or >33% across a proximal segment. All IvIg responsive patients had at least one nerve segment showing such CB. Employing some criteria from the literature would have denied treatment to over 30% of responsive patients.<br><br>CONCLUSION: In the clinical setting of suspected MMN, less stringent criteria for CB can improve the diagnosis of this treatable disorder. Exclusions on grounds of temporal dispersion may be over-restrictive. A little over one third of CBs occur proximally.}, }
@article {pmid16099509, year = {2006}, author = {Fleischer, A and Ghadiri, A and Dessauge, F and Duhamel, M and Rebollo, MP and Alvarez-Franco, F and Rebollo, A}, title = {Modulating apoptosis as a target for effective therapy.}, journal = {Molecular immunology}, volume = {43}, number = {8}, pages = {1065-1079}, doi = {10.1016/j.molimm.2005.07.013}, pmid = {16099509}, issn = {0161-5890}, mesh = {Apoptosis/*drug effects ; Autoimmunity ; *Drug Evaluation, Preclinical ; Humans ; Neoplasms/drug therapy/pathology ; Neurodegenerative Diseases/drug therapy/pathology ; }, abstract = {Alterations in cell proliferation and cell death are essential determinants in the pathogenesis and progression of several diseases such as cancer, neurodegenerative disorders or autoimmune diseases among others. Complex networks of regulatory factors determine whether cells proliferate or die. Recent progress in understanding the molecular changes offer the possibility of specifically targeting molecules and pathways to achieve more effective and rational therapies. Drugs that target molecules involved in apoptosis are used as treatment against several diseases. Candidates such as TNF death receptor family, caspase inhibitors, antagonists of the p53-MDM2 interaction, NF-kappaB and PI3K pathways and Bcl-2 family members have been targeted as cancer cell killing agents. Moreover, apoptosis of tumor cells can also be achieved by targeting the inhibitor of apoptosis proteins, IAPs, in addition to the classical antiproliferative approach. Disruption of STAT activation and interferon beta therapy have been used as a treatment to prevent the progression of some autoimmune diseases. In models of Parkinson's, Alzheimer's and amyotrophic lateral sclerosis, blocking of Par-4 expression or function, as well as caspase activation, prevents neuronal cell death. Finally, it has been shown that gene therapy may be an encouraging approach for treatment of neurodegenerative disorders.}, }
@article {pmid16097403, year = {2005}, author = {Schmidt, AJ and Krieg, JC and Vedder, H}, title = {Antioxidative and steroid systems in neurological and psychiatric disorders.}, journal = {The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry}, volume = {6}, number = {1}, pages = {26-35}, doi = {10.1080/15622970510029759}, pmid = {16097403}, issn = {1562-2975}, mesh = {Animals ; Antioxidants/*physiology/therapeutic use ; Brain/drug effects/physiopathology ; Brain Diseases/drug therapy/*physiopathology ; Brain Mapping ; Catalase/physiology ; Glutathione Peroxidase/physiology ; Humans ; Mental Disorders/drug therapy/*physiopathology ; Steroids/*physiology/therapeutic use ; Superoxide Dismutase/physiology ; }, abstract = {A large number of neurological and psychiatric diseases like Morbus Parkinson, amyotrophic lateral sclerosis, dementia, schizophrenia and probably also affective disorders show an enhanced production of reactive oxygen species. Moreover, alterations of antioxidative systems and beneficial effects of antioxidative substances including steroid compounds such as estrogens have been described in several of these diseases. This review focuses on alterations of antioxidative systems in the course of neurological diseases and psychiatric disorders and on the differential effects of steroids on these systems in the central nervous system. Moreover, a possible clinical relevance of alterations of circulating steroids and of steroid treatment under these conditions is discussed.}, }
@article {pmid16053424, year = {2005}, author = {Henderson, RD and McCombe, PA}, title = {Riluzole: a glimmer of hope in the treatment of motor neurone disease.}, journal = {The Medical journal of Australia}, volume = {183}, number = {3}, pages = {164; author reply 164-5}, pmid = {16053424}, issn = {0025-729X}, mesh = {Chemical and Drug Induced Liver Injury ; Drug Interactions ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*drug therapy ; Naltrexone/adverse effects ; Narcotic Antagonists/adverse effects ; Neuroprotective Agents/*therapeutic use ; Riluzole/*therapeutic use ; }, }
@article {pmid16049935, year = {2005}, author = {Crow, JP and Calingasan, NY and Chen, J and Hill, JL and Beal, MF}, title = {Manganese porphyrin given at symptom onset markedly extends survival of ALS mice.}, journal = {Annals of neurology}, volume = {58}, number = {2}, pages = {258-265}, doi = {10.1002/ana.20552}, pmid = {16049935}, issn = {0364-5134}, support = {P30 NS047546/NS/NINDS NIH HHS/United States ; P30 NS047546-01A1/NS/NINDS NIH HHS/United States ; R01 NS040819/NS/NINDS NIH HHS/United States ; R01 NS040819-03/NS/NINDS NIH HHS/United States ; }, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*drug therapy/mortality/pathology/physiopathology ; Animals ; Cell Count/methods ; Cell Survival/drug effects ; Disease Models, Animal ; Drug Administration Routes ; Free Radicals/chemistry/*therapeutic use ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Immunohistochemistry/methods ; Metalloporphyrins/chemistry/*therapeutic use ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects/pathology ; Neurofilament Proteins/metabolism ; Random Allocation ; Spinal Cord/drug effects/pathology ; Superoxide Dismutase/genetics ; Survival Analysis ; }, abstract = {Mice that overexpress the human Cu,Zn superoxide dismutase-1 mutant G93A develop a delayed and progressive motor neuron disease similar to human amyotrophic lateral sclerosis (ALS). Most current studies of therapeutics in these mice to date have involved administration of agents long before onset of symptoms, which cannot currently be accomplished in human ALS patients. We examined the effects of the manganese porphyrin AEOL 10150 (manganese [III] tetrakis[N-N'-diethylimidazolium-2-yl]porphyrin) given at symptom onset and found, in three separate studies, that it extended the survival after onset up to 3.0-fold. Immunohistochemical analysis of spinal cord for SMI-32, an abundant protein in motor neurons, indicated better preservation of motor neuron architecture, less astrogliosis (glial fibrillary acidic protein), and markedly less nitrotyrosine and malondialdehyde in porphyrin-treated spinal cords relative to vehicle-treated mice. These results show that the catalytic antioxidant AEOL 10150 provides a pronounced therapeutic benefit with onset administration and is, therefore, a promising agent for the treatment of ALS.}, }
@article {pmid16045483, year = {2005}, author = {Koh, SH and Lee, YB and Kim, KS and Kim, HJ and Kim, M and Lee, YJ and Kim, J and Lee, KW and Kim, SH}, title = {Role of GSK-3beta activity in motor neuronal cell death induced by G93A or A4V mutant hSOD1 gene.}, journal = {The European journal of neuroscience}, volume = {22}, number = {2}, pages = {301-309}, doi = {10.1111/j.1460-9568.2005.04191.x}, pmid = {16045483}, issn = {0953-816X}, mesh = {Alanine/genetics ; Animals ; Apoptosis/drug effects ; Blotting, Western/methods ; Caspase 3 ; Caspases/metabolism ; Cell Death/drug effects/genetics ; Cell Differentiation ; Cell Line, Tumor ; Cell Survival/drug effects ; Collagen Type XI/metabolism ; Cytochromes c/metabolism ; Enzyme Inhibitors/pharmacology ; Glycogen Synthase Kinase 3/antagonists &amp; inhibitors/*physiology ; Glycogen Synthase Kinase 3 beta ; Heat-Shock Proteins/metabolism ; Humans ; Hybrid Cells ; Indoles/metabolism ; Motor Neurons/drug effects/*physiology ; Mutagenesis/physiology ; Neuroblastoma ; Phosphatidylinositol 3-Kinases/metabolism ; Point Mutation/*genetics ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; Protein Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt ; Superoxide Dismutase/*genetics/physiology ; Tetrazolium Salts ; Thiazoles ; Time Factors ; Transfection/methods ; Trypan Blue ; Valine/genetics ; }, abstract = {Point mutations such as G93A and A4V in the human Cu/Zn-superoxide dismutase gene (hSOD1) cause familial amyotrophic lateral sclerosis (fALS). In spite of several theories to explain the pathogenic mechanisms, the mechanism remains largely unclear. Increased activity of glycogen synthase kinase-3 (GSK-3) has recently been emphasized as an important pathogenic mechanism of neurodegenerative diseases, including Alzheimer's disease and ALS. To investigate the effects of G93A or A4V mutations on the phosphatidylinositol-3-kinase (PI3-K)/Akt and GSK-3 pathway as well as the caspase-3 pathway, VSC4.1 motoneuron cells were transfected with G93A- or A4V-mutant types of hSOD1 (G93A and A4V cells, respectively) and, 24 h after neuronal differentiation, their viability and intracellular signals, including PI3-K/Akt, GSK-3, heat shock transcription factor-1 (HSTF-1), cytochrome c, caspase-3 and poly(ADP-ribose) polymerase (PARP), were compared with those of wild type (wild cells). Furthermore, to elucidate the role of the GSK-3beta-mediated cell death mechanism, alterations of viability and intracellular signals in those mutant motoneurons were investigated after treating the cells with GSK-3beta inhibitor. Compared with wild cells, viability was greatly reduced in the G93A and A4V cells. However, the treatment of G93A and A4V cells with GSK-3beta inhibitor increased their viability by activating HSTF-1 and by reducing cytochrome c release, caspase-3 activation and PARP cleavage. However, the treatment did not affect the expression of PI3-K/Akt and GSK-3beta. These results suggest that the G93A or A4V mutations inhibit PI3-K/Akt and activate GSK-3beta and caspase-3, thus becoming vulnerable to oxidative stress, and that the GSK-3beta-mediated cell death mechanism is important in G93A and A4V cell death.}, }
@article {pmid16042064, year = {2004}, author = {Nikolovski, M and Kotsev, Iu and Dimitrov, S and Nikolova, M and Panchev, P}, title = {[The role of polyclonal anti-T-lymphocyte antibodies (ATG) in the kidney transplantation].}, journal = {Khirurgiia}, volume = {60}, number = {4-5}, pages = {42-45}, pmid = {16042064}, issn = {0450-2167}, mesh = {Adult ; Antilymphocyte Serum/administration &amp; dosage/*therapeutic use ; Female ; Graft Rejection/immunology/*prevention &amp; control ; Humans ; Immunosuppressive Agents/administration &amp; dosage/*therapeutic use ; Kidney Transplantation/*immunology ; Male ; Middle Aged ; T-Lymphocytes/*immunology ; }, abstract = {UNLABELLED: The successes in the kidney transplantation are closely connected with the successes of the immunology and the advance of the immunosuppressive therapy. The main task of the modern immunosuppressive therapy is the insurance of medicines with a minimum nephro-toxicity, and the optimum protection regarding the adoptive body against an early reaction of rejection. The polycomponent anti-T-limphocitic antibodies (ATG) give us the opportunity of that. The polycomponent anti-T-limphocitic antibodies or the antilimphocitic serum (ALS) are xenogenetic polycomponent antibodies, that are directed to the human T-limphocites, i.e. antitimocitic globuline (ATG). They are received by immunization of rabbits or horses with human thymus limphoid cells. They are received for the first time by horses, and later on by rabbits. The last patent medicines have more powerful effect. In spite of the side effects of the polycomponent ATG, the patent medicine is used for inductive treatment after transplantation of organs and for a treatment of acutely rejection of the graft. We have treated 15 patients after kidney transplantation with ATG for a period of an year in the ward of kidney transplantation in The Clinic of Urology. The patients with transplantation are at the age of 21 to 50 years old, and by sex--11 male and 4 female patients. 9 of them are transplanted from alive donor and 6--from a dead body. We have applied the patent medicine of ATG Timoglobuline in a phial of 5 mg\ml intravenally in a bank of 500 ml physiological solution according to the weight and the blood test of the patients. We have applied a fourfold immunosuppressive therapy: Urbazon, Imuran, CyA(Neoral) +ATG.<br><br>CONCLUSIONS: ATG is a mixture of monocomponent polyspecific antibodies, which, in spite of its side effects, has been applied successfully in transplantation for more than 30 years. In the course of many years anti-CD3 patent medicine OKT3 has been the only one monocomponent antibody for the treatment of an acute rejection of the graft for inductive therapy in transplanted patients.A chimerical (baziliksimab) and humanized (daklizumab) monocomponent antibodies of the alpha-chain of the receptor for IL-2 (CD25) are used for the prophylaxis of the episodes of acutely rejection of the transplanted kidney during the last 10 years. ATG does not consists of anti-CD25 antibodies. That is why the simultaneously application of ATG with baziliksimab or daklizumab is expected to have an additional effect with a complementary mechanism of efficacy.}, }
@article {pmid16036795, year = {2005}, author = {Kim, HT and Qiang, W and Liu, N and Scofield, VL and Wong, PK and Stoica, G}, title = {Up-regulation of astrocyte cyclooxygenase-2, CCAAT/enhancer-binding protein-homology protein, glucose-related protein 78, eukaryotic initiation factor 2 alpha, and c-Jun N-terminal kinase by a neurovirulent murine retrovirus.}, journal = {Journal of neurovirology}, volume = {11}, number = {2}, pages = {166-179}, pmid = {16036795}, issn = {1355-0284}, support = {CA16672/CA/NCI NIH HHS/United States ; ES07784/ES/NIEHS NIH HHS/United States ; MH71583/MH/NIMH NIH HHS/United States ; NS43984/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Astrocytes/*metabolism ; Brain Stem/metabolism ; CCAAT-Enhancer-Binding Proteins/*metabolism ; Cell Line ; Cyclooxygenase 2 ; Endoplasmic Reticulum Chaperone BiP ; Heat-Shock Proteins/*metabolism ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Mice ; Molecular Chaperones/*metabolism ; *Moloney murine leukemia virus/genetics ; Mutation ; Prostaglandin-Endoperoxide Synthases/*metabolism ; Retroviridae Infections/*metabolism ; Transcription Factor CHOP ; Transcription Factors/*metabolism ; Tumor Virus Infections/*metabolism ; Up-Regulation ; eIF-2 Kinase/*metabolism ; }, abstract = {In susceptible strains of mice, infection with the mutant retrovirus MoMuLV-ts1 causes a neurodegeneration and immunodeficiency syndrome that resembles human human immunodeficiency virus-acquired immunodeficiency syndrome (HIV-AIDS). In this study the authors show increased expression of cyclooxygenase-2 (COX-2) in the brainstem tissues of ts1-infected mice. Up-regulated central nervous system (CNS) levels of this enzyme are associated with HIV-associated dementia and other inflammatory and neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. In brainstem sections, the authors find that astrocytes surrounding spongiform lesions contain increased amounts of immunoreactive COX-2. COX-2 is also up-regulated in cultured ts1-infected cells from the C1 astrocytic cell line, and activation of c-Jun N-terminal kinase, or JNK, pathway. Markers of endoplasmic reticulum (ER) stress, specifically the CCAAT/enhancer-binding protein (CHOP), the glucose-related protein 78 (GRP78), and phosphorylated eukaryotic initiation factor 2 alpha (eIF2 alpha), were also up-regulated in ts1-infected C1 astrocytes. Up-regulation of COX-2 and the above ER signaling factors was reversed by treatment of the infected cells with curcumin which specifically inhibits the JNK/c-Jun pathway. These findings indicate that the JNK/c-Jun pathway is most likely responsible for COX-2 expression induced by ts1 in astrocytes, and that ts1 infection in astrocytes may lead to up-regulation of both inflammatory and ER stress pathways in the central nervous system. Because COX-2 inhibitors are now widely used to treat inflammatory conditions in animals and humans, this finding suggests that these drugs may be useful for therapeutic intervention in neurodegenerative syndromes as well.}, }
@article {pmid16036433, year = {2005}, author = {Beck, M and Flachenecker, P and Magnus, T and Giess, R and Reiners, K and Toyka, KV and Naumann, M}, title = {Autonomic dysfunction in ALS: a preliminary study on the effects of intrathecal BDNF.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {6}, number = {2}, pages = {100-103}, doi = {10.1080/14660820510028412}, pmid = {16036433}, issn = {1466-0822}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*drug therapy/*physiopathology ; Autonomic Nervous System/drug effects/physiopathology ; Autonomic Nervous System Diseases/*drug therapy/*physiopathology ; Blood Pressure/drug effects ; Brain-Derived Neurotrophic Factor/*therapeutic use ; Double-Blind Method ; Epinephrine/metabolism ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Norepinephrine/metabolism ; Sweat/drug effects ; Time Factors ; Treatment Outcome ; }, abstract = {This pilot study aimed at exploring the effects of intrathecally administered brain derived neurotrophic factor (BDNF) on autonomic functions in patients with ALS. A battery of autonomic sympathetic and parasympathetic tests was performed at baseline and after nine months of treatment in 10 ALS patients participating in a double-blind placebo-controlled phase II/III study of intrathecally administered BDNF. Results of patients treated with BDNF (25 or 150 microg/day) were compared to those receiving placebo. Sudomotor function and blood pressure response to handgrip significantly worsened during the treatment period (55.4+/-26.1 vs. 38.9+/-23.9 g/m(2)h, p<0.05; 20+/-6 vs. 13+/-4 microHg, p<0.05) whereas other sympathetic and all parasympathetic function tests only tended to be more abnormal at follow-up. Serum norepinephrine levels increased significantly during the nine-months observation period. The results of autonomic function tests were not different between patients treated with BDNF and placebo, but norepinephrine levels were higher in the BDNF group. We conclude that autonomic nervous system function deteriorates along with poorer motor performance independently from treatment with BDNF. The elevation of norepinephrine levels might reflect a non-specific up-regulation, and its association with BDNF an autocrine effect.}, }
@article {pmid16036423, year = {2005}, author = {Vincent, AM and Backus, C and Taubman, AA and Feldman, EL}, title = {Identification of candidate drugs for the treatment of ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {6}, number = {1}, pages = {29-36}, doi = {10.1080/14660820510026171}, pmid = {16036423}, issn = {1466-0822}, support = {NS36778/NS/NINDS NIH HHS/United States ; NS38849/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/chemically induced/*drug therapy ; Animals ; Antioxidants/pharmacology/therapeutic use ; Cell Count/methods ; Cells, Cultured ; Disease Models, Animal ; Drug Evaluation, Preclinical/methods ; Drug Interactions ; Embryo, Mammalian ; Enzyme Inhibitors/pharmacology/therapeutic use ; GABA Modulators/pharmacology/therapeutic use ; *Glutamic Acid ; In Situ Nick-End Labeling/methods ; Ion Channels/antagonists &amp; inhibitors ; Motor Neurons/*drug effects/physiology ; Protein Synthesis Inhibitors/pharmacology/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/cytology ; }, abstract = {A consortium of investigators interested in neurodegenerative diseases collaborated to screen 1040 drugs in multiple neurodegenerative disease assays. One model of amyotrophic lateral sclerosis (ALS) pathogenesis in particular incorporated glutamate exposure in enriched primary rat motor neuron cultures. In this model 78 compounds decreased motor neuron death caused by 100 microM glutamate. Almost all these pharmacological agents act at one or more of the following cellular targets: 1) protein synthesis inhibition; 2) Cox inhibition; 3) regulation of anion flux; 4) modulation of GABA receptors; 5) antioxidant, and 6) cell cycle inhibition. The most prevalent mode of action was the regulation of intracellular calcium. These data extend the understanding of motor neuron degeneration and identify a number of cellular targets for the improvement of combined therapies for neurodegenerative disease.}, }
@article {pmid16026259, year = {2005}, author = {Kato, T and Ren, CH and Wada, M and Kawanami, T}, title = {Galectin-1 as a potential therapeutic agent for amyotrophic lateral sclerosis.}, journal = {Current drug targets}, volume = {6}, number = {4}, pages = {407-418}, doi = {10.2174/1389450054021846}, pmid = {16026259}, issn = {1389-4501}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Galectin 1/analysis/pharmacology/*therapeutic use ; Humans ; Mice ; Mice, Transgenic ; Molecular Sequence Data ; Neuroprotective Agents/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects almost selectively motor neurons in the central nervous system. Most ALS patients die within five years of onset. One of the neuropathological features of ALS is an "axonal spheroid," a large swelling of a motor axon within the anterior horn of the spinal cord; this abnormal structure seems to be related to the pathogenesis of motor neuron degeneration in ALS. In 2001, using biochemical and immunohistochemical methods, we found an accumulation of galectin-1 in ALS spheroids. By immuno-electron microscopy, the galectin-1 accumulated in the spheroids was observed to be closely associated with neurofilaments. Furthermore, we observed a marked depletion of galectin-1 in the skin of ALS patients; another abnormality frequently observed in ALS. These findings, therefore, suggest that galectin-1 may be involved in the pathogenesis of ALS. It is known that an oxidized form of galectin-1 promotes axonal regeneration; however, it is not known whether oxidized galectin-1 has a beneficial or an adverse effect on the pathophysiology of ALS. To examine this issue, we administered oxidized galectin-1 to transgenic mice with H46R mutant SOD1, an ALS model mouse. The results showed that the administration of oxidized galectin-1 improved the motor activity, delayed the onset of symptoms, and prolonged the survival of the galectin-1-treated mice. Furthermore, the number of remaining motor neurons in the spinal cord was more preserved in the galectin-1-treated mice than in the non-treated mice. We conclude that galectin-1 could be a candidate agent for the treatment of ALS.}, }
@article {pmid16023558, year = {2005}, author = {Bertók, L}, title = {Radio-detoxified endotoxin activates natural immunity: a review.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {12}, number = {2}, pages = {85-95}, doi = {10.1016/j.pathophys.2005.02.004}, pmid = {16023558}, issn = {0928-4680}, abstract = {It is well demonstrated that serial endotoxin injections produce endotoxin tolerance and elevate the natural immunity/resistance. However, such injections may also have harmful effects such as high fever, hypotension and abortion. For this reason endotoxin (LPS) injections are not suitable to enhance nonspecific resistance in endotoxin-sensitive species like man. Various techniques have been designed (physical, chemical, etc.) for the detoxification of endotoxins while the beneficial effects are maintained. Perhaps one of the best detoxification techniques is the treatment with ionizing radiation. The irradiation of LPS with 60Co (150 kGy) decreased its toxicity in a dose-dependent manner. Such radio-detoxified endotoxin (RD-LPS) preparations show decreased toxicity whereas the beneficial effects were preserved. Irradiation causes marked chemical alterations in LPS, such as a decrease of glucosamine, ketodeoxyoctonic and fatty acids. A single parenteral RD-LPS injection prevents various forms of shock in experimental animals. This preparation has a membrane-stabilizing effect, and thereby it can prevent the membrane-damaging effect of LPS and of some cytostatic agents. Unlike endotoxin, RD-LPS has little hypotensive effects, and the pretreatment with this preparation can prevent practically all the hemodynamic changes induced by LPS. LPS plays an important role in the pathogenesis of intestinal syndrome of radiation disease, which may be prevented by RD-LPS pretreatment up to 70% in rats. RD-LPS retains the adjuvant activity of LPS, and it serves as a good adjuvant for inactivated virus vaccines. RD-LPS can also evoke the regeneration of the immune system in irradiated animals. The decrease of nonspecific resistance in immunodeficient or immunosuppressed patients is the most important cause of opportunistic infections that may lead to sepsis like in endotoxaemia and pneumonia. Organ transplant recipients commonly die of septicaemia. Antilymphocyte serum (ALS) is used in such patients as an immunosuppressant. The augmentation of natural resistance and the induction of endotoxin tolerance are of major significance in such patients. In ALS-treated rats RD-LPS induces also tolerance against the lethal dose of LPS. This demonstrates that in spite of the suppressive effect of ALS on T-lymphocytes the induction of LPS tolerance (the enhancement of natural resistance) remains normal. Facultative pathogenic organisms may flourish and cause disease when specific and nonspecific resistance is impaired. RD-LPS can produce a significant proliferation of lymphoid cells in germ-free animals which are immunodeficient. Many other beneficial effects are preserved by RD-LPS preparations, such as the activation of macrophages and of the reticuloendothelial system and antitumor activity. On the basis of these favorable experimental results, RD-LPS has been tested on 350 surgical patients suffering from gastrointestinal tumors, patients suffering from acquired immunodeficiency syndrome (AIDS) and cancer patients treated with CYSPLATIN. RD-LPS treatment prevented sepsis and activated the bone marrow function in these patients.}, }
@article {pmid16013929, year = {2005}, author = {Giménez Poderós, T and Gaminde Inda, I and Iruin Sanz, A and Napal Lecumberri, V}, title = {[Taxanes in the adjuvant therapy of breastcancer with positive nodes: a meta-analysis].}, journal = {Farmacia hospitalaria : organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria}, volume = {29}, number = {2}, pages = {75-85}, doi = {10.1016/s1130-6343(05)73642-4}, pmid = {16013929}, issn = {1130-6343}, mesh = {Breast Neoplasms/*drug therapy ; Chemotherapy, Adjuvant ; Female ; Humans ; Lymphatic Metastasis ; Randomized Controlled Trials as Topic ; Taxoids/*therapeutic use ; Treatment Outcome ; }, abstract = {INTRODUCTION: Taxanes have demonstrated high activity in the treatment of metastatic breast cancer. Based on these promising results, clinical trials were initiated to assess their efficacy in non-metastatic breast cancer both in the adjuvant and neoadjuvant setting.<br><br>OBJECTIVE: To collect scientific evidence as needed for future decision making on the use of taxanes in the adjuvant therapy of breast cancer with positive nodes, and to assess the efficacy of chemotherapy regimens including a taxane using a meta-analysis.<br><br>SEARCH STRATEGY: a systematic search of randomized controlled phase-Ill trials comparing poly-chemotherapy with taxanes versus other drug combinations with-out taxanes was performed. Patients were to have non-metastatic breast cancer with positive nodes, and should have received chemotherapy following surgery. The search was performed by two investigators separately.<br><br>DATA COLLECTION AND ANALYSIS: data(relapses and mortality) were separately collected from clinical tri-als by two investigators to assess disease-free survival and overall survival at 5 years. Selected data underwent a meta-analysis using Peto's method. Peto odds ratio (ORp) and 95% confidence interval were calculated for each measured variable.<br><br>RESULTS: Only 3 clinical trials met inclusion criteria; 7,671 patients were studied. Combined OR was ORp 0.79 (95% Cl:0.71-0.87) for disease-free survival and OR, 0.82 (95% Cl: 0.73-0.92) for overall survival.<br><br>CONCLUSIONS: Chemotherapy regimens including a taxane in the adjuvant therapy setting for breast cancer with positive nodes provide a significant improvement regarding increased disease-free survival and overall survival at 5 years.}, }
@article {pmid16009378, year = {2005}, author = {Burchardi, N and Rauprich, O and Hecht, M and Beck, M and Vollmann, J}, title = {Discussing living wills. A qualitative study of a German sample of neurologists and ALS patients.}, journal = {Journal of the neurological sciences}, volume = {237}, number = {1-2}, pages = {67-74}, doi = {10.1016/j.jns.2005.05.013}, pmid = {16009378}, issn = {0022-510X}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*psychology ; Counseling ; Female ; Germany ; Health Care Surveys ; Humans ; Life Support Systems ; *Living Wills ; Male ; Middle Aged ; *Neurology ; Patient Education as Topic ; Physician-Patient Relations ; }, abstract = {Patients suffering from amyotrophic lateral sclerosis (ALS) eventually lose their ability to communicate their treatment preferences in later stages of the disease. A living will enables ALS patients to specify their choices concerning life-sustaining treatment in advance. Our premise was that completion of a living will should be preceded by a discussion between patient and physician. We conducted a qualitative study of a sample of 15 neurologists and 15 ALS patients from two neurology centers in Germany. Our aim was to explore how discussions about living wills are undertaken. Data analysis followed grounded theory techniques. Our findings showed that both the patients and the physicians considered living wills to be closely connected to forthcoming death. Physicians waited for respiratory failure to occur before they informed ALS patients about living wills, an information strategy that we called the "wait-and-see-policy". The patients completed their living will when they had accepted the hopelessness of their disease. They mostly used living will forms and did not see the necessity to set down disease-specific preferences. They intended to wait for symptoms to emerge before they made the decision about whether or not to accept life-sustaining treatment. The patients as well as the physicians pursued a wait-and-see policy towards end-of-life care, thus weakening the purpose of living wills. Our results point to the necessity and importance of an open and honest patient-physician communication which is a prerequisite for the discussion of living wills.}, }
@article {pmid16006557, year = {2005}, author = {Lüdemann, N and Clement, A and Hans, VH and Leschik, J and Behl, C and Brandt, R}, title = {O-glycosylation of the tail domain of neurofilament protein M in human neurons and in spinal cord tissue of a rat model of amyotrophic lateral sclerosis (ALS).}, journal = {The Journal of biological chemistry}, volume = {280}, number = {36}, pages = {31648-31658}, doi = {10.1074/jbc.M504395200}, pmid = {16006557}, issn = {0021-9258}, mesh = {Acetylglucosaminidase/antagonists &amp; inhibitors ; Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Animals, Genetically Modified ; Antibodies, Monoclonal ; Axons/metabolism ; Cattle ; Cell Line, Tumor ; Disease Models, Animal ; Epitopes/immunology ; Glycosylation ; Humans ; Mice ; Mitogen-Activated Protein Kinase Kinases/antagonists &amp; inhibitors ; Molecular Sequence Data ; NIH 3T3 Cells ; Neurofilament Proteins/immunology/*metabolism ; Neurons/*metabolism ; Protein Structure, Tertiary ; Rats ; Spinal Cord/*metabolism ; }, abstract = {Mammalian neurofilaments (NFs) are modified by post-translational modifications that are thought to regulate NF assembly and organization. Whereas phosphorylation has been intensely studied, the role of another common modification, the attachment of O-linked N-acetylglucosamine (GlcNAc) to individual serine and threonine residues, is hardly understood. We generated a novel monoclonal antibody that specifically recognizes an O-glycosylated epitope in the tail domain of NF-M and allows determination of the glycosylation state at this residue. The antibody displays strong species preference for human NF-M, shows some reactivity with rat but not with mouse or bovine NF-M. By immunohistochemistry and Western blot analysis of biopsy-derived human temporal lobe tissue we show that immunoreactivity is highly enriched in axons parallel to hyperphosphorylated NFs. Treatment of cultured neurons with the GlcNAcase inhibitor PUGNAc causes a 40% increase in immunoreactivity within 1 h, which is completely reversible and parallels the total increase in cellular O-GlcNAc modification. Treatment with the mitogen-activated protein kinase kinase inhibitor PD-98059 leads to a similar increase in immunoreactivity. In spinal cord tissue of a transgenic rat model for amyotrophic lateral sclerosis, immunoreactivity is strongly decreased compared with wild-type animals while phosphorylation is increased. The data suggest that hyperphosphorylation and tail domain O-glycosylation of NFs are synchronously regulated in axons of human neurons in situ and that O-glycosylation of NF-M is highly dynamic and closely interweaved with phosphorylation cascades and may have a pathophysiological role.}, }
@article {pmid16003612, year = {2005}, author = {Dodson, TB}, title = {Is there a role for reconstructive techniques to prevent periodontal defects after third molar surgery?.}, journal = {Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons}, volume = {63}, number = {7}, pages = {891-896}, doi = {10.1016/j.joms.2005.03.003}, pmid = {16003612}, issn = {0278-2391}, support = {K24-DE00448/DE/NIDCR NIH HHS/United States ; }, mesh = {Adult ; Alveolar Bone Loss/etiology/*prevention &amp; control ; Bone Matrix/transplantation ; Bone Transplantation/*methods ; Female ; Guided Tissue Regeneration, Periodontal/*methods ; Humans ; Male ; Middle Aged ; Molar, Third/*surgery ; Multivariate Analysis ; *Oral Surgical Procedures ; Periodontal Attachment Loss/prevention &amp; control ; Prospective Studies ; Tooth Extraction/*adverse effects ; Tooth Socket/surgery ; Treatment Outcome ; }, abstract = {PURPOSE: Among patients at high risk for second molar (M2) periodontal defects after third molar (M3) removal, does active treatment at the time of extraction, when compared with no treatment, alter the risk of postextraction M2 periodontal defects?<br><br>MATERIALS AND METHODS: We used a prospective cohort study design and a sample composed of subjects at high risk for developing M2 periodontal defects after M3 extraction, that is, age > or = 26 years, pre-existing periodontal defects (attachment level [AL] > or = 3 mm), and mesioangular or horizontal M3 impaction. The predictor variable was treatment status of the M3 extraction site. The M3 extraction sites were reconstructed with demineralized bone powder (DBP), bioresorbable guided tissue regeneration (GTR) therapy, or no treatment. The outcome variable was ALs measured at the M2 distobuccal line angle preoperatively and 26 weeks after extraction. Appropriate univariate, bivariate, and multivariate statistics were computed, and statistical significance was set at a value P < .05.<br><br>RESULTS: The cohort was composed of 12 subjects contributing 18 high-risk M3s. Twenty-six weeks after M3 removal, the ALs for GTR-treated (3.0 +/- 1.2 mm), DBP-treated (1.4 +/- 0.5 mm), and control (3.8 +/- 0.9) M3 sites were statistically significantly different (P = .002). Tukey post-hoc comparisons revealed a statistically significant difference between control and DBP ALs (P = .001) and GTR-treated and DBP-treated ALs (P = .037). There was no statistically significant difference in ALs between control and GTR-treated M3s (P = .35).<br><br>CONCLUSIONS: The results of this study suggest that subjects at high risk for developing M2 periodontal defects after M3 removal may benefit from the use of DBP placed at the time of M3 extraction to enhance periodontal healing.}, }
@article {pmid15996807, year = {2005}, author = {Koh, SH and Roh, H and Lee, SM and Kim, HJ and Kim, M and Lee, KW and Kim, HT and Kim, J and Kim, SH}, title = {Phosphatidylinositol 3-kinase activator reduces motor neuronal cell death induced by G93A or A4V mutant SOD1 gene.}, journal = {Toxicology}, volume = {213}, number = {1-2}, pages = {45-55}, doi = {10.1016/j.tox.2005.05.009}, pmid = {15996807}, issn = {0300-483X}, mesh = {Amyotrophic Lateral Sclerosis/enzymology ; Apoptosis/*physiology ; Blotting, Western ; Caspase 3 ; Caspases/metabolism ; Cell Survival/drug effects ; Chromones/pharmacology ; Enzyme Activation/drug effects ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Humans ; Morpholines/pharmacology ; Motor Neurons/cytology/drug effects/*enzymology ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Point Mutation ; Poly(ADP-ribose) Polymerases/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt ; Signal Transduction ; Superoxide Dismutase/genetics/*metabolism ; }, abstract = {The primary pathogenic mechanism of amyotrophic lateral sclerosis (ALS) remains largely unclear. We recently observed that motoneuron cell death mediated by G93A or A4V mutant SOD1, causing familial ALS, was related with decrease of survival signals, such as phosphatidylinositol 3-kinase (PI3-K) and Akt, which play a pivotal role in neuronal survival. Using a G93A or A4V mutant SOD1 transfected VSC4.1 motoneuron cells (G93A or A4V cells, respectively), we presently investigated whether PI3-K activator could reduce mutant SOD1-mediated motoneuron cell death. To investigate the effect of PI3-K activator on viability of G93A and A4V cells, these cells were treated with 10, 50 or 100ng/ml PI3-K activator for 24h and viability and intracellular signals, including Akt, glycogen synthase kinase-3 (GSK-3), heat shock transcription factor-1 (HSTF-1), cytosolic cytochrome c, caspase-3 and poly(ADP-ribose) polymerase (PARP), were compared with those without treatment (control). Compared with non-treated control G93A or A4V cells, the PI3-K activator treatment increased their viability by enhancing the survival signals, including pAkt, pGSK-3, and by inhibiting the death signals, including caspase-3 activation and PARP cleavage. These results suggest that PI3-K activator protects G93A or A4V cells from mutant SOD1-mediated motoneuron cell death by both activating survival signals and inactivating death signals.}, }
@article {pmid15992986, year = {2005}, author = {Morrison, LJ and Dorian, P and Long, J and Vermeulen, M and Schwartz, B and Sawadsky, B and Frank, J and Cameron, B and Burgess, R and Shield, J and Bagley, P and Mausz, V and Brewer, JE and Lerman, BB and , }, title = {Out-of-hospital cardiac arrest rectilinear biphasic to monophasic damped sine defibrillation waveforms with advanced life support intervention trial (ORBIT).}, journal = {Resuscitation}, volume = {66}, number = {2}, pages = {149-157}, doi = {10.1016/j.resuscitation.2004.11.031}, pmid = {15992986}, issn = {0300-9572}, mesh = {Adult ; Aged ; Chi-Square Distribution ; Defibrillators ; Electric Countershock/*methods ; Emergency Medical Services/*methods ; Female ; Follow-Up Studies ; Heart Arrest/diagnosis/mortality/*therapy ; Humans ; Life Support Systems ; Male ; Middle Aged ; Probability ; Prospective Studies ; Reference Values ; Risk Factors ; Sensitivity and Specificity ; Survival Rate ; Treatment Outcome ; Ventricular Fibrillation/diagnosis/*mortality/*therapy ; }, abstract = {BACKGROUND: Although biphasic defibrillation waveforms appear to be superior to monophasic waveforms in terminating VF, their relative benefits in out-of-hospital resuscitation are incompletely understood. Prior comparisons of defibrillation waveform efficacy in out-of-hospital cardiac arrest (OHCA) are confined to patients presenting in a shockable rhythm and resuscitated by first responder (basic life support). This effectiveness study compared monophasic and biphasic defibrillation waveform for conversion of ventricular arrhythmias in all OHCA treated with advance life support (ALS).<br><br>METHODS AND RESULTS: This prospective randomized controlled trial compared the rectilinear biphasic (RLB) waveform with the monophasic damped sine (MDS) waveform, using step-up energy levels. The study enrolled OHCA patients requiring at least one shock delivered by ALS providers, regardless of initial presenting rhythm. Shock success was defined as conversion at 5s to organized rhythm after one to three escalating shocks. We report efficacy results for the cohort of patients treated by ALS paramedics who presented with an initially shockable rhythm who had not received a shock from a first responder (MDS: n=83; RLB: n=86). Shock success within the first three ascending energy shocks for RLB (120, 150, 200J) was superior to MDS (200, 300, 360J) for patients initially presenting in a shockable rhythm (52% versus 34%, p=0.01). First shock conversion was 23% and12%, for RLB and MDS, respectively (p=0.07). There were no significant differences in return of spontaneous circulation (47% versus 47%), survival to 24h (31% versus 27%), and survival to discharge (9% versus 7%). Mean 24h survival rates of bystander witnessed events showed differences between waveforms in the early circulatory phase at 4-10 min post event (mean (S.D.) RLB 0.45 (0.07) versus MDS 0.31 (0.06), p=0.0002) and demonstrated decline as time to first shock increased to 20 min.<br><br>CONCLUSION: Shock success to an organized rhythm comparing step-up protocol for energy settings demonstrated the RLB waveform was superior to MDS in ALS treatment of OHCA. Survival rates for both waveforms are consistent with current theories on the circulatory and metabolic phases of out-of-hospital cardiac arrest.}, }
@article {pmid15992083, year = {1999}, author = {Lai, EC}, title = {Therapeutic developments in amyotrophic lateral sclerosis.}, journal = {Expert opinion on investigational drugs}, volume = {8}, number = {4}, pages = {347-361}, doi = {10.1517/13543784.8.4.347}, pmid = {15992083}, issn = {1744-7658}, abstract = {There is currently no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating disorder of the human nervous system that, due to motoneurone degeneration, causes progressive loss of muscle function and death. The relentless progression of ALS and the uniformly poor prognosis have been unhindered by a variety of therapeutic agents tested in previous clinical studies. Recently, two drugs, namely riluzole and recombinant human insulin-like growth factor-I (IGF-1), have been reported to benefit patients with ALS by improving survival or slowing disease progression. Several other drugs, such as gabapentin and various neurotrophic factors, are being investigated in on-going clinical trials. Therapeutic developments in ALS have been hampered by the fact that the precise cause of the disease remains unknown. In addition, there are considerable variations in disease related characteristics among patients, rendering accurate measurements of disease progression difficult. Advances in theories of pathogenesis, such as genetic factors, glutamate excitotoxicity, oxidative stress, autoimmune mechanism and cytoskeletal abnormality will help guide the development of future therapies. Newer approaches to therapy may include suitable glutamate antagonists, small molecules that augment neurotrophic factor function, and anti-oxidants. Combination therapy of effective agents should be considered.}, }
@article {pmid15991990, year = {1998}, author = {Dinsmore, JH}, title = {Treatment of neurodegenerative diseases with neural cell transplantation.}, journal = {Expert opinion on investigational drugs}, volume = {7}, number = {4}, pages = {527-534}, doi = {10.1517/13543784.7.4.527}, pmid = {15991990}, issn = {1744-7658}, abstract = {Neural cell transplantation is an emerging therapy that may provide an effective treatment for neurodegenerative disorders. The most extensive work with neural transplants has been carried out for Parkinson's and Huntington's diseases. However, intensive efforts are also being made for the treatment of other neurological indications, such as spinal cord repair, stroke, epilepsy, multiple sclerosis (MS), Alzheimer's disease and amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), to name just a few. The major barrier for the successful application of cells as therapeutics is achieving long-term survival and function. The CNS has proven to be ideal for transplantation, in part because immune rejection is attenuated in the CNS compared to peripheral locations. However, some form of immunosuppression is desirable for optimal allograft survival and required for xenograft survival. This review will focus on the challenges of restoring function to something as intricate as the CNS and on the limitations imposed by this complexity on any cellular therapeutic.}, }
@article {pmid15986307, year = {2005}, author = {Chung, KC and Shi, SF and Tang, YY and Wang, KY}, title = {[An experience nursing a patient with amyotrophic lateral sclerosis using the theory of self-care].}, journal = {Hu li za zhi The journal of nursing}, volume = {52}, number = {3}, pages = {82-89}, pmid = {15986307}, issn = {0047-262X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*nursing ; Female ; *Holistic Nursing ; Humans ; Male ; Middle Aged ; *Models, Nursing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and lethal motor neurodegenerative disease. The cause of the disease is unknown, and there is no cure current clinical treatment methods include Riluzole and supportive therapy. However, Riluzole only decelerates the patient's muscle strength loss and prolongs survival by about 3-5 months (Aventis Pharmaceutical, 2004). The patient will die eventually because of aspiration pneumonia or respiratory failure. This paper documents the use of Orem's self-care theory and holistic nursing assessment in a patient with amyotrophic lateral sclerosis. There are four areas of nursing concern: impaired self-care ability (dressing, feeding, toileting, and bathing), risk of falls, impaired verbal communication, and powerlessness. In terms of these problems suitable nursing activities are provided to develop the patient's ability to care for himself, prevent accidents, promote skills of non-verbal communication, and alleviate powerlessness in order to strengthen control.}, }
@article {pmid15975074, year = {2004}, author = {Galbusera, C and Facheris, M and Magni, F and Galimberti, G and Sala, G and Tremolada, L and Isella, V and Guerini, FR and Appollonio, I and Galli-Kienle, M and Ferrarese, C}, title = {Increased susceptibility to plasma lipid peroxidation in Alzheimer disease patients.}, journal = {Current Alzheimer research}, volume = {1}, number = {2}, pages = {103-109}, doi = {10.2174/1567205043332171}, pmid = {15975074}, issn = {1567-2050}, mesh = {Aged ; Alzheimer Disease/*blood/drug therapy/physiopathology ; Amyotrophic Lateral Sclerosis/blood ; Antioxidants/therapeutic use ; Apolipoproteins E/genetics ; Ascorbic Acid/therapeutic use ; Case-Control Studies ; Copper/pharmacology ; Female ; Humans ; *Lipid Peroxidation/drug effects ; Male ; Middle Aged ; Oxidation-Reduction ; Polymorphism, Genetic ; Severity of Illness Index ; Thiobarbituric Acid Reactive Substances/metabolism ; Vitamin E/therapeutic use ; }, abstract = {Oxidative stress, linked to Abeta-lipid interactions, plays a pathogenetic role in Alzheimer's disease. We investigated modifications of lipid peroxidation products in plasma of 52 AD patients, 42 healthy controls and 16 patients with amyotrophic lateral sclerosis, a neurodegenerative disease where oxidative stress also plays a pathogenetic role. Final lipid peroxidation products were measured in plasma by thiobarbituric acid reactive substances (TBARS) assay before and after ex vivo oxidative stress catalysed by copper. There were no significant changes at basal conditions, but after copper-induced oxidation TBARS levels were higher in AD patients (19.0 microM +/- 2.2) versus both controls (5.2 microM +/- 0.8, p<0.001) and ALS patients (7.6 microM +/- 2.1, p<0.01). Stimulated TBARS levels were significantly higher in mild and moderate AD (p<0.0001) with respect to controls, but not in severe AD patients, with a significant inverse correlation between disease severity and lipid peroxidation (p<0.005, r2=0.21). Treatment of a subgroup (13) of mild and moderate AD patients with vitamin C and E for three months decreased plasma lipoperoxidation susceptibility by 60%. Thus, oxidative stress, expressed as ex vivo susceptibility to lipid peroxidation, appears to be an early phenomenon, probably related to AD pathogenetic mechanisms.}, }
@article {pmid15974901, year = {2005}, author = {Klegeris, A and McGeer, PL}, title = {Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease.}, journal = {Current Alzheimer research}, volume = {2}, number = {3}, pages = {355-365}, doi = {10.2174/1567205054367883}, pmid = {15974901}, issn = {1567-2050}, mesh = {Alzheimer Disease/drug therapy/pathology ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use ; Humans ; Inflammation/etiology ; Microglia/drug effects ; Neurodegenerative Diseases/complications/*drug therapy/physiopathology ; Prostaglandin-Endoperoxide Synthases/metabolism ; }, abstract = {Inflammation is characteristic of a broad spectrum of neurodegenerative diseases. These include Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases, amyotrophic lateral sclerosis, all of the tauopathies, multiple sclerosis and many other less common conditions. Morphologically, the level of inflammation is determined by the concentration and degree of activation of microglial cells. Biochemically, it is judged by the presence of a spectrum of inflammatory mediators. Epidemiological evidence indicates that anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) have a sparing effect on AD and PD indicating that inflammation exacerbates the pathology in these diseases. NSAIDs are protective in transgenic animal models of AD, providing further evidence of the negative consequences of inflammation. Here we describe an in vitro model, which was used to study the protective effects of NSAIDs in AD. This model is based on neuronal cell killing by stimulated microglia or microglia-like cells. In this model NSAIDs show protective effects at a therapeutically relevant level, which is in the low micromolar range. There are reports suggesting that NSAIDs act independently of cyclooxygenase (COX) inhibition, but only at higher doses. Classical NSAIDs are still the most logical choice for agents that will slow the progression or delay the onset of AD and other neurodegenerative diseases despite failures of naproxen, celecoxib and rofecoxib in AD clinical trials. Several other classes of anti-inflammatory drugs have been identified as potentially beneficial in this and similar assay systems. Therefore combination therapy with other anti-inflammatory agents that work through different mechanisms of action might prove to be a superior therapeutic strategy.}, }
@article {pmid15957273, year = {2005}, author = {Zissin, R and Hertz, M and Paran, H and Osadchy, A and Gayer, G}, title = {Computed tomographic features of afferent loop syndrome: pictorial essay.}, journal = {Canadian Association of Radiologists journal = Journal l'Association canadienne des radiologistes}, volume = {56}, number = {2}, pages = {72-78}, pmid = {15957273}, issn = {0846-5371}, mesh = {Adult ; Afferent Loop Syndrome/*diagnostic imaging ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Tomography, X-Ray Computed ; }, abstract = {ALS, a rare condition, is often difficult to diagnose clinically but has a characteristic CT appearance as a U-shaped, fluid-filled tubular structure crossing the midline between the abdominal aorta and the superior mesenteric artery. Radiologists should be familiar with this rare entity, as awareness of its pathognomonic CT features will aid in establishing the correct diagnosis as well as in offering a tentative etiology as a guide for treatment.}, }
@article {pmid15956808, year = {2005}, author = {Millul, A and Beghi, E and Logroscino, G and Micheli, A and Vitelli, E and Zardi, A}, title = {Survival of patients with amyotrophic lateral sclerosis in a population-based registry.}, journal = {Neuroepidemiology}, volume = {25}, number = {3}, pages = {114-119}, doi = {10.1159/000086353}, pmid = {15956808}, issn = {0251-5350}, mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*mortality/pathology ; Brain Stem/pathology ; Female ; Humans ; Italy/epidemiology ; Male ; Middle Aged ; Prognosis ; *Registries ; Sex Factors ; Spinal Cord/pathology ; Survival Rate ; Time Factors ; }, abstract = {OBJECTIVE: To evaluate the survival of patients with amyotrophic lateral sclerosis (ALS) in an Italian population and to assess the effects of selected prognostic indicators on survival.<br><br>BACKGROUND: Median survival of ALS patients has been reported to range between 12 and 23 months from diagnosis and between 23 and 36 months from onset of symptoms. Although several negative prognostic factors have been identified, the overall picture still needs clarification.<br><br>METHODS: We included patients enrolled in an Italian ALS Regional Register (population 4,529,003) during the calendar year 1998. The diagnosis was confirmed by an ad hoc committee using the original El Escorial criteria. Each case was regularly followed up until death or December 31, 2002, whichever came first. Survival was assessed with the Kaplan-Meier method in the whole sample, by level of diagnostic certainty, and by selected prognostic indicators (age, sex, bulbar or spinal onset, and disease duration). Multivariate analysis was done with the Cox proportional hazard function.<br><br>RESULTS: The sample comprised 79 patients (33 female; 46 male) aged 28-85 years (mean age 64.4 years). Onset of symptoms was bulbar in 30% of cases. Mean symptom duration at diagnosis was 13.3 months. ALS was definite in 43%, probable in 29%, possible in 6%, and suspected in 22%. By December 31, 2002, 56 cases (71%) had died. The cumulative probability of surviving after diagnosis was 78% at 12 months, 56% at 24 months, and 32% at 48 months. Median survival from onset was 39.2 months and from diagnosis 30.6 months. Multivariate analysis confirmed definite ALS at diagnosis and older age as adverse prognostic factors.<br><br>CONCLUSIONS: Survival of ALS patients in the present sample was slightly longer than previously reported. Better palliative care and supportive treatment may explain the difference. Older age and the presence of definite ALS at diagnosis are poor prognostic predictors.}, }
@article {pmid15954054, year = {2005}, author = {Jensen, MP and Abresch, RT and Carter, GT and McDonald, CM}, title = {Chronic pain in persons with neuromuscular disease.}, journal = {Archives of physical medicine and rehabilitation}, volume = {86}, number = {6}, pages = {1155-1163}, doi = {10.1016/j.apmr.2004.11.028}, pmid = {15954054}, issn = {0003-9993}, support = {P01 HD 33988/HD/NICHD NIH HHS/United States ; }, mesh = {Activities of Daily Living ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Chronic Disease ; Female ; Humans ; Male ; Middle Aged ; Neuromuscular Diseases/*complications ; Pain/*etiology/*psychology ; Pain Management ; Pain Measurement ; Quality of Life ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: To examine the nature and scope of pain in persons with neuromuscular disorder (NMD).<br><br>DESIGN: Survey study.<br><br>SETTING: University-based rehabilitation research programs.<br><br>PARTICIPANTS: Adults with NMD (N=193).<br><br>INTERVENTIONS: Not applicable.<br><br>MAIN OUTCOME MEASURES: Pain presence or absence, pain severity, pain quality (Neuropathic Pain Scale), pain interference (Brief Pain Inventory), pain site, quality of life (Medical Outcomes Study 36-Item Short-Form Health Survey [SF-36]), and pain treatment.<br><br>RESULTS: Seventy-three percent of the sample reported pain, with 27% of these reporting that this pain was severe (> or =7 on a 0-10 scale), on average. "Deep," "tiring," "sharp," and "dull" were the words used most frequently to describe NMD pain. Patients with amyotrophic lateral sclerosis and myotonic muscular dystrophies reported the greatest pain interference, and patients with Charcot-Marie-Tooth the least, among all NMD diagnoses. The most frequent pain site, overall, was back (49%), followed by leg (47%), shoulder (43%), neck (40%), buttock and hip(s) (37%), feet (36%), arm(s) (36%), and hand(s) (35%). The study participants reported significantly greater dysfunction than subjects in the SF-36 normative sample (persons without health problems) on a number of the SF-36 scales. However, we found no significant differences between the study participants and the US norms on the SF-36 role-emotional or mental health scales. A number of pain treatments were used by the study sample, but no treatment appeared to be effective for all participants, and some of the treatments reported as most effective (eg, chiropractic care) were used by very few participants.<br><br>CONCLUSIONS: Pain is a common problem among patients with NMDs. There are many similarities, but also some important differences, between NMD diagnostic groups on the nature and scope of pain and its impact. More research is needed to identify and test effective treatments for NMD-related pain.}, }
@article {pmid15953369, year = {2005}, author = {Demestre, M and Pullen, A and Orrell, RW and Orth, M}, title = {ALS-IgG-induced selective motor neurone apoptosis in rat mixed primary spinal cord cultures.}, journal = {Journal of neurochemistry}, volume = {94}, number = {1}, pages = {268-275}, doi = {10.1111/j.1471-4159.2005.03184.x}, pmid = {15953369}, issn = {0022-3042}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/immunology/*pathology ; Animals ; *Apoptosis/immunology ; Cell Death/immunology ; Cells, Cultured ; Coculture Techniques ; Female ; Humans ; Immunoglobulin G/isolation &amp; purification/*physiology ; Male ; Middle Aged ; Motor Neurons/*cytology/immunology/metabolism ; Necrosis ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/*cytology/immunology/metabolism ; }, abstract = {There is evidence that in sporadic amyotrophic lateral sclerosis (ALS) immunological mechanisms may be involved in the pathophysiology of the disease. We tested whether purified IgG from ALS patients induce cell death in rat mixed primary spinal cord cultures and compared this with the effect of IgG purified from patients with Guillain-Barré syndrome (GBS) or from healthy donors. Treatment with ALS-IgG increases caspase-3 apoptosis when compared with control IgG or with GBS-IgG, but does not induce death by necrosis. Because ALS is characterized by the selective loss of motor neurones, we next assessed the differential effect of ALS-IgG on motor neurones or astrocytes. We showed, semiquantitatively, that motor neurones are more susceptible to apoptosis when cultures were treated with ALS-IgG compared with control-IgG. In conclusion, we have demonstrated in primary spinal cord cultures that IgG from patients with ALS induces apoptosis selectively in motor neurones, and that the caspase-3 pathway is involved. This suggests that immunological mechanisms may contribute to the selective loss of motor neurones in ALS.}, }
@article {pmid15947331, year = {2005}, author = {Farrero, E and Prats, E and Povedano, M and Martinez-Matos, JA and Manresa, F and Escarrabill, J}, title = {Survival in amyotrophic lateral sclerosis with home mechanical ventilation: the impact of systematic respiratory assessment and bulbar involvement.}, journal = {Chest}, volume = {127}, number = {6}, pages = {2132-2138}, doi = {10.1378/chest.127.6.2132}, pmid = {15947331}, issn = {0012-3692}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/diagnosis/*mortality/therapy ; Bulbar Palsy, Progressive/diagnosis/*mortality/therapy ; Cohort Studies ; Female ; *Home Care Services ; Humans ; Male ; Middle Aged ; Probability ; Prognosis ; Proportional Hazards Models ; Pulmonary Valve Insufficiency/diagnosis/*mortality/therapy ; Respiration, Artificial/*methods ; Respiratory Function Tests ; Retrospective Studies ; Risk Assessment ; Severity of Illness Index ; Survival Analysis ; Treatment Outcome ; }, abstract = {STUDY OBJECTIVES: To analyze (1) the impact of a protocol of early respiratory evaluation of the indications for home mechanical ventilation (HMV) in patients with amyotrophic lateral sclerosis (ALS), and (2) the effects of the protocol and of bulbar involvement on the survival of patients receiving noninvasive ventilation (NIV).<br><br>DESIGN AND SETTING: Retrospective study in a tertiary care referral center.<br><br>PATIENTS: HMV was indicated in 86 patients with ALS, with 22 patients (25%) presenting with intolerance to treatment associated with bulbar involvement. Treatment with HMV had been initiated in 15 of 64 patients prior to initiating the protocol (group A) and in the remaining 49 patients after protocol initiation (group B).<br><br>RESULTS: In group A, the majority of patients began treatment with HMV during an acute episode requiring ICU admission (p = 0.001) and tracheal ventilation (p = 0.025), with a lower percentage of patients beginning HMV treatment without respiratory insufficiency (p = 0.013). No significant differences in survival rates were found between groups A and B among patients treated with NIV. Greater survival was observed in group B (p = 0.03) when patients with bulbar involvement were excluded (96%). Patients without bulbar involvement at the start of therapy with NIV presented a significantly better survival rate (p = 0.03). Multivariate analysis showed bulbar involvement to be an independent prognostic factor for survival (relative risk, 1.6; 95% confidence interval, 1.01 to 2.54; p = 0.04). No significant differences in survival were observed between patients with bulbar involvement following treatment with NIV and those with intolerance, except for the subgroup of patients who began NIV treatment with hypercapnia (p = 0.0002).<br><br>CONCLUSIONS: Early systematic respiratory evaluation in patients with ALS is necessary to improve the results of HMV. Further studies are required to confirm the benefits of NIV treatment in patients with bulbar involvement, especially in the early stages.}, }
@article {pmid15947294, year = {2005}, author = {Servera, E and Sancho, J}, title = {Appropriate management of respiratory problems is of utmost importance in the treatment of patients with amyotrophic lateral sclerosis.}, journal = {Chest}, volume = {127}, number = {6}, pages = {1879-1882}, doi = {10.1378/chest.127.6.1879}, pmid = {15947294}, issn = {0012-3692}, mesh = {Amyotrophic Lateral Sclerosis/*complications/diagnosis ; Combined Modality Therapy ; Female ; Humans ; Male ; Oxygen Consumption/*physiology ; Prognosis ; Respiratory Function Tests ; Respiratory Insufficiency/*etiology/physiopathology/*therapy ; Risk Assessment ; Severity of Illness Index ; }, }
@article {pmid15934930, year = {2005}, author = {Ryu, H and Smith, K and Camelo, SI and Carreras, I and Lee, J and Iglesias, AH and Dangond, F and Cormier, KA and Cudkowicz, ME and Brown, RH and Ferrante, RJ}, title = {Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice.}, journal = {Journal of neurochemistry}, volume = {93}, number = {5}, pages = {1087-1098}, doi = {10.1111/j.1471-4159.2005.03077.x}, pmid = {15934930}, issn = {0022-3042}, support = {AG 13846/AG/NIA NIH HHS/United States ; AG12992/AG/NIA NIH HHS/United States ; NS 31248/NS/NINDS NIH HHS/United States ; NS 37912/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylation/drug effects ; Amyotrophic Lateral Sclerosis/genetics/mortality/pathology/*physiopathology ; Animals ; Apoptosis/*genetics ; Caspase Inhibitors ; Cell Survival/drug effects ; Curcumin/pharmacology ; Cytochromes c/antagonists &amp; inhibitors ; Disease Progression ; Gene Expression/*drug effects ; Histones/metabolism ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects ; NF-kappa B/metabolism ; NF-kappa B p50 Subunit ; Phenylbutyrates/*pharmacology ; Promoter Regions, Genetic/drug effects ; Protein Precursors/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Spinal Cord/drug effects/metabolism/pathology ; }, abstract = {Multiple molecular defects trigger cell death in amyotrophic lateral sclerosis (ALS). Among these, altered transcriptional activity may perturb many cellular functions, leading to a cascade of secondary pathological effects. We showed that pharmacological treatment, using the histone deacetylase inhibitor sodium phenylbutyrate, significantly extended survival and improved both the clinical and neuropathological phenotypes in G93A transgenic ALS mice. Phenylbutyrate administration ameliorated histone hypoacetylation observed in G93A mice and induced expression of nuclear factor-kappaB (NF-kappaB) p50, the phosphorylated inhibitory subunit of NF-kappaB (pIkappaB) and beta cell lymphoma 2 (bcl-2), but reduced cytochrome c and caspase expression. Curcumin, an NF-kappaB inhibitor, and mutation of the NF-kappaB responsive element in the bcl-2 promoter, blocked butyrate-induced bcl-2 promoter activity. We provide evidence that the pharmacological induction of NF-kappaB-dependent transcription and bcl-2 gene expression is neuroprotective in ALS mice by inhibiting programmed cell death. Phenylbutyrate acts to phosphorylate IkappaB, translocating NF-kappaB p50 to the nucleus, or to directly acetylate NF-kappaB p50. NF-kappaB p50 transactivates bcl-2 gene expression. Up-regulated bcl-2 blocks cytochrome c release and subsequent caspase activation, slowing motor neuron death. These transcriptional and post-translational pathways ultimately promote motor neuron survival and ameliorate disease progression in ALS mice. Phenylbutyrate may therefore provide a novel therapeutic approach for the treatment of patients with ALS.}, }
@article {pmid15933871, year = {2005}, author = {Vigh, L and Smith, RG and Soós, J and Engelhardt, JI and Appel, SH and Siklós, L}, title = {Sublethal dose of 4-hydroxynonenal reduces intracellular calcium in surviving motor neurons in vivo.}, journal = {Acta neuropathologica}, volume = {109}, number = {6}, pages = {567-575}, doi = {10.1007/s00401-004-0977-1}, pmid = {15933871}, issn = {0001-6322}, mesh = {Aldehydes/*toxicity ; Animals ; Calcium/*analysis/metabolism ; Cysteine Proteinase Inhibitors/*toxicity ; Female ; Intracellular Fluid/chemistry/drug effects ; Male ; Microscopy, Electron, Transmission ; Microscopy, Energy-Filtering Transmission Electron ; Motor Neurons/*drug effects/pathology/ultrastructure ; Movement Disorders/etiology ; Neurodegenerative Diseases/physiopathology ; Oxidative Stress/physiology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/*drug effects/pathology ; }, abstract = {4-Hydroxynonenal (4-HNE), a major lipid peroxidation product, induces oxidative stress, acts as an autonomous effector of cell death in motor neuron hybrid cell cultures, and is elevated in the cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). Elevation of the total intracellular calcium has also been demonstrated in motor axon terminals of ALS patients as well as in spinal motor neurons of animal models of familial and sporadic ALS. Since the association of intracellular calcium and oxidative stress has been suggested in ALS, the in vivo effect of intrathecally administered 4-HNE on the motor neuronal calcium level was examined in the spinal cord of rats. After 12 days of treatment, total intracellular calcium was assayed by electron microscopic histochemistry using the oxalate-pyroantimonate method. Morphology of spinal motor neurons was characterized by light and electron microscopy. In rats, 4-HNE treatment induced a mild impairment of gait, elevation of 4-HNE in the CSF, loss of spinal motor neurons, and reduction of total calcium in the surviving, structurally intact motor neurons. 4-HNE could only cause a lesion if glutathione synthesis was concomitantly inhibited in the animals. The results suggest that upstream components of the oxidative injury in relation to lipid peroxidation are necessary to compromise the glutathione system in ALS, allowing an increase of 4-HNE in the CSF, which further aggravates the primary oxidative lesion. The reduced intracellular calcium in the surviving motor neurons with no morphological features of degeneration may reflect an impaired ionic homeostasis, which may indicate a residual damage of an incomplete degenerative process.}, }
@article {pmid15924088, year = {2005}, author = {Danel-Brunaud, V and Perez, T and Just, N and Destée, A}, title = {[Management and treatment of respiratory failure associated with amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {161}, number = {4}, pages = {480-485}, doi = {10.1016/s0035-3787(05)85082-9}, pmid = {15924088}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Respiratory Insufficiency/*etiology/*therapy ; }, abstract = {INTRODUCTION: In amyotrophic lateral sclerosis (ALS), respiratory muscle involvement is highly predictive of survival and quality of life (QOL). There is compelling evidence that non invasive ventilation (NIV) prolongs survival by several months and improves QOL more than any other currently available treatment. Frequent testing of pulmonary function and regular evaluations are recommended since 1999 by the American Academy of Neurology in order to take appropriate treatment decisions.<br><br>STATE OF ART: There are numerous tests available to evaluate respiratory status in ALS and it is important to know their sensitivity and specificity to recognize clinical risk situations. Some recent data suggest that sniff nasal pressure and maximal inspiratory pressure (MIP) can be performed reliably by most ALS patients and are more sensitive to decrements in inspiratory muscle strength than spirometry or arterial blood gasometry.<br><br>PERSPECTIVES: Airway obstruction caused by ineffective coughing is the principal cause of intolerance to NIV. Several factors other than respiratory muscle strength may affect pulmonary function: postural changes, nutritional status, infectious disease, drugs.<br><br>CONCLUSION: The neurologist has to coordinate multidisciplinary care, with attention to individual patient preferences, and with a frank and compassionate discussion between the patient, the family, the physicians and the caregivers.}, }
@article {pmid15921624, year = {2005}, author = {Zhou, JC and Zhang, GS}, title = {[Expressive profile of retinoblastoma-associated protein 46 and its clinical significance in acute leukemias].}, journal = {Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi}, volume = {26}, number = {2}, pages = {86-89}, pmid = {15921624}, issn = {0253-2727}, mesh = {Acute Disease ; Adolescent ; Adult ; Aged ; Blotting, Western ; Bone Marrow Cells/*metabolism ; Carrier Proteins/*genetics/metabolism ; Female ; Fluorescent Antibody Technique, Indirect ; Humans ; Leukemia/*blood/pathology ; Male ; Middle Aged ; Nuclear Proteins/*genetics/metabolism ; Prognosis ; RNA, Messenger/genetics/metabolism ; Retinoblastoma Protein/genetics/metabolism ; Retinoblastoma-Binding Protein 7 ; Reverse Transcriptase Polymerase Chain Reaction ; Young Adult ; }, abstract = {OBJECTIVE: To investigate the expression of retinoblastoma-associated protein 46 (RbAp46) or RbAp 46 mRNA in bone marrow mononuclear cells (BMMNC) of acute leukemia (AL) patients and determine whether the expression is related to the classification and prognosis of ALs.<br><br>METHODS: The expression of RbAp46 protein in BMMNC was detected by Western blot in 46 AL patients and the expression of RbAp46 mRNA in BMMNC by semi-quantitative RT-PCR in 22 AL patients. The indirect immunofluorescence staining technique was applied to the localization of RbAp46 protein in BMMNC both in leukemia patients and control subjects.<br><br>RESULTS: (1) Both RbAp46 protein and mRNA were expressed in AL BMMNC and no significant difference was found among different leukemia types. (2) The expression of RbAp46 protein was lower in AL patients with high-degree tumor burden than in those with low-degree tumor burden (mean A, 93.4 +/- 37.2 vs 127.2 +/- 15.8, P < 0. 05). (3) The expression of RbAp46 protein was lower in refractory leukemia than those in non-refractory leukemia (mean A, 87.1 +/- 33.8 vs 126.6 +/- 21.2, P < 0. 05). (4) The expression of RbAp46 mRNA was lower in AL patients with high-degree tumor burden than in those with low-degree tumor burden (mean A R, 0.19 +/- 0.08 vs 0.31 +/- 0.12, P < 0. 05). (5) RbAp46 protein was mainly localized in nucleus of BMMNC in both AL patients and control subjects.<br><br>CONCLUSION: Both RbAp46 protein and mRNA are expressed in AL patients BMMNC. The downregulation of RbAp46 expression is associated with high leukemic burden and refractory to treatment. RbAp46 gene might be a tumor suppressor gene for leukemia.}, }
@article {pmid15920784, year = {2005}, author = {Zawoznik, MS and Tomaro, ML}, title = {Effect of chlorimuron-ethyl on Bradyrhizobium japonicum and its symbiosis with soybean.}, journal = {Pest management science}, volume = {61}, number = {10}, pages = {1003-1008}, doi = {10.1002/ps.1077}, pmid = {15920784}, issn = {1526-498X}, mesh = {Bradyrhizobium/*drug effects/physiology ; Herbicides/*pharmacology ; Plant Roots/drug effects/microbiology ; Pyrimidines/*pharmacology ; Glycine max/growth &amp; development/*microbiology ; Sulfonylurea Compounds/*pharmacology ; Symbiosis/*drug effects ; }, abstract = {Possible side-effects of the acetolactate synthase (ALS)-inhibiting herbicide chlorimuron-ethyl on Bradyrhizobium japonicum (Kirchner &amp; Jordan) in pure culture and on inoculated soybean plants growing under controlled conditions were investigated. Growth of B japonicum strain E109 was not affected by this herbicide even when exposed to concentrations 150 times higher than recommended field doses. However, nodulation of soybean plants treated 5 days after emergence with chlorimuron-ethyl at standard application rates was impaired: a 38% decrease in the number of nodules per plant was observed four weeks after treatment. Despite nodule number decrease, no changes in shoot nitrogen content could be detected. Total fresh biomass was diminished by 25% in herbicide-treated plants. Leghemoglobin content in nodules did not vary; nevertheless total nodule protein was diminished by 40% in the herbicide-treated group. ALS activity in different soybean tissues and their relative sensitivity to chlorimuron-ethyl were also investigated. Roots and bacteroids had the greatest specific ALS activities. On a fresh weight basis, the bacteroid fraction displayed the highest ALS activity and was also the most tolerant to in vitro chlorimuron addition: 72% of its activity was retained after including 10 microM chlorimuron-ethyl in the reaction mixture. These results indicate that standard application rates of chlorimuron-ethyl will have limited incidence on B japonicum survival, and effects on nodulation may have little long-term consequences on soybean nitrogen fixation potential. The differences found among soybean tissues not only in intrinsic ALS activity but also in their relative sensitivity to this herbicide suggests that, in leguminous plants living in symbiosis with rhizobia, nodules may contribute to an enhanced tolerance to ALS inhibitors.}, }
@article {pmid15919576, year = {2005}, author = {Zafren, K and Durrer, B and Herry, JP and Brugger, H and , }, title = {Lightning injuries: prevention and on-site treatment in mountains and remote areas. Official guidelines of the International Commission for Mountain Emergency Medicine and the Medical Commission of the International Mountaineering and Climbing Federation (ICAR and UIAA MEDCOM).}, journal = {Resuscitation}, volume = {65}, number = {3}, pages = {369-372}, doi = {10.1016/j.resuscitation.2004.12.014}, pmid = {15919576}, issn = {0300-9572}, mesh = {Camping ; Emergency Medical Services/*methods ; Humans ; Lightning Injuries/prevention &amp; control/*therapy ; *Mountaineering ; }, abstract = {Lightning is a hazard during outdoor activities, especially for hikers and mountaineers. Specific preventive measures include staying off ridges and summits, and away from single trees. If possible, stay close to a wall but keeping a distance of at least 1m away from the wall. All metal objects (carabiners, crampons, ice-axe, ski poles, etc.) should be removed and stored away safely. Lightning currents can follow wet ropes. To prevent blunt trauma the helmet should not be removed. Move as quickly as possible away from wire ropes and iron ladders. The crouch position should be adopted immediately if there is a sensation of hair "standing on end". Crackling noises or a visible glow indicate an imminent lightning strike. Rescue of lightning victims may be hazardous. Airborne helicopters can be struck by lightning with disastrous effects. It is prudent to wait until the danger of further strikes has passed. Treatment of lightning victims is based upon the ABCs - (Assessment) airway, breathing and circulation. Victims who are not breathing can often be resuscitated and should be helped first. Respiratory arrest may be prolonged, but the prognosis can be excellent if breathing is supported. Standard Advanced Life Support (ALS), if necessary, should be given at the scene.}, }
@article {pmid15919414, year = {2005}, author = {Margenthaler, JA and Flye, MW}, title = {The immunologic function of 1B2+ double negative (CD4-CD8-) T cells in the 2C transgenic mouse.}, journal = {The Journal of surgical research}, volume = {126}, number = {2}, pages = {160-166}, doi = {10.1016/j.jss.2005.01.018}, pmid = {15919414}, issn = {0022-4804}, support = {AI1060902/AI/NIAID NIH HHS/United States ; AI4296701/AI/NIAID NIH HHS/United States ; }, mesh = {Adoptive Transfer ; Animals ; Antilymphocyte Serum/pharmacology ; Biomarkers/*metabolism ; CD4 Antigens/*metabolism ; CD4-Positive T-Lymphocytes/drug effects ; CD8 Antigens/*metabolism ; CD8-Positive T-Lymphocytes/drug effects ; Cells, Cultured ; Clone Cells/immunology ; Flow Cytometry ; Gene Rearrangement ; Graft Rejection ; H-2 Antigens/*immunology ; Heart Transplantation ; Histocompatibility Antigen H-2D ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Transgenic ; Receptors, Antigen, T-Cell, alpha-beta/genetics ; T-Lymphocytes/*immunology/*metabolism ; T-Lymphocytes, Cytotoxic/*immunology ; Transplantation Tolerance ; }, abstract = {BACKGROUND: 2C mice bearing the cytotoxic TCR for class I L(d) on a C57BL/6 (B6) background have a preponderance of 1B2+CD8+ T cells directed against L(d). These naive CD8+ T cells are not directly cytotoxic without prior in vivo or in vitro activation. However, after in vitro sensitization, they become highly cytotoxic and will acutely and specifically reject a tolerant L(d+) BALB/c heart graft. Anti-lymphocyte serum (ALS) treatment eliminates CD4+ and CD8+ cells and a large double negative (CD4-CD8-) 1B2+ non-cytotoxic transgenic cell population remains. The immunological function of this unique peripheral population of T cells is investigated in the 2C transgenic mouse.<br><br>MATERIALS AND METHODS: To determine the activation characteristics of the 2C CD4-CD8- T cells, 2C peripheral T cells were analyzed for 1B2+, CD8+, and CD4+ marker by FACS before and 48-h after 0.5 cc ALS i.p. Similarly, in vitro, the response of these 2C CD4-CD8- T cells remaining after deletion of mature CD4+ and CD8+ T cells with ALS plus complement were evaluated by mixed lymphocyte culture and cytotoxic T lymphocyte after 7 days culture with BALB/c, IL-2, or BALB/c + IL-2. Parallel experiments were performed with control non-transgenic B6 mice. Following in vitro culture with BALB/c + IL-2, 2C CD4-CD8- T cells were injected into B6 mice with a tolerant BALB/c heart (tolerization via anti-CD4 mAb and intrathymic BALB/c) to determine their immunogenicity.<br><br>RESULTS: While peripheral T cells in control B6 mice have <5% CD4-CD8- cells, transgenic 2C mice have a significantly increased percentage at 29 to 35% (P < 0.01). After the deletion of CD4+ and CD8+ T cells with either in vivo or in vitro ALS, 2C CD4-CD8- T cells increased to 96 to 99%. After 7-day culture, the 2C CD4-CD8- T cells decreased again to 33 to 38%. Simultaneously, 2C CD8+ T cells decreased from 56 to 62% to 0.1 to 3% after ALS treatment, but again increased to 61 to 70% after in vitro culture. Untreated 2C cells responded to IL-2 or BALB/c antigen equally well. However, after ALS treatment, CD4-CD8- T cells responded to IL-2 and IL-2 plus antigen, but not BALB/c antigen alone. Finally, CD4-CD8- T cells cultured for 7 days with BALB/c + IL-2 rejected the tolerant BALB/c heart in 5.3 +/- 0.3 days.<br><br>CONCLUSION: In the periphery of transgenic 2C mice is a unique CD4-CD8- population of T cells bearing the transgenic specific marker 1B2. These non-cytotoxic cells can be optimally stimulated to develop marked specific L(d) cytotoxicity in parallel with the expression of the CD8+ epitope.}, }
@article {pmid15911831, year = {2005}, author = {Hingorani, VN and Kittrelle, JP}, title = {Treatment of pseudobulbar affect in ALS: October 26 highlight and commentary.}, journal = {Neurology}, volume = {64}, number = {10}, pages = {1821; author reply 1821}, doi = {10.1212/wnl.64.10.1821}, pmid = {15911831}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Antitussive Agents/metabolism/therapeutic use ; Clinical Trials as Topic/standards ; Cytochrome P-450 CYP2D6/genetics/metabolism ; Cytochrome P-450 CYP2D6 Inhibitors ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System/genetics/metabolism ; Dextromethorphan/metabolism/*therapeutic use ; Drug Combinations ; Drug Resistance/genetics ; Drug Synergism ; Enzyme Inhibitors/therapeutic use ; Genetic Testing/standards ; Genotype ; Humans ; Pseudobulbar Palsy/*drug therapy/*etiology/physiopathology ; Quinidine/*therapeutic use ; }, }
@article {pmid15911352, year = {2005}, author = {Tarabal, O and Calderó, J and Casas, C and Oppenheim, RW and Esquerda, JE}, title = {Protein retention in the endoplasmic reticulum, blockade of programmed cell death and autophagy selectively occur in spinal cord motoneurons after glutamate receptor-mediated injury.}, journal = {Molecular and cellular neurosciences}, volume = {29}, number = {2}, pages = {283-298}, doi = {10.1016/j.mcn.2005.03.003}, pmid = {15911352}, issn = {1044-7431}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; Animals ; Anterior Horn Cells/*metabolism/pathology/ultrastructure ; Apoptosis/drug effects/*physiology ; Autophagy/drug effects/*physiology ; Axotomy ; Chick Embryo ; Disease Models, Animal ; Endoplasmic Reticulum/*metabolism/pathology/ultrastructure ; Excitatory Amino Acid Agonists/pharmacology ; Glutamic Acid/metabolism ; Inclusion Bodies/*metabolism/pathology/ultrastructure ; Microscopy, Electron, Transmission ; Models, Neurological ; N-Methylaspartate/pharmacology ; Nerve Tissue Proteins/*metabolism ; Neurofilament Proteins/metabolism ; Neurotoxins/pharmacology ; Protein Biosynthesis/physiology ; Receptors, Glutamate/drug effects/*metabolism ; Stress, Physiological/metabolism/physiopathology ; }, abstract = {We previously showed that, in contrast to the acute administration of NMDA, chronic treatment of chick embryos from embryonic day (E) 5 to E9 with this excitotoxin rescues motoneurons (MNs) from programmed cell death. Following this protocol, MNs are also protected against later acute excitotoxic cell death. Previously, we found that MNs treated from E5 to E9 develop long-lasting changes involving vesicular trafficking and other organelle pathology similar to the abnormalities observed in certain chronic neurological diseases including amyotrophic lateral sclerosis (ALS). Here we extend these previous results by showing that protein aggregation within the endoplasmic reticulum (ER) takes place selectively in MNs as an early event of chronic excitotoxicity. Although protein aggregates do not induce appreciable MN death, they foreshadow the activation of a conspicuous autophagic response leading to long-lasting degenerative changes that causes dysfunction but not immediate cell death. Chronic early treatment with NMDA results in a transient (between E6 and E10) lack of vulnerability to undergo cell death induced by different types of stimuli. It is suggested that blockade of protein translation in stressed ER may inhibit apoptosis in NMDA-treated MNs. However, in embryos older than E12, degenerating MNs are sensitized to die after limb ablation (axotomy) and accumulate hyperphosphorylated neurofilaments. Moreover, chronic NMDA treatment does not induce the upregulation of molecular chaperones in spinal cord. These results represent a new model of glutamate receptor-mediated neurotoxicity that selectively occurs in spinal cord MNs and also demonstrate an experimental system that may be valuable for understanding the mechanisms involved in chronic MN degeneration and in certain cytological hallmarks of ALS-diseased MNs such as inclusion bodies.}, }
@article {pmid15910777, year = {2005}, author = {Holasek, SS and Wengenack, TM and Kandimalla, KK and Montano, C and Gregor, DM and Curran, GL and Poduslo, JF}, title = {Activation of the stress-activated MAP kinase, p38, but not JNK in cortical motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in transgenic mice.}, journal = {Brain research}, volume = {1045}, number = {1-2}, pages = {185-198}, doi = {10.1016/j.brainres.2005.03.037}, pmid = {15910777}, issn = {0006-8993}, support = {NS 38896/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics/physiopathology ; Animals ; Apoptosis/*physiology ; Caspase 3 ; Caspases/metabolism ; Disease Models, Animal ; Disease Progression ; Enzyme Activation/physiology ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Kinase 3 ; MAP Kinase Kinase Kinase 5/metabolism ; Mice ; Mice, Transgenic ; Motor Cortex/*enzymology/pathology/physiopathology ; Motor Neurons/*enzymology/pathology ; Mutation/genetics ; Oxidative Stress/*physiology ; Phosphorylation ; Signal Transduction/physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Up-Regulation/physiology ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, characterized by the degeneration of upper and lower motor neurons (MNs). Central nervous system features include a loss of Betz cells and other pyramidal cells from sensorimotor cortex. The intrinsic mechanism underlying this selective motor neuron loss has not been identified. A recent in vitro study has provided evidence of a novel programmed cell death (PCD) pathway that is unique to spinal cord MNs and is exacerbated by superoxide dismutase (SOD) mutations. This PCD pathway is triggered through the Fas receptor and involves the apoptosis signal-regulating kinase 1 (ASK1), the p38 MAP kinase, and the neuronal form of nitric oxide synthase (nNOS). Previously, we found significant increases in the numbers of ventral horn MNs immunopositive for these enzymes in the spinal cords of mutant SOD transgenic (G93A) mice as early as 60 days of age, suggesting that this pathway may be active in vivo. Since the upper MNs of ALS patients and G93A mice are also known to degenerate, the purpose of the present study was to investigate the possible activation of this PCD pathway in the MNs of the sensorimotor cortex of G93A transgenic mice. Compared to non-transgenic littermates, the G93A mice showed significant increases in the numbers of MNs immunopositive for the active (phosphorylated) forms of ASK1, p38, MKK3/6 (the known activator of p38), and also active caspase-3, as early as 60 days of age. Another stress-activated protein kinase, c-Jun N-terminal kinase (JNK), commonly activated in other neurodegenerative disorders such as Alzheimer's disease, showed no increases in G93A mice at any age. These results suggest that, not only has a PCD pathway been activated in the cortical MNs, but one that may be unique to ALS. Moreover, these findings suggest that earlier diagnosis and therapeutic intervention may be possible for successful treatment of ALS. Consequently, these enzymes may provide the biochemical markers to enable earlier diagnosis of ALS and molecular targets for the development of new therapeutic compounds.}, }
@article {pmid15893467, year = {2005}, author = {Platania, P and Seminara, G and Aronica, E and Troost, D and Vincenza Catania, M and Angela Sortino, M}, title = {17beta-estradiol rescues spinal motoneurons from AMPA-induced toxicity: a role for glial cells.}, journal = {Neurobiology of disease}, volume = {20}, number = {2}, pages = {461-470}, doi = {10.1016/j.nbd.2005.03.025}, pmid = {15893467}, issn = {0969-9961}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*metabolism/physiopathology ; Animals ; Animals, Newborn ; Anterior Horn Cells/drug effects/*metabolism/pathology ; Antibodies/pharmacology ; Astrocytes/drug effects/*metabolism ; Cell Death/drug effects/physiology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Estradiol/*metabolism/pharmacology ; Estrogen Receptor alpha/metabolism ; Glial Cell Line-Derived Neurotrophic Factor/antagonists &amp; inhibitors/metabolism ; Humans ; Middle Aged ; Nerve Degeneration/chemically induced/drug therapy/*metabolism ; Neuroprotective Agents/*metabolism/pharmacology ; Neurotoxins/antagonists &amp; inhibitors/toxicity ; Rats ; Rats, Sprague-Dawley ; Sex Factors ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/antagonists &amp; inhibitors/toxicity ; }, abstract = {The ability of astrocytes to mediate 17beta-estradiol neuroprotection of spinal motoneurons challenged with AMPA has been evaluated in a co-culture system in which pure motoneurons were pulsed with 20 microM AMPA and then transferred onto an astrocyte layer pretreated for 24 h with 10 nM 17beta-estradiol. Under these conditions, AMPA toxicity was reverted, an effect that was likely related to increased production and release of GDNF, as shown by RT-PCR, Western blot analysis and ELISA assay. In addition, treatment with GDNF during the 24 h that followed the AMPA pulse produced a similar neuroprotective effect, whereas addition of a neutralizing anti-GDNF antibody prevented neuroprotection. These data suggest a role for astrocytes in the neuroprotective effect of 17beta-estradiol against spinal motoneuron death and find strong support in the marked up-regulation of estrogen receptor alpha found in spinal astrocytes of amyotrophic lateral sclerosis patients.}, }
@article {pmid15875502, year = {2005}, author = {Zanini, R and Romano, M and Buffoli, F and Lettieri, C and Baccaglioni, N and Schiavone, G and Aroldi, M and Tomasi, L and Kuwornu, H and Izzo, A}, title = {[Telecardiology in the management of acute myocardial infarction: the experience of the provincial network of Mantova].}, journal = {Italian heart journal. Supplement : official journal of the Italian Federation of Cardiology}, volume = {6}, number = {3}, pages = {165-171}, pmid = {15875502}, issn = {1129-4728}, mesh = {Aged ; *Angioplasty, Balloon, Coronary ; Humans ; Italy ; Myocardial Infarction/*therapy ; *Telemedicine ; Time Factors ; }, abstract = {BACKGROUND: Since June 2001 we activated a program for the treatment of acute myocardial infarction, based on the early assessment of the patient's risk profile, on telematic connection among care centers and optimization of critical pathways for access to care. The aim of this work was to assess the effectiveness of telemedicine in the reduction of time to treatment.<br><br>METHODS: Mantova, a province of eastern Lombardy (northern Italy) is provided with one single sanitary district with one (tertiary hospital) referring hospital equipped with a cath lab on call 24/24 hours for primary coronary angioplasty (PTCA) and cardiac surgery and 6 community hospitals: 2 with coronary care units, 2 with a cardiology section, and 2 rehabilitation hospitals. The emergency medical system transport, activated 24/24 hours, consists of 6 advanced life support (ALS) ambulances and 11 basic life support (BLS) ambulances (2 with trained nurse staff). Each ALS ambulance is equipped with a semiautomatic defibrillator LIFEPACK 12 coupled with cellular telephone GSM transmission of the 12-lead ECG.<br><br>RESULTS: In the first 3-year activity of the project 340 patients with acute myocardial infarction underwent primary PTCA: 248 (73%) referred to first aid of the nearest hospital reached either by BLS ambulance or by their own means of transport and were hence transferred to the referring hospital for primary PTCA (group A), while 92 patients (27%) were aided at their own house by ALS ambulances and, after transmission of the 12-lead ECG to the referring coronary care unit, were directly transferred to the cath lab (group B). Decisional delay was 144 +/- 65 min in group A while 74 +/- 37 min in group B. Mean door-to-balloon time was 76 +/- 26 min in group A and 47 +/- 21 min in group B. High incidence of post-procedural TIMI 3 flow was achieved in both groups. In-hospital mortality was 6.8% in group A e 5.4% in group B.<br><br>CONCLUSIONS: Our data show that patients referring directly to ALS ambulances had a lower decisional delay. Transmission of the patient's ECG and clinical parameters allows an early and accurate diagnosis and assessment of the individual risk profile with a consistent reduction in time to treatment and positive effects on the mortality rate.}, }
@article {pmid15860692, year = {2005}, author = {Richmond, NJ and Silverman, R and Kusick, M and Matallana, L and Winokur, J}, title = {Out-of-hospital administration of albuterol for asthma by basic life support providers.}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {12}, number = {5}, pages = {396-403}, doi = {10.1197/j.aem.2004.12.013}, pmid = {15860692}, issn = {1553-2712}, mesh = {Administration, Inhalation ; Adolescent ; Adult ; Aged ; Albuterol/*administration &amp; dosage ; Asthma/diagnosis/*drug therapy ; Bronchodilator Agents/*administration &amp; dosage ; Child ; Child, Preschool ; Clinical Protocols ; Cohort Studies ; Emergency Medical Services/*methods/standards ; *Emergency Medical Technicians ; Female ; Humans ; Infant ; Male ; Middle Aged ; New York City ; Prospective Studies ; Respiratory Function Tests ; Treatment Outcome ; }, abstract = {BACKGROUND: Each year, approximately 40,000 patients with acute asthma are transported by the Fire Department of New York City (NYC) Emergency Medical Services (EMS). Out-of-hospital administration of bronchodilator therapy has, however, been restricted by scope of practice to advanced life support (ALS) providers. Since the rapid availability of ALS units cannot always be assured, some individuals with acute asthma may receive only basic life support (BLS) measures in the field.<br><br>OBJECTIVES: To demonstrate that basic emergency medical technicians (EMT-Bs) are able to effectively administer nebulized albuterol to asthma patients in the out-of-hospital environment.<br><br>METHODS: This was a prospective, observational cohort study of 9-1-1 asthma calls received by the NYC EMS system for patients between the ages of 1 and 65 years. Baseline peak expiratory flow rate (PEFR) and other clinical measures were obtained prior to and following BLS administration of one or two treatments with nebulized albuterol.<br><br>RESULTS: Data were available for 3,351 patients over a one-year study period. One out-of-hospital albuterol treatment was given in 60%, while 40% of the patients received two. The PEFRs increased from 40.4% predicted (SD +/-21.0) to 54.8% predicted (SD +/-26.1), for a posttreatment improvement of 14.4% points (95% CI = 13.8 to 15.1). Other clinical outcome measures, including dyspnea index, respiratory rate, and use of accessory muscles, also showed improvement.<br><br>CONCLUSIONS: This study demonstrates that EMT-Bs can effectively administer albuterol to acute asthma patients in the out-of-hospital environment.}, }
@article {pmid15857890, year = {2005}, author = {Huang, D and Wujek, J and Kidd, G and He, TT and Cardona, A and Sasse, ME and Stein, EJ and Kish, J and Tani, M and Charo, IF and Proudfoot, AE and Rollins, BJ and Handel, T and Ransohoff, RM}, title = {Chronic expression of monocyte chemoattractant protein-1 in the central nervous system causes delayed encephalopathy and impaired microglial function in mice.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {19}, number = {7}, pages = {761-772}, doi = {10.1096/fj.04-3104com}, pmid = {15857890}, issn = {1530-6860}, support = {3R01 NS32151-09/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Autoimmunity ; Blood-Brain Barrier/physiopathology ; Central Nervous System/*chemistry/pathology/physiopathology ; Cerebral Cortex/chemistry/pathology ; Chemokine CCL2/analysis/*genetics/*physiology ; Crosses, Genetic ; Flow Cytometry ; *Gene Expression ; Glial Fibrillary Acidic Protein/genetics ; Humans ; Immunoglobulin G/blood ; Leukocyte Common Antigens/analysis ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/immunology/pathology/*physiology ; Microscopy, Confocal ; Myelin Proteins/analysis/immunology ; Nervous System Diseases/*etiology/pathology/physiopathology ; Neurofilament Proteins/immunology ; Promoter Regions, Genetic/genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 ; Receptors, CCR2 ; Receptors, Chemokine/deficiency ; Signal Transduction ; Spinal Cord/chemistry/pathology ; }, abstract = {Increased central nervous system (CNS) levels of monocyte chemoattractant protein 1 [CC chemokine ligand 2 (CCL2) in the systematic nomenclature] have been reported in chronic neurological diseases such as human immunodeficiency virus type 1-associated dementia, amyotrophic lateral sclerosis, and multiple sclerosis. However, a pathogenic role for CCL2 has not been confirmed, and there is no established model for the effects of chronic CCL2 expression on resident and recruited CNS cells. We report that aged (>6 months) transgenic (tg) mice expressing CCL2 under the control of the human glial fibrillary acidic protein promoter (huGFAP-CCL2hi tg+ mice) manifested encephalopathy with mild perivascular leukocyte infiltration, impaired blood brain barrier function, and increased CD45-immunoreactive microglia, which had morphologic features of activation. huGFAP-CCL2hi tg+ mice lacking CC chemokine receptor 2 (CCR2) were normal, showing that chemokine action via CCR2 was required. Studies of cortical slice preparations using video confocal microscopy showed that microglia in the CNS of huGFAP-CCL2hi tg+ mice were defective in expressing amoeboid morphology. Treatment with mutant CCL2 peptides, a receptor antagonist and an obligate monomer, also suppressed morphological transformation in this assay, indicating a critical role for CCL2 in microglial activation and suggesting that chronic CCL2 exposure desensitized CCR2 on microglia, which in the CNS of huGFAP-CCL2hi tg+ mice, did not up-regulate cell-surface expression of major histocompatibility complex class II, CD11b, CD11c, or CD40, in contrast to recruited perivascular macrophages that expressed enhanced levels of these markers. These results indicate that huGFAP-CCL2hi tg+ mice provide a useful model to study how chronic CNS expression of CCL2 alters microglial function and CNS physiology.}, }
@article {pmid15852403, year = {2005}, author = {Kaspar, BK and Frost, LM and Christian, L and Umapathi, P and Gage, FH}, title = {Synergy of insulin-like growth factor-1 and exercise in amyotrophic lateral sclerosis.}, journal = {Annals of neurology}, volume = {57}, number = {5}, pages = {649-655}, doi = {10.1002/ana.20451}, pmid = {15852403}, issn = {0364-5134}, support = {AG21876/AG/NIA NIH HHS/United States ; }, mesh = {Aging/physiology ; Amyotrophic Lateral Sclerosis/drug therapy/pathology/*therapy ; Animals ; Brain Chemistry/genetics ; Cell Count ; Dependovirus/genetics ; *Exercise Therapy ; Gene Expression ; *Genetic Therapy ; Heterozygote ; Humans ; Immunohistochemistry ; Insulin-Like Growth Factor I/*genetics ; Longevity ; Mice ; Mice, Transgenic ; Motor Activity/physiology ; Plasmids/genetics ; Postural Balance/physiology ; RNA/biosynthesis/genetics ; Running ; Spinal Cord/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Survival Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the neuromuscular system resulting in paralysis and ultimately death. Currently, no effective therapy is prescribed for patients; however, several therapeutic strategies are showing promise. Either exercise or treatment with adeno-associated virus/insulin-like growth factor-1 alone has therapeutic benefits in an amyotrophic lateral sclerosis transgenic mouse model. We show here that activity duration affects the therapeutic benefit associated with exercise, with 6- and 12-hour exposure to a running wheel providing significant motor function benefits and increased survival. Remarkably, a combination of insulin-like growth factor-1 gene delivery and exercise has profound effects on survival and function, indicative of synergistic effects with exercise and insulin-like growth factor-1. Our results indicate that a drug treatment in combination with appropriate exercise may provide the most promising therapy for amyotrophic lateral sclerosis to date.}, }
@article {pmid15847840, year = {2005}, author = {Smith, RA and Brooks, BR}, title = {Treatment of pseudobulbar affect in ALS.}, journal = {The Lancet. Neurology}, volume = {4}, number = {5}, pages = {270}, doi = {10.1016/S1474-4422(05)70058-2}, pmid = {15847840}, issn = {1474-4422}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Animals ; Brain Chemistry/drug effects ; Dextromethorphan/administration &amp; dosage/*adverse effects ; Disease Models, Animal ; Drug Combinations ; Enzyme Inhibitors/therapeutic use ; Excitatory Amino Acid Antagonists/administration &amp; dosage/adverse effects ; Humans ; Pseudobulbar Palsy/*drug therapy/*physiopathology ; Quinidine/therapeutic use ; Serotonin/metabolism ; }, }
@article {pmid15847835, year = {2005}, author = {Simpson, EP}, title = {Antioxidant treatment for amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {4}, number = {5}, pages = {266}, doi = {10.1016/S1474-4422(05)70052-1}, pmid = {15847835}, issn = {1474-4422}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/*physiopathology ; Antioxidants/*administration &amp; dosage ; Biomarkers/analysis ; Central Nervous System/metabolism/*physiopathology ; Clinical Trials as Topic/trends ; Humans ; Oxidative Stress/*drug effects/physiology ; Treatment Outcome ; }, }
@article {pmid15846874, year = {2004}, author = {Peterson, BV and Hummerick, M and Roberts, MS and Krumins, V and Kish, AL and Garland, JL and Maxwell, S and Mills, A}, title = {Characterization of microbial and chemical composition of shuttle wet waste with permanent gas and volatile organic compound analyses.}, journal = {Advances in space research : the official journal of the Committee on Space Research (COSPAR)}, volume = {34}, number = {7}, pages = {1470-1476}, doi = {10.1016/j.asr.2003.11.005}, pmid = {15846874}, issn = {0273-1177}, mesh = {Aerobiosis ; Anaerobiosis ; Carbon Dioxide/analysis ; Environmental Microbiology ; Ethylenes/analysis ; Gases/*analysis ; Hydrogen Sulfide/analysis ; Methane/analysis ; Oxygen/analysis ; Sewage/*microbiology ; *Space Flight ; Waste Management/*methods ; Waste Products/analysis ; *Weightlessness ; }, abstract = {Solid-waste treatment in space for Advanced Life Support, ALS, applications requires that the material can be safely processed and stored in a confined environment. Many solid-wastes are not stable because they are wet (40-90% moisture) and contain levels of soluble organic compounds that can contribute to the growth of undesirable microorganisms with concomitant production of noxious odors. In the absence of integrated Advanced Life Support systems on orbit, permanent gas, trace volatile organic and microbiological analyses were performed on crew refuse returned from the volume F "wet" trash of three consecutive Shuttle missions (STS-105, 109, and 110). These analyses were designed to characterize the short-term biological stability of the material and assess potential crew risks resulting from microbial decay processes during storage. Waste samples were collected post-orbiter landing and sorted into packaging material, food waste, toilet waste, and bulk liquid fractions deposited during flight in the volume F container. Aerobic and anaerobic microbial loads were determined in each fraction by cultivation on R2A and by acridine orange direct count (AODC). Dry and ash weights were performed to determine both water and organic content of the materials. Experiments to determine the aerobic and anaerobic biostability of refuse stored for varying periods of time were performed by on-line monitoring of CO2 and laboratory analysis for production of hydrogen sulfide and methane. Volatile organic compounds and permanent gases were analyzed using EPA Method TO15 by USEPA et al. [EPA Method TO15, The Determination of Volatile Organic Compounds (VOCs) in Ambient Air using SUMMA, Passivated Canister Sampling and Gas Chromatographic Analysis,1999] with gas chromatography/mass spectrometry and by gas chromatography with selective detectors. These baseline measures of waste stream content, labile organics, and microbial load in the volume F Shuttle trash provide data for waste subsystem analysis and atmospheric management within the ALS Project.}, }
@article {pmid15835453, year = {2005}, author = {Fu, A}, title = {Neostigmine: an alternative treatment for constipation.}, journal = {Dynamics (Pembroke, Ont.)}, volume = {16}, number = {1}, pages = {13-15}, pmid = {15835453}, issn = {1497-3715}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications ; Colonic Pseudo-Obstruction/*drug therapy/etiology ; Constipation/*drug therapy/etiology ; Critical Illness ; Female ; Humans ; Neostigmine/*therapeutic use ; Parasympathomimetics/*therapeutic use ; }, abstract = {Constipation is a common complication of amyotrophic lateral sclerosis (ALS), especially as the disease progresses. While ALS patients may experience disturbed gastrointestinal motility due to the nature of the disease and decreased physical activity, the constipation is not usually caused by mechanical obstruction. Acute colonic pseudo-obstruction (ACPO) is a syndrome characterized by massive dilation of the colon without mechanical obstruction. Recent studies have shown neostigmine may be an effective treatment for ACPO. Through a case study, the author discusses the use of neostigmine and its nursing implications on a patient with ALS.}, }
@article {pmid15827736, year = {2005}, author = {Williams, MA and Turchan, J and Lu, Y and Nath, A and Drachman, DB}, title = {Protection of human cerebral neurons from neurodegenerative insults by gene delivery of soluble tumor necrosis factor p75 receptor.}, journal = {Experimental brain research}, volume = {165}, number = {3}, pages = {383-391}, pmid = {15827736}, issn = {0014-4819}, support = {P01 MH056287/MH/NIMH NIH HHS/United States ; R01 NS039253/NS/NINDS NIH HHS/United States ; R01 NS040778/NS/NINDS NIH HHS/United States ; T32 NS07368/NS/NINDS NIH HHS/United States ; }, mesh = {Adenoviridae/genetics ; Brain/cytology ; Cell Death/genetics ; Cells, Cultured ; Fetus/cytology ; Flow Cytometry ; Gene Products, tat/toxicity ; *Genetic Therapy ; Genetic Vectors ; HIV Envelope Protein gp120/toxicity ; Humans ; Neurodegenerative Diseases/chemically induced/*pathology/*prevention &amp; control ; Neurons/*physiology ; Neurotoxins/toxicity ; Receptors, Tumor Necrosis Factor, Type II/*genetics ; Transduction, Genetic ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Apoptosis plays an important role in neuronal cell death in both chronic and acute human neurodegenerative diseases, including amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and human immunodeficiency virus (HIV) encephalopathy. We evaluated the ability of the extracellular binding domain of a dimeric tumor necrosis factor receptor (p75TNFR) to prevent neurotoxicity and death of human fetal cerebral neurons that were exposed in vitro to toxic agents known to be implicated in human neurological disorders, including tumor necrosis factor (TNFalpha) and the HIV proteins Tat and gp120. The extracellular domain of p75TNFR is capable of binding and neutralizing both soluble and transmembrane-anchored TNFalpha. We efficiently transduced human neurons using adenoviral vectors expressing p75TNFR (Ad.p75TNFR) or a control gene (lacZ). Treatment of control cultures with the toxic agents TNFalpha, TNFalpha plus actinomycin D, or Tat and gp120, induced neurotoxic alterations and apoptotic death of neurons. By contrast, transduction of neurons with Ad.p75TNFR prevented apoptosis and cell death due to these agents. We conclude that viral vector transfer of the p75TNFR gene efficiently protects human neurons from TNFalpha-, Tat- or gp120-induced apoptosis and cell death. These results suggest that p75TNFR transduction of neurons by viral vectors could be therapeutically useful in the treatment of many human neurodegenerative diseases.}, }
@article {pmid15826737, year = {2005}, author = {Scott, J and Colom, F}, title = {Psychosocial treatments for bipolar disorders.}, journal = {The Psychiatric clinics of North America}, volume = {28}, number = {2}, pages = {371-384}, doi = {10.1016/j.psc.2005.01.002}, pmid = {15826737}, issn = {0193-953X}, mesh = {Antimanic Agents/adverse effects/therapeutic use ; Bipolar Disorder/diagnosis/psychology/*therapy ; Combined Modality Therapy ; Couples Therapy/methods ; Drug Resistance ; Evidence-Based Medicine ; Family Therapy/methods ; Humans ; Outcome and Process Assessment, Health Care ; Psychotherapy/*methods ; Randomized Controlled Trials as Topic ; Socioenvironmental Therapy ; }, abstract = {Psychosocial problems may be causes or consequences of BP relapses,and adding psychologic therapies to usual-treatment approaches may improve the prognosis of those at risk of persistent symptoms or frequent episodes. The three core individual manualized therapies (IPSRT, cognitive therapy, and FFT) have all developed specific models for use in BP. Colom et al's group psychoeducation model also has a clearly developed rationale and format, and it allows individuals to share their views of BP with others, to learn adaptive coping strategies from the other 8 to 12 members of the group, and to have regular contact with an expert therapist. Careful review of the four more extended and comprehensive approaches and the brief technique-driven interventions demonstrates that the effective therapies incorporate one or more of the modules show in Box 1. At present,the choice between the four extended models is more likely to be dictated by patient choice or the availability of a trained therapist. The technique-driven interventions are briefer than the specific therapies (about 6-9 sessions compared with about 20-22 sessions) and usually offer a generic, fixed treatment package targeted at a circumscribed issue such as medication adherence or managing early symptoms of relapse. These brief interventions can be delivered by a less-skilled or less-experienced professional than the specific model. They potentially seem to be useful in day-to-day clinical practice in general adult psychiatry settings; additional larger-scale, randomized trials should be encouraged. Given the reduction in relapse rates and hospitalizations associated with the use of psychologic therapy as an adjunct to medication, it is likely that these approaches will prove to be clinically and cost effective. They may provide a significant improvement in the quality of life of individuals with BP (and indirectly to that of their partners and family members). Brief,evidence-based therapies represent an important component of good clinical practice in the management of BP. Studies of a comprehensive, whole-system approach to the collaborative psychobiosocial management of BP are being undertaken in the United States. If these approaches improve the quality and continuity of care for individuals with BP, they will have further implications for the delivery and organization of mental health services. The number and variety of trials of psychosocial interventions is exciting for researchers and clinicians interested in BP. Enthusiasm for advocating these approaches should be tempered by an acknowledgment that the trials undertaken so far largely demonstrate efficacy in selected samples of patients treated at specialist BP clinics or psychologic treatment research centers. Translating efficacy into effectiveness requires evidence that the approaches used in the treatment trials are equally beneficial when used by the wider therapist community treating patients seen routinely in non-specialist or nonresearch centers. These patients often have multiple problems or complex presentations that preclude their involvement in pharmacologic or psychologic treatment studies, but monitoring the outcomes of these representative samples will be important in determining the true place of psychologic approaches in the management of BP. Large-scale studies are now underway on both sides of the Atlantic (the Medical Research Council study in the United Kingdom and the STEP-BD project in the United States). These trials are likely to answer basic questions about the benefits and limitations of psychologic therapies in the acute and maintenance treatment of BP in the clinical realm and will increase understanding of the effectiveness-versus-efficacy question.}, }
@article {pmid15824372, year = {2005}, author = {Scelsa, SN and MacGowan, DJ and Mitsumoto, H and Imperato, T and LeValley, AJ and Liu, MH and DelBene, M and Kim, MY}, title = {A pilot, double-blind, placebo-controlled trial of indinavir in patients with ALS.}, journal = {Neurology}, volume = {64}, number = {7}, pages = {1298-1300}, doi = {10.1212/01.WNL.0000156913.24701.72}, pmid = {15824372}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology/virology ; Central Nervous System/*drug effects/physiopathology/virology ; Double-Blind Method ; Female ; HIV Protease Inhibitors/administration &amp; dosage/adverse effects ; Humans ; Indinavir/*administration &amp; dosage/*adverse effects ; Kidney Calculi/chemically induced ; Male ; Middle Aged ; Neuroprotective Agents/administration &amp; dosage/adverse effects ; Pilot Projects ; Placebos ; Riluzole/administration &amp; dosage/adverse effects ; Treatment Failure ; }, abstract = {There is some evidence of retroviral infection in ALS. A randomized, double-blind, placebo-controlled trial of indinavir in ALS was performed to assess safety and efficacy trends. Nephrolithiasis and gastrointestinal side effects were frequent with indinavir treatment. Group differences in the rate of decline were not significant between the groups for the ALS Functional Rating Scale (p = 0.36) or for the secondary variables. The toxicity and negative efficacy trends discourage further indinavir trials in ALS.}, }
@article {pmid15823706, year = {2005}, author = {Longstreth, WT and Meschke, JS and Davidson, SK and Smoot, LM and Smoot, JC and Koepsell, TD}, title = {Hypothesis: a motor neuron toxin produced by a clostridial species residing in gut causes ALS.}, journal = {Medical hypotheses}, volume = {64}, number = {6}, pages = {1153-1156}, doi = {10.1016/j.mehy.2004.07.041}, pmid = {15823706}, issn = {0306-9877}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/microbiology/prevention &amp; control ; Animals ; Anti-Bacterial Agents/therapeutic use ; Axonal Transport ; Bacterial Toxins/*adverse effects/chemistry/pharmacokinetics ; Biological Assay ; Biological Transport ; Clostridium/*pathogenicity ; Gangliosides/metabolism ; Humans ; Intestinal Absorption ; Intestines/*microbiology ; Mice ; *Models, Biological ; Motor Neurons/*drug effects/pathology ; Neurotoxins/*adverse effects/chemistry/pharmacokinetics ; Protein Precursors/metabolism ; Substrate Specificity ; }, abstract = {We hypothesize that a yet-to-be-identified motor neuron toxin produced by a clostridial species causes sporadic amyotrophic lateral sclerosis (ALS) in susceptible individuals. This clostridial species would reside undetected in the gut and chronically produce a toxin that targets the motor system, like the tetanus and botulinum toxins. After gaining access to the lower motor neuron, the toxin would be transported back to the cell body, as occurs with the tetanus toxin, and destroy the lower motor neuron - the essential feature of ALS. Again like the tetanus toxin, some of the toxin would cross to neighboring cells and to the upper motor neuron and similarly destroy these motor neurons. Weakness would relentlessly progress until not enough motor neurons remained to sustain life. If this hypothesis were correct, treatment with appropriate antibiotics or antitoxins might slow or halt progression of disease, and immunization might prevent disease.}, }
@article {pmid15823582, year = {2005}, author = {Nakamizo, T and Kawamata, J and Yamashita, H and Kanki, R and Kihara, T and Sawada, H and Akaike, A and Shimohama, S}, title = {Stimulation of nicotinic acetylcholine receptors protects motor neurons.}, journal = {Biochemical and biophysical research communications}, volume = {330}, number = {4}, pages = {1285-1289}, doi = {10.1016/j.bbrc.2005.03.115}, pmid = {15823582}, issn = {0006-291X}, mesh = {Allosteric Regulation ; Animals ; Bungarotoxins/pharmacology ; Cell Death/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Cholinesterase Inhibitors/pharmacology ; Dihydro-beta-Erythroidine/pharmacology ; Fetus/cytology ; Galantamine/pharmacology ; Glutamic Acid/toxicity ; Immunohistochemistry ; Motor Neurons/*drug effects/physiology ; Nicotine/*pharmacology ; Nicotinic Agonists/*pharmacology ; Rats ; Rats, Wistar ; Receptors, Nicotinic/*drug effects/metabolism ; Spinal Cord/*drug effects/pathology ; alpha7 Nicotinic Acetylcholine Receptor ; }, abstract = {The present study demonstrated that administration of nicotine prevented glutamate-induced motor neuronal death in primary cultures of the rat spinal cord. The nicotine-induced neuroprotection was inhibited by either dihydro-beta-erythroidin (DHbetaE) or alpha-bungarotoxin (alphaBT), suggesting that it is mediated through both alpha4beta2 and alpha7 nicotinic acetylcholine receptors (nAChRs). Both alpha4beta2 and alpha7 nAChRs were identified on rat spinal motor neurons by immunohistochemical methods. We also demonstrated that galantamine, an acetylcholinesterase inhibitor with allosteric nAChR-potentiating ligand properties, prevented glutamate-induced motor neuronal death. These results suggest that stimulation of nAChR may be used as a treatment for ALS.}, }
@article {pmid15817916, year = {2005}, author = {Rooman, RP and De Beeck, LO and Martin, M and van Doorn, J and Mohan, S and Du Caju, MV}, title = {Ethinylestradiol and testosterone have divergent effects on circulating IGF system components in adolescents with constitutional tall stature.}, journal = {European journal of endocrinology}, volume = {152}, number = {4}, pages = {597-604}, doi = {10.1530/eje.1.01880}, pmid = {15817916}, issn = {0804-4643}, support = {AR31062/AR/NIAMS NIH HHS/United States ; }, mesh = {Adolescent ; *Body Height ; Carrier Proteins/blood ; Ethinyl Estradiol/*administration &amp; dosage ; Female ; Glycoproteins/blood ; Humans ; Insulin-Like Growth Factor Binding Protein 2/blood ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor Binding Protein 4/blood ; Insulin-Like Growth Factor Binding Protein 5/blood ; Insulin-Like Growth Factor Binding Protein 6/blood ; Insulin-Like Growth Factor Binding Proteins/*blood ; Insulin-Like Growth Factor I/*analysis ; Insulin-Like Growth Factor II/*analysis ; Male ; Testosterone/*administration &amp; dosage ; }, abstract = {OBJECTIVE: Pharmacological doses of estrogens or testosterone are used to limit the final height of girls or boys with constitutional tall stature but the mechanism behind this growth inhibition is still debated. We therefore studied the changes in the circulating components of the insulin-like growth factor (IGF) system during high dose sex steroid therapy.<br><br>DESIGN AND METHODS: Twenty three girls and twenty boys with constitutional tall stature were treated with 100 microg ethinylestradiol per day or 250 mg testosterone ester every 14 days respectively. In 19 girls and 18 boys, the levels of IGF-I, free IGF-I, IGF-II, acid-labile subunit (ALS) and IGF binding proteins (IGFBP)-2 to -6 were measured before and 3-6 months after the start of therapy (group 1). In 18 girls and 11 boys, samples were collected at the end of therapy and 3 to 6 months afterwards (group 2). Fourteen girls and nine boys belonged to both groups. All parameters were measured by radioimmunoassay or ELISA.<br><br>RESULTS: Levels of IGF-I were decreased significantly by estrogen treatment but remained unchanged during testosterone treatment. Free IGF-I decreased during estrogen treatment but increased during testosterone therapy. Estrogens increased IGF-II and testosterone reduced it. The important reduction of IGFBP-2 during estrogen therapy is not reproduced by androgen therapy, neither is the stimulation by estrogens of IGFBP-4. IGFBP-3 is not modulated by either sex steroid. We found that IGFBP-6 is up-regulated by testosterone but not by estrogens; the reverse is true for ALS, which increased during estrogen treatment but remained unchanged during testosterone treatment.<br><br>CONCLUSIONS: Our findings demonstrate that androgens and estrogens exert differential effects on the circulating levels of several IGF components.}, }
@article {pmid15816863, year = {2005}, author = {Kiaei, M and Kipiani, K and Petri, S and Choi, DK and Chen, J and Calingasan, NY and Beal, MF}, title = {Integrative role of cPLA with COX-2 and the effect of non-steriodal anti-inflammatory drugs in a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {93}, number = {2}, pages = {403-411}, doi = {10.1111/j.1471-4159.2005.03024.x}, pmid = {15816863}, issn = {0022-3042}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/drug therapy/*enzymology/pathology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/*therapeutic use ; Cyclooxygenase 2 ; Cytosol/enzymology ; Disease Models, Animal ; Female ; Group IV Phospholipases A2 ; Humans ; Male ; Membrane Proteins ; Mice ; Mice, Transgenic ; Middle Aged ; Phospholipases A/antagonists &amp; inhibitors/*physiology ; Prostaglandin-Endoperoxide Synthases/*physiology ; Spinal Cord/drug effects/enzymology/pathology ; }, abstract = {Cyclooxygenase-2 (COX-2) is a key molecule in the inflammatory pathway in amyotrophic lateral sclerosis (ALS). Cytosolic phospholipase A (cPLA2) is an important enzyme providing substrate for cyclooxygenases. We therefore examined cPLA2 expression in human ALS and mutant Cu/Zn superoxide dismutase (SOD1) transgenic mice and its relation to COX-2. Immunohistochemistry and real-time RT-PCR revealed elevated cPLA2 protein and its mRNA levels in the lumbar spinal cord of mutant SOD1 mice. COX-2 immunoreactivity was increased in lumbar spinal cord sections from both familial ALS (FALS) and sporadic ALS (SALS) as compared to controls, and cPLA2 immunoreactivity was increased in a patient with FALS. Oral administration of the non-selective cyclooxygenase (COX) inhibitor, sulindac, extended the survival (by 10%) of G93A SOD1 mice as compared to littermate controls. Sulindac, as well as the selective COX-2 inhibitors, rofecoxib and celecoxib reduced cPLA2 immunoreactivity in the lumbar spinal cord of G93A transgenic mice. Sulindac treatment preserved motor neurons, and reduced microglial activation and astrocytosis, in the spinal cord of G93A SOD1 transgenic mice. These results suggest that cPLA2 plays an important role in supplying arachidonic acid to the COX-2 driven inflammatory pathway in ALS associated with SOD1 mutations.}, }
@article {pmid15815202, year = {2005}, author = {Achem, SR and Devault, KR}, title = {Dysphagia in aging.}, journal = {Journal of clinical gastroenterology}, volume = {39}, number = {5}, pages = {357-371}, doi = {10.1097/01.mcg.0000159272.88974.54}, pmid = {15815202}, issn = {0192-0790}, mesh = {Aged ; Aged, 80 and over ; Aging/*physiology ; *Deglutition Disorders/epidemiology/etiology/physiopathology ; Esophagus/physiology ; Humans ; Netherlands/epidemiology ; Peristalsis ; Prevalence ; }, abstract = {Dysphagia is a common problem in older patients and is becoming a larger health care problem as the populations of the United States and other developed countries rapidly age. Changes in physiology with aging are seen in the upper esophageal sphincter and pharyngeal region in both symptomatic and asymptomatic older individuals. Age related changes in the esophageal body and lower esophageal sphincter are more difficult to identify, while esophageal sensation certainly is blunted with age. Stroke, Parkinson's disease, amyotrophic lateral sclerosis, Zenker's diverticula, and several other motility and structural disorders may cause oropharyngeal dysphagia in an older patient. Esophageal dysphagia can also be caused by both disorders of motility (achalasia, diffuse esophageal spasm, scleroderma and others) and structure (malignancy, strictures, rings, external compression, and others). Many of these disorders have an increased prevalence in older patients and should be sought with an appropriate diagnostic evaluation in older patients. The treatment of dysphagia in older patients is similar to that in younger patients, but more invasive therapies such as surgery may not be possible in some older patients making less aggressive medical and endoscopic therapy more attractive.}, }
@article {pmid15814196, year = {2005}, author = {Ermilova, IP and Ermilov, VB and Levy, M and Ho, E and Pereira, C and Beckman, JS}, title = {Protection by dietary zinc in ALS mutant G93A SOD transgenic mice.}, journal = {Neuroscience letters}, volume = {379}, number = {1}, pages = {42-46}, doi = {10.1016/j.neulet.2004.12.045}, pmid = {15814196}, issn = {0304-3940}, support = {ES00210/ES/NIEHS NIH HHS/United States ; P01 AT002034/AT/NCCIH NIH HHS/United States ; R01 NS033291/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diet therapy/genetics/mortality ; Analysis of Variance ; Animals ; Behavior, Animal ; Body Weight/drug effects ; *Dietary Supplements ; *Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic/physiology ; Reflex/physiology ; Sex Factors ; Superoxide Dismutase/genetics ; Time Factors ; Zinc/*therapeutic use ; }, abstract = {Mutations to the copper, zinc superoxide dismutase (SOD) gene are responsible for 2-3% of amyotrophic lateral sclerosis (ALS) cases. These mutations result in the protein having a reduced affinity for zinc. SOD becomes toxic to motor neurons when zinc is missing from its active site. Recently, high dosages of zinc (75 and 375 mg/kg/day) have been paradoxically reported to increase the death of G93A-mutant SOD transgenic mice [G.J. Groeneveld, J. de Leeuw van Weenen, F.L. van Muiswinkel, H. Veldman, J.H. Veldink, J.H. Wokke, P.R. Bar, L.H. van den Berg, Zinc amplifies mSOD1-mediated toxicity in a transgenic mouse model of amyotrophic lateral sclerosis, Neurosci. Lett. 352 (2003) 175-178]. In contrast, we have found that moderate supplementation of zinc (approximately 12 mg/kg/day) delayed death in G93A-mutant SOD mice by 11 days compared to mice on a zinc-deficient diet. Supplementing zinc with even 18 mg/kg/day resulted in a more rapid death of some mice, consistent with the results of Groenevelt et al. However, large amounts of zinc competitively inhibit copper absorption, which inhibits the copper-dependent ceruloplasmin, and can cause a lethal anemia. We found that supplementing the 18 mg/kg/day dosage of zinc with 0.3 mg/kg/day of copper prevented the early death from zinc treatment alone. These data support a role for moderate levels of dietary zinc potentially protecting against the toxicity of ALS-associated SOD and the protection does not result from depleting copper.}, }
@article {pmid15811488, year = {2005}, author = {Bourcigaux, N and Arnault-Ouary, G and Christol, R and Périn, L and Charbonnel, B and Le Bouc, Y}, title = {Treatment of hypoglycemia using combined glucocorticoid and recombinant human growth hormone in a patient with a metastatic non-islet cell tumor hypoglycemia.}, journal = {Clinical therapeutics}, volume = {27}, number = {2}, pages = {246-251}, doi = {10.1016/j.clinthera.2005.02.004}, pmid = {15811488}, issn = {0149-2918}, mesh = {Aged ; Blood Glucose/drug effects ; Drug Therapy, Combination ; Female ; Fibroma/pathology ; Glucocorticoids/administration &amp; dosage/*therapeutic use ; Human Growth Hormone/administration &amp; dosage/*therapeutic use ; Humans ; Hypoglycemia/*drug therapy/etiology ; Insulin/blood ; Insulin-Like Growth Factor Binding Protein 3/metabolism ; Insulin-Like Growth Factor I/metabolism ; Liver Neoplasms/*complications/secondary ; Pleural Neoplasms/pathology ; Prednisone/administration &amp; dosage/*therapeutic use ; Recombinant Proteins/administration &amp; dosage/therapeutic use ; }, abstract = {BACKGROUND: Non-islet cell tumor hypoglycemia(NICTH) is a rare cause of recurrent hypoglycemia. It has been associated with the tumoral overproduction of high-molecular-weight insulin-like growth factor (IGF)-2 ("big IGF-2"). Big IGF-2 suppresses growth hormone (GH) biosynthesis and impairs the storage of IGFs by suppressing the formation of the GH-dependent ternary complexes containing IGF, IGF binding protein 3 (IGFBP-3), and acid-labile subunit (ALS). Thus, big IGF-2 exerts hypoglycemic activity. The only effective treatment of NICTH is surgery. However, in inoperable patients with NICTH, treatment of hypoglycemia may require high doses of glucocorticoid (30-60 mg/d [0.5-1.0 mg/kg x d]) or recombinant human GH (rhGH) (2.6-12.0 mg/d [0.043-0.20 mg/kg x d]).<br><br>OBJECTIVE: We hypothesized that the association of low doses of glucocorticoid and rhGH could be an effective therapy for hypoglycemia in inoperable patients with NICTH.<br><br>METHODS: A 3-phase treatment regimen was conducted in an inoperable 67-year-old woman with NICTH. Decreasing dosages of prednisone (from 30 to 10 mg/d [from 0.50 to 0.15 mg/kg x d]), followed by decreasing doses of rhGH (from 2.6 to 1.3 mg/d [from 0.043 to 0.016 mg/kg x d]), and then a combination of the lowest doses of each, were tested. Glucose, insulin, and IGF monitoring were performed at each of the 3 treatment phases.<br><br>RESULTS: Fasting plasma glucose (FPG) level was normalized and the IGF-1 concentration was increased with high-dose prednisone monotherapy (30 mg/d [0.50 mg/kg x d]) or rhGH (2.6 mg/d [0.043 mg/kg x d]). Prednisone monotherapy partially suppressed big IGF-2 secretion, and rhGH monotherapy acted on IGFBP-3 and ALS concentrations. FPG level was normalized with combined low-dose prednisone and rhGH, and this combination was more effective than high-dose monotherapy with either drug in reestablishing the IGF system. No adverse effects (AEs) were found.<br><br>CONCLUSIONS: In this patient with inoperable NICTH, the combination of low doses of prednisone and rhGH was a successful long-term therapy for hypoglycemia, with no AEs. This therapy could be proposed for use in patients with inoperable NICTH.}, }
@article {pmid15808566, year = {2005}, author = {Witkowski, P and Fawwaz, RA and Jin, MX and DePaz, HA and Oluwole, OO and Hardy, MA and Oluwole, SF}, title = {Effect of streptavidin on cardiac allograft prolongation is due to host T-Cell suppression.}, journal = {Transplantation proceedings}, volume = {37}, number = {1}, pages = {116-118}, doi = {10.1016/j.transproceed.2004.12.075}, pmid = {15808566}, issn = {0041-1345}, mesh = {Animals ; Antilymphocyte Serum/therapeutic use ; Graft Survival/drug effects/*immunology ; Heart Transplantation/*immunology ; Immunosuppressive Agents/therapeutic use ; Lymphocyte Activation/drug effects/immunology ; Lymphocyte Transfusion ; Rats ; Rats, Inbred Lew ; Rats, Inbred WF ; Spleen/immunology/radiation effects ; Streptavidin/*therapeutic use ; T-Lymphocytes/drug effects/*immunology ; Transplantation, Homologous/immunology ; }, abstract = {AIM: The aim of this study was to evaluate the effectiveness of streptavidin immunomodulation in the high-responder WF-to-Lewis combination.<br><br>METHODS/RESULTS: We examined the effects of streptavidin on the proliferative response of T cells in coculture studies. Two to 200 microg/mL streptavidin significantly (P < .001) suppressed the proliferation of Lewis T cells to WF by 76%-83% compared with untreated responders. Next, we studied the survival of WF cardiac allografts in Lewis recipients pretreated with streptavidin. A 5-day course of peritransplantation recipient treatment with streptavidin doses of 8, 12, 20, 40, and 60 mg/kg combined with single dose of 0.5 mL antilymphocyte serum (ALS) significantly (P < .001) prolonged cardiac allograft survival from MST of 7 +/- 0.5 and 8 +/- 0.5 days in naive and ALS-treated controls to 15 +/- 1, 20 +/- 3, 16 +/- 3, 17 +/- 3, and 23 +/- 2 days, respectively. In contrast, posttransplantation administration of 80 mg/kg streptavidin resulted in animal death, suggesting toxicity of this dose. Additionally, 10 mg/kg or 20 mg/kg streptavidin administration for 10 consecutive days resulted in significant graft prolongation (MST of 18 +/- 1 and 21 +/- 1 days, respectively; P < .001).<br><br>CONCLUSION: Although peritransplantation streptavidin treatment is effective in prolonging rat cardiac allografts in the high-responder WF-to-Lewis combination, it does not induce permanent graft survival as observed in the low-responder combination of Lewis-to-ACI. Our finding of in vitro immunomodulatory effect of streptavidin on T-cell proliferation suggests that its in vivo effect is partly due to prevention of T-cell activation following antigen exposure.}, }
@article {pmid15804265, year = {2005}, author = {Azari, MF and Profyris, C and Le Grande, MR and Lopes, EC and Hirst, J and Petratos, S and Cheema, SS}, title = {Effects of intraperitoneal injection of Rofecoxib in a mouse model of ALS.}, journal = {European journal of neurology}, volume = {12}, number = {5}, pages = {357-364}, doi = {10.1111/j.1468-1331.2004.00987.x}, pmid = {15804265}, issn = {1351-5101}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Blotting, Western ; Cyclooxygenase Inhibitors/*administration &amp; dosage ; Dinoprostone/analysis ; Disease Models, Animal ; Disease Progression ; Female ; Humans ; Immunohistochemistry ; Injections, Intraperitoneal ; Lactones/*administration &amp; dosage ; Mice ; Mice, Transgenic ; Microglia/drug effects ; Motor Activity/drug effects ; Spinal Cord/drug effects/pathology ; Sulfones/*administration &amp; dosage ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {There is increasing evidence that inflammatory mechanisms are involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Inhibition of a key mediator of inflammation, cyclooxygenase 2 (COX-2), represents a promising therapeutic approach in ALS. Here we tested the in vivo effects of a specific COX-2 inhibitor, Rofecoxib, administered by intraperitoneal injection, in the SOD1(G93A G1H) mouse model of the familial form of ALS (fALS). Rofecoxib administration commenced at postnatal day 60 (P60), since the hallmarks of inflammation in the spinal cord were found to occur beyond this time-point in this mouse model of fALS. We found a significant but small delay in the onset of locomotor impairment in mice treated with Rofecoxib at the dose of 10 mg/kg of weight. However, survival was not effected by treatment. As prostaglandin E2 levels in spinal cord or in plasma were not reduced by Rofecoxib treatment, these results may suggest lack of sufficient bioavailability as the reason for the modest clinical changes observed.}, }
@article {pmid15804220, year = {2005}, author = {Kiernan, MC}, title = {Riluzole: a glimmer of hope in the treatment of motor neurone disease.}, journal = {The Medical journal of Australia}, volume = {182}, number = {7}, pages = {319-320}, pmid = {15804220}, issn = {0025-729X}, mesh = {Clinical Trials as Topic ; Humans ; Motor Neuron Disease/*drug therapy ; Neuroprotective Agents/pharmacology/*therapeutic use ; Riluzole/pharmacology/*therapeutic use ; }, abstract = {Early experience confirms that riluzole improves survival and is well tolerated.}, }
@article {pmid15799556, year = {2004}, author = {Steele, J and Matos, LA and Lopez, EA and Perez-Pinzon, MA and Prado, R and Busto, R and Arheart, KL and Bradley, WG}, title = {A Phase I safety study of hyperbaric oxygen therapy for amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {4}, pages = {250-254}, doi = {10.1080/14660820410021285}, pmid = {15799556}, issn = {1466-0822}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*physiopathology/*therapy ; Female ; Humans ; Hyperbaric Oxygenation/*adverse effects/*methods ; Linear Models ; Male ; Middle Aged ; }, abstract = {BACKGROUND: Vascular endothelial growth factor and mitochondrial abnormalities have been described in ALS and its animal models. We have reported that hyperbaric oxygen (HBO) treatment delayed the onset of weakness in the wobbler mouse.<br><br>OBJECTIVE: To perform a Phase I safety study of HBO in patients with ALS.<br><br>METHODS: Five patients with ALS were treated for 60min with 100% oxygen at 2 atmospheres pressure daily for five days a week for four weeks. The patients reported any deterioration in their condition after each treatment, and their neurological condition was measured serially during the four weeks of the treatment, and for four further weeks.<br><br>RESULTS: Four patients reported decreased fatigue, while one patient dropped out at three weeks because of increased fatigue. Maximum isometric voluntary contraction (MVIC) of all muscle groups except right hand grip improved significantly by up to 97%. Most improvement occurred during the four weeks after treatment. It is possible that the improvement in muscle strength was a placebo or a learning effect, though no such effects have been detected in prior therapeutic trials in ALS using MVIC. No change was detected in other measures of neuromuscular function.<br><br>CONCLUSIONS: A longer duration, placebo controlled trial in a larger number of patients is needed to determine the safety and efficacy of HBO. Until that is completed, it is not recommended that ALS patients should be treated with HBO.}, }
@article {pmid15799554, year = {2004}, author = {Bradley, WG and Anderson, F and Gowda, N and Miller, RG and , }, title = {Changes in the management of ALS since the publication of the AAN ALS practice parameter 1999.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {4}, pages = {240-244}, pmid = {15799554}, issn = {1466-0822}, mesh = {Academies and Institutes/*standards ; Amyotrophic Lateral Sclerosis/*epidemiology/*therapy ; *Databases, Factual ; Disease Management ; Humans ; Neurology/*standards ; Palliative Care/standards/statistics &amp; numerical data ; Practice Guidelines as Topic/*standards ; United States ; }, abstract = {OBJECTIVE: To determine if the publication in 1999 of the AAN Practice Parameter on ALS was associated with an improvement in the standard of management of the disease.<br><br>METHODS: Data on 646 patients enrolled in the ALS CARE database and on 465 patients who died in the period May 2001 to November 2002 were compared with similar data obtained from the database from 1996 to May 1999.<br><br>RESULTS: The specialty ALS clinics were the most important source of information about ALS. The internet was a source for 39%. The treatment of sialorrhea, pseudobulbar emotional lability, and failure of swallowing and breathing had all improved significantly in the period after the publication of the Practice Parameter. However many patients still did not receive a gastrostomy tube or non-invasive positive pressure ventilation when indicated by the Practice Parameter, mainly because of lack of patient compliance. Cost was the main reason why 41% of patients did not receive riluzole, though they spent a third of the cost of this medication on alternative medicines.<br><br>CONCLUSIONS: The publication of the AAN Practice Parameter was associated with improvement in the standard of care. Most cases in the database come from specialized ALS centers, and further information on the community care of ALS patients is needed.}, }
@article {pmid15799551, year = {2004}, author = {van den Berg, JP and de Groot, IJ and Joha, BC and van Haelst, JM and van Gorcom, P and Kalmijn, S}, title = {Development and implementation of the Dutch protocol for rehabilitative management in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {4}, pages = {226-229}, pmid = {15799551}, issn = {1466-0822}, mesh = {Activator Appliances ; Amyotrophic Lateral Sclerosis/diagnosis/*rehabilitation ; *Clinical Protocols/standards ; Disease Management ; Hospitals, Chronic Disease ; Humans ; Netherlands ; Occupational Therapy/instrumentation ; Patient Care Management/*methods ; Practice Guidelines as Topic/standards ; Referral and Consultation ; }, abstract = {INTRODUCTION: In the Netherlands, rehabilitation care plays an important role in the symptomatic and palliative treatment of ALS patients. However, until 1999 there were no guidelines or practice parameters available for the management of ALS. Therefore, the Dutch protocol for rehabilitative management in ALS was developed. We describe the development process, the outcome and implementation of the protocol.<br><br>METHODS: A concept management protocol was written and the Delphi method was selected to develop the protocol further. This method comprises repetitive discussion sessions from postulates, using a combination of written questionnaires and work-conferences. Between 80 and 90 persons (rehabilitation team members of different professional backgrounds and neurologists) were involved in this process. The protocol was implemented by sending it to all consultants in rehabilitation medicine in the Netherlands; they were asked to inform all the treatment team members about the final protocol and to implement it in their treatment of ALS patients.<br><br>RESULTS: The protocol was developed in 1999, implemented in 2000 and evaluated in 2001. Recommendations for improvement were made during the evaluation and improvements are currently being developed by an expert group. The protocol is widely used (88.9%) by consultants in rehabilitation medicine and their treatment teams in the Netherlands.<br><br>CONCLUSIONS: The Dutch protocol for rehabilitative management was developed to provide an optimal and adequate care plan for patients with ALS. It is widely used in the Netherlands.}, }
@article {pmid15799550, year = {2004}, author = {Groeneveld, GJ and van Muiswinkel, FL and de Leeuw van Weenen, J and Blauw, H and Veldink, JH and Wokke, JH and van den Berg, LH and Bär, PR}, title = {CGP 3466B has no effect on disease course of (G93A) mSOD1 transgenic mice.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {4}, pages = {220-225}, doi = {10.1080/14660820410019530}, pmid = {15799550}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*enzymology/genetics ; Animals ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; Motor Neurons/drug effects/enzymology ; Oxepins/pharmacology/*therapeutic use ; Superoxide Dismutase/*genetics ; }, abstract = {BACKGROUND: There is an accumulating body of evidence that apoptosis is involved in the motor neuron death that occurs in ALS, and in the (G93A) mSOD1 transgenic mouse model (mSOD1 mice). CGP 3466B, a tricyclic propargylamine structurally related to (-)-deprenyl, was found to inhibit apoptosis in a wide variety of in vitro and in vivo models. We therefore studied the effect of CGP 3466B in mSOD1 mice.<br><br>METHODS: As the effect of CGP 3466B was previously reported to have a bell-shaped curve, we performed a dose-ranging study. High-copy G93A mSOD1 mice were treated subcutaneously from the age of 50 days until death with four concentrations of CGP 3466B (0.39 microg kg(-1), 3.9 microg kg(-1), 39 microg kg(-1), and 390 microg kg(-1)). Behavioural tests were performed daily to determine disease onset, disease progression and survival. At the age of 110 days, two mice per group were sacrificed for histopathological analysis of the lumbar ventral horn and for semiquantitative analysis of motor neuron number.<br><br>RESULTS: We observed no effect on disease onset, disease progression, or survival of the mice. We also did not observe a significant effect on the number of motor neurons due to CGP 3466B.<br><br>CONCLUSIONS: We conclude that in high-copy G93A mSOD1 mice, chronic subcutaneous treatment with CGP 3466B offers no clinical benefit.}, }
@article {pmid15799548, year = {2004}, author = {Testa, D and Lovati, R and Ferrarini, M and Salmoiraghi, F and Filippini, G}, title = {Survival of 793 patients with amyotrophic lateral sclerosis diagnosed over a 28-year period.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {4}, pages = {208-212}, pmid = {15799548}, issn = {1466-0822}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*epidemiology ; Chi-Square Distribution ; Confidence Intervals ; Female ; Humans ; Male ; Middle Aged ; Proportional Hazards Models ; Retrospective Studies ; Survival Analysis ; }, abstract = {We reviewed retrospectively 793 consecutive patients discharged with ALS diagnosis between 1971 and 1998 to identify survival predictors. Vital status in July 2001 was known for all patients. Mean age at onset was 56 (SD 11.7) years and mean age at diagnosis was 57.4 (SD 11.5) years. Onset symptoms were bulbar in 20.8% of patients. The median survival time from symptoms onset was 2.9 years (95% CI 2.7-3.1). Survival from onset was 93% after one, 48% after three and 24% after five years. Median survival was shorter in patients with time between onset and diagnosis <12 months than in those diagnosed> 23 months; (2.1 years vs. 5.9 years; P<0.001). Patients with onset after age 65 had a 4.2 times greater risk of death than patients less than 40 years. Bulbar onset was associated with 1.4 times greater risk of death than spinal onset. Patients diagnosed after 1990 had longer median survival (3.3 years) than those diagnosed in 1971-1979 (2.4 years) (P<0.001). As expected, age, bulbar onset and short time from onset to diagnosis were independent predictors of survival. We also found a significant increase in survival over time, probably due to improved comprehensive treatment of ALS patients in Italy.}, }
@article {pmid15799547, year = {2004}, author = {Groeneveld, GJ and van der Tweel, I and Wokke, JH and van den Berg, LH}, title = {Sequential designs for clinical trials in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {4}, pages = {202-207}, pmid = {15799547}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Confidence Intervals ; Creatine/therapeutic use ; Double-Blind Method ; Humans ; Randomized Controlled Trials as Topic/*methods ; Research Design ; Sample Size ; Survival Analysis ; }, abstract = {BACKGROUND: The objective of this paper is to discuss the sequential trial design and its advantages in clinical trials for ALS. The sequential trial design is an alternative to the classical trial design, which permits stopping a study as soon as a treatment effect can be significantly demonstrated or denied.<br><br>METHODS: As an example of a sequential survival analysis, a recently completed clinical trial is described. A secondary outcome measure used in the same trial, the decline of the vital lung capacity, was re-analyzed sequentially, in order to illustrate the use of the sequential method for a non-survival variable. To compare the classical with the sequential trial design, the number of patients needed in trials aiming at survival effects ranging from 10% to 20% with a power of 80% or 90% was calculated for both designs.<br><br>RESULTS: In the given examples the time needed to prove the null hypothesis in the survival analysis, and the number of patients needed to prove the null hypothesis in the analysis of the vital capacity is lower than would have been the case in a classical analysis. In 18 of 24 different situations, the chance is at least 90% that with a sequential trial design fewer patients are needed.<br><br>CONCLUSIONS: We argue that, particularly for ALS trials, a sequential design may be superior to a classical trial design, as it most often requires fewer patients than classically designed trials of equal power, and more importantly may avoid unnecessary continuation.}, }
@article {pmid15799546, year = {2004}, author = {Chiò, A and Borasio, GD}, title = {Breaking the news in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {4}, pages = {195-201}, doi = {10.1080/14660820310017326}, pmid = {15799546}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*psychology ; Humans ; *Physician-Patient Relations/ethics ; *Truth Disclosure/ethics ; }, abstract = {Diagnosis communication is a mainstay of the patient-physician relationship and in ALS represents the beginning of the treatment. In Europe, the diagnosis is now communicated to most patients, but with some differences from north to south. Communication is the basis of the patient's autonomy. When adequately informed, patients are able to consider their preferences about life-extending interventions. However, this discussion is sometimes entertained too late. Both the style and the context of this discussion have profound impact on patient satisfaction. The content of the communication should include all relevant information about the disease and should be performed honestly while preserving hope. Collusion with relatives can create difficulties in the relationship with a patient and isolate them from their family. Diagnostic communication is an ongoing process and should form part of every follow-up visit. Communication with the dying patient is often reinforced by non-verbal messages, acknowledgements of patients' emotions, and by listening. Written material may increase satisfaction of patients and their relatives, but should never substitute for face-to-face discussion.}, }
@article {pmid15795816, year = {2005}, author = {Groeneveld, GJ and Beijer, C and Veldink, JH and Kalmijn, S and Wokke, JH and van den Berg, LH}, title = {Few adverse effects of long-term creatine supplementation in a placebo-controlled trial.}, journal = {International journal of sports medicine}, volume = {26}, number = {4}, pages = {307-313}, doi = {10.1055/s-2004-817917}, pmid = {15795816}, issn = {0172-4622}, mesh = {Administration, Oral ; Adolescent ; Adult ; Aged ; Albuminuria/chemically induced ; Amyotrophic Lateral Sclerosis/*diet therapy/metabolism ; Creatine/*administration &amp; dosage/*adverse effects/urine ; Creatinine/blood ; Diarrhea/chemically induced ; Dietary Supplements/*adverse effects ; Double-Blind Method ; Female ; Humans ; Kidney/metabolism ; Male ; Middle Aged ; Nausea/chemically induced ; Time ; Treatment Outcome ; Urea/metabolism ; }, abstract = {Although oral creatine supplementation is very popular among athletes, no prospective placebo-controlled studies on the adverse effects of long-term supplementation have yet been conducted. We performed a double-blind, placebo-controlled trial of creatine monohydrate in patients with the neurodegenerative disease amyotrophic lateral sclerosis, because of the neuroprotective effects it was shown to have in animal experiments. The purpose of this paper is to compare the adverse effects, and to describe the effects on indirect markers of renal function of long-term creatine supplementation. 175 subjects (age = 57.7 +/- 11.1 y) were randomly assigned to receive creatine monohydrate 10 g daily or placebo during an average period of 310 days. After one month, two months and from then on every fourth month, adverse effects were scored using dichotomous questionnaires, plasma urea concentrations were measured, and urinary creatine and albumin concentrations were determined. No significant differences in the occurrence at any time of adverse effects due to creatine supplementation were found (23 % nausea in the creatine group, vs. 24 % in the placebo group, 19 % gastro-intestinal discomfort in the creatine group, vs. 18 % in the placebo group, 35 % diarrhoea in the creatine group, vs. 24 % in the placebo group). After two months of treatment, oedematous limbs were seen more often in subjects using creatine, probably due to water retention. Severe diarrhoea (n = 2) and severe nausea (n = 1) caused 3 subjects in the creatine group to stop intake of creatine, after which these adverse effects subsided. Long-term supplementation of creatine did not lead to an increase of plasma urea levels (5.69 +/- 1.47 before treatment vs. 5.26 +/- 1.44 at the end of treatment) or to a higher prevalence of micro-albuminuria (5.4 % before treatment vs. 1.8 % at the end of treatment).}, }
@article {pmid15791286, year = {2005}, author = {Wilson, JM and Petrik, MS and Moghadasian, MH and Shaw, CA}, title = {Examining the interaction of apo E and neurotoxicity on a murine model of ALS-PDC.}, journal = {Canadian journal of physiology and pharmacology}, volume = {83}, number = {2}, pages = {131-141}, doi = {10.1139/y04-140}, pmid = {15791286}, issn = {0008-4212}, mesh = {Amino Acid Transport System X-AG/metabolism ; Amyotrophic Lateral Sclerosis/*etiology/metabolism/physiopathology ; Animals ; Apolipoproteins E/*genetics ; Apoptosis ; Behavior, Animal ; Brain/pathology ; Caspase 3 ; Caspases/metabolism ; Cell Count ; Cholesterol/blood ; Cycas/*adverse effects ; Dementia/*etiology/metabolism/physiopathology ; Disease Models, Animal ; Male ; Mice ; Mice, Inbred C57BL ; Motor Neurons/pathology ; Parkinsonian Disorders/*etiology/metabolism/physiopathology ; Spinal Cord/pathology ; Tyrosine 3-Monooxygenase/metabolism ; }, abstract = {Epidemiological studies have shown a positive relationship between cycad flour consumption and the development of the neurodegenerative disorder, amyotrophic lateral sclerosis - parkinsonism - dementia complex (ALS-PDC). Apolipoprotein E (apo E) allele variations have been associated with genetic susceptibility in neurodegenerative diseases, including ALS-PDC. We have studied cycad toxicity in a mouse model of ALS-PDC with a particular interest in its impact on the central nervous system (CNS) in both apo E knock-out (KO) mice and their wild-type (WT) counterparts. Behavioral motor tests, motor neuron counts, and immunohistochemical staining in brain and spinal cord, as well as routine histological examinations on internal organs, were performed to evaluate cycad toxicity. Plasma cholesterol levels were also measured before and during the study. Cycad treatment was associated with higher levels of plasma cholesterol only in apo E KO mice; increased levels of plasma cholesterol did not result in increased athero genesis. Cycad-fed wild-type mice developed progressive behavioral deficits including ALS-PDC-like pathological outcomes, while cycad-fed apo E KO mice were not significantly affected. Cycad-fed wild-type mice had shorter gait length measurements along with higher active caspase-3 levels in the striatum, substantia nigra, primary motor cortex, and spinal cord as compared with corresponding controls. These changes were associated with decreased labeling for glutamate transporter 1B and tyrosine hydroxylase activity levels. No evidence of cycad toxicity was observed in internal organs of either wild-type or apo E KO mice. Our data demonstrate that apo E KO mice are less susceptible to cycad toxicity, suggesting a role for apo E as a possible genetic susceptibility factor for some forms of toxin-induced neurodegeneration.}, }
@article {pmid15780490, year = {2005}, author = {Geier, MR and Geier, DA}, title = {The potential importance of steroids in the treatment of autistic spectrum disorders and other disorders involving mercury toxicity.}, journal = {Medical hypotheses}, volume = {64}, number = {5}, pages = {946-954}, doi = {10.1016/j.mehy.2004.11.018}, pmid = {15780490}, issn = {0306-9877}, mesh = {Autistic Disorder/chemically induced/*drug therapy ; Case-Control Studies ; Humans ; Mercury/*adverse effects/pharmacokinetics ; Testosterone/antagonists &amp; inhibitors/blood/*therapeutic use ; }, abstract = {Autism is a neurodevelopmental disorder that according to the Centers for Disease Control and Prevention (CDC) affects 1 in 150 children in the United States. Autism is characterized by impairments in social relatedness and communication, repetitive behaviors, abnormal movements, and sensory dysfunction. Recently emerging evidence suggests that mercury, especially from childhood vaccines, appears to be a factor in the development of the autistic disorders, and that autistic children have higher than normal body-burdens of mercury. In considering mercury toxicity, it has previously been shown that testosterone significantly potentates mercury toxicity, whereas estrogen is protective. Examination of autistic children has shown that the severity of autistic disorders correlates with the amount of testosterone present in the amniotic fluid, and an examination of a case-series of autistic children has shown that some have plasma testosterone levels that were significantly elevated in comparison neurotypical control children. A review of some of the current biomedical therapies for autistics, such as glutathione and cysteine, chelation, secretin, and growth hormone, suggests that they may in fact lower testosterone levels. We put forward the medical hypothesis that autistic disorders, in fact, represents a form of testosterone mercury toxicity, and based upon this observation, one can design novel treatments for autistics directed towards higher testosterone levels in autistic children. We suggest a series of experiments that need to be conducted in order to evaluate the exact mechanisms for mercury-testosterone toxicity, and various types of clinical manipulations that may be employed to control testosterone levels. It is hoped by devising therapies that address the steroid hormone pathways, in addition to the current treatments that successful lower heavy metal body-burdens of mercury, will work synergistically to improve clinical outcomes. In light of the fact that there are a number of other diseases that may have a chronic mercury toxicity component, such as Alzheimer's disease, heart disease, obesity, ALS, asthma, and other various forms of autoimmune disorders, it is imperative that further research should be conducted to understand mercury-testosterone toxicity.}, }
@article {pmid15777251, year = {2005}, author = {Czlonkowska, A and Ciesielska, A and Gromadzka, G and Kurkowska-Jastrzebska, I}, title = {Estrogen and cytokines production - the possible cause of gender differences in neurological diseases.}, journal = {Current pharmaceutical design}, volume = {11}, number = {8}, pages = {1017-1030}, doi = {10.2174/1381612053381693}, pmid = {15777251}, issn = {1381-6128}, mesh = {Animals ; Cytokines/*biosynthesis/physiology ; Estrogens/*physiology ; Female ; Humans ; Male ; Nervous System Diseases/metabolism/*physiopathology ; Sex Characteristics ; }, abstract = {Naturally occurring sexual dimorphism has been implicated in the risk, progression and recovery from numerous neurological disorders. These include head injury, multiple sclerosis (MS), stroke, and neurodegenerative diseases (Parkinson's disease (PD), Alzheimer's disease (AD) or amyotrophic lateral sclerosis (ALS). Accumulating evidence suggests that observed differences between men and women could result from estrogen's wide range of effects within the mammalian central nervous system (CNS), with it's neuroprotective effect being one of the most important. It seems possible that neuroprotective activity of estrogen could be partially a result of it's anti-inflammatory action. It has been well established that inflammation plays an important role in the etiopathogenesis and manifestation of brain pathological changes. In this regard, an important role has been suggested for pro-inflammatory cytokines produced by activated glial cells, neurons and immune cells that invade brain tissue. Within the CNS, cytokines stimulate inflammatory processes that may impair blood-brain barrier permeability as well as promote apoptosis of neurons, oligodendrocytes and induce myelin damage. Given that estrogen may modulate cytokine expression, coupled with the fact that gender differences of cytokine production are apparent in animal models of PD and MS, suggests an important connection between hormonal-cytokine link in neurodegeneration. Indeed, while MS patients and mice subjected to experimental autoimmune encephalomyelitis (EAE) display gender specific alterations of IFN-gamma and IL-12, variations of TNF and IL-6 were associated with PD. Also in case of more acute neurodegenerative conditions, such as stroke, the effect of IL-6 gene G-174C polymorphism was different in males and females. Given that our understanding of the role of estrogen on cytokine production and accompanying CNS pathological conditions is limited, the present reviews aims to present some of our recent findings in this area and further evaluate the evidence that may be relevant to the design of new hormonal anti-inflammatory treatment strategies for neurodegenerative diseases.}, }
@article {pmid15768029, year = {2005}, author = {Ralph, GS and Radcliffe, PA and Day, DM and Carthy, JM and Leroux, MA and Lee, DC and Wong, LF and Bilsland, LG and Greensmith, L and Kingsman, SM and Mitrophanous, KA and Mazarakis, ND and Azzouz, M}, title = {Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model.}, journal = {Nature medicine}, volume = {11}, number = {4}, pages = {429-433}, doi = {10.1038/nm1205}, pmid = {15768029}, issn = {1078-8956}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/therapy ; Animals ; Disease Models, Animal ; Genetic Therapy ; Genetic Vectors ; Humans ; Lentivirus/genetics ; Mice ; Mice, Transgenic ; Mutation ; *Nerve Degeneration ; *RNA Interference ; RNA, Small Interfering ; Superoxide Dismutase/*genetics ; Survival Rate ; Transfection ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in the selective death of motor neurons in the brain and spinal cord. Some familial cases of ALS are caused by dominant mutations in the gene encoding superoxide dismutase (SOD1). The emergence of interfering RNA (RNAi) for specific gene silencing could be therapeutically beneficial for the treatment of such dominantly inherited diseases. We generated a lentiviral vector to mediate expression of RNAi molecules specifically targeting the human SOD1 gene (SOD1). Injection of this vector into various muscle groups of mice engineered to overexpress a mutated form of human SOD1 (SOD1(G93A)) resulted in an efficient and specific reduction of SOD1 expression and improved survival of vulnerable motor neurons in the brainstem and spinal cord. Furthermore, SOD1 silencing mediated an improved motor performance in these animals, resulting in a considerable delay in the onset of ALS symptoms by more than 100% and an extension in survival by nearly 80% of their normal life span. These data are the first to show a substantial extension of survival in an animal model of a fatal, dominantly inherited neurodegenerative condition using RNAi and provide the highest therapeutic efficacy observed in this field to date.}, }
@article {pmid15752377, year = {2005}, author = {van Kan, HJ and Groeneveld, GJ and Kalmijn, S and Spieksma, M and van den Berg, LH and Guchelaar, HJ}, title = {Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis.}, journal = {British journal of clinical pharmacology}, volume = {59}, number = {3}, pages = {310-313}, pmid = {15752377}, issn = {0306-5251}, mesh = {Administration, Oral ; Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/drug therapy/*enzymology ; Anticonvulsants/*pharmacokinetics/therapeutic use ; Caffeine/metabolism ; Cytochrome P-450 CYP1A2/*metabolism ; Female ; Humans ; Male ; Middle Aged ; Riluzole/*pharmacokinetics/therapeutic use ; Theophylline/metabolism ; }, abstract = {AIMS: Riluzole is used in a fixed dosing schedule of 50 mg twice daily to treat patients with amyotropic lateral sclerosis (ALS), one form of motor neurone disease. The large variability in the pharmacokinetics of riluzole may be a factor contributing to its limited therapeutic benefit. Riluzole is assumed to be mainly metabolized by the cytochrome P450 enzyme 1A2 (CYP1A2). The aim of the study was to investigate the relationship between CYP1A2 activity and riluzole clearance with a view to optimize drug treatment.<br><br>METHODS: A group of 30 ALS patients participated in the study. In each patient the CYP1A2 activity was determined using caffeine as a metabolic probe. Riluzole clearance was estimated from serum drug concentration measurements followed by Bayesian fitting.<br><br>RESULTS: Riluzole clearance and the serum paraxanthine : caffeine (P/C) ratio showed a positive correlation (r = 0.693; P = 0.0002). Linear regression analysis identified the P/C ratio (beta: 1.16) and height (beta: 0.027) as independent predictors of riluzole clearance (adjusted r2 = 0.369).<br><br>CONCLUSIONS: The P/C ratio, used as measure of CYP1A2 activity, significantly correlated with the riluzole clearance, although only 37% of the observed variability could be explained.}, }
@article {pmid15736608, year = {2005}, author = {Carter, GT and Weiss, MD and Lou, JS and Jensen, MP and Abresch, RT and Martin, TK and Hecht, TW and Han, JJ and Weydt, P and Kraft, GH}, title = {Modafinil to treat fatigue in amyotrophic lateral sclerosis: an open label pilot study.}, journal = {The American journal of hospice &amp; palliative care}, volume = {22}, number = {1}, pages = {55-59}, doi = {10.1177/104990910502200112}, pmid = {15736608}, issn = {1049-9091}, support = {2P01 HD33988-06A1/HD/NICHD NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*complications/drug therapy ; Benzhydryl Compounds/*administration &amp; dosage/adverse effects ; Central Nervous System Stimulants/*administration &amp; dosage/adverse effects ; Fatigue/*drug therapy/*etiology ; Female ; Humans ; Male ; Modafinil ; Pilot Projects ; Severity of Illness Index ; Treatment Outcome ; Wakefulness/drug effects ; }, abstract = {An open label trial of modafinil was conducted to determine whether it would be tolerated and effective in treating fatigue for people with amyotrophic lateral sclerosis (ALS). Fifteen patients with ALS were treated for two weeks with either 200 mg or 400 mg of modafinil. Reported side effects of the medication were mild and included diarrhea, headache, nervousness, and insomnia. Side effects did not result in any study dropouts. Following treatment, mean scores on the Fatigue Severity Scale (FSS) decreased from 51.3 (SD 9.2) to 42.8 (SD 10.2). On the Epworth Sleepiness Scale (ESS), mean scores decreased from 8.2 (SD 2.0) to 4.5 (SD 2.4). Reductions in both the FSS and the ESS were significant at p < 0.001. Mean scores on the self-report version of the Functional Independence Measure (FIM-SR) increased from 115.2 (SD 5.6) to 118.1 (SD 5.4), with p < 0.01. This pilot study suggests that modafinil is well-tolerated and may reduce symptoms of fatigue in ALS. Further blinded, controlled studies of modafinil in larger numbers of ALS patients are warranted.}, }
@article {pmid15730716, year = {2004}, author = {Gu, WY and Chen, ZX and Cao, XS and Hu, SY and Zhu, J and Wang, ZL and Yan, F and Wang, W and Cen, JN and Shen, HL and Qian, J}, title = {[Detection of WT1 expression in bone marrow of acute leukemia patients with real-time quantitative RT-PCR].}, journal = {Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi}, volume = {25}, number = {12}, pages = {728-731}, pmid = {15730716}, issn = {0253-2727}, mesh = {Acute Disease ; Adolescent ; Adult ; Aged ; Bone Marrow Cells/*metabolism ; Child ; Female ; Gene Expression Regulation, Leukemic ; Humans ; K562 Cells ; Leukemia/blood/*genetics ; Leukemia, Monocytic, Acute/blood/genetics ; Leukemia, Myeloid/blood/genetics ; Male ; Middle Aged ; Reverse Transcriptase Polymerase Chain Reaction/*methods ; WT1 Proteins/*genetics ; Young Adult ; }, abstract = {OBJECTIVE: To investigate Wilms' tumor gene (WT1) expression levels in bone marrow (BM) of acute leukemia patients (ALs).<br><br>METHODS: A real-time quantitative reverse transcriptase polymerase chain reaction (RQ-RT-PCR) method was established for detecting WT1 and internal reference GAPDH expression levels in BM of 108 ALs and 23 non-leukemia controls by Light Cycler.<br><br>RESULTS: The median expression levels of WT1 in 70 newly diagnosed ALs and 11 relapsed ALs were statistically higher than those in 23 ALs in complete remission (CR) and 23 non-leukemic controls (75.10 and 89.56 vs 2.07 and 1.51 respectively). No statistic differences was found between the CR group and control group, nor between the newly diagnosed group and relapsed group. Of the 70 newly diagnosed ALs, median WT1 expression level of acute granulocytic leukemias was significantly higher than that of acute monocytic leukemias (M(5)), but there was no statistic differences among the M(1), M(2), M(3) and ALL subtypes. Furthermore the WT1 levels were not correlated to peripheral WBC counts, BM blast percentage and multidrug resistant gene (mdr1) expression at presentation, but correlated to chromosome karyotypes. Dynamic analysis of WT1 levels of 2 patients on treatment showed that WT1 expression levels predicted relapse.<br><br>CONCLUSION: WT1 expression levels in ALs were strikingly higher than that in non-leukemias. WT1 can be a marker for detecting MRD and evaluating therapy efficacy in leukemias.}, }
@article {pmid15723612, year = {2005}, author = {Langley, B and Gensert, JM and Beal, MF and Ratan, RR}, title = {Remodeling chromatin and stress resistance in the central nervous system: histone deacetylase inhibitors as novel and broadly effective neuroprotective agents.}, journal = {Current drug targets. CNS and neurological disorders}, volume = {4}, number = {1}, pages = {41-50}, doi = {10.2174/1568007053005091}, pmid = {15723612}, issn = {1568-007X}, mesh = {Acetylation/drug effects ; Acetyltransferases/antagonists &amp; inhibitors/metabolism ; Animals ; Cell Division/drug effects ; Central Nervous System/drug effects/*enzymology ; Chromatin/*metabolism ; Enzyme Inhibitors/*pharmacology/therapeutic use ; Gene Expression Regulation/drug effects ; Histone Acetyltransferases ; *Histone Deacetylase Inhibitors ; Histone Deacetylases/metabolism ; Humans ; Neoplasms/drug therapy ; Nervous System Diseases/*drug therapy ; Neuroprotective Agents/*pharmacology/therapeutic use ; Protein Processing, Post-Translational ; Stress, Physiological/drug therapy/enzymology ; }, abstract = {Acetylation and deacetylation of histone protein plays a critical role in regulating gene expression in a host of biological processes including cellular proliferation, development, and differentiation. Accordingly, aberrant acetylation and deacetylation resulting from the misregulation of histone acetyltransferases (HATs) and/or histone deacetylases (HDACs) has been linked to clinical disorders such as Rubinstein-Taybi syndrome, fragile X syndrome, leukemia, and various cancers. Of significant import has been the development of small molecule HDAC inhibitors that permit pharmacological manipulation of histone acetylation levels and treatment of some of these diseases including cancer. In this Review we discuss evidence that aberrant HAT and HDAC activity may also be a common underlying mechanism contributing to neurodegeneration during acute and chronic neurological diseases, including stroke, Huntington's disease Amyotrophic Lateral Sclerosis and Alzheimer's disease. With this in mind, a number of studies examining the use of HDAC inhibitors as therapy for restoring histone acetylation and transcriptional activation in in vitro and in vivo neurodegenerative models are discussed. These studies demonstrate that pharmacological HDAC inhibition is a promising therapeutic approach for the treatment of a range of central nervous system disorders.}, }
@article {pmid15723611, year = {2005}, author = {Shacka, JJ and Roth, KA}, title = {Regulation of neuronal cell death and neurodegeneration by members of the Bcl-2 family: therapeutic implications.}, journal = {Current drug targets. CNS and neurological disorders}, volume = {4}, number = {1}, pages = {25-39}, doi = {10.2174/1568007053005127}, pmid = {15723611}, issn = {1568-007X}, mesh = {Animals ; Apoptosis/drug effects/*physiology ; Drug Design ; Humans ; Nerve Degeneration/*metabolism ; Neurodegenerative Diseases/drug therapy/*metabolism ; Neurons/*metabolism ; Neuroprotective Agents/pharmacology ; Protein Structure, Tertiary/physiology ; Proto-Oncogene Proteins c-bcl-2/classification/drug effects/*metabolism ; }, abstract = {The Bcl-2 family of proteins contains both anti and pro-apoptotic members that have been shown to regulate neuronal cell death during development and in many models of acute and chronic neurodegeneration. This family of proteins can be divided into three distinct classes based on structure and function: the anti-apoptotic sub-group; the pro-apoptotic, multi-domain sub-group; and the pro-apoptotic, BH3 domain-only sub-group. Alterations in the expression of Bcl-2 family members occur in several animal and human neurodegenerative diseases including Alzheimer's, Huntington's and Parkinson's diseases and Amyotrophic Lateral Sclerosis. Similar changes are seen in in vivo and in vitro models of acute neurodegeneration, including stroke and traumatic brain injury. Methods to increase the overall expression and/or function of anti-apoptotic Bcl-2 family members, and thus promote neuron survival, have been studied extensively in these models. Most treatment efforts focus on either the targeted delivery via viral vectors of anti-apoptotic members of Bcl-2 family members into the affected brain regions of interest, the generation of direct interactions of small molecule inhibitors with Bcl-2 family members, or the induced expression of Bcl-2 family members secondary to pharmacological manipulation. Although many challenges exist in the design of safe and efficacious Bcl-2 family mimetics for the treatment of neurodegeneration, such strategies offer great promise for preserving neuron viability, and hopefully function, in a variety of human neurological diseases.}, }
@article {pmid15712243, year = {2005}, author = {Gillardon, F and Steinlein, P and Bürger, E and Hildebrandt, T and Gerner, C}, title = {Phosphoproteome and transcriptome analysis of the neuronal response to a CDK5 inhibitor.}, journal = {Proteomics}, volume = {5}, number = {5}, pages = {1299-1307}, doi = {10.1002/pmic.200400992}, pmid = {15712243}, issn = {1615-9853}, mesh = {Animals ; Binding Sites ; Cells, Cultured ; Chick Embryo ; Cyclin-Dependent Kinase 5 ; Cyclin-Dependent Kinases/*antagonists &amp; inhibitors/*metabolism ; DNA-Binding Proteins/metabolism ; *Gene Expression Profiling ; Indoles/chemistry/*metabolism ; MEF2 Transcription Factors ; Molecular Structure ; Myogenic Regulatory Factors ; Neurons/cytology/*physiology ; Oligonucleotide Array Sequence Analysis ; Phosphoproteins/*analysis ; Proteome/*analysis ; Rats ; Rats, Wistar ; Transcription Factors/metabolism ; }, abstract = {In Alzheimer's disease and amyotrophic lateral sclerosis deregulation of cyclin-dependent kinase 5 (CDK5) causes hyperphosphorylation of tau and neurofilament proteins, respectively, leading to neuronal cell death. We have demonstrated recently that pharmacological inhibition of CDK5 protects neurons under various stressful conditions (Weishaupt J. H., et al., Molec. Cell. Neurosci. 2003, 24, 489-502). To get an overview on the cellular mechanisms of action we analyzed global changes in protein phosphorylation in cultured cerebellar granule neurons by [(32)P]orthophosphate labeling after administration of a CDK5 inhibitor. Since CDK5 has recently been shown to phosphorylate and inactivate transcription factor MEF2, we included gene expression profiling using cDNA microarrays. By two-dimensional gel electrophoresis and matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF)-mass spectrometry we identified several phosphoproteins that were modulated by compound administration. Among them syndapin I which is involved in vesicle recycling, and dynein light intermediate chain 2 which represents a regulatory subunit of the dynein protein complex. These findings are consistent with the known physiological function of CDK5 in synaptic signaling and axonal transport. Moreover, we detected phosphoproteins acting in neuronal surival and/or neurite outgrowth, such as cofilin and collapsin response mediator protein. Subsequent testing in cell cultures revealed that the CDK5 inhibitor blocked mitochondrial translocation of pro-apoptotic cofilin in cerebellar granule neurons and enhanced neurite outgrowth in dorsal root ganglia. Numerous genes exhibiting MEF2 consensus binding sequences were modulated by CDK5 inhibitor treatment. Among them some that may contribute to neurite elongation or neuronal survival, but also several genes functioning in synaptic transmission. Taken together, phosphoproteome and transcriptome analysis indicate that the compound promotes both neuronal survival and neurite outgrowth, but also may affect synaptic function in cultured neurons.}, }
@article {pmid15705078, year = {2005}, author = {Gades, NM and Jacobson, DJ and Girman, CJ and Roberts, RO and Lieber, MM and Jacobsen, SJ}, title = {Prevalence of conditions potentially associated with lower urinary tract symptoms in men.}, journal = {BJU international}, volume = {95}, number = {4}, pages = {549-553}, doi = {10.1111/j.1464-410X.2005.05337.x}, pmid = {15705078}, issn = {1464-4096}, support = {AR30582/AR/NIAMS NIH HHS/United States ; DK58859/DK/NIDDK NIH HHS/United States ; }, mesh = {Adult ; Age Factors ; Aged ; Epidemiologic Methods ; Humans ; Male ; Middle Aged ; Prostatic Hyperplasia/*diagnosis/epidemiology/etiology ; Urination Disorders/*diagnosis/epidemiology/etiology ; }, abstract = {OBJECTIVE: To estimate the frequency of conditions associated with lower urinary tract symptoms (LUTS, typically included when assessing benign prostatic hyperplasia, BPH), as other causes of LUTS should be excluded when diagnosing BPH, using data from the Olmsted County Study of Urinary Symptoms and Health Status among Men.<br><br>SUBJECTS AND METHODS: During 1989-91, Caucasian men aged 40-79 years were randomly selected from the Olmsted County population. Before contact, eligibility was determined by reviewing the community medical records. Baseline exclusion criteria included comorbid pre-existing conditions or treatments, e.g. prostate, bladder or lower back surgery, bladder neck contracture or cancer, diabetes with lower extremity amputation, and neurological diseases, including Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, tabes dorsalis and stroke. Men with these conditions were excluded from the Olmsted County Study at baseline, because these conditions are potentially associated with LUTS.<br><br>RESULTS: Of the 5100 randomly sampled men, 13.4% met at least one of the pre-existing exclusion criteria. Individually, the frequency of exclusions was 7.8% for prostate cancer or surgery, 4.8% for back surgery, 1.3% for bladder surgery and 1.4% for neurological conditions. All other conditions represented <1.0% of the study exclusions. Older men were more likely to meet at least one of the exclusion criteria, with men in their fifth to eighth decade having a total exclusion frequency of 1.4%, 5.4%, 8.5% and 32.8%, respectively. The most common reason for men in their fifth decade to be excluded was lower back surgery (0.9%), whereas the most common reason in the eighth was prostate surgery (21.8%).<br><br>CONCLUSIONS: In men, conditions that may contribute to LUTS, other than BPH, are prevalent in the community and increase in frequency with age. It is important that other conditions associated with LUTS be excluded before a definitive diagnosis of BPH. Any oversight in this initial evaluation can potentially result in misclassification bias, misdiagnosis and incorrect treatment of patients.}, }
@article {pmid15691215, year = {2005}, author = {McGeer, EG and McGeer, PL}, title = {Pharmacologic approaches to the treatment of amyotrophic lateral sclerosis.}, journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy}, volume = {19}, number = {1}, pages = {31-37}, doi = {10.2165/00063030-200519010-00004}, pmid = {15691215}, issn = {1173-8804}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; *Excitatory Amino Acid Antagonists ; Humans ; Mice ; Mice, Transgenic ; Oxidative Stress/*drug effects ; Superoxide Dismutase/*genetics ; Treatment Failure ; Vascular Endothelial Growth Factor A/drug effects/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease for which no cure or effective treatment presently exists. Many different types of drugs have been tested; most are based on various hypotheses of mechanisms for neuronal death, including oxidative damage, loss of trophic factor support, glutamate-mediated excitotoxicity, and chronic inflammation. The discovery that a small percentage of ALS cases are familial and involve mutation in a superoxide dismutase gene (SOD1) led to the development of transgenic mouse models presently widely used for testing possible drugs. Mutations in the vascular endothelial growth factor gene (VEGF) also appear to be involved. Riluzole, an inhibitor of glutamate release and the only agent presently approved for clinical use, only extends survival by a few months. A number of trophic factors, anti-inflammatory agents, and inhibitors of oxidative stress have been reported to prolong survival in mouse models and some are now in clinical trials. Gene transfer of VEGF or glial cell-line derived neurotrophic factor, anti-inflammatory COX-2 inhibitors, and minocycline have had particularly promising results in mice. No breakthrough has yet occurred and present thinking is that combinations of drugs may be required to slow the multifactorial neurodegeneration process effectively.}, }
@article {pmid15684843, year = {2004}, author = {Mast, KR and Salama, M and Silverman, GK and Arnold, RM}, title = {End-of-life content in treatment guidelines for life-limiting diseases.}, journal = {Journal of palliative medicine}, volume = {7}, number = {6}, pages = {754-773}, doi = {10.1089/jpm.2004.7.754}, pmid = {15684843}, issn = {1096-6218}, mesh = {Chronic Disease/*therapy ; *Disease Management ; Hospice Care/*standards ; Humans ; Palliative Care/*standards ; Practice Guidelines as Topic/*standards ; Terminal Care/*standards ; United States ; }, abstract = {BACKGROUND: Clinical guidelines are systematically developed statements that influence medical practice, education, and funding. Guidelines represent the consensus of leaders, often based on systematic reviews of the literature, regarding the "state of the art."<br><br>OBJECTIVE: To assess the degree to which end-of-life care is integrated into nationally developed guidelines for chronic, noncurable, life-limiting diseases.<br><br>DESIGN: Four compendia were reviewed: The Healthcare Standards Directory ECRI, 2001; the Clinical Practice Guidelines Directory, 2000 edition; the National Guidelines Clearinghouse, (guideline.gov); and the National Library of Medicine's MEDLINE database on the OVID platform for guidelines on nine chronic diseases (chronic obstructive pulmonary disease, end-stage liver disease, amyotrophic lateral sclerosis, congestive heart failure, dementia, cerebrovascular accident, end-stage renal disease, cancer [breast, colon, prostate, lung], and human immunodeficiency virus). They were assessed by two reviewers for end-of-life content in 15 domains (e.g., epidemiology of death, symptom management, spiritual, family roles, and settings of care), the presence of eight specific terms dealing with palliative care, integration of palliative care information into the guideline, and descriptive variables.<br><br>SETTING/SUBJECTS: Not available.<br><br>MEASUREMENTS: Each guideline was examined and rated on a 0-2 scale (0, absent content; 1, minimal content; 2, helpful content) using 15 end-of-life content domains. Scores from domains were summed and classified into 3 categories: 4 or less, minimal; 5-12, moderate; and more than 12, significant content.<br><br>RESULTS: Ten percent of guidelines had significant palliative care content, 64% had minimal content, and 26% had moderate content. The least addressed domains dealt with spirituality, ethics, advocacy and family roles. When guidelines that dealt solely with prevention, acute exacerbations or complications of an illness, or specific treatment modalities were excluded 28% and 16% of these general guidelines (n = 58) had moderate and significant palliative care content, respectively, compared to 24% and 0% of all nongeneral guidelines. Similar results were found when analyzing the data by disease course or treatment focus. Only 14% of guidelines advised physicians to consider palliative care at a specific point in the disease course. Ninety-one percent of the guidelines mentioned death, dying, end of life, mortality, or terminal illness but only 36% mentioned palliation or hospice.<br><br>CONCLUSION: Current national guidelines on nine chronic, life-limiting illnesses offer little guidance in end-of-life care issues despite a recent increase in attention to this aspect of medical care.}, }
@article {pmid15680459, year = {2005}, author = {Shawcross, D and Jalan, R}, title = {Dispelling myths in the treatment of hepatic encephalopathy.}, journal = {Lancet (London, England)}, volume = {365}, number = {9457}, pages = {431-433}, doi = {10.1016/S0140-6736(05)17832-5}, pmid = {15680459}, issn = {1474-547X}, mesh = {Ammonia/blood ; Dietary Proteins/administration &amp; dosage ; Hepatic Encephalopathy/metabolism/physiopathology/*therapy ; Humans ; Lactulose/therapeutic use ; Sorption Detoxification ; }, abstract = {CONTEXT: Guidelines for the treatment of hepatic encephalopathy suggest ammonia reduction as the main focus, based on strategies to reduce ammonia's generation and absorption in the colon by using lactulose and a reduced protein diet.<br><br>STARTING POINT: Two studies provide compelling and provocative data questioning the relevance of these interventions. Bodils Als-Nielsen and colleagues, in a systematic review of randomised trials, found insufficient evidence about whether non-absorbable disaccharides are beneficial (BMJ 2004; 328: 1046-50). In a small randomised study, Juan Cordoba and colleagues showed that diets with normal protein content can be administered safely during episodic hepatic encephalopathy due to cirrhosis and that protein restriction does not have any beneficial effect during such episodes (J Hepatol 2004; 41: 38-43).<br><br>WHERE NEXT: Two approaches to new therapies for hepatic encephalopathy are needed. First, it is important to focus on the interorgan metabolism of ammonia. The small intestine and kidneys might be important producers of ammonia, and muscle is an important organ that can remove ammonia. Novel therapies targeting these organs reduce ammonia. Second, research is needed to explore factors other than ammonia that might be important in hepatic encephalopathy, including the synergistic role of inflammation. The lack of conclusive data about the efficacy of any treatment supports the view that placebo-controlled trials of newer agents are needed and ethical. The emphasis should shift to aggressive management of the precipitating event.}, }
@article {pmid15674899, year = {2005}, author = {Orrell, RW and Lane, RJ and Ross, M}, title = {Antioxidant treatment for amyotrophic lateral sclerosis / motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {1}, pages = {CD002829}, doi = {10.1002/14651858.CD002829.pub3}, pmid = {15674899}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Antioxidants/*therapeutic use ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Free radical accumulation and oxidative stress have been proposed as contributing to the progression of amyotrophic lateral sclerosis (or motor neuron disease). A range of antioxidant medications are available, and have been studied.<br><br>OBJECTIVES: To examine the effects of antioxidant medication in the treatment of people with amyotrophic lateral sclerosis.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (July 2003), MEDLINE (from January 1966 to July 2003), EMBASE (from January 1980 to July 2003) and other sources.<br><br>SELECTION CRITERIA: All randomized or quasi-randomized controlled trials of antioxidant treatment for amyotrophic lateral sclerosis.<br><br>DATA COLLECTION AND ANALYSIS: The reviewers independently applied the selection criteria, assessed study quality and two reviewers performed independent data extraction.<br><br>MAIN RESULTS: The search identified 21 studies for consideration but only eight studies met the inclusion criteria. Only two studies used our predetermined primary outcome measure, (survival at 12 months treatment). Sufficient data were available from three studies to allow analysis of the primary outcome measure, and a meta-analysis was performed. In the individual studies no significant effect was observed of vitamin E 500 mg twice daily; acetylcysteine 50 mg/kg daily subcutaneous infusion; or a combination of L-methionine 2 g, vitamin E 400 International Units, and selenium 3 x 10-5g three times daily (Alsemet). No significant effect on the primary outcome measure was observed in a meta-analysis of antioxidants in general when combining the results. No significant differences were demonstrated in secondary outcome measures.<br><br>AUTHORS' CONCLUSIONS: There is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect, but this was not supported by the analysis we used. Generally the studies were poorly designed, and underpowered, with low numbers of participants and of short duration. Further well-designed trials of medications such as vitamin C and E are unlikely to be performed. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trial. The high tolerance and safety, and relatively low cost of vitamins C and E, and other considerations related to the lack of other effective treatments for amyotrophic lateral sclerosis, explain the continuing use of these vitamins by physicians and patients. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.}, }
@article {pmid15670639, year = {2005}, author = {Sala, G and Beretta, S and Ceresa, C and Mattavelli, L and Zoia, C and Tremolizzo, L and Ferri, A and Carrì, MT and Ferrarese, C}, title = {Impairment of glutamate transport and increased vulnerability to oxidative stress in neuroblastoma SH-SY5Y cells expressing a Cu,Zn superoxide dismutase typical of familial amyotrophic lateral sclerosis.}, journal = {Neurochemistry international}, volume = {46}, number = {3}, pages = {227-234}, doi = {10.1016/j.neuint.2004.10.002}, pmid = {15670639}, issn = {0197-0186}, mesh = {Amino Acid Transport System X-AG/metabolism ; Amyotrophic Lateral Sclerosis/*enzymology ; Antioxidants/pharmacology ; Biological Transport, Active/physiology ; Brain Neoplasms/*enzymology/*metabolism ; Cell Line, Tumor ; Electrophoresis, Agar Gel ; Excitatory Amino Acid Transporter 1 ; Excitatory Amino Acid Transporter 2 ; Excitatory Amino Acid Transporter 3 ; Glutamate Plasma Membrane Transport Proteins ; Glutamic Acid/*metabolism ; Humans ; Kinetics ; Mutation/physiology ; Neuroblastoma/*enzymology/*metabolism ; Oxidants/pharmacology ; Oxidative Stress/*physiology ; RNA, Messenger/biosynthesis/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Sodium/physiology ; Superoxide Dismutase/*genetics/*metabolism ; Symporters/metabolism ; }, abstract = {Human neuroblastoma SH-SY5Y cells transfected with either familial amyotrophic lateral sclerosis-typical G93A mutant or wild-type copper/zinc superoxide dismutase were compared to untransfected cells in term of glutamate transport. Vmax of glutamate uptake was reduced in mutant cells, with no change in Km. No difference in EAAT1, EAAT2 and EAAT3 glutamate transporter mRNAs and immunoreactive proteins was found, suggesting that one or more transporters are functionally inactivated, possibly due to increased oxidative stress induced by the G93A mutation. Mutant cells showed a marked sensitivity to oxidants, resulting in a more pronounced reduction of glutamate uptake. Short-term antioxidant treatment did not reverse the impairment of glutamate uptake in G93A cells. Interestlingly, N-acetylcysteine was partially effective in preventing glutamate uptake reduction due to exogenous oxidative insults. Since the inhibition of the EAAT2 transporter subtype had no effect on glutamate re-uptake in this model, our study suggests an impaired function of the EAAT1/3 transporter subtypes, possibly due to oxidative inactivation, in the presence of mutant copper/zinc superoxide dismutase. Therefore, this model might prove to be a valuable tool to study the effects of mutant copper/zinc superoxide dismutase associated with amyotrophic lateral sclerosis on glutamate transport in neuronal cells, without the specific contribution of glial cells. These findings might lead to the identification of new therapeutic strategies aimed at preventing the damage associated with ALS.}, }
@article {pmid15664534, year = {2005}, author = {Meininger, V}, title = {Treatment of emotional lability in ALS.}, journal = {The Lancet. Neurology}, volume = {4}, number = {2}, pages = {70}, doi = {10.1016/S1474-4422(05)00970-1}, pmid = {15664534}, issn = {1474-4422}, mesh = {Affective Symptoms/*drug therapy/etiology ; Amyotrophic Lateral Sclerosis/*complications ; Animals ; Dextromethorphan/*therapeutic use ; Enzyme Inhibitors/therapeutic use ; Excitatory Amino Acid Antagonists/*therapeutic use ; Humans ; Quinidine/therapeutic use ; Randomized Controlled Trials as Topic ; }, }
@article {pmid15663483, year = {2005}, author = {Xia, XG and Zhou, H and Zhou, S and Yu, Y and Wu, R and Xu, Z}, title = {An RNAi strategy for treatment of amyotrophic lateral sclerosis caused by mutant Cu,Zn superoxide dismutase.}, journal = {Journal of neurochemistry}, volume = {92}, number = {2}, pages = {362-367}, doi = {10.1111/j.1471-4159.2004.02860.x}, pmid = {15663483}, issn = {0022-3042}, support = {R01 NS048145/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics/*therapy ; Animals ; Blotting, Western ; Cells, Cultured ; Gene Transfer Techniques ; Genetic Therapy/*methods ; Green Fluorescent Proteins/genetics ; Humans ; Kidney/cytology/metabolism ; Mice ; Mutation/genetics ; *RNA Interference ; RNA, Messenger/antagonists &amp; inhibitors/genetics ; RNA, Small Interfering/genetics/pharmacology ; Recombinant Fusion Proteins/biosynthesis/genetics ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is a neurodegenerative disease characterized by motor neuron degeneration, paralysis and death. One cause of this disease is mutations in the Cu,Zn superoxide dismutase (SOD1) gene. As mutant SOD1 acquires a toxic property that kills motor neurons, by reducing the mutant protein the disease progression may be slowed or prevented. While mutant SOD1 is toxic, the wild-type SOD1 is indispensable for motor neuron health. Therefore, the ideal therapeutic strategy would be to inhibit selectively the mutant protein expression. Previously we have demonstrated that RNA interference (RNAi) can selectively inhibit some mutant SOD1 expression. However, more than 100 SOD1 mutants can cause ALS and all mutants cannot be inhibited selectively by RNAi. To overcome this obstacle, we have designed a replacement RNAi strategy. Using this strategy, all mutants and wild-type genes are inhibited by RNAi. The wild-type SOD1 function is then replaced by designed wild-type SOD1 genes that are resistant to the RNAi. Here we demonstrate the concept of this strategy.}, }
@article {pmid15649489, year = {2005}, author = {Kiaei, M and Kipiani, K and Chen, J and Calingasan, NY and Beal, MF}, title = {Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {191}, number = {2}, pages = {331-336}, doi = {10.1016/j.expneurol.2004.10.007}, pmid = {15649489}, issn = {0014-4886}, mesh = {Administration, Oral ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology/physiopathology ; Animals ; Cell Count ; Disease Models, Animal ; Disease Progression ; Gliosis/pathology ; Lumbosacral Region ; Mice ; Mice, Transgenic ; NF-kappa B/metabolism ; Neurons/drug effects/pathology ; Neuroprotective Agents/*therapeutic use ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase Type II ; PPAR gamma/*agonists ; Pioglitazone ; Psychomotor Performance/drug effects ; Spinal Cord/*drug effects/pathology ; Superoxide Dismutase/genetics ; Survival Rate ; Thiazolidinediones/*therapeutic use ; Tyrosine/*analogs &amp; derivatives/metabolism ; Weight Loss/drug effects ; }, abstract = {Accumulating evidence suggests that inflammation plays a major role in the pathogenesis of motoneuron death in amyotrophic lateral sclerosis (ALS) both in humans and transgenic mouse models. Peroxisome proliferator-activated receptors (PPARs) are involved in the inflammatory process. Agonists of PPAR-alpha, -gamma, and -delta show anti-inflammatory effects both in vitro and in vivo. We investigated the therapeutic effect of pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, in the G93A SOD1 transgenic mouse model of ALS. Orally administered pioglitazone improved motor performance, delayed weight loss, attenuated motor neuron loss, and extended survival of G93A mice as compared to the untreated control littermate group. Pioglitazone treatment extended survival by 13%, and it reduced gliosis as assessed by immunohistochemical staining for CD-40 and GFAP. Pioglitazone also reduced iNOS, NFkappa-B, and 3-nitrotyrosine immunoreactivity in the spinal cords of G93A transgenic mice. These results suggest that pioglitazone may have therapeutic potential for human ALS.}, }
@article {pmid15645771, year = {2004}, author = {Kanatsu, H and Kitamikado, H and Sugihara, S and Kikukawa, F and Harada, K and Tani, M and Mori, H and Isobe, K}, title = {[Home care of an ALS patient using an artificial respirator].}, journal = {Gan to kagaku ryoho. Cancer &amp; chemotherapy}, volume = {31 Suppl 2}, number = {}, pages = {199-200}, pmid = {15645771}, issn = {0385-0684}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*nursing ; Caregivers ; Community-Institutional Relations ; *Home Care Services ; Humans ; *Insurance, Long-Term Care ; Male ; Ventilators, Mechanical/*statistics &amp; numerical data ; }, abstract = {Due to social changes, advancement of medical technology and introduction of home care insurance, it has become a reality that a patient using an artificial respirator could be treated at home. We report specific problems associated with an ALS patient using an artificial respirator through home care support. A 68-year-old male had a back problem in 2001 and developed a sudden difficulty in breathing. Since 2002, the patient was forced to use an artificial respirator, and without taking his informed consent, was treated at home. Primary caregivers are his wife and daughter. The specific problems we identified are (1) patient's caregivers were unnecessary confused due to a lack of coordination between visiting nurses from two hospitals in giving home care treatment direction, (2) the care giver's burden tends to increase as the duration of care is extended because the short-stay facility or transferring system for patient is not well equipped, (3) there is no particular place to ask for assistance in case of an emergency or an established communication method as the patient's disease status will progress. It appears that these identified problems cannot be resolved by one hospital. However, we believe that we have to establish a community-wide home care system as quickly as possible. Meanwhile, it is important to have a nationwide coordination involving government, corporations, and political institutions to make it to be a success.}, }
@article {pmid15645308, year = {2005}, author = {Yakar, S and Kim, H and Zhao, H and Toyoshima, Y and Pennisi, P and Gavrilova, O and Leroith, D}, title = {The growth hormone-insulin like growth factor axis revisited: lessons from IGF-1 and IGF-1 receptor gene targeting.}, journal = {Pediatric nephrology (Berlin, Germany)}, volume = {20}, number = {3}, pages = {251-254}, pmid = {15645308}, issn = {0931-041X}, mesh = {Animals ; *Gene Targeting ; Growth Hormone/biosynthesis/*genetics ; Insulin-Like Growth Factor Binding Protein 1/biosynthesis/*genetics ; Liver/metabolism ; Mice ; Mice, Transgenic ; Receptor, IGF Type 1/biosynthesis/*genetics ; }, abstract = {We have created a liver-specific igf1 gene-deletion mouse model (LID) with markedly reduced circulating IGF-I levels. They demonstrate that while they have normal growth and development they develop insulin resistance secondary to the elevation of circulating growth hormone. When mated with an acid-labile subunit (ALS) gene-deleted mouse they also show osteopenia suggesting that circulating IGF-I levels play a significant role in bone formation. In a separate transgenic mouse we created a model of severe insulin resistance and type 2 diabetes by the overexpression of a dominant-negative IGF-I receptor in skeletal muscle. In this model we show that lipotoxicity plays a major role in the progression of the disease and is affected by treatment with a fibrate, which reverses the insulin resistance and diabetic state. These models are therefore very useful in studying human physiology and disease states.}, }
@article {pmid15634772, year = {2005}, author = {Turner, BJ and Atkin, JD and Farg, MA and Zang, DW and Rembach, A and Lopes, EC and Patch, JD and Hill, AF and Cheema, SS}, title = {Impaired extracellular secretion of mutant superoxide dismutase 1 associates with neurotoxicity in familial amyotrophic lateral sclerosis.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {25}, number = {1}, pages = {108-117}, pmid = {15634772}, issn = {1529-2401}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics/*pathology/physiopathology ; Animals ; Animals, Genetically Modified ; COS Cells ; Cells, Cultured ; Chlorocebus aethiops ; Disease Models, Animal ; Humans ; Inclusion Bodies/pathology ; Mice ; Motor Neurons/*enzymology/*pathology ; Movement/physiology ; Mutation ; Rats ; Rats, Sprague-Dawley ; Recombinant Fusion Proteins ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Mutations in the intracellular metalloenzyme superoxide dismutase 1 (SOD1) are linked to neurotoxicity in familial amyotrophic lateral sclerosis (ALS) by an unclear mechanism. Golgi fragmentation and endoplasmic reticulum stress are early hallmarks of spinal motor neuron pathology in transgenic mice overexpressing mutant SOD1, suggesting that dysfunction of the neuronal secretory pathway may contribute to ALS pathogenesis. We therefore proposed that mutant SOD1 directly engages and modulates the secretory pathway based on recent evidence of SOD1 secretion in diverse human cell lines. Here, we demonstrate that a fraction of active endogenous SOD1 is secreted by NSC-34 motor neuron-like cells via a brefeldin-A (BFA)-sensitive pathway. Expression of enhanced green fluorescent protein-tagged mutant human SOD1 (hSOD1-EGFP) in NSC-34 cells induced frequent cytoplasmic inclusions and protein insolubility that correlated with toxicity. In contrast, transfection of non-neuronal COS-7 cells resulted in mutant hSOD1-EGFP cytoplasmic inclusions, oligomerization, and fragmentation without detectable toxicity. Importantly, impaired secretion of hSOD1-EGFP was common to all 10 SOD1 mutants tested relative to wild-type protein in NSC-34 cells. Treatment with BFA inhibited hSOD1-EGFP secretion with pronounced BFA-induced toxicity in mutant cells. Extracellular targeting of mutant hSOD1-EGFP via SOD3 signal peptide fusion attenuated cytoplasmic inclusion formation and toxicity. The effect of elevated extracellular SOD1 was then evaluated in a transgenic rat model of ALS. Chronic intraspinal infusion of exogenous wild-type hSOD1 significantly delayed disease progression and endpoint in transgenic SOD1(G93A) rats. Collectively, these results suggest novel extracellular roles for SOD1 in ALS and support a causal relationship between mutant SOD1 secretion and intraneuronal toxicity.}, }
@article {pmid15621213, year = {2005}, author = {Youdim, MB and Fridkin, M and Zheng, H}, title = {Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases.}, journal = {Mechanisms of ageing and development}, volume = {126}, number = {2}, pages = {317-326}, doi = {10.1016/j.mad.2004.08.023}, pmid = {15621213}, issn = {0047-6374}, mesh = {Alzheimer Disease/*drug therapy/pathology ; Amyloid beta-Protein Precursor/metabolism ; Brain/metabolism ; Chelating Agents/*pharmacology ; Cholinesterase Inhibitors/pharmacology ; Cholinesterases/metabolism ; Culture Media, Serum-Free/pharmacology ; Dementia/*drug therapy/pathology ; Dopamine/metabolism ; Dose-Response Relationship, Drug ; Humans ; Indans/chemistry/*pharmacology ; Iron/chemistry/*metabolism ; Lewy Bodies/drug effects/metabolism ; MAP Kinase Signaling System ; Models, Chemical ; Monoamine Oxidase/metabolism ; Monoamine Oxidase Inhibitors/*pharmacology ; Neurodegenerative Diseases/pathology ; Neurons/metabolism ; Piperazines/chemistry/*pharmacology ; Protein Kinase C/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Quinolines/chemistry/*pharmacology ; }, abstract = {Degeneration of nigrostriatal dopamine neurons and cholinergic cortical neurones are the main pathological features of Parkinson's disease (PD) and for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB), respectively. Many PD and DLB subjects have dementia and depression resulting from possible degeneration of cholinergic and noradrenergic and serotonergic neurons. On the other hand, AD patients may also develop extrapyramidal features as well as depression. In both PD and AD there is, respectively, accumulation of iron within the melanin containing dopamine neurons of pars compacta and with in the plaques and tangle. It has been suggested that iron accumulation may contribute to the oxidative stress induced apoptosis reported in both diseases. This may result from increased glia hydrogen peroxide producing monoamine oxidase (MAO) activity that can generate of reactive hydroxyl radical formed from interaction of iron and hydrogen peroxide. We have therefore prepared a series of novel bifunctional drugs from the neuroprotective-antiapoptotic antiparkinson monoamine oxidase B inhibitor, rasagiline, by introducing a carbamate cholinesterase (ChE) inhibitory moiety into it. Ladostigil (TV-3326, N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate), has both ChE and MAO-AB inhibitory activity, as potential treatment of AD and DLB or PD subjects with dementia Being a brain selective MAO-AB inhibitor it has limited potentiation of the pressor response to oral tyramine and exhibits antidepressant activity similar to classical non-selective MAO inhibitor antidepressants by increasing brain serotonin and noradrenaline. Ladostigil inhibits brain acetyl and butyrylcholinesterase in rats and antagonizes scopolamine-induced inhibition of spatial learning. Ladostigil like MAO-B inhibitor it prevents MPTP Parkinsonism in mice model and retains the in vitro and in vivo neuroprotective activity of rasagiline. Ladostigil, rasagiline and other propargylamines have been demonstrated to have neuroprotective activity in several in vitro and in vivo models, which have been shown be associated with propargylamines moiety, since propargylamines itself possess these properties. The mechanism of neuroprotective activity has been attributed to the ability of propargylamines-inducing the antiapoptotic family proteins Bcl-2 and Bcl-xl, while decreasing Bad and Bax and preventing opening of mitochondrial permeability transition pore. Iron accumulates in brain regions associated with neurodegenerative diseases of PD, AD, amyotrophic lateral sclerosis and Huntington disease. It is thought to be involved in Fenton chemistry oxidative stress observed in these diseases. The neuroprotective activity of propargylamines led us to develop several novel bifunctional iron chelator from our prototype brain permeable iron chelators, VK-28, possessing propargylamine moiety (HLA-20, M30 and M30A) to iron out iron from the brain. These compounds have been shown to have iron chelating and monoamine oxidase A and B selective brain inhibitory and neuroprotective-antiapoptotic actions.}, }
@article {pmid15609140, year = {2002}, author = {Tavakoli, M}, title = {Disease progression in amyotrophic lateral sclerosis. Identifying the cost-utility of riluzole by disease stage.}, journal = {The European journal of health economics : HEPAC : health economics in prevention and care}, volume = {3}, number = {3}, pages = {156-165}, doi = {10.1007/s10198-002-0110-0}, pmid = {15609140}, issn = {1618-7598}, abstract = {This study reports the results of a long-term economic evaluation of riluzole in the treatment of amyotrophic lateral sclerosis (ALS) versus best supportive care in the United Kingdom. The analysis included in this contribution aims to provide an update of the determination of the phase of the disease that is prolonged by riluzole and also to assess the quality of the life extension offered by riluzole by taking into account the patients' utility score. Specifically, the analysis provides a more specific estimate of the cost-utility of riluzole dependent disease stage, thereby providing a useful insight of the cost-effectiveness of therapy. A Markov model was used to assess the cost-effectiveness of riluzole versus best supportive care. Transition possibilities and the distribution of patients by health states were taken from a cohort of 954 patients drawn from a large randomised, double blind, placebo-controlled, multicentre trial between 1992 and 1994. Costs associated with riluzole included the acquisition cost and bi-monthly monitoring for raised ALT levels. Patient assessed utilities were collected by use of the SG technique from two centres (King's, London and Preston) in the UK. Four distinct health states were used corresponding to mild, moderate, severe and terminal states. Applying the Markov model and extending the transitional probabilities using linear interpolation, the base case cost per life year gained was estimated at 15,192 pounds while applying Standard Gamble utility scores, the base case cost per quality-adjusted life-year (QALY) was assessed at 22,086 pounds. Carrying out a probabilistic sensitivity analysis, the cost per QALY was estimated at 22,236 pounds with standard deviation of 612 pounds. The results of the long-term analysis also show that riluzole on average increases survival in ALS patients by 6 months with approximately 5 months of the additional life gained in the early disease states, of which 4 months is spent in disease state 2, where quality of life is relatively high. However, the model is sensitive in the way in which the long-term transitional probabilities are estimated. Using averages of the first nine cycles, the cost per QALY would increase to 33,420 pounds with standard deviation of 972 pounds. Thus, this analysis highlights some of the difficulties associated with extending the short clinical effectiveness data; one way forward would be to obtain long-term observations data for both groups.}, }
@article {pmid15590150, year = {2005}, author = {Satoi, H and Tomimoto, H and Ohtani, R and Kitano, T and Kondo, T and Watanabe, M and Oka, N and Akiguchi, I and Furuya, S and Hirabayashi, Y and Okazaki, T}, title = {Astroglial expression of ceramide in Alzheimer's disease brains: a role during neuronal apoptosis.}, journal = {Neuroscience}, volume = {130}, number = {3}, pages = {657-666}, doi = {10.1016/j.neuroscience.2004.08.056}, pmid = {15590150}, issn = {0306-4522}, mesh = {Aged ; Alzheimer Disease/cerebrospinal fluid/*metabolism/pathology ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/metabolism ; Animals ; Apoptosis/*physiology ; Astrocytes/*metabolism ; Cell Line, Tumor ; Cells, Cultured ; Ceramides/*biosynthesis/cerebrospinal fluid ; Extracellular Space/metabolism ; Glucosyltransferases/analysis/biosynthesis ; Humans ; Immunohistochemistry ; Indicators and Reagents ; Lipid Metabolism ; Mice ; Neurons/*pathology ; Serine/metabolism ; Solvents ; Transferases (Other Substituted Phosphate Groups)/analysis/biosynthesis ; Tretinoin/metabolism/pharmacology ; }, abstract = {Accumulating evidences indicate that ceramide is closely involved in apoptotic cell death in neurodegenerative disorders and aging. We examined ceramide levels in the cerebrospinal fluid (CSF) or brain tissues from patients with neurodegenerative disorders and the mechanism of how intra- and extracellular ceramide was regulated during neuronal apoptosis. We screened the ceramide levels in the CSF of patients with neurodegenerative disorders, and found that ceramide was significantly increased in patients with Alzheimer's disease (AD) than in patients with age-matched amyotrophic lateral sclerosis (ALS) and other neurological controls. With immunohistochemistry in AD brains, ceramide was aberrantly expressed in astroglia in the frontal cortices, but not detected in ALS and control brains. To explore for the regulation of ceramide in astroglia in Alzheimer's disease brains, we examined the metabolism of ceramide during neuronal apoptosis. In retinoic acid (RA)-induced neuronal apoptosis, RA slightly increased de novo synthesis of ceramide, but interestingly, RA dramatically inhibited conversion of [14C] ceramide to glucosylceramide (GlcCer), suggesting that the increase of ceramide mass is mainly due to inhibition of the ceramide-metabolizing enzyme GlcCer synthase. In addition, a significant increase of the [14C] ceramide level in the culture medium was detected by chasing and turnover experiments without alteration of extracellular [14C] sphingomyelin levels. A 2.5-fold increase of ceramide mass in the supernatant was also detected after 48 h of treatment with RA. These results suggest a regulatory mechanism of intracellular ceramide through inhibition of GlcCer synthase and a possible role of ceramide as an extracellular/intercellular mediator for neuronal apoptosis. The increased ceramide level in the CSF from AD patients, which may be derived from astroglia, raises a possibility of neuronal apoptosis by the response to intercellular ceramide in AD.}, }
@article {pmid15584767, year = {2004}, author = {Ellis, AC and Rosenfeld, J}, title = {The role of creatine in the management of amyotrophic lateral sclerosis and other neurodegenerative disorders.}, journal = {CNS drugs}, volume = {18}, number = {14}, pages = {967-980}, pmid = {15584767}, issn = {1172-7047}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology ; Animals ; Creatine/metabolism/*therapeutic use ; *Dietary Supplements ; Disease Models, Animal ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {Creatine is consumed in the diet and endogenously synthesised in the body. Over the past decade, the ergogenic benefits of synthetic creatine monohydrate have made it a popular dietary supplement, particularly among athletes. The anabolic properties of creatine also offer hope for the treatment of diseases characterised by weakness and muscle atrophy. Moreover, because of its cellular mechanisms of action, creatine offers potential benefits for diseases involving mitochondrial dysfunction. Recent data also support the hypothesis that creatine may have a neuroprotective effect. Amyotrophic lateral sclerosis (ALS) is characterised by progressive degeneration of motor neurons, resulting in weakening and atrophy of skeletal muscles. In patients with this condition, creatine offers potential benefits in terms of facilitating residual muscle contractility as well as improving neuronal function. It may also help stabilise mitochondrial dysfunction, which plays a key role in the pathogenesis of ALS. Indeed, the likely multifactorial aetiology of ALS means the combined pharmacodynamic properties of creatine offer promise for the treatment of this condition. Evidence from available animal models of ALS supports the utility of treatment with creatine in this setting. Limited data available in other neuromuscular and neurodegenerative diseases further support the potential benefit of creatine monohydrate in ALS. However, few randomised, controlled trials have been conducted. To date, two clinical trials of creatine monohydrate in ALS have been completed without demonstration of significant improvements in overall survival or a composite measure of muscle strength. These trials have also posed unanswered questions about the optimal dosage of creatine and its beneficial effects on muscle fatigue, a measure distinct from muscle strength. A large, multicentre, clinical trial is currently underway to further investigate the efficacy of creatine monohydrate in ALS and address these unresolved issues. Evidence to date shows that creatine supplementation has a good safety profile and is well tolerated by ALS patients. The purpose of this article is to provide a short, balanced review of the literature concerning creatine monohydrate in the treatment of ALS and related neurodegenerative diseases. The pharmacokinetics and rationale for the use of creatine are described along with available evidence from animal models and clinical trials for ALS and related neurodegenerative or neuromuscular diseases.}, }
@article {pmid15580100, year = {2004}, author = {Griffith, R}, title = {Living wills, duty of care and the right to treatment.}, journal = {British journal of community nursing}, volume = {9}, number = {11}, pages = {488-491}, doi = {10.12968/bjcn.2004.9.11.16875}, pmid = {15580100}, issn = {1462-4753}, mesh = {Community Health Nursing/*legislation &amp; jurisprudence ; Humans ; Living Wills/*legislation &amp; jurisprudence ; Mental Competency/legislation &amp; jurisprudence ; Parenteral Nutrition/*nursing ; Patient Rights/*legislation &amp; jurisprudence ; Personal Autonomy ; Refusal to Treat/legislation &amp; jurisprudence ; United Kingdom ; }, abstract = {Agnes Simon, a district nurse with 20 years' experience, has been caring for a man with motor neurone disease for the last 5 years. During this time the patient has shown remarkable tenacity but the disease has now progressed to the stage where artificial nutrition and hydration (ANH) is required. A percutaneous endoscopic gastrostomy tube has been inserted through which the patient receives food, water and medication. On her most recent visit the patient gave Agnes a signed and witnessed living will. Unusually, the living will did not indicate the patient's wishes regarding the limitation of treatment. Instead it made clear that the patient wished to continue to receive ANH up to the time of his death. He did not want the care team to withdraw this treatment without his permission, as he feared he would suffer from the indignity of slowly dying from thirst and starvation. Agnes has never seen a living will where a patient demands a right to treatment and wonders whether such a document is lawful and binding on her.}, }
@article {pmid15579172, year = {2004}, author = {Sugai, F and Yamamoto, Y and Miyaguchi, K and Zhou, Z and Sumi, H and Hamasaki, T and Goto, M and Sakoda, S}, title = {Benefit of valproic acid in suppressing disease progression of ALS model mice.}, journal = {The European journal of neuroscience}, volume = {20}, number = {11}, pages = {3179-3183}, doi = {10.1111/j.1460-9568.2004.03765.x}, pmid = {15579172}, issn = {0953-816X}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Cell Count/methods ; Cell Death/drug effects ; Dicarboxylic Acids/toxicity ; Disease Models, Animal ; Disease Progression ; Drug Interactions ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects ; Neuroprotective Agents/*therapeutic use ; Neurotoxicity Syndromes/etiology/prevention &amp; control ; Organ Culture Techniques ; Spinal Cord/cytology/drug effects ; Superoxide Dismutase/genetics ; Time Factors ; Valproic Acid/*therapeutic use ; }, abstract = {Valproic acid (VPA) has long been used as an antiepileptic drug and recently as a mood stabilizer, and evidence is increasing that VPA exerts neuroprotective effects through changes in a variety of intracellular signalling pathways including upregulation of Bcl-2 protein with an antiapoptotic property and inhibiting glycogen synthase kinase 3-beta, which is considered to promote cell survival. Although the neuroprotective effects of VPA have been demonstrated in a murine model of human immunodeficiency virus-1 encephalitis, there have been no reports on the effect of VPA in chronic progressing neurodegenerative disease models including amyotrophic lateral sclerosis (ALS). ALS is a devastating disease selectively affecting motoneurons, and its disease model mice bear a close resemblance to ALS symptomatically and pathologically. First, we used an organotypic slice culture using mouse spinal cord, and showed that VPA protected spinal motoneurons against death from glutamate toxicity in vitro. Then, we treated ALS model mice with VPA at the dose effective level for epileptic model mice after 45 days of age (pre-onset treatment) or the day of the disease onset (post-onset treatment). We found a significant prolongation of the disease duration in ALS model mice in both methods of treatment. Considering the long usage of VPA for epileptic patients with good tolerance and safety, these data strongly support the clinical application of VPA for ALS treatment.}, }
@article {pmid15571972, year = {2004}, author = {Blum, D and Chtarto, A and Tenenbaum, L and Brotchi, J and Levivier, M}, title = {Clinical potential of minocycline for neurodegenerative disorders.}, journal = {Neurobiology of disease}, volume = {17}, number = {3}, pages = {359-366}, doi = {10.1016/j.nbd.2004.07.012}, pmid = {15571972}, issn = {0969-9961}, mesh = {Animals ; Apoptosis ; Humans ; Huntington Disease/drug therapy ; Inflammation ; Minocycline/*therapeutic use ; Motor Neuron Disease/drug therapy ; Neurodegenerative Diseases/*drug therapy/pathology/physiopathology ; Neuroprotective Agents/*therapeutic use ; Parkinson Disease/drug therapy ; }, abstract = {Minocycline, an antibiotic of the tetracycline family, has been shown to display neurorestorative or neuroprotective properties in various models of neurodegenerative diseases. In particular, it has been shown to delay motor alterations, inflammation and apoptosis in models of Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease. Despite controversies about its efficacy, the relative safety and tolerability of minocycline have led to the launching of various clinical trials. The present review summarizes the available data supporting the clinical testing of minocycline for these neurodegenerative disorders. In addition, we extend our discussion to the potential applications of minocycline for combining this treatment with cellular and molecular therapy.}, }
@article {pmid15568021, year = {2005}, author = {Storkebaum, E and Lambrechts, D and Dewerchin, M and Moreno-Murciano, MP and Appelmans, S and Oh, H and Van Damme, P and Rutten, B and Man, WY and De Mol, M and Wyns, S and Manka, D and Vermeulen, K and Van Den Bosch, L and Mertens, N and Schmitz, C and Robberecht, W and Conway, EM and Collen, D and Moons, L and Carmeliet, P}, title = {Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS.}, journal = {Nature neuroscience}, volume = {8}, number = {1}, pages = {85-92}, doi = {10.1038/nn1360}, pmid = {15568021}, issn = {1097-6256}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*physiopathology ; Animals ; Axonal Transport ; Cell Survival/drug effects ; Disease Models, Animal ; Humans ; Injections, Intraventricular ; Motor Neurons/*drug effects ; Nerve Degeneration/*physiopathology ; Neuromuscular Junction/drug effects ; Neuroprotective Agents/*administration &amp; dosage/pharmacokinetics/pharmacology ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Recombinant Proteins/administration &amp; dosage/pharmacology ; Superoxide Dismutase/genetics ; Vascular Endothelial Growth Factor A/*administration &amp; dosage/pharmacokinetics/pharmacology ; }, abstract = {Neurotrophin treatment has so far failed to prolong the survival of individuals affected with amyotrophic lateral sclerosis (ALS), an incurable motoneuron degenerative disorder. Here we show that intracerebroventricular (i.c.v.) delivery of recombinant vascular endothelial growth factor (Vegf) in a SOD1(G93A) rat model of ALS delays onset of paralysis by 17 d, improves motor performance and prolongs survival by 22 d, representing the largest effects in animal models of ALS achieved by protein delivery. By protecting cervical motoneurons, i.c.v. delivery of Vegf is particularly effective in rats with the most severe form of ALS with forelimb onset. Vegf has direct neuroprotective effects on motoneurons in vivo, because neuronal expression of a transgene expressing the Vegf receptor prolongs the survival of SOD1(G93A) mice. On i.c.v. delivery, Vegf is anterogradely transported and preserves neuromuscular junctions in SOD1(G93A) rats. Our findings in preclinical rodent models of ALS may have implications for treatment of neurodegenerative disease in general.}, }
@article {pmid15566317, year = {2004}, author = {Strong, MJ}, title = {Amyotrophic lateral sclerosis: contemporary concepts in etiopathogenesis and pharmacotherapy.}, journal = {Expert opinion on investigational drugs}, volume = {13}, number = {12}, pages = {1593-1614}, doi = {10.1517/13543784.13.12.1593}, pmid = {15566317}, issn = {1744-7658}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/epidemiology/*physiopathology ; Drug Therapy/*trends ; Humans ; Mitochondria/metabolism ; Motor Neurons/*pathology ; Nerve Degeneration/pathology ; Superoxide Dismutase/metabolism ; }, abstract = {Among the neurodegenerative diseases associated with ageing, amyotrophic lateral sclerosis (ALS) remains the most devastating. The disease inexorably progresses, the vast majority of pharmacotherapies have failed to modify the disease course, death ensues on average within 5 years of symptom onset and increasing numbers of individuals are afflicted with the disease. However, significant advances in our understanding of the natural history of ALS and of the fundamental nature of the biological defect underlying motor neuron degeneration have been gained, providing hope for the development of novel pharmacotherapies for ALS. Among these is the recognition that ALS is a biologically heterogeneous disorder in which genetics, environment and ageing all interrelate. The observation of clinical heterogeneity, with initial clinical manifestations serving as predictors of survivorship, is of considerable importance in designing therapeutic trials. The presence of frontotemporal dysfunction in a subset of patients has led to increased interest in the relationship between ALS and the degenerative tauopathies. Ultimately, the degenerating motor neurons do not die alone. The contribution of both microglia and astrocytes to the degenerative process are increasingly recognised. Understanding how these processes interrelate has become critical to understanding the pharmacotherapy of ALS and in the design of clinical trials. This review will highlight recent epidemiological and neurochemical advances in our understanding of ALS, and place them into the context of understanding the development of novel treatment avenues for this devastating disease.}, }
@article {pmid15565532, year = {2004}, author = {Tomik, J and Tomik, B}, title = {[The importance of laryngological and phoniatric evaluation at the early stage of amyotrophic lateral sclerosis].}, journal = {Neurologia i neurochirurgia polska}, volume = {38}, number = {5}, pages = {423-426}, pmid = {15565532}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/complications/*physiopathology ; Humans ; Laryngeal Muscles/*physiopathology ; Severity of Illness Index ; Time Factors ; Voice Disorders/*diagnosis/etiology/*physiopathology ; }, abstract = {The bulbar symptoms of amyotrophic lateral sclerosis (ALS) include difficulty with the management of swallowing, saliva production, aspiration of secretion to the air ways and problems with spoken communication. These symptoms originate from the malfunction of the face muscles and pharynx sphincters. Patients with early symptoms of bulbar ALS are often referred to the otolaryngologist for the evaluation and management of dysphagia and dysarthria. The bulbar onset of ALS with hypernasality, articulation defects and voice harshness make the otolaryngologists the primary diagnostician for these signs. Careful examination of the speech quality and morphology as well as the function of vocal cords should be undertaken. Once the diagnosis of ALS is made, the otolaryngologist's involvement in medical treatment is necessary at different stages of the disease.}, }
@article {pmid15564998, year = {2004}, author = {Dimond, B}, title = {The refusal of treatment: living wills and the current law in the UK.}, journal = {British journal of nursing (Mark Allen Publishing)}, volume = {13}, number = {18}, pages = {1104-1106}, doi = {10.12968/bjon.2004.13.18.16146}, pmid = {15564998}, issn = {0966-0461}, mesh = {Accidents, Traffic ; Family/psychology ; Humans ; Living Wills/*legislation &amp; jurisprudence ; Mental Competency/legislation &amp; jurisprudence ; Motor Neuron Disease/therapy ; Treatment Refusal/*legislation &amp; jurisprudence ; Unconsciousness/therapy ; United Kingdom ; }, abstract = {David Browne was suffering from motor neurone disease and was anxious to ensure that as his disease progressed and he ceased to be mentally capacitated he would not be given artificial feeding and ventilation. He therefore arranged to draw up a living will in which he gave an advanced refusal of such treatments. The document was duly signed and witnessed. Only 3 months after signing the living will he was severely injured in a road accident and brought into hospital unconscious. He was carrying his living will in his pocket. The doctors were concerned that if they operated and he required ventilation in intensive care, would the living will prevent their providing such treatment and care? What is the law?}, }
@article {pmid15561247, year = {2004}, author = {Sekido, H and Matsuo, K and Takeda, K and Ueda, M and Morioka, D and Kubota, T and Tanaka, K and Endo, I and Togo, S and Shimada, H}, title = {Usefulness of artificial liver support for pretransplant patients with fulminant hepatic failure.}, journal = {Transplantation proceedings}, volume = {36}, number = {8}, pages = {2355-2356}, doi = {10.1016/j.transproceed.2004.06.040}, pmid = {15561247}, issn = {0041-1345}, mesh = {Adolescent ; Adult ; Blood Pressure ; Female ; Hepatic Encephalopathy/prevention &amp; control ; Humans ; Liver Failure, Acute/*therapy ; Liver Transplantation ; *Liver, Artificial ; Middle Aged ; Patient Selection ; Treatment Outcome ; }, abstract = {This study assessed the usefulness of artificial liver support (ALS) for pretransplant patients with fulminant hepatic failure (FHF). Five patients (age 14 to 52 years, 3 men and 2 women) with FHF who were being prepared for living donor liver transplantation (LDLTx) were enrolled in this study. ALS included plasma exchange, using 40 to 50 units of fresh frozen plasma per session, and high-flow hemodiafiltration, using a high-performance polysulfone membrane. Variables such as circulatory and respiratory function, coma grade, and neurologic disorders were evaluated. Although systolic and diastolic blood pressures showed no statistical differences between pre-ALS and post-ALS, the difference in heart rates was statistically significant. After ALS initiation in the pre-LDLTx period, one of the three patients who needed mechanical ventilation was weaned from it. After LDLTx, all patients recovered neurologically; no neurologic disorder was observed. These results suggested that ALS could predict neurologic status after LDLTx. The difference in coma grades also achieved statistical significance. Our study indicates that short-term ALS is useful for improving circulatory and respiratory function prior to liver transplantation, as well as for predicting posttransplantation neurologic status. Although some patients recover by ALS alone, the survival rate of ALS-only patients is less than 50%. ALS prolongs intensive treatment, thus increasing both the risk of infection and the medical costs. Further investigation to determine a precise marker for liver regeneration will be needed to establish a consensus on the indications for long-term ALS. We conclude that ALS is useful to improve circulatory and respiratory functions among pretransplant patients, and to predict neurologic status after LDLTx.}, }
@article {pmid15548498, year = {2004}, author = {Forbes, RB and Colville, S and Cran, GW and Swingler, RJ and , }, title = {Unexpected decline in survival from amyotrophic lateral sclerosis/motor neurone disease.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {75}, number = {12}, pages = {1753-1755}, doi = {10.1136/jnnp.2003.024364}, pmid = {15548498}, issn = {0022-3050}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*mortality/pathology ; Confounding Factors, Epidemiologic ; Female ; Humans ; Life Expectancy ; Male ; Middle Aged ; Motor Neuron Disease/*mortality/pathology ; Multivariate Analysis ; Prognosis ; Prospective Studies ; Scotland/epidemiology ; Survival Analysis ; }, abstract = {OBJECTIVES: To describe survival of 1226 Scottish adults with amyotrophic lateral sclerosis/motor neurone disease (ALS/MND).<br><br>METHODS: Ten year, prospective, population based disease register. Cox time dependent proportional hazards modelling for multivariate survival analyses.<br><br>RESULTS: Median survival from onset was 25 months (interquartile range 16-34 months). In multivariate models we found an increased hazard with more recently diagnosed cases-that is, there was an unexpected decline in survival over the 10 year period (hazard ratio (HR) 1.06 (95% CI 1.04 to 1.09). Positive effects on survival were demonstrated for longer time from onset to diagnosis (HR 0.38 (95% CI 0.33 to 0.42), assessment by a neurological specialist (HR 0.56 (95% CI 0.40 to 0.77), and treatment with riluzole (HR 0.24 (95% CI 0.14 to 0.42). Poor prognosis was associated with bulbar onset (HR 1.25 (95% CI 1.09 to 1.46) and a mixed lower and upper motor neurone syndrome (HR 1.23 (95% CI 1.01-1.49) and increasing age.<br><br>CONCLUSIONS: We found an unexpected decline in survival over the 10 year period, despite controlling for potential confounding variables. We would be cautious about over-interpreting these observations and suggest that further research is required to confirm or refute these findings.}, }
@article {pmid15539719, year = {2004}, author = {Bach, JR and Bianchi, C and Aufiero, E}, title = {Oximetry and indications for tracheotomy for amyotrophic lateral sclerosis.}, journal = {Chest}, volume = {126}, number = {5}, pages = {1502-1507}, doi = {10.1378/chest.126.5.1502}, pmid = {15539719}, issn = {0012-3692}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*blood/*therapy ; Female ; Humans ; Male ; Middle Aged ; *Oximetry ; *Respiration, Artificial ; Retrospective Studies ; *Tracheotomy ; }, abstract = {STUDY OBJECTIVE: To explore the use of oximetry as a guide for using respiratory aids and tracheotomy in the treatment of patients with amyotrophic lateral sclerosis (ALS).<br><br>SETTING: A retrospective review of all ALS patients presenting to a neuromuscular disease clinic since 1996.<br><br>METHODS: Patients who were symptomatic for nocturnal hypoventilation were prescribed noninvasive ventilation (NIV). Patients with assisted cough peak flows of < 300 L/min were prescribed oximeters and access to mechanically assisted coughing (MAC) to prevent or reverse decreases in baseline pulse oximetric saturation (Spo(2)) levels of < 95%. The number of decreases in baseline Spo(2) that could be normalized by any combination of NIV and MAC and the duration of normalization were recorded. When the baseline was not or could not be normalized, the time to acute respiratory failure and tracheotomy or death were recorded.<br><br>RESULTS: Twenty-five patients became dependent on NIV, including 13 patients who received NIV continuously for a mean (+/- SD) period of 19.7 +/- 16.9 months, without desaturation (group 1). For another 76 patients, the daytime baseline Spo(2) level decreased to < 95% 78 times. For 41 patients, the baseline level was corrected by NIV/MAC (group 2) for a mean duration of 11.1 +/- 8.7 months before desaturation reoccurred for 27 patients. Of the latter patients, 11 underwent tracheotomy, 14 died in < 2 months, and 2 had their condition again corrected by the addition of MAC therapy. For 35 patients, the desaturation was not or could not be normalized (group 3). Thirty-three of these 35 patients required tracheotomy or died within 2 months. The only significant difference between groups 1 and 2 and group 3 was significantly poorer glottic function in the patients in group 3.<br><br>CONCLUSION: Tracheotomy or death is highly likely within 2 months of a decrease in baseline Spo(2) that cannot be corrected by NIV or MAC. The long-term use of NIV and MAC, and the avoidance of tracheotomy is dependent on glottic function rather than on inspiratory or expiratory muscle failure.}, }
@article {pmid15539500, year = {2004}, author = {Raqib, R and Kamal, SM and Rahman, MJ and Rahim, Z and Banu, S and Bardhan, PK and Chowdhury, F and Ara, G and Zaman, K and Breiman, RF and Andersson, J and Sack, DA}, title = {Use of antibodies in lymphocyte secretions for detection of subclinical tuberculosis infection in asymptomatic contacts.}, journal = {Clinical and diagnostic laboratory immunology}, volume = {11}, number = {6}, pages = {1022-1027}, pmid = {15539500}, issn = {1071-412X}, mesh = {Antibodies, Bacterial/*analysis/immunology ; Antigens, Bacterial/*immunology ; Cells, Cultured ; Immunoglobulin G/*analysis/immunology ; Lymphocytes/*immunology ; Mycobacterium bovis/*immunology ; Mycobacterium tuberculosis/*immunology ; Predictive Value of Tests ; Sputum/cytology/*immunology ; Tuberculosis, Pulmonary/*diagnosis/pathology ; }, abstract = {We have previously demonstrated that Mycobacterium bovis BCG-specific immunoglobulin G antibodies in lymphocyte secretions (ALS) can be employed as a marker for active tuberculosis (TB). We aimed to determine whether the ALS method allows detection of subclinical TB infection in asymptomatic individuals. A prospective study of family contacts (FCs) of patients with active TB and healthy controls was performed. Thirteen of 42 FCs had high ALS responses, including 6 FCs who subsequently developed active TB. No correlation was observed between the tuberculin skin test and the ALS responses in the FCs (r = 0.1, P = 0.23). Among patients with active TB, BCG-specific ALS responses steadily declined from the time of diagnosis through 6 months following antimycobacterial chemotherapy (P = 0.001). The ALS assay enabled detection of infection in exposed symptom-free contacts, who are at greater risk for developing active TB. The method may also allow discrimination between effective treatment of active infection and suboptimal response to therapy.}, }
@article {pmid15537049, year = {2004}, author = {Mandel, RJ and Burger, C}, title = {Clinical trials in neurological disorders using AAV vectors: promises and challenges.}, journal = {Current opinion in molecular therapeutics}, volume = {6}, number = {5}, pages = {482-490}, pmid = {15537049}, issn = {1464-8431}, mesh = {*Clinical Trials as Topic ; Dependovirus/*genetics ; Genetic Therapy/*instrumentation/*trends ; Genetic Vectors/*genetics ; Humans ; Nervous System Diseases/*genetics/pathology/physiopathology/*therapy ; }, abstract = {Currently, there are five phase I clinical trials of recombinant adeno-associated viral vectors for the treatment of neurological disorders that are approved or likely to be approved shortly. Two trials are testing different strategies to treat Parkinson's disease (PD), the third trial is aimed at treating Canavan's disease, a pediatric leukodystrophy, the fourth trial targets Alzheimer's disease (AD), and the fifth will attempt to target the lysosomal storage disorder, Batten's disease. All four clinical trials rely on the de novo expression of an enzyme or a trophic factor to correct neuropathology. Ironically, the theories used to choose enzymes for the two PD trials were widely divergent, whereas the enzymatic strategy used for one of the PD trials and the Canavan's trial have remarkable similarities. Other gene therapy treatment strategies for PD and other disorders, such as amyotrophic lateral sclerosis, are also on the horizon.}, }
@article {pmid15533627, year = {2005}, author = {Pallàs, M and Verdaguer, E and Jordà, EG and Jiménez, A and Canudas, AM and Camins, A}, title = {Flavopiridol: an antitumor drug with potential application in the treatment of neurodegenerative diseases.}, journal = {Medical hypotheses}, volume = {64}, number = {1}, pages = {120-123}, doi = {10.1016/j.mehy.2004.03.047}, pmid = {15533627}, issn = {0306-9877}, mesh = {Animals ; Antineoplastic Agents/administration &amp; dosage ; Apoptosis/*drug effects ; Clinical Trials as Topic ; Cyclin-Dependent Kinases/*antagonists &amp; inhibitors/*metabolism ; Flavoproteins/*administration &amp; dosage ; Humans ; *Models, Neurological ; Neurodegenerative Diseases/*drug therapy/*metabolism ; Neurons/drug effects/*metabolism ; Neuroprotective Agents/administration &amp; dosage ; }, abstract = {Several lines of evidence show that cyclin-dependent kinases (CDKs) contribute to neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, and amyotrophic lateral sclerosis. Given their role in the neuronal apoptosis, the inhibition of CDKs by specific drugs such as flavopiridol may be a valid therapeutic approach. Expression of CDKs was observed in rodent models of excitotoxicity and stroke, and CDK inhibitors showed neuroprotective effects. Flavopiridol may provide significant improvement in neurodegenerative diseases in humans.}, }
@article {pmid15522870, year = {2005}, author = {Fujiwara, N and Miyamoto, Y and Ogasahara, K and Takahashi, M and Ikegami, T and Takamiya, R and Suzuki, K and Taniguchi, N}, title = {Different immunoreactivity against monoclonal antibodies between wild-type and mutant copper/zinc superoxide dismutase linked to amyotrophic lateral sclerosis.}, journal = {The Journal of biological chemistry}, volume = {280}, number = {6}, pages = {5061-5070}, doi = {10.1074/jbc.M406106200}, pmid = {15522870}, issn = {0021-9258}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/immunology/*metabolism ; Animals ; Antibodies, Monoclonal/*chemistry ; Blotting, Western ; Cell Line ; Circular Dichroism ; Dithiothreitol/chemistry ; Electrophoresis, Polyacrylamide Gel ; Enzyme-Linked Immunosorbent Assay ; Humans ; Mice ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis ; Mutation ; Peptides/chemistry ; Sodium Dodecyl Sulfate/chemistry ; Superoxide Dismutase/*chemistry ; Ultraviolet Rays ; }, abstract = {Although more than 100 mutations have been identified in the copper/zinc superoxide dismutase (Cu/Zn-SOD) in familial amyotrophic lateral sclerosis (FALS), the mechanism responsible for FALS remains unclear. The finding of the present study shows that FALS-causing mutant Cu/Zn-SOD proteins (FALS mutant SODs), but not wild-type SOD, are barely detected by three monoclonal antibodies (mAbs) in Western blot analyses. The enzyme-linked immunosorbent assay for denatured FALS mutant SODs by dithiothreitol, SDS, or heat treatment also showed a lowered immunoreactivity against the mAbs compared with wild-type SOD. Because all the epitopes of these mAbs are mapped within the Greek key loop (residues 102-115 in human Cu/Zn-SOD), these data suggest that different conformational changes occur in the loop between wild-type and FALS mutant SODs during the unfolding process. Circular dichroism measurements revealed that the FALS mutant SODs are sensitive to denaturation by dithiothreitol, SDS, or heat treatment, but these results do not completely explain the different recognition by the mAbs between wild-type and FALS mutant SODs under the denatured conditions. The study on the conformational changes in local areas monitoring with mAbs may provide a new insight into the etiology of FALS.}, }
@article {pmid15519748, year = {2004}, author = {Mancuso, M and Conforti, FL and Rocchi, A and Tessitore, A and Muglia, M and Tedeschi, G and Panza, D and Monsurrò, M and Sola, P and Mandrioli, J and Choub, A and DelCorona, A and Manca, ML and Mazzei, R and Sprovieri, T and Filosto, M and Salviati, A and Valentino, P and Bono, F and Caracciolo, M and Simone, IL and La Bella, V and Majorana, G and Siciliano, G and Murri, L and Quattrone, A}, title = {Could mitochondrial haplogroups play a role in sporadic amyotrophic lateral sclerosis?.}, journal = {Neuroscience letters}, volume = {371}, number = {2-3}, pages = {158-162}, doi = {10.1016/j.neulet.2004.08.060}, pmid = {15519748}, issn = {0304-3940}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*genetics ; Cohort Studies ; Confidence Intervals ; DNA, Mitochondrial/*genetics ; Female ; Haplotypes/*genetics ; Humans ; Male ; Middle Aged ; Mitochondria/genetics ; Odds Ratio ; Polymorphism, Genetic/genetics ; }, abstract = {Mitochondrial impairment has been implicated in the pathogenesis of the amyotrophic lateral sclerosis (ALS). Furthermore, mitochondrial-specific polymorphisms were previously related to other neurodegenerative diseases, such as Parkinson, Friedreich and Alzheimer disease. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of sporadic ALS (sALS), we have genotyped predefined European mtDNA haplogroups in 222 Italian patients with sALS and 151 matched controls. Individuals classified as haplogroup I demonstrated a significant decrease in risk of ALS versus individuals carrying the most common haplogroup, H (odds ratio 0.08, 95% confidence interval 0.04-0.4, p < 0.01). Further stratification of the dataset by sex, age and site of onset of disease and survival failed to reach significance for association. Our study provides evidence of the contribution of mitochondrial variation to the risk of ALS development in Caucasians. Further it may help elucidate the mechanism of the mitochondrial dysfunction detectable in ALS, and may be of relevance in development of strategies for the treatment of this disease.}, }
@article {pmid15519530, year = {2005}, author = {Sonkusare, SK and Kaul, CL and Ramarao, P}, title = {Dementia of Alzheimer's disease and other neurodegenerative disorders--memantine, a new hope.}, journal = {Pharmacological research}, volume = {51}, number = {1}, pages = {1-17}, doi = {10.1016/j.phrs.2004.05.005}, pmid = {15519530}, issn = {1043-6618}, mesh = {Alzheimer Disease/*drug therapy/metabolism ; Animals ; Clinical Trials as Topic/statistics &amp; numerical data ; Humans ; Memantine/chemistry/pharmacokinetics/*therapeutic use ; Neurodegenerative Diseases/drug therapy/metabolism ; Neuroprotective Agents/chemistry/pharmacokinetics/therapeutic use ; }, abstract = {Alzheimer's disease is the fourth largest cause of death for people over 65 years of age. Dementia of Alzheimer's type is the commonest form of dementia, the other two forms being vascular dementia and mixed dementia. At present, the therapy of Alzheimer's disease is aimed at improving both, cognitive and behavioural symptoms and thereby, quality of life for the patients. Since the discovery of Alzheimer's disease by Alois Alzheimer, many pathological mechanisms have been proposed which led to the testing of various new treatments. Until recently the available drugs for the treatment of Alzheimer's disease are cholinesterase inhibitors, which have limited success because these drugs improve cognitive functions only in mild dementia and cannot stop the process of neurodegeneration. Moreover, drugs of this category show gastrointestinal side effects. As the cells of central and peripheral nervous system cannot regenerate, newer strategies are aimed at preserving the surviving neurons by preventing their degeneration. NMDA-receptor-mediated glutamate excitotoxicity plays a major role in Abeta-induced neuronal death. Hence, it was thought that NMDA receptors could be a promising target for preventing the progression of Alzheimer's disease. All the compounds synthesized initially in this category showed toxicity mainly because of their high affinity for NMDA receptors. Memantine (1-amino adamantane derivative), NMDA-receptor antagonist was reported to be effective therapeutically in Alzheimer's disease. It was available in Germany as well as European Union and has been approved for moderate to severe dementia in United States of America recently. It is an uncompetitive, moderate affinity antagonist of NMDA receptors that inhibits the pathological functions of NMDA receptors while physiological processes in learning and memory are unaffected. Memantine is also reported to have beneficial effects in other CNS disorders viz., Parkinson's disease (PD), stroke, epilepsy, CNS trauma, amyotrophic lateral sclerosis (ALS), drug dependence and chronic pain. Mechanisms of neuroprotection, preclinical and clinical evidence for effectiveness of memantine have been provided. Pharmacology and pharmacokinetics of memantine and other NMDA-receptor antagonists in comparison with currently approved drugs for dementia treatment have been discussed. The focus is on 'glutamate excitotoxicity' and glutamate receptors as drug target. Various other novel strategies for the treatment of dementia of neurodegenerative disorders have also been discussed.}, }
@article {pmid15517433, year = {2005}, author = {Graf, M and Ecker, D and Horowski, R and Kramer, B and Riederer, P and Gerlach, M and Hager, C and Ludolph, AC and Becker, G and Osterhage, J and Jost, WH and Schrank, B and Stein, C and Kostopulos, P and Lubik, S and Wekwerth, K and Dengler, R and Troeger, M and Wuerz, A and Hoge, A and Schrader, C and Schimke, N and Krampfl, K and Petri, S and Zierz, S and Eger, K and Neudecker, S and Traufeller, K and Sievert, M and Neundörfer, B and Hecht, M and , }, title = {High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {112}, number = {5}, pages = {649-660}, doi = {10.1007/s00702-004-0220-1}, pmid = {15517433}, issn = {0300-9564}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Riluzole/*therapeutic use ; Treatment Outcome ; Vitamin E/*administration &amp; dosage/adverse effects/blood ; Vitamins/*administration &amp; dosage/adverse effects/blood ; }, abstract = {UNLABELLED: Increasing evidence has suggested that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of the paralysis in transgenic mice expressing a mutation in the superoxide dismutase gene found in certain forms of familial ALS. The current study, a double blind, placebo-controlled, randomised, stratified, parallel-group clinical trial, was designed to determine whether vitamin E (5000 mg per day) may be efficacious in slowing down disease progression when added to riluzole.<br><br>METHODS: 160 patients in 6 German centres with either probable or definite ALS (according to the El Escorial Criteria) and a disease duration of less than 5 years, treated with riluzole, were included in this study and were randomly assigned to receive either alpha-tocopherol (5000 mg per day) or placebo for 18 months. The Primary outcome measure was survival, calculating time to death, tracheostomy or permanent assisted ventilation, according to the WFN-Criteria of clinical trials. Secondary outcome measures were the rate of deterioration of function assessed by the modified Norris limb and bulbar scales, manual muscle testing (BMRC), spasticity scale, ventilatory function and the Sickness Impact Profile (SIP ALS/19). Patients were assessed at entry and every 4 months thereafter during the study period until month 16 and at a final visit at month 18. Vitamin E samples were taken for compliance check and Quality Control of the trial. For Safety, a physical examination was performed at baseline and then every visit until the treatment discontinuation at month 18. Height and weight were recorded at baseline and weight alone at the follow-up visits. A neurological examination as well as vital signs (heart rate and blood pressure), an ECG and VEP's were recorded at each visit. Furthermore, spontaneously reported adverse experiences and serious adverse events were documented and standard laboratory tests including liver function tests performed. For Statistical Analysis, the population to be considered for the primary outcome measure was an "intent-to-treat" (ITT) population which included all randomised patients who had received at least one treatment dose (n = 160 patients). For the secondary outcome measures, a two way analysis of variance was performed on a patient population that included all randomised patients who had at least one assessment after inclusion.<br><br>RESULTS: Concerning the primary endpoint, no significant difference between placebo and treatment group could be detected either with the stratified Logrank or the Wilcoxon test. The functional assessments showed a marginal trend in favour of vitamin E, without reaching significance.<br><br>CONCLUSION: Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol. Larger or longer studies might be needed. However, administration of this megadose does not seem to have any significant side effects in this patient population.}, }
@article {pmid15512906, year = {2004}, author = {Shahani, N and Gourie-Devi, M and Nalini, A and Rammohan, P and Shobha, K and Harsha, HN and Raju, TR}, title = {(-)-Deprenyl alleviates the degenerative changes induced in the neonatal rat spinal cord by CSF from amyotrophic lateral sclerosis patients.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {3}, pages = {172-179}, doi = {10.1080/14660820410017037}, pmid = {15512906}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*cerebrospinal fluid ; Animals ; Animals, Newborn ; Case-Control Studies ; Cell Count ; Dose-Response Relationship, Drug ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Immunohistochemistry/methods ; L-Lactate Dehydrogenase/metabolism ; Neurofilament Proteins/metabolism ; Neuroprotective Agents/*therapeutic use ; Phosphorylation/drug effects ; Rats ; Rats, Wistar ; Selegiline/*therapeutic use ; Spinal Cord/metabolism ; Spinal Cord Diseases/etiology/metabolism/*prevention &amp; control ; Time Factors ; }, abstract = {Previous studies from our laboratory suggest the presence of toxic factor(s) in the cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS) which induces degenerative changes in the spinal cord neurons. The present work was carried out to investigate the role of (-)-deprenyl in attenuating these degenerative changes. CSF samples from ALS and non-ALS neurological patients were injected into the spinal subarachnoid space of 3-day-old rat pups, followed by a single dose (0.01 mg/kg body weight) of (-)-deprenyl, administered 24 h after CSF injection. After a further period of 24 h, the rats were sacrificed and the spinal cord sections were stained with antibodies against phosphorylated neurofilament (NF, SMI-31 antibody) and glial fibrillary acidic protein (GFAP). Activity of lactate dehydrogenase (LDH) was also measured. (-)-Deprenyl injection resulted in a significant (61%) decrease in the number of SMI-31 stained neuronal soma in the ventral horn of the spinal cord of ALS CSF exposed rats. This was accompanied by a reduction in the astrocytes immunoreactive for GFAP. There was also a significant (35%) decrease in the LDH activity following (-)-deprenyl treatment. These results suggest that (-)-deprenyl may confer neuroprotection against the toxic factor(s) present in ALS CSF.}, }
@article {pmid15512903, year = {2004}, author = {Kidney, D and Alexander, M and Corr, B and O'toole, O and Hardiman, O}, title = {Oropharyngeal dysphagia in amyotrophic lateral sclerosis: neurological and dysphagia specific rating scales.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {3}, pages = {150-153}, doi = {10.1080/14660820410019675}, pmid = {15512903}, issn = {1466-0822}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*complications/diagnosis ; Deglutition Disorders/diagnosis/*etiology ; Diagnosis, Differential ; *Disability Evaluation ; Female ; Humans ; Male ; Middle Aged ; Neurologic Examination/methods ; Prospective Studies ; Reproducibility of Results ; *Severity of Illness Index ; }, abstract = {BACKGROUND: Oropharyngeal dysphagia is highly prevalent in amyotrophic lateral sclerosis (ALS). Patients with dysphagia and weight loss are frequently offered gastrostomy. Although the neurological basis of dysphagia in ALS is complex, there are currently no specifically validated scales for dysphagia in ALS, and the reliability of existing generic scales has not been assessed.<br><br>METHODS: We undertook a prospective study of 25 patients who fulfilled the criteria for definite or probable ALS. We examined the reliability of the Dysphagia Outcome Severity Scale (DOSS) and the Aspiration-Penetration Rating Scale (APRS) and the correlation between these scales and the Norris ALS Scale and ALS Functional Rating Scale-R (ALS FRS-R).<br><br>RESULTS: Using the Pearson Product-Moment Correlation, an expected high linear association between the two disease specific neurological scales was demonstrated. Both dysphagia scales were found to be reliable. Interrelationship evaluation showed a low association between Norris and ALS FRS-R scores and DOSS and APRS. However, examination found specific subsections to be significantly correlated, particularly the Norris bulbar sections (NBS) and the DOSS.<br><br>CONCLUSIONS: Generic dysphagia scales are reliable indicators of dysphagia in ALS. The bulbar components of the ALS specific scales is sensitive to dysphagia. The bulbar section of the Norris scale can be utilised as an independent and reliable indicator of the severity of dysphagia in ALS. In the absence of availability of detailed swallowing assessment using videofluoroscopy, these scales, i.e., the Norris and to a lesser degree the ALS FRS-R bulbar sections, are adequate to diagnose and follow clinically significant dysphagia in ALS, and can be used as an indicator for dysphagia treatment initiation.}, }
@article {pmid15512902, year = {2004}, author = {Rule, RR and Suhy, J and Schuff, N and Gelinas, DF and Miller, RG and Weiner, MW}, title = {Reduced NAA in motor and non-motor brain regions in amyotrophic lateral sclerosis: a cross-sectional and longitudinal study.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {3}, pages = {141-149}, pmid = {15512902}, issn = {1466-0822}, support = {R01 NS040321/NS/NINDS NIH HHS/United States ; R01 NS040321-03/NS/NINDS NIH HHS/United States ; R01 NS4032/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/diagnosis/*metabolism ; Aspartic Acid/*analogs &amp; derivatives/*metabolism ; Brain/metabolism/pathology ; Brain Mapping ; Choline/metabolism ; Creatine/metabolism ; Cross-Sectional Studies ; Female ; Functional Laterality/physiology ; Humans ; Image Processing, Computer-Assisted ; Longitudinal Studies ; Magnetic Resonance Imaging/methods ; Magnetic Resonance Spectroscopy/methods ; Male ; Middle Aged ; Motor Cortex/*metabolism/pathology ; Reference Values ; Tritium/metabolism ; }, abstract = {OBJECTIVES: After replication of previous findings we aimed to: 1) determine if previously reported (1)H MRSI differences between ALS patients and control subjects are limited to the motor cortex; and 2) determine the longitudinal metabolic changes corresponding to varying levels of diagnostic certainty.<br><br>METHODS: Twenty-one patients with possible/suspected ALS, 24 patients with probable/definite ALS and 17 control subjects underwent multislice (1)H MRSI co-registered with tissue-segmented MRI to obtain concentrations of the brain metabolites N-acetylaspartate (NAA), creatine, and choline in the left and right motor cortex and in gray matter and white matter of non-motor regions in the brain.<br><br>RESULTS: In the more affected hemisphere, reductions in the ratios, NAA/Cho and NAA/Cre+Cho were observed both within (12.6% and 9.5% respectively) and outside (9.2% and 7.3% respectively) the motor cortex in probable/definite ALS. However, these reductions were significantly greater within the motor cortex (P<0.05 for NAA/Cho and P<0.005 for NAA/Cre+Cho). Longitudinal changes in NAA were observed at three months within the motor cortex of both possible/suspected ALS patients (P<0.005) and at nine months outside the motor cortex of probable/definite patients (P<0.005). However, there was no clear pattern of progressive change over time.<br><br>CONCLUSIONS: NAA ratios are reduced in the motor cortex and outside the motor cortex in ALS, suggesting widespread neuronal injury. Longitudinal changes of NAA are not reliable, suggesting that NAA may not be a useful surrogate marker for treatment trials.}, }
@article {pmid15512890, year = {2004}, author = {Rosenfeld, J}, title = {ALS combination treatment. Drug cocktails.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5 Suppl 1}, number = {}, pages = {115-117}, doi = {10.1080/17434470410020067}, pmid = {15512890}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*pathology/physiopathology ; Cell Death/drug effects ; Clinical Trials as Topic/methods ; Disease Progression ; *Drug Therapy, Combination ; Humans ; Motor Neurons/drug effects ; Research Design ; }, }
@article {pmid15512888, year = {2004}, author = {Swash, M and de Carvalho, M}, title = {The Neurophysiological Index in ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5 Suppl 1}, number = {}, pages = {108-110}, doi = {10.1080/17434470410020067}, pmid = {15512888}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Evoked Potentials, Motor/physiology ; Humans ; Isometric Contraction/physiology ; Motor Neurons/physiology ; Muscle, Skeletal/physiopathology ; Neural Conduction/physiology ; Neurophysiology/*methods ; Reaction Time ; }, abstract = {The Neurophysiological Index (NI) consists of a mathematical derivation of three standardised neurophysiological measurements. Since these measurements are part of routine practice in any clinical neurophysiology laboratory, calculation of the NI is within the capability of any laboratory. The NI is derived from the CMAP, the DML and the F-wave frequency (CMAP amplitude/DML) x F frequency %), representing aspects of the effects of denervation and reinnervation, of degeneration of the terminal part of the motor axons, and of the excitability of anterior horn cells. We have shown that this simple index is reproducible in consecutive studies of normal subjects and of patients with ALS (intra-rater reliability), and is sensitive to change. In ALS, the NI differentiates rapidly and slowly progressive disease at least as sensitively as other measures in common use, including the ALS-FRS. We propose that the NI could be used as a sensitive measure of change during the course of ALS and its treatment. In combination with relevant measures of clinical benefit, such as ALS-FRS and a QoL measure, this could simplify trial design and allow more rapid determination of the efficacy of putative new therapies in clinical trials.}, }
@article {pmid15512875, year = {2004}, author = {Moore, DH and Miller, RG}, title = {Improving efficiency of ALS clinical trials using lead-in designs.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5 Suppl 1}, number = {}, pages = {57-60}, doi = {10.1080/17434470410019997}, pmid = {15512875}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials as Topic/*methods ; Data Interpretation, Statistical ; Humans ; *Research Design ; Single-Blind Method ; }, abstract = {We describe designs for clinical trials in ALS including two that are more efficient than the standard two-arm, parallel design. The more efficient designs incorporate a lead-in period followed by a randomized intervention (drug or placebo) period. Efficacy of the more efficient designs is based on measuring, within each patient, the difference in slope while on the new treatment compared to the lead-in period. We demonstrate, with sample size calculations, that the lead-in designs are considerably more efficient than the standard two-arm, parallel design. Sample sizes can be reduced by 44% for a 12-month study using ALSFRS rate of decline as a primary endpoint for a two-arm trial with 4 months lead-in compared to a parallel design. A sample size reduction of 70% can be realized with variable lead-in compared to a parallel design.}, }
@article {pmid15505150, year = {2004}, author = {Brooks, BR and Thisted, RA and Appel, SH and Bradley, WG and Olney, RK and Berg, JE and Pope, LE and Smith, RA and , }, title = {Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial.}, journal = {Neurology}, volume = {63}, number = {8}, pages = {1364-1370}, doi = {10.1212/01.wnl.0000142042.50528.2f}, pmid = {15505150}, issn = {1526-632X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*complications/*drug therapy/physiopathology ; Cytochrome P-450 CYP2D6/metabolism ; Cytochrome P-450 CYP2D6 Inhibitors ; Dextromethorphan/*administration &amp; dosage/adverse effects/blood ; Double-Blind Method ; Drug Combinations ; Drug Interactions/physiology ; Enzyme Inhibitors/administration &amp; dosage/adverse effects/metabolism ; Excitatory Amino Acid Antagonists/administration &amp; dosage/adverse effects/blood ; Female ; Glutamic Acid/metabolism ; Humans ; Male ; Metabolic Clearance Rate/drug effects/physiology ; Middle Aged ; Pseudobulbar Palsy/*drug therapy/*etiology/physiopathology ; Quinidine/*administration &amp; dosage/adverse effects/blood/metabolism ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors/metabolism ; Treatment Outcome ; }, abstract = {BACKGROUND: Patients with ALS commonly exhibit pseudobulbar affect.<br><br>METHODS: The authors conducted a multicenter, randomized, double-blind, controlled, parallel, three-arm study to test a defined combination of dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) (AVP-923) for the treatment of pseudobulbar affect in ALS. Q inhibits the rapid first-pass metabolism of DM. The effects of AVP-923 (30 mg of DM plus 30 mg of Q) given twice daily for 28 days were compared with those of its components. Patients were evaluated on days 1, 15, and 29. The primary efficacy variable was the change from baseline in the Center for Neurologic Study Lability Scale (CNS-LS) score. Secondary efficacy variables were laughing/crying episode rates and changes in Visual Analog Scales for Quality of Life (QOL) and Relationships (QOR). Efficacy was evaluated in intention-to-treat subjects who were not poor metabolizers of DM (n = 65 for AVP-923, n = 30 for DM, and n = 34 for Q). Safety was assessed in all randomized subjects (n = 140).<br><br>RESULTS: AVP-923 patients experienced 3.3-point greater improvements in CNS-LS than DM patients (p = 0.001) and 3.7-point greater improvements than Q patients (p < 0.001). AVP-923 patients exhibited lower overall episode rates, improved QOL scores, and improved QOR scores (p < 0.01 for all endpoints). Adverse effects were mostly mild or moderate; treatment-related discontinuation was 24% for AVP-923, 6% for DM, and 8% for Q.<br><br>CONCLUSIONS: AVP-923 palliates pseudobulbar affect in ALS. Overall benefits of treatment are reflected in fewer episodes of crying and laughing and improvements in overall quality of life and quality of relationships.}, }
@article {pmid15500412, year = {2004}, author = {Bensimon, G and Doble, A}, title = {The tolerability of riluzole in the treatment of patients with amyotrophic lateral sclerosis.}, journal = {Expert opinion on drug safety}, volume = {3}, number = {6}, pages = {525-534}, doi = {10.1517/14740338.3.6.525}, pmid = {15500412}, issn = {1744-764X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Asthenia/chemically induced ; Biotransformation ; Chemical and Drug Induced Liver Injury/etiology ; Clinical Trials, Phase IV as Topic ; Contraindications ; Disease Progression ; Drug Interactions ; Humans ; Liver Function Tests ; Middle Aged ; Multicenter Studies as Topic ; Nausea/chemically induced ; Neutropenia/chemically induced ; Randomized Controlled Trials as Topic ; Riluzole/adverse effects/pharmacokinetics/*therapeutic use ; Risk ; }, abstract = {Riluzole is the only disease-modifying drug approved for the treatment of amyotrophic lateral sclerosis (ALS), in which it has been demonstrated to extend survival. The overall tolerability of riluzole is good and the drug can be used in all patients with ALS except those with elevated transaminase levels or active liver disease. The most frequently encountered adverse events (AEs) that appear to be attributed to riluzole are asthenia and nausea, observed in 18 and 15% of patients taking riluzole in the randomised clinical trial programme, respectively. These same AEs, albeit at a lower frequency, are also reported in Phase IV observational studies and in pharmacovigilance surveys. No unexpected AE clearly related to riluzole has emerged in the seven years that riluzole has been in extensive use in ALS patients. The most important potential safety issue with riluzole is hepatic impact with elevations of transaminases. Serum alanine aminotransferase levels more than three times the upper limit of normal are observed in 10 - 15% of patients. For this reason, strict monitoring of liver enzymes is recommended in patients with ALS taking riluzole, and treatment is contraindicated in subjects with elevated transaminases before the start of treatment. There is a suspicion that riluzole may, in rare cases, cause neutropenia, and physicians should be vigilant towards this risk.}, }
@article {pmid15495036, year = {2004}, author = {Orrell, RW and Lane, JM and Ross, MA}, title = {Antioxidant treatment for amyotrophic lateral sclerosis / motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD002829}, doi = {10.1002/14651858.CD002829.pub2}, pmid = {15495036}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Antioxidants/*therapeutic use ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Free radical accumulation and oxidative stress have been proposed as contributing to the progression of amyotrophic lateral sclerosis (or motor neuron disease). A range of antioxidant medications are available, and have been studied.<br><br>OBJECTIVES: To examine the effects of antioxidant medication in the treatment of people with amyotrophic lateral sclerosis.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (July 2003), MEDLINE (from January 1966 to July 2003), EMBASE (from January 1980 to July 2003) and other sources.<br><br>SELECTION CRITERIA: All randomized or quasi-randomized controlled trials of antioxidant treatment for amyotrophic lateral sclerosis.<br><br>DATA COLLECTION AND ANALYSIS: The reviewers independently applied the selection criteria, assessed study quality and two reviewers performed independent data extraction.<br><br>MAIN RESULTS: The search identified 21 studies for consideration but only eight studies met the inclusion criteria. Only two studies used our predetermined primary outcome measure, (survival at 12 months treatment). Sufficient data were available from three studies to allow analysis of the primary outcome measure, and a meta-analysis was performed. In the individual studies no significant effect was observed of vitamin E 500 mg twice daily; acetylcysteine 50 mg/kg daily subcutaneous infusion; or a combination of L-methionine 2 g, vitamin E 400 International Units, and selenium 3 x 10-5g three times daily (Alsemet). No significant effect on the primary outcome measure was observed in a meta-analysis of antioxidants in general when combining the results. No significant differences were demonstrated in secondary outcome measures.<br><br>REVIEWERS' CONCLUSIONS: There is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect, but this was not supported by the analysis we used. Generally the studies were poorly designed, and underpowered, with low numbers of participants and of short duration. Further well-designed trials of medications such as vitamin C and E are unlikely to be performed. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trial. The high tolerance and safety, and relatively low cost of vitamins C and E, and other considerations related to the lack of other effective treatments for amyotrophic lateral sclerosis, explain the continuing use of these vitamins by physicians and patients. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.}, }
@article {pmid15494159, year = {2004}, author = {Wengenack, TM and Holasek, SS and Montano, CM and Gregor, D and Curran, GL and Poduslo, JF}, title = {Activation of programmed cell death markers in ventral horn motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in a transgenic mouse model.}, journal = {Brain research}, volume = {1027}, number = {1-2}, pages = {73-86}, doi = {10.1016/j.brainres.2004.08.054}, pmid = {15494159}, issn = {0006-8993}, support = {NS 38896/NS/NINDS NIH HHS/United States ; }, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism/*pathology ; Animals ; Anterior Horn Cells/cytology/*metabolism ; Apoptosis/*physiology ; Biomarkers/metabolism ; Blotting, Western/methods ; Caspase 3 ; Caspases/metabolism ; Cell Count ; Disease Models, Animal ; Humans ; Immunohistochemistry/methods ; MAP Kinase Kinase Kinase 5/metabolism ; Mice ; Mice, Transgenic/physiology ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase Type I ; Staining and Labeling/methods ; Superoxide Dismutase/genetics ; fas Receptor/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {The identification of the pathogenic mechanism of selective motor neuron (MN) death in amyotrophic lateral sclerosis (ALS) may lead to the development of new therapies to halt or slow the disease course. A novel, MN-specific, Fas-mediated programmed cell death (PCD) pathway has been reported in MNs which involves the activation of p38 MAP kinase (phospho-p38) and neuronal nitric oxide synthase (nNOS). PCD was found to be exacerbated in MNs expressing ALS-linked superoxide dismutase (SOD) mutations. Because this MN-specific pathway was investigated in vitro, we performed an in vivo study to evaluate its potential involvement in MN loss in the lumbar region of spinal cord of mutant SOD transgenic (G93A) mice. Compared to nontransgenic littermates, we found significant increases in the numbers of immunopositive ventral horn MNs of G93A mice as young as 60 days of age for several constituents of this putative PCD pathway, including phospho-p38, nNOS, phospho-ASK1 MAP kinase kinase, and active caspase-3. This study provides in vivo evidence of an MN-specific PCD pathway that may be a pathogenic mechanism of ALS and may be activated very early in the disease process, well before clinical symptoms are evident (200 days). These findings suggest that early diagnosis and therapeutic intervention may be critical for the successful treatment of the disease. These enzymes may provide new markers for earlier diagnosis of ALS and new molecular targets for therapeutic intervention.}, }
@article {pmid15469951, year = {2004}, author = {Corti, S and Locatelli, F and Donadoni, C and Guglieri, M and Papadimitriou, D and Strazzer, S and Del Bo, R and Comi, GP}, title = {Wild-type bone marrow cells ameliorate the phenotype of SOD1-G93A ALS mice and contribute to CNS, heart and skeletal muscle tissues.}, journal = {Brain : a journal of neurology}, volume = {127}, number = {Pt 11}, pages = {2518-2532}, doi = {10.1093/brain/awh273}, pmid = {15469951}, issn = {1460-2156}, mesh = {Amyotrophic Lateral Sclerosis/genetics/pathology/*therapy ; Animals ; *Bone Marrow Transplantation ; Cell Differentiation ; Cerebral Cortex/pathology ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Transgenic ; Muscle, Skeletal/pathology ; Myocardium/pathology ; Neurons/pathology ; Phenotype ; Spinal Cord/pathology ; Superoxide Dismutase/*genetics ; Survival Analysis ; Transplantation Chimera ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neurodegenerative disease without any effective therapy. To evaluate the potential of wild-type bone marrow (BM)-derived stem cells to modify the ALS phenotype, we generated BM chimeric Cu/Zn superoxide dismutase (SOD1) mice by transplantation of BM cells derived from mice expressing green fluorescent protein (GFP) in all tissues and from Thy1-YFP mice that express a spectral variant of GFP (yellow fluorescent protein) in neurons only. In the recipient cerebral cortex, we observed rare GFP+ and YFP+ neurons, which were probably generated by cell fusion, as demonstrated by fluorescence in situ hybridization (FISH) analysis, suggesting that this phenomenon is not limited to Purkinje cells. GFP-positive microglial cells were extensively present in both the brain and spinal cord of the affected animals. Completely differentiated and immature GFP+ myofibres were also present in the heart and skeletal muscles of SOD1 mice, confirming that BM cells can participate in striated muscle tissue regeneration. Moreover, wild-type BM chimeric SOD1 mice showed a significantly delayed disease onset and an increased life span, probably due to a positive 'non-neuronal environmental' effect rather than to neuronogenesis. This improvement in SOD1-G93A mouse survival is comparable with that previously obtained using some safer pharmacological agents. BM transplantation-related complications in humans preclude its clinical application for ALS treatment. However, our data suggest that further studies aimed at improving the degree of tissue chimerism by BM-derived cells may provide valuable insights into strategies to slow ALS progression.}, }
@article {pmid15466883, year = {2004}, author = {Vanoni, C and Massari, S and Losa, M and Carrega, P and Perego, C and Conforti, L and Pietrini, G}, title = {Increased internalisation and degradation of GLT-1 glial glutamate transporter in a cell model for familial amyotrophic lateral sclerosis (ALS).}, journal = {Journal of cell science}, volume = {117}, number = {Pt 22}, pages = {5417-5426}, doi = {10.1242/jcs.01411}, pmid = {15466883}, issn = {0021-9533}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Animals ; Biological Transport ; Biotinylation ; Blotting, Western ; Cell Line ; DNA, Complementary/metabolism ; Disease Models, Animal ; Dogs ; Down-Regulation ; Endocytosis ; Excitatory Amino Acid Transporter 2/*biosynthesis/*chemistry ; Glutamic Acid/*metabolism ; Humans ; Immunohistochemistry ; Microscopy, Fluorescence ; Models, Biological ; Mutation ; Neurons/metabolism ; Oxidative Stress ; Plasmids/metabolism ; Protein Isoforms ; Superoxide Dismutase/metabolism ; Time Factors ; Transfection ; }, abstract = {It has been suggested that glutamate-induced excitotoxicity plays a central role in the development of motor neuron diseases such as amyotrophic lateral sclerosis (ALS). The GLT-1 isoform of the glutamate transporter gene family is the most important transporter involved in keeping extracellular glutamate concentration below neurotoxic levels. Its loss and an increase in extracellular glutamate has been documented in cases of sporadic and familial ALS, as well as in animal models expressing ALS-linked Cu2+-Zn2+ superoxide dismutase (SOD1) mutations, but the underlying molecular mechanisms are still unclear. We developed and characterised a cell model consisting of polarised epithelial Madin-Darby Canine Kidney (MDCK) cell lines stably expressing wild-type SOD1 or the ALS-linked SOD1 G93A mutant, and analysed the expression of glutamate transporters after transient transfection of the corresponding cDNAs. Like ALS patients and animal models of ALS, the G93A-expressing MDCK cell system showed reduced total glial GLT-1 expression, with no change in the expression of the neuronal EAAC1 glutamate transporter isoform. Morphological analysis revealed the intracellular redistribution of GLT-1 to acidic compartments, whereas the surface distribution of other glutamate transporters (neuronal EAAC1 and glial GLAST) was not affected. Moreover, mutant SOD1 affected the cytosolic tail of GLT-1 because reduced protein expression of EAAC-GLT but not GLT-EAAC chimeras was found in G93A-expressing cell lines. GLT-1 downregulation was greatly induced by inhibition of protein synthesis, and prevented by treatment with chloroquine aimed at inhibiting the activity of acidic degradative compartments. Negligible effect on the protein level or distribution of GLT-1 was observed in cells overexpressing wild-type SOD1. The specific decrease in the GLT-1 isoform of glutamate transporters is therefore recapitulated in G93A-expressing MDCK cell lines, thus suggesting an autonomous cell mechanism underlying the loss of GLT-1 in ALS. Our data indicate that the continuous expression of mutant SOD1 causes the downregulation of GLT-1 by increasing the internalisation and degradation of the surface transporter, and suggest that the cytosolic tail of GLT-1 is required to target the transporter to degradation.}, }
@article {pmid15457847, year = {2004}, author = {Bonazzi, C and Urso, M and Dell'Anna, T and Sacco, S and Buda, A and Cantú, MG}, title = {Placental site trophoblastic tumor: an overview.}, journal = {The Journal of reproductive medicine}, volume = {49}, number = {8}, pages = {585-588}, pmid = {15457847}, issn = {0024-7758}, mesh = {Adult ; Age Factors ; Antineoplastic Combined Chemotherapy Protocols/administration &amp; dosage/*therapeutic use ; Cyclophosphamide/administration &amp; dosage ; Dactinomycin/administration &amp; dosage ; Etoposide/administration &amp; dosage ; Female ; Fertility ; Humans ; Methotrexate/administration &amp; dosage ; Neoplasm Metastasis ; *Neoplasm Recurrence, Local ; Placenta Diseases/*drug therapy/*pathology ; Pregnancy ; Retrospective Studies ; Treatment Outcome ; Trophoblastic Neoplasms/*drug therapy/*pathology ; Uterine Neoplasms/*drug therapy/*pathology ; Vincristine/administration &amp; dosage ; }, abstract = {OBJECTIVE: To analyze 15 consecutive cases of placental site trophoblastic tumor seen in a single reference institution for gestational trophoblastic disease, San Gerardo Hospital, Monza, Italy.<br><br>STUDY DESIGN: Consecutive patients affected by placental site trophoblastic tumors were selected from our computerized database.<br><br>RESULTS: There were 15 patients with placental site trophoblastic tumor, with a median age of 35 years. The antecedent pregnancy was a term one in 6 cases (40%), a miscarriage in 4 cases (27%), a termination in 2 cases (13%) and a molar abortion in 2 cases (13%). In 1 case the previous pregnancy was unrecognized. The median interval from the last pregnancy was 12 months, and the presenting symptom in 11 cases was vaginal bleeding, in 2 cases amenorrhea, in 1case a nephrotic syndrome and in 1 case, presenting with metastatic disease, hemoptysis. Six patients were treated using neoadjuvant chemotherapy with etoposide/methotrexate/actinomycin-etoposide/ vincristine (EMA-CO) followed in 5 of 6 (83%) cases by hysterectomy. One patient had only medical treatment with EMA-CO because of a strong desire for or childbearing and had a complete response; after 15 months she was free from disease. The last 9 patients underwent surgery as the first therapy. Among these patients 1 had presented with metastatic pulmonary disease and underwent chemotherapy, with complete disappearance of the pulmonary lesions. Two of these 9 patients had a relapse; the mirst patient had a pelvic and bladder relapse, and 14 months after multiple chemotherapy and surgery, she died. The second had a suburethral relapse 2 months after initial surgery; after chemotherapy and surgery she was well and free of disease.<br><br>CONCLUSION: Our experience suggests that the role of chemotherapy may be reconsidered not only for metastatic disease but als of or uterine disease when choosing conservative management in young, fertile patients who desire childbearing. Chemotherapy may play an important role in avoiding relapse or early metastases even in patients who underwent hysterectomy as primary treatment.}, }
@article {pmid15455310, year = {2004}, author = {Bernarducci, MP}, title = {Radiolabeled peptides: overcoming the challenges of post-surgical patient management of venous thromboembolism.}, journal = {Surgical technology international}, volume = {12}, number = {}, pages = {50-67}, pmid = {15455310}, issn = {1090-3941}, mesh = {Humans ; Oligopeptides ; *Organotechnetium Compounds ; *Peptides, Cyclic ; Platelet Glycoprotein GPIIb-IIIa Complex/antagonists &amp; inhibitors ; Postoperative Complications ; Radionuclide Imaging ; Risk Factors ; Sensitivity and Specificity ; Thrombolytic Therapy ; Thrombophlebitis/diagnostic imaging ; Ultrasonography, Doppler, Duplex ; Venous Thrombosis/diagnosis/*diagnostic imaging/physiopathology/surgery ; }, abstract = {The serious clinical and economic impact of venous thromboembolic (VTE) disease is undisputed. What concerns practitioners and researchers alike is the seeming inability to truly mitigate the ramification of VTE, especially in the post-surgical or postoperative subpopulation, in whom the risk of VTE is disproportionately high and often asymptomatic. Ironically, current approaches to the diagnostic evaluation of suspected VTE patients tend to favor the application of anatomic modalities, either invasive or technically challenging (eg, venography) or the performance of which is clinically inadequate (eg, ultrasonography) for post-surgical/postoperative patients. These modalities' primary principle of detection rely on the effects or results of an intricate pathophysiologic process, seemingly ignoring the critical role and potentially better prognostic value of endogenous hemostatic mechanisms. In other words, are we using the correct tools to seek the appropriate types of information in patients with suspected VTE? Research in nuclear medicine techniques for detecting VTE began approximately 25 years ago. Recently, the emergence of radiolabeled peptides as a clinically applicable technology platform has encouraged a different approach to evaluating VTE. Many radiolabeled peptide candidates are undergoing preclinical and clinical research. Currently,only one, 99'Tc-apcitide (AcuTect), has been approved (since 1998) for clinical use in the United States. The growing numbers of physicians with experience using 9mTc-apcitide (including those who remember using "'In-fibrinogen) has fueled ongoing clinical research to further elucidate the benefits of this unique peptide technology. Consequently, significant insight has been gained from large prospective clinical tri-als, of which one was conducted to support the approval of 99mTc-apcitide in Europe. Furthermore, this insight has kindled increasing interest in 99'Tc-apcitide and potential new entrants into this special " diagnostic class" (ie, radiolabeled peptides). Unlike the more popular anatomic modalities, radiolabeled pep-tides circumvent many of the clinical and anatomic challenges to objectively and accurately diagnose VTE. The importance of an objective and accurate diagnosis is understood, because it is paramount to a cost-effective treatment strategy. In addition to describing the current activities concerning the development and use of radiolabeled peptides for clinical practice, this manuscript is intended to promulgate a thought-provoking argument for changing our current approach to the diagnostic evaluation of VTE,which also may transcend the post-surgical/postoperative subpopulation.}, }
@article {pmid15454359, year = {2004}, author = {Bremer, BA and Simone, AL and Walsh, S and Simmons, Z and Felgoise, SH}, title = {Factors supporting quality of life over time for individuals with amyotrophic lateral sclerosis: the role of positive self-perception and religiosity.}, journal = {Annals of behavioral medicine : a publication of the Society of Behavioral Medicine}, volume = {28}, number = {2}, pages = {119-125}, doi = {10.1207/s15324796abm2802_7}, pmid = {15454359}, issn = {0883-6612}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*psychology ; Disease Progression ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Psychometrics ; *Quality of Life ; *Self Concept ; Social Support ; *Spirituality ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease with no known cure. Maintaining quality of life (QOL) as the disease progresses is an important treatment goal.<br><br>PURPOSE: the purpose of this study is to identify factors that support QOL as ALS progresses.<br><br>METHODS: Changes in QOL were monitored in 162 individuals with ALS at 3- to 4-month intervals. Forty-nine of the participants survived in the study for over 1 year and were included in a longitudinal comparison. The 49 long-term participants were younger and stronger at Time 1 than were the participants who died before reaching the 1-year point. The McGill Quality of Life Scale demonstrated a high and stable QOL despite physical deterioration.<br><br>RESULTS: Patients maintained a positive self-perception of their health despite the physical deterioration. Over time, self-perception of health and religiosity were shown to be significantly correlated with QOL.<br><br>CONCLUSIONS: Results support the need for better instrumentation to enable future studies to more precisely measure multiple dimensions of ALS-related QOL, to identify reference points for self-ratings of both health and QOL, and to capture the religious and spiritual mechanisms related to QOL as individuals face the end of life.}, }
@article {pmid15448912, year = {2005}, author = {Hagenah, J and Kahl, KG and Steinlechner, S and Lencer, R and Klein, C}, title = {[Treatment of sialorrhea with botulinum toxin: an overview].}, journal = {Der Nervenarzt}, volume = {76}, number = {4}, pages = {418-425}, pmid = {15448912}, issn = {1433-0407}, mesh = {Botulinum Toxins/*therapeutic use ; Humans ; *Randomized Controlled Trials as Topic ; Sialorrhea/*drug therapy ; Treatment Outcome ; }, abstract = {Hypersalivation (sialorrhea) is a common complaint of patients with neurodegenerative disorders such as Parkinson's disease or amyotrophic lateral sclerosis and a frequently disabling side effect of atypical antipsychotic drugs. Conventional treatment including oral anticholinergic or antihistamine medication is often limited by adverse effects and lack of efficacy. Over the past few years, several studies reported decreased drooling after injections of botulinum toxin into the salivary glands. This review describes the current state of treatment of sialorrhea with botulinum toxin.}, }
@article {pmid15389897, year = {2004}, author = {Zheng, C and Nennesmo, I and Fadeel, B and Henter, JI}, title = {Vascular endothelial growth factor prolongs survival in a transgenic mouse model of ALS.}, journal = {Annals of neurology}, volume = {56}, number = {4}, pages = {564-567}, doi = {10.1002/ana.20223}, pmid = {15389897}, issn = {0364-5134}, mesh = {Age Factors ; Alanine/genetics ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Disease Models, Animal ; Glycine/genetics ; Humans ; Mice ; Mice, Transgenic/*physiology ; Motor Activity/drug effects ; Mutation/genetics ; Probability ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Survival Analysis ; Vascular Endothelial Growth Factor A/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with the death of motor neurons in the spinal cord and brainstem. The cause of ALS is unknown and there is no cure. This study demonstrates, for the first time, that vascular endothelial growth factor (VEGF) delays progression of symptoms and prolongs survival in a Cu/Zn superoxide dismutase (SOD1) transgenic mouse model of ALS. These observations suggest that VEGF or related compounds, might be of value in the treatment of ALS patients.}, }
@article {pmid15384941, year = {2004}, author = {Azzouz, M and Mazarakis, N}, title = {Non-primate EIAV-based lentiviral vectors as gene delivery system for motor neuron diseases.}, journal = {Current gene therapy}, volume = {4}, number = {3}, pages = {277-286}, doi = {10.2174/1566523043346291}, pmid = {15384941}, issn = {1566-5232}, mesh = {Genetic Therapy/*methods ; *Genetic Vectors ; Humans ; Infectious Anemia Virus, Equine/*genetics ; Motor Neuron Disease/genetics/*therapy ; *Motor Neurons ; }, abstract = {Motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are neurodegenerative diseases, which cause progressive paralysis and premature death in affected adults and children. The treatment rational for these diseases is to halt or delay the degeneration of motor neurons but to date there are no effective drugs. This may however change with recent advances in gene therapy using lentiviral vectors. These vectors can transfer genes to motor neurons with high efficiency and give long term expression. One of these vector systems, based on the equine infectious anaemia virus (EIAV), can insert genes into the cells of the central nervous system after remote delivery including delivery into the muscle by exploiting retrograde transport pathways. This opens up the exciting possibility of rescuing the denervation of key muscle groups in patients by simple injections of these neurotropic lentiviral vectors into the muscle. This review will describe the general features of lentiviral vectors derived from the EIAV. It will then describe some key examples of gene transfer and genetic correction in animal models of motor neuron disease. The prospects for the clinical evaluation of lentiviral vectors for the treatment of human motor neuron disease will be outlined.}, }
@article {pmid15383947, year = {2004}, author = {Leder, SB and Novella, S and Patwa, H}, title = {Use of fiberoptic endoscopic evaluation of swallowing (FEES) in patients with amyotrophic lateral sclerosis.}, journal = {Dysphagia}, volume = {19}, number = {3}, pages = {177-181}, pmid = {15383947}, issn = {0179-051X}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*complications ; Deglutition Disorders/*diagnosis/etiology/therapy ; *Endoscopy, Digestive System ; Female ; *Fiber Optic Technology ; Humans ; Male ; Middle Aged ; Pharynx/physiopathology ; }, abstract = {This study investigated the use of fiberoptic endoscopic evaluation of swallowing (FEES) to both diagnose pharyngeal dysphagia and make treatment recommendations in 17 consecutive patients with a new diagnosis of amyotrophic lateral sclerosis (ALS) and complaints of dysphagia. Ten of 17 (59%) patients exhibited pharyngeal dysphagia with aspiration or aspiration risk with clear liquids, i.e., 5 of 8 (63%) limb and 5 of 9 (56%) bulbar. If depth of bolus flow was a problem, thickened liquids and single, small bolus sizes were recommended. If bolus retention was a problem, a small clear liquid bolus after each puree or solid bolus was recommended to aid pharyngeal clearing. Five of 17 (30%) patients required multiple FEES evaluations because of disease progression. For the first time in patients with ALS, FEES was shown to be successful in assessing preswallow anatomy and physiology, diagnosing pharyngeal dysphagia, and providing objective data for appropriate therapeutic interventions to promote safer oral intake. Visual biofeedback provided by FEES was successful for both patient and family education and to investigate individualized therapeutic strategies that, if successful, can be implemented immediately. Serial FEES allows for objective monitoring of dysphagia symptoms and timely implementation of diet changes and/or therapeutic strategies to continue safer oral intake and maintain optimum quality of life.}, }
@article {pmid15379894, year = {2004}, author = {West, M and Mhatre, M and Ceballos, A and Floyd, RA and Grammas, P and Gabbita, SP and Hamdheydari, L and Mai, T and Mou, S and Pye, QN and Stewart, C and West, S and Williamson, KS and Zemlan, F and Hensley, K}, title = {The arachidonic acid 5-lipoxygenase inhibitor nordihydroguaiaretic acid inhibits tumor necrosis factor alpha activation of microglia and extends survival of G93A-SOD1 transgenic mice.}, journal = {Journal of neurochemistry}, volume = {91}, number = {1}, pages = {133-143}, doi = {10.1111/j.1471-4159.2004.02700.x}, pmid = {15379894}, issn = {0022-3042}, support = {AG20783/AG/NIA NIH HHS/United States ; NS44154/NS/NINDS NIH HHS/United States ; }, mesh = {Administration, Oral ; Age Factors ; Animals ; Behavior, Animal/drug effects/physiology ; Blotting, Northern/methods ; Blotting, Western/methods ; Body Mass Index ; Cell Line ; Curcumin/pharmacology ; Dose-Response Relationship, Drug ; Drug Interactions ; Enzyme Inhibitors/pharmacology ; Enzyme-Linked Immunosorbent Assay/methods ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Immunohistochemistry/methods ; Inhibitory Concentration 50 ; *Lipoxygenase Inhibitors/*pharmacology/therapeutic use ; Masoprocol/*pharmacology/therapeutic use ; Mice ; Mice, Transgenic/physiology ; Microglia/*drug effects/physiology ; Models, Neurological ; Motor Activity/drug effects ; Nitric Oxide/metabolism ; Paralysis/*drug therapy/genetics ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Rotarod Performance Test/methods ; Spinal Cord/cytology/drug effects/metabolism ; Statistics, Nonparametric ; Superoxide Dismutase/genetics/physiology ; Survival/physiology ; Tumor Necrosis Factor-alpha/*antagonists &amp; inhibitors/pharmacology ; tau Proteins/metabolism ; }, abstract = {Familial forms of amyotrophic lateral sclerosis (ALS) can be caused by mutations in copper, zinc-superoxide dismutase (SOD1). Mice expressing SOD1 mutants demonstrate a robust neuroinflammatory reaction characterized, in part, by up-regulation of tumor necrosis factor alpha (TNFalpha) and its primary receptor TNF-RI. In an effort to identify small molecule inhibitors of neuroinflammation useful in treatment of ALS, a microglial culture system was established to identify TNFalpha antagonists. Walker EOC-20 microglia cells were stimulated with recombinant TNFalpha, with or without inhibitors, and the cell response was indexed by NO2- output. Three hundred and fifty-five rationally selected compounds were included in this bioassay. The arachidonic acid 5-lipoxygenase (5LOX) and tyrosine kinase inhibitor nordihydroguaiaretic acid (NDGA), a natural dicatechol, was one of the most potent non-cytotoxic antagonists tested (IC50 8 +/- 3 microm). Investigation of the G93A-SOD1 mouse model for ALS revealed increased message and protein levels of 5LOX at 120 days of age. Oral NDGA (2500 p.p.m.) significantly extended lifespan and slowed motor dysfunction in this mouse, when administration was begun relatively late in life (90 days). NDGA extended median total lifespan of G93A-SOD1 mice by 10%, and life expectancy following start of treatment was extended by 32%. Disease-associated gliosis and cleaved microtubule-associated tau protein, an indicator of axon damage, were likewise reduced by NDGA. Thus, TNFalpha antagonists and especially 5LOX inhibitors might offer new opportunities for treatment of ALS.}, }
@article {pmid15378612, year = {2004}, author = {Turner, BJ and Murray, SS and Piccenna, LG and Lopes, EC and Kilpatrick, TJ and Cheema, SS}, title = {Effect of p75 neurotrophin receptor antagonist on disease progression in transgenic amyotrophic lateral sclerosis mice.}, journal = {Journal of neuroscience research}, volume = {78}, number = {2}, pages = {193-199}, doi = {10.1002/jnr.20256}, pmid = {15378612}, issn = {0360-4012}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Blood-Brain Barrier/drug effects ; Carbazoles/pharmacology ; Cell Line ; Cell Survival/drug effects/physiology ; Disease Progression ; Indole Alkaloids ; Mice ; Mice, Transgenic ; Molecular Sequence Data ; Nerve Growth Factors/antagonists &amp; inhibitors/physiology ; Neuropeptides/pharmacology ; Oligopeptides/pharmacology ; Receptor Protein-Tyrosine Kinases/antagonists &amp; inhibitors/physiology ; Receptor, Nerve Growth Factor ; Receptors, Nerve Growth Factor/*antagonists &amp; inhibitors/*physiology ; }, abstract = {Neurotrophin level imbalances and altered p75 neurotrophin receptor (p75(NTR)) expression are implicated in spinal motor neuron degeneration in human and mouse models of amyotrophic lateral sclerosis (ALS). Recently, elevated reactive astrocyte-derived nerve growth factor (NGF) was linked to p75(NTR)-expressing motor neuron death in adult transgenic ALS mice. To test the role of NGF-dependent p75(NTR)-mediated signalling in ALS, we examined the effects of a cyclic decapeptide antagonist of p75(NTR) ligand binding by using neurotrophin-stimulated cell death assays and transgenic ALS mice. Murine motor neuron-like (NSC-34) cell cultures expressed full-length and truncated p75(NTR), tyrosine receptor kinase B (TrkB), and the novel neurotrophin receptor homolog-2 (NHR2) but were TrkA deficient. Accordingly, treatment of cells with NGF induced dose-dependent cell death, which was significantly blocked by the cyclic decapeptide p75(NTR) antagonist. Application of brain-derived neurotrophic factor, neurotrophin-3, or neurotrophin-4 to cultures increased cell proliferation, and such trophic effects were abolished by pretreatment with the tyrosine kinase inhibitor K-252a. Systemic administration of a modified cyclic decapeptide p75(NTR) antagonist conjugated to the TAT4 cell permeabilization sequence to presymptomatic transgenic SOD1(G93A) mice affected neither disease onset nor disease progression, as determined by hindlimb locomotor, grip strength, and survival analyses. These studies suggest that disrupting NGF-p75(NTR) interactions by using this approach is insufficient to alter the disease course in transgenic ALS mice. Thus, alternate ligand-independent pathways of p75(NTR) activation or additional NGF receptor targets may contribute to motor neuron degeneration in ALS mice.}, }
@article {pmid15378511, year = {2004}, author = {Albo, F and Pieri, M and Zona, C}, title = {Modulation of AMPA receptors in spinal motor neurons by the neuroprotective agent riluzole.}, journal = {Journal of neuroscience research}, volume = {78}, number = {2}, pages = {200-207}, doi = {10.1002/jnr.20244}, pmid = {15378511}, issn = {0360-4012}, mesh = {Animals ; Cells, Cultured ; Electrophysiology ; Excitatory Amino Acid Agonists/pharmacology ; Kainic Acid/antagonists &amp; inhibitors/pharmacology ; Mice ; Motor Neurons/*drug effects/physiology ; Receptors, AMPA/*drug effects ; Riluzole/*pharmacology ; Spinal Cord/cytology ; }, abstract = {We investigated the interaction of riluzole, a therapeutic agent used in amyotrophic lateral sclerosis (ALS), with alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor channels in mouse spinal motor neurons in culture using whole-cell patch-clamp recording techniques. Kainate elicited concentration-dependent (EC(50) = 35 microM) inward currents in all the patched cells. These responses were mediated primarily through the activation of AMPA receptors with a negligible contribution from kainate receptors, because bath application of 100 microM GYKI53655, a potent noncompetitive AMPA receptor antagonist, completely blocked the kainate-induced currents. Riluzole (0.5-100 microM) reduced in a dose-dependent manner the kainate-induced currents with an IC(50) of 1.54 microM in all tested neurons (n = 25) and this effect was found to be reversible. The response to kainate decreased in the presence of 1 microM riluzole in all spinal motor neurons tested, without changing its EC(50), indicating a noncompetitive mechanism of inhibition. The amplitude of the responses induced by kainate under control condition and during riluzole was a linear function of the membrane potential. The reversal potential of the current was not significantly different in the two experimental conditions, whereas the total conductance of the motor neurons for the currents induced by 100 microM kainate was reduced significantly in the presence of 1 microM riluzole (P < 0.05). These results reveal an interaction of riluzole with glutamatergic neurotransmission in spinal cord motor neurons and can contribute to explain its beneficial effect in the ALS treatment.}, }
@article {pmid15372249, year = {2004}, author = {Waibel, S and Reuter, A and Malessa, S and Blaugrund, E and Ludolph, AC}, title = {Rasagiline alone and in combination with riluzole prolongs survival in an ALS mouse model.}, journal = {Journal of neurology}, volume = {251}, number = {9}, pages = {1080-1084}, pmid = {15372249}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/genetics ; Animals ; *Disease Models, Animal ; Drug Therapy, Combination ; Humans ; Indans/*therapeutic use ; Mice ; Mice, Transgenic ; Riluzole/*therapeutic use ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Survival Rate ; }, abstract = {Rasagiline is an antiapoptotic compound with neuroprotective potential. We examined its neuroprotective effect alone and in combination with the putative glutamate release blocker riluzole in the G93A model of familial amyotrophic lateral sclerosis (fALS). Endpoints of experimental treatment were survival and motor activity. The drug had a significant dose-dependent therapeutic effect on both preclinical and clinical motor function and survival of the animals. We also found that the combination of rasagiline with riluzole is safe and increases survival by about 20 % in a dose-dependent manner. Therefore, we conclude that the combination of rasagiline and riluzole is a promising clinical combination for the improvement of current neuroprotective treatment strategies of ALS.}, }
@article {pmid15337584, year = {2004}, author = {Koh, SH and Kwon, H and Kim, KS and Kim, J and Kim, MH and Yu, HJ and Kim, M and Lee, KW and Do, BR and Jung, HK and Yang, KW and Appel, SH and Kim, SH}, title = {Epigallocatechin gallate prevents oxidative-stress-induced death of mutant Cu/Zn-superoxide dismutase (G93A) motoneuron cells by alteration of cell survival and death signals.}, journal = {Toxicology}, volume = {202}, number = {3}, pages = {213-225}, doi = {10.1016/j.tox.2004.05.008}, pmid = {15337584}, issn = {0300-483X}, mesh = {Apoptosis/*drug effects ; Blotting, Western ; Catechin/*analogs &amp; derivatives/*pharmacology ; Cell Line ; Cell Survival/*drug effects ; Dose-Response Relationship, Drug ; Drug Combinations ; Glycogen Synthase Kinase 3/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Motor Neurons/*drug effects/enzymology/pathology ; Mutation ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/*drug effects/physiology ; Phosphatidylinositol 3-Kinases/metabolism ; Superoxide Dismutase/genetics/*metabolism ; }, abstract = {This study was undertaken to evaluate the effect of the G93A mutation in the human Cu/Zn-superoxide dismutase gene (hSOD1) on the phosphatidylinositol-3-kinase (PI3K)/Akt and glycogen synthase kinase-3 (GSK-3) pathway in motoneuron, and to determine the role of epigallocatechin gallate (EGCG) on oxidative stress-injured motoneurons. The viability of G93A mutant cells was less than that of wild-type cells, and the activation of PI3K and the phosphorylation of Akt and GSK-3 in G93A mutant cells decreased compared with wild-type hSOD1 4.1 cells. In the experiment to evaluate the effect of oxidative stress and/or EGCG on these motoneurons, after exposure to 400 microM H2O2, the MTT assay revealed greatly reduced viability of G93A mutant cells compared with wild-type cells, and pre-treatment of these cells with EGCG before H2O2 exposure increased the viability of both cell lines. Western blot analysis showed that the G93A mutation and oxidative stress decreased survival signals including PI3K/Akt but increased death signals including GSK-3; however, pre-treatment with EGCG increased survival signals but decreased death signals. These results suggest that PI3K/Akt and GSK-3 activities are altered in G93A mutant cells and EGCG-induced activation of PI3K/Akt and inhibition of GSK-3 could be a new potential therapeutic strategy for ALS associated with oxidative injury.}, }
@article {pmid15331543, year = {2004}, author = {Shi, Q and Wang, D and Hadley, GA and Bingaman, AW and Bartlett, ST and Farber, DL}, title = {Long-term islet graft survival in NOD mice by abrogation of recurrent autoimmunity.}, journal = {Diabetes}, volume = {53}, number = {9}, pages = {2338-2345}, doi = {10.2337/diabetes.53.9.2338}, pmid = {15331543}, issn = {0012-1797}, support = {AI036532/AI/NIAID NIH HHS/United States ; AI50632/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; Autoimmunity/*immunology ; CD4-Positive T-Lymphocytes/immunology/metabolism ; Diabetes Mellitus, Type 1/*immunology/*surgery ; Graft Survival/*immunology ; Immune Tolerance/immunology ; Interferon-gamma/metabolism ; Interleukin-4/metabolism ; *Islets of Langerhans Transplantation ; Mice ; Mice, Inbred NOD ; Transplantation Chimera/immunology ; }, abstract = {Islet transplantation has great potential for curing type 1 diabetes; however, long-term islet survival using conventional immunosuppression remains elusive. We present a novel strategy for inducing long-lasting islet graft survival in diabetic NOD mice in the absence of posttransplant immunosuppression by initial treatment with antilymphocyte serum (ALS) followed by coadministration of donor pancreatic lymph node cells (PLNCs). When treated with ALS/PLNC, diabetic NOD mice become normoglycemic and tolerated minor antigen-disparate islet grafts for >100 days and syngeneic islet grafts indefinitely. Donor T-cells are required for graft prolongation, and tolerant hosts have long-term donor T-cell chimerism. Strikingly, host autoreactive T-cells from mice with long-surviving islet grafts predominantly produce interleukin-4, whereas autoreactive T-cells from mice that rejected their islet grafts predominantly produce interferon-gamma. We thus demonstrate a clinically relevant approach for ablation of recurrent autoimmunity in islet transplantation, involving donor lymphocyte-driven alteration of pathogenic autoreactive T-cells.}, }
@article {pmid15328040, year = {2004}, author = {Groeneveld, GJ and Van Muiswinkel, FL and Sturkenboom, JM and Wokke, JH and Bär, PR and Van den Berg, LH}, title = {Ovariectomy and 17beta-estradiol modulate disease progression of a mouse model of ALS.}, journal = {Brain research}, volume = {1021}, number = {1}, pages = {128-131}, doi = {10.1016/j.brainres.2004.06.024}, pmid = {15328040}, issn = {0006-8993}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology/*physiopathology ; Animals ; Disease Models, Animal ; Disease Progression ; Estradiol/*pharmacology ; Female ; Humans ; Mice ; Mice, Transgenic ; Neuroprotective Agents/*pharmacology ; *Ovariectomy ; Phenotype ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {The incidence of amyotrophic lateral sclerosis (ALS) is higher among men than women but rises in women after the menopause. Estrogens may play a protective role. Treatment with estrogens has been shown to be neuroprotective in models of several neurodegenerative diseases. We therefore determined the effect of ovariectomy on female G93A mSOD1 transgenic mice, and the effect of subsequent treatment with 17beta-estradiol (E2). Ovariectomy led to a significant acceleration of disease progression of the mice, and high-dose E2 treatment significantly delayed disease progression of ovariectomized G93A mSOD1 transgenic mice. We conclude that treatment with E2 may also delay disease progression of post-menopausal women with ALS.}, }
@article {pmid15319099, year = {2004}, author = {Volpi, A}, title = {Epstein-Barr virus and human herpesvirus type 8 infections of the central nervous system.}, journal = {Herpes : the journal of the IHMF}, volume = {11 Suppl 2}, number = {}, pages = {120A-127A}, pmid = {15319099}, issn = {0969-7667}, mesh = {Antiviral Agents/therapeutic use ; Central Nervous System Viral Diseases/cerebrospinal fluid/*diagnosis/drug therapy/pathology ; Epstein-Barr Virus Infections/cerebrospinal fluid/*diagnosis/drug therapy/pathology ; Herpesviridae Infections/cerebrospinal fluid/*diagnosis/drug therapy/pathology ; Herpesvirus 4, Human/*isolation &amp; purification ; Herpesvirus 8, Human/*isolation &amp; purification ; Humans ; Practice Guidelines as Topic ; }, abstract = {In developing guidelines for the improved management of herpesvirus infections of the central nervous system (CNS), the International Herpes Management Forum (IHMF) has studied Epstein-Barr virus (EBV) and human herpesvirus type 8 (HHV-8)- related diseases. EBV has been associated with numerous CNS diseases including meningitis, encephalitis and post transplant lymphoproliferative disorder (PTLD). The pathogenesis of EBV-associated CNS disorders is not completely understood but may be due to direct virus invasion of the CNS. Alternatively, damage may be immunologically mediated by infiltration of cytotoxic CD8+ lymphocytes into neural tissue or deposition of antibody-antigen complexes. The IHMF recommends that diagnosis of EBV infections of the CNS may involve polymerase chain reaction (PCR) of cerebrospinal fluid (CSF) for EBV DNA but the sensitivity and specificity of the technique remains to be determined. Furthermore, the value of PCR in this context may be limited as EBV DNA is often detected in patients without neurological symptoms. Antiviral therapy has not demonstrated clinical efficacy in the treatment of EBV-related CNS disorders. CNS complications of HHV-8 infection are rare, but the virus has been associated with AIDS-dementia complex, amyotrophic lateral sclerosis (ALS) and primary CNS lymphoma; however these links remain to be proven.}, }
@article {pmid15316983, year = {2004}, author = {Shefner, JM and Cudkowicz, ME and Zhang, H and Schoenfeld, D and Jillapalli, D and , }, title = {The use of statistical MUNE in a multicenter clinical trial.}, journal = {Muscle &amp; nerve}, volume = {30}, number = {4}, pages = {463-469}, doi = {10.1002/mus.20120}, pmid = {15316983}, issn = {0148-639X}, mesh = {Action Potentials/physiology ; Amyotrophic Lateral Sclerosis/*drug therapy/*pathology ; Cell Count ; Creatine/therapeutic use ; Data Interpretation, Statistical ; Disease Progression ; Electrodiagnosis ; Electrophysiology ; Humans ; Motor Neurons/*pathology ; Muscle, Skeletal/*pathology ; Observer Variation ; Quality Control ; Reproducibility of Results ; *Research Design ; Treatment Outcome ; }, abstract = {Techniques to estimate motor unit number (MUNE) measure the number of functioning motor units in a muscle. In diseases characterized by progressive motor unit loss, such as amyotrophic lateral sclerosis (ALS), MUNE may be useful to monitor disease progression or beneficial response to treatment. As part of a multicenter, placebo-controlled, randomized, double-blind clinical trial testing the efficacy of creatine in patients with ALS, statistical MUNE was measured in 104 patients tested monthly for 6 months. The objective was to determine whether MUNE was a reliable and sensitive outcome measure in the context of a multicenter trial. Formal training and reliability testing was required for all MUNE evaluators. Testing of normal controls showed a high degree of test-retest reliability. All patient data were combined as the experimental treatment showed no efficacy. There was a 23% decline in MUNE over 6 months. The technique as employed in this trial overemphasized the presence of small motor units; this problem was partially addressed by poststudy data monitoring and censuring. Thus, MUNE can be used reliably as an outcome measure in multicenter clinical trials; specific remedies are suggested for the difficulties encountered in this study.}, }
@article {pmid15313203, year = {2004}, author = {Wootz, H and Hansson, I and Korhonen, L and Näpänkangas, U and Lindholm, D}, title = {Caspase-12 cleavage and increased oxidative stress during motoneuron degeneration in transgenic mouse model of ALS.}, journal = {Biochemical and biophysical research communications}, volume = {322}, number = {1}, pages = {281-286}, doi = {10.1016/j.bbrc.2004.07.118}, pmid = {15313203}, issn = {0006-291X}, mesh = {Adaptation, Physiological/*physiology ; Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Apoptosis ; Caspase 12 ; Caspases/*metabolism ; Cells, Cultured ; Disease Models, Animal ; Disease Progression ; Mice ; Mice, Transgenic ; Motor Neuron Disease/metabolism/pathology ; Motor Neurons/*enzymology/pathology ; *Oxidative Stress ; Spinal Cord/*metabolism/pathology ; Superoxide Dismutase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of motoneurons in the spinal cord and brain stem. We have characterized motoneuron death in transgenic mice carrying the mutant human copper/zinc superoxide dismutase, as a model for familial ALS. Previous studies have shown the involvement of mitochondria in nerve cell demise in these animals. We report here an early cleavage of caspase-12, residing in the endoplasmic reticulum (ER), in the spinal cord during the course of the disease. Apart from caspase-12, caspase-9, and caspase-3 were activated in the transgenic ALS mice. Staining with an antibody for nitrotyrosine, as a marker for oxidative stress, showed a large increase in the ALS mice. The results indicate that oxidative and ER induced stress causing caspase-12 activation are involved in neuronal death and disease progression in ALS. Caspase-12 and the ER pathway for cell death may constitute potential novel targets for the treatment of ALS.}, }
@article {pmid15312178, year = {2004}, author = {Ferri, A and Nencini, M and Battistini, S and Giannini, F and Siciliano, G and Casali, C and Damiano, MG and Ceroni, M and Chiò, A and Rotilio, G and Carrì, MT}, title = {Activity of protein phosphatase calcineurin is decreased in sporadic and familial amyotrophic lateral sclerosispatients.}, journal = {Journal of neurochemistry}, volume = {90}, number = {5}, pages = {1237-1242}, doi = {10.1111/j.1471-4159.2004.02588.x}, pmid = {15312178}, issn = {0022-3042}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/drug therapy/genetics/*metabolism ; Blotting, Western/methods ; Calcineurin/*metabolism ; Case-Control Studies ; Female ; Humans ; Lymphocytes/drug effects/*metabolism ; Male ; Middle Aged ; Neuroprotective Agents/therapeutic use ; Nuclear Pore Complex Proteins/metabolism ; Riluzole/therapeutic use ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Calcineurin (CaN) is a Ser/Thr protein phosphatase involved in a wide range of cellular responses to calcium mobilizing signals. Previous evidence supports the notion that calcineurin is oxidatively inhibited by mutant Cu, Zn superoxide dismutase (SOD1) typical of familial ALS patients in vitro and in transgenic mice. We report that calcineurin activity is markedly inhibited in lymphocytes from 37 sporadic, eight familial ALS patients and an asymptomatic subject carrying an SOD1 mutation as compared to 28 healthy controls. Two other healthy subjects, heterozygous for the D90A mutation from a recessive pedigree, have normal calcineurin activity. Immunoreactive CaN protein, age, sex and riluzole treatment are not related to calcineurin activity in samples from patients. However, we have observed a marked increase in total protein oxidation in extracts from ALS lymphocytes, as compared to extracts from control subjects. These data confirm that modification of calcineurin activity and possibly of calcineurin-mediated pathways of signal transduction (including modulation of apoptotic neuronal death) may contribute to the pathogenesis of ALS.}, }
@article {pmid15307952, year = {2004}, author = {Miagkov, A and Turchan, J and Nath, A and Drachman, DB}, title = {Gene transfer of baculoviral p35 by adenoviral vector protects human cerebral neurons from apoptosis.}, journal = {DNA and cell biology}, volume = {23}, number = {8}, pages = {496-501}, doi = {10.1089/1044549041562311}, pmid = {15307952}, issn = {1044-5498}, support = {P01 MH056287/MH/NIMH NIH HHS/United States ; R01 NS039253/NS/NINDS NIH HHS/United States ; R01 NS040778/NS/NINDS NIH HHS/United States ; T32 NS07368/NS/NINDS NIH HHS/United States ; }, mesh = {Aborted Fetus ; Adenoviridae ; Analysis of Variance ; Apoptosis/*drug effects/physiology ; Cells, Cultured ; DNA Primers ; Dactinomycin ; Gene Products, tat ; Gene Transfer Techniques ; *Genetic Therapy ; Genetic Vectors ; *HIV ; *HIV Envelope Protein gp120 ; Humans ; Inhibitor of Apoptosis Proteins ; Nervous System Diseases/genetics/*therapy ; Neurons/*drug effects/physiology ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Necrosis Factor-alpha ; Viral Proteins/*pharmacology ; tat Gene Products, Human Immunodeficiency Virus ; }, abstract = {Apoptosis plays an important role in neuronal cell death in both chronic and acute human neurological diseases, including ALS, Huntington's disease, cerebral ischemia, and HIV encephalopathy. We evaluated the ability of an extremely powerful antiapoptotic agent, baculoviral p35, to prevent apoptosis and cell death of human cerebral neurons that undergo severe neurotoxic changes in a culture system when treated with agents that are implicated in human neurological disorders, that is, tumor necrosis factor (TNFalpha) and the HIV proteins Tat and gp120. P35 is a potent broad-spectrum antiapoptotic protein derived from baculovirus, that inhibits nearly all caspases, and has other antiapoptotic actions as well. Adenoviral vectors expressing p35 (Ad. p35) or a control gene (lacZ) efficiently transduced human neurons. Treatment of control cultures with the toxic agents TNFalpha, TNFalpha plus Actinomycin D, or Tat and gp120, induced neurotoxicity and death of neurons. Transduction of neurons with Ad. p35 blocked apoptosis, and eliminated cell death due to TNFalpha, or Tat and gp120. Viral vector transfer of the p35 gene efficiently protects human neurons from TNFalpha, or Tat and gp120-induced apoptosis and cell death. These results suggest that p35 transduction of neurons by viral vectors could be therapeutically useful in the treatment of human neurodegenerative diseases.}, }
@article {pmid15306257, year = {2004}, author = {Ishiyama, T and Okada, R and Nishibe, H and Mitsumoto, H and Nakayama, C}, title = {Riluzole slows the progression of neuromuscular dysfunction in the wobbler mouse motor neuron disease.}, journal = {Brain research}, volume = {1019}, number = {1-2}, pages = {226-236}, doi = {10.1016/j.brainres.2004.06.002}, pmid = {15306257}, issn = {0006-8993}, mesh = {Animals ; Disease Progression ; Female ; Mice ; Mice, Neurologic Mutants ; Motor Neuron Disease/*drug therapy/pathology/physiopathology ; Neuromuscular Diseases/*drug therapy/pathology/physiopathology ; Riluzole/*therapeutic use ; }, abstract = {In the wobbler mouse motor neuron disease (MND), we firstly evaluated the effect of riluzole, the only approved drug for amyotrophic lateral sclerosis, and compared it with that of brain-derived neurotrophic factor (BDNF). Wobbler mice received either daily subcutaneous treatment with BDNF (5, 20, and 40 mg/kg) or oral riluzole in drinking water (100 and 200 microg/ml), beginning immediately after the clinical onset of MND. We examined motor functions, such as grip strength and rota-rod walking performance, weekly, and the amplitude of the compound muscle action potential (CMAP) in the forelimb biceps at the end of treatment. BDNF treatment slowed the disease progression maximally at a dose of 20 mg/kg, consistent to the previous evidence. Only high-dose riluzole treatment increased grip strength at weeks 1 (P=0.0023) and 2 (P=0.021), time before falling in the rota-rod test throughout all 4 weeks of treatment (P=0.0022 to 0.0282), and CMAP amplitude (P=0.0069) at the end of treatment, compared with the vehicle. Furthermore, the riluzole treatment increased the number of the cervical cord anterior horn neurons that were immunoreactive for SMI-32, a specific motor neuron marker, by the end of treatment (P=0.0063), although it did not affect the vacuolar degeneration on the SMI-32-positive neurons. This study demonstrated that riluzole was comparable to BDNF in slowing the progression of neuromuscular dysfunction in the wobbler mouse MND, which may provide a useful model for examining the mechanisms of selective motor neuron degeneration.}, }
@article {pmid15288509, year = {2004}, author = {Taylor, DM and Minotti, S and Agar, JN and Durham, HD}, title = {Overexpression of metallothionein protects cultured motor neurons against oxidative stress, but not mutant Cu/Zn-superoxide dismutase toxicity.}, journal = {Neurotoxicology}, volume = {25}, number = {5}, pages = {779-792}, doi = {10.1016/j.neuro.2004.02.002}, pmid = {15288509}, issn = {0161-813X}, mesh = {Amyotrophic Lateral Sclerosis/chemically induced/physiopathology ; Animals ; Blotting, Western ; Cell Survival/drug effects ; Cells, Cultured ; Chlorides/toxicity ; Genetic Vectors/genetics ; Herbicides/toxicity ; Immunohistochemistry ; Inclusion Bodies/metabolism ; Isoenzymes/biosynthesis/genetics ; Isomerism ; Metallothionein/*biosynthesis ; Mice ; Motor Neurons/*pathology ; Mutation/*physiology ; Oxidative Stress/*genetics/*physiology ; Paraquat/toxicity ; Plasmids/genetics ; Superoxide Dismutase/biosynthesis/*genetics ; Zinc Compounds/toxicity ; }, abstract = {Mutations in Cu/Zn-superoxide dismutase 1 (SOD1) are responsible for a familial form of amyotrophic lateral sclerosis (FALS). It has been proposed that oxidative stress and abnormal metal homeostasis contribute to death of motor neurons in this disease. Also, inability of motor neurons to upregulate protective proteins under stress may contribute to their preferential vulnerability to toxicity. Metallothioneins (MT) are low molecular weight, metal-binding proteins with established antioxidant capabilities. This study investigated the ability of motor neurons to upregulate MT isoforms in response to expression of mutant SOD1(G93A) or exposure to other neurotoxicants, and the ability of MT-I gene transfer to protect motor neurons from these stresses. MT isoform-I and -II were expressed constitutively in astrocytes and other non-neuronal cells of dissociated spinal cord cultures, but not in motor neurons. MT-I/II was upregulated in astrocytes, but not motor neurons, following treatment with ZnCl(2) or excitotoxic concentrations of glutamate. MT-III expression was restricted to neurons and was unaffected by treatment with ZnCl(2), paraquat, or glutamate. Overexpression of MT-I in motor neurons by gene transfer reduced the toxicity of ZnCl(2) and paraquat, but failed to protect them against glutamate or SOD1(G93A). These data are evidence against metal-catalyzed, oxidative stress being the primary mechanisms of toxicity conferred by disease-causing mutations in SOD1.}, }
@article {pmid15287506, year = {2004}, author = {Hattori, N}, title = {[Etiology and pathogenesis of Parkinson's disease: from mitochondrial dysfunctions to familial Parkinson's disease].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {44}, number = {4-5}, pages = {241-262}, pmid = {15287506}, issn = {0009-918X}, mesh = {Chromosomes, Human, Pair 6 ; Electron Transport Complex I/genetics ; Family ; Female ; Humans ; Male ; Mitochondrial Diseases/genetics ; Mutation ; Parkinson Disease/*genetics ; Superoxide Dismutase/genetics ; Ubiquitin-Protein Ligases/genetics ; }, abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. It is urgently needed to elucidate the cause of the disease and to establish neuroprotective treatment. We have been working on the etiology and pathogenesis of PD for many years and we found selective loss of mitochondrial complex I and the alpha-ketoglutarate dehydrogenase complex in the nigral neurons of patients with PD. Our observation firmly established mitochondrial defects in PD. Mitochondrial respiratory failure induces oxidative damage in neurons, and we found increase in hydroxynonenal and 8-oxo-deoxyguanine, indices of oxidative damage, in the nigral neurons of PD. These abnormalities can trigger apoptotic cell death. The primary events which induce mitochondrial failure and oxidative damage are not known, however, it has been postulated that the interaction of genetic risk factors and environmental factors would initiate the degenerative process. Based on this assumption, we conducted genetic association studies by the candidate gene methods. We found that polymorphic mutations of superoxide dismutase-2 and 24-kDa subunit of mitochondrial complex I were associated increased risk of developing Parkinson's disease. While we were doing this genetic association study, we found a family, in which parkinsonian phenotype completely segregated with a polymorphic mutation of the superoxide dismutase-2 gene. In this family, 4 out of 6 siblings were affected with early onset parkinsonism and the parents were apparently normal. Thus the mode of inheritance appeared to be autosomal recessive and this type is now called as AR-JP or Park2. We confirmed the linkage of this type of familial Parkinson's disease to the superoxide dismutase loci that is located in the telomeric region of chromosome 6 by the linkage analysis using microsatellite markers in this region. Then we found another family, in which an affected patient showed lack of one of the microsatellite markers (D6S315), which we were using in the linkage analysis. This observation prompted us to initiate the molecular cloning of the disease gene utilizing D6S315 as the initial probe. The molecular cloning was done with the collaboration with Professor Nobuyoshi Shimizu of Keio University. We identified a novel gene and confirmed that mutations of this novel gene were found only in the patients with autosomal recessive Parkinson's disease. The novel gene was named parkin. We conducted mutational analysis on more than 700 families with Parkinson's disease. We also established a method to detect compound heterozygotes of parkin mutations. Mutinous of the parkin gene were found in approximately 50% of autosomal recessive families. Many kinds of exonic deletions and point mutations were found. This type of familial Parkinson's disease had been considered to be unique among Japanese, but since we started mutational analysis of the parkin gene, we confirmed the world wide distribution of parkin gene mutations. Then we analyzed functions of parkin protein with the collaboration with Dr. Keiji Tanaka of Tokyo Metropolitan Institute of Medical Sciences. We found that parkin protein was a ubiquitin-protein ligase of the ubiquitin system. Now we are working on the candidate substrates of parkin protein as a ubiquitin ligase. We found that CDCrel-1, a synaptic vesicle protein, was a candidate substrate of parkin protein. In addition, we found two additional candidate proteins, i.e., alpha-synuclein 22 and PAEL receptor, with the collaboration of Professor Denis Selkoe of Harvard Medical School and Dr. Ryosuke Takahashi of RIKEN, respectively. Accumulation of PAEL receptor in the endoplasmic reticulum causes endoplasmic reticulum stress and apoptotic cell death. We found evidence to indicate accumulation of PAEL receptor and the presence of endoplasmic reticulum stress in a patient with AR-JP (Park2). Thus our studies firmly established that a genetic defect of an enzyme in the ubiquitin-proteasome system induces selective nigral neuronal death. We indicated the important role of the ubiquitin-proteasome system in neurodegeneration in general. In many other neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease, Machado-Joseph disease, dentatorubral-pallidoluysian atrophy, and ALS, ubiquitinated proteins are accumulated in neurons. Thus protein handling in the ubiquitin-proteasome system appears to be affected in these neurodegenerative disorders despite the difference in the primary defects. Our studies also suggest many potential approaches for the discovery of neuroprotective treatment for not only Parkinson's disease but also other neurodegenerative disorders.}, }
@article {pmid15266526, year = {2004}, author = {Bongioanni, P and Reali, C and Sogos, V}, title = {Ciliary neurotrophic factor (CNTF) for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {2004}, number = {3}, pages = {CD004302}, pmid = {15266526}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Ciliary Neurotrophic Factor/*therapeutic use ; Disease Progression ; Humans ; Motor Neuron Disease/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis, also known as motor neuron disease, is a fatal neuromuscular disease characterized by progressive muscle weakness resulting in paralysis, which might be treated with ciliary neurotrophic factor.<br><br>OBJECTIVES: The objective of this review was to examine the efficacy of ciliary neutrophic factor in amyotrophic lateral sclerosis.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (searched June 2003) for randomized trials, MEDLINE (from January 1966 to October 2003) and EMBASE (from January 1980 to October 2003), checked the reference lists of papers identified and contacted the authors of studies identified to get additional unpublished results.<br><br>SELECTION CRITERIA: We considered the following selection criteria: Types of studies: randomized controlled clinical trials;<br><br>TYPES OF PARTICIPANTS: adults with a diagnosis of either probable or definite amyotrophic lateral sclerosis according to the El Escorial criteria; Types of interventions: treatment with ciliary neurotrophic factor for at least six months, in a placebo-controlled randomized format; Types of outcome measures Primary: survival; Secondary: muscle strength, respiratory function, changes in bulbar functions, changes in quality of life, proportion of patients with adverse side effects (such as cough, asthenia, nausea, anorexia, weight loss and increased salivation).<br><br>DATA COLLECTION AND ANALYSIS: We identified two randomized trials. The data were extracted and examined independently by the reviewers. Some missing data were obtained from investigators.<br><br>MAIN RESULTS: Two trials, with a total population of 1,300 amyotrophic lateral sclerosis patients treated with subcutaneous injections of recombinant human ciliary neurotrophic factor, were examined in this review. The methodological quality of these trials was considered adequate. No significant difference was observed between ciliary neurotrophic factor and placebo groups for survival, the primary outcome measure. The relative risk was 1.07 (95% CI 0.81 to 1.41). No significant differences between the groups were observed for most of the secondary outcomes. However, a significant increase of the incidence of several adverse events was noted in groups treated with higher doses of CNTF.<br><br>REVIEWERS' CONCLUSIONS: Ciliary neurotrophic factor treatment has no effect on amyotrophic lateral sclerosis progression. At high concentration, several side effects were observed. A combination of ciliary neurotrophic factor with other neurotrophic factors (as suggested by results on animal models), and more efficient delivery methods should be tested.}, }
@article {pmid15264227, year = {2004}, author = {Rembach, A and Turner, BJ and Bruce, S and Cheah, IK and Scott, RL and Lopes, EC and Zagami, CJ and Beart, PM and Cheung, NS and Langford, SJ and Cheema, SS}, title = {Antisense peptide nucleic acid targeting GluR3 delays disease onset and progression in the SOD1 G93A mouse model of familial ALS.}, journal = {Journal of neuroscience research}, volume = {77}, number = {4}, pages = {573-582}, doi = {10.1002/jnr.20191}, pmid = {15264227}, issn = {0360-4012}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics/*therapy ; Animals ; Antisense Elements (Genetics)/genetics/metabolism/*pharmacology ; Calcium/metabolism/toxicity ; Calcium Signaling/drug effects/physiology ; Cell Death/drug effects/genetics ; Cells, Cultured ; Disease Models, Animal ; Disease Progression ; Down-Regulation/*drug effects/genetics ; Excitatory Amino Acid Agonists/pharmacology ; Excitatory Amino Acid Antagonists/pharmacology ; Mice ; Mice, Transgenic ; Nerve Degeneration/enzymology/genetics/therapy ; Peptide Nucleic Acids/*pharmacology ; Receptors, AMPA/*antagonists &amp; inhibitors/genetics/metabolism ; Superoxide Dismutase/genetics/*metabolism ; Survival Rate ; }, abstract = {Glutamate excitotoxicity is strongly implicated as a major contributing factor in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Excitotoxicity results from elevated intracellular calcium ion (Ca(2+)) levels, which in turn recruit cell death signaling pathways. Recent evidence suggests that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit (GluR) stoichiometry is a dominant factor leading to excess Ca(2+) loading in neurodegeneration. In particular, the Ca(2+) permeable glutamate receptor subunit 3 (GluR3) has been implicated in several neurologic conditions such as bipolar disorder and epilepsy. Recent proteomic analysis within our group on the copper zinc superoxide dismutase (SOD1)(G93A) transgenic mouse model of familial ALS (FALS) reveals a potentially deleterious upregulation of GluR3 in spinal cord compared to that in wild-type littermates. Based on this finding we designed a 12mer antisense peptide nucleic acid (PNA) directed against GluR3. This sequence significantly reduced levels of GluR3 protein and protected neuroblastoma x spinal cord (NSC-34) cells against death induced by the AMPA receptor-specific agonist (S)-5-fluorowillardiine. We subsequently treated SOD1(G93A) mice thrice weekly with intraperitoneal injections of the antisense PNA (2.5 mg/kg) commencing at postnatal day 50. Mice treated with the antisense sequence had significantly extended survival compared to mice injected with a nonsense sequence. Western blot analysis, however, did not reveal a significant reduction in GluR3 protein levels in whole extracts of the lumbar spinal cord. These results suggest that interference with the GluR3 component of the AMPA receptor assembly may be a novel strategy for controlling excitotoxic destruction of motor neurons and may lead to new therapeutic opportunities for the treatment of human ALS.}, }
@article {pmid15257302, year = {2004}, author = {Cozzolino, M and Ferraro, E and Ferri, A and Rigamonti, D and Quondamatteo, F and Ding, H and Xu, ZS and Ferrari, F and Angelini, DF and Rotilio, G and Cattaneo, E and Carrì, MT and Cecconi, F}, title = {Apoptosome inactivation rescues proneural and neural cells from neurodegeneration.}, journal = {Cell death and differentiation}, volume = {11}, number = {11}, pages = {1179-1191}, doi = {10.1038/sj.cdd.4401476}, pmid = {15257302}, issn = {1350-9047}, support = {GGP030066/TI_/Telethon/Italy ; TCP99038/TI_/Telethon/Italy ; }, mesh = {Amyloid beta-Peptides/chemistry ; Animals ; *Apoptosis ; Apoptotic Protease-Activating Factor 1 ; Blotting, Western ; Bromodeoxyuridine/pharmacology ; Caspases/metabolism ; Cell Death ; Cell Differentiation ; Cell Proliferation ; Cell Survival ; Immunohistochemistry ; Immunoprecipitation ; Membrane Potentials ; Mice ; Mice, Transgenic ; Microscopy, Fluorescence ; Mitochondria/metabolism/pathology ; *Nerve Degeneration ; Neurodegenerative Diseases ; Neurons/*pathology ; Peptide Fragments/chemistry ; Plasmids/metabolism ; Proteins/*physiology ; Time Factors ; Transgenes ; }, abstract = {Deficiency of the apoptosome component Apaf1 leads to accumulation of supernumerary brain cells in mouse embryos. We observed that neural precursor cells (NPCs) in Apaf1(-/-) embryos escape programmed cell death, proliferate and retain their potential to differentiate. To evaluate the circumstances of Apaf1(-/-) NPC survival and investigate their fate under neurodegenerative conditions, we established cell lines of embryonic origin (ETNA). We found that Apaf1(-/-) NPCs resist common apoptotic stimuli and neurodegenerative inducers such as amyloid-beta peptide (typical of Alzheimer's disease) and mutant G93A superoxide dismutase 1 (typical of familial amyotrophic lateral sclerosis). Similar results were obtained in Apaf1(-/-) primary cells. When death is prevented by Apaf1 deficiency, cytochrome c is released from mitochondria and rapidly degraded by the proteasome, but mitochondria remain intact. Under these conditions, neither activation by cleavage of initiator caspases nor release of alternative apoptotic inducers from mitochondria takes place. In addition, NPCs can still differentiate, as revealed by neurite outgrowth and expression of differentiation markers. Our findings imply that the mitochondrion/apoptosome pathway is the main route of proneural and neural cells to death and that its inhibition prevents them from dismantling in neurodegenerative conditions. Indeed, the ETNA cell model is ideally suited for exploring the potential of novel cell therapies for the treatment of human neurodegenerations.}, }
@article {pmid15255263, year = {2004}, author = {Karlsson, J and Fong, KS and Hansson, MJ and Elmér, E and Csiszar, K and Keep, MF}, title = {Life span extension and reduced neuronal death after weekly intraventricular cyclosporin injections in the G93A transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of neurosurgery}, volume = {101}, number = {1}, pages = {128-137}, doi = {10.3171/jns.2004.101.1.0128}, pmid = {15255263}, issn = {0022-3085}, support = {2G12RR03061-16/RR/NCRR NIH HHS/United States ; }, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Anterior Horn Cells/drug effects/physiopathology ; Body Weight/drug effects ; Cell Survival/drug effects ; Cyclosporine/*administration &amp; dosage ; Disease Models, Animal ; Drug Administration Schedule ; Hindlimb/drug effects/physiopathology ; Injections, Intraventricular ; Longevity/*drug effects ; Mice ; Mice, Transgenic ; Motor Activity/drug effects ; Muscle Weakness/*prevention &amp; control ; Neuroprotective Agents/*administration &amp; dosage ; Substantia Nigra/drug effects/pathology/physiopathology ; Superoxide Dismutase ; Time Factors ; }, abstract = {OBJECT: The authors investigated whether cyclosporin A (CsA), a cyclophilin ligand with mitochondrial permeability transition pore-blocking and calcineurin-inhibiting properties, affects motor function, neuronal death, and life span in the G93A transgenic mouse model of familial amyotrophic lateral sclerosis (FALS).<br><br>METHODS: The G93A mice received weekly intracerebroventricular injections of CsA (20 microg/mouse/week) starting at the age of 65 days, and physical performance on an exercise wheel was monitored beginning at 84 days of age. Mice were allowed to survive for clinical observation of body weight, hindlimb weakness, and life span or until a defined end stage or were killed at 110 days of age for histological analysis.<br><br>CONCLUSIONS: Treatment with CsA significantly delayed the onset of hindlimb weakness and also extended the time from its onset to paralysis. The overall life span of CsA-treated G93A mice was significantly extended, by 12% compared with vehicle-treated transgenic littermates. The CsA also prolonged physical performance on the exercise wheel and delayed weight loss. Histologically, there was significant preservation of both cervical and lumbar spine motor neurons and also tyrosine hydroxylase-positive dopaminergic substantia nigra neurons in 110-day-old CsA-treated mice compared with their transgenic littermates. The local administration of CsA directly into the brain ventricles is an effective means of central nervous system drug delivery (because CsA does not readily cross the blood-brain barrier), which in this study ameliorated clinical and neuropathological features of FALS in G93A mice. The remarkably low intrathecal CsA dose required for neuroprotection reduces potential adverse effects of systemic immunosuppression or nephrotoxicity seen with chronic systemic delivery of the drug.}, }
@article {pmid15254942, year = {2004}, author = {Wermuth, L and Bünger, N and Von Weitzel-Mudersback, P and Pakkenberg, H and Jeune, B}, title = {Clinical characteristics of Parkinson's disease among Inuit in Greenland and inhabitants of the Faroe Islands and Als (Denmark).}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {19}, number = {7}, pages = {821-824}, doi = {10.1002/mds.20058}, pmid = {15254942}, issn = {0885-3185}, mesh = {Aged ; Brain Chemistry ; Catchment Area, Health ; Denmark/epidemiology ; Feeding Behavior ; Female ; Greenland/epidemiology ; Humans ; Hydrocarbons, Chlorinated ; Hypokinesia/epidemiology/physiopathology ; Insecticides/analysis ; *Inuit ; Male ; Middle Aged ; Parkinson Disease/epidemiology/*ethnology/*physiopathology ; Prevalence ; Tremor/epidemiology/physiopathology ; }, abstract = {In earlier studies, we found high age-adjusted prevalences of Parkinson's disease (PD) in the Faroe Islands (209 per 100,000 inhabitants) and in Greenland (187.5 per 100,000 inhabitants) compared to the age-adjusted prevalence on the island of Als in the southern part of Denmark (98.3 per 100,000 inhabitants). We thoroughly examined patients with suspected parkinsonism using internationally accepted diagnostic criteria. In the present study, we found no significant clinical differences between patients with PD in the three areas, despite this high difference in prevalence. However, comparing the age at examination and age at treatment, the patients were younger in Greenland, a higher proportion of patients had cognitive decline, and they had a higher mean Hoehn and Yahr rating score, although they received a lower levodopa dose. A higher proportion of the patients in Greenland were newly diagnosed than in the other two areas.}, }
@article {pmid15247881, year = {2004}, author = {Kreuter, M and Langer, C and Kerkhoff, C and Reddanna, P and Kania, AL and Maddika, S and Chlichlia, K and Bui, TN and Los, M}, title = {Stroke, myocardial infarction, acute and chronic inflammatory diseases: caspases and other apoptotic molecules as targets for drug development.}, journal = {Archivum immunologiae et therapiae experimentalis}, volume = {52}, number = {3}, pages = {141-155}, pmid = {15247881}, issn = {0004-069X}, mesh = {Animals ; Apoptosis/*physiology ; Caspases/*metabolism ; Cell Cycle/physiology ; Clinical Trials as Topic ; Cytokines/immunology ; *Drug Design ; Drug Industry ; Enzyme Activation ; Humans ; *Inflammation/drug therapy/metabolism/physiopathology ; *Myocardial Infarction/drug therapy/metabolism ; *Stroke/drug therapy/metabolism ; }, abstract = {Mapping of the human and other eukaryotic genomes has provided the pharmacological industry with excellent models for drug discovery. Control of cell proliferation, differentiation, activation and cell removal is crucial for the development and existence of multicellular organisms. Each cell cycle progression, with sequences of DNA replication, mitosis, and cell division, is a tightly controlled and complicated process that, when deregulated, may become dangerous not only to a single cell, but also to the whole organism. Regulation and the proper control of the cell cycle and of programmed cell death (apoptosis) is therefore essential for mammalian development and the homeostasis of the immune system. The molecular networks that regulate these processes are critical targets for drug development, gene therapy, and metabolic engineering. In addition to the primary, intracellular apoptotic suicide machinery, components of the immune system can detect and remove cells and tissue fragments that no longer serve their defined functions. In this review we will focus on apoptotic pathways converging on caspase family proteases, summarizing pharmacological attempts that target genes, proteins, and intermolecular interactions capable of modulating apoptosis and the inflammatory response. The upcoming pharmacological development for treatment of acute pathologies, such as sepsis, SIRS, stroke, traumatic brain injury, myocardial infarction, spinal cord injury, acute liver failure, as well as chronic disorders such as Huntington's disease, Parkinson's disease, ALS, and rheumatoid arthritis, will be discussed in details. We also suggest new potential molecular targets that may prove to be effective in controlling apoptosis and the immune response in vivo.}, }
@article {pmid15246734, year = {2004}, author = {Silani, V and Cova, L and Corbo, M and Ciammola, A and Polli, E}, title = {Stem-cell therapy for amyotrophic lateral sclerosis.}, journal = {Lancet (London, England)}, volume = {364}, number = {9429}, pages = {200-202}, doi = {10.1016/S0140-6736(04)16634-8}, pmid = {15246734}, issn = {1474-547X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Embryo, Mammalian/cytology ; Fetal Blood/cytology ; Hematopoietic Stem Cell Transplantation ; Humans ; Neurons/cytology ; Spinal Cord ; *Stem Cell Transplantation ; }, abstract = {CONTEXT: With the lack of effective drug treatments for amyotrophic lateral sclerosis (ALS), and compelling preclinical data, stem-cell research has highlighted this disease as a candidate for stem-cell treatment. Stem-cell transplantation is an attractive strategy for neurological diseases and early successes in animal models of neurodegnerative disease generated optimism about restoring function or delaying degeneration in human beings. The restricted potential of adult stem cells has been challenged over the past 5 years by reports on their ability to acquire new unexpected fates beyond their embryonic lineage (transdifferentiation). Therefore, autologous or allogeneic stem cells, undifferentiated or transdifferentiated and manipulated epigenetically or genetically, could be a candidate source for local or systemic cell-therapies in ALS.<br><br>STARTING POINT: Albert Clement and colleagues (Science 2003; 302: 113-17) showed that in SOD1G93A chimeric mice, motorneuron degeneration requires damage from mutant SOD1 acting in non-neuronal cells. Wild-type non-neuronal (glial) cells could delay degeneration and extend survival of mutant-expressing motorneurons. Letizia Mazzini and colleagues (Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4: 158-61) injected autologous bone-marrow-derived stem cells into the spinal cord of seven ALS patients. These investigators reported that the procedure had a reasonable margin of clinical safety. WHERE NEXT? The success of cell-replacement therapy in ALS will depend a lot on preclinical evidence, because of the complexity and precision of the pattern of connectivity that needs to be restored in degenerating motoneurons. Stem-cell therapy will need to be used with other drugs or treatments, such as antioxidants and/or infusion of trophic molecules.}, }
@article {pmid15224658, year = {2004}, author = {Petrucelli, L and Dawson, TM}, title = {Mechanism of neurodegenerative disease: role of the ubiquitin proteasome system.}, journal = {Annals of medicine}, volume = {36}, number = {4}, pages = {315-320}, doi = {10.1080/07853890410031948}, pmid = {15224658}, issn = {0785-3890}, support = {NS38377/NS/NINDS NIH HHS/United States ; NS41486/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/physiopathology ; Amyotrophic Lateral Sclerosis/physiopathology ; Animals ; Brain/physiopathology ; Cysteine Endopeptidases/*metabolism ; Endopeptidases/chemistry/*physiology ; Humans ; Huntington Disease/physiopathology ; Multienzyme Complexes/*metabolism ; Neurodegenerative Diseases/*physiopathology ; Parkinson Disease/physiopathology ; Proteasome Endopeptidase Complex ; Signal Transduction/physiology ; Ubiquitin/*metabolism ; Ubiquitin-Specific Proteases ; }, abstract = {Many neurodegenerative disorders such as Alzheimer's disease (AD) Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) are characterized by neuronal damage that may be caused by toxic, abnormal, aggregation-prone proteins. The purpose of this review is threefold: 1) to provide the reader with an overview of the genes involved in the abnormal processing and accumulation of misfolded proteins in neurodegenerative diseases using PD as a model disease; 2) to understand the cellular mechanisms for disposal of abnormal proteins, and the effects of toxic protein accumulation on ubiquitin proteasome system (UPS) and neuronal survival and 3) to discuss the development and challenges of cell culture and animal models for a rational and effective treatment for these disorders.}, }
@article {pmid15220193, year = {2004}, author = {Ogawa, N and List, JF and Habener, JF and Maki, T}, title = {Cure of overt diabetes in NOD mice by transient treatment with anti-lymphocyte serum and exendin-4.}, journal = {Diabetes}, volume = {53}, number = {7}, pages = {1700-1705}, doi = {10.2337/diabetes.53.7.1700}, pmid = {15220193}, issn = {0012-1797}, support = {DK30834/DK/NIDDK NIH HHS/United States ; DK60721/DK/NIDDK NIH HHS/United States ; }, mesh = {Adoptive Transfer ; Animals ; Antilymphocyte Serum/*administration &amp; dosage ; Blood Glucose/analysis ; Diabetes Mellitus, Type 1/blood/complications/*drug therapy/pathology ; Drug Administration Schedule ; Drug Synergism ; Drug Therapy, Combination ; Exenatide ; Female ; Hyperglycemia/etiology/pathology ; Immunosuppressive Agents/*administration &amp; dosage ; Insulin/metabolism ; Insulin Secretion ; Mice ; *Mice, Inbred NOD ; Mice, SCID ; Pancreas/metabolism/pathology ; Pancreas Transplantation/immunology ; Peptides/*administration &amp; dosage ; Venoms/*administration &amp; dosage ; }, abstract = {Treatment of overtly diabetic NOD mice with anti-lymphocyte serum (ALS), a polyclonal anti-T-cell antibody, abrogates autoimmunity and achieves partial clinical remission. Here we investigated whether the addition of exendin-4, a hormone that stimulates insulin secretion and beta-cell replication and differentiation, improves induction of remission by ALS. Transient treatment of overtly diabetic NOD mice with ALS and exendin-4 achieved complete remission in 23 of 26 mice (88%) within 75 days, accompanied by progressive normalization of glucose tolerance, improved islet histology, increased insulin content in the pancreas, and insulin release in response to a glucose challenge. Syngeneic islets transplanted into mice cured by treatment with ALS plus exendin-4 remained intact, and cotransfer of lymphocytes from cured mice delayed diabetes induction by adoptive transfer, suggesting the long-lasting presence of autoimmune regulatory cells. Although ALS alone also achieved reversal of diabetes, the frequency of remission was low (40%). No treatment or exendin-4 alone failed to produce remission. These results show that exendin-4 synergistically augments the remission-inducing effect of ALS. The addition of beta-cell growth factors, such as exendin-4, to immunotherapy protocols with anti-T-cell antibodies presents a potential novel approach to the cure of patients with new-onset type 1 diabetes.}, }
@article {pmid15212656, year = {2004}, author = {Minuto, F and Resmini, E and Boschetti, M and Arvigo, M and Sormani, MP and Giusti, M and Ferone, D and Barreca, A}, title = {Assessment of disease activity in acromegaly by means of a single blood sample: comparison of the 120th minute postglucose value with spontaneous GH secretion and with the IGF system.}, journal = {Clinical endocrinology}, volume = {61}, number = {1}, pages = {138-144}, doi = {10.1111/j.1365-2265.2004.02064.x}, pmid = {15212656}, issn = {0300-0664}, mesh = {Acromegaly/*diagnosis/metabolism ; Adult ; Aged ; Aged, 80 and over ; Biomarkers/blood ; Female ; Glucose Tolerance Test ; Growth Hormone/*metabolism ; Humans ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/*analysis ; Male ; Middle Aged ; }, abstract = {OBJECTIVE: It has been suggested that the threshold of 1 micro g/l of GH nadir after glucose load for definition of controlled acromegalic disease proposed in the 2000 consensus statement should be lowered to 0.30. We evaluated these two cut-off values in comparison with IGF-I, ALS and IGFBP-3 in a group of acromegalic patients. With the aim of simplifying the follow-up protocol in these patients we also tested if one single sample taken after glucose load could replace the nadir value.<br><br>DESIGN AND MEASUREMENTS: GH secretion was evaluated by oral glucose tolerance test (OGTT), and by studying spontaneous secretion (GH day curve) with sampling at hourly intervals from 08.00 to 18.00 h; from the day curve, mean (MGHDC) and minimum (TRGH) values were considered. IGF-I, ALS, and IGFBP-3 were measured in the basal state at the first testing. patients Fifty acromegalic patients (26-83 years, 31 females, 19 males) in various phases of disease activity. Forty-two patients had previously undergone pituitary surgery (10 also radiotherapy), 23 were treated with SMS analogues and three with dopamine agonist drugs.<br><br>RESULTS: The nadir GH value after glucose load correlated most significantly with the 120th-minute sample (R = 0.95). Comparison of the postglucose 120th minute at the two cut-off values with IGF-I, IGFBP-3 and ALS showed higher concordance of postglucose level at 0.3 with IGF-I, while concordance was similar for the two cut-off values with ALS and IGFBP-3. When the 120th minute postglucose GH value is lower than 1 micro g/l and IGF-I is within 2SD for age nearly all other parameters are normal. IGF-I correlated more with ALS (R = 0.78) than with IGFBP-3 (R = 0.50) and the latter was less concordant with GH secretion parameters than the previous two.<br><br>CONCLUSIONS: A sample taken at the 120th minute after glucose load, together with IGF-I and/or ALS evaluation can give sufficient information for a routine assessment of disease activity, both in the diagnosis and in the follow-up to treatment. If GH is lower than 1 micro g/l and IGF-I/ALS are normal, then the patient can be classified as 'nonactive' or 'controlled'; a pathological IGF-I and/or ALS value is a sign of disease activity irrespective of the GH values, while normal IGF-I/ALS with an elevated GH requires further assessment.}, }
@article {pmid15207271, year = {2004}, author = {Guillot, S and Azzouz, M and Déglon, N and Zurn, A and Aebischer, P}, title = {Local GDNF expression mediated by lentiviral vector protects facial nerve motoneurons but not spinal motoneurons in SOD1(G93A) transgenic mice.}, journal = {Neurobiology of disease}, volume = {16}, number = {1}, pages = {139-149}, doi = {10.1016/j.nbd.2004.01.017}, pmid = {15207271}, issn = {0969-9961}, mesh = {Animals ; Atrophy ; Facial Nerve/*metabolism/pathology ; Female ; Gene Expression Regulation/drug effects/physiology ; Genetic Vectors/genetics ; Glial Cell Line-Derived Neurotrophic Factor ; Lentivirus/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/*metabolism/pathology ; Nerve Growth Factors/*biosynthesis/genetics/*physiology ; Spinal Cord/*metabolism/pathology ; Superoxide Dismutase/*biosynthesis/genetics ; }, abstract = {Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are associated with mutations in the cytosolic Cu/Zn superoxide dismutase 1 (SOD1) gene. Transgenic SOD1 mice constitute useful models of ALS to screen therapeutical approaches. Glial cell line-derived neurotrophic factor (GDNF) holds promises for the treatment of motoneuron disease. In the present study, GDNF expression in motoneurons of SOD1(G93A) transgenic mice was assessed by facial nucleus or intraspinal injection of lentiviral vectors (LV) encoding GDNF. We show that lentiviral vectors allow the expression for at least 12 weeks of GDNF that was clearly detected in motoneurons. This robust intraspinal expression did, however, not prevent the loss of motoneurons and muscle denervation of transgenic mice. In contrast, LV-GDNF induced a significant rescue of motoneurons in the facial nucleus and prevented motoneuron atrophy. The differential effect of GDNF on facial nucleus versus spinal motoneurons suggests different vulnerability of motoneurons in ALS.}, }
@article {pmid15204023, year = {2004}, author = {Trail, M and Nelson, N and Van, JN and Appel, SH and Lai, EC}, title = {Major stressors facing patients with amyotrophic lateral sclerosis (ALS): a survey to identify their concerns and to compare with those of their caregivers.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {1}, pages = {40-45}, doi = {10.1080/14660820310016075}, pmid = {15204023}, issn = {1466-0822}, mesh = {Adaptation, Psychological ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/epidemiology/*psychology ; *Attitude to Health ; Caregivers/*psychology ; Cross-Sectional Studies ; Data Collection/statistics &amp; numerical data ; Family ; Female ; Health Services/*statistics &amp; numerical data ; Humans ; Male ; Middle Aged ; Patient Satisfaction ; Social Support ; *Stress, Physiological ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: To identify and compare the primary existential, physical, and psychosocial stressors affecting patients with ALS and their caregivers. Health care providers, together with patients and their caregivers, are challenged to identify both physical and psychosocial concerns that have the greatest impact on quality of life over the course of a serious illness. It is also helpful to understand the priorities of these concerns from the patients' and caregivers' perspectives so that we can render optimal care and help patients and their families with the myriad problems that accompany a progressive and fatal disease.<br><br>METHODS: We analyzed responses from the first 66 patients with ALS and 61 ALS caregivers who attended the Baylor College of Medicine, Department of Neurology, Vicki Appel MDA ALS Clinic and who completed our internally generated 19-item survey. Subjects were asked to choose their three most important concerns. For analysis purposes we categorized the data into three domains: existential, physical, and psychosocial. Demographic data were collected. The Appel ALS Rating Scale (AALS) was used to measure disease symptom severity.<br><br>RESULTS: Sixty-six patients (45 men, 21 women) with a mean age of 57.9 (range 30-82) years and 61 caregivers completed the checklist. At the time the patients completed the survey, their mean AALS total score was 77.0 (range 34-132), indicating mild to moderate disability. The most important stressors identified by patients and caregivers were existential concerns (86.4% of patients and 79.7% of caregivers) and physical stressors (80.3% of patients and 76.3% of caregivers). Less than 50% of both groups endorsed psychosocial stressors (38%). However, when we analyzed the domain specific items, there was a significant difference between patients and caregivers on worries about the patient's dependency (37.9% of patients and 6.8% of caregivers).<br><br>DISCUSSION: Health care professionals should apply a holistic approach to treatment and care of patients with ALS. Families should be included in the process, and it should not be assumed that patients and caregivers will agree on all issues. Future research should focus on therapeutic interventions to help ALS patients and their families cope with the multiple stressors accompanying a catastrophic illness.}, }
@article {pmid15204022, year = {2004}, author = {Raman, C and McAllister, SD and Rizvi, G and Patel, SG and Moore, DH and Abood, ME}, title = {Amyotrophic lateral sclerosis: delayed disease progression in mice by treatment with a cannabinoid.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {1}, pages = {33-39}, doi = {10.1080/14660820310016813}, pmid = {15204022}, issn = {1466-0822}, support = {NS 041639/NS/NINDS NIH HHS/United States ; }, mesh = {Age Factors ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Cannabinoids/antagonists &amp; inhibitors/*therapeutic use ; Cell Count/methods ; Cell Death/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; *Disease Models, Animal ; Dose-Response Relationship, Drug ; Dronabinol/*analogs &amp; derivatives/*therapeutic use ; Drug Interactions ; Embryo, Mammalian ; Humans ; L-Lactate Dehydrogenase ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects ; Piperidines/pharmacology ; Psychomotor Performance/drug effects ; Pyrazoles/pharmacology ; Rimonabant ; Spinal Cord/cytology/drug effects ; Superoxide Dismutase/genetics ; Time Factors ; tert-Butylhydroperoxide/toxicity ; }, abstract = {Effective treatment for amyotrophic lateral sclerosis (ALS) remains elusive. Two of the primary hypotheses underlying motor neuron vulnerability are susceptibility to excitotoxicity and oxidative damage. There is rapidly emerging evidence that the cannabinoid receptor system has the potential to reduce both excitotoxic and oxidative cell damage. Here we report that treatment with Delta(9)-tetrahydrocannabinol (Delta(9)-THC) was effective if administered either before or after onset of signs in the ALS mouse model (hSOD(G93A) transgenic mice). Administration at the onset of tremors delayed motor impairment and prolonged survival in Delta(9)-THC treated mice when compared to vehicle controls. In addition, we present an improved method for the analysis of disease progression in the ALS mouse model. This logistic model provides an estimate of the age at which muscle endurance has declined by 50% with much greater accuracy than could be attained for any other measure of decline. In vitro, Delta(9)-THC was extremely effective at reducing oxidative damage in spinal cord cultures. Additionally, Delta(9)-THC is anti-excitotoxic in vitro. These cellular mechanisms may underlie the presumed neuroprotective effect in ALS. As Delta(9)-THC is well tolerated, it and other cannabinoids may prove to be novel therapeutic targets for the treatment of ALS.}, }
@article {pmid15204010, year = {2004}, author = {Leigh, PN and Swash, M and Iwasaki, Y and Ludolph, A and Meininger, V and Miller, RG and Mitsumoto, H and Shaw, P and Tashiro, K and Van Den Berg, L}, title = {Amyotrophic lateral sclerosis: a consensus viewpoint on designing and implementing a clinical trial.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {5}, number = {2}, pages = {84-98}, doi = {10.1080/14660820410020187}, pmid = {15204010}, issn = {1466-0822}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/physiopathology/therapy ; Animals ; Clinical Trials as Topic/*methods/statistics &amp; numerical data ; *Consensus Development Conferences as Topic ; Humans ; Oxepins/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {In November 2002, an advisory board meeting was convened by Novartis Pharma to provide recommendations and rationale for clinical trials designed to evaluate new treatments, such as TCH346, for amyotrophic lateral sclerosis (ALS). In terms of selecting appropriate outcome measures, the panel recommended the use of the ALS Functional Rating Scale (ALSFRS-R) to measure primary endpoints. A review of other key issues in this area including regional variations in the epidemiology, diagnosis and management of ALS, defining patient populations and doses of trial medication, and accommodating the likelihood of co-medication with pre-existing treatment in trial design, are discussed.}, }
@article {pmid15197603, year = {2004}, author = {Beghi, E and Mennini, T and , }, title = {Basic and clinical research on amyotrophic lateral sclerosis and other motor neuron disorders in Italy: recent findings and achievements from a network of laboratories.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {25 Suppl 2}, number = {}, pages = {S41-60}, doi = {10.1007/s10072-004-0228-1}, pmid = {15197603}, issn = {1590-1874}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/epidemiology/*genetics ; Animals ; Central Nervous System/*enzymology/pathology/physiopathology ; Disease Models, Animal ; Humans ; Incidence ; Italy ; Motor Neurons/*enzymology/pathology ; Neurology/trends ; Neurosciences/trends ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {An Italian collaborative group on motor neuron disorders, including amyotrophic lateral sclerosis (ALS) and its variants, has been recently created, combining various academic groups and laboratories involved in basic and clinical research. The aim is to exploit all the specific expertise and combine efforts at a national level to better understand and fight these fatal diseases. This review summarizes the achievements of the different groups and outlines prospects for future research. Basic research deals with the etiopathogenesis of motor neuron diseases. In vitro and in vivo models of superoxide dismutase 1 (SOD1) mutations are used to investigate the mechanisms of motor neuron death associated with this gene defect. The role of excitotoxicity, immune response, intracellular aggregates and mitochondrial alterations is studied with an integrated approach, at the molecular and cellular levels. Transgenic mice carrying the human mutated SOD1, and the wobbler mouse, a spontaneous model for motor neuron degeneration, offer unique opportunities for testing new therapies in vivo related or not to SOD1 mutations. Clinical research has focused mostly on the incidence and determinants of ALS in several areas of Italy. The incidence of the disease is now among the highest according to the results of population-based regional registries. Compared to earlier studies, more recent Italian investigations show an increase in the incidence and mortality related to ALS. Findings on the role of environmental risk factors are inconsistent. Methodological issues have also been raised by Italian groups regarding the diagnosis and treatment. The validity of the El Escorial diagnostic classification has been questioned where investigators and carers have not received formal training. Pitfalls and methodological drawbacks of randomized clinical trials have been highlighted based on the results of collaborative trials by Italian investigators. Information is now available on non-pharmacological treatments and palliative care, and the economic aspects and quality of life of ALS patients are being investigated.}, }
@article {pmid15193297, year = {2004}, author = {Vincent, AM and Mobley, BC and Hiller, A and Feldman, EL}, title = {IGF-I prevents glutamate-induced motor neuron programmed cell death.}, journal = {Neurobiology of disease}, volume = {16}, number = {2}, pages = {407-416}, doi = {10.1016/j.nbd.2004.03.001}, pmid = {15193297}, issn = {0969-9961}, support = {NS36778/NS/NINDS NIH HHS/United States ; NS38849/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*drug effects/physiology ; Caspases/metabolism ; Cells, Cultured ; DNA Fragmentation/drug effects/physiology ; Dose-Response Relationship, Drug ; Fetus ; Glutamic Acid/*toxicity ; Insulin Receptor Substrate Proteins ; Insulin-Like Growth Factor I/*pharmacology ; Intracellular Signaling Peptides and Proteins ; Motor Neurons/*cytology/*drug effects ; Neuroprotective Agents/pharmacology ; Phosphoproteins/metabolism ; Phosphorylation/drug effects ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Spinal Cord/cytology ; }, abstract = {Insulin-like growth factor I (IGF-I) is currently in clinical trials for treatment of amyotrophic lateral sclerosis (ALS), but little is known about how it promotes the survival of motor neurons. In the current study, we examined IGF-I-mediated neuroprotection in an in vitro model of ALS utilizing enriched cultures of embryonic rat spinal cord motor neurons. IGF-I binds to the IGF-I receptor (IGF-IR) in motor neurons and activates MAPK and the downstream effector of phosphatidylinositol 3-kinase (PI-3K) signaling, Akt. IGF-I:IGF-IR signaling involves phosphorylation of IRS-1 and Shc, but not IRS-2. Glutamate, which is elevated in the cerebrospinal fluid of ALS patients, induced DNA fragmentation and caspase-3 cleavage in the spinal cord motor neurons. These effects of glutamate were blocked by co-treatment with IGF-I. However, a delay of IGF-I treatment for as little as 30 min eliminated its neuroprotective effect. Finally, alone, neither the MAPK pathway inhibitor PD98059 nor the PI-3K inhibitor LY294002 blocked the neuroprotective effect of IGF-I, but both inhibitors together were effective in this regard. These results suggest that the dose and timing of IGF-I administration are critical for producing a neuroprotective effect, and also suggest that both the MAPK and PI-3K/Akt pathways can promote the survival of motor neurons. We discuss our results in terms of novel strategies for ALS therapy.}, }
@article {pmid15177192, year = {2004}, author = {Lambrechts, D and Storkebaum, E and Carmeliet, P}, title = {VEGF: necessary to prevent motoneuron degeneration, sufficient to treat ALS?.}, journal = {Trends in molecular medicine}, volume = {10}, number = {6}, pages = {275-282}, doi = {10.1016/j.molmed.2004.04.004}, pmid = {15177192}, issn = {1471-4914}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics/metabolism/pathology ; Animals ; Disease Models, Animal ; Genetic Predisposition to Disease ; Humans ; Mice ; Mice, Knockout ; Motor Neurons/metabolism/*pathology ; Neuroprotective Agents/metabolism ; Risk Factors ; Vascular Endothelial Growth Factor A/*deficiency/genetics ; }, abstract = {Since Charcot recognized the devastating disorder amyotrophic lateral sclerosis (ALS) in 1874, many theories have been proposed to explain its pathogenesis, but it remains as deadly and incurable as ever. Three years ago it was reported that reduced levels of vascular endothelial growth factor (VEGF) caused ALS-like motoneuron degeneration in mice. Recent evidence indicates that insufficient VEGF is also a risk factor for ALS in humans. Although VEGF was once considered to be only a specific angiogenic factor, emerging evidence indicates that it also displays important neuroprotective activity. These insights have primed widespread interest in developing VEGF-based therapies for (moto)neuron degenerative disorders, raising new hope for the treatment of ALS and other neurodegenerative diseases.}, }
@article {pmid15172705, year = {2004}, author = {Timerman, S and Cardoso, LF and Ramires, JA and Halperin, H}, title = {Improved hemodynamic performance with a novel chest compression device during treatment of in-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {61}, number = {3}, pages = {273-280}, doi = {10.1016/j.resuscitation.2004.01.025}, pmid = {15172705}, issn = {0300-9572}, mesh = {Aged ; Aorta ; Blood Pressure ; Coronary Circulation ; Female ; Heart Arrest/*therapy ; Heart Atria ; Heart Massage/*instrumentation/methods ; *Hemodynamics ; Humans ; Male ; }, abstract = {INTRODUCTION: The purpose of this pilot clinical study was to determine if a novel chest compression device would improve hemodynamics when compared to manual chest compression during cardiopulmonary resuscitation (CPR) in humans. The device is an automated self-adjusting electromechanical chest compressor based on AutoPulse technology (Revivant Corporation) that uses a load distributing compression band (A-CPR) to compress the anterior chest.<br><br>METHODS: A total of 31 sequential subjects with in-hospital sudden cardiac arrest were screened with institutional review board approval. All subjects had received prior treatment for cardiac disease and most had co-morbidities. Subjects were included following 10 min of failed standard advanced life support (ALS) protocol. Fluid-filled catheters were advanced into the thoracic aorta and the right atrium and placement was confirmed by pressure waveforms and chest radiograph. The coronary perfusion pressure (CPP) was measured as the difference between the aortic and right atrial pressure during the chest compression's decompressed state. Following 10 min of failed ALS and catheter placement, subjects received alternating manual and A-CPR chest compressions for 90 s each. Chest compressions were administered without ventilation pauses at 100 compressions/min for manual CPR and 60 compressions/min for A-CPR. All subjects were intubated and ventilated by bag-valve at 12 breaths/min between compressions. Epinephrine (adrenaline) (1mg i.v. bolus) was given at the request of the attending physician at 3-5 min intervals. Usable pressure signals were present in 16 patients (68 +/- 6 years, 5 female), and data are reported from those patients only. A-CPR chest compressions increased peak aortic pressure when compared to manual chest compression (153 +/- 28 mmHg versus 115 +/- 42 mmHg, P < 0.0001, mean +/- S.D.). Similarly, A-CPR increased peak right atrial pressure when compared to manual chest compression (129 +/- 32 mmHg versus 83 +/- 40 mmHg, P < 0.0001). Furthermore, A-CPR increased CPP over manual chest compression (20 +/- 12 mmHg versus 15 +/- 11 mmHg, P < 0.015). Manual chest compressions were of consistent high quality (51 +/- 20 kg) and in all cases met or exceeded American Heart Association guidelines for depth of compression.<br><br>CONCLUSION: Previous research has shown that increased CPP is correlated to increased coronary blood flow and increased rates of restored native circulation from sudden cardiac arrest. The A-CPR system using AutoPulse technology demonstrated increased coronary perfusion pressure over manual chest compression during CPR in this terminally ill patient population.}, }
@article {pmid15171816, year = {2004}, author = {Appert-Collin, A and Duong, FH and Passilly-Degrace, P and Gies, JP and Warter, JM and Poindron, P}, title = {Quantification of neurotrophin mRNA expression in PMN mouse: modulation by xaliproden.}, journal = {International journal of immunopathology and pharmacology}, volume = {17}, number = {2}, pages = {157-164}, doi = {10.1177/039463200401700207}, pmid = {15171816}, issn = {0394-6320}, mesh = {Animals ; Brain Chemistry/genetics ; Brain-Derived Neurotrophic Factor/biosynthesis ; DNA Primers ; Female ; Glyceraldehyde-3-Phosphate Dehydrogenases/metabolism ; Male ; Mice ; Naphthalenes/*pharmacology ; Nerve Growth Factor/biosynthesis/drug effects ; Nerve Growth Factors/*biosynthesis/genetics ; Neurodegenerative Diseases/*genetics/*metabolism ; Neurotrophin 3/biosynthesis/genetics ; Pyridines/*pharmacology ; RNA, Messenger/*biosynthesis/genetics ; Receptor, trkA/biosynthesis/genetics ; Receptor, trkC/biosynthesis/drug effects ; Receptors, Nerve Growth Factor/biosynthesis/drug effects ; Reverse Transcriptase Polymerase Chain Reaction ; Spinal Cord/metabolism ; }, abstract = {Compounds possessing neurotrophic properties may represent a possible treatment for neurodegenerative disorders such as amyotrophic lateral sclerosis. Xaliproden (SR57746A), an orally-active non-peptide compound, which has been found to exhibit neurotrophic effects in vitro and in vivo, increased the lifespan and delayed the progression of the motor neuron degeneration in PMN mice. We have used a quantitative reverse transcription/polymerase chain reaction amplification technique to study the regulation of neurotrophin mRNA and trk mRNA expression in PMN mice. NGF and NT-3 mRNA are downregulated in PMN mice. These deficiencies can be overcome by a treatment with xaliproden. Such an effect could contribute to neurotrophic effects of xaliproden in vivo and in vitro.}, }
@article {pmid15164063, year = {2004}, author = {Azzouz, M and Ralph, GS and Storkebaum, E and Walmsley, LE and Mitrophanous, KA and Kingsman, SM and Carmeliet, P and Mazarakis, ND}, title = {VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model.}, journal = {Nature}, volume = {429}, number = {6990}, pages = {413-417}, doi = {10.1038/nature02544}, pmid = {15164063}, issn = {1476-4687}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/*therapy ; Animals ; *Axonal Transport ; Brain Stem/pathology ; *Disease Models, Animal ; Disease Progression ; Gene Expression ; Genetic Therapy/methods ; Genetic Vectors/administration &amp; dosage/genetics ; Humans ; Infectious Anemia Virus, Equine/*genetics ; Injections, Intramuscular ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Point Mutation/genetics ; Spinal Cord/pathology ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Survival Rate ; Time Factors ; Transgenes/genetics ; Vascular Endothelial Growth Factor A/adverse effects/*genetics/metabolism/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) causes adult-onset, progressive motor neuron degeneration in the brain and spinal cord, resulting in paralysis and death three to five years after onset in most patients. ALS is still incurable, in part because its complex aetiology remains insufficiently understood. Recent reports have indicated that reduced levels of vascular endothelial growth factor (VEGF), which is essential in angiogenesis and has also been implicated in neuroprotection, predispose mice and humans to ALS. However, the therapeutic potential of VEGF for the treatment of ALS has not previously been assessed. Here we report that a single injection of a VEGF-expressing lentiviral vector into various muscles delayed onset and slowed progression of ALS in mice engineered to overexpress the gene coding for the mutated G93A form of the superoxide dismutase-1 (SOD1(G93A)) (refs 7-10), even when treatment was only initiated at the onset of paralysis. VEGF treatment increased the life expectancy of ALS mice by 30 per cent without causing toxic side effects, thereby achieving one of the most effective therapies reported in the field so far.}, }
@article {pmid15159521, year = {2004}, author = {Fletcher, J}, title = {Patient page. Treatment and quality of life for people with ALS.}, journal = {Neurology}, volume = {62}, number = {10}, pages = {E22-3}, doi = {10.1212/wnl.62.10.e22}, pmid = {15159521}, issn = {1526-632X}, mesh = {Adult ; Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/psychology/therapy ; Caregivers/psychology ; Humans ; Interpersonal Relations ; Middle Aged ; Minocycline/therapeutic use ; Neuroprotective Agents/therapeutic use ; Quality of Life ; Riluzole/therapeutic use ; }, }
@article {pmid15152464, year = {2003}, author = {Fukunaga, H}, title = {[Intractable neurological diseases and neurology].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {43}, number = {11}, pages = {785-787}, pmid = {15152464}, issn = {0009-918X}, mesh = {Activities of Daily Living ; Amyotrophic Lateral Sclerosis/therapy ; Chronic Disease ; *Home Care Services/economics/statistics &amp; numerical data ; Home Health Aides ; Humans ; Insurance, Long-Term Care ; Japan/epidemiology ; *Long-Term Care/economics/statistics &amp; numerical data ; Neurodegenerative Diseases/economics/*rehabilitation/therapy ; Quality of Life ; Suction ; }, abstract = {In intractable neurological diseases, there are often no appropriate treatment methods even after admission and the course is frequently chronic. Therefore treatment at home is a major choice. In particular, in Parkinson's disease and amyotrophic lateral sclerosis, care at home while symptoms are stable is appropriate in terms of extension of ADL and the QOL of the patient and family. We have performed continuous treatment at home according to our plan for the previous 9 years. This treatment was favorably accepted by the patient and family without major problems. It is important to organize network to support patient with intractable neurological diseases. By virtue of the care insurance system established in 2000, services of medical care, health and welfare are being collectively provided at present. But, there still remain many issues awaiting solution on the support to advanced intractable neurological diseases. A pending problem about suction of sputa for the ALS patients serving at home are being allowed to non-medical profession like home helper.}, }
@article {pmid15152463, year = {2003}, author = {Nagoshi, K}, title = {[Neurological disease in measures against intractable diseases in Japan].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {43}, number = {11}, pages = {783-784}, pmid = {15152463}, issn = {0009-918X}, mesh = {Delivery of Health Care ; *Health Care Reform/organization &amp; administration ; Insurance, Long-Term Care ; Japan ; Neurodegenerative Diseases/economics/*rehabilitation/therapy ; Quality of Life ; }, abstract = {Japan has been taking measures to cope with intractable diseases centering on five principles: "promoting investigation and research", "providing medical care facilities", "reducing co-payment for medical costs", "improving and coordinating community-based health care", "medical care and welfare services", and "promoting welfare measures aimed at improving the quality of life (QOL)". As the object of measures, 118 diseases including serious neurological diseases (e.g. ALS, CJD, PD etc.) have been specified. Thirty years have passed since the specific diseases treatment research program was launched, during which the environment surrounding intractable diseases has changed significantly. In light of this, "Committee on Measures Against Intractable Diseases" was organized in Sept 2001 under the Health Science Council. Based on the interim report of the committee, the government is going to take new measures against the intractable diseases.}, }
@article {pmid15149126, year = {2003}, author = {Casado, C and Osuna, MD and De Prado, R}, title = {Evaluation of resistance in Amaranthus quitensis Kunth populations to imazethapyr and other imidazolinones.}, journal = {Communications in agricultural and applied biological sciences}, volume = {68}, number = {4 Pt A}, pages = {323-329}, pmid = {15149126}, issn = {1379-1176}, mesh = {Amaranthus/drug effects/genetics/*physiology ; Heterozygote ; Immunity, Innate ; Nicotinic Acids/*pharmacology ; Plant Shoots/drug effects/physiology ; }, abstract = {Six populations of Amaranthus quitensis (R1, R3-R7), taken from soybean fields in Córdoba (Argentina), continuously treated with imazethapyr escaped from control with this herbicide. In order to characterize this resistance, whole plant assays were carried out using imazethapyr. Treatments were made at different doses, from 0.5 g a.i.ha(-1) to 60 g a.i.ha(-1), at 200 1 ha(-1) and 200 kPa pressure. Shoot fresh weight was mesured 21 days after treatment. The results were expressed as resistance factor (ED50(R)/ED50(S)). Different degrees of resistance were found as its shown by the respective resistance factors: R1:22.5, R3:6.5, R4:43.1, R5:8.6, R6:4, R7:5. Due to the high variability in the response to imazethapyr treatments shown in some populations, and according to previous investigations on the ALS gene that proved heterozygosity a screening was made, at the recommended dose of imazethapyr. Plants were classified according to their state, dead, alive and affected (fallen but alive). Populations 3, 6 and 7 showed an important heterozygosity. Furthermore, in order to evaluate the existance of a possible cross-resistance, the recommended doses of 4 other imidazolinones (imazametabenz, imazapyr, imazamox, imazaquin) were applied to the plants. All populations were susceptible to both imazamox and imazapyr and showed cross-resistance to imazamethabenz and imazaquin.}, }
@article {pmid15147078, year = {2004}, author = {Siniscalchi, A}, title = {[Tolerability of riluzole: a review of the literature].}, journal = {La Clinica terapeutica}, volume = {155}, number = {1}, pages = {25-28}, pmid = {15147078}, issn = {0009-9074}, mesh = {Excitatory Amino Acid Antagonists/*adverse effects/pharmacokinetics ; Humans ; Riluzole/*adverse effects/pharmacokinetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with the fatal evolution. Recent studies in knowledge of the pathogenic mechanisms underlying ALS showed that the excitotoxicity has an important role in the neurodegeneration. The riluzole, an antagonist of glutamate, is the first drug approved by FDA for the treatment of patients with ALS. The efficacy of riluzole (dose recommended 50 mg twice a day) in prolonging the survival of patients with ALS has been demostrated in two principal controlled clinical trials. The most frequent adverse events related to riluzole treatment were: nausea, vomiting, anorexia, diarrhea, asthenia, somnolence, vertigo, circumoral paresthesia, abdominal pain and dizziness. Some events tend to be related to the dose: vertigo, diarrhea, nausea, circumoral paresthesia and anorexia appear more frequently with 200 mg/die that with lower dose. Generally with tree months from the beginning of the treatment with riluzole, an increase serum transaminase levels has been noted; mostly transient and regressing after two-sex months of treatment. A monitoring of serum transaminase levels is suggested during the first year of treatment with riluzole The clinical studies shows that the adverse events produced by riluzole are mostly reversible and dose-dependent, this demostrates a satifying profile of tolerability of the drug. Anyway, a deeper knowledge of its tolerability may lead us to a better use of riluzole, avoiding in this way the interruption of treatment.}, }
@article {pmid15144587, year = {2004}, author = {Li, YJ and Ding, WH and Gao, W and Huo, Y and Hong, T and Zhu, RY and Ma, DL}, title = {[The protective effect of interleukin-1 receptor antagonist on postischemic reperfused myocardium and its possible mechanism].}, journal = {Zhonghua yi xue za zhi}, volume = {84}, number = {7}, pages = {548-553}, pmid = {15144587}, issn = {0376-2491}, mesh = {Acute Disease ; Aged ; Animals ; Apoptosis/drug effects ; Disease Models, Animal ; Female ; Gene Expression/drug effects ; Genes, bcl-2/drug effects ; Granulocyte Colony-Stimulating Factor ; Hematopoietic Cell Growth Factors/analysis ; Humans ; Immunohistochemistry ; In Situ Nick-End Labeling ; Interleukin 1 Receptor Antagonist Protein ; Interleukin-1/*blood ; Interleukin-3 ; Male ; Middle Aged ; Myocardial Infarction/blood ; Myocardial Reperfusion Injury/physiopathology/*prevention &amp; control ; Myocardium/pathology ; Proto-Oncogene Proteins/genetics ; *Proto-Oncogene Proteins c-bcl-2 ; Rabbits ; Random Allocation ; Receptors, Interleukin-1/*antagonists &amp; inhibitors ; Recombinant Fusion Proteins/analysis ; Recombinant Proteins/pharmacology ; Sialoglycoproteins/*pharmacology ; bcl-2-Associated X Protein ; }, abstract = {OBJECTIVE: To observe the dynamic changes of plasma inflammatory cytokine interleukin-1 beta (IL-1 beta) in patients with acute myocardiac infarction (AMI) before and after recanalization of the infarct related artery (IRA) and to observe the effect of recombinant human IL-1 receptor antagonist (rhIL-1ra) on the postischemic reperfused myocardium in experimental rabbits.<br><br>METHODS: (1) ELISA was used to measure the plasma IL-1 beta of 22 AMI patients, 20 males and 2 females, aged 64 +/- 12, before emergency percutaneous coronary intervention (PCI), and 12 hours and 24 hours after-intervention, and measure the plasma IL-1 beta of 8 healthy controls, 6 males and 2 females, aged 56 +/- 9. (2) Forty rabbits underwent ligation of the left circumflex branch of coronary artery (LCX) for 50 minutes and reperfusion for 4 hours after the ligatures were untied. The rabbits were randomly divided into 4 groups of 10 rabbits to be injected into the left ventricle immediately before the reperfusion with rhIL-1ra 10 mg/kg (group A), 20 mg/kg (group B), or 40 mg/kg (group C), and normal saline (control group) respectively. After reperfusion of 4 hours, the LCX was re-ligated. Evans blue was injected into the left ventricle. 15% KCl was injected intravenously to kill the rabbits. Their hearts were taken out to weigh the non-ischemic, ischemic, and necrotic cardiac muscles so as to calculate the infarct size. The myoperoxidase (MPO) activity was measured by colorimetry. Sections of myocardium were made. The number of apoptotic cardiomyocytes was evaluated by TUNEL method. The apoptotic rate of cardiomyocyte was measured by annexin V method. The DNA expression of myocardium was detected by DNA laddering method. The expressions of Bcl-2 and Bax apoptosis genes were assessed.<br><br>RESULTS: (1) The average plasma IL-1 beta level of the 22 AMI patients before emergency PCI was significantly higher than that of the controls (28 pg/ml +/- 9 pg/ml vs. 20 pg/ml +/- 11 pg/ml, P < 0.05), and became the highest 12 hours after the intervention (86 pg/ml +/- 14 pg/ml), and the high level lasted to 24 hours after emergency PCI. (2) In the ischemia-reperfusion rabbit model, the infarct size was 47% +/- 7% in the group A, 34% +/- 8% in the group B, 31% +/- 6% in the group C, and 61% +/- 11% in the control group (P < 0.05, 0.01, and 0.01 respectively). The activity of myocardial MPO was 16.6 +/- 3.6 min(-1).g.w.w(-1) in the group A, 10.9 min(-1).g.w.w(-1) +/- 1.9 min(-1).g.w.w(-1) in the group B, 7.8 min(-1).g.w.w(-1) +/- 2.2 min(-1).g.w.w(-1) in the group C, and 20.5 min(-1).g.w.w(-1) +/- 4.5 min(-1).g.w.w(-1) in the control group (P < 0.05, 0.01, and 0.01 respectively). The cardiomyocyte apoptosis evaluated by TUNEL was 38.3 n/HP +/- 7.4 n/HP in the group A, 25.6 n/HP +/- 6.8 n/HP in the group B, 12.2 n/HP +/- 3.3 n/HP in the group C, and 44.4 n/HP +/- 9.5 n/HP in the control group (P < 0.05, and P < 0.01 respectively in comparison between the group B and the control group and between the group C and the control group). The apoptotic rate by annexin V method was 11.6% +/- 2.7% in the group A; 7.7% +/- 2.4% in the group B, 4.7% +/- 1.4% in the group C, and 15.6% +/- 3.5% in the control group (P < 0.05, 0.01, and 0.01 respectively). DNA electrophoresis showed scaling ladder pattern only in the control group. The fluorescent density of the apoptosis gene Bax in myocardium was 24.9 +/- 8.2 in the group A; 15.5 +/- 3.4 in the group B, 10.6 +/- 2.5 in the group C, and 33.3 +/- 9.4 in the control group (P = 0.0298, 0091, and 0052 respectively) and no significant difference in the expression of Bcl-2 was shown among the 4 groups. Myocardial MPO was correlated with cardiomyocyte apoptosis (r = 0.86 by TUNEL, P < 0.01; r = 0.75 by Annexin V method, P < 0.05).<br><br>CONCLUSION: Inflammatory cytokine IL-1 beta is involved in myocardial ischemia-reperfusion injury. With potential therapeutic value in prevention and treatment of ischemia-reperfusion injury to myocardium, rhIL-1ra may reduce myocardial ischemia-reperfusion injury by suppression of cardiomyocytes apoptosis mediated by IL-als; 0.86 by TUNEL, P < 0.01; r = 0.75 by Annexin V method, P < 0.05).<br><br>CONCLUSION: Inflammatory cytokine IL-1 beta is involved in myocardial ischemia-reperfusion injury. With potential therapeutic value in prevention and treatment of ischemia-reperfusion injury to myocardium, rhIL-1ra may reduce myocardial ischemia-reperfusion injury by suppression of cardiomyocytes apoptosis mediated by IL-1.}, }
@article {pmid15135890, year = {2004}, author = {Cheung, ZH and Ip, NY}, title = {Cdk5: mediator of neuronal death and survival.}, journal = {Neuroscience letters}, volume = {361}, number = {1-3}, pages = {47-51}, doi = {10.1016/j.neulet.2003.12.117}, pmid = {15135890}, issn = {0304-3940}, mesh = {Animals ; Cell Death/genetics ; Cell Survival/genetics ; Cyclin-Dependent Kinase 5 ; Cyclin-Dependent Kinases/genetics/*metabolism ; Humans ; Mice ; Nerve Tissue Proteins/genetics/metabolism ; Neurodegenerative Diseases/*enzymology/genetics/physiopathology ; Neurons/enzymology/*metabolism ; Oncogene Proteins v-erbB/genetics/metabolism ; Proto-Oncogene Proteins c-jun/genetics/metabolism ; Signal Transduction/genetics ; }, abstract = {Cdk5 (cyclin-dependent kinase 5) is a serine/threonine kinase implicated to play pivotal roles in neuronal development. Recently, its potential involvement as a regulator of neuronal death and survival has attracted considerable interests. Importantly, increasing evidence has linked Cdk5 to the etiopathology of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. Here we summarize the recent findings on Cdk5 not only as an important participant in neuronal death, but also a key player in neuronal survival. Elucidating the mechanisms of regulation of Cdk5 and its downstream signaling might prove to be crucial in the therapeutic treatment of neurodegenerative diseases.}, }
@article {pmid15134719, year = {2004}, author = {Di Lazzaro, V and Oliviero, A and Saturno, E and Pilato, F and Dileone, M and Sabatelli, M and Tonali, PA}, title = {Motor cortex stimulation for amyotrophic lateral sclerosis. Time for a therapeutic trial?.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {115}, number = {6}, pages = {1479-1485}, doi = {10.1016/j.clinph.2004.01.027}, pmid = {15134719}, issn = {1388-2457}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Animals, Genetically Modified ; Disease Models, Animal ; Disease Progression ; *Electric Stimulation Therapy ; Female ; Humans ; *Magnetics ; Male ; Middle Aged ; Motor Cortex/*physiology ; Pilot Projects ; Rats ; Superoxide Dismutase/genetics ; }, abstract = {OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) of the brain can modulate neurotransmission. The aim of this preliminary study was to investigate whether rTMS of the motor cortex at low (1 Hz) or high (20 Hz) frequencies can have any beneficial effect in a transgenic rat model of amyotrophic lateral sclerosis (ALS) and in a few patients with ALS.<br><br>METHODS: The effects of chronic rTMS were evaluated in 20 transgenic rats overexpressing the human G93A mutant superoxide dismutase 1 gene. Several cycles of rTMS were also performed in 4 ALS patients and the rate of progression of the disease before and during rTMS treatment was compared.<br><br>RESULTS: No effects of rTMS was observed in transgenic rats. The rTMS treatment was well tolerated by the patients. All ALS patients continued to deteriorate. However, in the patients exposed to low-frequency rTMS the rate of progression during treatment was slightly slower than that evaluated before treatment; an opposite tendency was observed in patients exposed to high frequencies.<br><br>CONCLUSIONS: Though we cannot be sure whether the effects observed in the patients can be attributed to rTMS, further investigation using low-frequency motor cortex stimulation on a larger group of ALS patients is warranted.<br><br>SIGNIFICANCE: The results of the pilot study in humans might open up a new therapeutic perspective in ALS based on neuromodulation.}, }
@article {pmid15125885, year = {2004}, author = {Zimmermann-Belsing, T and Juul, A and Juul Holst, J and Feldt-Rasmussen, U}, title = {The insulin-like growth axis in patients with autoimmune thyrotoxicosis: effect of antithyroid drug treatment.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {14}, number = {3}, pages = {235-244}, doi = {10.1016/j.ghir.2003.12.015}, pmid = {15125885}, issn = {1096-6374}, mesh = {Adult ; Body Composition ; Female ; Graves Disease/*drug therapy/metabolism ; Humans ; Immunoglobulins, Thyroid-Stimulating/blood ; Insulin/blood/metabolism ; Insulin-Like Growth Factor Binding Protein 3/blood/metabolism ; Insulin-Like Growth Factor I/analysis/metabolism ; Insulin-Like Growth Factor II/analysis/metabolism ; Iodide Peroxidase/blood/metabolism ; Leptin/blood/metabolism ; Male ; Methimazole/therapeutic use ; Middle Aged ; Somatomedins/*analysis ; Thyroid Hormones/blood/metabolism ; Thyrotoxicosis/*drug therapy/metabolism ; }, abstract = {OBJECTIVE: Hyperthyroidism is associated with altered growth hormone (GH) secretion. Many patients with thyroid dysfunction experience several poorly described complications such as symptoms and signs also seen in patients with growth hormone deficiency (GHD). We have therefore prospectively evaluated a possible relationship between the thyroid function, body composition, leptin levels and insulin-like growth factor (IGF) related peptides in patients with Graves' disease. DESIGN, PATIENTS, AND MEASUREMENTS: In a prospective group of 24 fasting female patients with Graves' disease (mean age (CI 95%): 40 years (33-47)), we measured serum thyroxine, triiodothyronine, thyrotropine (TSH), TSH receptor antibodies, anti-thyroid peroxidase, leptin, body composition, body mass index (BMI) and IGF-related peptides at diagnosis and after 12 months of treatment with thiamazol (ATD).<br><br>RESULTS: In thyrotoxic patients IGF-I plus IGF-II correlated positively with IGFBP-3 at baseline (r = 0.90, p < 0.1 x 10(16)) and after 12 months follow-up (r = 0.87, p < 0.1 x 10(-16)). In the thyrotoxic state total IGF-I, IGF-II, IGF binding protein 3 (IGFBP-3) and acid-labile subunit (ALS) but not free IGF-I decreased significantly from 223 microg/L (189-260) (mean (CI 95%), 877 microg/L (801-953), 4165 microg/L (3772-4577) and 22 mg/L (18-26)) to 198 microg/L (172-226), 788 microg/L (711-865), 3431 microg/L (3135-3741) and 19 mg/L (16-26) (p <0.006), respectively, after 12 months of ATD despite an increase in BMI from 22 (21-23) to 23 kg/m(2) (22-25) (p < 0.0004) but no significant changes in leptin.<br><br>CONCLUSIONS: The complex IGF systems seemed intact in thyrotoxic patients but change in body composition and the regulation of leptin and insulin secretion during treatment of autoimmune thyroid disease influence IGF-related peptides leaving the patient in a state somewhat similar to partial GHD, but the mechanism behind these alterations remains unclear.}, }
@article {pmid15111001, year = {2004}, author = {Boillée, S and Cleveland, DW}, title = {Gene therapy for ALS delivers.}, journal = {Trends in neurosciences}, volume = {27}, number = {5}, pages = {235-238}, doi = {10.1016/j.tins.2004.03.002}, pmid = {15111001}, issn = {0166-2236}, support = {R37 NS027036/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Clinical Trials as Topic ; Dependovirus ; Disease Models, Animal ; Genetic Therapy/*methods ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects ; Somatomedins/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease that kills motor neurons. Despite a long disappointing history of human trials with neurotrophins, including insulin-like growth factor 1 (IGF-1), Kaspar and colleagues have successfully slowed disease in transgenic ALS mice by forcing motor neurons to produce IGF-1 following retrograde delivery of recombinant adeno-associated virus (AAV) injected into muscle. With the clinical safety of both IGF-1 and AAV already established, this provides real hope for an effective treatment of ALS.}, }
@article {pmid15106490, year = {2004}, author = {Hamann, J and Langer, B and Kalbhenn, E and Kissling, W}, title = {[Shared decision making--from a model project towards implementation].}, journal = {Zeitschrift fur arztliche Fortbildung und Qualitatssicherung}, volume = {98}, number = {2}, pages = {115-119}, pmid = {15106490}, issn = {1431-7621}, mesh = {Germany ; Humans ; Patient Participation/legislation &amp; jurisprudence/*psychology ; *Physician-Patient Relations ; }, abstract = {The model study "Shared Decision Making in the Treatment of Schizophrenia" has indicated both the positive prospects of increased patient involvement in treatment decisions and the potential barriers to subsequent implementation of this model in routine care. Thus an expert panel consisting of patients and professionals within the scope of the research program "Der Patient als Partner im medizinischen Entscheidungsprozess" [The Patient as a Partner in Clinical Decision Making] sponsored by the German Ministry of Health concluded that approaches to changing the physicians' behaviour alone will be insufficient to implement shared decision making. Rather, there is an urgent need to encourage and empower patients to claim their rights to information and participation.}, }
@article {pmid15102560, year = {2004}, author = {Weiss, MD and Weydt, P and Carter, GT}, title = {Current pharmacological management of amyotrophic [corrected] lateral sclerosis and a role for rational polypharmacy.}, journal = {Expert opinion on pharmacotherapy}, volume = {5}, number = {4}, pages = {735-746}, doi = {10.1517/14656566.5.4.735}, pmid = {15102560}, issn = {1465-6566}, support = {HB133B98008/HB/NHLBI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Anti-Inflammatory Agents/administration &amp; dosage/therapeutic use ; Antioxidants/administration &amp; dosage/therapeutic use ; Apoptosis/drug effects ; Clinical Trials as Topic ; Disease Models, Animal ; Drug Delivery Systems ; Excitatory Amino Acid Antagonists/administration &amp; dosage/therapeutic use ; Humans ; Mice ; Mice, Transgenic ; Nerve Growth Factors/administration &amp; dosage/therapeutic use ; *Polypharmacy ; }, abstract = {Amyotrophic [corrected] lateral sclerosis (ALS) is a progressive degenerative condition of motor neurons that is ultimately fatal. Even though scientific discovery over the past few decades has led to a greater understanding of the pathogenic mechanisms of ALS, effective pharmacotherapy intended to slow, arrest or reverse the disease progression remains difficult to obtain. Riluzole, a drug that has only modest benefit in extending survival, is still the only medication approved by the FDA for the treatment of ALS. However, a number of pharmacological agents are currently being investigated as potential therapy for ALS. This paper will review the pathophysiology of ALS and current pharmacological management of the disease and recent directions in research and clinical trials. Based on the available data, it is our opinion that combination drug therapies should be considered for future clinical trials.}, }
@article {pmid15094866, year = {1998}, author = {Vos, PE and Koppeschaar, HP and de Vries, WR and Wokke, JH}, title = {Insulin-like growth factor-I: clinical studies.}, journal = {Drugs of today (Barcelona, Spain : 1998)}, volume = {34}, number = {1}, pages = {79-90}, doi = {10.1358/dot.1998.34.1.485208}, pmid = {15094866}, issn = {1699-3993}, abstract = {Insulin-like growth factor-I (IGF-I) has endocrine, autocrine and paracrine properties. Receptors for IGF-I are present on virtually all cell types but are located mainly on cells of mesenchymal origin, such as fibroblasts, chondrocytes and osteoblasts. Growth hormone (GH)-dependent and GH-independent actions of IGF-I have been implicated in normal and abnormal bone growth, diabetes mellitus, malnutrition, cancer, thyroid disease and hematological diseases. The availability of recombinant human IGF-I (rhIGF-I) has led to new treatments for GH-resistant Laron dwarfism and certain diseases associated with severe insulin resistance. IGF-I has recently been investigated as a neurotrophic factor. Phase II efficacy trials with patients with neurological disease such as traumatic brain injury, myotonic dystrophy and amyotrophic lateral sclerosis have shown that rhIGF-I has efficacy on various outcome parameters. Treatment with rhIGF-I may result in reversible side effects of which increased heart rate, papilledema, ophthalmologic and intracranial hypertension, facial and generalized edema, and weight gain are noteworthy.}, }
@article {pmid15083302, year = {2004}, author = {Veldink, JH and Van den Berg, LH and Wokke, JH}, title = {The future of motor neuron disease: the challenge is in the genes.}, journal = {Journal of neurology}, volume = {251}, number = {4}, pages = {491-500}, doi = {10.1007/s00415-004-0322-6}, pmid = {15083302}, issn = {0340-5354}, mesh = {Forecasting ; Genomics/*methods/*trends ; Humans ; Motor Neuron Disease/classification/diagnosis/*genetics/*therapy ; }, abstract = {Adult-onset motor neuron disease (MND) includes sporadic and familial forms of amyotrophic lateral sclerosis (ALS), lower motor neuron disease including progressive and segmental spinal muscular atrophy (LMND) and primary lateral sclerosis (PLS). ALS/MND can be considered to be a spectrum of neurodegenerative diseases characterised by a preferential degeneration of upper and/or lower motor neurons. ALS and LMND have a complex multifactorial aetiology and a large clinical variability. This combination warrants an increasing genomics approach in future research. Genomics is the structural and functional study of genomes--i. e. the complete set of chromosomes and the genes they contain. Several methods may help to understand gene functions, and every method has led to its own "omics". The study of the complex relationship between on the one hand genomics data, transcriptomics data, proteomics data, and interactomics data and on the other hand the phenotype, is called "phenomics". In phenomics, the extensive and detailed phenotyping by the clinician is a prerequisite for meaningful associations. As a consequence, in ALS/MND clinicians have the task to agree about different clinical subtypes in order to make these associations and hence to gain further insight into the complex pathogenesis and identification of diagnostic markers in ALS/MND. Also, several new approaches in the treatment of ALS/MND are here discussed, including the viral delivery of protective compounds, RNA-interference, and stem cell therapy. Further, we argue that a future challenge is to allow for patients to have early access to multidisciplinary centres with specialist knowledge of ALS/MND. These centres can apply specific models of care for people with ALS/MND, but must be designed in a patient-centred format. Ultimately, these models should be assessed according to their outcomes.}, }
@article {pmid15075439, year = {2004}, author = {Lorenzl, S and Calingasan, N and Yang, L and Albers, DS and Shugama, S and Gregorio, J and Krell, HW and Chirichigno, J and Joh, T and Beal, MF}, title = {Matrix metalloproteinase-9 is elevated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice.}, journal = {Neuromolecular medicine}, volume = {5}, number = {2}, pages = {119-132}, pmid = {15075439}, issn = {1535-1084}, mesh = {Animals ; Cell Death/drug effects/physiology ; Corpus Striatum/*enzymology/physiopathology ; Disease Models, Animal ; Dopamine/metabolism ; Enzyme Inhibitors/pharmacology ; Immunohistochemistry ; Male ; Matrix Metalloproteinase 9/*metabolism ; Matrix Metalloproteinase Inhibitors ; Mice ; Mice, Inbred C57BL ; Microglia/drug effects/enzymology ; Neurons/drug effects/enzymology ; Parkinsonian Disorders/*enzymology/physiopathology ; Reaction Time/drug effects/physiology ; Substantia Nigra/*enzymology/physiopathology ; Tyrosine 3-Monooxygenase/metabolism ; Up-Regulation/drug effects/*physiology ; }, abstract = {Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading components of the extracellular matrix. Recent evidence has implicated MMPs in the pathogenesis of neurodegenerative diseases as Alzheimer's disease and amyotrophic lateral sclerosis. In this study, we investigated the involvement of MMP-9 (gelatinase B) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease using zymography, immunohistochemistry, and Western blot analysis. The activity of MMP-9 was upregulated at 3 h after MPTP injection in the striatum and after 24 h in the substantia nigra. Although MMP-9 expression decreased in the striatum by 72 h, it remained elevated in the substantia nigra compared to controls up to 7 d after MPTP administration. Immunohistochemistry showed that neurons and microglia are the source of MMP-9 expression after MPTP administration to mice. Treatment with a hydroxamate-based MMP inhibitor, Ro 28-2653 significantly reduced dopamine depletion and loss of tyrosine hydroxylase immunoreactive neurons in the substantia nigra pars compacta. MMP-9 expression as measured via zymography in the substantia nigra was reduced by the MMP inhibitor. These results indicate that MMP-9 is induced after MPTP application in mice and that pharmacologic inhibition of MMPs protects against MPTP neurotoxicity.}, }
@article {pmid15068700, year = {2004}, author = {Cova, L and Ratti, A and Volta, M and Fogh, I and Cardin, V and Corbo, M and Silani, V}, title = {Stem cell therapy for neurodegenerative diseases: the issue of transdifferentiation.}, journal = {Stem cells and development}, volume = {13}, number = {1}, pages = {121-131}, doi = {10.1089/154732804773099326}, pmid = {15068700}, issn = {1547-3287}, mesh = {Animals ; *Cell Differentiation ; Cell Division ; Cell Fusion ; Humans ; Nerve Growth Factors/metabolism ; Neurodegenerative Diseases/*therapy ; Stem Cell Transplantation/*methods ; Stem Cells/*cytology ; }, abstract = {In the past few years research on stem cells has exploded as a tool to develop potential therapies to treat incurable neurodegenerative diseases. Stem cell transplantation has been effective in several animal models, but the underlying restorative mechanisms are still unknown. Several events such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation (adult cell acquisition of new unexpected identities) may explain therapeutic success, in addition to replacement of lost cells. This issue needs to be clarified further to maximize the potential for effective therapies. Preliminary stem transplantation trials have already been performed for some neurodegenerative diseases. There is no effective pharmacological treatment for amyotrophic lateral sclerosis, but recent preliminary data both in experimental and clinical settings have targeted it as an ideal candidate disease for the development of stem cell therapy in humans. This review summarizes recent advances gained in stem cell research applied to neurodegenerative diseases with a special emphasis to the criticisms put forward.}, }
@article {pmid15060856, year = {2004}, author = {Vilke, GM and Smith, AM and Ray, LU and Steen, PJ and Murrin, PA and Chan, TC}, title = {Airway obstruction in children aged less than 5 years: the prehospital experience.}, journal = {Prehospital emergency care}, volume = {8}, number = {2}, pages = {196-199}, doi = {10.1016/j.prehos.2003.12.014}, pmid = {15060856}, issn = {1090-3127}, mesh = {Age Factors ; Airway Obstruction/epidemiology/*etiology/*therapy ; Child, Preschool ; Emergency Medical Services/methods ; Emergency Medical Technicians/education ; Emergency Treatment/*methods ; Humans ; Infant ; Infant, Newborn ; Parents/education ; }, abstract = {BACKGROUND: Treatment of choking in children has been well studied, but few data are available on the various causes of the choking episodes in the pediatric population.<br><br>OBJECTIVES: To assess frequency and to stratify etiologies of children less than 5 years of age who had a 911 advanced life support (ALS) ambulance response for airway obstruction.<br><br>METHODS: A prehospital database was searched and information was collected defining type of obstruction, age of the child, parents' action, paramedic treatment, and incident outcome.<br><br>RESULTS: There were 182 patients with airway obstruction under 5 years of age, of whom 99 (55%) were less than 1 year old. Liquid obstructions (i.e., formula, juices) were most common in the youngest children, whereas solid food and nonfood solid obstructions were most prevalent in children over 1 year old. One hundred seven (59%) of these obstructions resolved before paramedic arrival (69% of liquid obstructions, 72% of food, and 36% of nonfood solid objects). Interventions used by parents included bulb suction (3%), finger sweeps (6%), Heimlich maneuver (3%), and back blows (12%). Paramedics used ALS skills in only three cases. After paramedic evaluation, 47% of parents refused transport against medical advice (AMA).<br><br>CONCLUSIONS: Although most episodes of pediatric airway obstruction will have been resolved by the time of paramedic arrival, age-specific and item-specific treatment skills need to be reinforced with parents and prehospital providers.}, }
@article {pmid15056438, year = {2004}, author = {Alvarez-Lerma, F and Palomar, M and Olaechea, P and León, C and Sánchez, M and Bermejo, B and , }, title = {[Observational study investigating the use of levofloxacin in ICU patients].}, journal = {Enfermedades infecciosas y microbiologia clinica}, volume = {22}, number = {4}, pages = {220-226}, doi = {10.1016/s0213-005x(04)73070-0}, pmid = {15056438}, issn = {0213-005X}, mesh = {Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Anti-Infective Agents/administration &amp; dosage/adverse effects/*therapeutic use ; Arrhythmias, Cardiac/chemically induced ; Bacterial Infections/*drug therapy/microbiology ; Chemical and Drug Induced Liver Injury/etiology ; Community-Acquired Infections/*drug therapy/microbiology ; Comorbidity ; Critical Care/*statistics &amp; numerical data ; Cross Infection/drug therapy/microbiology ; Diarrhea/chemically induced ; Drug Resistance ; Drug Therapy, Combination/administration &amp; dosage/therapeutic use ; Drug Utilization/statistics &amp; numerical data ; Female ; Humans ; Infusions, Parenteral ; Intensive Care Units/statistics &amp; numerical data ; *Levofloxacin ; Male ; Middle Aged ; Ofloxacin/administration &amp; dosage/adverse effects/*therapeutic use ; Prospective Studies ; Respiration, Artificial ; Respiratory Tract Infections/drug therapy/microbiology ; Spain/epidemiology ; }, abstract = {INTRODUCTION: There is little information on the use of levofloxacin, a new quinolone, in ICU patients.<br><br>OBJECTIVE: To investigate the criteria for the use of levofloxacin (indications, forms of prescription, doses, and routes of administration) and to study tolerance in patients admitted to the ICU. Method. Prospective, observational study performed from October 2000 to November 2001 in 35 ICUs and including the first 15 patients receiving levofloxacin as monotherapy or combined treatment. Descriptive data are expressed as mean and percentage. Statistical significance was set at P < .05.<br><br>RESULTS: A total of 543 indications for treatment with levofloxacin were analyzed. The patients were 70.7% men, with a mean (SD) age of 60.2 (16.7) years, mean APACHE II score of 18.9 (7.9), and a medical underlying disease in 79.2% of cases. The ICU mortality rate was 24.1%. A total of 60% of patients required mechanical ventilation and 44.3% needed inotropic drug treatment. Levofloxacin was predominantly prescribed for treating community-acquired infections (67.8%), mainly in the respiratory tract (88.1%). An etiological diagnosis was established in only 55.6% of cases. The most common pathogens were Streptococcus pneumoniae (12.7%), Haemophilus influenzae (9.1%), Escherichia coli (7.4%), methicillin-sensitive Staphylococcus aureus (7.2%), Pseudomonas aeruginosa (4.9%), and Legionella pneumophila (4.7%). In 87.1% of indications, levofloxacin was prescribed as empirical treatment. Susceptibility of the isolated pathogens to this antibiotic was confirmed in 32.2% of cases. The initial dose was 500 mg/24 h in 48.5% of indications and 500 mg/12 h in 48.3%. Combined treatment was given in 49.7% of cases. In 32.2% of cases, parenteral administration of levofloxacin was changed to oral route. Adverse events probably or possibly associated with levofloxacin occurred in only 12.5% of patients and mainly included increased ALT/ALS levels (4.4%), diarrhea (2.3%), and heart rhythm alterations (2.1%).<br><br>CONCLUSIONS: This study describes the profile of critically ill patients receiving levofloxacin and the different forms of its use in the ICU.}, }
@article {pmid15055508, year = {2004}, author = {Amtmann, D and Weydt, P and Johnson, KL and Jensen, MP and Carter, GT}, title = {Survey of cannabis use in patients with amyotrophic lateral sclerosis.}, journal = {The American journal of hospice &amp; palliative care}, volume = {21}, number = {2}, pages = {95-104}, doi = {10.1177/104990910402100206}, pmid = {15055508}, issn = {1049-9091}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy ; *Cannabis ; Female ; Humans ; Male ; Marijuana Smoking ; Middle Aged ; *Palliative Care ; *Phytotherapy ; Plant Preparations/pharmacology/*therapeutic use ; }, abstract = {Cannabis (marijuana) has been proposed as treatment for a widening spectrum of medical conditions and has many properties that may be applicable to the management of amyotrophic lateral sclerosis (ALS). This study is the first, anonymous survey of persons with ALS regarding the use of cannabis. There were 131 respondents, 13 of whom reported using cannabis in the last 12 months. Although the small number of people with ALS that reported using cannabis limits the interpretation of the survey findings, the results indicate that cannabis may be moderately effective at reducing symptoms of appetite loss, depression, pain, spasticity, and drooling. Cannabis was reported ineffective in reducing difficulties with speech and swallowing, and sexual dysfunction. The longest relief was reported for depression (approximately two to three hours).}, }
@article {pmid15054949, year = {2004}, author = {van den Berg, LH and van den Berg, JP and Mathus-Vliegen, EM and Kampelmacher, MJ and van Kesteren, RG and Jennekens, FG}, title = {[The symptomatic treatment of amyotrophic lateral sclerosis].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {148}, number = {11}, pages = {513-518}, pmid = {15054949}, issn = {0028-2162}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*therapy ; Deglutition Disorders/etiology/prevention &amp; control ; Dysarthria/etiology/prevention &amp; control ; Dyspnea/etiology/prevention &amp; control ; Humans ; Muscle Weakness/etiology/prevention &amp; control ; Pain/etiology/prevention &amp; control ; *Palliative Care ; Sialorrhea/etiology/prevention &amp; control ; Weight Loss ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) have symptoms of progressive muscle weakness, of disturbed speech and swallowing, and in the terminal phase those of respiratory weakness. Treatment options, in particular those for excessive weight loss and respiratory weakness, should be introduced to the patients and their families when the patient is emotionally capable and before dysarthria severely hampers communication. Special equipment for keeping the patient as mobile as possible should be made available much earlier than in the case of other diseases of the muscles as in ALS progression is much faster. Cramps, pathological crying or laughter, spasms, and spasticity can all be treated by medication. When speech can no longer be understood, adaptive strategies such as sign language, mime, posture and communication apparatus varying from a note pad to advanced computer systems can be used. Sialorrhoea, caused by difficulty swallowing with its accompanying danger of aspiration can be halted by the use of medication, by radiotherapy and by the injection into the salivary glands of botulin A toxin. Weight loss, also a result of dysphagia, can be avoided by eating frequent small meals or if necessary performing a percutaneous endoscopic or radiological gastroscopy. Excess mucus in the respiratory tract can be treated with anticholinergics. Difficulty in coughing up thick and sticky mucus cannot always be adequately helped. Respiratory weakness is treatable by external respiratory supportive therapy using a nasal mask, as well as invasive respiratory support via a trachcostoma and by treating the symptoms of respiratory weakness. The latter form of treatment is palliative and forms part of terminal care. During the terminal phase restlessness, anxiety, pain, and dyspnoea require the most attention. Treatment requires careful multidisciplinary cooperation.}, }
@article {pmid15052622, year = {2004}, author = {Van den Bergh, PY and Piéret, F}, title = {Electrodiagnostic criteria for acute and chronic inflammatory demyelinating polyradiculoneuropathy.}, journal = {Muscle &amp; nerve}, volume = {29}, number = {4}, pages = {565-574}, doi = {10.1002/mus.20022}, pmid = {15052622}, issn = {0148-639X}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Child ; Demyelinating Diseases/diagnosis/physiopathology ; Diagnosis, Differential ; *Electrodiagnosis ; Female ; Guillain-Barre Syndrome/*diagnosis/physiopathology ; Humans ; Male ; Middle Aged ; Motor Neurons/physiology ; Neural Conduction/physiology ; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/*diagnosis/physiopathology ; Sex Characteristics ; }, abstract = {Electrodiagnosis plays an important role in the early detection and characterization of inflammatory demyelinating polyradiculoneuropathies, because timely treatment reduces morbidity and disability. The challenge consists of defining electrodiagnostic criteria that are highly specific for primary demyelination but sufficiently sensitive to be useful in clinical practice. We compared 10 published sets of criteria in 53 patients with demyelinating Guillain-Barré syndrome (GBS) and 28 with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Specificity of criteria sets was tested in 40 patients with amyotrophic lateral sclerosis (ALS) and 32 with diabetic polyneuropathy (DPN). Sensitivity ranged from 24 to 83% (mean, 54.3%) in GBS and 39 to 89% (mean, 64.9%) in CIDP. With regard to ALS, specificity was 100% for nine sets but was 97% in one. In contrast, 3-66% of DPN patients fulfilled criteria in eight of ten sets. We propose a set of criteria with 72% and 75% sensitivity in our GBS and CIDP patient series, respectively, and 100% specificity with regard to ALS and DPN. Our data illustrate that most, but not all, patients can be electrodiagnostically ascertained.}, }
@article {pmid15049516, year = {2004}, author = {Frizzo, ME and Dall'Onder, LP and Dalcin, KB and Souza, DO}, title = {Riluzole enhances glutamate uptake in rat astrocyte cultures.}, journal = {Cellular and molecular neurobiology}, volume = {24}, number = {1}, pages = {123-128}, pmid = {15049516}, issn = {0272-4340}, mesh = {Animals ; Animals, Newborn ; Astrocytes/*drug effects/metabolism ; Brain Ischemia/drug therapy/metabolism/physiopathology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Glutamic Acid/*metabolism/pharmacokinetics ; Neurodegenerative Diseases/drug therapy/metabolism/physiopathology ; Neuroprotective Agents/*pharmacology ; Rats ; Rats, Wistar ; Riluzole/*pharmacology ; Synapses/*drug effects/metabolism ; Synaptic Transmission/*drug effects/physiology ; }, abstract = {1. Riluzole is used for the treatment of amyotrophic lateral sclerosis and reported to have neuroprotective effects in animal models of Parkinson's disease, Huntington's disease, and brain ischemia. The neuroprotective action of riluzole has been attributed to its ability to inhibit glutamate release (A. Doble, Neurology 47(4):233S-241S, 1996). 2. The effect of riluzole on L-[2,3-3H] glutamate uptake was investigated in rat cortical astrocyte cultures. 3. Riluzole showed a biphasic concentration-dependent effect on basal glutamate uptake. At low concentrations (1 and 10 microM) riluzole significantly increased glutamate uptake, whereas from 100 microM promoted a slight reduction. 4. Considering the large range of glutamate levels in the synaptic cleft, we studied the 1 microM riluzole effect on uptake of glutamate at different concentrations (1-1000 microM). Riluzole was more effective at low glutamate concentrations (10 microM), enhancing the basal glutamate uptake up to 42%. 5. The action of riluzole on astrocytic glutamate uptake could be an additional mechanism to its neuroprotective role, perhaps suggesting a modulatory action on glutamatergic system involving glutamate clearance from synaptic cleft.}, }
@article {pmid15043813, year = {2004}, author = {Corcoran, LJ and Mitchison, TJ and Liu, Q}, title = {A novel action of histone deacetylase inhibitors in a protein aggresome disease model.}, journal = {Current biology : CB}, volume = {14}, number = {6}, pages = {488-492}, doi = {10.1016/j.cub.2004.03.003}, pmid = {15043813}, issn = {0960-9822}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; COS Cells ; Cell Fractionation ; Chlorocebus aethiops ; DNA Primers ; Disease Models, Animal ; Dynactin Complex ; Green Fluorescent Proteins ; *Histone Deacetylase Inhibitors ; Hydroxylamines/*pharmacology ; Immunoblotting ; Inclusion Bodies/*metabolism ; Luminescent Proteins/metabolism ; Microtubule-Associated Proteins/metabolism ; Microtubule-Organizing Center/metabolism ; Quinolines/*pharmacology ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; }, abstract = {Protein inclusions are associated with a number of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Whether protein aggregates are toxic or beneficial to cells is not known. In ALS animal models, mutant SOD1 forms aggresome-like structures in motor neurons and astrocytes. To better understand the role of protein aggregation in the progression of disease etiology, we performed a screen for small molecules that disrupt aggresome formation in cultured cells. After screening 20,000 compounds, we obtained two groups of compounds that specifically prevented aggresome formation. One group consists mainly of cardiac glycosides and will be the subject of another study. The second group contains two compounds: one is a known histone deacetylase (HDAC) inhibitor, Scriptaid, and the other is a Flavin analog, DPD. Cells treated with these molecules still contained microaggregates, but these microaggregates were not transported to microtubule organizing centers (MTOCs). The defect in transport was linked to modulation of the dynein/dynactin machinery as treatment with Scriptaid or DPD reversed mSOD-induced insolubilization of the dynactin subunits P50 dynamitin and P150(glued). Our findings suggest a connection between HDAC activity and aggresome formation and also lay the groundwork for a direct test of the role of aggresome formation in ALS etiology.}, }
@article {pmid15034941, year = {2004}, author = {Turner, BJ and Lopes, EC and Cheema, SS}, title = {Inducible superoxide dismutase 1 aggregation in transgenic amyotrophic lateral sclerosis mouse fibroblasts.}, journal = {Journal of cellular biochemistry}, volume = {91}, number = {5}, pages = {1074-1084}, doi = {10.1002/jcb.10782}, pmid = {15034941}, issn = {0730-2312}, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Amyotrophic Lateral Sclerosis/*enzymology/genetics/metabolism ; Animals ; Animals, Newborn ; Blotting, Western ; Cell Survival/drug effects/genetics ; Chelating Agents/pharmacology ; Chlorides/pharmacology ; Copper/metabolism/pharmacology ; Detergents/chemistry ; Disease Models, Animal ; Ditiocarb/pharmacology ; Fibroblasts/cytology/drug effects/*metabolism ; Humans ; Immunohistochemistry ; Mice ; Mice, Transgenic ; Minocycline/pharmacology ; Mutation/genetics ; Oxidative Stress ; Paraquat/pharmacology ; Peroxynitrous Acid/pharmacology ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Inhibitors ; Protein Binding/drug effects ; Solubility ; Spinal Cord/chemistry ; Superoxide Dismutase/chemistry/genetics/*metabolism ; Superoxide Dismutase-1 ; Zinc Compounds/pharmacology ; }, abstract = {High molecular weight detergent-insoluble complexes of superoxide dismutase 1 (SOD1) enzyme are a biochemical abnormality associated with mutant SOD1-linked familial amyotrophic lateral sclerosis (FALS). In the present study, SOD1 protein from spinal cords of transgenic FALS mice was fractionated according to solubility in saline, zwitterionic, non-ionic or anionic detergents. Both endogenous mouse SOD1 and mutant human SOD1 were least soluble in SDS, followed by NP-40 and CHAPS, with an eight-fold greater detergent resistance of mutant protein overall. Importantly, high molecular weight mutant SOD1 complexes were isolated with SDS-extraction only. To reproduce SOD1 aggregate pathology in vitro, primary fibroblasts were isolated and cultured from neonatal transgenic FALS mice. Fibroblasts expressed abundant mutant SOD1 without spontaneous aggregation over time with passage. Proteasomal inhibition of cultures using lactacystin induced dose-dependent aggregation and increased the SDS-insoluble fraction of mutant SOD1, but not endogenous SOD1. In contrast, paraquat-mediated superoxide stress in fibroblasts promoted aggregation of endogenous SOD1, but not mutant SOD1. Treatment of cultures with peroxynitrite or the copper chelator diethyldithiocarbamate (DDC) alone did not modulate aggregation. However, DDC inhibited lactacystin-induced mutant SOD1 aggregation in transgenic fibroblasts, while exogenous copper slightly augmented aggregation. These data suggest that SOD1 aggregates may derive from proteasomal or oxidation-mediated oligomerisation pathways from mutant and endogenous subunits respectively. Furthermore, these pathways may be affected by copper availability. We propose that non-neural cultures such as these transgenic fibroblasts with inducible SOD1 aggregation may be useful for rapid screening of compounds with anti-aggregation potential in FALS.}, }
@article {pmid15034853, year = {2004}, author = {Bryant, PR and Geis, CC and Moroz, A and O'neill, BJ and Bogey, RA}, title = {Stroke and neurodegenerative disorders. 4. Neurodegenerative disorders.}, journal = {Archives of physical medicine and rehabilitation}, volume = {85}, number = {3 Suppl 1}, pages = {S21-33}, doi = {10.1053/j.apmr.2003.12.007}, pmid = {15034853}, issn = {0003-9993}, mesh = {Amyotrophic Lateral Sclerosis/complications/*diagnosis/*therapy ; Diagnosis, Differential ; Humans ; Multiple Sclerosis/complications/*diagnosis/*therapy ; Parkinson Disease/complications/*diagnosis/*therapy ; }, abstract = {UNLABELLED: This self-directed learning module highlights diagnosis, treatment, and rehabilitation issues in patients with neurodegenerative disorders, including multiple sclerosis (MS), Parkinson's disease, and amyotrophic lateral sclerosis (ALS). It is part of the study guide on stroke and neurodegenerative disorders in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article specifically focuses on the differential diagnosis, diagnostic evaluation, medical management, and rehabilitation issues in MS. Similarly, the differential diagnosis treatment and rehabilitation in Parkinson's disease is discussed. Electrodiagnosis, pharmacologic treatment, and rehabilitation options for ALS are also discussed.<br><br>OVERALL ARTICLE OBJECTIVES: To review the differential diagnosis, evaluation, medical treatment, and rehabilitation management of patients with MS, Parkinson's disease, and ALS.}, }
@article {pmid15034571, year = {2004}, author = {Kieran, D and Kalmar, B and Dick, JR and Riddoch-Contreras, J and Burnstock, G and Greensmith, L}, title = {Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice.}, journal = {Nature medicine}, volume = {10}, number = {4}, pages = {402-405}, doi = {10.1038/nm1021}, pmid = {15034571}, issn = {1078-8956}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/pathology/physiopathology ; Animals ; Disease Progression ; Heat-Shock Proteins/*biosynthesis ; Humans ; Hydroxylamines/pharmacology/*therapeutic use ; Mice ; Mice, Transgenic ; Motor Neurons/pathology ; Mutation ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in which motoneurons of the spinal cord and motor cortex die, resulting in progressive paralysis. This condition has no cure and results in eventual death, usually within 1-5 years of diagnosis. Although the specific etiology of ALS is unknown, 20% of familial cases of the disease carry mutations in the gene encoding Cu/Zn superoxide dismutase-1 (SOD1). Transgenic mice overexpressing human mutant SOD1 have a phenotype and pathology that are very similar to that seen in human ALS patients. Here we show that treatment with arimoclomol, a coinducer of heat shock proteins (HSPs), significantly delays disease progression in mice expressing a SOD1 mutant in which glycine is substituted with alanine at position 93 (SOD1(G93A)). Arimoclomol-treated SOD1(G93A) mice show marked improvement in hind limb muscle function and motoneuron survival in the later stages of the disease, resulting in a 22% increase in lifespan. Pharmacological activation of the heat shock response may therefore be a successful therapeutic approach to treating ALS, and possibly other neurodegenerative diseases.}, }
@article {pmid15027066, year = {2004}, author = {Naumann, M and Jost, W}, title = {Botulinum toxin treatment of secretory disorders.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {19 Suppl 8}, number = {}, pages = {S137-41}, doi = {10.1002/mds.20067}, pmid = {15027066}, issn = {0885-3185}, mesh = {Anti-Dyskinesia Agents/*therapeutic use ; Axilla/innervation ; Botulinum Toxins/*therapeutic use ; Hand/innervation ; Humans ; Hyperhidrosis/drug therapy ; Parkinson Disease/drug therapy ; Salivary Gland Diseases/*drug therapy ; Sialorrhea/drug therapy ; }, abstract = {Botulinum neurotoxin serotype A (BoNT/A) has revolutionised the treatment of a variety of autonomic hypersecretory disorders. Several open and controlled studies indicate that BoNT/A is a safe and effective treatment for focal hyperhidrosis of the axillae and palms, for gustatory sweating, and for some other rare conditions associated with focal hyperhidrosis. There is class I evidence for the efficacy of botulinum toxin in axillary hyperhidrosis and class II evidence for palmar hyperhidrosis and gustatory sweating. BoNT/A has the potential to replace current invasive and surgical techniques and should at least be considered as a viable alternative. The results of pilot studies to treat sialorrhea are encouraging. However, the optimal dose, best mode of application, side effects, and duration of BoNT/A action in this condition remain uncertain. We need further formal clinical trials to evaluate risks and benefits of BoNT/A for palliative treatment in of sialorrhea in Parkinson's disease and in bulbar amyotrophic lateral sclerosis. Based on the few reports published, BoNT/A injections into the lacrimal gland for hyperlacrimation may be an elegant method to treat this sometimes disabling condition. Again, larger studies are needed to evaluate the risks and long-term benefits of this treatment option.}, }
@article {pmid15002737, year = {2004}, author = {Iwasaki, Y and Ichikawa, Y and Igarashi, O and Konno, S and Aoyagi, J and Ikeda, K and Marabuchi, S and Ono, S and Iguchi, H and Kawabe, K and Fujioka, T}, title = {T-588 protects motor neuron death following axotomy.}, journal = {Neurochemical research}, volume = {29}, number = {2}, pages = {403-406}, pmid = {15002737}, issn = {0364-3190}, mesh = {Animals ; Animals, Newborn ; *Axotomy ; Cell Survival/drug effects ; Denervation ; Diethylamines/administration &amp; dosage/*pharmacology ; In Vitro Techniques ; Injections, Intraperitoneal ; Lumbar Vertebrae ; Motor Neurons/*drug effects/*physiology ; Nerve Growth Factors/administration &amp; dosage/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Sciatic Nerve ; Spinal Cord/cytology/drug effects/physiology ; Thiophenes/administration &amp; dosage/*pharmacology ; }, abstract = {R(-)-1-(benzo [b] thiophen-5-yl)-2-[2-(N,N-diethylamino)ethoxy] ethanol hydrochloride) (T-588) enhances acetylcholine release. This compound slows the motor deterioration of wobbler mouse motor neuron disease and enhances neurite outgrowth and choline acetyltransferase activity in cultured rat spinal motor neurons. We examined the ability of T-588 on axotomized spinal motor neuron death in the rat spinal cord. After the postnatal unilateral section of sciatic nerve, there was approximately a 50% survival of motor neurons in the fourth lumbar segment. In comparison with vehicle, intraperitoneal injection of T-588 for 14 consecutive days rescued spinal motor neuron death. Our results showing in vivo neurotrophic activity of T-588 for motor neurons support the applicability of T-588 for the treatment of motor neuron diseases, such as amyotrophic lateral sclerosis and motor neuropathies.}, }
@article {pmid14999909, year = {2004}, author = {Yamane, K}, title = {[Terminal care in the Department of Neurology].}, journal = {Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics}, volume = {41}, number = {1}, pages = {35-38}, doi = {10.3143/geriatrics.41.35}, pmid = {14999909}, issn = {0300-9173}, mesh = {Activities of Daily Living ; Aged ; *Amyotrophic Lateral Sclerosis/nursing ; Home Care Services ; Humans ; Neuromuscular Diseases/nursing ; *Parkinson Disease/nursing ; *Patient Care Team ; Quality of Life ; *Spinocerebellar Degenerations/nursing ; Terminal Care/*methods ; }, abstract = {Patients in the Department of Neurology undergoing treatment for disorders such as cerebrovascular disease, dementia, metabolic disease, neuromuscular disease and intractable disease, are included as subjects requiring terminal care. Intractable diseases ware defined by the Ministry of Health and Welfare (Ministry of Health, Welfare and Labor) in 1972 as being of unknown etiology, untreatable, chronically progressive and sometimes worsened by the care provided when nursing these patients. Intractable diseases in the Department of Neurology rank with those seen in other departments. Amyotrophic lateral sclerosis is the most difficult to treat due to the lack of effective drugs. On the other hand, Parkinson disease is the most treatable among intractable diseases in the Department of Neurology with the appearance of several new effective drugs. TRH (thyrotropin releasing hormone) is effective for ataxic gait in some patients with spinocerebellar degeneration. In the terminal care of intractable diseases in the Department of Neurology, common problems such as disturbances of swallowing, respiration and speaking develop in almost all patients and measures must be taken to treat these disturbances. Artificial respiration must be considered for respiratory distress. Artificial feeding by intubation must be considered for swallowing disturbance. All kinds of communication aids must be considered for speaking difficulties. The medical and nursing care team needs to manage these problems with consideration of the quality of life of the patients and their families as well as the complication of the diseases.}, }
@article {pmid14997748, year = {2004}, author = {Kawakami, M and Saji, S and Toi, M}, title = {[Controversies in endocrine therapy for breast cancer].}, journal = {Gan to kagaku ryoho. Cancer &amp; chemotherapy}, volume = {31}, number = {2}, pages = {181-187}, pmid = {14997748}, issn = {0385-0684}, mesh = {Anastrozole ; Androstadienes/therapeutic use ; Antineoplastic Agents, Hormonal/*therapeutic use ; *Aromatase Inhibitors ; Breast Neoplasms/*drug therapy/surgery ; Chemotherapy, Adjuvant ; Enzyme Inhibitors/*therapeutic use ; Estrogen Replacement Therapy ; Female ; Humans ; Letrozole ; Mastectomy, Segmental ; Neoplasms, Hormone-Dependent ; Nitriles/therapeutic use ; Postmenopause ; Randomized Controlled Trials as Topic ; Receptors, Estrogen/analysis ; Receptors, Progesterone/analysis ; Risk Factors ; Tamoxifen/therapeutic use ; Triazoles/therapeutic use ; }, abstract = {Major advances have been made in the treatment of postmenopausal women with hormone-sensitive breast cancer. Although tamoxifen has been the standard endocrine therapy for the past twenty years, the development of a third generation of aromatase inhibitors (Als), which effectively inhibit estrogen synthesis in extragonadal sites, gives us a wider range of choices in endocrine therapy. However, many questions remain with respect to the optimal use of Als. Differences between Als and tamoxifen as well as non-steroidal and steroidal Als in their long-term adverse effects on bone demineralization and lipid metabolism are only starting to emerge. The preferable orders for use of non-steroidal and steroidal Als, Als and pure anti-estrogen in patients with metastatic disease are emerging subjects to be examined, following several studies that showed non-cross reactivity between these types of drug. Neo-adjuvant endocrine therapy is now attempting to apply breast conserving surgery in larger numbers of elderly patients who are not suitable for neo-adjuvant chemotherapy. Moreover, many investigators are currently searching for surrogate markers in neo-adjuvant endocrine treatment that can predict the responsiveness and prognosis with adjuvant endocrine therapy. Further research concomitant with clinical trials may lead to a more reliable endocrine therapy modality in the treatment of breast cancer.}, }
@article {pmid14991690, year = {2004}, author = {Nomura, E and Katsuta, K and Ueda, T and Toriyama, M and Mori, T and Inagaki, N}, title = {Acid-labile surfactant improves in-sodium dodecyl sulfate polyacrylamide gel protein digestion for matrix-assisted laser desorption/ionization mass spectrometric peptide mapping.}, journal = {Journal of mass spectrometry : JMS}, volume = {39}, number = {2}, pages = {202-207}, doi = {10.1002/jms.578}, pmid = {14991690}, issn = {1076-5174}, mesh = {Alkanesulfonates/*chemistry ; Animals ; Cells, Cultured ; Electrophoresis, Gel, Two-Dimensional/*methods ; Peptide Mapping/*methods ; Proteomics/methods ; Rats ; Sodium Dodecyl Sulfate/*chemistry ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/*methods ; Surface-Active Agents/*chemistry ; }, abstract = {Mass spectrometry (MS) together with genome database searches serves as a powerful tool for the identification of proteins. In proteome analysis, mixtures of cellular proteins are usually separated by sodium dodecyl sulfate (SDS) polyacrylamide gel-based two-dimensional gel electrophoresis (2-DE) or one-dimensional gel electrophoresis (1-DE), and in-gel digested by a specific protease. In-gel protein digestion is one of the critical steps for sensitive protein identification by these procedures. Efficient protein digestion is required for obtaining peptide peaks necessary for protein identification by MS. This paper reports a remarkable improvement of protein digestion in SDS polyacrylamide gels using an acid-labile surfactant, sodium 3-[(2-methyl-2-undecyl-1,3-dioxolan-4-yl)methoxy]-1-propanesulfonate (ALS). Pretreatment of gel pieces containing protein spots separated by 2-DE with a small amount of ALS prior to trypsin digestion led to increases in the digested peptides eluted from the gels. Consistently, treatment of gel pieces containing silver-stained standard proteins and those separated from tissue extracts resulted in the detection of increased numbers of peptide peaks in spectra obtained by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOFMS). Hence the present protocol with ALS provides a useful strategy for sensitive protein identification by MS.}, }
@article {pmid14987785, year = {2004}, author = {Naess, AC and Steen, PA}, title = {Long term survival and costs per life year gained after out-of-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {60}, number = {1}, pages = {57-64}, doi = {10.1016/S0300-9572(03)00262-4}, pmid = {14987785}, issn = {0300-9572}, mesh = {Advanced Cardiac Life Support/economics ; Aged ; Ambulances/economics ; Coronary Care Units/economics ; Cost-Benefit Analysis ; Emergency Medical Services/economics ; Female ; Health Care Costs ; Heart Arrest/economics/*therapy ; Hospitalization/economics ; Humans ; Longitudinal Studies ; Male ; Mental Health Services/economics ; Middle Aged ; Norway ; Nursing Homes/economics ; Patient Discharge ; Quality-Adjusted Life Years ; Rehabilitation/economics ; Resuscitation/*economics ; Survival Rate ; }, abstract = {PURPOSE: To study long-term survival and estimate the costs per year of survival after out-of-hospital cardiac arrest of cardiac origin.<br><br>MATERIALS AND METHODS: Cardiac arrest patients treated by the physician-manned ambulance in Oslo from January 1971 to June 1992. The condition of the patient when discharged from hospital was noted and survival followed until June 2002. Costs of the Emergency Medical Service (EMS), hospital treatment, rehabilitation and nursing homes and psychiatric institutions after discharge from hospital were included in a cost-effectiveness analysis.<br><br>RESULTS: 1300 (42%) of 3065 patients receiving ALS were admitted to hospital after return of spontaneous circulation (ROSC). 1066 of these patients had a cardiac cause of the arrest, full hospital report and were found in the National Registry. Median age was 68 years (60-74) and 802 (75%) were men. 269 of the 1066 patients were discharged from hospital alive, 239 to their homes and 30 patients to rehabilitation/nursing homes or psychiatric institutions. The mean survival of the 1066 patients was 532 days. They spent mean 3.4 days in a CCU, 6.8 days in a general ward and 11.2 days in nursing/rehabilitation homes or psychiatric institutions. 30 patients were discharged to rehabilitation/nursing homes or psychiatric institutions. The mean survival time for the 269 patients discharged from hospital alive was 6.13 years. 110 patients were alive after five and 61 after 10 years. The cost per patient discharged alive was 40,642 or 6,632 per life year gained.<br><br>CONCLUSIONS: Cardiac arrest patients do not occupy intensive care beds too long, and few end up in a vegetative state. Methodological differences in different studies makes meaningful comparisons of costs difficult, but the costs per life year saved are not high compared to other publications.}, }
@article {pmid14981234, year = {2004}, author = {Maxwell, MM and Pasinelli, P and Kazantsev, AG and Brown, RH}, title = {RNA interference-mediated silencing of mutant superoxide dismutase rescues cyclosporin A-induced death in cultured neuroblastoma cells.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {101}, number = {9}, pages = {3178-3183}, pmid = {14981234}, issn = {0027-8424}, support = {R03 AG022152/AG/NIA NIH HHS/United States ; 5P01 AG12992-9/AG/NIA NIH HHS/United States ; P01 NS040828/NS/NINDS NIH HHS/United States ; P01 AG012992/AG/NIA NIH HHS/United States ; R03 AG 22152-01/AG/NIA NIH HHS/United States ; 5PO1 NS40828-02/NS/NINDS NIH HHS/United States ; }, mesh = {Base Sequence ; Cell Death/*drug effects/genetics ; Cell Survival/drug effects ; Cyclosporine/*toxicity ; DNA Primers ; DNA, Complementary/genetics ; *Gene Silencing ; HeLa Cells ; Humans ; Motor Neuron Disease/genetics ; Mutagenesis, Site-Directed ; Neuroblastoma/*genetics/pathology ; RNA, Small Interfering/*genetics ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Transfection ; Tumor Cells, Cultured ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder resulting from selective death of motor neurons in the brain and spinal cord. In approximately 25% of familial ALS cases, the disease is caused by dominantly acting point mutations in the gene encoding cytosolic Cu,Zn superoxide dismutase (SOD1). In cell culture and in rodent models of ALS, mutant SOD1 proteins exhibit dose-dependent toxicity; thus, agents that reduce mutant protein expression would be powerful therapeutic tools. A wealth of recent evidence has demonstrated that the mechanism of RNA-mediated interference (RNAi) can be exploited to achieve potent and specific gene silencing in vitro and in vivo. We have evaluated the utility of RNAi for selective silencing of mutant SOD1 expression in cultured cells and have identified small interfering RNAs capable of specifically inhibiting expression of ALS-linked mutant, but not wild-type, SOD1. We have investigated the functional effects of RNAi-mediated silencing of mutant SOD1 in cultured murine neuroblastoma cells. In this model, stable expression of mutant, but not wild-type, human SOD1 sensitizes cells to cytotoxic stimuli. We find that silencing of mutant SOD1 protects these cells against cyclosporin A-induced cell death. These results demonstrate a positive physiological effect caused by RNAi-mediated silencing of a dominant disease allele. The present study further supports the therapeutic potential of RNAi-based methods for the treatment of inherited human diseases, including ALS.}, }
@article {pmid14978757, year = {2004}, author = {Kremer, EJ}, title = {CAR chasing: canine adenovirus vectors-all bite and no bark?.}, journal = {The journal of gene medicine}, volume = {6 Suppl 1}, number = {}, pages = {S139-51}, doi = {10.1002/jgm.497}, pmid = {14978757}, issn = {1099-498X}, mesh = {Adenovirus Vaccines ; *Adenoviruses, Canine/immunology ; Animals ; Dogs ; Genes, Reporter ; *Genetic Therapy ; *Genetic Vectors/immunology ; Humans ; Mice ; Neurodegenerative Diseases/genetics ; Viral Hepatitis Vaccines/genetics/immunology ; }, abstract = {This review deals primarily with canine adenovirus serotype 2 (CAV-2) vectors and gives a simplified overview of how the various domains of virology, cellular and molecular biology, as well as immunology, come into play when trying to understand and ameliorate adenovirus (Ad)-mediated gene transfer. The generation of early region 1 (E1)-deleted (DeltaE1) CAV-2 vectors, the lack of pre-existing humoral immunity, trafficking, the use of the coxsackie B adenovirus receptor (CAR), the surprising neuronal tropism, and the ability to migrate via axons to afferent regions of the central and peripheral nervous system, are described. Due to these intrinsic properties, CAV-2 vectors may be powerful tools for the study of the pathophysiology and potential treatment of neurodegenerative diseases like lysosomal storage disorders, Parkinson's, Alzheimer's, Huntington's, amyotrophic lateral sclerosis, and others. Other potential uses include anti-tumoral and anti-viral vaccines, tracer of synaptic junctions, pain therapy, cancer therapy (e.g. K9 CRAds), and gene transfer to other somatic tissues.}, }
@article {pmid14977568, year = {2004}, author = {Ekshyyan, O and Aw, TY}, title = {Apoptosis in acute and chronic neurological disorders.}, journal = {Frontiers in bioscience : a journal and virtual library}, volume = {9}, number = {}, pages = {1567-1576}, doi = {10.2741/1357}, pmid = {14977568}, issn = {1093-9946}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; R01 DK044510-11/DK/NIDDK NIH HHS/United States ; DK 44510/DK/NIDDK NIH HHS/United States ; DK 43785/DK/NIDDK NIH HHS/United States ; }, mesh = {Acute Disease ; Animals ; *Apoptosis ; Brain Ischemia/pathology ; Caspases/metabolism ; Chronic Disease ; Humans ; Mice ; Nervous System Diseases/metabolism/*pathology ; Neurodegenerative Diseases/pathology ; Signal Transduction ; Stroke/pathology ; }, abstract = {Programmed cell death or apoptosis is a physiologically important process in neurogenesis wherein approximately 50% of the neurons apoptose during maturation of the nervous system. However, premature apoptosis and/or aberrations in apoptosis control contribute to the pathogenesis of a variety of neurological disorders including acute brain injury such as trauma, spinal cord injury, ischemic stroke and ischemia/reperfusion as well as chronic disease states such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, spinal muscular atrophy, and diabetic neuropathy. The current review will focus on two major topics, namely, the general concepts of our current understanding of the apoptosis death machinery, its mediators and regulation, and the relationship between aberrant apoptosis and genesis of neurodegenerative disorders. This knowledge of apoptosis mechanisms will underpin the basis for development of novel therapeutic strategies and treatment modalities that are directed at control of the neuronal apoptotic death program.}, }
@article {pmid14974059, year = {2004}, author = {Ashworth, NL and Satkunam, LE and Deforge, D}, title = {Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {1}, pages = {CD004156}, doi = {10.1002/14651858.CD004156.pub2}, pmid = {14974059}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; *Exercise Therapy ; Humans ; Muscle Spasticity/etiology/*therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Spasticity commonly affects patients with motor neuron disease and it is likely to contribute to worsening muscle dysfunction, increased difficulty with activities of daily living and deteriorating quality of life.<br><br>OBJECTIVES: The objective of this review is to systematically review all types of treatments for spasticity in amyotrophic lateral sclerosis, also known as motor neuron disease.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group specialised trials register (searched January 2003), MEDLINE (January 1966 to January 2003), EMBASE (January 1980 to January 2003), CINAHL (January 1982 to January 2003), AMED (January 1985 to January 2003) and LILACS (January 1982 to January 2003) for randomized controlled trials. We reviewed the bibliographies of the randomized trials identified, and contacted trial authors and known experts in the field.<br><br>SELECTION CRITERIA: We included quasi-randomized or randomized controlled trials of participants with probable or definite amyotrophic lateral sclerosis according to the El Escorial diagnostic criteria (or a revised version) or the Airlie House revision. We would have included trials of physical therapy, modalities, prescription medications, non-prescription medications, chemical neurolysis, surgical interventions, alternative therapies. Our primary outcome measure was reduction in spasticity at three months or greater as measured by Ashworth (or modified Ashworth) spasticity scale. Our secondary outcome measures were: validated measures based on history, physical examination, physiological measures, measures of function, measures of quality of life, serious adverse events, and measures of cost.<br><br>DATA COLLECTION AND ANALYSIS: We identified only one randomized controlled trial that met the inclusion criteria for this review. Two authors extracted the data. We also contacted the author of the paper and obtained further information not available in the published article.<br><br>MAIN RESULTS: The included study was a trial of moderate intensity, endurance type exercise versus 'usual activities' in 25 patients with amyotrophic lateral sclerosis. At three months patients performing the 15 minute twice daily exercises had significantly less spasticity (mean reduction of 0.43 Ashworth grades versus an increase of 0.25 in controls), as measured by the Ashworth scale.<br><br>REVIEWER'S CONCLUSIONS: Individualized, moderate intensity, endurance type exercises for the trunk and limbs may help to reduce spasticity in motor neuron disease. No other medical, surgical or alternative treatment and therapy has been evaluated in a randomized fashion in this patient population.}, }
@article {pmid14964446, year = {2003}, author = {Minuto, F and Barreca, A and Melioli, G}, title = {Indirect evidence of hormone abuse. Proof of doping?.}, journal = {Journal of endocrinological investigation}, volume = {26}, number = {9}, pages = {919-923}, pmid = {14964446}, issn = {0391-4097}, mesh = {Antibodies/analysis ; Biomarkers/*analysis ; *Doping in Sports ; Erythropoietin/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Gonadotropins/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Half-Life ; Hematocrit ; Human Growth Hormone/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Humans ; Substance Abuse Detection/*methods ; Time Factors ; }, abstract = {Besides anabolic steroids, the most common performance-enhancing hormones are erythropoietin (EPO), insulin, GH, and gonadotropins, mostly indistinguishable from endogenous hormones and with very short half-life. This makes virtually impossible to demonstrate their use by measuring their concentration in the blood or urine. A possible approach to the problem may lie in in-direct demonstration through detection of the biological effects of these substances. The finding of an increased hematocrit level is suspicious but not clearly demonstrative of EPO abuse. Very high levels of circulating EPO could be associated with a strong suspicion of doping, when associated to other abnormal parameters, such as Ht, sTFRr, EPO, RDW. The presence of antibodies against the polysaccharide fraction of lateral chains of EPO has been observed only in patients treated with rhEPO. Owing to the pulsatile pattern of GH, particularly during physical exercise, pathologically high values may be found in normal subjects. Therefore, as in the case of EPO, evidence of GH abuse can be gathered only indirectly by detecting the biological effects of its administration. In training subjects GH treatment increased GH, IGF-I, IGFBP-3 and ALS, and decreased IGBP-2. After cessation of treatment IGF-I, IGFBP-3 and ALS approached basal values between 49 and 96 h. Also the bone parameters PICP ICIP, PIUP and osteocalcin increased significantly. Four days after cessation of treatment, levels of PIIIP and ICTP were still abnormally elevated. In conclusion, increases in IGF-I, IGFBP-3, ALS, PIIIP and ICTP are all indicative of recent GH abuse or of acromegaly.}, }
@article {pmid14962622, year = {2004}, author = {Foster, HD and Hoffer, A}, title = {The two faces of L-DOPA: benefits and adverse side effects in the treatment of Encephalitis lethargica, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis.}, journal = {Medical hypotheses}, volume = {62}, number = {2}, pages = {177-181}, doi = {10.1016/S0306-9877(03)00318-9}, pmid = {14962622}, issn = {0306-9877}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Antioxidants/*therapeutic use ; Antiparkinson Agents/adverse effects/therapeutic use ; Dopamine Agents/adverse effects/therapeutic use ; Dyskinesia, Drug-Induced/etiology ; Gastrointestinal Diseases/chemically induced ; Hallucinations/chemically induced ; Humans ; Levodopa/*adverse effects/*therapeutic use ; Multiple Sclerosis/*drug therapy ; Oxidative Stress/drug effects ; Parkinson Disease/*drug therapy ; Parkinson Disease, Postencephalitic/drug therapy ; Psychoses, Substance-Induced/etiology ; Sleep Initiation and Maintenance Disorders/chemically induced ; Vitamin B Complex/*therapeutic use ; }, abstract = {Parkinson's disease, encephalitis lethargica, multiple sclerosis and amyotrophic lateral sclerosis patients all display two distinct types of symptoms. Some of these are due directly to a deficiency of dopamine and are quickly reduced by laevodihydroxyphenylalanine (L-DOPA). The second set, however, are the result of neurological damage caused by metabolites of dopamine, which include dopachrome and other chrome indoles that are both hallucinogenic and neurotoxic. If this hypothesis is correct, three corollaries follow. Patients of all four disorders should display excessive oxidative stress, natural methyl acceptors should delay development and elevated antioxidant supplementation, given with L-DOPA, ought to prolong the "honeymoon" period in which the benefits of the drug out weigh its subsequent disadvantages. A literature review suggests that all three corollaries are probably correct.}, }
@article {pmid14762675, year = {2004}, author = {Mochizuki, A and Komatsuzaki, Y and Iwamoto, H and Shoji, S}, title = {Frontotemporal dementia with ubiquitinated neuronal inclusions presenting with primary lateral sclerosis and parkinsonism: clinicopathological report of an autopsy case.}, journal = {Acta neuropathologica}, volume = {107}, number = {4}, pages = {377-380}, doi = {10.1007/s00401-003-0818-7}, pmid = {14762675}, issn = {0001-6322}, mesh = {Cerebral Cortex/metabolism/pathology ; Dementia/*complications ; Humans ; Immunohistochemistry/methods ; Inclusion Bodies/*metabolism ; Male ; Middle Aged ; Motor Neuron Disease/*etiology ; Neurons/*metabolism/pathology ; Parkinsonian Disorders/*etiology ; Postmortem Changes ; Pyramidal Tracts/pathology ; Ubiquitin/*metabolism ; }, abstract = {We report a case displaying upper motor sign, parkinsonism, and behavioral abnormality, with marked degeneration of the precentral cortex, neostriatum and frontotemporal lobes, as well as ubiquitinated neuronal inclusions. The patient was a 66-year-old male at the time of death. At age 57, he noticed progressive difficulties in speaking and swallowing. At age 60, he was severely anarthric and displayed emotional lability and incontinence. Neurologically, very poor movement of tongue was observed, but without atrophy or fasciculation. Deep tendon reflexes were hyperactive. Grasp reflex and snout reflex were also positive. Needle electromyography revealed no abnormalities. A diagnosis of primary lateral sclerosis and character change was made. At age 62, he developed bradykinesia and rigidity of the neck and all extremities. Treatment with carbidopa-levodopa was initiated, but resulted in minimal improvement. At age 65, he was bed-ridden, and had repeated occurrences of aspiration pneumonia; he died of pneumonia. Neuropathological examination revealed marked atrophy of the frontal and temporal lobes with Betz cells completely absent and moderate atrophy of the neostriatum. The spinal cord and nerve roots appeared normal. Immunohistochemically, ubiquitin-positive but tau-negative intraneuronal inclusions were found in the frontal and temporal cortices, including the precentral cortex and the hippocampal dentate gyrus, and the neostriatum. This case could be included with inclusion-associated disorders such as frontotemporal dementia or amyotrophic lateral sclerosis with dementia, and furthermore, predominant upper motor sign and parkinsonism could represent phenotypes of clinical manifestations with such inclusions.}, }
@article {pmid14756802, year = {2004}, author = {Kirkinezos, IG and Hernandez, D and Bradley, WG and Moraes, CT}, title = {An ALS mouse model with a permeable blood-brain barrier benefits from systemic cyclosporine A treatment.}, journal = {Journal of neurochemistry}, volume = {88}, number = {4}, pages = {821-826}, doi = {10.1046/j.1471-4159.2003.02181.x}, pmid = {14756802}, issn = {0022-3042}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics ; Age Factors ; Alanine/genetics ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Blood-Brain Barrier/*physiopathology ; Brain/drug effects/metabolism ; Cyclosporine/pharmacokinetics/*therapeutic use ; Disease Models, Animal ; Glycine/genetics ; Humans ; Immunosuppressive Agents/pharmacokinetics/*therapeutic use ; Liver/drug effects/metabolism ; Mice ; Mice, Knockout ; Mice, Transgenic ; Muscles/drug effects/metabolism ; Probability ; Sex Factors ; Spinal Cord/drug effects/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Survival Rate ; Tissue Distribution ; Tritium/metabolism ; }, abstract = {To test potentially beneficial drugs to amyotrophic lateral sclerosis (ALS), we created an ALS mouse model with a permeable blood-brain barrier, by crossing the G93A-SOD1 transgenic mouse with a multiple drug resistance type 1a/b (mdr1a/b) gene knockout mouse. To validate the model, we administered cyclosporine A intraperitoneally to the mice. Cyclosporine A accumulated in the brain and spinal cord of this mouse model, whereas it was unable to penetrate the CNS of mdr1a/b wild-type animals. Systemic administration of cyclosporine A extended the life of the double-mutant male mice by approximately 12%. Surprisingly, the effect was more robust in male mice and only marginal in female mice. These results demonstrate the usefulness of this combined mouse model for the testing of potentially therapeutic drugs and support the role of mitochondrial-mediated apoptosis in the pathway to motor neuron death in SOD1-associated ALS.}, }
@article {pmid14753660, year = {2003}, author = {Forshew, DA and Bromberg, MB}, title = {A survey of clinicians' practice in the symptomatic treatment of ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {4}, pages = {258-263}, doi = {10.1080/14660820310017344}, pmid = {14753660}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/*physiopathology/*therapy ; Constipation ; Depression ; Disease Management ; Emotions ; *Evidence-Based Medicine ; Fasciculation ; Fatigue ; *Health Care Surveys ; Humans ; Laryngismus ; Muscle Cramp ; Muscle Spasticity ; Retrospective Studies ; Sialorrhea ; Sleep Wake Disorders ; Surveys and Questionnaires ; Urination Disorders ; }, abstract = {UNLABELLED: Symptomatic management is the mainstay of ALS patient care, but there are few controlled trials of drugs and interventions for common symptoms.<br><br>METHODS: We queried ALS clinic neurologists to determine drugs and interventions of choice and neurologists' perceived efficacy for 14 symptoms.<br><br>RESULTS: The results are tabulations of the physicians' four most frequent choices for each symptom, the physicians' perception of efficacy, the average doses and average daily costs. A wide range of drugs and interventions were nominated for management of ALS symptoms. Consensus on treatment was rare for individual symptoms, and efficacy for any symptom was judged moderate at best. A few drugs were recommended for multiple symptoms. Comparisons of perceived efficacy compared to drug costs are informative.<br><br>DISCUSSION: The results of the survey emphasize the challenges of symptom management in ALS. These data aid clinical management and guide rational choices for randomized controlled trials.}, }
@article {pmid14753658, year = {2003}, author = {Kalra, S and Arnold, D}, title = {Neuroimaging in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {4}, pages = {243-248}, doi = {10.1080/14660820310011269}, pmid = {14753658}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Animals ; Brain Mapping ; Diagnosis, Differential ; *Diagnostic Imaging ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Tomography, Emission-Computed ; }, abstract = {Several neuroimaging modalities have been used with varying success to aid the clinical process of establishing the diagnosis of amyotrophic lateral sclerosis (ALS). By demonstrating evidence of occult upper motor neuron degeneration in vivo, a speedier and more definitive diagnosis in suspected cases could lead to earlier treatment and earlier enrollment in clinical trials. Findings compatible with ALS on routine MRI are not consistently found and are non-specific. Thus, routine anatomic imaging is useful in ruling out diseases that mimic ALS, but not in classification of new cases. Functional imaging techniques, such as PET and fMRI, have provided fascinating insights into the cortical functional reorganization that accompanies muscular weakness. PET and SPECT have revealed involvement of regions of the brain beyond the motor cortex, something not well appreciated by pathological examination. Of great need is a surrogate marker of therapeutic efficacy to make drug evaluation more efficient; neuroimaging, and magnetic resonance spectroscopy in particular, holds great promise in this regard in addition to helping us better understand the of neurodegeneration.}, }
@article {pmid14720207, year = {2004}, author = {Klivenyi, P and Kiaei, M and Gardian, G and Calingasan, NY and Beal, MF}, title = {Additive neuroprotective effects of creatine and cyclooxygenase 2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {88}, number = {3}, pages = {576-582}, doi = {10.1046/j.1471-4159.2003.02160.x}, pmid = {14720207}, issn = {0022-3042}, support = {AG 12992/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism ; Animals ; Creatine/pharmacology/*therapeutic use ; Cyclooxygenase 2 ; Cyclooxygenase 2 Inhibitors ; Cyclooxygenase Inhibitors/pharmacology/*therapeutic use ; *Disease Models, Animal ; Drug Synergism ; Drug Therapy, Combination ; Female ; Isoenzymes/antagonists &amp; inhibitors/metabolism ; Male ; Mice ; Mice, Transgenic ; Neuroprotective Agents/pharmacology/*therapeutic use ; Prostaglandin-Endoperoxide Synthases/metabolism ; Superoxide Dismutase/biosynthesis/genetics ; }, abstract = {There is substantial evidence implicating both inflammation and mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS) pathogenesis. We investigated the therapeutic effects of cyclooxygenase 2 (COX-2) inhibitors both alone and in combination with creatine in the G93A transgenic mouse model of ALS. Oral administration of either celecoxib or rofecoxib significantly improved motor performance, attenuated weight loss and extended survival. The administration of COX-2 inhibitors significantly reduced prostaglandin E2 levels at 110 days of age. The combination of creatine with COX-2 inhibitors produced additive neuroprotective effects and extended survival by approximately 30%. The COX-2 inhibitors significantly protected against depletion of anterior horn motor neurons and creatine with COX-2 inhibitors showed greater protection than COX-2 inhibitors alone. These results suggest that combinations of therapies targeting different disease mechanisms may be a useful strategy in the treatment of ALS.}, }
@article {pmid14717615, year = {2004}, author = {Rogers, SJ and Williams, CS and Román, GC}, title = {Myelopathy in Sjögren's syndrome: role of nonsteroidal immunosuppressants.}, journal = {Drugs}, volume = {64}, number = {2}, pages = {123-132}, pmid = {14717615}, issn = {0012-6667}, mesh = {Clinical Trials as Topic ; Humans ; Immunosuppressive Agents/*therapeutic use ; Myelitis, Transverse/diagnosis/drug therapy/etiology ; Sjogren's Syndrome/complications/*drug therapy ; Spinal Cord/pathology ; Spinal Cord Diseases/diagnosis/*drug therapy/etiology ; }, abstract = {The incidence, aetiology and optimal treatment of CNS Sjögren's syndrome, including myelopathy associated with Sjögren's syndrome, are unknown at the present time. CNS Sjögren's syndrome is thought to be the result of an autoimmune vasculitis, but other mechanisms may be important. Spinal cord involvement in CNS Sjögren's syndrome may present as acute transverse myelitis, progressive myelitis, Brown-Séquard syndrome, neurogenic bladder or lower motor neurone disease. Optic nerve pathology frequently accompanies spinal cord involvement. Acute transverse myelitis has a high mortality and appears to be the most frequent form of spinal cord involvement in CNS Sjögren's syndrome, occurring in about 1% of all patients with Sjögren's syndrome. The patient's symptomatology and clinical course dictate current treatment of myelopathy. First-line treatment appears to be corticosteroid therapy. However, when the patient's condition fails to improve or deteriorates a nonsteroidal immunosuppressant agent should be considered. Agents used to treat myelopathy include cyclophosphamide, chlorambucil, azathioprine, ciclosporin (cyclosporin) and methotrexate in conjunction with corticosteroids. Most data exist as anecdotal reports. The agent of first choice, based on adverse effect profile and efficacy, appears to be cyclophosphamide given intravenously in pulse doses. Other nonsteroidal immunosuppressant agents should be considered, especially when lack of efficacy of, or intolerance to, cyclophosphamide exists in the patient's history. Glandular and other extraglandular symptoms may benefit concomitantly from the immunosuppressant treatment. In addition, when acute relief of symptomatology is needed, the patient may benefit from a trial of plasmapheresis or intravenous immunoglobulin. Infliximab (anti-tumour necrosis factor-alpha antibodies) has not been used as a treatment modality for myelopathy, but has shown some usefulness in the treatment of extraglandular symptoms, as well as peripheral nervous system manifestations of Sjögren's syndrome. This agent might be considered when all other treatment modalities have failed given the presumed importance of tumour necrosis factor in the pathogenesis of Sjögren's syndrome.}, }
@article {pmid14703467, year = {2003}, author = {Xu, L and Meng, HX and Chen, ZB}, title = {[The effects of smoking on gingival crevicular fluid volume and elastase before and after initial periodontal treatment].}, journal = {Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology}, volume = {38}, number = {6}, pages = {405-407}, pmid = {14703467}, issn = {1002-0098}, mesh = {Adult ; Gingival Crevicular Fluid/*enzymology/physiology ; Humans ; Male ; Middle Aged ; Pancreatic Elastase/*analysis ; Periodontitis/metabolism/*therapy ; Smoking/*adverse effects ; }, abstract = {OBJECTIVE: To investigate the relationship between smoking and gingival crevicular fluid volume (GCF), level of elastase (EA) in 37 severe periodontitis patients before and after 1 month periodontal initial treatment.<br><br>METHODS: The GCF samples were collected from 122 sites in 22 heavy smokers (>or= 20 cigarettes/day) and 90 sites in 15 non-smokers before and after 1 month periodontal initial treatment. There is no difference (P > 0.05) on pocket depth between smoking sites (5.6 +/- 1.2) mm and non-smoking sites (5.4 +/- 1.2) mm at baseline. The volume of each GCF sample was measured by Periotron 6000 and the elastase in GCF were determined by substrate (meosuc-als-als-pro-val-NA) method.<br><br>RESULTS: After non-surgical treatment both GCF volume and elastase level were significantly decreased (P < 0.001) in both smokers and non-smokers. But the decrease of GCF volume (91 sites, 74.6%) and elastase level (70 sites, 76.1%) in smokers were significant lower (P < 0.01) than non-smokers (GCF, 88 sites, 97.8%; EA, 56 sites, 93.3%).<br><br>CONCLUSION: These findings suggest that smoking has effect on gingival crevicular fluid volume and elastase level of patients with periodontitis.}, }
@article {pmid14683462, year = {2003}, author = {Pong, K and Zaleska, MM}, title = {Therapeutic implications for immunophilin ligands in the treatment of neurodegenerative diseases.}, journal = {Current drug targets. CNS and neurological disorders}, volume = {2}, number = {6}, pages = {349-356}, doi = {10.2174/1568007033482652}, pmid = {14683462}, issn = {1568-007X}, mesh = {Animals ; Humans ; Immunophilins/chemistry/metabolism/*therapeutic use ; Immunosuppressive Agents/metabolism/therapeutic use ; Ligands ; Neurodegenerative Diseases/*drug therapy/metabolism ; }, abstract = {There is a significant unmet need for therapeutic agents in the treatment of neurodegenerative diseases. Given their clinical importance, prototypical molecules that clearly exhibit both neuroprotective and neuroregenerative activities have been highly sought after. The journey led to the exploitation of neurotrophins, a family of proteins that had extraordinary therapeutic properties in pre-clinical models of neurodegeneration. Although experimentally promising, clinical development of neurotrophins for various neurological indications, such as Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Parkinson's Disease was met with severe obstacles and setbacks, such as the inability to deliver these large proteins to target population of neurons, instability of the proteins, and non-specific activity. Immunophilins are proteins that act as receptors for immunosuppresant drugs, i.e. FK506 (tacrolimus), cyclosporin A, and rapamycin (sirolimus, Rapamune). Studies indicate immunophilins are expressed 10-100 fold higher in CNS and PNS tissue than in immune tissue. Subsequent studies revealed potent neuroprotective and neuroregenerative properties of immunophilin ligands in both culture and animal models. In contrast to neurotrophins, most immunophilin ligands are highly stable, small molecules that can readily cross the blood-brain barrier and are orally bioavailable. Taken together, these data prompted the development of nonimmunosuppressive immunophilin ligands with potent therapeutic activities, although the potency of select compounds has come into question in more recent studies. This review will examine the experimental evidence supporting the use of immunophilin ligands for the treatment of neurodegenerative diseases and the current progression of these molecules in clinical trials.}, }
@article {pmid14658053, year = {2003}, author = {Iłzecka, J and Stelmasiak, Z and Solski, J and Wawrzycki, S and Szpetnar, M}, title = {Effect of riluzole (Rilutek) treatment on plasma amino acid percentages in amyotrophic lateral sclerosis patients.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {24}, number = {4}, pages = {290-292}, doi = {10.1007/s10072-003-0160-9}, pmid = {14658053}, issn = {1590-1874}, mesh = {Amino Acids/*blood ; Amyotrophic Lateral Sclerosis/*blood/drug therapy ; Chromatography, Ion Exchange ; Excitatory Amino Acid Antagonists/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Riluzole/*therapeutic use ; Statistics, Nonparametric ; }, abstract = {The aim of the study was to investigate the effect of riluzole (Rilutek) treatment on plasma amino acids (AA) percentage capacity in amyotrophic lateral sclerosis (ALS) patients. Excitatory AA may be important in the pathogenesis of ALS. Riluzole is a neuroprotective drug that blocks glutamatergic neurotransmission in the central nervous system. The study was conducted at the Department of Neurology, University School of Medicine in Lublin. The study comprised 20 ALS patients. Plasma AA were measured by automated ion-exchange chromatography before and after 3 months of riluzole treatment. The study has shown a significant decrease in serine percentage capacity and a significant increase in isoleucine percentage capacity in the plasma of the ALS patients, however the plasma excitatory AA percentage capacity was not significantly changed after 3 months of the riluzole treatment. Our investigations revealed that riluzole does not significantly influence the majority of plasma AA percentage capacity in ALS patients.}, }
@article {pmid14648282, year = {2003}, author = {Yamada, M and Furukawa, Y and Hirohata, M}, title = {Amyotrophic lateral sclerosis: frequent complications by cervical spondylosis.}, journal = {Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association}, volume = {8}, number = {6}, pages = {878-881}, doi = {10.1007/s00776-003-0712-0}, pmid = {14648282}, issn = {0949-2658}, mesh = {Adult ; Age Distribution ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*epidemiology ; *Cervical Vertebrae ; Cohort Studies ; Comorbidity ; Female ; Humans ; Incidence ; Laminectomy/methods ; Magnetic Resonance Imaging/methods ; Male ; Middle Aged ; Prognosis ; Risk Assessment ; Severity of Illness Index ; Sex Distribution ; Spinal Osteophytosis/*diagnosis/*epidemiology ; Treatment Outcome ; }, abstract = {Cervical spondylosis is associated with myelopathy and radiculopathy, which sometimes mimic clinical manifestations of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder that affects upper and lower motor neurons. Cervical spondylosis may coexist with ALS because both diseases preferentially affect individuals of middle or old age. We investigated 63 patients with ALS to clarify the complications of cervical spondylosis and other spinal disorders and to explore the history of surgical treatment for them. We found cervical spondylosis in 30 patients (48%), lumbar spondylosis in 7 (13%), ossification of the posterior longitudinal ligament (OPLL) in 4 (6.3%), and ossification of the yellow ligament (OYL) in 4 (6.3%). Surgery was performed early in the course of the disease on the cervical spine in five patients (7.9%) and on the lumbar spine in one (1.6%); these patients consulted our clinic because their motor symptoms had progressed even after the spinal surgery. Our results indicate that nearly half of all ALS patients have their disease complicated by cervical spondylosis, and that a careful differential diagnosis for ALS is necessary before making decisions about spinal surgery.}, }
@article {pmid14644702, year = {2003}, author = {Hanisch, F and Zierz, S}, title = {Only transient increase of serum CoQ subset 10 during long-term CoQ10 therapy in mitochondrial ophthalmoplegia.}, journal = {European journal of medical research}, volume = {8}, number = {11}, pages = {485-491}, pmid = {14644702}, issn = {0949-2321}, mesh = {Adolescent ; Adult ; Aged ; Antioxidants/*administration &amp; dosage/metabolism/pharmacokinetics ; Coenzymes ; Female ; Humans ; Lactic Acid/metabolism ; Male ; Middle Aged ; Mitochondrial Diseases/*drug therapy/metabolism ; Muscle, Skeletal/metabolism ; Ophthalmoplegia/*drug therapy/metabolism ; Physical Exertion ; Rest ; Ubiquinone/*administration &amp; dosage/*analogs &amp; derivatives/blood/pharmacokinetics ; }, abstract = {BACKGROUND: Coenzyme Q10 (CoQ10) is frequently administered in mitochondrial diseases. Mitochondrial dysfunction and CoQ10 treatment was also proposed in neurodegenerative disorders as amyotrophic lateral sclerosis and Parkinsons disease.<br><br>PATIENTS AND METHODS: Seventeen patients with mitochondrial CPEO were treated with CoQ10 (dosage: 0.60 1.80 mg/kg body wt) in an open trial. Serum levels of CoQ10 were monitored before and after 6-9 and 12-15 months of CoQ10 therapy. CoQ10 concentration in muscle was measured in all patients before treatment.<br><br>RESULTS: Prior to treatment CoQ10 concentration in muscle was normal in all patients. Eight patients completed the study after 12-15 months. Prior to treatment there was no correlation between CoQ10 in muscle and serum. There was no inverse correlation of serum lactate with CoQ10 in muscle before and in serum before and during therapy. CoQ10 serum level and body weight related CoQ10 dosage correlated significantly after 6-9 months but not after 12-15 months (p = 0.043 and n. s., respectively). During continued administration of CoQ10 the CoQ10 serum level was increased 2.76 +/- 1.00-fold after 6-9 months (range: 1.04-3.80). but returned to 1.70 +/- 0.98-fold after 12-15 months (range: 0.91-3.83). Serum lactate did not significantly change during treatment. There was no effect of CoQ10 treatment on signs and symptoms.<br><br>CONCLUSION: The only transient increase of CoQ10 in serum has to be considered in any low dose long-term treatment with CoQ10.}, }
@article {pmid14649878, year = {2003}, author = {Jordán, J and Ceña, V and Prehn, JH}, title = {Mitochondrial control of neuron death and its role in neurodegenerative disorders.}, journal = {Journal of physiology and biochemistry}, volume = {59}, number = {2}, pages = {129-141}, pmid = {14649878}, issn = {1138-7548}, mesh = {Cell Death/*physiology ; Humans ; Mitochondria/*physiology ; Neurodegenerative Diseases/metabolism/*pathology/*physiopathology ; Neurons/pathology/*physiology ; }, abstract = {Genetic or functional mitochondrial alterations can result in the initiation of cell death programs that are believed to contribute to cell death in diabetes, ageing and neurodegenerative disorders. Mitochondria are being considered the main link between cellular stress signals activated during acute and chronic nerve cell injury, and the execution of nerve cell death. This second function of mitochondria is regulated by several families of proteins that can trigger an increase in permeability of the outer and/or inner mitochondrial membrane. One example of this is the formation of the mitochondrial permeability transition pore (MPTP). This process can trigger the release of cell death-inducing factors from mitochondria, as well as a dissipation of the mitochondrial transmembrane potential, depletion of ATP, and increased free radical formation. Among the factors released from mitochondria are cytochrome c, the apoptosis inductor factor (AIF), and caspases. We review the role of the MPTP in diverse physiological and pathological processes, including neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). The design of drugs that could interfere with the functions of the MPTP could allow novel therapeutic approaches for the treatment of acute and chronic nerve cell injury.}, }
@article {pmid14649724, year = {2003}, author = {Iwasaki, Y and Ichikawa, Y and Igarasi, O and Aoyagi, J and Konno, S and Ikeda, K and Iguchi, H and Kawabe, S and Marubuchi, S and Ono, S}, title = {T-588 protects motor neuron death against glutamate-induced neurotoxicity.}, journal = {Neurochemical research}, volume = {28}, number = {12}, pages = {1829-1832}, pmid = {14649724}, issn = {0364-3190}, mesh = {Animals ; Cell Death/*drug effects ; Choline O-Acetyltransferase/metabolism ; Diethylamines/*pharmacology ; Glutamic Acid/*toxicity ; Motor Neurons/cytology/*drug effects/enzymology ; Organ Culture Techniques ; Rats ; Rats, Sprague-Dawley ; Thiophenes/*pharmacology ; }, abstract = {To examine the possible neuroprotective effect of T-588 against glutamate-induced neurotoxicity, we analyzed the pharmacological utility of T-588 in a postnatal organotypic culture model of motor neuron degeneration. Treatment with 10(-5) M of glutamate resulted a motor neuron loss and decreased activity of choline acetyltransferase (ChAT). Cotreatment of 10(-5) M of glutamate and T-588 revealed a protective effect against motor neuron death and decreased ChAT activity. We concluded that T-588 may play important roles in the survival and maintenance of spinal motor neurons in its neuroprotection against glutamate-induced neurotoxicity. Our data may provide a rationale for designing a therapeutic strategy for protection against pathologically induced motor neuron damage or cell death such as amyotrophic lateral sclerosis and motor neuropathy.}, }
@article {pmid14643967, year = {2004}, author = {Speit, G and Schütz, P and Bonzheim, I and Trenz, K and Hoffmann, H}, title = {Sensitivity of the FPG protein towards alkylation damage in the comet assay.}, journal = {Toxicology letters}, volume = {146}, number = {2}, pages = {151-158}, doi = {10.1016/j.toxlet.2003.09.010}, pmid = {14643967}, issn = {0378-4274}, mesh = {Alkylation ; Animals ; Cells, Cultured ; Comet Assay/*methods ; Cricetinae ; *DNA Damage ; DNA-Formamidopyrimidine Glycosylase/*pharmacology ; Humans ; Hydrogen-Ion Concentration ; Oxidation-Reduction ; Sensitivity and Specificity ; }, abstract = {The comet assay (single cell gel electrophoresis) is widely used for the evaluation of DNA-damaging effects in genotoxicity testing and population monitoring. In its standard version at pH >13, DNA double strand breaks (DSB), DNA single strand breaks (SSB) and alkali-labile sites (ALS) lead to increased DNA migration. At reduced pH (12.5-12.1) the expression of ALS as SSB can be eliminated and the effect of SSB only can be identified. Specific endonucleases have been used to characterize specific classes of DNA damage. The formamido pyrimidine glycosylase (FPG) protein has been used to assess oxidative DNA base damage because it detects 8-OH guanine and other oxidatively damaged purines. Here, we show that the FPG protein also detects alkylation damage with high sensitivity in the comet assay. Human whole blood, isolated lymphocytes and V79 cells were treated with alkylating agents and post-incubated with FPG. FPG strongly enhanced MMS- and EMS-induced DNA damage but had no significant effect on ENU-induced DNA damage, indicating that the amount of N-7 guanine alkylation is responsible for the observed effect. Reducing the pH during alkali unwinding and electrophoresis to 12.5 to avoid the contribution of ALS to the comet assay effects, strongly decreased the sensitivity of the comet assay with and without FPG treatment and prevented DNA migration. We conclude that enhanced DNA effects in the comet assay by FPG after exposure to genotoxins with unknown mode of action should not directly be regarded as evidence for the presence of oxidative damage. Furthermore, reducing the pH leads to a considerable loss in sensitivity and should not be used in biomonitoring and other applications which require a sensitive protocol.}, }
@article {pmid14623841, year = {2003}, author = {Khan, AM and Lauffer, G and Haddad, F}, title = {A chapter in emergency: a surgical trainee's experience.}, journal = {Emergency medicine journal : EMJ}, volume = {20}, number = {6}, pages = {535-537}, pmid = {14623841}, issn = {1472-0213}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Child, Preschool ; *Education, Medical, Graduate ; Emergency Medicine/*education ; *Emergency Service, Hospital ; Female ; General Surgery/*education ; Humans ; Infant ; Infant, Newborn ; Male ; Medical Staff, Hospital/*education ; Middle Aged ; }, abstract = {OBJECTIVES: To assess (1) the exposure a senior house officer (SHO) gains while training in accident and emergency (A&amp;E) and (2) how much this experience benefits a surgical trainee.<br><br>METHODS: An SHO trained in A&amp;E for a period of six months as part of his surgical rotation. Besides regular daily duties, he prospectively collected details of patients in a logbook. For each patient records of name, age, sex, address, presenting symptoms, specialty, and treatment outcome were noted. Also recorded were courses attended, certificates achieved, and audits performed during this period.<br><br>RESULTS: A total of 1249 patients were seen during this period. This included 423 (33%) medical, 374 (30%) orthopaedic/trauma, and 268 (21%) paediatric cases. Some 153 (12%) were surgical, 55 urology, 41 patients presented with "pain" symptoms in different body regions (excluding abdominal pains), and 120 patients included all other specialties (psychiatry, ENT, ophthalmology, dental, gynaecology). Twenty (1.6%) practical procedures were performed. The SHO attended two courses (ATLS, ALS), achieved two certificates, and was involved in two audits.<br><br>CONCLUSIONS: Wide exposure in all specialties and branches of medicine including internal medicine, orthopaedics and trauma, paediatrics, and surgery was gained. As a surgical trainee, training in A&amp;E did not provide hands on practical experience, but was useful in contributing towards general clinical skills.}, }
@article {pmid14623733, year = {2003}, author = {Russman, BS and Iannaccone, ST and Samaha, FJ}, title = {A phase 1 trial of riluzole in spinal muscular atrophy.}, journal = {Archives of neurology}, volume = {60}, number = {11}, pages = {1601-1603}, doi = {10.1001/archneur.60.11.1601}, pmid = {14623733}, issn = {0003-9942}, mesh = {Age of Onset ; Child ; Child, Preschool ; Excitatory Amino Acid Antagonists/adverse effects/*therapeutic use ; Humans ; Infant ; Infant, Newborn ; Muscular Atrophy, Spinal/*drug therapy/mortality ; Riluzole/adverse effects/*therapeutic use ; }, abstract = {BACKGROUND: Severe spinal muscular atrophy (SMA) (Werdnig-Hoffmann disease, acute SMA, and SMA I) is a disease of the motor neuron characterized by onset before 6 months of age, failure ever to achieve sitting without support, and a life expectancy of 2 years or less. There is no known treatment for SMA, and, until recently, no therapeutic trials have been attempted. There is reason to believe that glutamate, an excitatory neurotransmitter, enhances programmed cell death of anterior horn cells. Riluzole, a glutamate inhibitor, has been shown to slow the rate of decline in patients with amyotrophic lateral sclerosis, another form of motor neuron disease.<br><br>OBJECTIVES: To determine whether a glutamate inhibitor might be tolerated by infants with SMA and, furthermore, whether this medication could have a positive effect on life expectancy.<br><br>DESIGN: Subjects with homozygous deletions of the survival motor neuron gene were recruited from pediatric neuromuscular clinics and randomized in a 2:1 ratio, 2 riluzole to 1 placebo. Neurologic examination was performed at the first visit by one of the investigators. Complete blood count, hepatic and renal screens, and urinalysis were performed at baseline, 2 weeks, 1 month, 2 months, 3 months, 6 months, and 9 months after drug or placebo was started. An electrocardiogram was done at baseline, 3 months, 6 months, and 12 months. Treatment was stopped after 9 months, and blood work was repeated at 12 months. Treatment was reinstituted at 1 year if requested by the parents. The enrollment goal was 30 patients; however, support from the pharmaceutical company was withdrawn when Rhone-Poulenc Rorer was taken over by Aventis. The investigational review boards of the participating centers approved the protocol and consent forms.<br><br>RESULTS: Seven patients received riluzole and 3 received placebo medication. All 3 patients in the placebo group died (mean age, 9 months). Three of 7 who received active drug are still living at ages 513 years, 4 years, and 30 months. None of the 10 subjects experienced adverse effects or changes in laboratory test results. None showed any change in motor abilities.<br><br>CONCLUSIONS: Riluzole appears to be safe in young children. This was a limited study with insufficient power to show a difference between the 2 groups. Because there is a suggestion of possible benefit in treated subjects, we recommend further study of riluzole in pediatric patients with SMA.}, }
@article {pmid14619409, year = {2003}, author = {de Paulis, T}, title = {ONO-2506. Ono.}, journal = {Current opinion in investigational drugs (London, England : 2000)}, volume = {4}, number = {7}, pages = {863-867}, pmid = {14619409}, issn = {1472-4472}, mesh = {Animals ; Caprylates/chemistry/*therapeutic use ; Clinical Trials as Topic/statistics &amp; numerical data ; Drugs, Investigational/chemistry/*therapeutic use ; Humans ; Nervous System Diseases/*drug therapy ; Technology, Pharmaceutical/methods ; }, abstract = {ONO-2506 is an enantiomeric, three carbon atom homolog of valproic acid under development by ONO Pharmaceutical for the potential treatment of stroke, as well as Alzheimer's and Parkinson's disease. The injectable formulation (Proglia) is undergoing phase II trials in the US and Japan for acute-phase cerebral infarction, and the oral formulation (Cereact) is in phase I trials in the UK for Alzheimer's disease (AD) and Parkinson's disease (PD). Japanese and European phase I trials for AD, PD and amyotropic lateral sclerosis (ALS) had commenced by March 2002 and phase II trials for ALS are underway in Europe.}, }
@article {pmid14612154, year = {2003}, author = {Kanai, Y and Hediger, MA}, title = {The glutamate and neutral amino acid transporter family: physiological and pharmacological implications.}, journal = {European journal of pharmacology}, volume = {479}, number = {1-3}, pages = {237-247}, doi = {10.1016/j.ejphar.2003.08.073}, pmid = {14612154}, issn = {0014-2999}, mesh = {Amino Acid Transport System X-AG/agonists/antagonists &amp; inhibitors/*physiology ; Amino Acid Transport Systems, Neutral/agonists/antagonists &amp; inhibitors/*physiology ; Animals ; Binding Sites/drug effects/physiology ; Biological Transport/drug effects/physiology ; Excitatory Amino Acid Antagonists/pharmacology ; Glutamic Acid/pharmacology ; Humans ; }, abstract = {The solute carrier family 1 (SLC1) is composed of five high affinity glutamate transporters, which exhibit the properties of the previously described system XAG-, as well as two Na+-dependent neutral amino acid transporters with characteristics of the so-called "ASC" (alanine, serine and cysteine). The SLC1 family members are structurally similar, with almost identical hydropathy profiles and predicted membrane topologies. The transporters have eight transmembrane domains and a structure reminiscent of a pore loop between the seventh and eighth domains [Neuron 21 (1998) 623]. However, each of these transporters exhibits distinct functional properties. Glutamate transporters mediate transport of L-Glu, L-Asp and D-Asp, accompanied by the cotransport of 3 Na+ and one 1 H+, and the countertransport of 1 K+, whereas ASC transporters mediate Na+-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. Given the high concentrating capacity provided by the unique ion coupling pattern of glutamate transporters, they play crucial roles in protecting neurons against glutamate excitotoxicity in the central nervous system (CNS). The regulation and manipulation of their function is a critical issue in the pathogenesis and treatment of CNS disorders involving glutamate excitotoxicity. Loss of function of the glial glutamate transporter GLT1 (SLC1A2) has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), resulting in damage of adjacent motor neurons. The importance of glial glutamate transporters in protecting neurons from extracellular glutamate was further demonstrated in studies of the slc1A2 glutamate transporter knockout mouse. The findings suggest that therapeutic upregulation of GLT1 may be beneficial in a variety of pathological conditions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) but not the glial glutamate transporters may be of therapeutic interest, allowing blockage of glutamate exit from neurons due to "reversed glutamate transport" of EAAC1, which will occur during pathological conditions, such as during ischemia after a stroke.}, }
@article {pmid14607308, year = {2003}, author = {Pamphlett, R and Todd, E and Vink, R and McQuilty, R and Cheema, SS}, title = {Magnesium supplementation does not delay disease onset or increase survival in a mouse model of familial ALS.}, journal = {Journal of the neurological sciences}, volume = {216}, number = {1}, pages = {95-98}, doi = {10.1016/s0022-510x(03)00216-8}, pmid = {14607308}, issn = {0022-510X}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/metabolism/prevention &amp; control/*therapy ; Animals ; Brain/drug effects/metabolism ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Antagonists/*pharmacology/therapeutic use ; Glutamic Acid/*metabolism ; Hand Strength ; Magnesium/*pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; Muscle Weakness/drug therapy/etiology/metabolism ; Receptors, N-Methyl-D-Aspartate/drug effects/metabolism ; Superoxide Dismutase/deficiency/genetics ; Superoxide Dismutase-1 ; Survival Rate ; Treatment Failure ; }, abstract = {Treatment of amyotrophic lateral sclerosis (ALS) with anti-glutamate agents has had some success, but the search continues for more effective glutamate blockers. Magnesium (Mg) ions inhibit the opening of some glutamate receptors, so we increased dietary Mg in a mouse model of ALS in an attempt to modify the course of the disease. From the age of 6 weeks, mutant superoxide dismutase 1 (SOD1) transgenic mice and wild-type controls had either 0, 21.5 or 43 g/l of Mg pidolate added to their drinking water. Disease onset was measured by tests for coordination and forelimb strength, and survival by standard endpoints. Mg levels in the brain were measured in wild-type mice using mass spectrometry. Mutant SOD1 mice on no added Mg became weak at about 105 days, and survived between 114 and 137 days. No difference in either time of onset of weakness, or survival, was seen in mutant SOD1 mice on different doses of Mg. No increase in wild-type brain Mg was found after supplemental Mg. From these results, it appears that a trial of oral Mg supplementation in human ALS is not warranted.}, }
@article {pmid14598305, year = {2003}, author = {Turner, BJ and Rembach, A and Spark, R and Lopes, EC and Cheema, SS}, title = {Opposing effects of low and high-dose clozapine on survival of transgenic amyotrophic lateral sclerosis mice.}, journal = {Journal of neuroscience research}, volume = {74}, number = {4}, pages = {605-613}, doi = {10.1002/jnr.10796}, pmid = {14598305}, issn = {0360-4012}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Animals ; Cell Death/drug effects ; Cells, Cultured ; Clozapine/*pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Gene Expression/drug effects ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects ; Neuroprotective Agents/*pharmacology ; Receptor, Nerve Growth Factor ; Receptors, Nerve Growth Factor/*drug effects ; Signal Transduction/drug effects ; Superoxide Dismutase/*drug effects ; }, abstract = {Clozapine is a potent atypical neuroleptic or antipsychotic agent used to relieve symptoms of early-diagnosed schizophrenia. Aside from well-described dopamine and serotonin receptor blockade effects, clozapine may also be neuroprotective through its modulation of the p75 neurotrophin receptor (p75(NTR)) and superoxide dismutase 1 (SOD1) expression. The death-signalling activities of both p75(NTR) and mutant SOD1 are implicated in motor neuron degeneration in humans and transgenic mice with amyotrophic lateral sclerosis (ALS). We therefore investigated the effects of clozapine in cell culture and mouse models of ALS. Clozapine dose-dependently inhibited full-length and cleaved p75(NTR) but not SOD1 protein expression in the motor neuron-like (NSC-34) cell line. Furthermore, low concentrations of clozapine protected NSC-34 cells from paraquat-mediated superoxide toxicity, nerve growth factor (NGF)-induced death signalling, and serum deprivation, whereas high concentrations potentiated death. Systemic thrice-weekly administration of low and high-dose clozapine to mutant superoxide dismutase 1 (SOD1(G93A)) mice produced differential effects on disease onset and survival. Low-dose treatment was associated with delayed locomotor impairment and death, compared to high-dose clozapine, which accelerated paralysis and mortality (P < 0.05). Increased death was not attributable to toxicity, as clozapine-induced agranulocytosis was not detected from blood analysis. High-dose clozapine, however, produced extrapyramidal symptoms in mice manifest by hindlimb rigidity, despite reducing spinal cord p75(NTR) levels overall. These results suggest that although clozapine may exert p75(NTR)-mediated neuroprotective activity in vitro, its profound antagonistic effects on dopaminergic and serotonergic systems in vivo at high doses may exacerbate the phenotype of transgenic ALS mice.}, }
@article {pmid14597108, year = {2003}, author = {Wilms, H and Sievers, J and Dengler, R and Bufler, J and Deuschl, G and Lucius, R}, title = {Intrathecal synthesis of monocyte chemoattractant protein-1 (MCP-1) in amyotrophic lateral sclerosis: further evidence for microglial activation in neurodegeneration.}, journal = {Journal of neuroimmunology}, volume = {144}, number = {1-2}, pages = {139-142}, doi = {10.1016/j.jneuroim.2003.08.042}, pmid = {14597108}, issn = {0165-5728}, mesh = {Age of Onset ; Aged ; Amyotrophic Lateral Sclerosis/*cerebrospinal fluid/immunology/*pathology ; Analysis of Variance ; Cell Movement/immunology ; Cerebrospinal Fluid Proteins/*biosynthesis/blood/cerebrospinal fluid ; Chemokine CCL2/*biosynthesis/blood/*cerebrospinal fluid ; Humans ; Microglia/immunology/*metabolism/*pathology ; Middle Aged ; Regression Analysis ; Statistics, Nonparametric ; Up-Regulation/immunology ; }, abstract = {Autopsy studies and animal experiments suggest that microglial inflammation contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). Monocyte-chemoattractant protein (MCP-1) might play an important role in microglial recruitment. We studied MCP-1 levels in sera and cerebrospinal fluid of 29 ALS patients and compared the results with 11 control patients with tension headache. The MCP-1 level was determined using enzyme-linked immunosorbent assays (ELISA). A significant increase in cerebrospinal fluid MCP-1 level but not serum level was seen in the patients with ALS compared to the control subjects. These results suggest that cerebrospinal fluid MCP-1 activity may be a sensitive marker for neuroinflammation in ALS useful for monitoring treatment trials in ALS.}, }
@article {pmid14583978, year = {2003}, author = {Parton, M and Mitsumoto, H and Leigh, PN}, title = {Amino acids for amyotrophic lateral sclerosis / motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD003457}, doi = {10.1002/14651858.CD003457}, pmid = {14583978}, issn = {1469-493X}, mesh = {Amino Acids, Branched-Chain/*therapeutic use ; Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Motor Neuron Disease/drug therapy ; Randomized Controlled Trials as Topic ; Threonine/*therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis, also known as motor neuron disease, is a progressive neuromuscular disease that causes disability and eventual death. Various amino acid preparations, the three branched-chain amino acids (L-leucine, L-valine and L-isoleucine) or, alternatively, L-threonine have been used as experimental therapy.<br><br>OBJECTIVES: To examine the efficacy of amino acid therapies in prolonging survival and/or slowing the progression of amyotrophic lateral sclerosis/motor neuron disease.<br><br>SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (searched February 2003), MEDLINE (from January 1966 to December 2002) and EMBASE (from January 1980 to December 2002) databases and reports of specialist conferences. Authors of known studies were contacted.<br><br>SELECTION CRITERIA: We included randomised or quasi-randomised trials of participants with a clinical diagnosis of amyotrophic lateral sclerosis/motor neuron disease treated with all combinations of amino acids. Our primary outcome measure was survival determined by a pooled hazard ratio of all studies. Our secondary outcome measures were (in order of priority): survival at six and 12 months, muscle strength, any validated rating scale of physical function, quality of life, proportion of patients completing therapy and proportion of patients reporting adverse events attributable to treatment.<br><br>DATA COLLECTION AND ANALYSIS: We identified six eligible trials and rejected a further seven because of incomplete data or inadequate duration. Eligible studies were rated for methodological quality and missing data sought from the authors. After this examination two studies were excluded from analysis. Our pooled survival analysis was performed by the Parmar method, other statistical calculations were done using the Review Manager 4.2 software package.<br><br>MAIN RESULTS: No benefit could be demonstrated for either branched-chain amino acids or L-threonine in improving survival in amyotrophic lateral sclerosis/motor neuron disease. Neither could we find evidence of an effect of either treatment on muscle strength or disability as measured by functional rating scales. No study assessed quality of life. Both branched-chain amino acids and L-threonine appeared well tolerated and caused a degree of adverse events comparable to that of the control medication.<br><br>REVIEWER'S CONCLUSIONS: There is no evidence to support a beneficial effect of either branched-chain amino acids or L-threonine in amyotrophic lateral sclerosis/motor neuron disease.}, }
@article {pmid14580812, year = {2003}, author = {Lee, A and Garner, A and Fearnside, M and Harrison, K}, title = {Level of prehospital care and risk of mortality in patients with and without severe blunt head injury.}, journal = {Injury}, volume = {34}, number = {11}, pages = {815-819}, doi = {10.1016/s0020-1383(02)00395-9}, pmid = {14580812}, issn = {0020-1383}, mesh = {Adult ; Analysis of Variance ; Emergency Medical Services/*standards ; Female ; Head Injuries, Closed/*mortality/therapy ; Humans ; Injury Severity Score ; Life Support Care/*methods ; Male ; Middle Aged ; Retrospective Studies ; Risk Factors ; }, abstract = {OBJECTIVES: To determine the association between mortality and the level of prehospital care in severely injured blunt trauma patients with or without severe head injury.<br><br>METHOD: Retrospective review of 2010 severe blunt trauma patients (injury severity score (ISS) >15) with or without severe head injury in a tiered trauma system involving ambulance officers (basic life support (BLS) and advanced life support (ALS)) and physicians, and a Level 1 trauma centre.<br><br>RESULTS: After adjusting for age, type of head injury, glasgow coma scale score (GCS), systolic blood pressure, ISS and prehospital time, intensive care unit (ICU) admission modified the association between level of prehospital care and mortality. In those patients without ICU admission, patients in the paramedic and physician-staffed emergency services group were more likely to die than patients in the BLS ambulance group (odds ratio (OR) 2.18, 95% confidence intervals (CI): 1.05-4.55; 4.27, 95% CI: 1.46-12.45, respectively). Among patients who survived to ICU treatment, however, there was no association between level of prehospital care and risk of mortality. Presence or absence of a head injury did not modify the risk of mortality.<br><br>CONCLUSIONS: The level of prehospital care was associated with the risk of mortality. This was modified by whether the patient survived long enough to be admitted to the ICU.}, }
@article {pmid14556941, year = {2003}, author = {Gilgun-Sherki, Y and Panet, H and Melamed, E and Offen, D}, title = {Riluzole suppresses experimental autoimmune encephalomyelitis: implications for the treatment of multiple sclerosis.}, journal = {Brain research}, volume = {989}, number = {2}, pages = {196-204}, doi = {10.1016/s0006-8993(03)03343-2}, pmid = {14556941}, issn = {0006-8993}, mesh = {Animals ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Encephalomyelitis, Autoimmune, Experimental/*drug therapy ; Female ; Immunohistochemistry ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Mice, Inbred Strains ; Multiple Sclerosis/*drug therapy ; Myelin Proteins ; Myelin-Associated Glycoprotein/pharmacology ; Myelin-Oligodendrocyte Glycoprotein ; Neurologic Examination ; Neuroprotective Agents/*therapeutic use ; Riluzole/*therapeutic use ; Spinal Cord/anatomy &amp; histology/metabolism/pathology ; Staining and Labeling ; T-Lymphocytes ; }, abstract = {Recent studies suggest that glutamate neurotoxicity is involved in the pathogenesis of multiple sclerosis (MS), and that treatment with glutamate receptor (AMPA/kainate) antagonists inhibits experimental autoimmune encephalomyelitis (EAE), the conventional model of MS. Therefore, we examined whether riluzole, an inhibitor of glutamate transmission, affects the pathogenesis and clinical features of MS-like disease in myelin oligodendrocyte glycoprotein (MOG)-induced EAE in mice. Here we report that riluzole (10 mg/kgx2/day, i.p.), administered before and even after the appearance of clinical symptoms, dramatically reduced the clinical severity of MOG-induced EAE, while all the MOG-immunized control mice developed significant clinical manifestations. Moreover, the riluzole-treated mice demonstrated only mild focal inflammation, and less demyelination, compared to MOG-treated mice, using histological methods. Furthermore, riluzole markedly reduced axonal disruption, as assessed by Bielshowesky's silver staining and by antibodies against non-phosphorylated neurofilaments (SMI-32). No difference was detected in the immune system potency, as T-cell proliferative responses to MOG were similar in both groups. In conclusion, our study demonstrates, for the first time, that riluzole can reduce inflammation, demyelination and axonal damage in the CNS and attenuate the clinical severity of MOG-induced EAE. These results suggest that riluzole, a drug used in amyotrophic lateral sclerosis (ALS), might be beneficial for the treatment of MS.}, }
@article {pmid14535957, year = {2003}, author = {Turner, BJ and Cheah, IK and Macfarlane, KJ and Lopes, EC and Petratos, S and Langford, SJ and Cheema, SS}, title = {Antisense peptide nucleic acid-mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice.}, journal = {Journal of neurochemistry}, volume = {87}, number = {3}, pages = {752-763}, doi = {10.1046/j.1471-4159.2003.02053.x}, pmid = {14535957}, issn = {0022-3042}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Caspase 3 ; Caspases/biosynthesis ; Cells, Cultured ; Disease Models, Animal ; Disease Progression ; Fluorescent Dyes ; Genetic Therapy/*methods ; Mice ; Mice, Transgenic ; Nerve Growth Factor/pharmacology ; Oligonucleotides, Antisense/*pharmacology ; Peptide Nucleic Acids/pharmacokinetics/*pharmacology ; Rats ; Rats, Wistar ; Receptor, Nerve Growth Factor ; Receptors, Nerve Growth Factor/*antagonists &amp; inhibitors/biosynthesis/genetics ; Schwann Cells/cytology/drug effects/metabolism ; Signal Transduction/drug effects ; Superoxide Dismutase/genetics ; }, abstract = {Re-expression of the death-signalling p75 neurotrophin receptor (p75NTR) is associated with injury and neurodegeneration in the adult nervous system. The induction of p75NTR expression in mature degenerating spinal motor neurons of humans and transgenic mice with amyotrophic lateral sclerosis (ALS) suggests a role of p75NTR in the progression of motor neuron disease (MND). In this study, we designed, synthesized and evaluated novel antisense peptide nucleic acid (PNA) constructs targeting p75NTR as a potential gene knockdown therapeutic strategy for ALS. An 11-mer antisense PNA directed at the initiation codon, but not downstream gene sequences, dose-dependently inhibited p75NTR expression and death-signalling by nerve growth factor (NGF) in Schwann cell cultures. Antisense phosphorothioate oligonucleotide (PS-ODN) sequences used for comparison failed to confer such inhibitory activity. Systemic intraperitoneal administration of this antisense PNA to mutant superoxide dismutase 1 (SOD1G93A) transgenic mice significantly delayed locomotor impairment and mortality compared with mice injected with nonsense or scrambled PNA sequences. Reductions in p75NTR expression and subsequent caspase-3 activation in spinal cords were consistent with increased survival in antisense PNA-treated mice. The uptake of fluorescent-labelled antisense PNA in the nervous system of transgenic mice was also confirmed. This study suggests that p75NTR may be a promising antisense target in the treatment of ALS.}, }
@article {pmid14527871, year = {2003}, author = {Turner, BJ and Lopes, EC and Cheema, SS}, title = {The serotonin precursor 5-hydroxytryptophan delays neuromuscular disease in murine familial amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {3}, pages = {171-176}, doi = {10.1080/14660820310009389}, pmid = {14527871}, issn = {1466-0822}, mesh = {5-Hydroxytryptophan/administration &amp; dosage/*therapeutic use ; Aging ; Alanine/genetics ; Amyotrophic Lateral Sclerosis/blood/complications/*drug therapy ; Animals ; Animals, Newborn ; Body Weight/drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Glycine/genetics ; Hindlimb ; Male ; Mice ; Mice, Transgenic ; Mortality ; Motor Activity/drug effects ; Mutation ; Paralysis/etiology/prevention &amp; control ; Serotonin/blood ; Superoxide Dismutase/genetics ; }, abstract = {INTRODUCTION: Reduction in the levels of whole-blood serotonin is a common feature of Down syndrome (DS) individuals and transgenic mice overexpressing wild-type SOD1. Administration of the metabolic precursor 5-hydroxytryptophan (5-HTP) leads to reversal of both serotonin deficits and hypotonia in humans. The effect of 5-HTP treatment on the progression of motor neuron disease in mutant SOD1 mice was examined.<br><br>METHODS: Pre-disease transgenic SOD1 G93A mice and wild-type littermates were systemically administered 5-HTP thrice weekly (0, 5 or 50 mg/kg). Animal weights, locomotor function and survival were recorded weekly. Plasma serotonin levels were measured post-mortem.<br><br>RESULTS: Treatment with 5-HTP significantly delayed hindlimb weakness and mortality in SOD1 G93A mice in a dose-dependent manner. Wild-type mice were not adversely affected by 5-HTP administration. Baseline serotonin levels did not differ between wild-type and ALS mice. Blood platelet serotonin levels increased proportionally with dose.<br><br>CONCLUSIONS: Increased blood serotonin by administration of 5-HTP in SOD1 G93A mice led to improved locomotor function and survival. A role for serotonin metabolism in mice with elevated SOD1 expression and motor neuron disease is suggested by these studies.}, }
@article {pmid14519086, year = {2003}, author = {Baker, SK and Tarnopolsky, MA}, title = {Targeting cellular energy production in neurological disorders.}, journal = {Expert opinion on investigational drugs}, volume = {12}, number = {10}, pages = {1655-1679}, doi = {10.1517/13543784.12.10.1655}, pmid = {14519086}, issn = {1354-3784}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Coenzymes ; Creatine/metabolism/therapeutic use ; Disease Models, Animal ; Energy Metabolism/*drug effects ; Humans ; Huntington Disease/drug therapy ; Nervous System Diseases/*drug therapy/metabolism/*therapy ; Neuroprotective Agents/therapeutic use ; Ubiquinone/*analogs &amp; derivatives/metabolism/therapeutic use ; }, abstract = {The concepts of energy dysregulation and oxidative stress and their complicated interdependence have rapidly evolved to assume primary importance in understanding the pathophysiology of numerous neurological disorders. Therefore, neuroprotective strategies addressing specific bioenergetic defects hold particular promise in the treatment of these conditions (i.e., amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, Friedreich's ataxia, mitochondrial cytopathies and other neuromuscular diseases), all of which, to some extent, share 'the final common pathway' leading to cell death through either necrosis or apoptosis. Compounds such as creatine monohydrate and coenzyme Q(10) offer substantial neuroprotection against ischaemia, trauma, oxidative damage and neurotoxins. Miscellaneous agents, including alpha-lipoic acid, beta-OH-beta-methylbutyrate, riboflavin and nicotinamide, have also been shown to improve various metabolic parameters in brain and/or muscle. This review will highlight the biological function of each of the above mentioned compounds followed by a discussion of their utility in animal models and human neurological disease. The balance of this work will be comprised of discussions on the therapeutic applications of creatine and coenzyme Q(10).}, }
@article {pmid14511332, year = {2003}, author = {Maihöfner, C and Probst-Cousin, S and Bergmann, M and Neuhuber, W and Neundörfer, B and Heuss, D}, title = {Expression and localization of cyclooxygenase-1 and -2 in human sporadic amyotrophic lateral sclerosis.}, journal = {The European journal of neuroscience}, volume = {18}, number = {6}, pages = {1527-1534}, doi = {10.1046/j.1460-9568.2003.02879.x}, pmid = {14511332}, issn = {0953-816X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/enzymology/*metabolism/pathology ; Blotting, Western ; Brain Chemistry ; Case-Control Studies ; Cell Count ; Cyclooxygenase 1 ; Cyclooxygenase 2 ; Dinoprostone/cerebrospinal fluid ; Female ; Humans ; Immunohistochemistry ; Isoenzymes/*metabolism ; Lumbosacral Region ; Male ; Membrane Proteins ; Middle Aged ; Neuroglia/metabolism ; Neurons/classification/enzymology/*metabolism ; Prostaglandin-Endoperoxide Synthases/*metabolism ; Spinal Cord/metabolism/pathology ; }, abstract = {Prostaglandins (PGs) are critical mediators of physiologic processes and inflammation. They are produced by two different isoforms of the cyclooxygenase (COX) enzyme, namely COX-1 and COX-2. In particular COX-2 was demonstrated to be crucial for PG-synthesis in inflammation. Recently, inhibition of COX-2 was shown to prevent the loss of motor neurons in a model of amyotrophic lateral sclerosis (ALS). Furthermore, spinal COX-2 expression was shown to be increased in transgenic mice that produce an ALS-like syndrome. Therefore, we investigated the expression of COX-1 and COX-2 in the spinal cord of seven human sporadic ALS patients by means of immunohistochemistry. Specimens from seven patients without any neurological disease served as controls. COX-2 expression was dramatically increased in the spinal cord of patients with ALS. Its protein was found in motor neurons, interneurons and glial cells. Statistical analysis showed a significantly higher expression of COX-2 in ALS for both neurons and glia. In contrast, COX-1 expression was predominantly confined to microglia and no apparent difference was detected between controls and ALS. In addition, we studied the concentration of prostaglandin E2 (PG E2) as a marker for COX activity in the cerebrospinal fluid of nine patients diagnosed for ALS and compared the results with those from nine patients without motor neuron disease. PG E2 levels were markedly increased in ALS cases (45.8 +/- 35.1 pg/mL) compared to the non-ALS specimens (15.8 +/- 3.7 pg/mL). The results of our study corroborate a potential role for COX-2 in the pathogenesis of motor neuron death in ALS. Selective COX-2 inhibition might therefore offer a new possibility in the treatment of human ALS. However, to determine the exact role of COX-2 in human ALS will require further research.}, }
@article {pmid14506939, year = {2003}, author = {Pattee, GL and Post, GR and Gerber, RE and Bennett, JP}, title = {Reduction of oxidative stress in amyotrophic lateral sclerosis following pramipexole treatment.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {2}, pages = {90-95}, doi = {10.1080/14660820310012736}, pmid = {14506939}, issn = {1466-0822}, support = {AG14373/AG/NIA NIH HHS/United States ; NS 35325/NS/NINDS NIH HHS/United States ; NS 39005/NS/NINDS NIH HHS/United States ; NS 39788/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism ; Antioxidants/*administration &amp; dosage/adverse effects ; Benzothiazoles ; Humans ; Hydroxybenzoates/blood ; Middle Aged ; Oxidative Stress/*drug effects ; Patient Dropouts ; Pramipexole ; Thiazoles/*administration &amp; dosage/adverse effects ; }, abstract = {Oxidative abnormalities have been identified both in familial amyotrophic lateral sclerosis (FALS) and the more prevalent sporadic ALS (SALS). Mitochondria dysfunction and toxic free radicals may play a role in this disease process, although the exact pathogenesis of both forms of ALS remains unknown. 2,3-DHBA is a hydroxylated salicylate by product that has been shown to be a reliable marker of increased free radical activity and is reliably assayed by HPLC. Following an oral salicylate load, we found elevated serum levels of 2, 3-dihydroxybenzoic acid (2,3-DHBA) and DHBA/salicylate in SALS subjects. Pramipexole has been shown to reduce oxidative stress and be neuroprotective in cell and animal models of neurodegeneration. We studied 12 SALS patients to determine the levels of 2,3-DHBA both before and after treatment with pramipexole. We found that pramipexole treatment up to 6 mg/day was well tolerated. The mean 2,3-DHBA serum levels were reduced by 45% and DHBA/salicylate ratios declined by 59% following treatment with pramipexole. SALS patients show apparent increases in systemic oxygen radical production that are reduced by pramipexole treatment at conventional doses, suggesting that pramipexole or related compounds may interrupt free radical production in SALS.}, }
@article {pmid13129806, year = {2003}, author = {Miller, RG and Mitchell, JD and Lyon, M and Moore, DH}, title = {Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {3}, pages = {191-206}, pmid = {13129806}, issn = {1466-0822}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy ; Databases as Topic ; Double-Blind Method ; Drug Evaluation ; Humans ; Motor Neuron Disease/classification/drug therapy/epidemiology/physiopathology ; Multicenter Studies as Topic ; Muscles/physiopathology ; Neuroprotective Agents/*therapeutic use ; Quality of Life ; Randomized Controlled Trials as Topic ; Riluzole/adverse effects/*therapeutic use ; Risk ; Survival Analysis ; Time Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: Riluzole 100 mg probably prolongs survival in patients with amyotrophic lateral sclerosis by about two months and the safety of the drug is not a major concern. The evidence from randomized controlled trials indicates that patients taking riluzole probably survive longer than patients taking placebo. The beneficial effects are very modest and the drug is expensive. Adverse effects from riluzole are relatively minor and for the most part reversible after stopping the drug. Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis in many countries but not all. Questions persist about its clinical utility because of high cost, modest efficacy and concern over adverse effects.<br><br>OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival.<br><br>SEARCH STRATEGY: Search of the Cochrane Neuromuscular Disease Group Register for randomized trials and enquiry from authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. The most recent search was November 2002.<br><br>SELECTION CRITERIA: Randomized trials of adults with diagnosis of amyotrophic lateral sclerosis (ALS), treated with riluzole or placebo. Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality as a function of time with riluzole 100 mg and other doses of riluzole; neurologic function, quality of life, muscle strength and adverse events.<br><br>We identified four eligible randomized trials. Each reviewer graded them for methodological quality. Data extraction was performed by a single reviewer and checked by two others. We obtained some missing data from investigators and regulatory agencies. We performed meta-analyses with Review Manager 4.1 software using a fixed effects model. A test of drug efficacy was based on the Parmar pooled hazard ratio.<br><br>RESULTS: The three trials examining tracheostomy-free survival included a total of 876 riluzole treated patients and 406 placebo treated patients. The data for tracheostomy-free survival was not available from the fourth trial. The methodological quality was acceptable and the three trials were easily comparable, although one trial included older patients in more advanced stages of amyotrophic lateral sclerosis. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (p=0.039, hazard ratio 0.80, 95% confidence interval 0.64 to 0.99) and there was no evidence of heterogeneity (p=0.33). When the third trial (which included older and more seriously affected patients) is added, there is evidence of heterogeneity (p<0.0001) and the random effects model, which takes this into account results in the overall treatment effect estimate falling just short of significance (p=0.056, hazard ratio 0.84, 95% confidence interval 0.70 to 1.01). This represents a 9% gain in the probability of surviving one year (57% in the placebo and 66% in the riluzole group). In secondary analyses of survival at separate time points, there was a significant survival advantage with riluzole 100 mg at six, nine, 12 and 15 months, but not at three or 18 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. There were no data on quality of life, but patients treated with riluzole remained in a more moderately affected health state significantly longer than placebo-treated patients (weighted mean difference 35.5 days, 95% confidence interval 5.9 to 65.0). A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (weighted mean difference 2.69, 95% confidence interval 1.65 to 4.38).<br><br>CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs survival by about two months in patients with ALS. More studies are needed, especially to clarify its effect in older patients (over 75 years), and those with more advanced disease.}, }
@article {pmid13129805, year = {2003}, author = {van den Berg, JP and Kalmijn, S and Lindeman, E and Wokke, JH and van den Berg, LH}, title = {Rehabilitation care for patients with ALS in The Netherlands.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {3}, pages = {186-190}, doi = {10.1080/aml.4.3.186.190}, pmid = {13129805}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*rehabilitation ; Follow-Up Studies ; Health Care Surveys ; Hospitals, Chronic Disease ; Humans ; Medicine ; Netherlands/epidemiology ; Palliative Care ; Patient Care Management ; Referral and Consultation ; *Rehabilitation Centers ; Specialization ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: In the Netherlands, rehabilitation medicine plays an important role in the symptomatic and palliative treatment of ALS patients. Detailed information about the actual care of ALS patients in the Netherlands and about the attitude of consultants in rehabilitation medicine towards the management of this disease was lacking.<br><br>OBJECTIVE: To obtain detailed information about the rehabilitation care for patients with ALS in the Netherlands.<br><br>METHODS: We have performed a survey among all consultants in rehabilitation medicine in the Netherlands, using a questionnaire about the organisation of care and the care management of ALS patients.<br><br>RESULTS: Two hundred eighty one questionnaires were gathered with a response rate of 98%. There were 14 specialised ALS centres spread throughout the country, except in the northwest and southwest. Most consultants worked with an ALS multidisciplinary team and most patients were treated in an outpatient rehabilitation clinic. Follow up visits were performed in most cases 5-6 times per year. The majority of the patients were followed up until death. The Dutch protocol for rehabilitative management in ALS was used in 89% of all treated ALS patients. Follow up and care management was not different in the specialised centres compared with the non-specialised centres.<br><br>CONCLUSION: In conclusion, this study indicated that the actual care for ALS patients was reasonably well organised in the Netherlands, based on the results and reactions of the consultants in rehabilitation medicine.}, }
@article {pmid12975723, year = {2003}, author = {Fiore, D}, title = {Diagnosis and treatment of multiple sclerosis and amyotrophic lateral sclerosis: neuropathies from Bordetella pertussis.}, journal = {American journal of therapeutics}, volume = {10}, number = {5}, pages = {377-379}, doi = {10.1097/00045391-200309000-00011}, pmid = {12975723}, issn = {1075-2765}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*immunology/*therapy ; *Antigen-Antibody Complex ; Antigen-Presenting Cells/immunology ; Antigens, Differentiation/immunology ; Antigens, Surface/immunology ; Astrocytes/immunology ; Blood-Brain Barrier ; *Bordetella pertussis ; Brain/immunology ; Humans ; Italy ; Male ; Multiple Sclerosis/*immunology/*therapy ; }, abstract = {Having found positive the research for anti-Bordetella antibodies in the 95.47% of 92 patients affected by defined multiple sclerosis and in the 100% of 55 patients affected by non-patched neuropathies (amyotrophic lateral sclerosis and correlated neuropathies), I reassessed the pathogenesis of the neuropathies from Bordetella pertussis. In the two categories of neuropathies (with and without patches), the beginning pathogenetic mechanisms are the same: 1) pertussis re-infection in patients with mucociliary barrier defect; 2) pertussis toxins passage in the blood; and 3) formation of circulating immune complexes. In multiple sclerosis, astrocytes produce class II human leukocyte antigens, the endothelia of the small brain vessels show the "adhesion molecules," and the immune complexes fall in the central nervous system (patches are formed). In amyotrophic lateral sclerosis and in the other non-patched neuropathies, the astrocytes do not produce the class II human leukocyte antigens, the endothelia do not show adhesion molecules, and immune complexes do not fall in the central nervous system; but they increase in blood until they inhibit the ulterior antibodies production. For relative antibodies lack, pertussis toxins fix directly on neuro-epithelia; their pathogenic power and physiopathologic astrocytes role in the central nervous system produce the damage. With a blood sample, we can assess Bordetella etiology. In all these neuropathies, an extended antibiotic therapy to clear mucosae and to prevent reinfections is necessary.}, }
@article {pmid12974347, year = {2003}, author = {Kuk, YI and Jung, HI and Kwon, OD and Lee, DJ and Burgos, NR and Guh, JO}, title = {Sulfonylurea herbicide-resistant Monochoria vaginalis in Korean rice culture.}, journal = {Pest management science}, volume = {59}, number = {9}, pages = {949-961}, doi = {10.1002/ps.722}, pmid = {12974347}, issn = {1526-498X}, mesh = {Acetolactate Synthase/antagonists &amp; inhibitors ; Algorithms ; Drug Resistance ; Herbicides/metabolism/*pharmacology ; Korea ; Models, Biological ; Oryza/*growth &amp; development ; Pontederiaceae/*drug effects ; Pyrazoles/pharmacology ; Pyridines/pharmacology ; Pyrimidines/pharmacology ; Sulfonylurea Compounds/*pharmacology ; }, abstract = {Nine Monochoria vaginalis Pres1 accessions from Chonnam province, Korea were tested for resistance to the sulfonylurea herbicide, imazosulfuron, in whole-plant response bioassay. All accessions were confirmed resistant (R) to imazosulfuron. The GR50 (imazosulfuron concentration that reduced shoot dry weight by 50%) values of R accessions were 1112-3172 (accession #9) times higher than that of the standard susceptible (S) accession. Accession #9 exhibited cross-resistance to other sulfonylurea herbicides, bensulfuron-methyl, cyclosulfamuron and pyrazosulfuron-ethyl, but not to the imidazolinone herbicides, imazapyr and imazaquin. The R biotype could be controlled by other herbicides with different modes of action, such as mefenacet and pyrazolate, applied to soil at recommended rates. Foliar-applied herbicides, 2,4-D and bentazone, also controlled both the R and S biotypes. Sulfonylurea-based mixtures, except ethoxysulfuron plus fentrazamide, did not control resistant M. vaginalis. Rice yield was reduced 70% by resistant M. vaginalis that escaped pyrazosulfuron-ethyl plus molinate, compared with hand weeding in direct-seeded rice culture. In contrast, rice yield was reduced 44% by resistant M. vaginalis that survived the pyrazosulfuron-ethyl plus molinate treatment, compared with pyrazolate plus butachlor in transplanted rice culture. In vitro acetolactate synthase (ALS) activity of the R biotype was 183, 35, 130 and 31 times more resistant to imazosulfuron, bensulfuron-methyl, cyclosulfamuron and pyrazosulfuron-ethyl, respectively, than the S biotype. Imidazolinone herbicides, imazapyr and imazaquin had similar effect on in vitro ALS activity of the R and S biotypes. The in vivo ALS activity of the R biotype was also less affected than the S biotype by the sulfonylurea herbicides imazosulfuron and pyrazosulfuron-ethyl. Results of in vitro and in vivo ALS assays indicate that the resistance mechanism of M. vaginalis to sulfonylurea herbicides may be due, in part, to an alteration in the target enzyme, ALS. Since the level of resistance in the enzyme assay was much lower than that in the whole-plant assay, other mechanisms of resistance, such as herbicide metabolism, may be involved.}, }
@article {pmid12967646, year = {2003}, author = {Feeney, SJ and Austin, L and Bennett, TM and Kurek, JB and Jean-Francois, MJ and Muldoon, C and Byrne, E}, title = {The effect of leukaemia inhibitory factor on SOD1 G93A murine amyotrophic lateral sclerosis.}, journal = {Cytokine}, volume = {23}, number = {4-5}, pages = {108-118}, doi = {10.1016/s1043-4666(03)00217-5}, pmid = {12967646}, issn = {1043-4666}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality/pathology ; Analysis of Variance ; Animals ; Astrocytes/drug effects/pathology ; Body Weight/drug effects/physiology ; Delayed-Action Preparations/pharmacology ; Disease Models, Animal ; Female ; Glial Fibrillary Acidic Protein/analysis ; Humans ; Immunohistochemistry ; Injections, Spinal/methods ; Injections, Subcutaneous/methods ; Interleukin-6/administration &amp; dosage/*pharmacology ; Knee Joint/surgery ; Leukemia Inhibitory Factor ; Ligation/methods ; Male ; Mice ; Mice, Transgenic/genetics ; Motor Activity/drug effects/physiology ; Motor Neurons/drug effects/pathology ; Neurodegenerative Diseases/drug therapy/pathology ; Paralysis/pathology ; Pelvis/surgery ; Recombinant Proteins/administration &amp; dosage/pharmacology ; Spinal Cord/chemistry/drug effects/pathology ; Superoxide Dismutase/*genetics ; Survival Rate ; Time Factors ; }, abstract = {Before potential therapeutic strategies for the treatment of amyotrophic lateral sclerosis (ALS) can be advanced to human clinical trials, there is a need to assess them in an animal model that best resembles the disease process. SOD1 G93A mice have close resemblance to familial ALS (fALS) and have been used in this study to evaluate the therapeutic potential of leukaemia inhibitory factor (LIF). LIF action was investigated by assessing three delivery methods: (1) daily subcutaneous injection; (2) through LIF rods placed adjacent to hind limb skeletal muscle and (3) continuous intrathecal infusion. The effect on disease progression was assessed by semi-quantitative and quantitative functional measurements, and histologically on the survival of motor neurons and number of reactive astrocytes. The results show that LIF had no beneficial effects when administered using the three methods of drug delivery. These results suggest that further evaluation of LIF in this transgenic model is required to fully characterize its' therapeutic potential.}, }
@article {pmid12946542, year = {2003}, author = {Litaker, JR and Chou, JY}, title = {Patterns of pharmacologic treatment of congestive heart failure in elderly nursing home residents and related issues: a review of the literature.}, journal = {Clinical therapeutics}, volume = {25}, number = {7}, pages = {1918-1935}, doi = {10.1016/s0149-2918(03)80196-0}, pmid = {12946542}, issn = {0149-2918}, mesh = {Aged ; Aged, 80 and over ; Angiotensin-Converting Enzyme Inhibitors/administration &amp; dosage/therapeutic use ; Cardiotonic Agents/administration &amp; dosage/therapeutic use ; Digoxin/administration &amp; dosage/therapeutic use ; Diuretics/administration &amp; dosage/therapeutic use ; Drug Utilization ; Heart Failure/*drug therapy ; Humans ; Nursing Homes ; }, abstract = {BACKGROUND: Congestive heart failure (CHF) is a serious clinical syndrome associated with increased morbidity, mortality, and health-related expenditure. In the United States, the incidence and prevalence of CHF have been shown to increase with age, particularly among the elderly (age >/=65 years). In addition, more elderly persons are living in or will be living in nursing homes. Given these trends, it is important to consider the quality of care, including pharmacologic treatment, received by elderly nursing home residents with a diagnosis of CHE There is currently a lack of clinical trial data on the pharmacologic treatment of CHF among elderly nursing home residents and, therefore, no standard of care. In lieu of clinical trial data, empiric studies based on nursing home populations may be useful.<br><br>OBJECTIVE: This article reviews empiric studies concerning the pharmacologic treatment of CHF in elderly nursing home residents.<br><br>METHODS: Empiric studies on the use of angiotensin-converting enzyme (ACE) inhibitors, digoxin, and diuretics in elderly nursing home residents with a diagnosis of CHF were identified through searches of MEDLINE, Cochrane Trials, and International Pharmaceutical Abstracts using the terms elderly, nursing home, geriatric, and heart failure. The search was limited to the past 11 years (1991-2002) to identify current patterns of treatment in the population of interest. Additional studies were identified through a manual search of the reference lists of the retrieved articles.<br><br>RESULTS: Thirteen empiric studies were identified: 9 examined ACE-inhibitor use, 4 digoxin use, and 7 diuretic use. The findings of these studies indicated that ACE inhibitors are underused, are often prescribed at clinically inefficient doses, and are used more often in "young" elderly nursing home residents (age 65-74 years). Among patients who received a prescription for digoxin, many did not have an appropriate indication (eg, no documented atrial fibrillation, normal sinus rhythm). Similarly, diuretics were found to be inappropriately prescribed to elderly nursing home residents for the treatment of CHF.<br><br>CONCLUSIONS: Based on the available empiric studies, elderly nursing home residents with a diagnosis of CHF do not appear to receive adequate treatment with ACE inhibitors, digoxin, or diuretics based on the recommendations of clinical or als or clinical guidelines. However, the clinical trials and clinical guidelines target the general elderly population and thus may not be applicable to elderly nursing home residents. Future research should explore factors influencing the pharmacologic treatment of CHF in elderly nursing home residents, and trials of new pharmacologic treatments for CHF should include elderly nursing home residents.}, }
@article {pmid12942157, year = {2003}, author = {Romano, G}, title = {Gene transfer in experimental medicine.}, journal = {Drug news &amp; perspectives}, volume = {16}, number = {5}, pages = {267-276}, doi = {10.1358/dnp.2003.16.5.829314}, pmid = {12942157}, issn = {0214-0934}, mesh = {Animals ; Clinical Trials as Topic/methods ; *Gene Transfer Techniques ; Genetic Therapy/adverse effects/statistics &amp; numerical data ; *Human Experimentation ; Humans ; }, abstract = {Gene transfer technology has many potential applications in medicine. Phase I and phase II gene-based clinical trials have been conducted for the treatment of cancer, monogenic disorders, some neurodegenerative illnesses, cardiopathies and infectious diseases. A phase I gene therapy clinical trial has recently been approved for the treatment of Parkinson's disease, while preclinical studies are in progress to develop gene-based interventions for the treatment of Alzheimer's disease and Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and diabetes type 1 and type 2. A number of gene transfer models have been generated for gene therapy and genetic immunization programs. Vector design is addressing several pressing issues in the matter of gene delivery improvement, stabilization of transgene expression and safety. This is necessary in order to achieve efficient gene-based therapeutic interventions. Indeed, considerable progress has been reported in the field of vector design, which has produced some encouraging results in clinical trials and preclinical studies. However, vector design should be further developed to allow for the successful application of gene transfer technology in therapy. This review summarizes the latest achievements and controversies in clinical trials and preclinical studies in the field of gene therapy.}, }
@article {pmid12939417, year = {2003}, author = {Cudkowicz, ME and Shefner, JM and Schoenfeld, DA and Brown, RH and Johnson, H and Qureshi, M and Jacobs, M and Rothstein, JD and Appel, SH and Pascuzzi, RM and Heiman-Patterson, TD and Donofrio, PD and David, WS and Russell, JA and Tandan, R and Pioro, EP and Felice, KJ and Rosenfeld, J and Mandler, RN and Sachs, GM and Bradley, WG and Raynor, EM and Baquis, GD and Belsh, JM and Novella, S and Goldstein, J and Hulihan, J and , }, title = {A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis.}, journal = {Neurology}, volume = {61}, number = {4}, pages = {456-464}, doi = {10.1212/wnl.61.4.456}, pmid = {12939417}, issn = {1526-632X}, support = {1R01NS39988/NS/NINDS NIH HHS/United States ; 5K08NS01896/NS/NINDS NIH HHS/United States ; M01RR00109/RR/NCRR NIH HHS/United States ; M01RR06192/RR/NCRR NIH HHS/United States ; M01RR07122/RR/NCRR NIH HHS/United States ; RR01032/RR/NCRR NIH HHS/United States ; RR01066/RR/NCRR NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Disease Progression ; Double-Blind Method ; Female ; Fructose/adverse effects/*analogs &amp; derivatives/pharmacology/*therapeutic use ; Hand Strength ; Humans ; Life Tables ; Male ; Middle Aged ; Muscle Contraction/drug effects ; Proportional Hazards Models ; Safety ; Survival Analysis ; Thromboembolism/chemically induced ; Topiramate ; Treatment Failure ; Vital Capacity/drug effects ; }, abstract = {OBJECTIVE: To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS.<br><br>METHODS: A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival.<br><br>RESULTS: Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis).<br><br>CONCLUSIONS: At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.}, }
@article {pmid12939412, year = {2003}, author = {Kaufmann, P and Lomen-Hoerth, C}, title = {ALS treatment strikes out while trying for a homer: the topiramate trial.}, journal = {Neurology}, volume = {61}, number = {4}, pages = {434-435}, doi = {10.1212/wnl.61.4.434}, pmid = {12939412}, issn = {1526-632X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Disease Progression ; Drug Evaluation, Preclinical ; Fructose/adverse effects/*analogs &amp; derivatives/*therapeutic use ; Humans ; Mice ; Randomized Controlled Trials as Topic ; Riluzole/therapeutic use ; Topiramate ; Treatment Failure ; }, }
@article {pmid12933929, year = {2003}, author = {Toosy, AT and Werring, DJ and Orrell, RW and Howard, RS and King, MD and Barker, GJ and Miller, DH and Thompson, AJ}, title = {Diffusion tensor imaging detects corticospinal tract involvement at multiple levels in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {74}, number = {9}, pages = {1250-1257}, pmid = {12933929}, issn = {0022-3050}, support = {491/MSS_/Multiple Sclerosis Society/United Kingdom ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Diffusion Magnetic Resonance Imaging/*methods ; Female ; Humans ; Male ; Middle Aged ; Pyramidal Tracts/*pathology ; Water ; }, abstract = {BACKGROUND: Histopathological studies of amyotrophic lateral sclerosis (ALS) are of end stage disease. Diffusion tensor imaging (DTI) provides the opportunity to investigate indirectly corticospinal tract pathology of ALS in vivo.<br><br>METHODS: DTI was used to study the water diffusion characteristics of the corticospinal tracts in 21 patients with ALS and 14 normal controls. The authors measured the fractional anisotropy (FA) and mean diffusivity (MD) along the pyramidal tracts from the internal capsules down to the pyramids. A mixed model regression analysis was used to compare FA and MD between the ALS and control groups.<br><br>RESULTS: FA showed a downward linear trend from the cerebral peduncles to the pyramids and was lower in the ALS group than controls at multiple levels of the corticospinal tract. At the internal capsules, FA was higher on the right. MD showed an upward trend, progressing caudally from the internal capsules to the pyramids. MD was higher at the level of the internal capsule in the ALS group, but caudally this difference was not maintained. No correlations were found between clinical markers of disability and water diffusion indices.<br><br>CONCLUSIONS: These findings provide insights into the pathological processes of ALS. Differences in diffusion characteristics at different anatomical levels may relate to underlying tract architecture or the distribution of pathological damage in ALS. Further development may permit monitoring of progression and treatment of disease.}, }
@article {pmid12901841, year = {2003}, author = {Derave, W and Van Den Bosch, L and Lemmens, G and Eijnde, BO and Robberecht, W and Hespel, P}, title = {Skeletal muscle properties in a transgenic mouse model for amyotrophic lateral sclerosis: effects of creatine treatment.}, journal = {Neurobiology of disease}, volume = {13}, number = {3}, pages = {264-272}, doi = {10.1016/s0969-9961(03)00041-x}, pmid = {12901841}, issn = {0969-9961}, mesh = {Adenosine Triphosphate/analysis/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/*physiopathology ; Animals ; Body Weight/drug effects ; Creatine/*therapeutic use ; Glycogen/analysis/metabolism ; Humans ; Mice ; Mice, Transgenic ; Models, Animal ; Motor Activity/drug effects/genetics ; Muscle Contraction/drug effects/genetics ; Muscle Fibers, Fast-Twitch/drug effects/metabolism ; Muscle Fibers, Slow-Twitch/drug effects/metabolism ; Muscle, Skeletal/chemistry/*drug effects/*metabolism/physiopathology ; Muscular Atrophy/genetics ; Mutation ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {The present study was undertaken to identify the metabolic and contractile characteristics of fast- and slow-twitch skeletal muscles in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). In addition, we investigated the effects of oral creatine supplementation on muscle functional capacity in this model. Transgenic mice expressing a mutant (G93A) or wild type human SOD1 gene (WT) were supplemented with 2% creatine monohydrate from 60 to 120 days of age. Body weight, rotorod performance and grip strength were evaluated. In vitro contractility was evaluated on isolated m. soleus and m. extensor digitorum longus (EDL), and muscle metabolites were determined. Body weight, rotorod performance and grip strength were markedly decreased in G93A compared to WT mice, but were unaffected by creatine supplementation. Muscle ATP content decreased and glycogen content increased in G93A versus WT in both muscle types, but were unaffected by creatine supplementation. Muscle creatine content increased following creatine intake in G93A soleus. Twitch and tetanic contractions showed markedly slower contraction and relaxation times in G93A versus WT in both muscle types, with no positive effect of creatine supplementation. EDL but not soleus of G93A mice showed significant atrophy, which was partly abolished by creatine supplementation. It is concluded that overexpression of a mutant SOD1 transgene has profound effects on metabolic and contractile properties of both fast- and slow-twitch skeletal muscles. Furthermore, creatine intake does not exert a beneficial effect on muscle function in a transgenic mouse model of ALS.}, }
@article {pmid12876198, year = {2003}, author = {Ghadge, GD and Slusher, BS and Bodner, A and Canto, MD and Wozniak, K and Thomas, AG and Rojas, C and Tsukamoto, T and Majer, P and Miller, RJ and Monti, AL and Roos, RP}, title = {Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {100}, number = {16}, pages = {9554-9559}, pmid = {12876198}, issn = {0027-8424}, support = {P01 NS021442/NS/NINDS NIH HHS/United States ; 5P01NS21442-18/NS/NINDS NIH HHS/United States ; }, mesh = {Adenoviridae/genetics ; Amyotrophic Lateral Sclerosis/*enzymology/*genetics/metabolism ; Animals ; Carboxypeptidases/*antagonists &amp; inhibitors ; Cell Death ; Cell Survival ; Enzyme Inhibitors/*pharmacology ; Glutamate Carboxypeptidase II ; Glutamic Acid/metabolism ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism ; Neurons/enzymology/*pathology ; Time Factors ; }, abstract = {Approximately 10% of cases of amyotrophic lateral sclerosis (ALS), a progressive and fatal degeneration that targets motor neurons (MNs), are inherited, and approximately 20% of these cases of familial ALS (FALS) are caused by mutations of copper/zinc superoxide dismutase type 1. Glutamate excitotoxicity has been implicated as a mechanism of MN death in both ALS and FALS. In this study, we tested whether a neuroprotective strategy involving potent and selective inhibitors of glutamate carboxypeptidase II (GCPII), which converts the abundant neuropeptide N-acetylaspartylglutamate to glutamate, could protect MNs in an in vitro and animal model of FALS. Data suggest that the GCPII inhibitors prevented MN cell death in both of these systems because of the resultant decrease in glutamate levels. GCPII inhibition may represent a new therapeutic target for the treatment of ALS.}, }
@article {pmid12874394, year = {2003}, author = {Bourke, SC and Bullock, RE and Williams, TL and Shaw, PJ and Gibson, GJ}, title = {Noninvasive ventilation in ALS: indications and effect on quality of life.}, journal = {Neurology}, volume = {61}, number = {2}, pages = {171-177}, doi = {10.1212/01.wnl.0000076182.13137.38}, pmid = {12874394}, issn = {1526-632X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*complications/mortality/psychology/therapy ; *Continuous Positive Airway Pressure ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Palliative Care ; Patient Acceptance of Health Care ; Polysomnography ; Prospective Studies ; Quality of Life ; Respiration Disorders/etiology/psychology/*therapy ; Respiratory Muscles/physiopathology ; Severity of Illness Index ; Sleep Wake Disorders/etiology/psychology/therapy ; Survival Analysis ; Treatment Outcome ; }, abstract = {BACKGROUND: Noninvasive ventilation (NIV) probably improves survival in ALS, but the magnitude and duration of any improvement in quality of life (QoL) and the optimal criteria for initiating treatment are unclear.<br><br>METHODS: QoL (Short Form-36 [SF-36], Chronic Respiratory Disease Questionnaire, Sleep Apnea Quality of Life Index) and respiratory function were assessed every 2 months and polysomnography every 4 months in 22 subjects with ALS. A trial of NIV was offered when subjects met one or more predefined criteria: orthopnea, daytime sleepiness, unrefreshing sleep, daytime hypercapnia, nocturnal desaturation, or an apnea-hypopnea index (AHI) of >10. Seventeen subjects were offered a trial of NIV; 15 accepted, and 10 continued treatment subsequently. Outcome was assessed by changes in QoL and NIV compliance (h/day). Subjects were followed to death or for at least 26 months.<br><br>RESULTS: QoL domains assessing sleep-related problems and mental health improved (effect sizes 0.88 to 1.77, p < 0.05) and were maintained for 252 to 458 days. Median survival following successful initiation of NIV was 512 days, and survival and duration of QoL benefit were strongly related to NIV compliance. Vital capacity declined more slowly following initiation of NIV. Orthopnea was the best predictor of benefit from, and compliance with, NIV. Daytime hypercapnia and nocturnal desaturation also predicted benefit but were less sensitive. Sleep-related symptoms were less specific, and AHI > 10 was unhelpful. Moderate or severe bulbar weakness was associated with lower compliance and less improvement in QoL.<br><br>CONCLUSIONS: NIV use was associated with improved QoL and survival. Subjects with orthopnea and preserved bulbar function showed the largest benefit.}, }
@article {pmid12873154, year = {2003}, author = {Festoff, BW and Suo, Z and Citron, BA}, title = {Prospects for the pharmacotherapy of amyotrophic lateral sclerosis : old strategies and new paradigms for the third millennium.}, journal = {CNS drugs}, volume = {17}, number = {10}, pages = {699-717}, pmid = {12873154}, issn = {1172-7047}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology/pathology ; Animals ; Cell Death ; Drug Design ; Excitatory Amino Acid Antagonists/therapeutic use ; Glutamic Acid/metabolism ; Humans ; Neurons/metabolism/pathology ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Riluzole/therapeutic use ; }, abstract = {Biomedical researchers interested in amyotrophic lateral sclerosis (ALS) must invoke newly developing technologies if we are to discover pharmaceutical treatments that will help a significant population of patients with the disease. The focus of ALS research over the last 10 years has been on reactive oxygen species (ROS) and glutamate excitotoxicity, resulting in several clinical trials and the launch of the only drug currently available for the treatment of ALS, riluzole. Unfortunately, the therapeutic benefits have been minimal, at best, and the prognosis for patients with ALS has not improved beyond very modest retardation of the disease course. By emphasising ROS and glutamate excitotoxicity, current ALS research has only partially been able to attenuate the rate of motor decline and neuronal loss associated with this illness. Clues to additional therapeutic potentialities will come from an increased understanding of the mode of cell death (apoptotic or other) and the pathways leading to neuronal demise. If death is apoptotic, inhibiting caspases may be useful. The regulatory modifications for cell death at the molecular level remain to be determined and exploited to prevent neuronal loss, although novel pathways have been recently elucidated that impact on protein aggregation and processing. Oxidative stress, seen in both familial and sporadic forms of ALS, may be only one post-translational mechanism likely to affect specific proteins essential for the health and stability of motor neurons. Protein cross-linking by transglutaminase paralleling that may lead to defects in proteasome function may also be a significant mechanism. The latest capabilities to screen protein changes in specific cells represent the kinds of advances needed to combat ALS in the third millennium.}, }
@article {pmid12872016, year = {2003}, author = {Butz, M and Wollinsky, KH and Wiedemuth-Catrinescu, U and Sperfeld, A and Winter, S and Mehrkens, HH and Ludolph, AC and Schreiber, H}, title = {Longitudinal effects of noninvasive positive-pressure ventilation in patients with amyotrophic lateral sclerosis.}, journal = {American journal of physical medicine &amp; rehabilitation}, volume = {82}, number = {8}, pages = {597-604}, doi = {10.1097/01.PHM.0000078239.83545.D0}, pmid = {12872016}, issn = {0894-9115}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/mortality/physiopathology/*therapy ; Female ; Humans ; Male ; Middle Aged ; *Positive-Pressure Respiration ; Prospective Studies ; Quality of Life ; Respiratory Function Tests ; Sleep ; Survival Rate ; }, abstract = {OBJECTIVE: To evaluate the duration of benefit on symptoms, quality of life, and survival derived from the use of noninvasive positive-pressure ventilation by patients with amyotrophic lateral sclerosis.<br><br>DESIGN: In this prospective, cohort study, 30 of 36 consecutively referred symptomatic patients tolerated nightly noninvasive positive-pressure ventilation and undertook pulmonary function testing and 12 symptom and quality-of-life instruments concerning sleep quality, daytime sleepiness, physical fatigue, mental fatigue, and depression that were administered during a 10-mo period.<br><br>RESULTS: With treatment, there was a significant improvement in the majority of patients in sleep quality, daytime sleepiness, physical fatigue, and depression; however, significant improvements lasted for up to 10 mo only in sleep quality. Partial pressure of arterial oxygen, partial pressure of arterial carbon dioxide, and oxyhemoglobin saturation remained stable or even improved for up to 7 mo during use of part-time noninvasive positive-pressure ventilation. A total of 14 patients had survival prolonged by continuous dependence on noninvasive positive-pressure ventilation.<br><br>CONCLUSIONS: Noninvasive positive-pressure ventilation provides a long-lasting benefit on symptoms and quality of life indicators for amyotrophic lateral sclerosis patients and should be offered to all patients with symptoms of sleep disordered breathing or inspiratory muscle dysfunction. It can also prolong tracheostomy-free survival.}, }
@article {pmid12871577, year = {2003}, author = {Hyun, DH and Lee, M and Halliwell, B and Jenner, P}, title = {Proteasomal inhibition causes the formation of protein aggregates containing a wide range of proteins, including nitrated proteins.}, journal = {Journal of neurochemistry}, volume = {86}, number = {2}, pages = {363-373}, doi = {10.1046/j.1471-4159.2003.01841.x}, pmid = {12871577}, issn = {0022-3042}, mesh = {Acetylcysteine/*analogs &amp; derivatives/*pharmacology ; Cell Line ; Cell Survival/drug effects/genetics ; Cysteine Endopeptidases ; Enzyme Inhibitors/pharmacology ; Gene Transfer Techniques ; Humans ; Ligases/biosynthesis/genetics ; Macromolecular Substances ; Multienzyme Complexes/*antagonists &amp; inhibitors ; Nerve Tissue Proteins/biosynthesis ; Neurofilament Proteins/biosynthesis ; Nitrates/*metabolism ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; Proteasome Endopeptidase Complex ; Proteins/*metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Synucleins ; Tubulin/biosynthesis ; Ubiquitin/metabolism ; *Ubiquitin-Protein Ligases ; alpha-Synuclein ; }, abstract = {Mutations in Cu,Zn-superoxide dismutase (SOD-1) are associated with some familial cases of amyotrophic lateral sclerosis (ALS), but it is not known how they result in cell death. We examined effects of overexpression of wild-type SOD-1 or the G37R or G85R mutations on the accumulation of ubiquitinated and nitrated proteins, and on loss of cell viability induced by the proteasome inhibitor, lactacystin. Wild-type SOD-1 had no effect on proteasomal activity, but the mutants decreased it somewhat. Treatment with lactacystin (1 micro m) caused only limited cell viability loss, even though it induced a marked inhibition of proteasomal activities. However, viability loss due to apoptosis was substantial in response to lactacystin when cells were overexpressing a mutant SOD-1. The frequency of cells showing immunoreactivity against ubiquitinated- or nitrated-proteins was enhanced when wild-type and mutant SOD-1 s were overexpressed. Ubiquitinated or nitrated alpha-tubulin, SOD-1, alpha-synuclein and 68K neurofilaments were observed in the aggregates. Similar aggregates were observed in cells overexpressing mutant parkin (Del3-5, T240R and Q311'X). The nitric oxide synthase inhibitor, l-NAME, decreased viability loss and aggregation, suggesting that nitration of proteins may play an important role in aggregation and in the cell death accompanying it.}, }
@article {pmid12858248, year = {2003}, author = {Ozer, K and Gurunluoglu, R and Zielinski, M and Izycki, D and Unsal, M and Siemionow, M}, title = {Extension of composite tissue allograft survival across major histocompatibility barrier under short course of anti-lymphocyte serum and cyclosporine a therapy.}, journal = {Journal of reconstructive microsurgery}, volume = {19}, number = {4}, pages = {249-256}, doi = {10.1055/s-2003-40581}, pmid = {12858248}, issn = {0743-684X}, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; Cyclosporine/*pharmacology ; Drug Therapy, Combination ; Graft Rejection/*prevention &amp; control ; Graft Survival/*drug effects/immunology ; Hindlimb/*transplantation ; Immunosuppressive Agents/*pharmacology ; Major Histocompatibility Complex/*drug effects/immunology ; Male ; Rats ; Rats, Inbred Lew ; Transplantation Chimera/immunology ; Transplantation Tolerance/*drug effects/immunology ; }, abstract = {In this study, the authors investigated the effects of combined use of cyclosporine A (CsA) and anti-lymphocyte serum (ALS) on the survival of rat hindlimb allografts across a fully allogeneic major histocompatibility complex (MHC) barrier between Brown-Norway rats (BN, RT1 n) and Lewis rats (LEW, RT1 l). Thirty transplantations were performed in five groups of six rats each: Group 1 was the isograft control; Group 2 was the allograft control; Group 3 received ALS, Group 4 received CsA, and Group 5 received CsA and ALS. Treatment was started 2 hr before surgery and was then given for 21 days. Donor-derived chimerism was monitored by FACS analysis. Survival time was calculated as the number of post-transplant days until the first signs of rejection. The allografts in Group 2, Group 3, and Group 4 survived a mean of 5, 6, and 33 days, respectively. The longest mean survival time-51 days-was noted in Group 5 (p<0.05). Donor- derived chimerism peaked at 17 percent and fell to 0 percent at the time of rejection. A combined protocol of ALS/CsA extended survival of rat hindlimb allografts across a fully allogeneic MHC barrier.}, }
@article {pmid12857367, year = {2003}, author = {Garbuzova-Davis, S and Willing, AE and Zigova, T and Saporta, S and Justen, EB and Lane, JC and Hudson, JE and Chen, N and Davis, CD and Sanberg, PR}, title = {Intravenous administration of human umbilical cord blood cells in a mouse model of amyotrophic lateral sclerosis: distribution, migration, and differentiation.}, journal = {Journal of hematotherapy &amp; stem cell research}, volume = {12}, number = {3}, pages = {255-270}, doi = {10.1089/152581603322022990}, pmid = {12857367}, issn = {1525-8165}, mesh = {Alanine ; Animals ; Cord Blood Stem Cell Transplantation/*methods ; Disease Models, Animal ; Disease Progression ; Fetal Blood/*cytology ; Glycine ; Hematopoietic Stem Cells/cytology ; Humans ; Infusions, Intravenous ; Mice ; Mice, Transgenic ; Motor Neuron Disease/physiopathology/*therapy ; Superoxide Dismutase/genetics ; Transplantation, Heterologous/*physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a multifactorial disease characterized by diffuse motor neuron degeneration, has proven to be a difficult target for stem cell therapy. The primary aim of this study was to determine the long-term effects of intravenous mononuclear human umbilical cord blood cells on disease progression in a well-defined mouse model of ALS. In addition, we rigorously examined the distribution of transplanted cells inside and outside the central nervous system (CNS), migration of transplanted cells to degenerating areas in the brain and spinal cord, and their immunophenotype. Human umbilical cord blood (hUCB) cells (10(6)) were delivered intravenously into presymptomatic G93A mice. The major findings in our study were that cord blood transfusion into the systemic circulation of G93A mice delayed disease progression at least 2-3 weeks and increased lifespan of diseased mice. In addition, transplanted cells survived 10-12 weeks after infusion while they entered regions of motor neuron degeneration in the brain and spinal cord. There, the cells migrated into the parenchyma of the brain and spinal cord and expressed neural markers [Nestin, III Beta-Tubulin (TuJ1), and glial fibrillary acidic protein (GFAP)]. Infused cord blood cells were also widely distributed in peripheral organs, mainly the spleen. Transplanted cells also were recovered in the peripheral circulation, possibly providing an additional cell supply. Our results indicate that cord blood may have therapeutic potential in this noninvasive cell-based treatment of ALS by providing cell replacement and protection of motor neurons. Replacement of damaged neurons by progeny of cord blood stem cells is probably not the only mechanism by which hUCB exert their effect, since low numbers of cells expressed neural antigens. Most likely, cord blood efficacy is partially due to neuroprotection by modulation of the autoimmune process.}, }
@article {pmid12849120, year = {2003}, author = {Isacson, O}, title = {The production and use of cells as therapeutic agents in neurodegenerative diseases.}, journal = {The Lancet. Neurology}, volume = {2}, number = {7}, pages = {417-424}, doi = {10.1016/s1474-4422(03)00437-x}, pmid = {12849120}, issn = {1474-4422}, mesh = {Animals ; Brain/pathology ; Brain Tissue Transplantation/*methods ; Cell Differentiation ; Fetal Tissue Transplantation/*methods ; Humans ; Neurodegenerative Diseases/*therapy ; Neurons/*transplantation ; Stem Cells/cytology ; }, abstract = {Although progressive neurodegenerative diseases have very different and highly specific causes, the dysfunction or loss of a vulnerable group of neurons is common to all these disorders and may allow the development of similar therapeutic approaches to the treatment of diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. When a disease is diagnosed, the first step is to instigate protective measures to prevent further degeneration. However, most patients are symptom-free until almost all of the vulnerable cells have become dysfunctional or have died. There are known molecular mechanisms and processes in stem cells and progenitor cells that may be of use in the future design and selection of cell-based replacement therapies for neurological diseases. This review provides examples of conceptual and clinical problems that have been encountered in the development of cell-based treatments, and specific criteria for the effective use of cells in the future treatment of neurodegenerative diseases.}, }
@article {pmid12847526, year = {2003}, author = {Lambrechts, D and Storkebaum, E and Morimoto, M and Del-Favero, J and Desmet, F and Marklund, SL and Wyns, S and Thijs, V and Andersson, J and van Marion, I and Al-Chalabi, A and Bornes, S and Musson, R and Hansen, V and Beckman, L and Adolfsson, R and Pall, HS and Prats, H and Vermeire, S and Rutgeerts, P and Katayama, S and Awata, T and Leigh, N and Lang-Lazdunski, L and Dewerchin, M and Shaw, C and Moons, L and Vlietinck, R and Morrison, KE and Robberecht, W and Van Broeckhoven, C and Collen, D and Andersen, PM and Carmeliet, P}, title = {VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death.}, journal = {Nature genetics}, volume = {34}, number = {4}, pages = {383-394}, doi = {10.1038/ng1211}, pmid = {12847526}, issn = {1061-4036}, mesh = {Aged ; Alleles ; Amyotrophic Lateral Sclerosis/drug therapy/etiology/*genetics/pathology ; Animals ; Cell Death/drug effects ; Child ; Child, Preschool ; Endothelial Growth Factors/*genetics/physiology/therapeutic use ; Female ; Genetic Variation ; Haplotypes ; Humans ; Intercellular Signaling Peptides and Proteins/*genetics/physiology/therapeutic use ; Ischemia/pathology ; Lymphokines/*genetics/physiology/therapeutic use ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; Middle Aged ; Motor Neurons/drug effects/pathology ; Nerve Degeneration/genetics ; Paralysis/etiology ; Spinal Cord Ischemia/drug therapy/pathology ; Sweden ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable degenerative disorder of motoneurons. We recently reported that reduced expression of Vegfa causes ALS-like motoneuron degeneration in Vegfa(delta/delta) mice. In a meta-analysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England, we now report that subjects homozygous with respect to the haplotypes -2,578A/-1,154A/-634G or -2,578A/-1,154G/-634G in the VEGF promoter/leader sequence had a 1.8 times greater risk of ALS (P = 0.00004). These 'at-risk' haplotypes lowered circulating VEGF levels in vivo and reduced VEGF gene transcription, IRES-mediated VEGF expression and translation of a novel large-VEGF isoform (L-VEGF) in vivo. Moreover, SOD1(G93A) mice crossbred with Vegfa(delta/delta) mice died earlier due to more severe motoneuron degeneration. Vegfa(delta/delta) mice were unusually susceptible to persistent paralysis after spinal cord ischemia, and treatment with Vegfa protected mice against ischemic motoneuron death. These findings indicate that VEGF is a modifier of motoneuron degeneration in human ALS and unveil a therapeutic potential of Vegfa for stressed motoneurons in mice.}, }
@article {pmid12843244, year = {2003}, author = {Kang, SJ and Sanchez, I and Jing, N and Yuan, J}, title = {Dissociation between neurodegeneration and caspase-11-mediated activation of caspase-1 and caspase-3 in a mouse model of amyotrophic lateral sclerosis.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {23}, number = {13}, pages = {5455-5460}, pmid = {12843244}, issn = {1529-2401}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics/pathology ; Animals ; Apoptosis/genetics ; Caspase 1/*metabolism ; Caspase 3 ; Caspases/deficiency/genetics/*metabolism ; Caspases, Initiator ; Disease Models, Animal ; Disease Progression ; Enzyme Activation ; Humans ; In Situ Nick-End Labeling ; Inflammation/pathology ; Interleukin-1/metabolism ; Mice ; Mice, Knockout ; Mice, Transgenic ; Spinal Cord/enzymology/*metabolism/pathology ; Superoxide Dismutase/genetics ; Survival Rate ; }, abstract = {Caspase-11 is a key regulator of caspase-1 and caspase-3 activation under pathological conditions. We show here that the expression of caspase-11 is upregulated in the spinal cord of superoxide dismutase 1 (SOD1) G93A transgenic mice, a mouse model of amyotrophic lateral sclerosis (ALS), before the onset of motor dysfunction and remains at the high levels throughout the course of disease. The caspase-1- and caspase-3-like activities, as well as the level of interleukin-1beta, were significantly reduced in the spinal cord of symptomatic caspase-11-/-;SOD1 G93A mice compared with that of caspase-11+/-; SOD1 G93A mice. However, neurodegeneration, inflammatory responses, and the disease onset and progression in SOD1 G93A transgenic mice were not altered by the ablation of caspase-11 gene. Thus, although caspases may contribute to certain aspects of pathology in this mouse model of ALS, their inhibition is not sufficient to prevent neurodegeneration. Our study urges caution when considering the inhibition of caspases as a direct therapeutic method for the treatment of chronic neurodegenerative diseases.}, }
@article {pmid12833127, year = {2003}, author = {Shi, L and Tang, GP and Gao, SJ and Ma, YX and Liu, BH and Li, Y and Zeng, JM and Ng, YK and Leong, KW and Wang, S}, title = {Repeated intrathecal administration of plasmid DNA complexed with polyethylene glycol-grafted polyethylenimine led to prolonged transgene expression in the spinal cord.}, journal = {Gene therapy}, volume = {10}, number = {14}, pages = {1179-1188}, doi = {10.1038/sj.gt.3301970}, pmid = {12833127}, issn = {0969-7128}, mesh = {Animals ; Apoptosis ; DNA/*administration &amp; dosage/adverse effects ; Gene Expression ; Genetic Therapy/adverse effects/*methods ; In Situ Nick-End Labeling ; Injections, Spinal ; Luciferases/genetics ; Male ; Polyethylene Glycols ; Polyethyleneimine ; Rats ; Rats, Wistar ; Spinal Cord/*metabolism/pathology ; Spinal Injuries/*therapy ; Time Factors ; }, abstract = {Gene delivery into the spinal cord provides a potential approach to the treatment of spinal cord traumatic injury, amyotrophic lateral sclerosis, and spinal muscular atrophy. These disorders progress over long periods of time, necessitating a stable expression of functional genes at therapeutic levels for months or years. We investigated in this study the feasibility of achieving prolonged transgene expression in the rat spinal cord through repeated intrathecal administration of plasmid DNA complexed with 25 kDa polyethylenimine (PEI) into the lumbar subarachnoid space. With a single injection, DNA/PEI complexes could provide transgene expression in the spinal cord 40-fold higher than naked plasmid DNA. The transgene expression at the initial level persisted for about 5 days, with a low-level expression being detectable for at least 8 weeks. When repeated dosing was tested, a 70% attenuation of gene expression was observed following reinjection at a 2-week interval. This attenuation was associated with apoptotic cell death and detected even using complexes containing a noncoding DNA that did not mediate any gene expression. When each component of the complexes, PEI polymer or naked DNA alone, were tested in the first dosing, no reduction was found. Using polyethylene glycol (PEG)-grafted PEI for DNA complexes, no attenuation of gene expression was detected after repeated intrathecal injections, even in those rats receiving three doses, administered 2 weeks apart. Lumbar puncture is a routine and relatively nontraumatic clinical procedure. Repeated administration of DNA complexed with PEG-grafted PEI through this less invasive route may prolong the time span of transgene expression when needed, providing a viable strategy for the gene therapy of spinal cord disorders.}, }
@article {pmid12829407, year = {2002}, author = {Pehar, M and Martínez-Palma, L and Peluffo, H and Kamaid, A and Cassina, P and Barbeito, L}, title = {Peroxynitrite-induced cytotoxicity in cultured astrocytes is associated with morphological changes and increased nitrotyrosine immunoreactivity.}, journal = {Neurotoxicity research}, volume = {4}, number = {2}, pages = {87-93}, pmid = {12829407}, issn = {1476-3524}, abstract = {We have established a cell culture model of spinal cord astrocytes to study the cytotoxicity of peroxynitrite. Nitric oxide (NO) has been implicated as a key contributor to neurotoxicity. NO reacts with superoxide to generate peroxynitrite, a strong oxidant and nitrating agent with deleterious cytotoxic and pro-apoptotic effects. Peroxynitrite and nitrotyrosine are formed in damaged motor neurons in amyotrophic lateral sclerosis (ALS), which are surrounded by reactive astrocytes. To determine the effects of extracellular addition of peroxynitrite, purified astrocyte monolayers prepared from neonatal rat spinal cords were exposed to peroxynitrite (0.25-0.75 mM) for 5 min and further incubated in culture medium for 24-72h. Peroxynitrite exposure did not result in apparent cell loss or damage of the monolayer. However, a substantial number of cells adopted reactive features, with long processes displaying intense immunoreactivity to glial fibrillary acidic protein (GFAP). Western blot analysis performed 24h after peroxynitrite treatment showed that GFAP levels were not modified by the oxidant. There were no changes in cell viability parameters in astrocyte cultures after peroxyintrite, indicating that astrocytes are more resistant to the oxidant than other cell types. Peroxynitrite reacts with protein-bound tyrosine residues to form nitrotyrosine. We observed a modest to strong nitrotyrosine immunoreactivity in astrocytes 24h following peroxynitrite exposure. There was a remarkable association between nitrotyrosine and high-intensity GFAP immunoreactivity in astrocytes bearing long processes. These results suggest that peroxynitrite induces a characteristic long-lasting reactive astrocytic phenotype and provide new insight into understanding the origin of reactive astrocytes occurring in ALS.}, }
@article {pmid12826943, year = {2003}, author = {Arslan, H and Kapukaya, A and Kesemenli, C and Subaşi, M and Kayikçi, C}, title = {Floating knee in children.}, journal = {Journal of pediatric orthopedics}, volume = {23}, number = {4}, pages = {458-463}, pmid = {12826943}, issn = {0271-6798}, mesh = {Adolescent ; Child ; Child, Preschool ; Female ; Femoral Fractures/*classification/therapy ; Humans ; Injury Severity Score ; Knee Injuries/*classification/therapy ; Male ; Retrospective Studies ; Risk Factors ; Tibial Fractures/*classification/therapy ; Treatment Outcome ; }, abstract = {The outcomes of 18 ipsilateral displaced femoral and tibial fractures in 17 children are assessed and a new classification system is proposed. Average age was 8.75 years, and follow-up averaged 3.2 years. In the modified Bohn and Durbin classification used, eight cases were type I, four were type II, three were type IIIa, one was type IIIb, and two were type IV. In tibial fractures there was angulation in three cases, and in femoral fractures there were dislocation and angulation in four cases, refracture in one case, leg length discrepancy in four cases, and asymptomatic knee ligament injury and meniscal tearing in five cases. According to Yue et al's criteria, seven outcomes were excellent, eight were good, two were fair, and two were poor. The cases with poor outcomes were those with open knee injury, and those with fair outcomes were those with angulation. It was concluded that knee ligament injuries do not affect the outcome of floating knee trauma in children, although they do in adults, but that open knee injuries do affect the outcome, and operative treatment of the femoral fracture is the treatment of choice for all ages.}, }
@article {pmid12818085, year = {2000}, author = {Niedźwiedzka, A}, title = {[Insulin-like growth factor 1 (somatomedin C) and its binding proteins 1 and 3 in children with special consideration of diabetes].}, journal = {Endokrynologia, diabetologia i choroby przemiany materii wieku rozwojowego : organ Polskiego Towarzystwa Endokrynologow Dzieciecych}, volume = {6}, number = {1}, pages = {51-58}, pmid = {12818085}, issn = {1234-625X}, abstract = {Insulin-like growth factor 1 (IGF-1, somatomedin C) belongs to a family of polypeptide hormones, which are structurally close relatives of insulin. Circulating IGF-1 is synthesised in the liver. Serum level of somatomedin is regulated by: growth hormone (GH), insulin and nutrition. It is also produced locally by most tissues, where it acts in auto- and paracrine manner. IGF-1 takes part in regulating growth after binding to IGF receptor during embryonic development and after birth. In adults somatomedin plays a role in the process of regeneration, mainly in the case of connective tissue. It is also a weak mitogen for most cultured cells and it can act like insulin. Somatomedin circulates in plasma in complex with a family of binding proteins. 85-95% of total IGF-1 is found in the complex consisting of IGF-1, binding protein 3 and ALS. This complex is a store of IGF and limits the access of somatomedin to specific receptors. After binding with IGFBP-1, IGFBP-2 and IGFBP-6, IGF-1 passes through epithelium and reaches the target cells. The serum concentration of this protein appears to be inversely related to insulin level. IGFBP-1 can modulate IGF growth-promoting effect. IGF and its binding proteins are important in the diagnosis and treatment of some pituitary diseases, catabolic states such as malnutrition, burns, AIDS, polytrauma and tumors with hypoglikemia. Insulin-like growth factors may be involved in the etiopathogenesis of diabetes and in diabetes complications. Abnormalities in functioning of GH-IGF-1 axis are regarded as a cause of the growth retardation in children with poor metabolic control of type 1 diabetes, insulin-resistance, dawn phenomenon and fat disorders. rhIGF has been used in the treatment of some diseases bringing positive results.}, }
@article {pmid12809687, year = {2003}, author = {Snow, RJ and Turnbull, J and da Silva, S and Jiang, F and Tarnopolsky, MA}, title = {Creatine supplementation and riluzole treatment provide similar beneficial effects in copper, zinc superoxide dismutase (G93A) transgenic mice.}, journal = {Neuroscience}, volume = {119}, number = {3}, pages = {661-667}, doi = {10.1016/s0306-4522(03)00212-4}, pmid = {12809687}, issn = {0306-4522}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/genetics ; Animals ; Anterior Horn Cells/*drug effects/enzymology/pathology ; Cell Death/drug effects/genetics ; Cerebral Cortex/drug effects/enzymology/physiopathology ; Creatine/*pharmacology/therapeutic use ; Disease Models, Animal ; Drug Synergism ; Drug Therapy, Combination ; Female ; Male ; Mice ; Mice, Transgenic ; Muscle, Skeletal/drug effects/enzymology ; Neuroprotective Agents/*pharmacology/therapeutic use ; Riluzole/*pharmacology/therapeutic use ; Superoxide Dismutase/*deficiency/genetics ; Treatment Outcome ; }, abstract = {This study investigated the effects of riluzole (Ril), creatine (Cr) and a combination of these treatments on the onset and progression of clinical signs and neuropathology in an animal model of familial amyotrophic lateral sclerosis, the G93A transgenic mouse (n=13-17 per group). The onset of clinical signs was delayed (P<0.05) by about 12 days in all treatment groups compared with control; however, no differences occurred between treatments. All animals were killed at 199 days of age. At the end of the experimental period the severity of clinical signs was less (P<0.05) with all treatments compared with control. Again no differences between treatments were observed. The treatments had no effect on the number of neurons in ventral horns of the lumbar region of the spinal cord. Transgenic mice ingesting Cr displayed elevated (P<0.05) total Cr levels in cerebral hemispheres (5%) and spinal cord (8%), but not skeletal muscles. These data demonstrate that treatment with Ril and Cr were both effective in delaying disease onset and clinical disability. To the age of killing, no additional benefit was conferred by co-administration of Ril and Cr.}, }
@article {pmid12807386, year = {2003}, author = {Ryberg, H and Askmark, H and Persson, LI}, title = {A double-blind randomized clinical trial in amyotrophic lateral sclerosis using lamotrigine: effects on CSF glutamate, aspartate, branched-chain amino acid levels and clinical parameters.}, journal = {Acta neurologica Scandinavica}, volume = {108}, number = {1}, pages = {1-8}, doi = {10.1034/j.1600-0404.2003.00111.x}, pmid = {12807386}, issn = {0001-6314}, mesh = {Adult ; Aged ; Amino Acids, Branched-Chain/*cerebrospinal fluid/*drug effects ; Amyotrophic Lateral Sclerosis/*cerebrospinal fluid/*drug therapy/physiopathology ; Aspartic Acid/*cerebrospinal fluid/*drug effects ; Cross-Over Studies ; Double-Blind Method ; Excitatory Amino Acid Antagonists/cerebrospinal fluid/*pharmacology/*therapeutic use ; Female ; Glutamic Acid/*cerebrospinal fluid/*drug effects ; Humans ; Lamotrigine ; Male ; Middle Aged ; Outcome Assessment, Health Care ; Triazines/cerebrospinal fluid/*pharmacology/*therapeutic use ; }, abstract = {OBJECTIVES: A study was conducted to examine the effect of lamotrigine (LTG) in amyotrophic lateral sclerosis (ALS).<br><br>MATERIAL AND METHODS: Patients were entered in a double-blind, placebo-controlled, crossover study. None of the patients were treated with riluzole, which was not approved for treatment of ALS in Sweden when the study started. After randomization, each patient was treated with placebo or LTG 300 mg daily, followed by a washout period and a second treatment period.<br><br>RESULTS: Thirty patients completed the study and were included in the analysis of the primary outcome, which was measured with clinical scales. The cerebrospinal fluid (CSF) levels of glutamate, aspartate, branched-chain amino acids and LTG were also measured. Changes for glutamate, valine and LTG were found during the progression of the disease. The clinical parameters and the levels of CSF amino acids were similar for the two treatment groups.<br><br>CONCLUSION: No clinical effect of LTG on ALS progression could be found.}, }
@article {pmid12792521, year = {2003}, author = {Dufour, JM and Rajotte, RV and Kin, T and Korbutt, GS}, title = {Immunoprotection of rat islet xenografts by cotransplantation with sertoli cells and a single injection of antilymphocyte serum.}, journal = {Transplantation}, volume = {75}, number = {9}, pages = {1594-1596}, doi = {10.1097/01.TP.0000058748.00707.88}, pmid = {12792521}, issn = {0041-1337}, mesh = {Animals ; Antilymphocyte Serum/*therapeutic use ; Graft Rejection/prevention &amp; control ; Graft Survival ; Islets of Langerhans Transplantation/*methods ; Male ; Mice ; Mice, Inbred BALB C ; Rats ; Rats, Inbred Lew ; Sertoli Cells/*transplantation ; Transplantation, Heterologous/*immunology ; }, abstract = {BACKGROUND: Islet transplantation has become a clinical reality; however, before it can be extended to young juvenile diabetics an unlimited supply of tissue is needed and the use of chronic immunosuppression should be eliminated. This study was designed to determine whether Sertoli cells can immunoprotect islet xenografts.<br><br>METHODS: Lewis rat islets were cotransplanted with Balb/c Sertoli cells in diabetic Balb/c mice treated with one injection of anti-mouse lymphocyte serum (ALS).<br><br>RESULTS: When islets were transplanted alone, in combination with Sertoli cells, or in combination with ALS, mean graft survival times were 10.9+/-0.8, 14.0+/-1.2, or 12.2+/-0.7, respectively. When islets were combined with Sertoli cells and ALS, mean graft survival time increased to 64.9+/-8.1.<br><br>CONCLUSIONS: Sertoli cells are able to prolong the survival of islet xenografts when combined with ALS, thereby supporting their use as a means to immunoprotect cellular grafts such as islets for the treatment of type 1 diabetes.}, }
@article {pmid12792307, year = {2003}, author = {Rojas-Marcos, I and Rousseau, A and Keime-Guibert, F and Reñé, R and Cartalat-Carel, S and Delattre, JY and Graus, F}, title = {Spectrum of paraneoplastic neurologic disorders in women with breast and gynecologic cancer.}, journal = {Medicine}, volume = {82}, number = {3}, pages = {216-223}, doi = {10.1097/01.md.0000076004.64510.ce}, pmid = {12792307}, issn = {0025-7974}, mesh = {Aged ; Antibodies, Neoplasm/immunology ; Antigens, Neoplasm/immunology ; Breast Neoplasms/*complications ; Female ; Genital Neoplasms, Female/*complications ; Humans ; Middle Aged ; Paraneoplastic Polyneuropathy/*complications/immunology ; Retrospective Studies ; }, abstract = {We conducted the current review of the paraneoplastic neurologic syndromes (PNSs) associated with gynecologic and breast carcinomas to describe their clinical and immunologic characteristics and their relative frequency. We retrospectively reviewed 92 patients whose serum was sent to our laboratories to detect onconeural antibodies and who were diagnosed as having PNSs associated with breast or gynecologic tumors. PNSs were defined as "definitive" and "possible" (atypical PNS, no onconeural antibodies, and no improvement after tumor treatment). Forty-nine patients had breast and 43 had gynecologic cancer. Sixty-three patients had onconeural antibodies (50 Yo-ab, 5 Hu-ab, 5 Ri-ab, and 3 amphiphysin-ab). Cerebellar ataxia represented 57 (62%) of all PNSs and was associated with anti-Yo in 88%. All Yo-abnegative patients had breast cancer; 4 of them had a mild cerebellar syndrome that improved after tumor treatment. Sensorypredominant neuropathies were present in 17 (18%) patients. Seven of them had Hu-ab (5) or amphiphysin-ab (2). Other PNSs were opsoclonus-myoclonus syndrome (4 cases, Ri-ab in 2), sensorimotor neuropathy (4 cases), paraneoplastic encephalomyelitis (4 cases, Ri-ab in 3), paraneoplastic retinopathy (2 cases), amyotrophic lateral sclerosis (2 cases), stiff-person syndrome (1 with amphiphysin-ab), and limbic encephalitis (1 case). All patients with gynecologic cancer presented definitive PNS, and onconeural antibodies were diagnosed in 93% of them. In contrast, 20% of PNSs associated with breast cancer were defined as possible and the incidence of onconeural antibodies was 51%, excluding the 2 patients with paraneoplastic retinopathy in whom antiretinal antibodies were not analyzed. In patients with possible PNS, a coincidental association between the tumor and the neurologic disorder cannot be excluded.}, }
@article {pmid12789618, year = {2003}, author = {Carter, GT and Krivickas, LS and Weydt, P and Weiss, MD and Miller, RG}, title = {Drug therapy for amyotrophic lateral sclerosis: Where are we now?.}, journal = {IDrugs : the investigational drugs journal}, volume = {6}, number = {2}, pages = {147-153}, pmid = {12789618}, issn = {1369-7056}, support = {HB133B980008/HB/NHLBI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/etiology ; Animals ; Antioxidants/therapeutic use ; Clinical Trials as Topic ; Creatine/therapeutic use ; Cyclooxygenase Inhibitors/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; Riluzole/therapeutic use ; Treatment Outcome ; }, abstract = {In the 60 years since Lou Gehrig died from amyotrophic lateral sclerosis (ALS) there have been numerous advances in our understanding of this disease. However, scant progress has been made regarding disease-altering treatments. Today most physicians still recommend vitamin E, which is the treatment Gehrig himself received. In this paper we will review what is currently known about the pathophysiology of ALS as well as the history of clinical trials in ALS. We indicate current and future directions in research and clinical trials, and also argue that a logical next step for clinical trials in ALS should be combination drug treatment.}, }
@article {pmid12769802, year = {2003}, author = {Di Matteo, V and Esposito, E}, title = {Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, journal = {Current drug targets. CNS and neurological disorders}, volume = {2}, number = {2}, pages = {95-107}, doi = {10.2174/1568007033482959}, pmid = {12769802}, issn = {1568-007X}, mesh = {Alzheimer Disease/*drug therapy/metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Antioxidants/metabolism/*therapeutic use ; Humans ; Parkinson Disease/*drug therapy/metabolism ; }, abstract = {Aging is a major risk factor for neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). An unbalanced overproduction of reactive oxygen species (ROS) may give rise to oxidative stress which can induce neuronal damage, ultimately leading to neuronal death by apoptosis or necrosis. A large body of evidence indicates that oxidative stress is involved in the pathogenesis of AD, PD, and ALS. Several studies have shown that nutritional antioxidants (especially vitamin E and polyphenols) can block neuronal death in vitro, and may have therapeutic properties in animal models of neurodegenerative diseases including AD, PD, and ALS. Moreover, clinical data suggest that nutritional antioxidants might exert some protective effect against AD, PD, and ALS. In this paper, the biochemical mechanisms by which nutritional antioxidants can reduce or block neuronal death occurring in neurodegenerative disorders are reviewed. Particular emphasis will be given to the role played by the nuclear transcription factor -kB (NF-kB) in apoptosis, and in the pathogenesis of neurodegenerative disorders, such as AD, PD, and ALS. The effects of ROS and antioxidants on NF-kB function and their relevance in the pathophysiology of neurodegenerative diseases will also be examined.}, }
@article {pmid12753090, year = {2003}, author = {Aquilano, K and Rotilio, G and Ciriolo, MR}, title = {Proteasome activation and nNOS down-regulation in neuroblastoma cells expressing a Cu,Zn superoxide dismutase mutant involved in familial ALS.}, journal = {Journal of neurochemistry}, volume = {85}, number = {5}, pages = {1324-1335}, doi = {10.1046/j.1471-4159.2003.01783.x}, pmid = {12753090}, issn = {0022-3042}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Cell Survival/physiology ; Cyclic N-Oxides/pharmacology ; Cysteine Endopeptidases/*metabolism ; Down-Regulation ; Enzyme Inhibitors/pharmacology ; Humans ; Multienzyme Complexes/antagonists &amp; inhibitors/*metabolism ; Mutation ; Neuroblastoma/drug therapy/*enzymology ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/*metabolism ; Nitric Oxide Synthase Type I ; Oxidation-Reduction/drug effects ; Proteasome Endopeptidase Complex ; Proteins/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/*biosynthesis/genetics ; Tumor Cells, Cultured ; }, abstract = {Reactive oxygen and nitrogen species have emerged as predominant effectors of neurodegeneration. We demonstrated that expression of the fully active G93A Cu,Zn superoxide dismutase mutant in neuroblastoma cells is associated with an increased level of oxidatively modified proteins, in terms of carbonylated residues. A parallel increase in proteasome activity was detected and this was mandatory in order to assure cell viability. In fact, proteasome inhibition by lactacystin or MG132 resulted in programmed cell death. Nitrosative stress was not involved in the oxidative unbalance, as a decrease in neuronal nitric oxide production and down-regulation of neuronal nitric oxide synthase (nNOS) level were detected. The nNOS down-regulation was correlated to increased proteolytic degradation by proteasome, because comparable levels of nNOS were detected in G93A and parental cells upon treatment with lactacystin. The altered rate of proteolysis observed in G93A cells was specific for nNOS as Cu,Zn superoxide dismutase (Cu,Zn SOD) degradation by proteasome was influenced neither by its mutation nor by increased proteasome activity. Treatment with the antioxidant 5,5'-dimethyl-1-pyrroline N-oxide resulted in inhibition of protein oxidation and decrease in proteasome activity to the basal levels. Overall these results confirm the pro-oxidant activity of G93A Cu,Zn SOD mutant and, at the same time, suggest a cross-talk between reactive oxygen and nitrogen species via the proteasome pathway.}, }
@article {pmid12750868, year = {2003}, author = {Kniess, A and Ziegler, E and Kratzsch, J and Thieme, D and Müller, RK}, title = {Potential parameters for the detection of hGH doping.}, journal = {Analytical and bioanalytical chemistry}, volume = {376}, number = {5}, pages = {696-700}, doi = {10.1007/s00216-003-1926-x}, pmid = {12750868}, issn = {1618-2642}, mesh = {Adult ; Biomarkers/blood ; Discriminant Analysis ; Doping in Sports/*prevention &amp; control ; Double-Blind Method ; False Positive Reactions ; Human Growth Hormone/*administration &amp; dosage/*blood ; Humans ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/analysis ; Leptin/blood ; Male ; Osteocalcin/blood ; Peptide Fragments/blood ; Procollagen/blood ; Reproducibility of Results ; Sensitivity and Specificity ; Substance Abuse Detection/*methods ; }, abstract = {The aim of our hGH application study with non-competitive athletes was the investigation of selected serum parameters from different processes affected by hGH. Fifteen athletes (age 21-33, mean 24) were treated with 0.06 IU hGH/kg BW per day or placebo (10 hGH, 5 placebo) respectively for 14 days. Blood samples were taken prior to, during and until 10 weeks after treatment. The concentrations of the following markers were determined in relevant serum samples: IGF-I, IGFBP-3, ALS, PIIINP, PINP, osteocalcin, and leptin. The IGF-I concentration increased rapidly within the hGH treatment group and showed significantly higher levels compared to baseline even 3 days after application. The response of the IGFBP-3 to the hGH applications was lower in comparison to IGF-I. The hGH group showed an increasing IGFBP-3 compared to baseline from day 4 till day 15. The response of PIIINP to hGH is clearly delayed compared to the IGF-I axis, but the PIIINP concentration remains on an increased level for a longer period (from day 4 until day 21). The time course and the extent of response varied strongly interindividually. PINP and osteocalcin showed only a small response to hGH applications. These parameters are characterised by a strong scattering of base values compared with the small response. In the hGH treatment group very different leptin concentrations were found at the beginning of the study, but after treatment decreasing leptin levels were observed in all cases. The determination of only one parameter will not be sufficient for detection of hGH abuse. A combination of markers by mathematical methods can be helpful to distinguish between placebo and hGH-treated athletes. By using the suggested discriminant function the data sets of hGH and placebo-treated athletes could be separated without false positive results.}, }
@article {pmid12747650, year = {2003}, author = {Cavallini, GM and Lugli, N and Campi, L and Pagliani, L and Saccarola, P}, title = {Bottle-cork injury to the eye: a review of 13 cases.}, journal = {European journal of ophthalmology}, volume = {13}, number = {3}, pages = {287-291}, doi = {10.1177/112067210301300308}, pmid = {12747650}, issn = {1120-6721}, mesh = {Adult ; Aged ; Aged, 80 and over ; *Alcoholic Beverages ; Anterior Chamber/injuries ; Eye Injuries/*etiology/therapy ; Female ; Glaucoma/etiology ; Humans ; Hyphema/etiology/therapy ; Lens Subluxation/etiology ; Macular Edema/etiology ; Male ; Middle Aged ; Retrospective Studies ; Treatment Outcome ; Visual Acuity ; Wounds, Nonpenetrating/*etiology/therapy ; }, abstract = {PURPOSE: To analyze the anatomic and functional consequences of wine-cork injury to the eye in relation to the patient's age and the type of cork and wine.<br><br>METHODS: We retrospectively studied 13 patients, six women and seven men, presenting to our department with bottle-cork injury to the eye between January 1999 and June 2001.<br><br>RESULTS: All patients presented with closed-globe injury according to Kuhn et al's classification. All the cases were injured by bottle corks from sparkling wine: white in ten cases and red in three. Mean visual acuity at admission was 20/100 (range, hand motion to 20/20). The most frequent early injury was anterior chamber hyphema (84.6%), followed by corneal injury (62.2%), ocular hypertension (46.1%), lens subluxation (30.8%), traumatic cataract (23.1%), and post-traumatic retinal edema (23.1%). Mean final visual acuity was 20/25; the follow-up ranged from 3 to 29 months, averaging 16.1 months. Late complications were as follows: pupil motility anomalies (38.5%), traumatic cataract (30.8%), iridodialysis (15.4%), traumatic optic neuropathy (7.7%), post-traumatic glaucoma (7.7%), and traumatic maculopathy (15.4%). Surgical treatment was necessary in two cases (15.4%).<br><br>CONCLUSIONS: Bottle-cork eye injuries account for 10.8% of post-traumatic hospital admissions to our department. Most of them are due to sparkling white wine served at room temperature. There is no correlation between ocular injury and the eye-bottle distance or the type of cork.}, }
@article {pmid12745614, year = {2003}, author = {Kalra, S and Genge, A and Arnold, DL}, title = {A prospective, randomized, placebo-controlled evaluation of corticoneuronal response to intrathecal BDNF therapy in ALS using magnetic resonance spectroscopy: feasibility and results.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {1}, pages = {22-26}, doi = {10.1080/14660820310006689}, pmid = {12745614}, issn = {1466-0822}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Aspartic Acid/*analogs &amp; derivatives/analysis/chemistry/*metabolism ; Biomarkers/analysis/chemistry ; Brain Chemistry ; Brain-Derived Neurotrophic Factor/*administration &amp; dosage ; Feasibility Studies ; Female ; Humans ; Infusion Pumps, Implantable ; Injections, Spinal ; Magnetic Resonance Spectroscopy/methods ; Male ; Middle Aged ; Motor Cortex/chemistry/*drug effects/metabolism ; Motor Neurons/chemistry/*drug effects/metabolism ; Placebos ; Prospective Studies ; Sensitivity and Specificity ; Treatment Outcome ; }, abstract = {During the multicenter, phase III trial of intrathecal BDNF in ALS, we evaluated the neuronal marker N-acetylaspartate (NAA) as a surrogate marker of therapeutic efficacy using proton magnetic resonance spectroscopic imaging (MRSI) in a prospective and blinded manner. Selected subjects tolerated the study well without pump malfunction. The NAA to creatine (Cr) intensity ratio (NAA/Cr) was measured in the precentral and postcentral gyri, the superior parietal lobule, the supplementary motor area, and the premotor cortex. After 4.5+/-0.6 weeks treatment, NAA/Cr did not change significantly in any of the regions in the BDNF-treated group (n=5) compared to the placebo group (n=6). The lack of change in NAA correlated with the lack of clinical efficacy and supports the validity of NAA/Cr as a surrogate in this setting. MRSI is a feasible and safe method to evaluate intrathecal therapies in ALS.}, }
@article {pmid12745612, year = {2003}, author = {Bryan, WW and Hoagland, RJ and Murphy, J and Armon, C and Barohn, RJ and Goodpasture, JC and Miller, RG and Parry, GJ and Petajan, JH and Ross, MA and Stromatt, SC and , }, title = {Can we eliminate placebo in ALS clinical trials?.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {1}, pages = {11-15}, doi = {10.1080/14660820310006661}, pmid = {12745612}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy/physiopathology ; Arm/physiopathology ; Double-Blind Method ; Follow-Up Studies ; Humans ; Leg/physiopathology ; Muscle Contraction ; Muscle, Skeletal/physiopathology ; Nerve Growth Factors/*therapeutic use ; Physical Examination/methods ; *Placebos ; Quality Control ; Randomized Controlled Trials as Topic/*methods/trends ; Research Design ; Respiratory Muscles/physiopathology ; Statistics as Topic ; Treatment Outcome ; Vital Capacity ; }, abstract = {BACKGROUND: Previous studies concluded that the decline in strength in patients with amyotrophic lateral sclerosis (ALS) is a linear function. If so, a patient's natural history might serve as the control, instead of placebo, in a clinical trial.<br><br>METHODS: A placebo-controlled ALS clinical trial included a natural history phase, followed by a 6-month treatment phase. Each patient's forced vital capacity (FVC) score and maximal voluntary isometric contraction (MVIC) raw scores were measured monthly, standardized, and averaged into megascores. For 138 patients, the arm, leg, FVC, arm+leg combination, and arm+leg+FVC combination megascore slopes during the natural history phase and during the placebo phase were compared.<br><br>RESULTS: The mean slope of megascores during the natural history phase and the mean slope during the placebo phase were not different for the arm, leg, and arm+leg megascores, but were different for the FVC and arm+leg+FVC combination megascores.<br><br>CONCLUSIONS: Natural history controls may be useful in ALS exploratory trials that use arm megascore slope as the primary outcome measure. However, there are distinct limitations to the use of natural history controls, so that Phase 3 ALS clinical trials require placebo controls.}, }
@article {pmid12745611, year = {2003}, author = {Silani, V and Leigh, N}, title = {Stem therapy for ALS: hope and reality.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {4}, number = {1}, pages = {8-10}, pmid = {12745611}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*surgery ; Animals ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons/*transplantation ; Nerve Regeneration/*physiology ; Stem Cell Transplantation/*methods ; Stem Cells/*physiology ; }, abstract = {All are agreed that there is pressing need for an effective treatment for Amyotrophic Lateral Sclerosis (ALS; MND). Such treatment may derive from a combination of therapeutic strategies aimed at different aspects of the disorder, and might include drugs directed at the initial, intermediate or terminal cascade of events leading to cell death, as well as the use of stem cells to replace dead motor neurons, or to protect those that remain. The attraction of cell implantation or transplantation is that it might help to overcome the inability of the CNS to replace lost neurons. It is also clear that neural implantation will yield little benefit if the donor cells fail to integrate functionally into the recipient CNS circuitry. In this respect, ALS poses an especially difficult problem. The recent breakthroughs in stem cell research might nevertheless provide possibilities for neural implantation and cell replacement therapy for patients with ALS. The potential impact of these new approaches to neurodegenerative diseases has been emphasised by the many experiments using human foetal cell grafts in patients affected by Parkinson's and Huntington's disease. Clinical benefits in Parkinson's disease seem to be associated with integration of the donor cells into the recipient brain. Despite promising results, however, significant constraints have hampered the use of foetal cells for neural implantation and transplantation. Besides ethical concerns, the viability, purity, and final destiny of the foetal tissue have not been completely defined. Foetal cells are, in addition, post-mitotic and cannot be expanded or stored for long periods, necessitating close synchronisation of tissue donation and neurosurgery.}, }
@article {pmid12728191, year = {2003}, author = {Mattson, MP}, title = {Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders.}, journal = {Neuromolecular medicine}, volume = {3}, number = {2}, pages = {65-94}, pmid = {12728191}, issn = {1535-1084}, mesh = {Animals ; Cell Death/drug effects/*physiology ; Cell Survival/drug effects/*physiology ; Central Nervous System/drug effects/*metabolism/physiopathology ; Humans ; Neurodegenerative Diseases/drug therapy/*physiopathology/prevention &amp; control ; Neurons/drug effects/*metabolism/pathology ; Neurotoxins/*pharmacology ; Oxidative Stress/drug effects/physiology ; Receptors, Glutamate/drug effects/*metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {Activation of glutamate receptors can trigger the death of neurons and some types of glial cells, particularly when the cells are coincidentally subjected to adverse conditions such as reduced levels of oxygen or glucose, increased levels of oxidative stress, exposure to toxins or other pathogenic agents, or a disease-causing genetic mutation. Such excitotoxic cell death involves excessive calcium influx and release from internal organelles, oxyradical production, and engagement of programmed cell death (apoptosis) cascades. Apoptotic proteins such as p53, Bax, and Par-4 induce mitochondrial membrane permeability changes resulting in the release of cytochrome c and the activation of proteases, such as caspase-3. Events occurring at several subcellular sites, including the plasma membrane, endoplasmic reticulum, mitochondria and nucleus play important roles in excitotoxicity. Excitotoxic cascades are initiated in postsynaptic dendrites and may either cause local degeneration or plasticity of those synapses, or may propagate the signals to the cell body resulting in cell death. Cells possess an array of antiexcitotoxic mechanisms including neurotrophic signaling pathways, intrinsic stress-response pathways, and survival proteins such as protein chaperones, calcium-binding proteins, and inhibitor of apoptosis proteins. Considerable evidence supports roles for excitotoxicity in acute disorders such as epileptic seizures, stroke and traumatic brain and spinal cord injury, as well as in chronic age-related disorders such as Alzheimer's, Parkinson's, and Huntington's disease and amyotrophic lateral sclerosis. A better understanding of the excitotoxic process is not only leading to the development of novel therapeutic approaches for neurodegenerative disorders, but also to unexpected insight into mechanisms of synaptic plasticity.}, }
@article {pmid12710513, year = {2002}, author = {Hecht, M and Hillemacher, T and Gräsel, E and Tigges, S and Winterholler, M and Heuss, D and Hilz, MJ and Neundörfer, B}, title = {Subjective experience and coping in ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {3}, number = {4}, pages = {225-231}, doi = {10.1080/146608202760839009}, pmid = {12710513}, issn = {1466-0822}, mesh = {*Adaptation, Psychological ; Aged ; Amyotrophic Lateral Sclerosis/physiopathology/*psychology ; *Awareness ; Female ; Follow-Up Studies ; Humans ; Interview, Psychological ; *Life Change Events ; Male ; Middle Aged ; Psychometrics ; Quality of Life ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis is a rapidly progressive and fatal disease which has no known cure and limited symptomatic treatment. While coping strategies in more common diseases are widely assessed, coping is poorly understood in ALS.<br><br>METHODS: We examined 41 ALS patients using a standardised interview, a validated coping self-rating questionnaire and a self-rating depression scale. The evaluation was repeated after six months.<br><br>RESULTS: "Loss of speech", "loss of mobility" and "the poor prognosis" were the most frequent answers in the standardised interview to questions regarding the worst aspect of the disease. Pain was seldom mentioned. "Family members" were most helpful in coping with the disease, followed by "unspecific mechanisms" and "technical aids". None of our patients expressed a wish for assisted suicide. In comparison with other fatal diseases, patients with ALS had similar rankings in the coping mechanism of "rumination", but lower rankings in "search for social integration", "defence of fear", "search for information and communication". In contrast,* "search for hold in the religion" was of high importance for our ALS patients. In the follow-up examination the importance of "search for information and communication" increased.<br><br>CONCLUSION: The results emphasise the importance of "loss of speech" and the importance of the caring family as well as the availability of technical aids in ALS. Coping in ALS seems to be based mainly on "rumination" and *"hold in the religion", but the increasing importance of "search for information" indicates that the sustained offer of information is essential.}, }
@article {pmid12710507, year = {2002}, author = {Hanemann, CO and Ludolph, AC}, title = {Hereditary motor neuropathies and motor neuron diseases: which is which.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {3}, number = {4}, pages = {186-189}, doi = {10.1080/146608202760839003}, pmid = {12710507}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/classification/*diagnosis/etiology ; Animals ; Diagnosis, Differential ; Humans ; Motor Neuron Disease/classification/*diagnosis/etiology ; Muscular Atrophy, Spinal/diagnosis/etiology ; Mutation ; Phenotype ; Syndrome ; }, abstract = {When Charcot first defined amyotrophic lateral sclerosis (ALS) he used the clinical and neuropathological pattern of vulnerability as a guideline. Similarly other motor neuron diseases such as the spinal muscular atrophies (SMA) and the motor neuropathies (MN) were grouped following clinical criteria. However, ever since the etiology of these diseases has started to be disclosed by genetics, we have learnt that the limits of the syndromes are not as well defined as our forefathers thought. A mutation leading to ALS can also be associated with the clinical picture of spinal muscular atrophy; even more unexpected is the overlap of the so-called motor neuropathies with the clinical syndrome of slowly progressive ALS or that primary lateral sclerosis (PLS) can be caused by the same gene as that responsible for some cases of ALS. In this review we summarise recent work showing that there is a considerable overlap between CMT, MN, SMA, ALS and PLS. Insights into these phenotypes should lead to study of the variants of motor neuron disease and possibly to a reclassification. This comprehensive review should help to improve understanding of the pathogenesis of motor neuron degeneration and finally may aid the research for urgently needed new treatment strategies, perhaps with validity for the entire group of motor neuron diseases.}, }
@article {pmid12710505, year = {2002}, author = {Silani, V and Fogh, I and Ratti, A and Sassone, J and Ciammola, A and Cova, L}, title = {Stem cells in the treatment of amyotrophic lateral sclerosis (ALS).}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {3}, number = {4}, pages = {173-181}, doi = {10.1080/146608202760839001}, pmid = {12710505}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*therapy ; Animals ; Central Nervous System ; Disease Models, Animal ; Humans ; In Vitro Techniques ; Mice ; Mice, Transgenic ; Motor Neurons ; Rats ; *Stem Cell Transplantation ; Stem Cells/*physiology ; }, abstract = {Until fairly recently, interest in stem cells was restricted to neurobiology studies on the principles of embryonic development. This situation has changed rapidly in the last few years when neuronal stems and precursors were isolated in vitro, thus allowing expansion and controlled differentiation of selective populations of neuronal cells. This theoretically unlimited reserve would then supply specific cells for transplantation in diseases characterized by widespread degeneration of selective cell populations as motor neurons in Amyotrophic Lateral Sclerosis (ALS). The recent evidence of cell transdifferentiation has further amplified the potential therapeutic use of stem cells. Stem cell technology is at an early stage but the desperate need for a therapy in ALS patients may legitimize clinical trials in absence of conclusive scientific evidence. This paper discusses the premises for stem cell therapy in ALS.}, }
@article {pmid12710113, year = {2003}, author = {Dawson, S and Kristjanson, LJ}, title = {Mapping the journey: family carers' perceptions of issues related to end-stage care of individuals with muscular dystrophy or motor neurone disease.}, journal = {Journal of palliative care}, volume = {19}, number = {1}, pages = {36-42}, pmid = {12710113}, issn = {0825-8597}, mesh = {Caregivers/education/*psychology ; Fear/psychology ; Female ; Grief ; Humans ; Interviews as Topic ; Male ; Motor Neuron Disease/parasitology/*therapy ; Muscular Dystrophies/parasitology/*therapy ; Needs Assessment ; Palliative Care/psychology ; Quality of Life ; Terminal Care/*psychology/standards ; }, abstract = {Progress in medical technology and treatment has resulted in more people with neurodegenerative conditions surviving for longer periods of time. This increased lifespan means that these individuals have a longer period of dependency on others, with a heightened need to maintain quality of life for both the individual and the family. Our paper reports on the findings of a study involving in-depth interviews with 16 carers to determine their perceived needs during the final stage of caring for someone with muscular dystrophy (MD) or motor neurone disease. Results suggest that the palliative care model has much to offer individuals with degenerative neuromuscular conditions and their families, but it is not yet recognized as an important part of care for young people with MD. Three major themes emerged in the analysis: reactions and responses, health system crossing points, reaching forward.}, }
@article {pmid12700914, year = {2003}, author = {Traynor, BJ and Alexander, M and Corr, B and Frost, E and Hardiman, O}, title = {An outcome study of riluzole in amyotrophic lateral sclerosis--a population-based study in Ireland, 1996-2000.}, journal = {Journal of neurology}, volume = {250}, number = {4}, pages = {473-479}, doi = {10.1007/s00415-003-1026-z}, pmid = {12700914}, issn = {0340-5354}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Drug Administration Schedule ; Female ; Humans ; Ireland ; Male ; Middle Aged ; Motor Neurons/pathology ; Neuroprotective Agents/administration &amp; dosage/*pharmacology ; Prognosis ; Registries/*statistics &amp; numerical data ; Retrospective Studies ; Riluzole/administration &amp; dosage/*pharmacology ; Survival ; Treatment Outcome ; }, abstract = {Riluzole is the only therapy proven in clinical trials to prolong amyotrophic lateral sclerosis (ALS) survival (approximately three months). Questions remain concerning riluzole's effectiveness in everyday practice, the appropriate duration of treatment, which certain subtypes of ALS specifically benefit from the medication, and whether early administration prolongs survival in ALS patients. We report the results of a population-based outcome study of riluzole in the Irish ALS population over a five-year period. Using data from the Irish ALS Register, we examined the survival of patients diagnosed with ALS between 1 January 1996 and 31 December 2000 who attended a general neurology clinic (n = 264 patients, MD = 16). An intention to treat analysis is employed. 149 (61 %) patients were prescribed riluzole and the remaining 99 (39 %) were not. Riluzole therapy reduced mortality rate by 23 % and 15 % at 6 and 12 months respectively and prolonged survival by approximately four months. This beneficial effect was lost in prolonged follow-up. Suspected or possible ALS patients receiving riluzole experienced similar improvement in survival as the overall cohort. Survival benefit was more marked among patients with bulbar-onset disease. Multivariate analysis did not show riluzole to be an independent predictor of survival. We conclude that riluzole therapy improves ALS survival in everyday clinical practice by a short period of time. This beneficial effect is transient and stopping the medication in advanced ALS should be reconsidered. Bulbar-onset patients appear to particularly benefit from riluzole for unclear reasons. Our initial observations support riluzole use in early ALS.}, }
@article {pmid12699624, year = {2003}, author = {Ferri, A and Sanes, JR and Coleman, MP and Cunningham, JM and Kato, AC}, title = {Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease.}, journal = {Current biology : CB}, volume = {13}, number = {8}, pages = {669-673}, doi = {10.1016/s0960-9822(03)00206-9}, pmid = {12699624}, issn = {0960-9822}, mesh = {Animals ; Apoptosis/*physiology ; Axons/*pathology ; Crosses, Genetic ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Motor Neuron Disease/*pathology/*physiopathology/therapy ; Nerve Tissue Proteins/genetics/therapeutic use ; Neuromuscular Junction/anatomy &amp; histology ; Staining and Labeling ; Synapses/*pathology ; }, abstract = {Apoptosis is a hallmark of motoneuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) [1]. In a widely used mouse model of motoneuron disease (progressive motor neuronopathy or pmn) [2-4], transgenic expression of the anti-apoptotic bcl-2 gene [5] or treatment with glial cell-derived neurotrophic factor [6] prevents the apoptosis of the motoneuron soma; however, they were unable to affect the life span of the animals. The goal of the present work was to determine whether the pmn phenotype could be rescued by means of a gene that inhibits axon degeneration. For this reason, the pmn mice were crossed with mice bearing the dominant Wlds ("slow Wallerian degeneration") mutation, which slows axon degeneration and synapse loss [7-9]. We show here that the Wlds gene product attenuates symptoms, extends life span, prevents axon degeneration, rescues motoneuron number and size, and delays retrograde transport deficits in pmn/pmn mice. These results suggest new pathogenic mechanisms and therapeutic avenues for motoneuron diseases.}, }
@article {pmid12698081, year = {2003}, author = {Li, H and Inverardi, L and Molano, RD and Pileggi, A and Ricordi, C}, title = {Nonlethal conditioning for the induction of allogeneic chimerism and tolerance to islet allografts.}, journal = {Transplantation}, volume = {75}, number = {7}, pages = {966-970}, doi = {10.1097/01.TP.0000058516.74246.71}, pmid = {12698081}, issn = {0041-1337}, mesh = {Animals ; Bone Marrow Transplantation ; Diabetes Mellitus, Experimental/surgery ; Graft Survival ; Islets of Langerhans/pathology/physiopathology ; *Islets of Langerhans Transplantation ; Male ; Mice ; Mice, Inbred Strains ; *Transplantation Chimera ; *Transplantation Conditioning ; *Transplantation Tolerance ; Transplantation, Homologous ; }, abstract = {BACKGROUND: We reported that tolerance to skin grafts can be achieved by chimerism induction by way of nonlethal conditioning. In the present study, we evaluated the outcome of islet allografts implanted either simultaneously or after donor bone marrow cell (BMC) infusion when nonlethal conditioning was used.<br><br>METHODS AND RESULTS: B10 (H-2b) mice were conditioned with antilymphocyte serum (ALS), 100 cGy total body irradiation (TBI), and given 30 x 10(6) allogeneic (B10.BR, H-2k) BMC on day 0. On day 2, cyclophosphamide was given intraperitoneally (IP), followed by a second BMC infusion on day 3. After chimeras were typed for allogeneic BMC engraftment on day 28, animals were rendered diabetic chemically and transplanted under the kidney capsule with islet allografts genetically matched or disparate to the BM. Donor-specific islet grafts were accepted (median survival time [MST] > 180 days, n=6), whereas all major histocompatibility complex (MHC)-disparate third-party BALB/c (H-2d) islet grafts were rejected (MST=13.8 days, n=4). When B10.BR BMC and islets were given simultaneously, graft acceptance (MST >140 days, n=4) was observed. Surprisingly, when MHC-disparate third-party islets (BALB/c) were given together with B10.BR BMC, long-term survival was also observed (MST >100 days, n=3). These findings suggested that conditioning alone at the time of islet implant might induce long-term engraftment without further treatment. However, only chimeric animals accepted a second-set donor-specific graft, whereas all other groups rejected it.<br><br>CONCLUSION: Our data indicates that stable allogeneic chimerism and islet indefinite survival can be achieved by the use of a nonmyeloablative protocol. The results of the conditioning-only experiments are consistent with the possibility of graft accommodation.}, }
@article {pmid12686407, year = {2003}, author = {Trail, M and Nelson, ND and Van, JN and Appel, SH and Lai, EC}, title = {A study comparing patients with amyotrophic lateral sclerosis and their caregivers on measures of quality of life, depression, and their attitudes toward treatment options.}, journal = {Journal of the neurological sciences}, volume = {209}, number = {1-2}, pages = {79-85}, doi = {10.1016/s0022-510x(03)00003-0}, pmid = {12686407}, issn = {0022-510X}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/complications/*psychology/therapy ; *Attitude to Health ; Caregivers/*psychology/statistics &amp; numerical data ; Depression/complications/diagnosis/*psychology ; Female ; Gastrostomy/psychology ; Humans ; Male ; Middle Aged ; Palliative Care/psychology ; Quality of Life/*psychology ; Texas ; }, abstract = {OBJECTIVE: To compare amyotrophic lateral sclerosis (ALS) patients and their caregivers on measures of quality of life (QOL), depression, and their attitudes toward treatment options.<br><br>METHODS: Over a 14-month period, we analyzed responses from 27 ALS patients and 19 ALS caregivers as they arrived at the Department of Neurology, Baylor College of Medicine, Vicki Appel MDA, ALS Clinic, and those who completed the study measures. Patients were given the Appel ALS Rating Scale (AALS), the ALS Functional Rating Scale (ALSFRS), McGill Quality of Life Questionnaire Single-Item Scale (MQOL-SIS), and the Beck Depression Inventory-II (BDI-II). An internally generated scale of 1-7 was used to measure perception of emotional support, QOL for others (i.e., the patient's perception of the caregiver's QOL and the caregiver's perception of the patient's QOL), and experience of pain. Attitudes toward treatment options were assessed by yes/no/uncertain responses. Caregivers were administered all of the above measures except the AALS, ALSFRS, and pain scale. Percentage, mean, and standard deviation values were determined. Significance levels were also calculated.<br><br>RESULTS: Twenty-seven patients with a mean age of 57.2 (range 34-81) years and nineteen caregivers with a mean age of 56.9 (range 28-82) years completed the study. The patients were of moderate disease severity with a mean AALS total score of 76.3 (range 39-134) and a mean ALSFRS score of 28.4 (range 12-40). The mean rating of QOL for patients was 5.9 and the mean rating of QOL for caregivers was 5.7 (range 1-7). The patients reported slightly less depression (9.8) than their caregivers (10.7) (range 0-63). There was, however, no significant difference between patients and caregivers on scores of QOL and depression. Patients tended to overestimate caregivers' QOL by a small degree, whereas caregivers tended to underestimate the patients' QOL by a greater degree. Over one-half of both groups would consider percutaneous esophageal gastrostomy (PEG) placement. Patient and caregiver responses to the use of BIPAP differed. Though over half of both groups endorsed the idea of future BIPAP use, more patients (41%) than caregivers (5%) were uncertain. Only 3% of patients responded negatively compared to 32% of caregivers. Both groups were only minimally interested in future invasive ventilation.<br><br>DISCUSSION: Factors contributing to quality of life, depression, and attitudes toward treatment options need to be periodically explored with patients and caregivers throughout the course of the illness. Health care professionals should recognize that the needs and goals of the two groups might differ. For both patients and caregivers, health care professionals should provide education and opportunities for discussion centered on the issues followed by referrals and interventions appropriate to the situation.}, }
@article {pmid12678784, year = {2003}, author = {Wu, SN}, title = {Large-conductance Ca2+- activated K+ channels:physiological role and pharmacology.}, journal = {Current medicinal chemistry}, volume = {10}, number = {8}, pages = {649-661}, doi = {10.2174/0929867033457863}, pmid = {12678784}, issn = {0929-8673}, mesh = {Animals ; Electrophysiology ; Humans ; Large-Conductance Calcium-Activated Potassium Channels ; Potassium Channel Blockers/*pharmacology ; Potassium Channels, Calcium-Activated/chemistry/*drug effects/*physiology ; }, abstract = {Large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels differ from most of other K(+) channels in that their activation is under dual control, i.e., activated by either increase in intracellular Ca(2+) or membrane depolarization. These channels, which are widely distributed in a variety of cells, can control Ca(2+) influx as well as a number of Ca(2+)-dependent physiological processes. In neurons or neuroendocrine cells, BK(Ca) channels are believed to play an important role in controlling hormonal secretion by altering the duration and frequency of action potentials. The activity of BK(Ca) channels functionally expressed in vascular endothelial cells can control K(+) efflux and affect intracellular Ca(2+) concentration. Experimental observations have revealed that a variety of compounds can directly modulate BK(Ca) channel activity. Epoxyeicosatrienoic acids, a metabolite of arachidonic acid, and the increase in intracellular cyclic GMP with vinpocetine or YC-1 can stimulate BK(Ca) channel activity. The increased activity of BK(Ca) channels thus serves as a negative feedback mechanism to limit Ca(2+) influx in excitable cells. Clotrimazole, an imidazole P-450 inhibitor used for the management of sickle cell anemia, can directly suppress BK(Ca) channel activity. Riluzole, a drug used for the treatment of amyotrophic lateral sclerosis, can directly enhance channel activity in neuroendocrine cells. This effect may explain its inhibitory action on excitatory neurotransmission. 2-Methoxyestradil, an endogenous metabolite of 17beta-estradiol, suppresses BK(Ca) channel activity, whereas resveratrol, a natural phytoalexin present in grapes and wine, directly stimulates BK(Ca) channel activity in vascular endothelial cells. These effects may be responsible for their actions on functional activities of endothelial cells. The fenamates, a family of nonsteroidal anti-inflammatory drugs, are also openers of BK(Ca) channels. Therefore, the modulation of BK(Ca) channel activity in excitable and non-excitable cells can be important for therapeutic interventions.}, }
@article {pmid12668759, year = {2003}, author = {Angelov, DN and Waibel, S and Guntinas-Lichius, O and Lenzen, M and Neiss, WF and Tomov, TL and Yoles, E and Kipnis, J and Schori, H and Reuter, A and Ludolph, A and Schwartz, M}, title = {Therapeutic vaccine for acute and chronic motor neuron diseases: implications for amyotrophic lateral sclerosis.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {100}, number = {8}, pages = {4790-4795}, pmid = {12668759}, issn = {0027-8424}, mesh = {Acute Disease ; Amyotrophic Lateral Sclerosis/genetics/immunology/*therapy ; Animals ; Axotomy ; Cell Death ; Chronic Disease ; Disease Models, Animal ; Facial Nerve/immunology/pathology/physiopathology ; Female ; Glatiramer Acetate ; Glutamic Acid/toxicity ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Motor Neuron Disease/genetics/immunology/*therapy ; Motor Neurons/immunology/pathology/physiology ; Nerve Degeneration/immunology/pathology/physiopathology/prevention &amp; control ; Peptides/*immunology/therapeutic use ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Vaccines/*therapeutic use ; }, abstract = {Therapeutic vaccination with Copaxone (glatiramer acetate, Cop-1) protects motor neurons against acute and chronic degenerative conditions. In acute degeneration after facial nerve axotomy, the number of surviving motor neurons was almost two times higher in Cop-1-vaccinated mice than in nonvaccinated mice, or in mice injected with PBS emulsified in complete Freund's adjuvant (P < 0.05). In mice that express the mutant human gene Cu/Zn superoxide dismutase G93A (SOD1), and therefore simulate the chronic human motor neuron disease amyotrophic lateral sclerosis, Cop-1 vaccination prolonged life span compared to untreated matched controls, from 211 +/- 7 days (n = 15) to 263 +/- 8 days (n = 14; P < 0.0001). Our studies show that vaccination significantly improved motor activity. In line with the experimentally based concept of protective autoimmunity, these findings suggest that Cop-1 vaccination boosts the local immune response needed to combat destructive self-compounds associated with motor neuron death. Its differential action in CNS autoimmune diseases and neurodegenerative disorders, depending on the regimen used, allows its use as a therapy for either condition. Daily administration of Cop-1 is an approved treatment for multiple sclerosis. The protocol for non-autoimmune neurodegenerative diseases such as amyotrophic lateral sclerosis, remains to be established by future studies.}, }
@article {pmid12666110, year = {2003}, author = {Kriz, J and Gowing, G and Julien, JP}, title = {Efficient three-drug cocktail for disease induced by mutant superoxide dismutase.}, journal = {Annals of neurology}, volume = {53}, number = {4}, pages = {429-436}, doi = {10.1002/ana.10500}, pmid = {12666110}, issn = {0364-5134}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/mortality ; Animals ; Anti-Bacterial Agents/*pharmacology ; Axons/drug effects ; Calcium Channel Blockers/*pharmacology ; Caspase 3 ; Caspases/metabolism ; Cyclin-Dependent Kinase 5 ; Cyclin-Dependent Kinases/metabolism ; Disease Models, Animal ; Drug Therapy, Combination ; Gliosis/drug therapy ; Mice ; Mice, Transgenic ; Microglia/drug effects ; Minocycline/*pharmacology ; Motor Neurons/drug effects/ultrastructure ; Muscle Contraction/drug effects ; Neuroprotective Agents/*pharmacology ; Nimodipine/*pharmacology ; Riluzole/*pharmacology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {There is currently no effective pharmacological treatment for amyotrophic lateral sclerosis (ALS). Because evidence suggests that multiple pathways may contribute to ALS pathogenesis, we tested in a mouse model of ALS (SOD1(G37R) mice) a combination approach consisting of three drugs for distinct targets in the complex pathway to neuronal death: minocycline, an antimicrobial agent that inhibits microglial activation, riluzole, a glutamate antagonist, and nimodipine, a voltage-gated calcium channel blocker. The efficacy of this three-drug cocktail was remarkable when administered in the diet from late presymptomatic stage (8-9 months). It delayed the onset of disease, slowed the loss of muscle strength, and increased the average longevity of SOD1(G37R) mice by 6 weeks. The protective effect of the treatment was corroborated by the reduced immunodetection signals for markers of gliosis and neurodegeneration in the spinal cord of SOD1(G37R) mice. These results indicate that such three-drug combination may represent an effective strategy for ALS treatment.}, }
@article {pmid12659697, year = {2000}, author = {Christova, I and Tasseva, E and Stamenov, B and Sabev, K}, title = {Neuroborreliosis in bulgaria: detection of Borrelia burgdorferi - specific intrathecal antibody production.}, journal = {International journal of immunopathology and pharmacology}, volume = {13}, number = {2}, pages = {99-106}, pmid = {12659697}, issn = {2058-7384}, abstract = {Borrelia burgdorferi, the causative agent of Lyme borreliosis may affect both the central and the peripheral nervous system causing neuroborreliosis. In Europe neuroborreliosis is the most frequent manifestation of late Lyme borreliosis. In this study we investigated characteristics of intrathecal antibody synthesis in patients with neuroborreliosis. Our goal was also to reveal to what extend anti - B.burgdorferi antibody detection in serum correlates to anti - B.burgdorferi antibody detection in CSF. We examined 266 patients with clinically suspected neuroborreliosis, and found serologic evidence of B.burgdorferi infection in 94 (35 percent). By calculation of IgG and IgM specific antibody indices, we detected intrathecal antibody production in 49 (18 percent) of patients. IgM antibody response dominated in the cerebrospinal fluid (CSF) samples and IgG antibody response was prevalent in the serum samples. Manifestations of neuroborreliosis included cranial nerve affection (n=12), radiculitis (n=10), meningoradiculitis (n=11), encephalopathy (n=7), radiculomyelitis (n=6), and encephalitis (n=3). No patients with either MS-like syndrome (n=15) or motor neurone disease (n=8) had intrathecal B.burgdorferi-specific antibody production despite positive serum reaction for the specific antibodies. Most of the patients with documented intrathecal antibody synthesis (42/49-86 percent) improved significantly after etiologic treatment. In the rest of patients, mainly those with long-terming neurological disorders, the improvement was partial and temporal. We concluded, that detection of antibodies against B.burgdorferi in serum should always be completed with detection of intrathecal antibody synthesis in CSF in order to confirm clinical diagnosis of neuroborreliosis.}, }
@article {pmid12657672, year = {2003}, author = {Nguyen, MD and Boudreau, M and Kriz, J and Couillard-Després, S and Kaplan, DR and Julien, JP}, title = {Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {23}, number = {6}, pages = {2131-2140}, pmid = {12657672}, issn = {1529-2401}, mesh = {Amino Acid Substitution ; Amyotrophic Lateral Sclerosis/*genetics/*metabolism/pathology ; Animals ; Anti-Bacterial Agents/pharmacology ; Cell Cycle Proteins/*metabolism ; Cell Death ; Cell Nucleus/metabolism ; Cyclin D1/metabolism ; Cyclin-Dependent Kinase 4 ; Cyclin-Dependent Kinase 5 ; Cyclin-Dependent Kinases/metabolism ; Disease Progression ; G1 Phase/physiology ; Humans ; Mice ; Mice, Neurologic Mutants ; Mice, Transgenic ; Minocycline/pharmacology ; Motor Neurons/drug effects/*metabolism/pathology ; Neurofilament Proteins/biosynthesis/genetics ; Phosphorylation/drug effects ; *Proto-Oncogene Proteins ; Retinoblastoma Protein/metabolism ; S Phase/physiology ; Signal Transduction ; Superoxide Dismutase/*biosynthesis/genetics ; Transgenes ; Up-Regulation ; }, abstract = {There is growing evidence for involvement of members of the cyclin-dependent kinase (Cdk) family in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults. After our recent report that a deregulation of Cdk5 activity by p25 may contribute to pathogenesis of amyotrophic lateral sclerosis (ALS), we further examined the possible involvement of other Cdks in mice expressing a mutant form of superoxide dismutase (SOD1(G37R)) linked to ALS. No substantial changes in Cdk2 or Cdk6 distribution and kinase activities were detected in spinal motor neurons from SOD1(G37R) mice when compared with normal mice. Of particular interest was the upregulation and mislocalization of Cdk4, a regulator of the G1-S checkpoint of the cell cycle, in motor neurons of SOD1(G37R) mice. The increase of Cdk4 activity in SOD1(G37R) mice was associated with an increase in nuclear Cdk4, cyclin D1, its coactivator, and with the abnormal phosphorylation of the retinoblastoma (Rb) protein at Cdk phosphorylation sites. Pharmacological treatment of SOD1(G37R) mice with minocycline, a compound that attenuates microgliosis and slows down disease, lessened the dysregulation of Cdk5/Cdk4 and the phosphorylation of Rb. Interestingly, phospho-Rb was immunoprecipitated with anti-Cdk4 but not with anti-Cdk5 antibodies, suggesting a key role for Cdk4 in the phosphorylation of Rb. Remarkably, the overexpression of a transgene coding for human neurofilament H, a phosphorylation sink for deregulated Cdk5 activity by p25, resulted in a reduction in levels of nuclear Cdk4 and Rb phosphorylation. These results indicate that a cell cycle signaling at the neuronal G1-S checkpoint subsequent to Cdk5 deregulation may constitute a critical step of the neuronal death pathway in ALS caused by mutant SOD1.}, }
@article {pmid12657369, year = {2003}, author = {Waldmeier, PC}, title = {Prospects for antiapoptotic drug therapy of neurodegenerative diseases.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {27}, number = {2}, pages = {303-321}, doi = {10.1016/S0278-5846(03)00025-3}, pmid = {12657369}, issn = {0278-5846}, mesh = {Alzheimer Disease/drug therapy/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/pathology ; Animals ; Apoptosis/*drug effects/physiology ; Brain Injuries/drug therapy/pathology ; Brain Ischemia/drug therapy/pathology ; Humans ; Models, Biological ; Neurodegenerative Diseases/*drug therapy/pathology ; Spinal Cord Injuries/drug therapy/pathology ; }, abstract = {The evidence for a role of apoptosis in the neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and in the more acute conditions of cerebral ischemia, traumatic brain injury (TBI), and spinal cord injury (SCI) is reviewed with regard to potential intervention by means of small antiapoptotic molecules. In addition, the available animal models for these diseases are discussed with respect to their relevance for testing small antiapoptotic molecules in the context of what is known about the apoptotic pathways involved in the diseases and the models. The principal issues related to pharmacotherapy by apoptosis inhibition, i.e., functionality of rescued neurons and potential interference with physiologically occurring apoptosis, are pointed out. Finally, the properties of a number of small antiapoptotic molecules currently under clinical investigation are summarized. It is concluded that the evidence for a role of apoptosis at present is more convincing for PD and ALS than for AD. In PD, damage to dopaminergic neurons may occur through oxidative stress and/or mitochondrial impairment and culminate in activation of an apoptotic, presumably p53-dependent cascade; some neurons experiencing energy failure may not be able to complete apoptosis, end up in necrosis and give rise to inflammatory processes. These events are reasonably well reflected in some of the PD animal models, notably those involving 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone. In sporadic ALS, an involvement of pathways involving p53 and Bcl-2 family members appears possible if not likely, but is not established. The issue is important for the development of antiapoptotic compounds for the treatment of this disease because of differential involvement of p53 in different mutant superoxide dismutase (SOD) mice. Most debated is the role of apoptosis in AD; this implies that little is known about potentially involved pathways. Moreover, there is a lack of suitable animal models for compound evaluation. Apoptosis or related phenomena are likely involved in secondary cell death in cerebral ischemia, TBI, and SCI. Most of the pertinent information comes from animal experiments, which have provided some evidence for prevention of cell death by antiapoptotic treatments, but little for functional benefit. Much remains to be done in this area to explore the potential of antiapoptotic drugs. There is a small number of antiapoptotic compounds in clinical development. With some of them, evidence for maintenance of functionality of the rescued neurons has been obtained in some animal models, and the fact that they made it to phase II studies in patients suggests that interference with physiological apoptosis is not an obligatory problem. The prospect that small antiapoptotic molecules will have an impact on the therapy of neurodegenerative diseases, and perhaps also of ischemia and trauma, is therefore judged cautiously positively.}, }
@article {pmid12641736, year = {2003}, author = {Wu, AS and Kiaei, M and Aguirre, N and Crow, JP and Calingasan, NY and Browne, SE and Beal, MF}, title = {Iron porphyrin treatment extends survival in a transgenic animal model of amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {85}, number = {1}, pages = {142-150}, doi = {10.1046/j.1471-4159.2003.01639.x}, pmid = {12641736}, issn = {0022-3042}, support = {AG 12992/AG/NIA NIH HHS/United States ; R01 NS40819/NS/NINDS NIH HHS/United States ; R29 NS35871/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Antioxidants/*therapeutic use ; Body Weight/drug effects ; Disease Models, Animal ; Free Radical Scavengers/*therapeutic use ; Lumbosacral Region ; Malondialdehyde/analysis/metabolism ; Metalloporphyrins/*therapeutic use ; Mice ; Mice, Transgenic ; Motor Activity/drug effects ; Oxidation-Reduction ; Spinal Cord/drug effects/metabolism/pathology ; Superoxide Dismutase/genetics ; Survival Rate ; Tissue Distribution ; Treatment Outcome ; }, abstract = {Oxidative damage, produced by mutant Cu/Zn superoxide dismutase (SOD1), may play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating motor neuron degenerative disease. A novel approach to antioxidant therapy is the use of metalloporphyrins that catalytically scavenge a wide range of reactive oxygen and reactive nitrogen species. In this study, we examined the therapeutic potential of iron porphyrin (FeTCPP) in the G93A mutant SOD1 transgenic mouse model of ALS. We found that intraperitoneal injection of FeTCPP significantly improved motor function and extended survival in G93A mice. Similar results were seen with a second group of mice wherein treatment with FeTCPP was initiated at the onset of hindlimb weakness-roughly equivalent to the time at which treatment would begin in human patients. FeTCPP-treated mice also showed a significant reduction in levels of malondialdehyde (a marker of lipid peroxidation), in total content of protein carbonyls (a marker of protein oxidation), and increased neuronal survival in the spinal cord. These results therefore provide further evidence of oxidative damage in a mouse model of ALS, and suggest that FeTCPP could be beneficial for the treatment of ALS patients.}, }
@article {pmid12637300, year = {2003}, author = {Kalra, S and Cashman, NR and Caramanos, Z and Genge, A and Arnold, DL}, title = {Gabapentin therapy for amyotrophic lateral sclerosis: lack of improvement in neuronal integrity shown by MR spectroscopy.}, journal = {AJNR. American journal of neuroradiology}, volume = {24}, number = {3}, pages = {476-480}, pmid = {12637300}, issn = {0195-6108}, mesh = {Acetates/adverse effects/*therapeutic use ; Aged ; *Amines ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Aspartic Acid/*analogs &amp; derivatives/metabolism ; Cell Survival/*drug effects/physiology ; Creatine/metabolism ; *Cyclohexanecarboxylic Acids ; Energy Metabolism/*drug effects/physiology ; Excitatory Amino Acid Antagonists/adverse effects/*therapeutic use ; Female ; Follow-Up Studies ; Gabapentin ; Humans ; *Magnetic Resonance Imaging ; *Magnetic Resonance Spectroscopy ; Male ; Middle Aged ; Motor Cortex/*drug effects/physiopathology ; Parietal Lobe/drug effects/physiopathology ; Reference Values ; Treatment Outcome ; *gamma-Aminobutyric Acid ; }, abstract = {BACKGROUND AND PURPOSE: Proton MR spectroscopy has revealed impaired neuronal integrity in the motor cortex of patients with amyotrophic lateral sclerosis (ALS). We hypothesized that the N-acetylaspartate (NAA)-creatine (Cr) ratios in the motor cortex and adjacent brain could reflect the therapeutic effectiveness of gabapentin (GBP) treatment in ALS.<br><br>METHODS: Eight patients with ALS underwent MR spectroscopy before and 26.5 days +/- 8.8 after starting GBP. In 10 patients with ALS who were not treated with GBP, paired spectra were obtained 21.4 days +/- 7.2 apart. Fourteen healthy subjects underwent a single MR spectroscopic examination. The NAA/Cr ratio was measured in the precentral gyrus, the postcentral gyrus, the superior parietal lobule, the supplementary motor area, and the premotor cortex.<br><br>RESULTS: The NAA/Cr ratio was decreased in the precentral and postcentral gyri of patients with ALS compared with healthy controls. In those with ALS, the change in the NAA/Cr ratio was not different between treated patients and untreated patients in any of the regions studied.<br><br>CONCLUSION: No improvement in neuronal integrity was detected in motor and nonmotor cerebral regions after GBP treatment. This result agrees with that of prior investigations showing the equivocal clinical effectiveness of GBP for ALS and supports the validity of the NAA/Cr ratio as a surrogate of therapeutic effectiveness.}, }
@article {pmid12618124, year = {2003}, author = {Nagano, S and Fujii, Y and Yamamoto, T and Taniyama, M and Fukada, K and Yanagihara, T and Sakoda, S}, title = {The efficacy of trientine or ascorbate alone compared to that of the combined treatment with these two agents in familial amyotrophic lateral sclerosis model mice.}, journal = {Experimental neurology}, volume = {179}, number = {2}, pages = {176-180}, doi = {10.1016/s0014-4886(02)00014-6}, pmid = {12618124}, issn = {0014-4886}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Antioxidants/*therapeutic use ; Ascorbic Acid/*therapeutic use ; Chelating Agents/*therapeutic use ; Disease Models, Animal ; Disease Progression ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Drug Therapy, Combination ; Humans ; Male ; Mice ; Mice, Transgenic ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Survival Rate ; Treatment Outcome ; Trientine/*therapeutic use ; }, abstract = {One of the hypotheses regarding the pathogenesis of familial ALS (FALS) is a copper-mediated oxidative toxicity derived from the mutant Cu, Zn-superoxide dismutase (SOD1). We have previously demonstrated the efficacy of the combined treatment with a copper chelator (trientine) and an antioxidant (ascorbate) on the disease expression of the FALS-linked mutated SOD1 transgenic mice. Here, we investigated the efficacy of trientine or ascorbate alone on FALS mice when administered before or after the onset of the disease. The mice with a high dose of trientine or ascorbate administered before the onset survived significantly longer than the control. In the combined treatment with a high dose of trientine and ascorbate initiated before the onset, survival lengthened and the motor function of the mice remained more significantly than the control. None of the treatments affected the mean age of the onset, and none of the agents administered after the onset prolonged survival. These findings suggest that better outcomes may be expected by the administration of these agents at the preonset stage of the disease, and the combination of the agents acting on different sites might be useful in preserving the motor performance in FALS.}, }
@article {pmid12615652, year = {2003}, author = {Kanai, K and Kuwabara, S and Arai, K and Sung, JY and Ogawara, K and Hattori, T}, title = {Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment.}, journal = {Brain : a journal of neurology}, volume = {126}, number = {Pt 4}, pages = {965-973}, doi = {10.1093/brain/awg073}, pmid = {12615652}, issn = {0006-8950}, mesh = {Adolescent ; Adult ; Anti-Arrhythmia Agents/*therapeutic use ; Axons/physiology ; Electromyography ; Female ; Humans ; Machado-Joseph Disease/*complications/physiopathology ; Male ; Mexiletine/*therapeutic use ; Middle Aged ; Motor Neurons/*physiology ; Muscle Cramp/drug therapy/*etiology/physiopathology ; Neural Conduction ; }, abstract = {Machado-Joseph disease is one of the most common hereditary spinocerebellar degenerative disorders with a wide range of clinical manifestations. Pathology studies have shown mild to moderate loss of anterior horn cells and, in terms of spinal pathology, Machado-Joseph disease is regarded as a type of lower motoneuron disease. Muscle cramps are often associated with lower motoneuron disorders, but features of cramps in Machado-Joseph disease patients have never been studied. We investigated the incidence and nature of muscle cramps in Machado-Joseph disease patients, the excitability properties of motor axons [strength-duration time constant (tau(SD)), threshold electrotonus, refractoriness and supernormality] using threshold tracking and the effects of mexiletine hydrochloride on those cramps. Of 20 consecutive patients, 16 (80%) had frequent, severe muscle cramps in the legs, trunk or arms that disturbed their daily activities. The frequency of pathological muscle cramps was similar to that for patients with amyotrophic lateral sclerosis (68%) and higher than those for patients with spinal muscular atrophy (33%) or peripheral axonal neuropathy (24%). Threshold-tracking studies showed that tau(SD), which in part reflects Na(+) conductance at the resting membrane potential, was significantly greater in the Machado-Joseph disease patients than in normal subjects; severe muscle cramps were associated with a longer tau(SD). Threshold electrotonus, refractoriness and supernormality were not significantly different between Machado-Joseph disease patients and normal subjects. Eight Machado-Joseph disease patients with severe cramps, who received mexiletine treatment, experienced nearly complete relief with a partial normalization of tau(SD) (P = 0.08). Muscle cramps are a very frequent and disabling factor in Machado-Joseph disease. Pathological muscle cramps responded well to mexiletine treatment, and this is consistent with the hypothesis that they are caused by an increase in persistent Na(+) conductance, possibly associated with axonal regeneration or collateral sprouting.}, }
@article {pmid12605121, year = {2003}, author = {DePaz, HA and Oluwole, OO and Adeyeri, AO and Witkowski, P and Jin, MX and Hardy, MA and Oluwole, SF}, title = {Immature rat myeloid dendritic cells generated in low-dose granulocyte macrophage-colony stimulating factor prolong donor-specific rat cardiac allograft survival.}, journal = {Transplantation}, volume = {75}, number = {4}, pages = {521-528}, doi = {10.1097/01.TP.0000048380.84355.4A}, pmid = {12605121}, issn = {0041-1337}, support = {R01 HL-57229/HL/NHLBI NIH HHS/United States ; }, mesh = {Adoptive Transfer ; Animals ; Biomarkers ; Bone Marrow Cells/cytology/drug effects ; Cell Differentiation/drug effects/immunology ; Dendritic Cells/*cytology/drug effects ; Flow Cytometry ; Graft Rejection/immunology ; Graft Survival/*immunology ; Granulocyte-Macrophage Colony-Stimulating Factor/*pharmacology ; Heart Transplantation/*immunology ; Lymphocyte Culture Test, Mixed ; Major Histocompatibility Complex/immunology ; Rats ; Rats, Inbred ACI ; Rats, Inbred Lew ; Rats, Inbred WF ; Transplantation, Homologous ; }, abstract = {BACKGROUND: Because the differential polarization of T cells in response to antigen presentation is dependent on the maturational state of dendritic cells (DCs), we hypothesized that the adoptive transfer of immature myeloid DCs (iMDCs) would prolong graft survival.<br><br>METHODS: To evaluate this hypothesis, we studied the effects of transfer of iMDCs and mature myeloid DCs (mMDCs) on rat cardiac allograft survival.<br><br>RESULTS: Whereas iMDCs that do not express costimulatory molecules induce allogeneic T-cell hyporesponsiveness in coculture studies, mMDCs that express high levels of major histocompatibility complex class II costimulatory and maturation molecules induce a robust allostimulatory T-cell response. Adoptive transfer of Wistar Furth iMDCs, unlike mMDCs, 7 days before cardiac transplantation significantly prolonged graft survival. It was important that adoptive transfer of iMDCs combined with 0.5 mL antilymphocyte serum (ALS) transient immunosuppression on day -7 led to donor-specific permanent graft survival in 50% of recipients. In contrast, adoptive transfer of mMDCs combined with ALS led to graft survival similar to that in recipients treated with ALS alone. Stimulation of CD4 T cells isolated from the spleen of unresponsive allograft recipients with donor antigen resulted in donor-specific hyporesponsiveness and production of interleukin (IL)-10 and transforming growth factor-beta but not IL-4 and interferon-gamma. The tolerant T-cell unresponsiveness was reversed by the addition of IL-2.<br><br>CONCLUSION: Our data confirming the immunoregulatory effect of immature DCs indicate that induction of transplant tolerance by iMDCs is partly dependent on in vivo generation of regulatory T cells. This finding suggests that immunization with immature donor DCs has therapeutic potential for the induction of transplant tolerance and treatment of autoimmune diseases.}, }
@article {pmid12590377, year = {2003}, author = {Morís, G and Vega, JA}, title = {[Neurotrophic factors: basis for their clinical application].}, journal = {Neurologia (Barcelona, Spain)}, volume = {18}, number = {1}, pages = {18-28}, pmid = {12590377}, issn = {0213-4853}, mesh = {Animals ; Brain Injuries/drug therapy ; Clinical Trials as Topic ; Glial Cell Line-Derived Neurotrophic Factor ; Humans ; Nerve Growth Factors/metabolism/*therapeutic use ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/metabolism/therapeutic use ; Somatomedins/metabolism ; }, abstract = {Neurotrophic factors are molecules that regulate neuronal survival, nervous system plasticity and many other physiological functions of neuronal and glial cells, as well as some non-neuronal tissues. They have been involved in the etiopathogenesis of some neurodegenerative disorders, and some of them have been proposed as potential treatments for these diseases on the basis of in vitro experiments and animal models. The main neurotrophic factor families with potential therapeutic applications include the family of neurotrophins (NGF, BDNF or NT-3), GDNF and related neurotrophic factor, CNTF and the members of the IGF family. Some of these molecules have already been tested in clinical trials with contradictory results. One of the major challenges to their clinical use is the difficulty to deliver them into the central nervous system. Nevertheless, solid rational exists for the possible use of neurotrophic factors in the treatment of Alzheimer's and Parkinson's diseases, peripheral neuropathies or amyotrophic lateral sclerosis. This review compiles the essential aspects of neurotrophic factors and the current studies of their clinical relevance and therapeutic potentialities. Future directions for further research are also discussed.}, }
@article {pmid12588757, year = {2003}, author = {Gervais, M and Pons, S and Nicoletti, A and Cosson, C and Giudicelli, JF and Richer, C}, title = {Fluvastatin prevents renal dysfunction and vascular NO deficit in apolipoprotein E-deficient mice.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {23}, number = {2}, pages = {183-189}, doi = {10.1161/01.atv.0000051404.84665.49}, pmid = {12588757}, issn = {1524-4636}, mesh = {Acetylcholine/pharmacology ; Animals ; Aorta, Thoracic/drug effects/pathology/physiology ; Apolipoproteins E/*deficiency/genetics ; Arteriosclerosis/blood/metabolism/pathology ; Carotid Arteries/drug effects/pathology/physiology ; Fatty Acids, Monounsaturated/*pharmacology ; Fluvastatin ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; In Vitro Techniques ; Indoles/*pharmacology ; Kidney/blood supply/drug effects ; Lipids/blood ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Nitric Oxide/*blood ; Nitroprusside/pharmacology ; Perfusion ; Renal Insufficiency/*blood/*prevention &amp; control ; Vascular Resistance/drug effects ; Vasoconstriction/drug effects/physiology ; Vasoconstrictor Agents/pharmacology ; Vasodilation/drug effects/physiology ; Vasodilator Agents/pharmacology ; }, abstract = {OBJECTIVE: The objective of this study was to investigate the effects of fluvastatin on atherosclerosis, systemic and regional hemodynamics, and vascular reactivity in apolipoprotein E-deficient (ApoE(-/-)) mice.<br><br>METHODS AND RESULTS: Hemodynamics (fluospheres) and vasomotor responses of thoracic aorta and carotid artery were evaluated in male wild-type (WT) and untreated (ApoE(-/-) Control) or fluvastatin-treated (50 mg/kg per day for 20 weeks) ApoE(-/-) mice, all fed a Western-type diet. Plasma cholesterol and aortic root atherosclerotic lesions (ALs) were greater in ApoE(-/-) Control mice (19+/-1 mmol/L and 63,0176+/-38,785 micro m(2), respectively) than in WT mice (2+/-1 mmol/L and 1+/-1 micro m(2), respectively, P<0.01). Fluvastatin significantly decreased plasma cholesterol (-53%) but failed to limit ALs. Renal blood flow was significantly reduced in ApoE(-/-) Control versus WT (-25%, P<0.05) mice. This reduction was prevented by fluvastatin. Aortic and carotid endothelium-dependent relaxations to acetylcholine were not altered in ApoE(-/-) Control versus WT mice. In carotid arteries from WT mice, these responses were abolished after nitro-L-arginine (L-NA), whereas those from ApoE(-/-) Control were only partially inhibited after L-NA but fully abolished after L-NA+diclofenac. Thus, in carotid arteries from ApoE(-/-) mice, vasodilating prostanoids compensate the deficit in NO availability. Fluvastatin prevented this carotid NO deficit.<br><br>CONCLUSIONS: In ApoE(-/-) mice, chronic fluvastatin treatment preserved renal perfusion and vascular NO availability independently from atherosclerotic lesion prevention.}, }
@article {pmid12586733, year = {2003}, author = {Pompl, PN and Ho, L and Bianchi, M and McManus, T and Qin, W and Pasinetti, GM}, title = {A therapeutic role for cyclooxygenase-2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {17}, number = {6}, pages = {725-727}, doi = {10.1096/fj.02-0876fje}, pmid = {12586733}, issn = {1530-6860}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/physiopathology ; Animals ; Cyclooxygenase 2 ; Cyclooxygenase 2 Inhibitors ; Cyclooxygenase Inhibitors/administration &amp; dosage/*therapeutic use ; Dinoprostone/blood/metabolism ; Disease Models, Animal ; Isoenzymes/drug effects/metabolism ; Mice ; Mice, Transgenic ; Motor Activity/drug effects ; Mutation ; Prostaglandin-Endoperoxide Synthases/drug effects/metabolism ; Spinal Cord/drug effects/metabolism ; Sulfonamides/administration &amp; dosage/blood/*therapeutic use ; Superoxide Dismutase/genetics ; }, abstract = {Recent studies indicate that the proinflammatory enzyme cyclooxygenase (COX)-2, an enzyme involved in inflammatory cascades but also normal neuronal activities, is elevated in the brain and spinal cord of amyotrophic lateral sclerosis (ALS) patients and ALS mouse model systems. On the basis of this evidence, we explored the impact of COX-2 inhibition on the onset and progression of ALS-like disease in the G93A human superoxide dismutase (SOD)1 mouse model of ALS. We found that prophylactic administration of nimesulide, a preferential COX-2 inhibitor, in the feed resulted in a significant delay in the onset of ALS type motor impairment. This delay of ALS symptomatology temporally overlapped with the inhibition of prostaglandin E2 elevation in the spinal cord of SOD1-G93A transgenic mice relative to untreated SOD1-G93A controls. This study strongly supports a role for COX-2 in the pathophysiology of ALS and provides the first experimental evidence that prophylactic treatment with COX-2 inhibitors can significantly delay the onset of motor dysfunction in the SOD1-G93A transgenic mouse model of ALS.}, }
@article {pmid12586554, year = {2002}, author = {Gonzalez Deniselle, MC and López-Costa, JJ and Saavedra, JP and Pietranera, L and Gonzalez, SL and Garay, L and Guennoun, R and Schumacher, M and De Nicola, AF}, title = {Progesterone neuroprotection in the Wobbler mouse, a genetic model of spinal cord motor neuron disease.}, journal = {Neurobiology of disease}, volume = {11}, number = {3}, pages = {457-468}, doi = {10.1006/nbdi.2002.0564}, pmid = {12586554}, issn = {0969-9961}, mesh = {Animals ; In Situ Hybridization ; Mice ; Mice, Neurologic Mutants ; Microscopy, Electron ; Motor Neuron Disease/drug therapy/*metabolism ; Motor Neurons/enzymology/*metabolism/ultrastructure ; Neuroprotective Agents/administration &amp; dosage/*metabolism ; Progesterone/administration &amp; dosage/*metabolism ; RNA, Messenger/drug effects/metabolism ; Sodium-Potassium-Exchanging ATPase/drug effects/metabolism ; Spinal Cord Diseases/drug therapy/*metabolism ; }, abstract = {Motor neuron degeneration characterizes the spinal cord of patients with amyotrophic lateral sclerosis and the Wobbler mouse mutant. Considering that progesterone (PROG) provides neuroprotection in experimental ischemia and injury, its potential role in neurodegeneration was studied in the murine model. Two-month-old symptomatic Wobbler mice were left untreated or received sc a 20-mg PROG implant for 15 days. Both light and electron microscopy of Wobbler mice spinal cord showed severely affected motor neurons with profuse cytoplasmic vacuolation of the endoplasmic reticulum and/or Golgi apparatus and ruptured mitochondria with damaged cristae, a profile indicative of a type II cytoplasmic form of cell death. In contrast to untreated mice, neuropathology was less severe in Wobbler mice receiving PROG; including a reduction of vacuolation and of the number of vacuolated cells and better conservation of the mitochondrial ultrastructure. In biochemical studies, we determined the mRNA for the alpha3 subunit of Na,K-ATPase, a neuronal enzyme controlling ion fluxes, neurotransmission, membrane potential, and nutrient uptake. In untreated Wobbler mice, mRNA levels in motor neurons were reduced by half compared to controls, whereas PROG treatment of Wobbler mice restored the expression of alpha3 subunit Na,K-ATPase mRNA. Therefore, PROG was able to rescue motor neurons from degeneration, based on recovery of histopathological abnormalities and of mRNA levels of the sodium pump. However, because the gene mutation in Wobbler mice is still unknown, further studies are needed to unveil the action of PROG and the mechanism of neuronal death in this genetic model of neurodegeneration.}, }
@article {pmid12581530, year = {2003}, author = {Woźniak, K and Blasiak, J}, title = {In vitro genotoxicity of lead acetate: induction of single and double DNA strand breaks and DNA-protein cross-links.}, journal = {Mutation research}, volume = {535}, number = {2}, pages = {127-139}, doi = {10.1016/s1383-5718(02)00295-4}, pmid = {12581530}, issn = {0027-5107}, mesh = {Calcium Chloride/pharmacology ; Comet Assay ; Cyclic N-Oxides/pharmacology ; DNA/metabolism ; DNA Damage/*drug effects ; DNA Repair/drug effects ; Endopeptidase K/metabolism ; Humans ; In Vitro Techniques ; Kinetics ; Lymphocytes/*drug effects ; Male ; Nitrogen Oxides/pharmacology ; Organometallic Compounds/*toxicity ; Proteins/metabolism ; }, abstract = {Lead is present in the natural and occupational environment and is reported to interact with DNA, but the mechanism of this interaction is not fully understood. Using the alkaline comet assay we showed that lead acetate at 1-100 microM induced DNA damage in isolated human lymphocytes measured the change in the comet tail length. At 1 and 10 microM we observed an increase in the tail length, whereas at 100 microM a decrease was seen. The former effect could follow from the induction of DNA strand breaks and/or alkali-labile sites (ALS), the latter from the formation of DNA-DNA and/or DNA-protein cross-links. No difference was observed between tail length for the alkaline and pH 12.1 versions of the assay, which indicates that strand breaks and not ALS are responsible for the tail length increase induced by lead. The neutral version of the test revealed that lead acetate induced DNA double-strand breaks at all concentrations tested. The presence of spin traps, 5,5-dimethyl-pyrroline N-oxide (DMPO) and N-tert-butyl-alpha-phenylnitrone (PBN) did not influence the level of DNA damage induced by lead. Post-treatment of the lead-damaged DNA (at 100 microM treatment concentration) by endonuclease III (Endo III) and formamidopyrimidine-DNA glycosylase (Fpg), enzymes recognizing oxidized DNA bases, as well as 3-methyladenine-DNA glycosylase II, an enzyme recognizing alkylated bases, gave rise to a significant increase in the extent of DNA damage. Proteinase K caused an increase in comet tail length, suggesting that lead acetate might cross-link DNA with nuclear proteins. Vitamin A, E, C, calcium chloride and zinc chloride acted synergistically on DNA damage evoked by lead. The results obtained suggest that lead acetate may induce single-strand breaks (SSB) and double-strand breaks (DSB) in DNA as well as DNA-protein cross-links. The participation of free radicals in DNA-damaging potential of lead is not important and it concerns other reactive species than could be trapped by DMPO or PBN.}, }
@article {pmid12578002, year = {2003}, author = {Wheeler, RM}, title = {Carbon balance in bioregenerative life support systems: some effects of system closure, waste management, and crop harvest index.}, journal = {Advances in space research : the official journal of the Committee on Space Research (COSPAR)}, volume = {31}, number = {1}, pages = {169-175}, doi = {10.1016/s0273-1177(02)00742-1}, pmid = {12578002}, issn = {0273-1177}, mesh = {*Biomass ; Carbohydrate Metabolism ; Carbon/*chemistry/metabolism ; Carbon Dioxide/metabolism ; *Ecological Systems, Closed ; Humans ; *Life Support Systems ; Oxygen/metabolism ; Photosynthesis ; Plant Physiological Phenomena ; Plants, Edible/*growth &amp; development/metabolism ; *Waste Management ; }, abstract = {In Advanced Life Support (ALS) systems with bioregenerative components, plant photosynthesis would be used to produce O2 and food, while removing CO2. Much of the plant biomass would be inedible and hence must be considered in waste management. This waste could be oxidized (e.g., incinerated or aerobically digested) to resupply CO2 to the plants, but this would not be needed unless the system were highly closed with regard to food. For example, in a partially closed system where some of the food is grown and some is imported, CO2 from oxidized waste when combined with crew and microbial respiration could exceed the CO2 removal capability of the plants. Moreover, it would consume some O2 produced from photosynthesis that could have been used by the crew. For partially closed systems it would be more appropriate to store or find other uses for the inedible biomass and excess carbon, such as generating soils or growing woody plants (e.g., dwarf fruit trees). Regardless of system closure, high harvest crops (i.e., crops with a high edible to total biomass ratio) would increase food production per unit area and O2 yields for systems where waste biomass is oxidized to recycle CO2. Such interlinking effects between the plants and waste treatment strategies point out the importance of oxidizing only that amount of waste needed to optimize system performance.}, }
@article {pmid12566164, year = {2003}, author = {Maragakis, NJ and Jackson, M and Ganel, R and Rothstein, JD}, title = {Topiramate protects against motor neuron degeneration in organotypic spinal cord cultures but not in G93A SOD1 transgenic mice.}, journal = {Neuroscience letters}, volume = {338}, number = {2}, pages = {107-110}, doi = {10.1016/s0304-3940(02)01386-1}, pmid = {12566164}, issn = {0304-3940}, support = {AG12992/AG/NIA NIH HHS/United States ; NS33958/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics/mortality/*prevention &amp; control ; Animals ; Animals, Newborn ; Fructose/*analogs &amp; derivatives/*pharmacology ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects/pathology ; Nerve Degeneration/pathology/*prevention &amp; control ; Neuroprotective Agents/*pharmacology ; Organ Culture Techniques ; Spinal Cord/*drug effects/pathology ; Survival Rate ; Topiramate ; }, abstract = {Topiramate is a novel anti-convulsant, structurally distinct from other known anti-convulsants. A number of independent studies suggest that topiramate has anti-excitotoxic properties. It has been found to diminish release of glutamate from neurons and block (-amino-3-hydoxy-5-methylisoxazole-4-proprionic acid glutamate receptor evoked currents. Since activation of non-N-methyl-D-aspartate glutamate receptors is thought to play a role in the selective loss of motor neurons in amyotrophic lateral sclerosis (ALS), we determined whether topiramate could protect against chronic glutamate-mediated motor neuron degeneration. An organotypic spinal cord culture system was used in which glutamate transport is inhibited by pharmacological blockade. After 3 weeks of treatment, topiramate was found to significantly prevent motor neuron degeneration in this culture model. However, the drug did not increase survival in G93A SOD1 transgenic mice, an animal model of ALS. These studies suggest that topiramate could be useful as a neuroprotectant, but were not effective in more complex motor injury paradigms such as the mouse model of ALS.}, }
@article {pmid12557297, year = {2003}, author = {Zhang, W and Narayanan, M and Friedlander, RM}, title = {Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS.}, journal = {Annals of neurology}, volume = {53}, number = {2}, pages = {267-270}, doi = {10.1002/ana.10476}, pmid = {12557297}, issn = {0364-5134}, support = {NS39324/NS/NINDS NIH HHS/United States ; NS41635/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/mortality ; Animals ; Anti-Bacterial Agents/*pharmacology ; Creatine/*pharmacology ; Disease Models, Animal ; Drug Therapy, Combination ; Mice ; Mice, Mutant Strains ; Minocycline/*pharmacology ; Neuroprotective Agents/*pharmacology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Survival Analysis ; }, abstract = {The known neuroprotective effects of minocycline and creatine in animal models of amyotrophic lateral sclerosis (ALS) led us to examine whether the combination of these agents would result in increased neuroprotection. As previously reported, we confirmed in ALS mice that either minocycline or creatine treatment results in improvement in motor performance and extended survival. We report that combination of minocycline and creatine resulted in additive neuroprotection, suggesting this to be a novel potential strategy for the treatment of ALS. To our knowledge, this is the first report demonstrating additive neuroprotection of a combinatorial approach in a mouse model of ALS. Adding relevancy to our findings, minocycline and creatine, are relatively safe, cross the blood-brain barrier, and are currently available for human evaluation.}, }
@article {pmid12548704, year = {2003}, author = {Nakamizo, T and Kawamata, J and Yoshida, K and Kawai, Y and Kanki, R and Sawada, H and Kihara, T and Yamashita, H and Shibasaki, H and Akaike, A and Shimohama, S}, title = {Phosphodiesterase inhibitors are neuroprotective to cultured spinal motor neurons.}, journal = {Journal of neuroscience research}, volume = {71}, number = {4}, pages = {485-495}, doi = {10.1002/jnr.10483}, pmid = {12548704}, issn = {0360-4012}, mesh = {Animals ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Glutamic Acid/toxicity ; Male ; Motor Neurons/cytology/*drug effects/enzymology ; Neuroprotective Agents/*pharmacology ; Phosphodiesterase Inhibitors/*pharmacology ; Rats ; Rats, Wistar ; Spinal Cord/cytology/drug effects/enzymology ; }, abstract = {We have previously reported that cyclic guanosine-3',5'-monophosphate (cGMP) protects spinal motor neurons against acute reactive oxygen species (ROS)-induced toxicity but not against chronic ROS-induced or glutamate (Glu)-induced toxicity. In this study, we investigated the effects of phosphodiesterase (PDE) inhibitors on the survival of cultured spinal motor neurons. Selective PDE5 inhibitors (dipyridamole, T-1032, and zaprinast) as well as a nonselective PDE inhibitor (aminophylline) protected motor and nonmotor neurons against both acute ROS-induced and chronic Glu-induced neurotoxicity, whereas selective inhibitors of PDE1-4 offered no protection. 8-Bromo-cGMP (8br-cGMP), a cGMP analogue, protected both motor and nonmotor neurons against acute ROS-induced toxicity but protected only nonmotor neurons against chronic Glu-induced toxicity. This neuroprotection was blocked by KT5823, a cGMP-dependent protein kinase (PKG) inhibitor. Immunohistochemical staining confirmed that PDE5 and PKG are located in almost all rat lumbar spinal neurons. Furthermore, semiquantitative analysis of the immunostaining intensity revealed that PDE5 was more abundant in motor neurons than in nonmotor neurons. Our results suggest that this difference in the amount of PDE5 may be responsible for the vulnerability of motor neurons to chronic excitotoxicity. In addition, the results of this study raise the possibility that PDE5 inhibitors might be used as a treatment for amyotrophic lateral sclerosis.}, }
@article {pmid12548374, year = {2002}, author = {Zoccolella, S and Palagano, G and Fraddosio, A and Russo, I and Ferrannini, E and Serlenga, L and Maggio, F and Lamberti, S and Iliceto, G}, title = {ALS-plus: 5 cases of concomitant amyotrophic lateral sclerosis and parkinsonism.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {23 Suppl 2}, number = {}, pages = {S123-4}, doi = {10.1007/s100720200100}, pmid = {12548374}, issn = {1590-1874}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Antiparkinson Agents/therapeutic use ; Dementia/*complications/physiopathology ; Female ; Humans ; Levodopa/therapeutic use ; Male ; Parkinsonian Disorders/*complications/physiopathology ; }, abstract = {According to El Escorial criteria, amyotrophic lateral sclerosis (ALS), combined with other neurologic disorders, such as dementia and parkinsonism, is defined as ALS-plus. These overlaping syndromes are extremely rare. Here we report 5 cases (3 men, 2 women) of ALS-plus; mean age at the onset of symptoms was 67 years (range, 65-72). In 3 patients, motoneuronal signs preceded the onset of parkinsonian syndrome. In 4 cases, the clinical picture was characterized by the prevalence of motoneuronal signs. Parkinsonism was poorly responsive to L-dopa treatment in all patients. The clinical course did not differ from that expected in patients with only ALS. Our clinical observations and neuropathological reports of nigral neuronal loss in ALS patients suggest a common pathogenic mechanism underlying these disorders.}, }
@article {pmid12546990, year = {2003}, author = {Mathisen, PM}, title = {Gene discovery and validation for neurodegenerative diseases.}, journal = {Drug discovery today}, volume = {8}, number = {1}, pages = {39-46}, doi = {10.1016/s1359644602025400}, pmid = {12546990}, issn = {1359-6446}, mesh = {Adult ; Alzheimer Disease/drug therapy/metabolism/physiopathology ; Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Animals ; Humans ; *Neurodegenerative Diseases/drug therapy/genetics/physiopathology ; Parkinson Disease/epidemiology/metabolism/physiopathology ; Pharmacogenetics/*trends ; }, abstract = {Treatment of neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis (ALS), represents a major challenge for the pharmaceutical industry. These disorders have common and unique molecular pathological characteristics that result in serious reductions in nervous-system functionality. Key to developing novel and efficacious therapeutics is the discovery of new gene targets. Genomic, proteomics and bioinformatic analyses are identifying vast amounts of genes whose expression is associated with the pathology of a specific disease. Extensive validation studies performed in parallel with drug development are crucial for the selection of appropriate target genes. This review outlines some of the current progress in gene discovery for neurodegenerative disease.}, }
@article {pmid12544867, year = {2003}, author = {Ozer, K and Oke, R and Gurunluoglu, R and Zielinski, M and Izycki, D and Prajapati, R and Siemionow, M}, title = {Induction of tolerance to hind limb allografts in rats receiving cyclosporine A and antilymphocyte serum: effect of duration of the treatment.}, journal = {Transplantation}, volume = {75}, number = {1}, pages = {31-36}, doi = {10.1097/00007890-200301150-00006}, pmid = {12544867}, issn = {0041-1337}, mesh = {Animals ; Antilymphocyte Serum/*administration &amp; dosage ; Bone Marrow Transplantation ; Cyclosporine/*administration &amp; dosage ; Flow Cytometry ; Graft Survival ; Hindlimb/*transplantation ; *Immune Tolerance ; Kidney Transplantation/*immunology ; Lymphocyte Culture Test, Mixed ; Male ; Rats ; Rats, Inbred Lew ; Time Factors ; Transplantation Chimera ; Transplantation, Homologous ; }, abstract = {BACKGROUND: This study assessed the ability of antilymphocyte serum (ALS) and cyclosporine A (CsA) to induce tolerance for hind limb composite tissue allograft in rats without chronic immunosuppression.<br><br>METHODS: Hind limb transplantations were performed in Lewis-Brown-Norway (LBN, RT1(1+n)) and Lewis (LEW, RT1(1)) rats. Treatment consisted of ALS only (0.4 mL/kg), CsA only (16 mg/kg), and a combination of CsA and ALS, and it was administered 12 hr before surgery at three different intervals (7, 14, and 21 days). Long-term survivors were tested for tolerance by standard skin grafting from the recipient (LEW), the donor (LBN), and the third party (ACI, RT1) 60 days after cessation of the treatment and by mixed lymphocyte reaction at 100 days. T-cell lines were analyzed with flow cytometry.<br><br>RESULTS: Single use of ALS in all treatment intervals did not prolong allograft survival. Single use of CsA extended survival up to 23 days in the 21-day protocol group. CsA and ALS caused indefinite survival in two of six rats in the 14-day protocol and in all six rats in the 21-day protocol (>420 days). The six long-term survivors in the 21-day protocol accepted the skin grafts from the donor (LBN) and the recipient (LEW) and rejected third-party grafts (ACI). Tolerant animals showed a donor-specific hematopoietic chimerism of 35% to 42% in the peripheral blood. Mixed lymphocyte reaction assay demonstrated tolerance to the host and donor alloantigens and increased response to the third party.<br><br>CONCLUSIONS: Administration of CsA and ALS for 21 days induced donor-specific tolerance in the recipients of the rat hind limb composite tissue allografts. The mechanism of tolerance should be investigated further.}, }
@article {pmid12539730, year = {2001}, author = {Xie, Y and Duan, Y and Wang, D and Zhu, S and Lu, X}, title = {[Changes of soft tissue profile in operated unilateral cleft lip and palate patients after maxillary protraction].}, journal = {Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology}, volume = {19}, number = {4}, pages = {237-239}, pmid = {12539730}, issn = {1000-1182}, mesh = {Cephalometry ; Child ; Cleft Lip/*therapy ; Cleft Palate/*therapy ; *Extraoral Traction Appliances ; Female ; Humans ; Lip/growth &amp; development ; Male ; Nose/growth &amp; development ; }, abstract = {OBJECTIVE: The aim of this study is to investigate effects of maxillary protraction on soft tissue profile in operated operated unilateral cleft lip and palate (UCLP) patients.<br><br>METHODS: A total of 10 growing UCLP patients (male 7, female 3), age from 8.2 to 12 years old (Average: 10.4 years old), were selected to be treated with maxillary protraction using head gear-chin cap-long hook protraction appliance. The appliance was worn 12-14 hours per day, and the protraction force was 400-500 g each side. The protraction direction was forward and slightly downward. The treatment period was 4.7 months (Average: 5.8 months). Cephalometrics were taken before and after treatment. The changes of soft-tissue profile were studied using the computer-aid X-ray cephalometric analysis.<br><br>RESULTS: After protraction, the points of Prn, Sn and Ls moved forward significantly. The distance from points Ls to E plane changed significantly from 0.46 mm before treatment to 1.18 mm after treatment. The angle G-Prn-Pg' decreased significantly, and G-Sn-Pg' changed significantly from -0.30 before treatment to 6.260 after treatment. The anterior-posterior position of mandible and lower lip did not change significantly, the changes of angles Cm-Sn-Ls, A'ls/SiLi had no statistical significance. The results indicated that maxillary protraction could make maxilla and upper lip move forward, and the convexity of soft tissue profile improve significantly.<br><br>CONCLUSION: Maxillary protraction is an effective way to improve the facial deformity of operated UCLP patients. UCLP patients should have early interrupted treatment.}, }
@article {pmid12534333, year = {2003}, author = {Dib, M}, title = {Amyotrophic lateral sclerosis: progress and prospects for treatment.}, journal = {Drugs}, volume = {63}, number = {3}, pages = {289-310}, pmid = {12534333}, issn = {0012-6667}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Antioxidants/therapeutic use ; Apoptosis/drug effects ; Clinical Trials as Topic ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Mice ; Mice, Transgenic ; Neuroprotective Agents/pharmacology/*therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {Fifteen years ago, a role for excitotoxic damage in the pathology of amyotrophic lateral sclerosis (ALS) was postulated. This stimulated the development of riluzole, the only available treatment for the disease. Since then, the identification of abnormal forms of superoxide dismutase as the genetic basis of certain familial forms of ALS has provided a huge impetus to the search for new effective treatments for this devastating disease. Transgenic mouse models have been developed expressing these aberrant mutants that develop a form of motor neurone disease the progress of which can be slowed by riluzole. Studies in these mice have provided evidence for a role for excitotoxic, apoptotic and oxidative processes in the development of pathology. The mice can be used for testing molecules targeting these processes as potential therapies, to allow the most promising to be evaluated in humans. Several such agents are currently in clinical trials. Many previous clinical trials in ALS were insufficiently powered to demonstrate any relevant effect on disease progression. This situation has been to some extent remedied in the more recent trials, which have recruited many hundreds of patients. However, with the exception of studies with riluzole, the results of these have been disappointing. In particular, a number of large trials with neurotrophic agents have revealed no evidence for efficacy. Nonetheless, the need for large multinational trials of long duration limits the number that can be carried out and makes important demands on investment. For this reason, surrogate markers that can be used for rapid screening in patients of potential treatments identified in the transgenic mice are urgently needed.}, }
@article {pmid12523114, year = {2002}, author = {Tomik, B and Szczudlik, A and Bobrzyński, A and Budzyński, A and Rembiasz, K and Banach, M and Pichór, A and Partyka, D}, title = {[Percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis patients with dysphagia. A preliminary report].}, journal = {Neurologia i neurochirurgia polska}, volume = {36}, number = {5}, pages = {891-901}, pmid = {12523114}, issn = {0028-3843}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*complications ; Deglutition Disorders/*etiology/surgery ; Enteral Nutrition/*methods ; Female ; *Gastroscopy/methods ; Gastrostomy/*adverse effects/*methods ; Humans ; Male ; Middle Aged ; Nutritional Support ; Survival Analysis ; Time Factors ; Treatment Outcome ; }, abstract = {Percutaneous endoscopic gastrostomy (PEG) has been proposed as symptomatic treatment of dysphagia in amyotrophic lateral sclerosis (ALS) patients. The aim of our study was to assess the safety and complications and survival after PEG implantations in 13 ALS patients. We discuss the factors related to survival in two groups: dead (6 out of 13 patients) and alive (7 out of 13) after PEG implantations. We demonstrate that the PEG procedure is quite safe and forced vital capacity (FVC) is a major factor related to survival after PEG implantation in studied patients.}, }
@article {pmid12520766, year = {2002}, author = {Polizzi, S and Pira, E and Ferrara, M and Bugiani, M and Papaleo, A and Albera, R and Palmi, S}, title = {Neurotoxic effects of aluminium among foundry workers and Alzheimer's disease.}, journal = {Neurotoxicology}, volume = {23}, number = {6}, pages = {761-774}, doi = {10.1016/S0161-813X(02)00097-9}, pmid = {12520766}, issn = {0161-813X}, mesh = {Aged ; Aluminum/blood/*toxicity ; *Alzheimer Disease/blood/chemically induced/epidemiology ; Case-Control Studies ; Cognition/*drug effects/physiology ; Cognition Disorders/blood/chemically induced/epidemiology ; Cross-Sectional Studies ; Humans ; Linear Models ; *Metallurgy ; Middle Aged ; *Neuropsychological Tests/statistics &amp; numerical data ; Occupational Exposure/*adverse effects/statistics &amp; numerical data ; }, abstract = {BACKGROUND: In a cross-sectional case-control study conducted in northern Italy, 64 former aluminium dust-exposed workers were compared with 32 unexposed controls from other companies matched for age, professional training, economic status, educational and clinical features. The findings lead the authors to suggest a possible role of the inhalation of aluminium dust in pre-clinical mild cognitive disorder which might prelude Alzheimer's disease (AD) or AD-like neurological deterioration.<br><br>METHODS: The investigation involved a standardised occupational and medical history with particular attention to exposure and symptoms, assessments of neurotoxic metals in serum: aluminium (Al-s), copper (Cu-s) and zinc (Zn-s), and in blood: manganese (Mn-b), lead (Pb-b) and iron (Fe-b). Cognitive functions were assessed by the Mini Mental State Examination (MMSE), the Clock Drawing Test (CDT) and auditory evoked Event-Related Potential (ERP-P300). To detect early signs of mild cognitive impairment (MCI), the time required to solve the MMSE (MMSE-time) and CDT (CDT-time) was also measured.<br><br>RESULTS: Significantly higher internal doses of Al-s and Fe-b were found in the ex-employees compared to the control group. The neuropsychological tests showed a significant difference in the latency of P300, MMSE score, MMSE-time, CDT score and CDT-time between the exposed and the control population. P300 latency was found to correlate positively with Al-s and MMSE-time. Al-s has significant effects on all tests: a negative relationship was observed between internal Al concentrations, MMSE score and CDT score; a positive relationship was found between internal Al concentrations, MMSE-time and CDT-time. All the potential confounders such as age, height, weight, blood pressure, schooling years, alcohol, coffee consumption and smoking habit were taken into account.<br><br>CONCLUSIONS: These findings suggest a role of aluminium in early neurotoxic effects that can be detected at a pre-clinical stage by P300, MMSE, MMSE-time, CDT-time and CDT score, considering a 10 micrograms/l cut-off level of serum aluminium, in aluminium foundry workers with concomitant high blood levels of iron. The authors raise the question whether pre-clinical detection of aluminium neurotoxicity and consequent early treatment might help to prevent or retard the onset of AD or AD-like pathologies.}, }
@article {pmid12519593, year = {2002}, author = {Hirst, A and Sloan, R}, title = {Benzodiazepines and related drugs for insomnia in palliative care.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD003346}, doi = {10.1002/14651858.CD003346}, pmid = {12519593}, issn = {1469-493X}, mesh = {Benzodiazepines/*therapeutic use ; Humans ; *Palliative Care ; Sleep Initiation and Maintenance Disorders/*drug therapy ; }, abstract = {BACKGROUND: Insomnia, a subjective complaint of poor sleep and associated impairment in daytime function, is a common problem. Currently, benzodiazepines are the most used pharmacological treatment for this complaint. They are considered helpful for occasional short-term use up to four weeks but longer term use is not advised due to potential problems regarding tolerance, dosing escalation, psychological addiction and physical dependence. There is no consensus on their utility in patients with progressive incurable conditions who may require assistance with sleep for many weeks as their condition deteriorates.<br><br>OBJECTIVES: To assess the effectiveness and safety of benzodiazepines or benzodiazepine receptor agonists such as Zolpidem, Zopiclone and Zaleplon for insomnia in palliative care.<br><br>SEARCH STRATEGY: Several electronic databases were searched including Cochrane PaPaS Group specialized register, Cochrane Library Issue 4, 2001, MEDLINE, EMBASE, BNI plus, CINAHL, BIOLOGICAL ABSTRACTS, PSYCINFO, CANCERLIT, HEALTHSTAR, WEB OF SCIENCE, SIGLE, Dissertation Abstracts, ZETOC and the MetaRegister of ongoing trials. These were searched from 1960 to 2001 or as much of this range as possible. Additional articles were sought by handsearching reference lists in standard textbooks and reviews in the field and by contacting academic centres in palliative care and pharmaceutical companies. There were no language restrictions.<br><br>SELECTION CRITERIA: Studies considered for inclusion were randomized controlled trials of adult patients in any setting, receiving palliative care or suffering an incurable progressive medical condition. (For example, cancers, AIDS, Motor Neurone Disease, Multiple Sclerosis, Parkinson's Disease, Chronic Obstructive Pulmonary Disease). There had to be an explicit complaint of insomnia in study participants, diagnosed by any of the three main classification systems (DSM-IV (APA 1994), ICSD (AASD 1990) or ICD (WHO 1992)), or as described in the study if it involved a subjective complaint of poor sleep. Studies had to compare a benzodiazepine or Zolpidem or Zopiclone or Zaleplon with placebo or active control for the treatment of insomnia. Any duration of therapy were considered.<br><br>DATA COLLECTION AND ANALYSIS: Abstracts were independently inspected by both reviewers, full papers were obtained where necessary. Where there was uncertainty advice was sought by a third (PW). Data extraction and quality assessments were undertaken independently by both reviewers.<br><br>MAIN RESULTS: No randomized controlled trials were identified meeting the a priori inclusion criteria. Thirty-seven studies were considered but all were excluded from the review.<br><br>REVIEWER'S CONCLUSIONS: Despite a comprehensive search no evidence from randomized controlled trials was identified. It was not possible to draw any conclusions regarding the use of benzodiazepines in palliative care.}, }
@article {pmid12509691, year = {2002}, author = {Howard, RS and Orrell, RW}, title = {Management of motor neurone disease.}, journal = {Postgraduate medical journal}, volume = {78}, number = {926}, pages = {736-741}, pmid = {12509691}, issn = {0032-5473}, mesh = {Deglutition Disorders/etiology/therapy ; Humans ; Motor Neuron Disease/diagnosis/*therapy ; Neuroprotective Agents/therapeutic use ; Palliative Care/methods ; Respiration Disorders/etiology/therapy ; Respiration, Artificial/methods ; Riluzole/therapeutic use ; }, abstract = {Motor neurone disease is a progressive neurodegenerative disorder leading to severe disability and death. It is clinically characterised by mixed upper and lower motor neurone involvement affecting bulbar, limb, and respiratory musculature. Recent guidelines have established diagnostic criteria and defined management of the condition. In a proportion of familial amyotrophic lateral sclerosis there is a mutation in the gene encoding the enzyme copper/zinc superoxide dismutase 1; this has allowed mutation screening and generated considerable laboratory based research. The diagnosis must be given with care and consideration and close follow up is essential. Management involves a multidisciplinary team based in the hospital and the community. Riluzole is the only drug shown to have a disease modifying effect and has been approved by the National Institute for Clinical Excellence. The essence of care is good symptomatic management, including nutritional support with percutaneous endoscopic gastrostomy and ventilatory care with non-invasive ventilation. Palliative care should be introduced before the terminal stages after careful discussion with the patient and carers. Knowledge of this condition has grown dramatically recently with a parallel improvement in treatment and ability to deal with the most troublesome problems.}, }
@article {pmid12507722, year = {2003}, author = {Lu, YY and Wang, LJ and Muramatsu, S and Ikeguchi, K and Fujimoto, K and Okada, T and Mizukami, H and Matsushita, T and Hanazono, Y and Kume, A and Nagatsu, T and Ozawa, K and Nakano, I}, title = {Intramuscular injection of AAV-GDNF results in sustained expression of transgenic GDNF, and its delivery to spinal motoneurons by retrograde transport.}, journal = {Neuroscience research}, volume = {45}, number = {1}, pages = {33-40}, doi = {10.1016/s0168-0102(02)00195-5}, pmid = {12507722}, issn = {0168-0102}, mesh = {Animals ; Dependovirus/genetics ; Enzyme-Linked Immunosorbent Assay ; Genetic Therapy/*methods ; Genetic Vectors/*administration &amp; dosage ; Glial Cell Line-Derived Neurotrophic Factor ; Humans ; Immunohistochemistry ; Injections, Intramuscular ; Mice ; Motor Neurons/metabolism ; Muscle, Skeletal/metabolism ; Nerve Growth Factors/*biosynthesis/*genetics ; Spinal Cord/cytology/metabolism ; Time Factors ; Transduction, Genetic/*methods ; Transgenes ; }, abstract = {Adeno-associated virus (AAV) vector has been developed as an attractive gene delivery system with proven safety. Glial cell line-derived neurotrophic factor (GDNF) is proposed to be a promising therapeutic agent for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases. The purpose of this report was to investigate transgenic GDNF expression at different time points post AAV mediated GDNF intramuscular delivery. An AAV vector was constructed to encode a recombinant fusion of GDNF tagged with a FLAG sequence at the C-terminal (AAV-GDNF) to distinguish it from its endogenous counterpart. A single intramuscular injection of AAV-GDNF led to substantial expression of transgenic GDNF which remained for at least 10 months in transduced gastrocnemius muscle. This transgenic GDNF was distributed in a large number of myofibers, mainly in the vicinity of the sarcolemma and predominantly concentrated at the sites of neuromuscular junctions (NMJs). Furthermore, transgenic GDNF, but not beta-galactosidase expressed as a control, was detected in the motoneurons that projected axons to the injected muscles, thus, indicating retrograde axonal transportation of the transgenic GDNF. This study provides a basis for a strategy of intramuscular AAV-GDNF delivery to protect motoneurons as a possible means of ALS treatment.}, }
@article {pmid12495575, year = {2002}, author = {Hilz, MJ and Hecht, MJ and Mittelhamm, F and Neundörfer, B and Brown, CM}, title = {Baroreflex stimulation shows impaired cardiovagal and preserved vasomotor function in early-stage amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {3}, number = {3}, pages = {137-144}, doi = {10.1080/146608202760834148}, pmid = {12495575}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/mortality/*physiopathology ; *Baroreflex ; Cardiovascular System/*physiopathology ; Carotid Arteries/innervation ; Female ; Humans ; Male ; Middle Aged ; Physical Stimulation ; Prognosis ; Quality of Life ; Survival Rate ; Vagus Nerve/*physiopathology ; }, abstract = {OBJECT: In ALS patients, autonomic nervous system dysfunction might account for an additional reduction of the quality and expectancy of life of individual patients and contribute to unexpected early fatalities. This study was undertaken to assess baroreflex-mediated vagal and sympathetic cardiovascular control of the heart and blood vessels in ALS patients.<br><br>METHODS: In 12 early-stage ALS patients (age 54 +/- 4 years) and 12 controls (age 55 +/- 3 years) we assessed resting baroreflex sensitivity (BRS) by spectral analysis, then stimulated the carotid baroreflex by oscillating neck suction at 0.1 Hz to assess the autonomic modulation of the heart and blood vessels and at 0.2 Hz to assess the effect of parasympathetic stimulation on the heart.<br><br>RESULTS: Resting heart rate was significantly higher in the ALS patients than in the controls (P < 0.05), but resting baroreflex sensitivity did not differ significantly between the groups. Stimulation at 0.2 Hz induced an oscillation in R-R interval that was significantly smaller (P < 0.05) in ALS patients than in controls. R-R interval responses to 0.1 Hz stimulation were significantly (P < 0.01) reduced in ALS patients compared to controls. Responses of blood vessels to 0.1 Hz stimulation did not differ significantly between the groups.<br><br>CONCLUSION: In early-stage ALS patients, BRS might be normal at rest. Only baroreflex activation reveals impaired cardiovagal responses while sympathetic vasomotor control is preserved. Treatment to restore sympathetic-parasympathetic balance to the heart could prevent early cardiovascular fatalities in some ALS patients.}, }
@article {pmid12495570, year = {2002}, author = {Armon, C and Guiloff, RJ and Bedlack, R}, title = {Limitations of inferences from observational databases in amyotrophic lateral sclerosis: all that glitters is not gold.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {3}, number = {3}, pages = {109-112}, doi = {10.1080/146608202760834094}, pmid = {12495570}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Databases, Factual/*standards/*statistics &amp; numerical data ; Evidence-Based Medicine/*methods ; Humans ; Neuroprotective Agents/*therapeutic use ; Randomized Controlled Trials as Topic ; Retrospective Studies ; Riluzole/*therapeutic use ; Treatment Outcome ; }, abstract = {Data from three observational databases have suggested that survival in patients with ALS who take riluzole is far greater than that reported in randomized controlled studies. This editorial discusses why therapeutic efficacy cannot be inferred from observational databases. Data in these databases cannot control for biases in treatment assignment or for differences in intensity of follow-up or supportive care. The retrospective riluzole data, as presented so far, have not demonstrated comparability between the treated and untreated groups across all known prognostic factors, including vital capacity at the start of the observation period. Furthermore, the similarity of untreated patients to historical cohorts likely reflects adverse selection. Optimization of analysis in retrospective studies may be accomplished by allowing full access to data to all interested parties.}, }
@article {pmid12457363, year = {2002}, author = {Siemionow, M and Oke, R and Ozer, K and Izycki, D and Prajapati, R}, title = {Induction of donor-specific tolerance in rat hind-limb allografts under antilymphocyte serum and cyclosporine A protocol.}, journal = {The Journal of hand surgery}, volume = {27}, number = {6}, pages = {1095-1103}, doi = {10.1053/jhsu.2002.36524}, pmid = {12457363}, issn = {0363-5023}, mesh = {Animals ; Antilymphocyte Serum/*therapeutic use ; Cyclosporine/*therapeutic use ; Flow Cytometry ; Graft Rejection/*prevention &amp; control ; Graft Survival ; Hindlimb/*transplantation ; Immune Tolerance/drug effects ; Immunosuppressive Agents/*therapeutic use ; Male ; Rats ; Rats, Sprague-Dawley ; T-Lymphocytes/immunology ; Transplantation Chimera ; Transplantation, Homologous/immunology ; }, abstract = {Composite tissue allograft (CTA) transplantation became a clinical reality despite major side effects associated with the administration of chronic immunosuppression. Development of new treatment modalities eliminating life-long immunosuppression is essential for the future of CTA transplantation. In this study, combined use of cyclosporine A (CsA) and antilymphocyte serum (ALS) was tested for the potential to induce tolerance in the rat hind-limb allograft recipients across a major histocompatibility (MHC) barrier (Lewis-Brown-Norway [LBN, RT1(l+n)] to Lewis [LEW, RT1(l)] rats). Thirty transplantations were performed in 5 experimental groups. Animals received CsA and ALS 12 hours before surgery for 21 days thereafter. Although the allograft controls rejected their limbs at day 7 combined treatment of CsA and ALS resulted in indefinite survival (over 420 d) in all allograft recipients. Long-term survivors showed 35% to 42% of donor-specific chimerism in the peripheral blood. Clinical tolerance was confirmed by acceptance of the donor-specific skin grafts and immunocompetence was confirmed by rejection of the third-party grafts. Mixed lymphocyte reaction revealed suppressed response against donor-type antigens and increased response to third-party antigens. Donor-specific tolerance across MHC barrier was induced in CTA allografts under 21 days protocol of ALS/CsA.}, }
@article {pmid12447931, year = {2002}, author = {Drachman, DB and Frank, K and Dykes-Hoberg, M and Teismann, P and Almer, G and Przedborski, S and Rothstein, JD}, title = {Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS.}, journal = {Annals of neurology}, volume = {52}, number = {6}, pages = {771-778}, doi = {10.1002/ana.10374}, pmid = {12447931}, issn = {0364-5134}, support = {AG 12992/AG/NIA NIH HHS/United States ; NS 33958/NS/NINDS NIH HHS/United States ; NS 36465/NS/NINDS NIH HHS/United States ; NS 37345/NS/NINDS NIH HHS/United States ; NS 38370/NS/NINDS NIH HHS/United States ; NS 3856/NS/NINDS NIH HHS/United States ; NS 38765/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*enzymology/*genetics ; Animals ; Celecoxib ; Cyclooxygenase 2 ; Cyclooxygenase 2 Inhibitors ; Cyclooxygenase Inhibitors/*pharmacology/therapeutic use ; Dinoprostone/antagonists &amp; inhibitors/metabolism ; *Disease Models, Animal ; Female ; Humans ; Isoenzymes/*antagonists &amp; inhibitors/metabolism ; Male ; Membrane Proteins ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects/*enzymology/pathology ; Prostaglandin-Endoperoxide Synthases/metabolism ; Pyrazoles ; Sulfonamides/pharmacology/therapeutic use ; Survival Rate ; }, abstract = {The pathogenesis of cell death in amyotrophic lateral sclerosis (ALS) may involve glutamate-mediated excitotoxicity, oxidative damage, and apoptosis. We used a transgenic mouse model of ALS to determine the effect of inhibition of cyclooxygenase-2 in treating the disease. Cyclooxygenase-2, present in spinal neurons and astrocytes, catalyzes the synthesis of prostaglandin E2. Prostaglandin E2 stimulates glutamate release from astrocytes, whereas cyclooxygenase-2 also plays a key role in the production of proinflammatory cytokines, reactive oxygen species, and free radicals. Treatment with a selective cyclooxygenase-2 inhibitor, celecoxib, markedly inhibited production of prostaglandin E2 in the spinal cords of ALS mice. Celecoxib treatment significantly delayed the onset of weakness and weight loss and prolonged survival by 25%. Spinal cords of treated ALS mice showed significant preservation of spinal neurons and diminished astrogliosis and microglial activation. Our results suggest that cyclooxygenase-2 inhibition may benefit ALS patients.}, }
@article {pmid12437574, year = {2002}, author = {Urushitani, M and Kurisu, J and Tsukita, K and Takahashi, R}, title = {Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {83}, number = {5}, pages = {1030-1042}, doi = {10.1046/j.1471-4159.2002.01211.x}, pmid = {12437574}, issn = {0022-3042}, mesh = {Amino Acid Substitution ; Amyotrophic Lateral Sclerosis/*enzymology/etiology ; Animals ; Cell Death ; Cells, Cultured ; Cysteine Endopeptidases/metabolism ; Disease Models, Animal ; Enzyme Activation ; Gene Expression ; Humans ; Kidney/cytology/metabolism ; Macromolecular Substances ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/cytology/*metabolism ; Multienzyme Complexes/*antagonists &amp; inhibitors/metabolism ; Neuroblastoma/metabolism ; Oxidative Stress ; Proteasome Endopeptidase Complex ; Protein Denaturation ; *Protein Folding ; Solubility ; Superoxide Dismutase/genetics/*metabolism ; Superoxide Dismutase-1 ; Ubiquitin/metabolism ; }, abstract = {Accumulating evidence indicates that abnormal conformation of mutant superoxide dismutase 1 (SOD1) is an essential feature underlying the pathogenesis of mutant SOD1-linked familial amyotrophic lateral sclerosis (ALS). Here we investigated the role of ubiquitin-proteasome pathway in the mutant SOD1-related cell death and the effect of oxidative stress on the misfolding of mutant SOD1. Transient overexpression of ubiquitin with human SOD1 (wild-type, ala4val, gly85arg, gly93ala) in Neuro2A cells decreased the amount of mutant SOD1, but not of wild-type, while only mutants were co-immunoprecipitated with poly-ubiquitin. Proteasome inhibition by lactacystin augmented accumulation of mutant SOD1 in the non-ionic detergent-insoluble fraction. The spinal cord lysates from mutant SOD1 transgenic mice showed multiple carbonylated proteins, including mutant SOD1 with SDS-resistant dimer formation. Furthermore, the treatment of hSOD1-expressing cells with hydrogen peroxide promoted the oligomerization, and detergent-insolubility of mutant SOD1 alone, and the oxidized mutant SOD1 proteins were more heavily poly-ubiquitinated. In Neuro2A cells stably expressing human SOD1 protein, the proteasome function measured by chymotrypsin-like activity, was decreased over time without a quantitative alteration of the 20S proteasomal component. Finally, primary motor neurons from the mouse embryonic spinal cord were more vulnerable to lactacystin than non-motor neurons. These results indicate that the sustained expression of mutant SOD1 leads to proteasomal inhibition and motor neuronal death, which in part explains the pathogenesis of mutant SOD1-linked ALS.}, }
@article {pmid12433120, year = {2002}, author = {Xing, L and Cotrutz, C and Hunjan, S and Boyer, AL and Adalsteinsson, E and Spielman, D}, title = {Inverse planning for functional image-guided intensity-modulated radiation therapy.}, journal = {Physics in medicine and biology}, volume = {47}, number = {20}, pages = {3567-3578}, doi = {10.1088/0031-9155/47/20/301}, pmid = {12433120}, issn = {0031-9155}, mesh = {*Algorithms ; Brain Neoplasms/diagnostic imaging/*radiotherapy ; Feasibility Studies ; Glioma/diagnostic imaging/radiotherapy ; Humans ; Magnetic Resonance Imaging/methods ; Phantoms, Imaging ; Quality Control ; Radiation Dosage ; Radiographic Image Interpretation, Computer-Assisted/*methods ; Radiometry/instrumentation/*methods ; Radiotherapy Planning, Computer-Assisted/instrumentation/*methods ; Radiotherapy, Conformal/instrumentation/*methods ; Sensitivity and Specificity ; Subtraction Technique ; Tomography, X-Ray Computed/*methods ; }, abstract = {Radiation therapy is an image-guided process whose success critically depends on the imaging modality used for treatment planning and the level of integration of the available imaging information. In this work, we establish a dose optimization framework for incorporating metabolic information from functional imaging modalities into the intensity-modulated radiation therapy (IMRT) inverse planning process and to demonstrate the technical feasibility of planning deliberately non-uniform dose distributions in accordance with functional imaging data. For this purpose, a metabolic map from functional images is discretized into a number of abnormality levels (ALs) and then fused with CT images. To escalate dose to the metabolically abnormal regions, we assume, for a given spatial point, a linear relation between the AL and the prescribed dose. But the formalism developed here is independent of the assumption and any other relation between AL and prescription is applicable. For a given AL and prescription relation, it is only necessary to prescribe the dose to the lowest AL in the target and the desired doses to other regions with higher AL values are scaled accordingly. To accomplish differential sparing of a sensitive structure when its functional importance (FI) distribution is known, we individualize the tolerance doses of the voxels within the structure according to their Fl levels. An iterative inverse planning algorithm in voxel domain is used to optimize the system with in homogeneous dose prescription. To model intra-structural trade-off, a mechanism is introduced through the use of voxel-dependent weighting factors, in addition to the conventional structure specific weighting factors which model the inter-structural trade-off. The system is used to plan a phantom case with a few hypothetical functional distributions and a brain tumour treatment with incorporation of magnetic resonance spectroscopic imaging data. The results indicated that it is technically feasible to produce deliberately non-uniform dose distributions according to the functional imaging requirements. Integration of functional imaging information into radiation therapy dose optimization allows for consideration of patient-specific biologic information and provides a significant opportunity to truly individualize radiation treatment. This should enhance our capability to safely and intelligently escalate dose and lays the technical foundation for future clinical studies of the efficacy of functional imaging-guided IMRT.}, }
@article {pmid12423246, year = {2002}, author = {Hyun, DH and Lee, MH and Halliwell, B and Jenner, P}, title = {Proteasomal dysfunction induced by 4-hydroxy-2,3-trans-nonenal, an end-product of lipid peroxidation: a mechanism contributing to neurodegeneration?.}, journal = {Journal of neurochemistry}, volume = {83}, number = {2}, pages = {360-370}, doi = {10.1046/j.1471-4159.2002.01125.x}, pmid = {12423246}, issn = {0022-3042}, mesh = {Aldehydes/*toxicity ; Apoptosis/drug effects ; Caspase 3 ; Caspases/metabolism ; Cell Membrane/drug effects/metabolism ; Cell Survival/drug effects ; Cysteine Endopeptidases/*drug effects/metabolism ; Cysteine Proteinase Inhibitors/*toxicity ; Cytochrome c Group/metabolism ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Humans ; Lipid Peroxidation/*physiology ; Multienzyme Complexes/*drug effects/metabolism ; Mutation ; Neuroblastoma/drug therapy/metabolism ; Neurodegenerative Diseases/etiology/*metabolism ; Proteasome Endopeptidase Complex ; Superoxide Dismutase/biosynthesis/genetics ; Teratocarcinoma/drug therapy/metabolism ; Tumor Cells, Cultured ; Ubiquitin/metabolism ; }, abstract = {4-Hydroxy-2,3-trans-nonenal (HNE) is a neurotoxic unsaturated aldehyde end-product of lipid peroxidation. The addition of HNE to NT-2 and SK-N-MC cell lines induces apoptosis and we now investigated the time-course of events occurring prior to apoptosis. Treatment of both NT-2 and SK-N-MC cell lines with HNE led to HNE association with the proteasome, increased levels of protein carbonyls and ubiquitinated proteins, and decreased proteasomal function. There was also decreased metabolic activity, cytochrome c release and activation of caspase 3, followed by apoptotic changes including chromatin condensation, cell shrinkage and DNA fragmentation and laddering. Overexpression of mutant superoxide dismutase 1 proteins associated with amyotrophic lateral sclerosis decreased proteasomal activities in the absence of HNE and accelerated the apoptosis induced by HNE. By contrast, overexpression of wild-type superoxide dismutase 1 did not affect basal levels of proteasomal activity. The data suggest that accumulation of ubiquitinated proteins and impairment of proteasomal function are important events in HNE toxicity. We propose that the proteasomal system is a significant target of HNE neurotoxicity in a wide range of neurodegenerative diseases, especially if abnormal proteins are being expressed.}, }
@article {pmid12413243, year = {2002}, author = {Vincent, E and Todd, S and Whitehead, J}, title = {A sequential procedure for comparing two experimental treatments with a control.}, journal = {Journal of biopharmaceutical statistics}, volume = {12}, number = {2}, pages = {249-265}, doi = {10.1081/bip-120015747}, pmid = {12413243}, issn = {1054-3406}, mesh = {Analysis of Variance ; Bayes Theorem ; Humans ; Randomized Controlled Trials as Topic/methods/*statistics &amp; numerical data ; Retrospective Studies ; Therapies, Investigational/methods/statistics &amp; numerical data ; }, abstract = {A procedure is described in which patients are randomized between two experimental treatments and a control. At a series of interim analyses, each experimental treatment is compared with control. One of the experimental treatments might then be found sufficiently superior to the control for it to be declared the best treatment, and the trial stopped. Alternatively, experimental treatments might be eliminated from further consideration at any stage. It is shown how the procedure can be conducted while controlling overall error probabilities. Data concerning evaluation of different doses of riluzole in the treatment of motor neurone disease are used for illustration.}, }
@article {pmid12394638, year = {2002}, author = {Cameron, A and Rosenfeld, J}, title = {Nutritional issues and supplements in amyotrophic lateral sclerosis and other neurodegenerative disorders.}, journal = {Current opinion in clinical nutrition and metabolic care}, volume = {5}, number = {6}, pages = {631-643}, doi = {10.1097/00075197-200211000-00005}, pmid = {12394638}, issn = {1363-1950}, mesh = {Amyotrophic Lateral Sclerosis/complications/*physiopathology/therapy ; Deglutition Disorders/etiology/therapy ; *Dietary Supplements ; *Enteral Nutrition ; Gastrostomy/methods ; Humans ; Motor Neuron Disease/complications/*physiopathology/therapy ; Nutrition Disorders/*etiology/prevention &amp; control/therapy ; Palliative Care ; Prognosis ; Respiratory Insufficiency/etiology ; }, abstract = {PURPOSE OF REVIEW: Aggressive nutritional intervention has become a cornerstone of treatment for many patients with neuromuscular diseases, in particular, motor neuron disease. Malnutrition is a common problem among patients with amyotrophic lateral sclerosis. Over the past decade, the recognition of nutrition as an independent, prognostic factor for survival and disease complications in amyotrophic lateral sclerosis has illustrated the importance of individualized nutritional management in symptomatic treatment. Paramount issues for nutritional management in amyotrophic lateral sclerosis include caloric supplementation, the diagnosis/treatment of dysphagia, and the timing/safety/efficacy of percutaneous endoscopic gastrostomy placement.<br><br>RECENT FINDINGS: In addition, many amyotrophic lateral sclerosis patients self-medicate with a variety of vitamins, herbs, and other dietary supplements. Outcome-based research for the use of nutraceuticals and functional foods in the treatment and prevention of amyotrophic lateral sclerosis and other neuromuscular diseases is in its early stages. In the past year, however, several interesting papers have been published that lend support to the use of dietary supplements as primary treatments for amyotrophic lateral sclerosis and other motor neuron disorders.<br><br>SUMMARY: Common or overlapping etiologies in disparate neurodegenerative diseases have led to the promise that optimal nutritional care and the appropriate use of dietary supplements in amyotrophic lateral sclerosis will have implications for the nutritional management of other degenerative conditions such as Parkinson's, Alzheimer's, and Huntington's disease. Furthermore, evidence supporting the efficacy of dietary supplements in amyotrophic lateral sclerosis may lend clues to the treatment of other neuromuscular disorders such as the muscular dystrophies.}, }
@article {pmid12392198, year = {2002}, author = {Iwasaki, Y and Ikeda, K and Ichikawa, Y and Igarashi, O and Iwamoto, K and Kinoshita, M}, title = {Protective effect of interleukin-3 and erythropoietin on motor neuron death after neonatal axotomy.}, journal = {Neurological research}, volume = {24}, number = {7}, pages = {643-646}, doi = {10.1179/016164102101200681}, pmid = {12392198}, issn = {0161-6412}, mesh = {Animals ; Animals, Newborn ; Anterior Horn Cells/*drug effects/pathology/physiopathology ; Axotomy ; Cell Count ; Cell Death/*drug effects/physiology ; Cell Survival/drug effects/physiology ; Dose-Response Relationship, Drug ; Erythropoietin/*pharmacology ; Interleukin-3/*pharmacology ; Motor Neuron Disease/*drug therapy/metabolism/physiopathology ; Neuroprotective Agents/*pharmacology ; Peripheral Nervous System Diseases/*drug therapy/metabolism/physiopathology ; Rats ; Rats, Sprague-Dawley ; Retrograde Degeneration/drug therapy/physiopathology/prevention &amp; control ; Sciatic Nerve/drug effects/injuries/surgery ; Sciatic Neuropathy/drug therapy/metabolism/physiopathology ; }, abstract = {Several members of hematopoietic factors are known to have neuroprotective effects against axotomized motor neuron death. We carried out a study to determine whether interleukin-3 (IL-3) and erythropoietin (EPO) rescue spinal motor neuron death following axotomy. Unilateral sciatic nerve was transected in neonatal rats. Different doses of IL-3, EPO, or vehicle were administered daily for two weeks by intraperitoneal injection. After treatment, the number of spinal motor neurons was determined at the level of L4 segment In comparison with vehicle, both IL-3 (10 microg kg(-1)) and EPO (5.0 mg kg(-1)) significantly prevented the loss of motor neurons. Protective potentials is the same between them. These results suggest that IL-3 and EPO play a role for motor neuron survival in vivo and suggest the potential use of these hematopoietic factors in treating diseases that involve degeneration and death of motor neurons, such as motor neuropathy and amyotrophic lateral sclerosis.}, }
@article {pmid12390974, year = {2002}, author = {Priori, A and Cinnante, C and Pesenti, A and Carpo, M and Cappellari, A and Nobile-Orazio, E and Scarlato, G and Barbieri, S}, title = {Distinctive abnormalities of motor axonal strength-duration properties in multifocal motor neuropathy and in motor neurone disease.}, journal = {Brain : a journal of neurology}, volume = {125}, number = {Pt 11}, pages = {2481-2490}, doi = {10.1093/brain/awf255}, pmid = {12390974}, issn = {0006-8950}, mesh = {Action Potentials/drug effects/*physiology ; Adult ; Aged ; Cell Membrane/drug effects/metabolism ; Female ; Humans ; Immunoglobulins, Intravenous/pharmacology ; Male ; Middle Aged ; Motor Neuron Disease/drug therapy/*physiopathology ; Motor Neurons/drug effects/*physiology ; Neural Conduction/drug effects/*physiology ; Peripheral Nervous System Diseases/drug therapy/*physiopathology ; Reaction Time/drug effects/physiology ; Sodium Channels/drug effects/metabolism ; Ulnar Nerve/drug effects/*physiopathology ; }, abstract = {The strength-duration function is a classic measure of neural excitability. When studied on peripheral motor axons it reflects the intrinsic nodal membrane properties, and its time-constant (tau(SD) or chronaxie) predominantly depends on non-voltage-gated, rest Na(+) inward conductances. We assessed the strength-duration curve of ulnar motor axons in 22 nerves of healthy controls, in 18 nerves of patients with multifocal motor neuropathy with conduction blocks (MMN), and in 19 nerves of patients with motor neurone disease (MND). The compound muscle action potential (CMAP) was smaller in nerves of both groups of patients than in controls (P < 0.05). The rheobasic current (rh(50%)) [mean +/- standard deviation (SD)] was higher in patients with MMN than in controls (13.3 +/- 16.3 mA; controls 4.7 +/- 1.7 mA, P < 0.05). The tau(SD) was differentially abnormal in the nerves of the two groups of patients: it was prolonged in the nerves of patients with MND for >or=40 years (227.2 +/- 34.5 micro s; controls 190.9 +/- 51.0 micro s, P < 0.05), but it was shortened in the nerves of patients with MMN (146.5 +/- 55.4 micro s; controls 208.6 +/- 51.2 micro s, P < 0.05) who had not been treated recently with high-dose intravenous immunoglobulin (IVIg). Nerves of patients with recently treated MMN (<6 weeks) who were under the therapeutic effect of IVIg had a normal tau(SD)(.) Our results suggest that, probably due to an immuno-mediated rest Na(+) channel dysfunction, Na(+) conductances are reduced in MMN. This abnormality is a function of the time after the last IVIg treatment and involves also the axonal membrane outside the conduction block. Conversely, in MND, possibly owing to the ionic leakage of degenerating membrane, rest Na(+) conductances are increased. Measuring the strength-duration curve of the ulnar motor axons might be useful in the differential diagnosis between de novo MMN and MND.}, }
@article {pmid12387703, year = {2002}, author = {Moosmann, B and Behl, C}, title = {Antioxidants as treatment for neurodegenerative disorders.}, journal = {Expert opinion on investigational drugs}, volume = {11}, number = {10}, pages = {1407-1435}, doi = {10.1517/13543784.11.10.1407}, pmid = {12387703}, issn = {1354-3784}, mesh = {Animals ; Antioxidants/classification/pharmacology/*therapeutic use ; Free Radicals/metabolism ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism ; }, abstract = {Oxidative stress is a ubiquitously observed hallmark of neurodegenerative disorders. Neuronal cell dysfunction and cell death due to oxidative stress may causally contribute to the pathogenesis of progressive neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, as well as acute syndromes of neurodegeneration, such as ischaemic and haemorrhagic stroke. Neuroprotective antioxidants are considered a promising approach to slowing the progression and limiting the extent of neuronal cell loss in these disorders. The clinical evidence demonstrating that antioxidant compounds can act as protective drugs in neurodegenerative disease, however, is still relatively scarce. In the following review, the available data from clinical, animal and cell biological studies regarding the role of antioxidant neuroprotection in progressive neurodegenerative disease will be summarised, focussing particularly on Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. The general complications in developing potent neuroprotective antioxidant drugs directed against these long-term degenerative conditions will also be discussed. The major challenges for drug development are the slow kinetics of disease progression, the unsolved mechanistic questions concerning the final causalities of cell death, the necessity to attain an effective permeation of the blood-brain barrier and the need to reduce the high concentrations currently required to evoke protective effects in cellular and animal model systems. Finally, an outlook as to which direction antioxidant drug development and clinical practice may be leading to in the near future will be provided.}, }
@article {pmid12387699, year = {2002}, author = {Jackson, M and Lladó, J and Rothstein, JD}, title = {Therapeutic developments in the treatment of amyotrophic lateral sclerosis.}, journal = {Expert opinion on investigational drugs}, volume = {11}, number = {10}, pages = {1343-1364}, doi = {10.1517/13543784.11.10.1343}, pmid = {12387699}, issn = {1354-3784}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Animals ; Anti-Inflammatory Agents/therapeutic use ; Antioxidants/therapeutic use ; Clinical Trials as Topic/statistics &amp; numerical data ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Technology, Pharmaceutical/*trends ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterised by the selective death of motor neurones. The mechanisms and processes responsible for the selective loss of motor neurones are still unknown, however several hypotheses have been put forward, including oxidative damage and/or toxicity from intracellular aggregates due to mutant superoxide dismutase-1 activity, axonal strangulation from cytoskeletal abnormalities, loss of trophic factor support and glutamate-mediated excitotoxicity. These theories are based on a better understanding of the genetics of amyotrophic lateral sclerosis and on biochemical and pathological analysis of post-mortem tissue. They have led to the development of appropriate animal and cell culture models, allowing the sequence of events in motor neuronal degeneration to be unravelled and potential therapeutic agents to be screened. Unfortunately, the majority of therapeutics found to be efficacious in the animal and cell culture models have failed in human trials. Riluzole is still the only proven therapy in humans, shown to extend survival of amyotrophic lateral sclerosis patients by approximately 3 months, but it has no effect on muscle strength. Other potential therapeutic approaches are being identified, including inhibition of caspase-mediated cell death, maintenance of mitochondrial integrity and energy production, regulation of glutamate homeostasis, reduction of inflammation and control of neurofilament synthesis. Hopefully, in the near future some new agents will be found that can alter the course of this devastating and fatal disease.}, }
@article {pmid12385607, year = {2002}, author = {McEachin, CC and McDermott, JT and Swor, R}, title = {Few emergency medical services patients with lower-extremity fractures receive prehospital analgesia.}, journal = {Prehospital emergency care}, volume = {6}, number = {4}, pages = {406-410}, doi = {10.1080/10903120290938030}, pmid = {12385607}, issn = {1090-3127}, mesh = {Age Factors ; Aged ; Analgesics/*therapeutic use ; *Drug Utilization Review ; Emergency Medical Services/*statistics &amp; numerical data ; Female ; Femoral Fractures/complications/*drug therapy ; Hip Fractures/*complications ; Humans ; Lower Extremity/*injuries ; Male ; Michigan ; Middle Aged ; Pain/*drug therapy/etiology ; Practice Patterns, Physicians' ; }, abstract = {UNLABELLED: Previous literature has identified prehospital pain management as an important emergency medical services (EMS) function, and few patients transported by EMS with musculoskeletal injuries receive prehospital analgesia (PA).<br><br>OBJECTIVES: 1) To describe the frequency with which EMS patients with lower-extremity and hip fracture receive prehospital and emergency department (ED) analgesia; 2) to describe EMS and patient factors that may affect administration of PA to these patients; and 3) to describe the time interval between EMS and ED medication administrations.<br><br>METHODS: This was a four-month (April to July 2000) retrospective study of patients with a final hospital diagnosis of hip or lower-extremity fracture who were transported by EMS to a single suburban community hospital. Data including patient demographics, fracture type, EMS response, and treatment characteristics were abstracted from review of EMS and ED records. Patients who had ankle fractures, had multiple traumatic injuries, were under the age of 18 years, or did not have fractures were excluded.<br><br>RESULTS: One hundred twenty-four patients met inclusion criteria. A basic life support (BLS)-only response was provided to 20 (16.0%). Another 38 (38.4%) received an advanced life support (ALS) response and were triaged to BLS transport. Of all the patients, 22 (18.3%) received PA. Patients who received PA were younger (64.0 vs. 77.3 years, p < 0.001) and more likely to have a lower-extremity fracture other than a hip fracture (31.8% vs. 10.7%, p < 0.004). Of all patients, 113 (91.1%) received ED analgesia. Patients received analgesia from EMS almost 2.0 hours sooner that in the ED (mean 28.4 +/- 36 min vs. 146 +/- 74 min after EMS scene arrival, p < 0.001).<br><br>CONCLUSION: A minority of the study group received PA. Older patients and patients with hip fracture are less likely to receive PA. It is unclear whether current EMS system design may adversely impact administration of PA. Further work is needed to clarify whether patient need or EMS practice patterns result in low rates of PA.}, }
@article {pmid12373010, year = {2002}, author = {De Benedetti, F and Meazza, C and Martini, A}, title = {Role of interleukin-6 in growth failure: an animal model.}, journal = {Hormone research}, volume = {58 Suppl 1}, number = {}, pages = {24-27}, doi = {10.1159/000064757}, pmid = {12373010}, issn = {0301-0163}, mesh = {Animals ; Endopeptidases/blood ; Growth Disorders/*etiology ; Humans ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/analysis/metabolism ; Interleukin-6/blood/genetics/*physiology ; Metabolic Clearance Rate ; Mice ; Mice, Transgenic ; Phosphopyruvate Hydratase/genetics ; Promoter Regions, Genetic ; Rats ; }, abstract = {Indirect evidence suggests a link between factors produced during the inflammatory response and stunted growth. The demonstration of this link was provided by the observation that mice transgenic for the inflammatory cytokine interleukin-6 (IL-6), expressing high circulating levels of IL-6 since birth, show a marked decrease in growth rate leading to adult mice 50-70% the size of wild-type littermates. The growth defect is completely abolished by neutralization of IL-6. In these mice the production of GH is normal, while circulating levels of IGF-I are markedly decreased. Administration of IL-6 to wild-type mice results in a marked decrease in IGF-I levels. These observations show that in vivo high levels of IL-6 are associated with low levels of IGF-I. However, IL-6 does not directly affect IGF-I production both in vitro and in vivo. In contrast, markedly decreased levels of IGFBP-3 are present in the IL-6 transgenic mice and administration of IL-6 to wild-type mice results in a marked decrease in IGFBP-3 levels. In these mice the decrease in IGFBP-3 levels is associated with impaired formation of the 150 kD ternary complex, even in the presence of normally functional ALS. As a consequence, IL-6 transgenic mice show increased clearance of circulating IGF-I, suggesting that IL-6 decreases IGF-I levels by increased clearance. Proteolytic degradation of IGFBP-3 occurs in the IL-6 transgenic mice, suggesting that the decrease in IGFBP-3 could be at least in part due to proteolysis. The abnormalities of the IGF-I system observed in the IL-6 transgenic mice are similar to those found in patients with systemic juvenile idiopathic arthritis, one of the chronic inflammatory diseases characterized by stunted growth and prominent production of IL-6. The IL-6 transgenic mice represent a faithful animal model of the growth impairment associated with chronic inflammation and may therefore provide information relevant to the understanding and treatment of this complication of inflammatory diseases.}, }
@article {pmid12365067, year = {1999}, author = {Jenkinson, C and Fitzpatrick, R and Brennan, C and Swash, M}, title = {Evidence for the validity and reliability of the ALS assessment questionnaire: the ALSAQ-40.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {1}, pages = {33-40}, doi = {10.1080/146608299300080022}, pmid = {12365067}, issn = {1466-0822}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/therapy ; Humans ; Longitudinal Studies ; *Quality of Life ; Reproducibility of Results ; *Surveys and Questionnaires ; Treatment Outcome ; }, abstract = {OBJECTIVES: The purpose of the study was to assess the validity and reliability of a new disease specific measure of health-related quality of life for ALS/MND: the 40-item ALS Assessment Questionnaire (ALSAQ-40).<br><br>DESIGN: We carried out a longitudinal postal survey. The two administrations of the questionnaire were separated by 3 months.<br><br>SAMPLE: Subjects were patients diagnosed with ALS/MND and registered with the UK MND Association.<br><br>RESULTS: Dimensions of the ALSAQ-40 were shown to have high levels of internal reliability. The ALSAQ-40 was found to be sensitive to changes in self reported overall health state.<br><br>CONCLUSION: We concluded that the ALSAQ-40 has high levels of reliability and validity and can be used as an outcome measure in studies evaluating new treatment regimes and therapies.}, }
@article {pmid12365066, year = {1999}, author = {Armon, C}, title = {How can physicians and their patients with ALS decide to use the newly-available treatments to slow disease progression?.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {1}, pages = {3-14}, doi = {10.1080/14660829952415945}, pmid = {12365066}, issn = {1466-0822}, mesh = {Acetates/therapeutic use ; *Amines ; Amyotrophic Lateral Sclerosis/*drug therapy/economics/pathology/physiopathology ; Anticonvulsants/therapeutic use ; Clinical Trials as Topic ; *Cyclohexanecarboxylic Acids ; Disease Progression ; Gabapentin ; Growth Substances/*therapeutic use ; Humans ; Intercellular Signaling Peptides and Proteins/*therapeutic use ; Neuroprotective Agents/therapeutic use ; Quality of Life ; Riluzole/*therapeutic use ; Sickness Impact Profile ; *gamma-Aminobutyric Acid ; }, abstract = {The 1990s decade has seen the testing of treatments to slow disease progression in patients with ALS. Two such treatments (riluzole and myotrophin) have shown minimal or modest efficacy. Of these, riluzole has been approved for marketing in the United States, in Europe and in other countries. Patients and physicians who are trying to decide whether to use these treatments require background information: (a) to place these treatments in the context of other treatments; (b) to understand the outcome measures used; and (c) to understand the significance of the efficacy these treatments have shown. For example, in some cases treatment efficacy has been shown by some measures, but not others. This paper attempts to assist in this process. In addition, we attempt to show how to integrate objective data with relative or subjective factors, such as patient values, economic considerations, and the role of hope.}, }
@article {pmid12364447, year = {2002}, author = {Cisternino, M and Draghi, M and Lauriola, S and Scarcella, D and Bernasconi, S and Cavallo, L and De Luca, F and Lomeo, A and Tatò, L}, title = {The acid-labile subunit of human ternary insulin-like growth factor-binding protein complex in girls with central precocious puberty before and during gonadotropin-releasing hormone analog therapy.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {87}, number = {10}, pages = {4629-4633}, doi = {10.1210/jc.2002-020308}, pmid = {12364447}, issn = {0021-972X}, mesh = {Carrier Proteins/*blood ; Child ; Child, Preschool ; Endopeptidases/blood ; Female ; Glycoproteins/*blood ; Humans ; Infant ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/analysis ; Leuprolide/administration &amp; dosage/*therapeutic use ; Puberty, Precocious/*blood/*drug therapy ; }, abstract = {The aim of the study was to evaluate serum acid-labile subunit (ALS) concentrations and their relationship with other parameters of the human ternary IGF-I-binding protein (IGFBP) complex in girls with central precocious puberty (CPP) before and after pharmacological arrest of puberty. We studied serum ALS, free IGF-I, total IGF-I, IGFBP-3 levels and IGFBP-3 protease activity in 13 girls, aged 1.6-7.8 yr (mean, 5.9 +/- 2.2), diagnosed as having CPP before and after 6 and 12 months of GnRH analog (GnRHa) therapy. The ALS SD score before treatment was high (1.4 +/- 0.72) and decreased significantly after 6 and 12 months of GnRHa therapy [0.4 +/- 0.54 (P < 0.01) and -0.4 +/- 0.61 (P < 0.01), respectively]. Serum IGF-I and IGFBP-3 were also increased before treatment, but both of these factors remained elevated after 6 and 12 months of GnRH-A therapy [IGF-I SD score, 3.20 +/- 1.64, 2.92 +/- 1.82, and 3.68 +/- 1.94 (P = NS), respectively; IGFBP-3 SD score, 1.02 +/- 0.53, 0.94 +/- 0.68, and 1.22 +/- 0.87 (P = NS), respectively]. Serum free IGF-I levels and IGFBP-3 proteolytic activity did not vary significantly from their pretreatment values during GnRHa therapy. In conclusion, serum ALS levels were elevated in girls with CPP and decreased significantly during the first year of GnRHa therapy. Serum IGF-I and IGFBP-3 levels were also increased before therapy, but their levels were not influenced by treatment. The ALS decrease seems to be the sole GH-dependent factor that parallels the decreases in steroid levels and growth velocity during GnRHa therapy.}, }
@article {pmid12358770, year = {2002}, author = {Lee, JP and Gerin, C and Bindokas, VP and Miller, R and Ghadge, G and Roos, RP}, title = {No correlation between aggregates of Cu/Zn superoxide dismutase and cell death in familial amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {82}, number = {5}, pages = {1229-1238}, doi = {10.1046/j.1471-4159.2002.01056.x}, pmid = {12358770}, issn = {0022-3042}, support = {P01NS21442/NS/NINDS NIH HHS/United States ; }, mesh = {Amino Acid Substitution ; Amyotrophic Lateral Sclerosis/genetics/*metabolism ; Animals ; Cathepsin B/antagonists &amp; inhibitors ; Cell Death ; Cell Survival/drug effects/genetics ; Cysteine Endopeptidases ; Enzyme Inhibitors/pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; Luminescent Proteins/genetics ; Macromolecular Substances ; Multienzyme Complexes/antagonists &amp; inhibitors ; Mutation ; Nerve Growth Factor/pharmacology ; Neurons/cytology/drug effects/*metabolism ; Oxidants/pharmacology ; Oxidative Stress/drug effects ; PC12 Cells ; Proteasome Endopeptidase Complex ; Rats ; Recombinant Fusion Proteins/genetics/metabolism ; Superoxide Dismutase/genetics/*metabolism ; Transduction, Genetic ; }, abstract = {Aggregates of Cu/Zn superoxide dismutase (SOD) have been demonstrated in familial amyotrophic lateral sclerosis (FALS) and other neurodegenerative diseases; however, their role in disease pathogenesis is unclear. In this study, we investigated the presence of SOD aggregates in nerve growth factor (NGF)-differentiated PC12 cells and cell viability following: (i) transduction with replication-deficient recombinant adenoviruses (AdVs) expressing wild-type SOD (SODWT) or mutant SOD (SODMT, V148G or A4V); (ii) transfection of yellow fluorescent protein-tagged SODWT (SODWT-YFP) or SODMT (SODA4V-YFP, SODV148G-YFP). SOD aggregates were more prominent in cells following transduction of AdSODMT than AdSODWT and following treatment with H2O2, suggesting that mutant SOD leads to oxidation of cellular components. In addition, cells expressing SODMT-YFP yielded SOD aggregates that were significantly larger and more frequent than SOD aggregates in cells expressing SODWT-YFP. Proteasome inhibitors, but not cathepsin B inhibitors, increased aggregate formation but did not increase cell death. In addition, treatments that increased cell viability did not significantly decrease SOD aggregates. Taken together, our data demonstrate that there is no association between SOD aggregates and cell death in FALS.}, }
@article {pmid12357010, year = {2002}, author = {Talbot, K}, title = {Motor neurone disease.}, journal = {Postgraduate medical journal}, volume = {78}, number = {923}, pages = {513-519}, pmid = {12357010}, issn = {0032-5473}, mesh = {Forecasting ; Humans ; Magnetic Resonance Imaging/methods ; Motor Neuron Disease/classification/*diagnosis/etiology/therapy ; Syndrome ; }, abstract = {Motor neurone disease (MND), or amyotrophic lateral sclerosis (ALS), is a neurodegenerative disorder of unknown aetiology. Progressive motor weakness and bulbar dysfunction lead to premature death, usually from respiratory failure. Confirming the diagnosis may initially be difficult until the full clinical features are manifest. For all forms of the disease there is a significant differential diagnosis to consider, including treatable conditions, and therefore specialist neurological opinion should always be sought. Clear genetic inheritance has been demonstrated in a minority of patients with familial ALS but elucidation of the biological basis of genetic subtypes is also providing important information which may lead to treatments for sporadic forms of the disease. In the absence of curative or disease modifying therapy, management is supportive and requires a multidisciplinary approach. If, as seems likely, complex inherited and environmental factors contribute to the pathogenesis of MND, future treatment may involve a combination of molecular based treatments or restoration of cellular integrity using stem cell grafts.}, }
@article {pmid12270689, year = {2002}, author = {Kriz, J and Nguyen, MD and Julien, JP}, title = {Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {10}, number = {3}, pages = {268-278}, doi = {10.1006/nbdi.2002.0487}, pmid = {12270689}, issn = {0969-9961}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/*genetics ; Animals ; Axons/drug effects/enzymology/pathology ; *Disease Models, Animal ; Disease Progression ; Mice ; Mice, Transgenic ; Microglia/drug effects/enzymology/pathology ; Minocycline/pharmacology/*therapeutic use ; Superoxide Dismutase/biosynthesis ; Superoxide Dismutase-1 ; }, abstract = {There is currently no effective pharmacological treatment for amyotrophic lateral sclerosis (ALS). Because recent evidence suggests that secondary inflammation and caspase activation may contribute to neurodegeneration in ALS, we tested the effects of minocycline, a second-generation tetracycline with anti-inflammatory properties, in mice expressing a mutant superoxide dismutase (SOD1(G37R)) linked to human ALS. Administration of minocycline into the diet, beginning at late presymptomatic stage (7 or 9 months of age), delayed the onset of motor neuron degeneration, muscle strength decline, and it increased the longevity of SOD1(G37R) mice by approximately 5 weeks for approximately 70% of tested mice. Moreover, less activation of microglia was detected at early symptomatic stage (46 weeks) and at the end stage of disease in the spinal cord of SOD1(G37R) mice treated with minocycline. These results indicate that minocycline, which is clinically well tolerated, may represent a novel and effective drug for treatment of ALS.}, }
@article {pmid12238623, year = {2002}, author = {Iwasaki, Y and Ichikawa, Y and Igarashi, O and Iwamoto, K and Kinoshitata, M and Ikeda, K}, title = {Neuroprotective actions of FK506 and cyclosporin A on motor neuron survival following neonatal axotomy.}, journal = {Neurological research}, volume = {24}, number = {6}, pages = {573-576}, doi = {10.1179/016164102101200555}, pmid = {12238623}, issn = {0161-6412}, mesh = {Animals ; Animals, Newborn ; Axotomy ; Cell Death ; Cyclosporine/*pharmacology ; Dose-Response Relationship, Drug ; Motor Neurons/cytology/*drug effects/physiology ; Nerve Degeneration ; Neuroprotective Agents/*pharmacology ; Rats ; Sciatic Nerve/cytology/*drug effects/physiology ; Spinal Cord/cytology/*drug effects ; Tacrolimus/*pharmacology ; }, abstract = {We show that nonimmunosuppressive analogues of the immunosuppressive drugs FK506 and cyclosporin A (CsA) rescue axotomized neonatal motor neuron death. Unilateral sciatic nerve was transected in neonatal rats. Animals were then treated daily with different doses of FK506 and CsA for 14 days with intraperitoneal injection. Control rats received phosphate buffer saline (PBS) in the same fashion. After treatment, the number of spinal motor neurons was determined at L4 level. In comparison with vehicle, both FK506 (5.0 mg kg(-1)) and CsA (10.0 mg kg(-1)) rescued motor neuron death in a similar way. These results indicate therapeutic relevance in the treatment of damaged motor neuron disorders, such as motor neuropathy or amyotrophic lateral sclerosis.}, }
@article {pmid12235840, year = {2001}, author = {Baba, M}, title = {[New trends in neuropathy practice: clinical approach to CIDP].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {41}, number = {12}, pages = {1210-1213}, pmid = {12235840}, issn = {0009-918X}, mesh = {Chronic Disease ; Electrodiagnosis ; Humans ; Polyneuropathies/classification/*diagnosis/physiopathology ; Reference Standards ; }, abstract = {Our recent study showed that the overall prevalence of CIDP was estimated as 2.2 per 100,000 population in Aomori Prefecture, in Northan Honshu of Japan. In our series of more than 80 cases with CIDP, a chronic acquired inflammatory demyelinating polyneuropathy, nearly 30% showed clear laterality of weakness, and electrophysiologic laterality or multifocality was apparent in almost all cases. Nearly 90% of patients were able to walk without walking aids or other assistance. Sixty% showed distal dominant muscular weakness. In 12 patients with age of onset under 15, pes cavus deformity was seen in 5. Two thirds complained numbness in the extremities during progressive phase. Four cases initially showed severe sensory ataxia associated with motor conduction block. It should be, thus, reminded that clinical spectrum of CIDP is enormously wide: chronic acquired demyelinating multiple mononeuropathy showing asymmetric involvement (Lewis-Summer syndrome) should be put on one side of the clinical presentation of CIDP. Multifocal motor neuropathy (MMN) is, on the other hand, an unique syndrome mimicking amyotrophic lateral sclerosis (ALS). There may be, however, true association syndrome of CIDP and ALS presenting both peripheral nerve demyelination and pyramidal sign with progressive bulbar involvement. Recently, several atypical varieties of CIDP showing only one-limb involvement, upper limb weakness rather than lower limb power loss, or proximal weakness, etc ... have been reported in the literature. To realize such clinical variations of chronic acquired demyelinating neuropathy is important for early diagnosis and commencement of treatment of CIDP. Clinical guideline for suspicion of CIDP could be useful for general physicians and neurologists unfamiliar to peripheral neuropathies.}, }
@article {pmid12235826, year = {2001}, author = {Abe, K and Manabe, Y and Murakami, T}, title = {[Gene therapy and neurotrophic factor treatment for amyotrophic lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {41}, number = {12}, pages = {1160-1161}, pmid = {12235826}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*therapy ; Animals ; Apoptosis ; Cells, Cultured ; Disease Models, Animal ; Free Radicals/adverse effects ; Genetic Therapy/*methods ; Glial Cell Line-Derived Neurotrophic Factor ; Glutamic Acid/adverse effects ; Humans ; Mice ; Mice, Transgenic ; Nerve Growth Factors/*genetics ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/cytology ; }, abstract = {Although excitotoxic and oxidative stress play important roles in spinal neuron death, the exact mechanisms are not fully understood. We examined cell damage of primary culture of 11-day-old rat spinal cord by addition of glutamate, nitric oxide (NO) or peroxynitrite (PN) with detection of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL). With addition of glutamate, NOC18 (a slow NO releaser) or PN, TUNEL positive nuclei were found in spinal large motor neurons from 24 h, and the positive cell proportion greatly increased at 48 h in contrast to the vehicle. The present results suggest that both excitotoxic and oxidative stress play important role in the apoptotic pathway in cultured rat spinal neurons. To examine a possible protective effect of exogenous glial cell line-derived neurotrophic factor (GDNF) gene expression in transgenic (Tg) mice carrying a Gly 93Ala (G93A) mutant SOD1 gene found in human familial ALS, a replication defective adenoviral vector containing GDNF gene was directly injected unilaterally into leg muscles. There were significantly more large motoneurons in GDNF-treated Tg mice than in untreated and Ad-Laz-treated group. The number of large motoneurons in GDNF-treated side of Tg mice were significantly more than that in untreated side. These observations demonstrate that GDNF gene therapy in a mouse model of FALS promotes the survival of motoneurons, suggesting that a similar approach might delay the progression of neurodegeneration of ALS.}, }
@article {pmid12235108, year = {2002}, author = {Yakar, S and Rosen, CJ and Beamer, WG and Ackert-Bicknell, CL and Wu, Y and Liu, JL and Ooi, GT and Setser, J and Frystyk, J and Boisclair, YR and LeRoith, D}, title = {Circulating levels of IGF-1 directly regulate bone growth and density.}, journal = {The Journal of clinical investigation}, volume = {110}, number = {6}, pages = {771-781}, pmid = {12235108}, issn = {0021-9738}, support = {R01 DK051624/DK/NIDDK NIH HHS/United States ; DK-51624/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Bone Density/*physiology ; Bone Development/*physiology ; Carrier Proteins/*genetics/metabolism ; Glycoproteins/*genetics/metabolism ; Growth Hormone/blood ; Insulin-Like Growth Factor Binding Proteins/blood ; Insulin-Like Growth Factor I/genetics/*metabolism ; Liver/metabolism ; Mice ; Mice, Inbred Strains ; Mice, Knockout ; Tibia/cytology/metabolism ; }, abstract = {IGF-1 is a growth-promoting polypeptide that is essential for normal growth and development. In serum, the majority of the IGFs exist in a 150-kDa complex including the IGF molecule, IGF binding protein 3 (IGFBP-3), and the acid labile subunit (ALS). This complex prolongs the half-life of serum IGFs and facilitates their endocrine actions. Liver IGF-1-deficient (LID) mice and ALS knockout (ALSKO) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-1 levels, respectively. Double gene disrupted mice were generated by crossing LID+ALSKO mice. These mice exhibited further reductions in serum IGF-1 levels and a significant reduction in linear growth. The proximal growth plates of the tibiae of LID+ALSKO mice were smaller in total height as well as in the height of the proliferative and hypertrophic zones of chondrocytes. There was also a 10% decrease in bone mineral density and a greater than 35% decrease in periosteal circumference and cortical thickness in these mice. IGF-1 treatment for 4 weeks restored the total height of the proximal growth plate of the tibia. Thus, the double gene disruption LID+ALSKO mouse model demonstrates that a threshold concentration of circulating IGF-1 is necessary for normal bone growth and suggests that IGF-1, IGFBP-3, and ALS play a prominent role in the pathophysiology of osteoporosis.}, }
@article {pmid12217886, year = {2002}, author = {Kong, SE and Firth, SM and Baxter, RC and Delhanty, PJ}, title = {Regulation of the acid-labile subunit in sustained endotoxemia.}, journal = {American journal of physiology. Endocrinology and metabolism}, volume = {283}, number = {4}, pages = {E692-701}, doi = {10.1152/ajpendo.00148.2002}, pmid = {12217886}, issn = {0193-1849}, mesh = {Animals ; Body Weight/drug effects ; Carrier Proteins/*genetics/*metabolism ; Eating/drug effects ; Endotoxemia/*metabolism/*physiopathology ; Gene Expression/physiology ; Glucose/metabolism ; Glycoproteins/*genetics/*metabolism ; Immediate-Early Proteins/genetics/metabolism ; Insulin/metabolism ; Insulin-Like Growth Factor Binding Protein 1/blood/genetics ; Insulin-Like Growth Factor Binding Protein 5/blood ; Lipopolysaccharides/pharmacology ; Liver/metabolism ; Male ; Phosphoenolpyruvate Carboxykinase (GTP)/genetics/metabolism ; Protein Structure, Tertiary ; Proteins/genetics/metabolism ; RNA, Messenger/analysis ; Radioimmunoassay ; Rats ; Rats, Sprague-Dawley ; Receptors, Somatotropin/genetics/metabolism ; *Repressor Proteins ; Signal Transduction/drug effects/physiology ; Suppressor of Cytokine Signaling 3 Protein ; Suppressor of Cytokine Signaling Proteins ; *Transcription Factors ; }, abstract = {The effect of sustained endotoxemia on expression of the acid-labile subunit (ALS) in relation to hepatic markers of altered GH and insulin sensitivity was examined. Juvenile rats were injected with endotoxin twice daily for 48 h, causing reduced food intake and attenuated growth. In pair-fed controls, food restriction caused marked suppression of ALS gene expression and circulating levels within 12 h, and endotoxemia augmented this effect. This acute effect of endotoxin corresponded temporally with transient induction of suppressor of cytokine signaling (SOCS)-3, cytokine-inducible SH2-containing protein (CIS), phosphoenolpyruvate carboxykinase (PEPCK), and insulin-like growth factor-binding protein (IGFBP)-1 and suppression of GH receptor (GHR). During the subsequent 36 h of sustained endotoxin treatment, expression of ALS recovered to, and then rose above, that of their pair-fed controls. This effect was paralleled by other ternary complex components. The inductive effect of sustained endotoxemia relative to pair-fed controls could not be explained by differences in expression of GHR, SOCS-3, or CIS but coincided with normalized PEPCK and IGFBP-1 levels, suggesting better hepatic insulin sensitivity in these animals. These data may indicate that, in sustained endotoxemia, ALS levels are regulated through modulation of hepatic insulin sensitivity.}, }
@article {pmid12213295, year = {2002}, author = {Takeuchi, H and Kobayashi, Y and Yoshihara, T and Niwa, J and Doyu, M and Ohtsuka, K and Sobue, G}, title = {Hsp70 and Hsp40 improve neurite outgrowth and suppress intracytoplasmic aggregate formation in cultured neuronal cells expressing mutant SOD1.}, journal = {Brain research}, volume = {949}, number = {1-2}, pages = {11-22}, doi = {10.1016/s0006-8993(02)02568-4}, pmid = {12213295}, issn = {0006-8993}, mesh = {Amyotrophic Lateral Sclerosis/metabolism ; Baculoviridae ; Blotting, Western ; Cell Culture Techniques ; Cell Death/genetics ; Cytoplasm/*metabolism/ultrastructure ; Fluorescent Antibody Technique ; Gene Expression Regulation, Enzymologic ; HSP40 Heat-Shock Proteins ; HSP70 Heat-Shock Proteins/biosynthesis/*metabolism ; Heat-Shock Proteins/biosynthesis/*metabolism ; Humans ; Microscopy, Confocal ; *Mutation ; *Neurites/metabolism ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Transfection ; Up-Regulation ; }, abstract = {Mutations of the superoxide dismutase 1 (SOD1) gene cause familial amyotrophic lateral sclerosis (FALS). Intracytoplasmic aggregate formation consisting of mutant SOD1 is the histological hallmark of FALS. Since a previous report revealed that Hsp70 reduced aggregate formation and cell death in a cell model of FALS, here we examined the combined effects of Hsp70 and its cofactor, Hsp40, on a cell model of FALS. The combination of Hsp70 and Hsp40 reduced intracytoplasmic aggregates and markedly improved neurite outgrowth. They also prevented cell death to a relatively lesser extent. Neurite outgrowth was recognized almost exclusively in the cells without intracytoplasmic aggregates. Hsp70 and Hsp40 were upregulated in cells expressing mutant SOD1, and were colocalized with intracytoplasmic aggregates of mutant SOD1. These findings suggest that heat shock proteins (HSPs) promote neurite outgrowth by suppressing intracytoplasmic aggregate formation and restoring cellular dysfunctions. This is the first demonstration that overexpression of HSPs improved neurite outgrowth as it suppressed intracytoplasmic aggregate formation and cell death in a cultured neuronal cell model of FALS. These findings may provide a basis for the utilization of HSPs in developing a treatment for FALS.}, }
@article {pmid12210870, year = {2002}, author = {Schiefer, J and Landwehrmeyer, GB and Lüesse, HG and Sprünken, A and Puls, C and Milkereit, A and Milkereit, E and Kosinski, CM}, title = {Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington's disease.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {17}, number = {4}, pages = {748-757}, doi = {10.1002/mds.10229}, pmid = {12210870}, issn = {0885-3185}, mesh = {Animals ; Cell Nucleus/genetics/*pathology/physiology ; Cerebral Cortex/pathology/physiopathology ; Corpus Striatum/pathology/physiopathology ; Excitatory Amino Acid Antagonists/*pharmacology ; Exons ; Glutamic Acid/physiology ; Humans ; Huntingtin Protein ; Huntington Disease/genetics/pathology/*physiopathology ; Immunoenzyme Techniques ; Mice ; Mice, Transgenic ; Motor Skills/physiology ; Nerve Tissue Proteins/genetics ; Neuroprotective Agents/*pharmacology ; Nuclear Proteins/genetics ; Riluzole/*pharmacology ; Survival Analysis ; Trinucleotide Repeats ; }, abstract = {Glutamate excitotoxicity has been suggested to contribute to the pathogenesis of Huntington's disease (HD). Riluzole is a substance with glutamate antagonistic properties that is used for neuroprotective treatment in amyotrophic lateral sclerosis and which is currently tested in clinical trials for treatment of HD. R6/2 transgenic mice, which express exon 1 of the human HD gene with an expanded CAG triplet repeat, serve as a well-characterized mouse model for HD with progressing neurological abnormalities and limited survival. We treated R6/2 HD transgenic mice with riluzole orally beginning at a presymptomatic stage until death to investigate its potential neuroprotective effects in this mouse model and found that survival time in the riluzole group was significantly increased in comparison to placebo-treated transgenic controls. Additionally, the progressive weight loss was delayed and significantly reduced by riluzole treatment; behavioral testing of motor coordination and spontaneous locomotor activity, however, showed no statistically significant differences. We also examined the formation of the HD characteristic neuronal intranuclear inclusions (NII) immunohistologically. At a late disease stage, striatal NII from riluzole-treated transgenic mice showed profound changes in ubiquitination, i.e., NII were less ubiquitinated and surrounded by ubiquitinated micro-aggregates. Staining with antibodies directed against the mutated huntingtin revealed no significant difference in this component of NII. Taken together, these data suggest that riluzole is a promising candidate for neuroprotective treatment in human HD.}, }
@article {pmid12208020, year = {2002}, author = {de Wolff, FA and Berend, K and van der Voet, GB}, title = {Subacute fatal aluminum poisoning in dialyzed patients: post-mortem toxicological findings.}, journal = {Forensic science international}, volume = {128}, number = {1-2}, pages = {41-43}, doi = {10.1016/s0379-0738(02)00159-7}, pmid = {12208020}, issn = {0379-0738}, mesh = {Aluminum/blood/pharmacokinetics/*poisoning ; *Forensic Medicine ; Humans ; Kidney Failure, Chronic/*therapy ; *Mortality ; Netherlands Antilles ; Renal Dialysis/*adverse effects ; Tissue Distribution ; }, abstract = {The population of Curaçao, Netherlands Antilles (133,000) shows a very high prevalence of end-stage renal disease (approximately 1 per 1,000). These patients are often treated chronically with haemodialysis. As the drinking water on the island is prepared by distillation of sea water, the haemodialysis fluid used to be prepared with tap water without further treatment. In 1996, the 27 patients of one of the dialysis centers on the island presented with nausea, vomiting, and hypercalcaemia in a short time span, which was initially diagnosed as 'hard water syndrome'. In spite of treatment with low-calcium dialysate, microcytic anaemia and neurological symptoms developed. Ten patients died of convulsions, sepsis, and coma. As aluminum (Al) intoxication was suspected, Al in serum (AlS) was measured. Ante mortem AlS was 808 microg/l (n = 7; range 359-1189); in the survivors AlS was 255 microg/l (n = 17; range 113-490). Normal AlS is < 10 microg/l, and <50 microg/l in asymptomatic dialyzed patients. The court requested post-mortem toxicological analysis of four patients. Al concentrations in liver, bone, and cerebral cortex were significantly increased as compared with background levels. Al intoxication was, therefore, considered to be the most likely cause of death in these patients. Investigations of the tap water supply revealed that a few weeks before the onset of the symptoms, a water conduit pipe to the dialysis unit had been replaced, which was lined with Al- and Ca-rich cement mortar. These ions leached into the distilled water and caused both Ca- and Al-intoxication through uptake from the dialysate into the patients' circulation. The symptoms of the latter were initially not recognized as they were masked by the symptoms of hypercalcaemia.}, }
@article {pmid12176796, year = {2002}, author = {Lee, KD and Liu, TW and Wu, CW and Tiu, CM and Liu, JM and Chung, TR and Chang, JY and Whang-Peng, J and Chen, LT}, title = {Non-surgical treatment for afferent loop syndrome in recurrent gastric cancer complicated by peritoneal carcinomatosis: percutaneous transhepatic duodenal drainage followed by 24-hour infusion of high-dose fluorouracil and leucovorin.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {13}, number = {7}, pages = {1151-1155}, doi = {10.1093/annonc/mdf212}, pmid = {12176796}, issn = {0923-7534}, mesh = {Adenocarcinoma/diagnosis/surgery ; Afferent Loop Syndrome/diagnosis/etiology/*therapy ; Aged ; Antineoplastic Combined Chemotherapy Protocols/*administration &amp; dosage ; Carcinoma/diagnosis/etiology/*therapy ; Combined Modality Therapy ; Dose-Response Relationship, Drug ; Drainage/methods ; Fluorouracil/administration &amp; dosage ; Follow-Up Studies ; Gastrectomy/methods ; Humans ; Infusions, Intravenous ; Leucovorin/administration &amp; dosage ; Male ; Middle Aged ; Neoplasm Recurrence, Local/complications/pathology/*therapy ; *Palliative Care ; Peritoneal Diseases/diagnosis/etiology/*therapy ; Peritoneal Neoplasms/diagnosis/etiology/*therapy ; Stomach Neoplasms/diagnosis/surgery ; Treatment Outcome ; }, abstract = {Afferent loop syndrome (ALS) is a debilitating complication of recurrent gastric cancer. Surgical intervention is usually not feasible in the face of poor general performance, presence of advanced peritoneal carcinomatosis and limited survival of the patients. Non-surgical approaches include internal drainage by stenting at the stenotic or anastomotic site and external drainage via the percutaneous routes. Percutaneous transhepatic duodenal drainage (PTDD) has been shown to provide effective palliation for ALS, but long-term catheterization is usually inevitable. We hereby present two cases of recurrent gastric cancer whose ALS was successfully treated with PTDD followed by weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin (HDFL). PTDD rapidly ameliorated the incapacitating symptoms of ALS, and the effective, low-toxicity chemotherapy subsequently led to tumor regression, restoration of bowel patency and removal of the drainage tube. At present, both patients have remained ALS-free and drainage-free for 16 and 17 months, respectively. Our results indicate that this non-surgical approach with PTDD followed by weekly HDFL could serve as a safe and effective treatment for ALS in recurrent gastric cancer complicated by peritoneal carcinomatosis.}, }
@article {pmid12154010, year = {2002}, author = {Katoh-Semba, R and Asano, T and Ueda, H and Morishita, R and Takeuchi, IK and Inaguma, Y and Kato, K}, title = {Riluzole enhances expression of brain-derived neurotrophic factor with consequent proliferation of granule precursor cells in the rat hippocampus.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {16}, number = {10}, pages = {1328-1330}, doi = {10.1096/fj.02-0143fje}, pmid = {12154010}, issn = {1530-6860}, mesh = {Animals ; Antibodies/administration &amp; dosage/pharmacology ; Brain Chemistry ; Brain-Derived Neurotrophic Factor/analysis/*biosynthesis ; Cell Division/drug effects ; Cell Survival/drug effects ; Hippocampus/cytology/drug effects/*metabolism ; Injections ; Injections, Intraventricular ; Models, Biological ; Neurons/drug effects/metabolism ; Rats ; Riluzole/administration &amp; dosage/antagonists &amp; inhibitors/immunology/*pharmacology ; Sodium Channel Blockers/administration &amp; dosage/antagonists &amp; inhibitors/*pharmacology ; Stem Cells/cytology/drug effects ; }, abstract = {The dentate gyrus of the hippocampus, generating new cells throughout life, is essential for normal recognition memory performance. Reduction of brain-derived neurotrophic factor (BDNF) in this structure impairs its functions. To elucidate the association between BDNF levels and hippocampal neurogenesis, we first conducted a search for compounds that stimulate endogenous BDNF production in hippocampal granule neurons. Among ion channel modulators tested, riluzole, a neuroprotective agent with anticonvulsant properties that is approved for treatment of amyotrophic lateral sclerosis, was highly effective as a single dose by an intraperitoneal injection, causing a rise in BDNF localized in dentate granule neurons, the hilus, and the stratum radiatum of the CA3 region. Repeated, but not single, injections resulted in prolonged elevation of hippocampal BDNF and were associated with increased numbers of newly generated cells in the granule cell layer. This appeared due to promoted proliferation rather than survival of precursor cells, many of which differentiated into neurons. Intraventricular administration of BDNF-specific antibodies blocked such riluzole effects, suggesting that BDNF increase is necessary for the promotion of precursor proliferation. Our results suggest the basis for a new strategy for treatment of memory dysfunction.}, }
@article {pmid12139328, year = {2002}, author = {Strayer, RF and Finger, BW and Alazraki, MP and Cook, K and Garland, JL}, title = {Recovery of resources for advanced life support space applications: effect of retention time on biodegradation of two crop residues in a fed-batch, continuous stirred tank reactor.}, journal = {Bioresource technology}, volume = {84}, number = {2}, pages = {119-127}, doi = {10.1016/s0960-8524(02)00036-6}, pmid = {12139328}, issn = {0960-8524}, mesh = {Aerobiosis ; *Bioreactors ; *Crops, Agricultural ; Reproducibility of Results ; *Space Flight ; }, abstract = {Bioreactor retention time is a key process variable that will influence costs that are relevant to long distance space travel or long duration space habitation. However. little is known about the effects of this parameter on the microbiological treatment options that are being proposed for Advanced Life Support (ALS) systems. Two bioreactor studies were designed to examine this variable. In the first one, six retention times ranging from 1.3 to 21.3 days--were run in duplicate, 81 working-volume continuous stirred tank reactors (CSTR) that were fed ALS wheat residues. Ash-free dry weight loss, carbon mineralization, soluble TOC reduction, changes in fiber content (cellulose, hemicellulose, and lignin), bacterial numbers, and mineral recoveries were monitored. At short retention times--1.33 days--biodegradation was poor (total: 16-20%, cellulose - 12%, hemicellulose - 28%) but soluble TOC was decreased by 75-80% and recovery of major crop inorganic nutrients was adequate, except for phosphorus. A high proportion of the total bacteria (ca. 83%) was actively respiring. At the longest retention time tested, 21.3 days, biodegradation was good (total: 55-60%, cellulose ca. 70%, hemicellulose - ca. 55%) and soluble TOC was decreased by 80%. Recovery of major nutrients, except phosphorus, remained adequate. A very low proportion of total bacteria was actively respiring (ca. 16%). The second bioreactor study used potato residue to determine if even shorter retention times could be used (range 0.25-2.0 days). Although overall biodegradation deteriorated, the degradation of soluble TOC continued to be ca. 75%. We conclude that if the goal of ALS bioprocessing is maximal degradation of crop residues, including cellulose, then retention times of 10 days or longer will be needed. If the goal is to provide inorganic nutrients with the smallest volume/weight bioreactor possible, then a retention time of 1 day (or less) is sufficient.}, }
@article {pmid12137643, year = {2002}, author = {Mitchell, JD and Wokke, JH and Borasio, GD}, title = {Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {3}, pages = {CD002064}, doi = {10.1002/14651858.CD002064}, pmid = {12137643}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Insulin-Like Growth Factor I/*therapeutic use ; Male ; Randomized Controlled Trials as Topic ; Recombinant Proteins/therapeutic use ; }, abstract = {BACKGROUND: Trophic factors, including recombinant human insulin-like growth factor I have been postulated as possible disease modifying therapies for amyotrophic lateral sclerosis. Randomised clinical trials of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis to date have yielded conflicting results.<br><br>OBJECTIVES: The main objective of this review was to examine the efficacy of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis. Occurrence of adverse events has also been reviewed.<br><br>SEARCH STRATEGY: A search was carried out using the Cochrane Neuromuscular Disease Group register for randomised clinical trials of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis. Enquiries were also made of authors of randomised clinical trials as well as the manufacturers of recombinant human insulin-like growth factor I regarding any other randomised clinical trials which had not yet been published.<br><br>SELECTION CRITERIA: Types of studies: all randomised controlled clinical trials involving recombinant human insulin-like growth factor I treatment of amyotrophic lateral sclerosis.<br><br>TYPES OF PARTICIPANTS: Adults with a clinical diagnosis of definite or probable amyotrophic lateral sclerosis according to the El Escorial Criteria. Types of interventions: Treatment with recombinant human insulin-like growth factor I or placebo. Types of outcome measures: Primary: Change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score with 0.1mg/kg/day of recombinant human insulin-like growth factor I after nine months treatment. Secondary: Change in AALSRS with recombinant human insulin like growth factor I 0.1mg/kg/day and 0.05mg/kg/day at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: We identified two randomised clinical trials. Each reviewer graded them for methodological quality. Data were extracted and entered by the lead reviewer and checked by the other two. Some missing data had to be regenerated by calculations based on ruler measurements of data presented in published graphs.<br><br>MAIN RESULTS: The primary outcome measure was change in disease progression as determined by the Appel ALS Rating Scale total score with 0.1 mg/kg/day of recombinant human insulin-like growth factor I subcutaneously after nine months treatment. The level of significance was lower in the European trial which compared 59 patients on placebo with 124 on insulin-like growth factor I 0.1 mg/kg/day (weighted mean difference -3.30, 95%CI -8.68 to 2.08) than in the North American trial which compared 90 patients on placebo with 89 on recombinant human insulin-like growth factor I 0.05 mg/kg/day 89 patients and 87 patients on 0.1mg/kg/day (weighted mean difference -6.00, 95%CI -10.99 to -1.01). The combined analysis from both randomised clinical trials showed a weighted mean difference of -4.75 (95% CI -8.41 to -1.09) favouring the treated group. The secondary outcome measures showed similar trends favouring recombinant human insulin-like growth factor I but these did not reach significance at the five per cent level. Similarly the data with the 0.05mg/kg/day dose showed trends favouring recombinant human insulin-like growth factor I at all time points but did not reach significance at the five per cent level at any point. Evaluation of adverse events showed an increased risk of injection site reactions/inflammation with recombinant human insulin-like growth factor I (relative risk 2.53, 95% CI 1.40 to 4.59). The drug was otherwise safe and well tolerated.<br><br>REVIEWER'S CONCLUSIONS: Recombinant human insulin-like growth factor I may be modestly effective but the evidence currently available is insufficient for a definitive assessment. Further randomised clinical trials need to be done.}, }
@article {pmid12134639, year = {2002}, author = {Christen, Y}, title = {[Proteins and mutations: a new vision (molecular) of neurodegenerative diseases].}, journal = {Journal de la Societe de biologie}, volume = {196}, number = {1}, pages = {85-94}, pmid = {12134639}, issn = {1295-0661}, mesh = {Aging ; Alzheimer Disease/genetics ; Amyloid beta-Peptides/genetics ; Dementia/genetics ; Humans ; *Mutation ; Neurodegenerative Diseases/*genetics ; Proteins/*genetics ; }, abstract = {Neurodegenerative diseases have long been considered to be poorly defined, misunderstood, and inadequately treated. In recent years, research on Alzheimer's disease has led to numerous advances that have improved our understanding of this form of dementia and also of the entire category of neurodegenerative diseases. It now appears that numerous neurodegenerative diseases of the central nervous system correspond to the aggregation of specific proteins: beta-amyloid in Alzheimer disease, tau protein in Alzheimer disease, fronto-temporal dementia, progressive supranuclear palsy and corticobasal degeneration, alpha-synuclein in Parkinson disease and Lewy body dementia, PrP protein in prion diseases, SOD in amyotrophic lateral sclerosis, polyglutamine expansions in Huntington's disease and other diseases, etc. It is remarkable that in all these cases mutations have been identified for genes coding for these proteins and able to cause the disease and, moreover, that the introduction of the corresponding gene into transgenic mice (or other transgenic animals) has made it possible to create animal models of these conditions. This suggests that the proteins in question play a determinative role in the pathogenesis of these diseases and are not simply consequences of it. Neurodegenerative diseases are proteinopathies. But they are also networkopathies because the neuronal proteins are organized in functional networks. We must also note that all these diseases are associated with the process of aging, for they do not appear in the young. This fact suggests that the anomaly (genetic or otherwise) concerning a given protein does not suffice by itself to induce the disease process. Many observations suggest that the additional event involved, common to all neurodegenerative conditions, may be the intervention of free radicals. We thus propose here the theory that the diversity of neurodegenerative diseases is explained by the combination of two pathogenic events: one specific and associated with the aggregation of a particular protein in the nervous system, the other, non-specific and associated with aging and with the production and harmful actions of free radicals. This unified interpretation leads directly to treatment hypotheses: the development of drugs capable either of inhibiting the production or aggregation of proteins specifically implicated in diverse diseases (or promoting their elimination) or of inhibiting the production or action of free radicals in the nervous system. The former should target one of these various diseases, and the latter should act on a wide range of diseases. The two approaches may conceivably be combined.}, }
@article {pmid12133810, year = {2002}, author = {Clark, JE and Brennan, A and Ramesh, TM and Heywood, JA}, title = {Novel trends in orphan market drug discovery: amyotrophic lateral sclerosis as a case study.}, journal = {Frontiers in bioscience : a journal and virtual library}, volume = {7}, number = {}, pages = {c83-96}, doi = {10.2741/A762}, pmid = {12133810}, issn = {1093-9946}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Chemistry, Pharmaceutical/economics/*trends ; Cooperative Behavior ; *Drug Design ; Drug Industry/economics/trends ; Foundations/trends ; Humans ; *Orphan Drug Production/economics ; Research Support as Topic/economics/trends ; }, abstract = {As new lead discovery technologies of high throughput screening and rational drug design have been incorporated into pharmaceutical and biotechnology drug discovery programs, researchers have focused on the applying these new technologies in diseases traditionally neglected by for-profit drug discovery efforts. This article reviews general trends in orphan disease lead discovery, identifies best practices of orphan market drug discovery and provides an overview of recent ALS lead discovery programs and drug development according to these metrics. Best practices in orphan market drug discovery embodied by programs like the NIH Anticonvulsant Screening Program include the (1) management of timelines and priorities, (2) engagement of for-profit partners, (3) creative application of technology, (4) collaboration, and (5) flexibility. Recent trends in ALS lead discovery have been shaped not only by the predominance of animal models of disease over in vitro models, but also by the successes and best practices of these earlier orphan market drug discovery programs. The ALS Treatment Initiative, the Johns Hopkins Center for ALS Research, the ALS Association, and the ALS Therapy Development Foundation have all initiated lead discovery programs in the past several years which seek to utilize existing experimental models of the disease and challenge assumptions about the linear nature of the lead discovery and development process. The compounds currently in clinical evaluation for ALS were identified as leads from a variety of sources, further reinforcing the transforming effect these new lead discovery programs have had on drug discovery and development in ALS. We conclude our review with an overview of the challenges and opportunities lead discovery in ALS currently faces, ultimately concluding that ALS lead discovery, and indeed orphan market drug discovery in general, would most benefit from more centralized lead discovery management, expanded national access to core facilities for lead discovery, and matrixed simultaneous screening of multiple compounds for multiple neglected diseases.}, }
@article {pmid12131695, year = {2002}, author = {Fawwaz, RA and Oluwole, OO and DePaz, HA and Jin, MX and Wang, TS and Hardy, MA and Oluwole, SF}, title = {Peritransplant streptavidin recipient treatment prolongs rat cardiac allograft survival.}, journal = {Transplantation}, volume = {73}, number = {12}, pages = {1954-1956}, doi = {10.1097/00007890-200206270-00019}, pmid = {12131695}, issn = {0041-1337}, support = {HL-57229/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Graft Survival/*drug effects ; *Heart Transplantation ; Rats ; Rats, Inbred ACI ; Rats, Inbred Lew ; Rats, Inbred WF ; Streptavidin/*therapeutic use ; Transplantation, Homologous ; Weight Loss ; }, abstract = {BACKGROUND: Because streptavidin shows high localization in inflamed tissues, it might also interfere with the proliferation of cells involved in allograft rejection.<br><br>METHODS AND RESULTS: Treatment of na&#xef;ve ACI recipients with 20 mg/kg streptavidin i.p. alone significantly prolonged Lewis cardiac allografts from a mean survival time of 9.8+/-0.7 days in controls to 19.8+/-6.5 days, with one recipient accepting the graft permanently (>250 days). Peritransplant streptavidin treatment combined with 0.5 ml of antilymphocyte serum (ALS) transient immunosuppression led to permanent graft survival (>250 days) in 6 of 10 recipients. Second-set skin grafts performed 60 days after the primary cardiac allograft were prolonged to 45 days, whereas the third party Wistar-Furth (WF) skin grafts were rejected in 15 days without the rejection of the primary Lewis cardiac allografts. Pathology of transplanted cardiac allografts at 100 days showed no mononuclear cell infiltration or chronic allograft vasculopathy. Streptavidin given for 5 days at 20 mg/kg caused a moderate initial weight loss but had no effect on hematologic, biochemical, and histologic parameters in the treated recipients.<br><br>CONCLUSION: This study demonstrates that peritransplant recipient treatment with streptavidin combined with peritransplant ALS induces prolonged cardiac and second-set skin allograft survival. We conclude that recipient peritransplant streptavidin treatment may provide a new strategy for the induction of transplant tolerance.}, }
@article {pmid12125078, year = {2002}, author = {Kikuchi, S and Shinpo, K and Takeuchi, M and Tsuji, S and Yabe, I and Niino, M and Tashiro, K}, title = {Effect of geranylgeranylaceton on cellular damage induced by proteasome inhibition in cultured spinal neurons.}, journal = {Journal of neuroscience research}, volume = {69}, number = {3}, pages = {373-381}, doi = {10.1002/jnr.10298}, pmid = {12125078}, issn = {0360-4012}, mesh = {Acetylcysteine/adverse effects/*analogs &amp; derivatives ; Animals ; Cell Survival/drug effects ; Cells, Cultured ; Cysteine Endopeptidases/*metabolism ; Cysteine Proteinase Inhibitors/adverse effects ; Diterpenes/*pharmacology ; Dose-Response Relationship, Drug ; Glutathione/drug effects/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Immunoblotting ; Immunohistochemistry ; Mitochondria/drug effects/metabolism ; Multienzyme Complexes/*antagonists &amp; inhibitors/*metabolism ; Neurons/drug effects/*metabolism ; Neuroprotective Agents/*pharmacology ; Oligopeptides/adverse effects ; Proteasome Endopeptidase Complex ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Spinal Cord/cytology/drug effects/*metabolism ; Thioredoxins/metabolism ; Time Factors ; }, abstract = {We investigated the effect of two proteasome inhibitors, lactacystin and epoxomicin, on cultured spinal cord neurons. The incubation of spinal neurons with proteasome inhibitors for 24 hr induced neurotoxicity in a dose-dependent manner. We found motor neurons to be more vulnerable to proteasome-induced neurotoxicity than nonmotor neurons. The staining of cell bodies in treated motor neurons was markedly disrupted and showed characteristic granular patterns. Proteasome-induced neurotoxicity is accompanied by apoptotic nuclear changes, posttranslational modification of the cellular proteins, generation of intracellular free radicals, reduction in the amount of reduced glutathione, and mitochondrial dysfunction. Neurotoxicity was reduced by the administration of low concentrations (1-100 nM) of geranylgeranylacetone (GGA), which is widely used as an antiulcer drug, although higher concentrations of this drug produced neurotoxicity in spinal cord neurons. GGA was found to induce the expression of heat shock protein 70 as well as thioredoxin, which may partly contribute to the protective effect of GGA. These data suggest that the inhibition of proteasome may play a role in the mechanism of neurodegenerative diseases of the spinal cord, such as amyotrophic lateral sclerosis, and that the use of GGA may be effective in the treatment of these conditions.}, }
@article {pmid12117078, year = {2002}, author = {Te, AE}, title = {A modern rationale for the use of phenoxybenzamine in urinary tract disorders and other conditions.}, journal = {Clinical therapeutics}, volume = {24}, number = {6}, pages = {851-61; discussion 837}, doi = {10.1016/s0149-2918(02)80003-0}, pmid = {12117078}, issn = {0149-2918}, mesh = {Adrenergic alpha-Antagonists/adverse effects/pharmacokinetics/*therapeutic use ; Animals ; Clinical Trials as Topic ; Half-Life ; Humans ; Male ; Phenoxybenzamine/adverse effects/pharmacokinetics/*therapeutic use ; Prostatic Hyperplasia/*drug therapy ; Rats ; Tissue Distribution ; Urinary Tract Infections/*drug therapy ; }, abstract = {BACKGROUND: Phenoxybenzamine (PBZ) is a nonselective, irreversible alpha-adrenergic receptor antagonist that is approved for the treatment of diaphoresis and hypertension associated with pheochromocytoma. It may also be useful in several chronic conditions whose pathogenesis is mediated or affected by alpha-adrenergic stimulation, such as lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH) and neurogenic bladder (eg, secondary to myelomeningocele and in sphincter dyssynergia and autonomic dysreflexia); in an adjunctive role after urogenital surgery or brachytherapy by relieving symptoms associated with increased alpha-adrenergic tone; and in the treatment of complex regional pain syndrome (CRPS) and prostatitis. However, carcinogenic concerns may have limited its potential application.<br><br>OBJECTIVE: The purpose of this article is to reassess the usefulness and contemporary application of PBZ for the control of urinary tract symptoms associated with BPH and neurogenic bladder, after urogenital surgery and brachytherapy, and in certain other conditions (eg, CRPS, prostatitis).<br><br>METHODS: A search of literature published from 1966 to 2002 was performed on MEDLINE using the search terms phenoxybenzamine, alpha-adrenergic blockers, benign prostatic hyperplasia, neurogenic bladder, urinary retention, and complex regional pain<br><br>RESULTS: Despite concerns about possible carcinogenicity, no reports of drug-related tumors have been made since PBZ's introduction in 1953. Investigators have used PBZ in off-label trials to alleviate symptoms of a variety of conditions that cause urinary retention. In adult male patients with retention due to inguinal hernioplasty and female patients with retention caused by vaginal repair, as well as in pediatric patients with myelomeningocele, treatment with PBZ improved bladder function and, in the patients with myelomeningocele, was associated with reduced incidence of urinary tract infection. Larger tri- als of PBZ in men with BPH produced significant urinary symptom relief (P < 0.05 in 2 studies). Moreover, studies suggest that PBZ may be useful in alleviating pain due to trauma and CRPS. The most common adverse events appear to be dizziness, impotence and ejaculatory dysfunction, and nasal stuffiness.<br><br>CONCLUSIONS: No drug-related tumors in humans have been reported after -50 years of clinical experience with PBZ. Clinical trials have demonstrated that it can relieve symptoms in patients with BPH and other urologic and pain-related conditions.}, }
@article {pmid12111820, year = {2002}, author = {Lee, YB and Nagai, A and Kim, SU}, title = {Cytokines, chemokines, and cytokine receptors in human microglia.}, journal = {Journal of neuroscience research}, volume = {69}, number = {1}, pages = {94-103}, doi = {10.1002/jnr.10253}, pmid = {12111820}, issn = {0360-4012}, mesh = {Brain/cytology/embryology ; Cells, Cultured ; Chemokines/*analysis/biosynthesis/genetics ; Cytokines/*analysis/biosynthesis/genetics ; Enzyme-Linked Immunosorbent Assay ; Gene Expression Regulation, Developmental ; Humans ; Microglia/cytology/*metabolism ; Receptors, Cytokine/*analysis/biosynthesis/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Enriched populations of human microglial cells were isolated from mixed cell cultures prepared from embryonic human telencephalon tissues. Human microglial cells exhibited cell type-specific antigens for macrophage-microglia lineage cells including CD11b (Mac-1), CD68, B7-2 (CD86), HLA-ABC, HLA-DR and ricinus communis aggulutinin lectin-1 (RCA-1), and actively phagocytosed latex beads. Gene expression and protein production of cytokines, chemokines and cytokine/chemokine receptors were investigated in the purified populations of human microglia. Normal unstimulated human microglia expressed constitutively mRNA transcripts for interleukin- 1beta (IL-1beta) -6, -8, -10, -12, -15, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and monocyte chemoattractant protein-1 (MCP-1), while treatment with lipopolysaccharide (LPS) or amyloid beta peptides (Abeta) led to increased expression of mRNA levels of IL-8, IL-10, IL-12, TNF-alpha, MIP-1alpha, MIP-1beta, and MCP-1. Human microglia, in addition, expressed mRNA transcripts for IL-1RI, IL-1RII, IL-5R, IL-6R, IL-8R, IL-9R, IL-10R, IL-12R, IL-13R, and IL-15R. Enzyme-linked immunosorbent assays (ELISA) showed increased protein levels in culture media of IL-1beta, IL-8, TNF-alpha, and MIP-1alpha in human microglia following treatment with LPS or Abeta. Increased TNF-alpha release from human microglia following LPS treatment was completely inhibited with IL-10 pretreatment, but not with IL-6, IL-9, IL-12, IL-13, or transforming growth factor-beta (TGF-beta). Present results should help in understanding the basic microglial biology, but also the pathophysiology of activated microglia in neurological diseases such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, stroke, and neurotrauma.}, }
@article {pmid12109945, year = {2002}, author = {Nitta, M and Hirasawa, H and Oda, S and Shiga, H and Nakanishi, K and Matsuda, K and Nakamura, M and Yokohari, K and Hirano, T and Hirayama, Y and Moriguchi, T and Watanabe, E}, title = {Long-term survivors with artificial liver support in fulminant hepatic failure.}, journal = {Therapeutic apheresis : official journal of the International Society for Apheresis and the Japanese Society for Apheresis}, volume = {6}, number = {3}, pages = {208-212}, doi = {10.1046/j.1526-0968.2002.00434.x}, pmid = {12109945}, issn = {1091-6660}, mesh = {Adult ; Female ; Hemodiafiltration/methods ; Hepatic Encephalopathy/physiopathology/*therapy ; Humans ; Intensive Care Units ; Liver Failure/physiopathology/*therapy ; Liver Regeneration ; Liver Transplantation ; *Liver, Artificial ; Male ; Middle Aged ; Plasma Exchange/instrumentation ; Survivors ; }, abstract = {Clinical ability of artificial liver support (ALS) has been improved greatly in recent years which has allowed us to encounter long-term survivors with fulminant hepatic failure (FHF) whose liver function has been almost completely lost. This suggests that application of ALS in patients with FHF gains time while awaiting transplantation as well as time for functional recovery and regeneration of the liver graft following receipt of the graft with marginal function and/or size. Thus, ALS will contribute greatly to extending the indications for liver transplantation and increase the number of patients receiving and benefiting from this treatment. On the other hand, introduction of ALS prolongs the duration of intensive treatment which increases the risk of infection and increases medical costs. In addition, when to discontinue intensive treatment of patients whose level of consciousness is maintained only by ALS is controversial. Thus, further investigation will be needed to establish a consensus on indications for long-term ALS in FHF.}, }
@article {pmid12105314, year = {2002}, author = {Chiò, A and Mora, G and Leone, M and Mazzini, L and Cocito, D and Giordana, MT and Bottacchi, E and Mutani, R and , }, title = {Early symptom progression rate is related to ALS outcome: a prospective population-based study.}, journal = {Neurology}, volume = {59}, number = {1}, pages = {99-103}, doi = {10.1212/wnl.59.1.99}, pmid = {12105314}, issn = {0028-3878}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/diagnosis/*mortality/*physiopathology ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Muscle Contraction ; Predictive Value of Tests ; Prognosis ; Prospective Studies ; Registries ; Respiratory Function Tests ; Survival Analysis ; }, abstract = {OBJECTIVE: To define the factors related to ALS outcome in a population-based, prospective survey.<br><br>METHODS: The 221 patients (120 men and 101 women) listed in the Piemonte and Valle d'Aosta ALS Register between 1995 and 1996 were enrolled in the study. The patients were prospectively monitored with a standard evaluation form after diagnosis.<br><br>RESULTS: Mean age at onset was 62.8 (SD = 11.2) years. According to El Escorial diagnostic criteria (EEDC), 112 patients had definite ALS, 85 probable ALS, 18 possible ALS, and six suspected ALS. The median survival time from symptom onset was 915 days (95% CI = 790 to 1065). The median survival time from diagnosis was 580 days (95% CI = 490 to 670). In univariate analysis, outcome was significantly related to age, onset site, EEDC classification, and symptom progression rate (i.e., the rate of decline of muscle strength and bulbar and respiratory function in the 6 months after diagnosis). In the Cox multivariate model, age, progression rate of respiratory, bulbar, and lower limb symptoms, EEDC classification, percutaneous endoscopic gastrostomy, and treatment with riluzole were significantly related to outcome.<br><br>CONCLUSIONS: The rate of progression of symptoms in early ALS is predictive of disease outcome.}, }
@article {pmid12101392, year = {2002}, author = {Manabe, Y and Nagano, I and Gazi, MS and Murakami, T and Shiote, M and Shoji, M and Kitagawa, H and Setoguchi, Y and Abe, K}, title = {Adenovirus-mediated gene transfer of glial cell line-derived neurotrophic factor prevents motor neuron loss of transgenic model mice for amyotrophic lateral sclerosis.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {7}, number = {4}, pages = {329-334}, doi = {10.1023/a:1016123413038}, pmid = {12101392}, issn = {1360-8185}, mesh = {Adenoviridae ; Amyotrophic Lateral Sclerosis/genetics/pathology/*therapy ; Animals ; Cell Death/genetics ; Gene Transfer Techniques ; *Genetic Therapy ; Genetic Vectors ; Glial Cell Line-Derived Neurotrophic Factor ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects/pathology ; Nerve Growth Factors/*genetics/therapeutic use ; Neuroglia/metabolism/pathology ; }, abstract = {Effects of adenovirus-mediated gene transfer of glial cell line-derived neurotrophic factor (GDNF) were studied in transgenic (Tg) mice model for amyotrophic lateral sclerosis (ALS). Adenoviral vector containing GDNF gene (Ad-GDNF), E. coli lacZ (Ad-LacZ), or vehicle was injected once a week from 35 weeks of age into the right gastrocnemius muscle of Tg mice carrying mutant human Cu/Zn superoxide dismutase (SOD1) gene, and histological analysis was performed at 46 W. Clinical data showed a tendency of improvement, but was not significantly different among the three animal groups. In contrast, total number of and phospho-Akt (p-Akt) positive large motor neurons in the treated side was significantly preserved in Ad-GDNF-treated group than in vehicle- and Ad-LacZ-treated groups (*p < 0.05). Immunoreactivity of phospho-ERK (p-ERK) and active caspases-3 and -9 showed no difference. These results indicate that the Ad-GDNF treatment prevented motor neuron loss with preserving survival p-Akt signal and without affecting caspase activations, suggesting a future possibility for the therapy of the disease.}, }
@article {pmid12100369, year = {2002}, author = {Tsuboi, Y and Kakimoto, K and Akatsu, H and Daikuhara, Y and Yamada, T}, title = {Hepatocyte growth factor in cerebrospinal fluid in neurologic disease.}, journal = {Acta neurologica Scandinavica}, volume = {106}, number = {2}, pages = {99-103}, doi = {10.1034/j.1600-0404.2002.01125.x}, pmid = {12100369}, issn = {0001-6314}, mesh = {Adult ; Aged ; Central Nervous System Diseases/*cerebrospinal fluid ; Demyelinating Diseases/*cerebrospinal fluid ; Female ; Hepatocyte Growth Factor/*cerebrospinal fluid ; Humans ; Male ; Middle Aged ; Muscular Diseases/cerebrospinal fluid ; Peripheral Nervous System Diseases/cerebrospinal fluid ; }, abstract = {OBJECTIVE: To investigate hepatocyte growth factor (HGF) concentration in cerebrospinal fluid (CSF) in neurologic disease.<br><br>MATERIALS AND METHODS: We determined CSF concentration of HGF with human-HGF-specific enzyme-linked immunosorbent assays (ELISA) in 121 patients: Alzheimer's disease (AD) (33), amyotrophic lateral sclerosis (ALS) (10), Parkinson's disease (PD) (5), progressive supranuclear palsy (PSP) (3), spinocerebellar degeneration (7), acute disseminating encephalomyelitis (ADEM) (6), human T-lymphotropic virus-1 (HTLV-1)-associated myelopathy (HAM) (6), multiple sclerosis (MS) (7), aseptic meningitis (AM) (12), and peripheral neuropathy and myopathy as control diseases (32).<br><br>RESULTS: HGF concentrations in CSF were significantly higher with diseases of the central nervous system (CNS) than control diseases and were slightly higher with AD than other neurodegenerative diseases. Values were highest with ADEM but decreased during corticosteroid treatment. We found no relationship between HGF in CSF and CSF cells or protein, immunoglobulin index, or Q albumin.<br><br>CONCLUSION: It is suggested that high concentrations of HGF in CSF may be partially related to CNS pathology, especially to demyelinating disease.}, }
@article {pmid12099360, year = {2001}, author = {Garrovillo, M and Ali, A and Depaz, HA and Gopinathan, R and Oluwole, OO and Hardy, MA and Oluwole, SF}, title = {Induction of transplant tolerance with immunodominant allopeptide-pulsed host lymphoid and myeloid dendritic cells.}, journal = {American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons}, volume = {1}, number = {2}, pages = {129-137}, pmid = {12099360}, issn = {1600-6135}, support = {R01 HL-57229/HL/NHLBI NIH HHS/United States ; }, mesh = {Adoptive Transfer ; Animals ; Bone Marrow Cells/cytology/immunology ; Cells, Cultured ; Dendritic Cells/immunology/*transplantation ; Heart Transplantation/*immunology ; *Immune Tolerance ; Immunosuppression Therapy/*methods ; Isoantigens/*immunology ; Lymphocyte Activation ; Lymphocyte Culture Test, Mixed ; *Lymphocyte Transfusion ; Rats ; Rats, Inbred ACI ; Rats, Inbred Lew ; Rats, Inbred WF ; T-Lymphocytes/immunology ; Thymectomy ; Thymus Gland/cytology/immunology ; Transplantation Immunology/*physiology ; Transplantation, Homologous/immunology ; }, abstract = {We have studied the effects of adoptive transfer of host thymic dendritic cells pulsed with immunodominant WF Class I peptide 5 (residues 93-109) on cardiac allograft survival in the WF-to-ACI rat combination. Our results showed that, whereas intrathymic inoculation of WF peptide 5-pulsed ACI thymic dendritic cells alone on day -7 did not prolong graft survival, similar treatment combined with 0.5 mL antilymphocyte serum (ALS) led to 100% permanent acceptance (> 200d) of donor-specific cardiac allografts. Extension of our study to systemic administration of peptide 5-pulsed host thymic dendritic cells confirmed that intravenous injection of peptide 5-pulsed self thymic dendritic cells combined with ALS transient immunosuppression resulted in 100% permanent donor-specific graft survival (> 200d). These results were reproducible in a clinically relevant model using intravenous injection of peptide-pulsed host myeloid dendritic cells. In contrast, thymectomy prior to adoptive transfer of peptide-pulsed host dendritic cells resulted in acute graft rejection at times equivalent to rejection in thymectomized controls. The long-term unresponsive recipients challenged with second-set grafts accepted permanently (> 100d) donor-type (WF) but not third party (Lewis) cardiac allografts. This study suggests that intravenous administration of genetically engineered dendritic cells expressing donor MHC molecules has the potential of inducing transplant tolerance.}, }
@article {pmid12098061, year = {2002}, author = {Wu, T and Sozen, H and Luo, B and Heuss, N and Kalscheuer, H and Lan, P and Sutherland, DE and Hering, BJ and Guo, Z}, title = {Rapamycin and T cell costimulatory blockade as post-transplant treatment promote fully MHC-mismatched allogeneic bone marrow engraftment under irradiation-free conditioning therapy.}, journal = {Bone marrow transplantation}, volume = {29}, number = {12}, pages = {949-956}, doi = {10.1038/sj.bmt.1703574}, pmid = {12098061}, issn = {0268-3369}, mesh = {Animals ; Antibiotics, Antineoplastic/administration &amp; dosage ; Bone Marrow Transplantation/immunology/*methods ; Graft Survival ; Graft vs Host Disease/prevention &amp; control ; Hematopoietic Stem Cell Transplantation/methods ; Histocompatibility ; Histocompatibility Testing ; Immunosuppressive Agents/*administration &amp; dosage ; Lymphocyte Depletion/*methods ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Sirolimus/*administration &amp; dosage ; Transplantation Chimera ; Transplantation Conditioning/*methods ; Transplantation, Homologous/methods ; }, abstract = {Hematopoietic macrochimerism, established by bone marrow transplantation, can be used as an approach for treating autoimmune disease and inducing transplant tolerance. In this study, we investigated whether a stable, high level of fully MHC-mismatched hematopoietic macrochimerism can be induced by using irradiation-free protocols, and whether rapamycin and T cell costimulatory blockades (anti-CD40L monoclonal antibody (mAb) and CTLA4Ig) as post-transplant treatment promote bone marrow engraftment. Donor-specific blood transfusion (DST), anti-lymphocyte serum (ALS), busulfan, and cyclophosphamide were given pretransplantation. Balb/c (H-2(d)) bone marrow cells, at a dose of 4 x 10(7), were infused into each C57BL/6 mouse (H-2(b)). Rapamycin, anti-CD40L mAb, and CTLA4Ig were then administered, either alone or in combination. Without ALS or busulfan and cyclophosphamide, macrochimerism can only rarely be induced. Donor-specific transfusion (DST) enhances induction of hematopoietic macrochimerism. Rapamycin, anti-CD40L mAb and CTLA4Ig, alone or in combination, induce a stable and high level of hematopoietic macrochimerism. In the chimeric mice, donor-derived cells were detected in all lymphohematopoietic tissues and donor-specific tolerance was induced in vitro. We conclude that a stable and high level of fully MHC-mismatched hematopoietic macrochimerism can be induced in mice after transplanting a single modest dose of bone marrow cells without irradiation. Rapamycin and T cell costimulatory blockade as post-transplant treatment promote bone marrow engraftment.}, }
@article {pmid12090150, year = {2002}, author = {Lacomblez, L and Dib, M and Doppler, V and Faudet, A and Robin, V and Salachas, F and Bensimon, G and Meininger, V}, title = {[Tolerance of riluzole in a phase IIIb clinical trial].}, journal = {Therapie}, volume = {57}, number = {1}, pages = {65-71}, pmid = {12090150}, issn = {0040-5957}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/drug therapy ; Female ; France/epidemiology ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*adverse effects/therapeutic use ; Product Surveillance, Postmarketing ; Riluzole/*adverse effects/therapeutic use ; }, abstract = {Within the framework of an early drug access programme launched in 1995, a multicentre open study was initiated in France in order to assess, inter alia, the safety of riluzole (50 mg twice a day) in a total of 2069 patients from 28 centres. This programme, a phase IIIb study with direct individual benefit, had two main objectives: to enable patients to receive riluzole therapy pending regulatory approval and commercial availability and to provide further data on the safety of riluzole in a broader ALS population. The most frequent adverse events related to riluzole treatment were: asthenia, nausea and elevation of serum transaminase levels. These observations, similar to data derived from previous pivotal clinical trials, confirm that riluzole has a satisfactory tolerability profile.}, }
@article {pmid12076984, year = {2002}, author = {Liu, B and Gao, HM and Wang, JY and Jeohn, GH and Cooper, CL and Hong, JS}, title = {Role of nitric oxide in inflammation-mediated neurodegeneration.}, journal = {Annals of the New York Academy of Sciences}, volume = {962}, number = {}, pages = {318-331}, doi = {10.1111/j.1749-6632.2002.tb04077.x}, pmid = {12076984}, issn = {0077-8923}, mesh = {Animals ; Cells, Cultured ; Cytokines/metabolism ; Humans ; Inflammation/*physiopathology ; Lipopolysaccharides/metabolism ; Narcotics/metabolism ; *Nerve Degeneration ; Neurodegenerative Diseases/*metabolism ; Neuroglia/metabolism ; Neurons/*metabolism ; Nitric Oxide/*metabolism ; }, abstract = {Increasing evidence has suggested that inflammation in the brain is closely associated with the pathogenesis of several degenerative neurologic disorders, including Parkinson's disease, Alzheimer's diseases, multiple sclerosis, amyotrophic lateral sclerosis, and AIDS dementia. The hallmark of brain inflammation is the activation of glial cells, especially that of microglia that produce a variety of proinflammatory and neurotoxic factors, including cytokines, fatty acid metabolites, free radicals--such as nitric oxide (NO) and superoxide. Excessive production of NO, as a consequence of nitric oxide synthase induction in activated glia, has been attributed to participate in neurodegeneration. Using primary mixed neuron-glia cultures and glia-enriched cultures prepared from embryonic rodent brain tissues, we have systemically studied the relationship between the production of NO and neurodegeneration in response to stimulation by the inflammagen lipopolysaccharide. This review summarizes our recent findings on the kinetics of NO generation, the relative contribution of microglia and astrocytes to NO accumulation, the relationship between NO production and neurodegeneration, and points of intervention along the pathways associated with NO generation to achieve neuroprotection. We also describe our results relating to the effect of several opioid-related agents on microglial activation and neuroprotection. Among these agents, the opioid receptor antagonist naloxone, especially its non-opioid enantiomer (+)-naloxone, promises to be of potential therapeutic value for the treatment of inflammation-related diseases.}, }
@article {pmid12076411, year = {2002}, author = {Miller, RG and Mitchell, JD and Lyon, M and Moore, DH}, title = {Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {2}, pages = {CD001447}, doi = {10.1002/14651858.CD001447}, pmid = {12076411}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Excitatory Amino Acid Antagonists/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole/*therapeutic use ; }, abstract = {BACKGROUND: Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis in many countries but not all. Questions persist about its clinical utility because of high cost, modest efficacy and concern over adverse effects.<br><br>OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival.<br><br>SEARCH STRATEGY: Search of the Cochrane Neuromuscular Disease Group Register for randomized trials and enquiry from authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. The most recent search was May, 2001 SELECTION CRITERIA: Types of studies: randomized trials<br><br>TYPES OF PARTICIPANTS: adults with a diagnosis of amyotrophic lateral sclerosis Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality as a function of time with riluzole 100 mg and other doses of riluzole; neurologic function, quality of life, muscle strength and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: We identified four eligible randomized trials. Each reviewer graded them for methodological quality. Data extraction was performed by a single reviewer and checked by two others. We obtained some missing data from investigators and regulatory agencies. We performed meta-analyses with Review Manager 4.1 software using a fixed effects model. A test of drug efficacy was based on the Parmar pooled hazard ratio.<br><br>MAIN RESULTS: The three trials examining tracheostomy-free survival included a total of 876 riluzole treated patients and 406 placebo treated patients. The data for tracheostomy-free survival was not available from the fourth trial. The methodological quality was acceptable and the three trials were easily comparable, although one trial included older patients in more advanced stages of amyotrophic lateral sclerosis. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (p=0.039, hazard ratio 0.80, 95% confidence interval 0.64 to 0.99) and there was no evidence of heterogeneity (p=0.33). When the third trial (which included older and more seriously affected patients) is added, there is evidence of heterogeneity (p<0.0001) and the random effects model, which takes this into account results in the overall treatment effect estimate falling just short of significance (p=0.056, hazard ratio 0.84, 95% confidence interval 0.70 to 1.01). This represents a 9% gain in the probability of surviving one year (57% in the placebo and 66% in the riluzole group). In secondary analyses of survival at separate time points, there was a significant survival advantage with riluzole 100 mg at six, nine, 12 and 15 months, but not at three or 18 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. There were no data on quality of life, but patients treated with riluzole remained in a more moderately affected health state significantly longer than placebo-treated patients (weighted mean difference 35.5 days, 95% confidence interval 5.9 to 65.0). A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (weighted mean difference 2.69, 95% confidence interval 1.65 to 4.38).<br><br>REVIEWER'S CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs survival by about two months in patients with amyotrophic lateral sclerosis. More studies are needed, especially to clarify its effect in older patients (over 75 years), and those with more advanced disease.}, }
@article {pmid12075860, year = {2002}, author = {Bonelli, RM and Niederwieser, G}, title = {Apraxia of eyelid closure in Huntington's disease.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {109}, number = {2}, pages = {197-201}, doi = {10.1007/s007020200016}, pmid = {12075860}, issn = {0300-9564}, mesh = {Apraxias/*etiology ; Benzodiazepines ; Drug Therapy, Combination ; Eyelid Diseases/*etiology ; Female ; Humans ; Huntington Disease/*complications/drug therapy ; Middle Aged ; Neuroprotective Agents/administration &amp; dosage/therapeutic use ; Olanzapine ; Pirenzepine/administration &amp; dosage/analogs &amp; derivatives/therapeutic use ; Riluzole/administration &amp; dosage/therapeutic use ; Selective Serotonin Reuptake Inhibitors/administration &amp; dosage/therapeutic use ; }, abstract = {We report a patient with genetically confirmed Huntington's disease (HD) presenting apraxia of eyelid closure (AEC). She was unable to close her eyes at command but was able to blink. Chorea and AEC ameliorated significantly during treatment with olanzapine and riluzole, an inhibitor of glutamate release. AEC is reported in progressive supranuclear palsy, Creutzfeldt-Jakob's disease, amyotrophic lateral sclerosis, and as post-stroke AEC. No report on HD is available so far, although oculomotor disturbances are quite common in this disease.}, }
@article {pmid12069110, year = {2002}, author = {Beal, MF}, title = {Coenzyme Q10 as a possible treatment for neurodegenerative diseases.}, journal = {Free radical research}, volume = {36}, number = {4}, pages = {455-460}, doi = {10.1080/10715760290021315}, pmid = {12069110}, issn = {1071-5762}, support = {AG12992/AG/NIA NIH HHS/United States ; AG14390/AG/NIA NIH HHS/United States ; NS38180/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*therapeutic use ; Coenzymes ; Cytoprotection ; Dietary Supplements ; Humans ; Mice ; Mice, Transgenic ; Neurodegenerative Diseases/*drug therapy ; Ubiquinone/*analogs &amp; derivatives/*therapeutic use ; }, abstract = {Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport gene as well as an important antioxidant, which is particularly effective within mitochondria. A number of prior studies have shown that it can exert efficacy in treating patients with known mitochondrial disorders. We investigated the potential usefulness of coenzyme Q10 in animal models of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). It has been demonstrated that CoQ10 can protect against striatal lesions produced by the mitochondrial toxins malonate and 3-nitropropionic acid. These toxins have been utilized to model the striatal pathology, which occurs in HD. It also protects against 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice. CoQ10 significantly extended survival in a transgenic mouse model of ALS. CoQ10 can significantly extend survival, delay motor deficits and delay weight loss and attenuate the development of striatal atrophy in a transgenic mouse model of HD. In this mouse model, it showed additive efficacy when combined with the N-methyl-D-aspartate (NMDA) receptor antagonist, remacemide. CoQ10 is presently being studied as a potential treatment for early PD as well as in combination with remacemide as a potential treatment for HD.}, }
@article {pmid12067327, year = {2002}, author = {Niebroj-Dobosz, I and Janik, P and Kwieciński, H}, title = {Effect of Riluzole on serum amino acids in patients with amyotrophic lateral sclerosis.}, journal = {Acta neurologica Scandinavica}, volume = {106}, number = {1}, pages = {39-43}, doi = {10.1034/j.1600-0404.2002.00206.x}, pmid = {12067327}, issn = {0001-6314}, mesh = {Adult ; Aged ; Amino Acids/*blood ; Amyotrophic Lateral Sclerosis/*blood/drug therapy ; Aspartic Acid/blood ; Chromatography, High Pressure Liquid ; Female ; Follow-Up Studies ; Glutamic Acid/blood ; Glycine/blood ; Humans ; Male ; Middle Aged ; Neurotransmitter Agents/blood ; Reference Values ; Riluzole/*therapeutic use ; Time ; gamma-Aminobutyric Acid/blood ; }, abstract = {OBJECTIVES: There is evidence that an imbalance between glutamatergic and inhibitory neurotransmission may contribute to selective neurodegeneration in amyotrophic lateral sclerosis (ALS). The efficacy of Riluzole in prolonging the survival of patients with ALS has been demonstrated in two large controlled trials. It is believed that Riluzole is a glutamate antagonist, but the exact mode of its action is not known. Data on the effects of Riluzole treatment on excitotoxic amino acid levels in serum are not available.<br><br>MATERIAL AND METHODS: We prospectively studied 17 patients with ALS (diagnosed according to the El Escorial criteria), who received long-term treatment with Riluzole (100 mg/day). The subjects were evaluated at baseline (before treatment) and after 6, 12 and 18 months on drug. Assessments included the functional status of the patients and serum levels of amino acids. Analysis of the serum amino acids was performed using high performance liquid chromatography techniques at baseline, and after 6, 12 and 18 months of the treatment.<br><br>RESULTS: At baseline, glutamate, GABA and total amino acid concentration in serum of the ALS patients, mainly in those with severe course of the disease, were increased. During the first 6 months of Riluzole treatment there was a significant decrease of glutamate and total amino acids, afterwards the values returned to the initial high values, or even an 'overshooting' in their levels appeared. We did not observe a similar effect of Riluzole on glutamate and other amino acids in patients with less advanced ALS.<br><br>CONCLUSIONS: It is suggested that the positive clinical effect of Riluzole in ALS patients may be related, at least partly, to its influence on amino acid metabolism in neural tissues.}, }
@article {pmid12067233, year = {2002}, author = {Gorio, A and Lesma, E and Madaschi, L and Di Giulio, AM}, title = {Co-administration of IGF-I and glycosaminoglycans greatly delays motor neurone disease and affects IGF-I expression in the wobbler mouse: a long-term study.}, journal = {Journal of neurochemistry}, volume = {81}, number = {1}, pages = {194-202}, doi = {10.1046/j.1471-4159.2002.00830.x}, pmid = {12067233}, issn = {0022-3042}, mesh = {Animals ; Behavior, Animal/drug effects ; Body Weight/drug effects ; Cell Size/drug effects ; Cell Survival/drug effects ; Disease Models, Animal ; Disease Progression ; Drug Therapy, Combination ; Female ; Forelimb/innervation/physiopathology ; Glycosaminoglycans/*administration &amp; dosage ; Injections, Subcutaneous ; Insulin-Like Growth Factor Binding Protein 1/blood ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/*administration &amp; dosage/*metabolism ; Male ; Mice ; Mice, Neurologic Mutants ; Motor Neuron Disease/pathology/*physiopathology/*prevention &amp; control ; Motor Neurons/drug effects/pathology ; Muscle Fibers, Skeletal/drug effects/pathology/ultrastructure ; Muscle, Skeletal/innervation/pathology ; Time ; }, abstract = {The study on wobbler mouse has shown that the combined treatment with low doses of glycosaminoglycans (GAGs) and insulin-like growth factor-I (IGF-I) fully prevented motor neurone death and forelimb impairment up to 9-12 weeks of a mouse's life. The effect was accompanied by the prevention of the early hypertrophy of wobbler neurones, an effect likely due to the promotion of neuronal survival. At the 18th week, wobbler mice treated with IGF-I + GAGs still showed significantly improved forelimb function, reduced muscle atrophy and a higher number of cervical motor neurones. IGF-I alone and GAGs alone were active up to the 3rd week of treatment; thereafter the beneficial effects of single treatments decreased drastically. GAGs and IGF-I treatments also affected IGF-I plasma and muscle levels. In wobbler mice there was a progressive reduction in IGF-I plasma levels that was prevented by IGF-I or GAGs alone and greatly increased, even above heterozygote levels, by the combination treatment. Such a powerful increase was correlated by a small enhancement in insulin-like growth factor binding protein-3 (IGFBP-3) plasma levels, while treatment with IGF-I alone affected very significantly both IGFBP-1 and IGFBP-3. Co-treatment also prevented the decrease in IGF-I content observed in vehicle-treated wobbler mice forelimb muscles.}, }
@article {pmid12065630, year = {2002}, author = {Festoff, BW and SantaCruz, K and Arnold, PM and Sebastian, CT and Davies, PJ and Citron, BA}, title = {Injury-induced "switch" from GTP-regulated to novel GTP-independent isoform of tissue transglutaminase in the rat spinal cord.}, journal = {Journal of neurochemistry}, volume = {81}, number = {4}, pages = {708-718}, doi = {10.1046/j.1471-4159.2002.00850.x}, pmid = {12065630}, issn = {0022-3042}, mesh = {Alternative Splicing ; Amino Acid Sequence ; Animals ; Base Sequence ; Blotting, Western ; Disease Models, Animal ; Female ; GTP-Binding Proteins/genetics/*metabolism ; Guanosine Triphosphate/*metabolism ; Immunohistochemistry ; In Situ Hybridization ; Molecular Sequence Data ; Protein Glutamine gamma Glutamyltransferase 2 ; Protein Isoforms/genetics/metabolism ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/*metabolism/pathology ; Spinal Cord Injuries/*metabolism ; Transglutaminases/genetics/*metabolism ; Up-Regulation ; Wounds, Nonpenetrating ; }, abstract = {We recently found that alternative transcripts of tissue transglutaminase (tTG or TG2) were present in hippocampal brain regions of Alzheimer's disease (AD), but not in control, non-demented, age-matched brains. Since antecedent non-severe trauma has been implicated in AD and other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), we were interested in whether alternative transcripts might be detected in a model of neurotrauma, controlled-contusion spinal cord injury (SCI) in the rat. Implicated in diverse roles from growth and differentiation to apoptotic cell death, only bifunctional tTG, of the nine member TG family, has dual catalytic activities: guanine trinucleotide (GTP) hydrolyzing activity (GTPase), as well as protein cross-linking. These functions imply two physiological functions: programmed cell life and death. These may have profound roles in the nervous system since studies in cultured astrocytes found tTG short (S) mRNA transcripts induced by treatment with injury-related cytokines. In the developing rat spinal cord, tTG activity is concentrated in ventral horn alpha motoneurons, but neither studies of spinal cord tTG gene expression, nor evaluation of the GTP-regulated isoforms in tissues, have been reported. We now report increased tTG protein and gene expression occurring rapidly after SCI. In parallel, novel appearance of a second, short form transcript, in addition to the normal long (L) isoform, occurs by 8 h of injury. Up-regulation of tTG message and activity following neural injury. with appearance of a truncated GTP-unregulated S form, may represent new approaches to drug targets in neurotrauma.}, }
@article {pmid12061948, year = {2002}, author = {Drory, VE and Gross, D}, title = {No effect of creatine on respiratory distress in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {3}, number = {1}, pages = {43-46}, doi = {10.1080/146608202317576534}, pmid = {12061948}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*complications/diagnosis/drug therapy ; Creatine/*therapeutic use ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Reproducibility of Results ; Respiratory Function Tests ; Respiratory Insufficiency/diagnosis/*drug therapy/*etiology ; Sensitivity and Specificity ; Treatment Outcome ; }, abstract = {OBJECTIVE: To evaluate the effect of creatine supplementation on the respiratory function of patients with advanced amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Five grams creatine daily were administered orally to 14 patients with definite advanced ALS. For comparison we used a group of 13 patients with a similar respiratory function. All patients performed pulmonary function testing including forced vital capacity (FVC), forced expiratory volume (FEV(1)), peak expiratory flow rate (PEF) and maximum voluntary ventilation (MVV) -- expressed as percent of the predicted value -- at baseline and each month thereafter.<br><br>RESULTS: There was no significant difference in any measured variable between the treatment group and the control group at 1, 2, 3 and 4 months follow-up. Thereafter the high patient drop-out rate did not allow statistical evaluation.<br><br>CONCLUSION: The present study did not show any clinically significant, long-term effect of creatine on the function of respiratory muscles in ALS patients with respiratory distress.}, }
@article {pmid12061946, year = {2002}, author = {Wang, FC and Bouquiaux, O and De Pasqua, V and Delwaide, PJ}, title = {Changes in motor unit numbers in patients with ALS: a longitudinal study using the adapted multiple point stimulation method.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {3}, number = {1}, pages = {31-38}, doi = {10.1080/146608202317576516}, pmid = {12061946}, issn = {1466-0822}, mesh = {*Action Potentials ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/*physiopathology ; Electric Stimulation ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; *Motor Neurons ; Muscle, Skeletal/innervation/*physiopathology ; Reproducibility of Results ; Sensitivity and Specificity ; Statistics as Topic ; Thumb/physiopathology ; }, abstract = {METHOD: The adapted multiple point stimulation (AMPS) method for calculating motor unit numbers (MUNE) was applied in 12 patients with amyotrophic lateral sclerosis (ALS) before riluzole therapy (T(0)) and again after 4, 8 and 12 months of treatment.<br><br>RESULTS: Paired Student's t-test indicated a significant decrease of thenar MUNE and compound muscle action potential (CMAP) size at each 4-monthly interval, while average surface motor unit potential (SMUP) size did not change significantly over time. The rate of motor unit (MU) loss at month 4 was more than 20% in six patients (group 1) and less than 20% in six other patients (group 2). Comparison of groups 1 and 2 by Mann-Whitney U-testing indicated that percent changes in thenar MUNE and CMAP size compared to baseline were significantly different at months 4, 8 and 12, while no difference between the two groups was found for average SMUP size variations. In the group with a slow rate of MU loss, CMAP size remained stable, while in the group with a rapid rate of MU loss, there was a dramatic reduction in size of the CMAP. A positive correlation was found between percent change in thenar MUNE at T(4) and at T(12) (P < 0.001).<br><br>CONCLUSION: AMPS is a useful technique to document MUNE, SMUP size and CMAP size changes over time in patients with ALS.}, }
@article {pmid12061945, year = {2002}, author = {Lacomblez, L and Bensimon, G and Leigh, PN and Debove, C and Bejuit, R and Truffinet, P and Meininger, V and , }, title = {Long-term safety of riluzole in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {3}, number = {1}, pages = {23-29}, doi = {10.1080/146608202317576507}, pmid = {12061945}, issn = {1466-0822}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/*mortality ; Canada/epidemiology ; Consumer Product Safety ; Europe/epidemiology ; Female ; Hematologic Diseases/*chemically induced ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Product Surveillance, Postmarketing ; Respiratory Tract Diseases/*chemically induced ; Riluzole/*adverse effects ; United States/epidemiology ; }, abstract = {OBJECTIVES: This international, open-label, multicentre extension of riluzole pivotal studies was designed to assess the long-term safety of riluzole in the treatment of amyotrophic lateral sclerosis (ALS).<br><br>METHOD: The studies were carried out at 31 different centres, 23 in Europe and eight in North America. 516 patients with diagnosed probable or definite ALS and who had participated previously in one of two international multicentre randomized double-blind placebo-controlled, parallel-group trials, were enrolled in the extensions. 58 of these patients had taken part in a randomized phase II trial (placebo or riluzole 100 mg/day) and 458 in a randomized, dose-ranging phase III trial (placebo or riluzole, 50, 100 or 200 mg/day). All participants in the open-label continuation received 100 mg/day of riluzole (50 mg b.i.d.)<br><br>RESULTS: At the end of the open-label study, the average exposure time of the patients to riluzole was 28.7 +/- 14.4 months, with a maximum exposure time of 81 months. Most of the adverse events recorded reflected the progression of ALS, in particular the deterioration of the respiratory status of the patients. No particular adverse event, or frequency of adverse event, appeared to be related to the dose level of the previous double-blind riluzole treatment. Nor were any adverse events associated with the switch-over from double-blind placebo to open-label riluzole.<br><br>CONCLUSIONS: This open-label extension study reinforces and extends the results of the preceding double-blind trials regarding the safety of riluzole and shows that the drug is well tolerated for long periods of up to almost 7 years.}, }
@article {pmid12061944, year = {2002}, author = {Turner, MR and Bakker, M and Sham, P and Shaw, CE and Leigh, PN and Al-Chalabi, A}, title = {Prognostic modelling of therapeutic interventions in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {3}, number = {1}, pages = {15-21}, doi = {10.1080/146608202317576499}, pmid = {12061944}, issn = {1466-0822}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*drug therapy/*mortality ; Cohort Studies ; Female ; Humans ; London/epidemiology ; Male ; Middle Aged ; *Models, Biological ; Models, Statistical ; Multivariate Analysis ; Prognosis ; Retrospective Studies ; Riluzole/*therapeutic use ; Risk Factors ; Sex Factors ; Survival Analysis ; Survival Rate ; Treatment Outcome ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease with a widely varying prognosis. The majority of patients survive about 3 years, but a significant number survive for 10 years or more, leading to problems in clinical trial design.<br><br>OBJECTIVE: To demonstrate that simple clinical variables can be used to construct a robust predictive model for survival, and to assess the effect of a known treatment within this model.<br><br>METHODS: We carried out a retrospective multivariate modelling of a database of 841 patients with ALS seen over a 10-year period in a specialist motor neuron disorders clinic. The use of riluzole was tested as a prognostic factor within the model.<br><br>RESULTS: A prognostic score generated from one cohort of patients predicted survival for a second cohort of patients (r(2) = 0.78). Prognostic variables included site of onset, age of onset, time from symptom onset to diagnosis, and El Escorial category at presentation. Riluzole therapy was an independently significant prognostic factor (relative risk of death 0.48, P < 0.0001, model chi(2) 297, P < 0.0001).<br><br>CONCLUSIONS: Clinical databases can be used to generate multivariate prognostic models in ALS. Such models could be used to predict survival, to improve criteria for matching of patients in future clinical trials, and to test the impact of interventions.}, }
@article {pmid12061943, year = {2002}, author = {Lechtzin, N and Rothstein, J and Clawson, L and Diette, GB and Wiener, CM}, title = {Amyotrophic lateral sclerosis: evaluation and treatment of respiratory impairment.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {3}, number = {1}, pages = {5-13}, doi = {10.1080/146608202317576480}, pmid = {12061943}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*complications/physiopathology/therapy ; Humans ; Positive-Pressure Respiration ; Respiration, Artificial ; Respiratory Function Tests ; Respiratory Insufficiency/*diagnosis/etiology/*therapy ; *Respiratory Mechanics ; Respiratory Muscles/physiopathology ; Respiratory Therapy ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) invariably develop respiratory muscle weakness and most die from pulmonary complications. There are numerous tests available to evaluate respiratory status in ALS and it is important to understand their various advantages and limitations. Forced vital capacity (FVC) is commonly used but can remain normal despite substantial inspiratory muscle weakness. Maximal pressures measured at the mouth are useful for excluding weakness if they are normal but are difficult to interpret if abnormal. Invasive testing, such as measurement of transdiaphragmatic pressure, provides an accurate measure of inspiratory strength but is not readily available and is not practical for serial measures. There are supportive respiratory techniques that have been shown to benefit patients with ALS. Clinicians should be familiar with these interventions, including mechanically assisted coughing, non-invasive ventilation and tracheostomy with mechanical ventilation. Observational studies have demonstrated improved survival and quality of life with noninvasive ventilation. Tracheostomy with long-term mechanical ventilation is not frequently used but can be an important component of care for ALS. This review describes an approach to respiratory evaluation and care of patients with ALS.}, }
@article {pmid12058891, year = {2002}, author = {Koyama, S and Aizawa, H and Haga, T and Nakatani-Enomoto, S and Kikuchi, K}, title = {An autopsy case of amyotrophic lateral sclerosis accompanied by syndrome of inappropriate secretion of antidiuretic hormone.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {41}, number = {5}, pages = {395-397}, doi = {10.2169/internalmedicine.41.395}, pmid = {12058891}, issn = {0918-2918}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/pathology ; Autopsy ; Humans ; Hyponatremia/etiology ; Inappropriate ADH Syndrome/*complications/pathology ; Male ; Respiratory Insufficiency/etiology ; Syndrome ; }, abstract = {We report an autopsy-confirmed case of amyotrophic lateral sclerosis (ALS) accompanied by syndrome of inappropriate secretion of antidiuretic hormone (SIADH). A 67-year-old man was admitted to our hospital with muscle weakness, dysarthria and dysphagia. During hospitalization, respiratory insufficiency was ingravescent, and hyponatremia, hypo-osmolarity, elevated osmotic pressure of urine, and elevated urinary sodium excretion were noted. Based on these findings we diagnosed ALS with SIADH, and treatment with infusion of concentrated NaCl was started. However, the patient died of respiratory failure on day 50. We assumed that severely restrictive ventilatory impairment was the cause of SIADH in this case.}, }
@article {pmid12058084, year = {2002}, author = {Visser, J and van den Berg-Vos, RM and Franssen, H and van den Berg, LH and Vogels, OJ and Wokke, JH and de Jong, JM and de Visser, M}, title = {Mimic syndromes in sporadic cases of progressive spinal muscular atrophy.}, journal = {Neurology}, volume = {58}, number = {11}, pages = {1593-1596}, doi = {10.1212/wnl.58.11.1593}, pmid = {12058084}, issn = {0028-3878}, mesh = {Adult ; Aged ; Aged, 80 and over ; Diagnosis, Differential ; *Diagnostic Errors ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/diagnosis ; Muscular Atrophy, Spinal/*diagnosis ; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis ; Prospective Studies ; }, abstract = {Described are patients initially diagnosed with progressive spinal muscular atrophy (PSMA), in whom further evaluation established another diagnosis. The authors prospectively investigated incident and prevalent cases of PSMA. Seventeen of 89 patients, after initial registration, were later excluded because reassessment revealed a diagnosis other than PSMA. In 11 of the 17 patients with a revised diagnosis, a potential treatment was available: multifocal motor neuropathy (7), chronic inflammatory demyelinating polyneuropathy (2), inflammatory myopathy (1), and MG (1). Other misdiagnoses included myopathy, syringomyelia, ALS, idiopathic chronic axonal polyneuropathy, and idiopathic brachial plexus neuropathy. One patient with a possible herniated lumbar disk recovered spontaneously.}, }
@article {pmid12052096, year = {2002}, author = {Ginsberg, G and Lowe, S}, title = {Cost effectiveness of treatments for amyotrophic lateral sclerosis: a review of the literature.}, journal = {PharmacoEconomics}, volume = {20}, number = {6}, pages = {367-387}, pmid = {12052096}, issn = {1170-7690}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*economics/*therapy ; Cost-Benefit Analysis ; Drug Costs ; Excitatory Amino Acid Antagonists/*economics/therapeutic use ; Forecasting ; Humans ; Insulin-Like Growth Factor I/*economics/therapeutic use ; Quality-Adjusted Life Years ; Respiration, Artificial/*economics/methods ; Riluzole/*economics/therapeutic use ; Risk Factors ; Survival Rate ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a difficult to diagnose, fatal, progressive degenerative disease with an average survival time of 2 to 5 years. Percutaneous endoscopic gastrotomy (PEG) and bi-level intermittent positive pressure (BIPAP) ventilation may be the major interventions leading to longer survival of patients with ALS. Riluzole has been shown to have modest effects on survival (as opposed to functional) gains and is currently the only drug approved for the treatment of ALS. There is conflicting evidence with regard to the ability of recombinant human insulin-like growth factor (rhIGF-I) to retard ALS progression. Mechanical ventilation (via a tracheostomy tube) is expensive, but is widely used in later stage patients with ALS in the US. A review of nine cost-effectiveness studies of riluzole and one of rhIGF-I found the following: drug costs and survival gains are the major drivers of cost effectiveness; survival gains are estimated from truncated databases with a high degree of uncertainty; more accurate stage-specific utility weights based on patients who agreed to treatment are needed; case incidence-based evaluations should be carried out; cost-effectiveness ratios are insensitive to discount rates; employment and caregiver issues or externalities have been widely ignored; threshold acceptance cost-effectiveness values are ill-defined and evaluations are not generalisable to other countries because of cost and treatment style differences. On account of the high degree of uncertainty pertaining to survival gains and the relatively high costs per life years or quality-adjusted life-years gained, and while acknowledging that not every therapy has to be cost effective (e.g. orphan drugs), it is still inconclusive as to whether or not riluzole or rhIGF-1 can be considered as cost-effective therapies for ALS.}, }
@article {pmid12032289, year = {2002}, author = {Kondo, M and Shibata, T and Kumagai, T and Osawa, T and Shibata, N and Kobayashi, M and Sasaki, S and Iwata, M and Noguchi, N and Uchida, K}, title = {15-Deoxy-Delta(12,14)-prostaglandin J(2): the endogenous electrophile that induces neuronal apoptosis.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {99}, number = {11}, pages = {7367-7372}, pmid = {12032289}, issn = {0027-8424}, mesh = {Adult ; Aged ; Apoptosis/*drug effects ; Female ; Flow Cytometry ; Gene Expression Regulation/drug effects ; Genes, p53 ; Humans ; Immunologic Factors/*pharmacology ; Male ; Middle Aged ; Motor Neuron Disease/pathology ; Motor Neurons/drug effects/pathology/physiology ; Neuroblastoma ; Neurons/cytology/*physiology ; Oligonucleotide Array Sequence Analysis ; Prostaglandin D2/*analogs &amp; derivatives/analysis/*pharmacology ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/genetics ; }, abstract = {Prostaglandin D(2) (PGD(2)), a major cyclooxygenase product in a variety of tissues and cells, readily undergoes dehydration to yield the bioactive cyclopentenone-type PGs of the J(2)-series, such as 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)). The observation that the level of 15d-PGJ(2) increased in the tissue cells from patients with sporadic amyotrophic lateral sclerosis suggested that the formation of 15d-PGJ(2) may be closely associated with neuronal cell death during chronic inflammatory processes. In vitro experiments using SH-SY5Y human neuroblastoma cells revealed that 15d-PGJ(2) induced apoptotic cell death. An oligonucleotide microarray analysis demonstrated that, in addition to the heat shock-responsive and redox-responsive genes, the p53-responsive genes, such as gadd45, cyclin G1, and cathepsin D, were significantly up-regulated in the cells treated with 15d-PGJ(2). Indeed, the 15d-PGJ(2) induced accumulation and phosphorylation of p53, which was accompanied by a preferential redistribution of the p53 protein in the nuclei of the cells and by a time-dependent increase in p53 DNA binding activity, suggesting that p53 accumulated in response to the treatment with 15d-PGJ(2) was functional. The 15d-PGJ(2)-induced accumulation of p53 resulted in the activation of a death-inducing caspase cascade mediated by Fas and the Fas ligand.}, }
@article {pmid12030918, year = {2002}, author = {Van den Berghe, G and Baxter, RC and Weekers, F and Wouters, P and Bowers, CY and Iranmanesh, A and Veldhuis, JD and Bouillon, R}, title = {The combined administration of GH-releasing peptide-2 (GHRP-2), TRH and GnRH to men with prolonged critical illness evokes superior endocrine and metabolic effects compared to treatment with GHRP-2 alone.}, journal = {Clinical endocrinology}, volume = {56}, number = {5}, pages = {655-669}, doi = {10.1046/j.1365-2265.2002.01255.x}, pmid = {12030918}, issn = {0300-0664}, support = {R01 AG 14799/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Case-Control Studies ; Critical Illness/*therapy ; Drug Therapy, Combination ; Gonadotropin-Releasing Hormone/*therapeutic use ; Growth Hormone/blood ; Humans ; Luteinizing Hormone/blood ; Male ; Middle Aged ; Oligopeptides/*therapeutic use ; Prospective Studies ; Thyrotropin/blood ; Thyrotropin-Releasing Hormone/*therapeutic use ; }, abstract = {OBJECTIVE: Central hyposomatotrophism, hypothyroidism and hypogonadism are present concomitantly in men with prolonged critical illness. This study evaluated the impact of combined treatment with GH-releasing peptide-2 (GHRP-2), TRH and GnRH for 5 days compared with GHRP-2 + TRH and with GHRP-2 alone.<br><br>PATIENTS AND DESIGN: Thirty-three men with prolonged critical illness participated at baseline compared to 50 age- and body mass index (BMI)-matched controls. Patients were randomly assigned to 5 days of placebo (n = 7), GHRP-2 (1 microg/kg/h; n = 9), GHRP-2 + TRH infusion (1 + 1 microg/kg/h; n = 9) or pulsatile GnRH (0.1 microg/kg every 90 min) together with GHRP-2 + TRH infusion (n = 8).<br><br>MEASUREMENTS: GH, TSH and LH secretion were quantified by deconvolution analysis of serum concentration time series obtained by sampling every 20 min from 2100 to 0600 h at baseline and on nights 1 and 5 of treatment. Serum concentrations of IGF-I, IGFBPs, thyroid hormones, gonadal and adrenal steroids, proinflammatory cytokines and selected metabolic and inflammation markers were measured daily.<br><br>RESULTS: Patients revealed suppressed pulsatile GH, TSH and LH secretion in the face of low serum concentrations of IGF-I, IGFBP-3 and the acid-labile subunit (ALS) (P < 0.0001 each), thyroid hormones (P < 0.0001) and total and estimated free testosterone (P < 0.0001) levels, whereas free oestradiol (E2) estimates were normal. Serum dehydroepiandrosterone sulphate (DHEAS) levels were also suppressed whereas morning cortisol was normal. Serum levels of type I procollagen (PICP) and bone alkaline phosphatase (sALP) were elevated whereas osteocalcin (OC) was low (P = 0.03). Ureagenesis (P < 0.0001) and breakdown of bone tissue (P < 0.0001) were increased. Baseline serum TNF-alpha, IL-6 and C-reactive protein level and white blood cell (WBC) count were elevated; serum lactate was normal. Only low T4 and high IGFBP-1 levels independently predicted mortality. GHRP-2 infusion reactivated GH secretion and normalized serum IGF-I, IGFBP-3 and ALS. GHRP-2 + TRH infusion reactivated both the GH axis and the thyroid axis, with normal levels of T4 and T3 reached within 1 day. Only GHRP-2 + TRH infusion combined with GnRH pulses reactivated the GH and TSH axis and at the same time increased pulsatile LH secretion compared to placebo. Only GnRH pulses together with GHRP-2 + TRH infusion increased testosterone significantly from day 2 (peak increase of + 312%) through day 5 and serum E2 with > 80% from day 1 through day 3 (all P = 0.05). Ureagenesis was reduced by GHRP-2 + TRH + GnRH (P = 0.01) and by GHRP-2 + TRH (P = 0.009) but not by GHRP-2 alone. Serum OC levels were increased only by GHRP-2 + TRH + GnRH (P = 0.03), with a trend for GHRP-2 + TRH (P = 0.09), but not by GHRP-2 alone. On day 5, serum lactate levels and WBC count were increased by GHRP-2 infused alone and in combination with TRH but not by GHRP-2 + TRH + GnRH.<br><br>CONCLUSIONS: Coadministration of GHRP-2, TRH and GnRH reactivated the GH, TSH and LH axes in prolonged critically ill men and evoked beneficial metabolic effects which were absent with GHRP-2 infusion alone and only partially present with GHRP-2 + TRH. These data underline the importance of correcting the multiple hormonal deficits in patients with prolonged critical illness to counteract the hypercatabolic state.}, }
@article {pmid12023997, year = {2002}, author = {Veldink, JH and Wokke, JH and van der Wal, G and Vianney de Jong, JM and van den Berg, LH}, title = {Euthanasia and physician-assisted suicide among patients with amyotrophic lateral sclerosis in the Netherlands.}, journal = {The New England journal of medicine}, volume = {346}, number = {21}, pages = {1638-1644}, doi = {10.1056/NEJMsa012739}, pmid = {12023997}, issn = {1533-4406}, mesh = {Advance Directives ; *Amyotrophic Lateral Sclerosis/classification ; Cohort Studies ; Decision Making ; Euthanasia/*statistics &amp; numerical data ; *Euthanasia, Active, Voluntary ; Humans ; Netherlands ; Regression Analysis ; Religion ; Severity of Illness Index ; Suicide, Assisted/*statistics &amp; numerical data ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease that causes progressive paralysis leading to respiratory failure. Patients with ALS may consider physician-assisted suicide. However, it is not known how many patients, if given the option, would actually decide to end their lives by physician-assisted suicide or euthanasia nor at what stage of the disease they would choose to do so.<br><br>METHODS: We identified physicians of 279 patients in the Netherlands with a diagnosis of ALS who died between 1994 and 1999. Physicians were asked to fill out a validated questionnaire about the end-of-life decisions that were made. Of 241 eligible physicians, 203 returned the questionnaire (84 percent).<br><br>RESULTS: Of the 203 patients, 35 (17 percent) chose euthanasia and died that way. An additional six patients (3 percent) died as a result of physician-assisted suicide. Patients to whom religion was important were less likely to have died as a result of euthanasia or physician-assisted suicide. The choice of euthanasia or physician-assisted suicide was not associated with any particular characteristics of the disease or of the patient's care, nor was it associated with income or educational level. Disability before death was significantly more severe in patients who died as a result of euthanasia than among those who died in other ways. Physician-assisted suicide appeared to occur somewhat earlier in the course of the disease than did euthanasia. An additional 48 patients (24 percent) received palliative treatment, which probably shortened their lives.<br><br>CONCLUSIONS: In the Netherlands, we found that one in five patients with ALS died as a result of euthanasia or physician-assisted suicide.}, }
@article {pmid12023539, year = {2002}, author = {Ferzaz, B and Brault, E and Bourliaud, G and Robert, JP and Poughon, G and Claustre, Y and Marguet, F and Liere, P and Schumacher, M and Nowicki, JP and Fournier, J and Marabout, B and Sevrin, M and George, P and Soubrie, P and Benavides, J and Scatton, B}, title = {SSR180575 (7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide), a peripheral benzodiazepine receptor ligand, promotes neuronal survival and repair.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {301}, number = {3}, pages = {1067-1078}, doi = {10.1124/jpet.301.3.1067}, pmid = {12023539}, issn = {0022-3565}, mesh = {Acetamides/chemistry/*metabolism/*pharmacology ; Aging/drug effects/physiology ; Animals ; Anti-Anxiety Agents/metabolism ; Axotomy ; Binding, Competitive ; Cell Survival/drug effects/physiology ; Facial Nerve/drug effects/metabolism ; *GABA-A Receptor Agonists ; GABA-A Receptor Antagonists ; Humans ; Imidazoles/metabolism ; Indoles/chemistry/*metabolism/*pharmacology ; Ligands ; Male ; Motor Neurons/*drug effects/metabolism ; Neuroprotective Agents/chemistry/metabolism/*pharmacology ; Pyridazines/chemistry/metabolism/pharmacology ; Pyridines/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA-A/metabolism ; }, abstract = {In the present study, we have investigated the potential neuroprotective effects of a novel peripheral benzodiazepine binding site (PBR) ligand, 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575), in models of central and peripheral neurodegeneration in vivo and its effect on steroid concentrations in plasma and nervous tissue. SSR180575 shows high affinity (IC(50), 2.5-3.5 nM) and selectivity for the rat and human PBR and potently inhibits the in vivo binding of [(3)H]alpidem to PBR in the rat brain and spleen after oral or i.p. administration (ID(50), 0.1-0.3 mg/kg). In an experimental model of motoneuron degeneration induced by facial nerve axotomy in the immature rat, SSR180575 given i.p. or orally for 8 days rescued facial motoneurons, increasing their survival by 40 to 72% at 6 and 10 mg/kg p.o. b.i.d. Moreover, in this model, SSR180575 (10 mg/kg p.o. b.i.d.) increased by 87% the number of motoneurons immunoreactive to peripherin, a type III intermediate filament, whose expression is up-regulated during nerve regeneration. SSR180575 also improved functional recovery in acrylamide-induced neuropathy in the rat when given therapeutically at 2.5 to 10 mg/kg/day p.o. Furthermore, SSR180575 (3 mg/kg i.p. b.i.d.) accelerated functional recovery of the blink reflex after local injury of the facial nerve in the rat. SSR180575 increased pregnenolone accumulation in the brain and sciatic nerve (+100% at 3 mg/kg i.p.), suggesting that its neuroprotective effects are steroid-mediated. These results indicate that PBR ligands (e.g., SSR180575) promote neuronal survival and repair in axotomy and neuropathy models and have potential for the treatment of neurodegenerative diseases (e.g., peripheral neuropathies or amyotrophic lateral sclerosis).}, }
@article {pmid12021952, year = {2002}, author = {Bensimon, G and Lacomblez, L and Delumeau, JC and Bejuit, R and Truffinet, P and Meininger, V and , }, title = {A study of riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {249}, number = {5}, pages = {609-615}, doi = {10.1007/s004150200071}, pmid = {12021952}, issn = {0340-5354}, mesh = {Age Factors ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Disease Progression ; Double-Blind Method ; Drug Tolerance/*physiology ; Female ; Humans ; Male ; Middle Aged ; Multicenter Studies as Topic ; Neuroprotective Agents/*administration &amp; dosage/adverse effects ; Patient Selection ; Riluzole/*administration &amp; dosage/*adverse effects ; Survival Rate ; Treatment Outcome ; }, abstract = {Treatment with the neuroprotective drug riluzole has previously been shown to increase the probability of survival in patients with amyotrophic lateral sclerosis. This report describes a placebo-controlled, double-blind randomised clinical trial of riluzole carried out in ALS patients with advanced stage disease or aged over 75 years. The primary objective was to enable access to treatment to patients excluded from the pivotal trial which was run in parallel. Another goal was to assess the safety of riluzole in patients with advanced-stage disease. One hundred and sixty-eight patients were included, randomised to either riluzole 50 mg b. i. d. or to placebo, and treated for eighteen months. Riluzole was well-tolerated in this patient population, and the adverse events observed were similar in nature and frequency to those observed in previously published clinical trials in patients included in pivotal trials. The study could not include enough patients to reach adequate power to detect differences in survival between the two treatment groups, and no such difference was in fact observed. In conclusion, riluzole is well-tolerated in ALS patients with advanced stage disease.}, }
@article {pmid12021937, year = {2002}, author = {Borasio, GD}, title = {Riluzole treatment in advanced ALS.}, journal = {Journal of neurology}, volume = {249}, number = {5}, pages = {505-506}, pmid = {12021937}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Disease Progression ; Humans ; Medical Futility ; Neuroprotective Agents/*therapeutic use ; Patient Education as Topic ; Patient Selection ; Riluzole/*therapeutic use ; Survival Rate ; }, }
@article {pmid11994965, year = {2002}, author = {Magnus, T and Beck, M and Giess, R and Puls, I and Naumann, M and Toyka, KV}, title = {Disease progression in amyotrophic lateral sclerosis: predictors of survival.}, journal = {Muscle &amp; nerve}, volume = {25}, number = {5}, pages = {709-714}, doi = {10.1002/mus.10090}, pmid = {11994965}, issn = {0148-639X}, mesh = {Age of Onset ; Aged ; Amyotrophic Lateral Sclerosis/epidemiology/*physiopathology ; Disease Progression ; Extremities/physiopathology ; Female ; Humans ; Male ; Medulla Oblongata/physiopathology ; Middle Aged ; Prognosis ; Retrospective Studies ; Survival Analysis ; }, abstract = {Predicting the rate of disease progression has become important as trials of new medical treatments for amyotrophic lateral sclerosis (ALS) are planned. Bulbar onset, early impairment of forced vital capacity, and older age have all been associated with shorter survival. We performed a retrospective study to compare survival factors with disease progression in a German ALS population. We analyzed disease progression in 155 patients at intervals of 4 months over a period of 3 years. To evaluate disease progression, the ALS functional rating scale (ALS-FRS), forced vital capacity (FVC%), and a Medical Research Council (MRC) compound score based on a nine-step modified MRC scale were used. We compared age (< 55 years vs. > or =55 years), different sites of disease onset (bulbar vs. limb), and gender to the rate of disease progression and performed survival analyses. No overall significant difference could be detected when analyzing these subgroups with regard to disease progression. By contrast, significantly longer survival was observed in the younger age group (56 months vs. 38 months, P < 0.0001) and in patients with limb-onset disease (51 months vs. 37 months, P = 0.0002). Using Cox analyses values we found that the declines of ALS-FRS, FVC%, and MRC compound score were predictive of survival (P < 0.0001, P = 0.002, and P = 0.003, respectively). Future studies are needed to clarify whether nonspecific factors including muscle atrophy, dysphagia, and coexisting diseases influence prediction of survival in ALS patients. A more precise set of predictors may help to better stratify patient subgroups for future treatment trials.}, }
@article {pmid11985383, year = {2002}, author = {Jenkinson, C and Hobart, J and Chandola, T and Fitzpatrick, R and Peto, V and Swash, M and , }, title = {Use of the short form health survey (SF-36) in patients with amyotrophic lateral sclerosis: tests of data quality, score reliability, response rate and scaling assumptions.}, journal = {Journal of neurology}, volume = {249}, number = {2}, pages = {178-183}, doi = {10.1007/pl00007861}, pmid = {11985383}, issn = {0340-5354}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/physiopathology/*psychology ; Disability Evaluation ; Female ; *Health Status ; *Health Surveys ; Humans ; Male ; Middle Aged ; Patient Compliance ; Quality of Life/psychology ; Reproducibility of Results ; Statistics as Topic ; *Surveys and Questionnaires ; }, abstract = {OBJECTIVES: To evaluate response rate, data quality, score reliability and scaling assumptions of the 36 item Short Form Health Survey (SF-36) in a large scale pan European survey of amyotrophic lateral sclerosis (ALS) patients.<br><br>DESIGN: A questionnaire based survey of patients diagnosed with ALS across 15 European countries. SAMPLE PATIENTS: presenting at neurological clinics for treatment of their condition were asked to partake in the survey.<br><br>RESULTS: 948 patients have been recruited into the survey, from whom responses have been gained in 754 (79.5%). Scores on the eight dimensions of the SF-36 were found to manifest high internal consistency reliability. Items were, in most instances, found to be most highly correlated with their own (corrected) scale score than with other scale scores. However, on two dimensions (role-physical and role-emotional) there was high levels of missing data, together with substantial floor and ceiling effects. The two factor model (of underlying constructs of physical and emotional health) for the SF-36 suggested by the developers was not supported in this patient group. CONCLUSION The SF-36 appears to provide reliable information for this patient group, and for the most part there are high levels of item completeness and good spread of scores. This is not, however, true for the role functioning dimensions. Furthermore, the underlying two factor model for the SF-36 was not supported. The implications for measuring health status in this patient group are discussed.}, }
@article {pmid11975725, year = {2002}, author = {Gaston, S and Zabalza, A and González, EM and Arrese-Igor, C and Aparicio-Tejo, PM and Royuela, M}, title = {Imazethapyr, an inhibitor of the branched-chain amino acid biosynthesis, induces aerobic fermentation in pea plants.}, journal = {Physiologia plantarum}, volume = {114}, number = {4}, pages = {524-532}, doi = {10.1034/j.1399-3054.2002.1140404.x}, pmid = {11975725}, issn = {1399-3054}, abstract = {Acetolactate synthase (ALS; EC 4.1.3.18) inhibition is the primary mechanism of action of imazethapyr (IM). However, the precise mechanisms that links ALS inhibition with plant death have not been elucidated. Supply of IM to pea (Pisum sativum L) plants produced an immediate cessation of growth, caused a 50% inhibition of the in vivo ALS activity within 1 day of treatment, and a remarkable accumulation (2.7-times) of free amino acids after 3 days. Carbohydrates (soluble and starch) were accumulated in both leaves and roots. Accumulation of soluble sugars in roots preceded that of starch in leaves, suggesting that the accumulation of carbohydrates in leaves is not the reason for the arrested root growth. A transient pyruvate accumulation was observed in roots, 1 day after the onset of IM supply. This was coincident with an increase in pyruvate decarboxylase (EC 4.1.1.1), and later increases in alcohol dehydrogenase (EC 1.1.1.1), lactate dehydrogenase (EC 1.1.1.27), and alanine amino transferase (EC 2.6.1.2) activities. This enhancement of fermentative activities was coincident with a slight decrease in aerobic respiration. The overall data suggest that the impairment of ALS activity may lead to a fermentative metabolism that may be involved in growth inhibition and plant death.}, }
@article {pmid11972141, year = {2002}, author = {Nguimfack Mbodie, PC}, title = {[Do the glutamate excitotoxicity theory and potential free radicals implication in schizophrenia aetiopathogenesis provide a new enlightenment to links between: genome, environment and biology in the determinism of that disorder?].}, journal = {L'Encephale}, volume = {28}, number = {2}, pages = {147-153}, pmid = {11972141}, issn = {0013-7006}, mesh = {Environment ; Free Radicals/*metabolism ; Glutamates/*metabolism ; Humans ; Neurotoxins/*metabolism ; Schizophrenia/*etiology/*metabolism ; Systems Theory ; }, abstract = {The aetiopathogenesis of schizophrenia constitutes nowadays one of the major points of interest for researchers on this cosmopolitan disorder which involves about 1% of the world population and which significantly alters the social functioning of the individual. Numerous studies have focused on the role played by genome, environmental factors and biology in the development of symptoms. The neurodevelopmental theory is an illustration with the perinatal period considered as the main provider of environmental factors (hypertension, infections, bleedings during pregnancy, acute and chronic fetal distress.). Many authors found significant associations between such factors, the occurrence of brain lesions and finally schizophrenic symptoms. Although no convincing genetic model had been established to date for schizophrenia, nevertheless it appears that a predisposition not inheritable under the mendelian mode exists and authors showed that disease gets more and more severe over schizophrenic descendants. The risk to be schizophrenic being a first degree relative of the schizophrenic person is about ten time superior than in general population. Indeed, this risk is also about ten time superior in biological parents of schizophrenic adoptees than in biological parents of healthy adoptees. Studies done in monozygotic comparing to dizygotic twins are in favour of an important role played by genetic factors more than socioeducational or psychological factors. Concerning biology, the dopaminergic hypothesis remains shared by numerous authors although direct links with incriminated factors are not well established. Now is suspected the glutamate excitotoxicity with implication of free radicals in schizophrenia. These free radicals are products of various enzymatic activations led by overstimulation of post synaptic receptors (NMDA and AMPA) by the excess glutamate. Therefore, according to that concept, some amino acids as glutamate and derivatives could have through free radicals a noxious effect on neuronal synapses. This could be due to a failing of their recapture at the presynaptic level in addition to a dysfunctioning of the antioxidizing system (glutathion, carnosine, superoxide dismutase, aspartate) to which dopamine and other monoamines might participate. The question is whether or not this theory contributes to shed light on links between: genome, environmental factors and biology in schizophrenia. Through the review and discussion of genetical aspects of schizophrenia, environmental factors and the biological aspect, we intend to revive debate on that question. The articles and authors were selected with regard to the aptness of their publications on that subject, their evolving ideas and finally the interest of their works for neurosciences. This new approach perhaps is opening the way to new therapeutic perspectives in the treatment of schizophrenia based on the antioxidizing substances as shown for some neurological diseases (amyotrophic lateral sclerosis, Parkinson's disease and Huntington's chorea) for which experiments are going on.}, }
@article {pmid11971099, year = {2002}, author = {Almer, G and Teismann, P and Stevic, Z and Halaschek-Wiener, J and Deecke, L and Kostic, V and Przedborski, S}, title = {Increased levels of the pro-inflammatory prostaglandin PGE2 in CSF from ALS patients.}, journal = {Neurology}, volume = {58}, number = {8}, pages = {1277-1279}, doi = {10.1212/wnl.58.8.1277}, pmid = {11971099}, issn = {0028-3878}, support = {NS42269/NS/NINDS NIH HHS/United States ; P50 NS38370/NS/NINDS NIH HHS/United States ; R01 NS38586/NS/NINDS NIH HHS/United States ; R29 NS37345/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*cerebrospinal fluid ; Biomarkers ; Dinoprostone/*cerebrospinal fluid ; Female ; Humans ; Immunoassay ; Luminescent Measurements ; Male ; Middle Aged ; }, abstract = {Levels of the potent pro-inflammatory prostaglandin E(2) (PGE(2)) are elevated in postmortem spinal cords from patients with ALS, and inhibition of a key PGE(2)-synthesizing enzyme, cylcooxygenase-2, is neuroprotective in an in vitro model of ALS. The authors report that 82% of the patients with ALS studied had 2 to 10 times higher PGE(2) levels in CSF compared with normal control subjects. That affected areas of the CNS are inflamed in ALS supports this. CSF PGE(2) measurement may be useful in monitoring treatment for ALS.}, }
@article {pmid11958731, year = {2001}, author = {Peto, V and Jenkinson, C and Fitzpatrick, R and Swash, M}, title = {Measuring mental health in amyotrophic lateral sclerosis (ALS): a comparison of the SF-36 Mental Health Index with the Psychological General Well-Being Index.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2}, number = {4}, pages = {197-201}, doi = {10.1080/14660820152882205}, pmid = {11958731}, issn = {1466-0822}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*epidemiology/*psychology ; Europe/epidemiology ; Female ; Health Surveys ; Humans ; Male ; *Mental Health/statistics &amp; numerical data ; Middle Aged ; *Psychological Tests/statistics &amp; numerical data ; }, abstract = {OBJECT: The purpose of this study was to compare the performance of the five-item mental health dimension of SF-36 (the Mental Health Index, MHI-5) with that of the 22-item Psychological General Well-Being Index (PGWB) in patients presenting with amyotrophic lateral sclerosis/motor neuron disease, using tests of reliability and validity.<br><br>DESIGN: A questionnaire-based survey of patients diagnosed with ALS across 15 European countries.<br><br>SAMPLE: Patients presenting at neurological clinics for treatment of their ALS were asked to join the survey.<br><br>RESULTS: 1048 patients with ALS have been recruited, of whom 861 (82.2%) have returned baseline questionnaires. There was evidence supporting the internal consistency of both instruments, and for their construct validity in distinguishing between groups, in terms of gender and age. The scores on the two instruments were highly correlated (Spearman rank correlation 0.85).<br><br>CONCLUSION: Both the MHI-5 and the PGWB showed high levels of construct validity and internal reliability in this patient group. The MHI-5 has comparable psychometric performance to the PGWB, and can be used to measure and compare mental health in defined populations.}, }
@article {pmid11939461, year = {2002}, author = {Poulsen, DJ and Harrop, JS and During, MJ}, title = {Gene therapy for spinal cord injury and disease.}, journal = {The journal of spinal cord medicine}, volume = {25}, number = {1}, pages = {2-9}, doi = {10.1080/10790268.2002.11753594}, pmid = {11939461}, issn = {1079-0268}, mesh = {*Genetic Therapy ; Humans ; Spinal Cord Diseases/*genetics/pathology/*therapy ; Spinal Cord Injuries/*genetics/pathology/*therapy ; }, abstract = {An incomplete understanding of the pathological processes involved in neurodegeneration and dysfunction of spinal cord injuries and diseases makes these disorders difficult to treat. Repair of damaged or genetically impaired spinal cord also has been limited by the complexity, cellular heterogeneity, and relative inaccessibility of the tissue. Thus, therapeutic options for the treatment of either chronic spinal cord diseases such as amyotrophic lateral sclerosis or acute spinal cord injuries have been rather limited. Potential new therapeutic targets are being identified as our understanding of the molecular pathology involved in neural injury and regeneration increases. Recent advances in gene transfer techniques have made gene therapy a more realistic and viable strategy for the treatment of a broad range of spinal cord disorders. This review summarizes the current state of knowledge regarding the limitations and recent advances in gene therapy and potential application of this technology toward spinal cord injury and disease.}, }
@article {pmid11930144, year = {2002}, author = {Sung, JJ and Kim, HJ and Choi-Kwon, S and Lee, J and Kim, M and Lee, KW}, title = {Homocysteine induces oxidative cytotoxicity in Cu,Zn-superoxide dismutase mutant motor neuronal cell.}, journal = {Neuroreport}, volume = {13}, number = {4}, pages = {377-381}, doi = {10.1097/00001756-200203250-00003}, pmid = {11930144}, issn = {0959-4965}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics ; Cell Survival/drug effects/genetics ; Dose-Response Relationship, Drug ; Homocysteine/*toxicity ; Humans ; Motor Neurons/cytology/*drug effects/*enzymology ; Mutation/*genetics ; Oxidative Stress/*drug effects/genetics ; Superoxide Dismutase/*genetics ; Tumor Cells, Cultured ; }, abstract = {Mutations in human Cu,Zn-superoxide dismutase (SOD1) cause approximately 20% of familial amyotrophic lateral sclerosis (FALS) cases. The mechanism of late-onset disease manifestation despite the innate mutation has no clear explanation. The relationship between homocysteine (HC) and amyotrophic lateral sclerosis (ALS) has not been investigated, in spite of the similarity in their pathogenesis. We investigated the effect of HC on the motor neuronal cell-line transfected with SOD1 of either wild-type or one of two mutant forms (G93A and A4V). In the MTT assay, HC induced significant cytotoxicity in A4V, but not in G93A, as compared with wild-type, even at the physiological concentration of 10 microM. This HC-induced cytotoxicity was inhibited by the antioxidant trolox and the Cu (I) chelator bathocuproinedisulfonate. Here we show that the vulnerability of the A4 V mutant involves the cytotoxic copper-mediated pathway, and that HC may be a lifelong precipitating factor in some forms of FALS, suggesting the possible treatment modality with vitamin supplements.}, }
@article {pmid11905995, year = {2002}, author = {Liu, R and Li, B and Flanagan, SW and Oberley, LW and Gozal, D and Qiu, M}, title = {Increased mitochondrial antioxidative activity or decreased oxygen free radical propagation prevent mutant SOD1-mediated motor neuron cell death and increase amyotrophic lateral sclerosis-like transgenic mouse survival.}, journal = {Journal of neurochemistry}, volume = {80}, number = {3}, pages = {488-500}, doi = {10.1046/j.0022-3042.2001.00720.x}, pmid = {11905995}, issn = {0022-3042}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism/mortality ; Animals ; Antioxidants/metabolism ; Cell Death/drug effects/physiology ; Cells, Cultured ; Cyclic N-Oxides/pharmacology ; Electron Transport Complex IV/metabolism ; Glutathione Peroxidase/genetics ; Lipid Peroxidation/drug effects/physiology ; Mice ; Mice, Transgenic ; Mitochondria/*metabolism ; Motor Neurons/cytology/*metabolism ; Oxidative Stress/drug effects/physiology ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Survival Rate ; }, abstract = {The molecular mechanisms of selective motor neuron degeneration in human amyotrophic lateral sclerosis (ALS) disease remain largely unknown and effective therapies are not currently available. Mitochondrial dysfunction is an early event of motor neuron degeneration in transgenic mice overexpressing mutant superoxide dismutase (SOD)1 gene and mitochondrial abnormality is observed in human ALS patients. In an in vitro cell culture system, we demonstrated that infection of mouse NSC-34 motor neuron-like cells with adenovirus containing mutant G93A-SOD1 gene increased cellular oxidative stress, mitochondrial dysfunction, cytochrome c release and motor neuron cell death. Cells pretreated with highly oxidizable polyunsaturated fatty acid elevated lipid peroxidation and synergistically exacerbated motor neuron-like cell death with mutant G93A-SOD1 but not with wild-type SOD1. Similarly, overexpression of mitochondrial antioxidative genes, MnSOD and GPX4 by stable transfection significantly increased NSC-34 motor neuron-like cell resistance to mutant SOD1. Pre-incubation of cells with spin trapping molecule, 5',5'-dimethylpryrroline-N-oxide (DMPO), prevented mutant SOD1-mediated mitochondrial dysfunction and cell death. Furthermore, treatment of mutant G93A-SOD1 transgenic mice with DMPO significantly delayed paralysis and increased survival. These findings suggest a causal relationship between enhanced oxidative stress and mutant SOD1-mediated motor neuron degeneration, considering that enhanced oxygen free radical production results from the SOD1 structural alterations. Molecular approaches aimed at increasing mitochondrial antioxidative activity or effectively blocking oxidative stress propagation can be potentially useful in the clinical management of human ALS disease.}, }
@article {pmid11889242, year = {2002}, author = {Suhy, J and Miller, RG and Rule, R and Schuff, N and Licht, J and Dronsky, V and Gelinas, D and Maudsley, AA and Weiner, MW}, title = {Early detection and longitudinal changes in amyotrophic lateral sclerosis by (1)H MRSI.}, journal = {Neurology}, volume = {58}, number = {5}, pages = {773-779}, pmid = {11889242}, issn = {0028-3878}, support = {R01 NS040321/NS/NINDS NIH HHS/United States ; R01 NS040321-03/NS/NINDS NIH HHS/United States ; F32 NS010578/NS/NINDS NIH HHS/United States ; R01 NS4032/NS/NINDS NIH HHS/United States ; F32 NS010578-04S1/NS/NINDS NIH HHS/United States ; NS10578/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*metabolism/pathology/physiopathology ; Aspartic Acid/*analogs &amp; derivatives/metabolism ; Choline/metabolism ; Creatine/metabolism ; Disease Progression ; Female ; Humans ; Magnetic Resonance Imaging/*methods ; Male ; Middle Aged ; Motor Cortex/*metabolism/pathology ; Reproducibility of Results ; }, abstract = {OBJECTIVE: To determine 1) the reproducibility of metabolite measurements by (1)H MRS in the motor cortex; 2) the extent to which (1)H MRS imaging (MRSI) detects abnormal concentrations of N-acetylaspartate (NAA)-, choline (Cho)-, and creatine (Cre)-containing compounds in early stages of ALS; and 3) the metabolite changes over time in ALS.<br><br>METHODS: Sixteen patients with definite or probable ALS, 12 with possible or suspected ALS, and 12 healthy controls underwent structural MRI and multislice (1)H MRSI. (1)H MRSI data were coregistered with tissue-segmented MRI data to obtain concentrations of NAA, Cre, and Cho in the left and right motor cortex and in gray matter and white matter of nonmotor regions in the brain.<br><br>RESULTS: The interclass correlation coefficient of NAA was 0.53 in the motor cortex tissue and 0.83 in nonmotor cortex tissue. When cross-sectional data for patients were compared with those for controls, the NAA/(Cre + Cho) ratio in the motor cortex region was significantly reduced, primarily due to increases in Cre and Cho and a decrease in NAA concentrations. A similar, although not significant, trend of increased Cho and Cre and reduced NAA levels was also observed for patients with possible or suspected ALS. Furthermore, in longitudinal studies, decreases in NAA, Cre, and Cho concentrations were detected in motor cortex but not in nonmotor regions in ALS.<br><br>CONCLUSION: Metabolite changes measured by (1)H MRSI may provide a surrogate marker of ALS that can aid detection of early disease and monitor progression and treatment response.}, }
@article {pmid11874201, year = {2001}, author = {Yamamoto, M and Kobayashi, Y and Li, M and Niwa, H and Mitsuma, N and Ito, Y and Muramatsu, T and Sobue, G}, title = {In vivo gene electroporation of glial cell line-derived neurotrophic factor (GDNF) into skeletal muscle of SOD1 mutant mice.}, journal = {Neurochemical research}, volume = {26}, number = {11}, pages = {1201-1207}, pmid = {11874201}, issn = {0364-3190}, mesh = {Animals ; Animals, Genetically Modified ; Cell Line ; Disease Models, Animal ; Electroporation ; Genetic Therapy/methods ; Glial Cell Line-Derived Neurotrophic Factor ; Humans ; Mice ; Motor Activity/*physiology ; Motor Neuron Disease/enzymology/genetics/physiopathology ; Motor Neurons/pathology ; Muscle, Skeletal/physiology ; *Nerve Growth Factors ; Nerve Tissue Proteins/administration &amp; dosage/*genetics/pharmacology ; Spinal Cord/pathology ; Superoxide Dismutase/*genetics ; Transfection ; }, abstract = {Motor neurons degenerate with intracellular vacuolar change and eventually disappear in spinal cords of SOD1 mutant mice, resembling human amyotrophic lateral sclerosis (ALS). The GDNF gene was electroporatically transferred into the leg muscles of SOD1 mutant mice and expressed in muscle cells. This gene therapy with GDNF delayed the deterioration of motor performance, being retrogradely transported into spinal motor neurons. However, the number of the motor neurons and survival of the mutant mice were not improved by GDNF treatment. These results indicate that in vivo gene electroporation of GDNF into muscles could be an appropriate therapeutic approach to ameliorate an early dysfunction of motor neurons in SOD1 mutant mice, but further improvement is needed to use this gene transfer as an effective treatment of ALS.}, }
@article {pmid11859558, year = {2002}, author = {Williams, T}, title = {Intercessory prayer and its effect on patients with rheumatoid arthritis.}, journal = {Kentucky nurse}, volume = {50}, number = {1}, pages = {16}, pmid = {11859558}, issn = {0742-8367}, mesh = {Aged ; Arthritis, Rheumatoid/nursing/*therapy ; Clinical Trials as Topic ; *Faith Healing ; Female ; Humans ; }, abstract = {Matthews et al's. (2000) study suggested that in person intercessory prayer was useful in the medical treatment of patients with RA, improving overall health. However, distant prayer showed no overall improvement. This study could be used to support a research utilization project to educate nurses on the potential benefits of prayer on the healthcare and health outcomes of patients with certain illnesses. An in-service could be made available for nurses to educate them on potential benefits of prayer. A feasibility issue would be cost. Religion and spiritual beliefs can influence a patient's level of health and self-care behaviors. It is essential for nurses to meet the spiritual needs of their patients. A nurse should also recognize that there are many different religions and not all patients have the same religion and beliefs.}, }
@article {pmid11854102, year = {2001}, author = {Borasio, GD and Voltz, R and Miller, RG}, title = {Palliative care in amyotrophic lateral sclerosis.}, journal = {Neurologic clinics}, volume = {19}, number = {4}, pages = {829-847}, doi = {10.1016/s0733-8619(05)70049-9}, pmid = {11854102}, issn = {0733-8619}, mesh = {Amyotrophic Lateral Sclerosis/complications/*therapy ; Deglutition Disorders/etiology ; Dysarthria/etiology ; Dyspnea/etiology ; Humans ; Hypoventilation/etiology ; Muscle Weakness/etiology ; Pain/etiology ; *Palliative Care ; Quality of Life ; Sialorrhea/etiology ; Sleep Wake Disorders/etiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common degenerative motor neuron disease in adults. The clinical picture consists of generalized fasciculations, progressive atrophy and weakness of the skeletal muscles, spasticity and pyramidal tract signs, dysarthria, dysphagia, and dyspnea. Pseudobulbar affect is common. Disease-specific treatment options are still unsatisfactory. Therapeutic nihilism is not justified as a large array of palliative measures available to enhance the quality of life of patients and their families. Because of its clinical characteristics, ALS represents a paradigm for palliative care in neurological diseases. Numerous projects are being undertaken worldwide in an effort to enlarge the evidence base for palliative interventions in ALS. Palliative care in ALS is a multidisciplinary effort requiring careful coordination. An open and empathic disclosure of the diagnosis is essential. Nutritional deficiency caused by dysphagia can be relieved by a percutaneous endoscopic gastrostomy. Respiratory insufficiency can be effectively treated by non-invasive home mechanical ventilation. The terminal phase of the disease should be discussed at the latest when symptoms of dyspnea appear, in order to prevent unwarranted fears of "choking to death." Psychological and spiritual care of patients and families are important. Collaboration with hospice institutions and completion of advance directives can be of invaluable help in the terminal phase.}, }
@article {pmid11839868, year = {2002}, author = {Winterholler, MG and Heckmann, JG and Hecht, M and Erbguth, FJ}, title = {Recurrent trismus and stridor in an ALS patient: successful treatment with botulinum toxin.}, journal = {Neurology}, volume = {58}, number = {3}, pages = {502-503}, doi = {10.1212/wnl.58.3.502}, pmid = {11839868}, issn = {0028-3878}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications ; Anti-Dyskinesia Agents/*therapeutic use ; Botulinum Toxins/*therapeutic use ; Female ; Humans ; Recurrence ; Respiratory Sounds/etiology ; Trismus/*drug therapy/etiology ; }, }
@article {pmid11835294, year = {2002}, author = {Byrne, SM and McLean, NJ}, title = {The cognitive-behavioral model of bulimia nervosa: a direct evaluation.}, journal = {The International journal of eating disorders}, volume = {31}, number = {1}, pages = {17-31}, doi = {10.1002/eat.10002}, pmid = {11835294}, issn = {0276-3478}, mesh = {Body Image ; Bulimia/psychology/*therapy ; Cognitive Behavioral Therapy/*methods ; Diet, Reducing/psychology ; Feeding Behavior ; Female ; Humans ; *Mathematical Computing ; *Models, Statistical ; Risk Assessment ; Self Concept ; Software ; }, abstract = {OBJECTIVE: This study represented the first attempt to directly evaluate Fairburn et al's (1986) cognitive-behavioral model of bulimia nervosa--the model on which the most widely used treatment for bulimia nervosa is based.<br><br>METHOD: The major predictions of the model were tested using structural equation modeling. Data were collected from the responses of 526 subjects to a number of self-report measures.<br><br>RESULTS: The factors of self-esteem, overconcern with weight and shape, and dietary restraint accounted for a large proportion of the variance in binge eating and purging. The key pathway in the model was the link between overconcern with weight and shape and the adoption of purgative behaviors, which then fed into a vicious cycle of binge eating and purging. Contrary to Fairburn's hypothesis, high levels of dietary restraint did not predict increased binge eating.<br><br>DISCUSSION: The results suggest that the components of Fairburn's model may operate to maintain the bulimic cycle in a slightly different way to that originally proposed.}, }
@article {pmid11815261, year = {2002}, author = {Woźniak, K and Błasiak, J}, title = {Free radicals-mediated induction of oxidized DNA bases and DNA-protein cross-links by nickel chloride.}, journal = {Mutation research}, volume = {514}, number = {1-2}, pages = {233-243}, doi = {10.1016/s1383-5718(01)00344-8}, pmid = {11815261}, issn = {0027-5107}, mesh = {Adult ; Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; Cell Survival ; Comet Assay ; Cross-Linking Reagents ; DNA/drug effects/*metabolism ; DNA Damage ; DNA Repair ; Free Radical Scavengers/pharmacology ; Free Radicals/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Lymphocytes/*drug effects/physiology ; Male ; Nickel/*pharmacology ; Oxidants/pharmacology ; Oxidation-Reduction ; Vitamin E/pharmacology ; }, abstract = {Using the comet assay, we showed that nickel chloride at 250-1000 microM induced DNA damage in human lymphocytes, measured as the change in comet tail moment, which increased with nickel concentration up to 500 microM and then decreased. Observed increase might follow from the induction of strand breaks or/and alkali-labile sites (ALS) by nickel, whereas decrease from its induction of DNA-DNA and/or DNA-protein cross-links. Proteinase K caused an increase in the tail moment, suggesting that nickel chloride at 1000 microM might cross-link DNA with nuclear proteins. Lymphocytes exposed to NiCl(2) and treated with enzymes recognizing oxidized and alkylated bases: endonuclease III (Endo III), formamidopyrimidine-DNA glycosylase (Fpg) and 3-methyladenine-DNA glycosylase II (AlkA), displayed greater extent of DNA damage than those not treated with these enzymes, indicating the induction of oxidized and alkylated bases by nickel. The incubation of lymphocytes with spin traps, 5,5-dimethyl-pyrroline N-oxide (DMPO) and PBN decreased the extent of DNA damage, which might follow from the production of free radicals by nickel. The pre-treatment with Vitamin C at 10 microM and Vitamin E at 25 microM decreased the tail moment of the cells exposed to NiCl(2) at the concentrations of the metal causing strand breaks or/and ALS. The results obtained suggest that free radicals may be involved in the formation of strand breaks or/and ALS in DNA as well as DNA-protein cross-links induced by NiCl(2). Nickel chloride can also alkylate DNA bases. Our results support thesis on multiple, free radicals-based genotoxicity pathways of nickel.}, }
@article {pmid11812279, year = {2002}, author = {Millecamps, S and Mallet, J and Barkats, M}, title = {Adenoviral retrograde gene transfer in motoneurons is greatly enhanced by prior intramuscular inoculation with botulinum toxin.}, journal = {Human gene therapy}, volume = {13}, number = {2}, pages = {225-232}, doi = {10.1089/10430340252769752}, pmid = {11812279}, issn = {1043-0342}, mesh = {Adenoviridae/*genetics ; Amyotrophic Lateral Sclerosis ; Animals ; Animals, Genetically Modified ; Botulinum Toxins, Type A/*pharmacology ; *Gene Transfer Techniques ; Mice ; Mice, Inbred C57BL ; *Motor Neurons ; Muscles ; Superoxide Dismutase ; Superoxide Dismutase-1 ; Tongue ; Transduction, Genetic ; Transgenes ; }, abstract = {Retrograde axonal transport of recombinant adenoviral vectors has been used successfully to deliver genes to motoneurons in rodents after injection of the vectors into muscles. However, only a small proportion of motoneurons take up and retrogradely transport adenoviral particles, limiting the value of this gene delivery method for the treatment of motor neuron diseases (MNDs). Here we validate a new pharmacological approach for enhancing motoneuronal gene transfer after intramuscular injection of recombinant adenoviruses. We injected botulinum neurotoxin A (BoNT) into muscles of normal C57BL/6 mice and transgenic mice expressing the G93A mutation in the superoxide dismutase 1 gene (SOD1-G93A mutation, a model of amyotrophic lateral sclerosis) several days before inoculation with adenoviruses. Treatment with BoNT significantly enhanced gene transfer to motoneurons innervating the injected muscles. Modifications in motoneuron transduction appear to be a consequence of toxin-induced nerve sprouting at the end plates. These findings have major implications for devising protocols for preclinical and clinical studies using intramuscular injection of retrogradely transported gene vectors.}, }
@article {pmid11796788, year = {2002}, author = {Marquardt, G and Seifert, V}, title = {Use of intrathecal baclofen for treatment of spasticity in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {72}, number = {2}, pages = {275-276}, doi = {10.1136/jnnp.72.2.275}, pmid = {11796788}, issn = {0022-3050}, mesh = {Adult ; Baclofen/*administration &amp; dosage ; Follow-Up Studies ; Humans ; Injections, Spinal ; Male ; Motor Neuron Disease/*drug therapy ; Muscle Spasticity/*drug therapy ; Quality of Life ; }, }
@article {pmid11786237, year = {2001}, author = {Willing, AE and Garbuzova-Davis, S and Saporta, S and Milliken, M and Cahill, DW and Sanberg, PR}, title = {hNT neurons delay onset of motor deficits in a model of amyotrophic lateral sclerosis.}, journal = {Brain research bulletin}, volume = {56}, number = {6}, pages = {525-530}, doi = {10.1016/s0361-9230(01)00625-6}, pmid = {11786237}, issn = {0361-9230}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*surgery ; Animals ; Body Weight/physiology ; Brain Tissue Transplantation ; Disease Models, Animal ; Graft Survival/*physiology ; Lumbar Vertebrae ; Mice ; Mice, Transgenic ; Movement Disorders/physiopathology/*surgery ; Neurons/cytology/*transplantation ; Recovery of Function/physiology ; Spinal Cord/*surgery ; Superoxide Dismutase/deficiency/genetics ; Superoxide Dismutase-1 ; Treatment Outcome ; Tumor Cells, Cultured/cytology/*transplantation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that manifests as a progressive muscular weakness leading to paralysis and death. Because of the diffuse nature of the motor neuron death, this disease is not considered a good candidate for treatment through neural transplantation. The purpose of this study was to show that transplantation of human neuron-like cells (hNT neurons) into the spinal cord of a transgenic ALS mouse model would improve motor deficits. The hNT neurons were transplanted bilaterally into L4-L5 spinal cord of the transgenic mice (approximately 8 weeks of age), and the animals were evaluated on health and behavioral measures. The animals were perfused, and immunohistochemistry was performed to identify the transplanted cells. Transplantation of the hNT neurons into the spinal cord delayed the onset of motor behavioral symptoms. This was the first demonstration that even localized transplantation of neural cells directly into the parenchyma could improve motor function in an ALS model. Further study is needed to delineate the mechanism underlying these effects. This therapeutic approach has the potential to restore neural transmission, thereby improving quality of life for the ALS patient and possibly extend life expectancy.}, }
@article {pmid11774729, year = {2001}, author = {Kido, M and Igase, M and Nomura, T and Kohara, K and Miki, T}, title = {[Early treatment with non-invasive positive pressure ventilation a successful case of bulbar type amyotrophic lateral sclerosis].}, journal = {Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics}, volume = {38}, number = {6}, pages = {816-818}, doi = {10.3143/geriatrics.38.816}, pmid = {11774729}, issn = {0300-9173}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Blood Gas Analysis ; Humans ; Male ; Middle Aged ; *Positive-Pressure Respiration ; }, abstract = {A 60-year-old man who has suffered dysarthria since 1999. He had noticed twitching of right upper extremity and orbicularis oris muscle since August 2000. The bulbar type of amyotrophic lateral sclerosis was diagnosed. He was admitted for evaluation of sleep disorder with respiratory distress on November 20, 2000. Arterial blood gas analysis on admission showed marked hypercapnea (PaCO2:51.6 Torr). Nocturnal hypoxia index, which was calculated using the nocturnal oximetry monitoring, was elevated. Non-invasive positive pressure ventilation started during sleep at night, although it was earlier than to start for mechanical ventilation. After one week, both hypercapnea and his nocturnal hypoxia index, together with symptoms, improved markedly. Respiratory insufficiency due to progressive fatigue of respiratory muscles, such as diaphragm and intercostal muscles, is a major cause of death in amyotrophic lateral sclerosis. In general mechanical ventilation is introduced when marked hypercapnea and dyspnea become clinically overt. However, the exact time to introduce noninvasive methods of ventilatory support for amyotrophic lateral sclerosis has not been established. Based on the observation in this patient, we would suggest that earlier introduction of non-invasive mechanical support for ventilation (nocturnal hypoxia index > 70) would be useful to improve the symptoms and to prolong the life of patients with ALS. The nocturnal hypoxia index is useful to decide the time of the introduction of non-invasive mechanical support for ventilation.}, }
@article {pmid11771773, year = {2001}, author = {Borasio, GD and Shaw, PJ and Hardiman, O and Ludolph, AC and Sales Luis, ML and Silani, V and , }, title = {Standards of palliative care for patients with amyotrophic lateral sclerosis: results of a European survey.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2}, number = {3}, pages = {159-164}, doi = {10.1080/146608201753275517}, pmid = {11771773}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/physiopathology/*therapy ; Community Health Services ; Europe/epidemiology ; Gastrostomy ; Health Care Surveys/*statistics &amp; numerical data ; Humans ; Nutritional Physiological Phenomena ; Palliative Care/methods/*standards/trends ; Patients/*statistics &amp; numerical data ; Respiratory Therapy ; Retrospective Studies ; Terminally Ill ; Vital Capacity ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) may be viewed as a paradigmatic disease for palliative care in neurodegenerative disorders. However, standards of care for ALS are known anecdotally to differ between and even within countries.<br><br>METHOD: A survey was conducted among the members of the European ALS Study Group on standards of palliative care in the clinical management of patients with ALS and their families, by means of a questionnaire of 111 questions in the following areas: giving the diagnosis, treatment of symptoms, nutrition, community services, respiratory support, and terminal care. Of 110 questionnaires sent out, 73 (66%) were completed and returned from 18 countries, including all major ALS centres in Europe.<br><br>RESULTS: The main areas of consensus included: presenting the diagnosis in the presence of a relative (85%) and offering a short-term follow-up (90%), regular weight checks (82%), availability of percutaneous endoscopic gastrostomy (PEG) (94%), and discussion of respiratory issues (90%). The main differences between centres concerned symptomatic drug treatment, availability of services, ventilation and terminal care. An additional survey shows considerable interest by the centres in palliative care trials.<br><br>CONCLUSION: Great efforts are made by the centres to offer the best possible palliative care to ALS patients. The discrepancies in the type of care offered might be resolved by adopting common standards, on the basis of available evidence and mutual consensus. Several areas of ALS patient care would benefit from controlled studies to establish an evidence base for treatment decisions.}, }
@article {pmid11771772, year = {2001}, author = {Debove, C and Zeisser, P and Salzman, PM and Powe, LK and Truffinet, P}, title = {The Rilutek (riluzole) Global Early Access Programme: an open-label safety evaluation in the treatment of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2}, number = {3}, pages = {153-158}, doi = {10.1080/146608201753275508}, pmid = {11771772}, issn = {1466-0822}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Alanine Transaminase/blood ; Amyotrophic Lateral Sclerosis/blood/*drug therapy/mortality ; Excitatory Amino Acid Antagonists/adverse effects/therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Neutropenia/blood/chemically induced ; Riluzole/*adverse effects/*therapeutic use ; Survival Analysis ; }, abstract = {OBJECTIVES: This study had two main objectives: 1. To enable patients with amyotrophic lateral sclerosis (ALS) who had not participated in previous riluzole trials to receive riluzole therapy, and 2. To expand safety experience with the drug in a broad patient population.<br><br>METHODS: This was a Phase IIIb multicentre, multinational, open-label, uncontrolled single treatment study of riluzole. Patients with diagnosed possible or probable ALS were administered 100 mg of riluzole/day (50 mg b.i.d.). Clinical and laboratory adverse events were recorded every month for the first 3 months and thereafter at 3-monthly intervals.<br><br>RESULTS: 8383 patients from 44 countries were entered into the study; 7916 of these patients with recorded data were administered the study drug. The mean duration of riluzole treatment was 202.1 days, with a range of 1-630 days. The most frequently reported serious and non-serious adverse events were common symptoms of ALS (respiratory symptoms and dysphagia), and only 1.9% of serious adverse events were considered to be related to the study drug.<br><br>CONCLUSIONS: The safety results with this broad population (over 10% of the estimated ALS population worldwide) were consistent with those previously reported from placebo-controlled trials. No increase in adverse events and no unexpected adverse events were observed.}, }
@article {pmid11771767, year = {2001}, author = {Iwasaki, Y and Ikeda, K and Kinoshita, M}, title = {The diagnostic pathway in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2}, number = {3}, pages = {123-126}, doi = {10.1080/146608201753275571}, pmid = {11771767}, issn = {1466-0822}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology/therapy ; Data Collection/methods/statistics &amp; numerical data ; Electromyography/statistics &amp; numerical data ; Female ; Humans ; Magnetic Resonance Imaging/statistics &amp; numerical data ; Male ; Middle Aged ; Neurologic Examination/statistics &amp; numerical data ; Orthopedics/statistics &amp; numerical data ; Physicians, Family/statistics &amp; numerical data ; Retrospective Studies ; }, abstract = {INTRODUCTION: We present the findings of a survey of the diagnostic pathways and treatment of 50 patients with amyotrophic lateral sclerosis (ALS).<br><br>RESULTS: The mean time between first symptoms and first consultation with a physician was 5.7 months; mean time between first symptoms and first consultation with a neurologist was 9.7 months; mean time from symptom onset to confirmation of diagnosis was 11.6 months. Patients with bulbar onset appeared to be diagnosed earlier than those with limb onset, but the difference was not statistically significant. The first physician seen was an orthopedist in 30%, a general practitioner (GP) in 28%, and a neurologist in 28% of cases. The mean diagnostic intervals were 9.4 months when the neurologist was the first physician seen, and 9.8 months when the neurologist saw a patient referred from a GP. Otherwise, when a neurologist saw patients referred from an orthopedist, the mean diagnostic interval was 14.9 months. Differences between the values of mean diagnostic interval were not statistically significant. EMG and MRI were performed in all patients, cerebrospinal fluid examination and muscle biopsy in most. Treatment was by vitamins in 38% of cases, thyrotropin-releasing hormone in 24%, physical therapy in 22%, and anticholinesterase agent in 12%.<br><br>CONCLUSION: The number of patients in our study is limited, and a further prospective nation-wide survey is necessary.}, }
@article {pmid11771037, year = {2001}, author = {Harriman, M and Morrison, M and Hay, J and Revonta, M and Eisen, A and Lentle, B}, title = {Use of radiotherapy for control of sialorrhea in patients with amyotrophic lateral sclerosis.}, journal = {The Journal of otolaryngology}, volume = {30}, number = {4}, pages = {242-245}, doi = {10.2310/7070.2001.19779}, pmid = {11771037}, issn = {0381-6605}, mesh = {Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Humans ; Radiation Dosage ; Salivary Glands/radiation effects ; Sialorrhea/etiology/*radiotherapy ; Treatment Outcome ; }, abstract = {Many patients with amyotrophic lateral sclerosis (ALS) develop progressive difficulty with swallowing secretions, and drooling becomes a significant problem. The production of saliva can be reduced with radiation of the submandibular and sublingual salivary gland tissue. This method has been used successfully in Europe and had limited use at Vancouver Hospital. This study was undertaken to determine the lowest effective dose of radiation necessary to control salivary production. Over a 3-year period, patients with ALS who developed significant problems with drooling were identified and treated with a predetermined dose of radiation. The first group received a single dose of 8 Gy in one fraction and the second received a total of 12.5 Gy in two fractions. They were followed over the next 6 months and were evaluated for effectiveness and side effects. Their saliva was measured pre- and postradiation treatment, and they were also asked to evaluate the change subjectively, using a questionnaire. The preliminary findings suggest that 8 Gy of radiation was effective in controlling drooling, and increasing the dose did not improve initial control. Long-term control was difficult to evaluate as the patients entered in the study were very ill and their life expectancy was very short. Radiation at this low dose resulted in very few side effects. Low-dose radiation can safely help control secretions in selected patients with ALS.}, }
@article {pmid11768283, year = {2001}, author = {Kao, WF and Kuo, CC and Chang, H and Chen, WL and Wei, CH and Huang, HH and Yen, DH and Wu, JK and Miao, S and Lee, CH}, title = {Characteristics of patients at a Taipei summer rock concert festival.}, journal = {Zhonghua yi xue za zhi = Chinese medical journal; Free China ed}, volume = {64}, number = {9}, pages = {525-530}, pmid = {11768283}, issn = {0578-1337}, mesh = {Adolescent ; Adult ; *Emergency Medical Services ; Female ; Holidays ; Humans ; Male ; Music ; Syncope/epidemiology ; Taiwan ; }, abstract = {BACKGROUND: Rock concerts are popular mass gatherings in Taiwan. Millions of fans participate in rock concerts in Taiwan each year. However, there were no reports on the characteristics of the patients seen in rock concerts in Taiwan.<br><br>METHODS: Medical care for a summer rock concert festival held in an outdoor stadium in Taipei was coordinated by emergency physicians of a medical center. About 50,000 attendees participated in the two-night concert. Three stations were set up to provide advanced medical care. A standardized form was used to collect information about patients.<br><br>RESULTS: A total of 28 cases visited the medical stations, fourteen cases each day. They were aged from 13 to 40 years, with an average of 20.8 +/- 6.4. Twenty-one cases were female and seven were male. Twenty-two (79%) were spectators, five (18%) were on-duty staff, and one was a by-stander. Based on an estimation of totally 50,000 participants in the stadium for this two-night festival, the medical use rate was roughly 5.6 PPTT (patients per ten thousand attendees). The most common major problem was fainting which accounted for 13 cases (46%). Of these 13 cases, three cases (23%) lost consciousness and 12 cases (92%) were female. Sixteen cases (57%) were classified as requiring ALS (advanced life support) and 12 cases (43%) as requiring BLS (basic life support). Most cases improved and were discharged after onsite treatment. Only one case was transferred by ambulance due to persistent chest pain. However, she recovered several hours later.<br><br>CONCLUSIONS: By this preliminary data, first reported in Taiwan, we found that the most common problem was fainting. More than half of the cases seen at the concert required advanced life support. A well-designed emergency medical service (EMS) system is mandatory to provide services for these events.}, }
@article {pmid11760877, year = {2001}, author = {Iwasaki, Y and Ikeda, K and Ichikawa, Y and Igarashi, O}, title = {Vasoactive intestinal peptide influences neurite outgrowth in cultured rat spinal cord neurons.}, journal = {Neurological research}, volume = {23}, number = {8}, pages = {851-854}, doi = {10.1179/016164101101199298}, pmid = {11760877}, issn = {0161-6412}, mesh = {Animals ; Cells, Cultured ; Motor Neurons/*drug effects/ultrastructure ; Neurites/*drug effects/physiology ; Peptide PHI/pharmacology ; Rats ; Rats, Sprague-Dawley ; Secretin/pharmacology ; Spinal Cord/*cytology ; Vasoactive Intestinal Peptide/*pharmacology ; }, abstract = {Vasoactive intestinal peptide (VIP) is a neuropeptide which has been shown to exhibit a wide range of neurotrophic effects both in vivo and in vitro. For the purpose of clarifying the effect of VIP on spinal cord neurons, we studied the effect of VIP on neurite outgrowth of fetal rat ventral and dorsal portions of spinal cord in cultures. VIP-treated ventral spinal cord cultures (VSCC), compared with control VSCC, had a significant neurite outgrowth at 10(-8), 10(-6), and 10(-4) M. The effect was considered to be concentration dependent. Morphological changes of the dorsal spinal cord cultures (DSCC) remained unchanged by VIP treatment. Because of their close sequence homology with VIP, PHI-27 (peptide, histidylisoleucine amide) and secretin were also examined with the same experimental conditions as was VIP. Both PHI-27 and secretin had neurite promoting effects in VSCC at 10(-8) and 10(-6) M, respectively. However, there were no neurite promoting effects in DSCC in both of them at any concentrations. VIP had the most potent effect on neurite outgrowth in VSCC, followed by PHI-27, and secretin in their effectiveness concentrations. Our data showing VIP, PHI-27 and secretin have neurotrophic action on VSCC and suggest that a potential therapeutic use of VIP and its related peptides in treating diseases that involve degeneration and death of spinal motor neurons, such as motor neuropathy and amyotrophic lateral sclerosis.}, }
@article {pmid11743956, year = {2001}, author = {Van Westerlaak, MG and Joosten, EA and Gribnau, AA and Cools, AR and Bär, PR}, title = {Differential cortico-motoneuron vulnerability after chronic mitochondrial inhibition in vitro and the role of glutamate receptors.}, journal = {Brain research}, volume = {922}, number = {2}, pages = {243-249}, doi = {10.1016/s0006-8993(01)03178-x}, pmid = {11743956}, issn = {0006-8993}, mesh = {6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology ; Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; Animals ; Animals, Newborn ; Cell Death/*drug effects/physiology ; Cell Survival/drug effects/physiology ; Cerebral Cortex/*drug effects/metabolism/physiopathology ; Dizocilpine Maleate/pharmacology ; Dose-Response Relationship, Drug ; Drug Interactions/physiology ; Energy Metabolism/*drug effects/physiology ; Excitatory Amino Acid Antagonists/pharmacology ; Glutamic Acid/metabolism ; Immunohistochemistry ; Malonates/toxicity ; Mitochondria/*drug effects/metabolism ; Motor Neurons/*drug effects/metabolism/pathology ; Neurofilament Proteins/metabolism ; Neuroprotective Agents/pharmacology ; Organ Culture Techniques ; Pyramidal Tracts/*drug effects/metabolism/physiopathology ; Rats ; Rats, Wistar ; Receptors, Glutamate/*drug effects/metabolism ; }, abstract = {Chronic treatment of rat cortical slices with a relative low concentration of mitochondrial inhibitor malonate leads to cortical motoneuron (CMN) death. In the neurodegenerative disease amyotrophic lateral sclerosis (ALS) corticospinal neurons, CMNs projecting to the spinal cord, degenerate. In the present study we compared the effect of chronic mitochondrial inhibition on the survival of CMNs located in the dorsal cortical areas (including corticospinal neurons) with that on ventrally located CMNs (non-corticospinal neurons) in vitro. In the explant culture model used, the dorsally located CMNs were less vulnerable to a 2-week period of mitochondrial inhibition with malonate as compared to ventrally located CMNs. Treatment with 5 mM malonate resulted in 50% surviving CMNs in the dorsal part and only 16% in the ventral part. Neuroprotection of the CMNs could be achieved with co-administration of the non-NMDA antagonist CNQX, the NMDA antagonist MK-801, or the glutamate release inhibitor riluzole, suggesting that chronic energy shortage leads to excitotoxicity. In the dorsal cortical areas CNQX, MK-801, and riluzole had a neuroprotective effect on the CMNs, whereas in the ventral cortical areas only MK-801 was neuroprotective. The sensitivity to energy depletion and consequently excitotoxicity may be related to glutamate receptor density and subunit composition in various cortical areas, but also to the projection length and input of CMNs in vivo. The present investigation gives insight in mechanisms leading to excitotoxic cell death of CMNs and may therefore be important for the development of treatment strategies in protection and survival of cortical motoneurons in ALS.}, }
@article {pmid11732280, year = {2001}, author = {Kwieciński, H}, title = {[Symptomatic treatment and palliative care of ALS].}, journal = {Neurologia i neurochirurgia polska}, volume = {35}, number = {1 Suppl}, pages = {51-59}, pmid = {11732280}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Pain Management ; *Palliative Care ; Positive-Pressure Respiration ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, affecting upper and lower motor neurons, which eventually progresses to respiratory deterioration and death in most of the patients. Only one drug, riluzole, has been approved for the treatment of ALS. The drug has a benefit, prolonging life by 3-6 months, but the disease progresses inexorably, with no better quality of life. The fundamental role of medicine is sometimes to cure, but always to bring comfort. In current situation, ALS patients need adequate palliative care more than anything else. Prognosis and treatment options should be discussed with the patient and the relatives, but full information about the prognosis may deprive the patient of hope. However, disclosure of the prognosis is necessary to obtain informed consent for management decisions such as tracheostomy and artificial ventilation. Nasal positive-pressure ventilation (BiPAP) is an alternative to tracheostomy, at least for some patients without advanced bulbar impairment. Nutritional status in patients who cannot swallow can be efficiently improved by a percutaneous endoscopic gastrostomy. (PEG).}, }
@article {pmid11732279, year = {2001}, author = {Münch, C and Ludolph, AC}, title = {Pharmacological treatment of ALS.}, journal = {Neurologia i neurochirurgia polska}, volume = {35}, number = {1 Suppl}, pages = {41-50}, pmid = {11732279}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/pathology ; Clinical Trials as Topic ; Humans ; Motor Neurons/pathology ; Neuroprotective Agents/*therapeutic use ; Point Mutation/genetics ; Riluzole/*therapeutic use ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting from chronic and selective loss of motor neurons in the brain and spinal cord. In 1993, the etiology of ALS has been clarified for a small sub-group of patients with an autosomal-dominant form of this disease. About 10 percent of familial ALS patients have been associated with more than 50 mutations of the gene of the Cu/Zn superoxide dismutase (SOD1). Mutations in the SOD1 gene account for 1 percent of all ALS patients and have therefore limited epidemological and clinical relevance; however, they are of fundamental importance for the understanding of the ALS pathogenesis, and the development of neuroprotective strategies. In two double-blind and placebo-controlled studies the membrane stabilisator riluzole has been shown to be the first neuroprotective compound with a significant effect on survival of ALS patients. The neuroprotective approach reduced therapeutic nihilism in ALS and is a first step in the treatment of this devastating disease.}, }
@article {pmid11732278, year = {2001}, author = {Silani, V and Braga, M and Cardin, V and Scarlato, G}, title = {The pathogenesis of ALS: implications for treatment strategies.}, journal = {Neurologia i neurochirurgia polska}, volume = {35}, number = {1 Suppl}, pages = {25-39}, pmid = {11732278}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/*physiopathology ; Clinical Trials as Topic ; Glutamic Acid/metabolism ; Humans ; Neurotoxins/metabolism ; }, abstract = {Besides the free radical hypothesis raised by the identification of Superoxide Dismutase I mutations in a subset of familiar Amyotrophic Lateral Sclerosis (ALS) patients, three etiopathogenic hypotheses for sporadic ALS, namely autoimmune, neurofilament, and glutamate toxicity, have attracted interest in the last few years. The role of autoimmunity in ALS has been seriously questioned. The excitotoxic hypothesis for ALS spurred two clinical trials with riluzole. The results of both studies showed a modest benefit in prolonging survival that was statistically significant. Riluzole was the first drug made available for ALS patients. It began a new era in both basic and clinical research. Various human recombinant neurotrophic molecules (CNTF, BDNF, IGF-I) were administered to ALS patients. IGF-I slowed the progression of functional impairment in patients with ALS with no adverse effects. The recent demonstration of the specific viral echovirus 7 RNA sequences in the spinal cord of ALS patients refocused research on the viral hypothesis of the disease and antiviral drugs are ready to be used in clinical settings. New treatment strategies are today under study: intrathecal infusion with BDNF, intrathecal capsules for neurotrophic factor secretion or in vivo gene therapy using viral vectors. New research findings are, more than for other diseases, immediately transferred to clinical ground for the desperate need of a curative treatment of the patients affected by ALS.}, }
@article {pmid11732275, year = {2001}, author = {Kwieciński, H and Janik, P and Jamrozik, Z and Opuchlik, A}, title = {[The effect of selegiline and vitamin E in the treatment of ALS: an open randomized clinical trials].}, journal = {Neurologia i neurochirurgia polska}, volume = {35}, number = {1 Suppl}, pages = {101-106}, pmid = {11732275}, issn = {0028-3843}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/administration &amp; dosage/*therapeutic use ; Selegiline/administration &amp; dosage/*therapeutic use ; Survival Rate ; Vitamin E/administration &amp; dosage/*therapeutic use ; }, abstract = {A role for oxidative stress in the etiology or progression of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases has been recently proposed. We conducted the 18-month, randomized treatment trial with oral vitamin E (600 IU daily) and selegiline (10 mg daily) in 67 patients with sporadic ALS. Thirty five patients were randomly assigned to receive antioxidative therapy (vitamin E plus selegiline) and the remaining 32 patients were the ALS controls who received symptomatic treatment. The primary end point was survival and functional status. At the end of 18-month study, 13 patients in the treatment group and 14 in the control group died or were tracheostomized. A decline in functional disability was also similar in both groups. Long-term antioxidative treatment did not benefit patients with ALS.}, }
@article {pmid11730713, year = {2001}, author = {Azari, MF and Galle, A and Lopes, EC and Kurek, J and Cheema, SS}, title = {Leukemia inhibitory factor by systemic administration rescues spinal motor neurons in the SOD1 G93A murine model of familial amyotrophic lateral sclerosis.}, journal = {Brain research}, volume = {922}, number = {1}, pages = {144-147}, doi = {10.1016/s0006-8993(01)03156-0}, pmid = {11730713}, issn = {0006-8993}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*pathology ; Animals ; Cachexia/chemically induced/pathology ; Cell Count ; Cell Survival/drug effects ; Growth Inhibitors/administration &amp; dosage/*pharmacology/toxicity ; Humans ; Injections, Intraperitoneal ; *Interleukin-6 ; Leukemia Inhibitory Factor ; Lymphokines/administration &amp; dosage/*pharmacology/toxicity ; Mice ; Mice, Transgenic ; Motor Neurons/*drug effects ; Mutation/genetics/physiology ; Pilot Projects ; Spinal Cord/*pathology ; Superoxide Dismutase/*genetics ; }, abstract = {Leukemia inhibitory factor (LIF) is a survival factor for motoneurons. In this study we investigated whether intense systemic LIF therapy prevents the loss of lumbar motoneurons in the transgenic SOD1 G93A mouse model of familial amyotrophic lateral sclerosis. Treatment involved daily 25 microg/kg intraperitoneal injection for a period of 6 weeks starting at 70 days of age. Using the unbiased optical dissector technique, significant rescue of motoneurons in the LIF-treated group (3809+/-455) was found compared to the vehicle group (1085+/-140).}, }
@article {pmid11723276, year = {2001}, author = {Shefner, JM and Brown, RH and Cole, D and Chaturvedi, P and Schoenfeld, D and Pastuszak, K and Matthews, R and Upton-Rice, M and Cudkowicz, ME}, title = {Effect of neurophilin ligands on motor units in mice with SOD1 ALS mutations.}, journal = {Neurology}, volume = {57}, number = {10}, pages = {1857-1861}, doi = {10.1212/wnl.57.10.1857}, pmid = {11723276}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Cell Count ; Cell Survival/drug effects/genetics ; Dose-Response Relationship, Drug ; Endothelial Growth Factors/genetics ; Humans ; Lymphokines/*drug effects/genetics ; Mice ; Mice, Transgenic ; Motor Activity/drug effects ; Motor Neurons/*drug effects ; Motor Skills/drug effects ; Mutation/*genetics ; Nerve Regeneration/*drug effects/genetics ; Neuroprotective Agents/*pharmacology ; Organic Chemicals ; Pyridines/*pharmacology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; }, abstract = {BACKGROUND: Mice with trangenes that express mutations in the gene for cytosolic copper/zinc superoxide dismutase (SOD1) develop motor neuron degeneration resembling human ALS. Neurophilin ligands are small molecules that promote neurite outgrowth.<br><br>OBJECTIVE: To test the hypothesis that treatment with two neurophilin ligands increases survival in these ALS mice by slowing the loss of motor neurons and increasing the sizes of motor units.<br><br>METHODS: Transgenic mice hemizygous for the G93A mutation were untreated or treated from 30 days of age with one of two doses of two neurophilin ligands (V-13,670; V-10,367, Vertex Pharmaceuticals, Boston, MA). Onset of behavioral abnormalities and survival were recorded. Motor unit number estimation (MUNE) was performed every 21 days starting at age 60 days.<br><br>RESULTS: In control animals, disease onset occurred at 77.0 days of age and death occurred at 137 days of age. Neither neurophilin ligand affected the disease course. In control animals, MUNE declined with time beginning before behavioral abnormalities were noted, and motor unit size increased concomitantly. There was no effect of drug on motor unit loss as assessed by MUNE; however, motor unit size increased more rapidly and to a greater degree in animals treated with V-13,670.<br><br>CONCLUSION: As in human ALS, the transgenic ALS mice show physiologic changes in the motor unit prior to the development of clinical signs: MUNE declines as motor unit size increases. Although neither neurophilin ligand significantly affected survival, one produced an increase in motor unit size. The fact that survival was not altered by the increase in motor unit size may reflect the rapid disease course in this animal model.}, }
@article {pmid11719252, year = {2001}, author = {Gallo, JM}, title = {Kennedy's disease: a triplet repeat disorder or a motor neuron disease?.}, journal = {Brain research bulletin}, volume = {56}, number = {3-4}, pages = {209-214}, doi = {10.1016/s0361-9230(01)00575-5}, pmid = {11719252}, issn = {0361-9230}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Humans ; Muscular Atrophy, Spinal/*classification/*genetics ; Neurofilament Proteins/genetics ; Peptides/genetics ; Receptors, Androgen/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Tubulin/genetics ; }, abstract = {Two definite genetic causes of adult motor neuron degeneration have been identified to date: CAG repeat expansion in the androgen receptor gene in Kennedy's disease and point mutations in the SOD1 gene, encoding the enzyme, Cu/Zn superoxide dismutase, in some familial forms of amyotrophic lateral sclerosis. Although both have unrelated genetic causes, Kennedy's disease and SOD1-linked amyotrophic lateral sclerosis share several pathogenic features. First, expanded androgen receptor and mutant Cu/Zn superoxide dismutase have a propensity to aggregate into insoluble complexes and form inclusion bodies in affected neurons. Deposits of mutant proteins could be detrimental to neuronal viability by interfering with the normal housekeeping functions of chaperones and of the ubiquitin/proteasome system. Secondly, cytoskeletal function may be impaired in both diseases as decreased transactivational activity of expanded androgen receptor may cause an abnormal pattern of tubulin expression in motor neurons in Kennedy's disease and disruption of neurofilament organisation is a hallmark of amyotrophic lateral sclerosis. The concept of activation of overlapping cell death cascades by two distinct genetic defects could help elucidating downstream pathogenic processes and may provide novel targets for pharmacological intervention or gene therapy for the treatment of motor neuron disorders.}, }
@article {pmid11719117, year = {2001}, author = {Allegra, J and Lavery, R and Cody, R and Birnbaum, G and Brennan, J and Hartman, A and Horowitz, M and Nashed, A and Yablonski, M}, title = {Magnesium sulfate in the treatment of refractory ventricular fibrillation in the prehospital setting.}, journal = {Resuscitation}, volume = {49}, number = {3}, pages = {245-249}, doi = {10.1016/s0300-9572(00)00375-0}, pmid = {11719117}, issn = {0300-9572}, mesh = {Adolescent ; Adult ; Aged ; Anti-Arrhythmia Agents/*therapeutic use ; Cardiopulmonary Resuscitation ; Combined Modality Therapy ; Double-Blind Method ; *Emergency Medical Services ; Female ; Heart Arrest/drug therapy/etiology ; Humans ; Magnesium Sulfate/*therapeutic use ; Male ; Middle Aged ; New Jersey/epidemiology ; Prospective Studies ; Time Factors ; Treatment Outcome ; Ventricular Fibrillation/complications/*drug therapy ; }, abstract = {OBJECTIVE: To determine if magnesium sulfate (MgSO(4)) improves outcome in cardiac arrest patients initially in ventricular fibrillation (VF).<br><br>METHODS: Randomized, prospective, double blind, placebo-controlled, multicenter prehospital trial using 2 g of MgSO(4). Eligible patients were non-traumatic cardiac arrest patients (> or =18 years of age) presenting in VF. The protocol included those patients refractory to three electroshocks. Epinephrine and either 2 g of MgSO(4) or placebo (normal saline) were then administered. The primary outcome variable was return of spontaneous circulation (ROSC) in the field and a perfusing pulse on arrival at the ED. Secondary endpoints included admission to the hospital (ADMT) and hospital discharge (DISC). IRB approval was obtained at all participating centers.<br><br>RESULTS: Total 116 patients (58 MgSO(4), 58 placebo) were enrolled during the period from 4/1992 to 10/96 with 109 available. There were no significant differences between the groups in baseline characteristics and times to cardio pulmonary resuscitation (CPR), advanced life support (ALS), and first defibrillation, except for time to study drug administration. There was no significant differences in ROSC (placebo, 18.5%, and MgSO(4), 25.5%, P=0.38), ADMT (placebo rate=16.7%, MgSO(4)=16.4%, P=1.0) or DISC (placebo rate=3.7%, MgSO(4)=3.6%, P=1.0).<br><br>CONCLUSIONS: We failed to demonstrate that the administration of 2 g of MgSO(4) to prehospital cardiac arrest patients presenting in VF improves short or long term survival.}, }
@article {pmid11699892, year = {2001}, author = {Martin-Rendon, E and Azzouz, M and Mazarakis, ND}, title = {Lentiviral vectors for the treatment of neurodegenerative diseases.}, journal = {Current opinion in molecular therapeutics}, volume = {3}, number = {5}, pages = {476-481}, pmid = {11699892}, issn = {1464-8431}, mesh = {Alzheimer Disease/therapy ; Amyotrophic Lateral Sclerosis/therapy ; Animals ; Genetic Therapy/adverse effects/*methods/trends ; *Genetic Vectors ; Humans ; Huntington Disease/therapy ; Lentivirus/*genetics ; Nervous System/metabolism ; Neurodegenerative Diseases/*therapy ; Parkinsonian Disorders/therapy ; Safety ; }, abstract = {A number of potential gene therapy applications in the adult nervous system include neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. During the last five years, lentiviral vectors have developed into extremely efficient gene transfer vehicles to the nervous system, revealing a wide range of possibilities for the treatment or such disorders. This review describes the most important and recent advances in the development of lentiviral vectors as well as the demonstration of proof-of-principle in animal models of human neurodegenerative diseases.}, }
@article {pmid11687111, year = {2001}, author = {Miller, RG and Mitchell, JD and Moore, DH}, title = {Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {4}, pages = {CD001447}, doi = {10.1002/14651858.CD001447}, pmid = {11687111}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Excitatory Amino Acid Antagonists/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole/*therapeutic use ; }, abstract = {BACKGROUND: Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis (ALS) in some countries but not others. Questions persist about its clinical utility because of high cost, modest efficacy and concern over adverse effects.<br><br>OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival.<br><br>SEARCH STRATEGY: Search of the Cochrane Neuromuscular Disease Group Register for randomized trials and enquiry from authors of trials and other experts in the field. The most recent search was conducted in June 1999.<br><br>SELECTION CRITERIA: Types of studies: randomized trials<br><br>TYPES OF PARTICIPANTS: adults with a diagnosis of ALS Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: per cent mortality at 12 months with riluzole 100 mg Secondary: per cent mortality as a function of time with 100 mg and with all doses of riluzole, scales of neurologic function, quality of life, muscle strength and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: We identified two randomized trials. Each reviewer graded them for methodological quality. Data extraction was performed by a single reviewer and checked by the other two. We obtained some missing data from investigators. We performed meta-analyses with RevMan software using a fixed effects model.<br><br>MAIN RESULTS: The two eligible trials included a total of 794 riluzole treated patients and 320 placebo treated patients. The methodological quality was acceptable and the trials were easily comparable. There were significant differences between the riluzole and placebo groups of both trials, in terms of the primary outcome measure, which was per cent mortality at 12 months with the 100 mg dose of riluzole. The odds ratio for the combined studies was 0.57 (95%CI 0.41 to 0.80) at 12 months. In the secondary outcome measures, there was a survival advantage with riluzole 100 mg at six, nine, 12 and 15 months, but not at three or 18 months. Pooled data from the 50, 100 and 200mg dose groups in the larger trial showed a lower per cent mortality with riluzole compared to placebo only at 12 months (odds ratio (OR) 0.64, 95% CI 0.47 to 0.88). There was no beneficial effect on bulbar function, or muscle strength. There were scant data on quality of life, but patients treated with riluzole remained in a more moderately affected health state significantly longer than placebo-treated patients (weighted mean difference (WMD) 35.5 days, 95% CI 5.9 to 65.0). A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (WMD 2.65, 95% CI 1.51 to 4.65).<br><br>REVIEWER'S CONCLUSIONS: Riluzole 100 mg per day appears to be modestly effective in prolonging survival for patients with ALS.}, }
@article {pmid11686950, year = {2001}, author = {Henderson-Smart, DJ and Bhuta, T and Cools, F and Offringa, M}, title = {Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {3}, pages = {CD000104}, doi = {10.1002/14651858.CD000104}, pmid = {11686950}, issn = {1469-493X}, mesh = {Chronic Disease ; *High-Frequency Ventilation ; Humans ; Infant, Newborn ; Infant, Premature ; *Intermittent Positive-Pressure Ventilation ; Lung Diseases/*prevention &amp; control ; Randomized Controlled Trials as Topic ; Respiratory Distress Syndrome, Newborn/therapy ; }, abstract = {BACKGROUND: Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although intermittent positive pressure ventilation (IPPV) saves lives, lung distortion during its use is associated with lung injury and chronic lung disease (CLD). Conventional IPPV is provided at 30-80 breaths per minute while a newer form of ventilation called high frequency oscillatory ventilation (HFOV) provides 'breaths' at 10-15 cycles per second. This has been shown to result in less lung injury in experimental studies.<br><br>OBJECTIVES: The objective of this review is to determine whether the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation (CV) in preterm infants who are mechanically ventilated for the respiratory distress syndrome decreases the incidence of chronic lung disease (CLD) without adverse effects.<br><br>SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching by the Cochrane Collaboration, mainly in the English language.<br><br>SELECTION CRITERIA: Randomized controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who are to be given IPPV. Randomization and commencement of treatment should have been as soon as possible after the start of IPPV and usually in the first 12 hours of life.<br><br>DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. Each author extracted data separately; they were compared and differences were resolved. The standard method of the Cochrane Neonatal Review Group was used to synthesize the data using relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) for benefits, and number needed to harm (NNH) for adverse effects, were calculated. 95% confidence intervals were used.<br><br>MAIN RESULTS: Meta-analysis of the eight eligible studies comparing HFOV with CV revealed that there is no difference in mortality. There are trends toward decreases in CLD in survivors at 28-30 days, 'death or CLD at 28-30 days' and a significant reduction in CLD in survivors at 36-37 weeks postmenstrual age or discharge in the HFOV group (six trials, summary RR 0.73 (0.57, 0.93). There is a significant increase in severe (grades 3 &amp; 4) intraventricular hemorrhage (IVH) and in any pulmonary air leak syndrome [summary RR 1.19 (1.03, 1.38)] in the HFOV group. Only 2 trials have included neurodevelopmental follow up and more survivors in the HFOV group are abnormal [summary RR 1.26 (1.01, 1.58)]. In the subgroup of six trials where a high volume strategy (HVS) was used for HFOV, this is associated with significantly lower rates of CLD in survivors at 28-30 days [three trials, summary RR 0.53 (0.36, 0.76)], of 'death or CLD at 28-30 days' [three trials, summary RR 0.56 (0.40, 0.77) and oxygen use at 36-37 weeks postmenstrual age or discharge [five trials, summary RR 0.72 (0.56, 0.93)]. There were no overall differences in the rates of IVH or PVL. One trial suggests that HFOV may reduce the cost of in-hospital care. In this group of trials HFOV is associated with a strong trend for an increased rate of gross pulmonary ALS (four trials, summary RR 1.54 (0.98, 2.42)] In the subgroup of two trials (HIFI 1989, Rettwitz-Volk 1998) not using a HVS there is no effect of HFOV on the rate of CLD; however, there is an increase in the rate of periventricular leukomalacia (PVL) [summary RR 1.64 (1.02, 2.64).<br><br>REVIEWER'S CONCLUSIONS: Benefits of HFOV in terms of CLD appear to be outweighed by concerns about increased rates of pulmonary air leak and severe IVH. Until these issues are resolved HFOV cannot be recommended as the routine method of giving mechanical ventilation to preterm infants with RDS. Future trials should target very preterm infants who are at most risk of CLD and infants should be randomized in gestational age strata. Important long term pulmonary and neurodevelopmental outcomes should be measured and reported. Economic effects should be assessed.}, }
@article {pmid11684877, year = {2001}, author = {Monson, JP}, title = {Biochemical markers of individual response to growth hormone replacement in adults.}, journal = {Hormone research}, volume = {55 Suppl 2}, number = {}, pages = {49-54}, doi = {10.1159/000063475}, pmid = {11684877}, issn = {0301-0163}, mesh = {*Biomarkers ; Growth Hormone/administration &amp; dosage/adverse effects/*therapeutic use ; *Hormone Replacement Therapy ; Humans ; Outcome Assessment, Health Care/*methods ; }, abstract = {Options for determining the response to growth hormone (GH) replacement in adults include symptomatic response, changes in body composition and measurement of biochemical markers of GH action. It has become apparent from various studies and during routine clinical practice that abnormal elevation of serum markers of GH action during GH therapy may not be associated with either adverse symptoms or abnormalities in body composition, thereby limiting the value of subjective assessment and physical characteristics as safety markers of over-treatment. Candidate biochemical markers include insulin-like growth factor I (IGF-I), IGF-binding protein 3 (IGFBP-3) and the acid-labile subunit (ALS), and markers of bone remodelling. No single measurement provides an ideal index of adequacy of GH replacement. Serum IGF-I has the greatest utility during GH dose titration as it is more sensitive to changes in GH status than IGFBP-3 and ALS, and is also more sensitive to excessive GH replacement. IGF-I, therefore, provides an important safety marker. Furthermore, changes in IGF-I correlate with improvements in body composition. Changes in circulating insulin and leptin occur during GH therapy, but are significantly influenced by changes in body fat and its distribution and do not provide useful information upon which to gauge responsiveness to GH. Markers of bone remodelling are an important indicator of GH action within individuals, but exhibit wide inter-individual variation which limits their usefulness in defining relative GH responsiveness.}, }
@article {pmid11677005, year = {2001}, author = {Mazzini, L and Balzarini, C and Colombo, R and Mora, G and Pastore, I and De Ambrogio, R and Caligari, M}, title = {Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results.}, journal = {Journal of the neurological sciences}, volume = {191}, number = {1-2}, pages = {139-144}, doi = {10.1016/s0022-510x(01)00611-6}, pmid = {11677005}, issn = {0022-510X}, mesh = {Administration, Oral ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*drug therapy/physiopathology ; Arm/physiopathology ; Body Mass Index ; Creatine/*administration &amp; dosage/adverse effects ; Diarrhea/chemically induced ; Dietary Supplements ; *Exercise Test ; Female ; Follow-Up Studies ; Humans ; Isometric Contraction/*drug effects ; Leg/physiopathology ; Male ; Middle Aged ; Muscle Fatigue/drug effects ; Muscle Weakness/*drug therapy/etiology/physiopathology ; Treatment Outcome ; Vital Capacity/drug effects ; }, abstract = {Creatine supplementation in humans has been reported to enhance power and strength both in normal subjects and in patients with various neuromuscular diseases. The purpose of this study was to examine the effects of supplementation on exercise performance and maximal voluntary isometric muscular contraction (MVIC) in Amyotrophic Lateral Sclerosis (ALS) patients. We report the results obtained in 28 patients with probable/definite ALS. In each patient we acquired the dynamometric measurement of MVIC in 10 muscle groups of upper and lower limbs and a measure of fatigue by means of an high-intensity intermittent protocol in elbow flexors and knee extensors muscles. All patients completed the protocols at the baseline and after supplementation of 20 g per day for 7 days and after supplementation of 3 g per day for 3 and 6 months. MVIC increased after 7 days of supplementation in 20 patients (70%) in knee extensors and in 15 (53%) of them also in elbow flexors. A statistically significant difference between pre and post-treatment mean values of MVIC was found both in elbow flexors (P<0.05) and knee extensors (p<0.04). The analysis of the slopes of fatigue test showed a statistically significant improvement after 7 days of supplementation in 11 patients (39%) in elbow flexors and in 9 patients (32%) also in knee extensors muscles. During the 6-month follow-up period all the examined parameters showed a linear progressive decline. In conclusion, our preliminary results have demonstrated that supplementation temporary increases maximal isometric power in ALS patients so it may be of potential benefit in situations such as high intensity activity and it can be proposed as a symptomatic treatment.}, }
@article {pmid11676998, year = {2001}, author = {Tavakoli, M and Malek, M}, title = {The cost utility analysis of riluzole for the treatment of amyotrophic lateral sclerosis in the UK.}, journal = {Journal of the neurological sciences}, volume = {191}, number = {1-2}, pages = {95-102}, doi = {10.1016/s0022-510x(01)00618-9}, pmid = {11676998}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*economics ; Cost-Benefit Analysis/statistics &amp; numerical data ; Disease Progression ; Drug Costs/*statistics &amp; numerical data ; Forecasting ; Health Status ; Humans ; Markov Chains ; Models, Econometric ; Multicenter Studies as Topic/statistics &amp; numerical data ; Neuroprotective Agents/*economics/therapeutic use ; Palliative Care/economics ; Quality-Adjusted Life Years ; Randomized Controlled Trials as Topic/statistics &amp; numerical data ; Riluzole/*economics/therapeutic use ; Sensitivity and Specificity ; Survival Analysis ; Survival Rate/trends ; Treatment Outcome ; United Kingdom ; Value of Life/*economics ; }, abstract = {This study reports the results of a long-term economic evaluation of riluzole in the treatment of amyotrophic lateral sclerosis (ALS) versus best supportive care in the United Kingdom. The aim was to assess the cost implications of the life extension offered by riluzole through cost utility analysis based on patient assessed utilities of different health states.A Markov model was used to assess the cost-effectiveness of Rilutek with best supportive care. Transition possibilities and the distribution of patients by health states were taken from a cohort of 954 patients drawn from a large randomised, double blind, placebo-controlled, multicentre trial between 1992 and 1994 in the first 18 months and used to extrapolate the model to assess the long-term prolongation of life. Four distinct health states were used corresponding to mild, moderate, severe and terminal states. Costs associated with Rilutek included the acquisition cost and bi-monthly monitoring for raised ALT levels. Patient assessed utilities were collected by use of the standard gamble technique. 77 patients were entered into the study from two centres (King's, London and Preston) in the UK. Mean utilities for each of the health states was generated and, given that the data were skewed, a sensitivity analysis was undertaken with the median utility values. The implications of life extension offered by riluzole versus best supportive care were assessed both in terms of life extension projected and quality adjusted survival using patient based utilities. Using the Markov model and the transitional probabilities the base case cost per life year gained was estimated at pound sterlings 14,370 and applying Standard Gamble utility scores, the base case cost per QALY was assessed as pound sterlings 20,904. The effect of discounting costs and benefits altered the cost effectiveness analysis to pound sterlings 17,760 per life year gained while a sensitivity analysis around median or mean scores for the utility weight resulted in a range of pound sterlings 19,020 to pound sterlings 25,794 per QALY gained.}, }
@article {pmid11676995, year = {2001}, author = {Jackson, CE and Rosenfeld, J and Moore, DH and Bryan, WW and Barohn, RJ and Wrench, M and Myers, D and Heberlin, L and King, R and Smith, J and Gelinas, D and Miller, RG}, title = {A preliminary evaluation of a prospective study of pulmonary function studies and symptoms of hypoventilation in ALS/MND patients.}, journal = {Journal of the neurological sciences}, volume = {191}, number = {1-2}, pages = {75-78}, doi = {10.1016/s0022-510x(01)00617-7}, pmid = {11676995}, issn = {0022-510X}, mesh = {Disease Progression ; Humans ; Hypoventilation/*diagnosis/etiology/*physiopathology ; Motor Neuron Disease/complications/*physiopathology/therapy ; Oximetry ; Positive-Pressure Respiration ; Predictive Value of Tests ; Prospective Studies ; Quality of Life ; *Respiratory Function Tests ; Severity of Illness Index ; Single-Blind Method ; Surveys and Questionnaires ; Vital Capacity ; }, abstract = {There is still no consensus as to which physiologic marker should be used as a trigger for the initiation of non-invasive positive pressure ventilation (NPPV) in patients with amyotrophic lateral sclerosis (ALS). Current practice parameters recommend that the decision to begin treatment be based upon forced vital capacity (FVC) measurements. A prospective, randomized study was performed in 20 ALS patients who had an FVC of 70-100%. Patients received baseline assessments including: ALS functional rating scale-respiratory version (ALSFRS-R), pulmonary symptom scale, Short form 36 (SF-36), FVC%, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and nocturnal oximetry. Patients were randomized to receive NPPV based upon nocturnal oximetry studies suggesting oxygen desaturation <90% for one cumulative minute ("early intervention") or a FVC <50% ("standard of care"). At enrollment, there was no significant correlation between FVC% and the ALSFRS-R, symptom score, MEP, MIP, or duration of nocturnal desaturation <90%. An increase in the vitality subscale of the SF-36 was demonstrated in 5/6 patients randomized to "early intervention" with NPPV. Our data indicate that FVC% correlates poorly with respiratory symptoms and suggests that MIP and nocturnal oximetry may be more sensitive measures of early respiratory insufficiency. In addition, intervention with NPPV earlier than our current standard of care may result in improved quality of life.}, }
@article {pmid11675876, year = {2001}, author = {Bilak, MM and Corse, AM and Kuncl, RW}, title = {Additivity and potentiation of IGF-I and GDNF in the complete rescue of postnatal motor neurons.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2}, number = {2}, pages = {83-91}, doi = {10.1080/146608201316949523}, pmid = {11675876}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*physiopathology ; Animals ; Choline O-Acetyltransferase/metabolism ; Culture Techniques ; Disease Models, Animal ; Glial Cell Line-Derived Neurotrophic Factor ; Immunohistochemistry ; Insulin-Like Growth Factor I/*pharmacology/therapeutic use ; Motor Neurons/chemistry/*drug effects/*metabolism ; *Nerve Growth Factors ; Nerve Tissue Proteins/*pharmacology/therapeutic use ; Neurites/metabolism ; Rats ; Spinal Cord/cytology/physiology ; }, abstract = {BACKGROUND: Both growth and survival of motor neurons may depend on multiple neurotrophic factors. Individually, insulin-like growth factor I (IGF-I) and glial cell line-derived neurotrophic factor (GDNF) are potent neurotrophic/survival factors for postnatal motor neurons.<br><br>METHODS: We used an organotypic spinal cord model of glutamatergic degeneration in ALS to investigate whether IGF-I and GDNF interact to enhance motor neuron survival, their trophic effect on choline acetyltransferase (ChAT) activity, and their effect on neurite outgrowth.<br><br>RESULTS: We show that the combination of IGF-I and GDNF at active doses (1) is additively neuroprotective, (2) completely rescues rat motor neurons from chronic glutamate-mediated toxicity, and (3) additively upregulates motor neuron ChAT activity. Further, IGF-I, which by itself does not promote neurite outgrowth in this model, potentiates the neurite promoting action of GDNF.<br><br>CONCLUSION: The results predict that IGF-I combined with GDNF may provide a better therapy for the treatment of motor neuron disorders such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy.}, }
@article {pmid11673613, year = {2001}, author = {Brigell, MG and Taylor, CP}, title = {ALS defeats gabapentin: reflections on another failed treatment.}, journal = {Neurology}, volume = {57}, number = {8}, pages = {1524-1525}, doi = {10.1212/wnl.57.8.1524-a}, pmid = {11673613}, issn = {0028-3878}, mesh = {Acetates/*therapeutic use ; *Amines ; Amyotrophic Lateral Sclerosis/*drug therapy ; *Cyclohexanecarboxylic Acids ; Excitatory Amino Acid Antagonists/*therapeutic use ; Gabapentin ; Humans ; Treatment Failure ; *gamma-Aminobutyric Acid ; }, }
@article {pmid11668883, year = {2001}, author = {Charles, T and Swash, M}, title = {Amyotrophic lateral sclerosis: current understanding.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {33}, number = {5}, pages = {245-253}, doi = {10.1097/01376517-200110000-00005}, pmid = {11668883}, issn = {0888-0395}, mesh = {Drug Approval ; England ; Humans ; Motor Neuron Disease/drug therapy/etiology/*nursing ; Riluzole/therapeutic use ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS), or motor neuron disease (MND) as it is usually termed in the United Kingdom, is a fatal degenerative disease resulting in progressive weakness and wasting of voluntary muscles. The disease is caused by degeneration of upper motor neurons in the motor cortex and of lower motor neurons in the brainstem and spinal cord. This combined loss of function causes spastic paralysis, flaccid muscle weakness, wasting, and fasciculations. The disease process spares the sensory, autonomic, and oculomotor neurons. ALS is the most common of the MND syndromes in adults. Although the cause of ALS is unknown, there is evidence that the excitatory neurotransmitter glutamate plays an important role in neuronal cell death in the disease. Several risk factors, such as exposure to welding and soldering, inhalation of lead vapor, exposure to chemicals, and electrical trauma are postulated as contributing to the pathogenesis of ALS. About 90% of all ALS patients have the sporadic form. Approximately 20% of all familial ALS cases are associated with mutations of the copper/zinc superoxide dismutase-1 gene. What is not clear is what factors contribute to the causation of the more common sporadic cases. The drug riluzole has neuroprotective effects in ALS and is the only disease-specific treatment available to date. Riluzole has been approved by the National Institute for Clinical Excellence for use in the National Health Service of the United Kingdom. Other treatments are aimed at managing the devastating symptoms of ALS.}, }
@article {pmid11665866, year = {2001}, author = {Ferrante, RJ and Klein, AM and Dedeoglu, A and Beal, MF}, title = {Therapeutic efficacy of EGb761 (Gingko biloba extract) in a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of molecular neuroscience : MN}, volume = {17}, number = {1}, pages = {89-96}, pmid = {11665866}, issn = {0895-8696}, support = {AG12992/AG/NIA NIH HHS/United States ; AG13846/AG/NIA NIH HHS/United States ; AT00613/AT/NCCIH NIH HHS/United States ; NS35255/NS/NINDS NIH HHS/United States ; NS37102/NS/NINDS NIH HHS/United States ; P01AG1292/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Body Weight ; Diet ; Disease Models, Animal ; Female ; Free Radical Scavengers/metabolism/therapeutic use ; *Ginkgo biloba ; Humans ; Lumbar Vertebrae ; Male ; Mice ; Mice, Transgenic ; Neurons/metabolism ; Neuroprotective Agents/administration &amp; dosage/*therapeutic use ; *Phytotherapy ; Plant Extracts/administration &amp; dosage/*therapeutic use ; Psychomotor Performance ; Rotation ; Spinal Cord/cytology/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Survival Rate ; }, abstract = {EGb761 is a standardized extract of green Gingko biloba, which exerts protective effects against mitochondrial damage and oxidative stress. We examined whether oral administration of 0.022% or 0.045% EGb761 in the diet could impart neuroprotective effects in a transgenic mouse model (G93A) of amyotrophic lateral sclerosis (ALS). EGb761 significantly improved motor performance and survival, and protected against a loss of spinal-cord anterior motor horn neurons in male G93A mutant transgenic ALS mice, but not in littermate female mutant transgene mice. While EGb761 extended survival in littermate female G93A mice, significance was not reached. EGb761, however, significantly improved weight loss in both male and female transgenic ALS mice. These findings provide evidence for a gender-specific neuroprotective effect of EGb761 in a transgenic model of ALS and suggest that EGb761 may be a potential effective treatment in patients with ALS.}, }
@article {pmid11642587, year = {2001}, author = {Kamper, M and Mahoney, BD and Nelson, S and Peterson, J}, title = {Feasibility of paramedic treatment and referral of minor illnesses and injuries.}, journal = {Prehospital emergency care}, volume = {5}, number = {4}, pages = {371-378}, doi = {10.1080/10903120190939535}, pmid = {11642587}, issn = {1090-3127}, mesh = {Ambulances/*statistics &amp; numerical data ; Cardiopulmonary Resuscitation/*statistics &amp; numerical data ; Emergency Medical Technicians/*standards ; Emergency Treatment/*standards ; Feasibility Studies ; Humans ; Minnesota ; *Referral and Consultation ; Retrospective Studies ; Wounds and Injuries/*therapy ; }, abstract = {BACKGROUND: Approximately 40% of Hennepin County Medical Center's (HCMC's) ambulance runs are for minor medical conditions as defined by billing criteria ["ALS minor," i.e., no advanced life support (ALS) procedures done in the field]. Current metropolitan guidelines mandate that all such patients must be transported to a hospital unless they refuse this service. It has been proposed that some patients with minor medical conditions could be better served by treatment in the field by paramedics and referred to a clinic or hospital for early follow-up care. It is proposed that this approach would save costs and improve paramedic availability for patients with more serious conditions.<br><br>OBJECTIVE: To evaluate the feasibility and safety of implementing such a program by identifying high-volume, low-complexity groupings of cases. Such high-volume, low-complexity cases would serve as the topics for curriculum development for paramedic training in field treatment and referral.<br><br>METHODS: Data were obtained from ambulance run sheets and emergency department (ED) records for all patients transported by the HCMC ambulance service in 1996 who were covered by the Metropolitan Health Plan (MHP) and who were categorized for billing purposes as "ALS minor" transports. The data included demographic information, vital signs, presenting problem, diagnoses in the ED, and procedures, laboratory studies, or x-rays done in the ED. Patients were classified as "potentially treatable" in the field if they were treated and discharged from the ED without undergoing any procedures or diagnostic studies. Patients who required more extensive evaluation in the ED, or who were admitted, were classified as likely too "complex" to be treated at the scene and then referred for early follow-up. The data were analyzed to find the most common presenting problems and the numbers, characteristics, and dispositions of "potentially treatable" and "complex" patients in each group. This information was used to determine what, if any, types of patients could potentially be treated safely and effectively according to this scheme.<br><br>RESULTS: The study group comprised 1,103 patients, representing 127 different presenting medical problems. There were 523 (47%) "potentially treatable" patients and 580 (53%) "complex" patients. The 127 medical problems were grouped and the 15 most common presenting problem groups were identified. Within these groups there was no single medical problem with high volume. Each of these 15 most common problem groups contained a substantial proportion of "complex" patients, ranging from 24% to 100%.<br><br>CONCLUSIONS: None of the 15 most frequently encountered problem groups consisted of a high enough proportion of "potentially treatable" cases to serve as a high-volume, low-complexity category for paramedic treatment in the field with early follow-up. Without any identified high-volume, low-complexity categories, a treatment and referral program as proposed in this article would require a substantial investment in development of appropriate criteria and in training paramedics to apply the criteria for numerous clinical entities. This would limit any cost saving, and require great care to avoid compromising patient safety accompanied by substantial professional liability exposure.}, }
@article {pmid11600812, year = {2001}, author = {Siegsmund, M and Musial, A and Weiss, J and Alken, P}, title = {[Ldr brachytherapy, a minimally invasive alternative in the treatment of organ-confined prostate cancer].}, journal = {Onkologie}, volume = {24 Suppl 5}, number = {}, pages = {46-50}, doi = {10.1159/000055186}, pmid = {11600812}, issn = {0378-584X}, mesh = {*Brachytherapy ; Clinical Trials as Topic ; Humans ; Male ; Neoplasm Staging ; Prostate-Specific Antigen/blood ; Prostatic Neoplasms/mortality/pathology/*radiotherapy ; Radiotherapy Dosage ; }, abstract = {LDR Brachytherapy, a Minimally Invasive Alternative in the Treatment of Organ-Confined Prostate Cancer In den letzten Jahren erlebte die Brachytherapie mit permanenten Implantaten beim organbegrenzten Prostatakarzinom besonders in den USA, wo im Jahre 1999 mehr als 40 000 Implantationen durchgeführt wurden, eine Renaissance. Mit einer gewissen Verzögerung nimmt die Popularität dieser Methode auch in Europa immer mehr zu. Dies, obwohl die Brachytherapie keine absolut neue Methode in der Behandlung des Prostatakarzinoms ist, sie hat im Gegenteil eine lange Tradition.}, }
@article {pmid11599635, year = {2001}, author = {Halliwell, B}, title = {Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment.}, journal = {Drugs &amp; aging}, volume = {18}, number = {9}, pages = {685-716}, pmid = {11599635}, issn = {1170-229X}, mesh = {Animals ; Antioxidants/metabolism/*therapeutic use ; Brain/drug effects/metabolism/pathology ; Free Radicals/adverse effects/*metabolism ; Humans ; Models, Biological ; Neurodegenerative Diseases/*drug therapy/etiology/metabolism ; Oxidative Stress ; }, abstract = {Free radicals and other so-called 'reactive species' are constantly produced in the brain in vivo. Some arise by 'accidents of chemistry', an example of which may be the leakage of electrons from the mitochondrial electron transport chain to generate superoxide radical (O2*-). Others are generated for useful purposes, such as the role of nitric oxide in neurotransmission and the production of O2*- by activated microglia. Because of its high ATP demand, the brain consumes O2 rapidly, and is thus susceptible to interference with mitochondrial function, which can in turn lead to increased O2*- formation. The brain contains multiple antioxidant defences, of which the mitochondrial manganese-containing superoxide dismutase and reduced glutathione seem especially important. Iron is a powerful promoter of free radical damage, able to catalyse generation of highly reactive hydroxyl, alkoxyl and peroxyl radicals from hydrogen peroxide and lipid peroxides, respectively. Although most iron in the brain is stored in ferritin, 'catalytic' iron is readily mobilised from injured brain tissue. Increased levels of oxidative damage to DNA, lipids and proteins have been detected by a range of assays in post-mortem tissues from patients with Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, and at least some of these changes may occur early in disease progression. The accumulation and precipitation of proteins that occur in these diseases may be aggravated by oxidative damage, and may in turn cause more oxidative damage by interfering with the function of the proteasome. Indeed, it has been shown that proteasomal inhibition increases levels of oxidative damage not only to proteins but also to other biomolecules. Hence, there are many attempts to develop antioxidants that can cross the blood-brain barrier and decrease oxidative damage. Natural antioxidants such as vitamin E (tocopherol), carotenoids and flavonoids do not readily enter the brain in the adult, and the lazaroid antioxidant tirilazad (U-74006F) appears to localise in the blood-brain barrier. Other antioxidants under development include modified spin traps and low molecular mass scavengers of O2*-. One possible source of lead compounds is the use of traditional remedies claimed to improve brain function. Little is known about the impact of dietary antioxidants upon the development and progression of neurodegenerative diseases, especially Alzheimer's disease. Several agents already in therapeutic use might exert some of their effects by antioxidant action, including selegiline (deprenyl), apomorphine and nitecapone.}, }
@article {pmid11595664, year = {2001}, author = {Sevette, A and Kee, AJ and Carlsson, AR and Baxter, RC and Smith, RC}, title = {Parenteral nutrition with lipid or glucose suppresses liver growth and response to GH in adolescent male rats.}, journal = {American journal of physiology. Endocrinology and metabolism}, volume = {281}, number = {5}, pages = {E1063-72}, doi = {10.1152/ajpendo.2001.281.5.E1063}, pmid = {11595664}, issn = {0193-1849}, mesh = {Animals ; Body Composition/drug effects ; Body Weight/drug effects ; DNA/metabolism ; Drug Resistance ; Fatty Acids, Nonesterified/blood ; Fatty Liver/etiology ; Glucose/*administration &amp; dosage ; Human Growth Hormone/*pharmacology ; Insulin-Like Growth Factor I/pharmacology ; Lipid Metabolism ; Lipids/*administration &amp; dosage ; Liver/*drug effects/*growth &amp; development/metabolism ; *Parenteral Nutrition ; Proteins/metabolism ; Rats ; }, abstract = {Our aim was to investigate the effects of modifying the carbohydrate-to-lipid ratio of parenteral nutrition (PN) on body composition and the anabolic actions of insulin-like growth factor I (IGF-I) and growth hormone (GH). Adolescent male Sprague-Dawley rats were randomized to receive 7 days of GH, IGF-I (3.5 mg. kg(-1). day(-1) for both) or placebo while receiving high-carbohydrate PN (CHO-PN), high-lipid PN (L-PN), or an oral diet (chow) (the PN protocols were isonitrogenous and isocaloric). PN impaired muscle growth, which was reversed by GH in the CHO-PN group only (P < 0.03). PN increased carcass lipid (P < 0.02), the effect being greater in the L-PN than in the CHO-PN group (P < 0.001). Visceral lean tissue growth was significantly impaired by PN (P < 0.001). IGF-I reversed this impairment, but GH had no effect. PN impaired the normal increase in hepatic protein and DNA (P < 0.001) and produced liver steatosis (P < 0.001). However, this steatosis was less in L-PN than in CHO-PN (P < 0.001). Serum IGF-I and the acid-labile subunit (ALS) were decreased by PN (P < 0.001) and were not affected by GH during PN treatment. However, GH significantly increased serum ALS concentrations in the chow-fed rats (P = 0.032). In conclusion, modifying the CHO-to-L ratio of PN had no significant effect on IGF-I action, but CHO-PN increased the peripheral effect of GH. L-PN increased carcass lipid significantly and decreased hepatic steatosis. Nevertheless, PN caused significant liver steatosis and profound impairment of hepatic cell growth, which was associated with relative hepatic GH resistance.}, }
@article {pmid11592722, year = {2001}, author = {Quintela, L and Peña, A and Barrio, M and Vega, MD and Diaz, R and Maseda, F and Garcia, P}, title = {Reproductive performance of multiparous rabbit lactating does: effect of lighting programs and PMSG use.}, journal = {Reproduction, nutrition, development}, volume = {41}, number = {3}, pages = {247-257}, doi = {10.1051/rnd:2001104}, pmid = {11592722}, issn = {0926-5287}, mesh = {Animals ; Estrus Synchronization/drug effects ; Female ; Fertility/*drug effects ; Gonadotropins, Equine/*pharmacology ; Insemination, Artificial/*veterinary ; Lactation ; *Lighting ; Litter Size ; Ovulation Induction ; Photoperiod ; Pregnancy ; Rabbits/*physiology ; Reproduction ; }, abstract = {This study aims to determine if Pregnant Mare Serum Gonadotrophin (PMSG), used for oestrous synchronization in multiparous lactating does, could be replaced by one of the following lighting schedules without impairing reproductive performance: (a) 12-h L (light)/12-h D (dark) or (b) 8-h L/16-h D, until day 6 before artificial insemination (AI), when in both cases photoperiod was changed to 16-h L/8-h D and maintained until the day of AI, and in the following 4 days post Al the light hours were progressively reduced to the initial schedules. Two groups of 20 does each were respectively submitted to one of the lighting schedules specified above. All does were artificially inseminated in 6 consecutive cycles at 42 days intervals. In the first, third and fifth AIs, PMSG (20 IU/doe via sc 48 h before AI) was used in the two groups of does, whereas in the second, fourth and sixth Als no hormonal treatment was used. Degree of oestrous synchronization (also referred in text as sexual receptivity) was estimated by the colour of the vulva at AI. Reproductive performance of does was evaluated based on fertility (kindling rates), prolificity, mortality at birth, mortality at 21 days post birth, weight of the litter at 21 days post birth and number of weaned rabbits. Oestrous was better synchronized when PMSG was used with any of the two lighting programs. Without using PMSG, a photoperiod of 12-h L/12-h D until 6 days before AI resulted in a better sexual receptivity of does than 8-h L/16-h D. Fertility, prolificity, mortality of young rabbits at 21 days, the weight of the litters at 21 days and the number of weaned rabbits did not vary with the lighting program and were not affected by the PMSG treatment. Mortality at birth, however, was higher (+1 dead kit per litter) in litters housed under a light program of 12-h L/12-h D. Global productivity (number of weaned rabbits per 100 inseminated does) was better when using PMSG, for both lighting schedules. When using a photoperiod of 12-h L/12-h D until 6 days before AI, and omitting the PMSG treatment, global productivity was scarcely reduced, however, it was considerably impaired when using a photoperiod of 8-h L/16-h D until 6 days before AI and no PMSG treatment.}, }
@article {pmid11585581, year = {2001}, author = {Mizuta, I and Ohta, M and Ohta, K and Nishimura, M and Mizuta, E and Kuno, S}, title = {Riluzole stimulates nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor synthesis in cultured mouse astrocytes.}, journal = {Neuroscience letters}, volume = {310}, number = {2-3}, pages = {117-120}, doi = {10.1016/s0304-3940(01)02098-5}, pmid = {11585581}, issn = {0304-3940}, mesh = {Animals ; Astrocytes/cytology/*drug effects/*metabolism ; Brain-Derived Neurotrophic Factor/biosynthesis ; Cells, Cultured ; Glial Cell Line-Derived Neurotrophic Factor ; Mice ; Mice, Inbred ICR ; Nerve Growth Factor/biosynthesis ; Nerve Growth Factors/*biosynthesis ; Nerve Tissue Proteins/biosynthesis ; Neuroprotective Agents/*pharmacology ; Riluzole/*pharmacology ; }, abstract = {Riluzole is an antiexcitotoxic agent used for the treatment of amyotrophic lateral sclerosis, and reported to have neuroprotective effects in animal models of Parkinson's disease, Huntington's disease and brain ischemia. We investigated the effects of riluzole on synthesis of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in cultured mouse astrocytes. The protein and mRNA levels were measured by enzyme-linked immunosorbent assay and semiquantitative reverse transcription-polymerase chain reaction, respectively. Treatment with riluzole at 100 microg/ml (426 microM) for 24 h increased the contents of NGF, BDNF, and GDNF in the culture medium 109-fold, 2.0-fold and 3.1-fold over the control, respectively. The drug-induced relative mRNA levels of NGF, BDNF, and GDNF were 7.3-fold at 2 h, 2.1-fold at 4 h, and 1.9-fold at 2 h, respectively. These results indicate that riluzole stimulates synthesis of NGF, BDNF and GDNF in cultured astrocytes. Riluzole might exert neuroprotective effects, at least in part, via stimulation of neurotrophic factors.}, }
@article {pmid11582516, year = {2001}, author = {Keir, SD and Xiao, X and Li, J and Kennedy, PG}, title = {Adeno-associated virus-mediated delivery of glial cell line-derived neurotrophic factor protects motor neuron-like cells from apoptosis.}, journal = {Journal of neurovirology}, volume = {7}, number = {5}, pages = {437-446}, pmid = {11582516}, issn = {1355-0284}, mesh = {Animals ; *Apoptosis ; Cell Line ; Culture Media, Conditioned ; Culture Media, Serum-Free ; Dependovirus/*genetics ; Genes, Reporter ; Genetic Therapy ; Genetic Vectors/*genetics ; Glial Cell Line-Derived Neurotrophic Factor ; Humans ; Hybrid Cells ; Kidney ; Mice ; Motor Neuron Disease/therapy ; Motor Neurons/metabolism/*pathology ; *Nerve Growth Factors ; Nerve Tissue Proteins/*genetics/physiology ; Neuroblastoma/pathology ; Recombinant Fusion Proteins/physiology ; Spinal Cord/cytology/embryology ; Transfection ; beta-Galactosidase/genetics ; }, abstract = {Motor neuron disorders including amyotrophic lateral sclerosis may benefit from the induction of neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) that are known to be trophic and protective for motor neurons. However, the application of such factors is limited by an inability to successfully target their expression in the nervous system. In this study we investigate the potential of using adeno-associated virus (AAV) as a vector for gene delivery into motor neuron-like cells. In initial experiments on the motor neuron cell line NSC-19 using a recombinant AAV vector expressing the reporter gene beta-galactosidase (AAV-LacZ), we successfully demonstrate the utility of AAV for gene transfer. In addition, a recombinant AAV vector expressing GDNF was shown to express and secrete high levels of the neurotrophic factor into the surrounding media of NSC-19 infected cells. Finally, the AAV-GDNF vector is demonstrated to act in a neuroprotective fashion. Withdrawal of trophic support from NSC-19 cells through serum deprivation results in a subsequent increase in the number of cells entering apoptosis. However, the percentage of apoptotic cells are significantly reduced in cells infected with the AAV-GDNF vector, as compared to AAV-LacZ or uninfected controls. This work demonstrates the potential of using AAV as a vector in motor neuron-like cells and should prove important in devising future gene therapy strategies for the treatment of in vivo motor neuron disorders.}, }
@article {pmid11579149, year = {2001}, author = {Tikka, T and Usenius, T and Tenhunen, M and Keinänen, R and Koistinaho, J}, title = {Tetracycline derivatives and ceftriaxone, a cephalosporin antibiotic, protect neurons against apoptosis induced by ionizing radiation.}, journal = {Journal of neurochemistry}, volume = {78}, number = {6}, pages = {1409-1414}, doi = {10.1046/j.1471-4159.2001.00543.x}, pmid = {11579149}, issn = {0022-3042}, mesh = {Animals ; Anti-Bacterial Agents/*pharmacology ; Apoptosis/*drug effects ; Ceftriaxone/*pharmacology ; Cells, Cultured ; Cephalosporins/*pharmacology ; Doxycycline/*pharmacology ; Minocycline/*pharmacology ; Neurons/*drug effects/*radiation effects ; Neuroprotective Agents/*pharmacology ; Radiation Injuries/*prevention &amp; control ; Rats ; Rats, Wistar ; }, abstract = {DNA damage induced by low doses of ionizing radiation causes apoptosis, which is partially mediated via the generation of free radicals. Both free radicals and apoptosis are involved in the majority of brain diseases, including stroke, Alzheimer's disease and amyotrophic lateral sclerosis. Because previous studies have shown that tetracycline derivatives doxycycline and minocycline have anti-inflammatory effects and are protective against brain ischemia, we studied whether minocycline and doxycycline or ceftriaxone, a cephalosporin antibiotic with the potential to inhibit excitotoxicity, protect neurons against ionizing radiation in primary cortical cultures. A single dose of 1 Gy significantly increased lactate dehydrogenase release, induced DNA fragmentation in neurons and triggered microglial proliferation. Treatment with minocycline (20 nM), doxycycline (20 nM) and ceftriaxone (1 microM) significantly reduced irradiation-induced lactate dehydrogenase release and DNA fragmentation. The most efficient protection was achieved by minocycline treatment, which also inhibited the irradiation-induced increase in microglial cell number. Our results suggest that some tetracycline derivatives, such as doxycycline and minocycline, and ceftriaxone, a cephalosporin derivative, protect neurons against apoptotic death.}, }
@article {pmid11574113, year = {2001}, author = {Tan, EK and Lo, YL and Seah, A and Auchus, AP}, title = {Recurrent jaw dislocation after botulinum toxin treatment for sialorrhoea in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {190}, number = {1-2}, pages = {95-97}, doi = {10.1016/s0022-510x(01)00565-2}, pmid = {11574113}, issn = {0022-510X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/pathology/physiopathology ; Botulinum Toxins/*adverse effects ; Electromyography ; Female ; Humans ; Injections, Intramuscular/adverse effects ; Joint Dislocations/*chemically induced/pathology/physiopathology ; Masticatory Muscles/*drug effects/pathology/physiopathology ; Muscle Weakness/chemically induced/pathology/physiopathology ; Parotid Gland/drug effects/pathology/physiopathology ; Sialorrhea/*drug therapy/etiology/physiopathology ; Temporomandibular Joint/*drug effects/pathology/physiopathology ; Temporomandibular Joint Disorders/*chemically induced/pathology/physiopathology ; }, abstract = {Botulinum toxin (BTX) has been used successfully to treat various movement disorders, and is increasingly used for many other medical conditions. Sialorrhoea is a disabling symptom in many neurological patients including those with Parkinson's disease, stroke and amyotrophic lateral sclerosis (ALS). BTX has recently been shown to be effective for treating sialorrhoea. We report an ALS patient who developed recurrent jaw dislocation following BTX treatment for sialorrhoea to highlight the observation that intraparotid BTX may be complicated by jaw dislocations in some at-risk ALS patients. Clinicians using BTX to treat sialorrhoea in ALS need to be aware of this potentially serious complication.}, }
@article {pmid11571341, year = {2001}, author = {MacGowan, DJ and Scelsa, SN and Waldron, M}, title = {An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy.}, journal = {Neurology}, volume = {57}, number = {6}, pages = {1094-1097}, doi = {10.1212/wnl.57.6.1094}, pmid = {11571341}, issn = {0028-3878}, mesh = {Adult ; Anti-HIV Agents/*therapeutic use ; Brain/pathology ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; HIV Infections/diagnosis/*drug therapy ; Humans ; Lamivudine/therapeutic use ; Magnetic Resonance Imaging ; Motor Neuron Disease/diagnosis/*drug therapy ; Nelfinavir/therapeutic use ; Neurologic Examination/drug effects ; Treatment Outcome ; Zidovudine/therapeutic use ; }, abstract = {A 32-year-old woman presenting with a rapidly progressive ALS-like syndrome was found to be HIV positive with a CD4 count of 44/mm(3). The patient recovered completely during 1 year after treatment with nelfinavir, zidovudine, and lamivudine, and recovery is sustained nearly 4 years later. Recovery was accompanied by HIV RNA becoming undetectable in plasma and CSF.}, }
@article {pmid11571323, year = {2001}, author = {Moulignier, A and Moulonguet, A and Pialoux, G and Rozenbaum, W}, title = {Reversible ALS-like disorder in HIV infection.}, journal = {Neurology}, volume = {57}, number = {6}, pages = {995-1001}, doi = {10.1212/wnl.57.6.995}, pmid = {11571323}, issn = {0028-3878}, mesh = {Adult ; CD4 Lymphocyte Count ; Disease Progression ; Female ; HIV Infections/*diagnosis/virology ; *HIV-1/pathogenicity ; Humans ; Male ; Motor Neuron Disease/*diagnosis/virology ; Neurologic Examination ; Retrospective Studies ; Virulence ; }, abstract = {OBJECTIVE: To describe the clinical features, treatment, and outcome of six cases of HIV-1-associated ALS-like disorder.<br><br>METHODS: The authors reviewed patients with HIV infection with neurologic symptoms seen over a 13-year period. Patients were identified by using the El Escorial research diagnostic criteria defining three categories of certainty for definite, probable, or possible ALS. Clinical features, EMG, CSF, serum analyses, and imaging and virological studies were assessed.<br><br>RESULTS: Six patients with immunodepression (mean CD4(+) cells = 86.2/mm(3); mean age = 34 years) developed distal motor weakness mimicking a monomelic amyotrophy that subacutely progressed regionally or assumed a symmetric distribution on more than one region. EMG was characteristic of motor neuron disease with no multifocal conduction block. Causes other than HIV-1 were ruled out. The unusual rapid extension of the disease and the positive response to antiretroviral therapy suggest that ALS syndrome and HIV infection are etiologically related. HIV-1 might cause an ALS-like disorder by several mechanisms-via neuronal infection, by secretion of toxic viral substance, by inducing the immune system to secrete cytokines, or by inducing an autoimmune disease.<br><br>CONCLUSION: These cases suggest that the association between some motor neuron diseases and HIV infection is not coincidental but pathogenetically related and that ALS-like disorder should be considered an HIV-related neurologic complication.}, }
@article {pmid11571316, year = {2001}, author = {Yasojima, K and Tourtellotte, WW and McGeer, EG and McGeer, PL}, title = {Marked increase in cyclooxygenase-2 in ALS spinal cord: implications for therapy.}, journal = {Neurology}, volume = {57}, number = {6}, pages = {952-956}, doi = {10.1212/wnl.57.6.952}, pmid = {11571316}, issn = {0028-3878}, mesh = {Aged ; Aged, 80 and over ; Cerebrovascular Disorders/pathology ; Cyclooxygenase 2 ; Female ; Gene Expression Regulation, Enzymologic/physiology ; Humans ; Isoenzymes/*genetics ; Male ; Membrane Proteins ; Middle Aged ; Motor Neuron Disease/*pathology ; Parkinson Disease/pathology ; Prostaglandin-Endoperoxide Synthases/*genetics ; RNA, Messenger/*genetics ; Spinal Cord/*pathology ; Up-Regulation/genetics ; }, abstract = {OBJECTIVE: To evaluate the hypothesis that cyclooxygenase-2 (COX-2) is linked to the pathology of ALS by determining whether COX-2 mRNA levels are upregulated in ALS spinal cord.<br><br>METHODS: Spinal cord from 11 ALS cases and 27 controls consisting of 15 cases of Alzheimer disease (AD), six cases of Parkinson disease (PD), three cases of cerebrovascular disease, and three control cases were analyzed. Total RNA was extracted and reverse transcriptase-PCR analysis performed for the mRNA of COX-2, COX-1, the microglial marker CD11b, and the housekeeping gene cyclophilin.<br><br>RESULTS: In ALS compared with non-ALS spinal cord, COX-2 mRNA was upregulated 7.09-fold (p < 0.0001), COX-1 1.14-fold (p = 0.05), and CD11b 1.85-fold (p = 0.0012). COX-2 mRNA levels in AD, PD, cerebrovascular disease, and control cases were each significantly lower than in ALS and were not significantly different from each other. Western blots of the protein products were in general accord with the mRNA data, with COX-2 protein levels being upregulated 3.79-fold compared with non-ALS cases (p = 0.015).<br><br>CONCLUSIONS: The strong upregulation of COX-2 mRNA in ALS is in accord with studies in the superoxide dismutase transgenic mouse model in which COX-2 upregulation occurs. Taken in conjunction with evidence of a neuroprotective effect of COX-2 inhibitors in certain animal models and in organotypic cultures, the data are supportive of a possible future role for COX-2 inhibitors in the treatment of ALS.}, }
@article {pmid11569536, year = {2001}, author = {González Deniselle, MC and González, SL and De Nicola, AF}, title = {Cellular basis of steroid neuroprotection in the wobbler mouse, a genetic model of motoneuron disease.}, journal = {Cellular and molecular neurobiology}, volume = {21}, number = {3}, pages = {237-254}, pmid = {11569536}, issn = {0272-4340}, mesh = {Animals ; Disease Models, Animal ; Mice ; Mice, Neurologic Mutants ; Motor Neuron Disease/*drug therapy/*genetics/pathology ; Neuroprotective Agents/*pharmacology ; Pregnatrienes/*pharmacology ; }, abstract = {1. The Wobbler mouse suffers an autosomal recessive mutation producing severe motoneuron degeneration and astrogliosis in the spinal cord. It has been considered a suitable model of human motoneuron disease, including the sporadic form of amyotrophic lateral sclerosis (ALS). 2. Evidences exist demonstrating increased oxidative stress in the spinal cord of Wobbler mice, whereas antioxidant therapy delayed neurodegeneration and improved muscle trophism. 21-Aminosteroids are glucocorticoid-derived hydrophobic compounds with antioxidant potency 3 times higher than vitamin E and 100 times higher than methylprednisolone. They do not bind to intracellular receptors, and prevent lipid peroxidation by insertion into membrane lipid bilayers. 3. In common with the spinal cord of ALS patients, Wobbler mice present astrocytosis with hyperexpression of glial fibrillary acidic protein (GFAP), and increased expression of nitric oxide synthase (NOS) and growth-associated protein (GAP-43) in motoneurons. Here, we review our studies on the effects of a 21-aminosteroid on GFAP, NOS, and GAP-43. 4. First, we showed that 21-aminosteroid treatment further increased GFAP-expressing astrocytes in gray matter of the Wobbler spinal cord. This effect may provide neuroprotection if one considers a trophic and beneficial function of astrocytes during the course of degeneration. Other neuroprotectans used in Wobbler mice (T-588) also increased pre-existing astrocytosis. 5. Second, histochemical determination of NADPH-diaphorase, a parameter indicative of neuronal NOS activity, showed that the 21-aminosteroid down-regulated the high activity of this enzyme in ventral horn motoneurons. Therefore, suppression of nitric oxide by decreasing NADPH-diaphorase (NOS) activity may provide neuroprotection considering that excess NO is highly toxic to motoneurons. 6. Finally, 21-aminosteroid treatment significantly attenuated the aberrant expression of both GAP-43 protein and mRNA in Wobbler motoneurons. Hyperexpression of GAP-43 possibly indicated abnormal synaptogenesis, denervation, and muscle atrophy, parameters which may return to normal following antioxidant steroid treatment. 7. Besides 21-aminosteroids, other steroids also behave as neuroprotectans. In this regard, degenerative diseases may constitute potential targets of these hormones, based on the fact that the spinal cord expresses in a regional and cell-specific fashion, receptors for androgens. progesterone, adrenal steroids, and estrogens.}, }
@article {pmid11563174, year = {2001}, author = {Cammarota, A and Nogués, M and Rivero, A and García, H}, title = {[Multifocal motor neuropathy. Immediate response to intravenous immunoglobulin].}, journal = {Medicina}, volume = {61}, number = {4}, pages = {441-444}, pmid = {11563174}, issn = {0025-7680}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Diagnosis, Differential ; Humans ; Immunoglobulins, Intravenous/*therapeutic use ; Male ; Middle Aged ; Motor Neuron Disease/diagnosis/*drug therapy ; Neural Conduction ; }, abstract = {Multifocal motor neuropathy, a rare insidious immune-mediated disorder, features muscular weakness and atrophy, as well as areflexia, due to nerve conduction block and is often associated with the presence of anti-GM1 antibody. We report a patient with a nine-year history of progressive upper limb weakness, misdiagnosed as amyotrophic lateral sclerosis, who responded within hours to intravenous immunoglobulin treatment with full recovery of muscle strength. This case highlights the need to search for conduction block in patients with lower motor neuron involvement.}, }
@article {pmid11561094, year = {2001}, author = {Canton, T and Böhme, GA and Boireau, A and Bordier, F and Mignani, S and Jimonet, P and Jahn, G and Alavijeh, M and Stygall, J and Roberts, S and Brealey, C and Vuilhorgne, M and Debono, MW and Le Guern, S and Laville, M and Briet, D and Roux, M and Stutzmann, JM and Pratt, J}, title = {RPR 119990, a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist: synthesis, pharmacological properties, and activity in an animal model of amyotrophic lateral sclerosis.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {299}, number = {1}, pages = {314-322}, pmid = {11561094}, issn = {0022-3565}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Anticonvulsants/chemical synthesis/pharmacology ; Disease Progression ; Electrophysiology ; Electroshock ; Excitatory Amino Acid Antagonists/chemical synthesis/pharmacokinetics/*pharmacology ; Glutamic Acid/drug effects ; Imidazoles/chemistry/pharmacokinetics/*pharmacology ; In Vitro Techniques ; Longevity/drug effects ; Mice ; Mice, Transgenic ; Muscle, Skeletal/drug effects ; Neurons/drug effects ; Patch-Clamp Techniques ; Pyrazines/chemistry/pharmacokinetics/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, AMPA/*antagonists &amp; inhibitors/metabolism ; Superoxide Dismutase/genetics ; }, abstract = {Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonists are of potential interest for the treatment of certain acute and chronic neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, we describe the synthesis and pharmacological properties of 9-carboxymethyl-4-oxo-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-phosphonic acid (RPR 119990). The compound displaced [3H]AMPA from rat cortex membranes with a K(i) of 107 nM. In oocytes expressing human recombinant AMPA receptors, RPR 119990 depressed ion flux with a K(B) of 71 nM. The antagonist properties of this compound were confirmed on rat native AMPA receptors in cerebella granule neurons in culture and in hippocampal slices where it antagonized electrophysiological responses with IC50 values of 50 and 93 nM, respectively. RPR 119990 antagonized hippocampal evoked responses in vivo, demonstrating brain penetration at active concentrations. RPR 119990 is a potent anticonvulsant in the supramaximal electroshock in the mouse with an ED50 of 2.3 mg/kg 1 h post s.c. administration, giving it a workably long action. Pharmacokinetic studies show good passage into the plasma after subcutaneous administration, whereas brain penetration is low but with slow elimination. This compound was found active in a transgenic mouse model of familial amyotrophic lateral sclerosis (SOD1-G93A) where it was able to improve grip muscle strength and glutamate uptake from spinal synaptosomal preparations, and prolong survival with a daily dose of 3 mg/kg s.c.}, }
@article {pmid11555629, year = {2001}, author = {Bordet, T and Lesbordes, JC and Rouhani, S and Castelnau-Ptakhine, L and Schmalbruch, H and Haase, G and Kahn, A}, title = {Protective effects of cardiotrophin-1 adenoviral gene transfer on neuromuscular degeneration in transgenic ALS mice.}, journal = {Human molecular genetics}, volume = {10}, number = {18}, pages = {1925-1933}, doi = {10.1093/hmg/10.18.1925}, pmid = {11555629}, issn = {0964-6906}, mesh = {Adenoviridae/genetics ; Amyotrophic Lateral Sclerosis/genetics/physiopathology/therapy ; Animals ; Animals, Newborn ; Atrophy ; Behavior, Animal/physiology ; Body Weight ; Cytokines/*genetics/physiology ; Female ; Gene Expression ; Gene Transfer Techniques ; Genetic Therapy ; Genetic Vectors/administration &amp; dosage/genetics ; Humans ; Injections, Intramuscular ; Male ; Mice ; Mice, Inbred Strains ; Mice, Transgenic ; Muscle, Skeletal/pathology ; Mutation ; Nerve Degeneration/genetics/physiopathology/*therapy ; Neuromuscular Diseases/genetics/physiopathology/*therapy ; Neuromuscular Junction/physiology ; Phrenic Nerve/pathology ; Superoxide Dismutase/genetics ; Survival Analysis ; Time Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is mainly a sporadic neurodegenerative disorder characterized by loss of cortical and spinal motoneurons. Some familial ALS cases (FALS) have been linked to dominant mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Transgenic mice overexpressing a mutated form of human SOD1 with a Gly93Ala substitution develop progressive muscle wasting and paralysis as a result of spinal motoneuron loss and die at 5 to 6 months. We investigated the effects of neurotrophic factor gene delivery in this FALS model. Intramuscular injection of an adenoviral vector encoding cardiotrophin-1 (CT-1) in SOD1G93A newborn mice resulted in systemic delivery of CT-1, supplying motoneurons with a continuous source of trophic factor. CT-1 delayed the onset of motor impairment as assessed in the rotarod test. Axonal degeneration was slowed and skeletal muscle atrophy was largely reduced by CT-1 treatment. By monitoring the amplitude of the evoked motor response, we showed that the time-course of motor impairment was significantly decreased by CT-1 treatment. Thus, adenovirus-mediated gene transfer of neurotrophic factors might delay neurogenic muscular atrophy and progressive neuromuscular deficiency in ALS patients.}, }
@article {pmid11550074, year = {2001}, author = {Klausmeier, WH}, title = {A patient-supported strategy for therapy development in amyotrophic lateral sclerosis (ALS).}, journal = {American journal of therapeutics}, volume = {8}, number = {5}, pages = {329-332}, doi = {10.1097/00045391-200109000-00006}, pmid = {11550074}, issn = {1075-2765}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Databases, Factual ; *Drug Evaluation, Preclinical ; Humans ; Mice ; Models, Biological ; Rats ; United States ; *United States Food and Drug Administration ; }, abstract = {Patient-supported foundations have had a significant impact on the scope of therapy development for the neurodegenerative disease, amyotrophic lateral sclerosis (ALS). In addition to sponsoring the investigation of potential curative therapies, the ALS Therapy Development Foundation (ALS-TDF) has also created an independent in vivo animal screening laboratory and is systematically evaluating the potential therapeutic benefit of drugs already approved by the FDA. A stepwise process of approved drug database development, in vitro drug screening using cell cultures, and 'theoretical' drug screening based on known drug mechanisms of action has narrowed the field from 1600 FDA-approved drugs to 90 candidates with potential therapeutic benefit. These drugs are now being evaluated in vivo using two animal models of ALS-the rat 'stroke' model and the transgenic SOD1 mouse model. Drug candidates showing significant benefit in these models compared with the current standard treatment for ALS will be selected for application in human patients.}, }
@article {pmid11543265, year = {1999}, author = {Vaccari, DA and Levri, J}, title = {Multivariable empirical modeling of ALS systems using polynomials.}, journal = {Life support &amp; biosphere science : international journal of earth space}, volume = {6}, number = {4}, pages = {265-271}, pmid = {11543265}, issn = {1069-9422}, mesh = {Biodegradation, Environmental ; Culture Media ; *Ecological Systems, Closed ; Hot Temperature ; *Life Support Systems ; Light ; Solanum lycopersicum/*growth &amp; development/*metabolism/radiation effects ; *Models, Biological ; Motion ; Multivariate Analysis ; Regression Analysis ; Temperature ; }, abstract = {Multivariable polynomial regression (MPR) was used to model plant motion time-series and nutrient recovery data for Advanced Life Support (ALS). MPR has capabilities similar to neural network models in terms of ability to fit multiple-input single-output nonlinear data. It has advantages over neural networks including: reduced overfitting, produces models that are more tractable for optimization, sensitivity analysis, and prediction of confidence intervals. MPR was used to produce nonlinear polynomial time-series models predicting plant projected canopy area versus time and temperature. Temperature was found to not have a statistically significant effect. Models were developed to relate rate and extent of nutrient recovery to treatment parameters, including temperature and use of heat pretreatment or nutrient supplementation. These applications demonstrate MPR's capability to fill "gaps" in an integrated model of ALS. Fundamental models should be used whenever available. However, some components may require empirical modeling. Furthermore, even fundamental models often have empirical constituents. MPR models are proposed to satisfy these needs.}, }
@article {pmid11527090, year = {2001}, author = {Morrison, KM and Wu, Z and Bidlingmaier, M and Strasburger, CJ}, title = {Findings and theoretical considerations on the usefulness of the acid-labile subunit in the monitoring of acromegaly.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {11 Suppl A}, number = {}, pages = {S61-3}, doi = {10.1016/s1096-6374(01)80010-1}, pmid = {11527090}, issn = {1096-6374}, mesh = {Acromegaly/*blood/diagnosis/*drug therapy ; Animals ; Biomarkers/blood ; Carrier Proteins/*blood ; Glycoproteins/*blood ; Human Growth Hormone/analogs &amp; derivatives/*therapeutic use ; Humans ; Insulin-Like Growth Factor Binding Protein 3/metabolism ; Predictive Value of Tests ; Receptors, Somatotropin/*antagonists &amp; inhibitors ; }, abstract = {Growth hormone (GH) action induces a variety of biochemical factors of which insulin-like growth factor I (IGF-I) is conventionally measured for the diagnosis and monitoring of GH-related disorders such as GH deficiency or acromegaly. IGF-I circulates predominantly as a ternary complex with IGF-binding protein 3 (IGFBP-3) and the acid labile subunit (ALS). In the treatment of active acromegaly with the GH receptor antagonist pegvisomant, ALS showed a closer correlation with the change in ring size, measured as a clinical indicator of disease activity, than did IGF-I or IGFBP-3. ALS thus seems to be a clinically useful marker of disease activity in acromegaly.}, }
@article {pmid11524646, year = {2001}, author = {Pointer, JE and Levitt, MA and Young, JC and Promes, SB and Messana, BJ and Adèr, ME}, title = {Can paramedics using guidelines accurately triage patients?.}, journal = {Annals of emergency medicine}, volume = {38}, number = {3}, pages = {268-277}, doi = {10.1067/mem.2001.117198}, pmid = {11524646}, issn = {0196-0644}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *Allied Health Personnel ; California ; Child ; Child, Preschool ; Emergency Service, Hospital ; Female ; Hospitals, Teaching ; Humans ; Male ; Middle Aged ; Patient Admission ; *Practice Guidelines as Topic ; *Triage ; }, abstract = {STUDY OBJECTIVE: We determine whether paramedics, using written guidelines, can accurately triage patients in the field.<br><br>METHODS: This prospective, descriptive study was conducted at an urban county emergency medical services (EMS) system and county hospital. Paramedics triaged patients, for study purposes only, according to 4 categories: (1) needing to come to the emergency department by advanced life support (ALS) transport, (2) needing to come to the ED by any transport, (3) needing to see a physician within 24 hours, or (4) not needing any further physician evaluation. Medical records that provided patient treatment information to the point of ED disposition were subsequently reviewed (blinded to the paramedic rating) to determine which of the categories was appropriate. The protocol of the EMS system of the study site dictates that all patients should be transported except for those who refuse care and leave against medical advice. Only transported patients were included in the present study. Fifty-four paramedics triaged 1,180 patients.<br><br>RESULTS: Mean patient age was 43.4+/-17 years; 62.0% were male. Paramedics rated 1,000 (84.7%) of the patients as needing to come to the ED and 180 (15.3%) as not needing to come to the ED. Ratings according to triage category were as follows: 804 (68.1%) category 1, 196 (16.6%) category 2, 148 (12.5%) category 3, and 32 (2.7%) category 4. Seven hundred thirty-six (62.4%) patients were discharged, 298 (25.3%) were admitted, 90 (7.6%) were transferred, 36 (3.1%) left against medical advice, and 20 (1.7%) died. The review panel determined that 113 (9.6%) patients were undertriaged; 55 (48.7%) of these patients were misclassified because the paramedics misused the guidelines. Ninety-nine patients (8.4% of the total sample) were incorrectly classified as not needing to come to the ED. This represented 55% of the patients (99/180) categorized as 3 or 4 by the paramedics. Fourteen patients (1.2% of total) were incorrectly classified as category 4 instead of 3. Of the 113 undertriaged patients, 22 (19.6%) were admitted, 86 (76.1%) were discharged, and 4 (3.5%) were transferred.<br><br>CONCLUSION: Paramedics using written guidelines fall short of an acceptable level of triage accuracy to determine disposition of patients in the field.}, }
@article {pmid11524608, year = {2001}, author = {Bruno, V and Battaglia, G and Copani, A and D'Onofrio, M and Di Iorio, P and De Blasi, A and Melchiorri, D and Flor, PJ and Nicoletti, F}, title = {Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs.}, journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, volume = {21}, number = {9}, pages = {1013-1033}, doi = {10.1097/00004647-200109000-00001}, pmid = {11524608}, issn = {0271-678X}, mesh = {Animals ; Brain Diseases/*drug therapy ; Humans ; Neuroprotective Agents/*pharmacology ; Receptors, Metabotropic Glutamate/*agonists/*antagonists &amp; inhibitors ; }, abstract = {Metabotropic glutamate (mGlu) receptors have been considered as potential targets for neuroprotective drugs, but the lack of specific drugs has limited the development of neuroprotective strategies in experimental models of acute or chronic central nervous system (CNS) disorders. The advent of potent and centrally available subtype-selective ligands has overcome this limitation, leading to an extensive investigation of the role of mGlu receptor subtypes in neurodegeneration during the last 2 years. Examples of these drugs are the noncompetitive mGlu1 receptor antagonists, CPCCOEt and BAY-36-7620; the noncompetitive mGlu5 receptor antagonists, 2-methyl-6-(phenylethynyl)pyridine, SIB-1893, and SIB-1757; and the potent mGlu2/3 receptor agonists, LY354740 and LY379268. Pharmacologic blockade of mGlu1 or mGlu5 receptors or pharmacologic activation of mGlu2/3 or mGlu4/7/8 receptors produces neuroprotection in a variety of in vitro or in vivo models. MGlu1 receptor antagonists are promising drugs for the treatment of brain ischemia or for the prophylaxis of neuronal damage induced by synaptic hyperactivity. MGlu5 receptor antagonists may limit neuronal damage induced by a hyperactivity of N-methyl-d-aspartate (NMDA) receptors, because mGlu5 and NMDA receptors are physically and functionally connected in neuronal membranes. A series of observations suggest a potential application of mGlu5 receptor antagonists in chronic neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer disease. MGlu2/3 receptor agonists inhibit glutamate release, but also promote the synthesis and release of neurotrophic factors in astrocytes. These drugs may therefore have a broad application as neuroprotective agents in a variety of CNS disorders. Finally, mGlu4/7/8 receptor agonists potently inhibit glutamate release and have a potential application in seizure disorders. The advantage of all these drugs with respect to NMDA or AMPA receptor agonists derives from the evidence that mGlu receptors do not "mediate," but rather "modulate" excitatory synaptic transmission. Therefore, it can be expected that mGlu receptor ligands are devoid of the undesirable effects resulting from the inhibition of excitatory synaptic transmission, such as sedation or an impairment of learning and memory.}, }
@article {pmid11522944, year = {2001}, author = {Anneser, JM and Gmerek, A and Gerkrath, J and Borasio, GD and Heumann, R}, title = {Immunosuppressant FK506 does not exert beneficial effects in symptomatic G93A superoxide dismutase-1 transgenic mice.}, journal = {Neuroreport}, volume = {12}, number = {12}, pages = {2663-2665}, doi = {10.1097/00001756-200108280-00015}, pmid = {11522944}, issn = {0959-4965}, mesh = {Amino Acid Substitution ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Behavior, Animal/drug effects ; *Calcineurin Inhibitors ; Disease Models, Animal ; Disease Progression ; Dose-Response Relationship, Drug ; Humans ; Immunosuppressive Agents/*administration &amp; dosage ; Injections, Intraperitoneal ; Mice ; Mice, Transgenic ; Motor Activity/drug effects ; Mutation ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Survival Rate ; Tacrolimus/*administration &amp; dosage ; Treatment Failure ; }, abstract = {The immunosuppressant drug FK506 has been shown to exert neuroprotective effects in various model systems via inhibition of the protein phosphatase calcineurin (CN). The enzyme Cu/Zn-superoxide dismutase (SOD1), which is mutated in a familial form of amyotrophic lateral sclerosis (ALS), is an endogenous regulator of CN. Altered function of CN may therefore be involved in the pathogenesis of ALS. We tested FK506 in a transgenic mouse model expressing mutated SOD1 for potential beneficial effects. This treatment, initiated after onset of symptoms, did not cause a reduction in the decline of motor function nor did it prolong survival. These results argue against a crucial role of CN in the process leading to motoneuronal degeneration in SOD1-mutated mice.}, }
@article {pmid11518135, year = {2001}, author = {Saiki, S and Yoshioka, A and Yamaya, Y and Hirose, G}, title = {Amyotrophic lateral sclerosis associated with sarcoidosis.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {40}, number = {8}, pages = {822-825}, doi = {10.2169/internalmedicine.40.822}, pmid = {11518135}, issn = {0918-2918}, mesh = {Amyotrophic Lateral Sclerosis/*complications/*diagnosis/pathology ; Autopsy ; Fatal Outcome ; Female ; Humans ; Middle Aged ; Sarcoidosis/*complications/*diagnosis/pathology ; }, abstract = {We report a rare association of amyotrophic lateral sclerosis (ALS) with incidental pulmonary and muscle sarcoidosis. A 63-year-old woman presented with slowly progressive weakness and atrophy of the extremities starting from the left leg. The biopsy of a small mass in the left gastrocnemius revealed a typical sarcoid nodule. She was treated with corticosteroid for possible sarcoid neuromyopathy. In spite of the treatment, her clinical course was relentlessly progressive and she died of bulbar palsy. Autopsy revealed a loss of motor neurons in the anterior horn, vacuolar degeneration of the lateral funiculus, and noncaseating granulomas in paratracheal lymph nodes and lungs. No granulomatous lesion or cellular infiltration was found in the spinal cord.}, }
@article {pmid11514524, year = {2001}, author = {Chandra, J and Kuhn, DM and Mukherjee, PK and Hoyer, LL and McCormick, T and Ghannoum, MA}, title = {Biofilm formation by the fungal pathogen Candida albicans: development, architecture, and drug resistance.}, journal = {Journal of bacteriology}, volume = {183}, number = {18}, pages = {5385-5394}, pmid = {11514524}, issn = {0021-9193}, support = {R01 AI035097/AI/NIAID NIH HHS/United States ; AIO7024/AI/NIAID NIH HHS/United States ; R01-DE13992/DE/NIDCR NIH HHS/United States ; R01 DE013992/DE/NIDCR NIH HHS/United States ; AI-36219/AI/NIAID NIH HHS/United States ; AI35097-03/AI/NIAID NIH HHS/United States ; P30 AI036219/AI/NIAID NIH HHS/United States ; }, mesh = {Antifungal Agents/pharmacology ; Biofilms/drug effects/*growth &amp; development ; Candida albicans/drug effects/genetics/metabolism/*physiology ; Candidiasis/*microbiology ; Drug Resistance, Microbial ; Fungal Proteins/genetics/metabolism ; Gene Expression Regulation, Fungal ; Humans ; Microbial Sensitivity Tests ; Microscopy, Confocal ; Polymethyl Methacrylate ; Silicones ; }, abstract = {Biofilms are a protected niche for microorganisms, where they are safe from antibiotic treatment and can create a source of persistent infection. Using two clinically relevant Candida albicans biofilm models formed on bioprosthetic materials, we demonstrated that biofilm formation proceeds through three distinct developmental phases. These growth phases transform adherent blastospores to well-defined cellular communities encased in a polysaccharide matrix. Fluorescence and confocal scanning laser microscopy revealed that C. albicans biofilms have a highly heterogeneous architecture composed of cellular and noncellular elements. In both models, antifungal resistance of biofilm-grown cells increased in conjunction with biofilm formation. The expression of agglutinin-like (ALS) genes, which encode a family of proteins implicated in adhesion to host surfaces, was differentially regulated between planktonic and biofilm-grown cells. The ability of C. albicans to form biofilms contrasts sharply with that of Saccharomyces cerevisiae, which adhered to bioprosthetic surfaces but failed to form a mature biofilm. The studies described here form the basis for investigations into the molecular mechanisms of Candida biofilm biology and antifungal resistance and provide the means to design novel therapies for biofilm-based infections.}, }
@article {pmid11495712, year = {2001}, author = {Warner, TD and Roberts, LW and Smithpeter, M and Rogers, M and Roberts, B and McCarty, T and Franchini, G and Geppert, C and Obenshain, SS}, title = {Uncertainty and opposition of medical students toward assisted death practices.}, journal = {Journal of pain and symptom management}, volume = {22}, number = {2}, pages = {657-667}, doi = {10.1016/s0885-3924(01)00314-1}, pmid = {11495712}, issn = {0885-3924}, support = {1K02 AI01738-02/AI/NIAID NIH HHS/United States ; }, mesh = {Adult ; Attitude of Health Personnel ; Ethics, Medical ; Female ; Humans ; Male ; Students, Medical/*psychology ; *Suicide, Assisted ; Surveys and Questionnaires ; }, abstract = {To explore medical students' views of assisted death practices in patient cases that describe different degrees and types of physical and mental suffering, an anonymous survey was administered to all students at one medical school. Respondents were asked about the acceptability of assisted death activities in five patient vignettes and withdrawal of life support in a sixth vignette. In the vignettes, actions were performed by four possible agents: the medical student personally; a referral physician; physicians in general; or non-physicians. Of 306 medical students, 166 (54%) participated. Respondents expressed opposition or uncertainty about assisted death practices in the five patient cases that illustrated severe forms of suffering which were secondary to amyotrophic lateral sclerosis, treatment-resistant depressive and somatoform disorders, antisocial and sexually violent behavior, or AIDS. Students supported the withdrawal of life support in the sixth vignette depicting exceptional futility secondary to AIDS. Students were especially opposed to their own involvement and to the participation of non-physicians in assisted death activities. Differences in views related to sex, religious beliefs, and personal philosophy were found. Medical students do not embrace assisted death practices, although they exhibit tolerance regarding the choices of medical colleagues. How these attributes of medical students will translate into future behaviors toward patients and peers remains uncertain. Medical educators must strive to understand the perspectives of physicians-in-training. Expanded, empirically informed education that is attuned to the attitudes of medical students may be helpful in fulfilling the responsibility of imparting optimal clinical care skills.}, }
@article {pmid11469788, year = {2001}, author = {Sampson, JB and Beckman, JS}, title = {Hydrogen peroxide damages the zinc-binding site of zinc-deficient Cu,Zn superoxide dismutase.}, journal = {Archives of biochemistry and biophysics}, volume = {392}, number = {1}, pages = {8-13}, doi = {10.1006/abbi.2001.2418}, pmid = {11469788}, issn = {0003-9861}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/etiology/genetics ; Animals ; Binding Sites ; Cattle ; Circular Dichroism ; Enzyme Inhibitors/pharmacology ; Humans ; Hydrogen Peroxide/*pharmacology ; In Vitro Techniques ; Kinetics ; Motor Neurons/enzymology ; *Mutation ; Oxidation-Reduction ; Protein Structure, Secondary ; Superoxide Dismutase/*antagonists &amp; inhibitors/chemistry/*genetics ; Zinc/*metabolism ; }, abstract = {Mutations in Cu,Zn superoxide dismutase (Cu,Zn SOD) account for approximately 20% of cases of familial amyotrophic lateral sclerosis (ALS), a late-onset neurodegenerative disease affecting motor neurons. These mutations decrease protein stability and lower zinc affinity. Zinc-deficient SOD (Cu,E SOD) has altered redox activities and is toxic to motor neurons in vitro. Using bovine SOD, we studied the effects of hydrogen peroxide (H(2)O(2)) on Cu,E SOD and Cu,Zn SOD. Hydrogen peroxide treatment of Cu,E SOD inactivated zinc binding activity six times faster than superoxide dismutase activity, whereas inactivation of dismutase activity occurred at the same rate for both Cu,Zn SOD and Cu,E SOD. Zinc binding by Cu,E SOD was also damaged by simultaneous generation of superoxide and hydrogen peroxide by xanthine oxidase plus xanthine. Although urate, xanthine, and ascorbate can protect superoxide dismutase activity of Cu,Zn SOD from inactivation, they were not effective at protecting Cu,E SOD. Hydrogen peroxide induced subtle changes in the tertiary structure but not the secondary structure of Cu,E SOD as detected by near and far UV circular dichroism. Our results suggest that low levels of hydrogen peroxide could potentially enhance the toxicity of zinc deficient SOD to motor neurons in ALS by rendering zinc loss from SOD irreversible.}, }
@article {pmid11467101, year = {2001}, author = {Carter, GT and Rosen, BS}, title = {Marijuana in the management of amyotrophic lateral sclerosis.}, journal = {The American journal of hospice &amp; palliative care}, volume = {18}, number = {4}, pages = {264-270}, doi = {10.1177/104990910101800411}, pmid = {11467101}, issn = {1049-9091}, mesh = {Amyotrophic Lateral Sclerosis/complications/*drug therapy/physiopathology/psychology ; Cannabis/*therapeutic use ; Drug and Narcotic Control/legislation &amp; jurisprudence ; Evidence-Based Medicine ; Humans ; Patient Selection ; *Phytotherapy ; Treatment Outcome ; }, abstract = {Marijuana has been proposed as treatment for a widening spectrum of medical conditions. Marijuana is a substance with many properties that may be applicable to the management of amyotrophic lateral sclerosis (ALS). These include analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. In addition, marijuana has now been shown to have strong antioxidative and neuroprotective effects, which may prolong neuronal cell survival. In areas where it is legal to do so, marijuana should be considered in the pharmacological management of ALS. Further investigation into the usefulness of marijuana in this setting is warranted.}, }
@article {pmid11466954, year = {2000}, author = {Strong, MJ and Pattee, GL}, title = {Creatine and coenzyme Q10 in the treatment of ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 4}, number = {}, pages = {17-20}, doi = {10.1080/14660820050515665}, pmid = {11466954}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Antioxidants/*therapeutic use ; Coenzymes ; Creatine/*therapeutic use ; Humans ; Ubiquinone/analogs &amp; derivatives/*therapeutic use ; }, }
@article {pmid11466953, year = {2000}, author = {Rosenfeld, J}, title = {Multi-drug therapy for the treatment of ALS. Introduction.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 4}, number = {}, pages = {1}, pmid = {11466953}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diet therapy/*drug therapy ; Drug Therapy, Combination ; Homeopathy ; Humans ; Nutritional Support ; }, }
@article {pmid11465936, year = {2001}, author = {Desnuelle, C and Dib, M and Garrel, C and Favier, A}, title = {A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2}, number = {1}, pages = {9-18}, doi = {10.1080/146608201300079364}, pmid = {11465936}, issn = {1466-0822}, mesh = {Aged ; Double-Blind Method ; Female ; Follow-Up Studies ; Glutathione Peroxidase/blood ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/diagnosis/*drug therapy/enzymology ; Neurologic Examination/drug effects ; Thiobarbituric Acid Reactive Substances/metabolism ; Treatment Outcome ; Vitamin E/*adverse effects ; }, abstract = {INTRODUCTION: Increasing evidence suggests that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of paralysis in transgenic mice expressing a mutation in superoxide dismutase found in certain forms of familial ALS. The current study was designed to determine whether alpha-tocopherol (500 mg b.i.d.) may be efficacious in the treatment of ALS.<br><br>METHODS: Two hundred and eighty-nine patients with ALS of less than 5 years duration, treated with riluzole, were enrolled in this study, and were randomly assigned to receive either alpha-tocopherol or placebo daily for one year. The primary outcome measure was the rate of deterioration of function assessed by the modified Norris limb scale. Patients were assessed at entry, and every 3 months thereafter during the study period. Survival was also recorded. Biochemical markers of oxidative stress were measured in a subset of patients on entry and after 3 months of treatment.<br><br>RESULTS: After 12 months of treatment, alpha-tocopherol had no effect on the primary outcome measure. Survival was not influenced by treatment. Among secondary outcome measures, patients given alpha-tocopherol were less likely to progress from the milder state A to the more severe state B (P=0.046) of the ALS Health State scale. After 3 months treatment, analysis of oxidative stress markers showed an increase in glutathione peroxidase activity in plasma (P = 0.0389) and a decrease in plasma levels of thiobarbituric acid reactive species (P = 0.0055) in the group of patients given alpha-tocopherol in combination with riluzole.<br><br>CONCLUSION: Although alpha-tocopherol did not appear to affect the survival and motor function in ALS, patients receiving riluzole plus alpha-tocopherol remained longer in the milder states of the ALS Health State scale and showed, after 3 months, changes in biochemical markers of oxidative stress. Further studies are required to confirm the greater sensitivity of the ALS Health State scale over other clinical endpoints.}, }
@article {pmid11465933, year = {2001}, author = {de Carvalho, M}, title = {Gabapentin for the treatment of spasticity in patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2}, number = {1}, pages = {47-48}, doi = {10.1080/14660820152415744}, pmid = {11465933}, issn = {1466-0822}, mesh = {Acetates/*therapeutic use ; Aged ; *Amines ; *Cyclohexanecarboxylic Acids ; Female ; Gabapentin ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*drug therapy ; Muscle Spasticity/*drug therapy ; Neurologic Examination/drug effects ; Treatment Outcome ; *gamma-Aminobutyric Acid ; }, }
@article {pmid11465930, year = {2001}, author = {Miller, RG}, title = {Examining the evidence about treatment in ALS/MND.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2}, number = {1}, pages = {3-7}, doi = {10.1080/146608201300079355}, pmid = {11465930}, issn = {1466-0822}, mesh = {Clinical Trials as Topic ; Critical Care ; Excitatory Amino Acid Antagonists/adverse effects/therapeutic use ; Humans ; Motor Neuron Disease/diagnosis/mortality/*therapy ; Palliative Care ; Practice Guidelines as Topic ; Riluzole/adverse effects/therapeutic use ; Survival Rate ; }, abstract = {The application of evidence-based medicine to the treatment of patients with amyotrophic lateral sclerosis (ALS) is just beginning. A small number of systematic reviews analyzing the pertinent evidence, grading the methodology and formulating recommendations to guide clinical decision-making have begun to appear. The American Academy of Neurology practice parameters for informing the patient and managing nutritional and respiratory issues and palliative care are discussed. In addition, the first systematic review in the field of ALS/MND from the Cochrane collaboration concerns riluzole treatment and this meta-analysis is also described. Some of the most important recommendations that have the potential to significantly prolong survival and enhance quality of life are the early institution of percutaneous endoscopic gastrostomy for patients with significant dysphagia, and the initiation of non-invasive positive pressure ventilation for patients with symptoms of early respiratory insufficiency. Assertive treatment of pain and dyspnea are also strongly recommended for patients with ALS. The North American ALS patient database, ALS C.A.R.E., is also described as a methodology for measuring clinical outcomes, and some early results are presented. The evidence on riluzole indicates effectiveness in prolonging survival with a good safety profile.}, }
@article {pmid11465927, year = {2001}, author = {Silani, V and Braga, M and Botturi, A and Cardin, V and Bez, A and Pizzuti, A and Scarlato, G}, title = {Human developing motor neurons as a tool to study ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2 Suppl 1}, number = {}, pages = {S69-76}, doi = {10.1080/146608201750138594}, pmid = {11465927}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*pathology ; Cells, Cultured ; Humans ; Motor Neurons/*cytology/*physiology ; }, abstract = {Defining the basis of the selective cell vulnerability of human motor neurons (hMNs) represents a crucial step in revealing the pathogenesis of amyotrophic lateral sclerosis (ALS). Tissue culture models offer an ideal system for identification of the hMN-specific features at the single cell level. Purified hMNs and astrocytes can today be isolated from the anterior horn of the human embryonic spinal cord. Cultures can be studied at the single cell level using cDNA/mRNA amplification techniques. The effects of molecules affecting hMN survival, neurite extension, and metabolism can be tested in vitro and the expression of selective genes assayed using DNA microarray technology. Crucial information of immediate clinical application for the treatment of patients affected by ALS can be derived after testing the efficacy of candidate pharmaceutical molecules using in vitro cell models. Adult nervous tissue or progenitor cells derived from different regions of the nervous system may be used as an alternative source of human neuronal cells. HMNs in culture, combined with the application of adequate technology, can contribute greatly to identifying the primitive critical events responsible for the cell degeneration observed in ALS, bypassing the intrinsic limitations of the non-human models of the disease.}, }
@article {pmid11465922, year = {2001}, author = {Borasio, GD}, title = {Palliative care in ALS: searching for the evidence base.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2 Suppl 1}, number = {}, pages = {S31-5}, pmid = {11465922}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/psychology/*therapy ; *Evidence-Based Medicine ; Humans ; Palliative Care/*standards ; *Quality of Life ; }, abstract = {The poor prognosis of amyotrophic lateral sclerosis (ALS) makes palliative care a challenge for the neurologist. Most of the disabilities from progressive disease can be effectively relieved by symptomatic treatment. Prognosis and treatment options should be openly discussed with patient and relatives. Adequate assistance and palliative treatment in the terminal phase are of paramount importance. Unfortunately, training in communication skills for young doctors and evidence-based recommendations for palliative care are insufficient at present. In addition, new data from a randomized study question the concept of "health-related quality of life" and favor an individualized approach to the definition of quality of life in ALS.}, }
@article {pmid11465921, year = {2001}, author = {Swash, M}, title = {ALS 2000: the past points to the future.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2 Suppl 1}, number = {}, pages = {S3-9}, pmid = {11465921}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/*pathology ; Cell Death ; Humans ; }, abstract = {In this introductory review a number of issues concerning the direction of future research in ALS are addressed in relation to current understanding of this disorder and its treatment. The importance of understanding the pathways leading to motor neuron dysfunction and death is emphasized. Contemporary epidemiology, understandably focussed on genetic markers for familial ALS, needs to be widened to include as yet undocumented susceptibility-related genetic traits. Potential avenues for therapy are considered, and the fundamental contemporary issue of clinical measurement is discussed. Neglected aspects of contemporary research, including disturbed axoplasmic flow, are brought to attention. The role of experiment derived from clinical observation, and vice versa, is described by reference to a number of past and recent contributions to the understanding of ALS.}, }
@article {pmid11465917, year = {2001}, author = {Mitsumoto, H}, title = {Clinical trials: present and future.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {2 Suppl 1}, number = {}, pages = {S10-4}, doi = {10.1080/14660820152415672}, pmid = {11465917}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Clinical Trials as Topic/*trends ; Enzyme Inhibitors/*therapeutic use ; Humans ; }, abstract = {The past decade has seen a major expansion of clinical trials in amyotrophic lateral sclerosis (ALS). However, the perfectly-designed ALS trial remains elusive. Attempts to track the progression of the disease are affected by continual improvements in the care of patients. Comparing the effectiveness of different drugs is difficult because different primary endpoints are used in different studies. We also need to decide how much benefit we are aiming to achieve when studying a new treatment. The interpretation of animal models has also proved problematic, with results not being replicated in human studies. Moreover, promising phase I/II trial results have often not been confirmed by phase III studies. Our patients, meanwhile, are anxious to try any medication that may help. The ALS research community has learned a great deal from past trials and this will be greatly beneficial when evaluating the novel and combination therapies currently being developed. Effort must also be directed towards the search for objective markers for ALS.}, }
@article {pmid11465020, year = {2000}, author = {Smith, PS and Crossley, B and Greenberg, J and Wilder, C and Carroll, B}, title = {Agreement among three quality of life measures in patients with ALS.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {4}, pages = {269-275}, doi = {10.1080/14660820050515098}, pmid = {11465020}, issn = {1466-0822}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*psychology ; Female ; Health Surveys ; Humans ; Male ; Middle Aged ; *Quality of Life ; Surveys and Questionnaires/*standards ; }, abstract = {AIM: To determine the concurrent validity of three self-administered health-related quality of life (HRQOL) questionnaires when administered to patients with amyotrophic lateral sclerosis (ALS).<br><br>BACKGROUND: ALS is the most common motor neuron disease among adults. As a rapidly progressive and fatal disease, ALS has devastating effects on the patient's relationships, functional capacity and mental health. HRQOL measures include information about patients' physical impairments, functional level, and psychosocial status. This study compares a tool designed for the ALS population, the Sickness Impact Profile ALS-19 (SIP/ALS19), and two tools designed to be used in any population, the Quality of Well-being Scale SA (QWB SA), and the SF-36 Health Survey (SF-36). Correlation of the scores would suggest that each tool is valid as a stand-alone measurement of quality of life for this patient population.<br><br>METHODS: The SIP/ALS-19, the SF-36, and the QWB SA were self-administered to 19 subjects diagnosed with ALS. The scores for each test were ranked and analyzed for agreement using the Spearman rank correlation coefficient.<br><br>RESULTS: The SIP/ALS-19 demonstrated moderate to good correlation with the QWB SA and fair correlation with the SF-36. The SF-36 had little to no correlation with the QWB SA.<br><br>CONCLUSIONS: The study did not demonstrate significant correlation among the three quality of life measures. The SIP/ALS-19, SF-36, and QWB SA each have a different focus in measuring HRQOL. The healthcare practitioner should consider the patient's stage of disease, treatment goals, and type of interventions planned when selecting a HRQOL tool for the ALS patient.}, }
@article {pmid11465016, year = {2000}, author = {Xu, Z}, title = {Mechanism and treatment of motoneuron degeneration in ALS: what have SOD1 mutants told us?.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {4}, pages = {225-234}, doi = {10.1080/14660820050515052}, pmid = {11465016}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology/*therapy ; Animals ; Humans ; Motor Neurons/enzymology/pathology ; Mutation ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motoneuron degeneration, skeletal muscle atrophy, paralysis and death. The identification of mutations in Cu,Zn superoxide dismutase (SOD1) as a genetic cause of this disease has led to the creation of a number of in-vitro and in-vivo models. Experiments have been carried out in these model systems to address fundamental questions related to the disease: (1) what is the nature of toxicity of the mutated SOD1? (2) what are the cellular targets and pathways that lead to neuronal degeneration? (3) what makes motoneurons particularly vulnerable to the toxicity of the mutant enzyme? and (4) are there effective treatments for ALS based on current hypotheses regarding the disease mechanism? Current research on these questions is reviewed.}, }
@article {pmid11464953, year = {2000}, author = {Ochs, G and Penn, RD and York, M and Giess, R and Beck, M and Tonn, J and Haigh, J and Malta, E and Traub, M and Sendtner, M and Toyka, KV}, title = {A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1}, number = {3}, pages = {201-206}, doi = {10.1080/14660820050515197}, pmid = {11464953}, issn = {1466-0822}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Brain-Derived Neurotrophic Factor/*administration &amp; dosage/*adverse effects ; Double-Blind Method ; Humans ; Injections, Spinal ; Middle Aged ; Paresthesia/chemically induced ; Recombinant Proteins/*administration &amp; dosage/*adverse effects ; Sleep Wake Disorders/chemically induced ; Smell/drug effects ; Taste/drug effects ; }, abstract = {BACKGROUND: Brain derived neurotrophic factor (BDNF) is a potent survival factor for motoneurons. This study investigated the safety and tolerability of recombinant methionyl human BDNF (r-metHuBDNF) infused intrathecally by means of an implanted pump in patients with ALS.<br><br>METHODS: Twenty-five patients with probable or definite ALS were treated with either r-metHuBDNF (25, 60, 150, 400 or 1000 microg/day) or placebo in a 12-week, randomized, double-blinded, sequential, dose-escalation study. Test treatment was interrupted by a washout period from days 11 to 25 to allow the evaluation of laboratory safety measures. In each dose cohort four patients received r-metHuBDNF and one received placebo. On completion of the double-blind period of the study all patients continued to receive r-metHuBDNF in an open-label extension for up to 60 weeks. Lumbar cerebrospinal fluid (CSF) samples were taken periodically from all patients for the measurement of r-metHuBDNF levels and in a minority of patients these were supplemented by cistemal samples.<br><br>RESULTS: Within days after the initiation of infusion the majority of patients receiving r-metHuBDNF reported mild sensory symptoms, including paraesthesias or a sense of warmth, which were usually confined to the lower limbs and were frequently exacerbated by neck flexion. In most instances these symptoms decreased or even disappeared over several weeks. Sleep disturbance, dry mouth, agitation and other behavioural effects were encountered at higher doses (>150 microg/day) and necessitated dose reductions. The spinal CSF levels of r-metHuBDNF were directly related to dose, with a lumbar to cervical ratio of approximately 4:1.<br><br>CONCLUSIONS: The intrathecal delivery of r-metHuBDNF in doses of up to 150 microg/day was well tolerated and appears feasible. The reversible CNS effects with higher dose indicate that BDNF can be delivered cranially against CSF flow. The small number of patients and the design of the study did not permit conclusions to be drawn about the efficacy of the treatment.}, }
@article {pmid11464940, year = {2000}, author = {Olney, RK and Lomen-Hoerth, C}, title = {Motor unit number estimation (MUNE): how may it contribute to the diagnosis of ALS?.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 2}, number = {}, pages = {S41-4}, doi = {10.1080/146608200300079473}, pmid = {11464940}, issn = {1466-0822}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Cell Count ; Electrophysiology/*methods ; Humans ; Motor Neurons/cytology/*physiology ; }, abstract = {Motor unit number estimation (MUNE) is a type of electrophysiological technique that measures the approximate number of lower motor neurons (LMNs) innervating a single muscle or a small group of muscles. Low MUNE counts provide evidence of LMN degeneration, but a single MUNE study does not determine if this loss is ongoing, recent or remote in time. Sequential change of MUNE count provides evidence for ongoing degeneration. Furthermore, sequential change in MUNE from a normal to abnormally low count provides evidence for progressive spread of signs within a region or to another region. MUNE has no established ability to identify other diseases that may provide a non-ALS explanation for the signs of LMN degeneration. If MUNE studies were to be incorporated into a future revision of the diagnostic criteria for ALS, prospective studies will be important to define more clearly the sensitivity and specificity of MUNE in patients with ALS and in patients with weakness that does not involve LMN degeneration. In addition to its potential contributions toward the diagnosis of ALS, MUNE may have greater potential in quantifying the rate of progression in studies of the natural history of ALS and the response to experimental treatment.}, }
@article {pmid11464933, year = {2000}, author = {Smith, RA}, title = {Effects of the early diagnosis of amyotrophic lateral sclerosis on the patient: disadvantages.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 1}, number = {}, pages = {S75-7}, doi = {10.1080/14660820050515610}, pmid = {11464933}, issn = {1466-0822}, mesh = {Cost of Illness ; Cost-Benefit Analysis ; Diagnostic Errors ; Ethics, Medical ; Humans ; Motor Neuron Disease/*diagnosis/economics/psychology ; Prognosis ; Quality of Life ; }, abstract = {While the early diagnosis of disease is generally desirable, this is not always so. There is reason to be concerned about the reliability of clinical diagnosis of amyotrophic lateral sclerosis (ALS), based on currently available methods, early in the disease process. Applying the standard of cost-effectiveness it is possible to estimate the effort required to extend the lifespan of persons who are detected through a screening programme. Until it is possible to alter the treatment outcome, patients have little to gain by the early detection of ALS.}, }
@article {pmid11464932, year = {2000}, author = {Gelinas, D}, title = {Effects of the early diagnosis of amyotrophic lateral sclerosis on the patient: advantages.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 1}, number = {}, pages = {S73-4}, doi = {10.1080/14660820050515601}, pmid = {11464932}, issn = {1466-0822}, mesh = {Adaptation, Psychological ; Humans ; Motor Neuron Disease/*diagnosis/psychology/rehabilitation ; Patient Care Team ; Patient Education as Topic ; Prognosis ; *Quality of Life ; }, abstract = {Advantages of early diagnoses in amyotrophic lateral sclerosis include validation of symptoms, avoidance of unnecessary procedures, enhanced preparation for disability and medical education. Most importantly, earlier in the course of the disease--while there is a greater motor neuron pool survival--diagnosis would enable earlier treatment intervention.}, }
@article {pmid11464931, year = {2000}, author = {Swash, M}, title = {Shortening the time to diagnosis in ALS: the role of electrodiagnostic studies.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 1}, number = {}, pages = {S67-72}, pmid = {11464931}, issn = {1466-0822}, mesh = {Algorithms ; Diagnosis, Differential ; *Electromyography ; Functional Laterality/physiology ; Humans ; Motor Neuron Disease/*diagnosis/physiopathology ; Motor Neurons/physiology ; Muscle, Skeletal/innervation ; Neurologic Examination ; Patient Care Team ; Predictive Value of Tests ; }, abstract = {The early diagnosis of ALS has become an issue in management of the disease with the introduction of a therapy. As more effective treatment becomes available early diagnosis will become increasingly important. Electromyography (EMG) has potential value in this area, but will need to be applied not only with conventional methods but also quantitatively in order to refine the accuracy of diagnosis itself, and to evaluate progression. If a treatment is effective then progression will not occur and one of the major cornerstones of current diagnosis will disappear. For early diagnosis much will depend on appropriate recognition of the possibility of amyotrophic lateral sclerosis by primary care physicians, and other specialists. A semi-quantitative evaluation, utilizing clinical and EMG assessments, would help in this appraisal.}, }
@article {pmid11464929, year = {2000}, author = {Wokke, JH}, title = {Confounding effects of mimicking disorders in the early diagnosis of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 1}, number = {}, pages = {S61-3}, doi = {10.1080/14660820050515773}, pmid = {11464929}, issn = {1466-0822}, mesh = {Diagnosis, Differential ; Humans ; Motor Neuron Disease/*diagnosis ; *Neurologic Examination ; Patient Care Team ; }, abstract = {A diagnosis of amyotrophic lateral sclerosis (ALS) should be given to the patient only when the doctor or the neurologist feels confident or certain about the diagnosis. Certainty of a diagnosis of ALS is important because there are a number of disorders that could mimic the symptoms of ALS but differ in prognosis and treatment. Early treatment of ALS is critical to offer optimal therapy to the patient. However, ALS is difficult to diagnose at an early stage. The fact that ALS is a rare disease means doctors and neurologists do not always have the necessary experience to diagnose confidently. Therefore, clear strategies involving criteria for clinical evaluation and ancillary tests such as electromyography, muscle biopsy and magnetic resonance imaging, must be set up to establish the presence of upper and lower motor neuron abnormalities.}, }
@article {pmid11464928, year = {2000}, author = {Belsh, JM}, title = {ALS diagnostic criteria of El Escorial Revisited: do they meet the needs of clinicians as well as researchers?.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 1}, number = {}, pages = {S57-60}, doi = {10.1080/14660820052415925}, pmid = {11464928}, issn = {1466-0822}, mesh = {Diagnosis, Differential ; Education, Medical, Continuing ; Humans ; Internet ; Motor Neuron Disease/*diagnosis ; *Neurologic Examination ; Patient Care Team ; }, abstract = {The El Escorial criteria for diagnosis of amyotrophic lateral sclerosis (ALS) have been in use for almost a decade. A revised set of criteria, meant to supersede the original set, was developed at a 1998 World Federation of Neurology (WFN) ALS meeting at Airlie House in Warrenton, Virginia, USA. This revised document, nicknamed El Escorial Revisited, has been published on the WFN-ALS website. El Escorial has proven useful in standardizing diagnostic criteria for entry into research trials and it is expected that El Escorial Revisited will help to liberalize such entry requirements. However, general neurologists and neuromuscular clinicians have found El Escorial to be unwieldy and generally unhelpful in achieving an earlier, accurate diagnosis of ALS. The El Escorial Revisited document is a step toward lessening these problems, but more 'user-friendly' criteria may be necessary for clinicians and those not conducting research. Such ALS criteria would improve categorization of ALS patients, would allow clinicians more latitude in beginning ALS treatment, and would educate practitioners to differentiate ALS from other motor neuron and non-motor neuron diseases. Intensive education of physicians will help improve earlier patient referral and accurate ALS diagnosis. There remains a group of 'difficult cases' that will continue to challenge the neuromuscular specialist. Earlier diagnosis in this latter group will require significant advances in the fields of electrodiagnosis, neuroimaging, immunobiochemistry, and neurogenetics.}, }
@article {pmid11464927, year = {2000}, author = {Rosenfeld, J}, title = {Fasciculations without fibrillations: the dilemma of early diagnosis.}, journal = {Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases}, volume = {1 Suppl 1}, number = {}, pages = {S53-6}, doi = {10.1080/14660820052415916}, pmid = {11464927}, issn = {1466-0822}, mesh = {Adolescent ; Adult ; Diagnosis, Differential ; *Electromyography ; Fasciculation/*diagnosis/physiopathology ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*diagnosis/physiopathology ; Motor Neurons/physiology ; Muscle, Skeletal/innervation ; }, abstract = {The challenge of identifying patients at the earliest stage of disease has highlighted the role of subtle markers of clinical pathology. Electrophysiological changes usually precede evidence of clinical weakness and have, therefore, been implicated. Specifically, the onset of fasciculations, particularly those widespread in distribution, in the absence of fibrillation potentials, have been suggested as an early indicator of motor neuron disease. Several cases will be presented here to highlight instances where diffuse fasciculations were not enough to accurately implicate the current diagnostic criteria for amyotrophic lateral sclerosis (ALS). In two instances, alternative diagnoses were eventually supported. If the purpose of early diagnosis is to lead to early treatment with experimental therapy, we must be certain that we study as homogenous a population of patients as possible. Fasciculations by themselves are not enough to implicate early diagnosis; disease progression is probably the single most important historical characteristic for diagnosis. Signs of active denervation (i.e. fibrillation potentials) are critical. Chronic weakness should be proportional to either atrophy or upper motor neuron signs in the affected muscle. This should be true for both early and late recognition of the disease.}, }
@article {pmid11464486, year = {2000}, author = {Kondo, K}, title = {[Current status and need for neurological practices from regional medical institutions].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {40}, number = {12}, pages = {1305-1307}, pmid = {11464486}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/rehabilitation ; *Community Health Services ; *Health Services Needs and Demand ; *Home Care Services ; Humans ; Insurance, Long-Term Care ; Japan ; Nervous System Diseases/*rehabilitation ; *Neurology ; }, abstract = {We studied the current status of, and need for, neurological practices from regional medical institutions, including in-home services. These institutions classify patients with neurological diseases into three categories: cerebrovascular disease, intractable diseases, and other diseases with neurological symptoms. As acute and chronic neurological diseases run their course, patients require appropriate care, including diagnosis, treatment, rehabilitation, and in-home medical care. Rehabilitation is essential for patients with intractable or progressive disease because it helps to prevent progression, enhances mental health, and encourages the use of abilities that are unaffected by disease. As neurologists, we must consider how we can have a positive impact on the patient, the hospital, and the community. In Japan, the majority of patients who receive in-home medical care have neurological disorders, such as cerebrovascular disease or other intractable diseases. We have provided in-home support to 18 patients with amyotrophic lateral sclerosis who use ventilators. This year, a long-term care insurance system was instituted in Japan. Now, a support system needs to be established to provide community-based medical care, health care, and welfare services. As our population ages, we believe neurologists will play an increasingly important role in this support system.}, }
@article {pmid11462792, year = {2001}, author = {Imam, SZ and el-Yazal, J and Newport, GD and Itzhak, Y and Cadet, JL and Slikker, W and Ali, SF}, title = {Methamphetamine-induced dopaminergic neurotoxicity: role of peroxynitrite and neuroprotective role of antioxidants and peroxynitrite decomposition catalysts.}, journal = {Annals of the New York Academy of Sciences}, volume = {939}, number = {}, pages = {366-380}, doi = {10.1111/j.1749-6632.2001.tb03646.x}, pmid = {11462792}, issn = {0077-8923}, mesh = {Animals ; Antioxidants/pharmacology ; Biomarkers/analysis ; Dopamine/*metabolism ; Dopamine Agents/*toxicity ; Enzyme Inhibitors/pharmacology ; Humans ; Indazoles/pharmacology ; Methamphetamine/*toxicity ; Nitrates/*metabolism ; Nitric Oxide Synthase/antagonists &amp; inhibitors/metabolism ; Nitric Oxide Synthase Type I ; PC12 Cells ; Rats ; Tyrosine/*analogs &amp; derivatives/*drug effects/metabolism ; }, abstract = {Oxidative stress, reactive oxygen (ROS), and nitrogen (RNS) species have been known to be involved in a multitude of neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Both ROS and RNS have very short half-lives, thereby making their identification very difficult as a specific cause of neurodegeneration. Recently, we have developed a high performance liquid chromatography/electrochemical detection (HPLC/EC) method to identify 3-nitrotyrosine (3-NT), an in vitro and in vivo biomarker of peroxynitrite production, in cell cultures and brain to evaluate if an agent-driven neurotoxicity is produced by the generation of peroxynitrite. We show that a single or multiple injections of methamphetamine (METH) produced a significant increase in the formation of 3-NT in the striatum. This formation of 3-NT correlated with the striatal dopamine depletion caused by METH administration. We also show that PC12 cells treated with METH has significantly increased formation of 3-NT and dopamine depletion. Furthermore, we report that pretreatment with antioxidants such as selenium and melatonin can completely protect against the formation of 3-NT and depletion of striatal dopamine. We also report that pretreatment with peroxynitrite decomposition catalysts such as 5, 10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato iron III (FeTMPyP) and 5, 10, 15, 20-tetrakis (2,4,6-trimethyl-3,5-sulfonatophenyl) porphinato iron III (FETPPS) significantly protect against METH-induced 3-NT formation and striatal dopamine depletion. We used two different approaches, pharmacological manipulation and transgenic animal models, in order to further investigate the role of peroxynitrite. We show that a selective neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7-NI), significantly protect against the formation of 3-NT as well as striatal dopamine depletion. Similar results were observed with nNOS knockout and copper zinc superoxide dismutase (CuZnSOD)-overexpressed transgenic mice models. Finally, using the protein data bank crystal structure of tyrosine hydroxylase, we postulate the possible nitration of specific tyrosine moiety in the enzyme that can be responsible for dopaminergic neurotoxicity. Together, these data clearly support the hypothesis that the reactive nitrogen species, peroxynitrite, plays a major role in METH-induced dopaminergic neurotoxicity and that selective antioxidants and peroxynitrite decomposition catalysts can protect against METH-induced neurotoxicity. These antioxidants and decomposition catalysts may have therapeutic potential in the treatment of psychostimulant addictions.}, }
@article {pmid11447512, year = {2001}, author = {Eckstein, M}, title = {Implementation of standing field treatment protocols in an urban EMS system.}, journal = {The American journal of emergency medicine}, volume = {19}, number = {4}, pages = {280-283}, doi = {10.1053/ajem.2001.22666}, pmid = {11447512}, issn = {0735-6757}, mesh = {Adult ; Child ; *Clinical Protocols ; *Concurrent Review ; Emergency Medical Services/*standards ; Emergency Medical Technicians/education ; Humans ; Life Support Care/*standards ; Los Angeles ; Retrospective Studies ; }, abstract = {The objective was to describe our experience with implementation of standing field treatment protocols (SFTP) in a large, urban EMS system. A prospective, consecutive observational study examining the first 21 days of implementation of SFTPs in the City of Los Angeles, California. SFTPs were developed for 7 medical chief complaints and all major trauma patients. There were 13,586 EMS incidents, of which 4,037 (30%) received ALS treatment. SFTPs were used on 2,177 of these incidents, representing 54% of all ALS runs and 16% of all EMS incidents. The most frequently used SFTPs were for altered level of consciousness (29%), and chest pain (25%). The most common errors found were failure to document reassessment of the patient after each medication administration (45% fallout rate), and failure to document and attach a copy of the ECG to the EMS report (40%). The mean fallout rate for failure to establish or attempt IV access, administer oxygen, or provide cardiac monitoring was 7%. Out of 1,450 incidents with outcome data provided by the receiving hospitals, only 3 cases (2%) involved incorrect treatment, with an additional 2 involving the unnecessary use of lidocaine. None of these instances resulted in adverse effects or complications. SFTPs were integrated into a large EMS system with few procedural errors or adverse outcomes.}, }
@article {pmid11442325, year = {2001}, author = {Turner, MR and Parton, MJ and Leigh, PN}, title = {Clinical trials in ALS: an overview.}, journal = {Seminars in neurology}, volume = {21}, number = {2}, pages = {167-175}, doi = {10.1055/s-2001-15262}, pmid = {11442325}, issn = {0271-8235}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Disease Progression ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Meta-Analysis as Topic ; Research Design ; Riluzole/therapeutic use ; }, abstract = {Clinical trials in amyotrophic lateral sclerosis (ALS) have been conducted for over half a century now and have incorporated a wide variety of drugs. Most of these trials have had negative results and a cure remains elusive. The explosion in our understanding of molecular biology and parallel developments in clinical epidemiology have opened up a vast number of novel therapeutic strategies. However, advances in statistical analysis, computing, and global communications have also put greater pressure on scientific investigators to improve the design and implementation of clinical trials so that they permit rigorous testing of hypotheses within a solid ethical framework. This article documents the first published trial for all drugs tried clinically in the treatment of ALS, focusing in more detail on the large, multicenter trials of recent years, namely those involving riluzole, ciliary neurotrophic factor, insulin-like growth factor-I, brain-derived neurotrophic factor, and SR57746A. The problems in the design of trials in ALS are discussed, including the selection of end points and surrogate markers of disease progression, and the major parameters in ALS assessment are reviewed.}, }
@article {pmid11442324, year = {2001}, author = {Borasio, GD and Miller, RG}, title = {Clinical characteristics and management of ALS.}, journal = {Seminars in neurology}, volume = {21}, number = {2}, pages = {155-166}, doi = {10.1055/s-2001-15268}, pmid = {11442324}, issn = {0271-8235}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*physiopathology/*therapy ; Hospice Care ; Humans ; Palliative Care ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of degenerative motor neuron disease in adulthood. The clinical picture was accurately described by Charcot over 125 years ago and consists of generalized fasciculations, progressive atrophy and weakness of the skeletal muscles, spasticity and pyramidal tract signs, dysarthria, dysphagia, and dyspnea. Pseudobulbar affect is common. Disease-specific treatment options are still unsatisfactory. However, therapeutic nihilism is not justified as a large array of palliative measures is available to enhance the quality of life of patients and their families. Palliative care in ALS is a multidisciplinary effort requiring careful coordination. An open and frank disclosure of the diagnosis is of paramount importance. Nutritional deficiency due to pronounced dysphagia can be relieved by a percutaneous endoscopic gastrostomy. Respiratory insufficiency can be effectively treated by noninvasive home mechanical ventilation. The terminal phase of the disease should be discussed, at the latest, when symptoms of dyspnea appear in order to prevent unwarranted fears of "choking to death." Collaboration with hospice and completion of advance directives can be of invaluable help in the terminal phase.}, }
@article {pmid11436263, year = {2001}, author = {Turner, M}, title = {The treatment of motor neurone disease.}, journal = {The Practitioner}, volume = {245}, number = {1623}, pages = {530-2, 536-8}, pmid = {11436263}, issn = {0032-6518}, mesh = {Analgesics/therapeutic use ; Enteral Nutrition ; Humans ; Motor Neuron Disease/drug therapy/*therapy ; Neuroprotective Agents/therapeutic use ; Patient Care Management ; Patient Education as Topic ; Physical Therapy Modalities ; Physician's Role ; Riluzole/therapeutic use ; }, }
@article {pmid11424053, year = {2001}, author = {Calzada Sierra, DJ}, title = {[Bioethical considerations in the approach to patients with amyotrophic lateral sclerosis].}, journal = {Revista de neurologia}, volume = {32}, number = {10}, pages = {952-957}, pmid = {11424053}, issn = {0210-0010}, mesh = {Amyotrophic Lateral Sclerosis/*psychology/therapy ; *Bioethics ; Cost of Illness ; Euthanasia/ethics ; Humans ; Palliative Care/ethics ; Physician-Patient Relations ; Quality of Life ; }, abstract = {INTRODUCTION: The traditional doctor-patient relation has become a great bioethical challenge due to the advances in science in recent years. This is particularly true when patients suffer diseases such as amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with a relentless course and in spite of modern treatment 50% of the patients die within three years of first having symptoms of the disease. It therefore causes great psychological and social impact.<br><br>OBJECTIVE: To analyze the great bioethical challenge which arises when diagnosing and treating a patient with ALS.<br><br>DEVELOPMENT: In this paper we analyze the doctor-patient relationship, the principles of doing no harm and of being beneficial, and more modern concepts such as informed consent, biomedical investigations and euthanasia, as well as the importance of palliative medicine and rehabilitation to alleviate suffering and improve quality of life. Biomedical investigations should conform to the relevant national and international rules. We discuss the right of patients to be given truthful information.<br><br>CONCLUSIONS: We recommend better training of doctors in all aspects of attention to these patients, with emphasis on the diagnosis and importance of rehabilitation, palliative medicine and the management of psychological aspects. Biomedical investigations should fulfil current regulations. We recommend discretion, complete or partial, with regard to information given to the patients and their relatives so as not to cause despair.}, }
@article {pmid11423475, year = {2001}, author = {Oluwole, OO and Depaz, HA and Gopinathan, R and Ali, A and Garrovillo, M and Jin, MX and Hardy, MA and Oluwole, SF}, title = {Indirect allorecognition in acquired thymic tolerance: induction of donor-specific permanent acceptance of rat islets by adoptive transfer of allopeptide-pulsed host myeloid and thymic dendritic cells.}, journal = {Diabetes}, volume = {50}, number = {7}, pages = {1546-1552}, doi = {10.2337/diabetes.50.7.1546}, pmid = {11423475}, issn = {0012-1797}, support = {HL-57229/HL/NHLBI NIH HHS/United States ; }, mesh = {*Adoptive Transfer ; Animals ; Biomarkers ; Bone Marrow Cells/immunology ; Cell Separation ; Dendritic Cells/*immunology ; Diabetes Mellitus, Type 1/immunology/therapy ; Disease Models, Animal ; Flow Cytometry ; *Immune Tolerance ; Islets of Langerhans/*immunology ; Islets of Langerhans Transplantation/*immunology ; Lymphocyte Culture Test, Mixed ; Rats ; T-Lymphocytes/*physiology ; Thymectomy ; Thymus Gland/*immunology ; }, abstract = {Pancreatic islet transplantation remains a promising approach to the treatment of type 1 diabetes. Unfortunately, graft failure continues to occur because of immunologic rejection, despite the use of potent immunosuppressive agents. It is therefore reasoned that induction of peripheral tolerance by the use of self-dendritic cells (DCs) as a vehicle to deliver specific target antigens to self-T-cells without ex vivo manipulation of the recipient is an attractive strategy in the treatment of type 1 diabetes. The finding that intrathymic inoculation of an immunodominant WF major histocompatibility complex (MHC) Class I (RT1.A(u)) peptide five (P5) or P5-pulsed host myeloid DCs induces acquired thymic tolerance raises the possibility that adoptive transfer of allopeptide-primed host myeloid or lymphoid DCs might induce transplant tolerance. To address this hypothesis, we studied the effects of intravenous transfer of in vitro P5-pulsed syngeneic myeloid DCs or in vivo P5-primed syngeneic lymphoid (thymic) DCs on islet survival in the WF-to-ACI rat combination. In vivo primed thymic DCs isolated from ACI rats given intrathymic inoculation of P5 for 2 days were capable of in vitro restimulation of in vivo P5-primed T-cells (memory cells). In the first series of studies, we showed that intravenous-like intrathymic-inoculation of in vitro P5-pulsed host myeloid DCs induced donor-specific permanent acceptance of islets in recipients transiently immunosuppressed with antilymphocyte serum (ALS). We next examined whether thymic DCs isolated from animals that had been previously intrathymically inoculated with P5 could induce T-cell tolerance. The results showed that intravenous adoptive transfer of in vivo P5-primed thymic DCs led to donor-specific permanent acceptance of islets in recipients transiently immunosuppressed with ALS. This finding suggested that the thymic DCs take up and present P5 to developing T-cells to induce T-cell tolerance, thus providing evidence of a direct link between indirect allorecognition and acquired thymic tolerance. The second series of studies examined the mechanisms involved in this model by exploring whether in vivo generation of peptide-specific alloreactive peripheral T-cells by intravenous inoculation of P5-pulsed self-DCs was responsible for the induction of T-cell tolerance. Intrathymic inoculation of splenic T-cells obtained from syngeneic ACI rats primed with intravenous injection of P5-pulsed DCs with a high in vitro proliferative response to P5 in the context of self-MHC induced donor-specific permanent acceptance of islets from WF donors. In addition, the clinically relevant model of intravenous injection of P5-activated T-cells combined with transient ALS immunosuppression similarly induced transplant tolerance, which was then abrogated by thymectomy of the recipient before intravenous injection of the activated T-cells. These data raise the possibility that circulation of peptide-activated T-cells to the host thymus plays a role in the induction and possibly the maintenance of T-cell tolerance in this model. Our findings suggest that intravenous administration of genetically engineered host DCs expressing alloMHC peptides might have therapeutic potential in clinical islet transplantation for the treatment of autoimmune diabetes.}, }
@article {pmid11395867, year = {2001}, author = {Andĕl, M}, title = {[Diabetology at the threshold of the 21st century].}, journal = {Vnitrni lekarstvi}, volume = {47}, number = {5}, pages = {277-280}, pmid = {11395867}, issn = {0042-773X}, mesh = {Diabetes Mellitus/diagnosis/*history/therapy ; Forecasting ; History, 16th Century ; History, 17th Century ; History, 18th Century ; History, 19th Century ; History, 20th Century ; Humans ; }, abstract = {Scientific advances in the 19th and 20th centuries led to the discovery of insulin, the fundamental therapeutic means for treatment of diabetes mellitus type 1 at the onset of the twenties, to the introduction of sulfonylurea derivatives and biguanides in the fifties and sixties. The discovery of the principle of radioimmunoassay at the end of the fifties made it possible to investigate insulin secretion and to achieve a more accurate understanding of the pathogenesis of type 1 and 2 diabetes. Understanding of insulin resistance made it possible to introduce an euglycaemic hyperinsulin clamp at the end of the seventies. Insulin resistance was presented in context with metabolic syndrome X. Insulin is administered at the break of the millenium in subcutaneous injections, insulin dispensers and insulin pumps, experimentally also by the intraperitoneal and inhalatory route. In the nineties in the practice of diabetes 1 therapy ultrashort-term and finally als long-term insulin analogues were developed. For type 2 diabetes mellitus inhibitors of alpha-amylase were introduced and as a quite new group of oral antidiabetics thiazolidindiones. The possibility of 24-hour monitoring of the blood sugar level by means of a subcutaneous glucose sensor was introduced. The end of the century is characterized also by attempts to administer growth factors in the treatment of non-patent vascular obstructions in the diabetic foot syndrome. In mice and rats transformation of the ductal cell of the exocrine pancreas to the Langerhans islet cell proved successful. Further progress in diabetology will depend, similarly as in the rest of medicine, in particular on advances in cellular and molecular biology and genetics, as well as advances in microelectronics and new materials. Emphasis on the community understanding of this disease and consequential primary prevention of diabetes and secondary prevention of its complications are important.}, }
@article {pmid11388661, year = {2001}, author = {Apfel, SC}, title = {Neurotrophic factor therapy--prospects and problems.}, journal = {Clinical chemistry and laboratory medicine}, volume = {39}, number = {4}, pages = {351-355}, doi = {10.1515/CCLM.2001.055}, pmid = {11388661}, issn = {1434-6621}, mesh = {Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Nerve Growth Factors/*therapeutic use ; Neurodegenerative Diseases/*drug therapy ; Peripheral Nervous System Diseases/drug therapy ; }, abstract = {Over the past 15 years neurotrophic factors have generated considerable excitement for their potential as therapy for a wide variety of degenerative neurological disorders, for which there is currently no treatment. The first part of this period was marked by the discovery, characterization, and cloning of many new growth factors, and by successful testing of these factors in animal models of neurological disease. In recent years the biotechnology industry and pharmaceutical industry have attempted to replicate the success of the animal studies in clinical trials. Although some studies have demonstrated moderate efficacy, for the most part the clinical trials have been less successful at demonstrating the therapeutic efficacy of this new class of drugs. For example, nerve growth factor appeared to be efficacious in two phase II clinical trials for peripheral neuropathy, but failed in a large scale phase III trial. Ciliary neurotrophic factor, brain derived neurotrophic factor and insulin like growth factor-1 have all been tested in clinical trials for the treatment of amyotrophic lateral sclerosis, with at best, variable indications of efficacy. Nevertheless, there are still many reasons to be optimistic that some of these agents may be useful clinically. Many technical and pharmacological issues remain to be adequately addressed, before neurotrophic factors can live up to their potential. Our collective experience with them has re-adjusted previously wild expectations, so that they are now much more realistic. This is necessary and beneficial for the maturation of this field of study.}, }
@article {pmid11382189, year = {2000}, author = {Anneser, J}, title = {Molecular basis of treatment in motor neurone disease.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {21}, number = {5 Suppl}, pages = {S913-8}, doi = {10.1007/s100720070003}, pmid = {11382189}, issn = {1590-1874}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*physiopathology/virology ; Animals ; Central Nervous System Viral Diseases/complications/genetics/physiopathology ; Glutamic Acid/genetics/*metabolism ; Humans ; Nerve Growth Factors/*therapeutic use ; Neurofilament Proteins/*genetics/metabolism ; Oxidative Stress/drug effects/*genetics ; Receptors, Glutamate/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {The pathways leading to motorneuron degeneration in amyotrophic lateral sclerosis (ALS) are complex. Excitotoxicity, oxidative damage and, maybe, abnormal aggregation of neurofilaments are key events on which therapeutical strategies can be designed. This paper reviews current knowledge on these strategies. Even though we should be aware that appropriate management of disease symptoms remains the most effective therapeutical intervention, understanding the pathophysiology of ALS is essential for developing new therapies.}, }
@article {pmid11378158, year = {2001}, author = {Grunnet, M and Jespersen, T and Angelo, K and Frøkjaer-Jensen, C and Klaerke, DA and Olesen, SP and Jensen, BS}, title = {Pharmacological modulation of SK3 channels.}, journal = {Neuropharmacology}, volume = {40}, number = {7}, pages = {879-887}, doi = {10.1016/s0028-3908(01)00028-4}, pmid = {11378158}, issn = {0028-3908}, mesh = {4-Aminopyridine/pharmacology ; Amitriptyline/*pharmacology ; Animals ; Antidepressive Agents, Tricyclic/*pharmacology ; Apamin/pharmacology ; Bicuculline/*analogs &amp; derivatives/pharmacology ; Cell Line ; Humans ; Neuroprotective Agents/*pharmacology ; Potassium Channels/*drug effects/metabolism ; *Potassium Channels, Calcium-Activated ; Rats ; Riluzole/*pharmacology ; Small-Conductance Calcium-Activated Potassium Channels ; }, abstract = {Small-conductance, calcium-activated K+ channels (SK channels) are voltage-insensitive channels that have been identified molecularly within the last few years. As SK channels play a fundamental role in most excitable cells and participate in afterhyperpolarization (AHP) and spike-frequency adaptation, pharmacological modulation of SK channels may be of significant clinical importance. Here we report the functional expression of SK3 in HEK293 and demonstrate a broad pharmacological profile for these channels. Brain slice studies commonly employ 4-aminopyridine (4-AP) to block voltage-dependent K+ channels or a methyl derivative of bicuculline, a blocker of gamma-aminobutyric acid (GABA)-gated Cl- channels, in order to investigate the role of various synapses in specialized neural networks. However, in this study both 4-AP and bicuculline are shown to inhibit SK3 channels (IC50 values of 512 microM and 6 microM, respectively) at concentrations lower than those used for brain slice recordings. Riluzole, a potent neuroprotective drug with anti-ischemic, anticonvulsant and sedative effects currently used in the treatment of amyotrophic lateral sclerosis, activates SK3 channels at concentrations of 3 microM and above. Amitriptyline, a tricyclic antidepressive widely used clinically, inhibits SK3 channels with an IC50 of 39.1 +/- 10 microM (n=6).}, }
@article {pmid11376852, year = {2001}, author = {Finegold, AA and Perez, FM and Iadarola, MJ}, title = {In vivo control of NMDA receptor transcript level in motoneurons by viral transduction of a short antisense gene.}, journal = {Brain research. Molecular brain research}, volume = {90}, number = {1}, pages = {17-25}, doi = {10.1016/s0169-328x(01)00062-6}, pmid = {11376852}, issn = {0169-328X}, mesh = {Adenoviridae/genetics ; Amino Acid Sequence ; Animals ; COS Cells ; Chlorocebus aethiops ; Cytomegalovirus/genetics ; DNA, Antisense/*genetics ; *Gene Expression Regulation ; Genes, Synthetic ; Genetic Therapy ; Genetic Vectors/genetics ; Injections ; Microscopy, Fluorescence ; Molecular Sequence Data ; Motor Neurons/*metabolism ; Nerve Tissue Proteins/biosynthesis/*genetics ; PC12 Cells ; Plasmids/genetics ; Posterior Horn Cells/*metabolism ; Promoter Regions, Genetic ; Protein Subunits ; RNA, Messenger/*biosynthesis ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/biosynthesis/*genetics ; Spinal Cord ; Transfection ; }, abstract = {Glutamate receptors play critical roles in normal and pathological processes. We developed an antisense gene delivery strategy to modulate the NMDA type of glutamate receptor. Using transient transfection in vitro and viral mediated gene transfer in vitro and in vivo, the effect of expression of an antisense gene fragment (60 bp) of the NR1 subunit was tested. Immunoblot analysis showed an antisense-concentration-dependent reduction in the NR1 subunit upon transient co-transfection of a plasmid expressing a sense NR1 gene and a plasmid expressing the antisense fragment into COS-7 cells. After recombination into an adenoviral vector, this antisense fragment reduced the amount of endogenous NR1 protein in PC12 cells. Finally, direct intraparenchymal injection of the viral vector into rat spinal cord resulted in diminished NR1 in motor neurons. Our results demonstrate the efficacy of this approach, which combines antisense with viral gene delivery to control the expression of specific genes in vivo. This approach may also be useful in reducing excitatory neurotransmission in vivo, with implications for the treatment of spinal disorders such as amyotrophic lateral sclerosis or chronic pain.}, }
@article {pmid11369517, year = {2001}, author = {Cifuentes, F and González, CE and Fiordelisio, T and Guerrero, G and Lai, FA and Hernández-Cruz, A}, title = {A ryanodine fluorescent derivative reveals the presence of high-affinity ryanodine binding sites in the Golgi complex of rat sympathetic neurons, with possible functional roles in intracellular Ca(2+) signaling.}, journal = {Cellular signalling}, volume = {13}, number = {5}, pages = {353-362}, doi = {10.1016/s0898-6568(01)00132-2}, pmid = {11369517}, issn = {0898-6568}, mesh = {Animals ; Anti-Bacterial Agents/pharmacology ; Antibody Specificity ; Boron Compounds/metabolism ; Brefeldin A/pharmacology ; Caffeine/pharmacology ; Calcium/metabolism ; Calcium Channels/metabolism ; Calcium Signaling/drug effects/*physiology ; Fluorescent Dyes ; Golgi Apparatus/chemistry/*metabolism ; Macrolides ; Membrane Potentials/drug effects/physiology ; Neurons/chemistry/*physiology/ultrastructure ; Phosphodiesterase Inhibitors/pharmacology ; Rats ; Ryanodine/*analogs &amp; derivatives/*metabolism ; Ryanodine Receptor Calcium Release Channel/analysis/immunology/*metabolism ; Superior Cervical Ganglion/cytology ; }, abstract = {The plant alkaloid ryanodine (Ry) is a high-affinity modulator of ryanodine receptor (RyR) Ca(2+) release channels. Although these channels are present in a variety of cell types, their functional role in nerve cells is still puzzling. Here, a monosubstituted fluorescent Ry analogue, B-FL-X Ry, was used to reveal the distribution of RyRs in cultured rat sympathetic neurons. B-FL-X Ry competitively inhibited the binding of [3H]Ry to rabbit skeletal muscle SR membranes, with an IC(50) of 150 nM, compared to 7 nM of unlabeled Ry. Binding of B-FL-X Ry to the cytoplasm of sympathetic neurons is saturable, reversible and of high affinity. The pharmacology of B-FL-X Ry showed marked differences with unlabeled Ry, which are partially explained by its lower affinity: (1) use-dependent reversible inhibition of caffeine-induced intracellular Ca(2+) release; (2) diminished voltage-gated Ca(2+) influx, due to a positive shift in the activation of voltage gated Ca(2+) currents. B-FL-X Ry-stained sympathetic neurons, viewed under confocal microscopy, showed conspicuous labeling of crescent-shaped structures pertaining to the Golgi complex, a conclusion supported by experiments showing co-localization with Golgi-specific fluorescent probes and the breaking up of crescent-shaped staining after treatment with drugs that disassemble Golgi complex. The presence of RyRs to the Golgi could be confirmed with specific anti-RyR(2) antibodies, but evidence of caffeine-induced Ca(2+) release from this organelle could not be obtained using fast confocal microscopy. Rather, an apparent decrease of the cytosolic Ca(2+) signal was detected close to this organelle. In spite of that, short-term incubation with brefeldin A (BFA) suppressed the fast component of caffeine-induced Ca(2+) release, and the Ca(2+) release process lasted longer and appeared less organized. These observations, which suggest a possible role of the Golgi complex in Ca(2+) homeostasis and signaling in nerve cells, could be relevant to reports involving derangement of the Golgi complex as a probable cause of some forms of progressive neuronal degeneration, such as Alzheimer's disease and amyotrophic lateral sclerosis.}, }
@article {pmid11360474, year = {2001}, author = {Ohashi, Y and Tashiro, K and Itoyama, Y and Nakano, I and Sobue, G and Nakamura, S and Sumino, S and Yanagisawa, N}, title = {[Study of functional rating scale for amyotrophic lateral sclerosis: revised ALSFRS(ALSFRS-R) Japanese version].}, journal = {No to shinkei = Brain and nerve}, volume = {53}, number = {4}, pages = {346-355}, pmid = {11360474}, issn = {0006-8969}, mesh = {*Activities of Daily Living ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*physiopathology ; Disease Progression ; Factor Analysis, Statistical ; Female ; Humans ; Male ; Middle Aged ; *Neuropsychological Tests ; Reproducibility of Results ; Severity of Illness Index ; }, abstract = {Amyotrophic lateral sclerosis(ALS) is progressive, degenerative, fatal disease of the motor neuron. No efficacious therapy is available to slow the progressive loss of function, but several new approaches including neurotrophic factors, antioxidants and glutamate antagonists, are currently being evaluated as potential therapies. Mortality, and/or time to tracheostomy, muscle strength and pulmonary function are used as primary endpoints in clinical trials for treatment of ALS. The effect of new therapies on the quality of patients' lives are also important, so we sought to develop a rating scale to measure it. The revised ALS Functional Rating Scale(ALSFRS-R), which has addition of items to ALSFRS to enhance the ability to assess respiratory symptoms, is an assessment determining the degree of impairment in ALS patients' abilities to function independently in activities of daily living. It consists of 12 items to evaluate bulbar function, motor function and respiratory function and each item is scored from 0(unable) to 4(normal). We translated the English score into Japanese one with minor modification considering the inter cultural difference. And we examined reliability of the translated scale. As a measure of reliability, the intraclass correlation coefficient(ICC) was evaluated for total score and the Kappa coefficient proposed by Cohen and Kraemer was calculated for each item. Moreover, we examined sensitivity to clinical change over time and carried out the factor analysis to analyze the factorial structure. The subjects were 27 ALS patients and each was scored twice for reliability or three times for sensitivity by 2 to 5 neurologists and if possible, nurses. The ICC for total score was 0.97(95% C. I.; 0.94-0.98). Extension of the Kappa coefficients were 0.48 to 1.00 for inter-rater reliability and the averaged Kappa coefficients were 0.63 to 1.00 for intra rater reliability, respectively. Concerning the factorial structure, the contribution of the first factor(the first principal component) were 53.5% principal factor solution. The factor loadings of items were 0.52-0.91 except "salivation" and this factor almost equal to the simple sum of all items was interpreted as the general degree of deterioration. The promax votation revealed the riginally supposed factor structure with 3 factors(groups of items): neuromuscuclar function, respiratory function and bulbar function. The rating scale correlated with Global clinical impression of change(GCIC) scored by neurologists and declined with time, indicating its sensitivity to change. On the bases of these results, ALSFRS-R(Japanese version) is considered to be highly reliable enough for clinical use.}, }
@article {pmid11346823, year = {2001}, author = {Gutiérrez Ronquillo, JH and Andrade Machado, R and Machado Rojas, A and García Espinosa, A}, title = {[Multifocal motor neuropathy with partial block of nerve conduction].}, journal = {Revista de neurologia}, volume = {32}, number = {5}, pages = {427-430}, pmid = {11346823}, issn = {0210-0010}, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*complications/diagnosis ; *Neural Conduction ; }, abstract = {INTRODUCTION: Multifocal motor neuropathy with partial conduction block is characterized by being a chronic, demyelinating, autoimmune severely disabling neuropathy. In Cuba three cases were reported by Dr. Estrada et al in 1999. This neuropathy presents clinically in relatively young persons. The arms are predominantly affected and the typical signs are of severe asymmetrical weakness, with atrophy which is less marked than the weakness, fasciculations, cramps and myokymiae of the affected muscle. Neurophysiological study shows partial block of motor nerve conduction. Clinical interest is due to it being potentially curable. Many cases are wrongly diagnosed as motor neurone disease.<br><br>CLINICAL CASES: We present five patients aged under 55 years with progressive chronic motor neuropathy mainly affecting their arms. Study of nerve conduction showed partial block of the conduction in motor nerves, in segments with no block of sensory neuroconduction. One patient had been diagnosed as having motor neurone disease; another had slight sensory involvement in the distal territory of the radial nerve; in two patients the symptoms affected all four limbs. In three patients good results were obtained with intacglobin, followed by azothroprine and prednisone. Two patients showed no improvement with this treatment so intravenous cyclophosphamide was given for nine months which stopped progression of the disorder.<br><br>CONCLUSIONS: Multifocal motor neuropathy is potentially treatable. In some cases intacglobin azathioprine and prednisone may be a useful alternative to cyclophosphamide.}, }
@article {pmid11346822, year = {2001}, author = {Gómez Fernández, L and Calzada Sierra, DJ}, title = {[The importance of multifactorial rehabilitation treatment in amyotrophic lateral sclerosis].}, journal = {Revista de neurologia}, volume = {32}, number = {5}, pages = {423-426}, pmid = {11346822}, issn = {0210-0010}, mesh = {Amyotrophic Lateral Sclerosis/*rehabilitation ; Humans ; Patient Care Team ; Retrospective Studies ; Vital Capacity ; }, abstract = {INTRODUCTION: The treatment of amyotrophic lateral sclerosis (ALS) is still a major challenge. Rehabilitation treatment is scarcely considered and its usefulness in these patients continues to be controversial.<br><br>PATIENTS AND METHODS: A multidisciplinary team made up of neurologists, physiotherapists, logopaedists, defectologists, psychologists and specialist physicians treated six patients with ALS in an intensive rehabilitation programme of 41 hours per week for four weeks. We follow certain basic principles in rehabilitation including: 1. Treatment by a multidisclipinary team; 2. Treatment tailored to the individual; 3. Avoidance of muscle fatigue and vigorous exercise, and 4. Intensive treatment with carefully measured amounts of different activities (logophoniatrics, occupational therapy, psychology, physical therapy, etc.) to avoid fatigue. The patients fulfilled the criteria of E1 Escorial for the diagnosis of definite ALS, and gave their informed consent to undergo the treatment. Forced Vital Capacity (FVC) and ALS Functional Rating Scale (ALSFRS) tests were done on all patients at the beginning and end of the treatment. The Wilcoxon test for paired series, comparing scores at the start and finish, were done in each case.<br><br>RESULTS: In all patients the FVC and ALSFRS improved after the treatment. The results were statistically significant (Z: 2.2013; p= 0.027) on the Wilcoxon paired series test and no complications were seen.<br><br>CONCLUSIONS: Intensive, multifactorial rehabilitation treatment for four weeks improved the FVC and ALSFRS in all patients with ALS and no complications were seen. Until there is a curative treatment for ALS, multifactorial rehabilitation remains the best hope for these patients.}, }
@article {pmid11345011, year = {2001}, author = {Jackson, CE and Rosenfeld, J}, title = {Motor neuron disease.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {12}, number = {2}, pages = {335-52, ix-x}, pmid = {11345011}, issn = {1047-9651}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/rehabilitation ; Antiviral Agents/*administration &amp; dosage ; Clinical Trials as Topic ; Combined Modality Therapy ; Humans ; Motor Neuron Disease/diagnosis/drug therapy/rehabilitation ; Neuroprotective Agents/*administration &amp; dosage ; Physical Therapy Modalities/methods ; Prognosis ; Riluzole/*administration &amp; dosage ; }, abstract = {Motor neuron disease refers to a spectrum of disorders resulting from degeneration of the upper or lower motor neurons or both. Amyotrophic lateral sclerosis is the most common form of motor neuron disease, in which patients demonstrate evidence of both anterior horn cell (lower motor neuron) and corticospinal tract (upper motor neuron) dysfunction. Several theories regarding the pathogenesis of amyotrophic lateral sclerosis have emerged, including glutamate excitotoxicity, free radical oxidative stress, cytoskeletal abnormalities, a deficiency of neurotrophic factor, autoimmunity, apoptosis, and viral infection. Numerous clinical trials have been completed based on these possible mechanisms of the disease propagation including treatment with antiglutamate agents, anti-oxidants, immunosuppressants, and neurotrophic factors. Several of these trials have shown modest effects in slowing the disease course. None, however, have yielded marked benefit in arresting disease progression. The most significant effect in abating disease progression has been our use and understanding of aggressive symptomatic therapy to reduce disability, enhance quality of life, and improve prognosis.}, }
@article {pmid11343826, year = {2001}, author = {Jung, C and Rong, Y and Doctrow, S and Baudry, M and Malfroy, B and Xu, Z}, title = {Synthetic superoxide dismutase/catalase mimetics reduce oxidative stress and prolong survival in a mouse amyotrophic lateral sclerosis model.}, journal = {Neuroscience letters}, volume = {304}, number = {3}, pages = {157-160}, doi = {10.1016/s0304-3940(01)01784-0}, pmid = {11343826}, issn = {0304-3940}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Catalase/*chemistry ; *Manganese ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic/genetics ; Organometallic Compounds/chemistry/*pharmacology ; Oxidative Stress/*drug effects ; Superoxide Dismutase/*chemistry/genetics/pharmacology ; Survival Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that causes motoneuron degeneration, paralysis and death. Mutations in Cu, Zn superoxide dismutase (SOD1) are one cause of this disease. It is widely suspected that increased reactive oxidative species (ROS) is involved in motoneuron degeneration but whether such an involvement plays a role in ALS progression in vivo is uncertain. We treated mice expressing human mutant SOD1 G93A with EUK-8 and EUK-134, two synthetic SOD/catalase mimetics that have shown efficacy in several animal models of human diseases. These treatments reduced levels of oxidative stress and prolonged survival. The results suggest that oxidative stress plays an active role in ALS and illustrate the potential for treatment strategies aimed specifically against ROS.}, }
@article {pmid11328670, year = {2001}, author = {Macmillan-Crow, LA and Cruthirds, DL}, title = {Invited review: manganese superoxide dismutase in disease.}, journal = {Free radical research}, volume = {34}, number = {4}, pages = {325-336}, doi = {10.1080/10715760100300281}, pmid = {11328670}, issn = {1071-5762}, mesh = {Animals ; Apoptosis ; Humans ; Mice ; Mice, Knockout ; Mitochondria/*enzymology ; Neoplasms/*enzymology ; Nitrates/pharmacology ; Organ Transplantation/*adverse effects ; Reactive Oxygen Species/metabolism ; Reperfusion Injury/*enzymology ; Superoxide Dismutase/deficiency/*physiology ; Superoxides/metabolism ; }, abstract = {Manganese superoxide dismutase (MnSOD) is essential for life as dramatically illustrated by the neonatal lethality of mice that are deficient in MnSOD. In addition, mice expressing only 50% of the normal compliment of MnSOD demonstrate increased susceptibility to oxidative stress and severe mitochondrial dysfunction resulting from elevation of reactive oxygen species. Thus, it is important to know the status of both MnSOD protein levels and activity in order to assess its role as an important regulator of cell biology. Numerous studies have shown that MnSOD can be induced to protect against pro-oxidant insults resulting from cytokine treatment, ultraviolet light, irradiation, certain tumors, amyotrophic lateral sclerosis, and ischemia/reperfusion. In addition, overexpression of MnSOD has been shown to protect against pro-apoptotic stimuli as well as ischemic damage. Conversely, several studies have reported declines in MnSOD activity during diseases including cancer, aging, progeria, asthma, and transplant rejection. The precise biochemical/molecular mechanisms involved with this loss in activity are not well understood. Certainly, MnSOD gene expression or other defects could play a role in such inactivation. However, based on recent findings regarding the susceptibility of MnSOD to oxidative inactivation, it is equally likely that post-translational modification of MnSOD may account for the loss of activity. Our laboratory has recently demonstrated that MnSOD is tyrosine nitrated and inactivated during human kidney allograft rejection and human pancreatic ductal adenocarcinoma. We have determined that peroxynitrite (ONOO-) is the only known biological oxidant competent to inactivate enzymatic activity, to nitrate critical tyrosine residues, and to induce dityrosine formation in MnSOD. Tyrosine nitration and inactivation of MnSOD would lead to increased levels of superoxide and concomitant increases in ONOO- within the mitochondria which, could lead to tyrosine nitration/oxidation of key mitochondrial proteins and ultimately mitochondrial dysfunction and cell death. This article assesses the important role of MnSOD activity in various pathological states in light of this potentially lethal positive feedback cycle involving oxidative inactivation.}, }
@article {pmid11313167, year = {2001}, author = {, }, title = {Clinical investigation of medicinal products for treatment of amyotrophic lateral sclerosis (ALS).}, journal = {European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology}, volume = {11}, number = {2}, pages = {187-189}, doi = {10.1016/s0924-977x(01)00067-0}, pmid = {11313167}, issn = {0924-977X}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy ; Neuroprotective Agents/pharmacokinetics/*therapeutic use ; Research Design ; }, }
@article {pmid11311291, year = {2001}, author = {Shahani, N and Gourie-Devi, M and Nalini, A and Raju, TR}, title = {Cyclophosphamide attenuates the degenerative changes induced by CSF from patients with amyotrophic lateral sclerosis in the neonatal rat spinal cord.}, journal = {Journal of the neurological sciences}, volume = {185}, number = {2}, pages = {109-118}, doi = {10.1016/s0022-510x(01)00479-8}, pmid = {11311291}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*cerebrospinal fluid/drug therapy/physiopathology ; Animals ; Animals, Newborn/metabolism ; Anterior Horn Cells/*drug effects/pathology ; Astrocytes/drug effects/pathology ; Cerebrospinal Fluid Proteins/*pharmacology ; Cyclophosphamide/*pharmacology ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Glial Fibrillary Acidic Protein/drug effects/metabolism ; Gliosis/chemically induced/physiopathology/prevention &amp; control ; Immunohistochemistry ; Immunosuppressive Agents/*pharmacology ; L-Lactate Dehydrogenase/drug effects/metabolism ; Nerve Degeneration/chemically induced/physiopathology/*prevention &amp; control ; Neurofilament Proteins/drug effects/metabolism ; Neuroprotective Agents/*pharmacology ; Phosphorylation/drug effects ; Rats ; Rats, Wistar ; }, abstract = {Our earlier studies have shown that cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS), when intrathecally injected into the neonatal rats, produces an aberrant phosphorylation of neurofilaments (NF) in the ventral horn neurons and reactive astrogliosis in the spinal cord. We wanted to investigate the effect of cyclophosphamide in the spinal cords of neonatal rats exposed to ALS-CSF. A single dose (5 microg in 5 microl saline) of cyclophosphamide was injected, 24 h after the administration of CSF samples from ALS and non-ALS neurological patients into the spinal subarachnoid space of 3-day-old rat pups. Rats were sacrificed after a period of 24 h, and stained with antibodies against the phosphorylated NF (SMI-31 antibody) and glial fibrillary acidic protein (GFAP). Cyclophosphamide treatment resulted in a 50% decrease in the number of SMI-31 stained neuronal soma in ventral horns of spinal cords of ALS-CSF exposed rats. This was accompanied by a decrease in the number of GFAP immunoreactive astrocytes. Furthermore, lactate dehydrogenase (LDH) activity was also decreased significantly, following cyclophosphamide treatment. These results suggest that cyclophosphamide could exert a neuroprotective effect against the neurotoxic action of factor(s) present in the ALS-CSF.}, }
@article {pmid11296462, year = {2000}, author = {Bory, M}, title = {[Does diabetes change the anti-ischemic therapeutic options in the symptomatic coronary patient?].}, journal = {Archives des maladies du coeur et des vaisseaux}, volume = {93 Spec No 4}, number = {}, pages = {45-50}, pmid = {11296462}, issn = {0003-9683}, mesh = {Adrenergic beta-Antagonists/therapeutic use ; Angioplasty, Balloon, Coronary/statistics &amp; numerical data ; Antihypertensive Agents/therapeutic use ; Atenolol/therapeutic use ; Comorbidity ; Coronary Artery Bypass/statistics &amp; numerical data ; Coronary Disease/complications/drug therapy/surgery/*therapy ; *Diabetes Complications ; Diabetes Mellitus/drug therapy ; Diabetic Nephropathies/complications ; Graft Occlusion, Vascular/epidemiology ; Humans ; Hyperlipidemias/epidemiology ; Hypertension/complications/drug therapy ; Internal Mammary-Coronary Artery Anastomosis/statistics &amp; numerical data ; Platelet Aggregation Inhibitors/therapeutic use ; Postoperative Complications/epidemiology ; Proteinuria/complications ; Randomized Controlled Trials as Topic ; Risk Factors ; Smoking/epidemiology ; Stents ; Treatment Outcome ; }, abstract = {The assessment of results of medical treatment, angioplasty and coronary bypass surgery in diabetic coronary patients is difficult because of the absence of distinction in the subgroups of type 1 and 2 diabetes and of stable and unstable angina. With respect to medical therapy, betablockers are practically without deleterious effects and are effective in diabetic populations. The same is true of other antianginal drugs. Conventional coronary angioplasty is associated with poorer results than the general population in the long-term, partly because of progression of the coronary artery disease and partly because of an increased incidence of restenosis. The use of stents improves these results, which are similar to those of the general population with single vessel disease or those without proteinuria. Coronary bypass surgery, despite a certain perioperative morbidity, is associated with an identical survival rate at 5 years as non-diabetics, providing the internal mammary artery is grafted. The comparison between these methods is resumed in the ACIP study which opposes the 3 strategies, in Morris et al's study comparing medical and surgical approaches and, finally, in the recent BARI trial where patients were randomly allocated to angioplasty or surgery. It would appear that the surgical strategy gives better results in multivessel disease. However, many reserves have been voiced because of the small numbers of patients, the high number of excluded patients and the fact that recent progress in angioplasty with widespread use of stenting associated with the prescription of new antiaggregant drugs was not taken into account.}, }
@article {pmid11294916, year = {2001}, author = {McDermott, MP and Rowland, LP}, title = {ALS defeats gabapentin: reflections on another failed treatment.}, journal = {Neurology}, volume = {56}, number = {7}, pages = {826-827}, doi = {10.1212/wnl.56.7.826}, pmid = {11294916}, issn = {0028-3878}, mesh = {Acetates/*therapeutic use ; *Amines ; Amyotrophic Lateral Sclerosis/*drug therapy ; *Cyclohexanecarboxylic Acids ; Gabapentin ; Humans ; Treatment Failure ; *gamma-Aminobutyric Acid ; }, }
@article {pmid11274309, year = {2001}, author = {Veldink, JH and van den Berg, LH and Cobben, JM and Stulp, RP and De Jong, JM and Vogels, OJ and Baas, F and Wokke, JH and Scheffer, H}, title = {Homozygous deletion of the survival motor neuron 2 gene is a prognostic factor in sporadic ALS.}, journal = {Neurology}, volume = {56}, number = {6}, pages = {749-752}, doi = {10.1212/wnl.56.6.749}, pmid = {11274309}, issn = {0028-3878}, mesh = {Age of Onset ; Amyotrophic Lateral Sclerosis/*genetics/*physiopathology ; Cyclic AMP Response Element-Binding Protein ; Female ; *Gene Deletion ; Humans ; Male ; Middle Aged ; Nerve Tissue Proteins/*genetics ; Prognosis ; RNA-Binding Proteins ; SMN Complex Proteins ; Survival of Motor Neuron 1 Protein ; Survival of Motor Neuron 2 Protein ; Time Factors ; }, abstract = {BACKGROUND: Spinal muscular atrophy (SMA) results from mutations of the survival motor neuron (SMN) gene on chromosome 5. The SMN gene exists in two highly homologous copies, telomeric (SMN1) and centromeric (SMN2). SMA is caused by mutations in SMN1 but not SMN2. The clinical phenotype of SMA appears to be related to the expression of SMN2. Patients suffering from the milder forms of SMA carry more copies of the SMN2 gene compared with patients with more severe SMA. It is suggested that the SMN2 gene is translated into an at least partially functional protein that protects against loss of motor neurons.<br><br>OBJECTIVE: To investigate whether genetic mechanisms implicated in motor neuron death in SMA have a role in ALS.<br><br>METHODS: The presence of deletions of exons 7 and 8 of SMN1 and SMN2 was determined in 110 patients with sporadic ALS and compared with 100 unaffected controls.<br><br>RESULTS: The presence of a homozygous SMN2 deletion was overrepresented in patients with ALS compared with controls (16% versus 4%; OR, 4.4; 95% CI, 1.4 to 13.5). Patients with a homozygous SMN2 deletion had a shorter median time of survival (p < 0.009). Furthermore, multivariate regression analysis showed that the presence of an SMN2 deletion was independently associated with survival time (p < 0.02). No homozygous deletions in SMN1 were found. Carrier status of SMA appeared to be equally present in patients and controls (1 in 20).<br><br>CONCLUSION: These results indicate that, similar to SMA, the SMN2 gene can act as a prognostic factor and may therefore be a phenotypic modifier in sporadic ALS. Increasing the expression of the SMN2 gene may provide a strategy for treatment of motor neuron disease.}, }
@article {pmid11271868, year = {2001}, author = {Ridsdale, L and Godfrey, E and Chalder, T and Seed, P and King, M and Wallace, P and Wessely, S and , }, title = {Chronic fatigue in general practice: is counselling as good as cognitive behaviour therapy? A UK randomised trial.}, journal = {The British journal of general practice : the journal of the Royal College of General Practitioners}, volume = {51}, number = {462}, pages = {19-24}, pmid = {11271868}, issn = {0960-1643}, mesh = {Adolescent ; Adult ; Aged ; Chronic Disease ; Cognitive Behavioral Therapy/*methods ; Counseling/*methods ; England ; Family Practice ; Fatigue/*therapy ; Fatigue Syndrome, Chronic/therapy ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Patient Satisfaction ; Treatment Outcome ; }, abstract = {BACKGROUND: Fatigue is a common symptom for which patients consult their doctors in primary care. With usual medical management the majority of patients report that their symptoms persist and become chronic. There is little evidence for the effectiveness of any fatigue management in primary care.<br><br>AIM: To compare the effectiveness of cognitive behaviour therapy (CBT) with counselling for patients with chronic fatigue and to describe satisfaction with care.<br><br>DESIGN OF STUDY: Randomised trial with parallel group design.<br><br>SETTING: Ten general practices located in London and the South Thames region of the United Kingdom recruited patients to the trial between 1996 and 1998. Patients came from a wide range of socioeconomic backgrounds and lived in urban, suburban, and rural areas.<br><br>METHOD: Data were collected before randomisation, after treatment, and six months later. Patients were offered six sessions of up to one hour each of either CBT or counselling. Outcomes include: self-report of fatigue symptoms six months later, anxiety and depression, symptom attributions, social adjustment and patients' satisfaction with care.<br><br>RESULTS: One hundred and sixty patients with chronic fatigue entered the trial, 45 (28%) met research criteria for chronic fatigue syndrome; 129 completed follow-up. All patients met Chalder et al's standard criteria for fatigue. Mean fatigue scores were 23 on entry (at baseline) and 15 at six months' follow-up. Sixty-one (47%) patients no longer met standard criteria for fatigue after six months. There was no significant difference in effect between the two therapies on fatigue (1.04 [95% CI = -1.7 to 3.7]), anxiety and depression or social adjustment outcomes for all patients and for the subgroup with chronic fatigue syndrome. Use of antidepressants and consultations with the doctor decreased after therapy but there were no differences between groups.<br><br>CONCLUSION: Counselling and CBT were equivalent in effect for patients with chronic fatigue in primary care. The choice between therapies can therefore depend on other considerations, such as cost and accessibility.}, }
@article {pmid11261599, year = {2001}, author = {Jayasree, RS and Gupta, AK and Rathinam, K and Mohanan, PV and Mohanty, M}, title = {The influence of photodynamic therapy on the wound healing process in rats.}, journal = {Journal of biomaterials applications}, volume = {15}, number = {3}, pages = {176-186}, doi = {10.1106/9335-Q0NC-5XCQ-KBYK}, pmid = {11261599}, issn = {0885-3282}, mesh = {Aminolevulinic Acid/*pharmacology ; Animals ; Female ; Hematoporphyrins/*pharmacology ; Male ; *Photochemotherapy ; Photosensitizing Agents/*pharmacology ; Rats ; Rats, Wistar ; Skin/anatomy &amp; histology/drug effects ; Wound Healing/*drug effects ; }, abstract = {In photodynamic therapy (PDT), photosensitisers (PS) are used along with lasers for the treatment of tumors. The combined effect of photosensitisers and lasers on the wound healing process is studied using delta-aminolevulinic acid (ALA) (5 mg/kg) and hematoporphyrin derivative (HPD) (5 mg/kg) as photosensitisers in the open excision wounds of rats. The lasers used were He-Ne laser (3 J/cm2) and Nd:YAG laser (30 J/cm2). This study is important for understanding the healing process involved after PDT. Open excision wounds treated with He-Ne lasers in animals that received ALA as photosensitiser showed complete wound closure at the earliest by 13 +/- 1 days, and with results obtained for HPD and the combination of lasers with complete closing by 14 +/- 1 days. However, the control group of animals that received ALS or HPD with no laser treatment showed wound healing on the twentieth and eighteenth days with a deviation of one day and two days, respectively. ALA with the combination of Nd:YAG and He-Ne lasers and HPD with He-Ne laser alone does not show quicker wound healing effects. Histopathological results also gave similar results. Tensile strength measurements do not vary significantly from control group to the test group. ALA along with He-Ne laser of HPD along with the combination of He-Ne and low power Nd-YAG lasers are found to be ideal methods for quickening the wound healing process in rat.}, }
@article {pmid11259130, year = {2001}, author = {Andreassen, OA and Dedeoglu, A and Friedlich, A and Ferrante, KL and Hughes, D and Szabo, C and Beal, MF}, title = {Effects of an inhibitor of poly(ADP-ribose) polymerase, desmethylselegiline, trientine, and lipoic acid in transgenic ALS mice.}, journal = {Experimental neurology}, volume = {168}, number = {2}, pages = {419-424}, doi = {10.1006/exnr.2001.7633}, pmid = {11259130}, issn = {0014-4886}, support = {P01-AG12292/AG/NIA NIH HHS/United States ; }, mesh = {Amphetamines/*pharmacology/therapeutic use ; Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Animals ; Female ; Male ; Mice ; Mice, Transgenic ; Motor Skills/*drug effects/physiology ; Neuroprotective Agents/*pharmacology/therapeutic use ; *Poly(ADP-ribose) Polymerase Inhibitors ; Survival ; Thioctic Acid/*pharmacology/therapeutic use ; Trientine/*pharmacology/therapeutic use ; Weight Loss/drug effects/physiology ; }, abstract = {The development of transgenic mouse models of amyotrophic lateral sclerosis (ALS) allows the testing of neuroprotective agents. We evaluated the effects of five agents in transgenic mice with the G93A Cu,Zn superoxide dismutase mutation. A novel inhibitor of poly(ADP-ribose) polymerase showed no effects on survival. Desmethylselegiline and CGP3466 are agents that exert antiapoptotic effects in vitro by preventing nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase. They had no significant effects on survival in the G93A mice. Trientine, a copper chelator, produced a modest significant increase in survival. Similarly administration of lipoic acid in the diet produced a significant improvement in survival. These results therefore provide evidence for potential therapeutic effects of copper chelators and lipoic acid in the treatment of ALS.}, }
@article {pmid11257787, year = {2000}, author = {Ichihara, N and Deguchi, K and Fujii, S and Ishibashi, T and Hatanaka, Y}, title = {[A case of amyotrophic lateral sclerosis presenting with circulatory collapse during artificial respiration].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {40}, number = {9}, pages = {906-910}, pmid = {11257787}, issn = {0009-918X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Autonomic Nervous System/physiopathology ; Humans ; Hypotension, Orthostatic/etiology ; Male ; *Respiration, Artificial ; Shock/*etiology ; }, abstract = {A 71-year-old man developed dysarthria and difficulty of swallowing in December 1997. He was diagnosed as having the bulbar type of amyotrophic lateral sclerosis (ALS). In November 1998, he was admitted to our hospital to undergo treatment for bulbar palsy and respiratory discomfort. In January 1999, ventilatory support (synchronous intermittent mandatory ventilation) during sleep at night was initiated. Severe progressive hypotension and loss of consciousness were observed soon after the start of artificial respiration, and both symptoms disappeared after artificial respiration was discontinued. This phenomenon was observed consistently during ventilatory support, while unpleasant stimuli such as bronchoscopy and replacement of the cannula tube induced severe hypertension. To clarify the mechanism of underlying these abnormal changes in blood pressure, autonomic function tests were performed while awake during the daytime. Ventilatory support induced a drop in blood pressure accompanied by a decrease in influx speed to the right ventriculum, the latter of which suggested a reduction in venous return. These values returned to the baseline following detachment of the ventilator. A 60 degrees head-up tilt (HUT) angle and standing from a supine position produced orthostatic hypotension, the latter of which was accompanied by a compensatory increase in pulse rate. The basal supine plasma noradrenaline (NA) level was high and the HUT showed a slight elevation of NA. The basal supine plasma arginine vasopressin (AVP) level was within the normal range, whereas the AVP level did not increase during HUT. Urinary secretion rates of NA and 3-methoxy-4-hydroxy-phenylglycol were elevated. A cold pressor test demonstrated reflex hypertension. The oculovagal reflex, coefficient of variation of R-R intervals. (CVR-R) and increase in pulse rate in response to atropine administration were within the normal range. The combination of midodrine, L-dihydroxyphenylserine (DOPS) and increasing intravascular volume via continuous intravenous drip infusion relieved the circulatory collapse during artificial respiration. In conclusion, the present case of ALS had sympathetic hyperactivity, somatosympathetic reflex and dysregulation of the baroreflex arc. Degeneration of central autonomic network, including the hypothalamus and the central nucleus of the amygdala, which has been shown in some ALS patients, might underlie the autonomic abnormalities in this patient.}, }
@article {pmid11251210, year = {2001}, author = {Keep, M and Elmér, E and Fong, KS and Csiszar, K}, title = {Intrathecal cyclosporin prolongs survival of late-stage ALS mice.}, journal = {Brain research}, volume = {894}, number = {2}, pages = {327-331}, doi = {10.1016/s0006-8993(01)02012-1}, pmid = {11251210}, issn = {0006-8993}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/immunology/mortality ; Animals ; Cyclosporine/*pharmacology ; Disease Models, Animal ; Humans ; Immunosuppressive Agents/*pharmacology ; Injections, Spinal ; Mice ; Mice, Neurologic Mutants ; Mice, Transgenic ; Mitochondria/enzymology ; Nerve Degeneration/drug therapy/mortality ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Survival Rate ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by upper and lower motor neuron death with ascending paralysis leading to death. In a transgenic mouse model of ALS (SOD1-G93A) weakness appears at 3 months of age, and because of progressive paralysis leads to death by 5 months. Cyclosporin A (CsA) is well known, for its extracerebral effect, as an immunosuppressant in organ transplantation. When able to access the brain, CsA is an effective neuroprotective agent mainly due to its protection of mitochondria through inhibition of the mitochondrial permeability transition. CsA does not cross the intact blood-brain barrier and was in the present study delivered to the brain through an infusion into the lateral cerebral ventricle. Injections started at the onset of late disease when weakness of the hindlimbs was apparent. CsA treatment prolonged the survival of ALS transgenic mice as compared to vehicle-treated controls. This finding implicates mitochondrial function in ALS and may have significance for human disease.}, }
@article {pmid11249671, year = {1999}, author = {Abicht, A and Lochmüller, H}, title = {Technology evaluation: CRIB (CNTF delivery) CytoTherapeutics Inc.}, journal = {Current opinion in molecular therapeutics}, volume = {1}, number = {5}, pages = {645-650}, pmid = {11249671}, issn = {1464-8431}, mesh = {Amyotrophic Lateral Sclerosis/therapy ; Animals ; Biotechnology ; Cell Transplantation ; Ciliary Neurotrophic Factor/*genetics ; *Gene Transfer Techniques ; Genetic Therapy/adverse effects/*methods ; Humans ; Huntington Disease/therapy ; Transplantation, Heterologous ; }, abstract = {To achieve continuous, site-specific delivery of therapeutic molecules to the central nervous system (CNS), a new therapeutic approach was developed combining in vitro gene transfer with a new delivery device. Xenogenic cells genetically modified to secrete specific bioactive substances were encapsulated into polymer-based fibers. A semipermeable membrane allows for passage of nutrients and cell-released therapeutic agents, but restricts inward diffusion of larger molecules and cells of the host's immune system, thus facilitating xenograft survival. This novel technique was successfully tested for the in vitro and in vivo delivery of various therapeutic agents, including neurotrophic factors, neurotransmitters and hormones. Phase I clinical trials were reported for the treatment of amyotrophic lateral sclerosis (ALS) and chronic cancer pain.}, }
@article {pmid11248905, year = {2001}, author = {Winterholler, MG and Erbguth, FJ and Wolf, S and Kat, S}, title = {Botulinum toxin for the treatment of sialorrhoea in ALS: serious side effects of a transductal approach.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {70}, number = {3}, pages = {417-418}, doi = {10.1136/jnnp.70.3.417}, pmid = {11248905}, issn = {0022-3050}, mesh = {Amyotrophic Lateral Sclerosis/complications/*drug therapy ; Botulinum Toxins/*therapeutic use ; Female ; Humans ; Middle Aged ; Sialorrhea/complications/*drug therapy ; }, }
@article {pmid11248742, year = {2001}, author = {Zhou, X and Loke, KY and Pillai, CC and How, HK and Yap, HK and Lee, KO}, title = {IGFs and IGF-binding proteins in short children with steroid-dependent nephrotic syndrome on chronic glucocorticoids: changes with 1 year exogenous GH.}, journal = {European journal of endocrinology}, volume = {144}, number = {3}, pages = {237-243}, doi = {10.1530/eje.0.1440237}, pmid = {11248742}, issn = {0804-4643}, mesh = {Adolescent ; Blotting, Western ; Body Height/drug effects ; Bone Development/drug effects ; Carrier Proteins/blood/metabolism/urine ; Child ; Cholesterol/blood ; Dwarfism/blood/drug therapy/*metabolism/urine ; Glucocorticoids/administration &amp; dosage/*pharmacology/therapeutic use ; Glycoproteins/blood/metabolism/urine ; Human Growth Hormone/administration &amp; dosage/*pharmacology/therapeutic use ; Humans ; Insulin-Like Growth Factor Binding Protein 2/blood/metabolism/urine ; Insulin-Like Growth Factor Binding Protein 3/blood/metabolism/urine ; Insulin-Like Growth Factor Binding Proteins/blood/*metabolism/urine ; Insulin-Like Growth Factor I/metabolism ; Insulin-Like Growth Factor II/metabolism ; Ligands ; Male ; Matched-Pair Analysis ; Nephrosis/blood/drug therapy/metabolism/urine ; Prednisolone/administration &amp; dosage/pharmacology/therapeutic use ; Somatomedins/*metabolism ; Syndrome ; }, abstract = {OBJECTIVE: Children with steroid-dependent nephrotic syndrome (SDNS), despite being in remission on glucocorticoids, continue to have growth retardation and short stature. The mechanism is uncertain as both chronic glucocorticosteroids and the nephrotic syndrome may independently affect growth. We investigated the changes in the IGFs and IGF-binding proteins (IGFBPs) in a group of short SDNS children, and studied the changes prospectively with 1 year's treatment with GH.<br><br>DESIGN AND METHODS: Total and 'free' IGF-I, IGFBP-3 and acid-labile subunit (ALS) were studied in eight SDNS boys (mean age=12.6 years; mean bone age=9.1 years) on long term oral prednisolone (mean dose 0.46 mg/kg per day) before, during, and after, 1 year's treatment with GH (mean dose 0.32 mg/kg per week). Pretreatment comparisons were made with two control groups, one matched for bone age (CBA; mean bone age=9.2 years), and another for chronological age (CCA; mean chronological age=13 years). Subsequently, three monthly measurements of serum and urine IGFBPs were carried out in the GH-treated SDNS patients using Western ligand blot and Western immunoblot.<br><br>RESULTS: Pre-treatment serum total IGF-I levels and the IGF-I/IGFBP-3 ratio were elevated significantly in SDNS compared with CBA, and were similar to CCA. Serum free IGF-I levels were elevated significantly compared with both control groups, but serum IGFBP-3 did not differ significantly. Urinary IGFBP-2, IGFBP-3 and ALS were detectable in the SDNS children only. With GH treatment, IGF-I and IGFBP-3, but not IGF-II, increased significantly compared with pre-treatment values, and returned to baseline after cessation of GH treatment. Urinary IGFBPs did not change significantly with GH treatment.<br><br>CONCLUSIONS: There is persistent urinary loss of IGFBP-2, IGFBP-3 and ALS in children with SDNS in remission with growth retardation. However, the significant elevation in serum IGF-I suggests that glucocorticoid-induced resistance to IGF is the main factor responsible for the persistent growth retardation in these children. Exogenous GH was able to overcome this resistance by further increasing serum IGF-I.}, }
@article {pmid11245731, year = {2001}, author = {Ansevin, CF}, title = {Treatment of ALS with pleconaril.}, journal = {Neurology}, volume = {56}, number = {5}, pages = {691-692}, doi = {10.1212/wnl.56.5.691}, pmid = {11245731}, issn = {0028-3878}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Male ; Oxadiazoles/*therapeutic use ; Oxazoles ; }, }
@article {pmid11238491, year = {2001}, author = {Arosio, M and Garrone, S and Bruzzi, P and Faglia, G and Minuto, F and Barreca, A}, title = {Diagnostic value of the acid-labile subunit in acromegaly: evaluation in comparison with insulin-like growth factor (IGF) I, and IGF-binding protein-1, -2, and -3.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {86}, number = {3}, pages = {1091-1098}, doi = {10.1210/jcem.86.3.7288}, pmid = {11238491}, issn = {0021-972X}, mesh = {Acromegaly/blood/*diagnosis/surgery ; Adenoma/surgery ; Adult ; Aging ; Carrier Proteins/*blood ; Female ; Glucose Tolerance Test ; Glycoproteins/*blood ; Human Growth Hormone/blood ; Humans ; Insulin-Like Growth Factor Binding Protein 1/*blood ; Insulin-Like Growth Factor Binding Protein 2/*blood ; Insulin-Like Growth Factor Binding Protein 3/*blood ; Insulin-Like Growth Factor I/*analysis ; Male ; Middle Aged ; Pituitary Neoplasms/surgery ; Sex Characteristics ; Treatment Outcome ; }, abstract = {In normal subjects the main form of circulating insulin-like growth factor (IGF) is the 150-kDa complex. This complex is formed by the IGF peptide, the acid-stable IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS). Experimental and clinical data have demonstrated that ALS is primarily under the control of GH and plays a critical role in maintaining constant levels of circulating IGF-I. In this study we evaluated ALS, IGF-I, and IGFBP-1, -2, and -3 in 45 acromegalic patients in basal conditions and, in 37 of these, twice after surgical therapy compared with 100 age- and sex-matched control subjects to estimate their value as parameter of GH secretory state. The results demonstrated that in acromegaly before treatment all parameters (ALS, 523 +/- 26; IGF-I, 129 +/- 6; IGFBP-1, 0.7 +/- 0.1; IGFBP-3, 234 +/- 21; nmol/L; mean +/- SEM) but IGFBP-2 were significantly different (P<0.0001) from those in healthy subjects (ALS, 281 +/- 4; IGF-I, 22 +/- 1; IGFBP-1, 1.6 +/- 0.1; IGFBP-3, 91 +/- 3). IGF-I was more sensitive (100%) than ALS (89%), and both were more predictive of disease status than IGFBP-3, in that 27% of the patients had IGFBP-3 levels within the normal range. Considering the ALS/IGFBP-3 molar ratio, almost 55% of ALS circulated in a free form in active acromegaly. Before treatment, the IGF-I/IGFBPs (-1 + -2 + -3) molar ratio, which can be regarded as free, biologically active, IGF-I, was greatly increased (0.77 +/- 0.06; P<0.0001) compared with that in control subjects (0.23 +/- 0.01). After surgery, all 10 patients with controlled disease showed normalization of ALS (100% sensitivity), whereas 9 of them had normal IGFBP-3; reevaluation after varying lengths of time showed all these parameters within the normal range. In the 27 patients with active disease, IGF-I and ALS were more predictive of disease status (91% and 83% negative predictive values, respectively) than IGFBP-3 (53%). The basal ALS concentration correlated only with IGFBP-3 (r = 0.70; P<0.001). In postsurgery samples (first control) a statistically significant (P<0.001) correlation was found between mean GH values as well as minimum GH after oral glucose tolerance test and ALS (r = 0.72 and 0.83, respectively), IGF-I (r = 0.69 and 0.77), IGFBP-3 (r = 0.50 and 0.72), and IGFBP-2 (r = -0.36 and -0.63). Similarly, IGF-I, IGFBP-3, and ALS were positively correlated among themselves and negatively correlated with IGFBP-2 (P<0.001). In conclusion, in the diagnosis of acromegaly, the measurement of total IGF-I appears to be the most sensitive parameter among the subunits of the 150K complex, and IGFBP-3 the least sensitive. For ALS, this subunit is quite sensitive and appears to be a useful parameter in reassessment after surgical treatment.}, }
@article {pmid11231032, year = {2001}, author = {Bromberg, MB and Fries, TJ and Forshew, DA and Tandan, R}, title = {Electrophysiologic endpoint measures in a multicenter ALS drug trial.}, journal = {Journal of the neurological sciences}, volume = {184}, number = {1}, pages = {51-55}, doi = {10.1016/s0022-510x(00)00489-5}, pmid = {11231032}, issn = {0022-510X}, mesh = {Amino Acids, Branched-Chain/therapeutic use ; Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Disease Progression ; Double-Blind Method ; Electrophysiology ; Endpoint Determination ; Humans ; Motor Neurons/physiology ; Reproducibility of Results ; }, abstract = {We report the analysis of a battery of secondary electrophysiologic measurements to assess the progression of amyotrophic lateral sclerosis (ALS) in a two center, six month, double-blind, three arm trial comparing branched chain amino acids to L-threonine with pyridoxal 5-phosphate to placebo. The endpoint measurements were chosen to separately assess the effects of lower motor neuron loss and collateral reinnervation. For tests of inter-center reliability, we found no differences that could not be readily explained by variations in electrophysiologic testing techniques. Since the drug study was negative for the primary endpoint measure (muscle strength), we combined data from both centers and the three treatment arms. For measures of progression, all measures changed in the expected direction during the 6 months of the trial. We conclude that a battery of electrophysiologic measures can be used in a multicenter ALS drug trial to provide information on changes in lower motor neuron numbers and the effects of collateral reinnervation.}, }
@article {pmid11220737, year = {2001}, author = {Almer, G and Guégan, C and Teismann, P and Naini, A and Rosoklija, G and Hays, AP and Chen, C and Przedborski, S}, title = {Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis.}, journal = {Annals of neurology}, volume = {49}, number = {2}, pages = {176-185}, pmid = {11220737}, issn = {0364-5134}, support = {P50 NS38370/NS/NINDS NIH HHS/United States ; R01 NS38586/NS/NINDS NIH HHS/United States ; R29 NS37345/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*enzymology ; Animals ; Brain/metabolism ; Cyclooxygenase 2 ; Inflammation/enzymology ; Isoenzymes/*metabolism ; Mice ; Mice, Transgenic/metabolism ; Prostaglandin-Endoperoxide Synthases/*metabolism ; Spinal Cord/metabolism ; }, abstract = {Mutations in the copper/zinc superoxide dismutase (mSOD1) gene are associated with a familial form of amyotrophic lateral sclerosis (ALS), and their expression in transgenic mice produces an ALS-like syndrome. Recent observations suggest a role for inflammatory-related events in the progression and propagation of the neurodegenerative process in ALS. Consistent with this view, the present study demonstrates that, during the course of the disease, the expression of cyclooxygenase type 2 (Cox-2), a key enzyme in the synthesis of prostanoids, which are potent mediators of inflammation, is dramatically increased. In both early symptomatic and end-stage transgenic mSOD1 mice, neurons and, to a lesser extent, glial cells in the anterior horn of the spinal cord exhibit robust Cox-2 immunoreactivity. Cox-2 mRNA and protein levels and catalytic activity are also significantly increased in the spinal cord of the transgenic mSOD1 mice. The time course of the spinal cord Cox-2 upregulation parallels that of motor neuronal loss in transgenic mSOD1 mice. We also show that Cox-2 activity is dramatically increased in postmortem spinal cord samples from sporadic ALS patients. We speculate that Cox-2 upregulation, through its pivotal role in inflammation, is instrumental in the ALS neurodegenerative process and that Cox-2 inhibition may be a valuable therapeutic avenue for the treatment of ALS.}, }
@article {pmid11211839, year = {2000}, author = {Liu, Z and Chen, J}, title = {[The research advance of brain derived neurotrophic factor].}, journal = {Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi}, volume = {17}, number = {4}, pages = {454-6, 460}, pmid = {11211839}, issn = {1001-5515}, mesh = {Animals ; Brain-Derived Neurotrophic Factor/chemistry/pharmacology/*physiology ; Central Nervous System Diseases/drug therapy/physiopathology ; Genetic Therapy ; Neurons/physiology ; }, abstract = {Recent research advances in neuroscience show that neurotrophic factors are proteins that affect selectively various kinds of neurons of CNS and PNS. Brain derived neurotrophic factor (BDNF) is another neurotrophic factor that was first reported by Barde, a German chemist, thirty years later after the nerve growth factor had been found out. BDNF plays an important role in the growth, development, differentiation, maintenance and regeneration of various types of neurons in the CNS and has potential application to the treatment of brain injury and neurodegenerative diseases such as Alzheimer's disease, Parkinson's syndrome, Huntington's chorea and amyotrophic lateral sclerosis. In this paper, the structure, function and potential clinical application of BDNF were reviewed.}, }
@article {pmid11208901, year = {2001}, author = {Nishijima, C and Kimoto, K and Arakawa, Y}, title = {Survival activity of troglitazone in rat motoneurones.}, journal = {Journal of neurochemistry}, volume = {76}, number = {2}, pages = {383-390}, doi = {10.1046/j.1471-4159.2001.00039.x}, pmid = {11208901}, issn = {0022-3042}, mesh = {Animals ; Antioxidants/*pharmacology ; Brain-Derived Neurotrophic Factor/pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Chromans/*pharmacology ; Drug Evaluation, Preclinical ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Hippocampus/cytology/drug effects ; Insulin-Like Growth Factor I/pharmacology ; Motor Neurons/cytology/*drug effects ; Neurons, Afferent/cytology/drug effects ; Phosphoinositide-3 Kinase Inhibitors ; Pioglitazone ; Rats ; Receptors, Cytoplasmic and Nuclear/agonists ; Septum of Brain/cytology/drug effects ; Spinal Cord/cytology/drug effects/embryology ; Sympathetic Nervous System/cytology/drug effects ; Thiazoles/*pharmacology ; *Thiazolidinediones ; Transcription Factors/agonists ; Troglitazone ; }, abstract = {Troglitazone (TGZ), an antidiabetic drug that improves insulin-resistance in the peripheral tissues, was tested for neurotrophic activity in motoneurones and other neurones in culture. In rat motoneurones, TGZ had a remarkable effect on survival, which was comparable or superior to that of brain-derived neurotrophic factor, a known potent neurotrophic factor for rat motoneurones. However, TGZ did not promote the survival of sensory, sympathetic, septal or hippocampal neurones. The effect of TGZ on motoneurones was additive to that of insulin-like growth factor-I and both activities were inhibited by phosphatidylinositol 3-kinase (PI3-kinase) inhibitors, wortmannin and LY294002, suggesting the involvement of the activation of PI3-kinase in the activity of TGZ. Pioglitazone, another antidiabetic drug structurally similar to TGZ, did not show any activity, indicating that the agonistic activity of TGZ for peroxisome proliferator-activated receptor-gamma is not involved in the survival activity. Chromanol, an antioxidant moiety of TGZ, showed little or no survival activity. These results indicate specific neurotrophic activity of TGZ for motoneurones through the activation of PI3-kinase and support the applicability of TGZ for the treatment of motor neurone diseases such as amyotrophic lateral sclerosis.}, }
@article {pmid11205563, year = {2000}, author = {Marés-Segura, R}, title = {[Spinal cord paraneoplastic syndromes].}, journal = {Revista de neurologia}, volume = {31}, number = {12}, pages = {1219-1223}, pmid = {11205563}, issn = {0210-0010}, mesh = {Antibodies, Neoplasm/immunology ; Autoantibodies/immunology ; Breast Neoplasms/complications/immunology ; Carcinoma, Small Cell/complications/immunology ; Demyelinating Autoimmune Diseases, CNS/etiology/immunology ; Disease Progression ; Female ; Humans ; Lung Neoplasms/complications/immunology ; Male ; Motor Neuron Disease/etiology/immunology ; Muscle Rigidity/etiology/immunology ; Myelitis/etiology ; Myelitis, Transverse/etiology/immunology ; Neoplasms, Unknown Primary/diagnosis ; Paraneoplastic Syndromes, Nervous System/*etiology/immunology ; Paraproteins/immunology ; Sensation Disorders/etiology/immunology ; Stiff-Person Syndrome/etiology/immunology ; }, abstract = {OBJECTIVE: We reviewed the bibliography of various paraneoplastic syndromes which may show spinal involvement.<br><br>DEVELOPMENT: Paraneoplastic sensory neuropathy, myelitis and rigidity syndromes may present alone or as part of a generalized syndrome of paraneoplastic encephalomyelitis/sensory neuronopathy, usually associated with small cell cancer of the lung and anti-Hu antibodies. Amyotrophic lateral sclerosis and subacute necrotizing myelopathy of paraneoplastic origin are very rare, although casual association of these conditions with cancer cannot be ruled out. Subacute motor neuronopathy is linked to lymphoproliferative syndromes and breast cancer has been reported associated with cases of primary lateral sclerosis and the stiff man syndrome.<br><br>CONCLUSIONS: Various conditions of paraneoplastic origin may affect the spinal cord. Neurological symptoms may precede the diagnosis of neoplasia, are serious and do not usually respond to either immunosuppressive treatment or treatment of the underlying neoplasm, although there are exceptions. The presence of specific antibodies in some cases facilitates early diagnosis and shows the importance of immune mechanisms in these diseases. The paraneoplastic motor neuron syndromes may present atypically: at early or late age, be of slow evolution and associated with raised protein levels of the cerebrospinal fluid or with paraproteinemia.}, }
@article {pmid11205140, year = {2000}, author = {Waldmeier, PC and Boulton, AA and Cools, AR and Kato, AC and Tatton, WG}, title = {Neurorescuing effects of the GAPDH ligand CGP 3466B.}, journal = {Journal of neural transmission. Supplementum}, volume = {}, number = {60}, pages = {197-214}, doi = {10.1007/978-3-7091-6301-6_13}, pmid = {11205140}, issn = {0303-6995}, mesh = {Animals ; Animals, Newborn ; Brain/drug effects/metabolism ; Cell Survival/*drug effects/physiology ; Cells, Cultured ; Disease Models, Animal ; Glyceraldehyde-3-Phosphate Dehydrogenases/*drug effects/metabolism ; Ligands ; Mice ; Mice, Inbred C57BL ; Neurons/*drug effects/metabolism ; Neuroprotective Agents/chemistry/*pharmacology ; Oxepins/chemistry/*pharmacology ; Parkinson Disease/*drug therapy ; Rats ; Rats, Wistar ; Selegiline/adverse effects/*analogs &amp; derivatives ; }, abstract = {(-)-Deprenyl, used for the treatment of Parkinson's disease, was reported to possess neurorescuing/antiapoptotic effects independent of its MAO-B inhibiting properties. It is metabolized to (-)-desmethyldeprenyl, which seems to be the active principle, and further to (-)-amphetamine and (-)-methamphetamine, which antagonize its rescuing effects. These complications may explain the limited neurorescuing potential of (-)-deprenyl observed clinically. CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine), structurally related to (-)-deprenyl, exhibits virtually no MAO-B nor MAO-A inhibiting properties and is not metabolized to amphetamines. It was shown to bind to glyceraldehyde-3-phosphate dehydrogenase, a glycolytic enzyme with multiple other functions including an involvement in apoptosis, and shows neurorescuing properties qualitatively similar to, but about 100-fold more potent than those of (-)-deprenyl in several in vitro and in vivo paradigms. In concentrations ranging from 10(-13)-10(-5) M, it rescues partially differentiated PC12 cells from apoptosis induced by trophic withdrawal, cerebellar granule cells from apoptosis induced by cytosine arabinoside, rat embryonic mesencephalic dopaminergic cells from death caused by MPP+, and PAJU human neuroblastoma cells from death caused by rotenone. However, it did not affect apoptosis elicited by a variety of agents in rapidly proliferating cells from thymus or skin or in liver or kidney cells. In vivo, it rescued facial motor neuron cell bodies in rat pups after axotomy, rat hippocampal CA1 neurons after transient ischemia/hypoxia, and mouse nigral dopaminergic cell bodies from death induced by MPTP, in doses ranging between 0.0003 and 0.1 mg/kg p.o. or s.c., depending on the model. It also partially prevented the loss of tyrosine hydroxylase immunoreactivity in the substantia nigra of 6-OHDA-lesioned rats and improved motor function in these animals. Moreover, it prolonged the life-span of progressive motor neuronopathy (pmn) mice (a model for ALS), preserved their body weight and improved their motor performance. This was accompanied by a decreased loss of motor neurons and motor neuron fibers, and protection of mitochondria. The active concentration- or dose-ranges in the different in vitro and in vivo paradigms were remarkably similar. In several paradigms, bell-shaped dose-response curves were observed, the rescuing effect being lost above about 1 mg/kg, a fact that must be considered in clinical investigations.}, }
@article {pmid11204616, year = {2001}, author = {Zhang, X and Yamamoto, N and Soramoto, S and Takenaka, I}, title = {Cisplatin-induced germ cell apoptosis in mouse testes.}, journal = {Archives of andrology}, volume = {46}, number = {1}, pages = {43-49}, doi = {10.1080/01485010150211146}, pmid = {11204616}, issn = {0148-5016}, mesh = {Animals ; Antineoplastic Agents/*toxicity ; *Apoptosis ; Cisplatin/*toxicity ; In Situ Nick-End Labeling ; Male ; Mice ; Mice, Inbred BALB C ; Spermatozoa/*drug effects ; Testis/*drug effects ; }, abstract = {The purpose of this study was to investigate whether exposure of male mice to cisplatin induces apoptosis in male germ cells and the possible role of apoptosis in cisplatin-induced testicular damage. Forty-eight male BALB/c mice were divided into cisplatin and control groups. The mice from the cisplatin group received a single intraperitoneal injection of cisplatin of either 1, 5, or 10 mg/kg. The control group received a single intraperitoneal injection of saline alone. The testes were removed on days 1, 3, and 7 after cisplatin administration, respectively. Following histological examination, apoptotic indices (AIs) were measured within seminiferous tubules of the mouse testes by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. A low incidence of spontaneous apoptosis was observed in controls, particularly in spermatogonia and spermatocytes of the mouse testes. After cisplatin administration, both increased Als and decreased spermatozoa and spermatids were found in the seminiferous tubules of the mouse testes. Cisplatin-induced apoptosis was found in spermatogonia, spermatocytes, and spermatids of the mouse testes. In comparison to the control values, AIs increased 2.6- to 6.8-fold in cisplatin-treated mouse testes. AIs reached the highest level on day 1 following 1 mg/ kg, on day 3 following 5 mg/kg, and on day 7 following treatment of 10 mg/kg cisplatin. The study showed that cisplatin-induced germ cell apoptosis in the mouse testes was related to both the dose response and the time course of response. It is suggested that cisplatin-induced germ cell apoptosis may result in decreased spermatogenesis, and the higher dose of cisplatin may delay the occurrence of apoptosis in the mouse testes.}, }
@article {pmid11200701, year = {2000}, author = {Meininger, V and Lacomblez, L and Salachas, F}, title = {What has changed with riluzole?.}, journal = {Journal of neurology}, volume = {247}, number = {}, pages = {19-22}, pmid = {11200701}, issn = {0340-5354}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Excitatory Amino Acid Antagonists/*therapeutic use ; Female ; Glutamic Acid ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Riluzole/*therapeutic use ; }, abstract = {Riluzole, after two significant trials, was introduced as the first standard treatment of amyotrophic lateral clerosis (ALS) in the early 95'. After 5 years what has changed in the field of ALS? In the field of basic science, riluzole as an active drug has largely contributed to stimulate the research of the possible role of glutamate in the genesis of ALS. However, the apparent simplicity of the relation between the drug and its mechanisms has to modulated in the light of the negativity of other trials (gabapentin) and the display of other mechanisms of the disease and of the compound. Possible relation with other putative mechanisms of ALS, as oxydative stress or growth factors, could be (and probably are) also involved. In the field of its activity, riluzole has an impact on the survival rate which has been largely debated. Comparison with historical databases are supporting the results of the two initial trials. Other information have been published supporting the probable activity of the drug on the muscle strength decline, a controversial matter. They strengthen the initial data and give additional reasons to use riluzole as a standard treatment of patients. In the field of the daily care, riluzole provided a real and unique hope for ALS sufferers. Even if its activity is not as complete as patients would have expected, it provides a hope for slowing down the rate of evolution and abolishes the myth of "no hope, no cure" which was the leitmotiv of patients care until recently. We have to better define the mode of administration with regard to the clinical status of the patients (respiratory disorders, fatigue, stiffness). In the field of care givers, riluzole was one major factor which provided the basis for national and international collaborations either for therapeutic trials or for standard of care. It made possible large collaborative programs in and among many countries. We do hope that this impulse will continue and be stimulated by additional results both in the field of basic science and clinical research.}, }
@article {pmid11200700, year = {2000}, author = {Ludolph, AC}, title = {Treatment of amyotrophic lateral sclerosis--what is the next step?.}, journal = {Journal of neurology}, volume = {247}, number = {}, pages = {13-18}, pmid = {11200700}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/etiology/genetics/prevention &amp; control/*therapy ; Animals ; Disease Models, Animal ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Mice ; Mice, Transgenic ; Mutation ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which was thought to be untreatable. However, recent evidence in both experimental animals and men indicates that antiglutamatergic strategies are the first to have an influence on its pathogenesis and slow down the disease process. Since the effect of drugs is still small, this progress cannot only be seen as a success of the present but must also be acknowledged as a basis for future developments. How will future studies be designed? They will have to take into account that the disease presumably has a long preclinical period and they will use a number of novel compounds and treatment strategies which have been shown to be effective in transgenic animal models. This also implies that we are likely to use a combination of therapies and we will try to treat patients early. The latter will be associated with the demand for a novel clinical attitude toward the diagnosis of the disease and the development of novel markers for both the preclinical period and the longitudinal course of the disease.}, }
@article {pmid11180750, year = {2001}, author = {Gelanis, DF}, title = {Respiratory Failure or Impairment in Amyotrophic Lateral Sclerosis.}, journal = {Current treatment options in neurology}, volume = {3}, number = {2}, pages = {133-138}, pmid = {11180750}, issn = {1092-8480}, abstract = {Respiratory complications account for the majority of deaths occurring in patients suffering from amyotrophic lateral sclerosis (ALS). Patients normally succumb to their illness within an average of 3 to 5 years from the time of diagnosis from complications such as hypoventilation, hypoxemia, hypercarbia, aspiration, and other pneumonia and pulmonary emboli. Although invariably disabling, ALS need not be fatal if respiratory involvement is detected early, which will allow sufficient time to discuss and implement treatment options. The recently published American Academy of Neurology guidelines for the management of ALS recommends the following: Serial measures of pulmonary function to guide management and determine prognosis. Noninvasive ventilatory support--an effective initial therapy for symptomatic chronic hypoventilation and prolonged survival. Invasive ventilatory support when long-term survival is the goal and noninvasive support is no longer sufficient. Physicians respect the right of the patient to choose, refuse, or withdraw ventilatory support. Liberal use of opiates and anxiolytics to relieve dyspnea and anxiety when ventilatory support is refused or withdrawn.}, }
@article {pmid11173059, year = {2001}, author = {Maimone, D and Dominici, R and Grimaldi, LM}, title = {Pharmacogenomics of neurodegenerative diseases.}, journal = {European journal of pharmacology}, volume = {413}, number = {1}, pages = {11-29}, doi = {10.1016/s0014-2999(00)00939-0}, pmid = {11173059}, issn = {0014-2999}, mesh = {Alzheimer Disease/drug therapy/genetics/metabolism/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; Animals ; Apoptosis ; Genetic Predisposition to Disease ; Humans ; Inflammation/pathology ; Nerve Growth Factors/genetics/metabolism/therapeutic use ; Neurodegenerative Diseases/drug therapy/*genetics/*metabolism/pathology ; Neuroprotective Agents/therapeutic use ; Neurotransmitter Agents/metabolism ; Oxidative Stress ; Parkinson Disease/drug therapy/genetics/metabolism/pathology ; *Pharmacogenetics ; Polymorphism, Genetic ; }, abstract = {Current knowledge of sporadic degenerative disorders suggests that, despite their multifactorial etiopathogenesis, genetics plays a primary role in orchestrating the pathological events, and even dramatically changes the disease phenotype from patient to patient. Genes may act as susceptibility factors, increasing the risk of disease development, or may operate as regulatory factors, modulating the magnitude and severity of pathogenic processes or the response to drug treatment. The goal of pharmacogenomics is the application of this knowledge to elaborate more specific and effective treatments and to tailor therapies to individual patients according to their genetic profile. Here, we outline the leading theories on the etiopathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer disease, and we review the potential role of genetic variations, such as gene mutations and polymorphisms, in each context. We also suggest potential targets for new therapeutic approaches and variability factors for current treatments based on genotype features. Finally, we propose a few options of preventive therapeutic interventions in patients with a high genetic risk of disease.}, }
@article {pmid11169982, year = {2001}, author = {Scharf, JG and Braulke, T and Hartmann, H and Ramadori, G}, title = {Regulation of the components of the 150 kDa IGF binding protein complex in cocultures of rat hepatocytes and Kupffer cells by 3',5'-cyclic adenosine monophosphate.}, journal = {Journal of cellular physiology}, volume = {186}, number = {3}, pages = {425-436}, doi = {10.1002/1097-4652(2000)9999:999&lt;000::AID-JCP1036&gt;3.0.CO;2-Y}, pmid = {11169982}, issn = {0021-9541}, mesh = {8-Bromo Cyclic Adenosine Monophosphate/pharmacology ; Animals ; Bucladesine/pharmacology ; Coculture Techniques ; Cyclic AMP/*physiology ; Gene Expression Regulation/drug effects ; Hepatocytes/cytology/drug effects/*physiology ; Insulin-Like Growth Factor Binding Protein 1/genetics/metabolism ; Insulin-Like Growth Factor Binding Protein 3/*genetics/metabolism ; Insulin-Like Growth Factor I/*genetics/metabolism ; Insulin-Like Growth Factor II/genetics/metabolism ; Kinetics ; Kupffer Cells/cytology/drug effects/*physiology ; Liver/*cytology/metabolism ; Male ; Molecular Weight ; Rats ; Rats, Wistar ; Recombinant Proteins/metabolism ; Transcription, Genetic/drug effects ; }, abstract = {In the circulation, most of IGFs are bound to a high molecular mass complex of 150 kDa that consists of IGF-I (or IGF-II), IGFBP-3 and the acid-labile subunit (ALS). Within rat liver, biosynthesis of these components has been localized to different cell populations with hepatocytes as source of ALS and nonparenchymal cells (endothelial and Kupffer cells (KC)) as source of IGFBP-3. In the present study, the regulatory effects of the cAMP analogs dibutyryl-cAMP (db-cAMP) and 8-bromo-cAMP (8-br-cAMP) on IGF-I, ALS, and IGFBP expression were evaluated in primary cultures of rat hepatocytes, KC as well as in cocultures of hepatocytes and KC. In cocultures, biosynthesis of IGFBP-3 and ALS was inhibited dose-dependently by db-cAMP and 8-br-cAMP while that of IGF-I, IGFBP-1, and -4 was stimulated as demonstrated by ligand and Northern blotting. IGFBP-3 expression in primary cultures of pure KC did not respond to cAMP treatment indicating the importance of a cellular interaction between KC and hepatocytes for the decreased IGFBP-3 synthesis. The inhibition of IGFBP-3 in db-cAMP-treated cocultures was due to a decrease of IGFBP-3 mRNA level accompanied by a reduced cellular degradation of IGFBP-3. We conclude that cAMP stimulate the biosynthesis of IGF-I, IGFBP-1, and -4 in cocultures of hepatocytes and KC thereby enabling the formation of binary IGF/IGFBP complexes while the formation of the 150 kDa complex is impaired through downregulation of IGFBP-3 and ALS. This complex regulation may be a prerequisite for the effects of cAMP-dependent hormones on the transfer of IGFs from circulation to peripheral tissues.}, }
@article {pmid11161628, year = {2001}, author = {Van Westerlaak, MG and Joosten, EA and Gribnau, AA and Cools, AR and Bär, PR}, title = {Chronic mitochondrial inhibition induces glutamate-mediated corticomotoneuron death in an organotypic culture model.}, journal = {Experimental neurology}, volume = {167}, number = {2}, pages = {393-400}, doi = {10.1006/exnr.2000.7570}, pmid = {11161628}, issn = {0014-4886}, mesh = {Animals ; Antigens, Differentiation/metabolism ; Cell Death/drug effects ; Cell Size ; Cells, Cultured ; Cerebral Cortex/cytology/drug effects/*metabolism ; Dizocilpine Maleate/pharmacology ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Antagonists/pharmacology ; Glutamic Acid/*metabolism/toxicity ; Immunohistochemistry ; In Vitro Techniques ; Malonates/pharmacology ; Mitochondria/drug effects/*metabolism ; Models, Biological ; Motor Neurons/cytology/drug effects/*metabolism ; Neurodegenerative Diseases/etiology/*metabolism ; Neurofilament Proteins/metabolism ; Neuroprotective Agents/pharmacology ; Pyramidal Cells/cytology/drug effects/metabolism ; Rats ; Rats, Wistar ; Time Factors ; }, abstract = {There is growing evidence that mitochondrial dysfunction is an important factor in a cascade of neurotoxic events as observed during pathogenesis of various neurodegenerative diseases. In the neurodegenerative disease amyotrophic lateral sclerosis (ALS) both spinal and cortical motoneurons degenerate, but in experimental studies most attention so far has been focussed on the spinal motoneurons. In order to study the role of mitochondrial dysfunction in the pathways leading to cortical (upper) motoneuron (CMN) death, a long-term culture system of rat cortical explants was used. CMNs were visualized by immunocytochemical labeling with antibodies directed against nonphosphorylated neurofilament, SMI-32, and for their identification we also used their location in layer V of the explant, their size, and their morphological appearance. In this model the effect of mitochondrial inhibition was studied through chronic malonate treatment. For 2 weeks, low doses of complex II inhibitor malonate were added to the cultures twice a week. The malonate-induced chronic mitochondrial inhibition resulted in a dose-dependent increase of CMN death in the slices. Neuroprotection was achieved with the NMDA antagonist MK-801 and the non-NMDA antagonist CNQX indicating the involvement of glutamate in the malonate-induced CMN death. Furthermore, our data indicate that chronic mitochondrial inhibition results in CMN death, which is mediated by glutamate excitotoxicity via both non-NMDA and NMDA receptors. In this respect the present in vitro approach may act as a model for understanding mechanisms underlying CMN death in ALS.}, }
@article {pmid11151414, year = {2000}, author = {Jenkinson, C and Fitzpatrick, R and Swash, M and Peto, V and , }, title = {The ALS Health Profile Study: quality of life of amyotrophic lateral sclerosis patients and carers in Europe.}, journal = {Journal of neurology}, volume = {247}, number = {11}, pages = {835-840}, doi = {10.1007/s004150070069}, pmid = {11151414}, issn = {0340-5354}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*epidemiology ; *Caregivers ; Europe/epidemiology ; Female ; *Health Status ; Humans ; Male ; Middle Aged ; *Quality of Life ; }, abstract = {The measurement of functioning and well-being from the perspective of the patient has in recent years become central to the assessment of health and the evaluation of treatment regimes. The past decade has seen an enormous growth in the application of measures designed to assess quality of life in a vast array of medical specialties. However, the use of such measures in neurology has been relatively limited, and this has certainly been the case in amyotrophic lateral sclerosis (ALS). The European ALS Health Profile Study is a longitudinal survey of patients diagnosed with ALS or other motor neurone diseases in which patients are asked to complete questionnaires concerning their subjective health status. Data from clinical assessments are also collected. It is intended that the information collected will provide more systematic and detailed evidence of the impact of the disease from the perspective of the patient. This contribution documents results from baseline assessment obtained from data supplied by clinicians, carers and patients themselves. Three outcome measures are assessed in this paper: the SF-36, a generic measure of well being and functioning, the ALS Functional Rating Scale and the Carer Strain Index. The evidence presented here suggests that these measures provide a meaningful and valid picture of the impact of the disease. The data indicate that ALS has substantial adverse effects both upon the functioning and well being of patients and carers, as well as an association between the emotional health status of patients and carers, and between the physical health status of patients and carers.}, }
@article {pmid11145996, year = {2001}, author = {Olivieri, G and Baysang, G and Meier, F and Müller-Spahn, F and Stähelin, HB and Brockhaus, M and Brack, C}, title = {N-acetyl-L-cysteine protects SHSY5Y neuroblastoma cells from oxidative stress and cell cytotoxicity: effects on beta-amyloid secretion and tau phosphorylation.}, journal = {Journal of neurochemistry}, volume = {76}, number = {1}, pages = {224-233}, doi = {10.1046/j.1471-4159.2001.00090.x}, pmid = {11145996}, issn = {0022-3042}, mesh = {Acetylcysteine/*pharmacology ; Amyloid beta-Peptides/*metabolism/pharmacology ; Blotting, Western ; Cell Survival/drug effects/radiation effects ; Dose-Response Relationship, Drug ; Enzyme-Linked Immunosorbent Assay ; Glutathione/metabolism ; Glutathione Reductase/antagonists &amp; inhibitors ; Humans ; Hydrogen Peroxide/pharmacology ; Neuroblastoma/*metabolism ; Oxidative Stress/*drug effects ; Peptide Fragments/metabolism/pharmacology ; Phosphorylation/drug effects/radiation effects ; Tetrazolium Salts/metabolism ; Thiazoles/metabolism ; Tumor Cells, Cultured ; Ultraviolet Rays ; tau Proteins/*metabolism ; }, abstract = {Redox changes within neurones are increasingly being implicated as an important causative agent in brain ageing and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD). Cells have developed a number of defensive mechanisms to maintain intracellular redox homeostasis, including the glutathione (GSH) system and antioxidant enzymes. Here we examine the effects of N-acetyl-L-cysteine (NAC) on beta-amyloid (A beta) secretion and tau phosphorylation in SHSY5Y neuroblastoma cells after exposure to oxidative stress inducing/cytotoxic compounds (H(2)O(2), UV light and toxic A beta peptides). A beta and tau protein are hallmark molecules in the pathology of AD while the stress factors are implicated in the aetiology of AD. The results show that H(2)O(2), UV light, A beta 1-42 and toxic A beta 25-35, but not the inactive A beta 35-25, produce a significant induction of oxidative stress and cell cytotoxicity. The effects are reversed when cells are pre-treated with 30 mM NAC. Cells exposed to H(2)O(2), UV light and A beta 25-35, but not A beta 35-25, secrete significantly higher amounts of A beta 1-40 and A beta 1-42 into the culture medium. NAC pre-treatment increased the release of A beta 1-40 compared with controls and potentiated the release of both A beta 1-40 and A beta 1-42 in A beta 25-35-treated cells. Tau phosphorylation was markedly reduced by H(2)O(2) and UV light but increased by A beta 25-35. NAC strongly lowered phospho-tau levels in the presence or absence of stress treatment.}, }
@article {pmid11139813, year = {1999}, author = {Braun, JS and Tuomanen, EI and Cleveland, JL}, title = {Neuroprotection by caspase inhibitors.}, journal = {Expert opinion on investigational drugs}, volume = {8}, number = {10}, pages = {1599-1610}, doi = {10.1517/13543784.8.10.1599}, pmid = {11139813}, issn = {1744-7658}, abstract = {In the majority of brain diseases, apoptosis causes or exacerbates neuronal damage. Caspases are the final executioners of the apoptotic cell death programme. This family of proteases is implicated in the pathogenesis of many forms of brain damage, including those induced by ischaemia, inflammation or trauma, as well as those arising in Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and epilepsy. Collectively, these conditions affect more than 10 million people in the USA alone. Apoptosis can be blocked by agents that inhibit caspase activity; these inhibitors have therapeutic benefit in the treatment of several model systems of brain diseases. In this review we focus on recent advances and summarise current knowledge concerning the use of these cell death inhibitors in neuroprotection.}, }
@article {pmid11136351, year = {2000}, author = {Wermuth, L and von Weitzel-Mudersbach, P and Jeune, B}, title = {A two-fold difference in the age-adjusted prevalences of Parkinson's disease between the island of Als and the Faroe Islands.}, journal = {European journal of neurology}, volume = {7}, number = {6}, pages = {655-660}, doi = {10.1046/j.1468-1331.2000.00131.x}, pmid = {11136351}, issn = {1351-5101}, mesh = {Age Distribution ; Aged ; Aged, 80 and over ; Denmark/epidemiology ; Female ; Geography ; Humans ; Male ; Middle Aged ; Parkinson Disease/classification/diagnosis/*epidemiology ; Prevalence ; Registries ; Surveys and Questionnaires ; }, abstract = {With the aim of comparing the previously found high prevalence of idiopathic Parkinson's disease (PD) in the Faroe Islands with the prevalence of PD in an area of Denmark, we used the same case-finding methods for case ascertainment and the same strict criteria to diagnose PD on the island of Als. During the last year before the prevalence date (1 January 1998), we found in various registries from pharmacies, hospital, private neurologist and general practitioners 121 patients with suspected Parkinsonism out of 56,839 inhabitants on the island of Als. After exclusion of those who had other diseases, a total of 79 patients were left for further examinations. Among these we found 58 with PD. The overall prevalence of PD was estimated to be 102.0 and the age-adjusted prevalence to be 98.3 per 100,000 persons compared with 187.6 and 209.0 in the Faroe Islands. Compared with the previous results from the Faroe Islands (prevalence date 1 July 1995) we found an even lower mean age at onset of PD symptoms and at onset of treatment, a lower proportion of definite PD and a lower average dose of levodopa. We therefore conclude that the two-fold higher prevalence in the Faroe Islands than on the island of Als was not due to an early diagnosis and a higher ascertainment of cases with mild PD, which was suggested as being one possible explanation for our previous finding of a high prevalence of PD in the Faroe Islands.}, }
@article {pmid11124425, year = {2000}, author = {Husseman, JW and Nochlin, D and Vincent, I}, title = {Mitotic activation: a convergent mechanism for a cohort of neurodegenerative diseases.}, journal = {Neurobiology of aging}, volume = {21}, number = {6}, pages = {815-828}, doi = {10.1016/s0197-4580(00)00221-9}, pmid = {11124425}, issn = {0197-4580}, support = {AG12721/AG/NIA NIH HHS/United States ; P50 AG 05136-16/AG/NIA NIH HHS/United States ; R35 AG 10917-06/AG/NIA NIH HHS/United States ; }, mesh = {AIDS Dementia Complex/metabolism/pathology ; Adult ; Aged ; Aged, 80 and over ; Alzheimer Disease/metabolism/*pathology ; Brain/cytology/metabolism/*pathology ; Cell Cycle/*physiology ; Cyclin-Dependent Kinases/*analysis ; Cyclins/*analysis ; Female ; Humans ; Male ; Middle Aged ; *Mitosis ; Motor Neuron Disease/metabolism/pathology ; Neurodegenerative Diseases/metabolism/*pathology ; Reference Values ; Supranuclear Palsy, Progressive/metabolism/pathology ; }, abstract = {Previous evidence from our lab and others has implicated the mitotic cdc2/cyclin B1 kinase in the neurofibrillary degeneration of Alzheimer's disease. To examine the specificity of this relationship, and define conditions leading to atypical activation of mitotic kinase in postmitotic neurons, we have applied antibodies specific for the cdc2 kinase, its activator, cyclin B1, and three cdc2 produced phosphoepitopes: the TG-3 phosphoepitope in tau and nucleolin, the MPM-2 phosphoepitope in a variety of substrates, and the H5 phosphoepitope in RNA polymerase II, to affected brain regions from a spectrum of neurodegenerative disorders. Our results demonstrate that neurons containing characteristic lesions in a subset of diseases including Down Syndrome (DS), Frontotemporal Dementia linked to chromosome 17 (FTD-17), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Parkinson-Amyotrophic Lateral Sclerosis of Guam (GP-ALS), Niemann Pick disease type C (NPDC), and Pick's disease, display mitotic indices, implicating diverse etiologies in mitotic activation. The convergence of various degenerative schemes into a unified mitotic kinase-driven pathway provides a common target for therapeutic treatment of these different disorders.}, }
@article {pmid11117030, year = {2000}, author = {Kovaćević, J and Basić, S}, title = {[Development and organization of the Education Center at the Institute of Emergency Medical Services in Sarajevo].}, journal = {Medicinski arhiv}, volume = {54}, number = {4}, pages = {223-225}, pmid = {11117030}, mesh = {*Academies and Institutes ; Allied Health Personnel/*education ; Bosnia and Herzegovina ; *Education, Medical, Graduate ; Emergency Medicine/*education ; *First Aid ; Humans ; }, abstract = {This paper presents an experience of the Educational Centre of EMSC Sarajevo in the postgraduate training of the various profiles of medical personnel (medical doctors and medical technicians) that are employed in the emergency services of the pre-hospital and hospital type in Bosnia and Herzegovina. A period of the last four years (1996-2000) when the Educational Centre was restructured, becoming a one of the most active services in the medical sector of the EMSC Sarajevo has been emphasised in particular. Educational Centre of EMSC was participating in a number of international projects related to the education. Forty-five (45) courses of the various levels and with different programs: BLS, ALS, ACLS, ACLS-instructor course, ATLS, EMT-course, EMT-advanced, EMT-instructor and EMT-dispatcher course were carried out in the mentioned period. Seven thousand eight hundred and twelve (7812) hours of theoretical teaching and practical training were provided for the 570 candidates who successfully completed training in various programs. First aid training for civilian population was also conducted. Twenty one first.aid courses were carried out and successfully achieved by 324 candidates. On this way, 196 hours of theoretical teaching and practical training were realised. In order to make first aid training popular, 160 children from pre-school institutions (kindergartens) of Sarajevo Canton were also introduced to first aid principles. It has been pointed out that well equipped and trained team for the urgent medical intervention with a necessary team work is a crucial factor for the successful treatment of emergency that means a patient in life threatening situation.}, }
@article {pmid11112052, year = {2000}, author = {Geissler, EK and Scherer, MN and Graeb, C}, title = {Soluble donor MHC class I gene transfer to thymus promotes allograft survival in a high-responder heart transplant model.}, journal = {Transplant international : official journal of the European Society for Organ Transplantation}, volume = {13 Suppl 1}, number = {}, pages = {S452-5}, doi = {10.1007/s001470050381}, pmid = {11112052}, issn = {0934-0874}, support = {AI39741-01/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Cell Transplantation ; Cells, Cultured ; *Genes, MHC Class I ; Graft Survival/*immunology ; Heart Transplantation/*immunology ; Hepatocytes/cytology/*immunology ; Immunosuppression Therapy/methods ; Rats ; Rats, Inbred ACI ; Rats, Inbred Lew ; Thymus Gland ; Transfection/*methods ; Transplantation, Homologous ; }, abstract = {Thymic selection of self and non-self-reactive lymphocytes is a process that may be targeted to induce donor-specific immunologic unresponsiveness in organ transplantation. In the present study, gene transfer was used to preexpose the recipient thymus to soluble donor-specific MHC class I molecules prior to heart transplantation in the high-responder ACI (RT1a) to Lewis (RT1l) rat strain combination. Specifically, cultured Lewis hepatocytes were transfected with DNA encoding a secreted form of the donor allo-MHC class I antigen, RT1.Aa. Seven days prior to ACI heart transplantation, genetically altered recipient-strain hepatocytes were injected into the thymus of Lewis recipients which also received a dose of antilymphocyte serum (ALS). Results showed that treatment with both ALS and soluble donor MHC-expressing hepatocytes prolonged transplant survival time by twofold, compared to injection of control hepatocytes and ALS. Therefore, intrathymic gene therapy delivery of soluble donor MHC molecules may be useful for promoting allograft survival in heart transplantation.}, }
@article {pmid11107559, year = {1999}, author = {Domzał, TM}, title = {[Achievements, disappointments and hopes in neurological therapy in the 20th century].}, journal = {Neurologia i neurochirurgia polska}, volume = {32 Suppl 6}, number = {}, pages = {9-13}, pmid = {11107559}, issn = {0028-3843}, mesh = {Antibodies, Monoclonal/therapeutic use ; Forecasting ; Genetic Therapy/trends ; Humans ; Nerve Growth Factors/therapeutic use ; Nervous System Diseases/*diagnosis/*therapy ; Nervous System Neoplasms/therapy ; Neurology/*trends ; }, abstract = {Only in the second half of the 20th century a breakthrough occurred in the traditional neurological therapeutic methods based up to that time mainly on bromine with valerian extract and vitamins B. Later on in that century several great discoveries were made which improved greatly the effectiveness of the neurological therapy: psychopharmacology which began with the introduction of chlorpromazine and reserpine, the use of corticosteroids for which the Nobel award was given, levodopa introduction for Parkinson's disease, non-steroid antiinflammatory agents and the demonstration of their action mechanism /also Nobel award/, immunotherapy, botulin toxin for the treatment of dystonias and thrombolytic drugs possibly the drugs of the future. The main disappointment is the broad chasm between the progress made in diagnostic methods and the low effectiveness of therapy in strokes, amyotrophic lateral sclerosis, Alzheimer's disease and other degenerative neurological diseases. Many problems arose with the introduction of levodopa changing the course and clinical pattern of Parkinson's disease. The problem of our times are the adverse effects of pharmacotherapy. The low effectiveness of the new drugs used in epilepsy is also disappointing. A hope for the future is the new direction in therapy--the use of genes and also the use of monoclonal antibodies and neurotrophic agents. It is to be expected that in the near future medicine will find effective methods for the treatment of malignant neoplasms.}, }
@article {pmid11096733, year = {2000}, author = {Demaerschalk, BM and Strong, MJ}, title = {Amyotrophic Lateral Sclerosis.}, journal = {Current treatment options in neurology}, volume = {2}, number = {1}, pages = {13-22}, pmid = {11096733}, issn = {1092-8480}, abstract = {More than a century after its initial clinicopathologic description, amyotrophic lateral sclerosis (ALS) remains a largely fatal, progressive neurodegenerative disorder for which few efficacious pharmacotherapies with an impact directly on the natural course of the illness exist. The only currently approved therapy, the antiglutamatergic agent riluzole, has been shown to have only a marginal survival benefit in the absence of changes in functional assessments during the disease course. The efficacy of recombinant human insulin-like growth factor (rhIGF-1) remains controversial. In light of this, the primary focus of treatment for individuals with ALS remains symptomatic, through a multidisciplinary team approach including physicians, nurses, speech/language pathologists, physical therapists, occupational therapists, dietitians, social workers, and respiratory therapists.}, }
@article {pmid11095506, year = {2000}, author = {Nakamizo, T and Urushitani, M and Inoue, R and Shinohara, A and Sawada, H and Honda, K and Kihara, T and Akaike, A and Shimohama, S}, title = {Protection of cultured spinal motor neurons by estradiol.}, journal = {Neuroreport}, volume = {11}, number = {16}, pages = {3493-3497}, doi = {10.1097/00001756-200011090-00019}, pmid = {11095506}, issn = {0959-4965}, mesh = {Animals ; Cell Death/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Estradiol/analogs &amp; derivatives/*pharmacology ; Estrogen Antagonists/pharmacology ; Fetus ; Fulvestrant ; Glutamic Acid/toxicity ; Glutathione/pharmacology ; Motor Neurons/*cytology/drug effects ; Neurons/*cytology/drug effects ; Rats ; Rats, Wistar ; Spinal Cord/*cytology ; Stereoisomerism ; }, abstract = {Estrogens have been reported to exert neuroprotection in the brain, but there have been no reports of such neuroprotection in spinal motor neurons, the neurons selectively involved in amyotrophic lateral sclerosis (ALS). In this study, we demonstrated that 17beta-estradiol and its biologically inactive stereoisomer, 17alpha-estradiol, prevented glutamate- and nitric oxide (NO)-induced selective motor neuronal death observed in primary cultures of the rat spinal cord. The dose of estradiols required for motor neuron protection was greatly reduced by co-administration with glutathione. The results of this study shows that estradiol protects spinal motor neurons from excitotoxic insults in vitro, and may have application as a treatment for ALS.}, }
@article {pmid11095453, year = {2000}, author = {Dall, R and Longobardi, S and Ehrnborg, C and Keay, N and Rosén, T and Jørgensen, JO and Cuneo, RC and Boroujerdi, MA and Cittadini, A and Napoli, R and Christiansen, JS and Bengtsson, BA and Sacca, L and Baxter, RC and Basset, EE and Sönksen, PH}, title = {The effect of four weeks of supraphysiological growth hormone administration on the insulin-like growth factor axis in women and men. GH-2000 Study Group.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {85}, number = {11}, pages = {4193-4200}, doi = {10.1210/jcem.85.11.6964}, pmid = {11095453}, issn = {0021-972X}, mesh = {Adolescent ; Adult ; Dose-Response Relationship, Drug ; Female ; Human Growth Hormone/*pharmacology ; Humans ; Insulin-Like Growth Factor Binding Protein 2/*blood ; Insulin-Like Growth Factor Binding Protein 3/*blood ; Insulin-Like Growth Factor I/*metabolism ; Male ; Placebos ; Protein Subunits ; Reference Values ; Sex Characteristics ; }, abstract = {Measurements of serum insulin-like growth factor I (IGF-I) and related markers are routinely used in the diagnosis and treatment of GH deficiency and excess. The validity of these markers for assessment of exogenous GH exposure in healthy adults is, however, unknown. We therefore conducted a double blind, placebo-controlled GH treatment trial in 99 healthy subjects [49 women and 50 men; mean +/- SE age, 25.6+/-0.6 (women)/25.7+/-0.6 yr (men)]. Blood was collected weekly during a 4-week treatment period (days 1-28), and the subjects were subsequently followed for additional 8 weeks (days 29-84). The treatment arms included: I) 0.1 IU/kg x day GH (n = 30; GH 0.1), II) 0.2 IU/kg x day GH (n = 29; GH 0.2), and III) placebo (n = 40). At baseline no gender-specific differences existed, except that the acid-labile subunit (ALS) levels were higher in females. Serum insulin-like growth factor I (IGF-I) levels in males receiving GH increased significantly through day 42 with no significant difference between the 2 doses. The absolute IGF-I response was significantly lower in females, and there was a clear dose-response relationship. ALS levels in males increased through day 30 (P < 0.001). In females ALS levels were only modestly increased on day 28 compared with those in the placebo group (P < 0.02). IGF-binding protein-3 (IGFBP-3) levels in males increased significantly in the GH 0.1 and the GH 0.2 groups on day 30 (P < 0.03), whereas no solid IGFBP-3 increase was detected in females. IGFBP-2 levels decreased insignificantly during GH exposure in both genders. A gender-specific upper normal range for each analyte was arbitrarily defined as 4 SD above the mean level at baseline. On the basis of IGF-I levels alone, GH exposure in the GH 0.2 group was detected in 86% of the males and in 50% of the females on day 21. On day 42 GH exposure was only weakly detectable in males and was not detectable in females. We conclude that 1) males are significantly more responsive than females to exogenous GH; 2) the increase in IGF-I is more robust compared with those in IGFBP-3 and ALS; 3) IGFBP-2 changes very little during GH treatment; and 4) among IGF-related substances, IGF-I is the most specific marker of supraphysiological GH exposure.}, }
@article {pmid11095437, year = {2000}, author = {Argüelles, B and Barrios, V and Pozo, J and Muñoz, MT and Argente, J}, title = {Modifications of growth velocity and the insulin-like growth factor system in children with acute lymphoblastic leukemia: a longitudinal study.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {85}, number = {11}, pages = {4087-4092}, doi = {10.1210/jcem.85.11.6943}, pmid = {11095437}, issn = {0021-972X}, mesh = {Body Height ; *Body Mass Index ; Child ; Child, Preschool ; Female ; Growth/*physiology ; Humans ; Infant ; Insulin-Like Growth Factor Binding Protein 1/blood ; Insulin-Like Growth Factor Binding Protein 2/blood ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor Binding Proteins/*blood ; Insulin-Like Growth Factor I/*metabolism ; Insulin-Like Growth Factor II/*metabolism ; Longitudinal Studies ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood/*physiopathology ; Protein Subunits ; Reference Values ; Time Factors ; }, abstract = {The basis of impaired growth in children with acute lymphoblastic leukemia (ALL) is multifactorial, including the disease itself, infections, undernutrition, and adverse effects of therapy. Because growth is regulated by the GH-insulin-like growth factor (IGF) system, which may be altered in catabolic states, we studied serum IGF-I, free IGF-I, IGF-II, the IGF-binding proteins (IGFBP-1 to -3), and total and free acid-labile subunit (ALS) levels in 26 prepubertal children with ALL at diagnosis (n = 26) and 6 (n = 21), 12 (n = 21), 18 (n = 21), 24 (n = 20), 30 (n = 16), and 36 months (n = 16) after beginning treatment to investigate the effects of disease and therapy on this system and its relationship with growth in these patients. Intensive chemotherapy compromised growth, with a catch-up period beginning when maintenance therapy began and increased growth after stopping therapy. Weight increased 6 months after chemotherapy withdrawal, whereas the body mass index was increased both at 6 months after diagnosis and 6 months after therapy suppression. Serum IGF-I, IGF-II, IGFBP-3, and total and free ALS levels were significantly decreased at diagnosis. Normalization of IGF-II and IGFBP-3 occurred 6 months after diagnosis, and normalization of IGF-I and total and free ALS occurred 1 yr after terminating therapy. IGFBP-1 and IGFBP-2 levels were significantly increased at diagnosis and decreased after stopping therapy. Free IGF-I was elevated throughout the study. IGF and IGFBP-3 levels showed a close relationship to growth velocity at the end of chemotherapy, with this correlation remaining until at least 1 yr after therapy withdrawal. In conclusion, intensive chemotherapy compromises linear growth in prepubertal ALL patients, and this phenomenon is associated with alterations in the IGF system. However, when therapy is reduced or stopped, catch-up growth occurs, but various parameters of the GH-IGF axis remain impaired. This suggests the need for a longer period of follow-up to assess the long-term risks of therapy and disease on this system.}, }
@article {pmid11090871, year = {2000}, author = {Dougan, CF and Connell, CO and Thornton, E and Young, CA}, title = {Development of a patient-specific dyspnoea questionnaire in motor neurone disease (MND): the MND dyspnoea rating scale (MDRS).}, journal = {Journal of the neurological sciences}, volume = {180}, number = {1-2}, pages = {86-93}, doi = {10.1016/s0022-510x(00)00415-9}, pmid = {11090871}, issn = {0022-510X}, mesh = {Adult ; Aged ; Aged, 80 and over ; Disability Evaluation ; Dyspnea/*diagnosis ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*diagnosis ; Reproducibility of Results ; Severity of Illness Index ; *Surveys and Questionnaires ; }, abstract = {Motor neurone disease (MND) is a progressive, unremitting and fatal disease. Respiratory dysfunction is common and a significant cause of morbidity. The relationship between subjective dyspnoea and objective measures of lung function have been unexplored in MND. Increasing interest in the specific treatment of respiratory symptoms in MND has highlighted the need for simple, reliable and valid measures to quantify the degree of dyspnoea in this condition. Several generic questionnaires have been developed to rate subjective breathlessness but are inappropriate for use in MND patients as they often assess dyspnoea by exercise-limitation. As yet, there are no published disease-specific measures to assess dyspnoea in MND. In order to accurately and reproducibly measure the subjective experience of dyspnoea in this patient group, we have developed and validated a novel patient-specific dyspnoea questionnaire, the MND dyspnoea rating scale (MDRS). It comprises three domains covering dyspnoea, emotion and mastery and is valid for use in MND patients at all stages of disease progression. In our cohort of 40 unselected patients with MND we have shown that the patients subjective experience of dyspnoea is closely related to emotion and psychological control over the disease. Dyspnoea is not related to objective measures of lung function such as vital capacity, irrespective of limb or bulbar presentation. In conclusion, vital capacity, although useful prognostically, is only one aspect of respiratory function in MND. The MDRS is a reliable and valid tool to rate subjective dyspnoea in MND.}, }
@article {pmid11090870, year = {2000}, author = {Pongratz, D and Neundörfer, B and Fischer, W}, title = {German open label trial of riluzole 50 mg b.i.d. in treatment of amyotrophic lateral sclerosis (ALS).}, journal = {Journal of the neurological sciences}, volume = {180}, number = {1-2}, pages = {82-85}, doi = {10.1016/s0022-510x(00)00426-3}, pmid = {11090870}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Dose-Response Relationship, Drug ; Female ; Germany ; Humans ; Liver/drug effects/enzymology/physiopathology ; Male ; Middle Aged ; Riluzole/administration &amp; dosage/*adverse effects ; }, abstract = {UNLABELLED: Riluzole is currently the only drug that holds any hope of prolonging life in amyotrophic lateral sclerosis (ALS) by slowing the rate of disease progression.<br><br>METHODS AND RESULTS: Between 1995 and 1997 a total of 7916 ALS patients in 39 countries, were given 100 mg riluzole per day for a mean of 7.2 months. The present report focuses on the German results in comparison to the total population. Nine hundred and nineteen patients were treated in 25 German centres; 162 (17.6%) died from the disease during the course of the study. Serious adverse events attributed to the study medication occurred in 16 patients (1.7%). Most frequently these were reversible changes in liver enzymes (0.9%) occurring during the first 3 months, none resulted in death. In all, 413 patients (44.9%) reported an adverse event. The most frequent were reduced lung function (7.3%), nausea (7.1%), asthenia (5.8%), pneumonia (2.5%) and abdominal pain (2.5%).<br><br>CONCLUSION: The results of the study allow the conclusion that riluzole is well tolerated. The majority of adverse events were symptoms of the underlying disease and were not attributed to riluzole. Overall the safety profile found in the German centres was very similar to the profile seen in the total patient population and was more favourable than in the two published double-blind studies [New Engl J Med 330 (1994) 585; Lancet 347 (1996) 1425].}, }
@article {pmid11090865, year = {2000}, author = {Kennel, P and Revah, F and Bohme, GA and Bejuit, R and Gallix, P and Stutzmann, JM and Imperato, A and Pratt, J}, title = {Riluzole prolongs survival and delays muscle strength deterioration in mice with progressive motor neuronopathy (pmn).}, journal = {Journal of the neurological sciences}, volume = {180}, number = {1-2}, pages = {55-61}, doi = {10.1016/s0022-510x(00)00423-8}, pmid = {11090865}, issn = {0022-510X}, mesh = {Animals ; Body Weight/drug effects ; Disease Models, Animal ; Hand Strength/physiology ; Mice ; Mice, Transgenic/genetics ; Motor Neuron Disease/*drug therapy/physiopathology ; Muscle Weakness/drug therapy/physiopathology/*prevention &amp; control ; Muscle, Skeletal/drug effects/physiopathology ; Riluzole/*pharmacology ; *Survival Rate ; Treatment Outcome ; }, abstract = {The neuroprotective drug riluzole (Rilutek) is a sodium channel blocker and anti-excitotoxic drug which is marketed for the treatment of amyotrophic lateral sclerosis (ALS). Previous studies have shown that riluzole prolongs survival of transgenic mice harboring the mutated form of Cu,Zn-superoxide dismutase found in familial forms of the human disease. In this study we have examined the effect of treatment with riluzole in mice suffering from progressive motor neuronopathy (pmn), a hereditary autosomal recessive wasting disease which shares some symptoms of ALS. These mutants display hind limb weakness starting during the 3rd week of life and leading to paralysis and death during the 7th week of life. Daily treatment with 8 mg/kg of riluzole by oral route significantly retarded the appearance of paralysis, increased life span and improved motor performance on grip test and electromyographic results in the early stage of the disease. There was no effect of riluzole on weight gain. These data demonstrate that riluzole significantly prolongs life span, retards the onset of paralysis and slows the evolution of functional parameters connected with muscle strength in the pmn mouse model of motor neuron disease.}, }
@article {pmid11090860, year = {2000}, author = {Hurko, O and Walsh, FS}, title = {Novel drug development for amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {180}, number = {1-2}, pages = {21-28}, doi = {10.1016/s0022-510x(00)00419-6}, pmid = {11090860}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; *Drug Design ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has become an increasingly attractive area for the pharmaceutical industry, the most experimentally tractable of the neurodegenerative diseases. Mechanisms underlying cell death in ALS are likely to be important in more common but more complex disorders. Riluzole, the only drug launched for treatment ALS is currently undergoing industrial trials for Alzheimer's, Parkinson's, Huntington disease, stroke and head injury. Other compounds in Phase III testing for ALS (mecamserin, xaliproden, gabapentin) are also in trials for other neurodegenerative disorders. Mechanisms of action of these advanced compounds are limited to glutamate antagonism, direct or indirect growth factor activity, as well as GABA agonism and interaction with calcium channels. A broader range of mechanisms is represented by compounds in Phase I trials: glutamate antagonism (dextramethorphan/p450 inhibitor; talampanel), growth factors (leukemia inhibiting factor; IL-1 receptor; encapsulated cells secreting CNTF) and antioxidants (TR500, a glutathione-repleting agent; recombinant superoxide dismutase; procysteine.) An even broader range of mechanisms is being explored in preclinical discovery programs. Recognition of the difficulties associated with delivery of protein therapeutics to the CNS has led to development of small molecules interacting either with neurotrophin receptors or with downstream intracellular signalling pathways. Other novel drug targets include caspaces, protein kinases and other molecules influencing apoptosis. High-throughput screens of large libraries of small molecules yield lead compounds that are subsequently optimized by chemists, screened for toxicity, and validated before a candidate is selected for clinical trials. The net is cast wide in early discovery efforts, only about 1% of which result in useful drugs at the end of a decade-long process. Successful discovery and development of novel drugs will increasingly depend on collaborative efforts between the academy and industry.}, }
@article {pmid11085257, year = {2000}, author = {Sonies, BC}, title = {Patterns of care for dysphagic patients with degenerative neurological diseases.}, journal = {Seminars in speech and language}, volume = {21}, number = {4}, pages = {333-44; quiz 334-5}, doi = {10.1055/s-2000-8386}, pmid = {11085257}, issn = {0734-0478}, mesh = {Deglutition Disorders/diagnosis/*etiology/*therapy ; Feeding Methods/*standards ; Humans ; Neurodegenerative Diseases/*complications ; Professional Practice/*standards ; Severity of Illness Index ; }, abstract = {Several of the most common neurodegenerative conditions associated with dysphagia are Parkinsons's disease, progressive supranuclear palsy, postpolio syndrome, and amyotrophic lateral sclerosis. The best clinical practices for treating dysphagic patients with these common conditions are discussed in relation to medication, surgery, diagnosis, and clinical management. Best practice patterns are explained as they relate to the following concepts of care, including comprehension and cognition; interaction with caregivers; dependence-independence during therapy; matching treatment plans to changes in physiology; and establishing realistic expectations including consideration of personal, cultural, and family needs for continuance or termination of care.}, }
@article {pmid11079544, year = {2000}, author = {Drachman, DB and Rothstein, JD}, title = {Inhibition of cyclooxygenase-2 protects motor neurons in an organotypic model of amyotrophic lateral sclerosis.}, journal = {Annals of neurology}, volume = {48}, number = {5}, pages = {792-795}, pmid = {11079544}, issn = {0364-5134}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Cyclooxygenase 2 ; Disease Models, Animal ; Isoenzymes/*metabolism ; Motor Neurons/*metabolism ; Organ Culture Techniques ; Prostaglandin-Endoperoxide Synthases/*metabolism ; Pyrazoles/metabolism ; Rats ; Spinal Cord/metabolism ; Sulfonamides/metabolism ; }, abstract = {The pathogenesis of motor neuron loss in amyotrophic lateral sclerosis (ALS) is thought to involve both glutamate-mediated excitotoxicity and oxidative damage due to the accumulation of free radicals and other toxic molecules. Cyclooxygenase-2 (COX-2) may play a key role in these processes by producing prostaglandins, which trigger astrocytic glutamate release, and by inducing free radical formation. We tested the effects of COX-2 inhibition in an organotypic spinal cord culture model of ALS. The COX-2 inhibitor (SC236) provided significant protection against loss of spinal motor neurons in this system, suggesting that it may be useful in the treatment of ALS.}, }
@article {pmid11061253, year = {2000}, author = {Galer, BS and Twilling, LL and Harle, J and Cluff, RS and Friedman, E and Rowbotham, MC}, title = {Lack of efficacy of riluzole in the treatment of peripheral neuropathic pain conditions.}, journal = {Neurology}, volume = {55}, number = {7}, pages = {971-975}, doi = {10.1212/wnl.55.7.971}, pmid = {11061253}, issn = {0028-3878}, mesh = {Adult ; Aged ; Aged, 80 and over ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Pain/*drug therapy ; Peripheral Nervous System Diseases/*drug therapy ; Prospective Studies ; Riluzole/administration &amp; dosage/*therapeutic use ; }, abstract = {OBJECTIVE: To assess the efficacy, tolerability, and safety of riluzole in the treatment of peripheral neuropathic pain conditions.<br><br>BACKGROUND: Both basic and clinical research has demonstrated that drugs with sodium channel and NMDA antagonism can be effective in alleviating neuropathic pain. Riluzole, a drug currently used for treatment of ALS, possesses these properties. It was hypothesized that riluzole would be effective in reducing the pain in subjects with peripheral neuropathic pain.<br><br>METHODS: Two randomized, placebo-controlled, crossover studies were performed at two sites. Study 1 compared 100 mg/day of riluzole (the currently recommended dosage for treatment of ALS) versus placebo, and Study 2 compared 200 mg/day of riluzole versus placebo. Each treatment phase (both studies) was 2 weeks long, separated by 2-week wash-out periods. Outcome measures included change in the score on a 100-mm pain intensity visual analog scale, the Neuropathic Pain Scale, allodynia, hyperalgesia, and preference for study treatment phase.<br><br>RESULTS: Twenty-two subjects completed Study 1, and 21 subjects completed Study 2. Four subjects (two from each study) discontinued the study because of intolerable side effects. No statistical difference was found for any study outcome measure between riluzole and placebo for either study. In Study 1, pain intensity was more likely to increase than decrease with riluzole (mean treatment difference 8.7 mm; 95% CI -19.5 to +2.1 mm). In Study 2, very slight pain reduction was observed with riluzole compared with placebo (mean treatment difference 1.4 mm; 95% CI -5.1 to +8.0 mm). In both studies, the majority of subjects chose "no change" in pain on the category relief scale after placebo and riluzole treatment phases. On study completion, no treatment preference was reported by 76% of the subjects in Study 1 and by 61% of the subjects in Study 2.<br><br>CONCLUSIONS: Doses of riluzole at (100 mg) or above (200 mg) those used for the treatment of ALS were not effective in alleviating peripheral neuropathic pain.}, }
@article {pmid11060751, year = {2000}, author = {Jain, KK}, title = {Evaluation of memantine for neuroprotection in dementia.}, journal = {Expert opinion on investigational drugs}, volume = {9}, number = {6}, pages = {1397-1406}, doi = {10.1517/13543784.9.6.1397}, pmid = {11060751}, issn = {1354-3784}, mesh = {Alzheimer Disease/prevention &amp; control ; Animals ; Dementia/*prevention &amp; control ; Humans ; Memantine/*therapeutic use ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Memantine, a non-competitive NMDA antagonist, has been approved for use in the treatment of dementia in Germany for over ten years. The rationale for use is excitotoxicity as a pathomechanism of neurodegenerative disorders. Memantine acts as a neuroprotective agent against this pathomechanism, which is also implicated in vascular dementia. HIV-1 proteins Tat and gp120 have been implicated in the pathogenesis of dementia associated with HIV infection and the neurotoxicity caused by HIV-1 proteins can be blocked completely by memantine. Memantine has been investigated extensively in animal studies and following this, its efficacy and safety has been established and confirmed by clinical experience in humans. It exhibits none of the undesirable effects associated with competitive NMDA antagonists such as dizocilpine. The efficacy of memantine in a variety of dementias has been shown in clinical trials. Memantine is considered to be a promising neuroprotective drug for the treatment of dementias, particularly Alzheimer's disease for which there is no neuroprotective therapy available currently. It can be combined with acetylcholinesterase inhibitors which are the mainstay of current symptomatic treatment of Alzheimer's disease. Memantine has a therapeutic potential in numerous CNS disorders besides dementias which include stroke, CNS trauma, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, drug dependence and chronic pain. If memantine is approved by the FDA for some of these indications by the year 2005, it can become a blockbuster drug by crossing the US$1 billion mark in annual sales.}, }
@article {pmid11044006, year = {2000}, author = {Craven, RA and Singletary, N and Bosken, L and Sewell, E and Payne, M and Lipsey, R}, title = {Use of bilevel positive airway pressure in out-of-hospital patients.}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {7}, number = {9}, pages = {1065-1068}, doi = {10.1111/j.1553-2712.2000.tb02102.x}, pmid = {11044006}, issn = {1069-6563}, mesh = {Adult ; Aged ; Aged, 80 and over ; *Emergency Medical Services ; Emergency Treatment/*methods ; Female ; Heart Failure/*therapy ; Humans ; Length of Stay ; Male ; Middle Aged ; *Positive-Pressure Respiration ; Prospective Studies ; Urban Health Services ; Virginia ; }, abstract = {OBJECTIVE: To evaluate the utility of bilevel positive airway pressure (BiPAP) in the out-of-hospital treatment of patients with presumed congestive heart failure (CHF).<br><br>METHODS: This was a prospective, sequential, parallel trial in an urban setting served by a single emergency medical services (EMS) system between January 4 and April 15, 1999. A convenience sampling of adults who were transported by rescue units judged to be in CHF by treating emergency medical technicians trained in advanced life support (ALS EMTs) was included. Rescue squads were divided into demographically matched pairs, and one of each was equipped with a BiPAP ventilatory support unit. Bilevel positive airway pressure therapy was added to the existing treatment protocols for eligible study patients. Main outcome measures were out-of-hospital treatment time, oxygen saturation changes, hospitalization length, need for endotracheal intubation, mortality rate, and ease of use of the device by EMS personnel.<br><br>RESULTS: Sixty-two of 71 enrolled patients completed the study. Out-of-hospital treatment times did not differ between groups (31.2 minutes vs 31.4 minutes; p = 0.931). The difference between pre- and post-treatment oxygen saturation levels was greater for the BiPAP group (13.71%) than the control group (6.69%) (p < 0.05). There was no statistical difference between groups in the length of hospital stay [control: 7.63 days, vs BiPAP: 6.33 days, p = 0.48], the intubation rate [control: 7 of 25 (28%) vs BiPAP: 4 of 37 (11%), p = 0.10], or death rate [control: 2 of 24, vs BiPAP: 6 of 37, p = 0.46]. All of the ALS EMTs who used BiPAP thought that it was safe to use, and 97% thought it was easy and appeared to improve patients' dyspnea and respiratory distress.<br><br>CONCLUSIONS: ALS EMTs can be trained to deliver noninvasive ventilation with BiPAP, find it easy to apply, and believe that it helps relieve dyspnea in patients with suspected CHF.}, }
@article {pmid11038039, year = {2000}, author = {Bajetta, E and Zilembo, N and Bichisao, E and Martinetti, A and Buzzoni, R and Pozzi, P and Bidoli, P and Ferrari, L and Celio, L}, title = {Tumor response and estrogen suppression in breast cancer patients treated with aromatase inhibitors.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {11}, number = {8}, pages = {1017-1022}, doi = {10.1023/a:1008388823113}, pmid = {11038039}, issn = {0923-7534}, mesh = {Aged ; Antineoplastic Agents, Hormonal/*therapeutic use ; *Aromatase Inhibitors ; Breast Neoplasms/*drug therapy/pathology ; Disease Progression ; Enzyme Inhibitors/*therapeutic use ; Estradiol/blood ; Estrone/blood ; Female ; Humans ; Middle Aged ; Retrospective Studies ; Treatment Outcome ; }, abstract = {BACKGROUND: The rationale for the hormonal treatment of breast cancer (BC) is based on depriving tumor cells of estrogenic stimulation. Aromatase inhibitors (Als) block the conversion of peripheral tissue androgens to estrogens with different levels of potency. In an attempt to investigate the relationship between tumor response and estrogen suppression, we reviewed the hormonal and clinical data of two previous studies with formestane (250 and 500 mg i.m. fortnightly) in advanced BC patients.<br><br>PATIENTS AND METHODS: Two hundred four BC patients were selected on the basis of the availability of records concerning their plasma estrone (El) and estradiol (E2) levels assessed at scheduled times. The degree of estrogen suppression and the best clinical response of each patient during the trials were considered.<br><br>RESULTS: There was a positive and significant (P < 0.05) correlation between baseline and post-formestane E1 and E2 levels, with a decrease in the levels of both hormones irrespective of any antitumor response. In particular, the degree of plasma estrogen suppression was similar in the patients who experienced a complete remission and those with progressive disease (PD).<br><br>CONCLUSIONS: The plasma estrogen suppression induced by aromatase inhibition is not the only mechanism accounting for its clinical activity. Many clinical trials have demonstrated that all AIs induce a similar antitumor response regardless of their potency, and further investigations are warranted in order to improve our understanding as to why the patients with PD also show a significant plasma estrogen suppression. It is possible that intratumoral aromatase activity may be a marker for selecting the BC patients most likely to respond to AI treatment.}, }
@article {pmid11033335, year = {2000}, author = {Bär, PR}, title = {Motor neuron disease in vitro: the use of cultured motor neurons to study amyotrophic lateral sclerosis.}, journal = {European journal of pharmacology}, volume = {405}, number = {1-3}, pages = {285-295}, doi = {10.1016/s0014-2999(00)00560-4}, pmid = {11033335}, issn = {0014-2999}, mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Cell Death ; Cells, Cultured ; Humans ; Motor Neuron Disease/*pathology ; Motor Neurons/*pathology/ultrastructure ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease in which motor neurons in the nervous system die. The cause is unknown, and no effective treatment exists. Mutations in the gene for superoxide dismutase found in a subpopulation have led to an animal model, but research with these mice has not produced complete insight into the disease mechanism. Studies with isolated motor neurons may produce important information. This review discusses approaches to culture motor neurons - single cells, cocultured with other cells, and in intact preparations, such as the spinal or cortical slice. Motor neurons in monoculture are suitable for acute but not for chronic studies, whereas cocultures and slices survive up to months and are used for chronic studies. Results with toxic substances believed to play a role in the disease, such as oxidants and glutamate, and of studies where the energy status of the cells is manipulated, are presented.}, }
@article {pmid11003062, year = {1998}, author = {Wang, FC and Delwaide, PJ}, title = {Number and relative size of thenar motor units in ALS patients: application of the adapted multiple point stimulation method.}, journal = {Electroencephalography and clinical neurophysiology}, volume = {109}, number = {1}, pages = {36-43}, doi = {10.1016/s0924-980x(97)00071-4}, pmid = {11003062}, issn = {0013-4694}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*physiopathology ; Electric Stimulation ; Electromyography ; Female ; Humans ; Male ; Middle Aged ; Muscles/*physiopathology ; Reproducibility of Results ; }, abstract = {In the present study, the adapted multiple point stimulation (AMPS) method was first applied to median innervated thenar muscles in 22 amyotrophic lateral sclerosis (ALS) patients who did not received any treatment. In all patients, a motor unit number estimate (MUNE) and an average surface-recorded motor unit action potential (S-MUAP) size have been derived even if the denervation was severe; and the results were reproducible. The thenar MUNE was less than the normal lower limit for age in 17 patients, and the mean MUNE (67.1 +/- 90.6) was significantly different from that estimated in control subjects (263.3 +/- 116.8). The mean S-MUAP size in the 22 ALS patients was 352.9 +/- 328.4 microV x ms versus 94.1 +/- 30.3 microV x ms in healthy volunteers. A control AMPS was achieved in 8 patients after 2 and 6 months of a glutamate-release antagonist (riluzole) treatment. The mean loss of motor units, based on control thenar MUNEs realized after 6 months of treatment, was 53%. In conclusion, we propose AMPS as a manageable, reproducible and non-invasive procedure which permits one to quantify peripheral denervation and to appreciate the effectiveness of collateral reinnervation in ALS patients.}, }
@article {pmid10998753, year = {2000}, author = {Chen, R and Ende, N}, title = {The potential for the use of mononuclear cells from human umbilical cord blood in the treatment of amyotrophic lateral sclerosis in SOD1 mice.}, journal = {Journal of medicine}, volume = {31}, number = {1-2}, pages = {21-30}, pmid = {10998753}, issn = {0025-7850}, mesh = {Amyotrophic Lateral Sclerosis/genetics/mortality/*therapy ; Animals ; Bone Marrow Transplantation ; DNA/analysis ; DNA Primers/chemistry ; *Fetal Blood ; Humans ; Infant, Newborn ; Leukocyte Transfusion/*methods ; Leukocytes, Mononuclear ; Mice ; Mice, Transgenic ; Radiation Injuries, Experimental/genetics/mortality ; Reverse Transcriptase Polymerase Chain Reaction ; Superoxide Dismutase/genetics ; Survival Rate ; Transplantation, Heterologous ; Transplantation, Isogeneic ; Whole-Body Irradiation ; }, abstract = {The SOD1 mice (transgenic B6SJL-TgN(SOD1-G93A)1GUR) have a mutation of the human transgene (CuZn superoxide dismutase gene SOD1) that has been associated with amyotrophic lateral sclerosis (ALS). In a preliminary study, we demonstrated that a megadose of human umbilical cord blood mononuclear cells given intravenously after 800 cGy of irradiation could substantially increase the life span of SOD1 mice. This report is an attempt to confirm and expand the preliminary findings. By repeating the study and raising the number of human cord blood cells from 33.2-34.0 x 10(6) to 70.2-73.3 x 10(6) there was a further significant increase in the life span of the SOD1 mice. The average life of the controls was 123.5 days while that of mice receiving the larger megadose of cells was 162 days. While all the controls were dead by 130 days, the treated group receiving 70.2-73.3 x 10(6) cells had one animal living up to 187 days and one 210 days. In order to obtain a megadose of cells, pooled blood from different donors was used and did not appear to have a negative effect, but indicated a beneficial effect on survival. The clinical significance of these findings may extend beyond the potential treatment for amyotrophic lateral sclerosis. This study confirms and extends the preliminary study whereby increasing the dose of human umbilical cord blood cells we were able to substantially further increase the survival of SOD1 mice.}, }
@article {pmid10997531, year = {2000}, author = {Young, WF}, title = {Cervical spondylotic myelopathy: a common cause of spinal cord dysfunction in older persons.}, journal = {American family physician}, volume = {62}, number = {5}, pages = {1064-70, 1073}, pmid = {10997531}, issn = {0002-838X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/diagnosis ; *Cervical Vertebrae ; Diagnosis, Differential ; Humans ; Hypesthesia/etiology ; Magnetic Resonance Imaging ; Muscle Weakness/etiology ; Neck Pain/etiology ; Neuralgia/etiology ; Neurosurgical Procedures ; Patient Education as Topic ; Spinal Cord/*physiopathology ; Spinal Osteophytosis/*complications/*diagnosis/physiopathology ; Teaching Materials ; Tomography, X-Ray Computed ; }, abstract = {Cervical spondylotic myelopathy is the most common cause of spinal cord dysfunction in older persons. The aging process results in degenerative changes in the cervical spine that, in advanced stages, can cause compression of the spinal cord. Symptoms often develop insidiously and are characterized by neck stiffness, arm pain, numbness in the hands, and weakness of the hands and legs. The differential diagnosis includes any condition that can result in myelopathy, such as multiple sclerosis, amyotrophic lateral sclerosis and masses (such as metastatic tumors) that press on the spinal cord. The diagnosis is confirmed by magnetic resonance imaging that shows narrowing of the spinal canal caused by osteophytes, herniated discs and ligamentum flavum hypertrophy. Choice of treatment remains controversial, surgical procedures designed to decompress the spinal cord and, in some cases, stabilize the spine are successful in many patients.}, }
@article {pmid10967703, year = {2000}, author = {Roch-Torreilles, I and Camu, W and Hillaire-Buys, D}, title = {[Adverse efects of riluzole (Rilutek) in the treatment of amyotrophic lateral sclerosis].}, journal = {Therapie}, volume = {55}, number = {2}, pages = {303-312}, pmid = {10967703}, issn = {0040-5957}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/drug therapy ; Female ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*adverse effects/therapeutic use ; Product Surveillance, Postmarketing ; Riluzole/*adverse effects/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly fatal degenerative disorder of the motoneurones which was without any effective therapy until 1997. Riluzole (Rilutek) has been the first patented drug used in its specific treatment. In order to evaluate the tolerability profile of this molecule, a Pharmacovigilance study was undertaken in the Department of Neurology B at the Montpellier University Hospital. A total of 153 patients were studied and all observed side-effects were listed in the French bank of Pharmacovigilance. Riluzole induced one or more adverse effects in 50.3 per cent of patients. The most frequent were gastrointestinal disturbances, hepatotoxicity and asthenia. Dermatological, haematological, neuropsychiatric and metabolic side-effects were also reported. This study shows an acceptable safety profile for riluzole. Due to its mode of action, riluzole could potentially be used in the treatment of other neurodegenerative diseases involving glutamate excitotoxicity. Subsequently, Pharmacovigilance will have to be carried out to establish the proper use of riluzole.}, }
@article {pmid10943709, year = {2000}, author = {Andreassen, OA and Dedeoglu, A and Klivenyi, P and Beal, MF and Bush, AI}, title = {N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis.}, journal = {Neuroreport}, volume = {11}, number = {11}, pages = {2491-2493}, doi = {10.1097/00001756-200008030-00029}, pmid = {10943709}, issn = {0959-4965}, mesh = {Acetylcysteine/*pharmacology ; Age Factors ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/physiopathology/prevention &amp; control ; Animals ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Motor Activity/*drug effects/physiology ; Mutation/physiology ; Superoxide Dismutase/genetics ; Survival Rate ; }, abstract = {Increasing evidence implicates oxidative damage as a major mechanism in the pathogenesis of amyotrophic lateral sclerosis (ALS). We examined the effect of preventative treatment with N-acetyl-L-cysteine (NAC), an agent that reduces free radical damage, in transgenic mice with a superoxide dismutase (SODI) mutation (G93A), used as an animal model of familial ALS. NAC was administered at 1% concentration in the drinking water from 4-5 weeks of age. The treatment caused a significantly prolonged survival and delayed onset of motor impairment in G93A mice treated with NAC compared to control mice. These results provide further evidence for the involvement of free radical damage in the G93A mice, and support the possibility that NAC, an over-the-counter antioxidant, could be explored in clinical trials for ALS.}, }
@article {pmid10942700, year = {2000}, author = {Missiaen, L and Robberecht, W and van den Bosch, L and Callewaert, G and Parys, JB and Wuytack, F and Raeymaekers, L and Nilius, B and Eggermont, J and De Smedt, H}, title = {Abnormal intracellular ca(2+)homeostasis and disease.}, journal = {Cell calcium}, volume = {28}, number = {1}, pages = {1-21}, doi = {10.1054/ceca.2000.0131}, pmid = {10942700}, issn = {0143-4160}, mesh = {Animals ; Calcium/*metabolism ; Calcium Channels/genetics ; Calcium Channels, L-Type/genetics ; Calcium Metabolism Disorders/*metabolism ; Calcium Signaling ; Calcium-Binding Proteins/metabolism ; Calcium-Transporting ATPases/genetics ; Homeostasis ; Humans ; Inositol 1,4,5-Trisphosphate Receptors ; Mice ; Models, Biological ; Muscle Contraction ; *Mutation ; Receptors, Cytoplasmic and Nuclear/genetics ; Ryanodine Receptor Calcium Release Channel/genetics ; Sarcoplasmic Reticulum Calcium-Transporting ATPases ; TRPC Cation Channels ; }, abstract = {A whole range of cell functions are regulated by the free cytosolic Ca(2+)concentration. Activator Ca(2+)from the extracellular space enters the cell through various types of Ca(2+)channels and sometimes the Na(+)/Ca(2+)-exchanger, and is actively extruded from the cell by Ca(2+)pumps and Na(+)/Ca(2+)-exchangers. Activator Ca(2+)can also be released from internal Ca(2+)stores through inositol trisphosphate or ryanodine receptors and is taken up into these organelles by means of Ca(2+)pumps. The resulting Ca(2+)signal is highly organized in space, frequency and amplitude because the localization and the integrated free cytosolic Ca(2+)concentration over time contain specific information. Mutations or functional abnormalities in the various Ca(2+)transporters, which in vitro seem to induce trivial functional alterations, therefore, often lead to a plethora of diseases. Skeletal-muscle pathology can be caused by mutations in ryanodine receptors (malignant hyperthermia, porcine stress syndrome, central-core disease), dihydropyridine receptors (familial hypokalemic periodic paralysis, malignant hyperthermia, muscular dysgenesis) or Ca(2+)pumps (Brody disease). Ca(2+)-pump mutations in cutaneous epidermal keratinocytes and cochlear hair cells lead to, skin diseases (Darier and Hailey-Hailey) and hearing/vestibular problems respectively. Mutated Ca(2+)channels in the photoreceptor plasma membrane cause vision problems. Hemiplegic migraine, spinocerebellar ataxia type-6, one form of episodic ataxia and some forms of epilepsy can be due to mutations in plasma-membrane Ca(2+)channels, while antibodies against these channels play a pathogenic role in all patients with the Lambert-Eaton myasthenic syndrome and may be of significance in sporadic amyotrophic lateral sclerosis. Brain inositol trisphosphate receptors have been hypothesized to contribute to the pathology in opisthotonos mice, manic-depressive illness and perhaps Alzheimer's disease. Various abnormalities in Ca(2+)-handling proteins have been described in heart during aging, hypertrophy, heart failure and during treatment with immunosuppressive drugs and in diabetes mellitus. In some instances, disease-causing mutations or abnormalities provide us with new insights into the cell biology of the various Ca(2+)transporters.}, }
@article {pmid10935831, year = {1998}, author = {Chiò, A and Cucatto, A and Terreni, AA and Schiffer, D}, title = {Reduced glutathione in amyotrophic lateral sclerosis: an open, crossover, randomized trial.}, journal = {Italian journal of neurological sciences}, volume = {19}, number = {6}, pages = {363-366}, pmid = {10935831}, issn = {0392-0461}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Cross-Over Studies ; Disease Progression ; Glutathione/*adverse effects ; Humans ; Middle Aged ; Treatment Outcome ; }, abstract = {The present study set out to define the possible effect of reduced glutathione (GSH), the substrate of glutathione peroxidase (GSH-Px), a free radical inactivating enzyme, in amyotrophic lateral sclerosis (ALS). Thirty-two patients affected by definite ALS seen in our institution between August 1993 and July 1994 were admitted to the study. The effect of GSH was studied in an open, crossover, randomized study. GSH was given at the dose of 600 mg each day intramuscularly for 12 weeks. The patients, taken sequentially, were randomly assigned to two groups. The first group received the drug while the second received only symptomatic therapies for 12 weeks. After a week of washout, the second group received GSH and the first only symptomatic therapies for 12 weeks. The rate of progression of the diseases was compared in the two groups. Clinical evaluation included manual test for muscle strength, Norris scale, bulbar scale, and forced vital capacity (FVC) percent. No significant difference was found in the progression of ALS in the two periods, although a slight slowing of the disease progression rate was found during the period of treatment, probably related to the open design of the study. Our data do not show any significant effect of reduced glutathione in modifying the progression of ALS.}, }
@article {pmid10931172, year = {2000}, author = {Schulz, JB and Lindenau, J and Seyfried, J and Dichgans, J}, title = {Glutathione, oxidative stress and neurodegeneration.}, journal = {European journal of biochemistry}, volume = {267}, number = {16}, pages = {4904-4911}, doi = {10.1046/j.1432-1327.2000.01595.x}, pmid = {10931172}, issn = {0014-2956}, mesh = {Alzheimer Disease/physiopathology ; Animals ; Friedreich Ataxia/physiopathology ; Glutathione/*metabolism ; Humans ; Mitochondria/metabolism ; Motor Neuron Disease/physiopathology ; Nerve Degeneration/*physiopathology ; Oxidative Stress/*physiology ; Parkinson Disease/physiopathology ; }, abstract = {There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species and mitochondrial dysfunction. Here, we review the evidence for a disturbance of glutathione homeostasis that may either lead to or result from oxidative stress in neurodegenerative disorders. Glutathione is an important intracellular antioxidant that protects against a variety of different antioxidant species. An important role for glutathione was proposed for the pathogenesis of Parkinson's disease, because a decrease in total glutathione concentrations in the substantia nigra has been observed in preclinical stages, at a time at which other biochemical changes are not yet detectable. Because glutathione does not cross the blood-brain barrier other treatment options to increase brain concentrations of glutathione including glutathione analogs, mimetics or precursors are discussed.}, }
@article {pmid10917377, year = {2000}, author = {North, WA and Khan, AM and Yamase, HT and Sporn, JR}, title = {Reversible granulocytopenia in association with riluzole therapy.}, journal = {The Annals of pharmacotherapy}, volume = {34}, number = {3}, pages = {322-324}, doi = {10.1345/aph.19153}, pmid = {10917377}, issn = {1060-0280}, mesh = {Agranulocytosis/blood/*chemically induced ; Amyotrophic Lateral Sclerosis/complications/drug therapy ; Female ; Humans ; Middle Aged ; Neuroprotective Agents/*adverse effects/therapeutic use ; Neutropenia/blood/chemically induced ; Riluzole/*adverse effects/therapeutic use ; }, abstract = {OBJECTIVE: To report a case of severe neutropenia developing in association with riluzole 200 mg/d.<br><br>CASE SUMMARY: A 63-year-old woman with amyotrophic lateral sclerosis (ALS) presented with nausea, anorexia, and fever two weeks following inadvertent dose escalation of riluzole from 100 to 200 mg/d. Granulocytopenia was diagnosed and evaluation for a possible causative infectious process was negative; riluzole was considered a possible offender. Blood counts returned to normal with discontinuation of riluzole and administration of filgramstim.<br><br>DISCUSSION: Riluzole is a glutamate release inhibitor used in the treatment of ALS, a devastating, progressive neurodegenerative disorder affecting motor neurons. A variety of adverse effects have been described with riluzole therapy, most commonly dizziness and gastrointestinal disorders. In this patient, multiple investigations failed to reveal an infectious cause or other drug-induced cause for the granulocytopenia.<br><br>CONCLUSIONS: Granulocytopenia has been reported as an adverse effect of riluzole but is not a complication well known to clinicians, and there are no detailed reports published in the literature. In this patient, several lines of evidence raise the possibility of a causal relationship between riluzole and granulocytopenia.}, }
@article {pmid10908190, year = {2000}, author = {Kaji, R and Bostock, H and Kohara, N and Murase, N and Kimura, J and Shibasaki, H}, title = {Activity-dependent conduction block in multifocal motor neuropathy.}, journal = {Brain : a journal of neurology}, volume = {123 (Pt 8)}, number = {}, pages = {1602-1611}, doi = {10.1093/brain/123.8.1602}, pmid = {10908190}, issn = {0006-8950}, mesh = {Action Potentials ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/physiopathology ; Electric Stimulation ; Fingers/physiopathology ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*physiopathology ; *Muscle Contraction ; Muscle Fatigue ; Muscle, Skeletal/physiopathology ; *Neural Conduction ; Thumb/physiopathology ; }, abstract = {Patients with multifocal motor neuropathy may complain of muscle fatigue, even though the degree of conduction block assessed at rest has improved with treatment. To explore the mechanism involved, we examined changes in muscle force during maximum voluntary contraction (MVC) and monitored conduction block before and after MVC in five patients with multifocal motor neuropathy. The results were compared with those for the contralateral unaffected homonymous muscles. For one patient, who had bilateral involvement, a normal subject of a similar age and stature served as the control. Results of conduction studies were also compared with those from six patients with amyotrophic lateral sclerosis (ALS) with similar compound muscle action potential (CMAP) amplitudes after proximal stimulation. During MVC for 60 s, the affected muscles developed prominent fatigue; the force at the end of contraction compared with the initial force was significantly lower for the affected muscles [42 +/- 19% (mean +/- standard deviation) of the initial force] than for the control muscles (94 +/- 9%; P = 0.01). After MVC, the amplitude ratio of CMAPs after proximal versus distal nerve stimulation transiently decreased to 19 +/- 14% of that before MVC in the affected muscles, but not in the control muscles (94 +/- 3.8% of that before MVC) and in patients with ALS (95 +/- 6.7%). In one patient with a focal lesion in the forearm, nerve excitability was monitored at the lesion site before and after MVC for 120 s. There were significant increases in axonal threshold (approximately 48%) and supernormality (approximately 135%) immediately after MVC, suggesting that the axonal membrane had undergone hyperpolarization and, by extrapolation, that this had precipitated the conduction block. This study is the first to show that activity-dependent conduction block plays a role in human disease by causing muscle fatigue.}, }
@article {pmid10906800, year = {2000}, author = {Weiss, JH and Sensi, SL}, title = {Ca2+-Zn2+ permeable AMPA or kainate receptors: possible key factors in selective neurodegeneration.}, journal = {Trends in neurosciences}, volume = {23}, number = {8}, pages = {365-371}, doi = {10.1016/s0166-2236(00)01610-6}, pmid = {10906800}, issn = {0166-2236}, support = {AG00836/AG/NIA NIH HHS/United States ; NS30884/NS/NINDS NIH HHS/United States ; NS36548/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain Chemistry/physiology ; Calcium/*metabolism ; Humans ; Nerve Degeneration/*metabolism ; Neurodegenerative Diseases/metabolism ; Receptors, AMPA/*metabolism ; Receptors, Kainic Acid/*metabolism ; Zinc/*metabolism ; }, abstract = {Neurological diseases, including global ischemia, Alzheimer's disease and amyotrophic lateral sclerosis, are characterized by selective patterns of neurodegeneration. Most studies of potential glutamate-receptor-mediated contributions to disease have focused on the highly Ca2+-permeable and widely distributed NMDA-receptor channel. However, an alternative hypothesis is that the presence of AMPA- or kainate-receptor channels that are directly permeable to Ca2+ ions (Ca-A/K-receptor channels) is of greater significance to the neuronal loss seen in these conditions. Besides a restricted distribution and high Ca2+ permeability, two other factors make Ca-A/K receptors appealing candidate contributors to selective injury: their high permeability to Zn2+ ions and the possibility that their numbers increase in disease-associated conditions. Further characterization of the functions of these channels should result in new approaches to treatment of these conditions.}, }
@article {pmid10886313, year = {2000}, author = {Barthlen, GM and Lange, DJ}, title = {Unexpectedly severe sleep and respiratory pathology in patients with amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {7}, number = {3}, pages = {299-302}, doi = {10.1046/j.1468-1331.2000.00044.x}, pmid = {10886313}, issn = {1351-5101}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Arousal ; Circadian Rhythm ; Humans ; Hypoventilation/etiology ; Male ; Middle Aged ; Oxygen/blood ; Polysomnography ; Positive-Pressure Respiration ; Respiration Disorders/blood/*etiology/physiopathology/therapy ; Sleep ; Sleep Apnea Syndromes/etiology ; Sleep Initiation and Maintenance Disorders/etiology ; Sleep Stages ; Sleep Wake Disorders/diagnosis/*etiology/physiopathology ; }, abstract = {Daytime fatigue and sleep disturbance are frequent complaints in patients with amyotrophic lateral sclerosis (ALS). However, polysomnographic data are sparse. Nocturnal respiratory insufficiency may occur despite nearly normal daytime pulmonary function. We describe the clinical presentation and polysomnographic findings in two patients with clinically and electrophysiologically confirmed ALS with minimal weakness but excessive daytime sleepiness. Polysomnography in the first patient showed a respiratory disturbance index of 43.5, and profound oxygen desaturations to 62%. The second patient had prolonged periods of hypoventilation, with oxygen saturations oscillating between 86 and 83%. Both patients showed severe sleep maintenance insomnia with a sleep efficiency < 40% and frequent arousals while asleep. Application of continuous positive airway pressure (CPAP) restored normal nocturnal ventilation, blood oxygenation and sleep parameters in the first patient; compliance, however, was poor. The second patient was unable to tolerate CPAP. We conclude that ALS patients with excessive daytime sleepiness or insomnia should undergo polysomnography to adequately diagnose nocturnal respiratory insufficiency and sleep disturbance. Compliance with treatment, however, may be poor.}, }
@article {pmid10899935, year = {2000}, author = {Ferri, A and Gabbianelli, R and Casciati, A and Paolucci, E and Rotilio, G and Carrì, MT}, title = {Calcineurin activity is regulated both by redox compounds and by mutant familial amyotrophic lateral sclerosis-superoxide dismutase.}, journal = {Journal of neurochemistry}, volume = {75}, number = {2}, pages = {606-613}, doi = {10.1046/j.1471-4159.2000.0750606.x}, pmid = {10899935}, issn = {0022-3042}, mesh = {Animals ; Ascorbic Acid/pharmacology ; Calcineurin/*metabolism ; Calcium/metabolism ; Dithiothreitol/pharmacology ; Hippocampus/metabolism ; Humans ; Mice ; Mice, Transgenic ; Motor Cortex/metabolism ; Motor Neuron Disease/*enzymology/genetics ; Neuroblastoma ; Oxidation-Reduction ; Oxidative Stress ; Recombinant Proteins/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase/*genetics/*metabolism ; Transfection ; Tumor Cells, Cultured ; }, abstract = {Calcineurin (CN) is a protein phosphatase involved in a wide range of cellular responses to calcium-mobilizing signals, and a role for this enzyme in neuropathology has been postulated. We have investigated the possibility that redox modulation of CN activity is relevant to neuropathological conditions where an imbalance in reactive oxygen species has been described. We have monitored CN activity in cultured human neuroblastoma SH-SY5Y cells and obtained evidence that CN activity is promoted by treatment with ascorbate or dithiothreitol and impaired by oxidative stress. Evidence for the existence of a redox regulation of this enzyme has been also obtained by overexpression of wild-type antioxidant Cu,Zn superoxide dismutase (SOD1) that promotes CN activity and protects it from oxidative inactivation. On the contrary, overexpression of mutant SOD1s associated with familial amyotrophic lateral sclerosis (FALS) impairs CN activity both in transfected human neuroblastoma cell lines and in the motor cortex of brain from FALS-transgenic mice. These data suggest that CN might be a target in the pathogenesis of SOD1-linked FALS.}, }
@article {pmid10896029, year = {2000}, author = {Ende, N and Weinstein, F and Chen, R and Ende, M}, title = {Human umbilical cord blood effect on sod mice (amyotrophic lateral sclerosis).}, journal = {Life sciences}, volume = {67}, number = {1}, pages = {53-59}, doi = {10.1016/s0024-3205(00)00602-0}, pmid = {10896029}, issn = {0024-3205}, mesh = {Adoptive Transfer ; Amyotrophic Lateral Sclerosis/genetics/mortality/*therapy ; Animals ; Autoimmune Diseases/genetics/mortality/therapy ; Bone Marrow Transplantation ; DNA/analysis ; DNA Primers/chemistry ; *Fetal Blood ; Humans ; Infant, Newborn ; Leukocyte Transfusion/*methods ; Leukocytes, Mononuclear/transplantation ; Mice ; Mice, Transgenic ; Radiation Injuries, Experimental/genetics/mortality/therapy ; Reverse Transcriptase Polymerase Chain Reaction ; Superoxide Dismutase/*genetics ; Survival Rate ; Transplantation, Heterologous ; Transplantation, Isogeneic ; Whole-Body Irradiation ; }, abstract = {In previous studies we observed that human umbilical cord blood (HUCB) could have a protective effect on the onset of disease and time of death in MRL Lpr/Lpr mice which have an autoimmune disease that may be considered similar to human lupus. We believed a temporary xenograph may have occurred in these animals with the disease process delayed and the life span markedly increased. When HUCB is stored at 4 degrees C in gas permeable bags, there is a decrease of the cell reaction in mixed lymphocyte cultures. The blood, however, maintains a significant number of cells capable of producing replatable colonies. This study attempted to determine the effect of HUCB on SOD1 mice (transgenic B6SJL-TgN(SOD1-G93A)1GUR), which have a mutation of the human transgene, (CuZn superoxide dismutase gene SOD1) that has been associated with amyotrophic lateral sclerosis. We previously developed evidence that the survival of lethally irradiated mice was related to the number of human mononuclear cells administered. In the present study, we decided to investigate the effect of a relatively large dose of human mononuclear cord blood cells on SOD1 mice subjected to a sublethal dose of irradiation preceded by antikiller sera (rabbit anti-asialo). The SOD1 mice show evidence of paralysis at 4 to 5 months. The average expected lifetime of these mice is reported to be 130 days (Jackson Laboratory). In this experiment, there were 23 mice. Two mice died before the onset of paralysis. The remainder were divided into three groups: group I: control group of 4 untreated mice; group II: an experimental group of 6 mice treated with antikiller sera, 800 cGy irradiation plus 5 x 10(6) congenic bone marrow mononuclear cells; group III: another experimental group of 11 mice treated with antikiller sera, 800 cGy irradiation plus 34.2-35.6 x 10(6) HUCB mononuclear cells, previously stored for 17-20 days at 4 degrees C in gas permeable bags. The results were as follows: the average age at death was: (I) 127 days for the untreated control group, (II) 138 days for the group that received 800 cGy of irradiation and congenic bone marrow (BM) and (III) 148 days for the group that received irradiation and HUCB. (P < 0.001 HUCB vs control, p < 0.01 HUCB vs BM). The longest surviving mouse in each group was 131, 153, and 182 days old respectively. In summary, large doses of HUCB mononuclear cells produced considerable delay in the onset of symptoms and death of SOD1 mice. These preliminary results may not only indicate that amyotrophic lateral sclerosis is an autoimmune disease, but may also indicate a possible treatment for a devastating disease and possibly others.}, }
@article {pmid10869062, year = {2000}, author = {Krajewski, KM and Lewis, RA and Fuerst, DR and Turansky, C and Hinderer, SR and Garbern, J and Kamholz, J and Shy, ME}, title = {Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A.}, journal = {Brain : a journal of neurology}, volume = {123 (Pt 7)}, number = {}, pages = {1516-1527}, doi = {10.1093/brain/123.7.1516}, pmid = {10869062}, issn = {0006-8950}, mesh = {Action Potentials/physiology ; Adolescent ; Adult ; Aged ; Axons/*pathology ; Charcot-Marie-Tooth Disease/*pathology/*physiopathology ; Child ; Child, Preschool ; Disease Progression ; Electrophysiology ; Female ; Humans ; Isometric Contraction/physiology ; Male ; Middle Aged ; Movement/physiology ; Muscle Weakness/pathology ; Muscle, Skeletal/innervation/pathology ; Nerve Degeneration/*pathology ; Nerve Regeneration/physiology ; Neural Conduction/physiology ; Neurons, Afferent/physiology ; Neuropsychological Tests ; Phenotype ; Walking/physiology ; }, abstract = {Charcot-Marie-Tooth disease type 1A (CMT1A), the most frequent form of CMT, is caused by a 1.5 Mb duplication on the short arm of chromosome 17. Patients with CMT1A typically have slowed nerve conduction velocities (NCVs), reduced compound motor and sensory nerve action potentials (CMAPs and SNAPs), distal weakness, sensory loss and decreased reflexes. In order to understand further the molecular pathogenesis of CMT1A, as well as to determine which features correlate with neurological dysfunction and might thus be amenable to treatment, we evaluated the clinical and electrophysiological phenotype in 42 patients with CMT1A. In these patients, muscle weakness, CMAP amplitudes and motor unit number estimates correlated with clinical disability, while motor NCV did not. In addition, loss of joint position sense and reduction in SNAP amplitudes also correlated with clinical disability, while sensory NCV did not. Taken together, these data strongly support the hypothesis that neurological dysfunction and clinical disability in CMT1A are caused by loss or damage to large calibre motor and sensory axons. Therapeutic approaches to ameliorate disability in CMT1A, as in amyotrophic lateral sclerosis and other neurodegenerative diseases, should thus be directed towards preventing axonal degeneration and/or promoting axonal regeneration.}, }
@article {pmid10864618, year = {2000}, author = {Giess, R and Naumann, M and Werner, E and Riemann, R and Beck, M and Puls, I and Reiners, C and Toyka, KV}, title = {Injections of botulinum toxin A into the salivary glands improve sialorrhoea in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {69}, number = {1}, pages = {121-123}, doi = {10.1136/jnnp.69.1.121}, pmid = {10864618}, issn = {0022-3050}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Botulinum Toxins, Type A/*administration &amp; dosage/adverse effects ; Female ; Humans ; Injections ; Male ; Middle Aged ; Parotid Gland/*drug effects ; Prospective Studies ; Sialorrhea/*drug therapy ; }, abstract = {Sialorrhoea is a socially disabling problem in bulbar amyotrophic lateral sclerosis (ALS). Botulinum toxin A (BoNT/A) was injected into the salivary glands in five patients with bulbar ALS and sialorrhoea. The effect of BoNT/A was measured by the number of paper handkerchiefs used each day and by salivary gland scintigraphy. BoNT/A ameliorated sialorrhoea and quality of life without major adverse effects. BoNT/A may be a relatively safe and effective treatment for sialorrhoea in selected patients.}, }
@article {pmid10843175, year = {2000}, author = {Kam, GY and Leung, KC and Baxter, RC and Ho, KK}, title = {Estrogens exert route- and dose-dependent effects on insulin-like growth factor (IGF)-binding protein-3 and the acid-labile subunit of the IGF ternary complex.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {85}, number = {5}, pages = {1918-1922}, doi = {10.1210/jcem.85.5.6527}, pmid = {10843175}, issn = {0021-972X}, mesh = {Administration, Cutaneous ; Administration, Oral ; Aged ; Cross-Over Studies ; Estradiol/administration &amp; dosage/analogs &amp; derivatives/*pharmacology ; *Estrogen Replacement Therapy ; Estrogens, Conjugated (USP)/*pharmacology ; Ethinyl Estradiol/administration &amp; dosage/pharmacology ; Female ; Human Growth Hormone/*blood ; Humans ; Insulin-Like Growth Factor Binding Protein 3/*blood ; Insulin-Like Growth Factor I/*metabolism ; Macromolecular Substances ; Middle Aged ; }, abstract = {We have previously shown that exogenous estrogens exert route-dependent effects on serum GH and insulin-like growth factor I (IGF-I) levels. IGF-I circulates as a ternary complex with IGF-binding protein-3 (IGFBP-3) and the acid-labile subunit (ALS). It is not known whether IGFBP-3 and ALS in blood are regulated by estrogen and, if so, whether this is also route dependent. In the present study we investigate the effects on IGFBP-3 and ALS of oral and transdermal estrogens (study 1), of different oral estrogen formulations (ethinyl estradiol, conjugated estrogen, and estradiol valerate; study 2), of different estrogen dosages (study 3) in normal postmenopausal women, and of oral estrogen in hypogonadal GH-deficient women (study 4). Administration of oral, but not transdermal, estrogen in normal postmenopausal women significantly decreased serum levels of IGFBP-3 and ALS (P < or = 0.005). The suppressive effects were similar with different oral estrogen formulations, and the degree of suppression increased with estrogen dosage. In hypogonadal GH-deficient women, oral estrogen treatment also significantly reduced IGFBP-3 and ALS (P = 0.02). The changes in IGF-I in each of the four studies paralleled the changes in both IGFBP-3 and ALS. In conclusion, exogenous estrogens suppress serum IGFBP-3 and ALS in a route- and dose-dependent manner, which are in parallel with the effects on serum IGF-I. These actions of oral estrogen are independent of endogenous GH status.}, }
@article {pmid10836614, year = {2000}, author = {Hardiman, O}, title = {Symptomatic treatment of respiratory and nutritional failure in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {247}, number = {4}, pages = {245-251}, doi = {10.1007/s004150050578}, pmid = {10836614}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Humans ; Nutrition Disorders/physiopathology/*therapy ; Nutritional Support ; Palliative Care ; Respiratory Insufficiency/physiopathology/*therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by death of upper and lower motor neurones. Nutritional and respiratory failure occurs in most patients with ALS. Nutritional failure occurs primarily as a result of dysphagia, although malnutrition may also develop in the absence of clinically apparent dysphagia. The optimal management of nutrition in early ALS has not been established. In later stages of the disease, parenteral nutritional support using percutaneous endoscopic gastrostomy confers a significant survival benefit in selected patients. Respiratory failure occurs as a result of bulbar, cervical and thoracic loss of motor neurones. Inspiratory muscles are preferentially affected. Management of respiratory failure includes the use of strategies that limit aspiration pneumonia, the reduction in secretions, and positioning of the patient to a maximal mechanical advantage. Use of non-invasive positive pressure ventilation in appropriate patients significantly enhances survival. The decision to undertake invasive mechanical ventilation should be made prior to the development of symptoms that might warrant this intervention. The progressive nature of the condition should be taken into account when such a decision is discussed with the patient and carer. Further studies are required to determine the optimal nutritional requirements of patients with ALS, and to elucidate the physiological changes involved in the decline in respiratory function.}, }
@article {pmid10829487, year = {2000}, author = {Plaza Mayor, G and Ried Goycoolea, E and Sierra Grañón, C and Martínez San Millán, J and Folgué Calvo, L and Bertrán Mendizábal, JM}, title = {[Maxillary mucocele: two case reports and review of literature].}, journal = {Anales otorrinolaringologicos ibero-americanos}, volume = {27}, number = {1}, pages = {77-86}, pmid = {10829487}, issn = {0303-8874}, mesh = {Adolescent ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Maxillary Diseases/*diagnostic imaging/*pathology/surgery ; Middle Aged ; Mucocele/*diagnostic imaging/*pathology/surgery ; Tomography, X-Ray Computed ; }, abstract = {Mucoceles are benign expansive conditions, chronically evolving, from paranasal sinuses. Most frequent localized in the ethmofrontal area and related with sinusal ostial drainage. Maxillary mucoceles are rarer and related with traumatic, tumoral or surgical pathologies, particularly with the Caldwell-Luc incision. These mucoceles demand an aggressive treatment als those etmofrontals in order to achieve a radical exeresis through an outer incision. We report 2 cases of maxillary mucocele. The first was a big one of idiopathic type, the other was associated to an inverted papilloma sitting in the external wall of the affected nasal cavity. Review of the literature in regard of pathogenesis, radiological diagnosis and management of these cases.}, }
@article {pmid10828653, year = {2000}, author = {Scelsa, SN and Khan, I}, title = {Blood pressure elevations in riluzole-treated patients with amyotrophic lateral sclerosis.}, journal = {European neurology}, volume = {43}, number = {4}, pages = {224-227}, doi = {10.1159/000008180}, pmid = {10828653}, issn = {0014-3022}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*drug therapy ; Blood Pressure/*drug effects ; Case-Control Studies ; Controlled Clinical Trials as Topic ; Excitatory Amino Acid Antagonists/*adverse effects/therapeutic use ; Female ; Humans ; Hypertension/complications/physiopathology ; Male ; Middle Aged ; Riluzole/*adverse effects/therapeutic use ; Risk Factors ; }, abstract = {OBJECTIVE: To determine whether riluzole is associated with blood pressure elevations in patients with amyotrophic lateral sclerosis (ALS).<br><br>BACKGROUND: Though previously reported, hypertension is not considered a frequent adverse effect of riluzole.<br><br>METHODS: We reviewed data from 35 consecutive ALS patients on riluzole, and 88 randomly selected controls without and 20 patients with ALS who were not on riluzole.<br><br>RESULTS: A significantly greater number of ALS patients on riluzole had blood pressure elevations (28 of 35 patients) compared to controls (26 of 88, p<0.001; 8 of 20, p = 0. 007). Median systolic and diastolic blood pressures were both significantly higher in riluzole-treated (140/86 mm Hg) than in control patients without ALS (120/70 mm Hg, p<0.001). Systolic, but not diastolic, blood pressures were significantly higher in riluzole-treated patients than in controls with ALS (126 mm Hg, p = 0.002).<br><br>CONCLUSIONS: Riluzole treatment may be associated with mild blood pressure elevations. Future prospective trials of riluzole should closely assess hypertension.}, }
@article {pmid10826922, year = {2000}, author = {Okado-Matsumoto, A and Myint, T and Fujii, J and Taniguchi, N}, title = {Gain in functions of mutant Cu,Zn-superoxide dismutases as a causative factor in familial amyotrophic lateral sclerosis: less reactive oxidant formation but high spontaneous aggregation and precipitation.}, journal = {Free radical research}, volume = {33}, number = {1}, pages = {65-73}, doi = {10.1080/10715760000300621}, pmid = {10826922}, issn = {1071-5762}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology/etiology/*genetics ; Animals ; Cell Line ; Copper/metabolism ; Cyclic N-Oxides/metabolism ; Humans ; Kinetics ; Macromolecular Substances ; Mutagenesis, Site-Directed ; *Mutation ; Reactive Oxygen Species/metabolism ; Recombinant Proteins/genetics/metabolism ; Spodoptera ; Superoxide Dismutase/chemistry/*genetics/*metabolism ; }, abstract = {Eight mutant Cu,Zn-superoxide dismutases (SODs) related to familial amyotrophic lateral sclerosis (FALS) were produced in a baculovirus/insect cell expression system and their molecular properties in terms of hydroxyl radical formation and aggregation were compared with the wild-type enzyme. Treatment of the enzymes with Chelex 100 resin decreased Cu contents as well as SOD activities in all mutant Cu,Zn-SODs, indicating that the affinities of the enzymes for copper ion were decreased. Contrary to previous reports, all the mutant Cu,Zn-SODs exhibited less reactive oxidant producing ability in the presence of hydrogen peroxide than the wild-type enzyme. Both SOD activities and their reactive oxidant forming correlated well with the copper ion content of the molecules. In addition, the proteins spontaneously aggregated and were precipitated by simple centrifugation at 12,000g for 20 min in keeping their enzyme activities. Since hyaline inclusions found in FALS patients with SOD1 mutations contained components which were reactive to anti-Cu,Zn-SOD antibody, a primary reaction caused by mutant SOD1 may be attributed to their propensity to form aggregates. Aggregated but still active mutant SOD1 would be expected to mediate the formation of reactive oxygen species and nitrosylation in a more condensed state.}, }
@article {pmid10814542, year = {2000}, author = {Shin, HJ and Chong, CK and Chang, SI and Choi, JD}, title = {Structural and functional role of cysteinyl residues in tobacco acetolactate synthase.}, journal = {Biochemical and biophysical research communications}, volume = {271}, number = {3}, pages = {801-806}, doi = {10.1006/bbrc.2000.2706}, pmid = {10814542}, issn = {0006-291X}, mesh = {Acetolactate Synthase/*chemistry/genetics ; Cysteine/*chemistry ; Disulfides/chemistry ; Electrophoresis, Polyacrylamide Gel ; Enzyme Inhibitors/pharmacology ; Flavin-Adenine Dinucleotide/metabolism ; Herbicides/pharmacology ; Kinetics ; Mutagenesis, Site-Directed ; Peptide Fragments/chemistry ; *Plants, Toxic ; Protein Binding/genetics ; Protein Conformation ; Spectrophotometry ; Thiocyanates/chemistry ; Nicotiana/*enzymology ; }, abstract = {Acetolactate synthase (ALS) is the common enzyme in the biosynthesis of valine, leucine, and isoleucine. The role of four cysteinyl residues in tobacco ALS was determined using site-directed mutagenesis and cysteine-specific cleavage. The C411A mutation abolished the enzymatic activity, as well as the binding affinity for the cofactor FAD. The activation constant of C411S for FAD is approximately 50-fold higher than that of wALS. The C607S mutation did not significantly affect the kinetic parameters. The IC(50) values of C411S and C607S for ALS-inhibiting herbicides are not much different from those of wALS. Two mutants, C163S and C309S, are labile and readily degraded to peptide fragments. The treatment of wALS with 2-nitro-5-thiocyanobenzoic acid, specific for cleavage of the N-terminal side of cysteine, yielded three peptides of 37.0, 22. 0, and 7.0 kDa. This fragmentation pattern is consistent with that deduced from the amino acid sequence of tobacco ALS, assuming the disulfide bond between Cys163 and Cys309. These results suggest that Cys411 is involved in the binding of FAD and that the intrachain disulfide bond between Cys163 and Cys309 plays a key role in maintaining the correct conformation of tobacco ALS.}, }
@article {pmid10812201, year = {2000}, author = {Gegelashvili, G and Dehnes, Y and Danbolt, NC and Schousboe, A}, title = {The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms.}, journal = {Neurochemistry international}, volume = {37}, number = {2-3}, pages = {163-170}, doi = {10.1016/s0197-0186(00)00019-x}, pmid = {10812201}, issn = {0197-0186}, mesh = {ATP-Binding Cassette Transporters/*metabolism ; Amino Acid Transport System X-AG ; Animals ; Astrocytes/metabolism ; Biotin ; Blotting, Western ; Cells, Cultured ; Fluorescent Antibody Technique, Direct ; Immunohistochemistry ; Rats ; Receptors, Cell Surface/metabolism ; Signal Transduction/*physiology ; Synaptic Transmission/physiology ; }, abstract = {High-affinity glutamate transporters ensure termination of glutamatergic neurotransmission and keep the synaptic concentration of this amino acid below excitotoxic levels. However, neuronal glutamate transporters, EAAC1 and EAAT4, are located outside the synaptic cleft and contribute less significantly to the glutamate uptake in the brain than two astroglial transporters, GLAST and GLT1. Aberrant functioning of the glutamate uptake system seems to be linked to some neurodegenerative disorders (eg amyotrophic lateral sclerosis, ALS). Expression of glutamate transporters is differentially regulated via distinct cellular mechanisms. GLT1, which is expressed at very low levels in cultured astrocytes, is strongly induced in the presence of neurons. The present immunocytochemical data provide further evidence that neuronal soluble factors, rather than physical contact between neurons and glia, determine the induction of GLT1 in astrocytes. This effect is apparently mediated by yet undefined growth factor(s) via the tyrphostin-sensitive receptor tyrosine kinase (RTK) signalling, that in turn, supports the downstream activation of p42/44 MAP kinases and the CREM and ATF-1 transcription factors. RTK-independent simultaneous activation of the CREB transcription factor suggests a possible involvement of complementary pathway(s). Neuronal soluble factors do not affect expression of GLAST, but induce supporting machinery for differential regulation of GLAST via the astroglial metabotropic glutamate receptors, mGluR3 and mGluR5. Thus, long-term treatment with the group I mGluR agonist, DHPG, causes down-regulation of GLAST, whereas the group II agonist, DCG-IV, has an opposite effect on the expression of GLAST in astrocytes. However, in BT4C glioma cells glutamate or other transportable substrates (D-aspartate and L-2,4-trans-PDC) induced cell-surface expression of EAAT4 in a receptor-independent manner. The activity-dependent trafficking of this transporter which also exhibits properties of a glutamate-gated chloride channel may play functional roles not only in neuronal excitability, but in glioma cell biology as well.}, }
@article {pmid10796796, year = {2000}, author = {Miller, RG and Mitchell, JD and Moore, DH}, title = {Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {2}, pages = {CD001447}, doi = {10.1002/14651858.CD001447}, pmid = {10796796}, issn = {1469-493X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Excitatory Amino Acid Antagonists/*therapeutic use ; Humans ; Riluzole/*therapeutic use ; }, abstract = {BACKGROUND: Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis (ALS) in some countries but not others. Questions persist about its clinical utility because of high cost, modest efficacy and concern over adverse effects.<br><br>OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival.<br><br>SEARCH STRATEGY: Search of the Cochrane Neuromuscular Disease Group Register for randomized trials and enquiry from authors of trials and other experts in the field. The most recent search was conducted in June 1999.<br><br>SELECTION CRITERIA: Types of studies: randomized trials<br><br>TYPES OF PARTICIPANTS: adults with a diagnosis of ALS Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: per cent mortality at 12 months with riluzole 100 mg Secondary: per cent mortality as a function of time with 100 mg and with all doses of riluzole, scales of neurologic function, quality of life, muscle strength and adverse events.<br><br>DATA COLLECTION AND ANALYSIS: We identified two randomized trials. Each reviewer graded them for methodological quality. Data extraction was performed by a single reviewer and checked by the other two. We obtained some missing data from investigators. We performed meta-analyses with RevMan software using a fixed effects model.<br><br>MAIN RESULTS: The two eligible trials included a total of 794 riluzole treated patients and 320 placebo treated patients. The methodological quality was acceptable and the trials were easily comparable. There were significant differences between the riluzole and placebo groups of both trials, in terms of the primary outcome measure, which was per cent mortality at 12 months with the 100 mg dose of riluzole. The odds ratio for the combined studies was 0.57 (95%CI 0.41 to 0.80) at 12 months. In the secondary outcome measures, there was a survival advantage with riluzole 100 mg at six, nine, 12 and 15 months, but not at three or 18 months. Pooled data from the 50, 100 and 200mg dose groups in the larger trial showed a lower per cent mortality with riluzole compared to placebo only at 12 months (odds ratio (OR) 0.64, 95% CI 0.47 to 0.88). There was no beneficial effect on bulbar function, or muscle strength. There were scant data on quality of life, but patients treated with riluzole remained in a more moderately affected health state significantly longer than placebo-treated patients (weighted mean difference (WMD) 35.5 days, 95% CI 5.9 to 65. 0). A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (WMD 2.65, 95% CI 1.51 to 4.65).<br><br>REVIEWER'S CONCLUSIONS: Riluzole 100 mg per day appears to be modestly effective in prolonging survival for patients with ALS.}, }
@article {pmid10796129, year = {2000}, author = {Henderson-Smart, DJ and Bhuta, T and Cools, F and Offringa, M}, title = {Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {2}, pages = {CD000104}, doi = {10.1002/14651858.CD000104}, pmid = {10796129}, issn = {1469-493X}, mesh = {*High-Frequency Ventilation ; Humans ; Infant, Newborn ; Infant, Premature ; *Intermittent Positive-Pressure Ventilation ; Randomized Controlled Trials as Topic ; Respiratory Distress Syndrome, Newborn/*therapy ; }, abstract = {BACKGROUND: Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although intermittent positive pressure ventilation (IPPV) saves lives, lung distortion during its use is associated with lung injury and chronic lung disease (CLD). Conventional IPPV is provided at 30-80 breaths per minute while a newer form of ventilation called high frequency oscillatory ventilation (HFOV) provides 'breaths' at 10-15 seconds. This has been shown to result in less lung injury in experimental studies.<br><br>OBJECTIVES: The objective of this review is to determine whether the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation in preterm infants who are mechanically ventilated for the respiratory distress syndrome decreases the incidence of chronic lung disease (CLD) without adverse effects.<br><br>SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal handsearching by the Cochrane Collaboration, mainly in the English language. Expert informant's search in the Japanese language was made by Prof. Y. Ogawa.<br><br>SELECTION CRITERIA: Randomized controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who are to be given IPPV. Randomization and commencement of treatment should have been as soon as possible after the start of IPPV and usually in the first 12 hours of life.<br><br>DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. Each author extracted data separately; they were compared and differences were resolved. The standard method of the Cochrane Neonatal Review Group was used to synthesize the data using relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) for benefits, and number needed to harm (NNH) for adverse effects, were calculated.<br><br>MAIN RESULTS: Meta-analysis of the six eligible studies comparing HFOV with CV revealed that there is no difference in mortality. There are trends toward decreases in CLD in survivors at 28-30 days, 'death or CLD at 28-30 days' and CLD in survivors at 36-37 weeks postmenstrual age or discharge in the HFOV group. However, there are trends towards increases in severe (grades 3 &amp; 4) intraventricular hemorrhage (IVH) and in periventricular leukomalacia (PVL) in the HFOV group. HFOV results in a small increase in any air leak syndrome (ALS), [summary RR 1.20 (1.03, 1.39)]. Only 2 trials have included neurodevelopmental follow up and more survivors in the HFOV group are abnormal [summary RR 1.26 (1.01, 1.58)]. In the subgroup of four trials where a high volume strategy (HVS) was used, HFOV results in more favourable pulmonary outcomes. There are significantly lower rates of CLD in survivors at 28-30 days [summary RR 0.53 (0.36, 0.76)] and of 'death or CLD at 28-30 days' [summary RR 0.56 (0.40, 0.77) with a non-significant trend towards a reduction in oxygen use at 36-37 weeks postmenstrual age or discharge [summary RR 0.74 (0.55, 1.01)]. There were no differences in the rates of IVH or PVL. Of the four trials in the subgroup using surfactant routinely, three also used the HVS. The trends in results were similar with surfactant to those for the HVS subgroup analysis. One trial suggests that HFOV may reduce the cost of in-hospital care. In the subgroup of two trials (HIFI 1989, Rettwitz-Volk 1998) not using a HVS there is no effect of HFOV on the rate of CLD; however, there is an increase in the rate of PVL [summary RR 1.64 (1.02, 2.64).<br><br>REVIEWER'S CONCLUSIONS: The overall meta-analyses is dominated by the large HIFI study which did not use the HVS recommended on the basis of animal studies, and in which surfactant was not available. Studies which used HVS have shown some benefits in short term measures of CLD without an in}, }
@article {pmid10795884, year = {2000}, author = {Silani, V and Braga, M and Ciammola, A and Cardin, V and Scarlato, G}, title = {Motor neurones in culture as a model to study ALS.}, journal = {Journal of neurology}, volume = {247 Suppl 1}, number = {}, pages = {I28-36}, doi = {10.1007/s004150050554}, pmid = {10795884}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*pathology/physiopathology ; Animals ; Astrocytes ; Calcium/metabolism ; Cell Survival ; Culture Techniques ; Disease Models, Animal ; Glutamic Acid/adverse effects/metabolism ; Humans ; Mitochondria/physiology ; Motor Neurons/*pathology ; Point Mutation ; Rats ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Defining the basis of the selective cell vulnerability of motor neurones (MN) represents the key issue in amyotrophic lateral sclerosis (ALS), and tissue culture models are the ideal system for the identification of the MN specific features at the single cell level. Neurone-astrocyte metabolic interactions, which have a critical role in MN through glutamatergic toxicity, have been mostly defined in vitro. Ca++ metabolism, which appears to play a critical role in inducing MN loss in ALS, has been successfully studied using in vitro cell models. Furthermore, primary cultures demonstrated that apoptotic or necrotic death of neurones after injury depends upon the cell energetic status. Superoxide dismutase- (SOD-1) mutations were successfully expressed in cultured rodent MNs, providing a critical assay to sequence the molecular processes responsible for MN degeneration due to the identified genetic defect. The recent identification of genes that separate humans from apes further increases the value of the human in vitro models to better understand specific human cellular properties. Purified human MNs and astrocytes can today be obtained from the human embryonic spinal cord anterior horns. Interactions at the single cell level can be dissected using the cDNA amplification techniques. The effects of molecules affecting MN survival, neurite extension, and metabolism can easily be defined in vitro, gaining a critical mass of information of immediate clinical application in the treatment of patients affected by ALS. Understanding the properties of human MNs in vitro represents today a significant and critical tool that can easily be reached after extension of the available knowledge from non-primate to human research. Human MN culture studies can greatly contribute to identifying the primitive critical cellular events responsible for the MN degeneration observed in ALS and to gaining crucial information on new therapeutical agents.}, }
@article {pmid10791091, year = {1999}, author = {Iwasaki, Y and Ikeda, K}, title = {[Cotreatment of amyotrophic lateral sclerosis patients].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {39}, number = {12}, pages = {1253-1255}, pmid = {10791091}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Drug Therapy, Combination ; Humans ; Mice ; Nerve Growth Factors/administration &amp; dosage ; Neuroprotective Agents/*administration &amp; dosage ; Riluzole/*administration &amp; dosage ; }, abstract = {In the treatment of cancers and infectious diseases, several drugs are administered simultaneously. Riluzole is a only drug which prolongs survival in amyotrophic lateral sclerosis (ALS) patients, however its effect is modest. We review the preclinical data supporting combination treatment for ALS and discuss the possible combination treatment in patients with ALS. In vitro studies showed favorable results in combination of neurotrophic factors. The combination of BDNF and GDNF reduced motor neuron death after axotomy for more than either factor alone. CNTF and BDNF combination treatment in wobbler mice arrested paw deformity. In the treatment of ALS, riluzole is the only drug available by prescription. When combination treatment is considered in ALS, the most effective combination need to be addressed.}, }
@article {pmid10779373, year = {2000}, author = {Duprat, F and Lesage, F and Patel, AJ and Fink, M and Romey, G and Lazdunski, M}, title = {The neuroprotective agent riluzole activates the two P domain K(+) channels TREK-1 and TRAAK.}, journal = {Molecular pharmacology}, volume = {57}, number = {5}, pages = {906-912}, pmid = {10779373}, issn = {0026-895X}, mesh = {Animals ; COS Cells ; Cyclic AMP/metabolism ; Neuroprotective Agents/*pharmacology ; Potassium Channels/chemistry/drug effects/*metabolism ; *Potassium Channels, Tandem Pore Domain ; Protein Structure, Tertiary/drug effects ; Riluzole/*pharmacology ; Transfection ; }, abstract = {Riluzole (RP 54274) is a potent neuroprotective agent with anticonvulsant, sedative, and anti-ischemic properties. It is currently used in the treatment of amyotrophic lateral sclerosis. This article reports that riluzole is an activator of TREK-1 and TRAAK, two important members of a new structural family of mammalian background K(+) channels with four transmembrane domains and two pore regions. Whereas riluzole activation of TRAAK is sustained, activation of TREK-1 is transient and is followed by an inhibition. The inhibitory process is attributable to an increase of the intracellular cAMP concentration by riluzole that produces a protein kinase A-dependent inhibition of TREK-1. Mutants of TREK-1 lacking the Ser residue where the kinase A phosphorylation takes place are activated in a sustained manner by riluzole. TRAAK is permanently activated by riluzole because, unlike TREK-1, it lacks the negative regulation by cAMP.}, }
@article {pmid10770197, year = {2000}, author = {Wilson, ME}, title = {Insulin-like growth factor I (IGF-I) replacement during growth hormone receptor antagonism normalizes serum IGF-binding protein-3 and markers of bone formation in ovariectomized rhesus monkeys.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {85}, number = {4}, pages = {1557-1562}, doi = {10.1210/jcem.85.4.6522}, pmid = {10770197}, issn = {0021-972X}, support = {HD-16305/HD/NICHD NIH HHS/United States ; RR-00165/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Biomarkers/*blood ; *Bone Development ; Carrier Proteins/blood ; Collagen/blood ; Collagen Type I ; Female ; Glycoproteins/blood ; Growth Hormone/administration &amp; dosage/*analogs &amp; derivatives/*antagonists &amp; inhibitors ; Human Growth Hormone/analogs &amp; derivatives ; Insulin-Like Growth Factor Binding Protein 3/*blood ; Insulin-Like Growth Factor I/*administration &amp; dosage ; Macaca mulatta ; Osteocalcin/blood ; *Ovariectomy ; Peptides/blood ; }, abstract = {Previous work from this laboratory has shown that the constant sc infusion of insulin-like growth factor I (IGF-I) to normal pituitary monkeys results in a sustained elevation in circulating concentrations of IGF-binding protein-3 (IGFBP-3), whereas the acute administration of IGF-I to monkeys pretreated with a GH receptor antagonist produces a brief, but significant, elevation in serum IGFBP-3. The present study tested the hypothesis that the constant infusion of IGF-I would normalize serum concentrations of IGFBP-3 in females treated with the GH receptor antagonist. To assess the biological significance of these effects, serum levels of the acid-labile subunit (ALS) and biomarkers for bone formation, osteocalcin, and collagen type I C-terminal propeptide, were also examined. Five female rhesus monkeys were studied over 21 consecutive days involving 7 days of baseline, 7 days of treatment with the GH receptor antagonist (1.0 mg/kg-week, sc), and 7 days of treatment with the GH receptor antagonist supplemented with IGF-I (120 microg/kg x day, sc infusion with osmotic minipump). Within 48 h of the initiation of treatment with the GH receptor antagonist, serum IGF-I and IGFBP-3 were decreased by 40% and 18% from baseline, respectively, and levels continued to decline through the remainder of treatment. However, within 48 h of the initiation of IGF-I administration during GH receptor antagonist treatment, both serum IGF-I and IGFBP-3 were elevated and normalized to baseline values. Serum concentrations of ALS were also decreased by GH antagonism, but levels increased in some (n = 2), but not all, subjects upon administration of IGF-I. Size exclusion ultrafiltration indicated that the amount of IGF-I found in the high molecular mass complex (>100 kDa) decreased significantly during GH antagonism, but was similar during the baseline and IGF-I infusion phases. Finally, treatment with the GH receptor antagonist also significantly reduced serum levels of osteocalcin and collagen type I C-terminal propeptide, an effect reversed by the addition of IGF-I. These data support the hypothesis that IGF-I increases serum concentrations of IGFBP-3 when endogenous GH action is compromised and that such treatment produces biologically active IGF-I, as evidenced by normalization of biomarkers for bone formation. These results indicate that IGF-I administration during GH receptor antagonism restores circulating levels of IGFBP-3 and the amount of IGF-I found in the high molecular mass complex to levels observed during baseline conditions. It remains to be determined whether IGF-I directly affects hepatic synthesis and secretion of IGFBP-3 and what role IGF-I has in the direct regulation of ALS in the monkey.}, }
@article {pmid10742999, year = {2000}, author = {González-Lorenzo, F and Díaz-Lobato, S}, title = {[Mechanical ventilation in patients with amyotrophic lateral sclerosis].}, journal = {Revista de neurologia}, volume = {30}, number = {1}, pages = {61-64}, pmid = {10742999}, issn = {0210-0010}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Chronic Disease ; Equipment Design ; Humans ; Quality of Life ; Respiration, Artificial/*instrumentation ; Respiratory Insufficiency/etiology/*therapy ; Terminal Care ; }, abstract = {In the final stage of amyotrophic lateral sclerosis, the majority of patients develop chronic respiratory failure. If these patients are not informed about the acute respiratory insufficiency, they run the risk of having to be intubated and stay in Intensive Care Unit over a long term; many of them die of respiratory failure without being informed about the available options. Prognosis and treatment options should be discussed with the patient and family. Their informed consent to prolonged mechanical ventilation of the lungs and stopped it under certain circumstances would be obtained before the condition progress to critical. The non invasive artificial home ventilation has led to advances in the management of patients with amyotrophic lateral sclerosis, as a longer period of survival with a higher level of quality of life. We also have analyzed ethical and social aspects and the results of long term mechanical ventilation in the literature.}, }
@article {pmid10742997, year = {2000}, author = {Tallón-Barranco, A and Ayuso-Peralta, L and Jiménez-Jiménez, FJ and Flores, J and Vázquez-Mezquita, M and Barcenilla, B and Zurdo, M}, title = {[Respiratory form of onset of motor neuron disease].}, journal = {Revista de neurologia}, volume = {30}, number = {1}, pages = {51-53}, pmid = {10742997}, issn = {0210-0010}, mesh = {Acute Disease ; Aged ; Amyotrophic Lateral Sclerosis/complications/*diagnosis/therapy ; Cardiomegaly/diagnosis ; Electrocardiography ; Electromyography/methods ; Extremities/physiopathology ; Humans ; Male ; Muscle, Skeletal/physiopathology ; Respiratory Function Tests ; Respiratory Insufficiency/diagnosis/*etiology ; }, abstract = {OBJECTIVE: To present a case of respiratory failure as the form of onset of amyotrophic lateral sclerosis, to review the main clinical findings, data of the investigations done which suggest the presence of this disorder and describe its therapeutic management.<br><br>CLINICAL CASE: A 68 year old man presented with a subacute illness characterized by a sleep disorder with sleep fragmentation, snoring of increasing intensity, without clear pauses of apnea, progressive diurnal hypersomnia accompanied by progressive dyspnea followed by respiratory failure with respiratory acidosis and difficulty in manipulating things with his hands. Diagnostic investigations showed a restrictive pattern without pulmonary fibrosis, due to paralysis of the diaphragm, and the presence of electromyographic signs compatible with motorneuron disease. The patient was treated with riluzole 100 mg/day and non-invasive mechanical ventilation and maintained an acceptable quality of life.<br><br>CONCLUSIONS: Motorneuron disease may start with acute or progressive respiratory failure without a clear etiological cause and may appear to be similar to obstructive sleep apnea syndrome. The treatment of choice for this respiratory problem is non-invasive mechanical ventilation. Absence of symptoms of bulbar involvement is essential for a favourable prognosis.}, }
@article {pmid10732838, year = {2000}, author = {Iwanaga, T and Hirota, T and Ikeda, T}, title = {Air leak syndrome as one of the manifestations of bronchiolitis obliterans organizing pneumonia.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {39}, number = {2}, pages = {163-165}, doi = {10.2169/internalmedicine.39.163}, pmid = {10732838}, issn = {0918-2918}, mesh = {Biopsy ; Bronchoalveolar Lavage Fluid/cytology ; Cryptogenic Organizing Pneumonia/*diagnosis/drug therapy ; Diagnosis, Differential ; Glucocorticoids/therapeutic use ; Humans ; Male ; Mediastinal Emphysema/*diagnosis ; Middle Aged ; Pneumothorax/*diagnosis ; Respiratory Distress Syndrome/*diagnosis ; Subcutaneous Emphysema/*diagnosis ; Tomography, X-Ray Computed ; }, abstract = {A 46-year-old man developed respiratory distress with air leak syndrome (ALS), including pneumothorax, pneumomediastinum, and subcutaneous emphysema. Open lung biopsy was performed and revealed the histopathologic evidence of bronchiolitis obliterans organizing pneumonia (BOOP), which responded well to steroid treatment. As far as we know, this appears to be the first case of BOOP presenting with ALS as one of its major complications.}, }
@article {pmid10721755, year = {2000}, author = {Sliwa, JA}, title = {Neuromuscular rehabilitation and electrodiagnosis. 1. Central neurologic disorders.}, journal = {Archives of physical medicine and rehabilitation}, volume = {81}, number = {3 Suppl 1}, pages = {S3-12; quiz S36-44}, pmid = {10721755}, issn = {0003-9993}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology/*rehabilitation ; Electrodiagnosis ; Humans ; Multiple Sclerosis/*diagnosis/physiopathology/*rehabilitation ; Muscle Fatigue ; Parkinson Disease/*diagnosis/physiopathology/*rehabilitation ; Patient Care Planning ; }, abstract = {This self-directed learning module highlights the medical treatment and rehabilitation intervention of certain central neurologic disorders encountered in physiatric practice. It is part of the chapter on neuromuscular rehabilitation and electrodiagnosis in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article contains sections on multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. Information covered in these sections includes discussions of the current medical management and the benefits of comprehensive rehabilitation and interventions for specific impairments seen in these conditions.}, }
@article {pmid10710808, year = {2000}, author = {Cottingham, JT and Maitland, J}, title = {Integrating manual and movement therapy with philosophical counseling for treatment of a patient with amyotrophic lateral sclerosis: a case study that explores the principles of holistic intervention.}, journal = {Alternative therapies in health and medicine}, volume = {6}, number = {2}, pages = {128, 120-7}, pmid = {10710808}, issn = {1078-6791}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; *Complementary Therapies ; *Holistic Health ; Humans ; Male ; Middle Aged ; }, abstract = {A patient (Travis) suffering from ALS received a holistic principle-based protocol that combined manual-movement techniques with philosophical counseling. After 4 sessions, he exhibited a remarkable improvement in head-neck alignment, balance/mobility, autonomic activity, and worldview for a 2-month span. These changes occurred only after his worldview underwent a shift from a dualistic split of mind and body to a nondualistic orientation. After this 2-month period of improvement, Travis' structural alignment and balance/mobility suddenly deteriorated rapidly. Yet, his enhanced worldview and autonomic tone continued through a final follow-up taken 17 weeks after the initial evaluation.}, }
@article {pmid10678522, year = {2000}, author = {McCullagh, S and Feinstein, A}, title = {Treatment of pathological affect: variability of response for laughter and crying.}, journal = {The Journal of neuropsychiatry and clinical neurosciences}, volume = {12}, number = {1}, pages = {100-102}, doi = {10.1176/jnp.12.1.100}, pmid = {10678522}, issn = {0895-0172}, mesh = {Aged ; *Crying ; Dose-Response Relationship, Drug ; Female ; Fluoxetine/*therapeutic use ; Humans ; *Laughter ; Male ; Middle Aged ; Mood Disorders/diagnosis/*drug therapy ; Motor Neuron Disease/diagnosis/*drug therapy ; Sertraline/*therapeutic use ; }, abstract = {Pathological laughing and crying (PLC) is increasingly recognized to accompany diverse neurologic conditions, although it remains poorly understood. The authors describe 3 cases of amyotrophic lateral sclerosis (ALS) with an unusual change from a predominance of pathological crying to laughter following drug treatment. Possible explanations for this phenomenon are discussed.}, }
@article {pmid10693948, year = {2000}, author = {Kaal, EC and Vlug, AS and Versleijen, MW and Kuilman, M and Joosten, EA and Bär, PR}, title = {Chronic mitochondrial inhibition induces selective motoneuron death in vitro: a new model for amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {74}, number = {3}, pages = {1158-1165}, doi = {10.1046/j.1471-4159.2000.741158.x}, pmid = {10693948}, issn = {0022-3042}, mesh = {Adenosine Triphosphate/metabolism ; Amyotrophic Lateral Sclerosis/etiology ; Animals ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Disease Models, Animal ; Enzyme Inhibitors/poisoning ; In Vitro Techniques ; Malonates/poisoning ; Mitochondria/drug effects/*physiology ; Motor Neurons/drug effects/*physiology ; Neurons/drug effects/physiology ; Neuroprotective Agents/pharmacology ; Rats ; Sodium Azide/pharmacology ; Spinal Cord/cytology ; Time Factors ; }, abstract = {Evidence is increasing that mitochondrial dysfunction is involved in amyotrophic lateral sclerosis, a neurodegenerative disease characterized by selective motoneuron death. To study the role of mitochondrial dysfunction in the pathways leading to motoneuron death, we developed an in vitro model of chronic motoneuron toxicity, based on malonate-induced inhibition of complex II in the mitochondrial electron transport chain. Treatment with malonate resulted in a dose-dependent decrease in cellular ATP levels. We observed that motoneurons were significantly more vulnerable to mitochondrial inhibition than control neurons in the dorsal horn. We could reproduce this dose-dependent phenomenon with the complex IV inhibitor sodium azide. The free radical scavenger alpha-phenyl-N-tert-butylnitrone, the AMPA/kainate receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione, and riluzole, a drug that is currently used for the treatment of amyotrophic lateral sclerosis, were protective against malonate-induced motoneuron death. Furthermore, the caspase inhibitors N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone and z-Asp-Glu-Val-Asp-fluoromethyl ketone were both protective against malonate toxicity. Our model shows that chronic mitochondrial inhibition leads to selective motoneuron death, which is most likely apoptotic.}, }
@article {pmid10670641, year = {2000}, author = {Smith, CR and Mohanakumar, T and Shimizu, Y and Yu, S and Otomo, N and Kaleem, Z and Flye, MW}, title = {Brief cyclosporine treatment prevents intrathymic (IT) tolerance induction and precipitates acute rejection in an IT rat cardiac allograft model.}, journal = {Transplantation}, volume = {69}, number = {2}, pages = {294-299}, doi = {10.1097/00007890-200001270-00016}, pmid = {10670641}, issn = {0041-1337}, support = {DK32253/DK/NIDDK NIH HHS/United States ; DK52232/DK/NIDDK NIH HHS/United States ; HL09906/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Cell Count/drug effects ; Cyclosporine/*therapeutic use ; Cytokines/pharmacology ; Graft Rejection/prevention &amp; control ; Heart Transplantation/*immunology ; Immune Tolerance/drug effects ; Immunosuppressive Agents/*therapeutic use ; Male ; Models, Cardiovascular ; Rats ; Rats, Inbred ACI ; Rats, Inbred BUF ; Rats, Inbred Lew ; T-Lymphocytes, Cytotoxic/cytology ; T-Lymphocytes, Helper-Inducer/cytology ; Thymus Gland/*immunology ; }, abstract = {BACKGROUND: Intrathymic (IT) alloantigen combined with administration of rabbit anti-rat anti-lymphocyte serum (ALS) intraperitoneally induces donor-specific tolerance to rat cardiac transplants. The purpose of this study was to examine the effect of a brief course (4 days) of cyclosporine (CsA) on the development of IT tolerance.<br><br>METHODS: Buffalo (BUF) (RT1b) rats were given 25x10(6) fully MHC-mismatched Lewis (LEW) (RT1l) splenocytes by IT injection plus 1.0 ml of ALS intraperitoneally. Twenty-one days later, IT donor-specific LEW (group 1) or third-party (ACI, RT1a) (group 2) hearts were heterotopically transplanted to the abdominal aorta A third group of BUF (group 3) were given daily CsA (10 mg/kg) by oral gavage for 4 days before administration of IT LEW cells and ALS. Rejection as defined by the cessation of a palpable heartbeat was confirmed by histology. Cytokine profiles of allografts from all groups were then analyzed using a multi-probe RNase protection assay.<br><br>RESULTS: Sixty-seven percent of IT/ALS-treated BUF recipients not pretreated with CsA accepted LEW heart grafts for greater than 90 days. However, 86% of animals treated with CsA for 4 days before IT injection and ALS rejected allografts at 10.7+/-3.2 days. Third-party allografts (ACI) were uniformly rejected (7.0+/-0.0 days). Histology confirmed cellular rejection in CsA-treated allografts and cytokine analysis detected increased interleukin (IL)-3, IL-5, and tumor necrosis factor-alpha when compared to increased IL-2 and interferon-gamma in rejecting untreated controls.<br><br>CONCLUSIONS: CsA can prevent the induction of intrathymic alloantigen tolerance. These results support the development of a CsA-sensitive, but IL-2-independent, active regulatory mechanism after intrathymic exposure to donor-specific alloantigen and depletion of mature peripheral T cells.}, }
@article {pmid10670630, year = {2000}, author = {Ali, A and Garrovillo, M and Jin, MX and Hardy, MA and Oluwole, SF}, title = {Major histocompatibility complex class I peptide-pulsed host dendritic cells induce antigen-specific acquired thymic tolerance to islet cells.}, journal = {Transplantation}, volume = {69}, number = {2}, pages = {221-226}, doi = {10.1097/00007890-200001270-00005}, pmid = {10670630}, issn = {0041-1337}, support = {HL 57229/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Antibody Affinity ; Dendritic Cells/*immunology ; Epitopes ; Graft Survival ; Heart Transplantation ; Histocompatibility Antigens Class I ; Immune Tolerance ; Islets of Langerhans/cytology ; Islets of Langerhans Transplantation/immunology ; Lymphocyte Culture Test, Mixed ; Rats ; Rats, Inbred ACI ; Rats, Inbred BN ; Rats, Inbred WF ; Thymus Gland/*immunology ; }, abstract = {BACKGROUND: As T-cell receptor-major histocompatibility complex (MHC) class I/self peptide interaction regulates T-cell development in the thymus, we reasoned that presentation of peptides by self dendritic cells (DC) to developing T cells in the thymus might induce acquired thymic tolerance. This hypothesis is based on the finding that intrathymic injection of allopeptides in the adult animal induces acquired tolerance. To examine this hypothesis, we studied the effects of intrathymic (IT) injection of a single immunodominant Wistar-Furth (WF) MHC class I (RT1.Au) peptide-pulsed host DC on islet allograft survival in the WF-to-ACI rat combination.<br><br>METHODS: Bone marrow-derived ACI DC expressing MHC class I and II, OX62, and ED2 present allopeptides to naive and specifically peptide-primed syngeneic T cells in mixed lymphocyte reaction. Host DC pulsed with RT1.Au peptide 5 (residues 93-109) were injected into the thymus of streptozotocin-induced diabetic ACI that were transplanted 7 days later with donor-type (WF) or third-party (Brown Norway [BN]) islets.<br><br>RESULTS: Whereas IT injection of 300 microg of peptide 5 alone led to normoglycemia and permanent islet survival in three of six diabetic ACI recipients, similar treatment combined with simultaneous intraperitoneal injection of 0.5 ml of anti-lymphocyte serum (ALS) on day -7 led to 100% permanent islet allograft survival (>200 days) compared to a mean survival time of 15.0+/-2.3 days in controls treated with ALS alone. In contrast, similarly prepared animals rejected the third-party (BN) islets in an acute fashion. To address the question of indirect allorecognition in acquired thymic tolerance, we examined the effect of peptide-pulsed host DC on graft survival. Whereas IT injection of peptide-pulsed host DC alone resulted in permanent islet survival in two of five animals, IT injection of peptide-pulsed host DC combined with 0.5 ml of ALS induced 100% donor-specific permanent islet allograft survival in the WF-to-ACI rat combination. These results suggest that thymic DC take up, process, and present the administered peptide to the developing T cells by the indirect allorecognition pathway in the induction of acquired thymic tolerance.<br><br>CONCLUSION: We have demonstrated a novel approach to inducing transplant tolerance to islet allografts with IT injection of allopeptide-pulsed host DC. This finding suggests that immunization strategies using DC expressing MHC allopeptides or peptide analogue might be potentially useful in the treatment of autoimmune diabetes mellitus.}, }
@article {pmid10668716, year = {2000}, author = {Beghi, E and Chiò, A and Inghilleri, M and Mazzini, L and Micheli, A and Mora, G and Poloni, M and Riva, R and Serlenga, L and Testa, D and Tonali, P}, title = {A randomized controlled trial of recombinant interferon beta-1a in ALS. Italian Amyotrophic Lateral Sclerosis Study Group.}, journal = {Neurology}, volume = {54}, number = {2}, pages = {469-474}, doi = {10.1212/wnl.54.2.469}, pmid = {10668716}, issn = {0028-3878}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/immunology/physiopathology ; Antiviral Agents/*administration &amp; dosage/adverse effects ; Electromyography ; Female ; Follow-Up Studies ; Humans ; Interferon Type I/*administration &amp; dosage/adverse effects ; Male ; Middle Aged ; Muscle, Skeletal/physiopathology ; Pilot Projects ; Recombinant Proteins ; T-Lymphocytes/immunology ; Treatment Outcome ; }, abstract = {OBJECTIVE: To evaluate the efficacy of recombinant interferon beta (IFNbeta)-1a in the treatment of ALS.<br><br>BACKGROUND: It has been proposed that IFNs affect the progression of ALS by interfering with putative immune mechanisms involved in the pathogenesis of the disease.<br><br>METHODS: Patients (n = 61) 40 to 70 years of age with a 6- to 24-month history of confirmed ALS with mild to moderate disability received IFNbeta-1a, 12 mIU (n = 31), or placebo (n = 30) subcutaneously three times a week for 6 months and were followed up for an additional 6 months. Patients were assessed after 4, 12, 24, 36, and 48 weeks. Medical Research Council scale, Norris scale, and bulbar scores as well as forced vital capacity were used to assess disability. Selected electrophysiologic measures (latency, amplitude, and duration of the compound muscle action potential) were also used.<br><br>RESULTS: Twenty patients randomized to IFNbeta-1a and 17 patients given placebo completed the study. A total of 16 patients receiving IFNbeta-1a became non-self-supporting compared with 16 on placebo (52% versus 53%). There were no significant differences between the two treatment groups for any of the measures of disease progression and disability. Deaths were reported in six patients treated with IFNbeta-1a and four patients on placebo. Adverse events were reported more frequently with IFNbeta-1a (77% of patients) compared with placebo (57%), with flu-like symptoms and local erythema being the commonest complaints.<br><br>CONCLUSIONS: This pilot study suggests that IFNbeta-1a is not effective in the treatment of ALS.}, }
@article {pmid10660535, year = {2000}, author = {Boisclair, YR and Wang, J and Shi, J and Hurst, KR and Ooi, GT}, title = {Role of the suppressor of cytokine signaling-3 in mediating the inhibitory effects of interleukin-1beta on the growth hormone-dependent transcription of the acid-labile subunit gene in liver cells.}, journal = {The Journal of biological chemistry}, volume = {275}, number = {6}, pages = {3841-3847}, doi = {10.1074/jbc.275.6.3841}, pmid = {10660535}, issn = {0021-9258}, support = {DK-51624/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Carrier Proteins/*genetics ; DNA-Binding Proteins/metabolism ; Glycoproteins/*genetics ; Growth Hormone/*pharmacology ; Interleukin-1/*pharmacology ; Liver/*metabolism ; Mice ; *Milk Proteins ; Promoter Regions, Genetic ; Proteins/*metabolism ; RNA, Messenger/metabolism ; Rats ; *Repressor Proteins ; STAT5 Transcription Factor ; Signal Transduction ; Suppressor of Cytokine Signaling 3 Protein ; Suppressor of Cytokine Signaling Proteins ; Trans-Activators/metabolism ; *Transcription Factors ; Transcription, Genetic/*drug effects ; Transcriptional Activation/drug effects ; Tumor Cells, Cultured ; }, abstract = {During catabolic diseases such as sepsis, inflammation, and infection, a state of growth hormone (GH) resistance develops in liver. This has been attributed in part to increased production of the proinflammatory cytokine interleukin-1beta (IL-1beta). To determine how IL-1beta induces GH resistance, we studied the acid-labile subunit (ALS) gene whose hepatic transcription is increased by GH via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. IL-1beta reduced the ability of GH to stimulate ALS mRNA in rat primary hepatocytes and ALS promoter activity in H4-II-E rat hepatoma cells. This inhibition was dependent on ALSGAS1, an element resembling a gamma-interferon activated sequence that mediates the transcriptional effects of GH. Inhibition by IL-1beta was also associated with a reduction of GH-dependent binding of STAT5 to this element after chronic (8 and 24 h), but not after acute treatment (15 min). Because these results indicated that the inhibition by IL-1beta was indirect, expression of the recently discovered suppressors of cytokine action (SOCS) was examined in liver cells. IL-1beta did not alter the expression of SOCS1, SOCS2, and CIS, indicating that they are not involved. In contrast, IL-1beta increased SOCS3 mRNA by 8-fold after 24 h of treatment, whereas GH had no effect. Forced expression of SOCS3 was just as effective as IL-1beta in reducing the GH induction of ALS promoter activity in H4-II-E rat hepatoma cells. Similar results were observed in primary rat hepatocytes. We conclude that the induction of SOCS3 by IL-1beta contributes to the development of GH resistance in liver, and represents a mechanism by which cytokines such as IL-1beta cross-talk with cytokines using the JAK-STAT pathway.}, }
@article {pmid10652752, year = {1999}, author = {Cabrera-Gómez, JA and López-Saura, P}, title = {[Recent advances in the treatment the nervous system disorders with interferon-alpha].}, journal = {Revista de neurologia}, volume = {29}, number = {12}, pages = {1225-1235}, pmid = {10652752}, issn = {0210-0010}, mesh = {Central Nervous System Diseases/*drug therapy ; Humans ; Interferon-alpha/*therapeutic use ; }, abstract = {INTRODUCTION: The interferons (IFN) have had considerable effect on the course of relapses and the natural course of the disability of patients with multiple sclerosis (MS). However, the effects of IFN in other neurological disorders are little known.<br><br>OBJECTIVES: To review the literature on the experimental and clinical applications of the IFN in disorders of the nervous system excluding MS.<br><br>DEVELOPMENT: We reviewed studies of the applications of the IFN in viral diseases (experimental and human rabies, herpes zoster, herpes virus, non-herpetic meningoencephalitic viruses, HTLV-I myelopathy, arbovirus in animals, subacute sclerosing panencephalitis (SSPE), progressive multifocal leukoencephalopathy); supposedly viral diseases (Reye's syndrome), continuous partial epilepsy (Kojewnikoff's syndrome); prion diseases (Creutzfeldt-Jakob disease); degenerative-hereditary diseases (amyotrophic lateral sclerosis, Alzheimer's disease, schizophrenia, Sturge-Weber-Dimitri syndrome); immuno-allergic disorders (experimental myasthenia gravis, chronic inflammatory demyelinating polyneuropathy-CIDP-); Landry-Guillain-Barr&#xe9;-Strohl syndrome, polyneuropathy associated with IgM monoclonal gammapathy; tumour disorders (benign and malignant primary tumours of the brain, metastatic tumours, meningeal carcinomatosis, extra-intracranial haemangiomas, meningiomas), and other causes (cuban epidemic neuropathy, neuro-Bec&#xe7;et).<br><br>CONCLUSIONS: Disorders of the nervous system in which IFN may be used in a clinical trial include: herpes zoster and herpes simplex infections, HTLV-I myelopathy; subacute sclerosing leukoencephalopathy, continuous partial epilepsy (Kojewnicoff's syndrome), intra-extracranial haemangiomas, CIDP, polyneuropathy associated with IgM gamma monoclonal disorder, malignant primary tumours, recurrent meningiomas, some cerebral metastases, Beh&#xe7;et's disease and schizophrenia.}, }
@article {pmid10643818, year = {1999}, author = {Weber, GF}, title = {Final common pathways in neurodegenerative diseases: regulatory role of the glutathione cycle.}, journal = {Neuroscience and biobehavioral reviews}, volume = {23}, number = {8}, pages = {1079-1086}, doi = {10.1016/s0149-7634(99)00041-x}, pmid = {10643818}, issn = {0149-7634}, mesh = {Animals ; Glutathione/*metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Reactive Oxygen Species/physiology ; }, abstract = {Attempts to unify diverse mechanisms of neurotoxicity have led to the concept of final common pathways which characterize frequently occurring cellular responses to disruption of homeostasis. The clinical presentation and common patho-biochemistry of reactive oxygen intermediates of Guam's disease have suggested that such pathways may be operative in three major neurodegenerative disorders: Alzheimer's dementia, amyotrophic lateral sclerosis and Parkinson's disease. A candidate-signaling pathway in this regard is characterized by the cascade arachidonic acid/HPETE/*OH/cGMP followed by activation of cGMP-dependent kinase and phosphorylation of NF-kB proteins and possibly CREB. This sequence may lead to apoptosis as well as long-term potentiation and memory and constitutes a biochemical correlate to excitotoxicity. The predominant control of *OH release from HPETE, a checkpoint in this pathway, is exerted by the glutathione cycle, a central biochemical process that is also intimately associated with the synthesis of the neurotransmitters glutamate and GABA and is connected to energy metabolism. Modifications in the activity of the glutathione cycle may provide treatment options.}, }
@article {pmid10637819, year = {1999}, author = {Puls, I and Beck, M and Giess, R and Magnus, T and Ochs, G and Toyka, KV}, title = {[Clenbuterol in amyotrophic lateral sclerosis. No indication for a positive effect].}, journal = {Der Nervenarzt}, volume = {70}, number = {12}, pages = {1112-1115}, doi = {10.1007/s001150050548}, pmid = {10637819}, issn = {0028-2804}, mesh = {Adrenergic beta-Agonists/adverse effects/*therapeutic use ; Clenbuterol/adverse effects/*therapeutic use ; Humans ; Motor Neuron Disease/diagnosis/*drug therapy ; Neurologic Examination/drug effects ; Treatment Failure ; }, abstract = {The anabolic effects of clenbuterol have been recognized for a long time. Clenbuterol augments the expression of specific muscle proteins with a differential effect on type I and type II fibres. Furthermore, clenbuterol induces the synthesis of endogenous nerve growth factor (NGF) and may itself be a myotrophic factor released by neuron endings. Side effects include tremor and headache and dose dependent abnormalities of laboratory values (hypokalemia, hypoglycemia). After long-term medication increasing fatigue of muscles has been observed. Decreased expression of beta 2-adrenergic receptors may limit the expected functional improvement. The efficacy of clenbuterol as symptomatic treatment of amyotrophic lateral sclerosis has not been proved. Controlled treatment trials are warranted to assess this question.}, }
@article {pmid10636126, year = {2000}, author = {Caramia, MD and Palmieri, MG and Desiato, MT and Iani, C and Scalise, A and Telera, S and Bernardi, G}, title = {Pharmacologic reversal of cortical hyperexcitability in patients with ALS.}, journal = {Neurology}, volume = {54}, number = {1}, pages = {58-64}, doi = {10.1212/wnl.54.1.58}, pmid = {10636126}, issn = {0028-3878}, mesh = {Acetates/therapeutic use ; *Amines ; Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Cerebral Cortex/*drug effects/*physiopathology ; *Cyclohexanecarboxylic Acids ; Diazepam/therapeutic use ; Drug Therapy, Combination ; Evoked Potentials, Motor ; Female ; GABA Agonists/therapeutic use ; GABA Modulators/therapeutic use ; Gabapentin ; Humans ; Magnetics ; Male ; Middle Aged ; Neural Inhibition/drug effects ; Neuroprotective Agents/therapeutic use ; Physical Stimulation/methods ; Riluzole/therapeutic use ; Synaptic Transmission/drug effects ; Treatment Outcome ; *gamma-Aminobutyric Acid ; }, abstract = {OBJECTIVE: To reverse the profile of abnormal intracortical excitability in patients with ALS by administering drugs that promote GABAergic transmission.<br><br>BACKGROUND: Transcranial magnetic stimulation (TMS) has revealed abnormalities of cortical inhibition in ALS, a reduction of the silent period, and the absence of intracortical inhibition normally occurring in response to paired TMS. Impaired inhibitory transmission could play a role in the physiopathology of this illness.<br><br>METHODS: Using paired TMS with conditioning stimuli from 1-to-6-msec-interstimulus intervals, we investigated 16 patients with ALS. The protocol included: (1) the "drug-free" profile of paired TMS; (2) paired TMS 30 minutes after the intake of diazepam (3.5 mg); (3) paired TMS after 3 weeks' treatment with gabapentin (GBP) (600 mg/day) or riluzole (50 mg/twice a day).<br><br>RESULTS: Intracortical inhibition is lost in patients with ALS, and this abnormal profile is reversed by diazepam or sustained treatment with GBP. We also noted that motor-evoked potential amplitudes to single stimuli increased (p<0.01) after diazepam and GBP.<br><br>CONCLUSIONS: The demonstration of pharmacologic reversal of hyperexcitability in patients with ALS makes a potentially significant contribution toward understanding the pathophysiology of a disease that has so far eluded an effective cure.}, }
@article {pmid10633027, year = {2000}, author = {Esposito, SJ and Mitsumoto, H and Shanks, M}, title = {Use of palatal lift and palatal augmentation prostheses to improve dysarthria in patients with amyotrophic lateral sclerosis: a case series.}, journal = {The Journal of prosthetic dentistry}, volume = {83}, number = {1}, pages = {90-98}, doi = {10.1016/s0022-3913(00)70093-x}, pmid = {10633027}, issn = {0022-3913}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/complications/physiopathology/*rehabilitation ; Dysarthria/etiology/physiopathology/*rehabilitation ; Humans ; *Maxillofacial Prosthesis ; Middle Aged ; *Palatal Obturators ; *Palate ; Prosthesis Design ; Prosthesis Fitting ; Retrospective Studies ; Speech Intelligibility ; Treatment Outcome ; }, abstract = {STATEMENT OF PROBLEM: Amyotrophic Lateral Sclerosis (ALS) is a progressive, adult onset neurodegenerative disorder manifesting itself as a loss of motor capabilities and untimely death. The dysarthria seen in patients with ALS who have bulbar symptoms causes severe problems with communication. The struggle to be understood comes at a time when progressive cumulative disabilities make communication with family, friends, and healthcare workers vital. The use of palatal lift/augmentation prostheses for dysarthria in ALS is not a frequently requested procedure by neurologists.<br><br>PURPOSE: The purpose of this retrospective outcomes study was to evaluate the effectiveness of this treatment on improving speech function and intelligibility in this group of patients. This study also reviews the history, incidence, pathogenesis, and speech characteristics of the patient with ALS.<br><br>METHODS: A retrospective study of 25 patients treated with a prosthesis was performed using chart reviews and phone/office interviews to evaluate the efficacy of a palatal lift and/or augmentation prosthesis to improve speech in ALS patients.<br><br>RESULTS: Twenty-one patients (84%) treated with a palatal lift demonstrated improvement in their dysarthria, specifically in reduction of hypernasality, with 19 (76%) benefiting at least moderately for 6 months. Of the 10 patients treated with a combination palatal lift and augmentation prosthesis, 6 (60%) demonstrated improvement in articulation. A majority of patients indicated it was easier to speak with less effort involved when wearing the prosthesis.<br><br>CONCLUSION: On the basis of this preliminary retrospective study, the use of a palatal lift/augmentation prosthesis should be considered in ALS patients with dysarthria.}, }
@article {pmid10631656, year = {1999}, author = {Jenkinson, C and Fitzpatrick, R and Brennan, C and Bromberg, M and Swash, M}, title = {Development and validation of a short measure of health status for individuals with amyotrophic lateral sclerosis/motor neurone disease: the ALSAQ-40.}, journal = {Journal of neurology}, volume = {246 Suppl 3}, number = {}, pages = {III16-21}, pmid = {10631656}, issn = {0340-5354}, mesh = {Activities of Daily Living ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*physiopathology/psychology ; Communication ; Eating ; Emotions ; Evaluation Studies as Topic ; Female ; *Health Status ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*physiopathology ; Movement ; *Surveys and Questionnaires/standards ; }, abstract = {In recent years there has been an increased appreciation of the importance of measuring health status from the patient's point of view, but until now no attempt has been made to develop an amyotrophic lateral sclerosis (ALS)-specific health status measure. The development of such an instrument is especially relevant now with the introduction of drugs that prolong life in ALS but limited data is available on the impact such treatments have on quality of life. This paper reports on the development of an ALS-specific measure, the forty item ALS assessment questionnaire (ALSAQ-40). The development of the ALSAQ-40 followed three main stages. Stage 1 consisted of in-depth, semi-structured exploratory interviews conducted on a sample of 18 patients to identify areas of salience and concern to patients with ALS. These interviews generated 78 candidate questions. In stage 2, the 78-item questionnaire was used in a postal survey to identify appropriate rephrasing/shortening and to determine the acceptability of the measure. In addition, this exercise helped identify sub-scales of the instrument addressing different dimensions of ALS. Finally in stage 3 the data collected in stage 2 was analysed to areas measured by the instrument and to remove redundant questions. The resulting measure contains forty questions measuring five areas of health status: Eating and Drinking, Communication, ADL/independence, Physical mobility, Emotional Functioning. The measure has high face, internal and construct validity and is likely to prove a useful measure in the evaluation of treatment regimes for ALS/MND.}, }
@article {pmid10631655, year = {1999}, author = {Bradley, WG}, title = {Biological markers in amyotrophic lateral sclerosis: help or hindrance?.}, journal = {Journal of neurology}, volume = {246 Suppl 3}, number = {}, pages = {III13-5}, pmid = {10631655}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*metabolism/physiopathology/therapy ; Biomarkers ; Clinical Trials as Topic ; Disease Progression ; Humans ; }, abstract = {Biological markers play an important role in the development of the understanding of a disease, its diagnosis and treatment. This is particularly true of amyotrophic lateral sclerosis (ALS) at this time. We need better biological markers for the diagnosis, for improved understanding of the underlying pathogenetic mechanisms, and for assistance in new drug development. This review of currently available biological and surrogate markers in ALS discusses novel approaches to the use of such markers, and new drugs for the treatment of ALS.}, }
@article {pmid10630215, year = {1999}, author = {Kitamikado, H and Sugihara, S and Enomoto, K and Sueda, M and Tanaka, T and Mori, H and Fukuyama, Y}, title = {[Visiting nurse for a terminal ALS patient].}, journal = {Gan to kagaku ryoho. Cancer &amp; chemotherapy}, volume = {26 Suppl 2}, number = {}, pages = {200-202}, pmid = {10630215}, issn = {0385-0684}, mesh = {*Amyotrophic Lateral Sclerosis/nursing/psychology ; *Community Health Nursing ; Female ; Home Care Services/*statistics &amp; numerical data ; Humans ; Middle Aged ; Quality of Life ; }, abstract = {The authors' hospital is a 585-bed hospital under the direct management of the National Health Insurance System. The hospital has been providing visiting nurses for the past 8 years, who work from local medical centers and the Visiting Nurses Department. Thirty-seven patients have received such home care, among whom 8 had intractable disease. Patient S was a 46-year-old woman who suffered from amyotrophic lateral sclerosis (ALS). The onset of the disease was in April, 1993, when the patient experienced muscular atrophy in both legs and deteriorating muscular strength. The diagnosis was definitive in 1995. On March 1, 1998, the patient received emergency hospitalization for breathing difficulties and aspiration pneumonia, and on March 5 underwent tracheotomy. A cannula had to be inserted for tubal feeding, and the physician in charge explained to her family that her prognosis was 3 months. Both the patient and her family desired home care, and the patient returned home on April 11. Respecting the wishes of the patient, the visiting nurse provided support so that home treatment could be continued. In the end, the patient lived at home while receiving home treatment for 7 months. Through the support provided by the visiting nurse, efforts were made to keep the patient's condition stable, and she was able to continue home treatment and living at home for a higher quality of life.}, }
@article {pmid10629166, year = {1999}, author = {Laursen, T and Møller, J and Fisker, S and Jorgensen, JO and Christiansen, JS}, title = {Effects of a 7-day continuous infusion of octreotide on circulating levels of growth factors and binding proteins in growth hormone (GH)-treated GH-deficient patients.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {9}, number = {6}, pages = {451-457}, doi = {10.1054/ghir.1999.0131}, pmid = {10629166}, issn = {1096-6374}, mesh = {Adult ; Carrier Proteins/blood ; Glycoproteins/blood ; Growth Hormone/*deficiency ; Hormones/*therapeutic use ; Human Growth Hormone/*therapeutic use ; Humans ; Insulin-Like Growth Factor Binding Proteins/blood/*metabolism ; Male ; Octreotide/*therapeutic use ; Somatomedins/*metabolism ; Time Factors ; }, abstract = {In patients with acromegaly, clinical improvement has been reported after octreotide (OCT) treatment, even in cases of only a moderate suppression of growth hormone (GH) levels. In rats, OCT suppresses IGF-I mRNA expression and generation of serum and tissue IGF-I levels. A direct effect of OCT on the IGF system could have therapeutical implications in diabetes mellitus, cardiovascular disease, and certain malignancies in which IGF-I might be involved. The aim of this study was to examine possible GH-independent effects of OCT on IGF components in humans. Six GH-deficient (GHD) patients were studied for 24 h after each of the following treatment regimens (each of 1 weeks duration): (a) daily s.c. GH injection (2 IU/m(2)); (b) as (a) + continuous s.c. infusion of OCT (200 microg/24 h) by means of a portable pump (Nordic Infuser); (c) no treatment. Serum GH binding protein (GHBP) levels tended to be lower after GH and OCT than after GH alone (P =0.10). OCT reduced the GH induced increase in serum IGF-I levels (P<0.05, ANOVA). Mean integrated levels (microg/l) were 359.1+/-49.6 (GH), and 301.6+/-58.9 (GH+OCT). OCT did not significantly reduce serum IGFBP-3 levels (microg/l) [3460+/-270 (GH), and 3112+/-435 (GH+/-OCT);P =0.14]. Serum levels of free IGF-I (P =0.39), IGF-II (P =0.54), and of the acid-labile subunit (ALS) of the ternary complex (P =0.50) were similar during GH+/-OCT as compared with GH alone. After 1 week off GH treatment, significantly lower levels of IGF-I, IGF-II, IGFBP-3, and ALS were recorded (P<0.001). Serum IGFBP-1 levels were significantly higher after GH+OCT than after GH alone (P<0.0001), and levels were even higher without GH. Serum insulin levels (pmol/l) were significantly higher after GH alone as compared with no GH (P<0.05, ANOVA), whereas OCT partly suppressed the insulinotropic effect of GH (P<0. 05) [mean: 114.5+/-33.0 (GH), 91.3+/-29.6 (GH+OCT), 65.9+/-22.5 (no GH)]. This was also reflected in higher blood glucose levels during GH+OCT. Finally, GH+OCT reduced glucagon levels significantly as compared with GH alone (P =0.02). In conclusion, 7 days' administration of OCT to GH-treated GHD patients slightly attenuated serum IGF-I generation, and tended to decrease levels of the other components of the 150 kDa ternary complex. Whether these effects are mediated directly by OCT or indirectly via the accompanying changes in insulin levels remains to be investigated.}, }
@article {pmid11124989, year = {2000}, author = {Vukosavic, S and Stefanis, L and Jackson-Lewis, V and Guégan, C and Romero, N and Chen, C and Dubois-Dauphin, M and Przedborski, S}, title = {Delaying caspase activation by Bcl-2: A clue to disease retardation in a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {20}, number = {24}, pages = {9119-9125}, pmid = {11124989}, issn = {1529-2401}, support = {R01 NS38586/NS/NINDS NIH HHS/United States ; P50 NS038370/NS/NINDS NIH HHS/United States ; P50 NS38370/NS/NINDS NIH HHS/United States ; R29 NS37345/NS/NINDS NIH HHS/United States ; R01 NS038586/NS/NINDS NIH HHS/United States ; }, mesh = {Actins/metabolism ; Amyotrophic Lateral Sclerosis/*enzymology/genetics ; Animals ; Anterior Horn Cells/enzymology/pathology ; Apoptosis ; Caspase 1/genetics/*metabolism ; Caspase 3 ; Caspases/genetics/*metabolism ; Cerebellum/enzymology/pathology ; Disease Models, Animal ; Disease Progression ; Enzyme Activation/genetics ; Gene Dosage ; Gene Expression ; Mice ; Mice, Transgenic ; Motor Neurons/enzymology/pathology ; Mutation ; Proto-Oncogene Proteins c-bcl-2/genetics/*metabolism ; RNA, Messenger/metabolism ; Spinal Cord/enzymology/pathology ; Superoxide Dismutase/*genetics ; Superoxide Dismutase-1 ; Transfection ; }, abstract = {Molecular mechanisms of apoptosis may participate in motor neuron degeneration produced by mutant copper/zinc superoxide dismutase (mSOD1), the only proven cause of amyotrophic lateral sclerosis (ALS). Consistent with this, herein we show that the spinal cord of transgenic mSOD1 mice is the site of the sequential activation of caspase-1 and caspase-3. Activated caspase-3 and its produced beta-actin cleavage fragments are found in apoptotic neurons in the anterior horn of the spinal cord of affected transgenic mSOD1 mice; although such neurons are few, their scarcity should not undermine the potential importance of apoptosis in the overall mSOD1-related neurodegeneration. Overexpression of the anti-apoptotic protein Bcl-2 attenuates neurodegeneration and delays activation of the caspases and fragmentation of beta-actin. These data demonstrate that caspase activation occurs in this mouse model of ALS during neurodegeneration. Our study also suggests that modulation of caspase activity may provide protective benefit in the treatment of ALS, a view that is consistent with our recent demonstration of caspase inhibition extending the survival of transgenic mSOD1 mice.}, }
@article {pmid10623568, year = {2000}, author = {Trieu, VN and Liu, R and Liu, XP and Uckun, FM}, title = {A specific inhibitor of janus kinase-3 increases survival in a transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Biochemical and biophysical research communications}, volume = {267}, number = {1}, pages = {22-25}, doi = {10.1006/bbrc.1999.1905}, pmid = {10623568}, issn = {0006-291X}, mesh = {Animals ; Antioxidants/*pharmacology ; Disease Models, Animal ; Enzyme Inhibitors/*therapeutic use ; Genetic Variation ; Genistein/pharmacology/*therapeutic use ; Heterozygote ; Humans ; Janus Kinase 3 ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; Motor Neuron Disease/*drug therapy/*genetics ; Neuroprotective Agents/*therapeutic use ; Paralysis ; Protein-Tyrosine Kinases/*antagonists &amp; inhibitors ; Quinazolines/pharmacology/*therapeutic use ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder involving the motor neurons of cortex, brain stem, and spinal cord. About 10% of all ALS patients are familial cases (FALS), of which 20% have mutations in the Cu, Zn-superoxide dismutase (SOD1) gene. The murine model for FALS, which overexpresses a FALS variant of the SOD1 gene, exhibits progressive limbic paralysis followed by death. Treatment of FALS mice with WHI-P131, a specific inhibitor of Janus kinase 3 (JAK3), increased survival by more than two months, suggesting that specific inhibitors of JAK3 may be useful in the treatment of human ALS. These results uniquely establish JAK3 as a novel molecular target for the treatment of FALS.}, }
@article {pmid10613049, year = {1999}, author = {Treuheit, T and Bartels, C and Hoffmann, B and Welte, T}, title = {[Our first experiences with intermittent assisted ventilation in patients with amyotrophic lateral sclerosis].}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {53 Suppl 2}, number = {}, pages = {S86-8}, pmid = {10613049}, issn = {0934-8387}, mesh = {Adult ; Humans ; *Intermittent Positive-Pressure Breathing ; Motor Neuron Disease/physiopathology/*therapy ; Palliative Care ; Practice Guidelines as Topic ; Respiratory Insufficiency/etiology/therapy ; }, abstract = {Amyotrophic lateral sclerosis is one of the most frequent neuromuscular diseases in adults. Chronic respiratory failures is an almost compulsory symptom in the progression of this disease, and in association with pulmonary infections, responsible for the majority of deaths. We report on a series of 43 patients. An advanced stage of clinical disease was seen in half of them. After detection of respiratory failure corresponding to the guidelines of muscle centres of the DGM (Deutsche Gesellschaft für Muskelerkrankungen), seven patients (16.3%) were willing to be provided with a system for intermittent non-invasive ventilation. All patients achieved stabilisation of respiratory function, both with respect to the normalisation of arterial gases and subjective improvement of well-being. During the course of treatment four patients deliberately underwent permanent invasive ventilation. In our opinion home ventilation is a valid additional tool in the palliative treatment of amyotrophic lateral sclerosis. The treatment, however, must be supported by an interdisciplinary team.}, }
@article {pmid10601567, year = {2000}, author = {Martin, LJ and Price, AC and Kaiser, A and Shaikh, AY and Liu, Z}, title = {Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death (Review).}, journal = {International journal of molecular medicine}, volume = {5}, number = {1}, pages = {3-13}, doi = {10.3892/ijmm.5.1.3}, pmid = {10601567}, issn = {1107-3756}, support = {NS34100/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Apoptosis/genetics ; Autoimmunity/immunology ; DNA Damage ; Disease Models, Animal ; Humans ; Motor Neurons/*pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also referred to as motor neurone disease, is a fatal neurological disease that is characterized clinically by progressive muscle weakness, muscle atrophy, and eventual paralysis. The neuropathology of ALS is primary degeneration of upper (motor cortical) and lower (brainstem and spinal) motor neurons. The amyotrophy refers to the neurogenic atrophy of affected muscle groups, and the lateral sclerosis refers to the hardening of the lateral white matter funiculus in spinal cord (corresponding to degeneration of the corticospinal tract) found at autopsy. Because the mechanisms for the motor neuron degeneration in ALS are not understood, this disease has no precisely known causes and no effective treatments. Very recent studies have identified that the degeneration of motor neurons in ALS is a form of apoptotic cell death that may occur by an abnormal programmed cell death (PCD) mechanism. In order to treat ALS effectively, we need to understand the mechanisms for motor neuron apoptosis more completely. Future studies need to further identify the signals for PCD activation in neurons as they relate to the pathogenesis of ALS and to clarify the molecular pathways leading to motor neuron apoptosis in animal and cell culture model systems. These studies should lead to a better understanding of motor neuron death and to the design of new therapeutic experiments critical for the future treatment of ALS.}, }
@article {pmid10540024, year = {1999}, author = {Iwasaki, Y and Ikeda, K}, title = {Prevention by insulin-like growth factor-I and riluzole in motor neuron death after neonatal axotomy.}, journal = {Journal of the neurological sciences}, volume = {169}, number = {1-2}, pages = {148-155}, doi = {10.1016/s0022-510x(99)00238-5}, pmid = {10540024}, issn = {0022-510X}, mesh = {Animals ; Animals, Newborn ; Axotomy ; Cell Death/drug effects/physiology ; Insulin-Like Growth Factor I/*pharmacology ; Motor Neurons/*drug effects/physiology ; Neuroprotective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Riluzole/*pharmacology ; Sciatic Nerve/drug effects/physiology ; Spinal Cord/*drug effects/physiology ; }, abstract = {Transection of the sciatic nerve in neonatal rats results discernable loss of motor neurons in the spinal cord. This neuronal death could be due to lack of retrogradely transported target derived neurotrophic factors, since some of these factors have been shown to be effective in injury induced motor neuron death. Another hypothesis suggests that glutamate and its receptors has been implicated as possible mechanism for motor neuron death, because inhibitor of glutamate release and antagonists of glutamate receptors are effective in preventing axotomized motor neuron death. To investigate the effect of insulin-like growth factor-I (IGF-I) and riluzole, a drug that inhibits glutamate release, on axotomy induced motor neuron death. Newborn rats were anesthetized with hypothermia. Sciatic nerve was cut near the obturator tendon in the left thigh. Animals were then treated daily with different doses of IGF-I and riluzole for 14 days with intraperitoneal injections. Control rats received PBS in the same fashion. After the treatment, the number of surviving motor neurons and the motor neuron diameter in the L(4) was assessed. Both IGF-I (1.0 mg/kg) and riluzole (5.0 mg/kg) rescued motor neuron death in a similar way. Co-administration of IGF-I (1.0 mg/kg) and riluzole (5.0 mg/kg) was more effective than either agent alone and there was a statistically significant difference between co-administration and IGF-I alone. However there was no significant difference between simultaneous treatment and riluzole alone. As for diameter of motor neurons, riluzole (5.0 mg/kg) preserved the motor neuron diameter in the lesion side. Nonetheless, no further increase in motor neuron diameter was seen when riluzole (5 mg/kg) and IGF-I (1.0 mg/kg) were applied in combination. Both agents did not affect diameter of motor neurons in the non-axotomy side. Riluzole is available in amyotrophic lateral sclerosis (ALS) and the positive results of clinical trials with IGF-I suggests that combination treatment of IGF-I and riluzole in ALS remains to be determined.}, }
@article {pmid10540016, year = {1999}, author = {Desiato, MT and Palmieri, MG and Giacomini, P and Scalise, A and Arciprete, F and Caramia, MD}, title = {The effect of riluzole in amyotrophic lateral sclerosis: a study with cortical stimulation.}, journal = {Journal of the neurological sciences}, volume = {169}, number = {1-2}, pages = {98-107}, doi = {10.1016/s0022-510x(99)00225-7}, pmid = {10540016}, issn = {0022-510X}, mesh = {Adult ; Aged ; *Amyotrophic Lateral Sclerosis ; Analysis of Variance ; Electric Stimulation ; Electromagnetic Phenomena ; Evoked Potentials, Motor/*drug effects ; Excitatory Amino Acid Antagonists/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; Riluzole/*therapeutic use ; }, abstract = {A population of 31 patients with sporadic amyotrophic lateral sclerosis (ALS) was selected for a prospective open study based on treatment with riluzole. A neurophysiological evaluation was performed by means of single and paired transcranial magnetic stimulation (TMS). The examined parameters, excitability threshold, motor evoked potential (MEP) duration, silent period (SP) duration and time course of intracortical inhibition to paired TMS after 6 months treatment, were matched against those recorded from the patients themselves before the beginning of treatment and from 20 (single TMS) or 10 (paired TMS) age-matched control subjects. Normal behaviour of the SP in response to increasing TMS was found in the treated patients; they showed a significant linear correlation between these two parameters (r=0.96) comparable to that calculated for controls (r=0.98), and significantly different with respect to drug-free patients (r=0.8, P=0.014). A significant reduced size of the 'conditioned' MEPs to paired stimulation was documented in the treated patients compared with the untreated patients (P=0.002). Our neurophysiological contribution to the assessment of the effect of riluzole on the motor cortical inhibitory property in ALS may be considered a setting for controlled trials in extended patient series, even in a pre-clinical phase.}, }
@article {pmid10540013, year = {1999}, author = {Bradley, WG and Bowen, BC and Pattany, PM and Rotta, F}, title = {1H-magnetic resonance spectroscopy in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {169}, number = {1-2}, pages = {84-86}, doi = {10.1016/s0022-510x(99)00221-x}, pmid = {10540013}, issn = {0022-510X}, mesh = {Adult ; Aged ; *Amyotrophic Lateral Sclerosis ; Aspartic Acid/*analogs &amp; derivatives/metabolism ; Brain Chemistry ; Creatine/*metabolism ; Humans ; *Magnetic Resonance Spectroscopy ; Middle Aged ; }, abstract = {1H-magnetic resonance spectroscopy (MRS) is potentially a powerful tool for the investigation of the chemicals of the brain in vivo in health and disease. Levels of N-acetyl-aspartate (NAA) in the motor cortex and brainstem of patients with amyotrophic lateral sclerosis (ALS) have been reported to be reduced by up to 68%, and in one report the level of glutamate in the brainstem was increased by 58%. We studied levels of metabolites in the cerebral cortex and brainstem of 20 ALS patients and 14 age-matched controls with a 1.5 Tesla Picker magnet using MRS. We used the same spectra for determining both the area of the metabolite peaks expressed as a ratio of the area of the creatine (Cr) peak, and the absolute concentrations using the Provencher LC model. These produced different results. With the LC model, the NAA content of the motor cortex of ALS patients was reduced by 7.7% (P=0.015), and that of the brainstem was reduced by 21.5% (P=0.035), compared with controls. The degree of reduction of NAA was related to the severity of upper motor neuron abnormalities. No effect of treatment with anti-glutamate agents on NAA concentration could be detected. Concentrations of other metabolites were not affected in ALS. It appears that MRS is a technique that is still in development, and that further refinement is required before it can be used to understand disease mechanisms and investigate treatment in ALS.}, }
@article {pmid10540012, year = {1999}, author = {de Carvalho, M and Nogueira, A and Pinto, A and Miguens, J and Sales Luís, ML}, title = {Reflex sympathetic dystrophy associated with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {169}, number = {1-2}, pages = {80-83}, doi = {10.1016/s0022-510x(99)00220-8}, pmid = {10540012}, issn = {0022-510X}, mesh = {Aged ; *Amyotrophic Lateral Sclerosis ; Female ; Humans ; Male ; Middle Aged ; Reflex Sympathetic Dystrophy/*complications/physiopathology ; }, abstract = {Reflex sympathetic dystrophy (RSD) is a syndrome characterised by severe distal pain and vasomotor changes. It is believed to be caused by sympathetic nervous system overactivity. Trauma is the most frequent precipitant event. An association with amyotrophic lateral sclerosis (ALS) has been reported only once. We report three patients with ALS in whom the occurrence of RSD, in one of them at a very early clinical stage, seemed to have precipitated a more rapid clinical evolution. New sprouting re-innervating fibres have abnormal ion channels which might increase the risk of RSD. On the other hand, motor changes have been described in RSD, as well as motor strength improvement after RSD treatment. The complex relation of ALS with RSD is discussed. In all ALS patients pain followed by further loss of function should prompt a search for RSD.}, }
@article {pmid10540003, year = {1999}, author = {Newsom-Davis, IC and Abrahams, S and Goldstein, LH and Leigh, PN}, title = {The emotional lability questionnaire: a new measure of emotional lability in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {169}, number = {1-2}, pages = {22-25}, doi = {10.1016/s0022-510x(99)00211-7}, pmid = {10540003}, issn = {0022-510X}, mesh = {Adult ; Affective Symptoms/*psychology ; Aged ; *Amyotrophic Lateral Sclerosis ; Case-Control Studies ; Female ; Humans ; Male ; Middle Aged ; Statistics, Nonparametric ; *Surveys and Questionnaires ; }, abstract = {In an ALS Clinic, use of the Pathological Laughter and Crying Scale of Robinson et al. [Robinson RG, Parikh RM, Lipsey JR, Starkstein SE, Price TR. Pathological laughter and crying following stroke: validation of a measurement scale and double-blind treatment study. American Journal of Psychiatry 1993;150(2):286-293] revealed several problems: reliance on self-rating, insufficient period of assessment, inadequate exploration of 'appropriateness of emotion', lack of an item for abnormal smiling, amusement rather than happiness being the cause of laughter in ALS, and a frequency-based rating system. The necessary modifications produced a new Emotional Lability Questionnaire (ELQ) that was tested in 43 ALS patients and 43 healthy controls. The self-rated version of the ELQ was administered as a structured interview to each participant, and the independent-relationship between subscales of the ELQ for both versions, thus confirming its internal validity. Greater emotional lability appeared associated with pseudobulbar symptoms. The question why 14 patients rated themselves as severely labile in the crying domain alone and four in the laughter domain alone, required further study.}, }
@article {pmid10590895, year = {1999}, author = {Bromberg, MB}, title = {Pathogenesis of amyotrophic lateral sclerosis: a critical review.}, journal = {Current opinion in neurology}, volume = {12}, number = {5}, pages = {581-588}, doi = {10.1097/00019052-199910000-00012}, pmid = {10590895}, issn = {1350-7540}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*etiology/physiopathology ; Animals ; Disease Models, Animal ; Humans ; Motor Neurons/physiology ; Sex Characteristics ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease with unknown pathogenesis. It is a relatively common disorder of adults (2-4 per 100,000 incidence) and leads to death from respiratory failure. There is no cure at this time, and available treatment and management can at best extend survival to a modest degree. Increasing our understanding of the pathogenesis of this disease is essential to the development of more effective treatments. The level of research interest is very high, and yearly reviews of the literature are helpful in assessing progress.}, }
@article {pmid10581372, year = {1999}, author = {Asahara, H and Taniwaki, T and Ohyagi, Y and Yamada, T and Kira, J}, title = {Glutamate enhances phosphorylation of neurofilaments in cerebellar granule cell culture.}, journal = {Journal of the neurological sciences}, volume = {171}, number = {2}, pages = {84-87}, doi = {10.1016/s0022-510x(99)00256-7}, pmid = {10581372}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/etiology/physiopathology ; Animals ; Animals, Newborn ; Cell Culture Techniques ; Cerebellum/*metabolism ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Antagonists/pharmacology ; Glutamic Acid/*pharmacology ; Neurofilament Proteins/*metabolism ; Neurons/*metabolism ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; }, abstract = {In amyotrophic lateral sclerosis (ALS), an abnormal increase of glutamate in the central nervous system indicates that it may play a key role in motor neuron death. The neuronal accumulation of phosphorylated neurofilaments (NFs) suggests an alteration of phosphorylation of NFs is also involved. Rat cerebellar granule cells (CGCs) are sensitive to glutamate neurotoxicity and provide a suitable model system for clarifying its mechanisms. Using cultured CGCs, we investigated the relationship between glutamate neurotoxicity and the phosphorylation of NFs. Because glutamate showed a dose-dependent neurotoxicity for CGCs, we adopted a 10 microM glutamate treatment, which produced no acute neurotoxicity during the experiments. The number of phosphorylated heavy subunits of neurofilaments (NF-Hs) increased to approximately twice that of the control after 72 h, although the total number of NF-Hs remained constant throughout the experiment. The phosphorylation of NF-Hs was significantly suppressed by the AMPA-receptor antagonist CNQX, but not by the NMDA-receptor antagonist MK-801. Our findings therefore suggest that exposure to a low concentration of glutamate enhances the phosphorylation of NF-Hs, mainly via the AMPA receptor.}, }
@article {pmid10570736, year = {1999}, author = {Sivak, ED and Shefner, JM and Sexton, J}, title = {Neuromuscular disease and hypoventilation.}, journal = {Current opinion in pulmonary medicine}, volume = {5}, number = {6}, pages = {355-362}, doi = {10.1097/00063198-199911000-00006}, pmid = {10570736}, issn = {1070-5287}, mesh = {Acute Disease ; Chronic Disease ; Dyspnea/etiology ; Fatigue/etiology ; Humans ; Hypercapnia/etiology ; Hypoxia/etiology ; Muscle Weakness/etiology ; Neuromuscular Diseases/*complications ; Randomized Controlled Trials as Topic ; Respiration Disorders/etiology ; Respiration, Artificial ; Respiratory Insufficiency/etiology ; Respiratory Mechanics/physiology ; Respiratory Muscles/physiopathology ; Sleep Apnea, Central/*etiology/therapy ; Sleep Wake Disorders/etiology ; Tachycardia/etiology ; Vital Capacity/physiology ; }, abstract = {Alveolar hypoventilation associated with neuromuscular disease can occur in acute and chronic forms. In the acute form, progressive weakness of respiratory muscles leads to rapid reduction in vital capacity followed by respiratory failure with hypoxemia and hypercarbia. Symptoms are those of acute respiratory failure, including dyspnea, tachypnea, and tachycardia. In the chronic form, impairment of the respiratory muscles affects mechanical properties of the lungs and chest wall, decreases the ability to clear secretions, and eventually may alter the function of the central respiratory centers. Symptoms include orthopnea, fatigue, disturbed sleep, and hypersomnolence. Treatment and outcome of the disease's chronic form are dependent on the underlying clinical cause of the alveolar hypoventilation. For chronic but stable diseases such as old polio, quadriplegia, or kyposcoliosis, mechanical support of minute ventilation can reverse symptoms. For chronic and progressive disease such as muscular dystrophy and amyotrophic lateral sclerosis, mechanical support of minute ventilation provides only symptomatic relief and is usually associated with deterioration to the point of complete ventilator dependency for survival. For the chronic progressive forms of alveolar hypoventilation, there is currently a need for quality randomized controlled clinical trials to define physiologic indicators and appropriate timing for mechanical support of minute ventilation.}, }
@article {pmid10565246, year = {1999}, author = {Andersen, PM and Binzer, M}, title = {[Treatment of amyotrophic lateral sclerosis].}, journal = {Ugeskrift for laeger}, volume = {161}, number = {41}, pages = {5697-5698}, pmid = {10565246}, issn = {0041-5782}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; Physical Therapy Modalities ; }, }
@article {pmid10560640, year = {1999}, author = {Brooks, BR}, title = {Earlier is better: the benefits of early diagnosis.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S53-4; discussion S55-7}, pmid = {10560640}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*psychology ; Employment/*statistics &amp; numerical data ; Humans ; *Quality of Life ; }, abstract = {The concept of earlier diagnosis of amyotrophic lateral sclerosis (ALS) requires in-depth investigation of its benefits and consequences. First, how good must a treatment be before ALS is determined to be a treatable condition? Analogy with cancer therapy suggests that a good quality of life after treatment is an essential feature of a "good" therapy. Survival in some diseases may be prolonged without a significant improvement in the patient's quality of life. Neurologists need to be clear about what they are trying to achieve in prolonging survival and maintaining a good quality of life for their patients with ALS. Second, can early diagnosis extend apparent survival in the absence of a therapeutic intervention that significantly affects the disease process? Earlier diagnosis on the basis of confirmed clinical signs and earlier institution of therapy may lead to a perception of improved survival, which is greater in young ALS patients. Third, can early diagnosis provide a benefit through prolongation of the time the patient remains able to work? Any therapeutic intervention to slow the early stages of the disease would benefit patients who wanted to maintain their self-esteem by continuing to work. Finally, earlier diagnosis of ALS requires decisions to be made concerning the acceptable rate of misdiagnosis, which at present reaches 10% false-positive and up to 44% false-negative.}, }
@article {pmid10560639, year = {1999}, author = {Cashman, NR}, title = {Do the benefits of currently available treatments justify early diagnosis and announcement? Arguments for.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S50-2; discussion S55-7}, pmid = {10560639}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Humans ; Neuroprotective Agents/*administration &amp; dosage ; Riluzole/*administration &amp; dosage ; }, abstract = {Both a biologic imperative and an ethical imperative exist for providing the diagnosis of amyotrophic lateral sclerosis (ALS) as soon as possible and involving patients and their families in therapeutic decisions. The participation of excitotoxic mechanisms in ALS and the availability of riluzole, which may slow the rate of progression of ALS, provide the biologic rationale for early therapy in ALS. A neuroprotective agent, such as riluzole, is more effective at an early stage of disease, when more undamaged neurons remain. The development of effective therapy for ALS also provides the ethical basis for early announcement of diagnosis. When no primary treatment was available, an accepted approach was one of "protecting" the patient from the diagnosis, which was one of exclusion, requiring almost 100% certainty before announcement. The availability of a primary therapy, albeit not a cure, means that a diagnosis of ALS can now be offered as the most likely diagnosis with 90-95% certainty. The logical corollary of this new model is that patients must be involved immediately, to help decide when therapy is appropriate and to balance the relative personal significance of therapeutic gains versus adverse effects.}, }
@article {pmid10560638, year = {1999}, author = {Ludolph, AC and Riepe, MW}, title = {Do the benefits of currently available treatments justify early diagnosis and treatment of amyotrophic lateral sclerosis? Arguments against.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S46-9; discussion S55-7}, pmid = {10560638}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Animals ; Humans ; Neuroprotective Agents/*adverse effects ; Riluzole/*adverse effects ; }, abstract = {Recent in vitro and experimental animal studies strongly indicate that motor neuron diseases, like other neurodegenerative diseases, may be preceded by a long preclinical period. Clinical studies have suggested that the beneficial effects of neuroprotection in human amyotrophic lateral sclerosis (ALS) may be due to a preferential effect on early phases of the disease. However, the aim of this article is to review the potential arguments that there is no justification for early neuroprotective treatment of ALS. Controversies concerning the clinical neuroprotective effects of riluzole in mice and humans exist. Side effects of riluzole are emphasized and the data that appear to indicate that ALS has a long preclinical period are questioned. On the basis of these doubts and skepticisms, we conclude that it may be premature to treat ALS early without addressing the major objections in future studies in a controlled manner.}, }
@article {pmid10560637, year = {1999}, author = {Brooks, BR}, title = {What are the implications of early diagnosis? Maintaining optimal health as long as possible.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S43-5; discussion S55-7}, pmid = {10560637}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*drug therapy ; Disease Progression ; Humans ; Neuroprotective Agents/*administration &amp; dosage ; Riluzole/*administration &amp; dosage ; }, abstract = {As yet, there is no staging system for amyotrophic lateral sclerosis (ALS). One early attempt to define disease stages consisted of post-hoc analysis of the international, placebo-controlled, clinical trials of riluzole. In this analysis, five health states were defined for ALS (mild, moderate, severe, terminal, death) to determine whether therapeutic intervention with riluzole could favorably influence the time spent in the different stages. The time spent in the mild and moderate disease states (taken together) was considerably longer in patients treated with riluzole than in those treated with placebo (317 days compared with 242 days). Riluzole did not influence the median time in the mild, severe, or terminal ALS stages but did slightly shorten the time in the moderate ALS stage compared with placebo. In all the ALS stages, the 75th percentile of time in that state appeared to be extended. Survival analysis indicated that the relative risk was less than 1.0 with riluzole treatment in the moderate, severe, and terminal health states but not in the mild health state, when it remained at 1.0. The time to failure was longer in patients in the moderate, severe, and terminal ALS stages but was significantly longer only in the moderate ALS stage. These findings indicate that future studies of therapeutic intervention should examine rigorously defined stages of disease to examine end points other than death. The development of a staging system, analogous to the ones used in oncology, has implications for the concept of early diagnosis.}, }
@article {pmid10560636, year = {1999}, author = {Silani, V and Borasio, GD}, title = {Honesty and hope: announcement of diagnosis in ALS.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S37-9; discussion S40-2}, pmid = {10560636}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*psychology ; Humans ; *Physician-Patient Relations ; *Truth Disclosure ; }, abstract = {Informing patients and their families about a diagnosis such as amyotrophic lateral sclerosis (ALS) is a daunting task for any physician. The way the diagnosis is communicated will have a major impact on the physician-patient relationship and the attitude of the patient toward the disease and toward symptomatic treatment measures. Breaking the news can be truly defined as the starting point of palliative care in ALS. It is an ongoing information process which, by its nature, escapes narrow definitions or standardization attempts. Nevertheless, a number of techniques exist to facilitate the process and ease the burden for physicians, patients, and families. We believe that the terminal phase should be discussed at the latest when first respiratory symptoms appear, to prevent unwarranted fears of "choking to death."}, }
@article {pmid10560632, year = {1999}, author = {Gelinas, D}, title = {Conceptual approach to diagnostic delay in ALS: a United States perspective.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S17-9; discussion S20-1}, pmid = {10560632}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; *Critical Pathways ; Humans ; Neurology ; Primary Health Care ; *Referral and Consultation ; Time Factors ; United States ; }, abstract = {The mean time from onset of symptoms to confirmation of diagnosis of amyotrophic lateral sclerosis (ALS) in the United States, as elsewhere, is 16-18 months. Delays may arise from the complex referral pathway, caused at least in part by the multiple types of insurance and health-care services available in the United States and also because physicians sometimes attempt to avoid medicolegal responsibility for a very undesirable diagnosis. In addition, initial symptoms are often intermittent and nonspecific and may be denied or not recognized by the patient. In the United States, the primary care physician is increasingly viewed by health maintenance organizations as a gatekeeper, with incentives to keep the diagnosis within the primary care realm. This may lead to misdiagnosis and inappropriate referral. Even after the patient reaches a neurologist, the differential diagnosis of ALS is large and may involve many tests, all of which may incur scheduling and reporting delays. Reluctance to give a bad diagnosis before it is absolutely certain may also cause delay. Delays after diagnosis may be the result of health insurance constraints, the prejudices of the neurologist in favor of or against particular therapies, and the patient's willingness to accept or ability to pay for therapy. Many of these delays may be lessened by both professional and lay educational initiatives to raise awareness of the symptoms of ALS and encourage more rapid presentation and referral to the neurologist. The availability of credible treatment options would undoubtedly encourage physicians to have hope and to seek an earlier diagnosis.}, }
@article {pmid10560631, year = {1999}, author = {Dubrovsky, AL and Sica, RE}, title = {Current treatment pathways in ALS: a South American perspective.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S11-6}, pmid = {10560631}, issn = {0028-3878}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnostic imaging/pathology/*therapy ; Argentina ; Biopsy ; Brazil ; *Critical Pathways ; Diagnostic Errors ; Evoked Potentials, Motor ; Family Practice/statistics &amp; numerical data ; Female ; *Health Care Surveys ; Humans ; Magnetic Resonance Imaging/statistics &amp; numerical data ; Male ; Middle Aged ; Neurology/statistics &amp; numerical data ; Referral and Consultation/statistics &amp; numerical data ; Spinal Puncture/statistics &amp; numerical data ; Tomography, X-Ray Computed/statistics &amp; numerical data ; }, abstract = {This article presents the findings relating to the South American subgroup of 60 patients in an international survey of the current diagnosis and treatment of patients with amyotrophic lateral sclerosis (ALS). The mean time between first symptoms and first consultation with a physician was 3.7 months, and mean delay in seeing a neurologist was then 5.6 months, giving a mean time from symptom onset to confirmation of diagnosis of 16.6 months. The time to confirmation of diagnosis was much longer for patients with symptoms of limb onset (17.5 months) than for those with bulbar onset (10.0 months). Cases with symptoms of upper-limb onset were diagnosed more rapidly (14.9 months) than those with symptoms of lower-limb onset (21.8 months). The diagnosis was confirmed in 48% of cases within 15 months of symptom onset, and a further 27% were diagnosed within 15-24 months; 47% of cases were confirmed within 4 months of consulation with a neurologist and a further 17% within 4-6 months. The first physician seen was the general practitioner in 47% of cases overall. When the neurologist was the first physician seen (27% of patients in Brazil, 0% in Argentina), diagnosis was achieved within 14 months in 88% of cases. EMG was performed in almost all patients. MRI and CT were widely used, which may cause delays. Announcement of the diagnosis was made immediately to 75% of patients overall. Riluzole was prescribed for 23% of patients in Brazil and for 67% of patients in Argentina.}, }
@article {pmid10560630, year = {1999}, author = {Dengler, R}, title = {Current treatment pathways in ALS: a European perspective.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S4-10; discussion S20-1}, pmid = {10560630}, issn = {0028-3878}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*diagnostic imaging/pathology/*therapy ; Biopsy/statistics &amp; numerical data ; *Critical Pathways ; Electromyography/statistics &amp; numerical data ; Evoked Potentials, Motor ; Family Practice/statistics &amp; numerical data ; Germany ; *Health Care Surveys ; Humans ; Italy ; Magnetic Resonance Imaging/statistics &amp; numerical data ; Middle Aged ; Neurology/statistics &amp; numerical data ; Professional Practice ; Referral and Consultation/statistics &amp; numerical data ; Spain ; Tomography, X-Ray Computed/statistics &amp; numerical data ; }, abstract = {This article presents the findings relating to the European subgroup of 91 patients in an international survey of the current diagnosis and treatment of patients with amyotrophic lateral sclerosis (ALS). The mean time between first symptoms and first consultation with a physician was 4.9 months, and mean delay in seeing a neurologist was then about 6 months, yielding a mean time from symptom onset to confirmation of diagnosis of 17.8 months. The time to confirmation of diagnosis was slightly longer for patients with symptoms of limb onset (18.5 months) than for those with bulbar onset (17.5 months). Cases with symptoms of upper-limb onset were diagnosed more rapidly (15.5 months) than those with symptoms of lower-limb onset (21.8 months). The diagnosis was confirmed in 51% of cases within 15 months of symptom onset, and a further 23% were diagnosed within 15-24 months; 55% of cases were confirmed within 4 months of consultation with a neurologist, and a further 14% within 4-6 months. The first physician seen was the general practitioner in 68% of cases. When the neurologist was the first physician seen (7% in Germany, 13% in Italy, 0% in Spain), diagnosis was achieved within 14 months in 67% of cases. EMG was performed in almost all patients. MRI and CT were widely used, possibly causing delays. Announcement of the diagnosis was made immediately to 85% of patients and within 1 month to a further 9%. Riluzole was prescribed for 76% of patients overall.}, }
@article {pmid10560629, year = {1999}, author = {Brooks, BR}, title = {Defining optimal management in ALS: from first symptoms to announcement.}, journal = {Neurology}, volume = {53}, number = {8 Suppl 5}, pages = {S1-3; discussion S20-1}, pmid = {10560629}, issn = {0028-3878}, mesh = {Algorithms ; Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; *Critical Pathways ; Decision Trees ; Humans ; }, abstract = {The advances in treatment for amyotrophic lateral sclerosis (ALS) have demonstrated the need to diagnose this disease precisely and directly. Two international initiatives, at El Escorial in 1990 and at Airlie House in 1998, have grappled with the clinical and laboratory elements that may accelerate the diagnostic process. Shortly after the Airlie House meeting in 1998, an international group of clinical neurologists met to discuss optimal management strategies in ALS. The goals were to examine current diagnosis and treatment pathways and to attempt to devise an algorithm that would foster early diagnosis, thus enhancing the possibility of optimal treatment.}, }
@article {pmid10549306, year = {1999}, author = {Camacho-Hübner, C and Woods, KA and Miraki-Moud, F and Clark, A and Savage, MO}, title = {Insulin-like growth factor-I deficiency caused by a partial deletion of the IGF-I gene: effects of rhIGF-I therapy.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {9 Suppl B}, number = {}, pages = {47-51; discussion 51-2}, doi = {10.1016/s1096-6374(99)80081-1}, pmid = {10549306}, issn = {1096-6374}, mesh = {Adolescent ; Fetal Growth Retardation/genetics ; Growth Disorders/drug therapy/genetics/metabolism ; Humans ; Insulin-Like Growth Factor I/*deficiency/*genetics/therapeutic use ; Male ; Phenotype ; Recombinant Proteins/therapeutic use ; *Sequence Deletion ; }, abstract = {Insulin-like growth factor-I (IGF-I) is one of the most important regulator of growth. IGF-I deficiency is associated with prenatal and post-natal growth failure and may arise primarily as a result of GH receptor/post-receptor abnormalities or defects in the synthesis and transport of IGF-I. We have previously reported a 17.2-year-old boy with severe growth retardation and undetectable serum levels of IGF-I caused by a partial deletion of the IGF-I gene. This short review will concentrate on results of a recent study which examined the effects of rhIGF-I therapy on the GH-IGF system of this patient. Similar to healthy individuals, this patient had normal IGFBP-3 but elevated ALS levels. IGF-I treatment has improved linear growth and insulin sensitivity in this patient by restoring IGF-I levels and by normalizing circulating GH, IGFBPs and insulin levels.}, }
@article {pmid10546990, year = {1999}, author = {González Deniselle, MC and Grillo, CA and González, S and Roig, P and De Nicola, AF}, title = {Evidence for down-regulation of GAP-43 mRNA in Wobbler mouse spinal motoneurons by corticosterone and a 21-aminosteroid.}, journal = {Brain research}, volume = {841}, number = {1-2}, pages = {78-84}, doi = {10.1016/s0006-8993(99)01783-7}, pmid = {10546990}, issn = {0006-8993}, mesh = {Animals ; Antioxidants/*pharmacology ; Corticosterone/*pharmacology ; Female ; GAP-43 Protein/*genetics ; Gene Expression Regulation/drug effects/*physiology ; In Situ Hybridization ; Male ; Mice ; Mice, Neurologic Mutants ; Motor Neurons/*metabolism ; Posterior Horn Cells/drug effects/metabolism ; Pregnatrienes/*pharmacology ; RNA, Messenger/genetics ; Spinal Cord/*metabolism ; Transcription, Genetic/drug effects ; }, abstract = {Expression of the growth-associated protein GAP-43 is increased in the spinal cord of ALS patients and Wobbler (wr) mice, murine models of the disease. In this work we examined if expression of GAP-43 mRNA in control and wr mice was sensitive to steroid treatment. A group of control and wr mice received s.c. a 50 mg pellet of the natural hormone corticosterone (CORT) or the antioxidant 21-aminosteroid U-74389F during 4 days. Basal levels of GAP-43 mRNA were 10-fold elevated in ventral horn motoneurons of untreated wr mice, compared to the low levels in controls. The high expression of GAP-43 mRNA in wr was attenuated by treatment with CORT (41%, p < 0.001) and U-74389F (36%, p < 0.001). Although specific GAP-43 mRNA labelling was present in some neurons around the central canal, its cellular expression was similar in controls and wr. Also, steroid treatment was ineffective in neurons around the central canal. Other regions of the spinal cord (i.e., dorsal horn neurons) expressed GAP-43 mRNA slightly above background levels. It is possible that attenuation of GAP-43 expression due to the natural hormone and the antioxidant steroid resulted from reversal of motoneuron degeneration or aberrant sprouting. Therefore, steroid therapy may be of value to prevent denervation and/or muscular atrophy in this animal model.}, }
@article {pmid10539396, year = {1999}, author = {Messori, A and Trippoli, S and Becagli, P and Zaccara, G}, title = {Cost effectiveness of riluzole in amyotrophic lateral sclerosis. Italian Cooperative Group for the Study of Meta-Analysis and the Osservatorio SIFO sui Farmaci.}, journal = {PharmacoEconomics}, volume = {16}, number = {2}, pages = {153-163}, pmid = {10539396}, issn = {1170-7690}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Cost-Benefit Analysis ; Drug Costs ; Humans ; Riluzole/*therapeutic use ; }, abstract = {OBJECTIVE: In patients with amyotrophic lateral sclerosis, long term treatment with riluzole has been reported to improve survival or tracheostomy-free survival in comparison with placebo. We conducted a pharmacoeconomic analysis for estimating the cost per life-year gained using this drug.<br><br>DESIGN: This study was an incremental cost-effectiveness lifetime analysis.<br><br>SETTING: The clinical material was derived from 2 placebo-controlled randomised controlled trials comparing riluzole versus usual care without riluzole, which were identified through a literature search based on the IOWA and the Medline systems.<br><br>PATIENTS AND INTERVENTIONS: The study included 633 patients with amyotrophic lateral sclerosis. Patient-level information was retrieved from 313 patients treated with riluzole and 320 patients assigned to placebo. Survival after randomisation was compared between the 2 groups using standard statistics (log-rank test and Cox analysis), whereas the lifetime survival gain was estimated using Gompertz extrapolation. Cost data relative to the expenditure for healthcare resources were obtained from published information (using the US average wholesale price for the acquisition cost of riluzole). Sensitivity testing assessed the impact of different cost-of-illness assumptions for treated and untreated patients.<br><br>Our primary analysis showed that treatment with riluzole significantly prolonged survival [death risk = 0.77; 95% confidence interval (CI): 0.62 to 0.96; p = 0.022]. The lifetime survival gain (including 3% annual discounting) was, on average, 2.3 months per patient, while the incremental cost was around $US12,000 per patient. Hence, the cost-effectiveness ratio of riluzole versus usual care without riluzole was $US62,609 per life-year gained (discounted dollars per discounted years; 95% CI: $US13,458 to $US205,714). The sensitivity analysis, considering different values of national cost for riluzole, suggested an interval for this parameter ranging from $US45,048 to $US62,609.<br><br>CONCLUSIONS: Our study indicates that in patients with amyotrophic lateral sclerosis, riluzole has an unfavourable cost-effectiveness ratio or, at best, a borderline pharmacoeconomic profile.}, }
@article {pmid10534037, year = {1999}, author = {Haynes, BE and Pritting, J}, title = {A rural emergency medical technician with selected advanced skills.}, journal = {Prehospital emergency care}, volume = {3}, number = {4}, pages = {343-346}, doi = {10.1080/10903129908958966}, pmid = {10534037}, issn = {1090-3127}, mesh = {Adolescent ; Adult ; Allied Health Personnel/*education ; California ; Clinical Competence ; Emergency Medical Services/*statistics &amp; numerical data ; Female ; Humans ; Male ; Middle Aged ; Rural Health Services/*statistics &amp; numerical data ; Time Factors ; }, abstract = {OBJECTIVE: To educate rural emergency medical technician basics (EMTs) in selected advanced skills, and then evaluate the safety and effectiveness of practice.<br><br>METHODS: After a minimum 72 hours of training, EMTs employed three skills (Combitube, glucometry, automated external defibrillation) and seven medications (albuterol, nitroglycerin, naloxone, epinephrine, glucagon, activated charcoal, and aspirin). Written patient care records and audiotapes were reviewed. Congruence between prehospital assessment and emergency department (ED) diagnosis was assessed, along with correct use of airway skills (18 of 36 months). The completeness of documentation, appropriateness of treatment, and patient response (by explicit criteria) were determined. Errors and complications were recorded.<br><br>RESULTS: During three years of the program, 266 patients were treated, primarily for chest pain and respiratory distress. No significant errors or complications occurred. Treatment was judged 94% appropriate, with improvement in 60% of patients. Documentation had major omissions in 3% of cases. Field and ED diagnostic congruence was present in 97/129 (75%) when evaluated during the first 18 months. EMT skill levels were maintained. The mean time to traditional advanced life support (ALS) care was 41 minutes.<br><br>CONCLUSIONS: Basic-level EMTs in rural areas can be trained in selected advanced skills, and provide ALS-level care quickly and appropriately. Close medical oversight involving review of care and follow-up education is an important part of the program.}, }
@article {pmid10534033, year = {1999}, author = {Dickinson, ET and Verdile, VP and Duncan, T and Bryant, KA}, title = {Managed care enrollee utilization of 911 medical services.}, journal = {Prehospital emergency care}, volume = {3}, number = {4}, pages = {321-324}, doi = {10.1080/10903129908958962}, pmid = {10534033}, issn = {1090-3127}, mesh = {Emergency Medical Services/*statistics &amp; numerical data ; Hospitalization/statistics &amp; numerical data ; Hotlines/classification/*statistics &amp; numerical data ; Humans ; Managed Care Programs/*statistics &amp; numerical data ; Prospective Studies ; Transportation of Patients/*statistics &amp; numerical data ; }, abstract = {OBJECTIVE: To determine the mechanism by which managed care organization (MCO) enrollees enter the emergency medical services (EMS) system.<br><br>METHODS: All enrollees belonging to the region's largest MCO and transported to emergency departments by a paramedic-level municipal EMS system were identified from billing records. Dispatch logs were examined to determine the time and origin of the call to the 911 communication center. Patient care records were used to obtain age, the level of care delivered (advanced or basic life support), and whether the patient received any medications while out of hospital. Hospital admission was also determined.<br><br>RESULTS: Over a six-month period, 195 enrollees were transported. Three modes of 911 EMS system entry were identified: group I-enrollees who called 911 directly; group II-enrollees who called the MCO triage center, who then called 911 on behalf of the patient; and group III--enrollees who were sent to the MCO health center for evaluation, and subsequently the MCO called 911 to transfer the patient to the hospital. Of the 195 patients transported to the emergency department, the dispositions of 108 (55%) patients were obtained. Group I (n = 109) patients were more likely to be transported in the evening (3 PM to 11 PM), less likely to require advanced life support therapies, and less likely to be admitted to the hospital when compared with groups II (n = 32) and III (n = 54) patients. Group III patients were the most likely to receive advanced life support care and require admission to the hospital.<br><br>CONCLUSION: The majority of MCO enrollees called 911 directly, and were most likely to do so during evening hours. Enrollees who called 911 directly (group I) had a trend toward lower acuity, based on the lowest ALS utilization of any group. Those enrollees who most frequently required advanced life support were those who received initial treatment at the MCO center prior to EMS transport. Though EMS system-specific, this type of descriptive analysis is helpful in assisting both EMS systems and MCOs to better assess utilization of 911 EMS resources by MCO enrollees. This study also challenges the prudent layperson paradigm.}, }
@article {pmid10529543, year = {1999}, author = {Ono, S and Imai, T and Igarashi, A and Shimizu, N and Nakagawa, H and Hu, J}, title = {Decrease in the ciliary neurotrophic factor of the spinal cord in amyotrophic lateral sclerosis.}, journal = {European neurology}, volume = {42}, number = {3}, pages = {163-168}, doi = {10.1159/000008092}, pmid = {10529543}, issn = {0014-3022}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/*pathology ; Case-Control Studies ; Ciliary Neurotrophic Factor/genetics/*metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Gene Expression ; Genotype ; Humans ; Japan ; Male ; Middle Aged ; Motor Neurons/pathology ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length ; Spinal Cord/*metabolism/*pathology ; }, abstract = {Ciliary neurotrophic factor (CNTF), a potent survival factor in spinal motoneurons of embryonic chick and rat, is currently being investigated in humans as a treatment for amyotrophic lateral sclerosis (ALS). However, its physiological and pathological activities in ALS remain unclear. We measured CNTF contents in the cervical enlargement of the spinal cord from 9 ALS patients and 12 age-matched control subjects using a sensitive enzyme-linked immunoassay. CNTF genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism method. In control subjects, there were 8 homozygotes and 4 heterozygotes, while in ALS patients there were 6 and 3, respectively. In both homozygotes and heterozygotes, CNTF expression in the spinal cord from ALS patients tended to decrease compared to control subjects. In homozygotes, the decrease was significant (p < 0.05). Concerning the regional concentrations of CNTF, in homozygotes, CNTF contents in the lateral corticospinal tract were markedly lower (p < 0.001) in ALS patients than in controls. The decrease in CNTF expression in the lateral corticospinal tract of the spinal cord from ALS patients may be a feature of ALS and could be related to motor neuron loss.}, }
@article {pmid10527800, year = {1999}, author = {Elliott, JL}, title = {Experimental models of amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {6}, number = {5}, pages = {310-320}, doi = {10.1006/nbdi.1999.0266}, pmid = {10527800}, issn = {0969-9961}, support = {NS01853/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Disease Models, Animal ; Humans ; In Vitro Techniques ; Motor Neuron Disease/pathology/*physiopathology ; Motor Neurons/pathology/physiology ; Nerve Growth Factors/physiology ; Rats ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by the progressive loss of motor neurons, leading to profound weakness and eventual death of affected individuals. For the vast majority of patients with ALS, the etiology of the disorder is unknown, and although multiple clinical trials of various therapeutic agents have been undertaken, truly effective therapy is not currently available for the disease. The selection of treatments used in ALS clinical trials frequently has its basis in promising data obtained from experimental model systems in which the proposed agent has shown some effect in protecting motor neurons from a particular insult. The likelihood of a successful clinical outcome for a given treatment in ALS would therefore depend on two principal factors, including the similarity of the model to the disease and the biologic action of the potential therapeutic agent. Partly because early experimental models of ALS failed to replicate the disease process, treatment success in these models did not carry over into human trials. Recently, however, a variety of newer model systems have been developed and utilized to investigate motor neuron degeneration as related to ALS. For example, in this issue, Corse et al. use a rat spinal cord organotypic slice subjected to glutamate excitotoxicity as a model system to test the effectiveness of neurotrophic factors in preventing motor neuron degeneration. This review will assess the strengths and weaknesses of differing ALS model systems that have been used to preclinically test potential drug efficacy in ALS.}, }
@article {pmid10523001, year = {1999}, author = {Wallace, JD and Cuneo, RC and Baxter, R and Orskov, H and Keay, N and Pentecost, C and Dall, R and Rosén, T and Jørgensen, JO and Cittadini, A and Longobardi, S and Sacca, L and Christiansen, JS and Bengtsson, BA and Sönksen, PH}, title = {Responses of the growth hormone (GH) and insulin-like growth factor axis to exercise, GH administration, and GH withdrawal in trained adult males: a potential test for GH abuse in sport.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {84}, number = {10}, pages = {3591-3601}, doi = {10.1210/jcem.84.10.6037}, pmid = {10523001}, issn = {0021-972X}, mesh = {Adult ; Carrier Proteins/blood ; *Exercise ; Glycoproteins/blood ; Human Growth Hormone/administration &amp; dosage/*blood/*pharmacology ; Humans ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/analysis ; Kinetics ; Male ; *Physical Education and Training ; Physical Endurance ; Recombinant Proteins/administration &amp; dosage/pharmacology ; Somatomedins/*analysis ; Sports Medicine/methods ; Substance-Related Disorders/diagnosis ; Time Factors ; }, abstract = {GH abuse by elite athletes is currently undetectable. To define suitable markers of GH doping, we assessed the effects of acute exercise, GH administration, and GH withdrawal on the GH/insulin-like growth factor (IGF) axis in athletic adult males. Acute endurance-type exercise increased serum GH, GH-binding protein (GHBP), total IGF-I, IGF-binding protein (IGFBP)-3, and acid-labile subunit (ALS), each peaking at the end of exercise. IGFBP-1 increased after exercise was completed. Free IGF-I did not change with exercise. Recombinant human GH treatment (0.15 IU/kg x day) for 1 week increased serum total IGF-I, IGFBP-3, and ALS, exaggerating the responses to exercise. IGFBP-2 and IGFBP-1 were trivially suppressed. After GH withdrawal, the GH response to identical exercise was suppressed. Total IGF-I, IGFBP-3, and ALS returned to baseline over 3-4 days. In summary, 1) acute exercise transiently increased all components of the IGF-I ternary complex, possibly due to mobilization of preformed intact complexes; 2) GH pretreatment augmented the exercise-induced changes in ternary complexes; 3) postexercise IGFBP-1 increments may protect against delayed onset hypoglycemia; 4) serum total IGF-I, IGFBP-3, and ALS may be suitable markers of GH abuse; and 5) differences in disappearance times altered the sensitivity of each marker for detecting GH abuse.}, }
@article {pmid10517046, year = {1999}, author = {Ochs, G and Giess, R and Bendszus, M and Krone, A}, title = {Epi-arachnoidal drug deposit: a rare complication of intrathecal drug therapy.}, journal = {Journal of pain and symptom management}, volume = {18}, number = {3}, pages = {229-232}, doi = {10.1016/s0885-3924(99)00067-6}, pmid = {10517046}, issn = {0885-3924}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; Arachnoid/*metabolism ; Brain-Derived Neurotrophic Factor/administration &amp; dosage/*adverse effects/therapeutic use ; Female ; Humans ; Injections, Spinal/adverse effects ; Middle Aged ; Recombinant Proteins/administration &amp; dosage/adverse effects/therapeutic use ; }, abstract = {Intrathecal (i.t.) drug application is accepted as a highly effective treatment option for various neurological conditions. Technical risks and potentially dangerous complications require appreciation. We present the case of a patient treated with i.t. recombinant, human brain-derived neurotrophic factor (rhBDNF) as an experimental therapy for amyotrophic lateral sclerosis (ALS). Five days after starting the i.t. drug infusion, she complained of severe headache and nausea. Radiological studies suggested the catheter was located within the epi-arachnoidal space. A deposit of more than 10 ml secluded from the subarachnoidal space was found within this space. I.t. contained a high concentration of the applied drug. Revision of the catheter resulted in complete recovery from symptoms and i.t. infusion could be continued. The epi-arachnoidal positioning of a spinal catheter is a potential cause for treatment failure. If the membrane around the fluid deposit ruptures, the drug could be released into the subarachnoidal space, with the consequence of a potentially life-threatening complication.}, }
@article {pmid10516713, year = {1999}, author = {Wyman, T and Rohrer, D and Kirigiti, P and Nichols, H and Pilcher, K and Nilaver, G and Machida, C}, title = {Promoter-activated expression of nerve growth factor for treatment of neurodegenerative diseases.}, journal = {Gene therapy}, volume = {6}, number = {10}, pages = {1648-1660}, doi = {10.1038/sj.gt.3300989}, pmid = {10516713}, issn = {0969-7128}, support = {DK53462/DK/NIDDK NIH HHS/United States ; HL42358/HL/NHLBI NIH HHS/United States ; RR00163/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Brain/metabolism ; Brain Tissue Transplantation ; Carcinoembryonic Antigen/genetics ; Cell Line ; Endothelial Growth Factors/genetics ; Fetal Tissue Transplantation ; Gene Transfer Techniques ; Genetic Therapy/*methods ; Humans ; Lac Operon ; Lymphokines/genetics ; Metallothionein/genetics ; Nerve Growth Factor/*genetics ; Neurodegenerative Diseases/metabolism/*therapy ; *Promoter Regions, Genetic ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; }, abstract = {Genetic transfer approaches have received recent consideration as potential treatment modalities for human central and peripheral nervous system (CNS and PNS, respectively) neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Transplantation of genetically modified cells into the brain represents a promising strategy for the delivery and expression of specific neurotrophic factors, neurotransmitter-synthesizing enzymes, and cellular regulatory proteins for intervention in neurodegenerative diseases. The use of specific regulatable promoters may also provide potential control of gene expression required for dose-specific or time-specific therapeutic strategies. In this article, we review the potential use of activated promoters in ex vivo systems for the potential genetic therapy of neurodegenerative disorders, and then describe our own studies using the zinc-inducible metallothionein promoter for the regulated expression of nerve growth factor (NGF) in rodent brain transplants.}, }
@article {pmid10516115, year = {1999}, author = {Mauras, N and Quarmby, V and Bloedow, DC}, title = {Pharmacokinetics of insulin-like growth factor I in hypopituitarism: correlation with binding proteins.}, journal = {The American journal of physiology}, volume = {277}, number = {4}, pages = {E579-84}, doi = {10.1152/ajpendo.1999.277.4.E579}, pmid = {10516115}, issn = {0002-9513}, support = {R01-DK-51360/DK/NIDDK NIH HHS/United States ; }, mesh = {Absorption ; Adolescent ; Adult ; Carrier Proteins/blood ; Female ; Glycoproteins/blood ; Growth Hormone/*deficiency ; Half-Life ; Human Growth Hormone/analysis/*pharmacokinetics ; Humans ; Hypopituitarism/blood/*metabolism ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor Binding Proteins/*blood ; Insulin-Like Growth Factor II/analysis ; Male ; Osmolar Concentration ; Recombinant Proteins/blood/pharmacokinetics ; }, abstract = {We investigated the pharmacokinetics of recombinant human insulin-like growth factor I (rhIGF-I) in growth hormone deficiency (GHD). Nine GHD adults [age 25 +/- 3 (SE) yr] received rhIGF-I (60 microgram/kg sc) twice, 10 h apart, and blood was sampled over 24 h. IGF-I and free IGF-I concentrations increased, whereas IGF binding protein 3 (IGFBP-3) and acid labile subunit (ALS) were unchanged during treatment. There was no correlation between absorption or terminal half-life of IGF-I and IGFBP-3 or ALS, but negative correlations with IGF-I clearance (CL/F) and volume of distribution (V/F). Positive correlations between both IGFBP-3 and ALS and IGF-I maximal concentration (C(max)) and time of C(max) (T(max)) were observed. Compared with normal individuals studied similarly (using 80 microgram/kg), GHD subjects showed a normal absorption half-life, a faster elimination half-life, lower C(max), yet normal T(max) and V/F. In conclusion, GHD is associated with normal absorption and distribution of IGF-I yet faster elimination kinetics. Additionally, IGFBP-3 and ALS concentrations modulate the peak concentrations of IGF-I achieved and correlate reciprocally with its V/F and CL/F, underscoring the critical importance of binding proteins in modulating the bioavailability of IGF-I in vivo in humans.}, }
@article {pmid10506523, year = {1999}, author = {Grassi, C and Martire, M and Altobelli, D and Azzena, GB and Preziosi, P}, title = {Characterization of Ca(2+)-channels responsible for K(+)-evoked [(3)H]noradrenaline release from rat brain cortex synaptosomes and their response to amyotrophic lateral sclerosis IgGs.}, journal = {Experimental neurology}, volume = {159}, number = {2}, pages = {520-527}, doi = {10.1006/exnr.1999.7164}, pmid = {10506523}, issn = {0014-4886}, mesh = {Animals ; Cadmium Chloride/pharmacology ; Calcium Channel Blockers/pharmacology ; Calcium Channels, N-Type/drug effects/*physiology ; Cerebral Cortex/*metabolism ; Humans ; Immunoglobulin G/blood/*pharmacology ; Kinetics ; Male ; Motor Neuron Disease/*immunology ; Nifedipine/pharmacology ; Norepinephrine/*metabolism ; Potassium/*pharmacology ; Rats ; Rats, Wistar ; Synaptosomes/drug effects/*metabolism ; Tritium ; omega-Agatoxin IVA/pharmacology ; omega-Conotoxin GVIA/pharmacology ; }, abstract = {The contribution of the different Ca(2+)-channel subtypes to the K(+)-evoked [(3)H]noradrenaline release from rat cerebral cortex synaptosomes has been investigated. In the same experimental model, it was also verified whether the calcium-mediated neurotransmitter release is influenced by IgGs purified from sera of seven patients affected by sporadic amyotrophic lateral sclerosis. Synaptosome treatment with 3.0 microM nifedipine or 2.0 microM calciseptine, which block L-type channels, slightly decreased [(3)H]noradrenaline release, the reduction being 7 and 13% of the control values, respectively. The blockade of N-type Ca(2+)-channels with omega-conotoxin-GVIA (0.001-1.0 microM) induced a concentration-dependent reduction of the neurotransmitter release, with maximum effect of 34%. omega-Agatoxin-IVA failed to significantly affect the studied release, which was instead markedly reduced by omega-conotoxin-MVIIC. After the blockade of N-type channels with maximal concentrations of omega-conotoxin-GVIA, 3.0 microM omega-conotoxin-MVIIC reduced the release by 58%. Synaptosome treatment with amyotrophic lateral sclerosis IgGs enhanced the K(+)-evoked [(3)H]noradrenaline release, which was mostly mediated by P/Q- and N-type Ca(2+)-channels. The increase induced by pathologic IgGs (0.2 mg/ml) ranged from 11 to 62% for the different patients, and it was concentration-dependent. The basal release was instead unaffected by IgG treatment. The results of the present study suggest that the K(+)-evoked [(3)H]noradrenaline release from brain cortex synaptosomes is mainly mediated by activation of P/Q- and N-type Ca(2+)-channels. Autoantibodies present in the sera of patients affected by sporadic amyotrophic lateral sclerosis may interact with these channels by producing an increased calcium influx, with consequent enhancement of the neurotransmitter release. Preliminary results of the present study have been published in abstract form (Martire et al., 1997, Pharmacol. Res. 35:9).}, }
@article {pmid10431792, year = {1999}, author = {Tran, HM and Patel, A and Allen, RD and O'Connell, PJ}, title = {Intrathymic inoculation of donor antigen: an ineffective strategy for prolonging xenograft survival.}, journal = {Xenotransplantation}, volume = {6}, number = {2}, pages = {147-154}, doi = {10.1034/j.1399-3089.1999.00018.x}, pmid = {10431792}, issn = {0908-665X}, mesh = {Animals ; Antigens, Heterophile/administration &amp; dosage/*immunology ; Diabetes Mellitus, Experimental/*therapy ; Graft Rejection/*immunology/prevention &amp; control ; *Islets of Langerhans Transplantation ; Lymphocyte Depletion ; Male ; Mice ; Mice, Inbred C57BL ; Rats ; Thymus Gland/*immunology ; *Transplantation Immunology ; Transplantation, Heterologous ; Transplantation, Homologous ; }, abstract = {The aim of this study was to determine whether intrathymic inoculation of the recipient with donor antigen and short-term depletion of peripheral lymphocytes would lead to donor-specific unresponsiveness to rat pancreatic islet xenografts. The results were compared directly with an allograft model to determine whether there were substantial differences in the mechanisms of graft prolongation between allografts and xenografts using an identical conditioning regimen. Streptozotocin-induced diabetic C57B6 mice were injected with up to 0.3 ml of rat anti-mouse lymphocyte serum (ALS) 1 day before intrathymic injection of donor splenocytes. DA rat islet xenografts or Balb/c mouse islet allografts were transplanted 3 days later. ALS depleted CD3+ and CD4+ peripheral blood T lymphocytes to less than 5% of values in control mice by 24 h. Median islet xenograft survival (MGS) was 9 days in untreated mice, 28 days in mice receiving 0.2 ml of ALS and 32 days in mice receiving 0.3 ml of ALS alone. Intrathymic injection of 5 x 10(6) DA splenocytes plus 0.2 ml of ALS did not improve islet xenograft survival beyond 28 days. Increasing the intrathymic inoculum to 10(7) DA splenocytes with or without a higher dose of ALS (0.3 ml) did not increase MGS beyond 26 days, although 2 out of 18 animals survived beyond 100 days. These long-term surviving mice rejected a second DA rat islet graft in less than 22 days, indicating that tolerance was not achieved. To confirm the efficacy of this treatment regimen in allotransplantation, diabetic C57B6 mice received 10(7) Balb/c splenocytes intrathymically and 0.3 ml of ALS. A Balb/c islet allograft was performed 3 days later. Allograft survival was similar to that of rat islet xenografts with 40%, (4 out of 10) of grafts surviving beyond 100 days. In contrast to the xenograft recipients, a second Balb/c islet allograft survived indefinitely, indicating that tolerance was achieved. Histology of the long-surviving allografts showed intact islets with a sparse cellular infiltrate, whereas the long-surviving xenografts (> 100 days) showed a large cellular infiltrate and significant islet destruction. To investigate further the role of the thymus, adult thymectomized C57B6 mice were treated with 0.3 ml of ALS and received a DA rat islet xenograft. The median graft survival was 52 days and no graft survived beyond 80 days, suggesting that peripheral xenoreactive T cells remained after ALS treatment and greater T-cell depletion was necessary to obtain permanent engraftment. These results show that peripheral xenoreactive T cells which remain after profound T-cell depletion are capable of rejecting an islet xenograft despite intrathymic inoculation of donor antigen. The T-cell-mediated xenograft response appears to be stronger and more difficult to suppress than the allograft response using this strategy.}, }
@article {pmid10499952, year = {1999}, author = {Nichol, G and Stiell, IG and Laupacis, A and Pham, B and De Maio, VJ and Wells, GA}, title = {A cumulative meta-analysis of the effectiveness of defibrillator-capable emergency medical services for victims of out-of-hospital cardiac arrest.}, journal = {Annals of emergency medicine}, volume = {34}, number = {4 Pt 1}, pages = {517-525}, pmid = {10499952}, issn = {0196-0644}, mesh = {*Electric Countershock ; *Emergency Medical Services ; Heart Arrest/mortality/*therapy ; Humans ; Linear Models ; Survival Analysis ; Time Factors ; Treatment Outcome ; United States/epidemiology ; }, abstract = {STUDY OBJECTIVE: More than 1,000 patients experience sudden cardiac arrest each day. Treatment for this includes cardiopulmonary resuscitation (CPR) and emergency medical services (EMS) that provide CPR-basic life support (BLS), BLS with defibrillation (BLS-D), or advanced life support (ALS). Our previous systematic review of treatments for sudden cardiac arrest was limited by suboptimal data. Since then, debate has increased about whether bystander CPR is effective or whether attention should focus instead on rapid defibrillation. Therefore a cumulative meta-analysis was conducted to determine the relative effectiveness of differences in the defibrillation response time interval, proportion of bystander CPR, and type of EMS system on survival after out-of-hospital cardiac arrest.<br><br>METHODS: A comprehensive literature search was performed by using a priori exclusion criteria. We considered EMS systems that provided BLS-D, ALS, BLS plus ALS, or BLS-D plus ALS care. A generalized linear model was used with dispersion estimation for random effects.<br><br>RESULTS: Thirty-seven eligible articles described 39 EMS systems and included 33,124 patients. Median survival for all rhythm groups to hospital discharge was 6.4% (interquartile range, 3.7 to 10.3). Odds of survival were 1.06 (95% confidence interval [CI], 1.03 to 1.09; P <.01) per 5% increase in bystander CPR. Survival was constant if the defibrillation response time interval was less than 6 minutes, decreased as the interval increased from 6 to 11 minutes, and leveled off after 11 minutes (P <.01). Compared with BLS-D, odds of survival were as follows: ALS, 1. 71 (95% CI, 1.09 to 2.70; P =.01); BLS plus ALS, 1.47 (95% CI, 0.89 to 2.42; P =.07); and BLS with defibrillation plus ALS, 2.31 (95% CI, 1.47 to 3.62; P <.01.)<br><br>CONCLUSION: We confirm that greater survival after sudden cardiac arrest is associated with provision of bystander CPR, early defibrillation, or ALS. More research is required to evaluate the relative benefit of early defibrillation versus early ALS.}, }
@article {pmid10496278, year = {1999}, author = {Chiò, A and Finocchiaro, E and Meineri, P and Bottacchi, E and Schiffer, D}, title = {Safety and factors related to survival after percutaneous endoscopic gastrostomy in ALS. ALS Percutaneous Endoscopic Gastrostomy Study Group.}, journal = {Neurology}, volume = {53}, number = {5}, pages = {1123-1125}, doi = {10.1212/wnl.53.5.1123}, pmid = {10496278}, issn = {0028-3878}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/mortality/*surgery ; Deglutition Disorders/*surgery ; Endoscopy/*adverse effects ; Gastrostomy/*adverse effects ; Humans ; Middle Aged ; Survival Analysis ; }, abstract = {Percutaneous endoscopic gastrostomy (PEG) has been proposed as symptomatic treatment of dysphagia in patients with ALS. Safety and factors related to survival after PEG were analyzed in 50 consecutive ALS patients. No major acute or long-term complications were observed. Stabilization or increase in weight were observed after PEG. Median survival after PEG was 185 days, with a worse outcome in patients with weight loss > or =10% healthy body weight and forced vital capacity <65%. PEG may be a useful option in the symptomatic treatment of dysphagia in ALS.}, }
@article {pmid10486188, year = {1999}, author = {Reinholz, MM and Merkle, CM and Poduslo, JF}, title = {Therapeutic benefits of putrescine-modified catalase in a transgenic mouse model of familial amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {159}, number = {1}, pages = {204-216}, doi = {10.1006/exnr.1999.7142}, pmid = {10486188}, issn = {0014-4886}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/mortality ; Animals ; Antioxidants/pharmacology ; Blood-Brain Barrier ; Buffers ; Catalase/metabolism/*pharmacology ; Disease Models, Animal ; Female ; Free Radicals/metabolism ; Injections, Intraperitoneal ; Injections, Subcutaneous ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/drug effects/enzymology ; Muscle Weakness/drug therapy/genetics ; Nerve Degeneration/drug therapy/genetics ; Phosphates ; Putrescine/analogs &amp; derivatives/*pharmacology ; Spinal Cord/cytology ; Superoxide Dismutase/genetics ; Survival Analysis ; }, abstract = {Dominant mutations in the copper/zinc superoxide dismutase (SOD1) gene have been observed in 15-20% of familial amyotrophic lateral sclerosis (FALS) cases. The mechanism by which SOD1 mutations result in motor neuron degeneration in FALS mice partly involves oxidative damage and an increased peroxidase activity of the mutant SOD1. A new therapeutic approach designed to eliminate the substrate of this peroxidase activity was examined in two lines of transgenic mice expressing the FALS-linked mutation glycine to alanine (G93A). We investigated the ability of putrescine-modified catalase (PUT-CAT), an antioxidant enzyme that removes hydrogen peroxide and has increased permeability at the blood-brain barrier, to modify the time course of the SOD1 mutation-induced motor neuron disease in these FALS mice. Continuous, subcutaneous administration of PUT-CAT significantly delayed the age at which onset of clinical disease occurred (indicated by loss of splay and/or tremors of hindlimbs) in a high-expressor line of FALS transgenic mice. Intraperitoneal injection of PUT-CAT given two times per week also significantly delayed the onset of clinical disease in a low-expressor line of FALS mice. PUT-CAT also significantly delayed the age at which clinical weakness developed (quantified by measuring the shortening of stride length) in both lines of FALS animals. No significant changes were observed in the survival times of the high-expressor FALS mice in any of the treatment groups. However, a trend toward a prolongation of survival was observed in the PUT-CAT-treated low-expressor FALS mice. These results support the role of free radical-mediated damage in the cascade of events leading to motor neurodegeneration in FALS and indicate that PUT-CAT interacts with a critical step in this cascade to delay the onset of clinical disease as well as the development of clinical weakness in FALS transgenic mice.}, }
@article {pmid10485190, year = {1999}, author = {Blanchet, V}, title = {[Palliative care in non-cancerous diseases].}, journal = {La Revue du praticien}, volume = {49}, number = {10}, pages = {1069-1072}, pmid = {10485190}, issn = {0035-2640}, mesh = {Acquired Immunodeficiency Syndrome/*therapy ; Amyotrophic Lateral Sclerosis/*therapy ; Anti-HIV Agents/administration &amp; dosage/therapeutic use ; Drug Therapy, Combination ; Humans ; Hypnotics and Sedatives/administration &amp; dosage ; *Palliative Care ; Quality of Life ; }, abstract = {Palliative treatment is instituted at a particular point in the course of a potentially fatal disease. This palliative phase is often less well-defined than in cancer. Treatment mainly aims at slowing the course of the disease and maintaining the best quality of life possible for the patient. Palliative management of acquired immuno-deficiency syndrome (AIDS) is complicated by the context of the disease, the specific symptoms during the palliative and terminal stages and by the discovery of new antiviral-treatments. The irreversible degeneration in successive steps observed in amyotrophic lateral sclerosis (ALS) requires coordination from the onset among the various actors participating in patient management. In extreme situations, when symptoms are uncontrollable, inducing sleep can be considered.}, }
@article {pmid10478717, year = {1999}, author = {Saborio, DV and Chowdhury, NC and Jin, MX and Chandraker, A and Sayegh, MH and Oluwole, SF}, title = {Regulatory T cells maintain peripheral tolerance to islet allografts induced by intrathymic injection of MHC class I allopeptides.}, journal = {Cell transplantation}, volume = {8}, number = {4}, pages = {375-381}, doi = {10.1177/096368979900800405}, pmid = {10478717}, issn = {0963-6897}, support = {AI 34965/AI/NIAID NIH HHS/United States ; HL 14799/HL/NHLBI NIH HHS/United States ; HL 57229/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Blood Glucose ; Diabetes Mellitus, Experimental/immunology/surgery ; Graft Survival/drug effects/immunology ; Histocompatibility Antigens Class I/*pharmacology ; Immune Tolerance/*drug effects ; Islets of Langerhans Transplantation/*immunology ; Male ; Peptide Fragments/immunology/pharmacology ; Rats ; Rats, Inbred WF ; Spleen/cytology/immunology ; T-Lymphocytes/*immunology ; Thymus Gland/*immunology ; Transplantation, Homologous ; }, abstract = {Although transplantation remains the treatment of choice for diabetes mellitus, immunological rejection of allografts continues to be a major problem. The search for strategies to prevent graft rejection led us to examine if the fate of developing T cells may be influenced by the presence of allo MHC class I peptides in the thymus because T cell receptor-MHC class I/self-peptide interaction regulates thymocyte development. We studied the effects of intrathymic (IT) injection of a short segment of a synthetic immunogenic MHC class I peptide (peptide 2, residues 67-85) of the hypervariable domain of RT1.A derived from WAG rat (RT1U) on islet graft survival in the WF(RT1U)-to-ACI combination. Adult diabetic male recipients were treated with IT injection of a single WAG-derived MHC class I peptide 7 days before intraportal islet transplantation. Long-term unresponsive islet recipients were examined for the development of alloantigen (Ag)-specific regulatory cells. The results showed that while IT injection of 150 microg peptide 2 on day -7 did not prolong graft survival in naive recipients [median survival time (MST) of 14.0 days vs. 9.6 in controls], IT injection of 300 or 600 microg peptide 2 led to normoglycemia and permanent islet survival (> 200 days) in 4/6 and 3/5 STZ-induced diabetic ACI recipients, respectively. IT injection of 150, 300, or 600 microg peptide 2 combined with 0.5 antilymphocyte serum (ALS) immunosuppression on day -7 led to 100% permanent islet allograft survival (> 200 days) compared to MST of 15.0 +/- 2.3 days in ALS alone-treated controls. Similarly prepared animals rejected third-party Brown Norway (BN) islets in an acute fashion, thus demonstrating donor specificity. Intravenous injection of 300 microg peptide 2 combined with 0.5 ml ALS did not prolong islet allograft survival. The long-term unresponsive islet allograft recipients challenged with second set grafts accepted permanently 100% donor-type cardiac allografts while rejecting third-party (BN) hearts without rejecting the primary Wistar Furth (WF) islets. In analyzing the underlying mechanisms of acquired systemic tolerance, we found no suppressor/regulatory cells in adoptive transfer studies in tolerant animals at 30 days after IT injection of allopeptides. In contrast, adoptive transfer of 5 x 10(7) unseparated spleen cells from tolerant animals at 60 and 100 days after islet transplantation into lightly irradiated [200 rad total body irradiation (TBI)] ACI recipients led to donor-specific permanent islet graft survival in 2/3 and 4/5 secondary recipients, respectively, compared to an MST of 13.8 days in lightly irradiated ACI given unmodified syngeneic spleen cells. In addition, adoptive transfer of 2 x 10(7) purified T cells obtained from long-term functioning islet recipients led to permanent donor-specific islet survival in secondary recipients. The finding that IT injection of a short segment of a synthetic immunodominant MHC class I peptide derived from WAG that shares the RT1.A(U) domain with the graft donor is capable of inducing acquired systemic tolerance to WF islets suggests that linked recognition or epitope suppression may be involved in the induction of unresponsiveness. Generation of peripheral Ag-specific regulatory cells that suppress Ag-specific alloreactive T cells is, in part, responsible for the maintenance of tolerance in this model.}, }
@article {pmid10465680, year = {1999}, author = {Parsons, CG and Danysz, W and Quack, G}, title = {Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist--a review of preclinical data.}, journal = {Neuropharmacology}, volume = {38}, number = {6}, pages = {735-767}, doi = {10.1016/s0028-3908(99)00019-2}, pmid = {10465680}, issn = {0028-3908}, mesh = {Animals ; Brain/metabolism ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Excitatory Amino Acid Antagonists/*adverse effects/pharmacokinetics ; Humans ; Learning/drug effects ; Memantine/*adverse effects/pharmacokinetics ; Neuroprotective Agents/adverse effects/pharmacokinetics ; Receptors, N-Methyl-D-Aspartate/*antagonists &amp; inhibitors ; }, abstract = {N-methyl-D-aspartate (NMDA) receptor antagonists have therapeutic potential in numerous CNS disorders ranging from acute neurodegeneration (e.g. stroke and trauma), chronic neurodegeneration (e.g. Parkinson's disease, Alzheimer's disease, Huntington's disease, ALS) to symptomatic treatment (e.g. epilepsy, Parkinson's disease, drug dependence, depression, anxiety and chronic pain). However, many NMDA receptor antagonists also produce highly undesirable side effects at doses within their putative therapeutic range. This has unfortunately led to the conclusion that NMDA receptor antagonism is not a valid therapeutic approach. However, memantine is clearly an uncompetitive NMDA receptor antagonist at therapeutic concentrations achieved in the treatment of dementia and is essentially devoid of such side effects at doses within the therapeutic range. This has been attributed to memantine's moderate potency and associated rapid, strongly voltage-dependent blocking kinetics. The aim of this review is to summarise preclinical data on memantine supporting its mechanism of action and promising profile in animal models of chronic neurodegenerative diseases. The ultimate purpose is to provide evidence that it is indeed possible to develop clinically well tolerated NMDA receptor antagonists, a fact reflected in the recent interest of several pharmaceutical companies in developing compounds with similar properties to memantine.}, }
@article {pmid10463350, year = {1999}, author = {Bouche, P and Le Forestier, N and Maisonobe, T and Fournier, E and Willer, JC}, title = {Electrophysiological diagnosis of motor neuron disease and pure motor neuropathy.}, journal = {Journal of neurology}, volume = {246}, number = {7}, pages = {520-525}, doi = {10.1007/s004150050397}, pmid = {10463350}, issn = {0340-5354}, mesh = {Diagnosis, Differential ; Disease Progression ; Electromyography ; Humans ; Motor Neuron Disease/*diagnosis/physiopathology ; Motor Neurons/*physiology ; Neural Conduction ; Peripheral Nervous System Diseases/diagnosis/physiopathology ; Severity of Illness Index ; }, abstract = {Motor neuron disease (MND) is a group of disorders in which there is degeneration of upper and lower motor neurons to a variable degree. Amyotrophic lateral sclerosis is the most frequent form of the disease, presenting with both upper and lower motor neuron involvement. Frequently, especially in the early stages of the disease, only lower motor neuron signs are present. In these conditions, some pure motor neuropathies may resemble MND. The diagnosis is of importance because some of these motor neuropathies are "dysimmune" disorders and may respond to immune therapies. In such diseases the multifocal motor neuropathy with conduction block appears to be the more frequent. In MND and pure motor neuropathies, the electrophysiological examination is the most decisive test. In MND, it is of diagnostic importance. In addition, it is useful in the assessment of disease severity and progression, in the evaluation of therapeutic trials and in the understanding of etiopathogenesis of the disease. In pure motor neuropathies, the presence of conduction block leads to immune treatment with good response in more than 50% of the cases.}, }
@article {pmid10461542, year = {1999}, author = {Kisby, GE and Kabel, H and Hugon, J and Spencer, P}, title = {Damage and repair of nerve cell DNA in toxic stress.}, journal = {Drug metabolism reviews}, volume = {31}, number = {3}, pages = {589-618}, doi = {10.1081/dmr-100101937}, pmid = {10461542}, issn = {0360-2532}, support = {NS19611/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Carcinogens/toxicity ; Cycadopsida/toxicity ; DNA Damage/*drug effects ; DNA Repair/*drug effects/physiology ; Gene Expression/drug effects ; Humans ; Methylazoxymethanol Acetate/analogs &amp; derivatives/toxicity ; Neurodegenerative Diseases/chemically induced/*genetics ; Stress, Physiological/genetics ; }, abstract = {It is generally agreed that ALS/PDC is triggered by a disappearing environmental factor peculiar to the lifestyle of people of the western Pacific (i.e., Guam, Irian Jaya, Indonesia, and the Kii Peninsula of Japan). A strong candidate is the cycad plant genotoxin cycasin, the beta-D-glucoside of methylazoxymethanol (MAM). We propose that prenatal or postnatal exposure to low levels of cycasin/MAM may damage neuronal DNA, compromise DNA repair, perturb neuronal gene expression, and irreversibly alter cell function to precipitate a slowly evolving disease ("slow-toxin" hypothesis). In support of our hypothesis, we have demonstrated the following: 1. DNA from postmitotic rodent central nervous system neurons is particularly sensitive to damage by MAM. 2. MAM reduces DNA repair in human and rodent neurons, whereas DNA-repair inhibitors potentiate MAM-induced DNA damage and toxicity in mature rodent nervous tissue. 3. Human neurons (SY5Y neuroblastoma) that are deficient in DNA repair are susceptible to MAM-induced cytotoxicity and DNA damage, whereas overexpression of DNA repair in similar cells is protective. 4. MAM alters gene expression in SY5Y human neuroblastoma cells and, in the presence of DNA damage and reduced DNA repair, enhances glutamate-modulated expression of tau mRNA in rat primary neurons; the corresponding protein (TAU) is elevated in ALS/PDC and Alzheimer's disease. These findings support a direct relationship between MAM-induced DNA damage and neurotoxicity and suggest the genotoxin may operate in a similar manner in vivo. More broadly, a combination of genotoxin-induced DNA damage (via exogenous and/or endogenous agents) and disturbed DNA repair may be important contributing factors in the slow and progressive degeneration of neurons that is characteristic of sporadic neurodegenerative disease. Preliminary studies demonstrate that DNA repair is reduced in the brain of subjects with western Pacific ALS/PDC, ALS, and Alzheimer's disease, which would increase the susceptibility of brain tissue to DNA damage by endogenous/exogenous genotoxins. Interindividual differences in the extent of prior exposure to DNA-damaging agents and/or the efficiency of its repair might produce population variety in the rate of damage accumulation and explain the susceptibility of certain individuals to sporadic neurodegenerative disease. Studies are underway using DNA-repair proficient and deficient neuronal cell cultures and mutant mice to explore gene-environment interplay with respect to MAM treatment, DNA damage, and DNA repair, and the age-related appearance of neurobehavioral and neuropathological compromise.}, }
@article {pmid10461424, year = {1999}, author = {Han, JY and Seo, EJ and Kwon, HJ and Min, KO and Kim, JS and Kang, JH and Hong, YS and Kim, HK and Lee, KS}, title = {Nasal angiocentric lymphoma with hemophagocytic syndrome.}, journal = {The Korean journal of internal medicine}, volume = {14}, number = {2}, pages = {41-46}, pmid = {10461424}, issn = {1226-3303}, mesh = {Adult ; Epstein-Barr Virus Infections/complications ; Female ; Histiocytosis, Non-Langerhans-Cell/*complications/pathology ; Humans ; Lymphoma/*complications/pathology ; Male ; Middle Aged ; Nose Neoplasms/*complications/pathology ; Syndrome ; }, abstract = {OBJECTIVES: Hemophagocytic syndrome (HS) is a fatal complication of nasal angiocentric lymphoma (AL) and difficult to distinguish from malignant histiocyosis. Epstein-Barr virus (EBV)-associated HS is frequently observed in lymphoma of T-cell lineage and EBV is highly associated with nasal AL. Clinicopathologic features of 10 nasal ALs with HS were reviewed to determine the clinical significance and the pathogenetic association with EBV.<br><br>METHODS: Ten patients of HS were identified from a retrospective analysis of 42 nasal ALs diagnosed from 1987 to 1996. Immunohistochemical study and in situ hybridization were performed on the paraffin-embedded tumor specimens obtained from 10 patients. Serologic study of EBV-Ab was performed in 3 available patients.<br><br>RESULTS: Five patients had HS as initial manifestation, 3 at the time of relapse and 2 during the clinical remission of AL. Four patients were treated by combination chemotherapy (CHOP) and others had only supportive care. The median survival of all patients with HS was 4.1 months (range 2 days-36.5 months) and all had fatal outcome regardless of the treatment-modality. All cases were positive for UCHL1 (CD45RO) and EBV by EBER in situ hybridization. The data of serologic tests indicated the active EBV infection.<br><br>CONCLUSIONS: HS is a fatal complication of nasal AL and has a high association with EBV. Reactivation of EBV may contribute to HS and further investigation of predictive factors and effective treatment of HS should be pursued in the future.}, }
@article {pmid10457404, year = {1999}, author = {Anguita, E and Villegas, A and Serra, A and González, FA and Ropero, P and Contra, T and Saglio, G}, title = {Cleavage of the ALL1 gene in acute lymphoid leukemia before treatment disappears in relapse.}, journal = {Haematologica}, volume = {84}, number = {8}, pages = {695-698}, pmid = {10457404}, issn = {0390-6078}, mesh = {Acute Disease ; Adult ; Antineoplastic Agents/therapeutic use ; Child ; Child, Preschool ; DNA-Binding Proteins/*genetics ; *Gene Rearrangement ; Histone-Lysine N-Methyltransferase ; Humans ; Leukemia, Lymphoid/drug therapy/*genetics/pathology ; Myeloid-Lymphoid Leukemia Protein ; Neoplastic Stem Cells ; *Proto-Oncogenes ; Recurrence ; *Transcription Factors ; }, abstract = {BACKGROUND AND OBJECTIVE: ALL1 gene rearrangements are frequently found in secondary acute leukemias (ALs). A site-specific cleavage of the ALL1 gene in a consensus sequence for topoisomerase II recognition has been considered to be the initial step leading to ALL1 rearrangement and subsequent therapy-related AL. The aim of the present study was to evaluate this cleavage in our patients, to analyze whether it is a laboratory-produced artefact and to check whether it persists or causes a real ALL1 gene rearrangement at relapse.<br><br>DESIGN AND METHODS: We studied ALL1 rearrangement in 74 cases of AL before treatment by Southern blot avoiding room temperature exposure or delay in processing the samples which could produce ALL1 cleavage. DNA was available for two cases with ALL1 cleavage; it was analyzed by three different Southern blots in one and two in the other. One case with ALL1 cleavage was also studied in relapse.<br><br>RESULTS: The presence of the cleavage of the ALL1 DNA was found in 3 of 74 (4%) patients. Two of these three patients had the ALL1 cleavage in three and two different analyses. One case was positive for ALL1 cleavage at diagnosis, but negative for both ALL1 cleavage and ALL1 rearrangement at relapse.<br><br>The fact that a constant pattern was obtained from the same patients in different DNA preparations, supports the notion that ALL1 cleavage is not a laboratory artefact. The absence of the cleavage in a sample from a relapsed patient suggests that the subclone with the ALL1 cleavage, in this case, did not play a clear role in the pathogenesis of disease recurrence.}, }
@article {pmid10455537, year = {1999}, author = {Finsterer, J and Mamoli, B}, title = {Liquorpheresis (CSF filtration) in familial amyotrophic lateral sclerosis.}, journal = {Spinal cord}, volume = {37}, number = {8}, pages = {592-593}, doi = {10.1038/sj.sc.3100857}, pmid = {10455537}, issn = {1362-4393}, mesh = {Amyotrophic Lateral Sclerosis/cerebrospinal fluid/*therapy ; Catheterization ; Cerebrospinal Fluid/*physiology ; Electromyography ; Female ; *Filtration ; Humans ; Injections, Spinal ; Middle Aged ; }, abstract = {OBJECTIVES: Liquorpheresis (CSF filtration) has been shown to be of benefit in various neurologic disorders, including sporadic ALS. Liquorpheresis in patients with familial ALS, has not been investigated so far.<br><br>METHODS: A 52-year-old woman with familial ALS is reported who underwent liquorpheresis during 4 consecutive days. During this period, 875 ml CSF were filtered off via an intrathecal catheter and a combined mechanical and ionic filter by means of a bi-directional syringe pump.<br><br>RESULTS: Immediately after treatment and 2 weeks later there was subjective, but no objective, improvement of her symptoms, assessed by the Norris score and measurements of the elbow extension, vital capacity, F-waves of both ulnar nerves and automatic EMG of the right brachial biceps and anterior tibial muscles.<br><br>CONCLUSION: Liquorpheresis does not seem to be helpful in the treatment of familial ALS.}, }
@article {pmid10454724, year = {1999}, author = {Beck, M and Giess, R and Würffel, W and Magnus, T and Ochs, G and Toyka, KV}, title = {Comparison of maximal voluntary isometric contraction and Drachman's hand-held dynamometry in evaluating patients with amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {22}, number = {9}, pages = {1265-1270}, doi = {10.1002/(sici)1097-4598(199909)22:9&lt;1265::aid-mus15&gt;3.0.co;2-f}, pmid = {10454724}, issn = {0148-639X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*physiopathology ; Feasibility Studies ; Female ; Hand Strength/physiology ; Humans ; Isometric Contraction/*physiology ; Male ; Middle Aged ; }, abstract = {Maximal voluntary isometric contraction (MVIC) is a standard tool for assessment of muscle strength in treatment trials for amyotrophic lateral sclerosis (ALS). There is need for more practical bedside techniques especially for severely disabled patients. Hand-held dynamometry (HH-Dyn) is an inexpensive and easy-to-handle device. MVIC was measured in five proximal muscle groups bilaterally and compared with HH-Dyn in 43 ALS patients. After a training period we found good intrarater correlation for HH-Dyn (r = 0.99), with a low coefficient of variation. Measurements tended to become more accurate after repeated testing due to practice effects in examiners and patients. Overall correlation between HH-Dyn and MVIC was good [r = 0.85 (P < 0.01)]. Strength-range-specific analysis showed a significant linear correlation up to 20 kg (44 lbs.) [r = 0.57 (P < 0.01)]. However, we found a tendency to underestimate muscle strength above 10 kg by HH-Dyn as compared with MVIC, but this became meaningful only above a force of 20 kg. HH-Dyn provides a strength estimate with a precision close to MVIC in weak muscle groups (MRC grade 4). With standardization and appropriate training, HH-Dyn is a useful bedside test, providing an alternative to MVIC for follow-up assessment in ALS.}, }
@article {pmid10453774, year = {1999}, author = {Francis, K and Bach, JR and DeLisa, JA}, title = {Evaluation and rehabilitation of patients with adult motor neuron disease.}, journal = {Archives of physical medicine and rehabilitation}, volume = {80}, number = {8}, pages = {951-963}, doi = {10.1016/s0003-9993(99)90089-8}, pmid = {10453774}, issn = {0003-9993}, mesh = {Activities of Daily Living ; Adult ; Amyotrophic Lateral Sclerosis/classification/diagnosis/epidemiology/etiology/psychology/rehabilitation ; Communication ; Death ; Female ; Humans ; Male ; Motor Neuron Disease/classification/*diagnosis/epidemiology/etiology/psychology/*rehabilitation ; Psychology, Social ; }, abstract = {Adult motor neuron disease (amyotrophic lateral sclerosis [ALS]) is a neurodegenerative disorder characterized by loss of motor neurons in the cortex, brain stem, and spinal cord, manifested by upper and lower motor neuron signs and symptoms affecting bulbar, limb, and respiratory musculature. Clinically, the disease course is characterized by progressive weakness, atrophy, spasticity, dysarthria, dysphagia, and respiratory compromise, ultimately resulting in death or mechanical ventilation in the vast majority of patients. Patterns of presentation and pathological features of the disease, along with clinical and electrophysiologic criteria for diagnosis, are discussed in this review. Since 8% to 22% of patients survive more than 10 years without ventilator use, meticulous medical and rehabilitation management is extremely important to ensure optimal health and quality of life in these patients. Major issues in the care of individuals with ALS include weakness and spasticity, impairments in activities of daily living and mobility, communication deficits and dysphagia in those with bulbar involvement, respiratory compromise, fatigue and sleep disorders, pain, and psychosocial distress. Research in ALS changes rapidly, but is currently focused on potential etiologic factors such as glutamate excitotoxicity, role of oxidative stress, autoimmunity to calcium channels, and cytoskeletal abnormalities, as well as related treatment initiatives including glutamate modulators, neurotrophic factors, antioxidants, antiapoptotic factors, and gene therapy. Recently, mutations in the gene encoding Cu/Zn superoxide dismutase were identified in a subset of familial ALS patients. Riluzole, a glutamate antagonist and Na-channel blocker, became the only drug currently approved for treatment of ALS after studies showed a small positive effect on survival. Until a definitive treatment or cure for ALS is found, the multifaceted rehabilitation team approach remains the best hope for improving health and survival in this devastating illness.}, }
@article {pmid10448978, year = {1999}, author = {Kalra, S and Arnold, DL and Cashman, NR}, title = {Biological markers in the diagnosis and treatment of ALS.}, journal = {Journal of the neurological sciences}, volume = {165 Suppl 1}, number = {}, pages = {S27-32}, doi = {10.1016/s0022-510x(99)00023-4}, pmid = {10448978}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology/*therapy ; Aspartic Acid/analogs &amp; derivatives/analysis ; Biomarkers/*analysis ; Brain/metabolism ; Creatine/analysis ; Disease Progression ; Electromyography ; Humans ; Magnetic Resonance Imaging ; Monitoring, Physiologic ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Tomography, Emission-Computed ; }, abstract = {The care of patients with amyotrophic lateral sclerosis (ALS), which has classically focused on treatment of symptomatology, has now entered an encouraging new era of therapy targeted at the pathophysiology of the disease. However, an objective measure of disease progression and therapeutic response is sorely needed. Quantitative neuromuscular examinations, measurement of pulmonary function, disability scales, and even survival, are limited by variability due to a number of poorly controlled factors. Quantitative electromyography, positron emission tomography scanning, and magnetic cortical stimulation, provide potential objective indicators of disease progression, but require a large number of patients and a long observation period for adequate statistical power. We have examined the role of magnetic resonance spectroscopic imaging in detecting acute changes in motor cortical metabolism in response to riluzole therapy. N-acetylaspartate (NAA), the most prominent signal in proton spectra of normal brain, is a neuron-specific molecule. ALS patients were found to experience a significant increase in the NAA/creatine ratio within 3 weeks of initiation of riluzole therapy. As glutamate can trigger the generation of reactive oxygen species in neurons, we speculate that acute changes in NAA levels may reflect oxidative injury to mitochondria where NAA is synthesised. The advent of a useful test for upper motor neuron metabolic compromise may provide an objective, non-invasive, short duration measure with which to screen the efficacy of potential therapeutic agents for ALS.}, }
@article {pmid10448976, year = {1999}, author = {Ludolph, AC and Knirsch, U}, title = {Problems and pitfalls in the diagnosis of ALS.}, journal = {Journal of the neurological sciences}, volume = {165 Suppl 1}, number = {}, pages = {S14-20}, doi = {10.1016/s0022-510x(99)00021-0}, pmid = {10448976}, issn = {0022-510X}, mesh = {Adult ; Age of Onset ; Amyotrophic Lateral Sclerosis/*diagnosis/pathology/physiopathology ; Clinical Laboratory Techniques ; Diagnosis, Differential ; Diagnostic Errors ; Humans ; Inclusion Bodies/pathology ; Male ; Middle Aged ; Neurodegenerative Diseases/diagnosis ; Neurologic Examination ; Spine/pathology ; }, abstract = {Although misdiagnosis of amyotrophic lateral sclerosis (ALS) is rare, it may be more difficult to make a diagnosis in some groups of patients than in others. If a patient presents in the later stages of the disease, only a small number of alternative diagnoses need to be considered. These include spinal muscular atrophies of adult onset, inclusion body myositis and motor neuropathies with conduction block. The latter group in particular may present a serious diagnostic problem, as several groups have recently reported patients suffering from lower motor neuron syndrome without detectable conduction block, who responded unexpectedly to treatment with immunoglobulins. As recent laboratory results suggest that a lengthy pre-clinical period may precede clinical ALS, there is increased pressure for clinicians to make an early diagnosis so that the maximum effect can be achieved from neuroprotective drugs. Thus, diseases such as distal motor amyotrophies, pressure palsies of motor branches of hand nerves, and cervical myelopathies, which can be differentiated mainly by their time-course, may be relevant in the differential diagnosis of ALS in some patients. During recent years, a few patients have been seen in our clinic who presented with pure motor deficits but later developed a more complex pattern of vulnerability suggestive of multisystem degeneration. The existence of patients with a disease that borders the spectrum of motor neuron diseases cannot be disputed. These patients include those carrying the Huntington mutation and those suffering from Guam and New Guinea disease ('ALS/PD'). From our experience, however, these 'difficult' diagnoses represent less than 10% of the patients seen in our clinic.}, }
@article {pmid10448050, year = {1999}, author = {Waggoner, DJ and Bartnikas, TB and Gitlin, JD}, title = {The role of copper in neurodegenerative disease.}, journal = {Neurobiology of disease}, volume = {6}, number = {4}, pages = {221-230}, doi = {10.1006/nbdi.1999.0250}, pmid = {10448050}, issn = {0969-9961}, support = {DK44464/DK/NIDDK NIH HHS/United States ; HL41536/HL/NHLBI NIH HHS/United States ; }, mesh = {Adenosine Triphosphatases/metabolism/physiology ; Alzheimer Disease/enzymology/metabolism/pathology ; Amino Acid Sequence ; Amyloid beta-Peptides/metabolism/physiology ; Amyotrophic Lateral Sclerosis/enzymology/metabolism/pathology ; Animals ; Carrier Proteins/metabolism/physiology ; *Cation Transport Proteins ; Ceruloplasmin/deficiency/metabolism/physiology ; Copper/*metabolism/*physiology ; Copper-Transporting ATPases ; Hepatolenticular Degeneration/enzymology/metabolism/pathology ; Humans ; Menkes Kinky Hair Syndrome/enzymology/metabolism/pathology ; Mice ; Molecular Sequence Data ; Neurodegenerative Diseases/enzymology/*metabolism/pathology ; Prion Diseases/metabolism/pathology ; Prions/metabolism/physiology ; *Recombinant Fusion Proteins ; Sequence Homology, Amino Acid ; }, abstract = {Copper is an essential trace metal which plays a fundamental role in the biochemistry of the human nervous system. Menkes disease and Wilson disease are inherited disorders of copper metabolism and the dramatic neurodegenerative phenotypes of these two diseases underscore the essential nature of copper in nervous system development as well as the toxicity of this metal when neuronal copper homeostasis is perturbed. Ceruloplasmin contains 95% of the copper found in human plasma and inherited loss of this essential ferroxidase is associated with progressive neurodegeneration of the retina and basal ganglia. Gain-of-function mutations in the cytosolic copper enzyme superoxide dismutase result in the motor neuron degeneration of amyotrophic lateral sclerosis and current evidence suggests a direct pathogenic role for copper in this process. Recent studies have also implicated copper in the pathogenesis of neuronal injury in Alzheimer's disease and the prion-mediated encephalopathies, suggesting that further elucidation of the mechanisms of copper trafficking and metabolism within the nervous system will be of direct relevance to our understanding of the pathophysiology and treatment of neurodegenerative disease.}, }
@article {pmid10443086, year = {1999}, author = {Chotmongkol, V}, title = {Amyotrophic lateral sclerosis syndrome and hyperthyroidism: report of 4 patients.}, journal = {Journal of the Medical Association of Thailand = Chotmaihet thangphaet}, volume = {82}, number = {6}, pages = {615-618}, pmid = {10443086}, issn = {0125-2208}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*complications/drug therapy ; Antithyroid Agents/therapeutic use ; Female ; Humans ; Hyperthyroidism/*complications/drug therapy ; Male ; Methimazole/therapeutic use ; Middle Aged ; Treatment Outcome ; }, abstract = {Four patients with clinical diagnosis of amyotrophic lateral sclerosis syndrome and laboratory results of hyperthyroidism were reported. There were 3 women aged 27, 59, 59 years and 1 man aged 50 years. All of them had symptoms and signs of dysarthria and dysphagia, fasciculations of the tongue, muscle weakness with generalized hyperreflexia. After treatment with antithyroid drugs, motor weakness and dysphagia improved.}, }
@article {pmid10442573, year = {1999}, author = {Simpson, H and Camcho-Hübner, C and Sönksen, P and Russell-Jones, D}, title = {Clinical experience in identical twins discordant for adult-onset growth hormone deficiency.}, journal = {Journal of endocrinological investigation}, volume = {22}, number = {5 Suppl}, pages = {61-63}, pmid = {10442573}, issn = {0391-4097}, mesh = {Adult ; Age of Onset ; Case-Control Studies ; Dose-Response Relationship, Drug ; Female ; Human Growth Hormone/*deficiency ; Humans ; Middle Aged ; Syndrome ; *Twins, Monozygotic ; }, abstract = {The syndrome of adult-onset growth hormone (GH) deficiency is well established. However uncertainties exist regarding monitoring of the therapeutic response. Currently the Growth Hormone Research Society consensus statement recommends monitoring GH replacement by taking a history, with attention to questions relating to quality of life, physical examination, body composition (by a suitable method) and measurement of insulin-like growth factor (IGF)-I. With the advent of commercially available assays for IGF binding protein (IGFBP)-3 and acid-labile subunit (ALS) it was hoped that it might prove possible to develop a more sensitive protocol for monitoring GH replacement therapy. We are in the unique position of having three patients with GH deficiency who are one of a pair of monozygotic twins, in which the second twin is healthy. We studied the effect of recombinant GH (rhGH) therapy (0.0375 U/kg) in the GH-deficient twin, and compared pre- and post-rhGH variables with similar observations in the healthy twin. Body composition, IGF-I, IGFBP-3 and ALS levels were measured before and after 3 months of rhGH therapy. Body composition changed as expected most impressively in twin 1; twins 1 and 2 had low IGF-I, IGFBP-3 and ALS prior to treatment with GH, but normal concentrations that were similar to those of their healthy twin were attained after 3 months of GH treatment. Twin 3 had normal IGF-I, IGFBP-3 and ALS concentrations before GH treatment, which were similar to those of her twin. Interestingly she also had a high fasting insulin level. After GH replacement these concentrations increased but remained within the normal range, similar to those of her healthy twin. Insulin and GH have both been shown to stimulate hepatic production of IGF-I and these results suggest that insulin may also be involved in the regulation of IGFBP-3 and ALS in vivo. Insulin has already been implicated in the regulation of IGFBP-3 and ALS in vitro and there is some evidence to suggest that this is also the case in vivo. We conclude that clinical state, body composition and IGF-I assessed together remain the best methods of monitoring GH replacement therapy and that measurements of IGFBP-3 and ALS do not confer any advantage over IGF-I.}, }
@article {pmid10430415, year = {1999}, author = {Carver, AC and Vickrey, BG and Bernat, JL and Keran, C and Ringel, SP and Foley, KM}, title = {End-of-life care: a survey of US neurologists' attitudes, behavior, and knowledge.}, journal = {Neurology}, volume = {53}, number = {2}, pages = {284-293}, doi = {10.1212/wnl.53.2.284}, pmid = {10430415}, issn = {0028-3878}, mesh = {Adult ; *Attitude of Health Personnel ; Data Collection ; Ethics, Medical ; Female ; *Health Knowledge, Attitudes, Practice ; Humans ; Male ; Middle Aged ; *Neurology ; Palliative Care ; Suicide, Assisted ; *Terminal Care ; United States ; }, abstract = {OBJECTIVE: The American Academy of Neurology (AAN) surveyed the attitudes, behavior, and knowledge of its members regarding care at the end of life. Three groups of AAN members were surveyed: neuro-oncologists, ALS specialists, and a representative sample of US neurologists.<br><br>METHODS: The survey presented two clinical scenarios involving end-of-life care. Neurologists were asked a series of questions to assess their knowledge of existing medical, ethical, and legal guidelines; their willingness to participate in physician-assisted suicide (PAS) or carry out voluntary euthanasia (VE); and their general attitudes regarding end-of-life care.<br><br>RESULTS: Neurologists support a patient's right to refuse life-sustaining treatment, but many believe that they are killing their patients in supporting such refusals. Thirty-seven percent think it is illegal to administer analgesics in doses that risk respiratory depression to the point of death. Forty percent believe they should obtain legal counsel when considering stopping life-sustaining treatment. One half believe that PAS should be made explicitly legal by statute for terminally ill patients. Under current law, 13% would participate in PAS and 4% would carry out VE; if those procedures were legalized, 44% would participate in PAS and 28% in VE. Approximately one third believe that physicians have the same ethical duty to honor a terminally ill patient's request for PAS as they do to honor a such a patient's refusal of life-sustaining therapy.<br><br>CONCLUSIONS: There is a gap between established medical, legal, and ethical guidelines for the care of dying patients and the beliefs and practices of many neurologists, suggesting a need for graduate and postgraduate education programs in the principles and practices of palliative care medicine. Many neurologists would participate in PAS and carry out VE if legalized.}, }
@article {pmid10430414, year = {1999}, author = {Albert, SM and Murphy, PL and Del Bene, ML and Rowland, LP}, title = {A prospective study of preferences and actual treatment choices in ALS.}, journal = {Neurology}, volume = {53}, number = {2}, pages = {278-283}, doi = {10.1212/wnl.53.2.278}, pmid = {10430414}, issn = {0028-3878}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*psychology/surgery ; *Choice Behavior ; Female ; Humans ; Male ; Middle Aged ; *Patient Participation ; Predictive Value of Tests ; Prospective Studies ; Tracheostomy/psychology ; }, abstract = {OBJECTIVE: To determine whether ALS patients' preferences for ameliorative or life-extending technologies elicited early in the disease were related to later treatment choices.<br><br>METHODS: In this prospective cohort study, 121 patients were seen at a tertiary ALS care center and followed for a median of 12 months. At baseline, patient preferences for use of tracheostomy and percutaneous endoscopic gastrostomy (PEG) placement were elicited. All patients received the same educational information before being interviewed about treatment preferences. Patients were then followed to determine if patients who viewed the interventions favorably at baseline were significantly more likely to use the interventions over follow-up.<br><br>RESULTS: Six to twelve percent of patients were certain they wanted tracheostomy and 28.2% wanted PEG. Preferences were related to later treatment choices: 20% of patients who found tracheostomy acceptable had one in the follow-up period, compared with 3.4% of those not in favor (p < 0.001). For PEG, similar findings were obtained: 48.5% who initially found it acceptable had PEG, versus 8.1% of those not in favor of this treatment (p < 0.001). Patients who found the interventions acceptable were more likely to be recently diagnosed, expressed greater attachment to life, and showed greater declines in pulmonary function over follow-up.<br><br>CONCLUSIONS: Patients with ALS were able to express their preferences for life-extending or ameliorative technologies and made choices consistent with these preferences. However, patient preferences may change over time, and clinical education efforts are required throughout the course of disease.}, }
@article {pmid10430408, year = {1999}, author = {Mitsumoto, H}, title = {Patient choices in ALS: life-sustaining treatment versus palliative care?.}, journal = {Neurology}, volume = {53}, number = {2}, pages = {248-249}, doi = {10.1212/wnl.53.2.248}, pmid = {10430408}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; *Choice Behavior ; Humans ; *Life Support Care ; *Palliative Care ; }, }
@article {pmid10416039, year = {1999}, author = {Beal, MF}, title = {Coenzyme Q10 administration and its potential for treatment of neurodegenerative diseases.}, journal = {BioFactors (Oxford, England)}, volume = {9}, number = {2-4}, pages = {261-266}, doi = {10.1002/biof.5520090222}, pmid = {10416039}, issn = {0951-6433}, support = {NS16367/NS/NINDS NIH HHS/United States ; NS31579/NS/NINDS NIH HHS/United States ; P01 AG12992/AG/NIA NIH HHS/United States ; }, mesh = {Administration, Oral ; Animals ; Antioxidants/*therapeutic use ; Coenzymes ; Humans ; Huntington Disease/blood/drug therapy ; Lactates/blood ; Mice ; Mice, Transgenic ; Neurodegenerative Diseases/*drug therapy ; Parkinson Disease/blood/drug therapy ; Ubiquinone/administration &amp; dosage/*analogs &amp; derivatives/blood/therapeutic use ; }, abstract = {Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport chain as well as an important antioxidant. Previous studies have suggested that it may exert therapeutic effects in patients with known mitochondrial disorders. We investigated whether it can exert neuroprotective effects in a variety of animal models. We have demonstrated that CoQ10 can protect against striatal lesions produced by both malonate and 3-nitropropionic acid. It also protects against MPTP toxicity in mice. It extended survival in a transgenic mouse model of amyotrophic lateral sclerosis. We demonstrated that oral administration can increase plasma levels in patients with Parkinson's disease. Oral administration of CoQ10 significantly decreased elevated lactate levels in patients with Huntington's disease. These studies therefore raise the prospect that administration of CoQ10 may be useful for the treatment of neurodegenerative diseases.}, }
@article {pmid10414596, year = {1999}, author = {Yu, H and Mistry, J and Nicar, MJ and Khosravi, MJ and Diamandis, A and van Doorn, J and Juul, A}, title = {Insulin-like growth factors (IGF-I, free IGF-I and IGF-II) and insulin-like growth factor binding proteins (IGFBP-2, IGFBP-3, IGFBP-6, and ALS) in blood circulation.}, journal = {Journal of clinical laboratory analysis}, volume = {13}, number = {4}, pages = {166-172}, pmid = {10414596}, issn = {0887-8013}, mesh = {Adult ; *Blood Circulation ; Blood Proteins/metabolism ; Carrier Proteins/blood ; Female ; Glycoproteins/blood ; Humans ; Immunoassay ; Insulin-Like Growth Factor Binding Protein 2/blood ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor Binding Protein 6/blood ; Insulin-Like Growth Factor I/analysis/metabolism ; Insulin-Like Growth Factor II/analysis ; Male ; Middle Aged ; Protein Binding ; Receptors, Somatomedin/*blood ; Reference Values ; Somatomedins/*analysis ; }, abstract = {Insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) play an important role in cell growth and differentiation. Clinical and epidemiological studies have indicated that measuring IGFs and IGFBPs in blood has potential implications in assessing growth-related abnormalities and risks of certain types of cancer. To facilitate the application, we reported a large collection of reference ranges of IGFs and IGFBPs in normal population and evaluations of these molecules in serum and plasma as well as the impact of freeze-thaw cycles on the measurement. IGF-I, IGFBP-3 andALS showed a similar pattern of change associated with age. Levels of these molecules were low at birth and increased with age through puberty. After puberty the levels declined slowly with age. Overall, IGF-I, IGFBP-3 and ALS were slightly higher in females than in males. Free IGF-I accounted for about 1% of the total IGF-I and its variation with age was similar to total IGF-I. IGF-II levels were also increased with age from birth to puberty, but became stable after puberty. There was little difference in IGF-II levels between genders. IGFBP-2 levels declined with age from birth to puberty. Levels of IGFBP-6 in contrast were increased with age. These IGF binding proteins were higher in males than in females. IGFs, IGFBP-3 and ALS were 5-10% higher in serum than in plasma. IGFBP-2 and IGFBP-6 differed substantially between serum and plasma. Freeze-thaw treatment up to five cycles had little impact on plasma levels of IGFs and IGFBP-3. Our observations suggest that levels of IGFs and their binding proteins are varied with age, gender, and types of specimen and that these variations need to be taken into consideration when IGFs and their binding proteins are utilized in clinic and research.}, }
@article {pmid10413388, year = {1999}, author = {Damiano, AM and Patrick, DL and Guzman, GI and Gawel, MJ and Gelinas, DF and Natter, HM and Ingalls, KK}, title = {Measurement of health-related quality of life in patients with amyotrophic lateral sclerosis in clinical trials of new therapies.}, journal = {Medical care}, volume = {37}, number = {1}, pages = {15-26}, doi = {10.1097/00005650-199901000-00004}, pmid = {10413388}, issn = {0025-7079}, mesh = {Activities of Daily Living ; Amyotrophic Lateral Sclerosis/physiopathology/*psychology/therapy ; Analysis of Variance ; Clinical Trials as Topic/*psychology ; Cost of Illness ; Discriminant Analysis ; Disease Progression ; Feasibility Studies ; Female ; Humans ; Insulin-Like Growth Factor I/therapeutic use ; Male ; Middle Aged ; Psychometrics ; *Quality of Life ; Reproducibility of Results ; *Sickness Impact Profile ; }, abstract = {OBJECTIVES: Recent trials of amyotrophic lateral sclerosis (ALS) therapies have included the Sickness Impact Profile (SIP) to evaluate health-related quality of life (HQL). The purpose of this study was to assess the feasibility, psychometric properties, and interpretation of the Sickness Impact Profile in this setting.<br><br>METHODS: The Sickness Impact Profile was administered at baseline, 3, 6, and 9 months during a double-blind, placebo-controlled study of recombinant human insulin-like growth factor I. The frequency of missing Sickness Impact Profile data and administration time were recorded. Patients' scores on the Appel ALS (AALS) Rating Scale were used to identify a stable subgroup for reliability testing and clinically distinct groups for validity testing. Internal consistency reliability and reproducibility were evaluated using Cronbach's alpha and intraclass correlation coefficients, respectively. Analysis of variance (ANOVA) models and t tests were used to assess validity. Effect sizes and the responsiveness index were used to assess responsiveness.<br><br>RESULTS: At baseline, 259 (97%) patients completed a 30-minute Sickness Impact Profile interview. At subsequent assessments, response rates ranged from 92% to 97% and mean administration times ranged from 25 to 27 minutes. The overall Sickness Impact Profile score demonstrated alpha reliability and 3-month stability coefficients of 0.94 and 0.80, respectively. Baseline overall Sickness Impact Profile scores discriminated between patients in the two AALS-defined groups with a mean of 13.0+/-7.8 and 24.0+/-11.7 in the better and worse AALS groups, respectively. Similarly, mean overall SIP change scores discriminated patients progressing at different rates (slow to moderate = 4.00+/-7.97; rapid = 10.74+/-8.76). With few exceptions, dimension and category scores met similar criteria. Responsiveness statistics for the physical and overall Sickness Impact Profile scores were lower at 3 months and higher at 6 and 9 months.<br><br>CONCLUSIONS: The feasibility, psychometric, and interpretive findings support the validity of the Sickness Impact Profile for assessing outcomes of amyotrophic lateral sclerosis and its treatment. Based on these findings, we recommend including the Sickness Impact Profile in future amyotrophic lateral sclerosis clinical trials.}, }
@article {pmid10409881, year = {1999}, author = {Mattle, HP}, title = {[New drugs in neurology].}, journal = {Praxis}, volume = {88}, number = {18}, pages = {827-834}, pmid = {10409881}, issn = {1661-8157}, mesh = {Adult ; Aged ; Central Nervous System Agents/adverse effects/*therapeutic use ; Central Nervous System Diseases/*drug therapy/etiology ; Female ; Humans ; Male ; Treatment Outcome ; }, abstract = {This article reviews new drugs and recent knowledge or indications for old drugs for the treatment of neurological disorders. Drugs for disorders such as migraine, epilepsy, Parkinson's disease, Alzheimer's disease, ischemic stroke, amyotrophic lateral sclerosis and multiple sclerosis are considered.}, }
@article {pmid10389300, year = {1999}, author = {Anderlik, P and Antmann, K and Bános, Z}, title = {[Effect of immunosuppressive agents and antilymphocyte serum on bacterial translocation in mice].}, journal = {Acta pharmaceutica Hungarica}, volume = {69}, number = {2}, pages = {69-71}, pmid = {10389300}, issn = {0001-6659}, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; Bacterial Translocation/*drug effects ; Chlorpromazine/pharmacology ; Dianhydrogalactitol/pharmacology ; Immunosuppressive Agents/*pharmacology ; Mice ; }, abstract = {Following intraperitoneally applied treatment with 0.5 ml of ana partes diluted antilymphocyte serum (ALS) of immunosuppressive effect no bacterial translocation (BT) was observed in mice. The ALS treatment applied in combination with other immunosuppressive agents such as lymphotropic cytostatics as dianhydrogalactitol (30 mg/kg) or chlorpromazine (75 mg/kg) did not increase the mice drug sensitivity to used agents. According to our results, ALS can be suitable for combined application with other immunosuppressive agents as it can increase immunosuppression without side-effects such as those induced by bacterial translocation.}, }
@article {pmid10376049, year = {1999}, author = {Avila, PC and Shusterman, DJ}, title = {Work-related asthma and latex allergy. Sorting out the types, causes, and consequences.}, journal = {Postgraduate medicine}, volume = {105}, number = {7}, pages = {39-46}, doi = {10.3810/pgm.1999.06.621}, pmid = {10376049}, issn = {0032-5481}, mesh = {Adult ; Asthma/diagnosis/epidemiology/*etiology/immunology ; Humans ; Latex Hypersensitivity/*complications ; Occupational Diseases/diagnosis/epidemiology/*etiology/immunology ; Risk Factors ; United States/epidemiology ; }, abstract = {Work-related asthma now has clear definitions based on criteria agreed upon by the American College of Chest Physicians. The clinician should suspect occupational asthma, irritant-induced asthma, or work-aggravated asthma in adults with new-onset asthma or asthma symptoms that worsen during work, after work (late allergic response), or over the course of workdays. The possible cause should be sought, and a skin test or immunoassay should be performed, if possible,to he;lp detect sensation. Workup als o includes objective documentation of worsening of symptoms and airway obstruction during occupational exposure. If this information is inconclusive, an inhalation challenge may be considered. Medical management is the same as for nonoccupational asthma, but cessation of exposure to the specific agent is necessary to improve long-term diagnosis. Latex allergy and latex-induced asthma are becoming more common in the workplace, particularly in the healthcare field. No commercially available standard serum or skin test are available for diagnosis. The principal treatment is avoidance of latex, which can be achieved in most cases without extensive changes to the workplace.}, }
@article {pmid10372706, year = {1999}, author = {Fukuda, I and Hotta, M and Hizuka, N and Takano, K and Ishikawa, Y and Asakawa-Yasumoto, K and Tagami, E and Demura, H}, title = {Decreased serum levels of acid-labile subunit in patients with anorexia nervosa.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {84}, number = {6}, pages = {2034-2036}, doi = {10.1210/jcem.84.6.5737}, pmid = {10372706}, issn = {0021-972X}, mesh = {Adult ; Anorexia Nervosa/*blood ; Biomarkers/blood ; Body Mass Index ; Carrier Proteins/*blood ; Female ; Glycoproteins/*blood ; Humans ; Insulin-Like Growth Factor Binding Protein 2/blood ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/metabolism ; Insulin-Like Growth Factor II/metabolism ; Somatomedins/*metabolism ; }, abstract = {One of the observations in malnutrition is that serum insulin-like growth factor (IGF)-I levels are decreased, and this decrease is associated with an altered profile of IGF binding proteins (IGFBPs). In human circulation, IGFs are mostly present as an approximately 150-kDa ternary protein complex consisting of IGFs, IGFBP-3, and acid-labile subunit (ALS). In the present study, to clarify the effect of nutrition on serum ALS levels, we investigated 33 patients with anorexia nervosa. Serum levels of ALS were measured by RIA. Furthermore, we measured serum IGF-I, IGF-II, IGFBP-2, and IGFBP-3 levels in the patients. From these data, we investigated which was the best predictor of body mass index (BMI) as a nutritional status marker. In the patients with anorexia nervosa, the serum ALS levels ranged from 0.7-16.9, with a mean of 10.6 +/- 0.7 mg/L, and the levels were significantly lower than those of normal subjects (13.8 +/- 0.8 mg/L, P < 0.05). Serum ALS levels positively correlated with BMI (r = 0.41, P < 0.05), and the levels increased during treatment. The serum IGFBP-2 levels in the patients were increased (871 +/- 91 microg/L), and the levels inversely correlated with BMI (r = -0.52, P < 0.01). The serum IGF-I and IGFBP-3 levels were low (152 +/- 14 microg/L and 2.56 +/- 0.12 mg/L, respectively), and the levels positively correlated with BMI (r = 0.46, P < 0.01; and r = 0.39, P < 0.05, respectively). The serum IGFBP-2, IGF-I, and IGFBP-3 levels returned toward normal ranges as BMI in the patients improved during treatment. Serum IGF-II levels did not correlate with BMI (r = 0.24, P = 0.17). Stepwise regression analysis revealed that serum IGFBP-2 was the best marker of BMI among these variables. The present study suggested that ALS was regulated by nutritional status, the same as IGF-I, IGFBP-2 and IGFBP-3; but the serum IGFBP-2 was the best predictor of BMI as nutritional status marker among the parameters in patients with anorexia nervosa.}, }
@article {pmid10370799, year = {1998}, author = {Fiedor, PS and Jin, MX and Zikria, BA and Garnuszek, P and Licińska, I and Mazurek, AP and Maroszyńska, I and Piaseczna-Piotrowska, A and Szymańska, K and Rowiński, WA and Hardy, MA and Oluwole, SF}, title = {Monitoring of rat islet allografts with dithizone after induction of donor specific transplant tolerance by intrathymic administration of soluble alloantigens.}, journal = {Annals of transplantation}, volume = {3}, number = {4}, pages = {21-30}, pmid = {10370799}, issn = {1425-9524}, mesh = {Animals ; *Dithizone ; Graft Survival ; *Indicators and Reagents ; Islets of Langerhans Transplantation/*immunology ; Isoantigens/*administration &amp; dosage/therapeutic use ; Rats ; Rats, Inbred Lew ; Rats, Inbred WF ; Thymus Gland ; *Transplantation Immunology ; }, abstract = {Transplantation of whole pancreas or pancreatic islets remains a promising approach to treatment of diabetes mellitus. Since there is no efficient method presently known for in vivo detection of pancreatic islet rejection, we have utilized dithizone [DTZ] to monitor the survival of transplanted islet allografts following the induction of tolerance by a new strategy of deliberate introduction of donor antigens into the adult thymus. In this study, we examined the morphology of islet allografts in vivo and in vitro following pretreatment with intrathymic (IT) inoculation of 2 mg soluble Ag obtained from 3M KCl extracts of resting T-cells with or without ALS immunosuppression in the WF-to-Lewis combination. Fresh isolated rat islets stained pink 3-5 minutes following exposure to medium containing 0.12 mM DTZ solution in DMSO. Intravenous (i.v.) injection of DTZ solution into unmodified recipients of islet allografts that had rejected their grafts showed massive degranulation of islets which did not stain pink with DTZ. This was confirmed by microscopic finding of fibrosis and lymphocytic infiltration. In contrast, i.v. injection of DTZ solution into long-term recipients of islet allografts at 50, 100, and 150 days after transplantation showed viable islet cells which stained crimson red with DTZ and the findings were confirmed with microscopic sections. This study demonstrates that DTZ is an effective means of in vivo and in vitro identification of transplanted pancreatic islets and suggests that this strategy may have potential clinical application in the diagnosis of the pancreatic islet rejection.}, }
@article {pmid10351191, year = {1999}, author = {Ackerman, SJ and Sullivan, EM and Beusterien, KM and Natter, HM and Gelinas, DF and Patrick, DL}, title = {Cost effectiveness of recombinant human insulin-like growth factor I therapy in patients with ALS.}, journal = {PharmacoEconomics}, volume = {15}, number = {2}, pages = {179-195}, pmid = {10351191}, issn = {1170-7690}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/*economics ; Cost-Benefit Analysis ; Female ; Humans ; Insulin-Like Growth Factor I/*economics/*therapeutic use ; Male ; Middle Aged ; Quality of Life ; Recombinant Proteins/*economics/*therapeutic use ; Sensitivity and Specificity ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative neuromuscular disease characterised by a progressive loss of voluntary motor activity. Recombinant human insulin-like growth factor I (rhIGF-I) has been shown to be useful in treating ALS. The purpose of this study was to examine the cost effectiveness of rhIGF-I therapy in patients who have ALS.<br><br>DESIGN: We performed a cost-effectiveness analysis from the societal perspective on 177 patients who received treatment with rhIGF-I or placebo in a North American randomised clinical trial. We estimated the incremental cost-effectiveness ratio of rhIGF-I using resource utilisation and functional status measurements from the clinical trial. Costs were estimated from 1996 US Medicare reimbursement schedules. Utility weights were elicited from ALS healthcare providers using the standard gamble technique.<br><br>The overall cost per quality-adjusted life-year (QALY) gained for rhIGF-I therapy compared with placebo was $US67,440. For the subgroups of patients who were progressing rapidly or were in earlier stages of disease at enrolment, rhIGF-I cost $US52,823 and $US43,197 per QALY gained, respectively.<br><br>CONCLUSIONS: Treatment with rhIGF-I is most cost effective in ALS patients who are either in earlier stages of the disease or progressing rapidly. The cost effectiveness of rhIGF-I therapy compares favourably with treatments for other chronic progressive diseases.}, }
@article {pmid10343179, year = {1999}, author = {Lutz-Bucher, B and González de Aguilar, JL and René, F and Sée, V and Gordon, JW and Loeffler, J}, title = {Oxidative stress and a murine superoxide dismutase-1 mutation promoting amyotrophic lateral sclerosis alter neurosecretion in the hypothalamo-neurohypophyseal axis.}, journal = {Neuroendocrinology}, volume = {69}, number = {5}, pages = {377-384}, doi = {10.1159/000054440}, pmid = {10343179}, issn = {0028-3835}, support = {AG10520/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*genetics ; Animals ; Blotting, Western ; Cyclic AMP/metabolism ; Cyclic GMP/biosynthesis ; Female ; Hydrogen Peroxide/pharmacology ; Hypothalamo-Hypophyseal System/drug effects/*metabolism ; Hypothalamus/drug effects/metabolism ; Lipid Peroxidation/drug effects/genetics ; Mice ; Mice, Transgenic ; Mutation/*physiology ; Neuropeptides/pharmacology ; Neurosecretory Systems/drug effects/*metabolism ; Nitric Oxide Synthase/biosynthesis ; Nitric Oxide Synthase Type I ; Oxidants/pharmacology ; Oxidative Stress/*physiology ; Pituitary Adenylate Cyclase-Activating Polypeptide ; Pituitary Gland/drug effects/metabolism ; Superoxide Dismutase/*genetics/pharmacology ; }, abstract = {In this study, we examined the effects of oxidative stress on a nitric oxide (NO)-regulated neuroendocrine function, the release of arginine vasopressin (AVP) by the hypothalamo-neurohypophyseal axis. Treatment of mouse-isolated hypothalami and neurointermediate lobes (NIL) with H2O2 increased AVP release. This effect was inhibited by copper-zinc superoxide dismutase-1 (SOD1) analogs. By measuring cGMP accumulation as an indicator of biologically active NO, we found that H2O2 treatment decreased cGMP formation in both hypothalami and NIL. We have previously shown that NO inhibits AVP release by a cGMP-independent mechanism. Given that H2O2 stimulated AVP release, while it reduced cGMP production, our findings strongly suggest that oxidative damage affects neurosecretion by reducing NO availability. To test whether such a mechanism may operate under pathological conditions with pronounced oxidative stress, we compared neurosecretion in wild-type and transgenic mice carrying a mutated form of SOD1 associated with human familial amyotrophic lateral sclerosis. Reminiscent of the data obtained from H2O2-treated tissues, hypothalami and NIL from SOD1 mutants displayed decreased cGMP accumulation and increased AVP release, compared with tissues from wild-type littermates. Since neuronal NO synthase expression was not modified, we conclude that the perturbed free radical metabolism associated with the SOD1 mutation is likely to trap NO, and thereby alter neurosecretion, a mechanism that can be exacerbated in specific physiopathological conditions.}, }
@article {pmid10335495, year = {1999}, author = {Ludolph, AC and Meyer, T and Riepe, MW}, title = {Antiglutamate therapy of ALS--which is the next step?.}, journal = {Journal of neural transmission. Supplementum}, volume = {55}, number = {}, pages = {79-95}, doi = {10.1007/978-3-7091-6369-6_8}, pmid = {10335495}, issn = {0303-6995}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Antioxidants/therapeutic use ; Apoptosis/drug effects ; Forecasting ; Humans ; Mice ; Mice, Transgenic ; Motor Neuron Disease/drug therapy ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Superoxide Dismutase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which was thought to be untreatable for a long time. However, recent evidence in men indicates that antiglutamatergic strategies are the first to have an influence on its pathogenesis and slow down the disease process. Since the effect of the drugs is still small, this progress cannot only be seen as a success of the present but most also be acknowledged as a starting point for the future. How will these future studies look like? They will have to take into account that ALS presumably has a long preclinical period and they will use a number of novel compounds and treatment strategies which have recently been shown to be effective in a transgenic animal model. This also implies that we are likely to use combination therapies and have to try to treat patients early. The latter will be necessarily connected with the demand for a novel clinical attitude to the diagnosis of the disease.}, }
@article {pmid10335362, year = {1999}, author = {Tanridag, T and Coskun, T and Hürdag, C and Arbak, S and Aktan, S and Yegen, B}, title = {Motor neuron degeneration due to aluminium deposition in the spinal cord: a light microscopical study.}, journal = {Acta histochemica}, volume = {101}, number = {2}, pages = {193-201}, doi = {10.1016/S0065-1281(99)80018-X}, pmid = {10335362}, issn = {0065-1281}, mesh = {Aluminum/metabolism/*toxicity ; Animals ; Dose-Response Relationship, Drug ; Electrophysiology ; Female ; Male ; *Microscopy ; Motor Neuron Disease/*chemically induced ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/*drug effects ; }, abstract = {For a long time, aluminium has been considered as an indifferent element from a toxicological point of view. In recent years, it became clear that aluminium is a potential toxic agent in humans and has been implicated in the pathogenesis of several clinical disorders, such as dementia, respiratory tract disorders and allergic reactions. Chronic exposure to aluminium fumes, inhalation of aluminium and aluminium-oxide powder increase the risk to develop serious central nervous system pathology, in particular Alzheimer's disease and amyotrophic lateral sclerosis (ALS). In the present study, 3 experimental and 1 control group of rats were used to study the effects of aluminium on the central nervous system. Aluminium was injected intracisternally as a single dose (50 micrograms for group I, 100 micrograms for group II and 300 micrograms for group III) to the experimental groups (n = 5 in each group). The same dose was given at 3 months after the first injection to all groups. The control group (n = 5) was intracisternally given a physiological salt solution. Electromyography (EMG) was applied to the rats of the experimental groups. Rats were decapitated at 3 months after the second injections. Spinal cord samples from lumbar and cervical regions were removed and histological examination was performed. Light microscopical investigations revealed severe degeneration in motor neurons of the rats treated with 300 micrograms. Neurofibrillary tangle formation, chromatolysis and abnormal localization of the nuclei were found in swollen perikarya. Extreme loss of motor neurons with "ghost cell" appearance was found in that group. Sections of spinal cords of rats treated with lower doses of aluminium showed a moderate degree of motor neuron damage. EMGs of rats treated with the high dose of aluminium revealed severe acute denervation whereas treatment with lower doses resulted in moderate denervation. We conclude that aluminium may cause severe motor neuron damage in rat spinal cord resembling ALS.}, }
@article {pmid10334661, year = {1999}, author = {Doble, A}, title = {The role of excitotoxicity in neurodegenerative disease: implications for therapy.}, journal = {Pharmacology &amp; therapeutics}, volume = {81}, number = {3}, pages = {163-221}, doi = {10.1016/s0163-7258(98)00042-4}, pmid = {10334661}, issn = {0163-7258}, mesh = {AIDS Dementia Complex/etiology ; Amyotrophic Lateral Sclerosis/etiology ; Calcium/*metabolism ; Excitatory Amino Acids/*physiology ; Glutamic Acid/metabolism/*toxicity ; Humans ; N-Methylaspartate/physiology ; Neurodegenerative Diseases/drug therapy/*etiology/physiopathology ; Neurotransmitter Agents/*antagonists &amp; inhibitors ; }, abstract = {Glutamic acid is the principal excitatory neurotransmitter in the mammalian central nervous system. Glutamic acid binds to a variety of excitatory amino acid receptors, which are ligand-gated ion channels. It is activation of these receptors that leads to depolarisation and neuronal excitation. In normal synaptic functioning, activation of excitatory amino acid receptors is transitory. However, if, for any reason, receptor activation becomes excessive or prolonged, the target neurones become damaged and eventually die. This process of neuronal death is called excitotoxicity and appears to involve sustained elevations of intracellular calcium levels. Impairment of neuronal energy metabolism may sensitise neurones to excitotoxic cell death. The principle of excitotoxicity has been well-established experimentally, both in in vitro systems and in vivo, following administration of excitatory amino acids into the nervous system. A role for excitotoxicity in the aetiology or progression of several human neurodegenerative diseases has been proposed, which has stimulated much research recently. This has led to the hope that compounds that interfere with glutamatergic neurotransmission may be of clinical benefit in treating such diseases. However, except in the case of a few very rare conditions, direct evidence for a pathogenic role for excitotoxicity in neurological disease is missing. Much attention has been directed at obtaining evidence for a role for excitotoxicity in the neurological sequelae of stroke, and there now seems to be little doubt that such a process is indeed a determining factor in the extent of the lesions observed. Several clinical trials have evaluated the potential of antiglutamate drugs to improve outcome following acute ischaemic stroke, but to date, the results of these have been disappointing. In amyotrophic lateral sclerosis, neurolathyrism, and human immunodeficiency virus dementia complex, several lines of circumstantial evidence suggest that excitotoxicity may contribute to the pathogenic process. An antiglutamate drug, riluzole, recently has been shown to provide some therapeutic benefit in the treatment of amyotrophic lateral sclerosis. Parkinson's disease and Huntington's disease are examples of neurodegenerative diseases where mitochondrial dysfunction may sensitise specific populations of neurones to excitotoxicity from synaptic glutamic acid. The first clinical trials aimed at providing neuroprotection with antiglutamate drugs are currently in progress for these two diseases.}, }
@article {pmid10329446, year = {1999}, author = {Trieu, VN and Uckun, FM}, title = {Genistein is neuroprotective in murine models of familial amyotrophic lateral sclerosis and stroke.}, journal = {Biochemical and biophysical research communications}, volume = {258}, number = {3}, pages = {685-688}, doi = {10.1006/bbrc.1999.0577}, pmid = {10329446}, issn = {0006-291X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics ; Animals ; Cerebrovascular Disorders/*drug therapy/genetics ; Disease Models, Animal ; Female ; Genistein/*therapeutic use ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS), whether sporadic or familial (FALS), is a progressive, fatal neurodegenerative disorder involving the motor neurons of the cortex, brain stem, and spinal cord. In some studies, the male/female ratio of ALS patients was as high as 2 to 1. In FALS mice, disease onset and mortality were earlier among males than among females. This sexual dimorphism was due to estrogen, as treatment with genistein, a phytoestrogen, eliminated the observed sexual dimorphism in FALS mice. Genistein treatment also protected against oxygen singlet-induced cerebral damage in vivo. However, sexual dimorphism was not observed in this model of stroke; and genistein was equally effective in males and females. These data suggest that genistein has both estrogen-dependent and estrogen-independent neuroprotective activities and it should be investigated as a prophylactic agent against pathologic conditions such as ALS and stroke.}, }
@article {pmid10327155, year = {1999}, author = {Nagano, S and Ogawa, Y and Yanagihara, T and Sakoda, S}, title = {Benefit of a combined treatment with trientine and ascorbate in familial amyotrophic lateral sclerosis model mice.}, journal = {Neuroscience letters}, volume = {265}, number = {3}, pages = {159-162}, doi = {10.1016/s0304-3940(99)00227-x}, pmid = {10327155}, issn = {0304-3940}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/mortality ; Animals ; Ascorbic Acid/*pharmacology ; Chelating Agents/*pharmacology ; Copper/metabolism ; Disease Models, Animal ; Gene Expression Regulation, Enzymologic ; Humans ; Mice ; Mice, Transgenic ; Superoxide Dismutase/genetics/metabolism ; Survival Analysis ; Trientine/*pharmacology ; }, abstract = {We previously reported that the common toxic gain-of-function in various mutant copper-zinc superoxide dismutases (SOD1) seen in patients with familial amyotrophic lateral sclerosis (ALS) was an abnormal copper release from the enzyme protein. In this study, trientine and ascorbate, known to have a beneficial effect in an animal model of Wilson disease, were administered to transgenic mice overexpressing a mutated human SOD1 (G93A). The onset of neurological signs in the treated group was significantly delayed compared with that in the control group, and the time to reach total paralysis in the treated group was delayed as well. Since the agents used in this study cause low toxicity in animals and humans, this treatment may be a good candidate for clinical application.}, }
@article {pmid10323388, year = {1999}, author = {Camacho-Hübner, C and Woods, KA and Miraki-Moud, F and Hindmarsh, PC and Clark, AJ and Hansson, Y and Johnston, A and Baxter, RC and Savage, MO}, title = {Effects of recombinant human insulin-like growth factor I (IGF-I) therapy on the growth hormone-IGF system of a patient with a partial IGF-I gene deletion.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {84}, number = {5}, pages = {1611-1616}, doi = {10.1210/jcem.84.5.5649}, pmid = {10323388}, issn = {0021-972X}, mesh = {Adolescent ; Antibodies/analysis ; Fluoroimmunoassay ; *Gene Deletion ; Half-Life ; Human Growth Hormone/*physiology ; Humans ; Immunoassay ; Insulin/blood ; Insulin-Like Growth Factor Binding Proteins/metabolism ; Insulin-Like Growth Factor I/genetics/immunology/pharmacokinetics/*therapeutic use ; Insulin-Like Growth Factor II/metabolism ; Kinetics ; Male ; Recombinant Proteins/pharmacokinetics/therapeutic use ; Somatomedins/*metabolism ; }, abstract = {We have previously reported a 17.2-yr-old boy with severe growth retardation and undetectable serum levels of insulin-like growth factor I (IGF-I) due to a partial deletion of the IGF-I gene. The aim of this study was to investigate the effects of recombinant human IGF-I (rhIGF-I) therapy on the GH-IGF system of this patient to gain further insights into its growth-promoting and metabolic actions. To assess the changes in GH, IGFs, IGF-binding proteins (IGFBPs), acid-labile subunit (ALS), and insulin levels, blood samples were obtained before therapy and during the first year of treatment. Hormones were analyzed by specific RIAs. Overnight GH profiles were performed before and at 1, 6, and 12 months of therapy. Fasting ALS, IGF-II, IGFBP-3, IGFBP-2, IGFBP-1, and insulin levels before rhIGF-I treatment were 46.3 mg/L, 1044 microg/L, 5.8 mg/L, 73 ng/mL, 4.7 ng/mL, and 27.3 mU/L, respectively. IGF-II, ALS, and insulin levels were elevated, whereas IGFBP-1 and IGFBP-2 levels were decreased compared to reference values. Twenty-four hours after a single s.c. injection of rhIGF-I (40 microg/kg), the concentrations were 46 mg/L, 888 microg/L, 6.9 mg/L, 112 ng/mL, 5.0 ng/mL, and 21.0 mU/L, respectively. After a single s.c. injection of rhIGF-I of 40 or 80 microg/kg x day and modelling the data using a two-compartment model, the half-lives of elimination were 15.7 and 14.3 h, with a maximum increase in IGF-I levels to 341 and 794 microg/L around 7 h, respectively. An increase in IGFBP-3 levels was observed with both doses of rhIGF-I, with a peak values of 9 mg/L. GH profiles showed a decrease in peak amplitude from 342 to 84 mU/L at 1 month, to 67 mU/L at 6 months, and to 40 mU/L at 1 yr of therapy, with no significant changes in peak number. A significant increase in IGFBP-1 levels was observed during treatment with 80 microg/kg x day IGF-I, reflecting the inhibitory effect of rhIGF-I on insulin secretion. The clinical response to rhIGF-I therapy was an increased height velocity from 3.8 cm/yr before treatment to 6.6 cm/yr. Increased lean body mass correlated with changes in the doses of rhIGF-I and, in turn, with the biochemical changes in the GH-IGF axis. Similar to healthy individuals, this patient had normal IGFBP-3 and ALS levels, which are the major regulators of the pharmacokinetics of rhIGF-I. In summary, rhIGF-I treatment has improved linear growth and insulin sensitivity in this patient by restoring IGF-I levels and by normalizing circulating GH, IGFBP, and insulin levels.}, }
@article {pmid10227631, year = {1999}, author = {Ganzini, L and Johnston, WS and Hoffman, WF}, title = {Correlates of suffering in amyotrophic lateral sclerosis.}, journal = {Neurology}, volume = {52}, number = {7}, pages = {1434-1440}, doi = {10.1212/wnl.52.7.1434}, pmid = {10227631}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/psychology ; Depressive Disorder/physiopathology ; Female ; Humans ; Male ; Middle Aged ; Pain/physiopathology ; *Quality of Life ; Surveys and Questionnaires ; }, abstract = {OBJECTIVES: 1) To determine the prevalence of pain, suffering, poor quality of life, depression, and hopelessness in people with ALS, and the correlates of suffering and poor quality of life; 2) to analyze the relationship between pain, suffering, quality of life, and attitudes toward life-sustaining medical treatment and physician-assisted suicide; and 3) to determine concordance between patients with ALS and their caregivers in rating the patients' pain, quality of life, and suffering.<br><br>METHODS: Subjects completed a single interview. We measured the subject's pain, quality of life, suffering, hopelessness, depression, social support, perception of burden to others, level of disability, desire for life-sustaining medical treatment, and interest in assisted suicide. Caregivers also rated the patient's quality of life, pain, and suffering.<br><br>RESULTS: A total of 100 subjects with ALS and 91 caregivers participated. Suffering was rated as 4 or greater on a six-point scale by 20% of subjects with ALS, and 19% rated their pain as 4 or greater on a six-point scale. Eleven percent had clinical depression. Physicians frequently failed to recognize and treat pain and depression. The correlates of suffering were increasing pain, hopelessness, and level of disability. The correlates of poor quality of life were poor social support and increasing hopelessness. The correlation between subjects' and caregivers' rating of the patient's suffering was r = 0.47. There was no relationship between subjects' ratings of pain, suffering, and quality of life, and their interest in life-sustaining treatment or physician-assisted suicide.<br><br>CONCLUSION: Many patients with ALS suffer, and their suffering is correlated to pain and hopelessness. Physicians caring for patients with ALS frequently fail to recognize and treat their patients' pain and depression.}, }
@article {pmid10227630, year = {1999}, author = {}, title = {A controlled trial of recombinant methionyl human BDNF in ALS: The BDNF Study Group (Phase III).}, journal = {Neurology}, volume = {52}, number = {7}, pages = {1427-1433}, doi = {10.1212/wnl.52.7.1427}, pmid = {10227630}, issn = {0028-3878}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Brain-Derived Neurotrophic Factor/*therapeutic use ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Recombinant Proteins/therapeutic use ; Survival Analysis ; }, abstract = {OBJECTIVE: To replicate the beneficial effect of brain-derived neurotrophic factor (BDNF) in 1,135 ALS patients in a multicenter trial.<br><br>BACKGROUND: In a phase I through II study, BDNF appeared to increase survival and retard loss of pulmonary function in ALS patients.<br><br>METHODS: Patients were randomized to placebo, or 25 or 100 microg/kg BDNF for 9 months.<br><br>RESULTS: The study failed to show benefit of BDNF treatment for the primary end points. Survival in patients treated with 25 microg/kg BDNF was identical to placebo, but there was a trend toward increased survival in the 100-microg/kg group. As a whole, survival was better than anticipated when planning the study. The 9-month probability of survival was approximately 85% across all groups. This diminished the power of the study. Among the 60% of patients with baseline forced vital capacity of < or = 91%, survival was significantly greater for 100 microg/kg BDNF versus placebo. For the 20% of patients treated with 100 microg/kg BDNF reporting altered bowel function as an adverse effect of BDNF in the first 2 weeks of dosing, defined as BDNF "responders," 9-month survival was significantly better than for placebo (97.5% versus 85%).<br><br>CONCLUSIONS: Although the primary end point analysis failed to demonstrate a statistically significant survival effect of BDNF in ALS, post hoc analyses showed that those ALS patients with early respiratory impairment and those developing altered bowel function showed statistically significant benefit. Further clinical trials of BDNF using either intrathecal delivery or high-dose subcutaneous administration are in progress.}, }
@article {pmid10226799, year = {1999}, author = {Bereket, A and Lang, CH and Wilson, TA}, title = {Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus.}, journal = {Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme}, volume = {31}, number = {2-3}, pages = {172-181}, doi = {10.1055/s-2007-978716}, pmid = {10226799}, issn = {0018-5043}, mesh = {Diabetes Mellitus, Type 1/*metabolism ; Human Growth Hormone/*metabolism ; Humans ; Insulin-Like Growth Factor Binding Proteins/metabolism ; Insulin-Like Growth Factor I/*metabolism ; Insulin-Like Growth Factor II/metabolism ; }, abstract = {The growth hormone (GH)-insulin-like growth factor (IGF) axis and insulin are major anabolic effectors in promoting weight gain and linear growth. These two anabolic systems are interlinked at many levels, thus abnormalities in one of these systems effect the other causing disordered metabolic homeostasis. Insufficient portal insulinization in insulin dependent diabetes mellitus (IDDM) results in hepatic GH resistance and increased production of IGF-binding proteins-1 (IGFBP-1) and IGFBP-2. GH resistance is reflected by decreased hepatic IGF-I production. In addition, changes in other GH-dependent proteins are also observed in IDDM. Increased proteolysis of IGFBP-3 results in reduction of intact IGFBP-3. Serum ALS levels are also slightly diminished in untreated diabetic patients. Hepatic resistance to GH is, at least in part, caused by diminished GH receptors as reflected by diminished circulating GHBP levels. In addition, there is also evidence from experimental and human studies suggesting post-receptor defect(s) in GH action. As a result of these changes, circulating total and free IGF-I levels are decreased during insulinopenia. Lack of negative feed-back effect of IGF-I on GH secretion causes GH hypersecretion which increases hyperglycemia by decreasing sensitivity to insulin. GH hypersecretion in poorly controlled diabetic patients may play a role in the pathogenesis of diabetic vascular complications. Most of these abnormalities in the GH-IGF axis in diabetes are reversed by effective insulinization of the patient. Addition of IGF-I treatment to insulin in adolescents with IDDM allows correction of GH hypersecretion, improves insulin sensitivity and glycemic control, and decreases insulin requirements. The effect of IGF-I treatment on diabetic complications has yet to be seen.}, }
@article {pmid10223093, year = {1999}, author = {Mackin, GA}, title = {Optimizing care of patients with ALS. Steps to early detection and improved quality of life.}, journal = {Postgraduate medicine}, volume = {105}, number = {4}, pages = {143-6, 151-6}, doi = {10.3810/pgm.1999.04.676}, pmid = {10223093}, issn = {0032-5481}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/psychology/*therapy ; Diagnosis, Differential ; Humans ; Neuroprotective Agents/therapeutic use ; Patient Care Team ; Quality of Life ; Riluzole/therapeutic use ; }, abstract = {Primary care physicians should be alert for early, purely motor neurologic signs and symptoms of ALS, a progressive and ultimately fatal motor neuron disease. Because many neuromuscular disorders mimic ALS, careful differential diagnosis is essential. All patients with signs of motor neuron dysfunction need prompt referral to a neurologist at a regional ALS care center to ensure that they receive an accurate diagnosis and disease-specific multidisciplinary care. Once the diagnosis is confirmed, primary care physicians should work closely with the ALS center to ensure continuity of care and provide emotional support for both patient and family. Patients may also benefit from enrollment in treatment trials and the ALS CARE database. Riluzole, the only medication approved for treatment of ALS, has been shown to slow disease progression and prolong survival. Such benefits have provided new hope to patients and have spurred investigators to search for other, more effective medications for use alone or in combination.}, }
@article {pmid10220104, year = {1999}, author = {Eisen, A and Weber, M}, title = {Treatment of amyotrophic lateral sclerosis.}, journal = {Drugs &amp; aging}, volume = {14}, number = {3}, pages = {173-196}, pmid = {10220104}, issn = {1170-229X}, mesh = {Amyotrophic Lateral Sclerosis/complications/*drug therapy ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Antioxidants/*therapeutic use ; Calcium Channel Blockers/therapeutic use ; Clinical Trials as Topic ; Excitatory Amino Acid Agents/*therapeutic use ; Forecasting ; Genetic Therapy ; Growth Substances/therapeutic use ; Humans ; Immunotherapy ; Nerve Growth Factors/therapeutic use ; Randomized Controlled Trials as Topic ; }, abstract = {Survival of patients with amyotrophic lateral sclerosis (ALS) is improving. Timely and more frequent implementation of bimodal passive airway pressure (BIPAP) and percutaneous endoscopically placed gastrostomy (PEG) may be the major factors impacting on longer survival. However, several drugs recently subjected to rigorous clinical trials have demonstrated significant results or encouraging trends. ALS is a complex disease in which aging neurons are subjected to a variety of susceptibility genes, most of which remain to be discovered, that interact with equally unrecognised environmental factors. This makes it unlikely that a single therapeutic agent will be of value. The thrust must be on polypharmacy. The 'cocktail' that will eventually be of greatest benefit has yet to be formulated. It might contain glutamate N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists, antioxidants or a combination of trophic factors and neuroprotective agents. This statement is made with the understanding that the aetiopathogenesis of ALS is far from clear. Drug delivery is a problem and better delivery systems are needed. The efficacy of some of the medications that presently only induce modest benefit may be improved by liposomal packaging, use of a patch or inhalation delivery or intraventricular pump reservoirs. There is a great need to develop an early marker of ALS and sensitive reproducible measures of disease progression. This will curtail the present need for large, lengthy and very expensive clinical trials. The new millennium will see the advent of targeted therapy using viral vectors which can deliver replacement genes, trophic factors and other drugs to degenerating neurons; transplantation of neural progenitor cells which can become mature functioning neurons; anti-apoptotic agents which will allow neurons to survive longer; and mechanisms that can protect the telomerase maintenance system which is so crucial in the immortalisation of cells.}, }
@article {pmid10208213, year = {1999}, author = {Rumbak, MJ and Walsh, FW and Anderson, WM and Rolfe, MW and Solomon, DA}, title = {Significant tracheal obstruction causing failure to wean in patients requiring prolonged mechanical ventilation: a forgotten complication of long-term mechanical ventilation.}, journal = {Chest}, volume = {115}, number = {4}, pages = {1092-1095}, doi = {10.1378/chest.115.4.1092}, pmid = {10208213}, issn = {0012-3692}, mesh = {Adult ; Aged ; Aged, 80 and over ; Bronchoscopy ; Female ; Humans ; Intubation, Intratracheal/*adverse effects/instrumentation ; Male ; Middle Aged ; Respiration, Artificial/*adverse effects ; Retrospective Studies ; Time Factors ; Tracheal Stenosis/diagnosis/*etiology/therapy ; *Ventilator Weaning ; }, abstract = {INTRODUCTION: Modern low-pressure, high-volume cuffed tracheotomy tubes have been shown to decrease tracheal injury. However, injury still occurs in patients requiring prolonged mechanical ventilation and prevents weaning, delays decannulation, prolongs hospitalization, and may totally obstruct the airway. We describe 37 patients, including the first reported case of failure to wean due to tracheal obstruction.<br><br>METHODS: Over a 3-year period, from September 1994 to August 1997, the hospital records of 37 patients requiring prolonged mechanical ventilation (> 4 weeks) and found to have tracheal obstruction were reviewed retrospectively. They were a subgroup of 756 patients admitted to hospitals during the same period. The average endotracheal/tracheostomy cannulation time was 3 weeks/12 weeks (range 2 to 4 weeks/8 to 14 weeks). Average age was 76 years (range, 34 to 81). Underlying diseases included COPD, postcoronary artery bypass graft surgery, postpneumonectomy, severe pneumonia, acute lung injury, and ischemic heart disease.<br><br>RESULTS: All 37 patients who initially failed to wean had difficulty in breathing and developed intermittent high peak airway pressures either early or during the weaning process or just on being ventilated. The insertion of a longer tracheal tube bypassed the obstruction, reestablished the airway, decreased peak airway pressures, and allowed the patient to breathe more easily. The obstruction was confirmed on bronchoscopy. Treatment consisted of either placement of a longer tracheal tube (34 of 37 patients) or placement of a tracheal stent. All but two of the patients (5.4%) were able to be weaned within a week. The two patients who still failed to be weaned were subsequently diagnosed as having amyotrophic lateral sclerosis.<br><br>CONCLUSION: Tracheal obstruction in patients requiring prolonged mechanical ventilation prevented weaning. Reestablishment of the airway with a longer tracheal tube or tracheal stent allowed most of the patients to be weaned.}, }
@article {pmid10190739, year = {1999}, author = {Remy, AJ and Camu, W and Ramos, J and Blanc, P and Larrey, D}, title = {Acute hepatitis after riluzole administration.}, journal = {Journal of hepatology}, volume = {30}, number = {3}, pages = {527-530}, doi = {10.1016/s0168-8278(99)80115-9}, pmid = {10190739}, issn = {0168-8278}, mesh = {Acute Disease ; Aged ; *Chemical and Drug Induced Liver Injury ; Excitatory Amino Acid Antagonists/administration &amp; dosage/*adverse effects ; Female ; Humans ; Male ; Middle Aged ; Riluzole/administration &amp; dosage/*adverse effects ; Scleroderma, Systemic/drug therapy ; }, abstract = {Riluzole is a new drug representing the first active treatment for amyotrophic lateral sclerosis. We report the cases of two patients who developed acute hepatitis after taking riluzole at the recommended dose (100 mg daily) for 7 and 4 weeks, respectively. In both cases, liver histology showed hepatocellular damage with inflammatory infiltration and microvesicular steatosis without fibrosis. Liver enzymes returned to normal 4 and 8 weeks, respectively, after riluzole withdrawal. In one case, the readministration of riluzole was followed by the relapse of hepatitis. These two observations strongly suggest that riluzole can induce acute hepatitis with associated hepatocellular damage and microvesicular steatosis. They also suggest that liver enzymes should be monitored during treatment with riluzole.}, }
@article {pmid10093584, year = {1999}, author = {Siemers, E}, title = {Multiple system atrophy.}, journal = {The Medical clinics of North America}, volume = {83}, number = {2}, pages = {381-392}, doi = {10.1016/s0025-7125(05)70110-3}, pmid = {10093584}, issn = {0025-7125}, mesh = {Brain/pathology ; Cognition Disorders/etiology ; Humans ; Multiple System Atrophy/complications/*diagnosis/pathology ; }, abstract = {MSA is a complex disorder, with regard to its pathology and cause as well as its clinical diagnosis and treatment. Although a number of clinical treatments may improve quality of life for these patients, given the widespread pathology present, symptomatic treatment, particularly that involving neurotransmitter replacement, is likely to remain difficult. Truly effective treatment for these patients is likely to depend on an understanding of the underlying pathogenic mechanisms and methods to halt or reverse disease progression. A firm understanding of the classification of these disorders is the first step to understanding the relevant pathogenic mechanisms. The finding of intracytoplasmic glial inclusion bodies provides a compelling piece of evidence that SND, OPCA, and SDS do, in fact, belong to one nosologic entity. These inclusions do not seem to be present in familial cases of OPCA; thus, they may provide a means to improve diagnostic specificity as well as sensitivity. With the ability to define clearly the entity of MSA, an understanding of the pathophysiology can be developed along with other degenerative neurologic diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease.}, }
@article {pmid10085759, year = {1999}, author = {Lund-Olesen, K}, title = {[Treatment of amyotrophic lateral sclerosis (ALS)].}, journal = {Ugeskrift for laeger}, volume = {161}, number = {10}, pages = {1433}, pmid = {10085759}, issn = {0041-5782}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*therapy ; Antioxidants/*administration &amp; dosage ; Humans ; Physical Therapy Modalities ; }, }
@article {pmid10084765, year = {1998}, author = {Holt, RI and Baker, AJ and Jones, JS and Miell, JP}, title = {The insulin-like growth factor and binding protein axis in children with end-stage liver disease before and after orthotopic liver transplantation.}, journal = {Pediatric transplantation}, volume = {2}, number = {1}, pages = {76-84}, pmid = {10084765}, issn = {1397-3142}, mesh = {Adolescent ; Biomarkers/blood ; Blotting, Western ; Carrier Proteins/metabolism ; Child ; Child, Preschool ; Chronic Disease ; Follow-Up Studies ; Humans ; Infant ; Infant, Newborn ; Insulin-Like Growth Factor Binding Proteins/*blood ; Insulin-Like Growth Factor I/*metabolism ; Liver Cirrhosis/blood/complications ; Liver Failure/*blood/etiology/surgery ; *Liver Transplantation ; Prognosis ; }, abstract = {Over 50% of children with established cirrhosis have evidence of growth failure and malnutrition. Orthotopic liver transplantation (OLT) is a successful treatment for many children and leads to improved growth and nutrition. Most of the anabolic actions of GH are mediated through the generation of the mitogenic polypeptide insulin-like growth factor-I (IGF-I). Although this is synthesised ubiquitously, the bulk of circulating IGF-I is derived from the liver. The actions of IGF-I are modulated by a family of at least six high-affinity binding proteins (IGFBPs). Growth failure in end-stage liver disease, both before and after OLT, may result from abnormalities in the IGF-IGFBP axis. Children who had undergone successful OLT were studied before and after OLT. Anthropometry was measured by standard techniques. Serum IGFs, IGFBPs and acid labile subunit (ALS) were measured by RIA, IRMA, ELISA, Western ligand and immunoblotting. The most severely affected anthropometric parameters were skin fold thickness and mid-arm circumference. After OLT there was a marked improvement in these parameters. Chronic liver disease was characterised by low serum IGF-I, IGF-II, IGFBP-3 and ALS levels with raised IGFBP-1 and -2 levels. Serum IGFBP-1 and -2 were negatively correlated with pre-OLT anthropometric parameters. After OLT, there was a rapid normalisation of serum IGF-I, while IGF-II and IGFBP-3 overshot to supranormal levels. ALS levels post-OLT remained below control levels. By 3 years post-OLT, IGFBP-3 had fallen to levels which were insignificantly different from controls. IGFBP-1 fell but remained above normal, while there was no significant change in IGFBP-2. Growth post-OLT correlated positively with serum IGF-I and negatively with IGFBP-1. In conclusion, chronic liver disease is associated with marked changes in body composition. These changes are associated with and may be caused by an impaired generation of IGF-I and altered production of IGFBPs. After OLT there is a marked improvement in growth associated with partial normalisation of the IGF-IGFBP axis. However, there are persistent abnormalities in this axis which may explain growth failure post-OLT.}, }
@article {pmid10080385, year = {1999}, author = {Mufson, EJ and Kroin, JS and Sendera, TJ and Sobreviela, T}, title = {Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases.}, journal = {Progress in neurobiology}, volume = {57}, number = {4}, pages = {451-484}, doi = {10.1016/s0301-0082(98)00059-8}, pmid = {10080385}, issn = {0301-0082}, support = {AG09466/AG/NIA NIH HHS/United States ; AG10161/AG/NIA NIH HHS/United States ; AG10668/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Axonal Transport ; Central Nervous System/cytology/*metabolism/pathology ; Fibroblast Growth Factors/administration &amp; dosage/metabolism ; Humans ; Nerve Growth Factors/administration &amp; dosage/*metabolism/pharmacology ; Nerve Tissue Proteins/administration &amp; dosage/*metabolism/pharmacology ; Neurodegenerative Diseases/metabolism/*therapy ; Receptors, Nerve Growth Factor/metabolism ; }, abstract = {Neurotrophins play a crucial role in the maintenance, survival and selective vulnerability of various neuronal populations within the normal and diseased brain. Several families of growth promoting substances have been identified within the central nervous system (CNS) including the superfamily of nerve growth factor related neurotrophin factors, glial derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF). In addition, other non-neuronal growth factors such as fibroblast growth factor (FGF) have also been identified. This article reviews the trophic anatomy of these factors within the CNS. Intraventricular and intraparenchymal injections of exogenous nerve growth factor result in retrograde labeling mainly within the cholinergic basal forebrain. Distribution of brain derived neurotrophic factor (BDNF) following intraventricular injection is minimal due to the binding to the trkB receptor along the ventricular wall. In contrast, intraparenchymal injections of BDNF results in widespread retrograde transport throughout the CNS. BDNF has also been shown to be transported anterogradely within the CNS. Infusion of GDNF into the CNS results in retrograde transport limited to the nigrostriatal pathway. Hippocampal injections of NT-3 retrogradely label mainly basal forebrain neurons. Retrograde transport of radiolabeled CNTF has only been observed in sensory neurons of the sciatic nerve. Following intraventricular and intraparenchymal infusion of radiolabeled bFGF, retrograde neuronal labeling was found in the telecephalon, diencephalon, mesencephalon and pons. In contrast retrograde labeling for aFGF was found only in the hypothalamus and midbrain. Since select neurotrophins traffic anterogradely and retrogradely within the nervous system, these proteins could be used to treat neurological diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.}, }
@article {pmid10072299, year = {1999}, author = {Barnéoud, P and Curet, O}, title = {Beneficial effects of lysine acetylsalicylate, a soluble salt of aspirin, on motor performance in a transgenic model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {155}, number = {2}, pages = {243-251}, doi = {10.1006/exnr.1998.6984}, pmid = {10072299}, issn = {0014-4886}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/physiopathology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/administration &amp; dosage/pharmacokinetics/*pharmacology ; Aspirin/administration &amp; dosage/*analogs &amp; derivatives/pharmacokinetics/pharmacology ; Body Weight/drug effects ; Brain/metabolism ; Humans ; Lysine/administration &amp; dosage/*analogs &amp; derivatives/pharmacokinetics/pharmacology ; Male ; Mice ; Mice, Transgenic ; Motor Activity/*drug effects ; Muscle, Skeletal/drug effects/physiopathology ; Mutation ; Postural Balance/drug effects ; Reflex/drug effects ; Salicylates/metabolism ; Solubility ; Superoxide Dismutase/deficiency/genetics ; }, abstract = {We have studied the effect of lysine acetylsalicylate (LAS; Aspegic), a soluble salt of aspirin, on motor deficits in transgenic mice expressing a human superoxide dismutase SOD1 mutation (Gly-93 --> Ala), an animal model of familial amyotrophic lateral sclerosis (FALS). In nontreated FALS mice, motor impairments appear at 12-14 weeks of age, whereas paralysis is not observed before 20 weeks of age. Life expectancy is 140-170 days. Early treatment with LAS from 5 weeks of age delayed the appearance of motor deficits in FALS mice as measured by extension reflex, loaded grid, and rotarod tests. This beneficial effect of treatment was maintained up to 18 weeks of age, until just before onset of end-stage disease. When treatment was started at 13 weeks, no significant beneficial effect was observed. These results demonstrate that chronic LAS treatment is able to delay the appearance of reflex, coordination, and muscle strength deficits in this animal model of ALS if the treatment is started early enough. However, neither the onset of paralysis nor end-stage disease were improved by the LAS treatment. In the absence of an effect on survival, the functional improvement demonstrated here is probably the maximum that this demanding model could allow. Although other properties of LAS may have contributed to its beneficial effect, we suggest that the antioxidant properties of aspirin are responsible for the positive effects in this model and support the use of antioxidants as effective therapy for ALS.}, }
@article {pmid10047920, year = {1999}, author = {Hernández Borge, J and García González, L and Martín Arroyo Caballero, JA and Ruiz Avalos, A}, title = {[Acute respiratory failure as the presentation of amyotrophic lateral sclerosis. Apropos a case].}, journal = {Archivos de bronconeumologia}, volume = {35}, number = {1}, pages = {48-50}, doi = {10.1016/s0300-2896(15)30324-0}, pmid = {10047920}, issn = {0300-2896}, mesh = {Acute Disease ; Amyotrophic Lateral Sclerosis/complications/*diagnosis ; Fatal Outcome ; Humans ; Hypercapnia/diagnosis/etiology ; Male ; Middle Aged ; Motor Neuron Disease/diagnosis/etiology ; Respiratory Insufficiency/*diagnosis/etiology ; }, abstract = {We report the case of a 61-year-old man with amyotrophic lateral sclerosis presenting with respiratory failure requiring long-term mechanical ventilation. Diagnostic difficulties are discussed along with the circumstances that give rise to suspicion of neuromuscular disease in a context of respiratory failure of unknown cause. The patient is at present in stable condition after 6 months of domiciliary mechanical ventilation. The treatment options in such cases and their indications are discussed.}, }
@article {pmid10029410, year = {1999}, author = {Haag, JD and Brasic, GM and Shepel, LA and Newton, MA and Grubbs, CJ and Lubet, RA and Kelloff, GJ and Gould, MN}, title = {A comparative analysis of allelic imbalance events in chemically induced rat mammary, colon, and bladder tumors.}, journal = {Molecular carcinogenesis}, volume = {24}, number = {1}, pages = {47-56}, doi = {10.1002/(sici)1098-2744(199901)24:1&lt;47::aid-mc7&gt;3.0.co;2-b}, pmid = {10029410}, issn = {0899-1987}, support = {N01-CN-25488-02/CN/NCI NIH HHS/United States ; }, mesh = {Alleles ; Animals ; Azoxymethane/toxicity ; Butylhydroxybutylnitrosamine/toxicity ; Carcinogens/*toxicity ; *Chromosome Mapping ; Codon ; Colonic Neoplasms/chemically induced/*genetics/pathology ; Female ; Genes, ras ; Genetic Markers ; Humans ; *Loss of Heterozygosity ; Male ; Mammary Neoplasms, Experimental/chemically induced/*genetics/pathology ; Methylnitrosourea/toxicity ; *Microsatellite Repeats ; *Point Mutation ; Rats ; Rats, Inbred F344 ; Rats, Inbred WF ; Urinary Bladder Neoplasms/chemically induced/*genetics/pathology ; }, abstract = {In this paper, patterns of allelic imbalances (Als) in chemically induced rat mammary, colon, and bladder tumors from (Wistar Furth x Fischer 344)F1 rats are described and compared. Male F1 rats were administered azoxymethane (AOM), and colon tumors were collected at 58 wk after treatment. Female F1 rats were given either N-nitroso-N-methylurea (NMU) or N-butyl-(hydroxybutyl)-nitrosoamine (BBN), and mammary and bladder tumors were collected at 15 and 52 wk after treatment, respectively. DNA was extracted from a subset of 18 of the largest tumors from each group, and a genome scan was performed by using polymerase chain reaction and 90 polymorphic microsatellite markers. Als, such as loss of heterozygosity, gene duplication, and microsatellite instability, were observed at low frequencies in all of the tumor models. Thirty random Als were observed in the AOM-induced colon tumors but only four in the NMU-induced mammary tumors. In both these models, all the tumors were classified as adenocarcinomas, and most of the Als observed were confined to single tumors with atypical histopathology. In contrast, 27 random Als were identified in the BBN-induced bladder tumors. Als were observed in both transitional-cell carcinomas and papillomas, although most were in the carcinomas. Statistical analysis of the Al data revealed no significant nonrandom Als within or among the tumor models, although several of the infrequently observed Al events identified in the rat tumors may also be observed in the corresponding human tumor type.}, }
@article {pmid10022415, year = {1999}, author = {Olivecrona, H and Hilding, A and Ekström, C and Barle, H and Nyberg, B and Möller, C and Delhanty, PJ and Baxter, RC and Angelin, B and Ekström, TJ and Tally, M}, title = {Acute and short-term effects of growth hormone on insulin-like growth factors and their binding proteins: serum levels and hepatic messenger ribonucleic acid responses in humans.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {84}, number = {2}, pages = {553-560}, doi = {10.1210/jcem.84.2.5466}, pmid = {10022415}, issn = {0021-972X}, mesh = {Adult ; Carrier Proteins/blood/genetics ; Female ; Glycoproteins/blood/genetics ; Human Growth Hormone/administration &amp; dosage/*pharmacology ; Humans ; Insulin-Like Growth Factor Binding Protein 1/blood/genetics ; Insulin-Like Growth Factor Binding Protein 2/blood/genetics ; Insulin-Like Growth Factor Binding Protein 3/blood/genetics ; Insulin-Like Growth Factor Binding Proteins/*blood/genetics ; Insulin-Like Growth Factor I/genetics/*metabolism ; Insulin-Like Growth Factor II/genetics/*metabolism ; Liver/*metabolism ; Male ; Middle Aged ; RNA, Messenger/*metabolism ; }, abstract = {We investigated the acute (4-5 h) and short-term (5 days) effects of GH treatment on hepatic messenger RNA (mRNA) levels of the genes for the insulin-like growth factors (IGFs), insulin-like growth factor binding protein-1, -2, and -3 (IGFBPs), and the acid labile subunit (ALS), as well as serum levels of these proteins in humans. At the mRNA level, we observed an increase in IGF-1 transcription (+173%) following GH treatment in the acute group, which remained elevated in the short-term treatment group. IGFBP-2 mRNA decreased after short-term GH treatment, without changes in IGFBP-1 or -3 expression. The ALS transcript level increased after 5 days. In serum, we found increased levels of IGF-I and insulin, and decreased levels of IGF-II, in the short-term treatment group. IGFBP-1 decreased in both treatment groups, whereas IGFBP-2 was reduced after 5 days treatment. ALS increased in the short-term group. We observed increased IGFBP-3 serum levels after 5 days of GH treatment, likely due to increased formation of the ternary complex. Our results show that the metabolic effects by GH on the IGF axis are complex. In addition to a direct stimulation of IGF-I and ALS expression, GH inhibits IGFBP-1 serum levels and IGFBP-2 expression in an indirect manner, possibly facilitating enhanced IGF bioavailability to target tissues.}, }
@article {pmid9951030, year = {1998}, author = {Borrás-Blasco, J and Plaza-Macías, I and Navarro-Ruiz, A and Perís-Martí, J and Antón-Cano, A}, title = {[Riluzole as a treatment for amyotrophic lateral sclerosis].}, journal = {Revista de neurologia}, volume = {27}, number = {160}, pages = {1021-1027}, pmid = {9951030}, issn = {0210-0010}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Neuroprotective Agents/pharmacology/*therapeutic use ; Riluzole/pharmacology/*therapeutic use ; }, abstract = {INTRODUCTION: The Amyotrophic Lateral Sclerosis (ALS) is a disease characterized by the selective degeneracy of the superior motoneurons of the cortex motor and of the inferior motoneurons at level of the encephalic trunk and spinal marrow. Exist sporadic and familiar forms, being estimated an incidence of 1-2 cases by 100,000 inhabitants. The cause of the neuronal degeneracy is yet unknown, being implied, between other mechanisms, the glutamic exotoxicity is the responsible for the death neuronal. The riluzol is a benzothiazole derivative whose neuroprotector mechanism still it has not been totally clarified, though seems that reduces the neuroexcitatory action of the glutamic acid blocking his transmission.<br><br>DEVELOPMENT: Two clinical trials have been accomplished with similar characteristics: multicentre, randomized, double blind, and placebo-controlled. Between both studies have been included more than 1,100 patient, obtained significant statistic results in the prolongation of the survival time, however this effect was not going accompanied of an improvement in the muscular force neither of the pulmonary capacity, what is translated in which the riluzol does not modify the quality of life of the patient. The drug presents good tolerance and mild adverse effects and as consequence of this in 1996, the FDA approved his marketing and utilization in the treatment of the ALS. The approval of the riluzol as first agent for the treatment of the ALS has raised an important number of problems about the efficiency and cost of the treatment.<br><br>CONCLUSION: Though its benefits are modest, it is considered a starting point in the pharmacotherapy of the ALS.}, }
@article {pmid9932448, year = {1998}, author = {Estévez, AG and Spear, N and Manuel, SM and Barbeito, L and Radi, R and Beckman, JS}, title = {Role of endogenous nitric oxide and peroxynitrite formation in the survival and death of motor neurons in culture.}, journal = {Progress in brain research}, volume = {118}, number = {}, pages = {269-280}, doi = {10.1016/s0079-6123(08)63214-8}, pmid = {9932448}, issn = {0079-6123}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/genetics ; Animals ; Apoptosis ; Brain-Derived Neurotrophic Factor/pharmacology ; Cell Death ; Cell Survival/drug effects/physiology ; Humans ; Motor Neurons/cytology/drug effects/*metabolism ; Nitrates/metabolism/*physiology ; Nitric Oxide/biosynthesis/*physiology ; Superoxide Dismutase/genetics ; Tyrosine/analogs &amp; derivatives/physiology ; }, abstract = {Motor neuron survival is highly dependent on trophic factor supply. Deprivation of trophic factors results in induction of neuronal NOS, which is also found in pathological conditions. Growing evidence suggests that motor neuron degeneration involves peroxynitrite formation. Trophic factors modulate peroxynitrite toxicity (Estévez et al., 1995; Shin et al., 1996; Spear et al., 1997). Whether a trophic factor prevents or potentiates peroxynitrite toxicity depends upon when the cells are exposed to the trophic factor (Table 1). These results strongly suggest that a trophic factor that can protect neurons under optimal conditions, but under stressful conditions can increase cell death. In this context, it is possible that trophic factors or cytokines produced as a response to damage may potentiate rather than prevent motor neuron death. A similar argument may apply to the therapeutic administration of trophic factors to treat neurodegenerative diseases. Similarly, the contrasting actions of NO on motor neurons may have important consequences for the potential use of nitric oxide synthase inhibitors in the treatment of ALS and other related neurodegenerative diseases.}, }
@article {pmid9918700, year = {1999}, author = {Esclaire, F and Kisby, G and Spencer, P and Milne, J and Lesort, M and Hugon, J}, title = {The Guam cycad toxin methylazoxymethanol damages neuronal DNA and modulates tau mRNA expression and excitotoxicity.}, journal = {Experimental neurology}, volume = {155}, number = {1}, pages = {11-21}, doi = {10.1006/exnr.1998.6962}, pmid = {9918700}, issn = {0014-4886}, support = {NS 19611/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; *DNA Damage/physiology ; DNA Repair/physiology ; Guam ; Methylazoxymethanol Acetate/*analogs &amp; derivatives/poisoning ; Neurons/*drug effects/metabolism ; Neurotoxins/*metabolism ; Plants, Toxic/chemistry ; RNA, Messenger/*metabolism ; Rats/embryology ; tau Proteins/*genetics/physiology ; }, abstract = {As in Alzheimer's disease, brains of Guam Chamorros with amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) contain intraneuronal-paired helical filaments composed of accumulated phosphorylated tau protein. Tau mRNA expression in rat neuronal cultures-normally modulated by glutamate-increases after treatment with the aglycone of cycasin, a cycad-derived toxin whose concentration in Chamorro food varies with disease incidence. Elevated Tau gene expression in vitro is coincident with increased cycasin-related DNA adducts and reduced DNA repair. Cycasin and endogenous glutamate may together promote the accumulation of tau protein and neuronal degeneration in Western Pacific ALS/PDC.}, }
@article {pmid9918699, year = {1999}, author = {Pedersen, WA and Cashman, NR and Mattson, MP}, title = {The lipid peroxidation product 4-hydroxynonenal impairs glutamate and glucose transport and choline acetyltransferase activity in NSC-19 motor neuron cells.}, journal = {Experimental neurology}, volume = {155}, number = {1}, pages = {1-10}, doi = {10.1006/exnr.1998.6890}, pmid = {9918699}, issn = {0014-4886}, support = {AG10836/AG/NIA NIH HHS/United States ; AG14554/AG/NIA NIH HHS/United States ; }, mesh = {Aldehydes/metabolism/*pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/physiology ; Biological Transport/drug effects ; Cell Line ; Choline O-Acetyltransferase/*antagonists &amp; inhibitors/metabolism ; Enzyme Activation/drug effects ; Ferrous Compounds/pharmacology ; Glucose/*metabolism ; Glutamic Acid/*metabolism ; Glutathione/pharmacology ; Lipid Peroxides/metabolism ; Mice ; Motor Neurons/drug effects/*metabolism/physiology ; Oxidative Stress/physiology ; }, abstract = {Both oxidative stress and excitotoxicity are implicated in the pathogenesis of a number of neurodegenerative disorders, such as amyotrophic lateral sclerosis. We previously reported increased modification of proteins by 4-hydroxynonenal (HNE), a product of membrane lipid peroxidation, in the spinal cords of patients with amyotrophic lateral sclerosis relative to controls. In the current study, we examined the functional consequences of protein modification by HNE in a cell line with a motor neuron phenotype, NSC-19. Treatment of NSC-19 cells with FeSO4, which catalyzes lipid peroxidation, or HNE induced concentration-dependent decreases in glucose and glutamate transport. Vitamin E and propyl gallate blocked the impairment of glucose and glutamate transport caused by FeSO4 in these cells, but not that caused by HNE, whereas glutathione blocked the effects of FeSO4 as well as HNE. Both FeSO4 and HNE caused an increase in the number of apoptotic nuclei in NSC-19 cultures, but this occurred subsequent to the impairment of glucose and glutamate transport. Reductions in choline acetyltransferase activity were also observed in FeSO4- or HNE-treated NSC-19 cells before induction of apoptosis. Our results suggest that, prior to cell death, oxidative stress and HNE down-regulate cholinergic markers and impair glucose and glutamate transport in motor neurons, the latter of which may lead to excitotoxic degeneration of the cells.}, }
@article {pmid9894144, year = {1998}, author = {Carter, GT and Miller, RG}, title = {Comprehensive management of amyotrophic lateral sclerosis.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {9}, number = {1}, pages = {271-84, viii-ix}, pmid = {9894144}, issn = {1047-9651}, mesh = {Algorithms ; Amyotrophic Lateral Sclerosis/physiopathology/psychology/*therapy ; Comprehensive Health Care/*organization &amp; administration ; Disease Progression ; Humans ; Patient Care Planning/*organization &amp; administration ; Patient Care Team/*organization &amp; administration ; Physical and Rehabilitation Medicine ; Terminal Care/organization &amp; administration ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disease that poses a myriad of clinical problems. Patients with ALS are best treated in a multidisciplinary setting involving physicians, clinical nursing specialists, and physical, occupational, speech, and respiratory therapists, as well as psychologists and social workers. Palliative and rehabilitative strategies may ease suffering, while new treatments provide hope for effective treatment of this disease.}, }
@article {pmid9886083, year = {1999}, author = {Koppal, T and Drake, J and Yatin, S and Jordan, B and Varadarajan, S and Bettenhausen, L and Butterfield, DA}, title = {Peroxynitrite-induced alterations in synaptosomal membrane proteins: insight into oxidative stress in Alzheimer's disease.}, journal = {Journal of neurochemistry}, volume = {72}, number = {1}, pages = {310-317}, doi = {10.1046/j.1471-4159.1999.0720310.x}, pmid = {9886083}, issn = {0022-3042}, support = {AG-05119/AG/NIA NIH HHS/United States ; AG-10836/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/*metabolism ; Animals ; Cell Survival/drug effects ; Cells, Cultured ; Cyclic N-Oxides ; Cytosol/metabolism ; Gerbillinae ; Glutathione/metabolism ; Hippocampus/cytology ; Male ; Membrane Proteins/metabolism ; Neurons/cytology/drug effects/*enzymology ; Nitrates/*pharmacology ; Nitric Oxide/metabolism ; Oxidants/*pharmacology ; Oxidation-Reduction ; Oxidative Stress/physiology ; Spin Labels ; Synaptosomes/drug effects/*metabolism ; }, abstract = {Peroxynitrite (ONOO) is a highly reactive, oxidizing anion with a half-life of <1 s that is formed by reaction of superoxide radical anion with nitric oxide. Several reports of ONOO--induced oxidation of lipids, proteins, DNA, sulfhydryls, and inactivation of key enzymes have appeared. ONOO- has also been implicated as playing a role in the pathology of several neurodegenerative disorders, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis, among others. Continuing our laboratory's interest in free radical oxidative stress in brain cells in AD, the present study was designed to investigate the damage to brain neocortical synaptosomal membrane proteins and the oxidation-sensitive enzyme glutamine synthetase (GS) caused by exposure to ONOO-. These synaptosomal proteins and GS have previously been shown by us and others to have been oxidatively damaged in AD brain and also following treatment of synaptosomes with amyloid beta-peptide. The results of the current study showed that exposure to physiological levels of ONOO- induced significant protein conformational changes, demonstrated using electron paramagnetic resonance in conjunction with a protein-specific spin label, and caused oxidation of proteins, measured by the increase in protein carbonyls. ONOO- also caused inactivation of GS and led to neuronal cell death examined in a hippocampal cell culture system. All these detrimental effects of ONOO- were successfully attenuated by the thiol-containing antioxidant tripeptide glutathione. This research shows that ONOO- can oxidatively modify both membranous and cytosolic proteins, affecting both their physical and chemical nature. These findings are discussed with reference to the potential involvement of ONOO- in AD neurodegeneration.}, }
@article {pmid9884069, year = {1998}, author = {Hubert, JP and Burgevin, MC and Terro, F and Hugon, J and Doble, A}, title = {Effects of depolarizing stimuli on calcium homeostasis in cultured rat motoneurones.}, journal = {British journal of pharmacology}, volume = {125}, number = {7}, pages = {1421-1428}, doi = {10.1038/sj.bjp.0702207}, pmid = {9884069}, issn = {0007-1188}, mesh = {Animals ; Calcium/*metabolism ; Cells, Cultured ; Cerebellar Nuclei/drug effects/metabolism ; Female ; Glutamic Acid/pharmacology ; Homeostasis ; Motor Neurons/cytology/drug effects/*metabolism ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Stimulation, Chemical ; Veratridine/pharmacology ; }, abstract = {Intracellular calcium concentrations in individual rat motoneurones in enriched primary cultures were measured by Indo-1 fluorimetry. Motoneurones in the cultures were characterized morphometrically and by cholineacetyltransferase immunocytochemistry. Depolarization of the cells with glutamic acid or veratridine increased intracellular calcium levels, which returned to baseline only slowly after removal of the depolarizing agent. The use of selective agonists (N-methyl-D-aspartic acid, AMPA, kainic acid, quisqualic acid and 1R-3S-ACPD) and antagonists (MK 801 and CNQX) showed that the excitatory amino acid-evoked responses were mediated by AMPA/kainate receptors rather than by NMDA receptors. Depolarization-evoked calcium transients in motoneurones are blocked by the neuroprotective drug riluzole Calcium transients reflected entry of calcium from without the cell, and their blockade by nitrendipine and lanthanum chloride suggested that this entry took place primarily through voltage-dependent calcium channels. These findings may be relevant for understanding the selective vulnerability of motoneurones to excitotoxicity in amyotrophic lateral sclerosis, and the therapeutic activity of riluzole in the treatment of this disease.}, }
@article {pmid9883348, year = {1998}, author = {Gliner, BE and Jorgenson, DB and Poole, JE and White, RD and Kanz, KG and Lyster, TD and Leyde, KW and Powers, DJ and Morgan, CB and Kronmal, RA and Bardy, GH}, title = {Treatment of out-of-hospital cardiac arrest with a low-energy impedance-compensating biphasic waveform automatic external defibrillator. The LIFE Investigators.}, journal = {Biomedical instrumentation &amp; technology}, volume = {32}, number = {6}, pages = {631-644}, pmid = {9883348}, issn = {0899-8205}, mesh = {Automation/instrumentation ; *Electric Countershock/instrumentation/methods ; Electric Stimulation ; Electrocardiography ; Heart Arrest/*therapy ; Humans ; Treatment Outcome ; Ventricular Fibrillation/*therapy ; }, abstract = {Few victims of sudden cardiac arrest survive. A new generation of automatic external defibrillators (AEDs), smaller, lighter, easier to use, and less costly, makes the goal of widespread AED deployment and early defibrillation feasible. A low-energy impedance-compensating biphasic waveform allows AED device characteristics more suitable to the goal of early defibrillation than high-energy waveforms. This study observed the performance of such a biphasic waveform in the out-of-hospital setting on 100 consecutive victims of sudden cardiac arrest treated by a wide range of first-responders. AEDs incorporating 150-J impedance-compensating biphasic waveforms were placed into service of 34 EMS systems. Data were obtained from the AED PC data card-recording system. The first endpoint was to determine the effectiveness of this waveform in terminating ventricular fibrillation (VF). The second endpoint was to determine whether or not the use of such an AED culminated in an organized rhythm at the time of patient transfer to an advanced life support (ALS) team or emergency department (ED). The third endpoint was to assess the efficiency of the human-factors design of the AED by measuring user time intervals. The 34 sites provided data from 286 consecutive AED uses, 100 from SCA victims with VF as their initial rhythm upon attachment of the AED. All 286 patients were correctly identified by the AED as requiring a shock (100% sensitivity for the 100 VF patients) or not (100% specificity to the 186 patients not presenting in VF). Times from emergency call to first shock delivery averaged 9.1 +/- 7.3 minutes. A single 150-J biphasic shock defibrillated the initial VF episode in 86% of patients. For all 450 episodes of VF in these 100 patients, an average of 86% +/- 24% of VF episodes were terminated with a single biphasic shock. Of the 449 VF episodes that received up to three shocks, 97% +/- 11% were terminated with three shocks or fewer. The average number of shocks per VF episode was 1.3 +/- 0.7. The average time from AED power-on and pads attached to first defibrillation was 25 +/- 23 sec. At the time of patient transfer, an organized rhythm was present in 65% of the VF patients; asystole was the result in 25%, and VF was in progress in 10%. It is concluded that low-energy impedance-compensating biphasic waveforms terminate long-duration VF at high rates in out-of-hospital cardiac arrest and provide defibrillation rates exceeding those previously achieved with high-energy shocks. Use of this waveform allows AED device characteristics consistent with widespread AED deployment and early defibrillation.}, }
@article {pmid9875779, year = {1998}, author = {Cerfolio, RJ and Tummala, RP and Holman, WL and Zorn, GL and Kirklin, JK and McGiffin, DC and Naftel, DC and Pacifico, AD}, title = {A prospective algorithm for the management of air leaks after pulmonary resection.}, journal = {The Annals of thoracic surgery}, volume = {66}, number = {5}, pages = {1726-1731}, doi = {10.1016/s0003-4975(98)00958-8}, pmid = {9875779}, issn = {0003-4975}, mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Algorithms ; Elective Surgical Procedures ; Female ; Forced Expiratory Volume ; Functional Residual Capacity ; Humans ; Male ; *Pneumonectomy ; Pneumothorax/etiology ; Postoperative Complications/*therapy ; Prospective Studies ; Talc/*administration &amp; dosage ; Total Lung Capacity ; Vital Capacity ; }, abstract = {BACKGROUND: Air leaks (ALs) are a common complication after pulmonary resection, yet there is no consensus on their management.<br><br>METHODS: An algorithm for the management of chest tubes (CT) and ALs was applied prospectively to 101 consecutive patients who underwent elective pulmonary resection. Air leaks were graded daily as forced expiratory only, expiratory only, inspiratory only, or continuous. All CTs were kept on 20 cm of suction until postoperative day 2 and were then converted to water seal. On postoperative day 3, if both a pneumothorax and AL were present, the CT was placed to 10 cm H2O of suction. If a pneumothorax was present without an AL, the CT was returned to 20 cm H2O of suction. Air leaks that persisted after postoperative day 7 were treated with talc slurry.<br><br>RESULTS: There were 101 patients (67 men); on postoperative day 1, 26 had ALs and all were expiratory only. Univariable analysis showed a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) (p = 0.005), increased age (p = 0.007), increased ratio of residual volume to total lung capacity (RV/TLC) (p = 0.04), increased RV (p = 0.02), and an increased functional residual capacity (FRC) (p = 0.02) to predict the presence of an AL on postoperative day 1. By postoperative day 2, 22 patients had expiratory ALs. After 12 hours of water seal, 13 of the 22 patients' ALs had stopped, and 3 more sealed by the morning of postoperative day 3. However, 2 of the 6 patients whose ALs continued experienced a pneumothorax. Five of the 6 patients with ALs on postoperative day 4 still had ALs on postoperative day 7, and all were treated by talc slurry through the CT. All ALs resolved within 24 hours after talc slurry.<br><br>CONCLUSIONS: Most ALs after pulmonary resection are expiratory only. A low FEV1/FVC ratio, increased age, increased RV/TLC ratio, increased RV, and an increased FRC were predictors of having an ALs on postoperative day 1. Conversion from suction to water seal is an effective way of sealing expiratory AL, and pneumothorax is rare. If an expiratory AL does not stop by postoperative day 4 it will probably persist until postoperative day 7, and talc slurry may be an effective treatment.}, }
@article {pmid9864711, year = {1998}, author = {Szczudlik, A and Tomik, B and Słowik, A and Kasprzyk, K}, title = {[Assessment of the efficacy of treatment with pimozide in patients with amyotrophic lateral sclerosis. Introductory notes].}, journal = {Neurologia i neurochirurgia polska}, volume = {32}, number = {4}, pages = {821-829}, pmid = {9864711}, issn = {0028-3843}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy ; Calcium Channel Blockers/*therapeutic use ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Pimozide/*therapeutic use ; Prognosis ; Selegiline/*therapeutic use ; Severity of Illness Index ; Vitamin E/*therapeutic use ; }, abstract = {The aim of the study was to assess the effect of pimozide voltage-dependent calcium channel blocker on the progression of ALS patients as compared to the potentially neuroprotective drugs, selegiline and vitamin E. There were 44 patients (17 females and 27 males, aged from 30 to 80 years, mean age: 56.2 years) diagnosed as either definite or possible ALS. The study design was open randomised. Patients were treated 3-12 months; the daily dose of pimozide was 1 mg. The disease progression index was calculated as a difference between scores of Norris scale before and after treatment. Statistical analysis showed a significant decrease of the index of progression of the disease in pimozide treated patients as compared to the others. This effect was neither related to the progression of the disease nor advance of the disease at the beginning of treatment.}, }
@article {pmid9859950, year = {1998}, author = {Dal Bello-Haas, V and Kloos, AD and Mitsumoto, H}, title = {Physical therapy for a patient through six stages of amyotrophic lateral sclerosis.}, journal = {Physical therapy}, volume = {78}, number = {12}, pages = {1312-1324}, doi = {10.1093/ptj/78.12.1312}, pmid = {9859950}, issn = {0031-9023}, mesh = {Activities of Daily Living ; Amyotrophic Lateral Sclerosis/classification/physiopathology/*therapy ; Female ; Humans ; Middle Aged ; Physical Therapy Modalities/*methods ; Prognosis ; Quality of Life ; Severity of Illness Index ; }, abstract = {BACKGROUND AND PURPOSE: This case report describes the use of Sinaki and Mulder's approach to staging amyotrophic lateral sclerosis (ALS) and functional outcome measures in designing a treatment program for a 59-year-old woman with ALS.<br><br>CASE DESCRIPTION AND OUTCOMES: As the patient progressed from stage I through stage VI, over 12 months, the physical therapy goals changed from optimizing remaining function, to maintaining functional mobility, and finally to maximizing quality of life.<br><br>DISCUSSION: Disease staging and the use of functional outcome measures provide a framework for physical therapy evaluation and treatment of patients with ALS throughout the disease process. Physical therapists can assist patients with ALS through the provision of education, psychological support, rehabilitation programs, and recommendations for appropriate equipment and community resources.}, }
@article {pmid9856861, year = {1998}, author = {Kaal, EC and Veldman, H and Sodaar, P and Joosten, EA and Dop Bär, PR}, title = {Oxidant treatment causes a dose-dependent phenotype of apoptosis in cultured motoneurons.}, journal = {Journal of neuroscience research}, volume = {54}, number = {6}, pages = {778-786}, doi = {10.1002/(SICI)1097-4547(19981215)54:6&lt;778::AID-JNR5&gt;3.0.CO;2-0}, pmid = {9856861}, issn = {0360-4012}, mesh = {Animals ; Antioxidants/*pharmacology ; *Apoptosis ; Ascorbic Acid/toxicity ; Embryo, Mammalian ; Free Radical Scavengers/toxicity ; Motor Neurons/*drug effects/physiology ; Rats ; Rats, Wistar ; *Reactive Oxygen Species ; Spinal Nerves/*drug effects/physiology ; }, abstract = {Evidence is growing that reactive oxygen species (ROS), by-products of (normal) cellular aerobic metabolism, are involved in the pathogenesis of neurodegenerative diseases. One of these diseases is amyotrophic lateral sclerosis (ALS), in which motoneurons die, leading to paralysis and death. It remains uncertain whether ROS are the cause of (apoptotic) motoneuron death in ALS. To further understand the role of ROS in motoneuron death, we investigated the effects of ROS on isolated spinal rat motoneurons in culture. ROS were generated with a combination of iron(III) and ascorbate, or with hydrogen peroxide. Both toxic treatments resulted in a dose-dependent motoneuron death. Iron(III)/ascorbate toxicity was completely prevented with the hydrogen peroxide detoxifying enzyme catalase and partially prevented with the antioxidant vitamin E. SOD1, the enzyme that removes superoxide, did not protect against iron(III)/ascorbate toxicity. ROS treatment caused apoptotic motoneuron death: low doses of iron(III)/ ascorbate or hydrogen peroxide resulted in complete apoptosis ending in nuclear fragmentation, while high doses of ROS resulted in incomplete apoptosis (nuclear condensation). Thus, depending on the dose of ROS, the motoneurons complete the apoptotic pathway (low dose) or are stopped somewhere during this route (high dose).}, }
@article {pmid9851664, year = {1998}, author = {Young, CA}, title = {Building a care and research team.}, journal = {Journal of the neurological sciences}, volume = {160 Suppl 1}, number = {}, pages = {S137-40}, doi = {10.1016/s0022-510x(98)00213-5}, pmid = {9851664}, issn = {0022-510X}, mesh = {Cooperative Behavior ; *Delivery of Health Care ; England ; Humans ; Motor Neuron Disease/*therapy ; Patient Care/*methods ; *Patient Care Team/organization &amp; administration ; Research/organization &amp; administration ; }, abstract = {The provision of high quality care for people with Motor Neurone Disease (MND) is challenging. The physical and psychological health needs experienced in this progressively disabling disease necessitate input from many disciplines. In order to integrate the delivery of care, the preferred model for MND is a disease-specific team. Such teams can offer a coordinated range of skills, expertise and clinical experience in a setting of interprofessional support. Teams may adopt several formats; multidisciplinary, interdisciplinary and transdisciplinary. In multidisciplinary teams the different professions work to individually set goals and meet to discuss their progress. In interdisciplinary teams goals are first agreed by the team, whose members then coordinate their input to the common treatment plan. In transdisciplinary teams, not only goals but skills are shared. Teamwork allows the coordination of input and the sharing of skills and experience in solving complex clinical problems. Greater flexibility and integration of work make best use of resources. Disease-specific teams act as an educational resource and stimulate awareness of the condition. Teams should undertake clinical research, to strengthen their practice and demonstrate their effectiveness. Effective teamwork, whether in a clinical or research team, requires issues of responsibility, leadership, interprofessional rivalry and communication to be addressed.}, }
@article {pmid9851661, year = {1998}, author = {Jenkinson, C and Swash, M and Fitzpatrick, R}, title = {The European Amyotrophic Lateral Sclerosis Health Profile Study. ALS-HPS Steering Group.}, journal = {Journal of the neurological sciences}, volume = {160 Suppl 1}, number = {}, pages = {S122-6}, doi = {10.1016/s0022-510x(98)00210-x}, pmid = {9851661}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; Caregivers/psychology ; Europe ; *Health Status Indicators ; Humans ; Longitudinal Studies ; Psychological Tests ; *Quality of Life ; }, abstract = {Quality of life is increasingly regarded as an important outcome measure in the evaluation of treatment regimes. The last decade has seen an enormous growth in the application of measures designed to assess quality of life in a vast array of medical specialities. However, the use of such measures in neurology has been limited and is virtually non-existent in amyotrophic lateral sclerosis (ALS). The European ALS Health Profile Study is a longitudinal survey of patients diagnosed with ALS or motor neurone disease in which patients are asked to complete questionnaires concerning their subjective health status. Data from clinical assessments is also collected. It is intended that the information collected will provide more systematic and detailed evidence of the impact of the disease from the perspective of the patient. This paper outlines the purpose and methodology of the project.}, }
@article {pmid9851659, year = {1998}, author = {Kurek, JB and Radford, AJ and Crump, DE and Bower, JJ and Feeney, SJ and Austin, L and Byrne, E}, title = {LIF (AM424), a promising growth factor for the treatment of ALS.}, journal = {Journal of the neurological sciences}, volume = {160 Suppl 1}, number = {}, pages = {S106-13}, doi = {10.1016/s0022-510x(98)00208-1}, pmid = {9851659}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Disease Models, Animal ; Drug Delivery Systems ; Growth Inhibitors/chemistry/physiology/*therapeutic use ; Humans ; *Interleukin-6 ; Leukemia Inhibitory Factor ; Lymphokines/chemistry/physiology/*therapeutic use ; Mice ; Mice, Neurologic Mutants ; Muscle, Skeletal/drug effects/physiology ; Nervous System/drug effects ; Neurons/drug effects ; Receptors, Cytokine/metabolism ; Regeneration/drug effects ; Signal Transduction ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; }, abstract = {Growth factors are theoretically promising agents for ALS therapy, but have been disappointing in subcutaneous delivery due to either toxicity or lack of major efficacy. Leukaemia inhibitory factor (LIF), was named after its effect on haemopoietic cells, and belongs to a group of cytokines which includes CNTF, IL-6, CT-1, OM and IL-11. All group members use the gp130 signal transducing subunit for intracellular signalling, but show differences in biological effect. In vitro and in vivo studies on axotomy and nerve crush models demonstrate a powerful effect of LIF in the survival of both motor and sensory neurones, while reducing denervation induced muscle atrophy. Its effects in muscle also include stimulating myoblast proliferation in vitro, and up-regulation after muscle injury. LIF will also stimulate muscle regeneration in vivo when applied exogenously after injury. In published studies of both axotomy induced neuronal death and in the Wobbler mouse models LIF is active at doses of 10 microg/kg delivered systemically, well below the expected maximum tolerated dose suggested by primate safety studies. LIF is expressed in low levels by spinal cord neurones with significant up-regulation when the neurones are damaged by BOAA toxin, an excitatory amino acid associated with a form of ALS. This augments other evidence suggesting LIF is a trauma factor playing a role in the injury response of adult neuronal tissue, and may be more effective than related growth factors. Taken together, the data suggests LIF is a physiologically relevant trophic factor with implications in clinical medicine as a therapy for ALS, and a human recombinant form (AM424), entered human clinical trials during 1998.}, }
@article {pmid9851658, year = {1998}, author = {Haase, G and Pettmann, B and Vigne, E and Castelnau-Ptakhine, L and Schmalbruch, H and Kahn, A}, title = {Adenovirus-mediated transfer of the neurotrophin-3 gene into skeletal muscle of pmn mice: therapeutic effects and mechanisms of action.}, journal = {Journal of the neurological sciences}, volume = {160 Suppl 1}, number = {}, pages = {S97-105}, doi = {10.1016/s0022-510x(98)00207-x}, pmid = {9851658}, issn = {0022-510X}, mesh = {Adenoviridae/genetics ; Animals ; Axonal Transport ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Electromyography ; Enzyme-Linked Immunosorbent Assay ; Gene Transfer Techniques ; Genetic Therapy/*methods ; HeLa Cells ; Humans ; Mice ; Mice, Neurologic Mutants ; Motor Neuron Disease/genetics/*therapy ; Muscle, Skeletal/drug effects/innervation/*metabolism ; Nerve Growth Factors/biosynthesis/*genetics/*therapeutic use ; Neurotrophin 3 ; }, abstract = {Several neurotrophic factors (CNTF, BDNF, IGF-1) have been suggested for the treatment of motor neuron diseases. In ALS patients, however, the repeated subcutaneous injection of these factors as recombinant proteins is complicated by their toxicity or poor bioavailability. We have constructed an adenovirus vector coding for neurotrophin-3 (AdNT-3) allowing for stable and/or targeted delivery of NT-3 to motoneurons. The intramuscular administration of this vector was tested in the mouse mutant pmn (progressive motor neuronopathy). AdNT-3-treated pmn mice showed prolonged lifespan, improved neuromuscular function, reduced motor axonal degeneration and efficient reinnervation of muscle fibres. NT-3 protein and also adenovirus vectors, when injected into muscle, can be transported by motoneurons via retrograde axonal transport to their cell bodies in the spinal cord. Using ELISA and RT-PCR analyses in muscle, spinal cord and serum of AdNT-3-treated pmn mice, we have investigated the contribution of these processes to the observed therapeutic effects. Our results suggest that most if not all therapeutic benefit was due to the continuous systemic liberation of adenoviral NT-3. Therefore, viral gene therapy vectors auch as adenoviruses, AAVs, lentiviruses and new types of gene transfer not based on viral vectors that allow for efficient in vivo liberation of neurotrophic factors have potential for the future treatment of human motor neuron diseases.}, }
@article {pmid9851653, year = {1998}, author = {Desai, J and Sharief, M and Swash, M}, title = {Riluzole has no acute effect on motor unit parameters in ALS.}, journal = {Journal of the neurological sciences}, volume = {160 Suppl 1}, number = {}, pages = {S69-72}, doi = {10.1016/s0022-510x(98)00201-9}, pmid = {9851653}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Cross-Over Studies ; Double-Blind Method ; Electromyography ; Humans ; Membrane Potentials/drug effects/physiology ; Motor Neurons/*drug effects/physiology ; Riluzole/*pharmacology ; }, abstract = {Riluzole is the only drug to have been approved for the treatment of amyotrophic lateral sclerosis (ALS/MND). Its mechanism of action is complex and includes actions on NMDA and kainate receptors and modulation of voltage gated Na channels. In ALS, its effects on measurable parameters of the motor units utilising current neurophysiological techniques are unknown. In an acute randomized, double-blind, placebo-controlled, cross-over experiment, we serially assessed the effects of riluzole on motor units in muscles affected by ALS/MND using EMG. We discuss the results of our observations in the light of previous clinical trials, and their implications.}, }
@article {pmid9851651, year = {1998}, author = {Mazzini, L and Mora, G and Balzarini, C and Brigatti, M and Pirali, I and Comazzi, F and Pastore, E}, title = {The natural history and the effects of gabapentin in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {160 Suppl 1}, number = {}, pages = {S57-63}, doi = {10.1016/s0022-510x(98)00199-3}, pmid = {9851651}, issn = {0022-510X}, mesh = {Acetates/*administration &amp; dosage/adverse effects ; Administration, Oral ; Adult ; Aged ; *Amines ; Amyotrophic Lateral Sclerosis/diagnosis/*drug therapy/mortality ; *Cyclohexanecarboxylic Acids ; Disability Evaluation ; Disease Progression ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Gabapentin ; Humans ; Male ; Middle Aged ; Prognosis ; Survival Analysis ; Survival Rate ; *gamma-Aminobutyric Acid ; }, abstract = {Glutamate excitotoxicity seems to play an important role in the aetiopathogenesis and progression of Amyotrophic Lateral Sclerosis (ALS). Gabapentin is a modulator of the glutamatergic system and has been shown to prolong survival in the transgenic model of familial ALS. It has also been demonstrated to slow the decline of arm strength in human sporadic cases. The aim of our study was to assess the effects of different dosages and duration of treatment of gabapentin on the natural history and survival of ALS patients. A total of 110 patients affected by definite ALS entered the study. After a 6-12 month period of observation, patients were randomly assigned to receive oral gabapentin 500 mg/day (Group A) or 1000 mg/day (Group B) for 6 months. In addition a group of patients received gabapentin 500 mg/day for 6 months and 1000 mg/day for a further 6 months (Group C). A group of 121 patients referred to our Institute, who received only symptomatic treatment, was considered as the control group (Group D). Each patient was seen at entry and every 3 months. All average slopes were negative but the comparison of all slopes showed a trend toward a slower rate of decline of muscle strength loss in all treated groups of patients compared with the control group. The differences were statistically significant. Analysis between the pretreatment and treatment period showed a statistically significant decrease of the decline of muscle strength and Norris score during the treatment period. Survival analysis showed a significantly longer survival in treated patients of Groups B and C. Our study suggests that gabapentin may be an effective drug for ALS; hence a controlled trial involving a sufficient large number of patients is warranted.}, }
@article {pmid9851648, year = {1998}, author = {Sostarko, M and Vranjes, D and Brinar, V and Brzovic, Z}, title = {Severe progression of ALS/MND after intervertebral discectomy.}, journal = {Journal of the neurological sciences}, volume = {160 Suppl 1}, number = {}, pages = {S42-6}, doi = {10.1016/s0022-510x(98)00197-x}, pmid = {9851648}, issn = {0022-510X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/diagnosis ; Disease Progression ; *Diskectomy ; Electromyography ; Fatal Outcome ; Female ; Humans ; Intervertebral Disc Displacement/*complications/surgery ; Male ; Middle Aged ; Muscle Weakness/etiology ; Pain/etiology ; }, abstract = {We observed seven patients who developed their first signs and symptoms of motor neuron disease together with signs of protrusion/prolapse of intervertebral disc. The age of the patients was between 55 and 67, of which one female and six male patients. All of them suffered from cervical spine pain or low back pain. The female patient and one male patient developed weakness in the small feet muscles as initial symptom and they complained of paresthesia along dermatomes L5S1 and of severe pain. The other five patients developed wasting of the hands muscles. They had a rather mild pain in the cervical spine and early morning paresthesia as well as severe causalgia along dermatomes C5C6 or C6C7. After the diagnosis of compressive radiculopathy in all patients, they underwent surgical treatment and very soon developed very severe progression of muscle wasting which included muscles of limbs, trunk and bulbar innervated muscles with signs and symptoms of lower and upper motor neuron lesion. Five patients died from 12 to 15 months after surgical treatment and two patients are still living.}, }
@article {pmid9851642, year = {1998}, author = {Gray, AM}, title = {ALS/MND and the perspective of health economics.}, journal = {Journal of the neurological sciences}, volume = {160 Suppl 1}, number = {}, pages = {S2-5}, doi = {10.1016/s0022-510x(98)00192-0}, pmid = {9851642}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*economics/mortality/therapy ; Cost-Benefit Analysis ; Delivery of Health Care/*economics ; Humans ; Quality-Adjusted Life Years ; Riluzole/*economics/therapeutic use ; Survival Rate ; Tracheostomy/*economics ; }, abstract = {In health care, choices are constantly being made about alternative uses of scarce resources, and health economics offers a framework for analysing these choices and for improving resource allocation. In cost-effectiveness analysis, the costs and consequences of alternatives are systematically measured and compared, with the objective of achieving maximum health gain with the available resources. Treatment options for patients with ALS/MND are severely limited, but riluzole has been shown to offer modest improvements in survival. However, decision-makers are likely to want convincing evidence on the cost-effectiveness of this therapy before recommending widespread adoption. Here, some initial estimates of cost-effectiveness are provided, using published effectiveness data and considering only the costs of therapy and of tracheostomy. Compared with placebo, the incremental cost per life year gained of 50 mg/day of riluzole is pound sterling 45630, and of 100 mg/day is pound sterling 44890. Increasing the estimated costs of tracheostomy reduces the cost per life year gained of 50 mg/day to pound sterling 34940. However, if quality of life during the increased period of survival is 80% of full health, the cost per quality adjusted life year gained of 50 mg/day becomes pound sterling 57040. These cost-effectiveness ratios are well in excess of the range that is normally considered to be acceptable in UK health technology assessment. However, the comparatively small number of ALS/MND patients and the lack of treatment alternatives should also be considered. Meanwhile, better information on costs is required in order to produce more precise estimates of cost-effectiveness.}, }
@article {pmid9537935, year = {1998}, author = {Sulmasy, DP and Terry, PB and Weisman, CS and Miller, DJ and Stallings, RY and Vettese, MA and Haller, KB}, title = {The accuracy of substituted judgments in patients with terminal diagnoses.}, journal = {Annals of internal medicine}, volume = {128}, number = {8}, pages = {621-629}, doi = {10.7326/0003-4819-128-8-199804150-00002}, pmid = {9537935}, issn = {0003-4819}, support = {NIH-RO1NR03045-01A1/NR/NINR NIH HHS/United States ; }, mesh = {Adult ; *Advance Directives ; Aged ; Aged, 80 and over ; *Consensus ; Cross-Sectional Studies ; *Decision Making ; Demography ; Female ; Humans ; Interviews as Topic ; Judgment ; Logistic Models ; Male ; Middle Aged ; Religion ; Resuscitation Orders ; Socioeconomic Factors ; Statistics as Topic ; Terminally Ill/*psychology ; }, abstract = {BACKGROUND: Patients' loved ones often make end-of-life treatment decisions, but the accuracy of their substituted judgments and the factors associated with accuracy are poorly understood.<br><br>OBJECTIVE: To assess the accuracy of judgments made by surrogate decision makers; ascertain the beliefs, practices, and clinical and sociodemographic factors associated with accuracy of surrogates' decisions; assess the preferences of patients for life-sustaining treatments; and compare differences in accuracy across diagnoses.<br><br>DESIGN: Cross-sectional paired interviews.<br><br>SETTING: Outpatient practices of three university hospitals.<br><br>PATIENTS: 250 patients with terminal diagnoses of congestive heart failure, AIDS, amyotrophic lateral sclerosis, lung cancer, and chronic obstructive pulmonary disease (50 patient-surrogate pairs in each group) and 50 general medical patients and their surrogates.<br><br>MEASUREMENTS: The accuracy of surrogate predictions was measured by using scales based on 10 potential treatments in each of three hypothetical clinical scenarios.<br><br>RESULTS: Preferences varied according to mode of treatment and scenario. On average, surrogates made correct predictions in 66% of instances. Accuracy was better for the permanent coma scenario than for the scenarios of severe dementia or coma with a small chance of recovery (P < 0.001). In a binary logit model, the accuracy of substituted judgments was positively associated with the patient having spoken with the surrogate about end-of-life issues (odds ratio [OR], 1.9 [95% CI, 1.6 to 2.3]), the patient having private insurance (OR, 1.4 [CI, 1.1 to 1.7]), the surrogate's level of education (OR, 1.5 [CI, 1.2 to 1.9]), and the patient's level of education (OR, 1.7 [CI, 1.4 to 2.2]). Accuracy was negatively associated with the patient's belief that he or she would live longer than 10 years (OR, 0.6 [CI, 0.5 to 0.7]), surrogate experience with life-sustaining treatment (OR, 0.4 [CI, 0.3 to 0.5]), surrogate participation in religious services (OR, 0.67 [CI, 0.50 to 0.91]), and a diagnosis of heart failure (OR, 0.6 [CI, 0.5 to 0.8]). Age, ethnicity, marital status, religion, and advance directives were not associated with accuracy.<br><br>CONCLUSIONS: The accuracy of substituted judgments is associated with multiple clinically apparent patient and surrogate factors. This information can help clinicians identify conditions under which substituted judgments are likely to be accurate or inaccurate and can help target populations for education designed to improve the accuracy of surrogate decision making.}, }
@article {pmid9843082, year = {1998}, author = {Kaji, R and Kodama, M and Imamura, A and Hashida, T and Kohara, N and Ishizu, M and Inui, K and Kimura, J}, title = {Effect of ultrahigh-dose methylcobalamin on compound muscle action potentials in amyotrophic lateral sclerosis: a double-blind controlled study.}, journal = {Muscle &amp; nerve}, volume = {21}, number = {12}, pages = {1775-1778}, doi = {10.1002/(sici)1097-4598(199812)21:12&lt;1775::aid-mus22&gt;3.0.co;2-v}, pmid = {9843082}, issn = {0148-639X}, mesh = {Action Potentials/drug effects ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Muscle, Skeletal/drug effects/*physiopathology ; Treatment Outcome ; Vitamin B 12/administration &amp; dosage/*analogs &amp; derivatives/therapeutic use ; }, abstract = {To develop a symptomatic treatment for amyotrophic lateral sclerosis, we compared the effects of ultrahigh-dose and low-dose (25 and 0.5 mg/day, intramuscularly, for 14 days) methylcobalamin on averaged compound muscle action potential amplitudes (CMAPs) in a double-blind trial. No significant changes in CMAP amplitude were found in 12 patients who had the low-dose treatment at either 2 or 4 weeks after start of treatment. By contrast, 12 patients assigned to the ultrahigh-dose group demonstrated a significant increase at 4 weeks. This method may provide a clinically useful measure to improve or retard muscle wasting, if a larger extended trial fulfills its promise.}, }
@article {pmid9822728, year = {1998}, author = {Roy, J and Minotti, S and Dong, L and Figlewicz, DA and Durham, HD}, title = {Glutamate potentiates the toxicity of mutant Cu/Zn-superoxide dismutase in motor neurons by postsynaptic calcium-dependent mechanisms.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {18}, number = {23}, pages = {9673-9684}, pmid = {9822728}, issn = {0270-6474}, mesh = {2-Amino-5-phosphonovalerate/pharmacology ; 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology ; Animals ; Calbindin 1 ; Calbindins ; Calcium/*physiology ; Calcium Channels/physiology ; Calcium Channels, L-Type ; Cells, Cultured ; Cyclic N-Oxides ; Excitatory Amino Acid Antagonists/pharmacology ; Free Radical Scavengers/pharmacology ; Ganglia, Spinal/cytology ; Glutamic Acid/*pharmacology ; Glutathione/metabolism ; Kynurenic Acid/pharmacology ; Mice ; Motor Neurons/chemistry/*enzymology ; Mutagenesis/physiology ; Nerve Tissue Proteins/metabolism ; Neurotoxins/pharmacology ; Nitrogen Oxides/pharmacology ; Oxidative Stress/physiology ; Receptors, AMPA/physiology ; S100 Calcium Binding Protein G/metabolism ; Spider Venoms/pharmacology ; Spinal Cord/cytology ; Superoxide Dismutase/*genetics/metabolism ; Synapses/chemistry/*enzymology ; }, abstract = {Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene are responsible for a subset of familial cases of amyotrophic lateral sclerosis. Using a primary culture model, we have demonstrated that normally nontoxic glutamatergic input, particularly via calcium-permeable AMPA/kainate receptors, is a major factor in the vulnerability of motor neurons to the toxicity of SOD-1 mutants. Wild-type and mutant (G41R, G93A, or N139K) human SOD-1 were expressed in motor neurons of dissociated cultures of murine spinal cord by intranuclear microinjection of plasmid expression vector. Both a general antagonist of AMPA/kainate receptors (CNQX) and a specific antagonist of calcium-permeable AMPA receptors (joro spider toxin) reduced formation of SOD-1 proteinaceous aggregates and prevented death of motor neurons expressing SOD-1 mutants. Partial protection was obtained by treatment with nifedipine, implicating Ca2+ entry through voltage-gated calcium channels as well as glutamate receptors in potentiating the toxicity of mutant SOD-1 in motor neurons. Dramatic neuroprotection was obtained by coexpressing the calcium-binding protein calbindin-D28k but not by increasing intracellular glutathione levels or treatment with the free radical spin trap agent, N-tert-butyl-alpha-phenylnitrone. Thus, generalized oxidative stress could have contributed in only a minor way to death of motor neurons expressing the mutant SOD-1. These studies demonstrated that the toxicity of these mutants is calcium-dependent and provide direct evidence that calcium entry during neurotransmission, coupled with deficiency of cytosolic calcium-binding proteins, is a major factor in the preferential vulnerability of motor neurons to disease.}, }
@article {pmid9819766, year = {1998}, author = {Abe, A and Kawazoe, C and Kondo, Y and Sato, K}, title = {Vascular responsiveness in alloxan-induced diabetes-susceptible (ALS) and resistant (ALR) mice.}, journal = {The Journal of veterinary medical science}, volume = {60}, number = {10}, pages = {1119-1125}, doi = {10.1292/jvms.60.1119}, pmid = {9819766}, issn = {0916-7250}, mesh = {Alloxan ; Animals ; Blood Glucose/metabolism ; Cromakalim/pharmacology ; Diabetes Mellitus, Experimental/*physiopathology ; Dinoprost/pharmacology ; Disease Models, Animal ; Disease Susceptibility/veterinary ; Glycosuria/metabolism ; Male ; Mice ; Muscle, Smooth, Vascular/*physiopathology ; Nitroprusside/pharmacology ; Norepinephrine/pharmacology ; Potassium/pharmacology ; Vasoconstriction/drug effects ; Vasoconstrictor Agents/pharmacology ; Vasodilation/drug effects ; Vasodilator Agents/pharmacology ; }, abstract = {Changes in reactivity of vascular smooth muscles of male alloxan-induced diabetes-susceptible (ALS) and resistant (ALR) mice aorta were investigated at 2 weeks, 1, 2 and 4 month(s) after the injection of alloxan (45 mg/kg, i.v.). The glucose levels in blood and urine of all the alloxan-treated ALS mice were markedly elevated while those in alloxan-treated ALR and non-treated ALS and ALR mice were not altered. The magnitude of high K+ (65.4 mM)-induced contractions were not affected by the treatment of alloxan. Norepinephrine-induced contractions in vascular smooth muscles of ALS mice in a diabetic state for 2 or 4 months were significantly potentiated. The contractile sensitivity to prostaglandin F2 alpha (PGF2 alpha) was increased in the 4-month-diabetic state. Responsiveness to 5-HT did not vary in the diabetic mouse. Vasorelaxation induced by nitroprusside was attenuated in 2 weeks, 2 or 4 month-diabetic ALS mice. Similarly the inhibitory effects of levcromakalim were attenuated at 2 and 4 months. The influences of diabetes on the inhibitory effects of forskolin or verapamil were very small or not detected. The effects of the vasomodulators used in this study on the vascular smooth muscles of alloxan-treated ALR mice did not differ from those of untreated ALR mice. The results from using ALS and ALR mice suggest that the vasoreactivities to some vasomodulators are changed especially in the long-term diabetic state and that when diabetes was not induced the dose of alloxan does not have any effect on vascular smooth muscle.}, }
@article {pmid9810502, year = {1998}, author = {Torchia, MG and Aitken, RM and Thliveris, A}, title = {The effect of thymic inoculation to induce tolerance of allogeneic thyroid grafts in the outbred rabbit.}, journal = {Histology and histopathology}, volume = {13}, number = {4}, pages = {1061-1068}, doi = {10.14670/HH-13.1061}, pmid = {9810502}, issn = {0213-3911}, mesh = {Animals ; Antilymphocyte Serum/immunology ; Cells, Cultured ; Graft Survival ; Immune Tolerance/*immunology ; Lymphocytes/cytology/immunology ; Rabbits ; Thymus Gland/cytology/*immunology ; Thyroid Gland/*immunology/*transplantation/ultrastructure ; Transplantation, Homologous/immunology ; }, abstract = {Many studies have demonstrated that allograft tolerance can be achieved in inbred rats and mice following intrathymic injection of donor cells or antigen and treatment with antilymphocyte serum (ALS). In outbred dogs, xenografts, and inbred rat strains with major MHC antigen difference, tolerance has not similarly been induced. The focus of this study was to determine whether allogeneic thyroid graft tolerance could be achieved in outbred rabbits. In the experimental group (n = 5), recipients received an intrathymic injection of donor lymphocytes and a single treatment of ALS. Controls (n = 5) received intrathymic cell culture medium and ALS treatment. Donor-recipient allogenicity was monitored with mixed lymphocyte culture (MLC) over 18 weeks. Donor thyroid tissue was placed into recipient gluteal muscle fibres one week following the last MLC measurement. A third group of rabbits (n = 4) received thyroid autografts without any other treatment. There were no differences in MLC stimulation indices (SI) between the control and experimental group nor did MLC (SI) change within groups. All thyroid autografts survived the two week monitoring period and demonstrated normal appearing thyroid follicles on histologic examination. All thyroid allografts showed severe acute rejection reactions on biopsy within one week. Further studies using outbred animals to examine the role of thymic inoculation are required to determine whether similar techniques might be successful in the human.}, }
@article {pmid9804538, year = {1998}, author = {Hardy, J and Gwinn-Hardy, K}, title = {Genetic classification of primary neurodegenerative disease.}, journal = {Science (New York, N.Y.)}, volume = {282}, number = {5391}, pages = {1075-1079}, doi = {10.1126/science.282.5391.1075}, pmid = {9804538}, issn = {0036-8075}, mesh = {Alzheimer Disease/classification/genetics/pathology ; Brain/pathology ; Genes, Dominant ; Humans ; Mutation ; Nerve Tissue Proteins/genetics ; Neurodegenerative Diseases/*classification/*genetics/pathology ; Parkinson Disease/classification/genetics/pathology ; Peptides/genetics/metabolism ; Synucleins ; Trinucleotide Repeats ; tau Proteins/genetics ; }, abstract = {Review During the past 10 years (the "decade of the brain"), some of the genetic causes of many of the primary neurodegenerative diseases, which include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion disease, and many ataxic syndromes, have been found. These breakthroughs mean that for many of these diseases we now know the initiating trigger as well as the final outcome. These diseases have many pathological mechanisms in common, and there may be relatively few pathways to neuronal death seen in these disorders. Thus, treatment strategies developed for a particular disease may be found to have efficacy in more than one disorder.}, }
@article {pmid9804111, year = {1998}, author = {Ikeda, K and Iwasaki, Y and Kinoshita, M}, title = {Neuronal nitric oxide synthase inhibitor, 7-nitroindazole, delays motor dysfunction and spinal motoneuron degeneration in the wobbler mouse.}, journal = {Journal of the neurological sciences}, volume = {160}, number = {1}, pages = {9-15}, doi = {10.1016/s0022-510x(98)00224-x}, pmid = {9804111}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis ; Animals ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Enzyme Inhibitors/administration &amp; dosage/*therapeutic use ; Hand Strength ; Indazoles/administration &amp; dosage/*therapeutic use ; Mice ; Mice, Neurologic Mutants ; Motor Neuron Disease/genetics/pathology/*prevention &amp; control ; Motor Neurons/pathology ; Muscle Denervation ; Muscle, Skeletal/pathology ; NG-Nitroarginine Methyl Ester/pharmacology/therapeutic use ; Nerve Tissue Proteins/*antagonists &amp; inhibitors/physiology ; Nitric Oxide Synthase/*antagonists &amp; inhibitors/physiology ; Nitric Oxide Synthase Type I ; Organ Size/drug effects ; Vacuoles/ultrastructure ; }, abstract = {Gene mutations of superoxide dismutase (SOD) have been discovered in familial amyotrophic lateral sclerosis (ALS). Neuronal nitric oxide synthase (NOS), endothelial NOS and 3-nitrotyrosine immunoreactivities are selectively increased in the spinal motoneurons of sporadic ALS. Other study suggests that 3-nitrotyrosine immunoreactivity is enhanced in the spinal motoneurons of sporadic and familial ALS patients. The hypothesis is postulated that increased production of radical species, such as superoxide and peroxynitrite, may cause motoneuron degeneration in ALS. There are increased amounts of nitric oxide and SOD hypoactivities in the brain and spinal cord of wobbler mice. NOS is also induced in the vacuolated spinal motoneurons or axons in this animal. Free radicals might contribute to the pathogenesis of wobbler mouse motoneuron disease. Lecithinized SOD treatment has retarded the progression of this disease. This evidence allowed us to determine whether NOS inhibitors delay progression of wobbler mouse motoneuron disease. After clinical diagnosis at age 3-4 weeks, wobbler mice were injected with intraperitoneal non-selective NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg), two doses of neuronal NOS inhibitor, 7-nitroindazole (5 or 50 mg/kg) or a vehicle solution, daily for 4 weeks in a blind fashion. In comparison with vehicle, 7-nitroindazole-treated mice potentiated grip strength and attenuated deformities in the forelimbs. 7-Nitroindazole treatment increased the biceps muscle weight, reduced denervation muscle atrophy, and suppressed degeneration of spinal motoneurons. To a lesser degree, L-NAME-treated mice displayed slowed progression of disease. The present studies indicate that neuronal NOS inhibitor may be a candidate for promising therapy in lower motoneuron disease or motor neuropathy.}, }
@article {pmid9801132, year = {1998}, author = {Zhang, X and Jin, L and Takenaka, I}, title = {MVAC chemotherapy-induced apoptosis and p53 alterations in the rat model of bladder cancer.}, journal = {Urology}, volume = {52}, number = {5}, pages = {925-931}, doi = {10.1016/s0090-4295(98)00364-1}, pmid = {9801132}, issn = {0090-4295}, mesh = {Animals ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; *Apoptosis ; Cisplatin/pharmacology ; Doxorubicin/pharmacology ; Genes, p53/*genetics ; Male ; Methotrexate/pharmacology ; Mutation ; Rats ; Rats, Wistar ; Urinary Bladder Neoplasms/*drug therapy/*genetics/pathology ; Vinblastine/pharmacology ; }, abstract = {OBJECTIVES: To investigate the induction of apoptosis by methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy as well as p53 alterations in a rat model of bladder cancer induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN).<br><br>METHODS: At 20 and 28 weeks after starting the administration of BBN, 60 rats (30 at 20 weeks, and 30 at 28 weeks) were divided into an MVAC treatment group (20 rats) and a control group of untreated rats (10 rats). After one intraperitoneal injection of MVAC, the rat bladder was obtained on day 1 or 7 for evaluation of apoptosis by biohistochemical and electron microscopic observations, and of p53 alterations immunohistochemically.<br><br>RESULTS: All tumors were noninvasive transitional cell carcinoma (TCC) at 20 weeks and invasive TCC at 28 weeks. In comparison with untreated tumors, a threefold increase of apoptotic indexes (Als) was noted in invasive TCC and a twofold increase in noninvasive TCC on day 1 after MVAC therapy. Both decreased Als and a frequent occurrence of apoptotic necrosis were observed on day 7. Occurrence of tumor necrosis was not affected by MVAC therapy, and the extent of necrosis was not related to apoptosis. Detection of p53 alterations, 45% and 40% in MVAC treated and untreated tumors, respectively, did not correlate with Als.<br><br>CONCLUSIONS: MVAC therapy may act through the induction of apoptosis, and invasive TCC cells may be much more sensitive to MVAC therapy in the rat model of bladder cancer. Neither spontaneous nor MVAC-induced apoptosis may be related to p53 alterations in the rat model of bladder cancer.}, }
@article {pmid9791781, year = {1998}, author = {Neatherlin, JS}, title = {Management of amyotrophic lateral sclerosis with riluzole.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {30}, number = {4}, pages = {257-260}, doi = {10.1097/01376517-199808000-00007}, pmid = {9791781}, issn = {0888-0395}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/nursing ; Humans ; Information Services ; Neuroprotective Agents/pharmacology/*therapeutic use ; Patient Selection ; Riluzole/pharmacology/*therapeutic use ; Self-Help Groups ; }, abstract = {In summary, riluzole is a recently-released drug for the treatment of ALS. While it will not cure the disease, it does prolong survival time and ventilator-free time. Riluzole has few adverse effects, but liver enzymes should be watched closely for elevations.}, }
@article {pmid9785755, year = {1998}, author = {Lasser, A and Vandenberg, TL and Vincent, MJ and Hellstrom, WJ}, title = {Intraplaque verapamil injection for treatment of Peyronie's disease.}, journal = {The Journal of the Louisiana State Medical Society : official organ of the Louisiana State Medical Society}, volume = {150}, number = {9}, pages = {431-434}, pmid = {9785755}, issn = {0024-6921}, mesh = {Adult ; Calcium Channel Blockers/*administration &amp; dosage ; Follow-Up Studies ; Humans ; Injections ; Male ; Middle Aged ; Pain Measurement ; Penile Induration/*therapy ; Treatment Outcome ; Verapamil/*administration &amp; dosage ; }, abstract = {We report our findings on the effects of intraplaque injection of verapamil for the treatment of Peyronie's disease. We followed 11 men with Peyronie's disease in a nonrandomized constant dose study. During our study, four men received testosterone supplementation; five received vitamin E and/or potassium aminobenzoate (potaba) concurrent with verapamil; two received injections of verapamil only. Plaque size decreased significantly in 7 of 11 patients (55%); softening occurred in 6 (55%); 4 of 8 patients (50%) had decreased curvature. Deformities and symptoms did not recur in any patients who reported improvement. Three of 11 (27%) patients failed treatment and elected to undergo surgical correction. All four (100%) of our study participants with pain had complete resolution after intraplaque verapamil injection compared with Levine et al's 91%. We have demonstrated that intraplaque verapamil injection is a promising treatment for Peyronie's disease in that it may circumvent surgical intervention and may be used with concurrent therapies.}, }
@article {pmid9773065, year = {1998}, author = {Couratier, P and Bernet-Bernady, P and Truong, T and Lagrange, E and Preux, PM and Lachatre, G and Vallat, JM}, title = {[Lead intoxication and amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {154}, number = {4}, pages = {345-347}, pmid = {9773065}, issn = {0035-3787}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/chemically induced/*physiopathology ; Chelating Agents/*therapeutic use ; Female ; Humans ; Lead Poisoning/*complications/drug therapy/etiology ; Succimer/*therapeutic use ; Treatment Outcome ; Water Supply ; }, abstract = {A seventy-six-year-old patient developed a bulbar form of amyotrophic lateral sclerosis, after chronic lead intoxication from drinking water. Treatment with 2,3 dimercaptosuccinic acid was administered for six months and had no effect on clinical course. We discuss the imputability of lead as a possible etiological factor.}, }
@article {pmid9768294, year = {1998}, author = {Anderlik, P and Antmann, K and Bános, Z}, title = {Effect of antilymphocyte serum on bacterial translocation in mice.}, journal = {Acta microbiologica et immunologica Hungarica}, volume = {45}, number = {2}, pages = {257-261}, pmid = {9768294}, issn = {1217-8950}, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; Bacterial Translocation/*drug effects ; Chlorpromazine/pharmacology ; Dianhydrogalactitol/pharmacology ; Female ; Immunosuppressive Agents/*pharmacology ; Liver/microbiology ; Lymph Nodes/microbiology ; Lymphocyte Count ; Male ; Mice ; Spleen/microbiology ; }, abstract = {Following intraperitoneally applied treatment with antilymphocyte serum (ALS) of immunosuppressive effect no bacterial translocation (BT) was observed in mice. The ALS treatment applied in combination with other immunosuppressive agents such as lymphotropic cytostatics as dianhydrogalactitol or chlorpromazine did not increase the mice's drug sensitivity to the used agents. According to our results, ALS can be suitable for combined application with other immunosuppressive agents as it can increase immunosuppression without side-effects such as those induced by bacterial translocation.}, }
@article {pmid9761381, year = {1998}, author = {Tze, WJ and Cheung, S and Tai, J and Tsang, A}, title = {Xenotransplantation of adult porcine islets in diabetic mice. A study of UVB irradiation, cryopreservation and immunosuppression on graft survival time.}, journal = {Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme}, volume = {30}, number = {8}, pages = {509-513}, doi = {10.1055/s-2007-978922}, pmid = {9761381}, issn = {0018-5043}, mesh = {Animals ; Blood Glucose/metabolism ; Cryopreservation ; Cyclosporine/therapeutic use ; Diabetes Mellitus, Experimental/*surgery ; Glucose Tolerance Test ; Graft Survival ; Immunosuppressive Agents/therapeutic use ; *Islets of Langerhans Transplantation ; Kinetics ; Mice ; Swine ; *Transplantation, Heterologous ; Ultraviolet Rays ; }, abstract = {The major obstacle for successful xenotransplantation of islets to large animals and human diabetics is the host rejection. To address the rejection problem, we studied the efficacy of UV-B irradiation, cryopreservation and immunosuppression on the in vivo functional time and immunogenicity of adult porcine islets (PI) in outbred CD1 mice. Exposure of PI to UV-B irradiation between 300-1800J/M2 did not affect the cellular viability as assessed by fluorescein diacetate or their daily insulin secretion in vitro. Fresh PI normalized the blood glucose (BG) of diabetic CD1 mice for 3.1+/-0.6 (n = 8, mean+/-SEM) days. Islets treated with 600J/M2 UV-B irradiation or cryopreservation had similar graft functional times to fresh islets upon transplantation in diabetic CD1 mice. Immunosuppression with cyclosporin A (CsA), antilymphocyte serum (ALS) and FK506 prolonged the functional time of fresh pig islets to 7.9+/-0.9 (n = 9), 6.2+/-1.3 (n = 5) and 24.2+/-10.4 (n = 12) days, respectively. However, additional pretransplant treatment with either UV-B irradiation or cryopreservation did not further increase the functional time of pig islets in mice immunosuppressed with CsA. Furthermore, there was no apparent difference in the frequency of appearance of cytotoxic antibodies and antibody titers in the recipients of UV-B irradiated or cryopreserved pig islet compared with non-treated islets. The UV-B irradiation and cryopreservation of PI before transplantation with the present protocols did not appear to have significant effect on the islet immunogenicity when assessed by in vivo survival duration and anti-donor antibody titer production.}, }
@article {pmid9757773, year = {1998}, author = {Ushikubo, M and Kawamura, S and Inaba, Y and Shima, C and Nakamura, T}, title = {[Characteristics of home care patients with intractable neurological diseases (Nanbyo) in Tokyo].}, journal = {[Nihon koshu eisei zasshi] Japanese journal of public health}, volume = {45}, number = {7}, pages = {653-663}, pmid = {9757773}, issn = {0546-1766}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/nursing ; Caregivers ; *Home Care Services ; Hospitalization ; Humans ; Middle Aged ; Nervous System Diseases/*nursing ; Parkinson Disease/nursing ; Respite Care ; Spinocerebellar Degenerations/nursing ; Surveys and Questionnaires ; Tokyo ; }, abstract = {The purpose of this study was to identify the characteristics of home care of patients with intractable neurological diseases. A survey was conducted of members of Tokyo Medical Association who were home visit doctors. They responded to questions about their patients who have suffered from either Parkinson's disease (PD), spinocerebellar degeneration (SCD), or amyotrophic lateral sclerosis (ALS), and whose home care have been supported by the care system for at least three months. Of 205 survey questionnaires collected, 198 were effective to be analyzed. The sample consisted of 105 patients with PD (53.0%), 63 patients with SCD (31.8%), and 30 patients with ALS (15.2%). The mean age of the PD was 75.5 years with a range of 53 to 90, SCD was 66.5 years with a range of 39 to 88, and ALS was 58.7 years with a range of 42 to 86. The major findings in this study were as follows: 1) The patients who had one or more medical equipment installed at the beginning of home care were 30% of ALS, 9% of PD and 18% of SCD. As time elapsed, patients who needed to have some medical equipment installed increased in ALS greater than in PD and SCD. 2) The home doctors predicted that the condition of 37% of ALS patients, 9% of PD, and 8% of SCD would probably be deteriorating within one month. 3) Of the 30 patients with ALS, 47% experienced hospitalization three times or more compared to 27% of PD and 21% of SCD. The most prevalent reason for hospitalization for ALS was respite of caregivers, PD and SCD, however, were hospitalized for control of prescription, a change for the worse, or treatment of other diseases. 4) Ninety percent of ALS caregivers felt extremely tired or slightly tired. Their home doctors responded that 83% of ALS caregivers did their best in caregiving. 5) ALS patients utilized social resources such as volunteers, care workers, services of supply and maintenance of medical equipment, and emergency care for 24 hours more than SCD and PD. In the conclusion, ALS patients experienced the highest hospitalization of the three diseases and respite of family caregivers was necessary. They showed a higher utilization of various social resources than other diseases. It is important to consider these characteristics of home care patients by diseases in order to prepare and develop the necessary support system of home care for the intractable neurological patients.}, }
@article {pmid9757416, year = {1998}, author = {Kuhlenbäumer, G and Bocchicchio, M and Kress, W and Young, P and Oberwittler, C and Stögbauer, F}, title = {[X-chromosomal recessive spinobulbar muscular atrophy (Kennedy type). Description of a family, clinical aspects, molecular genetics, differential diagnosis and therapy].}, journal = {Der Nervenarzt}, volume = {69}, number = {8}, pages = {660-665}, doi = {10.1007/s001150050325}, pmid = {9757416}, issn = {0028-2804}, mesh = {Diagnosis, Differential ; Genes, Recessive/*genetics ; Humans ; *Medulla Oblongata ; Muscular Atrophy, Spinal/diagnosis/*genetics ; Neurologic Examination ; Pedigree ; Receptors, Androgen/genetics ; Sex Chromosome Aberrations/diagnosis/*genetics ; Syndrome ; Trinucleotide Repeats/genetics ; *X Chromosome ; }, abstract = {The Kennedy-Syndrome is a X-linked recessive bulbospinal muscular atrophy, in some cases associated with endocrinological disturbances such as androgen resistance and diabetes mellitus. The age of onset is usually between 20 and 40. Presenting symptoms are proximal flaccid weakness, fasciculations, cramps or tremor. Disease progression is usually slow and live expectancy is normal. It is important to distinguish the Kennedy-Syndrome from amyotrophic lateral sclerosis, spinal muscular atrophy, muscular dystrophies and other types of motor neuron disease. Kennedy disease is caused by an expanded trinucleotide repeat in the androgen receptor gene. Genetic analysis allows a precise-diagnosis on an individual basis and reliable genetic counselling. An effective medical treatment does not yet exist.}, }
@article {pmid9747930, year = {1998}, author = {Matheron, L and Barrau, K and Blin, O}, title = {Disease management: the example of amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {245 Suppl 2}, number = {}, pages = {S20-8; discussion S29}, doi = {10.1007/pl00014806}, pmid = {9747930}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; *Disease Management ; Humans ; }, abstract = {Disease management is defined as any medical or pharmaceutical intervention designed to improve both outcomes for the patient and overall cost-effectiveness of the health plan. Disease management focuses on the patient throughout the entire course of the disease, involving both health providers and third-party payers. It requires structured management of change, inter- and intra-professional communication and access to information, identification of pertinent economic and clinical outcomes, and the establishment of guidelines, computerized systems and quality assurance. The concept of disease management remains controversial, primarily because its effectiveness is untested. Furthermore, if only economic outcomes are considered, ethical problems such as the selection of populations (for example, the exclusion from health care of people deemed 'too old') will emerge. As a model of neurodegenerative disease, amyotrophic lateral sclerosis (ALS) is a suitable condition for disease management. Many possible targets for disease management initiatives in ALS can be defined, including training, communication, education, guidelines for diagnosis, follow-up, clinical trials and treatments. Medico-economic studies need to be improved if accreditation is planned. Much remains to be done to improve the therapy and disease management of ALS. However, the identification of optimal treatment will improve care of ALS patients, particularly in less affluent countries.}, }
@article {pmid9747929, year = {1998}, author = {Silani, V and Kasarskis, EJ and Yanagisawa, N}, title = {Nutritional management in amyotrophic lateral sclerosis: a worldwide perspective.}, journal = {Journal of neurology}, volume = {245 Suppl 2}, number = {}, pages = {S13-9; discussion S29}, doi = {10.1007/pl00014805}, pmid = {9747929}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Cross-Cultural Comparison ; Humans ; *Nutritional Support ; }, abstract = {Although respiratory failure is the primary cause of death in patients with amyotrophic lateral sclerosis (ALS), the management of nutritional status is important to enhancing the quality of life and optimising the timing of interventive techniques. Progressively weakening muscles impair the patient's ability to eat, and nearly all patients with ALS develop severe dysphagia. If nutritional support is not provided, food and fluid consumption may be greatly restricted, leading to weight loss and malnutrition. This may be compounded by impaired respiratory functions, which place increased energy demands on the patient. This paper describes the nutritional needs of ALS patients from a worldwide and cross-cultural perspective. In particular, the differences between a paternalistic and a patient-centred approach to treatment are addressed. The need for further study into the nutritional status of ALS patients and the issue of parenteral and enteral nutritional therapy, particularly percutaneous endoscopic gastrostomy, are discussed.}, }
@article {pmid9739520, year = {1998}, author = {Tsuzaka, K and Mitsumoto, H}, title = {[Neurotrophic factor treatment in amyotrophic lateral sclerosis].}, journal = {No to shinkei = Brain and nerve}, volume = {50}, number = {7}, pages = {625-630}, pmid = {9739520}, issn = {0006-8969}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Brain-Derived Neurotrophic Factor/*therapeutic use ; Ciliary Neurotrophic Factor ; Glial Cell Line-Derived Neurotrophic Factor ; Humans ; Insulin-Like Growth Factor I/therapeutic use ; Nerve Growth Factors/*therapeutic use ; Nerve Tissue Proteins/*therapeutic use ; }, }
@article {pmid9739519, year = {1998}, author = {Kinoshita, M and Ikeda, K}, title = {[Treatment with lecithinized superoxide dismutase in amyotrophic lateral sclerosis].}, journal = {No to shinkei = Brain and nerve}, volume = {50}, number = {7}, pages = {615-624}, pmid = {9739519}, issn = {0006-8969}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Humans ; Mice ; Mutation ; *Phosphatidylcholines ; Rats ; Recombinant Proteins/therapeutic use ; Superoxide Dismutase/chemistry/genetics/*therapeutic use ; }, }
@article {pmid9726810, year = {1998}, author = {Apostolski, S and Marinković, Z and Nikolić, A and Blagojević, D and Spasić, MB and Michelson, AM}, title = {Glutathione peroxidase in amyotrophic lateral sclerosis: the effects of selenium supplementation.}, journal = {Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer}, volume = {17}, number = {3-4}, pages = {325-329}, pmid = {9726810}, issn = {0731-8898}, mesh = {Adult ; Aged ; Amino Acids/administration &amp; dosage ; Amyotrophic Lateral Sclerosis/blood/*diet therapy/*enzymology ; Calcium Channel Blockers/therapeutic use ; Catalase/blood ; *Dietary Supplements ; Double-Blind Method ; Erythrocytes/drug effects/enzymology ; Female ; Glutathione Peroxidase/*blood ; Glutathione Reductase/blood ; Glutathione Transferase/blood ; Humans ; Male ; Middle Aged ; Nimodipine/therapeutic use ; Selenium/*administration &amp; dosage ; Superoxide Dismutase/blood ; Vitamin E/administration &amp; dosage ; beta Carotene/administration &amp; dosage ; }, abstract = {The activity of glutathione peroxidase (GSH-Px) as well as the activities of other antioxidative enzymes: CuZn superoxide dismutase (CuZn SOD), catalase (CAT), glutathione reductase (GR) in erythrocytes, as well as the activity of plasma glutathione transferase (GST), and the plasma content of vitamins E and C were evaluated in 35 sporadic amyotrophic lateral sclerosis (sALS) patients. The results revealed significantly decreased activity of both GSH-Px and CuZn SOD in sALS patients compared with the control. These data showed that a disturbed oxidative/antioxidative balance in sALS patients exists not only in motoneurons but also in the blood. The effect of exogenously administered selenium (Se), antioxidants, amino acids, a Ca2+ channel blocker such as nimodipine, and their combination in Alsamin was evaluated by screening parameter levels after 9 weeks of treatment. Only the use of all components together enhanced the activity of GSH-Px and the amount of vitamin E in sALS patients. Judging by the results of clinical trials, this treatment slowed the course of the disease.}, }
@article {pmid9723527, year = {1998}, author = {Hale, D and Gottschalk, R and Maki, T and Monaco, AP}, title = {Use of pharmacologic immunosuppression to augment the specific unresponsiveness (tolerance) to skin allografts induced by donor-specific bone marrow in antilymphocyte serum-treated mice: the unique effect of sirolimus.}, journal = {Transplantation proceedings}, volume = {30}, number = {5}, pages = {2432-2434}, doi = {10.1016/s0041-1345(98)00676-9}, pmid = {9723527}, issn = {0041-1345}, mesh = {Animals ; Antilymphocyte Serum/*therapeutic use ; Bone Marrow Transplantation/*immunology ; Cytokines/biosynthesis/genetics ; Immunosuppression Therapy/*methods ; Immunosuppressive Agents/*therapeutic use ; Lymphocytes/immunology ; Mice ; Mice, Inbred Strains ; Polyenes/*therapeutic use ; Sirolimus ; Skin Transplantation/*immunology ; Transcription, Genetic ; Transplantation, Homologous ; }, abstract = {Tolerance produced with ALS treatment, DSBM, and sirolimus involves multiple mechanisms of a specific and nonspecific nature. In eventual clinical application for tolerance induction, sirolimus (rapamycin) has great potential for augmenting the tolerogenicity of the ALS/BM regimen.}, }
@article {pmid9715241, year = {1998}, author = {Schmidt, TA and Mann, NC and Federiuk, CS and Atcheson, RR and Fuller, D and Christie, MJ}, title = {Do patients refusing transport remember descriptions of risks after initial advanced life support assessment?.}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {5}, number = {8}, pages = {796-801}, doi = {10.1111/j.1553-2712.1998.tb02506.x}, pmid = {9715241}, issn = {1069-6563}, mesh = {*Emergency Medical Services ; Humans ; Mental Recall ; Resuscitation ; Risk ; Transportation of Patients ; *Treatment Refusal ; }, abstract = {OBJECTIVE: To determine patient recall and understanding of instructions given to patients who refuse transport after initial paramedic assessment and medical treatment.<br><br>METHODS: Following patient consent, a phone interview was completed for consecutive persons living in a large urban area for whom 9-1-1 was contacted but who subsequently refused transport after advanced life support (ALS) assessment. Subjects were asked about their recall of explained risks and benefits of transport, their understanding of those risks at the time of assessment, and subsequent use of medical care, including hospitalization.<br><br>RESULTS: From October 1, 1996, to February 23, 1997, 324 people refused transport after ALS arrival. Sixty-eight people could not be contacted, providing a response rate of 79% (256/324). Six percent were subsequently admitted to the hospital for the same problem and an additional 59% sought care from a health care provider (66 ED visits, 63 personal physician, 16 urgent care, 5 other). There were no unexpected deaths. Ninety (35%) respondents were still experiencing symptoms at the time of phone contact. Despite the routine practice of providing a verbal explanation of risks and written instructions, only 141 (55%) recalled receiving written instructions and 56 (22%) recalled an explanation of risks. Twenty-six percent believed they did not fully understand their conditions or circumstances surrounding the 9-1-1 call when they refused transport and 18% would now take an ambulance if the same incident were to recur.<br><br>CONCLUSION: A substantial proportion of patients refusing transport do not recall receiving verbal or written instructions and would reconsider their transport decision, raising doubts about people's ability to make informed decisions at a time of great vulnerability. The majority of patients accessed health care after refusing transport and 6% were hospitalized.}, }
@article {pmid9710040, year = {1998}, author = {Borasio, GD and Robberecht, W and Leigh, PN and Emile, J and Guiloff, RJ and Jerusalem, F and Silani, V and Vos, PE and Wokke, JH and Dobbins, T}, title = {A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group.}, journal = {Neurology}, volume = {51}, number = {2}, pages = {583-586}, doi = {10.1212/wnl.51.2.583}, pmid = {9710040}, issn = {0028-3878}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy ; Double-Blind Method ; Europe ; Humans ; Insulin-Like Growth Factor I/*therapeutic use ; Recombinant Proteins/therapeutic use ; }, abstract = {To test the safety and efficacy of recombinant human insulin-like growth factor-I (rhIGF-I) in ALS, 183 patients from eight European centers were randomized to receive double-blind placebo (n = 59) or rhIGF-I 0.1 mg/kg/day (n = 124) subcutaneously for 9 months. At study completion, the primary efficacy outcome measure (change in disease progression as assessed by the Appel ALS rating scale) showed no significant difference between treatment groups. RhIGF-I appeared to be safe and well-tolerated.}, }
@article {pmid9698746, year = {1998}, author = {Ferri-De-Barros, JE and Moreira, M}, title = {[Amyotrophic lateral sclerosis and herpes virus. Report of an unusual case: a cause or casual association?].}, journal = {Arquivos de neuro-psiquiatria}, volume = {56}, number = {2}, pages = {307-311}, doi = {10.1590/s0004-282x1998000200024}, pmid = {9698746}, issn = {0004-282X}, mesh = {Acyclovir/therapeutic use ; Amyotrophic Lateral Sclerosis/diagnosis/*virology ; Antiviral Agents/therapeutic use ; Herpesviridae Infections/cerebrospinal fluid/*diagnosis/drug therapy ; Herpesvirus 1, Human/*isolation &amp; purification ; Humans ; Male ; }, abstract = {OBJECTIVE: To present a curious case of amyotrophic lateral sclerosis (ALS).<br><br>CASE: A forty-seven year old man claimed of paresis in the arms since four years. The electrical study of the muscles and nerves diagnosis was ALS, type Vulpian-Bernardt. The cerebrospinal fluid study revealed an inflammatory process and the positivity of immulogical reactions for Herpes simplex I. The blood-brain barrier study showed the possibility that immunological response for Herpes simplex I was produced in the spinal fluid space. A magnetic resonance suggested cystic myelopathy of cervical spinal cord expanding from C2 to C4. The patient received endovenous acyclovir for 21 days. Until two months after the medication we did not submit the patient to other subsidiary examinations.<br><br>DISCUSSION: Until now there is no specific drug treatment for ALS. The notion that there is a "syndrome of ALS" related with various causes may help to treat some patients.}, }
@article {pmid9690875, year = {1998}, author = {Duong, F and Fournier, J and Keane, PE and Guénet, JL and Soubrié, P and Warter, JM and Borg, J and Poindron, P}, title = {The effect of the nonpeptide neurotrophic compound SR 57746A on the progression of the disease state of the pmn mouse.}, journal = {British journal of pharmacology}, volume = {124}, number = {4}, pages = {811-817}, doi = {10.1038/sj.bjp.0701885}, pmid = {9690875}, issn = {0007-1188}, mesh = {Animals ; Animals, Newborn ; Electrophysiology ; Mice ; Mice, Mutant Strains ; Motor Activity/drug effects ; Motor Neuron Disease/genetics/pathology/physiopathology/*prevention &amp; control ; Motor Neurons/drug effects/pathology ; Muscle, Skeletal/drug effects/innervation ; Naphthalenes/*pharmacology ; Nerve Degeneration/genetics/pathology/physiopathology/prevention &amp; control ; Nerve Fibers/drug effects/pathology ; Neuroprotective Agents/*pharmacology ; Pyridines/*pharmacology ; Sciatic Nerve/drug effects/pathology ; Time Factors ; }, abstract = {1. The progressive motor neuronopathy (pmn) mouse is an autosomal recessive mutant, in which the homozygotes suffer caudio-cranial degeneration of motor axons and die several weeks after birth. This strain provides the opportunity of testing potential therapeutic strategies for the treatment of motor neurone diseases such as amyotrophic lateral sclerosis. We have performed a study of the effects on the pmn mouse of SR 57746A, an orally-active, non-peptide compound which has been found to exhibit neurotrophic effects in vitro and in vivo. In order to treat the affected mice from birth, the mothers were administered 2.5 mg kg(-1). p.o., SR 57746A every two days until the weaning of the offspring (at day 20); then the offspring were given every two days a dose of 30 microg kg(-1), p.o., until their death. 2. Affected mice treated with SR 57746A had a lifespan 50% longer than that of the vehicle-treated mice (P=0.01). Compared to vehicle-treated pmn mice, SR 57746A improved the performance of the pmn mice in three different behavioural tasks. SR 57746A also maintained the amplitude of the motor evoked response of the gastrocnemius muscle, reduced the distal motor latency, and delayed the occurrence of the spontaneous denervation activity in this muscle. Histological studies indicated that at 20 days of age the mean surface areas of the fibres of the sciatic nerve were higher in SR 57746A-treated than in vehicle-treated mice. 3. At present, SR 57746A is the only orally active, nonpeptide compound known to be capable of delaying the progression of the motor neurone degeneration in pmn mice.}, }
@article {pmid9686839, year = {1998}, author = {Holló, G and Lakatos, P}, title = {Increase of endothelin-1 concentration in aqueous humour induced by argon laser trabeculoplasty in the rabbit. A preliminary study.}, journal = {Acta ophthalmologica Scandinavica}, volume = {76}, number = {3}, pages = {289-293}, doi = {10.1034/j.1600-0420.1998.760307.x}, pmid = {9686839}, issn = {1395-3907}, mesh = {Animals ; Anterior Chamber/surgery ; Aqueous Humor/*metabolism ; Endothelin-1/*metabolism ; Intraocular Pressure ; *Laser Therapy ; Rabbits ; Time Factors ; Tonometry, Ocular ; Trabeculectomy/*methods ; }, abstract = {PURPOSE: To investigate the impact of argon laser trabeculoplasty (ALT) on endothelin-1 (ET-1) concentration of aqueous humour and intraocular pressure (IOP) in the rabbit.<br><br>METHODS: Standard ALT was performed on one eye of 19 pigmented rabbits. A modified treatment in which the laser light was focused on the inner limbal surface (argon laser scleroplasty, ALS) was also performed on one eye of a further 15 rabbits. IOP was measured with a Tono-Pen-2 tonometer before treatment, under general anaesthesia. Post-laser IOP measurements followed by aqueous humour aspiration were performed under general anaesthesia 4, 24 and 120 hours after treatment. IOP readings were considered relative values, since the tonometer was calibrated to the human eye and not to the rabbit eyeball. Different groups of animals were used for the tests after each time period. The groups of 4 hours time consisted of 9 animals which had undergone ALT and 5 which had undergone ALS. All the other groups consisted of 5 animals each.<br><br>RESULTS: In the ALT group IOP decreased following treatment, and the IOP change (a relative change) showed a significant difference between the treated and the control eyes at all three follow-up times (paired t-test, p<0.05), and a significant interaction was found between treatment and follow-up time (ANOVA, p<0.05). Concentration of ET-1 in the aqueous humour of the treated eyes increased by about an order of magnitude 4 hours after ALT, compared to the contralateral control eyes (103.66+/-41.59 pg/ml versus 8.75+/-2.95 pg/ml, Wilcoxon matched pairs test, p<0.01). ET-1 concentration 24 and 120 hours after ALT, however, did not differ significantly from the corresponding contralateral control values. In the ALS group neither IOP change nor aqueous humour ET-1 concentration differed in a statistically significant manner between the treated and control eyes.<br><br>CONCLUSIONS: The results suggest that ALT is followed by an immediate and short-term increase of aqueous humour ET-1 concentration in the rabbit, probably due to leakage from the uveal tissue.}, }
@article {pmid9671775, year = {1998}, author = {Matthews, RT and Yang, L and Browne, S and Baik, M and Beal, MF}, title = {Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {95}, number = {15}, pages = {8892-8897}, pmid = {9671775}, issn = {0027-8424}, support = {P01 AG012992/AG/NIA NIH HHS/United States ; P50 NS016367/NS/NINDS NIH HHS/United States ; NS16367/NS/NINDS NIH HHS/United States ; P01 AG12992/AG/NIA NIH HHS/United States ; NS31579/NS/NINDS NIH HHS/United States ; }, mesh = {Administration, Oral ; Animals ; Brain/*drug effects/metabolism ; Coenzymes ; Humans ; Male ; Mice ; Mice, Transgenic ; Mitochondria/*drug effects/metabolism ; Neuroprotective Agents/*administration &amp; dosage ; Rats ; Rats, Inbred F344 ; Rats, Sprague-Dawley ; Superoxide Dismutase/genetics ; Ubiquinone/administration &amp; dosage/*analogs &amp; derivatives/metabolism ; }, abstract = {Coenzyme Q10 is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes. Feeding with coenzyme Q10 increased cerebral cortex concentrations in 12- and 24-month-old rats. In 12-month-old rats administration of coenzyme Q10 resulted in significant increases in cerebral cortex mitochondrial concentrations of coenzyme Q10. Oral administration of coenzyme Q10 markedly attenuated striatal lesions produced by systemic administration of 3-nitropropionic acid and significantly increased life span in a transgenic mouse model of familial amyotrophic lateral sclerosis. These results show that oral administration of coenzyme Q10 increases both brain and brain mitochondrial concentrations. They provide further evidence that coenzyme Q10 can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases.}, }
@article {pmid9665611, year = {1998}, author = {Hivert, B and Cerruti, C and Camu, W}, title = {Hydrogen peroxide-induced motoneuron apoptosis is prevented by poly ADP ribosyl synthetase inhibitors.}, journal = {Neuroreport}, volume = {9}, number = {8}, pages = {1835-1838}, doi = {10.1097/00001756-199806010-00031}, pmid = {9665611}, issn = {0959-4965}, mesh = {Animals ; Apoptosis/*drug effects ; Benzamides/pharmacology ; Cells, Cultured ; Embryo, Mammalian/cytology/drug effects ; Enzyme Inhibitors/*pharmacology ; Genetic Techniques ; Hydrogen Peroxide/*pharmacology ; Motor Neurons/cytology/*drug effects ; Niacinamide/pharmacology ; Oxidative Stress/drug effects ; *Poly(ADP-ribose) Polymerase Inhibitors ; Rats ; Rats, Sprague-Dawley ; }, abstract = {The impact of oxidative stress (H2O2) was observed using purified rat motoneuron cultures and H2O2-induced dose-dependent motoneuron death was demonstrated. The apoptotic characteristics of cell death were studied morphologically and using the TUNEL technique. This H2O2-induced motoneuron death was inhibited by the poly ADP ribosyl synthetase (PARS) inhibitors benzamide and nicotinamide. These findings suggest the potential utility of PARS inhibitors in the treatment of neurodegenerative disorders such as amyotrophic lateral sclerosis, in which oxidative stress has been suspected to play an important etiopathogenic role.}, }
@article {pmid9665596, year = {1998}, author = {Kalra, S and Cashman, NR and Genge, A and Arnold, DL}, title = {Recovery of N-acetylaspartate in corticomotor neurons of patients with ALS after riluzole therapy.}, journal = {Neuroreport}, volume = {9}, number = {8}, pages = {1757-1761}, doi = {10.1097/00001756-199806010-00016}, pmid = {9665596}, issn = {0959-4965}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/pathology ; Aspartic Acid/*analogs &amp; derivatives/metabolism ; Excitatory Amino Acid Antagonists/*therapeutic use ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Motor Cortex/*drug effects/metabolism ; Motor Neurons/*drug effects/metabolism ; Riluzole/*therapeutic use ; }, abstract = {Riluzole, a glutamate antagonist, has been shown to be efficacious in the treatment of patients with amyotrophic lateral sclerosis (ALS), allowing prolonged survival and time to tracheostomy. The efficacy of riluzole in thought to result from reduced glutamate excitotoxicity on motor neurons of patients with ALS, but this has never been demonstrated directly in vivo. N-acetylaspartate (NAA), a compound that is readily measured in vivo using proton magnetic resonance spectroscopy, can be used as a surrogate marker for neuronal loss or sublethal injury. To determine whether riluzole reverses sublethal corticomotoneuron damage in patients with ALS we measured NAA/creatine (Cr) relative intensity ratios in the motor cortex before and after treatment with riluzole 50 mg bid. After 3 weeks of riluzole therapy in 11 patients NAA/Cr increased from 2.14 +/- 0.26 to 2.27 +/- 0.24 (p = 0.044), whereas, in 12 untreated patients NAA/Cr decreased from 2.17 +/- 0.20 to 2.08 +/- 0.20 (p = 0.099). Thus the change in NAA/Cr between the treated and untreated groups was 0.22 +/- 0.095 (p = 0.008). The magnitude of increase in NAA/Cr in those treated was not correlated with age, sex, duration of treatment or disease, the presence of probable or definite upper motor neuron (UMN) signs, bulbar features, or pre-treatment NAA/Cr. We conclude that magnetic resonance spectroscopy can provide a novel surrogate measure of neuronal integrity that demonstrates reversal of sublethal UMN injury in patients with ALS within weeks of initiating riluzole therapy.}, }
@article {pmid9657073, year = {1997}, author = {Mandel, SH and Moreland, E and Rosenfeld, RG and Gargosky, SE}, title = {The effect of GH therapy on the immunoreactive forms and distribution of IGFBP-3, IGF-I, the acid-labile subunit, and growth rate in GH-deficient children.}, journal = {Endocrine}, volume = {7}, number = {3}, pages = {351-360}, pmid = {9657073}, issn = {1355-008X}, mesh = {Adolescent ; Blotting, Western ; Carrier Proteins/immunology/*metabolism ; Child ; Child, Preschool ; Densitometry ; Female ; Glycoproteins/immunology/*metabolism ; Glycosylation ; Growth/*drug effects ; Human Growth Hormone/deficiency/*therapeutic use ; Humans ; Infant ; Insulin-Like Growth Factor Binding Protein 3/immunology/*metabolism ; Insulin-Like Growth Factor I/immunology/*metabolism ; Male ; }, abstract = {We have previously shown that the major correlates of growth following growth hormone (GH) therapy in growth hormone-deficient (GHD) children are changes in circulating insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3), suggesting a synergistic interaction between IGF-I and IGFBP-3 (1). The first aim of this project was to examine the molecular forms of IGFBP-3 and the acid-labile subunit (ALS), and to assess the changes in these molecular forms during GH administration to GHD children. Plasma samples from prepubertal GHD patients, prior to therapy and during the first year of GH treatment, were subjected to Western ligand and immunoblot analysis. Densitometric analysis of Western ligand blotting (WLB) showed a 76% increase in IGFBP-3 (p = 0.02), but a 56% decrease in 36-kDa IGFBP-2 (p = 0.03) during GH therapy. Western immunoblot (WIB) analysis of IGFBP-3 revealed the presence of intact (40- to 45-kDa doublet) as well as a proteolyzed (28-kDa) form of IGFBP-3 in the serum of GHD and healthy children. Both immunoreactive forms of IGFBP-3 increased by 64% during GH therapy (intact p = 0.003; proteolyzed p = 0.0001). WIB analysis of the ALS showed an 84-to 86-kDa doublet, which increased by 41% with GH therapy (p = 0.01). The response to GH therapy, as measured by the height velocity standard deviation score (SDS) adjusted for bone age, correlated with the percent change in total IGFBP-3 (r = 0.772, p = 0.002 by WIB), intact IGFBP-3 (r = 0.845, p = 0.0005 by WLB; r = 0.541, p = 0.05 by WIB), and proteolyzed IGFBP-3 (r = 0.703, p = 0.007), as well as with the percent change in ALS (r = 0.813, p = 0.014). The second aim of this project was to assess the changes in distribution of the immunoreactive forms of IGFBP-3 and IGF-I among the ternary (ALS/IGFBP-3/IGF) complex, the binary (IGFBP-3/IGF) complex, and uncomplexed IGF during the first year of GH therapy, and to explore further the correlation with growth response to GH. Plasma samples, prior to therapy and after the first year of GH treatment, were separated by neutral size-exclusion chromatography and then subjected to IGFBP-3 immunoradiometric assay (IRMA), IGFBP-3 WIB, and IGF-I IRMA analysis. IGFBP-3 increased in both the ternary (p < 0.0001) and binary (p = 0.01) complexes, but there was a shift in the percentage of IGFBP-3 from the binary to the ternary complex during GH therapy. Both intact and proteolyzed forms of IGFBP-3 were found in both the ternary and binary complexes, but the shift occurred primarily for the proteolyzed (28-kDa) form (p = 0.001). There was a significant increase in IGF-I in the ternary (p = 0.001) and binary (p = 0.005) complexes, but not in uncomplexed IGF-I. The percentage of IGF-I in the ternary complex increased (p = 0.006), whereas the percentage of uncomplexed IGF-I decreased (p = 0.02), during GH therapy. Growth rate, assessed by the height velocity SDS for bone age, correlated best with the changes in ternary complex IGFBP-3 (r = 0.72, p = 0.01) and ternary complex IGF-I (r = 0.56, p = 0.10). In conclusion, GH treatment of GHD children results in significant increases of intact, proteolyzed, and total IGFBP-3, as well as an increase in ALS, which all correlate with the growth response to GH therapy. In addition, GH treatment results in increases in ternary complex IGFBP-3 and IGF-I, which also correlate with the response to therapy. We suggest that the formation of the ternary complex may be a determining factor in the somatic growth response.}, }
@article {pmid9634658, year = {1998}, author = {Lorigados, L and Pavón, N and Serrano, T and Robinson, MA}, title = {[Nerve growth factor and neurological diseases].}, journal = {Revista de neurologia}, volume = {26}, number = {153}, pages = {744-748}, pmid = {9634658}, issn = {0210-0010}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/blood/*drug therapy ; Antibodies, Monoclonal ; Female ; Humans ; Huntington Disease/blood/*drug therapy ; Male ; Middle Aged ; Multiple Sclerosis/blood/*drug therapy ; Nerve Growth Factors/blood/*therapeutic use ; Treatment Outcome ; }, abstract = {INTRODUCTION: The effects of Nerve Growth Factor (NGF) within and outside the nervous system have been amply discussed in recent decades. Recently clinical studies have shown the effectiveness of this growth factor in the treatment of neurodegenerative disorders. This clinical use makes it necessary to have sensitive, specific methods available to permit measurement of the level of this protein and to determine how it behaves during the course of treatment.<br><br>OBJECTIVE: To describe the measurement of NGF levels in human serum using an immunoenzymatic method and evaluating the levels of this protein in some neurological disorders. Materials and methods. NGF levels were measured in the serum of healthy persons and in patients with Alzheimer's disease (AD) Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington's chorea (HC) using a double site immune-enzymatic assay. Murine 27/21 anti-beta-NGF monoclonal antibody was used as the antibody to cover the plate and as conjugate.<br><br>RESULTS: Adding a block pass to the method, in which the sample was incubated with an excess of 27/21 antibody effectively reduced the signal observed in the immuno-enzymatic assay. A moderate reduction in beta-NGF levels was seen in the serum of patients with ALS and MS. There was a statistically significant reduction in the patients who were carriers of PD and HC.<br><br>CONCLUSIONS: The significant reduction in NGF levels in patients with PD and HC may be associated with a disorder in the use of this protein in central and peripheral tissues.}, }
@article {pmid9626243, year = {1998}, author = {Chan, KM and Doherty, TJ and Andres, LP and Porter, MM and Brown, T and Brown, WF}, title = {Longitudinal study of the contractile and electrical properties of single human thenar motor units.}, journal = {Muscle &amp; nerve}, volume = {21}, number = {7}, pages = {839-849}, doi = {10.1002/(sici)1097-4598(199807)21:7&lt;839::aid-mus1&gt;3.0.co;2-7}, pmid = {9626243}, issn = {0148-639X}, mesh = {Action Potentials/physiology ; Adult ; Axons/physiology ; Electromyography ; Humans ; Longitudinal Studies ; Middle Aged ; Motor Neurons/*physiology/ultrastructure ; Muscle Contraction/*physiology ; Muscle Fibers, Skeletal/*physiology ; Muscle, Skeletal/cytology/*innervation/*physiology ; Neural Conduction/physiology ; Reaction Time/physiology ; }, abstract = {Serial motor unit number estimates have shed important light on the extent and rates of motoneuron losses in aging and amyotrophic lateral sclerosis. However, the estimates alone provide few clues to the health and functional status of surviving motor units. A reliable means for assessing the functional status of the surviving motor units would therefore by a welcome addition to our present tools for studying motor units. Examining the physiological properties of samples of motor units drawn at intervals during the course of a motoneuronal disease suffers from the important limitation that the samples may not be representative of one another. The latter problem could be circumvented by serially studying the same motor units. This study describes a noninvasive technique capable of longitudinally tracking the contractile and electrical properties of specific single thenar motor units in healthy subjects, in some instances over several years. The technique proved to be reasonably reliable and provided information on a wide range of contractile and electrical properties of motor units. Such an approach could serve as a potentially powerful and sensitive means of studying the life histories of single motor units in aging, diseases of the motoneuron, and in the latter instances, the responses of the motoneurons to treatment.}, }
@article {pmid9625304, year = {1998}, author = {Galassi, G and Gentilini, M and Ferrari, S and Ficarra, G and Zonari, P and Mongiardo, N and Tommelleri, G and Di Rienzo, B}, title = {Motor neuron disease and HIV-1 infection in a 30-year-old HIV-positive heroin abuser: a causal relationship?.}, journal = {Clinical neuropathology}, volume = {17}, number = {3}, pages = {131-135}, pmid = {9625304}, issn = {0722-5091}, mesh = {Acquired Immunodeficiency Syndrome/*complications/pathology ; Adult ; Atrophy ; HIV Seropositivity/*complications/pathology ; Heroin Dependence/*complications/pathology ; Humans ; Male ; Motor Neuron Disease/etiology/*pathology ; }, abstract = {Although human retroviruses seem plausible agents of motor neuron diseases, there are only few reports of patients infected by the human immunodeficiency virus, with documented motor neuron disorder. That retroviral infections may cause motor neuron pathology by various mechanisms in animals and humans is known. Neurological symptoms potentially attributed to damage of lower motor neurons are often described during the course of HIV-1 infection and AIDS, however, it is often difficult to establish whether the disorder is primarily affecting the perikarya of lower motor neurons, or whether it is due to a focal proximal axonopathy, or to a dying-back process. We report a 30-year-old heroin abuser, HIV-1 positive, who presented a rapidly progressive limb weakness, muscle wasting, and bulbar signs, in absence of sensory loss of cerebellar and pyramidal signs. Imaging studies were negative. CSF showed increased protein content, negative cytology, and no oligoclonal bands. Serum protein electrophoresis, urinary heavy metal, and viral researches were negative. CD4 cells were counted 340 mm3 with a CD4-CD8 ratio equal to 0.4. Electrophysiology showed acute and chronic neurogenic changes, confirmed by muscle biopsy. Conduction studies along motor and sensory nerves fell within normal range. Biopsy of sural nerve revealed mild myelinated and unmyelinated fiber loss, occasional degeneration and regeneration, unremarkable inflammation. Despite treatment with AZT, zalcitabine, and steroids, the patient died after 3-month illness. Neuropathology showed normal cortical cell Betz's, and hemispheric white matter. Brain stem motor nuclei (inferior olival, dorsal motor of the vagus, hypoglossal) showed atrophy and intracytoplasmatic lipofuscin accumulation. Vacuolization, central chromatolysis, and neuronophagia were rarely seen. As associated pathology, in the fourth ventricle there were two small subependymal foci of demyelination, with reactive astrocytes and vascular proliferation. A possible crucial role of the HIV-1 infection in the development and progression of our patient's illness is considered in view of the known altered immunity proved in MND and ALS cases.}, }
@article {pmid9623518, year = {1998}, author = {Juul, A and Andersson, AM and Pedersen, SA and Jørgensen, JO and Christiansen, JS and Groome, NP and Skakkebaek, NE}, title = {Effects of growth hormone replacement therapy on IGF-related parameters and on the pituitary-gonadal axis in GH-deficient males. A double-blind, placebo-controlled crossover study.}, journal = {Hormone research}, volume = {49}, number = {6}, pages = {269-278}, doi = {10.1159/000023186}, pmid = {9623518}, issn = {0301-0163}, mesh = {Adrenocorticotropic Hormone/blood ; Adult ; Amyotrophic Lateral Sclerosis/blood ; *Antigens, Surface ; Carboxypeptidases/blood ; Cross-Over Studies ; Double-Blind Method ; Estradiol/blood ; Follicle Stimulating Hormone/blood ; Glutamate Carboxypeptidase II ; Gonadotropin-Releasing Hormone/blood ; Human Growth Hormone/*deficiency/*therapeutic use ; Humans ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/*metabolism ; Luteinizing Hormone/blood ; Male ; Peptides/blood ; Pituitary Gland/*drug effects/metabolism/physiopathology ; *Prostatic Secretory Proteins ; Sex Hormone-Binding Globulin/analysis ; Sperm Count ; Testis/*drug effects/metabolism/physiopathology ; Testosterone/blood ; }, abstract = {It has been suggested that growth hormone (GH) may play a regulatory role in male reproductive function. To express full anabolic effect in immature boys testosterone apparently requires the presence of GH. In GH-deficient adults, GH replacement therapy exerts a variety of anabolic actions, some of which are similar to the effects of gonadal steroids. However, little is known about the potential effects of GH on gonadal steroids and on dynamic tests of pituitary-gonadal function in adults with GH deficiency. We evaluated the pituitary-gonadal axis in a 4-month double-blind, placebo-controlled GH study in 13 young males with childhood-onset GH deficiency of which 6 had isolated GH deficiency. GH treatment significantly increased serum levels of total IGF-I from 98 (68) to 323 (126) microg/l, free IGF-I from 0.48 (0.47) to 2.24 (1.66) microg/l, IGFBP-3 from 1,874 (1,178) to 3,520 (778) microg/l and ALS levels from 9,182 (5,524) to 16,872 (6,278) microg/l (all p < 0.0001). We found no differences in basal testosterone levels in the 13 patients between the GH and placebo treatment periods (21.9 (5.1) vs. 24.5 (8.1) nmol/l, nonsignificant). Furthermore, no effect of GH on the testicular response to hCG after 72 h was seen compared to placebo (36.2 (6.4) vs. 38.8 (10.3) nmol/l). In addition, no differences existed in basal SHBG, DHT, free testosterone, delta4-adion and DHEA-S levels. There were no statistically significant differences in maximal FSH and LH response to a GnRH challenge between the GH and the placebo periods (15.7 (5.3) vs. 18.0 (8.8) U/l and 47.0 (26.4) vs. 40.4 (26.5) U/l, respectively). Furthermore, there was no effect on cortisol responses after ACTH between the GH and the placebo periods. However, significantly higher estradiol levels were seen after GH treatment (110 (50) pmol/l) compared to after placebo (89 (34) pmol/l, p = 0.03). Prostate-specific antigen levels decreased after GH treatment compared to after placebo (0.42 (0.54) vs. 0.47 (0.48) microg/l) and this difference almost reached statistical significance (p = 0.059). Inhibin-B levels were significantly lower in hypogonadal patients substituted with androgens, but GH had no effect on inhibin-B levels. In conclusion, GH replacement therapy in 13 GH-deficient young adult males resulted in significant increases in total and free IGF-I as well as in ALS levels in all patients, but had no significant effect on: (1) the pituitary FSH and LH response to GnRH; (2) basal and hCG-stimulated levels of androgens and SHBG; (3) basal inhibin-B levels; (4) ACTH-stimulated cortisol secretion. By contrast, GH administration had subtle anti-androgenic effects in terms of elevated elevated estradiol levels and decreased prostate-specific antigen levels, although both parameters remained within the normal range. Thus, at the level of blood chemistry the effects of GH administration do not appear to involve major alterations in the pituitary-gonadal axis.}, }
@article {pmid9618641, year = {1998}, author = {Ries, S and Wöhrle, JC and Samman, I and Huck, K}, title = {[Neurologic cause for a respiratory insufficiency].}, journal = {Deutsche medizinische Wochenschrift (1946)}, volume = {123}, number = {19}, pages = {594-596}, doi = {10.1055/s-2007-1024025}, pmid = {9618641}, issn = {0012-0472}, mesh = {Acute Disease ; Aged ; Amyotrophic Lateral Sclerosis/*complications/diagnosis/therapy ; Diagnosis, Differential ; Electrophysiology ; Humans ; Male ; Muscle, Skeletal/physiopathology ; Parasympathomimetics/therapeutic use ; Pyridostigmine Bromide/therapeutic use ; Respiration, Artificial ; Respiratory Insufficiency/*etiology/therapy ; Respiratory Muscles/physiopathology ; }, abstract = {HISTORY AND CLINICAL FINDING: A 73-year-old man developed progressive respiratory failure within 24 hours, requiring emergency admission for mechanical ventilation. The cause of the dyspnoea and tachypnoea could not be ascertained by routine medical and neurological examination. Neuromuscular disease or a cerebral lesion was considered in the differential diagnosis, together with a cardiovascular cause.<br><br>INVESTIGATIONS: Neither laboratory tests nor additional investigations (chest radiogram, echocardiography) gave a diagnosis. Magnetic resonance imaging and computed tomography excluded a focal cerebral or spinal lesion or a space-occupying lesion in the region of the phrenic nerve. An electrophysiological tests (EPT) failed to establish a neuromuscular disease. However, when signs of upper motor neurone irritation appeared, more detailed EPTs, also of the muscles of breathing, provided the diagnosis of amyotrophic lateral sclerosis (ALS).<br><br>TREATMENT AND COURSE: Symptomatic treatment with pyridostigmine made it possible gradually to wean the patients off the ventilator so that he could be sent home on intermittent mechanical ventilation.<br><br>CONCLUSION: In case of acute respiratory failure without cardiopulmonary cause motoneurone disease with initial involvement of respiratory musculature should be considered, even in the absence of clinical signs, and special electrophysiological tests may be necessary to recognize the underlying disease.}, }
@article {pmid10181926, year = {1998}, author = {Abbott, D and Brauer, K and Hutton, K and Rosen, P}, title = {Aggressive out-of-hospital treatment regimen for severe closed head injury in patients undergoing air medical transport.}, journal = {Air medical journal}, volume = {17}, number = {3}, pages = {94-100}, doi = {10.1016/s1067-991x(98)90102-x}, pmid = {10181926}, issn = {1067-991X}, mesh = {*Air Ambulances ; *Ambulances ; Case-Control Studies ; Clinical Protocols ; Craniocerebral Trauma/*mortality/*therapy ; Emergency Treatment ; Humans ; Survival Analysis ; Transportation of Patients/*methods ; *Treatment Outcome ; }, abstract = {The impact of aggressive out-of-hospital management on disposition for 1286 patients with closed head injuries in ground advanced life support (ALS) and helicopter services was evaluated over 60 months in San Diego County. The case group included 196 air medical patients with a scene Glascow coma scale (GCS) < 9 who were treated according to a standard head injury protocol. The frequency matched control group included 1090 ground ALS patients receiving airway management with hyperventilation but neither induction agents nor mannitol. The trauma registry provided admission and discharge dates, neurosurgical interventions, and disposition. Patient age, scene GCS, head and neck abbreviated injury scale (HNAIS), and injury severity score (ISS) served to stratify study groups. Case-control distribution of mortality was compared with the two-tailed Mantel-Haenszel weighted odds ratio (OR) and chisquared test; significance at P < or = 0.05. The case group displayed an 11% decreased mortality (P < 0.01), remaining significant after adjusting for age (P = 0.05) and scene GCS (P = 0.06). The case group displayed 10% (P < 0.01) greater survivor discharges to rehabilitation and 6% (P < 0.05) fewer discharges to extended care facilities. This study's data indicate a strong possibility for improved patient morbidity and mortality in severe closed head injuries treated with an aggressive treatment protocol and rapid air medical transport.}, }
@article {pmid9527898, year = {1998}, author = {Lindå, H and Hammarberg, H and Cullheim, S and Levinovitz, A and Khademi, M and Olsson, T}, title = {Expression of MHC class I and beta2-microglobulin in rat spinal motoneurons: regulatory influences by IFN-gamma and axotomy.}, journal = {Experimental neurology}, volume = {150}, number = {2}, pages = {282-295}, doi = {10.1006/exnr.1997.6768}, pmid = {9527898}, issn = {0014-4886}, mesh = {Animals ; Axotomy ; Cells, Cultured ; Female ; *Genes, MHC Class I ; Histocompatibility Antigens Class I/analysis/*biosynthesis ; In Situ Hybridization ; Interferon-gamma/*pharmacology ; Motor Neurons/drug effects/immunology/*physiology ; RNA, Messenger/biosynthesis ; Rats ; Rats, Sprague-Dawley ; Receptors, Interferon/analysis/*biosynthesis ; Recombinant Proteins ; Spinal Cord/immunology/*physiology ; *Transcription, Genetic/drug effects ; beta 2-Microglobulin/analysis/*biosynthesis ; Interferon gamma Receptor ; }, abstract = {The low expression of MHC antigens is believed to be one factor of importance contributing to the immune-privileged status of CNS neurons. We here describe that motoneurons, in contrast to other nerve cells in the lumbar spinal cord of the adult rat, express both MHC class I and beta2-microglobulin mRNA. The motoneurons also display in situ hybridization signal for IFN-gamma receptor mRNA. After a peripheral axotomy, the motoneurons show a clear upregulation of beta2-microglobulin mRNA. IFN-gamma treatment of cultured rat embryonic spinal motoneurons causes a similar upregulation of especially beta2-microglobulin. Based on these facts, we propose that spinal motoneurons can be influenced by IFN-gamma and recognized by cytotoxic CD8+ T-cells. These findings could be of relevance in the search for pathogenetic mechanisms in motoneuron-specific diseases, such as ALS.}, }
@article {pmid9588223, year = {1998}, author = {Fujii, Y and Sugawara, E and Hayashi, K and Sano, S}, title = {Neonatal intrathymic splenocyte injection yields prolonged cardiac xenograft survival.}, journal = {Acta medica Okayama}, volume = {52}, number = {2}, pages = {83-88}, doi = {10.18926/AMO/31313}, pmid = {9588223}, issn = {0386-300X}, mesh = {Animals ; Animals, Newborn/*physiology ; *Cell Transplantation ; Cricetinae ; Graft Survival/*physiology ; *Heart Transplantation ; Immune Tolerance/physiology ; Injections ; Male ; Mesocricetus ; Myocardium/pathology ; Rats ; Rats, Inbred Lew ; Spleen/*cytology ; Thymus Gland/pathology/*physiology ; Time Factors ; *Transplantation, Heterologous ; }, abstract = {Intrathymic (i.t.) injection of allogenic cells without administration of anti-lymphocyte serum (ALS) in neonatal recipients has induced donor-specific tolerance to subsequent cardiac allografts in rats. This study examines whether similar tactics can be successfully applied to a hamster-to-rat cardiac xenotransplantation model. Lewis neonates on their first day of life underwent i.t., subcutaneous (s.c.), intraperitoneal (i.p.), or intravenous (i.v.) injections of 5 x 10(7) Golden Syrian hamster splenocytes. After six weeks, the rats underwent heterotopic cardiac transplantation of hamster hearts. Cyclophosphamide (CyP) was administered on the day before surgery and postoperatively to suppress antibody-mediated graft rejection. Rats given splenocytes with 80 mg/kg of CyP had the following graft survival times: 8 to 12 days for i.t. injection (mean, 9.4 days); 5 to 7 days for s.c. injection (mean, 6.6 days); 4 to 11 days for i.p. injection (mean, 7.4 days); and 4 to 13 days for i.v. injection (mean, 7.9 days). Only the extension of graft survival produced by i.t. injection was statistically significant in comparison with the rats given only CyP treatment (mean, 7.5 days; P < 0.05). Thus, it appears that i.t. injection of xenogenic splenocytes in neonatal recipients with administration of CyP, but without ALS, can prolong xenograft survival. This biological intervention may be most useful in pediatric xenotransplantation when combined with other immunomodulation techniques.}, }
@article {pmid9562996, year = {1998}, author = {Maertens de Noordhout, A}, title = {[Applications of cortical magnetic stimulation].}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {28}, number = {1}, pages = {9-30}, doi = {10.1016/s0987-7053(97)89575-5}, pmid = {9562996}, issn = {0987-7053}, mesh = {Animals ; Cerebral Cortex/*physiology ; *Electromagnetic Fields ; Humans ; *Magnetoencephalography ; Motor Cortex/physiology ; }, abstract = {In the last decade, a new electrophysiological tool has become available since the development of painless magnetic stimulators able to activate the primary motor cortex and the motor roots in conscious man. Therefore, it became possible to measure the conduction time within fast-conducting central motor pathways by substracting from the total latency of muscle responses elicited by cortical stimuli the conduction time in peripheral nerves. This technique proved sensitive enough to illustrate early abnormalities of central motor conduction in various neurological diseases such as multiple sclerosis, amyotrophic lateral sclerosis, cervical spondylotic myelopathy, degenerative ataxias or hereditary spastic paraplegias. When recorded early after stroke, motor evoked potentials are also a valuable tool to predict functional outcome. They can also illustrate subtle pathophysiological disturbances in diseases where there is no direct involvement of central motor pathways such as Parkinson's disease, dystonia or epilepsy. Magnetic cortical stimulation also offers unique opportunities to explore intracerebral inhibitory and excitatory circuits and mechanisms of brain plasticity. The recent development of rapid rate stimulators also enables functional studies of non-motor cerebral regions such as visual or frontal cortices. Moreover, rapid rate stimulation seems useful in the treatment of drug-resistant depression but the safety of this procedure, particularly with regard to the production of seizures or kindling, remains to be fully documented.}, }
@article {pmid9561981, year = {1998}, author = {Riviere, M and Meininger, V and Zeisser, P and Munsat, T}, title = {An analysis of extended survival in patients with amyotrophic lateral sclerosis treated with riluzole.}, journal = {Archives of neurology}, volume = {55}, number = {4}, pages = {526-528}, doi = {10.1001/archneur.55.4.526}, pmid = {9561981}, issn = {0003-9942}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Excitatory Amino Acid Antagonists/*therapeutic use ; Humans ; Proportional Hazards Models ; Riluzole/*therapeutic use ; Risk Factors ; Survival Rate ; Treatment Outcome ; }, abstract = {BACKGROUND: In an attempt to better understand and define the progression of amyotrophic lateral sclerosis (ALS), we developed a classification of 5 discrete health states that reflect patients' activities of daily living. These health states were used to determine whether patients with ALS who are treated with riluzole differed from those treated with placebo.<br><br>SETTING: Clinics for patients with ALS.<br><br>DESIGN: Placebo-controlled trial of riluzole treatment in 959 patients with ALS.<br><br>INTERVENTIONS: Treatment with riluzole or placebo. MAIN DEPENDENT MEASURES: A Cox model was used to assess whether, from the initial randomization to the end of an 18-month follow-up, there was a difference in the times of transition into subsequent health states between patients treated with riluzole and those treated with placebo.<br><br>RESULTS: Our analysis showed a significant difference in the time to transit between the riluzole and the placebo groups in less severely affected cases, ie, state 2 and state A (the milder states) of ALS.<br><br>CONCLUSION: Patients receiving riluzole remained in the milder health states longer (P<.05).}, }
@article {pmid9559981, year = {1998}, author = {Su, M and Wakabayashi, K and Kakita, A and Ikuta, F and Takahashi, H}, title = {Selective involvement of large motor neurons in the spinal cord of rats treated with methylmercury.}, journal = {Journal of the neurological sciences}, volume = {156}, number = {1}, pages = {12-17}, doi = {10.1016/s0022-510x(98)00030-6}, pmid = {9559981}, issn = {0022-510X}, mesh = {Animals ; Body Weight/drug effects ; Methylmercury Compounds/*toxicity ; Microscopy, Electron ; Motor Neuron Disease/chemically induced ; Motor Neurons/*drug effects ; Rats ; Rats, Wistar ; Spinal Cord/*drug effects/ultrastructure ; }, abstract = {Mercury is thought to be a possible epidemiological factor for the pathogenesis of motor neuron disease, since it has been reported that metallic, inorganic and organic mercury causes a syndrome clinically resembling amyotrophic lateral sclerosis. We administered 10 mg/kg/day methylmercury chloride to adult rats for 10 consecutive days. The hind-limbs became flaccid and atrophic, and 14 out of the 34 rats had died by the 18th day after methylmercury treatment began. Light microscopical examination of the large motor neurons in the spinal anterior horn revealed cytoplasmic vacuolation and loss of Nissl substance on the 14th day, and neuronophagia appeared on the 16th day. On the 18th day, the loss of large motor neurons was almost complete, whereas small to medium-sized neurons were preserved. Silver acetate autometallography to detect mercury revealed the selective accumulation of mercury in the large motor neurons. These findings suggest that although a high dose is required, organic mercury can cause the definite loss of large spinal motor neurons in rats.}, }
@article {pmid9549636, year = {1997}, author = {Le Liboux, A and Lefebvre, P and Le Roux, Y and Truffinet, P and Aubeneau, M and Kirkesseli, S and Montay, G}, title = {Single- and multiple-dose pharmacokinetics of riluzole in white subjects.}, journal = {Journal of clinical pharmacology}, volume = {37}, number = {9}, pages = {820-827}, doi = {10.1002/j.1552-4604.1997.tb05630.x}, pmid = {9549636}, issn = {0091-2700}, mesh = {Adolescent ; Adult ; Amyotrophic Lateral Sclerosis/drug therapy ; Cross-Over Studies ; Dose-Response Relationship, Drug ; Double-Blind Method ; Excitatory Amino Acid Antagonists/*pharmacokinetics ; Humans ; Male ; Riluzole/administration &amp; dosage/*pharmacokinetics/therapeutic use ; }, abstract = {Riluzole is a novel neuroprotective agent that has been developed for the treatment of amyotrophic lateral sclerosis. A series of studies was undertaken to establish its pharmacokinetics on single- and multiple-dose administration in young white male volunteers. The mean absolute oral bioavailability of riluzole (50-mg tablet) was approximately 60%. Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) values were linearly related to dose for the range studied. Cmax occurred at 1.0 hour to 1.5 hours after administration. Plasma elimination half-life appeared to be independent of dose. After repeated administration of 100 mg riluzole for 10 days, some intraindividual variability in bioavailability was seen. A high-fat meal significantly reduced the rate (tmax = 2 hours compared with 0.8 hours; Cmax = 216 ng.mL-1 compared to 387 ng.mL-1) and extent of absorption (AUC = 1,047 ng.hr.mL-1 versus 1,269 ng.hr.mL-1). With multiple-dose administration, riluzole showed dose-related absorption, although the terminal plasma half-life was prolonged slightly. Steady-state plasma concentrations were achieved within 5 days. Steady-state trough plasma concentrations were significantly higher with a 75-mg dose twice daily than with a 50-mg dose three times daily, although AUC values did not differ.}, }
@article {pmid9536463, year = {1998}, author = {Dawson, R and Marschall, EG and Chan, KC and Millard, WJ and Eppler, B and Patterson, TA}, title = {Neurochemical and neurobehavioral effects of neonatal administration of beta-N-methylamino-L-alanine and 3,3'-iminodipropionitrile.}, journal = {Neurotoxicology and teratology}, volume = {20}, number = {2}, pages = {181-192}, doi = {10.1016/s0892-0362(97)00078-0}, pmid = {9536463}, issn = {0892-0362}, support = {T32 AG00196/AG/NIA NIH HHS/United States ; }, mesh = {Amino Acids/metabolism ; Amino Acids, Diamino/*toxicity ; Animals ; Animals, Newborn ; Behavior, Animal/*drug effects ; Brain/*drug effects/growth &amp; development/metabolism ; Cyanobacteria Toxins ; Female ; Hormones/metabolism ; Male ; Neurotoxins/*toxicity ; Nitriles/*toxicity ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/*drug effects/growth &amp; development/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is characterized by a loss of motor neurons in the spinal cord, brain stem, and cortex. The present study examined the neurochemical and neurobehavioral consequences of the neonatal administration of IDPN and BMAA, two neurotoxins previously considered as experimental models of ALS. Sprague-Dawley rat pups (male and female) were injected SC with IDPN or BMAA. The following treatment groups (n = 5-14 per group) were studied; IDPN [100 mg/kg on postnatal days (PNDs) 2, 4, and 6], BMAA-A (500 mg/kg PND 5 only), BMAA-B (500 mg/kg PND 2 and 5), and BMAA-C (100 mg/kg PND 2 and 5). Neurobehavioral testing was performed and the rats were sacrificed at 101 days of age. Monoamine and amino acid content was measured by HPLC in brain regions and the spinal cord. IDPN treatment impaired the righting reflex and decreased forepaw suspension times. BMAA-A and BMAA-B males exhibited an increase in open field behavior. The hindlimb splay of BMAA-A females was increased. Other significant behavioral and endocrine effects were also seen with neonatal IDPN or BMAA treatment. IDPN females had increased spinal cord content of norepinephrine (NE), serotonin, and 5-hydroxyindoleacetic acid (5-HIAA). IDPN males had no alterations in spinal cord content of NE or Glu, but serotonin and 5-HIAA content were increased. BMAA-A and BMAA-B males also had elevated spinal cord 5-HIAA content whereas females were unaffected. Glu and Asp content in the spinal cord was elevated in the female BMAA-C group. Monoamines were also altered in the cerebellum, mediobasal hypothalamus, and hippocampus by IDPN and BMAA treatment. alpha 2-Adrenergic binding sites were increased in the spinal cord by IDPN and in the cerebellum by BMAA treatment. The results of this study clearly demonstrated that both IDPN and BMAA given neonatally can produce changes in motor function and spinal cord neurochemistry, although the pattern of the effects is both treatment and sex dependent. Neonatal exposure to either IDPN or BMAA resulted in permanent changes in adult neurochemistry that may be related to reorganizational effects induced by toxin-mediated neuroplasticity in developing neurons.}, }
@article {pmid9528031, year = {1997}, author = {García-Moreno, JM and Izquierdo, G and Chacón, J and Angulo, S and Borobio, MV}, title = {[Neuroborreliosis in a patient with progressive supranuclear paralysis. An association or the cause?].}, journal = {Revista de neurologia}, volume = {25}, number = {148}, pages = {1919-1921}, pmid = {9528031}, issn = {0210-0010}, mesh = {Aged ; Antiparkinson Agents/therapeutic use ; Borrelia burgdorferi Group/*isolation &amp; purification ; Ceftriaxone/therapeutic use ; Cephalosporins/therapeutic use ; Dementia/etiology ; Electroencephalography ; Facies ; Frontal Lobe/diagnostic imaging ; Humans ; Lyme Disease/*complications/drug therapy ; Magnetic Resonance Imaging ; Male ; Parietal Lobe/diagnostic imaging ; Substantia Nigra/*microbiology/*pathology ; Supranuclear Palsy, Progressive/*diagnosis/drug therapy/*microbiology ; Temporal Lobe/diagnostic imaging ; Tomography, Emission-Computed, Single-Photon ; }, abstract = {INTRODUCTION: Many different neurological conditions may be seen in the later stages of Lyme's Disease, such as blindness, epileptic crises, CVA, extrapyramidal disorders, amyotrophic lateral sclerosis, and dementia may be yet another form of presentation of chronic infection due to Borrelia burgdorferi (Bb). Progressive Supranuclear Paralysis (PSP), a disorder of unknown aetiology, considered to be the commonest cause of Parkinsonism-plus, one of the symptoms of which is dementia, has never been mentioned in this type of differential diagnosis.<br><br>CLINICAL CASE: We present the case of a 78 year old man with sub-acute mental deterioration, Bb positive serology in both plasma and CSF, and with clinical and epidemiological features compatible with Lyme's Disease. Complementary tests were negative. The syndrome corresponded to Lyme's Disease and improved after treatment with ceftriaxona.<br><br>CONCLUSIONS: We consider aspects of the aetiology of PSP which are still not clear. In our patient, the aetiology seemed to be Bb infection, according to the criteria of the original description of the disease and in view of the neuropathological findings which have shown Bb in the substancia nigra of the mid-brain and the existence of an animal model in which Bb shows a particular tendency to colonize infratentorial structures.}, }
@article {pmid9512453, year = {1998}, author = {Andersen, JK}, title = {Use of genetically engineered mice as models for exploring the role of oxidative stress in neurodegenerative diseases.}, journal = {Frontiers in bioscience : a journal and virtual library}, volume = {3}, number = {}, pages = {c8-16}, doi = {10.2741/a259}, pmid = {9512453}, issn = {1093-9946}, support = {P01AG09793/AG/NIA NIH HHS/United States ; R29AG1241/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Disease Models, Animal ; Genetic Engineering/*methods ; Humans ; Mice ; Mice, Transgenic ; Neurodegenerative Diseases/*pathology ; Oxidative Stress/*physiology ; }, abstract = {A growing body of evidence has suggested that oxidative stress may play a major role in the degeneration of neurons associated with several neurological diseases of aging including ALS, Parkinson's, and Alzheimer's disease; this has been the topic of numerous previous reviews and opinion papers (e.g. 1-10). The ability to construct genetically engineered mouse lines containing targeted mutations has done much to aid in the assessment of the role of reactive oxygen species (ROS) in both the initiation as well as the progression of these diseases and has markedly advanced research in the field. Most importantly, the creation of genetic animal models has strengthened the argument that antioxidants may be a useful therapy in the treatment of these types of disorders.}, }
@article {pmid9511245, year = {1997}, author = {Popova, LM and Alferova, VP}, title = {[Respiratory insufficiency in amyotrophic lateral sclerosis and methods of treatment].}, journal = {Anesteziologiia i reanimatologiia}, volume = {}, number = {6}, pages = {35-40}, pmid = {9511245}, issn = {0201-7563}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Humans ; Prognosis ; Respiration, Artificial ; Respiratory Function Tests ; Respiratory Insufficiency/diagnosis/*etiology/therapy ; Time Factors ; Vital Capacity ; }, abstract = {Respiratory failure in amyotrophic lateral sclerosis is caused by paralysis and paresis of the respiratory and glossopharyngeolaryngeal muscles obstructing and restricting ventilation of the lungs. Examination of the external respiratory function helps early diagnose the condition. Monitoring of vital capacity of the lungs and respiratory rate is the most informative method. Analyzing the problem of progressive respiratory failure, we cannot neglect its ethical, social, and financial aspects. Informed consent of patients, families, and sponsors to prolonged forced ventilation of the lungs is to be obtained before the condition progresses to critical.}, }
@article {pmid9500619, year = {1998}, author = {Hale, DA and Gottschalk, R and Maki, T and Monaco, AP}, title = {Determination of an improved sirolimus (rapamycin)-based regimen for induction of allograft tolerance in mice treated with antilymphocyte serum and donor-specific bone marrow.}, journal = {Transplantation}, volume = {65}, number = {4}, pages = {473-479}, doi = {10.1097/00007890-199802270-00004}, pmid = {9500619}, issn = {0041-1337}, support = {R01 AI-14551/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/*therapeutic use ; Bone Marrow Transplantation/*immunology ; Cyclosporine/therapeutic use ; Drug Therapy, Combination ; Graft Survival/drug effects/*physiology ; Immunosuppression Therapy/*methods ; Immunosuppressive Agents/*therapeutic use ; Lymphocyte Culture Test, Mixed ; Mice ; Mice, Inbred DBA ; Mice, Inbred Strains ; Polyenes/*therapeutic use ; Rabbits ; Sirolimus ; Skin Transplantation/*immunology ; Time Factors ; Transplantation, Homologous ; }, abstract = {BACKGROUND: Posttransplant donor-specific bone marrow (BM) infusion in mice treated with antilymphocyte serum (ALS) induces specific unresponsiveness (tolerance) to skin allografts, which can be augmented by the adjuvant administration of chemotherapeutic immunosuppressive agents. The purpose of this study was to determine the optimal dose and timing of administration of sirolimus (rapamycin) to induce maximal skin allograft survival in ALS-treated, BM-infused recipients.<br><br>METHODS: DBA/2 donor skin grafts were placed on B6AF1 recipients (class I- and II-disparate). Groups of recipient mice (n=10 each) received combinations of the following treatment protocols: ALS, 0.5 ml on days -1 and 2; BM, 25x10(6) donor-specific cells on day 7; sirolimus, 6, 12, 18, or 24 mg/kg at times indicated; and cyclosporine, 50 mg/kg at times indicated. The immune status of putatively tolerant animals was examined with mixed lymphocyte cultures, cell-mediated lympholysis assays (CML), and limiting dilution analyses.<br><br>RESULTS: When administered in conjunction with ALS/BM, a single dose of sirolimus (6 mg/kg) on days 21, 18, 14, 10, or 7 resulted in median skin graft survival times of 35, 26, 40, 46, and 103 days, respectively, versus a median survival of 27 days in mice given ALS and BM alone. The addition of cyclosporine to sirolimus (6 mg/kg) given on day 7 or days 7 and 10 did not significantly increase graft survival over that achieved with sirolimus alone. A single dose (18 or 24 mg/kg) of sirolimus administered on day 7 to ALS/BM-treated recipients resulted in 100% 200-day skin graft acceptance. Tolerant mice demonstrated nonspecific suppression of the mixed lymphocyte culture assays at 90 and 200 days and a nonspecific reduction of the CML assay at 50 days. By 200 days, the third-party CML response was restored, whereas donor-specific cell-mediated cytotoxicity remained suppressed. There was a donor-specific reduction in the number of alloreactive cytotoxic T lymphocyte clones by limiting dilution assay at 120 days. In vivo specificity of immunosuppression induced with this protocol was demonstrated by indefinite survival of second donor-specific skin grafts placed on putatively tolerant mice at day 90, whereas third-party skin grafts were rejected in 14 days.<br><br>CONCLUSION: A single dose of sirolimus (18-24 mg/kg) administered on day 7, within the context of an ALS/BM immunosuppressive regimen, reliably induces permanent skin allograft acceptance in this model. In vitro measures of immunocompetence demonstrated an early nonspecific suppression of the recipients immune status and later recovery of third-party immunoreactivity. In vivo testing indicates an operationally tolerant state that is donor-specific 90 days after treatment.}, }
@article {pmid9497872, year = {1997}, author = {Labarta, JI and Gargosky, SE and Simpson, DM and Lee, PD and Argente, J and Guevara-Aguirre, J and Rosenfeld, RG}, title = {Immunoblot studies of the acid-labile subunit (ALS) in biological fluids, normal human serum and in children with GH deficiency and GH receptor deficiency before and after long-term therapy with GH or IGF-I respectively.}, journal = {Clinical endocrinology}, volume = {47}, number = {6}, pages = {657-666}, doi = {10.1046/j.1365-2265.1997.2581078.x}, pmid = {9497872}, issn = {0300-0664}, support = {FD-R-00860/FD/FDA HHS/United States ; R01-CA58110/CA/NCI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Age Factors ; Ascitic Fluid/chemistry ; Blotting, Western ; Carrier Proteins/*analysis ; Child ; Child, Preschool ; Female ; Follicular Fluid/chemistry ; Glycoproteins/*analysis ; Growth Disorders/drug therapy/*metabolism ; Growth Hormone/*deficiency/therapeutic use ; Humans ; Infant ; Infant, Newborn ; Insulin-Like Growth Factor I/*therapeutic use ; Receptors, Somatotropin/*deficiency ; Recombinant Proteins/therapeutic use ; Synovial Fluid/chemistry ; }, abstract = {OBJECTIVE: The aims of this investigation were (a) to study the presence of immunoreactive forms of the acid-labile subunit (ALS) in different human biological fluids, (b) to define the age dependence of serum ALS in normal children and adults and (c) to compare the regulation of ALS by GH or IGF-I in children with GH deficiency (GHD) and GH receptor deficiency (GHRD) before and after 1 year of therapy with GH or IGF-I, respectively.<br><br>DESIGN AND PATIENTS: Selected human biological fluids from different consenting volunteers and serum from 68 normal children and 5 adults were analysed. Four children diagnosed as GHD and 7 children diagnosed as GHRD were treated with recombinant human (rh) GH at a dosage of 0.05 mg/kg/day s.c. or rhIGF-I at a dosage of 120 micrograms/kg twice daily s.c., respectively, for 12 months.<br><br>MEASUREMENTS: Immunoreactive forms of ALS were studied by Western immunoblot using a specific rabbit antiserum derived against synthetic human ALS and quantified by laser densitometry analysis. Serum from children with GHD or GHRD were sampled before and at 6 and 12 months of therapy; serum from these patients had been also assayed at baseline for determination of IGF-I and IGF binding protein (IGFBP)-3 by radioimmunoassay and immunoradiometric assay, respectively.<br><br>RESULTS: An immunoreactive 85 kDa doublet of ALS was detected in serum, plasma, follicular, peritoneal and synovial fluid, but not in urine, seminal plasma, amniotic or extra-embryonic coelomic fluids. Assessment of serum from newborns to adults revealed an age dependence; the ALS doublet was low, but detectable, in newborns, increased during adolescence and remained constant in adulthood. ALS levels were significantly lower in GHD (P = 0.02) and in GHRD children (P = 0.001) than in age-matched controls. Treatment with rhGH in GHD children produced a 2.7-fold increase in serum ALS concentrations at 6 months of therapy (P = 0.01), which was maintained after 1 year of treatment (P = 0.006), leading to normalization of ALS concentrations. In contrast, administration of rhIGF-I to GHRD children failed to increase and normalize serum ALS levels either at 6 or 12 months of therapy.<br><br>CONCLUSIONS: Immunoreactive forms of acid-labile subunit are present in serum and plasma, as well as in follicular, peritoneal and synovial fluids, suggesting that acid-labile subunit can either cross the capillary barrier or be secreted locally. Acid-labile subunit concentrations are age-dependent with a sharp increase during adolescence, and are reduced in GH deficient and GH receptor deficient children. While treatment with rhGH is able to increase and normalize acid-labile subunit concentrations in GH deficient children, therapy with rhIGF-I fails to increase serum acid-labile subunit levels in GH receptor deficient patients. These data suggest that acid-labile subunit is directly GH-regulated, and that IGF-I cannot increase acid-labile subunit levels, as assessed by Western immunoblot.}, }
@article {pmid9466413, year = {1998}, author = {Annis, CM and Vaughn, JE}, title = {Differential vulnerability of autonomic and somatic motor neurons to N-methyl-D-aspartate-induced excitotoxicity.}, journal = {Neuroscience}, volume = {83}, number = {1}, pages = {239-249}, doi = {10.1016/s0306-4522(97)00329-1}, pmid = {9466413}, issn = {0306-4522}, support = {NS25784/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Autonomic Fibers, Preganglionic/cytology/*drug effects ; Cell Survival/drug effects ; Excitatory Amino Acid Agonists/*toxicity ; Immunohistochemistry ; Motor Neurons/*drug effects ; N-Methylaspartate/*toxicity ; NADP/metabolism ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/cytology/drug effects ; Sympathetic Nervous System/cytology/*drug effects ; }, abstract = {Two closely-related subsets of spinal motor neurons are differentially vulnerable in the degenerative neurological disease amyotrophic lateral sclerosis. Autonomic motor neurons (i.e. preganglionic sympathetic neurons) survive in this disorder, whereas most spinal somatic motor neurons do not. The present study was undertaken in order to begin to understand the phenotypic differences between the two motor neuronal subsets which might contribute to this differential survival. Organotypic slice cultures of postnatal rat thoracic spinal cord were maintained in defined medium for one to 12 days in the presence or absence of N-methyl-D-aspartate or its antagonist, D-amino-phosphonopentanoic acid. Autonomic motor neurons that were stained for either nicotinamide adenine dinucleotide phosphate reduced diaphorase or choline acetyltransferase only were both able to tolerate 50 microM N-methyl-D-aspartate treatment for over seven days in culture with no apparent adverse effects. In contrast, cultures maintained for only one day in medium containing 50 microM N-methyl-D-aspartate showed a dramatic and highly significant decrease in the numbers of neurofilament-positive somatic motor neurons, as well as nicotinamide adenine dinucleotide phosphate reduced diaphorase-positive interneurons. These N-methyl-D-aspartate-induced effects were dose-dependent and blockable. The results of this investigation indicated that autonomic motor neurons and somatic motor neurons were differentially susceptible to N-methyl-D-aspartate-induced excitotoxicity, and that the resistance of autonomic motor neurons to this insult appeared to be independent of the nicotinamide adenine dinucleotide phosphate reduced diaphorase phenotype.}, }
@article {pmid9464942, year = {1997}, author = {Giehl, KM and Schacht, CM and Yan, Q and Mestres, P}, title = {GDNF is a trophic factor for adult rat corticospinal neurons and promotes their long-term survival after axotomy in vivo.}, journal = {The European journal of neuroscience}, volume = {9}, number = {11}, pages = {2479-2488}, doi = {10.1111/j.1460-9568.1997.tb01665.x}, pmid = {9464942}, issn = {0953-816X}, mesh = {Animals ; Axotomy ; Body Weight/physiology ; Cell Size ; Cell Survival/drug effects/physiology ; Cerebral Cortex/cytology/drug effects/*physiology ; Glial Cell Line-Derived Neurotrophic Factor ; Immunohistochemistry ; Male ; *Nerve Growth Factors ; Nerve Tissue Proteins/*pharmacology ; Neurons/*physiology/ultrastructure ; Neuroprotective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/cytology/drug effects/*physiology ; }, abstract = {Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for several neuronal populations involved in motor control. The present study evaluates the trophic actions of GDNF on corticospinal neurons, an important central nervous system motor projection into the spinal cord. Death of spinal motoneurons and corticospinal neurons is observed in the neurodegenerative disease amyotrophic lateral sclerosis. Axotomy of adult rat corticospinal neurons at internal capsule levels induces half of them to die, and the surviving population displays severe atrophy. To examine the trophic effects of GDNF on corticospinal neurons, Fast Blue-labelled corticospinal neurons were stereotaxically axotomized at internal capsule levels and GDNF was infused intracortically to lesioned corticospinal neurons at total doses of 2, 4, 10, 20, 40, 100 and 300 microg for 7 days. GDNF prevented axotomy-induced death of corticospinal neurons at doses between 2 and 40 microg and abolished or attenuated their atrophy at all doses examined. In addition, treatment with 8 microg GDNF for the first 2 weeks after axotomy resulted in the long-term survival of corticospinal neurons for 42 days. With regard to the development of treatment strategies for upper motoneuron degeneration in amyotrophic lateral sclerosis, application of GDNF via the cerebrospinal fluid may be more relevant than intracortical delivery as its diffusion within the brain parenchyma is limited. Intraventricular as well as intracisternal infusion of GDNF (300 microg over 7 days) completely prevented corticospinal neuron death. These results show that GDNF promotes the long-term survival of corticospinal neurons and has a positive effect on their size in vivo. Furthermore, the survival-promoting effect of GDNF on corticospinal neurons after delivery via cerebrospinal fluid has important clinical implications for potential treatment of the upper motoneuron degeneration seen in amyotrophic lateral sclerosis.}, }
@article {pmid9462746, year = {1998}, author = {Melov, S and Schneider, JA and Day, BJ and Hinerfeld, D and Coskun, P and Mirra, SS and Crapo, JD and Wallace, DC}, title = {A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase.}, journal = {Nature genetics}, volume = {18}, number = {2}, pages = {159-163}, doi = {10.1038/ng0298-159}, pmid = {9462746}, issn = {1061-4036}, support = {AG13154/AG/NIA NIH HHS/United States ; HL45572/HL/NHLBI NIH HHS/United States ; NS21328/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain/pathology ; Brain Stem/pathology/ultrastructure ; Cerebral Cortex/pathology/ultrastructure ; DNA, Mitochondrial/*genetics ; Free Radical Scavengers/pharmacology ; Humans ; Lipid Metabolism ; Liver/metabolism ; Metalloporphyrins/*pharmacology ; Mice ; Mice, Knockout ; Mitochondria/enzymology ; Neurodegenerative Diseases/drug therapy/*genetics/pathology ; Neurons/pathology ; Superoxide Dismutase/*deficiency/*genetics ; Survival Rate ; Trigeminal Nuclei/pathology/ultrastructure ; Vacuoles/pathology/ultrastructure ; }, abstract = {Reactive oxygen species (ROS) have been implicated in a wide range of degenerative processes including amyotrophic lateral sclerosis, ischemic heart disease, Alzheimer disease, Parkinson disease and aging. ROS are generated by mitochondria as the toxic by-products of oxidative phosphorylation, their energy generating pathway. Genetic inactivation of the mitochondrial form of superoxide dismutase in mice results in dilated cardiomyopathy, hepatic lipid accumulation and early neonatal death. We report that treatment with the superoxide dismutase (SOD) mimetic Manganese 5, 10, 15, 20-tetrakis (4-benzoic acid) porphyrin (MnTBAP) rescues these Sod2tm1Cje(-/-) mutant mice from this systemic pathology and dramatically prolongs their survival. The animals instead develop a pronounced movement disorder progressing to total debilitation by three weeks of age. Neuropathologic evaluation reveals a striking spongiform degeneration of the cortex and specific brain stem nuclei associated with gliosis and intramyelinic vacuolization similar to that observed in cytotoxic edema and disorders associated with mitochondrial abnormalities such as Leighs disease and Canavans disease. We believe that due to the failure of MnTBAP to cross the blood brain barrier progressive neuropathology is caused by excessive mitochondrial production of ROS. Consequently, MnTBAP-treated Sod2tm1Cje(-/-) mice may provide an excellent model for examining the relationship between free radicals and neurodegenerative diseases and for screening new drugs to treat these disorders.}, }
@article {pmid9437033, year = {1998}, author = {Sagot, Y and Rossé, T and Vejsada, R and Perrelet, D and Kato, AC}, title = {Differential effects of neurotrophic factors on motoneuron retrograde labeling in a murine model of motoneuron disease.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {18}, number = {3}, pages = {1132-1141}, pmid = {9437033}, issn = {0270-6474}, mesh = {Animals ; Axonal Transport/genetics ; Axotomy ; Benzoxazines ; Cell Death/physiology ; Coloring Agents ; Disease Models, Animal ; Fluorescent Dyes ; Gene Expression/physiology ; Humans ; Mice ; Mice, Neurologic Mutants ; Mice, Transgenic ; Motor Neuron Disease/*physiopathology ; Motor Neurons/*chemistry/*drug effects/physiology ; Nerve Degeneration/physiopathology ; Nerve Growth Factors/*pharmacology ; Oxazines ; Proto-Oncogene Proteins c-bcl-2/genetics ; *Stilbamidines ; }, abstract = {It has been shown that abnormalities in axonal transport occur in several mouse models with motoneuron degeneration and also in the human disease amyotrophic lateral sclerosis. In this report, we have examined the potential of neurotrophic factors to act on axonal transport properties in a mouse mutant, progressive motor neuronopathy (pmn). This mouse mutant has been characterized as a "dying-back" motoneuronopathy, with a loss of motoneuron cell bodies and motor fibers. Retrograde transport to the spinal cord motoneurons was determined using fluorescent tracers either injected into the gastrocnemius muscle or applied directly onto the cut sciatic nerve. Because the rate of retrograde labeling was significantly reduced in the pmn, we examined the potential of neurotrophic factors to compensate for the impairment. Ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) but not glial-derived neurotrophic factor (GDNF) or nerve growth factor (NGF) were capable of significantly improving the rate of labeling. The differential effects of these factors agree with previous studies showing that molecules that promote cell survival do not necessarily compensate for axonal deficiency. Because impairment of axonal properties appears as an early event in motoneuron pathology, our results may have important clinical implications in the treatment of motoneuron diseases.}, }
@article {pmid9452309, year = {1998}, author = {Alexianu, ME and Robbins, E and Carswell, S and Appel, SH}, title = {1Alpha, 25 dihydroxyvitamin D3-dependent up-regulation of calcium-binding proteins in motoneuron cells.}, journal = {Journal of neuroscience research}, volume = {51}, number = {1}, pages = {58-66}, doi = {10.1002/(SICI)1097-4547(19980101)51:1&lt;58::AID-JNR6&gt;3.0.CO;2-K}, pmid = {9452309}, issn = {0360-4012}, support = {NS33186/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Calcitriol/*pharmacology ; Calcium-Binding Proteins/*biosynthesis ; Cell Differentiation/drug effects ; Cell Line ; Image Processing, Computer-Assisted ; Immunohistochemistry ; Motor Neurons/*drug effects/metabolism ; Rats ; Spinal Cord/cytology/drug effects/metabolism ; Up-Regulation ; }, abstract = {Our understanding of selective neuronal vulnerability as well as etiopathogenesis of sporadic neurodegenerative diseases is extremely limited. In ALS, altered calcium homeostasis appears to contribute significantly to selective neuronal injury. Further in ALS, the absence of calcium binding proteins (calbindin-D28K, parvalbumin, and calretinin) correlates with selective vulnerability and cell loss. In motoneuron cell culture models an ALS IgG-triggered and calcium-mediated destruction can be reversed by increased expression of calbindin-D28K following retroviral infection with calbindin-D28K cDNA. To increase calcium binding protein expression in motoneurons in vitro and in vivo, we have employed vitamin D3. Forty-eight hr treatment of differentiated VSC 4.1 cells with 0.1-30 nM 1,25 dihydroxyvitamin D3 induced a two-fold increase in the immunoreactivity for calbindin-D28K and parvalbumin. Injection of 80-120 ng, 1,25 dihydroxyvitamin D3 in the cerebral ventricles of adult rats also induced positive immunoreactivity for calcium binding proteins in ventral motoneurons which are completely devoid of such reactivity in the adult stage. These data suggest that analogs of 1,25 dihydroxyvitamin D3 may be useful tools in enhancing the expression of calcium binding proteins in the motor system and may have possible therapeutic value in neurodegenerative disease.}, }
@article {pmid9443715, year = {1998}, author = {Lange, DJ and Murphy, PL and Diamond, B and Appel, V and Lai, EC and Younger, DS and Appel, SH}, title = {Selegiline is ineffective in a collaborative double-blind, placebo-controlled trial for treatment of amyotrophic lateral sclerosis.}, journal = {Archives of neurology}, volume = {55}, number = {1}, pages = {93-96}, doi = {10.1001/archneur.55.1.93}, pmid = {9443715}, issn = {0003-9942}, mesh = {Administration, Oral ; Amyotrophic Lateral Sclerosis/*drug therapy ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Monoamine Oxidase Inhibitors/administration &amp; dosage/*therapeutic use ; Selegiline/administration &amp; dosage/*therapeutic use ; Treatment Outcome ; }, abstract = {BACKGROUND: The cause of amyotrophic lateral sclerosis (ALS) is not known, and there is no effective treatment. Cell death may be caused by oxidative damage. Selegiline hydrochloride (Eldepryl) is a monoamine oxidase-B inhibitor with antioxidant properties.<br><br>OBJECTIVE: To determine if selegiline affects the clinical course of patients with ALS.<br><br>DESIGN: Six-month, double-blind, placebo-controlled study of 133 patients with classical ALS and symptoms for less than 3 years. The primary end point to indicate effectiveness was the rate of change of the Appel ALS total score, an index of disease severity that incorporates strength and function in limbs, respiratory function, and bulbar function.<br><br>RESULTS: Of the 133 patients, 67 were randomized to receive selegiline and 66 to receive placebo. One hundred four patients (53 in the selegiline group and 51 in the placebo group) completed the 6-month trial. Both groups were comparable for baseline characteristics and mean Appel ALS total score (70.5 points for the selegiline group and 70.6 for the placebo group). There was no difference in the rate of progression as measured by the Appel ALS total score, showing an average increase of 22 points in 6 months. The monthly rate of change was 3.4 for the selegiline group and 3.5 for the placebo group. There was 1 adverse reaction: worsening depression. Seven patients died during the study (4 in the selegiline group and 3 in the placebo group).<br><br>CONCLUSION: Selegiline treatment had no significant effect on the rate of clinical progression or outcome of ALS.}, }
@article {pmid9443459, year = {1998}, author = {Stambler, N and Charatan, M and Cedarbaum, JM}, title = {Prognostic indicators of survival in ALS. ALS CNTF Treatment Study Group.}, journal = {Neurology}, volume = {50}, number = {1}, pages = {66-72}, doi = {10.1212/wnl.50.1.66}, pmid = {9443459}, issn = {0028-3878}, mesh = {Acid-Base Equilibrium ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism/*mortality ; Ciliary Neurotrophic Factor ; Cohort Studies ; Female ; Humans ; Male ; Middle Aged ; Nerve Growth Factors/*therapeutic use ; Nerve Tissue Proteins/*therapeutic use ; Prognosis ; Prospective Studies ; Respiratory Function Tests ; Survival Analysis ; }, abstract = {We analyzed data from the 245-patient placebo group of the ALS CNTF Treatment Study Group study, a large, prospective, multicenter study of recombinant human ciliary neurotrophic factor to determine prognostic factors for length of survival in ALS. Variables examined included baseline demographic characteristics, indices of disease severity, pulmonary function, and clinical laboratory tests. Shorter survival was associated with greater age, lower percent-predicted forced vital capacity (FVC%), and lower serum chloride at study entry. A shorter interval from symptom onset to diagnosis of ALS and greater weight loss in the 2 months before study entry also predicted shortened survival times. The rate of muscle strength loss before study entry did not predict risk of mortality. Serum chloride, reflecting the degree of respiratory acidosis, was identified for the first time as being correlated with prognosis in ALS. The relationship between a patient's FVC% and the probability of survival is described.}, }
@article {pmid9443458, year = {1998}, author = {Gurney, ME and Fleck, TJ and Himes, CS and Hall, ED}, title = {Riluzole preserves motor function in a transgenic model of familial amyotrophic lateral sclerosis.}, journal = {Neurology}, volume = {50}, number = {1}, pages = {62-66}, doi = {10.1212/wnl.50.1.62}, pmid = {9443458}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Disease Models, Animal ; Female ; Longevity ; Male ; Mice ; Mice, Inbred Strains ; Mice, Transgenic ; Motor Activity/*drug effects ; Neuroprotective Agents/*pharmacology ; Quality of Life ; Riluzole/*pharmacology ; }, abstract = {Riluzole was tested in a dose-ranging study for preservation of motor function in a transgenic mouse model of familial ALS. The model is based on expression of mutant human Cu,Zn superoxide dismutase in mouse brain and spinal cord. In contrast with the human ALS trials, in the mouse model, riluzole significantly preserved motor function as assessed by nightly running in a wheel. The effect of riluzole on motor performance was greater earlier in disease than later, suggesting that riluzole may have benefit for "quality-of-life" measures in ALS. Treatment with riluzole was initiated earlier in the transgenic model than in the human ALS trials, which may account for the significantly better outcome.}, }
@article {pmid9437227, year = {1997}, author = {Kanety, H and Silbergeld, A and Klinger, B and Karasik, A and Baxter, RC and Laron, Z}, title = {Long-term effects of insulin-like growth factor (IGF)-I on serum IGF-I, IGF-binding protein-3 and acid labile subunit in Laron syndrome patients with normal growth hormone binding protein.}, journal = {European journal of endocrinology}, volume = {137}, number = {6}, pages = {626-630}, doi = {10.1530/eje.0.1370626}, pmid = {9437227}, issn = {0804-4643}, mesh = {Carrier Proteins/*blood ; Child ; Dwarfism/*drug therapy/metabolism ; Female ; Glycoproteins/*blood ; Humans ; Infant ; Insulin-Like Growth Factor Binding Protein 3/*blood ; Insulin-Like Growth Factor I/*therapeutic use ; Male ; Pedigree ; Time Factors ; }, abstract = {A minority of patients with Laron syndrome have normal serum GH binding protein (GHBP), indicating that the defect is elsewhere than in the extracellular domain of the GH receptor. We have evaluated the effect of long-term IGF-I treatment on serum IGF-binding protein (IGFBP)-3 and the acid-labile subunit (ALS) in three sibling with Laron syndrome caused by a GH post-receptor defect and with normal GHBP. The children (a boy aged 3 years, a girl aged 4 years and a boy aged 10 years) were treated by daily s.c. injection of IGF-I in a dose of 150 micrograms/kg. IGFBP-3 was measured by RIA and Western ligand blotting, ALS by RIA. Based values of IGFBP-3 and ALS were low. During IGF-I treatment, the IGFBP-3 concentrations in the girl gradually increased, whereas in the boys there was a 60% decrease during the first week, followed by gradual increase towards baseline. The ALS concentrations followed a similar pattern. We conclude that IGF-I treatment induces and initial suppression and then an increase in the IGFBP-3 and ALS concentrations, confirming data from animal experiments that IGFBP-3 synthesis is not solely under GH control. The differences in responsiveness between the female and male siblings may reflect genetic differences, or lower circulating concentrations of IGF-I in the boys compared with the girl.}, }
@article {pmid9424550, year = {1997}, author = {Conradi, S and Ronnevi, LO}, title = {[Improved knowledge resulted in better care of ALS].}, journal = {Lakartidningen}, volume = {94}, number = {48}, pages = {4484-6, 4489-92}, pmid = {9424550}, issn = {0023-7205}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/etiology/therapy ; Clinical Competence ; Humans ; Patient Care Team ; Riluzole/therapeutic use ; }, abstract = {An example of the substantial advances in the management and treatment of patients with amyotrophic lateral sclerosis (ALS) in recent years is the introduction in 1996 of Riluzole, the first drug with verified effect on the disease course. The article consists in a review of recent advances in our knowledge of the pathogenic mechanisms, diagnosis, management and treatment of ALS.}, }
@article {pmid9419060, year = {1997}, author = {Rudnicki, SA}, title = {Factors influencing a patient's decision regarding riluzole: an early experience.}, journal = {Journal of the neurological sciences}, volume = {152 Suppl 1}, number = {}, pages = {S80-1}, doi = {10.1016/s0022-510x(97)00250-5}, pmid = {9419060}, issn = {0022-510X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology/*psychology ; Costs and Cost Analysis ; Female ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/adverse effects/economics/*therapeutic use ; Riluzole/adverse effects/economics/*therapeutic use ; Treatment Refusal ; }, abstract = {Riluzole is the first drug to be approved in the United States for the treatment of amyotrophic lateral sclerosis (ALS). During the first 8 months of the drug's availability by prescription, its use was discussed with 46 patients with probable or definite ALS as defined by the E1 Escorial criteria. Seventeen of the patients (37%) chose to take riluzole while 29 (63%) refused. Increased duration of symptoms, increased time since diagnosis, and participation in either the insulin-like growth factor-1 (IGF-1) and brain-derived neurotrophic factor (BDNF) trials were all associated with decreased likelihood of starting the drug. The most common reason given for not wanting to take the medication was insufficient benefit.}, }
@article {pmid9419051, year = {1997}, author = {David, WS and Bundlie, SR and Mahdavi, Z}, title = {Polysomnographic studies in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {152 Suppl 1}, number = {}, pages = {S29-35}, doi = {10.1016/s0022-510x(97)00241-4}, pmid = {9419051}, issn = {0022-510X}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*physiopathology ; Arousal/physiology ; Carbon Dioxide/blood ; Female ; Humans ; Male ; Middle Aged ; *Polysomnography ; Positive-Pressure Respiration ; Respiratory Function Tests ; Retrospective Studies ; Sleep/physiology ; Vital Capacity ; }, abstract = {We retrospectively reviewed 17 polysomnograms (PSG) in symptomatic amyotrophic lateral sclerosis (ALS) patients to assess the type and frequency of sleep disordered events and correlated these findings with pulmonary function tests (PFTs), presenting complaints, presence of bulbar dysfunction, and response to bi-level positive airway pressure (PAP) treatment. PSG revealed abnormalities in 16 patients. Complaints of orthopnea, daytime sleepiness (but not morning headaches) and a low negative inspiratory force (NIF) correlated with sleep disruption. However, neither the forced vital capacity (FVC) nor the NIF reliably predicted any specific PSG finding. Twelve of 13 patients treated with bi-level PAP responded favorably. Since the response to bi-level PAP is frequently gratifying, PSG should strongly be considered in ALS patients with suspected sleep disturbances.}, }
@article {pmid9419047, year = {1997}, author = {Cedarbaum, JM and Stambler, N}, title = {Performance of the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) in multicenter clinical trials.}, journal = {Journal of the neurological sciences}, volume = {152 Suppl 1}, number = {}, pages = {S1-9}, doi = {10.1016/s0022-510x(97)00237-2}, pmid = {9419047}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/*physiopathology ; Brain-Derived Neurotrophic Factor/therapeutic use ; Cross-Sectional Studies ; Double-Blind Method ; Humans ; Longitudinal Studies ; Multicenter Studies as Topic/*standards ; *Neuropsychological Tests ; Prospective Studies ; Recombinant Proteins/therapeutic use ; Reproducibility of Results ; Time Factors ; }, abstract = {The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) is a 10-item functional inventory which was devised for use in therapeutic trials in ALS. Each item is rated on a 0-4 scale by the patient and/or caregiver, yielding a maximum score of 40 points. The ALSFRS assesses patients' levels of self-sufficiency in areas of feeding, grooming, ambulation and communication. Rotated factor analysis of the ALSFRS found that the rating items group logically and consistently into four categories. The ALSFRS has been validated both cross-sectionally and longitudinally against muscle strength testing, the Schwab and England ADL rating scale, the Clinical Global Impression of Change (CGIC) scale, and independent assessments of patient's functional status. In this report, we use the data provided by the placebo patients who participated in the ALS CNTF Treatment Study (ACTS) to demonstrate the robustness, test-retest reliability and consistency of the ALSFRS as employed in a large, multicenter clinical trial.}, }
@article {pmid9409357, year = {1997}, author = {Lai, EC and Felice, KJ and Festoff, BW and Gawel, MJ and Gelinas, DF and Kratz, R and Murphy, MF and Natter, HM and Norris, FH and Rudnicki, SA}, title = {Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group.}, journal = {Neurology}, volume = {49}, number = {6}, pages = {1621-1630}, doi = {10.1212/wnl.49.6.1621}, pmid = {9409357}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology/*therapy ; Disease Progression ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Insulin-Like Growth Factor I/adverse effects/*therapeutic use ; Male ; Middle Aged ; Placebos ; Recombinant Proteins ; Severity of Illness Index ; Sickness Impact Profile ; Survival Analysis ; Treatment Outcome ; }, abstract = {The objective of this study was to investigate the safety and efficacy of recombinant human insulinlike growth factor-I (rhIGF-I) in the treatment of sporadic ALS. A double-blind, placebo-controlled, randomized study of 266 patients was conducted at eight centers in North America. Placebo or rhIGF-I (0.05 mg/kg/day or 0.10 mg/kg/day) was administered for 9 months. The primary outcome measure was disease symptom progression, assessed by the rate of change (per patient slope) in the Appel ALS rating scale total score. The Sickness Impact Profile (SIP), a patient-perceived, health-related quality of life assessment, was a secondary outcome variable. Progression of functional impairment in patients receiving high-dose (0.10 mg/kg/day) rhIGF-I was 26% slower than in patients receiving placebo (p = 0.01). The high-dose treatment group was less likely to terminate the study due to protocol-defined markers of disease symptom progression, and members in this group exhibited a slower decline in quality of life, as assessed by the SIP. Patients receiving 0.05 mg/kg/day of rhIGF-I exhibited trends similar to those associated with high-dose treatment, suggesting a dose-dependent response. The incidence of clinically significant adverse experiences was comparable among the three treatment groups. Recombinant human insulin-like growth factor-I slowed the progression of functional impairment and the decline in health-related quality of life in patients with ALS with no medically important adverse effects.}, }
@article {pmid9375696, year = {1997}, author = {Gegelashvili, G and Danbolt, NC and Schousboe, A}, title = {Neuronal soluble factors differentially regulate the expression of the GLT1 and GLAST glutamate transporters in cultured astroglia.}, journal = {Journal of neurochemistry}, volume = {69}, number = {6}, pages = {2612-2615}, doi = {10.1046/j.1471-4159.1997.69062612.x}, pmid = {9375696}, issn = {0022-3042}, mesh = {ATP-Binding Cassette Transporters/*metabolism ; Amino Acid Transport System X-AG ; Animals ; Astrocytes/*metabolism ; Cells, Cultured ; Cerebellum/cytology/metabolism ; Cerebral Cortex/cytology/metabolism ; Coculture Techniques ; Glucose Transporter Type 1 ; Mice ; Mice, Inbred BALB C ; Monosaccharide Transport Proteins/*metabolism ; Neurons/*metabolism ; Solubility ; }, abstract = {The glutamate transporters in the plasma membranes of neural cells secure termination of the glutamatergic synaptic transmission and keep the glutamate levels below toxic concentrations. Astrocytes express two types of glutamate transporters, GLAST (EAAT1) and GLT1 (EAAT2). GLT1 predominates quantitatively and is responsible for most of the glutamate uptake activity in the juvenile and adult brain. However, GLT1 is severely down-regulated in amyotrophic lateral sclerosis, a progressive neurodegenerative disease. Furthermore, selective loss of this transporter occurs in cultured astroglia. Expression of GLAST, but not of GLT1, seems to be regulated via the glutamate receptor signalling. The present study was undertaken to examine whether neuronal factors, other than glutamate, influence the expression of astroglial glutamate transporters. The expression of GLT1 and GLAST was examined in primary cultures of cerebellar granule neurons, cortical neurons, and astrocytes under different experimental conditions, including those that mimic neuron-astrocyte interactions. Pure astroglial cultures expressed only GLAST, whereas astrocytes grown in the presence of neurons expressed both GLAST (at increased levels) and GLT1. The induction of GLT1 protein and its mRNA was reproduced in pure cortical astroglial cultures supplemented with conditioned media from cortical neuronal cultures or from mixed neuron-glia cultures. This treatment did not change the levels of GLAST. These results suggest that soluble neuronal factors differentially regulate the expression of GLT1 and GLAST in cultured astroglia. Further elucidation of the molecular nature of the secreted neuronal factors and corresponding signalling pathways regulating the expression of the astroglial glutamate transporters in vitro may reveal mechanisms important for the understanding and treatment of neurological diseases.}, }
@article {pmid9402548, year = {1997}, author = {Borasio, GD and Voltz, R}, title = {Palliative care in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {244 Suppl 4}, number = {}, pages = {S11-7}, doi = {10.1007/pl00007719}, pmid = {9402548}, issn = {0340-5354}, mesh = {Advance Directives ; Amyotrophic Lateral Sclerosis/complications/psychology/*therapy ; Anxiety/prevention &amp; control ; Coma/etiology ; Deglutition Disorders/therapy ; Dysarthria/rehabilitation/therapy ; Dyspnea/etiology/therapy ; Gastrostomy/psychology ; Humans ; Hypercapnia/etiology ; Nutrition Disorders/prevention &amp; control ; *Palliative Care ; Physician-Patient Relations ; Respiratory Therapy ; Societies ; *Terminal Care ; Truth Disclosure ; }, abstract = {The poor prognosis of amyotrophic lateral sclerosis (ALS) makes palliative care a challenge for the neurologist. Most disabilities associated with progressive disease can be ameliorated by symptomatic treatment. Prognosis and treatment options should be openly discussed with the patient and his/her relatives. Nutritional deficiency due to pronounced dysphagia can be efficiently relieved by a percutaneous enterogastrostomy. Respiratory insufficiency can be treated by non-invasive ventilation at home, provided the familial environment is supportive. Adequate assistance and palliative treatment in the terminal phase is of paramount importance.}, }
@article {pmid9402538, year = {1997}, author = {Cappellari, A and Nobile-Orazio, E and Meucci, N and Levi Minzi, G and Scarlato, G and Barbieri, S}, title = {Criteria for early detection of conduction block in multifocal motor neuropathy (MMN): a study based on control populations and follow-up of MMN patients.}, journal = {Journal of neurology}, volume = {244}, number = {10}, pages = {625-630}, doi = {10.1007/s004150050157}, pmid = {9402538}, issn = {0340-5354}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Case-Control Studies ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*diagnosis/physiopathology ; Neural Conduction/*physiology ; }, abstract = {Motor conduction block (MCB) has been used as the main diagnostic criterion in multifocal motor neuropathy (MMN). Nonetheless, no agreed definition of block currently exists; the proposed required percent decrement of proximal compound muscle action potential (CMAP) amplitude varies from > 20% to > 50%. The aim of this work was to evaluate, through a follow-up study of patients with MMN, the behaviour of MCB over time. The percent decrement and temporal dispersion of proximal CMAP have also been calculated in normal controls and in patients affected by amyotrophic lateral sclerosis (ALS). The results show that MCB in patients with MMN is a dynamic entity which greatly varies over time and that a > 50% CMAP amplitued reduction may well be preceded by a smaller decrement that is nonetheless indicative of focal myelin damage in the appropriate clinical context. This datum and the results obtained in the control group and in patients with ALS suggest that a reappraisal of the diagnostic criteria for MCB, in cases with clinical and electrophysiological data strongly indicative of MMN, should be considered. Since MMN is a treatable disorder, the use of the proposed less restrictive criteria for the identification of MCB could allow for a promp and more effective treatment.}, }
@article {pmid9390108, year = {1997}, author = {Bruno, R and Vivier, N and Montay, G and Le Liboux, A and Powe, LK and Delumeau, JC and Rhodes, GR}, title = {Population pharmacokinetics of riluzole in patients with amyotrophic lateral sclerosis.}, journal = {Clinical pharmacology and therapeutics}, volume = {62}, number = {5}, pages = {518-526}, doi = {10.1016/S0009-9236(97)90047-3}, pmid = {9390108}, issn = {0009-9236}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*blood/drug therapy ; Chromatography, High Pressure Liquid ; Clinical Trials, Phase III as Topic ; Female ; Humans ; Male ; Middle Aged ; Multicenter Studies as Topic ; Neuroprotective Agents/administration &amp; dosage/*blood/*pharmacokinetics ; Prospective Studies ; Randomized Controlled Trials as Topic ; Riluzole/administration &amp; dosage/*blood/*pharmacokinetics ; }, abstract = {OBJECTIVES: To characterize the population pharmacokinetic of riluzole in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: One hundred patients with ALS who were participating in a multicenter phase III dose-ranging trial of riluzole were sampled on 179 visits. The sampling strategy (two samples per visit) was varied across patients to define the population kinetic profile (full screen). Riluzole plasma levels were determined by HPLC, and the data were analyzed by nonlinear mixed-effect modeling (NONMEM program) with use of a one-compartment structural model. The model incorporated interoccasion (visit-to visit) variability.<br><br>RESULTS: In the basic one-compartment pharmacokinetic model, interindividual variability in plasma clearance (51.4%) was higher than intraindividual (visit-to-visit) variability (28.0%), indicating uniform pharmacokinetic behavior during long-term therapy. Riluzole clearance was independent of dosage (25 to 100 mg twice daily), treatment duration (up to 10 months), age, and renal function; gender and smoking were the most important patient covariates, with hepatic function having lesser influence. Typical value of clearance was 51.4 L/hr for a nonsmoking male patient. It was 32% lower in women than in men and 36% lower in nonsmokers than in smokers. Gender- and smoking-related variations in riluzole exposure at the recommended dosage (50 mg twice daily) were within the range of exposures achieved (with no untoward effect) in this dose-ranging study.<br><br>CONCLUSION: The pharmacokinetics of riluzole has been characterized in patients during long-term therapy. Riluzole clearance is independent of dose and treatment duration. Within-patient variability is low. Gender and smoking status are the main covariates to explain interpatient variability.}, }
@article {pmid10176561, year = {1998}, author = {Jones, JB and Leicht, M and Dula, DJ}, title = {A 10-year experience in the use of air medical transport for medical scene calls.}, journal = {Air medical journal}, volume = {17}, number = {1}, pages = {7-11; discussion 11-2}, doi = {10.1016/s1067-991x(98)90081-5}, pmid = {10176561}, issn = {1067-991X}, mesh = {Air Ambulances/*statistics &amp; numerical data ; Classification ; *Emergencies ; Emergency Medical Services/standards/*statistics &amp; numerical data ; Evaluation Studies as Topic ; Humans ; Indiana/epidemiology ; Medical Audit ; Retrospective Studies ; Rural Health Services/standards/statistics &amp; numerical data ; Transportation of Patients/*statistics &amp; numerical data ; Utilization Review ; }, abstract = {OBJECTIVE: The objective of this retrospective descriptive study was to evaluate the use of air medical services in response to medical scene calls for transport to tertiary care in the rural setting.<br><br>METHODS: This study is a retrospective descriptive review of all medical scene calls during a 10-year study period. The cases were analyzed for demographics, transport time, medical indication, procedures, role of ground EMS services, effects on community hospitals, and patient outcomes. A case-by-case review by emergency medicine (EM) physicians was conducted to determine necessity of air medical transport.<br><br>RESULTS: A total of 8106 medical flights were conducted during the study period. Of these, 103 were scene calls for which 85 charts were available for review. The breakdown of medical scene calls is cardiac (29%), poisoning (17%), co poisoning (11%), neurologic (11%), and other (32%). Ground EMS was involved in 80% of the cases; ground advanced life support (ALS) was present in 58%. In 86% of the flights reviewed, an EM resident was aboard the helicopter. Of the 85 patients whose charts were available, 41 required admission to the ICU, five required hyperbaric oxygen (HBO) treatment, and 14 died before admission.<br><br>CONCLUSION: Evacuation of the rural patient with a medical emergency accounts for an extremely small percentage of an air medical service's use. ALS services, including emergency procedures at the scene and rapid transport to a tertiary care, were provided. Seventy-one percent of the flights reviewed required transport to a tertiary care facility, indicating that air medical transport was appropriate. Physician guidelines to ensure effective and cost-efficient use of these services should be developed. Responding for victims in cardiopulmonary arrest appears to provide little benefit with respect to outcome.}, }
@article {pmid9350622, year = {1997}, author = {Andjus, PR and Stevic-Marinkovic, Z and Cherubini, E}, title = {Immunoglobulins from motoneurone disease patients enhance glutamate release from rat hippocampal neurones in culture.}, journal = {The Journal of physiology}, volume = {504 (Pt 1)}, number = {Pt 1}, pages = {103-112}, pmid = {9350622}, issn = {0022-3751}, support = {823/TI_/Telethon/Italy ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/immunology/metabolism ; Animals ; Cells, Cultured ; Electric Stimulation ; Electrophysiology ; Female ; Glutamic Acid/*metabolism ; Hippocampus/cytology/drug effects/*metabolism ; Humans ; Immunoglobulins/metabolism/*pharmacology ; Male ; Membrane Potentials/physiology ; Middle Aged ; Motor Neuron Disease/immunology/*metabolism ; Neurons/drug effects/*metabolism ; Patch-Clamp Techniques ; Rats ; Receptors, Glutamate/drug effects/physiology ; Synapses/physiology ; }, abstract = {1. The whole-cell configuration of the patch-clamp technique was used to study the effects of immunoglobulins (IgGs) from patients affected by amyotrophic lateral sclerosis (ALS) on spontaneous glutamatergic currents in rat hippocampal cells in culture. 2. Focal application of ALS IgGs (100 micrograms ml-1) to hippocampal cells induced a rise in frequency but not in amplitude of spontaneous excitatory postsynaptic currents (SEPSC) which outlasted the period of IgG application. The mean frequency ratio (ALS over control) was 3.2 +/- 0.6 (n = 19). No changes in frequency or amplitude of SEPSCs were observed after treatment with IgGs obtained from healthy donors (n = 5) or from patients with Alzheimer's disease (n = 4). 3. ALS IgGs also increased the frequency (by a factor of 2.0 +/- 0.3) but not the amplitude of miniature excitatory postsynaptic currents (mEPSC) recorded in the presence of TTX (n = 19). A rise in frequency of mEPSC was also seen in cells superfused with a calcium-free solution (n = 4). 4. In the presence of TTX, ALS IgGs did not modify the amplitude or the shape of currents evoked by AMPA (100 microM), recorded at a holding potential of -50 mV. 5. It is concluded that ALS IgGs enhance both SEPSCs and mEPSCs through a presynaptic type of action. The excessive release of glutamate from nerve endings may be the cause of motoneurone death in ALS patients.}, }
@article {pmid9328050, year = {1998}, author = {Zurn, AD and Tseng, JL and Déglon, N and Joseph, JM and Aebischer, P}, title = {A gene therapy approach for the treatment of amyotrophic lateral sclerosis and Parkinson's disease.}, journal = {Advances in pharmacology (San Diego, Calif.)}, volume = {42}, number = {}, pages = {929-931}, doi = {10.1016/s1054-3589(08)60899-6}, pmid = {9328050}, issn = {1054-3589}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Cell Line ; Ciliary Neurotrophic Factor ; Cricetinae ; Disease Models, Animal ; Gene Transfer Techniques ; *Genetic Therapy ; Glial Cell Line-Derived Neurotrophic Factor ; Humans ; Nerve Growth Factors/*biosynthesis ; Nerve Tissue Proteins/biosynthesis/genetics ; Parkinson Disease/*therapy ; Rats ; Recombinant Fusion Proteins/biosynthesis ; Transfection ; }, }
@article {pmid9326417, year = {1997}, author = {Hale, DA and Gottschalk, R and Maki, T and Monaco, AP}, title = {Use of CTLA4-Ig in combination with conventional immunosuppressive agents to prolong allograft survival.}, journal = {Transplantation}, volume = {64}, number = {6}, pages = {897-900}, doi = {10.1097/00007890-199709270-00018}, pmid = {9326417}, issn = {0041-1337}, support = {R01 AI-14551/AI/NIAID NIH HHS/United States ; }, mesh = {Abatacept ; Animals ; Antigens, CD ; Antigens, Differentiation/*therapeutic use ; Antilymphocyte Serum/therapeutic use ; Bone Marrow Transplantation/*immunology ; CTLA-4 Antigen ; Cyclosporine/therapeutic use ; Drug Therapy, Combination ; Graft Survival/drug effects/*immunology ; Histocompatibility Testing ; Immunization, Passive ; *Immunoconjugates ; Immunosuppression Therapy/methods ; Immunosuppressive Agents/*therapeutic use ; Mice ; Mice, Inbred AKR ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Polyenes/therapeutic use ; Sirolimus ; Skin Transplantation/*immunology ; Transplantation, Homologous ; }, abstract = {BACKGROUND: The objective of our study was to determine the effectiveness of CTLA4-Ig, a novel immunosuppressive agent, in augmenting allograft survival when combined with either cyclosporine, sirolimus, donor-specific bone marrow alone (BM), or bone marrow in conjunction with antilymphocyte serum (ALS).<br><br>METHODS: Full-thickness skin allografts were used in C3H to B6AF1 (class I mismatch) and AKR to C57BL/6 (complete mismatch) models. Groups of mice (n=6-14) were treated with various combinations of the following treatment protocols: murine CTLA4-Ig, L-6 control Ig, sirolimus, cyclosporine, ALS, or ALS/BM.<br><br>RESULTS: In the class I mismatch model, L-6 control Ig had no effect whereas use of CTLA4-Ig alone resulted in a doubling of the median graft survival compared with controls. The addition of either sirolimus or cyclosporine to CTLA4-Ig increased graft survival over that achieved with CTLA4-Ig alone. CTLA4-Ig demonstrated no efficacy when used in combination with BM, ALS, or ALS/BM. CTLA4-Ig was clearly less effective in the complete mismatch model.<br><br>CONCLUSION: These data suggest that CTLA4-Ig may be effective clinically in combination with cyclosporine or sirolimus but offers no additional effectiveness in combination with antilymphocyte serum with or without donor-specific bone marrow.}, }
@article {pmid9376520, year = {1997}, author = {Barnéoud, P and Lolivier, J and Sanger, DJ and Scatton, B and Moser, P}, title = {Quantitative motor assessment in FALS mice: a longitudinal study.}, journal = {Neuroreport}, volume = {8}, number = {13}, pages = {2861-2865}, doi = {10.1097/00001756-199709080-00012}, pmid = {9376520}, issn = {0959-4965}, mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Cell Death/physiology ; Disease Models, Animal ; Electromyography ; Evaluation Studies as Topic ; Humans ; Longitudinal Studies ; Mice ; Mice, Transgenic ; Neurons/pathology ; *Point Mutation ; Psychomotor Performance/*physiology ; Superoxide Dismutase/*genetics ; }, abstract = {We have evaluated the G1H line of transgenic mice overexpressing a familial ALS mutation of SOD1 (Gly-93-->Ala) in tasks assessing different aspects of motor function to determine how early these deficits could be detected and their order of appearance. The earliest deficits were observed in tests of muscle strength and coordination as early as 8 weeks of age and their development appeared to be biphasic, whereas spontaneous activity was not impaired until 15 weeks of age. These studies show that, in addition to the previously demonstrated histological and electromyographic deficits, this transgenic mouse also presents changes in motor function reminiscent of the human disease, reinforcing and extending its validity as an animal model of familial amyotrophic lateral sclerosis (FALS) and allowing the investigation of novel drug treatment for ALS.}, }
@article {pmid9309687, year = {1997}, author = {Schulz, JB and Matthews, RT and Klockgether, T and Dichgans, J and Beal, MF}, title = {The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases.}, journal = {Molecular and cellular biochemistry}, volume = {174}, number = {1-2}, pages = {193-197}, pmid = {9309687}, issn = {0300-8177}, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/metabolism/pharmacology ; Animals ; Disease Models, Animal ; Dopamine Agents/metabolism/pharmacology ; Hydroxyl Radical/metabolism ; Mice ; Mitochondria/*metabolism/pathology ; Neurodegenerative Diseases/*metabolism/pathology ; Nitric Oxide/*metabolism ; Nitro Compounds ; Primates ; Propionates/metabolism/pharmacology ; Rats ; }, abstract = {Excitotoxicity, mitochondrial dysfunction and free radical induced oxidative damage have been implicated in the pathogenesis of several different neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease. Much of the interest in the association of neurodegeneration with mitochondrial dysfunction and oxidative damage emerged from animal studies using mitochondrial toxins. Within mitochondria 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), acts to inhibit NADH-coenzyme Q reductase (complex I) of the electron transport chain. MPTP produces Parkinsonism in humans, primates, and mice. Similarly, lesions produced by the reversible inhibitor of succinate dehydrogenase (complex II), malonate, and the irreversible inhibitor, 3-nitropropionic acid (3-NP), closely resemble the histologic, neurochemical and clinical features of HD in both rats and non-human primates. The interruption of oxidative phosphorylation results in decreased levels of ATP. A consequence is partial neuronal depolarization and secondary activation of voltage-dependent NMDA receptors, which may result in excitotoxic neuronal cell death (secondary excitotoxicity). The increase in intracellular Ca2+ concentration leads to an activation of Ca2+ dependent enzymes, including the constitutive neuronal nitric oxide synthase (cnNOS) which produces NO.. NO. may react with the superoxide anion to from peroxynitrite. We show that systemic administration of 7-nitroindazole (7-NI), a relatively specific inhibitor of cnNOS in vivo. attenuates lesions produced by striatal malonate injections or systemic treatment with 3-NP or MPTP. Furthermore 7-NI attenuated increases in lactate production and hydroxyl radical and 3-nitrotyrosine generation in vivo, which may be a consequence of peroxynitrite formation. Our results suggest that neuronal nitric oxide synthase inhibitors may be useful in the treatment of neurologic diseases in which excitotoxic mechanisms play a role.}, }
@article {pmid10174324, year = {1997}, author = {Ginsberg, GM and Lev, B}, title = {Cost-benefit analysis of riluzole for the treatment of amyotrophic lateral sclerosis.}, journal = {PharmacoEconomics}, volume = {12}, number = {5}, pages = {578-584}, pmid = {10174324}, issn = {1170-7690}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Cost-Benefit Analysis ; Health Care Costs ; Humans ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Riluzole/*therapeutic use ; Sensitivity and Specificity ; }, abstract = {We conducted a cost-benefit analysis of riluzole therapy in patients with amyotrophic lateral sclerosis (ALS; motor neuron disease; Lou Gehrig's disease). The survival of patients with ALS increased by around 3 months as a result of riluzole therapy, from 3 to 3.25 years. A 3-month delay in hospitalisation was also expected as a result of riluzole therapy, resulting in a saving of $US40 per patient (1996 values). This gain was opposed by the additional costs per patient of bi-monthly serum ALT monitoring ($US234), 2 days of extra day-hospital observation ($US369) and other medical costs ($US79), as well as extra outpatient visits ($US26) and costs of medication other than riluzole ($US90), resulting from increased longevity. Using riluzole (at a cost of $US2247 per patient) resulted in an extra burden of $US757 on health services for the gain of an extra 3 months of life expectancy. Thus, health-service costs per life-year gained were $US12,013. Despite the increase in health-service costs as a result of increased longevity, the overall resource benefits to society from using riluzole amounted to $US2884 due to increased productivity benefits, giving a benefit: cost ratio of 1.28:1. Total benefits to society, including a valuation of 3 extra months of life ($US3599), amounted to $US6483, giving a benefit: cost ratio of 2.89:1. Therefore, from a societal perspective, the potential benefits of riluzole in patients with ALS clearly exceed costs.}, }
@article {pmid9305318, year = {1997}, author = {}, title = {Practice advisory on the treatment of amyotrophic lateral sclerosis with riluzole: report of the Quality Standards Subcommittee of the American Academy of Neurology.}, journal = {Neurology}, volume = {49}, number = {3}, pages = {657-659}, doi = {10.1212/wnl.49.3.657}, pmid = {9305318}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials as Topic ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Excitatory Amino Acid Antagonists/administration &amp; dosage/*therapeutic use ; Humans ; Neurology ; Riluzole ; Societies, Medical ; Thiazoles/administration &amp; dosage/*therapeutic use ; Treatment Outcome ; }, }
@article {pmid9300407, year = {1997}, author = {Guyot, MC and Palfi, S and Stutzmann, JM and Mazière, M and Hantraye, P and Brouillet, E}, title = {Riluzole protects from motor deficits and striatal degeneration produced by systemic 3-nitropropionic acid intoxication in rats.}, journal = {Neuroscience}, volume = {81}, number = {1}, pages = {141-149}, doi = {10.1016/s0306-4522(97)00192-9}, pmid = {9300407}, issn = {0306-4522}, mesh = {Animals ; Antihypertensive Agents/*toxicity ; Corpus Striatum/pathology/*physiopathology ; Injections, Intraperitoneal ; Male ; Malonates/toxicity ; Microinjections ; Movement Disorders/*drug therapy/mortality ; Neuroprotective Agents/*pharmacology ; Neurotoxins/toxicity ; Nitro Compounds ; Propionates/*toxicity ; Rats ; Rats, Sprague-Dawley ; Riluzole/*pharmacology ; Succinate Dehydrogenase/antagonists &amp; inhibitors ; Survival Analysis ; }, abstract = {The putative neuroprotective effect of riluzole was investigated in a rat model of progressive striatal neurodegeneration induced by prolonged treatment (three weeks, intraperitoneal) with 3-nitropropionic acid, an irreversible inhibitor of succinate dehydrogenase. Quantitative analysis of motor behaviour indicated a significant protective effect (60%) of riluzole (8 mg/kg/day) on 3-nitropropionic acid-induced motor deficits as assessed using two independent motor tests. Furthermore, quantitative analysis of 3-nitropropionic acid-induced lesions indicated a significant 84% decrease in the volume of striatal damage produced by 3-nitropropionic acid, the neuroprotective effect apparently being more pronounced in the posterior striatum and pallidum. In addition, it was checked that this neuroprotective effect of riluzole against systemic 3-nitropropionic acid did not result from a decreased bioavailability of the neurotoxin or a direct action of riluzole on 3-nitropropionic acid-induced inhibition of succinate dehydrogenase. We found that riluzole significantly decreased by 48% the size of striatal lesions produced by stereotaxic intrastriatal injection of malonate, a reversible succinate dehydrogenase inhibitor. Furthermore, the inhibition of cortical and striatal succinate dehydrogenase activity induced by systemic 3-nitropropionic acid was left unchanged by riluzole administration. The present results, consistent with a beneficial effect of riluzole in amyotrophic lateral sclerosis, suggest that this compound may be useful in the treatment of chronic neurodegenerative diseases.}, }
@article {pmid9297980, year = {1997}, author = {Reavy, HJ and Traynor, NJ and Gibbs, NK}, title = {Photogenotoxicity of skin phototumorigenic fluoroquinolone antibiotics detected using the comet assay.}, journal = {Photochemistry and photobiology}, volume = {66}, number = {3}, pages = {368-373}, doi = {10.1111/j.1751-1097.1997.tb03160.x}, pmid = {9297980}, issn = {0031-8655}, mesh = {Animals ; Anti-Infective Agents/*toxicity ; Aphidicolin/pharmacology ; Cricetinae ; Cricetulus ; DNA/radiation effects ; DNA Repair ; Electrophoresis, Agar Gel/*methods ; Enzyme Inhibitors/pharmacology ; Fluoroquinolones ; Humans ; Mice ; Mutagens/*toxicity ; Nucleic Acid Synthesis Inhibitors ; Photosensitizing Agents/*toxicity ; Skin/*radiation effects ; }, abstract = {The fluoroquinolone (FQ) antibiotics photosensitize human skin to solar UV radiation and are reported to photosensitize tumor formation in mouse skin. As tumor initiation will not occur without genotoxic insult, we examined the potential of ciprofloxacin, lomefloxacin, fleroxacin, BAYy3118 (a recently developed monofluorinated quinolone) and a nalidixic acid to photosensitize DNA damage in V79 hamster fibroblasts in vitro. Cells were exposed to 37.5 kJ/m2 UVA (320-400 nm; glass filtered Sylvania psoralen + UVA (PUVA) tubes; calibrated Waldmann radiometer) at 4 degrees C in the presence of FQ and immediately afterwards embedded in agarose, lysed and placed in an electrophoretic field at pH 12. Under these denaturing conditions, the presence of DNA single-strand breaks (SSB), alkali-labile sites (ALS) and double-strand breaks (DSB) can be visualized as DNA migrating away from the nucleus (characteristic "comet" appearance) after staining with a specific fluorochrome. At FQ concentrations that induced minimal loss of cell viability (neutral red uptake assay) the compounds tested induced comets with a rank order of BAYy3118 > norfloxacin > ciprofloxacin > lomefloxacin > fleroxacin > nalidixic acid. If cells were incubated after treatment for 1 h at 37 degrees C, the comet score decreased, suggesting efficient removal of SSB/ALS/DSB. Addition of the DNA polymerase(alpha) inhibitor, aphidicolin, to cells treated with either ciprofloxacin alone or ciprofloxacin + UVA resulted in an accumulation of SSB due to the endo/exonuclease steps of excision repair. We have demonstrated that the FQ are photogenotoxic in mammalian cells but the FQ-photosensitized SSB are efficiently repaired. Preliminary evidence that ciprofloxacin photosensitizes the formation of DNA lesions warranting excision repair may indicate production of more mutagenic lesions.}, }
@article {pmid9294408, year = {1997}, author = {Stefani, A and Spadoni, F and Bernardi, G}, title = {Differential inhibition by riluzole, lamotrigine, and phenytoin of sodium and calcium currents in cortical neurons: implications for neuroprotective strategies.}, journal = {Experimental neurology}, volume = {147}, number = {1}, pages = {115-122}, doi = {10.1006/exnr.1997.6554}, pmid = {9294408}, issn = {0014-4886}, mesh = {Animals ; Anticonvulsants/*pharmacology ; Calcium/*physiology ; Calcium Channel Blockers/*pharmacology ; Cerebral Cortex/cytology/drug effects/*physiology ; Electric Conductivity ; Excitatory Amino Acid Antagonists/*pharmacology ; Lamotrigine ; Male ; Neurons/drug effects/physiology ; Neuroprotective Agents/pharmacology ; Phenytoin/*pharmacology ; Rats ; Rats, Wistar ; Riluzole ; Sodium/antagonists &amp; inhibitors/*physiology ; Thiazoles/*pharmacology ; Triazines/*pharmacology ; }, abstract = {Among the several classes of drugs currently studied as neuroprotective agents, glutamate release blockers have been indicated as being rather effective. In particular, lamotrigine and riluzole have shown promise in the treatment of either acutely developing cellular damages (stroke, posttraumatic lesions) or slowly progressing neurodegenerative diseases as amyotrophic lateral sclerosis. These drugs are supposed to interfere with the release of endogenous glutamate in situ, yet the mechanisms underlying this effect are not fully defined. One possibility is that lamotrigine and riluzole act by inhibiting voltage-dependent inward conductances active in the soma and/or in the axon terminal region. Therefore, we have investigated the effects of lamotrigine and riluzole on the voltage-gated sodium and calcium currents of acutely isolated neurons from the adult rat neocortex. In addition, since phenytoin is a well-known blocker of the sodium channel, we have compared lamotrigine and riluzole responses with the peak current inhibition produced by phenytoin in the same cells. Lamotrigine produced a large reduction of the high-voltage-activated calcium currents and a smaller; use-dependent inhibition of the sodium conductance. Riluzole inhibited significantly the sodium current at surprisingly low concentrations (nanomolar range) and by up to 80% at saturating doses (1-10 microM). Furthermore, riluzole inhibited both high- and low-voltage-activated calcium currents in neocortical neurons isolated from adult and young animals. By contrast, phenytoin caused only a slight reduction of high-voltage-activated calcium currents even at supratherapeutic doses (by < 12% at 10 microM). Taken together, the different pharmacological profiles of the tested agents might indicate that glutamate release blockers do not represent a homogenous class of drugs. Conversely, our findings could support their selective utilization in different disease status.}, }
@article {pmid9268246, year = {1997}, author = {Gourie-Devi, M and Nalini, A and Subbakrishna, DK}, title = {Temporary amelioration of symptoms with intravenous cyclophosphamide in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {150}, number = {2}, pages = {167-172}, doi = {10.1016/s0022-510x(97)00083-x}, pmid = {9268246}, issn = {0022-510X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Cyclophosphamide/*therapeutic use ; Dose-Response Relationship, Drug ; Female ; Humans ; Immunosuppressive Agents/*therapeutic use ; Injections, Intravenous ; Male ; Middle Aged ; Nervous System/drug effects/physiopathology ; Time Factors ; Treatment Outcome ; }, abstract = {Based on the evidence that autoimmunity may play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS), a variety of immunomodulating agents have been used in the treatment. In an uncontrolled trial we treated 44 patients of ALS with intravenous cyclophosphamide (IVCP) at a total dose of 1.5 g/m2 given over a period of 8 to 10 days. The patients were evaluated using neurological score which included bulbar, motor and daily activity scores before and following treatment. Twenty three patients showed a significant improvement (P=<0.001) in the composite and the individual scores. The improvement persisted only for 2 to 3 months. Amongst them the severely (7) and moderately (16) affected (score less than or more than 150) showed almost a similar response to treatment. A comparison of the improved group of 23 patients with the unimproved group of 21 patients did not reveal any significant factors which influenced the response to IVCP. However, there was a suggestion that patients below the age of 60 years and a duration of illness less than 12 months may respond to the drug. In conclusion, treatment with intravenous cyclophosphamide resulted in mild and temporary improvement in clinical status of the patients with amyotrophic lateral sclerosis. This may be considered as an alternative method of treatment in developing countries where newer drugs are not available and affordable.}, }
@article {pmid10179207, year = {1997}, author = {Hipskind, JE and Gren, JM and Barr, DJ}, title = {Patients who refuse transportation by ambulance: a case series.}, journal = {Prehospital and disaster medicine}, volume = {12}, number = {4}, pages = {278-283}, pmid = {10179207}, issn = {1049-023X}, mesh = {Adolescent ; Adult ; Age Factors ; Aged ; *Ambulances ; California ; Child ; Child, Preschool ; Data Collection ; Female ; Humans ; Incidence ; Male ; Middle Aged ; Risk Factors ; Sex Factors ; Transportation of Patients/*statistics &amp; numerical data ; Treatment Refusal/*statistics &amp; numerical data ; }, abstract = {INTRODUCTION: Patients refusing hospital transportation occurs in 5% to 25% of out-of-hospital calls. Little is known about these calls. This study was needed to determine the demographics, inherent risks, and timing of refused calls.<br><br>METHODS: This was a prospective review of all run sheets of patients who refused transportation were collected for a two month period. Demographic data and medical information was collected. Each run was placed into one of three categories of need for transport and further evaluation: 1) minimal; 2) moderate; and 3) definite. The Greater Elgin Area Mobile Intensive Care Program (GEA-MICP) based at Sherman Hospital in Elgin, Illinois, was the setting. The GEA-MICP is an Emergency Medical Services (EMS) system comprised of 17 advanced life support (ALS) ambulance agencies servicing northeastern Illinois. Study subjects were all patients who refused transportation to a hospital by ALS ambulance during July 1993 and February 1994. Paramedics were required to complete a run sheet for all calls.<br><br>RESULTS: Overall, 30% (683 of 2,270) of all runs resulted in refusal of transportation. Patients who most commonly refused transportation were asymptomatic, 11-40 years old and involved in a motor vehicle crash. They usually had no past medical history, normal vital signs, and a normal mental status. Patients generally signed for their own release after evaluation. The average time to arrival was 4.2 minutes and average time spent on scene by paramedics was 18.4 minutes. Of the patients, 72% were judged to have minimal need, 25% were felt to have a moderate need, and 3% were felt to definitely need transport to a hospital for further evaluation and/or treatment.<br><br>CONCLUSION: There are many cases when EMS are activated, but transportation is refused. Most refusals occur after paramedic evaluation. Providing paramedics with primary care training and protocols would standardize care given to patients and provide a mechanism for discharge instructions and follow-up for those who chose not to be transported to a hospital. Patients judged to require further treatment had unique characteristics. These data may be useful in identifying potentially sicker patients allowing a concentrated effort to transport this subset of patients to a hospital.}, }
@article {pmid9272109, year = {1997}, author = {Barreca, AM and Voci, A and Lee, PD and Arvigo, M and Ghigliotti, V and Fugassa, E and Giordano, G and Minuto, F}, title = {Effect of the somatostatin analog, octreotide, and of other hormones on the release of the acid-labile subunit of the 150 kDa complex by rat hepatocyte in primary culture.}, journal = {European journal of endocrinology}, volume = {137}, number = {2}, pages = {193-199}, doi = {10.1530/eje.0.1370193}, pmid = {9272109}, issn = {0804-4643}, mesh = {Acids/pharmacology ; Animals ; Cells, Cultured ; Chromatography, Gel ; Drug Stability ; Hormones/*pharmacology ; Immunoblotting ; Liver/cytology/*metabolism ; Male ; Molecular Weight ; Octreotide/*pharmacology ; Rats ; Rats, Wistar ; Somatomedins/antagonists &amp; inhibitors/chemistry/*metabolism ; Somatostatin/*analogs &amp; derivatives ; }, abstract = {OBJECTIVE: In normal subjects, the major form of circulating IGF is the GH-dependent 150 kDa complex. The liver appears to be the main source of the three components of the 150 kDa complex and, in particular, hepatocytes synthesize the insulin-like growth factor (IGF) peptide and the acid-labile subunit (ALS), whereas Kupffer and sinusoidal endothelial cells produce IGF-binding protein-3 (IGFBG-3). We have studied the effects of the somatostatin analog octreotide, IGF-II des(1-3)IGF-I, transforming growth factor (TGF)-beta 1 and tri-iodothyronine (T3) on ALS secretion into the medium conditioned by rat hepatocytes in primary culture.<br><br>METHODS: The regulation of ALS release was evaluated in the conditioned medium of adult rat hepatocytes exposed to increasing concentrations of test substances or to vehicle alone (control), after gel filtration in basic conditions, by immunoblot using an antiserum generated against the N-terminal 34 amino acids of human ALS.<br><br>RESULTS: The results demonstrate that: 1) octreotide in vitro produces a dose-dependent inhibition of both basal and GH-stimulated ALS secretion into the hepatocyte conditioned medium; 2) the release of ALS by adult rat hepatocytes is not affected by the presence during the incubation of des(1-3)IGF-I or IGF-II; 3) an inhibitory effect, although only with very high doses, can be observed after treatment with TGF-beta 1; and 4) a small but significant increase of ALS released into the medium can be seen when hepatocytes are treated with T3.<br><br>CONCLUSIONS: Evaluation of the effect of substances known to affect the production of IGF peptides, the IGFBPs, or both, on adult rat hepatocytes in primary culture revealed no powerful stimulator, but instead a potent inhibitor of ALS release/synthesis. Our data suggest that the effect of somatostatin on the 150 kDa complex is mediated not only by the reduction in GH concentration, but also by a direct inhibition of ALS release or synthesis.}, }
@article {pmid9263219, year = {1997}, author = {Iwasaki, Y and Ikeda, K and Shiojima, T and Tagaya, N and Kobayashi, T and Kinoshita, M}, title = {Bromocriptine prevents neuron damage following inhibition of superoxide dismutase in cultured ventral spinal cord neurons.}, journal = {Neurological research}, volume = {19}, number = {4}, pages = {389-392}, doi = {10.1080/01616412.1997.11740831}, pmid = {9263219}, issn = {0161-6412}, mesh = {Animals ; Bromocriptine/*pharmacology ; Cells, Cultured ; Chelating Agents/pharmacology ; Ditiocarb/pharmacology ; Dopamine Agonists/*pharmacology ; L-Lactate Dehydrogenase/metabolism ; Neurons/cytology/drug effects/*enzymology ; Neuroprotective Agents/pharmacology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/cytology ; Superoxide Dismutase/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Rosen et al. have reported point mutations in the cytosolic Cu/Zn superoxide dismutase (SOD 1) gene in some families with familial amyotrophic lateral sclerosis (ALS). To determine whether decreased SOD activity could contribute to neuronal damage, rat embryo ventral spinal cord neurons were incubated with diethyldithiocarbamate (DDC), an inhibitor of SOD. There was a marked increase in neuronal damage in cultures exposed to DDC and this phenomenon was dose-related. In this paradigm, these deteriorative changes were prevented by bromocriptine. DDC-treated ventral spinal cord neurons provide an in vitro model of free radical neurotoxicity secondary to decreased SOD activity. Simultaneous treatment with bromocriptine and DDC reduced neurotoxicity, indicating that bromocriptine has a neuroprotective effect against free radicals.}, }
@article {pmid9246719, year = {1997}, author = {Doré, S and Kar, S and Quirion, R}, title = {Rediscovering an old friend, IGF-I: potential use in the treatment of neurodegenerative diseases.}, journal = {Trends in neurosciences}, volume = {20}, number = {8}, pages = {326-331}, doi = {10.1016/s0166-2236(96)01036-3}, pmid = {9246719}, issn = {0166-2236}, mesh = {Humans ; Insulin-Like Growth Factor I/*pharmacology ; Nerve Degeneration/*physiology ; Nervous System Diseases/*drug therapy ; }, abstract = {Insulin-like growth factor-I (IGF-I) is a pleiotropic protein that acts on many tissues and organs. As it is one of the major trophic factors in the circulation, its actions in peripheral tissues are well established. It has been used for the treatment of several diseases, including growth deficiency, osteoporosis, catabolic disorders and diabetes. Recent evidence supports the significance of IGF-I in the maintenance of the integrity and homeostasis of the nervous system. The widespread distribution of its receptor allows IGF-I to affect the survival of numerous populations of neurones and glial cells in both the CNS and the PNS. Most recently, a clinical trial has revealed the beneficial effects of IGF-I in amyotrophic lateral-sclerosis (ALS), a degenerative disease of the motoneurones. We review briefly here experimental and clinical information that suggests the potential usefulness of IGF-I in the treatment of certain neurodegenerative diseases, including ALS, Alzheimer's disease, various neuropathies and brain trauma. The rather unique propensity of IGF-I to act on a variety of neuronal cells might provide a general means of reducing or slowing down neuronal losses that occur following various brain insults.}, }
@article {pmid9227949, year = {1997}, author = {Ross, MA}, title = {Acquired motor neuron disorders.}, journal = {Neurologic clinics}, volume = {15}, number = {3}, pages = {481-500}, doi = {10.1016/s0733-8619(05)70330-3}, pmid = {9227949}, issn = {0733-8619}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/etiology/therapy ; Diagnosis, Differential ; Humans ; Motor Neuron Disease/diagnosis/*etiology/therapy ; Neurologic Examination ; Palliative Care ; Poliomyelitis/complications/diagnosis/therapy ; Postpoliomyelitis Syndrome/diagnosis/etiology/therapy ; Prognosis ; }, abstract = {The acquired motor neuron disorders are a heterogeneous group of conditions in which motor neuron degeneration or dysfunction produces the predominant manifestation of weakness, while the sensory system is clinically spared. The disorders most commonly seen in clinical practice are amyotrophic lateral sclerosis, late manifestations of poliomyelitis, and lower motor neuron syndromes, including motor neuropathy. Less often, acquired motor neuron disorders may complicate metabolic, toxic, or systemic disorders. The pathogenesis of most acquired motor neuron disorders is poorly understood, and treatment is mainly supportive; however clues to understanding the pathogenesis of amyotrophic lateral sclerosis are emerging, and new pharmacologic therapies are available. There is a growing sense of hope that combinations of drugs that are currently being tested may impact the survival of amyotrophic lateral sclerosis.}, }
@article {pmid10420924, year = {1997}, author = {Zazpe, A and Del Río, J}, title = {[Neurotrophins. II: therapeutic potential].}, journal = {Revista de medicina de la Universidad de Navarra}, volume = {41}, number = {3}, pages = {180-184}, pmid = {10420924}, issn = {0556-6177}, mesh = {Alzheimer Disease/*drug therapy ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Apoptosis/drug effects ; Clinical Trials as Topic ; Disease Models, Animal ; Humans ; Mice ; Mice, Neurologic Mutants ; Nerve Degeneration/drug therapy ; Nerve Growth Factors/pharmacology/physiology/*therapeutic use ; Neurons/drug effects/pathology ; Parkinson Disease/*drug therapy ; }, abstract = {Neurodegenerative diseases are highly devastating disorders characterized by the damage and loss of discrete neuronal populations. Until recently, it was assumed that the ability of the central nervous system to recover from injury was extremely limited. However, many "in vitro" and "in vivo" studies have shown that neurotrophic factor are able to prevent or inhibit neuronal cell death induced by a variety of insults. Accordingly, trophic factors may represent a new tool for treating neuronal injury and death in a variety of neurodegenerative diseases. In his review, the therapeutic possibilities of neurotrophins in the treatment of Parkinson's disease, Alzheimer disease and amyotrophic lateral sclerosis are analysed.}, }
@article {pmid9709356, year = {1997}, author = {Joyce, SM and Dutkowski, KL and Hynes, T}, title = {Efficacy of an EMS quality improvement program in improving documentation and performance.}, journal = {Prehospital emergency care}, volume = {1}, number = {3}, pages = {140-144}, doi = {10.1080/10903129708958807}, pmid = {9709356}, issn = {1090-3127}, mesh = {Documentation/*standards ; Emergency Medical Services/organization &amp; administration/*standards ; Emergency Medical Technicians/*education/*standards ; *Employee Performance Appraisal ; Humans ; Prospective Studies ; Retrospective Studies ; *Total Quality Management ; Utah ; }, abstract = {OBJECTIVE: Change from quality assurance (QA) to quality improvement (QI) in EMS has been adopted by many systems. This study sought to determine whether QI is effective in this setting.<br><br>METHODS: A QI program comprised of prospective, concurrent, and retrospective components was instituted in 1994 by the Salt Lake City Fire Department. The retrospective component of the program consisted of monthly random audits of approximately 6% of EMS patient care reports (PCRs), both ALS and BLS. PCRs were evaluated for adequate documentation of six patient assessment parameters, appropriate treatment, and short-term outcome. Time intervals and adherence to protocol were also evaluated. Overall documentation and performance were rated. Monthly and cumulative QI reports were circulated to all providers, and both positive feedback and negative feedback were provided to specific crews. Continuing medical education sessions were tailored to address problems identified by the QI audits and scene observation. Results of 1,862 reviews from 1994-1995 were compared with baseline figures from 1993.<br><br>RESULTS: Response, scene, and transport times were acceptable in more than 90% of cases in both the baseline and the study periods. Statistically significant improvements were noted in the following parameters: documentation of patient assessment, protocol compliance, patient disposition, overall documentation, overall performance, and need for further review. In nontransport cases, both appropriateness of the release decision and acquisition of appropriate signatures improved, but not significantly.<br><br>CONCLUSION: Significant improvements were noted in 13 of 19 parameters and goals were met in 14, with results sustained over the two-year study period. A quality improvement program can effect significant and sustained improvement in documentation and performance in an EMS system.}, }
@article {pmid9267195, year = {1997}, author = {Hanayama, K and Ishikawa, Y and Bach, JR}, title = {Amyotrophic lateral sclerosis. Successful treatment of mucous plugging by mechanical insufflation-exsufflation.}, journal = {American journal of physical medicine &amp; rehabilitation}, volume = {76}, number = {4}, pages = {338-339}, doi = {10.1097/00002060-199707000-00017}, pmid = {9267195}, issn = {0894-9115}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications ; Cough ; Female ; Humans ; *Insufflation ; Intermittent Positive-Pressure Breathing ; *Mucus ; Respiratory Insufficiency/*etiology/*therapy ; Respiratory Therapy/*methods ; }, abstract = {Bronchial mucous plugging is the main precipitating factor of acute respiratory failure for patients with neuromuscular disease. Manually assisted coughing and mechanical insufflation-exsufflation can effectively eliminate airway secretions without resorting to tracheal intubation provided that bulbar muscle function is sufficient to permit assisted peak cough flows of 160 l/min or greater. We now report successful use of mechanical insufflation-exsufflation to prevent acute respiratory failure for a patient with amyotrophic lateral sclerosis with no measurable peak cough flow.}, }
@article {pmid9262126, year = {1997}, author = {Gredal, O and Werdelin, L and Bak, S and Christensen, PB and Boysen, G and Kristensen, MO and Jespersen, JH and Regeur, L and Hinge, HH and Jensen, TS}, title = {A clinical trial of dextromethorphan in amyotrophic lateral sclerosis.}, journal = {Acta neurologica Scandinavica}, volume = {96}, number = {1}, pages = {8-13}, doi = {10.1111/j.1600-0404.1997.tb00231.x}, pmid = {9262126}, issn = {0001-6314}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Dextromethorphan/*therapeutic use ; Double-Blind Method ; Excitatory Amino Acid Antagonists/*therapeutic use ; Humans ; Middle Aged ; Placebos ; Treatment Outcome ; }, abstract = {INTRODUCTION: Although the cause of amyotrophic lateral sclerosis (ALS) is unknown, excitotoxicity mediated by glutamate has been implicated. Dextromethorphan is a NMDA-glutamate receptor antagonist with neuroprotective properties.<br><br>MATERIAL AND METHODS: The effect of treatment with dextromethorphan (150 mg daily) in ALS patients was evaluated in a randomized, double-blind, placebo-controlled study. Forty-five patients were included in the analysis.<br><br>RESULTS: At the end of the treatment period, 12 months after randomization, 15 patients (65%) in the placebo group and 12 patients (55 %) in the dextromethorphan group were still alive (log rank test, P=0.49). Rates of disease progression, as expressed by rates of decline in pulmonary function and in functional disability, were similar in both groups except for a significantly less pronounced rate of decline in the ability scores for the lower extremities in the dextromethorphan group.<br><br>CONCLUSION: Treatment with a relatively low dose of dextromethorphan did not result in an improvement in 12-month survival in ALS.}, }
@article {pmid9241570, year = {1997}, author = {Tome, MB and Cloninger, CR and Watson, JP and Isaac, MT}, title = {Serotonergic autoreceptor blockade in the reduction of antidepressant latency: personality variables and response to paroxetine and pindolol.}, journal = {Journal of affective disorders}, volume = {44}, number = {2-3}, pages = {101-109}, doi = {10.1016/s0165-0327(97)00030-x}, pmid = {9241570}, issn = {0165-0327}, mesh = {Adrenergic beta-Agonists/*pharmacology/therapeutic use ; Adult ; Depressive Disorder/*drug therapy ; Double-Blind Method ; Ego ; Female ; Humans ; Male ; Middle Aged ; Paroxetine/*adverse effects/*metabolism/therapeutic use ; Patient Compliance ; Personality/*drug effects ; Personality Inventory ; Pindolol/*pharmacology/therapeutic use ; Selective Serotonin Reuptake Inhibitors/administration &amp; dosage/*pharmacology/*therapeutic use ; Temperament ; Time Factors ; }, abstract = {No antidepressant currently in use exerts a significant antidepressant effect for at least two to three weeks after the patient starts taking it. Open studies suggest that, for selective serotonergic re-uptake inhibitor (SSRI) antidepressants, this latency may be reduced when the drug is taken with the 5HT1A receptor blocker pindolol. We have undertaken a randomised, placebo controlled, double blind trial of augmentation of the selective SSRI antidepressant paroxetine in combination with pindolol. All our patients (n = 54; mean age 36 [range 19-65]) met criteria for major depression and received a standard dose (20 mg o.d.) of paroxetine plus, randomly, either pindolol (2.5 mg t.d.s.) or placebo for six weeks. We examined personality variables in 48 consecutive subjects according to a short version (TCI-125) of Cloninger et al's self-rated Temperament and Character Inventory (Cloninger et al., 1994) and correlated the results with clinical responses in the trial. The results suggest that personality can influence clinical outcome. After the double blind period patients were offered paroxetine 20 mg or 40 mg for up to 6 months. Twenty-six patients took this up. The results suggest that high scores in the temperament dimension of Reward Dependence and low scores in the temperament dimension of Harm Avoidance had a better outcome at 6 weeks. Patients who had received paroxetine and pindolol during the trial and who reported high Novelty Seeking and low Harm Avoidance scores had a better outcome at 6 weeks and 6 months. We suggest that temperament factors may influence outcome of antidepressant treatment.}, }
@article {pmid9225746, year = {1997}, author = {Palfi, S and Riche, D and Brouillet, E and Guyot, MC and Mary, V and Wahl, F and Peschanski, M and Stutzmann, JM and Hantraye, P}, title = {Riluzole reduces incidence of abnormal movements but not striatal cell death in a primate model of progressive striatal degeneration.}, journal = {Experimental neurology}, volume = {146}, number = {1}, pages = {135-141}, doi = {10.1006/exnr.1997.6520}, pmid = {9225746}, issn = {0014-4886}, mesh = {Acetylcholinesterase/analysis ; Animals ; Antiparkinson Agents/*pharmacology ; Apomorphine/pharmacology ; Caudate Nucleus/drug effects/pathology ; Corpus Striatum/*drug effects/pathology/physiopathology ; Movement Disorders/pathology/physiopathology/*prevention &amp; control ; Nerve Degeneration/*drug effects ; Neurons/drug effects/pathology/*physiology ; Neuroprotective Agents/*pharmacology ; Neurotoxins ; Nitro Compounds ; Papio ; Parkinson Disease, Secondary/pathology/*physiopathology/prevention &amp; control ; Propionates ; Putamen/drug effects/pathology ; Riluzole ; Thiazoles/*pharmacology ; }, abstract = {Riluzole has been shown recently to increase life expectancy in patients with amyotrophic lateral sclerosis. A number of experimental studies also suggest that this compound may be a neuroprotectant. We have investigated in baboons whether riluzole would protect striatal neurons from a prolonged 3-nitropropionic acid (3NP) treatment and ameliorate the associated motor symptoms. In animals receiving 3NP and the solvent of riluzole, 12 weeks of high-dose 3NP treatment resulted in the appearance of persistent leg dystonia and significant increases in the incidence of three categories of abnormal movements and in the dyskinesia index in the apomorphine test (0.5 mg/kg i.m.). Quantitative assessment of these behavioral deficits using a video movement analysis system demonstrated a significant decrease in locomotor activity and peak tangential velocity in 3NP-treated animals compared to controls. Histological analysis showed the presence of severe, bilateral, striatal lesions, localized in both caudate and putamen. Cotreatment with riluzole (4 mg/kg i.p., twice daily) significantly reduced the dyskinesia index (-35%, P < 0.02) in the apomorphine test. In the quantitative behavioral analysis, riluzole significantly ameliorated the decrease in peak tangential velocity (P < 0.02) but not the decrease in locomotor activity observed after 3NP. Comparative histological analysis of the two groups of treated animals did not demonstrate a clear neuroprotective effect of riluzole. The present study suggests that one potential therapeutic interest for riluzole in neurodegenerative disorders may reside in the reduction of motor symptoms associated with striatal lesions.}, }
@article {pmid9222193, year = {1997}, author = {Cudkowicz, ME and Warren, L and Francis, JW and Lloyd, KJ and Friedlander, RM and Borges, LF and Kassem, N and Munsat, TL and Brown, RH}, title = {Intrathecal administration of recombinant human superoxide dismutase 1 in amyotrophic lateral sclerosis: a preliminary safety and pharmacokinetic study.}, journal = {Neurology}, volume = {49}, number = {1}, pages = {213-222}, doi = {10.1212/wnl.49.1.213}, pmid = {9222193}, issn = {0028-3878}, support = {1PO1AG12992-01/AG/NIA NIH HHS/United States ; 1PO1NS31248-01/NS/NINDS NIH HHS/United States ; M01RR01066/RR/NCRR NIH HHS/United States ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Humans ; Injections, Spinal ; Middle Aged ; Recombinant Proteins/pharmacokinetics ; Sheep ; Superoxide Dismutase/*administration &amp; dosage/*adverse effects/pharmacokinetics ; }, abstract = {We undertook a safety and pharmacokinetic study of intrathecal (i.t.) recombinant human superoxide dismutase (rhSOD1). We administered rhSOD1 as an acute bolus in three sheep and 16 human subjects with amyotrophic lateral sclerosis (ALS). Two sheep received chronic i.t. infusion of rhSOD1 (one at 17.7 mg per day, the second at 38.0 mg per day) for six months. Two of the 16 subjects had familial ALS and mutations in the gene for Cu/Zn SOD1. They both received i.t. infusion of rhSOD1 (5 to 10 mg per day) for 3 to 6 months. Intrathecal rhSOD1 administration was safe. Bolus i.t. administration of 0.25 mg rhSOD1 in sheep revealed a mean elimination half-life of 0.4 (SD +/- 0.06) hours, clearance of 12.2 +/- 3.2 ml per hour, and volume of distribution of 7.3 +/- 0.9 ml. After chronic i.t. infusion, the initial alpha-phase half-life was estimated as 1.2 hours and the extended beta-phase half-life was 15.0 hours. The mean clearance rate was 25.9 ml per hour and the steady-state volume of distribution was 920.6 ml. Bolus i.t. administration of 20 micrograms of rhSOD1 in ALS subjects revealed a mean elimination half-life of 2.2 +/- 0.8 hours, clearance of 1.2 +/- 0.6 ml per hour, and volume of distribution of 3.5 +/- 0.4 ml. With chronic i.t. infusion of 5 mg per day, cerebrospinal SOD1 levels increased approximately fortyfold. We detected no benefit of this treatment in the two patients with familial ALS.}, }
@article {pmid10187020, year = {1997}, author = {Wittwer, LK and Muhr, MD}, title = {Adenosine for the treatment of PSVT in the prehospital arena: efficacy of an initial 6 mg dosing regimen.}, journal = {Prehospital and disaster medicine}, volume = {12}, number = {3}, pages = {237-239}, pmid = {10187020}, issn = {1049-023X}, mesh = {Adenosine/*administration &amp; dosage ; Adult ; Aged ; Anti-Arrhythmia Agents/*administration &amp; dosage ; Arrhythmias, Cardiac/diagnosis ; Diagnosis, Differential ; Drug Administration Schedule ; Emergency Medical Services/*methods ; Female ; Humans ; Male ; Middle Aged ; Tachycardia, Supraventricular/diagnosis/*drug therapy ; Treatment Outcome ; }, abstract = {OBJECTIVE: To confirm the efficacy of prehospital administration of adenosine, using a 6 milligram (mg) initial dosing regimen, for the treatment of paroxysmal supraventricular tachycardia (PSVT).<br><br>METHODS: Urban, suburban, rural emergency medical services (EMS) system in Clark County, Washington with advanced life support (ALS) patient transports. Concurrent, paramedic Medical Incident Report (MIR) review was conducted for 102 patients receiving prehospital adenosine during a 42-month period. Patients were administered 6 mg of adenosine using an intravenous (i.v.) bolus followed by 10 ml of balanced salt solution flush. If the patient's rhythm remained unchanged, the dosing regimen was increased to 12 mg followed by a 10 ml flush. This was repeated once more if the rhythm remained unchanged, to a total maximum dose of 30 mg. Medical direction for administration of adenosine was in the form of standing orders rather than direct (on-line) medical control.<br><br>RESULTS: Seventy-four of 102 patients had PSVT as determined by physician analysis of the initial six-second electrocardiographic rhythm strip (ECG) recording. Sixty-six of these patients converted their cardiac rhythm from PSVT using adenosine; 46 (70%) converted with the initial 6 mg bolus. Fifteen patients converted after receiving the second dose (12 mg); and five patients required 30 mg.<br><br>CONCLUSION: These results show that for paramedics, adenosine is an effective treatment for PSVT. An initial bolus of 6 mg converts the majority of cases. Eighty-nine percent of cases of confirmed PSVT converted with adenosine administration.}, }
@article {pmid9333422, year = {1997}, author = {Pekárek, J and Cech, K and Nevsímal, O}, title = {[Control of autoimmune processes by natural and other non-harmful methods].}, journal = {Bratislavske lekarske listy}, volume = {98}, number = {6}, pages = {315-320}, pmid = {9333422}, issn = {0006-9248}, mesh = {Adult ; Animals ; Antilymphocyte Serum/therapeutic use ; Arthritis, Experimental/therapy ; Autoimmune Diseases/immunology/*therapy ; CD8-Positive T-Lymphocytes ; Encephalomyelitis, Autoimmune, Experimental/therapy ; Female ; Guinea Pigs ; Humans ; Immunosuppressive Agents/therapeutic use ; Lymphocyte Count ; Male ; Middle Aged ; Rats ; Suppressor Factors, Immunologic/therapeutic use ; }, abstract = {At present an increase of some autoaggressive diseases can be observed. The commonly used treatment consists of the administration of some immunosuppressive drug of some hormonal preparations. This type of therapy is accompanied by some undesired side effects, as these drugs influence also some other cell systems besides the immunologically active cells. These drugs are also known to lower the resistance to some intercurrent infections. Due to these undesired side effects some naturally occurring factors are introduced into the therapy. These are e.g., TGF-beta, or some interleukins (IL-10 etc.). In our department and immunosuppressively acting substance was isolated from DHL which had the ability to inhibit the AA (adjuvant arthritis) in rats. In humans this SF (suppressive factor) stimulates the CD 8+ cells which are known to have suppressoric activity. This SF was successfully applied in some autoaggressive diseases, e.g., atopic eczema, multiple sclerosis, some polyradiculoenuritis, amyotropic lateral sclerosis etc. In this paper the results in the ALS patients are given. Amongst other possibilities of the therapy the application of antilymphocyte sera, monoclonal antibodies to some CD markers of lymphocytes and some methods of hyposensitizations of tolerance induction are mentioned. Further, an original method using antigen bound to isosoluble carrier is described. This administration of encephalitogen bound onto Sforon (polyacrylate spheres) sis not only inhibit the EAE manifestations but also enable the survival of guinea-pigs which had already manifested the clinical signs of EAE.}, }
@article {pmid9226998, year = {1997}, author = {Louvel, E and Hugon, J and Doble, A}, title = {Therapeutic advances in amyotrophic lateral sclerosis.}, journal = {Trends in pharmacological sciences}, volume = {18}, number = {6}, pages = {196-203}, doi = {10.1016/s0165-6147(97)01062-6}, pmid = {9226998}, issn = {0165-6147}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/genetics/physiopathology ; Animals ; Antioxidants/pharmacology/therapeutic use ; Clinical Trials as Topic/trends ; Disease Models, Animal ; Excitatory Amino Acid Antagonists/pharmacology/therapeutic use ; Free Radicals/adverse effects ; Gene Expression Regulation, Enzymologic/drug effects/genetics ; Humans ; Immunosuppressive Agents/pharmacology/therapeutic use ; Mutation/genetics ; Nerve Growth Factors/pharmacology/therapeutic use ; Neuroprotective Agents/pharmacology/therapeutic use ; Oxidative Stress ; Superoxide Dismutase/*genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and rapidly fatal neurodegenerative disease in which both upper and lower motoneurones are involved. The recent discovery of mutations affecting the superoxide dismutase (SOD) gene has given impetus to research on the role of oxidative stress in the pathogenesis of familial ALS, while further evidence for a role of excitotoxicity in the disease process has arisen. In this review, Erik Louvel, Jacques Hugon and Adam Doble discuss these findings and, in addition, describe how a number of large, well-controlled clinical trials have taken place to test potential therapies suggested by different aetiological hypotheses, including immunosuppressive therapies, neurotrophic factors, antioxidants and anti-excitotoxic drugs. These trials have led to the first modest steps in the treatment of this devastating neurological disease.}, }
@article {pmid9186890, year = {1997}, author = {Powell, DR and Liu, F and Baker, BK and Hintz, RL and Lee, PD and Durham, SK and Brewer, ED and Frane, JW and Watkins, SL and Hogg, RJ}, title = {Modulation of growth factors by growth hormone in children with chronic renal failure. The Southwest Pediatric Nephrology Study Group.}, journal = {Kidney international}, volume = {51}, number = {6}, pages = {1970-1979}, doi = {10.1038/ki.1997.268}, pmid = {9186890}, issn = {0085-2538}, support = {M01 RR00069/RR/NCRR NIH HHS/United States ; R01 DK-38773/DK/NIDDK NIH HHS/United States ; }, mesh = {Age Determination by Skeleton ; Anthropometry ; Body Height ; Child ; Child, Preschool ; Female ; Growth Substances/*metabolism ; Human Growth Hormone/*therapeutic use ; Humans ; Insulin/blood ; Insulin-Like Growth Factor Binding Proteins/blood ; Insulin-Like Growth Factor I/analysis ; Insulin-Like Growth Factor II/analysis ; Kidney Failure, Chronic/*drug therapy/*metabolism/pathology ; Male ; Recombinant Proteins ; }, abstract = {Anthropometric measurements and circulating growth factors were studied serially in 44 prepubertal children with growth failure and chronic renal failure (GFR = 10 to 40 ml/min/1.73 m2) who were randomized to receive either recombinant human growth hormone (rhGH; N = 30) or no treatment (N = 14). RhGH was given as Nutropin, 0.05 mg/kg/day, and the studies were carried out at baseline and after 3 and 12 months. At baseline, serum insulin-like growth factor binding protein (IGFBP)-1 and -2 levels were, while IGFBP-3 levels were not, higher than those of children with normal renal function. In addition, height SDS at baseline correlated inversely with serum IGFBP-2 levels (r = -0.461, P = 0.0016), but did not correlate significantly with any other factor. After 12 months of study, the 30 children receiving rhGH showed: (i) greater increase in height (9.1 +/- 2.8 vs. 5.5 +/- 1.9 cm, P < 0.0001); (ii) increases in serum levels of IGF-I, IGF-II, free IGF-I, IGFBP-3 and acid labile subunit (ALS); (iii) a greater decrease in serum IGFBP-1 levels; and (iv) no significant difference in serum IGFBP-2 levels, when compared to the 14 control patients. The change in height SDS after 12 months of rhGH (+0.8) in the 30 treated children correlated significantly and positively with serum ALS, IGFBP-3, total IGF, IGF-I, IGF-II and free IGF-I levels measured during treatment. These observations suggest that, in children with growth failure associated with chronic renal failure: (i) IGFBP-2, and not IGFBP-3, is likely to be a growth inhibitor; (ii) rhGH stimulates catch-up growth in part by increasing serum levels of IGF peptides; and (iii) linear growth is influenced by the balance between growth stimulating IGFs and growth inhibitory IGFBPs.}, }
@article {pmid9185453, year = {1997}, author = {Morita, H and Gotoh, N and Yoshimura, H}, title = {[A case of bilateral pneumothorax successfully treated with surgery associated with amyotrophic lateral sclerosis having been controlled with artificial ventilation].}, journal = {Kyobu geka. The Japanese journal of thoracic surgery}, volume = {50}, number = {6}, pages = {511-513}, pmid = {9185453}, issn = {0021-5252}, mesh = {Amyotrophic Lateral Sclerosis/*complications/therapy ; Humans ; Male ; Middle Aged ; Pneumothorax/etiology/*surgery ; *Respiration, Artificial ; }, abstract = {We reported a case of bilateral pneumothorax, which was successfully treated with surgery, associated with amyotrophic lateral sclerosis (ALS). The patient had been controlled with artificial ventilation at the time of surgery. Prognosis of ALS is absolutely poor, and the life expectancies for patients with ALS are presumed several years, even though they are controlled with artificial ventilation. We applied a surgical treatment for a patient with ALS who developed bilateral pneumothorax as a life saving procedure.}, }
@article {pmid9184724, year = {1997}, author = {Mitsumoto, H}, title = {Riluzole--what is its impact in our treatment and understanding of amyotrophic lateral sclerosis?.}, journal = {The Annals of pharmacotherapy}, volume = {31}, number = {6}, pages = {779-781}, doi = {10.1177/106002809703100619}, pmid = {9184724}, issn = {1060-0280}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Humans ; Neuroprotective Agents/administration &amp; dosage/*therapeutic use ; Riluzole ; Thiazoles/administration &amp; dosage/*therapeutic use ; }, abstract = {Riluzole marks the beginning of pharmacotherapy for patients with ALS. Our task is to fully identify the impact of riluzole in ALS treatment. The ALS Clinical Assessment Research and Education (ALS CARE) is an ambitious database in North America created to establish the benchmarks for patient care and management. Such a program may allow us to analyze the use and impact of riluzole in the treatment of ALS. In the spring of 1997, just 1 year since the approval of riluzole, several more potential drugs for ALS are on the horizon. If a single medication is not sufficient to alter the disease course significantly, we must investigate drug combinations to determine potential additive or synergistic benefits. Although far from ideal, riluzole is allowing clinicians and researchers to lift a corner of the veil surrounding ALS to glimpse the possibility of effective treatment.}, }
@article {pmid9184716, year = {1997}, author = {Wagner, ML and Landis, BE}, title = {Riluzole: a new agent for amyotrophic lateral sclerosis.}, journal = {The Annals of pharmacotherapy}, volume = {31}, number = {6}, pages = {738-744}, doi = {10.1177/106002809703100614}, pmid = {9184716}, issn = {1060-0280}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Drug Interactions ; Humans ; Neuroprotective Agents/adverse effects/pharmacokinetics/*therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole ; Thiazoles/adverse effects/pharmacokinetics/*therapeutic use ; }, abstract = {OBJECTIVE: To provide a comprehensive review of riluzole, including its mechanism of action, pharmacokinetics, adverse drug reactions, drug interactions, efficacy, and administration. A brief review of amyotrophic lateral sclerosis (ALS) is also included.<br><br>DATA SOURCES: A computerized search of the MEDLINE database in May 1996 was used to identify publications regarding ALS, riluzole, and metabolism by CYP1A2. Manufacturer's information on riluzole was used when there was no primary literature.<br><br>DATA SYNTHESIS: Riluzole is approximately 90% absorbed following an oral dose. Its bioavailability is 60%. Peak concentrations occur within 1-1.5 hours of administration. Riluzole extensively binds to lipoproteins and albumin. This agent primarily undergoes CYP1A2 hydroxylation and glucuronidation, after which it is eliminated by the kidneys. Clearance is reduced in native Japanese healthy subjects and may be reduced in patients with hepatic impairment. Two trials with a total of 1114 patients addressed the efficacy of riluzole in ALS. Riluzole extended the time to tracheostomy or death, and the effect was greatest with dosages of 100 mg/d or greater. No effect on patients' symptoms or global assessment was detected at 18 or 21 months. Several flaws in these trials have led to questions concerning the validity of these results. The most commonly reported adverse effects of riluzole have been transient elevation of liver enzyme concentrations (2-5 times the upper limit of normal), worsening of asthenia, nausea, vomiting, diarrhea, anorexia, dizziness, vertigo, somnolence, and mouth paresthesia. Not as commonly reported, but still very serious, is neutropenia, which occurred in 3 of 4000 patients.<br><br>CONCLUSIONS: Although the benefits of riluzole are questionable and it is expensive, this agent may extend the time to tracheostomy or death in patients with ALS. At present, this is the only agent approved for the treatment of ALS and should be made available for these patients.}, }
@article {pmid9166730, year = {1997}, author = {Müller, WE and Romero, FJ and Perovic, S and Pergande, G and Pialoglou, P}, title = {Protection of flupirtine on beta-amyloid-induced apoptosis in neuronal cells in vitro: prevention of amyloid-induced glutathione depletion.}, journal = {Journal of neurochemistry}, volume = {68}, number = {6}, pages = {2371-2377}, doi = {10.1046/j.1471-4159.1997.68062371.x}, pmid = {9166730}, issn = {0022-3042}, mesh = {Aminopyridines/*pharmacology ; Amyloid beta-Peptides/*toxicity ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cell Survival/drug effects ; Cerebral Cortex/cytology ; Glutathione/*metabolism ; Neurons/cytology/*drug effects ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/drug effects ; Peptide Fragments/*toxicity ; Rats ; Rats, Wistar ; }, abstract = {Effective drugs are not available to protect against beta-amyloid peptide (A beta)-induced neurotoxicity. Cortical neurons from rat embryos were treated with the toxic fragment A beta25-35 at 1 microM in the presence or absence of flupirtine, a triaminopyridine, successfully applied clinically as a nonopiate analgesic drug. Five days later 1 microM A beta25-35 caused reduction of cell viability to 31.1%. Preincubation of cells with flupirtine (1 or 5 microg/ml) resulted in a significant increase of the percentage of viable cells (74.6 and 65.4%, respectively). During incubation with A beta25-35 the neurons undergo apoptosis as determined by appearance of the characteristic stepladder-like DNA fragmentation pattern and by the TUNEL technique. A beta25-35-induced DNA fragmentation could be abolished by preincubation of the cells with 1 microg/ml flupirtine. Incubation with A beta25-35 reduces the intraneuronal level of GSH from 21.4 to 7.4 nmol/10(6) cells. This depletion could be partially prevented by preincubation of the cells with flupirtine. Thus, flupirtine may be adequate for the treatment of the neuronal loss in Alzheimer's disease (where A beta accumulates in senile plaques) and probably other neurological diseases such as amyotrophic lateral sclerosis.}, }
@article {pmid9149075, year = {1997}, author = {Hoagland, RJ and Mendoza, M and Armon, C and Barohn, RJ and Bryan, WW and Goodpasture, JC and Miller, RG and Parry, GJ and Petajan, JH and Ross, MA}, title = {Reliability of maximal voluntary isometric contraction testing in a multicenter study of patients with amyotrophic lateral sclerosis. Syntex/Synergen Neuroscience Joint Venture rhCNTF ALS Study Group.}, journal = {Muscle &amp; nerve}, volume = {20}, number = {6}, pages = {691-695}, doi = {10.1002/(sici)1097-4598(199706)20:6&lt;691::aid-mus5&gt;3.0.co;2-3}, pmid = {9149075}, issn = {0148-639X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*physiopathology ; Double-Blind Method ; Female ; Humans ; Isometric Contraction/*physiology ; Male ; Respiratory Function Tests ; }, abstract = {Maximal voluntary isometric contraction (MVIC) is becoming widely used for monitoring disease progression in amyotrophic lateral sclerosis (ALS). We evaluated the variability of MVIC in a large multicenter (29 sites) drug trial in ALS. Intra- and interrater variability were assessed twice during the 19-month study. Intrarater reliability increased from the first to the second test, approaching the reliability reported for a single experienced clinical evaluator, but interrater reliability did not. Multiple clinical evaluators in a single site increased the variability of MVIC measurements. Rigorous quality assurance standards and monitoring of clinical evaluators should be incorporated into the design of multicenter studies using MVIC, since low variability is necessary to detect a modest treatment effect.}, }
@article {pmid9435386, year = {1997}, author = {Guarniero, R and Ishikawa, MT and Luzo, CA and Montenegro, NB and de Godoy, RM}, title = {[Results of femoral varus osteotomy in the treatment of Legg-Calvé-Perthes disease].}, journal = {Revista do Hospital das Clinicas}, volume = {52}, number = {3}, pages = {132-135}, pmid = {9435386}, issn = {0041-8781}, mesh = {Adolescent ; Child ; Child, Preschool ; Female ; Femur Head/*surgery ; Humans ; Legg-Calve-Perthes Disease/*surgery ; Male ; Osteotomy/*methods ; Retrospective Studies ; Treatment Outcome ; }, abstract = {The authors studied a group of 52 patients with Legg-Calvé-Perthes disease who had been treated by femoral varus osteotomy (54 osteotomies) aiming to show the end results and complications of the procedure based on Stulberg et al's evaluation. Regarding this classification of results were found 19 osteotomies (35.1%) with a good result (Stulberg's Groups 1 and 2), 35 (64.8%) with a fair end result (Stulberg's Groups 3 and 4) and none poor result. Few complications were observed in this series: pseudarthrosis occurred in three cases; Trendelemburg was observed in five patients postoperatively and overgrowth of the greater trochanter was observed in seven patients. In nine patients it was observed a significant leg length discrepancy with more than 2.1 cm of difference. However by the end results observed we may say that good results can be obtained with this technique in the treatment of patients with Legg-Calvé-Perthes disease. It is very important the indication criteria adopted based on the prognosis of the individual case studied.}, }
@article {pmid9178169, year = {1997}, author = {Dengler, R and Tröger, M}, title = {Impact of riluzole on the relationship between patient and physician.}, journal = {Journal of neurology}, volume = {244 Suppl 2}, number = {}, pages = {S30-2}, pmid = {9178169}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*psychology ; Attitude ; Disease Progression ; Emotions ; Humans ; Neuroprotective Agents/*therapeutic use ; *Physician-Patient Relations ; Physicians/*psychology ; Riluzole ; Thiazoles/*therapeutic use ; }, abstract = {To date, there has been little systematic research on the patient-physician relationship in amyotrophic lateral sclerosis (ALS). Important factors in this relationship are the emotional state, or mood, of the patients and their expectations of successful therapeutic intervention. In many patients there is a gradual deterioration of mood with disease progression-a view supported by studies comparing the initial and late phases of the disease. The few studies examining patients' expectations of therapy revealed a strong desire to be informed about the disease and its course without destroying every hope. In the later stages of the disease patients expected compassion and help with immediate problems. To our knowledge there has been no systematic study on the attitude of physicians towards ALS patients. The lack of effective treatment and the wish to avoid full information about the poor prognosis are almost unique problems involved in dealing with ALS patients. The new option to treat with a drug that slows disease progression provides some alleviation for the physician. Riluzole, at least, partially meets this expectation. Although its efficacy is too limited to satisfy fully the wishes of patients and physicians, it is the first available drug that has been shown to slow disease progression. Thus, it may bring to an end the feeling that there is nothing that can be done for these patients. In our experience this provides relevant alleviation in the management of ALS patients.}, }
@article {pmid9178168, year = {1997}, author = {Swash, M}, title = {Health outcome and quality-of-life measurements in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {244 Suppl 2}, number = {}, pages = {S26-9}, pmid = {9178168}, issn = {0340-5354}, mesh = {Amyotrophic Lateral Sclerosis/*psychology/therapy ; Humans ; *Quality of Life ; Treatment Outcome ; }, abstract = {Quality of life has been used as a primary outcome measure in the treatment of cancer and cardiovascular disease, and as a secondary outcome measure in therapy of Parkinson's disease. However, it has been relatively neglected in studies of amyotrophic lateral sclerosis (ALS). Although there is need for the development of an ALS-specific quality-of-life measure, it will be necessary, nonetheless, to continue to use generic measures in order to ensure comparability of measurement between disease states. An argument is put forward for the use of quality-of-life measures as a primary end-point in future clinical trials in ALS. A distinction is drawn between the demonstration of biological efficacy and clinically useful benefit. The most likely instruments to prove useful are briefly discussed.}, }
@article {pmid9178167, year = {1997}, author = {Meininger, V and Dib, M and Aubin, F and Jourdain, G and Zeisser, P}, title = {The Riluzole Early Access Programme: descriptive analysis of 844 patients in France. ALS/Riluzole Study Group III.}, journal = {Journal of neurology}, volume = {244 Suppl 2}, number = {}, pages = {S22-5}, pmid = {9178167}, issn = {0340-5354}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Female ; France ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Riluzole ; Risk ; Survival Analysis ; Thiazoles/*therapeutic use ; Time Factors ; Tracheostomy ; Treatment Failure ; Treatment Outcome ; }, abstract = {Recent controlled trials in outpatients with amyotrophic lateral sclerosis (ALS) indicate that riluzole prolongs tracheostomy-free survival. After 12 months' treatment, riluzole 50 mg, 100 mg and 200 mg daily reduced the risk of death or tracheostomy (relative to placebo) by 24%, 34% and 31%, respectively (by 28%, 43% and 43%, respectively, after adjustment for known prognostic factors). This survival advantage (6-9 patients require treatment with riluzole to avoid 1 death/tracheostomy annually) compares favourably with that achieved therapeutically in breast cancer and coronary artery disease. Some 6000 ALS patients are currently receiving riluzole 50 mg twice daily within the Riluzole Early Access Program. In France, this programme is being implemented as an open-label multicentre trial to assess patients' functional status and quality of life. To date, 844 patients have been enrolled, and they will be followed up for 12 months on riluzole. Baseline demographic and clinical characteristics of this study population are presented here.}, }
@article {pmid9167437, year = {1997}, author = {Dixit, SN and Bushara, KO and Brooks, BR}, title = {Epidemic heat stroke in a midwest community: risk factors, neurological complications and sequelae.}, journal = {Wisconsin medical journal}, volume = {96}, number = {5}, pages = {39-41}, pmid = {9167437}, issn = {0043-6542}, mesh = {Adolescent ; Adult ; Aged ; Brain Diseases/*epidemiology/etiology ; Child ; Child, Preschool ; *Disease Outbreaks ; Female ; Heat Exhaustion/complications/*epidemiology ; Humans ; Male ; Middle Aged ; Patient Admission/statistics &amp; numerical data ; Risk Factors ; Wisconsin/epidemiology ; }, abstract = {We studied the admission rate, risk factors, neurological complications and sequelae of heat stroke (HS) during the 1995 heat wave in Madison, Wisconsin. HS was epidemic in 1995 (2.3 cases/1000 admissions), compared to the ten-fold lower endemic rate in 1994 (0.2/ 1000). There were 11 cases of HS, 9 males and 2 females. Contributing factors were athletic events (2), working outdoors (3) and indoor activity with malfunctioning air-conditioning (6). Medical conditions contributing to poor temperature regulation included schizophrenia with neuroleptic treatment (2), amyotrophic lateral sclerosis receiving nortriptiline (1), multiple sclerosis (1), attention deficit disorder (1), cystic fibrosis (1) and alcoholism (1). Acute neurological complications occurred in all patients on presentation including coma (8/11.73%), stupor (2/ 11.18%) and seizures (1/11.9%). Two patients (1856) had persistent neurological sequelae in the form of a pan-cerebellar syndrome while the remaining 9 recovered fully. Importantly, avoidable factors contributed to all of the patients with underlying diseases. These patients are particularly at risk and should take adequate precautions during summer months.}, }
@article {pmid9160251, year = {1997}, author = {Giménez y Ribotta, M and Revah, F and Pradier, L and Loquet, I and Mallet, J and Privat, A}, title = {Prevention of motoneuron death by adenovirus-mediated neurotrophic factors.}, journal = {Journal of neuroscience research}, volume = {48}, number = {3}, pages = {281-285}, doi = {10.1002/(sici)1097-4547(19970501)48:3&lt;281::aid-jnr11&gt;3.3.co;2-i}, pmid = {9160251}, issn = {0360-4012}, mesh = {Adenoviridae/*genetics ; Animals ; Animals, Newborn ; Axons/physiology ; Brain-Derived Neurotrophic Factor/*genetics/pharmacology ; Cell Death/drug effects ; Denervation ; Facial Nerve/cytology/enzymology ; Gene Transfer Techniques ; *Genetic Vectors ; Glial Cell Line-Derived Neurotrophic Factor ; Motor Neurons/drug effects/enzymology/*physiology ; *Nerve Growth Factors ; Nerve Tissue Proteins/*genetics/pharmacology ; *Neuroprotective Agents/administration &amp; dosage/pharmacology ; Rats ; Rats, Sprague-Dawley ; beta-Galactosidase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motoneurons, and has no effective treatment. Experimental studies in rodents have shown that motoneurons respond to a variety of molecules including brain-derived neurotrophic factor (BDNF). and the glial-cell line-derived neurotrophic factor (GDNF). Here we investigated the neuroprotective effect of these growth factors, encoded by an adenovirus, on the death of axotomized facial motoneurons in newborn rats. We used a new gene therapy strategy that involves gene transfer to motoneurons by intramuscular injection of an adenoviral vector, which is retrogradely transported from injected target muscle (Finiels et al.,: NeuroReport 7:373-378, 1995). A significant increased survival of motoneurons was observed in animals pretreated with adenovirus encoding BDNF (34.5%, P < 0.05) ou GDNF (41.9%, P < 0.05) 1 week after axotomy. These results indicate that pretreatment with BDNF or GDNF, using this therapeutic strategy, is able to prevent the massive death of motoneurons that normally follows axotomy in the neonatal period, opening new perspectives to limit neuronal death in degenerative disorders.}, }
@article {pmid9152108, year = {1997}, author = {Reider, CR and Paulson, GW}, title = {Lou Gehrig and amyotrophic lateral sclerosis. Is vitamin E to be revisited?.}, journal = {Archives of neurology}, volume = {54}, number = {5}, pages = {527-528}, doi = {10.1001/archneur.1997.00550170013008}, pmid = {9152108}, issn = {0003-9942}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*history ; Baseball/history ; Famous Persons ; History, 20th Century ; Humans ; United States ; Vitamin E/*history/therapeutic use ; }, abstract = {Investigators are beginning to reexamine the use of vitamin E for the treatment of amyotrophic lateral sclerosis. Vitamin E was isolated in the 1920s, and the results of animal studies led rapidly to clinical use. Regrettably, vitamin E did not ameliorate the progression of amyotrophic lateral sclerosis for Lou Gehrig, but more recent advances may identify subpopulations that do respond to vitamin E.}, }
@article {pmid9108073, year = {1997}, author = {Peled-Kamar, M and Lotem, J and Wirguin, I and Weiner, L and Hermalin, A and Groner, Y}, title = {Oxidative stress mediates impairment of muscle function in transgenic mice with elevated level of wild-type Cu/Zn superoxide dismutase.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {94}, number = {8}, pages = {3883-3887}, pmid = {9108073}, issn = {0027-8424}, support = {HD21229/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Gene Transfer Techniques ; Mice ; Mice, Transgenic/*physiology ; Muscle Contraction/genetics ; Muscle, Skeletal/*physiology ; *Oxidative Stress ; Superoxide Dismutase/*biosynthesis/genetics ; }, abstract = {Cases of familial amyotrophic lateral sclerosis (fALS; a neurodegenerative disorder) have been reported in which the gene for Cu/Zn superoxide dismutase (CuZnSOD) was mutated. Several studies with the fALS mutant CuZnSOD in transgenic mice and cells showed that the fALS mutations act through an as yet undefined dominant gain-of-function mechanism. Wild-type CuZnSOD catalyzes the dismutation of superoxide (O(2)(-).) but also produces hydroxyl radicals (.OH) with H(2)O(2) as substrate. Two laboratories have recently demonstrated that the .OH production ability was preferentially enhanced by the fALS mutant CuZnSOD, suggesting that this might be the function gained in fALS. In this study, we used transgenic CuZnSOD (Tg-CuZnSOD) mice with elevated levels of CuZnSOD to determine whether overexpression of wild-type CuZnSOD was also associated with increased .OH production and impaired muscle function. Enhanced formation of .OH was detected, by spin trapping, in brain and muscle extracts of the Tg-CuZnSOD mice. Three independently derived Tg-CuZnSOD lines showed muscle abnormalities, reflected by altered electromyography (EMG) and diminished performance in the rope grip test. After treatment with paraquat (PQ), a widely used herbicide and O(2)(-).-generating compound, muscle disability significantly deteriorated in Tg-CuZnSOD mice but not in control mice. The results indicate that elevated levels of CuZnSOD cause indigenous long-term oxidative stress leading to impairment of muscle function. These findings may provide valuable clues about the concurred role of indigenous oxidative stress and exogenous agents in the etiology of sporadic ALS and several other neurodegenerative diseases in which a specific subset of neurons is affected.}, }
@article {pmid9709343, year = {1997}, author = {Klein, KR and Spillane, LL and Chiumento, S and Schneider, SM}, title = {Effects of on-line medical control in the prehospital treatment of atraumatic illness.}, journal = {Prehospital emergency care}, volume = {1}, number = {2}, pages = {80-84}, doi = {10.1080/10903129708958793}, pmid = {9709343}, issn = {1090-3127}, mesh = {Critical Illness/*therapy ; *Emergency Medical Service Communication Systems ; Guideline Adherence/*statistics &amp; numerical data ; Humans ; New York ; Retrospective Studies ; Treatment Outcome ; }, abstract = {OBJECTIVE: On-line medical control (OLMC) is costly and time-consuming, yet little is known about the direct effect of OLMC on the quality of care provided. The objective of this study was to analyze the effect of OLMC on adherence to protocol and quality of care provided.<br><br>METHODS: Retrospective review of trip sheets completed by out-of-hospital personnel in an urban/suburban/rural emergency medical services system with a volume of 144,000 calls/year; approximately 15,000/year are ALS calls. Two levels of provider--paramedics and critical care technicians (CCTs)--work under single standard protocols and a single medical director. Prehospital trip sheets of 774 sequential patients with atraumatic illnesses for whom an ALS crew was dispatched were reviewed for adherence to standard protocol and for appropriateness of deviations from protocol, with and without the use of OLMC.<br><br>RESULTS: Adherence to protocols occurred in 78.3% of all patient encounters. OLMC was utilized in 61.5% of patient encounters. The CCTs were more likely to utilize OLMC than were the paramedics, 72% vs 56% (p < 0.001). There was a trend towards paramedics' adhering to protocol more frequently than did the CCTs, 80% vs 74%, which did not reach statistical significance (p = 0.057). Adherence to protocol was significantly less likely to occur with OLMC than without OLMC, regardless of the training of the provider, 72.8% vs 86.5% (95% CI 8.1-19.3%, p < 0.001). Adherence to protocol was significantly less likely to occur as the acuity of the patient's condition increased (p < 0.001). Nonadherence was more likely to be judged appropriate rather than inappropriate (p < 0.05) as the acuity level increased. When there was nonadherence to protocol, the use of OLMC did not improve the care provided.<br><br>CONCLUSIONS: OLMC does not improve adherence to protocol or the quality of care provided in the treatment of atraumatic illness.}, }
@article {pmid9182260, year = {1997}, author = {Vannucci, P and Castiglioni, M and Filidei, M and Riccioni, N}, title = {[Amyotrophic lateral sclerosis in a patient with Waldenstrom's macroglobulinemia].}, journal = {Minerva medica}, volume = {88}, number = {4}, pages = {167-170}, pmid = {9182260}, issn = {0026-4806}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*complications ; Humans ; Male ; Waldenstrom Macroglobulinemia/*complications ; }, abstract = {Although a peripheral neuropathy is the best known neurological complication of Waldenstrom's Macroglobulinemia (WM), the association of Amyotrophic Lateral Sclerosis (ALS), or other Motor Neuron Diseases (MND) with monoclonal gammopathies is described. We report the case of a male patient (41 years old) with WM and ALS. Whether monoclonal gammopathies play a role in the pathogenesis of MND is unclear but is la possible that patients might have antibodies against motor neurons. In our reported case neurologic symptoms were the first and the most important manifestations of the underlying hemopathy and despite plasmapheresis and immunosuppressive treatment ALS syndrome progressed. The neurologic disease worsened despite the improvement of WM.}, }
@article {pmid9168829, year = {1997}, author = {Kishino, A and Ishige, Y and Tatsuno, T and Nakayama, C and Noguchi, H}, title = {BDNF prevents and reverses adult rat motor neuron degeneration and induces axonal outgrowth.}, journal = {Experimental neurology}, volume = {144}, number = {2}, pages = {273-286}, doi = {10.1006/exnr.1996.6367}, pmid = {9168829}, issn = {0014-4886}, mesh = {Acetylcholinesterase/analysis ; Animals ; Axons/*drug effects ; Brain-Derived Neurotrophic Factor/administration &amp; dosage/pharmacology/*therapeutic use ; Cell Death ; Choline O-Acetyltransferase/analysis ; Drug Administration Schedule ; Ganglia, Spinal/*injuries/pathology ; Infusions, Parenteral ; Male ; Motor Neurons/*drug effects/pathology ; Nerve Tissue Proteins/analysis ; Neuroprotective Agents/administration &amp; dosage/pharmacology/*therapeutic use ; Rats ; Rats, Wistar ; Retrograde Degeneration/*drug effects ; Spinal Cord/pathology ; Spinal Nerve Roots/*injuries/pathology ; Subarachnoid Space ; }, abstract = {To assess the therapeutic potential of brain-derived neurotrophic factor (BDNF) in clinics, we extensively investigated the effects of BDNF on adult motor neurons in a rat spinal root avulsion model. Intrathecal administration of BDNF immediately after the spinal root avulsion greatly protected against the motor neuron cell death. BDNF also showed a protective effect on the atrophy of soma and on the reduction of transmitter-related enzymes such as choline acetyl transferase and acetylcholine esterase. Very interestingly, BDNF induced axonal outgrowth of severely damaged motor neurons at the avulsion site. The BDNF administration following 2-week treatment with phosphate-buffered saline after avulsion prevented further augmentation of cell death and reversed cholinergic transmitter-related enzyme deficiency. BDNF was demonstrated to possess a wide variety of biological effects on survival, soma size, cholinergic enzymes, and axonal outgrowth of adult motor neurons. These results provide a rationale for BDNF treatment in motor neuron diseases such as spinal cord injury and amyotrophic lateral sclerosis.}, }
@article {pmid9160288, year = {1997}, author = {Bushara, KO}, title = {Sialorrhea in amyotrophic lateral sclerosis: a hypothesis of a new treatment--botulinum toxin A injections of the parotid glands.}, journal = {Medical hypotheses}, volume = {48}, number = {4}, pages = {337-339}, doi = {10.1016/s0306-9877(97)90103-1}, pmid = {9160288}, issn = {0306-9877}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Botulinum Toxins, Type A/administration &amp; dosage/adverse effects/*therapeutic use ; Humans ; Models, Neurological ; *Parotid Gland ; Sialorrhea/*physiopathology ; }, abstract = {The inhibitory action of botulinum toxin is not confined to the neuromuscular junction. The toxin has long been known to block all the autonomic cholinergic fibers, including the major secretomotor parasympathetic fibers to salivary glands. The parotids are the largest of the salivary glands and their selective chemodenervation with botulinum toxin A is likely to result in substantial reduction of saliva production. Injection of the parotid glands with botulinum toxin is proposed as an new treatment for sialorrhea in patients with amyotrophic lateral sclerosis and other neurological diseases.}, }
@article {pmid9144851, year = {1997}, author = {Towheed, TE and Hochberg, MC}, title = {A systematic review of randomized controlled trials of pharmacological therapy in osteoarthritis of the knee, with an emphasis on trial methodology.}, journal = {Seminars in arthritis and rheumatism}, volume = {26}, number = {5}, pages = {755-770}, doi = {10.1016/s0049-0172(97)80043-1}, pmid = {9144851}, issn = {0049-0172}, mesh = {Humans ; *Knee Joint ; Osteoarthritis/*drug therapy ; Randomized Controlled Trials as Topic/methods ; Research Design ; }, abstract = {We systematically reviewed randomized controlled trials (RCTs) of pharmacological therapy in knee osteoarthritis (OA), published between 1966 and August 1994. RCTs were identified by MEDLINE, supplemented by a manual search of reference lists. Qualitative assessment of RCTs was performed using Gotzsche's method; design and analysis features were rated on a scale of 0 (worst) to 8 (best). Heller et al's method was used to compare efficacy of nonsteroidal antiinflammatory drugs (NSAIDs) in comparative trials. A total of 80 RCTs were analyzed (45 involved NSAIDs, 3 analgesics, 5 intraarticular [IA] steroids, 9 biological agents, including IA hyaluronic acid, and 18 mixed modalities, including topical capsaicin). The median design and analysis scores for all 80 RCTs were 2 and 5, respectively. NSAIDs were superior to placebo in all short-term trials, but in the 32 comparative NSAID trials, only five (16%) found significant differences in efficacy. Heller et al's method identified differences in 14 NSAID comparisons; etodolac (600 mg/day) was superior in five of its nine comparisons. Indomethacin and aspirin were the most toxic NSAIDs. IA steroids were superior to placebo in short-term efficacy (< 1 month). Biological agents were superior to placebo and generally well tolerated over a mean follow-up of 48 weeks. Acetaminophen was superior to placebo and was comparably efficacious to low-dose naproxen and ibuprofen (< 2,400 mg/day). The data support the use of acetaminophen, topical capsaicin, IA steroids, IA hyaluronic acid, and NSAIDs in the treatment of patients with knee OA.}, }
@article {pmid9095177, year = {1997}, author = {Haase, G and Kennel, P and Pettmann, B and Vigne, E and Akli, S and Revah, F and Schmalbruch, H and Kahn, A}, title = {Gene therapy of murine motor neuron disease using adenoviral vectors for neurotrophic factors.}, journal = {Nature medicine}, volume = {3}, number = {4}, pages = {429-436}, doi = {10.1038/nm0497-429}, pmid = {9095177}, issn = {1078-8956}, mesh = {Adenoviridae/genetics ; Animals ; Animals, Newborn ; Ciliary Neurotrophic Factor ; Electromyography ; Genetic Therapy/*methods ; Genetic Vectors ; Injections, Intramuscular ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Mice, Mutant Strains ; Motor Neuron Disease/mortality/*therapy ; Muscles/innervation ; Nerve Degeneration/drug effects ; Nerve Growth Factors/genetics/*therapeutic use ; Nerve Tissue Proteins/genetics/*therapeutic use ; Neurotrophin 3 ; Phrenic Nerve/pathology ; Survival Analysis ; }, abstract = {Motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy cause progressive paralysis, often leading to premature death. Neurotrophic factors have been suggested as therapeutic agents for motor neuron diseases, but their clinical use as injected recombinant protein was limited by toxicity and/or poor bioavailability. We demonstrate here that adenovirus-mediated gene transfer of neurotrophin-3 (NT-3) can produce substantial therapeutic effects in the mouse mutant pmn (progressive motor neuronopathy). After intramuscular injection of the NT-3 adenoviral vector, pmn mice showed a 50% increase in life span, reduced loss of motor axons and improved neuromuscular function as assessed by electromyography. These results were further improved by coinjecting an adenoviral vector coding for ciliary neurotrophic factor. Therefore, adenovirus-mediated gene transfer of neurotrophic factors offers new prospects for the treatment of motor neuron diseases.}, }
@article {pmid9173422, year = {1997}, author = {Ukena, D and Koper, I and Braun, H and Leutz, M and Schlimmer, P and Sybrecht, GW}, title = {[Therapy of nocturnal asthma: salmeterol versus nocturnal administration of retard theophylline--comparison of effectiveness and tolerance].}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {51}, number = {3}, pages = {317-323}, pmid = {9173422}, issn = {0934-8387}, mesh = {Adult ; Albuterol/administration &amp; dosage/adverse effects/*analogs &amp; derivatives ; Asthma/*drug therapy ; Bronchodilator Agents/*administration &amp; dosage/adverse effects ; Cross-Over Studies ; Delayed-Action Preparations ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Administration Schedule ; Female ; Forced Expiratory Volume/drug effects ; Humans ; Male ; Middle Aged ; Salmeterol Xinafoate ; Sleep Wake Disorders/*drug therapy ; Theophylline/*administration &amp; dosage/adverse effects ; }, abstract = {The aim of the present study was to compare the efficacy and the tolerability of salmeterol and theophylline in patients with nocturnal asthma. 16 patients were entered into a randomized, double-blind, crossover trial. Using a double-dummy technique, salmeterol (50 micrograms b.i.d. by MDI) or theophylline (Uniphyllin; 600 mg nocte orally) were given for periods of 7 days with a wash-out period of 7 days between treatment periods. With salmeterol the number of nights with an overnight fall in peak expiratory peak flow rate (PEFR) of at least 20% was reduced by about 20% compared to about 10% with theophyllin (p < 0.05 for the difference between salmeterol and theophylline). With respect to nocturnal symptoms 62.6% of the patients had rare or non symptoms without and 84.7% with salmeterol, compared to 46.5% without and 67.3% with theophylline (p < 0.05). With respect to the improvement of early morning symptoms, the increase of nights with none or rare symptoms was 46.2% with salmeterol compared to 25.8% with theophylline. The overall parameter of efficacy defined as a) the number of nights with an overnight fall in PEFR or less than 20% als well as b) none or rare nocturnal symptoms and c) none or rare early morning symptoms increased from 23.4% at baseline to 75.1% during treatment with salmeterol compared to an increase from 24.5% at baseline with 54.8% during treatment with theophylline (p < 0.05). 12 patients preferred salmeterol over theophylline (p < 0.05). 3 patients had gastrointestinal disturbances during theophylline treatment. It can be concluded that both salmeterol and theophylline are effective in the treatment of nocturnal asthma. With respect to the overall efficacy and the tolerability salmeterol is superior to theophylline.}, }
@article {pmid9126161, year = {1997}, author = {Davidson, BL and Bohn, MC}, title = {Recombinant adenovirus: a gene transfer vector for study and treatment of CNS diseases.}, journal = {Experimental neurology}, volume = {144}, number = {1}, pages = {125-130}, doi = {10.1006/exnr.1996.6398}, pmid = {9126161}, issn = {0014-4886}, support = {HD 33531/HD/NICHD NIH HHS/United States ; NS 34568/NS/NINDS NIH HHS/United States ; NS31957/NS/NINDS NIH HHS/United States ; }, mesh = {Adenoviridae/*genetics ; Animals ; Central Nervous System Diseases/*physiopathology/*therapy ; *Gene Transfer Techniques ; *Genetic Vectors ; Humans ; *Recombination, Genetic ; }, abstract = {Gene transfer to the CNS with recombinant adenoviral vectors is a relatively recent event. In initial reports it was clearly demonstrated that adenoviral vectors can transfer genetic material to multiple cell types within the CNS. The relative ease in generating recombinant adenovirus (Ad) led to feasibility studies in the CNS with application to animal models of inherited disease, neurodegenerative diseases (e.g., Parkinson's and amyotrophic lateral sclerosis), and cerebrovascular disease. In combination with Ad gene transfer to peripheral tissues, these experiments have identified specific limitations and directed further research to improve vector design, formulation, and delivery.}, }
@article {pmid9052812, year = {1997}, author = {Kasarskis, EJ and Berryman, S and English, T and Nyland, J and Vanderleest, JG and Schneider, A and Berger, R and McClain, C}, title = {The use of upper extremity anthropometrics in the clinical assessment of patients with amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {20}, number = {3}, pages = {330-335}, doi = {10.1002/(SICI)1097-4598(199703)20:3&lt;330::AID-MUS10&gt;3.0.CO;2-4}, pmid = {9052812}, issn = {0148-639X}, support = {M01 RRS2602/RR/NCRR NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/drug therapy/*pathology/*physiopathology ; *Anthropometry ; Arm/*pathology ; Ciliary Neurotrophic Factor ; Double-Blind Method ; Feasibility Studies ; Female ; Humans ; Lung/physiopathology ; Male ; Middle Aged ; Muscles/diagnostic imaging/physiopathology ; Nerve Tissue Proteins/therapeutic use ; Tomography, X-Ray Computed ; Torque ; }, abstract = {We evaluated the feasibility of using upper extremity anthropometrics to monitor the clinical status of 18 patients with amyotrophic lateral sclerosis (ALS). The bone-free arm muscle area (AMA) was computed using measurement of triceps skinfold thickness and the mid-upper arm circumference according to published formulae. The AMA correlated significantly with body mass, isokinetic muscle force generation, cross-sectional muscle area on computerized tomography scanning, and pulmonary functions including forced vital capacity and maximal voluntary ventilation. Serial determinations of AMA demonstrated a decline in 10 of 13 patients over 6 months. We pilot tested the use of AMA in a clinical trial of ciliary neurotrophic factor (CNTF) in the treatment of ALS. The AMA progressively decreased by 13%, 15%, and 30% in ALS patients treated with 0 microg CNTF/kg, 15 microg CNTF/kg, and 30/microg CNTF/kg, respectively, over a 9-month treatment period. We conclude that measurement of AMA provides a simple, inexpensive method to monitor the progression of muscle atrophy in ALS patients. The technique does not require effort on the part of the patient and as such, appears to have potential utility as an outcome measure in clinical drug trials.}, }
@article {pmid9039923, year = {1997}, author = {Hale, DA and Gottschalk, R and Fukuzaki, T and Wood, ML and Maki, T and Monaco, AP}, title = {Superiority of sirolimus (rapamycin) over cyclosporine in augmenting allograft and xenograft survival in mice treated with antilymphocyte serum and donor-specific bone marrow.}, journal = {Transplantation}, volume = {63}, number = {3}, pages = {359-364}, doi = {10.1097/00007890-199702150-00005}, pmid = {9039923}, issn = {0041-1337}, support = {R01 AI-14551/AI/NIAID NIH HHS/United States ; }, mesh = {Adjuvants, Immunologic/*therapeutic use ; Animals ; Antilymphocyte Serum/*therapeutic use ; Bone Marrow Transplantation/*immunology ; Cyclosporine/*therapeutic use ; Cytokines/biosynthesis ; *Graft Enhancement, Immunologic/methods ; Graft Survival/*drug effects ; Histocompatibility Antigens Class I/analysis ; Histocompatibility Antigens Class II/analysis ; Histocompatibility Testing ; Lymphocyte Activation ; Lymphocyte Culture Test, Mixed ; Mice ; Mice, Inbred A ; Mice, Inbred AKR ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Polyenes/*therapeutic use ; Sirolimus ; Skin Transplantation/immunology ; Tissue Donors ; Transplantation, Heterologous ; Transplantation, Homologous ; }, abstract = {BACKGROUND: Sirolimus is a potent immunosuppressive agent with great therapeutic potential. The objective of our study was to evaluate the efficacy of sirolimus versus cyclosporine in augmenting the unresponsiveness induced by an antilymphocyte serum (ALS)/donor-specific bone marrow (BM)-based regimen across three levels of histoincompatibility: class I and II disparate (DBA/2 to B6AF1), complete mismatch (AKR to C57BL/6), and xenograft (ACI rat to B6AF1).<br><br>METHODS: Full-thickness skin grafts were taken from donors and placed on recipients in standard fashion. Seven groups of recipient mice (n=10-28) received various combinations of the following treatment protocols: sirolimus, 1.5 mg/kg (3.0 mg/kg for xenografts) every other day from day 0 to day 12; cyclosporine, 50 mg/kg every other day from day 10 through 22; ALS, 0.5 ml on days -1 and 2 for allografts and days -1, 2, and 4 for xenografts; and BM, 25 million donor-specific cells IV on day 7.<br><br>RESULTS: The administration of ALS or ALS/BM resulted in modest but significant prolongation of skin graft survival in all combinations tested. Cyclosporine combined with ALS or ALS/BM significantly extended allograft survival compared with ALS or ALS/BM alone (P<0.05) but had no effect on xenograft survival. In contrast, the combination of sirolimus with ALS or ALS/BM resulted in a two- to threefold increase in allograft survival and over a fourfold increase in xenograft survival when compared with the comparable cyclosporine-based regimen. Additionally, lymphocytes isolated from class I and II incompatible mice with skin grafts surviving >100 days demonstrated markedly reduced interleukin 2 and interferon-gamma secretion in response to irradiated donor-specific lymphocytes in culture.<br><br>CONCLUSIONS: In the regimens tested, sirolimus was superior to cyclosporine in augmenting donor BM-induced skin graft prolongation in ALS-treated mice across all levels of histoincompatibility.}, }
@article {pmid9191978, year = {1997}, author = {González Deniselle, MC and González, S and Piroli, G and Ferrini, M and Lima, AE and De Nicola, AF}, title = {Glucocorticoid receptors and actions in the spinal cord of the Wobbler mouse, a model for neurodegenerative diseases.}, journal = {The Journal of steroid biochemistry and molecular biology}, volume = {60}, number = {3-4}, pages = {205-213}, doi = {10.1016/s0960-0760(96)00193-8}, pmid = {9191978}, issn = {0960-0760}, support = {NS 20866-08/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Astrocytes/cytology ; Cell Division ; Corticosterone/blood ; Dexamethasone/*metabolism ; Disease Models, Animal ; Female ; Glial Fibrillary Acidic Protein/analysis ; Glucocorticoids/*metabolism ; Lumbosacral Region ; Male ; Mice ; Mice, Mutant Strains ; Neck ; Ornithine Decarboxylase/analysis ; Receptors, Glucocorticoid/*metabolism ; Sex Factors ; Spinal Cord/enzymology/*metabolism/pathology ; Spinal Muscular Atrophies of Childhood/*metabolism ; }, abstract = {We have studied glucocorticoid receptors (GR) and actions in the spinal cord of the Wobbler mouse, a model for amyotrophic lateral sclerosis and infantile spinal muscular atrophy. Basal and stress levels of circulating corticosterone (CORT) were increased in Wobbler mice. Single point binding assays showed that cytosolic type II GR in the spinal cord of Wobbler mice of both sexes were slightly reduced compared with normal littermates. Saturation analysis further demonstrated a non-significant reduction in Bmax with increased Kd. In the hippocampus, however, we found down-regulation of GR, a probable response to increased CORT levels. We also found that the basal activity of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis, was higher in Wobbler mice than in control animals. Both groups showed a two-fold stimulation of ODC activity after treatment with dexamethasone (DEX). Additionally, Wobbler mice presented with an intense proliferation of astrocytes immunoreactive (ir) for glial fibrillary acidic protein (GFAP) in grey and white matter of the spinal cord. The enhanced GFAP-ir was attenuated after four days of treatment with a corticosterone (CORT) pellet implant, producing a pharmacological increase in peripheral circulating CORT. Taking into consideration the content of GR and the changes in ODC activity and GFAP-ir brought about by glucocorticoids, we suggest that Wobbler mice are hormone responsive. Further elucidation of glucocorticoid effects in this model may be relevant for understanding the possible use of hormones in human neurodegenerative diseases.}, }
@article {pmid9020331, year = {1997}, author = {Fiedor, P and Jin, MX and Hardy, MA and Oluwole, SF}, title = {Dependence of acquired systemic tolerance to rat islet allografts induced by intrathymic soluble alloantigens on host responsiveness, MHC differences, and transient immunosuppression in the high responder recipient.}, journal = {Transplantation}, volume = {63}, number = {2}, pages = {279-283}, doi = {10.1097/00007890-199701270-00018}, pmid = {9020331}, issn = {0041-1337}, support = {CA 52678/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Diabetes Mellitus, Experimental/*surgery ; Graft Survival/*immunology ; Histocompatibility Testing ; Immunosuppression Therapy/*methods ; Islets of Langerhans Transplantation/*immunology ; Isoantigens/administration &amp; dosage/*therapeutic use ; Major Histocompatibility Complex ; Rats ; Rats, Inbred BN ; Rats, Inbred Lew ; Rats, Inbred WF ; Spleen ; T-Lymphocytes/*immunology ; Thymus Gland ; Transplantation, Homologous ; }, abstract = {Recent studies suggest that the adult immune system can be manipulated by intrathymic (IT) inoculation of donor Ag to accept cardiac and islet allografts in the low responder rat combination of Lewis-to-WF. We have now extended this study to examine the effect of IT inoculation of soluble protein Ag obtained from 3M KCl extracts of resting T cells combined with transient ALS immunosuppression on islet allograft survival in the high responder combination of WF-to-Lewis. We first confirmed the earlier observation that IT injection of 2 mg soluble Ag on day -7 led to permanent islet graft survival (>200 days) in the Lewis-to-WF rat combination without the use of recipient immunosuppression and found this to be true in the Lewis-to-ACI rat combination. In the high responder combination of WF-to-Lewis, unmodified Lewis rats pretreated with IT inoculation of 2 mg soluble Ag acutely rejected WF and BN islet allografts. IT inoculation of donor Ag combined with 1 ml ALS transient immunosuppression on day -7 led to a modest graft prolongation [24.8+/-10.1 days as compared with 15.2+/-3.6 days in ALS only treated controls]. Intrathymic injection of soluble Ag on day -7 combined with 1 ml ALS on days -7 and 0 relative to allografting resulted in 100% permanent islet graft survival (>200 days) compared with an MST of 20.6+/-2.3 days in ALS only-treated controls. Similar treatment led to acute rejection of 3rd party (BN) grafts, thus demonstrating donor-specificity. In addition, extrathymic inoculation of donor Ag in similarly immunosuppressed animals did not result in islet graft prolongation, once again confirming the importance of the thymus in tolerance induction. To examine them for donor-specific tolerance, long-term unresponsive (>120 days) Lewis recipients of renal subcapsular islets underwent nephrectomy of the islet bearing kidneys and were challenged with intraportal donor- or third party-type islets after becoming diabetic. All the nonimmunosuppressed recipients of donor-type (WF) islets became permanently normoglycemic (>100 days) while the third-party (BN) grafts were promptly rejected, with an MST of 10.6 days. These findings confirm that acquired thymic tolerance induced by IT inoculation of soluble protein Ag in the low to moderate responder rat combinations is reproducible in the high responder combination provided that adequate peritransplant immunosuppression is used. This study suggests that acquired thymic tolerance in the rat model is dependent on host responsiveness to alloantigens, MHC differences between the donor-recipient pair, and the use of transient immunosuppression in the high responder recipient. This model may have potential clinical application in the development of strategies for specific transplantation tolerance.}, }
@article {pmid11542584, year = {1997}, author = {Mackowiak, CL and Stutte, GW and Garland, JL and Finger, BW and Ruffe, LM}, title = {Hydroponic potato production on nutrients derived from anaerobically-processed potato plant residues.}, journal = {Advances in space research : the official journal of the Committee on Space Research (COSPAR)}, volume = {20}, number = {10}, pages = {2017-2022}, doi = {10.1016/s0273-1177(97)00935-6}, pmid = {11542584}, issn = {0273-1177}, mesh = {Anaerobiosis ; Biodegradation, Environmental ; *Biomass ; *Bioreactors ; Culture Media ; Hydroponics ; Nitrates/metabolism ; Nitrogen/*metabolism ; Plant Stems/growth &amp; development/metabolism ; Quaternary Ammonium Compounds/metabolism ; Solanum tuberosum/*growth &amp; development/*metabolism ; Waste Management ; *Yeasts ; }, abstract = {Bioregenerative methods are being developed for recycling plant minerals from harvested inedible biomass as part of NASA's Advanced Life Support (ALS) research. Anaerobic processing produces secondary metabolites, a food source for yeast production, while providing a source of water soluble nutrients for plant growth. Since NH4-N is the nitrogen product, processing the effluent through a nitrification reactor was used to convert this to NO3-N, a more acceptable form for plants. Potato (Solanum tuberosum L.) cv. Norland plants were used to test the effects of anaerobically-produced effluent after processing through a yeast reactor or nitrification reactor. These treatments were compared to a mixed-N treatment (75:25, NO3:NH4) or a NO3-N control, both containing only reagent-grade salts. Plant growth and tuber yields were greatest in the NO3-N control and yeast reactor effluent treatments, which is noteworthy, considering the yeast reactor treatment had high organic loading in the nutrient solution and concomitant microbial activity.}, }
@article {pmid9440123, year = {1997}, author = {Wagey, R and Krieger, C and Shaw, CA}, title = {Abnormal dephosphorylation effect on NMDA receptor regulation in ALS spinal cord.}, journal = {Neurobiology of disease}, volume = {4}, number = {5}, pages = {350-355}, doi = {10.1006/nbdi.1997.0145}, pmid = {9440123}, issn = {0969-9961}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*metabolism ; Binding, Competitive/drug effects ; Carcinogens/pharmacology ; Dizocilpine Maleate/metabolism/pharmacology ; Enzyme Inhibitors/pharmacology ; Excitatory Amino Acid Antagonists/metabolism/pharmacology ; Humans ; Middle Aged ; Okadaic Acid/pharmacology ; Phorbol Esters/pharmacology ; Phosphoric Monoester Hydrolases/metabolism ; Phosphorylation ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Spinal Cord/*chemistry/enzymology/pathology ; Tritium ; }, abstract = {Previous studies have demonstrated a significant reduction of N-methyl-D-aspartate (NMDA) receptor binding in spinal cord sections from patients who died with amyotrophic lateral sclerosis (ALS) compared to that in control patients. The reduction in NMDA receptor binding in ALS could be increased toward control values by treatment with phorbol ester, suggesting a role for receptor protein phosphorylation in this disorder. In the present study we have evaluated the time course of recovery of [3H]MK-801 binding following phorbol ester treatment to assess protein phosphatase activity in spinal cord sections from ALS and control subjects. Phorbol ester-stimulated changes in [3H]MK-801 binding returned to untreated values significantly faster in ALS tissue compared to control and could not be blocked by the coapplication of the protein phosphatase inhibitors sodium vanadate or sodium beta-D-glycerol phosphate. Okadaic acid coapplication blocked recovery in both ALS and control tissue at a concentration range at which phosphatase 2B (calcineurin) would likely be inhibited. The results suggest that abnormal levels or activity of protein phosphatases, including calcineurin, may be involved in the abnormal levels of NMDA receptors in ALS and may play some role in the pathogenesis of the disease.}, }
@article {pmid9380959, year = {1997}, author = {Barthlen, GM}, title = {Nocturnal respiratory failure as an indication of noninvasive ventilation in the patient with neuromuscular disease.}, journal = {Respiration; international review of thoracic diseases}, volume = {64 Suppl 1}, number = {}, pages = {35-38}, doi = {10.1159/000196734}, pmid = {9380959}, issn = {0025-7931}, mesh = {Adrenergic Uptake Inhibitors/therapeutic use ; Amyotrophic Lateral Sclerosis/complications ; Cyanosis/etiology ; Headache/etiology ; Humans ; Hypertension/etiology ; Intermittent Positive-Pressure Ventilation ; Muscle Contraction/physiology ; Muscular Dystrophies/complications ; Myasthenia Gravis/complications ; Myotonic Dystrophy/complications ; Neuromuscular Diseases/*complications/physiopathology ; Oxygen Inhalation Therapy ; Polycythemia/etiology ; Polysomnography ; Positive-Pressure Respiration/methods ; Postpoliomyelitis Syndrome/complications ; Protriptyline/therapeutic use ; Psychomotor Agitation/etiology ; Respiration ; Respiratory Insufficiency/diagnosis/*etiology/physiopathology/therapy ; Sleep/physiology ; Sleep Apnea Syndromes/diagnosis/*etiology/physiopathology/therapy ; Sleep Initiation and Maintenance Disorders/etiology ; Sleep Stages ; Snoring/etiology ; Tracheostomy ; }, abstract = {Patients with neuromuscular disease may suffer from nocturnal respiratory failure despite normal daytime respiratory function. The physiological reduction in muscle tone during sleep may be life-threatening in a patient with impaired muscle strength. Nocturnal respiratory failure may occur in patients with the postpolio syndrome, amyotrophic lateral sclerosis, myasthenia gravis, myotonic dystrophy, and muscular dystrophy. Diagnosis of obstructive, central and mixed apneas, hypopneas, and hypoventilation is best made using polysomnography. Therapeutic options include noninvasive ventilation such as continuous positive airway pressure, bilevel positive airway pressure, intermittent positive pressure ventilation and, rarely, tracheostomy, oxygen, or protriptyline. Evaluation by a sleep specialist should be initiated in any neuromuscular patient with nocturnal symptoms such as air hunger, intermittent snoring or breathing, orthopnea, cyanosis, restlessness, and insomnia. Daytime symptoms may include morning drowsiness, headaches and excessive daytime sleepiness. Polycythemia, hypertension, and signs of heart failure may also be seen. Effective treatment is available, and may improve the quality of life, and possibly increase survival.}, }
@article {pmid9380813, year = {1997}, author = {Brola, W and Szafraniec, L}, title = {[Pathologic laughing and crying in neurologic disorders].}, journal = {Przeglad lekarski}, volume = {54}, number = {5}, pages = {356-359}, pmid = {9380813}, issn = {0033-2240}, mesh = {*Crying/psychology ; Humans ; *Laughter/psychology ; Mood Disorders/*etiology/psychology ; Multiple Sclerosis/psychology ; Nervous System Diseases/*complications/psychology ; }, abstract = {Affective disorders are complications of many nervous system diseases. Pathological laughing and crying may accompany cerebrovascular lesions, multiple sclerosis, ALS, Alzheimer disease or cerebral tumours. Precise mechanisms of how these disorders arise are still unknown. Reviews of the literature were been accomplished in the article where, taking the examples of stroke and multiple sclerosis, have been discussed: the clinic picture, pathogenesis in neuroanatomic and neurophysiologic aspects as well as diagnostic criteria and the treatment of uncontrolled pathological laughing and/or crying.}, }
@article {pmid9266433, year = {1997}, author = {Tatton, WG and Chalmers-Redman, RM and Ju, WY and Wadia, J and Tatton, NA}, title = {Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription.}, journal = {Journal of neural transmission. Supplementum}, volume = {49}, number = {}, pages = {245-268}, doi = {10.1007/978-3-7091-6844-8_25}, pmid = {9266433}, issn = {0303-6995}, mesh = {Alzheimer Disease/drug therapy/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/pathology ; Animals ; *Apoptosis ; Brain/metabolism/pathology ; Brain Diseases/*drug therapy/metabolism/*pathology ; Cerebrovascular Disorders/drug therapy/pathology ; Humans ; Mitochondria/metabolism ; Models, Neurological ; Necrosis ; Neurons/pathology ; Parkinson Disease/drug therapy/pathology ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Retinal Diseases/drug therapy/pathology ; Superoxide Dismutase/genetics/metabolism ; Transcription, Genetic/*drug effects ; bcl-2-Associated X Protein ; }, abstract = {Apoptotic, rather than necrotic, nerve cell death now appears as likely to underlie a number of common neurological conditions including stroke, Alzheimer's disease, Parkinson's disease, hereditary retinal dystrophies and Amyotrophic Lateral Sclerosis. Apoptotic neuronal death is a delayed, multistep process and therefore offers a therapeutic opportunity if one or more of these steps can be interrupted or reversed. Research is beginning to show how specific macromolecules play a role in determining the apoptotic death process. We are particularly interested in the critical nature of gradual mitochondrial failure in the apoptotic process and propose that a maintenance of mitochondrial function through the pharmacological modulation of gene expression offers an opportunity for the effective treatment of some types of neurological dysfunction. Our research into the development of small diffusible molecules that reduce apoptosis has grown from studies of the irreversible MAO-B inhibitor (-)-deprenyl. (-)-Deprenyl can reduce neuronal death independently of MAO-B inhibition even after neurons have sustained seemingly lethal damage. (-)-Deprenyl can also influence the process outgrowth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cells at concentrations too small to inhibit MAO. In accord with earlier work of others, we showed that (-)-deprenyl alters the expression of a number of mRNAs or of proteins in nerve and glial cells and that the alterations in gene expression/protein synthesis are the result of a selective action on transcription. The alterations in gene expression/protein synthesis are accompanied by a decrease in DNA fragmentation characteristic of apoptosis and the death of responsive cells. The onco-proteins Bcl-2 and Bax and the scavenger proteins Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD-2) are among the 40-50 proteins whose synthesis is altered by (-)-deprenyl. Since mitochondrial membrane potential correlates with mitochondrial ATP production, we have used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl result in a maintenance of mitochondrial membrane potential, a decrease in intramitochondrial calcium and a decrease in cytoplasmic oxidative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and decrease cytoplasmic oxidative radical levels and thereby reduces apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may lead to the development of new therapies for neurodegenerative diseases.}, }
@article {pmid9249935, year = {1997}, author = {Matsuura, T and Imanishi, M and Hara, Y and Nishioka, T and Kunikata, S and Akiyama, T and Kurita, T}, title = {Suppressed alloreactivity and mixed chimerism in rats with accepted cardiac allografts by intrathymic injection of donor bone marrow cells.}, journal = {Transplant international : official journal of the European Society for Organ Transplantation}, volume = {10}, number = {4}, pages = {262-267}, doi = {10.1007/s001470050055}, pmid = {9249935}, issn = {0934-0874}, mesh = {Animals ; *Bone Marrow Cells ; *Cell Transplantation ; Chimera ; Graft Survival ; Heart Transplantation/*immunology ; *Immune Tolerance ; Lymphocyte Culture Test, Mixed ; Male ; Rats ; Rats, Inbred BN ; Rats, Inbred Lew ; Skin Transplantation ; Transplantation, Homologous ; }, abstract = {Intrathymic injection of donor bone marrow cells (ITBMCs) at the time of transplantation and treatment with antilymphocyte serum (ALS) permitted the indefinite survival of Brown Norway (BN, RT1n) rat heart grafts in 6 out of 8 Lewis (LEW, RT1l) rat recipients, LEW recipients with long-surviving BN heart grafts (LSGs) also accepted additional BN heart grafts without further immunosuppression, though they rejected Piebald Virol Glaxo (PVG, RT1c) rat heart grafts in the usual fashion. In the in vitro study, the proliferative response of the lymphocytes from LEW recipients with LSGs remained suppressed when they were stimulated by BN spleen cells, but not when stimulated by PVG cells. Bone marrow cells (BMCs) from LEW rats with LSGs showed strong, nonspecific, suppressive effects on the proliferative response in the mixed lymphocyte culture reaction, suggesting that one of the possible explanations for tolerance might be the involvement of a suppressor mechanism.}, }
@article {pmid9204582, year = {1997}, author = {Calle, PA and Verbeke, A and Vanhaute, O and Van Acker, P and Martens, P and Buylaert, W}, title = {The effect of semi-automatic external defibrillation by emergency medical technicians on survival after out-of-hospital cardiac arrest: an observational study in urban and rural areas in Belgium.}, journal = {Acta clinica Belgica}, volume = {52}, number = {2}, pages = {72-83}, doi = {10.1080/17843286.1997.11718557}, pmid = {9204582}, issn = {1784-3286}, mesh = {Adult ; Aged ; Aged, 80 and over ; Belgium/epidemiology ; Cardiopulmonary Resuscitation ; Catheterization, Peripheral ; Critical Care ; *Electric Countershock ; *Emergency Medical Services/organization &amp; administration ; *Emergency Medical Technicians ; Female ; Heart Arrest/mortality/*therapy ; Humans ; Intubation, Intratracheal ; Life Support Care ; Male ; Middle Aged ; Mobile Health Units ; Patient Discharge ; *Rural Health/statistics &amp; numerical data ; Survival Rate ; Tachycardia, Ventricular/therapy ; *Urban Health/statistics &amp; numerical data ; Ventricular Fibrillation/therapy ; }, abstract = {The introduction of semi-automatic external defibrillators (SAEDs) allowed emergency medical technicians (EMTs) to deliver electroshocks in cases of out-of-hospital ventricular fibrillation (VF) or ventricular tachycardia (VT), often many minutes before the arrival of the mobile intensive care unit (MICU) team. In this observational study we report on the results obtained by the EMTs from the fire departments of Gent, Aalter and Brugge. In Gent, an SAED project started in May 1991. By December 1995, the SAED's electrodes had been attached in 367 cardiac arrest patients. The first rhythm detected by the device was asystole or electromechanical dissociation (EMD) in 241 patients (66%): only 5 of these patients survived to hospital discharge (2%). In the remaining 126 VF/VT cases (34%) the survival rate was 21% (26/126). In 14 of these 26 patients the shock(s) delivered by the EMTs restored spontaneous circulation before the arrival of the MICU team, with only venous cannulation and/or intubation being performed by the MICU team. In 4 other VF patients, the shock(s) delivered by EMTs converted the VF, with the MICU team successfully taking care of VF/VT relapses or postcountershock EMD. In the remaining 8 VF/VT cases, only the MICU attempts could resuscitate the patient. The SAED project in Aalter was set up in April 1993. By December 1995, care was taken for only 21 patients. None of the 4 VF/VT patients and the 17 asystole/EMD patients survived. In Brugge, there were 240 cardiac arrest cases treated with SAED between January 1991 and December 1995. Among the 89 VF/VT cases, there were 20 survivors (22%): 8 cases survived thanks to SAED shock(s) delivered by EMTs, in 3 cases survival was due to the combination of SAED shock(s) by EMTs and extensive ALS treatment by the MICU team, and in 9 cases restoration of spontaneous circulation was only obtained after application of ALS techniques by the MICU team. This observational study seems to show a beneficial effect of the introduction of SAED in Gent and Brugge. In Aalter the number of treated cases is tool low to draw conclusions. Anyhow, the global survival rate in the three areas remains low. Therefore, more efforts are needed to strengthen the other links of the chain of survival (early access to the emergency medical services-system, early basic cardiopulmonary resuscitation and early advanced life support.}, }
@article {pmid9125377, year = {1997}, author = {Peltékian, E and Parrish, E and Bouchard, C and Peschanski, M and Lisovoski, F}, title = {Adenovirus-mediated gene transfer to the brain: methodological assessment.}, journal = {Journal of neuroscience methods}, volume = {71}, number = {1}, pages = {77-84}, doi = {10.1016/s0165-0270(96)00128-8}, pmid = {9125377}, issn = {0165-0270}, mesh = {Adenoviridae/*genetics/immunology/pathogenicity ; Adult ; Animals ; Brain/immunology/*metabolism/pathology ; Brain Diseases/therapy ; Brain Neoplasms/therapy ; Cell Death ; Cells, Cultured ; Defective Viruses/*genetics/immunology/pathogenicity ; Genetic Therapy/adverse effects/*methods ; Genetic Vectors/administration &amp; dosage/adverse effects/*genetics/immunology ; Humans ; Injections, Intraventricular ; Nerve Degeneration ; Retroviridae/genetics ; Safety ; Transfection/*methods ; }, abstract = {The purpose of this short review is to analyse major advantages and limitations of the adenovirus (Ad), specifically with relevance to its use as a vector for gene transfer to the brain. The characteristics of Ad transduction include: the relative absence of cell type specificity; the limited spatial spread of the virus; and the long-term expression of the transgene. In the central nervous system, in contrast to that which occurs in other organs, Ad transduction in the adult does not systematically provoke cell death. Nevertheless, a proportion of the transduced cells do die, and this represents a conspicuous problem. Mechanisms leading to cell death in the brain may include immune rejection and inflammation-related toxicity, although this would not explain all of the results, and direct toxicity related to either inappropriate preparation or the transduction itself. Taking into account uncertainties concerning the innocuousness of Ad transduction, it may seem unwise to envisage Ad gene therapy for diseases that are not life-threatening and/or benefit from adequate drug or surgical treatments (e.g. Parkinson's disease or epilepsy). Ad vectors may not be easily used either in diseases displaying major immune dysfunction (e.g. multiple sclerosis). In contrast, malignant brain tumors and numerous neurodegenerative diseases (such as Huntington's, Alzheimer's diseases or amyotrophic lateral sclerosis) are directly life-threatening and deprived of any adequate treatment. They may be appropriate targets for Ad-mediated gene therapy, once both the vector and the gene of interest have been defined and optimized.}, }
@article {pmid8971830, year = {1997}, author = {Penn, RD and Kroin, JS and York, MM and Cedarbaum, JM}, title = {Intrathecal ciliary neurotrophic factor delivery for treatment of amyotrophic lateral sclerosis (phase I trial).}, journal = {Neurosurgery}, volume = {40}, number = {1}, pages = {94-9; discussion 99-100}, doi = {10.1097/00006123-199701000-00021}, pmid = {8971830}, issn = {0148-396X}, mesh = {Activities of Daily Living/classification ; Amyotrophic Lateral Sclerosis/diagnosis/*therapy ; Ciliary Neurotrophic Factor ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Humans ; Infusion Pumps, Implantable ; Injections, Spinal ; Metabolic Clearance Rate/physiology ; Nerve Growth Factors/*administration &amp; dosage/adverse effects/pharmacokinetics ; Nerve Tissue Proteins/*administration &amp; dosage/adverse effects/pharmacokinetics ; Recombinant Proteins/administration &amp; dosage/adverse effects/pharmacokinetics ; }, abstract = {OBJECTIVE: This Phase I trial of ciliary neurotrophic factor (CNTF) delivered intrathecally for the treatment of patients with amyotrophic lateral sclerosis was designed to determine the safety of this new mode of administration as well as the pharmacokinetics and drug distribution.<br><br>METHODS: CNTF was administered using a drug pump implanted into the lumbar subarachnoid space in each of four patients with amyotrophic lateral sclerosis. Escalating doses (0.4, 0.8, 1.6, 4, and 8 micrograms/h) were infused for 48 hours per week in 2-week cycles until the highest tolerated dose was achieved. Patients were observed for side effects, and standardized muscle and respiratory function tests were performed. Cerebrospinal fluid (CSF) levels of CNTF were determined using simultaneous lumbar and cervical taps. Plasma and CSF levels of antibodies, CSF cells and protein, and routine blood chemistries were monitored, as were weight and vital signs.<br><br>RESULTS: Pharmacokinetic studies of four patients demonstrated that the distribution and clearance of recombinant human (rH)CNTF are similar to those of many small, water-soluble agents (morphine, baclofen, clonidine) and that the steady-state concentration of rHCNTF at the cervical level was 18 to 36% of that at the lumbar level. Lumbar CSF levels were in the range of 44 to 1230 ng/ml. Intrathecally administered rHCNTF had different adverse effects than the systemically delivered drug. With intrathecal administration, no asthenia, fever, chills, nausea, weight loss, increased cough, or sputum production was found. All patients who received rHCNTF intrathecally experienced dose-related CSF pleocytosis (primarily lymphocytic) and rises in protein levels. No clinical signs of meningeal irritation, such as stiff neck, photophobias, or nausea, were seen. However, one patient who had lumbar spinal stenosis developed severe burning and cramping leg pain. A second patient developed a severe headache and leg and back cramping. No abnormal clinical chemistry or hematological findings were encountered. Plasma levels of rHCNTF were below detection. Antibodies to rHCNTF were found in the systemic circulation of only one patient. The gradual decline in motor strength and performance of standard skills did not improve or worsen.<br><br>CONCLUSIONS: In this first trial of a recombinant neurotrophic factor to be administered intrathecally by drug pump, the CNTF was well distributed along the spinal canal. Pain syndromes (headache, radicular pain) that were dose-related occurred in two patients, but systemic side effects, which had been observed with subcutaneous rHCNTF, did not occur. Intrathecal drug pump delivery of neurotrophic factors may be the most appropriate way in which to test the efficacy of these high-molecular weight proteins, because high CSF levels can be achieved without significant systemic side effects.}, }
@article {pmid8990380, year = {1996}, author = {Chowdhury, NC and Murphy, B and Sayegh, MH and Jin, MX and Roy, DK and Hardy, MA and Oluwole, SF}, title = {Acquired systemic tolerance to rat cardiac allografts induced by intrathymic inoculation of synthetic polymorphic MHC class I allopeptides.}, journal = {Transplantation}, volume = {62}, number = {12}, pages = {1878-1882}, doi = {10.1097/00007890-199612270-00034}, pmid = {8990380}, issn = {0041-1337}, support = {HL 14799/HL/NHLBI NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Animals ; Graft Survival/drug effects ; Heart Transplantation/*immunology ; Histocompatibility Antigens Class I/chemistry ; Immune Tolerance/*drug effects ; Injections, Intralymphatic ; Molecular Sequence Data ; Peptides/*immunology ; Rats ; Rats, Inbred ACI ; Rats, Inbred Lew ; Rats, Inbred WF ; Reoperation ; Thymus Gland ; Transplantation, Homologous ; }, abstract = {This study extends the finding that intrathymic (IT) injection of 3M KC1 extracts of T cells induces transplant tolerance to the use of well defined polymorphic MHC class I allopeptides derived from the hypervariable domain of RT1.Au (WF MHC class I). While three of the six synthetic RT1.Au peptides were immunogenic, three others were nonimmunogenic when tested in ACI responders. In our initial studies, we examined the effects of IT injection of a mixture of equal concentrations of the three nonimmunogenic RT1.Au peptides on WF cardiac allograft survival in ACI recipients. The results showed that a single IT injection of 100 and 300 microg class I MHC allopeptides on day -7 relative to cardiac transplant did not significantly prolong graft survival in naive ACI recipients (MST of 9.8, and 12.3 days vs. 10.5 days in controls). In contrast, 600 microg allopeptides injected IT resulted in modest prolongation of graft to an MST of 19.5 days. However, IT injection of 600 microg allopeptides combined with 0.5 ml ALS on day -7 led to permanent acceptance (>200 days) of cardiac allografts in 7/9 ACI recipients compared with survival of 24.2 days in ALS alone treated controls. In contrast, similar treatment led to acute rejection of third party (Lewis) cardiac allografts. Intravenous injection of 600 microg allopeptides combined with ALS did not result in prolonged graft survival (26.8 days). The long-term unresponsive ACI recipients (>100 days) challenged with second-set cardiac grafts accepted permanently donor-type (WF) grafts while rejecting the third party (Lewis) grafts, a finding that confirms acquired systemic tolerance. These findings confirm the role of IT injection of synthetic polymorphic allopeptides in the induction of acquired thymic tolerance and provide the rationale for testing this strategy in large animals and eventually in man.}, }
@article {pmid9201563, year = {1996}, author = {Clark, W and Kendall, MJ}, title = {Therapeutic advances: riluzole for the treatment of motor neurone disease.}, journal = {Journal of clinical pharmacy and therapeutics}, volume = {21}, number = {6}, pages = {373-376}, doi = {10.1111/j.1365-2710.1996.tb00035.x}, pmid = {9201563}, issn = {0269-4727}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Asthenia/chemically induced ; Excitatory Amino Acid Antagonists/adverse effects/*therapeutic use ; Health Care Costs ; Humans ; Quality of Life ; Riluzole ; Survivors ; Thiazoles/adverse effects/*therapeutic use ; Treatment Outcome ; }, abstract = {Amyotrophic laterial sclerosis is a fatal neurogenerative disorder, for which only symptomatic treatment was previously available. Riluzole was recently launched in the U.S.A. and Europe. This is the first drug to produce a modest increase in survival (approximately 3 months) in patients with this disease. Unfortunately, treatment causes a number of side-effects of which asthenia is particularly troublesome. Between 10 and 20 per cent of patients can be expected to withdraw from treatment due to these adverse effects. Data on the real time survival advantage and quality of life that can be expected whilst on treatment are needed to identify the place of riluzole in the management of this distressing disease.}, }
@article {pmid9082189, year = {1996}, author = {Abel, A and Danek, A and Borasio, GD and Witt, TN}, title = {[X chromosomal bulbospinal neuropathy (X-BSN, Kennedy syndrome): an illness with repetitive triplet sequences. Case report, differential diagnosis and molecular genetics aspects].}, journal = {Der Nervenarzt}, volume = {67}, number = {12}, pages = {1011-1019}, doi = {10.1007/s001150050084}, pmid = {9082189}, issn = {0028-2804}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*genetics ; Bulbar Palsy, Progressive/diagnosis/*genetics ; Genetic Carrier Screening ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/diagnosis/*genetics ; Neurologic Examination ; Pedigree ; Phenotype ; Receptors, Androgen/genetics ; Sex Chromosome Aberrations/*genetics ; Trinucleotide Repeats/*genetics ; *X Chromosome ; }, abstract = {X-chromosomal recessive bulbospinal neuronopathy (X-BNS, Kennedy's disease) is an important differential diagnosis of amyotrophic lateral sclerosis. We present the data of ten own patients along with a review of the literature on this uncommon disease which is caused by an expanded CAG-repeat in the androgen receptor gene. This mutation probably affects the transcription regulating activity of the androgen receptor in neurons. Signs and symptoms of X-BSN can be derived from partial insensitivity for androgens and a mixed, mainly motor neuronopathy. The clinical diagnosis is based on: 1. lower motor neuron weakness of bulbar and proximal limb muscles with onset in the third to fifth decade, 2. cramps and pronounced fasciculations, particularly of facial muscles, 3. postural tremor, 4. diminished or absent sensory action potentials inspite of only minor sensory impairment, 5. gynecomastia, and 6. infertility, diabetes mellitus and hyperlipoproteinemia in a minority of cases. Unlike amyotrophic lateral sclerosis, disease progression is slow with barely shortened life expectancy, which should be stressed in patient counselling. Causal treatment is as yet unavailable but several aspects of palliative medicine should be considered.}, }
@article {pmid9011143, year = {1996}, author = {Rowland, LP}, title = {Controversies about amyotrophic lateral sclerosis.}, journal = {Neurologia (Barcelona, Spain)}, volume = {11 Suppl 5}, number = {}, pages = {72-74}, pmid = {9011143}, issn = {0213-4853}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology/*therapy ; Chelation Therapy ; Humans ; Peripheral Nerves/physiopathology ; Thiamine/therapeutic use ; Venoms/therapeutic use ; Vitamin B 12/therapeutic use ; }, abstract = {Controversy regarding amyotrophic lateral sclerosis (ALS) concerns aspects of relatively little consequence (such as the role of lead intoxication or trauma in the pathogenesis of the disease) and others of greater relevance, particularly the two following questions regarding treatment options: 1) Are we in a new era of therapy for ALS? Prior to the 1990's no controlled study showed consistent benefit from any of the treatments tried. We have now had announcements of benefit for four entirely different agents: riluzole, insulin-like growth hormone, brain derived neurotrophic hormone and gabapentin. The benefit, at most, is marginal or questionable. The effect is of statistical significance but of little clinical relevance, and 2) what is the role of peripheral nerves in ALS? The syndrome of multifocal motor neuropathy and conduction block (MMNCB) shares some clinical data (active tendon jerks in weak, wasted and fasciculating muscles) and pathological features (anterior horn cell loss and glions) with "typical" ALS. This is relevant because MMNCB is reversible with immunoglobulin therapy. The rigid separation between ALS (a disease of the motor neuron perikaryon) and MMNCB (a disease of the motor neuron axon) is no longer tenable.}, }
@article {pmid8998034, year = {1996}, author = {Kent, MA}, title = {The ethical arguments concerning the artificial ventilation of patients with motor neurone disease.}, journal = {Nursing ethics}, volume = {3}, number = {4}, pages = {317-328}, doi = {10.1177/096973309600300405}, pmid = {8998034}, issn = {0969-7330}, mesh = {Cost of Illness ; Disclosure ; *Ethics, Nursing ; *Home Care Services ; Humans ; Internationality ; Motor Neuron Disease/*therapy ; Paternalism ; *Patient Advocacy ; Patient Selection ; *Personal Autonomy ; Resource Allocation ; *Respiration, Artificial ; United Kingdom ; *Withholding Treatment ; }, abstract = {This paper focuses on the ethical dilemmas created by advanced technology that would allow patients with motor neurone disease to be sustained by artificial ventilation. The author attempts to support the patient's right to informed choice, arguing from the perspective of autonomy as a first order principle. The counter arguments of caregiver burden and financial restraints are analysed. In the UK, where active euthanasia is not legalized, the dilemma of commencing ventilation is seen to be outweighed by the problems of withdrawing this treatment. The lack of accurate data and protocols that would clarify the current situation is emphasized and the conclusion takes the form of a recommendation for further research.}, }
@article {pmid8960715, year = {1996}, author = {Miller, RG and Moore, D and Young, LA and Armon, C and Barohn, RJ and Bromberg, MB and Bryan, WW and Gelinas, DF and Mendoza, MC and Neville, HE and Parry, GJ and Petajan, JH and Ravits, JM and Ringel, SP and Ross, MA}, title = {Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. WALS Study Group. Western Amyotrophic Lateral Sclerosis Study Group.}, journal = {Neurology}, volume = {47}, number = {6}, pages = {1383-1388}, doi = {10.1212/wnl.47.6.1383}, pmid = {8960715}, issn = {0028-3878}, mesh = {Acetates/*therapeutic use ; Adult ; Aged ; *Amines ; Amyotrophic Lateral Sclerosis/*drug therapy ; Anticonvulsants/*therapeutic use ; *Cyclohexanecarboxylic Acids ; Double-Blind Method ; Female ; Gabapentin ; Humans ; Male ; Middle Aged ; *gamma-Aminobutyric Acid ; }, abstract = {We designed a phase II trial to evaluate the efficacy of gabapentin in slowing the rate of decline in muscle strength of patients with amyotrophic lateral sclerosis (ALS) and to assess safety and tolerability. Gabapentin (800 mg) or placebo was administered t.i.d. in a randomized, double-blinded, placebo-controlled, trial for 6 months. We enrolled 152 patients at eight sites in the United States. The primary outcome measure was the slope of the arm megascore, the average maximum voluntary isometric strength from eight arm muscles standardized against a reference ALS population. A secondary outcome measure was forced vital capacity. Slopes of arm megascores for patients on gabapentin were compared with slopes of those taking placebo using a two-way ANOVA. We observed a nonstatistically significant trend (p = 0.057-0.08) toward slower decline of arm strength in patients taking gabapentin compared with those taking placebo (mean difference 24%, median 37%). We observed no treatment effect on forced vital capacity. Gabapentin was well tolerated by patients with ALS. These results suggest that further studies of gabapentin in ALS are warranted.}, }
@article {pmid8959996, year = {1996}, author = {Lacomblez, L and Bensimon, G and Leigh, PN and Guillet, P and Powe, L and Durrleman, S and Delumeau, JC and Meininger, V}, title = {A confirmatory dose-ranging study of riluzole in ALS. ALS/Riluzole Study Group-II.}, journal = {Neurology}, volume = {47}, number = {6 Suppl 4}, pages = {S242-50}, doi = {10.1212/wnl.47.6_suppl_4.242s}, pmid = {8959996}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality/physiopathology ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Antagonists/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Riluzole ; Survival Analysis ; Thiazoles/administration &amp; dosage/*therapeutic use ; }, abstract = {ALS is a progressive motor neuron disease with no effective treatment. The anti-excitotoxic drug riluzole (100 mg/day) has been shown to decrease mortality and muscular deterioration in ALS patients. To confirm and extend the therapeutic effect of riluzole, we performed a double-blind, placebo-controlled, multicenter, international, dose-ranging (50, 100, 200 mg/day), stratified study in 959 ALS outpatients treated for up to 18 months. Primary efficacy criterion was survival and the effect of treatment was analyzed before (Wilcoxon and log rank tests) and after adjustment on prognostic factors (Cox model). Secondary efficacy criterion was disease progression assessed through change in functional measures. Tracheostomy-free survival rates were: 50.4% (placebo), 55.3% (50 mg riluzole) (p = 0.23, Wilcoxon test; p = 0.25, log-rank test), 56.8% (100 mg riluzole) (p = 0.05, Wilcoxon test; p = 0.076, log-rank test), and 57.8% (200 mg riluzole) (p = 0.061, Wilcoxon test; p = 0.075, log-rank test). At the end of the 18-month study, there was a significant dose-related decrease in risk of death or tracheostomy (p = 0.04). Adjustment for baseline prognostic factors showed a 35% decreased risk of death with the 100-mg dose compared with placebo (p = 0.002). No significant treatment effects were detected for the functional assessments. The most frequent dose-related adverse events included nausea, asthenia, and elevated liver enzyme levels. This study confirms the therapeutic effect of riluzole in a large representative ALS sample, over an 18-month period. Riluzole is well tolerated and decreases the risk of death or tracheostomy in ALS patients.}, }
@article {pmid8937793, year = {1996}, author = {Iannaccone, S and Ferini-Strambi, L}, title = {Pharmacologic treatment of emotional lability.}, journal = {Clinical neuropharmacology}, volume = {19}, number = {6}, pages = {532-535}, doi = {10.1097/00002826-199619060-00008}, pmid = {8937793}, issn = {0362-5664}, mesh = {Affective Symptoms/*drug therapy ; Aged ; Amyotrophic Lateral Sclerosis/complications ; Female ; Fluvoxamine/*therapeutic use ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Multiple Sclerosis/complications ; Selective Serotonin Reuptake Inhibitors/*therapeutic use ; Tomography, X-Ray Computed ; }, abstract = {Emotional lability may be a part of the syndrome of pseudobulbar palsy. Here we report our experience with fluvoxamine, a selective serotonin reuptake inhibitor, used to treat 10 patients with emotional incontinence. Over a 7-month period, we studied and treated 10 consecutive patients (mean age, 61 +/- 8 years) attending our department: four had amyotrophic lateral sclerosis (progressive bulbar palsy form), four had clinically definite multiple sclerosis, and two had had strokes. They were given a single evening dose (100 mg) of fluvoxamine. All 10 patients had > 30 affective outbursts daily. It was observed that in 2 to 6 days, all the patients improved, the number of emotional outbursts dropping to none to five per day. This result suggests that the serotoninergic system may be implicated in emotional lability. The short latency of improvement we observed in our patients suggests that the mechanism of fluvoxamine for treating emotional lability differs from its mechanism for treating affective disorders.}, }
@article {pmid8922414, year = {1996}, author = {Henderson, JT and Javaheri, M and Kopko, S and Roder, JC}, title = {Reduction of lower motor neuron degeneration in wobbler mice by N-acetyl-L-cysteine.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {16}, number = {23}, pages = {7574-7582}, pmid = {8922414}, issn = {0270-6474}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Facial Nerve/drug effects/ultrastructure ; Forelimb ; Free Radical Scavengers/*pharmacology ; Glutathione Peroxidase/metabolism ; Mice ; Mice, Neurologic Mutants/*physiology ; Motor Neurons/*drug effects/physiology ; Muscle, Skeletal/anatomy &amp; histology/drug effects/physiology ; Neck ; Nerve Degeneration/*drug effects ; Spinal Cord/drug effects/pathology ; }, abstract = {The murine mutant wobbler is a model of lower motoneuron degeneration with associated skeletal muscle atrophy. This mutation most closely resembles Werdnig-Hofmann disease in humans and shares some of the clinical features of amyotrophic lateral sclerosis (ALS). It has been suggested that reactive oxygen species (ROS) may play a role in the pathogenesis of disorders such as ALS. To examine the relationship between ROS and neural degeneration, we have studied the effects of agents such as N-acetyl-L-cysteine (NAC), which reduce free radical damage. Litters of wobbler mice were given a 1% solution of the glutathione precursor NAC in their drinking water for a period of 9 weeks. Functional and neuroanatomical examination of these animals revealed that wobbler mice treated with NAC exhibited (1) a significant reduction in motor neuron loss and elevated glutathione peroxidase levels within the cervical spinal cord, (2) increased axon caliber in the medial facial nerve, (3) increased muscle mass and muscle fiber area in the triceps and flexor carpi ulnaris muscles, and (4) increased functional efficiency of the forelimbs, as compared with untreated wobbler littermates. These data suggest that reactive oxygen species may be involved in the degeneration of motor neurons in wobbler mice and demonstrate that oral administration of NAC effectively reduces the degree of motor degeneration in wobbler mice. This treatment thus may be applicable in the treatment of other lower motor neuropathies.}, }
@article {pmid8984377, year = {1996}, author = {Wokke, JH}, title = {[Riluzole treatment in amyotrophic lateral sclerosis].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {140}, number = {46}, pages = {2265-2268}, pmid = {8984377}, issn = {0028-2162}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Controlled Clinical Trials as Topic ; Drug Costs ; Excitatory Amino Acid Antagonists/*therapeutic use ; Humans ; Neuroprotective Agents/*therapeutic use ; Riluzole ; Thiazoles/economics/*therapeutic use ; }, }
@article {pmid8932289, year = {1996}, author = {Vaidya, S and Wang, CC and Roorda, C and Billings, A and Rajaraman, S and Fish, JC}, title = {Prevention of graft-versus-host disease by intrathymic injection of recipient-type splenocytes into donor.}, journal = {Transplantation}, volume = {62}, number = {9}, pages = {1366-1368}, doi = {10.1097/00007890-199611150-00035}, pmid = {8932289}, issn = {0041-1337}, mesh = {*Adoptive Transfer ; Animals ; Antilymphocyte Serum/*administration &amp; dosage ; Graft vs Host Disease/immunology/*prevention &amp; control ; Male ; Rats ; Rats, Inbred Lew ; Thymus Gland/*immunology/pathology ; }, abstract = {We have prevented graft-versus-host disease (GVHD) by tolerizing graft donors to host antigens by intrathymic injection of recipient-type splenocytes into donors. A unidirectional GVHD model was used in which intravenous injection of 3-4 x 10(8) Lewis rat (donor) lymphocytes into (Lewis x Brown Norway)F1 rats (recipients) causes lethal GVHD. The donor animals were divided into five treatment groups. The group 1 donor animals received no treatment. The group 2 donors received a single intraperitoneal injection of 1 ml of antilymphocyte antiserum (ALS). The group 3 donors received an intrathymic injection of 50x10(6) host splenocytes. The group 4 donors received both ALS (intraperitoneally) and intrathymic allograft. The group 5 donors received both ALS (intraperitoneally) and intravenous allograft. Two weeks after these treatments, 3-4x10(8) lymphocytes from each of these donors were injected (intravenously) into the recipients. The clinical signs of GVHD, as measured by profound weight loss, hair loss, inflammation of foot pads and ears, and profound splenomegaly, were evident in recipients of groups 1, 2, and 3 between days 9 and 10 and in the recipients (two of four) of group 5 on day 17. No GVHD was observed by histopathology in all 14 hosts that received lymphocyte injection from the group 4 donor animals (up to 300 days). These results demonstrate that GVHD can be eliminated by tolerizing donors toward host by intrathymic injection of the recipient-type lymphocytes into the donor. A single injection of ALS is necessary to possibly eliminate antihost response from the donor for the tolerance induction. The thymic route appears to be superior to the intravenous route for tolerance induction.}, }
@article {pmid8947945, year = {1996}, author = {Muma, NA and Singer, SM}, title = {Aluminum-induced neuropathology: transient changes in microtubule-associated proteins.}, journal = {Neurotoxicology and teratology}, volume = {18}, number = {6}, pages = {679-690}, doi = {10.1016/s0892-0362(96)00126-2}, pmid = {8947945}, issn = {0892-0362}, support = {NS 30460/NS/NINDS NIH HHS/United States ; }, mesh = {Aluminum/*toxicity ; Alzheimer Disease/pathology ; Animals ; Female ; Humans ; Immunohistochemistry ; Microtubule-Associated Proteins/analysis/*metabolism ; Microtubules/drug effects/pathology/ultrastructure ; Neurofibrillary Tangles/drug effects/pathology/*ultrastructure ; Neurons/drug effects/metabolism/*pathology ; Neurotoxins/*toxicity ; Rabbits ; Spinal Cord/drug effects/metabolism/*pathology ; tau Proteins/analysis ; }, abstract = {In susceptible species, aluminum induces cytoskeletal changes in which neurofilaments accumulate in neuronal cell bodies and proximal axonal enlargements. To determine if microtubule-associated proteins (MAPs) are altered in this model, we examined the spinal cords of aluminum- and saline-treated control rabbits at several time points after treatment. Transient decreases in tau and MAP2 immunoreactivity in neurons in aluminum-intoxicated rabbits were demonstrated with immunocytochemistry. An antibody directed against Alzheimer's disease paired helical filaments labeled neurons in aluminum-treated rabbits but not controls. MAP5 immunoreactivity in the cell body cytoplasm was displaced by aluminum-induced tangles. The transient decreases in MAP2 and tau immunoreactivity did not reflect alterations in protein levels measured using immunoblotting. The transient antigenic changes in tau and MAP2 may reflect conformational changes in these cytoskeletal proteins. Aluminum-induced pathology provides a model for studying perturbations in MAPs and neurofilament proteins that are characteristic of many human neurodegenerative diseases such as Alzheimer's disease, diffuse Lewy body disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, }
@article {pmid8923496, year = {1996}, author = {Chokroverty, S}, title = {Sleep and degenerative neurologic disorders.}, journal = {Neurologic clinics}, volume = {14}, number = {4}, pages = {807-826}, doi = {10.1016/s0733-8619(05)70286-3}, pmid = {8923496}, issn = {0733-8619}, mesh = {Aged ; Alzheimer Disease/physiopathology ; Cerebellar Diseases/physiopathology ; Dystonia Musculorum Deformans/physiopathology ; Humans ; Huntington Disease/physiopathology ; Motor Neuron Disease/physiopathology ; Nervous System Diseases/diagnosis/*physiopathology/therapy ; Parkinson Disease/physiopathology ; Shy-Drager Syndrome/physiopathology ; Sleep/*physiology ; Sleep Wake Disorders/physiopathology/therapy ; Supranuclear Palsy, Progressive/physiopathology ; Tourette Syndrome/physiopathology ; }, abstract = {This article summarizes sleep disturbances in a variety of neuro-degenerative diseases, including Parkinson's disease, multiple system atrophy, and amyotrophic lateral sclerosis. Sleep complaints in these conditions include insomnia, hypersomnia, abnormal motor activity and behavior during sleep, sleep-related breathing problems, and circadian rhythm sleep disturbances. Clinical examination followed in selected cases by polysomnographic, multiple sleep latency, and other laboratory tests is essential for correct diagnosis and treatment of these sleep disturbances.}, }
@article {pmid8909433, year = {1996}, author = {Tandan, R and Bromberg, MB and Forshew, D and Fries, TJ and Badger, GJ and Carpenter, J and Krusinski, PB and Betts, EF and Arciero, K and Nau, K}, title = {A controlled trial of amino acid therapy in amyotrophic lateral sclerosis: I. Clinical, functional, and maximum isometric torque data.}, journal = {Neurology}, volume = {47}, number = {5}, pages = {1220-1226}, doi = {10.1212/wnl.47.5.1220}, pmid = {8909433}, issn = {0028-3878}, support = {FD-U-000512-03-1/FD/FDA HHS/United States ; MO1 RR109/RR/NCRR NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amino Acids/*therapeutic use ; Amyotrophic Lateral Sclerosis/*drug therapy ; Analysis of Variance ; Double-Blind Method ; Female ; Humans ; Isoleucine/therapeutic use ; Leucine/therapeutic use ; Male ; Middle Aged ; Threonine/therapeutic use ; Valine/therapeutic use ; }, abstract = {We conducted a two center, double-blind, placebo-controlled treatment trial with oral branched chain amino acids (BCAA) (L-leucine 12 g, L-isoleucine 8 g, and L-valine 6.4 g daily) or L-threonine (4 g daily) with pyridoxal phosphate (160 mg daily) for six months in patients with amyotrophic lateral sclerosis (ALS). The effect of treatment on disease progression was estimated every two months by recording clinical muscle strength, maximum isometric muscle torque in selected muscles, forced vital capacity (FVC), activities of daily living pertaining to the upper and lower limbs, and timed tasks. Ninety-five patients were randomized to receive BCAA (n = 31), L-threonine (n = 32), or placebo (n = 32), of whom 77 (81%) completed the trial. Mean weight loss in the placebo group was 1.1 kg and in the L-threonine group was 3.2 kg; the BCAA group gained 0.2 kg (p = 0.04). The estimated decline in FVC was about 2.5 times greater in the BCAA and L-threonine groups as compared to placebo (p = 0.03). Otherwise, no significant differences were found in the changes observed in clinical, functional, timed, or maximum torque measures among treatment groups. The amino acids were well tolerated. The results of our study failed to show a beneficial effect of BCAA or L-threonine treatment for six months on the disease course in ALS. The higher rate of loss of pulmonary function in patients treated with BCAA or L-threonine may have been due to chance, but an adverse effect of these amino acids cannot be ruled out.}, }
@article {pmid8909267, year = {1996}, author = {White, RD and Asplin, BR and Bugliosi, TF and Hankins, DG}, title = {High discharge survival rate after out-of-hospital ventricular fibrillation with rapid defibrillation by police and paramedics.}, journal = {Annals of emergency medicine}, volume = {28}, number = {5}, pages = {480-485}, doi = {10.1016/s0196-0644(96)70109-9}, pmid = {8909267}, issn = {0196-0644}, mesh = {Adult ; Aged ; Aged, 80 and over ; *Electric Countershock ; *Emergency Medical Services ; *Emergency Medical Technicians ; Female ; Humans ; Male ; Middle Aged ; Outcome Assessment, Health Care ; *Police ; Retrospective Studies ; Survival Rate ; Ventricular Fibrillation/*mortality/*therapy ; }, abstract = {STUDY OBJECTIVE: To assess outcome in patients with ventricular fibrillation (VF) treated by defibrillator-equipped police and emergency medical technician-paramedics in an advanced life support (ALS) emergency medical services (EMS) system.<br><br>METHODS: We carried out a retrospective observational outcome study of all consecutive adult patients with atraumatic cardiac arrest treated from November 1990 through July 1995. The study was carried out in a city with a population of 76,865 in an area of 32.6 square miles. Central 911 dispatched police and an ALS ambulance simultaneously. Accurate intervals were obtained with the synchronization of all defibrillator clocks with the 911 dispatch clock. The personnel who arrived first delivered the initial shock. After shocks delivered by police, paramedics provided additional treatment if needed. Main outcome measures were time elapsed before delivery of the first shock, restoration of spontaneous circulation (ROSC), and survival to discharge home.<br><br>RESULTS: Of 84 patients, 31 (37%) were first shocked by police. Thirteen of the 31 demonstrated ROSC, without need for ALS treatment. All 13 survived to discharge. The other 18 patients required ALS; 5 (27.7%) survived. Among the 53 patients first shocked by paramedics, 15 had ROSC after shocks only, and 14 survived. The other 38 needed ALS treatment; 9 survived. Call-to-shock time for all patients was less in the police group than in the paramedic group (5.6 versus 6.3 minutes, P = .038). For all patients, call-to-shock time was less in those with ROSC after shocks only than in those who needed ALS (5.4 versus 6.3 minutes, P = .011). Survival to discharge was 49% (41 of 84), with 18 of 31 (58%) in the police group and 23 of 53 (43%) in the paramedic group. Call-to-shock time for survivors was 5.8 minutes; it was 6.4 minutes for the nonsurvivors (P = .020). Neither ROSC nor discharge survival was significantly different between police and paramedic-shocked patients. ROSC after initial shock and call-to-shock time were major determinants of survival, whether the first shocks were administered by police or by paramedics. With ROSC after shocks only, 27 of 28 (96%) survived, whereas 14 of 56 (25%) needing ALS survived (P < .001).<br><br>CONCLUSION: A high discharge-to-home survival rate was obtained with early defibrillation by both police and paramedics. When shocks resulted in ROSC, the overwhelming majority of patients survived (96%). Even brief time decreases (eg. 1 minute) in call-to-shock time increase the likelihood of ROSC from shocks only, with a consequent decrease in the need for ALS intervention. Short call-to-shock time and ROSC response to shocks only are major determinants of a high rate of survival after VF.}, }
@article {pmid8937834, year = {1996}, author = {Rothstein, JD}, title = {Therapeutic horizons for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurobiology}, volume = {6}, number = {5}, pages = {679-687}, doi = {10.1016/s0959-4388(96)80103-6}, pmid = {8937834}, issn = {0959-4388}, support = {NS33958/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/pathology/physiopathology/*therapy ; Animals ; Antioxidants/therapeutic use ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Insulin-Like Growth Factor I/therapeutic use ; Mice ; Mice, Transgenic ; Motor Neuron Disease/epidemiology/therapy ; Motor Neurons/pathology/physiology ; Nerve Degeneration ; Nerve Growth Factors/therapeutic use ; Nerve Regeneration ; Superoxide Dismutase/biosynthesis/genetics ; }, abstract = {Recent theories on the pathogenesis of motor neuron disease and research on motor neuron injury have resulted in new putative therapies, which include treatment with various neurotrophic factors, antioxidants and anti-excitotoxicity agents. Clinical and preclinical studies have now provided the first agents that reproducibly alter the course of amyotrophic lateral sclerosis.}, }
@article {pmid8911742, year = {1996}, author = {Hughes, RA and O'Leary, PD}, title = {Neurotrophic factors and the development of drugs to promote motoneuron survival.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {23}, number = {10-11}, pages = {965-969}, doi = {10.1111/j.1440-1681.1996.tb01150.x}, pmid = {8911742}, issn = {0305-1870}, mesh = {Cell Survival/drug effects ; Drug Design ; Humans ; Motor Neurons/*cytology/*drug effects ; Nerve Growth Factors/pharmacology/physiology ; Nerve Tissue Proteins/*pharmacology/*physiology ; }, abstract = {1. During embryonic development, neuronal populations undergo a period of naturally occurring cell death. In the vertebrate, the survival of neurons during this period is dependent upon specific neurotrophic factors. Recent advances in in vitro and in vivo assays have led to the identification of a number of neurotrophic factors for spinal motoneurons, including brain-derived neurotrophic factor, ciliary neurotrophic fibroblast growth factors, insulin-like growth factors and glial-derived neurotrophic factor. 2. The presence of multiple trophic factors promoting motoneuron survival suggests either that there is significant functional redundancy between the factors or that they act in concert to produce their effects. 3. In addition to their physiological role, neurotrophic factors show tremendous clinical potential for the treatment of human neurodegenerative diseases, such as amyotrophic lateral sclerosis. However, because they are poorly absorbed across biological membranes and are unstable in plasma, the recombinant neurotrophic factors themselves are not optimally suited as drugs. One means to circumvent these problems is to use the known three-dimensional structures of these factors as templates to design low molecular weight compounds that retain neurotrophic activity but exhibit better pharmacokinetic properties.}, }
@article {pmid8898266, year = {1996}, author = {Yorkston, KM}, title = {Treatment efficacy: dysarthria.}, journal = {Journal of speech and hearing research}, volume = {39}, number = {5}, pages = {S46-57}, doi = {10.1044/jshr.3905.s46}, pmid = {8898266}, issn = {0022-4685}, mesh = {Adolescent ; Amyotrophic Lateral Sclerosis/physiopathology ; Brain Injuries/physiopathology ; Brain Ischemia/physiopathology ; Cerebral Palsy/physiopathology ; Dysarthria/physiopathology/*therapy ; Family ; Humans ; Male ; Parkinson Disease/physiopathology ; Speech-Language Pathology ; Workforce ; }, abstract = {The dysarthrias form a group of diverse, chronic motor speech disorders. The disorders of Parkinson's disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis, and cerebral palsy are reviewed because they represent important clinical diagnoses in which dysarthria is a frequent and debilitating symptom. The roles played by speech-language pathologists include participation in differential diagnosis, provision of speech treatment, staging of treatment, and timely education so that clients and families can make informed decisions about communication alternatives. Both scientific and clinical evidence is presented that suggests that individuals with dysarthria benefit from the services of speech-language pathologists. Group-treatment studies, single-subject studies, and case reports illustrate the effectiveness of various types of speech treatment. Research into the effectiveness of augmentative and alternative communication systems for individuals with cerebral palsy is also presented.}, }
@article {pmid8891467, year = {1996}, author = {Bryson, HM and Fulton, B and Benfield, P}, title = {Riluzole. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in amyotrophic lateral sclerosis.}, journal = {Drugs}, volume = {52}, number = {4}, pages = {549-563}, pmid = {8891467}, issn = {0012-6667}, mesh = {Administration, Oral ; Animals ; Antiparkinson Agents/pharmacokinetics/pharmacology/*therapeutic use ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Tolerance ; Excitatory Amino Acid Antagonists/pharmacokinetics/pharmacology/*therapeutic use ; Humans ; In Vitro Techniques ; Mice ; Motor Neuron Disease/*drug therapy/mortality ; Multicenter Studies as Topic ; Neuroprotective Agents/pharmacokinetics/pharmacology/*therapeutic use ; Randomized Controlled Trials as Topic ; Riluzole ; Sodium Channels/drug effects ; Thiazoles/blood/pharmacokinetics/pharmacology/*therapeutic use ; Treatment Outcome ; }, abstract = {Riluzole, a benzothiazole, affects neurons by 3 mechanisms: by inhibiting excitatory amino acid release, inhibiting events following stimulation of excitatory amino acid receptors and stabilising the inactivated state of voltage-dependent sodium channels. It has demonstrated neuroprotective activity in vivo and in vitro. Results from 2 randomised double-blind placebo-controlled trials in patients with amyotrophic lateral sclerosis (ALS; motor neuron disease) have demonstrated that riluzole can extend survival and/or time to tracheostomy. After 18 months, the relative risk of death or tracheostomy with riluzole 100 mg/day was reduced by 21%. Although riluzole slowed the rate of deterioration in muscle strength in the first trial, this was not confirmed in the second, larger trial. Riluzole had no effect on any other functional or secondary variable. Gastrointestinal effects, anorexia, asthenia, circumoral paraesthesia and dizziness were reported more frequently with riluzole than placebo. Elevated alanine aminotransferase levels were observed in 10.6 versus 3.8% of patients treated with riluzole 100 mg/day versus placebo, leading to treatment withdrawal in 3.8 versus 2.1% of patients. In conclusion, riluzole is the first drug that has been shown to have an effect on survival in patients with ALS. Although the effect of riluzole was modest, it has allowed some insight into the pathogenesis of ALS from which future gains may be made.}, }
@article {pmid8858069, year = {1996}, author = {Klein, LM and Forshew, DA}, title = {The economic impact of ALS.}, journal = {Neurology}, volume = {47}, number = {4 Suppl 2}, pages = {S126-9}, doi = {10.1212/wnl.47.4_suppl_2.126s}, pmid = {8858069}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*economics ; *Health Care Costs ; Humans ; Patient Care Planning/*economics ; }, abstract = {ALS is a progressive degenerative neuromuscular disease for which there is no known cause, treatment, or cure. The steady disease progression of muscle weakness eventually causes paralysis, disabling the patient. Day-to-day patient care and management most frequently fall to family members. The resultant financial burden can be enormous. We review financial issues related to the diagnosis, management of disease progression, and issues of life support. Cost-effective solutions are discussed. It is believed the key to reduction of costs is education of the health care community, patients and families, and third-party payers.}, }
@article {pmid8858062, year = {1996}, author = {Mitsumoto, H and Olney, RK}, title = {Drug combination treatment in patients with ALS: current status and future directions.}, journal = {Neurology}, volume = {47}, number = {4 Suppl 2}, pages = {S103-7}, doi = {10.1212/wnl.47.4_suppl_2.103s}, pmid = {8858062}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; *Drug Combinations ; Fibroblast Growth Factor 2/therapeutic use ; Humans ; }, }
@article {pmid8812156, year = {1996}, author = {Dittrich, F and Ochs, G and Grosse-Wilde, A and Berweiler, U and Yan, Q and Miller, JA and Toyka, KV and Sendtner, M}, title = {Pharmacokinetics of intrathecally applied BDNF and effects on spinal motoneurons.}, journal = {Experimental neurology}, volume = {141}, number = {2}, pages = {225-239}, doi = {10.1006/exnr.1996.0157}, pmid = {8812156}, issn = {0014-4886}, mesh = {Animals ; Brain-Derived Neurotrophic Factor/*pharmacokinetics ; Chick Embryo ; Dose-Response Relationship, Drug ; Immunohistochemistry ; Injections, Spinal ; Motor Neurons/*drug effects ; Protein-Tyrosine Kinases/metabolism ; Sheep ; Spinal Cord/*drug effects ; }, abstract = {Brain-derived neurotrophic factor (BDNF) is a potential drug for treatment of amyotrophic lateral sclerosis. Previous studies have demonstrated little or no penetration of the blood-brain barrier by BDNF, hence systemic application does not result in significant penetration into the spinal cord to produce direct action on motoneurons. Intrathecal (i.th) application of BDNF to sheep was investigated as a mean of topical administration. After continuous infusion a caudalcranial gradient of BDNF concentration in cerebrospinal fluid (CSF) and at the meninges was observed. BDNF did not penetrate spinal parenchyma but accumulated in spinal motoneurons probably due to axonal uptake in ventral roots and subsequent retrograde transport. Spinal motoneurons showed reduced levels of tropomyosin receptor kinase (trk) B and increased levels of c-fos at high BDNF doses in comparison to treatment with saline, even after treatment periods of several months. After bolus injection and cessation of continuous delivery multiphasic reduction of the BDNF concentration in CSF was detected. Our study demonstrates that i.th. application of BDNF is feasible, setting the stage for future clinical trials.}, }
@article {pmid8883943, year = {1996}, author = {Doré, S and Krieger, C and Kar, S and Quirion, R}, title = {Distribution and levels of insulin-like growth factor (IGF-I and IGF-II) and insulin receptor binding sites in the spinal cords of amyotrophic lateral sclerosis (ALS) patients.}, journal = {Brain research. Molecular brain research}, volume = {41}, number = {1-2}, pages = {128-133}, doi = {10.1016/0169-328x(96)00081-2}, pmid = {8883943}, issn = {0169-328X}, support = {R01 NS046400/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Humans ; Insulin/physiology ; Insulin-Like Growth Factor I/physiology ; Insulin-Like Growth Factor II/physiology ; Middle Aged ; Nerve Tissue Proteins/*analysis ; Receptor, IGF Type 1/*analysis ; Receptor, IGF Type 2/*analysis ; Receptor, Insulin/*analysis ; Spinal Cord/*chemistry ; }, abstract = {The structurally related peptides, insulin and insulin-like growth factors (IGF-I and IGF-II), have neurotrophic properties and potentially could be of therapeutic value in human neurodegenerative disorders. In this study, we compared the anatomical distribution of [125I]IGF-I, [125I]IGF-II and [125I]insulin binding sites in thoracic spinal cords from patients who died of amyotrophic lateral sclerosis (ALS) and normal controls. For these three ligands, the greatest amounts of specific binding were located in the deeper layers of the dorsal horn > intermediate zone > lamina X > ventral horn > superficial layers of the dorsal horn > white matter of the spinal cord. Highly significant (P < 0.001) increases in the density of [125I]IGF-I and [125I]IGF-II binding were apparent in various laminae of the cord of ALS patients with increased binding being particularly evident in the ventral horn and the intermediate zone. Significant (P < 0.05) increases were also seen in lamina X and in the dorsal horn. In contrast, no significant differences in [125I]insulin binding were observed between ALS and control spinal cords. Taken together, these data reveal significant increases in both [125I]IGF-I and [125I]IGF-II binding levels in the spinal cords of ALS patients albeit to different extents. These findings may be of relevance for future therapeutic strategies aimed at slowing the progression of this chronic neurodegenerative disease, as recently suggested by the beneficial therapeutic effects of an IGF-I treatment in ALS patients.}, }
@article {pmid8889216, year = {1996}, author = {Tan, SA and Déglon, N and Zurn, AD and Baetge, EE and Bamber, B and Kato, AC and Aebischer, P}, title = {Rescue of motoneurons from axotomy-induced cell death by polymer encapsulated cells genetically engineered to release CNTF.}, journal = {Cell transplantation}, volume = {5}, number = {5}, pages = {577-587}, doi = {10.1177/096368979600500507}, pmid = {8889216}, issn = {0963-6897}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Axons/*ultrastructure ; Blotting, Northern ; Cell Death ; Cells, Cultured ; Chick Embryo ; Ciliary Neurotrophic Factor ; Cricetinae ; Drug Delivery Systems/*methods ; Enzyme-Linked Immunosorbent Assay ; Genetic Engineering/methods ; Humans ; Mice ; Motor Neurons/*cytology/transplantation ; Nerve Tissue Proteins/*metabolism ; Polymers ; Rats ; Rats, Sprague-Dawley ; }, abstract = {The neurodegenerative disease amyotrophic lateral sclerosis (ALS) results from the progressive loss of motoneurons, leading to death in a few years. Ciliary neurotrophic factor (CNTF), which decreases naturally occurring and axotomy-induced cell death, may result in slowing of motoneuron loss and has been evaluated as a treatment for ALS. Effective administration of this protein to motoneurons may be hampered by the exceedingly short half-life of CNTF, and the inability to deliver effective concentration into the central nervous system after systemic administration in vivo. The constitutive release of CNTF from genetically engineered cells may represent a solution to this delivery problem. In this work, baby hamster kidney (BHK) cells stably tranfected with a chimeric plasmid construct containing the gene for human or mouse CNTF were encapsulated in polymer fibers, which prevents immune rejection and allow long-term survival of the transplanted cells. In vitro bioassays show that the encapsulated transfected cells release bioactive CNTF. In vivo, systemic delivery of human and mouse CNTF from encapsulated cells was observed to rescue 26 and 27% more facial motoneurons, respectively, as compared to capsules containing parent BHK cells 1 wk postaxotomy in neonatal rats. With local application of CNTF on the nerve stump and by systemic delivery through repeated subcutaneous injections, 15 and 13% more rescue effects were observed. These data illustrate the potential of using encapsulated genetically engineered cells to continuously release CNTF to slow down motoneuron degeneration following axotomy and suggest that encapsulated cell delivery of neurotrophic factors may provide a general method for effective administration of therapeutic proteins for the treatment of neurodegenerative diseases.}, }
@article {pmid8797493, year = {1996}, author = {}, title = {Assessment of plasmapheresis. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.}, journal = {Neurology}, volume = {47}, number = {3}, pages = {840-843}, pmid = {8797493}, issn = {0028-3878}, mesh = {Humans ; Nervous System Diseases/*therapy ; *Plasmapheresis ; }, abstract = {Based on the review of the literature, therapeutic PP has a definite role in the treatment of patients with GBS, CIDP, polyneuropathies associated with MGUS, MG, and LEMS (table). PP may have a role in treating patients with Refsum's disease, acquired neuromyotonia, stiff-man syndrome, cryoglobulinemic polyneuropathy, CNS-SLE, ADEM, and MS, but these decisions should be made on a case-by-case basis. PP has no role in treating patients with ALS or paraneoplastic syndromes with circulating autoantibodies.}, }
@article {pmid8811891, year = {1996}, author = {Mendieta, J and Díaz-Cruz, MS and Tauler, R and Esteban, M}, title = {Application of multivariate curve resolution to voltammetric data. II. Study of metal-binding properties of the peptides.}, journal = {Analytical biochemistry}, volume = {240}, number = {1}, pages = {134-141}, doi = {10.1006/abio.1996.0340}, pmid = {8811891}, issn = {0003-2697}, mesh = {Cadmium/metabolism ; Glutathione/*metabolism ; Least-Squares Analysis ; Multivariate Analysis ; Polarography/*methods ; }, abstract = {The complexation of Cd2+ by glutathione (GSH), in 0.13 m borate buffer at pH 9.5, was studied by differential pulse polarography (DPP) and multivariate curve resolution. The Cd-GSH system has been chosen as a model to check the possibilities of this new polarographic approach to the study of metal ion complexation by peptides. Experimental data obtained by DPP for different Cd2+-to-GSH concentration ratios have been analyzed by a procedure which consists of using several chemometrical techniques based on factor analysis: principal component analysis, evolving factor analysis, and multivariate curve resolution with alternating least-squares (ALS) optimization. The use of different constraints during the ALS optimization process, such as nonnegativity and unimodality constraints, yields the optimal sought solution from a chemical point of view. In the present work, a new constraint has been implemented during ALS optimization to take into account the expected peak-shaped signal of DPP. This data treatment allows us to detect simultaneously the formation of 1:1 and 1:2 Cd:GSH complexes which were very difficult to detect by univariate analysis of DPP data. It is concluded that the described multivariate curve resolution method could be a reliable tool for studying metal-binding properties of peptides.}, }
@article {pmid8695837, year = {1996}, author = {Solary, E and Witz, B and Caillot, D and Moreau, P and Desablens, B and Cahn, JY and Sadoun, A and Pignon, B and Berthou, C and Maloisel, F and Guyotat, D and Casassus, P and Ifrah, N and Lamy, Y and Audhuy, B and Colombat, P and Harousseau, JL}, title = {Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study.}, journal = {Blood}, volume = {88}, number = {4}, pages = {1198-1205}, pmid = {8695837}, issn = {0006-4971}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Acute Disease ; Antineoplastic Agents/*administration &amp; dosage ; Cells, Cultured ; Cytarabine/*administration &amp; dosage ; *Drug Resistance, Multiple ; Female ; Hematopoiesis/drug effects ; Humans ; Leukemia/*drug therapy ; Male ; Middle Aged ; Mitoxantrone/*administration &amp; dosage ; Quinine/*administration &amp; dosage ; }, abstract = {A phase III prospective randomized multicenter study was performed to determine whether quinine could improve the response rate of poor-risk acute leukemias (ALs) to standard chemotherapy including a multidrug resistance (MDR)-related cytotoxic agent. The rationale of the study was based on the negative prognostic value of MDR phenotype in ALs and the ability of quinine to reverse this phenotype both in vitro and ex vivo. Three hundred fifteen patients (median age, 49 years; range, 16 to 65) with relapsed (n = 108) or refractory (n = 32) acute myeloblastic leukemia (AML), relapsed (n = 27) or refractory (n = 9) acute lymphoblastic leukemia (ALL), secondary AL (n = 22) or blastic transformation of myelodysplastic syndrome ([MDS] n = 74) or myeloproliferative syndrome ([MPS] n = 43) were randomly assigned to receive mitoxantrone ([MXN] 12 mg/m2/d, days 2 to 5) and cytarabine ([Ara-C] 1 g/m2/12 h, days 1 to 5) alone or in combination with quinine (30 mg/kg/d, days 1 to 5; continuous intravenous infusion beginning 24 hours before MXN infusion). Side effects of quinine were observed in 56 of 161 quinine-treated patients and disappeared in all but four cases after one or two 20% dose decreases. Sera from quinine-treated patients showed increased MXN uptake in an MDR-positive cell line compared with matched sera obtained before quinine infusion. Quinine induced a significant increase in the incidence of nausea, vomiting, mucositis, and cardiac toxicity. A complete response (CR) was observed in 85 of 161 patients (52.8%) from the quinine-treated group versus 70 of 154 patients (45.5%) in the control group (P = .19). The most important differences between quinine and control group CR rates were observed in patients with refractory AMLs and blastic transformation of MDS and MPS. The CR rate was higher in P-glycoprotein-positive cases, although the difference was not significant. Failure of the regimen due to blastic persistence or blast number increase was higher in the control group (61 of 154 patients) than in the quinine group (45 of 161, P = .04). Early death was observed in eight cases (four in each arm) and death in aplasia in 27 cases (20 in quinine group v seven in control group, P = .01). The significant increase of toxicity in the quinine arm could have masked the clinical benefit of MDR reversion in poor-risk ALs.}, }
@article {pmid8815407, year = {1996}, author = {Vos, PE and Wokke, JH}, title = {[Muscle cramps and fasciculations not always ominous: muscle cramp-fasciculation syndrome].}, journal = {Nederlands tijdschrift voor geneeskunde}, volume = {140}, number = {32}, pages = {1655-1658}, pmid = {8815407}, issn = {0028-2162}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/diagnosis ; Analgesics, Non-Narcotic/therapeutic use ; Benzodiazepines/therapeutic use ; Carbamazepine/therapeutic use ; Diagnosis, Differential ; Fasciculation/*diagnosis/drug therapy ; Humans ; Male ; Middle Aged ; Muscle Cramp/*diagnosis/drug therapy ; Muscle Fatigue ; }, abstract = {In three patients, men of 43, 44 and 55 years old with muscle cramps, fasciculations and easy fatiguability of muscles, cramp-fasciculation syndrome was diagnosed. This is a benign disorder which has to be differentiated from amyotrophic lateral sclerosis. Response to treatment (benzodiazepines or carbamazepine) is good.}, }
@article {pmid11990115, year = {1996}, author = {Schmidt, TA and Federiuk, CS and Zechnich, A and Forsythe, M and Christie, M and Andrews, C}, title = {Advanced life support in the wilderness: 5-year experience of the Reach and Treat team.}, journal = {Wilderness &amp; environmental medicine}, volume = {7}, number = {3}, pages = {208-215}, doi = {10.1580/1080-6032(1996)007[0208:alsitw]2.3.co;2}, pmid = {11990115}, issn = {1080-6032}, mesh = {Adolescent ; Adult ; Advanced Cardiac Life Support/statistics &amp; numerical data ; Aged ; Child ; Child, Preschool ; Clinical Competence ; Emergency Medical Services/organization &amp; administration/*statistics &amp; numerical data ; Female ; Humans ; Life Support Care/organization &amp; administration/*statistics &amp; numerical data ; Male ; Middle Aged ; Mountaineering ; Oregon/epidemiology ; Retrospective Studies ; Wounds and Injuries/*epidemiology/etiology/therapy ; }, abstract = {Increasing recreation in the wilderness raises questions about the value of providing advanced life support (ALS) care in the backcountry. Since 1989 the Reach and Treat (RAT) team has provided ALS care in the wilderness area that surrounds Mount Hood, Oregon. The purpose of our study was to describe patient demographics, terrain, injuries, and ALS treatment in the wilderness environment. We utilized a retrospective, observational analysis of RAT missions from 1989 to 1994 based on data sheets maintained by the RAT team, prehospital run sheets, and hospital charts. Of the 114 missions analyzed, the median time of missions was 3 h, 9 min (range, 44 min-76 h) and 20% required technical climbing skills. Of the 74 patients treated, 55 (90%) received ALS care: 8 were intubated, 52 had intravenous lines established, and 24 received morphine for pain. Twenty patients were entered into the local trauma system. The most common injuries were extremity injuries (58), head injuries (18), and hypothermia (15). Mean time from arrival to return to staging area was 95 min. No injuries to RAT team members occurred during these missions, although two minor injuries occurred during training and testing. We found that wilderness-trained paramedics safely provided ALS care in a backcountry environment. This care may improve patient comfort during long extrication and speeds the arrival of potentially life-saving interventions such as advanced airway management.}, }
@article {pmid8899667, year = {1996}, author = {Vyth, A and Timmer, JG and Bossuyt, PM and Louwerse, ES and de Jong, JM}, title = {Survival in patients with amyotrophic lateral sclerosis, treated with an array of antioxidants.}, journal = {Journal of the neurological sciences}, volume = {139 Suppl}, number = {}, pages = {99-103}, doi = {10.1016/0022-510x(96)00071-8}, pmid = {8899667}, issn = {0022-510X}, mesh = {Acetylcysteine/administration &amp; dosage ; Administration, Oral ; Amyotrophic Lateral Sclerosis/*drug therapy/*mortality ; Antioxidants/*administration &amp; dosage ; Capsules ; Chelating Agents/administration &amp; dosage ; Dithioerythritol/administration &amp; dosage ; Dithiothreitol/administration &amp; dosage ; Free Radical Scavengers/administration &amp; dosage ; Gastric Juice/chemistry ; Humans ; Injections, Subcutaneous ; Methionine/administration &amp; dosage/analogs &amp; derivatives ; Succimer/administration &amp; dosage ; Sulfhydryl Reagents/administration &amp; dosage ; Survival Analysis ; }, abstract = {Between 1983 and 1988 we treated 36 patients with sporadic amyotrophic lateral sclerosis (ALS) by an array of antioxidants and added other drugs to the regimen whenever a patient reported deterioration. Our customary prescription sequence was N-acetylcysteine (NAC); vitamins C and E; N-acetylmethionine (NAM); and dithiothreitol (DTT) or its isomer dithioerythritol (DTE). Patients with a history of heavy exposure to metal were also given meso 2,3-dimercaptosuccinic acid (DMSA). NAC, NAM, DTT, and DTE were administered by subcutaneous injection or by mouth or by both routes, the other vitamins and DMSA by mouth alone. The hospital pharmacy supplied NAC and NAM injections fluid as 100 ml bottles of 5.0 and 5.85% solutions, respectively. DTT was delivered in special double-walled capsules of 200 mg. DTT/DTE injection fluid was added to the NAC and NAM bottles, the final DTT/DTE concentrations never exceeding 0.5%. DMSA was provided in 250 mg capsules. All of the 36 patients used NAC and DTT/DTE; 29 also used vitamins C and E; 21 also used NAM; and 7 also used DMSA, DMSA, NAM, vitamins C and E were tolerated well. In many patients, DTT, DTE, NAC and NAM induced pain, redness and swelling at the injection sites in that order of decreasing frequency. DTT and DTE did often and NAC did sometimes cause gastric pain, nausea and other abdominal discomfort. Comparison of survival in the treated group and in a cohort of untreated historical controls, disclosed a median survival of 3.4 years (95% confidence interval: 3.0-4.2) in the treated and of 2.8 (95% confidence interval 2.2-3.1) years in the control patients. This difference may be explained by self-selection of our highly motivated treated group and by its initial survival of diagnosis for an average of 8.5 months before onset of treatment. We conclude that antioxidants neither seem to harm ALS patients, nor do they seem to prolong survival.}, }
@article {pmid8899666, year = {1996}, author = {Evangelista, T and Carvalho, M and Conceição, I and Pinto, A and de Lurdes, M and Luís, ML}, title = {Motor neuropathies mimicking amyotrophic lateral sclerosis/motor neuron disease.}, journal = {Journal of the neurological sciences}, volume = {139 Suppl}, number = {}, pages = {95-98}, doi = {10.1016/0022-510x(96)00120-7}, pmid = {8899666}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/therapy ; Biopsy ; Demyelinating Diseases/physiopathology ; Diagnosis, Differential ; Electric Stimulation ; Electromyography ; Female ; Hereditary Sensory and Autonomic Neuropathies/*diagnosis/therapy ; Humans ; Immunoglobulins/pharmacology ; Magnetics ; Male ; Middle Aged ; Motor Neuron Disease/*diagnosis/therapy ; Neural Conduction ; }, abstract = {We report three patients in whom the initial diagnosis was of possible A myotrophic lateral sclerosis (ALS/MND) according to the 'El Escorial Criteria'. All of them presented with monomelic paresis, atrophy of the paretic muscles and generalised brisk reflexes. The initial electromyograms showed a neurogenic pattern in the limbs with normal sensory and motor conduction velocities. Laboratory evaluation and imagiological investigations were normal in all of them. The previous diagnosis was changed in to demyelinating motor neuropathy with conduction block in 2 patients and tomaculous neuropathy in one after clinical and electromyographic follow-up and nerve biopsy. Patients 1 and 2 were given intravenous immunoglobulin treatment and showed moderate improvement.}, }
@article {pmid8899660, year = {1996}, author = {Conradi, S and Ronnevi, LO}, title = {Pitfalls in the evaluation of isometric strength (TQNE) data in ALS.}, journal = {Journal of the neurological sciences}, volume = {139 Suppl}, number = {}, pages = {60-63}, doi = {10.1016/0022-510x(96)00121-9}, pmid = {8899660}, issn = {0022-510X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*physiopathology ; Disease Progression ; Electromyography/standards ; Evaluation Studies as Topic ; Female ; Humans ; Isometric Contraction/*physiology ; Male ; Middle Aged ; Muscular Atrophy, Spinal/physiopathology ; Regression Analysis ; Respiratory Function Tests ; }, abstract = {The phase of rapid reduction of isometric strength in single muscle groups was identified and its slope was calculated in patients studied with the TQNE method. This parameter was studied in the extremities and in respiration in 4 ALS patients and 4 PMA (progressive spinal muscle atrophy) patients. The slopes of the strength reduction in these muscle groups and their mean values exceeded the slopes of the corresponding megascores; this difference was larger in the extremities than in respiration. It is concluded that repeated spirometry gives a good expression of reduction of muscle strength ir ALS, and is well suited for monitoring treatment effects.}, }
@article {pmid8865248, year = {1996}, author = {van Renen, MJ and Harrer, S and Jureidini, KF and Martin, AA}, title = {Effects of growth hormone on insulin-like growth factors and binding proteins before and after renal transplantation.}, journal = {Pediatric nephrology (Berlin, Germany)}, volume = {10}, number = {4}, pages = {483-487}, doi = {10.1007/s004670050144}, pmid = {8865248}, issn = {0931-041X}, mesh = {Blotting, Western ; Body Height/drug effects ; Child ; Female ; Growth Hormone/adverse effects/*therapeutic use ; Humans ; Insulin-Like Growth Factor Binding Proteins/*metabolism ; Iodine Radioisotopes ; Kidney Transplantation/*physiology ; Ligands ; Male ; Retrospective Studies ; Somatomedins/*metabolism ; }, abstract = {Three short children with severe chronic renal failure were treated with recombinant human growth hormone (rhGH) for 2 years. Each received a transplant in the 2nd year. Serum collected before and during rhGH therapy was analysed retrospectively by Western ligand blot and immunoblotting techniques. In addition, radioimmuno-assays for insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), acid-labile subunit (ALS) and IGFBP-1 were performed. IGFBPs in serum, detected by Western ligand blot, were identified as IGFBP-3, -2, -1 and -4 by immunoblot. The serum concentration of IGF-I in each child rose approximately fourfold with rhGH before transplantation and subsequently remained elevated. IGFBP-3 levels rose to double the pretreatment value, but dropped to normal levels following transplantation, while ALS rose with rhGH treatment and remained increased after transplantation. IGFBP-1 levels changed little with rhGH but fell following transplantation. A low molecular weight form of IGFBP-3 was noted at 30 kilodaltons on immunoblot which was not clearly seen on the ligand blot. IGFBP-2 was present as a distinct band on Western ligand blot before transplantation and appeared decreased in intensity subsequently. IGFBP-1, seen on immunoblot clearly before transplant, disappeared after the transplant. rhGH successfully improved growth in these children, in association with a fourfold increase in IGF-I levels, which was maintained following transplantation. The reduction in IGFBPs following transplantation suggests correction of impaired clearance by the diseased kidney.}, }
@article {pmid8759781, year = {1996}, author = {Lee, DA and Gross, L and Wittrock, DA and Windebank, AJ}, title = {Localization and expression of ciliary neurotrophic factor (CNTF) in postmortem sciatic nerve from patients with motor neuron disease and diabetic neuropathy.}, journal = {Journal of neuropathology and experimental neurology}, volume = {55}, number = {8}, pages = {915-923}, doi = {10.1097/00005072-199608000-00007}, pmid = {8759781}, issn = {0022-3069}, mesh = {Adult ; Aged ; Cadaver ; Ciliary Neurotrophic Factor ; Diabetic Neuropathies/*metabolism ; Humans ; Immunohistochemistry ; Middle Aged ; Motor Neuron Disease/*metabolism ; Nerve Growth Factors/metabolism ; Nerve Tissue Proteins/*metabolism ; Reference Values ; Sciatic Nerve/*metabolism ; Tissue Distribution ; }, abstract = {Ciliary neurotrophic factor (CNTF) is thought to play an important role in the maintenance of the mature motor system. The factor is found most abundantly in myelinating Schwann cells in the adult sciatic nerve. Lack of neuronal growth factors has been proposed as one possible etiology of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Growth factor replacement therapies are currently being evaluated as a treatment for motor neuron disease. In this report we determined whether the expression of CNTF in sciatic nerve differed in patients with motor neuron disease compared to controls or patients with another form of axonopathy. We identified 8 patients (7 with ALS and 1 with SMA) with motor neuron disease and 6 patients with diabetic motor neuropathy who had autopsy material available. Immunoperoxidase staining showed reduced CNTF expression in nerves of patients with motor neuron disease but not in patients with diabetic motor neuropathy. Decreased CNTF appears be associated with primary motor neuron disease rather than a generalized process of axon loss. This result supports suggestions that CNTF deficiency may be an important factor in the development of motor neuron disease.}, }
@article {pmid8657306, year = {1996}, author = {Sánchez, MP and Silos-Santiago, I and Frisén, J and He, B and Lira, SA and Barbacid, M}, title = {Renal agenesis and the absence of enteric neurons in mice lacking GDNF.}, journal = {Nature}, volume = {382}, number = {6586}, pages = {70-73}, doi = {10.1038/382070a0}, pmid = {8657306}, issn = {0028-0836}, mesh = {Animals ; Brain/embryology ; Cell Differentiation/genetics/physiology ; Cell Line ; Digestive System/*embryology/innervation ; Digestive System Abnormalities ; Dopamine/metabolism ; *Drosophila Proteins ; Embryonic and Fetal Development/genetics/physiology ; Gene Targeting ; Glial Cell Line-Derived Neurotrophic Factor ; Glial Cell Line-Derived Neurotrophic Factor Receptors ; Kidney/abnormalities/*embryology ; Mice ; Nerve Growth Factors/deficiency/genetics/*physiology ; Nerve Tissue Proteins/deficiency/genetics/*physiology ; Neurons/*cytology/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-ret ; Receptor Protein-Tyrosine Kinases/metabolism ; }, abstract = {Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for dopaminergic neurons and motor neurons in culture. It also protects these neurons from degeneration in vitro, and improves symptoms like Parkinson's disease induced pharmacologically in rodents and monkeys. Thus GDNF might have beneficial effects in the treatment of Parkinson's disease and amyotrophic lateral sclerosis. To examine the physiological role of GDNF in the development of the mammalian nervous system, we have generated mice defective in GDNF expression by using homologous recombination in embryonic stem cells to delete each of its two coding exons. GDNF-null mice, regardless of their targeted mutation, display complete renal agencies owing to lack of induction of the ureteric bud, an early step in kidney development. These mice also have no enteric neurons, which probably explains the observed pyloric stenosis and dilation of their duodenum. However, ablation of the GDNF gene does not affect the differentiation and survival of dopaminergic neurons, at least during embryonic development.}, }
@article {pmid8916290, year = {1996}, author = {Lapchak, PA}, title = {Therapeutic potentials for glial cell line-derived neurotrophic factor (GDNF) based upon pharmacological activities in the CNS.}, journal = {Reviews in the neurosciences}, volume = {7}, number = {3}, pages = {165-176}, doi = {10.1515/revneuro.1996.7.3.165}, pmid = {8916290}, issn = {0334-1763}, mesh = {Animals ; Central Nervous System/*drug effects ; Dopamine/physiology ; Glial Cell Line-Derived Neurotrophic Factor ; Humans ; Injections, Intraventricular ; Mice ; Nerve Degeneration/drug effects ; Nerve Growth Factors/*therapeutic use ; Nerve Tissue Proteins/*therapeutic use ; Neuroprotective Agents/*therapeutic use ; Oxidopamine/antagonists &amp; inhibitors ; Rats ; }, abstract = {Since the discovery of the novel neurotrophic factor GDNF in 1993 [25], the molecule has received a great deal of attention from neuroscientists studying all aspects of neurotrophic factor physiology and pharmacology. GDNF instantly became a focus of basic research when it was discovered that GDNF was a potent neurotrophic factor for at least two diverse neuronal populations including dopaminergic neurons and motor neurons [25,47] magnitude. A comprehensive review of the pharmacology of GDNF and hypotheses concerning its possible clinical uses is presented. Based upon our current knowledge of GDNF's pharmacology, it appears that the molecule may be useful in the treatment of neurodegenerative diseases, such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), other motor neuron diseases (MND) and cholinergic deficit-related dementia.}, }
@article {pmid8816181, year = {1996}, author = {Sporer, KA and Firestone, J and Isaacs, SM}, title = {Out-of-hospital treatment of opioid overdoses in an urban setting.}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {3}, number = {7}, pages = {660-667}, doi = {10.1111/j.1553-2712.1996.tb03487.x}, pmid = {8816181}, issn = {1069-6563}, support = {R49/CCR903697-06//PHS HHS/United States ; }, mesh = {Adult ; Chi-Square Distribution ; Cohort Studies ; Drug Overdose/diagnosis/therapy ; *Emergency Medical Services/methods ; Female ; Humans ; Life Support Care/methods ; Male ; Middle Aged ; Naloxone/administration &amp; dosage/*therapeutic use ; Narcotic Antagonists/administration &amp; dosage/*therapeutic use ; Narcotics/*poisoning ; Retrospective Studies ; Treatment Outcome ; Urban Population ; }, abstract = {OBJECTIVES: To investigate clinical outcomes in a cohort of opioid overdose patients treated in an out-of-hospital urban setting noted for a high prevalence of i.v. opioid use.<br><br>METHODS: A retrospective review was performed of presumed opioid overdoses that were managed in 1993 by the emergency medical services (EMS) system in a single-tiered, urban advanced life support (ALS) EMS system. Specifically, all patients administered naloxone by the country paramedics were reviewed. Those patients with at least 3 of 5 objective criteria of an opioid overdose [respiratory rate < 6/min, pinpoint pupils, evidence of i.v. drug use. Glasgow Coma Scale (GCS) score < 12, or cyanosis] were included. A response to naloxone was defined as improvement to a GCS > or = 14 and a respiratory rate > or = 10/min within 5 minutes of naloxone administration. ED dispositions of opioid-overdose patients brought to the county hospital were reviewed. All medical examiner's cases deemed to be opioid-overdose-related deaths by postmortem toxicologic levels also were reviewed.<br><br>RESULTS: There were 726 patients identified with presumed opioid overdoses. Most patients (609/726, 85.4%) had an initial pulse and blood pressure (BP). Most (94%) of this group responded to naloxone and all were transported. Of the remainder, 101 (14%) had obvious signs of death and 16 (2.2%) were in cardiopulmonary arrest without obvious signs of death. Of the patients in full arrest, 2 had return of spontaneous circulation but neither survived. Of the 609 patients who had initial BPs, 487 (80%) received naloxone i.m. (plus bag-valve-mask ventilation) and 122 (20%) received the drug i.v. Responses to naloxone were similar; 94% i.m. vs 90% i.v. Of 443 patients transported to the country hospital, 12 (2.7%) were admitted. The admitted patients had noncardiogenic pulmonary edema (n = 4), pneumonia (n = 2), other infections (n = 2), persistent respiratory depression (n = 2), and persistent alteration in mental status (n = 2). The patients with pulmonary edema were clinically obvious upon ED arrival. Hypotension was never noted and bradycardia was seen in only 2% of our presumed-opioid-overdose population.<br><br>CONCLUSIONS: The majority of the opioid-overdose patients who had initial BPs responded readily to naloxone, with few patients requiring admission. Noncardiogenic pulmonary edema was uncommon and when present, hypoxia was evident upon arrival to the ED. Naloxone administered i.m. in conjunction with bag-valve-mask ventilation was effective in this patient population. The opioid-overdose patients in cardiopulmonary arrest did not survive.}, }
@article {pmid8692898, year = {1996}, author = {Ho, BK and Alexianu, ME and Colom, LV and Mohamed, AH and Serrano, F and Appel, SH}, title = {Expression of calbindin-D28K in motoneuron hybrid cells after retroviral infection with calbindin-D28K cDNA prevents amyotrophic lateral sclerosis IgG-mediated cytotoxicity.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {93}, number = {13}, pages = {6796-6801}, pmid = {8692898}, issn = {0027-8424}, support = {AG08664/AG/NIA NIH HHS/United States ; NS31886/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*immunology/pathology ; Base Sequence ; Calbindin 1 ; Calbindins ; Calcium/metabolism ; Cell Division/genetics ; *Cytotoxicity, Immunologic/genetics ; DNA, Complementary/administration &amp; dosage ; Genetic Vectors ; Humans ; Immunoglobulin G/*immunology ; Immunohistochemistry ; Molecular Sequence Data ; Nerve Tissue Proteins/*genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Retroviridae/genetics ; S100 Calcium Binding Protein G/*genetics/metabolism ; Transfection ; }, abstract = {Calbindin-D28K and/or parvalbumin appear to influence the selective vulnerability of motoneurons in amyotrophic lateral sclerosis (ALS). Their immunoreactivity is undetectable in motoneurons readily damaged in human ALS, and in differentiated motoneuron hybrid cells [ventral spinal cord (VSC 4.1 cells)] that undergo calcium-dependent apoptotic cell death in the presence of ALS immunoglobulins. To provide additional evidence for the role of calcium-binding proteins in motoneuron vulnerability, VSC 4.1 cells were infected with a retrovirus carrying calbindin-D28K cDNA under the control of the promoter of the phosphoglycerate kinase gene. Differentiated calbindin-D28K cDNA-infected cells expressed high calbindin-D28K and demonstrated increased resistance to ALS IgG-mediated toxicity. Treatment with calbindin-D28K antisense oligodeoxynucleotides, which significantly decreased calbindin-D28K expression, rendered these cells vulnerable again to ALS IgG toxicity.}, }
@article {pmid10163380, year = {1996}, author = {Joyce, SM and Brown, DE and Nelson, EA}, title = {Epidemiology of pediatric EMS practice: a multistate analysis.}, journal = {Prehospital and disaster medicine}, volume = {11}, number = {3}, pages = {180-187}, doi = {10.1017/s1049023x00042928}, pmid = {10163380}, issn = {1049-023X}, mesh = {Adolescent ; Age Distribution ; Child ; Child, Preschool ; Databases, Factual ; Emergency Medical Services/*statistics &amp; numerical data ; Female ; Health Services Research ; Humans ; Incidence ; Infant ; Infant, Newborn ; Male ; Mississippi/epidemiology ; Morbidity ; Nevada/epidemiology ; *Pediatrics ; Pennsylvania/epidemiology ; Retrospective Studies ; Sex Distribution ; Tennessee/epidemiology ; Time Factors ; }, abstract = {OBJECTIVE: To describe the epidemiology of pediatric emergency medical services (EMS) practice in a large patient population from several geographic areas.<br><br>DESIGN: Retrospective computer analysis of EMS databases from four states using a common data set and analysis system.<br><br>SETTING: Pennsylvania, Tennessee, Mississippi, and Nevada (except Clark County), 1990 through 1992.<br><br>METHODS: All patient-care reports of patients 14 years old and younger were extracted from the EMS databases and analyzed for the following factors: age, gender, date, elapsed prehospital times, incident type, mechanism of injury, call disposition, illness or injuries encountered, severity of illness/injury (by abnormal vital signs), and basic life support (BLS) and advanced life support (ALS) treatment delivered.<br><br>RESULTS: A total of 1,512,907 patient care reports were reviewed. Those of 61,132 children were extracted for analysis. These children comprised about 4% of prehospital responses. Male subjects predominated (56%), and children aged 7 through 14 years represented 46% of cases. Most calls occurred in the evening and daylight hours. Children were transported by ambulance in 89% of cases, and care was refused in 7.7%. Mean response time was 9 +/- 16 minutes, mean scene time 12 +/- 14 minutes, and mean transport time 14 +/- 20 minutes. Traumatic incidents predominated at 42%, with motor vehicle accidents and falls the most common mechanisms. Blunt injuries accounted for 94% of trauma, whereas respiratory problems, seizures, and poisoning/overdose were the most common medical problems. Vital signs were obtained in 56% of cases. Abnormal vital signs were noted in 21% of these, and the presumptive causes were similar in distribution to those of the general population, with the addition of cardiac arrest. The most commonly used treatments were spinal immobilization, oxygen administration, intravenous access and several ALS medications. An ALS capability was available in more than half the runs, but ALS treatment was delivered in only 14% of those cases. Outcome data were not available.<br><br>CONCLUSION: This multistate analysis of pediatric EMS epidemiology confirms findings reported in smaller regional studies, with several exceptions. Excessive scene times were not noted. Few children had serious disorders as evidenced by abnormal vital signs. An ALS treatment, when available, was used infrequently. These findings have implications for EMS planners and educators.}, }
@article {pmid8843596, year = {1996}, author = {Walker, KG and Casey, JJ and Jaques, BC and Bradley, JA and Bolton, EM}, title = {Strain-dependent differences in prolongation of rat cardiac allograft survival after intrathymic injection of donor bone marrow and ALS treatment.}, journal = {Transplant immunology}, volume = {4}, number = {2}, pages = {177-179}, doi = {10.1016/s0966-3274(96)80013-x}, pmid = {8843596}, issn = {0966-3274}, mesh = {Animals ; Antilymphocyte Serum/*therapeutic use ; Bone Marrow Transplantation/*immunology ; Drug Administration Routes ; *Graft Enhancement, Immunologic ; Graft Survival/*immunology ; Heart Transplantation/*immunology ; Rats ; Rats, Inbred Lew ; Species Specificity ; Thymus Gland/immunology ; Transplantation, Homologous ; }, }
@article {pmid8843586, year = {1996}, author = {De Fazio, SR and Plowey, JM and Hartner, WC and Gozzo, JJ}, title = {Late adjunctive therapy with single doses of rapamycin in skin-allografted mice treated with antilymphocyte serum and donor bone marrow cells.}, journal = {Transplant immunology}, volume = {4}, number = {2}, pages = {105-112}, doi = {10.1016/s0966-3274(96)80003-7}, pmid = {8843586}, issn = {0966-3274}, support = {AI 29650/AI/NIAID NIH HHS/United States ; DK 33466/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Animals, Newborn/immunology ; Antilymphocyte Serum/*therapeutic use ; *Bone Marrow Transplantation ; Drug Administration Schedule ; Drug Therapy, Combination ; Graft Survival/drug effects ; Immunosuppressive Agents/*therapeutic use ; Injections, Intraperitoneal ; Male ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Polyenes/administration &amp; dosage/*therapeutic use ; Sirolimus ; Skin Transplantation/*immunology ; T-Lymphocytes, Regulatory/immunology ; Transplantation, Homologous ; }, abstract = {Temporary donor-specific unresponsiveness induced by treatment of skin allografted mice with antilymphocyte serum (ALS) and donor bone marrow cells (BMC) can be converted to long-term graft survival and tolerance by adding adjunctive immunosuppressive agents, including rapamycin (Rapa). Rapa was given in a suboptimal dosing schedule to probe several aspects of its use in the promotion of tolerization. Single doses were given at 2 weeks post-transplantation to recipients prepared with ALS and donor BMC. Graft survival was markedly prolonged in a dose-dependent fashion by day +14, Rapa doses ranging from 0.75 to 6.0 mg/kg. Indefinite (> 300 day) graft survival was observed in 26% of recipients given the highest Rapa dose. Short-term treatment with cyclosporin A (CsA) or deoxyspergualin (DSG) was ineffective when injected at this time. Rapa augmented the tolerizing effect of grafting with skin from newborn mice but had no significant additive or synergistic effects with the short course of CsA or with DSG given on days +1 to +3, even though the latter prolonged graft survival when added to the ALS/BMC protocol. Single doses of Rapa on day +1 also prolonged graft survival, but without any of the grafts surviving indefinitely. Later dosing on day +28 resulted in > 70% of grafts surviving > 300 days. Challenge grafting of these mice after day +300 resulted in delayed rejection of donor strain, but not third-party skin grafts. Rapa was very effective when given as widely spaced doses on days +14 and +49. Also, grafts showing the earliest signs of rejection could be rescued with a single Rapa dose in recipients treated with ALS and BMC but not ALS alone. Transfer of prolonged graft survival with spleen cells from ALS plus BMC treated recipients was not adversely affected by Rapa given to the suppressor-like spleen cell donors approximately 1 week before cell harvest. We conclude that the use of Rapa as an adjunctive agent in allograft recipients treated with ALS plus donor BMC is very flexible in terms of timing of administration, and that the drug can be effectively given as widely spaced doses or as a rescue agent after ALS/BMC treatment. Additionally, an active immunoregulatory mechanism induced by ALS/BMC treatment appears to be spared by Rapa.}, }
@article {pmid8791245, year = {1996}, author = {Aisen, ML and Sevilla, D and Edelstein, L and Blass, J}, title = {A double-blind placebo-controlled study of 3,4-diaminopyridine in amytrophic lateral sclerosis patients on a rehabilitation unit.}, journal = {Journal of the neurological sciences}, volume = {138}, number = {1-2}, pages = {93-96}, doi = {10.1016/0022-510x(96)00012-3}, pmid = {8791245}, issn = {0022-510X}, mesh = {4-Aminopyridine/*analogs &amp; derivatives/therapeutic use ; Administration, Oral ; Aged ; Amifampridine ; Amyotrophic Lateral Sclerosis/*drug therapy/rehabilitation ; Cross-Over Studies ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Muscle Weakness/*drug therapy ; Neural Conduction/*drug effects ; *Potassium Channel Blockers ; Psychomotor Performance/*drug effects ; }, abstract = {3,4-Diaminopyridine (DAP) enhances acetylcholine release from the nerve terminal and improves conduction in demyelinated axons. In this double-blinded placebo controlled cross over study we examined the effects of DAP combined with inpatient rehabilitation in nine patients with disabling motor weakness due to amyotrophic lateral sclerosis (ALS). A single dose of DAP or placebo was increased daily to the maximum (range: 10-80 mg) tolerated dose; after patients were assessed on the first treatment, the alternate drug was given in the same manner. Functional Independence Measurement (FIM), Ashworth, grip strength, limb strength measurements, nerve conduction studies and speech assessments were initiated 1/2 h after receiving the maximum tolerated dose of DAP or placebo. DAP was tolerated in all patients, but limited by gastrointestinal side effects in four patients. The mean peak serum level was 20.11 (S.D. = 5.11) ng/ml, occurring 1.25 (S.D. = 0.56) h after dose. A statistically significant improvement in FIM and speech assessment scores between admission and discharge occurred. However, no significant differences in clinical or electrophysiologic measures were seen between DAP and placebo treatments. This study suggests that intensive inpatient rehabilitation has a role in the management of patients with ALS, but DAP does not diminish motor impairment.}, }
@article {pmid8661177, year = {1996}, author = {Goldstein, C and Reiss, GR and Mohiuddin, M and Shen, Z and Yokoyama, H and DiSesa, VJ}, title = {Tolerance to cardiac allografts requires a time lag between intrathymic treatment and transplantation.}, journal = {The Journal of surgical research}, volume = {63}, number = {1}, pages = {83-85}, doi = {10.1006/jsre.1996.0227}, pmid = {8661177}, issn = {0022-4804}, mesh = {Animals ; Antilymphocyte Serum/*therapeutic use ; Graft Rejection/immunology/pathology ; *Graft Survival ; Heart Transplantation/*immunology/pathology ; Immunosuppression Therapy/*methods ; *Lymphocyte Transfusion ; Rats ; Rats, Inbred BN ; Rats, Inbred Lew ; Time Factors ; Transplantation, Heterotopic ; Transplantation, Homologous ; }, abstract = {Permanent tolerance to an experimental heterotopic cardiac allograft can be achieved by pretreatment with antilymphocyte serum (ALS) and intrathymic inoculation of donor cells. Most successful experimental protocols have employed a time lag of 2 to 3 weeks between intrathymic pretreatment and transplantation, which makes this treatment strategy impractical for clinical heart transplantation. In these experiments we modified the standard protocol by giving ALS 24 hr prior to both intrathymic injection of donor cells and heterotopic transplantation. Seven Lewis rats had intraperitoneal injection of 1 ml of ALS and 24 hr later underwent intrathymic injection of 5 X 10(7) donor Lewis-Brown Norway (LBN) splenocytes and heterotopic cardiac transplantation using an LBN donor. Mean graft survival was 24.4 days, significantly longer than the 7.8-day graft survival observed in untreated Lewis recipients (n = 5) (P < 0.02). However, graft survival was not different from that observed in Lewis rats pretreated with ALS alone (n = 5) (25.8 days, P = NS). Permanent graft survival was produced in two rats receiving only A-LS and in one rat receiving both ALS and intrathymic inoculation. In these experiments it appears that prolongation of graft survival may have been due to the effect of A-LS alone. These results suggest that there is a critical time period between intrathymic inoculation and transplantation that is needed for permanent tolerance to be induced consistently. This may be due to the kinetics of the effects of ALS on alloreactive T-lymphocytes or to a time-dependent requirement for antigen processing in the thymus.}, }
@article {pmid8640564, year = {1996}, author = {Aebischer, P and Schluep, M and Déglon, N and Joseph, JM and Hirt, L and Heyd, B and Goddard, M and Hammang, JP and Zurn, AD and Kato, AC and Regli, F and Baetge, EE}, title = {Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients.}, journal = {Nature medicine}, volume = {2}, number = {6}, pages = {696-699}, doi = {10.1038/nm0696-696}, pmid = {8640564}, issn = {1078-8956}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*genetics/therapy ; Animals ; Cell Transplantation/methods ; Ciliary Neurotrophic Factor ; Cricetinae ; Drug Implants/administration &amp; dosage/*chemistry ; Genetic Therapy/methods ; Genetic Vectors/chemistry/genetics ; Humans ; *Injections, Spinal ; Kidney/cytology/physiology ; Lumbar Vertebrae/surgery ; Nerve Tissue Proteins/*administration &amp; dosage/cerebrospinal fluid/*therapeutic use ; Recombinant Proteins/administration &amp; dosage/biosynthesis/therapeutic use ; }, abstract = {Neuronal growth factors hold promise for providing therapeutic benefits in various neurological disorders. As a means of ensuring adequate central nervous system delivery of growth factors and minimizing significant adverse side effects associated with systemic delivery methods, we have developed an ex vivo gene therapy approach for protein delivery using encapsulated genetically modified xenogeneic cells. Ciliary neurotrophic factor (CNTF) has been shown in various rodent models to reduce the motor neuron cell death similar to that seen in amyotrophic lateral sclerosis (ALS). The initial trials focusing on the systemic administration of CNTF for ALS have been discontinued as a result of major side effects, thus preventing determination of the potential efficacy of the molecule. In order to deliver CNTF directly to the nervous system, we conducted a phase I study in which six ALS patients were implanted with polymer capsules containing genetically engineered baby hamster kidney cells releasing approximately 0.5 microgram of human CNTF per day in vitro. The CNTF-releasing implants were surgically placed within the lumbar intrathecal space. Nanogram levels of CNTF were measured within the patients' cerebrospinal fluid (CSF) for at least 17 weeks post-transplantation, whereas it was undetectable before implantation. Intrathecal delivery of CNTF was not associated with the limiting side effects observed with systemic delivery. These results demonstrate that neurotrophic factors can be continuously delivered within the CSF of humans by an ex vivo gene therapy approach, opening new avenues for the treatment of neurological diseases.}, }
@article {pmid8676624, year = {1996}, author = {Lacomblez, L and Bensimon, G and Leigh, PN and Guillet, P and Meininger, V}, title = {Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II.}, journal = {Lancet (London, England)}, volume = {347}, number = {9013}, pages = {1425-1431}, doi = {10.1016/s0140-6736(96)91680-3}, pmid = {8676624}, issn = {0140-6736}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*administration &amp; dosage/adverse effects ; Prognosis ; Proportional Hazards Models ; Riluzole ; Survival Analysis ; Thiazoles/*administration &amp; dosage/adverse effects ; Time Factors ; Tracheostomy ; Treatment Outcome ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive disease with no effective treatment. In an initial study, riluzole decreased mortality and slowed muscle-strength deterioration in ALS patients. We have carried out a double-blind, placebo-controlled, multicentre study to confirm those findings and to assess drug efficacy at different doses.<br><br>METHODS: 959 patients with clinically probable or definite ALS of less than 5 years' duration were randomly assigned treatment with placebo or 50 mg, 100 mg, or 200 mg riluzole daily; randomisation was stratified by centre and site of disease onset (bulbar or limb). The primary outcome was survival without a tracheostomy. Secondary outcomes were rates of change in functional measures (muscle strength, functional status, respiratory function, patient's assessments of fasciculation, cramps, stiffness, and tiredness). The primary analysis was the comparison of the 100 mg dose with placebo by intention-to-treat. Drug-effect on survival was assessed before (log-rank test) and after adjustment for known prognostic factors (Cox's model).<br><br>FINDINGS: At the end of the study, after median follow-up of 18 months, 122 (50.4%) placebo-treated patients and 134 (56.8%) of those who received 100 mg/day riluzole were alive without tracheostomy (unadjusted risk 0.79, p = 0.076; adjusted risk 0.65, p = 0.002). In the groups receiving 50 mg and 200 mg riluzole daily, 131 (55.3%) and 141 (57.8%) patients were alive without tracheostomy (relative to placebo 50 mg adjusted risk 0.76, p = 0.04; 200 mg 0.61, p = 0.0004). There was a significant inverse dose response in risk of death. No functional scale discriminated between the treatment groups. The most common adverse reactions were asthenia, dizziness, gastrointestinal disorders, and rises in liver enzyme activities; they were commonest with the 200 mg dose.<br><br>INTERPRETATION: Overall, efficacy and safety results suggest that the 100 mg dose of riluzole has the best benefit-to-risk ratio. This study confirms that riluzole is well tolerated and lengthens survival of patients with ALS.}, }
@article {pmid8860837, year = {1996}, author = {Aebischer, P and Pochon, NA and Heyd, B and Deglon, N and Joseph, JM and Zurn, AD and Baetge, EE and Hammang, JP and Goddard, M and Lysaght, M and Kaplan, F and Kato, AC and Schluep, M and Hirt, L and Regli, F and Porchet, F and De Tribolet, N}, title = {Gene therapy for amyotrophic lateral sclerosis (ALS) using a polymer encapsulated xenogenic cell line engineered to secrete hCNTF.}, journal = {Human gene therapy}, volume = {7}, number = {7}, pages = {851-860}, doi = {10.1089/hum.1996.7.7-851}, pmid = {8860837}, issn = {1043-0342}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Animals ; Capsules/chemistry/therapeutic use ; Cell Line ; Cell Transplantation/methods ; Cells, Cultured ; Ciliary Neurotrophic Factor ; Clinical Protocols ; Cricetinae ; Ganciclovir/pharmacology ; Genetic Therapy/*methods ; Genetic Vectors/genetics/pharmacology/toxicity ; Humans ; Kidney/cytology ; Nerve Tissue Proteins/adverse effects/*genetics/*therapeutic use ; Polymers/chemistry/therapeutic use ; Primates ; *Prostheses and Implants ; Rats ; Sheep ; Simplexvirus/enzymology/genetics ; Thymidine Kinase/genetics ; Transfection ; }, abstract = {The gene therapy approach presented in this protocol employs a polymer encapsulated, xenogenic, transfected cell line to release human ciliary neurotrophic factor (hCNTF) for the treatment of Amyotrophic Lateral Sclerosis (ALS). A tethered device, containing around 10(6) genetically modified cells surrounded by a semipermeable membrane, is implanted intrathecally; it provides for slow continuous release of hCNTF at a rate of 0.25 to 1.0 micrograms/24 hours. The semipermeable membrane prevents immunologic rejection of the cells and interposes a physical, virally impermeable barrier between cells and host. Moreover, the device and the cells it contains may be retrieved in the event of side effects. A vector containing the human CNTF gene was transfected into a line of baby hamster kidney cells (BHK) with calcium phosphate using a dihydrofolate reductase-based selection vector with a SV40 promoter and contains a HSV-tk killer gene. hCNTF is a potent neurotrophic factor which may have utility for the treatment of ALS. Systemic delivery of hCNTF in humans has been frustrated by peripheral side effects, the molecule's short half life, and its inability to cross the blood-brain barrier. The gene therapy approach described in this protocol is expected to mitigate such difficulties by local intrathecal delivery of a known quantity of continuously-synthesized hCNTF from a retrievable implant.}, }
@article {pmid8762728, year = {1996}, author = {Bereket, A and Wilson, TA and Blethen, SL and Sakurai, Y and Herndon, DN and Wolfe, RR and Lang, CH}, title = {Regulation of the acid-labile subunit of the insulin-like growth factor ternary complex in patients with insulin-dependent diabetes mellitus and severe burns.}, journal = {Clinical endocrinology}, volume = {44}, number = {5}, pages = {525-532}, doi = {10.1046/j.1365-2265.1996.726547.x}, pmid = {8762728}, issn = {0300-0664}, mesh = {Acute Disease ; Adolescent ; Adult ; Blotting, Western ; Burns/blood/drug therapy/*metabolism ; Carrier Proteins/blood/*metabolism ; Child ; Child, Preschool ; Diabetes Mellitus, Type 1/blood/drug therapy/*metabolism ; Female ; Glycoproteins/blood/*metabolism ; Growth Hormone/blood/therapeutic use ; Humans ; Hydrocortisone/blood ; Infant ; Insulin/blood/therapeutic use ; Insulin-Like Growth Factor Binding Protein 3/analysis ; Insulin-Like Growth Factor I/analysis ; Longitudinal Studies ; Male ; Recombinant Proteins/therapeutic use ; }, abstract = {OBJECTIVE: Little information is available regarding the regulation of serum acid-labile subunit (ALS) in human disease. We have studied alterations in serum ALS of the insulin-like growth factor (IGF) ternary complex in children with untreated insulin-dependent diabetes mellitus (IDDM) and subjects with severe burns before and after insulin therapy. In addition, we have investigated the effect of insulin plus GH on serum ALS in burn patients.<br><br>DESIGN: Serum samples were obtained from children with newly diagnosed and untreated IDDM before the initiation of insulin therapy and 1 month thereafter. Serum samples were also obtained from adult patients with severe burns who were on a continuous infusion of a carbohydrate-rich enteral diet via nasogastric and duodenal catheters under basal conditions, after a 1-week period of continuous insulin infusion, and after an additional week of insulin plus recombinant GH.<br><br>PATIENTS: Twenty children and adolescents with untreated IDDM, aged 1.2-16 years, and 6 young adult patients with severe burns aged 17-28 years were studied longitudinally. Control sera were obtained from age, sex and pubertal status matched subjects (for children with IDDM) and from fed healthy adults.<br><br>MEASUREMENTS: Serum insulin, GH, cortisol and IGF-I were measured by radioimmunoassay, and serum ALS levels were assessed by Western immunoblot before and after treatment periods.<br><br>RESULTS: Serum ALS levels were lower in untreated children with IDDM (69 +/- 6% of control children). Insulin therapy significantly increased serum ALS (79 +/- 5%, P < 0.05) in these children. Patients with severe burns also had lower serum ALS levels (79 +/- 10% of control adults). After one week of insulin therapy serum ALS levels increased to 90 +/- 15% of control values (P < 0.05). Addition of GH to insulin therapy for another week did not significantly further increase serum ALS levels (95 +/- 27%). Serum IGF-I concentrations increased nearly 2.5-fold in diabetic subjects and fourfold in burn subjects at the end of the study periods. There were no proteolytic fragments of ALS in the sera studied. The deglycosylation pattern of ALS did not differ between diabetic and control sera.<br><br>CONCLUSION: Serum ALS levels were diminished in children with untreated IDDM and were partially restored after the initiation of insulin therapy. Serum ALS levels were also diminished in patients with severe burn injury and restored by insulin treatment. Addition of GH to insulin therapy did not significantly increase serum ALS levels over levels obtained during insulin therapy alone. These decreases in serum ALS were smaller than the decrease in serum IGF-I concentrations in both conditions, suggesting that IGF-I is the limiting factor for the ternary complex formation in the catabolic states. Insulin may regulate circulating ALS levels in catabolic states and helps to restore the IGF system.}, }
@article {pmid8754633, year = {1996}, author = {Martí-Fàbregas, J and Pradas, J and Illa, I}, title = {[Prognostic factors in amyotrophic lateral sclerosis].}, journal = {Neurologia (Barcelona, Spain)}, volume = {11}, number = {5}, pages = {174-181}, pmid = {8754633}, issn = {0213-4853}, mesh = {Adult ; Age of Onset ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/mortality ; Cohort Studies ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/diagnosis/mortality ; Prognosis ; Prospective Studies ; Spain/epidemiology ; Survival Rate ; }, abstract = {Survival in patients with amyotrophic lateral sclerosis is highly variable. In a prospective study of 71 patients, we analyzed the influence of several clinical factors on survival: age of onset, sex, initial involvement (bulbar, upper extremities or lower extremities) and familial history. Mean time of evolution was 2.6 years, with 25% survival 5 years after onset. Patients under 45 years old had better survival than those over 45 (5.8 and 2.2 years, respectively, p < 0.002). The prognosis for women was worse (2.07 and 3.6 years for women and men, respectively, p < 0.001), probably because age of onset was later in women (61 versus 53 years, respectively, p < 0.006). Neither first symptom or familial history of the disease affected prognosis. We conclude that age at onset is a decisive prognostic factor that is inversely related to survival. In the design of clinical trials in which survival is a variable, the treatment and control groups should be matched for age.}, }
@article {pmid8723221, year = {1996}, author = {Zurn, AD and Winkel, L and Menoud, A and Djabali, K and Aebischer, P}, title = {Combined effects of GDNF, BDNF, and CNTF on motoneuron differentiation in vitro.}, journal = {Journal of neuroscience research}, volume = {44}, number = {2}, pages = {133-141}, doi = {10.1002/(SICI)1097-4547(19960415)44:2&lt;133::AID-JNR5&gt;3.0.CO;2-E}, pmid = {8723221}, issn = {0360-4012}, mesh = {Animals ; Biomarkers ; Brain-Derived Neurotrophic Factor ; Cell Differentiation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Choline O-Acetyltransferase/metabolism ; Ciliary Neurotrophic Factor ; Drug Interactions ; Embryo, Mammalian ; Eye Proteins/analysis/biosynthesis ; Glial Cell Line-Derived Neurotrophic Factor ; Humans ; Intermediate Filament Proteins/analysis/biosynthesis ; *Membrane Glycoproteins ; Mesencephalon/cytology ; Motor Neuron Disease ; Motor Neurons/drug effects/*physiology ; Nerve Growth Factors/*pharmacology ; Nerve Tissue Proteins/*pharmacology ; Neurites/drug effects/physiology/ultrastructure ; Neuropeptides/analysis/biosynthesis ; Peripherins ; Phosphopyruvate Hydratase/analysis/metabolism ; Rats ; Recombinant Proteins/pharmacology ; }, abstract = {We have previously shown that glial cell line-derived neurotrophic factor (GDNF), in addition to promoting the survival of dopaminergic neurons in cultures from embryonic rat ventral mesencephalon,also increases the activity of choline acetyltransferase (ChAT) in the cranial motoneurons present in these cultures (Zurn et al.: Neuroreport 6:113-118, 1994). By using the intermediate filament protein peripherin as a motoneuron marker, we report here that GDNF increases the number of motoneurons as well as the length of their neurites. Brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) also promote ChAT activity, motoneuron survival, and neurite outgrowth in these cultures, but to varying degrees. Although these three molecules have similar effects on cultured motoneurons, we provide evidence for a distinct mode of action of GDNF, BDNF, and CNTF, since combinations of GDNF and BDNF, GDNF and CNTF, and BDNF and CNTF have either additive or synergistic effects on ChAT activity and motoneuron number. In addition to the previously described motoneuron-specific neurotrophic factors BDNF and CNTF, GDNF combined with the latter two factors may provide an important tool for the treatment of human motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy, both by increasing efficiency of treatment, and by decreasing the likelihood of deleterious side-effects.}, }
@article {pmid8636336, year = {1996}, author = {de Boer, H and Blok, GJ and Popp-Snijders, C and Stuurman, L and Baxter, RC and van der Veen, E}, title = {Monitoring of growth hormone replacement therapy in adults, based on measurement of serum markers.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {81}, number = {4}, pages = {1371-1377}, doi = {10.1210/jcem.81.4.8636336}, pmid = {8636336}, issn = {0021-972X}, mesh = {Adult ; Biomarkers/*blood ; Dihydrotestosterone/blood ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Monitoring ; Follow-Up Studies ; Growth Hormone/adverse effects/*deficiency/*therapeutic use ; Growth Hormone-Releasing Hormone/blood ; Humans ; Insulin-Like Growth Factor Binding Protein 3/blood ; Insulin-Like Growth Factor I/analysis ; Macromolecular Substances ; Male ; Placebos ; Testosterone/blood ; Thyroxine/blood ; Time Factors ; Triiodothyronine/blood ; }, abstract = {The optimal dose for GH replacement therapy in GH-deficient (GHD) adults is not known, nor is there a consensus as to which method is the most appropriate for the monitoring of treatment. To establish a general guideline for GH replacement therapy in adults, we evaluated the relationship between the administered GH dose and the achieved serum levels of three GH-dependent serum markers. Serum levels of insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) were measured in 46 GHD men participating in a 1-yr, double blind, and placebo-controlled dose-response study. The doses of recombinant human GH ranged from 0.33-3.0 IU/m(2)-day. During GH treatment, dose reduction was necessary because of side-effects in 18 of 46 patients, i.e. in 18% of the patients receiving a maintenance dose of 1 IU/M(2)-day, in 35% of the patients receiving a dose of 2 IU/m(2)-day, and in 67% of the patients receiving a dose of 3 IU/M(2)-day. In the untreated state, serum levels of all three markers were below the normal range in 90% of the patients. The rise in serum marker concentrations during the first month of treatment was dose dependent. Significant increases in IGF-I, IGFBP-3, and ALS levels were observed with a dose as low as 0.33 IU/M(2)-day. The minimal GH dose required for normalization of the serum IGF-I concentration was 0.66 IU/M(2)-day, and it was 1.0 IU/M(2)-day for ALS and IGFBP-3. In patients receiving 2.0 IU/M(2)-day, the mean serum IGF-I concentration rose to an abnormally high level, whereas at this dose, the mean IGFBP-3 and ALS levels were not different from normal. The lower sensitivity of IGFBP-3 and ALS to GH doses in the high range was also apparent during long term treatment. The number of patients who developed IGFBP-3 or ALS levels that exceeded the upper normal limit was substantially smaller than the number of patients with elevated IGF-I concentrations (2, 8, and 19 of 46 patients, respectively). In conclusion, serum IGF-I appears to be the preferred biochemical marker for the detection of GH excess in adults receiving GH replacement therapy, because it is more sensitive than IGFBP-3 and ALS to GH doses in the high range. If normalization of the serum IGF-I concentration is taken as the criterion for optimal GH replacement therapy, the predicted optimal GH dose for GHD men 20 - 40 yr old is 1.4 IU/M(2)-day, and the 95% confidence interval is 1.2-1.6 IU/M(2)-day.}, }
@article {pmid8650755, year = {1996}, author = {Timm, HU}, title = {[The meeting between patients and professionals who treat them. Qualitative interview of patients with amyotrophic lateral sclerosis and their closest relatives].}, journal = {Ugeskrift for laeger}, volume = {158}, number = {13}, pages = {1812-1817}, pmid = {8650755}, issn = {0041-5782}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*psychology/therapy ; Denmark ; Family/*psychology ; Female ; *Health Knowledge, Attitudes, Practice ; Humans ; Male ; Middle Aged ; Patient Satisfaction ; *Physician-Patient Relations ; Quality of Health Care ; Quality of Life ; Social Support ; Surveys and Questionnaires ; }, abstract = {The object of the present investigation was to know more about the experiences and the demands of patients with amyotrophic lateral sclerosis (ALS) and their closest relatives, and to relate these experiences and demands to the practice of the Danish health care system. Twelve patients and 11 relatives from two neurological wards were interviewed in the spring of 1993. The investigation shows that to patients and relatives the course of the illness and disease is a continuous one. Their experience of quality in treatment and care depends on whether the professional staff have knowledge of and see their own role in the entire course of the illness and disease. The conclusion of this investigation is that it is necessary to disseminate knowledge of amyotrophic lateral sclerosis and to strengthen a centralised professional competence in the treatment and support of patients with amyotrophic lateral sclerosis and their closest relatives.}, }
@article {pmid10159729, year = {1996}, author = {Adams, J and Aldag, G and Wolford, R}, title = {Does the level of prehospital care influence the outcome of patients with altered levels of consciousness?.}, journal = {Prehospital and disaster medicine}, volume = {11}, number = {2}, pages = {101-104}, doi = {10.1017/s1049023x00042722}, pmid = {10159729}, issn = {1049-023X}, mesh = {Adult ; Aged ; Cognition Disorders/classification/diagnosis/*therapy ; Emergency Medical Services/*standards ; Female ; Humans ; Life Support Care/*standards ; Male ; Middle Aged ; Retrospective Studies ; Statistics, Nonparametric ; Transportation of Patients ; }, abstract = {HYPOTHESIS: Significant differences exist in the outcome of patients with altered level of consciousness (ALOC) cared for by advanced life support (ALS) compared with basic life support (BLS) prehospital providers.<br><br>METHODS: Patients transported by ambulance to a community teaching hospital during an 11-month period were studied retrospectively. Study patients were those considered not alert by prehospital personnel. Exclusion criteria included; trauma, intoxication, drowning, shock, and cardiac arrest. Data were abstracted from the ambulance reports and hospital records.<br><br>RESULTS: Two hundred three patients with an ALOC were identified; 113 were transported by ALS providers (56%) and 90 (44%) by BLS providers. Prehospital levels of consciousness, according to the "alert, verbal, painful, unresponsive" scale (ALS vs BLS) were: "verbal" (40% vs 51%), "painful" (23% vs 23%), and "unresponsive" (37% vs 25%). The mean value for some time was 15 +/- 6 minutes for ALS versus 10 +/- 4 minutes for BLS (p < 0.001). On arrival in the emergency department, the LOC of 72 (64%) ALS patients and 58 (64%) BLS patients had improved to "alert." The level of consciousness in one ALS patient worsened. Fifty-two ALS (46%) and 38 (42%) BLS patients were admitted. Principal final diagnoses were seizure (27% ALS vs 38% BLS), hypoglycemia (23% ALS vs 23% BLS), and stroke (22% ALS vs 20% BLS). Remaining diagnoses each constituted less than 7% of total discharge diagnoses. No statistically significant differences in measures of outcome were noted between ALS or BLS patients. Diagnoses of seizure, stroke, and hypoglycemia were studied individually. No differences in admission rate, mortality rate, or disposition were identified. Hypoglycemic patients conveyed by ALS providers had significantly shorter emergency department treatment times than did those transported by BLS providers (160 +/- 62 minutes ALS vs 229 +/- 67 minutes BLS [p < 0.005]).<br><br>CONCLUSION: Advanced life support levels of care of patients with an ALOC does not significantly change outcome compared with those receiving BLS care with the exception of shorter emergency department treatment times for hypoglycemic patients.}, }
@article {pmid8815180, year = {1996}, author = {Veugelers, B and Theys, P and Lammens, M and Van Hees, J and Robberecht, W}, title = {Pathological findings in a patient with amyotrophic lateral sclerosis and multifocal motor neuropathy with conduction block.}, journal = {Journal of the neurological sciences}, volume = {136}, number = {1-2}, pages = {64-70}, doi = {10.1016/0022-510x(95)00295-d}, pmid = {8815180}, issn = {0022-510X}, mesh = {Action Potentials/physiology ; Amyotrophic Lateral Sclerosis/drug therapy/*pathology/physiopathology ; Brachial Plexus/pathology/physiopathology ; Cyclophosphamide/therapeutic use ; Electromyography ; Electrophysiology ; Fatal Outcome ; Female ; Humans ; Immunosuppressive Agents/therapeutic use ; Middle Aged ; Motor Neuron Disease/drug therapy/*pathology/physiopathology ; Muscle Weakness/drug therapy/pathology/physiopathology ; Neural Conduction/drug effects/*physiology ; Paralysis/pathology/physiopathology ; Spinal Cord/pathology/physiopathology ; }, abstract = {We studied a 53-year-old woman with progressive weakness of the left arm, gradually spreading to the other limbs. Neurological examination revealed a motor neuron syndrome with paresis, fasciculations and atrophy. Electrophysiological studies showed multiple motor conduction blocks. The anti-GM1 IgM titer was elevated. The patient was thought to have a multifocal motor neuropathy. Despite intravenous cyclophosphamide treatment, however, she died with respiratory insufficiency. On postmortem examination, the brachial plexus showed patches of demyelination underlying different areas of motor conduction block. The spinal cord, however, revealed severe neuronal loss in the ventral horn and axonal loss in the corticospinal tract, indicative of amyotrophic lateral sclerosis. Demyelination of peripheral nerves could have been responsible for the other conduction blocks in this patient. The prominent degeneration of motor neurons, however, must also have played a role in the clinical picture. Some patients with the syndrome of a multifocal motor neuropathy may have MND rather than, or in addition to, a demyelinating peripheral motor neuropathy.}, }
@article {pmid8772589, year = {1996}, author = {Katz, LE and Liu, F and Baker, B and Agus, MS and Nunn, SE and Hintz, RL and Cohen, P}, title = {The effect of growth hormone treatment on the insulin-like growth factor axis in a child with nonislet cell tumor hypoglycemia.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {81}, number = {3}, pages = {1141-1146}, doi = {10.1210/jcem.81.3.8772589}, pmid = {8772589}, issn = {0021-972X}, mesh = {Adenoma, Islet Cell/complications ; Carrier Proteins/blood ; Child, Preschool ; Endopeptidases/blood ; Female ; Glycoproteins/blood ; Growth Hormone/*therapeutic use ; Humans ; Hypoglycemia/*blood/etiology ; Insulin-Like Growth Factor Binding Proteins/blood ; Neuroblastoma/*complications/congenital ; Somatomedins/*metabolism ; }, abstract = {We have previously described a case of tumor-associated hypoglycemia secondary to the production of high molecular weight insulin-line growth factor (IGF)-II in a child with congenital neuroblastoma. The child's hypoglycemia resolved with GH therapy and has continued to be well controlled for 1 yr. This represents one of the first cases of nonislet cell tumor hypoglycemia (NICTH) treated successfully with long-term exogenous GH. We now present an in-depth analysis of the IGF axis in this patient, before and after GH treatment. Although IGF-II levels at presentation were in the normal range, they were inappropriate for the patient's low GH state. Furthermore, the percentage of "big" IGF-II was elevated, as was the level of the IGF-IIE peptide, which is normally cleaved in the processing of the mature peptide. On the initial evaluation, GH levels failed to rise in response to hypoglycemia, IGF-I levels were low, IGF binding protein-3 (IGFBP-3) levels were suppressed, and IGFBP-2 levels were elevated. We have shown that baseline IGFBP-3 levels were low by RIA and immunoblotting and have demonstrated that this decrease was not associated with IGFBP protease activity. We have also demonstrated the baseline suppression of the acid labile subunit (ALS) of the 150K ternary complex by a novel immunoblot assay. The ratio of IGFs to IGFBP-3 was dramatically elevated, presumably leading to hypoglycemia. Furthermore, the percentage of serum IGF-I and IGF-II present as part of a binary (50K) complex with IGFBPs was also increased. GH therapy resulted in a normalization of the levels of blood sugars, IGFBP-3, ALS, IGFBP-2, and IGF-I, as well as the IGF/IGFBP-3 ratio. In summary, we have presented evidence that the hypoglycemia in this patient resulted from tumor production of high molecular weight IGF-II, which suppressed GH secretion, leading to the described derangements in the IGF binding proteins. We speculate that as a result of the decreased IGFBP-3 and ALS levels, the IGF population was shifted from the stable 150K complex to lower molecular weight complexes with IGF binding proteins, increasing IGF availability to tissues due to rapid turnover of these low molecular weight complexes. We demonstrated the reversal of the abnormalities in the IGFBP levels with GH treatment, corresponding to the clinical response of euglycemia.}, }
@article {pmid8754163, year = {1996}, author = {Popova, LM}, title = {[Prolonged artificial ventilation of the lungs in nervous system diseases].}, journal = {Anesteziologiia i reanimatologiia}, volume = {}, number = {2}, pages = {4-9}, pmid = {8754163}, issn = {0201-7563}, mesh = {Adolescent ; Adult ; Child ; Female ; Humans ; Male ; Middle Aged ; Nervous System Diseases/*complications ; *Respiration, Artificial ; Respiratory Insufficiency/*etiology/*therapy ; Time Factors ; Ventilators, Mechanical ; }, abstract = {Artificial ventilation of the lungs (AVL) has been carried out for many years in 25 patients with nervous diseases. Spontaneous respiration ceased because of peripheral neuron involvement in malignant myasthenia (5 cases), chronic polyneuropathy (1), paralysis of motor muscles after poliomyelitis (1), amyotrophic lateral sclerosis (11), spinopontocerebellar atrophy (1), and because of the central neuron involvement in 5 patients, 3 of these with the apnea syndrome during sleeping caused by syringobulbomyelia, atrophic process in the cerebellum and stem, and Arnold-Chiari's syndrome, and 2 with an extensive infarction in the pons (deefferentiation or locked-in syndrome). AVL was the longest in patients with paralysis of the motor muscles following acute poliomyelitis (23 years) and with amyotrophic lateral sclerosis (about 14 years). Prolonged AVL is possible in malignant myasthenia, but it may be discontinued during obligatory specific treatment. Specific features of many-year AVL, somatic functions and metabolic disorders associated with it are described.}, }
@article {pmid8664560, year = {1996}, author = {Miller, RG and Shepherd, R and Dao, H and Khramstov, A and Mendoza, M and Graves, J and Smith, S}, title = {Controlled trial of nimodipine in amyotrophic lateral sclerosis.}, journal = {Neuromuscular disorders : NMD}, volume = {6}, number = {2}, pages = {101-104}, doi = {10.1016/0960-8966(95)00024-0}, pmid = {8664560}, issn = {0960-8966}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Nimodipine/adverse effects/*therapeutic use ; Prognosis ; }, abstract = {Calcium channel blocking drugs antagonize excitatory amino acid receptor activation, decrease calcium entry into damaged neurons, and might help to slow or reverse amyotrophic lateral sclerosis (ALS). We enrolled 87 patients with ALS in a randomized, placebo-controlled, prospective, double-blind crossover study of nimodipine therapy. Monthly measures of isometric muscle strength and respiratory function compared the effects of drug and placebo. No difference in adverse events occurred in placebo vs drug-treated patients, but diarrhoea, nausea, and lightheadedness were more common with nimodipine. There was no significant difference in the rate of decline of pulmonary function or limb strength during treatment with drug or placebo. Nimodipine was ineffective in slowing the progress of ALS.}, }
@article {pmid8967757, year = {1996}, author = {Miller, RG and Petajan, JH and Bryan, WW and Armon, C and Barohn, RJ and Goodpasture, JC and Hoagland, RJ and Parry, GJ and Ross, MA and Stromatt, SC}, title = {A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group.}, journal = {Annals of neurology}, volume = {39}, number = {2}, pages = {256-260}, doi = {10.1002/ana.410390215}, pmid = {8967757}, issn = {0364-5134}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*drug therapy ; Ciliary Neurotrophic Factor ; Dose-Response Relationship, Drug ; Double-Blind Method ; Humans ; Middle Aged ; Nerve Growth Factors/therapeutic use ; Nerve Tissue Proteins/adverse effects/*therapeutic use ; Prospective Studies ; Recombinant Proteins ; Survival Analysis ; }, abstract = {Preclinical investigations indicated that recombinant human ciliary neurotrophic factor (rhCNTF) may have potential as therapy for amyotrophic lateral sclerosis (ALS). We evaluated the safety and efficacy of rhCNTF in a prospective, double-blind, placebo-controlled trial in 570 patients with ALS. Patients were randomized to receive 0.5, 2, or 5 micrograms/kg/day rhCNTF, or placebo, for 6 months. The primary efficacy end point was the change from baseline to the last on-treatment value of a combination megascore for limb strength (maximum voluntary isometric contraction) and pulmonary function. Secondary end points included individual arm and leg megascores, pulmonary function tests, an activities-of-daily-living outcome measure, and survival. The four treatment groups were similar at baseline with respect to age, sex, disease duration, and muscle strength values. At all doses tested, rhCNTF had no beneficial effect on the primary or secondary end points. Certain adverse events, as follows, appeared to be dose related: injection site reactions, cough, asthenia, nausea, anorexia, weight loss, and increased salivation. There was an increased number of deaths at the highest dose level. rhCNTF had no beneficial effect on any measure of ALS progression. There were increased adverse events in the 5 micrograms/kg group and increased deaths.}, }
@article {pmid8750546, year = {1996}, author = {Meucci, N and Nobile-Orazio, E and Scarlato, G}, title = {Intravenous immunoglobulin therapy in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {243}, number = {2}, pages = {117-120}, pmid = {8750546}, issn = {0340-5354}, support = {486/TI_/Telethon/Italy ; }, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*therapy ; Female ; Humans ; Immunoglobulins, Intravenous/*therapeutic use ; Male ; Middle Aged ; Prognosis ; Time Factors ; }, abstract = {Seven consecutive patients with amyotrophic lateral sclerosis (ALS) were treated with intravenous immunoglobulins (IVIg; 0.4 g/kg per day for 5 consecutive days followed by monthly 2-day infusions at the same daily dosage) continued with oral cyclophosphamide (1-2 mg/kg per day), for 4-13 months (mean 8.1). Response to treatment was assessed by means of the Medical Research Council (MRC) rating scale for muscle strength on 40 muscles (10 per limb), a clinical scale for bulbar function and a modified Rankin disability scale. All patients continued to deteriorate during treatment on as regards both their MRC score and either their bulbar or Rankin score or both. The progression of the disease during treatment, expressed as the monthly variation in MRC score (mean = -2.71; SD = 1.36), was no slower than that estimated before therapy (mean = -1.81; SD = 0.93). Even if the results of this small, uncontrolled study do not permit the exclusion of an effect of IVIg on the progression of ALS, they also do not provide any evidence that this expensive form of therapy consistently slows the course of the disease.}, }
@article {pmid8639063, year = {1996}, author = {}, title = {The Amyotrophic Lateral Sclerosis Functional Rating Scale. Assessment of activities of daily living in patients with amyotrophic lateral sclerosis. The ALS CNTF treatment study (ACTS) phase I-II Study Group.}, journal = {Archives of neurology}, volume = {53}, number = {2}, pages = {141-147}, pmid = {8639063}, issn = {0003-9942}, mesh = {*Activities of Daily Living ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Cross-Sectional Studies ; Female ; Humans ; Longitudinal Studies ; Lung/physiopathology ; Male ; Middle Aged ; Muscle, Skeletal/physiopathology ; Predictive Value of Tests ; Reproducibility of Results ; United States ; }, abstract = {OBJECTIVES: To test the utility of a new, easy to administer instrument for assessing activities of daily living in patients with amyotrophic lateral sclerosis (ALS), to validate its accuracy, and to assess its ability to record disease progression in patients with ALS against other functional scales, quantitative isometric muscle testing, and global assessment scales.<br><br>DESIGN: Serial assessments of patients who presented to four ALS treatment centers in two multicenter studies.<br><br>PATIENTS: Study 1 (cross-sectional) evaluated 75 consecutive patients who presented to four ALS treatment centers during a 2-month period. Study 2 (longitudinal) evaluated the progression of 53 patients who were enrolled in a multicenter, phase I-II clinical trial of recombinant human ciliary neurotrophic factor for treatment of ALS.<br><br>OUTCOME MEASURES: The ALS Functional Rating Scale (ALSFRS) was compared with quantitative myometry and with other measures of daily function in patients with ALS both cross-sectionally and longitudinally.<br><br>RESULTS: The first study of 75 patients evaluated the internal consistency, the test-retest reliability, and the construct validity of the ALSFRS. Internal consistency and test-retest reliability were high. Patient self-rating of upper- and lower-extremity-dependent tasks were highly correlated with measures of upper- and lower-extremity strength, respectively. Thus, the ALSFRS has good construct validity. In the second study, ALSFRS scores declined in tandem with deterioration in motor and pulmonary function, indicating its sensitivity to change.<br><br>CONCLUSIONS: The ALSFRS is a useful instrument for evaluation of functional status and functional change in patients with ALS. Its results are in close agreement with objective measures of muscle strength and pulmonary function. The ALSFRS may be used as a screening measure for entry into clinical trials, as a surrogate measure of function in situations in which muscle strength cannot be measured directly, or as an adjunct to myometry.}, }
@article {pmid9012210, year = {1996}, author = {Bernat, E}, title = {[Legal limits of assisted death: exemplified by amyotrophic lateral sclerosis].}, journal = {Wiener medizinische Wochenschrift (1946)}, volume = {146}, number = {9-10}, pages = {195-198}, pmid = {9012210}, issn = {0043-5341}, mesh = {Amyotrophic Lateral Sclerosis/*psychology ; Austria ; *Ethics, Medical ; Euthanasia, Passive/*legislation &amp; jurisprudence ; Humans ; Life Support Care/*legislation &amp; jurisprudence ; Suicide, Assisted/legislation &amp; jurisprudence ; Terminal Care/legislation &amp; jurisprudence ; Treatment Refusal/legislation &amp; jurisprudence ; }, abstract = {The article discusses the question to what extent the physician may offer aid in dying to the terminally ill patient. The author comes to the conclusion that the withdrawal of artificial ventilation (after application of anesthesia) is allowed and even a physician's duty if the patient refuses further ventilation. Because the competent patient may refuse treatment at any time, a doctor's willful disregard of his patient's right to self-determination could also be regarded as battery [section 110 Penal Code).}, }
@article {pmid9012209, year = {1996}, author = {Meran, JG and Hamm, M and Ganser, A}, title = {[Patient education--support--help with decisions: ethical aspects in treatment of amyotrophic lateral sclerosis].}, journal = {Wiener medizinische Wochenschrift (1946)}, volume = {146}, number = {9-10}, pages = {190-194}, pmid = {9012209}, issn = {0043-5341}, mesh = {Amyotrophic Lateral Sclerosis/psychology/*therapy ; *Ethics, Medical ; Euthanasia ; Euthanasia, Passive ; Humans ; *Palliative Care ; *Patient Education as Topic ; *Physician-Patient Relations ; Respiratory Insufficiency/psychology/therapy ; *Sick Role ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) develop progressive, degenerative loss of muscle function while retaining mental capacity. This implies special problems of patient information, which should be phase-adapted and patient centered. The difficult task of the physicians requires to provide sufficient information, to enable shared decision-making, without leaving the patient alone. Respiratory failure due to loss of muscle function is often the limiting problem. However, the possible option of ventilatory support opens the question when to stop treatment. It is most important to differentiate between intended mercy-killing and foregoing treatment due to the patient's wish. Discontinuation of treatment is morally justifiable, even required, if the patient refuses further treatment. Advance directives may be helpful to make decisions according to patients' preferences in time.}, }
@article {pmid9012208, year = {1996}, author = {Mamoli, B}, title = {[Medical intensive care aspects in treatment of amyotrophic lateral sclerosis].}, journal = {Wiener medizinische Wochenschrift (1946)}, volume = {146}, number = {9-10}, pages = {188-190}, pmid = {9012208}, issn = {0043-5341}, mesh = {Amyotrophic Lateral Sclerosis/mortality/physiopathology/*therapy ; *Critical Care ; Humans ; Life Support Care ; Motor Neurons/physiology ; Patient Education as Topic ; Quality of Life ; *Respiration, Artificial ; Respiratory Muscles/innervation ; Survival Rate ; }, abstract = {Whereas it would be preferable to inform patients with amyotrophic lateral sclerosis (ALS) as early as possible about the possibilities of ventilatory support, not all of them are able to bear the required thorough information on the consequences of the diagnosis. The procedure therefore has to be individualized. Questionnaire studies have revealed, that in general patients hold the opinion that they themselves should decide, whether or not artificial ventilation should be applied. The non-invasive artificial home ventilation has led to advances in the management of patients with ALS, as a longer period of survival with a higher level of quality of life can be achieved. On the other hand, according to the author's opinion. Invasive artificial ventilation can not be the primary goal of medical support in the context of the prognosis (progressive differentiation). Much more this should focus on the appropriate steps to warrant increase of period of survival under conditions of at least minimal quality of life. Other opinions however have to be respected. Appropriate procedures for prevention and therapy of respiratory dysfunctions are discussed.}, }
@article {pmid8988464, year = {1996}, author = {Kuhn, W and Müller, T}, title = {The clinical potential of Deprenyl in neurologic and psychiatric disorders.}, journal = {Journal of neural transmission. Supplementum}, volume = {48}, number = {}, pages = {85-93}, doi = {10.1007/978-3-7091-7494-4_8}, pmid = {8988464}, issn = {0303-6995}, mesh = {Adult ; Aged ; Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Antidepressive Agents/therapeutic use ; Antipsychotic Agents/therapeutic use ; Child ; Clinical Trials as Topic ; Cross-Over Studies ; Depression/drug therapy ; Double-Blind Method ; Humans ; Mental Disorders/*drug therapy ; Middle Aged ; Monoamine Oxidase Inhibitors/therapeutic use ; Narcolepsy/drug therapy ; Nervous System Diseases/*drug therapy ; Neuroprotective Agents/*therapeutic use ; Nootropic Agents/*therapeutic use ; Parkinson Disease, Secondary/drug therapy ; Schizophrenia/drug therapy ; Selegiline/*therapeutic use ; Supranuclear Palsy, Progressive/drug therapy ; Tourette Syndrome/drug therapy ; Treatment Outcome ; }, abstract = {This article reviews the results of clinical studies with Deprenyl in various neurologic and psychiatric disorders except Parkinson's disease. Promising results could be observed both in narcolepsy in a dose of at least 20 mg/day in three different trials and in one study of Tourette's syndrome including attention hyperactivity disorders using an average dosis of 8.1 mg/ day. Controversial results were reported for Alzheimer's disease. On the one hand significant improvement of cognitive functions was found by various authors. On the other hand in a more recent study no effect on the progression of the disease could be observed. For depression a higher dosage of deprenyl between 30 to 60 mg/day appears to be necessary for effective treatment. No positive results were found in amyotrophic lateral sclerosis and in tardive dyskinesias.}, }
@article {pmid8959868, year = {1996}, author = {Marquet, RL and de Bruin, RW and IJzermans, JN}, title = {Induction of specific inhibition of alloreactivity in beagle dogs by intrathymic injection of donor splenocytes.}, journal = {Transplant international : official journal of the European Society for Organ Transplantation}, volume = {9 Suppl 1}, number = {}, pages = {S379-81}, doi = {10.1007/978-3-662-00818-8_92}, pmid = {8959868}, issn = {0934-0874}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; *Cell Transplantation ; Dogs ; Female ; Immune Tolerance ; Lymphocyte Culture Test, Mixed ; Male ; Spleen/*cytology ; Thymus Gland/*immunology ; }, abstract = {The aim of this study was to investigate whether intrathymic injection (ITI) of donor splenocytes in dogs might lead to specific immunomodulation as assessed by mixed lymphocyte culture (MLC) tests. Two groups of five beagles each were used. Group 1 contained animals that were 2 years old, group 2 consisted of animals that were 6 months old. One animal was splenectomized per experimental group and 1 x 10(9) splenocytes were injected into the thymic lobes or thymic remnant of the four remaining dogs. On the day of ITI the dogs were treated subcutaneously with a single dose of 2 ml/kg antilymphocyte serum (ALS). In group 1 the thymus of all dogs was found to be atrophic. ITI in this group did not result in a decreased immunoreactivity but rather in an enhanced immune response. In group 2 the thymus was still clearly present and ITI was easy to perform. ITI induced a significant reduction of specific MLC reactivity at 1 week after treatment. The effect was transient and not significantly further diminished at week 2. These results indicate that ITI is a technically feasible procedure in a preclinical animal model. It may induce temporary sensitization as well as immunosuppression, possibly depending on the age of the recipient.}, }
@article {pmid8950621, year = {1996}, author = {Baxter, RC}, title = {The role of insulin-like growth factors and their binding proteins in tumor hypoglycemia.}, journal = {Hormone research}, volume = {46}, number = {4-5}, pages = {195-201}, doi = {10.1159/000185023}, pmid = {8950621}, issn = {0301-0163}, mesh = {Humans ; Hypoglycemia/drug therapy/*etiology ; Insulin/blood ; Insulin-Like Growth Factor Binding Protein 3/physiology ; Insulin-Like Growth Factor Binding Proteins/*physiology ; Insulin-Like Growth Factor I/*physiology ; Insulin-Like Growth Factor II/*physiology ; Neoplasms/*complications/physiopathology ; }, abstract = {Tumors of nonislet cell origin may overexpress insulin-like growth factor (IGF)-II, leading to hypoglycemia with suppressed serum insulin levels (NICTH). Most of the serum IGF-II in NICTH patients is in precursor forms of 10-15 kD, and may be abnormally glycosylated. In NICTH, IGFs and IGF-binding protein-3 (IGFBP-3) are mainly found in binary complexes of 50-60 kD, instead of the normal ternary complex of about 140 kD with the acid-labile subunit (ALS). Factors contributing to the defect are: (1) low ALS levels, secondary to suppressed growth hormone (GH); (2) defective IGFBP-3 binding to ALS; (3) reduced ability of pro-IGF-II forms to complex normally, and (4) very high levels of other IGFBPs, including IGFBP-2 and IGFBP-6, which might limit the formation of complexes with IGFBP-3. While both GH and glucocorticoids can restore normoglycemia and increase high-molecular-weight IGFBP-3 complexes, corticosteroid treatment suppresses tumor IGF-II, whereas GH can restore normoglycemia despite continuing high IGF-II levels. Both treatments increase serum ALS, IGFBP-3, and IGF-I levels, and decrease IGFBP-2, whereas IGFBP-6 is unaffected. The reversal of hypoglycemia, by surgery, GH, or glucocorticoid treatment, is always accompanied by improved ternary complex formation, emphasizing the importance of the components of this complex, in particular ALS, in normal blood sugar regulation.}, }
@article {pmid8873431, year = {1996}, author = {Hugon, J}, title = {Riluzole and ALS therapy.}, journal = {Wiener medizinische Wochenschrift (1946)}, volume = {146}, number = {9-10}, pages = {185-187}, pmid = {8873431}, issn = {0043-5341}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality/physiopathology ; Double-Blind Method ; Excitatory Amino Acid Antagonists/*therapeutic use ; Glutamic Acid/metabolism ; Humans ; Motor Neurons/drug effects/physiology ; Neurologic Examination ; Riluzole ; Survival Analysis ; Thiazoles/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurological disorder clinically characterized by progressive muscle weakness, amyotrophy, fasciculations and signs of corticospinal tract deficits. The cause is unknown but several hypotheses are currently proposed. In familial forms of ALS, a mutation of the Cu-Zn superoxide dismutase gene was reported in some patients. Autoimmunity and neurofilament dysfunction were also observed. The last hypothesis is linked to excitotoxicity. This cellular phenomenon is associated with the overstimulation of glutamate post-synaptic receptors, leading to neuronal degeneration. Abnormal glutamate metabolism was also discovered in ALS patients. In these conditions, riluzole, a pharmacological agent that reduces glutamate release from nerve terminals, was administered to ALS patients. Riluzole is an anti-convulsant and a neuroprotective agent and specifically blocks sodium channels in their inactivated states. In a recent double blind placebo controlled study, riluzole was given to 77 patients (placebo 78 patients). After 1 year of treatment 58% of the placebo-treated patients were still alive compared to 74% of patients treated with riluzole. The prolonged survival was significant in the overall population and in the bulbar-onset group.}, }
@article {pmid8866126, year = {1996}, author = {Vaught, JL and Contreras, PC and Glicksman, MA and Neff, NT}, title = {Potential utility of rhIGF-1 in neuromuscular and/or degenerative disease.}, journal = {Ciba Foundation symposium}, volume = {196}, number = {}, pages = {18-27; discussion 27-38}, doi = {10.1002/9780470514863.ch3}, pmid = {8866126}, issn = {0300-5208}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Cells, Cultured ; Choline O-Acetyltransferase/metabolism ; Disease Models, Animal ; Female ; Humans ; Insulin-Like Growth Factor I/metabolism/*pharmacology ; Mice ; Motor Neurons/cytology/*drug effects/metabolism ; Nerve Degeneration ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins/pharmacology ; Spinal Cord/embryology ; }, abstract = {Neuromuscular/neurodegenerative disorders, such as the death of spinal cord motor neurons in amyotrophic lateral sclerosis (ALS) or the degeneration of spinal cord motor neuron axons in certain peripheral neuropathies, present a unique opportunity for therapeutic intervention with neurotrophic proteins. We have found that in mixed rat embryonic spinal cord cultures or in purified motor neuron preparations, recombinant human insulin-like growth factor 1 (rhIGF-1) enhances the survival of motor neurons at EC50 concentrations of 2 nM, consistent with an interaction at the tyrosine kinase-coupled rhIGF-1 receptor. In a model of programmed cell death in ovo, administration of rhIGF-1 produces a marked survival of motor neurons. In a variety of models of predominantly motor neuron or nerve injury in rodents, administration of rhIGF-1 prevents the death of motor neurons in neonatal facial nerve lesions, attenuates the loss of cholinergic phenotype in adult hypoglossal nerve axotomy and hastens recovery from sciatic nerve crush in mice. In a genetic model of motor neuron compromise, the wobbler mouse, rhIGF-1 (1 mg/kg s.c. daily) delayed the deterioration of grip strength and provided for a more normal distribution of fibre types. In addition, rhIGF-1 (0.3-1.0 mg/kg s.c. daily) prevents the motor and/or sensory neuropathy in rodents caused by vincristine, cisplatinum or Taxol. These combined data indicate that rhIGF-1 has marked effects on the survival of compromised motor neurons and the maintenance of their axons and functional connections. They also suggest the potential utility of rhIGF-1 for the treatment of diseases such as ALS and certain neuropathies.}, }
@article {pmid8821185, year = {1996}, author = {Johnston, M and Earll, L and Mitchell, E and Morrison, V and Wright, S}, title = {Communicating the diagnosis of motor neurone disease.}, journal = {Palliative medicine}, volume = {10}, number = {1}, pages = {23-34}, doi = {10.1177/026921639601000105}, pmid = {8821185}, issn = {0269-2163}, mesh = {*Adaptation, Psychological ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/complications/psychology ; *Attitude to Health ; *Communication ; Cross-Sectional Studies ; England ; Female ; Humans ; Male ; Middle Aged ; Mood Disorders/complications ; Motor Neuron Disease/complications/*psychology ; *Physician-Patient Relations ; Scotland ; Self Concept ; Severity of Illness Index ; Time Factors ; }, abstract = {Communication of the diagnosis of motor neurone disease (MND) is a particularly difficult task for doctors in view of the poor prognosis and the lack of significant treatment. This study examined patients' views of being given the diagnosis and of how it was communicated. Fifty people who had been diagnosed with MND more than six months previously were interviewed about their experience of the diagnosis. The majority reported positive aspects of being told, especially having a label for their condition. The most frequently mentioned critical aspect of how they were told was the directness and clarity with which they were given the information. Patients were more critical if the diagnosis was worse than expected (as it was for most patients) and more satisfied if they felt they had been able to ask questions. There was no evidence that unsatisfactory communications were associated with later mood disturbance. A longitudinal study is recommended to overcome limitations in this cross-sectional design.}, }
@article {pmid8773148, year = {1996}, author = {Greiner, A and Schmausser, B and Petzold, K and Krüger, H and Marx, A}, title = {Neuronal targets of serum and cerebrospinal fluid autoantibodies in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {91}, number = {1}, pages = {67-71}, doi = {10.1007/s004010050393}, pmid = {8773148}, issn = {0001-6322}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*immunology/pathology ; Autoantibodies/*blood/*cerebrospinal fluid ; Female ; Fetus ; Humans ; Immunohistochemistry ; Infant, Newborn ; Male ; Middle Aged ; Neurons/*immunology/pathology ; }, abstract = {Sera and cerebrospinal fluid (CSF) from 25 patients with amyotrophic lateral sclerosis (ALS) were tested by immunofluorescence on fetal, juvenile and adult central and peripheral neuronal (CNS/PNS) tissues and on nerve biopsy material from affected patients for the presence of autoantibodies. Results were compared with control sera from normal blood donors (n = 45) and patients with other neurological diseases (OND) (n = 11). Three different types of tissue reactivity (glial, axonal, and small blood vessels) were found. Antibodies binding to glial and axonal structures were found in 32% of ALS patients as compared to 12% in normal and 27% in OND controls. In contrast, staining of endothelial cells was found with 24% of ALS sera and CSF but not with normal and OND control sera and was demonstrated only with fetal and juvenile nervous tissue and with suralis nerve biopsies of two of five ALS patients. However, normal or inflamed adult CNS/PNS tissue was not stained with these sera. We conclude that ALS is most likely a heterogeneous group of diseases and only a subgroup of ALS may have an autoimmune pathogenesis. These findings may, therefore, have implications for the evaluation of any immunosuppressive treatment in ALS.}, }
@article {pmid8741231, year = {1996}, author = {Festoff, BW}, title = {Amyotrophic lateral sclerosis: current and future treatment strategies.}, journal = {Drugs}, volume = {51}, number = {1}, pages = {28-44}, pmid = {8741231}, issn = {0012-6667}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Apoptosis/drug effects ; Ciliary Neurotrophic Factor ; Clinical Trials as Topic ; Humans ; Insulin-Like Growth Factor I/therapeutic use ; Nerve Tissue Proteins/therapeutic use ; Riluzole ; Thiazoles/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, enigmatic disorder characterised by relentless progression of muscle wasting and weakness until death ensues due to respiratory muscle failure. Intellectual functions are usually spared. ALS, known also as motor neuron disease (MND) in the UK, maladie de Charcot in France and Lou Gehrig's disease in the US, is usually sporadic, but between 5 and 10% of all cases are hereditary, usually inherited as autosomal dominant. Previously thought to be untreatable, as well as incurable, just in the last 3 years ALS has been the greatest clinical application of recent exciting break-throughs in preclinical neurobiology research. Although definitive information regarding the cause(s) and pathogenesis of ALS still escapes us, meaningful demonstration of intercession in the downhill course with specific therapy has been suggested, giving reason to be hopeful, if cautiously and critically optimistic. This review focuses on the recent work from the fields of growth/trophic factors, glutamate/neurotoxicity, neuroprotection and proteases and inhibitors, as well as the approaches to measuring specific effects in patients with the illness. It ends with a eye to the horizon, and the future, and where ALS treatment strategies may be heading after the millennium.}, }
@article {pmid8838230, year = {1995}, author = {Aguilera, AJ}, title = {Molecular genetic advances in neurodegenerative disorders.}, journal = {Clinics in laboratory medicine}, volume = {15}, number = {4}, pages = {915-926}, pmid = {8838230}, issn = {0272-2712}, mesh = {Alzheimer Disease/etiology/genetics/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; DNA Mutational Analysis ; Genetics, Medical ; Humans ; Huntington Disease/genetics/pathology ; Nerve Degeneration ; Nervous System Diseases/*diagnosis/genetics/therapy ; }, abstract = {Advances in molecular genetics have had a major impact on our understanding of the pathogenesis of neurologic disorders. This article discusses molecular genetic contributions to our knowledge of Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease, as well as their implications for diagnosis and treatment. Specific, sensitive testing for Huntington's disease is now possible; elucidation of the pathogenesis of familial amyotrophic lateral sclerosis has been achieved and has launched promising drug trials; and the heterogeneity and pathogenetic complexity of Alzheimer's disease have been revealed.}, }
@article {pmid8787463, year = {1995}, author = {Shen, Z and Mohiuddin, M and DiSesa, VJ}, title = {Suppressor cells and intrathymic inoculation of donor alloantigens in cardiac transplantation.}, journal = {The Annals of thoracic surgery}, volume = {60}, number = {6}, pages = {1683-1685}, doi = {10.1016/0003-4975(95)00714-8}, pmid = {8787463}, issn = {0003-4975}, mesh = {Animals ; Antilymphocyte Serum/administration &amp; dosage/immunology ; Cell Transplantation ; Graft Rejection ; Heart Transplantation/*immunology ; Immune Tolerance ; Immunization, Passive ; Injections ; Isoantigens/*administration &amp; dosage/immunology ; Male ; Rats ; Rats, Inbred BN ; Rats, Inbred Lew ; Rats, Inbred WF ; Spleen/cytology ; T-Lymphocytes, Regulatory/*immunology ; Thymus Gland ; Tissue Donors ; Transplantation, Heterotopic ; Transplantation, Homologous ; }, abstract = {BACKGROUND: Donor-specific tolerance to a rat heterotopic cardiac allograft has been achieved by the pretransplantation intrathymic injection of donor splenocytes and a single intraperitoneal injection of antilymphocyte serum (ALS). Permanent tolerance is achieved without subsequent immunosuppression therapy. This study investigated the mechanisms responsible for maintenance of the tolerant state.<br><br>METHODS: Tolerance was produced in Lewis rats by the administration of 1 mL of ALS intraperitoneally and 5 x 10(7) Lewis Brown Norway (LBN) splenocytes intrathymically 21 days before heterotopic transplantation using an LBN donor.<br><br>RESULTS: In tolerant Lewis rats bearing LBN allografts for more than 100 days, rejection could not be produced by the intravenous injection of naive Lewis spleen cells (5 x 10(7) cells x 1 day, n = 5; 5 x 10(7) cells x 3 days, n = 5) or cells from Lewis rats sensitized to LBN tissues (5 x 10(7) cells x 3 days, n = 5). Naive Lewis recipients were pretreated with ALS and 6 days later with intravenous spleen cells (25 x 10(7), n = 5) or lymphoid cells (10 to 15 x 10(7), n = 5) from a tolerant animal bearing a viable LBN graft. When transplantation with an LBN donor was done the next day, significant prolongation of LBN allograft survival (mean survival time 32.8 days, p < 0.01; and 22.2 days, p < 0.01; respectively) was seen. Wistar-Furth allograft survival was not prolonged by treatment with ALS and intravenous spleen (n = 5) or lymph node (n = 5) cells from rats tolerant to LBN tissues (mean survival time 8.6 and 9.2 days, control 9 days; p = not significant). The administration of ALS alone (n = 5) did not prolong LBN graft survival (mean survival time 11.8 days).<br><br>CONCLUSION: These data suggest that transferable suppressor cells specific for the donor strain are at least in part responsible for the maintenance of long-term allograft survival after intrathymic pretreatment with allogeneic cells.}, }
@article {pmid8752462, year = {1995}, author = {Tayama, N}, title = {[Dysphagia in amyotrophic lateral sclerosis--the mechanism and managements].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {35}, number = {12}, pages = {1557-1559}, pmid = {8752462}, issn = {0009-918X}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Deglutition Disorders/*etiology/*prevention &amp; control ; Humans ; *Laryngectomy ; Pneumonia, Aspiration/etiology/prevention &amp; control ; Prognosis ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) raises progressive dysphagia that causes aspiration. This diseases affects oral phase first and then pharyngeal phase of swallowing. Aspiration pneumonia by dysphagia becomes major problem from clinical aspect to cause aggravation of vital prognosis. We explain the mechanism of dysphagia from deglutition dynamics and discuss the clinical managements. Several functional operations such as cricopharyngeal myotomy, laryngeal suspension and so forth, have been applied to prevent aspiration, with satisfactory results in cases with mild dysphagia. However, in cases of ALS patients with severe aspiration, the results are poor. Then we have to divide airway from digestive tract completely to prevent aspiration by laryngectomy. However, the larynx is a multi-functional organ, loss of the larynx does improve the swallowing but loose phonatory function. We need to evaluate a deglutition function before starting of treatments of dysphagia. Besides, we also need to put hopes and life style of patients in consideration. We have to be very careful to choose the way of surgical treatment and the time of operation. We can conclude that laryngectomy is useful for vital prognosis and amelioration of QOL in ALS patients.}, }
@article {pmid8747838, year = {1995}, author = {Iwasaki, Y and Ikeda, K and Shiojima, T and Kinoshita, M}, title = {CNQX prevents spinal motor neuron death following sciatic nerve transection in newborn rats.}, journal = {Journal of the neurological sciences}, volume = {134}, number = {1-2}, pages = {21-25}, doi = {10.1016/0022-510x(95)00217-6}, pmid = {8747838}, issn = {0022-510X}, mesh = {2-Amino-5-phosphonovalerate/pharmacology ; 6-Cyano-7-nitroquinoxaline-2,3-dione/*pharmacology ; Animals ; Animals, Newborn ; Dizocilpine Maleate/pharmacology ; Excitatory Amino Acid Antagonists/*pharmacology ; Motor Neurons/*drug effects/pathology ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/*antagonists &amp; inhibitors ; Sciatic Nerve/*physiology ; Spinal Cord/*drug effects/pathology ; }, abstract = {A rapid and reproducible spinal motor neuron death occurs after sciatic nerve transection in neonatal rats. This neuronal death could be due to lack of retrogradely transported target derived neurotrophic factors, such as ciliary neurotrophic factor, brain-derived neurotrophic factor, leukemia inhibitory factor and glial cell line-derived neurotrophic factor. Another hypothesis suggests that glutamate and its receptors has been implicated as possible mechanism for motor neuron death. In order to investigate the effect of N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists on axotomy-induced cell death in the spinal motor neurons of neonatal rats, we have studied neuroprotective effects of these receptor antagonists. Newborn rats were anesthetized with hypothermia. Sciatic nerve was transected near the obturator tendon in the left thigh. Animals were then treated daily with MK-801, APV, and CNQX for 14 days with intraperitoneal injections. Control animals received PBS in the same fashion. After the treatment, the number of spinal motor neurons in the L4-6 was counted. MK-801 and APV did not show any significant neuroprotective effect. By contrast, the number of surviving motor neurons was greater in animals that were treated with 1.0, 2.0 and 4.0 mg/kg of CNQX. This neuroprotective effect was not dose-related. We demonstrate that neuroprotective effect of CNQX on axotomized motor neurons, raises a possibility that such a agent may have therapeutic potential in motor neuronopathy and amyotrophic lateral sclerosis.}, }
@article {pmid8681312, year = {1995}, author = {}, title = {A phase I study of recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis. The ALS CNTF Treatment Study (ACTS) Phase I-II Study Group.}, journal = {Clinical neuropharmacology}, volume = {18}, number = {6}, pages = {515-532}, doi = {10.1097/00002826-199512000-00004}, pmid = {8681312}, issn = {0362-5664}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Ciliary Neurotrophic Factor ; Clinical Trials, Phase I as Topic ; Dose-Response Relationship, Drug ; Female ; Humans ; Leukocytes/drug effects ; Male ; Middle Aged ; Nerve Tissue Proteins/*therapeutic use ; }, abstract = {Fifty-seven patients with amyotrophic lateral sclerosis (ALS) were randomly assigned to receive 0.5, 1, 3, 7, 10, or 30 micrograms/kg recombinant human ciliary neurotrophic factor (rHCNTF) or placebo subcutaneously 3 times a week for 2 weeks. Dose-limiting toxicity, consisting of febrile reactions in some patients, fatigue, and nonproductive cough, was observed at a dose level of 30 micrograms/kg. Dose-related changes in parameters of the acute-phase response were noted, consistent with the relationship of CNTF and its receptor system to the cytokine interleukin-6 (IL-6) and its receptor. No adverse neurologic consequences of rHCNTF administration were observed. Antibodies to rHCNTF were observed in sera of most patients tested after 2 weeks of continuous treatment and 4 weeks' withdrawal period. rHCNTF was safe and tolerated within acceptable limits when administered to patients with ALS in this study at doses of up to 30 micrograms/kg 3 times a week for 2 weeks. Further studies to explore the efficacy of rHCNTF in the treatment of human motor neuron diseases are justified.}, }
@article {pmid8681311, year = {1995}, author = {}, title = {The pharmacokinetics of subcutaneously administered recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis: relation to parameters of the acute-phase response. The ALS CNTF Treatment Study (ACTS) Phase I-II Study Group.}, journal = {Clinical neuropharmacology}, volume = {18}, number = {6}, pages = {500-514}, doi = {10.1097/00002826-199512000-00003}, pmid = {8681311}, issn = {0362-5664}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Ciliary Neurotrophic Factor ; Dose-Response Relationship, Drug ; Humans ; Leukocytes/drug effects ; Middle Aged ; Nerve Tissue Proteins/*pharmacokinetics ; }, abstract = {Fifty-seven patients with amyotrophic lateral sclerosis (ALS) were randomly assigned to receive single subcutaneous doses of 0.5, 1, 3, 7, 10, or 30 micrograms/kg recombinant human ciliary neurotrophic factor (rHCNTF) or placebo. Peak plasma concentrations occurred 180 to 260 min after dosing. rHCNTF plasma concentrations then appeared to decay, with an apparent elimination half-life of 120-400 min. Eight of 12 patients who received the highest dose had measurable plasma rHCNTF levels 24 h after dosing. Peak plasma concentrations of rHCNTF in patients receiving 30 micrograms/kg rHCNTF were in the range that has been shown to support the survival of embryonic rat and human motor neurons in tissue culture. Systemic exposure to rHCNTF increased with increasing dose. The elimination of rHCNTF, over the dose range evaluated, appeared to follow first-order processes. Elevations in body temperature and evidence of activation of the acute phase response were observed.}, }
@article {pmid8968216, year = {1995}, author = {Kornberg, AJ and Pestronk, A}, title = {Chronic motor neuropathies: diagnosis, therapy, and pathogenesis.}, journal = {Annals of neurology}, volume = {37 Suppl 1}, number = {}, pages = {S43-50}, doi = {10.1002/ana.410370706}, pmid = {8968216}, issn = {0364-5134}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis ; Antibody Specificity ; Antigens/immunology ; Autoantibodies/blood/immunology ; *Autoimmune Diseases/diagnosis/etiology/therapy ; Chronic Disease ; Cyclophosphamide/therapeutic use ; Diagnosis, Differential ; Female ; G(M1) Ganglioside/immunology ; Humans ; Immunosuppressive Agents/therapeutic use ; Male ; Middle Aged ; Neural Conduction ; *Neuromuscular Diseases/diagnosis/etiology/immunology/therapy ; }, abstract = {Pure motor neuropathy syndromes resemble amyotrophic lateral sclerosis variants with no upper motor neuron signs. Their identification is important, as, in contrast to amyotrophic lateral sclerosis, they are often immune mediated and treatable. Typically the immune-mediated motor neuropathy syndromes are distal and asymmetrical and progress slowly. The clinical features may help alert the clinician to the diagnosis, but other ancillary evidence such as abnormalities on electrophysiological testing and the presence of serum autoantibodies to neural antigens are helpful in making the diagnosis more secure. Electrophysiological abnormalities include not only motor conduction block but also other evidence of a demyelinative process such as prolonged distal latencies or F-wave abnormalities. High-titer anti-GM1 antibodies occur frequently but more specific patterns of reactivity may be especially helpful. Treatment of these motor neuropathy syndromes includes cyclophosphamide, which we use in combination with plasma exchange, and in some patients, human immune globulin. Clinical responses to therapy may occur within the first 2 to 4 months in patients with motor neuropathy syndromes with demyelinative features, but only become obvious 6 months or later after starting treatment in patients with predominantly axonal disorders.}, }
@article {pmid11727689, year = {1995}, author = {Hollander, JE and Delagi, R and Sciammarella, J and Viccellio, P and Ortiz, J and Henry, MC}, title = {On-line telemetry: prospective assessment of accuracy in an all-volunteer emergency medical service system.}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {2}, number = {4}, pages = {280-286}, doi = {10.1111/j.1553-2712.1995.tb03223.x}, pmid = {11727689}, issn = {1069-6563}, mesh = {Chi-Square Distribution ; Clinical Competence ; Diagnosis, Differential ; Diagnostic Errors ; *Electrocardiography ; Emergency Medical Services/*standards ; Emergency Medical Technicians/*standards ; Heart Diseases/*diagnosis ; Humans ; Professional Competence ; Prospective Studies ; *Telemetry ; }, abstract = {OBJECTIVE: To evaluate the need for on-line telemetry control in an all-volunteer, predominantly advanced emergency medical technician (A-EMT) ambulance system.<br><br>METHODS: Emergency medical service (EMS) advanced life support (ALS) providers were asked to transmit the ECG rhythms of monitored patients over a six-month period in 1993. The ECG rhythm interpretations of volunteer EMS personnel were compared with those of the on-line medical control physician. All discordant readings were reviewed by a panel of physicians to decide whether the misdiagnosis would have resulted in treatment aberrations had transmission been unavailable.<br><br>RESULTS: Patients were monitored and rhythms were transmitted in 1,825 cases. 1,642 of 1,825 rhythms were correctly interpreted by the EMS providers (90%; 95% CI 89-91%). The accuracy of the EMS providers was dependent on the patient's rhythm (chi-square, p < 0.00001), the chief complaint (chi-square, p = 0.0001), and the provider's level of training (chi-square, p = 0.02). Correct ECG rhythm interpretations were more common when the out-of-hospital interpretation was sinus rhythm (95%), ventricular fibrillation (87%), paced rhythm (94%), or agonal rhythm (96%). The EMS providers were frequently incorrect when the out-of-hospital rhythm interpretation was atrial fibrillation/flutter (71%), supraventricular tachycardia (46%), ventricular tachycardia (59%), or atrioventricular block (50%). Of the 183 discordant cases, 124 (68%) involved missing a diagnosis of, or incorrectly diagnosing, atrial fibrillation/flutter. Review of the discordant readings identified 11 cases that could have resulted in treatment errors had the rhythms not been transmitted, one of which might have resulted in an adverse outcome.<br><br>CONCLUSIONS: In this all-volunteer, predominantly A-EMT ALS system, patients with a field interpretation of a sinus rhythm do not require ECG rhythm transmission. Field interpretations of atrial fibrillation/flutter, supraventricular tachycardia, ventricular tachycardia, and atrioventricular blocks are frequently incorrect and should continue to be transmitted.}, }
@article {pmid8817681, year = {1995}, author = {van Buul-Offers, S and Reijnen-Gresnigt, R and Bloemen, R and Hoogerbrugge, C and Van den Brande, JL}, title = {Co-administration of IGF-binding protein-3 differentially inhibits the IGF-I-induced total body and organ growth of Snell dwarf mice.}, journal = {Progress in growth factor research}, volume = {6}, number = {2-4}, pages = {377-383}, doi = {10.1016/0955-2235(95)00019-4}, pmid = {8817681}, issn = {0955-2235}, mesh = {Animals ; Body Weight/*drug effects ; Dwarfism/*physiopathology ; Female ; Insulin-Like Growth Factor Binding Protein 3/*administration &amp; dosage/pharmacology ; Insulin-Like Growth Factor I/*administration &amp; dosage/pharmacology ; Male ; Mice ; Mice, Inbred Strains ; Organ Size/drug effects ; Rats ; }, abstract = {In mammals IGF-I is part of a 150-kDa binding protein complex, which also contains a glycosylated acid-labile protein (ALS) and a glycosylated acid-stable IGF binding subunit IGFBP-3. Administration of free IGF-I in vivo induces not only acute insulin-like effects but also growth stimulation. Since co-injection with IGFBP-3 only partially blocked the hypoglycemic response of free IGF-I in hypophysectomized rats, we were interested in the growth stimulating activity of the IGFI-IGFBP-3 complex in pituitary-deficient mice compared to that obtained by IGF-I alone. Therefore, the effects of subcutaneously administered IGF-I, IGFBP-3 and the IGF-I-IGFBP-3 complex on somatic growth and organ growth of pituitary-deficient Snell dwarf mice were studied after 4 weeks of treatment. Treatment with IGF-I alone induced a significant increase in body length and weight, as well as in weights of the submandibular salivary glands, kidneys and quadriceps femoris muscles as compared to buffer treated controls. No significant changes were found in liver, brain, heart and thymus. IGFBP-3 alone had no effect. However, the stimulating effects of IGF-I alone on body length and weight, as well as on the weight of the kidneys, were fully neutralized by co-injection with IGFBP-3. In contrast, the weights of submandibular salivary glands and m. quadriceps femoris were increased by treatment with the complex compared to controls and not significantly different from animals treated with IGF-I alone. Our data show that in GH-deficient mice administration of IGFBP-3 differentially inhibits the IGF-I induced body and organ growth. This calls for extra vigilance when exploring presumed advantages of administering an IGF-I-IGFBP-3 complex to GH-deficient individuals in order to obtain stimulation of growth.}, }
@article {pmid9173991, year = {1994}, author = {Sanner, C and Elliott, JL and Snider, WD}, title = {Upregulation of NMDARI mRNA induced by MK-801 is associated with massive death of axotomized motor neurones in adult rats.}, journal = {Neurobiology of disease}, volume = {1}, number = {3}, pages = {121-129}, doi = {10.1006/nbdi.1994.0015}, pmid = {9173991}, issn = {0969-9961}, support = {5T32NS07205-13/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Axons/*physiology ; Cell Death ; Dizocilpine Maleate/*toxicity ; Female ; Motor Neurons/*drug effects/physiology ; RNA, Messenger/*analysis ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/*drug effects/genetics ; Up-Regulation ; }, abstract = {Studies on the pathogenesis of human motor neurone disease have suffered from the absence of models of motor neurone degeneration in adult animals. Normally in adult rodents, transection of motor neurone axons results in only a modest degree of neuronal death. We reasoned that axotomy-induced motor neurone death might be enhanced by modulating glutamatergic transmission. By axotomizing the facial nerve in adult rats and then administering MK-801 for the first week of a 4-week or 8-week post-lesion survival period, we induced a 67% motor neurone loss by 8 weeks as compared with a 19% loss in controls. A possible explanation for the increased motor neurone loss after MK-801 treatment is that transient blockade of NMDA receptors may upregulate synthesis of NMDA receptor components. In order to test this idea, we employed quantitative in situ hybridization to determine the response of NMDAR1 mRNA to axotomy and axotomy + MK-801 treatment. Quantification of the percentage of area occupied by NMDAR1 silver grains per motor neurone somata indicated that axotomy alone did not provoke a change in NMDAR1 mRNA. However, axotomy and MK-801 combined treatment resulted in a highly significant upregulation of NMDAR1 mRNA when compared with controls or animals treated solely with axotomy. Our results suggest that motor neurone death in adult animals can be enhanced after axotomy in association with the upregulation of NMDA receptor mRNA. Thus, abnormalities in glutamate receptor signalling may lead to subacute motor neurone death in vivo. Furthermore these results indicate that transient treatment with MK-801 is a convenient method for enhancing the degree of motor neurone death after axotomy in adult animals.}, }
@article {pmid10155522, year = {1994}, author = {Swor, R and Anderson, W and Jackson, R and Wilson, A}, title = {Effects of EMS transportation on time to diagnosis and treatment of acute myocardial infarction in the emergency department.}, journal = {Prehospital and disaster medicine}, volume = {9}, number = {3}, pages = {160-164}, doi = {10.1017/s1049023x00041273}, pmid = {10155522}, issn = {1049-023X}, mesh = {*Ambulances ; Case-Control Studies ; Confounding Factors, Epidemiologic ; Electrocardiography/methods ; Emergency Medical Services/*organization &amp; administration ; Emergency Service, Hospital ; Health Services Research ; Humans ; Myocardial Infarction/*diagnosis/drug therapy/*therapy ; Retrospective Studies ; Thrombolytic Therapy ; Time Factors ; Transportation of Patients/*methods ; }, abstract = {INTRODUCTION: Recent studies have documented decreased time to emergency department (ED) thrombolytic therapy with the use of prehospital electrocardiography.<br><br>PURPOSE: Is the time to ED diagnosis and treatment of acute myocardial infarction (AMI) patients with thrombolytic agents decreased by emergency medical services (EMS) transport when compared with those transported by other means (non-EMS)?<br><br>DESIGN: Retrospective, case-control study.<br><br>POPULATION: The AMI patients treated with thrombolytic agents at a 34,000-visit, community hospital ED during 1992.<br><br>METHODS: Review of records of patients who received thrombolytic therapy for AMI. Statistical analysis was performed using "Student's" t-test and Yates corrected Chi-square (chi 2).<br><br>RESULTS: Eighty-seven patients received thrombolytic agents for AMI during 1992; 33 arrived by ambulance, 54 arrived by other methods. There were no differences in age, gender, or time of ED arrival among these groups. Ambulance patients received standard advanced life support (ALS) care, but not a 12-lead electrocardiogram (ECG) or thrombolytic agents. Ambulance patients experienced a significantly shorter time to first ECG (12.9 +/- 9.1 min. versus 20.8 +/- 25.3 min.; p = .028) and received thrombolytic therapy sooner than did controls (56.0 +/- 31.5 min. versus 78.0 +/- 63.4 min.; p = .018). There was no difference in time from diagnosis to treatment between these groups.<br><br>CONCLUSION: Emergency medical services transport of AMI patients in this study decreased time to diagnosis and treatment and may be a confounder in studies that assess the value of field EMS interventions. Non-EMS AMI patients did not receive as rapid diagnosis and treatment, and emergency physicians should evaluate and address this issue in their departments.}, }
@article {pmid9422134, year = {1994}, author = {Deakin, C and Davies, G}, title = {Defining trauma patient subpopulations for field stabilization.}, journal = {European journal of emergency medicine : official journal of the European Society for Emergency Medicine}, volume = {1}, number = {1}, pages = {31-33}, doi = {10.1097/00063110-199403000-00007}, pmid = {9422134}, issn = {0969-9546}, mesh = {Clinical Competence ; Craniocerebral Trauma/therapy ; Decision Making ; Emergency Medical Services/*methods ; Humans ; Injury Severity Score ; Multiple Trauma/*diagnosis/*therapy ; Triage ; United Kingdom ; Wounds, Nonpenetrating/therapy ; Wounds, Penetrating/therapy ; }, abstract = {Despite several large studies, the scoop and run versus field stabilization debate in prehospital trauma care continues. It is unlikely that all trauma patients are best treated by either field stabilization or scoop and run and the most effective form of prehospital care may be dependent upon the type of injuries sustained. Studies suggest that penetrating trauma involving major vascular injury may be best treated by scoop and run since advanced life support (ALS) measures serve only to delay time to definitive surgical treatment. Conversely, patients with head injuries may benefit from rapid ALS performed on scene in order to control airway and breathing problems, and reduce intracranial pressure prior to transport. Between these two groups of patients lie those with blunt trauma in whom scoop and run may be most appropriate if there is major vascular damage or those in whom field stabilization may offer the patient a greater chance of survival if blood loss is not a life-threatening problem.}, }
@article {pmid12346134, year = {1994}, author = {Baker, AC}, title = {Issues of human rights and HIV. Guest commentary.}, journal = {AIDSlink : Eastern, Central &amp; Southern Africa}, volume = {}, number = {25}, pages = {6}, pmid = {12346134}, issn = {0856-3969}, mesh = {*Acquired Immunodeficiency Syndrome ; Americas ; *Delivery of Health Care ; Developed Countries ; Disease ; *Disease Outbreaks ; Economics ; *HIV Infections ; Health ; *Health Services Needs and Demand ; *Human Rights ; North America ; *Prejudice ; Social Problems ; United States ; Virus Diseases ; }, }
@article {pmid10155461, year = {1993}, author = {Moss, RL and Kolaric, D and Watts, A}, title = {Therapeutic agents utilized in urban/rural prehospital care.}, journal = {Prehospital and disaster medicine}, volume = {8}, number = {2}, pages = {161-164}, doi = {10.1017/s1049023x00040243}, pmid = {10155461}, issn = {1049-023X}, mesh = {Arizona ; *Drug Utilization ; *Emergency Medical Services ; Humans ; *Life Support Care ; Retrospective Studies ; *Rural Population ; *Urban Population ; }, abstract = {INTRODUCTION: Objectives of this study were to determine the number of prehospital emergency patients who were given advanced life support (ALS) drugs and to compare utilization rates for ALS drugs in urban and rural environments. Certified ALS emergency medical technicians (Arizona) have 29 therapeutic agents authorized for prehospital administration. These agents may be administered only under direction of a medical control authority or by following standing orders.<br><br>METHODS: A retrospective review was made of prehospital emergency encounter records. They were acquired by the Arizona Office of Emergency Medical Services (OEMS) from rural EMS providers who used optically scannable forms and from a metropolitan fire department's medical emergency response records.<br><br>RESULTS: In 1989 and 1990, 273,611 emergency patient encounter records were entered into the EMS database; 197,260 were urban responses and 76,351 were rural responses. Drugs (ALS) were administered to 16,730 (8.5%) urban emergency patients and to 5,359 (7%) rural emergency patients at the incident site or during transport to a medical care facility. Nitrostat, 0.4 mg sublingual tablet, was the drug most frequently administered to emergency patients in the prehospital setting. Utilization rates found in the urban and the rural data sets were consistent for the individual agents. Variations in use frequency between urban and rural setting were noted for some drugs. Of the 29 approved ALS drugs, seven (24%) were administered to 10% or more urban patients who received drugs. In the rural areas, eight (27.6%) were administered to 10% or more patients who received drugs. There were nine (31%) agents administered to less than 1% of all patients who received drugs. A majority of the approved drugs, 17 (59%) were administered at a rate below 5% of all patients receiving medications.<br><br>CONCLUSION: Severity of illness or injury prompted administration of ALS drugs to 8.1% of patients receiving prehospital emergency care. The most frequently utilized medication in the urban/rural areas was for treatment of cardiac symptoms. Variations between urban/rural drug utilization reflected the drugs of choice which are compatible with long transport times to a medical facility.}, }
@article {pmid10161251, year = {1993}, author = {Moss, RL}, title = {Vital signs records omissions on prehospital patient encounter forms.}, journal = {Prehospital and disaster medicine}, volume = {8}, number = {1}, pages = {21-27}, doi = {10.1017/s1049023x00039960}, pmid = {10161251}, issn = {1049-023X}, mesh = {Ambulances ; Arizona ; Blood Pressure Determination ; Emergency Medical Services/*standards/statistics &amp; numerical data ; Heart Rate ; Humans ; Medical Records/*standards/statistics &amp; numerical data ; Pulmonary Ventilation ; Retrospective Studies ; }, abstract = {INTRODUCTION: A reported in-field, prospective evaluation of 227 prehospital patient assessments by advanced life support (ALS) emergency medical technicians (EMTs) found a frequent failure to measure vital signs. The objective of this retrospective review was to report the omission frequency of vital signs found in a centralized emergency medical services (EMS) data collection system.<br><br>METHODS: The EMS database contained information from 90,480 optically scanned, prehospital patient encounter forms. Each record identified EMT skill levels, response times, dispatch type, vital signs, medical and trauma information, treatment, and patient disposition. Records for 1989 and 1990 were collected from 92 rural EMS providers who responded to emergency medical and trauma events.<br><br>RESULTS: Of 90,480 emergency responses, 14,129 (15.6%) were false alarms, deceased, or canceled without vital patient contact. Valid encounters were documented for 76,351 (84.4%) patient contacts. Systolic blood pressure measurements were not recorded for 13,262 (17.4%) patients. Diastolic blood pressure was not recorded for 14,272 (18.7%) patients. A pulse record was not recorded for 12,125 (15.9%) patients. A ventilatory rate was absent in 12,958 (17.0%) patient records.<br><br>CONCLUSION: This study found a frequent failure by non-metropolitan basic life support (BLS) and advanced life support (ALS) EMTs to record vital signs on prehospital emergency patient encounter forms. It supports a previous report of direct in-field observations of ALS EMTs failing to measure vital signs during patient assessment. The impact of vital sign omissions upon individual patient care can be assessed only by receiving medical control physicians. In the absence of effective emergency physician networking, the statewide magnitude of the problem among BLS and ALS EMTs has not been recognized as a system issue.}, }
@article {pmid16653216, year = {1992}, author = {Christopher, JT and Powles, SB and Holtum, JA}, title = {Resistance to Acetolactate Synthase-Inhibiting Herbicides in Annual Ryegrass (Lolium rigidum) Involves at Least Two Mechanisms.}, journal = {Plant physiology}, volume = {100}, number = {4}, pages = {1909-1913}, pmid = {16653216}, issn = {0032-0889}, abstract = {WLR1, a biotype of Lolium rigidum Gaud. that had been treated with the sulfonylurea herbicide chlorsulfuron in 7 consecutive years, was found to be resistant to both the wheat-selective and the nonselective sulfonylurea and imidazolinone herbicides. Biotype SLR31, which became cross-resistant to chlorsulfuron following treatment with the aryloxyphenoxypropionate herbicide diclofop-methyl, was resistant to the wheat-selective, but not the nonselective, sulfonylurea and imidazolinone herbicides. The concentrations of herbicide required to reduce in vitro acetolactate synthase (ALs) activity 50% with respect to control assays minus herbicide for biotype WLR1 was greater than those for susceptible biotype VLR1 by a factor of >30, >30, 7,4, and 2 for the herbicides chlorsulfuron, sulfometuron-methyl, imazapyr, imazathapyr, and imazamethabenz, respectively. ALS activity from biotype SLR31 responded in a similar manner to that of the susceptible biotype VLR1. The resistant biotypes metabolized chlorsulfuron more rapidly than the susceptible biotype. Metabolism of 50% of [phenyl-U-(14)C]chlorsulfuron in the culms of two-leaf seedlings required 3.7 h in biotype SLR31, 5.1 h in biotype WLR1, and 7.1 h in biotype VLR1. In all biotypes the metabolism of chlorsulfuron in the culms was more rapid than that in the leaf lamina. Resistance to ALS inhibitors in L. rigidum may involve at least two mechanisms, increased metabolism of the herbicide and/or a herbicide-insensitive ALS.}, }
@article {pmid11980064, year = {1991}, author = {Siddique, T and Hu, P and Hentati, A and Deng, G and Hung, WY and McInnis, MG and Warren, AC and Rimmler, J and Antonarakis, S and Pericak-Vance, MA}, title = {A molecular genetic approach to amyotrophic lateral sclerosis.}, journal = {International journal of neurology}, volume = {25-26}, number = {}, pages = {60-69}, pmid = {11980064}, issn = {0020-7446}, mesh = {Amyotrophic Lateral Sclerosis/classification/*genetics/physiopathology ; Animals ; Genetic Linkage/genetics ; Humans ; }, abstract = {Disorders of the motor neurons may affect both the upper and lower neurons, primarily the lower motor neurons as in the spinal muscular atrophies are primarily the upper motor neurons as in the familial spastic paraplegias. Amyotrophic lateral sclerosis is a degenerative disorder of the motor neuron that results in paralysis and wasting of voluntary muscles. Large motor neurons in the cerebral cortex, brain stem and spinal cord degenerate or are lost. Hyaline inclusions may be seen in the cytoplasm of surviving motor neurons. Acute axonal degeneration of peripheral motor fibers occurs at all levels, including the distal axon. Subclinical involvement of the spinecerebellar tracts, posterior column and Clarke's column as well as loss of large neurons in the dorsal root ganglia and neurons of oculomotor nuclei has been reported. The average duration of life onset of symptoms of amyotrophic lateral sclerosis is three years and ninety per cent of patients died within 5 years. The basic mechanism of disease in amyotrophic lateral sclerosis remains unknown. There is no known treatment that will prevent, reverse or otherwise alter the course of the disease. Autosomal dominant and autosomal recessive forms of amyotrophic lateral sclerosis are genetic models of amyotrophic lateral sclerosis which may provide insight into the disease mechanism of sporadic amyotrophic lateral sclerosis, five to ten percent of adult cases of amyotrophic lateral sclerosis with early onset of symptoms and a more benign course. It is conceivable that both genetic and sporadic forms of amyotrophic lateral sclerosis result from failure of the same or similar neuronal mechanism triggered by defective genes and by an environment agent in sporadic amyotrophic lateral sclerosis.}, }
@article {pmid10302355, year = {1988}, author = {Schneider, T and Fagnani, F and Lanoe, JL and Hourmant, M and Soulillou, JP}, title = {Economic analysis of an immunosuppressive strategy in renal transplantation.}, journal = {Health policy (Amsterdam, Netherlands)}, volume = {9}, number = {1}, pages = {75-89}, doi = {10.1016/0168-8510(88)90119-4}, pmid = {10302355}, issn = {0168-8510}, mesh = {*Antilymphocyte Serum ; Costs and Cost Analysis ; Cyclosporins/*therapeutic use ; Data Collection ; Dialysis/economics ; France ; Hospitalization/economics ; Humans ; Kidney Failure, Chronic/therapy ; *Kidney Transplantation ; Quality of Life ; Technology Assessment, Biomedical/*economics ; Value of Life ; }, abstract = {Recently introduced immunosuppressants, which have been shown to be more effective but apparently more costly than conventional regimens, have renewed interest in the economic evaluation of national policies regarding the management of end-stage renal disease. The present paper addresses these questions, together with the different methods of expressing the costs involved, with reference to a sequential protocol using anti-lymphocyte serum (ALS), followed by cyclosporine from the third post-graft month onwards. The analysis is based on the results of a randomized trial carried out at the University Hospital, Nantes (France), from 1982 to 1984, in which the above protocol was compared to conventional treatment with ALS alone. Despite the considerable cost of long-term cyclosporine treatment, analysis reveals collective financial and social benefits from the reduced rate of graft failure and subsequent return to dialysis.}, }
@article {pmid11648263, year = {1987}, author = {, }, title = {In re Farrell.}, journal = {Atlantic reporter}, volume = {529}, number = {}, pages = {404-419}, pmid = {11648263}, issn = {8750-2631}, mesh = {Amyotrophic Lateral Sclerosis ; Central Nervous System Diseases ; *Civil Rights ; Persons with Disabilities ; *Euthanasia, Passive ; Home Care Services ; Humans ; Informed Consent ; *Jurisprudence ; Mental Competency ; New Jersey ; Prognosis ; *Right to Die ; Terminally Ill ; *Treatment Refusal ; }, }
@article {pmid11644026, year = {1987}, author = {Nicholson, RH and Koch, HG and Ulshoefer, T and Qiu, RZ}, title = {"No feeding tubes for me!.}, journal = {The Hastings Center report}, volume = {17}, number = {3}, pages = {S23-6}, pmid = {11644026}, issn = {0093-0334}, mesh = {*Amyotrophic Lateral Sclerosis ; Attitude ; Central Nervous System Diseases ; China ; Decision Making ; *Enteral Nutrition ; Equipment and Supplies ; Euthanasia ; Euthanasia, Active ; Euthanasia, Active, Voluntary ; *Euthanasia, Passive ; Family ; *Freedom ; Health Care Rationing ; Humans ; *International Cooperation ; *Internationality ; Jurisprudence ; Life Support Care ; Moral Obligations ; *Nutritional Support ; Palliative Care ; Patients ; *Personal Autonomy ; Pharmaceutical Preparations ; Physicians ; Resource Allocation ; *Right to Die ; Social Responsibility ; Stress, Psychological ; Suicide ; Terminal Care ; Terminally Ill ; *Treatment Refusal ; United Kingdom ; United States ; Withholding Treatment ; }, }
@article {pmid16558050, year = {1971}, author = {Wilson, HR and Frenkel, JK}, title = {Immunosuppressive agents in intracellular infection: besnoitiosis in hamsters.}, journal = {Infection and immunity}, volume = {3}, number = {6}, pages = {756-761}, pmid = {16558050}, issn = {0019-9567}, abstract = {When tested for their activity in suppressing the acquisition of immunity during acute Besnoitia infection of hamsters, antilymphocyte serum (ALS), aminopterin, cyclophosphamide, cortisol, and whole-body irradiation were the most active agents and effectively blocked the development of immunity during 4 to 12 days of immunization. Actinomycin D and chlorambucil were moderately active, and nitrogen mustard, 6-mercaptopurine, and vinblastine exhibited slight immunosuppressive activity. Established immunity was especially labile to cortisol and cortisone administration with generalized Besnoitia relapse occurring consistently in all hamsters; this occurred infrequently during cyclophosphamide treatment. Focal relapse was seen in chronically irradiated and ALS-treated hamsters, but the location of the lesions differed. Irradiated hamsters had lesions in the lungs and brain, whereas ALS-treated hamsters showed splenic relapse. Acquisition of immunity was more sensitive to suppression than established immunity and did not necessarily parallel antibody development and vice versa, emphasizing the importance of cellular over humoral factors in immunity to this intracellular parasite.}, }
@article {pmid16557996, year = {1971}, author = {Borden, EC and Murphy, FA and Nathanson, N and Monath, TP}, title = {Effect of antilymphocyte serium on tacaribe virus infection in infant mice.}, journal = {Infection and immunity}, volume = {3}, number = {3}, pages = {466-471}, pmid = {16557996}, issn = {0019-9567}, abstract = {Tacaribe virus, a member of the arenovirus group, was demonstrated to have similarities in pathogenesis to the prototype virus of this group, lymphocytic choriomeningitis (LCM) virus. Treatment with antilymphocyte serum (ALS) doubled the survival time of mice neonatally infected with a lethal dose of Tacaribe virus. Twenty-one per cent of ALS-treated infected animals survived more than 30 days. All animals had recoverable virus in brains and serum for the duration of life, and there was no difference between virus growth curves of ALS-treated and control animals. No neutralizing or complement-fixing antibodies were present in infected animals at time of death, with the exception of one long-surviving ALS-treated animal. Certain differences between infections of mice with LCM and Tacaribe viruses were apparent. Tacaribe virus pathogenicity decreased with increasing mouse age, and earlier infection and a more prolonged course of ALS treatment than was needed for LCM virus were necessary to achieve increased survival. Histopathological changes observed in Tacaribe virus-infected control mice were focal choroiditis and focal cerebellar necrosis; these changes were not seen in asymptomic infected mice during the period of transient protection by ALS.}, }
@article {pmid14085758, year = {1963}, author = {HAUERT, L}, title = {GOOD NURSING CARE--THE ONLY TREATMENT.}, journal = {The American journal of nursing}, volume = {63}, number = {}, pages = {116-118}, pmid = {14085758}, issn = {0002-936X}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; *Nursing ; }, }
@article {pmid14450405, year = {1962}, author = {IAKUSHINA, VM}, title = {[Experience with clinical observations and treatment of patients with lateral amyotropic sclerosis].}, journal = {Zhurnal nevropatologii i psikhiatrii imeni S.S. Korsakova (Moscow, Russia : 1952)}, volume = {62}, number = {}, pages = {252-256}, pmid = {14450405}, issn = {0044-4588}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; *Motor Neuron Disease ; *Sclerosis ; }, }
@article {pmid14412124, year = {1959}, author = {KROLIUNITSKAIA, TL}, title = {[On the treatment of patients with lateral amyotrophic sclerosis with vitamin B12].}, journal = {Zhurnal nevropatologii i psikhiatrii imeni S.S. Korsakova (Moscow, Russia : 1952)}, volume = {59}, number = {}, pages = {1447-1450}, pmid = {14412124}, issn = {0044-4588}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; *Corrinoids ; *Hematinics ; Humans ; *Sclerosis ; Vitamin B 12/*therapy ; }, }
@article {pmid12994941, year = {1952}, author = {SCHWOB, RA and BONDUELLE, M}, title = {[Trypan blue and trypan red in the treatment of amyotrophic lateral sclerosis; application to the treatment of multiple sclerosis].}, journal = {La semaine des hopitaux : organe fonde par l'Association d'enseignement medical des hopitaux de Paris}, volume = {28}, number = {39}, pages = {1637-1642}, pmid = {12994941}, mesh = {*Amyotrophic Lateral Sclerosis ; *Azo Compounds ; *Coloring Agents ; Humans ; Multiple Sclerosis/*therapy ; *Trypan Blue ; }, }
@article {pmid8632636, year = {1996}, author = {Washburn, WK and Otsu, I and Gottschalk, R and Monaco, AP}, title = {PGG-glucan, a leukocyte-specific immunostimulant, does not potentiate GVHD or allograft rejection.}, journal = {The Journal of surgical research}, volume = {62}, number = {2}, pages = {179-183}, doi = {10.1006/jsre.1996.0192}, pmid = {8632636}, issn = {0022-4804}, mesh = {Adjuvants, Immunologic ; Animals ; Glucans/*immunology ; *Graft Rejection ; Graft vs Host Disease/*immunology ; Intestine, Small/transplantation ; Male ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Rats ; Rats, Inbred ACI ; Rats, Inbred BN ; Rats, Inbred Lew ; Transplantation, Homologous ; *beta-Glucans ; }, abstract = {PGG-glucan is an immunomodulator which can enhance the host response to infection. Phase I/II clinical trials have documented the safety and potential efficacy of this compound to reduce postoperative infectious complications in high risk surgical patients. Organ transplant recipients may benefit from this drug due to their high rates of postoperative infectious complications. A rat cardiac rejection model (ACI --> Lew) and a mouse skin graft model (C3H/HeJ --> B6AF1/J) were used with four treatment arms (control, Cyclosporine A (CsA), antilymphocyte serum (ALS), and CsA + ALS with and without PGG-glucan). Small intestinal allografts (Lew --> LBNF1) were performed in rats to evaluate GVHD. In the mouse GVHD model, donor splenocytes were given to irradiated recipients (C57BL/6 --> B6AF1), with and without PGG-glucan treatment. There was no difference in survival between PGG-glucan treatment and placebo for the control, CsA, and CsA + ALS groups in rat cardiac recipients. Recipients receiving ALS and treated with PGG-glucan survived a median of 42.5 days versus 63.5 days for those ALS-treated animals not receiving PGG-glucan (P = 0.045). In the remaining groups there was no difference in survival between PGG-glucan-treated groups and the control groups. PGG-glucan did not shorten survival in three of four treatment groups in the rat cardiac rejection model. High dose ALS with PGG-glucan did result in a marginal decrease in survival in cardiac allograft recipients. If the one outlying animal with indefinite survival is excluded, the difference is not statistically significant (P = 0.098). These results show that even though PGG-glucan has immunostimulatory properties, it does not significantly potentiate rejection or GVHD in these animal models. This preliminary work may be important in determining whether PGG-glucan can be safely given to immunosuppressed organ transplant recipients to reduce postoperative infectious complications.}, }
@article {pmid8629787, year = {1996}, author = {Callaham, M and Madsen, CD}, title = {Relationship of timeliness of paramedic advanced life support interventions to outcome in out-of-hospital cardiac arrest treated by first responders with defibrillators.}, journal = {Annals of emergency medicine}, volume = {27}, number = {5}, pages = {638-648}, doi = {10.1016/s0196-0644(96)70169-5}, pmid = {8629787}, issn = {0196-0644}, mesh = {Adult ; Aged ; Electric Countershock/*methods ; Emergency Medical Services/*methods ; *Emergency Medical Technicians ; Female ; Health Services Research ; Heart Arrest/*therapy ; Humans ; Life Support Care/*methods ; Male ; Middle Aged ; Odds Ratio ; Prospective Studies ; San Francisco ; Sensitivity and Specificity ; Survival Analysis ; Time Factors ; Treatment Outcome ; Urban Health ; }, abstract = {STUDY OBJECTIVE: We sought to determine whether the interval between the arrival of first responder/defibrillators and paramedic advanced life support (ALS) interventions is associated with outcome.<br><br>METHODS: We carried out a prospective observational study of adults in out-of-hospital cardiac arrest treated by both first responders and paramedics in an urban emergency medical services system between July 15, 1992, and May 27, 1993 (N = 544).<br><br>RESULTS: The gap between first-responder and medic arrival was short (3.2 minutes); medics arrived before first-responder shock in 22% of ventricular fibrillation (VF) cases. Just 10% of patients has a pulse when medics arrived, but the presence of pulse on medic arrival was a powerful predictor of hospital discharge (odds ratio [OR], 20.5; sensitivity, 39%; specificity, 98%; positive predictive value, 55%; negative predictive value, 97%) or a Cerebral Performance Category score on discharge of 1 or 2 (OR, 2.9). No response or individual ALS treatment interval was related to outcome, including the interval from first-responder to medic arrival. ALS interventions by medics were associated with poorer outcomes; even the need for nothing more than additional defibrillation by medics decreased the survival rate of VF patients threefold. By contrast, bystander CPR improved survival more than fourfold and early defibrillation of VF by first responders more than ninefold. Ninety-one percent of all patients discharged from the hospital who received only minimal ALS other than intubation had good neurologic outcome and longer survival after discharge. Half the total survivors of VF arrest (and 59% of all arrest survivors) were resuscitated by medics with aggressive ALS measures, but 80% had very poor neurologic outcomes and 50% died within a year of hospital discharge. Even the need for only additional defibrillation by medics worsened neurologic outcome by a factor of 2.8.<br><br>CONCLUSION: Faster response by medics, or any individual ALS intervention other than first-responder defibrillation, demonstrated no benefit in this urban population with short intervals between responder arrivals. Aggressive ALS increased the number of survivors but also decreased their neurologic quality. The benefit of rapid ALS backup to first responder/defibrillators needs further study in other systems. System performance cannot be judged without knowledge of neurologic outcome.}, }
@article {pmid8628460, year = {1996}, author = {}, title = {A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. ALS CNTF Treatment Study Group.}, journal = {Neurology}, volume = {46}, number = {5}, pages = {1244-1249}, doi = {10.1212/wnl.46.5.1244}, pmid = {8628460}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/mortality/physiopathology ; Body Weight ; Ciliary Neurotrophic Factor ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Humans ; Injections, Subcutaneous ; Isometric Contraction ; Male ; Middle Aged ; Nerve Growth Factors/therapeutic use ; Nerve Tissue Proteins/administration &amp; dosage/adverse effects/*therapeutic use ; Placebos ; Recombinant Proteins/administration &amp; dosage/adverse effects/therapeutic use ; }, abstract = {Ciliary neurotrophic factor (CNTF) is a neuroactive cytokine found in Schwann cells, which appears to be released in response to nerve injury. The ALS CNTF Treatment Study (ACTS) clinical trial was a phase II-III randomized, placebo-controlled, double-blind study designed to evaluate the safety, tolerability, and efficacy of subcutaneous administration of recombinantly produced human CNTF (rHCNTF) in slowing disease progression in 730 patients with amyotrophic lateral sclerosis (ALS). Patients were randomized to receive 30 micrograms/kg or 15 micrograms/kg rHCNTF or placebo subcutaneously three times a week for 9 months. The primary endpoint of the study, the slope of decline of isometric muscle strength in treated versus placebo patients, showed no statistically significant difference between rHCNTF and placebo-treated patients, and was complicated by an initial statistically significant decrease in strength early in rHCNTF-treated patients. Mortality was similar in all three study arms. There were no statistically significant treatment effects among the secondary measures. Side effects of rHCNTF included anorexia, weight loss, and cough and were sufficient to limit dosing in many patients.}, }
@article {pmid8622731, year = {1996}, author = {Miller, RG and Smith, SA and Murphy, JR and Brinkmann, JR and Graves, J and Mendoza, M and Sands, ML and Ringel, SP}, title = {A clinical trial of verapamil in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {19}, number = {4}, pages = {511-515}, doi = {10.1002/mus.880190405}, pmid = {8622731}, issn = {0148-639X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Analysis of Variance ; Arm/physiopathology ; Calcium Channel Blockers/*therapeutic use ; Female ; Humans ; Leg/physiopathology ; Lung/physiopathology ; Male ; Middle Aged ; Verapamil/*therapeutic use ; }, abstract = {Seventy-two patients with amyotrophic lateral sclerosis (ALS) were enrolled in a clinical trial of the efficacy of verapamil in the treatment of ALS. In period 1 (pretreatment, months 1-3) and period 3 (posttreatment, months 10-12), patients received no drug. In period 2 (months 4-9), patients received verapamil. The slopes of declining pulmonary function and limb megascores were not significantly different during drug treatment compared to natural history and washout periods. Thus, verapamil was ineffective in slowing the clinical progression in ALS patients. Controlled trials using a natural history period may represent a faster and less expensive method of screening drugs for ALS compared to placebo-controlled trials.}, }
@article {pmid8601813, year = {1996}, author = {Sagot, Y and Tan, SA and Hammang, JP and Aebischer, P and Kato, AC}, title = {GDNF slows loss of motoneurons but not axonal degeneration or premature death of pmn/pmn mice.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {16}, number = {7}, pages = {2335-2341}, doi = {10.1523/JNEUROSCI.16-07-02335.1996}, pmid = {8601813}, issn = {0270-6474}, mesh = {Animals ; Antibody Specificity ; Axons/*physiology ; Capsules ; Cell Death/drug effects ; Cells, Cultured/cytology/drug effects ; Cricetinae ; Drug Delivery Systems ; Glial Cell Line-Derived Neurotrophic Factor ; Kidney/cytology ; Mice ; Mice, Neurologic Mutants ; Motor Neurons/*cytology/drug effects ; Myelin Sheath/drug effects ; Nerve Degeneration/drug effects ; Nerve Growth Factors/*pharmacology ; Nerve Tissue Proteins/immunology/*pharmacology ; Rats ; Spinal Cord/cytology ; Survival Analysis ; }, abstract = {Glial cell line-derived neurotrophic factor (GDNF), a member of the TG F-beta superfamily, has been shown to be a highly potent neurotrophic factor that enhances survival of various neuronal cell types including motoneurons. To assess its therapeutic potential in treating neurodegenerative diseases such as amyotrophic lateral sclerosis, we treated mutant mice displaying motoneuron degeneration (progressive motor neuropathy; pmn) with encapsulated GDNF-secreting cells. Effects of GDNF treatment on pmn/pmn mice were compared with previous results obtained with ciliary neurotrophic factor (CNTF) [Sagot Y, Tan SA, Baetge E, Schmalbruch H, Kato AC, Aebischer P (1995) Eur J Neurosci 7:1313-1322]. In contrast to CNTF, GDNF did not increase the lifespan of pmn/pmn mice. However, GDNF significantly reduced the loss of facial motoneurons by 50%, a value similar to what was observed when CNTF was administered to the pmn/pmn mice. Surprisingly, myelinated axon counts revealed that GDNF had no effect on nerve degeneration. Therefore, despite its potential in rescuing motoneuron cell bodies, the inability of GDNF to prevent nerve degeneration in pmn/pmn mice suggests that its usefulness in the treatment of motor neuron diseases may be restricted to cotreatment with other factors that act on the nerve process.}, }
@article {pmid8606689, year = {1996}, author = {Parry, GJ}, title = {AAEM case report #30: multifocal motor neuropathy.}, journal = {Muscle &amp; nerve}, volume = {19}, number = {3}, pages = {269-276}, doi = {10.1002/(SICI)1097-4598(199603)19:3&lt;269::AID-MUS1&gt;3.0.CO;2-B}, pmid = {8606689}, issn = {0148-639X}, mesh = {Demyelinating Diseases/diagnosis/pathology ; Electromyography ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Motor Neuron Disease/*diagnosis/pathology ; Motor Neurons/physiology ; Neural Conduction/physiology ; }, abstract = {A 73-year-old man with a 16-year history of fasciculations and 15 years of weakness in his right arm was diagnosed with focal motor neuron disease. After 10 years of purely motor symptoms, he developed mild parasthesias although his sensory examination remained normal. Reflexes were reduced or absent in the weak muscles but were normal elsewhere. Nerve conduction was studied in nerves innervating weak muscles and showed severe motor conduction block. Sensory nerve conduction studies were minimally abnormal, showing reduced amplitudes with normal velocities. Based on the clinical picture and the presence of severe motor conduction block, the patient was diagnosed as multifocal motor neuropathy. Treatment with high-dose intravenous immunoglobulin was given with significant improvement in strength and partial resolution of the conduction block. As this case demonstrates, this treatable disorder may occasionally be mistaken for motor neuron disease although the resemblance is only superficial, and it should never be mistaken for amyotrophic lateral sclerosis. Multifocal motor neuropathy is an inflammatory, demyelinating neuropathy which, like chronic inflammatory demyelinating polyneuropathy (CIDP), is probably immune-mediated. It differs from typical CIDP by virtue of a marked predilection for motor axons, a strikingly restricted distribution, and a protracted course. Treatment with high-dose intravenous immunoglobulin is frequently helpful, but other forms of immune manipulation are less effective.}, }
@article {pmid8560547, year = {1996}, author = {De Fazio, SR and Masli, S and Gozzo, JJ}, title = {Effect of monoclonal anti-CD4 and anti-CD8 on skin allograft survival in mice treated with donor bone marrow cells.}, journal = {Transplantation}, volume = {61}, number = {1}, pages = {104-110}, doi = {10.1097/00007890-199601150-00021}, pmid = {8560547}, issn = {0041-1337}, support = {DK33466/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antibodies, Monoclonal/*administration &amp; dosage ; Bone Marrow Transplantation/immunology ; CD4 Antigens/*immunology ; CD8 Antigens/*immunology ; Graft Rejection/*prevention &amp; control ; Graft Survival/immunology ; Immunotherapy, Adoptive ; Mice ; Skin Transplantation/*immunology ; Transplantation, Homologous ; }, abstract = {Allograft unresponsiveness can be induced by donor bone marrow cells (BMC) in antilymphocyte serum (ALS)-treated recipients. The effect of administering monoclonal anti-CD4 and -CD8 at several points has been examined in a mouse skin allograft model of this protocol. Brief peritransplant administration of anti-CD4 and -CD8 was used to replace ALS. Anti-CD4 treatment prolonged graft survival only slightly and conditioned recipients poorly for the effect of posttransplantation donor BMC infusion. Anti-CD8 was ineffective in both capacities. A mixture of anti-CD4 and anti-CD8 was at least as effective as ALS in prolonging graft survival and in promoting the beneficial effects of donor BMC. Like the monoclonal antibodies, ALS also depleted splenic and lymph node CD4+ and CD8+ cells. Injection of ALS, but not the monoclonal antibodies, altered the CD4/CD8 phenotype of thymocytes, although persistent binding of both types of antibody to thymocytes was demonstrated. Abrogation of the positive effect of BMC by reconstitution of normal spleen cells on day +3 after ALS treatment confirmed that cell depletion is a requirement of this system. Monoclonal antibodies were also given to ALS/BMC-treated recipients after their grafts had become established. Anti-CD8 injection at either 2 or 4 weeks after transplantation further prolonged graft survival. In contrast, anti-CD4 injection at 2 or 6 weeks after grafting precipitated rejection, which suggests that continued allograft survival following ALS and donor BMC treatment is due to the activity of a CD4+ cell population.}, }
@article {pmid8630166, year = {1996}, author = {Hu, SC and Kao, WF}, title = {Outcomes in severely ill patients transported without prehospital ALS.}, journal = {The American journal of emergency medicine}, volume = {14}, number = {1}, pages = {86-88}, doi = {10.1016/S0735-6757(96)90023-6}, pmid = {8630166}, issn = {0735-6757}, mesh = {*Ambulances ; Chi-Square Distribution ; *Critical Illness ; Emergency Medical Services/*organization &amp; administration ; Health Services Needs and Demand ; Health Services Research ; Humans ; Life Support Care/*organization &amp; administration ; Multiple Trauma/*therapy ; Prospective Studies ; *Severity of Illness Index ; Taiwan ; Treatment Outcome ; Triage ; Urban Health ; }, abstract = {Because of the debate regarding the impact of advanced life support (ALS) care on the outcome of prehospital patients, we monitored the influence of lack of sophisticated prehospital treatment in cases of severe illness arriving by ambulance to the emergency department (ED). A prospective cohort study to examine and compare the outcome of trauma- and nontrauma-induced "ALS-eligible" cases in the setting of no prehospital care was carried out from August 1, 1993 through May 31, 1994. On arriving at the ED, patients meeting the criteria for ALS cases and sent by EMS public prehospital personnel were assessed for subjective and objective status and change in severity by triage nurses as well as being followed up for neurological status until discharged from the hospital. Chi-Square method was used to compare the data between two groups and P < .05 was considered statistically significant. Of 667 studied ALS cases (155 trauma and 512 nontrauma), < 20% had their condition change subjectively and < 10% had their condition change objectively; 68% of medical patients and 60% of trauma cases were discharged from the hospital (neurologically intact). However, subgroup analysis showed that objective measures worsened in transit in nearly 18% of trauma victims, a rate nearly 3 times greater than that of medical cases. Moreover, neurological outcome was particularly poor in trauma cases. These results suggest that ALS care may be valuable for severely ill trauma victims.}, }
@article {pmid8525533, year = {1995}, author = {Hartner, WC and Van der Werf, WJ and Lodge, JP and Gilchrist, B and De Fazio, SR and Markees, TG and Yatko, C and Monaco, AP and Gozzo, JJ}, title = {Effect of rapamycin on renal allograft survival in canine recipients treated with antilymphocyte serum, donor bone marrow, and cyclosporine.}, journal = {Transplantation}, volume = {60}, number = {11}, pages = {1347-1350}, pmid = {8525533}, issn = {0041-1337}, support = {DK33466/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/administration &amp; dosage ; Bone Marrow/immunology ; Cyclosporine/administration &amp; dosage ; Dogs ; Graft Survival/*drug effects ; Immunization ; Immunosuppressive Agents/*administration &amp; dosage ; Kidney Transplantation/*immunology ; Polyenes/*administration &amp; dosage/adverse effects ; Sirolimus ; Tissue Donors ; }, abstract = {Rapamycin (Rapa) monotherapy can promote renal allograft survival in dogs, but it is very toxic. To attempt to augment the effectiveness of Rapa and reduce its toxicity in a tolerance induction protocol, canine renal allograft recipients were treated briefly with antilymphocyte serum (ALS), donor bone marrow cells (BMC), and a limited course of cyclosporine (CsA). Rapa had little effect when CsA-treated recipients were given ALS on days -5 to -1 and BMC on day +1. When combined with CsA given days +13 to +42, ALS on days -5 to +7, and BMC on day +10, Rapa at 0.3 mg/kg on day +8 plus alternate days +15 to +39 significantly increased overall survival and was compatible with long-term survival after immunosuppression (6 grafts, 1 graft > 212 days, 1 graft > 470 days). Rapa appeared to prevent early rejections that can occur during treatment with these ALS/BMC/CsA protocols. Little toxicity of Rapa was observed with any treatment.}, }
@article {pmid8525521, year = {1995}, author = {Dono, K and Maki, T and Wood, ML and Monaco, AP}, title = {Induction of tolerance to skin allografts by intrathymic injection of donor splenocytes. Effect of donor-recipient strain combination and supplemental rapamycin.}, journal = {Transplantation}, volume = {60}, number = {11}, pages = {1268-1273}, pmid = {8525521}, issn = {0041-1337}, support = {R01 AI-14551/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/administration &amp; dosage ; Cyclosporine/pharmacology ; Graft Survival/drug effects ; Histocompatibility ; *Immune Tolerance ; Immunization, Passive ; Immunosuppression Therapy/*methods ; Immunosuppressive Agents/pharmacology ; Male ; Mice ; Mice, Inbred AKR ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Polyenes/*administration &amp; dosage ; Sirolimus ; Skin Transplantation/*immunology ; Spleen/*immunology ; Thymectomy ; Thymus Gland/*immunology ; }, abstract = {The effect of donor-recipient strain combination and supplemental rapamycin (Rapa) on tolerance induction by intrathymic (IT) injection of donor splenocytes was examined in a mouse skin allograft model. In an MHC class I-mismatched C3H/He skin to (C57BL/6 x A)F1 (B6AF1) mouse combination, IT injection of 50 x 10(6) donor splenocytes with transient immunosuppression by rabbit anti-mouse lymphocyte serum (ALS) induced significant prolongation of skin allograft survival with a median survival time (MST) of 115 days versus an MST of 24.5 days in controls given ALS alone. With an additional short course of supplemental Rapa treatment at a dose of 1.5 mg/kg i.p. every other day from day 0 to 12, all C3H/He skin allografts survived indefinitely (> 350 days) in ALS-treated, donor splenocyte intrathymically injected B6AF1 recipient mice. Tolerance was antigen-specific, since the second donor-type skin allografts were accepted while third-party skin allografts were acutely rejected in these mice bearing long-term C3H/He skin allografts. In MHC class I- and II-disparate (DBA/2 to B6AF1) and fully MHC-incompatible (AKR to B6) strain combinations, IT injection of donor splenocytes and ALS treatment failed to prolong skin allograft survival over ALS controls. When supplemental Rapa was used, long-term skin allograft acceptance was observed with an MST of 127 days for the DBA/2 to B6AF1 combination and 70 days for the AKR to B6 combination. In contrast, supplemental treatment with cyclosporine was not effective in these combinations, which suggests that supplemental Rapa may have a unique effect in augmenting IT tolerance induction. Thymectomy within 7 days after IT injection significantly shortened the allograft survival, which suggests that interaction of the host thymus and the injected donor splenocytes, which takes place early after IT injection, plays an important role in the induction of allograft tolerance in this model.}, }
@article {pmid8574175, year = {1995}, author = {Bastone, A and Micheli, A and Beghi, E and Salmona, M}, title = {The imbalance of brain large-chain aminoacid availability in amyotrophic lateral sclerosis patients treated with high doses of branched-chain aminoacids.}, journal = {Neurochemistry international}, volume = {27}, number = {6}, pages = {467-472}, doi = {10.1016/0197-0186(95)00051-9}, pmid = {8574175}, issn = {0197-0186}, mesh = {Adult ; Aged ; Amino Acids/*metabolism ; Amino Acids, Branched-Chain/*pharmacokinetics ; Amyotrophic Lateral Sclerosis/blood/*metabolism ; Biological Availability ; Biological Transport/physiology ; Brain/*metabolism ; Case-Control Studies ; Dose-Response Relationship, Drug ; Female ; Glutamic Acid/blood ; Humans ; Male ; Mathematics ; Middle Aged ; Models, Biological ; Placebos ; }, abstract = {Following the report of an increased mortality among patients with amyotrophic lateral sclerosis given high daily doses of branched-chain aminoacids, we assessed the plasma concentrations of large neutral aminoacids and glutamic acid and the large neutral aminoacid brain influx in 24 amyotrophic lateral sclerosis patients receiving placebo or branched-chain aminoacids (L-leucine 12 g, L-isoleucine 6 g, L-valine 6 g daily), in 15 untreated amyotrophic lateral sclerosis patients and in 15 healthy volunteers. The branched-chain aminoacid plasma concentrations increased three- to six-fold in the treated group compared to the patients receiving placebo or no treatment and to the healthy controls. Plasma glutamic acid concentrations in healthy volunteers were 51.59 +/- 7.53 nmol/ml while in the amyotrophic lateral sclerosis patients receiving no treatment, placebo or branched-chain aminoacids were 92.33 +/- 12.15 nmol/ml, 91.21 +/- 15.86 nmol/ml and 95.08 +/- 17.96 nmol/ml respectively. The glutamic acid concentration was significantly higher (P < 0.01) in amyotrophic lateral sclerosis patients than in healthy individuals. Plasma phenylalanine and tyrosine were lower in the amyotrophic lateral sclerosis patients than in healthy controls, regardless of treatment, whereas tryptophan levels were not significantly different. The branched-chain aminoacid brain influx of the treated group was 110-140% of that measured in the patients receiving placebo and in the healthy controls. The aromatic aminoacid brain influx was lower in the treated group than in the placebo group or healthy controls. An impairment of brain large neutral aminoacid availability might possible contribute to enhancing the progression of symptoms in patients with amyotrophic lateral sclerosis.}, }
@article {pmid8610492, year = {1995}, author = {Annunziata, P and Maimone, D and Guazzi, GC}, title = {Association of polyclonal anti-GM1 IgM and anti-neurofilament antibodies with CSF oligoclonal bands in a young with amyotrophic lateral sclerosis.}, journal = {Acta neurologica Scandinavica}, volume = {92}, number = {5}, pages = {387-393}, doi = {10.1111/j.1600-0404.1995.tb00152.x}, pmid = {8610492}, issn = {0001-6314}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*cerebrospinal fluid/diagnosis/*immunology ; Antibodies, Anti-Idiotypic/*cerebrospinal fluid/*immunology ; Antibodies, Monoclonal ; Brain Chemistry ; Chromatography, Thin Layer ; Enzyme-Linked Immunosorbent Assay ; Fatal Outcome ; G(M1) Ganglioside/*cerebrospinal fluid/*immunology ; Humans ; Immunoglobulin M/*cerebrospinal fluid/*immunology ; Immunohistochemistry ; In Vitro Techniques ; Magnetic Resonance Imaging ; Male ; Spinal Cord/ultrastructure ; }, abstract = {INTRODUCTION: The significance of the association of motor neuron syndromes with anti-GM1 antibodies remains unclear. We report the immunological study of a juvenile case of amyotrophic lateral sclerosis (ALS).<br><br>MATERIALS AND METHODS: Serum anti-Gm1 and anti-neurofilament antibodies were assayed by ELISA and western blotting and cerebrospinal fluid (CSF) isoelectrofocusing was performed. Immunocytochemical studies were carried out with the patient's serum and CSF on human brain and spinal cord sections.<br><br>RESULTS: Serum polyclonal IgM anti-GM1, anti-neurofilament antibodies and CSF oligoclonal bands were detected. Furthermore, an in vitro production of anti-GM1 IgM was demonstrated. Immunocytochemical studies showed cytoplasm motor neuron immunostaining, due to both IgG and IgM, that substantially decreased after immunoabsorption of the serum with bovine neurofilament proteins but not with GM1-containing liposomes. No immunostaining was obtained with CSF. Immunosuppressive treatment with cyclophosphamide and two cycles of plasma exchanges lowered anti-GM1 antibody levels, but did not determine any clinical improvement.<br><br>CONCLUSION: To our knowledge, this is the first report of ALS, associated with circulating levels and in vitro production of polyclonal IgM anti-GM1, anti-neurofilament antibodies and CSF oligoclonal bands. These findings suggest the occurrence in our patients of an autoimmune process that could be involved in the pathogenesis of ALS.}, }
@article {pmid8599726, year = {1995}, author = {Apfel, SC and Kessler, JA}, title = {Neurotrophic factors in the therapy of peripheral neuropathy.}, journal = {Bailliere's clinical neurology}, volume = {4}, number = {3}, pages = {593-606}, pmid = {8599726}, issn = {0961-0421}, mesh = {Diabetic Neuropathies ; Humans ; Insulin-Like Growth Factor I ; Insulin-Like Growth Factor II ; Nerve Growth Factors/therapeutic use ; Peripheral Nervous System Diseases/drug therapy/*etiology ; Receptors, Growth Factor/physiology ; }, abstract = {Neurotrophic factors are proteins that promote the survival and differentiation of specific populations of neurones. With the successful cloning and large-scale production of many different neurotrophic factors, it has become practical to consider their application in the treatment of neurological disease. Several groups of neurotrophic factors hold particular promise for the therapy of peripheral nervous system disease in the near future. These include the neurotrophin gene family, cytokines such as CNTF and the IGF family. Evidence is accumulating that an abnormal availability of some of these factors may contribute towards the pathophysiology of some types of neuropathy, most notably diabetic neuropathy. Pre-clinical studies in animal models have demonstrated the likely efficacy of factors such as NGF for small-fibre sensory neuropathy, BDNF, CNTF and IGF-I for motor neurone disease, and NT-3 for large-fibre neuropathy. Clinical trials of several growth factors are currently underway for the treatment of peripheral nerve disease, and other clinical trials are currently being planned.}, }
@article {pmid8599725, year = {1995}, author = {Sendtner, M}, title = {Molecular biology of neurotrophic factors.}, journal = {Bailliere's clinical neurology}, volume = {4}, number = {3}, pages = {575-591}, pmid = {8599725}, issn = {0961-0421}, mesh = {Animals ; Humans ; Insulin-Like Growth Factor I/cerebrospinal fluid ; Insulin-Like Growth Factor II/cerebrospinal fluid ; Mice ; Nerve Growth Factors/*therapeutic use ; Peripheral Nervous System Diseases/drug therapy ; RNA, Messenger ; Rats ; Receptors, Growth Factor/*physiology ; }, abstract = {The survival and functional maintenance of spinal motoneurones and of peripheral neurones, such as sensory, sympathetic and parasympathetic neurones, has been shown to depend on neurotrophic factors, both during the period of developmental cell death and in adulthood. A variety of such factors has been identified over recent years, among them factors of the NGF gene family, for example BDNF, NT-3, NT-4/5 and NT-6, and factors such as CNTF and LIF acting on neuronal target cells via receptor components shared with cytokines such as IL-6. In addition, pluripotent mitogens, such as IGF-I and IGF-II can support the survival of a variety of neuronal cell types, including spinal motoneurones both in cell culture and in vivo. The establishment of mice in which the genes for these factors and their receptors have been inactivated by homologous recombination has been a major step in the understanding of their physiological function. It is not clear so far whether or not similar gene defects in human are associated with any neurological disease. However, some of these factors have been demonstrated to be effective in animal models of neuropathy and motoneurone disorders, so that first clinical trials using these factors for symptomatic treatment of amyotrophic lateral sclerosis (ALS) and peripheral neuropathies have already been initiated.}, }
@article {pmid8573965, year = {1995}, author = {Welty, DF and Schielke, GP and Rothstein, JD}, title = {Potential treatment of amyotrophic lateral sclerosis with gabapentin: a hypothesis.}, journal = {The Annals of pharmacotherapy}, volume = {29}, number = {11}, pages = {1164-1167}, doi = {10.1177/106002809502901118}, pmid = {8573965}, issn = {1060-0280}, mesh = {Acetates/pharmacology/*therapeutic use ; *Amines ; Amino Acids, Branched-Chain/metabolism ; Amyotrophic Lateral Sclerosis/*drug therapy/etiology/metabolism ; Anticonvulsants/pharmacology/*therapeutic use ; Brain/metabolism ; *Cyclohexanecarboxylic Acids ; Excitatory Amino Acid Antagonists/pharmacology ; Gabapentin ; Glutamates/metabolism ; Humans ; *gamma-Aminobutyric Acid ; }, abstract = {OBJECTIVE: To provide the biochemical rationale for the use of the new anticonvulsant agent gabapentin as a treatment for amyotrophic lateral sclerosis (ALS).<br><br>BACKGROUND: ALS is a neuropathologic disorder of the central nervous system characterized by a progressive loss of upper and lower motor neurons. Although the etiopathology of ALS is incompletely known, it is hypothesized that glutamatergic neurotransmission is related to neuropathology. Glutamate is an excitatory amino acid neurotransmitter that is cytotoxic when overexpressed at synaptic terminals, probably through a calcium-related mechanism. The concentration of glutamate in cerebrospinal fluid is increased in patients with ALS. The increased extracellular concentrations of glutamate may be caused by a decreased capacity of glutamate transport in brain tissue and/or abnormal glutamate metabolism. Recent success with the glutamate release inhibitor riluzole in well-controlled clinical trials supports the excitotoxic mechanism of neuropathology in patients with ALS. POTENTIAL TREATMENT FOR ALS: Gabapentin has demonstrated neuroprotective properties in a model of chronic glutamate toxicity in vitro. Although the neuroprotective mechanism of action of gabapentin is currently unknown, it is hypothesized here that gabapentin decreases the rate of formation of glutamate derived from the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. The proposed decrease in formation of glutamate from BCAAs may decrease the pool of releasable glutamate and therefore compensate for diminished glutamate uptake capacity and/or abnormal glutamate metabolism in patients with ALS.<br><br>CONCLUSIONS: Based on this rationale, it is proposed that gabapentin may provide a beneficial effect in the treatment of patients with ALS.}, }
@article {pmid8573963, year = {1995}, author = {Cory, PR and Gidal, Be}, title = {Potential use of gabapentin and lamotrigine.}, journal = {The Annals of pharmacotherapy}, volume = {29}, number = {11}, pages = {1160-1161}, doi = {10.1177/106002809502901116}, pmid = {8573963}, issn = {1060-0280}, mesh = {Acetates/pharmacology/*therapeutic use ; *Amines ; Amyotrophic Lateral Sclerosis/*drug therapy ; Anticonvulsants/pharmacology/*therapeutic use ; Clinical Trials as Topic ; *Cyclohexanecarboxylic Acids ; Drugs, Investigational/pharmacology/therapeutic use ; Gabapentin ; Humans ; Lamotrigine ; Triazines/pharmacology/*therapeutic use ; *gamma-Aminobutyric Acid ; }, abstract = {Based on the proposed neurotoxic etiology of ALS and possible actions of gabapentin and lamotrigine, there is some reason to hope for a beneficial response when using these agents in patients with ALS. However, because of the lack of evidence supporting this use, the cost of treatment, and the risk of adverse effects, there is no rationale for this use before larger, controlled clinical trials are completed.}, }
@article {pmid7482739, year = {1995}, author = {Shimomura, K and Hardy, MA and Oluwole, SF}, title = {Tolerance induction to cardiac allografts by simultaneous or sequential intrathymic inoculation of disparate alloantigens.}, journal = {Transplantation}, volume = {60}, number = {8}, pages = {806-811}, pmid = {7482739}, issn = {0041-1337}, support = {CA52678/CA/NCI NIH HHS/United States ; HL14799/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Graft Rejection/immunology/*prevention &amp; control ; Graft Survival ; *Heart Transplantation ; Immunotherapy, Adoptive ; Isoantigens/*administration &amp; dosage ; Rats ; Rats, Inbred Strains ; Spleen/immunology ; Thymus Gland/immunology ; Transplantation, Homologous ; }, abstract = {Recent studies show that the adult immune system can be manipulated to accept allografts by the intrathymic (IT) inoculation of donor alloantigens (Ag). To make this model clinically applicable to cadaveric transplants, we have examined the effect of simultaneous or sequential IT injection of two disparate Ags on graft survival. In initial experiments, Wistar Furth (WF) rats received IT injections of a single or an admixture of 2 x 10(7) Lewis T cells and 2 x 10(7) BN T cells 7 days prior to cardiac transplantation. Untreated WF recipients acutely rejected single Lewis, BN, and ACI heart allografts, respectively, at times equivalent to rejection of double hearts while IT injection of single or double 2 x 10(7) Lewis and 2 x 10(7) BN T cells on day -7 also led to acute graft rejection. As expected, IT injection of donor-type resting T cells combined with 1 ml ALS recipient immunosuppression on day -7 led to donor-specific Lewis or BN permanent graft survival (> 200 days). The long-term unresponsive WF recipients challenged 100 days after cardiac transplantation with 2nd-set grafts specifically and permanently accepted 2nd-set donor cardiac allografts. IT injection of an admixture of 2 x 10(7) Lewis and 2 x 10(7) BN T-cells combined with 1 ml ALS on day -7 resulted in 100% permanent double (Lewis and BN) allograft survivals (> 150 days). Similar treatment led to acute rejection of third-party (ACI) grafts while the simultaneously transplanted Lewis hearts survived indefinitely (> 150 days). In the second group of experiments, unresponsive recipients of single (Lewis or BN) cardiac allografts were given IT inoculation of a second Ag in a sequential fashion 30 or 100 days after primary heart transplant. Unresponsive WF recipients of Lewis grafts accepted permanently (> 100 days) second BN grafts that were transplanted 30 or 100 days after primary Lewis graft and 7 days after IT injection of BN T-cells and 1 ml ALS. Similarly, unresponsive WF recipients of BN grafts accepted second Lewis grafts after IT injection of Lewis T cells combined with ALS, 30 or 100 days after primary BN grafts. To define the mechanism of peripheral tolerance in this model, we have shown that adoptive transfer of unseparated spleen cells from unresponsive recipients induces prolonged double (Lewis and BN) graft survivals (> 60 days) but not ACI grafts in sublethally irradiated (400 rads) syngeneic (WF) recipients, thus suggesting that maintenance of tolerance is, in part, dependent on suppressor/regulatory cell network.(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid7568215, year = {1995}, author = {Li, L and Wu, W and Lin, LF and Lei, M and Oppenheim, RW and Houenou, LJ}, title = {Rescue of adult mouse motoneurons from injury-induced cell death by glial cell line-derived neurotrophic factor.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {92}, number = {21}, pages = {9771-9775}, pmid = {7568215}, issn = {0027-8424}, support = {HD29435/HD/NICHD NIH HHS/United States ; NS20402/NS/NINDS NIH HHS/United States ; NS31380/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain-Derived Neurotrophic Factor ; Cell Count ; Cell Line ; Glial Cell Line-Derived Neurotrophic Factor ; Histocytochemistry ; Insulin-Like Growth Factor I/pharmacology ; Mice ; Mice, Inbred BALB C ; Motor Neurons/cytology/drug effects/*physiology ; NADPH Dehydrogenase/isolation &amp; purification ; Nerve Degeneration/*drug effects ; Nerve Growth Factors/*pharmacology ; Nerve Tissue Proteins/*pharmacology ; Nitric Oxide Synthase/isolation &amp; purification ; Rats ; Rats, Sprague-Dawley ; Spinal Nerve Roots/cytology/drug effects/*physiology/surgery ; }, abstract = {Glial cell line-derived neurotrophic factor (GDNF) has been shown to rescue developing motoneurons in vivo and in vitro from both naturally occurring and axotomy-induced cell death. To test whether GDNF has trophic effects on adult motoneurons, we used a mouse model of injury-induced adult motoneuron degeneration. Injuring adult motoneuron axons at the exit point of the nerve from the spinal cord (avulsion) resulted in a 70% loss of motoneurons by 3 weeks following surgery and a complete loss by 6 weeks. Half of the loss was prevented by GDNF treatment. GDNF also induced an increase (hypertrophy) in the size of surviving motoneurons. These data provide strong evidence that the survival of injured adult mammalian motoneurons can be promoted by a known neurotrophic factor, suggesting the potential use of GDNF in therapeutic approaches to adult-onset motoneuron diseases such as amyotrophic lateral sclerosis.}, }
@article {pmid8568533, year = {1995}, author = {Mazzini, L and Corrà, T and Zaccala, M and Mora, G and Del Piano, M and Galante, M}, title = {Percutaneous endoscopic gastrostomy and enteral nutrition in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {242}, number = {10}, pages = {695-698}, pmid = {8568533}, issn = {0340-5354}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/mortality/*therapy ; Case-Control Studies ; Endoscopy/*methods ; *Enteral Nutrition ; Female ; Gastrostomy/*methods ; Humans ; Male ; Middle Aged ; Muscle Weakness/*etiology ; Survival Rate ; }, abstract = {Bulbar involvement in amyotrophic lateral sclerosis (ALS) is often related to a worse prognosis on account of the higher risk of pulmonary aspiration and undernutrition due to dysphagia. The aim of our study was to assess the effects of enteral feeding by percutaneous endoscopic gastrostomy (PEG) in a long-term follow-up of ALS patients. We report the results of PEG in 31 ALS patients with bulbar involvement. The patients were observed at 3-monthly intervals over a period of 2 years after PEG. All the data were compared with those obtained from a control group of 35 ALS patients who refused PEG. Mortality did not differ significantly between the two groups of patients during the first 6 months of observation, whereas after this period it was lower in the PEG group. In the patients who had had PEG, the body mass index showed a mild but statistically significant improvement after tube insertion while in the control group it decreased significantly. The findings of this study demonstrate that PEG can improve survival in elderly and young ALS patients with bulbar involvement; it enhances their quality of life and helps their integration in their social and family surroundings. We think that PEG should be included symptomatic treatment of all ALS patients with bulbar involvement from the onset of symptoms.}, }
@article {pmid8560109, year = {1995}, author = {Zaritsky, A and Nadkarni, V and Hazinski, MF and Foltin, G and Quan, L and Wright, J and Fiser, D and Zideman, D and O'Malley, P and Chameides, L}, title = {Recommended guidelines for uniform reporting of pediatric advanced life support: the Pediatric Utstein Style. A statement for healthcare professionals from a task force of the American Academy of Pediatrics, the American Heart Association, and the European Resuscitation Council.}, journal = {Resuscitation}, volume = {30}, number = {2}, pages = {95-115}, doi = {10.1016/0300-9572(95)00884-v}, pmid = {8560109}, issn = {0300-9572}, mesh = {Child ; Data Collection/standards ; *Emergency Medical Services ; Europe ; Humans ; *Life Support Care ; *Pediatrics ; Records/standards ; *Resuscitation ; Terminology as Topic ; United States ; }, abstract = {This consensus document is an attempt to provide an organized method of reporting pediatric ALS data in out-of-hospital, emergency department, and in-hospital settings. For this methodology to gain wide acceptance, the task force encourages development of a common data set for both adult and pediatric ALS interventions. In addition, every effort should be made to ensure that consistent definitions are used in all age groups. As health care changes, we will all be challenged to document the effectiveness of what we currently do and show how new interventions or methods of treatment improve outcome and/or reduce cost. Only through collaborative research will we obtain the necessary data. For these reasons, and to improve the quality of care and patient outcomes, it is the hope of the task force that clinical researchers will follow the recommendations in this document. It is recognized that further refinements of this statement will be needed; these recommendations will improve only when researchers, clinicians, and EMS personnel use them, work with them, and modify them. Suggestions, recommendations, and other comments aimed at improving the reporting of pediatric resuscitation should be sent to Arno Zaritsky, MD, Eastern Virginia Medical School, Children's Hospital of The King's Daughter, Division of Critical Care Medicine, 601 Children's Lane, Norfolk, VA 23507.}, }
@article {pmid8541436, year = {1995}, author = {Fischer, M and Fischer, N and Schüttler, J}, title = {[Which dosage concept for adrenaline is correct in cardiopulmonary resuscitation? A data analysis of preclinical resuscitations].}, journal = {Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie : AINS}, volume = {30}, number = {6}, pages = {350-356}, doi = {10.1055/s-2007-996508}, pmid = {8541436}, issn = {0939-2661}, mesh = {Adolescent ; Adult ; Aged ; Cardiopulmonary Resuscitation/*methods ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Emergency Medical Services ; Epinephrine/*administration &amp; dosage/adverse effects ; Female ; Heart Arrest/*drug therapy/mortality ; Hemodynamics/drug effects ; Hospital Mortality ; Humans ; Male ; Middle Aged ; Survival Rate ; Treatment Outcome ; }, abstract = {AIM: Epinephrine is the drug of choice in cardiopulmonary resuscitation. Its dosage, however, is controversially discussed. The American Heart Association recommends for standard use in adults 1 mg epinephrine every 3-5 minutes, but classifies a medium dose, a high dose and a step-by-step escalating dosage concept as potentially useful alternatives. Aim of this study was to develop a rationale for the escalating dosage concept using an analysis of preclinical resuscitation data.<br><br>METHODS: Bonn city (141 km2, 310,000 residents, 52% female, 13.9% > 65 years) was served by a double-response system of two ALS-units (staffed by physicians) and four BLS-units (staffed by paramedics). All patients were included in this data analysis, which were cardiopulmonary resuscitated according to the AHA guidelines by the ALS-unit Bonn-North (66% of area and 240,000 residents) from 1989 to 1994. All relevant data were documented by the emergency physicians using preformed treatment sheets. Discharge rates were determined by reviewing the hospital records, and one-year survival data were collected by mail contact with the primary physicians. The correlations between duration of cardiac arrest, dosage of epinephrine and outcome were determined by regression analysis in patients older than 17 years suffering from unwitnessed and bystander-witnessed cardiac arrest. Statistical significance was assumed for p < 0.05.<br><br>RESULTS: Within 1989 to 1994 the ALS-team of Bonn-North resuscitated 685 cardiac arrest patients with presumed cardiac aetiology in 383 (56%) return of spontaneous circulation (ROSC) could be achieved. The epinephrine dosage required to achieve ROSC increased with prolongation of cardiac arrest interval (1989-1994; patients with ROSC selected, n = 263; r = 0.2276; p = 0.0002). Resuscitation success, however, decreased with increasing, dosage of epinephrine (1989-1992; n = 345; ROSC: r = -0.2643; p < 0.001; survival > 24 h: r = -0.3393; p < 0.001; discharge: r = -0.1677; p = 0.0018; survival > 1 year: r = -0.2685; p < 0.001).<br><br>CONCLUSION: Based on these data, we recommend an escalating epinephrine dosage concept, which facilitates titration of the drug to an effective level and meets the needs of the individual patient. This concept avoids overdosage in patients who had just collapsed shortly before initiation of CPR, attains higher levels of epinephrine in patients suffering from prolonged cardiac arrest, and takes into consideration that the effective epinephrine dose varies individually and increases with prolongation of the cardiac arrest interval.}, }
@article {pmid7671387, year = {1995}, author = {Zaritsky, A and Nadkarni, V and Hazinski, MF and Foltin, G and Quan, L and Wright, J and Fiser, D and Zideman, D and O'Malley, P and Chameides, L}, title = {Recommended guidelines for uniform reporting of pediatric advanced life support: the pediatric Utstein Style. A statement for healthcare professionals from a task force of the American Academy of Pediatrics, the American Heart Association, and the European Resuscitation Council. Writing Group.}, journal = {Circulation}, volume = {92}, number = {7}, pages = {2006-2020}, doi = {10.1161/01.cir.92.7.2006}, pmid = {7671387}, issn = {0009-7322}, mesh = {Child ; Data Collection/standards ; *Emergency Medical Services ; Europe ; Humans ; *Life Support Care ; *Pediatrics ; Records/standards ; *Resuscitation ; Terminology as Topic ; United States ; }, abstract = {This consensus document is an attempt to provide an organized method of reporting pediatric ALS data in out-of-hospital, emergency department, and in-hospital settings. For this methodology to gain wide acceptance, the task force encourages development of a common data set for both adult and pediatric ALS interventions. In addition, every effort should be made to ensure that consistent definitions are used in all age groups. As health care changes, we will all be challenged to document the effectiveness of what we currently do and show how new interventions or methods of treatment improve outcome and/or reduce cost. Only through collaborative research will we obtain the necessary data. For these reasons, and to improve the quality of care and patient outcomes, it is the hope of the task force that clinical researchers will follow the recommendations in this document. It is recognized that further refinements of this statement will be needed; these recommendations will improve only when researchers, clinicians, and EMS personnel use them, work with them, and modify them. Suggestions, emendations, and other comments aimed at improving the reporting of pediatric resuscitation should be sent to Arno Zaritsky, MD, Eastern Virginia Medical School, Children's Hospital of the King's Daughter, Division of Critical Care Medicine, 601 Children's Lane, Norfolk, VA 23507.}, }
@article {pmid7567346, year = {1995}, author = {Zaritsky, A and Nadkarni, V and Hazinski, MF and Foltin, G and Quan, L and Wright, J and Fiser, D and Zideman, D and O'Malley, P and Chameides, L}, title = {Recommended guidelines for uniform reporting of pediatric advanced life support: the pediatric Utstein style. A statement for healthcare professionals from a task force of the American Academy of Pediatrics, the American Heart Association, and the European Resuscitation Council.}, journal = {Pediatrics}, volume = {96}, number = {4 Pt 1}, pages = {765-779}, pmid = {7567346}, issn = {0031-4005}, mesh = {Child ; Data Collection/standards ; *Emergency Medical Services ; Europe ; Humans ; *Life Support Care ; *Pediatrics ; Records/standards ; *Resuscitation ; Terminology as Topic ; United States ; }, abstract = {This consensus document is an attempt to provide an organized method of reporting pediatric ALS data in out-of-hospital, emergency department, and in-hospital settings. For this methodology to gain wide acceptance, the task force encourages development of a common data set for both adult and pediatric ALS interventions. In addition, every effort should be made to ensure that consistent definitions are used in all age groups. As health care changes, we will all be challenged to document the effectiveness of what we currently do and show how new interventions or methods of treatment improve outcome and/or reduce cost. Only through collaborative research will we obtain the necessary data. For these reasons, and to improve the quality of care and patient outcomes, it is the hope of the task force that clinical researchers will follow the recommendations in this document. It is recognized that further refinements of this statement will be needed; these recommendations will improve only when researchers, clinicians, and EMS personnel use them, work with them, and modify them. Suggestions, emendations, and other comments aimed at improving the reporting of pediatric resuscitation should be sent to Arno Zaritsky, MD, Eastern Virginia Medical School, Children's Hospital of The King's Daughter, Division of Critical Care Medicine, 601 Children's Lane, Norfolk, VA 23507.}, }
@article {pmid7476305, year = {1995}, author = {Baxter, RC}, title = {Insulin-like growth factor binding proteins as glucoregulators.}, journal = {Metabolism: clinical and experimental}, volume = {44}, number = {10 Suppl 4}, pages = {12-17}, doi = {10.1016/0026-0495(95)90215-5}, pmid = {7476305}, issn = {0026-0495}, mesh = {Blood Glucose/*metabolism ; Humans ; Hypoglycemia/metabolism ; Insulin-Like Growth Factor Binding Protein 1/physiology ; Insulin-Like Growth Factor Binding Proteins/*physiology ; }, abstract = {Circulating insulin-like growth factors (IGFs) represent an important pool of potential hypoglycemic activity, which is largely inhibited by their sequestration in a heterotrimeric complex comprising growth factor, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS). Less than 1% of total IGFs circulate in the free form, yet even this amount might contribute significantly to circulating insulin-like activity. The ternary binding protein complex appears to inhibit insulin-like activity of bound IGFs by preventing their egress from the circulation. Although the integrity of this complex might be affected by limited proteolysis of IGFBP-3 in pregnancy and catabolic conditions, the evidence that this increases IGF bioavailability, and thus hypoglycemic potential, is as yet unclear. However, in patients with IGF-II-secreting tumors, hypoglycemia may result from a failure of the ternary complex to adequately sequester the IGFs. Improvement in complex formation, by treatment with corticosteroids or growth hormone, alleviates the hypoglycemia, even if (as seen with growth hormone treatment) IGF-II hypersecretion persists. In these patients, blood glucose levels are inversely correlated with IGFBP-2 levels, suggesting that this protein might play a part in transporting IGFs to their target tissues. Conversely, ALS levels correlate positively with blood glucose, emphasizing the importance of the ternary complex in preventing hypoglycemia. Unlike the other IGF-binding proteins, IGFBP-1 is acutely regulated in the circulation, in a manner consistent with its acting as a glucose counterregulator. It might act in this way by inhibiting the activity of free IGFs in the circulation.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7486597, year = {1995}, author = {Trembly, B}, title = {Clinical potential for the use of neuroprotective agents. A brief overview.}, journal = {Annals of the New York Academy of Sciences}, volume = {765}, number = {}, pages = {1-20; discussion 26-7}, doi = {10.1111/j.1749-6632.1995.tb16554.x}, pmid = {7486597}, issn = {0077-8923}, mesh = {Animals ; Brain Diseases/*drug therapy ; Brain Injuries/*drug therapy ; Brain Ischemia/*drug therapy ; Calcium Channel Blockers/therapeutic use ; Cerebrovascular Disorders/*drug therapy ; Epilepsy/drug therapy ; Humans ; Hypothermia/drug therapy/physiopathology ; Ischemic Attack, Transient/drug therapy ; Neuroprotective Agents/*therapeutic use ; Neurosurgery ; Nimodipine/therapeutic use ; Postoperative Complications/drug therapy ; Spinal Cord Injuries/*drug therapy ; Subarachnoid Hemorrhage/*drug therapy ; }, abstract = {"Stroke treatment seems to be entering a golden age ...." Fisher's observation not only applies to ischemic stroke, but to all the conditions described above, and in the future, possibly (and quite speculatively), to other neurologic diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, even radiation therapy and Bell's palsy. Physicians must sharpen their criteria for decisions regarding therapy and must" ... be prepared to accept what is actually known from scientific data ... rather than to rely on instinct, clinical impression, or the need to do something rather than nothing."}, }
@article {pmid8584093, year = {1995}, author = {Szczudlik, A and Słowik, A and Tomik, B}, title = {[The effect of amitriptyline on the pathological crying and other pseudobulbar signs].}, journal = {Neurologia i neurochirurgia polska}, volume = {29}, number = {5}, pages = {663-674}, pmid = {8584093}, issn = {0028-3843}, mesh = {Adult ; Aged ; Alzheimer Disease/*physiopathology/psychology ; Amitriptyline/*pharmacology/*therapeutic use ; Amyotrophic Lateral Sclerosis/physiopathology/psychology ; Antidepressive Agents/*pharmacology/*therapeutic use ; Brain/*drug effects/*physiopathology ; Crying/*psychology ; Female ; Humans ; Male ; Middle Aged ; Mood Disorders/*drug therapy/etiology ; }, abstract = {The efficacy and tolerability of amitriptyline on the pathologic crying and other pseudobulbar signs were investigated in 22 consecutive patients diagnosed mostly as ALS. The occurrence and intensity of pathologic crying, dysarthria, dysphagia, jaw reflex and primitive reflexes (snout, palmo-mental and oral), were assessed before and after 3 and 6 weeks of amitriptyline treatment. The drug administered in low dose (30-100 mg, mean 64 +/- 17.6 mg) significantly decreased the frequency of pathologic crying in 17 patients after 3 weeks and in 20 patients after 6 weeks of treatment. There were no changes in the intensity of the other pseudobulbar signs. Only few mild and transient side effects were observed. The authors conclude, that amitriptyline is an effective treatment of pathologic crying in ALS patients.}, }
@article {pmid7545698, year = {1995}, author = {Baxter, RC and Holman, SR and Corbould, A and Stranks, S and Ho, PJ and Braund, W}, title = {Regulation of the insulin-like growth factors and their binding proteins by glucocorticoid and growth hormone in nonislet cell tumor hypoglycemia.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {80}, number = {9}, pages = {2700-2708}, doi = {10.1210/jcem.80.9.7545698}, pmid = {7545698}, issn = {0021-972X}, mesh = {Aged ; Aged, 80 and over ; Carrier Proteins/*metabolism ; Female ; Fibroma/complications ; Growth Hormone/*therapeutic use ; Humans ; Hypoglycemia/*etiology/metabolism ; Insulin-Like Growth Factor Binding Proteins ; Insulin-Like Growth Factor II/metabolism ; Pleural Neoplasms/*complications ; Prednisone/*therapeutic use ; Somatomedins/*metabolism ; }, abstract = {Hypoglycemia in patients with nonislet cell tumors is often secondary to overexpression of tumor insulin-like growth factor (IGF) II. In these patients the formation of serum complexes between IGFs, IGF binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) is impaired. An 87-yr-old woman with nonislet cell tumor hypoglycemia resulting from a localized fibrous tumor of the pleura was treated for 97 days with graded doses of prednisolone (30, 10, and 5 mg/day) followed by GH (1, 4, 8, 4, and 2 U/day). Both prednisolone and GH alleviated the hypoglycemia, concomitantly with increases in IGF-I, IGFBP-3, and ALS levels. Pretreatment serum IGFBP-2 and IGFBP-6 levels were greatly elevated, but as glucose normalized with treatment, only IGFBP-2 decreased, showing an inverse correlation with glucose (r = 0.716). IGFBP-1 gave a variable pattern not clearly related to blood glucose. Both treatments caused a redistribution of serum IGFBP-3 from binary- to ternary-complexed forms. However, only prednisolone improved the ability of IGFBP-3 to bind ALS in vitro. Prednisolone also suppressed IGF-II, the effect being confined to pro-IGF-II forms. Compared with normal IGF-II, pro-IGF-II inhibited ALS binding to IGFBP-3 in vitro. Although prednisolone and GH reverse hypoglycemia by different mechanisms, with only prednisolone suppressing tumor IGF-II secretion, both increase the formation of ternary IGF-IGFBP-3 complexes. We conclude that the failure of serum IGFBP-3 and tumor IGF-II to complex with ALS is a primary cause of hypoglycemia in nonislet cell tumor hypoglycemia.}, }
@article {pmid7496172, year = {1995}, author = {Ikeda, K and Kinoshita, M and Iwasaki, Y and Tagaya, N and Shiojima, T}, title = {Lecithinized superoxide dismutase retards wobbler mouse motoneuron disease.}, journal = {Neuromuscular disorders : NMD}, volume = {5}, number = {5}, pages = {383-390}, doi = {10.1016/0960-8966(95)00003-6}, pmid = {7496172}, issn = {0960-8966}, mesh = {Animals ; Forelimb/abnormalities ; Liposomes ; Mice ; Mice, Neurologic Mutants ; Motor Neuron Disease/*drug therapy/genetics ; Muscle Denervation ; Muscle, Skeletal/drug effects ; Oxidative Stress ; Phosphatidylcholines ; Superoxide Dismutase/administration &amp; dosage/*therapeutic use ; }, abstract = {Gene mutations of Cu/Zn superoxide dismutase (SOD) have been discovered in familial amyotrophic lateral sclerosis (ALS). Oxidative stress also plays a role in the pathogenesis of sporadic ALS. Whether antioxidant therapy is beneficial in this fatal disease is now crucial. We have shown that SOD treatment improves neuromuscular dysfunction and morphological changes in wobbler mouse motoneuron disease. Progressive spinal motor neuronopathy and axonopathy, predominantly in the cervical cord, occur at postnatal age 3-4 weeks, leading to muscle weakness and contracture of the forelimbs in this animal. These motor deficits rapidly increase by postnatal age 6-8 weeks, and then slowly progress. Wobbler mice were given two doses daily of phosphatidyl choline-bound Cu/Zn SOD (PC-SOD, 10(4), 10(5) U/kg) or a vehicle solution by intraperitoneal injection from postnatal 3-4 to postnatal 7-8 weeks of age. PC-SOD treatment attenuated progression of motor dysfunction, prevented denervation muscle atrophy, and delayed degeneration of spinal motoneurons in wobbler mice. This raises the possibility that PC-SOD may have therapeutic potential in human motoneuron disease.}, }
@article {pmid7674346, year = {1995}, author = {Alonso, K and Medenica, R}, title = {Immunomodulation in the treatment of multiple sclerosis and amyotrophic lateral sclerosis: a model for autoimmune disorders.}, journal = {Journal of the National Medical Association}, volume = {87}, number = {8}, pages = {561-568}, pmid = {7674346}, issn = {0027-9684}, mesh = {Adjuvants, Immunologic/*therapeutic use ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*therapy ; Autoimmune Diseases/complications/*therapy ; Female ; Humans ; Male ; Middle Aged ; Multiple Sclerosis/complications/*therapy ; Treatment Outcome ; }, abstract = {Seventeen multiple sclerosis (MS) patients progressing under conventional therapy (average treatment duration: 3 years) with performance status 3-4 (mean Disability Status Scale [DSS]: 82) who demonstrated circulating lymphokine inhibitor factors were selected for a monthly immunomodulatory protocol using plasmapheresis, followed by 3 days of human intravenous immunoglobulin, and low-dose methylprednisolone, cyclophosphamide, interferon-a, and interferon-g, as well as octreide. Twelve of the 17 patients presented with visual problems, 12 had lower extremity weakness or paraperesis/paralysis, and 6 had bladder/bowel dysfunction. Following 4 months of therapy, 4 recovered completely, 7 showed loss of paralysis/paraparesis, and 5 had improvement in lower extremity weakness. One patient progressed (mean DSS: 51). Lymphokine inhibitor factors declined in 14 patients with concomitant normalization of circulating immune complexes. Eight patients experienced rises in CD4 levels with stabilization of CD8 levels. Hypotension and hypocalcemia were observed during plasmapheresis. Twelve patients with amyotrophic lateral sclerosis with poor performance status also were studied. Four of the 12 improved with the regimen, whereas six stabilized disease. Similar alterations in laboratory parameters were described. The rationale for this approach is discussed.}, }
@article {pmid7549102, year = {1995}, author = {Uchijima, Y and Takenaka, A and Takahashi, S and Noguchi, T}, title = {Production of insulin-like growth factors and their binding proteins in primary cultures of rat liver parenchymal and nonparenchymal cells.}, journal = {Bioscience, biotechnology, and biochemistry}, volume = {59}, number = {8}, pages = {1503-1515}, doi = {10.1271/bbb.59.1503}, pmid = {7549102}, issn = {0916-8451}, mesh = {Animals ; Base Sequence ; Cells, Cultured ; Hormones/pharmacology ; Insulin-Like Growth Factor Binding Proteins/*biosynthesis/genetics ; Liver/cytology/drug effects/*metabolism ; Male ; Molecular Sequence Data ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Receptors, Somatotropin/genetics/metabolism ; Somatomedins/*biosynthesis/genetics ; }, abstract = {Regulation of the production of insulin-like growth factor (IGF)-I, IGF-II, IGF binding proteins (IGFBPs), and their related proteins by various hormones was investigated in primary cultures of rat liver parenchymal and nonparenchymal cells. Freshly isolated parenchymal cells contained mRNAs of IGF-I, IGF-II, IGFBP-1, IGFBP-4, growth hormone (GH) receptor, and the acid-labile subunit (ALS), which forms a ternary complex with IGF-I and IGFBP-3; however, parenchymal cells did not express the IGFBP-3 gene. In contrast, nonparenchymal cells contained IGFBP-3 mRNA exclusively, as we reported previously [Takenaka et al. Agric. Biol. Chem., 55, 1191-1193 (1991)]. Cultured rat parenchymal cells produced IGF-I, IGFBP-1, and IGFBP-4 prominently. In these cells, secretion of IGF-I and the content of IGF-I mRNA was greatly increased in the presence of GH in the medium. Insulin also increased the production of IGF-I. Secretion of IGFBP-1 into the medium was enhanced by treatment with glucagon, dibutyrylcyclic AMP (Bu2cAMP), and dexamethasone (Dex) and these enhancements with glucagon and Dex reflected the increase in its mRNA content. Insulin depressed the secretion of IGFBP-1. The content of IGFBP-4 in the parenchymal cells was increased by insulin, Bu2cAMP, and triiodothyronine (T3), thereby enhancing the production of IGFBP-4 and secretion into the medium. Cultured liver nonparenchymal cells of rats produced IGFBP-1, IGFBP-3, and IGFBP-4. Secretion of IGFBP-1 was increased by Bu2cAMP in the medium, that of IGFBP-3 by IGF-I, and that of IGFBP-4 by both IGF-I and Bu2cAMP. Regulation of the production of IGFBP-3 by IGF-I was demonstrated in these investigations. These results suggest that GH increases production of IGF-I in the parenchymal cells and this IGF-I, in turn, increases the production of IGFBP-3 in nonparenchymal cells. As we found GH also increases ALS production in parenchymal cells, by these mechanisms, GH increases the formation of the ternary complex of IGF-I, IGFBP-3, and ALS. This study clearly demonstrates the interrelationship between parenchymal and nonparenchymal cells in the production of IGF-I and IGFBPs in the liver.}, }
@article {pmid7646537, year = {1995}, author = {Eizirik, DL and Kisby, GE}, title = {Cycad toxin-induced damage of rodent and human pancreatic beta-cells.}, journal = {Biochemical pharmacology}, volume = {50}, number = {3}, pages = {355-365}, doi = {10.1016/0006-2952(95)00150-x}, pmid = {7646537}, issn = {0006-2952}, support = {NS-19611/NS/NINDS NIH HHS/United States ; }, mesh = {Alkylating Agents/*toxicity ; Amino Acids, Diamino/toxicity ; Animals ; Cyanobacteria Toxins ; Cycasin/*toxicity ; DNA/analysis ; Diabetes Mellitus/chemically induced ; Environmental Exposure ; Glucose/metabolism/pharmacology ; Humans ; In Vitro Techniques ; Insulin/analysis/metabolism ; Insulin Resistance ; Insulin Secretion ; Islets of Langerhans/*drug effects/metabolism/pathology ; Methylazoxymethanol Acetate/analogs &amp; derivatives/toxicity ; Mice ; }, abstract = {Environmental toxins may be risk factors for some forms of diabetes mellitus and neurodegenerative diseases. The medicinal and food use of seed from the cycad plant (Cycas spp.), which contains the genotoxin cycasin, is a proposed etiological factor for amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC), a prototypical neurodegenerative disease found in the western Pacific. Patients with ALS/PDC have a very high prevalence of glucose intolerance and diabetes mellitus (in the range of 50-80%). We investigated whether the cycad plant toxin cycasin (methylazoxymethanol (MAM) beta-D-glucoside) or the aglycone MAM are toxic in vitro to mouse or human pancreatic islets of Langerhans. Mouse pancreatic islets treated for 6 days with cycasin impaired the beta-cell insulin response to glucose, but this effect was reversible after a further 4 days in culture without the toxin. When mouse islets were exposed for 24 hr to MAM/MAM acetate (MAMOAc; 0.1-1.0 mM), there was a dose-dependent impairment in insulin release and glucose metabolism, and a significant decrease in islet insulin and DNA content. At higher MAM/MAMOAc concentrations (1.0 mM), widespread islet cell destruction was observed. Glucose-induced insulin release remained impaired even after removal of MAM and a further culturing for 4 days without the toxin. MAM damages islets by two possible mechanisms: (a) nitric oxide generation, as judged by increased medium nitrite accumulation; and (b) DNA alkylation, as judged by increased levels of O6-methyldeoxyguanosine in cellular DNA. Incubation of mouse islets with hemin (10 or 100 microM), a nitric oxide scavenger, or nicotinamide (5-20 mM) protected beta-cells from a decrease in glucose oxidation by MAM. In separate studies, a 24 hr treatment of human beta-islet cells with MAMOAc (1.0 mM) produced a significant decrease in both insulin content and release in response to glucose. In conclusion, the present data indicate that cycasin and its aglycone MAM impair both rodent and human beta-cell function which may lead to the death of pancreatic islet cells. These data suggest that a "slow toxin" may be a common aetiological factor for both diabetes mellitus and neurodegenerative disease.}, }
@article {pmid7478239, year = {1995}, author = {Nishiyama, K and Kwak, S and Murayama, S and Watanabe, M and Goto, J and Asayama, K and Kanazawa, I}, title = {Increased Cu/Zn superoxide dismutase-like immunoreactivity in the swollen axons of rats intoxicated chronically with beta,beta'-iminodipropionitrile.}, journal = {Neuroscience letters}, volume = {194}, number = {3}, pages = {205-208}, doi = {10.1016/0304-3940(95)11762-l}, pmid = {7478239}, issn = {0304-3940}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology ; Animals ; Axons/*drug effects ; Disease Models, Animal ; Gene Expression ; Immunohistochemistry ; In Situ Hybridization ; Male ; Nitriles/*pharmacology/*toxicity ; Rats ; Rats, Wistar ; Spinal Cord/immunology ; Superoxide Dismutase/*genetics/*immunology ; }, abstract = {Demonstration of a genetic linkage between the Cu/Zn superoxide dismutase (SOD1) gene and familial amyotrophic lateral sclerosis (ALS) has aroused interest in the role of SOD1 in spinal motoneuronal death. We used chronically beta,beta'-iminodipropionitrile (IDPN)-intoxicated rats as a model of ALS and investigated SOD1 changes in the spinal cord by immunocytochemical and in situ hybridization techniques. Compared with control rats, SOD1-like immunoreactivity (SOD1-IR) increased in swollen axons of the proximal spinal roots, but not in motoneuronal and dorsal root ganglion neuronal cell bodies where SOD1 gene transcription did not increase. The present data indicate that treatment with IDPN induces accumulation of SOD1 in the swollen axons by blocking slow axonal flow, suggesting the possibility that increased SOD1-IR in ALS is induced by axonal flow blockade.}, }
@article {pmid8521204, year = {1995}, author = {Lindbeck, GH and Burns, DM and Rockwell, DD}, title = {Out-of-hospital provider use of epinephrine for allergic reactions: pilot program.}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {2}, number = {7}, pages = {592-596}, doi = {10.1111/j.1553-2712.1995.tb03595.x}, pmid = {8521204}, issn = {1069-6563}, mesh = {Adrenergic Agonists/administration &amp; dosage/*therapeutic use ; Anaphylaxis/*drug therapy ; *Emergency Medical Services/methods ; Epinephrine/administration &amp; dosage/*therapeutic use ; Female ; Humans ; Male ; Pilot Projects ; Retrospective Studies ; Treatment Outcome ; }, abstract = {OBJECTIVE: To describe experience with an out-of-hospital provider program for the recognition and field management of allergic reactions by advanced life support (ALS) and basic life support (BLS) providers.<br><br>METHODS: Data sheets completed between June 1, 1988, and August 31, 1993, and records from receiving sites (physicians' offices or EDs) were reviewed for information regarding the presentation of the allergic reaction, the time course and treatment provided out of hospital, and the clinical outcome at the receiving health care facility.<br><br>RESULTS: Thirty-seven data sheets were completed during the study period. Fourteen (38%) of the providers were BLS providers. The epinephrine was supplied from the emergency medical services (EMS) provider's personal kit in 35% of the cases, from an EMS vehicle in 57% of the cases, and by the patient in 8% of the cases. Availability of the kits allowed administration of epinephrine prior to the arrival of the first EMS vehicle in 41% of the instances and prior to physician on-line medical command in 65% of all the instances (predominantly by BLS providers). Overall, 77% of the patients experienced alleviation of their symptoms of respiratory difficulty, swelling, or rash after epinephrine administration, while 20% were unchanged and 3% worsened. All patients receiving epinephrine had an ED diagnosis of allergic reaction, and no adverse event was encountered on follow-up of the patients treated.<br><br>CONCLUSIONS: Severe allergic reactions can be reliably identified and safely managed by out-of-hospital providers, including BLS providers. Providing personal anaphylactic treatment kits and increasing the pool of providers trained to manage allergic reactions (including BLS providers) can often decrease the time to treatment.}, }
@article {pmid7605519, year = {1995}, author = {Wuerz, RC and Holliman, CJ and Meador, SA and Swope, GE and Balogh, R}, title = {Effect of age on prehospital cardiac resuscitation outcome.}, journal = {The American journal of emergency medicine}, volume = {13}, number = {4}, pages = {389-391}, doi = {10.1016/0735-6757(95)90120-5}, pmid = {7605519}, issn = {0735-6757}, mesh = {Adult ; Aged ; Aged, 80 and over ; *Emergency Medical Services ; Female ; Heart Arrest/mortality/*therapy ; Humans ; Male ; Middle Aged ; *Resuscitation ; Retrospective Studies ; Rural Population ; Survival Rate ; Time Factors ; Treatment Outcome ; }, abstract = {To compare resuscitation outcomes in elderly and younger prehospital cardiac arrest victims, we used a retrospective case series over 5 years in rural advanced life support (ALS) units and a University hospital base station. Participants included 563 adult field resuscitations. Excluded were patients with noncardiac etiologies, those less than 30 years old, and those with unknown initial rhythms. Patients were grouped by age. Return of spontaneous circulation (ROSC) and survival to hospital discharge were compared by Yates' chi-square test. ALS treatment of cardiac arrest was by regional protocols and on-line physician direction. Sixty percent (320/532) of patients were over 65 years old. The proportion with initial rhythm ventricular fibrillation (VF) was 50% in the elderly and 48% in younger patients. ROSC was achieved in 18% of elderly and 16% of younger patients; survival was 4% among the elderly and 5% for younger patients. The oldest survivor was 87 years old. Most survivors were discharged, in good Cerebral Performance Categories. There was no difference in outcome by age group when initial cardiac rhythm was considered. Early cardiopulmonary resuscitation (CPR) and ALS and initial rhythm VF were associated with the best resuscitation success. Age has less effect on resuscitation success than other well-known factors such as early CPR and ALS. Advanced age alone should probably not deter resuscitation attempts.}, }
@article {pmid7482387, year = {1995}, author = {Doble, A}, title = {Excitatory amino acid receptors and neurodegeneration.}, journal = {Therapie}, volume = {50}, number = {4}, pages = {319-337}, pmid = {7482387}, issn = {0040-5957}, mesh = {AIDS Dementia Complex/metabolism ; Animals ; Central Nervous System/injuries/metabolism ; Cerebrovascular Disorders/metabolism ; Glutamic Acid/metabolism ; Humans ; *Nerve Degeneration ; Receptors, Glutamate/classification/*metabolism ; }, abstract = {This review describes recent advances in our understanding of the pharmacology of excitatory amino acid receptors, and the application of this knowledge to the unravelling of the aetiology of neurodegenerative diseases, and to their therapy. Ionotropic excitatory amino acid receptors can be divided into two large families, the NMDA receptor family, and the AMPA/kainate receptor family. Receptor cloning studies have shown there to be a large number of potential subtypes of receptors in both these families. Antagonists have been developed for the NMDA receptor which can interact with at least four independent drug recognition sites on the receptor. For the AMPA/kainate receptor, two classes of antagonist have so far been identified. Reasonably potent, selective and brain-penetrating antagonists now exist for virtually all these sites, and compounds inhibiting the release of glutamic acid presynaptically have also been identified, such as riluzole. The ability of glutamic acid to kill neurons (excitotoxicity) seems to be mediated, in most cases, by an interaction with NMDA receptors, leading to an uncontrollable rise in intracellular calcium concentrations and thence cell lysis and death. The setting-up of glutamatergic loops seems to be a key process in the maintenance, spread and amplification of neurodegenerative foci. The existence of such processes has been amply demonstrated in animal models of stroke, in which both NMDA and AMPA/kainate receptor antagonists have neuroprotective effects. Clinical trials are underway with NMDA receptor antagonists in stroke. Excitotoxic mechanisms probably also contribute to pathology in head trauma and viral encephalopathy. Ingestion of excitatory amino acids may play a role in neurological conditions of dietary aetiology, such as neurolathyrism and domoic acid intoxication. For chronic neurodegenerative diseases, the role of excitatory amino acids is much less clear, although there is some evidence for the existence of excitotoxic mechanisms in amyotrophic lateral sclerosis. Evidence from animal models suggests that drugs that block glutamatergic neurotransmission might be beneficial in Parkinson's disease, Huntington's chorea and amyotrophic lateral sclerosis, but the relevance of these animal models to the human pathology is not clear. However, preliminary clinical results suggest riluzole to be efficacious in prolonging survival in amyotrophic lateral sclerosis, and certain weak NMDA receptor antagonists are currently used in the treatment of Parkinson's disease. The next few years could witness a breakthrough in the treatment of neurological conditions as drugs that interfere with glutamatergic transmission become available for clinical use.}, }
@article {pmid7604433, year = {1995}, author = {Shin, YT and Adams, DH and Wyner, LR and Akalin, E and Sayegh, MH and Karnovsky, MJ}, title = {Intrathymic tolerance in the Lewis-to-F344 chronic cardiac allograft rejection model.}, journal = {Transplantation}, volume = {59}, number = {12}, pages = {1647-1653}, doi = {10.1097/00007890-199506270-00001}, pmid = {7604433}, issn = {0041-1337}, support = {HL17747/HL/NHLBI NIH HHS/United States ; HL43318/HL/NHLBI NIH HHS/United States ; R29AI349965/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/immunology/pharmacology ; Arteriosclerosis/etiology/prevention &amp; control ; Cell Transplantation/physiology ; Chronic Disease ; Graft Rejection/*immunology/*prevention &amp; control ; Graft Survival/immunology ; Heart Transplantation/adverse effects/*immunology ; Immune Tolerance ; Immunosuppression Therapy/methods ; Injections, Intralymphatic ; Male ; Rats ; Rats, Inbred F344 ; Rats, Inbred Lew ; Spleen/cytology/immunology ; Thymus Gland ; }, abstract = {Successful induction of donor-specific unresponsiveness by intrathymic inoculation of alloantigen in several experimental acute rejection models has led us to hypothesize that similar immune manipulations can prevent chronic rejection and development of graft arteriosclerosis in the Lewis-to-F344 rat chronic cardiac allograft rejection model. Recipient F344 rats were treated with donor (Lewis) splenocytes by intrathymic injection (i.t.) alone (10 x 10(6) cells/lobe); with donor splenocytes i.t. plus a one-time dose of ALS (1 mg) by intraperitoneal injection (i.p.); or with ALS i.p. (1 mg) alone 2 and 6 weeks prior to heterotopic Lewis heart transplantation. Control F344 recipients received saline i.t. Allografts were monitored by daily palpation, and long-term surviving grafts were harvested on day 90 for histopathologic analysis. Control allografts had 28.6% long-term survival (> 90 days) with mean graft survival of 46.7 +/- 12.2 days. At day 90 the surviving control allografts were enlarged and fibrotic with barely palpable heartbeat (mean heartbeat grade 0.29 +/- 0.18), and histologically showed diffuse moderate mononuclear cell infiltrates and advanced graft arteriosclerosis (mean vessel score 3.57 +/- 0.10 and 89 +/- 1% vessels diseased). Recipient treatment with intrathymic donor splenocytes alone significantly prolonged graft survival (89% long-term survival; mean 83.8 +/- 6.2 days, P < 0.04), but did not significantly inhibit the development of graft arteriosclerosis (score 2.98 +/- 0.53 and 79 +/- 8% diseased, P = NS). By contrast, treatment with i.t. donor splenocytes plus ALS 2 weeks prior to transplantation prolonged graft survival (100% long-term; mean 90.0 +/- 0.0 days, P < 0.04), and markedly inhibited graft arteriosclerosis (score 0.80 +/- 0.14, P < 0.05; 27 +/- 4% diseased, P < 0.05). ALS alone given two weeks prior to transplantation also prolonged graft survival (100% long-term; mean 90.0 +/- 0.0 days, P < 0.04), and inhibited graft arteriosclerosis (score 0.89 +/- 0.31, P < 0.05; 25 +/- 7% diseased, P < 0.05). However, when ALS was given 6 weeks prior to heart transplantation the beneficial effect of ALS alone was abolished, suggesting that lymphocyte depletion may have been responsible for the observed effects when ALS was administered at 2 weeks. Interestingly, intrathymic donor splenocytes plus ALS 6 weeks prior to transplantation, on the other hand, showed significant prolongation of allograft survival (100% long-term, mean 90.0 +/- 0.0 days, P < 0.04), and inhibited graft arteriosclerosis (score 0.41 +/- 0.02, P < 0.05; 16 +/- 2% diseased, P < 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid7763202, year = {1995}, author = {Louwerse, ES and Weverling, GJ and Bossuyt, PM and Meyjes, FE and de Jong, JM}, title = {Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic lateral sclerosis.}, journal = {Archives of neurology}, volume = {52}, number = {6}, pages = {559-564}, doi = {10.1001/archneur.1995.00540300031009}, pmid = {7763202}, issn = {0003-9942}, mesh = {Acetylcysteine/*therapeutic use ; Amyotrophic Lateral Sclerosis/*drug therapy/mortality/physiopathology ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Placebos ; }, abstract = {BACKGROUND: Free radicals may play a role in the pathogenesis of amyotrophic lateral sclerosis.<br><br>OBJECTIVE: To investigate the efficacy of the free radical scavenging agent acetylcysteine in patients with amyotrophic lateral sclerosis.<br><br>DESIGN: Randomized, double-blind, placebo-controlled clinical trial to assess the effect of treatment with acetylcysteine on survival and disease progression.<br><br>SETTING: A university hospital referral setting.<br><br>PATIENTS: One hundred ten consecutive patients who fulfilled the diagnostic criteria for amyotrophic lateral sclerosis, followed up at monthly intervals for 12 months.<br><br>INTERVENTION: Acetylcysteine or placebo in a dose of 50 mg/kg per day subcutaneously for 12 months.<br><br>MAIN OUTCOME MEASURE: Survival.<br><br>RESULTS: After 12 months, 35 patients (65%) treated with acetylcysteine and 30 (54%) given placebo were still alive (hazard ratio, 0.74 in the acetylcysteine group relative to the placebo group; 95% confidence interval, 0.41 to 1.33; log-rank test, P = .31). Rates of disease progression, as expressed by decline in muscle strength, pulmonary function, disability, and bulbar function were similar in both groups. In the subgroup of 81 patients with limb onset of the disease, 28 patients (74%) in the acetylcysteine group and 22 (51%) in the placebo group survived 12 months (hazard ratio, 0.50; 95% confidence interval, 0.24 to 1.04; P = .06). In the bulbar subgroup of 29 patients, seven patients (44%) receiving acetylcysteine and eight (62%) receiving placebo were alive at the end of the study (hazard ratio, 1.66; 95% confidence interval, 0.56 to 4.99; P = .36).<br><br>CONCLUSION: In this trial, treatment with the free radical scavenger acetylcysteine did not result in a major increase in 12-month survival or a reduction in disease progression in patients with amyotrophic lateral sclerosis.}, }
@article {pmid7582105, year = {1995}, author = {Sagot, Y and Tan, SA and Baetge, E and Schmalbruch, H and Kato, AC and Aebischer, P}, title = {Polymer encapsulated cell lines genetically engineered to release ciliary neurotrophic factor can slow down progressive motor neuronopathy in the mouse.}, journal = {The European journal of neuroscience}, volume = {7}, number = {6}, pages = {1313-1322}, doi = {10.1111/j.1460-9568.1995.tb01122.x}, pmid = {7582105}, issn = {0953-816X}, mesh = {Animals ; Biological Assay ; Blotting, Northern ; Capsules ; Cell Line, Transformed ; Chick Embryo ; Ciliary Neurotrophic Factor ; Disease Progression ; Facial Nerve/pathology ; *Genetic Engineering ; Mice ; Mice, Mutant Strains ; Motor Activity/drug effects ; Motor Neuron Disease/*drug therapy/pathology/*physiopathology ; Motor Neurons/pathology ; Nerve Fibers, Myelinated/ultrastructure ; Nerve Growth Factors/administration &amp; dosage/therapeutic use ; Nerve Tissue Proteins/*administration &amp; dosage/therapeutic use ; Phrenic Nerve/pathology ; Polymers ; }, abstract = {Ciliary neurotrophic factor (CNTF) has recently generated great interest due to its potential as a therapeutic agent for the treatment of human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Because the systemic half-life of CNTF is only in the order of a few minutes, continuous delivery of this trophic factor could be attractive or even necessary in the therapy of these diseases. One promising technique involves the polymer encapsulation of cells which have been genetically modified to secrete neurotrophic factors. The polymer capsules can be implanted into animals and effect the slow release of the protein for several months. The encapsulation technique immuno-isolates the foreign cells from host immune cells and at the same time prevents tumour formation by the transplanted cells. In this study, we have used progressive motoneuronopathy (pmn) mice to determine the extent to which encapsulated cell lines secreting CNTF could alter the course of the disease. pmn/pmn homozygotes present severe loss of myelinated motor fibres and a significant reduction of facial motoneuron cell bodies. The mice develop weakness of the hindlimbs and die during the sixth week after birth. We found that CNTF delayed the disease progression by increasing the survival time by 40% and by improving motor function as assessed by three behavioural tests. Moreover, histological counts of the phrenic nerve myelinated axons and facial nucleus motoneurons indicated a significant reduction of motoneuron loss. These results suggest that polymer-encapsulated cells releasing neurotrophic factors may provide a potential delivery system for treating neurodegenerative diseases such as ALS.}, }
@article {pmid7572308, year = {1995}, author = {Kanzaki, S and Baxter, RC and Knutsen, R and Baylink, DJ and Mohan, S}, title = {Evidence that human bone cells in culture secrete insulin-like growth factor (IGF)-II and IGF binding protein-3 but not acid-labile subunit both under basal and regulated conditions.}, journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research}, volume = {10}, number = {6}, pages = {854-858}, doi = {10.1002/jbmr.5650100605}, pmid = {7572308}, issn = {0884-0431}, support = {AR 31062/AR/NIAMS NIH HHS/United States ; }, mesh = {Adult ; Bone Morphogenetic Protein 7 ; *Bone Morphogenetic Proteins ; Bone Neoplasms/pathology ; Bone and Bones/cytology/drug effects/*metabolism ; Carrier Proteins/*metabolism ; Cells, Cultured ; Culture Media, Conditioned ; Culture Media, Serum-Free ; Glycoproteins/*metabolism ; Growth Hormone/pharmacology ; Growth Inhibitors/*metabolism ; Humans ; Infant ; Insulin-Like Growth Factor Binding Protein 3/*metabolism ; Insulin-Like Growth Factor II/*metabolism/pharmacology ; Liver/cytology/metabolism ; Molecular Weight ; Osteoblasts/cytology/drug effects/metabolism ; Osteosarcoma/pathology ; Proteins/pharmacology ; Radioimmunoassay ; Recombinant Proteins/pharmacology ; Ribs/cytology/drug effects/metabolism ; Skull/cytology/drug effects/metabolism ; Somatomedins/*metabolism ; Transforming Growth Factor beta/pharmacology ; Tumor Cells, Cultured ; }, abstract = {Insulin-like growth factors (IGFs) are found in human circulation predominantly as part of a growth hormone (GH)-dependent complex of 125-150 kD, which is composed of three subunits: IGF-I or IGF-II, an acid stable IGF binding protein (IGFBP)-3, and an acid labile subunit (ALS). Although recent studies demonstrate that a number of cell types in culture secrete IGFs and IGFBP-3, very little is known with regard to the origin of circulating ALS. To test the hypothesis that human bone cells (HBCs), which produce abundant amounts of IGF-II and IGFBP-3, also produce ALS, we measured the IGF-I, IGF-II, IGFBP-3, and ALS levels using specific radioimmunoassays (RIAs) in the conditioned medium (CM) of untransformed normal HBCs and SaOS-2 osteosarcoma cells treated with various effectors (IGF-II, osteogenic protein-1 [OP-1, bone morphogenetic protein-7] and human GH) for 48 h. No detectable levels (< 3 ng/ml) of ALS were found in the CM of various HBC types under basal conditions. In contrast, CM collected from liver explants in culture contained significant amount of ALS prepared and assayed under identical conditions. The IGF-I level was also undetectable in the CM of various HBC types. In the IGF-II (3, 30 ng/ml)-treated HBC CM, the IGFBP-3 level was increased in a dose-dependent manner but neither IGF-I nor ALS could be detected. In the SaOS-2 cell culture, OP-1 (1, 100 ng/ml) increased both IGF-II and IGFBP-3 secretion but neither ALS nor IGF-I secretion. Treatment of HBCs with GH (1, 10, 100 ng/ml) had no significant effect on the secretion of either IGF-I, IGF-II, IGFBP-3, or ALS.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7664939, year = {1995}, author = {Márquez Márquez, RN and Tejada de Hernandez, I}, title = {Aflatoxin adsorbent capacity of two Mexican aluminosilicates in experimentally contaminated chick diets.}, journal = {Food additives and contaminants}, volume = {12}, number = {3}, pages = {431-433}, doi = {10.1080/02652039509374326}, pmid = {7664939}, issn = {0265-203X}, mesh = {Adsorption ; Aflatoxins/*pharmacokinetics ; *Aluminum Silicates ; Animals ; Chemical and Drug Induced Liver Injury ; Chickens ; Eating/drug effects ; Food Contamination/*prevention &amp; control ; Liver Diseases/pathology ; Weight Gain/drug effects ; *Zea mays ; }, abstract = {To study the aflatoxin-adsorbent capacity of two Mexican aluminosilicates (ALS) identified as Atapulgita (AT) and Füller earth (FE), these ALS were compared with a commercial aluminosilicate, Novasil (NV), at two concentrations (0.05 and 1.0%) added to chick diets with 55% of experimentally contaminated corn (200 micrograms/kg). Eight treatments were studied with two replicates for treatment and four chicks per cage. Results (weight gain, feed efficiency, gross and microscopic pathology) at 3 weeks showed that both Mexican ALS were as efficient as the commercial material in protecting chicks against the aflatoxin toxicity.}, }
@article {pmid7617465, year = {1995}, author = {Imai, Y}, title = {[Transcatheter arterial chemoembolization for postoperative recurrent hepatocellular carcinoma: therapeutic results in correlation with radiologic findings and treatment methods].}, journal = {Nihon Igaku Hoshasen Gakkai zasshi. Nippon acta radiologica}, volume = {55}, number = {6}, pages = {395-401}, pmid = {7617465}, issn = {0048-0428}, mesh = {Carcinoma, Hepatocellular/diagnostic imaging/*therapy ; *Chemoembolization, Therapeutic ; Cisplatin/administration &amp; dosage ; Doxorubicin/administration &amp; dosage ; Female ; Humans ; Liver Neoplasms/diagnostic imaging/*therapy ; Male ; Middle Aged ; Neoplasm Recurrence, Local/diagnostic imaging/*therapy ; Postoperative Period ; Prognosis ; Radiography ; Retrospective Studies ; }, abstract = {From January 1985 to June 1993, 61 patients with postoperative recurrent hepatocellular carcinoma (HCC) underwent transcatheter arterial chemoembolization (TACE) with Cis-Diammine dichloroplatinum-in-Lipiodol suspension (CLS) and/or Adriamycin-in-Lipiodol suspension (ALS). The effectiveness of TACE was retrospectively analyzed in relation to the presence of distant metastasis and portal vein involvement, and to the number and largest size of tumors which were evaluated by variable imaging modalities including US, CT, MR and hepatic angiography. Cumulative survival rates were calculated from the onset of TACE according to the Kaplan-Meier method. Cumulative survival rate of all cases after TACE was 69% for 1 year, 41% for 2 years, 21% for 3 years, 17% for 4 years and 8% for 5 years, respectively. Significant differences (P < 0.05) in survival rates were seen between the presence and absence of distant metastasis or portal vein involvement. In 52 patients without distant metastasis and/or portal vein involvement, there were significant differences (P < 0.05) in survival rates between single and multiple lesions, and between small (< or = 2.0cm) and large (> 5cm) lesions. In 48 patients, excluding the cases with distant metastasis, and/or portal vein involvement, and more than 5 cm in diameter, there were also significant differences (P < 0.05) in survival rates between combined therapy (CLS+ALS) and others, between CLS and ALS, and between once and multiple courses of TACE.}, }
@article {pmid7595630, year = {1995}, author = {Jones, AP and Gunawardena, WJ and Coutinho, CM and Gatt, JA and Shaw, IC and Mitchell, JD}, title = {Preliminary results of proton magnetic resonance spectroscopy in motor neurone disease (amytrophic lateral sclerosis).}, journal = {Journal of the neurological sciences}, volume = {129 Suppl}, number = {}, pages = {85-89}, doi = {10.1016/0022-510x(95)00072-a}, pmid = {7595630}, issn = {0022-510X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*pathology ; Aspartic Acid/analogs &amp; derivatives/metabolism ; Choline/metabolism ; Creatine/metabolism ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; }, abstract = {Possible changes in brain metabolites in motor neurone disease/amytrophic lateral sclerosis (MND/ALS) were investigated using 1H magnetic resonance spectroscopy (MRS). A series of normal, healthy volunteer controls and MND patients have been studied using a spin echo (SE) 135 ms sequence, acquiring spectra from the region of the motor cortex. A further limited series of studies have been made for similar groups of volunteers and MND patients using a STEAM 20 ms sequence (stimulated echo). Analysis of the SE 135 ms spectra indicates there are statistically significant differences in the ratios of N-acetyl-aspartate to creatine and N-acetyl-aspartate to choline between controls and MND patients. Furthermore, metabolites identified using the STEAM 20 ms may be of great importance in the investigations of free radical mediated mechanisms, which have been postulated as being important contributors to the disease process. Preliminary results indicate that 1H MRS may provide important data to help understand the disease processes in MND and it could form a useful method for monitoring the effects of future trial treatment regimens.}, }
@article {pmid7595617, year = {1995}, author = {Vincent, O and Rodríguez-Ithurralde, D}, title = {Amyotrophic lateral sclerosis and pregnancy.}, journal = {Journal of the neurological sciences}, volume = {129 Suppl}, number = {}, pages = {42-43}, doi = {10.1016/0022-510x(95)00059-b}, pmid = {7595617}, issn = {0022-510X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/chemically induced/*physiopathology ; Female ; Humans ; Male ; Pregnancy ; Pregnancy Complications/diagnosis/*physiopathology ; Respiration, Artificial ; }, abstract = {We describe the first case of pregnancy in a patient with amyotrophic lateral sclerosis (ALS) reported in Uruguay. The 27-year-old white woman who came to our clinic complaining of general weakness and gait symptoms was diagnosed as being pregnant and met the El Escorial criteria of probable ALS. The advised abortion caused her to abandon medical treatment, which was only resumed after a period of severe deterioration, at 32 weeks of gestation. After several days of serious vital risk, as evaluated by a multidisciplinary team, a normal male baby was born. Four months later, the patient had gradually improved and reached a stable condition, but presented with restrictive ventilatory distress.}, }
@article {pmid7595602, year = {1995}, author = {Hantaï, D and Akaaboune, M and Lagord, C and Murawsky, M and Houenou, LJ and Festoff, BW and Vaught, JL and Rieger, F and Blondet, B}, title = {Beneficial effects of insulin-like growth factor-I on wobbler mouse motoneuron disease.}, journal = {Journal of the neurological sciences}, volume = {129 Suppl}, number = {}, pages = {122-126}, doi = {10.1016/0022-510x(95)00081-c}, pmid = {7595602}, issn = {0022-510X}, mesh = {Animals ; Body Weight/physiology ; Choline O-Acetyltransferase/metabolism ; Hand Strength ; Humans ; Insulin-Like Growth Factor I/*therapeutic use ; Mice ; Mice, Inbred C57BL ; Mice, Neurologic Mutants ; Motor Neuron Disease/*drug therapy/enzymology/pathology ; Muscles/enzymology/pathology ; Neuromuscular Agents/*therapeutic use ; Phenotype ; Recombinant Proteins/therapeutic use ; Spinal Cord/enzymology/pathology ; }, abstract = {Recombinant human insulin-like growth factor-I (IGF-I) is being considered as a possible therapeutic agent for the treatment of motoneuron diseases like amyotrophic lateral sclerosis. The neurological mutant mouse wobbler, carries an autosomal recessive gene (wr) and has been characterized as a model of lower motoneuron disorders with associated muscle atrophy, denervation and reinnervation. The purpose of the present study was to determine the possible beneficial effect of IGF-I administration in this mouse model. Upon diagnosis at 4 weeks of age, affected mice and their control normal littermates received human recombinant IGF-I (1 mg/kg) or vehicle solution, once a day, for 6 weeks. Body weight and grip strength were evaluated periodically during the treatment period. Mean muscle fiber diameter on biceps brachii sections, choline acetyltransferase activity in muscle extracts, and motoneuron numbers in spinal cord sections were determined. IGF-I treated wobbler mice showed a marked weight increase from 3 to 6 weeks of treatment in comparison with placebo treated mutant mice. At the end of the treatment, grip strength, estimated by dynamometer resistance, was 40% higher in IGF-I treated versus placebo treated animals. Mean muscle fiber diameter which is smaller in wobbler mice than in normal mice was increased in IGF-I treated mutants. However, in this study the muscle choline acetyltransferase activity and the number of spinal cord motoneurons were unchanged. Thus, IGF-I administration mainly results in a significant effect on the behavioral and skeletal muscle histochemical parameters of the wobbler mouse mutant.}, }
@article {pmid7595601, year = {1995}, author = {Festoff, BW and Yang, SX and Vaught, J and Bryan, C and Ma, JY}, title = {The insulin-like growth factor signaling system and ALS neurotrophic factor treatment strategies.}, journal = {Journal of the neurological sciences}, volume = {129 Suppl}, number = {}, pages = {114-121}, doi = {10.1016/0022-510x(95)00080-l}, pmid = {7595601}, issn = {0022-510X}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/*physiopathology ; Animals ; Humans ; Insulin-Like Growth Factor Binding Proteins/metabolism ; Mice ; Neuromuscular Agents/*therapeutic use ; Signal Transduction/drug effects/*physiology ; Somatomedins/metabolism/*physiology/*therapeutic use ; }, abstract = {Because of its multi-faceted potential as a neurotrophic factor, insulin-like growth factor I (IGF-I) has been given to hundreds of ALS patients world-wide. Unlike some patients with post-polio syndrome and fragile elderly males, it is unclear whether any of these patients possess disturbances in IGF signaling. We found that about 25% of ALS patients in a controlled trial of human growth hormone (hGH) had lower or higher than normal IGF-I serum levels. Many ALS patients do have some of the characteristics of type II diabetes mellitus, where IGF-I therapy is also under way. In addition, in type I diabetes significant increase in a circulating molecule that binds IGF-I, IGF-I binding protein 1 (IGFBP-1), occurs along with reduced IGF-I, when neuropathic complications are prominent. We have studied the response of IGFBPs in ALS patients to subcutaneous rhIGF-I and found transient induction of IGFBP-1. Studies related to the IGFBPs have not been done in familial ALS (FALS) patients. However, the gene for another IGFBP, BP-2, co-localizes with the gene for juvenile ALS (ALSJ) on chromosome 2. IGF-I has been given to several models of motor neuron degeneration in the mouse, including motor neuron disease and wobbler, with beneficial effects. However, it is also not known whether any accepted genetic mouse model of motor neuron degeneration possesses any disturbance in the IGF signaling system.}, }
@article {pmid7709451, year = {1995}, author = {Dono, K and Wood, ML and Ozato, H and Otsu, I and Gottschalk, R and Maki, T and Monaco, AP}, title = {Marked prolongation of rat skin xenografts induced by intrathymic injection of xenogeneic splenocytes and a short course of rapamycin in antilymphocyte serum-treated mice.}, journal = {Transplantation}, volume = {59}, number = {7}, pages = {929-932}, doi = {10.1097/00007890-199504150-00001}, pmid = {7709451}, issn = {0041-1337}, support = {R01 AI-14551/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; Female ; Graft Survival/drug effects ; Guinea Pigs ; Immunosuppressive Agents/*pharmacology ; Immunotherapy, Adoptive ; Injections ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Polyenes/*pharmacology ; Rats ; Rats, Inbred ACI ; Rats, Inbred Lew ; Sirolimus ; Skin Transplantation/*immunology ; Spleen/*cytology ; Thymus Gland ; Time Factors ; Transplantation Chimera ; Transplantation, Heterologous/*immunology ; }, abstract = {The effect of intrathymic (IT) injection of donor splenocytes and a short course of rapamycin (Rapa) treatment on rat to mouse skin xenograft survival was investigated. ACI rat skin xenografts were transplanted to (C57BL/6 x A)F1 mice treated with rabbit anti-mouse lymphocyte serum (ALS) on days -1, +2, and +4 relative to skin grafting on day 0. Fifty million donor-type splenocytes were injected intrathymically on day 7 after transplantation. Rapa was given intraperitoneally every other day from day 0 to day 12 at a dose of 3.0 mg/kg. Prolonged skin xenograft survival was observed in ALS- and Rapa-treated recipients (no IT injection) with a median survival time of 47 days. However, skin graft survival was markedly more prolonged in the group treated with ALS, Rapa, and IT injection of donor splenocytes did not have a beneficial effect on skin xenograft survival in ALS-treated recipients. An increased presence of donor-type cells was observed in the thymus of the ALS- and Rapa-treated recipients for 7 days after IT injection of donor splenocytes. In conclusion, a short course of Rapa markedly augments rat skin xenograft survival in ALS-treated mice injected intrathymically with donor-type splenocytes.}, }
@article {pmid7898136, year = {1995}, author = {Gay, PC and Edmonds, LC}, title = {Severe hypercapnia after low-flow oxygen therapy in patients with neuromuscular disease and diaphragmatic dysfunction.}, journal = {Mayo Clinic proceedings}, volume = {70}, number = {4}, pages = {327-330}, doi = {10.4065/70.4.327}, pmid = {7898136}, issn = {0025-6196}, mesh = {Adult ; Aged ; Blood Gas Analysis ; Diaphragm/*physiopathology ; Humans ; Hypercapnia/blood/*etiology ; Middle Aged ; Neuromuscular Diseases/blood/physiopathology/*therapy ; Oxygen/administration &amp; dosage ; Oxygen Inhalation Therapy/*adverse effects ; Predictive Value of Tests ; Retrospective Studies ; Sensitivity and Specificity ; Severity of Illness Index ; }, abstract = {OBJECTIVE: To increase the general awareness of the possible exacerbation of hypercapnia by the administration of low-flow oxygen in patients with neuromuscular disorders.<br><br>DESIGN: We retrospectively reviewed the medical records of 118 consecutive adult patients with a diagnosis of neuromuscular disease who underwent phrenic nerve conduction studies during a 5-year period, and we analyzed pulmonary function data for 8 patients who underwent arterial blood gas studies before and after the administration of low-flow oxygen.<br><br>MATERIAL AND METHODS: In the eight patients with neuromuscular disease and diaphragmatic dysfunction (three with polymyositis, three with amyotrophic lateral sclerosis or nonspecific motor neuron disease, and one each with inflammatory motor neuropathy and chronic poliomyelitis), we analyzed the response of the arterial carbon dioxide tension (PaCO2) after low-flow supplemental oxygen therapy (0.5 to 2 L/min). Linear analysis was used to attempt to find correlations between respiratory variables and the PaCO2 response after oxygen therapy.<br><br>RESULTS: For the overall study group, the mean PaCO2 increased 28.2 +/- 23.3 torr after low-flow oxygen treatment; in five patients, it increased by 27 torr or more. Four patients who were subsequently treated with nocturnal assisted ventilation were able to use supplemental oxygen during the day with less severe hypercapnia. Statistical analysis failed to reveal specific correlations between increased PaCO2 values after oxygen therapy and any respiratory variables.<br><br>CONCLUSION: In patients with neuromuscular disease and diaphragmatic dysfunction, even low-flow supplemental oxygen should be administered with caution, and assisted ventilation should be strongly considered as an initial intervention.}, }
@article {pmid7751843, year = {1995}, author = {Gredal, O and Møller, SE}, title = {Effect of branched-chain amino acids on glutamate metabolism in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {129}, number = {1}, pages = {40-43}, doi = {10.1016/0022-510x(94)00243-h}, pmid = {7751843}, issn = {0022-510X}, mesh = {Adult ; Amino Acids, Branched-Chain/*pharmacology ; Amyotrophic Lateral Sclerosis/*blood ; Aspartic Acid/blood ; Female ; Glutamic Acid/*blood/pharmacology ; Humans ; Male ; Middle Aged ; }, abstract = {Data from the literature about glutamate metabolism remain controversial. To refine such analysis we have studied plasma glutamate and aspartate levels after glutamate loading (60 mg/kg) in 6 fasting controls and ALS patients, before and after at least 2 weeks treatment with branched-chain amino acids. ALS patients showed no difference from age-matched controls in basal plasma glutamate or aspartate levels, but significantly elevated levels of glutamate and aspartate at 30 and 45 min after loading, and an increased area under the curve in plasma for glutamate following oral glutamate loading. Two weeks BCAAs treatment did not affect plasma glutamate metabolism in ALS patients.}, }
@article {pmid7751839, year = {1995}, author = {Aisen, ML and Sevilla, D and Gibson, G and Kutt, H and Blau, A and Edelstein, L and Hatch, J and Blass, J}, title = {3,4-diaminopyridine as a treatment for amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {129}, number = {1}, pages = {21-24}, doi = {10.1016/0022-510x(94)00225-d}, pmid = {7751839}, issn = {0022-510X}, mesh = {4-Aminopyridine/adverse effects/*analogs &amp; derivatives/therapeutic use ; Affect/drug effects ; Aged ; Amifampridine ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology/rehabilitation ; Cognition/drug effects ; Female ; Humans ; Male ; Middle Aged ; Movement/drug effects ; Neural Conduction/drug effects ; }, abstract = {The slow potassium channel blocker 3,4-diaminopyridine (DAP) enhances acetylcholine release from the nerve terminal and improves conduction in unmyelinated nerve. In this open label pilot study, we examined the effect of DAP combined with inpatient rehabilitation in seven patients with motor weakness due to amyotrophic lateral sclerosis (ALS). A single daily 20 mg oral dose of DAP was gradually increased to the maximum tolerated dose, and serum DAP concentrations were measured. Videotaped motor examination (for subsequent "blinded" review and assignment of a quantitative motor score), Functional Independence Measure (FIM) assessment, nerve conduction studies and neuropsychological evaluations were performed on admission, 1 h after maximum DAP dose, and post-treatment. DAP was tolerated in all patients, though dose was limited by gastrointestinal side effects in five patients. The mean peak serum level was 128 (+/- 50) ng/ml, occurring 1.0 (+/- 0.50) h after dose. A modest but statistically significant (p = 0.045) peak in motor score occurred on DAP. A significant (p = 0.045) improvement from baseline in FIM performance was apparent with DAP. Nerve conduction studies showed small increases in evoked response amplitudes and conduction velocities on DAP, but they did not reach statistical significance. No cognitive or affective changes were apparent. This unblinded pilot study shows that DAP is tolerated in ALS patients, and may be associated with functional and electrophysiologic improvement.}, }
@article {pmid7838549, year = {1995}, author = {MacDougall, G and Wilson, JA and Pryde, A and Grant, R}, title = {Analysis of the pharyngoesophageal pressure profile in amyotrophic lateral sclerosis.}, journal = {Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery}, volume = {112}, number = {2}, pages = {258-261}, doi = {10.1016/S0194-59989570247-4}, pmid = {7838549}, issn = {0194-5998}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*physiopathology ; Bread ; Case-Control Studies ; Deglutition/physiology ; Deglutition Disorders/etiology/physiopathology/surgery ; Esophageal Motility Disorders/physiopathology ; Esophagogastric Junction/physiopathology ; Esophagus/*physiopathology ; Female ; Humans ; Male ; Manometry ; Middle Aged ; Peristalsis ; Pharyngeal Muscles/physiopathology ; Pharynx/*physiopathology ; Pressure ; Spasm/physiopathology ; Water ; }, abstract = {Treatment of dysphagia resulting from bulbar amyotrophic lateral sclerosis has included cricopharyngeal myotomy for many years but is successful in only a minority of cases. The purpose of this study was to explore the rationale for this procedure with modern manometric techniques. The results of pharyngoesophageal manometry in 13 patients with amyotrophic lateral sclerosis were compared with 13 age- and sex-matched healthy volunteers by Mann-Whitney analysis. There was no significant difference between patients and control subjects in distal esophageal or lower esophageal sphincter motility nor any pressure parameter of pharyngoesophageal motility. Separate analysis of the seven significantly dysphagic subjects showed a significantly reduced upper esophageal sphincter after-contraction amplitude during water and bread swallows in patients than in control subjects. These data suggest that the dysphagia of amyotrophic lateral sclerosis is not due to upper esophageal sphincter spasm and that treatment by cricopharyngeal myotomy may be inappropriate.}, }
@article {pmid7788965, year = {1995}, author = {Grisold, W and Drlicek, M and Liszka-Setinek, U and Wondrusch, E}, title = {Anti-tumour therapy in paraneoplastic neurological disease.}, journal = {Clinical neurology and neurosurgery}, volume = {97}, number = {1}, pages = {106-111}, doi = {10.1016/0303-8467(95)00003-3}, pmid = {7788965}, issn = {0303-8467}, mesh = {Antineoplastic Agents/administration &amp; dosage ; Autoantibodies/analysis ; Autoimmune Diseases/immunology/*therapy ; Brain/immunology ; Combined Modality Therapy ; Humans ; Immunosuppressive Agents/administration &amp; dosage ; Lambert-Eaton Myasthenic Syndrome/immunology/therapy ; Nervous System Diseases/immunology/*therapy ; Neurologic Examination ; Paraneoplastic Syndromes/immunology/*therapy ; Prognosis ; }, abstract = {Paraneoplastic neurological syndromes have attracted attention in recent years. Detection of auto-antibodies directed against CNS and PNS structures have suggested an autoimmune etiology. This review is based on reports from the past 10 years and summarizes the therapeutic results in 258 patients suffering from paraneoplastic neurological disease including paraneoplastic encephalomyelitis, sensory neuronopathy, cerebellar degeneration, motor neurone disease and stiff man syndrome. The results show that in some entities such as Lambert-Eaton syndrome successful treatment can be expected. In other syndromes such as subacute sensory neuronopathy or paraneoplastic cerebellar degeneration therapeutic success varies from 5 to 10%.}, }
@article {pmid7796839, year = {1995}, author = {Aebischer, P and Kato, AC}, title = {Treatment of amyotrophic lateral sclerosis using a gene therapy approach.}, journal = {European neurology}, volume = {35}, number = {2}, pages = {65-68}, doi = {10.1159/000117095}, pmid = {7796839}, issn = {0014-3022}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Capsules ; Cell Line ; Ciliary Neurotrophic Factor ; *Genetic Therapy ; Humans ; Nerve Growth Factors/therapeutic use ; Nerve Tissue Proteins/genetics/therapeutic use ; Polymers ; }, abstract = {Neurotrophic factors which act on motor neurons may provide an efficient treatment for amyotrophic lateral sclerosis. In order to overcome the difficulty of administering proteins into the central nervous system, it is possible to use a gene therapy approach, i.e. the polymer encapsulation of cells which have been genetically engineered to release one of these neurotrophic factors. The polymer-encapsulated cells can be implanted subcutaneously or even intrathecally and permit continuous, slow release of proteins. There is no rejection of the cells due to their isolation by a semi-permeable membrane, no risk of tumor formation and the polymer device can be removed in the event of a problem.}, }
@article {pmid7742172, year = {1995}, author = {Williams, LR}, title = {Oxidative stress, age-related neurodegeneration, and the potential for neurotrophic treatment.}, journal = {Cerebrovascular and brain metabolism reviews}, volume = {7}, number = {1}, pages = {55-73}, pmid = {7742172}, issn = {1040-8827}, mesh = {Aging/*physiology ; Animals ; Humans ; *Nerve Degeneration ; Nerve Growth Factors/*therapeutic use ; Nervous System Diseases/etiology ; *Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease are major human neurodegenerative disorders, the etiologies for which remain unknown. Although a unique subset of neurons is particularly affected in each of the three diseases, they have several intriguing overlapping similarities. Evidence is reviewed supporting the hypothesis that these diseases result from an inability to protect against accumulated damage by free radicals due to oxidative stress. If oxidative stress underlies or exacerbates the etiology of these diseases, then agents that effectively attenuate brain tissue lipid peroxidation or otherwise limit free radical damage may hold promise for the treatment of these neurodegenerative diseases. Although antioxidant chemical supplementation may provide effective therapy, the most effective therapy for neurodegenerative diseases may be treatment with specific neurotrophic, survival-promoting proteins. For example, brain-derived neurotrophic factor promotes survival of spinal motor neurons and mesencephalic dopaminergic neurons. One mechanism through which these proteins may exert their protection may be by stimulating endogenous defenses against oxidative stress and damage by free radicals. This hypothesis is being tested in several laboratories and provides exciting direction both for basic neurobiological research and therapeutic drug discovery.}, }
@article {pmid7666750, year = {1995}, author = {Pasetti, C}, title = {The teaching of bioethics to the health care team: the neurologist's role.}, journal = {Medicine and law}, volume = {14}, number = {1-2}, pages = {87-91}, pmid = {7666750}, issn = {0723-1393}, mesh = {Coma/therapy ; Critical Care ; Decision Making ; Ethics, Medical/*education ; Humans ; Life Support Care ; *Neurology ; Patient Care Team ; *Physician's Role ; }, abstract = {The term 'bioethics' connotes not only the complexity of the subject but also the importance of adopting an interdisciplinary approach to it. Any given bioethical issue should be considered from a biological as well as anthropological and social perspective. Treating and evaluating ethical ideas without regard for these three aspects means diminishing and limiting them. Owing to the progress in intensive care and thanks to our increased sensitivity towards patients affected by irreversible diseases, many ethical problems have emerged relating to new conditions (for instance persistent vegetative state) or to already known ones (for example the later stages of amyotrophic lateral sclerosis or dementias). In future, it is likely that neurologists will be called upon to address an increasing number of ethical concerns, as primary care givers, consultants or members of ethics consultative teams, given that they are the most qualified to throw light on individual cases with regard to their diagnostic and prognostic, as well as on ethical, rational and emotional aspects. Neurologists are eminently suitable to play a crucial part in medical decision making regarding issues such as the administration or withdrawal of life-sustaining treatment. Furthermore, neurologists have much to contribute to the education of the health care team. This is because they are used to formulating judgments grounded on their professional experience in dealing with problems both physical and psychological. On the basis of these considerations, the author believes that neurologists are among the most qualified to bridge the gap between the two major components of bioethics: natural and human science. These components should find their synthesis and completeness in the bioethical debate.}, }
@article {pmid7618430, year = {1995}, author = {Robberecht, W}, title = {New treatment strategies in amyotrophic lateral sclerosis: solutions or illusions?.}, journal = {Acta neurologica Belgica}, volume = {95}, number = {2}, pages = {65-69}, pmid = {7618430}, issn = {0300-9009}, mesh = {Amyotrophic Lateral Sclerosis/metabolism/*therapy ; Antioxidants/therapeutic use ; Autoimmune Diseases/metabolism ; Excitatory Amino Acid Antagonists ; Free Radicals/toxicity ; Glutamates/metabolism ; Humans ; Nerve Growth Factors/metabolism ; Nerve Tissue Proteins/metabolism/therapeutic use ; }, }
@article {pmid7998084, year = {1994}, author = {De Fazio, SR and Plowey, J and Hartner, WC and Gozzo, JJ}, title = {Effect of single-dose, late treatment with rapamycin on skin allograft survival in ALS- and donor bone marrow cell-treated mice.}, journal = {Transplantation proceedings}, volume = {26}, number = {6}, pages = {3102-3103}, pmid = {7998084}, issn = {0041-1345}, support = {DK33466/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/*therapeutic use ; Bone Marrow Transplantation/*immunology ; Drug Administration Schedule ; Graft Survival/drug effects/*physiology ; Immunosuppressive Agents/*therapeutic use ; Mice ; Mice, Inbred C3H ; Mice, Inbred Strains ; Polyenes/*therapeutic use ; Sirolimus ; Skin Neoplasms/*immunology ; Transplantation, Homologous ; }, }
@article {pmid7985721, year = {1994}, author = {Stein, RS and Means, RT and Krantz, SB and Flexner, JM and Greer, JP}, title = {Treatment of aplastic anemia with an investigational antilymphocyte serum prepared in rabbits.}, journal = {The American journal of the medical sciences}, volume = {308}, number = {6}, pages = {338-343}, doi = {10.1097/00000441-199412000-00005}, pmid = {7985721}, issn = {0002-9629}, mesh = {Adolescent ; Adult ; Aged ; Anemia, Aplastic/drug therapy/mortality/*therapy ; Animals ; Antilymphocyte Serum/adverse effects/isolation &amp; purification/*therapeutic use ; Combined Modality Therapy ; Cyclosporine/therapeutic use ; Female ; Horses ; Humans ; Male ; Middle Aged ; Rabbits ; Survival Rate ; Time Factors ; }, abstract = {The authors evaluated antilymphocyte serum prepared in rabbits (ALS-R) as an alternative to antilymphocyte serum prepared in horses (ALG-H) in the therapy of aplastic anemia. Between 1980 and 1993, 57 evaluable patients received ALS-R and prednisone +/- cyclosporine +/- androgens. Standard response criteria were used and patients were evaluated at 3 months from the start of therapy. Median age was 43 years. Disease was present for up to 2 months in 24 patients, 2-5 months in 14 patients, and 6 months or more in 19 patients. Disease was severe in 30 patients and moderate in 27. Responses occurred in 16 (28%) of 57 patients. Responses were more frequent in females, in patients treated within 6 months of diagnosis, and in patients with severe disease. Among patients receiving ALS-R and cyclosporine within 2 months of diagnosis, 46% responded. After ALS-R therapy, 20 patients received ALG-H; 8 (40%) of 20 responded. Eight patients receiving ALS-R previously had received ALG-H; 2 (25%) of these 8 patients responded. Toxicity of ALS-R was minimal. Antilymphocyte serum prepared in rabbits, in conjunction with other immunosuppressive agents, represents an effective alternative to ALG-H in aplastic anemia, especially in patients previously treated with ALG-H.}, }
@article {pmid7867282, year = {1994}, author = {Kaplan, LM and Hollander, D}, title = {Respiratory dysfunction in amyotrophic lateral sclerosis.}, journal = {Clinics in chest medicine}, volume = {15}, number = {4}, pages = {675-681}, pmid = {7867282}, issn = {0272-5231}, mesh = {Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Female ; Humans ; Male ; Respiration, Artificial ; Respiratory Function Tests ; Respiratory Insufficiency/etiology/*physiopathology/therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the voluntary motor system. Involvement of the respiratory system is inevitable and leads to the development of respiratory failure, the usual cause of death in this disorder. ALS at present is incurable, and only symptomatic treatment is available. This article presents guidelines for the recognition and management of respiratory failure.}, }
@article {pmid7527417, year = {1994}, author = {Liu, F and Hintz, RL and Khare, A and Diaugustine, RP and Powell, DR and Lee, PD}, title = {Immunoblot studies of the IGF-related acid-labile subunit.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {79}, number = {6}, pages = {1883-1886}, doi = {10.1210/jcem.79.6.7527417}, pmid = {7527417}, issn = {0021-972X}, mesh = {Acromegaly/blood ; Animals ; Antibody Specificity ; Carrier Proteins/chemistry/immunology/*metabolism ; Female ; Glycoproteins/chemistry/immunology/*metabolism ; Glycosylation ; Growth Hormone/deficiency/pharmacology ; Humans ; Hydrogen-Ion Concentration ; Immune Sera/immunology ; *Immunoblotting ; Insulin-Like Growth Factor Binding Proteins ; Insulin-Like Growth Factor II/metabolism ; Macromolecular Substances ; Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase/metabolism ; Molecular Weight ; Postmenopause/blood ; Pregnancy ; }, abstract = {Insulin-like growth factors I and II (IGF-I and II) are present in serum primarily within a ternary complex consisting of IGF, IGF-binding protein-3 (IGF-3) and acid-labile subunit (ALS). Relatively little is known about ALS as compared to the other components of the complex. We report immunoblot studies of ALS using a new rabbit antiserum to human ALS1-34. The antiserum shows high specificity for ALS, labelling only the intact 82-88 kDa doublet in whole serum. Treatment with endoglycosidase-F leads to only a partial deglycosylation of ALS in whole serum, while purified ALS is reduced to M(r) approximately 58 kDa. Acidification of both whole serum and purified ALS leads to a complete loss of ALS ability to bind to cross-linked IGFBP-3:[125I]IGF-II tracer; however, immunoblot studies show no change in the apparent M(r) of the major ALS band. Immunoblot studies of human serum shows that intact ALS is decreased in growth-hormone (GH) deficiency, increases with GH treatment, is elevated in GH excess and is unchanged with IGF-I treatment. These data provide new information regarding the characteristics of ALS and demonstrate the research utility of a highly-specific antiserum for this protein.}, }
@article {pmid7527331, year = {1994}, author = {Dai, J and Baxter, RC}, title = {Regulation in vivo of the acid-labile subunit of the rat serum insulin-like growth factor-binding protein complex.}, journal = {Endocrinology}, volume = {135}, number = {6}, pages = {2335-2341}, doi = {10.1210/endo.135.6.7527331}, pmid = {7527331}, issn = {0013-7227}, mesh = {Acids/pharmacology ; Animals ; Base Sequence ; Carrier Proteins/*blood/chemistry/genetics ; Dexamethasone/pharmacology ; Diabetes Mellitus, Experimental/blood ; Drug Stability ; Fasting ; Female ; Food ; Growth Hormone/pharmacology ; Insulin/pharmacology ; Insulin-Like Growth Factor Binding Proteins ; Liver/metabolism ; Male ; Molecular Probes/genetics ; Molecular Sequence Data ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; }, abstract = {The acid-labile subunit (ALS) and insulin-like growth factor (IGF)-binding protein-3 are glycoproteins that form a complex carrying about 90% of the circulating IGFs. This study investigates the regulation of ALS expression by Northern hybridization, and serum ALS levels by RIA, in the rat. Northern analysis of ALS messenger RNA (mRNA) from adult rat brain, heart, lung, muscle, spleen, testis or ovary, kidney, and liver showed a liver-specific predominant 2-kilobase transcript. The steady state abundance of rat ALS mRNA was greatly reduced in neonatal and weanling liver compared to adult liver, with an age dependence similar to that of rat serum ALS levels. Fasting for 24 or 48 h decreased serum IGF-I and ALS levels, but not hepatic ALS mRNA. Streptozotocin-diabetic rats, untreated or treated with human GH for 5 days, had significantly decreased serum ALS levels and liver ALS mRNA abundance. Insulin treatment normalized serum ALS without fully restoring ALS mRNA. Dexamethasone, an inhibitor of ALS synthesis by hepatocytes, significantly reduced both serum ALS and hepatic ALS mRNA. The discrepancies between hepatic expression and serum ALS levels in fasting and diabetes point to a complex regulatory mechanism in which events at the translational level or later may be as important as regulation of gene expression or mRNA stability.}, }
@article {pmid7832434, year = {1994}, author = {Chiueh, CC and Wu, RM and Mohanakumar, KP and Sternberger, LM and Krishna, G and Obata, T and Murphy, DL}, title = {In vivo generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia.}, journal = {Annals of the New York Academy of Sciences}, volume = {738}, number = {}, pages = {25-36}, doi = {10.1111/j.1749-6632.1994.tb21786.x}, pmid = {7832434}, issn = {0077-8923}, mesh = {Animals ; Antioxidants/pharmacology ; Basal Ganglia/drug effects/*metabolism/pathology ; Corpus Striatum/drug effects/*metabolism ; Dopamine/*metabolism ; Free Radical Scavengers ; Free Radicals/metabolism ; Humans ; Hydroxyl Radical/analysis/*metabolism ; *MPTP Poisoning ; Melanins/biosynthesis ; Nerve Degeneration/drug effects ; Parkinson Disease/*drug therapy/*metabolism ; Rats ; Salicylates ; Selegiline/pharmacology/therapeutic use ; Substantia Nigra/drug effects/*metabolism/pathology ; }, abstract = {The in vivo generation of .OH free radicals in specific brain regions can be measured by intracerebral microdialysis perfusion of salicylate, avoiding many of the pitfalls inherent in systemic administration of salicylate. Direct infusion of salicylate into the brain can minimize the hepatic hydroxylation of salicylate and its contribution to brain levels of 2,5-DHBA. Levels of 2,5-DHBA detected in the brain dialysate may reflect the .OH adduct plus some enzymatic hydroxylation of salicylate in the brain. After minimizing the contribution of enzyme and/or blood-borne 2,5-DHBA, the present data demonstrate the validity of the use of 2,3-DHBA and apparently 2,5-DHBA as indices of .OH formation in the brain. Therefore, intracranial microdialysis of salicylic acid and measurement of 2,3-DHBA appears to be a useful .OH trapping procedure for monitoring the time course of .OH generation in the extracellular fluid of the brain. These results indicate that nonenzymatic and/or enzymatic oxidation of the dopamine released by MPTP analogues in the extracellular fluid may play a key role in the generation of .OH free radicals in the iron-rich basal ganglia. Moreover, a site-specific generation of cytotoxic .OH free radicals and quinone/semiquinone radicals in the striatum may cause the observed lipid peroxidation, calcium overload, and retrograde degeneration of nigrostriatal neurons. This free-radical-induced nigral injury can be suppressed by antioxidants (i.e., U-78517F, DMSO, and deprenyl) and possibly hypothermia as well. In the future, this in vivo detection of .OH generation may be useful in answering some of the fundamental questions concerning the relevance of oxidants and antioxidants in neurodegenerative disorders during aging. It could also pave the way for the research and development of novel neuroprotective antioxidants and strategies for the early or preventive treatment of neurodegenerative disorders, such as Parkinson's disease (Wu et al., this issue), amyotrophic lateral sclerosis, head trauma, and possibly Alzheimer's cognitive dysfunction as well. In conclusion, this in vivo free-radical trapping procedure provides evidence to support a current working hypothesis that a site-specific formation of cytotoxic .OH free radicals in the basal ganglia may be one of the neurotoxic mechanisms underlying nigrostriatal degeneration and Parkinsonism caused by the dopaminergic neurotoxin MPTP. Addendum added in proof: The controversy concerning possible neurotoxic and/or neuroprotective roles of NO. in cell cultures was discussed and debated at the symposium (Wink et al., this issue; Dawson et al., this issue; Lipton et al., this issue).(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid7974727, year = {1994}, author = {Markees, TG and De Fazio, SR and Gozzo, JJ}, title = {Tolerogenic behavior of skin allografts from neonatal mice.}, journal = {Transplantation}, volume = {58}, number = {9}, pages = {1008-1014}, doi = {10.1097/00007890-199411150-00006}, pmid = {7974727}, issn = {0041-1337}, support = {AI 29650/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Animals, Newborn ; Graft Survival ; Immune Tolerance ; Immunosuppressive Agents/administration &amp; dosage ; Injections, Intraperitoneal ; Male ; Mice ; Mice, Inbred C3H ; Skin Transplantation/*immunology ; Transplantation, Homologous ; }, abstract = {Neonatal skin allografts can be tolerogenic when transplanted to appropriately immunosuppressed hosts. Single grafts of neonatal skin survive longer than adult skin grafts when recipients are treated with antilymphocyte serum (ALS) and donor bone marrow cells (BMC). Neonatal skin grafts can also prolong the survival of adult grafts of the same donor strain simultaneously cotransplanted with the neonatal grafts. To probe the mechanisms involved in this cotransplantation phenomenon, we delayed placement of the neonatal cotransplants relative to grafting with adult skin. Neonatal allografts placed either 7-9 days or 14 days after grafting with adult skin significantly prolonged adult graft survival in mice treated with ALS and BMC. However, day 0-placed neonatal cotransplants must remain on the recipient for > 2 weeks to prolong adult graft survival. Removal of cotransplants from ALS- and BMC-treated recipients after 7 or 14 days abrogated the cotransplantation effect. If left in place until day 21, neonatal cotransplants could significantly prolong adult graft survival, but did not induce the long-term graft survival observed in approximately 50% of the recipients whose cotransplants were not removed. Cotransplant removal after 1 year did not affect subsequent adult graft survival. Additionally, cotransplants were removed from recipients either on day 14 or from long-term graft-bearing mice and retransplanted to other ALS/BMC-treated recipients. These retransplanted grafts were unable to prolong survival of adult grafts on the new recipients. After transplant, but not before transplant, cyclophosphamide treatment of recipients prevented expression of the cotransplant effect in ALS-treated mice. However, recipient splenectomy > or = 1 week before grafting did not interfere with the effect. These results reflect on the contributions of the donor tissue, and the recipients' response, to the tolerogenic signals that permit a neonatal cotransplant to prolong adult graft survival.}, }
@article {pmid7894219, year = {1994}, author = {Danek, A and Witt, TN and Mann, K and Schweikert, HU and Romalo, G and La Spada, AR and Fischbeck, KH}, title = {Decrease in androgen binding and effect of androgen treatment in a case of X-linked bulbospinal neuronopathy.}, journal = {The Clinical investigator}, volume = {72}, number = {11}, pages = {892-897}, pmid = {7894219}, issn = {0941-0198}, mesh = {Anabolic Agents/*therapeutic use ; Follow-Up Studies ; Genetic Linkage ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/*drug therapy/genetics/metabolism ; Muscular Atrophy, Spinal/*drug therapy/genetics ; Nandrolone/*analogs &amp; derivatives/therapeutic use ; Nandrolone Decanoate ; Receptors, Androgen/metabolism ; X Chromosome ; }, abstract = {X-linked recessive bulbospinal neuronopathy is a motoneuron disorder to be distinguished from amyotrophic lateral sclerosis, Effective treatment is not known. Patients with X-linked recessive bulbospinal neuronopathy may show gynecomastia and testicular atrophy, and a mutation in the androgen receptor gene has been found associated with the disease. Intermediate steps leading from the androgen receptor abnormality to the clinical syndrome have not yet been elucidated. Therefore, binding of androgen ([3H]dihydrotestosterone) to its specific receptor by genital skin fibroblasts cultured from a patient with X-linked recessive bulbospinal neuronopathy and confirmed androgen receptor mutation was studied. Markedly decreased binding capacity was found. We treated the patient for 6 months with nandrolone-decanoate. No effect on his neuromuscular status was observed during 2 years of follow-up.}, }
@article {pmid7812703, year = {1994}, author = {Stephens, RJ and Girling, DJ and Machin, D}, title = {Treatment-related deaths in small cell lung cancer trials: can patients at risk be identified? Medical Research Council Lung Cancer Working Party.}, journal = {Lung cancer (Amsterdam, Netherlands)}, volume = {11}, number = {3-4}, pages = {259-274}, doi = {10.1016/0169-5002(94)90546-0}, pmid = {7812703}, issn = {0169-5002}, mesh = {Aged ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Carcinoma, Small Cell/*mortality/*therapy ; Clinical Trials, Phase II as Topic ; Combined Modality Therapy ; Humans ; Lung Neoplasms/*mortality/*therapy ; Middle Aged ; Prognosis ; Proportional Hazards Models ; Radiotherapy/adverse effects ; Randomized Controlled Trials as Topic/*adverse effects ; Risk Factors ; Surgical Procedures, Operative/adverse effects ; }, abstract = {OBJECTIVES: This paper investigates the problem of treatment-related deaths in small cell lung cancer (SCLC).<br><br>DESIGN: To observe and define increased hazard levels, and to identify factors relating to these excess deaths.<br><br>SETTING: The United Kingdom.<br><br>SUBJECTS: A total of 2196 patients entered into the series of six randomised clinical trials in SCLC conducted by the Medical Research Council (MRC) Lung Cancer Working Party (LCWP).<br><br>RESULTS: In this large series of patients an increased risk of death in the second week after commencing the first cycle of chemotherapy was observed, suggesting that of the 10% of patients who died within 3 weeks of starting chemotherapy, half may have been treatment-related. Much less additional risk was associated with subsequent cycles of chemotherapy, and no additional risk with either initial surgery or radiotherapy. Radford et al. [Eur J Cancer 1993; 29A: 81-86] suggested that the risk factors for death from sepsis were a Karnofsky Performance (KP) score of < or = 50 (translated as a WHO performance grade (PS) > or = 3), age > 50 years and three or more drugs in the chemotherapy regimen utilised. Starting with this model we found that our data suggest it can be refined by omitting age and including a white blood cell count > or = 10,000/mm3 (this variable was not tested by Radford), and changing the other categories to WHO PS > or = 2 (KP < or = 70), and four or more drugs. Within our data this revised model identified a high risk group of patients with an excess death rate of more than 15% in the second week after starting chemotherapy. Radford et als' suggestion that high risk patients be given half doses of drugs at the first cycle should be tested in a randomised clinical trial.}, }
@article {pmid7888098, year = {1994}, author = {Adem, A and Ekblom, J and Gillberg, PG}, title = {Growth factor receptors in amyotrophic lateral sclerosis.}, journal = {Molecular neurobiology}, volume = {9}, number = {1-3}, pages = {225-231}, pmid = {7888098}, issn = {0893-7648}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Autoradiography/methods ; Binding Sites ; Humans ; Receptor, IGF Type 1/*analysis ; Receptors, Nerve Growth Factor/*analysis ; Spinal Cord/metabolism/pathology ; }, abstract = {The regional distribution of nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1) receptors in human spinal cords from controls and amyotrophic lateral sclerosis (ALS) patients was studied by quantitative autoradiography. High-affinity nerve growth factor receptors were found to be distributed to a similar extent within the various segments of the human spinal cord and predominantly within the substantia gelatinosa of the dorsal horn, whereas no significant binding could be detected in the motor-neuron areas. A similar pattern of binding was obtained in the ALS spinal cords. Moreover, no reexpression of NGF receptors could be demonstrated in the motor-neuron areas of ALS spinal cords. When comparing 125I-IGF-1 binding in the different spinal levels of normal spinal cord, the same distribution pattern was found in which the binding was highest in the central canal > dorsal horn > ventral horn > white matter. In the ALS cases, although a general upregulation of IGF-1 receptors was observed throughout the spinal cord, significant increases were observed in the cervical and sacral segments compared to controls. The cartography of IGF-1 receptors in the normal spinal cord as well as the change of these receptors in diseased spinal cord may be of importance in future treatment strategies of ALS.}, }
@article {pmid8044087, year = {1994}, author = {Orrell, RW and Lane, RJ and Guiloff, RJ}, title = {Recent developments in the drug treatment of motor neurone disease.}, journal = {BMJ (Clinical research ed.)}, volume = {309}, number = {6948}, pages = {140-141}, pmid = {8044087}, issn = {0959-8138}, mesh = {Clinical Trials as Topic ; Humans ; Motor Neuron Disease/*drug therapy/etiology ; }, }
@article {pmid7520644, year = {1994}, author = {Bak, S and Bak, L}, title = {[Symptomatic treatment of amyotrophic lateral sclerosis].}, journal = {Ugeskrift for laeger}, volume = {156}, number = {28}, pages = {4138-4140}, pmid = {7520644}, issn = {0041-5782}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications/diagnosis/*therapy ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Palliative Care ; Prognosis ; Retrospective Studies ; }, abstract = {During a twelve year period 58 patients with motor neurone disease were admitted to the Department of Neurology, Odense University Hospital. The medical records were reviewed and different aspects of symptomatic treatment for these patients were recorded retrospectively. After the first admission 55% of the patients received out-patient treatment, while 31% had no further contact to the Department of Neurology. Forty-nine patients developed bulbar symptoms. Of these patients 41% were referred to a laryngologist, 27% were referred to a speech therapist and 10% to a nutritionist. Seven patients had a gastrostomy, while feeding tube was used by at least six patients. At the time of follow up 49 patients had died, 63% in hospital. At least 22 patients were treated with morphine in the last period of their lives. In order to improve the symptomatic treatment in motor neurone disease we suggest that these patients are treated at the neurological departments by interdisciplinary teams with particular interest in motor neurone disease.}, }
@article {pmid7967418, year = {1994}, author = {Reiter, A and Tiemann, M and Ludwig, WD and Wacker, HH and Yakisan, E and Schrappe, M and Henzler, D and Sykora, KW and Brandt, A and Odenwald, E}, title = {[NHL-BFM 90 therapy study in treatment of malignant non-Hodgkin's lymphomas in children and adolescents. Part 1: Classification and allocation to strategic therapy groups. BIF study group].}, journal = {Klinische Padiatrie}, volume = {206}, number = {4}, pages = {222-233}, doi = {10.1055/s-2008-1046608}, pmid = {7967418}, issn = {0300-8630}, mesh = {Adolescent ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Child ; Child, Preschool ; Female ; Follow-Up Studies ; Humans ; Infant ; Lymphoma, Non-Hodgkin/classification/*drug therapy/mortality ; Male ; Survival Rate ; }, abstract = {One of the goals of the study NHL-BFM 90 was to investigate the distribution and prognosis of the different subtypes of Non-Hodgkin's Lymphoma (NHL) in children and adolescents according to histological, cytomorphological and immunological characteristics. From 4/1990 to 12/1992, 346 patients (pts) (84 females, 262 males) were enrolled (median age: 9.1 years; range: 0.8-17.9 years). Histology was available from 290 pts (84%), cytomorphology from 155 (44%), and immunophenotyping from 245 (70%). Cases with L1 oder L2 cytomorphology according to the French-American-British Classification were classified as lymphoblastic lymphoma and those with L3 cytomorphology as Burkitt-Type lymphoma or acute B-cell leukemia (B-ALL) if a histological classification was not available. By means of the combined analysis of all three diagnostic criterias the classification of the NHL according to the updated Kiel-classification was possible in 312 cases: 49% were classified as Burkitt-type-lymphoma (incl. B-ALL), 22% als lymphoblastic lymphoma, 10% as large cell anaplastic lymphoma (LCAL), 6% as centroblastic lymphoma, only few cases were classified as NHL of other subtypes, 3 pts (1%) suffered from low grade malignant lymphomas, and in 34 pts (10%) the NHL was not further classified. Patients were stratified according to NHL-subentities in 3 branches (Non-B-NHL, B-NHL, LCAL) of different treatment modalities. The estimated probability of a 3-year event free survival (pEFS) was 88 +/- 2% for the whole group (follow up 7 to 40 months, median 23 months) while pEFS of different subtypes was: lymphoblastic lymphoma: 91 +/- 4%; Burkitt-type-lymphoma/B-ALL: 90 +/- 2%; centroblastic lymphoma: 94 +/- 6%, LCAL: 88 +/- 6%. We conclude that the stratification of treatment modalities in study NHL-BFM 90 according to biological entities provided patients of different NHL-subtypes an equal chance to survive event free. The efficacy of the treatment strategy for rare subtypes, however, is not evaluable yet.}, }
@article {pmid7922294, year = {1994}, author = {Chalmers, RM and Howard, RS and Wiles, CM and Spencer, GT}, title = {Use of the rocking bed in the treatment of neurogenic respiratory insufficiency.}, journal = {QJM : monthly journal of the Association of Physicians}, volume = {87}, number = {7}, pages = {423-429}, pmid = {7922294}, issn = {1460-2725}, mesh = {Adult ; Aged ; *Beds ; Female ; Glucan 1,4-alpha-Glucosidase/deficiency ; Home Care Services ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/complications ; Muscular Dystrophies/complications ; Physical Therapy Modalities/*instrumentation ; Poliomyelitis/complications ; Posture ; Respiratory Insufficiency/etiology/*rehabilitation ; Respiratory Therapy ; }, abstract = {We describe 53 patients who received ventilatory support with a rocking bed. Diagnoses included previous poliomyelitis (30), muscular dystrophy (12), motor neurone disease (4), adult-onset acid maltase deficiency (4) and a miscellaneous group (3). Patients presented with respiratory insufficiency characterized by diaphragm weakness, progressive nocturnal hypoventilation and/or acute or chronic respiratory failure. Domiciliary rocking beds were used by 43 patients for a mean of 16.0 years (range 1 month to 35 years). Most patients were able to breathe adequately by day when sitting or standing, but needed assistance by rocking bed for 6-11 h when lying down for sleep. The rocking bed was well-tolerated, and associated with both symptomatic relief and amelioration of arterial blood gas abnormalities. Seventeen of these 43 patients discontinued its use, either because of discomfort (9) or increasing respiratory insufficiency (8). The rocking bed is a valuable adjunct in the management of the respiratory insufficiency associated with neuromuscular disease.}, }
@article {pmid7807153, year = {1994}, author = {Smith, SA and Miller, RG and Murphy, JR and Ringel, SP}, title = {Treatment of ALS with high dose pulse cyclophosphamide.}, journal = {Journal of the neurological sciences}, volume = {124 Suppl}, number = {}, pages = {84-87}, doi = {10.1016/0022-510x(94)90188-0}, pmid = {7807153}, issn = {0022-510X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Cyclophosphamide/administration &amp; dosage/*therapeutic use ; Female ; Humans ; Injections, Intravenous ; Male ; Middle Aged ; }, abstract = {Autoimmune abnormalities have been described in sporadically acquired amyotrophic lateral sclerosis (ALS), but ALS patients do not benefit from conventional immunosuppressive therapy. Because Multifocal Motor Neuropathy causes a syndrome mimicking the lower motor neuron involvement in ALS and responds to high dose cyclophosphamide, we tested whether ALS patients would respond to the same treatment. Eighteen patients with classical ALS initially received a high loading dose of intravenous cyclophosphamide (3 g/m2) followed by 6-monthly injections of 750-1000 mg/m2. We monitored isometric strength, fine motor coordination and pulmonary function monthly for 3 months prior to the study, during the treatment phase, and for 6 months after treatment. Treatment subjects were matched to control subjects from the WALS natural history data base and compared on the basis of decline rate (megaslopes). Treatment did not alter the course of ALS.}, }
@article {pmid7515002, year = {1994}, author = {Chin, E and Zhou, J and Dai, J and Baxter, RC and Bondy, CA}, title = {Cellular localization and regulation of gene expression for components of the insulin-like growth factor ternary binding protein complex.}, journal = {Endocrinology}, volume = {134}, number = {6}, pages = {2498-2504}, doi = {10.1210/endo.134.6.7515002}, pmid = {7515002}, issn = {0013-7227}, mesh = {Animals ; Carrier Proteins/biosynthesis/*genetics ; Female ; *Gene Expression Regulation ; Glycoproteins/genetics ; Humans ; Hypophysectomy ; In Situ Hybridization ; Insulin-Like Growth Factor Binding Proteins ; Kidney/metabolism ; Liver/growth &amp; development/metabolism ; Male ; RNA, Messenger/analysis/metabolism ; Rats ; Rats, Sprague-Dawley ; Tissue Distribution ; }, abstract = {Insulin-like growth factors (IGFs) are present in the circulation, largely as part of a high mol wt complex including IGF-binding protein-3 (IGFBP-3) and an acid-labile subunit (ALS). This study used in situ hybridization to investigate the cellular sites of synthesis of these factors in the rat and to evaluate changes in transcript levels during development and after hypophysectomy and GH treatment. IGFBP-3 transcripts are considerably more abundant and widely expressed than ALS at birth, but both are present in liver and kidney. Hepatic IGFBP-3 gene expression increases slightly, whereas ALS increases dramatically in the first few weeks after birth. IGFBP-3 mRNA is concentrated in portal venous and sinusoidal endothelium, but is not detected in hepatocytes, whereas ALS mRNA is diffusely expressed by hepatocytes, but is not detected in nonparenchymal cells. Both transcripts are localized in the renal cortex; however, IGFBP-3 mRNA is concentrated in interstitial cells, whereas ALS is expressed in proximal tubule epithelium. Hypophysectomy results in a 90% reduction in hepatic ALS and an approximately 50% decrease in IGFBP-3 mRNA level. ALS, but not IGFBP-3, transcripts were also reduced in the kidney. GH receptor mRNA is coexpressed with ALS in liver and kidney, suggesting that the effects of GH on ALS gene expression may be direct. In summary, the fact that IGFBP-3 gene expression is far more widespread than that of ALS in both spatial and temporal parameters suggests that IGFBP-3 has a role apart from contribution to the ternary complex. We have also shown that IGFBP-3 and ALS are synthesized by distinct hepatic cell types in an anatomical organization that may serve to ensure efficient formation of the ternary complex in the blood passing through the sinusoids. Finally, the present data suggest that regulation of ALS synthesis may be the primary site of GH regulation of ternary complex formation.}, }
@article {pmid7936396, year = {1994}, author = {Westarp, ME and Bartmann, P and Kornhuber, HH}, title = {Immunoglobulin-G isotype changes in human sporadic amyotrophic lateral sclerosis (ALS).}, journal = {Neuroscience letters}, volume = {173}, number = {1-2}, pages = {124-126}, doi = {10.1016/0304-3940(94)90164-3}, pmid = {7936396}, issn = {0304-3940}, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*immunology ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Immunoglobulin G/analysis/*immunology ; Isomerism ; Male ; Middle Aged ; Nephelometry and Turbidimetry ; }, abstract = {Out of 50 patients with sporadic amyotrophic lateral sclerosis (sALS), excluding 8 patients with recent immunosuppressive medication or low total IgG, we examined all available 92 sera of 11 women and 31 men nephelometrically for serum immunoglobulin concentrations including IgG isotypes IgG1-4. Mean serum levels of IgA and IgM remained within references in all cases. Isotypes IgG1 and IgG3 were the most frequently altered immunoglobulins. Without specific treatment, 34 out of 42 patients (= 80%) and 58 out of 92 sera (= 63%) demonstrated low IgG3 concentrations (< 0.41 g/l), while 14 patients (= 33%) and 20 sera (= 22%) demonstrated low IgG1 serum levels (< 4.22 g/l). In patients with normal total IgG, isotypes IgG1 and IgG2 often changed in a complementary way, and IgG1/IgG2 serum concentrations correlated significantly (rs = -0.518, P < 0.001). In four longitudinally monitored patients, the IgG3 isotype ranged from 1.3% to 8.2% of serum IgG and demonstrated a remarkable individual variability over time, corresponding to the relatively short half-life of IgG3. Since elevated circulating immune complexes may fluctuate rapidly, altered serum immunoglobulin isotypes could become more convenient parameters in a still enigmatic disease. To assess their role and relevance, their association with clinical course, cerebrospinal fluid and circulating immune complexes has to be examined.}, }
@article {pmid7512499, year = {1994}, author = {Gargosky, SE and Tapanainen, P and Rosenfeld, RG}, title = {Administration of growth hormone (GH), but not insulin-like growth factor-I (IGF-I), by continuous infusion can induce the formation of the 150-kilodalton IGF-binding protein-3 complex in GH-deficient rats.}, journal = {Endocrinology}, volume = {134}, number = {5}, pages = {2267-2276}, doi = {10.1210/endo.134.5.7512499}, pmid = {7512499}, issn = {0013-7227}, support = {DK-36054/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Carrier Proteins/*metabolism ; Chromatography, Gel ; Drinking ; Eating ; Female ; Growth Hormone/administration &amp; dosage/*deficiency/*pharmacology ; Heart/growth &amp; development ; Insulin-Like Growth Factor Binding Proteins ; Insulin-Like Growth Factor I/metabolism/*pharmacology ; Kidney/growth &amp; development ; Liver/growth &amp; development ; Lung/growth &amp; development ; Male ; Organ Size/drug effects ; Rats ; Rats, Mutant Strains ; Spleen/growth &amp; development ; Weight Gain/drug effects ; }, abstract = {In the adult circulation, 70-90% of the serum insulin-like growth factors (IGFs) are carried by IGF-binding protein-3 (IGFBP-3), which exists as part of a 150-kilodalton (kDa) ternary complex including IGF and an acid-labile subunit (ALS). We have examined the hormonal regulation and molecular distribution of IGFBP-3 in the circulation of a uniquely GH-deficient (GHD) rat model. For 7 days, GHD rats were given GH by either twice daily injections (1 mg/kg) or continuous infusion (2.4 mg/kg.day) or IGF-I by continuous infusion (1.4 mg/kg.day). Each day, weight and feed and water intake were monitored, and on day 7, liver, kidney, spleen, heart, and lung were weighted, and sera were collected. Serum IGF-I was analyzed by immunoassay, and the molecular distribution of the IGFBPs was determined by neutral size-exclusion chromatography combined with Western ligand blot and Western immunoblot. The GHD rats were 40-60% lighter than their normal littermates, and all organs examined were proportionately smaller. Serum IGF-I and IGFBP-3 levels were less than 10% of those in normal rats. Incubation of serum from GHD rats with [125I]IGF-II showed that radiolabel was incorporated only into a 44-kDa IGFBP region that contained the smaller IGFBPs. IGFBP-3 eluted around 60 kDa. No 150-kDa IGFBP region was detected. The administration of GH or IGF-I to GHD rats resulted in significant increases in weight gained, although food and water intake remained unaltered. Weight gain was observed in all three treatments groups. Both GH treatment regimens significantly increased liver, spleen, and lung weight, whereas IGF-I therapy increased spleen, kidney, and heart. Administration of GH twice daily did not increase serum IGF-I or IGFBP-3 concentrations, and the molecular distribution of IGFBP-3 remained unchanged. In contrast, continuous infusion of GH resulted in 5-fold increases in serum IGF-I and increases in IGFBP-3 levels. Size-exclusion chromatography combined with Western ligand blot analysis revealed that radioligand was incorporated into 150- and 60-kDa regions, and that IGFBP-3 was detectable in both regions. Thus, GH infusion was able to induce formation of the 150-kDa ternary complex by increasing circulating levels of IGF-I, IGFBP-3, and presumably ALS. Administration of IGF-I also increased serum IGF-I and IGFBP-3 levels, although the increase in IGFBP-3 was only in the 60-kDa region of the chromatograph, suggesting that IGF-I can induce neither ALS nor formation of the 150-kDa complex.(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid8029260, year = {1994}, author = {Poutiainen, E and Hokkanen, L and Niemi, ML and Färkkilä, M}, title = {Reversible cognitive decline during high-dose alpha-interferon treatment.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {47}, number = {4}, pages = {901-905}, doi = {10.1016/0091-3057(94)90294-1}, pmid = {8029260}, issn = {0091-3057}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/psychology/*therapy ; Central Nervous System/drug effects ; Cognition/*drug effects ; Female ; Humans ; Infusions, Intravenous ; Interferon-alpha/administration &amp; dosage/*adverse effects ; Male ; Middle Aged ; Neuropsychological Tests ; Time Factors ; }, abstract = {The cognitive effects of high-dose human leukocyte alpha-interferon (IFN-alpha) treatment were evaluated among 15 patients with the newly diagnosed spinal form of amyotrophic lateral sclerosis (ALS). To confirm the earlier findings showing reversible effects on cognitive performance and to exclude confounding effects, a randomized blinded placebo controlled study was conducted. Twelve patients with continuous intravenous IFN-alpha-infusion treatment over five days and 3 placebo control patients were neuropsychologically evaluated. The neuropsychological examination included tests of intelligence, memory, complex mental processing, visuoconstructional skills, writing, and calculation. A clear difference in the performance profiles of the placebo and the IFN-alpha-treated patient groups was detected: The IFN-alpha group showed significant deterioration during treatment in the digit span backwards task, logical verbal memory task, calculation ability, and writing time, while improvement was seen after treatment. Concomitant fever did not explain the findings. In the placebo group an improvement indicating a learning effect in the three consecutive measurements was found. The reversible cognitive deterioration indicates a clear CNS effect during the IFN-alpha treatment.}, }
@article {pmid8302347, year = {1994}, author = {Rowland, LP}, title = {Riluzole for the treatment of amyotrophic lateral sclerosis--too soon to tell?.}, journal = {The New England journal of medicine}, volume = {330}, number = {9}, pages = {636-637}, doi = {10.1056/NEJM199403033300911}, pmid = {8302347}, issn = {0028-4793}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; *Excitatory Amino Acid Antagonists ; Humans ; Riluzole ; Thiazoles/*therapeutic use ; }, }
@article {pmid8302340, year = {1994}, author = {Bensimon, G and Lacomblez, L and Meininger, V}, title = {A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group.}, journal = {The New England journal of medicine}, volume = {330}, number = {9}, pages = {585-591}, doi = {10.1056/NEJM199403033300901}, pmid = {8302340}, issn = {0028-4793}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/mortality/physiopathology ; Double-Blind Method ; *Excitatory Amino Acid Antagonists ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Prognosis ; Proportional Hazards Models ; Prospective Studies ; Riluzole ; Survival Analysis ; Thiazoles/adverse effects/*therapeutic use ; Treatment Outcome ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis is a progressive motor neuron disease for which there is no adequate treatment. Some research suggests that the excitatory amino acid neurotransmitter glutamate may be involved in the pathogenesis.<br><br>METHODS: To evaluate the efficacy and safety of the antiglutamate agent riluzole, we conducted a prospective, double-blind, placebo-controlled trial in 155 outpatients with amyotrophic lateral sclerosis. The dose of riluzole was 100 mg per day. Randomization was stratified according to the site of disease onset (the bulbar region or the limbs). The primary end points were survival and rates of change in functional status. The main secondary end point was change in muscle strength. Analyses were undertaken after 12 months of treatment and at the end of the placebo-controlled period (median follow-up, 573 days).<br><br>RESULTS: After 12 months, 45 of 78 patients (58 percent) in the placebo group were still alive, as compared with 57 of 77 patients (74 percent) in the riluzole group (P = 0.014). For patients with bulbar-onset disease, one-year survival rates were 35 percent (6 of 17) with placebo and 73 percent (11 of 15) with riluzole (P = 0.014), whereas for those with limb-onset disease one-year survival was 64 percent and 74 percent, respectively (P = 0.17). The survival advantage with riluzole was smaller (37 percent [29 of 78] with placebo vs. 49 percent [38 of 77] with riluzole) at the end of the placebo-controlled period, but it remained significant in the overall population (P = 0.046) as well as in the patients with bulbar-onset disease (18 percent [3 of 17] vs. 53 percent [8 of 15], P = 0.013). The deterioration of muscle strength was significantly slower in the riluzole group than in the placebo group (P = 0.028). Adverse reactions to riluzole included asthenia, spasticity, and mild elevations in aminotransferase levels. Twenty-seven patients in the riluzole group withdrew from the study, as compared with 17 in the placebo group.<br><br>CONCLUSIONS: The antiglutamate agent riluzole appears to slow the progression of amyotrophic lateral sclerosis, and it may improve survival in patients with disease of bulbar onset.}, }
@article {pmid8107702, year = {1994}, author = {Denys, EH}, title = {AAEM case report #5: Amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {17}, number = {3}, pages = {263-268}, doi = {10.1002/mus.880170302}, pmid = {8107702}, issn = {0148-639X}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*diagnosis/physiopathology ; Electromyography ; Humans ; Male ; Neural Conduction ; Peripheral Nerves/physiopathology ; }, abstract = {A 40-year-old man presented with a gradual onset of gait unsteadiness and weakness in the arms. The stretch reflexes were normal in the upper extremities but hyperactive in the lower extremities with bilateral Babinski signs. A myelogram revealed a partial obstruction at C-5-6. Two prior electromyograms, 7 and 5 months prior to admission, reportedly showed positive waves only in two peroneal supplied muscles. Repeat electromyographic testing demonstrated normal nerve conduction velocities and needle electrode abnormalities in upper and lower extremities as well as thoracic paraspinal muscles allowing a diagnosis of amyotrophic lateral sclerosis (ALS). The importance of electromyographic testing in clinically nonaffected areas is stressed as well as its role in patients presenting with upper motor neuron signs. It is the task of the clinical electromyographer to consider other entities in the differential diagnosis, such as a multifocal motor neuropathy with conduction blocks and design the tests accordingly. The role of electromyography in the prediction of the course of ALS by assessing the degree of reinnervation is discussed. This will become increasingly important in the design of treatment trials.}, }
@article {pmid8047225, year = {1994}, author = {Hausmanowa-Petrusewicz, I}, title = {[Conduction bloc in peripheral nerves. Facts and hypotheses].}, journal = {Neurologia i neurochirurgia polska}, volume = {28}, number = {2}, pages = {157-166}, pmid = {8047225}, issn = {0028-3843}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Demyelinating Diseases/physiopathology ; Diagnosis, Differential ; Humans ; Median Nerve/physiopathology ; Nerve Fibers ; Peripheral Nerves/*physiopathology ; Peripheral Nervous System Diseases/diagnosis/*physiopathology ; Polyradiculoneuropathy/immunology ; }, abstract = {In the terminological dictionary of the AAEE conduction block is defined as inability of impulse to pass through a certain point in nerve fibre, although conduction is preserved below that point. Conduction block is manifested as a quantitatively corresponding drop of the amplitude and area of motor evoked potential (MEP) in the distal part in relation to the values of these parameters proximal to the block. Excessive desynchronization of conduction in nerve fibres and certain technical factors should be excluded. Multifocal conduction block is found in many neuropathies, particularly purely motor ones. The probable mechanisms responsible for the difference between motor and sensory nerve fibres with respect to their susceptibility to block development have been discussed. The understanding of conduction block could have important clinical implications, especially in the differential diagnosis of chronic demyelinative neuropathies, in the selection of immunological research methods, in the choice of treatment and prognostication of possible improvement (e.g. in the Guillain-Barre syndrome). Purely motor neuropathy with multifocal conduction block may simulate amyotrophic lateral sclerosis. The development of block in neuropathies is associated frequently with increased level of antibodies against GM1 and the interrelation between these phenomena is not known; the development of block may be due to deposition of GM1 antibodies in internodes or Ranvier's nodes with production of demyelination or with damage to ion channels. Although the concept of conduction block has been introduced in electroneurographic diagnosis there are still many doubts as to the correctness of diagnostic criteria, indispensable technical conditions, and also to the basic problems, such as e.g. 1) is conduction block really limited to acquired neuropathies (its possible occurrence in congenital neuropathies is discussed), 2) why is conduction block not reflecting clinical improvement, 3) in what degree is block reflecting the loss of motor units. These questions are discussed by the author in the light of literature reports and own experience.}, }
@article {pmid8036558, year = {1994}, author = {Fidelio, T and Licata, C and Serra, A and Scalzo, B and Deabate, MC and Sancipriano, GP and Iacono, G and Calitri, V}, title = {[Evolution of the serum aluminum values in the Piedmont dialysis population. Dialysis Centers of the Piedmont].}, journal = {Minerva urologica e nefrologica = The Italian journal of urology and nephrology}, volume = {46}, number = {1}, pages = {73-76}, pmid = {8036558}, issn = {0393-2249}, mesh = {Aluminum/*blood ; Hemodialysis Solutions/adverse effects ; Hemodialysis, Home ; Humans ; Italy ; Kidney Failure, Chronic/blood/therapy ; Peritoneal Dialysis, Continuous Ambulatory ; *Renal Dialysis ; }, abstract = {The authors have evaluated the evolution of values of serum aluminium concentration (Als) in the whole pool of patients undergoing RDT in Piedmont in the years 1982-1990. We have compared the data of the Piedmont Regional Registry of Dialysis and Transplantation at the end of 1990 to those obtained in 1982, 1986 and 1989. A progressive reduction has been observed in the percentage of patients with Als > 100 micrograms/l, who were 13.5% of the pool in 1982 and 7.5% in 1986 and finally decreased to 1.5% in 1990. This is yet more evident for patients dialyzing at home as in 1982 43% of them had a Als > 100 micrograms/l, whereas in 1986 only 8.2% did and in 1990 this percentage had decreased to 3.6%. The values of Als (distinguished by type of treatment of chronic renal failure) show end confirm the improvement of the situation of aluminium accumulation, specially as regards bicarbonate HD where the percentage of patients with Als > 100 micrograms/l decreases from 10.5% in 1986 to 1.7% in 1990. These data point out the efficacy of prevention and control programs regarding aluminium pathology performed in the last years in Piedmont. This has led to a reduction of the severe accumulation syndromes observed in the first years of '80 and has allowed the nephrologist to prepare more correct therapeutic prescriptions.}, }
@article {pmid7838303, year = {1994}, author = {Lindsay, RM}, title = {Neurotrophic growth factors and neurodegenerative diseases: therapeutic potential of the neurotrophins and ciliary neurotrophic factor.}, journal = {Neurobiology of aging}, volume = {15}, number = {2}, pages = {249-251}, doi = {10.1016/0197-4580(94)90124-4}, pmid = {7838303}, issn = {0197-4580}, mesh = {Animals ; Ciliary Neurotrophic Factor ; Humans ; Nerve Degeneration/physiology ; Nerve Growth Factors/*physiology/*therapeutic use ; Nerve Tissue Proteins/*therapeutic use ; Nervous System Diseases/*drug therapy/*physiopathology ; Receptors, Nerve Growth Factor/physiology ; }, abstract = {The recent molecular cloning of BDNF and CNTF based on traditional protein purification and protein sequencing and the identification and cloning of NT-3 and NT-4 by homology cloning strategies has led to a tremendous flurry of interest in the biology of these proteins and initiation of studies to assess their potential utility in neurological disorders ranging through degenerative disease, stroke and ischemia, trauma and peripheral neuropathies. Tissue culture studies have been very useful in identifying neuronal specificities of the neurotrophins and CNTF and in combination with localization studies of these growth factors and their receptors have provided the basis for in vivo studies. Initial animal studies with BDNF indicate efficacy of BDNF in models of Alzheimer's and Parkinson's disease and small fiber sensory neuropathy. Studies with CNTF have similarly progressed from in vitro findings, especially the discovery that CNTF is a growth factor for motor neurons, to in vivo findings where CNTF has been shown to be effective in slowing symptoms of motor neuron dysfunction in three genetic models. Based on these positive animal data, CNTF is currently in clinical trials for the potential treatment of motor neuron disease or amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.}, }
@article {pmid8304845, year = {1994}, author = {Tan, E and Lynn, DJ and Amato, AA and Kissel, JT and Rammohan, KW and Sahenk, Z and Warmolts, JR and Jackson, CE and Barohn, RJ and Mendell, JR}, title = {Immunosuppressive treatment of motor neuron syndromes. Attempts to distinguish a treatable disorder.}, journal = {Archives of neurology}, volume = {51}, number = {2}, pages = {194-200}, doi = {10.1001/archneur.1994.00540140104020}, pmid = {8304845}, issn = {0003-9942}, support = {M01-RR-00034/RR/NCRR NIH HHS/United States ; M01-RR-01346/RR/NCRR NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/drug therapy/immunology ; Cyclophosphamide/*therapeutic use ; Female ; G(M1) Ganglioside/analysis ; Humans ; Immunosuppressive Agents/therapeutic use ; Male ; Middle Aged ; Motor Neuron Disease/*drug therapy/immunology/physiopathology ; Neural Conduction ; Prednisone/*therapeutic use ; Prospective Studies ; }, abstract = {OBJECTIVE: To determine if response to immunosuppressive treatment in motor neuron syndromes could be predicted on the basis of clinical features, anti-GM1 antibodies, or conduction block.<br><br>DESIGN: Prospective, uncontrolled, treatment trial using prednisone for 4 months followed by intravenous cyclophosphamide (3 g/m2) continued orally for 6 months.<br><br>SETTING: All patients were referred to university hospital medical centers.<br><br>PATIENTS: Sixty-five patients with motor neuron syndromes were treated with prednisone; 11 patients had elevated GM1 antibody titers, and 11 patients had conduction block. Forty-five patients received cyclophosphamide, eight of whom had elevated GM1 antibodies and 10 had conduction block.<br><br>RESULTS: One patient responded to prednisone, and five patients responded to cyclophosphamide treatment. Only patients with a lower motor neuron syndrome and conduction block improved with either treatment. Response to treatment did not correlate with GM1 antibodies.<br><br>CONCLUSIONS: GM1 antibodies did not serve as a marker for improvement in patients with motor neuron syndrome treated with immunosuppressive drugs. Patients with amyotrophic lateral sclerosis failed to improve irrespective of laboratory findings.}, }
@article {pmid8129492, year = {1994}, author = {Rutledge, R and Smith, CY and Azizkhank, RG}, title = {A population-based multivariate analysis of the association of county demographic and medical system factors with per capita pediatric trauma death rates in North Carolina.}, journal = {Annals of surgery}, volume = {219}, number = {2}, pages = {205-210}, pmid = {8129492}, issn = {0003-4932}, mesh = {Adolescent ; Catchment Area, Health/statistics &amp; numerical data ; Child ; Child, Preschool ; *Demography ; Emergency Medical Services/*statistics &amp; numerical data ; Humans ; Infant ; Multivariate Analysis ; North Carolina/epidemiology ; Wounds and Injuries/*mortality ; }, abstract = {OBJECTIVE: This study analyzed the association between demographic and medical system factors and the pediatric trauma death rate in North Carolina.<br><br>SUMMARY BACKGROUND DATA: Trauma is the leading cause of death in children. Various medical system factors have been suggested to reduce pediatric morbidity and mortality rates, but the association with these rates has not been tested.<br><br>METHODS: Data were obtained from the North Carolina medical examiner's database. The dependent variable was the county per capita pediatric trauma death rate. Twenty-one demographic and medical system measures were selected as independent variables.<br><br>RESULTS: Nine hundred forty-one pediatric trauma deaths from 1986 to 1989 were included in our sample. Multivariate analysis identified the variables most highly associated with the dependent variables. The presence of advanced life support (ALS) training was the only medical system factor associated significantly with pediatric trauma death rates. Trauma centers, emergency (911) telephone access, and other medical resource variables had no significant association.<br><br>CONCLUSIONS: The study confirms other reports showing that demographic factors have an important predictive association with the trauma death rate in children. Advanced life support was the only medical system resource associated significantly with pediatric trauma death rates. This study underlines the significance of pre-hospital care in the treatment of pediatric trauma.}, }
@article {pmid8114793, year = {1994}, author = {Huard, J and Roy, R and Guérette, B and Verreault, S and Tremblay, G and Tremblay, JP}, title = {Human myoblast transplantation in immunodeficient and immunosuppressed mice: evidence of rejection.}, journal = {Muscle &amp; nerve}, volume = {17}, number = {2}, pages = {224-234}, doi = {10.1002/mus.880170214}, pmid = {8114793}, issn = {0148-639X}, mesh = {Animals ; Antibodies/analysis ; Antilymphocyte Serum/pharmacology ; Clone Cells/transplantation ; Cyclosporine/pharmacology ; Dystrophin/metabolism ; Fluorometry ; *Graft Rejection ; Humans ; Immune System Diseases/genetics/*physiopathology ; Immunohistochemistry ; *Immunosuppression Therapy ; Injections, Intramuscular ; Mice ; Mice, Inbred mdx ; Mice, Nude ; Mice, SCID ; Muscles/*cytology/immunology/metabolism ; *Tissue Transplantation ; }, abstract = {Normal human myoblasts were cloned and transplanted in the tibialis anterior of immunodeficient nude and SCID mice and in mdx mice under different immunosuppressive treatments (cyclosporine A, CsA; antilymphocyte serum, ALS) or not immunosuppressed. This permitted us to show the interaction of the immune system in the myoblast transplantation. The graft success was assessed by verifying signs of humoral and cellular immune reactions and the presence of dystrophin produced by the fusion of the donor myoblasts. This study showed that clones of human myoblasts were able to fuse and produce dystrophin in injected muscles of immunodeficient mice and mdx mice receiving an effective immunosuppressive treatment (i.e., ALS+CsA). However, the same pool of human myoblasts injected in mdx mice inadequately immunosuppressed (i.e., CsA alone or ALS alone) triggered an immune reaction and was rejected. Cells expressing CD4 and CD8 antigens were observed in the injected muscles of mice treated with CsA alone. Therefore, evidence of humoral and cellular rejection was observed following human myoblasts transplantation.}, }
@article {pmid8109896, year = {1994}, author = {Dittrich, F and Thoenen, H and Sendtner, M}, title = {Ciliary neurotrophic factor: pharmacokinetics and acute-phase response in rat.}, journal = {Annals of neurology}, volume = {35}, number = {2}, pages = {151-163}, doi = {10.1002/ana.410350206}, pmid = {8109896}, issn = {0364-5134}, mesh = {*Acute-Phase Reaction ; Animals ; Ciliary Neurotrophic Factor ; Injections, Intravenous ; Iodine Radioisotopes ; Liver/metabolism ; Male ; Muscles/metabolism ; Nerve Tissue Proteins/administration &amp; dosage/*pharmacokinetics ; Nervous System/metabolism ; Rats ; Rats, Wistar ; }, abstract = {Ciliary neurotrophic factor (CNTF) supports the survival of motoneurons in vitro and in vivo. Recombinant CNTF is an investigational drug for the treatment of amyotrophic lateral sclerosis. We determined the pharmacokinetics of radioiodinated CNTF after intravenous injection into rats. CNTF shows a biphasic clearance with an initial plasma half-life of 2.9 minutes and is removed from the circulation by the liver. No accumulation of radioactivity was detectable in nerve tissue or skeletal muscle after intravenous injection of 0.1 microgram and 0.5 microgram of CNTF. Radioactive degradation products accumulate in the skin. Liver cells express specific binding proteins for CNTF, and the incorporation and degradation of intravenously injected CNTF by the liver may occur after association of CNTF with the soluble CNTF receptor alpha in the circulation. Probably as a consequence of its binding to hepatocytes, CNTF induces acute-phase responses in liver. The short half-life and the inflammatory side effect may limit the clinical usefulness of systematically administered CNTF in the treatment of human motoneuron disorders.}, }
@article {pmid8109895, year = {1994}, author = {Drachman, DB and Chaudhry, V and Cornblath, D and Kuncl, RW and Pestronk, A and Clawson, L and Mellits, ED and Quaskey, S and Quinn, T and Calkins, A}, title = {Trial of immunosuppression in amyotrophic lateral sclerosis using total lymphoid irradiation.}, journal = {Annals of neurology}, volume = {35}, number = {2}, pages = {142-150}, doi = {10.1002/ana.410350205}, pmid = {8109895}, issn = {0364-5134}, support = {NCRR OPD-GCRC RR00722/RR/NCRR NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/immunology/*radiotherapy ; CD4-CD8 Ratio ; Double-Blind Method ; Humans ; Immunity ; *Immunosuppression Therapy ; Leukocyte Count ; Placebos ; }, abstract = {Although the cause of amyotrophic lateral sclerosis (ALS) remains unknown, recent studies have suggested an autoimmune mechanism of pathogenesis. Previous trials of immunosuppressive treatment have yielded inconclusive results. Our study was designed to determine whether more powerful and prolonged immunosuppression, produced by total lymphoid irradiation (TLI), would alter the course of ALS. In a double-blind, randomized, placebo-controlled study, 30 patients with classic ALS were treated with TLI, and 31 were given sham radiation. Quantitative measurements of muscle strength, functional motor activity, and humoral and cellular immune status were followed for 2 years, or until death or respirator dependence. Motor function in the TLI-treated and control groups showed no significant differences throughout the study. Overall survival was not significantly different in the TLI-treated and control groups. TLI effectively suppressed cellular and humoral immune function throughout the 2-year study period. Analysis of the relationship between immunosuppression and motor functions showed no consistent effect of treatment. We conclude that powerful and prolonged immunosuppression produced by TLI did not benefit patients with ALS. This fails to support the concept of an autoimmune mechanism of pathogenesis of ALS.}, }
@article {pmid8264698, year = {1994}, author = {Lange, DJ}, title = {AAEM minimonograph #41: neuromuscular diseases associated with HIV-1 infection.}, journal = {Muscle &amp; nerve}, volume = {17}, number = {1}, pages = {16-30}, doi = {10.1002/mus.880170104}, pmid = {8264698}, issn = {0148-639X}, mesh = {Acute Disease ; Axons ; Chronic Disease ; Cytomegalovirus Infections/complications ; Demyelinating Diseases/etiology/therapy ; HIV Infections/*complications ; Humans ; Muscular Diseases/complications ; Neuromuscular Diseases/*etiology/therapy ; Peripheral Nervous System Diseases/etiology/microbiology ; Spinal Nerve Roots ; }, abstract = {Neuromuscular diseases occur in as many as 50% of patients infected with human immunodeficiency virus type 1 (HIV-1). All forms of neuromuscular disease have been reported, including axonal neuropathy, demyelinating neuropathy, mononeuropathy multiplex, polyradiculitis, ALS-like syndromes, disorders of neuromuscular transmission, myopathy, and toxic neuropathies due to medication side effects. Neuromuscular disease is often the presenting manifestation of HIV-1 infection. Infection with cytomegalovirus (CMV) is associated with different types of neuropathy including mononeuritis multiplex and polyradiculopathy. There is effective treatment for many of the associated disorders including chronic inflammatory demyelinating neuropathy, CMV-mediated neuropathies, and myopathy. Treatment of CMV-mediated mononeuropathy multiplex may be life saving. The different neuromuscular syndromes associated with different stages of HIV-1 infection may be due, in part, to different levels of immunocompetence.}, }
@article {pmid8138845, year = {1994}, author = {Betemps, EJ and Buncher, CR and Clark, CS}, title = {Proportional mortality analysis of wastewater treatment system workers by birthplace with comments on amyotrophic lateral sclerosis.}, journal = {Journal of occupational medicine. : official publication of the Industrial Medical Association}, volume = {36}, number = {1}, pages = {31-35}, pmid = {8138845}, issn = {0096-1736}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/ethnology/etiology/*mortality ; Causality ; Chicago/epidemiology ; Cohort Studies ; Death Certificates ; Ethnicity/*statistics &amp; numerical data ; Humans ; Male ; Middle Aged ; Neoplasms/ethnology/etiology/mortality ; Occupational Diseases/ethnology/etiology/*mortality ; Occupational Exposure/*adverse effects ; Proportional Hazards Models ; Risk Factors ; Transients and Migrants/statistics &amp; numerical data ; *Waste Disposal, Fluid ; }, abstract = {There is concern that wastewater treatment system workers are at risk for cancers and diseases affecting the neurological and digestive systems. However, these diseases have also been linked to early exposures. A proportional mortality study was conducted on a large cohort of wastewater treatment system workers who were divided into two groups, migrants and nonmigrants, by place of birth as reported on their death certificates. The migrant worker group was significantly higher than the US white male population for cancer of the stomach, leukemia, and all lymphopoietic cancers. Migrant workers also had an elevated ratio for all diseases of the nervous system and sense organs. No cases of amyotrophic lateral sclerosis were found. The American-born workers had an elevated rate of death for arteriosclerotic heart disease compared with the US white male population. We suggest that place of birth may present a confounding factor when evaluating exposures in employee groups.}, }
@article {pmid8041989, year = {1994}, author = {Cellerin, L and Ordronneau, J and Chollet, S and Feve, JR and Chailleux, E}, title = {[Prognostic factors in the survival of patients with neuromuscular diseases after an episode of acute respiratory insufficiency].}, journal = {Revue des maladies respiratoires}, volume = {11}, number = {3}, pages = {263-270}, pmid = {8041989}, issn = {0761-8425}, mesh = {Acute Disease ; Adolescent ; Adult ; Aged ; Chronic Disease ; Female ; Humans ; Intensive Care Units ; Length of Stay ; Male ; Middle Aged ; Neuromuscular Diseases/etiology/*mortality/therapy ; Prognosis ; Proportional Hazards Models ; Respiration, Artificial ; Respiratory Insufficiency/*complications/therapy ; Retrospective Studies ; Risk Factors ; Survival Rate ; }, abstract = {We have studied the survival of 49 patients suffering from neuromuscular disease, who were hospitalised in the Respiratory Intensive Care Unit between 1981 and 1990 (29 males and 20 females with a mean age of 49.3 +/- 17 years with a range of 15 to 79). The neuromuscular diseases consisted of 8 with multiple sclerosis, 9 with amyotrophic lateral sclerosis, 8 with Steinert's disease, 11 myopathies, and 10 suffering from miscellaneous neurological diseases. Initially 27 of the 49 patients had been intubated and ventilated. During the hospital stay long-term ventilation was undertaken in 27 patients (21 by tracheotomy and 6 by nasal mask). The principal prognostic factor was the aetiology. Three groups of varying degrees of severity could be individualized: progressive neuromuscular disease (amyotrophic lateral sclerosis and multiple sclerosis), primary muscle disorders (myopathies and Steinert's disease), and neuromuscular disease with little or no evolution (survival at two years was 15%, 45% and 71% respectively for three groups. p = 0.001 by log-rank testing). The other factors which influence survival are age (p < 0.01), the presence of false route (p < 0.01), and the reason for hospitalisation (acute as opposed to chronic progressive deterioration, p < 0.05). In a multivariate analysis the most significant factors associated with the diagnosis were age, the reason for hospitalisation, and the existence of false routes. The initial treatment (intubation) and the prescription of long-term ventilation did not bring with it any significant further information as to prognosis, compared to the model which included these four factors.}, }
@article {pmid8008989, year = {1994}, author = {Sherman, MS and Paz, HL}, title = {Review of respiratory care of the patient with amyotrophic lateral sclerosis.}, journal = {Respiration; international review of thoracic diseases}, volume = {61}, number = {2}, pages = {61-67}, doi = {10.1159/000196308}, pmid = {8008989}, issn = {0025-7931}, mesh = {Amyotrophic Lateral Sclerosis/*complications/physiopathology ; Humans ; Respiration, Artificial ; Respiratory Function Tests ; Respiratory Insufficiency/etiology/physiopathology/*therapy ; Respiratory Therapy ; }, abstract = {Respiratory failure is the leading cause of death in patients with amyotrophic lateral sclerosis (ALS). We review the physiology of respiratory compromise in ALS and techniques of monitoring respiratory function. Treatment options, including pharmacologic interventions, aspiration precautions, and invasive and noninvasive modes of mechanical ventilation are reviewed. Our clinical experience with respiratory failure in ALS demonstrates significantly prolonged survival in subjects who elect to receive noninvasive mechanical ventilation (19.25 vs. 80.4 days, p < 0.01). Four of 18 patients who elected to receive noninvasive ventilation decided to discontinue treatment. Four of 13 patients who were receiving mechanical ventilation elected to discontinue life support. The decision to utilize these modalities must be made with realistic considerations of the patient's quality of life.}, }
@article {pmid7931231, year = {1994}, author = {Jossan, SS and Ekblom, J and Gudjonsson, O and Hagbarth, KE and Aquilonius, SM}, title = {Double blind cross over trial with deprenyl in amyotrophic lateral sclerosis.}, journal = {Journal of neural transmission. Supplementum}, volume = {41}, number = {}, pages = {237-241}, doi = {10.1007/978-3-7091-9324-2_30}, pmid = {7931231}, issn = {0303-6995}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Blood Platelets/enzymology ; Cross-Over Studies ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Monoamine Oxidase/metabolism ; Monoamine Oxidase Inhibitors/therapeutic use ; Nervous System/drug effects/physiopathology ; Selegiline/*therapeutic use ; Treatment Outcome ; }, abstract = {In this paper we present results from a double blind cross over trial with deprenyl, a selective and irreversible monoamine oxidase-B (MAO-B) inhibitor, in 10 patients suffering from amyotrophic lateral sclerosis. The patients were randomised in such a way that half of the patients started with the active drug and half with the placebo treatment. Each patient was given 10 mg deprenyl (eldepryl, 10 mg tablets) per day for 12 weeks and then placebo for the same length of time. There was a drug free period of 12 weeks between the courses. The neurological status of the patients were evaluated every six weeks by using Norris, spinal and bulbar scores and it was observed that all cases deteriorated in their clinical status during the 36 weeks of the controlled study. MAO-B activity in blood platelets was completely inhibited during treatment with deprenyl. In the preliminary analysis performed so far, no obvious retardation in the progress of the disease could be observed with deprenyl treatment.}, }
@article {pmid7925318, year = {1994}, author = {Goonetilleke, A and de Belleroche, J and Guiloff, RJ}, title = {Motor neurone disease.}, journal = {Essays in biochemistry}, volume = {28}, number = {}, pages = {27-45}, pmid = {7925318}, issn = {0071-1365}, mesh = {*Amyotrophic Lateral Sclerosis/etiology/metabolism/pathology/therapy ; Brain/metabolism/pathology ; Carbohydrate Sequence ; Female ; Humans ; Male ; Molecular Sequence Data ; Motor Neurons/pathology ; Nerve Degeneration ; Spinal Cord/metabolism/pathology ; }, abstract = {Motor neurone disease, or amyotrophic lateral sclerosis, is a serious progressive neurological disorder, characterized by loss of UMN and LMN. Pathological features include characteristic intracytoplasmic MN inclusion bodies and appearances on ubiquitin staining. The aetiopathogenesis of the disease remains unknown and there is, to date, no effective treatment. Several abnormalities have been demonstrated in neurotransmitter, neuropeptide and gene expression studies. Abnormalities in glutamate metabolism have led to the excitotoxin hypothesis of MN destruction. Other theories include deficits in MN trophic factors, trans-synaptic degeneration, impaired ability to detoxify putative toxic agents and impaired DNA/RNA metabolism. The existence of familial forms, some of which show linkage to markers in chromosome 21, allows a genetic approach to the mechanisms of disease. Recent studies suggest that mutations in the Cu/Zn SOD gene may be important in some of the familial forms. The atypical forms seen in the Western Pacific have stimulated a search for environmental agents. Agents undergoing therapeutic trials at present include CNTF, IGF1 glutamate antagonists, branched-chain amino acids and TRH analogue.}, }
@article {pmid7888151, year = {1994}, author = {Adem, A and Ekblom, J and Gillberg, PG and Jossan, SS and Höög, A and Winblad, B and Aquilonius, SM and Wang, LH and Sara, V}, title = {Insulin-like growth factor-1 receptors in human spinal cord: changes in amyotrophic lateral sclerosis.}, journal = {Journal of neural transmission. General section}, volume = {97}, number = {1}, pages = {73-84}, pmid = {7888151}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Female ; Humans ; Image Processing, Computer-Assisted ; Immunohistochemistry ; Iodine Radioisotopes ; Male ; Motor Neurons/physiology ; Receptor, IGF Type 1/*metabolism ; Spinal Cord/*metabolism/pathology ; }, abstract = {Neurotrophic factors are important for neuronal survival and maintenance in the adult nervous system. The regional distribution of insulin-like growth factor-1 (IGF-1) receptors in human spinal cords from controls and amyotrophic lateral sclerosis (ALS) patients was studied by immunohistochemistry and quantitative autoradiography. When comparing 125I-IGF-1 binding in the different spinal levels of normal spinal cord the same distribution pattern was found in which the binding was highest in the central canal > dorsal horn > ventral horn > white matter. In the ALS cases although a general upregulation of IGF-1 receptors was observed throughout the spinal cord, significant increases were observed in the cervical and sacral segments compared to controls. IGF-1 receptor immunoreactivity showed a similar pattern to that for 125I-IGF-1 binding, with immunoreactivity being found in the gray matter of the spinal cord and enhanced immunoreactivity occuring in ALS patients compared to controls. In agreement with the distribution of IGF-1 receptors, IGF-1 immunoreactivity was found within the gray matter of the spinal cord. The cartography of IGF-1 receptors in the normal spinal cord as well as the change of these receptors in diseased spinal cord may be of importance in future treatment strategies of ALS.}, }
@article {pmid7705221, year = {1994}, author = {Lipton, SA}, title = {Neuronal injury associated with HIV-1 and potential treatment with calcium-channel and NMDA antagonists.}, journal = {Developmental neuroscience}, volume = {16}, number = {3-4}, pages = {145-151}, doi = {10.1159/000112101}, pmid = {7705221}, issn = {0378-5866}, mesh = {AIDS Dementia Complex/*drug therapy/*pathology ; Calcium Channel Blockers/*therapeutic use ; HIV Infections/complications/*pathology ; *HIV-1 ; Humans ; N-Methylaspartate/*antagonists &amp; inhibitors ; Neurons/*physiology ; }, abstract = {A substantial number of adults and half of the children with acquired immunodeficiency syndrome (AIDS) suffer from neurological manifestations. Among the various pathologies reported in brains of patients with AIDS is neuronal injury and loss, although neurons themselves do not appear to be infected by HIV-1. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells, especially after interacting with astrocytes, secrete neurotoxic substances. Not all of these substances are yet known, but they may include eicosanoids, platelet-activating factor, quinolinate, cysteine, cytokines, and free radicals. Macrophages activated by HIV-1 envelope protein gp120 also appear to release similar toxins. Some of these factors can lead to increased glutamate release or decreased glutamate reuptake. A final common pathway for neuronal suceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-asparate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.}, }
@article {pmid8255440, year = {1993}, author = {}, title = {Branched-chain amino acids and amyotrophic lateral sclerosis: a treatment failure? The Italian ALS Study Group.}, journal = {Neurology}, volume = {43}, number = {12}, pages = {2466-2470}, doi = {10.1212/wnl.43.12.2466}, pmid = {8255440}, issn = {0028-3878}, mesh = {Amino Acids, Branched-Chain/adverse effects/*therapeutic use ; Amyotrophic Lateral Sclerosis/*drug therapy/mortality/physiopathology ; Double-Blind Method ; Female ; Humans ; Male ; Meta-Analysis as Topic ; Middle Aged ; Multivariate Analysis ; Patient Advocacy ; Safety Management ; Severity of Illness Index ; Survival Analysis ; Treatment Failure ; Vital Capacity ; }, abstract = {We initiated a double-blind, placebo-controlled trial to test the efficacy and safety of branched-chain amino acids (BCAA) (L-leucine 12 g, L-isoleucine 6 g, and L-valine 6 g daily) in amyotrophic lateral sclerosis (ALS) patients. There was an excess mortality in subjects randomized to active treatment (24 BCAA, 13 placebo) when a total of 126 ALS patients had been recruited. This finding, associated with the lack of efficacy of BCAA (measured by comparing the disability scales in the two treatment groups), led the Data Monitoring Committee to require cessation of the trial.}, }
@article {pmid8179830, year = {1993}, author = {Cho, HK and Park, YW and Kim, YJ and Shyn, KH}, title = {Histopathologic and ultrastructural findings of photocoagulation lesions produced by transpupillary diode laser in the rabbit retina.}, journal = {Journal of Korean medical science}, volume = {8}, number = {6}, pages = {420-430}, doi = {10.3346/jkms.1993.8.6.420}, pmid = {8179830}, issn = {1011-8934}, mesh = {Animals ; Laser Coagulation/*adverse effects ; Rabbits ; Retina/pathology/*radiation effects/ultrastructure ; }, abstract = {Transpupillary retinal photocoagulations were performed on ten eyes of five pigmented rabbits using a diode laser (Nidek Co., LTD, Aichi, Japan) emitting infrared radiation at 800 nm wavelength. A histological and an ultrastructural study on the treated eyes were done at 1, 3, 5, and 7 days after retinal photocoagulations. The purpose of this study was to observe the sequential changes in the retina and the choroid following transpupillary diode laser retinal photocoagulations at the parameters of laser power which produced a grayish white retinal discoloration with distinct white center. It seemed that the lesion was grade 3 retinal photocoagulation by Tso et al's classification. It appeared that the parameters necessary to produce grade 3 photocoagulation lesions were 160 mW power, and 0.2 second duration at 200 microns size. In general, with an agreement to other reports, histologic study of the diode laser lesions showed that the outer retina was damaged more severely than the inner retina. However, on day 1 after laser treatment, the alterations were more profound in the inner retina than in the outer retina and an occasional swelling of the axons in the nerve fiber layer was observed on the ultrastructural study. The results observed have not been found in other previous studies and suggest that the inner retina might be injured directly by 800 nm wavelength diode laser radiations. Thus we could conclude that 800 nm wavelength diode radiation might be absorbed by melanin pigment and also by other chromophores contained in inner retinal tissues. Further studies must follow to verify the laser-tissue interactions in diode laser retinal photocoagulations.}, }
@article {pmid8106826, year = {1993}, author = {Tidwell, J}, title = {Pulmonary management of the ALS patient.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {25}, number = {6}, pages = {337-342}, doi = {10.1097/01376517-199312000-00003}, pmid = {8106826}, issn = {0888-0395}, mesh = {Advance Directives ; Amyotrophic Lateral Sclerosis/*complications/diagnosis/physiopathology/therapy ; Diagnosis, Differential ; Ethics, Nursing ; Humans ; Male ; Middle Aged ; Respiration, Artificial ; Respiratory Paralysis/etiology/*nursing/physiopathology/therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic progressive motor neuron disease with a poor prognosis which eventually weakens and paralyzes the respiratory muscles. ALS is characterized by progressive degeneration of both cortical and alpha motor neurons of the final common pathway. Early symptoms usually begin with alpha motor neuron involvement and then progress to include cortical motor neuron involvement. Degeneration of respiratory nerve centers in the anterior horn at the C3-C5 levels results in respiratory muscle fatigue, respiratory failure and eventually death. Treatment consists of preventing respiratory complications and supporting lung function for as long as possible. One case example of a critically ill patient with ALS highlights nursing concerns. With advanced directives and durable power of attorney, the patient now has better means available for making known the decision of whether to accept or reject mechanical ventilation.}, }
@article {pmid8282084, year = {1993}, author = {Lewis, ME and Neff, NT and Contreras, PC and Stong, DB and Oppenheim, RW and Grebow, PE and Vaught, JL}, title = {Insulin-like growth factor-I: potential for treatment of motor neuronal disorders.}, journal = {Experimental neurology}, volume = {124}, number = {1}, pages = {73-88}, doi = {10.1006/exnr.1993.1177}, pmid = {8282084}, issn = {0014-4886}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Cell Survival ; Humans ; Insulin-Like Growth Factor I/pharmacology/*therapeutic use ; Models, Biological ; Molecular Sequence Data ; Motor Neuron Disease/*drug therapy/physiopathology ; Motor Neurons/cytology/drug effects/physiology ; Nervous System/drug effects ; Nervous System Physiological Phenomena ; Receptor, IGF Type 1/physiology ; }, abstract = {Motor neuronal disorders, such as the loss of spinal cord motor neurons in amyotrophic lateral sclerosis or the degeneration of spinal cord motor neuron axons in certain peripheral neuropathies, present a unique opportunity for therapeutic intervention with neurotrophic proteins. Normally, such proteins do not cross the blood-brain barrier, but spinal cord motor neuron axons and nerve terminals lie outside the barrier and thus may be targeted by systemic administration of protein growth factors. Insulin-like growth factor-I (IGF-I) receptors are present in the spinal cord, and, like members of the neurotrophin receptor family, IGF-I receptors mediate signal transduction via a tyrosine kinase domain. IGF-I was found to prevent the loss of choline acetyltransferase activity in embryonic spinal cord cultures, as well as to reduce the programmed cell death of motor neurons in vivo during normal development or following axotomy or spinal transection. Consistent with earlier reports that IGF-I enhances motor neuronal sprouting in vivo, subcutaneous administration of IGF-I increases muscle endplate size in rats. Subcutaneous injections of IGF-I also accelerate functional recovery following sciatic nerve crush in mice, as well as attenuate the peripheral motor neuropathy induced by chronic administration of the cancer chemotherapeutic agent vincristine in mice. Doses of IGF-I that accelerate recovery from sciatic nerve crush in mice result in elevated serum levels of IGF-I which are similar to those obtained following subcutaneous injections of formulated recombinant human IGF-I (Myotrophin) in normal human subjects. Based on these findings, together with evidence of safety in animals and man, clinical trials of recombinant human IGF-I have been initiated in patients with amyotrophic lateral sclerosis and are planned to begin soon in patients with chemotherapy-induced peripheral neuropathies.}, }
@article {pmid8282083, year = {1993}, author = {Seeburger, JL and Springer, JE}, title = {Experimental rationale for the therapeutic use of neurotrophins in amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {124}, number = {1}, pages = {64-72}, doi = {10.1006/exnr.1993.1176}, pmid = {8282083}, issn = {0014-4886}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Animals ; Brain-Derived Neurotrophic Factor ; Humans ; Motor Neurons/drug effects/*physiology ; Nerve Growth Factors/pharmacology/physiology/*therapeutic use ; Nerve Tissue Proteins/pharmacology/therapeutic use ; Neurotrophin 3 ; Receptors, Nerve Growth Factor/drug effects/physiology ; }, abstract = {Current therapeutic efforts to treat chronic and progressive neurodegenerative disease include, for the first time, attempts to regenerate affected nervous tissue using neurotrophic factors. The rationale for using trophic factors includes the understanding that they support neuronal survival and regrowth processes. The potential benefits of trophic factor therapy will be no more realized in the near future than in the treatment of amyotrophic lateral sclerosis (ALS). ALS is pathologically characterized by the selective degeneration of specific populations of cranial and spinal motoneurons. Evidence for the existence of factors that support motoneurons has come from studies demonstrating that motoneurons receive trophic influences from various tissues, both central and peripheral, within their local environment. Although the identity of these putative tissue-derived factors has remained enigmatic, recent studies have demonstrated that several previously characterized trophic factors exhibit trophic influences on motoneurons. Among these are several members of the neurotrophin family, most notably brain-derived neurotrophic factor. These neurotrophins meet most of the criteria to be considered motoneuron trophic factors: they are locally available to motoneurons in vivo; motoneurons express specific receptors for these factors; and exogenous application of these factors mimicks the effects of the uncharacterized endogenous agents. The clinical use of these factors for the treatment of ALS, therefore, appears to be scientifically justified.}, }
@article {pmid8282074, year = {1993}, author = {Springer, JE}, title = {Experimental evidence for growth factor treatment and function in certain neurological disorders.}, journal = {Experimental neurology}, volume = {124}, number = {1}, pages = {2-4}, doi = {10.1006/exnr.1993.1166}, pmid = {8282074}, issn = {0014-4886}, mesh = {Alzheimer Disease/*drug therapy/physiopathology ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Growth Substances/*physiology/*therapeutic use ; Humans ; Parkinson Disease/*drug therapy/physiopathology ; }, abstract = {This issue focuses on the potential utilization or involvement of growth factors in Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and epilepsy. Certainly, the role of growth factors in other neurological disorders associated with stroke, trauma, and neurodegeneration needs to be considered. While there is no direct evidence to indicate that a neurological disorder is associated with the compromised function of a specific growth factor, the use of these molecules as therapeutic agents is justifiable. Undoubtedly, the outcome of current clinical trials will certainly influence future decisions on the use of growth factor therapies.}, }
@article {pmid8249119, year = {1993}, author = {Serie, JR and Pringle, JA and Cooper, HN and Roth, CM and Hegre, OD}, title = {Long-term survival and strain-specific tolerance induction in rat-to-mouse neonatal islet xenografts.}, journal = {Transplantation}, volume = {56}, number = {5}, pages = {1166-1170}, doi = {10.1097/00007890-199311000-00023}, pmid = {8249119}, issn = {0041-1337}, support = {DK-32237/DK/NIDDK NIH HHS/United States ; DK-40077/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Animals, Newborn ; *Graft Survival ; *Immune Tolerance ; *Islets of Langerhans Transplantation ; Male ; Mice ; Mice, Inbred C57BL ; Rats ; Rats, Inbred F344 ; Rats, Inbred WF ; Species Specificity ; Transplantation, Heterologous/*immunology ; }, abstract = {These studies were designed to determine (1) if culture-isolated, neonatal rat islets are capable of inducing xenogeneic tolerance in mice and (2) whether this tolerance is species- or strain-specific. We attempted to induce xenogeneic tolerance by transplanting culture-isolated neonatal FSH islets to 26 diabetic C57B1/6 recipients. These animals received one injection of ALS at the time of transplant. Fifteen (58%) animals remained reversed by xenotransplant for > 173 days. To assess the development of strain or species-specific tolerance, 14 of the animals bearing long-term surviving FSH grafts were divided into 3 treatment groups. Animals in group 1 were nephrectomized to remove the initial graft and then retransplanted with uncultured, adult FSH islets; animals in group 2 were retransplanted with uncultured, adult FSH islets without nephrectomy; and group 3 animals were nephrectomized and retransplanted with uncultured, adult third-party islets (WF). In naive controls, adult FSH islets were rejected in 9 +/- 2 days. The MST for adult FSH grafts transplanted to nephrectomized recipients was 104 +/- 54 days, with 4 out of 5 (80%) surviving until sacrifice 90-171 days posttransplant. The MST for FSH grafts transplanted to nonnephrectomized recipients was 120 +/- 70 days with 3 out of 4 (75%) surviving until sacrifice 143-154 days posttransplant. Thus, it appears that the initial neonatal FSH transplant induced the development of immune tolerance to highly immunogenic FSH islet tissue. In contrast, the MST for third-party adult WF grafts was 27 +/- 13 days compared with an MST of 36 +/- 24 days in naive controls. Thus, it appears that the xenogeneic tolerance induced by neonatal FSH islets was strain rather than species-specific. Factors such as the close evolutionary relationship between rats and mice, the neonatal condition of the initial graft, and its relative lack of donor APCs are included in a discussion of possible mechanisms of tolerance induction.}, }
@article {pmid8042132, year = {1993}, author = {Asher, RS and Alfred, T}, title = {Dental management of long-term amyotrophic lateral sclerosis: case report.}, journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry}, volume = {13}, number = {6}, pages = {241-244}, doi = {10.1111/j.1754-4505.1993.tb01475.x}, pmid = {8042132}, issn = {0275-1879}, mesh = {Adult ; *Amyotrophic Lateral Sclerosis ; Chronic Disease ; Dental Care for Persons with Disabilities/*methods ; Dental Restoration, Permanent ; Fatal Outcome ; Gagging ; Humans ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease. Methods of dental treatment of a young male patient with ALS are presented. This case is unusual in several respects: the early age of onset, the long survival time, and the period of time in which the case was followed in our dental clinic. Aspects of ALS which are of concern to dentistry, as related to clinical care and strategies for effective oral health delivery, are presented.}, }
@article {pmid7692367, year = {1993}, author = {Krutsay, M and Jakubovits, E}, title = {[Rapid course amyotrophic lateral sclerosis].}, journal = {Orvosi hetilap}, volume = {134}, number = {40}, pages = {2209-2211}, pmid = {7692367}, issn = {0030-6002}, mesh = {Amyotrophic Lateral Sclerosis/pathology/*physiopathology ; Brain Stem/pathology ; Cerebral Cortex/pathology ; Female ; Humans ; Middle Aged ; Motor Neurons/pathology ; Nerve Degeneration ; Paraplegia/etiology ; Pyramidal Tracts/pathology ; Reflex Sympathetic Dystrophy/etiology ; Spinal Cord/pathology ; }, abstract = {The case of a 58-year-old woman is reported, whose illness began with a pain in the left shoulder. Later a spastic palsy developed in the hands, and a flaccid one in the arms and lower limbs. After a treatment for 12 months she died from respiratory failure. The motor nerve cells in the spinal cord, brainstem and cerebral cortex together with the pyramidal tracts had degenerated symmetrically.}, }
@article {pmid8405291, year = {1993}, author = {Ekblom, J and Aquilonius, SM and Jossan, SS}, title = {Differential increases in catecholamine metabolizing enzymes in amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {123}, number = {2}, pages = {289-294}, doi = {10.1006/exnr.1993.1161}, pmid = {8405291}, issn = {0014-4886}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*enzymology ; Animals ; Catechol O-Methyltransferase/*metabolism ; Humans ; Male ; Monoamine Oxidase/*metabolism ; Rats ; }, abstract = {The activity of three catecholamine-metabolizing enzymes, monoamine oxidase type A and type B (MAO-A and MAO-B) as well as catechol-O-methyltransferase (COMT), were estimated in homogenates of human spinal cord using radiometric assays. The enzyme activities were determined in postmortem spinal cord tissue from controls and cases with amyotrophic lateral sclerosis (ALS). The activity of MAO-A was below the limit of detectability in both controls and ALS cases. The activities of MAO-B and COMT were evenly distributed at the various spinal levels. The MAO-B activity was substantially elevated in ALS spinal homogenates, whereas only a slight, but not statistically significant, increase in COMT activity was observed. A significant correlation between COMT and MAO-B activities was observed for controls. However, this covariation was not apparent for the ALS cases. These results suggest that the two enzyme proteins are regulated by more complex mechanisms in the spinal cord in amyotrophic lateral sclerosis than simple general increases caused by elevated astroglial cell numbers. In addition, the MAO-A, MAO-B, and COMT activities were estimated in spinal cords from rats treated with the selective MAO-B inhibitor L-deprenyl, a drug with putative neuroprotective effects in neurodegenerative disorders. After 3 weeks of L-deprenyl treatment (0.25 mg/kg/day, sc), the spinal MAO-A and MAO-B activities were decreased by 50 and 80%, respectively. In contrast, the COMT activity was not altered by L-deprenyl administration.}, }
@article {pmid8244400, year = {1993}, author = {Donaldson, DH and Britt, DE and Jones, C and Jackson, CL and Patterson, D}, title = {Localization of the gene for the ciliary neurotrophic factor receptor (CNTFR) to human chromosome 9.}, journal = {Genomics}, volume = {17}, number = {3}, pages = {782-784}, doi = {10.1006/geno.1993.1409}, pmid = {8244400}, issn = {0888-7543}, support = {AG-00452/AG/NIA NIH HHS/United States ; AG00029/AG/NIA NIH HHS/United States ; HG00044/HG/NHGRI NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/genetics ; Animals ; Base Sequence ; CHO Cells ; Chromosome Mapping ; *Chromosomes, Human, Pair 9 ; Cricetinae ; DNA/genetics ; Humans ; Hybrid Cells ; Molecular Sequence Data ; Receptor, Ciliary Neurotrophic Factor ; Receptors, Growth Factor/*genetics ; }, abstract = {Ciliary neurotrophic factor (CNTF) has recently been found to be important for the survival of motor neurons and has shown activity in animal models of amyotrophic lateral sclerosis (ALS). CNTF therefore holds promise as a treatment for ALS, and it and its receptor (CNTFR) are candidates for a gene involved in familial ALS. The CNTFR gene was mapped to chromosome 9 by PCR on a panel of human/CHO somatic cell hybrids and localized to 9p13 by PCR on a panel of radiation hybrids.}, }
@article {pmid8351519, year = {1993}, author = {Deng, HX and Hentati, A and Tainer, JA and Iqbal, Z and Cayabyab, A and Hung, WY and Getzoff, ED and Hu, P and Herzfeldt, B and Roos, RP}, title = {Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase.}, journal = {Science (New York, N.Y.)}, volume = {261}, number = {5124}, pages = {1047-1051}, doi = {10.1126/science.8351519}, pmid = {8351519}, issn = {0036-8075}, mesh = {Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/enzymology/*genetics ; Base Sequence ; Binding Sites ; Erythrocytes/enzymology ; Exons ; Free Radicals/metabolism ; Humans ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Protein Folding ; Protein Structure, Tertiary ; Superoxide Dismutase/blood/chemistry/*genetics/metabolism ; X-Ray Diffraction ; }, abstract = {Single-site mutants in the Cu,Zn superoxide dismutase (SOD) gene (SOD1) occur in patients with the fatal neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS). Complete screening of the SOD1 coding region revealed that the mutation Ala4 to Val in exon 1 was the most frequent one; mutations were identified in exons 2, 4, and 5 but not in the active site region formed by exon 3. The 2.4 A crystal structure of human SOD, along with two other SOD structures, established that all 12 observed FALS mutant sites alter conserved interactions critical to the beta-barrel fold and dimer contact, rather than catalysis. Red cells from heterozygotes had less than 50 percent normal SOD activity, consistent with a structurally defective SOD dimer. Thus, defective SOD is linked to motor neuron death and carries implications for understanding and possible treatment of FALS.}, }
@article {pmid8213033, year = {1993}, author = {Kuisma, MJ and Saarinen, KV and Teirmaa, HT}, title = {Undiagnosed amyotrophic lateral sclerosis and respiratory failure.}, journal = {Acta anaesthesiologica Scandinavica}, volume = {37}, number = {6}, pages = {628-630}, doi = {10.1111/j.1399-6576.1993.tb03778.x}, pmid = {8213033}, issn = {0001-5172}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/diagnosis ; Chronic Disease ; Diagnosis, Differential ; Dyspnea/diagnosis/etiology ; Female ; Humans ; Lung Diseases, Obstructive/diagnosis/etiology ; Middle Aged ; Respiratory Insufficiency/*etiology ; }, abstract = {Two patients suffering from exacerbation of chronic respiratory insufficiency due to previously undiagnosed amyotrophic lateral sclerosis are reported. Both patients had a false diagnosis of asthma with a restrictive component. The diagnosis had been made after pulmonary function studies, and both patients had also received treatment for asthma. A central etiology was suspected when weaning from mechanical ventilation proved unsuccessful during respiratory failure, necessitating intensive care. A neurologic examination and a typical electroneuromyography recording confirmed the diagnosis of amyotrophic lateral sclerosis. Neuromuscular disorders must be excluded when treating patients with respiratory failure, even if they already have the diagnosis of chronic pulmonary disease.}, }
@article {pmid8369483, year = {1993}, author = {Krieger, C and Wagey, R and Lanius, RA and Shaw, CA}, title = {Activation of PKC reverses apparent NMDA receptor reduction in ALS.}, journal = {Neuroreport}, volume = {4}, number = {7}, pages = {931-934}, doi = {10.1097/00001756-199307000-00023}, pmid = {8369483}, issn = {0959-4965}, mesh = {1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine ; Aged ; Amyotrophic Lateral Sclerosis/enzymology/*metabolism ; Autoradiography ; Dizocilpine Maleate/pharmacokinetics ; Enzyme Activation/drug effects ; Humans ; In Vitro Techniques ; Isoquinolines/pharmacology ; Phorbol 12,13-Dibutyrate/pharmacology ; Piperazines/pharmacology ; Protein Kinase C/antagonists &amp; inhibitors/*metabolism ; Receptors, N-Methyl-D-Aspartate/drug effects/*metabolism ; Spinal Cord/drug effects/metabolism ; }, abstract = {The binding of [3H]MK-801 to NMDA receptors was reduced by 40-45% in the dorsal and ventral horns of spinal cords from patients who died with amyotrophic lateral sclerosis (ALS) compared with controls. These results reflect either neurone death with concomitant receptor loss or regulation-related receptor decreases independent of motoneurone degeneration. To distinguish between these possibilities we explored aspects of NMDA receptor regulation using phorbol ester to activate protein kinase C (PKC). Spinal cord sections were exposed to phorbol ester before incubation with [3H]MK-801 to determine levels of NMDA binding. Phorbol ester treatment increased [3H]MK-801 binding in both ALS and control tissue to almost identical levels of specific binding for both groups. The increased [3H]MK-801 binding could be completely blocked by concurrent exposure of spinal cord sections to H-7, a general protein kinase inhibitor. These results suggest that NMDA receptors in ALS spinal cord are decreased as a result of abnormal enzyme activity independent of motoneurone degeneration.}, }
@article {pmid8333035, year = {1993}, author = {Jamshidi, F and De Fazio, SR and Gozzo, JJ}, title = {Allograft and xenograft unresponsiveness induced by transplantation of neonatal skin.}, journal = {Transplantation}, volume = {56}, number = {1}, pages = {135-138}, doi = {10.1097/00007890-199307000-00025}, pmid = {8333035}, issn = {0041-1337}, support = {AI 29650/AI/NIAID NIH HHS/United States ; DK33466/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Animals, Newborn ; Antilymphocyte Serum/therapeutic use ; Bone Marrow Transplantation/immunology ; Cyclosporine/therapeutic use ; Graft Survival/immunology/*physiology ; Immunosuppression Therapy/methods ; Mice ; Mice, Inbred Strains ; Skin Transplantation/immunology/*physiology ; Species Specificity ; Time Factors ; Transplantation, Heterologous/immunology/*physiology ; Transplantation, Homologous/immunology/physiology ; }, abstract = {Class I MHC-disparate skin allografts from neonatal donors survive longer than adult grafts in mice treated with antilymphocyte serum (ALS; days -1, +2) or ALS plus donor bone marrow cells (BMC; day +7 relative to grafting on day 0) or ALS, BMC, and a 2-week course of post-transplant CsA. We have now investigated whether this phenomenon extends to more strongly histoincompatible allografts (H2-KI and H2-KID mismatched) made to recipients treated with ALS, ALS plus BMC, or ALS, BMC, and CsA. Survival of neonatal grafts was longer than that of adult grafts in all experimental groups (P < 0.05). In ALS/BMC/CsA-treated mice, for example, median survival of neonatal C3H grafts was 46 days, with adult grafts surviving 22 days on C57BL/6 recipients (full MHC disparity). Survival of neonatal hamster skin grafted to B6AF1 mice was not augmented beyond that for adult skin using a similar immunosuppressive protocol. But if alternate day ALS and CsA injections were begun on day -5, and ALS and CsA continued as in the allograft models, a significant xenogeneic neonatal survival advantage was demonstrated. (Donor BMC had no graft-prolonging effect in the xenograft model.) Donor BMC significantly prolonged full MHC-mismatched grafts from newborn, but not adult donors in ALS-treated recipients. Also, addition of CsA to ALS/BMC treatment prolonged the survival of neonatal, but not adult grafts mismatched at KI or KID. These results indicate that the survival advantage of neonatal grafts in immunosuppressed recipients extends to strong allogeneic incompatibilities and even to a xenograft model.}, }
@article {pmid8367780, year = {1993}, author = {Lehmann, TR and Spratt, KF and Lehmann, KK}, title = {Predicting long-term disability in low back injured workers presenting to a spine consultant.}, journal = {Spine}, volume = {18}, number = {8}, pages = {1103-1112}, doi = {10.1097/00007632-199306150-00023}, pmid = {8367780}, issn = {0362-2436}, mesh = {Adult ; Attitude to Health ; *Disability Evaluation ; Female ; Follow-Up Studies ; Humans ; Low Back Pain/*epidemiology/rehabilitation ; Male ; Models, Statistical ; Occupational Diseases/*epidemiology/rehabilitation ; Pain Measurement ; Physical Examination ; Predictive Value of Tests ; Referral and Consultation ; Risk Factors ; Time Factors ; }, abstract = {Low back pain (LBP) is the most common, costly, and disabling musculoskeletal condition. Although most LBP patients recover within two months, 2-3% eventually develop disabling chronic low back pain (DCLBP). Due to the prevalence of DCLBP problems, models have been developed to predict which acute low back pain patients are predisposed to the problems associated with this condition. Many see the development of these models as a first step that must be taken before useful approaches for containing and reducing the problem can be conceptualized, implemented, and tested. A recent publication by Cats-Baril and Frymoyer considered this specific problem. While the results of their study indicate considerable success in predicting DCLBP patients, the high prediction rates they obtained may be spurious because of the characteristics of their sampled patient population in conjunction with some of the predictors they found useful in identifying DCLBP patients. The purpose of the present study was to focus on the crucial patient population (i.e., acute LBP patients who perceive their problem as work-related and who have been unable to work for more than two but less than six weeks), and evaluate the ability of various personal, medical, occupational, and psychological factors to predict predisposition to DCLBP. Fifty-five patients referred by occupational physicians were evaluated and followed successfully for at least 6 months. Patients in the study were given a physical examination that included Spratt et al's assessment of pain behavior. They were then asked to fill out an extensive battery of self-report questionnaires, addressing issues associated with personal demographics, health history, work requirements, job satisfaction, injury information, and pain/function factors. At the 6-month follow-up, a structured telephone interview was used to obtain outcome information regarding patient status, including ability to return to work and general outcomes of treatment. Average patient age was 37.2 years (range, 22-57) and 67% of the patients were male. On average, patients had been unable to work for approximately 4 weeks when initially surveyed. Overall, 12.7% of the patients returned to work within 1 month of injury, 40% returned within 2 months, 54.5% within 3 months, 69% within 4 months, 74.5% within 5 months, 76.3% within 6 months, 80% within 7 months, and 83.6% after 7 months. Approximately 16% never successfully returned to work within the follow-up period of this study. DCLBP was found to be correlated only with marital status, as married patients returned to work more quickly than single patients (P < 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid8511157, year = {1993}, author = {Thomas, S}, title = {Motor neurone disease: a progressive disease requiring a coordinated approach.}, journal = {Professional nurse (London, England)}, volume = {8}, number = {9}, pages = {583-585}, pmid = {8511157}, issn = {0266-8130}, mesh = {Female ; Humans ; Male ; Middle Aged ; *Motor Neuron Disease/diagnosis/epidemiology/nursing ; Self-Help Groups ; }, abstract = {1. Such a variety of causes are implicated for MND that it is unlikely a single cause exists. 2. There is no actual treatment for the disease other than alleviating symptoms and improving function by the use of aids and appliances. 3. Care of people with MND is highly specialised, requiring multidisciplinary cooperation to ensure effective patient care. 4. Nurses owe it to their patients to acquaint themselves with the disease and support networks available.}, }
@article {pmid8502260, year = {1993}, author = {Smith, RA and Melmed, S and Sherman, B and Frane, J and Munsat, TL and Festoff, BW}, title = {Recombinant growth hormone treatment of amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {16}, number = {6}, pages = {624-633}, doi = {10.1002/mus.880160608}, pmid = {8502260}, issn = {0148-639X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/blood/*drug therapy/mortality ; Cohort Studies ; Double-Blind Method ; Female ; Growth Hormone/*analogs &amp; derivatives/therapeutic use ; Human Growth Hormone ; Humans ; Insulin-Like Growth Factor I/*analysis ; Male ; Middle Aged ; Recombinant Proteins/therapeutic use ; Severity of Illness Index ; Survival Analysis ; Weight Loss ; }, abstract = {Based on the known trophic effects of growth hormone (GH) on nerve and muscle 75 patients with ALS were treated for up to 18 months with synthetic human growth hormone (Protropin) or a placebo. The course of ALS was assessed serially using a quantitative (TQNE) neuromuscular and manual exam (MRC) and laboratory chemistries. Average insulin-related growth factor (IGF-I) values increased from 1.2 to 2.3 U/mL in the treated group. Surprisingly, serum insulin levels did not increase. Hyperglycemia was noted in only 2 patients of the 38 patients receiving hGH, and this resolved with cessation of treatment. Over the 12 months of treatment there were 11 deaths (6 controls, 5 treated). Survival analysis, performed approximately 12 months following cessation of treatment, did not reveal a difference between the treatment and placebo group. The TQNE scores declined inexorably in both the control and treated group. Retrospective analysis of the TQNE data indicated a poor prognosis for patients who lost arm strength early. A correlation between the TQNE and MRC scores was evident at early stages of motor unit loss, less so when muscle weakness was advanced.}, }
@article {pmid7691501, year = {1993}, author = {Faulds, D and Goa, KL and Benfield, P}, title = {Cyclosporin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders.}, journal = {Drugs}, volume = {45}, number = {6}, pages = {953-1040}, pmid = {7691501}, issn = {0012-6667}, mesh = {Arthritis, Rheumatoid/drug therapy ; Clinical Trials as Topic ; Cyclosporine/administration &amp; dosage/pharmacokinetics/pharmacology/*therapeutic use ; Diabetes Mellitus, Type 1/drug therapy ; Digestive System Diseases/drug therapy ; Eye Diseases/drug therapy ; Humans ; Immune System Diseases/*drug therapy ; Nephrotic Syndrome/drug therapy ; Nervous System Diseases/drug therapy ; Skin Diseases/drug therapy ; }, abstract = {Cyclosporin is a lipophilic cyclic polypeptide which produces calcium-dependent, specific, reversible inhibition of transcription of interleukin-2 and several other cytokines, most notably in T helper lymphocytes. This reduces the production of a range of cytokines, inhibiting the activation and/or maturation of various cell types, including those involved in cell-mediated immunity. Thus, cyclosporin has immunosuppressive properties, and has a proven place as first line therapy in the prophylaxis and treatment of transplant rejection. Cyclosporin has also been evaluated in a large range of disorders where immunoregulatory dysfunction is a suspected or proven aetiological factor, and this is the focus of the present review. In patients with severe disease refractory to standard treatment, oral cyclosporin is an effective therapy in acute ocular Behçet's syndrome, endogenous uveitis, psoriasis, atopic dermatitis, rheumatoid arthritis, active Crohn's disease and nephrotic syndrome. Concomitant low dose corticosteroid therapy may improve response rates in some disorders. The drug can be considered as a first line therapy in patients with moderate or severe aplastic anaemia who are ineligible for bone marrow transplantation, with the additional benefit of reducing platelet alloantibody titres. It may also be of considerable therapeutic benefit in patients with primary biliary cirrhosis, particularly those with less advanced disease. Limited evidence suggests cyclosporin is effective in patients with intractable pyoderma gangrenosum, polymyositis/dermatomyositis or severe, corticosteroid-dependent asthma. Indeed, the steroid-sparing effect of cyclosporin is a significant advantage in a number of indications. Furthermore, the drug has shown some efficacy in a wide range of other, generally uncommon disorders in which controlled clinical trials are lacking and/or are unlikely to be performed. Cyclosporin does not appear to be effective in patients with allergic contact dermatitis, multiple sclerosis or amyotrophic lateral sclerosis. It is only temporarily effective in patients with type I (insulin-dependent) diabetes mellitus and should not be used in this indication. To avoid relapse after control of active disease, patients should receive cyclosporin maintenance therapy at the lowest effective dosage. However, maintenance therapy appears to be of no benefit in patients with Crohn's disease and cyclosporin should be discontinued in these patients once active disease is controlled. Hypertrichosis, gingival hyperplasia, and neurological and gastrointestinal effects are the most common adverse events in cyclosporin recipients, but are usually mild to moderate and resolve on dosage reduction. Changes in laboratory variables indicating renal dysfunction are relatively common, although serious irreversible damage is rare.(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid8361174, year = {1993}, author = {Goss, JA and Nakafusa, Y and Flye, MW}, title = {Prolongation of small bowel allografts after intrathymic injection of donor alloantigen and ALS.}, journal = {The Journal of surgical research}, volume = {54}, number = {5}, pages = {494-498}, doi = {10.1006/jsre.1993.1076}, pmid = {8361174}, issn = {0022-4804}, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; *Graft Survival ; Heart Transplantation ; Intestine, Small/pathology/*transplantation ; Isoantigens/*immunology ; Male ; Rats ; Rats, Inbred BUF ; Rats, Inbred Lew ; Receptors, Antigen, T-Cell, gamma-delta/analysis ; Transplantation, Homologous ; }, abstract = {The increasing success of clinical small bowel transplantation in recent years has been due largely to improved nonspecific immunosuppression of the recipient, which carries significant morbidity. The induction of donor-specific tolerance would eliminate the risk of long-term immunosuppression while ensuring graft function and survival. We have demonstrated that the intrathymic injection of donor splenocytes with the simultaneous intraperitoneal administration of rabbit anti-rat lymphocyte serum results in indefinite donor-specific cardiac allograft survival in > 85% of recipients. In this study, we further examined the effect of this tolerance induction protocol on the more immunogenic small bowel allograft. Male Buffalo (RT1b) rats were exposed to donor alloantigen by an intrathymic injection of 25 x 10(6) MHC mismatched unfractionated Lewis (RT1(1)) splenocytes. The Buffalo recipients were given 1 ml of rabbit anti-rat lymphocyte serum intra-peritoneally at the time of the donor antigen injection and 21 days later underwent a heterotopic 15-cm Lewis small bowel transplant. Pretransplant intrathymic Lewis alloantigen and anti-rat lymphocyte serum treatment prolonged Lewis small bowel survival by approximately 2.5 times (mean survival time = 18.0 vs 7.0 days for controls, P < 0.05). These small bowel allografts demonstrated pericryptic T cell infiltrates, areas of cryptic necrosis, and a dense submucosal lymphocytic infiltrate, all consistent with acute resection. In contrast to our studies achieving donor-specific cardiac allograft survival, this protocol did not result in indefinite intestinal allograft survival. No Buffalo recipients developed evidence of graft-versus-host disease.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid8482980, year = {1993}, author = {Robison, SH and Tandan, R and Bradley, WG}, title = {Repair of N-methylpurines in DNA from lymphocytes of patients with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {115}, number = {2}, pages = {201-207}, doi = {10.1016/0022-510x(93)90225-n}, pmid = {8482980}, issn = {0022-510X}, support = {R01-AG-06163/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*metabolism ; Cell Survival ; DNA/*metabolism ; *DNA Repair ; Female ; Humans ; Male ; Methyl Methanesulfonate/pharmacology ; Middle Aged ; Purine Nucleotides/*genetics ; T-Lymphocytes/*metabolism/physiology ; Tetrahydrofolate Dehydrogenase/genetics ; }, abstract = {We have previously reported reduced ability of ALS fibroblasts to repair genomic DNA damage produced by alkylating agents. This report presents our experience of studying DNA repair in lymphocytes from ALS patients. The repair of N-methylpurines produced by treatment with the alkylating agent, methyl methanesulfonate, was studied in T-lymphocytes from patients with sporadic and familial ALS, and appropriate controls. Repair of damage was quantitated by using alkaline elution for genomic DNA repair, and methoxyamine protection of abasic sites in DNA fragments for gene-specific repair in the dihydrofolate reductase (dhfr) gene, at time points 0, 6 h and 24 h. No significant repair rate differences were observed between ALS and control lymphocytes in either genomic or gene-specific DNA repair. The possible reasons for the discrepancy with our earlier results in lymphocytes and fibroblasts are discussed.}, }
@article {pmid8475688, year = {1993}, author = {Ostermeyer-Shoaib, B and Patten, BM}, title = {IgG subclass deficiency in amyotrophic lateral sclerosis.}, journal = {Acta neurologica Scandinavica}, volume = {87}, number = {3}, pages = {192-194}, doi = {10.1111/j.1600-0404.1993.tb04099.x}, pmid = {8475688}, issn = {0001-6314}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/genetics/*immunology ; B-Lymphocytes/immunology ; Breath Tests ; Chromosomes, Human, Pair 14 ; Colony Count, Microbial ; Female ; Gene Expression Regulation ; Humans ; IgG Deficiency/genetics/*immunology ; Immunoglobulin G/analysis/*classification/genetics ; Intestinal Mucosa/microbiology ; Male ; Middle Aged ; T-Lymphocytes/immunology ; Xylose ; }, abstract = {In order to get to clues about T-cell independent versus T-cell dependent immune mechanism in ALS, we measured IgG subclasses in 25 ALS-patients: 16 patients had deficiency of T-cell dependent expressed IgG1 or IgG3 or both with essentially normal levels of T-cell independent expressed IgG2 and IgG4. Ten of these patients had no prior treatment and five of these 10 had normal total IgG. Six patients had some immunosuppressive treatment before measurements of subclasses were done and all of them had deficiency of total IgG. Eight of 14 patients who underwent a d-xylose breath test, had evidence of small bowel overgrowth, which was confirmed by cultures of duodenal aspirate. IgG1 and IgG3 are T-cell dependent antibodies against protein antigens with close linkage on chromosome 14. The findings suggest a defect in the IgG subclass expression in ALS.}, }
@article {pmid8459466, year = {1993}, author = {Sampalis, JS and Lavoie, A and Williams, JI and Mulder, DS and Kalina, M}, title = {Impact of on-site care, prehospital time, and level of in-hospital care on survival in severely injured patients.}, journal = {The Journal of trauma}, volume = {34}, number = {2}, pages = {252-261}, doi = {10.1097/00005373-199302000-00014}, pmid = {8459466}, issn = {0022-5282}, mesh = {Adult ; Case-Control Studies ; Cohort Studies ; *Emergency Medical Services ; Emergency Medical Technicians ; Female ; *Hospitalization ; Humans ; Life Support Care ; Male ; Odds Ratio ; Prospective Studies ; Quebec/epidemiology ; Regression Analysis ; Risk ; Survival Analysis ; Wounds and Injuries/*mortality/*therapy ; }, abstract = {A sample of 360 severely injured patients was selected from a cohort of 8007 trauma victims followed prospectively from the time of injury to death or discharge. A case referent study was used to test the association between on-site care, total prehospital time, and level of care at the receiving hospital with short-term survival. Multiple logistic regression analyses showed that use of Advanced Life Support (ALS) at the scene was not associated with survival, whereas treatment at a level I compatible hospital was associated with a 38% reduction in the odds of dying, which approached statistical significance. Total prehospital time over 60 minutes was associated with a statistically significant adjusted relative odds of dying (OR = 3.0). The results of this study support the need for regionalization of trauma care and fail to show a benefit associated with ALS.}, }
@article {pmid8437010, year = {1993}, author = {Askmark, H and Aquilonius, SM and Gillberg, PG and Liedholm, LJ and Stålberg, E and Wuopio, R}, title = {A pilot trial of dextromethorphan in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {56}, number = {2}, pages = {197-200}, pmid = {8437010}, issn = {0022-3050}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Dextromethorphan/*therapeutic use ; Double-Blind Method ; Electromyography/drug effects ; Female ; Humans ; Male ; Middle Aged ; Neurologic Examination/drug effects ; Pilot Projects ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors ; }, abstract = {Assuming the presence of glutamate-induced neurotoxicity in amyotrophic lateral sclerosis 14 patients were treated with dextromethorphan, an N-methyl-D-aspartate receptor antagonist. The patients were treated with 150 mg dextromethorphan or placebo daily for 12 weeks in a double-blind crossover trial, with a wash out period of 4 weeks between the two treatment periods. Thereafter the surviving patients were treated with 300 mg dextromethorphan daily for up to 6 months in an open trial. No positive effects on clinical or neurophysiological parameters (relative number of axons, and compound muscle action potentials in the abductor digiti minimi muscle) were observed either in the double-blind trial or in the open trial.}, }
@article {pmid7519064, year = {1993}, author = {Shanina, NA and Sveĭkata, AP and Zavalishin, IA and Gel'fand, VI}, title = {[Analysis of serum antibodies to nerve tissue antigens in patients with lateral amyotrophic sclerosis].}, journal = {Biulleten' eksperimental'noi biologii i meditsiny}, volume = {115}, number = {2}, pages = {169-173}, pmid = {7519064}, issn = {0365-9615}, mesh = {Amyotrophic Lateral Sclerosis/*immunology ; Antigens/*immunology ; Autoantibodies/*blood ; Chromatography, Affinity ; Epitopes/immunology ; Humans ; Microscopy, Fluorescence ; Molecular Weight ; Nerve Tissue/*immunology ; }, abstract = {We used non-direct immunofluorescence microscopy, immunoblotting and affinity chromatography on A-protein Superose to study antibodies to neural tissue antigens in sera from 11 patients with ALS and from 10 healthy donors. In all sera the majoric antigens had molecular masses of 150-200kD, 70kD and 50kD. No consistent differences were found between ALS patients and controls. Antibodies to 50kD and 70kD proteins from patients with ALS were found to be mostly IgM, whereas antibodies from control sera were mostly IgG. Antibodies to high molecular weight proteins (150-200kD) in ALS and controls belonged to both classes of immunoglobulins. Immunoblotting studies of neural tissue proteins after treatment blots with alkaline phosphatase showed considerable decrease of antibodies binding to neural tissue antigens in sera of ALS patients. The same results were obtained by immunofluorescence assay. The alkaline phosphatase experiments suggest that in ALS patients the sera antibodies are directed mainly against phosphoepitopes in protein antigenic determinants of the neural tissue. This results can lead to conclusion of a role for the altered phosphorylation of the neural proteins in the ALS pathogenesis.}, }
@article {pmid8420042, year = {1993}, author = {Cattral, MS and Warnock, GL and Kneteman, NM and Halloran, PF and Rajotte, RV}, title = {The effect of cryopreservation on the survival and MHC antigen expression of murine islet allografts.}, journal = {Transplantation}, volume = {55}, number = {1}, pages = {159-163}, doi = {10.1097/00007890-199301000-00029}, pmid = {8420042}, issn = {0041-1337}, mesh = {Animals ; *Cryopreservation ; Dimethyl Sulfoxide ; Graft Survival/*immunology/physiology ; Histocompatibility Antigens Class I/*analysis ; Histocompatibility Antigens Class II/*analysis ; Islets of Langerhans Transplantation/*immunology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred CBA ; }, abstract = {Cryopreservation is an effective method of islet storage that can facilitate clinical trials of islet transplantation. In the present study we examined the effect of cryopreservation on the survival of islet allografts and the quantity of islet MHC antigen expression. Islets isolated from CBA/J (H-2k) mice were transplanted into streptozotocin-induced diabetic BALB/c (H-2d) mice treated with or without antilymphocyte serum (ALS). Frozen/thawed (F/T) grafts were cooled slowly to -40 degrees C, stored at -196 degrees C, and thawed rapidly. Fresh and F/T isograft controls reversed diabetes promptly and maintained normoglycemia > 100 days. Allografts of fresh and F/T islets induced normoglycemia initially, but graft failure ensued at 18.2 +/- 1.5 and 16.4 +/- 1.9 days, respectively. ALS treatment prolonged allograft survival significantly to 35.3 +/- 3.9 and 37.5 +/- 6.3 days for fresh and F/T islets, respectively. Following cryopreservation, the quantity of class I antigen expression was reduced by 40%, while the quantity of class II expression was variable. These data indicate that murine islet MHC class I expression is reduced after cryopreservation. This decrease was not associated with altered survival of allogeneic grafts.}, }
@article {pmid8379175, year = {1993}, author = {Cavini-Ferreira, PC}, title = {[Pioneer experience with buflomedil in the form of retrograde venous pulse therapy for treatment of ischemia and severe extremity infections].}, journal = {Wiener medizinische Wochenschrift (1946)}, volume = {143}, number = {7-8}, pages = {193-194}, pmid = {8379175}, issn = {0043-5341}, mesh = {Bacterial Infections/blood/*drug therapy ; *Chemotherapy, Cancer, Regional Perfusion ; Dexamethasone/administration &amp; dosage/pharmacokinetics ; Drug Therapy, Combination ; Gentamicins/*administration &amp; dosage/pharmacokinetics ; Humans ; Infusions, Intravenous ; Ischemia/blood/*drug therapy ; Leg/*blood supply ; Metabolic Clearance Rate/physiology ; Microcirculation/drug effects ; Pyrrolidines/*administration &amp; dosage/pharmacokinetics ; Vasodilator Agents/*administration &amp; dosage/pharmacokinetics ; }, abstract = {Retrograde venous pulse therapy (RVP) allows faster healing of the infection, shortening of hospitalization time, and recovering of the chronic ischemia. RVP als has a dramatic effect on diabetic foot by passing the functional disorder of the microcirculation produced by diabetic neuropathy and micro-angiopathy, with important reduction of amputation rates in these patients. We credit these results to the very high concentration of Buflomedil provided by RVP in the target tissues, which allows the penetration and impregnation of other active substances (7).}, }
@article {pmid8272733, year = {1993}, author = {Confavreux, C and Moreau, T and Jouvet, A and Tommasi, M and Aimard, G}, title = {[Association of amyotrophic lateral sclerosis and multiple sclerosis].}, journal = {Revue neurologique}, volume = {149}, number = {5}, pages = {351-353}, pmid = {8272733}, issn = {0035-3787}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*complications/diagnosis/etiology ; Female ; Humans ; Multiple Sclerosis/*complications/diagnosis ; Time Factors ; }, abstract = {A twenty-five year old woman developed a progressive right hemiparesis which remitted within three months, without treatment. The diagnosis was a first relapse of multiple sclerosis. After a 10 year fully asymptomatic period, the patient developed weakness of the legs with falls and swallowing difficulties. Fasciculations and amyotrophy were present in the limbs and the tongue. There were no sensory abnormalities. The electromyogram confirmed the peripheral neurogenic degeneration with signs of anterior horn involvement. Motor and sensory nerve conductions were normal. Muscle weakness and atrophy increased in the limbs and the bulbar territory and the patient died nine months later. The autopsy showed characteristic "old" plaques of multiple sclerosis in the cerebrum with anterior horn cell and pyramidal tracts degeneration, typical of amyotrophic lateral sclerosis, in the spinal cord. Although exceptional, this association of amyotrophic lateral sclerosis and multiple sclerosis leads to the discussion of an etiological immunological dysregulation common to these two diseases.}, }
@article {pmid8269176, year = {1993}, author = {Earll, L and Johnston, M and Mitchell, E}, title = {Coping with motor neurone disease--an analysis using self-regulation theory.}, journal = {Palliative medicine}, volume = {7}, number = {4 Suppl}, pages = {21-30}, doi = {10.1177/0269216393007004S05}, pmid = {8269176}, issn = {0269-2163}, mesh = {*Adaptation, Psychological ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/etiology/*psychology ; Analysis of Variance ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; Motor Neuron Disease/etiology/*psychology ; *Stress, Psychological ; }, abstract = {Medicine and environmental changes have had tremendous success in controlling the infectious diseases that were the major causes of death in the last century. However, the consequential extension of life has been accompanied by an increase in the number of persons living with and dying of chronic illness. Despite these changes and their implications, the means by which people cope with such illnesses has only recently begun to receive the attention the subject warrants. Such diseases have a high prevalence in the population and self-detection and self-management are critical to the treatment and control of chronic disease and disability. This paper examines how people cope with motor neurone disease and sets this in the context of earlier research on psychological aspects of chronic disease and current theoretical approaches to coping with long-term ill health.}, }
@article {pmid1436531, year = {1992}, author = {Uchitel, OD and Scornik, F and Protti, DA and Fumberg, CG and Alvarez, V and Appel, SH}, title = {Long-term neuromuscular dysfunction produced by passive transfer of amyotrophic lateral sclerosis immunoglobulins.}, journal = {Neurology}, volume = {42}, number = {11}, pages = {2175-2180}, doi = {10.1212/wnl.42.11.2175}, pmid = {1436531}, issn = {0028-3878}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*immunology ; Animals ; Electric Stimulation ; Evoked Potentials/physiology ; Female ; Humans ; Immunoglobulins/*physiology ; Male ; Mice ; Middle Aged ; Motor Neurons/*immunology/physiology ; Muscles/immunology/physiology ; Neuromuscular Junction/physiology ; }, abstract = {We investigated the role of the immune system in the pathogenesis of amyotrophic lateral sclerosis (ALS) by studying the long-term consequences of ALS immunoglobulin (Ig) application on the levator auris muscle of the mouse. We applied Ig from seven ALS patients, four disease controls, and a pool of normal Ig (6 mg of Ig in 2 weeks) by subcutaneous injection; removed the muscles 4 to 12 weeks after the beginning of treatment; and recorded both spontaneous and evoked release of transmitter. None of the control Ig induced changes in transmitter, whereas five of seven ALS Ig induced a significant increase in the rate of spontaneous release, and all ALS Ig produced significant changes in the quantal content of evoked release. In muscles treated with one of the ALS Igs, synaptic activity was completely absent. Cholinesterase and silver staining demonstrated intact neuromuscular junctions in the control Ig-treated muscles and also in many areas of ALS Ig-treated muscles. Axonal degeneration and denervation were present in most muscles treated with ALS Ig. There was complete denervation when no synaptic activity could be recorded. Thus, ALS Ig appears to lead to long-lasting effects at the neuromuscular junction, and such effects may be an early stage in the immune-mediated pathogenesis of ALS.}, }
@article {pmid1335040, year = {1992}, author = {Swash, M and Schwartz, MS}, title = {What do we really know about amyotrophic lateral sclerosis?.}, journal = {Journal of the neurological sciences}, volume = {113}, number = {1}, pages = {4-16}, doi = {10.1016/0022-510x(92)90258-m}, pmid = {1335040}, issn = {0022-510X}, mesh = {*Amyotrophic Lateral Sclerosis/complications/etiology/genetics ; Autoimmunity ; Dementia/complications ; Electrophysiology ; Humans ; Inclusion Bodies/ultrastructure ; Models, Neurological ; Movement Disorders/classification ; Nervous System/drug effects ; Poliomyelitis/complications ; Prognosis ; Risk Factors ; Spinal Cord/pathology/physiopathology ; }, abstract = {The cause of amyotrophic lateral sclerosis is unknown. In this review clinical and scientific data that are pertinent to understanding this disease are reviewed. There are currently several major controversies concerning the possible role of immunological factors, genetic factors, environmental toxins, and viral infection in pathogenesis. These concepts must be considered in relation to what is known about the disease in all its aspects, including epidemiological data, information on the classical and molecular pathology of the disease, and on associated involvement of other systems, e.g., the spinocerebellar pathways and frontal dementia. Only when all this information is assimilated can full understanding of the disease and, hopefully, a logical approach to treatment and prevention, be achieved.}, }
@article {pmid1622326, year = {1992}, author = {Carter, GT and Johnson, ER and Bonekat, HW and Lieberman, JS}, title = {Laryngeal diversion in the treatment of intractable aspiration in motor neuron disease.}, journal = {Archives of physical medicine and rehabilitation}, volume = {73}, number = {7}, pages = {680-682}, pmid = {1622326}, issn = {0003-9993}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications ; Humans ; Male ; Motor Neuron Disease/*complications ; Tracheostomy ; Vocal Cord Paralysis/*surgery ; }, abstract = {Motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) often causes bulbar palsy with subsequent aspiration. Laryngeal diversion procedures are not commonly mentioned in the literature. However, they are viable but infrequently used surgical treatment options that have several advantages over a routine tracheostomy. We report a case of a 67-year-old man with MND/ALS and severe aspiration. He underwent a laryngeal diversion procedure with complete relief of signs and symptoms of aspiration. Laryngeal diversion, unlike tracheostomy, completely eliminates the possibility of aspiration as well as the need for suctioning. The primary disadvantage is complete loss of phonation. These procedures appear worthy of trial in patients with MND/ALS, and may ultimately be the preferred treatment in this setting.}, }
@article {pmid1565635, year = {1992}, author = {Maki, T and Ichikawa, T and Blanco, R and Porter, J}, title = {Long-term abrogation of autoimmune diabetes in nonobese diabetic mice by immunotherapy with anti-lymphocyte serum.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {89}, number = {8}, pages = {3434-3438}, pmid = {1565635}, issn = {0027-8424}, support = {R01-DK 41255./DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antibodies, Monoclonal/*therapeutic use ; Antilymphocyte Serum/*therapeutic use ; Autoimmune Diseases/blood/pathology/*therapy ; Blood Glucose/metabolism ; CD4 Antigens/immunology ; CD8 Antigens/immunology ; Diabetes Mellitus, Type 1/blood/pathology/*therapy ; Flow Cytometry ; Immunotherapy/*methods ; *Islets of Langerhans Transplantation/pathology ; Lymph Nodes/immunology ; Mice ; Mice, Inbred NOD ; Pancreas/pathology ; Transplantation, Isogeneic ; }, abstract = {We investigated the therapeutic effect of anti-lymphocyte serum (ALS) on clinically overt diabetes by using a nonobese diabetic (NOD) mouse model of type I diabetes mellitus. ALS given within 14 days of disease onset gradually reversed hyperglycemia with a 76% cumulative incidence of remission. Combined use of anti-CD4 and anti-CD8 monoclonal antibodies, but not anti-CD4 or anti-CD8 antibody alone, was also effective with overall 64% remission. Diabetic NOD mice that failed to respond to ALS treatment accepted subsequent islet isografts for a prolonged period (mostly greater than 100 days), whereas islet isografts in diabetic NOD mice previously treated with normal rabbit serum were all destroyed as acutely as isografts in untreated diabetic NOD mice. These results suggest that persistence of diabetes was due to irreversible beta-cell destruction and that ALS has indeed abrogated autoimmunity. In addition, ALS treatment at the time of islet isografting achieved significant prolongation of graft survival with 8 of 13 mice maintaining euglycemia for greater than 100 days. Although ALS prolonged islet allograft survival in diabetic NOD mice, the degree of prolongation was much less for allografts than for isografts, suggesting that ALS is capable of suppressing autoimmunity more effectively than allograft responses.}, }
@article {pmid1549842, year = {1992}, author = {Markees, TG and De Fazio, SR and Gozzo, JJ}, title = {Prolongation of impure murine islet allografts with antilymphocyte serum and donor-specific bone marrow.}, journal = {Transplantation}, volume = {53}, number = {3}, pages = {521-527}, doi = {10.1097/00007890-199203000-00005}, pmid = {1549842}, issn = {0041-1337}, support = {AI29650/AI/NIAID NIH HHS/United States ; DK 33466/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/*therapeutic use ; Bone Marrow Cells ; Graft Survival ; Islets of Langerhans Transplantation/*immunology ; Male ; Mice ; Mice, Inbred C3H ; Mice, Inbred DBA ; Mice, Inbred Strains ; Nephrectomy ; Time Factors ; }, abstract = {The inclusion of contaminating nonislet tissue in allografts of purified islets of Langerhans has been shown to decrease allograft survival times in unimmunosuppressed mice. Our current work examines the effectiveness of antilymphocyte serum and donor bone marrow cell infusion on the survival of very impure islet allografts. Treatment of B6AF1 mice with peritransplant antilymphocyte serum plus posttransplant infusion of donor (C3H/HeJ) bone marrow was very effective at prolonging contaminated allograft survival. ALS plus BMC was also effective for even more immunogenic allograft situations; mice that received contralateral transplants of adult and neonatal tissue, and mice that received dual transplants of adult islets. Long-term graft-bearing mice that originally received ALS and BMC were challenged with C3H/HeJ skin grafts. These mice exhibited several different types of response. Four of thirteen appeared sensitized to donor antigen, four rejected the skin grafts in approximate first-set fashion, and five showed limited prolongation, with skin grafts surviving 20-48 days. Long-term graft-bearing mice were also tested in in vitro proliferative assays. As responders in mixed lymphocyte reactions, splenocytes (SPC) from only one of eight appeared to show specific unresponsiveness to donor cells. Four of eight had a normal proliferative response and stimulation index to stimulation with C3H/HeJ SPC. SPC from three did not produce a normal stimulation index, but had an abnormally high (3x normal) background proliferation. SPC from seven of eight of these mice were able to suppress the proliferative response of naive B6AF1 SPC to C3H/HeJ cells. Our conclusions are that while ALS plus BMC are very effective in prolonging islet allograft survival, this treatment does not appear to be uniformly inducing a state of immunologic unresponsiveness in these mice. It appears that multiple mechanisms are acting to maintain islet allografts in this system, either independently or sequentially.}, }
@article {pmid1506122, year = {1992}, author = {Westarp, ME and Westphal, KP and Kolde, G and Wollinsky, KH and Westarp, MP and Dickob, M and Kornhuber, HH}, title = {Dermal, serological and CSF changes in amyotrophic lateral sclerosis with and without intrathecal interferon beta treatment.}, journal = {International journal of clinical pharmacology, therapy, and toxicology}, volume = {30}, number = {3}, pages = {81-93}, pmid = {1506122}, issn = {0174-4879}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/pathology/*therapy ; Antigen-Antibody Complex/blood/cerebrospinal fluid ; Blood Sedimentation ; Creatine Kinase/blood ; Female ; Humans ; Injections, Spinal ; Interferon-beta/administration &amp; dosage/*therapeutic use ; Male ; Microscopy, Electron ; Middle Aged ; Prospective Studies ; Skin/*ultrastructure ; }, abstract = {In 12 patients with amyotrophic lateral sclerosis (ALS) participating in a therapeutic trial with intrathecally applied human fibroblast interferon-beta (IFN-beta) and in 9 untreated ALS patients, we found significantly elevated circulating serum IgG immune complexes (CIC), quantitative immunoglobulin changes, and creatine kinase (CK) elevation; CK reached significantly more often pathological levels in non-bulbar disease. Dermal ultrastructural changes were equally present in all treated as well as untreated ALS patients. Some time ago IL-6 was quantitatively cleaned out of the Fiblaferon-preparation. Erythrocyte sedimentation rate (ESR) rose during intrathecal IFN therapy in 9/10 ALS patients. In 4/4 adequately monitored motoneuron patients, this elevation coincided with a decrease of serum CK, while ESR and CK did not correlate in 60 non-ALS non-IFN neurological controls. Collagen ultrastructure, CSF total protein or barrier function, immune complexes, immunoglobulin quantitation and serum CK may contribute to differentiated diagnosis and should be included in future study protocols.}, }
@article {pmid1547416, year = {1992}, author = {O'Brien, T and Kelly, M and Saunders, C}, title = {Motor neurone disease: a hospice perspective.}, journal = {BMJ (Clinical research ed.)}, volume = {304}, number = {6825}, pages = {471-473}, pmid = {1547416}, issn = {0959-8138}, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; *Hospice Care ; Humans ; Length of Stay ; Male ; Middle Aged ; Morphine/therapeutic use ; Motor Neuron Disease/mortality/*therapy ; Pain/drug therapy ; Respiratory Insufficiency/mortality ; Retrospective Studies ; Terminal Care ; }, abstract = {OBJECTIVE: To describe and evaluate the management of patients with motor neurone disease from the perspective of a hospice.<br><br>DESIGN: Retrospective analysis of hospice medical and nursing notes.<br><br>SETTING: Established 62 bed teaching and research hospice.<br><br>SUBJECTS: 124 patients with motor neurone disease cared for by the hospice between January 1980 and November 1990.<br><br>MAIN OUTCOME MEASURES: Patient profile; functional status; symptom control and use of opioids; insight; mode and management of death.<br><br>RESULTS: 124 patients (67 women, 57 men) had a mean age 63.9 years. The median length of admission was 61.5 days (range 1 to 2147). 84 patients (68%) were aware of their diagnosis and its implications when first seen by a hospice doctor. Functionally, the patients were very dependent. Symptoms such as pain, dyspnoea, and insomnia were major problems that responded well to opioids. Many patients were noted to deteriorate "suddenly," and in 58% of cases death occurred within 24 hours of this deterioration. When dying, 106 patients (94%) were peaceful and settled. 101 patients (89%) received opioids during this dying period. No patient chocked to death.<br><br>CONCLUSIONS: Although motor neurone disease is an uncommon disorder, many of its symptoms occur commonly in medical practice and must be actively treated. Opioids are both safe and effective for such treatment. The term chocking is both inaccurate and inappropriate in describing the cause of death in motor neurone disease and its use should be abandoned.}, }
@article {pmid1346577, year = {1992}, author = {Estey, EH and Kurzrock, R and Kantarjian, HM and O'Brien, SM and McCredie, KB and Beran, M and Koller, C and Keating, MJ and Hirsch-Ginsberg, C and Huh, YO}, title = {Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA).}, journal = {Blood}, volume = {79}, number = {4}, pages = {882-887}, pmid = {1346577}, issn = {0006-4971}, mesh = {2-Chloroadenosine/administration &amp; dosage/adverse effects/*analogs &amp; derivatives/therapeutic use ; Antineoplastic Agents/*therapeutic use ; Cladribine ; Deoxyadenosines/administration &amp; dosage/adverse effects/*therapeutic use ; Drug Resistance ; Humans ; Leukemia, Hairy Cell/*drug therapy/pathology ; Leukocyte Count ; Leukopenia/chemically induced ; Male ; Middle Aged ; Neutrophils/pathology ; Platelet Count ; Remission Induction ; T-Lymphocytes, Helper-Inducer/pathology ; T-Lymphocytes, Regulatory/pathology ; }, abstract = {We administered one course of 2-chlorodeoxyadenosine (2CdA) at 4 mg/m2 daily for 7 days by continuous intravenous infusion to 46 patients with hairy cell leukemia. Complete remissions occurred in 36 patients (78%; 95% confidence limits, 63% to 89%), partial remissions in five (11%), and a minor response in one. One patient died of candida sepsis 3 weeks after beginning treatment and three patients were clearly resistant to therapy. These three either had morphologically atypical hairy cells, less than 20% of which expressed Ig light chain on the cell surface, or had failed prior treatment with deoxycoformycin and interferon-alpha. At a median of 37 weeks since discontinuation of therapy, recurrent thrombocytopenia has developed in one patient, whose marrow remains normal, while a bone marrow relapse has occurred in another patient, whose blood counts remain normal. Treatment produced a greater than 50% decrease in neutrophil count in 26 patients, which lasted 3 to 4 weeks and was associated with an increased incidence of febrile episodes. These episodes occurred in 21 patients but were associated with documented infection in only four patients. Decreases in the number of CD4+ lymphocytes appeared to occur regularly after treatment and have persisted for a median of 18 weeks without obvious clinical significance. Although years of follow-up will be needed, our results confirm Piro et al's observation (N Engl J Med 322: 1117, 1990) that 2CdA appears to be highly effective in the treatment of hairy cell leukemia.}, }
@article {pmid1603698, year = {1992}, author = {Lavery, RF and Tortella, BJ and Griffin, CC}, title = {The prehospital treatment of pediatric trauma.}, journal = {Pediatric emergency care}, volume = {8}, number = {1}, pages = {9-12}, doi = {10.1097/00006565-199202000-00004}, pmid = {1603698}, issn = {0749-5161}, mesh = {Adolescent ; Child ; Child, Preschool ; *Emergency Medical Services/standards ; Female ; Humans ; Infant ; Infant, Newborn ; *Life Support Care ; Male ; Wounds and Injuries/epidemiology/*therapy ; }, abstract = {Prehospital pediatric trauma care is an important part of the EMS system. Review of 458 pediatric ALS trauma responses over two years treated in an urban, tiered ALS system revealed a male predominance. Violence (gunshot, stab, or assault) accounted for 46% of injuries, followed by vehicular accidents (occupant or pedestrian), with 35%. Important ALS resuscitation interventions were commonly performed en route, with a high degree of success (IVs = 93%, intubation = 79%), and did not greatly prolong field times (9 min BLS vs 11.7 min ALS). ALS procedure success rates and field times reported here are lower than previously described. Benchmark standards for the prehospital care of pediatric trauma are proposed.}, }
@article {pmid1741452, year = {1992}, author = {Compaan, JC and de Ruiter, AJ and Koolhaas, JM and van Oortmerssen, GA and Bohus, B}, title = {Differential effects of neonatal testosterone treatment on aggression in two selection lines of mice.}, journal = {Physiology &amp; behavior}, volume = {51}, number = {1}, pages = {7-10}, doi = {10.1016/0031-9384(92)90197-a}, pmid = {1741452}, issn = {0031-9384}, mesh = {Aggression/*physiology ; Animals ; Brain/physiology ; Female ; Male ; Mice ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Receptors, Androgen/genetics/physiology ; *Selection, Genetic ; Sex Differentiation/*genetics/*physiology ; Sexual Maturation/genetics/physiology ; Testosterone/*physiology ; }, abstract = {Selection lines of mice, artificially selected for aggression based upon the attack latency score (ALS), were used. In order to determine the relative contribution of neonatal testosterone (T) in the development of aggression, we vary the plasma-T level in males of both selection lines on the day of birth. At 14 weeks the ALS was measured. Neonatal T treatment results in a reduction of aggression in the long attack latency (LAL) line, whereas aggressive behaviour of the short attack latency (SAL) line is not affected. Both selection lines show reduction in testicular weight, although the total amount of T-producing Leydig cells was not affected. Neonatal T may cause a permanent reduction in aggressive behaviour in in the LAL line only, probably due to differential appearance of critical periods. It is suggested that the difference in aggressive behaviour between SAL and LAL selection lines is due to a prenatally determined difference in neonatal T sensitivity of the brain.}, }
@article {pmid1596403, year = {1992}, author = {Patrignani, J and Proaño, J and Morales, MD}, title = {[Treatment of amyotrophic lateral sclerosis with daily intrathecal TRH. A year's experience. Pilot study II].}, journal = {Neurologia (Barcelona, Spain)}, volume = {7}, number = {1}, pages = {4-9}, pmid = {1596403}, issn = {0213-4853}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Drug Evaluation ; Female ; Humans ; Infusion Pumps, Implantable ; Injections, Spinal/instrumentation ; Male ; Middle Aged ; Pilot Projects ; Severity of Illness Index ; Thyrotropin-Releasing Hormone/administration &amp; dosage/*therapeutic use ; }, abstract = {This study presents the experience of one year of treatment in patients with amyotrophic lateral sclerosis, with intrathecal TRH administered daily by a subcutaneous reservoir connected to the intrathecal lumbar space by a double catheter system as to provide continuous circulation of CSF and to avoid sac formation since this would be a source of infection. Clinical evaluation was carried out with a scale developed by the authors with the main aim of evaluating the loss of vital motor abilities and not as a localized evaluation. Secondary effects due to the implantation of the reservoir in addition to its use are presented although data were not important. Intrathecal administration of TRH was carried out similarly (600 micrograms/day) with secondary effects being the same as those by other routes of administration although of a lesser intensity. The results of the clinical evaluation at the beginning and end of the treatment as well as after patient follow up demonstrated that beneficial effects do not occur equally in all patients but rather are transitory and do not improve the natural evolution of the disease. The authors conclude that, methodologically, this series study does not enter within the frame of an advisable statistical study since the aim is to provide data for a future controlled study.}, }
@article {pmid1554521, year = {1992}, author = {Majkowski, J}, title = {Long-term treatment of amyotrophic lateral sclerosis with phthalazinol.}, journal = {Advances in second messenger and phosphoprotein research}, volume = {25}, number = {}, pages = {409-416}, pmid = {1554521}, issn = {1040-7952}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Female ; Humans ; Male ; Phosphodiesterase Inhibitors/administration &amp; dosage/*therapeutic use ; Phthalazines/administration &amp; dosage/*therapeutic use ; }, }
@article {pmid1353650, year = {1992}, author = {Omura, Y and Losco, BM and Omura, AK and Takeshige, C and Hisamitsu, T and Shimotsuura, Y and Yamamoto, S and Ishikawa, H and Muteki, T and Nakajima, H}, title = {Common factors contributing to intractable pain and medical problems with insufficient drug uptake in areas to be treated, and their pathogenesis and treatment: Part I. Combined use of medication with acupuncture, (+) Qi gong energy-stored material, soft laser or electrical stimulation.}, journal = {Acupuncture &amp; electro-therapeutics research}, volume = {17}, number = {2}, pages = {107-148}, doi = {10.3727/036012992816357774}, pmid = {1353650}, issn = {0360-1293}, mesh = {Acupuncture Therapy/methods/*standards ; Aged ; Analgesics/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Combined Modality Therapy ; Comorbidity ; Electric Stimulation Therapy/standards ; Electromagnetic Phenomena/standards ; Female ; Humans ; Infections/complications ; Laser Therapy ; Male ; Metals/poisoning ; Middle Aged ; Moxibustion/standards ; Pain, Intractable/epidemiology/etiology/*therapy ; Risk Factors ; Thromboxane B2/blood ; }, abstract = {Most frequently encountered causes of intractable pain and intractable medical problems, including headache, post-herpetic neuralgia, tinnitus with hearing difficulty, brachial essential hypertension, cephalic hypertension and hypotension, arrhythmia, stroke, osteo-arthritis, Minamata disease, Alzheimer's disease and neuromuscular problems, such as Amyotrophic Lateral Sclerosis, and cancer are often found to be due to co-existence of 1) viral or bacterial infection, 2) localized microcirculatory disturbances, 3) localized deposits of heavy metals, such as lead or mercury, in affected areas of the body, 4) with or without additional harmful environmental electro-magnetic or electric fields from household electrical devices in close vicinity, which create microcirculatory disturbances and reduced acetylcholine. The main reason why medications known to be effective prove ineffective with intractable medical problems, the authors found, is that even effective medications often cannot reach these affected areas in sufficient therapeutic doses, even though the medications can reach the normal parts of the body and result in side effects when doses are excessive. These conditions are often difficult to treat or may be considered incurable in both Western and Oriental medicine. As solutions to these problems, the authors found some of the following methods can improve circulation and selectively enhance drug uptake: 1) Acupuncture, 2) Low pulse repetition rate electrical stimulation (1-2 pulses/second), 3) (+) Qi Gong energy, 4) Soft lasers using Ga-As diode laser or He-Ne gas laser, 5) Certain electro-magnetic fields or rapidly changing or moving electric or magnetic fields, 6) Heat or moxibustion, 7) Individually selected Calcium Channel Blockers, 8) Individually selected Oriental herb medicines known to reduce or eliminate circulatory disturbances. Each method has advantages and limitations and therefore the individually optimal method has to be selected. Applications of (+) Qi Gong energy stored paper or cloth every 4 hours, along with effective medications, were often found to be effective, as Qigongnized materials can often be used repeatedly, as long as they are not exposed to rapidly changing electric, magnetic or electro-magnetic fields. Application of (+) Qi Gong energy-stored paper or cloth, soft laser or changing electric field for 30-60 seconds on the area above the medulla oblongata, vertebral arteries or endocrine representation area at the tail of pancreas reduced or eliminated microcirculatory disturbances and enhanced drug uptake.(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid1353011, year = {1992}, author = {Testa, D and Caraceni, T and Fetoni, V and Girotti, F}, title = {Chronic treatment with L-threonine in amyotrophic lateral sclerosis: a pilot study.}, journal = {Clinical neurology and neurosurgery}, volume = {94}, number = {1}, pages = {7-9}, doi = {10.1016/0303-8467(92)90110-o}, pmid = {1353011}, issn = {0303-8467}, mesh = {Administration, Oral ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Drug Administration Schedule ; Female ; Follow-Up Studies ; Glutamates/physiology ; Glutamic Acid ; Glycine/physiology ; Humans ; Male ; Middle Aged ; Neurologic Examination/drug effects ; Receptors, N-Methyl-D-Aspartate/drug effects/physiology ; Threonine/*administration &amp; dosage ; }, abstract = {Thirty patients suffering from amyotrophic lateral sclerosis were included in an open therapeutical trial. They were randomized to receive either L-threonine (Thr), a precursor of the inhibitory amino acid glycine, or vitamin B or carnitine. Thirteen patients (9 patients on Thr and 4 control subjects) completed the 1-year trial. No statistical differences were observed between the treated group and the control patients in the decline of the clinical assessment score. Nevertheless, Thr-treated patients complained less frequently of respiratory failure than the control group despite bulbar involvement being more common in the Thr group at entry.}, }
@article {pmid1792854, year = {1991}, author = {Formisano, R and Ruggieri, S and Cerbo, R and Lucarelli, F and De Vuono, G and Parmegiani, M and Agnoli, A and Attanasio, A and Capria, A and Piccolo, CG}, title = {Continuous intravenous infusion of TRH-T: clinical, cardiovascular and endocrinological effects.}, journal = {Acta neurologica Scandinavica}, volume = {84}, number = {6}, pages = {514-518}, doi = {10.1111/j.1600-0404.1991.tb05005.x}, pmid = {1792854}, issn = {0001-6314}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Electrocardiography, Ambulatory/drug effects ; Friedreich Ataxia/*drug therapy/physiopathology ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Neurologic Examination/drug effects ; Thyroid Hormones/blood ; Thyrotropin-Releasing Hormone/administration &amp; dosage ; }, abstract = {Seven patients, six suffering from amyotrophic lateral sclerosis (ALS) and one from Friedreich ataxia, were treated with a placebo i.v. infusion during the first day and with TRH-T i.v. infusion at a rate of 2 mg/h for 8 h daily (total daily dosage 16 mg) on the 2 consecutive days. Continuous blood pressure (BP) and EKG monitorings were performed during 3 days infusion. Blood samples were collected for endocrinological evaluations. The neurological evaluation after acute TRH-T treatment showed an objective improvement in 3 of the 8. We found significantly higher values of systolic (max. difference of 10.1 mm Hg) and diastolic (max. difference of 8.8 mm Hg) BP than during placebo, beginning from the 5th h of the infusion (p less than 0.05). A trend in progressive increase of the heart rate (HR) reached statistical significance (p less than 0.01) at the 8th h of the second TRH-T infusion. The cardiovascular changes during the i.v. continuous TRH-T infusions were clinically irrelevant and never required the interruption of the treatment.}, }
@article {pmid1835194, year = {1991}, author = {Hartner, WC and Markees, TG and De Fazio, SR and Khouri, W and Maki, T and Monaco, AP and Gozzo, JJ}, title = {The effect of antilymphocyte serum, fractionated donor bone marrow, and cyclosporine on renal allograft survival in mongrel dogs.}, journal = {Transplantation}, volume = {52}, number = {5}, pages = {784-789}, doi = {10.1097/00007890-199111000-00005}, pmid = {1835194}, issn = {0041-1337}, support = {AI14551/AI/NIAID NIH HHS/United States ; DK33466/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/*therapeutic use ; Bone Marrow Purging ; *Bone Marrow Transplantation ; Creatinine/blood ; Cyclosporine/*therapeutic use ; Dogs ; Dose-Response Relationship, Drug ; Graft Rejection ; Graft Survival/*drug effects ; Immunosuppression Therapy/*methods ; Kidney Transplantation/*immunology ; Lymphocyte Culture Test, Mixed ; }, abstract = {The effect of combined treatment with antilymphocyte serum, fractionated donor bone marrow, and a limited course of cyclosporine on renal allograft survival in mongrel dogs was examined. Recipients were treated with ALS from day -5 to day +7, relative to transplantation on day 0 with an MLR-mismatched donor. Fractionated donor bone marrow cells (BMFr3) obtained by density gradient separation were infused 3-7 days after ALS treatment. CsA treatments were begun either 3-7 days after ALS plus BMFr3 infusion or 3-7 days after treatments with ALS alone. Extended allograft survival was achieved at all CsA doses in BMFr3-infused, ALS-treated recipients. Allografts were sustained throughout the CsA treatment period without rejection in the majority of recipients (6 of 8) receiving ALS plus BMFr3 and CsA at 20 Mg/kg/day for 60 days. By contrast, few grafts were sustained through 30 days of treatment with CsA at 3.2 (1 of 12) or 10 mg/kg/day (2 of 9) in ALS plus BMFr3-treated recipients. Cyclosporine treatment was ineffective at all doses in augmenting allograft prolongation in ALS-treated recipients that did not receive BMFr3. Nearly all (6 of 7) long-term survivors (greater than 180 days) were BMFr3-treated. Peripheral blood lymphocytes or bone marrow cells of these long-term survivors proliferated normally in response to Con A and PWM, and were MLR responsive to third-party cells but did not have reduced MLR responsiveness to donor alloantigen in all cases. These long-term survivors promptly rejected third-party renal allografts without adverse effects on the original transplant's function. These results show that long-term renal allograft survival with specific unresponsiveness to the donor can result from the combined treatment with ALS plus donor BMFr3 and a limited course of CsA.}, }
@article {pmid1844350, year = {1991}, author = {Tucker, T and Layzer, RB and Miller, RG and Chad, D}, title = {Subacute, reversible motor neuron disease.}, journal = {Neurology}, volume = {41}, number = {10}, pages = {1541-1544}, doi = {10.1212/wnl.41.10.1541}, pmid = {1844350}, issn = {0028-3878}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Electrophysiology ; Female ; Humans ; Male ; Middle Aged ; *Motor Neurons ; Neuromuscular Diseases/diagnosis/*physiopathology ; Remission, Spontaneous ; }, abstract = {Four patients with a clinical syndrome closely resembling amyotrophic lateral sclerosis recovered completely, without treatment, 5 to 12 months after onset. Electrodiagnostic tests revealed acute and chronic denervation, with normal motor and sensory nerve conduction studies. The CSF was normal, and tests for paraproteinemia, heavy metal intoxication, and systemic illness were negative. Although such cases are rare, the possibility of spontaneous recovery should always be considered when counseling patients with suspected ALS.}, }
@article {pmid1839869, year = {1991}, author = {Moulding, MB and Koroluk, LD}, title = {An intraoral prosthesis to control drooling in a patient with amyotrophic lateral sclerosis.}, journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry}, volume = {11}, number = {5}, pages = {200-202}, doi = {10.1111/j.1754-4505.1991.tb01731.x}, pmid = {1839869}, issn = {0275-1879}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*physiopathology ; *Dental Care for Persons with Disabilities ; Denture Design ; Denture, Complete, Lower ; Female ; Humans ; Lip/*physiopathology ; *Prostheses and Implants ; Sialorrhea/etiology/*therapy ; }, abstract = {Many alternatives exist for treating chronic drooling. The treatment of a patient with amyotrophic lateral sclerosis who complained of chronic drooling and lack of retention of fluids while drinking is presented. In this case, an alternative type of intraoral prosthesis, not previously reported in the dental literature, was used to treat chronic drooling. A lip plumper prosthesis was fabricated to approximate the partially incompetent lips and create an oral seal. The results of the prosthesis therapy for this patient are encouraging both physically and psychologically.}, }
@article {pmid1809521, year = {1991}, author = {Nevsímal, O and Pekárek, J and Koubek, K and Cech, K and Sonková, Z}, title = {[Low-molecular transfer factor and its use in the treatment of amyotrophic lateral sclerosis].}, journal = {Ceskoslovenska neurologie a neurochirurgie}, volume = {54}, number = {4}, pages = {220-222}, pmid = {1809521}, issn = {0301-0597}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*therapy ; Female ; Humans ; Male ; Middle Aged ; Molecular Weight ; Transfer Factor/*therapeutic use ; }, abstract = {A low-molecular leukocyte dialysate, suppressor transfer factor (STF), exerting a stimulating effect on CD8 subpopulations in man, was administered to 17 patients with amyotrophic lateral sclerosis (ALS). Following three s.c. injections of STF, activation of CD8 subpopulations was noted in 11 patients while a decrease in CD4 in seven. Progression of the disease was found to slow in nine outpatients administered STF injections at an interval of 3-4 weeks. No therapeutic effect was seen in four patients in whom STF injection failed to show stimulating activity on lymphocyte subpopulations. Remission of the stimulating effect of STF occurs within four weeks. No side effects were seen in any of the patients treated. The effect of STF on immune reactivity and on the clinical course of ALS supports the hypothesis of autoimmune character of the disease.}, }
@article {pmid1764867, year = {1991}, author = {Moriwaka, F and Tashiro, K and Doi, R and Satoh, H and Fukuchi, Y}, title = {[A clinical evaluation of the inorganic mercurialism--its pathogenic relation to amyotrophic lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {31}, number = {8}, pages = {885-887}, pmid = {1764867}, issn = {0009-918X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*chemically induced ; Chronic Disease ; Humans ; Mercury Poisoning/*complications/metabolism ; Middle Aged ; }, abstract = {The pathogenic relation of chronic mercurialism and amyotrophic lateral sclerosis (ALS) was evaluated clinically on 83 ex-mercury workers who were poisoned or exposed to mercury vapor about 18 years ago at one of the biggest mercury mines in Hokkaido, as well as on the causes of 65 expired workers in the cohort. The 83 ex-mercury workers were subdivided into two groups according to severity of mercury poisoning: 31 ex-workers who had been hospitalized for treatment of mercury poisoning and the remaining 52 ex-workers severely exposed to mercury vapor but not hospitalized. Neurologic examinations and measurements of mercury contents in the blood, urine, and hair samples in the 83 cases, failed to disclose any pathogenicity of mercury to ALS. Among these 148 including the 65 deceased cases, no ALS cases were found. Further clinical and epidemiological studies should be required on mercury poisoning as one of the risk factors in the development of ALS, especially in relation to selenium.}, }
@article {pmid1721746, year = {1991}, author = {Lindvall, O}, title = {Prospects of transplantation in human neurodegenerative diseases.}, journal = {Trends in neurosciences}, volume = {14}, number = {8}, pages = {376-384}, doi = {10.1016/0166-2236(91)90167-s}, pmid = {1721746}, issn = {0166-2236}, mesh = {Animals ; Brain Tissue Transplantation/*physiology ; Humans ; Huntington Disease/therapy ; Nerve Degeneration/*physiology ; Nervous System Diseases/*therapy ; Parkinson Disease/therapy ; }, abstract = {Over the past decade experimental data obtained from animals have suggested that restoration or preservation of function through cell transplantation into the CNS might be developed into a useful therapeutic approach in human neurodegenerative disorders. Clinical trials in patients with Parkinson's disease have provided evidence that grafts of fetal dopaminergic neurons can survive and induce functional effects in the human brain, but no treatment based on transplantation is available yet. Initiation of studies of patients with striatal neural grafts in Huntington's disease is supported by findings in animal models, and is motivated by the lack of therapy and the severity of the symptoms in this disorder. Application of cell transplantation to other neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and hereditary ataxia is definitely premature. Further progress can be made only by systematic studies in animals of the scientific issues that can now be defined, but will also require clinical trials in a few well-monitored patients.}, }
@article {pmid2072756, year = {1991}, author = {Gay, PC and Westbrook, PR and Daube, JR and Litchy, WJ and Windebank, AJ and Iverson, R}, title = {Effects of alterations in pulmonary function and sleep variables on survival in patients with amyotrophic lateral sclerosis.}, journal = {Mayo Clinic proceedings}, volume = {66}, number = {7}, pages = {686-694}, doi = {10.1016/s0025-6196(12)62080-1}, pmid = {2072756}, issn = {0025-6196}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*mortality/physiopathology ; Female ; Humans ; Male ; Middle Aged ; Oxygen/blood ; Prognosis ; Prospective Studies ; Respiration Disorders/*etiology/mortality/physiopathology ; *Respiratory Function Tests ; Sensitivity and Specificity ; Sleep Apnea Syndromes/blood/complications ; Sleep Wake Disorders/blood/*complications ; Speech Intelligibility ; Survival Rate ; }, abstract = {Breathing abnormalities and nocturnal hypoventilation occur in patients with amyotrophic lateral sclerosis (ALS). A prospective study was undertaken to determine the relationship of pulmonary function test abnormalities with quality of sleep and survival in 21 patients with ALS. Results of spirometry including determination of maximal respiratory pressures and arterial blood gases were compared with several formal polysomnographic variables and then also with 18-month survival. The patients had mild to moderate pulmonary function deficits, but the quality of sleep was best related to age (mean age, 58.5 years). The results of pulmonary function tests and arterial blood gas measurements did not correlate well with the presence of nocturnal breathing events or survival time, but the maximal inspiratory pressure was 86% sensitive for predicting the presence of a nocturnal oxygen saturation nadir of 80% or less and 100% sensitive for predicting 18-month survival. Although obstructive breathing events occurred, the primary explanation for the decline in nocturnal oxygen saturation was hypoventilation. We conclude that routine pulmonary function tests may be useful for screening for reductions in nocturnal oxygen saturation and also may have prognostic value. Further studies may determine whether treatment of nocturnal hypoventilation will have an effect on survival in patients with ALS who have breathing impairment.}, }
@article {pmid1724585, year = {1991}, author = {Chernenko, OD and Grinevich, IuA}, title = {[The possibility of the restoration of interferon formation by biologically active thymus factors in experimentally induced immunodepression].}, journal = {Voprosy virusologii}, volume = {36}, number = {4}, pages = {309-310}, pmid = {1724585}, issn = {0507-4088}, mesh = {Adjuvants, Immunologic/*therapeutic use ; Animals ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Immunologic Deficiency Syndromes/blood/*drug therapy ; Interferon Inducers/*therapeutic use ; Interferons/blood ; Mice ; Mice, Inbred CBA ; Thymus Extracts/*therapeutic use ; Time Factors ; }, abstract = {Interferon production was investigated in mice of CBA line with experimentally induced immunosuppression. With all types of treatment (irradiation, administration of hydrocortisone, cyclophosphane, ALS) the capacity of host cells for interferon production was shown to be reduced. Administration of biologically active thymus factor, thymostimulin, to experimental animals resulted in significant restoration of alpha/beta and gamma interferon production.}, }
@article {pmid2046943, year = {1991}, author = {Overgaard, K and Werdelin, L and Sørensen, H and Mogensen, P and Boysen, G}, title = {Cytotoxic activity in plasma from patients with amyotrophic lateral sclerosis.}, journal = {Neurology}, volume = {41}, number = {6}, pages = {925-927}, doi = {10.1212/wnl.41.6.925}, pmid = {2046943}, issn = {0028-3878}, mesh = {Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*blood/drug therapy ; Azathioprine/therapeutic use ; Female ; *Hemolysis ; Humans ; Male ; Middle Aged ; Prednisone/therapeutic use ; }, abstract = {The present study evaluates an assay of cytotoxic effect of plasma from patients with amyotrophic lateral sclerosis. Plasma from 20 recently diagnosed ALS patients induced hemolysis of normal red blood cells with a significantly greater intensity than that of normal controls. After at least 1 month of treatment with prednisone and azathioprine, the hemolytic activity of ALS plasma was reduced but was still higher than that of control plasma.}, }
@article {pmid2031261, year = {1991}, author = {Jamshidi, F and De Fazio, SR and Markees, TG and Gozzo, JJ}, title = {Induction of allograft tolerance with neonatal skin.}, journal = {Transplantation}, volume = {51}, number = {5}, pages = {1048-1052}, doi = {10.1097/00007890-199105000-00023}, pmid = {2031261}, issn = {0041-1337}, support = {AI29650/AI/NIAID NIH HHS/United States ; DK33466/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Animals, Newborn ; Antilymphocyte Serum/pharmacology ; Bone Marrow Transplantation ; Cyclosporins/pharmacology ; Graft Rejection ; Graft Survival ; *Immune Tolerance ; Male ; Mice ; Mice, Inbred Strains ; *Skin Transplantation ; Transplantation, Homologous ; }, abstract = {B6AF1 recipients treated with various combinations of ALS, CsA, and BMC were grafted with C3H skin from adult or neonatal donors. A survival advantage of neonatal skin compared with adult skin was clearly demonstrated in groups treated with ALS and CsA (median survival time [MST] = 89 days, neonatal skin; 50 days, adult skin), ALS and BMC, (MST = 92 days, neonatal; 64 days, adult skin), or with ALS only (MST = 55 days and 35 days, respectively). In these groups only neonatal grafts were observed to survive greater than 100 days. Also, once it was underway, rejection of the neonatal skin proceeded more slowly than that of adult skin. ALS/BMC/CsA treatment of adult skin recipients improved graft survival modestly (MST = 77 days, 20% of grafts surviving greater than 100 days). But neonatal graft survival was prolonged remarkably by the ALS/BMC/CsA treatment, with 95% of grafts surviving greater than 100 days and 84% surviving greater than 240 days. After bearing neonatal grafts for greater than 150 days, these mice were challenged with C3H adult skin grafts. The second grafts were uniformly accepted for greater than 135 additional days, but third-party grafts were rejected promptly. This specific tolerance could not be abrogated by injection of normal B6AF1 spleen cells, and rejection of the grafts by adoptively transferred sensitized cells was delayed (MST = 35 days). That the tolerance developed in response to grafting neonatal skin to ALS/BMC/CsA-treated recipients extends to adult tissue suggests that understanding of the immunoregulatory signal provided by the neonatal tissue might lead to a tolerogenic protocol for use with adult allografts.}, }
@article {pmid1906441, year = {1991}, author = {Congia, S and Tronci, S and Ledda, M and Porcella, A and Coppola, G}, title = {Low doses of TRH in amyotrophic lateral sclerosis and in other neurological diseases.}, journal = {Italian journal of neurological sciences}, volume = {12}, number = {2}, pages = {193-198}, pmid = {1906441}, issn = {0392-0461}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Electromyography ; Female ; Humans ; Male ; Middle Aged ; Nervous System Diseases/*drug therapy/physiopathology ; Psychomotor Performance/physiology ; Thyrotropin-Releasing Hormone/*administration &amp; dosage ; }, abstract = {30 subjects--23 with amyotrophic lateral sclerosis (ALS), 4 with Charcot-Marie Tooth atrophy, 2 with progressive spinal muscle atrophy and 1 with radiation myelopathy--were given chronic low-dose TRH therapy. The effects of treatment were assessed on the scale of Norris et al. (1974). The outcome of the study, in agreement with some and at variance with other studies, was that TRH induced a statistically significant neurological improvement in 17 of the 23 ALS patients but little or none in the other ALS patients and in patients with other neurological diseases.}, }
@article {pmid1844830, year = {1991}, author = {Quentel, P and Beurton, D and Charbit, L and Broyer, M and Cukier, J}, title = {[Do posterior urethral valves alter the results of renal transplantation in children?].}, journal = {Progres en urologie : journal de l'Association francaise d'urologie et de la Societe francaise d'urologie}, volume = {1}, number = {2}, pages = {286-294}, pmid = {1844830}, issn = {1166-7087}, mesh = {Actuarial Analysis ; Child ; Child, Preschool ; Congenital Abnormalities/epidemiology ; Graft Survival ; Humans ; Infant ; Infant, Newborn ; Kidney Failure, Chronic/epidemiology/etiology/*surgery ; Kidney Transplantation/adverse effects/mortality/*standards ; Retrospective Studies ; Treatment Outcome ; Urethra/*abnormalities/surgery ; Urinary Diversion ; }, abstract = {The authors conducted a retrospective study based on a series of 715 renal transplantations in children performed between January 1973 and December 1989 at the Hôpital Necker-Enfants Malades in order to determine whether the long-term result of renal transplantation was as good in children with posterior urethral valves (PUV) as in children with a normal lower urinary tract. Group 1 consisted of 50 renal transplantations performed in 41 children in whom the primary urological disease was PUV. The bladder was able to be used without modification in 36 cases and had to be enlarged in 5 cases. A permanent cutaneous urinary diversion was not required in any of these transplanted patients. Group 2 consisted of 665 renal transplantations performed in children without PUV. There was no significant difference between the two groups in terms of the distribution of cadaver kidney and living related donor transplantations. Immunosuppressive treatment consisted of various combinations of prednisone, azathioprine, ALS for the earlier patients in the series, OKT 3 and cyclosporin for the more recent patients. In group 1, we observed a urological complication rate of 20% and a vascular complication rate of 14%, while, in group 2, the urological complication rate was 16.9% and the vascular complication rate was 9.5%. The actuarial 5-year and 10-year graft survival rates were 63% and 49% in group 1 and 63% and 49% in group 2, respectively. The actuarial graft survival rates were therefore identical in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid1994937, year = {1991}, author = {Eastham, JN and Thompson, ME and Ryan, PA}, title = {Treatment and career attitudes of prehospital care providers associated with potential exposure to HIV/AIDS.}, journal = {The American journal of emergency medicine}, volume = {9}, number = {2}, pages = {122-126}, doi = {10.1016/0735-6757(91)90171-f}, pmid = {1994937}, issn = {0735-6757}, mesh = {Adolescent ; Adult ; Aged ; *Attitude to Health ; Career Choice ; Education/standards ; Educational Status ; Emergency Medical Technicians/education/*psychology/supply &amp; distribution ; Female ; HIV Infections/prevention &amp; control/*therapy/transmission ; *HIV-1 ; Humans ; Male ; Maryland ; Middle Aged ; *Occupational Exposure ; Personnel Turnover ; Stress, Psychological/epidemiology/etiology/psychology ; Surveys and Questionnaires ; }, abstract = {Career and treatment attitudes related to potential human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) exposure are reported based on a survey of 1,228 Maryland career and volunteer prehospital care providers trained to provide basic (BLS) and advanced (ALS) life support. Sixty-five percent stated potential exposure to HIV/AIDS was a major occupational stressor. Ninety-two percent stated they would treat HIV/AIDS patients if protected. Given a choice, 38% would avoid providing treatment to HIV/AIDS patients. Eighteen percent considered resigning from emergency medical services (EMS) work. An attitudinal scale (AIDSTRESS) was developed to evaluate overall treatment and career reactions. Respondents with significantly higher (more negative reactions) AIDSTRESS scores were: BLS providers, men, paid providers, personnel with more than 3 years of field experience, those working in urban areas, personnel with no formal education beyond high school, and those who stated that their HIV/AIDS training was inadequate. Implications of the findings for quality of care, career decision making, and inservice education are discussed.}, }
@article {pmid1990590, year = {1991}, author = {Hartner, WC and Shaffer, D and Markees, TG and De Fazio, SR and Monaco, AP and Gozzo, JJ}, title = {Effect of cyclosporine A treatment on induction of donor specific unresponsiveness in mongrel dogs following a short course of ALS and donor bone marrow infusion on canine renal allograft function.}, journal = {Transplantation proceedings}, volume = {23}, number = {1 Pt 1}, pages = {477-479}, pmid = {1990590}, issn = {0041-1345}, support = {DK 33466/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/*therapeutic use ; Bone Marrow Transplantation/*immunology ; Combined Modality Therapy ; Creatinine/blood ; Cyclosporins/*therapeutic use ; Dogs ; Graft Survival ; Kidney Transplantation/immunology/*physiology ; Transplantation, Homologous ; }, }
@article {pmid1905383, year = {1991}, author = {Roufs, JB}, title = {L-threonine as a symptomatic treatment for amyotrophic lateral sclerosis (ALS).}, journal = {Medical hypotheses}, volume = {34}, number = {1}, pages = {20-23}, doi = {10.1016/0306-9877(91)90059-8}, pmid = {1905383}, issn = {0306-9877}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Central Nervous System/metabolism ; Glycine/metabolism ; Humans ; Models, Biological ; Threonine/*therapeutic use ; }, abstract = {ALS is a fatal, neurological disease of unknown origin with no present cure. A recent pilot study has shown that L-threonine, an essential amino acid, may be effective in the symptomatic treatment of ALS. Relevant information discussing the potential role of L-threonine in the treatment of ALS is presented.}, }
@article {pmid1904280, year = {1991}, author = {Lynn, AG and Bennett, GW}, title = {Development of a radioimmunoassay for RX77368 (pGlu-His-3,3-dimethyl proline amide)--a stable analogue of thyrotrophin releasing hormone (TRH).}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {9}, number = {1}, pages = {9-18}, doi = {10.1016/0731-7085(91)80230-7}, pmid = {1904280}, issn = {0731-7085}, mesh = {Animals ; Cross Reactions ; Humans ; Immune Sera/immunology ; Pyrrolidonecarboxylic Acid/analogs &amp; derivatives ; Rabbits ; Radioimmunoassay ; Sheep ; Thyrotropin-Releasing Hormone/*analogs &amp; derivatives/analysis/immunology ; }, abstract = {The recent interest in RX77368 for the treatment of Motor Neurone Disease (MND) has led to the requirement for an assay (RIA) capable of detecting the peptide at low levels in plasma. Several drug conjugates were prepared in which RX77368 was covalently linked to larger proteins, e.g. bovine serum albumin, keyhole limpet haemocyanin or bovine thyroglobulin, the best yield being obtained with the bis-diazotized benzidine reaction (BDB) linking RX77368 to KLH. The latter conjugate was injected into sheep and ultimately produced an antibody of sufficiently high titre to be used. This combined with an iodinated radiolabel formed the basis of the radioimmunoassay. Cross-reactivity studies using similar analogues and RX77368 metabolites showed that the antibody was specific for RX77368. The greatest cross-reactivity was exhibited by the pGlu-His-monomethylProNH2 peptide (RX74355), but, not being a natural metabolite, this did not interfere with the assay. The RIA was used to measure RX77368 in MND patients in a recent clinical study, where RX77368 was administered both by the intravenous and oral routes. High plasma concentrations of RX77368 were found in the patients given intravenous drug by infusion. The oral route exhibited much lower levels, but had a sustained duration of action of up to 12 h.}, }
@article {pmid1862391, year = {1991}, author = {Lobzin, VS and Orlov, AB and Zvegintsova, TN}, title = {[Immunocorrective treatment of amyotrophic lateral sclerosis].}, journal = {Sovetskaia meditsina}, volume = {}, number = {1}, pages = {70-71}, pmid = {1862391}, issn = {0038-5077}, mesh = {Adjuvants, Immunologic ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/immunology ; Drug Therapy, Combination ; Female ; Humans ; Leukocyte Count/drug effects ; Levamisole/*administration &amp; dosage ; Lymphopenia/*drug therapy/*etiology ; Male ; Middle Aged ; Ribonucleases/*administration &amp; dosage ; T-Lymphocytes/drug effects/*immunology/pathology ; }, }
@article {pmid1853784, year = {1991}, author = {McManaman, JL and Haverkamp, LJ and Oppenheim, RW}, title = {Skeletal muscle proteins rescue motor neurons from cell death in vivo.}, journal = {Advances in neurology}, volume = {56}, number = {}, pages = {81-88}, pmid = {1853784}, issn = {0091-3952}, mesh = {Animals ; Cell Survival ; Chick Embryo ; Choline O-Acetyltransferase/metabolism/physiology ; Motor Neurons/*physiology ; Muscle Proteins/isolation &amp; purification/*physiology ; Nerve Growth Factors/physiology ; Rats ; }, abstract = {Because embryonic neurons are more sensitive to the effects of target derived factors than adult neurons, the developing nervous system provides a sensitive model for investigating the in vivo actions of target-derived growth factors. We have used the developing chick embryo to document that skeletal muscle contains substances that selectively enhance the in vivo survival of motor neurons. We have also shown that a single purified skeletal muscle protein (CDF) is capable of rescuing motor neurons during the period of naturally occurring cell death. The rescue of motor neurons in vivo by CDF is consistent with the hypothesis that distinct neurotrophic factors exist which regulate the timing and extent of the naturally occurring death of specific populations of neurons. The effects of CDF appear to be specific for cholinergic somatic motor neurons, since the survival of other types of spinal cord neurons, which also exhibit cell loss during the treatment period, was not affected by CDF treatment. In contrast, treatment of the embryos with extracts of tissues not innervated by motor neurons, or with NGF or bFGF, does not affect motor neuron survival. Thus the ability to rescue motor neurons during the period of cell death appears to be a distinct property of CDF and provides indirect evidence that this molecule may play a role in the survival and development of motor neurons. The role of neurotrophic factor involvement in the pathophysiology of degenerative diseases such as ALS remains entirely speculative. However, the demonstration that such factors affect the neuronal subtypes at risk in these diseases provides experimental support for this possibility.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid1822786, year = {1991}, author = {Clowry, G and Sieradzan, K and Vrbová, G}, title = {Grafts of embryonic tissue into spinal cord: a possible strategy for treating neuromuscular disorders.}, journal = {Neuromuscular disorders : NMD}, volume = {1}, number = {2}, pages = {87-92}, doi = {10.1016/0960-8966(91)90054-v}, pmid = {1822786}, issn = {0960-8966}, mesh = {*Fetal Tissue Transplantation ; Humans ; Neuromuscular Diseases/*therapy ; Spinal Cord/*physiology ; Spinal Cord Injuries/therapy ; }, abstract = {The article describes various approaches used to bring about repair of damaged spinal cord by using embryonic grafts of neuronal tissue. One approach is to stimulate the host's neuronal elements to grow and regenerate. Indeed embryonic grafts have been found to reduce the effects of spinal cord injury, and promote regrowth of axons across a lesion site at least to a limited extent. Attempts have also been made to restore the loss of supraspinal influences with grafts from embryonic brain, and transplants of aminergic neurones have been shown to compensate for the loss of aminergic supraspinal inputs. Finally, it is possible to replace loss of highly specialised cells such as motoneurones by grafts of embryonic spinal cord. Grafted embryonic motoneurones are able to survive within adult host cord although both their chances of survival and maturation seem improved by prior depletion of the host motoneurones. They are able to innervate a skeletal muscle via its peripheral nerve if this is co-implanted at the site of grafting but no axon growth has yet been detected into the host ventral root. However, grafted embryonic neurones are able to migrate away from the graft to sites once occupied by missing motoneurones in the host anterior horn. Within the context of the treatment of neuromuscular disease, the research described suggests possible stratagems for the treatment of disorders such as amyotrophic lateral sclerosis, spinal muscular atrophies or poliomyelitis either by employing grafts that could release neuroactive substances which might prevent existing cells from dying, or even by replacing missing motoneurones with transplanted embryonic motoneurones.}, }
@article {pmid1745428, year = {1991}, author = {Garruto, RM}, title = {Pacific paradigms of environmentally-induced neurological disorders: clinical, epidemiological and molecular perspectives.}, journal = {Neurotoxicology}, volume = {12}, number = {3}, pages = {347-377}, pmid = {1745428}, issn = {0161-813X}, mesh = {Aluminum/adverse effects/toxicity ; Alzheimer Disease/chemically induced ; Amyotrophic Lateral Sclerosis/chemically induced ; Animals ; *Environmental Exposure ; Humans ; Nervous System Diseases/*chemically induced/epidemiology/pathology ; Pacific Islands/epidemiology ; Parkinson Disease, Secondary/chemically induced ; }, abstract = {During the past quarter century biomedical scientists have begun to recognize the unique opportunities for studying disease etiology and mechanisms of pathogenesis in non-Western anthropological populations with focal, endemic diseases. Such natural experiments as they are called, are important paradigms for solving etiological and epidemiological problems of widespread medical significance, with an ultimate goal towards treatment and prevention. The systematic search for etiological factors and mechanisms of pathogenesis of neurodegenerative disorders is perhaps nowhere better exemplified than in the western Pacific. During the past three decades, the opportunistic and multidisciplinary study of hyperendemic foci of amyotrophic lateral sclerosis and parkinsonism-dementia which occur in different cultures, in different ecological zones and among genetically divergent populations have served as natural models that have had a major impact on our thinking and enhanced our understanding of these and other neurodegenerative disorders such as Alzheimer disease and the process of early neuronal aging. Our cross-disciplinary approach to these intriguing neurobiological problems and the accumulated epidemiological, genetic, cellular and molecular evidence strongly implicates environmental factors in their causation, specifically the role of aluminum and its interaction with calcium in neuronal degeneration. As a direct consequence of our studies in these Pacific populations, we have undertaken the long-term development of experimental models of neuronal degeneration, in an attempt to understand the cellular and molecular mechanisms by which these toxicants affect the central nervous system. Our experimental studies have resulted in the establishment of an aluminum-induced chronic myelopathy in rabbits and the development of neurofilamentous lesions after low-dose aluminum administration in cell culture. These studies clearly demonstrate the philosophy that chronic rather than acute experimental models of toxicity are necessary in order to enhance our understanding of human neurodegenerative disorders with long-latency and slow progression. Finally, the ultimate significance of these Pacific paradigms may well depend on our ability to comprehensively evaluate and synthesize the growing body of relevant scientific data from other human disorders and from widely divergent academic fields, as well as our ability to recognize emerging new models in nature.}, }
@article {pmid1716905, year = {1991}, author = {Sofic, E and Riederer, P and Gsell, W and Gavranovic, M and Schmidtke, A and Jellinger, K}, title = {Biogenic amines and metabolites in spinal cord of patients with Parkinson's disease and amyotrophic lateral sclerosis.}, journal = {Journal of neural transmission. Parkinson's disease and dementia section}, volume = {3}, number = {2}, pages = {133-142}, doi = {10.1007/BF02260888}, pmid = {1716905}, issn = {0936-3076}, mesh = {3,4-Dihydroxyphenylacetic Acid/analysis ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Autopsy ; Biogenic Monoamines/*analysis ; Dopamine/analysis ; Female ; Homovanillic Acid/analysis ; Humans ; Hydroxyindoleacetic Acid/analysis ; Male ; Middle Aged ; Norepinephrine/analysis ; Parkinson Disease/*metabolism/pathology ; Reference Values ; Serotonin/analysis ; Spinal Cord/*chemistry/pathology ; }, abstract = {In four human controls, four cases of Parkinson's disease and three cases of amyotrophic lateral sclerosis analysis of dopamine, noradrenaline, serotonin and the metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid was performed in various segments of postmortem spinal cord. In controls the concentrations of dopamine are about 1/3 to 1/4 that of noradrenaline; the significantly highest content of noradrenaline was found in the lumbar, and dopamine in thoracic, lumbar and sacral segments of the spinal cord. Intersegmental distribution of monoamines was only present in spinal cord of controls, while in the spinal cord of parkinsonian patients such a difference was not found. Otherwise, biogenic amine and metabolite concentrations in spinal cord segments of parkinsonian patients did not differ significantly from those in the control subjects. However, it cannot be excluded that these segments are sensitive to drugs including neuroleptics and combined L-DOPA treatment. In subjects with amyotrophic lateral sclerosis significantly lower concentrations of noradrenaline in the cervical and thoracic, and of dopamine and homovanillic acid in the thoracic and lumbar segments were found in comparison with controls. The concentrations of serotonin and 5-hydroxyindoleacetic acid in the thoracic segments of amyotrophic lateral sclerosis were significantly lower than that of controls. Differences in the inter-segmental distribution of noradrenaline in lumbar, lumbar-sacral, and serotonin in lumbar segments of spinal cord were found in this group.}, }
@article {pmid1670970, year = {1991}, author = {Monaco, AP and Wood, ML and Gottschalk, R and Seiler, FR}, title = {Effect of granulocyte-macrophage colony-stimulating factor on the induction of unresponsiveness by lymphoid cells.}, journal = {Transplantation}, volume = {51}, number = {1}, pages = {213-218}, doi = {10.1097/00007890-199101000-00035}, pmid = {1670970}, issn = {0041-1337}, support = {5R01-A114551//PHS HHS/United States ; }, mesh = {Animals ; Antigens, Surface/analysis ; Antilymphocyte Serum/pharmacology ; Bone Marrow/drug effects/immunology ; Bone Marrow Transplantation ; Graft Survival/*drug effects ; Granulocyte-Macrophage Colony-Stimulating Factor/*pharmacology ; Lymph Nodes/drug effects/immunology ; Lymphocytes/*immunology ; Male ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Skin Transplantation ; Spleen/drug effects/immunology ; Thy-1 Antigens ; }, abstract = {Skin grafts can be significantly prolonged in ALS-treated mice by the injection of 25 x 10(6) donor bone marrow cells or 50 x 10(6) spleen cells. Lymph node cells and thymocytes are only minimally effective in prolonging grafts. The effect of a hematopoietic growth factor, granulocyte-macrophage colony stimulating factor (GM-CSF) was studied in this model of unresponsiveness. C3H/He lymphoid cell donors were treated with GM-CSF. Either normal or GM-CSF-treated cells were injected into ALS-treated B6AF1 mice grafted with C3H/He skin. GM-CSF treatment significantly augmented the effect of marrow in prolonging graft survival at doses of 1 to 25 x 10(6) cells. In contrast, GM-CSF had no effect on the graft-prolonging effect of spleen cells when 50 x 10(6) cells were given. When the dose of cells was reduced to 25 x 10(6), graft survival in the group given GM-CSF-treated cells was prolonged compared with survival in the group given normal cells. Grafts in the group given GM-CSF-treated lymph node cells were rejected in sensitized fashion. When marrow and spleen are separated on a Percoll gradient, the cell active in promoting graft survival is recovered primarily in the 52.5% fraction. The graft-prolonging effect of the 52.5% marrow fraction was not affected by GM-CSF treatment. In contrast, GM-CSF-treated marrow cells in the 60% fraction significantly prolonged graft survival, while normal marrow cells in this fraction had no effect on graft survival. GM-CSF-treated spleen cells in the 52.5% and 60% fractions significantly decreased graft survival compared with normal cells when given at a dose equal to the number of cells recovered from 50 x 10(6) cells. When the dose of fractionated spleen cells was reduced, GM-CSF-treated spleen cells were more effective than normal cells in prolonging graft survival. These results indicate that GM-CSF activates a cell in marrow that promotes graft survival. This cell is recovered in the 60% Percoll fraction. In contrast, GM-CSF appears to affect two cell populations in spleen, one beneficial and one detrimental to graft survival. The predominant effect depends on the dose of spleen cells that is given.}, }
@article {pmid1670969, year = {1991}, author = {Wood, ML and Monaco, AP and Gottschalk, R}, title = {Characterization of spleen cells capable of inducing unresponsiveness in ALS-treated mice.}, journal = {Transplantation}, volume = {51}, number = {1}, pages = {208-213}, doi = {10.1097/00007890-199101000-00034}, pmid = {1670969}, issn = {0041-1337}, support = {5R01-AI14551/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antigens, Differentiation/analysis ; Antigens, Surface/analysis ; Antilymphocyte Serum/*pharmacology ; *Graft Survival ; Histocompatibility Antigens Class II/analysis ; Immunoglobulins/analysis ; Lymph Nodes/immunology ; Male ; Mice ; Mice, Inbred C3H ; Receptors, Fc/analysis ; Receptors, IgG ; Skin Transplantation ; Spleen/*immunology ; T-Lymphocytes/immunology ; Thy-1 Antigens ; }, abstract = {C3H/He skin allografts are significantly prolonged in ALS-treated B6AF1 mice by the injection of 50 x 10(6) C3H/He spleen cells 1 week postgrafting. To identify and characterize the spleen cell active in promoting graft survival, C3H/He spleen cells were separated on a discontinuous Percoll gradient and the various fractions were assayed for the ability to prolong skin graft survival in ALS-treated B6AF1 mice. In addition, unfractionated spleen and spleen fractions were depleted of specific cell populations before injection to determine the effect of various cell populations on graft prolongation. The active cell was recovered primarily in the 52.5% Percoll fraction. Cells in the 60% fraction also had a graft-prolonging effect, but not as significant as that of the 52.5% fraction. Depletion of Thy 1, Ia and Ig-positive cells from unfractionated spleen or spleen fractions did not decrease the graft-prolonging effect. Both Fc gamma R-positive and Fc gamma R-negative cells prolonged graft survival, but the Fc gamma R- cells were the most effective. In contrast to the effect of spleen cells, lymph node cells and thymocytes are relatively ineffective in prolonging graft survival in ALS-treated mice. When lymph node lymphocytes and thymocytes were separated on a Percoll gradient, the cell population active in prolonging graft survival was recovered primarily in the 52.5% fraction. Treatment of the 52.5% fraction of lymph node lymphocytes or thymocytes with monoclonal antibody to Thy 1 before injection abrogated the graft-prolonging effect. These results indicate that the spleen cell(s) active in prolonging graft survival in ALS-treated mice is a non-T, non-B cell, as it lacks Thy 1, Ia, and Ig surface markers. Both Fc gamma R+ and Fc gamma R- spleen cells are effective in prolonging grafts, but Fc gamma R- cells are the most effective. In contrast, the active cell in lymph node and thymus is Thy 1-positive, indicating that it is a T lymphocyte.}, }
@article {pmid2287168, year = {1990}, author = {Kim, YH and Shin, HS}, title = {[The comparative study on parent-adolescent communication between the model student family and the delinquent adolescent family].}, journal = {Taehan kanho. The Korean nurse}, volume = {29}, number = {5}, pages = {69-83}, pmid = {2287168}, issn = {0047-3618}, mesh = {Adolescent ; *Adolescent Behavior ; *Communication ; Female ; Humans ; *Juvenile Delinquency ; Korea ; Male ; Nuclear Family ; *Parent-Child Relations ; Reference Values ; }, abstract = {This research is based on the communication system theory which considers the family as a communication system or a communication network and which understand interpersonal relations among family members through a communication. This research is intended to define the difference of Parent-Adolescent Child communication between the model student family and the delinquent adolescent family, and also found the factors affecting parent-adolescent child communication. This aims to clarify wether a delinquent behavior is associated with family members' relations caused by dysfunctional communication between parents and their child, moreover explorate their problem to find the method of nursing intervention for prevention and treatment for delinquency. Subjects are 190 families (570 persons: father, mother, adolescent child) of model high school students and 87 families (261 persons) of delinquent adolescents. The employed tool is Olson et al's Parent-Adolescent Communication Scale (PAC, 20 items). The followings are the results derived through hypotheses verification. First, Comparison of two groups showed a significant difference in Parent-Adolescent Communication (t = 2.77, p less than 0.1). In the communication of delinquent group showed lower response than the model group. And also communication of the model group was more opened and positive (t = 2.41, p less than .05), and showed fewer problems (t = 2.06, p less than .05), the delinquent group had more problems. 2ndary, the delinquent group showed significantly more disagreement in response to variable of PAC than the model group. As analyzing of factors affects the Parents-Adolescent Communication, the best method to protect juvenile from delinquency are consistent open-hearted, congruent communication with mutual concern and warm mind between parents and child. And even though the all family don't hardly send together their time for their job, parents have to arrange many times to hold communication with children and to listen attentively to and respond to them, and so to increase their satisfaction for their parents. In conclusion, it seems that delinquent behavior is the outcome caused by dysfunctional communication between the parents and the child because of severe generation gap at adolescence period when the child needs communication with their parents. Therefore, it seems that the delinquent adolescent is the scape-goat of the family. Finally, it seems that more effective method to solve juvenile delinquents increasing day by day, is the family therapy that all family members participate than the individual therapy.}, }
@article {pmid2240754, year = {1990}, author = {Eitel, DR and Meador, SA and Drawbaugh, R and Hess, D and Sabulsky, NK and Bernini, R}, title = {Prehospital administration of inhaled metaproterenol.}, journal = {Annals of emergency medicine}, volume = {19}, number = {12}, pages = {1412-1417}, doi = {10.1016/s0196-0644(05)82610-1}, pmid = {2240754}, issn = {0196-0644}, mesh = {Administration, Inhalation ; Adult ; Aged ; Asthma/*drug therapy ; Drug Evaluation ; *Emergency Medical Services ; Humans ; Lung Diseases, Obstructive/*drug therapy ; Male ; Metaproterenol/administration &amp; dosage/*therapeutic use ; Middle Aged ; Nebulizers and Vaporizers ; Pennsylvania ; Prospective Studies ; Respiration/*drug effects ; }, abstract = {STUDY OBJECTIVES: We conducted a study of the prehospital use of inhaled metaproterenol. DESIGN, SETTING, TYPE OF PARTICIPANTS, AND INTERVENTIONS: Advanced life support (ALS) providers were trained with a standardized curriculum to identify patients likely to benefit from prehospital inhaled metaproterenol administration. Unit doses of metaproterenol were used in a small-volume nebulizer. We prospectively included 122 patients in an initial study (71 men; age, 63 +/- 19 years) to evaluate the safety and effectiveness of metaproterenol in the field, and 150 patients (including the original 122) in an additional study to evaluate patient selection criteria.<br><br>MEASUREMENTS AND MAIN RESULTS: The treatments resulted in an increase in peak flows, a decrease in respiratory rates, and no change in heart rates. In 62% of patients, the increase in peak flow exceeded 15%. Wheezing improved in 59% of the patients, worsened in 4%, and did not change in the remainder. Air entry by auscultation improved subjectively in 59% of patients. Mild tremor occurred in 8% of patients, moderate tremor occurred in 1%, and no tremor occurred in the remainder. Significant dysrhythmias did not occur.<br><br>CONCLUSIONS: ALS providers correctly identified patients for this therapy. No technical problems were encountered in the field with this treatment approach. We conclude that ALS providers can be taught to identify patients likely to benefit from inhaled metaproterenol, that inhaled metaproterenol can be administered in the field, and that metaproterenol is both safe and effective when used in the prehospital setting.}, }
@article {pmid2127925, year = {1990}, author = {Testa, D and Chiodini, PG and Girotti, F and Attanasio, R}, title = {Amyotrophic lateral sclerosis: thyroid and prolactin hormone changes in thyrotropin-releasing hormone therapy.}, journal = {Italian journal of neurological sciences}, volume = {11}, number = {6}, pages = {601-603}, pmid = {2127925}, issn = {0392-0461}, mesh = {Amyotrophic Lateral Sclerosis/blood/*drug therapy/physiopathology ; Female ; Growth Hormone-Releasing Hormone/pharmacology ; Humans ; Male ; Middle Aged ; Prolactin/*blood/metabolism ; Secretory Rate/drug effects ; Stimulation, Chemical ; Thyrotropin-Releasing Hormone/pharmacology/*therapeutic use ; Thyroxine/*blood/metabolism ; Triiodothyronine/*blood/metabolism ; }, abstract = {13 patients with amyotrophic lateral sclerosis (ALS) were treated with intravenous infusion of thyrotropin-releasing hormone (TRH). In 6 patients 2 mg/day of TRH was i.v. given over 2 hours for 10 days. In 7 others 2 mg/day of TRH was continuously infused by means of a pump. An increase of thyroid hormones related to the duration of the treatment was observed. A surprising finding was the onset of prolactin (PRL) response to growth hormone releasing hormone (GHRH), previously absent.}, }
@article {pmid2287632, year = {1990}, author = {Churchill, ME and Schmitz, AM and Peak, JG and Peak, MJ}, title = {Photosensitized damage to supercoiled plasmid DNA induced by 334-nm radiation in the presence of 2-thiouracil consists of alkali- and piperidine-labile sites as well as frank strand breaks.}, journal = {Photochemistry and photobiology}, volume = {52}, number = {5}, pages = {1017-1023}, doi = {10.1111/j.1751-1097.1990.tb01819.x}, pmid = {2287632}, issn = {0031-8655}, support = {R01-CA34492/CA/NCI NIH HHS/United States ; R01-CA37848/CA/NCI NIH HHS/United States ; }, mesh = {*DNA Damage ; DNA, Superhelical/drug effects/*radiation effects ; Escherichia coli/genetics ; Hydrogen-Ion Concentration ; Piperidines ; Plasmids/drug effects/*radiation effects ; Thiouracil/*pharmacology ; *Ultraviolet Rays ; }, abstract = {A covalently closed, supercoiled plasmid was irradiated with 334-nm ultraviolet radiation in the presence of the naturally occurring photosensitizer 2-thiouracil (s2Ura). After irradiation, some DNA samples were treated to reveal labile sites. Agarose gel electrophoresis was then used to resolve the unrelaxed supercoils from the relaxed forms, and the DNA bands were quantitated by fluorescence scanning. Irradiation of the plasmid in the absence of s2Ura induced small numbers of frank DNA strand breaks (FSB), alkali-labile sites (ALS), and piperidine-labile sites (PLS). The induction of each of these lesions was enhanced 30 times when s2Ura was present during aerobic irradiation. Anoxia, as well as the hydroxyl radical scavengers acetate and formate, inhibited the formation of all three lesion types. The relative proportions of the three lesion types produced by several DNA damaging treatments were measured. Hydrogen peroxide, gamma-irradiation, and s2Ura photosensitization produced nearly identical damage proportions, with PLS: FSB ratios of 1.25:1, 0.78:1, and 0.84:1, respectively. Treatment with singlet oxygen [data from Blazek et al. (1989) Photochem. Photobiol. 48, 607-613] produced much different proportions, with a PLS:FSB ratio of 4.1:1. These results may indicate a role for hydroxyl radical in s2Ura-photosensitized DNA damage.}, }
@article {pmid2241057, year = {1990}, author = {Wilson, PS and Bruce-Lockhart, FJ and Johnson, AP}, title = {Videofluoroscopy in motor neurone disease prior to cricopharyngeal myotomy.}, journal = {Annals of the Royal College of Surgeons of England}, volume = {72}, number = {6}, pages = {375-377}, pmid = {2241057}, issn = {0035-8843}, mesh = {Aged ; Aged, 80 and over ; Cricoid Cartilage/surgery ; Deglutition Disorders/*surgery ; Fluoroscopy/*methods ; Humans ; Middle Aged ; *Motor Neurons ; Neuromuscular Diseases/*complications ; Pharynx/*surgery ; Preoperative Care ; *Videotape Recording ; }, abstract = {Cricopharyngeal myotomy is a recognised treatment for the dysphagia in motor neurone disease, although the results are sometimes disappointing. In this study, 27 patients with motor neurone disease causing significant dysphagia have been investigated by the technique of videofluoroscopy, in order to determine the nature of their swallowing disability; those patients found suitable have been offered cricopharyngeal myotomy. Of the 27 patients, only seven were found to have cricopharyngeal dysfunction as the predominant disability and, of these, six underwent myotomy, resulting in relief of dysphagia in five, three of whom returned to a near normal diet. Previous studies showed poor overall benefit from cricopharyngeal myotomy. Videofluoroscopy allows accurate patient selection, and a much improved outcome in the selected group.}, }
@article {pmid2075175, year = {1990}, author = {Martinius, J}, title = {[Changes in diagnostic and therapeutic viewpoints: biological psychiatry aspects].}, journal = {Praxis der Kinderpsychologie und Kinderpsychiatrie}, volume = {39}, number = {9-10}, pages = {353-357}, pmid = {2075175}, issn = {0032-7034}, mesh = {Adolescent ; Autistic Disorder/etiology/therapy ; Child ; Combined Modality Therapy ; Humans ; Neurocognitive Disorders/*etiology/therapy ; }, abstract = {The beginnings of child als adolescent psychiatry were dominated by biological thinking. Due to its unidirectionality it was bound to fail. Instead, psychological and social conditions for the development of psychic disturbances gained recognition and preference. Child and adolescent psychiatry presently favours a synthesis of all conditions, including the biological ones. Early infantile autism is taken as an example for a change of views towards a primary biological causation, with all consequences for diagnosis and treatment. Change in child and adolescent psychiatry means development and synthesis of all components.}, }
@article {pmid2270755, year = {1990}, author = {Askmark, H and Aquilonius, SM and Gillberg, PG and Hartvig, P and Hilton-Brown, P and Lindström, B and Nilsson, D and Stålberg, E and Winkler, T}, title = {Functional and pharmacokinetic studies of tetrahydroaminoacridine in patients with amyotrophic lateral sclerosis.}, journal = {Acta neurologica Scandinavica}, volume = {82}, number = {4}, pages = {253-258}, doi = {10.1111/j.1600-0404.1990.tb01615.x}, pmid = {2270755}, issn = {0001-6314}, mesh = {Administration, Oral ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/blood/*drug therapy ; Drug Therapy, Combination ; Electromyography/drug effects ; Female ; Humans ; Injections, Intravenous ; Male ; Middle Aged ; Muscle Contraction/*drug effects ; *Neurologic Examination ; Reaction Time/drug effects ; Tacrine/*administration &amp; dosage/adverse effects/pharmacokinetics ; }, abstract = {Assuming the presence of clinically significant cholinergic hypofunction in amyotrophic lateral scleroses (ALS), seven patients with ALS were treated with 100-200 mg tetrahydroaminoacridine (THA) together with 11 g lecithin daily for up to 7 weeks. In a separate experiment pharmacokinetics and effects on muscle strength and neurophysiological parameters were studied following the injection of 30 mg THA intravenously. Following the injection of THA an increase in muscle strength was observed in two patients. There were no consistent pharmacokinetic differences that could explain the effect on intravenous THA on muscle strength in these two patients. The plasma clearance of THA was high and the oral bioavailability low with large interindividual differences (6-36%). No beneficial effect was seen during oral medication and side-effects were common. There were no conclusive changes observed regarding neurophysiological parameters after drug administration. THA has probably no place in the treatment of ALS.}, }
@article {pmid2125610, year = {1990}, author = {Chiodini, PG and Attanasio, R and Liuzzi, A and Cozzi, R and Orlandi, P and De Palo, C and Dallabonzana, D and Girotti, F and Testa, D}, title = {Prolactin response to growth hormone-releasing hormone during chronic thyrotropin-releasing hormone infusion in the treatment of amyotrophic lateral sclerosis.}, journal = {Journal of endocrinological investigation}, volume = {13}, number = {8}, pages = {631-636}, pmid = {2125610}, issn = {0391-4097}, mesh = {Amyotrophic Lateral Sclerosis/*blood/drug therapy ; Down-Regulation/drug effects ; Female ; Growth Hormone/blood ; Growth Hormone-Releasing Hormone/*pharmacology ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Prolactin/*blood ; Radioimmunoassay ; Thyrotropin/blood ; Thyrotropin-Releasing Hormone/administration &amp; dosage/*pharmacology/therapeutic use ; Thyroxine/blood ; Triiodothyronine/blood ; }, abstract = {In six patients suffering from amyotrophic lateral sclerosis we evaluated changes of T4, T3, TSH, PRL, and GH during treatment by continuous iv infusion of TRH for at least 15 days. No clinical improvement was detected. A significant rise of thyroid hormone levels was observed, as well as an upward trend of basal TSH levels and no change of basal PRL and GH levels. TRH acute test-induced TSH and PRL responses became blunted. Treatment provoked also the onset of a responsiveness of PRL to GHRH. The reduced TSH and PRL responses to acute TRH test during treatment could be explained by a down-regulation of TRH pituitary receptors. On the contrary, the onset of PRL responsiveness to GHRH is at present without a satisfactory explanation.}, }
@article {pmid2256442, year = {1990}, author = {Werdelin, L and Boysen, G and Jensen, TS and Mogensen, P}, title = {Immunosuppressive treatment of patients with amyotrophic lateral sclerosis.}, journal = {Acta neurologica Scandinavica}, volume = {82}, number = {2}, pages = {132-134}, doi = {10.1111/j.1600-0404.1990.tb01602.x}, pmid = {2256442}, issn = {0001-6314}, mesh = {Administration, Oral ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Azathioprine/administration &amp; dosage/*therapeutic use ; Female ; Humans ; Infusions, Intravenous ; Male ; Methylprednisolone/administration &amp; dosage/*therapeutic use ; Middle Aged ; Prednisolone/administration &amp; dosage/*therapeutic use ; }, abstract = {Documented treatment for amyotrophic lateral sclerosis (ALS) is not available. Several studies have suggested an immunological etiology and an effect on the course of disease, when ALS-patients were treated with immunosuppressants. The aim of the present study was to evaluate the effect of immunosuppressive therapy in ALS-patients comparing the course of disease in treated patients and in historic controls with ALS; 21 patients were included in the study, 17 men and 4 women. Median age at admission was 54 years for men and 61 years for women. 5 had progressive bulbar palsy, 7 both upper and lower motor neuron affections and 9 progressive muscular atrophy. Patients were treated with prednisolone and azathioprine for 1 year and examined regularly; 12 were treated and followed for more than a year. No definite difference between survival in treated patients and their controls was found.}, }
@article {pmid2236471, year = {1990}, author = {Böcker, FM and Seibold, I}, title = {[Assessment of "coping with disease" in patients with amyotrophic lateral sclerosis (ALS): on the use of an interviewer assessment rating scale].}, journal = {Psychotherapie, Psychosomatik, medizinische Psychologie}, volume = {40}, number = {8}, pages = {285-292}, pmid = {2236471}, issn = {0937-2032}, mesh = {*Adaptation, Psychological ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*psychology ; Defense Mechanisms ; Female ; Humans ; Male ; Middle Aged ; *Personality Assessment ; Psychometrics ; *Sick Role ; Social Support ; }, abstract = {Theories on "Coping" try to explain which resources people use to master crises and conflict situations. Reactions to challenges of life are considered as "coping strategies". In psychosomatic research, the notion of "coping" serves to describe how patients can handle physical or mental illness. Myatrophic (or amyothrophic) lateral sclerosis (ALS) is a rare chronic progressive disease of the nervous system with a gradual loss of motor neurons, resulting in muscular atrophy, weakness and spasticity. Since the etiology is unknown and no curative treatment available, most patients die from respiratory failure within a few years. In a follow-up study on physical disability, medical care and social support in 21 patients with advanced ALS, we tried to address the question how patients get along with such a threatening condition. After semi-standardized clinical interviews with patients and close relatives, two investigators gave independent descriptions of reported or observed "coping strategies" (rated as "not at all-barely-possibly-probably-very probably present"). Considering 17 patients assessed by both raters, significant agreement (Kendall's W) was achieved in three patients only. A comparison of aggregated answers (chi 2-Test) revealed different response sets, since one rater tended to choose extreme scale points, while the other preferred undecided answers. Differences of mean scores were observed in 8 out of 21 items, while significant correlations between investigators were obtained in another 8, including, though, only 2 of those 5 items which both had rated as "probably present" in no less than 50% of the patient sample ("Dejection &amp; Flight-Brooding-Keeping the Situation Open-Distraction-Self-Isolation").(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid2189083, year = {1990}, author = {Evans, BK and Fagan, C and Arnold, T and Dropcho, EJ and Oh, SJ}, title = {Paraneoplastic motor neuron disease and renal cell carcinoma: improvement after nephrectomy.}, journal = {Neurology}, volume = {40}, number = {6}, pages = {960-962}, doi = {10.1212/wnl.40.6.960}, pmid = {2189083}, issn = {0028-3878}, mesh = {Aged ; Carcinoma, Renal Cell/*surgery ; Humans ; Kidney Neoplasms/*surgery ; Male ; *Motor Neurons ; *Nephrectomy ; Neuromuscular Diseases/*etiology/surgery ; Paraneoplastic Syndromes/*etiology/surgery ; }, abstract = {A 74-year-old man had a paraneoplastic motor neuron disease mimicking amyotrophic lateral sclerosis. He had an elevated erythrocyte sedimentation rate, other laboratory abnormalities, and a previously undiagnosed renal cell carcinoma. Four months after nephrectomy, his strength had improved and he had no fasciculations. Seven other patients with cancer and motor neuron disease improved or stabilized after tumor treatment. Even though it is rare, paraneoplastic motor neuron disease is important to diagnose because it may be treatable.}, }
@article {pmid2190313, year = {1990}, author = {Frey, FJ}, title = {[Cyclosporin in autoimmune diseases].}, journal = {Schweizerische medizinische Wochenschrift}, volume = {120}, number = {21}, pages = {772-786}, pmid = {2190313}, issn = {0036-7672}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; Anemia, Aplastic/drug therapy ; Arthritis, Rheumatoid/drug therapy ; Autoimmune Diseases/*drug therapy ; Clinical Trials as Topic ; Cyclosporins/adverse effects/*therapeutic use ; Diabetes Mellitus, Type 1/drug therapy ; Graves Disease/drug therapy ; Humans ; Liver Cirrhosis, Biliary/drug therapy ; Multiple Sclerosis/drug therapy ; Myasthenia Gravis/drug therapy ; Nephrosis, Lipoid/drug therapy ; Psoriasis/drug therapy ; Sjogren's Syndrome/drug therapy ; Uveitis/drug therapy ; }, abstract = {The efficacy of cyclosporine (Sandimmun) is well established in the field of organ transplantation. More recently, prospective controlled trials were performed in patients with other diseases. The efficacy of cyclosporine for the following clinical entities was proven by the trials: endogenous uveitis, rheumatoid arthritis, Sjögren's syndrome, myasthenia gravis, psoriasis and Crohn's disease. Furthermore, there is evidence from a controlled trial of some benefit for patients with aplastic anemia. The proteinuria of patients with glomerulonephritis was reduced by cyclosporine, though no improvement in glomerular filtration rate was observed. Large controlled trials in patients with multiple sclerosis or amyotrophic lateral sclerosis revealed a beneficial effect on some clinical parameters. Nevertheless, cyclosporine cannot be recommended for these patients at the present time, since the ratio between the (slight) beneficial effects and the side effects was unfavourable. In patients with primary biliary cirrhosis, cholestasis slightly diminished after the administration of cyclosporine. Whether this improvement in laboratory parameters predicts an improved outcome in patients with primary biliary cirrhosis has yet to be demonstrated. Some patients with recently diagnosed insulin dependent diabetes needed no further insulin therapy as long as cyclosporine was administered. This is an observation of tremendous potential practical relevance for the future, when methodology may be available for diagnosing autoimmune destruction of beta-cells before clinically overt diabetes is present. Cyclosporine combined with prednisone was slightly more efficacious in patients with Graves' ophthalmopathy than prednisone alone. For all other autoimmune diseases, no controlled studies with cyclosporine are available at the present time. The most important side effects of cyclosporine are renal dysfunction, hypertension, gout, tremor, gingival hyperplasia and hypertrichosis. These side effects are manageable by appropriate dosage of cyclosporine and prophylactic measures. Side effects caused interruption of cyclosporine therapy in less than 5% of the patients. Thus, cyclosporine appears to be an efficacious new agent for treatment of some groups of patient with immune diseases.}, }
@article {pmid2341751, year = {1990}, author = {Färkkilä, AM and Iivanainen, MV and Färkkilä, MA}, title = {Disturbance of the water and electrolyte balance during high-dose interferon treatment.}, journal = {Journal of interferon research}, volume = {10}, number = {2}, pages = {221-227}, doi = {10.1089/jir.1990.10.221}, pmid = {2341751}, issn = {0197-8357}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Infusions, Intravenous ; Interferon Type I/administration &amp; dosage/*adverse effects/therapeutic use ; Random Allocation ; Single-Blind Method ; Water-Electrolyte Imbalance/*chemically induced ; }, abstract = {Ten patients with amyotrophic lateral sclerosis were treated during 5 consecutive days with intravenous infusion of high-dose human leukocyte interferon-alpha (IFN-alpha) or placebo in a single-blinded randomized trial. To assess the effect of IFN on the water and electrolyte balance, serum electrolytes, creatinine, and antidiuretic hormone as well as urine excretion of electrolytes, aldosterone, and cortisol were measured before the trial and during the fourth day of IFN infusion. Compared with placebo the results showed a significant reduction of the mean serum calcium level (from 2.28 +/- 0.03 mmole/liter to 2.01 +/- 0.06 mmole/liter; p less than 0.01), that of the mean serum osmolality (from 296 +/- 9.9 mosm/kgH2O to 281 +/- 2.5 mosm/kgH2O; p less than 0.05) and that of the mean urinary excretion of magnesium (from 5.32 +/- 2.04 mmoles/liter to 2.65 +/- 1.68 mmoles/liter; p less than 0.05). Careful observation of water and electrolyte balance is emphasized during high-dose IFN treatment.}, }
@article {pmid2157280, year = {1990}, author = {Meier, T and Meyer, M}, title = {[Peripheral neuropathy with monoclonal gammopathy].}, journal = {Schweizerische medizinische Wochenschrift}, volume = {120}, number = {12}, pages = {417-425}, pmid = {2157280}, issn = {0036-7672}, mesh = {Demyelinating Diseases/etiology/physiopathology ; Diagnosis, Differential ; Humans ; *Immunoglobulin M ; Immunoglobulin kappa-Chains ; Male ; Middle Aged ; Neural Conduction ; Paraproteinemias/*complications ; Peripheral Nervous System Diseases/diagnosis/*etiology ; }, abstract = {The case is reported of a patient with IgM-kappa paraproteinemia and polyneuropathy (PN) with very slow nerve conduction velocities. The association of demyelinating PN with severely decreased nerve conduction velocities and an IgM-kappa paraprotein usually suggests the diagnosis of monoclonal gammopathy of undetermined significance (MGUS), but less often of clinically manifest macroglobulinemia. Demyelinating PN with IgG-lambda- or IgA-lambda paraproteinemia occurs often in the uncommon but readily treatable osteosclerotic myeloma. A monoclonal protein combined with peripheral neuropathy involving predominant pain, temperature and autonomic loss (small fibre neuropathy) is by and large pathognomonic for primary systemic amyloidosis or amyloidosis associated with multiple myeloma or Waldenström's macroglobulinemia. Mild sensorimotor axonal polyneuropathy is an unspecific syndrome found in all gammopathies. It is important to differentiate between paraproteinemia with clinically pure chronic sensory PN and paraneoplastic sensory polyneuropathy. Unlike amyotrophic lateral sclerosis (ALS), paraproteinemias associated with a motor neuron disease-like syndrome sometimes evolve unusually slowly and exhibit neurophysiologically subclinical lesions of sensory nerve fibers. Mononeuropathy or multifocal neuropathy with a monoclonal protein is typical of cryoglobulinemia. Demyelinating PN of osteosclerotic myelomas presenting with one or a small number of bone lesions usually regress after excision or irradiation of the plasma cell proliferations. Immunosuppressants and plasmapheresis in the treatment of the demyelinating IgM-kappa neuropathies, of paraproteinemia with the motor neuron disease-like syndrome, and of mononeuropathy or multifocal neuropathy with cryoglobulinemia, are of doubtful value.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid1970145, year = {1990}, author = {Levy, DI and Sucher, NJ and Lipton, SA}, title = {Redox modulation of NMDA receptor-mediated toxicity in mammalian central neurons.}, journal = {Neuroscience letters}, volume = {110}, number = {3}, pages = {291-296}, doi = {10.1016/0304-3940(90)90862-4}, pmid = {1970145}, issn = {0304-3940}, support = {EY05477/EY/NEI NIH HHS/United States ; NS00879/NS/NINDS NIH HHS/United States ; }, mesh = {2-Amino-5-phosphonovalerate/pharmacology ; Action Potentials/drug effects ; Animals ; Cells, Cultured ; Dithionitrobenzoic Acid/pharmacology ; Dithiothreitol/*toxicity ; Oxidation-Reduction ; Rats ; Receptors, N-Methyl-D-Aspartate ; Receptors, Neurotransmitter/drug effects/*physiology ; Retina/*physiology ; Retinal Ganglion Cells/cytology/drug effects/*physiology ; }, abstract = {Acute neurological injury from hypoxia-ischemia, hypoglycemia, and trauma is thought to be predominantly mediated by activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in the brain and the subsequent influx of calcium ions through receptor-operated channels. Several chronic degenerative diseases, such as Huntington's disease and the amyotrophic lateral sclerosis-Parkinsonism-dementia complex found on Guam, may share a similar pathogenesis due to a glutamate-like toxin. This laboratory recently reported that exposure to a reducing agent, such as dithiothreitol (DTT), selectively increases ionic current flow through NMDA-activated channels in several types of central neurons; conversely, oxidizing agents reverse this effect. To investigate the novel influence of redox modulation on NMDA neurotoxicity, in the present in vitro study we monitored survival of an identified central neuron, the retinal ganglion cell, approximately 24 h after a brief exposure to DTT. To determine the degree of killing specifically related to activation of the NMDA receptor, 2-amino-5-phosphonovalerate (APV, a selective NMDA antagonist) was added to sibling cultures. APV-preventable, glutamate-induced death was increased 70 +/- 9% with DTT treatment. This effect was totally blocked by the concomitant addition of an oxidizing agent, 5,5-dithiobis-2-nitrobenzoic acid (DTNB). These findings suggest that the enhanced killing following chemical reduction with DTT is mediated at the NMDA receptor site, and that the redox state of the NMDA receptor is crucial for the survival of neurons facing glutamate-related injury.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid2408129, year = {1990}, author = {el Alaoui-Faris, M and Medejel, A and al Zemmouri, K and Yahyaoui, M and Chkili, T}, title = {[Amyotrophic lateral sclerosis syndrome of syphilitic origin. 5 cases].}, journal = {Revue neurologique}, volume = {146}, number = {1}, pages = {41-44}, pmid = {2408129}, issn = {0035-3787}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/drug therapy/*etiology/physiopathology ; Cerebrospinal Fluid/analysis ; Cerebrospinal Fluid Proteins/analysis ; Female ; Follow-Up Studies ; Humans ; Lymphocytosis/cerebrospinal fluid ; Male ; Middle Aged ; Neurosyphilis/*complications ; Penicillin G/therapeutic use ; Syndrome ; Syphilis Serodiagnosis ; }, abstract = {We studied 5 cases of syphilitic lateral amyotrophic sclerosis. The diagnosis was based on the presence of a lymphocytic reaction in the CSF and positive VDRL and TPHA reactions in both blood and CSF. Clinically, the disease affected the arms in 3 cases and produced paraplegia in 2 cases. The gradual extension of amyotrophy over several months, the diffusion of electromyographic abnormalities and the finding of spinal cord atrophy at myelography and CT suggested a subacute ischemic mechanism with meningo-myelic arteritis involving the anterior horns. After treatment with penicillin G in high doses, the outcome was constantly favourable, with improvement of motor deficit in 4 cases and stabilisation in 1 case in a 5 to 13 years' follow-up.}, }
@article {pmid2340845, year = {1990}, author = {Hartvig, P and Askmark, H and Aquilonius, SM and Wiklund, L and Lindström, B}, title = {Clinical pharmacokinetics of intravenous and oral 9-amino-1,2,3,4-tetrahydroacridine, tacrine.}, journal = {European journal of clinical pharmacology}, volume = {38}, number = {3}, pages = {259-263}, pmid = {2340845}, issn = {0031-6970}, mesh = {Administration, Oral ; Adult ; Aged ; Aminoacridines/*pharmacokinetics ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Biological Availability ; Chromatography, High Pressure Liquid ; Dizziness/chemically induced ; Female ; Humans ; Injections, Intravenous ; Male ; Middle Aged ; Models, Biological ; Tacrine/administration &amp; dosage/*pharmacokinetics/therapeutic use ; }, abstract = {The pharmacokinetics of 9-amino-1,2,3,4-tetrahydroacridine; tacrine, THA, was studied after intravenous administration and following the first and last oral doses of a seven week clinical trial involving 8 patients with amyotrophic lateral sclerosis, ALS. Two surgical patients given intravenous THA for reversal of postoperative sedation were also included. Plasma concentration of THA and in some cases the metabolite, 1-hydroxy-THA, were assayed using a selective and sensitive method with high performance liquid chromatography. After an intravenous dose of 30 mg THA, the plasma concentrations were fitted to a two-compartment model. Plasma clearance showed a threefold interindividual variation with a mean of 2.42 l.h-1. Volume of distribution, V alpha varied 100-680 l with a mean of 349 l. The plasma half-lives of distribution and elimination were 1.8 and 98.2 min, respectively. Oral bioavailability showed large interindividual differences and ranged 6-36% in the four subjects studied. After seven weeks treatment with oral THA, plasma concentrations immediately prior to medication were below 10 ng/ml in three patients and above 100 ng/ml in two patients. At the same occasion the plasma metabolite concentrations considerably exceeded those of THA. THA medication was associated with side effects in the majority of the patients.}, }
@article {pmid2330466, year = {1990}, author = {Pou Serradell, A and Roquer Gonzalez, J and Corominas Torres, JM and Lloreta Trull, J and Oliva Bielsa, J and Ugarte Elola, A}, title = {[Amyotrophic lateral sclerosis syndrome and hyperthyroidism. Cure with antithyroid drugs].}, journal = {Revue neurologique}, volume = {146}, number = {3}, pages = {219-220}, pmid = {2330466}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/*etiology ; Carbimazole/*therapeutic use ; Humans ; Hyperthyroidism/*complications/drug therapy ; Male ; Middle Aged ; }, abstract = {We report the case of a 62-year old man presenting with generalized muscular weakness, amyotrophy, dysarthria and dysphagia. Neurological examination showed bilateral pyramidal signs and lingual fasciculations. The clinical diagnosis was amyotrophic lateral sclerosis, since only shivers and weight loss pointed to hyperthyroidism. However, after several months the patient developed typical manifestations of hyperthyroidism. After treatment of hyperthyroidism, the neurological symptoms disappeared. Although this association is extremely rare, one must have in mind the possibility of thyroid dysfunction when studying patients with amyotrophic lateral sclerosis.}, }
@article {pmid2310461, year = {1990}, author = {Lamprecht, A}, title = {[Dysarthria, dysphagia or dyspnea as a reason for the initial consultation in pseudoparalytic myasthenia gravis and amyotrophic lateral sclerosis].}, journal = {Laryngo- rhino- otologie}, volume = {69}, number = {1}, pages = {48-51}, doi = {10.1055/s-2007-998140}, pmid = {2310461}, issn = {0935-8943}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*complications/diagnosis ; Deglutition Disorders/*etiology ; Diagnosis, Differential ; Dysarthria/*etiology ; Dyspnea/*etiology ; Female ; Humans ; Male ; Middle Aged ; Myasthenia Gravis/*complications/diagnosis ; Speech Disorders/*etiology ; }, abstract = {In myasthenia gravis and amyotrophic lateral sclerosis the ENT specialist or the phoniatrician may be consulted first, because in about 30 percent of all cases the initial symptoms are dysarthria, dysphagia or dyspnea. Three typical cases of each condition are presented. The quality of life of the patients can be improved considerably by early diagnosis and treatment. Special diagnostic and therapeutic procedures are described.}, }
@article {pmid2132052, year = {1990}, author = {Szulc-Kuberska, J and Klimek, A and Stepień, H and Woszczak, M}, title = {[Clinical trial of the treatment of amyotrophic lateral sclerosis with bromocriptine].}, journal = {Neurologia i neurochirurgia polska}, volume = {24}, number = {1-2}, pages = {37-41}, pmid = {2132052}, issn = {0028-3843}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Bromocriptine/administration &amp; dosage/*therapeutic use ; Dose-Response Relationship, Drug ; Female ; Humans ; Hypothalamus/drug effects ; Male ; Middle Aged ; Receptors, Dopamine/drug effects ; Time Factors ; }, abstract = {The authors accepting the hypotesis that in amyotrophic lateral sclerosis the hypothalamic dopamine receptor function is impaired tried to treat this disease with bromocryptine as an agonist of this receptor. The observation was carried out in 19 patients with moderately advanced amyotrophic lateral sclerosis. Bromocryptine was given to the patients in tablets Parlodel Sandoz 7.5 mg daily. No improvement was noted in the efficiency of the muscles of extremities in most patients. The improvement in the function of isolated muscles tested by Lovette's test was transient. A trial of treatment with low bromocryptine doses for short time periods (3 weeks to 4 months) was considered by the authors as unsuccessful.}, }
@article {pmid2132051, year = {1990}, author = {Klimek, A and Szulc-Kuberska, J and Stepień, H}, title = {[Effect of thyroliberin treatment on the thyrotropin and prolactin levels in patients with amyotrophic lateral sclerosis].}, journal = {Neurologia i neurochirurgia polska}, volume = {24}, number = {1-2}, pages = {31-36}, pmid = {2132051}, issn = {0028-3843}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/blood/*drug therapy ; Female ; Humans ; Male ; Middle Aged ; Prolactin/*blood ; Thyrotropin/*blood ; Thyrotropin-Releasing Hormone/*therapeutic use ; }, abstract = {The blood serum TSH and PRL levels were studied in 12 ALS patients after TRH stimulation. The TSH test was repeated after 4-weeks TRH treatment. The results were compared with the data obtained in the control group. It was shown that after TRH stimulation the TSH responses did not reveal greater abnormalities, but PRL responses were significantly diminished. The results could confirm our previous observations concerning the dysregulation of dopamine metabolism in ALS patients.}, }
@article {pmid1691801, year = {1990}, author = {Iwamura, Y and Yoshiba, M and Sugata, F}, title = {[Treatment of fulminant hepatitis with highly reliable artificial liver support and administration of interferon].}, journal = {Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology}, volume = {87}, number = {1}, pages = {109-118}, pmid = {1691801}, issn = {0446-6586}, mesh = {Acute Disease ; Adult ; Aged ; Combined Modality Therapy ; Evaluation Studies as Topic ; Female ; *Hemofiltration/methods ; Hepatitis, Viral, Human/pathology/*therapy ; Humans ; Interferons/*therapeutic use ; Male ; Membranes ; Methylmethacrylates ; Middle Aged ; *Plasma Exchange ; *Renal Dialysis/methods ; }, abstract = {We treated 10 patients with viral fulminant hepatitis (FH) and subacute hepatitis (SH) by highly reliable artificial liver support (ALS), the combination of plasma exchange (PE) and hemodiafiltration (HDF) using polymethyl methacrylate (PMMA) membrane. All patients regained clear consciousness by the ALS. Even the patients with long term hepatic failure up to for 108 days were sustained in a favorable clinical condition. Five patients finally survived. Interferon was administered to one case with type B FH with positive HBeAg, four cases with NANB FH and SH who were assumed to have persistent viral replication. Two of them showed favorable clinical responses and definite liver regeneration was confirmed. The intensive liver support which can sustain patient with severe fulminant hepatic failure accompanied by the administration interferon is believed to be the most effective treatment for FH and SH especially caused by NANB virus in our country.}, }
@article {pmid1690486, year = {1990}, author = {Dreikorn, K and Richter, R and Schönhöfer, PS}, title = {[Conservative, non-hormonal treatment of benign prostatic hyperplasia].}, journal = {Der Urologe. Ausg. A}, volume = {29}, number = {1}, pages = {8-16; discussion 17-8}, pmid = {1690486}, issn = {0340-2592}, mesh = {Adrenergic alpha-Antagonists/therapeutic use ; Anticholesteremic Agents/therapeutic use ; Humans ; Male ; Palliative Care/methods ; Plant Extracts/therapeutic use ; Prostatic Hyperplasia/*therapy ; Tissue Extracts/therapeutic use ; Urinary Bladder Neck Obstruction/therapy ; }, abstract = {The indications for and efficacy of non-hormonal drugs in the treatment of benign prostatic hyperplasia (BPH) are the subject of some controversy. However, a critical evaluation of the available literature shows that no clinically relevant reduction of prostatic size has been reached with any drug tested so far. It is suggested that alpha-adrenergic blockers exert a beneficial effect by reducing the "dynamic" component associated with prostatic obstruction. The application of objective criteria has not shown cholesterol-lowering and phytotherapeutic drugs to have any significant and clinically relevant advantage over placebos. The evaluation of drug therapy in BPH patients is complicated by the fact that the obstructive signs are masked by irritative symptoms ("prostatism", "unstable bladder"), the causes of which are also unknown. A causal drug therapy should have an impact on biochemically and/or biologically confirmed changes that are responsible for the development of BPH. Als long as the cause of BPH remains unknown, drugs cannot fulfil these requirements. The efficacy of drug therapy in patients with BPH can only, therefore, be evaluated in double blind controlled studies including modern urodynamic investigations. However, these standards should also be applied to the decision as to whether operative treatment is indicated and to evaluation of the results.}, }
@article {pmid2697901, year = {1989}, author = {Bonduelle, M}, title = {[Amyotrophic lateral sclerosis. In search of its etio-pathogenic mechanisms].}, journal = {Recenti progressi in medicina}, volume = {80}, number = {12}, pages = {659-664}, pmid = {2697901}, issn = {0034-1193}, mesh = {Amyotrophic Lateral Sclerosis/*etiology/genetics/immunology/physiopathology/therapy ; Humans ; }, abstract = {The etiological problem of ALS has still not been resolved although a large amount of work, more and more technical, has been devoted in the fields of immunology, virology, environment and genetics. This research is related to spinal amyotrophies in general--to motor neuron diseases--and it is only as an analogy or as a model that the results may be used in the specific case of ALS. The genetic hypothesis of ALS is suggested by family cases (in adults) and seems to be linked to Parkinson and Alzheimer diseases; all of these are 'degenerative' nervous diseases and there are examples of their association. Research is being done in anatomy, embryogenesis, neurochemistry, molecular genetics to investigate the pathophysiology of neuron considered the only way to develop a specific therapy. The treatment, although still symptomatic, is improving due to technical progress in management.}, }
@article {pmid2685660, year = {1989}, author = {Lacomblez, L and Bouche, P and Bensimon, G and Meininger, V}, title = {A double-blind, placebo-controlled trial of high doses of gangliosides in amyotrophic lateral sclerosis.}, journal = {Neurology}, volume = {39}, number = {12}, pages = {1635-1637}, doi = {10.1212/wnl.39.12.1635}, pmid = {2685660}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials as Topic ; Double-Blind Method ; Drug Administration Schedule ; Gangliosides/*administration &amp; dosage/adverse effects/therapeutic use ; Humans ; Placebos ; }, abstract = {We performed a 3-month, double-blind, placebo-controlled trial of 300 mg of gangliosides (Cronassial) in 40 outpatients with amyotrophic lateral sclerosis (ALS). We evaluated drug effect through physical examinations and symptom scales. Though this dosage had no major toxic effect, Cronassial treatment did not significantly benefit ALS patients.}, }
@article {pmid2614587, year = {1989}, author = {Ryan, DP and Carson, MG and Zorzitto, ML}, title = {The first international conference on the Palliative Care of the Elderly: an overview.}, journal = {Journal of palliative care}, volume = {5}, number = {4}, pages = {40-42}, pmid = {2614587}, issn = {0825-8597}, mesh = {Aged ; Attitude to Death ; *Congresses as Topic ; Cross-Cultural Comparison ; Ethics, Medical ; Humans ; Models, Theoretical ; Ontario ; Patient Advocacy ; *Terminal Care ; }, abstract = {The effort to examine and improve palliative care for the elderly is actively joined. In Europe, Scandinavia, and North America, at least, issues are slowly being examined in clinical research. The response to the conference was enthusiastic, and new information emerged, for example: British Columbia's "Levels of Intervention" guidelines, Dr Doyle's description of new developments in Geriatric and Palliative Care training and service in the United Kingdom, Dr Triau et al's (Psychogeriatric Nursing Home, Leuven, Belgium) normalization model of care for dementia, and Dr Rory Fisher's argument that instead of using negative DNR orders in palliative care we should instead take a positive approach of specifying what palliative care can provide. Palliative care is not "no treatment;" increasingly we are able to be concrete and specific in our ability to prescribe a range of measures to ensure that our dying elderly die in comfort and without medical, legal, or social intrusion.}, }
@article {pmid2614487, year = {1989}, author = {Testa, D and Caraceni, T and Fetoni, V}, title = {Branched-chain amino acids in the treatment of amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {236}, number = {8}, pages = {445-447}, pmid = {2614487}, issn = {0340-5354}, mesh = {Aged ; Amino Acids, Branched-Chain/*therapeutic use ; Amyotrophic Lateral Sclerosis/*drug therapy ; Female ; Humans ; Male ; Middle Aged ; }, abstract = {Thirty-two patients affected by amyotrophic lateral sclerosis (ALS) were included in a controlled, open therapeutic trial with branched chain amino acids (BCAA). Patients with bulbar muscle involvement were evaluated separately. No statistically significant differences were found in the clinical outcome between the patients treated and the control groups. Blood L-glutamate levels measured in eight patients were normal. The failure of BCAA in the treatment of the patients could be due to different disorders with unpredictable outcome included under the diagnosis of ALS.}, }
@article {pmid2532666, year = {1989}, author = {Kim, TS}, title = {Hope as a mode of coping in amyotrophic lateral sclerosis.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {21}, number = {6}, pages = {342-347}, doi = {10.1097/01376517-198912000-00003}, pmid = {2532666}, issn = {0888-0395}, mesh = {*Adaptation, Psychological ; Adult ; Amyotrophic Lateral Sclerosis/*nursing/psychology ; Existentialism ; Humans ; Male ; *Morale ; Nurse-Patient Relations ; *Patient Care Planning ; Quality of Life ; Self Concept ; }, abstract = {The purpose of this article is to emphasize the role of hope as a mode of coping in patients with amyotrophic lateral sclerosis (ALS). When taking care of patients with ALS, a rapidly progressing fatal disease which has no known cure or treatment and obscure etiology, the nurse's primary aim is to assist the patient to live as fully as possible within limitations imposed by the disease. An analysis of tasks involved in the hoping process can be used as guidelines for nursing intervention with ALS patients and their families.}, }
@article {pmid2686140, year = {1989}, author = {Hansen, PR}, title = {[Autoimmune neuropathy].}, journal = {Ugeskrift for laeger}, volume = {151}, number = {44}, pages = {2870-2873}, pmid = {2686140}, issn = {0041-5782}, mesh = {Autoantibodies/analysis ; Chronic Disease ; Demyelinating Diseases/immunology ; Humans ; Immunoglobulin M/analysis ; Nervous System Diseases/*immunology ; }, abstract = {Chronic progressive polyneuropathy is frequently cryptogenic but occurs in association with monoclonal gammopathy. In cases of this type, a relatively mild, mainly axonal sensomotor neuropathy is frequently present and may be difficult to distinguish from carcinomatous neuropathy in malignant conditions without the presence of the M-component. In benign essential gammopathy (MGUS) with an M-component of IgM-kappa class, the neuropathy is frequently demyelinizing and the paraprotein reacts specifically with carbohydrate determinants in myelin-associated glycoprotein (MAG) and other glycoproteins and glycolipids in peripheral nerve tissue. Demonstration is undertaken by immune fluorescence investigation (eg on skin biopsy material) whereas serological diagnosis involves difficulties. There is much evidence to suggest that the autoimmune reaction is of significance for the development of nerve damage and uncontrolled trials have shown beneficial effects of immune suppression including plasmapherisis. The latter treatment should be considered in the Guillain-Barré syndrome, neuropathy and HIV-infection and also in motor neurone disease and IgM-MGUS, in which autoimmunological mechanisms may also be of pathophysiological significance.}, }
@article {pmid2791569, year = {1989}, author = {Barrier, G}, title = {Emergency medical services for treatment of mass casualties.}, journal = {Critical care medicine}, volume = {17}, number = {10}, pages = {1062-1067}, doi = {10.1097/00003246-198910000-00020}, pmid = {2791569}, issn = {0090-3493}, mesh = {Disaster Planning/*methods ; Emergency Medical Services/*organization &amp; administration ; France ; Humans ; Regional Medical Programs ; Trauma Severity Indices ; Triage ; Violence ; Wounds and Injuries/classification/*therapy ; }, abstract = {The French emergency medical system (EMS) is the Service d'Aide Médicale Urgente (SAMU). In case of mass casualties, involving 100 simultaneous victims, SAMU has developed a disaster plan, "The White Plan." This plan is closely correlated to the Red Plan of the Fire Department, to provide advanced life support (ALS) at the incident site, followed in a continuum by medical transport and hospitalization in the appropriate services. To obtain the best chance of survival and recovery, there must be optimal coordination among all rescuers. This objective was approached by adopting a formal protocol designed for each city. In France, the medical organization for the treatment of casualties is operated by anesthesiologists who are qualified to perform ALS, preanesthetic evaluation en route, anesthesia for the multitrauma patient, and postanesthetic resuscitation in a continuum from the accident scene to the ICU.}, }
@article {pmid2473065, year = {1989}, author = {Baxter, RC and Martin, JL and Beniac, VA}, title = {High molecular weight insulin-like growth factor binding protein complex. Purification and properties of the acid-labile subunit from human serum.}, journal = {The Journal of biological chemistry}, volume = {264}, number = {20}, pages = {11843-11848}, pmid = {2473065}, issn = {0021-9258}, mesh = {Carrier Proteins/*isolation &amp; purification/physiology ; Chromatography, Liquid ; Electrophoresis, Polyacrylamide Gel ; Humans ; Insulin-Like Growth Factor Binding Proteins ; Molecular Weight ; Radioimmunoassay ; Somatomedins/*isolation &amp; purification/physiology ; }, abstract = {In the human circulation, the insulin-like growth factors (IGFs) circulate as part of a growth hormone-dependent 125- to 150-kDa complex. This complex has been postulated to contain, in addition to IGFs and one or more IGF-binding proteins, an acid-labile subunit (ALS) which does not itself bind IGFs. In this study, the ALS has been purified 1600-fold from human serum, and its binding properties have been examined. Fresh serum was fractionated on DEAE-Sephadex, and active fractions (determined by radioimmunoassay) were purified by affinity chromatography on an IGF-agarose column saturated with the plasma IGF-binding protein BP-53. After further high performance anion exchange chromatography, an ALS preparation was obtained which contained only an 84-86-kDa protein doublet, converting to a single 70-kDa band on N-glycanase treatment, and having an amino-terminal sequence unrelated to IGF-binding proteins or receptors. Pure ALS formed a complex with BP-53 (Ka approximately 5 x 10(8) M-1), immunoprecipitable by anti-BP-53 antiserum, only in the presence of IGF-I or IGF-II. This complex appeared at approximately 150 kDa on high performance gel chromatography. Pure ALS had no intrinsic IGF-binding activity and no effect on the binding of IGF-I or IGF-II to BP-53. These studies suggest that formation of the high molecular weight IGF-binding protein complex requires ALS, BP-53, and IGF.}, }
@article {pmid2733125, year = {1989}, author = {Ballantyne, CM and Podet, EJ and Patsch, WP and Harati, Y and Appel, V and Gotto, AM and Young, JB}, title = {Effects of cyclosporine therapy on plasma lipoprotein levels.}, journal = {JAMA}, volume = {262}, number = {1}, pages = {53-56}, pmid = {2733125}, issn = {0098-7484}, support = {RR-00350/RR/NCRR NIH HHS/United States ; }, mesh = {Adult ; Age Factors ; Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Arteriosclerosis/chemically induced ; Cholesterol/blood ; Cyclosporins/administration &amp; dosage/*pharmacology ; Double-Blind Method ; Fasting ; Humans ; Lipoproteins/*blood ; Lipoproteins, LDL/blood ; Liver/metabolism ; Male ; Middle Aged ; Prospective Studies ; Random Allocation ; Triglycerides/blood ; }, abstract = {Accelerated atherosclerosis is a leading cause of death in long-term survivors of heart and renal transplantation and may be exacerbated by the frequent occurrence of posttransplant hyperlipidemia. Attempts to define the mechanism for hyperlipidemia in transplant recipients are confounded by dramatic changes in metabolism and nutritional status after transplantation, as well as by treatment with multiple immunosuppressive and antihypertensive drugs. To avoid these pitfalls and to determine if cyclosporine alone adversely affects lipid levels, we measured lipoprotein levels in a prospective, double-blind, randomized, placebo-controlled trial of cyclosporine in 36 men with amyotrophic lateral sclerosis. Plasma total cholesterol, triglyceride, high-density lipoprotein cholesterol, and apolipoprotein B levels were measured at baseline, 2 weeks, 1 month, and 2 months. Significant increases of 21% in total cholesterol, 31% in low-density lipoprotein cholesterol, and 12% in apolipoprotein B levels occurred only in the cyclosporine group. Cyclosporine therapy alone adversely affects plasma lipoprotein levels by increasing total cholesterol levels, primarily due to an increase in low-density lipoprotein cholesterol level.}, }
@article {pmid2593966, year = {1989}, author = {Alessio, L and Apostoli, P and Ferioli, A and Di Sipio, I and Mussi, I and Rigosa, C and Albertini, A}, title = {Behaviour of biological indicators of internal dose and some neuro-endocrine tests in aluminium workers.}, journal = {La Medicina del lavoro}, volume = {80}, number = {4}, pages = {290-300}, pmid = {2593966}, issn = {0025-7818}, mesh = {Aluminum/adverse effects/*analysis ; Biomarkers/*analysis ; Blood Donors ; Environmental Exposure ; Female ; Humans ; Hypothalamo-Hypophyseal System/drug effects ; Italy ; Male ; *Metallurgy ; Metals/adverse effects/*analysis ; Occupational Diseases/*prevention &amp; control ; Pituitary Hormones, Anterior/*blood ; Reference Values ; *Welding ; }, abstract = {The authors present the results of toxicological studies on aluminium from 1983 to 1988. In order to obtain reference values for serum and urine aluminium, 506 healthy adults, not occupationally exposed to the metal, residing in the Brescia area were studied. The following values were obtained: AlS = 5.8 +/- 2.9 micrograms/l; AlU 11.9 +/- 4.3 micrograms/l. The AlU and AlS values did not differ in relation to age, sex, alcohol consumption, smoking habits and residence, contrary to what has been found for some metals determined in the urine and/or blood of the same subjects. In a group of 227 subjects with occupational exposure to aluminium within the range 0.1-1.0 mg/m3, the mean levels of AlU were higher than that of the reference population; however the AlU of the workers were generally lower than 20 micrograms/l which is the upper limit for the reference population; 4 workers who were under treatment with antiacid preparations showed AlU values higher than 150 micrograms/l. Seven workers exposed to atmospheric aluminium concentrations around the TLV-TWA had higher AlU values at the end of their shift on all working days and on Friday morning the values where higher than those encountered on Monday morning. On the other hand no daily and weekly fluctuations were evident for AlS. For 14 workers the relationship between AlU and AlS values were examined in three subsequent periods after the start of working activity. Considering the same values of AlU, it was observed that the AlS increased with the duration of exposure. These results seem to indicate that AlU could be considered as indicator of current exposure and AlS as an indicator of cumulative exposure. Neuroendocrine tests were performed every 6 months in 21 workers after they had been hired. PRL and TSH values were reduced after 1 year of work and were still reduced 6 months later. Further analyses showed a different behaviour: in fact the levels of the two hormones rose above the reference values, while the HGH and other gonadotropins showed no alterations. These results seem to indicate that at the start of exposure to aluminium concentrations below TLV-TWA there is an effect on the hypothalamus-pituitary axis. This phenomenon is probably transient perhaps because of an adaptation mechanism. Further studies are however necessary to verify these results.}, }
@article {pmid2660234, year = {1989}, author = {Meininger, V}, title = {[Treatment of amyotrophic lateral sclerosis].}, journal = {La Revue du praticien}, volume = {39}, number = {14}, pages = {1237-1240}, pmid = {2660234}, issn = {0035-2640}, mesh = {Amyotrophic Lateral Sclerosis/drug therapy/physiopathology/*therapy ; Humans ; }, }
@article {pmid2706418, year = {1989}, author = {van der Voet, GB and Dijkmans, BA and Frankfort, C and de Wolff, FA}, title = {Elevation of serum aluminium concentrations in patients with rheumatoid arthritis treated with drugs containing aluminium.}, journal = {British journal of rheumatology}, volume = {28}, number = {2}, pages = {144-146}, doi = {10.1093/rheumatology/28.2.144}, pmid = {2706418}, issn = {0263-7103}, mesh = {Adult ; Aged ; Aged, 80 and over ; Aluminum/blood/*therapeutic use ; Arthritis, Rheumatoid/blood/*drug therapy ; Creatinine/blood ; Female ; Humans ; Male ; Middle Aged ; Osmolar Concentration ; }, abstract = {In a group of 19 rheumatoid arthritis (RA) patients with normal renal function, serum levels of aluminium (AlS) were monitored during treatment with drugs containing this metal (Al). The AlS levels during treatment were significantly higher (0.005 less than p less than 0.01) than those before treatment, i.e. 19.4 (SEM 2.3) micrograms/l and 12.3 (1.7), respectively. This increase in AlS was significantly (0.025 less than p less than 0.05) correlated with the pretreatment serum creatinine level (mean value for the whole group 80.5 (SEM 4.7) mumol/l) but showed no correlation with the predicted creatinine clearance. Although the increase in AlS during therapy with A1 containing drugs is not dramatic in RA patients with normal renal function, the rheumatologist should be aware of the risk of increased AlS concentration in RA patients, especially those with impaired renal function.}, }
@article {pmid2563937, year = {1989}, author = {Miller, SC and Warnick, JE}, title = {Protirelin (thyrotropin-releasing hormone) in amyotrophic lateral sclerosis. The role of androgens.}, journal = {Archives of neurology}, volume = {46}, number = {3}, pages = {330-335}, doi = {10.1001/archneur.1989.00520390096025}, pmid = {2563937}, issn = {0003-9942}, support = {NS-21312/NS/NINDS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/etiology ; Androgens/pharmacology ; Animals ; Humans ; Neurotransmitter Agents/pharmacology ; Rats ; Receptors, Neurotransmitter/metabolism ; Receptors, Thyrotropin-Releasing Hormone ; Sex Factors ; Spinal Cord/drug effects ; Thyrotropin-Releasing Hormone/administration &amp; dosage/pharmacology/*therapeutic use ; }, abstract = {Protirelin (thyrotropin-releasing hormone) appears to be a neuromodulator in the extrahypothalamic nervous system and has been suggested as an adjunct in the treatment of amyotrophic lateral sclerosis (ALS). Clinical studies have been divided on the efficacy of protirelin (TRH) despite strong experimental findings that are consistent with a role for the peptide in ALS. Recent findings provide evidence of a gender-related specificity in the ability of protirelin to potentiate the monosynaptic reflex. While castration in male neonatal rats lowered the sensitivity to protirelin, testosterone treatment restored that sensitivity. An examination of the clinical studies reveals a failure either to identify patients' sex or to separate the results on the basis of sex. These findings provide convincing evidence for the potential efficacy of protirelin in ALS if the patient's sex and underlying hormonal status are taken into account.}, }
@article {pmid2703145, year = {1989}, author = {Bortolotti, M}, title = {Laryngospasm and reflex central apnoea caused by aspiration of refluxed gastric content in adults.}, journal = {Gut}, volume = {30}, number = {2}, pages = {233-238}, pmid = {2703145}, issn = {0017-5749}, mesh = {Airway Obstruction/etiology ; Esophagitis/complications ; Esophagus/physiopathology ; Gastric Emptying ; Gastroesophageal Reflux/*complications ; Humans ; Hydrogen-Ion Concentration ; Laryngismus/*etiology ; Male ; Middle Aged ; Pneumonia, Aspiration/*complications ; Pressure ; Respiratory Insufficiency/etiology ; Sleep Apnea Syndromes/*etiology ; }, abstract = {Two patients with attacks of choking caused by aspiration of gastric contents in the laryngotracheal tube are presented. One had such severe attacks of respiratory arrest, that tracheostomy was done. The common symptoms of gastro-oesophageal reflux such as pirosis, acid regurgitation, or retrosternal burning were absent in both patients and upper gut radiological and endoscopic examinations were negative. Histology of the oesophageal mucosa showed a deep chronic eosophagitis, and the 24-hour pH-monitoring of the upper oesophagus showed frequent gastro-oesophageal refluxes. Manometry showed hypotonic lower oesophageal sphincter with marked alterations of peristalsis. In the patient with tracheostomy a 24 pH monitoring of the hypolaryngeal zone showed decreased pH at the time of choking attacks. In the other patient further investigations showed that amyotrophic lateral sclerosis was the cause of the oesophageal motility disorder. An intense antireflux treatment abolished the respiratory attacks in both patients.}, }
@article {pmid2921111, year = {1989}, author = {Hillel, AD and Miller, R}, title = {Bulbar amyotrophic lateral sclerosis: patterns of progression and clinical management.}, journal = {Head &amp; neck}, volume = {11}, number = {1}, pages = {51-59}, doi = {10.1002/hed.2880110110}, pmid = {2921111}, issn = {1043-3074}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications/*diagnosis/physiopathology ; Bulbar Palsy, Progressive/etiology ; Female ; Humans ; Lip Diseases/etiology ; Medulla Oblongata/*physiopathology ; Middle Aged ; Respiratory Paralysis/etiology ; Speech Disorders/etiology ; Tongue Diseases/etiology ; }, abstract = {Patients with bulbar amyotrophic lateral sclerosis (ALS) are often referred to the otolaryngologist/head and neck surgeon and speech pathologist for evaluation and management of dysphagia and dysarthria. These patients comprise an unusual group because of the progressive and multi-system nature of their illness. The neuromuscular disabilities associated with bulbar ALS cause a myriad of related symptoms associated with swallowing, speech, and respiration. Although the rate of progression cannot be predicted, a general pattern of progression is noted. Bulbar disease accounts for the majority of the worst symptoms of ALS. The loss of the ability to swallow changes eating from a pleasurable task to a burden of survival. Loss of communication effectively imprisons the patient in a state of isolation. The progressive weakness of respiration, predominantly a spinal rather than bulbar manifestation, is the cause of death for nearly all ALS patients and is also discussed. The general patterns of progression of bulbar ALS are outlined in this paper. The development of symptoms are correlated with specific treatment recommendations to aid the clinician in devising an orderly plan of management for this progressive disease.}, }
@article {pmid2911875, year = {1989}, author = {Diflo, T and Maki, T and Balogh, K and Monaco, AP}, title = {Graft-versus-host disease in fully allogeneic small bowel transplantation in the rat.}, journal = {Transplantation}, volume = {47}, number = {1}, pages = {7-11}, doi = {10.1097/00007890-198901000-00003}, pmid = {2911875}, issn = {0041-1337}, support = {AI14551-10/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Graft vs Host Disease/*immunology/pathology ; Intestine, Small/*transplantation ; Lymph Nodes/pathology ; Organ Size ; Rats ; Rats, Inbred Strains ; Skin/pathology ; Spleen/pathology ; }, abstract = {Small bowel and its mesentery contain considerable amounts of lymphoid tissue that can mediate graft-versus-host disease in small bowel transplant (SBT) recipients. Present studies determined the existence of GVHD in a fully allogeneic SBT model and examined the effect of donor pretreatment with ALS in eliminating GVHD. Adult male Lewis (Lew) rats received orthotopic small bowel transplants from untreated (LewxBN)F1 (LBNF1) donors (group 1) or Brown Norway (BN) donors that were untreated (group 2) or pretreated with ALS (days -2 and -1) (group 3). All recipients were treated with cyclosporine 15 mg/kg/day i.m. on days 0-6 postoperatively. Animals were weighed and examined daily for signs of rejection and GVHD. No animals in groups 1 or 3 showed any physical signs of GVHD, but all of those in group 2 had characteristic weight loss, diarrhea, and dermatitis between 4 and 6 weeks postoperatively, from which they all recovered. Histologic examination of skin and spleen at this time confirmed the presence of GVHD. The relative spleen weight [(spleen weight/body weight] x 100) of group 2 animals was also significantly greater than that of unoperated control Lew animals. Spleen cells obtained from group 2 animals at the time of subclinical GVHD, but not cells from group 1 or 3 animals, caused enlargement of popliteal lymph nodes when they were injected into the footpads of Lew rats. This study shows that GVHD can manifest itself in recipients of a fully allogeneic small bowel transplant even when rejection is prevented by effective immunosuppression with CsA. However, combined use of recipient treatment with CsA and pretreatment of donor animals with ALS eliminates all manifestations of GVHD.}, }
@article {pmid2725806, year = {1989}, author = {Hillel, AD and Miller, RM and Yorkston, K and McDonald, E and Norris, FH and Konikow, N}, title = {Amyotrophic lateral sclerosis severity scale.}, journal = {Neuroepidemiology}, volume = {8}, number = {3}, pages = {142-150}, doi = {10.1159/000110176}, pmid = {2725806}, issn = {0251-5350}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis ; Arm ; Deglutition ; Female ; Follow-Up Studies ; Humans ; Leg ; Male ; Middle Aged ; Movement ; Speech Articulation Tests ; Vital Capacity ; }, abstract = {The amyotrophic lateral sclerosis (ALS) severity scale has been developed to provide an ordinal staging system and a means of rapid functional assessment for patients with ALS. The scale allows an examiner to evaluate the symptoms of ALS numerically in four categories that describe speech, swallowing, lower extremity, and upper extremity abilities. These scores, combined with a vital capacity measured on a hand-held respirometer, provide a rapid, accurate assessment of a patient's disease status and can be used for treatment planning. The ALS severity scale has been shown to have an average estimated reliability coefficient of 0.95 between examiners. Speech ratings were correlated greater than 0.80 for objective speech measures. Rates of progression of the total score in a small group of patients ranged from -3.4 to -24.0 points/year with a mean of -11.3 points/year.}, }
@article {pmid2646683, year = {1989}, author = {Mathe, JF and Fève, JR and Labat, JJ and De Kersaint Gilly, A and Potagas, C and Dubois, C}, title = {[Ischemia of the anterior horn of the spinal cord].}, journal = {Revue neurologique}, volume = {145}, number = {1}, pages = {60-64}, pmid = {2646683}, issn = {0035-3787}, mesh = {Adolescent ; *Anterior Horn Cells ; Female ; Humans ; Ischemia/diagnosis/*etiology ; Male ; Middle Aged ; *Motor Neurons ; Spinal Cord/*blood supply ; }, abstract = {Ischemia of the motoneurons in the anterior horn is a well known pathological entity. Their clinical signs and symptoms are similar to those of amyotrophic lateral sclerosis. Evidence by selective angiography of angiomas of the spinal cord or compression or deviation of Adamkiewicz artery may be suggestive of an initial vascular lesion. Various data (knowledge of development or lesions during experimental ischemia, selective electrophysiologic analysis of anterior horn neurons, evidence of precise circumstances of spinal vascular disorder or spinal arteriography) suggest that anterior horn ischemia is a multiple aspect phenomenon. Our 4 cases illustrate this hypothesis and demonstrate under confirmed vascular circumstances the different clinical aspects of anterior horn ischemic lesions. In addition to typical amyotrophic paralysis unusual or misleading symptoms may occur such as claudication, paroxysmal contractures or progressive spastic paraparesis. Investigations required and possible treatment of the lesions are simplified by awareness of these various clinical aspects.}, }
@article {pmid2561585, year = {1989}, author = {Cruz Martínez, A and Lara, M and Villoslada, C}, title = {[Peripheral neuropathy in HIV infection].}, journal = {Archivos de neurobiologia}, volume = {52 Suppl 1}, number = {}, pages = {79-92}, pmid = {2561585}, issn = {0004-0576}, mesh = {Acquired Immunodeficiency Syndrome/*complications ; Adult ; Biopsy ; Female ; Humans ; Male ; Middle Aged ; Peripheral Nervous System Diseases/*etiology/pathology/physiopathology/therapy ; }, abstract = {Neuropathy may complicate all stages of human immunodeficiency virus infection (HIV). Different types of peripheral neuropathy and myelopathy have been reported associated with HIV infection: sensory symmetrical polyneuropathy, acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, mononeuropathy multiplex, sensory ataxic neuropathy (ganglioneuronitis), cauda equina syndrome, amyotrophic lateral sclerosis, spastic paraparesia, and subclinical neuropathy diagnosed by electrophysiologic study. We describe the main clinical, electrophysiological and pathological features in these different types of neuropathy and comment their pathogenesis and treatment. Results in our series of twenty-two patients are also reported. In this series we want to underline three cases in which a chronic demyelinating polyneuropathy was the first manifestation of HIV infection. Thus, patients with predominantly motor demyelinating neuropathies and suspicious risk factors should be screened for silent HIV infection.}, }
@article {pmid2497685, year = {1989}, author = {Brooks, BR}, title = {A summary of the current position of TRH in ALS therapy.}, journal = {Annals of the New York Academy of Sciences}, volume = {553}, number = {}, pages = {431-461}, pmid = {2497685}, issn = {0077-8923}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Research Design ; Thyrotropin-Releasing Hormone/adverse effects/*therapeutic use ; }, abstract = {The critical points that must be addressed in evaluating ergotropic drugs are exemplified by the current morass of positive and negative results that have been obtained in clinical investigations of TRH or its analogues. Appropriate subject selection is crucial. These patients may have bulbar symptoms, and those features of ALS should be specifically assayed for treatment effects relative to placebo. Gender-specific effects of TRH need to be accounted for in study design. In addition, electrophysiological techniques such as single fiber density may help determine the responsiveness of patients to TRH or its analogues. The clinical significance of an increase in fiber density following TRH or other drugs should be determined, as it will provide insight into the state of motor neurons in the spinal cord of patients with ALS and possibly could be important in determining those who may respond to TRH if such a response is possible. Clinical studies have quite clearly shown conflicting results. Basic studies, however, have shown that response to TRH is state dependent, that is, whether the patient is male or female. Clinical studies have shown that response to TRH is state dependent, that is, it depends on whether the patient has bulbar or nonbulbar signs and is male or female. Future studies must take into consideration this state dependence as a specific feature of the pharmacological action of TRH and its analogues.}, }
@article {pmid2493673, year = {1989}, author = {Bouche, P and Castaigne, P and Meininger, V}, title = {[Management of amyotrophic lateral sclerosis].}, journal = {Revue neurologique}, volume = {145}, number = {1}, pages = {49-54}, pmid = {2493673}, issn = {0035-3787}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Delivery of Health Care ; Health Services ; Humans ; Long-Term Care ; Time Factors ; }, abstract = {There is no specific treatment for patients with amyotrophic lateral sclerosis. Nevertheless several associations of patients have been created to stimulate the research to find the causes and treatments of the disease and to help the patients. In spite of the absence of a specific treatment, new symptomatic therapeutic resources have been recently introduced in order to modify the management and in some cases to improve the condition of patients with ALS. Among these resources, it is worth outlining those which are devoted to the medulla trouble such as the permanent gastric tubes. The respiratory insufficiency is an early phenomenon and is considered the main prognostic factor. Its management should become soon one of the main therapeutic targets. In some countries the indications of devices for respiratory assistance at home are not rare. It is not impossible that in a near future we shall propose such devices to our patients. Beside these therapeutic resources which are difficult to manage, there are numerous drugs used to improve spasticity, cramps or drooling. Physiotherapy and speech therapy are of great importance. The management of such patients needs the cooperation of all the medical and paramedical members and the family whose role is essential.}, }
@article {pmid2492008, year = {1989}, author = {Selawry, HP and Whittington, KB and Bellgrau, D}, title = {Abdominal intratesticular islet-xenograft survival in rats.}, journal = {Diabetes}, volume = {38 Suppl 1}, number = {}, pages = {220-223}, doi = {10.2337/diab.38.1.s220}, pmid = {2492008}, issn = {0012-1797}, mesh = {Abdomen ; Animals ; Diabetes Mellitus, Experimental/surgery ; *Graft Survival ; *Islets of Langerhans Transplantation ; Male ; Rats ; Rats, Inbred Strains ; Testis ; }, abstract = {We investigated the survival of islet xenografts in the abdominal testes of normal, diabetes-resistant ACl and Wistar-Lewis (W-L) and in diabetes-prone BB/Wor rats. Islets were isolated from hamster donors, and after a period in tissue culture, they were injected into the abdominal testes of diabetic rats. Postoperatively, the rats were divided into two treatment groups. Four ACl rats received antilymphocyte serum (ALS) injections over a period of 30 days, and 13 ACl, 15 W-L, and 13 BB/Wor rats were given cyclosporin (CsA) according to the following regimen: 25 mg/kg i.p. for 7 days, then 7 mg/kg i.p. for 23 days. On day 30, immunosuppression was stopped. The results showed that none of the ALS-treated ACl rats remained normoglycemic for greater than 9 days. However, CsA therapy resulted in an extended mean duration of normoglycemia in the ACl and W-L rats of 160.0 +/- 36.0 and 131.0 +/- 31 days, respectively. By contrast, the mean duration of normoglycemia in the BB/Wor rats was 33.0 +/- 4.0 days. Furthermore, all of the BB/Wor rats reverted to diabetes after CsA was stopped. Therefore, the concomitant administration of an antigenic islet xenograft with CsA led to a state of unresponsiveness only in diabetes-resistant but not in diabetes-prone rats. Because the BB/Wor rats have demonstrable T-lymphocyte dysfunction, they may be unable to generate the CsA-induced suppressor T-lymphocytes required for the long-term acceptance of the graft by the host.}, }
@article {pmid3070967, year = {1988}, author = {Stern, H and Genz, T and Emmrich, P and Bühlmeyer, K}, title = {[Hemodynamic effect of captopril in children with dilated cardiomyopathy].}, journal = {Wiener klinische Wochenschrift}, volume = {100}, number = {24}, pages = {814-818}, pmid = {3070967}, issn = {0043-5325}, mesh = {Adolescent ; Captopril/adverse effects/*therapeutic use ; Cardiomyopathy, Dilated/*drug therapy ; Child ; Child, Preschool ; Drug Therapy, Combination ; Echocardiography, Doppler ; Follow-Up Studies ; Hemodynamics/*drug effects ; Humans ; Infant ; Infant, Newborn ; Myocarditis/complications ; Prospective Studies ; }, abstract = {Hemodynamic effects of captopril were prospectively studied in 12 children suffering from dilative cardiomyopathy. Before the administration of the drug all patients were put on a stable medication of diuretics and/or glycosides. A median daily dose of 1.83 mg captopril/kg body weight was given in 3 or 4 single doses depending on age. Median body weight of the children was 18.6 kg (range 2.7-42.2) and the median age was 5.8 years (range 0.2-15). Left ventricular volume was determined in systole and diastole using 2-D echo, and the stroke volume als well as the ejection fraction were calculated. Cardiac index (CI) and systemic resistance (Rs) were measured by Doppler echo. Blood pressure and heart rate were recorded at each echo registration. ESVI (-32%), EDVI (-21%) and SVI (-7%) were significantly (p less than 0.05) reduced by short-term captopril treatment. This effect was maintained under long-term therapy. EF, CI, Rs, blood pressure and heart rate showed only minor changes under captopril. Adverse effects were recorded only in one child. They disappeared after dose reduction.}, }
@article {pmid3221239, year = {1988}, author = {Sindhuphak, R and Karlsson, E and Conradi, S and Ronnevi, LO}, title = {Immunoglobulins from patients with amyotrophic lateral sclerosis affect human erythrocyte acetylcholinesterase.}, journal = {Journal of the neurological sciences}, volume = {86}, number = {2-3}, pages = {195-202}, doi = {10.1016/0022-510x(88)90098-6}, pmid = {3221239}, issn = {0022-510X}, mesh = {Acetylcholinesterase/*blood/immunology ; Amyotrophic Lateral Sclerosis/*immunology ; Erythrocytes/*enzymology ; Humans ; Immunoglobulins/isolation &amp; purification/*physiology ; Membrane Lipids/blood/physiology ; Micelles ; Phospholipids/blood/physiology ; Reference Values ; Thermodynamics ; }, abstract = {Human erythrocyte acetylcholinesterase (AChE) solubilized with Triton X-100 and obtained as a complex with micelles containing Triton and membrane phospholipids was incubated with immunoglobulins (Igs) from patients with amyotrophic lateral sclerosis (ALS) and from normal individuals. The temperature dependence of the AChE activity was determined. Biphasic (broken) Arrhenius plots were obtained with control Igs with the break point at 32.8 +/- 0.3 degrees C (SD, n = 18) indicating that the enzyme changes its conformation at this temperature. With ALS-Igs monophasic (linear) plots were observed in 14 cases and a biphasic in one case. ALS-Igs prevent the conformational change occurring at the break point temperature. The activation energy at physiological temperature increased by 60% from 2.4 to 3.8 kcal/mol (10.0-15.9 kJ/mol) which implies that ALS-Igs inhibit AChE. Thus, ALS-patients have autoantibodies that change the normal behaviour of erythrocyte AChE and which bind to the enzyme molecule or/and to phospholipids associated with the enzyme. At least part of the autoantibodies should be directed against the enzyme molecule, since a change in the Arrhenius plot was also observed in a control experiment with AChE which probably had micelles without any phospholipids. This enzyme was isolated by affinity chromatography and was washed with a buffer containing Triton X-100 before desorption from the affinity column, a treatment known to remove all phospholipids from erythrocyte AChE.}, }
@article {pmid2901101, year = {1988}, author = {Hahn, JS and Aizenman, E and Lipton, SA}, title = {Central mammalian neurons normally resistant to glutamate toxicity are made sensitive by elevated extracellular Ca2+: toxicity is blocked by the N-methyl-D-aspartate antagonist MK-801.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {85}, number = {17}, pages = {6556-6560}, pmid = {2901101}, issn = {0027-8424}, support = {EY05477/EY/NEI NIH HHS/United States ; NS00879/NS/NINDS NIH HHS/United States ; NS07264/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Anticonvulsants/*pharmacology ; Aspartic Acid/analogs &amp; derivatives/antagonists &amp; inhibitors ; Calcium/*pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Dibenzocycloheptenes/*pharmacology ; Dizocilpine Maleate ; Glutamates/*pharmacology/toxicity ; Glutamic Acid ; N-Methylaspartate ; Rats ; Retina/*cytology ; Retinal Ganglion Cells/*cytology/drug effects ; }, abstract = {It is widely held that a glutamate-like toxin that resembles N-methyl-D-aspartate may be responsible for the death of nerve cells seen after severe neurological insults including stroke, seizures, and degenerative disorders, such as Huntington disease, Alzheimer disease, and the amyotrophic lateral sclerosis-parkinsonism-dementia complex found on Guam. One puzzling fact about these maladies is the differential vulnerability of specific groups of neurons peculiar to each condition. We report here that an identified population of central neurons, rat retinal ganglion cells, are resistant to the neurotoxic effects of millimolar concentrations of glutamate under otherwise normal culture conditions. Patch-clamp experiments show that this resistance is associated with a very small ionic current response to N-methyl-D-aspartate. Varying the ionic milieu by increasing the extracellular Ca2+ concentration, however, results in a striking increase in glutamate-induced cell death in this population. Under these conditions, Mg2+ or the amino acid antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo-(alpha,gamma)-cyclohepten-5 ,10-imine maleate], blockers of N-methyl-D-aspartate receptor-coupled ion channels, completely abrogate the lethal effects of glutamate. These findings strongly suggest that Ca2+ entry through N-methyl-D-aspartate-activated channels is responsible for this type of neuronal death and suggest strategies that may be clinically useful in the treatment of various neurological disorders.}, }
@article {pmid3208215, year = {1988}, author = {Noseworthy, JH and Rae-Grant, AD and Brown, WF}, title = {An unusual subacute progressive motor neuronopathy with myasthenia-like features.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {15}, number = {3}, pages = {304-309}, doi = {10.1017/s0317167100027797}, pmid = {3208215}, issn = {0317-1671}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/pathology/physiopathology ; Diagnosis, Differential ; Electric Stimulation ; Female ; Humans ; Middle Aged ; Myasthenia Gravis/*diagnosis/pathology/physiopathology ; }, abstract = {The initial presentation and clinical course of this 60-year old woman suggested a diagnosis of myasthenia gravis. The subsequent development of tongue fasciculations and the lack of response to treatment made a diagnosis of amyotrophic lateral sclerosis (ALS) more likely despite the presence of conjugate gaze paresis and the absence of many of the typical clinical and electromyographic (EMG) findings seen in this condition. The pathological findings were consistent with either a motor neuronopathy or an unusual variant of ALS. We review the clinical and pathological features of this unusual case in this report.}, }
@article {pmid2843079, year = {1988}, author = {Pestronk, A and Cornblath, DR and Ilyas, AA and Baba, H and Quarles, RH and Griffin, JW and Alderson, K and Adams, RN}, title = {A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside.}, journal = {Annals of neurology}, volume = {24}, number = {1}, pages = {73-78}, doi = {10.1002/ana.410240113}, pmid = {2843079}, issn = {0364-5134}, support = {1RO1 NS23719/NS/NINDS NIH HHS/United States ; P01 NS22849/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Autoantibodies/*analysis ; Autoimmune Diseases/*drug therapy/immunology ; Cyclophosphamide/*therapeutic use ; Female ; G(M1) Ganglioside/*immunology ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Motor Neurons/*immunology ; Neuromuscular Diseases/*drug therapy/immunology ; Synaptic Transmission/drug effects ; }, abstract = {We report 2 patients with a treatable, immune-mediated motor polyneuropathy associated with antibodies to defined neural antigens. In these patients asymmetrical weakness developed in one arm and progressed over 2 to 3 years to involve the other arm, legs, and trunk. Both patients were initially diagnosed as having lower motor neuron forms of amyotrophic lateral sclerosis. However, repeated electrophysiological testing eventually showed multifocal conduction blocks in motor but not sensory fibers compatible with patchy selective demyelination. Serum testing by thin-layer chromatography and enzyme-linked immunosorbent assay revealed that both patients had high titers of antibody directed against GM1 and other gangliosides. Initial therapeutic trials of prednisone (100 mg daily for 4 to 6 months) and plasmapheresis were unsuccessful. Treatment with cyclophosphamide, however, was followed by marked improvement in strength in both patients.}, }
@article {pmid2896868, year = {1988}, author = {Plaitakis, A and Smith, J and Mandeli, J and Yahr, MD}, title = {Pilot trial of branched-chain aminoacids in amyotrophic lateral sclerosis.}, journal = {Lancet (London, England)}, volume = {1}, number = {8593}, pages = {1015-1018}, doi = {10.1016/s0140-6736(88)91841-7}, pmid = {2896868}, issn = {0140-6736}, support = {NS-11631/NS/NINDS NIH HHS/United States ; NS-16871/NS/NINDS NIH HHS/United States ; RR-71/RR/NCRR NIH HHS/United States ; }, mesh = {Amino Acids, Branched-Chain/*therapeutic use ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Clinical Trials as Topic ; Drug Combinations ; Female ; Humans ; Isoleucine/administration &amp; dosage ; Leucine/administration &amp; dosage ; Locomotion ; Male ; Middle Aged ; Muscles/physiopathology ; Neurologic Examination ; Patient Compliance ; Spinal Cord/physiopathology ; Valine/administration &amp; dosage ; }, abstract = {22 patients with amyotrophic lateral sclerosis were entered into a double-blind, randomised, placebo-controlled trial of treatment with branched-chain aminoacids. 11 received daily 12 g L-leucine, 8 g L-isoleucine, and 6.4 g L-valine, by mouth, and the remainder received placebo. During the one-year trial, patients in the placebo group showed a linear decline in functional status consistent with the natural history of the disease. Those treated with aminoacids showed significant benefit in terms of maintenance of extremity muscle strength and continued ability to walk.}, }
@article {pmid3367399, year = {1988}, author = {Reines, HD and Bartlett, RL and Chudy, NE and Kiragu, KR and McKnew, MA}, title = {Is advanced life support appropriate for victims of motor vehicle accidents: the South Carolina Highway Trauma Project.}, journal = {The Journal of trauma}, volume = {28}, number = {5}, pages = {563-570}, doi = {10.1097/00005373-198805000-00001}, pmid = {3367399}, issn = {0022-5282}, mesh = {*Accidents, Traffic ; Blood Pressure ; *Emergency Medical Services ; Evaluation Studies as Topic ; Female ; Humans ; Male ; Resuscitation/*methods ; Rural Population ; South Carolina ; Wounds and Injuries/mortality/*therapy ; }, abstract = {There is continuing controversy over the use of Advanced Life Support (ALS) in the treatment of multisystem injury. In this study, performed to define the role of ALS in the management of motor vehicle accidents (MVA), 538 ambulance run reports (ARR) and hospital records of patients involved in MVA in South Carolina for 1983 were examined. Of these, 248 were reviewed in depth by a trauma review committee (TRC). Paramedics were present in 81% (93% urban, 80% rural) of cases. ALS crews averaged 24.8 minutes on the scene compared to 18.1 minutes for Basic Life Support (BLS). It took 6 minutes longer to transport rural patients than urban patients (15.7 vs. 9.6 min). Total EMS time (response, on scene, transport) was 46 +/- 20 minutes. Extrication increased on-scene time from 20.5 to 31.1 minutes. Endotracheal intubation attempts were 67% successful and IV's were placed in 88% of attempts. Thirty-two per cent of ALS patients demonstrated an increased blood pressure en route compared to 12% of BLS patients. The TRC felt prehospital care was beneficial in 85% of cases, while 11.7% had inappropriate or inadequate care. Resuscitation and ALS in MVA appears to be beneficial in the treatment of multisystem trauma in a rural state.}, }
@article {pmid3146705, year = {1988}, author = {Klimek, A and Szulc-Kuberska, J and Czernielewska-Rutkowska, I and Głuszcz-Zielińska, A}, title = {[Treatment of amyotrophic lateral sclerosis with TRH].}, journal = {Neurologia i neurochirurgia polska}, volume = {22}, number = {3}, pages = {206-210}, pmid = {3146705}, issn = {0028-3843}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Clinical Trials as Topic ; Female ; Hormones/therapeutic use ; Humans ; Male ; Middle Aged ; Muscle Tonus/drug effects ; Thyrotropin-Releasing Hormone/*therapeutic use ; }, abstract = {In view of earlier reports in the literature it was tried to use TRH (thyrotropin releasing hormone) in cases of amyotrophic lateral sclerosis. TRH was given during 3 weeks once daily intravenously in drip infusions in a 0.4 mg dose. For objectivization of the results the muscle power was assessed using a five-grade scale of Lovette. TRH effect on EMG was analysed also. It was found that in only 3 out of 14 patients with moderately progressed disease no improvement was achieved, while in 11 cases the improvement was from 10 to 20%. However, the improvement was transient, and TRH treatment failed to stop the progression of the disease.}, }
@article {pmid3348337, year = {1988}, author = {Johnson, CR}, title = {Aquatic therapy for an ALS patient.}, journal = {The American journal of occupational therapy : official publication of the American Occupational Therapy Association}, volume = {42}, number = {2}, pages = {115-120}, doi = {10.5014/ajot.42.2.115}, pmid = {3348337}, issn = {0272-9490}, mesh = {Amyotrophic Lateral Sclerosis/*rehabilitation ; Humans ; *Hydrotherapy ; Male ; Middle Aged ; Swimming ; }, abstract = {The opportunity to participate in wellness programming can be particularly valuable to persons who must be prepared to deal with continuing gradual physical deterioration for the rest of their lives. During time periods when his health was stable, without evidence of a rapid progression of the illness, Charlie was able to devote some energy to the pursuit of swimming, an activity he had enjoyed for many years. The WETSwim program provided the opportunity for Charlie to take an active role in the management of his physical and psychological status. In an environment where he was able to overcome barriers to participation, Charlie could explore aquatic recreation activities and resume a leisure role. He experienced the opportunity to learn and practice swimming skills, develop an area of performance to a mastery level, and improve his quality of life. Occupational therapists are no longer confined to the traditional locations for and methods of providing treatment. Encouraged by the changing economics of health care, they seek alternative ways of providing quality health care (Frazian, 1985). Persons with short-term physical dysfunction, as modern consumers, are taking greater initiative in the medical management of their dysfunction and seek alternatives to passive forms of treatment. Persons with chronic or long-term physical disabilities, in addition to having basic needs for optimal sensory-motor function and ADL independence, are becoming increasingly interested in physical fitness. The WETSwim program offers a wide range of opportunities, medical and recreational, functional and social, to the consumer with physical dysfunctions.}, }
@article {pmid3125634, year = {1988}, author = {Shaffer, D and Maki, T and DeMichele, SJ and Karlstad, MD and Bistrian, BR and Balogh, K and Monaco, AP}, title = {Studies in small bowel transplantation. Prevention of graft-versus-host disease with preservation of allograft function by donor pretreatment with antilymphocyte serum.}, journal = {Transplantation}, volume = {45}, number = {2}, pages = {262-269}, pmid = {3125634}, issn = {0041-1337}, support = {AI14551-10/AI/NIAID NIH HHS/United States ; AM31933/AM/NIADDK NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/administration &amp; dosage/*therapeutic use ; Body Weight ; Enteral Nutrition ; Graft vs Host Disease/metabolism/physiopathology/*prevention &amp; control ; Injections, Intraperitoneal ; Injections, Subcutaneous ; Intestine, Small/cytology/physiology/*transplantation ; Male ; Nitrogen/metabolism ; Preoperative Care ; Rats ; Rats, Inbred Lew ; *Tissue Donors ; Transplantation, Homologous/adverse effects ; Transplantation, Isogeneic ; }, abstract = {Donor pretreatment with antilymphocyte serum (ALS) effectively prevents graft-versus-host disease (GVHD) in a unidirectional (parent-to-F1 hybrid) rat small bowel transplantation model. ALS must be administered prior to or at the time of transplantation, and the intraperitoneal route is more effective than subcutaneous administration. Donor pretreatment with ALS uniformly prevents GVHD without impairing subsequent allograft function as measured by absorption of dietary energy and nitrogen, weight gain, and bowel morphology. These rodent studies suggest that ALS treatment of donors as well as recipients in small bowel transplantation may be a highly effective, simple, and easily applicable method to prevent or ameliorate GVHD in human small bowel transplantation.}, }
@article {pmid2449750, year = {1988}, author = {Gotoh, M and Porter, J and Monaco, AP and Maki, T}, title = {Induction of antigen-specific unresponsiveness to pancreatic islet allografts by antilymphocyte serum.}, journal = {Transplantation}, volume = {45}, number = {2}, pages = {429-433}, doi = {10.1097/00007890-198802000-00037}, pmid = {2449750}, issn = {0041-1337}, support = {AI 14551-09/AI/NIAID NIH HHS/United States ; AI 20686/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antigens/administration &amp; dosage ; Antilymphocyte Serum/*administration &amp; dosage ; Epitopes/*immunology ; *Immune Tolerance ; Immunization, Passive ; Islets of Langerhans/immunology ; *Islets of Langerhans Transplantation ; Male ; Mice ; Mice, Inbred A ; Mice, Inbred DBA ; Skin/immunology ; Skin Transplantation ; Spleen/immunology/transplantation ; T-Lymphocytes, Regulatory/immunology ; Transplantation, Homologous ; }, abstract = {The mechanism (or mechanisms) underlying the indefinite survival of DBA/2 islet allografts in strongly histoincompatible (C57BL/6xA)F1 (B6AF1) mice, induced either by the combined use of Ficoll-prepared crude islets and treatment of recipients with antilymphocyte serum (ALS), or by the use of handpicked, purified islets in nonimmunosuppressed recipients, was examined. B6AF1 mice bearing DBA/2 crude islet allografts for more than 100 days following ALS treatment accepted secondary DBA/2 crude islet allografts, but acutely rejected third-party A.SW crude islet allografts. This antigen-specific unresponsiveness to islet allografts can be successfully transferred into syngeneic B6AF1 mice by spleen cells. However, the state of unresponsiveness to donor antigen observed in these animals appears to be relatively weak, since transplantation of DBA/2 skin allografts or injection of DBA/2 spleen cells (5 x 10(7] caused acute rejection of long-term-accepted islet allografts. In contrast, B6AF1 mice bearing DBA/2 purified islet allografts over 100 days without immunosuppression rejected the secondary DBA/2 crude islet allografts acutely. Transfer of spleen cells obtained from these animals to syngeneic B6AF1 mice failed to induce prolongation of DBA/2 crude islet allografts. Thus, the mechanism (or mechanisms) involved in the long-term acceptance of islet allografts induced by the use of ALS and crude islets appears to be different from that involved in the long-term acceptance of purified islet allografts. The possible roles played by ALS in the induction of specific unresponsiveness to islet allografts are discussed.}, }
@article {pmid3433786, year = {1987}, author = {Chalubinski, K and Brunner, H}, title = {[Positive diagnosis of irritable colon: a scored chart or standardized anamnesis?].}, journal = {Wiener klinische Wochenschrift}, volume = {99}, number = {23}, pages = {819-824}, pmid = {3433786}, issn = {0043-5325}, mesh = {Colonic Diseases, Functional/*diagnosis ; Diagnosis, Differential ; Dyspepsia/diagnosis ; Humans ; Medical History Taking ; }, abstract = {The diagnostic score of Kruis to diagnose the irritable bowel syndrome (IBS) has recently gained widespread application. We therefore evaluated the case histories of 373 patients attending the gastroenterological outpatient department retrospectively using the questionnaire of these authors. In contrast to Kruis et al's findings, by applying their discriminating score the diagnosis of irritable bowel syndrome was made in only 51% of the patients who underwent complete gastrointestinal survey without pathological findings. However, the group of IBS was significantly separable from malignant or inflammatory disease. We therefore conclude that the diagnosis of IBS should only be made by ruling out organic disease (except in the case of young people with normal physical and laboratory check up findings and a good response to treatment). For these patients we simplified the questionnaire, omitting calculations.}, }
@article {pmid3683880, year = {1987}, author = {Braun, SR and Sufit, RL and Giovannoni, R and O'Connor, M and Peters, H}, title = {Intermittent negative pressure ventilation in the treatment of respiratory failure in progressive neuromuscular disease.}, journal = {Neurology}, volume = {37}, number = {12}, pages = {1874-1875}, doi = {10.1212/wnl.37.12.1874}, pmid = {3683880}, issn = {0028-3878}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*therapy ; Humans ; Male ; Middle Aged ; Muscular Dystrophies/complications/*therapy ; *Respiration, Artificial ; Respiratory Insufficiency/etiology/*therapy ; }, abstract = {Five men with degenerative neuromuscular diseases (three with amyotrophic lateral sclerosis [ALS] and two with Duchenne's muscular dystrophy [DMD]) who had respiratory failure were treated with intermittent negative pressure ventilation (NPV). One patient with ALS in severe acute respiratory failure was successfully treated with NPV alone. This patient and two other ALS patients in chronic respiratory failure with PaCO2 elevation stabilized or improved their vital capacity (VC) and lowered their PaCO2 after 5 to 11 weeks of therapy. Finally, intermittent NPV was used to replace 24-hour positive pressure ventilation in two patients with DMD. It is concluded that intermittent NPV may stabilize or temporarily improve the respiratory status in patients with progressive neuromuscular diseases.}, }
@article {pmid3437954, year = {1987}, author = {Kim, LY and Day, AL and Normann, SJ and Abela, GS and Mehta, JL}, title = {The argon contact laser scalpel: a study of its effect on atherosclerosis.}, journal = {Neurosurgery}, volume = {21}, number = {6}, pages = {861-866}, doi = {10.1227/00006123-198712000-00013}, pmid = {3437954}, issn = {0148-396X}, mesh = {Animals ; Aorta/surgery/ultrastructure ; Argon ; Arteriosclerosis/*surgery ; Endarterectomy/*instrumentation/methods ; Laser Therapy/*instrumentation/methods ; Lasers/*instrumentation ; Male ; Microscopy, Electron, Scanning ; Rabbits ; }, abstract = {A new argon laser scalpel (ALS) that delivers radiation to tissue by direct contact was used to perform endarterectomies on atherosclerotic rabbit aortas in vivo. The resultant effects were compared to those induced by CO2 laser (CO2) and conventional surgical endarterectomy (END) to determine whether this instrument might be useful in the treatment of occlusive cerebrovascular disease. Light microscopy of the treated aortic segments revealed significantly more atheroma removed and less damage to the underlying media in the ALS segments compared to the CO2 segments. Electron microscopy showed that the ALS surface and distal intima-media interface were smoother and more even than those of the CO2 or END groups. Prostacyclin synthesis, as measured by 6-keto-prostaglandin F1a levels, was significantly reduced in the ALS compared to the END and control segments. These results indicate that the ALS is superior to CO2 in performing open laser endarterectomies, but such treatment places the atherosclerotic blood vessel at greater risk for thrombotic complications during the early postoperative period that does surgical endarterectomy. It is conceivable that a contact laser may be useful in the smooth welding of the distal edge of an atheroma (i.e., during carotid endarterectomy) and for the transcatheter ablation of surgically inaccessible obstructions of the cerebral circulation.}, }
@article {pmid3423904, year = {1987}, author = {Lee, KS and Kelly, DL}, title = {Amyotrophic lateral sclerosis and severe cervical spondylotic myelopathy in a patient with a posterior fossa arachnoid cyst: diagnostic dilemma.}, journal = {Southern medical journal}, volume = {80}, number = {12}, pages = {1580-1583}, doi = {10.1097/00007611-198712000-00023}, pmid = {3423904}, issn = {0038-4348}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications/diagnostic imaging ; *Arachnoid ; *Cervical Vertebrae ; Cranial Fossa, Posterior ; Cysts/*complications ; Diagnosis, Differential ; Female ; Humans ; Radiography ; Spinal Osteophytosis/*complications/diagnostic imaging ; }, abstract = {Distinguishing between cervical spondylotic myelopathy and ALS can be difficult, as illustrated by this report of a patient who had both disorders, as well as a relatively rare arachnoid cyst of the posterior fossa. Attempts to differentiate between ALS and cervical spondylotic myelopathy must persist until diagnosis of one (or both) of the disorders is made, since both the prognosis and treatment of the two are different. Careful neurologic examination with attention to clinical details, muscle biopsy in some patients, and routine EMG will usually lead to the proper diagnosis.}, }
@article {pmid3119415, year = {1987}, author = {Deshpande, SB and Pilotte, NS and Warnick, JE}, title = {Gender-specific action of thyrotropin-releasing hormone in the mammalian spinal cord.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {1}, number = {6}, pages = {478-482}, doi = {10.1096/fasebj.1.6.3119415}, pmid = {3119415}, issn = {0892-6638}, support = {NS-21312/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Female ; In Vitro Techniques ; Male ; Orchiectomy ; Ovariectomy ; Rats ; Rats, Inbred Strains ; Reflex/*drug effects ; Sex Factors ; Spinal Cord/drug effects/*physiology ; Synapses/drug effects/physiology ; Thyrotropin-Releasing Hormone/*pharmacology ; }, abstract = {Thyrotropin-releasing hormone (TRH) potentiated the monosynaptic reflex in isolated spinal cords obtained from 7- to 9-day-old rats. A concentration-dependent increase in the monosynaptic reflex was observed in spinal cords obtained from male but not from female or castrated male rats. In contrast, the magnitude of potentiation in cords from ovariectomized control female rats and in ovariectomized female rats treated with testosterone approached that seen in intact males. The results provide evidence that gender plays a prominent role in the variability of response both of humans with amyotrophic lateral sclerosis and of animal tissues to TRH. Furthermore, exposure to androgen during the neonatal period may determine the responsiveness of motoneurons to TRH. Thus the use of TRH in the treatment of amyotrophic lateral sclerosis may be more effective in males than in females.}, }
@article {pmid3651832, year = {1987}, author = {Bellinger, DL and Anderson, WJ}, title = {Postnatal development of cell columns and their associated dendritic bundles in the lumbosacral spinal cord of the rat. I. The ventrolateral cell column.}, journal = {Brain research}, volume = {432}, number = {1}, pages = {55-67}, doi = {10.1016/0165-3806(87)90008-3}, pmid = {3651832}, issn = {0006-8993}, mesh = {Animals ; *Dendrites ; Female ; Male ; Motor Neurons/*cytology ; Rats ; Spinal Cord/cytology/*growth &amp; development ; Time Factors ; }, abstract = {The postnatal development of the ventrolateral dendrite bundle (LDB) in the rat lumbosacral cord was studied quantitatively with Golgi-Cox impregnation. At birth, motoneuronal perikarya and their dendrites were not fully developed, and had not begun to form bundles; varicose dendritic shafts radiated symmetrically from motoneurons. Dendrites contained numerous spines and growth cones. At 5 days, dendritic shafts began to arrange themselves longitudinally, and by 10 days of age, dendrite bundling was apparent. Dendritic growth and bundling appeared complete by two months of age. LDB formation was a dynamic process; rapid dendritic growth occurred in discrete phases with brief intervals of slower dendritic development between them. The mean number of secondary and tertiary dendrites, and the mean branch length of all orders progressively increased. Motoneurons of the LDB primarily innervate the pelvic musculature. Selective horizontal orientation of dendrites into discrete compact bundles suggests that the LDB may serve as a specialized receiving and integrating system for autonomic control over excretory and reproductive functions. It is interesting to note that in patients suffering from amyotrophic lateral sclerosis, motoneurons in the LDB are resistant to destruction. This finding suggests that motoneurons in the LDB may express unique features that protect them from certain disease processes. A better understanding of the developmental anatomical, physiological and biochemical properties of the LDB may provide insight into the treatment of patients with disease processes involving spinal cord and brainstem lower motoneurons.}, }
@article {pmid3299924, year = {1987}, author = {De Fazio, SR and Hartner, WC and Monaco, AP and Gozzo, JJ}, title = {Effect of posttransplantation administration of peripheral blood lymphocytes in skin-grafted mice treated with antilymphocyte serum or antilymphocyte serum plus bone marrow.}, journal = {Transplantation}, volume = {44}, number = {1}, pages = {70-75}, doi = {10.1097/00007890-198707000-00016}, pmid = {3299924}, issn = {0041-1337}, support = {AM 33466/AM/NIADDK NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/*administration &amp; dosage ; *Bone Marrow Transplantation ; Centrifugation, Density Gradient ; *Graft Enhancement, Immunologic ; Graft Survival ; *Lymphocyte Depletion ; *Lymphocyte Transfusion ; Male ; Mice ; Mice, Inbred C3H ; Mice, Inbred Strains ; *Skin Transplantation ; T-Lymphocytes/immunology ; Transplantation, Homologous ; }, abstract = {Posttransplantation administration of donor-specific bone marrow cells to ALS-treated allograft recipients produces graft survival that is greater than that produced by ALS treatment alone. We have now studied the effect of peripheral blood lymphocytes (PBLs) in a mouse skin allograft model using this protocol (C3H skin grafted to B6AF1 mice, day 0; i.p. ALS on days -1 and +2; i.v. bone marrow days +6 or +7). When PBLs are injected in place of bone marrow cells, graft survival is extended beyond that noted for control mice given ALS only. The timing and specificity of this phenomenon suggest that it resembles the effect produced by posttransplant bone marrow administration and not that associated with pretransplant blood transfusion. The PBLs active in graft prolongation are Thy-1-negative and display a density in Percoll gradients similar to that of the active marrow cells. In contrast, when PBLs are injected in combination with bone marrow cells, the length of graft survival is shortened in comparison with that produced by bone marrow alone. The cells associated with this partial abrogation of the effectiveness of bone marrow appear to be mature T cells; this abrogation cannot be produced by PBLs treated with anti-Thy-1 plus complement or by thymocytes, but it is a property of lymph node cells enriched for T cells by nylon-wool fractionation. This study suggests that clinical application of this posttransplantation induction of specific allograft unresponsiveness can be facilitated by the use of peripheral blood lymphocytes rather than marrow, sparing a living organ donor from having to undergo bone marrow harvest. Additionally, the data indicate that contamination of marrow with blood lymphocytes should be minimized. However, the density gradient fractionation method that we have found to be effective in preparing the graft prolonging bone marrow cells simultaneously removes the PBLs deleterious to graft survival.}, }
@article {pmid3572515, year = {1987}, author = {Dagi, TF and Tarkington, MA and Leech, JJ}, title = {Tandem lumbar and cervical spinal stenosis. Natural history, prognostic indices, and results after surgical decompression.}, journal = {Journal of neurosurgery}, volume = {66}, number = {6}, pages = {842-849}, doi = {10.3171/jns.1987.66.6.0842}, pmid = {3572515}, issn = {0022-3085}, mesh = {Aged ; Female ; Gait ; Humans ; Intermittent Claudication/complications/diagnosis ; Lumbosacral Region ; Male ; Middle Aged ; Motor Neurons ; Neuromuscular Diseases/complications/diagnosis ; Prognosis ; Radiography ; Retrospective Studies ; Spinal Stenosis/*complications/diagnosis/diagnostic imaging/surgery ; }, abstract = {Spondylotic degeneration can give rise to concurrent stenosis of the lumbar and cervical portions of the spinal canal in tandem. Symptomatic tandem spinal stenosis (TSS) is characterized by the triad of intermittent neurogenic claudication, progressive gait disturbance, and findings of mixed myelopathy and polyradiculopathy in both the upper and lower extremities. Nineteen patients with clinically symptomatic and myelographically proven disease were studied retrospectively. Surgical intervention was directed at decompression of the stenotic lesions in both the cervical and lumbar regions. The most symptomatic level was usually treated first. After a mean follow-up period of 22 months, an excellent outcome was obtained in five patients (26%), four improved (21%), five deteriorated despite initial improvement (26%), and one was unchanged. Three patients could not be traced for follow-up review, and there was one postoperative death. Postoperative improvement correlated inversely with symptom duration. Sphincter disturbance, radiculopathy, myelography, cerebrospinal fluid analysis, and electrophysiological data were not prognostically significant. The presentation of TSS mimics amyotrophic lateral sclerosis and other forms of motor-neuron disease. In contrast to these conditions, however, TSS is amenable to treatment. Operative sequence and technique could not be related to outcome. Functional recovery in TSS depends on early diagnosis and timely surgical intervention.}, }
@article {pmid3112312, year = {1987}, author = {Tandan, R and Robison, SH and Munzer, JS and Bradley, WG}, title = {Deficient DNA repair in amyotrophic lateral sclerosis cells.}, journal = {Journal of the neurological sciences}, volume = {79}, number = {1-2}, pages = {189-203}, doi = {10.1016/0022-510x(87)90272-3}, pmid = {3112312}, issn = {0022-510X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*metabolism ; Cell Survival ; Cells, Cultured ; DNA/biosynthesis/drug effects/radiation effects ; *DNA Repair/radiation effects ; Fibroblasts/metabolism/radiation effects ; Humans ; Methyl Methanesulfonate/pharmacology ; Middle Aged ; Mitomycin ; Mitomycins/pharmacology ; Ultraviolet Rays ; X-Rays ; }, abstract = {We studied survival and DNA repair capacity in cultured sporadic ALS and control skin fibroblasts after treatment with DNA damaging agents producing different types of lesions. Mean survival in ALS and control fibroblasts was similar after exposure to ultraviolet (UV) light, x-rays and mitomycin C (MMC). Both mean survival and mean unscheduled (repair) DNA synthesis (UDS) were significantly reduced in ALS fibroblasts following treatment with the alkylating agent methyl methane sulfonate (MMS). These data suggest that ALS cells are relatively deficient in the repair of alkylation damage, possibly of apurinic/apyrimidinic sites, and that they are not unduly sensitive to DNA damage produced by UV light, x-rays and MMC. Normal survival and UDS seen in some patients' cells after MMS treatment indicate a spectrum of repair efficiency, and suggest heterogeneity of the biochemical defect in ALS.}, }
@article {pmid2952712, year = {1987}, author = {Gorczynski, RM and Boulanger, M and Lau, C}, title = {T cell-derived factor alone or in combination with immunosuppressive drugs augments prolongation of allogeneic skin graft survival in mice receiving donor-specific transfusion.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {138}, number = {10}, pages = {3197-3202}, pmid = {2952712}, issn = {0022-1767}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; *Blood Transfusion ; Cyclosporins/pharmacology ; Female ; *Graft Enhancement, Immunologic ; Graft Survival/drug effects ; Immunization, Passive ; Immunosuppressive Agents/*pharmacology ; Lymphocyte Activation ; Mice ; Mice, Inbred A/immunology ; Mice, Inbred BALB C/immunology ; Mice, Inbred C57BL/immunology ; *Skin Transplantation ; Suppressor Factors, Immunologic/*pharmacology ; T-Lymphocytes, Regulatory/immunology ; Transplantation, Homologous ; }, abstract = {Limiting dilution cytotoxicity or proliferation assays were performed with cells taken from A/J mice pretransfused with BALB/c blood. The data obtained indicate that donor-specific transfusion decreased both the frequency of reactive precursors and their proliferative potential after activation. Additional studies implied that these changes may be associated with a serum- or cell-mediated antigen-specific suppressive mechanism. Further manipulations aimed at preferentially sparing or enhancing the activity of suppressor T cells prolonged skin graft survival in pretransfused mice and led to the presence of suppressor T cells in the spleen of such mice, which were active upon adoptive transfer. These manipulations included the use of pretransplant donor-specific transfusion, administration of ALS or cyclosporin-A, or the use of posttransplant injection with a T suppressor activating factor (SAF). Optimum graft survival was associated with combined treatment when using transfusion, SAF, and cyclosporin-A.}, }
@article {pmid3104820, year = {1987}, author = {Hawley, RJ and Kratz, R and Goodman, RR and McCutchen, CB and Sirdofsky, M and Hanson, PA}, title = {Treatment of amyotrophic lateral sclerosis with the TRH analog DN-1417.}, journal = {Neurology}, volume = {37}, number = {4}, pages = {715-717}, doi = {10.1212/wnl.37.4.715}, pmid = {3104820}, issn = {0028-3878}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Drug Evaluation ; Hormones/*therapeutic use ; Humans ; Male ; Middle Aged ; Muscles/physiopathology ; Thyrotropin-Releasing Hormone/*analogs &amp; derivatives/therapeutic use ; }, abstract = {Thyrotropin-releasing hormone has been reported to increase strength in patients with amyotrophic lateral sclerosis (ALS). DN-1417 is an analog of thyrotropin-releasing hormone, which has less endocrinologic activity, but more anterior horn cell stimulating effect (with no "autorefractory state"). However, 2 mg DN-1417, IM twice a day for 1 month in an open-label trial, produced no objective improvement of strength in nine patients with ALS. No patient entered the double-blind, placebo-controlled phase of the trial.}, }
@article {pmid3104819, year = {1987}, author = {Munsat, TL and Taft, J and Jackson, IM}, title = {Pharmacokinetics of intrathecal thyrotropin-releasing hormone.}, journal = {Neurology}, volume = {37}, number = {4}, pages = {597-601}, doi = {10.1212/wnl.37.4.597}, pmid = {3104819}, issn = {0028-3878}, support = {AM 34540/AM/NIADDK NIH HHS/United States ; M01RR00054/RR/NCRR NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Half-Life ; Humans ; Infusion Pumps ; Injections, Spinal ; Kinetics ; Thyrotropin-Releasing Hormone/cerebrospinal fluid/*metabolism ; }, abstract = {An investigation of the efficacy of thyrotropin-releasing hormone in amyotrophic lateral sclerosis included study of the intrathecal pharmacokinetics of this neuropeptide. Its mean elimination half-life in CSF was 0.90 hours and was monoexponential. During a 2-hour infusion, 2.75% crossed the CSF/blood-brain barrier. Infusion for 12 months with an implanted pump in three patients at a rate of 3 mg/24 hr resulted in a mean CSF steady state of 2.88, 2.42, and 2.74 micrograms/ml, respectively. Pharmacokinetic data were similar at 6 and 12 months. This is an effective system with potential uses in the treatment of other degenerative diseases.}, }
@article {pmid3572233, year = {1987}, author = {Hawthorne, M and Gray, R and Cottam, C}, title = {Conservative laryngectomy (an effective treatment for severe aspiration in motor neurone disease).}, journal = {The Journal of laryngology and otology}, volume = {101}, number = {3}, pages = {283-285}, pmid = {3572233}, issn = {0022-2151}, mesh = {Aged ; Humans ; *Laryngectomy ; Male ; *Motor Neurons ; Neuromuscular Diseases/*complications ; Pneumonia, Aspiration/*prevention &amp; control ; }, abstract = {Four cases are presented to illustrate that conservative laryngectomy is a simple and reliable treatment for severe aspiration in patients with motor neurone disease whose symptoms are predominantly bulbar. This treatment leads to a rapid return of the patients to their home, thus reducing their dependency on skilled nursing care.}, }
@article {pmid3808319, year = {1987}, author = {Rudnicki, S and Chad, DA and Drachman, DA and Smith, TW and Anwer, UE and Levitan, N}, title = {Motor neuron disease and paraproteinemia.}, journal = {Neurology}, volume = {37}, number = {2}, pages = {335-337}, doi = {10.1212/wnl.37.2.335}, pmid = {3808319}, issn = {0028-3878}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/immunology/*therapy ; Humans ; Male ; Middle Aged ; *Motor Neurons ; Muscular Atrophy/immunology/*therapy ; Neuromuscular Diseases/immunology/*therapy ; Paraproteinemias/immunology/*therapy ; }, abstract = {We studied two patients with motor neuron disease and paraproteinemia. One had amyotrophic lateral sclerosis (ALS) and IgG lambda monoclonal gammopathy. The second had slowly progressive muscular atrophy and an IgM kappa paraprotein, followed by a biclonal gammopathy when an IgA kappa paraprotein appeared. Treatment with immunosuppressive agents and plasmapheresis lowered the serum concentration of the paraproteins. The ALS syndrome progressed despite therapy. The other patient improved, was stable for several years, but then deteriorated despite continued therapy.}, }
@article {pmid3561383, year = {1987}, author = {Finger, S}, title = {The family support group in the treatment of amyotrophic lateral sclerosis.}, journal = {Neurologic clinics}, volume = {5}, number = {1}, pages = {83-100}, pmid = {3561383}, issn = {0733-8619}, mesh = {Amyotrophic Lateral Sclerosis/psychology/*therapy ; Continuity of Patient Care ; *Family ; Grief ; Group Structure ; Humans ; Leadership ; Motivation ; *Psychotherapy, Group ; Social Support ; }, abstract = {Support groups are effective means of addressing the psychosocial needs of patients with amyotrophic lateral sclerosis and their families. An education-support group for family members of patients with ALS has been functioning at New England Medical Center in Boston and has been found to be successful in helping families and, therefore, patients to cope with this stressful illness. This article discusses the benefits of this group to families and patients, family members' roles in caring for and coping with this illness, the group's structure and development, and gives suggestions to others who are considering running a group of this kind. Our experience has shown that group participants feel less isolated, less fearful, and less threatened than prior to their involvement in the group and gain a sense of empowerment that enables them to meet the extensive caretaking demands of the patient with ALS. The contribution that an ALS Family Support Group provides is a component in the care of the patient with ALS that can be critical to families dealing with this illness.}, }
@article {pmid3550594, year = {1987}, author = {Neal, GD and Clarke, LR}, title = {Neuromuscular disorders.}, journal = {Otolaryngologic clinics of North America}, volume = {20}, number = {1}, pages = {195-201}, pmid = {3550594}, issn = {0030-6665}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/complications ; Child ; Female ; Humans ; Infant, Newborn ; Male ; Myasthenia Gravis/complications ; Neuromuscular Diseases/*complications ; Otorhinolaryngologic Diseases/*etiology ; }, abstract = {Laryngeal innervation and the functional disorders associated with lower motor neuron paralyses are reviewed. Causes of diffuse denervation, such as drug toxicities and demyelinating disease, are also discussed. Symptoms and treatment of myasthenia gravis, amyotrophic lateral sclerosis, and botulism are discussed as examples of neuromuscular blockade at various levels.}, }
@article {pmid3550417, year = {1987}, author = {Braun, SR}, title = {Respiratory system in amyotrophic lateral sclerosis.}, journal = {Neurologic clinics}, volume = {5}, number = {1}, pages = {9-31}, pmid = {3550417}, issn = {0733-8619}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*physiopathology/therapy ; Biomechanical Phenomena ; Cough/physiopathology ; Humans ; Respiration ; Respiration, Artificial/methods ; Respiratory Function Tests ; Respiratory Insufficiency/diagnosis/physiopathology/therapy ; Respiratory Muscles/physiopathology ; Respiratory System/*physiopathology ; }, abstract = {Failure of the respiratory system is the most common cause of death in amyotrophic lateral sclerosis. This is due to weakened respiratory musculature resulting in respiratory failure, ineffective cough, and failure to protect the lungs from aspiration. Treatment is only supportive at present, but mechanical ventilation with either negative or positive pressure offer some life-extending possibilities. The respiratory system should be closely monitored as early identification of problems may allow better insight into the immediate prognosis.}, }
@article {pmid3274810, year = {1987}, author = {Hartner, WC and De Fazio, SR and Markees, TG and Maki, T and Monaco, AP and Gozzo, JJ}, title = {Specific tolerance to canine renal allografts following treatment with fractionated bone marrow and antilymphocyte serum.}, journal = {Transplantation proceedings}, volume = {19}, number = {1 Pt 1}, pages = {476-477}, pmid = {3274810}, issn = {0041-1345}, support = {AM33466/AM/NIADDK NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/*therapeutic use ; Bone Marrow Transplantation/*immunology ; Dogs ; *Immune Tolerance ; *Immunosuppression Therapy ; Kidney Transplantation/*immunology ; Lymphocyte Activation ; Lymphocytes/immunology ; Transplantation, Homologous ; }, abstract = {These results suggest (1) that ALS + BM fractions can be used to promote tolerance in long-term graft survivors; (2) that the presence of apparent BM cells of donor origin in the allograft in normally functioning kidneys may be related to the mechanism of allograft prolongation, and (3) that some promise of possible specific long-term immunosuppression exists clinically.}, }
@article {pmid3577911, year = {1987}, author = {Hillel, AD and Miller, RM}, title = {Management of bulbar symptoms in amyotrophic lateral sclerosis.}, journal = {Advances in experimental medicine and biology}, volume = {209}, number = {}, pages = {201-221}, doi = {10.1007/978-1-4684-5302-7_32}, pmid = {3577911}, issn = {0065-2598}, mesh = {Airway Obstruction/etiology/*therapy ; Amyotrophic Lateral Sclerosis/complications/physiopathology/*therapy ; Combined Modality Therapy ; Deglutition Disorders/etiology/physiopathology/*therapy ; Humans ; Medulla Oblongata/physiopathology ; Sialorrhea/etiology/*therapy ; Speech Disorders/etiology/*therapy ; }, abstract = {The bulbar symptoms of ALS include difficulty with the management of swallowing, saliva, aspiration, and communication. These symptoms originate from the disability of the oropharyngeal muscles and actually represent varying degrees of severity of a single problem. The management of these symptoms requires the concerted effort of a rehabilitation team, which should include a surgeon, speech pathologist, neurologist, psychosocial worker, and dietitian. Early education of the patient and patient's family greatly facilitates successful management of bulbar symptoms. Early recognition of the signs of dysphagia, aspiration, and communicative disability are important in order to provide solutions before severe and possibly life-threatening debilitation occurs. The treatments and techniques presented in this chapter must be applied to each patient on an individual basis. The moral and social decisions regarding the providing or withholding of treatment to ALS patients are difficult ones. It is important, however, to realize that management decisions of ALS patients must deal not only with the quantity of life but also the quality of life. This distinction often falls into a 'gray zone' with management of bulbar symptoms since swallowing difficulties are life-threatening as well as uncomfortable. One of the difficulties that we present ourselves as health care providers in ALS is that, more often than not, our patient is in a noncommunicative position and cannot contribute to treatment decisions. If careful and aggressive care is taken to preserve the communicative abilities of our patients, the difficult situation of making decisions based on the family's inclinations and our own inclinations can be avoided. When we are confronted with a decision to maintain or cease support for a patient, the moral and emotional issues that present can be overwhelming. However, the patient's input, if it were direct and included the ability to express complex thoughts, could often provide the information necessary to make the decisions more clear.}, }
@article {pmid3577909, year = {1987}, author = {Norris, FH and Smith, RA and Denys, EH}, title = {The treatment of amyotrophic lateral sclerosis.}, journal = {Advances in experimental medicine and biology}, volume = {209}, number = {}, pages = {175-182}, doi = {10.1007/978-1-4684-5302-7_29}, pmid = {3577909}, issn = {0065-2598}, mesh = {Amyotrophic Lateral Sclerosis/complications/*therapy ; Combined Modality Therapy ; Constipation/etiology/therapy ; Deglutition Disorders/etiology/therapy ; Exercise Therapy ; Humans ; Mood Disorders/drug therapy/etiology ; Muscle Cramp/drug therapy/etiology ; Respiratory Insufficiency/etiology/therapy ; Self-Help Devices ; Sialorrhea/drug therapy/etiology ; Sleep Wake Disorders/drug therapy/etiology ; }, }
@article {pmid3102155, year = {1986}, author = {Formisano, R and Antonini, G and Bove, R and Millefiorini, M and Ruggieri, S}, title = {[Preliminary clinical study on the treatment of amyotrophic lateral sclerosis with TRH].}, journal = {La Clinica terapeutica}, volume = {119}, number = {6}, pages = {479-481}, pmid = {3102155}, issn = {0009-9074}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Female ; Humans ; Male ; Middle Aged ; Thyrotropin-Releasing Hormone/adverse effects/*therapeutic use ; }, }
@article {pmid3098925, year = {1986}, author = {Uchida, H and Nemoto, H and Kinoshita, M}, title = {Action of thyrotropin-releasing hormone (TRH) on the occurrence of fibrillation potentials and miniature end-plate potentials (MEPPs). An experimental study.}, journal = {Journal of the neurological sciences}, volume = {76}, number = {2-3}, pages = {125-130}, doi = {10.1016/0022-510x(86)90162-0}, pmid = {3098925}, issn = {0022-510X}, mesh = {Animals ; Evoked Potentials/drug effects ; Female ; Injections, Intravenous ; Male ; Motor Endplate/*drug effects/physiology ; Muscle Contraction/drug effects ; Muscle Denervation ; Muscles/*drug effects/physiology ; Neuromuscular Junction/*drug effects ; Rats ; Rats, Inbred Strains ; Thyrotropin-Releasing Hormone/*pharmacology ; }, abstract = {The effect of TRH on fibrillation potentials and MEPPs were studied to determine the sites of action of TRH on muscle weakness. Intravenous administration of 10(-4) U thyroid-stimulating hormone (TSH) did not change the fibrillation-frequency of the denervated muscles of rats, but subsequent intravenous administration of 1 mg TRH did. Drip application of 0.6 mg TRH directly onto the denuded denervated muscles of rats did not cause an increase in fibrillation. Application of 1 mg TRH to the rat diaphragm increased the frequency of MEPPs. Both the increase in frequency of fibrillation potentials and the increase in frequency of MEPPs by application of TRH suggest that TRH influences nerve terminals, and that TRH seems suitable for treatment of muscle weakness in patients with ALS.}, }
@article {pmid2947358, year = {1986}, author = {Hartner, WC and De Fazio, SR and Maki, T and Markees, TG and Monaco, AP and Gozzo, JJ}, title = {Prolongation of renal allograft survival in antilymphocyte-serum-treated dogs by postoperative injection of density-gradient-fractionated donor bone marrow.}, journal = {Transplantation}, volume = {42}, number = {6}, pages = {593-597}, doi = {10.1097/00007890-198612000-00004}, pmid = {2947358}, issn = {0041-1337}, support = {AI 14551/AI/NIAID NIH HHS/United States ; AM 33466/AM/NIADDK NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/therapeutic use ; Bone Marrow Cells ; Bone Marrow Transplantation ; Cell Separation ; Centrifugation, Density Gradient ; Creatinine/blood ; Dogs ; Female ; Graft Survival ; *Kidney Transplantation ; Lymphocyte Culture Test, Mixed ; Male ; Transplantation, Homologous ; }, abstract = {Posttransplant injection of fractionated donor bone marrow cells results in the prolonged survival of mouse skin allografts. In this investigation, we extended the study to the use of donor bone marrow fractionated by density-gradient centrifugation in a larger animal model, canine renal transplantation. Renal allografts were placed in outbred, histoincompatible dogs treated daily with rabbit or horse antilymphocyte serum (ALS) from days -6 to +7 relative to kidney transplantation on day 0. Fresh, unfractionated donor bone marrow (BM) or a bone marrow fraction (BM Fr3) produced by centrifugation in a discontinuous Percoll density gradient was intravenously infused into recipients on days +13 or +14. Alternatively, frozen/thawed (F/Th) BM or BM Fr3 was infused after storage at -80 degrees C for two weeks. BM Fr3 and unfractionated BM significantly (P less than 0.005) prolonged for median allograft function time (MFT) beyond the controls treated only with ALS (46 and 35 days vs. 18 days). The longer MFT with BM Fr3 was achieved with 20-40% of the unfractionated BM cell dose. In addition, BM Fr3-treated dogs exhibited a slower rate of loss of kidney function. F/Th BM was as effective as fresh BM in prolonging graft survival. A reduced mixed lymphocyte response to donor and third-party cells and markedly reduced responsiveness to Con A, PHA, and pokeweed mitogens at 30-45 days posttransplant suggested that animals were nonspecifically immunosuppressed during this period. By 60 days posttransplant, in two dogs treated with BM Fr3, the MLR to third-party cells, but not to donor cells, and the responsiveness to mitogens had returned to pre-ALS treatment values. Thus, treatment with ALS combined with fresh or F/Th BM that has been fractionated is an effective method for the prolongation of kidney allografts in dogs. The development of specific, long-term immunosuppression induced by fractionated bone marrow and success with F/Th BM in this canine renal allograft model suggests that application to human transplantation may be effective with fresh or F/Th BM fractions obtained from living-related or cadaveric donors.}, }
@article {pmid2877227, year = {1986}, author = {Calne, DB and Eisen, A and McGeer, E and Spencer, P}, title = {Alzheimer's disease, Parkinson's disease, and motoneurone disease: abiotrophic interaction between ageing and environment?.}, journal = {Lancet (London, England)}, volume = {2}, number = {8515}, pages = {1067-1070}, doi = {10.1016/s0140-6736(86)90469-1}, pmid = {2877227}, issn = {0140-6736}, support = {NS 19611/NS/NINDS NIH HHS/United States ; }, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Adult ; *Aging ; Alzheimer Disease/*etiology/pathology ; Animals ; Environmental Exposure ; Guam ; Humans ; Lathyrism/pathology/physiopathology ; Life Style ; *Motor Neurons ; Neuromuscular Diseases/*etiology/pathology ; Neurons/pathology/physiopathology ; Parkinson Disease/*etiology/pathology ; Poliomyelitis/pathology/physiopathology ; Pyridines/adverse effects ; Time Factors ; }, abstract = {The hypothesis is that Alzheimer's disease, Parkinson's disease (PD), and motoneurone disease are due to environmental damage to specific regions of the central nervous system and that the damage remains subclinical for several decades but makes those affected especially prone to the consequences of age-related neuronal attrition. This proposal is based on the association between environmental factors and certain neurodegenerative diseases (eg, methylphenyltetra-hydropyridine and parkinsonism, poliovirus infection and post-poliomyelitis syndrome, chickling pea ingestion and lathyrism, an unidentified environmental factor and amyotrophic lateral sclerosis-PD complex of Guam, and trauma and pugilist's encephalopathy) and on the long latent period between exposure to environmental factor and the appearance of symptoms in some of these disorders. The practical implications of this hypothesis are that epidemiological attention should be focussed on the environment in early rather than late life, prevention may be a realistic goal if the cause of subclinical damage can be identified, a search should be undertaken for causal mechanisms linking subclinical neuronal damage due to an environmental factor and the normal ageing process, and (4) better understanding of the regional selective vulnerability of the nervous system to the ageing process might allow a rational approach to treatment.}, }
@article {pmid3091628, year = {1986}, author = {Kaplan, MM and Taft, JA and Reichlin, S and Munsat, TL}, title = {Sustained rises in serum thyrotropin, thyroxine, and triiodothyronine during long term, continuous thyrotropin-releasing hormone treatment in patients with amyotrophic lateral sclerosis.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {63}, number = {4}, pages = {808-814}, doi = {10.1210/jcem-63-4-808}, pmid = {3091628}, issn = {0021-972X}, support = {R01-AM-35141/AM/NIADDK NIH HHS/United States ; RR-00054/RR/NCRR NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/blood/*drug therapy ; Female ; Humans ; Long-Term Care ; Male ; Pituitary Function Tests ; Prolactin/blood ; Thyroid Function Tests ; Thyrotropin/*blood ; Thyrotropin-Releasing Hormone/*therapeutic use ; Thyroxine/*blood ; Triiodothyronine/*blood ; }, abstract = {In a pilot therapeutic trial, four patients with amyotrophic lateral sclerosis (ALS) were treated with long term, continuous infusions of TRH, three intrathecally and one epidurally. They had prompt increases in serum TSH and thyroid hormone concentrations, averaging 120% for TSH, 49% for serum T4, 68% for the serum free T4 index, 49% for serum T3, and 67% for the serum free T3 index. These elevations were statistically significant for all but serum T3 and persisted for the duration of treatment (4-7 months). Mean values during treatment were near the upper limit of normal for each of these hormone measurements. After TRH withdrawal, serum TSH fell transiently below the normal range. A comparison group of four patients with ALS treated by twice weekly intrathecal bolus doses of TRH had no significant changes in serum TSH, T4, or T3. During continuous TRH treatment, the responsiveness of both TSH and PRL to a standard iv TRH stimulation test was blunted, but not abolished. Basal serum PRL was occasionally elevated in the two women during continuous TRH treatment, but was normal in the men, and serum GH was normal in all patients. In the patients receiving continuous TRH treatment, indexes of end-organ effects of thyroid hormone were inconclusive; none had a rise in serum ferritin, one of four had a rise in serum sex hormone-binding globulin, and three had increased creatinuria. These results provide direct evidence in man that chronic TRH administration can cause modest sustained increases in serum TSH and thyroid hormones, though the metabolic consequences of these changes are uncertain, and appears to raise the set-point of the pituitary-thyroid axis, i.e. the serum T4 and T3 concentrations needed for a given degree of suppression of basal TSH secretion.}, }
@article {pmid3741210, year = {1986}, author = {Dalakas, MC and Aksamit, AJ and Madden, DL and Sever, JL}, title = {Administration of recombinant human leukocyte alpha 2-interferon in patients with amyotrophic lateral sclerosis.}, journal = {Archives of neurology}, volume = {43}, number = {9}, pages = {933-935}, doi = {10.1001/archneur.1986.00520090061018}, pmid = {3741210}, issn = {0003-9942}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; Interferon Type I/*therapeutic use ; Middle Aged ; }, abstract = {Recombinant leukocyte alpha 2-interferon (with greater than 98% purity) was evaluated in a pilot treatment in six patients with amyotrophic lateral sclerosis and one patient with slowly progressive postpoliomyelitis motor neuron disease. Interferon, administered subcutaneously in doses of 2 million units three times per week for four months, was ineffective in improving, arresting, or slowing the pace of progression in all the patients who were followed up for ten to 14 months after the end of therapy.}, }
@article {pmid3744799, year = {1986}, author = {Breuer, A}, title = {Can a healthy subject volunteer to be injured in research?.}, journal = {The Hastings Center report}, volume = {16}, number = {4}, pages = {31-33}, pmid = {3744799}, issn = {0093-0334}, mesh = {Codes of Ethics ; *Ethics, Medical ; Female ; *Human Experimentation ; Humans ; *Informed Consent ; Male ; Middle Aged ; *Nontherapeutic Human Experimentation ; *Risk Assessment ; }, }
@article {pmid3526180, year = {1986}, author = {Mora, JS and Munsat, TL and Kao, KP and Finison, LJ and Hedlund, W and Bradley, GA and Scheife, R and Georgiades, JA}, title = {Intrathecal administration of natural human interferon alpha in amyotrophic lateral sclerosis.}, journal = {Neurology}, volume = {36}, number = {8}, pages = {1137-1140}, doi = {10.1212/wnl.36.8.1137}, pmid = {3526180}, issn = {0028-3878}, mesh = {Amyotrophic Lateral Sclerosis/cerebrospinal fluid/*drug therapy ; Clinical Trials as Topic ; Female ; Humans ; Injections, Spinal ; Interferon Type I/administration &amp; dosage/adverse effects/blood/*therapeutic use ; Male ; }, abstract = {Ten patients with amyotrophic lateral sclerosis were given intrathecal injections of natural interferon alpha, 1 million units weekly for 7 to 24 weeks. Six patients completed the trial. Four voluntarily withdrew after 7 to 13 injections. The slopes of deterioration for 40 quantitative tests of neuromuscular function for the control and treatment periods were compared by paired t test in the six patients who completed the trial and in the patient who withdrew after 13 injections. No significant differences were found. The patients tolerated treatment well. The CSF reaction was modest and spontaneously reversible. Indomethacin and ibuprofen blocked interferon side effects.}, }
@article {pmid3748635, year = {1986}, author = {Dalessio, DJ}, title = {A possible treatment for amyotrophic lateral sclerosis.}, journal = {The Pavlovian journal of biological science}, volume = {21}, number = {3}, pages = {124}, doi = {10.1007/BF02699347}, pmid = {3748635}, issn = {0093-2213}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Female ; Humans ; Male ; Middle Aged ; Poliovirus Vaccine, Inactivated/*therapeutic use ; }, }
@article {pmid3097367, year = {1986}, author = {Yamane, K and Osawa, M and Kobayashi, I and Maruyama, S}, title = {Treatment of amyotrophic lateral sclerosis with thyrotropin-releasing hormone (TRH).}, journal = {The Japanese journal of psychiatry and neurology}, volume = {40}, number = {2}, pages = {179-187}, doi = {10.1111/j.1440-1819.1986.tb03140.x}, pmid = {3097367}, issn = {0912-2036}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Female ; Humans ; Injections, Intramuscular ; Injections, Intravenous ; Male ; Middle Aged ; Thyrotropin-Releasing Hormone/*therapeutic use ; }, abstract = {Despite the efforts of many workers, the cause and therapy has not been clarified. We carried out the therapeutic trial of thyrotropin releasing hormone (TRH) for amyotrophic lateral sclerosis (ALS) from January, 1979 to January, 1983. There were 16 subjects. The patients were given a low dose (0.5-2 mg) of TRH intravenously or intramusculary. Mild to moderate improvement was found in 9 (56%) of 16 patients. TRH has been reported to have the activating effects on the pyramidal tract, brainstem motor nuclei, and motoneuron in the spinal cord as a neurotransmitter or neuromodulator. We thought such action of TRH to be useful to the therapy of ALS.}, }
@article {pmid3954622, year = {1986}, author = {Brown, RH and Hauser, SL and Harrington, H and Weiner, HL}, title = {Failure of immunosuppression with a ten- to 14-day course of high-dose intravenous cyclophosphamide to alter the progression of amyotrophic lateral sclerosis.}, journal = {Archives of neurology}, volume = {43}, number = {4}, pages = {383-384}, doi = {10.1001/archneur.1986.00520040063021}, pmid = {3954622}, issn = {0003-9942}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Cyclophosphamide/*therapeutic use ; Female ; Humans ; Injections, Intravenous ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disorder of the nervous system for which there is no known treatment. Because recent studies have suggested that there may be abnormalities of the immune function in patients with ALS and since we have found a beneficial effect from a short course of intensive immunosuppression with cyclophosphamide in progressive multiple sclerosis, we treated six patients with ALS with a ten- to 14-day course of intensive immunosuppression in a pilot study. At 18 months following therapy, all patients showed a continued progression of the disease; four of the six patients died. We conclude that this form of immunosuppression does not alter the course of ALS.}, }
@article {pmid3522415, year = {1986}, author = {Sundaresan, P and Sainis, KB and Phondke, GP and Sundaram, K}, title = {Suppression of skin allograft rejection by post-transplantation administration of specific anti-lymphocyte serum.}, journal = {Immunology letters}, volume = {12}, number = {4}, pages = {201-205}, doi = {10.1016/0165-2478(86)90005-2}, pmid = {3522415}, issn = {0165-2478}, mesh = {Animals ; Antibody Specificity ; Antilymphocyte Serum/administration &amp; dosage/immunology/*pharmacology ; Female ; Graft Rejection/*drug effects ; Immunosuppression Therapy/methods ; Injections, Intraperitoneal ; Lymph Nodes/immunology ; Lymphocytes/immunology ; Male ; Mice ; Mice, Inbred Strains/immunology ; Rabbits/immunology ; Skin/immunology ; *Skin Transplantation ; Transplantation, Homologous ; }, abstract = {An heterologous anti-lymphocyte serum ALS(I-GR), was raised in rabbits by immunization with draining lymph node cells of AKR mice which had rejected DBA/2 skin allografts. Treatment of AKR mice with this ALS on the 4th day after DBA/2 skin grafting, significantly prolonged the survival of the graft in comparison with that in allografted mice treated with normal rabbit serum. In contrast, ALS prepared against unsensitized lymph node cells was found to be ineffective when administered after transplantation. A further prolongation of allograft survival was obtained when ALS(I-GR) was administered to recipients on days +4 and +7. ALS(I-GR) seemed to specifically suppress the rejection of DBA/2, but not of C57 BL/6 skin grafts. The suppressive action of ALS(I-GR) was not due to cross reactive (anti-DBA) antibodies and was probably directed against idiotypic determinants on antigen-stimulated cells.}, }
@article {pmid3954330, year = {1986}, author = {D'Ambrosio, SM and Su, C and Chang, MJ and Oravec, C and Stoica, G and Koestner, A}, title = {DNA damage, repair, replication, and tumor incidence in the BDIV rat strain following administration of N-ethyl-N-nitrosourea.}, journal = {Anticancer research}, volume = {6}, number = {1}, pages = {49-54}, pmid = {3954330}, issn = {0250-7005}, mesh = {Animals ; Brain/drug effects/metabolism ; *Cell Transformation, Neoplastic/drug effects ; *DNA Repair ; *DNA Replication ; *Ethylnitrosourea ; Female ; Kidney/drug effects/metabolism ; Liver/drug effects/metabolism ; Male ; Mammary Neoplasms, Experimental/chemically induced/genetics ; Neoplasms, Experimental/*chemically induced/genetics ; Rats ; Rats, Inbred Strains ; }, abstract = {Berlin-Druckrey (BD-IV) rats were used to evaluate the level of neoplastic transformation, initiation of DNA damage and repair following treatment with N-ethyl-N-nitrosourea (ENU). ENU, a potent neurocarcinogen in the Sprague-Dawley (CD) and BDIX rat strains, was a less potent neurocarcinogen when administered to 30 day old BDIV rats. ENU induced significantly higher levels of tumors of the nervous system, kidney, and liver in CD rats than in BDIV rats. Initial DNA damage was determined by quantitating and comparing the number of alkaline labile sites (ALS) and alkylation of [14C]ENU to deoxyguanosine in the brain, kidney, and liver of BDIV rats. A smaller percentage of ALS were lost from the DNA of the brain (10-15%) than from the kidney (19-27%) and liver (30%). Similarly, loss of 0(6)-ethylguanine was greatest in liver (100%), next in kidney (73%), and least in brain (23%) DNA during a seven-day period. Loss of N7-ethylguanine ranged between 23-44%. These levels of repair are similar to those previously observed in the more sensitive Sprague-Dawley rat. Cellular replication was highest in the liver and lowest in the brain of BDIV rats at 30 days of age and was inhibited to varying extents in all three tissues by ENU. These data indicate, that while there is a good correlation between organ sensitivity to ENU induced carcinogenesis and the persistence of DNA lesions and levels of DNA replication in the same strain of rat, there is no correlation across strains with different carcinogenic potential.}, }
@article {pmid3551109, year = {1986}, author = {Akimov, GA and Golovkin, VI and Ankhimova, ES and Maiorova, LP and Reshetniak, AV}, title = {[Interferon in the treatment of amyotrophic lateral sclerosis].}, journal = {Sovetskaia meditsina}, volume = {}, number = {12}, pages = {51-55}, pmid = {3551109}, issn = {0038-5077}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*therapy ; Clinical Trials as Topic ; Female ; Humans ; Interferon Type I/*therapeutic use ; Male ; Middle Aged ; }, }
@article {pmid3540991, year = {1986}, author = {Billingham, RE and Head, JR}, title = {Recipient treatment to overcome the allograft reaction, with special reference to nature's own solution.}, journal = {Progress in clinical and biological research}, volume = {224}, number = {}, pages = {159-185}, pmid = {3540991}, issn = {0361-7742}, support = {AI10678/AI/NIAID NIH HHS/United States ; HD18717/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Cyclosporins/therapeutic use ; Female ; *Graft Rejection/drug effects ; Humans ; Immune Tolerance ; Immunosuppression Therapy ; Maternal-Fetal Exchange ; Pregnancy/immunology ; Transplantation, Homologous ; Trophoblasts/immunology ; }, abstract = {The 6th decade of this century was particularly important for transplantation immunology. The universality of allograft rejection by normal hosts had won general acceptance and, experimentally, several means of abrogating host reactivity to allografts were discovered. These included sub-lethal whole body irradiation, administration of certain corticosteroid hormones and inoculation of very young animals with living cellular inocula from the future graft donor--i.e., classic, neonatal tolerance. The latter was particularly important since it indicated the feasibility of a specific, permanent solution to the clinical allograft problem. Radiation and drug-induced tolerance in adult subjects came along and chemical immunosuppressants, which led to successful clinical use of azathioprine. The important rediscovery of ALS pointed towards the development and clinical application of monoclonal antibodies many years later. With the development of immunogenetics and transplantation biology came recognition that the conceptus is a highly successful allograft, raising the question of how it is able to withstand rejection by its immunocompetent mother for the duration of pregnancy. Hopefully, knowledge of the principle(s) involved when they are finally elucidated will be applicable to clinical allograft recipients. Although functional hypoantigenicity of the syncytial trophoblast probably plays a major role in protecting the allogeneic conceptus, a strong case now exists that local, cell-based, immunosuppressive and immunoprotective activity within the placenta and decidua, mediated by suppressor and other cells, is important.}, }
@article {pmid3512457, year = {1986}, author = {Mottram, PL and Mirisklavos, A and Dumble, LJ and Clunie, GJ}, title = {Effects of cyclosporin A, antilymphocyte serum and donor-specific transfusions on murine delayed-type hypersensitivity and skin graft survival.}, journal = {International archives of allergy and applied immunology}, volume = {79}, number = {3}, pages = {296-304}, doi = {10.1159/000233990}, pmid = {3512457}, issn = {0020-5915}, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; *Blood Transfusion ; Cyclosporins/*pharmacology ; Female ; Graft Rejection ; *Graft Survival ; Histocompatibility Antigens Class II/analysis ; Hypersensitivity, Delayed/*immunology ; Immunosuppression Therapy ; Isoantigens/immunology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred CBA ; Rabbits ; Skin Transplantation ; T-Lymphocytes/immunology ; Transplantation, Homologous ; }, abstract = {The effect of immunosuppressive reagents cyclosporin A (CsA) and rabbit anti-mouse antilymphocyte serum (ALS) on the response to alloantigens was studied in inbred mouse strains. Alloantigen was given either as a cell suspension which induced a delayed-type hypersensitivity reaction (DTH), or as a full-thickness skin graft. Dose-response studies showed that DTH reactions in CBA mice sensitised to BALB/c cells were reduced to background levels when recipient mice were treated with 100 mg/kg CsA on days 0, 4 and 6 after primary alloantigenic challenge. The response to a second challenge was significantly decreased by CsA treatment during primary or secondary exposure to alloantigen and CsA was as effective as ALS in abrogating both primary and secondary DTH reactions. Survival of full-thickness grafts of BALB/c skin on CBA mice was increased from 9 to 23 days by ALS treatment on days -1 and +2, with grafts given on day 0. Long-term treatment with CsA, from day -14 to +12, also prolonged graft survival from 9 to 18 days but donor-specific transfusions, with or without concomitant ALS or CsA treatment, decreased graft survival and often sensitised the recipients. This occurred with transfusions administered from -63 to -7 days and on the day of grafting. Thus, in H-2 mismatched mice, both CsA and ALS treatments produced a state of tolerance when administered during short-term exposure to alloantigen.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid3510490, year = {1986}, author = {De Fazio, SR and Hartner, WC and Monaco, AP and Gozzo, JJ}, title = {Mouse skin graft prolongation with donor-strain bone marrow and antilymphocyte serum. Effect of bone marrow cell storage.}, journal = {Transplantation}, volume = {41}, number = {1}, pages = {26-28}, doi = {10.1097/00007890-198601000-00004}, pmid = {3510490}, issn = {0041-1337}, support = {AM 33466/AM/NIADDK NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/*administration &amp; dosage ; *Bone Marrow Transplantation ; Cold Temperature ; Freezing ; *Graft Survival ; Immunosuppression Therapy/*methods ; Mice ; *Skin Transplantation ; Tissue Preservation ; }, abstract = {Significant extended survival of C3H/He skin grafts in antilymphocyte serum (ALS)-treated B6AF1 mice can be brought about by the injection of donor-strain bone marrow on day 6 or 7 after grafting. In the present study, survival of the active graft-prolonging bone marrow cells under several storage conditions was investigated. The bone marrow cells retained their effectiveness if stored at 4 degrees C in 10% fetal calf serum for 18 hr prior to injection, but not if maintained at 37 degrees C under standard lymphocyte culture conditions. Freezing the cells for 10 days in a cryoprotective medium preserved the ability of the cells to prolong graft survival. In fact, freeze-thawed cells were more effective than fresh cells. Extension of the ALS-bone marrow treatment protocol to human transplantation is expected to be facilitated by frozen and short-term refrigerated storage of the donor bone marrow.}, }
@article {pmid3488280, year = {1986}, author = {John, J}, title = {Failure of electrical myofeedback to augment the effects of physiotherapy in stroke.}, journal = {International journal of rehabilitation research. Internationale Zeitschrift fur Rehabilitationsforschung. Revue internationale de recherches de readaptation}, volume = {9}, number = {1}, pages = {35-45}, doi = {10.1097/00004356-198603000-00004}, pmid = {3488280}, issn = {0342-5282}, mesh = {Adolescent ; Adult ; Cerebrovascular Disorders/*rehabilitation ; *Electric Stimulation Therapy ; *Feedback ; Female ; Humans ; Male ; Middle Aged ; Muscles/*physiology ; *Physical Therapy Modalities ; }, abstract = {Electromyographic biofeedback has been used with some success to treat patients with disturbances of muscle tone resulting from neurological disease. The aim of this study was to incorporate electrical myofeedback as an integral part of a physiotherapeutic regime designed to improve quality of movement and function in limbs weakened or paralysed by stroke. A portable, inexpensive E. M. G. biofeedback machine was used. Stainless steel skin electrodes were applied which needed minimal skin preparation. Twelve adults, (five male, seven female, mean age 44.2 years and 51.3 years respectively) who were referred for treatment due to weakness of limb muscles due to disease of the brain or spinal cord, were treated. The mean time from onset of incidence to treatment was 75.5 days. Each patient received six weeks of treatment. This was divided into two phases. Phase 1, (weeks 1, 2, 3) and phase 2 (weeks 4, 5, 6). Physiotherapy, and physiotherapy with biofeedback was randomly allocated to either phase. Each patient acted as his/her own control. A validated assessment was carried out by an independent therapist at the start of treatment, after three weeks and after six weeks of treatment. General function, knee function, range of movement of the affected side and timed tests were measured. Results show an overall improvement in general function. The second phase of treatment was slightly more favourable to improvement, but there was no indication that biofeedback significantly improved the outcome. In three tests it was equally significant to the physiotherapy applied; in one test it improved the effectiveness of physiotherapy and in one test it reduced the effectiveness of physiotherapy. This suggests that a six week course of physiotherapy improved muscular function and range of movements in patients with weakness due to upper motor neurone disease, but that these effects are not enhanced by myofeedback.}, }
@article {pmid3154372, year = {1986}, author = {Sanfilippo, F and Vaughn, WK and Lefor, WM}, title = {HLA matching for cadaver renal transplantation in SEOPF: the impact of cyclosporine. Southeastern Organ Procurement Foundation.}, journal = {Clinical transplants}, volume = {}, number = {}, pages = {109-120}, pmid = {3154372}, issn = {0890-9016}, mesh = {Cyclosporins/therapeutic use ; Foundations ; Graft Survival ; HLA Antigens ; Humans ; Kidney Transplantation/*immunology/statistics &amp; numerical data ; Southeastern United States ; Tissue and Organ Procurement ; }, abstract = {Since the introduction of CsA in 1983, several changes in SEOPF activity have been observed: 1. Organ recovery has increased at a rate slower than candidate registration, whereas the utilization rate has increased substantially. 2. Overall organ sharing has decreased for both CsA and non-CsA-treated patients. 3. The percentage of poor HLA-A,B matched recipients has increased for both CsA- and non-CsA-treated patients. 4. The use of cold storage preservation has increased for both CsA- and non-CsA-treated patients. 5. The use of ALS has decreased, predominantly in CsA-treated patients. 6. A majority of diabetics are being treated with CsA. 7. There is substantial individual variation in SEOPF center preferences for CsA use, HLA matching, and use of shared kidneys. In terms of graft outcome, the following associations have been observed: 1. The incidence of delayed graft function has increased with shared kidneys only, suggesting sharing of poorer quality as well as fewer kidneys. 2. First transplant recipients receiving CsA tend to have lower delayed graft function rates, possibly as a result of treatment selection. However, the risk of graft failure associated with delayed function is greater in patients receiving CsA. 3. By univariate analysis, there is an additive benefit of HLA-A,B matching and CsA use in patients receiving local kidneys with immediate function. 4. By multivariate analysis, there is a significant relative risk of graft rejection associated with poor HLA-A,B matching in patients receiving CsA. 5. By multivariate analysis, there is an apparent risk of graft loss associated with shared organs, but only in patients receiving CsA. One possible explanation is that poorer quality kidneys are being accepted for patients treated with CsA. 6. By multivariate subset analysis, there is a significant benefit of CsA use in patients whose HLA is poorly matched, but no observed benefit in well-matched patients. 7. Definitive evaluation of the relative effects of CsA and HLA matching on cadaver renal allograft survival must await long-term follow-up data on survival and function, and the ability to control for center bias in sharing, HLA matching, and CsA use.}, }
@article {pmid3088700, year = {1986}, author = {Serratrice, G and Desnuelle, C and Crevat, A and Guelton, C and Meyer-Dutour, A}, title = {[Treatment of amyotrophic lateral sclerosis with thyrotropin releasing hormone].}, journal = {Revue neurologique}, volume = {142}, number = {2}, pages = {133-139}, pmid = {3088700}, issn = {0035-3787}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Female ; Humans ; Male ; Middle Aged ; Thyrotropin-Releasing Hormone/administration &amp; dosage/adverse effects/*therapeutic use ; Time Factors ; }, abstract = {Nine patients (7 with amyotrophic lateral sclerosis, 1 with progressive spinal amyotrophy and 1 with chronic anterior poliomyelitis) were treated by sequential intravenous administration of 240 mg of TRH over one hour every two weeks. Results were assessed by an analytical evaluation of muscle strength before and 24 h after each infusion and by objective and subjective evaluation of spasticity. Significant improvement, as shown by statistical analysis, was noted in muscle strength in the 9 patients by 5 infusions over a 4-week period and a sub-group of 5 patients treated by 8 infusions over 10 weeks. Continued use of this therapy is justified by the need to determine its long-term effects and the psychological improvement noted in some patients after an even transient improvement in motor performance. However this treatment is obviously not curative.}, }
@article {pmid2952486, year = {1986}, author = {Laragh, JH}, title = {Endocrine mechanisms in congestive cardiac failure. Renin, aldosterone and atrial natriuretic hormone.}, journal = {Drugs}, volume = {32 Suppl 5}, number = {}, pages = {1-12}, pmid = {2952486}, issn = {0012-6667}, mesh = {Aldosterone/*blood ; Atrial Natriuretic Factor/*blood ; Endocrine Glands/*physiopathology ; Heart Failure/*physiopathology ; Humans ; Renin/*blood ; }, abstract = {Overactivity of the renin-angiotensin-aldosterone system occurs in the syndrome of congestive cardiac failure. Aldosterone overactivity is crucially involved in maintaining the oedematous state as evidenced by its often complete correction by adrenalectomy, or by aldosterone antagonists, in both experimental and clinical heart failure. The hyperaldosteronism of heart failure can also be attacked by angiotensin-converting enzyme (ACE) inhibition, which not only blocks the angiotensin drive to aldosterone, but also unloads the heart by blocking renin-angiotensin-mediated vasoconstriction. Accordingly, ACE inhibition alone, if continued in full dosage, can often reduce or obviate the need for daily thiazide diuretic therapy. This specific, two-pronged therapy with fewer side effects emerges as a primary strategy for the treatment of congestive heart failure. To learn more about why and how the renin system becomes involved in heart failure, the renal functional abnormalities have been re-examined. The effects of sodium administration on central haemodynamics and on the activity of the renin system have als been studied. This research has led to a consideration of the role of atrial natriuretic hormone in this pathophysiological interplay. The study recharacterized renal haemodynamic patterns and indicated that in congestive heart failure there is a disproportionate diversion of blood away from the kidneys because of afferent vasoconstriction. However, the glomerular filtration rate is maintained by concurrent efferent arteriolar constriction, expressed by a rising filtration fraction. As heart failure advances, the filtration fraction can no longer rise. At this point, the glomerular filtration rate becomes flow-dependent and falls commensurately with the declining cardiac output. These intrarenal patterns may be mediated in part by increased intrarenal renin activity resulting from heart failure and diuretic therapy. A further study of the abnormal renin system activity operating in heart failure has shown it to be very sensitive to dietary salt intake. Thus, consuming modest amounts of salt (100 mEq/day) was sufficient to markedly suppress renin and aldosterone values. However, since peripheral resistance was not changed, another non-renin, sodium-related mechanism must take over to sustain increased arterial constriction. The fact that captopril challenge evoked no response before and a large response after sodium depletion supports this concept. preliminary data suggest that atrial natriuretic hormone may also be important in congestive heart failure by opposing renin system activity at 4 sites.(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid4095339, year = {1985}, author = {Bady, B and Chauplannaz, G and Girard-Madoux, M and Chan, V and Trillet, M and Lapras, C}, title = {[Electro-clinical data in medullary forms of the Chiari malformation without syringomyelia].}, journal = {Revue d'electroencephalographie et de neurophysiologie clinique}, volume = {15}, number = {3}, pages = {243-249}, doi = {10.1016/s0370-4475(85)80006-x}, pmid = {4095339}, issn = {0370-4475}, mesh = {Adult ; Arnold-Chiari Malformation/*diagnosis ; Electromyography ; Female ; Humans ; Male ; Middle Aged ; Syringomyelia/*diagnosis ; }, abstract = {The electrophysiological findings in 18 patients with Arnold-Chiari malformation (ACM) revealed by spinal symptoms excluding syringomyelic syndrome (Brown-Sequard syndrome, paraparesis with or without posterior column involvement, motor neuron syndrome or more complex myelopathies) are reported. In 16 cases, EMG disclosed abnormalities consistent with lesion of anterior horn cells restricted to upper limb in 7 cases, and generalized in 9 cases. In 2 cases, motor and sensory conductions were abnormal. The occurrence of such abnormalities in patients with ACM is emphasized as they could lead to confusion with amyotrophic lateral sclerosis or spinal muscular atrophy. Neuroradiological studies are therefore necessary owing to possible surgical treatment. The hypothesis relating lower motor involvement and ACM are reviewed.}, }
@article {pmid4082913, year = {1985}, author = {Iivanainen, M and Laaksonen, R and Niemi, ML and Färkkilä, M and Bergström, L and Mattson, K and Niiranen, A and Cantell, K}, title = {Memory and psychomotor impairment following high-dose interferon treatment in amyotrophic lateral sclerosis.}, journal = {Acta neurologica Scandinavica}, volume = {72}, number = {5}, pages = {475-480}, doi = {10.1111/j.1600-0404.1985.tb00904.x}, pmid = {4082913}, issn = {0001-6314}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*therapy ; Brain Diseases/etiology ; Brain Stem ; Electroencephalography ; Female ; Frontal Lobe ; Humans ; Interferon Type I/*adverse effects ; Male ; Memory Disorders/diagnosis/*etiology ; Middle Aged ; Neuropsychological Tests ; Psychomotor Disorders/diagnosis/*etiology ; }, abstract = {Patients with amyotrophic lateral sclerosis were treated with high-dose intravenous infusion of human leukocyte interferon for six days. Neuropsychological examinations were carried out before, during and after the treatment. Marked reversible dysfunction was detected in immediate memory functions, coordination of hand movements, and drawing. Motor perseveration, micrographia, and slowing of behaviour were also observed. Changes appeared four to 12 days after start of treatment, with the peak on days six to eight. Recovery was almost complete by day 15. Intellectual ability, as measured by three WAIS subtests, praxis of hand movements, visuognostic functions, speech, reading, writing, and calculation remained essentially unaffected. The profile of the neuropsychological deficits observed, the absence of defects typical of focal posterior cortical lesions, the simultaneously slowed electroencephalographic activity with frontal accentuation, and the increased central conduction times of brain stem auditory evoked potentials suggest frontobasal involvement.}, }
@article {pmid2864375, year = {1985}, author = {De Fazio, S and Hartner, WC and Monaco, AP and Gozzo, JJ}, title = {Mouse skin graft prolongation with donor strain bone marrow and anti-lymphocyte serum: surface markers of the active bone marrow cells.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {135}, number = {5}, pages = {3034-3038}, pmid = {2864375}, issn = {0022-1767}, support = {AM 33466/AM/NIADDK NIH HHS/United States ; }, mesh = {Animals ; Antigens, Surface/analysis ; Antilymphocyte Serum/*therapeutic use ; Bone Marrow/immunology ; Bone Marrow Cells ; *Bone Marrow Transplantation ; Cell Separation/methods ; *Graft Enhancement, Immunologic/*methods ; Histocompatibility Antigens Class II/analysis ; Male ; Mice ; Mice, Inbred C3H ; Phenotype ; Receptors, Antigen/*analysis ; Receptors, Antigen, B-Cell/analysis ; Receptors, Complement/analysis ; Receptors, Fc/analysis ; Receptors, IgG ; *Skin Transplantation ; Thy-1 Antigens ; }, abstract = {The survival of C3H/HeJ skin grafts on B6AF1 mice treated with anti-lymphocyte serum (ALS) can be significantly prolonged by the injection of the host with C3H/HeJ bone marrow. Although the prolongation is apparently due at least in part to the ultimate presence in the host of specific suppressor cells of donor origin, little is known about the nature of the cells in the marrow inoculum that are responsible for this effect. The present investigation was undertaken to characterize surface markers of the active bone marrow cells. Marker-positive populations were either depleted and enriched by panning techniques or depleted by killing with specific antibody and complement, and then were assayed for their ability to prolong graft survival. Cells that were adherent to anti-Ia-coated plates extended graft survival only slightly better than did treatment with ALS alone, whereas nonadherent (Ia-depleted) cells, as well as cells treated with anti Ia and complement, retained good prolonging activity. Similarly, panning on anti-immunoglobulin (Ig)-coated plates produced an active, Ig+-depleted population and an inactive adherent population, and killing of Thy-1+ cells with antibody and complement did not compromise the ability of the bone marrow inoculum to prolong graft survival. Complement receptor-positive (EAC+) and Fc gamma receptor-positive cells (EA+) were separated by panning on plates coated with sheep erythrocytes/antibody/complement and erythrocytes/7S antibody respectively. Adherent, EAC+-enriched cells were only slightly active, whereas the nonadherent, EAC-depleted population was fully active in graft prolongation. However, both Fc gamma R+ (EA+)-enriched and depleted populations were active, with the enriched fraction producing significantly better prolongation than the depleted population. Thus, the bone marrow cells that can prolong skin graft survival in ALS-treated mice appear to be Ia-, Thy-1+, largely complement receptor negative, and Ig-, but are largely positive for Fc gamma receptors.}, }
@article {pmid4034539, year = {1985}, author = {Fletcher-McGruder, BL and Gerritsen, GC}, title = {Effect of antilymphocyte serum and neonatal thymectomy upon onset of diabetes in the Chinese hamster.}, journal = {Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)}, volume = {180}, number = {1}, pages = {92-97}, doi = {10.3181/00379727-180-42148}, pmid = {4034539}, issn = {0037-9727}, support = {AM 21933-02/AM/NIADDK NIH HHS/United States ; }, mesh = {Animals ; Animals, Newborn ; Blood Glucose/analysis ; Cricetinae ; Cricetulus ; Diabetes Mellitus, Experimental/*physiopathology ; *Immune Sera ; Lymphocyte Transfusion ; Lymphocytes/*immunology ; Mice ; Mice, Nude ; *Thymectomy ; Transplantation, Heterologous ; }, abstract = {Prediabetic Chinese hamsters were treated with antilymphocyte serum (ALS), or thymectomized in order to test the hypothesis that beta-cell loss leading to diabetes in this animal model was related to cell-mediated autoimmunity. In addition, passive transfer of diabetes from the Chinese hamster to the nude mouse was attempted by transplantation of lymphocytes. Treatment of prediabetic Chinese hamsters with ALS or thymectomy did not alter development or severity of diabetes in this animal model. Lymphocytes from newly diagnosed diabetic Chinese hamsters did not cause hyperglycemia in nude mice. These three lines of evidence suggest that cell-mediated autoimmunity does not contribute to the etiology of diabetes in the Chinese hamster. The Chinese hamster remains a good model for the study of those forms of diabetes not related to cell-mediated autoimmune phenomena.}, }
@article {pmid4010949, year = {1985}, author = {Olarte, MR and Shafer, SQ}, title = {Levamisole is ineffective in the treatment of amyotrophic lateral sclerosis.}, journal = {Neurology}, volume = {35}, number = {7}, pages = {1063-1066}, doi = {10.1212/wnl.35.7.1063}, pmid = {4010949}, issn = {0028-3878}, support = {MH 30906-05/MH/NIMH NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Female ; Humans ; Levamisole/*therapeutic use ; Male ; Middle Aged ; Placebos ; }, abstract = {Fifty-nine patients with amyotrophic lateral sclerosis participated in a 12-month, double-blind crossover trial. The patients were given either levamisole 150 mg or placebo in identical tablets once a week orally, and a rating of neurologic signs and symptoms was recorded on monthly visits. The patients were crossed over at 6 months. Levamisole had no effect on the rate of score decline in the 20 patients who completed the trial.}, }
@article {pmid3994083, year = {1985}, author = {Aprahamian, C and Darin, JC and Thompson, BM and Mateer, JR and Tucker, JF}, title = {Traumatic cardiac arrest: scope of paramedic services.}, journal = {Annals of emergency medicine}, volume = {14}, number = {6}, pages = {583-586}, doi = {10.1016/s0196-0644(85)80785-x}, pmid = {3994083}, issn = {0196-0644}, mesh = {Adolescent ; Adult ; Aged ; *Allied Health Personnel ; Child ; Child, Preschool ; Electrocardiography ; *Emergencies ; Emergency Medical Services ; *Emergency Medical Technicians ; Evaluation Studies as Topic ; Female ; Heart Arrest/etiology/mortality/*therapy ; Humans ; Infant ; Infusions, Parenteral ; Intubation ; Male ; Middle Aged ; Time Factors ; Trauma Centers ; Urban Population ; Wisconsin ; Wounds and Injuries/complications ; }, abstract = {The challenge of the 1960s to ambulance care provision was the stimulus for the emergence of prehospital advanced life support (ALS) being provided by paramedic personnel. While services for cardiac disease have been accepted, paramedic activities for the trauma victim continue to be a concern for many trauma surgeons. The capability and success rate of treatment, and the time spent at the scene and during transport to the hospital have raised questions about the overall need for paramedic services. Our study period was from January 1, 1981, to December 31, 1982, and it covered 95 clinically dead trauma victims who were first seen and subsequently treated by paramedics working in a medically controlled emergency medical services system. Endotracheal intubation was successful in 81 of the patients (85%). Esophageal obturator airway use was viewed as unsuccessful intubation. Intravenous (IV) access utilizing 16-gauge angiocaths was placed successfully by a peripheral or jugular vein in 70 patients (74%). Thirty-three patients averaged 860 mL volume infusion (30 to 3,000 mL). Average scene time was 22 minutes. Scene time of patients with unsuccessful IV and endotracheal intubation was 14 minutes (P = .07). Fourteen patients (14.7%) were admitted to the operating room or intensive care unit. Only three of the study group (3.2%) survived.}, }
@article {pmid3924191, year = {1985}, author = {Dennerstein, L and Spencer-Gardner, C and Gotts, G and Brown, JB and Smith, MA and Burrows, GD}, title = {Progesterone and the premenstrual syndrome: a double blind crossover trial.}, journal = {British medical journal (Clinical research ed.)}, volume = {290}, number = {6482}, pages = {1617-1621}, pmid = {3924191}, issn = {0267-0623}, mesh = {Adolescent ; Adult ; Clinical Trials as Topic ; Double-Blind Method ; Female ; Humans ; Middle Aged ; Premenstrual Syndrome/*drug therapy ; Progesterone/adverse effects/*therapeutic use ; Random Allocation ; }, abstract = {A double blind, randomised, crossover trial of oral micronised progesterone (two months) and placebo (two months) was conducted to determine whether progesterone alleviated premenstrual complaints. Twenty three women were interviewed premenstrually before treatment and in each month of treatment. They completed Moos's menstrual distress questionnaire, Beck et al's depression inventory, Spielberger et al's state anxiety inventory, the mood adjective checklist, and a daily symptom record. Analyses of data found an overall beneficial effect of being treated for all variables except restlessness, positive moods, and interest in sex. Maximum improvement occurred in the first month of treatment with progesterone. Nevertheless, an appreciably beneficial effect of progesterone over placebo for mood and some physical symptoms was identifiable after both one and two months of treatment. Further studies are needed to determine the optimum duration of treatment.}, }
@article {pmid3893843, year = {1985}, author = {Linn, PL and Horowitz, FD and Fox, HA}, title = {Stimulation in the NICU: is more necessarily better?.}, journal = {Clinics in perinatology}, volume = {12}, number = {2}, pages = {407-422}, pmid = {3893843}, issn = {0095-5108}, support = {MO1 RR00210/RR/NCRR NIH HHS/United States ; }, mesh = {Acoustic Stimulation ; Animals ; Child Behavior ; Female ; Fetus/physiology ; Humans ; Individuality ; Infant, Newborn ; Infant, Premature ; *Intensive Care Units, Neonatal ; *Physical Stimulation ; Pregnancy ; Sensory Deprivation ; Touch/physiology ; }, abstract = {Animal studies and studies with human full-term infants suggest that the stimulation present in utero affects postnatal preferences and levels of response. The premature infant does not necessarily benefit from a re-creation of the in utero environment. Each aspect of the in utero environment should be assessed independently as a potential source of added stimulation in the NICU to determine its possible effects on the development of the premature infant. The NICU environment cannot be accurately labeled by global descriptors of "deprivation" or "overstimulation." When compared with the home environments of full-term infants from lower SES homes, different aspects of the NICU environment were recorded more often, less often, or equally as often as in the full-term infants' homes. Baseline levels of stimulation should be recorded in any NICU environment prior to the institution of an intervention program. NICU caregivers tended to respond contingently to their premature patients' behaviors. However, the prematures provided few opportunities for the nurses to respond, when visual and vocal behaviors used by full-term infants were employed as the expected norm. Perhaps both the medical staff and parents should be trained to recognize and respond to the more subtle, different cues described by Als et al. as being prevalent in the behavioral repertoire of the premature infant. Based on ecologic descriptions of NICU's, researchers have suggested that an inappropriate pattern of stimulation may characterize the environment, rather than an inappropriate amount of stimulation. The NICU environment has been characterized as providing little cross-modal stimulation, few temporally patterned stimuli, and little diurnal rhythmicity. In addition, the premature infant may have few opportunities to control the environment, contrary to the full-term infant's experiences. There is evidence of some negative effects of added NICU stimulation. Individual infants should be assessed prior to intervention for their level of behavioral maturation. Interventions should be individualized for the particular needs of each infant, rather than subjecting all infants assigned to a treatment condition with a stimulation "package." The worthy goal of promoting the development of premature infants carries with it the responsibility of ensuring that no harmful effects could befall any one infant.}, }
@article {pmid3842105, year = {1985}, author = {de Wolff, FA}, title = {Toxicological aspects of aluminum poisoning in clinical nephrology.}, journal = {Clinical nephrology}, volume = {24 Suppl 1}, number = {}, pages = {S9-14}, pmid = {3842105}, issn = {0301-0430}, mesh = {Aluminum/analysis/*poisoning ; Dose-Response Relationship, Drug ; Hair/analysis ; Humans ; Kidney Failure, Chronic/complications/therapy ; Quality Control ; Renal Dialysis/adverse effects ; Spectrophotometry, Atomic ; }, abstract = {Several dialysis-related diseases can be ascribed to an increased body burden of aluminum (Al). Determination of this metal in clinical samples is of great assistance in the diagnosis, treatment and prevention of Al intoxication. As there are many pitfalls in the estimation of Al in biological fluids, the performance of these assays should be restricted to laboratories specializing in the human toxicology of metals, which are experienced in flameless atomic absorption spectrophotometry and which participate in an external quality assessment scheme. One laboratory can serve ten dialysis centers. Serum, plasma or blood are equivalent samples for the biological monitoring of Al. The assay should be performed once in a three month period, but when oral Al-containing medication is changed, toxic symptoms are suspected, or levels exceeding 100 micrograms/l are observed, Al should be determined much more frequently, e.g., once weekly. A high incidence of symptoms associated with Al poisoning is seen in patients with serum concentrations (AlS) greater than 100 micrograms/l, and it is therefore recommended to keep AlS well below this level. Scalp hair appears to be of no use for the assessment of the body burden of Al in the individual patient. For "environmental monitoring", regular analysis of the dialysis fluid is necessary. The concentration of Al in this fluid should not exceed 5 micrograms/l; higher levels lead to a positive Al balance during dialysis and may eventually result in poisoning.}, }
@article {pmid6442976, year = {1984}, author = {Hayashi, H}, title = {[Care and treatment of patients with ALS in advanced stages].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {24}, number = {12}, pages = {1274-1276}, pmid = {6442976}, issn = {0009-918X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*therapy ; Female ; Humans ; Long-Term Care ; Male ; Middle Aged ; Prognosis ; Quality of Life ; Ventilators, Mechanical ; }, }
@article {pmid6439824, year = {1984}, author = {Imoto, K and Saida, K and Iwamura, K and Saida, T and Nishitani, H}, title = {Amyotrophic lateral sclerosis: a double-blind crossover trial of thyrotropin-releasing hormone.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {47}, number = {12}, pages = {1332-1334}, pmid = {6439824}, issn = {0022-3050}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Clinical Trials as Topic ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Motor Skills/drug effects ; Thyrotropin-Releasing Hormone/*therapeutic use ; }, abstract = {A double-blind crossover trial was conducted of thyrotropin releasing hormone treatment in six patients with amyotrophic lateral sclerosis. Patients received 4 mg of thyrotropin releasing hormone intramuscularly daily during the two-week treatment period. Although three patients reported subjective improvement, objective evaluation failed to demonstrate therapeutic effectiveness of thyrotropin releasing hormone in this dosage.}, }
@article {pmid6334386, year = {1984}, author = {Tatum, AH and Bollinger, RR and Sanfilippo, F}, title = {Rapid serologic diagnosis of serum sickness from antithymocyte globulin therapy using enzyme immunoassay.}, journal = {Transplantation}, volume = {38}, number = {6}, pages = {582-586}, doi = {10.1097/00007890-198412000-00006}, pmid = {6334386}, issn = {0041-1337}, support = {AI-19368/AI/NIAID NIH HHS/United States ; }, mesh = {Antibodies, Anti-Idiotypic/immunology ; Antilymphocyte Serum/*immunology ; Enzyme-Linked Immunosorbent Assay ; Humans ; Serum Sickness/*diagnosis ; T-Lymphocytes/*immunology ; }, abstract = {Although the use of antithymocyte globulin/antilymphocyte serum (ATG/ALS) has been shown to be beneficial in treating renal allograft rejection, the incidence and nature of serum sickness reactions following such treatment have received limited attention. In the setting of rejection or infection, the diagnosis of serum sickness is often difficult on clinical grounds, and biopsy may be an undesirable means of obtaining documentation. A sensitive enzyme-linked immunosorbent assay (ELISA) was developed to detect antibodies against ATGAM (Upjohn) and was utilized in 35 patients treated for rejection with ATGAM following clinical unresponsiveness to bolus methylprednisolone therapy. Serum sickness was diagnosed clinically in 7 of these patients (20%) during or immediately following ATGAM therapy. Significant titers of anti-ATGAM antibody were found in these 7 cases, as well as 5 additional cases (14%). Upon retrospective review, the diagnosis of serum sickness was also made in each of these 5 additional cases based upon the immunopathologic detection of horse immunoglobulin deposits in vessels of tissue (lung or kidney) examined. In 2 other cases where serologic testing was negative, there was some clinical suggestion of serum sickness that could not be documented pathologically. ELISA for anti-ATGAM antibodies was negative in testing 46 control patients and pooled normal sera. In one case, retrospective testing of pre-ATGAM therapy serum samples showed significant antihorse antibodies. Despite a negative skin test prior to administration, this patient developed symptoms of serum sickness 15 days after the onset of ATGAM therapy. Extremely high titers of antibody were detected 5 days earlier (10 days posttherapy), and the presence of horse immunoglobulin immune complexes in the kidney was documented following graft loss that occurred within 4 weeks. These findings indicate (1) serologic testing for anti-ATGAM antibodies using a sensitive ELISA method provides a quick, inexpensive, noninvasive means for the presumptive diagnosis of serum sickness in complicated clinical situations, and (2) screening of patient sera prior to administration of ATGAM may be useful in avoiding potential serum sickness reactions.}, }
@article {pmid6235993, year = {1984}, author = {Lens, JW and van den Berg, WB and van de Putte, LB and Berden, JH and Lems, SP}, title = {Flare-up of antigen-induced arthritis in mice after challenge with intravenous antigen: effects of pre-treatment with cobra venom factor and anti-lymphocyte serum.}, journal = {Clinical and experimental immunology}, volume = {57}, number = {3}, pages = {520-528}, pmid = {6235993}, issn = {0009-9104}, mesh = {Animals ; Antigens/*immunology ; Antilymphocyte Serum/*pharmacology ; Arthritis/etiology/*immunology ; Arthus Reaction ; Complement System Proteins/immunology ; Elapid Venoms/*pharmacology ; Hindlimb ; Hypersensitivity, Delayed ; Male ; Mice ; Mice, Inbred C57BL ; Serum Albumin, Bovine/immunology ; T-Lymphocytes/immunology ; }, abstract = {Intravenous injection of methylated bovine serum albumin (mBSA) into mice with unilateral chronic mBSA-induced arthritis (AIA) causes a flare-up of the joint inflammation without affecting the contralateral non-arthritic knee joint. We studied the mechanism of the flare-up by decomplementation with cobra venom factor (CoVF) and by treatment with anti-lymphocyte serum (ALS) prior to the induction of the flare-up. Treatment of mice with CoVF had no effect on the induction of the flare-up reaction whereas a reversed passive Arthus reaction (RPA) in the ear of similarly treated mice was clearly suppressed. The complement activity in the serum was zero at 2 h after CoVF treatment and remained for 24 h. This indicates that this type of flare-up reaction is not complement-dependent. On the other hand, the flare-up reaction was completely abolished after treatment with ALS. Control experiments revealed that ALS treatment diminished the number of lymphocytes in the peripheral blood and clearly suppressed a delayed hypersensitivity reaction in the ear, but had no effect on an RPA. These results suggest an important role of T lymphocytes in the mechanism of the flare-up of arthritis. T lymphocytes were demonstrated in the synovial tissue of chronically inflamed joints by immunofluorescence and appeared to be diminished after ALS treatment. Interaction between exogenous antigen and antigen reactive T lymphocytes present in chronically inflamed joints, may be an important principle in the exacerbation and propagation of joint inflammation.}, }
@article {pmid6206681, year = {1984}, author = {Färkkilä, M and Iivanainen, M and Roine, R and Bergström, L and Laaksonen, R and Niemi, ML and Cantell, K}, title = {Neurotoxic and other side effects of high-dose interferon in amyotrophic lateral sclerosis.}, journal = {Acta neurologica Scandinavica}, volume = {70}, number = {1}, pages = {42-46}, doi = {10.1111/j.1600-0404.1984.tb00801.x}, pmid = {6206681}, issn = {0001-6314}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy/physiopathology ; Central Nervous System Diseases/chemically induced ; Cognition Disorders/chemically induced ; Electroencephalography ; Evoked Potentials, Auditory/drug effects ; Evoked Potentials, Visual/drug effects ; Humans ; Interferons/*administration &amp; dosage/*adverse effects/metabolism ; Middle Aged ; Muscles/drug effects ; Nervous System/*drug effects ; Neural Conduction/drug effects ; Papilledema/chemically induced ; }, abstract = {6 patients with amyotrophic lateral sclerosis were treated with intravenous infusion of 100-200 million IU per day of human leukocyte interferon. Side effects of treatment included fever, chills, malaise, nausea, marked leukopenia, mild anemia, and thrombocytopenia. Tiredness, confusion, papilledema, and overall signs of acute encephalitis were observed. Tendon reflexes and muscle force decreased. EEG activity was slowed, and evoked potentials showed significant slowing of conduction times. Neuropsychological tests revealed congitive dysfunction. The syndrome of inappropriate antidiuretic hormone secretion developed in all patients. All side effects were reversible with cessation of interferon treatment.}, }
@article {pmid6731761, year = {1984}, author = {Schuchardt, V and Biniek, R and Heitmann, R}, title = {[Limitations of neurologic intensive care].}, journal = {Anasthesie, Intensivtherapie, Notfallmedizin}, volume = {19}, number = {2}, pages = {65-70}, pmid = {6731761}, issn = {0174-1837}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*therapy ; *Critical Care ; *Ethics, Medical ; Humans ; Male ; Middle Aged ; Multiple Sclerosis/*therapy ; Prognosis ; }, abstract = {The indication for intensive care in incurable neurological diseases is discussed. An attempt is made to analyse the problem by presenting two cases of multiple sclerosis and two other cases of amyotrophic lateral sclerosis. There is a clear indication for intensive-care treatment in all cases with life-threatening symptoms and complications, provided there seems to be a chance of reversibility in spite of an eventually poor prognosis. If there is no chance of improvement, and the illness has reached its terminal stage, we do not think, that intensive care is of any benefit for the patient. However, we are not able to make a decision should he insist on such a treatment. When the patient is doomed to die in any case, there is no obligation to inform him about a life-prolonging treatment which is not indicated.}, }
@article {pmid6145348, year = {1984}, author = {Sharova, OK and Rozina, EE and Gordienko, NM and Shteinberg, LS}, title = {Effect of immunosuppression on morphological changes in CNS of monkeys infected with different measles virus vaccine strains.}, journal = {Acta virologica}, volume = {28}, number = {2}, pages = {144-147}, pmid = {6145348}, issn = {0001-723X}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; Brain/*pathology ; Chlorocebus aethiops ; Cortisone/pharmacology ; Encephalomyelitis/*pathology ; *Immunosuppression Therapy ; Measles/immunology/*pathology ; Measles Vaccine ; Measles virus/*pathogenicity ; Spinal Cord/*pathology ; Vaccines, Attenuated ; Virulence/drug effects ; }, abstract = {Residual neurovirulence of measles virus vaccine strains "Leningrad-16", "Moscow-5" and of cloned variant of L-16 strain--clone 3, differing in the degree of attenuation, was studied in intracerebrally (i.c.) infected Cercopithecus aethiops monkeys, receiving cortisone and/or antilymphocyte serum (ALS). Whereas the sensitivity for detection of the potential neurovirulence of vaccine strains was not increased by cortisone treatment. ALS had such effect in detection of neurotropic properties of the L-16 strain and its cloned variants.}, }
@article {pmid6694745, year = {1984}, author = {Gurney, ME}, title = {Suppression of sprouting at the neuromuscular junction by immune sera.}, journal = {Nature}, volume = {307}, number = {5951}, pages = {546-548}, doi = {10.1038/307546a0}, pmid = {6694745}, issn = {0028-0836}, support = {HD05940/HD/NICHD NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Animals ; Botulinum Toxins/pharmacology ; Humans ; Molecular Weight ; *Muscle Denervation ; Muscle Proteins/*immunology ; Nerve Growth Factors/*immunology ; Neuromuscular Junction/*physiology ; Rats ; }, abstract = {Injury of afferent motor axons or pathological loss of motoneurones from the spinal cord causes the remaining axons within a muscle to sprout and to reinnervate the denervated muscle fibres. Sprouting occurs at two sites along intramuscular axons, at nodes of Ranvier (nodal sprouting) and at the neuromuscular junction (terminal sprouting). Terminal sprouting is also produced by treatment with botulinum toxin and by other agents that render muscle inactive. The muscle probably provides a signal for terminal sprouting as restoration of muscle activity by direct electrical stimulation prevents sprouting. Such a signal might be a local change on the muscle fibre surface or a 'soluble' sprouting factor, although the failure to induce terminal sprouting in one muscle by denervating adjacent muscles argues against the latter hypothesis. I now report that rabbit antisera against a 56,000 (56K)-molecular weight protein secreted by denervated rat muscle suppress botulinum toxin-induced terminal sprouting in the mouse gluteus muscle. An immune response against this protein has also been detected in serum of patients with amyotrophic lateral sclerosis (ALS), a disease in which loss of motoneurones from the spinal cord is not accompanied by the degree of sprouting and reinnervation seen in other motoneurone diseases.}, }
@article {pmid6694231, year = {1984}, author = {Jacobs, LM and Sinclair, A and Beiser, A and D'Agostino, RB}, title = {Prehospital advanced life support: benefits in trauma.}, journal = {The Journal of trauma}, volume = {24}, number = {1}, pages = {8-13}, doi = {10.1097/00005373-198401000-00002}, pmid = {6694231}, issn = {0022-5282}, mesh = {Adult ; Ambulances ; Boston ; *Emergency Medical Services ; Female ; Humans ; Life Support Care/*methods ; Male ; Resuscitation ; Triage ; Wounds and Injuries/mortality/*therapy ; }, abstract = {The Boston Emergency Medical Service system was studied to determine the effects of Advanced Life Support (ALS) prehospital trauma care compared to Basic Life Support (BLS) treatment. The severity of injury and clinical status of patients was defined and monitored using the Trauma Score (TS) described by Champion. The TS on arrival at the hospital increased significantly more for patients receiving field ALS care than for patients transported by BLS ambulances (p = 0.01). ALS resuscitation had most influence on patients with TS 4-13 and did not delay transport time. Furthermore, a positive change in prehospital TS was significantly related to an increased chance of long-term survival for any given severity of injury (p = 0.0002). From these data we conclude that the TS is useful for prehospital triage and that appropriate field ALS resuscitation results in more favorable outcomes following major trauma.}, }
@article {pmid6364487, year = {1984}, author = {Wood, ML and Monaco, AP}, title = {Induction of unresponsiveness to skin allografts in adult mice disparate at defined regions of the H-2 complex. II. Effect of pre-graft donor-specific blood transfusions in ALS-treated mice.}, journal = {Transplantation}, volume = {37}, number = {1}, pages = {39-42}, doi = {10.1097/00007890-198401000-00012}, pmid = {6364487}, issn = {0041-1337}, support = {AI 14551-06/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/immunology ; *Blood Transfusion ; *Graft Enhancement, Immunologic ; Graft Survival ; H-2 Antigens/genetics/*immunology ; *Immune Tolerance ; Male ; Mice ; Mice, Inbred Strains ; *Skin Transplantation ; Transplantation Immunology ; }, abstract = {The effect of pretransplant donor-specific blood transfusions on the survival of subsequent skin allografts was studied in adult congenic B10 mice disparate at various regions of the H-2 complex. Donor-host combinations were used that were disparate either at isolated K or I regions or at combined K/D and I regions. Recipient mice were given a single donor-specific blood transfusion ten days before antilymphocyte serum (ALS) treatment and skin grafting. A beneficial effect of donor-specific blood transfusions on skin graft survival was observed only in donor-recipient combinations that differed at the K and I regions. Disparity at the IA and IJ subregions appeared to be particularly important in obtaining the transfusion effect. Donor-specific transfusion had no effect on graft survival in donors and recipients disparate at only the K region, the D region plus part of the I region, or the entire H-2 complex. Pregraft transfusion in mice disparate at the I region sensitized the recipients to subsequent skin grafts from the blood donor. These results indicate that both antibody and suppressor cells play a role in the induction of the beneficial effect obtained from pretransplant donor specific transfusions.}, }
@article {pmid6644326, year = {1983}, author = {Lange, DJ and Good, PF and Bradley, WG}, title = {A therapeutic trial of gangliosides and thymosin in the Wobbler mouse model of motor neuron disease.}, journal = {Journal of the neurological sciences}, volume = {61}, number = {2}, pages = {211-216}, doi = {10.1016/0022-510x(83)90006-0}, pmid = {6644326}, issn = {0022-510X}, mesh = {Animals ; Body Weight ; Drug Evaluation, Preclinical ; Gangliosides/physiology/*therapeutic use ; Mice ; Mice, Neurologic Mutants ; *Motor Neurons ; Nerve Regeneration ; Neuromuscular Diseases/*drug therapy ; Thymosin/*therapeutic use ; }, abstract = {Mixed bovine gangliosides have been reported to enhance neuronal regeneration and sprouting. The Wobbler mouse model of motor neuron disease was used to test the clinical effects of long-term ganglioside administration on the course of the disease. Mixed gangliosides were injected subcutaneously into a group of 5 Wobbler mice and compared to a control group of 5 Wobbler mice which received saline. Because of several reports implicating involvement of the immune system in ALS, a 3rd group of 5 Wobbler mice received thymosin. All mice were 4 weeks old at commencement of injections. The 3 groups were examined weekly and graded with respect to front leg power, ability to climb a vertical grating, and walking posture. After 4 months of treatment, no significant difference between either experimental group and the controls was found.}, }
@article {pmid6192149, year = {1983}, author = {Shouval, D and Rager-Zisman, B and Quan, P and Shafritz, DA and Bloom, BR and Reid, LM}, title = {Role in nude mice of interferon and natural killer cells in inhibiting the tumorigenicity of human hepatocellular carcinoma cells infected with hepatitis B virus.}, journal = {The Journal of clinical investigation}, volume = {72}, number = {2}, pages = {707-717}, pmid = {6192149}, issn = {0021-9738}, support = {5F05TW02764/TW/FIC NIH HHS/United States ; AM17609/AM/NIADDK NIH HHS/United States ; AM17702/AM/NIADDK NIH HHS/United States ; }, mesh = {Animals ; Antibodies, Viral/analysis ; Antilymphocyte Serum/administration &amp; dosage ; Carcinoma, Hepatocellular/complications/*immunology ; Cell Line ; Cytotoxicity, Immunologic/radiation effects ; Hepatitis B/complications/*immunology ; Hepatitis B Surface Antigens/analysis/immunology ; Humans ; Immunosuppression Therapy ; Interferons/analysis/immunology/*physiology ; Killer Cells, Natural/*immunology/radiation effects ; Liver Neoplasms ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Nude ; Serum Globulins/administration &amp; dosage ; }, abstract = {The human hepatoma cell line, PLC/PRF/5, which is persistently infected with hepatitis B virus (HBV), has integrated HBV-DNA, secretes HBV surface antigen (HBsAg), and does not grow readily in congenitally athymic (nu/nu) mice. The present investigation was undertaken to ascertain whether the low tumorigenicity of this cell line was governed by a host immune response and/or was related to expression of HBsAg. Subcutaneous injection of 4-5 X 10(6) cells into BALB/c nude mice produced localized encapsulated tumors with morphologic features of primary hepatocellular carcinoma in 25% of the animals within 29-40 d. No tumor growth was observed at lower cell inocula. In contrast, SK-HEP-1, an HBV-negative human hepatoma cell line, produced tumors at 1-5 X 10(6) cells inocula in 66% of the animals. Immunosuppression of mice with antilymphocyte serum (ALS) or irradiation increased tumor incidence in mice inoculated with 1 X 10(6) PLC/PRF/5 cells to almost 100% and produced local invasiveness. Immunosuppression also reduced the latency, i.e., time to tumor appearance, and increased mean tumor weight. These results suggest that tumorigenicity was limited by the host immune response. The nature of the response was delineated by treating nude mice challenged with tumor cells with sheep anti-mouse interferon globulin (anti-IFN). When 2 X 10(6) cells were injected, tumor growth occurred in 75% of anti-IFN-treated mice, whereas controls injected with the same number of cells, but not receiving anti-IFN, failed to develop tumors. The tumors in the anti-IFN-treated mice were highly invasive and the latency period until tumor appearance was reduced to 3-5 d. An inverse correlation was found between susceptibility of the hepatoma cells to natural killer (NK) activity in vitro and resistance to tumor growth in vivo. In vitro cytotoxicity for PLC/PRF/5 cells was eliminated by anti-NK 1.1 and complement, establishing the effector cell as an NK cell. NK cell activity 14 d after inoculation of mice with PLC/PRF/5 cells was augmented against PLC/PRF/5 target cells but not against SK-HEP-1 cells. Treatment of mice with ALS, irradiation, or anti-IFN abolished NK activity against PLC/PRF/5 cells. Co-cultivation of nude mouse spleen cells with PLC/PRF/5 but not with HBsAg or SK-HEP-1 cells induced secretion of murine IFNalpha. These results suggest that the IFN/NK cell system may play a role in limiting tumorigenicity and invasiveness of HBV-infected human hepatocellular carcinoma cells by a mechanism similar to that found for other cells persistently infected with viruses.}, }
@article {pmid6134961, year = {1983}, author = {Engel, WK and Siddique, T and Nicoloff, JT}, title = {Effect on weakness and spasticity in amyotrophic lateral sclerosis of thyrotropin-releasing hormone.}, journal = {Lancet (London, England)}, volume = {2}, number = {8341}, pages = {73-75}, doi = {10.1016/s0140-6736(83)90060-0}, pmid = {6134961}, issn = {0140-6736}, support = {RR-43/RR/NCRR NIH HHS/United States ; }, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Double-Blind Method ; Female ; Humans ; Infusions, Parenteral ; Male ; Middle Aged ; Motor Neurons/drug effects ; Muscle Spasticity/drug therapy ; Sex Factors ; Thyrotropin-Releasing Hormone/*administration &amp; dosage/adverse effects/pharmacology ; }, abstract = {Very high intravenous doses (2-19 mg/min) of thyrotropin-releasing hormone (TRH, L-pyroglutamyl-L-histidyl-L-prolinamide) given to 12 patients with amyotrophic lateral sclerosis (ALS) produced a moderate to marked improvement of functions caused by deficiency of lower motor neurons (weakness) and upper motor neurons (spasticity). The improvement was sustained throughout the infusion and for about 1 h thereafter; sometimes a slight improvement was evident 20 h after infusion. At a given dose benefits and side-effects were more evident in men than in women. Whether TRH is replacing an ALS-associated deficiency or is simply a symptomatic treatment is unknown. The results of this study raise the possibility of a treatment for ALS, and may provide new insight into its pathogenesis. The potential response to TRH of spasticity and/or lower motor neuron involvement of other causes is proposed.}, }
@article {pmid6665786, year = {1983}, author = {Frelon, JH and Merigot, P and Garnier, R and Bismuth, C and Efthymiou, ML}, title = {[Prognostic factors in acute paraquat poisoning. A retrospective study of cases registered by the Poison Control Center of Paris in 1981].}, journal = {Toxicological European research. Recherche europeenne en toxicologie}, volume = {5}, number = {4}, pages = {163-169}, pmid = {6665786}, issn = {0249-6402}, mesh = {Adolescent ; Adult ; Aged ; Child ; Child, Preschool ; Emetics/therapeutic use ; Female ; Gastric Lavage ; Gastrointestinal Diseases/complications ; Humans ; Kidney Diseases/complications ; Liver Diseases/complications ; Male ; Middle Aged ; Paraquat/*poisoning ; Paris ; Poison Control Centers ; Prognosis ; Respiratory Function Tests ; Retrospective Studies ; Sex Factors ; }, abstract = {Twenty years after the publication of the first cases, the intoxication with the herbicide Paraquat still has a low prognosis because of no efficient treatment. But many studies have allowed the definition of prognostic factors. Nearly, BISMUTH and als(2) demonstrated that the following criteria are significant: the oral route, the gastric lesions, the organic renal failure, the plasma-Paraquat concentration. Through a series of cases collected in 1981 at the Poison Control Center of Paris, the following prognostic factors have been studied: route of administration, sex of patient, circumstances of the poisoning, ingested volume, concentration of the solution, existence of an emetic in the commercial solution, gastric content, lesions of the upper digestive tract (mouth, oesophagus, stomach), renal impairment, hepatic failure, blood gasometry, lung function tests, plasma and urine paraquat concentrations. Forty-one cases were collected during this period, with thirty-four concerning acute Paraquat poisonings in humans. We studied twenty-seven of them caused by acute oral poisoning, with accidental circumstances in nine cases (two died) and intentional circumstances in eighteen cases (all died) (other cases concerned two ocular projections, four inhalations and one skin projection). The interest of this new investigation is the particularity of our series. Because of our recruitment (larger geographic distribution of patients, larger diversity of circumstances, of routes of administration, of ingested quantities, of treatments...). This series of cases is quite different from others previously published. This study confirms the validity of prognostic factors defined by BISMUTH and als(2). The factors, which look significant, strictly depend on the ingested quantity.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid6346615, year = {1983}, author = {Sanfilippo, FP and Vaughn, WK and Peters, TG and Bollinger, RR and Spees, EK}, title = {Transplantation for polycystic kidney disease.}, journal = {Transplantation}, volume = {36}, number = {1}, pages = {54-59}, doi = {10.1097/00007890-198307000-00012}, pmid = {6346615}, issn = {0041-1337}, mesh = {Adolescent ; Adult ; Antilymphocyte Serum/therapeutic use ; Blood Transfusion ; Graft Survival ; HLA Antigens/analysis/genetics ; Humans ; *Kidney Transplantation ; Middle Aged ; Nephrectomy ; Polycystic Kidney Diseases/genetics/mortality/*therapy ; Prospective Studies ; }, abstract = {During the 4-year period from June 1977 to May 1981, a total of 108 patients with polycystic kidney disease and 2440 nonpolycystic patients received cadaver renal allografts in the Southeastern Organ Procurement Foundation (SEOPF) Prospective Study. There were no significant differences between the groups with and without polycystic disease in terms of recipient blood group, history of splenectomy, or preformed antibody status. As a group, transplanted polycystic patients underwent native nephrectomy more often, had a better HLA match, received less antilymphocyte serum (ALS), and were slightly older than nonpolycystic patients. Although proportionately fewer polycystic patients received pretransplant transfusions than nonpolycystic patients (P = .002), transfusion was associated with a significant increase in graft survival in the polycystic group (P less than .05), as well as in the nonpolycystic group (P less than .0001). Gene frequency analysis showed no HLA-A, or -B antigen linkage with polycystic disease. No significant differences existed between the polycystic and nonpolycystic groups in terms of overall graft and patient survival. However, transplanted polycystic patients died more frequently from bacterial sepsis (P less than .05), especially from gram-positive organisms (P = .01). Pretransplant bilateral nephrectomy did not affect the incidence of sepsis. However, following graft failure, patients with bilateral native nephrectomy had a greater incidence of severe anemia (50% versus 39%) and death (58% versus 25%; P less than .05) than those with unilateral nephrectomy or no nephrectomy. Treatment with ALS did not significantly improve graft survival in those with polycystic disease. A strong positive correlation was found between patient death and treatment with ALS only in the polycystic group (P less than .01). These findings indicate that the use of pretransplant bilateral native nephrectomy and posttransplant ALS should be judicious in the polycystic patient because they may be associated with increased morbidity and mortality.}, }
@article {pmid6348186, year = {1983}, author = {Festoff, BW and Perurena, OH and Singer, PA}, title = {"Untreatable" neuromuscular disease. Treatment trials and symptomatic treatment of amyotrophic lateral sclerosis.}, journal = {The Journal of the Kansas Medical Society}, volume = {84}, number = {6}, pages = {312-317}, pmid = {6348186}, issn = {0022-8699}, mesh = {Amyotrophic Lateral Sclerosis/etiology/*therapy ; Clinical Trials as Topic ; Humans ; Neuromuscular Depolarizing Agents/therapeutic use ; Peptide Hydrolases/metabolism ; }, }
@article {pmid6832488, year = {1983}, author = {Like, AA and Anthony, M and Guberski, DL and Rossini, AA}, title = {Spontaneous diabetes mellitus in the BB/W rat. Effects of glucocorticoids, cyclosporin-A, and antiserum to rat lymphocytes.}, journal = {Diabetes}, volume = {32}, number = {4}, pages = {326-330}, doi = {10.2337/diab.32.4.326}, pmid = {6832488}, issn = {0012-1797}, support = {AM-19155/AM/NIADDK NIH HHS/United States ; AM-25306/AM/NIADDK NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/*therapeutic use ; Blood Glucose ; Cyclosporins/*therapeutic use ; Diabetes Mellitus/immunology/*prevention &amp; control/veterinary ; Drug Therapy, Combination ; Immunosuppression Therapy ; Methylprednisolone/*analogs &amp; derivatives/therapeutic use ; Methylprednisolone Acetate ; Rats ; Rodent Diseases/prevention &amp; control ; }, abstract = {Combination immunosuppression therapy with long-acting glucocorticoids, cyclosporin-A, and antiserum to rat lymphocytes (ALS) reduced the severity of spontaneous diabetes among BioBreeding/Worcester rats and decreased the frequency of diabetes in susceptible littermates. Combination therapy with glucocorticoids and three injections of ALS reversed hyperglycemia in a significant number of acutely diabetic animals. These results strengthen the hypothesis that autoimmunity plays a role in the pathogenesis of diabetes in these animals and increase our understanding of the requirements of treatment protocols for the prevention and cure of this spontaneous syndrome.}, }
@article {pmid6339077, year = {1983}, author = {Finesilver, AG and Braley-Mullen, H}, title = {Characterization of a concanavalin A-induced amplifier T cell which augments in vitro antibody responses to DNP-Ficoll.}, journal = {Cellular immunology}, volume = {75}, number = {2}, pages = {199-213}, doi = {10.1016/0008-8749(83)90320-9}, pmid = {6339077}, issn = {0008-8749}, support = {AI-00322/AI/NIAID NIH HHS/United States ; CA25054/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antibody-Producing Cells/immunology ; Antilymphocyte Serum/pharmacology ; B-Lymphocytes/immunology ; Cell Adhesion ; Complement System Proteins/physiology ; Concanavalin A/*pharmacology ; Dose-Response Relationship, Radiation ; Female ; Ficoll/analogs &amp; derivatives/*immunology ; Hemolytic Plaque Technique ; Histocompatibility Antigens Class II/analysis ; Isoantibodies/physiology ; *Lymphocyte Cooperation ; Mice ; Mice, Inbred A ; Mice, Inbred BALB C ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Mice, Nude ; Polysaccharides/*immunology ; Rabbits ; T-Lymphocytes/*classification/immunology/radiation effects ; Thymectomy ; }, abstract = {The addition of the T-cell mitogen concanavalin A (Con A) on Day 2 of a 4-day in vitro culture of murine spleen cells with the thymus-independent (TI) antigen DNP39-Ficoll resulted in significant enhancement of the direct antitrinitrophenyl (TNP) plaque-forming cell (PFC) response. This enhancement was mediated by a nylon wool- and antiimmunoglobulin-nonadherent amplifier T cell (TA). TA activity was not eliminated by in vitro treatment of T cells with anti-Thy 1.2 and complement (C). TA activity could be eliminated by pretreatment of mice with antilymphocyte serum (ALS) in vivo, followed by in vitro treatment of T cells with anti-Thy 1.2 + C. Thus, TA appear to bear a low surface density of Thy-1 antigen. These TA were relatively resistant to ALS used alone, to cyclophosphamide, and to low dose in vitro irradiation. TA were still present in the spleen 14 weeks after adult thymectomy (ATx). They were I-J positive and apparently belonged to the Lyt 1+2- T-cell subset.}, }
@article {pmid6219027, year = {1983}, author = {Busby, BE and Rodman, HM}, title = {Impairment of T-cell regulation of the humoral immune response to type III pneumococcal polysaccharide in diabetic mice.}, journal = {Diabetes}, volume = {32}, number = {2}, pages = {156-164}, doi = {10.2337/diab.32.2.156}, pmid = {6219027}, issn = {0012-1797}, support = {AM 21259/AM/NIADDK NIH HHS/United States ; }, mesh = {Animals ; Antibody Formation ; Antilymphocyte Serum/immunology ; Diabetes Mellitus, Experimental/*immunology ; Hemolytic Plaque Technique ; Immunization ; *Lymphocyte Activation ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Polysaccharides, Bacterial/*pharmacology ; Streptozocin ; T-Lymphocytes/drug effects/*immunology ; T-Lymphocytes, Regulatory/drug effects ; }, abstract = {The peak plaque-forming-cell (PFC) and serum antibody responses of diabetic mice to type III pneumococcal capsular polysaccharide (S3) were delayed compared with normals. Proliferation of PFC precursors was not inhibited in an insulin-deficient environment. The delay in the PFC response to S3 did not occur in diabetic nude mice but was demonstrable in their thymus-bearing heterozygote littermates. Therefore, T-cells appear to mediate the delay in the response of diabetic mice to S3 probably by delaying their differentiation into PFC. Diabetic mice responded normally to the induction of low-dose tolerance to S3, indicating the presence of active suppressor T-cells (Ts) in these mice. However, inactivation of Ts by anti-lymphocyte serum (ALS) required a higher dose in the diabetic mice. Furthermore, inactivation of Ts by ALS totally abolished the delay in peak PFC response. These findings suggest that the delayed PFC response to S3 in diabetic mice was the result of excessive splenic Ts activity. In peripheral blood, diabetic mice appeared to have more amplifier T-cell activity or less suppressor T-cell activity than normals. This response was normalized by insulin treatment. DIABETES 32:156-164, February 1983.}, }
@article {pmid6347649, year = {1983}, author = {Jokelainen, M}, title = {[Treatment of amyotrophic lateral sclerosis].}, journal = {Duodecim; laaketieteellinen aikakauskirja}, volume = {99}, number = {5}, pages = {355-360}, pmid = {6347649}, issn = {0012-7183}, mesh = {Amyotrophic Lateral Sclerosis/*therapy ; Humans ; }, }
@article {pmid6295586, year = {1983}, author = {Gagic, NM}, title = {Cricopharyngeal myotomy.}, journal = {Canadian journal of surgery. Journal canadien de chirurgie}, volume = {26}, number = {1}, pages = {47-49}, pmid = {6295586}, issn = {0008-428X}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/complications ; Body Weight ; Carcinoma, Small Cell/surgery ; Cerebrovascular Disorders/complications ; Cricoid Cartilage/surgery ; Deglutition Disorders/etiology/surgery ; Diverticulum, Esophageal/complications ; Female ; Follow-Up Studies ; Humans ; Lung Neoplasms/surgery ; Male ; Methods ; Middle Aged ; Muscles/*surgery ; Pharyngeal Muscles/*surgery ; Postoperative Complications ; }, abstract = {Cricopharyngeal myotomy has been used in the treatment of pharyngoesophageal diverticulum and various neurogenic, myogenic and myoneurogenic disorders. An appreciable number of patients with pseudobulbar palsy due to cerebrovascular accidents and patients with idiopathic hypertrophy of the cricopharyngeal muscle will greatly benefit from this procedure. This paper describes the indications for, and results of, 20 consecutive cricopharyngeal myotomies carried out with or without diverticulectomy. All 20 patients experienced cervical esophageal dysphagia and 55% had substantial weight loss. The most valuable investigation is roentgenography of the pharynx and esophagus, which will confirm megapharynx, hypopharyngeal stasis, weak or absent pharyngeal contractions and regurgitation. Hypertrophic cricopharyngeal muscle was demonstrated in 9 of the 20 patients. The diagnostic value of endoscopy and esophageal manometry is limited. The results were considered excellent in all patients with pharyngoesophageal diverticulum and idiopathic hypertrophy of the cricopharyngeal muscle. Marked symptomatic and objective improvement was achieved in patients with cerebrovascular accidents, vagal injuries and amyotrophic lateral sclerosis. However, the result was poor in patients with myoneurogenic disorders.}, }
@article {pmid6187131, year = {1983}, author = {Valbonesi, M and Garelli, S}, title = {Plasma exchange in neurological diseases. A critical approach.}, journal = {Vox sanguinis}, volume = {44}, number = {2}, pages = {65-80}, doi = {10.1111/j.1423-0410.1983.tb04105.x}, pmid = {6187131}, issn = {0042-9007}, mesh = {Acute Disease ; Amyotrophic Lateral Sclerosis/therapy ; Autoimmune Diseases/complications/therapy ; Chronic Disease ; Humans ; Immune Complex Diseases/complications/*therapy ; Multiple Sclerosis/drug therapy/therapy ; Myasthenia Gravis/complications/therapy ; Myositis/drug therapy/therapy ; Nervous System Diseases/complications/immunology/*therapy ; *Plasma Exchange/methods ; Polyradiculoneuropathy/therapy ; Refsum Disease/therapy ; Subacute Sclerosing Panencephalitis/therapy ; Syndrome ; }, abstract = {The rationale for and results of plasma exchange (PE) in the therapy of different immune-mediated neurological diseases such as myasthenia gravis, multiple sclerosis, acute and chronic-relapsing Guillain-Barré syndromes, polymyositis, dermatomyositis and amyotrophic lateral sclerosis are reviewed. Dialysis dementia and Refsum's disease, subacute sclerosing panencephalitis and schizophrenia are mentioned, too. If we exclude the treatment of acute Guillain-Barré syndrome, where PE alone appears to be sufficient to produce recovery or improvement, the combined use of immunosuppressive drugs and/or lymphocytapheresis is probably needed in the treatment of the other diseases. PE allows the disease to be controlled rapidly while long-term pharmacological control is established. An underlying theme in this review is the need of adequately controlled studies or at least of large case lists with exhaustive reports concerning both positive and negative results since a new perspective is needed for this topic. Nonetheless, a number of uncontrolled observations suggest that probably PE effectiveness in most immune-mediated neurological diseases could be proven if the requisite trials were performed.}, }
@article {pmid6186056, year = {1982}, author = {Maki, T and Simpson, M and Monaco, AP}, title = {Development of suppressor T cells by antilymphocyte serum treatment in mice.}, journal = {Transplantation}, volume = {34}, number = {6}, pages = {376-381}, doi = {10.1097/00007890-198212000-00013}, pmid = {6186056}, issn = {0041-1337}, support = {AI 14554/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; Cell Differentiation ; Cytotoxicity, Immunologic ; Epitopes ; Lymphocyte Activation ; Lymphocyte Culture Test, Mixed ; Mice ; Mice, Inbred A ; Mice, Inbred BALB C ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Skin Transplantation ; Spleen/cytology ; T-Lymphocytes, Regulatory/*cytology/immunology ; }, abstract = {Administration of rabbit anti-mouse lymphocyte serum (ALS) in mice results in the development of suppressor cells which can be detected by coculture mixed lymphocyte culture experiments. The putative suppressor cells inhibit nonspecifically the proliferative response as well as generation of cytotoxicity of normal responder cells. Suppressor activity is dose dependent and is not attributable to cell crowding, shifting of peak activity, or release of cell-bound ALS. Additional antigenic stimulation by skin allografting in ALS-treated mice shifts the specificity of suppressor cells from nonspecific to specific for skin donor alloantigen. ALS-induced suppressor cells are Lyt-1+2- T cells while suppressor cells present in ALS-treated, skin allograft-bearing mice are Lyt-1-2+ T cells. Both types of suppressor cells appear to bear I-J determinants. The possible mechanisms of suppressor cell induction by ALS and skin allografting are discussed.}, }
@article {pmid7149441, year = {1982}, author = {Jakab, GJ}, title = {Immune impairment of alveolar macrophage phagocytosis during influenza virus pneumonia.}, journal = {The American review of respiratory disease}, volume = {126}, number = {5}, pages = {778-782}, doi = {10.1164/arrd.1982.126.5.778}, pmid = {7149441}, issn = {0003-0805}, support = {HL-00415/HL/NHLBI NIH HHS/United States ; HL-22029/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Antibodies, Viral/immunology ; Antilymphocyte Serum/administration &amp; dosage ; Female ; Immunosuppression Therapy ; Macrophages/*immunology ; Mice ; Opsonin Proteins/immunology ; Orthomyxoviridae/immunology ; Orthomyxoviridae Infections/*immunology ; *Phagocytosis ; Pneumonia, Viral/*immunology ; Pulmonary Alveoli/*cytology ; Rabbits ; Staphylococcus aureus/immunology ; }, abstract = {The pathogenesis of viral pneumonia is associated with an intact antiviral immune response. To determine the degree of involvement of the host response in influenza virus-induced impairment of pulmonary antibacterial defenses, mice were immunosuppressed by treatment with antilymphocyte serum (ALS). Eight days after infection, pulmonary defense mechanisms were quantitated by aerogenic challenge with Staphylococcus aureus; the ingestion of opsonized erythrocyte (EA) was used to monitor the phagocytic capability of alveolar macrophages obtained by pulmonary lavage. The ALS treatment alone caused no significant alteration in pulmonary antibacterial defenses or macrophage phagocytosis, nor did it interfere with viral multiplication. In noninfected lungs, less than 1% of the initial viable staphylococci remained viable at 24 h compared with proliferation to 490 +/- 147% in virus-infected lungs. Treatment with ALS prevented staphylococcal multiplication, the bactericidal value being 28 +/- 12% at the same time period. The phagocytic index (EA ingested/100 macrophages) in cells retrieved from normal lungs was 783 +/- 22 compared with 235 +/- 29 in macrophages from virus-infected lungs. The ALS ameliorated the impairment in phagocytic ingestion, the index being 505 +/- 34. Incubation of alveolar macrophages from virus-infected, ALS-treated animals with specific viral antibody reestablished the phagocytic defect in a dose-dependent manner; the index being 215 +/- 30 at the lowest dilution of antiviral globulin. The data demonstrate that the virus-induced suppression of pulmonary antibacterial defenses caused by dysfunction in alveolar macrophage phagocytosis is, in part, immunologically mediated.}, }
@article {pmid6213717, year = {1982}, author = {Gozzo, JJ and Crowley, M and Maki, T and Monaco, AP}, title = {Functional characteristics of a Ficoll-separated mouse bone marrow cell population involved in skin allograft prolongation.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {129}, number = {4}, pages = {1584-1588}, pmid = {6213717}, issn = {0022-1767}, support = {AI-16591/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum ; *Bone Marrow Cells ; Cell Separation/methods ; Colony-Forming Units Assay ; Ficoll ; *Graft Survival ; Immune Tolerance ; Lymphocyte Activation ; Macrophages/immunology ; Male ; Mice ; Skin Transplantation ; Spleen/immunology ; T-Lymphocytes, Regulatory/*immunology ; }, abstract = {Treatment of recipient mice with donor bone marrow cells and anti-lymphocyte serum (ALS) results in extensive skin graft prolongation beyond that achieved in animals given only ALS. In this study, B6AF1 recipient mice were grafted with C3H/He skin on day 0, treated with ALS on days -1 and +2 and infused on day +7 with donor strain (C3H/He) bone marrow cells. Extensive graft prolongation was achieved either with 25 X 10(6) whole bone marrow cells or with 1 X 10(6) lymphoid-like cells derived from donor marrow that sediment at a rate of 3 mm/hr in a 2 to 4% Ficoll gradient at unit gravity. These allograft-prolonging lymphoid-like cells appear not to be CFUs cells, have suppressive activity in in vitro MLC assays, and contain both nylon wool adherent and non-adherent cells. These studies thus show that allograft promoting cells can be isolated from bone marrow utilizing Ficoll gradients. Functional studies suggest that 3 mm/hr sedimenting donor bone marrow suppressor cells may be involved in the induction of allograft prolongation.}, }
@article {pmid7187268, year = {1982}, author = {Koh, LY and Jones, WR}, title = {The rosette inhibition test in early pregnancy diagnosis.}, journal = {Clinical reproduction and fertility}, volume = {1}, number = {3}, pages = {229-233}, pmid = {7187268}, issn = {0725-556X}, mesh = {Animals ; Antilymphocyte Serum/analysis ; Complement System Proteins/analysis ; Female ; Guinea Pigs ; Humans ; Pregnancy ; *Pregnancy Tests, Immunologic ; *Rosette Formation ; }, abstract = {The rosette inhibition test (RIT) was used to detect pregnancy around the time of implantation. Using an antiserum to peripheral blood lymphocytes, it was possible to diagnose 80 per cent of pregnancies. These results substantiate the view that there is an early pregnancy factor (EPF) present in the serum at a very early stage of gestation.}, }
@article {pmid6985194, year = {1982}, author = {Sampi, K and Hattori, M}, title = {[High dose methotrexate with leucovorin rescue in the treatment of malignant lymphoma].}, journal = {Gan to kagaku ryoho. Cancer &amp; chemotherapy}, volume = {9}, number = {6}, pages = {1068-1073}, pmid = {6985194}, issn = {0385-0684}, mesh = {Adolescent ; Adult ; Aged ; Drug Administration Schedule ; Drug Therapy, Combination ; Female ; Humans ; Infusions, Parenteral ; Leucovorin/*administration &amp; dosage ; Lymphoma/blood/*drug therapy ; Male ; Methotrexate/*administration &amp; dosage/blood ; Middle Aged ; }, abstract = {Nineteen patients with malignant lymphomas were treated with 52 courses of high dose methotrexate with leucovorin rescue (HDMTX-LCV): 17 non-Hodgkin's lymphoma (11 nodal primary, and 6 Waldeyer's ring), 1 Hodgkin's disease, and 1 Burkitt's lymphoma; 10 No prior chemotherapy, 9 prior chemotherapy; Median age 50 years (18-67); Sex M 13:F 6. MTX was given according to Frei III et al's regimen(1975). In brief, alkalinization of the urine was achieved by administration of NaHCO3 both by oral and by intravenous route. Hydration with at least 3 liters of fluid per day was maintained throughout each course. MTX was administered as a six-hour infusion at an initial dose of 0.5-1.0 g/m2 with gradual escalation to 3-5 g/m2. Thirty minutes before the infusion of MTX, 1.4 mg/m2 of vincristine (VCR) (maximum dose 2 mg) was given intravenously in each course. MTX levels were not monitored. The overall response rate was 63% with 7 partial responses and 5 complete responses. Five of 10 previously untreated patients and 7 of 9 patients with prior chemotherapy achieved an objective response. Our excellent result may be contributed in part by VCR. Although, in general, during this study HDMTX-LCV was well-tolerated, a 67 year-old male had severe and unpredictable toxicity which resulted in shock condition, leukopenia and thrombocytopenia. Accordingly, we feel that HDMTX-LCV is dangerous without monitoring plasma MTX level. In other side effects, peripheral neuropathy and constipation possibly due to VCR occurred especially in elderly patients.}, }
@article {pmid7102959, year = {1982}, author = {Garfinkle, TJ and Kimmelman, CP}, title = {Neurologic disorders: amyotrophic lateral sclerosis, myasthenia gravis, multiple sclerosis, and poliomyelitis.}, journal = {American journal of otolaryngology}, volume = {3}, number = {3}, pages = {204-212}, doi = {10.1016/s0196-0709(82)80056-2}, pmid = {7102959}, issn = {0196-0709}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*diagnosis/therapy ; Diagnosis, Differential ; Female ; Humans ; Male ; Middle Aged ; Multiple Sclerosis/*diagnosis/therapy ; Myasthenia Gravis/*diagnosis/therapy ; Otorhinolaryngologic Diseases/diagnosis ; Poliomyelitis/*diagnosis/therapy ; }, abstract = {The patient who has multiple cranial neuropathies may pose a diagnostic dilemma. The neurologic disorders of amyotrophic lateral sclerosis, multiple sclerosis, myasthenia gravis, and poliomyelitis often cause bulbar dysfunctions such as diplopia, facial weakness, slurred or hypernasal speech, dysphagia, and hoarseness. In general, treatment is supportive and is directed toward restoring or aiding lost function (i.e., tracheostomy, esophagostomy, and cricopharyngeal myotomy). The relative infrequency of these disorders can lead to delays in diagnosis and rehabilitative therapy.}, }
@article {pmid7080805, year = {1982}, author = {Conradi, S and Ronnevi, LO and Nise, G and Vesterberg, O}, title = {Long-time penicillamine-treatment in amyotrophic lateral sclerosis with parallel determination of lead in blood, plasma and urine.}, journal = {Acta neurologica Scandinavica}, volume = {65}, number = {3}, pages = {203-211}, doi = {10.1111/j.1600-0404.1982.tb03078.x}, pmid = {7080805}, issn = {0001-6314}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/blood/*drug therapy/urine ; Drug Therapy, Combination ; Female ; Humans ; Lead/*analysis ; Male ; Middle Aged ; Penicillamine/administration &amp; dosage/adverse effects/*therapeutic use ; Pyridoxine/administration &amp; dosage ; }, }
@article {pmid7172622, year = {1982}, author = {Gormus, BJ and Vessella, RL and Martin, LN and Kaplan, ME}, title = {Heterogeneity of human lymphocyte Fc receptors: studies using heat-aggregated and antigen-complexed IgG from human, rabbit, guinea pig, horse and goat.}, journal = {Comparative immunology, microbiology and infectious diseases}, volume = {5}, number = {4}, pages = {483-499}, doi = {10.1016/0147-9571(82)90074-1}, pmid = {7172622}, issn = {0147-9571}, support = {RR 00164/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Antibody-Dependent Cell Cytotoxicity ; Antigen-Antibody Complex/*immunology ; Erythrocytes/immunology ; Goats/immunology ; Guinea Pigs/immunology ; Horses/immunology ; Hot Temperature ; Humans ; Immunoglobulin G/*immunology ; Killer Cells, Natural/immunology ; Lymphocytes/*analysis ; Rabbits/immunology ; Receptors, Fc/*analysis ; Species Specificity ; }, abstract = {We have studied the ability of human peripheral blood lymphocytes (HuPBL)4 to interact with IgG from several animal species. Three functions or activities that are reported to depend on an interaction between complexed IgG and HuPBL receptors (R) for the Fc piece of IgG (Fc gamma R) were compared: (1) antibody-dependent cell-mediated cytotoxicity (ADCC); (2) binding of heat-aggregated IgG (aggG); and (3) rosette formation with IgG-sensitized erythrocytes [RBC-A(gamma)]. IgG (and IgM) antibodies to chicken erythrocytes (CRBC) were purified from the sera of the following species after injection with CRBC stroma: (1) horse (Ho); (2) goat (Go); (3) rabbit (Ra); and (4) guinea pig (Gp). Good IgG-agglutinating antibody titers were obtained from each injected species. Using 51Cr-labeled CRBC targets and HuPBL effector cells, only Ra anti-CRBC IgG gave good ADCC at high dilutions. Ho and Go anti-CRBC (IgG) failed to give ADCC, and Gp anti-CRBC (IgG) gave approx. 30% of the level of kill as Ra. Ra Fab2 fragments of IgG antibody failed to produce ADCC. Treatment of HuPBL with Ra anti-lymphocyte serum (ALS) almost totally ablated ADCC, whereas HoALS failed to alter ADCC. Pretreatment of HuPBL with aggG showed that Ra or Hu aggG gave essentially equal inhibition of ADCC, Gp gave approx. 30% of the degree of inhibition as Hu and Ra, and Ho or Go aggG had essentially no effect of ADCC. These results confirmed the following order of ability of IgG to interact with HuPBL ADCC killer (K) cells: (Hu greater than or equal to)Ra greater than Gp much greater than Ho, Go. The data suggest that Gp IgG interacts with only a subpopulation (approximately 30%) of HuPBL K cells. The binding of aggG to total HuPBL failed to strictly correlate with the ADCC results or with the results of rosette formation between total HuPBL and CRBC-A(gamma). The observations suggest that there is a heterogeneity of Fc gamma R between K and non-K cell subpopulations of HuPBL both in terms of the type of complexed IgG they are able to bind, and in terms of species of origin of the IgG. The data also support contentions that Fc gamma R that bind RBC-A (gamma) complexes differ from those that bind aggG.}, }
@article {pmid7039021, year = {1982}, author = {Mullen, Y and Shintaku, IP}, title = {Fetal pancreas allografts for reversal of diabetes in rats. II. Induction of life-term-specific unresponsiveness to pancreas allografts across nonmajor histocompatibility complex barriers.}, journal = {Transplantation}, volume = {33}, number = {1}, pages = {3-11}, doi = {10.1097/00007890-198201000-00002}, pmid = {7039021}, issn = {0041-1337}, support = {AM 17980/AM/NIADDK NIH HHS/United States ; AM 20827/AM/NIADDK NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/therapeutic use ; Diabetes Mellitus, Experimental/*therapy ; Female ; *Graft Survival ; *Immunosuppression Therapy ; Liver Transplantation ; Male ; *Pancreas Transplantation ; Rats ; Rats, Inbred F344/immunology ; Skin Transplantation ; Transplantation Immunology ; }, abstract = {Specific unresponsiveness to LEW whole fetal pancreases was induced in F344 rats across non-RT1 incompatibilities. Our treatment regimen was a modification of that developed by Brent and Opara and used an i.v. injection of donor liver extracts (equivalent to 250 to 500 mg wet tissues) between days -18 and -24 followed by a single i.p. injection each of procarbazine hydrochloride (one-third of the LD50 dose) and 0.5 ml of antilymphocyte serum (ALS) within a few days of transplantation. Complete and life-term (greater than 1 year) reversal of streptozotocin (SZ)-induced diabetes was observed in 13 of 16 treated recipients, while the reversal of diabetes was only transient in 2 recipients as a result of graft rejection which occurred between days 30 and 50. The remaining one recipient did not respond to the treatment. Allograft viability was confirmed by the visual observations and histological examination of tissues, by the recurrence of diabetes after the graft removal, and by the reversal of diabetes in the secondary recipients in which long-term surviving allografts were retransplanted. Specificity of the induced unresponsiveness was demonstrated by the prolonged survival times of donor-type skin but the normal rejection of third-party skin which was grafted onto the diabetes-reversed F344 recipients carrying viable LEW pancreases. Prolonged but limited survival times of donor-type skin grafts suggested that the induced unresponsiveness is specific to donor alloantigens as well as organ-specific antigens. This immunosuppressed state was transferable into ALS-treated syngeneic F344 rats by nylon-wool-nonadherent spleen cells. Thus, LEW skin grafts survived for 30 days in ALS-treated F344 rats receiving test spleen cells, while those in controls survived for 19 days. LEW pancreases surviving for more than 300 days were fully capable of eliciting rejection reaction when the grafts were retransplanted into a nonimmunosuppressed secondary F344 recipient along with the primary host kidney.}, }
@article {pmid6280455, year = {1982}, author = {Epstein, JA and Janin, Y and Carras, R and Lavine, LS}, title = {A comparative study of the treatment of cervical spondylotic myeloradiculopathy. Experience with 50 cases treated by means of extensive laminectomy, foraminotomy, and excision of osteophytes during the past 10 years.}, journal = {Acta neurochirurgica}, volume = {61}, number = {1-3}, pages = {89-104}, pmid = {6280455}, issn = {0001-6268}, mesh = {Adult ; Aged ; *Cervical Vertebrae/surgery ; Female ; Humans ; *Laminectomy ; Male ; Middle Aged ; Peripheral Nervous System Diseases/surgery ; Radiography ; Retrospective Studies ; Spinal Cord/*surgery ; Spinal Cord Diseases/diagnostic imaging/*surgery ; *Spinal Nerve Roots ; Spinal Osteophytosis/*surgery ; }, abstract = {This paper reviews management by means of the posterior approach of 50 patients with cervical myeloradiculopathy caused by spondylosis and stenosis of the spinal canal seen in the past 10 years. Careful selection of patients is an absolute necessity since a primary cause of failure occurred in individuals who subsequently proved to have motor neurone disease. Older individuals with long-standing neurological deficits, especially long tract signs indicative of fixed lesions, were benefited primarily by a lack of further progression of their disorder and occasional improvement in hand function and gait. Diagnostic evaluation should include electromyography, nerve conduction studies, and sensory evoked cortical potentials. With the introduction of the fourth generation CAT scanning equipment, additional diagnostic information is available regarding the internal configuration of the spinal canal, its contents, and the amount of available space at various levels. Supplementary myelography remains of basic importance. Laminectomy includes two levels above and below the areas of significant canal encroachment. Foraminal decompression with removal of only the innermost third of the foramen permits mobilization of the nerve roots, removal of osteophytes and untethering of the dural sac. A great deal of importance is attached to the preservation of the cervical lordotic curve since, with an adequate decompression and an intact dura, the cord moves dorsally into an expanded canal, rising above the ventrally situated osteophytes. In those patients with reversal of the cervical curve and swan neck deformities, posterior decompression has not been of value. Recent more radical procedures in such cases, such as vertebrectomy, remain to be evaluated. Any procedure which will permit further kyphotic deformity, such as laminectomy, is contraindicated. Eighty-five percent of the patients operated upon by the recommended surgical approach improved.}, }
@article {pmid7041350, year = {1981}, author = {Vaughn, WK and Mendez-Picon, G and Humphries, AL and Spees, EK}, title = {Method of preservation is not a determinant of graft outcome in kidneys transplanted by Southeastern Organ Procurement Foundation Institutions.}, journal = {Transplantation}, volume = {32}, number = {6}, pages = {490-494}, doi = {10.1097/00007890-198112000-00008}, pmid = {7041350}, issn = {0041-1337}, mesh = {Antilymphocyte Serum/therapeutic use ; Blood Transfusion ; *Graft Survival ; HLA Antigens/immunology ; Histocompatibility Testing ; Humans ; *Kidney Transplantation ; Organ Preservation/*methods ; Tissue Preservation/*methods ; }, abstract = {We report the observation that the major sources of variation in cadaver renal allograft survival rates are not related to the technique of donor organ preservation but are related solely to other factors including pretransplant blood transfusion of the recipient, antilymphocyte serum (ALS) treatment of the recipient, and high HLA match. In contrast to prior studies which used univariate methods to analyze similar data, our analysis shows that it is imperative that comparisons of different methods of cadaver preservation must include adjustments for the effects of pretransplant blood transfusions, antilymphocyte serum, and HLA match.}, }
@article {pmid6461952, year = {1981}, author = {Maki, T and Okazaki, H and Wood, ML and Monaco, AP}, title = {Suppressor cells in mice bearing intact skin allografts after blood transfusions.}, journal = {Transplantation}, volume = {32}, number = {6}, pages = {463-466}, doi = {10.1097/00007890-198112000-00002}, pmid = {6461952}, issn = {0041-1337}, support = {AI 14551-03/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/therapeutic use ; *Blood Transfusion ; Graft Rejection ; Lymphocyte Culture Test, Mixed ; Mice ; Mice, Inbred C3H/immunology ; Mice, Inbred C57BL/immunology ; *Skin Transplantation ; Spleen/immunology ; T-Lymphocytes, Regulatory/*immunology ; }, abstract = {Evidence for the presence of suppressor cells in B6AF1 mice bearing long-term C3H skin grafts after multiple blood transfusions and antilymphocyte serum (ALS) treatment is described. Transfer of spleen cells from these mice into secondary B6AF1 recipients given ALS and C3H skin grafts resulted in marked prolongation of graft survival. The spleen cells were also capable of specifically inhibiting the proliferative response of normal B6AF1 responders to C3H stimulator cells in coculture mixed lymphocyte culture (MLC) experiments.}, }
@article {pmid6173010, year = {1981}, author = {Appel, SH}, title = {A unifying hypothesis for the cause of amyotrophic lateral sclerosis, parkinsonism, and Alzheimer disease.}, journal = {Annals of neurology}, volume = {10}, number = {6}, pages = {499-505}, doi = {10.1002/ana.410100602}, pmid = {6173010}, issn = {0364-5134}, mesh = {Alzheimer Disease/*etiology/physiopathology ; Amyotrophic Lateral Sclerosis/*etiology/physiopathology ; Axonal Transport ; Brain/physiopathology ; Cell Survival ; Dementia/*etiology ; Humans ; Motor Neurons/physiology ; Nerve Degeneration ; Nerve Growth Factors ; Nerve Regeneration ; Nerve Tissue Proteins/deficiency/physiology ; Parkinson Disease/*etiology/physiopathology ; Synapses/physiology ; }, abstract = {The causes of amyotrophic lateral sclerosis, Parkinson disease, and Alzheimer disease are unknown. Furthermore, treatment for two of these conditions is almost totally lacking. The thesis is presented that each of these disorders is due to lack of a disorder-specific neurotrophic hormone. The hormone would be elaborated or stored in the target of the affected neurons. It would be released by the postsynaptic cell and then exert its effects in a retrograde fashion after being taken up by the presynaptic terminal. In the lower motor neuron syndromes of amyotrophic lateral sclerosis, failure of muscle cells to release the appropriate motor neurotrophic hormone would result in impaired function of anterior horn cells. In Parkinson disease, the neurotrophic failure would be characterized by inability of striatal cells to provide the required dopamine neurotrophic hormone with resulting impairment of substantia nigra cells. In Alzheimer disease, the abnormalities would lie in failure of the hippocampus and cortical cells to supply the relevant cholinergic neurotrophic hormone with resulting impairment of medial septal and nucleus basalis neurons. Central nervous system tissue culture provides a convenient system in which to assay these neurotrophic hormones and should permit a test of the hypothesis.}, }
@article {pmid6168692, year = {1981}, author = {Maki, T and Gottschalk, R and Wood, ML and Monaco, AP}, title = {Specific unresponsiveness to skin allografts in anti-lymphocyte serum-treated, marrow-injected mice: participation of donor marrow-derived suppressor T cells.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {127}, number = {4}, pages = {1433-1438}, pmid = {6168692}, issn = {0022-1767}, support = {AI-14554-03/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; *Bone Marrow Transplantation ; Cytotoxicity, Immunologic ; Epitopes ; *Immune Tolerance ; Lymphocyte Activation ; Lymphocyte Culture Test, Mixed ; Male ; Mice ; Mice, Inbred C3H ; Mice, Inbred DBA ; Mitogens/pharmacology ; *Skin Transplantation ; Spleen/cytology ; T-Lymphocytes, Regulatory/immunology ; }, abstract = {Sequential changes of cell-mediated immune reactivities were examined in anti-lymphocyte serum-(ALS) treated, C3H/He (C3H; H-2k) bone marrow-injected (C57BL/6 X A)F1 (B6AF1; H-2b/k.d) mice bearing enhanced C3H skin grafts. Spleen cells of these mice exhibited marked suppression of the proliferative response to phytohemagglutinin and concanavalin A. When the spleen cells were assayed for the direct lymphocyte-mediated cytotoxicity against H-2k targets, their lytic activity remained low until the time of graft rejection, in contrast to the increasingly high cytotoxic activity exhibited by spleen cells of control B6AF1 mice given only ALS and C3H skin grafts. When spleen cells of marrow-injected B6AF1 mice were cultured with mitomycin-C treated C3H spleen cells, the proliferative response was significantly suppressed the throughout the course, despite the early appearance of high "secondary-type" cytotoxic activity. Co-culture experiments demonstrated the presence of C3H antigen-specific suppressor cells in the ALS-treated, marrow-injected mice bearing intact allografts. Treatment of spleen cells with anti-H-2, anti-Thy 1 and anti-I-J sera and C revealed that the suppressor cells present late in the marrow-injected mice were T cells of donor C3H bone marrow cell origin.}, }
@article {pmid7293780, year = {1981}, author = {Gundersen, S and Wibe, E and Gidlund, M and Godal, T}, title = {Cellular and humoral factors in host susceptibility to Lewis lung carcinoma.}, journal = {Acta pathologica et microbiologica Scandinavica. Section C, Immunology}, volume = {89}, number = {2}, pages = {123-132}, doi = {10.1111/j.1699-0463.1981.tb02675.x}, pmid = {7293780}, issn = {0304-1328}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; Cells, Cultured ; *Cytotoxicity, Immunologic/drug effects ; *Immunity, Innate/drug effects ; Killer Cells, Natural/immunology ; Lung Neoplasms/*immunology ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Mice, Nude ; Neoplasms, Experimental/*immunology ; }, abstract = {Cellular and humoral anti-tumour reactivity in strains of mice highly susceptible (C57Bl/6) or less susceptible (C57Cl/6 x DBA/2 = B6D2F1) to Lewis lung carcinoma (LLC) was investigated. Natural killer cell activity in a 51Cr release assay against this tumour could be demonstrated with a good correlation to in vivo susceptibility. This has not been demonstrated earlier for solid, spontaneous tumours. T-cell deficiency (congenital athymic (nude mice)) did not affect the cumulative incidence of tumour take. However, the number of lung metastases was significantly reduced in nude mice. Treatment with antilymphocyte serum (ALS) increased the susceptibility to LLC in both strains. In a soft agar colony assay a marked reduction in the number of colonies was observed when tumour cells were incubated with serum from B6D2F1 mice as compared to serum from C57Bl/6 mice, prior to seeding. Apparently naturally occurring cellular, as well as humoral effector mechanisms are involved in host resistance to Lewis lung carcinoma in the mouse.}, }
@article {pmid7022949, year = {1981}, author = {Mullen, Y}, title = {Permanent reversal of experimental diabetes in rats by allogeneic fetal pancreases across minor histocompatibility loci: effects and characteristics of immunosuppression induced by alloantigen, PCH, and ALS treatment.}, journal = {Transplantation proceedings}, volume = {13}, number = {1 Pt 2}, pages = {823-825}, pmid = {7022949}, issn = {0041-1345}, support = {AM 17980/AM/NIADDK NIH HHS/United States ; AM 20827/AM/NIADDK NIH HHS/United States ; }, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; Diabetes Mellitus, Experimental/*therapy ; Female ; Fetus/*anatomy &amp; histology/immunology ; *Graft Survival/drug effects ; Histocompatibility Antigens/immunology ; Immunosuppressive Agents ; Male ; *Pancreas Transplantation ; Procarbazine/pharmacology ; Rats ; Rats, Inbred Strains/immunology ; }, }
@article {pmid7044255, year = {1981}, author = {Laplace, JP and De Riberolles, C and Lecompte, Y and Martelli, H}, title = {[Heterotopic cardiac allograft in the newborn piglet (author's transl)].}, journal = {Annales de recherches veterinaires. Annals of veterinary research}, volume = {12}, number = {1}, pages = {27-33}, pmid = {7044255}, issn = {0003-4193}, mesh = {Animals ; Animals, Newborn/surgery ; Animals, Suckling/surgery ; Antilymphocyte Serum/administration &amp; dosage ; Aorta, Abdominal/surgery ; *Heart Transplantation ; Immunosuppression Therapy/methods ; Nephrectomy ; Swine/*surgery ; Thymectomy ; Transplantation, Homologous/methods/mortality ; Vena Cava, Inferior/surgery ; }, abstract = {Heterotopic cardiac allografts were performed in unrelated Large White piglets to test (i) if such a technique could be used in young (12 days) and neonates (less than five days); (ii) if tolerance to histocompatibility antigens could be induced by donor-cells injection to piglets that were immunosuppressed with heterologous antilymphocyte serum (ALS). The experimentation included two different series. The first one involved ten allografts done in early weaned (10 days), 12-day-old piglets (mean live weight 3.5 kg). They received or not ALS 2 ml per kg per day by subcutaneous route during five consecutive days after transplantation. In addition, two of the ALS treated piglets received endovenously, on day 7 after transplantation, cryoconservated cells from the spleen of the heart-donor. The second series involved ten allografts performed in suckling piglets just after birth at a mean live weight of 1.4 kg. These animals were first thymectomized at day 0 (6 h to 44 h after birth), and then received ALS (4 ml per kg by intraperitoneal route) on day 1. The heterotopic cardiac allograft was performed on day 2. Out of them, two received endovenously, on day 3, conservated splenic cells from the heart donor. In both series the heterotopic cardiac allograft was done, after right nephrectomy, anastomosing the donor thoracic aorta end to side to the recipient abdominal aorta, and the donor pulmonary artery end to side to the recipient inferior vena cava. From the surgical point of view, it appeared that the heterotopic cardiac allograft was easy to perform, and successful in most cases, in 12-day-old piglets. The same operation in neonates was as easy to perform as in older animals, but most failed to survive due to hemorragic leakage and post operative shock (repetitive anesthesia, insufficient suckling). From the immunological point of view, we failed to obtain any active enhancement of heart allograft with significant prolongation of the survival of the allogenic heart allograft (electro-cardiogram from epicardic electrodes). Rejection usually occurred in 6 to 8 days whatever the treatment (ALS with or without splenic cells from the donor, or nothing).}, }
@article {pmid7024284, year = {1981}, author = {Anderson, MJ and Oeljeschlager, H and Müller-Hermelink, HK and Müller-Ruchholtz, W}, title = {Patterns of antibody reactivity against selected human leukemia cell lines.}, journal = {Journal of cancer research and clinical oncology}, volume = {101}, number = {1}, pages = {101-107}, pmid = {7024284}, issn = {0171-5216}, mesh = {Antilymphocyte Serum/*immunology ; Bone Marrow/*immunology ; Bone Marrow Transplantation ; Cell Line ; Cross Reactions ; *Cytotoxicity, Immunologic ; Granulocytes/immunology ; Humans ; Immunoenzyme Techniques ; Leukemia/*immunology ; Lymphocytes/immunology ; Plasma Cells/immunology ; }, abstract = {Absorption procedures which allow the production of a selectively cytotoxic anti-human lymphocyte serum are described. Although the production of a reagent whose reactivity is restricted. Although the production of a reagent whose reactivity is restricted exclusively to lymphocytes may be achieved by exhaustive absorption steps using fresh human erythrocytes, CML cells, and fetal liver cells, a more realistic alternative is the use of appropriately selected cultured human leukemia cell lines. Data are presented which show how these cell lines may be employed to selectively manipulate the cross-reactivity spectrum of ALS. Pre-treatment of donor bone marrow cells prior to transplantation with a selectively lymphocytotoxic ALS has been shown to allow transplantation of bone marrow across major histocompatibility barriers in rodents without the occurrence of GvH reactions, and it is the purpose of the present investigations to show that an analogous anti-human ALS can be prepared which possesses the required degree of selectivity to allow its application for human bone marrow transplantation.}, }
@article {pmid6942794, year = {1981}, author = {Guo, F and Ding, BF}, title = {Treatment of bone and soft tissue malignant tumours of the extremities by radical resection. A preliminary report of 12 cases.}, journal = {Archives of orthopaedic and traumatic surgery. Archiv fur orthopadische und Unfall-Chirurgie}, volume = {98}, number = {3}, pages = {201-208}, pmid = {6942794}, issn = {0344-8444}, mesh = {Adolescent ; Adult ; Amputation, Surgical ; Arm/*surgery ; Bone Neoplasms/*surgery ; Chondrosarcoma/surgery ; Female ; Fibrosarcoma/surgery ; Giant Cell Tumors/surgery ; Humans ; Leg/*surgery ; Male ; Middle Aged ; Osteosarcoma/surgery ; Outcome and Process Assessment, Health Care ; Replantation ; Sarcoma, Ewing/surgery ; Soft Tissue Neoplasms/*surgery ; }, abstract = {Radical local resection is undoubtedly the method of choice in treating malignant bone and soft tissue tumours in the extremities, provided there is no local recurrence after radical resection. This is even truer today when the chemotherapy of osteosarcoma has achieved encouraging advances in preventing lung metastasis. The diagnostic methods for the evaluation of the tumour infiltration are at a more complete stage, and operative reconstruction techniques have als made rapid progress. Radical local resection is especially suitable for sarcomata of the extremities which are at an early stage, with less infiltrative low-grade malignancy. Amputation is better when the tumour grows rapidly and is large, if the soft tissue is widely infiltrated, if the patient is from 20 to 30 years old, and especially if the tumour is located in the upper tibia where it is difficult to carry out local resection. In this article, we report and discuss the definition, necessity, and possibility of radical local resection as well as the method of surgical reconstruction and our results. The results and prognosis for radical resection of giant-cell sarcoma, chondrosarcoma, and fibrosarcoma are rather good. Three of five cases of osteosarcoma died of lung metastasis one year after surgery. Therefore, improving the results in local resection of osteosarcoma calls for further investigation.}, }
@article {pmid7429410, year = {1980}, author = {Langohr, HD}, title = {[Biochemical studies on muscles in neurogenic atrophies and central paralysis. Studies of the trophic functions of neurons].}, journal = {Fortschritte der Medizin}, volume = {98}, number = {39}, pages = {1512-1516}, pmid = {7429410}, issn = {0015-8178}, mesh = {Denervation ; Humans ; Motor Neurons/*physiology ; Muscles/enzymology/*metabolism ; Muscular Atrophy/*enzymology ; Phosphorylases/metabolism ; Polyneuropathies/enzymology ; }, abstract = {Enzyme activities of the energy supplying metabolism were investigated in muscle specimens of brachial biceps, deltoid or anterior tibial muscles of patients with traumatic nerve lesions, polyneuropathies, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, spinal muscular atrophy and hemiparesis. The key enzymes of glycogenolysis (glycogen phosphorylase), glycolysis (triosephosphate dehydrogenase, lactate dehydrogenase), alpha-glycerophosphate cycle (alpha-glycerophosphate dehydrogenase), beta-oxidation of fatty acids (beta-hydroxy-acyl-CoA-dehydrogenase), citrate acid cycle (citrate synthase, malate dehydrogenase), hexokinase reaction (hexokinase) and pentosephosphate shunt (6-phosphogluconate dehydrogenase) were measured. The present study shows that in case of disorders of the lower motor neuron--especially those with impaired axoplasmic transport--changes in the enzyme patterns of muscles occur at an early stage. The glycolytic enzyme activities are of particular significance because they are the most sensitive indicators of the onset, extent and course of neurogenic atrophy. There is a good correlation between severity of the lesion, functional state of the muscles and reduction of these enzyme activities. In case of traumatic nerve lesions re-innervation can prevent a permanent reduction of glycolytic enzymes only if it occurs during the first months after denervation. In all cases in which operative revision is considered, it is therefore not advisible to wait since the regenerative capacity of the motor neuron is not the only limiting factor but also the biochemical and morphological changes in the muscle fibre. These are permanent after long lasting denervation without re-innervation within the first months. Primary neuroaxonal degeneration of the nerve fibre which was found in the majority of our alcoholic patients obviously impairs the metabolism of the muscle to a greater extent than primary demyelination most frequently observed in diabetics with polyneuropathy. Corresponding to the chronic course of the illness over years and to the severity of the pareses, drastic reduction in the activities of glycolytic enzymes was found in patients with Charcot-Marie-Tooth disease. Simultaneously the activity of 6-phosphogluconate dehydrogenase was significantly increased as a result of the chronic neurogenic lesion of the muscle fibres. Follow-up during the treatment of diseases of the lower motor neuron can be performed because the enzyme activities can be measured even in small muscle specimens. In patients with hemiparesis slight but not significant reduction in the glycolytic enzyme activities was found by comparison with a normal control group. We assume that this reduction is due to general inactivity which is caused by the movement disorder rather than to the particular influence of the upper motor neuron.}, }
@article {pmid6934635, year = {1980}, author = {Floersheim, GL and Nassenstein, D and Torhorst, J}, title = {Growth of human tumors in mice after short-term immunosuppression with procarbazine, cyclophosphamide, and antilymphocyte serum.}, journal = {Transplantation}, volume = {30}, number = {4}, pages = {275-280}, doi = {10.1097/00007890-198010000-00007}, pmid = {6934635}, issn = {0041-1337}, mesh = {Adenocarcinoma/pathology ; Adolescent ; Adult ; Animals ; Antilymphocyte Serum/*pharmacology ; Bone Neoplasms/pathology ; Carcinoma/pathology ; Child ; Colonic Neoplasms/pathology ; Cyclophosphamide/*pharmacology ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Female ; Humans ; Male ; Mice ; Neoplasm Transplantation ; Neoplasms/*pathology ; Osteosarcoma/pathology ; Procarbazine/*pharmacology ; Sarcoma, Ewing/pathology ; Transplantation, Heterologous ; }, abstract = {A simple combine treatment with immunosuppressive agents permitting the growth of human tumor xenografts in conventional mice is presented. It consists of two simultaneous applications of 90 mg of procarbazine (PCH) per kg and 30 mg of cyclophosphamide (CY) per kg, alternating with two doses of 0.15 ml/10 g of antilymphocyte serum (ALS) for 4 days before grafting. No postgraft treatment is used. With a take rate of 100%, at 60 days after subcutaneous transplantation into male C3H mice, fragments of a human colon adenocarcinoma had grown (on the average) into cherry-sized tumors. Two osteosarcomas, an Ewing sarcoma, and a bronchogenic carcinoma were also studied and grew similarly. Tumors could be established in the three tested mouse strains but grew better in male animals. Synergy of PCH and CY and ALS depends upon the alternating sequence of both drugs and ALS. The histology of the colon carcinoma and the Ewing sarcoma was unchanged as compared to the tumors growing in nude mice. In contrast, the osteosarcoma developed in a more differentiated fashion in the immunosuppressed mice. The presented model may serve as a screening system for anticancer drugs.}, }
@article {pmid7401852, year = {1980}, author = {McGuirt, WF and Blalock, D}, title = {The otolaryngologist's role in the diagnosis and treatment of amyotrophic lateral sclerosis.}, journal = {The Laryngoscope}, volume = {90}, number = {9}, pages = {1496-1501}, pmid = {7401852}, issn = {0023-852X}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/complications/*diagnosis ; Deglutition Disorders/etiology/therapy ; Female ; Humans ; *Otolaryngology ; *Physician's Role ; Referral and Consultation ; *Role ; Speech Disorders/etiology/therapy ; Voice Disorders/etiology/therapy ; }, abstract = {In the early insidious phase of Amyotrophic Lateral Sclerosis (ALS), the patient will often present initially to the otolaryngologist for a presumed speech problem or dysphagia. Adult onset hypernasality, breathiness, articulation defects and voice harshness should all be seen as possible early signs of ALS and may allow the otolaryngologist to be the primary diagnostician for that disease; three such cases are reported here. Once the diagnosis of ALS is made, the otolaryngologist may be involved at different stages in the disease, offering treatment such as Teflon¿ injections, pharyngeal flap, obturator fitting, cricopharyngeal myotomy, tracheostomy, and cervical esophagostomy for speech, swallowing and aspiration problems. Although they do not halt the progression of this fatal disease, these procedures provide an improved quality of life for the patient whose intellectual function is preseved while his motor functions progressively deteriorate. This is more important for the minority of patients having prolonged survival.}, }
@article {pmid7417042, year = {1980}, author = {Silani, V and Scarlato, G and Valli, G and Marconi, M}, title = {Plasma exchange ineffective in amyotrophic lateral sclerosis.}, journal = {Archives of neurology}, volume = {37}, number = {8}, pages = {511-513}, doi = {10.1001/archneur.1980.00500570059009}, pmid = {7417042}, issn = {0003-9942}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Humans ; Male ; Middle Aged ; Motor Neurons/physiology ; *Plasma Exchange ; }, abstract = {The effectiveness of plasma exchange in amyotrophic lateral sclerosis (ALS) was tested in four patients. Electromyography (EMG) and clinical examinations were carried out before, during, and after the treatment. The EMG data showed a progressive unaffected motor neuronal decay. Clinically the course of the disease was not dissimilar to that usually encountered, although a momentary improvement was observed in two patients after the first procedure. Plasma exchange appears to be of no value in treating ALS.}, }
@article {pmid6995042, year = {1980}, author = {Kiss, GT and Rao, K}, title = {Treatment of refractory lobar atelectasis in amyotrophic lateral sclerosis with PEEP.}, journal = {Chest}, volume = {78}, number = {2}, pages = {353-354}, doi = {10.1378/chest.78.2.353-b}, pmid = {6995042}, issn = {0012-3692}, mesh = {Amyotrophic Lateral Sclerosis/*complications ; Female ; Humans ; Middle Aged ; *Positive-Pressure Respiration ; Pulmonary Atelectasis/etiology/*therapy ; }, }
@article {pmid6903360, year = {1980}, author = {Regan, WA}, title = {Treatment accidents: government nurses. Case in point: Gregory v. Martyak, Kapish et als (404 A. 2d 188-PA.).}, journal = {The Regan report on nursing law}, volume = {20}, number = {11}, pages = {4}, pmid = {6903360}, issn = {0034-3196}, mesh = {Accidents ; Emergencies ; Hospitals, General ; Humans ; Male ; *Malpractice ; *Nursing ; Pennsylvania ; }, }
@article {pmid6107015, year = {1980}, author = {Burri, C and Lob, G and Rudzki, M}, title = {[Nebacetin and taurolin as intraoperative disinfectant solutions in surgery of the locomotor system (author's transl)].}, journal = {Aktuelle Traumatologie}, volume = {10}, number = {2}, pages = {65-72}, pmid = {6107015}, issn = {0044-6173}, mesh = {Anti-Infective Agents, Local/*administration &amp; dosage ; Bacitracin/*administration &amp; dosage ; Drug Combinations ; Intraoperative Period ; Neomycin/*administration &amp; dosage ; Orthopedics ; Surgical Wound Infection/*prevention &amp; control ; Taurine/*analogs &amp; derivatives ; *Therapeutic Irrigation ; Thiadiazines/*administration &amp; dosage ; Thiazines/*administration &amp; dosage ; Wound Healing/drug effects ; }, abstract = {The anti-infective preventive action of intraoperative disinfection with physiological solution containing antibiotics, appears to be firmly established, judging from numerous publications. Since germs are showing a world-wide increasing resistance, the search for antibiotics which continue to be effective must be kept up, but alternative suggestions are equally necessary. Some publications have already been presented indicating that success similar to that previously obtained with antibiotics is possible by using disinfectants in the prophylaxis and treatment of infections. Hence, a comparative study was conducted using the non-absorbable broad-spectrum antibiotic Nebacetin and the disinfectant Taurolin in a 1% solution with a group of patients subjected to a total of 7699 major and minor surgical operations. Prospectively, early infections during the stay of the patient in the hospital, als well as disturbed wound healing, were included. No significant difference was found in the number of infections and the rate of disturbed wound healing. Indirectly, it is possible to conclude with the help of results from literature that the disinfectant Taurolin is suitable as an addition to intra-operative rinsing in the prophylaxis of infections.}, }
@article {pmid6449472, year = {1980}, author = {Rudnicka, W}, title = {Suppressor activity of blood lymphocytes from guinea-pigs treated with ALS.}, journal = {Immunology}, volume = {39}, number = {3}, pages = {435-440}, pmid = {6449472}, issn = {0019-2805}, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; Cells, Cultured ; Guinea Pigs ; Lymphocyte Activation ; Lymphocytes/immunology/metabolism ; T-Lymphocytes, Regulatory/*immunology ; Thymidine/metabolism ; }, abstract = {PHA-induced transformation of guinea-pig lymphocytes was profoundly inhibited by the injection of antilymphocyte serum (ALS). This effect, seen 24 h after ALS administration, disappeared within 3 days. Lymphocytes of animals injected with ALS 24 h earlier inhibited the blast transformation of autologous normal lymphocytes. The supernatants of short term cultures of such cells, even after pre-treatment with puromycin, exhibited the same inhibitory activity. It is suggested that the immunosuppressive effect of ALS is not limited to its direct action on lymphocytes.}, }
@article {pmid6444769, year = {1980}, author = {Wood, ML and Monaco, AP}, title = {Suppressor cells in specific unresponsiveness to skin allografts in ALS-treated, marrow-injected mice.}, journal = {Transplantation}, volume = {29}, number = {3}, pages = {196-200}, doi = {10.1097/00007890-198003000-00006}, pmid = {6444769}, issn = {0041-1337}, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; Bone Marrow/immunology ; Bone Marrow Transplantation ; Graft Survival ; *Immunologic Memory ; Lymph Nodes/immunology ; Mice ; Mice, Inbred A ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Inbred DBA ; *Skin Transplantation ; Spleen/immunology ; T-Lymphocytes, Regulatory/*immunology ; Thymus Gland/immunology ; Transplantation, Homologous ; }, abstract = {Lymphoid cells from ALS-treated (C57BL/6 x A/J)F1 (B6AF1) mice bearing enhanced C3H/He grafts were assayed for their ability to suppress the response to C3H/He grafts after transfer to syngeneic B6AF1 recipients. Cells were transferred from ALS-treated B6AF1 mice that had received either a C3H/He graft alone, C3H/He marrow alone, or both a graft and marrow. Suppressor cells appeared in the spleens of ALS-treated B6AF1 mice that had received either a graft alone or both graft and marrow as early as day +13. They persisted only in the spleens of mice that had received both a graft and marrow, i.e., mice whose grafts showed significant prolongation. Suppressor cells did not appear in the lymph nodes of mice bearing enhanced grafts until day +42. Thymocytes and bone marrow cells were unable to transfer unresponsiveness. The cells which transferred unresponsiveness were specific for the graft donor strain as they did not transfer unresponsiveness to third-party grafts. The ability of cells to transfer suppression was abrogated by treatment with anti-theta serum.}, }
@article {pmid6970512, year = {1980}, author = {Plotkin, R}, title = {Pisces stimulation for motor neurone disease.}, journal = {Acta neurochirurgica. Supplementum}, volume = {30}, number = {}, pages = {429-433}, doi = {10.1007/978-3-7091-8592-6_56}, pmid = {6970512}, mesh = {Electric Stimulation Therapy/instrumentation/methods ; Female ; Humans ; Male ; Middle Aged ; *Motor Neurons ; Neuromuscular Diseases/*therapy ; *Spinal Cord ; }, abstract = {Electrical stimulation of the spinal cord using the Pisces system (Medtronic Inc.) has been used for treating five patients with motor neurone disease. A short clinical description is given of each case, together with results of stimulation. In all five patients improvement was dramatic, but in two of them the progress of the disease was not halted. One, with advanced bulbar symptoms and signs, died two months after the implantation of the stimulating electrodes, although there had been initial improvement in her condition. One patient was lost to follow up. The period of stimulation in the remaining four patients ranged from eleven to six months. No medication was given other than antibiotics during the initial test phase, and all patients had physiotherapy. The results in these patients warrants continuation of this form of treatment in suitably selected patients.}, }
@article {pmid6253098, year = {1980}, author = {Kogelnik, HD}, title = {Clinical experience with misonidazole: high dose fractions versus daily low doses.}, journal = {Cancer clinical trials}, volume = {3}, number = {2}, pages = {179-186}, pmid = {6253098}, issn = {0190-1206}, mesh = {Adult ; Aged ; Blood Pressure/drug effects ; Clinical Trials as Topic ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Eruptions/etiology ; Epilepsy/chemically induced ; Female ; Hearing Loss/chemically induced ; Humans ; Male ; Middle Aged ; Misonidazole/*administration &amp; dosage/adverse effects/blood ; Neurocognitive Disorders/chemically induced ; Nitroimidazoles/*administration &amp; dosage ; Peripheral Nervous System Diseases/chemically induced ; }, abstract = {In April 1976 clinical experience with misonidazole began at the University Clinic for Radiotherapy and Radiobiology of Vienna. Initially the drug was given mainly in four to six divided large doses ranging from 50 to 80 mg/kg (2.1-3.1 g/m2). Since October 1977 daily low doses in the range of 1-2g (0.45-1.3 g/m2) were used. So far over 100 patients with advanced tumor stages have been under investigation. Serum levels for the different treatment schedules are reviewed and sensitizer enhancement ratios larger than 1.3 may be expected even with daily low doses of misonidazole. Neurological side effects are analyzed and related to the cumulative dose (in g/m2) and overall treatment time. Depending on the overall time of drug administration the total dose of misonidazole can be adjusted to avoid undersirable side effects. It is our impression that normal tissue reactions are unchanged by the use of misonidazole. Preliminary results of a randomized clinical trial in patients with high-grade astrocytomas appear to be favorable for the sensitizer group. Als some impressive clinical results were seen in patients when using daily low doses of misonidazole.}, }
@article {pmid389405, year = {1979}, author = {Auclerc, G and Jacquillat, C and Auclerc, MF and Weil, M and Bernard, J}, title = {Post-therapeutic acute leukemia.}, journal = {Cancer}, volume = {44}, number = {6}, pages = {2017-2025}, doi = {10.1002/1097-0142(197912)44:6&lt;2017::aid-cncr2820440609&gt;3.0.co;2-a}, pmid = {389405}, issn = {0008-543X}, mesh = {Acute Disease ; Adolescent ; Adult ; Aged ; Antineoplastic Agents/*adverse effects ; Arthritis, Rheumatoid/drug therapy ; Child ; Child, Preschool ; Female ; Hodgkin Disease/therapy ; Humans ; Leukemia/*etiology ; Leukemia, Lymphoid/drug therapy ; *Leukemia, Radiation-Induced ; Male ; Middle Aged ; Multiple Myeloma/therapy ; Neoplasms/therapy ; Neoplasms, Multiple Primary/etiology ; Nephrotic Syndrome/drug therapy ; }, abstract = {This study reports 35 cases of posttherapeutic acute leukemia and reviews the literature on this subject. These AL's are characterized by a high incidence of anemia, in particular refractory anemia, preceding the hematological disorder by several months, by the frequent finding of myelofibrosis, by the essentially granulocytic nature of the AL, and by the low rate of remission and the, in general, extremely short sruvival of a few months. These leukemias may develop following continuous chemotherapy with an alkylating agent, radiotherapy of various extent, or most commonly following intensive treatment with extensive irradiation and polychemotherapy as in the management of Hodgkin's disease. In view of these therapeutic hazards, the present objectives are the modification of alkylating agent therapy by the use of other drugs and sequential administration, and a reduction in the dose and field of irradiation and the duration of polychemotherapy, as in Hodgkin's disease; all present protocols are orientated in this direction.}, }
@article {pmid391699, year = {1979}, author = {Reuben, C and Phondke, GP}, title = {Specific suppression of delayed hypersensitivity response to sheep erythrocytes by heterologous anti-lymphocyte serum.}, journal = {Immunology}, volume = {38}, number = {3}, pages = {547-551}, pmid = {391699}, issn = {0019-2805}, mesh = {Animals ; Antigens/immunology ; Antilymphocyte Serum/*immunology ; Erythrocytes/immunology ; Hemolytic Plaque Technique ; Hypersensitivity, Delayed ; *Immunity, Cellular ; Immunoglobulin G/biosynthesis ; Immunoglobulin M/biosynthesis ; *Immunosuppression Therapy ; Rats ; Time Factors ; }, abstract = {The development of a heterologous anti-lymphocyte serum (ALS) capable of specifically suppressing the delayed hypersensitivity (DH) response is reported. This ALS, termed ALS(CMI), was prepared against lymph node cells from rats which had been immunized against sheep erythrocytes (SRBC) following treatment with cyclophosphamide which is known to enhance the DH response and suppress the humoral immune response. The effect of ALS(CMI) on the primary DH response to SRBC using the footpad swelling test was studied. Its effect on the primary humoral immune response to SRBC was also studied using the Jerne plaque assay technique. ALS(CMI) suppressed the humoral antibody response to SRBC and the DH response to a third party antigen only when administered before the antigen, having no effect when administered post-antigenically. On the other hand, ALS(CMI) significantly suppressed the primary DH response to SRBC when administered either before or after the antigen.}, }
@article {pmid160636, year = {1979}, author = {Wood, ML and Gottschalk, R and Monaco, AP}, title = {Suppressor cells in specific unresponsiveness to skin allografts in thymectomized, ALS-treated, marrow-injected mice.}, journal = {Transplantation}, volume = {28}, number = {5}, pages = {387-388}, doi = {10.1097/00007890-197911000-00008}, pmid = {160636}, issn = {0041-1337}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; Bone Marrow Transplantation ; *Immunization, Passive ; *Immunosuppression Therapy ; Mice ; Mice, Inbred A/immunology ; Mice, Inbred Strains/immunology ; Skin Transplantation ; Spleen/*immunology ; T-Lymphocytes/immunology ; T-Lymphocytes, Regulatory/*immunology ; Thymus Gland/immunology ; Transplantation, Homologous ; }, abstract = {Spleen cells from thymectomized antilymphocyte serum (ALS)-treated B6AF1 mice bearing enhanced C3H/He grafts after the infection of C3H/He marrow were assayed for their ability to suppress the response to C3H/He grafts after transfer to syngeneic B6AF1 recipients. Cells were transferred from thymectomized ALS-treated B6AF1 mice that had received either a C3H/He graft alone, C3H/He marrow alone, or both a graft and marrow. Cells were removed from donors and transferred at either day +13, +42, +62, +100, or +150. Spleen cells from thymectomized mice were unable to transfer unresponsiveness regardless of donor treatment or time of transfer.}, }
@article {pmid92537, year = {1979}, author = {Monstad, I and Dale, I and Petlund, CF and Sjaastad, O}, title = {Plasma exchange in motor neuron disease. A controlled study.}, journal = {Journal of neurology}, volume = {221}, number = {1}, pages = {59-66}, pmid = {92537}, issn = {0340-5354}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/*blood ; Humans ; Middle Aged ; Plasma/*analysis ; *Plasmapheresis ; }, abstract = {In vitro studies seem to indicate that a serum factor may be involved in the pathogenesis of motor neuron disease. If so, plasmaphoresis might influence the course of amyotrophic lateral sclerosis (ALS) favorably. In the present study, therefore, ALS patients were subjected to weekly 21 plasma exchanges, using a Haemonetics blood separator. Seven other ALS patients, matched as closely as possible with the treatment group regarding age, sex, duration of symptoms as well as degree of involvement, served as control group. The progression of the disease was followed by an arbitrary grading system, assessment of muscular power by Zadig's dynamometer, and by tests for motor speed, coordination and for pulmonary function. Duration of treatment was from 6 to 15 months. Monthly evaluations indicated that the rate of deterioration was approximately the same in treatment and control groups. Plasmaphoresis carried out in this way does thus not alter the downhill course of ALS.}, }
@article {pmid425866, year = {1979}, author = {DeLisa, JA and Mikulic, MA and Miller, RM and Melnick, RR}, title = {Amyotrophic lateral sclerosis: comprehensive management.}, journal = {American family physician}, volume = {19}, number = {3}, pages = {137-142}, pmid = {425866}, issn = {0002-838X}, mesh = {Activities of Daily Living ; Amyotrophic Lateral Sclerosis/complications/psychology/*therapy ; Deglutition Disorders/etiology/therapy ; Humans ; Locomotion ; Muscle Spasticity/drug therapy ; Quality of Life ; Respiratory Insufficiency/etiology/prevention &amp; control ; Speech Disorders/etiology/therapy ; }, abstract = {The cause of amyotrophic lateral sclerosis remains unknown, and no curative treatment is available. From a rehabilitation perspective, however, comprehensive management and symptomatic treatment can minimize complications, increase function and improve the patient's quality of life. Quinine, diazepam (Valium) and phenytoin (Dilantin) may relieve muscle cramps, and orthoses may permit greater participation in daily activities. Problems with respiration and swallowing may require surgical procedures and the use of feeding tubes. Decisions regarding surgical intervention must be made in the context of the patient's overall status.}, }
@article {pmid313615, year = {1979}, author = {Gordon, MY and Zola, H}, title = {Removal of myelotoxicity from antilymphocytic sera.}, journal = {Transplantation}, volume = {27}, number = {2}, pages = {106-109}, doi = {10.1097/00007890-197902000-00008}, pmid = {313615}, issn = {0041-1337}, mesh = {Animals ; Antilymphocyte Serum/*immunology ; Bone Marrow/immunology ; Cytotoxicity Tests, Immunologic ; Cytotoxicity, Immunologic ; Humans ; Immune Adherence Reaction ; Leukemia/immunology ; Rabbits ; Sezary Syndrome/immunology ; T-Lymphocytes/*immunology ; }, abstract = {Antilymphocyte sera (ALS) were prepared by different methods and examined for their myelotoxicity by bone marrow colony-forming assay, both before and after absorption with B cell antigens. The results show that myelotoxicity can readily be removed from some, but not all, ALS. The source of antigen and the immunisation protocol used determine the degree of myelotoxicity and hence the number of absorptions required. Non-myelotoxic ALS may be suitable for the prevention of graft-versus-host disease (GVHD) by in vitro treatment of bone marrow before transplantation.}, }
@article {pmid518307, year = {1979}, author = {Roos, RP and Wollmann, R}, title = {Non-productive paramyxovirus infection: Nariva virus infection in hamsters.}, journal = {Archives of virology}, volume = {62}, number = {3}, pages = {229-240}, pmid = {518307}, issn = {0304-8608}, mesh = {Animals ; Antibodies, Viral/analysis ; Antigens, Viral/analysis ; Brain/*microbiology/pathology ; Cricetinae ; Encephalitis/etiology ; Meningitis, Viral/etiology ; Mesocricetus ; Paramyxoviridae/*growth &amp; development ; Respirovirus Infections/immunology/*microbiology/pathology ; Time Factors ; }, abstract = {The pathogenesis of infection with Nariva virus (NV)--recently classified as a paramyxovirus--was studied in the hamster, an animal closely related to the natural host. Intracranial inoculation of suckling hamsters produces an acute necrotizing encephalitis with large amounts of infectious virus and virus antigen in the brain. In contrast, weanling hamsters have only small amounts of infectious virus and only early in the disease, when they are well; later, when clinically ill, they have a non-productive infection with continuing evidence of viral antigen, but no detectable infectious virus. Weanlings die later than sucklings with less cerebral parenchymal necrosis. The integrity of the immune system affects the expression of NV since brain tissue from anti-lymphocyte serum (ALS) treated infected weanling hamsters have more infectious virus, and for longer periods, than brain tissue from untreated infected weanling hamsters. Changing susceptibility of the host's neural cells may also be involved in determining the course of the illness and expression of the virus since: 1) ALS treatment does not influence the clinical course of the disease or pathology, 2) ALS treated weanlings still have much lower levels of infectious virus than sucklings, 3) infected weanling and suckling hamsters have a similar time course of development of NV neutralizing antibody.}, }
@article {pmid463344, year = {1979}, author = {Ladipo, OA and Ojo, OA}, title = {Suppression of lactation comparing stilboestrol and bromocriptine (CB154).}, journal = {Nigerian medical journal : journal of the Nigeria Medical Association}, volume = {9}, number = {1}, pages = {77-79}, pmid = {463344}, issn = {0300-1652}, mesh = {Adult ; Bromocriptine/*therapeutic use ; Depression, Chemical ; Diethylstilbestrol/*therapeutic use ; Drug Evaluation ; Female ; Humans ; Lactation/*drug effects ; Nigeria ; Pregnancy ; Prolactin/blood ; }, }
@article {pmid425761, year = {1979}, author = {Viktorov, IV and Bunina, TL}, title = {[Cytotoxic effect of the serum of amyotrophic lateral sclerosis patients on spinal cord motoneurons in tissue culture].}, journal = {Zhurnal nevropatologii i psikhiatrii imeni S.S. Korsakova (Moscow, Russia : 1952)}, volume = {79}, number = {2}, pages = {169-171}, pmid = {425761}, issn = {0044-4588}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*blood ; Animals ; Culture Techniques ; Cytotoxicity, Immunologic ; Humans ; Immune Sera/*pharmacology ; Mice ; Middle Aged ; *Motor Neurons ; Organ Specificity ; *Spinal Cord ; }, abstract = {Organotypical cultures of the spinal cord of the fetal mouse were used to study the neurocytotoxic effect of sera from patients with amyotrophic lateral sclerosis (ALS). Sera from 16 patients with ALS were used in two experiments: 1. short-term treatment (up to 6 days) of the mature cultures with nutrient medium containing 30% of ALS serum; 2. long-term cultivation from the explantation up to 4 weeks of spinal cord in the medium containing 5-25% of ALS serum. No specific neurotoxic effect of ALS sera on the motor neurons of the cultured spinal cord were observed in acute or chronic experiments.}, }
@article {pmid381610, year = {1979}, author = {Yamamoto, S and Ishikura, A}, title = {Delayed hypersensitivity reactions in guinea-pigs using cotton pellets; demonstration of macrophage migration inhibition activity in the cell free exudate.}, journal = {The Journal of pathology}, volume = {127}, number = {1}, pages = {1-10}, doi = {10.1002/path.1711270102}, pmid = {381610}, issn = {0022-3417}, mesh = {Animals ; Antilymphocyte Serum ; *Cell Migration Inhibition ; Chemotaxis, Leukocyte ; Guinea Pigs ; Hypersensitivity, Delayed/immunology/*pathology ; Macrophage Migration-Inhibitory Factors/metabolism ; Macrophages/immunology/*ultrastructure ; Male ; Skin/immunology ; }, abstract = {Subcutaneous implantation of cotton pellets containing PPD into CFA sensitised guinea-pigs produced a reaction of having many characteristics of the delayed hypersensitivity (DH) reaction, together with less conspicuous features of a non-immunological response. The time course of the cellular response in the reaction showed a slow onset, attaining maximum levels between 18 and 24 hr. Mononuclear cells dominated the reaction from 18 to 48 hr. In animals treated with ALS the reaction diminished to the level of a non-immunological reaction. The model made it possible to detect macrophage migration inhibition factor (MIF) activity in the skin exudates. From 6--48 hr high molecular weight antigen-dependent MIF activity was found associated with immunoglobulin. At 18 hr, two types of low molecular weight MIF activity were demonstrated. One was antigen-dependent and the other was antigen-independent. Treatment of sensitised guinea-pigs with ALS abolished the appearance of these factors, suggesting that they might be related to cell-mediated immunity. At 48 hr, the low molecular weight antigen-dependent MIF activity was still evident whereas the low molecular weight antigen-independent activity was not detected. High molecular weight antigen-independent MIF activity was also found at 18 hr. No MIF activity was demonstrated in any of the control exudates.}, }
@article {pmid226473, year = {1979}, author = {Warchalowski, GA and Strausser, HR}, title = {Altered immune reactivity in encephalomyocarditis-M variant (EMC-M)-induced diabetes in mice.}, journal = {Immunological communications}, volume = {8}, number = {4}, pages = {443-455}, doi = {10.3109/08820137909050058}, pmid = {226473}, issn = {0090-0877}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; Concanavalin A/pharmacology ; Diabetes Mellitus, Experimental/*immunology ; Encephalomyocarditis virus ; Enterovirus Infections/etiology/*immunology ; Genetic Variation ; Glycosuria/etiology ; *Immunosuppression Therapy ; Indomethacin/pharmacology ; Levamisole/pharmacology ; Male ; Mice ; Mice, Inbred DBA ; Phytohemagglutinins/pharmacology ; Pokeweed Mitogens/pharmacology ; }, abstract = {Approximately 50% of DBA/2j male mice infected with EMC-M develop glycosuria with suppressed immune responsiveness to the mitogens PHA, Con A and PWM. The greatest degree of suppression was noted with Con A treated cultures. In vivo treatment with Levamisole, a known T cell stimulant, especially increased the response to Con A but exacerbated the diabetogenic state as reflected by increased occurrence of glycosuria. Virus infected mice, given anti-lymphocyte serum (ALS), showed marked amelioration of the diabetic syndrome. Indomethacin, a non-steroidal anti-inflammatory agent as well as a prostaglandin-synthetase inhibitor, partially reversed the in vitro splenic cell suppression of infected animals.}, }
@article {pmid159195, year = {1979}, author = {Rieger, M and Hilgert, I and Kristofová, H and Vlachov, K}, title = {Induction of suppressor cell mechanism in antilymphocyte serum-induced skin allograft tolerance in mice.}, journal = {Folia biologica}, volume = {25}, number = {4}, pages = {220-230}, pmid = {159195}, issn = {0015-5500}, mesh = {Animals ; Antilymphocyte Serum/*administration &amp; dosage ; Bone Marrow Transplantation ; Cyclophosphamide/pharmacology ; Female ; *Graft Survival/drug effects/radiation effects ; Lymphocyte Transfusion ; Mice ; *Skin Transplantation ; T-Lymphocytes, Regulatory/*immunology ; Transplantation, Homologous ; }, abstract = {In the B10.D2 leads to B10.D2(M504) strain combination (H-2D incompatibility), 20--40% of skin allografts survive for more than 100 days in ALS-treated recipients. Allograft tolerance in ALS-treated recipients could not be abolished by adoptively transferred normal or immune syngeneic spleen cells, but it could be adoptively transferred by spleen or lymph node cells to sublethally irradiated syngeneic mice. The suppressive activity of transferred cell population markedly declined after treatment with anti Thy-1.2 serum and complement. Cells with suppressor activity could be demonstrated by adoptive transfers as early as 5 days after skin grafting and ALS treatment. The results showed that the long-term allograft-promoting effect of ALS was caused not only by a decrease in the graft-rejection cell potential of the recipients (as demonstrated by other authors earlier) but also by the activation of a T cell-mediated suppressor mechanism.}, }
@article {pmid310508, year = {1978}, author = {Dooley, DM and Sharkey, J and Keller, W and Kasprak, M}, title = {Treatment of demyelinating and degenerative diseases by electro stimulation of the spinal cord.}, journal = {Medical progress through technology}, volume = {6}, number = {1}, pages = {1-14}, pmid = {310508}, issn = {0047-6552}, mesh = {Amyotrophic Lateral Sclerosis/therapy ; Atrophy ; Cerebellar Diseases/*therapy ; Demyelinating Diseases/*therapy ; *Electric Stimulation Therapy ; Humans ; Multiple Sclerosis/therapy ; Myelitis, Transverse/therapy ; Spinal Cord ; Spinal Cord Injuries/*therapy ; Urinary Bladder, Neurogenic/therapy ; }, abstract = {Electrical stimulation was applied to the spinal cord of 75 patients who had demyelinating and degenerative diseases of the central nervous system, and 3 patients who had sustained spinal cord injuries. The electrical energy was delivered to the central nervous system by the percutaneous technique. The amount of electrical energy required to produce the perception of paresthesias was measured in 11 patients. The minimum power necessary was 76.89 muW, the maximum was 868 muW, and the average was 448.8 muW. The patients were evaluated by 4 examiners by means of routine neurologic examination, videotape movies, and measurement of urinary bladder function. Continued improvement in neurological status, which allowed the patient to live a better lifestyle, occurred in 30 of the 61 patients with multiple sclerosis, and 6 of the 10 patients with ataxia. The patient with transverse Myelitis, the patient with primary lateral sclerosis, and 1 patient with olivopontocerebellar atrophy; also noted similar enhancement of neurological function. The patients with amyotrophic lateral sclerosis and spinal cord injuries had no changes of significance. Thirty-two out of 44 patients who were ambulatory had significant improvement, whereas 10 of the 19 patients who were not ambulatory had improvement. There was no evidence that electrical stimulation of the spinal cord, when applied via dorsally placed percutaneous electrodes and when carried only to the perception of a paresthesias, has any adverse effect on neurological function. It is hypothecated that the electrical current alters neurotransmitters to enhance the transmission along nervous and neurochemical pathways. The exact mechanisms are unknown at the present time.}, }
@article {pmid360051, year = {1978}, author = {Sutor, AH}, title = {[Diagnosis of hemorrhagic diseases (author's transl)].}, journal = {Monatsschrift fur Kinderheilkunde}, volume = {126}, number = {10}, pages = {588-596}, pmid = {360051}, mesh = {Blood Coagulation Disorders/*diagnosis ; Blood Coagulation Tests ; Blood Platelet Disorders/diagnosis ; Capillary Resistance ; Child ; Disseminated Intravascular Coagulation/diagnosis ; Fibrin Fibrinogen Degradation Products/analysis ; Humans ; Medical History Taking ; Platelet Adhesiveness ; Platelet Aggregation ; Thrombocytopenia/diagnosis ; }, abstract = {Bleeding symptoms require in many instances immediate professional care. In order to avoid unnecessary treatment, an exact diagnosis is mandatory. In most cases a differentiation between primary humoral and thrombocytogenic bleeding disorders and a secondary bleeding diathesis due to consumption coagulopathy is possible by means of anamnestic, clinical and laboratory parameters. As a single test, the bleeding time gives the best information, followed by the heparin-tolerance-time, the PTT and the platelet count. Withe Quick-test alone, only 5% of children with severe bleeding diathesis are detected. For preoperative laboratory evaluation we recommend a combination of PTT, Quick-test, platelet count and bleeding-time. For the diagnosis of disseminated intravascular coagulation, anamnestic criteria (procoagulant triggers) and clinical evaluation [thrombohemorrhagic syndrome of organ(s)] are as important als laboratory parameters (platelet count, plasminogenproactivator, splits, PTT, Quick-test).}, }
@article {pmid355549, year = {1978}, author = {Jayawardena, AN and Waksman, BH and Eardley, DD}, title = {Activation of distinct helper and suppressor T cells in experimental trypanosomiasis.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {121}, number = {2}, pages = {622-628}, pmid = {355549}, issn = {0022-1767}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; Cattle ; Hemolytic Plaque Technique ; *Immunosuppression Therapy ; *Lymphocyte Cooperation ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CBA ; T-Lymphocytes/*immunology ; Thymectomy ; Trypanosoma brucei brucei/immunology ; Trypanosomiasis, Bovine/*immunology ; }, abstract = {Spleen cells taken from mice soon after infection with Trypanosoma brucei S 42 enhance the primary in vitro antibody response of normal spleen cells to sheep red blood cells (SRBC), but do not affect their response to DNP-Ficoll. Spleen cells harvested later in the infection (day 6 onwards) suppress the antibody response of normal spleen cells to both SRBC and DNP-Ficoll. The enhancing and suppressive effects of "infected" spleen cells are sensitive to treatment with anti-Thy 1.2 anti-serum and complement, and can be mediated by nylon wool-purified populations of T cells. The enhancing T cell is sensitive to ALS, not lost within 4 weeks of adult thymectomy, and bears the Ly-1+, 23- phenotype. The suppressor T cell is insensitive to ALS, lost within 20 weeks of adult thymectomy, and bears the Ly-1+, 23+ phenotype. The significance of the activation of distinct helper and suppressor T cells is discussed in relation to the pathogenesis of trypanosomiasis.}, }
@article {pmid634781, year = {1978}, author = {Gluckman, E and Devergie, A and Faille, A and Barrett, AJ and Bonneau, M and Boiron, M and Bernard, J}, title = {[The action of antilymphocyte serum in severe aplastic anemia (author's transl)].}, journal = {La Nouvelle presse medicale}, volume = {7}, number = {6}, pages = {439-443}, pmid = {634781}, issn = {0301-1518}, mesh = {Adolescent ; Adult ; Anemia, Aplastic/blood/mortality/*therapy ; Antilymphocyte Serum/*therapeutic use ; Child ; Child, Preschool ; Erythrocyte Count ; Evaluation Studies as Topic ; Female ; Granulocytes ; Humans ; Leukocyte Count ; Male ; Middle Aged ; Reticulocytes ; }, abstract = {The etiology of aplastic anemia is unknown. A stem cell lesion caused by a toxic or a virus or a microenvironment defect are the main hypothesis. An auto-immune origin has been recently suspected but never proved. To demonstrate the auto-immune origin of the disease. We have treated 17 patients with severe aplastic anemia with antilymphocyte serum (ALS). Nine patients showed no improvement and seven patients died within two months of infectious or hemorrhagic complications. In contrast, eight patients had a prompt rise of granulocytes and reticulocytes counts. Although the hematological reconstitution is not complete. This eight patients are still alive between 4 months and 15 months after treatment. This study shows that A.L.G. may have a beneficial effect in the treatment of patients with severe aplastic anemia.}, }
@article {pmid203124, year = {1978}, author = {Maida, E and Gerstenbrand, F and Gründig, E and Binder, H}, title = {[The application of guanidine hydrochloride to the treatment of degenerative nervous and muscular diseases. I. Clinical results (author's transl)].}, journal = {Wiener klinische Wochenschrift}, volume = {90}, number = {2}, pages = {43-48}, pmid = {203124}, issn = {0043-5325}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Cerebellar Diseases/drug therapy ; Drug Evaluation ; Female ; Guanidines/adverse effects/*therapeutic use ; Humans ; Leukopenia/chemically induced ; Male ; Middle Aged ; Muscular Dystrophies/drug therapy ; Peripheral Nervous System Diseases/*drug therapy ; Spinal Cord Diseases/drug therapy ; }, abstract = {This paper reports the results obtained on using guanidine hydrochloride in the treatment of patients with amyotrophic lateral sclerosis, degenerative diseases of the spinocerebellar system or the peripheral nervous system and dystrophic muscle diseases. A long-term effect of the substance was a diminution in the rate of progression of the diseases, with the exception of the group with dystrophic muscle diseases. Initial clinical improvement occurred in certain patients of both groups. The substance seems to be more effective in less-advanced cases than on administration in the later stages of the disease. The therapeutic dosage was 20 to 40 mg/kg/day. The most frequent side-effect was paraesthesia and sometimes gastric disturbance was reported. Therapy had to be discontinued in 3 patients due to leucopenia. In these patients the symptoms rapidly increased in severity after discontinuation of treatment. This supports the assumption that guanidine hydrochloride treatment slows down the progress of the disease.}, }
@article {pmid350127, year = {1978}, author = {Février, M and Ventura, M and Lambert, F and Liacopoulos-Briot, M and Bouvet, JP and Liacopoulos, P}, title = {The capacity of histocompatibility antigens solubilized in hypertonic salt solution to induce allograft tolerance in rats.}, journal = {Annales d'immunologie}, volume = {129}, number = {1}, pages = {47-61}, pmid = {350127}, issn = {0300-4910}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; Graft Survival ; *Histocompatibility ; Hypertonic Solutions ; *Immune Tolerance ; Immunity, Cellular ; Isoantigens ; Rats ; Rats, Inbred BN ; Rats, Inbred Lew ; Skin Transplantation ; Solubility ; Transplantation, Homologous ; }, abstract = {Treatment of Fisher rats (AgB 1,26,28) with a soluble extract of histocompatibility antigens (SAE) prepared from the liver of donor August rats (AgB 5, 28, 31) associated with a few injections of anti-lymphocyte serum (ALS) provoked a specific prolongation of the median survival time of skin grafts from 27.6 +/- 11.4 days in ALS-treated controls to 55.1 +/- 8.8 days (p less than 0.01). The SAE was obtained from liver homogenates by hypertonic KCl (3M) extraction. Further purification by chromatography in DEAE-cellulose column resulted in the separation of fractions possessing a specific inhibitory activity on a Fisher anti-August cytotoxic serum that was almost 100 times higher than that of the initial SAE preparation. Analysis of the state of unresponsiveness induced by SAE and ALS showed that most of the unresponsive animals had in their serum blocking factors. On the other hand, in vitro study of proliferative and cytotoxic components of cell-mediated immunity by mixed lymphocyte reaction and cell-mediated lympholysis, respectively, showed that the proliferative reactivity remained unimpaired whereas the cytotoxic reactivity was clearly inhibited in the tested animals. These results suggest that a central tolerance to histocompatibility antigens (equivalent to those coded by the K and D end in the mouse) could have been induced in the experimental animals whereas reactivity to Ia region antigens was not affected.}, }
@article {pmid85238, year = {1978}, author = {Onuma, M and Okada, K and Yamazaki, Y and Fujinaga, K and Fujimoto, Y and Mikami, T}, title = {Induction of C-type virus in cell lines derived from calf form bovine lymphosarcoma.}, journal = {Microbiology and immunology}, volume = {22}, number = {11}, pages = {683-691}, doi = {10.1111/j.1348-0421.1978.tb00421.x}, pmid = {85238}, issn = {0385-5600}, mesh = {Animals ; Cattle ; Cell Line ; Cells, Cultured ; Deoxyuridine/pharmacology ; Dexamethasone/pharmacology ; Haplorhini ; Immune Sera/pharmacology ; Leukemia Virus, Bovine/immunology/ultrastructure ; Lymphoma, Non-Hodgkin/*microbiology ; RNA-Directed DNA Polymerase ; Rats ; Retroviridae/*isolation &amp; purification ; }, abstract = {For attempt to detect an etiological agent, cultures from bovine lymphosarcoma cases (adult form (ALS), calf form (CLS), and thymic form (TLS) were maintained in vitro for over a 18 month period. In two cultures from ALS, bovine leukemia virus (BLV) antigen was constantly detected. On the other hand, BLV antigen remained negative in cultures from two CLS and one TLS cases up to 40 passages. The RNA dependent DNA polymerase activities in these cultures were also negative. Treatment of a culture from CLS (3178) originated from liver tumor with 5'-iodo-2'-deoxyuridine (IdU) and dexamethasone (DXM) resulted in production of an agent serologically and morphologically similar to BLV and in alteration of cell morphology. No virus was detected in culture from TLS after treatment with IdU and DXM.}, }
@article {pmid22439, year = {1977}, author = {Braley-Mullen, H}, title = {Secondary IgG responses to type 3 pneumococcal polysaccharide. III. T cell requirement for development of B memory cells.}, journal = {European journal of immunology}, volume = {7}, number = {11}, pages = {775-781}, doi = {10.1002/eji.1830071106}, pmid = {22439}, issn = {0014-2980}, mesh = {Animals ; *Antibody Formation ; B-Lymphocytes/immunology ; Erythrocytes/immunology ; Immunization, Secondary ; Immunoglobulin G ; Immunologic Memory ; Lymphocyte Depletion ; Mice ; *Polysaccharides, Bacterial ; Streptococcus pneumoniae ; T-Lymphocytes/*immunology ; }, abstract = {Mice primed with a thymus-dependent form of Type 3 pneumococcal polysaccharide (S3), i.e. S3 coupled to erythrocytes (S3-RBC) produces S3-specific IgG antibody after secondary challenge with S3-RBC. When mice are depleted of T cells by treatment with anti-lymphocyte serum (ALS) at the time of priming, no IgG antibody is produced after secondary challenge. In order to determine the cellular basis for this phenomenon, various combinations of T and/or B cells from ALS-treated or normal primed mice were transferred to irradiated recipients prior to secondary challenge with S3-RBC. The results indicated that T cells were required at the time of priming with S3-RBC in order to (a) prevent the induction of tolerance in S3-specific B cells in mice primed with high doses of S3-RBC, and (b) induced differentiation of IgG-producing B cell precursors to Bgamma memory cells in mice primed with low doses of antigen.}, }
@article {pmid19533, year = {1977}, author = {Markham, RB and Reed, ND and Stashak, PW and Prescott, B and Amsbaugh, DF and Baker, PJ}, title = {Effect of concanavalin A on lymphocyte interactions involved in the antibody response to type III pneumococcal polysaccharide. II. Ability of suppressor T cells to act on both B cells and amplified T cells to limit the magnitude of the antibody response.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {119}, number = {3}, pages = {1163-1168}, pmid = {19533}, issn = {0022-1767}, mesh = {Animals ; *Antibody Formation ; B-Lymphocytes/immunology ; Concanavalin A/*pharmacology ; Dose-Response Relationship, Immunologic ; Female ; Hemolytic Plaque Technique ; Immunity, Cellular ; Immunosuppression Therapy ; Kinetics ; *Lymphocyte Activation ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Polysaccharides, Bacterial/*immunology ; Streptococcus pneumoniae/*immunology ; T-Lymphocytes/immunology ; Time Factors ; Vinblastine/pharmacology ; }, abstract = {When administered 2 days after immunization with 0.5 microgram Type III pneumococcal polysaccharide (SSS-III), the T lymphocyte mitogen concanavalin A (Con A) stimulates a 2.6-to 7-fold enhancement of the plaque-forming cells (PFC) response to SSS-III in vivo. This enhancement requires the presence of amplified T cells, which act by driving PFC or their precursors to extra rounds of proliferation. The extra proliferation that can be stimulated by Con A is not seen in the normal primary response to SSS-III; but treatment with anti-lymphocyte serum (ALS) to remove suppressor T cells will permit the additional proliferation to occur. This indicates that in the primary response to SSS-III, suppressor T cells act on amplifier T cells to limit the magnitude of the antibody response. Only suppression of B cells can account for the further suppression induced by Con A given at the time of immunization or by low-dose paralysis of the SSS-III response. The relatively late development of amplified activity compared to suppressor activity appears to account for the absence of amplifier activity after primary immunization with SSS-III. It is apparent that one can explain the regulatory effects observed during the development of an immune response to SSS-III only by considering both T cell- B cell and T cell- T cell interactions, together with the temporal relationships involved in those interactions.}, }
@article {pmid19532, year = {1977}, author = {Markham, RB and Stashak, PW and Prescott, B and Amsbaugh, DF and Baker, PJ}, title = {Sensitivity of amplifier T cells involved in the antibody response to type III pneumococcal polysaccharide to anti-lymphocyte serum.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {119}, number = {3}, pages = {1159-1162}, pmid = {19532}, issn = {0022-1767}, mesh = {Animals ; *Antibody Formation ; Antilymphocyte Serum/*pharmacology ; Concanavalin A/pharmacology ; Dose-Response Relationship, Immunologic ; Female ; Hemolytic Plaque Technique ; Mice ; Mice, Inbred BALB C ; Polysaccharides, Bacterial/*immunology ; Streptococcus pneumoniae/*immunology ; T-Lymphocytes/*immunology ; Time Factors ; }, abstract = {Amplifier T cells responsible for enhancement of the antibody response to type III pneumococcal polysaccharide have been shown to be resistant to the effects of antilymphocyte serum (ALS) given at the time of immunization, a treatment that eliminates suppressor T cell activity. The resistance of amplifier T cells to ALS can be attributed to the fact that their activity develops after that of suppressor T cells. ALS given 1 or 2 days after immunization does abrogate amplifier T cell activity, independent of the mode by which that activity is elicited. The data emphasize the importance of kinetic considerations in understanding the effects produced by immunologically active agents such as ALS.}, }
@article {pmid193547, year = {1977}, author = {Jones, PD and Castro, JE}, title = {Immunological mechanisms in metastatic spread and the antimetastatic effects of C. parvum.}, journal = {British journal of cancer}, volume = {35}, number = {5}, pages = {519-527}, pmid = {193547}, issn = {0007-0920}, mesh = {Animals ; Antigens, Bacterial ; Antilymphocyte Serum/pharmacology ; Cortisone/analogs &amp; derivatives/pharmacology ; Depression, Chemical ; Immunity/drug effects ; Lung Neoplasms/immunology ; Macrophages/drug effects ; Mice ; Mice, Inbred C57BL ; Neoplasm Metastasis/*immunology/prevention &amp; control ; Neoplasm Transplantation ; Neoplasms, Experimental/immunology ; Phagocytosis/drug effects ; Propionibacterium acnes/*immunology ; Silicon Dioxide/pharmacology ; T-Lymphocytes/immunology ; Trypan Blue/pharmacology ; }, abstract = {The effects of the host's immune response on metastatic spread was investigated by observing the numbers of pulmonary metastases that developed from an s.c. implant of the Lewis lung carcinoma in C57BL mice in which different cell populations had been suppressed. Macrophage function was impaired by treatment with silica (Si), cortisone acetate (CA), or trypan blue (TB). T-cell function was depressed by adult thymectomy and sublethal irradiation, or by treatment with antilymphocyte serum (ALS). Metastasis was significantly increased and phagocytic activity decreased by Si and CA, but were unaffected by TB. Thymectomy and irradiation had no effect on metastases, whereas ALS when given before, but not after tumour growth, reduced their number. The antimetastatic action of the immunopotentiating agent C. parvum was investigated in these immunologically impaired mice. It was unaffected by Si, CA or TB. However, the inhibiting effect of these agents on phagocytic activity was overcome by treatment with C. parvum. Its antimetastatic action was unaffected in mice which had been thymectomized and irradiated, but could be abrogated by ALS. However, ALS was only able to prevent this activity if given before tumour growth; it was ineffective if given after tumour growth. This study showed that metastatic spread was inversely related to phagocytic activity. The antimetastatic effect of C. parvum appears to be mediated through macrophages in concert with a subpopulation of T lymphocytes, which were considered to be necessary in the sensitization arm of the response as opposed to the effector arm of this response.}, }
@article {pmid16767, year = {1977}, author = {Vuitton, D and Eloy, R and Gosse, F and Pousse, A and Grenier, JF}, title = {Subpopulations of T-lymphocytes in Peyer's patches: sensitivity to antilymphocyte serum and adult thymectomy.}, journal = {Experientia}, volume = {33}, number = {4}, pages = {526-528}, pmid = {16767}, issn = {0014-4754}, mesh = {Animals ; *Antilymphocyte Serum ; Cell Division ; Graft vs Host Reaction ; Hybridization, Genetic ; Lymphoid Tissue/*immunology ; Peyer's Patches/*immunology ; Rats ; T-Lymphocytes/*immunology ; Thymectomy ; }, abstract = {Anti-lymphocyte (ALS) treatment or adult thymectomy of the donor have been shown to depress respectively the cell proliferation and the cytotoxicity in the graft-versus-host (GVH) reaction. A quantitative assay and the histological criteria of the GVH reaction have been used to demonstrate that all the known subpopulations of T-lymphocytes involved in the GVH reaction are present in the Peyer's patches as well as in the spleen and mesenteric lymph nodes in the rat.}, }
@article {pmid322771, year = {1977}, author = {Scheel, J and Duswald, KH and Ring, J and Seifert, J and Scholz, S and Brendel, W}, title = {[Long-term therapy using horse anti-dog lymphocyte globulin without sensitization against horse protein].}, journal = {Blut}, volume = {34}, number = {4}, pages = {305-316}, pmid = {322771}, issn = {0006-5242}, mesh = {Animals ; Antilymphocyte Serum/*administration &amp; dosage ; Carnivora ; Dogs ; Drug Hypersensitivity ; Female ; Horses/immunology ; Immunoglobulin G/administration &amp; dosage ; Lymphopenia ; Male ; Prednisolone/administration &amp; dosage ; Skin Transplantation ; Time Factors ; Transplantation, Heterologous ; }, abstract = {Eight mongrel dogs received a standard daily i.v. infusion of 20 mg/kg b.w. deaggregated horse-anti-dog-lymphocyte-globulin (ALG) and additional prednisolone (1 mg/kg b.w. daily i.v.) over a maximum period of 82 days following pretreatment with deaggregated normal horse IgG. No sensitization against horse protein was observed during therapy of afterwards as proved by lack of humoral antibodies against horse antigens, maintained lymphopenia, good compatibility, longterm prolongation of xenogeneic skin graft survival (85.6+/-20.6 days, n=8' untreated controls 12.5+/-1.3 days, n=4) and longterm suppression of cytotoxic antibodies against donor lymphocytes. The level of preformed agglutinating antibodies against horse erythrocytes was significantly reduced, while preformed antibodies against other species remained normal. The immune response to a challenge injection of anti-lymphocyte-serum (ALS) 6-11 weeks after termination of treatment was significantly lower in the ALG treated animals as compared to the control group. These results suggest the involvement of a specific mechanism of unresponsiveness against ALG other than immunosuppression only. It is concluded, that by the described method sensitization against ALG can be prevented during longterm treatment.}, }
@article {pmid300403, year = {1977}, author = {Levy-Leblond, E and Dupuy, JM}, title = {Neonatal susceptibility to MHV3 infection in mice. I. Transfer of resistance.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {118}, number = {4}, pages = {1219-1222}, pmid = {300403}, issn = {0022-1767}, mesh = {Age Factors ; Animals ; *Animals, Newborn ; Antilymphocyte Serum ; Cell Adhesion ; Hepatitis, Viral, Animal/*immunology ; *Immunity ; Immunity, Cellular ; Immunosuppression Therapy ; Mice ; Mice, Inbred A ; Spleen/immunology/transplantation ; T-Lymphocytes/immunology ; Thymus Gland/immunology ; Transplantation, Isogeneic ; }, abstract = {Up to 3 weeks of age, mice of the resistant A/J strain are fully susceptible to mouse hepatitis virus type 3 infection (MHV3). Immune deficiency, however, resulting from neonatal thymectomy or long term ALS administration led A/J animals to remain susceptible when tested at adult age. Whole spleen cells transferred from normal adult A/J donor mice protected suckling syngeneic recipients from i.p. infection with MHV3. Such a protective capacity of spleen cells was abolished after treatment with anti-theta serum and complement. Spleen cell separation by means of adherence to plastic also showed that neither the nonadherent nor the adherent populations injected separately were able to confer resistance to young mice challenged with the virus. Protection was not achieved with peritoneal cells originating from adult syngeneic animals. Transfer of resistance to MHV3 was obtained, however, when peritoneal cells were associated with adherent spleen cells. This study indicated that two types of mature cells, at least, were required for transferring MHV3 resistance into newborn mice of the A/J strain: T lymphocytes and an adherent spleen cell population.}, }
@article {pmid862241, year = {1977}, author = {Cooke, A and Playfair, JH}, title = {Hyper-responsiveness in NZB mice to the experimental induction of anti-red cell autoantibody.}, journal = {Clinical and experimental immunology}, volume = {27}, number = {3}, pages = {538-544}, pmid = {862241}, issn = {0009-9104}, mesh = {Animals ; Antibody Formation/drug effects ; Antilymphocyte Serum/pharmacology ; *Autoantibodies ; Autoimmune Diseases/chemically induced ; Coombs Test ; Erythrocytes/*immunology ; Mice ; Mice, Inbred NZB ; Thymectomy ; }, abstract = {Strain differences in ease of induction of autoantibody production were observed when mice were injected with rat RBC. Responsiveness was not linked to the H-2 locus. NZB and (NZB X BALB/c)F1 mice were hyper-responsive both in terms of the induction of autoantibody and in the production of agglutinating antibody to rat RBC. C57BL/c and (C57BL X BALB/c)F1 were poor responders. Injection of the rat RBC in FCA converted a poor responder into a good responder. Adult thymectomy and ALS treatment did not significantly enhance autoantibody production.}, }
@article {pmid405774, year = {1977}, author = {Nelken, D and Friedman, EA and Morse, SI and Beyer, MM}, title = {Islet of Langerhans allotransplantation in the rat.}, journal = {Transplantation proceedings}, volume = {9}, number = {1}, pages = {333-336}, pmid = {405774}, issn = {0041-1345}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; Blood Glucose/analysis ; Graft Survival ; Immunosuppressive Agents ; *Islets of Langerhans Transplantation ; Male ; Prednisolone/pharmacology ; Rats ; Rats, Inbred Lew ; Rats, Inbred WF ; Transplantation, Homologous ; Transplantation, Isogeneic ; }, abstract = {Normoglycemia in rats allotransplanted with islets of Langerhans was studied. It was found that pretreatment with donor liver extract and pertussis followed by a short course of ALS treatment results in much better overall survival of functioning islets of Langerhans allotransplants than with other forms of immunosuppression tested.}, }
@article {pmid15032, year = {1977}, author = {Markham, RB and Stashak, PW and Prescott, B and Amsbaugh, DF and Baker, PJ}, title = {Effect of concanavalin A on lymphocyte interactions involved in the antibody response to type III pneumococcal polysaccharide I. Comparison of the suppression induced by con A and low dose paralysis.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {118}, number = {3}, pages = {952-956}, pmid = {15032}, issn = {0022-1767}, mesh = {Animals ; *Antibody Formation ; Concanavalin A/*pharmacology ; Dose-Response Relationship, Immunologic ; Female ; Hemolytic Plaque Technique ; *Immunosuppression Therapy ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Polysaccharides, Bacterial/*immunology ; Streptococcus pneumoniae ; }, abstract = {Concanavalin A (Con A) administered at the time of immunization induces suppression of the in vivo splenic plaque-forming cell (PFC) response to type III pneumococcal polysaccharide (SSS-III). As with low dose paralysis of the PFC response to SSS-III, Con A-induced suppression could not be demonstrated in congenitally athymic (nu/nu) mice and could be eliminated partially by treatment with anti-lymphocyte serum (ALS). The kinetics for Con A-induced suppression paralleled those for low dose paralysis of the antibody response to SSS-III. These findings support the view that Con A-induced suppression is produced in vivo by suppressor T cells and that this form of suppression shares with low dose paralysis a common pathway through which suppression is mediated.}, }
@article {pmid839167, year = {1977}, author = {Peterson, DI and Dayes, LA}, title = {Myelopathy associated with cervical spondylosis: a frequently unrecognized disease.}, journal = {The Journal of family practice}, volume = {4}, number = {2}, pages = {233-236}, pmid = {839167}, issn = {0094-3509}, mesh = {*Cervical Vertebrae/diagnostic imaging ; Humans ; Myelography ; Prognosis ; Spinal Cord Diseases/diagnosis/*etiology/therapy ; Spondylitis/*complications/etiology/therapy ; }, abstract = {Cervical spondylosis or chronic diskogenic disease of the cervical spine is a relatively common cause of myelopathy, but it is often not recognized or is incorrectly diagnosed. The clinical presentation may mimic several types of neurological disease including multiple sclerosis and amyotrophic lateral sclerosis. Even more frequently, and especially early in the course of the disease, neurologic impairment is not recognized and the symptoms are thought to be due to osteoarthritis. Early recognition of this condition is important since adequate treatment can prevent slowly progressive neurologic impairment. Knowledge of the pathophysiology of myelopathy due to cervical spondylosis and adequate radiographic evaluation will often lead to treatment that can prevent progressive spinal cord damage. Cervical spondylosis with myelopathy is one of the most frequently unrecognized and misdiagnosed, yet treatable, conditions affecting the nervous system.}, }
@article {pmid888739, year = {1977}, author = {Goldblatt, D}, title = {Treatment of amyotrophic lateral sclerosis.}, journal = {Advances in neurology}, volume = {17}, number = {}, pages = {265-283}, pmid = {888739}, issn = {0091-3952}, mesh = {Aging ; Amitriptyline/therapeutic use ; Amyotrophic Lateral Sclerosis/etiology/microbiology/*therapy ; Baclofen/therapeutic use ; Braces ; Dantrolene/therapeutic use ; Deglutition Disorders/therapy ; Environmental Exposure ; Exercise Therapy ; Guanidines/therapeutic use ; Humans ; Male ; Middle Aged ; Physician-Patient Relations ; Spasm/drug therapy ; Speech Disorders/therapy ; Syndrome ; Virus Diseases ; }, }
@article {pmid13523, year = {1977}, author = {Lie, TS and Kanda, M and Kim, WI and Oehr, P and Holst, A and Choi, SK and Biersack, HJ}, title = {Detection of serum-blocking factors by inhibition of allorosette formation in rats with long-surviving renal allografts following short-term postoperative ALS treatment.}, journal = {Transplantation}, volume = {23}, number = {1}, pages = {1-6}, doi = {10.1097/00007890-197701000-00001}, pmid = {13523}, issn = {0041-1337}, mesh = {Animals ; Antibodies/*analysis ; Antigen-Antibody Complex ; Antilymphocyte Serum/*administration &amp; dosage ; Creatinine/blood ; Cytotoxicity Tests, Immunologic ; *Graft Survival ; Graft vs Host Reaction ; Hemagglutinins/analysis ; *Immunologic Techniques ; Immunosuppression Therapy ; *Kidney Transplantation ; Male ; Rats ; Rats, Inbred BN ; Rats, Inbred Lew ; Skin Transplantation ; Transplantation Immunology ; Transplantation, Homologous ; }, abstract = {Thirty-nine (LEW x BN)F1 kidneys were transplanted to LEW rats. Twenty-four untreated recipients survived for a mean time of 16.1 +/- 1.7 days (group 1). Fifteen recipients received 4 ml of antilymphocytic serum per rat (group 3). In the last group 10 recipients survived for more than 4 months. The spleen cells of these permanently surviving 10 rats were obtained by splenectomy and used in a graft-versus-host assay, and this assay showed that the reactivity of these cells was normal. Following splenectomy the animals were given an (LEW x BN)F1 skin allograft, followed 18 days by a second. After another 18 days (LEW x Buf)F1 "third party" skin allografts were transplanted to the same animals. Animals of group 2 rejected their first grafts with a mean survival time of 12.2 +/- 1.2 days, whereas the second grafts were rejected normally as were the third party grafts. Attempts were made to detect lymphocytotoxic antibodies and haemagglutinins before and after the transplantation of skin grafts and none could be found up to day 53. The sera of group 2 inhibited allorosette formation by 38%. This serum-blocking factor was donor specific. It is probable that the survival of the kidney transplants following antilymphocytic serum treatment was brought about by the development of blocking antibodies.}, }
@article {pmid1051412, year = {1976}, author = {Benos, J}, title = {[Neuropsychiatric disorders of the diseases of exocrine pancreas (author's transl)].}, journal = {Fortschritte der Neurologie, Psychiatrie, und ihrer Grenzgebiete}, volume = {44}, number = {12}, pages = {683-701}, pmid = {1051412}, issn = {0015-8194}, mesh = {Acute Disease ; Alcoholism/complications ; Amyotrophic Lateral Sclerosis/complications ; Chronic Disease ; Cystic Fibrosis/complications ; Humans ; Neurocognitive Disorders/*etiology ; Pancreatic Cyst/complications ; Pancreatic Diseases/*complications ; Pancreatic Neoplasms/complications ; Pancreatitis/complications ; Parathyroid Diseases/complications ; }, abstract = {Neuropsychiatric and psychosomatic disorders occurring the exocrine pancreatic diseases are not rare, nevertheless didn't it seem to be very interesting in research and there exists no summarizing work of this disorders. Therefore we tried to give a comprehensive representation of those neuropsychiatric problems which are connected with the function of this organ. At first we give a description of psychopathology and pathogenesis of the functional pancreatic psychosis. The problematic of the reciprocal relationship of nervous system and pancreatitis, alcoholism and pancreatitis are demonstrated as well as the psychic disorders occurring the pancreas insufficiency, cystes of pancreas and congenital pancreatic diseases. Psychosomatic and mental disorders of pancreas carcinoma and mucoviscidosis are shown in detail. The question of the interrelation between pancreatic function and amyotrophic lateral sclerosis or parathyreotic diseases are discussed just as themes of neuropsychiatric pharmacotherapie and pancreatic function and mental disorders in pancreatic treatment.}, }
@article {pmid793111, year = {1976}, author = {Jeekel, J and Obertop, H and Westbroek, DL and Vriesendorp, HM}, title = {Prolonged survival of renal allografts in tissue typed beagles by treatment with ALS and donor bone marrow.}, journal = {Transplantation}, volume = {22}, number = {5}, pages = {534-537}, pmid = {793111}, issn = {0041-1337}, mesh = {Animals ; Antilymphocyte Serum/*therapeutic use ; Bone Marrow Cells ; Bone Marrow Transplantation ; Dogs ; *Graft Survival ; *Histocompatibility Testing ; *Kidney Transplantation ; Time Factors ; Transplantation, Homologous ; }, }
@article {pmid791215, year = {1976}, author = {Kollmer, WE and Märkl, R}, title = {[Effect of ALS treatment in the uptake and release of 85sr by allogeneic bone transplants (author's transl)].}, journal = {Archiv fur orthopadische und Unfall-Chirurgie}, volume = {86}, number = {1}, pages = {95-100}, pmid = {791215}, issn = {0003-9330}, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; *Bone Transplantation ; Bone and Bones/drug effects/metabolism ; Mice ; Minerals/metabolism ; Strontium Radioisotopes ; Time Factors ; Transplantation, Homologous ; }, abstract = {After a treatment of the recipients with antilymphocyte serum shortly before and after grafting of 85Sr uptake of bone grafts as well as the release of 85Sr from the grafted mineral was increased. The difference of these parameters between allogeneic grafts to untreated recipients and allogeneic grafts to ALS treated recipients was similar to that between allogeneic grafts in untreated recipients and syngeneic grafts. This finding indicates a marked improvement of mineral metabolism in allogeneic bone grafts by treatment with antilymphocyte serum.}, }
@article {pmid790732, year = {1976}, author = {Stuart, FP}, title = {New approaches to immunosuppression in renal transplantation.}, journal = {The Urologic clinics of North America}, volume = {3}, number = {3}, pages = {575-596}, pmid = {790732}, issn = {0094-0143}, mesh = {Animals ; Antilymphocyte Serum/therapeutic use ; Cadaver ; Female ; Graft Rejection/drug effects/radiation effects ; Histocompatibility Antigens/administration &amp; dosage ; Humans ; Immune Tolerance ; Immunity, Cellular/drug effects ; Immunosuppression Therapy/*methods ; Kidney/immunology ; *Kidney Transplantation ; Methylprednisolone/therapeutic use ; Mice ; Postoperative Complications/mortality ; Pregnancy ; Radiotherapy Dosage ; Rats ; Renal Dialysis ; Splenectomy ; Transplantation Immunology/drug effects ; Transplantation, Homologous ; Uremia/therapy ; }, abstract = {Although the incidence of 1 year kidney graft survival has been on a plateau for the past 7 or 8 years, the likelihood of recipient survival has increased. These observations reflect the limits of our current nonspecific immunosuppressive techniques and the acquisition of knowledge about when to discontinue their use and allow rejection of the kidney rather than death from sepsis. Yet, there are many leads from the laboratory which, when applied clinically in the next few years, should allow safe kidney transplantation to become a routine clinical event. Among these are safer, more effective antilymphocyte preparations; precise indications for splenectomy; accurate identification of presensitized states in potential recipients; methods of reducing the immunogenicity of grafts by removing donor passenger leukocytes or flushing the kidney with substances that alter surface antigens; and possibly new classes of chemical immunosuppressive drugs. In addition, it is likely that techniques will evolve for selective suppression of the immune response to donor antigens. This will be achieved by using cytotoxic agents coupled to donor antigen to destroy specific antigen recognition lymphocytes. Other forms of noncytotoxic donor antigen and antibody with or without ALS will be used to manipulate the recipient's immune response prior to and after transplantation. These manipulations will leave intact most of the potential for immune response to antigens other than those introduced with the graft. Together, these manipulations and their effect in experimental animals have been called immunologic enhancement. Intentional enhancement in man by means of antigen treatment or passive immunization has just barely begun. Clinical trials will be difficult and, initially at least, they will be confined to only a few transplantation centers. Yet, the "antigen pretreatment" of natural pregnancy, blood transfusion, prior unsuccessful organ transplantation, and bacterial infection have at times inadvertently conditioned a potential host so as to allow enhancement of a subsequent graft. It is likely that much can be done with current clinical assays of cellular and humoral immunity to detect those patients who are already conditioned to enhance a subsequent graft.}, }
@article {pmid790694, year = {1976}, author = {Goodnight, JE and Coleman, DA and Steinmuller, D}, title = {Serum-blocking factors versus specific cellular tolerance in long-term survival of rat heart allografts.}, journal = {Transplantation}, volume = {22}, number = {4}, pages = {391-397}, doi = {10.1097/00007890-197610000-00012}, pmid = {790694}, issn = {0041-1337}, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; *Graft Survival ; *Heart Transplantation ; *Immune Tolerance ; *Immunity, Cellular ; *Immunization, Passive ; Male ; Rats ; Rats, Inbred Lew ; Skin Transplantation ; Time Factors ; Transplantation, Homologous ; }, abstract = {Long-term survival of Ag-B compatible rat heart allografts was obtained by short-term treatment of the recipients with antilymphocytic serum (ALS). Graft survival apparently was based on a specific change in the hosts rather than on persistent nonspecific effects of ALS. The hosts were not fully tolerant in that they were able to reject secondary skin allografts from the heart donor strain, although in a delayed fashion. The long-surviving heart allografts retained their immunogenicity as they were rejected when retransplanted to new hosts. The passive transfer of serum from long-term heart graft acceptors to new hosts receiving fresh allografts delayed rejection by several days. This effect was seen only with the serum from long-term acceptors suggesting that serum-blocking factors were involved in long-term survival of the heart allografts. However, the ability of adoptively transferred lymphoid cells to break tolerance to a heart allograft residing in a classically tolerant host was tested. In contrast to normal lymphoid cells, cells from the long-term acceptors were unable to break tolerance, suggesting that a specific cellular tolerance had been induced in this cell population. Moreover, a serum from the long-term acceptors failed to block the breakage of tolerance by normal lymphoid cells.}, }
@article {pmid981496, year = {1976}, author = {Bendorf, G and Doubrawa, R and Klaffki, EL}, title = {["Therapeutic play" als clinical short-term group therapy in rehabilitative and preventive internal medicine (author's transl)].}, journal = {Psychotherapie, medizinische Psychologie}, volume = {26}, number = {5}, pages = {158-163}, pmid = {981496}, issn = {0302-8984}, mesh = {Adolescent ; Adult ; Female ; Humans ; Interpersonal Relations ; *Psychotherapy, Brief ; *Psychotherapy, Group ; Role Playing ; Self Concept ; Sensitivity Training Groups ; }, abstract = {A method of therapeutic play was presented which was used with young patients in treatment at a health resort. The patients were diagnosed as suffering from the vegetative syndrome. They also exhibited psychological problems such as difficulty in establishing interpersonal relationships, inhibition and depressive tendencies. This method consisting of a three-stage program of self-perception, interaction and role playing has been used successfully as short-term group therapy in the context of treatment at a health resort as the investigation of 49 participants shows.}, }
@article {pmid1084371, year = {1976}, author = {Geczy, CL and Geczy, AF and De Weck, AL}, title = {Antibodies to guinea pig lymphokines. II. Suppression of delayed hypersensitivity reactions by a "second generation" goat antibody against guinea pig lymphokines.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {117}, number = {1}, pages = {66-72}, pmid = {1084371}, issn = {0022-1767}, mesh = {Animals ; Antibodies, Anti-Idiotypic/administration &amp; dosage/analysis ; *Antibody Formation ; Capillary Permeability ; Cytotoxicity Tests, Immunologic ; Goats ; Guinea Pigs ; Hypersensitivity, Delayed/*immunology ; Immune Adherence Reaction ; *Immunosuppression Therapy ; Injections, Intradermal ; Injections, Intravenous ; Intradermal Tests ; Leukocyte Count ; Lymph Nodes/immunology ; Lymphocyte Activation ; Lymphokines/*immunology ; Tuberculin ; Turpentine/administration &amp; dosage ; }, abstract = {A "second generation" antibody to a highly purified lymphocyte product was raised in a goat against material eluted from a rabbit anti-guinea pig lymphokine immunoadsorbent column. This anti-lymphokine serum, in constrast to anti-lymphocyte serum (ALS) did not appear to contain cytotoxic antibodies directed against membrane antigens on guinea pig lymph node lymphocytes. Furthermore, the anti-lymphokine serum did not inhibit the formation of spontaneous T rosettes nor significantly depress lymphocyte response to mitogens. The anti-lymphokine serum totally suppressed the delayed skin reactivity to PPD and contact sensitivity to DNCB when injected intradermally around the site of antigen challenge. By contrast, intradermally injected ALS did not appear to suppress the PPD response in sensitized guinea pigs. Intravenously and i.p. administered anti-lymphokine serum was somewhat less effective in suppressing the delayed skin response to PPD. The intradermal injection of the antiserum had no effect on nonspecific inflammation evoked by turpentine-olive oil or on the extravasation of circulating Evans blue evoked by intradermally injected histamine. Histologic examination of 24-hr DNCB-induced skin lesions from sensitized guinea pigs treated with intradermally injected anti-lymphokine serum showed marked reduction of mononuclear infiltration of the dermis and of epidermal lesions, as compared with skin sites taken from sensitized animals pretreated with normal goat serum. The anti-lymphokine serum injected i.v. also markedly reduced the perivascular infiltration of the dermis and subcutis in skin reaction sites from sensitized animals challenged with PPD. Intravenous treatment with ALS for 3 consecutive days caused extensive depletion of the paracortical areas of peripheral lymph nodes whereas treatment with normal serum and anti-lymphokine serum caused no such depletion. It is proposed that the anti-lymphokine serum is directed against activated lymphocyte products, one of them being MIF. These products are involved in the mediation of delayed hypersensitivity reactions. This is in marked contrast to ALS, the suppressive action of which appears to be central rather than peripheral.}, }
@article {pmid59438, year = {1976}, author = {Turianskyj, FH and Gyenes, L}, title = {The effect of neuraminidase on the sensitivity of tumor cells toward lysis by antibody and complement or by sensitized lymphocytes.}, journal = {Transplantation}, volume = {22}, number = {1}, pages = {24-30}, doi = {10.1097/00007890-197607000-00004}, pmid = {59438}, issn = {0041-1337}, mesh = {Animals ; Antibodies ; Antigens, Neoplasm ; Complement System Proteins ; Cytotoxicity Tests, Immunologic ; Epitopes ; *Immunity, Cellular ; Lymphocytes/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Neoplasms, Experimental/*immunology ; Neuraminidase/*pharmacology ; }, abstract = {The effect of neuraminidase treatment on the antigenicity of sarcoma I (Sal) and mastocytoma P-815-X2 cells was compared, both in terms of their reaction with various antisera (C57BL/6 anti-SaI, C57BL/6 anti-mastocytoma, rabbit and horse ALS) and complements (guinea pig, rabbit) or with sensitized lymphocytes (C57BL/6 anti-SaI, C57BL/6 anti-mastocytoma, A anti-mastocytoma). With sensitized lymphocytes the reactivity of neuraminidase-treated tumor cells was similar to that of nontreated cells. In contrast, after neuraminidase treatment, the tumor cells showed increased specific lysis with the antisera and complement. Rabbit complement was highly cytotoxic to the neuraminidase-treated cells but this nonspecific activity could be removed by absorption with agar or agarose. The results of this study would strongly suggest that neuraminidase treatment does not change the antigenic determinants of tumor cells but increases their interaction with complement after removal of negatively charged sialic acids.}, }
@article {pmid786757, year = {1976}, author = {Köstler, E}, title = {[The trophedema (Nonne-Milroy-Meige). Carcinogenesis as a rare complication].}, journal = {Dermatologische Monatschrift}, volume = {162}, number = {6}, pages = {465-477}, pmid = {786757}, issn = {0011-9083}, mesh = {Adrenal Cortex Hormones/therapeutic use ; Adult ; Anticoagulants/therapeutic use ; Carcinoma, Squamous Cell/*complications ; Dimethyl Sulfoxide/therapeutic use ; Diuretics/therapeutic use ; Female ; Humans ; *Lymphedema/complications/genetics ; Physical Therapy Modalities ; Prednisone/therapeutic use ; }, abstract = {The trophedema Nonne-Milroy-Meige has an exceptional position within the group of the primary lymphatic edemas (l.e.) because of its hereditary. Its frequency less than 1% of primary l.e. The trophedema is caused by a genetic determined defect of the morphogenese of parts of lymphatic system, which is mainly autosomal dominantly transmitted. It is morphologically and lymphografically characterized by a lack and reduction respectively of the number of lymphatic vessels. The trophedema results an emotional (cosmetic) and physical stress. Complicationes will rarely arise. In this paper it is described the case of the development of a cancer upon a trophedema, which seems to be the first case ever published. It will be shown, that an test-section have to be carried out in all cases of damages at a l.e. als soon as possible. The best conservative method at present used is the treatment with cortisone and hyaluronidase including bandage. However a real cure of the primary l.e. including the trophedema can not be attained by therapeutic methods presently used, because the defect of the lymphatic-vessels-system is hereditary. On the other hand therapeutic nihilism cannot be recommended.}, }
@article {pmid10609, year = {1976}, author = {Lie, TS and Kanda, M and Kim, WI and Holst, A and Kawamura, A and Biersack, HJ}, title = {[Immune status of indefinitely surviving rat renal allograft recipients after short course of ALS-treatment Detection of a serum blocking factor by allorosette formation inhibition test (author's transl)].}, journal = {Research in experimental medicine. Zeitschrift fur die gesamte experimentelle Medizin einschliesslich experimenteller Chirurgie}, volume = {167}, number = {2}, pages = {171-183}, doi = {10.1007/BF01851598}, pmid = {10609}, issn = {0300-9130}, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; Graft vs Host Reaction ; Immune Adherence Reaction ; Immunity, Active ; Immunization, Passive ; *Kidney Transplantation ; Male ; Rats ; Skin Transplantation ; Spleen/immunology ; *Transplantation Immunology ; Transplantation, Homologous ; }, abstract = {53 LBNF1 kidneys were grafted into L-rats. 24 untreated recipients served as control and survived 16.1 +/- 1.7 days. 14 recipients were treated with 4 ml alloantiserum (ADS) each, and the other 15 animals with 4 ml ALS each. 9 and 10 of these 14 and 15 animals survived for more than 4 months. We performed GvH-reaction with spleen cells of these 19 animals. It showed normal cellular immune response. After splenectomy first donor specific skin was transplanted, 18 days later second skin of same origin (LBNF1) and 18' days after third party skin (LBufF1). The first grafts survived 13.1 +/- 1.9 days in the recipients of ADS treatment and 12.2 +/- 1.2 days in the recipients of ALS. Second skin grafts were rejected delayed in the former recipients as the first grafts, in the later more accelerated than the first grafts. The third grafts survived as the controls. Before and after skin grafting we could not detect lymphocytotoxin and hemagglutinin. The sera of animals with ADS therapy inhibited the spontaneous allorosette formation to 46.0 +/- 4.4% and of ALS therapy 37.7 +/- 9.2%. Our results suggest that after ALS treatment blocking antibodies were produced in the recipients and they cause the enhancement of kidney allograft.}, }
@article {pmid58834, year = {1976}, author = {Waldmann, H and Poulton, P and Desaymard, C}, title = {Antigen-non-specific T-cell factor in B-cell activation. Origin, biological properties and failure to show a relationship to H-2.}, journal = {Immunology}, volume = {30}, number = {5}, pages = {723-733}, pmid = {58834}, issn = {0019-2805}, mesh = {Animals ; B-Lymphocytes/*immunology ; Clone Cells ; Concanavalin A/pharmacology ; *Epitopes ; Erythrocytes/immunology ; Histocompatibility Antigens ; Lymphocyte Activation ; Macrophages/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitosis ; Species Specificity ; T-Lymphocytes/*immunology ; }, abstract = {A population of T cells sensitive to ALS treatment release a non-specific factor (NSF) capable of replacing T cells in the response of nude spleen cells to erythrocyte antigens. This factor cannot be removed by immunoadsorbents with specificities directed towards products of the H2 complex, nor by lentil lectin, unlike certain specific T-cell factors. Furthermore, it functions across histocompatibility differences between mouse strains. It has been directly demonstrated that this factor can influence both proliferation and differentiation of B cells in response to a restricted group of T-dependent antigens, of which donkey and sheep erythrocytes are such special cases.}, }
@article {pmid3609, year = {1976}, author = {Braley-Mullen, H}, title = {Secondary IgG responses to type III pneumococcal polysaccharide. II. Different cellular requirements for induction and elicitation.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {116}, number = {4}, pages = {904-910}, pmid = {3609}, issn = {0022-1767}, mesh = {Animals ; *Antibody Formation ; Antilymphocyte Serum/pharmacology ; Female ; Hemolytic Plaque Technique ; *Immunity, Cellular ; Immunoglobulin G/*biosynthesis ; *Immunologic Memory ; Mice ; Mice, Inbred BALB C ; Polysaccharides, Bacterial/*immunology/pharmacology ; Spleen/immunology ; Streptococcus pneumoniae/*immunology ; T-Lymphocytes/immunology ; Time Factors ; }, abstract = {Mice primed with a thymus- (T) dependent form of Type III pneumococcal polysaccharide (S3), i.e., S3 coupled to erythrocytes (S3-RBC) produce S3-specific IgG antibody after secondary challenge with either S3 or S3-RBC. The production of IgG antibody by mice challenged with S3 was shown to be T independent since secondary responses were enhanced when mice were treated with anti-lymphocyte serum (ALS) at the time of secondary challenge with S3 and T-depleted spleen cells responded as well as unfractionated spleen cells to S3 in an adoptive transfer system. Secondary S3-specific IgG responses in mice challenged with S3-RBC were shown to be T dependent by the same criteria. The results obtained by using S3 as the antigen indicate that IgG-producing B cells (B lambda cells) can recognize and respond to antigen in the absence of helper T cells. On the other hand, T cells were required for the induction of S3-specific memory B lambda cells since mice depleted of T cells by treatment with ALS at the time of priming with S3-RBC failed to produce S3-specific IgG antibody after secondary challenge with either S3-specific IgG antibody after secondary chall-nge with either S3 or S3rbc. Since RBC-specific memory cells were induced in T-deprived mice the results suggest that T cell regulation of IgG antibody production may vary for different antigens.}, }
@article {pmid1258710, year = {1976}, author = {Rosin, AJ}, title = {The problems of motor neurone disease.}, journal = {Age and ageing}, volume = {5}, number = {1}, pages = {37-42}, doi = {10.1093/ageing/5.1.37}, pmid = {1258710}, issn = {0002-0729}, mesh = {Adult ; Aged ; Constipation/complications ; Deglutition Disorders/etiology ; Humans ; Male ; Middle Aged ; *Motor Neurons ; *Neuromuscular Diseases/diagnosis/physiopathology/therapy ; Respiratory Insufficiency/etiology ; }, abstract = {The course of Motor Neurone Disease (MND) is described in 22 patients in respect of the extent and duration of the disabilities. The average stay in hospital in the terminal phase in 20 patients followed to the time of their death was 6.6 months for men and 4.7 months for women. The total duration of the disease ranged from 11 to 45 months, with an average of 28.7 months for men and 22.2 months for women. Between the bulbar cervical lumbar and mixed forms of the disease at the onset there emerged no difference in average survival. On woman of 32 is still alive 10 years after the onset, and one after 2-1/2 years. The hospital staff were exposed over many months to the progressive deterioration in breathing, swallowing, posture and mobility, and emotional crises and dysarthria aggravated the problems of management. Pain was a feature in one-third of the patients. In the treatment, physiotherapy with the accent on passive movements was found helpful. Although formal occupational therapy was not accepted by half of the patients, it was important to talk to them frequently, and encourage any means of expression such as painting, writing or dictating diaries, poems or essays. The indications for gastrostomy feeding are discussed, and the problem is raised of assisted respiration in this disease.}, }
@article {pmid1266475, year = {1976}, author = {Bunina, TL and Khondkarian, OA and Korshunova, TS and Larskiĭ, EG and Fuks, BB}, title = {[Treatment of amyotrophic lateral sclerosis with ribonucleotides].}, journal = {Zhurnal nevropatologii i psikhiatrii imeni S.S. Korsakova (Moscow, Russia : 1952)}, volume = {76}, number = {2}, pages = {166-174}, pmid = {1266475}, issn = {0044-4588}, mesh = {Adult ; Amyotrophic Lateral Sclerosis/blood/*drug therapy/urine ; Female ; Humans ; Male ; Middle Aged ; Nucleotides/blood/urine ; Ribonucleotides/administration &amp; dosage/*therapeutic use ; Time Factors ; }, abstract = {In the treatment of 31 patients with lateral amyotrophical sclerosis the authors used the preparation ENKAD containing a complex of mono- and oligoribonucleotides. In 6 cases there was aggravation of the condition while in 18 of the observed cases--improvement. In 7 patients the condition was not altered. The treatment was convened under biochemical control (the assessment of the uric acid in the blood serum and urine and the excretion of oxypurine in the urine). It was possible to depict definite clinicobiochemical correlations. The conclusion is made that ENKAD can be used in the early stages of the disease and mainly in focal segmentary-nuclear lesions. The preparation is contraindicated in generalization of the process and in impetuous development of the disorder.}, }
@article {pmid957782, year = {1976}, author = {Bushkin, FL and Woodward, ER}, title = {The afferent loop syndrome.}, journal = {Major problems in clinical surgery}, volume = {20}, number = {}, pages = {34-48}, pmid = {957782}, issn = {0025-1062}, mesh = {Acute Disease ; Afferent Loop Syndrome/diagnosis/*surgery ; Chronic Disease ; Gastrectomy ; Humans ; Jejunum/surgery ; Methods ; Pylorus/surgery ; Stomach/surgery ; Time Factors ; Vagotomy ; }, abstract = {The afferent loop syndromes result from obstruction to the afferent jejunal loop. Acute ALS results from complete obstruction, usually occurs early after surgery and runs a devastatingly lethal course unless promptly treated by reoperation. In chronic ALS the obstruction is intermittent and produces a clinical syndrome from which a diagnostic histroy can usually be obtained. Although the exact incidence is unknown, it is certainly not rare, especially in antecolic Billroth II gastrectomies. Treatment consists of doing away with the afferent loop. In gastroenterostomy alone takedown of the anastomosis with a Weinberg pyloroplasty is the treatment of choice. The safest and simplest treatment for patients whose original operation was Billroth II gastrectomy is conversion to a Roux-en-Y procedure. In all cases vagotomy should be added unless previously performed. No medical treatment is available and patients with no other contraindication should have revisional surgery if symptoms are clinically significant. Both acute and chronic afferent loop syndromes should be completely prevented by appropriate choice of the initial operative procedure. The vagotomized stomach should be drained by pyloroplasty, not gastrojejunostomy. Vagotomy and antrectomy should be reconstructed with a Billroth I gastroduodenostomy. The Braun enteroanastomosis should be utilized after subtotal gastrectomy for carcinoma. The wider application of parietal cell vagotomy for duodenal ulcer deserves close observation and further consideration.}, }
@article {pmid801562, year = {1976}, author = {Lie, TS and Kanda, M and Ehlenz, H and Kim, WI and Holst, A and Biersack, HJ}, title = {[Demonstration of blocking factors in permanently surviving rat-kidney allograft recipients after short postoperative treatment with alloantiserums].}, journal = {Langenbecks Archiv fur Chirurgie}, volume = {Suppl}, number = {}, pages = {6-10}, pmid = {801562}, issn = {0023-8236}, mesh = {Animals ; Graft Survival/*drug effects ; Immune Sera/*pharmacology ; Immunity, Cellular ; *Kidney Transplantation ; Male ; Postoperative Care ; Postoperative Complications/immunology ; Rats ; Rats, Inbred Strains ; Rosette Formation ; Time Factors ; Transplantation, Homologous ; }, abstract = {GvHR tests were performed on spleen cells of 9 recipients surviving rat renal allografts for more than 120 days. The recipients had undergone a short term ALS-treatment. The GvHR tests showed normal cell-mediated immunity. After splenectomy and again 18 days later LBNF1 skin was grafted to the renal recipients. After a further period of 18 days LBufF1 skin was grafted. After some delay the specific grafts were rejected. The unspecific skin was rejected in a normal way. Before and after skin grafting the authors could not find the lymphocytotoxin and hemagglutinin. Instead a blocking factor which inhibited the spontaneous allorosette formation was detected in the sera of recipients. The authors compared the results with passive enhanced renal recipients. The two groups did not differ significantly from each other.}, }
@article {pmid793567, year = {1976}, author = {Radzikowski, C and Szkudlarek, J and Czarnomska, A and Steuden, J and Krajewski, L}, title = {Use of antilymphocyte globulin for leukemia induction in mice.}, journal = {Archivum immunologiae et therapiae experimentalis}, volume = {24}, number = {5}, pages = {697-711}, pmid = {793567}, issn = {0004-069X}, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; Cytotoxicity Tests, Immunologic ; Female ; Hemolytic Plaque Technique ; *Immunoglobulin G ; Immunologic Memory ; Leukemia L1210/*etiology/immunology ; Leukocyte Count ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Neoplasm Transplantation ; Organ Size ; Rabbits ; Spleen/anatomy &amp; histology ; Time Factors ; Transplantation, Homologous ; }, abstract = {Biological activity of rabbit antimouse lymphocyte sera (ALS) and their IgG fractions was studied. Several ALS and ALG pools were cytotoxic in vitro for normal and leukemic mouse lymphocytes, causing temporary depletion of circulating leukocytes, prolongation of skin allografts, and progressive growth of L-1210/V leukemia transplanted across an H-2 barrier. As a rule, splenomegaly and a significant increase in the number of spleen cells were observed after i.p. injection of ALG. In experiments on the influence of prolonged treatment with ALG on tumor incidence in mice, one ALG pool appeared to be highly and repeatedly leukemogenic. The possible mechanism of leukemia induction by ALG was discussed.}, }
@article {pmid66787, year = {1976}, author = {Viola, MV}, title = {RNA tumor viruses as causative agents of chronic neurological disease.}, journal = {UCLA forum in medical sciences}, volume = {}, number = {19}, pages = {235-249}, pmid = {66787}, issn = {0082-7134}, mesh = {Amyotrophic Lateral Sclerosis/enzymology/*microbiology ; Brain/enzymology ; DNA-Directed DNA Polymerase/metabolism ; Guam ; Humans ; Oncogenic Viruses/*enzymology ; Parkinson Disease/enzymology/*microbiology ; RNA Viruses/*enzymology ; RNA-Directed DNA Polymerase/isolation &amp; purification/*metabolism ; }, abstract = {These studies were designed to determine if RIDP was present in a particulate fraction of brains from patients with ALS and PD. Evidence that we have detected RIDP is as follows: (a) DNA polymerase activity persists in the presence of concentrations of actinomycin D and distamycin that inhibit most DNA-directed DNA synthesis (25); (b) the majority of endogenous DNA polymerase activity is sensitive to prior treatment with RNase; (c) the early reaction product is a 4-5 S DNA heteropolymer joined by hydrogen bonds to an RNA molecule; and (d) the purified [3H]DNA product anneals to RNA extracted from the enzyme-containing pellet more extensively than to normal brain RNA or poly(rA). The enzyme activity is in a cytoplasmic particle that can be sedimented at high speed and has the buoyant density of RNA tumor viruses (1.16-1.18 gm/ml). This particulate fraction is not disrupted by physical manipulation and maintains its characteristic density with repeated centrifugations. Treatment with the nonionic surfactant Sterox changes the buoyant density of the enzyme-containing particle to 1.24 gm/ml, the density of the onconavirus virion core. Synthesis of RNA-DNA hybrids by an endogenous reverse transcriptase reaction was found only in normal and diseased Chamorro brains. Examination of a limited number of normal and diseased brains from individuals who lived in the United States produced negative results (39). Definitive characterization of this polymerase activity and identification as a true viral polymerase will depend on purification of biochemically active quantities of this polymerase to determine its template specificities, its cation preference, the fidelity of its transcription product, as well as its antigenic relationship to animal virus and human leukemic RIDP. Of critical importance in these studies will be differentiation of this activity from normal brain DNA polymerase gamma and terminal deoxynucleotidyltransferase.}, }
@article {pmid56138, year = {1976}, author = {Ringle, DA and Herndon, BL}, title = {Effect of antilymphocyte serum (ALS) on shock in rats.}, journal = {The American journal of physiology}, volume = {230}, number = {1}, pages = {178-187}, doi = {10.1152/ajplegacy.1976.230.1.178}, pmid = {56138}, issn = {0002-9513}, mesh = {Animals ; Antilymphocyte Serum/pharmacology/*therapeutic use ; Blood Platelets ; Edema/drug therapy ; Erythrocyte Count ; Female ; Graft Rejection ; Immunoglobulins ; Immunosuppression Therapy ; Leukocyte Count ; Lymph Nodes/immunology ; Lymphocytes/metabolism ; Phagocytosis/drug effects ; Rats ; Shock/*therapy ; Shock, Hemorrhagic/therapy ; Shock, Septic/therapy ; Spleen/immunology ; T-Lymphocytes/immunology ; Thymidine/metabolism ; gamma-Globulins ; }, abstract = {Effects of treatment with rabbit antirat anti-lymphocyte serum and globulin (ALS and ALG) on shock survival were studied in Sprague-Dawley derived male rats. Because of their known cytotoxic capability, it was postulated that lymphocytes might play a role in the pathogenesis of shock and that suppression of lymphocyte function by ALS/ALG treatment should then protect against shock. Shock models used were tourniquet, endotoxin, and hemorrhagic shock. Protection against tourniquet shock was found for ALS made against thymocytes but not for ALS against spleen cells or lymph node cells. The shock-protective factor was found in the ALG-containing serum fraction but not in the primarily albumin fraction. No significant protection was found for ALS treatment against either endotoxin or hemorrhagic shock. ALS effects on blood cell counts, reticulo endothelial system clearance, and inflammation were studied to help identify effects of ALS on shock survival. It was concluded from these studies that thymic or thymus-processed lymphocytes could play a role in the pathogenesis of shock but that multiple effects of ALS/ALG treatment necessitate further studies to elucidate any role for lymphocytes in shock.}, }
@article {pmid129963, year = {1975}, author = {Weiss, J and Gründig, E and Gerstenbrand, F}, title = {[The activity of aminotransferases in serum and cerebrospinal fluid in neurological diseases (author's transl)].}, journal = {Wiener klinische Wochenschrift}, volume = {87}, number = {23}, pages = {799-803}, pmid = {129963}, issn = {0043-5325}, mesh = {Alanine Transaminase/blood/cerebrospinal fluid ; Amyotrophic Lateral Sclerosis/enzymology ; Aspartate Aminotransferases/blood/cerebrospinal fluid ; Craniocerebral Trauma/enzymology ; Friedreich Ataxia/enzymology ; Guanidines/therapeutic use ; Hepatolenticular Degeneration/enzymology ; Humans ; Huntington Disease/enzymology ; Levodopa/therapeutic use ; Nervous System Diseases/drug therapy/*enzymology ; Parkinson Disease/enzymology ; Penicillins/therapeutic use ; Phenylketonurias/enzymology ; Transaminases/blood/cerebrospinal fluid/*metabolism ; }, abstract = {The activities of the aminotransferases, GOT and GPT, were determined in the serum and cerebrospinal fluid of patients with Parkinson's disease, Huntington's chorea, Wilson's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, phenylketonuria, and head injuries. 1. In patients with Huntington's chorea the activity of SGOT was lower than in controls (P = 0.02); in Friedreich's ataxia LGPT activity was decreased (P less than 0.001); in patients suffering from ALS SGOT (P = 0.005), SGPT (P less than 0.001) and LGOT (P less than 0.001) activities were increased. 2. Long-term treatment of Parkinson's disease and Wilson's disease with L-dopa resulted in an increase in SGOT, LGOT, and SGPT activity over approximately 2 months, with subsequent normalization of these enzyme activities in spite of continued therapy. Guanidine treatment led to an increase in aminotransferase activities in patients with ALS. Penicillamine caused a decrease in SGOT and SGPT activities in Wilson's disease. These results illustrate the necessity of taking therapeutic measures into account in the interpretation of data on aminotransferase activities.}, }
@article {pmid1345, year = {1975}, author = {Barth, RF and Singla, O and Liu, C}, title = {Suppressor T cells and host resistance to tye 111 pneumococcus after treatment with antilymphocyte serum.}, journal = {Infection and immunity}, volume = {12}, number = {6}, pages = {1307-1312}, pmid = {1345}, issn = {0019-9567}, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; Immunosuppression Therapy ; Mice ; Mice, Inbred BALB C ; Pneumococcal Infections/mortality ; Polysaccharides, Bacterial/immunology ; Streptococcus pneumoniae/*immunology ; T-Lymphocytes/*immunology ; }, abstract = {The antibody response to type III pneumococcal polysaccharide (SS-II) was significantly increased in mice treated with antilymphocyte serum (ALS). BALG/c mice given 0.25 ml of ALS on days -1, 0, and 1 relative to the days of immunization with 0.5 mug of SSS-II had a 20-fold increment (11,383 increased to 199,917) in the number of splenic plaque-forming cells enumerated on day 5 compared with untreated, immunized controls. This effect has been attributed to the elimination of subpopulation of thymus-derived lymphocytes (T cells) that has suppressor function. The present series of experiments relate the augmented antibody response to SSS-II in mice treated with ALS to increased host resistance after infection with Streptococcus pneumoniae, type III (Pn-II). The 50% lethal dose of Pn-III in niminnunized mice was 102 and the 100% lethal dose was 103 organisms. Mice immunized with 0.5 mug of SSS-III and challenged 5 days later with Pn-III were completely protected against a dose of up to 108 organisms. Mice treated with 0.25 ml of ALS on days -1, 0, and 1, immunized with SSS-III on day 0, and challenged with 2.5 X 10(9) Pn-III on day 5 had a mean survival time of greater than 100 h compared with 16 h for immunized non-serum-treated controls. Animals given a single injection of ALS before immunization showed no increase in resistance, whereas mice treated after immunization had significant prolongation of survival times. Untreated, immunized mice challenged with 5 X 10(9), 1 X 5 X 10(8) Pn-II survived 14 to 19 h, whereas ALS-treated animals had mean survival times of 48, 174, and 222 h, respectively. These findings suggest that immunoregulatory T cells may have a biologically significant effect in a narrow zone in which the normal host immune response is insufficient but still potentially capable of providing some additional degree of protection if suppressor cells are elimated.}, }
@article {pmid52730, year = {1975}, author = {Smith, RA and Norris, FH}, title = {Symptomatic care of patients with amyotrophic lateral sclerosis.}, journal = {JAMA}, volume = {234}, number = {7}, pages = {715-717}, pmid = {52730}, issn = {0098-7484}, mesh = {Amitriptyline/therapeutic use ; Amyotrophic Lateral Sclerosis/drug therapy/*therapy ; Aphonia/therapy ; Braces ; Deglutition Disorders/surgery ; Edetic Acid/therapeutic use ; Esophagus/surgery ; Guanidines/therapeutic use ; Humans ; Muscle Cramp/drug therapy ; Muscle Relaxants, Central/therapeutic use ; Palliative Care ; Physical Therapy Modalities ; Salivary Gland Diseases/drug therapy ; Terminal Care ; Walkers ; }, abstract = {Until a definitive treatment is found for amyotrophic lateral sclerosis, there will continue to be a need to provide symptomatic care. Experience with caring for a large number of patients has proved that symptomatic therapy can be based on rational principles. Treatment should be limited to procedures that are simple and low-cost, with low risk of serious morbidity. When all remedies fail, the physician can still provide a comforting presence and foster a dignified death.}, }
@article {pmid1165111, year = {1975}, author = {Kinnaert, P and Mahieu, A and Van Geertruyden, N and d'Orchimont, R and Goossens, R}, title = {Organ distribution of sheep red blood cells in ALS-treated rats.}, journal = {Immunology}, volume = {29}, number = {3}, pages = {555-557}, pmid = {1165111}, issn = {0019-2805}, mesh = {Animals ; Antigens/*analysis ; Antilymphocyte Serum/*pharmacology ; Erythrocytes/*immunology ; Intestines/immunology ; Liver/immunology ; Lymph Nodes/immunology ; Rabbits/immunology ; Rats ; Sheep/immunology ; Spleen/immunology ; Thymus Gland/immunology ; }, abstract = {The inter-organ distribution of radioactivity in rats injected with 51Cr-labelled SRBC is altered after treatment with ALS absorbed with this antigen. The alteration is due to the presence of soluble SRBC antigens in the serum and subsequent immunization of the tested animals. The 51Cr distribution does not correspond to the uptake of antigenic material in immunized rats.}, }
@article {pmid49390, year = {1975}, author = {Viola, MV and Frazier, M and White, L and Brody, J and Spiegelman, S}, title = {RNA-instructed DNA polymerase activity in a cytoplasmic particulate fraction in brains from Guamanian patients.}, journal = {The Journal of experimental medicine}, volume = {142}, number = {2}, pages = {483-494}, pmid = {49390}, issn = {0022-1007}, mesh = {Amyotrophic Lateral Sclerosis/*enzymology ; Autopsy ; Brain/*enzymology ; Brain Chemistry ; Cell Fractionation ; Centrifugation, Density Gradient ; Cytoplasm/*enzymology ; DNA ; Humans ; Nucleic Acid Hybridization ; Parkinson Disease/*enzymology ; RNA ; RNA-Directed DNA Polymerase/*analysis ; Rauscher Virus/analysis ; Tritium ; Visna-maedi virus/analysis ; }, abstract = {Nervous system tissues from a number of patients with idiopathic neurological disorders were examined for biochemical evidence of RNA tumor virus infection. RNase-sensitive DNA polymerase activity was found in a cytoplasmic particulate fraction from two patients with Guamanian amyotrophic lateral sclerosis (ALS) but not in brains from two normal U.S. individuals. The buoyant density of the enzyme-containing fraction was 1.16-1.18 g/ml and could be converted to a denser region of the gradient (1.24 g/ml) by treatment with the nonionic surfactant, Sterox. The cation and detergent requirements for the endogenous RNase-sensitive DNA polymerase reaction were determined. The early (5 min) endogenous reverse transcriptase product was analyzed by cesium sulfate gradient centrifugation. RNase- and heat-sensitive RNA-DNA hybrids were detected in the product analysis of two ALS, one Parkinsonism-dementia (PD) brain, and two brains from asymptomatic Chamorros but not in brains from normal U.S. individuals and a number of patients with neuro-psychiatric disorders. The DNA product was a 4.5S heteropolymer that hybridized more extensively to RNA extracted from the enzyme-containing pellet from PD brain as compared to a similar fraction from normal U.S. brain. The DNA product appeared to be unrelated to Rausvher or visna virus 70S RNA as determined by RNA-[-3H]DNA hybridization.}, }
@article {pmid1097498, year = {1975}, author = {Gelfand, MC and Paul, WE}, title = {Prolongation of allograft survival in mice by administration of anti-Thy 1 serum. I. Mediation by in vivo activation of regulatory T cells.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {115}, number = {1}, pages = {1-4}, pmid = {1097498}, issn = {0022-1767}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; *Cell Biology ; Graft Rejection ; Immune Sera/*administration &amp; dosage ; *Immunity, Cellular ; Injections, Intraperitoneal ; Lymphocyte Activation ; Mice ; Mice, Inbred AKR ; Mice, Inbred BALB C ; Mice, Inbred C3H ; Mice, Inbred C57BL ; *Skin Transplantation ; T-Lymphocytes/drug effects/*metabolism ; Thymectomy ; Thymus Gland/physiology ; *Tissue Survival ; Transplantation, Homologous ; }, abstract = {A single 0.5-ml dose of anti-Thy 1.2 serum raised in AKR (H-2k, Thy 1.1) mice by immunization with C3H (H-2k, Thy 1.2) thymocytes prolonged mean graft survival (MGS) of C57BL/L (H-2b, Thy 1.2) skin on BALB/c (H-2d, Thy, 1.2) mice from 9.2 to 13.0 days (p less than 0.01). Absorption of anti-Thy 1.2 serum with C3H but not AKR brain removed this activity. MGS was prolonged by anti-Thy 1.2 serum given as long as 2 weeks before grafting. Four separately raised anti-Thy 1.2 preparations prolonged MGS, one to a dilution of 1:128. Anti-Thy 1.1 serum prolonged MGS on AKR mice but not on BALB/c mice. Thymectomy 3 weeks or more before graft placement or treatment of BALB/c mice with anti-lymphocyte serum (ALS) diminished the effectiveness of anti-Thy 1.2 serum. Furthermore, infusion of 25 times 10(6) spleen cells from BALB/c mice given anti-Thy 1.2 serum prolonged MGS on syngeneic recipients to 15.6 days whereas spleen cells from mice given no treatment or ALS had no effect. Thymocytes from anti-Thy 1.2 serum treated donors were ineffective in prolonging MGS on transfer. Transfer or serum from anti-Thy 1.2 serum-treated mice also had no effect. The transfer of graft prolongation with lymphoid cells from anti-Thy 1 serum treated mice suggests anti-Thy 1 serum may prolong MGS by activating suppressor T cells.}, }
@article {pmid1100444, year = {1975}, author = {Liska, M and Hatala, M and Hasková, V and Bednarík, T}, title = {Effects of various immunosuppressive drugs on the development of experimental renal infection in rats.}, journal = {Folia biologica}, volume = {21}, number = {3}, pages = {171-175}, pmid = {1100444}, issn = {0015-5500}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; Azathioprine/pharmacology ; Dose-Response Relationship, Drug ; Escherichia coli/isolation &amp; purification ; Escherichia coli Infections/*immunology ; Hydrocortisone/pharmacology ; Immunosuppressive Agents/*pharmacology ; Kidney Diseases/*immunology/microbiology ; Pyelonephritis/immunology/microbiology ; Rats ; }, abstract = {The effect of azathioprine, hydrocortisone and antihymocyte serum on the development of experimental colibacillary renal infection in rats was assessed by macroscopical findings in the kidneys, especially by determining the number of microbes in the infected organ, on day 7 after injection of the infectious agent. The greatest multiplication of bacteria and so the most pronounced macroscopical changes occurred after ALS treatment. There was statistically significant difference between ALS-treated group and the control group, whereas the differences between controls and the other experimental groups (Imuran, hydrocortisone) were non-significant.}, }
@article {pmid1100442, year = {1975}, author = {Kaulen, DR and Golovanova, TA and Pyatikhina, DP and Khorobrikh, VV}, title = {Inhibition of haemopoietic stem cells by syngeneic lymphocytes treated with antilymphocyte serum.}, journal = {Folia biologica}, volume = {21}, number = {2}, pages = {95-102}, pmid = {1100442}, issn = {0015-5500}, mesh = {Animals ; *Antilymphocyte Serum ; Cell Division ; Cell Migration Inhibition ; Clone Cells/immunology ; Female ; Hematopoietic Stem Cells/*immunology ; Lectins ; Lymphocyte Activation ; Lymphocytes/*immunology ; Macrophage Migration-Inhibitory Factors ; Male ; Mice ; Mice, Inbred C57BL/immunology ; Mice, Inbred CBA/immunology ; Thymus Gland/immunology ; }, abstract = {Some aspects of the mechanisms by which antilymphocyte serum, its globulin fraction, or phytohaemagglutinin act to reduce the stem cell content of murine haemopoietic tissues were studied, using the method of clonal proliferation of stem cells in the spleens of lethally irradiated (830R) mice. The transplants were treated in vitro with ALS, ALG or PHA for 30 min. at 37 degrees C. Direct treatment of spleen or bone marrow cells with ALS or PHA resulted in pronounced inhibition of the colony-forming capacity of haemopoietic tissues in syngeneic irradiated recipients. The degree of inhibition was dependent on the concentration of ALS or PHA. It was found that the inhibition of CFC with ALS was mediated by lymphoid cells: bone marrow CFC were reduced after 30-min incubation at 37 degrees C with syngeneic lymph node or thymus cell pretreated with ALG and washed free of its excess. It was further demonstrated that ALG-treated thymocytes released, upon 30-min. incubation at 37 degrees C, some material capable of inhibiting bone marrow CFC. No release was observed with PHA-treated thymocytes. Some properties of the active supernatants are described and it is suggested to designate the observed inhibitory activity as Stem-cell Inhibitory Factor.}, }
@article {pmid1079193, year = {1975}, author = {Taylor, G and Taylor-Robinson, D}, title = {The part played by cell-mediated immunity in mycoplasma respiratory infections.}, journal = {Developments in biological standardization}, volume = {28}, number = {}, pages = {195-210}, pmid = {1079193}, issn = {0301-5149}, mesh = {Animals ; Antibodies, Bacterial/analysis ; Antigens, Bacterial ; Antilymphocyte Serum/administration &amp; dosage ; Cilia/immunology ; Cricetinae ; *Immunity, Cellular ; Immunosuppression Therapy ; Injections, Intraperitoneal ; Lung/immunology/pathology ; Lymphocyte Depletion ; Mice ; Mycoplasma Infections/*immunology/pathology ; Radiation ; Respiratory Tract Infections/*immunology/pathology ; T-Lymphocytes/immunology/physiology ; Thymectomy ; }, abstract = {Intranasal inoculation of M. pulmonis in mice and M. pneumoniae in hamsters results in pneumonia characterised by peribronchiolar and perivascular cuffing by lymphocytes. Thymus-dependent lymphocytes were depleted in mice by thymectomy and X-irradiation or treatment with anti-lymphocyte serum (ALS), and in hamsters by treatment with ALS. These procedures caused a reduction in the severity of pneumonic lesions in infected animals compared with infected immunologically normal animals. In addition, the organisms were present in slightly greater numbers in the lungs of the immunosuppressed animals. These results indicate the importance of thymus-dependent lymphocytes in the pathogenesis of mycoplasma-induced pulmonary disease. However, the role that these cells play in resistance to infection is not known and it may be that local secretory antibody is also important. Results of preliminary experiments involving hamster tracheal organ cultures infected with M. pneumoniae indicate that there is a factor present in lung washings from immune hamsters that protects against loss of ciliary activity brought about by M. pneumoniae.}, }
@article {pmid234261, year = {1975}, author = {Krueger, GR and Graw, RG and Rogentine, GN and Darrow, CC and Neefe, JR and Luetzeler, J}, title = {Pathology of modified graft-versus-host disease in bone marrow allografted monkeys treated with antilymphocyte serum.}, journal = {Blut}, volume = {30}, number = {1}, pages = {19-30}, pmid = {234261}, issn = {0006-5242}, mesh = {Animals ; Antilymphocyte Serum/*therapeutic use ; *Bone Marrow Cells ; *Bone Marrow Transplantation ; *Graft vs Host Reaction ; Immunosuppression Therapy ; Intestinal Mucosa/pathology ; Jejunum/pathology ; Liver/pathology ; Lymph Nodes/pathology ; Macaca ; Pulmonary Veins/pathology ; *Radiation Injuries, Experimental ; Time Factors ; Transplantation, Autologous ; Transplantation, Homologous ; }, abstract = {Lethally irradiated rhesus monkeys were used for bone marrow allografting and autografting. Monkeys receiving allogeneic bone marrow developed acute graft-versus-host reaction (GVHR) and had a mean survival time of 9.1 days as compared to autografted monkeys which survived above 500 days. Treatment with antilymphocyte sera (ALS) before allografting modified the GVHR and extended the survival time to an average of 43 days. Histologically, such animals showed evidence of "chronic" GVHR and septicemia secondary to a lack in lymphoreticular recovery. Subsequently, severe GI-tract infections followed which usually served as portal of entry for septicemia.}, }
@article {pmid4839886, year = {1974}, author = {Domzal, T and Ilnicki, S}, title = {[Attempts at treatment of amyotrophic lateral sclerosis].}, journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)}, volume = {27}, number = {11}, pages = {955-957}, pmid = {4839886}, issn = {0043-5147}, mesh = {Administration, Oral ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/*drug therapy ; Drug Evaluation ; Female ; Humans ; Male ; Middle Aged ; Quinones/administration &amp; dosage/*therapeutic use ; Uracil Nucleotides/*therapeutic use ; Vitamin E/administration &amp; dosage/*therapeutic use ; }, }
@article {pmid4743906, year = {1973}, author = {Baroni, CD and Scelsi, R and Peronace, ML and Uccini, S}, title = {Heterologous antilymphocyte serum hastens the growth of 7,12-dimethylbenz(alpha)anthracene induced tumours in mice.}, journal = {British journal of cancer}, volume = {28}, number = {3}, pages = {221-226}, pmid = {4743906}, issn = {0007-0920}, mesh = {Animals ; Animals, Newborn ; *Antilymphocyte Serum ; *Benz(a)Anthracenes ; Drug Synergism ; Kinetics ; Lung Neoplasms/chemically induced ; Lymphoma/chemically induced ; Mice ; Neoplasms, Experimental/*chemically induced ; Skin Neoplasms/chemically induced ; }, abstract = {The present paper describes the effects of repeated administration of rabbit anti-mouse lymphocyte serum (ALS) or normal rabbit serum (NRS) on tumours induced in Charles-River mice by 7,12-dimethylbenz(α)anthracene (DMBA) given at birth. ALS or NRS were given either at the time of DMBA administration and subsequently at weekly intervals for the first 10 weeks of life, or at daily intervals for 7 days during the first, second, third or fourth week of life. The incidence and histology of the tumours were studied. It was found that treatment of very young mice with ALS greatly reduced the mean survival time of mice and significantly increased the incidence of malignant lymphoma. The incidence of lung tumours was found to be significantly increased in the animals injected with ALS during the second week of life.Treatment with ALS in the other experimental groups gave results essentially similar to those observed in DMBA control and NRS treated mice.}, }
@article {pmid4718269, year = {1973}, author = {David-West, TS and Osunkoya, BO}, title = {The effect of anti-lymphocytic serum of infection by congo virus (Crimean haemorrhagic fever virus related) and Mokola virus (rabies virus related).}, journal = {British journal of experimental pathology}, volume = {54}, number = {3}, pages = {274-282}, pmid = {4718269}, issn = {0007-1021}, mesh = {Absorption ; Age Factors ; Animals ; Antigens, Viral ; *Antilymphocyte Serum ; *Arboviruses ; Brain/pathology ; Erythrocytes/immunology ; Immunosuppression Therapy ; Inflammation ; Lymphocytic Choriomeningitis/immunology ; Mice ; *RNA Viruses ; Spleen/pathology ; Splenomegaly/etiology ; Thymus Gland/*cytology ; Time Factors ; Virus Cultivation ; Virus Diseases/*immunology/mortality/pathology ; }, abstract = {Antilymphocytic serum (ALS) raised in white New Zealand rabbits with Swiss albino mice thymocytes significantly protected mice challenged with Congo virus (Crimean haemorrhagic fever virus related) from the lethal episodes of the infection. There was a delaying as well as a sparing effect on morbidity and mortality, which was particularly striking in adult mice. Histopathological examination of brain sections of treated mice showed a complete suppression of the characteristic inflammatory tissue reactions, which marked similar sections prepared from mice treated with normal rabbit serum (NRS) or from the virus control group. Unlike Congo virus infection, ALS did not have a demonstrable effect on Mokola virus (rabies virus related) infection. A comparison of the effect of ALS on Congo virus infection and its effect on murine lymphocytic choriomeningitis is made. It was observed that a constant feature of ALS treatment was gross splenic enlargement in the animals. It is suggested that this might have been due, at least in part, to a gross sequestration of sensitized red blood cells, as revealed by the histopathology of the organ. Other possible causes of splenomegaly in immunosuppressed mice are also discussed.}, }
@article {pmid4145387, year = {1973}, author = {Baker, PJ and Reed, ND and Stashak, PW and Amsbaugh, DF and Prescott, B}, title = {Regulation of the antibody response to type 3 pneumococcal polysaccharide. I. Nature of regulatory cells.}, journal = {The Journal of experimental medicine}, volume = {137}, number = {6}, pages = {1431-1441}, pmid = {4145387}, issn = {0022-1007}, mesh = {Animals ; *Antibody Formation ; Antibody-Producing Cells ; Antilymphocyte Serum ; B-Lymphocytes/*immunology ; Bone Marrow/immunology ; Bone Marrow Cells ; Immunity, Cellular ; Mice ; Mice, Inbred BALB C ; *Polysaccharides, Bacterial ; Streptococcus pneumoniae/*immunology ; T-Lymphocytes/*immunology ; Viral Plaque Assay ; }, abstract = {The effect of treatment with antilymphocyte serum (ALS) on the magnitude of the plaque-forming cell (PFC) response to Type III pneumococcal polysaccharide (SSS-III) was assessed in athymic nude mice and thymus-bearing littermate controls. Without ALS treatment, the PFC response was slightly higher in nude than in control mice. Treatment with ALS had no effect on the response of nude mice; however, considerable enhancement was noted in thymus-bearing controls. Such enhancement was ALS dose-dependent and demonstrable under conditions in which there was substantial inactivation of thymic-derived "helper" cells required for an antibody response to erythrocyte antigens. These findings suggest that amplifier and suppressor cells, which have been reported to regulate the magnitude of the antibody response to SSS-III, represent populations of thymic-derived cells (T cells) that are not present in nude mice. The activities of "helper" T cells and regulatory T cells appear to be independent of one another and mediated by separate subpopulations of T cells.}, }
@article {pmid4123951, year = {1973}, author = {Husberg, BS}, title = {In vitro studies of the cell-bound and antibody-mediated immunity evoked by murine renal allotransplants. Influence of presensitization, total body irradiation and immunosuppressive agents.}, journal = {Clinical and experimental immunology}, volume = {14}, number = {2}, pages = {271-292}, pmid = {4123951}, issn = {0009-9104}, mesh = {Animals ; *Antibody Formation ; Antilymphocyte Serum ; Azathioprine/pharmacology ; Cells, Cultured ; Dactinomycin/pharmacology ; Disease Models, Animal ; Female ; *Hot Temperature ; *Immunity, Cellular ; Immunosuppressive Agents/*pharmacology ; Kidney/drug effects/radiation effects ; *Kidney Transplantation ; Leucovorin/pharmacology ; Male ; Methotrexate/pharmacology ; Methylprednisolone/pharmacology ; *Radiation Effects ; Rats ; Thoracic Duct/immunology ; Transplantation Immunology/radiation effects ; }, abstract = {The influence of presensitization, total body irradiation and several immunosuppressive drugs on the immune response evoked by allogeneic rat kidneys was studied in vitro and in vivo. The cytotoxic effect of recipient thoracic duct lymphoid cells and fresh or heat-inactivated recipient serum against donor target cells was measured with [51]Cr assay. Rats that had undergone two consecutive allogeneic transplantations from isogenous donors had thoracic duct lymphoid cells and serum with an increased cytotoxic effect against donor strain target cells as compared to control rats transplanted only once. Heat-inactivated recipient serum from such animals also had an increased blocking effect on cell-mediated cytotoxicity. ALS had the strongest depressive effect on the cell-bound immunological responses evoked by the transplants in the recipient rats, decreasing both the number of lymphoid cells in the thoracic duct lymph and the cytotoxic activity of the remaining cells. Methylprednisolone and methotrexate also strongly suppressed the cellular immunological events in the way just mentioned. Actinomycin-C and total body irradiation depressed cell-bound immune response only by causing a decrease in the number of cells in the thoracic duct lymph. Azathioprine did not influence cell-bound immunological responses to allogeneic kidney transplants. Total body irradiation, methotrexate and methylprednisolone treatment markedly diminished the cytotoxic effect of fresh recipient serum against target cells and reduced the blocking effect of heat-inactivated recipient serum on lymphoid cell-mediated cytotoxicity. The other tested agents all caused a moderate depression of the cytotoxic and blocking effect of fresh and heat-inactivated recipient serum, respectively. When folinic acid was given regularly between consecutive methotrexate injections, the depression of the lymphoid cell amount in the thoracic duct lymph was markedly less. The results of the cytotoxicity tests were similar to those obtained with methotrexate treatment alone.}, }
@article {pmid4576561, year = {1973}, author = {Franks, CR and Curtis, K and Perkins, FT}, title = {Long-term survival of HeLa tumours in mice treated with antilymphocyte serum.}, journal = {British journal of cancer}, volume = {27}, number = {5}, pages = {390-395}, pmid = {4576561}, issn = {0007-0920}, mesh = {Animals ; Antibodies ; Antibody Formation/drug effects ; Antigen-Antibody Complex ; Antigens ; Antilymphocyte Serum/*pharmacology ; Cytotoxicity Tests, Immunologic ; Female ; Fluorescent Antibody Technique ; *HeLa Cells ; Immunity, Cellular/drug effects ; *Immunosuppression Therapy ; Mice ; Mice, Inbred CBA ; *Neoplasms, Experimental ; Transplantation Immunology ; }, abstract = {During studies of the ability of antilymphocyte serum (ALS) to suppress the immune mechanism of mice and thereby allow HeLa cells to grow into a large tumour in the mice, it was observed that many tumours continued to grow even after the ALS treatment had been stopped and full immunological competence of the mice had returned. The HeLa cells of such tumours appeared to be unchanged in their ability to induce further tumours in ALS treated mice to which they were transferred and, furthermore, the mice which were carrying such tumours in the presence of immunological competence were able to reject additional injections of HeLa cells or other human tumour cells. The four possible explanations for this phenomenon, (i) depression of cellular response; (ii) local reaction at the graft site; (iii) the presence of a blocking factor; and (iv) the elevation of the humoral response, have been investigated.}, }
@article {pmid4572113, year = {1973}, author = {Shanfield, I and Wolf, JS and Wren, SF and MacLean, LD and Hume, DM}, title = {Mechanism of permanent survival of canine renal allografts following a limited course of ALS treatment.}, journal = {Transplantation proceedings}, volume = {5}, number = {1}, pages = {533-534}, pmid = {4572113}, issn = {0041-1345}, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; Dogs ; Graft Rejection ; Horses/immunology ; Immunization, Passive ; Immunization, Secondary ; *Kidney Transplantation ; *Transplantation Immunology ; Transplantation, Homologous ; }, }
@article {pmid4694386, year = {1973}, author = {Van den Brenk, HA and Sharpington, C and Orton, C}, title = {Macrocolony assays in the rat of allogeneic Y-P388 and W-256 tumour cells injected intravenously: dependence of colony forming efficiency on age of host and immunity.}, journal = {British journal of cancer}, volume = {27}, number = {2}, pages = {134-152}, pmid = {4694386}, issn = {0007-0920}, mesh = {Age Factors ; Animals ; Animals, Newborn ; Antilymphocyte Serum ; Body Weight ; Carcinoma 256, Walker ; *Cell Line ; Female ; Germ-Free Life ; Immunity/radiation effects ; Injections, Intravenous ; Kidney ; Lung ; *Neoplasm Transplantation ; Neoplasms, Experimental/*immunology ; Radiation Effects ; Rats ; Sarcoma, Yoshida ; Spleen ; Splenectomy ; }, abstract = {Two rapidly growing allogeneic tumours, sublines of Yoshida (Y-P388) and Walker (W-256) injected intravenously in single cell suspensions produced tumour macrocolonies in the lungs of rats within 7 days. Y-P388 produced similar but fewer colonies in the kidneys. Colony forming efficiency (CFE) in lung was high in weanling rats given either sublethal whole body irradiation (WBI) or a single dose of rabbit anti-rat lymphocytic serum (ALS) to suppress immunity. In immunologically intact weanlings CFE was much lower and many 7-day old colonies showed signs of regression. CFE for primary tumour cell challenges decreased rapidly and markedly with increase in age of host during the first 1-2 weeks after weaning. This resistance to growth of a primary challenge in lungs of older rats was not significantly reduced by WBI but was decreased by ALS. CFE of a secondary challenge of tumour cells injected intravenously in rats which had been previously immunized with heavily irradiated (HR) tumour cells was very low; it was not significantly increased by WBI but was moderately increased by ALS. In weanling rats given lethal (900 rad) WBI, 1 hour before intravenous injection of tumour cells, treatment with bone marrow (BM) cells derived from normal adult donors increased CFE, whereas BM (or spleen) cells from immunized donors decreased CFE. The results suggest that ALS and WBI not only increase tumour CFE by suppressing immunity to tumour growth but also "condition" host tissue (tumour bed) in such a way as to facilitate the survival, "take" and initial replication of grafted tumour cells before the rats recover from the immunosuppressive effects of these treatments.}, }
@article {pmid4264649, year = {1972}, author = {Bona, C and Anteunis, A and Robineaux, R and Halpern, B}, title = {Structure of the lymphocyte membrane. 3. Chemical nature of the guinea-pig lymphocyte membrane macromolecules reacting with heterologous ALS.}, journal = {Clinical and experimental immunology}, volume = {12}, number = {3}, pages = {377-390}, pmid = {4264649}, issn = {0009-9104}, mesh = {Agglutination Tests ; Animals ; Antigen-Antibody Reactions ; *Antilymphocyte Serum ; Binding Sites, Antibody ; Cell Membrane/analysis ; Cytotoxicity Tests, Immunologic ; Electrophoresis ; Glucosidases ; Glycoproteins/analysis ; Glycosaminoglycans/analysis ; Guinea Pigs ; Hydrolases ; Lymph Nodes/cytology ; Lymphocytes/*analysis ; Macromolecular Substances/*analysis ; Mannose/analysis ; Microscopy, Electron ; Neuraminic Acids/analysis ; Peroxidases ; Rabbits/immunology ; Sheep/immunology ; }, abstract = {Behaviour of normal and hydrolase-treated guinea-pig lymph node lymphocytes versus heterologous ALS was studied by means of biophysical and immunological techniques i.e. electrophoretic mobility, leucoagglutination, cytotoxicity and visualization of antigen–antibody reaction in electron microscopy. Our results clearly revealed that heterologous ALS antibodies reacted with mannose and sialic acid containing glycoproteins located on the lymphocyte surface. Sialic acid and other main constituents of the lymphocyte cell coat, i.e. the sulphated mucopolysaccharides have an important role in the electronegative charges of the cell and in binding of the ALS antibodies. β-Glycosidase as well as α-maltase treatment of the lymph node lymphocyte increased from 45% to 100% the reactivity to ALS as revealed by the peroxidase reaction in electron microscopy. These results suggest that all lymph node lymphocytes can react with ALS antibodies, but that the reactive sites of 45% of these cells are masked by glucidic sub-units.}, }
@article {pmid5046868, year = {1972}, author = {Turk, JL and Poulter, LW}, title = {Selective depletion of lymphoid tissue by cyclophosphamide.}, journal = {Clinical and experimental immunology}, volume = {10}, number = {2}, pages = {285-296}, pmid = {5046868}, issn = {0009-9104}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; Cyclophosphamide/*pharmacology ; Guinea Pigs ; Lymph Nodes/drug effects ; Lymphocytes ; Lymphoid Tissue/*drug effects/pathology ; Mice ; Rabbits/immunology ; Spleen/drug effects/pathology ; Thymectomy ; Time Factors ; }, abstract = {Selective depletion of lymphocytes from the lymph follicles and cortico-medullary junction in lymph nodes and equivalent non thymus dependent areas of the spleen can be produced by cyclophosphamide (CY) (300 mg/kg) in the mouse and guinea-pig. Despite three such injections on alternate days, thymus dependent areas still contained lymphocytes. Total depletion of lymphocytes from lymph nodes and spleen was produced by combining neonatal thymectomy in the mouse or ALS treatment in the guinea-pig with CY. CY produced depletion of lymphocytes in the cortex of the thymus before the medulla. Maximal depletion occurred at 3 days and in surviving animals repopulation was evident by 7 days at the cortico-medullary junction only. Lymph follicles were found in lymph nodes of neonatally thymectomized CY treated mice following repopulation with bone marrow. These findings suggest that the lymphocytes of the lymph follicles are derived from a population of rapidly dividing cells, part of which at least can be found in the bone marrow.}, }
@article {pmid4550853, year = {1972}, author = {Anderson, HR and Dresser, DW and Iverson, GM and Lance, EM and Wortis, HH and Zebra, J}, title = {The effects of ALG on the murine immune response to sheep erythrocytes.}, journal = {Immunology}, volume = {22}, number = {2}, pages = {277-289}, pmid = {4550853}, issn = {0019-2805}, mesh = {Acetates ; Animals ; Antibody Formation/*drug effects ; Antibody-Producing Cells ; Antilymphocyte Serum/*pharmacology ; Erythrocytes/immunology ; Female ; Haptens ; Hemocyanins ; Hemolytic Plaque Technique ; Immune Tolerance ; Immunoglobulin G/biosynthesis ; Immunoglobulins/biosynthesis ; Male ; Mice ; Nitrophenols ; Rabbits ; Serum Globulins ; Sheep ; }, abstract = {Antilymphocyte globulin (ALG), and to a lesser extent normal rabbit globulin (NRG), when given to mice prior to immunization with sheep-RBC suppress both the γM and γG2a responses. Globulin injected after the antigen suppresses the γG2a response, augments the γG1 response and has little effect on the γM response. These effects are also observed in mice partially paralysed to rabbit γ globulin. In another system—the response to hapten—protein conjugates precursors of antibody producing cells were found to be more resistant to ALS treatment in vivo than were helper cells. It is concluded that the suppressive effects of ALG treatment are largely due to the direct action of ALG on helper cells (T-cells). The mechanism of the adjuvant-like effect is unclear.}, }
@article {pmid5142707, year = {1971}, author = {Göpel, W}, title = {[Amyotrophic lateral sclerosis with basilar impression and successful neurosurgical treatment (case report)].}, journal = {Zeitschrift fur arztliche Fortbildung}, volume = {65}, number = {17}, pages = {931-935}, pmid = {5142707}, issn = {0044-2178}, mesh = {Amyotrophic Lateral Sclerosis/diagnosis/*etiology/surgery ; Electroencephalography ; Humans ; Male ; Middle Aged ; Neurologic Examination ; Neurosurgery ; Platybasia/*complications/diagnostic imaging/surgery ; Radiography ; }, }
@article {pmid5556585, year = {1971}, author = {Oberling, F and Hiebel, G}, title = {Intravenous ALS in the treatment of severe rectocolitis.}, journal = {The New England journal of medicine}, volume = {285}, number = {7}, pages = {409-410}, pmid = {5556585}, issn = {0028-4793}, mesh = {Adult ; Antilymphocyte Serum/*therapeutic use ; Colitis/*drug therapy ; Female ; Humans ; Male ; Middle Aged ; }, }
@article {pmid5102758, year = {1971}, author = {Jones, VE and Ogilvie, BM}, title = {Protective immunity to Nippostrongylus brasiliensis: the sequence of events which expels worms from the rat intestine.}, journal = {Immunology}, volume = {20}, number = {4}, pages = {549-561}, pmid = {5102758}, issn = {0019-2805}, mesh = {Anaphylaxis/immunology ; Ancylostomatoidea/enzymology/immunology ; Animals ; Antibodies ; Antilymphocyte Serum/pharmacology ; Complement System Proteins ; Female ; Hookworm Infections/*immunology ; *Immunity/drug effects/radiation effects ; Immunity, Active ; Immunity, Maternally-Acquired ; Immunoglobulin G/metabolism ; Intestinal Mucosa/immunology ; Intestine, Small/*immunology ; Mast Cells/immunology ; Rabbits ; Radiation Effects ; Rats ; Venoms ; }, abstract = {In these experiments, adult Nippostrongylus brasiliensis worms were damaged by protective antibodies in either actively or passively immunized rats. These damaged worms were then transplanted into the intestines of normal recipient rats, from which they were rapidly expelled. The rapid expulsion of damaged worms from normal recipients was an active process because when recipients were irradiated, the damaged worms were not expelled. Furthermore, when irradiated recipients were given protective antibodies as well as damaged worms they were still unable to expel the damaged worms. The active expulsion mechanism present in normal rats seems unlikely to be a specific immunological event because treatment of recipients with anti-lymphocytic serum (ALS) did not mimic the effect of irradiation. That is, ALS treatment did not prevent the expulsion of the damaged worms although it suppressed the induction of active immunity. These experiments show that, when immunity acts to expel adult worms from the rat small intestine, two separate and sequential steps which do not require complement are involved: (1) The initial and essential first step is the action of protective antibodies on the worms. In this process the worms are damaged; changes occur in some enzymes and the structure of their gut cells deteriorates. Once these antibody-induced changes have occurred, they are irreversible and the damaged worms are susceptible to the second step. (2) The second step expels the worms. It acts completely independently of the presence of protective antibodies but cannot act unless step (1) has already occurred. The factors involved are present in normal rats. In this report, no evidence of the nature of this step is presented except that it is prevented by irradiation and slightly affected by ALS treatment. If the release of pharmacologically active amines from mast cells is important in immunity, as suggested by other workers, it would be involved in this step. This work refutes the `leak lesion' hypothesis for worm expulsion. The `leak lesion' hypothesis proposed that, in order for protective antibodies to affect the worms, the intestinal mucosa had first to be damaged by a local anaphylactic reaction and that worm expulsion was the direct consequence of the action of protective antibodies on the worms. It is now clear that the action of protective antibodies alone cannot cause the worms to be expelled and that, if anaphylaxis is involved, its action is subsequent to the antibody-mediated damage to the worms.}, }
@article {pmid4106806, year = {1971}, author = {Barker, CF and Billingham, RE}, title = {The lymphatic status of hamster cheek pouch tissue in relation to its properties as a graft and as a graft site.}, journal = {The Journal of experimental medicine}, volume = {133}, number = {3}, pages = {620-639}, pmid = {4106806}, issn = {0022-1007}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; Cheek/*immunology ; Cricetinae ; Ear ; Graft vs Host Reaction ; Immune Tolerance ; Lymph Nodes/cytology ; Lymphatic System/*anatomy &amp; histology ; Organ Size ; Quaternary Ammonium Compounds ; Skin/immunology ; *Skin Transplantation ; Staining and Labeling ; *Transplantation Immunology ; Transplantation, Homologous ; }, abstract = {Hamster cheek pouch skin, transplanted to the side of an isogenic host's chest wall, retains its immunologically privileged status as evidenced by the prolonged survival of inlaid homografts of ordinary skin. Various findings sustain the premise that exemption from rejection by otherwise susceptible homografts in both intact pouch tissue and in established pouch skin isografts is due to an impediment in the afferent pathway of the immunologic reflex, i.e., to deficient lymphatic drainage. Although lymphatics were not apparent when dye was injected into pouch skin grafts or into grafts of ordinary skin sustained by them, lymph vessels were readily and consistently revealed by dye injected into intact trunk skin or established isografts of trunk skin. When suspensions of viable lymph node cells from specifically sensitized parental strain donors were injected superficially into either the intact skin or established grafts of normal skin on F(1) hybrid hamsters, a striking hypertrophy of the regional lymph nodes occurred, due to graft-versus-host reactivity. However, similar cell suspensions inoculated into intact pouch tissue or into pouch skin grafts on F(1) hamsters incited no regional lymphadenopathy, indicating the lack of appropriate pathways to the nodes. When skin homografts were inlaid eccentrically into pouch skin isografts, so that they were in contact with host skin at one edge, rejection occurred. Furthermore, rejection of long-established intrapouch skin homografts resulted if the hosts received: (a) small homografts of ordinary skin transplanted to conventional beds; (b) suspensions of donor strain pouch skin epidermal cells, injected intracutaneously; (c) lymph node cells from specifically sensitized donors of the same strain, i.e. adoptive immunization; or, (d) if a portion of the target homograft's perimeter was surgically approximated to body skin. Treatment of normal hamsters with two closely spaced pulses of ALS, although only marginally effective in prolonging the lives of homografts of trunk skin, enabled pouch skin homografts to survive for very long periods. The influence of this brief treatment with immunosuppressant was still demonstrable if challenge of hosts with the weakly immunogenic pouch skin homografts was delayed for 100 days.}, }
@article {pmid5159109, year = {1971}, author = {Mendell, JR and Chase, TN and Engel, WK}, title = {Amyotrophic lateral sclerosis: metabolism of central monoamines and treatment with L-dopa.}, journal = {Transactions of the American Neurological Association}, volume = {96}, number = {}, pages = {284-286}, pmid = {5159109}, issn = {0065-9479}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/drug therapy/*metabolism ; Central Nervous System/*metabolism ; Dihydroxyphenylalanine/*therapeutic use ; Dopamine/*metabolism ; Female ; Humans ; Hydroxyindoleacetic Acid/cerebrospinal fluid ; Male ; Middle Aged ; Phenylacetates/cerebrospinal fluid ; Probenecid/therapeutic use ; Serotonin/*metabolism ; }, }
@article {pmid4993197, year = {1971}, author = {Rodriguez-Paradisi, E and Thierfelder, S and Götze, D and Eulitz, M and Beil, E}, title = {Cytology and histology of haemopoietic cell transplantation under the influence of antilymphocyte serum (ALS) in mice. I. The in vivo effect of antilymphocytic globulin on haemopoietic tissue.}, journal = {Clinical and experimental immunology}, volume = {8}, number = {1}, pages = {107-119}, pmid = {4993197}, issn = {0009-9104}, mesh = {Animals ; Antigens ; Antilymphocyte Serum/*pharmacology ; Bone Marrow/drug effects ; Bone Marrow Cells ; Cell Count ; Erythrocytes/drug effects ; Hematopoietic System/cytology/*drug effects ; Immune Tolerance ; Immunodiffusion ; Immunoglobulin G/pharmacology ; Iodine Isotopes ; Lymphocytes/drug effects ; Megakaryocytes/drug effects ; Mice ; Plasma ; Rabbits ; Spleen/cytology/drug effects ; Ultracentrifugation ; }, abstract = {C57BL/6J mice were treated with ALS, ALG, normal rabbit serum (NRS) or IgG of the rabbit for a period of 6 days. To study the xenogeneic antigenicity of ALG and its antilymphocytic effect separately, half the mice were made tolerant to IgG of the rabbit. While a short schedule of injections of ultracentrifuged IgG induced tolerance to IgG, this tolerance was eliminated by the subsequent treatment with ALG. A prolonged injection schedule over 44 days did, however, lead to a tolerance which persisted after ALG treatment. [[131]I]IgG elimination proved to be a more sensitive control of tolerance than immunodiffusion. Semiquantitative cytology revealed a decline in lymphocytes, erythroblasts and megakaryocytes in the bone marrow and erythroblastosis and megakaryocytosis in the spleen. Cells of the myeloid series invariably increased in number. The effect on erythroblasts persisted after removal of contaminating haemagglutinins. ALG-treated animals intolerant to IgG had about four times more splenic plasma cells than ALG-treated mice tolerant to IgG. The 6 days' treatment with ALS reduced the absolute number of nucleated bone marrow cells by 16% and doubled the spleen indices. Under this treatment, relative and absolute cell counts revealed an ALG-induced shift of erythroblasts, megakaryocytes and perhaps also of plasma cells from the bone marrow to the spleen. The effect of NRS or IgG was similar to that of ALS or ALG but remained on a lower level. The remarkable changes in the histologic structure of the splenic follicles after ALG treatment were almost completely reversed by a prior induction of tolerance to IgG.}, }
@article {pmid4924199, year = {1971}, author = {Cinader, B and Jeejeebhoy, HF and Koh, SW and Rabbat, AG}, title = {Immunosuppressive and graft-rejecting anti--bodies in heterologous anti-lymphocytic serum.}, journal = {The Journal of experimental medicine}, volume = {133}, number = {1}, pages = {81-99}, pmid = {4924199}, issn = {0022-1007}, mesh = {*Antibodies ; Antilymphocyte Serum/*pharmacology ; Complement System Proteins ; Cyclophosphamide/pharmacology ; Erythrocytes/immunology ; Immunosuppressive Agents/*pharmacology ; *Skin Transplantation ; Spleen/immunology ; *Transplantation Immunology ; Transplantation, Homologous ; }, abstract = {Skin allografts survived longer on ALS-treated, complement-deficient (C5 negative) recipients than on ALS-treated, complement-competent (C5 positive) recipients. Administration of C5-positive serum to C5-negative, ALS-treated recipients resulted in reduced graft survival. A percentage of grafts from ALS-treated, C5-positive donors was rejected when transferred to untreated syngeneic recipients; this was not observed when C5-negative, syngeneic animals served as ALS-treated donors and untreated recipients. It was concluded that ALS has graft-rejecting properties which are promoted by late acting complement components. Unlike ALS-mediated graft rejection, ALS-mediated immunosuppression appeared to be independent of the late acting complement components. The effect of ALS on the humoral response to sheep erythrocytes was examined in complement-deficient and complement-competent mice. Immune-suppression was determined by ALS treatment of C5-competent and C5-deficient mice and also by transfer of in vitro ALS-treated spleen cells from C5-negative and C5-positive donors to cyclophosphamide-treated recipients. The ability of ALS to depress the humoral response to sheep cells and to decrease immunological competence of spleen cells was the same in the presence as in the absence of C5.}, }
@article {pmid4395674, year = {1971}, author = {Thierfelder, S and Rodriguez-Paradisi, E and Mempel, W and Beil, E}, title = {Cytology and histology of haemopoietic cell transplantation under the influence of ALS in mice. II. The effect of marrow from donors pretreated with antilymphocyte serum (ALS) on the recipient.}, journal = {Clinical and experimental immunology}, volume = {8}, number = {1}, pages = {121-129}, pmid = {4395674}, issn = {0009-9104}, mesh = {Animals ; Antilymphocyte Serum/*pharmacology ; Bone Marrow Cells ; *Bone Marrow Transplantation ; Cesium Isotopes ; Chronic Disease ; Disease Models, Animal ; Graft vs Host Disease/pathology/therapy ; Graft vs Host Reaction ; Hematopoietic System/*pathology ; Histocompatibility ; Hybridization, Genetic ; Lymphocytes ; Lymphopenia/pathology ; Mice ; Radiation Effects ; Spleen/pathology ; Transplantation Immunology ; Transplantation, Homologous ; }, abstract = {Cytology and histology of recipients of allogeneic bone marrow were studied 13. 20, 24, 30 and 34 days after transplantation. The developing chronic secondary disease was characterized by increased numbers of myeloid cells, by lymphopenia and by erythroblastopenia in the bone marrow and the spleen. Erythroblastopenia together with lymphopenia and augmented myeloid cells also occurred in irradiated F1-hybrids suffering from a chronic homologous disease. The latter model eliminated the following as a cause of erythroblastopenia in secondary disease: (1) host-versus-graft reaction against donor-type erythroblasts for immunogenetical reasons, and (2) graft-versus-host reaction against recipient-type erythroblasts since they had already been destroyed by irradiation. Treatment of the donor with ALS resulted in a suppression of homologous disease in F1-hybrids with a cytology resembling that of recipients of syngeneic spleen cells. The same treatment only delayed the onset of chronic secondary disease in recipients of allogeneic bone marrow. These allogeneic recipients, in contrast to the F1-hybrid recipients, died with the typical morphology of a chronic secondary disease. In recipients of syngeneic bone marrow from donors treated with ALS, repopulation with lymphocytes was somewhat delayed and transient erythroblastosis in the spleen occurred 20 days after transplantation.}, }
@article {pmid5503605, year = {1970}, author = {Riches, AC and Thomas, DB}, title = {The effects of x-irradiation and anti-lymphocyte serum on the responses to tumour allografts.}, journal = {British journal of cancer}, volume = {24}, number = {4}, pages = {833-842}, pmid = {5503605}, issn = {0007-0920}, mesh = {Adenocarcinoma/immunology ; Animals ; Antibody Formation/drug effects/radiation effects ; Antigens ; Antilymphocyte Serum/*pharmacology ; Female ; Histocompatibility ; Immunity, Cellular/drug effects/radiation effects ; Male ; Mammary Neoplasms, Experimental/*immunology/pathology ; Mice ; Neoplasm Transplantation ; Rabbits ; *Radiation Effects ; Sex Factors ; Transplantation Immunology/*drug effects/*radiation effects ; Transplantation, Homologous ; }, abstract = {The growth of a CBA mammary adenocarcinoma has been studied following transplantation to syngeneic and allogeneic recipients, with particular reference to the susceptibilities of the primary and secondary responses elicited by the tumour allografts, to impairment by whole-body X-irradiation and by treatment with rabbit-anti-mouse lymphocyte serum. In syngeneic recipients, the diameter of tumour implants increases linearly with time and there is no difference in the growth curves in females and in males. Later tumour generations grow faster than earlier generations. In allogeneic recipients, there is a relationship between the tumour diameter on day 21 (T) and the dose of X-irradiation (D) administered before implantation:T = 0.028 D - 9.17for early tumour generations (SMT4) but this is obscured for later generations (SMT21). The primary response to tumour allografts was radiosensitive whereas the secondary response was radioresistant. This radioresistance of the secondary response persisted for at least 5 months after primary sensitization. Unlike whole-body X-irradiation, treatment with rabbit-anti-mouse lymphocyte serum suppresses both the primary and secondary responses to tumour allografts. The possibility is considered that after exposure to antigenic stimulation, an immunologically reactive cell population is formed which is radioresistant but sensitive to ALS, unlike the precursor cells from which this population is derived, which are radiosensitive and sensitive to ALS.}, }
@article {pmid5497881, year = {1970}, author = {Campbell, AM and Williams, ER and Barltrop, D}, title = {Motor neurone disease and exposure to lead.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {33}, number = {6}, pages = {877-885}, pmid = {5497881}, issn = {0022-3050}, mesh = {Biopsy ; Bone Diseases/chemically induced ; Bone Resorption ; Calcium/metabolism ; Chelating Agents/therapeutic use ; }, abstract = {Disease of the lower motor neurone is a recognized hazard of lead toxicity, but the importance of contact with lead in the causation of motor neurone disease has not previously been ascertained. In 74 cases of motor neurone disease, 15% had a history of extensive exposure to lead, compared with 5·4% of a control group. The five year survival rate of these patients was 54%, compared with 16% in the remainder. The more benign course of the disease in some of these cases may be due to treatment with chelating agents. A history of either disease of the axial skeleton or previous fracture was obtained in 25% of patients compared with 9·4% of controls. There may be a relationship between skeletal demineralization and the development of motor neurone disease. The lead content of iliac crest bone biopsy specimens in 25 patients with motor neurone disease was no greater than that of a control group, but this does not exclude the possibility that lead liberated from bone might affect the motor neurone.}, }
@article {pmid4920601, year = {1970}, author = {Seller, MJ}, title = {The establishment of tolerance in adult anaemic mice of the W-series treated with anti-lymphocytic serum and allogeneic haemopoietic cells.}, journal = {Clinical and experimental immunology}, volume = {6}, number = {5}, pages = {639-643}, pmid = {4920601}, issn = {0009-9104}, mesh = {Anemia, Macrocytic/*therapy ; Animals ; *Antilymphocyte Serum ; Fetus ; Genotype ; Hematopoietic System/*transplantation ; Histocompatibility ; *Immune Tolerance ; Liver/cytology ; Mice ; Mosaicism ; Rabbits ; Skin Transplantation ; Transplantation Immunology ; Transplantation, Homologous ; }, abstract = {The genetically determined macrocytic anaemia of adult W[v]W[v] mice was cured by treatment with allogeneic (CBA) haemopoietic cells following 7 days immunosuppression with antilymphocytic serum (ALS). The immunological status of these mice was studied by following the fate of two skin grafts—one derived from the same allogeneic donor as the haemopoietic cells (CBA), and the other (A strain) completely unrelated to both the host and the haemopoietic cells. The A strain grafts were rejected while the CBA strain grafts were never rejected. It was concluded that the mice had become specifically tolerant to the CBA genotype. Following studies with chromosome markers, it was found that this tolerance was associated with a high degree of cellular chimaerism.}, }
@article {pmid5804536, year = {1969}, author = {Shellam, GR}, title = {Mechanism of induction of immunological tolerance. VI. Tolerance induction following thoracic duct drainage or treatment with anti-lymphocyte serum.}, journal = {Immunology}, volume = {17}, number = {2}, pages = {267-280}, pmid = {5804536}, issn = {0019-2805}, mesh = {Animals ; Antigens ; Antilymphocyte Serum ; Drainage ; Female ; Flagella/immunology ; *Immune Sera ; *Immune Tolerance ; Injections ; Iodine Isotopes ; Lymph/immunology ; Lymphocytes/*immunology ; Male ; Mice ; Rabbits ; Rats ; Salmonella/immunology ; Thoracic Duct/*physiology ; Time Factors ; }, abstract = {Adult Wistar rats were injected with flagellin from Salmonella adelaide three times weekly for different periods of time. With the range of doses 100 fg to 100 μg (fg, femtograms), varying levels of immune responsiveness were demonstrable following challenge, but not one of the doses induced complete immunological tolerance, although a reduced antibody response was elicited in rats which received injections of 100 μg of flagellin. In contrast to this finding, complete tolerance could be demonstrated following challenge if rats, previously drained of lymph and lymphocytes from the thoracic duct for 5 days, were injected with either 100 μg of flagellin three times weekly or with 1 μg/g body weight/day for 6 weeks. Similarly, anti-lymphocyte serum treatment prior to the injection of antigen resulted in partial tolerance in adult rats and nearly complete tolerance in adult C57BL/Brad mice. The primary response to flagellin of C57BL mice was abrogated if ALS was administered prior to but not after the injection of antigen. The implications of these findings are discussed.}, }
@article {pmid5819254, year = {1969}, author = {Dorman, JD}, title = {Treatment of amyotrophic lateral sclerosis.}, journal = {JAMA}, volume = {209}, number = {1}, pages = {112}, pmid = {5819254}, issn = {0098-7484}, mesh = {Amitriptyline/*therapeutic use ; Amyotrophic Lateral Sclerosis/*drug therapy ; Humans ; }, }
@article {pmid5688077, year = {1968}, author = {Taub, RN and Lance, EM}, title = {Histopathological effects in mice of heterologous antilymphocyte serum.}, journal = {The Journal of experimental medicine}, volume = {128}, number = {6}, pages = {1281-1307}, pmid = {5688077}, issn = {0022-1007}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; Immune Sera/*pharmacology ; Lymph Nodes/*pathology ; Lymphatic Diseases/etiology ; Lymphocytes/*immunology ; Mice ; Rabbits ; Species Specificity ; Spleen/pathology ; Thymus Gland/anatomy &amp; histology ; }, abstract = {The effects of heterologous rabbit anti-mouse lymphocyte antiserum on the morphology of lymphoid and other tissues was investigated in CBA mice. The lymphoid tissues exhibited characteristic changes specific for ALS treatment, which were an invariable accompaniment to its immunosuppressive effects. These consisted of peripheral lymphopenia occurring at some time during a course of ALS treatment and persistent depletion of small lymphocytes in lymph node paracortical areas and splenic follicular periarteriolar zones. The thymic histology was generally well preserved. It is suggested that the relevant lesions reflect a rapid depletion of the pool of recirculating lymphocytes, possibly by a primary cytotoxic effect exerted on cells peripheral to lymphoid tissue. Other histologic features attendant to the administration of ALS were accounted for as consequences of immunization of ALS recipients to rabbit serum constituents or by the deleterious effects of antibodies directed against tissues other than lymphoid cells.}, }
@article {pmid5697011, year = {1968}, author = {Taub, RN and Lance, EM}, title = {Effects of heterologous anti-lymphocyte serum on the distribution of 51-Cr-labelled lymph node cells in mice.}, journal = {Immunology}, volume = {15}, number = {5}, pages = {633-642}, pmid = {5697011}, issn = {0019-2805}, mesh = {Animals ; Antibodies/analysis ; Antilymphocyte Serum ; Chromium Isotopes ; Complement System Proteins ; Hot Temperature ; Immune Sera/*pharmacology ; Injections, Intravenous ; Lymph Nodes/*drug effects ; Lymphocytes/*drug effects/immunology/physiopathology ; Mice ; Rabbits ; Spleen/physiopathology ; Time Factors ; }, abstract = {The effects of heterologous anti-lymphocyte serum (ALS) were studied in a syngeneic cell transfer system, in which lymph node cells from donor CBA mice were labelled in vitro with [51]Cr and transferred intravenously into syngeneic recipients. Labelled cells treated in vitro with ALS were unable to migrate to lymph nodes or spleens of recipients, as did normal cells, but instead distributed themselves very similarly to cells which had been killed by exposure to heat. It is thus likely that cells treated in vitro with ALS are killed after transfer by the cytotoxic action of ALS mediated by the complement of the recipient. ALS administered directly to the recipients of labelled lymphocytes could also reduce their uptake into lymphoid tissue; however, the magnitude of this effect appeared to be critically dependent upon the timing of the antiserum dose with respect to the labelled cell dose. ALS given immediately prior to labelled cells showed the greatest effect, while treatment given either 24 hours before or after the labelled cells was much less effective. While with prior treatment the reduced effect could be due to a fall off in antibody titre during the interval between the dose of antiserum and cells, in the latter situation no drop in titre would have occurred. It thus seems that lymphocytes that have already established themselves in lymphoid tissue may be less susceptible to the action of ALS. ALS given chronically to lymphoid cell donors resulted in a population of cells which upon transfer to normal recipients were distributed differently from either normal or NRS-treated donor cells. These data support the hypothesis that the effects of ALS may be exerted preferentially on circulating lymphocytes, and that ALS may act to selectively reduce the representation of this cell type in lymphoid tissue.}, }
@article {pmid5718504, year = {1968}, author = {Boak, JL and Dagher, RK and Corson, JM and Wilson, RE}, title = {Modification of the graft-versus-host syndrome by anti-lymphocyte serum treatment of the host.}, journal = {Clinical and experimental immunology}, volume = {3}, number = {8}, pages = {801-808}, pmid = {5718504}, issn = {0009-9104}, mesh = {Animals ; Antilymphocyte Serum/pharmacology ; Carbon ; Graft vs Host Disease/*immunology ; Immune Sera/*pharmacology ; Injections, Intraperitoneal ; Lymph Nodes/immunology ; Lymphocytes/drug effects/*immunology ; Male ; Mice ; Organ Size ; Phagocytosis ; Rabbits ; Spleen/anatomy &amp; histology/immunology ; Time Factors ; }, abstract = {The effect of administering anti-lymphocyte serum (ALS) to the F1 hybrid recipient at various time intervals before and after the injection of parental donor cells has been investigated. The graft-versus-host (GVH) response can be completely inhibited by a single ALS injection given a short while before the injection of parental cells. ALS injected after the injection of donor cells fails to influence the GVH response. It is considered that these studies confirm the view that ALS acts mainly on circulating lymphocytes and that a single ALS injection does not influence lymphocytes resident in spleen and lymph nodes.}, }
@article {pmid5718503, year = {1968}, author = {Boak, JL and Wilson, RE}, title = {Modification of the graft-versus-host syndrome by anti-lymphocyte serum treatment of the donor.}, journal = {Clinical and experimental immunology}, volume = {3}, number = {8}, pages = {795-800}, pmid = {5718503}, issn = {0009-9104}, mesh = {Animals ; Animals, Newborn ; Antilymphocyte Serum/pharmacology ; Graft vs Host Disease/*immunology ; Immune Sera/*pharmacology ; Injections, Intraperitoneal ; Lymph Nodes/immunology ; Lymphocytes/*immunology ; Mice ; Rabbits ; Spleen/immunology ; Thoracic Duct/immunology ; }, abstract = {Spleen and lymph node suspensions prepared from parental donor mice pretreated with four daily anti-lymphocyte serum (ALS) injections have been demonstrated to be incapable of inducing a graft-versus-host (GVH) syndrome when injected into F1 hybrid recipient mice. A single ALS injection to the parental donor renders thoracic duct lymphocytes incapable of inducing a GVH response but the activity of spleen cell suspensions is retained. It is suggested that this observation supports the view that ALS acts mainly on circulating lymphocytes.}, }
@article {pmid4965698, year = {1968}, author = {Volkert, M and Lundstedt, C}, title = {The provocation of latent lymphocytic choriomeningitis virus infections in mice by treatment with antilymphocytic serum.}, journal = {The Journal of experimental medicine}, volume = {127}, number = {2}, pages = {327-339}, pmid = {4965698}, issn = {0022-1007}, mesh = {Animals ; Antigens ; Complement Fixation Tests ; Freund's Adjuvant ; *Immune Sera ; Lymph Nodes/immunology ; Lymphocytes/*immunology ; Lymphocytic Choriomeningitis/*etiology/immunology/pathology ; Mice ; Rabbits ; Spleen/immunology ; Viruses, Unclassified/*pathogenicity ; }, abstract = {The hypothesis that treatment with antilymphocytic serum (ALS) can provoke latent virus infections has been investigated. In adult mice infections with sublethal doses of LCM virus usually result in the development of immunity to the virus and at the same time to a prolonged latent infection. In the experiments described an intensive treatment with large doses of ALS was given to mice which had recovered from LCM virus infection. At the beginning of the treatment the mice had high titers of complement-fixing antibodies in their blood and no detectable virus. The data presented show that in spite of the immunity the ALS treatment provoked the occult virus and led to the development of viremia in all the treated mice. In some, very high virus titers were demonstrable. When the ALS treatment was discontinued the viremia disappeard again. In most of the mice the ALS did not suppress the complement-fixing antibody titers and in some there was even a considerable increase in titer. In such cases the increases in virus titers and in antibody titers were closely related to one another. These results demonstrate once again that the complement-fixing antibodies to the LCM virus in mice probably do not influence the virus.}, }